PMID- 20943023 TI - Detection of Toxoplasma gondii in the reproductive system of male goats. AB - Male goats of mating age serologically negative for Toxoplasma gondii were divided into three groups: GI--controls (placebo) (n = 2); GII--infected with 1 x 106 tachyzoites (RH strains) (n = 2); and GIII--infected with 2 x 105 oocysts (P strains) (n = 2). Clinical, hematology, parasite and serology tests and studies of parasites in the semen through bioassay and polymerase chain reaction (PCR), and in reproductive organs (bioassay) were performed to assess toxoplasma infection. Serological titers peaked at 4096 in two animal groups infected with the protozoan. The bioassays allowed an early detection of protozoa in semen samples of tachyzoite-inoculated animals. T. gondii DNA was identified through PCR in the semen in five (Days 5, 7, 28, 49, and 70) and two (both at day 56) different days post-inoculation in GII and GIII animals, respectively. It was also possible to detect T. gondii DNA in reproductive organs (prostate pool, testicles, seminal vesicle and epididymis) of goats inoculated with either tachyzoites or oocysts. The present study suggests the possibility of venereal transmission of T. gondii among goats and it should be further assessed. PMID- 20943024 TI - Evaluation of reduction in egg shedding of gastrointestinal nematodes in cattle following administration of anthelmintics. AB - To evaluate the necessary time and to identify the differences among anthelmintics for the reduction of parasite eggs shed in feces, five groups of cattle were treated with moxidectin, ivermectin, levamisole phosphate, and albendazole sulphoxide. Levamisole promoted a reduction in egg count per gram (EPG-R) of 97.4% after 24 hours, moxidectin 98.3% after 36 hours, and albendazole sulphoxide 95.9% after 36 hours post- treatment. Cooperia spp. and Haemonchus spp. showed resistance to ivermectin. The results demonstrated that the diagnosis of parasite resistance in cattle can be based on a count of eggs per gram (EPG) carried out as soon as seven days after the treatment. PMID- 20943025 TI - Real time polymerase chain reaction to diagnose Anaplasma marginale in cattle and deer (Ozotoceros bezoarticus leucogaster) of the Brazilian Pantanal. AB - Epizootiological study of Anaplasma marginale in regions that contain various reservoir hosts, co-existence of rickettsia pathogens, and common vectors is a complicated task. To achieve diagnosis of this rickettsia in cattle and campeiro deer of Brazilian Pantanal, a comparison was made between a real time polymerase chain reaction (RT-PCR) with intercalating Sybr Green fluorochrome and primers based on msp5 gene of A. marginale; a conventional PCR (C-PCR); and parasitological examination using thin blood smear stained with Giemsa MayGrunwald. Both PCRs showed good performance in the diagnosis of A. marginale in cattle, and were superior to the parasitological exam. The RT-PCR detected seven positive campeiro deer (16.3%). This rate was significantly higher compared to C-PCR, which identified one animal as positive (2.3%), and also compared to parasitological diagnosis, which did not find any positive animals. The dissociation temperature average of positive reactions in cattle (81.72 degrees C +/- 0.20) was identical to dissociation temperature found in the cervids (81.72 degrees C +/- 0.12), suggesting that both animal species were infected with A. marginale. We concluded that RT-PCR can be used for A. marginale diagnosis and in epizootiological studies of cattle and cervids; in spite of the small number of campeiro deer samples, the results indicated that this wildlife species has importance in the Anaplasma epizootiology in the Brazilian Pantanal. PMID- 20943026 TI - Amblyomma aureolatum (Acari: Ixodidae) parasitizing margay (Leopardus wiedii) in Rio Grande do Sul. AB - We report the finding of Amblyomma aureolatum (Acari: Ixodidae) parasitizing margay (Leopardus wiedii) in the locality of Gravatai (29 degrees 47' 12.9" S and 50 degrees 53' 44.1" W; 241 m alt.), State of Rio Grande do Sul, Southern Brazil. This is the first report of this species of Ixodidae on margay in Southern Brazil. This finding indicates an increased number of hosts for this tick species. PMID- 20943027 TI - New tick records in Rondonia, Western Brazilian Amazon. AB - In the present study, we provide new tick records from Vilhena Municipality, in the Southeast of the State of Rondonia, Northern Brazil. Ticks collected from a capybara, Hydrochoerus hydrochaeris (Linnaeus), were identified as Amblyomma romitii Tonelli-Rondelli (1 female), and Amblyomma sp. (1 larva). Ticks collected from a harpy eagle, Harpia harpyja (Linnaeus), were identified as Amblyomma cajennense (Fabricius) (16 nymphs) and Haemaphysalis juxtakochi Cooley (1 nymph). Ticks collected from a yellow-footed tortoise, Chelonoidis denticulada (Linnaeus), were identified as Amblyomma rotundatum Koch (10 females, 2 nymphs), and Amblyomma sp. (2 larvae). The present record of A. romitii is the first in the State of Rondonia, and represents the southernmost record for this tick species, indicating that its distribution area is much larger than currently recognized. Although both A. cajennense and H. juxtakochi have been reported parasitizing various bird species, we provide the first tick records on a harpy eagle. A. rotundatum is widespread in the State of Rondonia, and has been previously reported on the yellow-footed tortoise. The present records increase the tick fauna of Rondonia to 26 species. PMID- 20943028 TI - Bilateral neurogenic masses: a diagnostic challenge. PMID- 20943029 TI - Facial cellulitis secondary to dens invaginatus: a case report. AB - We describe a case of dens invaginatus in an unerupted permanent maxillary lateral incisor, which led to facial cellulitis in a 10-year-old girl. We review the importance of recognizing dens invaginatus and present strategies for preventing loss of vitality in the affected tooth. PMID- 20943030 TI - Revision of the American Association of Dental Research's Science Information Statement about Temporomandibular Disorders. PMID- 20943031 TI - Porcelain laminate veneer on a highly discoloured tooth: a case report. AB - Esthetic treatment of a single darkened tooth represents a great challenge to the dental practitioner. The properties of dental ceramic-colour stability, mechanical strength, clinical longevity, esthetic appearance and compatibility with periodontal tissues-make this material a good choice for such treatment. We present a case of restoration of a single, highly darkened anterior tooth with a feldspathic porcelain veneer. Resolution involved preparation of the dental structure guided by orientation grooves and provisional restoration using composite resin, a silicone impression and adhesive luting. Conservative use of porcelain laminate veneers provides satisfactory esthetic outcomes and preserves sound tooth structure. The patient was very satisfied with the result and had no complaints during 2 years of follow-up. PMID- 20943032 TI - Cranberry polyphenols: potential benefits for dental caries and periodontal disease. AB - Over the past decade, cranberries and their molecular components have received increasing attention from researchers in human health. In particular, the properties of the high-molecular-weight polyphenols isolated from cranberries have shown promise with regard to dental caries and periodontal disease. These potential anticaries agents inhibit the production of organic acids and the formation of biofilms by cariogenic bacteria. In addition, cranberry polyphenols may reduce the inflammatory response, as well as the production and activity of proteolytic enzymes contributing to the destruction of the extracellular matrix in periodontal disease. The polyphenols of cranberries also interfere with various activities (including formation of biofilm and adhesion) of Porphyromonas gingivalis, the main etiologic agent in chronic periodontitis. This article summarizes the scientific evidence supporting the potential of cranberry polyphenols to prevent and/or treat diseases of the mouth. PMID- 20943034 TI - Pitching in for society and our profession. PMID- 20943033 TI - Improving nutrition for better oral health. PMID- 20943035 TI - Our global connection. PMID- 20943036 TI - Magnet-retained implant-supported overdentures: review and 1-year clinical report. AB - Open-field aluminum-nickle-cobalt magnets have been used in prosthodontics for many years, but success has been limited because these magnets are susceptible to corrosion by the saliva and because their retentive force is weak relative to the initial retention offered by mechanical attachments. More recently, magnets have been made from alloys of the rare earth elements samarium and neodymium, which provide stronger magnetic force per unit size. In addition, a new generation of laser-welded containers has improved protection from salivary corrosion. The current resurgence of interest in this type of attachment appears justified because, unlike mechanical attachments, magnets have potential for unlimited durability and might therefore be superior to mechanical ball or bar attachments for the retention of removable prostheses on implants. To date, no long-term prospective trials have been conducted to confirm the clinical durability of this new generation of magnets for retaining dentures on either teeth or implants. The aim of this study was to document initial clinical experiences and levels of satisfaction among edentulous patients treated with mandibular implant-supported overdentures retained using a new generation of rare-earth magnetic attachments. At the outset, all but one of the 17 patients had had several years of experience with implant-supported overdentures. During the first year, the mean overall satisfaction among these 17 patients increased from less than 70 to over 90 out of 100 (standardized visual analogue scale). No unusual difficulties were encountered in rendering the treatment or maintaining the attachments. This report offers preliminary evidence of the excellent potential of these magnets for retaining mandibular implant-supported overdentures. PMID- 20943037 TI - Possible involvement of advanced glycation end products in periodontal diseases. AB - Periodontal diseases are considered as multifactorial conditions initiated by infection with pathogenic bacteria, promoted by inflammation and immune response against bacteria and modified by different environmental and genetic factors. Recently, interest in periodontal diseases has been increasing due to the awareness that the hyperinflammatory status associated with this disorder could impose a significant increase of reactive oxygen species (ROS) relevant to numerous systemic diseases driven by a pro-oxidant profile. A highly complex interplay occurs between oxidative stress and AGEs (Advanced Glycation End products), a group of heterogeneous compounds that form constantly under physiologic conditions, although their rate of formation is markedly increased in hyperglycemia and oxidizing conditions. Starting from the most relevant hypotheses on the pathogenesis of periodontal diseases, the present review outlines its relationship with oxidative stress and inflammation response in order to make a critical evaluation of the potential role of AGEs in periodontal deterioration. Although direct evidence for the presence of AGEs in the periodontal ligament is still lacking, valuable approaches based on the use of periodontal cells along with genetic and biochemical studies in animal models and chronic periodontal patients support a potential role for protein glycation in the aetiology and severity of this disease. Following a review of the current literature, the present study highlights the need for further investigation on the presence of AGEs in the periodontal ligament as a means for the comprehension of the pathogenic mechanisms underlying periodontal diseases in order to develop prevention and treatment modalities for this dysfunction. PMID- 20943038 TI - HIV-related acute inflammatory leukoencephalopathy of undetermined origin: review of the literature. AB - HIV-related acute inflammatory leukoencephalopathy of undetermined origin (AIL) has been anecdotally described in literature as being responsible for cognitive and motor deficits. We carried out a review of all the cases of AIL published in literature. Articles were selected according to 2 criteria: acute onset of symptoms; undetermined aetiology and non-fulfilment of multiple sclerosis diagnostic criteria. They were then analyzed in terms of clinical, biological and instrumental features, therapy, diagnostic classification and prognosis. Although rare (21 patients out of about 4,000 publications), AIL is of particular interest, as the comprehension of its mechanisms could give some insight into the direct and immune-mediated actions of HIV within the brain. All the reported patients share several clinical, histopathological, radiological and CSF features, leading to hypothesize a similar aetiopathogenetic mechanism. Conversely, we observed a high heterogeneity of treatment and diagnostic classification, which could have conditioned the broad prognostic variability. The absence of a defined aetiology leads to consider these forms as a particular subgroup of not determined leucoencephalopathies (NDLE), with both MRI and histological pattern dominated by inflammation as distinctive feature. PMID- 20943039 TI - Role of etanercept in the treatment of tumor necrosis factor receptor-associated periodic syndrome: personal experience and review of the literature. AB - Tumor necrosis factor-alpha receptor (TNFR1)-associated periodic syndrome (TRAPS) is the most common autosomal-dominant autoinflammatory condition and is caused by mutations in the TNFRSF1A gene. TRAPS is characterized by recurrent attacks of fever typically lasting from 1 to 3 weeks; in addition to fever, common clinical features include mainly periorbital oedema, conjunctivitis, a migratory erythematous plaque simulating erysipela with underlying myalgia, and arthritis or arthralgia; serosal membrane inflammation is also possible. The identification of TNFRSF1A mutations as the genetic cause of TRAPS coincided with the wider use of biological agents in medicine and raised the possibility that blocking TNF could potentially represent the primary therapeutic goal in TRAPS, thus disclosing new treatment choices for this complex disease. In the past few years, isolated reports and case-series have been published suggesting that inhibition of TNF-alpha might represent a promising therapeutic approach in TRAPS. We present here our experience with etanercept in the treatment of patients affected with TRAPS, and we also add a review of the literature. PMID- 20943040 TI - IL-31 a Th2 cytokine involved in immunity and inflammation. AB - Cytokines are immunal regulatory proteins, however they also play a relevant role in inflammatory diseases. IL-31 is a newly discovered cytokine expressed primarily in TH2 cells, introduced by activated CD4+ T cells. IL-31 is capable of inducing chemokines and other cytokines in several inflammatory diseases via its surface receptor. This cytokine is also produced by mast cells and mast cell line, suggesting a role in allergic diseases. In this editorial we revisit the biological role of IL-31 in immunity and inflammation. PMID- 20943041 TI - Divergent and synergistic regulation of matrix metalloprotease production by cytokines in combination with C-C chemokines. AB - The chemotactic effects of chemokines on cells has long been known, but it is now clear that chemokines also have much broader activities and are also involved in a number of disease pathologies, such as rheumatoid arthritis, cancer metastasis and other inflammatory processes. This study investigates the effects of four C-C chemokines, CCL2, CCL3, CCL4 and CCL5 either alone or in the presence of two regulatory cytokines TNF-alpha and TGF-beta and their effect on secretion of two matrix metalloproteases MMP, MMP-2 and MMP-9, and the expression of one membrane bound MMP, MMP-14, by a monocytic human cell line, MonoMac6. All four C-C chemokines were shown to be chemotactic, but only CCL2 and CCL4 had any significant stimulatory effect on MMP-9 and MMP-2, respectively. Both TNF-alpha and TGF-beta were found to divergently enhance MMP-9 and MMP-2 secretion respectively, with stimulation indexes of two and five respectively. Simultaneous treatment with TNF-alpha and chemokine resulted in up to a fifteen-fold stimulation of MMP-9 secretion and treatment with TGF-beta and chemokine resulted in up to a fifteen-fold stimulation of MMP-2 secretion, while TNF-alpha in combination with CCL4 stimulated MMP-14 expression five-fold. Chemokine receptor expression was also investigated using a calcium-sensitive dye and FACS analysis. CCL2, CCL3, and CCL5 all resulted in a detectable enhancement of cytoplasmic Ca2+concentration. CCL4 was unable to activate Ca2+ mobilization, despite the presence of CCR5, the receptor for CCL4. There appeared to be no correlation between MMP production and chemotaxis. The strong synergy between chemokines and cytokines and the enhanced production of MMP may signify the differential regulatory mechanisms of the two cytokines and chemokines in disease pathology. PMID- 20943042 TI - Dietary supplementation with fructooligosaccharides attenuates airway inflammation related to house dust mite allergen in mice. AB - Fructooligosaccharides (FOS) are prebiotic supplements that can enhance immunological responses in the host to activate mucosal immunity, probably through regulation of gastrointestinal microflora. An area that has not been investigated, however, is the therapeutic potential of prebiotics on allergic airway diseases. The purpose of this study is to evaluate the effects of dietary supplementation with FOS on a murine model of allergic airway inflammation induced by the house dust mite allergen Dermatophagoides farinae (Der f). Male C3H/HeN mice were intratracheally administered with Der f and were fed a diet containing 0% or 2.5% FOS ad libitum. Supplementation with FOS alleviated mite allergen-related airway inflammation characterized by eosinophilic inflammation and goblet cell hyperplasia, which was evidenced by cytological and histological examinations. In addition, the FOS-supplemented diet reduced the serum allergen specific IgG1 level as compared with a control diet in the presence of the mite allergen. Moreover, FOS tended to suppress the expression of IL-5 and eotaxin in the lungs, which is enhanced by mite allergen. These results suggest that dietary supplementation with FOS can prevent/improve allergic airway inflammation induced by the mite allergen. This effect can be at least partially associated with the inhibition of allergen-specific Ig production and probably with that of IL-5 and eotaxin expression. PMID- 20943043 TI - Benzene metabolites inhibit the release of proinflammatory mediators and cytokines from human basophils. AB - Benzene and its metabolites have been involved in the pathogenesis of chronic lung inflammation and allergic disorders such as bronchial asthma. However, the effects of these xenobiotics on human basophils, key cells in the development of respiratory allergy, have not been investigated. We examined the effects of hydroquinone (HQ) and benzoquinone (BQ), two important chemicals implicated in benzene toxicity, on the release of preformed (histamine) and de novo synthesized mediators (cysteinyl leukotriene C4, LTC4, and IL-4) from human basophils. Preincubation of basophils purified from normal donors with HQ (3-100 microM) inhibited up to 30% histamine release induced by anti-IgE and up to 55% of that induced by the Ca2+ ionophore A23187. HQ had no effect on histamine release induced by formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe). Preincubation of basophils with BQ (3-100 microM) resulted in the concentration-dependent inhibition of histamine release (up to 70%) induced by anti-IgE, A23187 and f-Met Leu-Phe. HQ completely suppressed the de novo synthesis of LTC4 from basophils challenged with anti-IgE or f-Met-Leu-Phe and the production of IL-4 in cells stimulated with anti-IgE. These results indicate that two major benzene metabolites, HQ and BQ, inhibit the release of proinflammatory mediators and Th2 promoting cytokines from basophils activated by different stimuli. These results suggest that benzene metabolites interfere with multiple intracellular signals involved in the activation of human basophils. PMID- 20943044 TI - T cell activation state in the induced sputum of asthmatics treated with budesonide. AB - Bronchial hyperresponsiveness and airway infiltration with eosinophils and T lymphocytes are key features of asthma. In particular, CD4+ T cells are currently believed to play a pivotal role as initiators and coordinators of the asthmatic inflammatory response and, therefore, they represent a crucial target of corticosteroid treatment. The aim of the present investigation is thus to evaluate, in patients with mild asthma, the effects of inhaled corticosteroid therapy on the following parameters: (i) functional state of CD4+ T cells; (ii) airway eosinophilia; (iii) bronchial hyperresponsiveness to methacholine. The study was completed by twenty asthmatic, atopic subjects, subdivided into two groups of ten and treated for 12 weeks with either inhaled budesonide (200 microg twice daily) or terbutaline alone (500 microg twice daily), respectively. Expression of CD4+ T cell activation markers was measured in induced sputum at baseline and after 1, 4, 8 and 12 weeks of treatment by flow cytometry, which showed a down-regulation of HLA-DR and CD25 surface proteins in the budesonide group, compared with the control group; these differences resulted as being statistically significant through weeks 4-12. Budesonide also induced a quick, sharp reduction in the percentage of eosinophils detectable in induced sputum, as well as a more gradual progressive improvement in airway hyperresponsiveness to methacholine. Therefore, in addition to assessing various indices of bronchial inflammation, flow cytometry can be reliably applied to induced sputum in order to monitor, even in mildly symptomatic patients, the effects of anti-asthma treatments on T cell activation. PMID- 20943045 TI - NA+/H+ exchanger 1- and aquaporin-1-dependent hyperosmolarity changes decrease nitric oxide production and induce VCAM-1 expression in endothelial cells exposed to high glucose. AB - Since diabetic hyperglycaemia causes hyperosmolarity, we investigated the contribution of hyperosmolarity in the proinflammatory endothelial effects of hyperglycemia, and investigated the mechanisms involved. Human aortic endothelial cells (HAEC) were incubated for short-term (1-3 days) or long-term (1-2 weeks) exposures to 5.5 mmol/L glucose (normoglycemia, basal), high glucose (25 and 45 mmol/L, HG), or a hyperosmolar control (mannitol 25 and 45 mmol/L, HM), in the presence or absence of the aquaporin-1 (AQP1) inhibitor dimethylsulfoxide (DMSO), the Na+/H+ exchanger 1 (NHE-1) inhibitor cariporide (CA), the protein kinase C (PKC) inhibitor calphostin C or the PKCbeta isoform inhibitor LY379196 (LY). Both short- and long-term exposures to HG and HM decreased the expression of the active, phosphorylated form of endothelial nitric oxide synthase (Ser1146-eNOS) and, in parallel, increased vascular cell adhesion molecule(VCAM)-1 protein at immunoblotting. After 24 h incubation with HG/HM, we observed a significant similar and concentration-dependent enhancement of AQP1 expression. DMSO and CA inhibited hyperosmolarity-induced VCAM-1 expressions, while increasing nitrite levels and Ser1146-eNOS expression. Gene silencing by small interfering RNA reduced the expression of AQP1, and suppressed HG and HM-stimulated VCAM-1 expression. Calphostin C and LY blunted hyperosmolarity-induced VCAM-1 expression, while increasing the expression of Ser1146-eNOS and nitrite production. HG decreases eNOS activation and induces total VCAM-1 expression in HAEC through a hyperosmolar mechanism. These effects are mediated by activation of the water channels AQP1 and NHE-1, and a PKCbeta-mediated intracellular signaling pathway. Targeting osmosignaling pathways may represent a novel strategy to reduce vascular effects of hyperglycemia. PMID- 20943046 TI - The role of etanercept on the expression of markers of T helper 17 cells and their precursors in skin lesions of patients with psoriasis vulgaris. AB - Very recently, it has been demonstrated that CD161, retinoic acid-related orphan receptor gamma-t (RORgamma-t) and CC-chemokin receptor 6 (CCR6) can be considered good surface markers to detect T helper 17 cells and their precursors, T cell populations that are considered to play an important role in the pathogenesis of psoriasis. In the present study, we evaluate the clinical involvement by calculating the PASI score and the number of CD4+, CD161+, RORgammat+ and CCR6+ cells before and after a 12-week course with etanercept or acitretin in patients with moderate-to-severe, plaque-type psoriasis vulgaris. Ten patients were given etanercept 50 mg twice weekly and 10 patients acitretin 0.4 mg/kg per day, both for 12 weeks. At the baseline and at the end of the treatment PASI was calculated, and skin biopsies were taken to evaluate the expression of CD4, CD161, RORgammat and CCR6 by immunohistochemistry. As controls, 10 patients with atopic dermatitis (AD) were included in the study. After 12 weeks, PASI was significantly lower than at the baseline for both groups. However, etanercept treated patients showed lower PASI than acitretin-treated ones. While CD4+ cell numbers were similar in both diseases, all the other markers, that are considered more specific for Th17 cells and their precursors, were more expressed in psoriasis than in AD. Furthermore, only etanercept, but not acitretin, was able to significantly reduce CD161+, RORgammat+ and CCR6+ cells in skin lesions of patients with psoriasis. Our study provides further evidence of the role of Th17 pathway in the pathogenesis of psoriasis. Furthermore, our findings suggest that etanercept is able to downregulate the expression of the recently recognized markers of Th17 cells and their precursors CD161, RORgammat and CCR6, while acitretin is not. This activity on the Th17 lineage may contribute to the efficacy of etanercept in the treatment of psoriasis. PMID- 20943047 TI - Identification of IP-10 and IL-5 as proteins differentially expressed in human complicated and uncomplicated carotid atherosclerotic plaques. AB - Inflammation plays a crucial role in the development and progression of atherosclerotic plaques. The aim of this study is to compare culture supernatants from uncomplicated and complicated carotid atherosclerotic plaques by a multiplex approach, to assess the molecular mediators associated with a plaque complicated phenotype. Atherosclerotic plaques were obtained from 17 patients undergoing carotid endarterectomy. Supernatants from plaque cultures were evaluated by Bio Plex cytokine assay to determine 27 pro- and anti-inflammatory cytokines, chemokines and growth factors. Complicated plaques secreted higher levels of IP 10 (p = 0.027) and lower levels of IL-5 (p = 0.045) than did uncomplicated ones. Distinctive secretory patterns of cytokines, chemokines and growth factors were present in the two types of plaque. Our study identifies IP-10 and IL-5 as proteins differentiating complicated and uncomplicated plaques from human carotid arteries and provides new insights into the interplay of molecular mediators with atherosclerotic plaque progression. PMID- 20943048 TI - Can Cyclosporine-A associated to methotrexate maintain remission induced by anti TNF agents in rheumatoid arthritis patients? (Cynar pilot study). AB - Biological therapies, such as etanercept, adalimumab and infliximab, have demonstrated good efficacy in inducing rheumatoid arthritis to low disease activity levels. Nevertheless, their cost, as well as the related risk of side effects, especially in long-term therapies, are still high. Furthermore, there is a good deal of evidence proving loss of efficacy of such therapies in the long term, often necessitating the shift from one specific anti-TNF biological treatment to another. There are also other open debates on the amount of time a patient should undergo an anti-TNF therapy, on the possibility of inducing a complete remission in early arthritis and, once remission or low disease activity is obtained, on the possibility of interrupting the anti-TNF-based therapy. In this study we investigated whether A-Cyclosporin and Methotrexate association may be effective in maintaining low disease activity obtained by anti-TNF therapies. Twenty-three rheumatoid arthritis-affected patients, whose diagnosis was made according to ACR criteria, with a disease duration of less than 3 years, and DAS28<3.2 that reached a level of low disease activity within 6-8 months from beginning anti-TNF and Methotrexate therapy, were enrolled in the study. After the suspension of anti-TNF therapy, patients were started on A-Cyclosporine (2-3 mg/kg/day) and Methotrexate (15mg/week) therapy. DAS28, Pain VAS, Erythrosedimentation Rate (ESR), and C Reactive Protein (CRP) were all tested at time 0 and at 6 months, as well as liver and kidney profiles, after the interruption of the anti-TNF therapy and the beginning of A-Cyclosporine and Methotrexate therapy. Side effects were also recorded. Of 23 patients undergoing the A-Cyclosporin and Methotrexate therapy for maintaining low disease activity in rheumatoid arthritis obtained by 6-8 months of anti-TNF therapy, 21 completed the study with a 6 month follow-up. Thirteen patients maintained clinical parameters within low disease activity values, while 8 patients showed an increase in DAS28 and other parameters. Only two patients showed an increase in blood pressure that was diagnosed after two months from the beginning of the A Cyclosporin and Methotrexate therapy. The reduction in the dosage of A Cyclosporin from 3mg/kg/day to 2mg/kg/day caused a slow normalization of blood pressure values. Our data seem to suggest that more than half of the patients undergoing A-Cyclosporin and Methotrexate therapy seemed to maintain low disease activity parameters of rheumatoid arthritis, obtained after 6-8 months of anti TNF therapy. Further studies on larger populations are necessary in order to confirm such results and identify predictor factors for different responses. PMID- 20943049 TI - A study of Adenosine-Deaminase genetic polymorphism in rheumatoid arthritis. AB - Recent investigations suggest that Adenosine Deaminase (ADA) could play a role in susceptibility to rheumatoid arthritis (RA). The purpose of our study is to investigate the possible role of genetic variability of ADA in the susceptibility to RA. We studied three intragenic ADA polymorphisms, ADA1, ADA2 and ADA6, in a sample of 91 subjects with RA and in 246 healthy subjects from the same Caucasian population and compared genotype and pairwise haplotype distributions between cases and controls. No statistically significant differences between RA and controls are observed for ADA genotypes. A border line difference for ADA1-ADA2 haplotype distribution is observed due to a decreased proportion of ADA1 *2/ADA2 *2 haplotype in RA compared to controls. Our data indicate a border line effect of ADA gene polymorphism on susceptibility to RA that need to be confirmed in other clinical settings. PMID- 20943050 TI - Treatment of psoriasis with different dosage regimens of etanercept: preliminary results from the Talpharanta Plastic Study Group. AB - This pilot open-label study is aimed to assess clinical response in psoriasis patients receiving diverse dose regimens of etanercept, consisting of the same global cumulative dose of etanercept administered over different treatment periods. Eligible patients were assigned sequentially in a 1:1 ratio to receive: etanercept 50 mg once weekly (QW) or 50 mg twice weekly (BIW) for 12 weeks. The final analysis included a total of 72 patients. At week 12 the Psoriasis Area and Severity Index (PASI) and Skindex-29 scores notably improved in both treatment arms, without significant differences between the two groups. The rate of patients attaining a PASI improvement >or= 50% (PASI 50) at week 12 was 92% in the high-dose group. In these patients, etanercept dosage was decreased to 50 mg QW from week 13, with persistence of the PASI 50 response at week 24 in all cases. Thereafter, treatment was discontinued up to week 36 and almost 30 % of patients experienced a gradual relapse of their psoriasis within this period. In the low-dose group, the PASI 50 response was observed in 75% of patients. These responders continued to be treated with etanercept 50 mg QW up to week 36 with persistence of the PASI 50 in 100% of cases at week 24 and 93% at week 36. In the low-dose regimen, 8 patients who did not respond at week 12 underwent dose escalation to 50 mg BIW for a further 12 weeks. At week 24, six of these patients gained the PASI 50 response, 4 of whom maintained the response up to week 36, after treatment discontinuation from week 24. Our results confirm that etanercept is very effective and well-tolerated in psoriasis and that the drug dosages and treatment duration may be modulated and adapted to clinical needs in a flexible way. PMID- 20943051 TI - Lipopolysaccharide from Porphyromonas gingivalis stimulates rat mast cells to cysteinyl leukotriene generation and upregulates Toll-like receptor -2 and -4 expression. AB - Mast cells are found in all tissues of the oral cavity and it is suggested that they take part in the development of oral inflammation. As Porhyromonas gingivalis is widely recognized as a major pathogen in the development and progression of gingivitis and periodontitis, the aim of our study is to determine the effect of P. gingivalis lipopolysaccharide (LPS) on mast cell degranulation, cysteinyl leukotriene (cysLT) generation, and migration, as well as Toll-like receptor (TLR)-2 and -4 expression. Experiments were carried out in vitro on rat peritoneal mast cells. LPS-induced mast cell histamine release was estimated by a spectrofluorometric method and cysLT generation by ELISA test. Mast cell migration in response to this antigen was examined according to Boyden's modified method and TLR expression was determined by flow cytometry. We found that P. gingivalis LPS did not induce mast cell degranulation and histamine release. However, activation of mast cells with this bacterial antigen resulted in generation and release of significant amounts of cysLTs. We also documented that LPS from P. gingivalis did not stimulate mast cell migration, even in the presence of laminin, whereas it strongly upregulated TLR2 and TLR4 expression on mast cells. Observations that P. gingivalis LPS activates mast cells to generate and release proinflammatory mediators such as cysLTs and modulates TLR2 and TLR4 expression indicates that these cells might be involved in the emergency of inflammatory processes evolved in response to P gingivalis infection. PMID- 20943052 TI - Beneficial effects of Chlorella-11 peptide on blocking LPS-induced macrophage activation and alleviating thermal injury-induced inflammation in rats. AB - Chlorella possesses various remarkable biological activities. One component, Val Glu-Cys-Tyr-Gly-Pro-Asn-Arg-Pro-Gln-Phe (Chlorella-11 peptide) was found to be able to suppress LPS-induced NO production and inflammation. However, the molecular mechanism behind these findings and the consistency between in vitro and in vivo data have not been investigated. LPS-activated RAW 264.7 macrophages were used to study in vitro molecular anti-inflammatory effects of Chlorella-11 peptide. After activation, NO production and the expression of iNOS and NF-kappaB proteins as well as iNOS mRNA were measured using Griess colorimetric assay, Western blotting and RT-PCR, respectively. Alterations in PGE2 and TNF-alpha contents were also monitored by ELISA. For in vivo studies, thermal injury Wistar rats were used and inflammatory indications e.g. serum malondialdehyde (MDA), TNF alpha levels and skin erythema were evaluated 48 h after injury implementation. In vitro results showed that Chlorella-11 peptide produced a dose- and time dependent inhibition on NO production. The effective inhibition could remain for at least 6 h after LPS activation. It was also found that the expression of LPS induced iNOS mRNA, iNOS and NF-kappaB proteins were diminished by the peptide treatment. Concurrently, the levels on TNF-alpha and PGE2 production after LPS activation were also inhibited. These findings are in agreement with the in vivo data that animal serum MDA and TNF-alpha levels and skin erythema in rats were considerably reduced compared to the control group (saline-treated). The significance of this study sheds light on the effectiveness of Chlorella-11 peptide in preventing inflammation progression in vitro and in vivo and its potential for clinical applications. PMID- 20943053 TI - Microarray analysis of NF-kappaB signaling pathways in PBMC of mice infected by Trichinella spiralis. AB - The NF-kappaBeta pathway gene expression profiles were compared between 10, 20 and 39 days after Trichinella spiralis experimental infection in BALB/c mice. Out of 128 genes, 19 (14.8%) genes were present in non-infected and post-infected mice. The expression of 7 (36.8%) genes was downregulated 10 and 20 days post infection while 3 (15.8%) genes were upregulated 39 days post-infection. The present study lists the candidate genes of the NF-kappaB signaling pathway that were commonly and differentially expressed between the specific points of T. spiralis infection, thus suggesting that these genes need to be further investigated to reveal the mechanism of the T. spiralis modulation of the NF kappaB signaling pathways. PMID- 20943054 TI - In vitro activity of cefditoren versus other antibiotics against S. pneumoniae clinical strains isolated in Italy. AB - Over the last twenty years there has been an alarming increase in isolation of Streptococcus pneumoniae strains with a reduced susceptibility not only to penicillin, but also to other betalactams and macrolides. This phenomenon justifies the great interest in new antibiotics. Cefditoren, a new aminothiazolyl oral cephalosporin, recently commercialized in Italy, is characterized by an extended activity against penicillin-resistant S. pneumoniae. The aim of this study is to evaluate the incidence of the resistance/susceptibility to various antibiotics in 1000 strains of S. pneumoniae (678 SPSS, 219 SPPI and 103 SPPR), clinically isolated during 2009. The data obtained by our in vitro study show that cefditoren is the most active agent against S. pneumoniae. In fact, the MIC90 values of 0.5 micrograms/ml obtained could be particularly significant in therms of therapeutic predictivity. PMID- 20943055 TI - In vivo characterization of Zirconia Toughened Alumina material: a comparative animal study. AB - The development of a new chromia-doped Zirconia Toughened Alumina (ZTA) material was previously reported as displaying mechanical properties suitable for implants with load bearing applications, such as orthopaedic and dental implants. This type of biomaterial is expected to be in contact with living tissues for a long period of time and its long-term toxicity must be carefully evaluated. In this study the suitability of this ZTA material as a candidate biomaterial for orthopaedic implants and dental devices was further investigated in vivo in comparison to alumina and zirconia, which are currently used in orthopaedic and dental surgery. Cylinders of the materials were implanted in vivo in white rabbits, and local and systemic tissue reactions were analyzed at different time intervals after surgery. Radiologic examinations displayed the absence of radiolucence around cylinders and no signs of implant loosening up to twelve months. No tumours developed in the animals either locally (at the site of implantation), or systemically in the peripheral organs. The results obtained suggest that this new ZTA material does not display any long term pathogenic effect in vivo. These findings extend our previous observations on the biocompatibility and the absence of any long-term carcinogenic effect in vitro of this material which displays interesting properties for biomedical applications. In conclusion, we report the in vivo characterization of a new chromia-doped ZTA material and confirm its suitability as a candidate biomaterial for orthopaedic implants and dental devices since it does not give any local nor systemic toxicity even after a long period of time after implantation. PMID- 20943056 TI - The effects of alcoholism pharmacotherapy on immune responses in alcohol dependent patients. AB - Chronic alcohol use has profound modulatory effects on the immune system. Both the innate and the acquired immunity are compromised. The use of pharmacotherapy is increasingly applied to enhance the percentage of success in maintaining alcoholic patients in remission. Disulfiram, naltrexone and gamma hydroxybutiric acid are the drugs used for this purpose in Italian Addiction Services. In this study we analyze the effect of pharmacotherapy of alcohol dependence on immune responses in alcoholics. Six groups were studied. Group A included 10 patients who were still using alcohol. Group B consisted of 10 patients abstinent from alcohol in treatment only with group therapy. Groups C, D and E were composed of 10 patients each, treated for at least 6 months with oral doses of gamma hydroxybutiric acid, naltrexone or disulfiram respectively. Ten age- and sex matched healthy volunteers who never misused alcohol were included as a control group. Lymphoproliferation and peripheral mononuclear cell production of the Th1 cytokines IL-2 and IFN-gamma, the Th2 cytokine IL-4, and of the pro-inflammatory cytokines IL-1 and TNF-alpha were evaluated in all the patients and controls. The level of activity of the hypothalamus pituitary adrenal axis was assessed. Both ACTH and cortisol levels in plasma were elevated in alcoholic patients with no treatment. In this group a significant alteration of cytokine production was observed. TNF and IFN-gamma were lower than controls, while the Th2 cytokine IL-4 was increased. These altered levels state for a Th1/Th2 unbalance characterized by decreased Th1 response in the presence of Th2 predominance. In patients undergoing pharmacological treatment, none of the immune parameters were different from those observed in healthy controls, independently of the type of drug administered. These data indicate that pharmacotherapy more than group therapy treatment is able to ameliorate the immune system functioning in alcoholic patients. PMID- 20943057 TI - Interkeratin peptide-protein interactions that promote HPV16 E7 gene expression. AB - Human papillomavirus (HPV) 16 E7 gene product encodes the major transforming activity of the virus so as to induce neoplastic transformation. Continued expression of HPV16 E7 protein is required for both the establishment and maintenance of the transformed cellular phenotype. Therefore, understanding of the molecular and biochemical factors leading to the expression of E7 protein is important in relation to HPV-associated diseases. Previously, we identified a rare codon usage and a specific interaction between cytokeratin (CK) 7 and HPV16 E7 mRNA as factors modulating HPV16 E7 expression. In the present study we report that CK19, a biochemical marker of squamous oral and cervical cancer carcinogenesis, promotes the expression of HPV16 E7 oncoprotein by binding to the CK792-97SEQIKA peptide. These findings shed light on the dynamic functionality of the intermediate filament cytoskeleton, open new perspectives for investigating the role of CKs in controlling HPV16 E7 expression, and suggest new therapeutic avenues for HPV-associated carcinomas. PMID- 20943058 TI - Long-term safety and efficacy of topical cyclosporine in 156 children with vernal keratoconjunctivitis. AB - Vernal keratoconjunctivitis (VKC) is a chronic and potentially sight-threatening disease. Topical corticosteroids (Cs) seem to be the only effective treatment for this condition, although severe side effects may occur owing to their prolonged use. More recently, cyclosporine (Cyc) eye drops have been reported as a valid alternative, but so far such treatment has only been successfully experimented for a short time and in small numbers of patients. The aim of our study is to evaluate the long term safety and efficacy of topical cyclosporine eye drops in children suffering from VKC. Over a period of 7 years we followed a large group of children suffering from severe VKC. They were selected to start cyclosporine eye drop treatment, because of the prompt relapse of their disease as soon as they stopped topical corticosteroids administration. All patients were followed up in an ambulatory care assessment. A total of 156 children with VKC were treated with topical cyclosporine eye drops over a period ranging from two to seven years [mean time 3.8 +/- 1.09 years] during the seasonal relapse [range 9 66 months; mean time 24.7+/-10.4 months]. Two formulations, at 1% and 2% (82% and 18%, respectively) concentrations, of cyclosporine eye drops were made. The dosage administered was one drop in each eye from two to four times a day, depending on the severity of the disease and the season. The ocular objective scores were determined and compared every year, at the beginning and at the end of each treatment period. Blood samples were collected once a year in order to check both kidney and liver functions, as well as cyclosporine serum levels. We enrolled 156 patients (mean age 8.31+/-2.79 years; 116 males and 40 females) who were followed-up over a period of 7 years [156 (100%) children during the first and the second year; 138 (88.5%) patients until the third year; 90 (57.7%) until the fourth year; 32 (20.5%) until the fifth year; 10 (6.4%) until the sixth year and 2 (1.3%) until the seventh year]. The ocular objective scores significantly improved (p less than 0.001) over the years when comparing them at the beginning and the end of each seasonal treatment period, except for the last year. Over the treatment period, non-significant changes were recorded in terms of kidney and liver enzymatic activities and also in terms of cyclosporine serum levels. Cyclosporine eye drops, either at 1% or 2% concentrations, resulted safe and effective for long-term treatment of VKC in 156 children. The lack of significance of the score results during the seventh year can be explained by the small number of subjects treated for such a long period. A systematic ocular examination and both liver and kidney functional investigations allowed us to exclude the possibility of local or systemic side effects due to cyclosporine. If either transient or long-lasting, the occurrence of burning was referred by some of the patients treated, but none of them required to discontinue the drug. In conclusion, this is the first study showing that topical cyclosporine is easily handled even by children, with safe and effective results even when it is used over a long period of time. Our findings, though encouraging, need to be confirmed by further studies. PMID- 20943059 TI - Attention-deficit hyperactivity disorder and intellectual disability: a study of association with brain-derived neurotrophic factor gene polymorphisms. AB - Symptoms of attention-deficit hyperactivity disorder (ADHD) have been found in several studies of children with intellectual disabilities (ID) but the two diseases are not always associated. Several lines of evidence implicate the involvement of brain-derived neurotrophic factor (BDNF) in ADHD, and it may also be relevant in ID due to its known involvement in the development of the central nervous system (CNS) and in learning/memory functions. We genotyped paediatric patients with ADHD and ID for the Val66Met and 270 C/T polymorphisms in BDNF. Diagnosis of ADHD and ID was confirmed by the clinicians in accordance with DSM IV criteria. The G/A genotype of the Val66Met SNP was associated with both ADHD and ID, and the G allele was significantly associated with ADHD. The C/C genotype of the C270T SNP was significantly overrepresented in both ADHD and ID groups compared with the controls. Data suggest that both BDNF polymorphisms could play a role in the etiology of ADHD. In addition, we present the first results suggesting that these BDNF SNPs are significantly associated with ID. PMID- 20943060 TI - Allergic and non-allergic drug hypersensitivity reactions in children. AB - Adverse drug reactions (ADR) are an important medical problem. The aim of this study is to investigate the clinical characteristics of children with ADR and to assess the tolerability of alternative drugs in children (under 16 yrs of age) with a history of ADR. We studied 278 children (132 males and 146 females). Patients were studied by recording personal history and performing in vivo skin testing, in vitro laboratory tests and challenge tests. Patients who had experienced mild adverse reactions underwent challenge tests without any premedication; patients with a clinical history of moderate reactions, received a premedication with sodium chromolyn 30 min before the oral challenge; patients with a clinical history of severe reactions or undergoing parenteral challenges, were given an antihistamine 30 minutes before. A total of 660 adverse events were reported with 126 different drugs involved. Antimicrobial agents were the most involved drugs (51.7%). Non-steroidal anti-inflammatory drugs were involved in 22.7% of episodes. The most reported symptoms were cutaneous. Allergy testing was negative in 272 patients. A diagnosis of drug allergy was reported for 6 patients. A total of 669 challenge tests were performed. 639 were negative at first attempt while 22 were positive. Eight were repeated using a different premedication and resulted negative. Hypersensitivity drug reactions in children are mainly non-allergic. A premedication with sodium cromolyn or with oral H1 antihistamines may be useful in preventing ADR. PMID- 20943061 TI - The plasminogen activator system in fibroblasts from systemic sclerosis. AB - Systemic sclerosis (SSc) is characterized by excessive fibrosis throughout the body. There are two major subsets of SSc, diffuse cutaneous Systemic sclerosis (dSSc) and limited cutaneous Systemic sclerosis (lSSc). Fibroblasts play a key role in SSc. The expression and function of the urokinase (uPA)-mediated plasminogen activation (PA) system, a well-characterized system of serine proteases involved in several pathological processes, has been investigated in SSc fibroblasts. The expression of the components of the PA system, including uPA, its type-1 and type-2 inhibitors (PAI-1 and PAI-2) and its receptor (uPAR), was examined by Western blot in fibroblasts from patients affected by limited and diffuse forms of SSc. uPA and PAI-1 secretion increased only in fibroblasts from lSSc lesions compared to normal fibroblasts. PAI-2 levels were decreased in fibroblasts from both SSc forms. Interestingly, fibroblasts from areas not adjacent to the lesions (not-affected) of the diffuse form showed reduced levels of PAI-1 and increased uPAR expression. Adhesion experiments showed reduced adherence to VN of fibroblasts from lSSc lesions and from non-affected areas of the diffuse form, as compared to normal controls. These results suggest a role for uPA and PAI-1 in the lSSc form, likely related to the activation of latent forms of cytokines and to the accumulation of ECM components, whereas a role for uPAR can be hypothesized in the evolvement of the diffuse form, based on its up regulation in the non-affected areas. PMID- 20943062 TI - Serum proteome of patients with systemic sclerosis: molecular analysis of expression and prevalence of haptoglobin alpha chain isoforms. AB - Haptoglobin (Hpt) is an acute phase protein characterized by three major phenotypes (Hpt 1-1, Hpt 2-1 and Hpt 2-2). The Hpt 2-2 phenotype is associated with increased prevalence of various systemic diseases, including autoimmune disorders. Moreover, the Hpt 2-2 phenotype induces a shift from Th1 to Th2 response and increases fibrotic processes. On this basis, we performed serum proteomic analysis of patients with Systemic Sclerosis (SSc), a connective tissue disorder associated with Th2-type immune response and characterized by interstitial and perivascular fibrosis due to different factors (including genetic, environmental, immunological and microchimeric factors). Serum of 23 SSc outpatients patients (4 males, 19 females, mean age 54+-5.3 years) diagnosed according to the American Rheumatism Association (ARA) criteria, were considered for the proteomic analysis and compared to serum of 21 control subjects. Serum depleted of HAP was analyzed by 2-DE, and Hpt chain spots were identified by WB. The expression frequency of each Hpt alpha chain in SSc patients and controls was compared and quantitative analysis of spot expression (percent Vol) was performed. Above all,, our study amplifies the limited data in the literature on proteomic analysis in SSc, also confirming previous data that revealed a significant increase of haptoglobin type 2-2 and a concomitant decrease of the 1 1 phenotype in SSc patients. Moreover, our results demonstrate that c spots are more prevalent in SSc patients than in controls (91.3% vs 55.5%, p<0.05), while the expression frequency of a and b spots does not change. In patients Hpt 2-1 or Hpt 1-1 e spot is less abundant. According to our results, the c and e spots can be considered markers for SSc and thus be of use for the early diagnosis of connective tissue disorders and in establishing appropriate treatment. PMID- 20943063 TI - Homocysteine, vitamin B12 and folic acid levels in psoriatic patients and correlation with disease severity. AB - Hyperhomocysteinaemia represents an independent risk factor for atherosclerotic cardiovascular disease, stroke, peripheral arterial occlusive disease and venous thrombosis. Psoriasis is a chronic inflammatory skin disease associated with increased atherothrombosis and cardiovascular risk profile. The aim of this study is to investigate homocysteine, folic acid and vitamin B12 levels in a cohort of psoriatic patients and its relationship with the severity of the disease. A retrospective observational study in 98 patients with chronic plaque psoriasis and 98 healthy controls was performed. Total plasma homocysteine level, folic acid, vitamin B12 and PASI index were assessed in every patient. Patients with psoriasis had plasma homocysteine levels higher than controls (57% of cases and 25% of controls; p<0.0001). Folic acid and vitamin B12 plasma levels were lower in psoriatic patients than in controls (p = NS), lower levels of vitamin B12 were found in patients with hyperhomocysteinaemia compared to patients with a normal value of homocysteine (p = 0.0009). The severity of psoriasis assessed according to PASI (19.51+/-16.26) did not directly correlate either with higher levels of homocysteine or with vitamin B12 and folic acid plasma levels. In conclusion, a significantly higher prevalence of hyperhomocysteinaemia was found in psoriatic patients compared to healthy controls. A significant correlation between hyperhomocysteinaemia and lower vitamin B12 levels, but not folic acid, was evidenced. On the contrary, our data do not correlate the high level of homocysteine with higher PASI scores or psoriasis type, suggesting that homocysteine level can be considered an independent risk factor in psoriatic patients. PMID- 20943064 TI - Apelin plasma levels predict arrhythmia recurrence in patients with persistent atrial fibrillation. AB - Low levels of the regulatory peptide apelin have been reported in patients with lone atrial fibrillation (AF). We evaluate the potential utility of assessing apelin plasma levels as a predictor of AF recurrence in individuals presenting for electrical cardioversion. Plasma levels of apelin, brain natriuretic peptide (BNP) and high-sensitivity C-reactive protein were measured in 93 patients, with persistent AF before successful external electrical cardioversion. Significantly lower apelin plasma levels were found in patients with AF recurrence as respect to population with persistence of sinus rhythm during a six months follow-up. The hazard increased with duration of AF, left atrial dimension, BNP concentrations. Subjects with apelin levels below the median had a hazard ratio of 3.1 of arrhythmia recurrence with respect to those with high apelin levels (p<0.05). A significant difference in BNP levels was found between patients with and without AF recurrence during the follow-up. After adjusting for potential confounders, both BNP and apelin retained their statistical significance as independent predictors of arrhythmia recurrence. Patients with both low apelin and elevated BNP had a worse prognosis compared with those with either low apelin or elevated BNP alone. Low plasma apelin levels before external electrical cardioversion are an independent prognostic factor for arrhythmia recurrence in patients with AF treated with antiarrhythmic drugs. Apelin may be of particular value for the identification of high-risk patients in addition to BNP. PMID- 20943065 TI - Pharmacological functional MRI assessment of the effect of ibuprofen-arginine in painful conditions. AB - Pharmacological functional magnetic resonance imaging (phMRI) is a valuable tool for the investigation of pharmacological effects of a drug on pain processing. We hypothesized that the ibuprofen-arginine combination, in line with its characteristic analgesic properties, may influence the phMRI response at the central level, as compared to placebo. Ten healthy subjects underwent a double blind, placebo-controlled, randomized, cross-over phFMRI study with somatosensory painful stimulation of the right median nerve. We measured the blood oxygen level dependent (BOLD) signal variations induced in conditions of pain after oral administration of either ibuprofen-arginine or placebo formulations. Independent component analysis (ICA) was used for the analysis of the fMRI data, without assuming a specific hemodynamic response function (HRF), which may be altered by drug administration. Median nerve electrical painful stimulation mainly activated the primary contralateral and the secondary somatosensory cortices, the insula, the supplementary motor area, and the middle frontal gyrus. Placebo and ibuprofen arginine administration induced activation bilaterally in the premotor cortex, and an overall reduction in the other pain-related areas, which was more prominent in the left hemisphere. A task-related increase of BOLD signal between drug and placebo was observed bilaterally in the primary somatosensory area and the middle frontal gyrus without any changes in subjective pain scores. Overall, our findings show that ibuprofen-arginine, in line with the characteristic analgesic properties of ibuprofen, influences the BOLD response in specific pain related brain areas with respect to placebo, with a vasoactive effect possibly due to arginine. PMID- 20943066 TI - The clinical efficacy of a sublingual monomeric allergoid at different maintenance doses: a randomized controlled trial. AB - Sublingual immunotherapy is widely recognized as a viable treatment for allergic rhinitis and asthma, but the optimal dosage is still under debate, especially with modified allergens. We assessed the clinical effects of a monomeric allergoid across 3 different maintenance doses in mite-monosensitized patients with rhinitis and intermittent asthma. Eighty-nine patients allergic to HDM were randomized to 3 maintenance doses of monomeric allergoid (Lais, Lofarma) or medications only. All the patients recorded their symptoms and rescue drug consumption in a diary card from November to February. Additionally, nasal eosinophil count, spirometry and methacholine bronchial challenge were performed at the beginning of the study and after 3 years. The symptom scores showed a clear improvement in all the three active arms versus baseline and versus the controls, irrespective of the dose. Likewise, a similar improvement versus baseline was seen for nasal inflammation and bronchial hyperreactivity. The SLIT with monomeric allergoids produces clinically significant results across a wide range of doses. The absence of significant side effects, even at high doses, is probably due to their low level of allergeni city. PMID- 20943067 TI - Large granular lymphocyte leukemia with pure red cell aplasia associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy: an unfortuitous association? AB - Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a recessively inherited monogenic disease caused by a mutation in the autoimmune regulator (AIRE) gene. AIRE plays a major role in central (thymic) immune tolerance. In the absence of AIRE, autoimmunity develops that is especially targeted at endocrine tissues. T-cell large granular lymphocyte (T-LGL) leukemia is a monoclonal lymphoproliferative disease characterized by persistent and indolent lymphocytosis. Autoimmune manifestations, such as rheumatoid arthritis or autoimmune cytopenia, are also common. We report the case of a patient with APECED, who presented with pure red cell aplasia associated with T-LGL leukemia. The association of T-LGL leukemia and APECED is very rare and may not be fortuitous. The immunological mechanisms of this association are discussed. PMID- 20943068 TI - A long-lasting response to sorafenib treatment in an advanced hepatocellular carcinoma patient. AB - Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. No effective systemic treatment has been established, except for sorafenib chemotherapy. In fact, sorafenib has proved to provide a statistically significant survival extension of about two months in two phase III trials in the North America-Europe area and in the Asia-Pacific area, which respectively reported a median survival after treatment of 10.7 and 6.5 months, respectively. We report the case of an HCC patient, who received a four-month therapy with sorafenib with a clinical, biochemical and radiographic response, but had to interrupt treatment because of a myocardial infarction. Surprisingly, despite no antitumor treatment having been administered for about a year, the patient has shown no tumor progression and is currently on a close follow-up. Should other similar cases be presented, a subset of patients with long-lasting response to sorafenib might be identified. PMID- 20943069 TI - JC Viral reactivation in a pediatric patient with Crohn's disease. AB - This is a report concerning human polyomavirus JC (JCV) reactivation in a pediatric patient with Crohn's disease (CD) during the treatment with 5 aminosalicylic acid (5-ASA), a non-steroidal anti-inflammatory drug (NSAID). We examined 9 bioptic samples from three different bowel districts (ileum, cecum, rectum) of this child. These samples were analyzed by Quantitative PCR (Q-PCR) to investigate the presence of JCV DNA. JCV DNA was detected in one rectum biopsy taken two months after 5-ASA treatment. Although our result must be validated in a larger group of subjects and with a longer follow-up period, it underlines the importance of JVC monitoring in CD patients. PMID- 20943070 TI - Sudden progression from impaired glucose tolerance to type 2 diabetes after discontinuation of administration of anti-tumor necrosis factor-alpha antibody infliximab. AB - We present the case of a 45-year-old man with psoriasis and psoriatic arthritis and concomitant impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). In this patient, refractory to DMARD's, infliximab was started to control the arthritis. After achieving clinical remission of the disease, infliximab was discontinued and a 75 g- oral glucose tolerance test (OGTT) was performed. After the test, we observed a conversion from IFG/IGT glucose tolerance status to type 2 diabetes. No diet, lifestyle or therapy modifications were made during the observation period. Autoimmune diabetes was ruled out by serum antibodies determination and body weight remained constant, sustaining a protective role in infliximab in the worsening of glucose tolerance. PMID- 20943071 TI - Etanercept therapy in patients with psoriasis and concomitant HCV infection. AB - Treatment of patients with psoriasis and/or psoriatic arthritis and concomitant hepatitis C infection remains difficult. Except for cyclosporine, other drugs have proved unacceptable because of hepatotoxicity in patients with HCV. With the advent of anti-TNF-alpha drugs, including etanercept, new therapeutic options have become available. Our study population was five patients with psoriasis and/or psoriatic arthritis and concomitant chronic HCV infection undergoing etanercept therapy. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and viral load were used as markers for liver damage and disease progression, respectively. The Psoriasis Area Severity Index (PASI) was used as a reference parameter for evaluating the therapeutic efficacy of etanercept therapy in improving the clinical skin picture. AST, ALT, viral load and PASI were monitored at 3-month intervals starting from the beginning of therapy up to two years after initiation of etanercept therapy. In four out of five patients, liver enzyme levels and viral load remained substantially unchanged during the course of therapy. In the one remaining patient, viral load and liver enzyme levels increased during etanercept therapy, and then decreased following the initiation of Peg-IFN/ribavirin in combination with anti-TNF-alpha therapy. PASI scores decreased in all five patients. Our data suggest that etanercept therapy is safe and provides an efficacious therapeutic alternative in patients with psoriasis and concomitant HCV infection. PMID- 20943072 TI - [Comparison of fluorescence quantitative PCR and direct PCR sequencing in the detection of HBV polymerase RT region]. AB - OBJECTIVE: To explore the feasibility of Direct PCR sequencing in clinic and the significance of Direct PCR sequencing for retrieval treatment plan. METHODS: To address this issue, a cross-sectional study on the drug resistance in the HBV polymerase RT region was performed using Fluorescence quantitative PCR and Direct PCR sequencing in 60 chronic hepatitis B patients, who responded failure to long term LAM and/or ADV therapy. RESULT: Compared with Fluorescence quantitative PCR, Direct PCR sequencing expressed a higher positive rate (43.2% vs 38.6%; 66.7% vs 54.2%, respectively) and a lower missing rate (9.5% vs 19.0%; 5.9% vs 23.5%, respectively) in the detection of drug resistance in the patients treated with LAM or combination therapy of LAM with ADV. The sensitivity of experiment using Direct PCR sequencing seemed better than Fluorescence quantitative PCR, although the difference was not significant. Further analysis on sensitivity and specificity of detection between high and low viral loads groups indicated that the consensus of two experiments in high viral load group is better than that in low viral load group (Chi-square test = 5.18, probability value = 0.023). In low viral load group, Direct PCR sequencing expressed higher sensitivity and higher specificity than Fluorescence quantitative PCR, although the difference did not approach significant. CONCLUSION: Direct PCR sequencing is better than Fluorescence quantitative PCR in the detection of drug resistance in clinic, not only with higher sensitivity and specificity, but also with comprehensive information of HBV polymerase RT region. PMID- 20943073 TI - [Programmed death-1 (PD-1) and PD-L1 expression during antiviral treatment of chronic hepatitis B]. AB - OBJECTIVE: To study PD-1 and PD-L1 expressions during 24 weeks telbivudine antiviral treatment in patients with chronic hepatitis B (CHB) and to explore the relationship between PD-1 expression and HBeAg/HBeAb seroconversion. METHODS: Ten CHB cases with HLA-A2 and HBeAg positive were treated with telbivudine 600 mg/d orally for 24 weeks. Fresh blood samples were collected at week 0, 12 and 24 after treatment. HBV-specific CD8+ T cells were expanded in vitro. Cell culture medium were collected for interferon gamma (IFNgamma) detection. Flow cytometry was used to detect the HLA-A type, PD-1, PD-L1 and HBV specific CD8+ T cells. The expressions of PD-1 and PD-L1, the counts of HBV-specific CD8+ T cells in circulating CD8+ lymphocytes, and IFNgamma concentration in culture medium were evaluated during antiviral treatment. RESULTS: At week 0, 12 and 24 after telbivudine treatment, 7 of 10 patients were HBV DNA undetectable, 2 were HBeAg seroconversion and 2 were HBeAg lose but anti-HBe negative. The frequency of PD-1 positive PBMCs were 52.1%+/-17.0%, 39.1%+/-18.2% and 23.4%+/-16.3% (week 24 vs week 0, P < 0.01) respectively; PD-L1 positive PBMCs were 45.6%+/-15.4%, 34.6%+/ 16.2% and 20.9%+/-9.5% respectively(week 24 vs week 0, P < 0.01; week 24 vs week 12, P < 0.05). The frequency of PD-1-positive CD8+ T cells were 76.2%+/-10.4%, 66.5%+/-15.4% and 49.5%+/-25.3% respectively (week 24 vs week 0, P < 0.01; week 12 vs week 0, P < 0.05; week 24 vs week 12, P < 0.05); HBV-specific CD8 cells were 1.3%+/-0.5%, 1.5%+/-1.0% and 2.2%+/-1.5%; IFNgamma levels in cell culture medium were (91.7+/-82.1) pg/ml, (99.4+/-93.5) pg/ml and (109.5+/-86.6) pg/ml. A remarkable decrease of PD-1 and PD-L1 expressions and increase of HBV-specific CD8+ T cells were observed in patients who had HBeAg/HBeAb seroconversion at week 24. CONCLUSIONS: Direct suppression of HBV replication by telbivudine in CHB patients can decrease PD-1 and PD-L1 expressions and restore HBV-specific CD8+T cells. The relationship between the changes of PD-1 expression and HBeAg/HBeAb seroconversion during antiviral therapy in HBeAg-positive patients need to confirm by future study. PMID- 20943074 TI - [Effects of lipopolysaccharide on the maturation and secretion of human peripheral dendritic cells]. AB - OBJECTIVE: To study the effects of Lipopolysaccharide (LPS) on the maturation and secretion of human peripheral dendritic cells (DCs). METHODS: DCs from healthy human peripheral monocytes (PBMCs) were induced in vitro with rhGM-CSF, rhIL-4, Flt3-L and TNFalpha. The subjects were divided into 3 groups: the long-term group stimulated with LPS 1 microg/ml at day 1, 4, 7, 9 post culture; the short-term group stimulated with LPS 1 microg/ml at day 7 and 8 post culture, and the DCs without LPS stimulation was control group. After 10 days of culture, the morphologic features of DCs were observed by light and electron microscopes, the phenotypic patterns were characterized by flow cytometry, the proliferation of T cell were evaluated with mixed leukocytes reaction (MLR) and the levels of IL-12 and IFNgamma produced by DCs were analyzed with ELISA. RESULTS: Compared with the short-term group, the expressions of HLA-DR (65.81%+/-10.96%), CD86 (48.81%+/ 18.13%), CD80 (13.56%+/-5.48%), CD83 (11.52%+/-5.09%), the secretions of IFNgamma(15.60+/-5.83 pg/ml) and IL-12 (51.77+/-11.02 pg/ml) by the DCs in long term group were decreased obviously (P is less than 0.05) and the proliferation of homogenic lymphocyte cells (1.548+/-0.365) stimulated by DCs was also impaired (P < 0.05). CONCLUSION: Long-term LPS stimulation can suppress the maturation and secretion of DCs, which might be the reason of poor immunity in the patients with intestinal endotoxemia. PMID- 20943075 TI - [Effects of blueberry on the expression patterns of heme oxygenase-1 in rats with hepatic fibrosis]. AB - OBJECTIVE: To study the protective effect of Blueberry against rat hepatic fibrosis and the effect of Blueberry on HO-1 expression patterns. METHODS: A total of 45 SD rats were randomly divided into five groups namely control group (group A), model group (group B), blueberry group (group C), Dan-shao-hua-xian (DSHX) capsule group (group D) and blueberry +Dan-shao-hua-xian group (group E). Fibrous liver models in rats were induced by subcutaneous injection of CCl4 and high-lipid/low-protein diet for 8 weeks except the control group which accepted saline alone. The level of alanine aminotransferase (ALT) in serum was examined. The activities of superoxide dismutase (SOD) and malondialdehyde (MDA) in liver homogenates were determined. by the xanthine oxidase method and the thiobarbituric acid method. The pathology of hepatic fibrosis was evaluated by hematoxylin and eosin (H and E) staining. The Expression of HO-1 was detected by real-time RT-PCR, immunohistochemical techniques and western blotting. RESULTS: Serum ALT levels in every prevention group was lower than the group B [(149.44+/ 16.51), (136.88+/-10.07), (127.38+/-11.03) vs (203.25+/-31.62) U/L, F = 92.498, P < 0.05], the SOD of liver homogenate in prevention group was significantly higher and the MDA was lower compared with the group B [SOD: (1.36+/-0.09), (1.42+/ 0.13), (1.50+/-0.15) vs (1.08+/-0.19) U/mg, F = 13.671, P < 0.05; MDA: (0.294+/ 0.026), (0.285+/-0.025), (0.284+/-0.028) vs (0.335+/-0.056) nmol/mg, F = 20.809, P < 0.05]. The pathological stages of hepatic fibrosis were all significantly reduced in prevention group (Chi2 test = 24.956, P < 0.05). Compared with group A, the mRNA and protein expressions of HO-1 were elevated (F = 4.549, 22.926, P < 0.05) in group B and increased in group C-E, but there is no significant difference existed. CONCLUSION: Blueberry may have preventive and protective effects on CCl4-induced hepatic fibrosis by reducing lipid peroxidation. However, these effects may not be related to the activation of HO-1 during long-term of CCl4. PMID- 20943076 TI - [Expression and its clinicopathological features of tumor rejective antigen 1 in human tissues of hepatocellular carcinoma and liver cirrhosis]. AB - OBJECTIVE: To investigate the expression of tumor rejective antigen 1 in hepatocellular carcinoma (HCC) and liver cirrhosis(LC) tissues, and the relationship between clinicopathological feature and HCC. METHODS: The expressions of TRA1 mRNA and its protein were detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blot respectively. Immunohistochemical staining was used to further examine the expression of TRA1 protein in LC, HCC and control tissues. The relationship between clinicopathological feature and HCC was analyzed. Data of RT-PCR and Western blot were analyzed by One-way ANOVA; results of immunohistochemical staining were analyzed by Fisher's exact test and correlation analysis using Spearman rank correlation. RESULTS: RT-PCR data showed that the expression of TRA1 mRNA was higher in HCC and LC tissues than that in the normal liver tissues (F values were 20.821 and 12.311 respectively, P is less than 0.05). The expression of TRA1 protein in HCC and LC tissues was signifIcantly higher than that in control by Western blot (F values were 21.231 and 20.125 respectively, P < 0.05). The immunohistochemical data showed the expression of TRA1 protein was gradually increased in HCC group than that in the LC group and control group, and the positive expression rate of TRA1 was 57.14%, 78.95% and 93.75% respectively. The expression of TRA1 protein was negatively correlated with HCC differentiation (r = -0.4655, P = 0.0073) and positively correlated with HCC TNM staging (r = 0.5157, P = 0.0025). CONCLUSION: The over-expression of TRA1 in hepatocirrhosis and HCC is correlated with the formation and development of HCC. It may be a prognostic marker for the diagnosis of HCC and be associated with the degree of differentiation and HBV infection. It can be used as a marker for prognostic prediction of HCC. PMID- 20943077 TI - [Effects of AKR1B10 gene silence on the growth and gene expression of HCC cell line MHCC97H]. AB - OBJECTIVE: To explore the biological function and possible underlying mechanism of aldo-keto reductase family 1 member B10 (AKR1B10) gene during hepatocarcinogenesis. METHODS: A pair of chemically synthesized small interfering RNA (siRNA) targeting on AKR1B10 was transfected into liver cancer cell line MHCC97H by LipofectamineTM 2000. After confirming the interfering effects of AKR1B10-siRNAs through Quant SYBR Green polymerase chain reaction (Real-time PCR), Western blot and enzymatic activity assay, the capabilities of proliferation and apoptosis of the transfected cells were observed by CCK-8 assay and flow cytometry analysis, and the expressions of a group of tumor-related gene such as c-myc, c-fos, N-ras were observed through Real-time PCR. RESULTS: The expressions of AKR1B10 and the enzymatic activity were down-regulated significantly in AKR1B10-siRNA-transfected cells. Compared with mock and blank control groups, cell growth in AKR1B10-siRNA-transfected group was inhibited by 26.6%+/-3.1% at 72h after transfection. The ratio of apoptotic cells was 37.3%+/ 1.0% in AKR1B10-siRNA-transfected group, which was significantly higher than that in mock and blank control groups (P < 0.01). Real-time PCR showed that the expressions of oncogene c-myc, c-fos and N-ras, and the proliferation-associated gene ki-67 were down-regulated in AKR1B10-siRNA-transfected cells, while the expressions of apoptosis-promoting gene caspas-3 and bax were up-regulated. CONCLUSIONS: AKR1B10 might promote proliferation, inhibit apoptosis and then induce malignant transformation of hepatocytes by regulating the expression level of some tumor-related genes. PMID- 20943078 TI - [The role and significance of Wnt/beta-catenin signaling pathway regulating the signaling molecules in hepatocellular carcinoma]. AB - OBJECTIVE: To investigate the role and significance of Wnt/beta-catenin signaling pathway regulating GSK-3beta, STAT3, Smad3 and TERT in hepatocellular carcinoma (HCC). METHODS: The HCC cell line HepG2 was transfected with small interfering RNA (siRNA) directed against beta-catenin. Proteins were extracted and the expressions of beta-catenin, GSK-3beta, p-GSK-3beta, STAT3, Smad3 and TERT were detected by Western blot at 72 h and 96 h respectively after transfection. RESULTS: beta-catenin expression was inhibited at both time points and the expression at 96 h was higher than that at 72 h (t = 4.43, P < 0.05). Interestingly, GSK-3beta and p-GSK-3beta expressions increased gradually at 72 and 96 h (tGSK-3beta= 4.98, tp-GSK-3beta= 29.83, P < 0.05) respectively, and STAT3 expression showed no alteration after transfection (F = 0.49, P > 0.05). Smad3 expression was increased at 72 h (t = 10.67, P < 0.05) and decreased to normal at 96 h (t = 1.26, P < 0.05), while TERT expression decreased at 72 h (t = 4.18, P is less than 0.05) and increased to normal at 96 h (t = 1.26, P > 0.05). CONCLUSIONS: Wnt/beta-catenin signaling pathway is related to the expressions of GSK-3beta, Smad3 and TERT, but perhaps not related to STAT3 protein expression in HCC. It suggested that Wnt/beta-catenin signaling pathway might participate in HCC genesis and development through regulating the above three factors. PMID- 20943079 TI - [Effect of body weight mass and its change on the incidence of nonalcoholic fatty liver disease]. AB - OBJECTIVE: To determine the effect of body mass index (BMI) at baseline and its change during follow-up on the incidence of non-alcoholic fatty liver diseases (NAFLD) in apparently healthy adults. METHODS: Subjects free of previous liver injury, alcohol consumption of more than 140 g/week and hepatitis B virus infection were identified from employees of Shanghai BaoSteel Group who underwent voluntary medical checkups at a 2-year interval. The analyzed population consisted of 5402 non-drinking subjects (4633 men) of age 36.5+/-9.3 years (18-65 years), who had normal livers at baseline. Among them 327 subjects (6.05%) developed fatty liver in 2 years. Those who developed NAFLD showed advanced age (especially in females), elevated BMI, high levels of serum triglyceride and total cholesterol, high prevalence rates of obesity, hyperlipidemia, hypertension and hyperglyceridemia at baseline, more weight gain and increase of serum triglycerides during the 2-year period. The incidence of NAFLD increased significantly with the changes of BMI at baseline, from 1.4% in subjects with normal weight, 6.4% in overweight, 16.8% in obese patients to 24.5% in severe obesity (Chi2 test = 389.01, P = 0.000 in trend analysis). Logistic regression analysis showed a significant interaction occurred between NAFLD age, BMI and serum triglyceride at baseline, and subtle gain of BMI and triglyceride during follow-up. CONCLUSIONS: There is a high incidence of NAFLD in a Chinese workplace. Obesity and related metabolic disorders at baseline, and more weight gain and increased serum triglyceride during follow-up are important predictors for the development of NAFLD. PMID- 20943080 TI - [The role of heme oxygenase-1 in non-alcoholic steatohepatitis]. AB - OBJECTIVE: To investigate the potential role of heme oxygenase-1 on preventing non-alcoholic steatohepatitis (NASH) in mice. METHODS: Experimental models of NASH were established by feeding male C57BL/6J mice with choline-methionine deficient diet (MCD) for four weeks. Control animals were fed with choline methionine supplemented diet. The treatment groups were fed with MCD diet combined with HO-1 inducer hemin or inhibitor zinc protoporphyrin IX (ZnPP-IX). Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were tested by enzymic method with automatic biochemistry analyzer. The degree of hepatic steatosis, inflammation and fibrosis were examined under HE staining. The hepatic mRNA and protein expressions of HO-1, TNFalpha and IL-6 were analyzed by RT-PCR and Western blot respectively. MCD fed mice showed increased serum ALT and AST levels and moderate to severe hepatic steatosis with inflammatory infiltration, hepatic spot or focal necrosis, light portal and sinus hepaticus fibrosis in the liver sections, which associated with enhanced expression of HO 1, TNFalpha and IL-6 mRNA and protein (1.13+/-0.11, 1.74+/-0.05; 0.20+/-0.01, 1.92+/-0.10; 0.58+/-0.02, 2.06+/-0.05 vs 0.43+/-0.02, 0.75+/-0.05; 0.08+/-0.00, 0.59+/-0.02; 0.22+/-0.01, 0.91+/-0.02). Administration of hemin significantly decreased serum ALT and AST levels and attenuated hepatic steatosis and necroinflammation which associated with up-regulation of antioxidative gene HO-1 and down-regulation of pro-inflammatory cytokines TNFalpha and IL-6 (P < 0.01). A contrary effect on serum aminotransferase levels and liver histopathology was observed in mice injected with ZnPP-IX (P < 0.01). CONCLUSIONS: The effect was associated with suppressed HO-1 expression and increased TNFaLPHA and IL-6 expression. The data provided a biochemical, morphological and molecular biological evidence for the protective role of HO-1 in ameliorating hepatic steatosis, necroinflammation in experimental nutritional steatohepatitis. PMID- 20943081 TI - [Clinical and pathological features of 27 cases of primary sclerosing cholangitis]. AB - OBJECTIVE: To elucidate clinical and pathological features of primary sclerosing cholangitis (PSC) in order to improve clinician's awareness of this rare disease. METHODS: We retrospectively analyzed clinical data and follow-up information of 27 PSC patients who were admitted to Beijing Friendship Hospital from January 1990 to November 2009. The patients were classified into classic PSC and small duct PSC according to biochemistry and imaging results. After 3 to 6 months of therapy, those patients with serum ALT < or = 1.5, TBil < or = 2 and ALP < or = 2.5 ULN were determined as good responders. The treatment results between the two groups were compared. RESULTS: 9 out of 27 cases of PSC were small duct PSC and 18 cases were large bile duct or classic PSC. Male patients (7) were less than females (20) and the average age was 47.6 years. Main clinical symptoms included jaundice (85.2%), pruritis (48.1%),fatigue (68.4 %), abdominal pain (40.7%) and fever (14.8%), main physical sign included hepatomegaly (44.4%), splenomegaly (48.1 %) and ascites (14.8%). Laboratory features included elevated IgG (81.8%), positive ANA (69.6%) and pANCA (52.9%). 22% of these PSC patients had ulcerative colitis or Sjogren's syndrome. A small percentage of patients were responsive to standard therapy, of which small duct PSC had a better response than classic PSC (66.7 % vs 33.3%, P = 0.041). CONCLUSIONS: Ulcerative colitis (22.2%) is not as common as reported by western countries. Small duct PSC has a better treatment response. Searching of effective treatment regimen for large bile duct PSC is warranted in future studies. PMID- 20943082 TI - [Nevirapine related hepatotoxicity: the prevalence and risk factors in a cohort of ART naive Han Chinese with AIDS]. AB - OBJECTIVE: To investigate the incidence of hepatotoxicity in acquired immunodeficiency syndrome (AIDS) patients on combined anti-retroviral therapy (cART) containing nevirapine (NVP) and to assess the risk factors and its impact on cART. METHODS: 330 AIDS patients from March 2003 to June 2008 at local county were enrolled and a retrospective study using Kaplan-meier survival and Multivariate logistic regression modeling was conducted. RESULTS: 267 out of 330 patients received NVP based cART and 63 cases received EFV-based cART. The deference of prevalences of hepatotoxicity between the two groups is statistically significant (Chi2 = 6.691, P = 0.01). 133 out of 267 (49.8%) patients on NVP based cART had at least one episode of ALT elevation during a median 21 months (interquartile ranges, IQR 6, 37) follow-up time, amounts for 28.5 cases per 100 person-years. Baseline ALT elevation (OR = 14.368, P = 0.017)and HCV co-infection (OR = 3.009, P = 0.000) were risk factors for cART related hepatotoxicity, while greatly increased CD4+ T(CD4) cell count was protective against hepatotoxicity development (OR = 0.996, P = 0.000). Patients co-infected with HCV received NVP-based cART had the higher probability of hepatotoxicity than those without HCV co-infection (Log rank: Chi2 = 16.764, P = 0.000). 23 out of the 133 subjects (17.3%) with NVP related hepatotoxicity discontinued cART temporarily or shifted NVP to efavirenz. CONCLUSION: NVP related hepatotoxicity was common among ARV naive HIV infected subjects in our cohort. Baseline ALT elevation and HCV co-infection were associated statistically with the development of hepatotoxicity. Hepatotoxicity led to discontinuing cART temporarily or switching to other regimens in some subjects. It suggested that NVP should be used with caution in patients co-infected with HCV among whom anti HCV therapy before cART initiation may contribute to minimizing the probability of NVP associated hepatotoxicity. PMID- 20943083 TI - [Clinical significance of histopathologic and ultrastructural pathologic examination in etiological diagnosis of infantile cholestatic diseases]. AB - OBJECTIVE: To study the features of histopathologic and ultrastructural pathologic changes of liver biopsy in patients with infantile cholestatic disease, and to investigate its diagnostic significance combining with the clinical data. METHODS: Thirty-six children diagnosed as infantile cholestatic disease and received liver biopsy in Chongqing Medical University Children's Hospital from Jun 2007 to Oct 2008 were enrolled and the pathologic and ultrastructural pathologic changes of liver were analyzed. RESULTS: Morphologic changes under light microscope in liver tissues included hepatocyte swelling, hepatocyte denaturation, hepatocyte necrosis, multinucleated giant cell formation, bile duct proliferation, fiber tissues proliferation and inflammatory cells infiltration in liver lobules and portal regions. The characteristics of cholestasis including intralobular cholestasis, acinus formation, feather-like cytoplasmic filaments and bile stasis in bile canaliculi were observed. The morphologic changes of biliary atresia were observed in 7 cases whose image investigations showed no obstruction of biliary tract. Nuclear changes, resolution of cytoplasm, inflammatory cell infiltration, collagen fiber proliferation and increased number of lysosomes were observed under electromicroscope. Two cases of glycogen storage disease, 1 case of Niemann-Pick disease and 1 case of lipid storage disease with unknown cause were confirmed by the combination of histological changes and clinical manifestations. CONCLUSION: Common pathologic changes of liver tissues existed under light microscope or electroscope. The diagnosis of hereditary metabolic disorders could be made increasingly by application of these two technologies in clinical practice. It is difficult to diagnose biliary atresia in early childhood by image investigations and the pathological changes of liver tissues are helpful. PMID- 20943084 TI - [The relationship of CPS-I, OCT and hepatic encephalopathy]. AB - OBJECTIVE: To study the role of carbamyl phosphate I (CPS-I)and ornithine transcarbamoylase (OCT) levels in cirrhosis patients with and without hepatic encephalopathy, and to analyze the correlations between CPS-Iand OCT with the development of hepatic encephalopathy. METHODS: CPS-I, OCT, plasma ammonia and liver function of 95 cirrhosis patients with hepatic encephalopathy and 25 cirrhosis patients without hepatic encephalopathy in our hospital from January 2008 to December 2009 were analyzed. 60 healthy controls were recruited in the control group. The differences of serum CPS-I, OCT levels among the cirrhosis patients with and without hepatic encephalopathy and the healthy controls were analyzed; the correlations of CPS-I, OCT levels with plasma ammonia and total protein in cirrhosis patients,and the correlations of CPS-I, OCT levels with Child-Pugh classification of cirrhosis symptom severity in cirrhosis were analyzed. the clinical characteristics between patients who had HE and no HE with chi-square tests were compared. Comparisons of CPS-I, OCT levels across patients based on the Child-Pugh classification were performed with One-Way ANOVA and Student-Newman-Keuls, correlation of CPS-I, OCT with other indicators were performed with Pearson correlation analysis. RESULTS: Serum CPS-I and OCT levels in cirrhosis patients with hepatic encephalopathy were (143.3+/-48.5) U/L, (297.0+/-102.6) is multiplied by 10 U/L, which were lower than that in cirrhosis patients without hepatic encephalopathy (180.3+/-51.5) U/L, (351.8+/-109.0) is multiplied by 10 U/L (t = 2.53, t = 2.78, P < 0.01). Compared with healthy controls, serum CPS-I and OCT levels in cirrhosis patients with and without hepatic encephalopathy were all lower (t = 3.21, t = 4.16, t = 2.12, t = 3.15, P < 0.05). CPS-I was correlated with OCT, (r = 0.946, P < 0.05); CPS-I and OCT were negatively correlated with ALT and AST (r = -0.284, r = -0.239, r = -0.303, r = 0.322, P < 0.05). Additionally, CPS-I and OCT levels were negatively correlated with the Child-Pugh classification in Cirrhosis (F = 10.13, F = 20.28, P < 0.01). CONCLUSION: The serum CPS-I and COT levels were important factors affecting plasma ammonia in patients with cirrhosis and played an important role in the development of hepatic encephalopathy. PMID- 20943085 TI - [p38 mitogen-activated protein kinase inhibitor suppresses the expression of pro inflammatory cytokines in liver from brain dead rats]. AB - OBJECTIVE: To observe the suppressive effect on the expression of pro inflammatory cytokines in liver from brain dead (BD) rats through inhibition of p38 mitogen-activated protein kinase (MAPK) signaling pathway by SB203580. METHODS: A total of 30 male Wistar rats weighing from 180 to 200 g were randomly divided into 3 experimental groups: (1) BD group (n = 10): brain death was induced in rats; (2) BD+SB203580 group (n = 10): brain death was successfully induced and SB203580 (10 mg/kg) was given through dorsal vein of penis. After brain death artificial ventilation was maintained for 6 hours and only those with mean arterial blood pressure more than 80 mm Hg (1 mm Hg = 0.133 kPa) were accepted as BD donors. (3) Control group (n = 10): living healthy rats. The expressions of TNFalpha and IL-1beta mRNA in liver tissues were analyzed by RT PCR and the protein expressions of TNFalpha, IL-1beta and phosphorylated p38MAPK were detected by Western blot. RESULTS: The phosphorylated p38MAPK detected in the liver in BD group was significantly increased compared with the control group (q = 172.53, P < 0.01), and the expressions of TNFalpha and IL-1beta mRNA and proteins in liver were also significantly increased in BD group compared with the control group (q = 123.99, 135.35, 243.09 and 192.23, respectively, P < 0.01). The phosphorylated p38MAPK was decreased in BD+SB203580 group and significantly decreased compared with the BD group (q = 63.90, P is less than 0.05), but higher than that in control group (q = 108.63, P < 0.01). The expressions of TNFalpha and IL-1beta mRNA and proteins in liver were significantly decreased in BD+SB203580 group compared with the BD group (q = 55.11, 98.13, 61.03 and 50.85, respectively, P < 0.01), but higher than that in control group (q = 68.89, 37.22, 182.06 and 141.38, respectively, P < 0.01). SB203580 can suppress the expression of pro-inflammatory cytokines in the liver of brain dead rats through the inhibition of p38MAPK signaling pathway which may reduce the immunogenicity of donor livers. PMID- 20943086 TI - [The expression of cannabinoid receptor 1 in liver tissue of chronic hepatitis B patients involved in liver fibrosis]. PMID- 20943087 TI - [Clinical diagnosis and histological diagnosis in chronic hepatitis B patients: a comparative analysis]. PMID- 20943088 TI - [Baicalin regulates lipid metabolism in high-fat feeding SD rat liver and the mechanism involves modulation of AMPK-alpha pathway]. PMID- 20943089 TI - [Effects of HBx protein on the proliferation and differentiation of SMMC-7721 liver cancer cell in vitro and in vivo]. PMID- 20943090 TI - [An analysis of 66 cases of drug-induced liver injury]. PMID- 20943091 TI - [4 cases of fulminant Wilson's disease: the clinical features and treatments]. PMID- 20943092 TI - [IgA nephropathy associated with hepatitis C virus infection: a case report]. PMID- 20943093 TI - [Antiviral treatment of kidney transplant patients with hepatitis C recurrence: a case report]. PMID- 20943094 TI - [Job satisfaction: a comparative study between public and private practice]. AB - The article describes the results of a study comparing job satisfacion in nurses working in public and private health structures in the same city, in the light of a wider study at national level. BACKGROUND: Job satisfaction in nurses also affects patients, improving care and preventing stress that may cause burnout, increased turnover or even professional abandonment. Methods and instruments: a quantatitive-descriptive study was performed using a socio-demographical questionnaire composed of 44 items (Index of Work Satisfacion di Stamps, 1972) related to autonomy, professional status, tasks involved , retribution, interaction and organizational policy. RESULTS: the outcome of the study confirmed previous findings and corresponded to national and international averages. The satisfaction/insatisfaction index was 12.75 (range 0.9-37.1) for the public sector and 13.08 (range 0.9-37.1)for the private one, indicating a low to medium job satisfaction rate. PMID- 20943095 TI - [Health risks associated with night shifts: trasversal study in a sample of nurses at the Cassino hospital]. AB - For nurses, night work can have a negative influence not only on the quality of care and the incidence of accidents and errors but also affect their private life and health. In shift workers sleep pattern disturbances are particularly frequent. Females are more at risk than males due to their different health conditions and socio-family pressure. This transversal study , by means of a self administered questionnaire, evaluated the incidence of mental and physical problems in 58 nurses at the "Santa Scolastica" Hospital in Cassino to identify the principal factors responsible for sleep disturbances and to implement preventive strategies. Results showed that in many cases disturbances were attributable to lack of rest . Shorter and more irregular sleep was associated with age and amount of working years, together with poor organizational capacities : irregular shifts , upbringing of children and family burdens aggravated this situation. More than half the nurses replied that they slept before starting a night shift and again when they finished in a dark room , rather than in silence with the telephone turned off.. The authors conclude that a system to monitor disturbances deriving from night work should be implemented so that preventive measures can be taken. PMID- 20943096 TI - [Health, death, illness, and nursing care concepts in Malagasi Antemoro Tribe]. AB - A collaboration experience with the Fondation Medical d'Ampasimanjeva nurses, in an international cooperation project,permits to analyse the basic nursing concepts, starting from the local cultural approach. Research main outcome is to describe health, death, illness, and nursing care concepts in the Malgasi Antemoro tribe. Closing to the ethnographic research, work has been developed in three different moments: a first job organization starting from a spread literature analysis, the follow work on field about collecting data, and the last data elaboration and discussion Collecting data tool was the focus group which has done with the complete hospital nursing staff, divided by ward places. A fourth one was addressed to a twenty medical patients group. Focus group questions came from the Rising Sun Model guide, by Madeleine Leininger, adapted to the research own needs. Outcomes show an important traditional medicine influence, explained by the way people conceive health, illness, and even life, all elements directly affected the nursing care. It stands out a strong belief that health depends by the ability of person to work. The death concept is saw as a passage's phase to the Razana's spiritual condition. This is the reason supporting fatalism as approach to the death, that appear as an inevitable event managed by God. Disease's concept is related to traditional healers; as a matter of facts, it exists a strong belief that diseases find origin from magician. PMID- 20943097 TI - [Student nurses' percepted evaluation toward on clinical tutors]. AB - The practice of assigning a tutor to nursing students is becoming more common. The aim of this study was to assess how nursing students perceived their tutors in the light of the personal and professional characteristics of both trainers and trainees. Nursing students were asked to anonymously fill in a questionnaire to evaluate how they perceived their tutors that included an Italian translation of the Nursing Students' Perceptions of Instructor Caring -Short Version (NSPIC). A total of 243 students , predominantly female (74%) with an average age of 24.6 years were included in the study. On the whole ,tutor evaluation was positive (average 146.3 on a scale ranging from 31-186) and results showed that the personal and professional characteristics of trainers and trainees are not very influential. PMID- 20943098 TI - [The choice of the method for body temperature measurement in intensive care patients: a literature review]. AB - INTRODUCTION: Measuring body temperature in intensive care patients is a routine nursing task, but there is no common practice regarding the site of measurement. AIM: to identify which method is most suitable and therefore advisable in critical patients METHODS: the available databases were consulted and the pertinent literature was reviewed. RESULTS: many studies have been performed regarding the different methods, more or less invasive, of body temperature monitoring and their accuracy, reliability and patient tolerability . CONCLUSIONS: in the literature , it is agreed that the gold standard site for body temperature measurement is the pulmonary, femoral or brachial artery but that further studies are necessary in this field. PMID- 20943099 TI - [Vescical catheter management in patients with vertebro-medullary pathologies: a rating instrument for removal]. AB - About 35-40% of hospital infections arise from the urinary tract and 75-80% of these are attributable to vesical catheterization. In patients operated for vertebro-medullary pathologies, removal of the catheter represents a delicate moment, due to the possibility of neurological bladder . To date, no rating method exists to determine when the catheter should be removed. The aim of this study was to test a system for determining catheter removal in such patients, to reduce the incidence of urinary infections and the need for further catheterization. A case-control study was performed on 139 patients surgically treated for vertebro-medullary pathologies in the Neurosurgical Division of Rome "Sapienza" University Hospital between May 2008 and February 2009, collecting and monitoring data for all patients and creating an assessment scale for the study group comprising 4 variables influencing minction: sensory perception, mobility, pain, pre-existing sphincter disturbances. RESULTS: In the experimental group, catheterization times were shorter in comparison to the control group and the incidence of both urinary retention and permanent catheterization after removal were lower.. There was a complete absence of urinary infections in the experimental group compared to 6.52% in the control group. PMID- 20943100 TI - [Nursing education for the management of cardiocirculatory emergency in a hospital environment]. AB - The aim of the study is to evaluate how nurses are trained to deal with in hospital emergencies . Cardiocirculatory arrest represents the epitome of extreme emergency since lack of perfusion to vital organs can cause death in a few minutes and immediate life-saving measures are necessary. Hence, all health workers , and nurses in particular , must be specifically trained. The study was performed in a central Italian hospital to assess the level of knowledge regarding these techniques, the relative equipment and their practical application. PMID- 20943101 TI - [Mental and physical equilibrium for better quality of care: experience of the Ravenna CNAI group]. AB - The current orientation of health services is a progressive reduction of resources and a constant increase of efficiency and efficacy: this implies a greater demand on health personnel with the risk of stress and demotivation. In this context , well-balanced mental and physical conditions are essential and health workers should be given all the support they need to obtain and maintain such conditions, also to avoid repercussions on patients. For this purpose a satellite group of the CNAI nursing association organized two formative events based on guided imagery and mindfulness , to increase self-awareness, aimed not only at nurses but also rehabilitation and other health care workers. Results were evaluated using a questionnaire and demonstrated better awareness , less psychosomatic stress-related problems , improved quality of life and well-being. PMID- 20943102 TI - Basal-like carcinomas of the breast--an intriguing entity. PMID- 20943103 TI - Replacement of resin-based composite restorations in permanent teeth. AB - OBJECTIVE: To determine the reasons for replacement of composite resin restorations and evaluate the association between the reasons for replacement of restorations with gender, duration of failure and different class of cavities. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Operative Department of Fatima Jinnah Dental Hospital, Karachi, from January to May 2009. METHODOLOGY: Patients were selected randomly who had presented with post restoration complaint after composite filling. Specially designed proformas were used to get the information such as the name of the patient, age, gender, teeth in need for replacement of restorations, age of the replaced restorations, and the reasons for replacement. The criteria for replacement of composite restorations were secondary caries, discoloration, improper proximal contact, fractured restoration and gingival irritation due to overhang. The significance of results was obtained by applying chi-square test. RESULTS: A total of 413 patients ranging in age from 17 to 63 years were examined; 263 were males while 150 were females. Secondary caries (52.3%) was the most frequent reason for replacement of restorations in permanent teeth followed by discoloration (16.9%) and fracture of fillings (12.6%). Chi-square test shows significant relationship between gender and reasons for replacement (p < 0.001). Highly significant difference was found between different class of cavities and reasons for replacement of composite fillings (p < 0.001). The median longevity of the replaced composite restorations was about 3 years. CONCLUSION: Secondary caries was the most common reason for replacement of composite fillings. The median longevity in this sample was calculated to be 3.0 years. PMID- 20943104 TI - Molecular studies of ichthyosis vulgaris in Pakistani families. AB - OBJECTIVE: To target and amplify a 1.5 kb FLG gene fragment known to carry R501X mutation responsible for causing ichthyosis vulgaris. STUDY DESIGN: A case series. PLACE AND DURATION OF STUDY: Centre for Molecular Genetics, University of Karachi and Dermatology Department, Jinnah Postgraduate Medical Centre (JPMC), Karachi, from October 2007 to December 2008. METHODOLOGY: Clinically examined seven ichthyosis vulgaris families were included in this study. The 1.5 kb FLG gene fragment was located in the genomic DNA of both the affected (patients) and unaffected (normal, controls) members of the families by PCR amplification using known primers FilF3 and RPTIP6. RESULTS: Amplification of 1.5 kb FLG gene fragment was successful in four families while one family showed amplification of the gene fragment in 3 members (one affected and two normal). Two families showed no amplification. CONCLUSION: The results obtained during this study suggested the possibility of the R501X mutation as being one of the major causes of ichthyosis vulgaris in Pakistan. In addition, the study also revealed the possibility of the presence of novel FLG gene mutations in our population. PMID- 20943105 TI - Laparoscopic evaluation of female factors in infertility. AB - OBJECTIVE: To find out different causes of female infertility with diagnostic laparoscopy and their comparative frequency in primary and secondary infertility. STUDY DESIGN: A case series. PLACE AND DURATION OF STUDY: Department of Obstetric and Gynaecology, Liaquat University Hospital (LUH), Hyderabad, rom January 2006 to December 2007. METHODOLOGY: All infertile women underwent diagnostic laparoscopy for primary and secondary infertility during the study period were included. Couples who had not lived together for at least 12 months, and those with male factor infertility were excluded. Data were collected on a proforma, and analysed on SPSS package for windows version 10. Frequencies were calculated for laparoscopic findings regarding primary and secondary infertility. RESULTS: Fifty infertile women underwent laparoscopy during the study period, 32 (64%) had primary infertility while 18 (36%) secondary infertility. Eight (25.0%) patients with primary and 2 (11.1%) patients with secondary infertility had no visible abnormality. The common finding was tubal blockage in 7 (21.9%) and 6 (33.3%) cases of primary and secondary infertility respectively. Five (15.6%) cases of primary infertility were detected as polycystic ovaries (PCO) which was not found in cases of secondary infertility. Endometriosis was found in 4 (12.5%) cases with primary infertility and 2 (11.1%) cases with secondary infertility. Pelvic inflammatory disease (PID) was found in 1 (3.1%) and 2 (16.7%) cases of primary and secondary infertility respectively. Peritubal and periovarian adhesions were detected in 2 (6.3%) cases with primary infertility and 4 (22.2%) cases with secondary infertility. Fibriod was found in 2 (6.3%) and 1 (5.6%) cases of primary and secondary infertility respectively. Ovarian cyst detected in 2 (6.3%) cases with primary infertility while none was found in cases of secondary infertility. CONCLUSION: Most common causes responsible for infertility were tubal occlusion, endometriosis, peritubal and periovarian adhesions. Ovarian causes were seen in primary infertility only. PMID- 20943106 TI - Relative protection from ischaemic heart disease in beta-thalassaemia carriers. AB - OBJECTIVE: To compare the frequency of beta thalassaemia trait in individuals with Ischaemic Heart Disease (IHD) and a control population without IHD. STUDY DESIGN: Case control study. PLACE AND DURATION OF STUDY: Department of Haematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from September 2007 to May 2009. METHODOLOGY: Using non-probability consecutive sampling, a total of 544 subjects were selected, including 272 IHD patients and an equal number of age and gender matched normal controls. The subjects were tested for the presence of beta-thalassaemia trait by performing their blood counts, haemoglobin electrophoresis and Haemoglobin A2 (HbA2) estimation. Proportions were compared using chi-square test. Odds ratio was also calculated. RESULTS: The frequency of beta-thalassaemia trait was determined in IHD patients and was compared to the frequency in normal Pakistani population. Six out of the 272 control subjects (2.2%) had beta-thalassaemia trait and one of the control subject had Haemoglobin D trait. In contrast, none of the 272 IHD patients had beta-thalassaemia trait. The calculated odds ratio was less than 1, which shows a significant negative association of beta-thalassaemia trait with IHD. The difference in the frequency of beta-thalassaemia trait in the two groups was statistically significant (p=0.033). CONCLUSION: The results suggest that beta thalassaemia carriers have some protection against IHD, though it is not an absolute cardio protection due to the role of other risk factors in IHD. This beneficial information may be communicated to the concerned individuals in their counselling sessions and as part of general awareness on thalassaemia. PMID- 20943107 TI - Correlation of serum alanine aminotransferase and aspartate aminotransferase levels to liver histology in chronic hepatitis C. AB - OBJECTIVE: To assess the correlation of serum alanine aminotransferase and aspartate aminotransferase levels to severity of disease on liver biopsy in patients of chronic hepatitis C. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Gastroenterology at Military Hospital, Rawalpindi, from January 2006 to February 2007. METHODOLOGY: One hundred and seven diagnosed non-cirrhotic chronic hepatitis C adult patients were included. Serum alanine aminotransferase and aspartate aminotransferase levels were determined. Knodell histopathological Index was determined on liver biopsy. The correlation and regression value between serum alanine aminotransferase levels and liver histology and serum aspartate aminotransferase and liver histology in chronic hepatitis C patients was determined using Pearson correlation analysis. RESULTS: Patients of chronic hepatitis C had raised serum alanine aminotransferase and levels with the mean baseline level of 93 International units per litre (IU/L) with a range of 13-383 IU/L. Serum aspartate aminotransferase levels were also elevated with mean baseline level of 59.65 IU/L ranging from 18-370 IU/L. On liver biopsy based on Knodell histopathological Index, 47.7% of patients had mild, 39.9% had moderate and 13.1% had severe disease. There was significant association between serum alanine aminotransferase levels severity of the disease on liver biopsy (p < 0.03) with weak positive correlation between the two (r = 0.217). There was also significant association between serum aspartate aminotransferase levels and severity of the disease on liver biopsy (p < 0.001) with weak positive correlation between the two (r = 0.32). CONCLUSION: The serum alanine aminotransferase and serum aspartate aminotransferase levels do not indicate the severity of the disease on liver biopsy in chronic hepatitis C patients. PMID- 20943108 TI - Frequency of hepatitis C viral RNA in anti-hepatitis C virus non- reactive blood donors with normal alanine aminotransferase. AB - OBJECTIVE: To determine the frequency of HCV RNA in an anti-HCV non-reactive blood donor population with normal ALT, and its cost effectiveness. STUDY DESIGN: An observational study. PLACE AND DURATION OF STUDY: Baqai Institute of Haematology, Baqai Medical University, Karachi, and Combined Military Hospital, Malir Cantt, Karachi, from May 2006 to April 2008. METHODOLOGY: After initial interview and mini-medical examination, demographic data of blood donors was recorded, and anti-HCV, HBsAg and HIV were screened by third generation ELISA. Those reactive to anti-HCV, HbsAg and/or HIV were excluded. Four hundred consecutive donors with ALT within the reference range of 15-41 units/L were included in study. HCV RNA RT-PCR was performed on 5 sample mini-pools using Bio Rad Real time PCR equipment. RESULTS: All 400 donors were male, with mean age 27 years SD + 6.2. ALT of blood donors varied between 15-41 U/L with mean of 31.5+6.4 U/L, HCV RNA was detected in 2/400 (0.5%) blood donors. Screening one blood bag for HCV RNA costs Rs 4,000.00 equivalent to 50 US dollars, while screening through 5 sample mini-pools was Rs. 800.00 equivalent to approximately 10 US dollars. CONCLUSION: HCV RNA frequency was 0.5% (2/400) in the studied anti HCV non-reactive normal ALT blood donors. Screening through mini-pools is more cost-effective. PMID- 20943109 TI - Epidemiology of non-disaster spinal injuries at a spine unit. AB - OBJECTIVE: To describe the demography, types of injuries and their management in all non-disaster spinal injury patients admitted to the Spine Unit of a tertiary care hospital in Pakistan from 2001-2008. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Spine Unit, Orthopaedic Department, Combined Military Hospital, Rawalpindi, from April 2001 to December 2008. METHODOLOGY: Data of all new non-disaster spinal injury patient admissions, kept in a custom-built database at Spine Unit, was analyzed. Demography, type of injuries and their management was described in percentages. RESULTS: Five hundred and twenty one non disaster patients were selected out of a total 671 new admissions with spinal injuries. Mean age was 39.1 years and 77% were males. Mechanisms of injury included; fall in 62% and road traffic accidents in 32%. Fracture dislocations and burst fractures were equally distributed (36% each). Most of the injuries (43.6%) were at T11-L1 level. Forty three percent patients had complete spinal cord injury (SCI), 33% had incomplete SCI and 24% did not have any SCI. Eight patients had concomitant spinal injury at a different level. Twelve percent patients had associated other major injuries. Seventy percent patients were treated surgically. Average follow-up was for 4 years. CONCLUSION: Non-disaster spinal injury was frequent in young males usually due to fall or road traffic accident. It involved fracture dislocation or burst fracture at T11-L1, level in most cases requiring surgical treatment. PMID- 20943110 TI - Predictors of clinical course of subacute sclerosing panencephalitis: experience at the Children's Hospital, Lahore. AB - OBJECTIVE: To determine the clinical course of Subacute Sclerosing Panencephalitis (SSPE) and different factors affecting the clinical course. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: The Children's Hospital, Lahore, from October 2005 to May 2008. METHODOLOGY: All serologically confirmed patients of SSPE were registered and clinical staging of these patients were done from stage-I to stage-IV. Clinical course of these patients was classified by using neurological disability index as fulminant, acute, subacute, and chronic course. Clinical course was analyzed for any difference with age, gender, immunization for measles, measles infection, nutritional status and correlation with age of onset of SSPE, (Spearman's correlation), using statistic package for social science (SPSS) V. 14. RESULTS: A total of 57 cases (41 males, 16 females) with mean age of 7.45 years were studied. Forty (71.4%) of them were vaccinated with single dose at about 9 months of age, 41% (23/57) had measles infections <= 2 years of age. Using the Neurology Disability Index for these patients 10.5% had fulminant, 17.5% had acute, 49.2% subacute and 22.8% had chronic course. Age, gender, age at measles infection, SSPE onset age and nutritional status were poor predictors of clinical course of SSPE. Unvaccinated patients showed significantly more rapid course of disease (p = 0.04). CONCLUSION: Clinical course of SSPE cannot be predicted at the onset of this catastrophic disorder. Children not immunized against measles had a significant rapid course of disease. PMID- 20943111 TI - Vacuum-assisted closure therapy as a pretreatment for split thickness skin grafts. AB - OBJECTIVE: To evaluate the effect of vacuum-assisted closure (VAC) therapy on wound management by measuring the graft take, wound healing time, need for any re grafting and duration of hospitalization. STUDY DESIGN: Single blinded randomized controlled trial. PLACE AND DURATION OF STUDY: This study was carried out in the Department of Plastic and Reconstructive Surgery, Pakistan Institute of Medical Sciences (PIMS), Islamabad, from October 2007 to December 2009. METHODOLOGY: A total of 100 adult patients of either gender with acute traumatic wounds were included. Patients who needed flap coverage as the primary intervention, and those with Diabetes, malignancy, bleeding diathesis were excluded. Half of the patients were randomly assigned to the intervention group and the rest to the control group with lottery method. All wounds were initially subjected to thorough excision. Wound bed preparation for STSG (split thickness skin graft) was achieved using 10 days pre-treatment with VAC dressings in the intervention group while employing normal saline gauzes in the control group. All patients were subsequently treated with STSG. The primary outcome measure was graft take while the secondary outcome measures included wound healing time, need for any re grafting and duration of hospital stay. Results were compared in both groups using chi-square test. RESULTS: Marked differences were found in favour of the VAC therapy group with respect to the various wound management outcome measures studied. i.e. graft take (greater than 95% graft take in 90% of VAC therapy group vs. 18% of controls), wound healing time (2 weeks postgrafting in 90% of VAC therapy group vs. 18% of controls), need for regrafting (none among VAC therapy group vs. 8% of controls) and duration of hospital stay (less than 3 weeks in 90% of VAC therapy group vs. 18% of controls). CONCLUSION: VAC therapy should be employed in the pre-treatment of wounds planned to be reconstructed with STSG, since it has marked advantages in the wound bed preparation compared with the traditional normal saline gauze dressings. PMID- 20943112 TI - Minor psychiatric morbidity in young saudi mothers using Mini International Neuropsychiatric Interview (MINI). AB - OBJECTIVE: To determine the prevalence of postpartum psychiatric disorders in young mothers using a brief structured psychiatric interview, the Mini International Neuropsychiatric Interview (MINI). STUDY DESIGN: A cross-sectional study. PLACE AND DURATION OF STUDY: The Primary Health Care Centres (PHCCs) in Al Ahsa region, Saudi Arabia, during the period 2008 to 2009. METHODOLOGY: Young primigravid mothers (in their teen age) were interviewed using MINI. Psychiatric morbidity was analyzed in relation to the different sociodemographic, psychiatric and obstetric characteristics. The distribution and frequency of the MINI subscales were presented in number and percentage. To quantify the risk, Univariate analysis was employed with reporting of crude Odds Ratio (OR) and 95% Confidence Intervals (CI); p-value of < 0.05 was considered significant. RESULTS: The prevalence of psychiatric disorders was 22.6% with preponderance of anxiety disorders due to increased prevalence of generalized anxiety disorder and social phobia. Postpartum anxiety disorders were significantly associated with urban residency, poor husband support, past history of psychiatric illness, anemia, caesarean mode of delivery and female baby gender. CONCLUSION: These results highlighted importance of addressing screening for psychiatric morbidity particularly anxiety disorders in the implementation of perinatal care for the pregnant Saudi adolescents. PMID- 20943113 TI - Pleuro pericardial cyst. AB - A 68-year-old male, presented with exertional dyspnoea and chest pain in his anterior chest wall for 3 months. He had no previous history of cardiac disease. Clinical examination failed to show anything significant. Chest X-ray showed a mass superimposed over the upper cardiac silhouette. He was further evaluated by chest CT, which showed a cystic mass in the anterior mediastinum measuring 9 x 7 cm in its maximum diameter. On surgical excision and histopathological examination, findings were consistent with benign pleuropericardial cyst, confirming the earlier diagnosis. PMID- 20943114 TI - Spindle cell tumour presenting as an abdominal mass. AB - Hyalinizing spindle cell tumour with giant rosettes (HSTGR) is a rare and recently described tumour that arises most commonly from the peripheral and deep soft tissues. It can present as a large abdominal mass. We report the case of a 60 year old man who presented with abdominal distention. CT scan showed a mass occupying the whole of the abdomen and pelvis. Exploration of abdomen revealed a jelly like mass about 20 x 20 cm in size. Mass was excised completely and confirmed as spindle cell tumour between grade I-II on histopathology. PMID- 20943115 TI - Carcinoma caecum--a rare presentation. AB - Caecal and right sided colonic cancers mostly present with fatigue, weakness and iron deficiency anemia. Such tumours rarely perforate posteriorly and involve the retroperitoneum. We report a case of an old Omani lady who came with insidious sign and symptoms of perforated caecum leading to retroperitoneal collection and necrotizing fasciitis of abdominal wall due to carcinoma of caecum. She underwent surgery but despite active intervention, she died because of septicemic shock. PMID- 20943116 TI - Pontine haemorrhage due to chondrosarcoma of the skull base. AB - A young adult presented with acute weakness of right side of body and slurring of speech. An initial brain CT scan showed a pontine haemorrhage, however MRI done a few days later revealed a mass in the left parapharyngeal space. Histopathology of the mass revealed that it was a chondrosarcoma. Subsequently the patient was initially treated with chemotherapy and radiotherapy and later surgery. Skull base chondrosarcomabe is to be included in the differentials of a young patient presenting with signs consistent with pontine haemorrhage. PMID- 20943117 TI - Primary chiasmal sarcoid granuloma masquerading as glioma of the optic chiasm. AB - A 37-year-old woman presented with a 6 months history of headaches and memory impairment. Examination showed no neurological deficit with normal vision. MRI scans showed an enlarged optic chiasm. There was no dural or leptomeningeal enhancement or hydrocephalus. Open biopsy of the suprasellar mass showed non caseating chronic granulomatous inflammation compatible with sarcoidosis. Systemic features of sarcoid were absent. Patient showed marked improvement on steroid therapy. PMID- 20943118 TI - Floating forearm: perilunar and elbow dislocation without a fracture. AB - Traumatic perilunar and elbow dislocation is rarely seen together. There are only a few reported cases in the literature. Limitation of joint movement, deformity and pain are generally the presenting symptoms. A case of perilunar and elbow dislocation without fracture admitted to the emergency department due to a traffic accident and treated with closed reduction after sedoanalgesia and benefited from closed reduction. PMID- 20943119 TI - Big toe metastases as first clinical sign of occult bronchogenic carcinoma. AB - Metastasis to bone is a common manifestation of malignant tumours. However, metastasis to the bones of the foot is exceedingly rare. It usually arise from genitourinary tract and colon, with the tarsal bones accounting for half of all metastases. We report a rare case of pain and destruction of the distal phalanx of great toe, initially suspected as osteomyelitis, which on biopsy proved to be metastases from a clinically silent bronchogenic carcinoma. PMID- 20943120 TI - Students' research: tradition ahead of its time. AB - This view point describes the experience of introducing research at an undergraduate level during clinical rotation in psychiatry. Objective of this initiative was to encourage critical thinking, self directed learning and sensitization to mental health issues. This contributed to student learning besides galvanizing their interest in the subject. The opinion piece aims to expose various issues to students' research in the context of medical education in Pakistan. PMID- 20943121 TI - Co-morbid anxiety and depression among pulmonary tuberculosis patients. AB - The need to recognize and manage psychiatric co-morbidity in tuberculosis (TB) patients in primary care settings in order to improve adherence to the treatment is now well documented. Pulmonary TB patients at the District TB Control Office and TB Centre in Haripur from December 2007 to March 2008 were evalute in order to assess the frequency of anxiety and depression and continuation of treatment. Forty seven out of 65 (72%) TB patients had severe/moderate level of anxiety and depression according to Hospital Anxiety and Depression Scale (HADS). Fourteen (22%) TB patients with co-morbid anxiety and depression showed multi drug resistance (MDR-TB). PMID- 20943122 TI - Epigastric heteropagus conjoined twin: a cause of obstructed labour. PMID- 20943123 TI - All stressed out. Salmonella pathogenesis and reactive nitrogen species. AB - Bacterial pathogens must overcome a range of challenges during the process of infecting their host. The ability of a pathogen to sense and respond appropriately to changes in host environment is vital if the pathogen is to succeed. Mammalian defense strategies include the use of barriers like skin and epithelial surfaces, the production of a chemical arsenal, such as stomach acid and reactive oxygen and nitrogen species, and a highly coordinated cellular and humoral immune response. Salmonella serovars are significant human and animal pathogens which have evolved several mechanisms to overcome mammalian host defense. Here we focus on the interplay which occurs between Salmonella and the host during the infection process, with particular emphasis on the complex bacterial response to reactive nitrogen species produced by the host. We discuss recent advances in our understanding of the key mechanisms which confer bacterial resistance to nitrogen species, which in response to nitric oxide include the flavohemoglobin, HmpA, the flavorubredoxin, NorV, and the cytochrome c nitrite reductase, NrfA, whilst in response to nitrate include a repertoire of nitrate reductases. Elucidating the precise role of different aspects of microbial physiology, nitrogen metabolism, and detoxification during infection will provide valuable insight into novel opportunities and potential targets for the development of therapeutic approaches. PMID- 20943124 TI - Microbial metropolis. AB - Microorganisms can form tightly knit communities such as biofilms. Many others include marine snow, anaerobic digester granules, the ginger beer plant and bacterial colonies. This chapter is devoted to a survey of the main properties of these communities, with an emphasis on biofilms. We start with attachment to surfaces and the nature of adhesion. The growing community then forms within a matrix, generally of organic macromolecules. Inevitably the environment within such a matrix is different from that outside. Organisms respond by forming crowd detection and response units; these quorum sensing systems act as switches between planktonic life and the dramatically altered conditions found inside microbial aggregates. The community then matures and changes and may even fail and disappear. Antimicrobial resistance is discussed as an example of multicellular behavior. The multicellular lifestyle has been modeled mathematically and responded to powerful molecular biological techniques. Latterly, microbial systems have been used as models for fundamental evolutionary processes, mostly because of their high rates of reproduction and the ease of genetic manipulation. The life of most microbes is a duality between the yin of the community and the yang of planktonic existence. Sadly far less research has been devoted to adaptation to free-living forms than in the opposite direction. PMID- 20943125 TI - Carbon monoxide in biology and microbiology: surprising roles for the "Detroit perfume". AB - Carbon monoxide (CO) is a colorless, odorless gas with a reputation for being an anthropogenic poison; there is extensive documentation of the modes of human exposure, toxicokinetics, and health effects. However, CO is also generated endogenously by heme oxygenases (HOs) in mammals and microbes, and its extraordinary biological activities are now recognized and increasingly utilized in medicine and physiology. This review introduces recent advances in CO biology and chemistry and illustrates the exciting possibilities that exist for a deeper understanding of its biological consequences. However, the microbiological literature is scant and is currently restricted to: 1) CO-metabolizing bacteria, CO oxidation by CO dehydrogenase (CODH) and the CO-sensing mechanisms that enable CO oxidation; 2) the use of CO as a heme ligand in microbial biochemistry; and 3) very limited information on how microbes respond to CO toxicity. We demonstrate how our horizons in CO biology have been extended by intense research activity in recent years in mammalian and human physiology and biochemistry. CO is one of several "new" small gas molecules that are increasingly recognized for their profound and often beneficial biological activities, the others being nitric oxide (NO) and hydrogen sulfide (H2S). The chemistry of CO and other heme ligands (oxygen, NO, H2S and cyanide) and the implications for biological interactions are briefly presented. An important advance in recent years has been the development of CO-releasing molecules (CO-RMs) for aiding experimental administration of CO as an alternative to the use of CO gas. The chemical principles of CO-RM design and mechanisms of CO release from CO-RMs (dissociation, association, reduction and oxidation, photolysis, and acidification) are reviewed and we present a survey of the most commonly used CO RMs. Amongst the most important new applications of CO in mammalian physiology and medicine are its vasoactive properties and the therapeutic potentials of CO RMs in vascular disease, anti-inflammatory effects, CO-mediated cell signaling in apoptosis, applications in organ preservation, and the effects of CO on mitochondrial function. The very limited literature on microbial growth responses to CO and CO-RMs in vitro, and the transcriptomic and physiological consequences of microbial exposure to CO and CO-RMs are reviewed. There is current interest in CO and CO-RMs as antimicrobial agents, particularly in the control of bacterial infections. Future prospects are suggested and unanswered questions posed. PMID- 20943127 TI - Phenology of epigeous macrofungi found in red gum woodlands. AB - The timing of fruiting body production by epigeous macrofungi is thought to be mostly determined by substrate moisture and temperature. Understanding the environmental cues that influence fruiting can help when designing surveys, interpreting results, and predicting effects of an altered climate. Species fruiting in 22 river red gum (Eucalyptus camaldulensis) woodland sites in southeastern Australia was recorded at regular intervals over 2 y. Models were constructed to explain the phenology of 25 of the most common species, as well as the total number of species found fruiting on each survey occasion. We found that rainfall minus evaporation and the time of year each influenced fruiting of the common fungi, but to varying degrees depending on species. Using these same variables, the model predictions for the total number of species expected to be found on each survey occasion fit the observations reasonably well (R(2)=0.49). The models could be used to estimate the probability of presence for species of conservation interest, to optimise survey timing, or to predict effects of climate change on fruiting. PMID- 20943128 TI - Isolate-specific conidiation in Trichoderma in response to different nitrogen sources. AB - A characteristic feature of Trichoderma is the production of concentric rings of conidia in response to alternating light/dark conditions and a single ring of conidia in response to a single burst of light. In this study, conidiation was investigated in four biocontrol isolates (T. hamatum, T. atroviride, T. asperellum, T. virens) and one isolate from the mushroom pathogen species, T. pleuroticola. All five isolates produced concentric conidial rings under alternating light/dark conditions on potato-dextrose agar (PDA), however, in response to a 15min burst of blue light, only T. asperellum and T. virens produced a clearly defined conidial ring. Both T. pleuroticola and T. hamatum photoconidiated in a disk-like fashion and T. atroviride produced a broken ring with a partially filled in appearance. In the presence of primary nitrogen, T. asperellum and T. pleuroticola conidiated in a disk, whereas, when grown in the presence of secondary nitrogen, a ring of conidia was produced. Primary nitrogen promoted photoconidiation and competency to conidiate in response to light appeared dependent on the nitrogen catabolite repression state of the cell. Mycelial injury was also investigated in the same five isolates of Trichoderma on PDA and under different nitrogen statuses. For the first time, we report that conidiation in response to injury is differentially regulated in different isolates/species of Trichoderma. PMID- 20943129 TI - Amphotericin B resistance leads to enhanced proteinase and phospholipase activity and reduced germ tube formation in Candida albicans. AB - Resistance to amphotericin B is an emerging phenomenon in Candida albicans. Amphotericin B-resistant strain of C. albicans was developed under laboratory conditions and the stability of acquired resistance was confirmed in vitro as well as in vivo. This AMB-resistant strain exhibited reduced germ tube formation as compared to parent strain of C. albicans (ATCC10231). Enzymatic activity of virulence factors like secreted aspartyl proteinase and phospholipase were found to be significantly high in AMB-R as compared to parent strain whereas ergosterol content of AMB-R was drastically reduced. The behavior of AMB-R strain is an interesting phenomenon and opens up a wide area of research regarding pathways and mechanisms. PMID- 20943130 TI - Ambient pH intrinsically influences Trichoderma conidiation and colony morphology. AB - Conidiation in Trichoderma has been demonstrated to be favoured by a low ambient pH and more recently PacC (Pac1) mediated pH-regulation has been implicated in the control of conidiation. In this study, ambient pH effects on conidiation were investigated in three isolates (Trichoderma hamatum, Trichoderma atroviride and Trichoderma pleuroticola) exposed to a single blue-light burst or to mycelial injury. Disks of conidiation were observed for T. atroviride in response to a single light exposure, which clearly demonstrates that all cells are potentially competent for photoconidiation. Previous studies have suggested T. hamatum does not conidiate in response to mycelial injury, however, in this study a clear injury response was observed from pH 2.8 to 3.2. T. pleuroticola displayed three distinct pH-dependent colony morphologies from pH 2.8 to 5.2. Conidiation was strictly low pH-dependent on buffered media and observed at all pH values on unbuffered media. The dependence of the conidial phenotype on the buffering state of the medium rather than the pH per se, was unexpected as it has been suggested that conidiation is PacC regulated. Conversely, excretion of an anthraquinone was strictly pH-dependent regardless of the buffering state. These studies highlight the complexity of ambient pH effects on Trichoderma spp. and demonstrate a need to widen the scope of research to multiple species. PMID- 20943131 TI - DNA sequence analysis of conserved genes reveals hybridization events that increase genetic diversity in Verticillium dahliae. AB - The hybrid origin of a Verticillium dahliae isolate belonging to the vegetative compatibility group (VCG) 3 is reported in this work. Moreover, new data supporting the hybrid origin of two V. dahliae var. longisporum (VDLSP) isolates are provided as well as information about putative parentals. Thus, isolates of VDLSP and V. dahliae VCG3 were found harboring multiple sequences of actin (Act), beta-tubulin (beta-tub), calmodulin (Cal) and histone 3 (H3) genes. Phylogenetic analysis of these sequences, the internal transcribed sequences (ITS-1 and ITS-2) of the rRNA genes and of a V. dahliae-specific sequence provided molecular evidences for the interspecific hybrid origin of those isolates. Sequence analysis suggests that some of VDLSP isolates may have resulted from hybridization events between a V. dahliae isolate of VCG1 and/or VCG4A and, probably, a closely related taxon to Verticillium alboatrum but not this one. Similarly, phylogenetic analysis and PCR markers indicated that a V. dahliae VCG3 isolate might have arisen from a hybridization event between a V. dahliae VCG1B isolate and as yet unidentified parent. This second parental probably does not belong to the Verticillium genus according to the gene sequences dissimilarities found between the VCG3 isolate and Verticillium spp. These results suggest an important role of parasexuality in diversity and evolution in the genus Verticillium and show that interspecific hybrids within this genus may not be rare in nature. PMID- 20943132 TI - Rhythmic conidiation in the blue-light fungus Trichoderma pleuroticola. AB - Trichoderma species conidiate in response to blue light, however, unlike in the blue-light model fungus Neurospora crassa, conidiation in Trichoderma spp. has been considered to be non-circadian. In this study we uncovered evidence for circadian conidiation in Trichoderma pleuroticola and identified orthologues of the key N. crassa clock components, wc-1 (blr-1) and frq. PMID- 20943133 TI - Phylogenetic relationships of the Gomphales based on nuc-25S-rDNA, mit-12S-rDNA, and mit-atp6-DNA combined sequences. AB - Phylogenetic relationships among Geastrales, Gomphales, Hysterangiales, and Phallales were estimated via combined sequences: nuclear large subunit ribosomal DNA (nuc-25S-rDNA), mitochondrial small subunit ribosomal DNA (mit-12S-rDNA), and mitochondrial atp6 DNA (mit-atp6-DNA). Eighty-one taxa comprising 19 genera and 58 species were investigated, including members of the Clathraceae, Gautieriaceae, Geastraceae, Gomphaceae, Hysterangiaceae, Phallaceae, Protophallaceae, and Sphaerobolaceae. Although some nodes deep in the tree could not be fully resolved, some well-supported lineages were recovered, and the interrelationships among Gloeocantharellus, Gomphus, Phaeoclavulina, and Turbinellus, and the placement of Ramaria are better understood. Both Gomphus sensu lato and Ramaria sensu lato comprise paraphyletic lineages within the Gomphaceae. Relationships of the subgenera of Ramaria sensu lato to each other and to other members of the Gomphales were clarified. Within Gomphus sensu lato, Gomphus sensu stricto, Turbinellus, Gloeocantharellus and Phaeoclavulina are separated by the presence/absence of clamp connections, spore ornamentation (echinulate, verrucose, subreticulate or reticulate), and basidiomal morphology (fan-shaped, funnel-shaped or ramarioid). Gautieria, a sequestrate genus in the Gautieriaceae, was recovered as monophyletic and nested with members of Ramaria subgenus Ramaria. This agrees with previous observations of traits shared by these two ectomycorrhizal taxa, such as the presence of fungal mats in the soil. Clavariadelphus was recovered as a sister group to Beenakia, Kavinia, and Lentaria. The results reaffirm relationships between the Geastrales, Gomphales, Hysterangiales, and the Phallales, suggesting extensive convergence in basidiomal morphology among members of these groups. A more extensive sampling that focuses on other loci (protein-coding genes have been shown to be phylogenetically informative) may be useful to answer questions about evolutionary relationships among these fungal groups. PMID- 20943134 TI - Genetic variability and mycohost association of Ampelomyces quisqualis isolates inferred from phylogenetic analyses of ITS rDNA and actin gene sequences. AB - Ampelomyces quisqualis complex is well known as the most common and widespread hyperparasite of the family Erysiphaceae, the cause of powdery mildew diseases. As commercial biopesticide products it is widely used to control the disease in field and plastic houses. Although genetic diversity within Ampelomyces isolates has been previously recognized, a single name A. quisqualis is still applied to all pycnidial intracellular hyperparasites of powdery mildew fungi. In this study, the phylogenetic relationships among Ampelomyces isolates originating from various powdery mildew fungi in Korea were inferred from Bayesian and maximum parsimony analyses of the sequences of ITS rDNA region and actin gene. In the phylogenetic trees, the Ampelomyces isolates could be divided into four distinct groups with high sequence divergences in both regions. The largest group, Clade 1, mostly accommodated Ampelomyces isolates originating from the mycohost Podosphaera spp. (sect. Sphaerotheca). Clade 2 comprised isolates from several genera of powdery mildews, Golovinomyces, Erysiphe (sect. Erysiphe), Arthrocladiella, and Phyllactinia, and was further divided into two subclades. An isolate obtained from Podosphaera (sect. Sphaerotheca) pannosa was clustered into Clade 3, with those from powdery mildews infecting rosaceous hosts. The mycohosts of Ampelomyces isolates in Clade 4 mostly consisted of species of Erysiphe (sect. Erysiphe, sect. Microsphaera, and sect. Uncinula). The present phylogenetic study demonstrates that Ampelomyces hyperparasite is indeed an assemblage of several distinct lineages rather than a sole species. Although the correlation between Ampelomyces isolates and their mycohosts is not obviously clear, the isolates show not only some degree of host specialization but also adaptation to their mycohosts during the evolution of the hyperparasite. PMID- 20943135 TI - The siderophore ferricrocin produced by specific foliar endophytic fungi in vitro. AB - Production of extracellular siderophores is typical for many plant-associated microbes, both mutualistic and antagonistic. Various strains of mycorrhizal fungi produce siderophores, and siderophore production by pathogenic fungi is typically associated with virulence. We analyzed extracellular siderophore production along with production of antibacterial and antioxidant compounds in foliar endophytic fungi of Scots pine (Pinus sylvestris L.) and Labrador tea (Rhododendron tomentosum Harmaja). The siderophore produced in vitro was ferricrocin, quantities ranging between 7.9 and 17.6 MUg/l. Only the fungi with antibacterial activity produced ferricrocin and any well-known siderophores were not detected in the broths of antioxidant-producing fungi. Therefore, production of ferricrocin is typical for some, but not all foliar endophytic fungi. Ferricrocin was detected in the leaves of Labrador tea, which suggests that ferricrocin may play a role in vivo in the interaction between the endophyte and plant host. PMID- 20943136 TI - Primers for mating-type diagnosis in Diaporthe and Phomopsis: their use in teleomorph induction in vitro and biological species definition. AB - Sexual reproduction in ascomycete fungi is governed by the mating-type (MAT) locus. The MAT loci of Diaporthe and its Phomopsis anamorphs differ in only one gene: MAT1-1-1 in mating-type MAT1-1 and MAT1-2-1 in mating-type MAT1-2. In order to diagnose mating-types in Diaporthe and Phomopsis and evaluate their usefulness in teleomorph induction in vitro and biological species delimitation, we designed primers that amplify part of the MAT1-1-1 and MAT1-2-1 genes. MAT phylogenies were generated and compared with ITS and EF1-alpha phylograms. Species recognised in the EF1-alpha phylogeny corresponded directly with those determined in the MAT phylogenies. ITS was shown to be highly variable resulting in a large number of phylogenetic species that were discordant with MAT and EF1-alpha species. Mating experiments were conducted to evaluate the existence of reproductive barriers between some isolates, and their anamorphic morphologies were compared. The primers proved to be useful in the mating-type diagnosis of isolates, selection of compatible mating pairs, and in the assessment of biological species boundaries. PMID- 20943137 TI - Critical assessment of the Lactarius gerardii species complex (Russulales). AB - This paper investigates species delimitation within the Lactarius gerardii species complex and explores its taxonomic and geographical extent. A combined molecular phylogeny based on ITS, LSU and rpb2 gene sequences is constructed and morphological characters are evaluated. While L. gerardii was originally described from North America, it has later been reported from all over Asia. Therefore a worldwide sampling range was aimed at, including species exhibiting morphological affinities with L. gerardii. The phylogenetic analyses indicate that intercontinental conspecificity in L. gerardii is absent. Thirty strongly supported clades are retrieved of which 18 are morphologically identifiable species. The group is elevated to Lactarius subg. Gerardii stat. nov. It includes, apart from L. gerardii s.l., L. atrovelutinus, L. bicolor, L. ochrogalactus, L. petersenii, L. reticulatovenosus, L. sepiaceus, L. subgerardii and L. wirrabara, as well as the pleurotoid L. uyedae. The paraphyletic nature of the genus Lactarius is confirmed. Lactarius subg. Gerardii appears not affiliated with L. subg. Plinthogalus and this can be substantiated morphologically. No representatives are known from Europe, Africa or South America. The high frequency of intercontinental sister relationships observed between America, Asia and the Australian region, suggests multiple migration and speciation events have occurred across continents. PMID- 20943138 TI - Synchronicity of pollination and inoculation with Claviceps africana and its effects on pollen-pistil compatibility and seed production in sorghum. AB - Sorghum ergot (caused by Claviceps africana) is a disease that affects sorghum seed development and yield. The interaction between pollen tube growth and hyphal development determines whether ovaries will be fertilized or colonized. Thus their respective deposition times on the stigma are critical. The effect of the time interval between pollination and inoculation on stigma receptivity and seed production was measured under field conditions in the male-sterile line A9 at Montecillo, State of Mexico (2240m altitude). Pollination and inoculation treatments, from simultaneous application to 2 and 4h difference, were imposed when all stigmas on the panicle had emerged. Control panicles were either only pollinated or only inoculated. Eighteen hours later, pollen grains that adhered to, and germinated within the stigma, pollen tubes in the style and ovary, and fertilized pistils were counted. Pistils showing some disease expression (germinated spores, mycelium growth, or tissue necrosis) at 18, 48, and 72h were recorded. The number of diseased florets was registered at the dough growth stage, while number of seeds, grain yield and 100-seeds weight was measured at the physiological maturity. The pathogen applied in a water suspension of macro and secondary conidia caused a decrease in stigma receptivity; the greatest decrease (40-60%) occurred when the pollen and the inoculum were deposited almost simultaneously, regardless of which was deposited first. The route of the pollen tube was also the route for fungal infection. On average, treatments first inoculated had 60% more diseased florets and 36% less grain yield, 30% fewer seeds and seed size decreased 8%, than those first pollinated. PMID- 20943139 TI - Characterisation of New Zealand Fusarium populations using a polyphasic approach differentiates the F. avenaceum/F. acuminatum/F. tricinctum species complex in cereal and grassland systems. AB - The purpose of this study was to determine the diversity and prevalence of Fusarium species in a survey of cereal and grassland systems from the South Island of New Zealand by applying morphological and molecular techniques. Isolates were collected from soil, roots, and stems from 21 cereal and grassland sites. Ten Fusarium species were identified using morphological characters, including F. acuminatum, F. avenaceum, F. crookwellense, F. culmorum, F. equiseti, F. oxysporum, F. poae, F. pseudograminearum, F. sambucinum, and F. tricinctum. In general, their distribution was found to be unrelated to biogeographical location, although agricultural practice increased the overall diversity of Fusarium. Phylogenetic analyses were successfully used to identify morphologically similar isolates belonging to the F. avenaceum/F. acuminatum/F. tricinctum species complex and to resolve previously undetermined relationships amongst these species. Fifty-eight isolates classified as either F. avenaceum, F. acuminatum, or other closely related species as well as several well characterised isolates from international culture collections were examined using DNA sequence data for beta-tubulin (betaTUB), translation elongation factor 1alpha (EF1alpha), and mitochondrial small subunit ribosomal RNA (mtSSU). Analyses of DNA sequence data from both betaTUB and EF1alpha discriminated among isolates of F. avenaceum, F. acuminatum, and F. tricinctum and determined that these three distinct sequence groups formed a single clade. By contrast, mtSSU was unable to differentiate F. avenaceum from F. acuminatum and other closely related species believed to be F. tricinctum. Comparison of the EF1alpha sequences with the international FUSARIUM-ID database supported the identification of isolates in this study. As in other studies, F. avenaceum was found to be widespread in agricultural and native ecosystems. However, F. acuminatum in New Zealand was found only on non-wheat hosts. The reason for the absence of this wheat pathogen in cereal-based ecosystems in New Zealand remains unknown. PMID- 20943140 TI - Metarhizium anisopliae host-pathogen interaction: differential immunoproteomics reveals proteins involved in the infection process of arthropods. AB - Metarhizium anisopliae is an entomopathogenic fungus well characterized for the biocontrol of a wide range of plagues. Its pathogenicity depends on the secretion of hydrolytic enzymes that degrade the host cuticle. To identify proteins involved in the infection process and in host specify, immunoproteomic analysis was performed using antiserum produced against crude extract of M. anisopliae cultured in the presence of Rhipicephalus (Boophilus) microplus and Dysdercus peruvianus cuticles. Spots detected using antisera produced against M. anisopliae cultured in cuticles and spore surface proteins, but not with antiserum against M. anisopliae cultured in glucose, were identified so as to give insights about the infection process. An MS/MS allowed the identification of proteases, like elastase, trypsin, chymotrypsin, carboxypeptidase and subtilisin (Pr1A, Pr1I and PR1J), chitinases, DNase I and proline-rich protein. Chymotrypsin and Pr1I were inferred as host specific, being recognized in D. peruvianus infection only. This research represents an important contribution to the understanding the adaptation mechanisms of M. anisopliae to different hosts. PMID- 20943141 TI - Hydrodynamics of raindrop impact stimulate ascospore discharge of Venturia inaequalis. AB - Ascospores of Venturia inaequalis are released from leaves following the impact of raindrops during rain events. Atmospheric humidity or moisture from dew does not have an inductive effect on ascospore release. The hydrodynamics of raindrop impact on leaf surfaces was investigated. Raindrops induced dampened periodic vibrations on leaf surfaces. Vibrations, linear, and/or oscillatory flows of water applied to the leaves all induced spore releases at low energy thresholds. The fungal perceptibility of kinetic energy enables selective discharge of spores when environmental conditions are most conducive to survival. Identification of kinetic effects of rain which reveal start, thresholds, and proportional distribution is not only important for disease prognosis research, but may also serve as a model for a common fungal sensing mechanism. PMID- 20943142 TI - Phylogenetic relationship of Phytophthora cryptogea Pethybr. & Laff and P. drechsleri Tucker. AB - The phylogeny and taxonomy of Phytophthora cryptogea and Phytophthora drechsleri has long been a matter of controversy. To re-evaluate this, a worldwide collection of 117 isolates assigned to either P. cryptogea, P. drechsleri or their sister taxon, Phytophthora erythroseptica were assessed for morphological, physiological (pathological, cultural, temperature relations, mating) and molecular traits. Multiple gene phylogenetic analysis was performed on DNA sequences of nuclear (internal transcribed spacers (ITS), beta-tubulin, translation elongation factor 1alpha, elicitin) and mitochondrial (cytochrome c oxidase subunit I) genes. Congruence was observed between the different phylogenetic data sets and established that P. drechsleri and P. cryptogea are distinct species. Isolates of P. drechsleri form a monophyletic grouping with low levels of intraspecific diversity whereas P. cryptogea is more variable. Three distinct phylogenetic groups were noted within P. cryptogea with an intermediate group providing strong evidence for introgression of previously isolated lineages. This evidence suggests that P. cryptogea is an operational taxonomic unit and should remain a single species. Of all the morphological and physiological traits only growth rate at higher temperatures reliably discriminated isolates of P. drechsleri and P. cryptogea. As a homothallic taxon, P. erythroseptica, considered the cause of potato pink rot, is clearly different in mating behaviour from the other two species. Pathogenicity, however, was not a reliable characteristic as all isolates of the three species formed pink rot in potato tubers. The phylogenetic evidence suggests P. erythroseptica has evolved from P. cryptogea more recently than the split from the most recent common ancestor of all three species. However, more data and more isolates of authentic P. erythroseptica are needed to fully evaluate the taxonomic position of this species. PMID- 20943143 TI - Neoerysiphe kerribeeensis sp. nov. (Ascomycota: Erysiphales), a new species of Neoerysiphe on native and introduced species of Senecio (Asteraceae) in Australia. AB - Anamorphic powdery mildew fungi on introduced taxa of Senecio and Pericallis * hybrida in Australia have previously been identified as Neoerysiphe cumminsiana on the basis of a combination of Euoidium-type conidiophores and lobed mycelial and germ tube appressoria. But, two specimens with chasmothecia on the indigenous Senecio glossanthus did not agree with published descriptions of N. cumminsiana. The teleomorph of the S. glossanthus mildew differed from that of N. cumminsiana in the morphology of its peridial cells, the pigmentation of its appendages, and the morphology and pigmentation of some secondary hyphae. Ribosomal DNA ITS sequences from the two S. glossanthus mildew specimens and five other specimens of Senecio mildews from south-eastern Australia demonstrated that all Australian Senecio mildews are conspecific and distinct from the northern hemisphere Senecio mildew (N. cumminsiana) and from other Neoerysiphe taxa. Based on morphological characters and rDNA sequence data, the Australian Senecio mildew is described as a new species, Neoerysiphe kerribeeensis. This is the first native teleomorphic powdery mildew described from Australia. PMID- 20943144 TI - Non-dermatophyte moulds as skin and nail foot mycosis agents: Phoma herbarum, Chaetomium globosum and Microascus cinereus. AB - The increased prevalence of dermatomycoses along with the wide range of organisms now recognized as potential pathogens needs accurate laboratory isolation and identification of the aetiological agents. In this report three cases of foot dermatomycoses due to filamentous fungi commonly present in the environment with ubiquitous distribution are described in immunocompetent subjects. Skin and nail samples were collected, suspended in 20% KOH solution, examined under a light microscope and cultured in Mycobiotic agar and Sabouraud dextrose agar containing chloramphenicol to detect fungal growth. Phoma herbarum, Chaetomium globosum, and Microascus cinereus were isolated and identified. PMID- 20943145 TI - Phylogenetic relationships in European Ceriporiopsis species inferred from nuclear and mitochondrial ribosomal DNA sequences. AB - The aim of this work was to clarify taxonomy and examine evolutionary relationships within European Ceriporiopsis species using a combined analysis of the large subunit (nLSU) nuclear rRNA and small subunit (mtSSU) mitochondrial rRNA gene sequences. Data from the ITS region were applied to enhance the view of the phylogenetic relationships among different species. The studied samples grouped into four complex clades, suggesting that the genus Ceriporiopsis is polyphyletic. The generic type Ceriporiopsis gilvescens formed a separate group together with Ceriporiopsis guidella and Phlebia spp. in the phlebioid clade. In this clade, the closely related species Ceriporiopsis resinascens and Ceriporiopsis pseudogilvescens grouped together with Ceriporiopsis aneirina. C. resinascens and C. pseudogilvescens have identical LSU and SSU sequences but differ in ITS. Ceriporiopsis pannocincta also fell in the phlebioid clade, but showed closer proximity to Gloeoporus dichrous than to C. gilvescens or C. aneirina-C. pseudogilvescens-C. resinascens group. Another clade was composed of a Ceriporiopsis balaenae-Ceriporiopsis consobrina group and was found to be closely related to Antrodiella and Frantisekia, with the overall clade highly reminiscent of the residual polyporoid clade. The monotypic genus Pouzaroporia, erected in the past for Ceriporiopsis subrufa due to its remarkable morphological differences, also fell within the residual polyporoid clade. Ceriporiopsis subvermispora held an isolated position from the other species of the genus. Therefore, the previously proposed name Gelatoporia subvermispora has been adopted for this species. Physisporinus rivulosus appeared unrelated to two other European Physisporinus species. Moreover, Ceriporiopsis (=Skeletocutis) jelicii grouped in a separate clade, distinct from Ceriporiopsis species. Finally, the ITS data demonstrated the proximity of some Ceriporiopsis species (Ceriporiopsis portcrosensis and Ceriporiopsis subsphaerospora) to Skeletocutis amorpha. PMID- 20943146 TI - Genome-wide prediction of G protein-coupled receptors in Verticillium spp. AB - G protein-coupled receptors (GPCRs) are critical factors in regulating morphogenesis, mating, infection and virulence in fungi. In this study, various computational strategies were applied to identify GPCR-like proteins from the genomes of both Verticillium dahliae and Verticillium albo-atrum. The putative GPCRs were distributed over 13 classes, and significantly, three of those represented novel classes of GPCR-like proteins in fungi. The three novel GPCRs had high levels of identity to their counterparts in higher eukaryotes, including Homo sapiens. The numbers of GPCR-like proteins in the two Verticillium spp. were similar to those seen in other filamentous fungi, such as Magnaporthe grisea, Neurospora crassa and Fusarium graminearum. Additionally, the carbon/amino acid receptors were divided into three different subclasses, indicating that differences among the GPCRs existed not only among different classes but also within classes. In conclusion, the identification and classification of GPCRs and their homology to some well-studied fungi will be an important starting point for future research in Verticillium spp. PMID- 20943147 TI - Oospores progenies from Phytophthora ramorum. AB - Oospores of Phytophthora ramorum were produced from intraspecific pairings between a European A1 and European or American A2 strains. Their viability was evaluated through colouration with tetrazolium bromide. The distribution of oospores in the different classes of colouration was similar to that found in other Phytophthora species (homothallic and heterothallic): most of the oospores stained purple, which corresponds to spores in dormancy. In order to produce single-oospore cultures, a method was developed to separate oospores from mycelium and chlamydospores. Germination of oospores was observed in 110, 250, 350 and 500-d-old cultures at a low proportion. Microsatellite marker analyses on oospore progenies revealed that the oospores resulted from hybridisation. More than 50 oospore progenies were characterised in terms of mating type, aggressiveness on Rhododendron leaves, and growth rate on two different media. The results are discussed in the context of pest risk analysis. PMID- 20943148 TI - Type III polyketide synthases in lichen mycobionts. AB - Lichenized and non-lichenized fungi produce a wide range of secondary metabolites. So far, type I polyketide synthases (PKSs) are the suggested catalysts for the biosynthesis of lichen compounds. We were interested whether lichen mycobionts also contain type III PKSs, representing a class that was only recently discovered in fungi. With an alignment of known type III CHS-like genes we applied the CODEHOP strategy to design degenerate PCR primers. We further screened available fungal genomes for type III PKS genes and aligned these sequences for a phylogenetic analysis. Type III-like genes from lichen mycobionts are closely related to those known from non-lichenized fungi, but not to those of bacteria and/or plants. We conclude that type III PKS genes are ubiquitous in fungi. They are present in diverse unrelated lichen mycobionts, but their function in lichens is so far unclear. PMID- 20943149 TI - Superoxide radical is involved in the sclerotial differentiation of filamentous phytopathogenic fungi: identification of a fungal xanthine oxidase. AB - This study shows that the direct indicator of oxidative stress superoxide radical (O.2-) is involved in the sclerotial differentiation of the phytopathogenic filamentous fungi Rhizoctonia solani, Sclerotinia sclerotiorum, Sclerotium rolfsii, and Sclerotinia minor. The production rate of O.2- and the antioxidant enzyme superoxide dismutase (SOD) levels in the sclerotiogenic fungi were significantly higher and lower, respectively, than those of their non differentiating counterpart strains, which strongly suggests that the oxidative stress of the sclerotium differentiating fungi is higher than that of the non differentiating ones. Xanthine oxidase (XO), which was detected for the first time in fungi in general, was localized in the cytoplasmic membrane. The contribution of XO in the overall O.2-production was very significant, reaching 30-70% among the strains, especially in the transition developmental stage between the undifferentiated and the differentiated state, suggesting a sclerotium triggering and a phytopathogenic role of XO during plant infection. The additional finding that these fungi secrete extracellular SOD can be related to their protection from the response of plants to produce O.2- at infection sites. PMID- 20943150 TI - Systematics of Catenulifera (anamorphic Hyaloscyphaceae) with an assessment of the phylogenetic position of Phialophora hyalina. AB - Catenulifera, typified by C. rhodogena (=Scopulariopsis rhodogena), was established to accommodate the anamorphs of Hyphodiscus (Ascomycota, Helotiales) and to delimit these taxa from members of Phialophora section Catenulatae. Catenulifera rhodogena has been inferred as monophyletic, but its relationship to ascomycetes with poorly differentiated phialidic anamorphs remains enigmatic. To test the hypothesis that C. rhodogena is closely related to morphologically similar species of Phialophora and to further explore the systematics of Catenulifera, we analyzed nuclear rDNA and beta-tubulin gene sequences of isolates identified as C. rhodogena, Hyphodiscus hymeniophilus, P. brachyconia, P. brevicollaris and P. hyalina. ITS-LSU and ITS-LSU-beta-tubulin phylogenies positioned all isolates except P. hyalina in a single, well-supported clade that consisted of three subclades. Subclade 1 included fungicolous isolates of C. rhodogena and H. hymeniophilus that did not fluoresce when exposed to long-wave UV light. Subclade 2 contained fungicolous and lignicolous strains of C. rhodogena that produced fluorescent colonies and possessed a 366bp indel in the LSU rRNA gene. Neither lineage encompassed the ex-type strains of Cistella rubescens (=H. hymeniophilus) or S. rhodogena, but the former isolate was inferred as sister to Subclade 2. Subclade 3 included all isolates of P. brachyconia, a species recognized here as C. brachyconia comb. nov. A fourth isolate of P. brachyconia that was extralimital to Subclade 3 is described as C. luxurians sp. nov. The positions of C. brevicollaris comb. nov., a species based on P. brevicollaris, and C. luxurians were not resolved in the ITS-LSU phylogeny. P. hyalina is not closely related to Catenulifera. PMID- 20943151 TI - Ontogeny and phylogeny of a Scutellospora heterogama mutant, with implications for morphological recognition of species in Glomeromycota. AB - A putative mutant of Scutellospora heterogama has been maintained for 19 pot culture generations over 15y. The mutant differed phenotypically from the wild type parental lineage in characteristics of the spore wall: albino versus pigmented red-brown color, high plasticity in acidic mutants versus rigid and finely laminate, deep red-purple reaction versus no reaction in Melzer's reagent, respectively. This variation was equivalent to or greater than that between any two species in Scutellospora or any other genus in Glomeromycota. Comparison of spore ontogenesis revealed that the terminal (mature) state of the albino mutant was similar to a transient intermediate stage in the wild-type. The albino phenotype, therefore, did not result from emergence of a unique morphological innovation. Rather, it arose from a mutation that led to premature termination of spore ontogenesis so that a unique transient juvenile stage became permanent in mature spores. Because this mutation was homogeneous in all progeny populations, it is hypothesized to be a recessive trait expressed only after the allele was distributed in all nuclei of the fungal thallus. Sampling of the genomes of the putative mutant and wild-type isolates by microsatellite-primed PCR suggested a local mutation. The profile of the mutant was identical to that of the wild-type parent and was 60-97 % similar to those of four other S. heterogama isolates. Phylogenetic analysis of the D1-D2 domains of the 25S rRNA gene and a beta tubulin gene with and without three variable introns placed the albino mutant solidly within the S. heterogama clade. These results suggest that stability of morphological traits is not a suitable criterion by itself to recognize species. The albino phenotype was a discrete and heritable mutation that became fixed in a population and was stable through time and space. In the absence of negative selection, this mutation could persist, disperse and then be misinterpreted as a new species in nature. Genetic markers expose this mutation as a population-level variant and therefore of no macroevolutionary significance. Assessment of genetic divergence amongst multiple isolates is important in ascertaining the contribution of morphological characters toward recognition of species in glomeromycotan clades. PMID- 20943152 TI - Pleurotus eryngii species complex: sequence analysis and phylogeny based on partial EF1alpha and RPB2 genes. AB - The Pleurotus eryngii species complex comprises at least six varieties (var. eryngii (DC.: Fr) Quel., ferulae Lanzi, elaeoselini Venturella et al., nebrodensis (Inzenga) Sacc., tingitanus Lewinsohn et al. and tuoliensis C.J. Mou). This species is unique among the genus Pleurotus because in nature it is found in association with certain species of the Apiaceae (Umbelliferae) and Asteraceae (Compositae) families. Sequences of partial regions of the translation elongation factor (EF1alpha) and RNA polymerase II (RPB2) genes were analyzed in order to detect nucleotide polymorphisms that might unequivocally distinguish varieties eryngii, ferulae, elaeoselini and nebrodensis. A phylogenetic analysis was also performed with an aim to establish phylogenetic relationships among those. Sequence analysis of the partial EF1alpha and RPB2 genes contained nucleotide polymorphisms able to unequivocally distinguish variety nebrodensis from the rest. However, distinction among eryngii, elaeoselini and ferulae was achieved only through the RPB2 gene. The phylogenetic analyses from the combined data sets (EF1alpha and RPB2) indicated that P. eryngii is a monophyletic group and that varieties eryngii, elaeoselini and ferulae are closely related. P. eryngii var. nebrodensis was placed in a distinct clade clearly differentiated from the other varieties but still monophyletic with the P. eryngii complex. The limited nucleotide variation in partial EF1alpha and RPB2 among varieties eryngii, ferulae and elaeoselini supports the placement of these groups as varieties and not species within the complex. PMID- 20943153 TI - Comparative analysis of secreted enzymes between the anthropophilic-zoophilic sister species Trichophyton tonsurans and Trichophyton equinum. AB - Trichophyton tonsurans (TT) and Trichophyton equinum (TE) are two closely related dermatophytes with very different host preferences. This study was designed to examine the genetic and transcript level variations of secreted enzymes between TT and TE. Thirty-one genes representing 10 gene families were selected for comparison and complete genomic and cDNA sequences were elucidated. Sequence analyses of the selected genes identified 104 polymorphisms between the two dermatophytes, 37 of which are expected to encode changes in their polypeptide sequence. Quantitative RT-PCR was used to examine the differences in levels of transcript between TT and TE grown over 14d in aqueous keratin medium. Differences in transcript expression between TT and TE were gene specific and ranged from 1.1-fold to 33-fold. Intra-specific variability across all genes ranged from 41% to 250%. Despite their overall genetic similarity, TT and TE exhibit a moderate degree of variability in the genomic make-up of their secreted enzymes and the extent to which they are transcribed when grown in an aqueous keratin medium. Such differences may contribute to how these genetically similar organisms have adapted to infect divergent host organisms. PMID- 20943154 TI - Molecular characterization and evaluation of virulence factors of Cryptococcus laurentii and Cryptococcus neoformans strains isolated from external hospital areas. AB - Cryptococcosis is a common opportunistic fungal infection that is mainly caused by the species Cryptococcus neoformans and Cryptococcus gattii, but there have recently been several reports of infection by non-neoformans Cryptococcus species. The aims of this study were to genetically characterize Cryptococcus spp. isolated from external hospital areas in Minas Gerais State, Brazil, and to evaluate their pathogenic potential, analyzing their phospholipase and melanin production and the capacity for capsule enlargement. Seventy-three different samples were collected: 62 from bird droppings and 11 from tree detritus. C. neoformans alone was isolated from 43.8% of the samples, Cryptococcus laurentii alone from 23.3% and both fungi were found together in 10.9%. C. laurentii was exclusively isolated from 45% (5/11) of the tree samples (Anacardium occidentale, Guazuma ulmifolia, Mangifera indica and Ficus benjamina). Among the 51 C. neoformans isolates, 47 were classified as type VNI and four as type VNII. All of the C. neoformans isolates were of MATalpha type. Among the 21 isolates of C. laurentii genotyped using the URA5-RFLP technique, 16 amplified a 1.6kb amplicon which produced a specific restriction profile in 15 isolates. In C. neoformans, 76.4% of the isolates were capable of capsule enlargement in the induction medium and 92.1% were phospholipase producers. In C. laurentii, 7.4% of the isolates were capable of capsule enlargement and 85.1% were phospholipase producers. Characterization of the genotypes and the pathogenic potential of the Cryptococcus spp. isolates studied may contribute towards better understanding of the epidemiology of cryptococcosis and the ecology of agents causing this disease in our region. PMID- 20943155 TI - A fossil peronosporomycete oogonium with an unusual surface ornament from the Carboniferous of France. AB - A new fossil peronosporomycete from the upper Visean (Mississippian) of France occurs as a globose oogonium at the tip of a thin-walled hypha. The oogonium surface is prominently ornamented by densely spaced, long and subtle, straight or once to several times furcated thread-like extensions; many possess an opaque, bulb-like swelling at base. Antheridia adpressed to the oogonium are clavate and paragynous. This fossil represents only the third record of an unequivocal peronosporomycete from the Carboniferous, and thus provides important details about the evolutionary history of this group of organisms. PMID- 20943156 TI - New fungal pathogens of the red ant, Myrmica rubra, from the UK and implications for ant invasions in the USA. AB - The red ant, Myrmica rubra, is an increasingly invasive pest species in north eastern USA, where it is known as the European fire ant. During surveys for natural enemies in part of its native range in the UK, three previously unreported fungal pathogens developed on ants when incubated in the laboratory. These are described and illustrated: Paraisaria myrmicarum sp. nov., Hirsutella stilbelliformis var. myrmicarum var. nov., and Hirsutella subramanianii var. myrmicarum var. nov. Based on analyses of the protein coding region EF-1alpha and LSU rDNA, all three described taxa are shown to be affiliated with the hypocrealean family Ophiocordycipitaceae. The implications for the management of M. rubra in its exotic North American range using classical biological control are discussed. PMID- 20943157 TI - Susceptibility of ectomycorrhizal fungi to soil heating. AB - Ectomycorrhizal (EcM) fungi are an important biotic factor for successful tree recruitment because they enhance plant growth and alleviate drought stress of their hosts. Thus, EcM propagules are expected to be a key factor for forest regeneration after major disturbance events such as stand-replacing forest fires. Yet the susceptibility of soil-borne EcM fungi to heat is unclear. In this study, we investigated the heat tolerance of EcM fungi of Scots pine (Pinus sylvestris L., Pinaceae). Soil samples of three soil depths were heated to the temperature of 45, 60 and 70 degrees C, respectively, and surviving EcM fungi were assessed by a bioassay using Scots pine as an experimental host plant. EcM species were identified by a combination of morphotyping and sequencing of the ITS region. We found that mean number of species per sample was reduced by the 60 and 70 degrees C treatment, but not by the 45 degrees C treatment. Species composition changed due to heat. While some EcM fungi species did not survive heating, the majority of species was also found in the heated samples. The most frequent species in the heat treatment were Rhizopogon roseolus, Cenococcum geophilum and several unidentified species. PMID- 20943158 TI - Fungal tyrosine betaine, a novel secondary metabolite from conidia of entomopathogenic Metarhizium spp. fungi. AB - Fungi, including the entomopathogenic deuteromycete Metarhizium anisopliae, produce a wide diversity of secondary metabolites that either can be secreted or stored in specific developmental structures, e.g., conidia. Some secondary metabolites, such as pigments, polyols and mycosporines, are associated with pathogenicity and/or fungal tolerance to several stress-inducing environmental factors, including temperature and solar radiation extremes. Extracts of M. anisopliae var. anisopliae (strain ESALQ-1037) conidia were purified by chromatographic procedures and the isolated compounds analyzed by 1H and 13C nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. LC MS analyses were carried out to search for mycosporines (the initial targets), but no compounds of this class were detected. A molecule whose natural occurrence was previously undescribed was identified. It consists of betaine conjugated with tyrosine, and the structure was identified as 2-{[1-carboxy-2-(4 hydroxyphenyl)ethyl]amino}-N,N,N-trimethyl-2-oxoethanammonium. Mannitol was the predominant compound in the alcoholic conidial extract, but no amino acids other than tyrosine were found to be conjugated with betaine in conidia. The fungal tyrosine betaine was detected also in conidial extracts of three other M. anisopliae var. anisopliae (ARSEF 1095, 5626 and 5749) and three M. anisopliae var. acridum isolates (ARSEF 324, 3391 and 7486), but it was not detected in Aspergillus nidulans conidial extract (ATCC 10074). PMID- 20943159 TI - Lepraric acid derivatives as chemotaxonomic markers in Hypoxylon aeruginosum, Chlorostroma subcubisporum and C. cyaninum, sp. nov. AB - Hypoxylon aeruginosum (Xylariaceae), an infrequently encountered predominantly tropical pyrenomycete, of which two varieties are known to science, is characterised by having a cyan blue stromatal surface or subsurface. In the course of our ongoing chemotaxonomic evaluation of the Xylariaceae, specific profiles of H. aeruginosum were observed by high performance liquid chromatography, coupled with diode array detection and mass spectrometry (hplc DAD/MS). By comparison with an authentic standard, lepraric acid and several yet unidentified metabolites with similar hplc-DAD/MS characteristics were detected in the stromata of the type material and other specimens of this species. Interestingly, lepraric acid was hitherto only known from lichenised ascomycetes. Hypoxylon aeruginosum, which is here reported first from Africa and Asia, contained none of the metabolites that were previously detected in other Xylariaceae, except for stromata growing hyperparasitically on other Hypoxylon species. A different lepraric acid derivative was also detected in the type specimen of Chlorostroma subcubisporum, which differs from H. aeruginosum by having a green stromatal surface, cuboid ascospores, and in lacking an amyloid ascal apical apparatus. A second species of Chlorostroma, which showed essentially the same metabolite profile as H. aeruginosum, is described from Thailand. We conclude that Chlorostroma and H. aeruginosum are closely related. However, no taxonomic conclusions are drawn from these findings because no cultures have so far become available to study their anamorphic morphology, their secondary metabolites in culture, and their molecular phylogeny. Taxonomic novelty: Chlorostroma cyaninum Laessoe, Srikitikulchai & J. Fournier, sp. nov. PMID- 20943160 TI - Use of response surface methodology to optimise environmental stress conditions on Penicillium glabrum, a food spoilage mould. AB - Fungi are ubiquitous microorganisms often associated with spoilage and biodeterioration of a large variety of foods and feedstuffs. Their growth may be influenced by temporary changes in intrinsic or environmental factors such as temperature, water activity, pH, preservatives, atmosphere composition, all of which may represent potential sources of stress. Molecular-based analyses of their physiological responses to environmental conditions would help to better manage the risk of alteration and potential toxicity of food products. However, before investigating molecular stress responses, appropriate experimental stress conditions must be precisely defined. Penicillium glabrum is a filamentous fungus widely present in the environment and frequently isolated in the food processing industry as a contaminant of numerous products. Using response surface methodology, the present study evaluated the influence of two environmental factors (temperature and pH) on P. glabrum growth to determine 'optimised' environmental stress conditions. For thermal and pH shocks, a large range of conditions was applied by varying factor intensity and exposure time according to a two-factorial central composite design. Temperature and exposure duration varied from 30 to 50 degrees C and from 10 min to 230 min, respectively. The effects of interaction between both variables were observed on fungal growth. For pH, the duration of exposure, from 10 to 230 min, had no significant effect on fungal growth. Experiments were thus carried out on a range of pH from 0.15 to 12.50 for a single exposure time of 240 min. Based on fungal growth results, a thermal shock of 120 min at 40 degrees C or a pH shock of 240 min at 1.50 or 9.00 may therefore be useful to investigate stress responses to non-optimal conditions. PMID- 20943161 TI - Development of a single-nucleotide polymorphism (SNP) assay for genotyping of Pandora neoaphidis. AB - Pandora neoaphidis (Entomophthoromycotina, Entomophthorales) is one of the most important fungal pathogens of aphids with great potential as a biological control agent. Development of tools that allow high-resolution monitoring of P. neoaphidis in the environment is a prerequisite for the successful implementation of biological control strategies. In this study, a single-nucleotide polymorphism (SNP) assay was developed. The assay targets 13 SNPs identified in 6 genomic regions including the largest subunit of nuclear RNA polymerase II (RPB1) gene, the second-largest subunit of nuclear RNA polymerase II (RPB2) gene, the beta tubulin (BTUB) gene, the elongation factor 1alpha-like (EFL) gene, the large subunit (LSU) rRNA gene, and the small subunit (SSU) rRNA gene together with the internal transcribed spacer (ITS). The assay allowed the discrimination of 15 different SNP profiles among 19 P. neoaphidis isolates and 4 P. neoaphidis infected cadavers. Results showed that the assay is applicable to DNA extracted from infected aphids allowing genotyping of the fungus without cultivation. The SNP assay provides an efficient tool for investigation of population structures and dynamics of P. neoaphidis, as well as its persistence and epidemiology in agro-ecosystems. Furthermore, it constitutes a powerful approach for monitoring potential biological control strains of P. neoaphidis in the environment. PMID- 20943162 TI - Particle and naked RNA mycoviruses in industrially cultivated mushroom Pleurotus ostreatus in China. AB - Many cultivated mushroom strains, such as Pleurotus ostreatus TD300, displayed symptoms of degeneration. A spherical virus POSV and four dsRNA segments were extracted from mycelium of P. ostreatus TD300. POSV had a diameter of 23 nm and encapsidated a 2.5kb dsRNA segment with coat proteins whose molecular weights were 39 kDa and 30 kDa. Four dsRNA segments were 8.2 kb, 2.5 kb, 2.0 kb, and 1.1 kb in size, respectively. The 1.1 kb dsRNA segment often escaped detection. The cDNA and the amino acid sequences of the 8.2 kb dsRNA were homologous to those of RNA-dependent RNA polymerases (RDRP) of ssRNA oyster mushroom spherical virus (OMSV), and contained conserved motifs A to D which were almost identical to those in RDRP of OMSV. The cDNA and amino acid sequences of the 2.5 kb and 2.0 kb dsRNA segments were homologous to that of RDRP and capsid protein of dsRNA virus P. ostreatus virus 1 (PoV1), respectively. In particular, the amino acid sequence of 2.5 kb dsRNA segment had high identity with the conserved motifs A to C in RDRP of PoV1, a Partiviridae virus. After eliminating the viruses in P. ostreatus TD300, the symptoms of degeneration completely disappeared. The results reveal that P. ostreatus TD300 was at least infected by a particle virus POSV, and two naked viruses, one was a dsRNA virus with a 2.0 kb dsRNA segment, the other was an ssRNA virus whose replicating form of genome was an 8.2 kb dsRNA segment. Mycoviruses infection is a causative agent of mushroom strain degeneration. PMID- 20943163 TI - Fusarium ananatum sp. nov. in the Gibberella fujikuroi species complex from pineapples with fruit rot in South Africa. AB - Pineapple (Ananas comosus) is native to South America and widely planted as a fruit crop in the tropics and sub-tropics. This plant is susceptible to a number of fungal diseases of which the most severe is fusariosis. The disease is caused by Fusarium guttiforme and occurs only in South and Central America. The occurrence of a similar disease on pineapples in South Africa has prompted a re evaluation of the Fusarium sp. associated with pineapple fruit rot. Phylogenetic relationships of isolates from pineapples collected in Brazil and South Africa were assessed based on sequence data for the translation elongation factor-1 alpha, histone H3 and beta-tubulin gene regions. Analyses showed that the South African isolates represent a species distinct from Brazilian isolates. The South African isolates are characterised by a concentration of aerial mycelium at the centres of the colonies, different to the Brazilian isolates that have an even distribution of aerial mycelium. Both phylogenetic and morphological data show that the disease on pineapple in South Africa is caused by a new Fusarium species described here as F. ananatum sp. nov. PMID- 20943164 TI - A two-gene phylogeny shows the lichen genus Niebla (Lecanorales) is endemic to the New World and does not occur in Macaronesia nor in the Mediterranean basin. AB - The generic segregates of the widespread fruticose genus Ramalina (mostly based on empirical data on morphology, cortex anatomy and secondary metabolites) are studied using maximum parsimony, maximum likelihood and Bayesian analyses of nuclear LSU and ITS sequences. The species examined include the three species aggregates within Niebla from the western coasts of North America, all species except one assumed to belong to the same genus from Macaronesia and the Mediterranean basin, the type species of Dievernia and Ramalina, and representatives of the genus Fistulariella. The genus Niebla is strongly supported when restricted to species from the New World, and all species referred to it from Macaronesia and the Mediterranean basin belong to Ramalina (R. bourgeana, R. crispatula, R. cupularis, R. hamulosa, R. portosantana, R. rosacea, R. subwebbiana and R. webbii). No support is found for the genera Dievernia and Fistulariella. The internal topology of the large genus Ramalina is unresolved and needs further studies. PMID- 20943165 TI - Highly variable microsatellite markers for the fungal and algal symbionts of the lichen Lobaria pulmonaria and challenges in developing biont-specific molecular markers for fungal associations. AB - The availability of highly variable markers for the partners of a fungal symbiosis enables the integrated investigation of ecological and evolutionary processes at the symbiotic level. In this article we analyze the specificity of the first and to date only microsatellite markers that had been developed for an epiphytic lichen (Lobaria pulmonaria). We used DNA extracts from cultures of the fungal and of the green algal symbionts of L. pulmonaria as well as total DNA extracts from related Lobaria species associated with the same algal partner, and got evidence that five of the previously described microsatellite markers, proposed to be fungus-specific, are indeed alga-specific. Hence, highly variable microsatellite primer sets available for both, the algal and the fungal symbionts of L. pulmonaria are now at our hands, which allow us to investigate so far unexplored biological processes of lichen symbionts, such as codispersal and coevolution. In a broader sense, our work evaluates and discusses the challenges in developing biont-specific molecular markers for fungi forming close associations with other organisms. PMID- 20943166 TI - Sydowia polyspora associated with current season needle necrosis (CSNN) on true fir (Abies spp.). AB - Current season needle necrosis (CSNN) has been a serious foliage disorder on true fir Christmas trees and bough material in Europe and North America for more than 25y. Approximately 2-4 weeks after bud break, needles develop chlorotic spots or bands that later turn necrotic. The symptoms have been observed on noble fir (Abies procera), Nordmann fir (A. nordmanniana) and grand fir (A. grandis) on both continents. CSNN was reported as a physiological disorder with unknown aetiology from USA, Denmark, and Ireland, but was associated with the fungus Kabatina abietis in Germany, Austria and Norway. In 2007, a fungus that morphologically resembled K. abietis was isolated from symptomatic needle samples from Nordmann fir from Austria, Denmark, Germany, Norway, and USA. Sequencing of the internal transcribed spacer (ITS) region of ribosomal DNA of these cultures, plus a K. abietis reference culture from Germany (CBS 248.93), resulted in Hormonema dematioides, the imperfect stage of Sydowia polyspora, and thus the taxonomy is further discussed. Inoculation tests on Nordmann fir seedlings and transplants with isolates of S. polyspora from all five countries resulted in the development of CSNN symptoms. In 2009, S. polyspora was also isolated from symptomatic needles from Nordmann fir collected in Slovakia. PMID- 20943167 TI - The infection biology of Fusarium graminearum: defining the pathways of spikelet to spikelet colonisation in wheat ears. AB - Fusarium graminearum is one of the main causal agents of Fusarium Ear Blight on wheat. How the pathogen colonises the entire ear is not known. There is controversy over whether this mycotoxin producing pathogenic fungus invades wheat floral tissue using a necrotrophic or another mode of nutrition. A detailed microscopic investigation has revealed how wild-type fungal hyphae, of the sequenced strain PH-1, colonised susceptible wheat ears and spread from spikelet to spikelet. At the advancing infection front, colonisation of the host cortex occurred ahead of any vascular colonisation and the hyphae adapted to the available intercellular space between host cells. Intercellular hyphae then became abundant and host cells lost their entire cellular contents just prior to intracellular colonisation. No host cells died ahead of the infection. However, while these deep cortex infections progressed, just below the surface the highly photosynthetic chlorenchyma cells were observed to have died prior to colonisation. Behind the infection front, hyphae were abundant in the vasculature and the cortex, often growing through the pit fields of thick walled cells. This high level of inter- and intracellular fungal colonisation resulted in the collapse of the non-lignified cell-types. In this middle zone of infection, hyphal diameters were considerably enlarged. Far behind the infection front inter and intracellular hyphae were devoid of contents and had often collapsed. At later stages of infection, the pathogen switched from predominately vertical to lateral growth and accumulated below the surface of the rachis. Here the lignified host cell walls became heavily degraded and hyphae ruptured the epidermis and produced an aerial mycelium. PMID- 20943168 TI - A proteomic approach to identifying proteins differentially expressed in conidia and mycelium of the entomopathogenic fungus Metarhizium acridum. AB - Metarhizium spp. is an important worldwide group of entomopathogenic fungi used as an interesting alternative to chemical insecticides in programs of agricultural pest and disease vector control. Metarhizium conidia are important in fungal propagation and also are responsible for host infection. Despite their importance, several aspects of conidial biology, including their proteome, are still unknown. We have established conidial and mycelial proteome reference maps for Metarhizium acridum using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF MS). In all, 1130+/-102 and 1200+/-97 protein spots were detected in ungerminated conidia and fast-growing mycelia, respectively. Comparison of the two protein-expression profiles reveled that only 35% of the protein spots were common to both developmental stages. Out of 94 2-DE protein spots (65 from conidia, 25 from mycelia and two common to both) analyzed using mass spectrometry, seven proteins from conidia, 15 from mycelia and one common to both stages were identified. The identified protein spots exclusive to conidia contained sequences similar to known fungal stress-protector proteins (such as heat shock proteins (HSP) and 6-phosphogluconate dehydrogenase) plus the fungal allergen Alt a 7, actin and the enzyme cobalamin-independent methionine synthase. The identified protein spots exclusive to mycelia included proteins involved in several cell housekeeping biological processes. Three proteins (HSP 90, 6 phosphogluconate dehydrogenase and allergen Alt a 7) were present in spots in conidial and mycelial gels, but they differed in their locations on the two gels. PMID- 20943169 TI - Afforestation alters community structure of soil fungi. AB - Relatively little is known about the effect of afforestation on soil fungal communities. This study demonstrated that afforestation altered fungal community structure and that changes were correlated to pools of soil C. Pasture at three locations on the same soil type was afforested with Eucalyptus globulus or Pinus pinaster. The structure of fungal communities under the three land uses was measured after 13y using automated ribosomal intergenic spacer analysis (ARISA). Afforestation significantly altered the structure of fungal communities. The effect of location on the structure of fungal communities was limited to pasture soils; although these contained the same plant species, the relative composition of each species varied between locations. Differences in the structure of fungal communities between pasture, E. globulus and P. pinaster were significantly correlated with changes in the amount of total organic C and microbial biomass-C in soil. Afforestation of patches of agricultural land may contribute to conserving soil fungi in agricultural landscapes by supporting fungal communities with different composition to agricultural soils. PMID- 20943170 TI - First fungal community analyses of endophytic ascomycetes associated with Viscum album ssp. austriacum and its host Pinus sylvestris. AB - The endophytic fungal communities in the hemi-parasitic epiphyte Viscum album and in its phorophyte Pinus sylvestris were compared to reveal the fungal distribution patterns in their hosts. The ITS nrDNA of 208 multiple-isolated fungal strains was sequenced and a newly designed process was applied for assigning taxon names to the obtained sequences. Furthermore, the isolates were grouped as clusters, by subjecting a sequence similarity matrix to various cluster analyses, the results of which were compared and verified by data from phylogenetic reconstructions. In contrast to a previously reported dominance of Leotiomycetes among Pinus inhabiting fungi, the endophytic communities of the two host plant species studied here were dominated by Xylariaceae (Sordariomycetes). This is in accordance with the finding that host selectivity was only a minor factor in explaining the distribution patterns of the endophytic fungi in Viscum and Pinus. Organ and, probably, tissue selectivity had a more pronounced effect. The composition and condition of the woods in the surrounding, however, are concluded to be the major determinants, due to the following circumstantial evidence: The highest similarities in fungal community compositions were found for the leaves of the two host plant species, especially when considering only the older leaves. The finding that the inhabitants of matured or senescent organs are less host-selective is in accordance with decreasing defence capabilities of ageing host plant tissue and an increased nutrient supply for saprobic taxa. Therefore, the composition of the fungal communities in ageing leaves seems to be predominantly ascribed to contagious spread and to depend on the spectrum of nearby sporulating fungal taxa. We suggest that because a broad range of suitable substrates for Xylariaceae was present in immediate vicinity of the study sites, these fungi also dominated among the recorded endophytic taxa. PMID- 20943171 TI - Opposing developmental functions of Agrocybe aegerita galectin (AAL) during mycelia differentiation. AB - Mycelia of basidiomycetes differentiating into fruiting body is a controlled developmental process, however the underlying molecular mechanism remains unknown. In previous work, a novel fungal Agrocybe aegerita galectin (AAL) was isolated from A. aegerita in our laboratory. AAL was shown to promote mycelial differentiation in A. aegerita and Auricularia polytricha, indicating that AAL might function as a conserved fruiting initiator during basidiomycete mycelia development. In the current work, we investigate the role of AAL in mycelia differentiation and fruiting body formation. First, the expression and localization of AAL in mycelia, primordium and fruiting body were assessed by Western blotting and immunohistochemistry. AAL was found to be ubiquitously expressed in the primordium and fruiting body but not in the mycelia. AAL facilitated mycelia congregation and promoted fruiting body production when AAL was applied on mycelia. At the same time, when AAL was spread on potato dextrose agar (PDA) medium prior to mycelia inoculation, mycelia exhibited slowed growth rates, resulting in mycelia cords formation and inhibition of fruiting body formation. The 5' regulatory sequence of aal was cloned by 'genome walking'. Here, we show that aal lack introns in the coding region and the upstream 740 bp sequence was characterized by the existence of core promoter elements, which included: two CCAAT boxes (-535/-280), a GC box (-145), a TATA box (-30) and a fungal leader intron within the 5' UTR. The identification of regulatory expression elements may provide an explanation to the stage-specific and high level expression of aal during fruiting development. PMID- 20943172 TI - Characterization of an extracellular laccase, PbLac1, purified from Polyporus brumalis. AB - Polyporus brumalis (strain ibrc05015) secreted high amounts of laccases (Lacs) in liquid medium. With 2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) as a substrate, Lac activity was 7.72 U ml-1 and this strain secreted a maximum 0.23 mg ml-1 of total protein. The enzyme, PbLac1 was purified to homogeneity using hydrophobic and anion-exchange chromatography. The purified PbLac1 had a molecular mass of 63.4 kDa as determined by polyacrylamide gel electrophoresis. PbLac1 oxidized a wide range of substrates such as 3,4 dihydroxy l-phenylalanine (l-DOPA) and catechol, but not tysorine. The activity of PbLac1 was increased by addition of 10.0 mM Cu(2+). PbLac1 could decolorize several industrial dyes, such as Remazol Brilliant Blue R known as model dyes of environmental xenobiotics. In addition, PbLac1 decolorized a wide range of substrates, such as the carcinogen, Poly R-478, in the presence of violuric acid as mediator. The E degrees value of PbLac1 was 0.80 V+/-0.01 versus normal hydrogen electrode, which is a very high redox potential compared to those of other basidiomycetous Lacs. These results suggest the potential utility of PbLac1 for industrial applications. PMID- 20943173 TI - Developmentally induced changes in the sclerotial proteome of Sclerotinia sclerotiorum. AB - Sclerotinia sclerotiorum (Lib.) de Bary is a necrotrophic fungal phytopathogen with a broad host range. The fungus produces sclerotia, long-term survival and dissemination structures that serve as the primary source of inoculum during seasonal crop infection cycles. Herein, we report the first proteomics-based analysis of sclerotial development. A total of 88 protein spots were observed by two-dimensional gel electrophoresis (2-DE) to exhibit significant temporal differences in abundance at three representative stages of sclerotial development, and the identities of these proteins were established using LC MS/MS. The proteins were classified into several functional categories including metabolism, energy, transcription and protein fate, cell defense, differentiation, and proteins with as of yet unknown functions. In addition, proteins involved in the process of melanogenesis were found to be differentially abundant during sclerotial development, as was the development-specific protein, Ssp. This study provides a starting point towards achieving a comprehensive understanding of the proteins and molecular events associated with sclerotial development. PMID- 20943174 TI - Impact of wildfire return interval on the ectomycorrhizal resistant propagules communities of a Mediterranean open forest. AB - Ectomycorrhizal (ECM) fungi, in particular their spores and other resistant propagules, play an important role in secondary succession processes that facilitate regeneration after disturbance events. In this study, the effects of high and low wildfire frequencies (respectively short and long fire return intervals) on the resistant propagules communities (RPCs) of a Mediterranean open pine forest were compared. Soil samples were collected in four mountain sites with different fire return intervals and used to test ectomycorrhiza development in two hosts, Pinus pinaster and Quercus suber. RPCs were characterized by direct sequencing of fungal internal transcribed spacer (ITS) regions from individual ECM root tips. Eighteen ECM species were detected in the bioassay. The most frequently found fungi were Cenococcum geophilum, Inocybe jacobi, Thelephora terrestris, Tomentella ellisii on both hosts and Rhizopogon luteolus and R. roseolus on maritime pine. A short fire return interval reduced the species richness of the ECM community found on Q. suber, promoted species like R. roseolus and reduced the abundance of other species (e.g. R. luteolus). The abundance of I. jacobi was positively affected by long fire return interval, but decreased significantly with recurrent fires. These results indicate that changes in fire frequency can alter the structure, composition and diversity of ECM communities, which could compromise the resilience of the ecosystem in highly disturbed areas. PMID- 20943175 TI - Comparative analysis of the Metarhizium anisopliae secretome in response to exposure to the greyback cane grub and grub cuticles. AB - Metarhizium anisopliae is a well-characterized biocontrol agent of a wide range of insects including cane grubs. In this study, a two-dimensional (2D) electrophoresis was used to display secreted proteins of M. anisopliae strain FI 1045 growing on the whole greyback cane grubs and their isolated cuticles. Hydrolytic enzymes secreted by M. anisopliae play a key role in insect cuticle degradation and initiation of the infection process. We have identified all the 101 protein spots displayed by cross-species identification (CSI) from the fungal kingdom. Among the identified proteins were 64-kDa serine carboxypeptidase, 1,3 beta-exoglucanase, Dynamin GTPase, THZ kinase, calcineurin like phosphoesterase, and phosphatidylinositol kinase secreted by M. ansiopliae (FI-1045) in response to exposure to the greyback cane grubs and their isolated cuticles. These proteins have not been previously identified from the culture supernatant of M. anisopliae during infection. To our knowledge, this the first proteomic map established to study the extracellular proteins secreted by M. ansiopliae (FI 1045) during infection of greyback cane grubs and its cuticles. PMID- 20943176 TI - Microarray analysis of differential gene expression elicited in Trametes versicolor during interspecific mycelial interactions. AB - Trametes versicolor is an important white rot fungus of both industrial and ecological interest. Saprotrophic basidiomycetes are the major decomposition agents in woodland ecosystems, and rarely form monospecific populations, therefore interspecific mycelial interactions continually occur. Interactions have different outcomes including replacement of one species by the other or deadlock. We have made subtractive cDNA libraries to enrich for genes that are expressed when T. versicolor interacts with another saprotrophic basidiomycete, Stereum gausapatum, an interaction that results in the replacement of the latter. Expressed sequence tags (ESTs) (1920) were used for microarray analysis, and their expression compared during interaction with three different fungi: S. gausapatum (replaced by T. versicolor), Bjerkandera adusta (deadlock) and Hypholoma fasciculare (replaced T. versicolor). Expression of significantly more probes changed in the interaction between T. versicolor and S. gausapatum or B. adusta compared to H. fasciculare, suggesting a relationship between interaction outcome and changes in gene expression. PMID- 20943177 TI - Phytophthora kernoviae oospore maturity, germination, and infection. AB - Limited information is known on the basic biology of the recently described Phytophthora kernoviae that produces homothallic oospores. In this study, different P. kernoviae isolates were used to investigate oospore maturity, germination, and infection. All isolates produced oospores in V8 broth at 20 degrees C in the dark by 6d. Oospores also formed at 10 and 15 degrees C, but did not form at 25 and 28 degrees C. Continuous light inhibited oospore production of some isolates but had no negative effect on others. Maturation time of the oospores, as noted by germination and staining with tetrazolium bromide, was not much different among the isolates between 2 and 14 weeks. Oospore germination was optimal at 18 and 20 degrees C, and did not occur at 5, 25, and 30 degrees C. Oospore germination under continuous light was higher than in the dark, but individual isolates showed variable results. Rhododendron leaf disks inoculated with oospores and maintained in the dark at 20 degrees C were necrotic after 1 week, while those kept under continuous light did not develop necrosis. The percentage of leaf disks infected with P. kernoviae was lower in the leaves exposed to continuous light (40%) compared to those kept in the dark (100%). PMID- 20943178 TI - Evidence for a new lineage of primary ambrosia fungi in Geosmithia Pitt (Ascomycota: Hypocreales). AB - Geosmithia is a genus of mitosporic filamentous fungi typically associated with phloeophagous bark beetles world-wide. During this study, the fungal associates of ambrosia beetles Cnesinus lecontei, Eupagiocerus dentipes, and Microcorthylus sp. from Costa Rica, were studied using morphology and DNA sequences. Fungal associates belonged to four undescribed Geosmithia species. Geosmithia eupagioceri sp. nov. and G. microcorthyli sp. nov. are evidently primary ambrosia fungi of their respective vectors E. dentipes and Microcorthylus species. They both have convergently evolved distinct morphological adaptations including the production of large, solitary and globose conidia, and yeast-like cells. Tunnels of C. lecontei contained an undescribed Geosmithia species, but its nutritional importance for its vector is unclear. An auxiliary ambrosia fungus, Geosmithia rufescens sp. nov., was found associated with both G. eupagioceri and the Geosmithia species associated with C. lecontei. G. microcorthyli is genetically quite similar to the phloem-associated Geosmithia sp. 8 from Europe. Large differences in morphology between these two species suggest the rapid co evolution resulting from the close symbiosis of the former with its beetle host. The ITS rDNA sequences of G. microcorthyli and Geosmithia sp. 8 were not diagnostic, suggesting that alternative markers such as EF-1alpha, IGS rDNA or beta-tubulin should be used, together with morphological and ecological data, for species delimitation in this genus. The primary ambrosia fungi described here are derived from phloem-associated ancestors, and represent two independent lineages of ambrosia fungi in the Hypocreales and a new ecological strategy within Geosmithia. PMID- 20943179 TI - Characterization of field isolates of Trichoderma antagonistic against Rhizoctonia solani. AB - The aim of the present study was to characterize sixteen isolates of Trichoderma originating from a field of sugar beet where disease patches caused by Rhizoctonia solani were observed. Use of both molecular and morphological characteristics gave consistent identification of the isolates. Production of water-soluble and volatile inhibitors, mycoparasitism and induced systemic resistance in plant host were investigated using in vitro and in vivo tests in both sterilized and natural soils. This functional approach revealed the intra specific diversity as well as biocontrol potential of the different isolates. Different antagonistic mechanisms were evident for different strains. The most antagonistic strain, T30 was identified as Trichoderma gamsii. This is the first report of an efficient antagonistic strain of T. gamsii being able to reduce the disease in different conditions. The ability to produce water-soluble inhibitors or coil around the hyphae of the pathogen in vitro was not related to the disease reduction in vivo. Additionally, the strains collected from the high disease areas in the field were better antagonists. The antagonistic activity was not characteristic of a species but that of a population. PMID- 20943180 TI - Identification of appressorial and mycelial cell wall proteins and a survey of the membrane proteome of Phytophthora infestans. AB - Proteins embedded in the cell wall and plasma membrane of filamentous oomycetes and fungi provide a means by which these organisms can interact with their local environment. However, cell wall and membrane proteins have often proved difficult to isolate using conventional proteomic techniques. Here we have used liquid chromatography tandem mass spectrometry (LC-MS/MS) to facilitate rapid and sensitive quantification of the cell wall proteome. We report the use of LC-MS/MS to identify differentially regulated proteins from the cell walls of three different lifecycle stages of the oomycete plant pathogen Phytophthora infestans: non-sporulating vegetative mycelium, sporulating mycelium, and germinating cysts with appressoria. We have also used quantitative real-time RT-PCR to confirm that the transcripts corresponding to some of these proteins, namely those identified in cell walls of germinating cysts with appressoria, accumulate differentially throughout the lifecycle. These proteins may, therefore, be important for pre infective development and early pathogenicity. Up to 31 covalently and non covalently bound cell wall-associated proteins were identified. All of the proteins identified in germinating cysts with appressoria, and several of those from mycelial fractions, were classified as putative effector or pathogen associated molecular pattern (PAMP) molecules, including members of the CBEL family, the elicitin family, the crinkler (CRN) family and two transglutaminases. Thus, the cell wall of P. infestans may represent an important reservoir for surface-presented, apoplastic effectors or defence activation molecules. Proteins predicted to be cell surface proteins included IPI-B like proteins, mucins, cell wall-associated enzymes and annexin family members. Additionally we identified up to 27 membrane-associated proteins from Triton X-114 phase partitioned mycelial membrane preparations, producing the first inventory of oomycete membrane associated proteins. Four of these proteins are small Rab-type G-proteins and several are associated with secretion. PMID- 20943181 TI - Identification of a new member of Pleurotus ostreatus laccase family from mature fruiting body. AB - Laccases (benzenediol:oxygen oxidoreductases, EC 1.10.3.2) are blue multicopper oxidases, catalyzing the oxidation of an array of aromatic substrates concomitantly with the reduction of molecular oxygen to water. Most of the known laccases have fungal or plant origins, although few laccases have been also identified in bacteria and insects. Most of the fungal laccases reported thus far are extra-cellular enzymes, whereas only few enzymes from fruiting bodies have been described so far. Multiple isoforms of laccases are usually secreted by each fungus depending on species and environmental conditions. As a fact, a laccase gene family has been demonstrated in the white-rot fungus Pleurotus ostreatus. This work allowed identification and characterization of the first laccase isoenzyme from the fruiting body of P. ostreatus. Discovery through mass spectrometry of LACC12 proves the expression of a functional protein by the related deduced encoding transcript. The topology of phylogenetic tree of fungal laccases proves that LACC12 falls in cluster with the members of P. ostreatus LACC10 (=POXC) subfamily, although lacc12 deduced intron-exon structure differs from that of the subfamily members and the related locus is located in a different chromosome. Results show that the evolutionary pattern of lacc12 and that of the other laccase isozyme genes may have evolved independently, possibly through duplication-divergence events. The reported data add a new piece to the knowledge about P. ostreatus laccase multigene family and shed light on the role(s) played by individual laccase isoforms in P. ostreatus. PMID- 20943182 TI - Molecular and structural characterization of GTP-cyclohydrolase II in Eremothecium ashbyi NRRL Y-1363: cDNA cloning, comparative sequence analysis and molecular modeling. AB - GTP-cyclohydrolase II (GCH II) encoded by RIB1 gene catalyzes the first committed step in the riboflavin biosynthetic pathway. We report here the cloning and characterization of the entire RIB1 ORF (EaRIB1) of 942bp by reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE-PCR) in Eremothecium ashbyi where it was found to be present as a single-copy gene. EaRIB1 sequence is available at the GenBank Accession Number EF565374. The putative peptide of 313-aa has a high similarity of 60-70% with GCH II sequences from other ascomycete fungi. Gene expression and alignment studies confirmed the functional annotation of this gene. Homology model was developed with Escherichia coli (PDB 2BZ1) as template to identify the catalytic domains and to explore its functional architecture. We report here the first three dimensional model of any fungal GCH II which due to its absence in humans assumes significance for anti-fungal drug targeting. PMID- 20943183 TI - Ophiocordyceps barnesii and its relationship to other melolonthid pathogens with dark stromata. AB - A hypocrealean Coleoptera pathogen with characteristic part-spores, collected from Khao Yai National Park and Kaeng Krachan National Park in Thailand, is reported. The overall morphology was similar to Cordyceps barnesii, which is known from Sri Lanka, with ascospores disarticulating into four unusually long part-spores that were 30-40 MUm long. This disarticulation and part-spore size is, so far, unique within Cordyceps sensu lato. The Thai material was identified with C. barnesii and its placement in the genus Ophiocordyceps was confirmed. Multigene analyses based on the ribosomal small subunit, RPB1 and RPB2 genes revealed the close relationship of the Thai material to Ophiocordyceps konnoana as well as O. ravenelii, O. superficialis, and O. nigrella (all of which have significantly smaller part-spores). However, Ophiocordyceps barnesii and these related species were all characterised by dark-brown to purplish stromata and an affinity for melolonthid larval hosts. No anamorph was seen in the field and was not produced in the slow-growing cultures. PMID- 20943184 TI - AFLP analysis reveals a clonal population of Phytophthora pinifolia in Chile. AB - Phytophthora pinifolia is the causal agent of the recently discovered needle disease of Pinus radiata in Chile, referred to as "Dano Foliar del Pino" (DFP). The genetic structure of the pathogen population is unknown, which hinders our understanding of its appearance and spread in Chile since 2004. In this study, a population of 88 cultures of P. pinifolia isolated from P. radiata at several localities in Chile was evaluated for genotypic diversity using amplified fragment length polymorphisms (AFLPs). Results of the AFLP analyses showed that the P. pinifolia population in Chile consists of two near identical genotypes but with no genetic differentiation based on geography, year of isolation or the part of the tree from which the isolates were obtained. Mating experiments did not lead to the production of gametangia suggesting that the organism is sterile. The fact that a single clonal genotype dominates the population of P. pinifolia in Chile supports the hypothesis that P. pinifolia was recently introduced into this country and that its impact is due to a new and susceptible host encounter. PMID- 20943185 TI - Fusarium culmorum is a single phylogenetic species based on multilocus sequence analysis. AB - Fusarium culmorum is a major pathogen of wheat and barley causing head blight and crown rot in cooler temperate climates of Australia, Europe, West Asia and North Africa. To better understand its evolutionary history we partially sequenced single copy nuclear genes encoding translation elongation factor 1-alpha (TEF), reductase (RED) and phosphate permease (PHO) in 100 F. culmorum isolates with 11 isolates of Fusarium crookwellense, Fusarium graminearum and Fusarium pseudograminearum. Phylogenetic analysis of multilocus sequence (MLS) data using Bayesian inference and maximum parsimony analysis showed that F. culmorum from wheat is a single phylogenetic species with no significant linkage disequilibrium and little or no lineage development along geographic origin. Both MLS and TEF and RED gene sequence analysis separated the four Fusarium species used and delineated three to four groups within the F. culmorum clade. But the PHO gene could not completely resolve isolates into their respective species. Fixation index and gene flow suggest significant genetic exchange between the isolates from distant geographic regions. A lack of strong lineage structure despite the geographic separation of the three collections indicates a frequently recombining species and/or widespread distribution of genotypes due to international trade, tourism and long-range dispersal of macroconidia. Moreover, the two mating type genes were present in equal proportion among the F. culmorum collection used in this study, leaving open the possibility of sexual reproduction. PMID- 20943186 TI - The Nox/Ferric reductase/Ferric reductase-like families of Eumycetes. AB - Reactive Oxygen Species (ROS) are involved in plant biomass degradation by fungi and development of fungal structures. While the ROS-generating NADPH oxidases from filamentous fungi are under strong scrutiny, much less is known about the related integral Membrane (or Ferric) Reductases (IMRs). Here, we present a survey of these enzymes in 29 fungal genomes covering the entire available range of fungal diversity. IMRs are present in all fungal genomes. They can be classified into at least 24 families, underscoring the high diversity of these enzymes. Some are differentially regulated during colony or fruiting body development, as well as by the nature of the carbon source of the growth medium. Importantly, functional characterization of IMRs has been made on proteins belonging to only two families, while nothing or very little is known about the proteins of the other 22 families. PMID- 20943187 TI - Spanish population of Gremmeniella abietina is genetically unique but related to type A in Europe. AB - Genetic structure of the European Gremmeniella abietina var. abietina was analyzed in this study. Ninety-two Spanish isolates, six Swiss isolates of Alpine biotype, 76 Finnish isolates of biotype A and 54 Finnish and seven Russian isolates of biotype B were collected. Genetic variation of different populations was analyzed using sequence analysis of specifically amplified markers GAAA1000, GAAA800 and ACA900. Variation in the GAAA1000 marker was significant, and composed of 33 alleles divided into the following four studied populations: five alleles in the Alpine type, 12 in biotype B, 16 in biotype A and two in the Spanish population. Based on variation in GAAA1000 marker, a subset of isolates were further analyzed using GAAA800 and ACA900 sequences, which showed lower overall genetic variability, and no variation among the Spanish population. Genetic differentiation analysis revealed a high genetic differentiation among populations. Finally, clustering analysis of GAAA1000 sequences showed that the Spanish isolates clearly separated from the rest of the biotypes, whereas the Alpine type was closely related to the B type. However, one of the A-type isolates had an identical GAAA1000 allele with the prevailing allele among Spanish isolates. Altogether, our data suggest that the Spanish population is genetically highly differentiated from any other G. abietina population in Europe with a probable A-type origin. PMID- 20943188 TI - Inocybe tauensis, a new species from the Samoan Archipelago with biogeographic evidence for a Paleotropical origin. AB - Inocybe tauensis is described as a new species from the island of Ta'u, American Samoa. The species occurs in native littoral forest and is associated with the ectomycorrhizal tree Pisonia grandis. Based on an analysis of nLSU, RPB1, and RPB2 sequence data, I. tauensis appears to be derived from ancestors with a Paleotropical biogeographical distribution. Alternative explanations for the unexpected presence of an Inocybe species in the Samoan Archipelago are discussed. PMID- 20943189 TI - Muscodor fengyangensis sp. nov. from southeast China: morphology, physiology and production of volatile compounds. AB - The fungal genus Muscodor was erected on the basis of Muscodor albus, an endophytic fungus originally isolated from Cinnamomum zeylanicum. It produces a mixture of volatile organic compounds (VOCs) with antimicrobial activity that can be used as mycofumigants. The genus currently comprises five species. Here we describe the isolation and characterization of a new species of Muscodor on the basis of five endophytic fungal strains from leaves of Actinidia chinensis, Pseudotaxus chienii and an unidentified broad leaf tree in the Fengyangshan Nature Reserve, Zhejiang Province, Southeast of China. They exhibit white colonies on potato dextrose agar (PDA) media, rope-like mycelial strands, but did not sporulate. The optimum growth temperature is 25 degrees C. The results of a phylogenetic analysis based on four loci (ITS1-5.8S-ITS2, 28S rRNA, rpb2 and tub1) are consistent with the hypothesis that these five strains belong to a single taxon. All five strains also produce volatile chemical components with antimicrobial activity in vitro, which were different from those previously described for other Muscodor species. PMID- 20943190 TI - 1,3-beta-d-Glucan synthase of Paracoccidioides brasiliensis: recombinant protein, expression and cytolocalization in the yeast and mycelium phases. AB - Paracoccidioides brasiliensis is a thermo-dimorphic human pathogenic fungus that in the mycelium phase lives at 23 degrees C in environment and in the yeast phase at 37 degrees C in the host tissues. In P. brasiliensis, the main polymers that compound the cell wall are chitin, 1,3-beta-D-glucan and 1,3-alpha-glucan. They make a primary barrier responsible for the structural integrity and form of the cell wall. In P. brasiliensis, just one homologue of 1,3-beta-D-glucan synthase gene (PbFKS1) was found. Here, the active recombinant protein (PbFks1pc) containing the catalytic region was obtained in Escherichia coli. In addition, a paradoxical dissociation was detected between the expression of the PbFKS1 transcript and the level of the corresponding protein PbFks1p, which was higher in the yeast phase, versus the amount of 1,3-beta-D-glucan polymer, which was higher in the mycelium phase. Western blot analysis using protein extracts of cellular fractions showed that PbFks1p is present in the membrane-enriched fraction of mycelium and yeast cells and in the cell wall-enriched fractions of yeast cells. Confocal-immunocytolocalization of PbFks1p identified the protein in the apical growing region of the mycelium and distributed on the surface of the yeast cell. Two possible mechanisms could explain the above-mentioned discrepancy between the data: (a) overexpression of Rho1 GTPase as a regulator of 1,3-beta-D glucan synthase; (b) possible post-translational regulation of PbFks1p in P. brasiliensis isolates. PMID- 20943191 TI - Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents. AB - A number of benzoic acid analogues showed antifungal activity against strains of Aspergillus flavus, Aspergillus fumigatus and Aspergillus terreus, causative agents of human aspergillosis, in in vitro bioassays. Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids were increased by addition of a methyl, methoxyl or chloro group at position 4 of the aromatic ring, or by esterification of the carboxylic acid with an alkyl group, respectively. Thymol, a natural phenolic compound, was a potent chemosensitizing agent when co-applied with the antifungal azole drugs fluconazole and ketoconazole. The thymol-azole drug combination demonstrated complete inhibition of fungal growth at dosages far lower than the drugs alone. Co-application of thymol with amphotericin B had an additive effect on all strains of aspergilli tested with the exception of two of three strains of A. terreus, where there was an antagonistic effect. Use of two mitogen-activated protein kinase (MAPK) mutants of A. fumigatus, sakADelta and mpkCDelta, having gene deletions in the oxidative stress response pathway, indicated antifungal and/or chemosensitization activity of the benzo analogues was by disruption of the oxidative stress response system. Results showed that both these genes play overlapping roles in the MAPK system in this fungus. The potential of safe, natural compounds or analogues to serve as chemosensitizing agents to enhance efficacy of commercial antifungal agents is discussed. PMID- 20943192 TI - Target-specific PCR primers can detect and differentiate ophiostomatoid fungi from microbial communities associated with the mountain pine beetle Dendroctonus ponderosae. AB - The aim of this study was to develop DNA probes that could identify the major fungal species associated with mountain pine beetles (MPB). The beetles are closely associated with fungal species that include ophiostomatoid fungi that can be difficult to differentiate morphologically. The most frequently isolated associates are the pine pathogens Grosmannia clavigera and Leptographium longiclavatum, the less pathogenic Ophiostoma montium, and an undescribed Ceratocystiopsis species (Cop. sp.). Because growing, isolating and extracting DNA from fungi vectored by MPB can be time and labour intensive, we designed three rDNA primer sets that specifically amplify short rDNA amplicons from O. montium, Cop. sp. and the pine Leptographium clade. We also designed two primer sets on a gene of unknown function that can differentiate G. clavigera and L. longiclavatum. We tested the primers on 76 fungal isolates that included MPB associates. The primers reliably identified their targets from DNA obtained from pure fungal cultures, pulverized beetles, beetle galleries, and tree phloem inoculated with G. clavigera. The primers will facilitate large-scale work on the ecology of the MPB-fungal-lodgepole pine ecosystem, as well as phytosanitary/quarantine sample screening. PMID- 20943193 TI - Genetic structure of South Australian Pyrenophora teres populations as revealed by microsatellite analyses. AB - The aim of this study was to determine the genetic structure of South Australian field populations of the barley net blotch pathogens, Pyrenophora teres f. sp. teres (PTT) and P. teres f. sp. maculata (PTM), using microsatellite DNA markers. Three PTT populations (76 isolates total) and two PTM populations (43 isolates total) were sampled from separate fields during a single growing season. The results showed that of the 20 microsatellite loci examined, 17 (85%) were polymorphic within the PTT and PTM populations. In total, 120 distinct alleles were identified of which only 11 (9%) were shared between the two population types. Nei's measure of gene diversity across the PTT and PTM populations was similar at 0.38 and 0.40, respectively, and also much higher than previously reported from studies in which other types of molecular markers were used. The coefficient of genetic differentiation among both populations was the same (G(ST)=0.03) and the low and insignificant estimates of F(ST), as indicated by theta, between populations of the same type (PTT: theta<0.008, PTM: theta=0.014) indicated that isolates sampled from different areas within the same field were genetically similar. In contrast, high and significant genetic differentiation was observed among and between populations of different type (G(ST)=0.42, theta>0.567). The high number of unique multilocus haplotypes observed within the PTT (84%) and PTM (100%) populations, combined with a 1:1 distribution of both mating types, suggested that sexual reproduction was predominant among these populations. However, tests for multilocus associations showed that both PTT and PTM populations were in significant linkage disequilibrium. Although the levels of disequilibrium were low, an asexual reproductive component could not be excluded. PMID- 20943194 TI - Searching for Moniliophthora perniciosa pathogenicity genes. AB - The basidiomycete Moniliophthora perniciosa is the causal agent of witches' broom disease of Theobroma cacao (cacao). Pathogenesis mechanisms of this hemibiotrophic fungus are largely unknown. An approach to identify putative pathogenicity genes is searching for sequences induced in mycelia grown under in vitro conditions. Using this approach, genes from M. perniciosa induced under limiting nitrogen and light were identified from a cDNA library enriched by suppression subtractive hybridization as potential putative pathogenicity genes. From the 159 identified unique sequences, 59 were annotated and classified by gene ontology. Two sequences were categorized as "Defence genes, Virulence, and Cell response" presumably coding for allergenic proteins, whose homologues from other fungi are inducers of animal or plant defences. Differential gene expression was evaluated by quantitative amplification of reversed transcripts (RT-qPCR) of the putative identified genes coding for the two allergenic proteins (Aspf13 and 88KD), and for the enzymes Arylsulfatase (AS); Aryl-Alcohol Oxidase; Aldo-Keto Reductase (AK); Cytochrome P450 (P450); Phenylalanine Ammonia-Lyase; and Peroxidase from mycelia grown under contrasting N concentrations. All genes were validated for differential expression, except for the putative Peroxidase. The same eight genes were analysed for expression in susceptible plants inoculated with M. perniciosa, and six were induced during the early asymptomatic stage of the disease. In infected host tissues, transcripts of 88KD and AS were found more abundant at the biotrophic phase, while those from Aspf13, AK, PAL, and P450 accumulated at the necrotrophic phase, enabling to suggest that mycelia transition from biotrophic to necrotrophic might occur earlier than currently considered. These sequences appeared to be virulence life-style genes, which encode factors or enzymes that enable invasion, colonization or intracellular survival, or manipulate host factors to benefit the pathogen's own survival in the hostile environment. PMID- 20943195 TI - Influence of sorbitol on protein production and glycosylation and cell wall formation in Trichoderma reesei. AB - Sorbitol is often used at 1 mol/liter as an osmotic stabilizer for cultivation of fungi with a fragile cell wall phenotype. On the other hand, at this concentration sorbitol causes an osmotic stress in fungal cells resulting in intensive production of intracellular glycerol. The highly increased consumption of glucose for glycerol synthesis may lead to changes in processes requiring carbohydrate residues. This study provides new information on the consequences of osmotic stress to the cell wall composition, protein production and glycosylation, and cell morphology of Trichoderma reesei. We observed that high osmolarity conditions enhanced biomass production and strongly limited synthesis of cell wall glucans and chitin. Moreover, in these conditions the amount of secreted protein decreased nearly ten-fold and expression of cbh1 and cbh2 genes coding for cellobiohydrolase I and cellobiohydrolase II, the main secretory proteins in T. reesei, was inhibited resulting in a lack of the proteins in the cell and cultivation medium. The activity of DPM synthase, enzyme engaged in both N- and O-glycosylation pathways, was reduced two-fold, suggesting an overall inhibition of protein glycosylation. However, the two modes of glycosylation were affected divergently: O-glycosylation of secreted proteins decreased in the early stages of growth while N-glycosylation significantly increased in the stationary phase. PMID- 20943196 TI - Laccase activity and putative laccase genes in marine-derived basidiomycetes. AB - Studies of laccases from marine-derived fungi are limited. In the present work, putative laccase genes from three marine-derived basidiomycetes and their laccase activities were evaluated. High amounts of laccase were produced by the fungal strains Marasmiellus sp. CBMAI 1062 (971.2UL-1) and Peniophora sp. CBMAI 1063 (709.03UL-1) when grown for 21d at 28 degrees C in MA2ASW medium prepared with artificial seawater. Marine-derived basidiomycetes produced multiple distinct laccase sequences of about 200bp with 73-90% similarity to terrestrial basidiomycete laccases. Marasmiellus sp. CBMAI 1062 and Tinctoporellus sp. CBMAI 1061 showed the greatest laccase gene diversity with three and four distinct putative laccase sequences, respectively. This is the first report of laccase genes from marine-derived fungi, and our results revealed new putative laccases produced by three basidiomycetes. PMID- 20943197 TI - Growth responses to and accumulation of mercury by ectomycorrhizal fungi. AB - Heavy metals have been shown to negatively affect the growth of ectomycorrhizal fungi (ECMF). In addition, ECMF have been shown to accumulate heavy metals and to protect host trees from metal toxicity. However, specific literature on the interactions between ECMF and mercury (Hg) is scant. This paper describes the responses of ECMF to Hg in axenic culture conditions. Six ECMF from an area with no known history of direct Hg contamination were tested to determine their sensitivity to Hg. ECMF were incubated on solid medium amended with Hg (0-50MUM) as HgCl2 and the effect of Hg on radial growth was determined. The effect of preexposure cultivation on Hg sensitivity, the effect of Hg on biomass production, and the ability to accumulate Hg were determined for four of the ECMF. At micromolar concentrations, Hg significantly inhibited the radial growth rate of ECMF. This inhibitory effect was lessened in some ECMF when an established colony was exposed to Hg. Mercury lowered biomass production by some ECMF, and ECMF accumulate Hg from a solid growth substrate in direct relation to the amount of Hg added to the media. Possible implications for ECMF communities in Hg-impacted areas are discussed. PMID- 20943198 TI - Taxonomic study of stripe rust, Puccinia striiformis sensu lato, based on molecular and morphological evidence. AB - Phylogenetic analyses of ITS and beta-tubulin DNA sequences for 30 Puccinia striiformis specimens from wide geographic and host ranges revealed four strongly supported monophyletic lineages. Based on comparisons of morphological characteristics, and after consideration of previous classifications, the lineages were recognized as P. striiformis sensu stricto, Puccinia pseudostriiformis, Puccinia striiformoides and one new species, Puccinia gansensis. A new series (Puccinia Series Striiformis) was erected to accommodate this strongly supported monophyletic group of four species within Puccinia. Expanded descriptions, illustrations and a tabular identification key are provided. The morphological differences among species are subtle but host association and combinations of other characters can be used successfully for identification. Puccinia striiformis s.str. has the widest host range, within the tribe Triticeae (Aegilops, Elymus, Hordeum and Triticum) but it is less diverse than previously documented. The other three species are restricted to single genera in Poeae (P. pseudostriiformis on Poa; P. striiformoides on Dactylis) or Stipeae (P. gansensis on Achnatherum). Urediniospore size and surface echinulation, especially as seen by SEM, germ pore number, shape of uredinial paraphyses, and teliospore hilum width were the main features used to differentiate species. Relying solely on the symptom of linearly aligned uredinia on chlorotic stripes on leaves, from which the common name "stripe rust" was derived, is not recommended because sori of other leaf rust species may also form in a linear series. PMID- 20943199 TI - Retrospective analysis of vivax malaria patients presenting to tertiary referral centre of Uttarakhand. AB - INTRODUCTION: despite the high prevalence of Plasmodium vivax (P vivax) malaria, research into its complications has lagged disproportionately as compared to Plasmodium falciparum (P falciparum) malaria. MATERIAL AND METHODS: the present retrospective observational study was conducted on cases with P vivax mono infection presenting with severe malaria on the basis of one or more criteria as per the World Health Organization guidelines being used for severe falciparum malaria in children, as well as other manifestations been classified as complicated malaria, during an outbreak of malaria in a single tertiary referral hospital of north India. RESULTS: seventy-four patients of acute malaria presented during the outbreak, of which 50 cases with P vivax mono-infection were included for the study. Complicated malaria was diagnosed in 41/50 cases, with thrombocytopenia being the commonest manifestation. Other presentations of severe malaria in our patients were liver dysfunction (with or without jaundice) 31/50 cases, respiratory involvement 14/50 cases, renal impairment 11/50 cases, circulatory collapse (Shock) 8/50 cases, severe anaemia 3/50 cases and central nervous system (CNS) involvement 2/50 cases. CONCLUSION: the term "benign tertian malaria" no longer holds true for P vivax mono-infection. The authors wish to open a new front for researches on the possible genotypic abnormalities that the parasite or its carrier might have acquired over decades and has transformed into a species with the malignant potential of P falciparum. PMID- 20943200 TI - Interaction of mitoxantrone, as an anticancer drug, with chromatin proteins, core histones and H1, in solution. AB - In the present study, for the first time we have investigated the interaction of anticancer drug mitoxantrone with histone H1 and core histone proteins in solution using fluorescence, UV/Vis, CD spectroscopy and thermal denaturation techniques. The results showed that mitoxantrone reduced the absorbencies of H1 and core histone proteins at 210 nm (hypochromicity) and fluorescence emission intensity was decreased in a dose dependent. Binding of mitoxantrone changed secondary structures of the proteins as circular dichroism analysis confirmed it. Also, mitoxantrone increased the melting temperature of core histones at the final step of denaturation. The results suggest higher affinity of mitoxantrone to histone H1 compared to core histones providing histone proteins as a new target for mitoxantrone action at the chromatin level. PMID- 20943201 TI - Combination of peramivir and rimantadine demonstrate synergistic antiviral effects in sub-lethal influenza A (H3N2) virus mouse model. AB - Efficacy of combination of the intramuscularly administered neuraminidase (NA) inhibitor, peramivir, and the orally administered M2 ion channel blocker, rimantadine was evaluated in mouse influenza A/Victoria/3/75 (H3N2) model. Mice were challenged with a sub-lethal virus dose (0-40% mortality in placebo group) and changes in body weights were analyzed by three-dimensional effect analysis to assess mode of drug interactions. Compounds were administered in a 5-day treatment course starting 1h before viral inoculation. The peramivir and rimantadine doses ranged from 0.3-3 mg/kg/d and 5-30 mg/kg/d, respectively. The maximum mean weight loss of 5.19 g was observed in the vehicle-infected group on day 10. In the 1 and 3 mg/kg/d peramivir monotherapy groups, the weight losses were 4.3 and 3.55 g, respectively. In the rimantadine monotherapy group, the weight losses were 3.43, 2.1, and 1.64 g for the 5, 10, and 30 mg/kg/d groups, respectively. Combination of 1mg/kg/d peramivir with 5 and 10 mg/kg/d rimantadine produced weight losses of 1.69 and 0.69 (p<0.05 vs. vehicle and individual agent), respectively, whereas the combination of 3.0 mg/kg/d peramivir with 10 and 30 mg/kg/d rimantadine did not show any weight loss (p<0.05 vs. vehicle and individual agent). The three-dimensional analysis of the weight loss for the majority of the drug combinations of peramivir and rimantadine tested demonstrated synergistic antiviral effects. PMID- 20943202 TI - Lever pressing responses under a fixed-ratio schedule of mice with 6 hydroxydopamine-induced dopamine depletion in the nucleus accumbens. AB - In order to investigate the relationship between dopamine transmission in the nucleus accumbens and operant behavior in mice, mice with 6-hydroxydopamine (6 OHDA)-induced dopamine depletion in the nucleus accumbens were tested for their performance in lever pressing tasks under FR schedules with 8 ratios from FR5 to FR120. The mice were given one 20-mg food pellet per completed FR schedule in FR5, FR10, and FR20; they were given 2 pellets in FR40, and one more cumulatively in the rest of the schedules. Before the 6-OHDA injection surgery, all mice were trained to press a lever under all FR schedules. Then, 6-OHDA or ascorbate was injected into the nucleus accumbens. Postoperatively, the mice were tested under each FR schedule, with 3 sessions per schedule. 6-OHDA-treated mice exhibited an increase in lever pressing latency, i.e., the time interval between the last presentation of the reward and the next lever press, and a decrease in inter response intervals, i.e., the time interval between 2 lever presses excluding lever pressing latency, irrespective of the FR ratios. Furthermore, in these 6 OHDA-treated mice, the number of lever presses during the first 300s of the session decreased under FR schedules with low ratios (5, 10, and 20). Open field activity, food motivation, and the amount of food consumed were not affected by dopamine depletion in the nucleus accumbens. These results suggest that the dopamine system in the nucleus accumbens had an important role in the control of lever pressing latency and inter-response intervals under FR reinforcement schedules. PMID- 20943203 TI - Estrogen regulation of human with-no-lysine (K) kinase-4 gene expression involves AP-1 transcription factor. AB - With-no-lysine (K) kinase-4 (WNK4) is a serine/threonine protein kinase and plays a crucial role in the regulation of blood pressure and electrolyte homeostasis. Whether or not estrogen, an important regulator of physiologic functions, modulates human WNK4 (hWNK4) gene expression is unknown. In the current study, real-time PCR assay showed that 17beta-estradiol (E(2)) with estrogen receptor alpha (ERalpha) suppressed the level of hWNK4 mRNA in cultured human embryo kidney 293 cells (HEK293). Luciferase activity analysis of the truncated hWNK4 promoters indicated that a regulatory region from -216 to -202 is essential for the basal transcriptional activity and response to E(2)/ERalpha. Using an electrophoresis mobility shift assay and a chromatin immunoprecipitation assay, we identified an activator protein-1 (AP-1) element at position -215/-205, to which AP-1 binding was enhanced by E(2)/ERalpha. Accordingly, AP-1 protein was increased by E(2)/ERalpha using Western blot analysis. Moreover, re-chromatin immunoprecipitation and co-immunoprecipitation assays showed a direct interaction between ERalpha and AP-1 in HEK293 cells. In summary, these data document that E(2)/ERalpha regulates hWNK4 expression partly through AP-1 binding to the hWNK4 promoter. PMID- 20943204 TI - miR-29a levels are elevated in the db/db mice liver and its overexpression leads to attenuation of insulin action on PEPCK gene expression in HepG2 cells. AB - MicroRNAs comprise a class of small (~22 nucleotide) non-coding RNA species and they bind to their complementary sequence on the 3'UTR of target genes and cause translational repression. In the present study, we report that miR-29a levels are significantly elevated in the diabetic db/db mice liver. Further, we report the effects of such elevation on insulin action in HepG2 cells. Overexpression of miR 29a narrowed down insulin mediated Akt phosphorylation without altering the total Akt levels presumably due to another upstream mediator being directly targeted by miR-29a. This hunt led us to the discovery that the p85alpha subunit of PI3K (phosphoionositide-3-kinase), the upstream molecule in the insulin signaling cascade harbors the miR-29a binding site on its 3'UTR and a marked inhibition of PI3Kp85alpha was observed by this microRNA. This was consequently accompanied by attenuation of insulin inhibition of PEPCK gene expression. All these events could be significantly prevented in the presence of the miR-29a inhibitor. Our results, for the first time, show the effect of miR-29a in counteracting insulin action on PEPCK gene expression by primarily targeting PI3K and abrogating downstream insulin signaling in HepG2 cells. PMID- 20943205 TI - Andrographolide attenuates tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes. AB - Andrographolide (AG), the primary bioactive component of Andrographils paniculate Nees, has showed an anti-diabetic effect. However, the molecular mechanism has not been clarified. In this study, we demonstrated that AG increased glucose uptake in 3T3-L1 cells in a time- and dosedependent manner. The activation of insulin signaling by AG was initiated from phosphotyrosine of IRS-1 and further passed on through phosphatidylinositol 3-kinase (PI3K) and the downstream signaling cascades. Moreover importantly, pretreatment cells with AG suppressed the TNF-alpha induced activation of NF-kappaB signaling pathway and its downstream inflammatory factors expression, therefore ameliorating insulin resistance. In conclusion, AG can improve insulin sensitivity through inhibition of NF-kappaB pathway. These findings are helpful in understanding the anti diabetic properties of AG and can be of interest for the therapeutic application of AG in glucose controlling. PMID- 20943206 TI - Age affects reciprocal cellular interactions in neuromuscular synapses following peripheral nerve injury. AB - Studies of the influence of age on regeneration and reinnervation in the peripheral nervous system (PNS) and neuromuscular junction (NMJ) are reviewed, with a particular focus on aged and denervated skeletal muscles. The morphological and functional features of incomplete regeneration and reinnervation are compared between adult and aged animals. In addition, some possible mechanisms of the age-related defects will be discussed. Increased fragmentation or damage in individual components of the NMJ (terminal Schwann cells (TSCs), axon terminals and acetylcholine receptor sites occurs during muscle reinnervation following PNS injury in the aged animals. The capacity to produce ultraterminal sprouting or multiple innervation secondary to PNS injury is maintained, but not the capacity to eliminate such anomalous axonal profiles. The frequency and accuracy of reoccupation of the synaptic sites by TSCs and axon terminals are impaired. Thus, despite the capability of extending neural processes, the rate at which regenerating nerve fibers grow, mature and precisely appose the postsynaptic muscle fiber is impaired, resulting in the failure of re establishment of the normal single motor innervation in the NMJ. A complex set of cellular interactions in the NMJ are known to participate in the neurotrophism and neurotrophism to support growth of the regenerating and sprouting axons and their pathfinding to direct the target muscle fiber. Besides the capability of alpha-motoneurons, signaling originating from the TSCs and muscle may be impaired during aging. PMID- 20943207 TI - The current status of invasive pneumococcal disease in Poland. AB - The objectives of this study were to assess the incidence of invasive pneumococcal disease (IPD) in Poland (2006-2009), where mass vaccination had not been implemented, and to determine the serotype distribution and antimicrobial susceptibility of Streptococcus pneumoniae isolates. The IPD incidence rates were highest among children under 2 years of age (3.39/100,000 in 2009) and children 2 5 years old (2.44/100,000). The most common serotypes were 14, 3, 1, 4, 19F, 23F, 6B, and 12F (61.7% of all isolates). In children aged less than 5 years, isolates of serotypes 14, 6B, and 19F were most prevalent (52.7% of the IPD cases). The PCV7, PCV10, and PCV13 covered 43.3%, 54.8%, and 68.8% of all IPD cases, and 68.7%, 76.3%, and 86.3% of cases involving children under 5 years of age. Penicillin resistance was found in 21.3% of the isolates responsible for meningitis and in 1.2% of isolates responsible for other invasive infections. Introduction of antipneumococcal conjugated vaccines into the national immunisation programme would likely lead to a significant reduction of IPD associated morbidity among Polish children in particular, as well as in the population as a whole, especially in cases involving pneumococci with a decreased susceptibility to antibiotics. PMID- 20943208 TI - In vivo electroporation enhances the potency of poly-lactide co-glycolide (PLG) plasmid DNA immunization. AB - Immunization with plasmid DNA that has been encapsulated in poly lactide-co glycolide (PLG) microparticles targets the plasmid DNA to antigen presenting cells and elicits immune responses to the encoded antigen(s). Application of a series of electrical pulses (EPT) immediately following unformulated DNA injection enhances expression of the encoded antigen and increases immune responses. The combination of using EPT before or after PLG-encapsulated plasmid DNA immunization was tested to determine if enhanced immune responses would be generated. The results show that the combination lead to both enhanced expression of antigen and more robust T cell responses, even if EPT was applied prior to immunization. The data also demonstrate that recruitment of phagocytes to the injection site was markedly enhanced by EPT, and this resulted in an increase of the antigen expression levels in these cells. Co-administration of microparticles and EPT also effected localized necrosis of muscle fibers, caused persistent Th-1 modulated cytokine production, and lead to the release of two endogenous adjuvants, uric acid and HMGB1. In all, we describe that increased immunogenicity observed with the combination of PLG-encapsulated plasmid DNA microparticle with EPT was caused by an increase in the recruitment of antigen presenting cells which mediated a more robust T cell response than observed with immunization alone. PMID- 20943209 TI - Comparison of the safety and immunogenicity of an investigational and a licensed quadrivalent meningococcal conjugate vaccine in children 2-10 years of age. AB - BACKGROUND: Routine administration of quadrivalent meningococcal conjugate vaccine to adolescents and certain high risk groups is recommended in the United States and Canada. We compared the immunogenicity and safety of an investigational quadrivalent meningococcal vaccine conjugated to CRM-197 (MenACWY CRM) with a licensed quadrivalent vaccine conjugated to diphtheria toxoid (MCV4) in children aged 2-10 years. METHODS: Eligible 2-5-year-olds were randomized 1:2:2 to receive either 2 doses of MenACWY-CRM, or 1 dose of MenACWY-CRM or MCV4; 6-10-year-olds were randomized 1:1 to receive a single dose of MenACWY-CRM or MCV4. The primary immunogenicity assessment was seroresponse separately for the two age cohorts 28 days following a single dose of MenACWY-CRM or MCV4. Noninferiority and superiority criteria were predefined. Solicited injection-site and systemic reactions were collected for the 7 days postvaccination. RESULTS: A total of 2907 children were randomized to receive study vaccine. MenACWY-CRM met statistical superiority criteria vs. MCV4 for groups W and Y and was noninferior for group C in both age strata. For group A, noninferiority criteria were not met; the group A seroresponse rates for MenACWY-CRM and MCV4, respectively were 72% (95% confidence interval 68-75%) and 77% (73-80%) in 2-5-year-olds and 77% (73-80%) and 83% (79-86%) in 6-10-year-olds. When the two age strata were combined (2-10-year-old children), MenACWY-CRM was noninferior to MCV4 for all four groups, and statistically superior for groups C, W, and Y. Safety parameters were similar across age cohorts and vaccines groups. CONCLUSIONS: MenACWY-CRM and MCV4 were immunogenic and well tolerated in children aged 2-10 years. Seroresponse to MenACWY-CRM was statistically noninferior to MCV4 for all groups, and statistically superior for groups C, W, and Y. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00616421. PMID- 20943210 TI - Effects of gender on serum biomarkers of systemic inflammation coincident to experimentally-induced periapical lesions. AB - OBJECTIVE: The literature suggests that females have less adverse effects to infection than males, due to the protective effects of oestrogen. The purpose of our study is to compare the systemic effects of induced periapical lesions between groups of animals with various serum concentrations of oestrogen. METHODS: To induce periapical inflammation, two molar tooth pulps were exposed in ovariectomized (OVX) and normal female (F) and castrated (Cast-M) and normal male (M) Sprague-Dawley rats (Experimental group, E). Sham-operated control animals from each group were also studied (Control group, C). Twenty-eight days later, serum and maxillas were collected. Serum 17beta-oestradiol, testosterone, MMP-9, IL-18, IL-6, TNF-alpha, and IL-1beta concentrations were measured by ELISA. Maxillas were cleaned of residual tissue and digital radiographs were made to verify the presence of periapical lesions. Data were compared by factorial ANOVA, post hoc Tukey, and Pearson correlation tests. Groups were considered to be significantly different when p<0.05. RESULTS: The serum concentration of IL-18, TNF-alpha, IL-1-beta, IL-6 and MMP-9 was greatest in OVX-E animals, compared to all other groups (p<0.001). F-E rats had significantly higher serum concentrations of these cytokines, compared to F-C. The fold difference in serum concentration of the biomarkers (between E and C groups) was significantly greater in females than males, even though males had higher baseline concentrations of all these biomarkers. CONCLUSION: When females are oestrogen deficient, their systemic response to periapical lesions is significantly greater than males, suggesting that oestrogen is essential in protecting females from the effects of this type of inflammation. PMID- 20943211 TI - Effects of ovariectomy on turnover of alveolar bone in the healed extraction socket in rat edentulous mandible. AB - OBJECTIVE: The number of patients with postmenopausal osteoporosis receiving dental implants because of edentulism is increasing. Since osseointegration around implants requires formation and maintenance of new bone, knowledge of how ovariectomy (OVX) affects turnover of mandibular and maxillary bone is required. In the present study, we investigated the effects of OVX on turnover of alveolar bone in the healed extraction socket of the rat left mandibular incisor. METHODS: The molars and the incisor on left side in 6-month-old Sprague-Dawley female rats (n=38) were extracted and left to heal for 4 months. Animals were then ovariectomized and killed at the time of OVX (baseline) (n=4), 6 weeks (n=10), 6 months (n=12) and 9 months (n=12) post-OVX. Changes in bone mass and bone turnover were assessed using static and dynamic histomorphometric parameters. RESULTS: Bone turnover was increased by ovariectomy (OVX) as reflected by increased static parameters of bone formation and resorption. The changes in dynamic parameters were not statistically significant. Cancellous bone volume/total volume (%) in the post-OVX group decreased more than that in the control group. CONCLUSIONS: Our results suggest that OVX increases the turnover of alveolar bone in the healed extraction socket of rat mandibular incisor, resulting in a decrease of cancellous bone volume with time. PMID- 20943212 TI - Low concentration alcohol intake may inhibit spontaneous alveolar bone loss in Wistar rats. AB - OBJECTIVE: The aim of the present study was to evaluate the influence of ethanol in low concentration (5%) in ligature-induced alveolar bone loss in Wistar rats. MATERIAL AND METHODS: Thirty rats were randomly assigned to test and control groups (n=15). Test group received a liquid diet containing ethanol 5% (vol./vol.) and standard rat chow. Control group received only tap water as the liquid diet and the same rat chow. In both groups, diet was delivered ad libitum. Alveolar bone loss was induced prior to the beginning of the study by means of ligatures placed around the upper second molars. The contra-lateral tooth remained as intra-group control. At the end of the nine weeks, the animals were killed and morphometric analysis of alveolar bone loss was performed by a blinded and calibrated examiner. Intra-group comparisons were performed by paired sample T-test and inter-group differences were compared by independent sample T-test (alpha=.05). RESULTS: Animals that drank ethanol in low concentration systematically presented less alveolar bone loss than the control group, regardless of the presence of ligature. Test group showed less alveolar bone loss (p=0.04) in unligated teeth when compared to control group (0.32 +/- 0.07 and 0.37 +/- 0.07 mm, respectively). However, no significant difference (p=0.14) was observed between Test and Control groups (0.78 +/- 0.14 and 0.84 +/- 0.18 mm, respectively) in ligated teeth. CONCLUSION: The results of this study lead to the conclusion that low concentration alcohol intake did not affect the alveolar bone loss in ligature induced periodontal breakdown. PMID- 20943213 TI - Total synthesis of a protected form of sphingofungin E using the [3,3] sigmatropic rearrangement of an allylic thiocyanate as the key reaction. AB - An approach to the stereocontrolled synthesis of the protected form of sphingofungin E (32) starting from the known protected d-glucose derivative 3 is described herein. For the construction of a tetrasubstituted carbon atom that is substituted with nitrogen, the [3,3]-sigmatropic rearrangement of thiocyanate 8 was employed. Subsequent functional group interconversions afforded the highly functionalized fragment, allylic bromide 26. Its coupling reaction with the known C(12) hydrophobic segment 2, followed by further manipulation, completed the total synthesis. PMID- 20943214 TI - Preparation of 4'-benzenesulfonyl-3'-deoxythymidine and its reaction with organoaluminum and organosilicon reagents. AB - The 4'-benzenesulfonyl derivative of 3'-deoxythymidine was prepared from 3' deoxythymidine-5'-aldehyde. The 4'-benzenesulfonyl leaving group undergoes a nucleophilic substitution with organoaluminum and organosilicon reagents to furnish a variety of 4'-substituted (Me, Et, i-Bu, trimethylsilylethynyl, CH(2)CH=CH(2), CN, N(3)) analogues. PMID- 20943215 TI - An efficient conversion of N-acetyl-D-glucosamine to N-acetyl-D-galactosamine and derivatives. AB - 2-Acetamido-2-deoxy-D-galactose (d-GalNAc) is an important monosaccharide widely distributed in nature. However, unlike its 4-epimer, the 2-acetamido-2-deoxy-D glucose (D-GlcNAc), D-GalNAc is very expensive to obtain from commercial sources. Herein we report an efficient transformation that allows for the conversion of D GlcNAc to a D-GalNAc derivative 7 in three steps and in 58.4-75% overall yields. The process was carried out on a greater than 20-g scale without the need of chromatography. The versatility of compound 7 was demonstrated by the synthesis of several useful monosaccharides and thiodisaccharides containing a D-GalNAc residue. PMID- 20943216 TI - Direct conversion of xylan into alkyl pentosides. AB - Xylan has been used as a raw material in the synthesis of butyl, octyl and decyl glycosides. Mixtures of D-xylose-, L-arabinose- and D-glucose-based surfactants were obtained under smooth conditions with high yields in a one-pot process. The surface activities of octyl and decyl glycosides thus obtained have been studied and compared with that of pure alkyl D-xylosides. The results have confirmed that the new synthetic approach described in this paper is a potentially economical and efficient method for the preparation of environmentally friendly surfactants. PMID- 20943217 TI - Synthesis and delivery activity of new cationic cholesteryl glucosides. AB - Cholesterol amphiphiles containing positively charged groups (pyridinium, N methylimidazolium, N-methylmorpholinium, and N-methylpiperidinium) linked via beta-glucosyl spacer were prepared by alkylation of the corresponding bases with 6-O-mesyl-beta-D-cholesteryl glucopyranoside. IC(50) values were in the range 20 35MUM for the series of compounds and liposomal formulations with DOPE (1:1) were significantly less toxic. The liposomal formulations provided the accumulation of FITC-labeled oligonucleotide in cells, and the efficiency of this process was comparable to that of Lipofectamine 2000. Cationic liposomes were able to deliver siRNA into the cells, and the liposomal formulation 7d/DOPE provided the most pronounced down-regulation of EGFP expression both in the presence and in the absence of serum (up to 30%). PMID- 20943218 TI - Simulations of dynamics of actin filaments by remodeling them in shear flows. AB - A mechanochemical relationship between intracellular flow fields of actin and remodeling of actin filaments is important to the realization of cell motility. In this study, to investigate this mechanochemical relationship, we present a mathematical model describing motions of actin filament and remodeling of the filaments in shear flows. We perform simulations of the dynamics of actin filaments remodeled by polymerization, depolymerization, and severing, and investigate contributions of these remodeling processes to effective shear viscosities of the system. PMID- 20943219 TI - Elevated manganese and cognitive performance in school-aged children and their mothers. AB - BACKGROUND: Growing evidence suggests that excess manganese (Mn) in children is associated with neurobehavioral impairments. In Brazil, elevated hair Mn concentrations were reported in children living near a ferro-manganese alloy plant. OBJECTIVES: We investigated these children's and caregivers' cognitive function in relation to bioindicators of Mn exposure. METHODS: In this cross sectional study, the WISC-III was administered to 83 children aged between 6 and 12 years; the Raven Progressive Matrix was administered to the primary caregivers (94% mothers), who likewise responded to a questionnaire on socio demographics and birth history. Mn in hair (MnH) and blood (MnB) and blood lead (PbB) were measured by graphite furnace atomic absorption spectrometry (GFAAS). RESULTS: Children's mean MnB and MnH were 8.2 MUg/L (2.7-23.4) and 5.83 MUg/g (0.1-86.68), respectively. Mean maternal MnH was 3.50 MUg/g (0.10-77.45) and correlated to children's MnH (rho=0.294, p=0.010). Children's MnH was negatively related to Full-Scale Intelligence Quotient (IQ) and Verbal IQ; beta coefficients for MnH were -5.78 (95% CI -10.71 to -0.21) and -6.72 (-11.81 to -0.63), adjusted for maternal education and nutritional status. Maternal MnH was negatively associated with performance on the Raven's (beta=-2.69, 95% CI -5.43 to 0.05), adjusted for education years, family income and age. CONCLUSIONS: These findings confirm that high MnH in children is associated with poorer cognitive performance, especially in the verbal domain. Primary caregiver's IQ is likewise associated to Mn exposure, suggesting that, in this situation, children's cognition may be affected directly and indirectly by Mn exposure. PMID- 20943220 TI - Bone transport and compression-distraction in the treatment of bone loss of the lower limbs. AB - A clinical series of 17 adult patients operated due to significant by bone loss of the long bones of the lower extremity (3 femurs and 11 tibias), is presented. Their management consisted of 6 bone transports (6 tibias) and 11 compression distraction procedures (3 femurs and 8 tibiae) using monolateral external fixators. Bone loss ranged from 3.9 cm to 14.7 cm. Mean healing time was 301 days with a mean healing index of 45.6 days for cm of lengthening achieved. The clinical and radiological results were excellent in 9, good in 6 and fair in 2 patients according to the utilised criteria of assessment. Consolidation was achieved in all but one patient who developed an aseptic stiff non-union. Two patients developed residual limb-length discrepancy less than 1.5 cm, three tibias ended up with less than 5 degrees of valgus deviation. In two cases the half-pins were re-inserted due to early loosening. In two cases reoperation was needed for late bending of the callus after fixator removal. Three cases of bone transport and 1 case of compression distraction needed bone grafting at the docking site. Bone transport and compression-distraction are effective methods for treating bone loss in the lower extremity. It is suggested that the compression-distraction technique is preferable, since this is associated with a lower incidence of complications than bone transport procedures. The deciding factor, however, is the actual extent of the bone loss. PMID- 20943221 TI - A bilateral C7 pedicle fracture following a low energy injury. PMID- 20943222 TI - Donor site reconstruction in iliac crest tricortical bone graft: surgical technique. AB - BACKGROUND AND PURPOSE: Autogenous bone grafts from the iliac crest are frequently harvested for autologous bone transplantation, because this is still the gold standard in the treatment of many bone defects. However, significant donor site morbidity must be considered. We have developed a simple method to treat the bone defect in the donor site in order to reduce some of the morbidity. In this method, the bone defect size and shape determines its application. METHOD: After the conventional method of tricortical bone harvesting from the iliac crest, bone defect is repaired by means of a transversal fence of appropriate thin tricortical chips obtained from the posterior lateral wall of the bone defect itself. The mechanical stability of this fence results from impactation of the ends of the tricortical chips into both lateral cancellous bone walls of the repaired bone defect. Thus, no hardware is required, and both the bone defect and ilium contour are restored. RESULTS: This simple method allows ilium bone defect healing and bone contour recovery after graft harvest, by using the same gold standard graft. Although not much time is necessary to reconstruct the donor site, the bone defect size and shape determine its application. INTERPRETATION: This method may be a recommendable option for bone defect reconstruction after iliac crest tricortical bone graft harvest as the primary procedure. The advantages of this technique are bone defect healing and bone contour restoration with prevention of a visible deformity over the groin, with no foreign material insertion, thus avoiding additional cost. PMID- 20943223 TI - The effects of clinical experience on nurses' critical event risk assessment judgements in paper based and high fidelity simulated conditions: a comparative judgement analysis. AB - BACKGROUND: Paper based simulated patients are widely used to analyse nurses' clinical judgements. However, developments in the physical simulation of clinical environments offer exciting, but relatively underexploited, opportunities for exploring nurses' judgements. Critical event risk assessment is an element of acute care practice which lends itself well to simulation and in which more clinical experience is often assumed to lead to better quality judgements. OBJECTIVES: To model nurses' judgements of critical event risk using physical and paper simulation and to examine whether improving fidelity via physical clinical simulation impacts on the apparent benefits of clinical experience on nurses' judgement performance. DESIGN: A comparative clinical judgement analysis. SETTING: A university in Northern England. METHODS: Sixty-three nursing students and 34 experienced nurses made dichotomous risk assessment judgements ("at risk" or "not at risk") in response to 25 paper and physical simulated scenarios. These were randomly generated from a dataset of real patient case records. Clinical outcomes (the judgement criteria) for a 'correct' judgement were derived from the same case records. Logistic regression models were constructed to derive statistics for each nurse representing various measures of judgement performance: achievement (r(a)), consistency (R(s)) and clinical information use (G). These statistics were known as Lens Model statistics (from the psychological theory of Brunswik's Lens Model of judgement). Performance measures for novice and experienced nurses were compared. RESULTS: No significant differences in judgemental achievement (r(a)) between experienced nurses and students were observed in either paper or high fidelity clinical simulations. Similarly, there were no significant differences in the nurses' abilities to correctly match the ways they synthesised clinical information with the optimum synthesis required by the task (policy matching) (G). When faced with "paper patients" experienced nurses exercised more cognitive control/consistency (R(s)) than students (P=0.04). However, this heightened control in experienced nurses was absent when those same nurses made judgements in the higher fidelity clinical simulation environment. CONCLUSION: Clinical experience made no difference to nurses' judgement achievement (accuracy) in either the lower fidelity paper scenarios or the higher fidelity setting of the clinical simulation unit. The significant impact of clinical experience on judgement consistency was negated by the increases in fidelity offered through clinical simulation. PMID- 20943224 TI - Topical HDL administration reduces vein graft atherosclerosis in apo E deficient mice. AB - OBJECTIVE: Use of autologous vein grafts for surgical revascularisation is limited by vein graft failure. Topical high-density lipoprotein (HDL) administration on the adventitial side of vein grafts was evaluated as a new therapeutic modality to improve vein graft patency and function. METHODS: Caval veins of C57BL/6 apo E(-/-) mice were grafted to the right carotid arteries of recipient 3 month-old C57BL/6 TIE2-LacZ/apo E(-/-) mice. HDL (200 MUg/ml; 50 MUl) in 20% pluronic F-127 gel was applied on the adventitial side of vein grafts. RESULTS: Topical HDL application reduced intimal area by 55% (p < 0.001) at day 28 compared to control mice. Blood flow quantified by micro magnetic resonance imaging at day 28 was 2.8-fold (p < 0.0001) higher in grafts of topical HDL treated mice than in control mice. Topical HDL potently reduced intimal inflammation and resulted in enhanced endothelial regeneration as evidenced by a 1.9-fold (p < 0.05) increase in the number of CD31 positive endothelial cells. HDL potently enhanced migration and adhesion of endothelial colony-forming cells (ECFCs) in vitro, and these effects were dependent on signaling via scavenger receptor-BI, extracellular signal-regulated kinases, and NO, and on increased beta1 integrin expression. Correspondingly, the number of CD31 beta-galactosidase double positive cells, reflecting incorporated circulating progenitor cells, was 3.9-fold (p < 0.01) higher in grafts of HDL treated mice than in control grafts. CONCLUSIONS: Topical HDL administration on the adventitial side of vein grafts attenuates vein graft atherosclerosis via increased incorporation of circulating progenitor cells in the endothelium, enhanced endothelial regeneration, and reduced intimal inflammation. PMID- 20943225 TI - An efficient and reusable silica/dendrimer supported platinum catalyst for electron transfer reactions. AB - A series of Pt nanoparticles (NPs) smaller than 3 nm were successfully encapsulated in dendrimer/SBA-15 organic and inorganic hybrid composite. The obtained catalysts were characterized by XPS, XRD and TEM. The results of XPS and XRD indicate the existence of Pt NPs in the hybrid matrix. TEM images display the Pt NPs with narrow size distribution are monodispersed in SBA-15 channels. Catalytic property of the supported Pt catalysts was investigated in inorganic (ferricyanide to ferrocyanide by thiosulfate) and organic (p-nitrophenol to p aminophenol by sodium borohydride) electron transfer (redox) reactions. In both cases, the reduction reactions followed smoothly and the catalysts showed excellent catalytic activity. Moreover, the catalysts can be easily separated and reused several times preserving good catalytic performance. PMID- 20943226 TI - Silver nanoparticles stabilized by crosslinked poly(vinyl pyrrolidone) and its application for facilitated olefin transport. AB - Positively polarized silver nanoparticles by poly(vinyl pyrrolidone) (PVP) have been demonstrated for use as stable olefin carriers for facilitated olefin transport membranes. The formation and size of silver nanoparticles stabilized by PVP were monitored using X-ray diffraction (XRD) and transmission electron microscopy (TEM). Nanocomposite membranes consisting of polymer and silver nanoparticles stabilized by PVP exhibited the high separation performance for olefin/paraffin mixtures. X-ray photoelectron spectroscopy (XPS) showed that silver nanoparticles stabilized by PVP exhibited a high positive polarity, resulting in the reversible interaction between the surface of silver nanoparticles and olefin molecules. PMID- 20943227 TI - Constrained photophysics of an ESIPT probe within beta-cyclodextrin nanocavity and chaotrope-induced perturbation of the binding phenomenon: implication towards hydrophobic interaction mechanism between urea and the molecular probe. AB - The present work demonstrates the effect of beta-cyclodextrin (beta-CD) nanocaging on the photophysical properties of Excited-State Intramolecular Proton Transfer (ESIPT) probe 3,5,6-trichlorosalicylic acid (TCSA) through steady-state absorption, emission and time-resolved emission spectroscopy. The remarkable enhancement of tautomer (proton transferred form) emission of TCSA as a result of inclusion complex formation with beta-CD has been argued to be principally due to retardation of radiationless decay channels within the encapsulated state. A quantitative assessment of the emission intensity data on Benesi-Hildebrand equation reveals a 1:1 stoichiometry for TCSA:beta-CD complex. The steady-state anisotropy, REES, and time-resolved fluorescence decay measurements are consistent with other experimental findings. Additionally, chaotrope (urea) induced perturbation of the phenomenon of host-guest inclusion complex formation has been elucidated for a series of urea concentration. The present findings have been interpreted on the basis of the hydrophobic interaction mechanism of urea, rather than water 3-D structure rupture. The data unravel that the perturbation of solvation of the beta-CD receptor is not important in the presence of urea, while the hydrophobic interaction with free probe molecules could be instrumental behind the observed lowering of TCSA:beta-CD binding strength in the presence of urea. PMID- 20943228 TI - Highly viscous wormlike micellar phases formed from the mixed AOT/C14DMAO/H2O system. AB - The phase behavior and rheological properties of an anionic surfactant, bis(2 ethylhexyl) sulfosuccinate (AOT), mixed with a zwitterionic tetradecyldimethylamine oxide (C(14)DMAO) in aqueous solutions, were studied at different ratios, R=w(AOT)/(w(C(14)DMAO + w(AOT)). When R=1, the 6.0 wt% AOT solution is two-phase with dense vesicles as the lower phase. With an increase of C(14)DMAO fraction (decreasing R) at a total concentration of 6.0 wt%, the lower vesicle-phase (L(alphav)-phase) extends to generate a single L(alphav)-phase. Then the L(alphav)-phase turns into a viscoelastic wormlike micellar phase and finally rod-like or spherical C(14)DMAO micelles. The wormlike micellar solutions (from R=0.3 to 0.2) are highly viscoelastic, indicating the formation of rigid network structures. The rheological properties of the viscoelastic solutions exhibit a typical Maxwell characteristic at low and intermediate oscillatory frequencies. A pronounced temperature effect on the wormlike micellar structures can be observed by rheological studies. With an increase in temperature, the samples become less structured due to shortening of the micelles. After introducing certain additives, e.g., octanol and divalent metal ions, a transition from wormlike micellar phases to birefringent L(alphav)-phases was observed. PMID- 20943229 TI - Surface-dependent chemical equilibrium constants and capacitances for bare and 3 cyanopropyldimethylchlorosilane coated silica nanochannels. AB - We present a combined theoretical and experimental analysis of the solid-liquid interface of fused-silica nanofabricated channels with and without a hydrophilic 3-cyanopropyldimethylchlorosilane (cyanosilane) coating. We develop a model that relaxes the assumption that the surface parameters C(1), C(2), and pK(+) are constant and independent of surface composition. Our theoretical model consists of three parts: (i) a chemical equilibrium model of the bare or coated wall, (ii) a chemical equilibrium model of the buffered bulk electrolyte, and (iii) a self consistent Gouy-Chapman-Stern triple-layer model of the electrochemical double layer coupling these two equilibrium models. To validate our model, we used both pH-sensitive dye-based capillary filling experiments as well as electro-osmotic current-monitoring measurements. Using our model we predict the dependence of zeta potential, surface charge density, and capillary filling length ratio on ionic strength for different surface compositions, which can be difficult to achieve otherwise. PMID- 20943230 TI - In situ loading of palladium nanoparticles on mica and their catalytic applications. AB - Mica supported Pd nanocatalysts were prepared by a two-step approach, in which SnCl(2) was first grafted onto mica via its reaction with hydroxyl groups on mica, followed by the in situ reduction of Pd(2+) by Sn(2+) on the surface of mica. The as-prepared Pd-Sn/mica catalysts were characterized by different techniques including transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and ICP analysis. The loaded Pd particles existed in the form of Pd(0) confirmed by XPS analysis, and distributed uniformly on mica with average size about 2.6 nm, as confirmed by TEM examination. The activities of the resultant catalysts for Heck reactions of iodobenzene and its derivatives with olefins and selective hydrogenation of citral were investigated. It was demonstrated that the as-prepared catalysts exhibited very high efficiency for these reactions. PMID- 20943231 TI - The influence of salinity on surfactant miscibility in mixed dipalmitoylphosphatidylcholine-perfluorooctadecanoic acid monolayer films. AB - The miscibility, mechanical and morphological properties of mixed Langmuir and Langmuir-Blodgett monolayers prepared from the phospholipid 1,2-dipalmitoyl-sn glycero-3-phosphocholine and the perfluorinated fatty acid perfluorooctadecanoic acid have been studied as a function of film composition and subphase salinity. It was demonstrated here, for the first time, that the extent of surfactant miscibility in mixed phospholipid-perfluoroacid monolayers, and hence the resulting mechanical properties of the monolayer film, can be controlled by altering the concentration of sodium ions in the underlying subphase. Elevated Na(+) concentrations resulted in lower net attractive interactions between film components, likely through specific ion adsorption to the negatively-charged perfluoroacid, along with decreased film elasticities. These results differ significantly from conventional fatty-acid-carboxylate monolayer systems in which film cohesion is typically enhanced through adsorption of cations to surfactant headgroups. Atomic force microscope images of films deposited onto solid mica substrates revealed that the films deposited from pure water formed multimolecular aggregates of surfactant, which could be attributed to the highly cohesive nature of the films, but the use of salt in the subphase diminished aggregate formation and resulted in the production of homogeneous monolayer films. PMID- 20943232 TI - Phonological working memory impairments in children with specific language impairment: where does the problem lie? AB - PURPOSE: The purpose of this study was to determine which factors contribute to the lexical learning deficits of children with specific language impairment (SLI). METHOD: Participants included 40 7-8-year old participants, half of whom were diagnosed with SLI and half of whom had normal language skills. We tested hypotheses about the contributions to word learning of the initial encoding of phonological information and the link to long-term memory. Children took part in a computer-based fast-mapping task which manipulated word length and phonotactic probability to address the hypotheses. The task had a recognition and a production component. Data were analyzed using mixed ANOVAs with post-hoc testing. RESULTS: Results indicate that the main problem for children with SLI is with initial encoding, with implications for limited capacity. There was not strong evidence for specific deficits in the link to long-term memory. CONCLUSIONS: We were able to ascertain which aspects of lexical learning are most problematic for children with SLI in terms of fast-mapping. These findings may allow clinicians to focus intervention on known areas of weakness. Future directions include extending these findings to slow mapping scenarios. LEARNING OUTCOMES: The reader will understand how different components of phonological working memory contribute to the word learning problems of children with specific language impairment. PMID- 20943234 TI - Unclear clinical significance of findings on the use of referenced-EEG-guided pharmacotherapy. PMID- 20943235 TI - Variants and polymorphisms of DNA base excision repair genes and Alzheimer's disease. PMID- 20943236 TI - Mitochondrial dementia: a sporadic case of progressive cognitive and behavioral decline with hearing loss due to the rare m.3291T>C MELAS mutation. AB - We report the case of a 23-year-old Italian female harboring the rare m.3291T>C mutation in the MT-TL1 gene, that encodes the mitochondrial transfer RNA for leucine 1 (UUA/G). MT-TL1 mutations usually cause the MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome. Our patient, however, suffered from a non-syndromic mitochondrial disorder (MID), clinically characterized by progressive cognitive and behavioral decline, and hearing loss; brain MRI disclosed diffuse supratentorial and infratentorial atrophy; EKG revealed a Wolff-Parkinson-White syndrome; combined neuroleptic and antidepressant treatment markedly improved her behavioral symptoms. This case expands the clinical spectrum of non-syndromic MIDs, and further confirms that no obvious genotype-phenotype correlation exists for the m.3291T>C DNA mutation; indeed, this mutation has been previously reported in a Japanese child, who suffered from MELAS, and in an Italian child, who presented an apparently isolated mild myopathy. Moreover, it supports the hypothesis that at least in MT TL1-related MIDs, dementia may be caused by a progressive neurodegenerative process, rather than by injury accumulation due to stroke-like episodes. Finally, our case suggests that common neuroleptic and antidepressant drugs may be clinically efficacious in the management of psychiatric symptoms associated with MIDs. PMID- 20943237 TI - Time course of Hashimoto's encephalopathy revealed by MRI: report of two cases. AB - The MRI manifestations of Hashimoto's Encephalopathy (HE) can vary from normal appearance, ischemic lesions, demyelination, vasogenic edema to atrophy. The diverse MRI features of HE reported in the literature made it difficult to understand the pathological process and monitoring the prognosis. To investigate the dynamic changes of MRI manifestations in HE, two cases of HE were retrospectively analyzed with a series of longitudinal MRI data, including T2 weighted image (T2WI), T1 weighted image (T1WI), fluid attenuated inversion recovery image (FLAIR), diffusion weighted image and diffusion tensor image(DTI). Although similar acute ischemic manifestations were observed at the onset of HE in both cases, at follow-up, we observed different evolutions of HE on MRI between the two cases. It might partially account for the diversity of MRI findings (for example, a certain stage of HE). Clinical and MRI findings at follow-up also indicated that early treatment contributed to the recovery of lesions. PMID- 20943238 TI - The factors controlling the partitioning of polybrominated diphenyl ethers and polychlorinated biphenyls in the water-column of the Pearl River Estuary in South China. AB - In this study, the distribution and partition of polybrominateddiphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in water from the Pearl River Estuary were investigated. A seasonal dependence for dissolved and particle phase PCB and PBDE levels was observed. A high dissolved phase level occurred in the dry season. The positive correlation between POC content in the particles and phase distribution coefficients (K(p)) suggested that POC may play an important role in determining the partition of PBDEs and PCBs. A linear correlation between the observed log K(OC) and log K(OW) for PBDEs and PCBs was found with slopes less than one. The observed log K(OC) values were lower than the predicted log K(OC) values for PBDEs (except for BDE28). The log K(OC) values were higher than the predicted values for PCBs. A combination of sorption to colloids (10-98% for PBDEs and less than 25% for PCBs) and adsorption to BC was responsible for this observation. PMID- 20943239 TI - Cassava: an appraisal of its phytochemistry and its biotechnological prospects. AB - The present state of knowledge of the phytochemistry of small molecules isolated from the roots and leaves of cassava, Manihot esculenta Crantz (Euphorbiaceae), is reviewed. Cassava roots are an important source of dietary and industrial carbohydrates, mainly eaten as a source of starch, forming the staple food to over 500 million; additionally, the roots have value as a raw material for industrial starch production and for animal feed giving the crop high economic value, but it suffers markedly from post-harvest physiological deterioration (PPD). The hydroxycoumarins scopoletin and its glucoside scopolin as well as trace quantities of esculetin and its glucoside esculin are identified from cassava roots during PPD. The biotechnological prospects for cassava are also reviewed including a critical appraisal of transgenic approaches for crop improvement, together with its use for bioethanol production, due to cassava's efficient ability to fix carbon dioxide into carbohydrate. PMID- 20943240 TI - Public toilets down the drain? Why privies are a public health concern. AB - Whether you call it the loo, john, privy, lavatory or toilet, this facility is essential wherever humans gather or live: toilet provision has even been called the barometer of civilization. The modern development of public toilets dates from the late 19th century when sewer systems and water supplies provided hygienic means of dealing with waste, facilitated by public health legislation that also permitted local authorities to provide toilets in town centres. Yet the statutes in the United Kingdom, where the flushing toilet as we know it was invented, never went so far as to require provision of these facilities outside the home. Pressure on resources during the last 20 years has led to many public toilets being closed, for example, 40% of those in London, or to entry charges that reduce accessibility. At the same time an increasingly mobile population has made public toilets even more necessary. Recent public inquiries into public toilet provision in the UK have revealed the impact of the paucity of facilities on the elderly, women, families with young children, ill health that increases the need for toilet use, visitors and poor or homeless members of the community. There has been little attention in public health on the provision of public toilets. With street urination on the increase and less free access to toilets, it is time for public health to recognize a great need and to campaign to turn the tide on public toilet closures, with imaginative planning strategy and associated opportunities to encourage hand washing and other hygiene health promotion. PMID- 20943241 TI - [Farewell to the SERAM's director of publications (2006-2010): Impressions of the editor-in-chief of Radiologia]. PMID- 20943242 TI - [Severe dysautonomia revealing Wernicke's encephalopathy]. AB - INTRODUCTION: Wernicke's encephalopathy, a pathology caused by vitamin B1 (thiamin) deficiency, is often difficult to diagnose and can lead to severe cognitive sequels if left untreated. CASE REPORT: We report the case of a 42-year old HIV-positive women who, four days after recurrent episodes of vomiting, developed severe dysautonomia and symptoms suggestive of Wernicke's encephalopathy. Treatment with parenteral thiamine induced dramatic improvement within a few days. CONCLUSION: This case report highlights an unusual presentation of symptomatic thiamin deficiency associating severe dysautonomia with the classical manifestations of Wernicke's encephalopathy. As dysautonomia is frequently the earliest sign of beriberi, this case illustrates the continuum between these two diseases whose cause, symptomatic thiamin deficiency, is the same. It also draws attention to the multiple risk factors that may be associated, leading to symptomatic thiamin deficiency. This deficiency, while often overlooked, is frequent in HIV-infected patients. Finally, this case contributes to the discussion on the possible genetic polymorphism that may make a limited deficiency symptomatic. PMID- 20943243 TI - Boron-doped diamond anodic treatment of landfill leachate: evaluation of operating variables and formation of oxidation by-products. AB - Landfill leachate with a low BOD/COD ratio was electrochemically oxidized by means of a boron-doped diamond anode. In addition to organic matter removal, this study addressed the issue of formation of both chlorinated organic compounds and nitrate ions as a result of organic matter and ammonia and/or organic nitrogen electro-oxidation in the presence of chloride ions. A factorial design methodology was implemented to evaluate the statistically important operating variables: treatment time (1-4 h), pH (5-8), current intensity (6.3-8.4 A) and addition of chloride (2500-4500 mg L(-1)). The process was evaluated on COD, total nitrogen (TN) and colour removal, as well as on the formation of nitrate, nitrite and chlorinated organics. Of the four variables studied, treatment time and pH had a considerable influence on COD and colour removal. On the contrary, none of the variables had a significant effect on the elimination of TN for which an average removal of 61 mg L(-1) was obtained. The studied variables exhibited different effects on the four groups of organo-chlorinated compounds considered in this study, namely trihalomethanes (THMs), haloacetonitriles (HANs), haloketons (HKs) and 1,2-dichloroethane (DCA). Further analysis at more intense conditions, i.e. current intensity up to 18 A and reaction time up to 8 h revealed that high levels of decolourization (84%) could be achieved followed by low COD (51%) and ammonia (32%) removals. Apart from DCA, the concentration of chlorinated organics increased continuously with treatment time reaching values as high as 1.9 mg L(-1), 753 MUg L(-1) and 431 MUg L(-1) of THMs, HANs and HKs, respectively. PMID- 20943244 TI - Cost-effectiveness analysis of risk-reduction measures to reach water safety targets. AB - Identifying the most suitable risk-reduction measures in drinking water systems requires a thorough analysis of possible alternatives. In addition to the effects on the risk level, also the economic aspects of the risk-reduction alternatives are commonly considered important. Drinking water supplies are complex systems and to avoid sub-optimisation of risk-reduction measures, the entire system from source to tap needs to be considered. There is a lack of methods for quantification of water supply risk reduction in an economic context for entire drinking water systems. The aim of this paper is to present a novel approach for risk assessment in combination with economic analysis to evaluate risk-reduction measures based on a source-to-tap approach. The approach combines a probabilistic and dynamic fault tree method with cost-effectiveness analysis (CEA). The developed approach comprises the following main parts: (1) quantification of risk reduction of alternatives using a probabilistic fault tree model of the entire system; (2) combination of the modelling results with CEA; and (3) evaluation of the alternatives with respect to the risk reduction, the probability of not reaching water safety targets and the cost-effectiveness. The fault tree method and CEA enable comparison of risk-reduction measures in the same quantitative unit and consider costs and uncertainties. The approach provides a structured and thorough analysis of risk-reduction measures that facilitates transparency and long-term planning of drinking water systems in order to avoid sub-optimisation of available resources for risk reduction. PMID- 20943245 TI - The effects of engineered nanoparticles on survival, reproduction, and behaviour of freshwater snail, Physa acuta (Draparnaud, 1805). AB - Increasing uses of engineered nanoparticles (ENPs) in commercial products and industrial applications has eventually resulted to their releases into atmospheric, terrestrial, and aquatic environments. However, knowledge gaps in ENPs toxicity, fate, and behaviour currently limit our ability to quantify risk assessment of materials with nanoscale dimensions, and therefore, the extent of the resultant environmental impacts remains unknown. In the present study, we evaluated the effects of gamma-alumina, alpha-alumina, modified TiO(2) (M TiO(2)), and commercial TiO(2) (C-TiO(2)) ENPs on the survival, behaviour, and early life stages of the freshwater snail Physa acuta (Draparnaud). The toxicity evaluation was carried out after spiking commercial sand with ENPs concentrations of 0.005, 0.05, or 0.5 gk g(-1). Our findings suggest that increases of gamma alumina and alpha-alumina concentrations at sub-lethal level concentrations caused significant reduction in the embryo growth rate and embryo hatchability. In addition, these ENPs induced observable developmental deformities of the embryos. In addition, toxicity evaluations using acute 96-h and chronic 28-d tests showed exposure duration may be a significant factor in ENPs-induced toxicity. Therefore, long-term exposure of aquatic organisms to ENPs - potentially can alter certain ecological populations at different trophic levels and may compromise the entire aquatic ecological functionality. The percentage hatchlings in test chambers containing 0.5 gk g(-1) gamma-alumina and alpha alumina concentration was 50% less to those observed in the controls. Our results suggest the embryonic growth and hatchability tests are useful endpoints in chronic sediment toxicity tests for determining the toxic thresholds of ENPs in sediment environment. Although no snail mortalities were observed during the static 96-h test containing sediment spiked with different concentrations of M TiO(2), C-TiO(2), gamma-alumina and alpha-alumina - the antioxidant enzymatic assay results indicated a significant change in antioxidant levels which altered peroxidation at 0.05 or 0.5 gk g(-1)concentrations for both gamma-alumina and alpha-alumina. PMID- 20943246 TI - Evolution of bacterial community during bioremediation of PAHs in a coal tar contaminated soil. AB - The monitoring of a windrow treatment applied to soil contaminated by mostly 2-, 3- and 4-ring PAHs produced by coal tar distillation was performed by following the evolution of both PAH concentration and the bacterial community. Total and PAH-degrading bacterial community structures were followed by 16S rRNA PCR-DGGE in parallel with quantification by bacterial counts and 16 PAH measurements. Six months of biological treatment led to a strong decrease in 2-, 3- and 4-ring PAH concentrations (98, 97 and 82% respectively). This result was associated with the activity of bacterial PAH-degraders belonging mainly to the Gamma-proteobacteria, in particular, the Enterobacteria and Pseudomonas genera, which were detected over the course of the treatment. This group was considered to be a good bioindicator to determine the potential PAH biodegradation of contaminated soil. Conversely, other species, like the Beta-proteobacteria, were detected after 3months, when 2-, 3- and 4-ring PAHs were almost completely degraded. Thus, presence of the Beta-proteobacteria group could be considered a good candidate indicator to estimate the endpoint of biotreatment of this type of PAH contaminated soil. PMID- 20943247 TI - Ubiquitination and carbonylation of proteins in the clam Ruditapes decussatus, exposed to nonylphenol using redox proteomics. AB - Ubiquitination and carbonylation of proteins were investigated in the gill and digestive gland of Ruditapes decussatus exposed to NP (nonylphenol) (100 MUgL( 1)) using redox proteomics. After 21 d of exposure, clams were dissected and cytosolic proteins of both tissues separated by 2DE SDS-PAGE. Protein expression profiles were tissue-dependent and differently affected by NP exposure. Ubiquitination and carbonylation were also tissue-specific. NP exposure induced significantly more ubiquitinated proteins in gills than in digestive glands, compared to controls. Digestive gland showed a significant higher number of carbonylated proteins than gills after NP exposure. Protein ubiquitination and carbonylation are therefore independent processes. Results showed that NP exposure generated ROS in gill and digestive gland of R. decussatus that significantly altered the proteome. Results also highlighted the advantage of using redox proteomics in the assessment of protein ubiquitination and carbonylation, which may be markers of oxidative stress in R. decussatus. PMID- 20943248 TI - Some flame retardants and the antimicrobials triclosan and triclocarban enhance the androgenic activity in vitro. AB - Contaminants including flame retardants, antimicrobial agents and phthalates, occurring as residues in human tissues were associated with altered endocrine function. In our study we analysed the flame retardants tetrabromobisphenol A (TBBPA), hexabromocyclodecane (HBCD), penta-bromodiphenylether (BDE-100) and hexa BDE (BDE-155), the antimicrobial compounds triclosan (TCS) and triclocarban (TCC) and eight phthalates for their androgenic and antiandrogenic activity in vitro in the MDA-kb2 cell line. No or only weak androgenic activity was observed for all the tested compounds. TBBPA showed weak antiandrogenic activity, which was demonstrated for the first time. The flame retardants HBCD, BDE-100 and BDE-155 enhanced the dihydrotestosterone-dependent activation of androgen receptor responsive gene expression but exhibited little or no agonistic activity. The enhancement reached 150%, which was similar to the antimicrobials (TCS up to 180%, and TCC up to 130%). This enhancement of androgenic activity represents a novel mode of action of the endocrine activity of flame retardants. In contrast, most phthalates showed antiandrogenic activity. Butylbenzyl phthalate (BBP), dibutyl phthalate (DBP) and diethyl phthalate (DEP) showed strong antiandrogenicity, whereas the action of diethylhexyl phthalate (DEHP), dipentyl phthalate (DPP), dimethyl phthalate (DMP), and the DEHP metabolite monoethylhexyl phthalate (MEHP) was lower. Our in vitro study demonstrates for the first time a weak antiandrogenic activity of TBBPA, and a significant enhancement of the androgenic activity of HBCD, BDE-100 and BDE-155, which represents a novel mechanism of hormonal activity of flame retardants. PMID- 20943249 TI - Runoff effect on eutrophic lake water quality and heavy metal distribution in recent littoral sediment. AB - Multivariate statistical methods (hierarchical clustering analysis: HCA, and principal component analysis: PCA) were used to study the influence of runoff and other diffuse pollution sources on lake water chemistry of Hough Park lake in Central Missouri. In addition, heavy metal concentrations in lake littoral sediment were evaluated for enrichment and probable ecological risk. The abundance of macronutrients in the lake water column followed the order: Ca > Mg > TIC > K > Na > S > NO3 - N > Fe > NH3 - N > TP. Heavy metal concentrations in the lake water column were below acute and chronic level ecological guidelines. TN:TP ratios (range: 4.1-6.8) revealed nitrogen limitation of algal and other photosynthetic plant growth. The HCA showed two major clusters of similarity between the sampling points suggesting different pollution levels for the clusters. PCA 1, 2 and 3 reflected the influence of natural biochemical processes, atmospheric deposition and runoff respectively on lake water chemistry. The abundance of heavy metals and the normalizing element (Li) in littoral sediment (<63 MUm fraction) samples analyzed in decreasing order were: Mn > Zn > Cr > Ni > Li > Cu > Pb > Cd > Hg. The average concentration of Cr, Mn and Ni in littoral sediment fraction exceeded the respective lowest effects level (LEL) threshold limit. Metal bioavailability in sediment fraction was low since the most labile metal species contained between 0% and 11% of the total metal content. Using the risk assessment code (RAC) criteria, only Mn posed a medium risk to the lake system. PMID- 20943250 TI - Phytoremediation of ethylene glycol and its derivatives by the burhead plant (Echinodorus cordifolius (L.)): effect of molecular size. AB - Ethylene glycol (EG) is a group of dihydroxy alcohol that has been utilised in a variety of industrial and residential settings. EG contaminated wastewater has a high chemical oxygen demand (COD), which causes environmental problems. The aim of this research was to investigate the efficiency of the burhead plant (Echinodorus cordifolius (L.)) in the removal of mono-, di- and triethylene glycol (MEG, DEG and TEG), the first three members of the dihydroxy alcohol group, from synthetic wastewaters, to examine the toxic effect of EG on the plant and to identify differences among MEG, DEG, and TEG removal. It was found that the COD of synthetic wastewaters decreased to levels below the standard effluent (COD=120 mg L-1) on day 18, 21 and 33 for MEG, DEG and TEG, respectively. On day 18 of the experiment, the burhead plant removed approximately 2000, 1950 and 730 mg L-1 of MEG, DEG and TEG, respectively. The removal rate of MEG was faster than that of DEG and TEG, suggesting that the molecular size of the EG had affected its rate of removal. The concentrations of MEG, DEG, and TEG in plant tissue were measured to show that burhead can take up EG, and the major site of EG accumulation is the leaf. The molar of MEG that was taken up into the plant leaf was higher than that of DEG and TEG. This suggested that EG of smaller molecular sizes can be taken up more rapidly by the plant than EG of larger molecular sizes. EG concentrations in the leaf increased to a peak concentration and then slowly decreased. GC-MS analysis of DEG-treated plant tissue found MEG, 1,4 dioxan-2-one, neophytadiene, and 2-propenamide, that may be DEG-degradation products and/or compounds that are induced when plants are exposed to DEG. The result indicates that burhead can potentially be used for EG removal. PMID- 20943251 TI - Biodegradation and biotransformation of wastewater organics as precursors of disinfection byproducts in water. AB - Laboratory experiments were carried out to investigate wastewater organics as the precursors of disinfection byproducts (DBPs) in drinking water supply. The focus was on the change in wastewater DBP precursors during biological degradation under simulated natural conditions. The wastewater and its treated secondary effluent were characterized for DBP formation potential (DBPFP) and DBP speciation profile, including trihalomethanes, haloacetic acids, chloral hydrate, and nitrogen-containing DBPs. Several model organic compounds, including humic acid, tannic acid, glucose, starch, glycine, and bovine serum albumin (BSA), were used to represent the different types of organic pollutants in wastewater discharge. The results show that the DBPFP of wastewater decreased after biodegradation, but the remaining organic matter had a greater DBPFP yield with chlorine. Different model organics displayed different changes in DBPFP during biodegradation. The DBPFP remained largely unchanged for the glycine solution, decreased greatly for the tannic acid and BSA solutions, and increased nearly 3 fold for the glucose and starch solutions after 10d of biodegradation. Meanwhile, the DBPFP yield increased from 3 for glycine to 51MUg DBP mg(-1) C for its degradation residue, and from 1 for glucose and starch to 87 and 38MUg DBP mg(-1) C for their organic residues, respectively. Although biodegradation may effectively remove some DBP precursors, biotransformation during the process produces new DBP precursors in the form of soluble microbial products (SMPs). The experimental results reveal that SMPs may be an important source of wastewater derived DBP precursors in natural waters. PMID- 20943252 TI - Adsorption of As(III) on chitosan-Fe-crosslinked complex (Ch-Fe). AB - It was reported the adsorption of As(III) on the surface of the chitosan-Fe crosslinked complex. Theoretical correlation of the experimental equilibrium adsorption data for As(III)/Ch-Fe system is best explained by the non-linearized form Langmuir-Freundlich isotherm model. At optimum conditions, pH 9.0, the maximum adsorption capacity, calculated using the Langmuir-Freundlich isotherm model was 13.4 mg g-1. The adsorption kinetics of As(III) onto Ch-Fe are described by the pseudo-first-order kinetic equation. The results of the Mossbauer spectroscopy showed that there is no redox process on the surface of the adsorbent. PMID- 20943253 TI - Pentachlorophenol induced physiological-biochemical changes in Chlorella pyrenoidosa culture. AB - Present study investigated physiological and biochemical changes in a green alga culture (Chlorella pyrenoidosa) upon exposure to varied concentrations of pentachlorophenol (PCP) (0, 0.4 mgL(-1), 2.5 mgL(-1) and 10 mgL(-1)). The results revealed that with the increase of PCP concentration, a decrease of the algal biomass, levels of photosynthetic pigments (chlorophyll a, b and carotenoid), soluble protein and an increase of nitrate reductase (NR) activity were observed. This suggests that the PCP may serve as an uncoupler, causing low ATP level within the algal cells and led most of the NR molecules to be in the dephosphoration state (i.e. active from). Moreover, it shows that photosynthetic pigments especially carotenoid were more sensitive indicators to indicate PCP toxicity as compared to the other parameters. PMID- 20943254 TI - A multi-biomarker approach to assess the impact of farming systems on black tiger shrimp (Penaeus monodon). AB - This study examined the advantages of the use of biomarkers as an early warning system by applying it to different shrimp farming systems in Soctrang and Camau provinces, main shrimp producers in Mekong River Delta, Vietnam. Shrimp were collected at 15 different farms divided into four different farming systems: three farms were converted from originally rice paddies into intensive shrimp farming systems (IS1, IS2, IS3); three farms were rice-shrimp integrated farming systems (RS4, RS5, RS6); three farms were intensive farming systems (IS7, IS8, IS9); six farms were extensive shrimp farming systems (From ES1 to ES6). Lipid peroxidation (LPO) and total glutathione (GSH) were measured as well as catalase (CAT), glutathione peroxidase (GPX), glutathione S-transferase (GST) and acetylcholinesterase activities (ACHE). Organ specificity was observed between gills and hepatopancreas with generally higher activity of GST in gills (GSTG) whereas the contrary was observed for LPO level in gills (LPOG). Hierarchical clustering and principal component analysis clearly indicated that shrimp reared in extensive culture system formed a distinct group from those reared in intensive or rice-shrimp integrated systems. CAT in gills (CATG), GPX in gills (GPXG) and hepatopancreas (GPXHP) and ACHE in muscle (ACHEM) of shrimp collected in extensive farms showed a general higher level than those in intensively farmed shrimp. On the contrary, we observed clear high levels of GSTG and GST in hepatopancreas (GSTHP) and LPOG and hepatopancreas (LPOHP) of shrimp sampled in intensive and rice-shrimp integrated systems. Thus, we propose that LPO and CAT, GPX, GST and ACHE can be used as a set of biomarkers for the assessment of health condition and can discriminate between shrimp cultivated in different farming systems. These findings provide the usefulness of integrating a set of biomarkers to define the health status of shrimp in different shrimp culture systems. PMID- 20943255 TI - Geochemical investigations of metals release from submerged coal fly ash using extended elutriate tests. AB - A storage pond dike failure occurred at the Tennessee Valley Authority Kingston Fossil Plant that resulted in the release of over 3.8 million cubic meters (5 million cubic yards) of fly ash. Approximately half of this material deposited in the main channel of the Emory River, 3.5 km upstream of the confluence of the Emory and Clinch Rivers, Tennessee, USA. Remediation efforts to date have focused on targeted removal of material from the channel through hydraulic dredging, as well as mechanical excavation in some areas. The agitation of the submerged fly ash during hydraulic dredging introduces river water into the fly ash material, which could alter the redox state of metals present in the fly ash and thereby change their sorption and mobility properties. A series of extended elutriate tests were used to determine the concentration and speciation of metals released from fly ash. Results indicated that arsenic and selenium species released from the fly ash materials during elutriate preparation were redox stable over the course of 10d, with dissolved arsenic being present as arsenate, and dissolved selenium being present as selenite. Concentrations of certain metals, such as arsenic, selenium, vanadium, and barium, increased in the elutriate waters over the 10d study, whereas manganese concentrations decreased, likely due to oxidation and precipitation reactions. PMID- 20943256 TI - Selection of sustainable sanitation technologies for urban slums--a case of Bwaise III in Kampala, Uganda. AB - Provision of sanitation solutions in the world's urban slums is extremely challenging due to lack of money, space, access and sense of ownership. This paper presents a technology selection method that was used for the selection of appropriate sanitation solutions for urban slums. The method used in this paper takes into account sustainability criteria, including social acceptance, technological and physical applicability, economical and institutional aspects, and the need to protect and promote human health and the environment. The study was carried out in Bwaise III; a slum area in Kampala (Uganda). This was through administering of questionnaires and focus group discussions to obtain baseline data, developing a database to compare different sanitation options using technology selection criteria and then performing a multi-criteria analysis of the technology options. It was found that 15% of the population uses a public pit latrine; 75% uses a shared toilet; and 10% has private, non-shared sanitation facilities. Using the selection method, technologies such as Urine Diversion Dry Toilet (UDDT) and biogas latrines were identified to be potentially feasible sanitation solutions for Bwaise III. Sanitation challenges for further research are also presented. PMID- 20943257 TI - Expression of nestin, mesothelin and epithelial membrane antigen (EMA) in developing and adult human meninges and meningiomas. AB - The spatial and temporal pattern of appearance of nestin, epithelial membrane antigen (EMA) and mesothelin proteins was immunohistochemically determined in the cells of normal developing and adult human meninges and meningiomas. Human meninges developed as two mesenchymal condensations in the head region. The simple squamous epithelium on the surface of leptomeninges developed during mesenchymal to epithelial transformation. Nestin appeared for the first time in week 7, EMA in week 8, while mesothelin appeared in week 22 of development. In the late fetal period and after birth, nestin expression decreased, whereas expression of EMA and mesothelin increased. EMA appeared in all surface epithelial cells and nodules, while mesothelin was found only in some of them. In adult meninges, all three proteins were predominantly localized in the surface epithelium and meningeal nodules. In meningothelial meningiomas (WHO grade I), EMA was detected in all tumor cells except in the endothelial cells, mesothelin characterized nests of tumor cells, while nestin was found predominantly in the walls of blood vessels. The distribution pattern of those proteins in normal meningeal and tumor cells indicates that nestin might characterize immature cells, while EMA and mesothelin appeared in maturing epithelial cells. Neoplastic transformation of these specific cell lineages contributes to the cell population in meningiomas. PMID- 20943258 TI - Fertility considerations in the management of gynecologic malignancies. AB - GOALS: Gynecologic cancers represent a significant proportion of malignancies affecting women. Historically, cancer treatment focused primarily on eradicating disease, irrespective of the impact on fertility. The implementation of early detection protocols and advanced treatment regimens has resulted in improved prognosis for gynecologic cancer patients. With this improvement, more attention is now paid to quality-of-life issues. Fertility preservation (FP) has become an integral component in the selection and execution of gynecological cancer management. In this report we address gynecologic malignancies as they relate to future fertility potential. METHODS: We review reproductive principles such as ovarian reserve, uterine function, cervical competence, and early obstetrical management, as well as available FP methods. In addition, we discuss the potential damage that cancer and cancer treatments can impart on the female reproductive system. We offer general recommendations regarding baseline screening tests useful in assessing the feasibility of FP. Lastly, cancer specific FP methods are presented. RESULTS: Oocyte quantity and quality naturally decline with advancing age. In most patients, the slope of decline steepens significantly after the age of 35. Reliable ovarian reserve measures exist and should be utilized to assess and triage potential candidates for FP. Advancements in FP, particularly in oocyte cryopreservation (OC), have improved the success rates associated with the techniques available to cancer patients. Currently, where successfully available, OC appears to be the preferred method for single women diagnosed with a gynecologic malignancy as it affords reproductive autonomy, whereas embryo cryopreservation using a donor gamete remains an alternative. CONCLUSIONS: In gynecologic oncology, effective treatments to achieve cancer survival can compromise the ability to subsequently conceive and/or carry a child. Therefore, as the field of oncofertility continues to expand, a discussion regarding FP should be initiated when tailoring a cancer treatment protocol. PMID- 20943259 TI - Robotic-assisted resection of liver and diaphragm recurrent ovarian carcinoma: description of technique. AB - GOALS: To describe port placement and operative technique for resection of right hepatic and full-thickness diaphragm metastatic ovarian carcinoma in a patient with recurrent disease using the da Vinci(r) Surgical System. CASE: A 60-year-old female with recurrent platinum sensitive ovarian cancer presented with disease confined to the liver by PET-CT scan. The lesion measured 3.4 cm on the dome of the right hepatic lobe. After two attempts at intra-hepatic arterial chemo embolization the lesion remained stable. She subsequently agreed to robotic assisted resection of the right lobe liver mass after refusing laparotomy for 9 months. PROCEDURE: Pnuemoperitoneum was established in the left upper quadrant by directly inserting a 5-mm laparoscope. There were no midline adhesions. The 12-mm camera port was placed in the midclavicular line on the right 10 cm off the costal margin with the right and left operative arms 10 cm from the camera near the costal margin, and the third arm in the right flank. The robot was docked from the right shoulder. Resection was accomplished with a monopolar spatula in the right, fenestrated bipolar grasper in the left, and double fenestrated grasper in the third operative arm. Adhesions between diaphragm and liver were separated, the liver lesion was excised, the diaphragm lesion was resected full thickness, and diaphragm was closed with running prolene. Surgicel(r) was placed on the liver for hemostasis. Console time was 82 min and the patient discharged on day-5 after drainage of a cytology negative pleural effusion day-4. CONCLUSIONS: Robotic resection of liver and full-thickness diaphragm lesions is possible. The port placement used in this patient was efficient and without operative arm collisions. Patients with isolated upper-abdominal recurrence are candidates for robotic secondary cytoreduction. PMID- 20943260 TI - Primary immunodeficiencies may reveal potential infectious diseases associated with immune-targeting mAb treatments. AB - mAbs directed against immunologic molecules have emerged as a new class of drugs for treating patients with various immunologic conditions. However, mAb-based treatments may confer a predisposition to various infections. The authors argue that infections in individuals treated with mAbs directed against molecules of the immune system may display some similarities to those in patients with primary immunodeficiency of the corresponding mAb target. A comprehensive dissection of the tremendously diverse human primary immunodeficiencies and the careful description of their clinical features in different populations living in diverse environments thus represents an original, neglected, but promising approach to assessing the potential risk of infection associated with therapeutic mAbs, or with any therapeutic compound inhibiting a specific immunologic molecule. PMID- 20943261 TI - What artificial grammar learning reveals about the neurobiology of syntax. AB - In this paper we examine the neurobiological correlates of syntax, the processing of structured sequences, by comparing FMRI results on artificial and natural language syntax. We discuss these and similar findings in the context of formal language and computability theory. We used a simple right-linear unification grammar in an implicit artificial grammar learning paradigm in 32 healthy Dutch university students (natural language FMRI data were already acquired for these participants). We predicted that artificial syntax processing would engage the left inferior frontal region (BA 44/45) and that this activation would overlap with syntax-related variability observed in the natural language experiment. The main findings of this study show that the left inferior frontal region centered on BA 44/45 is active during artificial syntax processing of well-formed (grammatical) sequence independent of local subsequence familiarity. The same region is engaged to a greater extent when a syntactic violation is present and structural unification becomes difficult or impossible. The effects related to artificial syntax in the left inferior frontal region (BA 44/45) were essentially identical when we masked these with activity related to natural syntax in the same subjects. Finally, the medial temporal lobe was deactivated during this operation, consistent with the view that implicit processing does not rely on declarative memory mechanisms that engage the medial temporal lobe. In the context of recent FMRI findings, we raise the question whether Broca's region (or subregions) is specifically related to syntactic movement operations or the processing of hierarchically nested non-adjacent dependencies in the discussion section. We conclude that this is not the case. Instead, we argue that the left inferior frontal region is a generic on-line sequence processor that unifies information from various sources in an incremental and recursive manner, independent of whether there are any processing requirements related to syntactic movement or hierarchically nested structures. In addition, we argue that the Chomsky hierarchy is not directly relevant for neurobiological systems. PMID- 20943262 TI - "Turn that thing off!" parent and adolescent predictors of proactive media monitoring. AB - Though much research has focused on the positive outcomes of parents' monitoring of adolescents' media use, few studies have examined predictors of parents' media monitoring. Accordingly, the current study was designed to assess both parent and child predictors of proactive media monitoring during adolescence. Participants consisted of 478 families who completed parenting and media questionnaires at two time points, approximately one year apart. Results revealed that both maternal and paternal authoritative parenting predicted proactive media monitoring. Specifically, parental connection and regulation were associated with increased levels of prearming (also called active mediation); regulation was associated with higher levels of cocooning (also called restrictive mediation); and autonomy was associated with higher levels of deference. Additionally, adolescents' self regulation, media use, and age all predicted lower levels of parental cocooning. This research highlights the importance of examining both parent and child factors when determining what strategies parents use to monitor the media. PMID- 20943263 TI - Stroke, infective endocarditis and a blood filled cyst. PMID- 20943264 TI - Phosphorylation-dependent mineral-type specificity for apatite-binding peptide sequences. AB - Apatite-binding peptides discovered by phage display provide an alternative design method for creating functional biomaterials for bone and tooth tissue repair. A limitation of this approach is the absence of display peptide phosphorylation--a post-translational modification important to mineral-binding proteins. To refine the material specificity of a recently identified apatite binding peptide, and to determine critical design parameters (net charge, charge distribution, amino acid sequence and composition) controlling peptide affinity for mineral, we investigated the effects of phosphorylation and sequence scrambling on peptide adsorption to four different apatites (bone-like mineral, and three types of apatite containing initially 0, 5.6 and 10.5% carbonate). Phosphorylation of the VTKHLNQISQSY peptide (VTK peptide) led to a 10-fold increase in peptide adsorption (compared to nonphosphorylated peptide) to bone like mineral, and a 2-fold increase in adsorption to the carbonated apatite, but there was no effect of phosphorylation on peptide affinity to pure hydroxyapatite (without carbonate). Sequence scrambling of the nonphosphorylated VTK peptide enhanced its specificity for the bone-like mineral, but scrambled phosphorylated VTK peptide (pVTK) did not significantly alter mineral-binding suggesting that despite the importance of sequence order and/or charge distribution to mineral binding, the enhanced binding after phosphorylation exceeds any further enhancement by altered sequence order. Osteoblast culture mineralization was dose dependently inhibited by pVTK and to a significantly lesser extent by scrambled pVTK, while the nonphosphorylated and scrambled forms had no effect, indicating that inhibition of osteoblast mineralization is dependent on both peptide sequence and charge. Computational modeling of peptide-mineral interactions indicated a favorable change in binding energy upon phosphorylation that was unaffected by scrambling. In conclusion, phosphorylation of serine residues increases peptide specificity for bone-like mineral, whose adsorption is determined primarily by sequence composition and net charge as opposed to sequence order. However, sequence order in addition to net charge modulates the mineralization of osteoblast cultures. The ability of such peptides to inhibit mineralization has potential utility in the management of pathologic calcification. PMID- 20943265 TI - Bioengineering of living renal membranes consisting of hierarchical, bioactive supramolecular meshes and human tubular cells. AB - Maintenance of polarisation of epithelial cells and preservation of their specialized phenotype are great challenges for bioengineering of epithelial tissues. Mimicking the basement membrane and underlying extracellular matrix (ECM) with respect to its hierarchical fiber-like morphology and display of bioactive signals is prerequisite for optimal epithelial cell function in vitro. We report here on a bottom-up approach based on hydrogen-bonded supramolecular polymers and ECM-peptides to make an electro-spun, bioactive supramolecular mesh which can be applied as synthetic basement membrane. The supramolecular polymers used, self-assembled into nano-meter scale fibers, while at micro-meter scale fibers were formed by electro-spinning. We introduced bioactivity into these nano fibers by intercalation of different ECM-peptides designed for stable binding. Living kidney membranes were shown to be bioengineered through culture of primary human renal tubular epithelial cells on these bioactive meshes. Even after a long term culturing period of 19 days, we found that the cells on bioactive membranes formed tight monolayers, while cells on non-active membranes lost their monolayer integrity. Furthermore, the bioactive membranes helped to support and maintain renal epithelial phenotype and function. Thus, incorporation of ECM-peptides into electro-spun meshes via a hierarchical, supramolecular method is a promising approach to engineer bioactive synthetic membranes with an unprecedented structure. This approach may in future be applied to produce living bioactive membranes for a bio-artificial kidney. PMID- 20943266 TI - Entrapment and release of drugs by a strict "on-off" mechanism in pullulan microspheres with pendant thermosensitive groups. AB - Here, we report a new method to predict the appropriate size of drugs which can be entrapped in and released from a hydrogel with pendant thermosensitive units by a strict "on-off" mechanism. Moreover, the valve-type action of the thermosensitive arms has been investigated. Inverse size exclusion chromatography (ISEC) and environmental scanning electron microscopy (ESEM) have been used to characterize the extension and collapse of the pendant thermosensitive units, below and above the lower critical solution temperature (LCST) under physiological conditions, confirming the hypothesis postulated by the "arid" theoretical models. The functionalized pullulan (Pul) microspheres, here prepared, were coupled with thermoresponsive oligomers by reaction between the NH2 end-group of oligomers and chlorine present on Pul microspheres. The Pul microspheres with temperature sensitive moieties were packed in a glass column and the elution volume of standard molecule with well-known molecular weights (radius of gyration) was determined below and above the LCST. FITC-Dextran 4000 diffused through the pores of Pul microspheres with short thermosensitive arms (Mw = 1500 g/mol) both below and above the LCST of the thermosensitive units. In contrast, Pul microspheres with long thermosensitive arms (Mw = 3300 g/mol) allowed the diffusion of FITC-Dextran 4000 only above the LCST of the thermosensitive units. Indeed, the long thermosensitive arms are extended below the LCST and FITC-Dextran 4000 is completely excluded from the pores. The loading/release profile of this model molecule follows an "on-off" mechanism, confirming the results obtained by ISEC. ESEM was used as a new technique, taking images of the surface of the thermosensitive pullulan microspheres in their natural swollen state, with no prior specimen preparation, below and above the LCST. The low toxicity of pullulan microspheres observed below and above the LCST of thermosensitive units at high concentrations (10 mg/ml) recommends their potential use for controlled drug delivery applications. PMID- 20943267 TI - Interferon-gamma secretion by t(9;22) acute lymphoblastic leukemia-derived dendritic cells. AB - Interferon (IFN)-gamma plays an important role in immunity and anti-tumor activity. It is produced by lymphocytes, but was recently shown to be also produced by human myeloid dendritic cells (DCs). We have shown that human mature t(9;22) acute lymphoblastic leukemia-derived (ALL) DCs induced autologous cytotoxic T cell responses and therefore asked whether t(9;22) ALL-DC secreted IFN-gamma. IFN-gamma varied among three cell line-derived ALL-DCs; median production from seven patient ALL-DCs was 3450 pg/ml (range 1450-8675). IFN-gamma production was dependent on maturation of ALL-DCs. This is the first demonstration of IFN-gamma production by t(9;22) ALL-DCs. PMID- 20943268 TI - De novo translocation involving two chromosomes in adult prolymphocytic leukemia- a rare case. PMID- 20943269 TI - KIAA1524: A novel MLL translocation partner in acute myeloid leukemia. AB - The Mixed Lineage Leukemia gene on chromosome 11q23 is a frequent site of recurrent translocations in acute leukemias. Its promiscuous character is reflected by the more than 60 different translocation partners described in literature. Prompted by karyotype and atypical FISH results, we identified a new translocation partner in infant acute myeloid leukemia, KIAA1524 on 3q13.13, also known as 'Cancerous Inhibitor of Protein phosphatase 2A (CIP2A)'. This gene was recently identified as a proto-oncogene stabilizing MYC protein in gastric carcinoma. KIAA1524 has never been related to hematologic malignancies before, and the current AML case is the first case in which an MLL-KIAA1524 fusion was described. PMID- 20943270 TI - Associations between childhood adversity and depression, substance abuse and HIV and HSV2 incident infections in rural South African youth. AB - OBJECTIVES: To describe prevalence of childhood experiences of adversity in rural South African youth and their associations with health outcomes. METHODS: We analyzed questionnaires and blood specimens collected during a baseline survey for a cluster randomized controlled trial of a behavioral intervention, and also tested blood HIV and herpes simplex type 2 virus at 12- and 24-month follow up; 1,367 male and 1,415 female volunteers were recruited from 70 rural villages. RESULTS: Both women and men before 18 had experienced physical punishment (89.3% and 94.4%), physical hardship (65.8% and 46.8%), emotional abuse (54.7% and 56.4%), emotional neglect (41.6% and 39.6%), and sexual abuse (39.1% and 16.7%). Incident HIV infections were more common in women who experienced emotional abuse (IRR 1.96, 95% CI 1.25, 3.06, p=.003), sexual abuse (IRR 1.66 95% CI 1.04, 2.63, p=.03), and physical punishment (IRR 2.13 95% CI 1.04, 4.37, p=.04). Emotional neglect in women was associated with depression (aOR 1.82, 95% CI 1.15, 2.88, p=.01), suicidality (aOR 5.07, 95% CI 2.07, 12.45, p<.0001), alcohol abuse (aOR 2.17, 95% CI .99, 4.72, p=.05), and incident HSV2 infections (IRR 1.62, 95% CI 1.01, 2.59, p=.04). In men emotional neglect was associated with depression (aOR 3.41, 95% CI 1.87, 6.20, p<.0001) and drug use (aOR 1.98, 95% CI 1.37, 2.88, p<.0001). Sexual abuse was associated with alcohol abuse in men (aOR 3.68, 95% CI 2.00, 6.77, p<.0001) and depression (aOR 2.16, 95% CI 1.34, 3.48, p=.002) and alcohol abuse in women (aOR 3.94, 95% CI 1.90, 8.17, p<.0001). PRACTICE IMPLICATIONS: Childhood exposure to adversity is very common and influences the health of women and men. All forms of adversity, emotional, physical and sexual, enhance the risk of adverse health outcomes in men and women. Prevention of child abuse need to be included as part of the HIV prevention agenda in sub-Saharan Africa. Interventions are needed to prevent emotional, sexual, and physical abuse and responses from health and social systems in Africa to psychologically support exposed children must be strengthened. PMID- 20943271 TI - Morphological biomarkers in the Rhinocricus padbergi midgut exposed to contaminated soil. AB - Morphological studies have been performed in invertebrates to elucidate cellular and/or tissue damage caused by environmental contamination. In present work, the exposure to industrial soil contaminated with polycyclic aromatic hydrocarbons and metals led to histological alterations in the midgut of Rhinocricus padbergi (Diplopoda). The following alterations were observed: increase of cytoplasmic granules in the fat body; increase in the number of regions of the epithelium in the process of renewal; increase in the number of hemocytes present among the cells of the fat body and degenerative changes in the midgut epithelium. Based on the results, we concluded that R. padbergi proved to be an excellent bioindicator for the evaluation of soil quality. The observed changes could be used as biomarkers for assessing sublethal effects of contaminated soils. PMID- 20943272 TI - Combination of family history of suicidal behavior and childhood trauma may represent correlate of increased suicide risk. AB - BACKGROUND: There is a need to try to identify patients at highest risk for suicidal behavior. A family history of suicidal behavior (FHS) and childhood trauma are two important risk factors for suicidal behavior. It was therefore decided to combine them and examine if the combination would identify patients at even increased risk for suicidal behavior. METHODS: Two hundred and eighty one substance dependent patients with a FHS completed the Childhood Trauma Questionnaire (CTQ) and were interviewed about their lifetime history of suicidal behavior. Patients with the combination of a FHS and CTQ score above the mean were examined and compared with FHS patients with a CTQ score below the mean. RESULTS: One hundred and two of the 129 (79.1%) FHS patients with a CTQ score above the mean had attempted suicide. Thirty five of the 40 female (87.5%) FHS patients with a CTQ score above the mean had attempted suicide .Patients with a CTQ score above the mean were found significantly more among FHS patients who had attempted suicide than among FHS patients who had never attempted. FHS attempters with a CTQ score above the mean had a significantly earlier age of first attempting and had made more attempts than FHS attempters with a CTQ score below the mean. LIMITATIONS: Childhood trauma data derived from self-report questionnaire. No consistent collateral information about FHS. CONCLUSION: The combination of a FHS and childhood trauma may represent a correlate of increased risk of attempting suicide, attempting earlier, and making more attempts. PMID- 20943273 TI - Self-help behaviors for sleep and depression: a Japanese nationwide general population survey. AB - OBJECTIVE: The aim of this study was to examine the relationship between self help behaviors for sleep (SHBS) and depression among the general adult population in Japan. METHODS: The survey was conducted in June 2000 using self-administered questionnaires for subjects living in 300 communities randomly selected throughout Japan. A total of 24,686 responses were analyzed from individuals aged 20 years or older. The Center for Epidemiologic Studies Depression Scale was used to assess the prevalence of depression with two cut-off points: 16 and 25. Details of 6 types of SHBS were asked, based on given examples of actual behavior and frequency. RESULTS: After adjusting for sociodemographic variables, sleep problems and other SHBS, multiple logistic regression analyses revealed that "snacking on food and/or beverages" was independently associated with an increased odds ratio for depression, whereas "maintaining lifestyle regularity" was independently associated with a decreased odds ratio for depression. "Drinking alcoholic beverages," "having a bath," and "reading books or listening to music" were associated with an increased odds ratio for depression in crude analyses, but the significance of the association disappeared after adjusting for sociodemographic variables, sleep problems and other SHBS. LIMITATION: Complex constructs are being correlated. CONCLUSIONS: These results suggest that individual SHBS are differentially associated with depression, thus providing important clues for establishing sleep hygiene for treatment and prevention of depression. PMID- 20943274 TI - Comment on "do clinical outcome measures assess consumer-defined recovery?". PMID- 20943275 TI - Inflammation and gliosis in neurological diseases--clinical implications. AB - The inflammatory reaction accompany all acute processes in the central nervous system (CNS), (as stroke or traumatic brain injury) and chronic neurodegenerative processes (as Parkinson's or Alzheimer's disease), and through the stage of cleaning of damage tissue, contribute to recovery and regeneration and eventually to restoration of the function. However many studies showed that inflammation in the CNS may be harmful because of an excessive vulnerability of the nervous tissue or impaired regulation. Manipulation of the inflammation is now one of the approaches in the treatment of the various diseases of the CNS. PMID- 20943276 TI - The immunological basis for treatment of stiff person syndrome. AB - Antibodies against autoantigens involved in GABAergic neurotransmission are a shared feature of the different subtypes of stiff person syndrome (SPS). The autoantigens can be either presynaptic such as the smaller isoform of glutamic acid decarboxylase (GAD65), postsynaptic such as GABA-A receptor-associated protein and gephyrin, or located at the pre- and postsynaptic side such as amphiphysin. Most of these autoantigens are intracellular, and antibodies against GAD65 also occur in diabetes mellitus type 1 as well as other neurological diseases. Their pathogenic role has therefore been questioned. We here discuss the role of autoantibodies and T cells in SPS. PMID- 20943277 TI - Identification of three novel mutations in the CHD7 gene in patients with clinical signs of typical or atypical CHARGE syndrome. AB - CHARGE syndrome is an autosomal dominant disorder characterized by features represented in its acronym: Coloboma, Heart defect, Atresia of the choanae, Retarded growth and development, Genital abnormalities, Ear anomalies/deafness. We report two patients with a diagnosis of typical CHARGE syndrome and one with atypical clinical diagnosis. All the three patients had uni- or bilateral choanal atresia and sensorineural hearing loss. The patients were screened for CHD7 gene mutations. Three novel occurring de novo heterozygous mutations were identified: a mutation in the donor splice site of intron 24, a missense mutation in exon 2 and a deletion in exon 11. PMID- 20943278 TI - The effect of geriatric rehabilitation on physical performance and pain in men and women. AB - In the developed countries, people are living longer and the number of aged persons is growing. Knowledge on the effectiveness of rehabilitative procedures is needed and information in physical performance between men and women is scarce. An intervention study was carried out in two war veterans' rehabilitation centers in Finland to examine the effects of geriatric inpatient rehabilitation on physical performance and pain in elderly men and women. The study included 441 community-dwelling persons with a mean age of 83 years. A clinical assessment and a structured interview were carried out. Cognitive capacity was evaluated with the mini-mental state examination (MMSE). Physical performance was measured through several validated tests. Pain was measured with the visual analogy scale (VAS). The rehabilitation was carried out with the standard rehabilitation protocol. Both men and women showed a statistically significant improvement in physical performance tests. The experience of pain and disease symptoms diminished significantly in both sexes (p<0.001). The intervention showed that women improved more than men. It showed significant interactions of group by time in knee extension strength (p=0.033), the experience of pain reduction (p=0.002) and disease symptoms (p=0.040). Inpatient geriatric rehabilitation appeared to have a positive effect on physical performance and the experience of pain in elderly people. The differences between the sexes in the experience of pain, disease symptoms and in the knee extension strength could provide a new perspective in the planning of more individual rehabilitation interventions. PMID- 20943279 TI - Mortality and refusal in the longitudinal 90+ project. AB - Attrition is one of the most important threats for longitudinal studies on aging mainly due to refusal and mortality. This study deals with those individuals who were assessed in the base line of 90+ project but died, dropped out or were examined in the follow-up. Participants of the 90+ project baseline consist of a sample of 188 older than 90 years, independent individuals (mean age = 92.9; 67 men and 121 women) living in the community (n = 76) or in residences (n = 112). They were assessed through the European Survey on Aging Protocol (ESAP) by collecting anthropometric, health and life styles, bio-behavioral, psychological and social data. After 6-14 months from the baseline, 55% individuals were re assessed, 11% died and 34% dropped out for several reasons. Comparisons between the individuals deceased, interviewed and those who dropped out yielded significant differences mainly due to contextual variables. The mortality rate of participants living in residences is three times greater than those of participants living in the community. Trying to determine the differences between these three groups due to bio-psycho-social variables, we found that regular physical activity, mental status, leisure activities, fitness, perceived control and openness assessed at the baseline differentiate our three groups. Finally, 90% of those individuals who died were identified at the baseline as "non successful agers", while more than a half of those who participated and a third of the non-participants were identified as "successful agers". It can be concluded that among those independent but very old people, mortality is less important than willing to participate and contextual, behavioral and psychological factors are relevant for distinguishing mortality, survival and participation. PMID- 20943280 TI - Evaluation of quality of life (QoL) of students of the University of Third Age (U3A) on the basis of socio-demographic factors and health status. AB - In times of the modern global societies, concern for QoL is a priority for gerontology, being an interdisciplinary field. The aim of this study was to assess the QoL of students of the U3A based on socio-demographic factors, subjectively reported diseases and/or discomfort, and well-being. The study comprised 257 students of the U3A in Poland, located in the city of Bydgoszcz. The study group consisted of 237 women and 20 men at an average age of 64.54 +/- 6.01 years. The vast majority of the study group were married individuals and individuals with a secondary education. Just over half of the group stated that they are in good health and have no afflictions. All of the respondents were fully mobile. The QoL was assessed using the Polish version of the WHOQOL-Bref and the geriatric depression screening (GDS) scale. The QoL in its different areas balanced out at a medium level (average range: 13.30-13.87). The level of education of the U3A students proved to have a significant relation ith the environmental domain of QoL. No significant influence of age, gender, or marital statues on the QoL of the U3A students was found. A significant relation between subjectively reported diseases and/or discomfort with the QoL was demonstrated in the physical domain. Nearly 75% of the respondents showed no signs of depressive moods. The occurrence of depression indeed disrupted the QoL in all the studied domains, although least in the physical domain. Elderly individuals participating in permanent education display, in the face of progressive senile involution, average and at the same time stable parameters of QoL in all areas of functioning, which can be considered satisfactory, given this phase of life. The level of QoL of the U3A students significantly denotes the level of education of respondents, existing illnesses and afflictions, and the presents of depression. PMID- 20943281 TI - Assessment of different surveillance systems for avian influenza in commercial poultry in Catalonia (North-Eastern Spain). AB - Compulsory surveillance programmes for avian influenza (AI) have been implemented in domestic poultry and wild birds in all the European Member States since 2005. The implementation of these programmes is complex and requires a close evaluation. A good indicator to assess their efficacy is the sensitivity (Se) of the surveillance system. In this study, the sensitivities for different sampling designs proposed by the Spanish authorities for the commercial poultry population of Catalonia were assessed, using the scenario tree model methodology. These samplings were stratified throughout the territory of Spain and took into account the species, the types of production and their specific risks. The probabilities of detecting infection at different prevalences at both individual and holding level were estimated. Furthermore, those subpopulations that contributed more to the Se of the system were identified. The model estimated that all the designs met the requirements of the European Commission. The probability of detecting AI circulating in Catalonian poultry did not change significantly when the within holding design prevalence varied from 30% to 10%. In contrast, when the among holding design prevalence decreased from 5% to 1%, the probability of detecting AI was drastically reduced. The sampling of duck and goose holdings, and to a lesser extent the sampling of turkey and game bird holdings, increased the Se substantially. The Se of passive surveillance in chickens for highly pathogenic avian influenza (HPAI) and low pathogenicity avian influenza (LPAI) were also assessed. The probability of the infected birds manifesting apparent clinical signs and the awareness of veterinarians and farmers had great influence on the probability of detecting AI. In order to increase the probability of an early detection of HPAI in chicken, the probability of performing AI specific tests when AI is suspected would need to be increased. PMID- 20943282 TI - The effect of obesity on the assessment of diabetic peripheral neuropathy: a comparison of Michigan patient version test and Michigan physical assessment. AB - OBJECTIVE: Nerve conduction studies (NCS) and Michigan Neuropathy Screening Instrument (MNSI) are commonly used to make the diagnosis of diabetic peripheral neuropathy. The objective of this study was to compare the diagnostic values of MNSI patient version test and physical test for the assessment of the diabetic peripheral neuropathy in obese vs. non-obese patients. METHOD: This study was conducted on 70 type 2 diabetic patients. We carried out the MNSI patient version test and MNSI physical assessment test. Nerve conduction studies were performed for the diagnosis of the diabetic peripheral neuropathy. RESULTS: In diabetic peripheral neuropathy (DPN) determined by NCS, the independent prediction of peripheral neuropathy was the score of Michigan physical assessment (odds 2.0; CI: 1.3-3.0). In BMI (body mass index) >= 30 diabetic patients who have peripheral neuropathy, Michigan patient version test is not significant. But the score of Michigan physical assessment is significantly increased in these patients compared to patients without peripheral neuropathy. In BMI<30 diabetic patients who have peripheral neuropathy, scores of both Michigan patient version and physical assessment instruments are significantly increased. CONCLUSION: To screen diabetic peripheral neuropathy, Michigan physical assessment may be more useful instrument than Michigan patient version test in obese diabetic patients. PMID- 20943283 TI - Association of ABCC2 polymorphisms with platinum-based chemotherapy response and severe toxicity in non-small cell lung cancer patients. AB - Platinum-based chemotherapy is the most common treatment for non-small cell lung cancer (NSCLC), and expression levels of drug metabolism and transport proteins are correlated with its efficacy and toxicity. In this study, we investigated the association of three putative functional polymorphisms of ABCC2 (C-24T, G1249A, and C3972T) with tumor response and occurrence of the grade 3 or 4 toxicity in 445 patients with stage III and IV NSCLC treated with platinum-based chemotherapy. We determined the genotypes of these three polymorphisms by the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MassArray) method. We found that the common homozygotes of -24C was associated with a better treatment response (adjusted odds ratios [ORs], 1.84; 95% confidence interval [CI], 1.05-3.23; P=0.032). Furthermore, patients with 3972T had increased risk of severe thrombocytopenia toxicity (adjusted OR, 2.43; 95% CI, 1.06-5.56; P=0.034); and in female subgroup analyses, this variant was associated with significantly increased risk of overall toxicity (adjusted OR, 2.63; 95% CI, 1.17-5.95; P=0.02), particularly of hematologic toxicity (adjusted OR, 3.80; 95% CI, 1.62-8.87; P=0.002). Moreover, -24T/3972T haplotype was also associated with significantly increased risk of hematologic toxicity. Our results suggested that C-24T variants had an effect on treatment response and that C3972T had an effect on severe toxicities among platinum-treated non-small cell lung cancer patients. PMID- 20943284 TI - Dynamics of the cyanobacterial photosynthetic network: communication and modification of membrane protein complexes. AB - Cyanobacterial photosystem 2 and cytochrome b(6)f complexes have been structurally resolved up to the molecular level while the adjustment of their function in response to environmental and intracellular parameters is based on various modifications of these complexes which have not yet been resolved in detail. This minireview summarizes recent results on two central modifications for each complex: (a) for the cytochrome b(6)f complex the implication of PetP, a new subunit, and of three copies of PetC, the Rieske protein, for the fine-tuning of the photosynthetic electron transport is evaluated; (b) for photosystem 2, the heterogeneity of the D1 subunit and the role of subunit Psb27 is discussed in relation to stress response and the biogenesis/repair cycle. The presented "dynamic" models for both complexes should illustrate the need to complement structural by more extensive functional models which consider the flexibility of individual complexes in the physiological context - beyond structure. PMID- 20943285 TI - Correlated accumulation of anthocyanins and rosmarinic acid in mechanically stressed red cell suspensions of basil (Ocimum basilicum). AB - A red basil cell line (T2b) rich in rosmarinic acid (RA) was selected for the stable production of anthocyanins (ACs) in the dark. Cell suspension cultures were subjected to mechanical stress through increased agitation (switch from 90 to 150 rpm) to determine the relationship between AC and RA accumulation. Cell extracts were analyzed by HPLC and LC-MS, and the resulting data were processed with multivariate statistical analysis. MS and MS/MS spectra facilitated the putative annotation of several complex cyanidin-based ACs, which were esterified with coumaric acid and, in some cases, also with malonic acid. It was also possible to identify various RA-related molecules, some caffeic and coumaric acid derivatives and some flavanones. Mechanical stress increased the total AC and RA contents, but reduced biomass accumulation. Many metabolites were induced by mechanical stress, including RA and some of its derivatives, most ACs, hydroxycinnamic acids and flavonoids, whereas the abundance of some RA dimers was reduced. Although AC and RA share a common early biosynthetic pathway (from phenylalanine to 4-coumaroyl-CoA) and could have similar or overlapping functions providing antioxidant activity against stress-generated reactive oxygen species, there appeared to be no competition between their individual pathways. PMID- 20943286 TI - Quantitative disease resistance and fungal pathogenicity in Triticeae. PMID- 20943287 TI - Staphylococcus epidermidis: a possible role in the pustules of rosacea. AB - BACKGROUND: Rosacea is a common skin and ocular disease. Cutaneous rosacea is characterized by facial flushing, telangiectasia, papules, and pustules. It is generally regarded as inflammatory in nature. We believed that the role of bacteria as a contributory factor in pustular and ocular rosacea needed to be revisited. OBJECTIVES: We sought to ascertain whether there is an increase in the bacteria isolated from the (1) pustules of rosacea; and (2) eyelid margins of persons with cutaneous pustular rosacea. METHODS: Bacterial swabs were taken and cultured from an incised rosacea pustule, the ipsilateral cheek skin, and the eyelid margin of 15 patients with pustular rosacea. Swabs were also taken from the cheek skin and ipsilateral eyelid margin of 15 matched control subjects. RESULTS: A pure growth of Staphylococcus epidermidis was isolated from a pustule of 9 of 15 patients with pustular rosacea, and no pure growth of S epidermidis was isolated from their ipsilateral cheek skin. This was a highly statistically significant increase (P = .0003). A pure growth of S epidermidis was isolated from the eyelid margins of 4 of 15 patients with pustular rosacea, and no pure growth was isolated from the eyelids of age- and sex-matched control subjects. This was a statistically significant increase (P = .05). LIMITATIONS: This study focuses on the microbial basis of rosacea. CONCLUSION: Our findings suggest S epidermidis may play a role in pustular and ocular rosacea. PMID- 20943288 TI - [Hyperplastic-serrated polyps of the large intestine with multinuclear epithelial cells. A potential mimic of dysplasia or virus-induced changes in endoscopic biopsies]. PMID- 20943289 TI - [Incidence and risk factors for acute gastroenteritis among pilgrims following the French way to Santiago de Compostela (Spain) in summer 2008]. AB - OBJECTIVES: To determine the incidence of acute gastroenteritis in pilgrims on St. James' Way, as well as associated risk factors and microbiological characteristics. METHODS: Two studies were designed simultaneously: a cross sectional study through self-completed questionnaires among pilgrims reaching Santiago, and a case-control study of pilgrims traveling along the Way. Multivariate analysis was performed using logistic regression. RESULTS: In the cross-sectional study, the incidence rate was 23.5 episodes of acute gastroenteritis/103 pilgrims-day (95% CI: 18.9-2.4/103. In the case-control study, the major risk factors were age <20 years (OR=4.72; 95% CI: 2.16-10.28), traveling in groups (three or more) (OR=1.49; 95% CI: 0.98-2.28), and drinking unbottled water (OR=2.09; 95% CI: 0.91-4.82). The most frequent etiologic agent was norovirus (56%). CONCLUSIONS: Age less than 20 years, traveling in groups and drinking unbottled water were important risk factors for acute gastroenteritis. PMID- 20943290 TI - Synthesis and biological evaluation of new N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H pyrazole-3-carboxamides as cannabinoid receptor ligands. AB - A series of N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as new ligands of the human recombinant receptor hCB1. n-Alkyl carboxamides brought out different SARs from the branched subgroup. Unsubstituted pyrrole derivatives bearing a tert-alkyl chain at the 3-carboxamide nitrogen showed greater hCB1 receptor affinity than the corresponding unbranched compounds. In particular, the tert-butyl group as a chain terminal moiety strongly improved hCB1 receptor affinity (compound 24: Ki=45.6 nM; 29: Ki=37.5 nM). Acute administration of either compound 12 or 29 resulted in a specific, dose-dependent reduction in food intake in rats. Such results provide an useful basis for the design of new CB1 ligands. PMID- 20943291 TI - [Small fibre neuropathy in primary Sjogren syndrome]. AB - PURPOSE: About forty percent of the patients with primary Sjogren's syndrome (pSS) experience chronic neuropathic pain with normal electrodiagnostic studies. Two previous studies suggest that chronic neuropathic pain in pSS is due to small fiber neuropathy (SFN). Quantification of epidermal nerve fiber density after skin biopsy has been validated to diagnose small fiber neuropathy. METHODS: Skin biopsy was performed in 14 consecutive pSS patients (satisfying the american european classification criteria) with chronic neuropathic pain and normal electrodiagnostic studies suggesting SFN. RESULTS: Fourteen female pSS patients exhibited chronic neuropathic pain [burning sensation (n=14), prickling (n=4), dysesthesia (n=8)] with paroxystic exacerbations (n=10) and allodynia (n=13), for a mean period of 18.4+/-12.4 months. Neuropathic pain involved mostly hands and feet (n=13), with a distal (n=9) and leg (n=4) predominant distribution. Neurological examination disclosed normal deep tendon responses and absence of motor weakness (n=14). Small fiber neuropathy was confirmed by skin biopsy in 13 cases. Epidermal nerve fiber density was decreased in distal [(n=12), mean 3.5+/ 1.7 fibers/mm (N>6.9)] and proximal site of biopsy [(n=9), mean 7.04+/-2.63 fibers/mm (N>9.3)]. CONCLUSION: Small fiber neuropathy is commonly responsible of chronic neuropathic pain in pSS. Prevalence, physiopathology and neurological evolution of such neuropathies still remain unknown. PMID- 20943292 TI - [Oncogenic osteomalacia: increased production of fibroblast growth factor 23 is not the unique actor]. AB - The importance of fibroblast growth factor 23 (FGF 23) has been highlighted in the mechanism of urinary leakage of phosphate in the oncogenic osteomalacia (OO). It is now a component of diagnosis of this disease. We report a 58-year-old man who presented with osteomalacia and hypophosphatemia secondary to urinary leakage of phosphorus. Although serum FGF 23 was normal, the diagnosis of OO was obtained after another cause of acquired prolonged hypophosphatemia has been excluded (hyperparathyroidism and Fanconi syndrome in particular). The search for a deep tumor was performed, allowing the detection of a 12 mm hemangiopericytoma in the upper thigh. Its removal allowed the rapid resolution of clinical symptoms and laboratory abnormalities. The importance of functional sequelae in OO depends on prompt diagnosis. Tumorectomy remains the optimal treatment. Thus, the search for a secreting tumor is essential even in the absence of elevated serum FGF 23. PMID- 20943293 TI - Inadequate energy delivery during early critical illness correlates with increased risk of mortality in patients who survive at least seven days: a retrospective study. AB - BACKGROUND & AIMS: We examined associations between the first-week energy and protein intake and clinical outcomes in medical ICU (MICU) patients who survived at least seven days. METHODS: We retrospectively studied 295 patients admitted to a 28-bed MICU between 2005 and 2007. High and low energy delivery (ED) and protein delivery (PD) were defined as having a mean daily intake relative to recommendation at >= 60% and <60%, respectively, during the 1st to 7th day of ICU stay. RESULTS: The high and low ED or PD groups did not differ with regard to length of ICU stay, length of hospital stay, or ventilator free time. Patients with low ED or low PD intake were at greater risk of mortality than their high intake counterparts (OR = 3.7 and 3.6; both p < 0.001). After adjusting for confounders, we found patients receiving low ED to be at 2.43 times the risk of ICU mortality than high ED (p = 0.020). Low PD was unrelated to ICU mortality. CONCLUSIONS: Patients receiving less than 60% of recommended energy intake during the first week of critical illness are at greater risk of mortality. There is a need for future randomized trials to investigate optimal energy delivery during critical illness. PMID- 20943294 TI - Influence of intestinal resections on biliary composition and liver ultrastructure. AB - BACKGROUND & AIMS: Among the multiple factors that can influence bile acid (BA) metabolism and biliary poles, intestinal resections could do so directly (through absorption alterations) and/or indirectly (bacterial translocation, alterations of the hepato-intestinal hormonal axis). Our aim was to study the influence of partial intestinal resections on bile metabolism and biliary structure in an animal model. METHODS: Dunkin Hartley guinea pigs were used: Group A with only jejunum resection, Group B with only ileum resection, and Group CtrG, the control group. They were monitored for 21 days, with oral nutrition. At the end of this period, samples of the bile were taken from the hepatic duct and vena cava. After liver perfusion, samples of hepatic tissue were taken for optical and electron microscopy. RESULTS: There was a significant decrease in serum cholesterol in both GA & GB. The levels of biliary phospholipids (Ph) and cholic acid decreased only in Group B, but not ketolithocholic acid nor total conjugated BA. Slight liver macrosteatosis was observed in GB, but there were no changes in the biliary poles or canaliculi in the electron microscopy samples. CONCLUSIONS: Ileum resections affect the biliary Ph and BA composition, which could increase bile lithogenicity but do not seem to affect biliary duct anatomy. PMID- 20943295 TI - Measured and modelled tritium concentrations in freshwater Barnes mussels (Elliptio complanata) exposed to an abrupt increase in ambient tritium levels. AB - To improve understanding of environmental tritium behaviour, the International Atomic Energy Agency (IAEA) included a Tritium and C-14 Working Group (WG) in its EMRAS (Environmental Modelling for Radiation Safety) program. One scenario considered by the WG involved the prediction of time-dependent tritium concentrations in freshwater mussels that were subjected to an abrupt increase in ambient tritium levels. The experimental data used in the scenario were obtained from a study in which freshwater Barnes mussels (Elliptio complanata) were transplanted from an area with background tritium concentrations to a small Canadian Shield lake that contains elevated tritium. The mussels were then sampled over 88 days, and concentrations of free-water tritium (HTO) and organically-bound tritium (OBT) were measured in the soft tissues to follow the build-up of tritium in the mussels over time. The HTO concentration in the mussels reached steady state with the concentration in lake water within one or two hours. Most models predicted a longer time (up to a few days) to equilibrium. All models under-predicted the OBT concentration in the mussels one hour after transplantation, but over-predicted the rate of OBT formation over the next 24h. Subsequent dynamics were not well modelled, although all participants predicted OBT concentrations that were within a factor of three of the observation at the end of the study period. The concentration at the final time point was over predicted by all but one of the models. The relatively low observed concentration at this time was likely due to the loss of OBT by mussels during reproduction. PMID- 20943296 TI - Influence of asymmetry on the flexion relaxation response of the low back musculature. AB - BACKGROUND: the flexion relaxation phenomenon has been extensively studied in sagittally symmetric postures. Knowledge about this phenomenon in asymmetric trunk postures is less well understood, and may help to reveal the underlying physiology of the passive tissue/active tissue load-sharing mechanism in the lumbar region. METHODS: twelve participants performed fifteen controlled, full range trunk flexion-extension motions toward three asymmetric lifting postures (0 degrees (sagittally symmetric), 15 degrees , and 30 degrees from the mid sagittal plane). The electromyographic activity data from the paraspinals at the L3 and L4 levels and trunk kinematics data from motion sensors over the C7, T12 and S1 vertebrae were recorded. The lumbar flexion angles at which these muscles' activities were reduced to resting levels during forward flexion provided quantitative data describing the effects of asymmetry on the passive tissue/active tissue interaction. FINDINGS: flexion relaxation was observed in the muscles contralateral to the direction of the asymmetric trunk flexion motion. The response of the ipsilateral extensor musculature was much less consistent, with many trials indicating that flexion relaxation was never achieved. Increasing asymmetry from 0 degrees to 30 degrees led to a 10% reduction in the maximum lumbar flexion. Lumbar flexion angles necessary to achieve flexion relaxation in the contralateral muscles also decreased (L4 paraspinal-related angle decreasing by 15% and the L3 paraspinal-related angle decreasing by 21%). INTERPRETATION: under asymmetric conditions the lumbar flexion angle at which the transition from active muscle to passive ligamentous extension moment is altered from that seen in symmetric motions and this transition can have implications for the loading of the spine in full flexion (or near full flexion) postures. PMID- 20943297 TI - Factors associated with partner referral among patients with sexually transmitted infections in Bangladesh. AB - Understanding the demographic, behavioural and psychosocial factors associated with partner referral for patients with sexually transmitted infections (STIs) is important for designing appropriate intervention strategies. A survey was conducted among STI clients in three government and three non-governmental organization-operated clinics in Dhaka and Chittagong city in Bangladesh. Demographic and psychosocial information was collected using a questionnaire guided by the Attitude-Social Influence-Self Efficacy model. Partner referral data were collected by verification of referral cards when partners appeared at the clinics within one month of interviewing the STI clients. Of the 1339 clients interviewed, 81% accepted partner referral cards but only 32% actually referred their partners; 37% of these referrals were done by clients randomly assigned to a single counselling session vs. 27% by clients not assigned to a counselling session (p < 0.0001). Among psychosocial factors, partner referral intention was best predicted by attitudes and perceived social norms of the STI clients. Actual partner referral was significantly associated with intention to refer partner and attitudes of the index clients. Married clients were significantly more likely to refer their partners, and clients with low income were less likely to refer partners. Intervention programmes must address psychosocial and socio-economic issues to improve partner referral for STIs in Bangladesh. PMID- 20943298 TI - False hope: effects of social class and health policy on oral health inequalities for migrant farmworker families. AB - Few studies have engaged issues of social class and access related to dental health care policy from an ethnographic perspective. The state of Florida in the US has one of the poorest records in the nation for providing dental care for low income children, falling especially short for Medicaid-enrolled children. In this paper, we discuss unmet dental health needs of children in migrant farmworker families. Although one of the most marginalized populations, most are eligible for Medicaid and are thus covered for dental services. However, serious disparities have been linked to the lack of access through the public insurance system. This study was informed by participant observation at dental clinics and a Migrant Head Start Center and interviews with dental health providers (n = 19) and migrant farmworker parents (n = 48) during 2009. Our results indicate that some typical factors associated with poor oral health outcomes, such as low dental health literacy, may not apply disproportionately to this population. Instead, we argue that structural features and ineffective policies contribute to oral health care disparities. Dental Medicaid programs are chronically underfunded, resulting in low reimbursement rates, low provider participation, and a severe distribution shortage of dentists within poor communities. We characterize the situation for families in Florida as one of "false hope" because of the promise of services with neither adequate resources nor the urgency to provide them. The resulting system of charity care, which leads dentists to provide pro bono care instead of accepting Medicaid, serves to only further persistent inequalities. We provide several recommendations, including migrant specific efforts such as programs for sealants and new mothers; improvements to the current system by removing obstacles for dentists to treat low-income children; and innovative models to provide comprehensive care and increase the number of providers. PMID- 20943299 TI - Do self-perceived health changes predict longevity? AB - Researchers can rely either on retrospectively reported or on prospectively measured health changes to identify and quantify recent changes in respondents' health status. The two methods typically do not provide the same answers. We compare the validity of prospective versus retrospective measures of health changes by investigating their predictive power for subsequent mortality. Data from a cohort study conducted in the Netherlands are used to compare the ability of changes in self-assessed health (SAH) - either reported retrospectively or measured prospectively in three waves (1991, 1993 and 1995) - to predict survival until 2004. We examine the relationship between health changes and mortality with a proportional hazard models controlling for individual unobserved heterogeneity, with and without control for pre-existing chronic conditions and the onset of new chronic diseases. For a high proportion of reports (39.8%), prospectively measured health changes in SAH do not concur with retrospectively reported health changes. Our results show that both measures of health changes are predictive of mortality in the model controlling for levels of SAH and socioeconomic characteristics only. Controlling for SAH, prior presence of chronic conditions, the onset of new conditions and unobserved characteristics, we find that prospectively reported health changes still predict longevity, whereas retrospective changes do not. These results suggest that the collection of longitudinal information on health changes has advantages over the - easier and cheaper - option of retrospective collection of the same information. PMID- 20943300 TI - Joining-up thinking: loss in childbearing from inter-disciplinary perspectives. Introduction. PMID- 20943301 TI - A life-cycle approach to the analysis of the relationship between social capital and health in Britain. AB - I examine to what extent social capital can promote individual well-being in the form of good physical and mental health. Our analysis is based on multiple waves of data from the National Child Development Survey and the British Cohort Study, two large cohort studies following the lives of children who were born in Britain in one particular week in 1958 and 1970. I use waves that are comparable across the surveys in childhood and adulthood to explore the association between aspects of social capital and several measures of health when adopting a life-cycle approach. The findings suggest that individuals with high levels of social capital generally fare better than individuals with lower levels of social capital and that such associations are robust to the inclusion of controls such as physical and mental health in childhood and circumstances of the family of origin. PMID- 20943302 TI - Extending transaction cost economics: towards a synthesised approach for analysing contracting in health care markets with experience from the Australian private sector. AB - Transaction cost economics (TCE) has been the dominant economic paradigm for analysing contracting, and the framework has been applied in a number of health care contexts. However, TCE has particular limitations when applied to complex industry settings and there have been calls to extend the framework to incorporate dynamic theories of industrial organisation, specifically the resource-based view (RBV). This paper analyses how such calls for theoretical pluralism are particularly germane to health care markets and examines whether a combined TCE-RBV provides a more comprehensive approach for understanding the nature of contractual arrangements that have developed within the Australian private health care sector and its implications for informing policy. This Australian case study involved a series of interviews with 14 senior contracting executives from the seven major health funds (i.e. 97% of the insured population) and seven major private hospital groups (i.e. 73% of the private hospital beds). Study findings reveal that both the TCE perspective with its focus on exchange hazards, and the RBV approach with its emphasis on the dynamic nature of capabilities, each provide a partial explanation of the developments associated with contracting between health funds and hospital groups. For a select few organisations, close inter-firm relational ties involving trust and mutual commitment attenuate complex exchange hazards through greater information sharing and reduced propensity to behave opportunistically. Further, such close relational ties also provide denser communication channels for creating and transmitting more complex information enabling organisations to tap into each other's complementary resources and capabilities. For policymakers, having regard to both TCE and RBV considerations provides the opportunity to apply competition policy beyond the current static notions of efficiency and welfare gains, and cautions policymakers against specifying ex ante the specific nature of contractual arrangements that ought to prevail in health care markets. PMID- 20943303 TI - Income-related health inequalities in the Nordic countries: examining the role of education, occupational class, and age. AB - Numerous studies have concluded that people's socioeconomic position is related to mortality and morbidity, but that the strength of this association varies considerably both within and between European regions. This has spurred several researchers to more closely examine educational and occupational gradients in health in the Nordic countries to clarify the causes of cross-national differences. However, comparable studies using income as an indicator of socioeconomic position are still lacking. This study uses recent and highly comparable data to fill this gap. The aim of this study is threefold. First, we ask to what extent there is an income gradient in health in the Nordic countries, and to what extent the association differs between these countries. Second and third, we examine whether differences in the attenuation of the income gradient by education and occupational class, and age-specific differences between countries, may act as explanations for differences in the income gradient between the Nordic countries. The data source are three waves of the European Social Survey (ESS, 2002/2004/2006), which included 17,801 people aged 25 and over from Denmark, Finland, Norway, and Sweden. Two subjective health measures (physical/mental self reported health and limiting longstanding illness) were analysed by means of logistic regression. The results show that, in all countries, people reported significantly better health and were less likely to suffer from longstanding illness as they had a higher income. This association is strongest in Norway and Finland and weakest in Denmark. The income gradient in health, but not country differences in this gradient, is partly explained by education and occupational class. Additionally, the strength of the income gradient in health varies between age groups. The relatively high health inequalities between income groups in Norway and Finland are already visible in the youngest age groups. The results imply that the socioeconomic gradient in health will arguably not be strongly reduced in the near future as a result of cohort replacement, as has been suggested in previous studies. Health policy interventions may be particularly important five to ten years prior to retirement and in early adulthood. PMID- 20943304 TI - Hemispheric specialization for emotional word processing is a function of SSRI responsiveness. AB - Vulnerability to depression and non-response to Selective Serotonin Reuptake Inhibitors (SSRIs) are associated with specific neurophysiological characteristics including greater right hemisphere (RH) relative to left hemisphere (LH) activity. The present study investigated the relationship between hemispheric specialization and processing of emotional words using a divided visual field paradigm administered to never-depressed and previously-depressed individuals, who were subdivided into SSRI responders and non-responders. SSRI responders and never-depressed participants were similar in their left hemispheric lateralization for evaluating emotional words. In contrast, SSRI non responders showed a relative shift towards RH processing of negative words, and a strong bias toward negative evaluation of words presented to the RH. The results are discussed within the context of a biological-cognitive model of vulnerability to depression. PMID- 20943305 TI - [Blauth classification of thumb hypoplasia: thought and proposition of modification]. AB - Using the conclusions of the previous article concerning the therapeutic indications for handling hypoplastic thumb, we suggest an amendment to the current Blauth classification. This alteration is based on the management of this congenital anomaly, whereas the Blauth classification describes the morphological characteristics of the malformation. It appears for us more usable in practice by its easiness to be memorized. PMID- 20943306 TI - Thermodynamics of radicicol binding to human Hsp90 alpha and beta isoforms. AB - Radicicol is a natural antibiotic that specifically inhibits chaperone Hsp90 activity and binds to its active site with nanomolar affinity. Radicicol has been widely used as a lead compound to generate synthetic analogs with reduced toxicity and increased stability that could be employed clinically. Here we present a detailed thermodynamic description of radicicol binding to human Hsp90 and yeast Hsc82 studied by isothermal titration calorimetry and thermal shift assay. Titrations as a function of pH showed a linked protonation event upon radicicol binding. The intrinsic binding constant and the thermodynamic parameters (including the enthalpy, entropy, and heat capacity) were determined for yeast Hsc82, and human alpha and beta Hsp90. Recent experimental evidence in literature shows that yeast Hsc82 has significant differences from human Hsp90 isozymes. Here we support this by demonstrating differences in radicicol binding thermodynamics to these proteins. The intrinsic enthalpy of radicicol binding to Hsc82 was -46.7 kJ/mol, to Hsp90alpha -70.7 kJ/mol, and to Hsp90beta was -66.8 kJ/mol. The enthalpies of binding were significantly different, while the intrinsic dissociation constants were quite similar, equal to 0.25, 0.04, and 0.15 nM, respectively. The structural features responsible for such large difference in binding enthalpy but small difference in the intrinsic binding Gibbs free energy are discussed. PMID- 20943307 TI - Enhanced hepatic differentiation of mesenchymal stem cells after pretreatment with injured liver tissue. AB - Liver failure represents a serious challenge for cell based therapies. Mesenchymal stem cells (MSCs) possess potential for regeneration of fibrotic liver; however, there is a dire need to improve their hepatic differentiation. This study examines a pretreatment strategy to augment the differentiation potential of MSCs towards hepatic lineage. MSCs were isolated from C57BL/6 wild type mice and were characterized by flow cytometry for CD44 (92.4%), CD90 (96.6%), CD105 (94.7%), CD45 (0.8%) and CD34 (1.4%) markers. To improve the differentiation potential of MSCs towards hepatic lineage, cells were pretreated with injured liver tissue in an in-vitro model, which resulted in high expression of albumin, cytokeratin 8, 18, TAT and HNF1alpha as compared to untreated MSCs. The efficacy of pretreated MSCs was evaluated by preparing in-vivo mouse model with liver fibrosis by intraperitoneal administration of CCl(4). Pretreated MSCs were transplanted in the left lateral lobe of mice with liver fibrosis and showed enhanced localization and differentiation abilities after 1 month. The expression for cytokeratin 8, 18, albumin and Bcl-xl was up-regulated and that of HGF, Bax and Caspase- 3 was down-regulated in animals transplanted with pretreated MSCs. Sirus red staining also confirmed a significant reduction in the fibrotic area in liver tissue transplanted with pretreated MSCs as compared to untreated MSCs and was concomitant with improved serum levels of bilirubin and alkaline phosphatase (ALP). Therefore, it was concluded that pretreatment with injured liver tissue augment homing and hepatic differentiation abilities of MSCs and provides an improved procedure for the treatment of liver fibrosis. PMID- 20943308 TI - An inexact reverse logistics model for municipal solid waste management systems. AB - This paper proposed an inexact reverse logistics model for municipal solid waste management systems (IRWM). Waste managers, suppliers, industries and distributors were involved in strategic planning and operational execution through reverse logistics management. All the parameters were assumed to be intervals to quantify the uncertainties in the optimization process and solutions in IRWM. To solve this model, a piecewise interval programming was developed to deal with Min-Min functions in both objectives and constraints. The application of the model was illustrated through a classical municipal solid waste management case. With different cost parameters for landfill and the WTE, two scenarios were analyzed. The IRWM could reflect the dynamic and uncertain characteristics of MSW management systems, and could facilitate the generation of desired management plans. The model could be further advanced through incorporating methods of stochastic or fuzzy parameters into its framework. Design of multi-waste, multi echelon, multi-uncertainty reverse logistics model for waste management network would also be preferred. PMID- 20943309 TI - Lymph node dissection is not obsolete in clinically node-negative renal cell carcinoma patients. PMID- 20943310 TI - Sensorimotor manifestations without autonomic symptoms in two siblings with TTR Val107 familial amyloid polyneuropathy. PMID- 20943312 TI - Adsorption characteristics of UO(2)(2+) and Th(4+) ions from simulated radioactive solutions onto chitosan/clinoptilolite sorbents. AB - Adsorption features of UO(2)(2+) and Th(4+) ions from simulated radioactive solutions onto a novel chitosan/clinoptilolite (CS/CPL) composite as beads have been investigated compared with chitosan cross-linked with epichlorohydrin. The effects of contact time, the initial metal ion concentration, sorbent mass and temperature on the adsorption capacity of the CS-based sorbents were investigated. The adsorption kinetics was well described by the pseudo-second order equation, and the adsorption isotherms were better fitted by the Sips model. The maximum experimental adsorption capacities were 328.32 mg Th(4+)/g composite, and 408.62 mg UO(2)(2+)/g composite. The overall adsorption tendency of CS/CPL composite toward UO(2)(2+) and Th(4+) radiocations in the presence of Cu(2+), Fe(2+) and Al(3+), under competitive conditions, followed the order: Cu(2+)>UO(2)(2+)>Fe(2+)>Al(3+), and Cu(2+)>Th(4+)>Fe(2+)>Al(3+), respectively. The negative values of Gibbs free energy of adsorption indicated the spontaneity of the adsorption of radioactive ions on both the CS/CPL composite and the cross linked CS. The desorption level of UO(2)(2+) from the composite CS/CPL, by using 0.1M Na(2)CO(3), was around 92%, and that of Th(4+) ions, performed by 0.1M HCl, was around 85%, both values being higher than the desorption level of radiocations from the cross-linked CS, which were 89% and 83%, respectively. PMID- 20943313 TI - Mechanistic pathways differences between P25-TiO(2) and Pt-TiO(2) mediated CV photodegradation. AB - The Crystal Violet (CV) dye represented one of the major triphenylmethane dyes used in textile-processing and some other industrial processes. Various metals doped titanium dioxide (TiO(2)) photocatalysts have been studied intensively for the photodegradation of dye in wastewater treatment. In order to understand the mechanistic detail of the metal dosage on the activities enhancement of the TiO(2) based photocatalyst, this study investigated the CV photodegradation reactions under UV light irradiation using a Pt modified TiO(2) photocatalyst. The results showed that Pt-TiO(2) with 5.8% (W/W) Pt dosage yielded optimum photocatalytic activity. Also the effect of pH value on the CV degradation was well assessed for their product distributions. The degradation products and intermediates were separated and characterized by HPLC-ESI-MS and GC-MS techniques. The results indicated that both the N-de-methylation reaction and the oxidative cleavage reaction of conjugated chromophore structure occurred, but with significantly different intermediates distribution implying that Pt doped TiO(2) facilitate different degradation pathways compared to the P25-TiO(2) system. PMID- 20943311 TI - miRNAs in the pathogenesis of oncogenic human viruses. AB - Tumor viruses are a class of pathogens with well established roles in the development of malignant diseases. Numerous bodies of work have highlighted miRNAs (microRNAs) as critical regulators of tumor pathways and it is clear that the dysregulation of cellular miRNA expression can promote tumor formation. Tumor viruses encode their own miRNAs and/or manipulate the expression of cellular miRNAs to modulate their host cell environment, thereby facilitating their respective infection cycles. The modulation of these miRNA responsive pathways, however, often influences certain signal transduction cascades in ways that favor tumorigenesis. In this review, we discuss the roles of virally-encoded and virally-regulated cellular miRNAs in the respective viral life cycles and in virus associated pathogenesis. PMID- 20943314 TI - Stabilization/solidification of a municipal solid waste incineration residue using fly ash-based geopolymers. AB - The stabilization/solidification (S/S) of a municipal solid waste incineration (MSWI) fly ash containing hazardous metals such as Pb, Cd, Cr, Zn or Ba by means of geopolymerization technology is described in this paper. Different reagents such as sodium hydroxide, potassium hydroxide, sodium silicate, potassium silicate, kaolin, metakaolin and ground blast furnace slag have been used. Mixtures of MSWI waste with these kinds of geopolymeric materials and class F coal fly ash used as silica and alumina source have been processed to study the potential of geopolymers as waste immobilizing agents. To this end, the effects of curing conditions and composition have been tested. S/S solids are submitted to compressive strength and leaching tests to assess the results obtained and to evaluate the efficiency of the treatment. Compressive strength values in the range 1-9 MPa were easily obtained at 7 and 28 days. Concentrations of the metals leached from S/S products were strongly pH dependent, showing that the leachate pH was the most important variable for the immobilization of metals. Comparison of fly ash-based geopolymer systems with classical Portland cement stabilization methods has also been accomplished. PMID- 20943315 TI - Carminic acid modified anion exchanger for the removal and preconcentration of Mo(VI) from wastewater. AB - Removal and preconcentration of Mo(VI) from water and wastewater solutions was investigated using carminic acid modified anion exchanger (IRA743). Various factors influencing the adsorption of Mo(VI), e.g. pH, initial concentration, and coexisting oxyanions were studied. Adsorption reached equilibrium within <10 min and was independent of initial concentration of Mo(VI). Studies were performed at different pH values to find the pH at which maximum adsorption occurred and was determined to be at a pH between 4.0 and 6.0. The Langmuir adsorption capacity (q(max)) was found to be 13.5mg Mo(VI)/g of the adsorbent. The results showed that modification of IRA743 with carminic acid is suitable for the removal of Mo(VI), as molybdate, from water and wastewater samples. The concentration of Mo(VI) was determined spectrophotometrically using bromopyrogallol red as a complexation reagent. This allows the determination of Mo(VI) in the range 1.0 100.0 MUg/mL. The obtained material was subjected to efficient regeneration. PMID- 20943316 TI - Modeling and evaluation on removal of hexavalent chromium from aqueous systems using fixed bed column. AB - Removal of hexavalent chromium by xanthated chitosan was investigated in a packed bed up-flow column. The experiments were conducted to study the effect of important design parameters such as bed height and flow rate. At a bed height of 20 cm and flow rate of 5 mL min(-1), the metal-uptake capacity of xanthated chitosan and plain chitosan flakes for hexavalent chromium was found to be 202.5 and 130.12 mg g(-1) respectively. The bed depth service time (BDST) model was used to analyze the experimental data. The computed sorption capacity per unit bed volume (N(0)) was 4.6 +/- 0.3 and 78.3 +/- 2.9 g L(-1) for plain and xanthated flakes respectively at 10% breakthrough concentration. The rate constant (K(a)) was recorded as 0.0507 and 0.0194 L mg(-1)h(-1) for plain and xanthated chitosan respectively. In flow rate experiments, the results confirmed that the metal uptake capacity and the metal removal efficiency of plain and xanthated chitosan decreased with increasing flow rate. The Thomas model was used to fit the column sorption data at different flow rates and model constants were evaluated. The column was successfully applied for the removal of hexavalent chromium from electroplating wastewater. Five hundred bed volumes of electroplating wastewater were treated in column experiments using this adsorbent, reducing the concentrations of hexavalent chromium from 10 mg L(-1) to 0.1 mg L(-1). PMID- 20943317 TI - Pain tests provoke modality-specific cardiovascular responses in awake, unrestrained rats. AB - Nociception modulates heart rate (HR) and mean arterial pressure (MAP), suggesting their use of HR and MAP as indicators of pain in animals. We explored this with telemetric recording in unrestrained control and neuropathic (spinal nerve ligation) rats. Plantar stimulation was performed emulating techniques commonly used to measure pain, specifically brush stroke, von Frey fiber application, noxious pin stimulation, acetone for cooling, and radiant heating, while recording MAP, HR, and specific evoked somatomotor behaviors (none; simple withdrawal; or sustained lifting, shaking, and grooming representing hyperalgesia). Pin produced elevations in both HR and MAP, and greater responses accompanied hyperalgesia behavior compared to simple withdrawal. Von Frey stimulation depressed MAP, and increased HR only when stimulation produced hyperalgesia behavior, suggesting that minimal nociception occurs without this behavior. Brush increased MAP even when no movement was evoked. Cold elevated both HR and MAP whether or not there was withdrawal, but MAP increased more when withdrawal was triggered. Heating, consistently depressed HR and MAP, independent of behavior. Other than a greater HR response to pin in animals made hyperalgesic by injury, cardiovascular events evoked by stimulation did not differ between control and neuropathic animals. We conclude that (a) thermoregulation rather than pain may dominate responses to heat and cooling stimuli; (b) brush and cooling stimuli may be perceived and produce cardiovascular activation without nocifensive withdrawal; (c) sensations that produce hyperalgesia behavior are accompanied by greater cardiovascular activation than those producing simple withdrawal; and (d) von Frey stimulation lacks cardiovascular evidence of nociception except when hyperalgesia behavior is evoked. PMID- 20943318 TI - Neural bases of conditioned placebo analgesia. AB - Despite growing interest in the placebo effect, the neural correlates of conditioned analgesia are still incompletely understood. We investigated herein on brain activity during the conditioning and post-conditioning phases of a placebo experimental paradigm, using event-related fMRI in 31 healthy volunteers. Brief laser heat stimuli delivered to one foot (either right or left) were preceded by different visual cues, signalling either painful stimuli alone, or painful stimuli accompanied by a (sham) analgesic procedure. Cues signalling the analgesic procedure were followed by stimuli of lower intensity in the conditioning session, whereas in the test session both cues were followed by painful stimuli of the same intensity. During the first conditioning trials, progressive signal increases over time were found during anticipation of analgesia compared to anticipation of pain, in a medial prefrontal focus centered on medial area BA8, and in bilateral lateral prefrontal foci. These frontal foci were adjacent to, and partially overlapped, those active during anticipation of analgesia in the test session, whose signal changes were related to the magnitude of the placebo behavioral response, and those active during placebo analgesia. Specifically, a large focus in the right prefrontal cortex showed activity related to analgesia, irrespective of the expected side of stimulation. Analgesia was also related to decreased activity, detectable immediately following noxious stimulation, in parietal, insular and cingulate pain-related clusters. Our findings of dynamic changes in prefrontal areas during placebo conditioning, and of direct placebo effects on cortical nociceptive processing, add new insights into the neural bases of conditioned placebo analgesia. PMID- 20943319 TI - Anticoccidial and antiinflammatory activity of garlic in murine Eimeria papillata infections. AB - Coccidiosis with the protozoan parasite Eimeria as the infectious agent causes enormous economic losses, particularly in poultry farms. Here, we investigated the effects of garlic on the outcome of coccidiosis caused by Eimeria papillata in male Balb/c mice. The data showed that mice infected with E. papillata revealed an output of 3260 +/- 680 oocysts per gram faeces on day 4 p.i.. This output is significantly decreased to 1820 +/- 415 oocysts in garlic-treated mice. Infection also induced inflammation and injury of the liver. This was evidenced (i) as increases in inflammatory cellular infiltrations, dilated sinusoids, and vacuolated hepatocytes, (ii) as increased mRNA levels of inducible nitric oxide synthase (iNOS) and of the cytokines interferon gamma (IFN-gamma), and interleukin-6 (IL-6), (iii) as increased plasma levels of alanine and aspartate aminotransferases, alkaline phosphatase, gamma-glutamyl transferase and total bilirubin, (iv) as increased production of nitric oxide derived products (nitrite/nitrate) and malondialdehyde, and (v) as lowered glutathione levels and decreased activities of catalase and superoxide dismutase, respectively. All these infection-induced parameters were significantly less altered during garlic treatment. In particular, garlic counteracted the E. papillata-induced loss of glutathione and the activities of catalase and superoxide dismutase. Our data indicated that garlic treatment significantly attenuated inflammation and injury of the liver induced by E. papillata infections. PMID- 20943320 TI - Survey on blood-sucking lice (Phthiraptera: Anoplura) of ruminants and pigs with molecular detection of Anaplasma and Rickettsia spp. AB - Lice may serve as biological or mechanical vectors for various infectious agents. To investigate louse infestation of ruminants and pigs, and pathogens potentially transmitted by them, anopluran lice (n=1182) were collected in Hungary, and evaluated for the presence of anaplasma, rickettsia and haemotropic mycoplasma DNA. On cattle the following species were found: Linognathus vituli (57%), Haematopinus eurysternus (38%) and Solenopotes capillatus (5%). L. vituli had a lower mean individual count/host when compared to H. eurysternus. On calves only L. vituli was observed, with a higher louse burden than on full-grown cattle. H. eurysternus and S. capillatus were more likely to occur simultaneously with another species on the same host, than L. vituli. Goats infested with Linognathus stenopsis had the overall highest prevalence (68%), while pigs harbouring Haematopinus suis showed the lowest (<1%). Anaplasma DNA was detected in 50% of pools analysed. In L. vituli Anaplasma ovis (or a closely related novel Anaplasma marginale genotype) was identified. Anaplasma-positivity of H. suis suggests that pigs may extend the reservoir and/or host spectrum of relevant species. Anaplasma infected L. stenopsis pools show for the first time that caprine anaplasmosis is endemic in Hungary. Rickettsia spp. were demonstrated from Linognathus spp. and H. eurysternus. No haemotropic mycoplasmas were detected in any samples. In conclusion, this is the first molecularly confirmed report of bovine and ovine Anaplasma spp. in L. vituli, L. stenopsis and H. suis. The present results suggest that phthirapterosis of domestic animals deserves more attention, and lice should be evaluated among the broad range of potential vectors of arthropod borne pathogens. PMID- 20943321 TI - Performance of second-season grazing cattle following different levels of parasite control in their first grazing season. AB - A 3-year grazing trial was performed during 2003-2005 on a commercial steer producing farm in Sweden to study performance of second-season grazing (SSG) cattle following different levels of parasite exposure during their first grazing season. Initially, groups of 10 first-season grazing (FSG) cattle were each year assigned to four parasite control strategies: (1) turn-out onto pasture that during the previous year was grazed by SSG cattle, followed by a mid-July move to aftermath, (2) supplementation with concentrate and roughage for 4 weeks after turn-out, (3) no treatment, or (4) anthelmintic treatment (injectable doramectin) every fourth week. All animals were set stocked, except for those in group one. Next spring and following housing the cattle were turned out for their second grazing season onto approximately 25 ha communal pasturelands as a common mob. Weighing, faecal sampling and blood collection were performed at turn-out and then every 4 weeks for the 20-week grazing season. Faecal samples were also collected on day 10 after turn-out for detection of coccidian oocysts. Antibodies to Dictyocaulus viviparus were analysed at the time of their second housing period, and when elevated levels were recorded, stored serum samples from seropositive animals were analysed retrospectively. Results showed early-season weight losses of up to 47 kg in the SSG cattle. However, faecal egg counts were generally low and there was no correlation between SSG performance and treatment history as FSG cattle. Still, cumulative egg counts were significantly higher in animals that had been treated with anthelmintic as FSG cattle but serum pepsinogen concentrations showed no significant differences and the output of Eimeria alabamensis oocysts seldom exceeded 10,000 oocysts per gram faeces. Antibodies to D. viviparus were observed from July 2004 and from June 2005 but not in 2003. In 2004 and 2005, 64% and 83% of the animals, respectively, were seropositive for D. viviparus. It is concluded that weight gain penalties resulting from different levels of parasite infections the first grazing season remained during the second grazing season in 2004 and 2005 but no differences in weight gain could be identified in SSG cattle that had experienced different parasite control measures during their first grazing season. This was under conditions where the level of pasture infectivity was low to moderate during the second grazing period. However, D. viviparus was demonstrated in SSG animals during the two last years of the study and was an important confounding factor. PMID- 20943322 TI - Efficacy of a moxidectin/triclabendazole oral formulation against mixed infections of Fasciola hepatica and gastrointestinal nematodes in sheep. AB - We have evaluated the efficacy in sheep of a combination drench formulation at the recommended dose rate of 0.2 mg moxidectin/kg bodyweight and 10 mg triclabendazole/kg bodyweight against an experimental infection with Fasciola hepatica and a natural infection with gastrointestinal nematodes. We confirmed that the efficacy of reducing fecal egg output was 98.3% for trichostrongyle eggs and 100% for F. hepatica eggs. Based on adult worm and fluke recovery, the efficacy varied according to the target species. A reduction was found in the number of Teladorsagia circumcincta, Trichostrongylus spp., Nematodirus spp., and Trichuris spp. greater than 95%, but the efficacy for Oesophagostomum spp. varied, with values below 90%. The reduction in F. hepatica was higher than 95% for all stages. The effectiveness of the formulation was also confirmed by an increase in total proteins and albumin following treatment. PMID- 20943323 TI - Effects of artemisinin and Artemisia extracts on Haemonchus contortus in gerbils (Meriones unguiculatus). AB - Haemonchus contortus is a blood-sucking abomasal parasite of small ruminants that is responsible for major losses to producers worldwide. Resistance of this nematode to commercial anthelmintics has produced a demand for alternative control methods. Plants in the genus Artemisia have traditionally been used as anthelmintics and whole plants and plant extracts have demonstrated activity against gastrointestinal nematodes in several studies. In addition, Artemisia annua is the sole commercial source of artemisinin, the raw material used to produce drugs effective against the hemoprotozoan malaria parasites (Plasmodium species). Artemisinin derivatives have also shown efficacy against some trematodes, including Fasciola hepatica and Schistosoma species. In this study, artemisinin was tested for efficacy against H. contortus in a gerbil model of infection. Also tested in the gerbil model were an aqueous extract, an ethanolic extract and the essential oil of A. annua, and an ethanolic extract of Artemisia absinthium. In all experiments, gerbils were infected with 600 third-stage H. contortus larvae. In experiment 1, gerbils were treated orally with 400 milligrams per kilogram body weight (mg/kg BW) artemisinin once or 200mg/kg BW artemisinin daily for 5 days (Days 4-8 post-infection). In experiment 2, gerbils were treated daily for 5 days with 600 mg/kg BW of A. annua ethanolic or aqueous extract. In Experiment 3, gerbils were treated with 1000 mg/kg BW of A. annua or A. absinthium ethanolic extract or with 300 mg/kg BW of A. annua essential oil daily for five consecutive days (Days 4-8 post-infection). No significant effects of treatment were seen with artemisinin or any of the Artemisia species extracts at the dosages studied. The non-ionic surfactant Labrosol((r)) was an effective nontoxic solvent for delivery of hydrophilic plant extracts and the lipophilic essential oil used in the study. PMID- 20943324 TI - Epigenetic regulation of glucocorticoid receptor and infantile spasms. AB - IS is one of the few seizure syndromes that can be alleviated by adrenocorticotropic hormone (ACTH) or glucocorticoids (GCs) that are considered effective drugs of choice. This indicates that, indeed, IS may be fundamentally different from most other seizure disorders owing to the dysregulation of the hypothalamic-hypophysial-adrenal axis. GCs have multiple critical effects on fetal development, especially in normal brain development. Most glucocorticoid effects are mediated by the glucocorticoid receptor (GR), a steroid-activated nuclear receptor that translocates to the nucleus upon binding to cortisol. In the nucleus, GR targets genes related to neuronal metabolism and plasticity. The GR has also been characterized as a critical checkpoint in the delicate hormonal control of energy homeostasis. Recent studies suggest a possible correlation between prenatal stress and the onset of infantile spasms. In this paper, we propose a hypothesis that connects the adverse events in early life with the onset of IS through methylation of the GR gene, which is an epigenetic mechanism. PMID- 20943325 TI - The evolutionary atavistic endotoxin and neoplastic growth. AB - A hypothesis on the potential role of atavistic endotoxin in carcinogenesis is proposed. The presence of an antigen identical to the endotoxin of gram-negative bacteria in tumour cells is confirmed by IgM class natural specific antibodies to endotoxin (IgMNAE) in rats by immunizing them with rat tumour tissue extracts. Rat normal tissue extracts do not increase the endogenous level of natural immunity to endotoxin, indicating the absence of a foreign antigen such as endotoxin in normal cells which are naturally devoid also of other parasitic features such as invasiveness and metastases, whereas tumour cells, during a prolonged latent period of carcinogenesis, acquire resistance to harmful factors, lose most of their genetic, antigenic, morphological and biochemical properties and become parasitic so as to survive in unfavourable conditions. With the regression of the mentioned properties of cells to the atavistic parasitic state, the synthesis of dormant endotoxin is activated together with an enhanced expression of evolutionary resistance-related genes and oncogenes. Atavistic endotoxin, produced and secreted by proliferating tumour cells, should cause chronic cachexia and septic states in cancer patients, similarly as in cases of endotoxemic septic shock where the endotoxin of gram-negative bacteria is the main pathogenic factor. Thus, the implications of the hypothesis indicate the diagnostic as well as prognostic and preventive significance of evolutionary atavistic endotoxin and also of endotoxin from gram-negative bacteria in human cancers. Natural specific antibodies to endotoxin can be helpful in creating new immunotherapeutic methods. PMID- 20943326 TI - Targeting glutamate mediated excitotoxicity in Huntington's disease: neural progenitors and partial glutamate antagonist--memantine. AB - Huntington's disease (HD) is a fatal progressive neurodegenerative disorder with autosomal dominant inheritance. In humans mutated huntingtin (htt) induces a preferential loss of medium spiny neurons (MSN) of the striatum and causes motor, cognitive and emotional deficits. One of the proposed cellular mechanism underlying medium spiny neurons degeneration is excitotoxic pathways mediated by glutamate receptors. The hypothesis proposed is restoration of medium spiny neurons in Huntington's disease using neural progenitor cell implantation and attenuation of glutamate mediated excitotoxicity using a partial glutamate antagonist - Memantine. Memantine can block the NMDA receptors and will prevent excess calcium influx into the neurons decreases the vulnerability of medium spiny neurons to glutamate mediated excitotoxicity. Neural progenitor cell implantation can enhance endogenous neurogenesis process replacing the degenerated medium spiny neurons in the striatum. This has immense significance in the management of Huntington's disease. PMID- 20943327 TI - Hepatocellular carcinoma arising from ectopic liver tissue in the spleen producing insulin-like growth factor II. AB - We report a case of splenic tumor associated with severe hypoglycemia. The patient was a 69-year-old man with a large splenic tumor. He had suffered from relapsing hypoglycemic attacks and the lowest serum glucose level (4 mg/dl). He died 34 months after the onset of symptoms of left abdominal pain. Autopsy revealed large tumors in the spleen, 3 medium sized tumors in the lungs, and several small tumors in the liver. Microscopic studies of the splenic tumors revealed a hepatocellular carcinoma which showed a strongly positive reaction against anti-PIVKA-II and anti-"hepatocyte" antibodies. Several bile ductules thought to be heterotopic remnants of the liver tissues were found in the capsule of the spleen, adjoining the splenic tumor. It was suggested that the tumor originated from one of these ductules. Electron microscopic analysis showed numerous endocrine-like granules of every tumor cell, and 87-165 times stronger mRNA expression of insulin-like growth factor-II was measured in the tumor tissues when compared with normal liver tissue. Owing to these results, we believe that this is the first report of hepatocellular carcinoma that had developed from a liver tissue in the spleen. PMID- 20943328 TI - [Peritoneal closure using absorbable knotless device during laparoscopic sacrocolpopexy]. AB - Laparoscopic sacrocolpopexy is one of the gold standards of pelvic organ surgery. However, this intervention is associated with long operation duration. One of the steps of this intervention (peritoneal closure) can be shortened using several methods of suturing (e.g. staples). Recently, a self-anchoring barbed suture has been described for wound closure. The goal of this initial feasibility study was to describe the use of the barbed suture (V-LocTM) in peritoneal closure during laparoscopic sacrocolpopexy. PMID- 20943329 TI - [Toward the acceptance of using vaginal prosthetic reinforcement implants: a new step?]. PMID- 20943330 TI - Molecular characterization of equine rotaviruses circulating in Argentinean foals during a 17-year surveillance period (1992-2008). AB - P[12]G3 and P[12]G14 equine rotaviruses (ERVs) are epidemiologically important in horses. In Argentina, the prevalent ERV strains have been historically P[12]G3. The aim of this study was the detection and characterization of ERV strains circulating in foals in Argentina during a 17-year study (1992-2008). Additionally, the gene sequences of VP7, VP4 and NSP4 encoding genes of representative Argentinean ERV strains were determined and phylogenetic analyses were performed to elucidate the evolutionary relationships of the ERV strains in Argentina. ERVs were detected in 165 (21%) out of 771 diarrheic stool samples, which corresponded to 45 (39%) of 116 outbreaks from the surveyed thoroughbred horse farms. From the positive cases, 51% (n=23) were G3, 33% (n=15) were G14, 4% (n=2) represented a G3+G14 mixed infection and 11% (n=5) of the cases could not be characterized. G3 ERV was detected during the entire period, while G14 ERV was first detected in 2000 and increased its incidence specially in 2006 and 2007. All the analyzed strains belonged to the VP4 P[12] genotype, except for one G3 case which belonged to the P[3] genotype, constituting the first report of a P[3]G3 ERV strain. Phylogenetic analysis of VP7 protein revealed that the G3 Argentinean ERV strains clustered with ERVs from Ireland, while the G14 Argentinean ERV strains formed a distinct cluster within the G14 genotype. The VP4 of the P[12] ERV strains clustered with P[12] strains from Ireland and France. The NSP4 of the Argentinean ERV strains clustered with the NSP4 genotype E12, along with those of guanaco and bovine strains from Argentina, suggesting the a close evolutionary relationship among these Argentinean strains. The results of this study showed changes in the incidence of G3 and G14 during the studied period. The increase in the frequency of G14 ERV, not included in the vaccine, in the second half of the period, may have implications for vaccine design. PMID- 20943331 TI - Susceptibility of Muscovy (Cairina Moschata) and mallard ducks (Anas Platyrhynchos) to experimental infections by different genotypes of H5N1 avian influenza viruses. AB - It is a fact that in Viet Nam, Muscovy ducks are raised in large populations (approximately 8 million), usually kept in small flocks together with mallards and chickens. As a result, it is a great concern for epidemiologists to elucidate possible differences in relation to these species being exposed to infection with H5N1. To do this, an experimental study on infections with different genotypes of H5N1 in mallards and Muscovy ducks have been conducted, where it was found that the mortality of the inoculated Muscovy ducks was at least 80%, regardless of the virus strain employed. In contrast, the mortality of the mallards ranged from nil to 100%, which suggests that Muscovy ducks are more susceptible to HPAIV H5N1 infection in terms of disease development and mortality. It was also found that higher virus titers developed in vital organs of Muscovy ducks compared to mallards, particularly in the brain. Due to their high susceptibility, it is unlikely that Muscovy ducks act as a silent reservoir. The virus strains used in this study, to a certain degree, differed in their virulence properties to the bird species in question. PMID- 20943332 TI - Effect of Vitamin E supplementation on the enzymatic activity of selected markers in Aohan fine-wool sheep testis. AB - The aim of this study was to evaluate the effects of dietary Vitamin E supplementation on the testicular 'marker' enzyme activity and Vitamin E content in Aohan fine-wool sheep. Thirty male Aohan fine-wool sheep (5 months of age) with similar body weight were selected from the Aohan fine-wool sheep-breeding farm of Inner Mongolia Autonomous Region, China. The sheep were randomly divided into five groups and supplemented with 0, 20, 200, 1000 or 2400 IU sheep(-1)d(-1) Vitamin E for 12 months. Three sheep in each group were slaughtered at 17 months to collect a testis sample for testicular marker enzyme analysis. The results showed that, compared to Control, supplementing the diet with Vitamin E at 200 IU sheep(-1)d(-1) significantly increased the content of Vitamin E in testis and improved the activity of testicular mitochondrial ATPase (P<0.01), lactate dehydrogenase (LDH) (P<0.01), sorbitol dehydrogenase (SDH) (P<0.01), and alkaline phosphatase (ALP) (P<0.05). The present study demonstrated that supplementing Vitamin E can have a positive role in improving testicular marker enzyme activity and that the optimum range of dose appeared to be 100-200 IU sheep(-1)d(-1). PMID- 20943333 TI - Cardiovascular risk in postmenopausal women with the polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is one of the commonest endocrine disorders, affecting 5-10% of the female population of reproductive age. "Classic" PCOS is characterized by clinical or biochemical hyperandrogenism and oligo-ovulation. According to the 2003 Rotterdam criteria, two additional phenotypes are recognized: (1) the ovulatory patient with androgen excess and polycystic ovarian morphology and (2) the anovulatory patient with polycystic ovarian morphology without androgen excess. PCOS is associated with an adverse cardiometabolic profile, consisting of increased total or central adiposity, increased blood pressure, a pro-atherogenic lipid profile, increased inflammatory markers, insulin resistance and abnormal glucose metabolism. Furthermore, the incidence of overt or gestational diabetes mellitus, as well as of preeclampsia is significantly higher in PCOS patients. Among the various PCOS phenotypes, those with evidence of androgen excess have the highest burden of cardiovascular risk. Studies evaluating the incidence of cardiovascular disease in postmenopausal women with PCOS are extremely sparse. The available data so far indicate that coronary heart disease, as well as cerebrovascular disease is more common in postmenopausal PCOS patients. Persisting high androgen levels through the menopause, obesity and maturity onset diabetes mellitus are proposed as the main mechanisms accounting for the increased risk. PMID- 20943334 TI - Bullying behaviour and criminality: a population-based follow-up study of adolescent psychiatric inpatients in Northern Finland. AB - The recent school shootings in Europe and the USA have raised the question of whether victims of bullying run an increased risk of committing violent crimes later in life, but scientific research in this area is scarce. The aim of this work was to investigate whether bullying behaviour is associated with later criminal offences committed in adolescence and young adulthood. We studied a sample of 508 Finnish adolescents (age 12-17 years) admitted to psychiatric inpatient care between April 2001 and March 2006. Data on crimes committed and the age of onset of criminal activity were extracted from the official criminal records of the national Legal Register Centre in October 2008. The Schedule for Affective Disorder and Schizophrenia for School-Age Children, Present and Lifetime (K-SADS-PL) was used to define bullying status, and to obtain DSM-IV based psychiatric diagnoses for the adolescents. Violent crimes were statistically significantly associated with bullying behaviour, but not non violent crimes. Furthermore, being a bully was predictive of an early onset of severe violent offences. When controlled for the psychiatric diagnoses of the adolescents, we observed decreased likelihood of criminality among victims. Thus bullying others may increase the risk of violent offences, while being a victim is not a risk factor for criminality. PMID- 20943335 TI - A simple magneto-optical method for the restoration of erased markings in metals. AB - There are different techniques for the restoration of erased markings in metals. Non-destructive methods are generally preferable. The only frequently used non destructive method is the magnetic technique. The different kinds of magnetic restoration methods are discussed in the article. In the experiments described, the applicability of magneto-optical methods for the restoration of obliterated markings was examined. The results show that the methods are suitable and the required equipment does not cause high expenses. PMID- 20943336 TI - Sir James Black (1924-2010), beta-blockers and liver disease. PMID- 20943337 TI - Lung perfusion analysis with dual energy CT in patients with suspected pulmonary embolism--influence of window settings on the diagnosis of underlying pathologies of perfusion defects. AB - PURPOSE: On lung perfusion analysis with dual energy CT (DECT) in patients with suspected pulmonary embolism (PE) commonly three patterns of perfusion defects (PD) are observed: wedge-shaped, circumscribed but not wedge-shaped, and patchy. We investigated the influence of different window settings on the identification of the underlying pathologies for these types of PD. MATERIALS AND METHODS: 3724 segments in 196 consecutive patients who underwent pulmonary DECT angiography for clinically suspected acute PE were analyzed. Iodine distribution in the lung parenchyma was calculated from the dual energy data and displayed as color map in axial, sagittal and coronal view. Afterwards, lung and angiography window were applied separately and assessed for pulmonary embolism and pathologies of the lung parenchyma. RESULTS: 1420 segments in 141 patients showed PD, of which 276 were wedge-shaped, 287 circumscribed and 857 patchy. Circumscribed PD were associated in 99% with interstitial or alveolar fluid collections and in 1% with located bullae. Patchy PD were associated in 65% with emphysematous or fibrotic changes, in 38% with diffuse infiltrations or interstitial fluid collections and in 0.2% with PE. The underlying pathologies for wedge-shaped PD were in 78% PE, in 3% tumors compressing pulmonary arteries, in another 3% located bullae and in further 3% infiltrations. 13% (n=15) of the segments in this group did not show vascular or parenchymal pathologies, but in 80% (n=10) of these cases patients had PE in another segment. Totally n=6 of wedge-shaped PD in 5 patients remained with unclear direct cause. CONCLUSION: Whereas patchy and circumscribed PD are almost exclusively associated with pathologies of the lung parenchyma, wedge shaped PD are mostly associated with PE. For a small number of wedge-shaped PD the underlying cause cannot be detected with DECT. Very small peripherally situated micro-emboli may be discussed as a reason. However, prospective trials are needed to clarify the value of this finding. PMID- 20943338 TI - Development and validation of a normal-phase HPTLC method for the simultaneous analysis of lamivudine, stavudine and nevirapine in fixed-dose combination tablets. AB - This paper presents the development and validation of an improved method for the simultaneous analysis of lamivudine (LVD), stavudine (STV) and nevirapine (NVP) using high-performance thin-layer chromatography (HPTLC) with densitometric detection. Separation was performed on silica gel 60F(254) plates. The mobile phase is comprised of ethylacetate, methanol, toluene and concentrated ammonia (38.7:19.4:38.7:3.2, v:v:v:v). Detection wavelength was 254 nm. The R(f) values were 0.24+/-0.03, 0.38+/-0.04 and 0.69+/-0.04 (n=8) for LVD, STV and NVP, respectively. An F-test indicated that calibration graphs were adequately linear at the evaluated concentration ranges. The pooled %RSD for repeatability of the percentage amount recovered for LVD, STV and NVP were found to be 0.62, 0.54, and 0.79, and the pooled %RSD for time-different intermediate precision were 1.66, 1.27 and 1.21. The percentage recoveries for the trueness were 99.2%+/-1.5 for LVD, 98.6%+/-1.5 for STV and 99.3%+/-1.7 for NVP (n=3). Most factors evaluated in the robustness test were found to have an insignificant effect on the selected responses at 95% confidence level. This method was successfully used to analyze fixed-dose tablets samples of LVD, STV and NVP. PMID- 20943339 TI - Enantiomeric separation of antimalarial drugs by capillary electrophoresis using neutral and negatively charged cyclodextrins. AB - Capillary electrophoresis (CE) methods for chiral resolution of five antimalarial drugs (primaquine, tafenoquine, mefloquine, chloroquine and quinacrine) were developed by using a wide selection of neutral and anionic cyclodextrin (CD) derivatives. The use of sulfobutyl-beta-CD and carboxymethyl-beta-CD (CMBCD) resulted in good resolution of quinacrine and tafenoquine, respectively. New results are presented for resolutions of chloroquine and mefloquine. Application of carboxyalkyl- and sulfobutyl-CD derivatives provided improved resolution for primaquine. The impurity in primaquine sample detected by CE was identified as quinocide by MS and NMR. CMBCD provided not only the best separation of primaquine from quinocide but also the simultaneous complete resolution of both compounds. PMID- 20943340 TI - Evaluation of a synthetic peptide as a replacement for the recombinant fusion protein of respiratory syncytial virus in a potency ELISA. AB - This report describes the development of a potency ELISA using a peptide derived from the motavizumab binding epitope of respiratory syncytial virus (RSV) F protein. Motavizumab is an antibody therapeutic studied for the prevention of RSV disease. It binds to the RSV glycoprotein F (F-protein), blocking the ability of RSV to fuse with target cells. This binding is the basis for a potency ELISA, however, due to inefficient F-protein production, development of an alternative ligand for the potency ELISA was investigated. A series of synthetic peptides spanning the motavizumab epitope on F-protein were evaluated for motavizumab binding activity. A 26-mer peptide was identified with desirable motavizumab binding kinetics, as shown by ELISA and surface plasmon resonance. The peptide corresponds to a portion of the motavizumab binding domain on the F-protein, and is referred to as F-peptide. The binding of motavizumab to the F-peptide is used in a new motavizumab potency ELISA, which was shown to be robust and statistically comparable to the F-protein ELISA. In addition, based on a qualitative observation, this new ELISA may be able to detect motavizumab degradation with greater sensitivity compared to the F-protein ELISA. PMID- 20943341 TI - A powder X-ray diffraction method for detection of polyprenylated benzophenones in plant extracts associated with HPLC for quantitative analysis. AB - A robust, direct, rapid and non-destructive X-ray diffraction crystallography method to detect the polyprenylated benzophenones 7-epi-clusianone (1) and guttiferone A (2) in extracts from Garcinia brasiliensis is presented. Powder samples of benzophenones 1 and 2, dried hexane extracts from G. brasiliensis seeds and fruit's pericarp, and the dried ethanolic extract from G. brasiliensis seeds were unambiguously characterized by powder X-ray diffractometry. The calculated X-ray diffraction peaks from crystal structures of analytes 1 and 2, previously determined by single-crystal X-ray diffraction technique, were overlaid to those of the experimental powder diffractograms, providing a practical identification of these compounds in the analyzed material and confirming the pure contents of the powder samples. Using the X-ray diffraction crystallography method, the studied polyprenylated benzophenones were selectively and simultaneously detected in the extracts which were mounted directly on sample holder. In addition, reference materials of the analytes were not required for analyses since the crystal structures of the compounds are known. High performance liquid chromatography analyses also were comparatively carried out to quantify the analytes in the same plant extracts showing to be in agreement with X-ray diffraction crystallography method. PMID- 20943342 TI - Development and validation of discriminating method of dissolution for fosamprenavir tablets based on in vivo data. AB - The aim of this work is to develop and validate a dissolution test for fosamprenavir tablets (Telzir((r))) based on in vivo data. The appropriate conditions were determined after testing sink conditions in dissolution medium, rotation speed and stability of the drug. In vivo release profiles were obtained from the literature. The fraction (and percentage) of dose absorbed (FA) was calculated by deconvolution, using the Wagner-Nelson method. For this formulation, the best dissolution conditions were achieved using a USP apparatus 1 900 ml of medium containing HCl 0.01 M at a rotation speed of 75 rpm. Under these conditions a significant linear relationship between fraction of drug absorbed versus dissolved was obtained (R(2)=0.984) and a level-A IVIVC was established. The in vitro dissolution samples were analyzed using a HPLC method and the validation was performed according to USP protocol. The method showed accuracy, precision, linearity and specificity within the acceptable range. The discriminatory power of the dissolution method was challenged. The kinetics of dissolution was determined using model-dependent methods. The dissolution profiles were best described by the Hixson-Crowell model. The dissolution test was validated and could be applied to evaluate the dissolution profile of fosamprenavir tablets. PMID- 20943343 TI - Does questionnaire-based patient feedback reflect the important qualities of clinical consultations? Context, benefits and risks. AB - OBJECTIVE: To explore perceptions of clinical consultations and how they relate to questionnaire-based patient feedback. METHODS: Telephone interviews with 35 junior doctors and 40 general practice patients who had used the Doctors' Interpersonal Skills Questionnaire (DISQ). RESULTS: Doctors and patients had similar views of 'good consultations' as relying on doctors' listening and explaining skills. Preferences for a consultation style focused on an outcome or on the doctor-patient relationship may be independent of informational and/or affective consultation content. Respondents felt the important consultation elements were similar in different contexts, and so DISQ feedback would be useful in different settings. Benefits of feedback were identified in the form of patient empowerment and doctors' learning. Risks were identified in the inappropriate use of feedback, both inadvertent and deliberate. CONCLUSION: The style and content of consultations may be considered as separate dimensions, an approach that may help doctors adapt their communication appropriately to different consultations. Patient feedback focused on communication skills is appropriate, but there are potential risks. PRACTICE IMPLICATIONS: Doctors should consider the transactional or relational preference of a patient in approaching a consultation. Patient feedback can deliver benefits to doctors and patients, but risks must be acknowledged and mitigated against. PMID- 20943345 TI - Gait development during lifespan in subjects with Down syndrome. AB - In this work we studied and evaluated the effects of aging in a group of individuals with Down syndrome, using gait analysis as tool of investigation. 32 individuals suffering from Down syndrome (DS) were enrolled in this study as group of pathological participants. The control group (CG) was composed by 36 healthy subjects (10 children, 15 teenagers and 16 adults) in order to evidence the differences between the normal and the pathological gait evolution in age matched comparisons. The assessment consisted of 3D gait analysis: all pathological participants performed gait analysis in a longitudinal examination, from childhood to adulthood. Participants with DS evidenced how the delay in cognitive aspects and the typical orthopedic features of DS, as ligament laxity, led to the development of different motor strategies. During childhood, for both the considered populations, we found large variability in the gait indexes, but after this age a split in gait development was evidenced: the participants with DS developed a strategy focused on the reduction of the degrees of freedom, increasing the dispersion of generated power in the frontal plane, while in healthy participants the strategy was focused on the use of all the degrees of freedom, in order to reach the effectiveness of the gesture and finalize their movements in sagittal progression. The present study reinforces the idea that early intervention aimed to improve muscle tone, in order to supply for the excessive ligament laxity and to improve motor coordination, could represent a real goal for a more effective movement and for the prevention of compensatory strategies that increase energy cost. PMID- 20943346 TI - Effects of chronic cigarette smoking on endothelial function in young men. AB - The aim of this study was to elucidate endothelial dysfunction due to chronic cigarette smoking in young smokers and to determine practical markers of the functional derangement. The subjects were young, healthy, male non-smokers (n=11) and smokers (n=9). Endothelium-dependent and -independent vasodilation was assessed by flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID), respectively, and possible markers of endothelial function were measured. FMD in smokers was significantly lower than in control subjects (5.0 +/- 2.6% and 9.5 +/- 5.2%, p<0.05). Plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator levels were significantly (p<0.05) higher in smokers (6.7 +/- 4.5 ng/ml and 4.3 +/- 2.0 ng/ml) compared with control subjects (2.9 +/- 1.9 ng/ml and 3.0 +/- 0.6 ng/ml). Furthermore, PAI-1 levels correlated inversely with FMD (r=-0.451, p<0.05). No significant differences were observed for NID, or plasma NO(2)(-), NO(X), thrombomodulin, von Willebrand factor, and tissue factor pathway inhibitor levels. Chronic cigarette smoking induced endothelial dysfunction and the PAI-1 level could be a good marker of endothelial dysfunction in young smokers. PMID- 20943347 TI - Common knowledge regarding prevention of infective endocarditis among general dentists in Japan. AB - BACKGROUND: Infective endocarditis (IE) is known as a life-threatening disease, with bacteremia-inducing dental procedures considered to be one of the major factors. Thus, prevention of IE onset with antibiotics is widely recommended. Guidelines composed in the USA for prevention and treatment are well known, while the Japanese Circulation Society recently presented their own guidelines. On the other hand, there are few studies of the general knowledge of dentists regarding IE prevention. METHODS AND RESULTS: Questionnaires were distributed by postal mail to dentists who graduated from the Osaka University Faculty of Dentistry. Those with special backgrounds, such as oral surgeons, anesthesiologists, and orthodontists, were excluded. We analyzed a total of 159 questionnaires that were returned by the owners and staff of private dental clinics throughout Japan, whose careers as dentists ranged from 5 to 53 years. Approximately 90% reported encountering fewer than several patients at risk for IE per year and only 40% of the respondents were aware of the guidelines for its prevention. Furthermore, only 23 dentists reported the use of amoxicillin for prevention of IE, with diverse dosages and timing noted. CONCLUSIONS: These findings suggest that promotion of guidelines for prevention of IE to general dentists is important, although the frequency of cases encountered by general dentists is extremely low. PMID- 20943348 TI - Hair follicle is a target of stress hormone and autoimmune reactions. AB - Interest in the hair follicle (HF) has recently increased, yet the detailed mechanisms of HF function and immune privilege (IP) have not yet been elucidated. This review discusses the critical points of immunobiology and hormonal aspects of HFs. The HF is a unique mini-organ because it has its own immune system and hormonal milieu. In addition, the HF immune and hormonal systems may greatly affect skin immunobiology. Therefore, knowledge of HF immunobiology and hormonal aspects will lead to a better understanding of skin biology. The HF has a unique hair cycle (anagen, catagen and telogen) and contains stem cells in the bulge area. The HF is closely related to sebaceous glands and the nervous system. This article reviews the interaction between the endocrine/immune system and HFs, including the pathogenesis of alopecia areata associated with stress. PMID- 20943349 TI - Long-term psychopathology changes among the injured and members of the community after a massive terrorist attack. AB - BACKGROUND AND AIM: To document long-term prevalence trends and changes in post traumatic stress disorder (PTSD), current major depression (MD), agoraphobia, generalized anxiety disorder (GAD), and panic disorder, in two groups of people with different levels of exposure to a massive terrorist attack. METHODS: Cohort study. Two random samples of people exposed to a terrorist attack, the injured (n=127) and community residents (n=485) were followed and assessed, 2 and 18 months after the event. RESULTS: Among the injured, 2 and 18 months after the attack, the prevalences were respectively, PTSD: 44.1% and 34%, MD: 31.5% and 23.7%, agoraphobia: 23.8% and 20.7%, GAD: 13.4% and 12.4% and panic disorder: 9.4% and 11.3%. The corresponding figures among residents were PTSD: 12.3% and 3.5%, MD: 8.5% and 5.4%, agoraphobia: 10.5% and 8.7%, GAD: 8.6%, and 8.2% and panic disorder 2.1% and 2.7%. CONCLUSIONS: Two months after the event, the prevalence of mental disorders among both injured and residents was higher than expected levels at baseline conditions. Eighteen months after the event, psychopathological conditions did not change significantly among the injured but returned to the expected baseline rates among community residents. PMID- 20943350 TI - Epistatic interaction of CREB1 and KCNJ6 on rumination and negative emotionality. AB - G protein-activated K+ channel 2 (GIRK2) and cAMP-response element binding protein (CREB1) are involved in synaptic plasticity and their genes have been implicated depression and memory processing. Excessive rumination is a core cognitive feature of depression which is also present in remission. High scores on the Ruminative Response Scale (RRS) questionnaire are predictive of relapse and recurrence. Since rumination involves memory, we tested the hypothesis that variation in the genes encoding GIRK2 (KCNJ6) and CREB1 mechanisms would influence RRS scores. GIRK2 and CREB1 polymorphisms were studied in two independent samples (n=651 and n=1174) from the general population. Strongly significant interaction between the TT genotype of rs2070995 (located in KCNJ6) and the GG genotype of rs2253206 (located in CREB1) on RRS were found in both samples. These results were validated in an independent third sample (n=565; individuals with personality disorders) showing significant main effect of the variants mentioned as well as significant interaction on a categorical diagnosis of Cluster C personality disorder (obsessional-compulsive, avoidant and dependent) in which rumination is a prominent feature. Our results suggest that genetic epistasis in post-receptor signaling pathways in memory systems may have relevance for depression and its treatment. PMID- 20943351 TI - Differential effects of etifoxine on anxiety-like behaviour and convulsions in BALB/cByJ and C57BL/6J mice: any relation to overexpression of central GABAA receptor beta2 subunits? AB - Dysfunction of GABAergic transmission related to abnormal expression of GABA(A) receptor subunits in specific brain regions underlies some pathological anxiety states. Besides involvement of the benzodiazepine recognition site of GABA(A) receptor in the expression of anxiety-like behaviour, the roles of the beta(2)/beta(3) subunits are not well characterized. To address this issue, the experimental design of this study utilized the GABAergic compound etifoxine (with a preferential effectiveness after binding to a specific site at beta(2)/beta(3) subunits) tested in two inbred mouse strains: BALB/cByJ and C57BL/6J mice using three behavioural paradigms (light/dark box, elevated plus maze and restraint stress-induced small intestinal transit inhibition) and the t butylbicyclophosphorothionate-induced convulsions model. Etifoxine plasma and brain levels and beta(2)/beta(3) mRNAs and protein expression levels in various brain regions were compared between the two strains. The two mouse strains differed markedly in basal anxiety level. Etifoxine exhibited more pronounced anxiolytic and anticonvulsant effects in the BALB/cByJ mice compared to the C57BL/6J mice. The etifoxine brain/plasma ratios of the two strains were not different. Beta2 subunit mRNA and protein expression levels were around 25 and 10% higher respectively in the anterodorsal nucleus of the thalamus and the CA3 field of hippocampus of BALB/cByJ mice compared to C57BL/6J mice. Beta3 subunit mRNA and protein expression levels did not differ between the two strains. Based on these results, it is suggested that overexpression of GABA(A) receptor beta(2) subunit in BALB/cByJ mice relative to C57BL/6j mice contributes to the dysfunction in GABA(A) transmission in regions of brain known to regulate responses to stress. The dysregulated GABA(A) function in BALB/cByJ mice may be corrected by the administration of etifoxine. PMID- 20943352 TI - Emotional processing as a predictor of symptom change: an acute tryptophan depletion study in depressed patients. AB - Acute tryptophan depletion (ATD) in currently depressed patients has no immediate effect on symptoms, but leads to transient symptom improvement or worsening the next day. In view of recent findings concerning the cognitive effects of serotonin manipulations, we used ATD in fourteen depressed patients to investigate whether cognitive effects following ATD predict symptom changes. We found that symptom improvement 24h after ATD was associated with an improved recall of positive words and with less attentional bias and recall of negative words, 5h after ATD. These results indicate that serotonergic alterations affect emotional processing which may subsequently lead to symptom changes. PMID- 20943353 TI - [Cystic lymphangioma of the pancreas: an exceptional location]. AB - Cystic lymphangioma of the pancreas is a rare benign vascular tumor. Its histogenesis is still hypothetical and preoperative diagnosis is difficult. We report a new case in a 14-year-old girl hospitalized for pain in the epigastrium and vomiting. Radiologic findings concluded in a cystic tumor of the head of the pancreas. The mass was completely excised. The pathological examination of the surgical specimen revealed cystic formations whose wall consisted of a squamous endothelial epithelium on a fibrous tissue and a few scattered lymphoid clusters, arguing in favor of a cystic lymphangioma. PMID- 20943354 TI - [Is there a risk of steroid-induced adrenal deficit after induction treatment of acute lymphoblastic leukemia?]. AB - The occurrence of eight cases of adrenal deficit in children hospitalized for acute lymphoblastic leukemia (ALL) led us to conduct a prospective study from May 2006 to May 2007 to better characterize this corticoid-induced adrenal deficit. Forty of the 48 patients hospitalized for ALL were given a low-dose Synacthen test (1 MUg), a mean 7 days after the induction phase. An adrenal deficit was diagnosed in 27 patients (67.5%). No significant clinical or hematological difference was identified between the "with deficit" (n = 27) and "without deficit" (n = 13) groups. The diagnosis of adrenal deficit was not more common for children who had received dexamethasone (13/19) or prednisone (14/21), or for those who had (19/29) or had not (8/11) experienced corticoid toxicity during induction. The clinical signs suggesting adrenal deficit were identical in the two groups and none of the children presented an acute episode. In biological terms, only hypoprotidemia was significantly more common in patients with adrenal deficit (p = 0.0004). Of 13 patients with a deficit at the end of the induction who had received a 2nd low-dose Synacthene((r)) test before intensification no. 1, 3 weeks on average after the end of corticotherapy, only two still had a deficit. Thus, corticoid-induced adrenal deficit is a common complication in children treated for ALL, although it is not highly symptomatic. Most of these children recover normal adrenal function before intensification no. 1, but it does not eliminate the risk of a secondary deficit after other courses of corticotherapy. Systematic repeated Synacthene((r)) tests in common practice among children treated for ALL does not seem justified. However, the results of this study encouraged us to propose a hydrocortisone substitution to children treated for ALL in the event of stress. PMID- 20943355 TI - [Botryoid Wilms tumor extending into the duodenum]. AB - We report on a rare case of botryoid Wilms tumor extending into the duodenum. This uncommon macroscopic form of nephroblastoma consists entirely of a polypoid renal intrapelvic mass. The main differential diagnosis of this unusual tumor is botryoid rhabdomyosarcoma. A 14-month-old boy presented with a painful abdominal mass. Radiology revealed a large heterogeneous mass in the renal calyx, protruding into the ureter. A right radical nephroureterectomy was carried out. The tumor was found to extend into the 2nd portion of the duodenum. The pathologic diagnosis was mixed type nephroblastoma, SIOP 2001 stage III. The patient was given a course of postoperative chemotherapy. No local recurrence or metastatic spread has been detected after 2 years. Only few such cases have been previously reported, some of them extending into the bladder. To our knowledge, botryoid nephroblastoma has not previously been described as extending into the digestive system. PMID- 20943356 TI - [Pertussis infection and fatal pulmonary hypertension]. AB - Pertussis is ranked among the leading causes of childhood mortality. The most catastrophic clinical complication of pertussis in infants, intractable pulmonary hypertension with shock, is not very well known. We describe the clinical course of a fatal case of severe pertussis complicated by refractory pulmonary hypertension and shock in a 2-month-old infant. PMID- 20943357 TI - [A global, evidence-based consensus on the definition of gastroesophageal reflux disease in the pediatric population]. PMID- 20943358 TI - Different clinical significance of pre- and post-treatment plasma Epstein-Barr virus DNA load in nasopharyngeal carcinoma treated with radiotherapy. AB - AIMS: To correlate the pre-treatment plasma Epstein-Barr virus (EBV) DNA with tumour burden and to explore the prognostic implications of pre- and post treatment plasma EBV DNA load in nasopharyngeal carcinoma patients treated with radiotherapy. MATERIALS AND METHODS: Plasma EBV DNA load was measured using a real-time quantitative polymerase chain reaction assay in 69 patients with nasopharyngeal carcinoma before and after radiation treatment and correlated with tumour volume and treatment outcome. Tumour volume was calculated by multiplying the sum of the areas of gross extent of the primary tumour and regional lymph nodes shown by computed tomography images and/or magnetic resonance imaging. Prognostic models for distant metastasis and overall survival were constructed using a multivariable fractional polynomial algorithm. RESULTS: The pre-treatment plasma EBV DNA concentration was significantly associated with tumour volume (Spearman correlation coefficient, 0.61; P<0.001). The multivariable fractional polynomial algorithm selected post-treatment EBV DNA and administration of chemotherapy as prognostic factors for distant metastasis (P<0.001, P=0.021, respectively), as well as for overall survival (P<0.001, P=0.018, respectively). CONCLUSIONS: Pre- and post-treatment plasma EBV DNA load have important clinical significance. Pre-treatment plasma EBV DNA concentration reflects tumour burden, whereas clearance of circulating plasma EBV DNA after treatment predicts the risk of distant metastasis and overall survival. PMID- 20943359 TI - The involvement of sand disturbance, cannibalism and intra-guild predation in competitive interactions among pit-building antlion larvae. AB - Competition in trap-building predators such as antlion larvae is a complex biotic interaction, potentially involving exploitation competition, sand throwing (i.e., interference competition), cannibalism and intra-guild predation. We investigated the short-term behavioral and developmental responses of the strict sit-and-wait antlion predator Myrmeleon hyalinus to sand disturbance (i.e., quantification of the impact of severe sand throwing), and to con- and hetero-specific competition by a larger sit-and-pursue antlion species Lopezus fedtschenkoi. We found that antlions subjected to sand disturbances reduced their pit construction activity and relocated less often. Furthermore, the reduction in pit construction activity was stronger among antlions subjected to disturbances prior to feeding. Almost no death occurred during the sand disturbance experiment, but as expected, disturbances caused reductions in the relative growth rates of antlions. This negative effect was stronger in the group exposed to sand disturbances prior to feeding. The presence of the sit-and-pursue competitor led to reductions both in pit construction and in relocation activities of M. hyalinus. Although the per capita food supply was identical in both experiments, only 48% of M. hyalinus larvae survived the competition experiment, and this pattern was consistent between the con- and hetero-specific treatments. However, in the presence of hetero-specific competitors, the relative growth rate of surviving larvae was significantly lower than that measured in the presence of con-specific competitors. Our study demonstrates that investigating the different components of complex biotic interactions can markedly improve our understanding of how these different factors interact to influence the behavior and life history of organisms. PMID- 20943360 TI - Regulation of selenoprotein mRNA expression by hormones and retinoic acid in bovine mammary cells. AB - Selenium is essential for maintaining many body functions through the actions of selenoproteins. To find factors regulating selenoprotein biosynthesis in the bovine mammary cell line MAC-T, the effects of supplementation with selenite and also with retinoic acid, insulin, hydrocortisone and prolactin on the mRNA expression of a number of selenoproteins were investigated. It was found that MAC T cells express glutathione peroxidase (GPx) 1 and 4, thioredoxin reductase 1 and selenoprotein P, but not GPx 3, which is interesting considering that GPx 3 is one of the only few selenoproteins detected in milk so far. Addition of selenite to the cell culture resulted in a large increase in GPx 1 expression and an increase in selenoprotein P expression, which is similar to the findings made in other systems investigated. Increased mRNA levels of GPx 1 were also observed in cells treated with insulin and hydrocortisone or with retinoic acid. The expression of thioredoxin reductase 1 was increased in cells treated with retinoic acid, whereas that of selenoprotein P was decreased in cells exposed to insulin. The results indicate that several hormones, selenium, and retinoic acid regulate the biosynthesis of various selenoproteins differently in the bovine mammary cell. The possible implications of the findings for processes related to milk formation and mammary carcinogenesis will need additional investigation. Further study of the detailed mechanisms involved is also necessary. PMID- 20943361 TI - Con: the treatment of the granulomatous response is beneficial in acute sarcoidosis. PMID- 20943362 TI - Control of the oocyte-to-embryo transition by the ubiquitin-proteolytic system in mouse and C. elegans. AB - In metazoans the oocyte-to-embryo transition occurs in the absence of mRNA transcription and relies entirely on maternally provided mRNA and proteins. We review here recent findings illustrating the importance of degradation of key proteins allowing essential cell cycle transitions as well as important remodelling of the oocyte to produce a totipotent zygote. By following the chronological order of events, we update recent discoveries on the instrumental role of the cullin-RING and APC/C ubiquitin-ligases in promoting meiosis resumption and the oocyte-to-embryo transition. PMID- 20943363 TI - Spatial variability of soil gas concentration and methane oxidation capacity in landfill covers. AB - In order to devise design criteria for biocovers intended to enhance the microbial oxidation of landfill methane it is critical to understand the factors influencing gas migration and methane oxidation in landfill cover soils. On an old municipal solid waste landfill in north-western Germany soil gas concentrations (10, 40, 90 cm depth), topsoil methane oxidation capacity and soil properties were surveyed at 40 locations along a 16 m grid. As soil properties determine gas flow patterns it was hypothesized that the variability in soil gas composition and the subsequent methanotrophic activity would correspond to the variability of soil properties. Methanotrophic activity was found to be subject to high spatial variability, with values ranging between 0.17 and 9.80 g CH(4)m( 2)h(-1)(.) Considering the current gas production rate of 0.03 g CH(4)m(-2)h(-1), the oxidation capacity at all sampled locations clearly exceeded the flux to the cover, and can be regarded as an effective instrument for mitigating methane fluxes. The methane concentration in the cover showed a high spatial heterogeneity with values between 0.01 and 0.32 vol.% (10 cm depth), 22.52 vol.% (40 cm), and 36.85 vol.% (90 cm). The exposure to methane raised the oxidation capacity, suggested by a statistical correlation to an increase in methane concentration at 90 cm depth. Methane oxidation capacity was further affected by the methanotroph bacteria pH optimum and nutrient availability, and increased with decreasing pH towards neutrality, and increased with soluble ion concentration). Soil methane and carbon dioxide concentration increased with lower flow resistance of the cover, as represented by the soil properties of a reduced bulk density, increase in air capacity and in relative ground level. PMID- 20943364 TI - End-of-Life Vehicles management: Italian material and energy recovery efficiency. AB - Each European Member State must comply with Directive 2000/53/EC recycling and recovery targets by 2015, set to 85% and 95%, respectively. This paper reports a shredder campaign trial developed and performed in Italy at the beginning of 2008. It turns out to be the first assessment about the critical aspects belonging to the Italian End-of-Life Vehicles (ELVs) reverse supply chain involving 18 dismantling plants, a shredder plant and 630 ELV representatives of different categories of vehicles treated in Italy during 2006. This trial aims at improving the experimental knowledge related to ELVs added waste, pre-treatment, part reuse, recycling and final metal separation and car fluff disposal. Finally, the study also focuses on the calculation of the effective Italian ELV recycling rate, which results equal to 80.8%, and auto shredder residue (ASR) characterization. According to the results obtained in this work, ASR still contains up to 8% of metals and 40% of polymers that could be recovered. Moreover, physical-chemical analysis showed a Lower Heat Value of almost 20,000 kJ/kg and revealed the presence of pollutants such as heavy metals, mineral oils, PCBs and hydrocarbons. PMID- 20943365 TI - Construction materials as a waste management solution for cellulose sludge. AB - Sustainable waste management system for effluents treatment sludge has been a pressing issue for pulp and paper sector. Recycling is always recommended in terms of environmental sustainability. Following an approach of waste valorisation, this work aims to demonstrate the technical viability of producing fiber-cement roof sheets incorporating cellulose primary sludge generated on paper and pulp mills. From the results obtained with preliminary studies it was possible to verify the possibility of producing fiber-cement sheets by replacing 25% of the conventional used virgin long fiber by primary effluent treatment cellulose sludge. This amount of incorporation was tested on an industrial scale. Environmental parameters related to water and waste, as well as tests for checking the quality of the final product was performed. These control parameters involved total solids in suspension, dissolved salts, chlorides, sulphates, COD, metals content. In the product, parameters like moisture, density and strength were controlled. The results showed that it is possible to replace the virgin long fibers pulp by primary sludge without impacts in final product characteristics and on the environment. This work ensures the elimination of significant waste amounts, which are nowadays sent to landfill, as well as reduces costs associated with the standard raw materials use in the fiber-cement industrial sector. PMID- 20943366 TI - Mathematical model analysis of Fenton oxidation of landfill leachate. AB - The treatment of concentrated landfill leachate rejected from reverse osmosis (RO) with Fenton process was studied, and the system model was developed through the examination of reaction kinetics. The leachate is typically non-biodegradable with low BOD(5)/COD ratio 0.01. The oxidation reactions of Fenton process was found to be a two-stage process, where a fast initial reaction (H(2)O(2)/Fe(2+)) was followed by a much slower one (H(2)O(2)/Fe(3+)). A simple and more accurate mathematics model based on COD and TOC removals has been derived successfully to describe the two-stage reaction kinetics. The two corresponding parameters involved in this model have been identified as the initial reaction rate and the maximum oxidation removal efficiency, respectively. It was found to be very useful for evaluating the performance of Fenton system and/or for process design using the two parameters under different experimental conditions. PMID- 20943367 TI - Ultrasensitive microchip sensor based on boron-containing polyfluorene nanofilms. AB - A fluorene-based pi-conjugated copolymer with on-chain dibenzoborole units was used in the development of a nanocoated gold interdigitated microelectrode array device which successfully detects fluoride in a broad range of concentrations (10(-11)-10(-4) M) in aqueous solution, upon impedance spectroscopy measurements. A calibration curve obtained over this range of concentrations and a new analytical method based on impedance spectroscopy measurements in aqueous solution is proposed. The sensor nanofilm was produced by spin-coating and diagnosed via spectroscopic ellipsometry, AFM, and electrically conductivity techniques. Changes in the conductivity due to the boron-fluoride complex formation seem to be the major mechanism behind the dependence of impedimetric results on the fluoride concentration. PMID- 20943368 TI - Olfactory receptor cells respond to odors in a tissue and semiconductor hybrid neuron chip. AB - Olfactory systems of human beings and animals have the abilities to sense and distinguish varieties of odors. In this study, a bioelectronic nose was constructed by fixing biological tissues onto the surface of light-addressable potentiometric sensor (LAPS) to mimic human olfaction and realize odor differentiation. The odorant induced potentials on tissue-semiconductor interface was analyzed by sensory transduction theory and sheet conductor model. The extracellular potentials of the receptor cells in the olfactory epithelium were detected by LAPS. Being stimulated by different odorants, such as acetic acid and butanedione, olfactory epithelium activities were analyzed on basis of local field potentials and presented different firing modes. The signals fired in different odorants could be distinguished into different clusters by principal component analysis (PCA). Therefore, with cellular populations well preserved, the epithelium tissue and LAPS hybrid system will be a promising neuron chip of olfactory biosensors for odor detecting. PMID- 20943370 TI - Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies. AB - BACKGROUND: Due to the rising trend of delaying pregnancy to later in life, more women are diagnosed with breast cancer before completing their families. Therefore, enquiry into the feasibility and safety of pregnancy following breast cancer diagnosis is on the rise. Available evidence suggests that women with a history of breast cancer are frequently advised against future conception for fear that pregnancy could adversely affect their breast cancer outcome. Hence, we conducted a meta-analysis to understand the effect of pregnancy on overall survival of women with a history of breast cancer. METHODS: Two of the authors independently performed a literature search up to September 2009 with no language restrictions. Eligible studies were published retrospective control-matched, population-based and hospital-based studies that have addressed the impact of pregnancy on the overall survival of women with history of breast cancer. Pooling of data was done using the random effect model. Unpublished statistics from three studies were obtained to perform further subgroup and sensitivity analyses. This included examining the effect of pregnancy according to age at diagnosis, healthy mother effect, type of study, nodal status and other parameters. RESULTS: Fourteen studies were included in this meta-analysis (1244 cases and 18,145 controls). Women who got pregnant following breast cancer diagnosis had a 41% reduced risk of death compared to women who did not get pregnant [PRR: 0.59 (90% confidence interval (CI): 0.50-0.70)]. This difference was seen irrespective of the type of the study and particularly in women with history of node-negative disease. In a subgroup analysis, we compared the outcome of women with history of breast cancer who became pregnant to breast cancer patients who did not get pregnant and were known to be free of relapse. In this analysis, we did not find significant differences in survival between either group [PRR: 0.85; 95% CI: 0.53 1.35]. CONCLUSIONS: This study confirms that pregnancy in women with history of breast cancer is safe and does not compromise their overall survival. Hence, breast cancer survivors should not be denied the opportunity of future conception. PMID- 20943369 TI - A bird's eye view of neural circuit formation. AB - Neural circuits underlying complex learned behaviors, such as speech in humans, develop under genetic constraints and in response to environmental influences. Little is known about the rules and mechanisms through which such circuits form. We argue that songbirds, with their discrete and well studied neural pathways underlying a complex and naturally learned behavior, provide a powerful model for addressing these questions. We briefly review current knowledge of how the song circuit develops during learning and discuss new possibilities for advancing the field given recent technological advances. PMID- 20943371 TI - Grifolin, a potent antitumour natural product upregulates death-associated protein kinase 1 DAPK1 via p53 in nasopharyngeal carcinoma cells. AB - Grifolin, a secondary metabolite isolated from the fresh fruiting bodies of the mushroom Albatrellus confluens, has been shown to inhibit the growth of some cancer cell lines in vitro by induction of apoptosis in previous studies of our group. However, the mechanisms of action are not completely understood. An apoptosis-related gene expression profiling analysis provided a clue that death associated protein kinase 1 (dapk1) gene was upregulated at least twofold in response to grifolin treatment in nasopharyngeal carcinoma cell CNE1. Here, we further investigated the role of DAPK1 in apoptotic effect induced by grifolin. We observed that protein as well as mRNA level of DAPK1 was induced by grifolin in a dose-dependent manner in nasopharyngeal carcinoma cell CNE1. We found that grifolin increased both Ser392 and Ser20 phosphorylation levels of transcription factor p53 protein, which could promote its transcriptional activity. Moreover, induced by grifolin, the recruitment of p53 to dapk1 gene promoter was confirmed to enhance markedly using EMSA and ChIP assays analysis. The involvement of DAPK1 in grifolin-induced apoptosis was supported by the studies that introducing siRNA targeting DAPK1 to CNE1 cells remarkably interfered grifolin-caused apoptotic effect as well as the activation of caspase-3. Grifolin induced upregulation of DAPK1 via p53 was also observed in tumour cells derived from human breast cancer and human colon cancer. The findings suggest that upregulation of DAPK1 via p53 DAPK1 pathway is an important mechanism of grifolin contributing to its ability to induce apoptotic effect. Since growing evidence found a significant loss of DAPK1 expression in a large variety of tumour types, grifolin may represent a promising candidate in the intervention of cancer via targeting DAPK1. PMID- 20943372 TI - Follow-up care amongst long-term childhood cancer survivors: a report from the Swiss Childhood Cancer Survivor Study. AB - In the Swiss Childhood Cancer Survivor Study, we aimed to assess the proportion of long-term survivors attending follow-up care, to characterise attendees and to describe the health professionals involved. We sent a questionnaire to 1252 patients, of whom 985 (79%) responded, aged in average 27 years (range 20-49). Overall, 183 (19%) reported regular, 405 (41%) irregular and 394 (40%) no follow up. For 344, severity of late effects had been classified in a previous medical examination. Only 17% and 32% of survivors with moderate and severe late effects respectively had made regular visits a decade later. Female gender, after a shorter time since diagnosis, had radiotherapy, and having suffered a relapse predicted follow-up. In the past year, 8% had seen a general practitioner only, 10% a paediatric or adult oncologist and 16% other health specialists for a cancer related problem. These findings underline the necessity to implement tailored national follow-up programmes. PMID- 20943374 TI - Phase II study of gemcitabine combined with oxaliplatin in relapsed or refractory paediatric solid malignancies: An innovative therapy for children with Cancer European Consortium Study. AB - AIM: To assess objective response rates after 4 cycles of gemcitabine in combination with oxaliplatin in children and adolescents with relapsed or refractory solid tumours. METHODS: This multicentre, non-randomised Phase II study included five strata: neuroblastoma, osteosarcoma, medulloblastoma and other CNS tumours strata with two-stage Simon designs and a miscellaneous, extra cranial solid tumour stratum with descriptive design. Eligibility criteria included: age 6 months to 21 years; measurable, relapsed or refractory solid malignancy; no more than one previous salvage therapy. Gemcitabine was administered intravenously at 1000 mg/m(2) over 100 min followed by oxaliplatin at 100mg/m(2) over 120 min on Day 1 of a 14-d cycle. Tumour response was assessed every 4 cycles according to WHO criteria. RESULTS: Ninety-three out of 95 patients enrolled in 25 centres received treatment: 12 neuroblastoma; 12 osteosarcoma; 14 medulloblastoma; 13 other CNS tumours and 42 miscellaneous non CNS solid tumours. Median age was 11.7 years (range, 1.3-20.8 years). Tumour control (CR+PR+SD) at 4 cycles was obtained in 30/93 evaluable patients (32.3%; 95% confidence interval (CI), 22.9-42.7%), including four PR: 1/12 patients with osteosarcoma, 1/12 with medulloblastoma, 1/12 with rhabdomyosarcoma and 1/4 with other sarcoma. Five out of 12 eligible patients with neuroblastoma experienced stable disease. During a total of 481 treatment cycles (median 4, range 1-24 per patient), the most common treatment-related toxicities were haematologic (leukopenia, neutropenia, thrombocytopenia) and neurological (dysesthesia, paresthesia). CONCLUDING STATEMENT: The gemcitabine-oxaliplatin combination administered in a bi-weekly schedule has acceptable safety profile with limited activity in children with relapsed or refractory solid tumours. PMID- 20943375 TI - Up-to-date estimates of breast cancer survival for the years 2000-2004 in 11 European countries: the role of screening and a comparison with data from the United States. AB - INTRODUCTION: We investigated survival in breast cancer patients by age group, focussing on those covered by screening programmes, using data from 12 European population-based cancer registries participating in the European Network for Indicators on Cancer Survival Working Group. METHODS: We calculated period estimates of 5-year relative survival for 2000-2004 and examined the change in survival estimates for four age groups between 1990-1994 and 2000-2004. Trends in age specific incidence, survival and mortality were additionally compared to those in the United States based on results from the Surveillance Epidemiology and End Results (SEER) programme. RESULTS: Breast cancer survival uniformly increased particularly in areas with lower breast cancer survival for patients diagnosed in 1990-1994. With the exception of Geneva, Scotland and Estonia, the rise in survival was always larger among the younger age groups than in the 70+ age group and the age-gradient widened over time. The 5-year relative survival of patients aged 70 and above in the European registries was at least 7 percentage points lower than the 5-year relative survival of patients in the same age group in the US in 2000-2004. During the study period, incidence increased in all age groups and populations with a few exceptions, an observation paralleled by declining mortality. CONCLUSIONS: Results showed that some of the geographical differences in overall survival are even larger when considering age groups, in particular between Western and Eastern European countries. Furthermore, some of the differences in survival within the Northern and Western European areas could be due to variations in the implementation of screening programmes rather than economic inequalities. PMID- 20943376 TI - Preparation and characterization of bio-oils from internally circulating fluidized-bed pyrolyses of municipal, livestock, and wood waste. AB - Fast pyrolyses of sewage sludge (SS), pig compost (PC), and wood chip (WC) were investigated in an internally circulating fluidized-bed to evaluate bio-oil production. The pyrolyses were performed at 500 degrees C and the bio-oil yields from SS, PC, and WC were 45.2%, 44.4%, and 39.7% (dried and ash-free basis), respectively. The bio-oils were analyzed with an elemental analyzer, Karl-Fischer moisture titrator, bomb calorimeter, Fourier transformation infrared spectrometer, gel permeation chromatograph, and gas chromatography/mass spectrometry. The results show that the bio-oil from SS is rich in aliphatic and organonitrogen species, while the bio-oil from PC exhibits higher caloric value due to its higher carbon content and lower oxygen content in comparison with that from SS. The bio-oils from SS and PC have similar chemical composition of organonitrogen species. Most of the compounds detected in the bio-oil from WC are organooxygen species. Because of its high oxygen content, low H/C ratio, and caloric value, the bio-oil from WC is unfeasible for use as fuel feedstock, but possible for use as chemical feedstock. PMID- 20943377 TI - Nitrogen transformations under different conditions in open ponds by means of microalgae-bacteria consortium treating pig slurry. AB - Four open ponds inoculated with microalgae-bacteria consortium treating different swine slurries (fresh and anaerobically digested) were evaluated in terms of nitrogen transformation under optimal and real conditions of temperature and illumination. Ammonium complete depletion was not achieved. Ponds operated under real conditions presented lower ammonium removal. Elimination capacities were around 26 mg N/Ld and were subsequently increased with increasing inlet ammonium loading rate. Different nitrogen transformation was observed depending on substrate source. When anaerobically digested slurry was fed to the ponds, nitrification followed by biomass uptake and denitrification were the main nitrogen transformation taking place depending on inlet ammonium loading rate and operational conditions. Ponds fed with fresh slurry exhibited denitrification as the main nitrogen removal mechanism for the pond operated under real conditions while under optimal conditions stripping, denitrification and biomass uptake contributed similarly. Therefore, this study confirmed that the so-claimed nitrogen recovery by microalgae biomass is frequently overestimated. PMID- 20943378 TI - High temperature dilute acid pretreatment of coastal Bermuda grass for enzymatic hydrolysis. AB - Dilute sulfuric acid was used to pretreat coastal Bermuda grass at high temperature prior to enzymatic hydrolysis. After both pretreatment and enzymatic hydrolysis processes, the highest yield of total sugars (combined xylose and glucose) was 97% of the theoretical value. The prehydrolyzate liquor was analyzed for inhibitory compounds (furfural, hydroxymethylfurfural (HMF)) in order to assess potential risk for inhibition during the following fermentation. Accounting for the formation of the inhibitory compounds, a pretreatment with 1.2% acid at 140 degrees C for 30 min with a total sugar yield of 94% of the theoretical value may be more favorable for fermentation. From this study, it can be concluded that dilute sulfuric acid pretreatment can be successfully applied to coastal Bermuda grass to achieve high yields of monomeric glucose and xylose with acceptable levels of inhibitory compound formation. PMID- 20943379 TI - Bioaugmentation of a biological contact oxidation ditch with indigenous nitrifying bacteria for in situ remediation of nitrogen-rich stream water. AB - In this study, specialized bacteria were domesticated and cultivated with polluted stream water. The bioaugmentation of specialized bacteria would significantly enhance the removal efficiency of TN and NH4+-N from 25.9% to 50.3%, and from 34.5% to 60.1%, respectively. Concomitant increases in the number of microbial communities and the proportion of nitrifying bacteria were also identified by the most probable number (MPN) method. PCR-DGGE profiles revealed that the bacterial community could be successfully enriched and the ammonia oxidizing bacteria communities were shown predominant by the species of Nitrosomonas. The biological contact oxidation ditch (BCOD) system augmented with specialized bacteria can be a viable alternative for treating polluted stream water to achieve improved nitrogen removal. PMID- 20943380 TI - Influence of supports on catalytic behavior of nickel catalysts in carbon dioxide reforming of toluene as a model compound of tar from biomass gasification. AB - A series of supported Ni catalysts including Ni/MgO, Ni/gamma-Al2O3, Ni/alpha Al2O3, Ni/SiO2 and Ni/ZrO2 was tested in CO2 reforming of toluene as a model compound of tar from biomass gasification in a fluidized bed reactor, and characterized by the means of temperature programmed reduction with hydrogen (H2 TPR), XRD, TEM and temperature programmed oxidation (TPO). Combining the characterization results with the performance tests, the activity of catalyst greatly depended on Ni particles size, and the stability was affected by the coke composition. Both of them (Ni particle size and coke composition) were closely related to the interaction between nickel and support which would determine the chemical environment where Ni inhabited. The best catalytic performance was observed on Ni/MgO due to the strong interaction between NiO and MgO via the formation of Ni-Mg-O solid solution, and the highest dispersion of Ni particle in the basic environment. PMID- 20943381 TI - Hydrolysis of different chain length xylooliogmers by cellulase and hemicellulase. AB - Commercial cellulase complexes produced by cellulolytic fungi contain enzyme activities that are capable of hydrolyzing non-cellulosic polysaccharides in biomass, primarily hemicellulose and pectins, in addition to cellulose. However, xylanase activities detected in most commercial enzyme preparations have been shown to be insufficient to completely hydrolyze xylan, resulting in high xylooligomer concentrations remaining in the hydrolysis broth. Our recent research showed that these xylooligomers are stronger inhibitors of cellulase activity than others have previously established for glucose and cellobiose, making their removal of great importance. In this study, a HPLC system that can measure xylooligomers with degrees of polymerization (DP) up to 30 was applied to assess how Spezyme CP cellulase, Novozyme 188 beta-glucosidase, Multifect xylanase, and non-commercial beta-xylosidase enzymes hydrolyze different chain length xylooligomers derived from birchwood xylan. Spezyme CP cellulase and Multifect xylanase partially hydrolyzed high DP xylooligomers to lower DP species and monomeric xylose, while beta-xylosidase showed the strongest ability to degrade both high and low DP xylooligomers. However, about 10-30% of the higher DP xylooligomers were difficult to be breakdown by cellulase or xylanase and about 5% of low DP xylooligomers (mainly xylobiose) proved resistant to hydrolysis by cellulase or beta-glucosidase, possibly due to low beta-xylosidase activity in these enzymes and/or the precipitation of high DP xylooligomers. PMID- 20943382 TI - Lactic acid production from corn stover using mixed cultures of Lactobacillus rhamnosus and Lactobacillus brevis. AB - Mixed cultures of Lactobacillus rhamnosus and Lactobacillus brevis was studied for improving utilization of both cellulose- and hemicellulose-derived sugars from corn stover for lactic acid production. During simultaneous saccharification and fermentation (SSF) of NaOH-treated corn stover by the mixed cultures, a lactic acid yield of 0.70 g/g was obtained, which was about 18.6% and 29.6% higher than that by single cultures of L. rhamnosus and L. brevis, respectively. Our results indicated that lactic acid yield from NaOH-pretreated corn stover by mixed cultures of L. rhamnosus and L. brevis was comparable to that from pure sugar mixtures (0.73 g/g of glucose/xylose mixture at 3:1 w/w). PMID- 20943383 TI - Modelling mono-digestion of grass silage in a 2-stage CSTR anaerobic digester using ADM1. AB - This paper examines 174 days of experimental data and modelling of mono-digestion of grass silage in a two stage wet process with recirculation of liquor; the two vessels have an effective volume of 312 L each. The organic loading rate is initiated at 0.5 kg VS m(-3) d(-1) (first 74 days) and subsequently increased to 1 kg VS m(-3) d(-1). The experimental data was used to generate a mathematical model (ADM1) which was calibrated over the first 74 days of operation. Good accuracy with experimental data was found for the subsequent 100 days. Results of the model would suggest starting the process without recirculation and thus building up the solids content of the liquor. As the level of VFA increases, recirculation should be employed to control VFA. Recirculation also controls solids content and pH. Methane production was estimated at 88% of maximum theoretical production. PMID- 20943384 TI - Changes in composition and sugar release across the annual rings of Populus wood and implications on recalcitrance. AB - Understanding structural characteristics that are responsible for biomass recalcitrance by identifying why it is more difficult for some plants, or portions of plants, to release their sugars would be extremely valuable in overcoming this barrier. With this in mind, this study investigated the recalcitrance of wood by considering the effects of aging in two Populus tremuloides cross sections. By applying our novel small scale systems, including a multi-well pretreatment and enzymatic hydrolysis system and a downscaled compositional analysis procedure, we were able to follow ring-by-ring compositions and sugar release patterns. Observed variations were then related to structural changes that occur across the radial direction of trees, providing an important step toward understanding the influence of these changes on recalcitrance. PMID- 20943385 TI - The structure and antimalarial activity of dispiro-1,2,4,5-tetraoxanes derived from (+)-dihydrocarvone. AB - An unsaturated dispiro 1,2,4,5-tetraoxane formed by peroxidation of (+) dihydrocarvone was converted into four structurally diverse derivatives. X-ray crystallographic analysis shows that the structures possess central tetraoxane rings with spiro-2,5-disubstituted cyclohexylidene substituents and 6-membered rings in classical chair conformations. As polarity in the tetraoxane series increased, in vitro potency against Plasmodium falciparum decreased. PMID- 20943386 TI - Apoptotic action of ursolic acid isolated from Corni fructus in RC-58T/h/SA#4 primary human prostate cancer cells. AB - Ursolic acid (3beta-hydroxy-urs-12-en-28-oic acid) is a major biological active component of Corni fructus that is known to induce apoptosis. However, the apoptotic mechanism of ursolic acid using primary malignant tumor (RC-58T/h/SA#4) derived human prostate cells is not known. In the present study, ursolic acid significantly inhibited the growth of RC-58T/h/SA#4 cells in dose- and time dependent manners. Ursolic acid induced cell death as evidenced by an increased proportion of cells in sub-G1 phase, the formation of apoptotic bodies, nuclear condensation, and DNA fragmentation. After ursolic acid treatment at concentrations above 40 MUM, the activities of caspase-3, -8, and -9 were significantly increased compared that of control. Ursolic acid modulated the upregulation of Bax (pro-apoptotic) as well as the downregulation of Bcl-2 (anti apoptotic). Ursolic acid also stimulated Bid cleavage, which indicates that the apoptotic action of caspase-8-mediated Bid cleavage leads to the activation of caspase-9. Thus, the apoptotic effect of ursolic acid was involved in extrinsic and intrinsic signaling pathways. In addition, ursolic acid increased the expression of the caspase-independent mitochondrial apoptosis factor (AIF) in RC 58T/h/SA#4 cells. The present results suggest that ursolic acid from Corni fructus activated apoptosis in RC-58T/h/SA#4 cells via both caspase-dependent and -independent pathways. PMID- 20943387 TI - Synthesis and biological evaluation of 3-substituted-benzofuran-2-carboxylic esters as a novel class of ischemic cell death inhibitors. AB - A series of 3-substituted-benzofuran-2-carboxylic esters was synthesized and evaluated for biological activity as ischemic cell death inhibitors in H9c2 cells and rat primary cardiac myocytes under conditions of oxygen and glucose deprivation. The introduction of a sulfur atom at the three-position substituent of the benzofuran ring markedly improved ischemic cell death inhibitory potency. In particular, 3-[2-(4-nitro-phenylsulfanyl)-acetylamino]-benzofuran-2-carboxylic acid ester (10) (EC(50)=0.532 MUM, cell death=6.18%) and 4-chloro-3-[3-(pyridin-2 ylsulfanyl)-propionylamino]-benzofuran-2-carboxylic ester (18) (EC(50)=0.557 MUM, cell death=7.02%) were shown to be the most potent in this series of benzofuran analogs. PMID- 20943388 TI - Detection of Rap1A as a yessotoxin binding protein from blood cell membranes. AB - As is the case with other ladder-shaped polyether compounds, yessotoxin is produced by marine dinoflagellate, and possesses various biological activities beside potent toxicity. To gain a better understanding of the molecular mechanism for high affinity between these polyethers and their binding proteins, which accounts for their powerful biological activities, we searched for its binding proteins from human blood cells by using the biotin-conjugate of desulfated YTX as a ligand. By a protein pull-down protocol with use of streptavidin beads, a band of specifically binding proteins was detected in SDS-PAGE. HPLC-tandem mass spectrometry (MS/MS) indicated that Rap 1A, one of Ras superfamily proteins, binds to the YTX-linked resins. Western blotting and surface plasmon resonance experiments further confirmed that Rap1A specifically binds to YTX with the K(D) value around 4 MUM. PMID- 20943389 TI - Triazolyl tryptoline derivatives as beta-secretase inhibitors. AB - Tryptoline, a core structure of ochrolifuanine E, which is a hit compound from virtual screening of the Thai herbal database against BACE1 was used as a scaffold for the design of BACE1 inhibitors. The tryptoline was linked with different side chains by 1,2,3-triazole ring readily synthesized by catalytic azide-alkyne cycloaddition reactions. Twenty two triazolyl tryptoline derivatives were synthesized and screened for the inhibitory action against BACE1. JJCA-140 was the most potent inhibitor (IC(50)=1.49 MUM) and was 100 times more selective for BACE1 than for Cat-D. PMID- 20943390 TI - Synthesis and biological evaluation of [D-lysine]8cyclosporin A analogs as potential anti-HCV agents. AB - An efficient synthesis of [D-lysine](8)cyclosporin A has been developed. Several analogs of [D-lysine](8)cyclosporin A have been synthesized and show promising anti-HCV activity, particularly compounds 39 and 43, which each exhibit an anti HCV EC(50)<200 nM, and are each >=50-fold less immunosuppressive than cyclosporin A. PMID- 20943391 TI - Design, synthesis and biological evaluation of quinoline amide derivatives as novel VEGFR-2 inhibitors. AB - Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in the process of cancer angiogenesis. A series of quinoline amide derivatives were prepared and found to be good inhibitors of VEGFR-2. The inhibitory activities were investigated against VEGFR-2 kinase and human umbilical vein endothelial cells (HUVEC) in vitro. Compound 6 (5-chloro-2-hydroxy-N-(quinolin-8 yl)benzamide) exhibited the most potent inhibitory activity (IC(50)=3.8 and 5.5 nM for VEGFR-2 kinase and HUVEC, respectively). Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the ATP-binding site of VEGFR-2, which demonstrates that compound 6 is a potential agent for cancer therapy deserving further researching. PMID- 20943392 TI - A protecting group-free synthesis of deazathiamine: a step toward inhibitor design. AB - The discovery of 3-deazathiamine diphosphate (deazaThDP) as a potent inhibitor analog of the cofactor thiamine diphosphate (ThDP) has highlighted the need for an efficient and scalable synthesis of deazaThDP. Such a method would facilitate development of analogs with the ability to inhibit individual ThDP-dependent enzymes selectively. Toward the goal of developing selective inhibitors of the mycobacterial enzyme 2-hydroxy-3-oxoadipate synthase (HOAS), we report an improved synthesis of deazaThDP without use of protecting groups. Tribromo-3 methylthiophene served as a versatile starting material whose selective functionalization permitted access to deazaThDP in five steps, with potential to make other analogs accessible in substantial amounts. PMID- 20943393 TI - Postural control in women with multiple sclerosis: effects of task, vision and symptomatic fatigue. AB - People with multiple sclerosis (MS) often report problems with balance, which may be most apparent during challenging postural tasks such as leaning or reaching, and when relying on non-visual sensory systems. An additional obstacle facing people with MS is a high incidence of symptomatic fatigue (>70%). The purpose of this study was to investigate the changes in balance during upright stance in individuals with mild-to-moderate disability due to MS under normal and restricted vision and different levels of self-reported fatigue. Limb loading asymmetry, sway and magnitude of postural shift in center of pressure, and time to-contact the stability boundary of the center of mass and center of pressure were assessed during quiet standing and maximal lean and reach tasks. Compared to controls, people with MS displayed greater postural sway, greater loading asymmetry, and shorter time-to-contact during quiet standing. In the postural perturbation tasks the MS group had smaller postural shifts and reduced stability compared to controls in the direction perpendicular to the lean and reach. Limiting vision increased loading asymmetry during quiet standing and postural instability during backward lean in the MS group. Inducing additional fatigue in the MS group did affect postural control in the more challenging balance conditions but had no impact during quiet upright standing. The results of this study indicate subtle changes in postural control during standing in people with mild-to-moderate impairments due to MS. PMID- 20943394 TI - High angiogenic potential in an in vivo rat corneal model is associated with shorter disease-free survival in low-grade oligodendrogliomas. AB - This study aimed to examine the association between time to tumor recurrence, angiogenic potential and tumor contrast-enhancement. Tumor samples were taken from 20 patients with low-grade oligodendroglioma and examined for their angiogenic potential using an in vivo rat corneal model of angiogenesis. Patients were evaluated for tumor contrast enhancement prior to surgical excision using MRI and they were followed for tumor recurrence. Patients who had tumors without contrast enhancement had longer disease-free survival (median time to tumor recurrence, 72 months) compared to those who had tumors with contrast enhancement (median, 42 months; p=0.0068). Based on corneal angiogenesis assay results, a high angiogenic potential was associated with a significantly shorter disease free survival. Our findings suggest that radiological contrast enhancement and a high angiogenic potential based on an in vivo corneal angiogenesis assay were related to a shorter disease-free survival. This might have important prognostic implications in patients with low-grade oligodendrogliomas. PMID- 20943395 TI - 4-Phenylcoumarins from Mesua elegans with acetylcholinesterase inhibitory activity. AB - A significant acetylcholinesterase (AChE) inhibitory activity was observed for the hexane extract from the bark of Mesua elegans (Clusiaceae). Thus, the hexane extract was subjected to chemical investigation, which led to the isolation of nine 4-phenylcoumarins, in which three are new; mesuagenin A (1), mesuagenin C (3), mesuagenin D (4) and one new natural product; mesuagenin B (2). The structures of the isolated compounds were characterized by spectroscopic data interpretation, especially 1D and 2D NMR. Four compounds showed significant AChE inhibitory activity, with mesuagenin B (2) being the most potent (IC(50)=0.7MUM). PMID- 20943396 TI - Anticonvulsant activity of 2,4(1H)-diarylimidazoles in mice and rats acute seizure models. AB - 2,4(1H)-Diarylimidazoles have been previously shown to inhibit hNa(V)1.2 sodium (Na) channel currents. Since many of the clinically used anticonvulsants are known to inhibit Na channels as an important mechanism of their action, these compounds were tested in two acute rodent seizure models for anticonvulsant activity (MES and scMet) and for sedative and ataxic side effects. Compounds exhibiting antiepileptic activity were further tested to establish a dose response curve (ED(50)). The experimental data identified four compounds with anticonvulsant activity in the MES acute seizure rodent model (compound 10, ED(50)=61.7mg/kg; compound 13, ED(50)=46.8mg/kg, compound 17, ED(50)=129.5mg/kg and compound 20, ED(50)=136.7mg/kg). Protective indexes (PI=TD(50)/ED(50)) ranged from 2.1 (compound 10) to greater than 3.6 (compounds 13, 17 and 20). All four compounds were shown to inhibit hNa(V)1.2 in a dose dependant manner. Even if a correlation between sodium channel inhibition and anticonvulsant activity was unclear, these studies identify four Na channel antagonists with anticonvulsant activity, providing evidence that these derivatives could be potential drug candidates for development as safe, new and effective antiepileptic drugs (AEDs). PMID- 20943397 TI - Molecular modeling study on potent and selective adenosine A(3) receptor agonists. AB - Adenosine A(3) receptor (A(3)AR) is involved in a variety of key physio pathological processes and its agonists are potential therapeutic agents for the treatment of rheumatoid arthritis, dry eye disorders, asthma, as anti inflammatory agents, and in cancer therapy. Recently reported MECA (5'-N methylcarboxamidoadenosine) derivatives bearing a methyl group in N(6)-position and an arylethynyl substituent in 2-position demonstrated to possess sub nanomolar affinity and remarkable selectivity for the human A(3)AR, behaving as full agonists of this receptor. In this study, we made an attempt to get a rationalization of the high affinities and selectivities of these molecules for the human A(3)AR, by using adenosine receptor (AR) structural models based on the A(2A)AR crystal structure and molecular docking analysis. Post-docking analysis allowed to evaluate the ability of modeling tools in predicting AA(3)R affinity and in providing interpretation of compound substituents effect on the A(3)AR affinity and selectivity. PMID- 20943398 TI - Redox-silent tocotrienol esters as breast cancer proliferation and migration inhibitors. AB - Tocotrienols are vitamin E members with potent antiproliferative activity against preneoplastic and neoplastic mammary epithelial cells with little or no effect on normal cell growth or functions. However, physicochemical and pharmacokinetic properties greatly limit their use as therapeutic agents. Tocotrienols' chemical instability, poor water solubility, NPC1L1-mediated transport, and rapid metabolism are examples of such obstacles which hinder the therapeutic use of these valuable natural products. Vitamin E esters like alpha-tocopheryl succinate were prepared to significantly improve chemical and metabolic stability, water solubility, and potency. Thus, 12 semisynthetic tocotrienol ester analogues 4-15 were prepared by direct esterification of natural tocotrienol isomers with various acid anhydrides or chlorides. Esters 4-15 were evaluated for their ability to inhibit the proliferation and migration of the mammary tumor cells +SA and MDA-MB-231, respectively. Esters 5, 9, and 11 effectively inhibited the proliferation of the highly metastatic +SA rodent mammary epithelial cells with IC(50) values of 0.62, 0.51, and 0.86MUM, respectively, at doses that had no effect on immortalized normal mouse CL-S1 mammary epithelial cells. Esters 4, 6, 8-10, and 13 inhibited 50% of the migration of the human metastatic MDA-MB-231 breast cancer cells at a single 5MUM dose in wound-healing assay. The most active ester 9 was 1000-fold more water-soluble and chemically stable versus its parent alpha-tocotrienol (1). These findings strongly suggest that redox-silent tocotrienol esters may provide superior therapeutic forms of tocotrienols for the control of metastatic breast cancer. PMID- 20943399 TI - Synthesis and evaluation of 2'-O-allyl substituted dinucleotide cap analog for mRNA translation. AB - The first example of the synthesis and biological evaluation of a new analog containing 2'-OH modification on m(7)G moiety, that is, m(7,2'-)(O-Allyl)GpppG is reported. The effect of the 2'-O-allyl substitution on cap analog has been evaluated with respect to its in vitro transcription by using T7 RNA polymerase, capping efficiency, and translational activity. The gel shift assay indicates that the new cap analog has 59% capping efficiency whereas the standard cap analog, m(7)GpppG has a capping efficiency of 70%. The capping efficiency experiment clearly demonstrates that the new analog was a substrate for T7 RNA polymerase. The nature of the orientation has been determined by HPLC that reveals that the new analog incorporates exclusively in the forward orientation. It is noteworthy that the mRNA poly(A) capped with 2'-O-allyl substituted cap analog was translated ~1.7-fold more efficiently than the mRNA capped with standard cap analog. Based on the higher translational data compared to the standard cap analog, it is likely that the new analog may find application that utilize mRNA transfection such as protein production, anti-cancer immunization, and gene therapy. PMID- 20943400 TI - Inhibition of Helicobacter pylori aminoacyl-tRNA amidotransferase by chloramphenicol analogs. AB - Genomic studies revealed the absence of glutaminyl-tRNA synthetase and/or asparaginyl-tRNA synthetase in many bacteria and all known archaea. In these microorganisms, glutaminyl-tRNA(Gln) (Gln-tRNA(Gln)) and/or asparaginyl-tRNA(Asn) (Asn-tRNA(Asn)) are synthesized via an indirect pathway involving side chain amidation of misacylated glutamyl-tRNA(Gln) (Glu-tRNA(Gln)) and/or aspartyl tRNA(Asn) (Asp-tRNA(Asn)) by an amidotransferase. A series of chloramphenicol analogs have been synthesized and evaluated as inhibitors of Helicobacter pylori GatCAB amidotransferase. Compound 7a was identified as the most active competitive inhibitor of the transamidase activity with respect to Asp-tRNA(Asn) (K(m)=2MUM), with a K(i) value of 27MUM. PMID- 20943401 TI - Synthesis and anticancer activity of new 1-[(5 or 6-substituted 2 alkoxyquinoxalin-3-yl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives. AB - A series of novel quinoxalinyl-piperazine compounds, 1-[(5 or 6-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives were synthesized and evaluated as an anticancer agent. From screening of quinoxalinyl piperazine compound library, we identified that many compounds inhibited proliferation of various human cancer cells at nanomolar concentrations. Among them, one of the fluoro quinoxalinyl-piperazine derivatives showed its IC(50) values ranging from 11 to 21nMU in the growth inhibition of cancer cells. This compound also displayed a more potent effect than paclitaxel against paclitaxel resistant HCT-15 colorectal carcinoma cells. The potency of this novel compound was further confirmed with the synergistic cytotoxic effect with several known cancer drugs such as paclitaxel, doxorubicin, cisplatin, gemcitabine or 5 fluorouracil in cancer cells. This strong cell killing effect was derived from the induction of apoptosis. Mechanistic studies have shown that this quinoxalinyl piperazine compound is a G2/M-specific cell cycle inhibitor and inhibits anti apoptotic Bcl-2 protein with p21 induction. Thus the results suggest that our compound has potential use in the growth inhibition of drug resistant cancer cells and the combination therapy with other clinically approved anticancer agents as well. PMID- 20943402 TI - Pro-apoptotic activity of lipidic alpha-amino acids isolated from Protopalythoa variabilis. AB - Lipidic alpha-amino acids (LAAs) have been described as non-natural amino acids with long saturated or unsaturated aliphatic chains. In the continuing prospect to discover anticancer agents from marine sources, we have obtained a mixture of two cytotoxic LAAs (1a and 1b) from the zoanthid Protopalythoa variabilis. The anti-proliferative potential of 14 synthetic LAAs and 1a/1b were evaluated on four tumor cell lines (HCT-8, SF-295, MDA-MB-435, and HL-60). Five of the synthetic LAAs showed high percentage of tumor cell inhibition, while 1a/1b completely inhibited tumor cell growth. Additionally, apoptotic effects of 1a/1b were studied on HL-60 cell line. 1a/1b-treated cells showed apoptosis morphology, loss of mitochondrial potential, and DNA fragmentation. PMID- 20943403 TI - Bioengineering functional copolymers. XIV. Synthesis and interaction of poly(N isopropylacrylamide-co-3,4-dihydro-2H-pyran-alt-maleic anhydride)s with SCLC cancer cells. AB - Novel antitumor active functional polymers with supramacromolecular structures were synthesized by a complex-radical terpolymerization of N-isopropylacrylamide (NIPAm), 3,4-dihydro-2H-pyran (DHP), and maleic anhydride (MA) with 2,2' azoisobisbutyronitrile as a radical initiator in 1,4-dioxane at 65 degrees C under nitrogen atmosphere. The structure and composition of terpolymers were investigated by (1)H ((13)C) NMR spectroscopy. Interaction of terpolymers with human lung small cell carcinoma (SCLC) were investigated by using different methods such as cytotoxicity, statistical, apoptotic and necrotic cell indexes, double staining and caspase-3 immunostaining, light and fluorescence inverted microscopy analyses. Investigations into structure, composition, and antitumor activity relationships revealed that terpolymers containing a combination of ionisable amide-pyran linkages and H-bonded carboxylic groups exhibited higher cytotoxicity. It was observed that terpolymer with nearly alternating structure provides a maximum concentration of ionisable and H-bonded antitumor sites, and therefore, exhibits higher in vitro cytotoxicity, apoptotic and necrotic effects towards SCLC cancer cells. PMID- 20943404 TI - 1-Bromo-3-(1',1'-dimethylalkyl)-1-deoxy-Delta(8)-tetrahydrocannabinols: New selective ligands for the cannabinoid CB(2) receptor. AB - Delta(8)-Tetrahydrocannabinol (26), 3-(1',1'-dimethylbutyl)- (12), 3-(1',1' dimethylpentyl)- (13), 3-(1',1'-dimethylhexyl)- (14) and 3-(1',1'-dimethylheptyl) Delta(8)-tetrahydrocannabinol (15) have been converted into the corresponding 1 bromo-1-deoxy-Delta(8)-tetrahydrocannabinols (25, 8-11). This was accomplished using a protocol developed in our laboratory in which the trifluoromethanesulfonate of a phenol undergoes palladium mediated coupling with pinacolborane. Reaction of this dioxaborolane with aqueous-methanolic copper(II) bromide provides the aryl bromide. The affinities of these bromo cannabinoids for the cannabinoid CB(1) and CB(2) receptors were determined. All of these compounds showed selectivity for the CB(2) receptor and one of them, 1-bromo-1-deoxy-3 (1',1'-dimethylhexyl)-Delta(8)-tetrahydrocannabinol (10), exhibits 52-fold selectivity for this receptor with good (28nM) affinity. PMID- 20943405 TI - Synthesis and evaluation of 5-substituted 9-hydroxypyrrolo[3,4-c]carbazole 1,3(2H,6H)-diones as check point 1 kinase inhibitors. AB - The structure-activity relationship (SAR) of 5-substituted pyrrolo[3,4 c]carbazole-1,3(2H,6H)-dione derivatives 5 was investigated for their potential as Chk1 inhibitors for possible chemo- and radio-potentiators in anticancer chemotherapies. In silico virtual screening helped to optimize the substituent on the phenyl ring, and led to identification of the m-carbamoyl group among the 117 analogues tested. Further optimization studies focusing on the docking model of 15 in the active site of Chk1 revealed that 32b (IC(50)=2.8nM) was a more potent inhibitor than UNC-01. PMID- 20943406 TI - Synthesis of new antifungal peptides selective against Cryptococcus neoformans. AB - Many drugs are available for the treatment of systemic or superficial mycoses, but only a limited number of them are effective antifungal drugs, devoid of toxic and undesirable side effects. Furthermore, resistance development and fungistatic rather than fungicidal activities represent limitations of current antifungal therapy. Therefore there remains an urgent need for a new generation of antifungal agents. According to a polypharmacological approach, the present work concerns the synthesis and antifungal activity of a set of peptides designed to simultaneously target the fungal cell surface and lanosterol demethylase, a key enzyme involved in ergosterol synthesis. Our peptides include amino acid sequences characteristic of membrane-active antimicrobial peptides (AMP), and due to the presence of His residues, they carry the imidazole ring characteristic of azole compounds. The peptides synthesized by us, were tested against different yeast species, and displayed general antifungal activity, with a therapeutically promising antifungal specificity against Cryptococcus neoformans. PMID- 20943407 TI - Electron backscattering diffraction and X-ray diffraction studies of interface relationships in Sr3Ru2O7/Sr2RuO4 eutectic crystals. AB - Sr3Ru2O7/Sr2RuO4 eutectic system is investigated by electron backscattering diffraction (EBSD) and X-ray diffraction (XRD). The eutectic growth enables the solidification of the two phases in an ordered lamellar pattern extending along the growth direction, namely the b-axis direction. The eutectic material thus provides in the a-c plane two distinct interfaces having different microstructures with respect to the growth direction. Our analysis shows that, across the inplane c-axis direction (characterized by a poor lattice matching), the b-axis orientation is not constant at the individual interfaces, showing an orientation spread of about 5 degrees . However, across the in-plane a-axis direction (characterized by a good lattice matching), the b-axis orientation does not change within a few tenths of degree (about 0.25 degrees ). Such information at nanoscale is also verified on a macroscopic level by standard XRD investigation. PMID- 20943408 TI - EPR-TL correlation studies on Bi co-doped CaSO4:Dy phosphor. AB - CaSO(4):Dy, CaSO(4):(Dy, Bi) and CaSO(4):Bi phosphors were prepared through re crystallization method. Thermoluminescence (TL) characteristics of these phosphor samples were investigated. The radiation induced radical ions formed in these phosphors were investigated using electron paramagnetic resonance (EPR) spectroscopy. The main signals observed in both CaSO(4):(Dy, Bi) and CaSO(4):Bi were identified as SO(4)(-) (II), SO(4)(-) (?) and SO(3)(-) (isotropic) with "g" values 2.023, 2.0089 and 2.004, respectively. In order to understand the TL mechanism, CaSO(4):(Dy, Bi) phosphor samples were annealed between 100 and 250 degrees C and their EPR spectra were studied. It was observed that EPR signal intensities reduce drastically in 250 degrees C annealed phosphor confirming the role of SO(4)(-) and SO(3)(-) types of defect centers in the dosimetric peak. The reduction in the TL sensitivity with increase in Bi(3+) co-dopant in the phosphor samples was correlated with quenching of TL by Bi(3+) ions rather than the reduction in the concentration of the above defect centers. An effort was also made to use the Bi(3+) co-doped CaSO(4):Dy phosphor for dosimetry of chilled or frozen food irradiation. PMID- 20943409 TI - Coronary artery anatomy in anatomically corrected malposition of the great arteries and their surgical implications. AB - OBJECTIVES: Coronary artery (CA) anatomy of anatomically corrected malposition of the great arteries (ACM) has not been well elucidated. We studied the CA pattern and their association with the aortopulmonary rotation (APR). METHODS: CA anatomy and APR of ACM were identified by image or surgical intervention. The degree of APR was defined by the pattern of the aortic sinus of Valsalva on the lateral angiogram or computed tomography (CT). RESULTS: Four CA types were presented in 10 patients and literatures. Six patients had the same CA type as the usual pattern in transposition of the great arteries (type 1); and two had left anterior descending (LAD) from the left-hand facing sinus that also gave rise to the right CA (RCA) (type 0). One patient had LAD from the left-hand facing sinus while RCA and circumflex artery from the right-hand facing sinus (type 10); and single CA from the anterior left-hand sinus (type 3c) was identified in another. APR was left anterior in type 1 and more lateral in types 0 and 3c; and left posterior in type 10 (p=0.001). The usual pulmonary trans-annular incision can only be performed in case of type 10 CA after posterior APR (10%, 1/10). In the majority (90%, 9/10 with the CA type 1, 0, and 3c), the RCA is in front of the pulmonary annulus, and the atrioventricular groove patch plasty posterior to the RCA had to be adopted for a trans-annular patch. CONCLUSIONS: The observed CA pattern was correlated with APR. APR identified by the aortic sinus pattern could implicate the CA patterns and the surgical options in ACM. PMID- 20943410 TI - Primary major airway tumors; management and results. AB - OBJECTIVE: Primary major airway tumors are rare. A retrospective analysis of referral centers experience could be helpful for their management. METHODS: Fifty one patients, including 44 (86%) malignant and seven (14%) benign with primary tumors of subglottis, trachea, carina, and main stem bronchi, were managed in a 14-year period. Based on computed tomography (CT) scan and rigid bronchoscopy findings, those who evaluated as resectable underwent airway resection and reconstruction. The others were managed by one or a combination of these methods: core out, laser, chemotherapy, radiotherapy, and tracheostomy. Follow-up was completed in 88.2%, mean (35.2 +/- 33.2 months). RESULTS: Extraluminal extension of the tumor found in CT scan was significantly associated with unresectability (p = 0.006). Thirty-two patients underwent resection with three complications (9%) and one mortality (3%). Nineteen were managed by non-resectional methods; of these, 15 were found unresectable, because of tumor length, extensive local invasion or diffuse distant metastases, and four due to risk-benefit ratio or patient preference. Among 18 patients with adenoid cystic carcinoma 13 (72%) were resected (seven with negative margins). Overall 1-, 2-, 5-, and 8-year survival was 90.9%, 90.9%, 77.9%, and 19.5%, respectively. In unresectable tumors with adenoid cystic carcinoma, overall 1- and 2-year survival was 60% and 40%, respectively. Data analysis found significant association of long-term survival with resection (p = 0.005) but not with negative margins in adenoid cystic carcinoma. Among 15 patients with carcinoid tumors, all were alive at the end of follow-up, except one who died after surgery. CONCLUSIONS: Airway resection, if feasible, may extend survival and may even be curative, with low morbidity and mortality, in most patients with major airway tumors. PMID- 20943411 TI - The study of mitral valve annular dimension in relation to the body surface area in the Indian population. AB - OBJECTIVE: We compare the mitral valve annular dimension in relation to the body surface area of the Indian population as against the standard values. METHODS: The study was conducted between September 2004 and February 2006 on 406 subjects, out of which 252 were males and 154 were females. A spatially oriented B-mode scan echocardiogram was used, with the long-axis plane running parallel to the heart or the left ventricle, the short-axis plane being perpendicular to the long axis, and the four-chamber plane orthogonal to the other two and somewhat representing a frontal plane. Mitral valvular dimensions were recorded in early diastole. RESULTS: The mitral valve showed a steady rise in its diameter with rise in body surface area. For body surface area ranging from 0.61 to 0.7 m2, the mitral valve diameter was 15.5mm. There was a sudden increase from 15.5mm to 18 mm for body surface area ranging from 0.71 to 0.8 m2. After this sudden increase, the mitral valve diameter steadily increased by 0.2-0.6 mm for every 0.1 m2 increase in body surface area. The values obtained from the Indian population were definitely lower than the lower end of standard deviation of the standard values, which are derived in relation to body surface area. CONCLUSIONS: Although the annular dimensions of the mitral valve increased correspondingly with body surface area, they still remained very low in the Indian population as compared with the standard values, which might cause patient-prosthesis mismatch during mitral-valve replacement surgeries. PMID- 20943412 TI - Super-highly hydroxylated fullerene derivative protects human keratinocytes from UV-induced cell injuries together with the decreases in intracellular ROS generation and DNA damages. AB - Polyhydroxylated fullerenes (fullerenols: C(60)(OH)(n)) are known as the major water-soluble fullerene derivatives which possess particular significance as free radical scavengers or antioxidants in biological systems. Recently, the novel polyhydroxylated fullerene (C(60) (OH)(44).8H(2)O: SHH-F) was successfully synthesized. In the present study, we investigated the radical-scavenging effects and cytoprotective effects of three types of fullerenols (C(60)(OH)(6-12): LH-F, C(60) (OH)(32-34).7H(2)O: HH-F, and C(60) (OH)(44).8H(2)O: SHH-F) on UV irradiation-induced cell injuries. HH-F and SHH-F exerted hydroxyl-radical scavenging activities as shown by DMPO-spin trap/ESR method, more markedly than LH-F. UVA or UVB irradiation-induced injuries in human skin keratinocytes HaCaT were significantly suppressed by HH-F and SHH-F, but scarcely by LF-H. The cytoprotective effects of SHH-F had a tendency to be superior to that of HH-F. And the cytoprotective effects of SHH-F against UVB-induced injuries were more effective than those of UVA. Irradiation with UVB to HaCaT cells was shown to cause rapid increases in cell-injury-associated symptoms such as intracellular oxidative stress levels, the formation of cyclobutane pyrimidine dimers and chromatin condensation, all of which were repressed by SHH-F. Thus, UVB-induced diverse harmful effects could be prevented by SHH-F, which was suggested to exert the cytoprotective effects through intracellular reactive oxygen species scavenging in the keratinocytes. PMID- 20943414 TI - DNA sequencing of 13 cytokine gene fragments of Aotus infulatus and Saimiri sciureus, two non-human primate models for malaria. AB - Aotus and Saimiri are non-human primate models recommended by the World Health Organization for experimental studies in malaria, especially for vaccine pre clinical trials. However, research using these primates is hindered by the lack of specific reagents to evaluate immune responses to infection or vaccination. As a step toward developing molecular tools for cytokine expression studies in these species, primer pairs for 18 cytokine gene fragments were designed based on human DNA sequences and used to amplify the corresponding genes in Aotus infulatus and Saimiri sciureus genomic DNA samples. IFNgamma, TNFalpha, LTA, IL2, IL3, IL4, IL5, IL6, IL10, IL12, IL13, CSF2 and TGFbeta2 gene fragments were amplified and sequenced. Primer pairs for IL8, IL17, IL18, IL27 and MIF failed to generate amplification products. When compared to the available corresponding human and non-human primate sequences, most--except IL3 and IL4--showed identity degrees above 90%. Small variations in sequence can help to explain the failure to amplify certain genes or the amplification only at lower annealing temperatures as compared to human DNA samples for several primer pairs. The sequences made available provide the basis for designing molecular tools such as primers for real time PCR specific for A. infulatus and/or S. sciureus. The nucleotide sequences reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned accession numbers DQ985386 to DQ985389, DQ989356 to DQ989369, FJ89020 to FJ89024, and FJ89029. PMID- 20943413 TI - The differential activity of interferon-alpha subtypes is consistent among distinct target genes and cell types. AB - IFN-alpha proteins have been described to originate from 14 individual genes and allelic variants. However, the exceptional diversity of IFN-alpha and its functional impact are still poorly understood. To characterize the biological activity of IFN-alpha subtypes in relation to the cellular background, we investigated the effect of IFN-alpha treatment in primary fibroblasts and endothelial cells of vascular or lymphatic origin. The cellular response was evaluated for 13 distinct IFN-alpha proteins with respect to transcript regulation of the IFN-stimulated genes (ISGs) IFIT1, ISG15, CXCL10, CXCL11 and CCL8. The IFN-alpha proteins displayed a remarkably consistent potency in gene induction irrespective of target gene and cellular background which led to the classification of IFN-alpha subtypes with low (IFN-alpha1), intermediate (IFN alpha2a, -4a, -4b, -5, -16, -21) and high (IFN-alpha2b, -6, -7, -8, -10, -14) activity. The differential potency of IFN-alpha classes was confirmed at the ISG protein level and the functional protection of cells against influenza virus infection. Differences in IFN activity were only observed at subsaturating levels of IFN-alpha proteins and did not affect the time course of ISG regulation. Cell type specific responses were apparent for distinct target genes independent of IFN-alpha subtype and were based on different levels of basal versus inducible gene expression. While fibroblasts presented with a high constitutive level of IFIT1, the expression in endothelial cells was strongly induced by IFN-alpha. In contrast, CXCL10 and CXCL11 transcript levels were generally higher in endothelial cells despite a pronounced induction by IFN-alpha in fibroblasts. In summary, the divergent potency of IFN-alpha proteins and the cell-type specific regulation of individual IFN target genes may allow for the fine tuning of cellular responses to pathogen defense. PMID- 20943415 TI - Misdirected by the gap: the relationship between inattentional blindness and attentional misdirection. AB - In several of our articles we have drawn analogies between inattentional blindness paradigms and misdirection. Memmert (2010) however, has criticized this analogy and urged for caution in assuming too much of a close relationship between these two phenomena. Here we consider the points raised by Memmert and highlight some misunderstandings and omissions in his interpretation of our work, which substantially undermine his argument. Debating the similarities and differences between aspects of misdirection and inattentional blindness is valuable and has the potential to highlight the utility of these two phenomena. However, it is important not to be misdirected by subtle differences between particular instances of each phenomenon, at the expense of failing to detect the opportunities that these phenomena present for extending our understanding of attention and awareness. PMID- 20943416 TI - Fluency and positivity as possible causes of the truth effect. AB - Statements' rated truth increases when people encounter them repeatedly. Processing fluency is a central variable to explain this truth effect. However, people experience processing fluency positively, and these positive experiences might cause the truth effect. Three studies investigated positivity and fluency influences on the truth effect. Study 1 found correlations between elicited positive feelings and rated truth. Study 2 replicated the repetition-based truth effect, but positivity did not influence the effect. Study 3 conveyed positive and negative correlations between positivity and truth in a learning phase. We again replicated the truth effect, but positivity only influenced judgments for easy statements in the learning phase. Thus, across three studies, we found positivity effects on rated truth, but not on the repetition-based truth effect: We conclude that positivity does not explain the standard truth effect, but the role of positive experiences for truth judgments deserves further investigation. PMID- 20943417 TI - Embodiment, ownership and disownership. AB - There are two main pathways to investigate the sense of body ownership, (i) through the study of the conditions of embodiment for an object to be experienced as one's own and (ii) through the analysis of the deficits in patients who experience a body part as alien. Here, I propose that E is embodied if some properties of E are processed in the same way as the properties of one's body. However, one must distinguish among different types of embodiment, and only self specific embodiment can lead to feelings of ownership. I address issues such as the functional role and the dynamics of embodiment, degrees and measures of ownership, and shared body representations between self and others. I then analyse the interaction between ownership and disownership. On the one hand, I show that there is no evidence that in the Rubber Hand Illusion, the rubber hand replaces the biological hand. On the other hand, I argue that the sense of disownership experienced by patients towards their body part cannot be reduced to the mere lack of ownership. PMID- 20943418 TI - Overexpression of scavenger receptor LOX-1 in endothelial cells promotes atherogenesis in the ApoE(-/-) mouse model. AB - AIMS: The oxidized low-density lipoprotein receptor LOX-1 is up-regulated on activated endothelial cells, for example, the endothelium of atherosclerosis prone sites, in both human and animal models. We examined whether endothelial LOX 1 overexpression may contribute to atherogenesis. METHODS: Adenoviral vectors expressing LOX-1 or LOXIN (a splice variant of LOX-1 with inhibitory function) were created and used to transduce the normally lesion-free common carotid artery, in high fat-fed female ApoE(-/-) mice. Mice were placed on high-fat diet for 4 weeks prior to gene transfer with either LOX-1 or a combination of LOX-1 and LOXIN, and assessment of plaque development analyzed 6 weeks following gene transfer. RESULTS: Compared to controls, LOX-1 transduction induced a significant increase in plaque coverage within the common carotid artery to 91% compared to 50% after RAd66 control virus infection (P<=.05). This was inhibited by co expression of LOXIN (62%). CONCLUSIONS: These results demonstrate that up regulation of LOX-1 promotes atherogenesis, highlighting LOX-1 function as a target for intervention. In addition, this study further demonstrated the inhibitory function of LOXIN. PMID- 20943419 TI - Minimally invasive proximal biceps tenodesis: an anatomical study for optimal placement and safe surgical technique. AB - BACKGROUND: An anatomic study specifically investigating the optimal location for proximal biceps tenodesis and detailing the topographic relationship to neurovascular structures has not been conducted. METHODS: Twelve cadaveric upper extremities were dissected to identify the proximal biceps musculotendinous junction and topographic relationships to neighboring neurovascular structures. RESULTS: The musculotendinous junction of the long head of the biceps tendon was on average 2.2 cm distal to the superior border and 3.1 cm proximal from the inferior border of the pectoralis major tendon. The musculocutaneous nerve was on average 2.6 cm medial to the long head of the biceps at the musculotendinous junction. The distance from the lesser tuberosity to the musculotendinous junction of the long head of the biceps averaged 5.4 cm. The distance from the anterior humeral circumflex vessels to the musculotendinous junction of the long head of the biceps was 4.6 cm on average. The distance from the musculotendinous junction of the long head of the biceps to the musculocutaneous nerve as it pierces the coracobrachialis was 4.6 cm. CONCLUSION: In order to restore the appropriate length-tension relationship of the biceps muscle, proximal biceps tenodesis should possibly be placed closer to the superior border of the pectoralis major tendon than previously thought. The lesser tuberosity can be used as a tactile landmark for appropriate intraoperative placement. Although there is a relatively safe "buffer zone" between the location of the tenodesis and adjacent neurovascular structures, extreme caution must be used. PMID- 20943420 TI - MRI abnormalities following repeated and incoming seizures. AB - Neuroimaging, an important diagnostic tool frequently used in the evaluation of patients with epilepsy, has mainly the aim to identify structural abnormalities needing a treatment and to contribute to the definition of the aetiology. Brain magnetic resonance imaging (MRI) in epilepsy is more sensitive than computerized tomography (CT) scan for detecting abnormalities. Status epilepticus (SE) and repeated incoming seizures may determine extensive and transient or long lasting pronounced MRI changes. We describe a case of a 41-year-old woman with a history of brain neoplasm, whose contrast-enhanced MRI images following repeated and incoming seizures were characterized either by reversible and irreversible abnormalities. PMID- 20943422 TI - In vivo detection of Staphylococcus aureus in biofilm on vascular prostheses using non-invasive biophotonic imaging. AB - OBJECTIVES: Biophotonic imaging was compared to standard enumeration method both for counting Staphylococcus aureus in biofilm and bacterial susceptibility tests of different graft materials. DESIGN: Prospective, randomized, controlled animal study. MATERIAL AND METHODS: Five types of vascular grafts were placed subcutaneously in 35 mice and challenged with bioluminescent S. aureus. The mice were divided into equal groups as follows: group A (polyester), group B (polytetrafluoroethylene), group C and D (two types of silver acetate-coated polyester) and group E (bovine pericardium). Controls were given only the bacteria. The bioluminescence signal of S. aureus, able to predict number of viable bacteria in biofilm without any manipulation, was measured at different time points. Five days postinfection, regular cultures of adherent bacteria on grafts were obtained. Comparative analyses between bioluminescence activity and culture enumeration were performed. RESULTS: The number of viable bacteria on silver-coated prostheses was the slightest, indicating superior bacterial resistance. The density of bacteria on polytetrafluoroethylene and polyester was comparable, with a non-significant advantage for polytetrafluoroethylene. Moreover, bioluminescence detected the number of viable S. aureus in biofilm more exactly compared to enumeration of bacteria. CONCLUSION: Bioluminescence imaging can be considered a useful tool to characterize susceptibility of any graft material to bacterial biofilm prior to implantation. PMID- 20943423 TI - Morphometry of the canine intestine with reference to the use of double balloon endoscopy. AB - Double balloon endoscopy (DBE) enables the diagnosis and treatment of small intestinal disease. The dog is a potential animal model for DBE training and also a candidate for the clinical application of this technique. However, the anatomy of the canine small intestine may limit the use of DBE by restricting the push and-pull manoeuvres required for DBE. To establish what these limitations are, the length and width of different portions of the small intestine as well as the mesenteric dependences were measured in 55 dogs. Several external parameters related to body size plus the age, weight, sex and breed were recorded. Potential restriction of the progress of the enteroscope due to narrow intestinal diameter is expected in the jejunum of mid- and small size dogs. PMID- 20943424 TI - Ultrasonographic assessment of maternal cardiac function and peripheral circulation during normal gestation in dogs. AB - The aim of this study was to describe changes in cardiac morphology, systolic function and some peripheral hemodynamic parameters during normal pregnancy in dogs. Twenty healthy bitches, 10 pregnant (PG) and 10 non-pregnant controls (CG), were evaluated every 10 days using echocardiography from day 0 of the estrus cycle to parturition or to day 65 for the PG and CG groups, respectively. Systolic blood pressure (SBP) and uterine artery resistance index (RI) were also assessed. Throughout the study, the shortening fraction and cardiac output increased up to 30% vs. 5% (P<0.01) and 45% vs. 2% (P<0.01) in the PG and CG groups, respectively. In contrast, SBP and RI diminished up to 20% vs. 1% (P<0.01) and 29% vs. 0% (P<0.01) in the PG and CG groups, respectively. In conclusion, a decrease in afterload, an increase in cardiac output and cardiac hypertrophy appear to be the result of the hemodynamic modifications occurring during pregnancy in dogs. PMID- 20943425 TI - The role of insulin-like growth factor-1 and growth hormone in the mortality of patients with acromegaly after trans-sphenoidal surgery. AB - CONTEXT: Acromegaly is associated with a significant increase in mortality. With the development of new modalities of treatment, it has become important to identify prognostic factors relating to mortality. OBJECTIVE: This study aimed to determine the all-cause mortality of patients with acromegaly after trans sphenoidal surgery, and assess the impact of biochemical markers on survival. DESIGN: Two hundred thirty-four patients were admitted to the Taipei Veterans General Hospital for acromegaly between 1979 and 2007. Of the 163 patients who underwent trans-sphenoidal surgery, 142 had data available for insulin-like growth factor-1 (IGF-1), and their survival status was analyzed. Serial data for fasting growth hormone (GH) and IGF-1 were collected. This study also used the last follow-up data for mortality analysis. The patients with acromegaly were grouped according to the last follow-up GH level (<=2 or >2 MUg/L) and IGF-1 SD score (<=2 or >2). All-cause mortality was followed to the end of 2007 and compared to the general Taiwanese population by standardized mortality ratios. RESULTS: Serial GH and IGF-1 data revealed that the GH levels in the first 3 years after surgery were important predictors of mortality in acromegaly. However, there are insufficient IGF-1 data for deceased patients to determine the significance of a raised IGF-1 immediately following treatment. Comparison of crude death rates suggests that a fasting GH level of 2 MUg/L and normalization of the IGF-1 level are appropriate targets. After subgroup analysis to assess the impact of discordant GH and IGF-1 levels on survival, the data showed that the elevated GH group had a trend toward a higher mortality than the elevated IGF-1 group. CONCLUSIONS: An elevated GH value in the first 3 years after surgery may be the best predictor of mortality. Thus, the follow-up of patients with acromegaly at relatively frequent intervals after trans-sphenoidal surgery should be routine. PMID- 20943426 TI - Spatial variation of blood viscosity: modelling using shear fields measured by a MUPIV based technique. AB - The spatial characteristics of blood viscosity were investigated by combining a newly developed constitutive equation with shear deformation fields calculated from velocity measurements obtained by a MUPIV based technique. Blood at physiological hematocrit levels and in the presence of aggregation was sheared in a narrow gap plate-plate geometry and the velocity and aggregation characteristics were determined from images captured using a high resolution camera. Changes in the microstructure of blood caused by aggregation were observed to affect the flow characteristics. At low shear rates, high aggregation and network formation caused the RBC motion to become essentially two dimensional. The measured velocity fields were used to estimate the magnitude of shear which was subsequently used in conjunction with the new model to assess the spatial variation of viscosity across the flow domain. It was found that the non uniform microstructural characteristics of blood influence its viscosity distribution accordingly. The viscosity of blood estimated in the core of the examined flow, using a zero-gradient core velocity profile assumption, was found to be significantly higher than the overall effective viscosity determined using other velocity profile assumptions. PMID- 20943427 TI - Searching for a photocycle of the cryptochrome photoreceptors. AB - The initial photochemistry of plant cryptochromes has been extensively investigated in recent years. It is hypothesized that cryptochrome photoexcitation involves a Trp-triad-dependent photoreduction. According to this hypothesis, cryptochromes in the resting state contain oxidized FAD; light triggers a sequential electron transfer from three tryptophan residues to reduce FAD to a neutral semiquinone (FADH*); FADH* is the presumed signaling state and it is re-oxidized to complete the photocycle. However, this photoreduction hypothesis is currently under debate. An alternative model argues that the initial photochemistry of cryptochromes involves a photolyase-like cyclic electron shuttle without a bona fide redox reaction mediated by the Trp-triad residues, leading to conformational changes, signal propagation, and physiological responses. PMID- 20943428 TI - How cotton fibers elongate: a tale of linear cell-growth mode. AB - Cotton fibers (cotton lint) are single-celled trichomes that differentiate from the ovule epidermis. Unidirectional and fast-growing cells generally expand at the dome-shaped apical zone (tip-growth mode); however, previous studies suggest that elongating fiber cells expand via a diffuse-growth mode. Tip-localized Ca(2+) gradient and active secretary vesicle trafficking are two important phenomena of tip-growth. Recently, a high Ca(2+) gradient is found in the cytoplasm of fast-elongating cotton fiber cells near the growing tip. Several protein coding genes participating in vesicle coating and transport are highly expressed in elongating fiber cells. Taken together with the observation that ethylene acts as a positive regulator for cotton fiber and several Arabidopsis tissues that are known to elongate via tip growth prompted us to propose a linear growth mode for similar cell types. PMID- 20943429 TI - Four easy pieces: mechanisms underlying circadian regulation of growth and development. AB - The circadian clock confers rhythms of approximately 24 hours to biological events. It elevates plant fitness by allowing plants to anticipate predictable environmental changes and organize life process to coincide with the most favorable environmental conditions. Many developmental events are circadian regulated to ensure that growth occurs at the ideal time or season relative to available resources. Circadian clock control over growth and development is often achieved through regulation of key phytohormone action. Circadian influence over the genome is widespread and the clock modulates genes involved in phytohormone synthesis and signaling, in addition to other pathways shaping growth and development. This review presents four nonmutually exclusive mechanisms by which temporal information is gleaned from the core oscillator and passed to pathways regulating plant growth and development. PMID- 20943431 TI - First fluorescence spectroscopic investigation of Am(III) complexation with an organic carboxylic ligand, pyromellitic acid. AB - For the first time Am(III) complexation with a small organic ligand could be identified and characterized with time-resolved laser-induced fluorescence spectroscopy (TRLFS) at room temperature and trace metal concentration. With pyromellitic acid (1,2,4,5-benzene-tetracarboxylic acid, BTC) as ligand spectroscopic characteristics for the Am-BTC complex system were determined at pH 5.0, an ionic strength of 0.1 M (NaClO4) and room temperature. The fluorescence lifetimes were determined to be 23.2+/-2.2 ns for Am3+(aq) and 27.2+/-1.2 ns for the Am-BTC 1:1 complex; the emission maximum for the 5D1-(7)F1 transition is 691 nm for both species. The complex stability constant for the Am-BTC 1:1 complex was calculated to be logbeta110=5.42+/-0.16. PMID- 20943430 TI - Advances in understanding E. coli cell fission. AB - Much of what we know about cytokinesis in bacteria has come from studies with Escherichia coli, and efforts to comprehensively understand this fundamental process in this organism continue to intensify. Major recent advances include in vitro assembly of a membrane-tethered version of FtsZ into contractile rings in lipid tubules, in vitro dynamic patterning of the Min proteins and a deeper understanding of how they direct assembly of the FtsZ-ring to midcell, the elucidation of structures, biochemical activities and interactions of other key components of the cell fission machinery, and the uncovering of additional components of this machinery with often redundant but important roles in invagination of the three cell envelope layers. PMID- 20943432 TI - Molecular structure and vibrational investigation of benzenesulfonic acid methyl ester using DFT (LSDA, B3LYP, B3PW91 and MPW1PW91) theory calculations. AB - The FT-Raman and FT-IR spectra for benzenesulfonic acid methyl ester (BSAME) have been recorded in the region 4000-100 cm(-1) and compared with the harmonic vibrational frequencies calculated using DFT (LSDA, B3LYP, B3PW91 and MPW1PW91) method by employing 6-311G (d, p) basis set with appropriate scale factors. IR intensities and Raman activities are also calculated by DFT (LSDA, B3LYP, B3PW91 and MPW1PW91) methods. Optimized geometries of the molecule have been interpreted and compared with the reported experimental values for sulfonic acid and some substituted sulfonic acids. The experimental geometrical parameters show satisfactory agreement with the theoretical prediction from DFT. The scaled vibrational frequencies at LSDA/B3LYP/6-311G (d, p) seem to coincide with the experimentally observed values with acceptable deviations. The theoretical spectrograms (IR and Raman) have been constructed and compared with the experimental FT-IR and FT-Raman spectra. Some of the vibrational frequencies of the sulfonic acid are effected upon profusely with the methyl substitution in comparison to benzene sulfonamide and these differences are interpreted. PMID- 20943433 TI - Synthesis, X-ray crystallography characterization, vibrational spectroscopic, molecular electrostatic potential maps, thermodynamic properties studies of N,N' di(p-thiazole)formamidine. AB - In this work, we will report a combined experimental and theoretical study on molecular and vibrational structure of N,N'-di(p-thiazole)formamidine (DpTF). DpTF has been synthesized and characterized by elemental analysis, FT-IR, FT Raman, 1H NMR, 13C NMR spectroscopy and X-ray single crystal diffraction. The FT IR and FT-Raman spectra of DpTF were recorded in the solid phase. The optimized geometry was calculated by HF and B3LYP methods using 6-31G(d) basis set. The FT IR and FT-Raman spectra of DpTF was calculated at the HF/B3LYP/6-31G(d) level and were interpreted in terms of potential energy distribution (PED) analysis. The scaled theoretical wavenumber showed very good agreement with the experimental values. A detailed interpretation of the infrared and Raman spectra of DpTF was reported. On the basis of vibrational analyses, the thermodynamic properties of the title compound at different temperatures have been calculated, revealing the correlations between Cp,m degrees , Sm degrees , Hm degrees and temperatures. Furthermore, molecular electrostatic potential maps (MESP) and total dipole moment properties of the compound have been calculated. PMID- 20943434 TI - Both L-DOPA and HFS-STN restore the enhanced group II spinal reflex excitation to a normal level in patients with Parkinson's disease. AB - OBJECTIVE: To investigate the contribution of group II spinal pathways in Parkinsonian upper limb rigidity and the modulation of spinal excitability of group I and group II pathways by L-DOPA and subthalamic nucleus-high-frequency stimulation (STN-HFS). METHODS: The effect of ulnar nerve electrical stimulation on Flexor Carpi Radialis Electromyogram (FCR EMG) was investigated in two groups of patients: patients receiving medication (MED group) and chronically surgically implanted patients (DBS group). Results were compared in patients ON and OFF treatment, and between patients and control subjects. RESULTS: The resulting long lasting facilitation in FCR EMG had similar characteristics in all groups, and surface area was assessed in analysis windows corresponding to the parts supposed to be mediated by non-monosynaptic spinal pathways to FCR motoneurones, fed by hand muscle group I and group II afferents (Lourenco et al., 2006). In both the MED and DBS groups, the group I excitation was not altered but the group II excitation was particularly enhanced when OFF treatment, compared to controls, and both L-DOPA and STN-HFS restored the group II spinal excitation to normal level. CONCLUSION: Both L-DOPA and STN-HFS influence the metabolism of monoamines in the midbrain, and restore the descending neuromodulation on group II spinal reflex. SIGNIFICANCE: These results further support a group II contribution to the enhanced long latency response (LLR) to muscle stretch observed in wrist muscles of rigid Parkinson's disease (PD) patients. PMID- 20943435 TI - Relation between P300 and event-related theta-band synchronization: a single trial analysis. AB - OBJECTIVE: Recent reports show that theta-band (4-7 Hz) power is enhanced by target detection in the standard oddball paradigm, which, together with increased P300, is considered as providing complementary neural mechanisms supporting memory and attention processes. We hypothesize that the increased theta event related synchronization (ERS) may stem largely from not accounting for the trial to-trial variability of the P300 evoked component and may not reflect a separate mechanism for target detection and related cognitive processing. METHODS: EEG was recorded from healthy volunteers performing visual and auditory odd-ball tasks. Ongoing-activity was obtained using two methods: (a) subtracting the ASEO estimated (analysis of single-trial event-related potentials and ongoing activity) single-trial ERP from corresponding single-trial EEG time series and (b) subtracting the average event-related potential (AERP) from single-trial EEG time series. Event-related oscillatory activities obtained from the two methods were compared. RESULTS: The amount of power increase in the theta-band was greatly attenuated for the single-trial based method relative to the traditional AERP method. CONCLUSIONS: Our results suggest that the theta-ERS arises largely from not modeling the trial-to-trial variability of the P300. SIGNIFICANCE: ERP components such as the P300 vary from trial-to-trial in both amplitude and latency. The traditional AERP method leaves traces of evoked responses in the residual data which can negatively impact the inference of ongoing oscillatory dynamics. Thus, caution should be exercised in interpreting such phenomena in basic and clinical contexts. PMID- 20943436 TI - Quantifying muscle asymmetries in cervical dystonia with electrical impedance: a preliminary assessment. AB - OBJECTIVE: Cervical dystonia (CD) lacks an objective quantitative measure. Electrical impedance myography (EIM) is a non-invasive assessment method sensitive to changes in muscle structure and physiology. We evaluate the potential role of EIM in quantifying CD, hypothesizing that patients would demonstrate differences in the symmetry of muscle electrical resistance compared to controls, and that this asymmetry would decrease after botulinum neurotoxin (BoNT) treatment. METHODS: EIM was performed on the sternocleidomastoid (SCM) and cervical paraspinal (PS) muscles of CD patients and age-matched controls. 50 kHz resistance was analyzed, comparing side-to-side asymmetry in patients and controls, and, in patients, before and after BoNT treatment. RESULTS: Sixteen patients and 10 controls were included. Resistance asymmetry was on average 3-5 times higher in patients than controls. Receiver operating characteristic analysis demonstrated 91% accuracy of discriminating CD from normal. From pre treatment to maximum BoNT effect, asymmetry decreased from 20.8(13.9-26.1)% to 6.2(3.1-9.9)% (SCM), and from 16.0(14.3-16.0)% to 8.4(7.0-9.2)% (PS), p<0.05 (median, interquartile range). CONCLUSIONS: EIM effectively differentiates normal subjects from CD patients by revealing asymmetries in resistance values and detects improvement in muscle symmetry after treatment. SIGNIFICANCE: These results suggest that EIM, a painless, non-invasive measure, can provide a useful quantitative metric in CD evaluation and deserves further study. PMID- 20943437 TI - Recognition of the mom's voice with an emotional content in a PVS patient. PMID- 20943438 TI - Prevalence of Propionibacterium acnes in diseased prostates and its inflammatory and transforming activity on prostate epithelial cells. AB - Prostate cancer (PCa) is the second leading cause of male cancer deaths in the Western world. Mounting evidence has revealed that chronic inflammation can be an important initiating factor of PCa. Recent work has detected the anaerobic Gram positive bacterium Propionibacterium acnes in cancerous prostates, but with wide ranging detection rates. Here, using in situ immunofluorescence (ISIF), P. acnes was found in 58 out of 71 (81.7%) tested cancerous prostate tissue samples, but was absent from healthy prostate tissues (20 samples) and other cancerous tissue biopsies (59 mamma carcinoma samples). Live P. acnes bacteria were isolated from cancerous prostates and cocultured with the prostate epithelial cell line RWPE1. Microarray analysis showed that the host cell responded to P. acnes with a strong multifaceted inflammatory response. Active secretion of cytokines and chemokines, such as IL-6 and IL-8, from infected cells was confirmed. The host cell response was likely mediated by the transcriptional factors NF-kappaB and STAT3, which were both activated upon P. acnes infection. The P. acnes-induced host cell response also included the activation of the COX2-prostaglandin, and the plasminogen-matrix metalloproteinase pathways. Long-term exposure to P. acnes altered cell proliferation, and enabled anchorage-independent growth of infected epithelial cells, thus initiating cellular transformation. Our results suggest that P. acnes infection could be a contributing factor to the initiation or progression of PCa. PMID- 20943439 TI - Adaptation of Pseudomonas aeruginosa during persistence in the cystic fibrosis lung. AB - The long-term persistance of P. aeruginosa in the cystic fibrosis (CF) lung is characterized by the selection of a variety of genotypes and phenotypes that typically descend from one infecting P. aeruginosa clone, a process known as adaptive radiation. This adaptation process of P. aeruginosa includes complex physiological changes that likely confer a selective advantage to better thrive in the diverse niches and microenvironments of the inflamed and hostile CF airways. The occurrence of P. aeruginosa variants is fixed by mutation and selection. Common loss-of-function mutations in genes such as lasR, mucA and mexT lead to a general adaptation pattern and P. aeruginosa variants with increased antimicrobial resistance, alginate overproduction, reduced acute virulence, and improved metabolic fitness. Strikingly, several virulence-associated traits and immunostimulatory components of P. aeruginosa are turned off. In contrast, other cellular factors are positively selected such as the outer membrane protein OprF, the blue copper protein azurin, the cytochrome c peroxidase c551, and the enzymes of the arginine deiminase pathway ArcA-ArcD. These metabolic components probably are required for the optimal anaerobic or microaerobic growth and viability of P. aeruginosa within CF airways. Besides these common adaptations found by the comparison of P. aeruginosa isolates from different CF patients, the overall diversity of isogenic isolates from one CF patient is extended by variable changes in the expression of regulatory-, transport-, metabolic-, and virulence associated genes. A better understanding of the microevolution of P. aeruginosa towards niche specialists according the selection pressure in the CF lung is a prerequisite to develop new strategies for the detection of P. aeruginosa variants, the antipseudomonal treatment, the prediction of the infectious disease state, and the development of efficient vaccines. PMID- 20943440 TI - Dynamic Changes in ST Segment Resolution After Myocardial Infarction and the Association with Microvascular Injury on Cardiac Magnetic Resonance Imaging. AB - BACKGROUND: persistent ST elevation after reperfused ST elevation myocardial infarction (STEMI) is believed to be related to poor microvascular perfusion. Cardiac magnetic resonance imaging (CMR) can evaluate microvascular obstruction (MVO) and intramyocardial haemorrhage (IMH) both of which represent severe microvascular damage, have independent prognostic value and are dynamic and evolving over the first 48hours after reperfusion. The aim of this study was to assess whether the development of MVO or IMH has an impact upon ST segment resolution. METHODS: patients undergoing primary percutaneous coronary intervention (PCI) for STEMI had serial 12 lead electrocardiograms (ECG) from one hour after PCI until discharge. Persistent single lead maximal residual ST elevation (maxSTE) at each time point was calculated. ST segment deterioration (re-elevation) was calculated on each ECG until discharge compared with one hour post PCI ECG. CMR was performed within seven days post infarct utilising T2 weighted imaging to evaluate culprit artery area at risk (AAR) and IMH. Gadolinium delayed enhancement CMR quantified infarct size and MVO. RESULTS: in the 41 patients studied 58% had MVO and 41% had IMH. ST segment deterioration was more common in those with MVO or IMH (p=0.03 and p=0.008 respectively). MaxSTE was higher at each time point after PCI in those with MVO but only became statistically significant after 24hours. The measurement of maxSTE at 48 or 72hours after revascularisation provided the best correlation with the combination of infarct size, AAR, MVO and intramyocardial haemorrhage. CONCLUSION: microvascular injury as defined on CMR is associated with dynamic changes and persistence of ST segment elevation in the first 72hours after reperfusion. PMID- 20943441 TI - Can the nucleic acid amplification test (NAT) be an alternative to the serologic tests? A prospective study, the results of 18,200 blood donors from the Turkish Red Crescent. AB - AIM: Serologic tests having high sensitivity and specificity are used in order to prevent contamination with infectious agents from blood and blood products for transfusion safety. The present serologic tests have problems such as low sensitivity and weak detection capacity of infectious agents in the "window period". We aimed to test the use of NAT (Nucleic Acid Amplification Test) in routine blood screening in the Blood Bank. METHOD: We used the Procleix Ultrio (Chiron Ltd., USA) test kit based TMA (Transcription Mediated Amplification) for the NAT study of serum samples from 18,200 donors who came to the Turkish Red Crescent between February 2007 and September 2008. The NAT positive samples were studied twice. The discrimination of HIV, HCV and HBV NAT positive samples was performed by the Procleix Discrimination (Chiron Ltd., USA) test. Otherwise, Micro ELISA were used in parallel for routine serological screening of Anti-HIV, Anti-HCV, and HBsAg with Vironoste HIV Uni-form, AG/Ab innotest HCV Ab and Hepanostika Ultra HBsAg test kits. RESULTS: The results of serum samples with serology (+) and NAT (+) (13/18,200 and 0.05%) for anti-HIV, anti-HCV and HBsAg were higher than in other NAT studies; we also detected that a transfusion risk can occur in every 1400 transfusions. PMID- 20943442 TI - Identification of Hnrph3 as an autoantigen for acute anterior uveitis. AB - Acute anterior uveitis (AAU) is the most common form of autoimmune uveitis in the eye with few known autoantigens. Identification of autoantigens will improve our understanding of the molecular mechanisms and capability for disease diagnosis. Phage display is a powerful technology for autoantigen identification. However, because of uncontrollable reading frames, phage display with conventional cDNA libraries identifies high percentage of non-open reading frames (non-ORFs) with minimal implications for autoantigen identification. We recently developed ORF phage display technology with minimal reading frame problem. Herein we used ORF phage display to identify 18 patient-specific clones, including 16 ORFs encoding endogenous proteins as candidate autoantigens for AAU. One of the identified antigens was heterogeneous nuclear ribonucleoprotein H3 (Hnrph3) that was further characterized for AAU relevance and independently verified by Western blot. These results demonstrate that ORF phage display is a valuable approach for identification of unknown autoantigens. PMID- 20943443 TI - Preferential loss of Th17 cells is associated with CD4 T cell activation in patients with 2009 pandemic H1N1 swine-origin influenza A infection. AB - Very limited evidence has been reported on host T cell responses to the pandemic H1N1 swine-origin influenza A virus (S-OIV) infection in humans. Therefore, we investigated the proportions of peripheral T cell subsets and analyzed the relationship of T helper subset changes with T cell activation during this infection. We found that these S-OIV-infected patients exhibited rapid lymphopenia, T cell activation and preferential loss of Th17 subset at the early stage of acute infection. Statistical analysis indicated that CD4 depletion and loss of Th17 cells, rather than Th1 or Treg cells, were correlated with CD4 T cell activation. More importantly, up-regulated IFN-alpha likely contributed to the functional loss of Th17 cells. Thus, rapidly generalized lymphopenia, preferential loss of Th17 population and T cell activation presented as characteristics of the early immune response in S-OIV-infected patients. These findings, therefore, may be helpful for an earlier diagnosis and further studies of immune pathogenesis of S-OIV infection. PMID- 20943444 TI - The effect of stress induction on working memory in patients with psychogenic nonepileptic seizures. AB - Although psychogenic nonepileptic seizures (PNES) are considered a stress-induced paroxysmal disintegration of cognitive functions, it remains unknown whether stress indeed impairs cognitive integrative functions, such as working memory (WM), in patients with PNES. An N-back task with emotional distracters (angry, happy, and neutral faces) was administered at baseline and after stress induction (Cold Pressor Test) to 19 patients with PNES and 20 matched healthy controls. At baseline, patients displayed increased WM interference for the facial distracters. After stress induction, group differences generalized to the no distracter condition. Within patients, high cortisol stress responses were associated with larger stress-induced WM impairments in the no-distracter condition. These findings demonstrate that patients' cognitive integrative functions are impaired by social distracters and stress induction. Moreover, the stress- and cortisol-related generalization of the relative WM impairments offers a promising experimental model for the characteristic paroxysmal disintegration of attentional and mnemonic functions in patients with PNES associated with stress. PMID- 20943445 TI - Oxcarbazepine-related male infertility. PMID- 20943446 TI - Elevated plasma levels of urotensin II do not correlate with systemic haemodynamics in patients with cirrhosis. AB - BACKGROUND: The hyperdynamic circulation of hepatic cirrhosis is related to decreased systemic vascular resistance due to arterial vasodilation. Urotensin II plasma levels are increased in cirrhotic patients, and have been suggested to play a role in the pathogenesis of systemic haemodynamic alterations. AIM: To evaluate the relationships between systemic haemodynamics and urotensin II plasma levels. METHODS: Thirty-six consecutive in-patients with cirrhosis and no alteration of plasma creatinine, and 20 age- and gender-matched healthy volunteers underwent noninvasive assessment of systemic haemodynamics and measurement of urotensin II plasma levels. RESULTS: In comparison to healthy controls, cirrhotic patients had signs of hyperdynamic circulation and higher plasma urotensin II levels. Plasma urotensin II was neither significantly different amongst patients with different severity of cirrhosis nor between patients with or without ascites. Both in controls and cirrhotic patients no significant correlations were found between parameters of systemic haemodynamics and plasma urotensin II levels. CONCLUSIONS: In patients with cirrhosis and hyperdynamic circulation, but with normal serum creatinine, urotensin II is higher than in healthy subjects. However, no correlation with cardiac index or other haemodynamic parameters was observed, indicating that other mechanisms prevail. PMID- 20943447 TI - High resolution esophageal manometry evaluation in symptomatic patients after gastric banding for morbid obesity. AB - BACKGROUND: Dysphagia and vomiting are frequent after laparoscopic gastric banding (LAGB). These symptoms could be secondary to esophageal motility disorders. Our aim was to assess esophageal motility and clearance in symptomatic LAGB patients using high resolution manometry (HRM). METHODS: Twenty-two LAGB patients with esophageal symptoms (dysphagia, vomiting, and regurgitations) were included. Esophageal motility was studied using HRM (ManoScan(r), Sierra Systems) and classified according to the Chicago classification. RESULTS: The median delay between surgery and manometry evaluation was 6.3 years (range 1-10). Manometric data were considered as normal in only 2 patients. Achalasia was diagnosed in 3 cases, functional EGJ obstruction in 15, hypotensive peristalsis in 2. During swallowing pan-esophageal pressurization was observed in 6 patients, hiatal hernia pressurization in 7 and gastric pouch pressurization in 2. The intra-bolus pressure was elevated in 18 patients. LAGB was deflated in 6 patients and removed in 12. In 2 patients with unchanged symptoms after LAGB removal motility disorders persisted (1 achalasia, 1 functional EGJ obstruction). CONCLUSION: In symptomatic LAGB patients, esophageal dysmotility is frequent. High resolution manometry allows the assessment of esophageal clearance and provides guidance for the choice of treatment. PMID- 20943448 TI - Biological effects of treatment of an animal skin wound with honeybee (Apis mellifera. L) venom. AB - BACKGROUND: Wound healing is a dynamic and complex process of tissue repair, which involves a number of cellular and molecular events. It progresses from an inflammatory response to re-epithelialisation and, finally, to the formation of a permanent scar. The pharmacological activities of honeybee (Apis mellifera L.) venom (BV) have been used in wound healing for centuries. METHODS: To study wound healing, full-thickness skin defects were produced on the dorsal area of mice. We measured the relative sizes and conducted histological assays of the wounds on days 3, 5 and 7. The expressions of transforming growth factor (TGF)-beta1, fibronectin, vascular endothelial growth factor (VEGF) and collagen-I mRNA in the wound healing area was measured by reverse transcription polymerase chain reaction (RT-PCR). The amount of TGF-beta1, fibronectin, VEGF and collagen-I was determined using immunohistochemical staining. RESULTS: The wound sizes were small in the BV group compared with the control and Vaseline groups. The BV group demonstrated decreased TGF-beta1, fibronectin and VEGF mRNA levels and increased collagen-I mRNA levels. The expressions of TGF-beta1, fibronectin and VEGF proteins were significantly lower in the BV group compared with the control group, while the expression of collagen-I was increased in the BV group as indicated by immunohistochemical staining. CONCLUSION: These data suggested that BV had significant wound-healing activity. The results from this study indicated that the effects of BV on wound healing may involve biological mechanisms associated with the expressions of TGF-beta1, fibronectin, VEGF and collagen-I. PMID- 20943449 TI - The ankle extensor-tendon-sheath flap--a versatile fascial flap for coverage of the tibia and pretibial area: a preliminary report. AB - In April 2003, the author presented the use of the common peroneal tendon sheath as a vascularised fascial flap serving to cover exposed Achilles tendons in four patients. This flap was referred to as the peroneal tendofascial flap. The gross anatomy and blood supply of the tendon sheaths in the extensor compartment of the leg were studied in 15 below-knee amputation specimens. The tendon sheath was found to possess two distinct layers: an inner one that harbours the synovial sheath and belongs to each tendon separately, and a common outer layer ensheathing all the tendons within the extensor compartment. The outer layer was mainly nourished via five septal perforators anastomosing with each other. These anastomoses result in forming longitudinal sizeable vessels along the septum. The dissection of this newly described layer resulted in a proximally based axial fascial flap in four cases. The flaps with overlying split-thickness skin grafts (STSGs) were used successfully to cover soft-tissue defects overlying the tibia and pretibial area. Follow-up for at least 6 months proved the durability and sufficient coverage of the ankle extensor-tendon-sheath flap. PMID- 20943450 TI - Multiparous women's confidence to have a publicly-funded homebirth: a qualitative study. AB - BACKGROUND: Hospital birth is commonly thought to be a safer option than homebirth, despite many studies showing similar rates of safety for low risk mothers and babies when cared for by qualified midwives with systems of back-up in place. Recently in Australia, demand has led to the introduction of a small number of publicly-funded homebirth programs. Women's confidence in having a homebirth through a publicly-funded homebirth program in Australia has not yet been explored. AIM: The aim of the study was to explore the reasons why multiparous women feel confident to have a homebirth within a publicly-funded model of care in Australia. METHODS: Ten multiparous English-speaking women who chose to have a homebirth with the St George Hospital Homebirth Program were interviewed in the postnatal period using semi-structured, open-ended questions. Interviews were transcribed, then a thematic analysis was undertaken. RESULTS: Women, having already experienced a normal birth, demonstrated a strong confidence in their ability to give birth at home and described a confidence in their bodies, their midwives, and the health system. Women weighed up the risks of homebirth through information they gathered and integration with their previous experience of birth, their family support and self-confidence. DISCUSSION: Women choosing publicly-funded homebirth display strong confidence in both themselves to give birth at home, and their belief in the health system's ability to cope with any complications that may arise. IMPLICATIONS FOR PRACTICE: Many women may benefit from access to publicly-funded homebirth models of care. This should be further investigated. PMID- 20943451 TI - Development and characterization of two mini-X chromosomal short tandem repeat multiplexes. AB - This study presents the development and characterization of two X chromosomal short tandem repeat (STR) multiplexes utilizing reduced-size amplicons (less than 200 base pairs) for identity and kinship testing with degraded DNA. Approximately 1360 samples across 4 U.S. population groups were typed for 15 X chromosomal STR markers: DXS6789, DXS7130, DXS9902, GATA31E08, DXS7424, GATA165B12, DXS101, DXS6795, GATA172D05, DXS10147, DXS8378, DXS7132, DXS6803, HPRTB, and DXS7423. A high degree of polymorphism was observed for each marker and both multiplexes were sensitive down to 200pg of pristine DNA. The two proposed multiplexes are suitable for forensic use, and show potential for improved analysis of compromised bone samples. PMID- 20943453 TI - Selection of patients with hepatocellular carcinoma before liver transplantation: need to combine alpha-fetoprotein with morphology? PMID- 20943454 TI - Interferon and lamivudine combination therapy versus lamivudine monotherapy for hepatitis B e antigen-negative hepatitis B treatment: a meta-analysis of randomized controlled trials. AB - BACKGROUND: It has been demonstrated that only a minority of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) obtain a sustained response after either interferon (IFN) or nucleos(t)ide analogue monotherapy. Therefore, combination therapy of drugs with synergistic antiviral effects was proposed to have a sustained response in these patients. We compared the effect and safety of lamivudine monotherapy and its combination with IFN including conventional interferon (CON-IFN) and pegylated interferon (PEG-IFN) for HBeAg-negative CHB patients. DATA SOURCES: A group of three independent reviewers identified 9 eligible randomized controlled trials through electronic searches (MEDLINE, OVID, EMBASE, the Cochrane Library Clinical Trials Registry, and the Chinese Medical Database), manual searches, and contact with experts. Sustained virological and biochemical responses were defined as primary efficacy measures. We performed quantitative meta-analyses to assess differences between CON-IFN plus lamivudine combination and lamivudine monotherapy groups. RESULTS: No greater sustained virological and biochemical rates were found in patients receiving CON-IFN/lamivudine combination therapy [29.1% vs. 26.7%, odds ratio (OR)=0.98, 95% confidence interval (CI) 0.65-1.50, P=0.94, and 41.8% vs. 40.3%, OR=1.13, 95% CI 0.78-1.65, P=0.51, respectively], though a reduced YMDD mutation rate was achieved in the combination group [8.39% vs. 30.0%, OR=0.16, 95% CI 0.076-0.33, P<0.001]. However, data from one PEG-IFN trial showed greater sustained virological and biochemical rates in patients receiving combination therapy [response rate 19.5% vs. 6.6%, OR=3.42, 95% CI 1.71-6.84, P<0.001 and 60.0% vs. 44.2%, OR=1.88, 95% CI 1.23-2.85, P=0.003, respectively]. CONCLUSIONS: Addition of CON-IFN to lamivudine did not improve treatment efficacy but suppressed YMDD mutation by lamivudine. Combination of PEG-IFN and lamivudine might increase the sustained response, and further clinical trials are needed for confirmation. PMID- 20943455 TI - Methods of vascular control technique during liver resection: a comprehensive review. AB - BACKGROUND: Significant hemorrhage together with blood transfusion increases postoperative morbidity and mortality of hepatic resection. Hepatic vascular occlusion is effective in minimizing bleeding during hepatic parenchymal transection. This article aimed to review the current role and status of various techniques of hepatic vascular occlusion during hepatic resection. DATA SOURCES: The relevant manuscripts were identified by searching MEDLINE, and PubMed for articles published between January 1980 and April 2010 using the keywords "vascular control", "vascular clamping", "vascular exclusion" and "hepatectomy". Additional papers were identified by a manual search of the references from the key articles. RESULTS: One randomized controlled trial (RCT) and 5 RCTs showed intermittent Pringle maneuver and ischemic preconditioning followed by continuous Pringle maneuver were superior to continuous Pringle maneuver alone, respectively. Two RCTs compared the outcomes of hepatectomy with and without intermittent Pringle maneuver. One showed Pringle maneuver to be beneficial, while the other failed to show any benefit. One RCT showed that ischemic preconditioning had significantly less blood loss than using intermittent Pringle maneuver. Four RCTs evaluated the use of hemihepatic vascular occlusion. One RCT showed it had significantly less blood loss than Pringle maneuver, while the other 3 showed no significant difference. Only 1 RCT showed it had significantly less liver ischemic injury. No RCT had been carried out to assess segmental vascular occlusion. Two RCTs compared the outcomes of total hepatic vascular exclusion (THVE) and Pringle maneuver. One RCT showed THVE resulted in similar blood loss, but a higher postoperative complication. The other RCT showed less blood loss using THVE but the postoperative complication rate was similar. Both studies showed similar degree of liver ischemic injury. Only one RCT showed that selective hepatic vascular exclusion (SHVE) had less blood loss and liver ischemic injury than Pringle maneuver. CONCLUSION: Due to the great variations in these studies, it is difficult to draw a definitive conclusion on the best technique of hepatic vascular control. PMID- 20943456 TI - Advances in prognostic factors in acute pancreatitis: a mini-review. AB - BACKGROUND: Early assessment of the severity of acute pancreatitis is essential to the proper management of the disease. It is dependent on the criteria of the Atlanta classification system. DATA SOURCES: PubMed search of recent relevant articles was performed to identify information about the severity and prognosis of acute pancreatitis. RESULTS: The scoring systems included the Ranson's or Glasgow's criteria >=3, the APACHE II classification system >=8, and the Balthazar's criteria >=4 according to the computed tomography enhanced scanning findings. The single factors on admission included age >65 years, obesity, hemoconcentration (>44%), abnormal chest X-ray, creatinine >2 mg/dl, C-reactive protein >150 mg/dl, procalcitonin >1.8 ng/ml, albumin <2.5 mg/dl, calcium <8.5 mg/dl, early hyperglycemia, increased intra-abdominal pressure, macrophage migration inhibitory factor, or a combination of IL-10 >50 pg/ml with calcium <6.6 mg/dl. CONCLUSION: The prediction of the severity of acute pancreatitis is largely based on well defined multiple factor scoring systems as well as several single risk factors. PMID- 20943457 TI - Resection of hepatic caudate lobe hemangioma: experience with 11 patients. AB - BACKGROUND: Caudate lobectomy is now considered to be the most appropriate surgical treatment for benign tumors in the caudate lobe. But how to resect the caudate lobe safely is a major challenge to current liver surgery and requires further study. This research aimed to analyze the perioperative factors and explore the surgical technique associated with liver resection in hepatic caudate lobe hemangioma. METHODS: Eleven consecutive patients with symptomatic hepatic hemangiomas undergoing caudate lobectomy from November 1990 to August 2009 at our hospital were investigated retrospectively. All patients were followed up to the present. RESULTS: In this series, 9 were subjected to isolated caudate lobectomy and 2 to additional caudate lobectomy (in addition to left lobe and right lobe resection, respectively). The average maximum diameter of tumors was 9.65+/-4.11 cm. The average operative time was 232.73+/-72.16 minutes. Five of the 11 patients required transfusion of blood or blood products during surgery. Ascites occurred in l patient, pleural effusion in the perioperative period in 1, and multiple organ failure in l on the 6th day after operation as a result of massive intraoperative blood loss, who had received multiple transcatheter hepatic arterial embolization preoperatively. The alternating left-right-left approach produced the best results for caudate lobe surgery in most of our cases. All patients who recovered from the operation are living well and asymptomatic. CONCLUSIONS: For large hemangioma of the caudate lobe, surgery is only recommended for symptomatic cases. Caudate lobectomy of hepatic hemangioma can be performed safely, provided it is carried out with optimized perioperative management and innovative surgical technique. PMID- 20943458 TI - Expression level of augmenter of liver regeneration in patients with hepatic failure and hepatocellular carcinoma. AB - BACKGROUND: Augmenter of liver regeneration (ALR) is an important polypeptide in the process of liver regeneration. This study aimed to determine the expression level of ALR in different liver diseases and its significance. METHODS: We prepared murine polyclonal antibody against ALR protein from Balb/C mice and purified the IgG fraction, which specifically combined to ALR protein as shown by Western blotting. Serum ALR levels in patients with hepatocellular carcinoma (HCC), hepatic failure (HF), chronic hepatitis B, and healthy persons were compared by ELISA. ALR mRNA expression levels in liver tissues in some of these patients were also compared by real-time RT-PCR. Immunohistochemical analysis was carried out on HF and HCC liver tissues. RESULTS: Different serum ALR levels foreshowed completely different prognoses in 18 HF patients. Higher ALR levels were noted in 6 improved patients (1613.5+/-369.6 pmol/ml) than in 12 deteriorating patients (462.3+/-235.8 pmol/ml). Similar levels were found in 20 HCC patients (917.9+/-332.7 pmol/ml), 24 chronic hepatitis B patients (969.2+/ 332.5 pmol/ml) and 10 healthy persons (806.9+/-240.8 pmol/ml). ALR mRNA levels in HCC liver tissues [10E6.24 (1.74X10(6)) copies/MUl] were much higher than in those of HF patients receiving orthotopic liver transplantation [10E3.45 (2.82X10(3)) copies/MUl] or in healthy liver tissues [10E4.31 (2.04X10(4)) copies/MUl]. In immunohistochemical analysis, positive immunostaining in HCC liver tissue was more intense than that in HF liver tissue. CONCLUSION: Serum ALR level is helpful in estimating the survival time of patients with HF, and ALR may play an important role in hepatocarcinogenesis. PMID- 20943459 TI - High mobility group box-1 protein inhibits regulatory T cell immune activity in liver failure in patients with chronic hepatitis B. AB - BACKGROUND: Liver failure in chronic hepatitis B (CHB) patients is a severe, life threatening condition. Intestinal endotoxemia plays a significant role in the progress to liver failure. High mobility group box-1 (HMGB1) protein is involved in the process of endotoxemia. Regulatory T (Treg) cells maintain immune tolerance and contribute to the immunological hyporesponsiveness against HBV infection. However, the roles of HMGB1 and Treg cells in the pathogenesis of liver failure in CHB patients, and whether HMGB1 affects the immune activity of Treg cells are poorly known at present, and so were explored in this study. METHODS: The levels of HMGB1 expression were detected by ELISA, real-time RT-PCR, and Western blotting, and the percentage of CD4+CD25+CD127low Treg cells among CD4+ cells was detected by flow cytometry in liver failure patients with chronic HBV infection, CHB patients, and healthy controls. Then, CD4+CD25+CD127low Treg cells isolated from the peripheral blood mononuclear cells from CHB patients were stimulated with HMGB1 at different concentrations or at various intervals. The effect of HMGB1 on the immune activity of Treg cells was assessed by a suppression assay of the allogeneic mixed lymphocyte response. The levels of forkhead box P3 (Foxp3) expression in Treg cells treated with HMGB1 were detected by RT-PCR and Western blotting. RESULTS: A higher level of HMGB1 expression and a lower percentage of Treg cells within the population of CD4+ cells were found in liver failure patients than in CHB patients (82.6+/-20.1 MUg/L vs. 34.2+/-13.7 MUg/L; 4.55+/-1.34% vs. 9.52+/-3.89%, respectively). The immune activity of Treg cells was significantly weakened and the levels of Foxp3 expression were reduced in a dose- or time-dependent manner when Treg cells were stimulated with HMGB1 in vitro. CONCLUSIONS: The high level of HMGB1 and the low percentage of Treg cells play an important role in the pathogenesis of liver failure in patients with chronic HBV infection. Moreover, HMGB1 can weaken the immune activity of Treg cells. It is suggested that effectively inhibiting HMGB1 expression could be a feasible way to treat liver failure by suppressing endotoxemia and enhancing Treg cell activity. PMID- 20943460 TI - Serine protease HtrA1 expression in human hepatocellular carcinoma. AB - BACKGROUND: HtrA1, a serine protease, is down-regulated in various human solid tumors. Overexpression of HtrA1 in human cancer cells inhibits cell growth and proliferation in vitro and in vivo, suggesting its possible role as a tumor suppressor. METHODS: Immunohistochemistry was used to determine the expression of HtrA1 in 50 hepatocellular carcinoma specimens and adjacent liver tissues. The correlation between the expression of HtrA1 and the clinico-pathologic data were analyzed. RESULTS: The levels of HtrA1 were lower in tumor tissues than in their adjacent liver tissues. Moreover, an inverse relationship was found between HtrA1 expression and the differentiation of hepatocellular carcinoma. Loss of HtrA1 was more frequently found in tumors in Edmondson grade III-IV, especially in those with venous invasion, compared to tumors in Edmondson grade I-II. Most importantly, patients with higher HtrA1 expression had a better survival rate. CONCLUSION: All these data suggest an important role of HtrA1 in hepatocellular carcinoma development and progression, which may be a new target for its treatment. PMID- 20943461 TI - Increased susceptibility to experimental steatohepatitis induced by methionine choline deficiency in HBs-Tg mice. AB - BACKGROUND: Worldwide, about 25% of individuals with chronic hepatitis B have fatty liver disease. Lipogenic diets that are completely devoid of methionine and choline induce nonalcoholic fatty liver disease. However, no animal model of nonalcoholic steatohepatitis associated with HBV infection is available, and the influence of viral infection on nutritional hepatic steatosis is unclear. METHODS: We used HBV surface antigen transgenic mice (HBs-Tg mice), which mimic healthy human carriers with hepatitis B surface antigen. The mice were fed with a high-fat methionine-choline-deficient diet (MCD) to build a reliable rodent nutritional model of nonalcoholic steatohepatitis associated with HBV infection, and the changes in body weight and serum triglycerides were measured. Hepatocyte ballooning changes were determined by hematoxylin and eosin staining. The extent of hepatic fat accumulation was evaluated by oil red O staining. Immunohistochemical assays were performed to detect proliferating cell nuclear antigen as an index of cell proliferation. RESULTS: MCD feeding provoked systemic weight loss and liver injury. MCD feeding caused more macrovesicular fat droplets and fat accumulation in the livers of HBs-Tg mice than in wild-type C57BL/6 mice. In addition, within 30 days of MCD exposure, more PCNA-positive nuclei were found in the livers of HBs-Tg mice. CONCLUSIONS: HBs-Tg mice fed with a lipogenic MCD form more macrovesicular fat droplets earlier, coincident with more hepatocyte proliferation, resulting in the appearance of increased susceptibility to experimental steatohepatitis in these mice. PMID- 20943462 TI - Profile of hepatocyte apoptosis and bile lakes before and after bile duct decompression in severe obstructive jaundice patients. AB - BACKGROUND: Excessive hepatocyte apoptosis and bile lakes in severe obstructive jaundice might impair liver functions. Although decompression of the bile duct has been reported to improve liver functions in animal studies, the mechanism of obstruction differs from that in humans. This study aimed to determine the profiles of hepatocyte apoptosis and bile lakes following bile duct decompression in patients with severe obstructive jaundice in the clinical setting. METHODS: We conducted a "before and after study" on severe obstructive jaundice patients as a model of inhibition of the excessive process by bile duct decompression. Specimens of liver biopsies were taken before and after decompression of the bile duct and then stained by terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL) to identify hepatocyte apoptosis and by hematoxilin-eosin (HE) to identify bile lakes. All measurements were independently done by 2 observers. RESULTS: Twenty-one severe obstructive jaundice patients were included. In all patients, excessive hepatocyte apoptosis and bile lakes were apparent. After decompression, the hepatocyte apoptosis index decreased from 53.1 (SD 105) to 11.7 (SD 13.6) (P<0.05), and the bile lakes from 23.6 (SD 14.8) to 10.9 (SD 6.9) (P<0.05). CONCLUSION: Bile duct decompression improves hepatocyte apoptosis and bile lakes in cases of severe obstructive jaundice, similar to the findings in animal studies. PMID- 20943463 TI - Salmonella typhi and gallbladder cancer: report from an endemic region. AB - BACKGROUND: Evidence exists of a link between chronic infection by Salmonella typhi (S. typhi) and the development of gallbladder cancer (GBC), but several studies from endemic regions contradict its role in the etiopathogenesis of GBC. This study used various tools to assess the prevalence of S. typhi in patients with GBC and gallstone disease (GSD) in this region with a high incidence of GBC. METHODS: S. typhi was detected in tissue and bile by PCR and culture and in serum by the Widal test and indirect hemagglutination assay (IHA). PCR with two pairs of S. typhi specific primers (flagellin gene H1d and SOP E gene) could detect 0.6 ng of S. typhi DNA. Fifty-four patients with GBC (cases) were matched with 54 patients with GSD (controls). RESULTS: Of the 54 cases, 24 (44.44%) were positive on the Widal test and 12 (22.22%) on IHA, compared to 13 (24.07%) and 5 (9.26%) respectively in the controls. Eighteen (33.33%) cases showed a positive result on PCR (tissue) and 2 on PCR (bile) vs. none in the controls. Bile culture revealed no Salmonella colonies in either cases or controls. Only 3 cases were positive for Salmonella on tissue culture compared to none in the controls. The sensitivity of PCR (tissue) relative to the Widal test, IHA, culture (bile and tissue) and PCR (bile) was 100% vs. 66.67%, 11.11%, and 11.11%, and the specificity was 83.33% vs. 100%, 100%, and 100%, respectively. CONCLUSIONS: S. typhi is significantly associated with GBC compared to GSD (33% vs. 0%). PCR appears to be the most specific diagnostic tool, the gold standard for S. typhi in tissue samples. PMID- 20943464 TI - Roles of Smad3 and Smad7 in rat pancreatic stellate cells activated by transforming growth factor-beta 1. AB - BACKGROUND: Pancreatic stellate cells (PSCs) play a major role in promoting pancreatic fibrosis. Transforming growth factor beta 1 (TGF-beta1) is a critical mediator of this process. This study aimed to determine the expression of the Smad3 and Smad7 genes in the process of PSC activation, and explore the mechanisms of chronic pancreatitis. METHODS: The expressions of Smad3 and Smad7 in PSCs before and after TGF-beta1 treatment were detected by reverse transcription-polymerase chain reaction and Western blotting analysis. Smad3 expression was detected in PSCs after treatment with 5 ng/ml of TGF-beta1 for 24 hours. RESULTS: Smad7 expression was decreased in TGF-beta1-activated PSCs (P<0.05) in a dose-dependent manner. When TGF-beta1 concentration reached 10 ng/ml, the expression of p-Smad3, Smad3, and Smad7 was inhibited (P<0.05). CONCLUSIONS: TGF-beta1 promotes the expression of Smad3 and inhibits the expression of Smad7 during the activation of PSCs. In contrast, high-dose TGF beta1 downregulates the expression of Smad3 in completely activated PSCs. PMID- 20943465 TI - Effect of Danshen on apoptosis and NF-kappaB protein expression of the intestinal mucosa of rats with severe acute pancreatitis or obstructive jaundice. AB - BACKGROUND: Intestinal mucosa injury in cases of severe acute pancreatitis (SAP) or obstructive jaundice (OJ) is one of the main reasons for the accelerated aggravation of these diseases. Besides being an organ to digest and absorb nutrients, the intestine is also a unique immune organ. When SAP and OJ develop, the destruction of the intestinal mucosa barrier is an important contributing factor for the development of bacterial translocation, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome. It is important to protect the intestinal mucosa in the therapy for SAP and OJ. In this study, we determined the effect of Radix Salviae Miltiorrhizae (Danshen) injection on apoptosis and NF-kappaB P65 protein expression in the intestinal mucosa of rats with SAP or OJ, and explored the protective mechanism of Danshen in their mucosa. METHODS: Sprague-Dawley rats were used in the SAP and OJ experiments. These rats were randomly divided into sham-operated, model control, and treated groups. At various times after operation, the mortality rates were calculated. Subsequently, the rats were killed to assess the pathological changes, the expression levels of Bax and NF-kappaB proteins, and the apoptosis indices in the intestinal mucosa. RESULTS: Compared to the corresponding model control group, the number of SAP or OJ rats that died in the treated group decreased but showed no statistically significant difference. At all time points after operation, there was no significant difference between the treated and model control groups in the staining intensity as well as the product of staining intensity and positive staining rate of Bax protein in the intestinal mucosa of SAP and OJ rats . At 3 hours after operation, the apoptosis index of the intestinal mucosa of SAP rats in the treated group was lower than that in the model control group (P<0.01). At 12 hours after operation in SAP rats and 28 days after operation in OJ rats, the staining intensity as well as the product of staining intensity and positive staining rate of NF-kappaB protein of the intestinal mucosa in the treated group were lower than those in the model control group (P<0.01). CONCLUSION: Danshen exerts protective effects on the intestinal mucosa of SAP and OJ rats perhaps by inhibiting apoptosis and down-regulating NF-kappaB protein. PMID- 20943466 TI - Life made easy: simplifying reconstruction for dual portal veins in adult right lobe live donor liver transplantation. AB - In live donor liver transplantation, anatomical anomalies of the portal vein are more frequently encountered in right lobe than left lobe grafts. Of these, a dual portal vein is one of the most common anatomical anomalies encountered. We hereby report our method of using a recipient portal vein patch after venoplasty for reconstruction in a right lobe graft with separate anterior and posterior portal vein branches. PMID- 20943467 TI - Hepatocellular carcinoma metastatic to the kidney mimicking renal oncocytoma. AB - BACKGROUND: Renal metastases of hepatocellular carcinoma (HCC) are very rare. To our knowledge only five cases have been reported to the present; all had a well known primary HCC. METHODS: We describe the clinico-pathological features of a rare case of HCC metastatic to the kidney in which the renal mass was the clinical debut of disease. The patient was a 54-year-old woman previously submitted to orthotopic liver transplantation, who underwent left nephrectomy for a renal mass. RESULTS: Histologically, the tumor was composed mainly of epithelioid cells with homogeneous acidophilic cytoplasm resembling oncocytoma or primary renal carcinoma with oncocytic features. A correct diagnosis was made on the basis of positive immunostaining for hepatocyte paraffin 1. CONCLUSIONS: Metastasis to the kidney is a rare complication that should be considered whenever a renal mass is present in patients with HCC. Since HCC may histologically resemble primary renal tumors such as oncocytoma, pathologists must be aware of this possibility above all in patients referred for liver transplantation and treated with immunosuppressant drugs. Immunohistochemistry is particularly helpful to establish a precise diagnosis in cases of doubt. PMID- 20943468 TI - Simultaneous breast and ovarian metastasis from gallbladder carcinoma. AB - BACKGROUND: Gallbladder carcinoma is a common malignancy in the Indian subcontinent. It commonly metastasizes through lymphatics, direct invasion, and hematogenous spread. A common extra-abdominal site of metastasis is the lungs. Simultaneous metastasis to breast and ovary is extremely rare. METHOD: This report describes an unusual case of carcinoma gallbladder metastasizing to the breast and ovary at the same time. RESULTS: A 45-year-old woman came to us with complaints of flatulent dyspepsia associated with weight loss and anorexia. Ultrasound of the abdomen revealed hepatomegaly with thick-walled gallbladder with multiple stones and a mass at the fundus, but normal uterus and ovary. Contrast-enhanced computer tomography of the abdomen showed a gallbladder mass infiltrating the liver parenchyma. The patient underwent radical cholecystectomy. Histopathological examination revealed a poorly-differentiated adenocarcinoma with mar-gins free from tumor infiltration. One month after surgery she developed a breast lump. Ultrasound of the abdomen for metastatic workup revealed an ovary mass. Simple mastectomy and salphingo-opherectomy were performed, and histopathological examination revealed a metastatic adenocarcinoma. The patient is now on chemotherapy with gemcitabin. CONCLUSION: This is an unusual case of carcinoma of the gallbladder with metastasis to the breast and ovary, which has not been documented before. PMID- 20943471 TI - The transition beyond a carbon-fueled economy--the time is now. PMID- 20943472 TI - Workers' Compensation in the United States: cost shifting and inequities in a dysfunctional system. AB - Workers' Compensation is a far more significant expense to the U. S. economy than is commonly recognized. The total annual cost of the health care and disability benefits in the United States is at least $300 billion. The health care costs shifted by employers to Medicare/Medicaid and the disability costs shifted to the Social Security system far exceed the total costs of all the state Workers' Compensation programs. Most of the responsibility for compensating disabled workers now resides in the federal government, not in the state system. Federal funding of Workers' Compensation is at least four times that of state programs. State and federal Workers' Compensation programs are a costly and inefficient segment of health care that should be included in any consideration of health care reform. PMID- 20943473 TI - Workers' Compensation reform requires an agenda ... and a strategy. AB - In a response to Joseph LaDou's article in this issue, Michael Lax focuses on the broader issues. If we are agreed that we need significant change in Workers' Compensation, what should the nature of those changes be? Of equal importance to knowing what we want is the development of a strategy for how to get there. Without an effective strategy, we will be consigned to discussing the issues again and again, developing attractive alternatives that live only on paper or at conferences. PMID- 20943474 TI - Why are the Workers' Compensation systems dysfunctional? From scientists we ought also to expect science! AB - In the context of the history of science and the American labor movement, this comment in response to Joseph LaDou's in this issue briefly addresses impediments to Workers' Compensation reform: intellectual lapses in understanding the key concept of causation and political mistakes rooted in professional timidity. The result is the perpetuation of failures of government. PMID- 20943475 TI - Boundary networks and Rochester's "smart" lead law: the use of multidisciplinary information in a collaborative policy process. AB - The Rochester, New York, Coalition to Prevent Lead Poisoning formed in 2001 with the goal of eliminating childhood lead poisoning by 2010. The Coalition recruited diverse community stakeholders into a collaborative process committed to using the best available science. The Coalition successfully infused the debate about a new lead poisoning law with local data, national analyses, and the latest medical research. We argue that this was facilitated by a boundary network of individuals who provided technical input throughout the process. As a result of the Coalition's advocacy, in 2005 the Rochester City Council unanimously passed an ordinance that has been hailed as one of the nation's "smartest" lead laws. Many communities are looking to Rochester's new lead ordinance as a model. Both the process and outcome of this case provide valuable lessons for collaborative efforts to promote scientifically sound local environmental health policy. PMID- 20943476 TI - Perspectives of residential contractors on nail gun safety. AB - Perspectives on nail gun safety were sought from residential contractors as part of an injury surveillance and prevention effort (2005-2008). Anonymous surveys inquired about tool use, training, injury risk, and awareness of the 2003 American National Standards Institute (ANSI) standard calling for shipment of pneumatic nail guns used in wood framing with sequential actuation. Despite some awareness of inexperience, lack of training, speed and tool design in injury causation, 55 percent consistently reported injuries resulted from worker carelessness. Contractors reported safety experiences of their employees were considerably better than those of other residential contractors. After five years, only 16 percent reported any awareness of the voluntary standard. These findings raise questions as to what gains can realistically be expected from passage of voluntary standards such as the one described here. Given that the epidemiology of acute injuries from pneumatic nail guns is now well-described, the safer sequential trigger should be required to protect workers. PMID- 20943478 TI - Committed to social justice and research with the people: an interview with Professor Richard Clapp by Ema Rodrigues and Madeleine Kangsen Scammell. AB - As retirement nears, public health scientist and professor Richard Clapp of Boston University reviews his long career, discusses his past and current work interests, and their rewards and drawbacks. PMID- 20943477 TI - Toyotism in Brazil: the contrast between discourse and practice and the consequences for workers' health. AB - In recent decades, a predominant discourse has emerged in the media, particularly in the business management literature, that affirms moving beyond rigid Taylorism Fordism to a more flexible work organization model considered to be more humanized. This article presents some results of a study that analyzed the experiences of workers in two Japanese automobile plants in Brazil with respect to aspects of the organization of work that have been promoted as positive by this predominant business management discourse. The plants studied employ the Japanese production model which has served as the principal reference for the idea of increased flexibility. The ethnographic methodology used included open ended interviews (individual and in groups), informal conversation with workers, and participation in activities promoted by the union that represented the workers interviewed. The data analyzed took into account the experience of more than 40 workers. We conclude that the consequences of the work experiences of the workers who participated in the study are mental suffering and illness, and not a more humane work environment, as many business management publications have argued. PMID- 20943479 TI - Hope in cooperatives? An organizer's thoughts for the future. AB - In an address at a Jobs with Justice conference, a veteran organizer takes a look at the value of cooperatives in boosting economic conditions and at his union's agreement with one such organization. PMID- 20943480 TI - System change-not climate change: a people's declaration from Klimaforum09. PMID- 20943481 TI - Workers' Compensation reform policy. PMID- 20943484 TI - [WANG Jin-Ling.]. PMID- 20943485 TI - [Research and development of Lipin family.]. AB - Lipin family including at least three members Lipin 1, Lipin 2, and Lipin 3 is a critical regulatory enzyme identified recently, which plays dual roles in lipid metabolisms. Lipin family has physiological effects not only on regulating lipid metabolism, but also on maintaining normal peripheral nervous functions, liver lipoprotein secretion, cell morphous, reproductive functions, and energy homeostasis. Since mutations in Lipin gene express may be associated with AIDS, insulin resistance, obesity, diabetes mellitus, and the other diseases of metabolic syndrome, Lipin may be a new useful target in treatment of above mentioned clinical-related diseases. In this article, we focused on discovery, construction features, expression, regulatory mechanism, and biological functions of Lipin, as well as its correlation research with clinical-related diseases. PMID- 20943486 TI - [Advances in early diagnosis of colorectal cancer based on detection of RNAs in stool.]. AB - Colorectal cancer (CRC) is one of the most malignant cancers in gastrointestinal tract. In China, there are increasing rates of morbidity and mortality for CRC. As the mortality is closely related to the stage of disease at time of diagnosis, early diagnosis of CRC is important. However, current techniques used for clinical diagnosis have limitations which made them difficult to achieve the early diagnosis. The detection of RNAs in stool is a newly developed noninvasive technique for early diagnosis of CRC at molecular levels. Compared with the techniques including colonoscopy, fecal occult-blood test and stool DNA-based mutation detection, diagnosis based on the detection of RNAs in stool has the advantages of low-cost and high sensitivity. Moreover, stool RNA-based techniques are able to analyze multiplexed gene expression simultaneously and monitor cancer progression dynamically. This paper introduced the feasibility of stool RNA analysis, and systematically reviewed the genes associated with stool RNA analysis, methods of RNA isolation from stool sample, and techniques for gene expression analysis in stool RNA. Finally, further applications of stool RNA based techniques for early diagnosis of CRC were briefly discussed. PMID- 20943487 TI - [Mechanism of regulating deacetylase SIRT1 expression and activity.]. AB - SIRT1 is an NAD+-dependent deacetylase in mammalian cells and plays important roles in senescence, cell death and tumorigenesis. To clarify the regulation of SIRT1 expression and activity is crucial for scientists to understand the biological function of SIRT1. This review mainly focuses on the mechanisms by which SIRT1 expression and activity are regulated. PMID- 20943488 TI - [The databases of transcription factors.]. AB - The control of gene transcription is a critical level of gene expression regulation. The interactions between transcription factors (TF) and their DNA binding sites (TFBS) play a key role at this level. In order to decipher the molecular mechanism of the interactions of TFs with TFBSs and construct transcription regulatory network, it is necessary to systematically collect, save, and analyze the information of discovered TFs and their TFBSs. In recent years, multiple TF and TFBS-related databases have been established. These databeses significantly promoted the TF-related studies in the fields of molecular biology, bioinformatics, and system biology. This paper summarized the contents, characteristics, access, and advances of main TFs and TFBSs-related databases, including TRANSFAC, JASPAR, TFDB, TRRD, TRED, PAZAR, MAPPER and others. PMID- 20943489 TI - [Advances in plant microRNA and stresses response.]. AB - MicroRNAs (miRNAs) are endogenous 16-29 nt non-coding small RNAs that were are generally found in species and typically encoded by endogenous genes. They play an important regulatory role at post-transcription level by targeting mRNA cleavage and translation repression. More and more plant miRNAs had been predicted and identified along with the development of bioinformatics and experimental techniques. At stress conditions, plant miRNAs also play a role in adaptation by up-regulating or down-regulating the miRNA expression. The biogenesis, action mode with target genes, bio-logical functions of plant miRNAs, as well as the stress-responsive miRNAs, were reviewed and the methodologies of miRNA study were also briefly summarized in this paper. PMID- 20943490 TI - [Meta-analysis of LPL PvuII polymorphism with hyperlipoidemia and coronary heart disease in the Chinese population.]. AB - Multiple studies reported the association of LPL PvuIIpolymorphism (rs285) with hyperlipoidemia and coronary heart disease in the Chinese population; however, the sample sizes of these studies were small (119-647) and the results were not consistent. A Meta-analysis was undertaken to evaluate the role of LPL PvuIIpolymorphism in hyperlipoidemia and coronary heart disease in Chinese. A total of 11 case-control studies were collected. Among them, 6 studies on hyperlipoidemia contained 943 cases and 1,093 controls, and 5 studies on coronary heart disease contained 821 cases and 727 controls. No significant publication bias was found and significant heterogeneity between these studies was observed. The results of Meta-analysis indicated that the allele P+ increased the risk of hyperlipoidemia (OR=1.36, 95%CI 1.07~1.73, P=0.011), and no evidence of association (P=0.755) was found for coronary heart disease. Our study suggested that the LPL PvuIIpolymorphism was significantly associated with hyperlipoidemia but not with coronary heart disease in the Chinese population. PMID- 20943491 TI - [Cloning, expression and functional analysis of CuZnSOD gene in swine.]. AB - In order to understand the structure and function of CuZnSOD gene, reveal the effect of the anti-oxidant in swine, and find the molecule marker correlated with meat traits, the cDNA of CuZnSOD gene was cloned and sequenced from muscle of Laiwu black swine by RACE (rapid amplification of cDNA end) techniques. The structure and function of CuZnSOD were analyzed by bioinformatics, and the gene expression profile in different tissues was examined by real-time PCR. The results showed that the full sequence of CuZnSOD cDNA is 658 bp (GU944822), containing 76 bp sequence of 5' UTR and 120 bp sequence of 3' UTR, and coding region (CDS, 462 bp) encodes 153 amino acids. The isoelectric point (pI) of the protein is 6.03, and the molecular weight is 15.9 kDa. There were one O glycosylation site at the third amino acid and one N-glycosylation site at the eighty-fourth amino acid. The percentage of alpha helix was 1.31%. The alignment similarities of the CDS sequence of swine CuZnSOD with those of cattle, human, rat, and mouse were 87.74%, 87.66%, 83.44%, and 83.23%, and the similarities of amino acid sequence were 90.26%, 94.12%, 92.21%, and 91.50%, respectively. CuZnSOD possesses the typical metal binding ligands (GFHVHQFGDNT). The phylogenic tree based on CuZnSOD protein sequence detected the closest relationship between swine and cattle. CuZnSOD mRNA is a broad-spectrum expression gene, which was detected in brain, heart, spleen, liver, kidney, lung, large intestine, small intestine, spinal cord, muscle, backfat, and stomach. In particular, high expression levels of CuZnSOD mRNA were detected in kidney, small intestine and lung, but low expressions were observed in heart and muscle tissues. PMID- 20943492 TI - [Differential expression of MAPK-pathway genes during liver regeneration of mouse.]. AB - To investigate the different expression profiles of MAPK pathway genes and their corresponding functions during liver regeneration, we used a CCl4 induced mouse liver regeneration model in this study. Mouse was injected with CCl4 in the abdominal cavity to cause damage in the liver and followed by liver histology examination and measurement of serum ALT levels in blood sample collected at 0, 0.5, 1.5, 4.5, and 7 d after CCl4 injection. Differentially expressed genes in the MAPK pathway during liver regeneration were analyzed using mouse cDNA microarray method (Affymetrix). The results obtained were further subjected to hierarchical clustering study and were validated with real-time PCR. Microarray hybridization identified 31 out of the 93 MAPK pathway component genes, which have significantly altered their expression levels during liver regeneration. Among them, both up- and down-regulated genes were classified into various groups according to clustering studies and functional analysis. At the initial stage of liver regeneration, the number of up-regulated genes was greater than the down regulated genes, while at the late stage the situation was reversed. Our results suggest that MAPK pathway might play different regulatory roles in responding to different stages of liver regeneration. PMID- 20943493 TI - [A new balancer of chapped wing on chromosome 3 and a gathering line with double balancers of chapped wing (L) and Cy in Drosophila melanogaster.]. AB - The balancers of Drosophila melanogaster are widely used in genetic research. By analyzing the phenotype of offspring from hybridization of chapped wing (L) mating with OR, 982p and e, respectively, we mapped the chapped wing mutation on chromosome 3 for the first time and demonstrated the chapped wing mutation as a new balancer of D. melanogaster with dominant wing nicking phenotype. Finally, we bred a novel gathering line with double balancers of L and Cy in D. melanogaster. The mutant L provided a legible dominant marker for the balancer of chromosome 3, and the cultivation of double balancers chapped-curly wing enriches the balancer stock, which is often used in mapping and screening. PMID- 20943494 TI - [Isolation of microsatellite markers from Paralichthys olivaceus and its application in genetic structure analysis]. AB - Magnetic bead enrich-method and plasmid detection-method were used to isolate microsatellite DNA from Paralichthys olivaceus genome. The microsatellite markers were applied to analyze natural population structure of four populations, which were collected from Dalian, Beidaihe, Dandong, and Qingdao. Two thousand eight hundred and five microsatellite sequence clones were isolated and 3120 microsatellite loci were obtained. From these sequences, 57.97% were perfect, 7.25% were imperfect and 34.78% were compound. This allowed to design 135 pairs of primers with the software Primer Premier 3.0. Seventy-eight pairs were synthesized and 30 pairs were polymorphic. The effective number of alleles ranged from 3.93 to 9.94 (6.95 in average) with observed and expected heterozygosities ranging from 0.532 to 0.895 (0.753 in average) and 0.635 to 0.902 (0.820 in average), respectively. Hardy-Weinberg equilibrium analysis in 30 microsatellite loci by genetic deviation index (d) ranged from -0.247 to 0.512, among which 7 loci had heterozygote excess (d>0) and the rest showed heterozygote deficit (damp;0). A dendrogram was constructed based on NJ methods using MEGA3.0 software package. Four populations were divided into two clusters. Dalian population and Dandong population were grouped in one cluster, while Beidaihe population and Qingdao population were classified into another cluster. PMID- 20943495 TI - [Genetic analysis and molecular mapping of a high-tillering mutant (ht1) in rice.]. AB - A rice (Oryza sativa L.) mutant with a high-tillering capacity, designated as ht1, was found from a japonica rice variety Xindao18. This high-tillering mutant phenotype was stably expressed through successive five self-crossed generations, and the number of tillers in mutants was three times more than that in wild-type rice. Genetic analysis showed that the phenotype of ht1was controlled by a single dominant nuclear gene, temporarily designated as HT1. By means of molecular marker technique, the HT1 gene was mapped to an interval between two SSR markers RM25435 and RM25552 on chro-mosome 10. Through high-resolution linkage analysis, the HT1 gene was further restricted to a 0.1 cM region flanked by two SSR markers RM25523 and RM25532. The physical distance between these two markers is about 130kb. PMID- 20943496 TI - [Construction of a methylation filtration library in Hevea brasiliensis.]. AB - In order to enrich gene encoding region of Hevea brasiliensis, a methylation filtration library was constructed using Escherichia coli McrBC restriction modification system. The titers of the non-amplified library and the amplified library were 2.6*106 pfu/ml and 9.0*109, respectively. The rate of positive clones was 86.4%. The lengths of inserted DNA sequence ranged from 1 kb to 2.5 kb and the average size of inserts was 1.2 kb. One hundred clones were selected randomly for sequencing, resulting in splicing out of 81 non-redundant sequences, including 6 contigs and 75 singlets. The redundancy was 17.35%. Blast analysis showed that 39.5% of non-redundant sequences were homologous with the Nr database, 14.81% with the EST database, and 32.1% were unknown sequences. Some sequences were related genes for flowering, insect and disease resistance. Therefore, the rubber tree methylation library is helpful for discovery and cloning of functional genes. PMID- 20943497 TI - [Dynamic QTL and correlated characters of tomato soluble solid content.]. AB - Two hundred and six F2:3 families from the cross between TD22 and HT-1-1-1-1 were used for dynamic QTL research of tomato soluble solid content and correlative traits, and correlation analysis of soluble solid content (SSC) with fruit weight (FW), fruit shape index (FSI), soluble sugar, vitamin C (VC), and organic acid at three different development stages. The results showed that there were differences in QTL loci for soluble solid content during the three stages of tomato fruit development. Four and eight QTLs were detected in green ripe stage and red ripe stage, respectively. These QTLs showed dynamic changes, and two markers LEaat006 and Tomato|TC162363 were detected in two stages, which might be useful in molecular-marker assisted selection (MAS). The result also showed that there was extremely significant difference in SSC at the three different stages, and its main correlative traits were different at different stages. Soluble solid content was positively correlated with soluble sugar, but negatively correlated with FW at green ripe stage; SSC was positively correlated with soluble sugar and organic acid at yellow ripe stage; SSC was positively correlated with soluble sugar and organic acid, but negatively correlated with fruit weight at red ripe stage. Based on correlation analysis of these traits, linear regression model was constructed. Non-tested varieties were used to test the fitness, and the result showed that it is well fitted, and the fitness is above 95%. PMID- 20943498 TI - [Practice and research into multi-unit teaching of Medical Genetics.]. AB - In order to fully arise the enthusiasm of students in active learning and promote their development, we attempted such multiple class teaching methods in teaching medical science of genetics as elaboration of the basic theory of genetics, synopsis on the advance of this field, application of multimedia teaching, case based teaching, role-play change in class teaching, instructions on writing of reviewing articles and academic assessment by diverse examination. The results suggest that multiple teaching methods can greatly enhance the efficiency of class teaching and comprehensively cultivate the academic ability of the students as well as improve the quality of teachers. Compared with the conventional class teaching, students are much interested in giving lessons by case-based study, CAI teaching and role change of teachers and students in class teaching, which resulted in improvement of self-disciplined study of students, problem settlement, class performance, awareness of the importance of scientific research and reinforcement of team work. PMID- 20943499 TI - Gibberellin production and plant growth promotion from pure cultures of Cladosporium sp. MH-6 isolated from cucumber (Cucumis sativus L.). AB - Gibberellin (GA) production by soil fungi has received little attention, although substantial work has been carried out on other aspects of plant growth promoting fungi (PGPF). In our studies we investigated GA production and growth-promoting capacity of a novel fungal strain isolated from the roots of soil-grown cucumber. Pure cultures of 19 endophytic fungi were tested for shoot length promotion of Waito-C rice to identify the GA production capacity of these fungal isolates. Isolate MH-6 significantly increased shoot length (12.9 cm) of Waito-C, in comparison to control treatments. Bioassay with culture filtrate (CF) of MH-6 also significantly promoted growth attributes of cucumber plants. Analysis of MH 6 CF showed the presence of physiologically active (GA1, 1.97 ng/mL; GA3, 5.18 ng/mL; GA4, 13.35 ng/mL and GA7, 2.4 ng/ mL) in conjunction with physiologically inactive (GA9 [0.69 ng/mL], GA12 [0.24 ng/mL], GA15 [0.68 ng/ mL, GA19 [1.94 ng/mL and GA20 [0.78 ng/mL]) gibberellins. The CF of MH-6 produced greater amounts of GA3, GA4, GA7 and GA19 than wild type Fusarium fujikuroi, a fungus known for high production of GA. The fungal isolate MH-6 was identified as a new strain of Cladosporium sp. on the basis of sequence homology (99%) and phylogenetic analysis of 18S rDNA sequence. PMID- 20943500 TI - Dictyostelid cellular slime molds associated with grasslands of the central and western United States. AB - Dictyostelid cellular slime molds (dictyostelids) associated with grassland ecosystems of the central and western United States were investigated at nine sites that included examples of the three major ecological types of grasslands (tall grass, mixed grass and short grass) generally recognized for the region. Samples of soil/humus collected from each site were examined with the Cavender method of isolating dictyostelids. For each of those six sites with well developed gallery forests present, an additional set of forest soil/humus samples was collected. A more intensive sampling effort was carried out at one site (Konza LTER) to assess the possible effects of burning and grazing on dictyostelid diversity and density. Twelve species of dictyostelids were recovered from grassland sites, whereas gallery forest sites yielded only nine species. Four cosmopolitan species (Dictyostelium giganteum, D. mucoroides, D. sphaerocephalum and Polysphondylium pallidum) were represented by the greatest densities of clones, with D. sphaerocephalum particularly common. The general pattern across all sites was that both species richness and density of dictyostelids decreased with decreasing precipitation. Samples collected from ungrazed grassland plots yielded higher numbers of both species and clones as compared to grazed plots, and the general pattern was for both values to increase as the interval between fires increased. For numbers of clones this correlation was statistically significant. PMID- 20943501 TI - Contamination by uranium mine drainages affects fungal growth and interactions between fungal species and strains. AB - The presence of aquatic hyphomycetes has been reported for several heavy metal contaminated waters. Tolerance probably is one adaptation to coping with heavy metals. To help clarify this issue strains of two species of aquatic hyphomycetes (Tricladium splendens Ingold and Varicosporium elodeae Kegel) were isolated from a reference stream and a stream contaminated with heavy metals and grown on malt extract agar prepared with reference and contaminated water to characterize colony morphology, growth rate, growth inhibition and interaction among species and strains. In V. elodeae the morphology of colonies differed between strains. Colony diameter increased linearly over time with growth rates being lower for strains isolated from contaminated than from reference streams (mostly for V. elodeae). Strains from the contaminated stream grew faster in medium prepared with contaminated water than in medium prepared with reference water, while for strains from the reference stream there was no significant difference in growth rates on the two media. In interacting isolates radial growth toward the opposing colony was generally lower than toward the dish edge. Percentage growth inhibition was higher for isolates in intraspecific interactions (13-37%) than in interspecific interactions (3-27%). However differences in growth inhibition experienced by interacting isolates were observed only in three cases out of 16. The difference between the percentage inhibition caused and experienced by a given isolate was highest in interactions involving isolates with distinct growth rates. Our results suggest that strains from the reference stream tolerate heavy metals while strains from the contaminated stream seem to be adapted to contaminated waters. We hypothesize that in natural environments fungal species specific limits of tolerance to metal contamination might determine an abrupt or gradual response of the original fungal community to mine pollution giving origin to a poorer fungal community dominated by adapted strains with distinct functional efficiency. PMID- 20943502 TI - Shifting fungal endophyte communities colonize Bouteloua gracilis: effect of host tissue and geographical distribution. AB - Communities of root-associated fungi (RAF) commonly have been studied under the auspices of arbuscular mycorrhizal fungi (AMF) or ectomycorrhizal fungi. However many studies now indicate that other groups of endophytic RAF, including dark septate endophytes (DSE) are more abundant in some plants and environments. The common forage grass, Bouteloua gracilis, was used as a model to examine whether RAF also colonize different organs within the same plant and to compare RAF communities from sites across North America, spanning the latitudinal range of B. gracilis (from Canada to Mexico). We compared the RAF communities of organs within individual plants at one site and within plant roots among six sites. With the possible exception of one group related to genus Paraphaeosphaeria there was little evidence that RAF colonized vertically beyond the crowns. Furthermore, although there was some variation in the constitution of rare members of the RAF communities, several taxonomically related groups dominated the RAF community at all sites. These dominant taxa included members in the Pleosporales (related to the DSE, Paraphaeosphaeria spp.), Agaricales (related to Moniliophthora spp., or Campanella spp.) and Hypocreales (related to Fusarium spp.). AMF were notable by their near absence. Similar phylotypes from the dominant groups clustered around adjacent sites so that similarity of the RAF communities was negatively correlated to site inter-distance and the RAF communities appeared to group by country. These results increase the possibility that at least some of these common and widely distributed core members of the RAF community form important, intimate and long lasting relationships with grasses. PMID- 20943503 TI - Vertical distribution of fungal communities in tallgrass prairie soil. AB - We used 454 sequencing of the internal transcribed spacer region to characterize fungal communities in tallgrass prairie soils subdivided into strata 0-10, 10-20, 30-40 and 50-60 cm deep. The dataset included more than 14000 fungal sequences distributed across Basidiomycota, Ascomycota, basal fungal lineages and Glomeromycota in order of decreasing frequency. As expected the community richness and diversity estimators tended to decrease with increasing depth. Although species richness was significantly reduced for samples from the deeper profiles, even the deepest stratum sampled contained richness of more than a third of that in the topmost stratum. More importantly, nonparametric multidimensional scaling (NMS) ordination analyses indicated that the fungal communities differed across vertical profiles, although only the topmost and deepest strata were significantly different when the NMS axis scores were compared by ANOVA. These results emphasize the importance of considering the fungal communities across the vertical strata because the deeper soil horizons might maintain a distinct community composition and thus contribute greatly to overall richness. The majority of operational taxonomic units (OTUs) declined in frequency with increasing depth, although a linear regression analysis indicated that some increased with increasing depth. The OTUs and BLAST-assigned taxa that showed increasing frequencies were mainly unculturable fungi, but some showed likely affinities to families Nectriaceae and Venturiaceae or to genus Pachnocybe. Although the ecological roles of the fungi in the deeper strata remain uncertain, we hypothesize that the fungi with preferences for deeper soil have adequate access to substrates and possess environmental tolerances that enable their persistence in those environments. PMID- 20943504 TI - Improved resolution of major clades within Tuber and taxonomy of species within the Tuber gibbosum complex. AB - Tuber gibbosum Harkn., described from northern California, originally was thought to be a single, variable species that fruited from autumn through winter to spring. It has become popular as a culinary truffle in northwestern USA, where it is commercially harvested. Morphological studies suggested it might be a complex that includes at least two species. We conducted morphological and phylogenetic studies of the complex to determine how many species it might contain and how they differed morphologically, geographically and seasonally. We also provide the first LSU phylogeny for the genus Tuber. Phylogenetic analyses resolve nine major clades in the genus with high bootstrap support and distinguish the Gibbosum clade from the Aestivum, Excavatum, Macrosporum, Magnatum, Melanosporum, Puberulum, Rufum and Spinoreticulatum clades. Further analyses of ITS and LSU regions revealed four distinct species in the Gibbosum complex. Although morphologically similar the four species differ in spore size and shape and in peridial anatomy. These species share the synapomorphy of having suprapellis hyphae with distinctive, irregular wall swellings at maturity; we have not seen this hyphal type in any other Tuber spp. worldwide. The three new species are named and described as T. bellisporum Bonito & Trappe, T. castellanoi Bonito & Trappe and T. oregonense Trappe, Bonito & Rawlinson. PMID- 20943505 TI - Kalapuya brunnea gen. & sp. nov. and its relationship to the other sequestrate genera in Morchellaceae. AB - Kalapuya is described as a new, monotypic truffle genus in the Morchellaceae known only from the Pacific northwestern United States. Its relationship to other hypogeous genera within Morchellaceae is explored by phylogenetic analysis of the ribosomal LSU and EF1alpha protein coding region. The type species, K. brunnea, occurs in Douglas-fir forests up to about 50 y old on the west slope of the Cascade Range in Oregon and in the Coastal Ranges of Oregon and northern California. It has a roughened, warty, reddish brown to brown peridium, a solid whitish gleba that develops grayish brown mottling as the spores mature, and produces a cheesy-garlicky odor at maturity. Its smooth, ellipsoid spores resemble those of Morchella spp. but are much larger. The four hypogeous genera known in the Morchellaceae, Kalapuya, Fischerula, Imaia and Leucangium, are distinct from the epigeous genera Morchella and Verpa, but it is uncertain whether they resulted from a single transition to a hypogeous fruiting habit or from multiple independent transitions. Kalapuya, locally known as the Oregon brown truffle, has been commercially harvested for culinary use. PMID- 20943507 TI - Morchella tomentosa: a unique belowground structure and a new clade of morels. AB - Mechanisms involved in post-fire morel fructification remain unclear. A new undescribed belowground vegetative structure of Morchella tomentosa in a burned boreal forest was investigated north of Fairbanks, Alaska. The name "radiscisclerotium" is proposed to define this peculiar and elaborate below ground vegetative structure of M. tomentosa. Bayesian and maximum parsimony analyses based on ITS rRNA regions and nLSU gene strongly supported a new clade composed of M. tomentosa within the genus Morchella. PMID- 20943506 TI - Systematic reappraisal of species in Phoma section Paraphoma, Pyrenochaeta and Pleurophoma. AB - Sequence data from the 18S nrDNA (SSU) and 28S nrDNA (LSU) regions of isolates of Phoma section Paraphoma were compared with those of representative isolates of the morphologically similar anamorph genera Pleurophoma and Pyrenochaeta and of the type species of Phoma sections Phoma, Pilosa and Plenodomus. Phoma section Paraphoma was found to be highly polyphyletic within the Pleosporales and only distantly related to Phoma section Phoma. The genus Paraphoma, which is based on Paraphoma radicina, is reintroduced in the Phaeosphaeriaceae with two additional taxa. The new genera Setophoma and Neosetophoma, type species Setophoma terrestris comb. nov. and Neosetophoma samarorum comb. nov., are introduced and represent species that are closely related to Paraphoma but differ based on morphological characters and molecular phylogeny. Phoma coonsii is transferred to genus Chaetosphaeronema that also belongs to the Phaeosphaeriaceae. Pyrenochaetopsis gen. nov. is introduced to accommodate the type species Pyrenochaetopsis leptospora comb. nov., as well as several other species formerly accommodated in Phoma and Pyrenochaeta. Pyrenochaetopsis is closely related to Pyrenochaeta and classified in the Cucurbitariaceae. Pleurophoma cava is transferred to genus Pyrenochaeta. The new genera elucidate the confusing taxonomy of species in genera Phoma, Pyrenochaeta and Pleurophoma and recognize monophyletic genera with distinct teleomorph affinities. PMID- 20943508 TI - Northern species of earth tongue genus Thuemenidium revisited, considering morphology, ecology and molecular phylogeny. AB - Thuemenidium is a small earth tongue genus with three recognized white-spored species. Within Thuemenidium, T. atropurpureum and T. arenarium have been reported only from the northern hemisphere while T. berteroi is known solely in the southern hemisphere. We reviewed the ecology, examined the morphology and inferred the systematic positions of northern species of Thuemenidium from LSU rDNA gene phylogeny of 48 taxa in Pezizomycotina including recent collections. Our results suggest that Thuemenidium in its current sense is polyphyletic and that T. atropurpureum, closely related to Microglossum and Leotia species, is a member of Leotiaceae (Helotiales, Leotiomycetes). Our phylogeny placed the other northern species, T. arenarium, in Geoglossaceae (Geoglossales, Geoglossomycetes), retaining genus Thuemenidium, pending further investigation. PMID- 20943509 TI - New species and nomenclature in Prospodium (Uropyxidaceae, Pucciniales) and the new anamorphic genus Canasta in the neotropics. AB - Ten new teleomorphic species, two status novus taxa and two new combinations in the genus Prospodium are established. The following anamorphs, all closely related to the genus Prospodium, also are proposed: the genus Canasta, its two new species and a new combination, three new combinations for the genus Uredo. PMID- 20943510 TI - Botrytis fabiopsis, a new species causing chocolate spot of broad bean in central China. AB - The current study was conducted to identify Botrytis spp. isolated from symptomatic broad bean plants grown in Hubei Province, China. Among 184 Botrytis strains, three distinct species, B. cinerea, B. fabae and a previously undescribed Botrytis sp., were identified based on morphology of colonies, sclerotia and conidia. The novel Botrytis sp. is described herein as a new species, Botrytis fabiopsis sp. nov. At 20 C B. fabiopsis grew on potato dextrose agar (PDA) at 12-13 mm d(-1), similar to B. fabae (13 mm d(-1)), but slower than B. cinerea (17-19 mm d(-1)). It formed pale gray colonies with short aerial mycelia and produced gray to black sclerotia in concentric rings on PDA. B. fabiopsis produced greater numbers of sclerotia than B. cinerea but fewer than B. fabae. Conidia produced by B. fabiopsis on broad bean leaves are hyaline to pale brown, elliptical to ovoid, wrinkled on the surface and are larger than conidia of B. fabae and B. cinerea. Phylogenetic analysis based on combined DNA sequence data of three nuclear genes (G3PDH, HSP60 and RPB2) showed that B. fabiopsis is closely related to B. galanthina, the causal agent of gray mold disease of Galanthus sp., but distantly related to B. fabae and B. cinerea. Sequence analysis of genes encoding necrosis and ethylene-inducing proteins (NEPs) indicated that B. fabiopsis is distinct from B. galanthina. Inoculation of broad bean leaves with conidia of B. fabiopsis caused typical chocolate spot symptoms with a similar disease severity to that caused by B. fabae but significantly greater than that caused by B. cinerea. This study suggests that B. fabiopsis is a new causal agent for chocolate spot of broad bean. PMID- 20943511 TI - Co-occurrence and genotypic distribution of Phytophthora species recovered from watersheds and plant nurseries of eastern Tennessee. AB - In 2008 statewide surveys of symptomatic foliage of nursery plants from Tennessee resulted in isolation of 43 isolates of Phytophthora spp. This sample set includes four described species (P. citrophthora, P. citricola, P. nicotianae, P. syringae), and a provisional species of Phytophthora ('P. hydropathica'). At the same time a stream-baiting survey was initiated to recover Phytophthora from eight watersheds in eastern Tennessee, some of which are near plant nurseries. Baiting was accomplished by submerging healthy Rhododendron leaves approximately 1 wk and isolation onto selective media. Six baiting periods were completed, and in total 98 Phytophthora isolates and 45 isolates of Pythium spp. were recovered. Three described species (P. citrophthora, P. citricola and P. irrigata) and the provisional species 'P. hydropathica' were obtained as well as three undescribed Phytophthora taxa and Pythium litorale. Isolates from both surveys were identified to species with morphology and the internal transcribed spacer (ITS) sequence. Isolates from species co-occurring in streams and nurseries (P. citricola, P. citrophthora and 'P. hydropathica') were characterized further with amplified fragment length polymorphism (AFLP) analyses and mefenoxam tolerance assays. Isolates representing a putative clonal genotype of P. citricola were obtained from both environmental and nursery sample sets. PMID- 20943512 TI - Effect of light exposure on in vitro germination and germ tube growth of eight species of rust fungi. AB - The effects of light on urediniospore germination and germ tube elongation was studied with eight species of rust fungi that infect ornamental plants or row crops. Exposure of six species of fungi to cool white fluorescent light at 400 or 600 micromol s(-1) m(-2) for 24 h significantly reduced germination with largest decreases typically observed at 600 micromol s(-1) m(-2). Germination and germ tube elongation did not recover during 24 h dark incubation after 18 h exposure to fluorescent light at 600 micromol s(-1) m(-2), indicating the effects were not reversible. Germ tube elongation of all fungi was negatively affected by increased length of exposure to fluorescent light. Increased exposure to fluorescent light differentially affected germination of the fungi with Puccinia hemerocallidis, Phakopsora pachyrhizi, Pucciniastrum vaccinii and Puccinia menthae negatively affected and Puccinia sorghi, Puccinia triticina, Puccinia pelargonii-zonalis and Puccinia iridis relatively unaffected in 10 h incubation. Exposure of Ph. pachyrhizi and P. triticina urediniospores to sunlight rapidly reduced germination and germ tube elongation with no germination observed for Ph. pachyrhizi after 2.5 h. Germ tube elongation but not germination of hydrated urediniospores of Ph. pachyrhizi and P. triticina was significantly reduced compared to dry urediniospores exposed to 10 h fluorescent light followed by 24 h dark incubation. Exposure to fluorescent light (all fungi) or sunlight (two fungi) negatively affected urediniospore germ tube elongation. Differences observed in urediniospore germination between fungi suggest some species have co evolved with their host for differing light conditions. Our data suggests exposure of urediniospores to strong light could inactivate rust fungi on plant surfaces or in the atmosphere. PMID- 20943513 TI - Two new unusual Leucoagaricus species (Agaricaceae) from tropical China with blue green staining reactions. AB - Most species of the genus Leucoagaricus have been described from temperate regions in North America and Europe, but little is known about the genus from tropical areas. In this report we describe two new species of Leucoagaricus, namely La. flavovirens and La. atroazureus, from tropical China. The two species are characterized by turning blue-green or dark blue where bruised and by unique phylogenetic placement. Two new combinations, namely La. viriditinctus and La. caerulescens, are proposed. A collection examined and cited under the name of La. viridiflavus by Kumar & Manimohan (2009b), who designated the neotype of the species, (Petch) TKA Kumar & Manimohan, was found to differ from La. flavovirens based on morphology and ITS sequence comparison. [corrected] A monophyletic group of four bluing species from Old World tropics is recovered but with poor measures of branch PMID- 20943514 TI - Three new species of corticioid fungi with hyphal pegs. AB - Dendrodontia taiwaniana, Epithele cylindricosterigmata and E. lutea are described and illustrated as new species. Dendrodontia taiwaniana is similar to D. bicolor in having a similar hymenial surface and hyphal system, but the former has smaller basidia and basidiospores and lacks dendrohyphidia. Epithele cylindricosterigmata resembles E. sulphurea in sharing similar basidiospores, but the former has a thinner, membranous basidiocarp with a white hymenial surface, the hyphal pegs are composed of tortuous and convolute hyphae, and its sterigmata are uniformly cylindrical. Epithele lutea is close to E. typhae in the color of the hymenial surface and has similar basidiospores, but the former bears sparsely scattered, longer hyphal pegs that have a ceraceous core; microscopically its hyphal pegs are composed of slightly thick-walled, tortuous hyphae, but a sheath of dendritic hyphae as in E. typhae is lacking. PMID- 20943515 TI - Hypochnella verrucospora (Basidiomycota, Atheliales), a neotropical new species with ornamented basidiospores. AB - Hypochnella verrucospora sp. nov. is described and illustrated from material collected in Brazil and Argentina. The new species is characterized by dark purplish, violaceous to dark lilaceous, resupinate and membranous basidiomes and ellipsoid to subcylindrical, pale brown, slightly thick-walled, amyloid and delicately ornamented basidiospores. The monotypic genus Hypochnella was represented so far by H. violacea, which is distinctly characterized by smooth basidiospores, and is restricted to temperate regions in the northern hemisphere, whereas H. verrucospora seems to be Neotropical. Morphological comparison of the two species and a discussion of the genus description of Hypochnella are provided. PMID- 20943516 TI - Plurispermiopsis: a new capnodiaceous genus from the Brazilian Cerrado. AB - A new ascomycete genus placed in family Capnodiaceae found in the Brazilian Cerrado is described and designated Plurispermiopsis, type species P. cerradensis. PMID- 20943517 TI - Xylogone ganodermophthora sp. nov., an ascomycetous pathogen causing yellow rot on cultivated mushroom Ganoderma lucidum in Korea. AB - Yellow rot, caused by an ascomycetous fungus having a distinctive arthroconidial anamorph, is the most destructive disease of cultivated Ganoderma lucidum in Korea, but the identity of the yellow rot pathogen (YRP) remains uncertain. Isolates have been identified as Xylogone sphaerospora (with putative anamorph Sporendonema purpurascens) or as Arthrographis cuboidea. Therefore we used morphological features, pathogenicity tests and phylogenetic analyses of DNA sequences from the nuclear ribosomal genes, including partial small subunit and internal transcribed spacer regions, and from the gene encoding RNA polymerase second largest subunit to evaluate the relationship between YRP isolates and these species. YRP isolates formed a distinct subgroup within a clade that included X. sphaerospora, A. cuboidea and Scytalidium lignicola, the type species of Scytalidium, but the disposition of the clade within the Leotiomycetes was uncertain. We describe Xylogone ganodermophthora sp. nov. and Scytalidium ganodermophthorum sp. nov. for the teleomorph and anamorph of YRP respectively. Arthrographis cuboidea is reclassified as Scytalidium cuboideum comb. nov., and the anamorph of X. sphaerospora is named Scytalidium sphaerosporum sp. nov. In pathogenicity tests only X. ganodermophthora caused disease in Ganoderma lucidum. Amplified fragment length polymorphism analyses showed that X. ganodermophthora populations from diseased fruiting bodies or from oak wood in Korea consisted of two clonal groups. PMID- 20943518 TI - Licea eremophila, a new myxomycete from arid areas of South America. AB - A new stipitate species of myxomycete of the genus Licea is described based on material from arid areas in Argentina and Chile. It was isolated from moist chamber cultures and found fruiting on field collections, usually on the same substrate, Puya sp. (Bromeliaceae). It differs from all described species in the genus in that it has stipitate sporocarps with dehiscence by defined preformed platelets and a smooth inner peridial surface. The new species has polyhedral, yellow spores with a uniform thick spore wall and dense warts except on irregularly dispersed raised bands with fewer warts, visible by SEM, an ornamentation not previously observed in the genus. Life-cycle events are described and illustrated, from germination to sporulation, based on moist chamber and agar cultures. The morphology of the myxomycete specimens was examined with scanning electron microscopy and light microscopy, and both light and SEM micrographs of relevant details are included. PMID- 20943519 TI - Sporothrix brunneoviolacea and Sporothrix dimorphospora, two new members of the Ophiostoma stenoceras-Sporothrix schenckii complex. AB - Sporothrix inflata is a saprobic member of the Ophiostoma stenoceras-Sporothrix schenckii species complex, reported mainly from soil. Ophiostoma bragantinum, an ascomycete described from Brazil, has been proposed as its possible teleomorph. Previous studies revealed that Sporothrix inflata is phenotypically and genetically variable, suggesting the existence of cryptic species. During a continued survey on the biodiversity of microfungi from different countries, seven isolates morphologically similar to S. inflata were obtained from soil samples collected in Spain and USA. In this study their phenotypic features and phylogenetic relationships were assessed. DNA sequence data of two nuclear loci revealed that these isolates correspond to two unnamed clades in S. inflata s.l., one of which also included the type strain of Humicola dimorphospora, a species that traditionally has been considered a synonym of S. inflata. These two groups are proposed herein as Sporothrix brunneoviolacea sp. nov. and Sporothrix dimorphospora comb. nov. S. brunneoviolacea is characterized phenotypically by the production of a diffusible violet-brown pigment in culture and mostly globose, pigmented, lateral blastoconidia. On the other hand S. dimorphospora lacks diffusible pigments and shows mostly subglobose to obovoid pigmented lateral blastoconidia. In contrast to the type strain of S. inflata S. brunneoviolacea and S. dimorphospora assimilate raffinose. The phylogenetic analysis suggested that the proposed anamorph-teleomorph connection between S. inflata and O. bragantinum might not be correct. PMID- 20943520 TI - Compatibility between Clonostachys isolates with a view to mixed inocula for biocontrol. AB - To aid the development of compatible biocontrol inocula, a prescreening method for the prediction of compatibility of fungal antagonists was developed. Compatibility between 18 Clonostachys isolates with known antagonistic capabilities against Phytophthora palmivora was tested using intra- or interisolate pairings (dual cultures) on water agar plates, a hyphal interaction experiment and a modified double host-range experiment. Almost all inter- or intraisolate pairings of Clonostachys isolates showed growth inhibition zones and did not show free hyphal intermingling. A hyphal interaction experiment on water agar demonstrated that the aggressiveness of a Clonostachys isolate and its susceptibility to mycoparasitism were unrelated phenomena. However the level of aggressiveness and/or susceptibility of an isolate were largely dependant on the isolate with which it was challenged. The degree of growth-inhibition caused by an isolate was unrelated to the hyphal damaged it caused or received. In the double host-range experiment all possible pairs from four Clonostachys isolates were inoculated in different ratios (10 000-fold range) on plates precolonized with one of two P. palmivora isolates. The results showed that antagonistic capabilities of certain combinations were affected by the Clonostachys isolates. The primary host, P. palmivora, did not affect antagonistic capabilities; whereas inoculum ratio did. Of note, it was not possible to predict the outcome of the double host range on the basis of the results of the hyphal interaction experiment. In conclusion the competitive abilities of Clonostachys isolates depend on the partner with which they are applied and less on resource availability. The double host-range test as developed here might provide the most representative tool to date to test compatibility of fungal antagonists to be used in biocontrol inocula. However the link between the results of the double host-range test and field efficacy of biocontrol inocula remains to be investigated. PMID- 20943521 TI - Trifoliellum bioblitzii, a new genus of trichomycete from mayfly nymphs in Nova Scotia, Canada. AB - Trichomycetes are an ecological group of fungi and protists that colonize the gut lining of invertebrates in aquatic and moist terrestrial habitats. The diversity of this group appears to be high with many new species discovered each year. A new genus of fungal trichomycete, Trifoliellum (Harpellales), is described here with the type species T. bioblitzii. This genus is characterized by having unique, trefoil-shaped asexual spores (trichospores). Another new species, Legeriosimilis halifaxensis, also is described from the same mayfly host, Eurylophella temporalis, collected from the same site near Halifax, Nova Scotia. PMID- 20943522 TI - Nectria eustromatica sp. nov., an exceptional species with a hypocreaceous stroma. AB - A new species with remarkable morphology, Nectria eustromatica, is described, based on morphology of the teleomorph and anamorph, ecology and molecular phylogenetic analyses. Nectria eustromatica is characterized by sphaeroid perithecia immersed in pseudoparenchymatous stromata formed singly or collectively on a subiculum. Despite its deviating teleomorph morphology, it is placed within Nectria sensu stricto in phylogenetic analyses of a combined dataset of LSU, ITS, rpb2 and tef1 sequences with high internal support. Nectria eustromatica has been collected specifically on Hippocrepis (Coronilla) emerus in southern Europe. The anamorph of N. eustromatica shares morphological traits with the genera Stilbella and Tubercularia but produces non-phialidic macroconidia in addition to phialoconidia. PMID- 20943523 TI - A revision of the genus Lomaantha, with the description of a new species. AB - Lomaantha phragmitis sp. nov. is described and illustrated from a specimen collected on dead culms of Phragmites communis in southern China. The fungus differs from other described Lomaantha species in its conidiophores, conidiogenous cells and conidial appendages. Conidial morphology and presence or absence of percurrent proliferation of conidiogenous cells are the main characters distinguishing species within this genus. We provided a key and synoptic table of morphological characters of all three Lomaantha species. PMID- 20943524 TI - Prevalence of an intraspecific Neotyphodium hybrid in natural populations of stout wood reed (Cinna arundinacea L.) from eastern North America. AB - Members of genus Neotyphodium are asexual derivatives of sexual Epichloe species and maintain endophytic relationships with many cool-season grasses. Most Neotyphodium species analyzed so far are interspecific hybrids with combined or partial genomes of two or three ancestral species. In this study we characterized Neotyphodium isolates from Cinna arundinacea, a perennial cool-season grass from eastern North America. A total of 23 isolates grouping into two distinct morphotypes were obtained from five local populations of C. arundinacea. PCR amplification and cloning of translation-elongation factor 1-alpha (tefA) and beta-tubulin (tubB) genes of 10 isolates comprising both morphotypes (two isolates per location) revealed that all 10 contain two copies of tefA and tubB genes. Surprisingly phylogenetic analysis of mainly non-coding sequence from these genes revealed that both copies in each isolate were inherited from Epichloe typhina ancestors, indicating that the C. arundinacea endophytes arose through intraspecific hybridization between two E. typhina progenitors with extant relatives infecting hosts Poa nemoralis and Poa pratensis. Furthermore the tefA sequences were identical between isolates, as were tubB sequences, despite obvious morphological differences. Profiling of alkaloid biosynthetic genes from these isolates indicated the presence of the peramine biosynthetic gene (perA) and the absence of genes required for biosynthesis of lolines, indole-diterpenes and ergot alkaloids. Thus this endophyte is potentially capable of producing peramine in planta and providing protection to its host from insect pests. The absence of genes for indole-diterpenes and ergot alkaloid biosynthesis makes this endophyte a candidate for agricultural applications. Based on our phylogenetic analysis, alkaloid profiling and description of morphological characteristics, we propose the name Neotyphodium schardlii for these isolates from C. arundinacea, a new member of genus Neotyphodium and the first described to have arisen through intraspecific hybridization. PMID- 20943525 TI - Two new species of Acervus (Pezizales) with a key to species of the genus. AB - Studies on the genus Acervus from China are reviewed briefly. Six of the seven known species of the genus are currently recorded in this country. Acervus beijingense and A. changchunense are described as new based on morphological features and molecular data, and A. flavidus with minor emendation is added to the Chinese fungus flora. Phylogenetic relationships among four of the seven species of the genus are investigated based on the 28S rDNA sequence analysis. Species of the genus formed a single clade with high bootstrap support. The sequences of A. epispartius forma epispartius and that of A. flavidus obtained from materials in different geographical regions together formed a group with 100% bootstrap support. Ascospore size and shape are important criteria in the taxonomy of the genus and are phylogenetically informative. A dichotomous key to all described species of the genus is provided. PMID- 20943526 TI - Occurrence and distribution of zoosporic organisms in water bodies from Brazilian Cerrado. AB - Zoosporic organisms are commonly found in different aquatic ecosystems; however little is known about the influence of environmental factors and seasonal fluctuations on their occurrence and distribution. This study investigated patterns of abundance, frequency and diversity of these organisms and their relationship with some abiotic factors and seasonality in a cerrado remnant in Sao Paulo, Brazil. Water samples were collected at four dates in two areas of this remnant during the rainy and dry seasons, and 13 abiotic factors were analyzed. From 48 samples collected, 32 taxa were isolated with the multiple baiting technique. The community structure of the zoosporic organisms showed some changes in response to different spatial distribution and seasonal fluctuations, probably influenced by distinct abiotic characteristics of each area or climatic period. Still, the similarity between areas and seasons indicated by Sorensen index and diversity (richness, evenness, Shannon and Simpson indices) were high. PMID- 20943527 TI - A new taxon in the Infundibulicybe gibba complex (Basidiomycota, Agaricales, Tricholomataceae) from Sardinia (Italy). AB - A new species of Infundibulicybe (viz. I. mediterranea sp. nov.) is described from Sardinia based both on morphological and molecular ITS data. The species, a close ally of I. gibba, differs from the latter in the darker tinges of the basidiomata, the stipe, which is nearly concolorous with the pileus, and smaller basidiospores. Drawings of the main micro-morphological features as well as a color photograph of fresh basidiomata in situ are provided. PMID- 20943528 TI - Geosmithia morbida sp. nov., a new phytopathogenic species living in symbiosis with the walnut twig beetle (Pityophthorus juglandis) on Juglans in USA. AB - Widespread morbidity and mortality of Juglans nigra has occurred in the western USA over the past decade. Tree mortality is the result of aggressive feeding by the walnut twig beetle (Pityophthorus juglandis) and subsequent canker development around beetle galleries caused by a filamentous ascomycete in genus Geosmithia (Ascomycota: Hypocreales). Thirty-seven Geosmithia strains collected from J. californica, J. hindsii, J. major and J. nigra in seven USA states (AZ, CA, CO, ID, OR, UT, WA) were compared with morphological and molecular methods (ITS rDNA sequences). Strains had common characteristics including yellowish conidia en masse, growth at 37 C and absence of growth on Czapek-Dox agar and belonged to a single species described here as G. morbida. Whereas Geosmithia are common saprobes associated with bark beetles attacking hardwoods and conifers worldwide, G. morbida is the first species documented as a plant pathogen. PMID- 20943529 TI - Two new species of Rhynchosporium. AB - Rhynchosporium consists of two species, R. secalis and R. orthosporum. Both are pathogens of grasses with R. secalis infecting a variety of Poaceae hosts and R. orthosporum infecting Dactylis glomerata. Phylogenetic analyses of multilocus DNA sequence data on R. secalis isolates originating from cultivated barley, rye, triticale and other grasses, including Agropyron spp., Bromus diandrus and Hordeum spp., resolved the monophyletic groups into three species according to their respective hosts. Host specificity according to phylogenetic lineages was confirmed with pathogenicity studies. Because R. secalis was described first on rye this name is retained for Rhynchosporium isolates infecting rye and triticale. Rhynchosporium isolates infecting cultivated barley and other Hordeum spp. and Bromus diandrus belong to a distinct species, R. commune. Similarly isolates infecting Agropyron spp. represent a distinct species of Rhynchosporium, namely R. agropyri. A PCR-RFLP assay was developed as a rapid tool for species identification of R. secalis and R. commune. PMID- 20943530 TI - New species of Laboulbenia from Ecuador, with evidence for host switch in the Laboulbeniales. AB - Ten new species of Laboulbenia from Ecuador are described. These are L. barraganii, parasitic on Platamops sp. (Salpingidae); L. biformis, parasitic on Diploharpus rossii Moret (Carabidae); L. davidsonii, parasitic on Odontocheila spp. (Carabidae); L. gregaria, parasitic on Philonthus sp. (Staphylinidae); L. micrandra, parasitic on Lobrathium sp. (Staphylinidae); L. mycotreti, parasitic on Mycotretus spp. (Erotylidae); L. opima, parasitic on Chrysodinopsis sp. (Chrysomelidae); L. otongaensis, parasitic on Diploharpus iridescens Moret (Carabidae); L. tapiae, parasitic on Priocera sp. (Cleridae); and L. trogacti, parasitic on Trogactus sp. (Staphylinidae). Laboulbenia barraganii is the first of the Laboulbeniales to be reported on beetles of the family Salpingidae. L. biformis displays a moderate dimorphism associated with the position on the host insect. L. davidsonii, which is very different from the other species of Laboulbenia reported so far on the Cicindelinae but similar to a group of species parasitic on Galerita spp., provides evidence for the occurrence of host switch in Laboulbeniales. PMID- 20943531 TI - Sexual reproduction in aflatoxin-producing Aspergillus nomius. AB - Sexual reproduction was examined in the aflatoxin-producing fungus Aspergillus nomius. Crosses between sexually compatible strains resulted in the formation of multiple nonostiolate ascocarps within stromata, which places the teleomorph in genus Petromyces. Ascocarp and ascospore morphology in Petromyces nomius were similar to that in P. flavus and P. parasiticus, and differences between teleomorphs were insufficient for species separation. Formation of mature ascocarps was infrequent, with only 24% of the 83 crosses producing viable ascospores. The majority of P. nomius strains contained a single mating-type gene (MAT1-1 or MAT1-2), but several strains contained both genes. MAT1-1/MAT1-2 strains were self-sterile and capable of mating with both MAT1-1 and MAT1-2 strains; hence P. nomius appears to be functionally heterothallic. PMID- 20943532 TI - Pseudotripoconidium, a new anamorph genus connected to Orbilia. AB - A new anamorphic fungus is described based on four isolates from ascospores of Orbilia aff. luteorubella. This fungus differs from previously known Orbilia anamorphs in producing inversely pyramidal, unicellular conidia with several protuberances at their distal end. Conidia produce 1-7 prominent denticles that emerge from a node at the conidiophore apex. Conidiogenesis is holoblastic. Because phylogenetic analysis indicated greater than 90% ITS sequence similarities among the four isolates they are treated here as a single species. In the sequence analysis of the internal transcribed spacer region (ITS) these isolates and other sequences identified as O. aff. luteorubella were nested within Orbilia and formed a clade with 99% bootstrap support. This clade is separated from nematode-trapping species of Orbilia. Based on both morphological and molecular analyses, we propose a new genus, Pseudotripoconidium. PMID- 20943533 TI - Leptographium tereforme sp. nov. and other Ophiostomatales isolated from the root feeding bark beetle Hylurgus ligniperda in California. AB - The redhaired pine bark beetle Hylurgus ligniperda (F.) is native to Europe but was discovered in Los Angeles, California, in 2003. This root-and stump-feeding beetle is a common vector of Ophiostomatales, which are potential tree pathogens or causes of blue stain of conifer sapwood. In this study Ophiostomatales were isolated on a cycloheximide-amended medium from 118 adult H. ligniperda collected from infested logs of Pinus halepensis and P. pinea at two sites in California. In total eight species of Ophiostomatales were identified and seven species that occasionally were isolated were unidentified. The most frequently isolated species were Ophiostoma ips and Grosmannia galeiforme, which were isolated respectively from 31% and 23% of the 118 beetles. The other species isolated included O. piceae (isolated from 9% of the beetles), O. querci (8%) and Leptographium tereforme sp. nov. (6%). Grosmannia huntii, L. serpens, three Sporothrix species, O. floccosum, O. stenoceras, two unidentified Hyalorhinocladiella sp. and a sterile fungus each were isolated from fewer then 5% of beetles. Most of the identified species already were known in USA and have been found in association with H. ligniperda in other countries. However the new species, L. tereforme, and G. galeiforme were recorded from USA for the first time, and this is the first report of L. serpens from western North America. PMID- 20943534 TI - Trichoderma amazonicum, a new endophytic species on Hevea brasiliensis and H. guianensis from the Amazon basin. AB - A new species of Trichoderma (teleomorph Hypocrea, Ascomycota, Sordariomycetes, Hypocreales, Hypocreaceae), T. amazonicum, endophytic on the living sapwood and leaves of Hevea spp. trees is described. Trichoderma amazonicum is distinguished from closely related species in the Harzianum clade (e.g. Hypocrea alni, H. brunneoviridis, H. epimyces, H. parepimyces, T. aggressivum, T. harzianum, T. pleuroticola and T. pleuroti) by morphological and ecological characteristics and phylogenetic analysis of three loci (ITS nrDNA, tef1 and rpb2). The closest relatives of this species are the facultatively fungicolous species T. pleuroticola and T. pleuroti. PMID- 20943535 TI - Fungal and algal gene expression in early developmental stages of lichen symbiosis. AB - How plants and microbes recognize each other and interact to form long-lasting relationships remains one of the central questions in cellular communication. The symbiosis between the filamentous fungus Cladonia grayi and the single-celled green alga Asterochloris sp. was used to determine fungal and algal genes upregulated in vitro in early lichen development. cDNA libraries of upregulated genes were created with suppression subtractive hybridization in the first two stages of lichen development. Quantitative PCR subsequently was used to verify the expression level of 41 and 33 candidate fungal and algal genes respectively. Induced fungal genes showed significant matches to genes putatively encoding proteins involved in self and non-self recognition, lipid metabolism, and negative regulation of glucose repressible genes, as well as to a putative d arabitol reductase and two dioxygenases. Upregulated algal genes included a chitinase-like protein, an amino acid metabolism protein, a dynein-related protein and a protein arginine methyltransferase. These results also provided the first evidence that extracellular communication without cellular contact can occur between lichen symbionts. Many genes showing slight variation in expression appear to direct the development of the lichen symbiosis. The results of this study highlight future avenues of investigation into the molecular biology of lichen symbiosis. PMID- 20943537 TI - Syncephalis aggregata, a new species from the semiarid region of Brazil. AB - A new species of Syncephalis (Zoopagales) was isolated from soil in a semiarid area of northeastern Brazil. Syncephalis aggregata is distinguished from the other species of the genus by the production of merosporangiophores in dense tufts and with randomly spaced, irregular swellings and simple merosporangia produced over the upper 50% of a globose to ovoid vesicle. An identification key for the species of Syncephalis found in Brazil is provided. PMID- 20943536 TI - Molecular phylogeny reveals a core clade of Rhytismatales. AB - Rhytismatales (Leotiomycetes, Pezizomycotina, Ascomycota) are an order of mostly plant-associated ascomycetes with a global distribution. Well known taxa include the Rhytisma tar spots on Acer spp. and several needle-cast pathogens in genera Lophodermium and Meloderma. Critical studies are lacking at all taxonomic ranks from order to species, and in particular the genus taxonomy in the order has been criticized for being unnatural. We used nuclear LSU and mitochondrial SSU sequences in Bayesian phylogenetic analyses to define a core clade of Rhytismatales sensu stricto. Some of the genera traditionally placed within the Rhytismatales, Ascodichaena, Marthamyces, Mellitiosporium, Potebniamyces, Propolis and Pseudophacidium, are shown to be phylogenetically distinct, all related to various other taxa at present placed in the polyphyletic Helotiales. Within the core clade only Cudonia, Spathularia and Terriera are supported as monophyletic. The large genera Coccomyces, Hypoderma and Lophodermium all are polyphyletic as are a few smaller genera. The traditionally used characters of ascoma and spore shape are shown to be unreliable for the delimitation of monophyletic genera but in some cases can be useful when combined with other characters. In this study we provide 72 new nrLSU and 64 new mtSSU sequences. Together with publicly available sequences data for 103 specimens representing 91 species of Rhytismatales are now available. Despite this taxon sampling intensity is still too low to propose an alternative generic taxonomy. PMID- 20943538 TI - Cophylogeny and biogeography of the fungal parasite Cyttaria and its host Nothofagus, southern beech. AB - The obligate, biotrophic association among species of the fungal genus Cyttaria and their hosts in the plant genus Nothofagus often is cited as a classic example of cophylogeny and is one of the few cases in which the biogeography of a fungus is commonly mentioned or included in biogeographic analyses. In this study molecular and morphological data are used to examine hypotheses regarding the cophylogeny and biogeography of the 12 species of Cyttaria and their hosts, the 11 species of Nothofagus subgenera Lophozonia and Nothofagus. Our results indicate highly significant overall cophylogenetic structure, despite the fact that the associations between species of Cyttaria and Nothofagus usually do not correspond in a simple one to one relationship. Two major lineages of Cyttaria are confined to a single Nothofagus subgenus, a specificity that might account for a minimum of two codivergences. We hypothesize other major codivergences. Numerous extinction also are assumed, as are an independent parasite divergence followed by host switching to account for C. berteroi. Considering the historical association of Cyttaria and Nothofagus, our hypothesis may support the vicariance hypothesis for the trans-Antarctic distribution between Australasian and South American species of Cyttaria species hosted by subgenus Lophozonia. It also supports the hypothesis of transoceanic long distance dispersal to account for the relatively recent relationship between Australian and New Zealand Cyttaria species, which we estimate to have occurred 44.6-28.5 mya. Thus the history of these organisms is not only a reflection of the breakup of Gondwana but also of other events that have contributed to the distributions of many other southern hemisphere plants and fungi. PMID- 20943539 TI - Phylogeny of Cyttaria inferred from nuclear and mitochondrial sequence and morphological data. AB - Cyttaria species (Leotiomycetes, Cyttariales) are obligate, biotrophic associates of Nothofagus (Hamamelididae, Nothofagaceae), the southern beech. As such Cyttaria species are restricted to the southern hemisphere, inhabiting southern South America (Argentina and Chile) and southeastern Australasia (southeastern Australia including Tasmania, and New Zealand). The relationship of Cyttaria to other Leotiomycetes and the relationships among species of Cyttaria were investigated with newly generated sequences of partial nucSSU, nucLSU and mitSSU rRNA, as well as TEF1 sequence data and morphological data. Results found Cyttaria to be defined as a strongly supported clade. There is evidence for a close relationship between Cyttaria and these members of the Helotiales: Cordierites, certain Encoelia spp., Ionomidotis and to a lesser extent Chlorociboria. Order Cyttariales is supported by molecular data, as well as by the unique endostromatic apothecia, lack of chitin and highly specific habit of Cyttaria species. Twelve Cyttaria species are hypothesized, including all 11 currently accepted species plus an undescribed species that accommodates specimens known in New Zealand by the misapplied name C. gunnii, as revealed by molecular data. Thus the name C. gunnii sensu stricto is reserved for specimens occurring on N. cunninghamii in Australia, including Tasmania. Morphological data now support the continued recognition of C. septentrionalis as a species separate from C. gunnii. Three major clades are identified within Cyttaria: one in South America hosted by subgenus Nothofagus, another in South America hosted by subgenera Nothofagus and Lophozonia, and a third in South America and Australasia hosted by subgenus Lophozonia, thus producing a non-monophyletic grade of South American species and a monophyletic clade of Australasian species, including monophyletic Australian and New Zealand clades. Cyttaria species do not sort into clades according to their associations with subgenera Lophozonia and Nothofagus. PMID- 20943540 TI - Tubariomyces, a new genus of Inocybaceae from the Mediterranean region. AB - The taxonomic position of Inocybe inexpectata is reconsidered on the basis of new molecular and morphological data from four published records. Up to three species can be recognized to which the name I. inexpectata has been applied. In addition to distinct morphological features present in this lineage it is proposed here as the new genus Tubariomyces. A complete taxonomical description of the genus and the species Tubariomyces inexpectatus and T. hygrophoroides sp. nov. also is provided. PMID- 20943541 TI - Genome size variation in the pine fusiform rust pathogen Cronartium quercuum f.sp. fusiforme as determined by flow cytometry. AB - The genome size of the pine fusiform rust pathogen Cronartium quercuum f.sp. fusiforme (Cqf) was determined by flow cytometric analysis of propidium iodide stained, intact haploid pycniospores with haploid spores of two genetically well characterized fungal species, Sclerotinia sclerotiorum and Puccinia graminis f.sp. tritici, as size standards. The Cqf haploid genome was estimated at ~90 Mb, similar to other Pucciniales species for which reference genome sequences are available. Twenty-three Cqf pycniospore samples were compared that comprised three samples obtained from naturally occurring pine galls and 20 samples obtained after artificial inoculation with parental isolates and their progeny. Significant variation in genome size (>10% of mean) was detected among unrelated as well as sibling Cqf samples. The unexpected plasticity in Cqf genome size observed among sibling samples is likely to be driven by meiosis between parental genomes that differ in size. PMID- 20943542 TI - The species of Coniolariella. AB - Morphological and molecular analyses demonstrate that Coniolariella gamsii and Coniolaria murandii are distinct species. The latter species is validated here as Coniolariella macrothecia. A key to the five species of the genus is provided. PMID- 20943543 TI - ITS rDNA phylogeny of Iranian strains of Cytospora and associated teleomorphs. AB - Cytospora spp. and associated teleomorphic species (Ascomycota, Diaporthales, Valsaceae) are among the most common and widespread canker- and dieback-causing fungi on trees, shrubs and herbaceous plants worldwide. From specimens collected all over Iran a total of 114 isolates were morphologically identified, representing 20 Cytospora, one Leucostoma and five Valsa species from 38 plant species. Nine of the identified taxa were new records for Iran, and many new hosts were identified. The phylogenetic relationships of the Iranian strains, along with sequences of 13 reference strains from GenBank, were inferred from ITS1-5.8S-ITS2 nuclear rDNA sequences. Parsimony analysis established five distinct major clades and 12 subclades, which represented accepted species and genera. Some of these subclades corresponded to morphologically based taxonomic concepts of single Cytospora species, while others contained more than one morphospecies. Teleomorphic states were present in six subclades, and most clustered with the corresponding anamorphs. This suggests that morphological and phylogenetic species concepts overlap and that in most cases they are meaningful for correct species identification. PMID- 20943544 TI - Diplomitoporus rimosus is found in Asia and belongs to the Hymenochaetales. AB - Diplomitoporus rimosus is a white rot polypore widely distributed in western N America, collected once in Africa, and is reported here from Iran. Molecular phylogenetic analyses of partial nuclear ribosomal LSU and ITS revealed that, unlike the generic type D. flavescens nested within the polyporoid clade, D. rimosus is positioned in the hymenochaetoid clade. A new genus is introduced to accommodate the species. Cyanotrama gen. nov. is recognized by its resupinate habit, narrow and strongly cyanophilous skeletal hyphae, barrel-shaped to short clavate basidia, variable presence of hyphal pegs and growth on conifers, especially Juniperus. Comparisons are made with representatives of polypores having similar morphological characteristics especially with cyanophilous skeletals. The biogeography of Cyanotrama rimosa with regard to its association with Juniperus woodlands is discussed briefly. PMID- 20943545 TI - RNA editing is absent in a single mitochondrial gene of Didymium iridis. AB - An open reading frame (ORF) was found in the mitochondrial genome of the Pan2-16 strain of Didymium iridis that showed high similarity to the NADH dehydrogenase subunit 3 (nad3) gene in other organisms. So far all other typical mitochondrial genes identified in this organism require RNA editing to generate ORFs capable of directing protein synthesis. The D. iridis sequence was compared to the putative nad3 gene in the related myxomycete Physarum polycephalum, which would require editing. Based on this comparison, editing sites could be predicted for the P. polycelphalum gene that would result in the synthesis of a highly conserved ND3 protein between the two organisms. To determine the editing status of the nad3 gene in other D. iridis strains, PCR was used to amplify this region from eight other independent isolates of the A1 Central American interbreeding series. In each case a 378 base pair ORF was detected by PCR amplification and sequencing. Three patterns of sequence variation were observed; however all base substitutions were in the third codon position and silent with respect to the amino acids encoded. The distribution of the sequence variants was mapped geographically. The requirement for RNA editing in all other typical mitochondrial genes of D. iridis and P. polycephalum and the presence of RNA editing in the nad3 gene of P. polycephalum suggest that the D. iridis nad3 gene might have been edited at one time. We propose that the D. iridis nad3 gene may have lost the requirement for RNA editing by reverse transcription of an edited transcript that subsequently was inserted into the genome. PMID- 20943546 TI - A multi-laboratory comparative study of spore trap analyses. AB - Fungal spore trap analyses currently are being marketed to the medical and environmental industries as a means of evaluating fungal bioaerosols. No studies comparing the results of these analyses have been conducted among laboratories providing these services. In the current study we compared the results from seven such laboratories with four different commercial spore trap cassettes with samples from four environmental conditions. The conditions included indoor air from a single location in a building under low, moderate and high agitation, and a sample from outside the same building. The means, ranges and standard deviations of total spore counts per cubic meter were respectively: low agitation indoor 514, 40-1933, 395; moderate agitation indoor 446, 80-1120, 290; high agitation indoor, 5154, 1510-15278, 3335; and outdoor 16012, 3700-28959, 6600. Results were similarly variable for the 27 spore categories that contribute to the total count. No consistent difference was observed in the precision of the kinds of spore traps. We concluded that spore trap analyses should be used with caution and should not be used as a sole method of assessing fungal spore populations and that standardized methods of analysis must be developed that include information about analytical precision of the sample data. PMID- 20943547 TI - Phytophthora species in forest streams in Oregon and Alaska. AB - Eighteen Phytophthora species and one species of Halophytophthora were identified in 113 forest streams in Alaska, western Oregon and southwestern Oregon that were sampled by baiting or filtration of stream water with isolation on selective media. Species were identified by morphology and DNA characterization with single strand conformational polymorphism, COX spacer sequence and ITS sequence. ITS Clade 6 species were most abundant overall, but only four species, P. gonapodyides (37% of all isolates), P. taxon Salixsoil, P. taxon Oaksoil and P. pseudosyringae, were found in all three regions. The species assemblages were similar in the two Oregon regions, but P. taxon Pgchlamydo was absent in Alaska and one new species present in Alaska was absent in Oregon streams. The number of Phytophthora propagules in Oregon streams varied by season and in SW Oregon, where sampling continued year round, P. taxon Salixsoil, P. nemorosa and P. siskiyouensis were recovered only in some seasons. PMID- 20943548 TI - Single origin and subsequent diversification of central Andean endemic Umbilicaria species. AB - We studied an Andean endemic group of species of the lichen-forming fungal genus Umbilicaria from the subalpine and low-alpine zone, with their biogeographic center in Bolivia and Peru. A number of species and varieties have been described from this element, but apparent instability in several morphological traits has made it difficult to precisely delimit taxa. Based on DNA sequences of nuclear ITS, LSU and mitochondrial SSU from extensive collections from Argentina, Bolivia, Chile, Colombia, Ecuador and Peru, we present here a molecular phylogenetic analysis of this Andean endemic element within genus Umbilicaria. All analyses (MP, ML and Bayesian) support a single origin for the element and a division into two major groups characterized by different apothecium types: the Umbilicaria dichroa group and U. calvescens group. Taxa U. krempelhuberi, U. peruviana and U. subcalvescens are nested withinn U. calvescens and are treated as conspecific with the latter species. The endemic element shares a most recent common ancestor with the Umbilicaria vellea group, which has a worldwide distribution and contains several asexually reproducing (sorediate) species. Independent reversals to sexual reproduction might explain the evolution of two types of apothecia in this monophyletic endemic lineage. A number of cosmopolitan, mostly high-alpine, species of Umbilicaria also present in the central Andes are related only remotely to the endemic element and do not exhibit speciation into endemics. Because the An-dean element dominates the Umbilicaria habitats of the low- and subalpine zones we propose that the founder colonized the Andes at a time when the mountains had not yet reached their current elevation while the high-alpine species arrived more recently. PMID- 20943549 TI - Taxonomic revision transferring species in Kuklospora to Acaulospora (Glomeromycota) and a description of Acaulospora colliculosa sp. nov. from field collected spores. AB - In a phylogenetic study of arbuscular mycorrhizal fungal species in Acaulospora (Acaulosporaceae, Glomeromycota) we discovered that species classified in genus Kuklospora, a supposed sister clade of Acaulospora, did not partition as a monophyletic clade. Species in these two genera can be distinguished only by the position of the spore relative to a precursor structure, the sporiferous saccule, as either within (entrophosporoid) or laterally (acaulosporoid) on the saccule subtending hypha. Subsequent spore differentiation follows identical patterns and organization. Molecular phylogeny reconstructed from nrLSU gene sequences, together with developmental data, support the hypothesis that the entrophosporoid mode of spore formation evolved many times and thus represents a convergent trait of little phylogenetic significance. Therefore genus Kuklospora is rejected as a valid monophyletic group and it is integrated taxonomically into genus Acaulospora. Thus Acaulospora colombiana and Acaulospora kentinensis are erected as new combinations (formerly Kuklospora colombiana and Kuklospora kentinensis). Mode of spore formation is demoted from a genus-specific character to one that is included with other traits to define Acaulospora species. In addition we describe a new AM fungal species, Acaulospora colliculosa (Acaulosporaceae), that originated from a tallgrass prairie in North America. Field-collected spores of A. colliculosa are small (<100 MUm diam), hyaline or subhyaline to pale yellow and form via entrophosporoid development based on structure and organization of cicatrices and attached hyphae. Each spore consists of a bilayered spore wall and two bilayered inner walls. A germination orb likely forms after the completion of spore development to initiate germination, but this structure was not observed. A character distinguishing A. colliculosa from other Acaulospora species is hyaline to subhyaline hemispherical protuberances on the surface of the outer spore wall layer. A phylogeny reconstructed from partial nrLSU gene sequences unambiguously placed A. colliculosa in the Acaulospora clade. PMID- 20943550 TI - New species of Stigmatomyces from Asia. AB - Four new species of Stigmatomyces (Ascomycota, Laboulbeniomycetes, Stigmatomycetinae) parasitic on flies (Diptera) are described. These are S. aphaniosomae, parasitic on an undescribed species of Aphaniosoma (Chyromyidae) from Jordan; S. deemingii, parasitic on Milichia pubescens (Milichiidae) from Yemen; S. macanus, parasitic on Phortica spp. (Drosophilidae) from Taiwan; and S. mosilli, parasitic on Mosillus subsultans (Ephydridae) from Pakistan. Chyromyidae is a new host family for Laboulbeniales, and S. aphaniosomae is the first of the Laboulbeniales to be reported from Jordan. PMID- 20943551 TI - A six locus phylogeny reveals high species diversity in Botryosphaeriaceae from California almond. AB - Botryosphaeriaceae are important pathogens on a variety of woody hosts, including almond, a major crop in California. Almond is susceptible to Botryosphaeria dothidea that forms band cankers on almond trunks, and the same fungus was also isolated from cankers of the canopy. To study the diversity and host range of B. dothidea and allied species from almond we used 132 isolates from 36 plant hosts from five continents, including 45 strains from almond in California. Species were identified by comparison to 13 ex-type strains with phylogenetic analyses based on six loci, including the internal transcribed spacer (ITS) regions of the nuclear ribosomal RNA gene repeat and portions of the coding genes elongation factor 1-alpha, glyceraldehyde-3-phosphate dehydrogenase, heat shock protein, histone-3 and beta-tubulin. Seven species were found from almond: Botryosphaeria dothidea, Neofusicoccum parvum, Neof. mediterraneum, Neof. nonquaesitum, Diplodia seriata and Macrophomina phaseolina were identified from band cankers, and B. dothidea, Neof. mediterraneum, Neof. parvum and Dothiorella sarmentorum from canopy cankers. All were capable of inducing cankers on inoculated almond branches in the field. All species found on almond also occurred on other hosts, suggesting that infected vegetation adjacent to almond orchards could serve as source of inoculum of virulent almond strains. Of the 19 monophyletic groups obtained at the species level, 13 contained ex-type strains, five were morphologically similar to established species and one was morphologically distinct from its closest relatives, Neof. andinum and Neof. arbuti, as well as from the more than 190 described species of Fusicoccum and Neofusicoccum, and thus was described as the new species, Neof. nonquaesitum. Evidence for cryptic speciation was found in B. dothidea, Neof. ribis and Spencermartinsia viticola. Botryosphaeria dothidea and Neof. ribis comprised lineages that formed the morphologically distinct Dichomera anamorph not found in any other isolates recognized as B. dothidea and Neof. ribis. An S. viticola isolate from California was phylogenetically divergent and had conidia that differed morphologically from the type. Neofusicoccum parvum was diverse but lacked any morphological features correlating with molecular diversity. Phylogenetic analyses of combinations of datasets showed that pooled analyses of all six datasets resulted in the highest number of supported branches, suggesting that addition of more data might yet improve phylogenetic resolution. PMID- 20943552 TI - Systematics of genus Gnomoniopsis (Gnomoniaceae, Diaporthales) based on a three gene phylogeny, host associations and morphology. AB - Species of Gnomoniopsis are leaf- and stem-inhabiting pyrenomycetes that infect plants in Fagaceae, Onagraceae and Rosaceae. Morphology and analyses of DNA sequences from three ribosomal DNA and protein coding regions, namely beta tubulin, translation elongation factor 1alpha (tef-1alpha) and the ITS region including ITS1, 5.8S rDNA and ITS2, were used to define species in Gnomoniopsis. Secondary structural alignment of the ITS region across four genera in Gnomoniaceae was used to increase the potential number of homologous positions in the ITS alignment. Ascospore isolates were grown from newly collected specimens. Type specimens were compared with these specimens to determine their identity. In this paper a recent concept of Gnomoniopsis is confirmed with phylogenetic resolution of additional species. Four new combinations and one new species are proposed. Nine species are described and illustrated, and a key is provided to the 13 species currently recognized in Gnomoniopsis. PMID- 20943553 TI - Molecular phylogenetic and zoospore ultrastructural analyses of Chytridium olla establish the limits of a monophyletic Chytridiales. AB - Chytridium olla A. Braun, the first described chytrid and an obligate algal parasite, is the type for the genus and thus the foundation of family Chytridiaceae, order Chytridiales, class Chytridiomycetes and phylum Chytridiomycota. Chytridium olla was isolated in coculture with its host, Oedogonium capilliforme. DNA was extracted from the coculture, and 18S, 28S and ITS1-5.8S-ITS2 rDNA were amplified with universal fungal primers. Free swimming zoospores and zoospores in mature sporangia were examined with electron microscopy. Molecular analyses placed C. olla in a clade in Chytridiales with isolates of Chytridium lagenaria and Phlyctochytrium planicorne. Ultrastructural analysis revealed C. olla to have a Group II-type zoospore, previously described for Chytridium lagenaria and Phlyctochytrium planicorne. On the basis of zoospore ultrastructure, family Chytridiaceae is emended to include the type of Chytridium and other species with a Group II-type zoospore, and the new family Chytriomycetaceae is delineated to include members of Chytridiales with a Group I type zoospore. PMID- 20943554 TI - A new genus to accommodate Gymnopus acervatus (Agaricales). AB - Phylogenies based on ITS and LSU nrDNA sequences show Agaricus (Gymnopus) acervatus as unique within the Gymnopus/Rhodocollybia complex. These phylogenies imply that a separate genus is necessary, and Connopus is proposed. Infraspecific morphological and DNA-based variation within C. acervatus suggests that a western North American clade might be reproductively isolated from the eastern North American/Scandinavian clade and that in this species complex the European and eastern North American clade might be conspecific. A Scandinavian exemplar is selected for bar-coding. Two GenBank sequences with name-phylogenetic placement inconsistencies are identified. PMID- 20943555 TI - Phylogeny of Pilobolaceae. AB - The three genera traditionally classified as Pilobolaceae have been identified on the basis of morphological characteristics. In the absence of distinctive morphological differences phylogenetic techniques have proven to be superior for developing phylogenies. Molecular techniques have been used primarily for studies of higher fungi; there are few investigations of the Zygomycota using genetic sequences for classification. DNA sequences coding for three regions of rRNA were used to investigate phylogenetic relationships of the three genera traditionally considered within the Pilobolaceae. Evidence indicates that Pilaira should be removed from Pilobolaceae and the family redescribed. Sporangiospore size is the morphological characteristic that most closely correlates with rDNA clades of phylogenetic trees. This study demonstrates that traditional morphological characteristics alone are not adequate to differentiate species of Pilobolus. PMID- 20943556 TI - Description and identification of Alnus acuminata ectomycorrhizae from Argentinean alder stands. AB - The objective of this study was to describe the morphological and anatomical features of five unidentified ectomycorrhizal types of Alnus acuminata and to complement their identification based on ITS-rDNA sequence analysis. The combined approach of morphotyping and sequence analysis based on ITS sequence comparison with sequences contained in GenBank and the UNITE database let us assign three of the five field-collected ectomycorrhiza morphotypes to the tomentella-thelephora lineage that closely matched European and North American species. The sequencing results within Tomentella point toward alder specific clades within T. sublilacina, T. ellisii and T. stuposa sensu lato. The two other EcM morphotypes matched Lactarius omphaliiformis and a Russula sp. Better focused, concomitant fruit body surveys are needed for accurate identification of South American ectomycorrhizal fungi because of the evidence of cryptic speciation in both agaricoid and resupinate mycobionts. PMID- 20943557 TI - Population genetic structure of the seed pathogen Pyrenophora semeniperda on Bromus tectorum in western North America. AB - We examined genetic variation in the ascomycete pathogen Pyrenophora semeniperda cultured from seeds of the invasive grass Bromus tectorum in the Intermountain West of North America. We sequenced the internal transcribed spacer (ITS) region of the nuclear ribosomal RNA genome in 417 monoconidial cultures collected from 20 sites in Washington, Idaho, Utah and Colorado, USA. ITS sequence diversity was surprisingly high; 12 unique haplotypes were identified, averaging 1.3% pairwise sequence divergence. All sites had at least two haplotypes present, and three sites had seven or more. One haplotype composed 60% of the isolates and occurred at all 20 locations; the remaining haplotypes generally occurred at low frequencies within sites but at multiple sites throughout the region. Sites in Washington and Idaho were more diverse than those in Utah and Colorado, averaging two more haplotypes and 67% more pairwise differences among haplotypes at a site. Analysis of molecular variance (AMOVA) indicated that more than 80% of the genetic variation was found within sampling locations, while 7-11% of the variation can be attributed to differences between northern (Washington and Idaho) and southern (Utah and Colorado) populations. The wide distribution of even uncommon haplotypes among sampling sites and weak correlations between genetic and geographic distances among populations (< 0.2) suggested that these populations recently were established from a common source. We hypothesize that the strains of P. semeniperda infecting B. tectorum in western North America probably arrived with the invasive grass from its native Eurasian range. PMID- 20943558 TI - Glomus africanum and G. iranicum, two new species of arbuscular mycorrhizal fungi (Glomeromycota). AB - Two new arbuscular mycorrhizal fungal species (Glomeromycota) of genus Glomus, G. africanum and G. iranicum, are described and illustrated. Both species formed spores in loose clusters and singly in soil and G. iranicum sometimes inside roots. G. africanum spores are pale yellow to brownish yellow, globose to subglobose, (60-)87(-125) MUm diam, sometimes ovoid to irregular, 80-110 x 90-140 MUm. The spore wall consists of a semipermanent, hyaline, outer layer and a laminate, smooth, pale yellow to brownish yellow, inner layer, which always is markedly thinner than the outer layer. G. iranicum spores are hyaline to pastel yellow, globose to subglobose, (13-)40(-56) MUm diam, rarely egg-shaped, prolate to irregular, 39-54 x 48-65 MUm. The spore wall consists of three smooth layers: one mucilaginous, short-lived, hyaline, outermost; one permanent, semirigid, hyaline, middle; and one laminate, hyaline to pastel yellow, innermost. Only the outermost spore wall layer of G. iranicum stains red in Melzer's reagent. In the field G. africanum was associated with roots of five plant species and an unrecognized shrub colonizing maritime sand dunes of two countries in Europe and two in Africa, and G. iranicum was associated with Triticum aestivum cultivated in southwestern Iran. In one-species cultures with Plantago lanceolata as the host plant G. africanum and G. iranicum formed arbuscular mycorrhizae. Phylogenetic analyses of partial SSU sequences of nrDNA placed the two new species in Glomus group A. Both species were distinctly separated from sequences of described Glomus species. PMID- 20943559 TI - New species of dictyostelids from Patagonia and Tierra del Fuego, Argentina. AB - In late Jan and early Feb 2005 samples for isolation of dictyostelid cellular slime molds (dictyostelids) were collected in five different provinces and from six national parks (all located 39-55 degrees S) in Patagonia and Tierra del Fuego, Argentina. Southern beech (Nothofagus) forests represented the primary vegetation type investigated, but some samples were obtained from Patagonian steppe, alpine meadows, Valdivian temperate rainforests and coniferous forests dominated by Araucaria, Austrocedrus and Fitzroya. Among the dictyostelids isolated from the samples we collected were seven species new to science. These species (Dictyostelium austroandinum, D. chordatum, D. fasciculoideum, D. gargantuum, D. leptosomopsis, D. valdivianum and Polysphondylium patagonicum) are described herein on the basis of both morphology and molecular (SSU rDNA) data. One of the new species, D. gargantuum, is one of the largest representatives of the group reported to date. Another unusual species, D. chordatum, produces long interwoven sorocarps that do not appear to respond to a spacing gas similar to the condition first noted in D. implicatum. PMID- 20943561 TI - The Puccinia species of Berkheya (Asteraceae) with description of four new species from South Africa. AB - Puccinia species (rust fungi, Pucciniales, formerly Uredinales) occurring on Berkheya (syn. Stobaea) of Asteraceae are critically evaluated. Puccinia berkheyicola, P. stobaeae var. stobaeae and P. stobaeae var. woodii are recognized as valid species and varieties, while P. berkheyae is relegated to a synonym of P. stobaeae var. stobaeae. Lectotypes are selected for P. stobaeae var. stobaeae and P. stobaeae var. woodii. P. clanwilliamensis, P. garstfonteinii and P. monsfontium are proposed as new species for three rust fungi previously assigned to P. stobaeae; P. berkheyaephila is described as new on B. bipinnatifida. A key to the accepted species is presented. PMID- 20943562 TI - Barcoding and microcoding using "identiprimers" with Leptographium species. AB - Leptographium species provide an ideal model to test the applications of a PCR microcoding system for differentiating species of other genera of ascomycetes. Leptographium species are closely related and share similar gross morphology. Probes designed for a PhyloChip for Leptographium have been transferred and tested as primers for PCR diagnostic against Leptographium species. The primers were combined with complementary universal primers to identify known and suspected undescribed species of Leptographium. The primer set was optimized for 56 species, including the three varieties of L. wageneri, then blind-tested against 10 random DNA samples. The protocols established in this study successfully identified species from the blind test as well as eight previously undescribed isolates of Leptographium. The undescribed isolates were identified as new species of Leptographium with the aid of the microcoding PCR identification system established in this study. The primers that were positive for each undescribed isolate were used to determine close relatives of these species and some of their biological characteristics. The transfer of oligonucleotides from a micro-array platform to a PCR diagnostic was successful, and the identification system is robust for both known and unknown species of Leptographium. PMID- 20943563 TI - Scanning electron microscopy observations of the interaction between Trichoderma harzianum and perithecia of Gibberella zeae. AB - Chronological events associated with the interaction between a strain of Trichoderma harzianum, T472, with known biological control activity against perithecial production of G. zeae, were studied with scanning electron microscopy to investigate the mechanisms of control. Large clusters of perithecia consisting of 5-15 perithecia formed on the autoclaved, mulched wheat straw inoculated with G. zeae alone (control) with an average of 157 perithecia per plate. Small clusters consisting of 3-6 and an average of 15 perithecia per plate perithecia formed on straw that was treated with T. harzianum. The mature perithecia from straw treated with T. harzianum produced less pigment and were lighter in color than those from the control plates. Furthermore the cells of the outer wall of these perithecia were abnormal in appearance and unevenly distributed across the surface. Immature perithecia were colonized by T. harzianum approximately 15 d after inoculation (dai) with the biocontrol agent and pathogen. Few perithecia were colonized at later stages. The affected perithecia collapsed 21 dai, compared to the perithecia in the control samples that began to collapse 28 dai. Abundant mycelium of T. harzianum was seen on the perithecia of treated samples. Perithecial structures may be resistant to penetration by the mycelium because direct penetration was not observed. Trichoderma harzianum colonized the substrate quickly and out-competed the pathogen, G. zeae. PMID- 20943564 TI - Phylogeny and taxonomy of Aspicilia and Megasporaceae. AB - Phylogenetic analyses based on nuLSU and mtSSU indicate that Megasporaceae is monophyletic. Aspicilia species were distributed among three main well supported groups and one group with low support that included the type species; a division of the family into five genera is proposed. The old names Circinaria and Sagedia are reintroduced for groups not including A. cinerea, the type of Aspicilia. The monotypic Megaspora is closely related to Circinaria, while Lobothallia is the sister group of the other Megasporaceae genera. Aspicilia recedens and A. farinosa are transferred to Lobothallia. Species of the 'Sphaerothallia group' are nested in Circinaria. Aspilidea is not a member of Megasporaceae but seems to be more closely related to Ochrolechiaceae. Aspilidea myrinii is neotypified, and lectotypes are designated for Aspicilia gibbosa, A. leprosescens and Lecanora gibbosula. PMID- 20943565 TI - Colletotrichum gloeosporioides s.l. associated with Theobroma cacao and other plants in Panama: multilocus phylogenies distinguish host-associated pathogens from asymptomatic endophytes. AB - Colletotrichum interacts with numerous plant species overtly as symptomatic pathogens and cryptically as asymptomatic endophytes. It is not known whether these contrasting ecological modes are optional strategies expressed by individual Colletotrichum species or whether a species' ecology is explicitly pathogenic or endophytic. We explored this question by inferring relationships among 77 C. gloeosporioides s.l. strains isolated from asymptomatic leaves and from anthracnose lesions on leaves and fruits of Theobroma cacao (cacao) and other plants from Panama. ITS and 5'-tef1 were used to assess diversity and to delineate operational taxonomic units for multilocus phylogenetic analysis. The ITS and 5'-tef1 screens concordantly resolved four strongly supported lineages, clades A-D: Clade A includes the ex type of C. gloeosporioides, clade B includes the ex type ITS sequence of C. boninense, and clades C and D are unidentified. The ITS yielded limited resolution and support within all clades, in particular the C. gloeosporioides clade (A), the focal lineage dealt with in this study. In contrast the 5'-tef1 screen differentiated nine distinctive haplotype subgroups within the C. gloeosporioides clade that were concordant with phylogenetic terminals resolved in a five-locus nuclear phylogeny. Among these were two phylogenetic species associated with symptomatic infections specific to either cacao or mango and five phylogenetic species isolated principally as asymptomatic infections from cacao and other plant hosts. We formally describe two new species, C. tropicale and C. ignotum, that are frequent asymptomatic associates of cacao and other Neotropical plant species, and epitypify C. theobromicola, which is associated with foliar and fruit anthracnose lesions of cacao. Asymptomatic Colletotrichum strains isolated from cacao plants grown in China included six distinct C. gloeosporioides clade taxa, only one of which is known to occur in the Neotropics. PMID- 20943566 TI - A re-evaluation of Hypochnicium (Polyporales) based on morphological and molecular characters. AB - Hypochnicium is a genus of corticioid, wood-inhabiting fungi in the Polyporales with a worldwide distribution. The genus has been characterized by the nature of the spores; they are thick-walled, smooth or ornamented, and cyanophilous. Nine new ITS nrDNA sequences from species of this genus were aligned with 32 sequences from GenBank, and phylogenetic analyses were performed. Six clades were determined within the genus; one contains taxa with smooth spores, and the other three with ornamented spores. Hypochnicium versatum must be included in Gloeohypochnicium, and the new combination Gloeohypochnicium versatum is proposed. Two new species, Hypochnicium michelii from Spain and Hypochnicium guineensis from Equatorial Guinea, are described. PMID- 20943560 TI - Diversity and distribution of soil fungal communities in a semiarid grassland. AB - The fungal loop model of semiarid ecosystems integrates microtopographic structures and pulse dynamics with key microbial processes. However limited data exist about the composition and structure of fungal communities in these ecosystems. The goal of this study was to characterize diversity and structure of soil fungal communities in a semiarid grassland. The effect of long-term nitrogen fertilization on fungi also was evaluated. Samples of rhizosphere (soil surrounding plant roots) and biological soil crust (BSC) were collected in central New Mexico, USA. DNA was amplified from the samples with fungal specific primers. Twelve clone libraries were generated with a total of 307 (78 operational taxonomic units, OTUs) and 324 sequences (67 OTUs) for BSC and rhizosphere respectively. Approximately 40% of soil OTUs were considered novel (less than 97% identity when compared to other sequences in NCBI using BLAST). The dominant organisms were dark-septate (melanized fungi) ascomycetes belonging to Pleosporales. Effects of N enrichment on fungi were not evident at the community level; however the abundance of unique sequences, sampling intensity and temporal variations may be uncovering the effect of N in composition and diversity of fungal communities. The fungal communities of rhizosphere soil and BSC overlapped substantially in composition, with a Jaccard abundance similarity index of 0.75. Further analyses are required to explore possible functions of the dominant species colonizing zones of semiarid grassland soils. PMID- 20943567 TI - The genus Coltricia in Brazil: new records and two new species. AB - Genus Coltricia is re-evaluated in Brazil and 10 species are accepted, namely C. barbata, C. cinnamomea, C. duportii, C. focicola, C. globispora, C. hamata, C. montagnei, C. perennis, C. permollis and C. velutina. Coltricia focicola and C. montagnei are reported respectively for the first time from South America and Brazil. Coltricia permollis and C. velutina are described as new species. Description of the new species, illustrations and a key to species of Coltricia known from the Neotropics are provided. The current knowledge of the genus in Brazil is discussed. PMID- 20943568 TI - Alternaria hungarica sp. nov., a minor foliar pathogen of wheat in Hungary. AB - During routine wheat disease surveys in Hungary in 2007 Alternaria was isolated from leaf samples collected in Debrecen. Macro- and micro-morphological examinations and ITS sequence analyses indicated that the isolates represented a new Alternaria species, which we described as A. hungarica. The usually solitary conidia of A. hungarica resemble those of A. mouchaccae and A. molesta. However growth and sporulation pattern are more like those of A. geniostomatis and A. soliaridae. Phylogenetic analysis of ITS sequences indicated that this new species can be distinguished from all other examined Alternaria and Embellisia species. Pathogenicity tests indicated that A. hungarica can be considered a minor pathogen of wheat. PMID- 20943569 TI - Foliar mycobiota of Coussapoa floccosa, a highly threatened tree of the Brazilian Atlantic forest. AB - We studied the foliicolous mycobiota associated with Coussapoa floccosa. This is a tree belonging to the Cecropiaceae, endemic to the Brazilian tropical seasonal semideciduous montane forest. It is listed as an endangered species because of habitat destruction. Until now no fungus has been recorded in association with this plant species. This paper describes six foliicolous fungi associated with this plant that were collected during a survey of the mycobiota occurring in a locality where a small population of C. floccosa was discovered. All fungi described here are new to science, namely Dennisiella coussapoae, Mycosphaerella coussapoae, Pseudoallosoma nervisequens (which also represents a newly proposed genus), Pseudocercospora coussapoae, Pseudocercospora atrofuliginosa and Tripospermum acrobaticum. The high proportion of taxonomic novelties revealed in this study reflects the general lack of mycological information for forest ecosystems in Brazil and also indicates that vulnerable plant species such as C. floccosa may harbor unique mycobiota. Such mycobiota may depend on their nearly extinct hosts and consequently can be equally endangered with extinction and therefore also deserve consideration for in situ and ex situ conservation. PMID- 20943571 TI - Fomitiporia in sub-Saharan Africa: morphology and multigene phylogenetic analysis support three new species from the Guineo-Congolian rainforest. AB - Fomitiporia nobilissima sp. nov., F. gabonensis sp. nov. and F. ivindoensis sp. nov., three species from the rainforest of the Guineo-Congolian phytogeographic region in Gabon, are described and illustrated. These species share a pileate basidiome, small basidiospores and an absence of setae. The critical morphological features that differentiate them are the pileus habit or shape, pore surface color, pore diameter and possibly ecology. Each new species forms distinct but closely related clades in phylogenetic analysis of DNA sequences from nuclear ribosomal LSU, ITS and translation elongation factor 1-alpha. Other species in sub-Saharan Africa are discussed briefly. A key to six species of Fomitiporia from sub-Saharan Africa is provided. The new combination Fomitiporia apiahyna is proposed. PMID- 20943572 TI - A circadian rhythm regulating hyphal melanization in Cercospora kikuchii. AB - Many metabolic and developmental processes in fungi are controlled by biological rhythms. Circadian rhythms approximate a daily (24 h) cycle and have been thoroughly studied in the model fungus, Neurospora crassa. However relatively few examples of true circadian rhythms have been documented among other filamentous fungi. In this study we describe a circadian rhythm underlying hyphal melanization in Cercospora kikuchii, an important pathogen of soybean. After growth in light or light : dark cycles, colonies transferred to darkness produced zonate bands of melanized hyphae interspersed with bands of hyaline hyphae. Rhythmic production of bands was remarkably persistent in the absence of external cues, lasting at least 7 d after transfer to darkness, and was compensated over a range of temperatures. As in N. crassa, blue light but not red light was sufficient to entrain the circadian rhythm in C. kikuchii, and a putative ortholog of white collar-1, one of the genes required for light responses in N. crassa, was identified in C. kikuchii. Circadian regulation of melanization is conserved in other members of the genus: Similar rhythms were identified in another field isolate of C. kikuchii as well as field isolates of C. beticola and C. sorghi, but not in wild-type strains of C. zeae-maydis or C. zeina. This report represents the first documented circadian rhythm among Dothideomycete fungi and provides a new opportunity to dissect the molecular basis of circadian rhythms among filamentous fungi. PMID- 20943573 TI - Macrofungi associated with vegetation and soils at Ha Ha Tonka State Park, Missouri. AB - Fungi and vascular plant interactions are necessary components of natural community establishment, productivity and degradation. While many fungal species serve as decomposers of organic matter, others have evolved mutualistic or parasitic relationships with vascular plants. This research focused on characterizing associations among macrofungi, vascular plant communities and soils. Ha Ha Tonka State Park is in central Missouri and has a varying landscape with numerous natural community types that provide diverse habitats and microhabitats that are ideally suited to the investigation of fungal, floral and soil associations. Five communities sampled within the park included glades, open woodlands, flatwoods, closed-canopy forests and karst sinks. Permanent 0.01 ha. plots were surveyed in the 2006 and 2007 growing seasons. Surveys of plots and entire communities yielded 249 fungal taxa and approximately 265 floral taxa. Soils were analyzed to help define specific edaphic components of each community and used to associate soil attributes with plant and fungal communities. Forest communities contained the most ectomycorrhizal (ECM) fungi species. Karst sinks and glades had higher soil pH and phosphorus and fewer ectomycorrhizal fungi. Statistical analyses included non-metric multidimensional scaling, multiresponse permutation procedure and indicator species analysis. Indicator species were identified for flatwood, forest and karst communities, but results were inconclusive for glades and open woodlands. PMID- 20943574 TI - Executive summary: what do we know? Key findings from 50 years of medical sociology. PMID- 20943570 TI - Culturing and direct PCR suggest prevalent host generalism among diverse fungal endophytes of tropical forest grasses. AB - Most studies examining endophytic fungi associated with grasses (Poaceae) have focused on agronomically important species in managed ecosystems or on wild grasses in subtropical, temperate and boreal grasslands. However grasses first arose in tropical forests, where they remain a significant and diverse component of understory and forest-edge communities. To provide a broader context for understanding grass-endophyte associations we characterized fungal endophyte communities inhabiting foliage of 11 species of phylogenetically diverse C(3) grasses in the understory of a lowland tropical forest at Barro Colorado Island, Panama. Our sample included members of early-arising subfamilies of Poaceae that are endemic to forests, as well as more recently arising subfamilies that transitioned to open environments. Isolation on culture media and direct PCR and cloning revealed that these grasses harbor species-rich and phylogenetically diverse communities that lack the endophytic Clavicipitaceae known from diverse woodland and pasture grasses in the temperate zone. Both the incidence and diversity of endophytes was consistent among grass species regardless of subfamily, clade affiliation or ancestral habitat use. Genotype and phylogenetic analyses suggest that these endophytic fungi are predominantly host generalists, shared not only among distinctive lineages of Poaceae but also with non-grass plants at the same site. PMID- 20943575 TI - Reflections on fifty years of medical sociology. PMID- 20943576 TI - Medical sociology and health services research: past accomplishments and future policy challenges. AB - The rising costs and inconsistent quality of health care in the United States have raised significant questions among professionals, policy makers, and the public about the way health services are being delivered. For the past 50 years, medical sociologists have made significant contributions in improving our understanding of the nature and impact of the organizations that constitute our health care system. In this article, we discuss three central findings in the sociology of health services: (1) health services in the U.S. are unequally distributed, contributing to health inequalities across status groups; (2) social institutions reproduce health care inequalities by constraining and enabling the actions of health service organizations, health care providers, and consumers; and (3) the structure and dynamics of health care organizations shape the quality, effectiveness, and outcomes of health services for different groups and communities. We conclude with a discussion of the policy implications of these findings for future health care reform efforts. PMID- 20943577 TI - Medical sociology and technology: critical engagements. AB - In this selective review of the literature on medical sociology's engagement with technology, we outline the concurrent developments of the American Sociological Association section on medicine and advances in medical treatment. We then describe theoretical and epistemological issues with scholars' treatment of technology in medicine. Using symbolic interactionist concepts, as well as work from the interdisciplinary field of science and technology studies, we review and synthesize critical connections in and across sociology's intellectual relationship with medical technology. Next, we discuss key findings in these literatures, noting a shift from a focus on the effects of technology on practice to a reconfiguration of human bodies. We also look toward the future, focusing on connections between technoscientific identities and embodied health movements. Finally, we call for greater engagement by medical sociologists in studying medical technology and the process of policy-making--two areas central to debates in health economics and public policy. PMID- 20943578 TI - Bioethics, raw and cooked: extraordinary conflict and everyday practice. AB - This article explains the emergence, growth, and institutional anchoring of bioethics in both policy and clinical arenas. Under the heading of principlism, bioethics developed a public language for resolving disputes that allowed it to transform disputes involving sacred matters into profane work routines. At the same time, having principlism as a common language for solving practical disputes allowed "ethics work" in health care to be separated from moral theorizing as a practical activity. Two issues--the right to die and the protection of research subjects--serve to illustrate the process through which bioethics established a large institutional footprint in health care. PMID- 20943579 TI - Sociology of health care reform: building on research and analysis to improve health care. AB - Health reform efforts in the United States have focused on resolving some of the fundamental irrationalities of the system whereby costs and services utilization are often not linked to improved patient outcomes. Sociologists have contributed to these efforts by documenting the extent of problems and by confronting central questions around issues of accountability, reimbursement, and rationing that must be addressed in order to achieve meaningful reform that controls costs, expands access, and improves quality. Major reform rarely occurs without "paying off" powerful interests, a particularly difficult challenge in the context of a large and growing deficit. Central to achieving increased coverage and access, high quality, and cost control is change in reimbursement arrangements, increased accountability for both costs and outcomes, and criteria for rationing based on the evidence and accepted as legitimate by all stakeholders. Consensus about health reform requires trust. The traditional trust patients have in physicians provides an important base on which to build. PMID- 20943580 TI - Understanding racial-ethnic disparities in health: sociological contributions. AB - This article provides an overview of the contribution of sociologists to the study of racial and ethnic inequalities in health in the United States. It argues that sociologists have made four principal contributions. First, they have challenged and problematized the biological understanding of race. Second, they have emphasized the primacy of social structure and context as determinants of racial differences in disease. Third, they have contributed to our understanding of the multiple ways in which racism affects health. Finally, sociologists have enhanced our understanding of the ways in which migration history and status can affect health. Sociological insights on racial disparities in health have important implications for the development of effective approaches to improve health and reduce health inequities. PMID- 20943581 TI - Social conditions as fundamental causes of health inequalities: theory, evidence, and policy implications. AB - Link and Phelan (1995) developed the theory of fundamental causes to explain why the association between socioeconomic status (SES) and mortality has persisted despite radical changes in the diseases and risk factors that are presumed to explain it. They proposed that the enduring association results because SES embodies an array of resources, such as money, knowledge, prestige, power, and beneficial social connections that protect health no matter what mechanisms are relevant at any given time. In this article, we explicate the theory, review key findings, discuss refinements and limits to the theory, and discuss implications for health policies that might reduce health inequalities. We advocate policies that encourage medical and other health-promoting advances while at the same time breaking or weakening the link between these advances and socioeconomic resources. This can be accomplished either by reducing disparities in socioeconomic resources themselves or by developing interventions that, by their nature, are more equally distributed across SES groups. PMID- 20943582 TI - Stress and health: major findings and policy implications. AB - Forty decades of sociological stress research offer five major findings. First, when stressors (negative events, chronic strains, and traumas) are measured comprehensively, their damaging impacts on physical and mental health are substantial. Second, differential exposure to stressful experiences is a primary way that gender, racial-ethnic, marital status, and social class inequalities in physical and mental health are produced. Third, minority group members are additionally harmed by discrimination stress. Fourth, stressors proliferate over the life course and across generations, widening health gaps between advantaged and disadvantaged group members. Fifth, the impacts of stressors on health and well-being are reduced when persons have high levels of mastery, self-esteem, and/or social support. With respect to policy, to help individuals cope with adversity, tried and true coping and support interventions should be more widely disseminated and employed. To address health inequalities, the structural conditions that put people at risk of stressors should be a focus of programs and policies at macro and meso levels of intervention. Programs and policies also should target children who are at lifetime risk of ill health and distress due to exposure to poverty and stressful family circumstances. PMID- 20943583 TI - Social relationships and health: a flashpoint for health policy. AB - Social relationships--both quantity and quality--affect mental health, health behavior, physical health, and mortality risk. Sociologists have played a central role in establishing the link between social relationships and health outcomes, identifying explanations for this link, and discovering social variation (e.g., by gender and race) at the population level. Studies show that social relationships have short- and long-term effects on health, for better and for worse, and that these effects emerge in childhood and cascade throughout life to foster cumulative advantage or disadvantage in health. This article describes key research themes in the study of social relationships and health, and it highlights policy implications suggested by this research. PMID- 20943584 TI - The social construction of illness: key insights and policy implications. AB - The social construction of illness is a major research perspective in medical sociology. This article traces the roots of this perspective and presents three overarching constructionist findings. First, some illnesses are particularly embedded with cultural meaning--which is not directly derived from the nature of the condition--that shapes how society responds to those afflicted and influences the experience of that illness. Second, all illnesses are socially constructed at the experiential level, based on how individuals come to understand and live with their illness. Third, medical knowledge about illness and disease is not necessarily given by nature but is constructed and developed by claims-makers and interested parties. We address central policy implications of each of these findings and discuss fruitful directions for policy-relevant research in a social constructionist tradition. Social constructionism provides an important counterpoint to medicine's largely deterministic approaches to disease and illness, and it can help us broaden policy deliberations and decisions. PMID- 20943585 TI - Examining critical health policy issues within and beyond the clinical encounter: patient-provider relationships and help-seeking behaviors. AB - Among notable issues in health care policy and practice over the past 50 years have been those centered on the changing dynamics in clinical encounters, predominantly the relationship between physicians and patients and access to health care. Patient roles have become more active, diverse, long-term, and risk based, while patient-provider relationships are multifaceted, less paternalistic, and more pivotal to health outcomes. Extensive literatures on help-seeking show how much social influences affect both undertreatment and inappropriate high utilization of health care. The challenge in trying to contain the growth of health care costs is two-fold: developing better ways of defining need for care and promoting better access for those who could benefit most from health care. Both of these strategies need to be considered in the context of addressing racial, ethnic, socioeconomic, and health status disparities. Rebuilding the primary care sector as a sociologically informed strategy and a key component of health care reform may optimize both health care delivery and patient outcomes. PMID- 20943586 TI - The continued social transformation of the medical profession. AB - A pressing concern in contemporary health policy is whether the medical profession's mandate to take care of clients has been undermined by the influx of money into health care. We examine the medical profession's transformation over the past decades. First, we review how sociologists have viewed the medical profession over the past half-century as one stakeholder among other stakeholders vying for market share and power in the health care field. We then examine three recent challenges to the profession that exemplify the tension between self interest and collective altruism to act in the best interest of patients: (1) the rise of patient consumerism, (2) the advent of evidence-based medicine, and (3) the increasing power of the pharmaceutical industry. We show the resilience of the medical profession as it adapts and transforms in response to these challenges. We conclude with implications to help inform policy makers' assessments of how the medical profession will react to policy initiatives. PMID- 20943587 TI - Gene-environment correlations in the stress-depression relationship. AB - A critical feature of the social stress model is the apparent relationship between stress and depression. Although many studies have demonstrated a connection between the two, the relationship may be contaminated by genes affecting both stress and depression. Using a sample of identical and fraternal twins, this study explores genetic influences on depression and assorted sources of stress while explicitly estimating, and thereby controlling for, gene environment correlations. I consider both stress and depression in a fine-grained fashion. For the former, the study explores assorted sources of stress, including health and disability, family, unemployment, discrimination, and perceived neighborhood safety, as gene-environment correlations may be stronger for some forms of stress than others. For the latter, the study explores both depressive symptoms and major depressive disorders, as each may entail a different epidemiological process, especially with respect to genes. The results reveal that most, but not all, measures of stress have moderate heritabilities, suggesting that genes influence exposure to the environment in a broad fashion. Yet, despite this, the relationship between stress and depression is generally robust to gene-environment correlations. There are some notable exceptions. For example, allowing for gene-environment correlations, marital conflict is generally unrelated to depression. Moreover, gene-environment correlations are generally stronger for major depression than for depressive symptoms, encouraging further elaboration of the distinction between the onset of depression and its recurrence, especially in the context of genes. These exceptions do not put limits on environmental influence, but do suggest that genes operate in a complex life-course fashion. PMID- 20943588 TI - A Life-course Perspective on the "Gateway Hypothesis". AB - Drawing on stress and life-course perspectives and using panel data from 1,286 south Florida young adults, we assess three critical questions regarding the role of marijuana in the "gateway hypothesis." First, does teen marijuana use independently (causally) affect subsequent use of more dangerous substances? Second, if so, does that effect apply to the abuse of other illicit substances, as defined by the DSM-IV, or only to the use of such substances? Finally, does any causal effect of teen marijuana use survive beyond adolescence, or is it a short-term effect that subsides as adolescents transition to adulthood? Our results indicate a moderate relation between early teen marijuana use and young adult abuse of other illicit substances; however, this association fades from statistical significance with adjustments for stress and life-course variables. Likewise, our findings show that any causal influence of teen marijuana use on other illicit substance use is contingent upon employment status and is short term, subsiding entirely by the age of 21. In light of these findings, we urge U.S. drug control policymakers to consider stress and life-course approaches in their pursuit of solutions to the "drug problem." PMID- 20943589 TI - What makes you stronger: age and cohort differences in personal growth after cancer. AB - Using two waves of the National Survey of Midlife Development in the United States, I compare changes in personal growth over a 10 year period among cancer survivors and individuals without cancer. Moreover, I examine joint effects of age and cohort on personal growth after a cancer diagnosis. The theoretical framework of this study integrates impairment, resilience, and thriving perspectives. Findings reveal that, although personal growth declines with age for all individuals regardless of cohort and cancer status, cancer slows the decline in personal growth with age in 1940s, 1950s, and 1960s birth cohorts, yet accelerates the age-related decline in the 1920s cohort. I argue that a sociological perspective can enhance our understanding of the interplay of developmental and sociocultural influences on psychological adjustment to cancer. Seemingly idiosyncratic psychological reactions to cancer partly reflect macrolevel processes represented by cohort differences. PMID- 20943591 TI - The effects of childhood neighborhood conditions on self-reports of adult health. AB - Studies have shown that neighborhood conditions and experiences may individually or collectively impact health. Using 38 years of longitudinal data from the Panel Study of Income Dynamics (PSID), we clarify the relationship between child and adult neighborhood quality and self-reported adult health, using sibling fixed effects models. Overall, we find support for positive long-term health effects, both for growing up in affluent neighborhoods and for growing up in neighborhoods where one is surrounded by comparative advantage. Relative to childhood neighborhood factors, adult neighborhoods have little to no effect in almost every model specification. We find mixed evidence, as well, that these relationships are stronger for nonwhites than for whites. Our findings suggest that childhood is a critical point for intervention in the long-term health effects of residential conditions. PMID- 20943590 TI - Mothers' depression and educational attainment and their children's academic trajectories. AB - In this study, we take a dynamic approach to studying the connections among mothers' education, their depression, and their children's academic trajectories during elementary school. Applying latent growth curve modeling to longitudinal data from the National Institute of Child Health and Human Development's Study of Early Child Care and Youth Development (N = 1,012), we find that maternal depression does not mediate the association between mothers' education and children's achievement. Instead, maternal education moderates the association between maternal depression and children's achievement. Specifically, maternal depression only predicted lower achievement for children of women who did not pursue higher education. These results highlight the role of mothers' mental health in the intergenerational linkage between mothers' and children's educational experiences. PMID- 20943593 TI - High-cost religion, religious switching, and health. AB - Previous research has devoted significant attention to understanding the link between health and personal religious beliefs and practices, typically finding that more religious people tend to have better health. However, almost no attention has been given to how switching religious groups or leaving religion altogether is related to self-reported health. Due to selection and causation mechanisms, switching from high-cost groups that are theologically and culturally exclusive could be associated with poor health more than switching from other religious groups. Using data from the 1972 through 2006 General Social Surveys, we examine the relationship between health and religious switching as moderated by the religious tradition of origin. We find that people who are raised and stay in high-cost sectarian groups, such as the Latter-day Saints and Jehovah's Witnesses, have better self-reported health than those raised and staying in other religious traditions. However, people who leave such groups are more likely to report worse health than those who leave other groups. PMID- 20943592 TI - Collective efficacy, family attachment, and urban adolescent suicide attempts. AB - The suicide rate among American adolescents between the ages of 14-25 has dramatically increased during the last 50 years, and this fact has been the focus of extensive social-scientific investigation. To date, however, research focusing on the joint effects of mental health, family, and contextual-level predictors on adolescents' suicidal behaviors is scarce. Drawing on Durkheim's classic macro level approach to suicide and collective efficacy theory, we use data from the Project on Human Development in Chicago Neighborhoods (PHDCN) to examine the effect of informal social controls on adolescents' suicide attempts. Analyzing reports from 990 youth, we examine the hypothesis that neighborhood-level collective efficacy and family-level integration and social control independently affect suicide attempts. We also examine the extent to which they interact in their effects on suicidal behavior. Overall, results from multilevel logit models support the Durkheimian expectation that family attachment reduces the probability that adolescents will attempt suicide. The effect of collective efficacy is interactive in nature. Specifically, we find that collective efficacy significantly enhances the protective effect of family attachment and support on adolescent suicidal behaviors. We discuss findings within the context of social control theory. PMID- 20943594 TI - Depression, anxiety, and religious life: a search for mediators. AB - We examine several potential mechanisms linking religious involvement to depressive symptoms, major depression, and anxiety. Logistic and OLS regression estimations test five sets of potential psychosocial religion mediators: perceived attitudes toward and motivations for attendance; positive and negative religious coping; religious attitudes, beliefs, and spirituality; congregational support and criticism; and interpersonal and self-forgiveness. Compared to attending services less than once a month or never, attending services once a week but no more is associated with fewer depressive symptoms and anxiety symptoms. Hypothesized mediators, including meaning, interpersonal and self forgiveness, congregational criticism, social attendance beliefs, and negative coping are independently associated with one or more mental health outcomes. PMID- 20943595 TI - Increased haematopoietic progenitor cells are associated with poor outcome in patients with metastatic renal cancer treated with sunitinib. AB - BACKGROUND: Haematopoietic progenitor cells (HPCs) are present in blood in metastatic renal cell cancer (mRCC). We investigate their expression in mRCC patients treated with sunitinib and correlate their expression with plasma growth factor levels [insulin-like growth factor (IGF)-1]. METHODS: Circulating HPCs (CD34(+)/CD45(+)) and plasma IGF-1 levels were measured at specific sequential time points (0, 6, 18 and 28 weeks) in 43 untreated mRCC patients receiving sunitinib (50 mg for 28 days followed by 14-day off treatment). Univariate and multivariate analysis assessed the prognostic significance of HPCs and IGF-1. RESULTS: HPCs levels were raised in 40 of 43 (93%) of patients. IGF-1 levels were raised in 9 of 43 patients (21%). Univariate and multivariate analysis revealed that high HPCs before treatment were associated with a significantly shorter overall survival (hazard ratio 3.3, 95% confidence interval 1.23-8.8, P=0.01), which was not the case for IGF-1 levels. Both HPC and IGF-1 levels fell with sunitinib (61% and 14% fall, respectively, P <0.05 for both). A positive correlation between the falls in HPC and IGF-1 occurred (P<0.001). CONCLUSIONS: HPCs are over expressed in the peripheral blood in the majority of patients with mRCC. Higher levels are associated with poor prognosis. A concurrent fall in HPCs and growth factor expression (IGF-1) with sunitinib occurs. PMID- 20943596 TI - Maternal and cord blood hormone levels in the United States and China and the intrauterine origin of breast cancer. AB - BACKGROUND: Breast cancer is less common in China than in the United States and perinatal characteristics predict breast cancer risk in the offspring. We determined levels of pregnancy hormones in Boston and Shanghai to identify those possibly involved in the intrauterine origin of breast cancer. PARTICIPANTS AND METHODS: We compared maternal and cord blood levels of estradiol, estriol, testosterone, progesterone, prolactin, insulin-like growth factors (IGF) 1 and 2, insulin-like growth factor-binding protein 3, adiponectin and sex hormone-binding globulin (SHBG) in 241 Caucasian and 295 Chinese women. RESULTS: In both centers, hormone levels at the 16th were predictive of those at the 27th gestational week, but there was little correlation between maternal and cord blood levels. In cord blood, we found significantly (P < 0.01) higher levels of estradiol (44.2%), testosterone (54.5%), IGF-2 (22.7%) and strikingly SHBG (104.6%) in Shanghai women, whereas the opposite was true for IGF-1 (-36.8%). CONCLUSIONS: Taking into account the current understanding of the plausible biological role of the examined endocrine factors, those likely to be involved in the intrauterine origin of breast cancer are SHBG and IGF-2, with higher cord blood levels among Chinese, and IGF-1, with higher cord blood levels among Caucasian women. PMID- 20943597 TI - Coffee and cancers of the upper digestive and respiratory tracts: meta-analyses of observational studies. AB - BACKGROUND: Data of epidemiological studies on the relation between coffee drinking and upper aerodigestive tract cancer risk are scattered and inconclusive. We therefore conducted systematic meta-analyses of observational studies published before October 2009. MATERIALS AND METHODS: We combined relative risks (RR) with 95% confidence intervals (CI) for cancers of the oral cavity/pharynx (OP) and larynx, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), comparing the highest versus the lowest categories of coffee consumption, using random-effects models. RESULTS: For OP cancer, the pooled RR was 0.64 (95% CI 0.51-0.80) for highest versus lowest coffee drinking, based on a total of 2633 cases from one cohort and eight case control studies, with no significant heterogeneity across studies. The RRs were 0.61 (95% CI 0.41-0.89) for European, 0.58 (95% CI 0.36-0.94) for American and 0.74 (95% CI 0.48-1.15) for Asian studies, where coffee consumption is lower. The corresponding RRs were 1.56 (95% CI 0.60-4.02) for laryngeal cancer (732 cases from three case-control studies), 0.87 (95% CI 0.65-1.17) for ESCC (2115 cases from one cohort and six case-control studies) and 1.18 (95% CI 0.81-1.71) for EAC (415 cases from three case-control studies). CONCLUSION: Coffee drinking is inversely related to OP cancer risk, while there is no relation with laryngeal cancer, ESCC and EAC. PMID- 20943599 TI - Technological innovation revisited. PMID- 20943601 TI - Treatment of pT1N0 breast cancer: multigene predictors to assess risk of relapse. AB - Breast cancer is a complex disease and even at a favourable stage, such as the pT1N0 one, it is unlikely to be understood and cured by focusing only on single gene or protein alterations determined with suboptimal technologies, as the standard clinico-pathological predictors are. Improving breast cancer treatment will require a more systematic, structured and multidimensional approach able to integrate tumour biology, disease burden and host-related factors. In this scenario, multigene predictors capturing gene-expression profiling or other molecular measurements have great potential for improving breast cancer management. Nevertheless, even if the gene signatures generated so far clearly represent a step forward in the prediction of patient outcome, they are still showing some limitations that nowadays are the basis for the development of a second generation of multigene predictors. Their strength will stand in the investigation of the tumour-surrounding stroma and tumour microenvironment, in the interrogation of different molecular subtypes of breast cancer as distinct entities and in the ability to predict both early and late relapse. It is prospected that the greater accuracy of this new wave of predictors will provide substantial support to the existing decision tools and will significantly ameliorate our current ability to define breast cancer prognosis. PMID- 20943600 TI - Global profiling of proteolysis during rupture of Plasmodium falciparum from the host erythrocyte. AB - The obligate intracellular parasite pathogen Plasmodium falciparum is the causative agent of malaria, a disease that results in nearly one million deaths per year. A key step in disease pathology in the human host is the parasite mediated rupture of red blood cells, a process that requires extensive proteolysis of a number of host and parasite proteins. However, only a relatively small number of specific proteolytic processing events have been characterized. Here we describe the application of the Protein Topography and Migration Analysis Platform (PROTOMAP) (Dix, M. M., Simon, G. M., and Cravatt, B. F. (2008) Global mapping of the topography and magnitude of proteolytic events in apoptosis. Cell 134, 679-691; Simon, G. M., Dix, M. M., and Cravatt, B. F. (2009) Comparative assessment of large-scale proteomic studies of apoptotic proteolysis. ACS Chem. Biol. 4, 401-408) technology to globally profile proteolytic events occurring over the last 6-8 h of the intraerythrocytic cycle of P. falciparum. Using this method, we were able to generate peptographs for a large number of proteins at 6 h prior to rupture as well as at the point of rupture and in purified merozoites after exit from the host cell. These peptographs allowed assessment of proteolytic processing as well as changes in both protein localization and overall stage-specific expression of a large number of parasite proteins. Furthermore, by using a highly selective inhibitor of the cysteine protease dipeptidyl aminopeptidase 3 (DPAP3) that has been shown to be a key regulator of host cell rupture, we were able to identify specific substrates whose processing may be of particular importance to the process of host cell rupture. These results provide the first global map of the proteolytic processing events that take place as the human malarial parasite extracts itself from the host red blood cell. These data also provide insight into the biochemical events that take place during host cell rupture and are likely to be valuable for the study of proteases that could potentially be targeted for therapeutic gain. PMID- 20943598 TI - The surprising composition of the salivary proteome of preterm human newborn. AB - Saliva is a body fluid of a unique composition devoted to protect the mouth cavity and the digestive tract. Our high performance liquid chromatography (HPLC) electrospray ionization-MS analysis of the acidic soluble fraction of saliva from preterm human newborn surprisingly revealed more than 40 protein masses often undetected in adult saliva. We were able to identify the following proteins: stefin A and stefin B, S100A7 (two isoforms), S100A8, S100A9 (four isoforms), S100A11, S100A12, small proline-rich protein 3 (two isoforms), lysozyme C, thymosins beta(4) and beta(10), antileukoproteinase, histone H1c, and alpha and gamma globins. The average mass value reported in international data banks was often incongruent with our experimental results mostly because of post translational modifications of the proteins, e.g. acetylation of the N-terminal residue. A quantitative label-free MS analysis showed protein levels altered in relation to the postconceptional age and suggested coordinate and hierarchical functions for these proteins during development. In summary, this study shows for the first time that analysis of these proteins in saliva of preterm newborns might represent a noninvasive way to obtain precious information of the molecular mechanisms of development of human fetal oral structures. PMID- 20943602 TI - Benefits and adverse effects of endocrine therapy. AB - Endocrine-responsive tumors that are small and without nodal involvement (i.e. tumors classified as pT1 pN0) are a heterogeneous group of tumors that are associated with a low risk of relapse in the majority of the cases. Therefore, the costs and benefits of adjuvant endocrine therapy should be carefully considered within this subgroup of patients. Treatment decisions should take into consideration co-morbidities as well as the presence of other classical risk factors such as HER2 overexpression or extensive peritumoral vascular invasion. Tamoxifen or tamoxifen plus ovarian function suppression should be considered as proper endocrine therapies in premenopausal patients. Ovarian function suppression alone or ovarian ablation might also be considered adequate in selected patients (e.g. very low-risk patients, in the presence of co-morbidities or patient preference). An aromatase inhibitor should form part of standard endocrine therapy for most postmenopausal women with receptor-positive breast cancer, although patients at low risk or with co-morbid musculoskeletal or cardiovascular risk factors may be considered suitable for tamoxifen alone. Tailored endocrine treatments should be considered in patients with endocrine responsive tumors classified as pT1 pN0. Issues focusing on safety, quality of life and subjective side effects should be routinely discussed. PMID- 20943603 TI - Chemotherapy with or without trastuzumab. AB - The prognosis of pT1N0M0/stage I breast cancer has generally been considered so favourable that these patients are not routinely offered adjuvant systemic therapy. However, biological heterogeneity within pT1N0M0 dictates diverse outcomes within the subgroup. HER2 gene amplification or protein overexpression is uncommon in pT1N0M0 disease, but, when present, is clearly associated with a higher risk of recurrence. The role of anti-HER2 therapy in these patients is controversial. Few women with node-negative, small tumours were included in the adjuvant trastuzumab trials. There are no robust data on trastuzumab in this patient subset, although subgroup analyses suggest that proportional benefits are independent of T and N. With current guidelines and scheduling, committing to adjuvant trastuzumab involves concurrent chemotherapy, 1 year of treatment and potential cardiotoxicity. A further challenge with anti-HER2 therapy is the potential benefit in patients with demonstrable HER2 positivity within a predominantly HER2-negative tumour. The decision for therapy requires a yes/no answer, but HER2 status derives from a continuum of gene copy number and protein expression. The diagnostic threshold is made more complex by heterogeneity of the HER2 status within a tumour. This review focuses on available data for HER2 positive pT1N0M0 disease and explores the significance of intratumoural HER2 heterogeneity. PMID- 20943604 TI - What can the molecular pathologist offer for optimal decision making? AB - As a consequence of new innovative therapies and therapeutic combinations, the treatment of advanced colorectal cancer is becoming increasingly complex. Validated molecular biomarkers could contribute to patient management, but until recently, none has been routinely used. With the recognition that activating mutations of the KRAS oncogene can predict resistance to anti-epidermal growth factor receptor agents, the clinical value of biomarkers in advanced colorectal cancer has been brought to the fore. Prognostic and predictive biomarkers that reflect the molecular and therapeutic complexities of advanced colorectal cancer may provide valuable information regarding likely clinical outcome and therapeutic response and thus may improve patient management and therapeutic agent selection. Such biomarkers are discussed herein. PMID- 20943605 TI - Chemotherapy: which drug and when? AB - The treatment of advanced colorectal cancer has become very complex due to: (i) the relative efficacy of therapy, which has turned a rapidly fatal cancer into a more indolent disease in the last 10 years; (ii) the availability of four active chemotherapeutic agents and three biologics; (iii) the efficacy of several lines of therapy; (iv) the rare, but real, chance of curing stage IV patients through the combined use of chemotherapy and surgery. This article will concentrate on chemotherapy (leaving out the biologics) and will review the determinants of how aggressive the initial approach should be, the key factors of our initial treatment choices, when an intense treatment is better than just waiting or using single-agent chemotherapy; which chemotherapy is best for first, second and subsequent lines of treatment. PMID- 20943606 TI - How to integrate molecular targeted agents in the continuum of care. AB - Molecular targeted agents have enriched the therapeutic options. The VEGF inhibitor Bevacizumab has no single agent activity. It was studied in several phase III chemotherapy trials. The best results were achieved when bevacizumab was combined with fluoropyrimidies (infusional 5-FU and capecitabine) alone or with IFL (bolus 5-FU), while randomized data for the infusional schedule FOLFIRI is missing and data on FOLFOX is negative. The EGF receptor antibodies cetuximab or panitumumab have single agent activity but are only active in k-ras wt tumors. In combination with FOLFIRI or FOLFOX they can improve RR, PFS and OS according to randomized trials. For the use of targeted agents clinicians have to determine the treatment strategy. If cure is the aim or a rapid relieve of tumor related symptoms in aggressive tumors is necessary regimens inducing a high RR such as FOLFOXIRI or FOLFOX / FOLFIRI plus an EGFR antibody are optimal. The treatment of patients with a slow tumor progression or a low tumor burden may start with 5-FU or capecitabine alone of in combination with bevacizumab. According to recently published data of the CRYSTAL study FOLFIRI plus cetuxcimab is also an options in k-ras wt tumors as this is the only regimen that prolongs survival statistically significant and clinically relevant. FOLFOX should not be combined with an EGFR antibody in k-ras mut tumors and combinations of EGFR and VEGF antibodies in combinations with chemotherapy should be avoided outside a clinical trial, as inferior outcomes have been observed. PMID- 20943607 TI - Multiple myeloma. AB - Multiple myeloma (MM) is the second most common hematological malignancy, with an incidence of 6/100,000 in Europe. Interactions between myeloma cells and the microenvironment are essential for MM cell survival. Better knowledge of disease biology has led to the introduction of novel agents for the management of myeloma patients. Patients with asymptomatic MM may remain stable for a long time without any therapy, and treatment is needed only in symptomatic disease. Patients who are eligible for high-dose therapy and autologous stem cell transplantation (ASCT) are usually treated with bortezomib- or immunomodulatory drug (IMiD)-based regimens as induction therapy pre-ASCT. In elderly patients, the combination of melphalan and prednisone with either thalidomide (MPT) or bortezomib (MPV) is considered as the standard of care in this setting. Novel agent-based therapies are used for the management of relapsed/refractory disease. However, previous therapies, age, comorbidities and drug safety have to be taken into consideration before deciding the appropriate therapy for patients with relapsed/refractory myeloma. Patients with renal impairment or with extended bone disease may be treated with bortezomib-based regimens, while patients with pre-existing peripheral neuropathy may be treated with lenalidomide-based combinations. Maintenance therapy with thalidomide can be administered post-ASCT; however, caution is needed due to thalidomide toxicity. PMID- 20943608 TI - Follicular lymphoma. AB - Follicular lymphoma is an indolent and usually incurable disease. It has been therefore traditionally approached either by watch and wait or with single-agent treatments. The purpose was to maintain a good quality of life for a prolonged time. More aggressive regimens, including polychemotherapy, high-dose chemotherapy with stem-cell rescue and the emergence of new cytotoxic drugs have significantly improved the remission duration but could never demonstrate an impact on overall survival. In the past decade, through the addition of drugs acting on the immune system such as interferon or rituximab, the survival of follicular lymphoma patients could be improved by the range of several years. As a consequence several clinicians believe that we are near to a cure for follicular lymphoma so that the first-line treatment should be more aggressive to reach this goal. Nevertheless, at present, none of the new strategies can be shown to cure. We believe that even in the presence of many possible treatment options, watch and wait remains a good option for many patients with follicular lymphoma. When treatment is needed, chemotherapy with rituximab is the standard even though none of the chemotherapy regimens can be shown to be superior. As quality of life remains an issue, the combination of rituximab and bendamustine, a drug with high efficacy and a favourable toxicity profile, is a good new option for patients. PMID- 20943609 TI - Chronic lymphocytic leukemia. AB - The management of chronic lymphocytic leukemia (CLL) is currently undergoing a profound change. First, several new drugs have been approved (fludarabine, bendamustine and two monoclonal antibodies, alemtuzumab and rituximab). In addition, novel monoclonal antibodies targeting CD20, CD23, CD37 or CD40, as well as drugs designed to interfere with central pathways regulating the cell cycle, the apoptotic machinery, or the leukemic microenvironment (flavopiridol, oblimersen, ABT-263 or lenalidomide) are being tested in clinical trials. Furthermore, improved protocols using reduced-intensity allogeneic progenitor cell transplantation makes it possible to offer this procedure to more patients with CLL. Finally, new prognostic markers that may influence therapeutic decisions have been identified. This review attempts to summarize the current knowledge in this rapidly moving field. PMID- 20943610 TI - Anemia in cancer. AB - Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), among others, play a major role in the pathophysiology of anemia in the cancer patient not only through complex mechanisms of the purely inflammatory situation but also through genetic regulatory aspects of erythropoiesis via GATA-1 and GATA-2, and other factors. In terms of therapy, iron is used more and more; the late side effects of transfusions are not really understood and the recent controversy regarding erythropoietin usage has resulted in regulatory authorities and scientific societies providing several recommendations and guidelines. These various aspects are addressed herein. PMID- 20943611 TI - Cardiotoxicity. AB - Cancer treatment has improved extraordinarily in recent years. The development of targeted therapies has widened the cardiotoxic spectrum of antineoplastic drugs. Optimum management of cardiovascular disease before and during antineoplastic treatment is essential to reduce morbidity and mortality in cancer patients. This article reviews the incidence and characteristics of cardiotoxic effects of antineoplastic drugs with special focus on the pathophysiological mechanisms. It also emphasizes the importance of early detection and correction of cardiovascular risk factors and the relevance of close cardiac monitoring during antineoplastic treatment in order to reduce cardiotoxicity. PMID- 20943612 TI - Prevention and treatment of side-effects of systemic treatment: bone loss. AB - Cancer treatment-induced bone loss (CTIBL) is generally more rapid and severe than bone loss associated with menopause in women or ageing in men and women. In premenopausal women with breast cancer, CTIBL is mainly caused by chemotherapy with resultant ovarian failure, by GnRH agonists or by tamoxifen. In postmenopausal women, steroidal and non-steroidal aromatase inhibitors (AIs) increase bone turnover, decrease bone mass and increase fracture rate (hazard ratio increased to 1.38-1.55 compared with tamoxifen). Zoledronic acid can prevent bone loss in premenopausal women receiving adjuvant therapy with goserelin in combination with either anastrozole or tamoxifen and in postmenopausal women receiving AIs. Denosumab has been shown in a placebo controlled study to significantly increase bone mineral density in postmenopausal women under AIs. More limited studies indicate that oral bisphosphonates used at licensed doses for the treatment of postmenopausal osteoporosis can also prevent AI-induced bone loss. In prostate cancer, bone loss that occurs with androgen deprivation therapy (ADT) also leads to an increased fracture rate. The bisphosphonates pamidronate and alendronate can prevent bone loss whereas zoledronic acid can increase bone mass under ADT. As for breast cancer, delay in bisphosphonate therapy is detrimental to bone health. The protective effects of denosumab on bone loss and incidental vertebral fractures have been demonstrated in a 3-year placebo-controlled trial. PMID- 20943613 TI - Early stage non-small-cell lung cancer: challenges in staging and adjuvant treatment: evidence-based staging. AB - Staging of non-small-cell lung cancer is a multidisciplinary process involving imaging, endoscopic and surgical techniques. Accuracy is vital in order to avoid false-positive interpretations leading to a false stage III or IV diagnosis in early stage patients, or false-negative findings leading to a false early stage diagnosis in patients with mediastinal lymph node disease. CT scan offers great anatomical detail of tumour spread, but radiological imaging lacks information on the biological nature of the lesions. The latter is brought in by 2-[fluorine-18] fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) scan as a metabolic imaging tool, which, however, has clearly lower spatial resolution. Therefore, contemporary staging relies on the combination of both, preferably in a fusion PET-CT scan. Absence of suspected lymph node metastasis on both CT and PET has a high negative predictive value, and these patients may in general proceed to surgery. In most others, tissue confirmation of the locoregional lymph node status is needed. The historical standard of mediastinoscopy is nowadays complemented by endoscopic techniques by the bronchial or esophageal approach. Each of these techniques remains important in modern staging algorithms. A practical scheme for rational staging in clinical practice is discussed. PMID- 20943614 TI - Adjuvant chemotherapy for resectable non-small-cell lung cancer: where is it going? AB - Following the 1995 meta-analysis on the role of postoperative chemotherapy in NSCLC, many randomized controlled trials (RCTs) have evaluated the effect of adjuvant cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC), adding substantially to the existing evidence. The LACE pooled analysis included a total of 4584 patients accrued in five recent cisplatin-based adjuvant trials. It confirmed the benefit of adjuvant chemotherapy (P = 0.0043). In addition, it showed that adjuvant cisplatin-based chemotherapy is detrimental in stage IA resected NSCLC; it also indicated that the combination of vinorelbine and cisplatin offered a higher benefit compared with older doublets or triplets. The individual-databased meta-analysis was also updated with a total of >10,000 patients. It confirmed the significant effect of postoperative chemotherapy, with or without postoperative radiotherapy, with an overall significant benefit of 4% at 5 years. The recent results of biological programmes indicate that the expression of some tumour markers including ERCC1 be evaluated in order to determine which patients are more likely to benefit from chemotherapy. If these results are confirmed, tailored therapy might be the next progress for resected NSCLC. PMID- 20943615 TI - Do we have markers to select patients for adjuvant therapies of non-small-cell lung cancer? AB - Adjuvant platinum-based chemotherapy represents the standard of care in fit stage II and IIIA non-small-cell lung cancer patients after surgical resection. This review discusses current knowledge on molecular prognostic and predictive tumor features for benefit from adjuvant therapies with emphasis on ongoing clinical trials that prospectively assess the biomarker utility. Until the results of these trials are available, use of these markers is not recommended in routine clinical care. PMID- 20943616 TI - Proteomics as a guiding tool for more effective personalized therapy. AB - Ovarian cancer remains the deadliest gynecological malignancy in the Western world and is most often diagnosed at a rarely curable late stage. Examination of protein end points has been employed as an investigative mechanism to guide targeted therapy and to stratify ovarian cancer. Proteomics allows characterization of the proteins and the associated protein and peptide modifications. This has given us insight into the perturbations of signaling pathways within tumor cells and has improved the discovery of new drug targets and possible prognostic indicators of outcome and disease response to therapy. Development of validated assays that survey the genetic and/or proteomic make-up of an individual tumor will add greatly to the histological classification of the tumor and may lead to different treatment approaches tailored to the unique expression pattern of each individual patient. It is anticipated that application of proteomics may bring to reality the clinical adoption of molecular stratification, e.g. not, 'is the gene overexpressed?', but 'is the pathway upregulated?' This will be successful if validated peptide biomarkers are applied for patient selection prospectively and with inclusion of preplanned biological correlates. These events will guide future directions of proteomics as a selector and as a validator and will guide how we integrate proteomics information daily into patient care and into selecting therapy of advanced and recurrent ovarian cancer and other cancers. PMID- 20943617 TI - The addition of new drugs to standard therapy in the first-line treatment of ovarian cancer. AB - Advanced-stage epithelial ovarian cancer is generally managed with cytoreductive surgery and chemotherapy consisting of carboplatin and paclitaxel, achieving clinical complete remission in the majority of patients. However, most tumors recur, and are associated with progressive chemotherapy resistance. Techniques to optimize chemotherapy have included intraperitoneal administration and weekly scheduling of paclitaxel. Efforts to improve on the long-term results of primary therapy through addition of a third cytotoxic agent have not been successful, including extended maintenance, as well as strategies to overcome chemotherapy resistance. Limited data emerging from phase III trials using bevacizumab suggest some advantage in progression-free survival, particularly in the maintenance setting, and further data are awaited. At present, primary therapy with carboplatin and paclitaxel remains a well-tolerated standard regimen, including the option of weekly paclitaxel dosing, intraperitoneal delivery and neoadjuvant therapy in selected patients. Emerging biological paradigms will hopefully contribute to individualized treatment options in the future. PMID- 20943618 TI - Optimal treatment for relapsing ovarian cancer. AB - The cure rate for women with ovarian cancer has not significantly changed over the past 10 years. However, overall survival from relapsed disease has shown improvement despite a lack of increase in progression-free survival. There are now many therapeutic options for women with relapsed disease. Treatment strategies are still led by the description of relapse as platinum sensitive or resistant/refractory using somewhat arbitrary definitions. Now that there is increased choice of treatment, these definitions are becoming outdated. The current challenges in managing relapsed ovarian cancer are defining the optimal sequence of available drugs as well as timing of treatment for relapsed disease. The abundance of novel therapeutics and molecular targets has compounded the difficulty in identifying best practice but has undoubtedly provided an opportunity to improve the treatment we can offer our patients. The lack of validated biomarkers to inform patient selection remains an area of real need in ovarian cancer. Efforts should be made to increase the use of biomarkers in trial design to aid rational targeting of new therapies. In this review we discuss current practice in the treatment of relapsed ovarian cancer and highlight the most promising emerging therapeutics and strategies being employed in randomized clinical trials. PMID- 20943619 TI - Should we continue to use the term non-small-cell lung cancer? AB - Until recently the major clinical question was 'Is it small-cell or non small cell cancer'. However, advances in conventional and targeted therapy have completely changed the landscape. Identification of the major non-small-cell lung cancer (NSCLC) types (adenocarcinoma and squamous carcinoma) are important for a number of predictive and prognostic reasons, including pemetrexed treatment, anti angiogenic therapy and administration of tyrosine kinase inhibitors. Fortunately, advances in pathology of lung cancer have kept abreast, with newer, simplified methods to identify the major NSCLC types in small diagnostic samples, and modifications of the pathological classification of adenocarcinomas reflecting changing clinical and molecular concepts. For the patient to obtain maximum benefit from the recent developments in therapeutics, a multidisciplinary approach is required with co-operation between oncologists, surgeons, radiologists and pathologists. PMID- 20943620 TI - How to integrate current knowledge in selecting patients for first line in NSCLC? AB - Non-small-cell lung cancer (NSCLC) accounts for 80% of all lung cancer, which is the leading cause of cancer mortality. The majority of NSCLC patients present with advanced disease at diagnosis. Standard chemotherapy using platinum containing doublets has reached a therapeutic plateau with a median survival of ~1 year. The development of more effective strategies in the first-line setting remains challenging. In selected chemotherapy-naive, advanced, non-squamous patients, the combination of bevacizumab with chemotherapy was shown to produce better outcomes than chemotherapy alone. The potential benefit of maintenance/sequential treatment after initial platinum-based chemotherapy should be discussed in detail with each patient. Epidermal growth factor receptor (EGFR) mutation determination should be carried out in subgroups of patients characterized by a high prevalence of sensitizing mutations. When a mutation is present, first-line treatment with an EGFR tyrosine kinase inhibitor may be considered. Finally, a phase I study using an oral ALK inhibitor has produced promising results in NSCLC patients with ALK rearrangements, indicating that ALK represents a new therapeutic target in a molecularly defined subset of NSCLC. Ongoing studies in first-line therapy are focusing on targeted therapies and patient selection. PMID- 20943621 TI - Consequences of targeted treatments for second-line therapy. AB - The paradigm for first-line treatment of relapsed or metastatic non-small cell lung cancer (NSCLC) is changing. Large phase III trials demonstrated that, in 2010, we cannot select a therapy without an accurate definition of tumor histology and epidermal growth factor receptor (EGFR) status. Patients harboring an EGFR-activating mutation have a better prognosis and certainly are extremely sensitive to EGFR-tyrosine kinase inhibitors, while other agents, such as bevacizumab or pemetrexed, are more effective and less toxic in patients with non squamous histology. Moreover, data from large phase III trials demonstrated that maintenance therapy with pemetrexed, docetaxel or erlotinib is an effective strategy against metastatic NSCLC. Overall, the changing paradigm in first-line treatment of NSCLC inevitably is changing the second-line strategy. In addition, the emerging role of maintenance therapy is leading to early use of all agents potentially active in a second- or third-line setting, with the consequence that very few options are available at disease progression. The aim of this article is to discuss the consequences of targeted treatments for second-line therapy in metastatic NSCLC. PMID- 20943622 TI - The role of human papillomavirus infection in head and neck cancers. AB - The link between head and neck squamous cell cancer (HNSCC), especially oropharyngeal cancer, and HPV has become established. HPV16 is the most common genotype in these tumours but HPV6 and HPV11 can also be found in a minority of these cancers, implying that these low-risk HPV types are not entirely benign in the head and neck region. HPV status is also associated with p16 expression and HPV+ tumours are less likely to harbour p53 mutations. HPV DNA is closely associated with poorly differentiated cancers, positive lymph nodes and late stage disease, which all indicate poor prognosis. Contradictory to this, patients with HPV+ HNSCC seem to have significantly improved response to chemotherapy and radiotherapy as compared with HPV-negative tumours. Interestingly, the risk factors of HNSCC are the same as for HPV, including the number of sexual partners, younger age at first sexual intercourse, practice of oral sex, history of genital warts and younger age. PMID- 20943623 TI - Integrating systemic agents into multimodality treatment of locally advanced head and neck cancer. AB - Although highly debated in the 1980s, randomized clinical trials have provided undeniable evidence that systemic chemotherapy, as part of a multimodality treatment collaboration, is effective in improving survival, organ preservation and local-regional control in locally advanced head and neck cancer (HNC). We are entering an exciting period in which new chemotherapy agents, new paradigms of treatment, new surgical and radiation technology, and new prognostic factors are rapidly becoming available. Information on how to integrate these new tools and on how they affect long-term outcomes are lacking, making decision making and treatment planning more difficult. With unprecedented survival and the changing demographics of HNC we must now consider long-term consequences in addition to survival and local and regional control as important factors in therapeutic decision making. The availability of different treatment plans that incorporate systemic chemotherapy, radiotherapy and surgery give us many tools with which to craft a treatment for each individual patient. Today, in this exciting and chaotic period, a multidisciplinary and collaborative approach for each HNC patient at the start of decision making and planning is a necessity and the absolute standard of medical treatment for excellent patient care. PMID- 20943624 TI - Optimal treatment for recurrent/metastatic head and neck cancer. AB - While a large proportion of patients presenting with stage I and II squamous cell carcinoma of the head and neck (SCCHN) will remain disease free after single modality treatment, the majority of patients presenting in a more advanced disease stage and very often treated with a form of combined modality treatment, will eventually relapse, either locoregionally only, at distant sites only or both. A few patients with a locoregional recurrence can be salvaged by surgery or reirradiation. However, most patients with recurrent or metastatic (R/M) disease only qualify for palliative treatment. Treatment options in these patients include supportive care only, or in addition single agent chemotherapy, combination chemotherapy or targeted therapies either alone or in combination with cytotoxic agents. Prognostic factors analysis in such patients treated with (platinum-based) chemotherapy has identified five adverse prognostic factors, which seems worthwhile to take into consideration when performing trials; one pathologic feature (tumor cell differentiation) and four clinical baseline characteristics (ECOG performance status, weight loss, location of the primary tumor and prior radiotherapy). Moreover, it has been shown that response to systemic therapy has a major impact on survival. None of the trials performed in the past, even those with a reasonable sample size, have shown that aggressive platinum-based combination chemotherapy leads to survival benefit when compared to single agent methotrexate, cisplatin or 5-fluorouracil. After decades without real progress, a recent European randomized trial showed that adding cetuximab, the first clinically available EGFR-directed monoclonal antibody, to a standard chemotherapy regimen (platinum/5-fluorouracil) leads to an important survival benefit and this, with support of an additional smaller study in the US, has changed practice. PMID- 20943625 TI - Soft tissue sarcoma: from molecular diagnosis to selection of treatment. Pathological diagnosis of soft tissue sarcoma amid molecular biology and targeted therapies. AB - During the past few years, differential diagnosis of soft tissue tumours has improved due to novel molecular diagnostic tools. Besides a better differentiation between different tumour entities the recognition of specific molecular aberrations may also help to identify novel therapeutic targets. One of the most promising examples of effective molecularly driven treatment is the gastrointestinal stromal tumour. Shortly after the detection of gain-of-function mutations in the type III receptor tyrosine kinases KIT and PDGFRalpha a targeted treatment with the tyrosine kinase inhibitor imatinib was introduced and became the gold standard in advanced GIST disease. The success of this therapy with response rates of >80% stable disease and partial remission is still unmatched. Since then, many groups aim to identify other potential molecular targets. Genomic and proteomic signatures may pinpoint potential areas of interest for diagnostic tools, prediction of clinical outcome and potential response to therapeutic targets. This article gives an overview of the most important genomic aberrations in sarcomas, their differential diagnosis and the relevance of molecular biology for treatment strategies. PMID- 20943626 TI - What can the pathologist offer for optimal treatment choice? AB - The choice of the most appropriate systemic treatment of patients with metastatic breast carcinoma is a multifaceted decision-making process. The role for the pathologist is to provide a definite diagnosis of metastatic breast carcinoma, whenever needed, and especially to assess the biological parameters with prognostic and predictive value. Although the vast majority of breast carcinomas maintain the same biological features both in the primary and in the metastases, some undergo changes that may indicate that a targeted systemic treatment should be stopped or started, be it endocrine or anti-HER2. Unfortunately these tumours cannot be easily identified clinically, and it may be useful to biopsy the metastatic sites for reassessment of the biological characteristic of the tumours. Intra-tumoural heterogeneity and clonal selection due to the therapy could explain changes in biological features during tumour progression, but it should also be taken into account that the available assays for evaluating hormone receptor and HER2 status are not 100% accurate, even in the hands of expert pathologists. To minimize the risk of inducing inappropriate changes in systemic treatments due to false-positive or false-negative results, the pathologists should make all efforts to improve accuracy and reproducibility of the assay procedures. PMID- 20943627 TI - Histology-driven chemotherapy of soft-tissue sarcoma. AB - Soft-tissue sarcomas are rare diseases with >50 subtypes. Surgery is the most important treatment in localized disease, sometimes combined with radiotherapy. Chemotherapy is used as palliation in advanced disease, sometimes also with a potential to decrease tumour size and eradicate micro-metastases, making meaningful surgery possible. The role of chemotherapy as adjuvant treatment in localized disease is not finally settled. Doxorubicin and ifosfamide are the two drugs with the best established response rates in soft-tissue sarcoma, and a combination of these drugs has been a 'gold standard' for several years. However, there is an emerging knowledge of the biology and sensitivity to treatment for different histological subtypes. New drugs such as gemcitabine, taxanes and trabectedin have been explored in several studies, showing promising results. Even if most studies have encompassed many different subtypes and were limited in size, knowledge related to specific treatment for different subtypes is emerging. Examples are trabectedin in lyposarcoma and leiomyosarcoma, and taxanes in angiosarcoma. PMID- 20943628 TI - Targeted therapies in soft tissue sarcomas. AB - Soft tissue sarcomas are rare cancers but because of their association with characteristic chromosomal translocations and activating mutations they may be particularly susceptible to molecularly targeted therapies. Gastrointestinal stromal tumour (GIST) became the paradigm for targeted therapy in solid tumours owing to the success of imatinib, which has transformed the prognosis in this disease. Translocation-driven tumours have proved harder to target, but the impact of fusion proteins on gene expression is beginning to be understood and may also reveal new targets for therapy, such as insulin-like growth factor 1 receptor, now that effective inhibitors have been discovered. Angiogenesis inhibition also appears to be a promising area for research in sarcomas and many new targets are emerging at the same time as agents capable of investigating them in the clinic are being developed. It is not unrealistic to hope that targeted therapies will play an increasing role in the management of sarcomas in the near future. PMID- 20943629 TI - Is there any role for surgery in the multidisciplinary treatment of esophageal cancer? AB - Due to the poor prognosis of patients after unimodal therapy like surgical resection or radiotherapy multidisciplinary treatment is regarded as standard of care in localized esophageal cancer. Within the last decade phase III trials investigating the curative potential of radiochemotherapy alone have challenged surgery to be an indispensible part of curative therapy. Nevertheless, surgical resection does play an important role in the multidisciplinary treatment. But its role is limited to subgroups of patients with a distinct clinical situation. Today it appears that particularly patients with adenocarcinomas of the lower esophagus and esophagogastric junction and those patients with squamous cell carcinomas not responding to induction chemo- or radiochemotherapy benefit from surgery. Patient selection according to their individual operative risk is most important to guide multidisciplinary therapy. Early molecular or diagnostic markers to predict response to chemo- or radiotherapy and also recurrence despite complete surgical resection are urgently needed. PMID- 20943630 TI - Multimodality treatment for localized gastro-oesophageal cancer. AB - Surgery alone remains an international standard of care for early stage (Ia) oesophagogastric cancers. There is also international consensus that multimodality therapy is appropriate for more advanced stage operable disease, however there is marked geographical variation in standard practice. For gastric adenocarcinomas, adjuvant oral fluoropyrimidines became the standard of care in Japan after improved survival was demonstrated following resection with D2 nodal dissection, compared to surgery alone. Adjuvant chemoradiation improves survival following surgery with any level of nodal dissection compared to observation and is the accepted standard of care in the US. Similarly, perioperative triplet chemotherapy improves survival compared to surgery alone in gastroesophageal adenocarcinomas and is widely used across Europe and Australasia. For oesophageal adenocarcinoma, neo-adjuvant chemotherapy and neo-adjuvant chemoradiation are further accepted standards, widely utilized in the UK and US respectively, with similar survival benefits reported for each strategy. Patients with localized squamous cell carcinomas of the oesophagus benefit from chemoradiation, which may be delivered as a neo-adjuvant or definitive strategy, the latter avoiding surgical morbidity and mortality. Targeted agents are currently under evaluation in localized oesophagogastric cancer, with translational sub-studies attempting to define which patients may benefit from the addition of these high cost drugs. PMID- 20943631 TI - New trends for staging and therapy for localized gastroesophageal cancer: the role of PET. AB - Treatment options for localized gastroesophageal cancers reach from limited resection to multimodality treatment. Accurate clinical assessment, prognostic and predictive information are needed to select the most appropriate treatment approach. Positron emission tomography (PET) in combination with computed tomography (CT) in a hybrid imaging modality PET-CT may refine the staging accuracy and add prognostic information. Moreover, experiences from diverse centers indicate that PET also might improve significantly the assessment of response to preoperative chemotherapy and chemoradiotherapy. This article outlines the current value of PET in the staging and multidisciplinary care of gastroesophageal cancer. At this stage, it remains unclear whether the prognosis of patients can be improved by implementing PET in the management of localized disease. Prospective multicenter studies have to be carried out to validate metabolic cut-off values and to prove the benefit of PET-guided treatment decisions. PMID- 20943633 TI - Cancer of unknown primary site: 20 questions to be answered. AB - Cancer of unknown primary (CUP) is a common, well-recognized and heterogeneous clinical syndrome. Patients with CUP present with metastatic disease in the absence of an identifiable primary tumour despite a diagnostic work-up. Aetiologically, CUP might either harbor primaries that cannot be detected by the standardized diagnostic investigations or carry distinct genetic and epigenetic aberrations. In this article we try to clarify the clinical and pathological enigma of CUP by answering 20 important questions related to this entity. PMID- 20943632 TI - Treatment of triple-negative metastatic breast cancer: toward individualized targeted treatments or chemosensitization? AB - Triple-negative [estrogen receptor (ER)-/progesterone receptor (PR)-/HER2-] breast cancers account for ~15% of overall breast cancers. Triple-negative breast cancers demonstrate a panel of specific molecular alterations including a high rate of p53 mutations, frequent loss of function of BRCA1, phosphatase and tensin homolog (PTEN) loss and a specific panel of tyrosine kinase activation [fibroblast growth factor receptor 2 (FGFR2)]. This molecular entity is considered as sensitive to chemotherapy in the adjuvant setting. When metastatic, the disease is usually aggressive and drug resistant, leading to cancer death within 18 months for the majority of patients. There is no evidence from randomized trials that triple-negative breast cancers have a different sensitivity to specific chemotherapy compared with other molecular classes. Similar findings have been reported for bevacizumab. Several recent research efforts have focused on this entity in the last few years. DNA alkylating agents have shown promising activity in the neoadjuvant setting, but no evidence from a phase III trial currently supports its use. Several targeted therapies are also being successfully developed. Poly(ADP ribose) polymerase 1 (PARP1) inhibitors induce tumor response as a single agent in BRCA1-mutated breast cancer, and could sensitize cisplatin in the whole triple negative population. Several other targeted agents are being developed in this setting, including epidermal growth factor receptor (EGFR), FGFR2, mammalian target of rapamycin (mTOR) and NOTCH inhibitors. PMID- 20943634 TI - Nasopharyngeal carcinoma. AB - With the improvement in local control achieved by more precise imaging and radiotherapy, the predominant mode of failure for nasopharyngeal carcinoma is distant metastases. Concurrent cisplatin-radiotherapy with or without adjuvant chemotherapy is the standard treatment approach for stages IIB and above disease. The addition of neoadjuvant chemotherapy has been most promising, and phase III trial results are awaited. Quantitative Epstein-Barr virus (EBV) DNA can be applied clinically for disease monitoring and follow-up, and may in future be used for risk stratification strategies. Targeted therapies against epidermal growth factor receptor and angiogenesis have demonstrated activity, and immunotherapeutic approaches are being investigated. PMID- 20943636 TI - Osteosarcoma. AB - The successful treatment of patients with osteosarcoma requires close cooperation within an experienced multidisciplinary team including pediatric or medical oncologists, surgeons, pathologists and radiologists. Therefore, therapy should be performed in specialized centers able to provide access to the full spectrum of care. As in other rare malignancies, treatment should be administered within prospective multicenter trials. Therapy must include complete surgical removal of all detectable tumor sites as well as multiagent chemotherapy. The chemotherapy regimen should include several or all of the following four drugs: doxorubicin, high-dose methotrexate with leukovorin-rescue, cisplatin and ifosfamide. Preoperative (neoadjuvant) plus postoperative (adjuvant) polychemotherapy should be preferred, because it allows preparation for safe surgery and preparation of the appropriate prosthesis for the individual patient. The choice of the postponed definitive surgical procedure should be influenced by the anatomical site of the primary tumor, its relationship to neighboring structures, such as vessels and nerves, age and growth potential of the patient, and probably also by the response of the tumor to preoperative chemotherapy. A major, as yet unsolved, problem is the dismal prognosis for patients with unresectable or relapsed osteosarcomas. Novel approaches are needed in order to improve their prognosis. PMID- 20943635 TI - Multiple myeloma. AB - Multiple myeloma (MM) constitutes 1% of malignant diseases and 15% of haematological malignancies. In virtually all patients MM is preceded by monoclonal gammopathy of undetermined significance (MGUS). The cause of monoclonal gammopathies and the mechanisms of progression are unknown. The diagnosis of MM requires the presence of an M-protein in serum and/or urine, increased bone marrow plasma cells and related organ or tissue impairment. Cytogenetic status, serum beta2-microglobulin and response to therapy are the key prognostic factors. The treatment of younger patients with MM should include a triple-agent induction regimen (i.e. bortezomib/thalidomide/dexamethasone), autologous stem cell transplantation (ASCT) and consolidation and maintenance incorporating novel agents along with sequential minimal residual disease studies to determine for how long treatment is still of benefit. Allogeneic transplantation with reduced-intensity conditioning is promising but remains experimental. For patients not eligible for ASCT the best initial regimens are melphalan/prednisone/thalidomide (MPT), melphalan/prednisone/bortezomib (MPV) and lenalidomide/dexamethasone. In relapsing patients, the choice of salvage therapy should depend on: (i) the components of initial therapy, (ii) the degree and duration of response, (iii) type of relapse: aggressive versus indolent, (iv) previous toxicities and (v) age and performance status. A sequential approach is preferred over combination of multiple agents. Supportive measures include the use of bisphosphonates and erythropoietin according to the updated guidelines. PMID- 20943637 TI - Mesothelioma. PMID- 20943638 TI - Genetic counselling for hereditary predisposition to ovarian and breast cancer. AB - Since the identification of BRCA 1 and 2 in 1995, testing for mutations in these genes has been offered to cancer patients and their families by clinical genetics services. These services are provided across Europe by a small number of health professionals, and are therefore low volume, and low capacity and patients experience considerable delays, both in seeing a clinician and in laboratory testing. The UK private sector, driven by consumer demand and professional competition, has significantly reduced these delays. The development of a new class of therapeutic agent, the PARP inhibitors, is likely to drive the BRCA testing services towards the UK private sector model with much faster turnaround times. Several new genetic tests are now available including CYP 2D6 genotype analysis and the BCtect test. The clinical interpretation of these tests is complex, and the professional community has been naturally cautious about adopting new tests in clinical care. This article will examine the consequences of expected changes in BRCA testing practice, and consider the positioning of new tests in the patient pathway, and the messages given by health professionals. PMID- 20943639 TI - Advances in systemic treatment of melanoma. AB - After decades of phase III trials failing to demonstrate an impact on survival of various drugs in metastatic melanoma there are finally significant advances in systemic therapies for melanoma emerging. Novel ways to modulate the immune system by monoclonal antibodies as well as various signalling pathway inhibitors are responsible for creating a whole new therapeutic landscape. For the first time it is likely that a number of new drugs with completely different mechanisms of action will be approved in the near future. The imminent candidates are the anti-CTLA-4 antibody ipilimumab, and the highly selective BRAF inhibitor PLX4032. But in each class other molecules are under development with good perspectives. Various new combinations will have to be explored and it is reasonable to expect synergies between the different classes of drugs as well as between novel molecules within the same class of drugs. Here, an overview of current developments and the most important new drugs under consideration is provided. PMID- 20943640 TI - Advances in the treatment of metastatic or unresectable biliary tract cancer. AB - The prognosis for advanced/inoperable biliary tract cancer is poor and the management of biliary obstruction and sepsis remains the cornerstone of best supportive care (BSC). Many phase II studies have reported some activity of chemotherapy, usually involving one or more of a fluoropyrimidine, a platinum agent and gemcitabine. No adequately powered study has shown conclusively a benefit for chemotherapy compared with BSC alone although three small randomized studies have suggested an improved survival. Results from the randomized phase III ABC-02 study demonstrated a survival advantage of cisplatin and gemcitabine doublet-chemotherapy over gemcitabine monotherapy {median survival of 11.7 compared with 8.1 months, hazard ratio (HR), 0.64 [95% confidence interval (CI) 0.52 to 0.80]; log rank P < 0.001} as well as a significantly longer progression free survival [median 8 compared with 5 months; HR 0.63 (95% CI 0.51 to 0.77); log rank P < 0.001]. A similar magnitude of benefit was seen in Japanese patients in a second study using the same treatment regimens (the BT-22 study). Ongoing studies are underway evaluating other chemotherapy regimens in first-line although attention is turning to the addition of targeted therapies; these will be reviewed. Pivotal to success in this process is both the identification of appropriate targets across this heterogeneous group of malignancies (e.g. EGFR, VEGF, MEK inhibition, amongst others) and collaboration between investigators to deliver relevant, timely and adequately powered studies. PMID- 20943641 TI - Treatment of HER2-overexpressing breast cancer. AB - The HER family of receptors consists of four closely related type 1 transmembrane TK receptors: HER1 (EGFR), HER2, HER3 and HER4. Signalling via the HER family of receptors underpins the majority of the intricate array of cellular activities on which cell survival and functionality depend. Aberrant HER2 expression and/or functionality have been implicated in the evolution of breast cancer and this receptor has proved to be a potent target for anticancer therapies, including antibody-based therapies to prevent ligand binding, dimer formation or the recruitment of antibody-dependent cell-mediated cytotoxicity, and direct kinase inhibition to prevent molecular activation and recruitment of downstream signalling partners. Novel strategies against HER2 include HER tyrosine kinase inhibitors, HSP90 inhibitors and antibody-chemotherapy conjugates. This latter approach is exemplified by T-DM1, a potent antibody that has a good safety profile and that has shown remarkable activity in patients with advanced disease. In addition, pertuzumab, an mAb that directly inhibits the formation of HER2 dimers including the HER2:HER3 dimer, offers a unique mechanism of HER3 inhibition. All these approaches have shown substantial clinical activity in patients refractory to trastuzumab. It is anticipated that with the increased availability of novel anti-HER2 agents together with a better understanding of the mechanisms of resistance to anti-HER2 agents we should be able to further improve the outcome of patients with HER2 breast cancer. There will also be an increasing tendency towards moving the study of these agents to earlier stages of the disease, namely in the adjuvant and neoadjuvant setting. PMID- 20943642 TI - Horizon scanning for novel therapeutics for the treatment of prostate cancer. AB - Treatment options for patients with advanced prostate cancer (PCa) remain limited. Improved understanding of the underlying molecular drivers of PCa pathogenesis, progression and resistance development has provided the fundamental basis for rational targeted drug design. Key findings in recent years include the identification of ETS gene rearrangements, the dissection of PCa molecular heterogeneity and the discovery that castration-resistant prostate cancer (CRPC) remains androgen driven despite the androgen-depleted milieu, thus making androgen receptor (AR) signaling a continued focus of molecularly targeted treatments. AR ligand-independent activation of tyrosine kinase prosurvival signaling cascades and angiogenesis have also been implicated in disease progression. A multitude of new molecularly targeted agents that abrogate AR signaling, inhibit the mitogenic and prosurvival signal transduction pathways, perturb the tumor-bone microenvironment, impair tumor vasculature, facilitate immune modulation and induce apoptosis are in clinical development and are highly likely to change the current treatment paradigm. It is clear that the success of these molecular targeted therapies hinges in part on optimal patient selection based on the molecular disease profile and an improved understanding of the mechanistic basis of acquired resistance. This review outlines the current clinical development of molecular targeted treatments in CRPC, with particular emphasis on agents that are in the later stages of clinical development, and details the challenges and future direction of developing these antitumor agents. PMID- 20943643 TI - New agents for bladder cancer. AB - Muscle-invasive bladder cancer is an aggressive disease with at least 50% of patients dying from metastases within 2 years of diagnosis. The 5-year survival rate for metastatic bladder cancer is <15%. Although modern combination chemotherapy regimens have improved median survival from 6 to 14 months compared with best supportive care, there is still a great opportunity for improvement. New therapies and strategies for better patient and treatment selection are now being investigated for advanced bladder cancer. These include agents that target several pathways involved in the pathogenesis of the disease--such as growth factor receptors, angiogenic pathways, p53, cell cycle checkpoints and apoptosis- as well as novel chemotherapeutic agents. Results from recent and ongoing trials suggest that some of these agents could soon emerge as useful players to overcome the limitations of our present therapies. PMID- 20943644 TI - How to select targeted therapy in renal cell cancer. AB - Treatment of renal cell carcinoma has dramatically changed in the past 5 years, with the approval of six new drugs since 2006. Although treatment algorithms have been reported and updated every year since 2006, the choice of targeted therapy is not always easy. Selecting a targeted agent in metastatic renal cell carcinoma should take into account various parameters, including the status of the disease, the histology, the status of the patient and finally the availability of the drugs in each country. In addition, in front of every patient, the physician will need to raise important questions such as whether the patient should be treated, should receive surgery and also what is his prognosis. The different options are described here. PMID- 20943645 TI - Advances in neuroendocrine lung tumors. AB - Pulmonary neuroendocrine (NE) tumors include a spectrum of tumors from the low grade typical carcinoid (TC) and intermediate-grade atypical carcinoid (AC) to the high-grade large-cell neuroendocrine carcinoma (LCNEC) and small-cell carcinoma (SCLC). Nodular NE proliferations >= 0.5 cm are classified as carcinoid tumors and smaller ones are called tumorlets. When NE cell hyperplasia and tumorlets are extensive they represent the rare preinvasive lesion for carcinoids known as diffuse idiopathic pulmonary NE cell hyperplasia. Carcinoid tumors have significant clinical, epidemiologic and genetic differences from the high-grade SCLC and LCNEC. Multiple endocrine neoplasia type I can be found in TC and AC patients but not those with LCNEC and SCLC. Also both LCNEC and SCLC can demonstrate histologic heterogeneity with other major histologic types of lung carcinoma such as adenocarcinoma or squamous cell carcinoma, but is not characteristic of TC or AC. Genetic changes are very high in SCLC and LCNEC, but usually low for TC, intermediate for AC. The diagnosis of SCLC, TC and AC can be made by light microscopy without the need for special tests in most cases, but for LCNEC it is required to demonstrate NE differentiation by immunohistochemistry or electron microscopy. PMID- 20943646 TI - Gastrointestinal neuroendocrine tumors. AB - Gastrointestinal neuroendocrine tumors (GI-NETs) are a genetically diverse group of malignancies that sometimes produce peptides causing characteristic hormonal syndromes. NETs can be clinically symptomatic (functioning) or silent (non functioning); both types frequently synthesize more than one peptide, although often these are not associated with specific syndromes. Based on data from various sources the incidence and prevalence of GI-NETs is increasing. Surgery is the only possible curative approach and so represents the traditional first-line therapy. However, as most patients with NETs are diagnosed once metastases have occurred, curative surgery is generally not possible. Patients therefore require medical management with the aim of relieving symptoms and suppressing tumor growth and spread. Somatostatin analogues can improve the symptoms of carcinoid syndrome and stabilize tumor growth (PROMID study) in many patients. An antiproliferative effect can also be achieved with the m-TOR inhibitor everolimus, alone or in combination with octreotide LAR. The vascular endothelial growth factor inhibitor sunitinib has demonstrated antitumor effects in pancreatic NETs. Pasireotide, the multi-receptor targeted somatostatin analogue, has the potential to be an effective therapy for de novo or octreotide-refractory carcinoid syndrome. Peptide receptor radiotherapy with yttrium 90-DOTATOC or lutetium 177-DOTATE are also new interesting treatment options for NETs. PMID- 20943647 TI - Merkel cell carcinoma. AB - Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin. The incidence of this rare tumor is increasing rapidly; the American Cancer Society estimates for 2008 almost 1500 new cases in the USA. Thus, the incidence of MCC will exceed the incidence of cutaneous T-cell lymphoma. Moreover, the mortality rate of MCC at 33% is considerably higher than that of cutaneous melanoma. These clinical observations are especially disturbing as we are only recently beginning to understand the pathogenesis of MCC. For the same reason, the therapeutic approach is often unclear; reliable data are only available for the therapy of locoregional disease. PMID- 20943648 TI - The epithelial-mesenchymal transition (EMT) phenomenon. AB - The epithelial-mesenchymal transition (EMT) describes a rapid and often reversible modulation of phenotype by epithelial cells. EMT was originally defined in the context of developmental stages, including heart morphogenesis, mesoderm and neural crest formation. Epithelial cells loosen cell-cell adhesion structures throughout EMT. They modulate their polarity, cytoskeleton organization and typically express vimentin filaments and downregulate cytokeratins. They become isolated, mobile and resistant to anoikis. The EMT at least superficially resembles the evolution from normal to transformed cell phenotype during carcinoma progression. The relevance of the concept of EMT in this context was indicated by in vitro models using transformed epithelial cells. Transduction pathways typical of embryogenic EMT in vivo were also found to be activated during cancer progression. More recently, it has been found that such pathways indicate an increased plasticity linked to cellular stemness and ability to generate tumors. However, in the absence of direct evidence, a number of oncologists and pathologists remain skeptical about applying the EMT concept to human tumor progression. Typically in the cancer field, EMT concept appears to be fully relevant in some situations, but the concept has to be adjusted in other situations to reflect tumor cell renewal and plasticity during carcinoma progression and metastasis. PMID- 20943649 TI - Cancer stem cells. PMID- 20943650 TI - Circulating cancer cells. AB - Circulating tumour cells (CTCs) can be detected in the blood of many patients with different types of early or advanced cancer using antibody-based assays or molecular methods. In many studies the detection and quantification of CTCs has been linked to unfavourable prognosis. CTC detection offers the opportunity for individualized risk assessment beyond that determined by TNM staging. However, discordant results have been reported when different methodologies for CTC detection were used. Therefore, well-standardized detection methods cross validated between different laboratories are still needed. CTCs are a heterogeneous population of cells with biological characteristics often different from those of their respective primary tumour cells. Pilot studies have shown that phenotyping of CTCs could be used to predict response to targeted therapies. In the era of biological therapeutics, CTC characterization at different time points during the course of disease may provide useful predictive information for the selection of the most appropriate treatment. Therefore, in the future, CTC detection and characterization might become a valuable tool to refine prognosis and serve as a real-time tumour biopsy for individually tailored cancer therapy. Prospective randomized studies are warranted to evaluate the utility of assessing and monitoring CTCs and modifying accordingly treatment strategies in order to improve the clinical outcome of cancer patients. PMID- 20943651 TI - Green spruce aphid infestations cause larger growth reductions to Sitka spruce under shade. AB - Light availability and infestation by the green spruce aphid (Elatobium abietinum) are key factors affecting the growth of Sitka spruce (Picea sitchensis) seedlings under a mature tree canopy, but their combined effect on seedling growth has not previously been quantified. A controlled outdoor experiment in which light levels (high light (HL): 100%, intermediate light (IL): 24%) and aphid infestation (absence/presence) were manipulated was conducted over 2 years to look at the effects on seedling growth and biomass distribution patterns. Aphid population assessments showed a significantly increased population density under IL, with three to four times higher cumulative aphid densities than that under HL. Defoliation rates of infested seedlings were directly related to aphid density. Total seedling biomass was strongly reduced in IL, and aphid infestation caused additional reductions in the biomass of particular components of the seedlings. Dry weight (DW) of older (>=1-year-old) needles in infested trees was significantly decreased in both years. Total root DW at the end of the second year was significantly affected by aphid infestation, and the reduction (14-18%) was similar in IL and HL treatments despite large differences in aphid density. Biomass distribution patterns in infested trees were similar to that of uninfested trees within each light treatment, indicating that the relative decreases in root biomass were accompanied by similar reductions in distribution to the above-ground parts of the seedlings. Leader extension growth of infested seedlings was reduced by 15-17% compared with uninfested seedlings under IL, whereas only a 2-3% reduction in leader extension of infested seedlings under HL was observed. The results showed that the response of seedlings to E. abietinum were primarily dependent on the light environment. The significant reduction caused by aphids on the total DW of older needles and roots, and on leader extension growth, does suggest the potential for effects to accumulate over time. PMID- 20943652 TI - Small molecule mimetics of an HIV-1 gp41 fusion intermediate as vaccine leads. AB - We describe here a novel platform technology for the discovery of small molecule mimetics of conformational epitopes on protein antigens. As a model system, we selected mimetics of a conserved hydrophobic pocket within the N-heptad repeat region of the HIV-1 envelope protein, gp41. The human monoclonal antibody, D5, binds to this target and exhibits broadly neutralizing activity against HIV-1. We exploited the antigen-binding property of D5 to select complementary small molecules using a high throughput screen of a diverse chemical collection. The resulting small molecule leads were rendered immunogenic by linking them to a carrier protein and were shown to elicit N-heptad repeat-binding antibodies in a fraction of immunized mice. Plasma from HIV-1-infected subjects shown previously to contain broadly neutralizing antibodies was found to contain antibodies capable of binding to haptens represented in the benzylpiperidine leads identified as a result of the high throughput screen, further validating these molecules as vaccine leads. Our results suggest a new paradigm for vaccine discovery using a medicinal chemistry approach to identify lead molecules that, when optimized, could become vaccine candidates for infectious diseases that have been refractory to conventional vaccine development. PMID- 20943653 TI - Disulfide bond that constrains the HIV-1 gp120 V3 domain is cleaved by thioredoxin. AB - A functional disulfide bond in both the HIV envelope glycoprotein, gp120, and its immune cell receptor, CD4, is involved in viral entry, and compounds that block cleavage of the disulfide bond in these proteins inhibit HIV entry and infection. The disulfide bonds in both proteins are cleaved at the cell surface by the small redox protein, thioredoxin. The target gp120 disulfide and its mechanism of cleavage were determined using a thioredoxin kinetic trapping mutant and mass spectrometry. A single disulfide bond was cleaved in isolated and cell surface gp120, but not the gp160 precursor, and the extent of the reaction was enhanced when gp120 was bound to CD4. The Cys(32) sulfur ion of thioredoxin attacks the Cys(296) sulfur ion of the gp120 V3 domain Cys(296)-Cys(331) disulfide bond, cleaving the bond. Considering that V3 sequences largely determine the chemokine receptor preference of HIV, we propose that cleavage of the V3 domain disulfide, which is facilitated by CD4 binding, regulates chemokine receptor binding. There are 20 possible disulfide bond configurations, and, notably, the V3 domain disulfide has the same unusual -RHStaple configuration as the functional disulfide bond cleaved in CD4. PMID- 20943654 TI - Transcription factor redundancy ensures induction of the antiviral state. AB - The transcriptional response to virus infection is thought to be predominantly induced by interferon (IFN) signaling. Here we demonstrate that, in the absence of IFN signaling, an IFN-like transcriptome is still maintained. This transcriptional activity is mediated from IFN-stimulated response elements (ISREs) that bind to both the IFN-stimulated gene factor 3 (ISGF3) as well as to IFN response factor 7 (IRF7). Through a combination of both in vitro biochemistry and in vivo transcriptional profiling, we have dissected what constitutes IRF specific, ISGF3-specific, or universal ISREs. Taken together, the data presented here suggest that IRF7 can induce an IFN-like transcriptome in the absence of type-I or -III signaling and therefore provides a level of redundancy to cells to ensure the induction of the antiviral state. PMID- 20943655 TI - The ankyrin repeat-rich membrane spanning (ARMS)/Kidins220 scaffold protein is regulated by activity-dependent calpain proteolysis and modulates synaptic plasticity. AB - The expression of forms of synaptic plasticity, such as the phenomenon of long term potentiation, requires the activity-dependent regulation of synaptic proteins and synapse composition. Here we show that ARMS (ankyrin repeat-rich membrane spanning protein)/Kidins220, a transmembrane scaffold molecule and BDNF TrkB substrate, is significantly reduced in hippocampal neurons after potassium chloride depolarization. The activity-dependent proteolysis of ARMS/Kidins220 was found to occur through calpain, a calcium-activated protease. Moreover, hippocampal long-term potentiation in ARMS/Kidins220(+/-) mice was enhanced, and inhibition of calpain in these mice reversed these effects. These results provide an explanation for a role for the ARMS/Kidins220 protein in synaptic plasticity events and suggest that the levels of ARMS/Kidins220 can be regulated by neuronal activity and calpain action to influence synaptic function. PMID- 20943656 TI - Activity and cellular functions of the deubiquitinating enzyme and polyglutamine disease protein ataxin-3 are regulated by ubiquitination at lysine 117. AB - Deubiquitinating enzymes (DUbs) play important roles in many ubiquitin-dependent pathways, yet how DUbs themselves are regulated is not well understood. Here, we provide insight into the mechanism by which ubiquitination directly enhances the activity of ataxin-3, a DUb implicated in protein quality control and the disease protein in the polyglutamine neurodegenerative disorder, Spinocerebellar Ataxia Type 3. We identify Lys-117, which resides near the catalytic triad, as the primary site of ubiquitination in wild type and pathogenic ataxin-3. Further studies indicate that ubiquitin-dependent activation of ataxin-3 at Lys-117 is important for its ability to reduce high molecular weight ubiquitinated species in cells. Ubiquitination at Lys-117 also facilitates the ability of ataxin-3 to induce aggresome formation in cells. Finally, structure-function studies support a model of activation whereby ubiquitination at Lys-117 enhances ataxin-3 activity independent of the known ubiquitin-binding sites in ataxin-3, most likely through a direct conformational change in or near the catalytic domain. PMID- 20943657 TI - The dyslexia-associated KIAA0319 protein undergoes proteolytic processing with {gamma}-secretase-independent intramembrane cleavage. AB - The KIAA0319 gene has been associated with reading disability in several studies. It encodes a plasma membrane protein with a large, highly glycosylated, extracellular domain. This protein is proposed to function in adhesion and attachment and thought to play an important role during neuronal migration in the developing brain. We have previously proposed that endocytosis of this protein could constitute an important mechanism to regulate its function. Here we show that KIAA0319 undergoes ectodomain shedding and intramembrane cleavage. At least five different cleavage events occur, four in the extracellular domain and one within the transmembrane domain. The ectodomain shedding processing cleaves the extracellular domain, generating several small fragments, including the N terminal region with the Cys-rich MANEC domain. It is possible that these fragments are released to the extracellular medium and trigger cellular responses. The intramembrane cleavage releases the intracellular domain from its membrane attachment. Our results suggest that this cleavage event is not carried out by gamma-secretase, the enzyme complex involved in similar processing in many other type I proteins. The soluble cytoplasmic domain of KIAA0319 is able to translocate to the nucleus, accumulating in nucleoli after overexpression. This fragment has an unknown role, although it could be involved in regulation of gene expression. The absence of DNA-interacting motifs indicates that such a function would most probably be mediated through interaction with other proteins, not by direct DNA binding. These results suggest that KIAA0319 not only has a direct role in neuronal migration but may also have additional signaling functions. PMID- 20943659 TI - The 1.5 A crystal structure of human receptor for advanced glycation endproducts (RAGE) ectodomains reveals unique features determining ligand binding. AB - Interaction of the pattern recognition receptor, RAGE with key ligands such as advanced glycation end products (AGE), S100 proteins, amyloid beta, and HMGB1 has been linked to diabetic complications, inflammatory and neurodegenerative disorders, and cancer. To help answer the question of how a single receptor can recognize and respond to a diverse set of ligands we have investigated the structure and binding properties of the first two extracellular domains of human RAGE, which are implicated in various ligand binding and subsequent signaling events. The 1.5-A crystal structure reveals an elongated molecule with a large basic patch and a large hydrophobic patch, both highly conserved. Isothermal titration calorimetry (ITC) and deletion experiments indicate S100B recognition by RAGE is an entropically driven process involving hydrophobic interaction that is dependent on Ca(2+) and on residues in the C'D loop (residues 54-67) of domain 1. In contrast, competition experiments using gel shift assays suggest that RAGE interaction with AGE is driven by the recognition of negative charges on AGE proteins. We also demonstrate that RAGE can bind to dsDNA and dsRNA. These findings reveal versatile structural features of RAGE that help explain its ability to recognize of multiple ligands. PMID- 20943658 TI - Expression, localization, and biochemical characterization of nicotinamide mononucleotide adenylyltransferase 2. AB - Nicotinamide mononucleotide (NMN) adenylyltransferase 2 (Nmnat2) catalyzes the synthesis of NAD from NMN and ATP. The Nmnat2 transcript is expressed predominately in the brain; we report here that Nmnat2 is a low abundance protein expressed in neurons. Previous studies indicate that Nmnat2 localizes to Golgi. As Nmnat2 is not predicted to contain a signal sequence, lipid-binding domain, or transmembrane domain, we investigated the nature of this interaction. These experiments reveal that Nmnat2 is palmitoylated in vitro, and this modification is required for membrane association. Surprisingly, exogenous Nmnat2 is toxic to neurons, indicating that protein levels must be tightly regulated. To analyze Nmnat2 localization in neurons (previous experiments relied on exogenous expression in HeLa cells), mouse brains were fractionated, showing that Nmnat2 is enriched in numerous membrane compartments including synaptic terminals. In HeLa cells, in addition to Golgi, Nmnat2 localizes to Rab7-containing late endosomes. These studies show that Nmnat2 is a neuronal protein peripherally attached to membranes via palmitoylation and suggest that Nmnat2 is transported to synaptic terminals via an endosomal pathway. PMID- 20943660 TI - Cardiac myosin light chain kinase is necessary for myosin regulatory light chain phosphorylation and cardiac performance in vivo. AB - In contrast to studies on skeletal and smooth muscles, the identity of kinases in the heart that are important physiologically for direct phosphorylation of myosin regulatory light chain (RLC) is not known. A Ca(2+)/calmodulin-activated myosin light chain kinase is expressed only in cardiac muscle (cMLCK), similar to the tissue-specific expression of skeletal muscle MLCK and in contrast to the ubiquitous expression of smooth muscle MLCK. We have ablated cMLCK expression in male mice to provide insights into its role in RLC phosphorylation in normally contracting myocardium. The extent of RLC phosphorylation was dependent on the extent of cMLCK expression in both ventricular and atrial muscles. Attenuation of RLC phosphorylation led to ventricular myocyte hypertrophy with histological evidence of necrosis and fibrosis. Echocardiography showed increases in left ventricular mass as well as end-diastolic and end-systolic dimensions. Cardiac performance measured as fractional shortening decreased proportionally with decreased cMLCK expression culminating in heart failure in the setting of no RLC phosphorylation. Hearts from female mice showed similar responses with loss of cMLCK associated with diminished RLC phosphorylation and cardiac hypertrophy. Isoproterenol infusion elicited hypertrophic cardiac responses in wild type mice. In mice lacking cMLCK, the hypertrophic hearts showed no additional increases in size with the isoproterenol treatment, suggesting a lack of RLC phosphorylation blunted the stress response. Thus, cMLCK appears to be the predominant protein kinase that maintains basal RLC phosphorylation that is required for normal physiological cardiac performance in vivo. PMID- 20943661 TI - Structural bases of PAS domain-regulated kinase (PASK) activation in the absence of activation loop phosphorylation. AB - Per-Arnt-Sim (PAS) domain-containing protein kinase (PASK) is an evolutionary conserved protein kinase that coordinates cellular metabolism with metabolic demand in yeast and mammals. The molecular mechanisms underlying PASK regulation, however, remain unknown. Herein, we describe a crystal structure of the kinase domain of human PASK, which provides insights into the regulatory mechanisms governing catalysis. We show that the kinase domain adopts an active conformation and has catalytic activity in vivo and in vitro in the absence of activation loop phosphorylation. Using site-directed mutagenesis and structural comparison with active and inactive kinases, we identified several key structural features in PASK that enable activation loop phosphorylation-independent activity. Finally, we used combinatorial peptide library screening to determine that PASK prefers basic residues at the P-3 and P-5 positions in substrate peptides. Our results describe the key features of the PASK structure and how those features are important for PASK activity and substrate selection. PMID- 20943663 TI - Chronic and acute models of retinal neurodegeneration TrkA activity are neuroprotective whereas p75NTR activity is neurotoxic through a paracrine mechanism. AB - In normal adult retinas, NGF receptor TrkA is expressed in retinal ganglion cells (RGC), whereas glia express p75(NTR). During retinal injury, endogenous NGF, TrkA, and p75(NTR) are up-regulated. Paradoxically, neither endogenous NGF nor exogenous administration of wild type NGF can protect degenerating RGCs, even when administered at high frequency. Here we elucidate the relative contribution of NGF and each of its receptors to RGC degeneration in vivo. During retinal degeneration due to glaucoma or optic nerve transection, treatment with a mutant NGF that only activates TrkA, or with a biological response modifier that prevents endogenous NGF and pro-NGF from binding to p75(NTR) affords significant neuroprotection. Treatment of normal eyes with an NGF mutant-selective p75(NTR) agonist causes progressive RGC death, and in injured eyes it accelerates RGC death. The mechanism of p75(NTR) action during retinal degeneration due to glaucoma is paracrine, by increasing production of neurotoxic proteins TNF-alpha and alpha(2)-macroglobulin. Antagonists of p75(NTR) inhibit TNF-alpha and alpha(2)-macroglobulin up-regulation during disease, and afford neuroprotection. These data reveal a balance of neuroprotective and neurotoxic mechanisms in normal and diseased retinas, and validate each neurotrophin receptor as a pharmacological target for neuroprotection. PMID- 20943664 TI - Chemical reactivities of cysteine substitutions in subunit a of ATP synthase define residues gating H+ transport from each side of the membrane. AB - Subunit a plays a key role in coupling H(+) transport to rotations of the subunit c-ring in F(1)F(o) ATP synthase. In Escherichia coli, H(+) binding and release occur at Asp-61 in the middle of the second transmembrane helix (TMH) of F(o) subunit c. Based upon the Ag(+) sensitivity of Cys substituted into subunit a, H(+) are thought to reach Asp-61 via aqueous pathways mapping to surfaces of TMH 2-5. In this study we have extended characterization of the most Ag(+)-sensitive residues in subunit a with cysteine reactive methanethiosulfonate (MTS) reagents and Cd(2+). The effect of these reagents on ATPase-coupled H(+) transport was measured using inside-out membrane vesicles. Cd(2+) inhibited the activity of all Ag(+)-sensitive Cys on the cytoplasmic side of the TMHs, and three of these substitutions were also sensitive to inhibition by MTS reagents. On the other hand, Cd(2+) did not inhibit the activities of substitutions at residues 119 and 120 on the periplasmic side of TMH2, and residues 214 and 215 in TMH4 and 252 in TMH5 at the center of the membrane. When inside-out membrane vesicles from each of these substitutions were sonicated during Cd(2+) treatment to expose the periplasmic surface, the ATPase-coupled H(+) transport activity was strongly inhibited. The periplasmic access to N214C and Q252C, and their positioning in the protein at the a-c interface, is consistent with previous proposals that these residues may be involved in gating H(+) access from the periplasmic half channel to Asp-61 during the protonation step. PMID- 20943662 TI - Calcineurin signaling regulates human islet {beta}-cell survival. AB - The calcium-regulated phosphatase calcineurin intersects with both calcium and cAMP-mediated signaling pathways in the pancreatic beta-cell. Pharmacologic calcineurin inhibition, necessary to prevent rejection in the setting of organ transplantation, is associated with post-transplant beta-cell failure. We sought to determine the effect of calcineurin inhibition on beta-cell replication and survival in rodents and in isolated human islets. Further, we assessed whether the GLP-1 receptor agonist and cAMP stimulus, exendin-4 (Ex-4), could rescue beta cell replication and survival following calcineurin inhibition. Following treatment with the calcineurin inhibitor tacrolimus, human beta-cell apoptosis was significantly increased. Although we detected no human beta-cell replication, tacrolimus significantly decreased rodent beta-cell replication. Ex-4 nearly normalized both human beta-cell survival and rodent beta-cell replication when co administered with tacrolimus. We found that tacrolimus decreased Akt phosphorylation, suggesting that calcineurin could regulate replication and survival via the PI3K/Akt pathway. We identify insulin receptor substrate-2 (Irs2), a known cAMP-responsive element-binding protein target and upstream regulator of the PI3K/Akt pathway, as a novel calcineurin target in beta-cells. Irs2 mRNA and protein are decreased by calcineurin inhibition in both rodent and human islets. The effect of calcineurin on Irs2 expression is mediated at least in part through the nuclear factor of activated T-cells (NFAT), as NFAT occupied the Irs2 promoter in a calcineurin-sensitive manner. Ex-4 restored Irs2 expression in tacrolimus-treated rodent and human islets nearly to baseline. These findings reveal calcineurin as a regulator of human beta-cell survival in part through regulation of Irs2, with implications for the pathogenesis and treatment of diabetes following organ transplantation. PMID- 20943665 TI - Crystal structure of hexokinase KlHxk1 of Kluyveromyces lactis: a molecular basis for understanding the control of yeast hexokinase functions via covalent modification and oligomerization. AB - Crystal structures of the unique hexokinase KlHxk1 of the yeast Kluyveromyces lactis were determined using eight independent crystal forms. In five crystal forms, a symmetrical ring-shaped homodimer was observed, corresponding to the physiological dimer existing in solution as shown by small-angle x-ray scattering. The dimer has a head-to-tail arrangement such that the small domain of one subunit interacts with the large domain of the other subunit. Dimer formation requires favorable interactions of the 15 N-terminal amino acids that are part of the large domain with amino acids of the small domain of the opposite subunit, respectively. The head-to-tail arrangement involving both domains of the two KlHxk1 subunits is appropriate to explain the reduced activity of the homodimer as compared with the monomeric enzyme and the influence of substrates and products on dimer formation and dissociation. In particular, the structure of the symmetrical KlHxk1 dimer serves to explain why phosphorylation of conserved residue Ser-15 may cause electrostatic repulsions with nearby negatively charged residues of the adjacent subunit, thereby inducing a dissociation of the homologous dimeric hexokinases KlHxk1 and ScHxk2. Two complex structures of KlHxk1 with bound glucose provide a molecular model of substrate binding to the open conformation and the subsequent classical domain closure motion of yeast hexokinases. The entirety of the novel data extends the current concept of glucose signaling in yeast and complements the induced-fit model by integrating the events of N-terminal phosphorylation and dissociation of homodimeric yeast hexokinases. PMID- 20943666 TI - Structural and biochemical studies on the chromo-barrel domain of male specific lethal 3 (MSL3) reveal a binding preference for mono- or dimethyllysine 20 on histone H4. AB - We have determined the human male specific lethal 3 (hMSL3) chromo-barrel domain structure by x-ray crystallography to a resolution of 2.5 A (r = 0.226, R(free) = 0.270). hMSL3 contains a canonical methyllysine binding pocket made up of residues Tyr-31, Phe-56, Trp-59, and Trp-63. A six-residue insertion between strands beta(1) and beta(2) of the hMSL3 chromo-barrel domain directs the side chain of Glu-21 into the methyllysine binding pocket where it hydrogen bonds to the NH group of a bound cyclohexylamino ethanesulfonate buffer molecule, likely mimicking interactions with a histone tail dimethyllysine residue. In vitro binding studies revealed that both the human and Drosophila MSL3 chromo-barrel domains bind preferentially to peptides representing the mono or dimethyl isoform of lysine 20 on the histone H4 N-terminal tail (H4K20Me(1) or H4K20Me(2)). Mutation of Tyr-31 to Ala in the hMSL3 methyllysine-binding cage resulted in weaker in vitro binding to H4K20Me(1). The same mutation in the msl3 gene compromised male survival in Drosophila. Combined mutation of Glu-21 and Pro-22 to Ala in hMSL3 resulted in slightly weaker in vitro binding to H4K20Me(1), but the corresponding msl3 mutation had no effect on male survival in Drosophila. We propose MSL3 plays an important role in targeting the male specific lethal complex to chromatin in both humans and flies by binding to H4K20Me(1). Binding studies on the related dMRG15 chromo-barrel domain revealed that MRG15 prefers binding to H4K20Me(3). PMID- 20943667 TI - Crystal structure of cardiac-specific histone methyltransferase SmyD1 reveals unusual active site architecture. AB - SmyD1 is a cardiac- and muscle-specific histone methyltransferase that methylates histone H3 at lysine 4 and regulates gene transcription in early heart development. The unique domain structure characterized by a "split" SET domain, a conserved MYND zinc finger, and a novel C-terminal domain (CTD) distinguishes SmyD1 from other SET domain containing methyltransferases. Here we report the crystal structure of full-length SmyD1 in complex with the cofactor analog sinefungin at 2.3 A. The structure reveals that SmyD1 folds into a wrench-shaped structure with two thick "grips" separated by a large, deep concave opening. Importantly, our structural and functional analysis suggests that SmyD1 appears to be regulated by an autoinhibition mechanism, and that unusually spacious target lysine-access channel and the presence of the CTD domain both negatively contribute to the regulation of this cardiovascularly relevant methyltransferase. Furthermore, our structure also provides a structural basis for the interaction between SmyD1 and cardiac transcription factor skNAC, and suggests that the MYND domain may primarily serve as a protein interaction module and cooperate SmyD1 with skNAC to regulate cardiomyocyte growth and maturation. Overall, our data provide novel insights into the mechanism of SmyD1 regulation, which would be helpful in further understanding the role of this protein in heart development and cardiovascular diseases. PMID- 20943668 TI - Decreased interhemispheric functional connectivity in autism. AB - The cortical underconnectivity theory asserts that reduced long-range functional connectivity might contribute to a neural mechanism for autism. We examined resting-state blood oxygen level-dependent interhemispheric correlation in 53 males with high-functioning autism and 39 typically developing males from late childhood through early adulthood. By constructing spatial maps of correlation between homologous voxels in each hemisphere, we found significantly reduced interhemispheric correlation specific to regions with functional relevance to autism: sensorimotor cortex, anterior insula, fusiform gyrus, superior temporal gyrus, and superior parietal lobule. Observed interhemispheric connectivity differences were better explained by diagnosis of autism than by potentially confounding neuropsychological metrics of language, IQ, or handedness. Although both corpus callosal volume and gray matter interhemispheric connectivity were significantly reduced in autism, no direct relationship was observed between them, suggesting that structural and functional metrics measure different aspects of interhemispheric connectivity. In the control but not the autism sample, there was decreasing interhemispheric correlation with subject age. Greater differences in interhemispheric correlation were seen for more lateral regions in the brain. These findings suggest that long-range connectivity abnormalities in autism are spatially heterogeneous and that transcallosal connectivity is decreased most in regions with functions associated with behavioral abnormalities in autism. Autism subjects continue to show developmental differences in interhemispheric connectivity into early adulthood. PMID- 20943669 TI - Relationship between circulating levels of RANTES (regulated on activation, normal T-cell expressed, and secreted) and carotid plaque characteristics: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study. AB - AIMS: To assess the relationship between regulated on activation, normal T-cell expressed and secreted (RANTES) and carotid atherosclerotic plaque burden and plaque characteristics. METHODS AND RESULTS: Gadolinium-enhanced magnetic resonance imaging (MRI) of the carotid artery was performed in 1901 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Wall thickness and volume, lipid-core volume, and fibrous cap thickness (by MRI) and plasma RANTES levels (by ELISA) were measured. Regression analysis was performed to study the associations between MRI variables and RANTES. Among 1769 inclusive participants, multivariable regression analysis revealed that total wall volume [beta coefficient (beta) = 0.09, P = 0.008], maximum wall thickness (beta = 0.08, P = 0.01), vessel wall area (beta = 0.07, P = 0.02), mean minimum fibrous cap thickness (beta = 0.11, P = 0.03), and high-sensitivity C-reactive protein (beta = 0.09, P = 0.01) were positively associated with RANTES. Total lipid-core volume showed positive association in unadjusted models (beta = 0.18, P = 0.02), but not in fully adjusted models (beta = 0.13, P = 0.09). RANTES levels were highest in Caucasian females followed by Caucasian males, African-American females, and African-American males (P < 0.0001). Statin use attenuated the relationship between RANTES and measures of plaque burden. CONCLUSION: Positive associations between RANTES and carotid wall thickness and lipid-core volume (in univariate analysis) suggest that higher RANTES levels may be associated with extent of carotid atherosclerosis and high-risk plaques. Associations between fibrous cap thickness and RANTES likely reflect the lower reliability estimate for fibrous cap measurements compared with wall volume or lipid-core volume measurements. Statin use may modify the association between RANTES and carotid atherosclerosis. Furthermore, RANTES levels vary by race. PMID- 20943670 TI - CD14++CD16+ monocytes and cardiovascular outcome in patients with chronic kidney disease. AB - AIMS: Patients with chronic kidney disease (CKD) pose a worldwide growing burden to health care systems due to accelerated atherosclerosis and subsequent high cardiovascular (CV) morbidity. Atherogenesis is prominently driven by monocytes and monocyte-derived macrophages. The expression of CD14 and CD16 characterizes three monocyte subsets: CD14(++)CD16(-), CD14(++)CD16(+), and CD14((+))CD16(+) cells; the latter two are often denoted as 'proinflammatory' CD16(+) monocytes. Despite an association between CD16(+) monocyte counts and higher CV risk in cross-sectional cohorts, the prognostic impact of elevated CD16(+) monocyte counts is poorly understood. METHODS AND RESULTS: We assessed monocyte heterogeneity using flow cytometry in 119 patients with non-dialysis CKD, who were prospectively followed for a median of 4.9 (inter-quartile range 4.8-5.0) years for the occurrence of CV events. In addition, we assessed expression of chemokine receptors on monocyte subsets. CD14(++)CD16(+) monocyte were independently associated with CV events [hazard ratio (for an increase of 10 cells/MUL) 1.26 (confidence interval: 1.04-1.52; P = 0.018)] after adjustment for variables that significantly affected CD14(++)CD16(+) cell counts at baseline. Across the spectrum of CKD, CD14(++)CD16(+) monocytes selectively expressed CCR5. CONCLUSION: We found that CD14(++)CD16(+) monocytes were independently associated with CV events in non-dialysis CKD patients. Our results support the notion that CD16(+) monocytes rather than CD16(-) monocytes are involved in human atherosclerosis. PMID- 20943671 TI - Benefit of atrial septal defect closure in adults: impact of age. AB - AIMS: To evaluate the effect of age on the clinical benefit of atrial septal defect (ASD) closure in adults. METHODS AND RESULTS: Functional status, the presence of arrhythmias, right ventricular (RV) remodelling, and pulmonary artery pressure (PAP) were studied in 236 consecutive patients undergoing transcatheter ASD closure [164 females, mean age of 49 +/- 18 years, 78 younger than 40 years (Group A), 84 between 40 and 60 years (Group B) and 74 older than 60 years (Group C)]. Defect size [median 22 mm (inter-quartile range, 19, 26 mm)] and shunt ratio [Qp:Qs 2.2 (1.7, 2.9)] did not differ among age groups. Older patients had, however, more advanced symptoms and both, PAP (r = 0.65, P < 0.0001) and RV size (r = 0.28, P < 0.0001), were significantly related to age. Post-interventionally, RV size decreased from 41 +/- 7, 43 +/- 7, and 45 +/- 6 mm to 32 +/- 5, 34 +/- 5, and 37 +/- 5 mm for Groups A, B, and C, respectively (P < 0.0001), and PAP decreased from 31 +/- 7, 37 +/- 10, and 53 +/- 17 mmHg to 26 +/- 5, 30 +/- 6, and 43 +/- 14 mmHg (P < 0.0001), respectively. Absolute changes in RV size (P = 0.80) and PAP (P = 0.24) did not significantly differ among groups. Symptoms were present in 13, 49, and 83% of the patients before and in 3, 11, and 34% after intervention in Groups A, B, and C. Functional status was related to PAP. CONCLUSIONS: At any age, ASD closure is followed by symptomatic improvement and regression of PAP and RV size. However, the best outcome is achieved in patients with less functional impairment and less elevated PAP. Considering the continuous increase in symptoms, RV remodelling, and PAP with age, ASD closure must be recommended irrespective of symptoms early after diagnosis even in adults of advanced age. PMID- 20943672 TI - Diabetics with acute coronary syndrome: advances, challenges, and uncertainties. PMID- 20943675 TI - Deciphering the structural and biological properties of the lipid A moiety of lipopolysaccharides from Burkholderia cepacia strain ASP B 2D, in Arabidopsis thaliana. AB - Lipopolysaccharides (LPSs) are major, indispensable cell surface components of Gram-negative bacteria that have diverse roles in bacterial pathogenesis of plants. Environmental strains of Burkholderia cepacia have been described as phytopathogens, growth promotors, biocontrol agents and bioremediation agents. We have previously shown that LPSs from B. cepacia can be recognized as microbe associated molecular pattern molecules, to elicit defense responses in plants. Recent findings suggest that the lipid A moiety might be partially responsible for LPSs perception. These studies were extended by analysis of the structure and biological activity of the lipid A moiety of LPSs of B. cepacia(.) The full structure was determined by a combination of negative/positive-ion matrix assisted laser desorption ionization (MALDI) mass spectrometry (MS) on intact and partially degraded substrates. B. cepacia lipid A was found to contain a tetra- or penta-acylated, 1,4'-diphosphorylated, beta-(1-6)-linked D-GlcN disaccharide and further substituted by L-Ara4N in position 4'. As primary fatty acids, R configurated 16:0(3-OH) (amide-linked in 2 and 2') and 14:0(3-OH) (ester-linked in 3 and 3', nonstoichiometric) were identified. A secondary 14:0 was located at position 2'. Its biological activity to elicit defense-related responses was subsequently investigated by monitoring the changes in the transcriptome of Arabidopsis thaliana seedlings. Genes found to be upregulated code for proteins involved in signal perception and transduction, transcriptional regulation, defense and stress responses. Furthermore, genes encoding proteins involved in chaperoning, protein interactions and protein degradation were differentially expressed as part of the metabolic reprogramming of cellular activities in support of immunity and defense. PMID- 20943674 TI - Comprehensive characterization of the site-specific N-glycosylation of wild-type and recombinant human lactoferrin expressed in the milk of transgenic cloned cattle. AB - The glycosylation profile of a recombinant protein is important because glycan moieties can play a significant role in the biological properties of the glycoprotein. Here we determined the site-specific N-glycosylation profile of human lactoferrin (hLF) and recombinant human lactoferrin (rhLF) expressed in the milk of transgenic cloned cattle. We used combined approaches of monosaccharide composition analysis, lectin blot, glycan permethylation and sequential exoglycosidase digestion and analyzed samples using high-performance ion chromatography and mass spectrometry (MS). N-glycans from hLF are comprised entirely of highly branched, highly sialylated and highly fucosylated complex type structures, and many contain Lewis(x) epitopes. Six of these structures are reported here for the first time. However, N-glycans from rhLF are of the high mannose-, hybrid- and complex-type structures, with less N-acetylneuraminic acid and fucose. Some contain a terminal N-acetylgalactosamine-N-acetylglucosamine (LacdiNAc) disaccharide sequence. Monosaccharide composition analysis of rhLF revealed small amounts of N-glycolylneuraminic acid, which were not detected by MS. hLF and rhLF appear to be glycosylated at the same two sites: Asn138 and Asn479. The third putative glycosylation site, at Asn624, is unglycosylated in both hLF and rhLF. The relative abundance of each N-glycan at each site was also determined. The different N-glycosylation profile of rhLF when compared with that of hLF is in consistent with the widely held view that glycosylation is species- and tissue/cell-specific. These data provide an important foundation for further studies of glycan structure/function relationships for hLF and rhLF and help to better understand the glycosylation mechanism in bovine mammary epithelial cells. PMID- 20943673 TI - The ryanodine receptor channel as a molecular motif in atrial fibrillation: pathophysiological and therapeutic implications. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with substantial morbidity and mortality. It causes profound changes in sarcoplasmic reticulum (SR) Ca(2+) homeostasis, including ryanodine receptor channel dysfunction and diastolic SR Ca(2+) leak, which might contribute to both decreased contractile function and increased propensity to atrial arrhythmias. In this review, we will focus on the molecular basis of ryanodine receptor channel dysfunction and enhanced diastolic SR Ca(2+) leak in AF. The potential relevance of increased incidence of spontaneous SR Ca(2+) release for both AF induction and/or maintenance and the development of novel mechanism-based therapeutic approaches will be discussed. PMID- 20943676 TI - Three-dimensional evaluation of an independent multi-walled carbon nanotube probe by tomography with high-resolution transmission electron microscope. AB - We evaluated an independent multi-walled carbon nanotube (MWNT) probe by using tomography with a high-resolution transmission electron microscope to verify the three-dimensional structure of the probe tip. The new method of probe evaluation revealed the following features: (i) cutting the end of the MWNT probe caused the wall structure to disintegrate and encapsulated the graphene sheets fragmented by the discharged pulse; (ii) the cap of the MWNT probe was an open cylinder covered by walls similar in shape to a rectangular slit; (iii) the grooves of the inner walls of the MWNT probe, which were created by the discharge cutting method, maintained a cylindrical shape that was different from the peeling-off mechanism. PMID- 20943677 TI - To breed or not to breed: a seabird's response to extreme climatic events. AB - Intermittent breeding is an important life-history strategy that has rarely been quantified in the wild and for which drivers remain unclear. It may be the result of a trade-off between survival and reproduction, with individuals skipping breeding when breeding conditions are below a certain threshold. Heterogeneity in individual quality can also lead to heterogeneity in intermittent breeding. We modelled survival, recruitment and breeding probability of the red-footed booby (Sula sula), using a 19 year mark-recapture dataset involving more than 11,000 birds. We showed that skipping breeding was more likely in El-Nino years, correlated with an increase in the local sea surface temperature, supporting the hypothesis that it may be partly an adaptive strategy of birds to face the trade off between survival and reproduction owing to environmental constraints. We also showed that the age-specific probability of first breeding attempt was synchronized among different age-classes and higher in El-Nino years. This result suggested that pre-breeders may benefit from lowered competition with experienced breeders in years of high skipping probabilities. PMID- 20943678 TI - A quarter of a world away: female humpback whale moves 10,000 km between breeding areas. AB - Fidelity of individual animals to breeding sites is a primary determinant of population structure. The degree and scale of philopatry in a population reflect the fitness effects of social facilitation, ecological adaptation and optimal inbreeding. Patterns of breeding-site movement and fidelity are functions of social structure and are frequently sex biased. We report on a female humpback whale (Megaptera novaeangliae) first identified by natural markings off Brazil that subsequently was photographed off Madagascar. The minimum travel distance between these locations is greater than 9800 km, approximately 4000 km longer than any previously reported movement between breeding grounds, more than twice the species' typical seasonal migratory distance and the longest documented movement by a mammal. It is unexpected to find this exceptional long-distance movement between breeding groups by a female, as models of philopatry suggest that male mammals move more frequently or over longer distances in search of mating opportunities. While such movement may be advantageous, especially in changeable or unpredictable circumstances, it is not possible to unambiguously ascribe causality to this rare observation. This finding illustrates the behavioural flexibility in movement patterns that may be demonstrated within a typically philopatric species. PMID- 20943679 TI - The evolution of eusociality in allodapine bees: workers began by waiting. AB - Understanding how sterile worker castes in social insects first evolved is one of the supreme puzzles in social evolution. Here, we show that in the bee tribe Allodapini, the earliest societies did not entail a foraging worker caste, but instead comprised females sharing a nest with supersedure of dominance. Subordinates delayed foraging until they became reproductively active, whereupon they provided food for their own brood as well as for those of previously dominant females. The earliest allodapine societies are, therefore, not consistent with an 'evo-devo' paradigm, where decoupling of foraging and reproductive tasks is proposed as a key early step in social evolution. Important features of these ancestral societies were insurance benefits for dominants, headstart benefits for subordinates and direct reproduction for both. The two lineages where morphologically distinct foraging worker castes evolved both occur in ecosystems with severe constraints on independent nesting and where brood rearing periods are very seasonally restricted. These conditions would have strongly curtailed dispersal options and increased the likelihood that dominance supersedure occurred after brood rearing opportunities were largely degraded. The origins of foraging castes, therefore, represented a shift towards assured fitness gains by subordinates, mediated by the dual constraints of social hierarchies and environmental harshness. PMID- 20943680 TI - Will krill fare well under Southern Ocean acidification? AB - Antarctic krill embryos and larvae were experimentally exposed to 380 (control), 1000 and 2000 uatm pCO2 in order to assess the possible impact of ocean acidification on early development of krill. No significant effects were detected on embryonic development or larval behaviour at 1000 uatm pCO2; however, at 2000 uatm pCO2 development was disrupted before gastrulation in 90 per cent of embryos, and no larvae hatched successfully. Our model projections demonstrated that Southern Ocean sea water pCO2 could rise up to 1400 uatm in krill's depth range under the IPCC IS92a scenario by the year 2100 (atmospheric pCO2 788 uatm). These results point out the urgent need for understanding the pCO2-response relationship for krill developmental and later stages, in order to predict the possible fate of this key species in the Southern Ocean. PMID- 20943681 TI - Prediction of human protein-protein interaction by a mixed Bayesian model and its application to exploring underlying cancer-related pathway crosstalk. AB - Protein-protein interaction (PPI) prediction method has provided an opportunity for elucidating potential biological processes and disease mechanisms. We integrated eight features involving proteomic, genomic, phenotype and functional annotation datasets by a mixed model consisting of full connected Bayesian (FCB) model and naive Bayesian model to predict human PPIs, resulting in 40 447 PPIs which contain 2740 common PPIs with the human protein reference database (HPRD) by a likelihood ratio cutoff of 512. Then we applied them to exploring underlying pathway crosstalk where pathways were derived from the pathway interaction database. Two pathway crosstalk networks (PCNs) were constructed based on PPI sets. The PPI sets were derived from two different sources. One source was strictly the HPRD database while the other source was a combination of HPRD and PPIs predicted by our mixed Bayesian method. We demonstrated that PCNs based on the mixed PPI set showed much more underlying pathway interactions than the HPRD PPI set. Furthermore, we mapped cancer-causing mutated somatic genes to PPIs between significant pathway crosstalk pairs. We extracted highly connected clusters from over-represented subnetworks of PCNs, which were enriched for mutated gene interactions that acted as crosstalk links. Most of the pathways in top ranking clusters were shown to play important roles in cancer. The clusters themselves showed coherent function categories pertaining to cancer development. PMID- 20943682 TI - Targeting vaccination against novel infections: risk, age and spatial structure for pandemic influenza in Great Britain. AB - The emergence of a novel strain of H1N1 influenza virus in Mexico in 2009, and its subsequent worldwide spread, has focused attention to the question of optimal deployment of mass vaccination campaigns. Here, we use three relatively simple models to address three issues of primary concern in the targeting of any vaccine. The advantages of such simple models are that the underlying assumptions and effects of individual parameters are relatively clear, and the impact of uncertainty in the parametrization can be readily assessed in the early stages of an outbreak. In particular, we examine whether targeting risk-groups, age-groups or spatial regions could be optimal in terms of reducing the predicted number of cases or severe effects; and how these targeted strategies vary as the epidemic progresses. We examine the conditions under which it is optimal to initially target vaccination towards those individuals within the population who are most at risk of severe effects of infection. Using age-structured mixing matrices, we show that targeting vaccination towards the more epidemiologically important age groups (5-14 year olds and then 15-24 year olds) leads to the greatest reduction in the epidemic growth and hence reduces the total number of cases. Finally, we consider how spatially targeting the vaccine towards regions of country worst affected could provide an advantage. We discuss how all three of these priorities change as both the speed at which vaccination can be deployed and the start of the vaccination programme is varied. PMID- 20943683 TI - Supermacroprous chitosan-agarose-gelatin cryogels: in vitro characterization and in vivo assessment for cartilage tissue engineering. AB - The study focuses on the synthesis of a novel polymeric scaffold having good porosity and mechanical characteristics synthesized by using natural polymers and their optimization for application in cartilage tissue engineering. The scaffolds were synthesized via cryogelation technology using an optimized ratio of the polymer solutions (chitosan, agarose and gelatin) and cross-linker followed by the incubation at sub-zero temperature (-12 degrees C). Microstructure examination of the chitosan-agarose-gelatine (CAG) cryogels was done using scanning electron microscopy (SEM) and fluorescent microscopy. Mechanical analysis, such as the unconfined compression test, demonstrated that cryogels with varying chitosan concentrations, i.e. 0.5-1% have a high compression modulus. In addition, fatigue tests revealed that scaffolds are suitable for bioreactor studies where gels are subjected to continuous cyclic strain. In order to confirm the stability, cryogels were subjected to high frequency (5 Hz) with 30 per cent compression of their original length up to 1 * 10(5) cycles, gels did not show any significant changes in their mass and dimensions during the experiment. These cryogels have exhibited degradation capacity under aseptic conditions. CAG cryogels showed good cell adhesion of primary goat chondrocytes examined by SEM. Cytotoxicity of the material was checked by MTT assay and results confirmed the biocompatibility of the material. In vivo biocompatibility of the scaffolds was checked by the implantation of the scaffolds in laboratory animals. These results suggest the potential of CAG cryogels as a good three dimensional scaffold for cartilage tissue engineering. PMID- 20943684 TI - Stimulus-responsive liquids for encapsulation storage and controlled release of drugs from nano-shell capsules. AB - Drug-delivery systems with a unique capability to respond to a given stimulus can improve therapeutic efficacy. However, development of such systems is currently heavily reliant on responsive polymeric materials and pursuing this singular strategy limits the potential for clinical translation. In this report, with a model system used for drug-release studies, we demonstrate a new strategy: how a temperature-responsive non-toxic, volatile liquid can be encapsulated and stored under ambient conditions and subsequently programmed for controlled drug release without relying on a smart polymer. When the stimulus temperature is reached, controlled encapsulation of different amounts of dye in the capsules is achieved and facilitates subsequent sustained release. With different ratios of the liquid (perfluorohexane): dye in the capsules, enhanced controlled release with real time response is provided. Hence, our findings offer great potential for drug delivery applications and provide new generic insights into the development of stimuli drug-release systems. PMID- 20943685 TI - Mite dispersal among the Southern Ocean Islands and Antarctica before the last glacial maximum. AB - It has long been maintained that the majority of terrestrial Antarctic species are relatively recent, post last glacial maximum, arrivals with perhaps a few microbial or protozoan taxa being substantially older. Recent studies have questioned this 'recolonization hypothesis', though the range of taxa examined has been limited. Here, we present the first large-scale study for mites, one of two dominant terrestrial arthropod groups in the region. Specifically, we provide a broad-scale molecular phylogeny of a biologically significant group of ameronothroid mites from across the maritime and sub-Antarctic regions. Applying different dating approaches, we show that divergences among the ameronothroid mite genera Podacarus, Alaskozetes and Halozetes significantly predate the Pleistocene and provide evidence of independent dispersals across the Antarctic Polar Front. Our data add to a growing body of evidence demonstrating that many taxa have survived glaciation of the Antarctic continent and the sub-Antarctic islands. Moreover, they also provide evidence of a relatively uncommon trend of dispersals from islands to continental mainlands. Within the ameronothroid mites, two distinct clades with specific habitat preferences (marine intertidal versus terrestrial/supralittoral) exist, supporting a model of within-habitat speciation rather than colonization from marine refugia to terrestrial habitats. The present results provide additional impetus for a search for terrestrial refugia in an area previously thought to have lacked ice-free ground during glacial maxima. PMID- 20943686 TI - Maladaptive choice behaviour by pigeons: an animal analogue and possible mechanism for gambling (sub-optimal human decision-making behaviour). AB - Consistent with human gambling behaviour but contrary to optimal foraging theory, pigeons showed maladaptive choice behaviour in experiment 1 by choosing an alternative that provided on average two food pellets over an alternative that provided a certain three food pellets. On 20 per cent of the trials, choice of the two-pellet alternative resulted in a stimulus that always predicted ten food pellets; on the remaining 80 per cent of the trials, the two-pellet alternative resulted in a different stimulus that always predicted zero food pellets. Choice of the three-pellet alternative always resulted in three food pellets. This choice behaviour mimics human monetary gambling in which the infrequent occurrence of a stimulus signalling the winning event (10 pellets) is overemphasized and the more frequent occurrence of a stimulus signalling the losing event (zero pellets) is underemphasized, compared with the certain outcome associated with not gambling (the signal for three pellets). In experiment 2, choice of the two-pellet alternative resulted in ten pellets with a probability of 20 per cent following presentation of either stimulus. Choice of the three pellet alternative continued to result in three food pellets. In this case, the pigeons reliably chose the alternative that provided a certain three pellets over the alternative that provided an average of two pellets. Thus, in experiment 1, the pigeons were responding to obtain the discriminative stimuli signalling reinforcement and the absence of reinforcement, rather than to obtain the variability in reinforcement. PMID- 20943687 TI - How within-group behavioural variation and task efficiency enhance fitness in a social group. AB - How task specialization, individual task performance and within-group behavioural variation affects fitness is a longstanding and unresolved problem in our understanding of animal societies. In the temperate social spider, Anelosimus studiosus, colony members exhibit a behavioural polymorphism; females either exhibit an aggressive 'asocial' or docile 'social' phenotype. We assessed individual prey-capture success for both phenotypes, and the role of phenotypic composition on group-level prey-capture success for three prey size classes. We then estimated the effect of group phenotypic composition on fitness in a common garden, as inferred from individual egg-case masses. On average, asocial females were more successful than social females at capturing large prey, and colony level prey-capture success was positively associated with the frequency of the asocial phenotype. Asocial colony members were also more likely to engage in prey capture behaviour in group-foraging situations. Interestingly, our fitness estimates indicate females of both phenotypes experience increased fitness when occupying colonies containing unlike individuals. These results imply a reciprocal fitness benefit of within-colony behavioural variation, and perhaps division of labour in a spider society. PMID- 20943688 TI - Birth order, individual sex and sex of competitors determine the outcome of conflict among siblings over parental care. AB - Success in competition for limiting parental resources depends on the interplay between parental decisions over allocation of care and offspring traits. Birth order, individual sex and sex of competing siblings are major candidates as determinants of success in sib-sib competition, but experimental studies focusing on the combined effect of these factors on parent-offspring communication and within-brood competitive dynamics are rare. Here, we assessed individual food intake and body mass gain during feeding trials in barn swallow chicks differing for seniority and sex, and compared the intensity of their acoustic and postural solicitation (begging) displays. Begging intensity and success in competition depended on seniority in combination with individual sex and sex of the opponent. Junior chicks begged more than seniors, independently of satiation level (which was also experimentally manipulated), and obtained greater access to food. Females were generally weaker competitors than males. Individual sex and sex of the opponent also affected duration of begging bouts. Present results thus show that competition with siblings can make the rearing environment variably harsh for developing chicks, depending on individual sex, sex of competing broodmates and age ranking within the nest. They also suggest that parental decisions on the allocation of care and response of kin to signalling siblings may further contribute to the outcome of sibling competition. PMID- 20943689 TI - Spatial niche partitioning in dinosaurs from the latest cretaceous (Maastrichtian) of North America. AB - We examine patterns of occurrence of associated dinosaur specimens (n = 343) from the North American Upper Cretaceous Hell Creek Formation and equivalent beds, by comparing their relative abundance in sandstone and mudstone. Ceratopsians preferentially occur in mudstone, whereas hadrosaurs and the small ornithopod Thescelosaurus show a strong association with sandstone. By contrast, the giant carnivore Tyrannosaurus rex shows no preferred association with either lithology. These lithologies are used as an indicator of environment of deposition, with sandstone generally representing river environments, and finer grained sediments typically representing floodplain environments. Given these patterns of occurrence, we argue that spatial niche partitioning helped reduce competition for resources between the herbivorous dinosaurs. Within coastal lowlands ceratopsians preferred habitats farther away from rivers, whereas hadrosaurs and Thescelosaurus preferred habitats in close proximity to rivers, and T. rex, the ecosystem's sole large carnivore, inhabited both palaeoenvironments. Spatial partitioning of the environment helps explain how several species of large herbivorous dinosaurs coexisted. This study emphasizes that different lithologies can preserve dramatically dissimilar vertebrate assemblages, even when deposited in close proximity and within a narrow window of time. The lithology in which fossils are preserved should be recorded as these data can provide unique insights into the palaeoecology of the animals they preserve. PMID- 20943690 TI - Unravelling the structure of species extinction risk for predictive conservation science. AB - Extinction risk varies across species and space owing to the combined and interactive effects of ecology/life history and geography. For predictive conservation science to be effective, large datasets and integrative models that quantify the relative importance of potential factors and separate rapidly changing from relatively static threat drivers are urgently required. Here, we integrate and map in space the relative and joint effects of key correlates of The International Union for Conservation of Nature-assessed extinction risk for 8700 living birds. Extinction risk varies significantly with species' broad-scale environmental niche, geographical range size, and life-history and ecological traits such as body size, developmental mode, primary diet and foraging height. Even at this broad scale, simple quantifications of past human encroachment across species' ranges emerge as key in predicting extinction risk, supporting the use of land-cover change projections for estimating future threat in an integrative setting. A final joint model explains much of the interspecific variation in extinction risk and provides a remarkably strong prediction of its observed global geography. Our approach unravels the species-level structure underlying geographical gradients in extinction risk and offers a means of disentangling static from changing components of current and future threat. This reconciliation of intrinsic and extrinsic, and of past and future extinction risk factors may offer a critical step towards a more continuous, forward-looking assessment of species' threat status based on geographically explicit environmental change projections, potentially advancing global predictive conservation science. PMID- 20943691 TI - Adaptation to local ultraviolet radiation conditions among neighbouring Daphnia populations. AB - Understanding the historical processes that generated current patterns of phenotypic diversity in nature is particularly challenging in subdivided populations. Populations often exhibit heritable genetic differences that correlate with environmental variables, but the non-independence among neighbouring populations complicates statistical inference of adaptation. To understand the relative influence of adaptive and non-adaptive processes in generating phenotypes requires joint evaluation of genetic and phenotypic divergence in an integrated and statistically appropriate analysis. We investigated phenotypic divergence, population-genetic structure and potential fitness trade-offs in populations of Daphnia melanica inhabiting neighbouring subalpine ponds of widely differing transparency to ultraviolet radiation (UVR). Using a combination of experimental, population-genetic and statistical techniques, we separated the effects of shared population ancestry and environmental variables in predicting phenotypic divergence among populations. We found that native water transparency significantly predicted divergence in phenotypes among populations even after accounting for significant population structure. This result demonstrates that environmental factors such as UVR can at least partially account for phenotypic divergence. However, a lack of evidence for a hypothesized trade-off between UVR tolerance and growth rates in the absence of UVR prevents us from ruling out the possibility that non-adaptive processes are partially responsible for phenotypic differentiation in this system. PMID- 20943692 TI - Predation selects for increased immune function in male damselflies, Calopteryx splendens. AB - Predation selects for numerous traits in many animal species, with sick or parasitized prey often being at high risk. When challenged by parasites and pathogens, prey with poor immune functions are thus likely to be at a selective disadvantage. We tested the hypothesis that predation by birds selects for increased immune function in a wild population of male damselflies Calopteryx splendens, while controlling for a trait known to be under selection by bird predation, dark wing-spots. We found that selection on both immune function and wing-spot size was significantly positive, and that selection on either trait was independent of selection on the other. We found no evidence of nonlinear quadratic or correlational selection. In contrast to previous studies, we found no phenotypic correlation between immune function and wing-spot size. There was also no difference in immune response between territorial and non-territorial males. Our study suggests that predation may be an important agent of selection on the immune systems of prey, and because the selection we detected was directional, has the potential to cause phenotypic change in populations. PMID- 20943693 TI - Spatial and temporal signatures of fragility and threshold proximity in modelled semi-arid vegetation. AB - Understanding the behaviour of complex environmental systems, particularly as critical thresholds are approached, is vitally important in many contexts. Among these are the moisture-limited vegetation systems in semi-arid (SA) regions of the World, which support approximately 36 per cent of the human population, maintain considerable biodiversity and which are susceptible to rapid stress induced collapse. Change in spatially self-organized vegetation patterning has previously been proposed as a means of identifying approaching thresholds in these systems. In this paper, a newly developed cellular automata model is used to explore spatial patterning and also the temporal dynamics of SA vegetation cover. Results show, for the first time, to my knowledge, in a cellular automata model, that 'critical slowdown' (a pronounced reduction in post-perturbation recovery rates) provides clear signals of system fragility as major thresholds are approached. A consequence of slowing recovery rates is the appearance of quasi-stable population states and increased potential for perturbation-induced multi-staged population collapse. The model also predicts a non-patterned cover where environmental stress levels are high, or where more moderate stress levels are accompanied by frequent perturbations. In the context of changing climatic and environmental pressures, these results provide observable indicators of fragility and threshold proximity in SA vegetation systems that have direct relevance to management policies. PMID- 20943694 TI - Smells like aphids: orchid flowers mimic aphid alarm pheromones to attract hoverflies for pollination. AB - Most insects are dependent on chemical communication for activities such as mate finding or host location. Several plants, and especially orchids, mimic insect semiochemicals to attract insects for unrewarded pollination. Here, we present a new case of pheromone mimicry found in the terrestrial orchid Epipactis veratrifolia. Flowers are visited and pollinated by several species of aphidophagous hoverflies, the females of which also often lay eggs in the flowers. The oviposition behaviour of these hoverflies is mainly guided by aphid derived kairomones. We show that the flowers produce alpha- and beta-pinene, beta myrcene and beta-phellandrene, and that these compounds attract and induce oviposition behaviour in female hoverflies. This floral odour profile is remarkably similar to the alarm pheromone released by several aphid species, such as Megoura viciae. We therefore suggest that E. veratrifolia mimics aphid alarm pheromones to attract hoverflies for pollination; this is the first time, to our knowledge, that such a case of mimicry has been demonstrated. PMID- 20943695 TI - Individual differences in plasticity and sampling when playing behavioural games. AB - When engaged in behavioural games, animals can adjust their use of alternative tactics until groups reach stable equilibria. Recent theory on behavioural plasticity in games predicts that individuals should differ in their plasticity or responsiveness and hence in their degree of behavioural adjustment. Moreover, individuals are predicted to be consistent in their plasticity within and across biological contexts. These predictions have yet to be tested empirically and so we examine the behavioural adjustment of individual nutmeg mannikins (Lonchura punctulata), gregarious ground-feeding passerines, when playing two different social foraging games: producer-scrounger (PS) and patch-choice (PC) games. We found: (i) significant individual differences in plasticity and sampling behaviour in each of the two games, (ii) individual differences in sampling behaviour were consistent over different test conditions within a game (PC) and over a six month period (PS), (iii) but neither individual plasticity nor sampling behaviour was correlated from one social foraging game to another. The rate at which birds sampled alternative tactics was positively associated with seed intake in PS trials but negatively associated in PC trials. These results suggest that games with frequency dependence of pay-offs can maintain differences in behavioural plasticity but that an important component of this plasticity is group- and/or context-specific. PMID- 20943696 TI - Efficacy model for antibody-mediated pre-erythrocytic malaria vaccines. AB - Antibodies to the pre-erythrocytic antigens, circumsporozoite protein (CSP), thrombospondin-related adhesive protein (TRAP) and liver-stage antigen 1, have been measured in field studies of semi-immune adults and shown to correlate with protection from Plasmodium falciparum infection. A mathematical model is formulated to estimate the probability of sporozoite infection as a function of antibody titres to multiple pre-erythrocytic antigens. The variation in antibody titres from field data was used to estimate the relationship between the probability of P. falciparum infection per infectious mosquito bite and antibody titre. Using this relationship, we predict the effect of vaccinations that boost baseline CSP or TRAP antibody titres. Assuming the estimated relationship applies to vaccine-induced antibody titres, then single-component CSP or TRAP antibody mediated pre-erythrocytic vaccines are likely to provide partial protection from infection, with vaccine efficacy of approximately 50 per cent depending on the magnitude of the vaccine-induced boost to antibody titres. It is possible that the addition of a TRAP component to a CSP-based vaccine such as RTS,S would provide an increase in infection-blocking efficacy of approximately 25 per cent should the problem of immunological interference between antigens be overcome. PMID- 20943697 TI - Over-imitation is better explained by norm learning than by distorted causal learning. AB - In over-imitation, children copy even elements of a goal-directed action sequence that appear unnecessary for achieving the goal. We demonstrate in 4-year olds that the unnecessary action is specifically associated with the goal, not generally associated with the apparatus. The unnecessary action is performed flexibly: 4-year olds usually omit it if it has already been performed by an adult. Most 5-year olds do not verbally report the unnecessary action as necessary when achieving the goal, although most of them report an equivalent but necessary action as necessary. Most 5-year olds explain the necessary action in functional terms, but are unsure as to the function of the unnecessary action. These verbal measures do not support the hypothesis that children over-imitate primarily because they encode unnecessary actions as causing the goal even in causally transparent systems. In a causally transparent system, explanations for over-imitation fitting the results are that children are ignorant of the unnecessary action's purpose, and that they learn a prescriptive norm that it should be carried out. In causally opaque systems, however, for children and for adults, any action performed before achieving the goal is likely to be inferred as causally necessary-this is not over-imitation, but ordinary causal learning. PMID- 20943698 TI - Plasmodium relictum infection and MHC diversity in the house sparrow (Passer domesticus). AB - Antagonistic coevolution between hosts and parasites has been proposed as a mechanism maintaining genetic diversity in both host and parasite populations. In particular, the high level of genetic diversity usually observed at the major histocompatibility complex (MHC) is generally thought to be maintained by parasite-driven selection. Among the possible ways through which parasites can maintain MHC diversity, diversifying selection has received relatively less attention. This hypothesis is based on the idea that parasites exert spatially variable selection pressures because of heterogeneity in parasite genetic structure, abundance or virulence. Variable selection pressures should select for different host allelic lineages resulting in population-specific associations between MHC alleles and risk of infection. In this study, we took advantage of a large survey of avian malaria in 13 populations of the house sparrow (Passer domesticus) to test this hypothesis. We found that (i) several MHC alleles were either associated with increased or decreased risk to be infected with Plasmodium relictum, (ii) the effects were population specific, and (iii) some alleles had antagonistic effects across populations. Overall, these results support the hypothesis that diversifying selection in space can maintain MHC variation and suggest a pattern of local adaptation where MHC alleles are selected at the local host population level. PMID- 20943699 TI - Primate extinction risk and historical patterns of speciation and extinction in relation to body mass. AB - Body mass is thought to influence diversification rates, but previous studies have produced ambiguous results. We investigated patterns of diversification across 100 trees obtained from a new Bayesian inference of primate phylogeny that sampled trees in proportion to their posterior probabilities. First, we used simulations to assess the validity of previous studies that used linear models to investigate the links between IUCN Red List status and body mass. These analyses support the use of linear models for ordinal ranked data on threat status, and phylogenetic generalized linear models revealed a significant positive correlation between current extinction risk and body mass across our tree block. We then investigated historical patterns of speciation and extinction rates using a recently developed maximum-likelihood method. Specifically, we predicted that body mass correlates positively with extinction rate because larger bodied organisms reproduce more slowly, and body mass correlates negatively with speciation rate because smaller bodied organisms are better able to partition niche space. We failed to find evidence that extinction rates covary with body mass across primate phylogeny. Similarly, the speciation rate was generally unrelated to body mass, except in some tests that indicated an increase in the speciation rate with increasing body mass. Importantly, we discovered that our data violated a key assumption of sample randomness with respect to body mass. After correcting for this bias, we found no association between diversification rates and mass. PMID- 20943701 TI - Self-monitoring for patients on warfarin? AB - One estimate suggests that at least 1 million people in the UK are on the anticoagulant warfarin.1 This number could increase as more people are treated with the drug for atrial fibrillation and as the elderly population increases.1 Careful control of anticoagulation is essential with warfarin therapy and, traditionally, patients on the drug have had to travel to a clinic to have their blood coagulation time tested. However, the availability of portable self-testing machines makes it possible for some patients to monitor their blood coagulation time at home. Here we examine the evidence on the efficacy and safety of such self-monitoring and consider which patients it most suits and whether more widespread use of the approach is justified. PMID- 20943702 TI - Sex hormone-binding globulin concentrations before conception as a predictor for gestational diabetes in women with polycystic ovary syndrome. AB - BACKGROUND: Low plasma sex hormone-binding globulin (SHBG) concentrations during pregnancy have been associated with the risk of developing gestational diabetes mellitus (GDM). Women presenting with polycystic ovary syndrome (PCOS) often exhibit low plasma SHBG concentration and are at increased risk of developing GDM. In this study, we investigate whether SHBG levels before conception are predictive of GDM in women with PCOS. METHODS: A total of 50 women with PCOS were enrolled and followed up during pregnancy. Initial endocrine, metabolic and physical features were assessed according to a standardized preconception screening program. At 24-26 weeks of gestational age a 100-g glucose tolerance test was performed to screen for GDM. RESULTS: Of the 50 women, 21 (42%) were diagnosed with GDM by a 100-g glucose tolerance test. Waist circumference, BMI, blood pressure, plasma glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR) and SHBG levels before conception were significantly different between women who did and did not develop GDM. Stepwise logistic regression analysis showed that SHBG was the most significant predictive parameter for GDM (odds ratio 0.92; 95% confidence interval 0.87-0.97), without significant contribution of waist circumference and HOMA-IR. Receiver operator characteristic (ROC) analysis indicated that plasma SHBG (area under the curve 0.86) had the highest predictive value for subsequent development of GDM, however, the limited group size did not allow for calculation of a threshold value of SHBG. CONCLUSIONS: In women with PCOS, preconception SHBG levels are strongly associated with subsequent development of GDM. Regression and ROC analysis show that preconception SHBG levels may be a better predictor for GDM in PCOS women compared with waist circumference or HOMA-IR. CLINICAL TRIAL REGISTRATION NUMBER: NCT00821379. PMID- 20943703 TI - Comparison of IVF cycles reported in a voluntary ART registry with a mandatory registry in Spain. AB - BACKGROUND: Monitoring assisted reproductive technology (ART) is essential to evaluate the performance of fertility treatment and its impact on birth rates. In Europe, there are two kinds of ART registers: voluntary and mandatory. The validity of register data is very important with respect to the quality of register-based observational studies. The aim of this paper is to determine the degree of agreement between voluntary and mandatory ART registers. METHODS: The two sources for the data compared in this study (referring to 2005 and 2006) were FIVCAT.NET (an official compulsory Assisted Reproduction Registry within the Health Ministry of the Regional Government of Catalonia, to which all authorized clinics, both public and private, performing assisted reproduction in the region are obliged to report) and the register of the Spanish Fertility Society (SEF), to which data are provided on a voluntary basis. The SEF register data were divided into two groups: (i) data from clinics in Catalonia (SEF-CAT); (ii) data from the rest of Spain, excluding Catalonia (SEF-wCAT). The techniques compared were IVF cycle using patients' own eggs (IVF cycle) versus donor egg cycles. RESULTS: For IVF cycles, the voluntary ART register reflected 77.2% of those on the official one, but the corresponding figure was only 34.4% with respect to donated eggs. The variables analysed in the IVF cycle (insemination technique used, patients' age, number of embryos transferred, pregnancy rates, multiple pregnancies and deliveries) were similar in the three groups studied. However, we observed significant differences in donor egg cycles with regard to the insemination technique used, pregnancy rates and multiple pregnancies between the voluntary and the official register. CONCLUSIONS: Data from the voluntary ART register for IVF cycles are valid, but those for donor egg cycles are not. Further study is necessary to determine the reasons for this difference. PMID- 20943704 TI - Y chromosome microdeletions are not associated with spontaneous recurrent pregnancy loss in a Sinhalese population in Sri Lanka. AB - BACKGROUND: Many advances have been made in reproductive medicine, yet the spontaneous loss of a pregnancy remains the most common complication of pregnancy. The aetiology of spontaneous recurrent pregnancy loss (RPL) is multifactorial. Y chromosome microdeletions are found in ~7% of men with low sperm counts and, compared with the general population, a higher frequency of spontaneous pregnancy loss occurs in infertile couples. The current study was designed to examine whether Y chromosome microdeletions were associated with RPL in a Sinhalese population in Sri Lanka. METHODS: The subjects were 76 male partners of couples where the female partner had experienced three or more RPLs. One hundred and twenty random males from the general population were also analysed as a control group. DNA extracted from peripheral blood was tested for Y chromosome microdeletions in the azoospermic factor (AZF), AZFa, AZFb, AZFc regions using a multiplex PCR amplification system. Partial deletions within the AZFc region were also tested. RESULTS: None of the men (76 with RPL, and the 120 controls) had any microdeletions in the AZFa, AZFb, AZFc regions or partial deletions in the AZFc region. CONCLUSIONS: Y chromosome microdeletions do not appear to be important in the aetiology of RPL in this population in Sri Lanka. PMID- 20943705 TI - Low-dose aspirin therapy and hypertensive pregnancy complications in unselected IVF and ICSI patients: a randomized, placebo-controlled, double-blind study. AB - BACKGROUND: Low-dose aspirin therapy could improve remodelling of maternal spiral arteries during early placentation and prevent subsequent pregnancy-related hypertensive disorders. We investigated whether low-dose aspirin therapy reduces the incidence of hypertensive pregnancy complications in unselected IVF and ICSI patients when medication was started prior to pregnancy. METHODS: A total of 487 patients who underwent IVF/ICSI were randomized to receive 100 mg aspirin (n = 242) or placebo (n = 245) daily, starting on the first day of gonadotrophin stimulation. Pregnant women continued the medication until delivery. A total of 107 patients (52 with aspirin and 55 with placebo) experienced live birth and were included in this follow-up study. The main outcome measure was the incidence of hypertensive pregnancy complications. RESULTS: Embryo transfer took place in 227 (94%) women in the aspirin group and in 229 (93%) women in the placebo group. The live birth rate between the aspirin (22.9%) and placebo (24.0%) groups did not differ significantly (P = 0.78). The overall incidence of hypertensive pregnancy complications was 15.4% (8/52) in the aspirin group and 18.2% (10/55) in the placebo group (P = 0.70, 95% confidence interval for the difference of proportions -17 to 11%). There were two cases of severe pre-eclampsia in the aspirin group and three cases in the placebo group. CONCLUSIONS: In the present study, the incidence of hypertensive pregnancy complications did not differ statistically significantly between low-dose aspirin and placebo groups in unselected IVF/ICSI patients, when medication was started concomitantly with gonadotrophin stimulation and continued until delivery. The study was registered at clinicaltrials.gov. NCT00683202. PMID- 20943706 TI - No influence of body mass index on first trimester fetal growth. PMID- 20943707 TI - Changes in the nuclear deposition of histone H2A variants during pre-implantation development in mice. AB - Histone H2A has several variants, and changes in chromatin composition associated with their replacement might involve chromatin structure remodeling. We examined the dynamics of the canonical histone H2A and its three variants, H2A.X, H2A.Z and macroH2A, in the mouse during oogenesis and pre-implantation development when genome remodeling occurs. Immunocytochemistry with specific antibodies revealed that, although H2A and all variants were deposited in the nuclei of full-grown oocytes, only histone H2A.X was abundant in the pronuclei of one-cell embryos after fertilization, in contrast with the low abundance of histone H2A and the absence of H2A.Z. The decline in H2A and the depletion of H2A.Z and macroH2A after fertilization were confirmed using Flag epitope-tagged H2A, H2A.Z and macroH2A transgenic mouse lines. Microinjection experiments with mRNA encoding the Flag-tagged proteins revealed a similar pattern of nuclear incorporation of the H2A variants. Fusion protein experiments using H2A, H2A.Z and macroH2A fused with the C-terminal 23 amino acids of H2A.X showed that the C-terminal amino acids of H2A.X function specifically to target this variant histone into chromatin in embryos after fertilization and that the absence of H2A.Z and macroH2A from the chromatin is required for normal development. These results suggest that global changes in the composition of histone H2A variants in chromatin play a role in genome remodeling after fertilization. PMID- 20943708 TI - Id2a influences neuron and glia formation in the zebrafish retina by modulating retinoblast cell cycle kinetics. AB - Inhibitor of differentiation (Id) family helix-loop-helix proteins regulate the proliferation, survival and differentiation of numerous cell types during development; however, their functions during retinal development have not been analyzed. Using loss-of-function and overexpression assays in zebrafish, we demonstrate that Id2a levels modulate retinoblast cell cycle kinetics and thereby influence neuron and glia formation in the retina. Id2a-deficient retinas possess increased numbers of cells occupying S phase, at the expense of mitotic cells, and kinetic analyses demonstrate that Id2a is required for S-phase progression and/or the transition from S to M phase. Id2a-dependent defects in retinoblast proliferation lead to microphthalmia and to an absence of nearly all differentiated inner and outer nuclear layer cell types. Overexpression of id2a has the opposite effect on retinoblast cell cycle kinetics: id2a-overexpressing retinoblasts progress from S to M phase more rapidly and they undergo mitosis more frequently, which results in macrophthalmia. Mosaic analyses reveal that Id2a function in facilitating both cell cycle progression and neuronal differentiation in the retina is non-cell-autonomous, suggesting that Id2a functions upstream of the extrinsic pathways that regulate retinogenesis. PMID- 20943709 TI - OSBP- and FAN-mediated sterol requirement for spermatogenesis in Drosophila. AB - Members of the oxysterol binding protein (OSBP) family are involved in diverse biological processes, including non-vesicular sterol transport and vesicle trafficking. The mechanisms by which OSBPs integrate functionally with developmental and physiological processes remain elusive. Here, we report the in vivo analysis of OSBP function in the model organism Drosophila. Osbp mutants are male-sterile and exhibit defects in individualization, the process by which each spermatid is packaged into its own membrane. Overexpression of OSBP leads to post eclosion behaviour defects that can be suppressed by co-expression of endoplasmic reticulum-specific VAP family proteins. Most notably, FAN, a testis-specific VAP protein, acts together with OSBP genetically and physically to regulate the individualization process. OSBP-positive and sterol-enriched speckles are found at the leading edge of the individualization complex in wild type but not in Osbp or fan mutants, suggesting that sterol trafficking might play key roles during the membrane-remodelling phase of individualization. In addition, Osbp mutants that are fed additional sterols partially recover fertility, implying that male sterility is attributable to sterol shortage. Thus, we have identified an OSBP- and FAN-mediated sterol requirement in Drosophila spermatogenesis. PMID- 20943710 TI - The effectiveness of continuous passive motion on range of motion, pain and muscle strength following rotator cuff repair: a systematic review. AB - OBJECTIVE: To systematically review the evidence on the effect of continuous passive motion, combined with usual physiotherapy management, on increasing shoulder joint range of motion and muscle strength, and reducing shoulder pain in adults following rotator cuff repair, compared with standard physiotherapy. DATA SOURCES: A comprehensive search in available bibliographic electronic databases was undertaken to locate eligible studies. Reference tracing was also used to locate studies. REVIEW METHODS: Randomized controlled trials reporting on the effect of continuous passive motion on increasing shoulder joint range of motion and muscle strength and reducing shoulder pain in adults following rotator cuff repair were included in the review. The PEDro scale was used to determine the methodological quality of the studies. Data were summarized in a narrative form because of their heterogeneity. RESULTS: Four randomized controlled trials were eligible for this review. One Japanese article was excluded as the text was unavailable in English. The methodological quality of the included studies averaged 7.67. Continuous passive motion was found to improve shoulder range of motion in two studies. One study found a decrease in pain in the intervention group and one study found that continuous passive motion improves muscle strength. CONCLUSION: Continuous passive motion is safe to use with physiotherapy treatment following rotator cuff repair surgery. It may help to prevent secondary complications post operatively. PMID- 20943711 TI - Comparison of different treatment protocols in the treatment of idiopathic detrusor overactivity: a randomized controlled trial. AB - OBJECTIVE: To investigate and compare the effectiveness of various treatment protocols for the treatment of women with idiopathic detrusor overactivity. DESIGN: Prospective, randomized controlled trial. SETTING: Departments of Physiotherapy and Rehabilitation and Obstetrics and Gynaecology, Hacettepe University. SUBJECTS: Forty-six subjects were randomized to three groups. INTERVENTIONS: The first group received only pharmacotherapy, the second group received only physiotherapy and in the third group pharmacotherapy was combined with physiotherapy (combined therapy group). MAIN MEASURES: All patients were evaluated at the beginning and at the end of treatment. Assessment parameters were maximum cystometric capacity, electromyographic activity of pelvic floor muscles, voiding diary parameters, the amount of urine leakage and the quality of life score. RESULTS: The maximum cystometric capacity and the electromyographic activity of pelvic floor muscles increased significantly and the number of voids/day and incontinence episodes/day, and the amount of urine leakage reduced significantly (P < 0.05) in both physiotherapy and combined therapy groups while there was no significant difference in the pharmacotherapy group. After treatment, the number of voids/day increased by 0.3 +/- 3.4 in the pharmacotherapy group (P > 0.05) and decreased by 5.1 +/- 5.5 and 4.7 +/- 5.6 in the physiotherapy and combined therapy groups, respectively (P < 0.05). Statistically significant improvements were observed in all groups according to the number of voids/night and the quality of life scores at the end of the treatment. CONCLUSION: The physiotherapy protocol we introduced in the present study with or without anticholinergic therapy has a substantial positive impact on the treatment of female patients with idiopathic detrusor overactivity. PMID- 20943712 TI - Psychometric validation of the Multidimensional Acceptance of Loss Scale. AB - OBJECTIVE: To develop and field test the Multidimensional Acceptance of Loss Scale to measure disability acceptance based on the four value changes identified by Beatrice Wright. DESIGN: Quantitative descriptive design using exploratory factor analysis to determine the factorial validity of the Multidimensional Acceptance of Loss Scale. SETTING: The Canadian Paraplegic Association. SUBJECTS: One hundred and sixty-one members of the Alberta, Saskatchewan, Nova Scotia and Manitoba chapters of the Canadian Paraplegic Association were recruited for the current study. RESULTS: A four-factor structure accounting for 50% of the total variance was found for the Multidimensional Acceptance of Loss Scale. The internal consistency reliability coefficients (Cronbach's alpha) for the four factors ranged from 0.80 to 0.88. Three clusters of participants with high, moderate and low disability acceptance were identified based on their profiles of Multidimensional Acceptance of Loss Scale subscale scores using cluster analysis. MANOVA results indicated that participants in the three clusters significantly differed on self-esteem, F(2, 154) = 19.78, P < 0.001 and quality of life, F(8, 236) = 5.16, P < 0.001. Participants with high Multidimensional Acceptance of Loss Scale scores have higher self-esteem and quality of life scores than those with lower scores. CONCLUSION: The Multidimensional Acceptance of Loss Scale was found to measure the four value changes in Beatrice Wright's disability acceptance theory in a sample of Canadians with spinal cord injuries. It demonstrated good internal consistency reliability and construct validity. PMID- 20943713 TI - Daily physical activity of patients with the chronic fatigue syndrome: a systematic review. AB - OBJECTIVE: To give an overview of the physical activity level of patients with chronic fatigue syndrome in comparison with asymptomatic controls. DATA SOURCES: MEDLINE, Web of Science, EMBASE, PsycINFO, Picarta, the Cochrane Controlled Trial Register that is included in the Cochrane Library and reference tracking. REVIEW METHODS: A systematic literature search was conducted focusing on studies concerning physical activity levels of patients with chronic fatigue syndrome compared to controls. A meta-analysis was performed to pool data of the studies. RESULTS: Seventeen studies were included with 22 different comparisons between patients with chronic fatigue syndrome and controls. Fourteen studies, including 18 comparisons, showed lower physical activity levels in patients with chronic fatigue syndrome as compared to controls. Four studies, including four comparisons, showed no differences between both groups. The meta-analysis included seven studies and showed a daily physical activity level in patients with chronic fatigue syndrome of only 68% of the physical activity level observed in control subjects. The pooled mean coefficient of variation in patients with chronic fatigue syndrome was higher as compared to control subjects (34.3% versus 31.5%), but this difference did not reach significance. CONCLUSION: Patients with chronic fatigue syndrome appear to be less physically active compared with asymptomatic controls. There is no difference in variation of physical activity levels between patients with chronic fatigue syndrome and healthy control subjects, but the validity and reliability of some methods of measuring physical activity is questionable or unknown. PMID- 20943714 TI - Pedometer-based gait training in children with spastic hemiparetic cerebral palsy: a randomized controlled study. AB - OBJECTIVE: To study the effect of pedometer-based gait training on changing gait parameters in children with spastic hemiparetic cerebral palsy. DESIGN: Two group randomized controlled trial with pre-treatment and post-treatment measures. SETTING: Rehabilitation clinics. SUBJECTS: Thirty spastic hemiparetic children with cerebral palsy of both sexes (13 females and 17 males) ranging in age from six to eight years old with mean age 7.05 +/- 0.78 years. INTERVENTIONS: Children were randomized equally to receive pedometer-based gait training or a traditional gait training programme three times per week for three successive months. MAIN MEASURES: Assessment was done before and after three months of treatment application using 3D motion analysis system with six pro-reflex cameras to evaluate spatiotemporal gait parameters. The primary outcome measure was the walking velocity while the secondary outcome measures were stride length, cadence and cycle duration. RESULTS: There was a high statistically significant improvement in favour of the study group more than the control group concerning all the measured gait parameters. T-test results showed that velocity was 0.68 +/ 0.09 m/sec (0.26 +/- 0.07 change score) for study group and 0.42 +/- 0.11 m/sec (0.06 +/- 0.05 change score) for control group (t = 6.2) (P < 0.0001) while cadence was much less significant 124.3 +/- 4.3 step/min (-5.8 +/- 2.1 change score) for study group and 128.7 +/- 4.1 step/min (-0.86 +/- 0.05 change score) for control group (t = 2.8) (P < 0.008). CONCLUSION: Pedometer-based gait training is a useful tool that can be used in improving gait parameters in children with spastic hemiparetic cerebral palsy. PMID- 20943715 TI - Visual and kinesthetic locomotor imagery training integrated with auditory step rhythm for walking performance of patients with chronic stroke. AB - OBJECTIVE: To compare the effect of visual and kinesthetic locomotor imagery training on walking performance and to determine the clinical feasibility of incorporating auditory step rhythm into the training. DESIGN: Randomized crossover trial. SETTING: Laboratory of a Department of Physical Therapy. SUBJECTS: Fifteen subjects with post-stroke hemiparesis. INTERVENTION: Four locomotor imagery trainings on walking performance: visual locomotor imagery training, kinesthetic locomotor imagery training, visual locomotor imagery training with auditory step rhythm and kinesthetic locomotor imagery training with auditory step rhythm. MAIN OUTCOME MEASURES: The timed up-and-go test and electromyographic and kinematic analyses of the affected lower limb during one gait cycle. RESULTS: After the interventions, significant differences were found in the timed up-and-go test results between the visual locomotor imagery training (25.69 +/- 16.16 to 23.97 +/- 14.30) and the kinesthetic locomotor imagery training with auditory step rhythm (22.68 +/- 12.35 to 15.77 +/- 8.58) (P < 0.05). During the swing and stance phases, the kinesthetic locomotor imagery training exhibited significantly increased activation in a greater number of muscles and increased angular displacement of the knee and ankle joints compared with the visual locomotor imagery training, and these effects were more prominent when auditory step rhythm was integrated into each form of locomotor imagery training. The activation of the hamstring during the swing phase and the gastrocnemius during the stance phase, as well as kinematic data of the knee joint, were significantly different for posttest values between the visual locomotor imagery training and the kinesthetic locomotor imagery training with auditory step rhythm (P < 0.05). CONCLUSIONS: The therapeutic effect may be further enhanced in the kinesthetic locomotor imagery training than in the visual locomotor imagery training. The auditory step rhythm together with the locomotor imagery training produces a greater positive effect in improving the walking performance of patients with post-stroke hemiparesis. PMID- 20943716 TI - Which treatment approach is better for hemiplegic shoulder pain in stroke patients: intra-articular steroid or suprascapular nerve block? A randomized controlled trial. AB - OBJECTIVE: To determine which injection technique was effective for patients with hemiplegic shoulder pain. DESIGN: Randomized prospective double-blind study. SETTING: Brain Injury Rehabilitation Unit. INTERVENTION: Patients with hemiplegic shoulder pain were recruited over a 12-month period and all were hospitalized in our clinic. Intra-articular steroid injection or suprascapular nerve block was performed on all patients. MAIN MEASURES: Range of motion values at the moment that pain started (range of motion A) and passive maximum range of motion values (range of motion B) were recorded. Pain intensity levels (visual analogue scale) at these two range of motion values (pain A and pain B) were also taken. Evaluations were made before the injection, and 1 hour, one week and one month after the injection. RESULTS: Twenty-six patients were enrolled in the study, the mean age was 61.53 +/- 10.30 years. The mean time since injury was 8.69 +/- 15.71 months. The aetiology was ischaemic in 16 (61%) patients. Intra-articular steroid injection was performed in 11 (42 %) patients, and suprascapular nerve block in 15 (57%) patients. Range of motion A and range of motion B were changed statistically in repeated measures. There were important differences in repeated measures of pain intensity levels at these two range of motion values (P < 0.05). However, no significant differences were determined in all measurements between intra-articular steroid injection and suprascapular nerve block groups (P > 0.05). CONCLUSIONS: Our results showed that neither injection technique was superior to the other. Both injection procedures are safe and have a similar effect in stroke patients with hemiplegic shoulder pain. PMID- 20943717 TI - Effects of long-term exercise training on cardiac baroreflex sensitivity in patients with coronary artery disease: a randomized controlled trial. AB - OBJECTIVE: To investigate whether a structured long-term exercise training programme in patients with coronary artery disease affects baroreflex function and cardiorespiratory efficiency. PATIENTS: Twenty-five elderly male patients with coronary artery disease. METHODS: The patients were randomized into exercise (group A) or control group (group B). Group A followed a seven-month supervised exercise programme, consisting of three sessions of aerobic interval training weekly at moderate intensity. Twenty patients completed the study (group A: 10 patients and group B: 10 patients). At the beginning and end of the study, all subjects underwent a tilt test for the baroreflex sensitivity assessment and a graded exercise treadmill test with spiroergometry for the evaluation of their cardiorespiratory efficiency. RESULTS: There were no differences between the two groups for any baseline variable. After training in group A, peak oxygen consumption, maximal treadmill tolerance time and anaerobic threshold were significantly increased by 21.9% (P < 0.001), 19.8% (P < 0.001) and 18.6% (P < 0.05), respectively. There were also significant increases in baroreflex sensitivity by 21.2% (P < 0.01), in baroreflex effectiveness index by 23.9% (P < 0.01), in event count by 45.1% (P < 0.01) and in ramp count by 13.2% (P < 0.05). Moreover, significant correlations were observed between the autonomic and cardiorespiratory parameters in group A at the end. CONCLUSION: The results suggest that long-term exercise training leads to beneficial effects on baroreflex activity and cardiorespiratory performance in coronary patients, and thus could constitute an efficient nonpharmacological intervention in this population. PMID- 20943718 TI - Simultaneous detection of anti-C1q and anti-double stranded DNA autoantibodies in lupus nephritis: predictive value for renal flares. AB - Clinical difficulties in predicting systemic lupus erythematosus (SLE) renal flares are still encountered. Biological markers such as autoantibodies (aAbs) may be of major interest for clinicians in the follow-up of SLE patients. The aim of our study was to investigate the clinical utility of one of these biological markers, anti-C1q aAbs, in predicting renal flares of SLE nephritis in comparison with the 'gold standard' anti-double stranded DNA (anti-dsDNA) aAbs. Anti-C1q aAbs and anti-dsDNA aAbs were analysed through a longitudinal retrospective study of 23 SLE patients presenting with one or more renal flares. Anti-C1q and/or anti dsDNA aAbs were found in 20 (87%) of 23 patients, of whom 16 (69%) displayed both. Thirty-three renal flares occurred during the course of the study, and anti C1q aAbs and anti-dsDNA aAbs were positive in 25 (76%) and 24 (73%) of these flares respectively. The sensitivity of anti-C1q and/or anti-dsDNA aAbs in predicting renal flares reached 85%. The specificity of anti-C1q aAbs was 84%, of anti-dsDNA aAbs 77% and of both aAbs 97%. Positive and negative predictive values were as follows: 56% and 70% for anti-C1q aAbs, 53% and 72% for anti-dsDNA aAbs. The combination of both aAbs had the highest positive predictive value (69%), whereas absence of both aAbs was associated with the highest negative predictive value (74%). In conclusion, our results confirm that anti-C1q aAbs are present in a significant percentage of SLE patients with active renal involvement, suggesting that these aAbs could be a useful additional marker. The presence of anti-C1q and anti-dsDNA aAbs was associated with a high risk of renal flare, whereas the absence of both aAbs excluded such an event. These data confirm that systematic detection of anti-C1q and anti-dsDNA aAbs is of interest for the follow-up in SLE patients with renal involvement. PMID- 20943719 TI - The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells. AB - Oncogenic conversion of the RET tyrosine kinase is a frequent feature of medullary thyroid carcinoma (MTC). ZD6474 (vandetanib) is an ATP-competitive inhibitor of RET, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptors kinases. In this study, we have studied ZD6474 mechanism of action in TT and MZ-CRC-1 human MTC cell lines, carrying cysteine 634 to tryptophan (C634W) and methionine 918 to threonine (M918T) RET mutation respectively. ZD6474 blunted MTC cell proliferation and RET, Shc and p44/p42 mitogen-activated protein kinase (MAPK) phosphorylation. Single receptor knockdown by RNA interference showed that MTC cells depended on RET for proliferation. Adoptive expression of the ZD6474-resistant V804M RET mutant rescued proliferation of TT cells under ZD6474 treatment, showing that RET is a key ZD6474 target in these MTC cells. Upon RET inhibition, adoptive stimulation of EGFR partially rescued TT cell proliferation, MAPK signaling, and expression of cell-cycle-related genes. This suggests that simultaneous inhibition of RET and EGFR by ZD6474 may overcome the risk of MTC cells to escape from RET blockade through compensatory over-activation of EGFR. PMID- 20943720 TI - FSH inhibits ovarian cancer cell apoptosis by up-regulating survivin and down regulating PDCD6 and DR5. AB - Ovarian epithelial cancer is the leading cause of death among gynecological malignancies. FSH may increase the risk of ovarian malignancy and play an important role in ovarian carcinogenesis. Our previous studies showed that FSH increases the expression of VEGF through survivin. In this study, the function and mechanism of FSH in ovarian cancer were further explored. We found that FSH promoted proliferation and prevented apoptosis of ovarian cancer cells by activating survivin through the SAPK/JNK and PI3K/AKT pathways. FSH also down regulated the expression of programmed cell death gene 6 (PDCD6) and death receptor 5 (DR5), two molecules required for induction of apoptosis. RNA interference was applied to knock down survivin and PDCD6 expression, and we found that the blockage of survivin reversed the effects of FSH on apoptosis and proliferation, whereas knock down of PDCD6 enhanced these effects. The expression of DR5, cyclin D1, and cyclin E correlated with survivin expression, but PDCD6 did not. Using immunohistochemical staining, we further showed that ovarian serous cystadenocarcinoma samples had higher expression of survivin than did benign ovarian cystadenoma and borderline cystadenoma samples (P<0.01). Furthermore, survivin expression in the ovarian serous cystadenocarcinoma specimens was correlated with disease stage (P<0.05). Our results suggest that FSH promotes ovarian cancer development by regulating the expression of survivin, PDCD6, and DR5. Greater understanding of the molecular mechanisms of FSH in ovarian epithelial carcinogenesis and development will ultimately help in the development of a novel targeted therapy for ovarian cancer. PMID- 20943721 TI - Single photon emission computed tomography imaging for temporal dynamics of thyroidal and salivary radionuclide accumulation in 17-allyamino-17 demothoxygeldanamycin-treated thyroid cancer mouse model. AB - Selective iodide uptake and prolonged iodine retention in the thyroid is the basis for targeted radioiodine therapy for thyroid cancer patients; however, salivary gland dysfunction is the most frequent nonthyroidal complications. In this study, we have used noninvasive single photon emission computed tomography functional imaging to quantify the temporal dynamics of thyroidal and salivary radioiodine accumulation in mice. At 60 min post radionuclide injection, radionuclide accumulation in the salivary gland was generally higher than that in thyroid due to much larger volume of the salivary gland. However, radionuclide accumulation per anatomic unit in the salivary gland was lower than that in thyroid and was comparable among mice of different age and gender. Differently, radionuclide accumulation per anatomic unit in thyroid varied greatly among mice. The extent of thyroidal radioiodine accumulation stimulated by a single dose of exogenous bovine TSH (bTSH) in triiodothyronine (T3)-supplemented mice was much less than that in mice received neither bTSH nor T3 (nontreated mice), suggesting that the duration of elevated serum TSH level is important to maximize thyroidal radioiodine accumulation. Furthermore, the extent and duration of radioiodine accumulation stimulated by bTSH was less in the thyroids of the thyroid-targeted RET/PTC1 (thyroglobulin (Tg)-PTC1) mice bearing thyroid tumors compared with the thyroids in wild-type (WT) mice. Finally, the effect of 17-allyamino-17 demothoxygeldanamycin on increasing thyroidal, but not salivary, radioiodine accumulation was validated in both WT mice and Tg-PTC1 preclinical thyroid cancer mouse model. PMID- 20943722 TI - Investigation and management of uveitis. PMID- 20943723 TI - Safer administration of insulin: summary of a safety report from the National Patient Safety Agency. PMID- 20943724 TI - Industry sponsored bias in cost effectiveness analyses. PMID- 20943727 TI - Refugees lack access to tertiary health care, says UN agency. PMID- 20943725 TI - Macromastia (large breasts): request for breast reduction. PMID- 20943729 TI - EU commissioner pursues smoking ban in enclosed public spaces for Europe. PMID- 20943731 TI - Inflammatory bowel disease: a classic case of Dalziel's disease. PMID- 20943730 TI - Mother-adolescent agreement regarding decision-making autonomy: a longitudinal comparison of families of adolescents with and without spina bifida. AB - OBJECTIVE: Longitudinal comparison of mother and adolescent agreement regarding decision-making autonomy for adolescents with and without spina bifida (SB). METHODS: Forty-two mother-adolescent dyads of adolescents with SB and 55 comparison dyads reported on who was responsible for decision-making across five waves of data collection, beginning at age 8 or 9 years through age 16 or 17 years. RESULTS: The proportion of tasks that dyads agreed were decided by adolescents increased over time for both samples beginning at age 12 or 13 years, but appeared to be delayed by roughly two years for youth with SB and was lower for youth with SB from lower socioeconomic (SES) backgrounds. Mothers and adolescents with low SES demonstrated higher proportions of tasks that dyads agreed were decided by mothers. CONCLUSIONS: SB and low SES are risk factors for lower levels of agreed-upon decision-making autonomy. Future studies should examine how parent-adolescent agreement regarding autonomy relates to psychosocial outcomes. PMID- 20943733 TI - A step change in operational performance is needed. PMID- 20943734 TI - Antipsychotics and venous thrombosis. Confounding factors may account for the association. PMID- 20943735 TI - Antipsychotics and venous thrombosis. How do the data change practice decisions in long term care? PMID- 20943736 TI - Antipsychotics and venous thrombosis. Dutch experience differs. PMID- 20943737 TI - Research governance. There is nothing streamlined about the system. PMID- 20943738 TI - White matter hyperintensities on MRI. Lesions are seen in young users of stimulant drugs. PMID- 20943739 TI - Electronic health records. The naked truth. PMID- 20943741 TI - Gates Foundation and UN urge emphasis on positive benefits of vaccination. PMID- 20943745 TI - Debate on sale of donor organs shows equal division of opinion. PMID- 20943746 TI - Exercise-induced abdominal pain: an unusual presentation of chronic mesenteric ischaemia. PMID- 20943747 TI - Enterovirus RNA in blood is linked to the development of type 1 diabetes. AB - OBJECTIVE: To assess whether the detection of enterovirus RNA in blood predicts the development of clinical type 1 diabetes in a prospective birth cohort study. Further, to study the role of enteroviruses in both the initiation of the process and the progression to type 1 diabetes. RESEARCH DESIGN AND METHODS: This was a nested case-control study where all case children (N = 38) have progressed to clinical type 1 diabetes. Nondiabetic control children (N = 140) were pairwise matched for sex, date of birth, hospital district, and HLA-DQ-conferred genetic susceptibility to type 1 diabetes. Serum samples, drawn at 3- to 12-month intervals, were screened for enterovirus RNA using RT-PCR. RESULTS: Enterovirus RNA-positive samples were more frequent among the case subjects than among the control subjects. A total of 5.1% of the samples (17 of 333) in the case group were enterovirus RNA-positive compared with 1.9% of the samples (19 of 993) in the control group (P < 0.01). The strongest risk for type 1 diabetes was related to enterovirus RNA positivity during the 6-month period preceding the first autoantibody-positive sample (odds ratio 7.7 [95% CI 1.9-31.5]). This risk effect was stronger in boys than in girls. CONCLUSIONS: The present study supports the hypothesis that enteroviruses play a role in the pathogenesis of type 1 diabetes, especially in the initiation of the beta-cell damaging process. The enterovirus associated risk for type 1 diabetes may be stronger in boys than in girls. PMID- 20943748 TI - Downregulation of adipose tissue fatty acid trafficking in obesity: a driver for ectopic fat deposition? AB - OBJECTIVE: Lipotoxicity and ectopic fat deposition reduce insulin signaling. It is not clear whether excess fat deposition in nonadipose tissue arises from excessive fatty acid delivery from adipose tissue or from impaired adipose tissue storage of ingested fat. RESEARCH DESIGN AND METHODS: To investigate this we used a whole-body integrative physiological approach with multiple and simultaneous stable-isotope fatty acid tracers to assess delivery and transport of endogenous and exogenous fatty acid in adipose tissue over a diurnal cycle in lean (n = 9) and abdominally obese men (n = 10). RESULTS: Abdominally obese men had substantially (2.5-fold) greater adipose tissue mass than lean control subjects, but the rates of delivery of nonesterified fatty acids (NEFA) were downregulated, resulting in normal systemic NEFA concentrations over a 24-h period. However, adipose tissue fat storage after meals was substantially depressed in the obese men. This was especially so for chylomicron-derived fatty acids, representing the direct storage pathway for dietary fat. Adipose tissue from the obese men showed a transcriptional signature consistent with this impaired fat storage function. CONCLUSIONS: Enlargement of adipose tissue mass leads to an appropriate downregulation of systemic NEFA delivery with maintained plasma NEFA concentrations. However the implicit reduction in adipose tissue fatty acid uptake goes beyond this and shows a maladaptive response with a severely impaired pathway for direct dietary fat storage. This adipose tissue response to obesity may provide the pathophysiological basis for ectopic fat deposition and lipotoxicity. PMID- 20943749 TI - FTO is increased in muscle during type 2 diabetes, and its overexpression in myotubes alters insulin signaling, enhances lipogenesis and ROS production, and induces mitochondrial dysfunction. AB - OBJECTIVE: A strong association between genetic variants and obesity was found for the fat mass and obesity-associated gene (FTO). However, few details are known concerning the expression and function of FTO in skeletal muscle of patients with metabolic diseases. RESEARCH DESIGN AND METHODS: We investigated basal FTO expression in skeletal muscle from obese nondiabetic subjects and type 1 and type 2 diabetic patients, compared with age-matched control subjects, and its regulation in vivo by insulin, glucose, or rosiglitazone. The function of FTO was further studied in myotubes by overexpression experiments. RESULTS: We found a significant increase of FTO mRNA and protein levels in muscle from type 2 diabetic patients, whereas its expression was unchanged in obese or type 1 diabetic patients. Moreover, insulin or glucose infusion during specific clamps did not regulate FTO expression in skeletal muscle from control or type 2 diabetic patients. Interestingly, rosiglitazone treatment improved insulin sensitivity and reduced FTO expression in muscle from type 2 diabetic patients. In myotubes, adenoviral FTO overexpression increased basal protein kinase B phosphorylation, enhanced lipogenesis and oxidative stress, and reduced mitochondrial oxidative function, a cluster of metabolic defects associated with type 2 diabetes. CONCLUSIONS: This study demonstrates increased FTO expression in skeletal muscle from type 2 diabetic patients, which can be normalized by thiazolidinedione treatment. Furthermore, in vitro data support a potential implication of FTO in oxidative metabolism, lipogenesis and oxidative stress in muscle, suggesting that it could be involved in the muscle defects that characterize type 2 diabetes. PMID- 20943750 TI - The Opdc missense mutation of Pax2 has a milder than loss-of-function phenotype. AB - Renal-coloboma syndrome, also known as papillorenal syndrome, is an autosomal dominant human disorder in which optic disc coloboma is associated with kidney abnormalities. Mutations in the paired domain transcription factor PAX2 have been found to be the underlying cause of this disease. Disease severity varies between patients, and in some cases, renal hypoplasia has been found in the absence of any retinal defects. Here we report an N-ethyl-N-nitrosourea-induced mouse mutation, Opdc, which is an isoleucinetothreonine missense mutation, I40T, in the first alpha-helix of the Pax2 paired domain. The mutant protein binds target DNA sequences less strongly than the wild-type protein and acts poorly to transactivate target promoters in culture. The phenotypic consequence of this mutation on the development of the eye and ear is similar to that reported for null alleles of Pax2. However, in homozygotes, cerebellar development is normal on a genetic background in which loss of Pax2 results in failure of cerebellar formation. Moreover, there is a genetic background effect on the heterozygous phenotype such that on some strain backgrounds, kidney development is unaffected. Opdc is the first hypomorphic mutation reported for Pax2 that differs in phenotype from loss-of-function mutations. These results suggest that PAX2 is a strong candidate gene for cases in which human patients have optic disc coloboma not associated with renal dysplasia. PMID- 20943751 TI - Induction of ketosis in rats fed low-carbohydrate, high-fat diets depends on the relative abundance of dietary fat and protein. AB - Low-carbohydrate/high-fat diets (LC-HFDs) in rodent models have been implicated with both weight loss and as a therapeutic approach to treat neurological diseases. LC-HFDs are known to induce ketosis; however, systematic studies analyzing the impact of the macronutrient composition on ketosis induction and weight loss success are lacking. Male Wistar rats were pair-fed for 4 wk either a standard chow diet or one of three different LC-HFDs, which only differed in the relative abundance of fat and protein (percentages of fat/protein in dry matter: LC-75/10; LC-65/20; LC-55/30). We subsequently measured body composition by nuclear magnetic resonance (NMR), analyzed blood chemistry and urine acetone content, evaluated gene expression changes of key ketogenic and gluconeogenic genes, and measured energy expenditure (EE) and locomotor activity (LA) during the first 4 days and after 3 wk on the respective diets. Compared with chow, rats fed with LC-75/10, LC-65/20, and LC-55/30 gained significantly less body weight. Reductions in body weight were mainly due to lower lean body mass and paralleled by significantly increased fat mass. Levels of beta-hydroxybutyate were significantly elevated feeding LC-75/10 and LC-65/20 but decreased in parallel to reductions in dietary fat. Acetone was about 16-fold higher with LC-75/10 only (P < 0.001). In contrast, rats fed with LC-55/30 were not ketotic. Serum fibroblast growth factor-21, hepatic mRNA expression of hydroxymethylglutaryl-CoA-lyase, peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and peroxisome proliferator-activated receptor-gamma coactivator-1beta were increased with LC-75/10 only. Expression of phosphoenolpyruvate carboxykinase and glucose-6 phosphatase was downregulated by 50-70% in LC-HF groups. Furthermore, EE and LA were significantly decreased in all groups fed with LC-HFDs after 3 wk on the diets. In rats, the absence of dietary carbohydrates per se does not induce ketosis. LC-HFDs must be high in fat, but also low in protein contents to be clearly ketogenic. Independent of the macronutrient composition, LC-HFD-induced weight loss is not due to increased EE and LA. PMID- 20943752 TI - Coffee polyphenols suppress diet-induced body fat accumulation by downregulating SREBP-1c and related molecules in C57BL/6J mice. AB - The prevalence of obesity is increasing globally, and obesity is a major risk factor for type 2 diabetes and cardiovascular disease. We investigated the effects of coffee polyphenols (CPP), which are abundant in coffee and consumed worldwide, on diet-induced body fat accumulation. C57BL/6J mice were fed either a control diet, a high-fat diet, or a high-fat diet supplemented with 0.5 to 1.0% CPP for 2-15 wk. Supplementation with CPP significantly reduced body weight gain, abdominal and liver fat accumulation, and infiltration of macrophages into adipose tissues. Energy expenditure evaluated by indirect calorimetry was significantly increased in CPP-fed mice. The mRNA levels of sterol regulatory element-binding protein (SREBP)-1c, acetyl-CoA carboxylase-1 and -2, stearoyl-CoA desaturase-1, and pyruvate dehydrogenase kinase-4 in the liver were significantly lower in CPP-fed mice than in high-fat control mice. Similarly, CPP suppressed the expression of these molecules in Hepa 1-6 cells, concomitant with an increase in microRNA-122. Structure-activity relationship studies of nine quinic acid derivatives isolated from CPP in Hepa 1-6 cells suggested that mono- or di caffeoyl quinic acids (CQA) are active substances in the beneficial effects of CPP. Furthermore, CPP and 5-CQA decreased the nuclear active form of SREBP-1, acetyl-CoA carboxylase activity, and cellular malonyl-CoA levels. These findings indicate that CPP enhances energy metabolism and reduces lipogenesis by downregulating SREBP-1c and related molecules, which leads to the suppression of body fat accumulation. PMID- 20943753 TI - Impact of electro-acupuncture and physical exercise on hyperandrogenism and oligo/amenorrhea in women with polycystic ovary syndrome: a randomized controlled trial. AB - Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenism, oligo/amenorrhea, and polycystic ovaries. We aimed to determine whether low-frequency electro acupuncture (EA) would decrease hyperandrogenism and improve oligo/amenorrhea more effectively than physical exercise or no intervention. We randomized 84 women with PCOS, aged 18-37 yr, to 16 wk of low-frequency EA, physical exercise, or no intervention. The primary outcome measure changes in the concentration of total testosterone (T) at week 16 determined by gas and liquid chromatography mass spectrometry was analyzed by intention to treat. Secondary outcome measures were changes in menstrual frequency; concentrations of androgens, estrogens, androgen precursors, and glucuronidated androgen metabolites; and acne and hirsutism. Outcomes were assessed at baseline, after 16 wk of intervention, and after a 16-wk follow-up. After 16 wk of intervention, circulating T decreased by 25%, androsterone glucuronide by -30%, and androstane-3alpha,17beta-diol-3 glucuronide by -28% in the EA group (P = 0.038, 0.030, and 0.047, respectively vs. exercise); menstrual frequency increased to 0.69/month from 0.28 at baseline in the EA group (P = 0.018 vs. exercise). After the 16-wk follow-up, the acne score decreased by -32% in the EA group (P = 0.006 vs. exercise). Both EA and exercise improved menstrual frequency and decreased the levels of several sex steroids at week 16 and at the 16-wk follow-up compared with no intervention. Low frequency EA and physical exercise improved hyperandrogenism and menstrual frequency more effectively than no intervention in women with PCOS. Low-frequency EA was superior to physical exercise and may be useful for treating hyperandrogenism and oligo/amenorrhea. PMID- 20943755 TI - Limited predictive ability of surrogate indices of insulin sensitivity/resistance in Asian-Indian men. AB - Insulin resistance is highly prevalent in Asian Indians and contributes to worldwide public health problems, including diabetes and related disorders. Surrogate measurements of insulin sensitivity/resistance are used frequently to study Asian Indians, but these are not formally validated in this population. In this study, we compared the ability of simple surrogate indices to accurately predict insulin sensitivity as determined by the reference glucose clamp method. In this cross-sectional study of Asian-Indian men (n = 70), we used a calibration model to assess the ability of simple surrogate indices for insulin sensitivity [quantitative insulin sensitivity check index (QUICKI), homeostasis model assessment (HOMA2-IR), fasting insulin-to-glucose ratio (FIGR), and fasting insulin (FI)] to predict an insulin sensitivity index derived from the reference glucose clamp method (SI(Clamp)). Predictive accuracy was assessed by both root mean squared error (RMSE) of prediction as well as leave-one-out cross-validation type RMSE of prediction (CVPE). QUICKI, FIGR, and FI, but not HOMA2-IR, had modest linear correlations with SI(Clamp) (QUICKI: r = 0.36; FIGR: r = -0.36; FI: r = -0.27; P < 0.05). No significant differences were noted among CVPE or RMSE from any of the surrogate indices when compared with QUICKI. Surrogate measurements of insulin sensitivity/resistance such as QUICKI, FIGR, and FI are easily obtainable in large clinical studies, but these may only be useful as secondary outcome measurements in assessing insulin sensitivity/resistance in clinical studies of Asian Indians. PMID- 20943754 TI - Somatostatin and its receptors contribute in a tissue-specific manner to the sex dependent metabolic (fed/fasting) control of growth hormone axis in mice. AB - Somatostatin (SST) inhibits growth hormone (GH) secretion and regulates multiple processes by signaling through its receptors sst1-5. Differential expression of SST/ssts may contribute to sex-specific GH pattern and fasting-induced GH rise. To further delineate the tissue-specific roles of SST and sst1-5 in these processes, their expression patterns were evaluated in hypothalamus, pituitary, and stomach of male and female mice under fed/fasted conditions in the presence (wild type) or absence (SST-knockout) of endogenous SST. Under fed conditions, hypothalamic/stomach SST/ssts expression did not differ between sexes, whereas male pituitary expressed more SST and sst2A/2B/3/5A/5TMD2/5TMD1 and less sst1, and male pituitary cell cultures were more responsive to SST inhibitory actions on GH release compared with females. This suggests that local pituitary SST/ssts can contribute to the sexually dimorphic pattern of GH release. Fasting (48 h) reduced stomach sst2A/B and hypothalamic SST/sst2A expression in both sexes, whereas it caused a generalized downregulation of pituitary sst subtypes in male and of sst2A only in females. Thus, fasting can reduce SST sensitivity across tissues and SST input to the pituitary, thereby jointly contributing to enhance GH release. In SST-knockout mice, lack of SST differentially altered sst subtype expression levels in both sexes, supporting an important role for SST in sex dependent control of GH axis. Evaluation of SST, IGF-I, and glucocorticoid effects on hypothalamic and pituitary cell cultures revealed that these hormones could directly account for alterations in sst2/5 expression in the physiological states examined. Taken together, these results indicate that changes in SST output and sensitivity can contribute critically to precisely define, in a tissue dependent manner, the sex-specific metabolic regulation of the GH axis. PMID- 20943756 TI - BACE2 plays a role in the insulin receptor trafficking in pancreatic beta-cells. AB - BACE1 (beta-site amyloidogenic cleavage of precursor protein-cleaving enzyme 1) is a beta-secretase protein that plays a central role in the production of the beta-amyloid peptide in the brain and is thought to be involved in the Alzheimer's pathogenesis. In type 2 diabetes, amyloid deposition within the pancreatic islets is a pathophysiological hallmark, making crucial the study in the pancreas of BACE1 and its homologous BACE2 to understand the pathological mechanisms of this disease. The objectives of the present study were to characterize the localization of BACE proteins in human pancreas and determine their function. High levels of BACE enzymatic activity were detected in human pancreas. In normal human pancreas, BACE1 was observed in endocrine as well as in exocrine pancreas, whereas BACE2 expression was restricted to beta-cells. Intracellular analysis using immunofluorescence showed colocalization of BACE1 with insulin and BACE2 with clathrin-coated vesicles of the plasma membrane in MIN6 cells. When BACE1 and -2 were pharmacologically inhibited, BACE1 localization was not altered, whereas BACE2 content in clathrin-coated vesicles was increased. Insulin internalization rate was reduced, insulin receptor beta subunit (IRbeta) expression was decreased at the plasma membrane and increased in the Golgi apparatus, and a significant reduction in insulin gene expression was detected. Similar results were obtained after specific BACE2 silencing in MIN6 cells. All these data point to a role for BACE2 in the IRbeta trafficking and insulin signaling. In conclusion, BACE2 is hereby presented as an important enzyme in beta-cell function. PMID- 20943757 TI - Nuclear organization and dosage compensation. AB - Dosage compensation is a strategy to deal with the imbalance of sex chromosomal gene products relative to autosomes and also between the sexes. The mechanisms that ensure dosage compensation for X-chromosome activity have been extensively studied in mammals, worms, and flies. Although each entails very different mechanisms to equalize the dose of X-linked genes between the sexes, they all involve the co-ordinate regulation of hundreds of genes specifically on the sex chromosomes and not the autosomes. In addition to chromatin modifications and changes in higher order chromatin structure, nuclear organization is emerging as an important component of these chromosome-wide processes and in the specific targeting of dosage compensation complexes to the sex chromosomes. Preferential localization within the nucleus and 3D organization are thought to contribute to the differential treatment of two identical homologs within the same nucleus, as well as to the chromosome-wide spread and stable maintenance of heterochromatin. PMID- 20943758 TI - Cytosolic Ca2+ buffers. AB - "Ca(2+) buffers," a class of cytosolic Ca(2+)-binding proteins, act as modulators of short-lived intracellular Ca(2+) signals; they affect both the temporal and spatial aspects of these transient increases in [Ca(2+)](i). Examples of Ca(2+) buffers include parvalbumins (alpha and beta isoforms), calbindin-D9k, calbindin D28k, and calretinin. Besides their proven Ca(2+) buffer function, some might additionally have Ca(2+) sensor functions. Ca(2+) buffers have to be viewed as one of the components implicated in the precise regulation of Ca(2+) signaling and Ca(2+) homeostasis. Each cell is equipped with proteins, including Ca(2+) channels, transporters, and pumps that, together with the Ca(2+) buffers, shape the intracellular Ca(2+) signals. All of these molecules are not only functionally coupled, but their expression is likely to be regulated in a Ca(2+) dependent manner to maintain normal Ca(2+) signaling, even in the absence or malfunctioning of one of the components. PMID- 20943759 TI - Riboswitches: structures and mechanisms. AB - A critical feature of the hypothesized RNA world would have been the ability to control chemical processes in response to environmental cues. Riboswitches present themselves as viable candidates for a sophisticated mechanism of regulatory control in RNA-based life. These regulatory elements in the modern world are most commonly found in the 5'-untranslated regions of bacterial mRNAs, directly interacting with metabolites as a means of regulating expression of the coding region via a secondary structural switch. In this review, we focus on recent insights into how these RNAs fold into complex architectures capable of both recognizing a specific small molecule compound and exerting regulatory control over downstream sequences, with an emphasis on transcriptional regulation. PMID- 20943761 TI - The insulin-like growth factor I receptor/insulin receptor tyrosine kinase inhibitor PQIP exhibits enhanced antitumor effects in combination with chemotherapy against colorectal cancer models. AB - PURPOSE: There is growing evidence implicating the importance of the insulin-like growth factor (IGF) pathway in colorectal cancer based upon the results of population studies and preclinical experiments. However, the combination of an IGF-I receptor (IGF-IR) inhibitor with standard colorectal cancer chemotherapies has not yet been evaluated. In this study, we investigated the interaction between PQIP, the dual IGF-IR/insulin receptor tyrosine kinase inhibitor, and standard chemotherapies in colorectal cancer cell line models. EXPERIMENTAL DESIGN: The antiproliferative effects of PQIP, as a single agent and in combination with 5-fluorouracil, oxaliplatin, or SN38, were analyzed against four colorectal cancer cell lines. Downstream effector proteins, apoptosis, and cell cycle were also assessed in the combination of PQIP and SN-38. Lastly, the efficacy of OSI-906 (a derivative of PQIP) combined with irinotecan was further tested using a human colorectal cancer xenograft model. RESULTS: Treatment with the combination of PQIP and each of three chemotherapies resulted in an enhanced decrease in proliferation of all four colorectal cancer cell lines compared with single-agent treatment. This inhibition was not associated with a significant induction of apoptosis, but was accompanied by cell cycle arrest and changes in phosphorylation of Akt. Interestingly, antitumor activity between PQIP and SN-38 in vitro was also reflected in the human colorectal cancer xenograft model. CONCLUSIONS: Combination treatment with PQIP, the dual IGF-IR/insulin receptor tyrosine kinase inhibitor, and standard colorectal cancer chemotherapy resulted in enhanced antiproliferative effects against colorectal cancer cell line models, providing a scientific rationale for the testing of OSI-906 and standard colorectal cancer treatment regimens. PMID- 20943762 TI - No evidence of sex-related survival disparities among head and neck cancer patients receiving similar multidisciplinary care: a matched-pair analysis. AB - PURPOSE: It is unknown whether there are survival disparities between men and women with squamous cell carcinoma of the head and neck (SCCHN), although some data suggest that men have worse outcomes. We conducted a matched-pair study that controlled for several potentially confounding prognostic variables to assess whether a survival advantage exists for female compared with male SCCHN patients receiving similar care. EXPERIMENTAL DESIGN: We selected 286 female patients and 286 matched male patients from within a prospective epidemiologic study on 1,654 patients with incident SCCHN evaluated and treated at a single large multidisciplinary cancer center. Matching variables included age (+/-10 y), race/ethnicity, smoking status (never versus ever), tumor site (oral cavity versus oropharynx versus larynx versus hypopharynx), tumor classification (T(1-2) versus T(3-4)), nodal status (negative versus positive), and treatment (surgery, radiation therapy, surgery and radiation therapy, surgery and chemotherapy, chemoradiotherapy, or surgery and chemoradiotherapy). RESULTS: Matched-pair and log-rank analyses showed no significant differences between women and men in recurrence-free, disease-specific, or overall survival. When the analysis was restricted to individual sites (oral cavity, oropharynx, or larynx/hypopharynx), there was also no evidence of a disparity in survival associated with sex. CONCLUSIONS: We conclude that there is no evidence to suggest that a survival advantage exists for women as compared with men with SCCHN receiving similar multidisciplinary directed care at a tertiary cancer center. PMID- 20943760 TI - Lipid signaling in T-cell development and function. AB - Second messenger molecules relay, amplify, and diversify cell surface receptor signals. Two important examples are phosphorylated D-myo-inositol derivatives, such as phosphoinositide lipids within cellular membranes, and soluble inositol phosphates. Here, we review how phosphoinositide metabolism generates multiple second messengers with important roles in T-cell development and function. They include soluble inositol(1,4,5)trisphosphate, long known for its Ca(2+) mobilizing function, and phosphatidylinositol(3,4,5)trisphosphate, whose generation by phosphoinositide 3-kinase and turnover by the phosphatases PTEN and SHIP control a key "hub" of TCR signaling. More recent studies unveiled important second messenger functions for diacylglycerol, phosphatidic acid, and soluble inositol(1,3,4,5)tetrakisphosphate (IP(4)) in immune cells. Inositol(1,3,4,5)tetrakisphosphate acts as a soluble phosphatidylinositol(3,4,5)trisphosphate analog to control protein membrane recruitment. We propose that phosphoinositide lipids and soluble inositol phosphates (IPs) can act as complementary partners whose interplay could have broadly important roles in cellular signaling. PMID- 20943763 TI - Phase I study of NK012, a novel SN-38-incorporating micellar nanoparticle, in adult patients with solid tumors. AB - PURPOSE: We conducted a first-in-human phase I study to determine the dose limiting toxicity (DLT), evaluate the pharmacokinetic profile, and document any antitumor activity of NK012, a novel SN-38-incorporating micellar nanoparticle. EXPERIMENTAL DESIGN: Patients with solid tumors refractory to standard therapy, or for which no standard therapy is available, were enrolled. NK012 was administered as a 30-minute infusion every 3 weeks. The starting dose was 2 mg/m(2) as SN-38 equivalent, and an accelerated titration schedule was used. Pharmacokinetic analysis was conducted in cycles 1 and 2. RESULTS: Twenty-four patients were enrolled in the study. No UGT1A1*28 homozygous patients were enrolled. Predominant toxicity was neutropenia. Nonhematologic toxicity, especially diarrhea, was mostly grade 1 or 2 during study treatments. Two of nine patients had DLT during cycle 1 at the 28 mg/m(2) dose level. DLTs were mostly neutropenia or a related event. Polymer-bound SN-38 (NK012) and SN-38 released from NK012 were slowly eliminated from the plasma, with a terminal-phase half life of approximately 140 and 210 hours, respectively. Systemic exposure to both polymer-bound SN-38 and SN-38 increased in proportion to the dose. A refractory esophageal cancer patient and a lung carcinoid tumor patient had an objective response and continued the study treatment for 5 and 12 months, respectively. CONCLUSIONS: NK012 was well tolerated and showed antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing. PMID- 20943764 TI - Expression and distribution of transient receptor potential (TRP) channels in bladder epithelium. AB - The urothelium is proposed to be a sensory tissue that responds to mechanical stress by undergoing dynamic membrane trafficking and neurotransmitter release; however, the molecular basis of this function is poorly understood. Transient receptor potential (TRP) channels are ideal candidates to fulfill such a role as they can sense changes in temperature, osmolarity, and mechanical stimuli, and several are reported to be expressed in the bladder epithelium. However, their complete expression profile is unknown and their cellular localization is largely undefined. We analyzed expression of all 33 TRP family members in mouse bladder and urothelium by RT-PCR and found 22 specifically expressed in the urothelium. Of the latter, 10 were chosen for closer investigation based on their known mechanosensory or membrane trafficking functions in other cell types. Western blots confirmed urothelial expression of TRPC1, TRPC4, TRPV1, TRPV2, TRPV4, TRPM4, TRPM7, TRPML1, and polycystins 1 and 2 (PKD1 and PKD2) proteins. We further defined the cellular and subcellular localization of all 10 TRP channels. TRPV2 and TRPM4 were prominently localized to the umbrella cell apical membrane, while TRPC4 and TRPV4 were identified on their abluminal surfaces. TRPC1, TRPM7, and TRPML1 were localized to the cytoplasm, while PKD1 and PKD2 were expressed on the apical and basolateral membranes of umbrella cells as well as in the cytoplasm. The cellular location of TRPV1 in the bladder has been debated, but colocalization with neuronal marker calcitonin gene-related peptide indicated clearly that it is present on afferent neurons that extend into the urothelium, but may not be expressed by the urothelium itself. These findings are consistent with the hypothesis that the urothelium acts as a sentinel and by expressing multiple TRP channels it is likely it can detect and presumably respond to a diversity of external stimuli and suggest that it plays an important role in urothelial signal transduction. PMID- 20943765 TI - Ribosomal biogenesis induction by high glucose requires activation of upstream binding factor in kidney glomerular epithelial cells. AB - Diabetes promotes protein synthesis to induce kidney hypertrophy and increase renal matrix proteins. Increased capacity for mRNA translation by way of ribosomal biogenesis facilitates sustained stimulation of protein synthesis. We tested the hypothesis that high glucose induces ribosomal biogenesis as indicated by an increase in rRNA synthesis in the setting of augmented protein synthesis. High glucose (30 mM) increased global protein synthesis, expression of matrix proteins, laminin gamma1 and fibronectin, and rDNA transcription in glomerular epithelial cells (GECs) compared with 5 mM glucose. High glucose induced Ser388 phosphorylation of upstream binding factor (UBF), an rDNA transcription factor, along with increased phosphorylation of Erk and p70S6 kinase. Inactivation of Erk and p70S6 kinase either by their respective chemical inhibitors or by expression of their inactive mutant constructs blocked high-glucose-induced UBF phosphorylation. High glucose reduced nuclear content of p19ARF and promoted dissolution of inactive UBF-p19ARF complex. High glucose also promoted association of UBF with RPA194, a subunit of RNA polymerase I. Inhibition of Erk, p70S6 kinase, and UBF1 by transfecting GECs with their respective inactive mutants abolished laminin gamma1 synthesis, protein synthesis, and rDNA transcription. Renal cortex from type 1 diabetic rats and type 2 diabetic db/db mice showed increased phosphorylation of UBF, Erk, and p70S6 kinase coinciding with renal hypertrophy and onset of matrix accumulation. Our data suggest that augmented ribosome biogenesis occurs in an UBF-dependent manner during increased protein synthesis induced by high glucose in the GECs that correlates with UBF activation and renal hypertrophy in rodents with type 1 and type 2 diabetes. PMID- 20943766 TI - VEGF-modified human embryonic mesenchymal stem cell implantation enhances protection against cisplatin-induced acute kidney injury. AB - The implantation of mesenchymal stem cells (MSC) has been reported as a new technique to restore renal tubular structure and improve renal function in acute kidney injury (AKI). Vascular endothelial growth factor (VEGF) plays an important role in the renoprotective function of MSC. Whether upregulation of VEGF by a combination of MSC and VEGF gene transfer could enhance the protective effect of MSC in AKI is not clear. We investigated the effects of VEGF-modified human embryonic MSC (VEGF-hMSC) in healing cisplatin-injured renal tubular epithelial cells (TCMK-1) with a coculture system. We found that TCMK-1 viability declined 3 days after cisplatin pretreatment and that coculture with VEGF-hMSC enhanced cell protection via mitogenic and antiapoptotic actions. In addition, administration of VEGF-hMSC in a nude mouse model of cisplatin-induced kidney injury offered better protective effects on renal function, tubular structure, and survival as represented by increased cell proliferation, decreased cellular apoptosis, and improved peritubular capillary density. These data suggest that VEGF-modified hMSC implantation could provide advanced benefits in the protection against AKI by increasing antiapoptosis effects and improving microcirculation and cell proliferation. PMID- 20943767 TI - Early glomerular alterations in genetically determined low nephron number. AB - An association between low nephron number and subsequent development of hypertension in later life has been demonstrated. The underlying pathomechanisms are unknown, but glomerular and postglomerular changes have been discussed. We investigated whether such changes are already present in prehypertensive "glial cell line-derived neurotrophic growth factor" heterozygous mice (GDNF+/-) with lower nephron number. Twenty-six-week-old mice [22 GDNF+/-, 29 C57B6 wild-type control (wt)] were used for in vivo experiments with intra-arterial and tail cuff blood pressure measurements. After perfusion fixation, kidneys were investigated with morphological, morphometric, stereological, and immunohistochemical techniques and TaqMan PCR analysis. As expected at this age, blood pressure was comparable between GDNF+/- and wt. Nephron number per kidney was significantly lower in GDNF+/- than in wt (-32.8%, P < 0.005), and mean glomerular volume was significantly higher (+49.5%, P < 0.001). Renal damage scores, glomerular and tubular proliferation, analysis of intrarenal arteries and peritubular capillaries, expression of relevant tubular transporter proteins, as well as gene expression of profibrotic, proinflammatory, or prohypertensive markers were not significantly different between GDNF+/- and wt. Compensatory glomerular hypertrophy in GDNF+/- was accompanied by higher numbers of endothelial and mesangial cells as well as PCNA-positive glomerular cells, whereas podocyte density was significantly reduced. Further electron microscopic analysis showed marked thickening of glomerular basement membrane. In conclusion, lower nephron number is associated with marked early glomerular structural changes, in particular lower capillary supply, reduced podocyte density, and thickened glomerular basement membrane, that may predispose to glomerular sclerosis. PMID- 20943768 TI - Transient and sustained increases in glomerular permeability following ANP infusion in rats. AB - The present study was performed to investigate the effects of systemic atrial natriuretic peptide (ANP) infusion on the glomerular permeability to macromolecules in rats. In anesthetized Wistar rats (250-280 g), the left urether was cannulated for urine collection while simultaneously blood access was achieved. Rats were continuously infused intravenously with ANP [30 ng.kg( 1).min(-1) (Lo-ANP; n=8) or 800 ng.kg(-1).min(-1) (Hi-ANP; n=10)] or 0.9% NaCl (SHAM; n=16), respectively, and with polydisperse FITC-Ficoll-70/400 (molecular radius 13-90 A) and 51Cr-EDTA for 2 h. Plasma and urine samples were taken at 5, 15, 30, 60, and 120 min of ANP infusion and analyzed by high-performance size exclusion chromatography (HPLC) for determination of glomerular sieving coefficients (theta) for Ficoll. GFR was also assessed (51Cr-EDTA). In Hi-ANP, there was a rapid (within 5 min), but bimodal, increase in glomerular permeability. theta to high-molecular-weight Ficoll thus reached a maximum at 15 min, after which theta returned to near control at 30 min, to again increase moderately at 60 and 120 min. In Lo-ANP, there was also a rapid, reversible increase in glomerular theta, returning to near control at 30 min, followed by just a tendency of a sustained increase in permeability, but with a significant increase in "large-pore" radius. In conclusion, in Hi-ANP there was a rapid increase in glomerular permeability, with an early, partly reversible permeability peak, followed by a (moderate) sustained increase in permeability. In Lo-ANP animals, only the initial permeability peak was evident. In both Lo-ANP and Hi-ANP, the glomerular sieving pattern observed was found to mainly reflect an increase in the number and radius of large pores in the glomerular filter. PMID- 20943769 TI - Oxidative stress alters renal D1 and AT1 receptor functions and increases blood pressure in old rats. AB - Aging is associated with an increase in oxidative stress and blood pressure (BP). Renal dopamine D1 (D1R) and angiotensin II AT1 (AT1R) receptors maintain sodium homeostasis and BP. We hypothesized that age-associated increase in oxidative stress causes altered D1R and AT1R functions and high BP in aging. To test this, adult (3 mo) and old (21 mo) Fischer 344 * Brown Norway F1 rats were supplemented without/with antioxidant tempol followed by determining oxidative stress markers (urinary antioxidant capacity, proximal tubular NADPH-gp91phox, and plasma 8 isoprostane), D1R and AT1R functions, and BP. The D1R and AT1R functions were determined by measuring diuretic and natriuretic responses to D1R agonist (SKF 38393; 1 MUg.kg(-1).min(-1) iv) and AT1R antagonist (candesartan; 10 MUg/kg iv), respectively. We found that the total urinary antioxidant capacity was lower in old rats, which increased with tempol treatment. In addition, tempol decreased the elevated NADPH-gp91phox and 8-isoprostane levels in old rats. Systolic, diastolic, and mean arterial BPs were higher in old rats and were reduced by tempol. Although SKF-38393 produced diuresis in both adult and old rats, urinary sodium excretion (UNaV) increased only in adult rats. While candesartan increased diuresis and UNaV in adult and old rats, the magnitude of response was greater in old rats. Tempol treatment in old rats reduced candesartan-induced increase in diuresis and UNaV. Our results demonstrate that diminished renal D1R and exaggerated AT1R functions are associated with high BP in old rats. Furthermore, oxidative stress may cause altered renal D1R and AT1R functions and high BP in old rats. PMID- 20943770 TI - mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease. AB - Rapamycin slows disease progression in the male Han:SPRD (Cy/+) rat with polycystic kidney disease (PKD). The aim of this study was to determine the effect of rapamycin on PKD and the relative contributions of the proproliferative mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) in female Cy/+ rats. Female Cy/+ rats were treated with rapamycin from 4 to 12 wk of age. In vehicle-treated Cy/+ rats, kidney volume increased by 40% and cyst volume density (CVD) was 19%. Phosphorylated S6 (p-S6) ribosomal protein, a marker of mTORC1 activity, was increased in Cy/+ rats compared with normal littermate controls (+/+) and decreased by rapamycin. Despite activation of mTORC1 in female Cy/+ rats, rapamycin had no effect on kidney size, CVD, number of PCNA-positive cystic tubular cells, caspase-3 activity, or the number of terminal deoxynucleotidyl transferase dUTP-mediated nick-end label-positive apoptotic cells. To determine a reason for the lack of effect of rapamycin, we studied the mTORC2 signaling pathway. On immunoblot of kidney, phosphorylated (Ser473) Akt (p Akt), a marker of mTORC2 activity, was increased in female Cy/+ rats treated with rapamycin. Phosphorylated (Ser657) PKCalpha, a substrate of mTORC2, was unaffected by rapamycin in females. In contrast, in male rats, where rapamycin significantly decreases PKD, p-Akt (Ser473) was decreased by rapamcyin. PKCalpha (Ser657) was increased in male Cy/+ rats but was unaffected by rapamycin. In summary, in female Cy/+ rats, rapamycin had no effect on PKD and proproliferative p-Akt (Ser473) activity was increased by rapamycin. There were differential effects of rapamycin on mTORC2 signaling in female vs. male Cy/+ rats. PMID- 20943771 TI - Mouse model of foreign body reaction that alters the submesothelium and transperitoneal transport. AB - To address the hypothesis that sterile intraperitoneal (ip) catheters alone promote a progressive foreign body reaction (FBR), silicone catheters were surgically implanted in C57BL mice. Controls (CON) underwent sham operations. After 1-5 wk (E1-E5 for catheter-bearing mice), catheters were recovered, and the adherent cell layer (ACL) was separated and cultured to demonstrate sterility. Transperitoneal transport experiments were performed to determine the mass transfer coefficients of mannitol (MTCM) and albumin (MTCA) and the osmotic filtration flux (Josm). After euthanasia, tissue samples were analyzed for submesothelial thickness, angiogenesis, and cytokine immunohistochemistry (IHC). Progressive increases with time were observed in submesothelial thickness (MUm: CON, 18.8+/-12.3; E1, 46.1+/-20.0; E2, 72.0+/-17.9; E4, 97.3+/-20.0; E5, 131.7+/ 10.3; P<0.003), angiogenesis (no. of vessels/mm of peritoneum: CON, 10.7+/-9.4; E1, 15.4+/-15.6; E2, 27.0+/-14.0; E4, 39.8+/-15.7; E5, 90.1+/-8.1; P<0.0003), MTCA (6.5+/-1.5*10(-5) cm/min, mean CON; 18.0+/-1.1*10(-5) cm/min, mean E1-E5, P<0.0001), Josm (0.0013+/-0.0001 cm/min, mean CON; 0.0017+/-0.0001 cm/min, mean E1-E5, P<0.01). No significant differences were found for MTCM. IHC demonstrated strong staining for all treated animals and correlated with the ACL. This mouse model demonstrates that ip silicone catheters result in progressive FBR, altering the submesothelial anatomy and transperitoneal transport, and will form the basis for mechanistic studies in genetically-altered animals. PMID- 20943773 TI - Pharmacological characterization of MK-7246, a potent and selective CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) antagonist. AB - The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2) is a G protein-coupled receptor that has been reported to modulate inflammatory responses in various rodent models of asthma, allergic rhinitis and atopic dermatitis. In this study, we describe the biological and pharmacological properties of {(7R)-7-[[(4-fluorophenyl)sulfonyl](methyl)amino]-6,7,8,9 tetrahydropyrido[1,2-a]indol-10-yl}acetic acid (MK-7246), a novel synthetic CRTH2 antagonist. We show that MK-7246 1) has high affinity for the human, monkey, dog, rat, and mouse CRTH2, 2) interacts with CRTH2 in a reversible manner, 3) exhibits high selectivity over all prostanoid receptors as well as 157 other receptors and enzymes, 4) acts as a full antagonist on recombinant and endogenously expressed CRTH2, 5) demonstrates good oral bioavailability and metabolic stability in various animal species, 6) yields ex vivo blockade of CRTH2 on eosinophils in monkeys and sheep, and 7) significantly blocks antigen-induced late-phase bronchoconstriction and airway hyper-responsiveness in sheep. MK-7246 represents a potent and selective tool to further investigate the in vivo function of CRTH2. PMID- 20943772 TI - Gastrin-releasing peptide/neuromedin B receptor antagonists PD176252, PD168368, and related analogs are potent agonists of human formyl-peptide receptors. AB - N-Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) involved in host defense and sensing cellular dysfunction. Thus, FPRs represent important therapeutic targets. In the present studies, we screened 32 ligands (agonists and antagonists) of unrelated GPCRs for their ability to induce intracellular Ca2+ mobilization in human neutrophils and HL-60 cells transfected with human FPR1, FPR2, or FPR3. Screening of these compounds demonstrated that antagonists of gastrin-releasing peptide/neuromedin B receptors (BB1/BB2) PD168368 [(S)-a-methyl-a-[[[(4-nitrophenyl)amino]carbonyl]amino]-N-[[1-(2 pyridinyl) cyclohexyl]methyl]-1H-indole-3-propanamide] and PD176252 [(S)-N-[[1-(5 methoxy-2-pyridinyl)cyclohexyl]methyl]-a-methyl-a-[[-(4 nitrophenyl)amino]carbonyl]amino-1H-indole-3-propanamide] were potent mixed FPR1/FPR2 agonists, with nanomolar EC50 values. Cholecystokinin-1 receptor agonist A-71623 [Boc-Trp-Lys(epsilon-N-2-methylphenylaminocarbonyl)-Asp-(N methyl)-Phe-NH2] was also a mixed FPR1/FPR2 agonist, but with a micromolar EC50. Screening of 56 Trp- and Phe-based PD176252/PD168368 analogs and 41 related nonpeptide/nonpeptoid analogs revealed 22 additional FPR agonists. Most were potent mixed FPR1/FPR2/FPR3 agonists with nanomolar EC50 values for FPR2, making them among the most potent nonpeptide FPR2 agonists reported to date. In addition, these agonists were also potent chemoattractants for murine and human neutrophils and activated reactive oxygen species production in human neutrophils. Molecular modeling of the selected agonists using field point methods allowed us to modify our previously reported pharmacophore model for the FPR2 ligand binding site. This model suggests the existence of three hydrophobic/aromatic subpockets and several binding poses of FPR2 agonists in the transmembrane region of this receptor. These studies demonstrate that FPR agonists could include ligands of unrelated GPCR and that analysis of such compounds can enhance our understanding of pharmacological effects of these ligands. PMID- 20943774 TI - Rab GTPases bind at a common site within the angiotensin II type I receptor carboxyl-terminal tail: evidence that Rab4 regulates receptor phosphorylation, desensitization, and resensitization. AB - The human angiotensin II type 1 receptor (AT1R) is a member of the G protein coupled receptor (GPCR) superfamily and represents an important target for cardiovascular therapeutic intervention. Agonist-activation of the AT1R induces beta-arrestin-dependent endocytosis to early endosomes in which the receptor resides as a protein complex with the Rab GTPase Rab5. In the present study, we examined whether other Rab GTPases that regulate receptor trafficking through endosomal compartments also bind to the AT1R. We find that Rab4, Rab7, and Rab11 all bind to the last 10 amino acid residues of the AT1R carboxyl-terminal tail. Rab11 binds AT1R more effectively than Rab5, whereas Rab4 binds less effectively than Rab5. Alanine scanning mutagenesis reveals that proline 354 and cysteine 355 contribute to Rab protein binding, and mutation of these residues does not affect G protein coupling. We find that the Rab GTPases each compete with one another for receptor binding and that although Rab4 interacts poorly with the AT1R, it effectively displaces Rab11 from the receptor. In contrast, Rab11 overexpression does not prevent Rab4 binding to the AT1R. Overexpression of wild-type Rab4, but not Rab11, facilitates AT1R dephosphorylation, and a constitutively active Rab4 Q67L mutant reduces AT1R desensitization and promotes AT1R resensitization. Taken together, our data indicate that multiple Rab GTPases bind to a motif localized to the distal end of the AT1R tail and that increased Rab4 activity may contribute to the regulation AT1R desensitization and dephosphorylation. PMID- 20943775 TI - alpha4beta2 nicotinic receptors partially mediate anti-inflammatory effects through Janus kinase 2-signal transducer and activator of transcription 3 but not calcium or cAMP signaling. AB - Despite evidence that smoking confers protection against neurological disorders, how and whether specific nicotinic receptor subtypes are involved is unknown. We reported previously that nicotine suppresses constitutive nuclear factor kappaB (NF-kappaB) activity and thereby proinflammatory cytokine (PIC) production in SHEP1 cells stably transfected with alpha4beta2 nicotinic receptors. Here, we report the anti-inflammatory effects of nicotine pretreatment in lipopolysaccharide (LPS)-stimulated SHEP1 cells. Nicotine (100-300 nM, concentrations found in smoker's blood) blocked LPS-induced NF-kappaB translocation and production of PICs interleukin (IL)-1beta and IL-6 but only partially blocked inhibitor of nuclear factor-kappaBalpha (IkappaBalpha) phosphorylation. These effects were exclusively in cells transfected with alpha4beta2 receptors but not in wild types. The cell-permeable calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester, the adenylate cyclase stimulant forskolin, and a specific protein kinase A (PKA) inhibitor PKI 14-22-amide failed to block the effect of nicotine on LPS-induced NF-kappaB translocation and IkappaBalpha phosphorylation. However, the effects of nicotine on NF-kappaB activity were significantly blocked by the highly specific janus kinase 2 (JAK2) inhibitor alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG 490) and the signal transducer and activator of transcription 3 (STAT3) inhibitor 2-hydroxy-4-[[[[(4-methylphenyl)sulfonyl]oxy]acetyl]amino]-benzoic acid (NSC74859). These findings reveal a calcium- and cAMP-PKA-independent signaling cascade and suggest a role for JAK2-STAT3 transduction in alpha4beta2-mediated attenuation of LPS-induced inflammation. Anti-inflammatory effects of nicotine may therefore be mediated through alpha4beta2 receptors, the predominant high affinity binding sites for nicotine in the central nervous system, in addition to the better-established alpha7 receptors. PMID- 20943776 TI - The human aldose reductase AKR1B1 qualifies as the primary prostaglandin F synthase in the endometrium. AB - CONTEXT: Prostaglandins (PGs) E2 and PGF2alpha are produced in the endometrium and are important for menstruation and fertility. Dysmenorrhea is associated with increased production of PGF2alpha relative to PGE2, and the opposite is true for menorrhagia. The pathways leading to PGE2 biosynthesis are well described, but little is known for PGF2alpha. Aldoketoreductase (AKR)-1C3, the only PGF synthase identified in the human, cannot explain the production of PGF2alpha by endometrial cells. AKR1B1 appears to be an alternate candidate with promising therapeutic value. OBJECTIVE: The objective of the study was to address whether AKR1B1 (gene ID 231) is a functional PGF2alpha synthase in the human endometrium and a valid therapeutic target for menstrual pain. DESIGN: The design of the study was basic laboratory analyses to identify gene expression and protein levels associated with PGF2alpha production in endometrial tissues and endometrial cells from cycling women aged between 23 and 52 yr undergoing biopsies or hysterectomy for diverse gynecological disorders. RESULTS: AKR1B1 is expressed at a high level during the menstrual cycle during the secretory phase and in both epithelial and stromal cells, whereas AKR1C3 was found only in epithelial cells. Purified recombinant AKR1B1 protein, gene silencing, and transient transfection experiments all concur to demonstrate that this enzyme is a functional PGF synthase. Ponalrestat, a specific inhibitor developed to block AKR1B1 activity, reduced PGF2alpha production in response to IL-1beta in both cultured endometrial cells and endometrial explants. CONCLUSIONS: The human aldose reductase AKR1B1 currently associated with diabetes complications is also a highly functional PGF synthase responsible for PGF2alpha production in the human endometrium and a potential target for treatment of menstrual disorders. PMID- 20943777 TI - Effects of a growth hormone-releasing hormone analog on endogenous GH pulsatility and insulin sensitivity in healthy men. AB - CONTEXT AND OBJECTIVE: Strategies to augment pulsatile GH may be beneficial in patients with excess visceral adiposity, in whom GH secretion is reduced. The objective of this study was to determine the effects of a novel GHRH (GHRH(1-44)) analog, tesamorelin, on endogenous GH pulsatility and insulin sensitivity in healthy men. DESIGN, PARTICIPANTS, AND INTERVENTION: Thirteen males (mean age 45 +/- 3 yr and body mass index 27.3 +/- 1.2 kg/m(2)) received tesamorelin 2 mg sc once daily for 2 wk, with assessment made at baseline, after 2 wk of treatment, and after 2 wk of withdrawal. OUTCOME MEASURES: The primary end point was change in mean overnight GH as determined by overnight frequent sampling. Secondary end points included insulin-stimulated glucose uptake as measured by euglycemic hyperinsulinemic clamp; IGF-I; and GH secretion parameters, including pulse area, pulse frequency, and basal secretion. RESULTS: Tesamorelin treatment increased mean overnight GH (change +0.5 +/- 0.1 MUg/liter, P = 0.004), average log(10) GH peak area (change +0.4 +/- 0.1 log(10) MUg/liter, P = 0.001), and basal GH secretion (change +0.008 +/- 0.003 MUg/liter . min, P = 0.008). IGF-I increased by 181 +/- 22 MUg/liter (P < 0.0001). Neither fasting glucose (P = 0.93) nor insulin-stimulated glucose uptake (P = 0.61) was significantly affected by tesamorelin. CONCLUSIONS: Once-daily short-term treatment with a GHRH(1-44) analog, tesamorelin, augments basal and pulsatile GH secretion. Moreover, although tesamorelin significantly increases IGF-I, peripheral insulin-stimulated glucose uptake appears to be preserved. PMID- 20943778 TI - Autosomal recessive mental retardation, deafness, ankylosis, and mild hypophosphatemia associated with a novel ANKH mutation in a consanguineous family. AB - CONTEXT: Mutations in ANKH cause the highly divergent conditions familial chondrocalcinosis and craniometaphyseal dysplasia. The gene product ANK is supposed to regulate tissue mineralization by transporting pyrophosphate to the extracellular space. OBJECTIVE: We evaluated several family members of a large consanguineous family with mental retardation, deafness, and ankylosis. We compared their skeletal, metabolic, and serological parameters to that of the autosomal recessive progressive ankylosis (ank) mouse mutant, caused by a loss-of function mutation in the murine ortholog Ank. PARTICIPANTS: The studied patients had painful small joint soft-tissue calcifications, progressive spondylarthropathy, osteopenia, mild hypophosphatemia, mixed hearing loss, and mental retardation. RESULTS: After mapping the disease gene to 5p15, we identified the novel homozygous ANK missense mutation L244S in all patients. Although L244 is a highly conserved amino acid, the mutated ANK protein was detected at normal levels at the plasma membrane in primary patient fibroblasts. The phenotype was highly congruent with the autosomal recessive progressive ankylosis (ank) mouse mutant. This indicates a loss-of-function effect of the L244S mutation despite normal ANK protein expression. Interestingly, our analyses revealed that the primary step of joint degeneration is fibrosis and mineralization of articular soft tissues. Moreover, heterozygous carriers of the L244S mutation showed mild osteoarthritis without metabolic alterations, pathological calcifications, or central nervous system involvement. CONCLUSION: Beyond the description of the first human progressive ankylosis phenotype, our results indicate that ANK influences articular soft tissues commonly involved in degenerative joint disorders. Furthermore, this human disorder provides the first direct evidence for a role of ANK in the central nervous system. PMID- 20943779 TI - Familial focal congenital hyperinsulinism. AB - BACKGROUND: Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia. Histologically, there are two subgroups, diffuse and focal. Focal CHI is a consequence of two independent events, inheritance of a paternal mutation in ABCC8/KCNJ11 and paternal uniparental isodisomy of chromosome 11p15 within the embryonic pancreas, leading to an imbalance in the expression of imprinted genes. The probability of both events occurring within siblings is rare. AIM: We describe the first familial form of focal CHI in two siblings. PATIENTS AND METHODS: The proband presented with medically unresponsive CHI. He underwent pancreatic venous sampling and Fluorine-18-L-dihydroxyphenylalanine positron emission tomography scan, which localized a 5-mm focal lesion in the isthmus of the pancreas. The sibling presented 8 yr later also with medically unresponsive CHI. An Fluorine-18-L-dihydroxyphenylalanine positron emission computerised tomography scan showed a 7-mm focal lesion in the posterior section of the head of the pancreas. Both siblings were found to be heterozygous for two paternally inherited ABCC8 mutations, A355T and R1494W. Surgical removal of the focal lesions in both siblings cured the Hyperinsulinaemic hypoglycaemia. CONCLUSION: This is the first report of focal CHI occurring in siblings. Genetic counseling for families of patients with focal CHI should be recommended, despite the rare risk of recurrence of this disease. PMID- 20943780 TI - Longitudinal association between growth hormone therapy and obstructive sleep apnea in a child with Prader-Willi syndrome. AB - CONTEXT: Descriptions of the development of symptoms of upper airway obstruction and sudden death of children with Prader-Willi Syndrome (PWS) while on GH therapy have led to concern about GH contributing to obstructive sleep apnea (OSA), especially early in treatment. However, two studies using monitoring with polysomnography (PSG) have not shown deterioration in OSA after 6 wk on GH, except as related to upper respiratory tract infections. OBJECTIVE: The aim was to describe the evolution of OSA in a girl with PWS on GH treatment in order to highlight important aspects of long-term clinical monitoring for patients with PWS on GH treatment. PATIENT AND RESEARCH DESIGN: GH was commenced when the patient was 2.9 yr of age. PSG was performed at baseline and 7 wk after commencing GH, plus at intervals throughout treatment based on symptoms of OSA. INTERVENTION: GH was given at doses ranging from 4.2 to 4.7 mg/m(2) . wk over a period of 3 yr. MAIN OUTCOME MEASURE: OSA was quantified by PSG. RESULTS: OSA was not present at baseline or after 7 wk on GH but developed after 6 months, following a small increase in GH dose. Cessation of GH was accompanied by resolution of OSA. GH was restarted 2 yr later, again associated with the development of OSA that resolved after cessation of GH. CONCLUSION: This case highlights that OSA may develop late in GH treatment. Children should be monitored for the symptoms of OSA throughout GH treatment, and PSG should be repeated if symptoms develop. PMID- 20943781 TI - Molecular and clinical analysis of Japanese patients with persistent congenital hyperinsulinism: predominance of paternally inherited monoallelic mutations in the KATP channel genes. AB - BACKGROUND: Preoperative identification of the focal form of congenital hyperinsulinism is important for avoiding unnecessary subtotal pancreatectomy. However, neither the incidence nor the histological spectrum of the disease is known for Japanese patients. AIMS: The aim of the study was to elucidate the molecular and histological spectrum of congenital hyperinsulinism in Japan. SUBJECTS: Thirty-six Japanese infants with persistent congenital hyperinsulinism were included in the study. METHODS: All exons of the ATP-sensitive potassium channel (K(ATP) channel) genes (KCNJ11 and ABCC8), the GCK gene, and exons 6 and 7 and 10-12 of the GLUD1 gene were amplified from genomic DNA and directly sequenced. In patients with K(ATP) channel mutations, the parental origin of each mutation was determined, and the results were compared with the histological findings of surgically treated patients. In one of the patients with scattered lesions, islets were sampled by laser capture microdissection for mutational analysis. RESULTS: Mutations were identified in 24 patients (66.7%): five in GLUD1 and 19 in the K(ATP) channel genes. Sixteen had a paternally derived, monoallelic K(ATP) channel mutation predictive of the focal form. In 10 patients who underwent pancreatectomy, the molecular diagnosis correctly predicted the histology, more accurately than [18F]-3,4-dihydroxyphenylalanine positron emission tomography scans. Three patients showed focal lesions that occupied larger areas of the pancreas. Preferential loss of the maternal allele was observed in these islets. CONCLUSION: The majority of the Japanese patients with K(ATP) channel hyperinsulinism (84.2%) demonstrated paternally inherited monoallelic mutations that accurately predicted the presence of the focal form. PMID- 20943782 TI - Elevated FGF23 levels are associated with impaired calcium-mediated suppression of PTH in ESRD. AB - CONTEXT: The positive association of elevated fibroblast growth factor-23 (FGF23) with PTH levels in the setting of secondary hyperparathyroidism is paradoxical to the purported effects of FGF23 to suppress PTH secretion. OBJECTIVE: We used dynamic calcium-mediated suppression of PTH levels in hemodialysis (HD) patients to determine the relationship between FGF23 levels and parathyroid gland function. DESIGN: HD patients with elevated PTH were washed out of vitamin D analogs and/or calcimimetics and then exposed them to a high-calcium dialysate bath designed to suppress PTH. SETTING: The study was conducted at an outpatient HD unit of an academic medical center. PARTICIPANTS: Eighteen maintenance HD patients with elevated PTH levels participated in the study. MAIN OUTCOME MEASURES: Ionized calcium (iCa), PTH, and FGF23 levels were measured during HD. The slope of the relationship between iCa and PTH (a marker of parathyroid gland mass) and the iCa level required for a 50% reduction in PTH were determined, and the association of these with FGF23 levels was determined. RESULTS: Increased baseline log FGF23 levels were associated with putative alterations in gland mass as estimated by significantly shallower slopes of the iCa/PTH suppression curves (P = 0.0004), but there was no association between FGF23 and calcium sensing as measured by ionized Ca associated with a 50% suppression of PTH (P = 0.38). FGF23 levels decreased significantly during HD, but this change was not correlated with decrements in either renal phosphate or PTH. CONCLUSIONS: High FGF23 levels may be a marker for parathyroid gland hyperplasia in HD patients. Acute reductions in neither PTH nor renal phosphate during dialysis correlated with PTH suppression. PMID- 20943783 TI - Cinacalcet HCl reduces hypercalcemia in primary hyperparathyroidism across a wide spectrum of disease severity. AB - CONTEXT: Primary hyperparathyroidism (PHPT) is characterized by elevated serum calcium (Ca) and increased PTH concentrations. OBJECTIVE: The objective of the investigation was to establish the efficacy of cinacalcet in reducing serum Ca in patients with PHPT across a wide spectrum of disease severity. DESIGN AND SETTING: The study was a pooled analysis of data from three multicenter clinical trials of cinacalcet in PHPT. PATIENTS: Patients were grouped into three disease categories for analysis based on the following: 1) history of failed parathyroidectomy (n = 29); 2) meeting one or more criteria for parathyroidectomy but without prior surgery (n = 37); and 3) mild asymptomatic PHPT without meeting criteria for either above category (n = 15). INTERVENTION: The intervention in this study was treatment with cinacalcet for up to 4.5 yr. OUTCOMES: Measurements in the study included serum Ca, PTH, phosphate, and bone-specific alkaline phosphatase, and areal bone mineral density (aBMD). Vital signs, safety biochemical and hematological indices, and adverse events were monitored throughout the study period. RESULTS: The extent of cinacalcet-induced serum Ca reduction, proportion of patients achieving normal serum Ca (<=10.3 mg/dl), reduction in serum PTH, and increase in serum phosphate were similar across all three categories. Except for decreased aBMD at the total femur indicated for parathyroidectomy group at 1 yr, no significant changes in aBMD occurred. The efficacy of cinacalcet was maintained for up to 4.5 yr of follow-up. AEs were mild and similar across the three categories. CONCLUSIONS: Cinacalcet is equally effective in the medical management of PHPT patients across a broad spectrum of disease severity, and overall cinacalcet is well tolerated. PMID- 20943784 TI - Increased circulating and visceral adipose tissue expression levels of YKL-40 in obesity-associated type 2 diabetes are related to inflammation: impact of conventional weight loss and gastric bypass. AB - CONTEXT: Plasma YKL-40 is elevated in patients with type 2 diabetes. The potential role of visceral adipose tissue (VAT) as a significant source of YKL-40 is unknown. OBJECTIVE: In the study circulating and expression levels of YKL-40 were examined in VAT analyzing the contribution of adipocytes and stromovascular fraction cells (SVFCs). We also explored YKL-40's implication in insulin resistance and inflammation and the effect of weight loss on plasma YKL-40 concentrations. PATIENTS AND METHODS: Samples obtained from 53 subjects were used in the study. Gene and protein expression levels of YKL-40 were analyzed in VAT as well as in both adipocytes and SVFCs. In addition, circulating YKL-40 concentrations were measured before and after weight loss achieved either by Roux en-Y gastric bypass (n = 26) or after a conventional dietetic program (n = 20). RESULTS: Circulating concentrations and VAT expression of YKL-40 were increased in obese patients with type 2 diabetes (P < 0.01) as well as associated with variables of insulin resistance and inflammation. No differences in YKL-40 expression levels between adipocytes and SVFCs were detected. Monocyte chemoattractant protein-1 and homeostasis model assessment emerged (P < 0.01) as independent factors predicting circulating YKL-40. Elevated levels of YKL-40 in obese patients decreased after weight loss following a conventional hypocaloric diet (P < 0.05) but not via a surgery-induced negative energy balance mediated by the Roux-en-Y gastric bypass. CONCLUSIONS: The association of increased YKL-40 mRNA and protein levels in VAT with its circulating concentrations indicates an important contribution of VAT in YKL-40 regulation. Furthermore, our data suggest a relevant role of glucose metabolism and inflammation on YKL-40 regulation. PMID- 20943785 TI - Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. AB - CONTEXT: In humans, the prevalence, mass, and glucose-uptake activity of (18)F fluorodeoxyglucose ((18)F-FDG)-detected brown adipose tissue (BAT), which are expectedly enhanced by a cold stimulus, also appear modulated by other factors that still have to be disentangled. OBJECTIVE: The objective of the study was to investigate the factors determining the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT in humans. RESEARCH DESIGN AND METHODS: We retrospectively analyzed all (18)F-FDG positron emission tomography/computed tomography examinations performed between January 2007 and December 2008 at our institution for (18)F-FDG uptake within the cervical/supraclavicular, mediastinal, paravertebral, and perirenal fat areas. The influence of outdoor temperature, sex, age, body mass index (BMI), plasma glucose level, diabetes diagnosis, day length, and cancer status on the prevalence, mass, and glucose uptake activity of (18)F-FDG-detected BAT depots was investigated. RESULTS: Three hundred twenty-eight of the 4842 patients (6.8%) had (18)F-FDG-detected BAT. The prevalence of (18)F-FDG BAT was negatively associated with outdoor temperature (P < 0.0001), age (P < 0.0001), BMI (P < 0.0001), and diabetes status (P = 0.0003). Moreover, there was a significant age * sex interaction for the prevalence of (18)F-FDG BAT (the younger the subjects, the greater the sex difference). The mass and glucose-uptake activity of (18)F-FDG-detected BAT also decreased with increasing outdoor temperature (P < 0.0001), age (P < 0.0001), and BMI (P < 0.0001). They were lower in men than in women (P < 0.001) and lower in diabetic than in nondiabetic patients (P = 0.0002). CONCLUSIONS: The present study identifies outdoor temperature, age, sex, BMI, and diabetes status as determinants of the prevalence, mass, and glucose-uptake activity of (18)F-FDG detected BAT. PMID- 20943786 TI - Enhanced excretion of vitamin D binding protein in type 1 diabetes: a role in vitamin D deficiency? AB - CONTEXT: Vitamin D deficiency is an increasingly recognized comorbidity in patients with both type 1 (T1D) and type 2 diabetes, particularly associated with the presence of diabetic nephropathy. OBJECTIVE: Because we have previously reported enhanced excretion of megalin in the urine of T1D patients with microalbuminuria, we hypothesized that concurrent urinary loss of the megalin ligand, vitamin D binding protein, might contribute mechanistically to vitamin D deficiency. DESIGN AND PARTICIPANTS: Examining a study cohort of 115 subjects with T1D, aged 14-40 yr, along with 55 age-matched healthy control subjects, we measured plasma and urine concentrations of vitamin D binding protein (VDBP) along with serum concentrations of total calcium, parathyroid hormone, 25 hydroxyvitamin D, and 1, 25-dihydroxyvitamin D; these results were compared between groups and investigated for relationships with metabolic control status or with albuminuria. MAIN OUTCOME MEASURE: Between-group differences in urinary VDBP concentration were the main outcome measures. RESULTS: A marked increase in the urinary excretion of VDBP was apparent in subjects with T1D, compared with control subjects. Using multivariate regression modeling, significant correlates of urinary VDBP excretion included microalbuminuria (P = 0.004), glycosylated hemoglobin (P = 0.010), continuous glucose monitoring system average capillary glucose (P = 0.047), and serum 1,25(OH)(2)D concentrations (P = 0.037). Vitamin D deficiency or insufficiency was slightly more prevalent in diabetic subjects with albuminuria, coincident with the increase in urine VDBP excretion. CONCLUSIONS: These findings suggest that, theoretically, exaggerated urinary loss of VDBP in T1D, particularly in persons with albuminuria, could contribute mechanistically to vitamin D deficiency in this disease. PMID- 20943787 TI - Elevated corticotropin releasing hormone (CRH) during pregnancy and risk of postpartum depression (PPD). AB - CONTEXT: Perinatal depression has a prevalence of 10% with devastating consequences for mother and baby. The prospective identification of those at risk for postpartum (PPD) or prenatal (PND) depression has led to biomarker searches in pregnancy. There are conflicting reports of associations between midpregnancy placental CRH (pCRH) and PPD or PND. OBJECTIVE: The objective of the study was to quantify the association of maternal pCRH with PPD and PND. DESIGN: This was a prospective cohort study (the Pregnancy, Infection, and Nutrition Study). SETTING: The study was conducted at a prenatal clinics at the University of North Carolina at Chapel Hill. PATIENTS: Patients included 1230 pregnant women. MAIN OUTCOME MEASURES: The relationship between pCRH at less than 20 wk and 24-29 wk and maternal depression assessed in pregnancy [Center for Epidemiologic Studies Depression Scale (CES-D)] and postpartum (12 wk and 1 yr) with the Edinburgh Postnatal Depression Scale (EPDS). RESULTS: At 24-29 wk, 24.8% of women had CES-D score of 17 or greater, and 9.7% had a CES-D score of 25 or greater. At 12 wk postpartum, 18.2% of women had an EPDS score of 10 or greater and 7.6% had an EPDS score of 13 or greater. CRH measures at less than 20 wk and 24-29 wk were inversely correlated with a CES-D score at 24-29 wk (n = 1080, P < 0.05 and P < 0.01, respectively). Pregnancy pCRH was not correlated with the EPDS score at 12 wk (n = 484) or 1 yr postpartum (n = 391). In covariate-adjusted models, higher pCRH was not associated with a CES-D of 17 or greater at 24-29 wk (odds ratio 0.88 per sd change in pCRH at 24-29 wk, 95% confidence interval 0.76-1.03). There was no association between log CRH at 24-29 wk and PPD (covariate-adjusted odds ratio per sd 0.99, 95% confidence interval 0.69-1.42). CONCLUSION: Higher midpregnancy pCRH was not associated with an increased risk of PND or PPD. PMID- 20943788 TI - The prevalence of occult medullary thyroid carcinoma at autopsy. AB - CONTEXT: The prevalence of occult medullary thyroid carcinoma (MTC) in the general population is unknown but may be important when considering strategies to diagnose clinically relevant MTC in nodular goiter or other populations. OBJECTIVE: Our objective was to determine the prevalence of occult MTC in a series of autopsies. DESIGN: We conducted a systematic review of autopsy series from 1970 to present using a PubMed search. PATIENTS: The patients came from 21 countries, ages ranged from 6-95 yr, both genders were represented, and none had clinical evidence of thyroid disease before autopsy. INTERVENTION: Three series were excluded based on tumor size less than 500 MUm, non-English language, or insufficient information. MAIN OUTCOME MEASURE: Prevalence of occult MTC was calculated. RESULTS: An average prevalence of 0.14 and 7.6% for occult MTC and papillary thyroid carcinoma, respectively, was found among 7897 autopsies from 24 published series. Greater than 75% of patients with MTC were more than 60 yr old, and male to female ratio was comparable. Tumor size was virtually all subcentimeter, and there was no lymph node spread, extrathyroidal extension, or distant metastases reported. CONCLUSIONS: A small number of people in the general population, who do not have known thyroid disease, have occult MTC and die of other causes. This finding of untreated occult MTC without morbidity or mortality should be considered in population prevalence studies, when strategies to detect thyroid neoplasia are considered (e.g. serum calcitonin or ultrasound), and included in cost-effectiveness models of routine serum calcitonin screening for nodular thyroid disease. PMID- 20943789 TI - Twist1 in human white adipose tissue and obesity. AB - CONTEXT: Twist1 is a transcription factor implicated in the regulation of TNFalpha signaling and was recently shown to be highly expressed in both human and murine adipose tissue, but its role in obesity is unknown. OBJECTIVE: Our objective was to assess the expression of twist1 in human white adipose tissue (WAT), its relationship to obesity and insulin sensitivity, and how it modifies TNFalpha-mediated inflammation in adipocytes. PROCEDURE: Twist mRNA levels were measured in WAT from 130 nonobese and obese subjects, and its relation to clinical parameters was assessed. Twist1 expression was measured before and after weight loss as well as in different adipose regions. Human in vitro differentiated adipocytes were treated with TNFalpha under control conditions or after twist1 gene silencing by RNA interference. Gene expression and secretion of proinflammatory proteins were measured. RESULTS: Twist1 expression was low in obese subjects and increased after weight loss. Twist1 mRNA levels correlated with adiponectin levels and inversely with insulin resistance as well as adipocyte volume (P < 0.001 for all). Low twist1 expression associated with a hypertrophic adipose tissue and high secretion of TNFalpha and monocyte chemoattractant protein-1 from WAT. Finally, twist1 silencing in human adipocytes enhanced TNFalpha-induced monocyte chemoattractant protein-1 expression and secretion, which was paralleled by an increase in the mRNA expression of the nuclear factor-kappaB gene RelA. CONCLUSIONS: Low twist1 expression in human WAT correlates with obesity and an insulin-resistant phenotype, which may be mediated by an increased sensitivity to the proinflammatory effect of TNFalpha. PMID- 20943790 TI - Cortisol stimulates secretion of dehydroepiandrosterone in human adrenocortical cells through inhibition of 3betaHSD2. AB - CONTEXT: Initiating factors leading to production of adrenal androgens are poorly defined. Cortisol is present in high concentrations within the adrenal gland, and its production rises with growth during childhood. OBJECTIVE: Our aim was to characterize the effect of cortisol and other glucocorticoids on androgen secretion from a human adrenocortical cell line and from nonadrenal cells transfected with CYP17A1 or HSD3B2. DESIGN/SETTING: This study was performed in cultured cells, at an academic medical center. METHODS: The effects of cortisol upon steroid production in human adrenal NCI-H295R cells were measured by immunoassay, tandem mass spectrometry, and thin-layer chromatography. The effects of cortisol upon the activities of 17, 20 lyase and 3betaHSD2 were measured in NCI-H295R cells and in transfected COS-7 cells. RESULTS: Cortisol markedly and rapidly stimulated dehydroepiandrosterone (DHEA) in a dose-dependent manner at cortisol concentrations >=50 MUM. Cortisone and 11-deoxycortisol were also potent stimulators of DHEA secretion, whereas prednisolone and dexamethasone were not. Treatment with cortisol did not affect expression of CYP17A1 or HSD3B2 mRNAs. Stimulation of DHEA secretion by cortisol was associated with competitive inhibition of 3betaHSD2 activity. CONCLUSIONS: Cortisol inhibits 3betaHSD2 activity in adrenal cells and in COS-7 cells transfected with HSD3B2. Thus, it is possible that intraadrenal cortisol may participate in the regulation of adrenal DHEA secretion through inhibition of 3betaHSD2. We hypothesize that a rise in intraadrenal cortisol during childhood growth may lead to inhibition of 3betaHSD2 activity and contribute to the initiation of adrenarche. PMID- 20943791 TI - Acid-labile subunit (ALS) gene expression and protein content in human placentas: differences according to birth weight. AB - CONTEXT: In humans, IGF-I and -II have an important role in pre- and postnatal growth. The IGFs circulate in plasma principally as a ternary complex with the IGF binding protein-3 and an acid-labile subunit (ALS), which increases their half life. OBJECTIVES: The objectives of the study were to determine whether the human placenta expresses the mRNA and protein for ALS and to evaluate any possible differences in the mRNA and protein for ALS in placentas from small (SGA) and appropriate (AGA) or gestational age newborns. SUBJECTS/METHODS: We studied the placentas from 47 AGA and 42 SGA pregnancies. IGF-I, IGF-II, IGF binding protein-3, and ALS placental mRNA and protein contents were determined in both the basal and the chorionic plates of the placenta. RESULTS: We observed that the human placenta expresses the gene and protein for ALS. The ALS mRNA in SGA was higher compared with AGA placentas (0.15 +/- 0.01 vs. 0.12 +/- 0.01 arbitrary units, respectively, P < 0.05). In addition, the ALS protein content in SGA (31.7 +/- 3.3 pmol/g) was higher compared with AGA (22.1 +/- 2.3 pmol/g, P < 0.05) placentas. CONCLUSION: We describe that the human placenta expresses the mRNA and the protein for ALS, and we observed an increase in ALS mRNA expression and protein content in SGA compared with AGA placentas. PMID- 20943792 TI - Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-{alpha}-mediated inflammation and insulin resistance in primary human adipocytes. AB - BACKGROUND: Quercetin and trans-resveratrol (trans-RSV) are plant polyphenols reported to reduce inflammation or insulin resistance associated with obesity. Recently, we showed that grape powder extract, which contains quercetin and trans RSV, attenuates markers of inflammation in human adipocytes and macrophages and insulin resistance in human adipocytes. However, we do not know how quercetin and trans-RSV individually affected these outcomes. OBJECTIVE: The aim of this study was to examine the extent to which quercetin and trans-RSV prevented inflammation or insulin resistance in primary cultures of human adipocytes treated with tumor necrosis factor-alpha (TNF-alpha)-an inflammatory cytokine elevated in the plasma and adipose tissue of obese, diabetic individuals. DESIGN: Cultures of human adipocytes were pretreated with quercetin and trans-RSV followed by treatment with TNF-alpha. Subsequently, gene and protein markers of inflammation and insulin resistance were measured. RESULTS: Quercetin, and to a lesser extent trans-RSV, attenuated the TNF-alpha-induced expression of inflammatory genes such as interleukin (IL)-6, IL-1beta, IL-8, and monocyte chemoattractant protein-1 (MCP-1) and the secretion of IL-6, IL-8, and MCP-1. Quercetin attenuated TNF alpha-mediated phosphorylation of extracellular signal-related kinase and c-Jun NH2 terminal kinase, whereas trans-RSV attenuated only c-Jun-NH2 terminal kinase phosphorylation. Quercetin and trans-RSV attenuated TNF-alpha-mediated phosphorylation of c-Jun and degradation of inhibitory kappaB protein. Quercetin, but not trans-RSV, decreased TNF-alpha-induced nuclear factor-kappaB transcriptional activity. Quercetin and trans-RSV attenuated the TNF-alpha mediated suppression of peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgamma target genes and of PPARgamma protein concentrations and transcriptional activity. Quercetin prevented the TNF-alpha-mediated serine phosphorylation of insulin receptor substrate-1 and protein tyrosine phosphatase 1B gene expression and the suppression of insulin-stimulated glucose uptake, whereas trans-RSV prevented only the TNF-alpha-mediated serine phosphorylation of insulin receptor substrate-1. CONCLUSION: These data suggest that quercetin is equally or more effective than trans-RSV in attenuating TNF-alpha-mediated inflammation and insulin resistance in primary human adipocytes. PMID- 20943793 TI - Genetic variation in TAS1R2 (Ile191Val) is associated with consumption of sugars in overweight and obese individuals in 2 distinct populations. AB - BACKGROUND: Taste is an important determinant of food consumption, and genetic variations in the sweet taste receptor subunit TAS1R2 may contribute to interindividual variations in sugar consumption. OBJECTIVE: We determined whether Ser9Cys and Ile191Val variations in TAS1R2 were associated with differences in the consumption of sugars in 2 populations. DESIGN: Population 1 included 1037 diabetes-free young adults in whom we assessed dietary intake by using a 1-mo, 196-item food-frequency questionnaire. Population 2 consisted of 100 individuals with type 2 diabetes with dietary intakes assessed by using 2 sets of 3-d food records administered 2 wk apart. Dietary counseling was provided between food records 1 and 2. Dietary intakes between genotypes were compared by using analysis of covariance adjusted for potential confounders. RESULTS: In population 1, a significant Ile191Val * body mass index (BMI; in kg/m2) interaction was detected for the consumption of sugars, and the effect of genotype was significant only in individuals with a BMI >= 25 (n = 205). In comparison with individuals homozygous for the Ile allele, Val carriers consumed fewer sugars (122 +/- 6 compared with 103 +/- 6 g sugar/d, respectively; P = 0.01). Regression estimates that associated BMI with total sugar consumption by Ile/Ile and Val carrier genotype intersected at a BMI of 23.5. In population 2, Val carriers also consumed less sugar than did individuals with the Ile/Ile genotype (99 +/- 6 compared with 83 +/- 6 g sugar/d, respectively; P = 0.04) on food record 2, and sugar was the only macronutrient that decreased significantly (-9 +/- 4 g sugar/d, P = 0.02) in Val carriers who received dietary counseling. CONCLUSION: Our findings show that a genetic variation in TAS1R2 affects habitual consumption of sugars and may contribute to interindividual differences in changing behaviors in response to dietary counseling. PMID- 20943794 TI - Plasma concentration of 3-hydroxyisovaleryl carnitine is an early and sensitive indicator of marginal biotin deficiency in humans. AB - BACKGROUND: Blood-based indicators of biotin status in humans were shown to be useful tools in several clinical situations, including pregnancy. We previously validated the activity of the biotin-dependent enzyme propionyl-coenzyme A carboxylase (PCC) in lymphocytes as a sensitive and specific blood-based indicator of marginal degrees of biotin deficiency. However, the measurement of PCC activity in population studies presents substantial analytic challenges. 3 Hydroxyisovaleryl carnitine (3HIA-carnitine) increases in response to the decreased activity of the biotin-dependent enzyme methylcrotonyl-coenzyme A carboxylase and might reflect biotin status. OBJECTIVE: We sought to determine whether the plasma concentration of 3HIA-carnitine increases significantly in marginal biotin deficiency. DESIGN: We experimentally induced marginal, asymptomatic biotin deficiency in 10 healthy adults (8 women) by having the subjects consume undenatured egg white for 28 d; biotin status was then repleted. Plasma concentrations of 3HIA-carnitine were measured on days 0, 14, 28, 35, and 50 by liquid chromatography-mass spectroscopy. RESULTS: The mean plasma 3HIA carnitine concentration increased with depletion (P < 0.0001) and decreased with repletion (P < 0.0001). Plasma 3HIA-carnitine concentrations were greater than the upper limit of normal concentrations in 7 of 10 subjects by day 14 and in 9 of 10 subjects by day 28 and decreased to within normal limits in 9 of 10 subjects by day 50. CONCLUSIONS: These studies provide evidence that 3HIA carnitine is an early and sensitive indicator of marginal biotin deficiency. The ease of sample collection, small sample volume requirement, and stability of 3HIA carnitine during storage suggest that plasma 3HIA-carnitine concentration is likely to be a useful indicator of marginal biotin deficiency for larger population studies. PMID- 20943795 TI - Circulating palmitoleic acid and risk of metabolic abnormalities and new-onset diabetes. AB - BACKGROUND: Animal experiments suggest that circulating palmitoleic acid (cis 16:1n-7) from adipocyte de novo fatty acid synthesis may directly regulate insulin resistance and metabolic dysregulation. OBJECTIVE: We investigated the independent determinants of circulating palmitoleate in free-living humans and whether palmitoleate is related to lower metabolic risk and the incidence of diabetes. DESIGN: In a prospective cohort of 3630 US men and women in the Cardiovascular Health Study, plasma phospholipid fatty acids, anthropometric variables, blood lipids, inflammatory markers, and glucose and insulin concentrations were measured between 1992 and 2006 by using standardized methods. Independent determinants of plasma phospholipid palmitoleate and relations of palmitoleate with metabolic risk factors were investigated by using multivariable adjusted linear regression. Relations with incident diabetes (296 incident cases) were investigated by using Cox proportional hazards. RESULTS: The mean (+/- SD) palmitoleate value was 0.49 +/- 0.20% (range: 0.11-2.55%) of total fatty acids. Greater body mass index, carbohydrate intake, protein intake, and alcohol use were each independent lifestyle correlates of higher palmitoleate concentrations. In multivariable analyses that adjusted for these factors and other potential confounders, higher palmitoleate concentrations were independently associated with lower LDL cholesterol (P < 0.001), higher HDL cholesterol (P < 0.001), lower total:HDL-cholesterol ratio (P = 0.04), and lower fibrinogen (P < 0.001). However, palmitoleate was also associated with higher triglycerides (P < 0.001) and (in men only) with greater insulin resistance (P < 0.001). Palmitoleate was not significantly associated with incident diabetes. CONCLUSIONS: Adiposity (energy imbalance), carbohydrate consumption, and alcohol use-even within typical ranges-are associated with higher circulating palmitoleate concentrations. Circulating palmitoleate is robustly associated with multiple metabolic risk factors but in mixed directions, perhaps related to divergent lifestyle determinants or endogenous sources (liver, adipose tissue) of fatty acid synthesis. PMID- 20943796 TI - Adherence to a Mediterranean diet and plasma concentrations of lipid peroxidation in premenopausal women. AB - BACKGROUND: A Mediterranean diet has been associated with a reduced risk of cardiovascular disease and mortality. A possible mechanism is through a decrease in lipid peroxidation (LPO); however, evidence linking the Mediterranean diet with lower LPO in premenopausal women is sparse. OBJECTIVE: We investigated whether adherence to a Mediterranean diet was associated with lower LPO concentrations in premenopausal women. DESIGN: Two hundred fifty-nine healthy women aged 18-44 y were followed for <= 2 menstrual cycles. Plasma concentrations of F(2)-isoprostane (8-iso-PGF2alpha), 9-hydroxyoctadecadieneoic acid (9-HODE), and thiobarbituric acid reactive substances (TBARS) were measured <= 8 times per cycle at visits scheduled by using fertility monitors. Diet was assessed <= 4 times per cycle by using 24-h dietary recalls. The alternate Mediterranean Diet Score (aMED) (range: 0-9) was calculated on the basis of intake of vegetables, legumes, fruit, nuts, whole grains, red and processed meat, fish, and alcohol and the ratio of monounsaturated to saturated fat. RESULTS: A 1-unit increase in aMED was associated with a 4.50% decrease in 8-iso-PGF2alpha concentrations (95% CI: 6.32%, -2.65%) and a 14.01% decrease in 9-HODE concentrations (95% CI: -17.88%, 9.96%) after adjustment for energy intake, age, race, body mass index, plasma ascorbic acid, and serum cholesterol. No significant association was observed between aMED and TBARS. A 1-unit increase in aMED was associated with a 1.39% increase (95% CI: 0.07%, 2.72%) in plasma ascorbic acid concentrations. CONCLUSIONS: Adherence to a Mediterranean diet is associated with lower LPO and higher ascorbic acid concentrations. These results confirm that decreased LPO is a plausible mechanism linking a Mediterranean diet to reduced cardiovascular disease risk. PMID- 20943797 TI - The role of molecular weight and viscosity of oat beta-glucan in hypocholesterolemic effect. PMID- 20943798 TI - Intake of artificially sweetened soft drinks and risk of preterm delivery. PMID- 20943800 TI - Automated reporting of QT interval and other issues in the channelopathies. PMID- 20943801 TI - How to use C reactive protein: postscript. PMID- 20943799 TI - Heritability and seasonal variability of vitamin D concentrations in male twins. AB - BACKGROUND: Serum 25-hydroxyvitamin D [25(OH)D] concentrations can be affected by several environmental and individual factors. It is not clear to what extent genetic influences play a role in determining vitamin D status. Thus far, studies on the heritability of vitamin D have provided conflicting results. OBJECTIVE: We estimated the heritability of vitamin D concentrations and the effect of season on heritability estimates. DESIGN: We measured serum 25(OH)D concentrations in 510 middle-aged, male twins (310 monozygotic and 200 dizygotic twins) selected from the Vietnam Era Twin Registry. Generalized estimating equations were used to test the association between 25(OH)D and other study factors. Structural equation modeling was used to estimate the heritability of 25(OH)D. RESULTS: The twins' mean (+/-SD) age was 55 +/- 2.8 y. The mean (+/-SD) 25(OH)D concentration was 38.4 +/- 23.3 ng/mL with a substantial seasonal variation (a 6.1-ng/mL lower value during the winter than during the summer, P = 0.003). Approximately 70% of the variation in 25(OH)D concentrations during the winter was explained by genetic factors. However, in the summer, 25(OH)D concentrations were not heritable. During the summer, 53% of the variation in 25(OH)D concentrations was due to shared environmental factors, and 47% of the variation in 25(OH)D concentrations was due to unique environmental factors. CONCLUSIONS: Serum 25(OH)D concentrations are highly heritable during the winter season only. In the summer, environmental conditions (eg, sun exposure) prevail over genetic backgrounds in determining serum 25(OH)D concentrations. This trial was registered at clinicaltrials.gov as NCT00017836. PMID- 20943802 TI - Long-term care following paediatric liver transplantation. PMID- 20943803 TI - Personal resuscitation plans and end of life planning for children with disability and life-limiting/life-threatening conditions. AB - This article discusses the need for person-specific planning for the increasing numbers of disabled children with life-limiting and life-threatening conditions. It describes the system developed in Nottingham for this client group to have a family-held personal resuscitation plan, (PRP) which is developed with the child and family by their lead paediatrician. The PRP is an emergency medical care plan which supports the provision of the most appropriate level of intervention for the child whether they are at home, school, short break unit or hospital. The PRP template is presented with advice on implementation and case examples. Feedback from families, medical and nursing staff is that PRPs are useful and empowering. The system supports timely discussions about appropriate care in an emergency and the communication of decisionsmade jointly by the child, family and medical team to all concerned. A flexible and person-specific PRP stating what interventions to do such as airway clearance, facial oxygen, trial of bag and mask ventilation is preferable to a do not attempt resuscitation form which is an 'all or nothing system' and can seem very negative to families. A PRP in the home can support appropriate action from local rapid response teams set up to review unexpected child deaths. PMID- 20943804 TI - UK treatment of malaria. AB - Imported malaria has become an increasingly significant cause of mortality and morbidity in children travelling to areas of the world endemic for malaria. Malaria is one of the commonest imported tropical diseases in the UK, with children accounting for 15-20% of all cases. Over 80% of all cases of malaria are due to Plasmodium falciparum infection, which can cause severe or life threatening multi-organ disease in children. The clinical features of malaria in children are often non-specific, resulting in missed or delayed diagnosis. Children are more likely than adults to deteriorate rapidly and to develop severe malaria, particularly cerebral malaria. Malaria should be suspected in all children with a history of travel to a malaria-endemic country who present with fever. Diagnosis is usually made with repeated thick and thin blood films. Delays in diagnosis are associated with an increased risk of developing severe malaria and death. Appropriate antimalarial therapy and supportive care should be instituted as soon as possible, particularly in children with severe malaria. Advice should be sought from an appropriate specialist. PMID- 20943805 TI - Getting to the bones of the matter. PMID- 20943806 TI - Transgenerational inheritance of glucose intolerance in a mouse model of neonatal overnutrition. AB - Epidemiological and clinical data show that rapid weight gain early in life is strongly associated with several components of the metabolic syndrome. Strikingly, abnormal growth rates in early life can additionally influence diabetes risk in subsequent generations. Here we aim to study whether neonatal overgrowth induces diabetes in offspring and grand-offspring of affected individuals using a mouse model of neonatal overfeeding. We induced neonatal overgrowth (ON-F0) by culling offspring to four pups per dam during lactation. By age 4 months, ON-F0 mice developed many features of the metabolic syndrome, including obesity, insulin resistance, and glucose intolerance. We then studied whether male offspring (ON-F1) and grand-offspring (ON-F2) of ON-F0 male mice, which were not overfed during lactation, developed features of the metabolic syndrome with aging. ON-F1 mice developed fed and fasting hyperinsulimemia, hypertryglyceridemia, insulin resistance, and glucose intolerance, but not obesity, by age 4 months. In contrast, ON-F2 male mice showed a more moderate phenotype and only developed fasting hyperglycemia and glucose intolerance by age 4 months. Impaired glucose tolerance in ON-F1 and ON-F2 mice appeared to be accounted for primarily by peripheral insulin resistance, because beta-cell function remained normal or even increased in these cohorts. Nutritional challenges occurring during sensitive periods of development may have adverse metabolic consequences well beyond the lifespan of affected individuals and manifest in subsequent generations. Transgenerational progression of metabolic phenotypes through the male lineage supports a potential role for epigenetic mechanisms in mediating these effects. PMID- 20943807 TI - Mechanical loading-related bone gain is enhanced by tamoxifen but unaffected by fulvestrant in female mice. AB - Accumulating evidence indicates that estrogen receptors (ERs) are involved in the mechano-adaptive mechanisms by which loading influences the mass and architecture of bones to establish and maintain their structural load-bearing competence. In the present study, we assessed the effects of the ER modulators tamoxifen and fulvestrant (ICI 182,780) on loading-related changes in the volume and structure of trabecular and cortical bone in the tibiae of female mice. Ten days after actual or sham ovariectomy, 17-wk-old female C57BL/6 mice were treated with vehicle (peanut oil), tamoxifen (0.02, 0.2, or 2 mg/kg . d), fulvestrant (4 mg/kg . d), or their combination and the right tibiae subjected to a short period of noninvasive axial loading (40 cycles/d) on 5 d during the subsequent 2 wk. In the left control tibiae, ovariectomy, tamoxifen, or fulvestrant did not have any significant effect on cortical bone volume, whereas trabecular bone volume was decreased by ovariectomy, increased by tamoxifen, and unaffected by fulvestrant. In the right tibiae, loading was associated with increases in both trabecular and cortical bone volume. Notably, the medium dose of tamoxifen synergistically enhanced loading-related gain in trabecular bone volume through an increase in trabecular thickness. Fulvestrant had no influence on the effects of loading but abrogated the enhancement of loading-related bone gain by tamoxifen. These data demonstrate that, at least in female mice, the adaptive response to mechanical loading of trabecular bone can be enhanced by ER modulators, in this case by tamoxifen. PMID- 20943808 TI - Estrogen-induced apoptosis of breast epithelial cells is blocked by NO/cGMP and mediated by extranuclear estrogen receptors. AB - Estrogen action, via both nuclear and extranuclear estrogen receptors (ERs), induces a variety of cellular signals that are prosurvival or proliferative, whereas nitric oxide (NO) can inhibit apoptosis via caspase S-nitrosylation and via activation of soluble guanylyl cyclase to produce cGMP. The action of 17beta estradiol (E(2)) at ER is known to elicit NO signaling via activation of NO synthase (NOS) in many tissues. The MCF-10A nontumorigenic, mammary epithelial cell line is genetically stable and insensitive to estrogenic proliferation. In this cell line, estrogens or NOS inhibitors alone had no significant effect, whereas in combination, apoptosis was induced rapidly in the absence of serum; the presence of inducible NOS was confirmed by proteomic analysis. The application of pharmacological agents determined that apoptosis was dependent upon NO/cGMP signaling via cyclic GMP (cGMP)-dependent protein kinase and could be replicated by inhibition of the phosphatidylinositol 3 kinase/serine-threonine kinase pathway prior to addition of E(2). Apoptosis was confirmed by nuclear staining and increased caspase-3 activity in E(2) + NOS inhibitor-treated cells. Apoptosis was partially inhibited by a pure ER antagonist and replicated by agonists selective for extranuclear ER. Cells were rescued from E(2)-induced apoptosis after NOS blockade, by NO-donors and cGMP pathway agonists; preincubation with NO donors was required. The NOS and ER status of breast cancer tissues is significant in etiology, prognosis, and therapy. In this study, apoptosis of preneoplastic mammary epithelial cells was triggered by estrogens via a rapid, extranuclear ER-mediated response, after removal of an antiapoptotic NO/cGMP/cGMP-dependent protein kinase signal. PMID- 20943810 TI - Functions of xyloglucan in plant cells. AB - While an increase in the number of xyloglucan tethers between the cellulose microfibrils in plant cell walls increases the walls' rigidity, the degradation of these tethers causes the walls to loosen. Degradation can occur either through the integration of xyloglucan oligosaccharides due to the action of xyloglucan endotransglucosylase or through direct hydrolysis due to the action of xyloglucanase. This is why the addition of xyloglucan and its fragment oligosaccharides causes plant tissue tension to increase and decrease so dramatically. Experiments involving the overexpression of xyloglucanase and cellulase have revealed the roles of xyloglucans in the walls. The degradation of wall xyloglucan in poplar by the transgenic expression of xyloglucanase, for example, not only accelerated stem elongation in the primary wall, but also blocked upright-stem gravitropism in the secondary wall. Overexpression of cellulase also reduced xyloglucan content in the walls as cellulose microfibrils were trimmed at their amorphous region, resulting in increased cell volume in Arabidopsis leaves and in sengon with disturbed leaf movements. The hemicellulose xyloglucan, in its function as a tether, plays a key role in the loosening and tightening of cellulose microfibrils: it enables the cell to change its shape in growth and differentiation zones and to retain its final shape after cell maturation. PMID- 20943811 TI - Efficient silencing of endogenous microRNAs using artificial microRNAs in Arabidopsis thaliana. AB - We report here that the expression of endogenous microRNAs (miRNAs) can be efficiently silenced in Arabidopsis thaliana (Arabidopsis) using artificial miRNA (amiRNA) technology. We demonstrate that an amiRNA designed to target a mature miRNA directs silencing against all miRNA family members, whereas an amiRNA designed to target the stem-loop region of a miRNA precursor transcript directs silencing against only the individual family member targeted. Furthermore, our results indicate that amiRNAs targeting both the mature miRNA and stem-loop sequence direct RNA silencing through cleavage of the miRNA precursor transcript, which presumably occurs in the nucleus of a plant cell during the initial stages of miRNA biogenesis. This suggests that small RNA (sRNA)-guided RNA cleavage in plants occurs not only in the cytoplasm, but also in the nucleus. Many plant miRNA gene families have been identified via sequencing and bioinformatic analysis, but, to date, only a small tranche of these have been functionally characterized due to a lack of effective forward or reverse genetic tools. Our findings therefore provide a new and powerful reverse-genetic tool for the analysis of miRNA function in plants. PMID- 20943809 TI - Clinically relevant progestins regulate neurogenic and neuroprotective responses in vitro and in vivo. AB - Previously, we demonstrated that progesterone (P(4)) promoted adult rat neural progenitor cell (rNPC) proliferation with concomitant regulation of cell-cycle gene expression via the P(4) receptor membrane component/ERK pathway. Here, we report the efficacy of seven clinically relevant progestins alone or in combination with 17beta-estradiol (E(2)) on adult rNPC proliferation and hippocampal cell viability in vitro and in vivo. In vitro analyses indicated that P(4), norgestimate, Nestorone, norethynodrel, norethindrone, and levonorgestrel (LNG) significantly increased in rNPC proliferation, whereas norethindrone acetate was without effect, and medroxyprogesterone acetate (MPA) inhibited rNPC proliferation. Proliferative progestins in vitro were also neuroprotective. Acute in vivo exposure to P(4) and Nestorone significantly increased proliferating cell nuclear antigen and cell division cycle 2 expression and total number of hippocampal 5-bromo-2-deoxyuridine (BrdU)-positive cells, whereas LNG and MPA were without effect. Mechanistically, neurogenic progestins required activation of MAPK to promote proliferation. P(4), Nestorone, and LNG significantly increased ATP synthase subunit alpha (complex V, subunit alpha) expression, whereas MPA was without effect. In combination with E(2), P(4), Nestorone, LNG, and MPA significantly increased BrdU incorporation. However, BrdU incorporation induced by E(2) plus LNG or MPA was paralleled by a significant increase in apoptosis. A rise in Bax/Bcl-2 ratio paralleled apoptosis induced by LNG and MPA. With the exception of P(4), clinical progestins antagonized E(2)-induced rise in complex V, subunit alpha. These preclinical translational findings indicate that the neurogenic response to clinical progestins varies dramatically. Progestin impact on the regenerative capacity of the brain has clinical implications for contraceptive and hormone therapy formulations prescribed for pre- and postmenopausal women. PMID- 20943812 TI - Differential neonatal testosterone imprinting of GH-dependent liver proteins and genes in female mice. AB - Abnormal exposure to steroid hormones within a critical developmental period elicits permanent alterations in female reproductive physiology in rodents, but the impact on the female GH axis and the underlying sexual differences in hepatic enzymes have not been described in detail. We have investigated the effect of neonatal androgenization of female mice (achieved by s.c. injection of 100 MUg testosterone propionate (TP) on the day of birth: TP females) on the GHRH somatostatin-GH axis and downstream GH targets, which included female and male predominant liver enzymes and secreted proteins. At 4 months of age, an organizational effect of neonatal testosterone was evidenced on hypothalamic Ghrh mRNA level but not on somatostatin (stt) mRNA level. Ghrh mRNA levels were higher in males than in females, but not in TP females. Increased expression in TP females correlated with increased pituitary GH content and somatotrope population, increased serum and liver IGF-I concentration, and ultimately higher body weight. Murine urinary proteins (MUPs) that were excreted at higher levels in male urine, and whose expression requires pulsatile occupancy of liver GH receptors, were not modified in TP females and neither was liver Mup 1/2/6/8 mRNA expression. Furthermore, a male predominant liver gene (Cyp2d9) was not masculinized in TP females either, whereas two female predominant genes (Cyp2b9 and Cyp2a4) were defeminized. These data support the hypothesis that neonatal steroid exposure contributes to the remodeling of the GH axis and defeminization of hepatic steroid-metabolizing enzymes, which may compromise liver physiology. PMID- 20943813 TI - Research resource: Genome-wide mapping of in vivo androgen receptor binding sites in mouse epididymis. AB - Epididymal function depends on androgen signaling through the androgen receptor (AR), although most of the direct AR target genes in epididymis remain unknown. Here we globally mapped the AR binding regions in mouse caput epididymis in which AR is highly expressed. Chromatin immunoprecipitation sequencing indicated that AR bound selectively to 19,377 DNA regions, the majority of which were intergenic and intronic. Motif analysis showed that 94% of the AR binding regions harbored consensus androgen response elements enriched with multiple binding motifs that included nuclear factor 1 and activator protein 2 sites consistent with combinatorial regulation. Unexpectedly, AR binding regions showed limited conservation across species, regardless of whether the metric for conservation was based on local sequence similarity or the presence of consensus androgen response elements. Further analysis suggested the AR target genes are involved in diverse biological themes that include lipid metabolism and sperm maturation. Potential novel mechanisms of AR regulation were revealed at individual genes such as cysteine-rich secretory protein 1. The composite studies provide new insights into AR regulation under physiological conditions and a global resource of AR binding sites in a normal androgen-responsive tissue. PMID- 20943814 TI - Regulation of thyrotropin-releasing hormone-expressing neurons in paraventricular nucleus of the hypothalamus by signals of adiposity. AB - Fasting-induced suppression of thyroid hormone levels is an adaptive response to reduce energy expenditure in both humans and mice. This suppression is mediated by the hypothalamic-pituitary-thyroid axis through a reduction in TRH levels expressed in neurons of the paraventricular nucleus of the hypothalamus (PVN). TRH gene expression is positively regulated by leptin. Whereas decreased leptin levels during fasting lead to a reduction in TRH gene expression, the mechanisms underlying this process are still unclear. Indeed, evidence exists that TRH neurons in the PVN are targeted by leptin indirectly via the arcuate nucleus, whereas correlative evidence for a direct action exists as well. Here we provide both in vivo and in vitro evidence that the activity of hypothalamic-pituitary thyroid axis is regulated by both direct and indirect leptin regulation. We show that both leptin and alpha-MSH induce significant neuronal activity mediated through a postsynaptic mechanism in TRH-expressing neurons of PVN. Furthermore, we provide in vivo evidence indicating the contribution of each pathway in maintaining serum levels of thyroid hormone. PMID- 20943815 TI - Dax1 up-regulates Oct4 expression in mouse embryonic stem cells via LRH-1 and SRA. AB - Dax1 (Nr0b1) is an atypical orphan nuclear receptor that has recently been shown to play a role in mouse embryonic stem (mES) cell pluripotency. Here we describe a mechanism by which Dax1 maintains pluripotency. In steroidogenic cells, Dax1 protein interacts with the NR5A nuclear receptor steroidogenic factor 1 (Nr5a1) to inhibit transcription of target genes. In mES cells, liver receptor homolog 1 (LRH-1, Nr5a2), the other NR5A family member, is expressed, and LRH-1 has been shown to interact with Dax1. We demonstrate by coimmunoprecipitation that Dax1 is, indeed, able to form a complex with LRH-1 in mES cells. Because Dax1 was historically characterized as an inhibitor of steroidogenic factor 1-mediated transcriptional activation, we hypothesized that Dax1 would inhibit LRH-1 action in mES cells. Therefore, we examined the effect of Dax1 on the LRH-1-mediated activation of the critical ES cell factor Oct4 (Pou5f1). Chromatin immunoprecipitation localized Dax1 to the Oct4 promoter at the LRH-1 binding site, and luciferase assays together with Dax1 overexpression and knockdown experiments revealed that, rather than repress, Dax1 accentuated LRH-1-mediated activation of the Oct4 gene. Similar to our previously published studies that defined the RNA coactivator steroid receptor RNA activator as the critical mediator of Dax1 coactivation function, Dax1 augmentation of LRH-1-mediated Oct4 activation is dependent upon steroid receptor RNA activator. Finally, utilizing published chromatin immunoprecipitation data of whole-genome binding sites of LRH 1 and Dax1, we show that LRH-1 and Dax1 commonly colocalize at 288 genes (43% of LRH-1 target genes), many of which are involved in mES cell pluripotency. Thus, our results indicate that Dax1 plays an important role in the maintenance of pluripotency in mES cells through interaction with LRH-1 and transcriptional activation of Oct4 and other genes. PMID- 20943816 TI - Metabolomics identifies novel Hnf1alpha-dependent physiological pathways in vivo. AB - Mutations in the HNF1A gene cause maturity-onset diabetes of the young type 3, one of the most common genetic causes of non-insulin-dependent (type 2) diabetes mellitus. Although the whole-body Hnf1a-null mouse recapitulates the low insulin levels and high blood glucose observed in human maturity-onset diabetes of the young type 3 patients, these mice also suffer from Laron dwarfism and aminoaciduria, suggesting a role for hepatocyte nuclear factor 1alpha (Hnf1alpha) in pathophysiologies distinct from non-insulin-dependent (type 2) diabetes mellitus. In an effort to identify pathways associated with inactivation of Hnf1alpha, an ultraperformance liquid chromatography coupled to mass spectrometry based metabolomics study was conducted on urine samples from wild-type and Hnf1a null mice. An increase in phenylalanine metabolites is in agreement with the known regulation of the phenylalanine hydroxylase gene by Hnf1alpha. This metabolomic approach also identified urinary biomarkers for three tissue-specific dysfunctions previously unassociated with Hnf1alpha function. 1) Elevated indolelactate coupled to decreased xanthurenic acid also indicated defects in the indole and kynurenine pathways of tryptophan metabolism, respectively. 2) An increase in the neutral amino acid proline in the urine of Hnf1a-null mice correlated with loss of renal apical membrane transporters of the Slc6a family. 3) Further investigation into the mechanism of aldosterone increase revealed an overactive adrenal gland in Hnf1a-null mice possibly due to inhibition of negative feedback regulation. Although the phenotype of the Hnf1a-null mouse is complex, metabolomics has opened the door to investigation of several physiological systems in which Hnf1alpha may be a critical regulatory component. PMID- 20943817 TI - The activation of the rat insulin gene II by BETA2 and PDX-1 in rat insulinoma cells is repressed by Pax6. AB - The transcriptional transactivator Pax6 binds the pancreatic islet cell-specific enhancer sequence (PISCES) of the rat insulin I gene. However the human, mouse, and rat insulin gene II promoters do not contain a PISCES element. To analyze the role of Pax6 in those PISCES-less promoters, we investigated its influence on rat insulin gene II expression and included in our studies the main activators: pancreatic and duodenal homeobox protein-1 (PDX-1) and BETA2/E47. Luciferase assays, Northern blots, and RIA were used to study effects of Pax6 overexpression, gel shift and chromatin precipitation assays to study its binding to the DNA, and yeast two-hybrid assays and glutathione S transferase capture assays to investigate its interactions with PDX-1 and BETA2. Finally, glucose dependent intracellular transport of Pax6 was demonstrated by fluorescence microscopy. Overexpression of Pax6 prevents activation of the rat insulin II gene by BETA2 and PDX-1 and hence suppresses insulin synthesis and secretion. In vitro, Pax6 binds to the A-boxes, thereby blocking binding of PDX-1, and at the same time, its paired domain interacts with BETA2. Fluorescence microscopy demonstrated that the nuclear-cytoplasmic localization of Pax6 and PDX-1 are oppositely regulated by glucose. From the results, it is suggested that at low concentrations of glucose, Pax6 is localized in the nucleus and prevents the activation of the insulin gene by occupying the PDX-1 binding site and by interacting with BETA2. PMID- 20943818 TI - Inhibition of translation by cytotrienin A--a member of the ansamycin family. AB - The ansamycins are a diverse and often physiologically active group of compounds that include geldanamycin and rifamycin, inhibitors of heat shock protein 90 and prokaryotic DNA-dependent RNA synthesis, respectively. Cytotrienin A is an ansamycin-type small molecule with potent antiproliferative and proapoptotic properties. Here, we report that this compound inhibits eukaryotic protein synthesis by targeting translation elongation and interfering with eukaryotic elongation factor 1A function. We also find that cytotrienin A prevents HUVEC tube formation and diminishes microvessel formation in the chorioallantoic membrane assay. These results provide a molecular understanding into cytotrienin A's previously reported properties as an anticancer apoptosis-inducing drug. PMID- 20943819 TI - Genotypic and phenotypic characterisation of invasive Streptococcus pneumoniae isolates from Hungary, and coverage of the conjugate vaccines. AB - BACKGROUND AND AIMS: The 7-valent conjugate pneumococcal vaccine (Prevenar) was introduced as a recommended (but not yet obligatory) vaccine in Hungary in April 2009 and there was a sharp increase in the number of children vaccinated. Hence there is an urgent need for in-depth epidemiological data on invasive pneumococci before vaccination becomes widespread. Such a study has never been done before in Hungary. METHODS: 144 pneumococcal isolates, obtained from invasive infections or pneumonia, were collected from eight Hungarian diagnostic laboratories between 2000 and 2008. After confirmation of species identity, their susceptibilities to nine antibiotics were determined by Etest and agar dilution method. The serotypes and pulsed-field gel electrophoresis genotypes of the strains were also determined. RESULTS: In this cohort, most of the isolates were from patients at the extreme of life. Only 1.4% of the strains were resistant to penicillin, but nearly 40% were resistant to erythromycin (mainly due to erm(B) gene). Higher incidences of resistance were found in the very young and very old. The most prevalent serotypes in the cohort in descending order were 14, 6A, 6, 6B, 23F, 3, 19F and 11A. CONCLUSIONS: Results showed a similar but not identical profile to previously examined strains causing pulmonary infections in Hungary. The serotypes could be correlated to patient groups. Furthermore, there were examples of serotype switching in strains showing identical genotype but different serotype. The study also shows a good coverage by the conjugate vaccines over the invasive pneumococcal strains in Hungary based on the detected serotypes. PMID- 20943820 TI - Human papillomavirus prevalence in invasive cervical carcinomas in Bulgaria. AB - BACKGROUND: Although Bulgaria has one of the highest rates of cervical cancer incidence and mortality in the EU, data on HPV type distribution are limited. AIM: To determine the prevalence of HPV types 16 and 18 in archival specimens from cervical cancer cases from Bulgaria. METHODS: A total of 145 formalin-fixed, paraffin-embedded tissue samples from women with histologically proven invasive squamous cell carcinoma of the uterine cervix were available for this study. Detection of HPV types 16 and 18 was based on two parallel PCRs from each sample using type-specific primers for these genotypes. The quality of the extracted DNA was evaluated by PCR using PC03/PC04 beta-globin-specific primers. Sections from each block were H&E stained and assessed by the study pathologist to confirm the histological diagnosis. RESULTS: Of the 127 beta-globin-positive squamous cell carcinoma cases, 98 (77.2%) were positive for HPV16 and/or HPV18 DNA. HPV16 was the more prevalent type and was found as a single infection in 86 (67.7%) cases. HPV type 18 as a single infection was detected in eight (6.3%) cases. Four specimens (3.2%) were double infected with HPV types 16 and 18. CONCLUSIONS: HPV types 16 and 18 are important risk factors for cervical cancer in Bulgaria. These data are helpful for estimating the potential impact of HPV vaccines in Bulgaria and indicate that ~77% of cervical cancer cases in the country are potentially preventable by vaccination with currently available prophylactic HPV16/18 vaccines. PMID- 20943821 TI - Cross-national comparisons of socioeconomic differences in the prevalence of leisure-time and occupational physical activity, and active commuting in six Asia Pacific countries. AB - BACKGROUND: This study describes physical activity patterns and their association with socioeconomic factors in six countries in the Asia-Pacific region, and examines whether physical activity associations with socioeconomic status follow similar patterns across the six countries. METHODS: Population-wide representative surveys of non-communicable disease risk factors and socioeconomic factors conducted in Australia, China, Fiji, Malaysia, Nauru and the Philippines between 2002 and 2006 were used. Survey respondents aged 18-64 years who provided information on their socioeconomic status (age, education, income, area of residence) and physical activity level in three domains (leisure-time, occupation, commuting) were included in the study (Australia N=15,786; China N=142,693; Fiji N=6763; Malaysia N=2572; Nauru N=2085; Philippines N=3307). RESULTS: Leisure-time physical activity increased with age in China, showed inverse associations for Fiji and Nauru men, and there were no age relationships in other countries. Individuals in China, Fiji and Malaysia living in urban areas, with higher educational attainment and affluence were physically active during leisure time but less active at work and during commuting compared to those in rural areas, with lower educational attainment and lower income. CONCLUSION: There is a link between types of physical activity participation and socioeconomic factors in developing countries. Associations with socioeconomic indicators are likely to reflect economic growth. The findings strongly support the need for a comparable non-communicable risk factors surveillance system in developing countries. PMID- 20943824 TI - How you ask really matters: randomised comparison of four sexual behaviour questionnaire delivery modes in Zimbabwean youth. AB - OBJECTIVE: A sexual health survey among rural Zimbabwean youth was used to compare the validity and reliability of sexual behaviour measures between four questionnaire delivery modes. METHODS: Using a random permuted block design, 1495 youth were randomised to one of four questionnaire delivery modes: self administered questionnaire (SAQ=373); SAQ accompanied by an audio soundtrack (Audio-SAQ=376); face-to-face interview with sensitive questions placed in a confidential voting box (Informal confidential voting interview; ICVI=365); and audio computer-assisted survey instrument (ACASI=381). Key questions were selected a priori to compare item non-response and rates of reporting of sensitive behaviours between questionnaire delivery modes. Qualitative data were collected on perceived method acceptability (n=115). RESULTS: Item non-response was significantly higher with SAQ and Audio-SAQ than with ICVI and ACASI (p<0.001). After adjusting for covariates, the odds of reporting sexual activity among Audio-SAQ and ACASI users were twice as high as the odds for SAQ users (Audio-SAQ AOR=2.05 (95% CI 1.2 to 3.4); ACASI AOR=2.0 (95% CI 1.2 to 3.2)), with no evidence of reporting difference between ICVI and SAQ users (ICVI AOR=1.0 (95% CI 0.6 to 1.8)). ACASI users reported a lower age at first intercourse and were more likely to report a greater number of partners (mean difference=1.06; 95% CI 0.33 to 1.78; p=0.004). They reported an increased ability to answer questions honestly (p=0.004) and believed their answers would be kept secret. Participants claimed increased comprehension when hearing questions while reading them. ICVI users expressed difficulty answering sensitive questions, despite understanding that their answers were unknown to the interviewer. CONCLUSION: ACASI appears to reduce bias significantly, and is feasible and acceptable in resource-poor settings with low computer literacy. Its increased use would likely improve the quality of questionnaire data in general and sexual behaviour data specifically. PMID- 20943825 TI - Circumcision and herpes simplex virus-2 infection among spouses. PMID- 20943826 TI - Nitrogen metabolism responses to water deficit act through both abscisic acid (ABA)-dependent and independent pathways in Medicago truncatula during post germination. AB - The modulation of primary nitrogen metabolism by water deficit through ABA dependent and ABA-independent pathways was investigated in the model legume Medicago truncatula. Growth and glutamate metabolism were followed in young seedlings growing for short periods in darkness and submitted to a moderate water deficit (simulated by polyethylene glycol; PEG) or treated with ABA. Water deficit induced an ABA accumulation, a reduction of axis length in an ABA dependent manner, and an inhibition of water uptake/retention in an ABA independent manner. The PEG-induced accumulation of free amino acids (AA), principally asparagine and proline, was mimicked by exogenous ABA treatment. This suggests that AA accumulation under water deficit may be an ABA-induced osmolyte accumulation contributing to osmotic adjustment. Alternatively, this accumulation could be just a consequence of a decreased nitrogen demand caused by reduced extension, which was triggered by water deficit and exogenous ABA treatment. Several enzyme activities involved in glutamate metabolism and genes encoding cytosolic glutamine synthetase (GS1b; EC 6.3.1.2.), glutamate dehydrogenase (GDH3; EC 1.4.1.1.), and asparagine synthetase (AS; EC 6.3.1.1.) were up regulated by water deficit but not by ABA, except for a gene encoding Delta(1) pyrroline-5-carboxylate synthetase (P5CS; EC not assigned). Thus, ABA-dependent and ABA-independent regulatory systems would seem to exist, differentially controlling development, water content, and nitrogen metabolism under water deficit. PMID- 20943827 TI - The role of parents, friends and teachers in adolescents' cigarette smoking and tombak dipping in Sudan. AB - OBJECTIVE: To assess the influence of smoking and tombak (local smokeless tobacco) dipping by parents, teachers and friends on cigarette smoking and tombak dipping by school-going Sudanese adolescents. METHODS: This was a school-based cross-sectional survey was conducted in 2005-2006. Logistic regression was used for the analysis. A total of 4277 Sudanese school-going adolescents (aged 11-17 years) from 23 schools who completed an anonymous self-administered questionnaire on the use of tobacco products. Main outcome measures were self-reported tobacco use during the previous month defined current tobacco use. Ever smoking, tombak dipping and other tobacco products were also considered as outcomes. RESULTS: After adjusting for sex, age and school grade, adolescents' smoking habits were strongly associated with the habit in their parents and friends and, more weakly, with tombak dipping by teachers. When adjusted for each other, the association with smoking in friends was unaffected and remained significant (prevalence OR (POR) of having ever smoked was 1.94, 95% CI 1.64 to 2.29; OR of being current smoker was 3.77, 95% CI 2.80 to 5.07). Tobacco smoking in friends was positively associated with adolescents ever tombak dipping (POR 1.81, 95% CI 1.41 to 2.33) and current dipping (OR 3.33, 95% CI 2.20 to 5.05). The association with parental habits was reduced but still significantly elevated. Tombak dipping by teachers was only associated with adolescents ever tobacco smoking. CONCLUSIONS: Tobacco use by parents, teachers and friends was associated with adolescents' tobacco habits. The influence of friends was the strongest. In developing programmes against adolescents' tobacco habits, there is need to target the influence of these 'significant others'. Sudan needs to develop and implement comprehensive anti-smoking and anti-tombak dipping legislation to reduce the growing prevalence of such habits. PMID- 20943828 TI - International trade versus public health during the FCTC negotiations, 1999-2003. AB - OBJECTIVE: To examine why the Framework Convention on Tobacco Control did not include an explicit trade provision and delineate the central arguments in the debate over trade provision during the negotiations. METHODS: Triangulate interviews with participants in the FCTC negotiations, the FCTC negotiations documents, and tobacco industry documents. RESULTS: An explicit FCTC trade provision on relation between international trade and public health became a contentious issue during the negotiations. As a result, two conflicting positions, health-over-trade and opposition to health-over-trade emerged. Opposition to explicit trade language giving health priority was by both tobacco industry and countries that generally supported strong FCTC provisions because of concerns over 'disguised protectionism' and setting a precedent whereby governments could forfeit their obligations under pre-existing treaties. Owing to lack of consensus among political actors involved in the negotiations, a compromise position eliminating any mention of trade emerged, which was predicated on belief among some in the public health community that public health would prevail in future trade versus health conflicts. CONCLUSION: The absence of an explicit FCTC trade provision was due to a political compromise rather than the impact of international trade agreements and decisions on public health and lack of consensus among health advocates. This failure to include an explicit trade provision in the FCTC suggests that the public health community should become more involved in trade and health issues at all levels of governance and press the FCTC Conference of the Parties for clarification of this critical issue. PMID- 20943829 TI - Qualitative analysis of Camel Snus' website message board--users' product perceptions, insights and online interactions. AB - BACKGROUND: In 2006, RJ Reynolds began test-marketing Camel Snus, a new smokeless tobacco (SLT) product. Promotion included use of a brand website, a relatively new marketing channel used by tobacco companies, which allowed visitors to learn about the product and discuss it with others on the website's message board. Our study aimed to examine early experiences with and perceptions of Camel Snus as described by board contributors and also to consider the use and benefits of the message board for both consumers and the company. METHODS: We conducted a qualitative analysis, coding each message in Atlas.Ti and analysing it for emerging themes and patterns. Messages were also coded for demographic information where evident, such as tobacco use status and geographical location. Descriptive data and illustrative quotes are presented. RESULTS: Board participants described being introduced to Camel Snus through free samples. Favourable evaluations were posted by current smokers who had never tried SLT before as well as current users of other SLT brands. Messages indicated both initiation of dual product use among smokers and product substitution. Participants used the board to advise each other on how to use the product, where to get more, suggest ways RJ Reynolds could improve the product and to encourage RJ Reynolds to release it nationally. DISCUSSION: Camel Snus has appeal for at least some smokers and SLT users. Camel Snus' website message board may have been a doubly beneficial marketing feature in both connecting product users and providing product feedback to the company during test-marketing. PMID- 20943830 TI - Genome nucleotide composition shapes variation in simple sequence repeats. AB - Simple sequence repeats (SSRs) or microsatellites are a common component of genomes but vary greatly across species in their abundance. We tested the hypothesis that this variation is due in part to AT/GC content of genomes, with genomes biased toward either high AT or high CG generating more short random repeats that are long enough to enhance expansion through slippage during replication. To test this hypothesis, we identified repeats with perfect tandem iterations of 1-6 bp from 25 protists with complete or near-complete genome sequences. As expected, the density and the frequency are highly related to genome AT content, with excellent fits to quadratic regressions with minima near a 50% AT content and rising toward both extremes. Within species, the same trends hold, except the limited variation in AT content within each species places each mainly on the descending (GC rich), middle, or ascending (AT rich) part of the curve. The base usages of repeat motifs are also significantly correlated with genome nucleotide compositions: Percentages of AT-rich motifs rise with the increase of genome AT content but vice versa for GC-rich subgroups. Amino acid homopolymer repeats also show the expected quadratic relationship, with higher abundance in species with AT content biased in either direction. Our results show that genome nucleotide composition explains up to half of the variance in the abundance and motif constitution of SSRs. PMID- 20943831 TI - Video-assisted thoracoscopic surgery or transsternal thymectomy in the treatment of myasthenia gravis? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was how video-assisted thoracoscopic surgery (VATS) compares to median sternotomy in the surgical management of patients with myasthenia gravis (MG)? Overall 74 papers were found using the reported search, of which 15 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results are tabulated. We conclude that VATS produces equivalent postoperative mortality and complete stable remission (CSR) rates, with superior results in terms of hospital stay, operative blood loss and patient satisfaction at the expense of a doubling of operative time. Six studies comparing VATS and transsternal sternotomy in non-thymomatous myasthenia gravis (NTMG) patients found VATS to have lower operative blood loss (73.8+/-70.7 vs. 155.3+/-91.7 ml; P<0.05), reduced total hospital stay (5.6+/-2.2 vs. 8.1+/-3.0 days; P=0.008), whilst maintaining equivalent remission rates (33 vs. 44.7%; P=0.16) and mass of thymic tissue resection (37 vs. 34 g; P>0.05). One study comparing video-assisted thoracoscopic extended thymectomy to transsternal thymectomy in only thymoma-associated myasthenia gravis (T-MG) patients found equivalent CSR (11.3 vs. 8.7%, P=0.1090) at six-year follow-up. Thymoma recurrence rate (9.64%) was not significantly different (P=0.1523) between the two groups. Eight studies comparing VATS and transsternal approach in mixed T-MG and NTMG patients found a lower hospital stay (1.9+/-2.6 vs. 4.6+/-4.2 days, P<0.001), reduced need for postoperative medication (76.5 vs. 35.7%, P=0.022), lower intensive care unit stay (1.5 vs. 3.2 days, P=0.018), greater symptom improvement (100 vs. 77.9%, P=0.019) and better cosmetic satisfaction (100 vs. 83, P=0.042) with VATS. In concordance with NTMG and T-MG alone patient groups, VATS and transsternal methods had equivalent complication rates (23 vs. 19%, P=0.765) with no mortalities in either group. Even though VATS has a longer operative time (268+/-51 vs. 177+/-92 min, P<0.05), its improved cosmesis, reduced need for postoperative medication and equivalent disease resolution outcomes make it a preferable surgical option to the transsternal approach. PMID- 20943832 TI - Age-based formulae to estimate children's weight in the emergency department. AB - OBJECTIVE: To develop an age-based weight estimation rule in a Chinese population and to compare its performance with existing formulae. DESIGN: Population-based observational study. SETTING: Schools and kindergartens in Hong Kong. SUBJECTS: Healthy Chinese children aged 1-10 years old on their last birthday. INTERVENTIONS: Weight was measured to the nearest 0.2 kg. MAIN OUTCOME MEASURES: Linear regression was used to derive a simple formula relating weight to the child's age on his or her last birthday. The accuracy and precision of different age-based weight formulae was compared using coefficient of variation, Bland Altman plots, and by determining the proportion of children with estimates >30% outside the actual weight. RESULTS: The Chinese Age Weight Rule is a simple linear formula that is more accurate than and at least as precise as any other age-based weight estimation rule: weight in kg=(3 * age last birthday)+5. It is accurate and precise in children <7 years old, but all age-based weight estimates are imprecise in older children. CONCLUSIONS: The Chinese Age Weight Rule should be used in a Chinese population in preference to any other age-based weight estimation rule. Caution should be taken when using it in older children in whom other weight-estimation tools may be more appropriate. PMID- 20943834 TI - Experience of a screening centre for influenza A/H1N1: the first 50 days. AB - BACKGROUND: The authors' emergency department (ED) served as Singapore's screening centre for influenza H1N1 cases. The aims of the study were to describe their screening experience and to compare clinical and laboratory features of H1N1 versus seasonal flu cases. METHODOLOGY: The authors conducted a prospective observational study on consecutive patients aged 16 years and above presenting to a busy, urban ED for H1N1 screening over 50 days. Clinical, laboratory, radiological and PCR data were collected from the hospital electronic databases. Primary outcomes were proportions of confirmed H1N1 cases and their distribution of clinical, laboratory and radiological features. Secondary outcomes were comparison of clinical and laboratory features of H1N1 versus seasonal flu cases. Data were analysed using descriptive statistics and univariate analysis was used to compare factors between the two groups. A p value <0.05 was considered statistically significant. RESULTS: 1205 patients were screened. 31 (2.6%) and 133 (11%) of them had H1N1 and seasonal flu infections, respectively. The two groups had similar symptoms. There were six clinical and two laboratory features with statistically significant differences between H1N1 and seasonal flu cases. Clinical factors were travel or contact history, median age, respiratory rate, diastolic blood pressure and length of hospital stay. Laboratory factors were median platelet and lymphocyte counts. CONCLUSIONS: The authors report their experience as the nation's H1N1 screening centre. They identified factors that were different between H1N1 and seasonal flu cases. Future research is needed to elucidate if and how this information can be used as a screening tool for H1N1. PMID- 20943835 TI - Sensitivity and specificity of a rapid influenza diagnostic test in children and clinical utility during influenza A (H1N1) 2009 outbreak. AB - INTRODUCTION: The influenza A (H1N1) 2009 outbreak caused death and a disruption of public health services. Rapid influenza diagnostic tests (RIDT) could be helpful to ease the triage of patients and prevent an overload of emergency and laboratory facilities. OBJECTIVES: To compare the sensitivity and specificity of the Clearview Exact Influenza A&B test and real-time reverse transcription(RT) PCR to detect influenza A (H1N1) 2009 in a paediatric emergency department of a paediatric teaching hospital in Paris, France. METHODS: 76 children with an influenza-like illness and either severe symptoms or an underlying medical condition were prospectively recruited between July 2009 and October 2009. RIDT and RT-PCR were simultaneously performed and compared. RESULTS: Among 39 influenza A (H1N1) 2009 RT-PCR-positive children (median age 5 years), 23 Clearview Exact Influenza A&B tests were positive. Sensitivity was 59% (95% CI 42.2 to 74) and specificity was 94.6% (95% CI 80.5 to 99.1). CONCLUSIONS: This study shows a sensitivity of RIDT of 59%, in agreement with other prospective studies, which could be useful in clinical practice for diagnosis influenza A (H1N1) 2009 in children. In outbreaks of a high prevalence, such as the 2009 outbreak, this test can help to prevent an overload of public health services. PMID- 20943837 TI - How common are palliative care needs among older people who die in the emergency department? AB - OBJECTIVE: To determine the prevalence and nature of palliative care needs in people aged 65 years or more (65+) who die in emergency departments (EDs). METHODS: This was a retrospective analysis of routine hospital data from two EDs in South London. Patients aged 65+ living in the hospitals' catchment area who died in the ED during a 1 year period (2006-2007) were included. Palliative care needs identified by diagnosis and symptoms, and problems likely to benefit from palliative care documented in clinical records 3 months prior to the final ED attendance were extracted. RESULTS: Over 1 year, 102 people aged 65+ died in the ED, frequently following an acute event (n = 90). 63.7% presented out of hours. 98/102 were admitted by ambulance, over half (n = 59) from home. Half (n = 50) had attended the same ED or been admitted to the same hospital in the previous 12 months. Over half (58/102) presented with diagnoses that signalled palliative care need. Of these, 29 had recorded symptoms a week before death and 28 had complex social issues 3 months prior to death. Only eight were known to palliative care services. CONCLUSIONS: There is considerable palliative care need among older people who ultimately died in the ED, of whom only a minority were known to palliative care services in this study. Previous ED and hospital admission suggest opportunities for referral and forward planning. More older people in need of palliative care must be identified and managed earlier to avoid future undesired admissions and deaths in hospital. PMID- 20943838 TI - Validation of weight estimation by age and length based methods in the Western Cape, South Africa population. AB - OBJECTIVE: To evaluate four paediatric weight estimation methods (APLS, Luscombe and Owens, Best Guess and Broselow tape) in order to determine which are accurate for weight estimation in South African children. METHOD: From a database of 2832 children aged 1-10 years seen at Red Cross Hospital in Cape Town, measured weight was compared to estimated weights from all four methods. RESULTS: APLS formula and the Broselow Tape showed the best correlation with measured weight. Mean error was 3.3% for APLS (for 1-10-year olds) and 0.9% for Broselow tape (children <145 cm length and <35 kg). Both the Best Guess and Luscombe and Owens formulae tended to overestimate weight (15.4% and 12.4%, respectively). CONCLUSION: The Broselow tape and APLS estimation methods are most accurate in estimating weight in the Western Cape paediatric population, even though they have a small tendency to underestimate weight. Clinicians need to bear in mind that none of the formulae are infallible and constant reassessment and clinical judgement should be used, as well as a measured weight as soon as possible in an emergency situation. PMID- 20943839 TI - Lessons learnt from the past and preparedness for the future: how a developing country copes with major incidents. AB - OBJECTIVE: Research shows that previous experience of major incidents has positive impacts on awareness and preparedness of organisations. This manuscript aims to examine the preparedness indicators of health organisations against major incidents in two different types of organisation: those with direct involvement in response to the Bam earthquake and other organisations. METHOD: A descriptive study was conducted, and 230 questionnaires were distributed among the health managers in both types of organisations to compare the questionnaire results between them. RESULT: A total of 114 questionnaires were returned. 85% of the respondents were male, and 15% were female. Considering the organisational factor, a significant difference between the organisations was observed. Considering the communication factor, only differences in relationship with outside stakeholders and knowing the responsibility of other organisations were significant. Rehearsal and multiagency plans for warning were considerably different in the organisations. In planning, coordination, training, business continuity and cultural factors, there were no important differences. For resource variables, only the statement of sufficient resources and tools for the employees was significantly different, and, for the policy factor, there were significant differences in two variables: incorporation of major incident issues into the service design and management of voluntary efforts in a major incident. CONCLUSION: The findings have implications for health organisations in developing countries, especially in the Middle East. A major incident-management system re engineering is required to bring the lessons learnt from previous major incidents into preparedness efforts and to shift individual-based activities toward systematic approaches in major incident management. PMID- 20943840 TI - 'Core' emergency medicine training in the United Kingdom: regional variations in training standards. PMID- 20943841 TI - The sonographic Ottawa Foot and Ankle Rules study (the SOFAR study). AB - INTRODUCTION: Foot and ankle injuries are common in the Emergency Department (ED). Of those requiring radiographs in accordance with the Ottawa Foot and Ankle Rules, approximately 22% have a fracture. Ultrasound is developing as a tool for emergency musculoskeletal assessment--it is inexpensive and rapid, and visualises soft tissue and bony structures. METHODS: This diagnostic cohort study examined if ultrasound could detect acute bony foot and ankle injuries. Ottawa Rules positive patients over 16 years were eligible. An ultrasound scan (USS) was performed blind to radiograph findings by an ED member. Patient management was according to radiograph. Significant fractures were defined as per the Ottawa Foot and Ankle Rules study group. All radiographic reporting was conducted blind to USS findings. All USS operators received specific 2-day training in musculoskeletal ultrasound. RESULTS: 110 subjects were recruited. 11 had significant radiological fractures, and 10 were seen on ultrasound. The single missed fracture arose due to the operator not scanning proximally enough on the fibula. On rescanning following radiograph review, the fracture was clearly seen. The sensitivity of USS is 90.9% (95% CI 65.7 to 98.3), and the specificity is 90.9% (95% CI 88.1 to 91.7). The positive predictive value is 0.526 (95% CI 0.380 to 0.569). The negative predictive value is 0.989 (95% CI 0.959 to 0.998). The positive likelihood ratio is 10.00 (95% CI 5.526 to 11.901), and the negative likelihood ratio is 0.100 (95% CI 0.018 to 0.389). CONCLUSION: This pilot study demonstrates that ultrasound shows great promise for the sensitive detection of foot and ankle fractures, thus identifying patients who require radiographic evaluation more efficiently. PMID- 20943842 TI - Awareness and attitudes of Chinese students towards cardiopulmonary resuscitation. AB - BACKGROUND: A large number of sudden cardiac arrests occur annually, but the worldwide survival rate is less than 1%. Early initiation of bystander Cardiopulmonary resuscitation (CPR) would improve the survival rate of out-of hospital sudden cardiac arrests. Students play an important role as bystanders on and off campus both now and in the future. So we wanted to investigate the awareness and attitudes towards CPR of Chinese students, in order to improve the dissemination of bystander CPR in China. METHODS: The survey was conducted by questionnaire in November 2007. We had chosen 3500 students from the city of Wuhan in China randomly according to the stratified cluster sampling technique. RESULTS: There were 3248 questionnaires answered, and 2763 questionnaires were considered valid. Few respondents reported that they had heard (28%) and studied (27%) of CPR, and only 3% of the respondents had attended a CPR course. The two major sources of information about CPR for Chinese students were television and books. Most respondents expressed a desire to learn CPR (77%), and were willing to disseminate CPR (73%). CONCLUSION: Dissemination of CPR among Chinese students has not been executed satisfactorily. The finding highlights the importance of CPR dissemination and efforts should be made to provide more convenient, effective and attractive ways for the Chinese public, especially students, to learn CPR. PMID- 20943844 TI - Rescue efforts management and characteristics of casualties of the Wenchuan earthquake in China. AB - OBJECTIVE: On 12 May 2008, the Wenchuan earthquake, registering 8 on the Richter scale, hit the Sichuan province, China. Management of the rescue efforts and characteristics of casualties were studied. METHODS: This is an observational descriptive study. Data were gathered from health services reports from the day of the earthquake on 12 May to 8 September 2008, as well as from field research. Information on the types of injuries from other studies of this earthquake was also reviewed. RESULTS: Casualties were concentrated in the hardest-hit areas of the province, and the number of deaths in those areas accounted for 77.10% of the total. Within the first 7 days, the types of injuries reported were mainly within the trauma/wound category (74.1-98.6%). After the seventh day, acute upper respiratory-tract infections were the leading problem. Rescue forces included local, regional, military and foreign health personnel. The rescue work followed the principle of 'centralising the wounded, the experts, the resources, and the treatment,' and a three-level medical evacuation system was established. CONCLUSIONS: The Wenchuan medical rescue effort presented several problems. The experience is reflected in these points: (1) establish an effective command and communication centre to ensure that medical rescue resources are deployed in time; (2) treat the wounded within the first 7 days; (3) prepare healthcare resources for both surgical and general medicine services; (4) establish contingency rescue plans with a coordinated effort; (5) insist on the principles of triage and adopt flexible evacuation and transfer methods. PMID- 20943845 TI - Validation of the Full Outline of Unresponsiveness (FOUR) Scale for conscious state in the emergency department: comparison against the Glasgow Coma Scale. AB - OBJECTIVES: To determine (a) the inter-rater reliability of pairs of emergency doctors' and/or nurses' ratings of the Glasgow Coma Scale (GCS) and the Full Outline of Unresponsiveness (FOUR) Scale in emergency department (ED) patients, (b) the concurrent validity of the FOUR Scale using the GCS as the reference scale and (c) doctors' and nurses' knowledge and attitudes towards the GCS and FOUR Scale. METHODS: A prospective observational study was conducted using staff participants' ratings for a convenience sample of ED patients requiring quantification of conscious state. Participating doctors and nurses attended a formal training session on the correct use of the GCS and FOUR Scale. Pairs of clinicians then independently completed the GCS and FOUR Scale on patients within 5 min of each other. RESULTS: 140 clinicians were recruited and trained in the use of the GCS and FOUR Scale. A total of 217 observations were performed on 203 patients presenting to the ED with various conditions. The inter-rater reliability for the FOUR Scale was greater than that of the GCS (FOUR: k = 0.76, p < 0.01; GCS: k = 0.59, p < 0.01). The reliability for both the GCS and the FOUR Scale was poorest within doctor-nurse pairs. CONCLUSION: The FOUR Scale showed greater reliability than the GCS in ED patients using ED clinicians as raters. A larger study of ED patients is warranted to determine the predictive validity of the FOUR Scale and to further examine the reliability of the scale in various patient populations. PMID- 20943846 TI - International Year of Chemistry 2011: Clinical Chemistry celebrates. PMID- 20943847 TI - Analytical ancestry: evolution of the array in analysis. AB - BACKGROUND: Macro-, micro-, and nanosized arrays of test sites at various densities have emerged as important types of analytical devices in response to the need for high volume parallel analysis in both the research and the clinical laboratory. CONTENT: This review explores the diversity of arrays of reaction vessels and arrays of reagents and of samples, with an emphasis on the earliest descriptions of the different variations. The scope of such arrays includes linear and 2-dimensional arrays of reaction vessels (e.g., microwell strips, microplates); linear and 2-dimensional arrays of reagents arrayed on pillars and posts; beads in wells; and reagents randomly arrayed (or dis-ordered) for use in next-generation sequencing. Micro- and nanofabrication technologies have been applied to the miniaturization of arrays to increase array density (e.g., DNA probe arrays) and produce arrays of analytical structures (e.g., cantilevers, nanoelectrospray nozzles). SUMMARY: Arrays are now firmly established in many types of analytical devices, and this analytical format has gained widespread acceptance owing to the advantages of high-throughput automation and multiplex analysis. Ongoing "big biology" genomic and proteomic studies will ensure the continued dominance of array-based methods into the foreseeable future. PMID- 20943848 TI - CA125 immune complexes in ovarian cancer patients with low CA125 concentrations. AB - BACKGROUND: About 20% of women with ovarian cancer have low concentrations of serum cancer antigen 125 (CA125), and this important tumor marker cannot be used to monitor their disease. The measured concentration for mucin 1 (MUC1), or CA15 3, another tumor marker, can be lowered in breast and ovarian cancer patients when circulating immune complexes (CICs) containing antibodies bound to the free antigen are present. Because CA125 and MUC1 are related members of the mucin family, we sought to determine whether CICs might also exist for CA125 and interfere with its clinical assay. METHODS: We developed an antigen capture-based assay to determine the presence of CICs for CA125. We spotted mouse antibodies to CA125 onto nanoparticle slides, incubated them with patient serum, and added Cy5 tagged goat antihuman IgG antibodies. Fluorescence intensities were read and normalized to the intensities for glutathione S-transferase A1 as a control. RESULTS: Assay results for 23 ovarian cancer cases with high CA125 concentrations, 43 cases with low CA125 concentrations, and 19 controls (mean CA125 concentrations, 2706, 23, and 11 kilounits/L, respectively) revealed mean fluorescence intensities for CA125 CIC of 2.30, 2.72, and 1.99 intensity units (iu), respectively. A generalized linear model adjusted for batch and age showed higher CA125 CIC fluorescence intensities in low-CA125 cases than in high-CA125 cases (P = 0.03) and controls (P = 0.0005). Four ovarian cancer patients who had recurrent disease and always had low CA125 values had a mean CA125 CIC value of 3.06 iu (95% CI, 2.34-4.01 iu). CONCLUSIONS: These preliminary results suggest the existence of CICs involving CA125, which may help explain some ovarian cancer cases with low CA125 concentrations. PMID- 20943849 TI - Single-molecule ELISA. PMID- 20943850 TI - Expression profile of microRNAs in serum: a fingerprint for esophageal squamous cell carcinoma. AB - BACKGROUND: Sensitive and specific biomarkers for the early detection of esophageal squamous cell carcinoma (ESCC) are urgently needed to reduce the high morbidity and mortality of the disease. The discovery of serum microRNAs (miRNAs) and their unique concentration profiles in patients with various diseases makes them attractive, novel noninvasive biomarkers for tumor diagnosis. In this study, we investigated the serum miRNA profile in ESCC patients to develop a novel diagnostic ESCC biomarker. METHODS: Serum samples were taken from 290 ESCC patients and 140 age- and sex-matched controls. Solexa sequencing technology was used for an initial screen of miRNAs in serum samples from 141 patients and 40 controls. A hydrolysis probe-based stem-loop quantitative reverse-transcription PCR (RT-qPCR) assay was conducted in the training and verification phases to confirm the concentrations of selected miRNAs in serum samples from 149 patients and 100 controls. RESULTS: The Solexa sequencing results demonstrated marked upregulation of 25 serum miRNAs in ESCC patients compared with controls. RT-qPCR analysis identified a profile of 7 serum miRNAs (miR-10a, miR-22, miR-100, miR 148b, miR-223, miR-133a, and miR-127-3p) as ESCC biomarkers. The area under the ROC curve for the selected miRNAs ranged from 0.817 to 0.949, significantly higher than for carcinoembryonic antigen (0.549; P < 0.0005). More importantly, this panel of 7 miRNAs clearly distinguished stage I/II ESCC patients from controls. CONCLUSIONS: This panel of 7 serum miRNAs holds promise as a novel blood-based biomarker for the diagnosis of ESCC. PMID- 20943852 TI - Two putative RNA-binding proteins function with unequal genetic redundancy in the MOS4-associated complex. AB - The MOS4-associated complex (MAC) is a highly conserved nuclear protein complex associated with the spliceosome. We recently purified the MAC from Arabidopsis (Arabidopsis thaliana) nuclei, identified its potential components by mass spectrometry, and showed that at least five core proteins in the MAC are required for defense responses in plants. Here, we report the characterization of a putative RNA-binding protein identified in the MAC named MAC5A and its close homolog MAC5B. We confirmed that MAC5A is a component of the MAC through coimmunoprecipitation with the previously described MAC protein CELL DIVISION CYCLE5 from Arabidopsis. In addition, like all other characterized MAC proteins, MAC5A fused to the Green Fluorescent Protein localizes to the nucleus. Double mutant analysis revealed that MAC5A and MAC5B are unequally redundant and that a double mac5a mac5b mutant results in lethality. Probably due to this partial redundancy, mac5a and mac5b single mutants do not exhibit enhanced susceptibility to virulent or avirulent pathogen infection. However, like other MAC mutations, mac5a-1 partially suppresses the autoimmune phenotypes of suppressor of npr1-1, constitutive1 (snc1), a gain-of-function mutant that expresses a deregulated Resistance protein. Our results suggest that MAC5A is a component of the MAC that contributes to snc1- mediated autoimmunity. PMID- 20943851 TI - Expression and functional analyses of EXO70 genes in Arabidopsis implicate their roles in regulating cell type-specific exocytosis. AB - During exocytosis, Golgi-derived vesicles are tethered to the target plasma membrane by a conserved octameric complex called the exocyst. In contrast to a single gene in yeast and most animals, plants have greatly increased number of EXO70 genes in their genomes, with functions very much unknown. Reverse transcription-polymerase chain reactions were performed on all 23 EXO70 genes in Arabidopsis (Arabidopsis thaliana) to examine their expression at the organ level. Cell-level expression analyses were performed using transgenic plants carrying beta-glucuronidase reporter constructs, showing that EXO70 genes are primarily expressed in potential exocytosis-active cells such as tip-growing and elongating cells, developing xylem elements, and guard cells, whereas no expression was observed in cells of mature organs such as well-developed leaves, stems, sepals, and petals. Six EXO70 genes are expressed in distinct but partially overlapping stages during microspore development and pollen germination. A mutation in one of these genes, EXO70C1 (At5g13150), led to retarded pollen tube growth and compromised male transmission. This study implies that multiplications of EXO70 genes may allow plants to acquire cell type- and/or cargo-specific regulatory machinery for exocytosis. PMID- 20943853 TI - Metabolic engineering of seeds can achieve levels of omega-7 fatty acids comparable with the highest levels found in natural plant sources. AB - Plant oils containing omega-7 fatty acids (FAs; palmitoleic 16:1Delta(9) and cis vaccenic 18:1Delta(11)) have potential as sustainable feedstocks for producing industrially important octene via metathesis chemistry. Engineering plants to produce seeds that accumulate high levels of any unusual FA has been an elusive goal. We achieved high levels of omega-7 FA accumulation by systematic metabolic engineering of Arabidopsis (Arabidopsis thaliana). A plastidial 16:0-ACP desaturase has been engineered to convert 16:0 to 16:1Delta(9) with specificity >100-fold than that of naturally occurring paralogs, such as that from cat's claw vine (Doxantha unguis-cati). Expressing this engineered enzyme (Com25) in seeds increased omega-7 FA accumulation from <2% to 14%. Reducing competition for 16:0 ACP by down-regulating the beta-ketoacyl-ACP synthase II 16:0 elongase further increased accumulation of omega-7 FA to 56%. The level of 16:0 exiting the plastid without desaturation also increased to 21%. Coexpression of a pair of fungal 16:0 desaturases in the cytosol reduced the 16:0 level to 11% and increased omega-7 FA to as much as 71%, equivalent to levels found in Doxantha seeds. PMID- 20943854 TI - Endothelins participate in the central and peripheral regulation of submandibular gland secretion in the rat. AB - We previously reported that endothelins (ETs) are involved in the rat central and peripheral regulation of bile secretion. In this study we sought to establish whether ET-1 and ET-3 modulated submandibular gland secretion when locally or centrally applied. Animals were prepared with gland duct cannulation to collect saliva samples and jugular cannulation to administer sialogogues. ETs were given either into the submandibular gland or brain lateral ventricle. Intraglandularly administered ETs failed to elicit salivation per se. However, ET-1, but not ET-3, potentiated both cholinergic- and adrenergic-evoked salivation through ET(A) receptors. ET-1 decreased cAMP content but increased phosphoinositide hydrolysis, whereas ET-3 attenuated both intracellular pathways. The expression of ET(A) and ET(B) receptor mRNAs as well as that of ETs was revealed in the submandibular gland by RT-PCR. Immunohistochemical studies showed that ET(A) receptor staining was localized around the interlobular ducts and acini, compatible with the myoepithelial cells' location, whereas ET(B) receptor staining was restricted to small blood vessels. When applied to the brain, both ETs induced no salivation but enhanced cholinergic- and adrenergic-evoked salivary secretion through parasympathetic pathways. ET-1 response was mediated by brain ET(A) receptors, whereas that of ET-3 was presumably through nonconventional ET receptors. Present findings show that ETs are involved in the brain regulation of cholinergic- and adrenergic-stimulated submandibular gland secretion through the activation of distinct brain ET receptors and parasympathetic pathways. However, when ETs were administered into the gland, only ET-1 enhanced cholinergic and adrenergic salivation likely through myopithelial cell contraction by activating ET(A) receptors coupled to phospholipase C. The presence of ETs and ET receptors suggests the existence of an endothelinergic system in the submandibular gland. PMID- 20943855 TI - Phagocyte-like NADPH oxidase promotes cytokine-induced mitochondrial dysfunction in pancreatic beta-cells: evidence for regulation by Rac1. AB - Reactive oxygen species (ROS) are important mediators of cellular signal transduction cascades such as proliferation, migration, and apoptosis. Chronic exposure of isolated beta-cells to proinflammatory cytokines elevates intracellular oxidative stress leading to the demise of pancreatic beta-cells culminating in the onset of diabetes. Although the mitochondrial electron transport chain is felt to be the primary source of ROS, several lines of recent evidence suggest that phagocyte-like NADPH oxidase plays a central role in cytokine-mediated ROS generation and apoptosis of beta-cells. However, the precise mechanisms underlying the regulation of NADPH oxidase remain unknown. To address this, insulin-secreting INS 832/13 cells were treated with cytomix (IL 1beta, IFN-gamma, and TNF-alpha; 10 ng/ml each) for different time intervals (0 24 h). A significant, time-dependent increase in NADPH oxidase activation/intracellular ROS production, p47(phox) subunit, but not p67(phox) subunit, expression of the phagocyte-like NADPH oxidase were demonstrable under these conditions. Furthermore, siRNA-p47(phox) transfection or exposure of INS 832/13 cells to apocynin, a selective inhibitor of NADPH oxidase, markedly attenuated cytomix-induced ROS generation in these cells. Cytomix-mediated mitochondrial dysfunction in INS 832/13 cells was evident by a significant loss of mitochondrial membrane potential (MMP) and upregulated caspase 3 activity. Cytomix treatment also caused a transient (within 15 min) activation of Rac1, a component of the NADPH oxidase holoenzyme. Furthermore, GGTI-2147 and NSC23766, known Rac1 inhibitors, not only attenuated the cytomix-induced Rac1 activation but also significantly prevented loss of MMP (NSC23766 > GGTI-2147). However, NSC23766 had no effect on cytomix-induced NO generation or caspase 3 activation, suggesting additional regulatory mechanisms might underlie these signaling steps. Together, these findings suggested that Rac1-mediated regulation of phagocyte like NADPH oxidase contributes to cytokine-mediated mitochondrial dysfunction in the beta-cell. PMID- 20943856 TI - Downstream mechanisms of nitric oxide-mediated skeletal muscle glucose uptake during contraction. AB - There is evidence that nitric oxide (NO) is required for the normal increases in skeletal muscle glucose uptake during contraction, but the mechanisms involved have not been elucidated. We examined whether NO regulates glucose uptake during skeletal muscle contractions via cGMP-dependent or cGMP-independent pathways. Isolated extensor digitorum longus (EDL) muscles from mice were stimulated to contract ex vivo, and potential NO signaling pathways were blocked by the addition of inhibitors to the incubation medium. Contraction increased (P < 0.05) NO synthase (NOS) activity (~40%) and dichlorofluorescein (DCF) fluorescence (a marker of oxidant levels; ~95%), which was prevented with a NOS inhibitor N(G) monomethyl-L-arginine (L-NMMA), and antioxidants [nonspecific antioxidant, N acetylcysteine (NAC); thiol-reducing agent, DTT], respectively. L-NMMA and NAC both attenuated glucose uptake during contraction by ~50% (P < 0.05), and their effects were not additive. Neither the guanylate cyclase inhibitor 1H [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, which prevents the formation of cGMP, the cGMP-dependent protein (PKG) inhibitor Rp-8-bromo-beta-phenyl-1,N2 ethenoguanosine 3',5'-cyclic monophosphorothioate sodium salt nor white light, which breaks S-nitrosylated bonds, affects glucose uptake during contraction; however, DTT attenuated (P < 0.05) contraction-stimulated glucose uptake (by 70%). NOS inhibition and antioxidant treatment reduced contraction-stimulated increases in protein S-glutathionylation and tyrosine nitration (P < 0.05), without affecting AMPK or p38 MAPK phosphorylation. In conclusion, we provide evidence to suggest that NOS-derived oxidants regulate skeletal muscle glucose uptake during ex vivo contractions via a cGMP/PKG-, AMPK-, and p38 MAPK independent pathway. In addition, it appears that NO and ROS may regulate skeletal muscle glucose uptake during contraction through a similar pathway. PMID- 20943857 TI - HIF-1alpha response to hypoxia is functionally separated from the glucocorticoid stress response in the in vitro regenerating human skeletal muscle. AB - Injury of skeletal muscle is followed by muscle regeneration in which new muscle tissue is formed from the proliferating mononuclear myoblasts, and by systemic response to stress that exposes proliferating myoblasts to increased glucocorticoid (GC) concentration. Because of its various causes, hypoxia is a frequent condition affecting skeletal muscle, and therefore both processes, which importantly determine the outcome of the injury, often proceed under hypoxic conditions. It is therefore important to identify and characterize in proliferating human myoblasts: 1) response to hypoxia which is generally organized by hypoxia-inducible factor-1alpha (HIF-1alpha); 2) response to GCs which is mediated through the isoforms of glucocorticoid receptors (GRs) and 11beta-hydroxysteroid dehydrogenases (11beta-HSDs), and 3) the response to GCs under the hypoxic conditions and the influence of this combination on the factors controlling myoblast proliferation. Using real-time PCR, Western blotting, and HIF-1alpha small-interfering RNA silencing, we demonstrated that cultured human myoblasts possess both, the HIF-1alpha-based response to hypoxia, and the GC response system composed of GRalpha and types 1 and 2 11beta-HSDs. However, using combined dexamethasone and hypoxia treatments, we demonstrated that these two systems operate practically without mutual interactions. A seemingly surprising separation of the two systems that both organize response to hypoxic stress can be explained on the evolutionary basis: the phylogenetically older HIF-1alpha response is a protection at the cellular level, whereas the GC stress response protects the organism as a whole. This necessitates actions, like downregulation of IL-6 secretion and vascular endothelial growth factor, that might not be of direct benefit for the affected myoblasts. PMID- 20943858 TI - Acute starvation alters lipopolysaccharide-induced fever in leptin-dependent and independent mechanisms in rats. AB - A decrease in leptin levels with the onset of starvation triggers a myriad of physiological responses including immunosuppression and hypometabolism/hypothermia, both of which can counteract the fever response to pathogens. Here we examined the role of leptin in LPS-induced fever in rats that were fasted for 48 h prior to inflammation with or without leptin replacement (12 MUg/day). The preinflammation fasting alone caused a progressive hypothermia that was almost completely reversed by leptin replacement. The LPS (100 MUg/kg) induced elevation in core body temperature (T(core)) was attenuated in the fasted animals at 2-6 h after the injection, an effect that was not reversed by leptin replacement. Increasing the LPS dose to 1,000 MUg/kg caused a long-lasting fever that remained unabated for up to 36 h after the injection in the fed rats. This sustained response was strongly attenuated in the fasted rats whose T(core) started to decrease by 18 h after the injection. Leptin replacement almost completely restored the prolonged fever. The attenuation of the prolonged fever in the fasted animals was accompanied by the diminution of proinflammatory PGE(2) in the cerebrospinal fluid and mRNA of proopiomelanocortin (POMC) in the hypothalamus. Leptin replacement prevented the fasting-induced reduction of POMC but not PGE(2). Moreover, the leptin-dependent fever maintenance correlated closely with hypothalamic POMC levels (r = 0.77, P < 0.001). These results suggest that reduced leptin levels during starvation attenuate the sustained fever response by lowering hypothalamic POMC tone but not PGE(2) synthesis. PMID- 20943859 TI - Prolactin promotes oxytocin and vasopressin release by activating neuronal nitric oxide synthase in the supraoptic and paraventricular nuclei. AB - Prolactin (PRL) stimulates the secretion of oxytocin (OXT) and arginine AVP as part of the maternal adaptations facilitating parturition and lactation. Both neurohormones are under the regulation of nitric oxide. Here, we investigate whether the activation of neuronal nitric oxide synthase (nNOS) in the hypothalamo-neurohypophyseal system mediates the effect of PRL on OXT and AVP release and whether these effects operate in males. Plasma levels of OXT and AVP were measured in male rats after the intracerebroventricular injection of PRL or after inducing hyperprolactinemia by placing two anterior pituitary glands under the kidney capsule. NOS activity was evaluated in the paraventricular (PVN) and supraoptic (SON) hypothalamic nuclei by NADPH-diaphorase histochemistry and in hypothalamic extracts by the phosphorylation/inactivation of nNOS at Ser(847). Elevated central and systemic PRL correlated with increased NOS activity in the PVN and SON and with higher OXT and AVP circulating levels. Notably, treatment with 7-nitroindazole, a selective inhibitor of nNOS, prevented PRL-induced stimulation of the release of both neurohormones. Also, phosphorylation of nNOS was reduced in hyperprolactinemic rats, and treatment with bromocriptine, an inhibitor of anterior pituitary PRL secretion, suppressed this effect. These findings suggest that PRL enhances nNOS activity in the PVN and SON, thereby contributing to the regulation of OXT and AVP release. This mechanism likely contributes to the regulation of processes beyond those of female reproduction. PMID- 20943860 TI - Evaluation of the Cepheid Xpert Clostridium difficile Epi assay for diagnosis of Clostridium difficile infection and typing of the NAP1 strain at a cancer hospital. AB - Clostridium difficile is the most common cause of health care-associated diarrhea. Accurate and rapid diagnosis is essential to improve patient outcome and prevent disease spread. We compared our two-step diagnostic algorithm, an enzyme immunoassay for glutamate dehydrogenase (GDH) followed by the cytotoxin neutralization test (CYT) with a turnaround time of 24 to 48 h, versus the Cepheid Xpert C. difficile Epi assay, a PCR-based assay with a turnaround time of <1 h. In the first phase of the study, only GDH-positive stool samples were tested by both CYT and Xpert PCR. Discordant results were resolved by toxigenic culture. In the second phase, all stool samples were tested by GDH and Xpert PCR. Only GDH-positive stools were further tested by CYT. Genotypic characterization of 45 Xpert PCR-positive stools was performed by sequencing of the tcdC gene and PCR ribotyping. In phase 1, the agreement between the GDH-CYT and the GDH-Xpert PCR was 72%. The sensitivities and specificities of GDH-CYT and GDH-Xpert PCR were 57% and 97% and 100% and 97%, respectively. In phase 2, the agreement between GDH-CYT and Xpert PCR alone was 95%. As in phase 1, sensitivity of the Xpert PCR was higher than that of the GDH-CYT. The correlation between PCR ribotyping, sequencing, and Xpert PCR for detection of NAP1 strains was excellent (>90%). The excellent sensitivity and specificity and the rapid turnaround time of the Xpert PCR assay as well as its strain-typing capability make it an attractive option for diagnosis of C. difficile infection. PMID- 20943861 TI - Pacemaker lead endocarditis due to multidrug-resistant Corynebacterium striatum detected with sonication of the device. AB - Corynebacterium striatum is a commensal of human skin and has been recently recognized as an emerging pathogen. A case of nosocomial pacemaker lead endocarditis due to a multidrug-resistant C. striatum strain is described, highlighting the role of sonication as a diagnostic tool in cardiac device infections. PMID- 20943862 TI - Differential circulation of Streptococcus pneumoniae serotype 6C clones in two Israeli pediatric populations. AB - We genotyped Streptococcus pneumoniae serotype 6C (Sp6C) isolates collected from Jewish and Bedouin children in southern Israel during the decade before vaccination. Sp6C constituted 8.2% of the presumed Sp6A isolates. All of the Sp6C clonal clusters were associated with serogroup 6, mainly Sp6A. Different clonal distributions were found in the two subpopulations. PMID- 20943863 TI - Identification of a novel t17 genotype of acanthamoeba from environmental isolates and t10 genotype causing keratitis in Thailand. AB - We analyzed the nuclear small-subunit rRNA genes of Acanthamoeba isolates from freshwater sources (n=16) and from patients (n=6) in Bangkok and surrounding areas. The T10 genotype from a keratitis patient and a novel T17 genotype from water samples were diagnosed for the first time in this study. PMID- 20943865 TI - Influence of extraction protocol on physical properties of parvovirus B19 DNA. AB - While establishing a quantification standard for parvovirus B19 diagnostics, we extracted viral DNA from a high-titered human plasma by using three commercial kits. Despite similar viral DNA yields being obtained, striking differences in electrophoretic mobilities of the extracted nucleic acids were observed. PMID- 20943864 TI - Complete nucleotide sequence analysis of plasmids in strains of Staphylococcus aureus clone USA300 reveals a high level of identity among isolates with closely related core genome sequences. AB - A community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strain known as pulsed-field type USA300 (USA300) is epidemic in the United States. Previous comparative whole-genome sequencing studies demonstrated that there has been recent clonal emergence of a subset of USA300 isolates, which comprise the epidemic clone. Although the core genomes of these isolates are closely related, the level of diversity among USA300 plasmids was not resolved. Inasmuch as these plasmids might contribute to significant gene diversity among otherwise closely related USA300 isolates, we performed de novo sequencing of endogenous plasmids from 10 previously characterized USA300 clinical isolates obtained from different geographic locations in the United States. All isolates tested contained small (2- to 3-kb) and/or large (27- to 30-kb) plasmids. The large plasmids encoded heavy metal and/or antimicrobial resistance elements, including those that confer resistance to cadmium, bacitracin, macrolides, penicillin, kanamycin, and streptothricin, although all isolates were sensitive to minocycline, doxycycline, trimethoprim-sulfamethoxazole, vancomycin, teicoplanin, and linezolid. One of the USA300 isolates contained an archaic plasmid that encoded staphylococcal enterotoxins R, J, and P. Notably, the large plasmids (27 to 28 kb) from 8 USA300 isolates--those that comprise the epidemic USA300 clone--were virtually identical (99% identity) and similar to a large plasmid from strain USA300_TCH1516 (a previously sequenced USA300 strain from Houston, TX). These plasmids are largely divergent from the 37-kb plasmid of FPR3757, the first sequenced USA300 strain. The high level of plasmid sequence identity among the majority of closely related USA300 isolates is consistent with the recent clonal emergence hypothesis for USA300. PMID- 20943866 TI - Genetic evolution of the Spanish multidrug-resistant Salmonella enterica 4,5,12:i:- monophasic variant. AB - We analyzed a collection of 60 Salmonella enterica 4,5,12:i:- phage type U302 multidrug-resistant monophasic variant strains, isolated in Spain between 2000 and 2007. Most strains showed resistance to ampicillin (A), chloramphenicol (C), sulfamethoxazole (Su), gentamicin (G), streptomycin (S), tetracycline (T), and co trimoxazole (SxT) (an ACSuGSTSxT resistance pattern). Only one pulsed-field gel electrophoresis (PFGE) type was detected, with 19 subtypes (Simpson's index of diversity [SID]=0.89). Multiple-locus variable-number tandem-repeat analysis (MLVA) showed more variability, with 32 profiles (SID=0.97), but only showed diversity at the STTR5 and STTR6 loci. PCR and sequencing demonstrated all strains contained the same allantoin-glyoxylate pathway deletion. Four types of deletions were detected in the fljAB operon, all starting at the same position, at the STM2758 gene, and followed by an IS26 insertion. Furthermore, a representative set of strains of the four deletion types harbored plasmids with IS26. We propose that a Salmonella enterica serotype Typhimurium U302 multidrug resistant (ACSuGSTSxT) strain, defective for the allantoin-glyoxylate pathway and containing IS26 at plasmid pU302L, could be the ancestor of the variant in Spain. PMID- 20943867 TI - Novel multiplex PCR using dual-priming oligonucleotides for detection and discrimination of the Mycobacterium tuberculosis complex and M. bovis BCG. AB - We developed a novel multiplex PCR assay using dual-priming oligonucleotide primers targeting the RD1 gene for simultaneous identification of the Mycobacterium tuberculosis complex and M. bovis bacillus Calmette-Guerin (BCG). This assay would be useful both for detection of the M. tuberculosis complex and for differentiation of M. bovis BCG from pathogenic M. tuberculosis complex species. PMID- 20943868 TI - Clinical features of infections and colonization by Acinetobacter genospecies 3. AB - Two hundred twenty-one isolates of Acinetobacter baumannii and 15 of Acinetobacter genospecies 3 (AG3) were consecutively collected in a 30-day period during the nationwide project GEIH-Ab2000. Nosocomial acquisition (P=0.01), intensive care unit admission (P=0.02), and antibiotic pressure (P = 0.03) were observed to be lower in the AG3 group. AG3 isolates were more frequently implied in wound infections (P=0.05), while A. baumannii tended to be recovered from respiratory samples (P=0.08). To our knowledge, this is the first report analyzing the clinical differences among Acinetobacter genospecies, with our findings suggesting that clinical features of AG3 may not be equivalent to those traditionally described for A. baumannii. PMID- 20943869 TI - Evaluation of molecular assays for rapid detection of methicillin-resistant Staphylococcus aureus. AB - The diagnostic sensitivities of the BD GeneOhm and Cepheid Xpert assays were compared using culture on log-serial dilutions of well-characterized methicillin resistant Staphylococcus aureus (MRSA) and non-MRSA strains and on nasal and groin swabs from patients with histories of MRSA carriage. The sensitivities of GeneOhm and Xpert were high at 10(3)-CFU/ml MRSA concentrations (92.3% and 96.3%, respectively) although decreased considerably (<35%) at a 1-log-lower concentration. Unexpectedly, both assays also detected select coagulase-negative staphylococci, which requires further evaluation. PMID- 20943870 TI - Innovation for reducing blood culture contamination: initial specimen diversion technique. AB - We hypothesized that diversion of the first milliliter of venipuncture blood-the initial specimen diversion technique (ISDT)-would eliminate incompletely sterilized fragments of skin from the culture specimen and significantly reduce our blood culture contamination rate (R). We studied our hypothesis prospectively beginning with our control culture (C) definition: one venipuncture with two sequentially obtained specimens, 10 ml each, the first specimen (M1) for aerobic and the second (M2) for anaerobic media. The test ISDT culture (D) was identical, with the exception that each was preceded by diverting a 1-ml sample (DS) from the same venipuncture. During the first of two sequential 9-month periods, we captured D versus C data (n=3,733), where DMXR and CMXR are R for D and C specimens. Our hypothesis predicted DS would divert soiled skin fragments from DM1, and therefore, CM1R would be significantly greater than DM1R. This was confirmed by CM1R (30/1,061 [2.8%]) less DM1R (37/2,672 [1.4%]; P=0.005), which equals 1.4%. For the second 9-month follow-up period, data were compiled for all cultures (n=4,143), where ADMXR is R for all (A) diversion specimens, enabling comparison to test ISDT. Our hypothesis predicted no significant differences for test ISDT versus all ISDT. This was confirmed by DM1R (37/2,672 [1.4%]) versus ADM1R (42/4,143 [1.0%]; P=0.17) and DM2R (21/2,672 [0.80%]) versus ADM2R (39/4,143 [0.94%]; P=0.50). We conclude that our hypothesis is valid: venipuncture needles soil blood culture specimens with unsterilized skin fragments and increase R, and ISDT significantly reduces R from venipuncture obtained blood culture specimens. PMID- 20943871 TI - TROCAI (tropism coreceptor assay information): a new phenotypic tropism test and its correlation with Trofile enhanced sensitivity and genotypic approaches. AB - The only clinically validated assay available to determine HIV tropism is Trofile, an assay that possesses some limitations. Our first aim was to develop a new phenotypic tropism test (TROCAI [tropism coreceptor assay information]) and to categorize results generated by this test according to the virological response to a short-term exposure to the CCR5 receptor antagonist maraviroc (maraviroc clinical test). Our second aim was to compare TROCAI results to those obtained by Trofile enhanced sensitivity (ES) and to different genotypic algorithms. TROCAI assayed HIV tropism in 33 HIV-infected patient viral isolates obtained from a modified coculture, followed by multiple infection cycles of indicator cells. TROCAI obtained a reportable result in all patients with viral loads of >500 HIV RNA copies/ml and in 3/6 patients with <500 HIV RNA copies/ml (30/33 patients, 91.9%). Patients who responded to maraviroc had an X4-using virus proportion in indicator cell supernatant of 0 to 0.41%. Hence, we used the threshold of 0.5% to categorize TROCAI results as R5 (<0.5%) or dual/mixed (>0.5%). The concordance between TROCAI and Trofile (ES) was 22/24 (91.6%), and with genotypic approaches it was 22/26 (84.6%). TROCAI results, which were categorized in this study by the maraviroc clinical test, could be used as a test in addition to those currently used to select patients for treatment with CCR5 antagonists. PMID- 20943872 TI - Evaluation of Spectra VRE, a new chromogenic agar medium designed to screen for vancomycin-resistant Enterococcus faecalis and Enterococcus faecium. AB - Spectra VRE (Remel, Lenexa, KS) is a chromogenic medium designed to recover and differentiate vancomycin-resistant Enterococcus faecium and Enterococcus faecalis (VRE). This medium was compared to bile esculin azide agar (BEAV) and was 98.2% sensitive and 99.3% specific compared to BEAV, which was 87.6% sensitive and 87.1% specific at 24 h. PMID- 20943873 TI - Performance of commercial enzyme-linked immunosorbent assays for detection of antibodies to Bordetella pertussis. AB - Measuring antibodies to Bordetella pertussis antigens is mostly done by enzyme linked immunosorbent assays (ELISAs). We compared the performance of ELISA kits that were commercially available in Germany. Eleven measured IgG antibodies, and nine measured IgA antibodies. An in-house ELISA with purified antigens served as a reference method. Samples included two WHO reference preparations, the former Food and Drug Administration (FDA)/Center for Biologics Evaluation and Research (CBER) reference preparations, serum samples from patients with clinically suspected pertussis, and serum samples from patients having received a combined tetanus, diphtheria, and pertussis (Tdap) vaccination. Kits using pertussis toxin (PT) as an antigen showed linearity compared to the WHO Reference preparation (r2 between 0.82 and 0.99), and these kits could quantify antibodies according to the reference preparation. ELISA kits using mixed antigens showed no linear correlation to the reference preparations. Patient results were compared to results of in-house ELISAs using a dual cutoff of either >=100 IU/ml anti-PT IgG or >=40 IU/ml anti-PT IgG together with >=12 IU/ml anti-PT IgA. The sensitivities of kits measuring IgG antibodies ranged between 0.84 and 1.00. The specificities of kits using PT as an antigen were between 0.81 and 0.93. The specificities of kits using mixed antigens were between 0.51 and 0.59 and were thus not acceptable. The sensitivities of kits measuring IgA antibodies ranged between 0.53 and 0.73, and the specificities were between 0.67 and 0.94, indicating that IgA antibodies may be of limited diagnostic value. Our data suggest that ELISAs should use purified PT as an antigen and be standardized to the 1st International Reference preparation. PMID- 20943874 TI - Rapid identification of mycobacterial whole cells in solid and liquid culture media by matrix-assisted laser desorption ionization-time of flight mass spectrometry. AB - Mycobacterial identification is based on several methods: conventional biochemical tests that require several weeks for accurate identification, and molecular tools that are now routinely used. However, these techniques are expensive and time-consuming. In this study, an alternative method was developed using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). This approach allows a characteristic mass spectral fingerprint to be obtained from whole inactivated mycobacterial cells. We engineered a strategy based on specific profiles in order to identify the most clinically relevant species of mycobacteria. To validate the mycobacterial database, a total of 311 strains belonging to 31 distinct species and 4 species complexes grown in Lowenstein-Jensen (LJ) and liquid (mycobacterium growth indicator tube [MGIT]) media were analyzed. No extraction step was required. Correct identifications were obtained for 97% of strains from LJ and 77% from MGIT media. No misidentification was noted. Our results, based on a very simple protocol, suggest that this system may represent a serious alternative for clinical laboratories to identify mycobacterial species. PMID- 20943875 TI - First report of Salmonella enterica serotype paratyphi A azithromycin resistance leading to treatment failure. AB - The prevalence of Salmonella enterica serotype Paratyphi A infection is increasing, and multidrug resistance is a well-recognized problem. Resistance to fluoroquinolones is common and leads to more frequent use of newer agents like azithromycin. We report the first case of azithromycin resistance and treatment failure in a patient with S. Paratyphi A infection. PMID- 20943876 TI - Prevalence of antibodies to four human coronaviruses is lower in nasal secretions than in serum. AB - Little is known about the prevalence of mucosal antibodies induced by infection with human coronaviruses (HCoV), including HCoV-229E and -OC43 and recently described strains (HCoV-NL63 and -HKU1). By enzyme-linked immunosorbent assay, we measured anti-HCoV IgG antibodies in serum and IgA antibodies in nasal wash specimens collected at seven U.S. sites from 105 adults aged 50 years and older (mean age, 67 +/- 9 years) with chronic obstructive pulmonary disease. Most patients (95 [90%]) had at least one more chronic disease. More patients had serum antibody to each HCoV strain (104 [99%] had antibody to HCoV-229E, 105 [100%] had antibody to HCoV-OC43, 103 [98%] had antibody to HCoV-NL63, and 96 [91%] had antibody to HCoV-HKU1) than had antibody to each HCoV strain in nasal wash specimens (12 [11%] had antibody to HCoV-229E, 22 [22%] had antibody to HCoV OC43, 8 [8%] had antibody to HCoV-NL63, and 31 [31%] had antibody to HCoV-HKU1), respectively (P < 0.0001). The proportions of subjects with IgA antibodies in nasal wash specimens and the geometric mean IgA antibody titers were statistically higher for HCoV-OC43 and -HKU1 than for HCoV-229E and -NL63. A higher proportion of patients with heart disease than not had IgA antibodies to HCoV-NL63 (6 [16%] versus 2 [3%]; P = 0.014). Correlations were highest for serum antibody titers between group I strains (HCoV-229E and -NL63 [r = 0.443; P < 0.0001]) and between group II strains (HCoV-OC43 and -HKU1 [r = 0.603; P < 0.0001]) and not statistically significant between HCoV-NL63 and -OC43 and between HCoV-NL63 and -HKU1. Patients likely had experienced infections with more than one HCoV strain, and IgG antibodies to these HCoV strains in serum were more likely to be detected than IgA antibodies to these HCoV strains in nasal wash specimens. PMID- 20943877 TI - Safety and immunogenicity of a novel Staphylococcus aureus vaccine: results from the first study of the vaccine dose range in humans. AB - Merck V710 is a novel vaccine containing the conserved Staphylococcus aureus iron surface determinant B shown to be protective in animal models. A phase I, multicenter, double-blind study of the dose range was conducted to assess the immunogenicity and safety of an adjuvanted liquid formulation of V710. A total of 124 adults (18 to 55 years of age) were randomized 1:1:1:1 to receive one 0.5-ml intramuscular injection of V710 (5 MUg, 30 MUg, or 90 MUg) or saline placebo. A positive immune response was defined as at least a 2-fold increase in IsdB specific IgG levels from baseline levels. Local and systemic adverse events were assessed for 5 and 14 days, respectively, following vaccination. Positive immune responses were detected in 12 (67%) of the 18 subjects in the groups receiving 30 and 90 MUg V710 tested at day 10. At day 14, a significantly greater proportion of subjects manifested a positive immune response with higher geometric mean concentrations in the V710 30-MUg (86%; geometric mean concentration of 116 MUg/ml) and 90-MUg (87%; geometric mean concentration of 131 MUg/ml) dose groups than in the V710 5-MUg (29%; geometric mean concentration of 51 MUg/ml) or placebo (4%; geometric mean concentration of 23 MUg/ml) groups. Immune responses were durable through day 84. Subjects <40 and >=40 years of age had comparable immune responses. The most common adverse events were injection-site pain, nausea, fatigue, and headache, usually of mild intensity. No immediate reactions or serious adverse events were reported. In this first study of V710 in humans, a single 30-MUg or 90-MUg dose was more immunogenic than the 5-MUg dose or placebo. Immune responses were evident by 10 to 14 days after vaccination in most responders. PMID- 20943878 TI - Evaluation of gamma interferon release assays using Mycobacterium tuberculosis antigens for diagnosis of latent and active tuberculosis in Mycobacterium bovis BCG-vaccinated populations. AB - T-cell-based gamma interferon (IFN-gamma) release assays (IGRAs) using Mycobacterium tuberculosis-specific antigens have shown higher sensitivity and specificity than the routine tuberculin skin test (TST). However, the effects of Mycobacterium bovis BCG vaccination and anti-tuberculosis (TB) treatment on dynamic T-cell responses to M. tuberculosis-specific antigens in active TB cases have rarely been investigated in regions where TB is endemic. Eighty-nine patients with active pulmonary TB (ATB) and 57 healthy controls (HC) from China were recruited and tested by sputum smear and culture, TSTs, and IGRAs with M. tuberculosis-specific antigens ESAT-6 and CFP-10 (T-SPOT.TB) as well as purified protein derivative (PPD) stimulation. All 146 participants were screened by the T SPOT.TB assay at recruitment. T-SPOT.TB-positive rates in ATB and HC groups were 87.6% (78/89) and 21.1% (12/57), respectively. Of 38 ATB patients who were both TST and T-SPOT.TB tested, the positive rates were 73.7% (28/38) and 94.7% (36/38), respectively (P = 0.0215), and those in the HC group were 62.3% (33/53) and 18.9% (10/53), respectively (P < 0.0001). The T-SPOT.TB-positive rates declined during TB treatment and were 94.4% (51/54), 86.4% (19/22), and 61.5% (8/13) for ATB patients receiving 0- to 1-month, 1- to 3-month, and 3- to 6-month anti-TB treatment, respectively. The IGRA is a most promising test for both active TB and latent TB infection (LTBI) diagnosis due to the improvement of its specificity and convenience, especially in the Mycobacterium bovis BCG-vaccinated population. Furthermore, the T-SPOT.TB assay using ESAT-6 and CFP-10 in ATB patients during anti-TB treatment could serve as a potential predictor of therapeutic efficacy. PMID- 20943879 TI - Antibody responses in mice stimulated by various doses of the potato-derived major surface antigen of hepatitis B virus. AB - The ability of potato-derived major surface antigen of hepatitis B virus (P HBsAg) to elicit antibody responses to different dosages of P-HBsAg ranging from 0.02 to 30 MUg administered orally in mice was examined. All immunized groups produced specific serum IgG and fecal IgA antibodies against P-HBsAg, even at low levels (<5 MUg), after administration of a 0.5-MUg yeast-derived HBsAg (Y-HBsAg; LG Life Sciences, Republic of Korea) booster. PMID- 20943880 TI - Does hepatitis B virus prenatal transmission result in postnatal immunoprophylaxis failure? AB - The objective of this work was to evaluate whether postnatal hepatitis B immunization failure in children is caused by prenatal infections. A prospective study was conducted from October 2006 to September 2008. Fetal samples from HBsAg positive mothers were retrieved by either amniocentesis or cordocentesis (percutaneous umbilical blood sampling [PUBS]). Hepatitis B virus (HBV) serologic markers (HBVM) and quantitative HBV DNA assays were performed to assess prenatal infection. All neonates were given combined HBV immunoprophylaxis after delivery. The newborns were followed up with HBV serologic testing at 1 year old. For the 252 pregnant women recruited, 16 fetuses were found to be HBV DNA positive, with all HBV DNA levels under 10(4) copies/ml. HBsAg and HBV DNA detected in the uterus were uncommon and were expressed at low levels. In contract to the case with prenatal statuses, neonatal serologies were more similar to their mothers'. The response rate of vaccination was 95%. Six children for whom immunoprophylaxis failed were born to HBeAg-positive mothers with high HBV DNA levels (>10(8) copies/ml), but only one of them was found to be positive for intrauterine HBV DNA (8.5 * 10(2) copies/ml). The presence of intrauterine hepatitis B antigen and DNA does not indicate postnatal HBV infection and vaccination failure. PMID- 20943881 TI - Immune responses and protection against experimental Brucella suis biovar 1 challenge in nonvaccinated or B. abortus strain RB51-vaccinated cattle. AB - Twenty Hereford heifers approximately 9 months of age were vaccinated with saline (control) or 2 * 10(10) CFU of the Brucella abortus strain RB51 (RB51) vaccine. Immunologic responses after inoculation demonstrated significantly greater (P < 0.05) antibody and proliferative responses to RB51 antigens in cattle vaccinated with RB51 than in the controls. Pregnant cattle received a conjunctival challenge at approximately 6 months of gestation with 10(7) CFU of B. suis bv. 1 strains isolated from naturally infected cattle. The fluorescence polarization assay and the buffered acid plate agglutination test had the highest sensitivities in detecting B. suis-infected cattle between 2 and 12 weeks after experimental infection. Serologic responses and lymphocyte proliferative responses to B. suis antigens did not differ between control and RB51 vaccinees after experimental infection. No abortions occurred in cattle in either treatment group after challenge, although there appeared to be an increased incidence of retained placenta after parturition in both the control and the RB51 vaccination treatment groups. Our data suggest that the mammary gland is a preferred site for B. suis localization in cattle. Vaccination with RB51 did not reduce B. suis infection rates in maternal or fetal tissues. In conclusion, although B. suis is unlikely to cause abortions and fetal losses in cattle, our data suggest that RB51 vaccination will not protect cattle against B. suis infection after exposure. PMID- 20943882 TI - Pneumococcal nasopharyngeal carriage following reduced doses of a 7-valent pneumococcal conjugate vaccine and a 23-valent pneumococcal polysaccharide vaccine booster. AB - This study was conducted to evaluate the effect of a reduced-dose 7-valent pneumococcal conjugate vaccine (PCV) primary series followed by a 23-valent pneumococcal polysaccharide vaccine (23vPPS) booster on nasopharyngeal (NP) pneumococcal carriage. For this purpose, Fijian infants aged 6 weeks were randomized to receive 0, 1, 2, or 3 PCV doses. Within each group, half received 23vPPS at 12 months. NP swabs were taken at 6, 9, 12, and 17 months and were cultured for Streptococcus pneumoniae. Isolates were serotyped by multiplex PCR and a reverse line blot assay. There were no significant differences in PCV vaccine type (VT) carriage between the 3- and 2-dose groups at 12 months. NP VT carriage was significantly higher (P, <0.01) in the unvaccinated group than in the 3-dose group at the age of 9 months. There appeared to be a PCV dose effect in the cumulative proportion of infants carrying the VT, with less VT carriage occurring with more doses of PCV. Non-PCV serotype (NVT) carriage rates were similar for all PCV groups. When groups were pooled by receipt or nonreceipt of 23vPPS at 12 months, there were no differences in pneumococcal, VT, or NVT carriage rates between the 2 groups at the age of 17 months. In conclusion, there appeared to be a PCV dose effect on VT carriage, with less VT carriage occurring with more doses of PCV. By the age of 17 months, NVT carriage rates were similar for all groups. 23vPPS had no impact on carriage, despite the substantial boosts in antibody levels. PMID- 20943883 TI - Equine neonates have attenuated humoral and cell-mediated immune responses to a killed adjuvanted vaccine compared to adult horses. AB - The objectives of this study were to compare relative vaccine-specific serum immunoglobulin concentrations, vaccine-specific lymphoproliferative responses, and cytokine profiles of proliferating lymphocytes between 3-day-old foals, 3 month-old foals, and adult horses after vaccination with a killed adjuvanted vaccine. Horses were vaccinated intramuscularly twice at 3-week intervals with a vaccine containing antigens from bovine viral respiratory pathogens to avoid interference from maternal antibody. Both groups of foals and adult horses responded to the vaccine with a significant increase in vaccine-specific IgGa and IgG(T) concentrations. In contrast, only adult horses and 3-month-old foals mounted significant vaccine-specific total IgG, IgGb, and IgM responses. Vaccine specific concentrations of IgM and IgG(T) were significantly different between all groups, with the highest concentrations occurring in adult horses, followed by 3-month-old foals and, finally, 3-day-old foals. Only the adult horses mounted significant vaccine-specific lymphoproliferative responses. Baseline gamma interferon (IFN-gamma) and interleukin-4 (IL-4) concentrations were significantly lower in 3-day-old foals than in adult horses. Vaccination resulted in a significant decrease in IFN-gamma concentrations in adult horses and a significant decrease in IL-4 concentrations in 3-day-old foals. After vaccination, the ratio of IFN-gamma/IL-4 in both groups of foals was significantly higher than that in adult horses. The results of this study indicate that the humoral and lymphoproliferative immune responses to this killed adjuvanted vaccine are modest in newborn foals. Although immune responses improve with age, 3-month-old foals do not respond with the same magnitude as adult horses. PMID- 20943884 TI - Anaplasma marginale infection with persistent high-load bacteremia induces a dysfunctional memory CD4+ T lymphocyte response but sustained high IgG titers. AB - Control of blood-borne infections is dependent on antigen-specific effector and memory T cells and high-affinity IgG responses. In chronic infections characterized by a high antigen load, it has been shown that antigen-specific T and B cells are vulnerable to downregulation and apoptosis. Anaplasma marginale is a persistent infection of cattle characterized by acute and chronic high-load bacteremia. We previously showed that CD4(+) T cells primed by immunization with an A. marginale outer membrane protein were rapidly deleted following infection. Furthermore, peripheral blood T cell responses to bacteria were not observed after acute infection was controlled, suggesting dysfunctional T cell priming to other A. marginale antigens. The current study more closely investigated the kinetics of A. marginale-specific CD4(+) T cell responses primed during infection. Frequent sampling of peripheral blood and spleens revealed that antigen-specific CD4(+) T cell responses were first detected at 5 to 7 weeks, but the responses were sporadic and transient thereafter. A similar pattern was observed in animals sampled weekly for nearly 1 year. Paradoxically, by 2 weeks of infection, cattle had developed high titers of A. marginale-specific IgG, which remained high throughout persistent infection. This dysfunctional CD4(+) T cell response to infection is consistent with continual downregulation or deletion of newly primed effector T cells, similar to what was observed for immunization-induced T cells following A. marginale infection. The failure to establish a strong memory T cell response during A. marginale infection likely contributes to bacterial persistence. PMID- 20943885 TI - Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy. AB - Leber's hereditary optic neuropathy, the most frequent mitochondrial disease due to mitochondrial DNA point mutations in complex I, is characterized by the selective degeneration of retinal ganglion cells, leading to optic atrophy and loss of central vision prevalently in young males. The current study investigated the reasons for the higher prevalence of Leber's hereditary optic neuropathy in males, exploring the potential compensatory effects of oestrogens on mutant cell metabolism. Control and Leber's hereditary optic neuropathy osteosarcoma-derived cybrids (11778/ND4, 3460/ND1 and 14484/ND6) were grown in glucose or glucose free, galactose-supplemented medium. After having shown the nuclear and mitochondrial localization of oestrogen receptors in cybrids, experiments were carried out by adding 100 nM of 17beta-oestradiol. In a set of experiments, cells were pre-incubated with the oestrogen receptor antagonist ICI 182780. Leber's hereditary optic neuropathy cybrids in galactose medium presented overproduction of reactive oxygen species, which led to decrease in mitochondrial membrane potential, increased apoptotic rate, loss of cell viability and hyper-fragmented mitochondrial morphology compared with control cybrids. Treatment with 17beta oestradiol significantly rescued these pathological features and led to the activation of the antioxidant enzyme superoxide dismutase 2. In addition, 17beta oestradiol induced a general activation of mitochondrial biogenesis and a small although significant improvement in energetic competence. All these effects were oestrogen receptor mediated. Finally, we showed that the oestrogen receptor beta localizes to the mitochondrial network of human retinal ganglion cells. Our results strongly support a metabolic basis for the unexplained male prevalence in Leber's hereditary optic neuropathy and hold promises for a therapeutic use for oestrogen-like molecules. PMID- 20943886 TI - Adaptive mutations in the genomes of enterovirus 71 strains following infection of mouse cells expressing human P-selectin glycoprotein ligand-1. AB - We recently identified human P-selectin glycoprotein ligand-1 (PSGL-1) as a functional enterovirus 71 (EV71) receptor and demonstrated PSGL-1-dependent replication for some EV71 strains in human leukocytes. Here, we report that four out of five PSGL-1-binding strains of EV71 replicated poorly in mouse L929 cells stably expressing human PSGL-1 (L-PSGL-1 cells). Therefore, we compared the replication kinetics and entire genomic sequence of five original EV71 strains and the corresponding EV71 variants (EV71-LPS), which were propagated once in L PSGL-1 cells. Direct sequence comparison of the entire genome of the original EV71 strains and EV71-LPS variants identified several possible adaptive mutations during the course of replication in L-PSGL-1 cells, including a putative determinant of the adaptive phenotype in L-PSGL-1 cells at VP2-149. The results suggest that an adaptive mutation, along with a PSGL-1-binding phenotype, may facilitate efficient PSGL-1-dependent replication of the EV71 strains in L-PSGL-1 cells. PMID- 20943887 TI - Keep it in the subfamily: the conserved alphaherpesvirus US3 protein kinase. AB - The US3 protein kinase is conserved over the alphaherpesvirus subfamily. Increasing evidence shows that, although the kinase is generally not required for virus replication in cell culture, it plays a pivotal and in some cases an essential role in virus virulence in vivo. The US3 protein is a multifunctional serine/threonine kinase that is involved in viral gene expression, virion morphogenesis, remodelling the actin cytoskeleton and the evasion of several antiviral host responses. In the current review, both the well conserved and virus-specific functions of alphaherpesvirus US3 protein kinase orthologues will be discussed. PMID- 20943888 TI - BSE infectivity in the absence of detectable PrP(Sc) accumulation in the tongue and nasal mucosa of terminally diseased cattle. AB - The pathogenesis of bovine spongiform encephalopathy (BSE) infections in cattle has been studied in recent years by using highly sensitive transgenic-mouse bioassays. It has been shown that in this species, the BSE agent amplifies almost exclusively in the central and peripheral nervous system. Even in animals that were killed in the clinical end stage of the disease, the lymphoreticular system was shown to be free of the infectious agent. No other animal species investigated to date exhibits such a restricted BSE-infectivity distribution pattern. However, there is growing evidence for a radial spread of infection from the central nervous system (CNS) into the periphery during the late stages of the disease. In this study, we challenged transgenic mice overexpressing the bovine prion protein with homogenates prepared from a wide variety of tissue samples collected from BSE-infected cattle. As prion infections involve the conversion of the cellular prion protein into its abnormally folded isoform (PrP(Sc)), we applied various detection methods, such as the purification of scrapie-associated fibrils, immunohistochemistry, and the protein misfolding cyclic amplification technique. Despite negative results using these highly sensitive biochemical methods, we were, for the first time, able to detect BSE infectivity in the tongue and in the nasal mucosa of terminally diseased BSE field cases as well as experimentally challenged cattle by transgenic-mouse bioassay. This shows that BSE infectivity can be present in the peripheral tissues of terminally diseased cattle, including tissues used for human consumption. PMID- 20943889 TI - Differentiation of ruminant transmissible spongiform encephalopathy isolate types, including bovine spongiform encephalopathy and CH1641 scrapie. AB - With increased awareness of the diversity of transmissible spongiform encephalopathy (TSE) strains in the ruminant population, comes an appreciation of the need for improved methods of differential diagnosis. Exposure to bovine spongiform encephalopathy (BSE) has been associated with the human TSE, variant Creutzfeldt-Jakob disease, emphasizing the necessity in distinguishing low-risk TSE types from BSE. TSE type discrimination in ruminants such as cattle, sheep, goats and deer, requires the application of several prion protein (PrP)-specific antibodies in parallel immunochemical tests on brain homogenates or tissue sections from infected animals. This study uses in a single incubation step, three PrP-specific antibodies and fluorescent Alexa dye-labelled anti-mouse Fabs on a Western blot. The usual amount of brain tissue needed is 0.5 mg. This multiplex application of antibodies directed towards three different PrP epitopes enabled differential diagnosis of all established main features of classical scrapie, BSE and Nor98-like scrapie in sheep and goats, as well as the currently known BSE types C, H and L in cattle. Moreover, due to an antibody-dependent dual PrP-banding pattern, for the first time CH1641 scrapie of sheep can be reliably discriminated from the other TSE isolate types in sheep. PMID- 20943890 TI - Amino acid changes within the Bunyamwera virus nucleocapsid protein differentially affect the mRNA transcription and RNA replication activities of assembled ribonucleoprotein templates. AB - The genome of Bunyamwera virus (BUNV) comprises three RNA segments that are encapsidated by the virus-encoded nucleocapsid (N) protein to form ribonucleoprotein (RNP) complexes. These RNPs are the functional templates for RNA synthesis by the virus-encoded RNA-dependent RNA polymerase (RdRp). We investigated the roles of conserved positively charged N-protein amino acids in RNA binding, in oligomerization to form model RNPs and in generating RNP templates active for both RNA replication and mRNA transcription. We identified several residues that performed important roles in RNA binding, and furthermore showed that a single amino acid change can differentially affect the ability of the resulting RNP templates to regulate the transcription and replication activities of the RdRp. These results indicate that the BUNV N protein possesses functions outside of its primary role of RNA encapsidation. PMID- 20943891 TI - Genetic analysis of murine hepatitis virus non-structural protein 16. AB - MHV-Wuts18 is an RNA-negative, temperature-sensitive mutant of mouse coronavirus, strain murine hepatitis virus (MHV)-A59. We have previously identified the putative causal mutation of MHV-Wuts18 as a C to U transition at codon 2446 in ORF1b, which results in a substitution of proline 12 with serine in non structural protein 16. Here, we have used a vaccinia virus-based reverse genetic system to produce a recombinant virus, inf-MHV-Wuts18((AGC)) that encodes nsp16 serine 12 with AGC rather than UCU; a difference that facilitates the isolation of second-site revertants. Sequence analysis of nine inf-MHV-Wuts18((AGC)) revertant viruses suggests that their phenotype is most probably due to the intra molecular substitution of amino acids in nsp16. However, the revertant viruses displayed different plaque sizes and whole genome sequencing of two revertants showed that they were isogenic apart from a mutation in nsp13. These results are discussed in the context of a model of coronavirus MHV nsp16 structure. PMID- 20943892 TI - An RGG sequence in the replication-associated protein (Rep) of Tomato yellow leaf curl Sardinia virus is involved in transcriptional repression and severely impacts resistance in Rep-expressing plants. AB - Truncated versions of the replication-associated protein (Rep) of Tomato yellow leaf curl Sardinia virus (TYLCSV) can interfere with various viral functions and the N-terminal 130 aa are sufficient for strongly inhibiting C1-gene transcription and virus replication and confer resistance in transgenic plants. In this work, we analysed the relevance of an RGG sequence at aa 124-126, highly conserved in begomoviruses, in these inhibitory functions as well as in the subcellular localization of Rep. Although no role of this RGG sequence was detected by cell fractionation and immunogold labelling in Rep localization, this sequence appears relevant for the transcriptional control of the C1-gene and for the inhibition of viral replication and dramatically impacts resistance in transgenic plants. These results are discussed in the context of the model of Rep mediated resistance against TYLCSV. PMID- 20943893 TI - The complete genome sequence and proteomics of Yersinia pestis phage Yep-phi. AB - Yep-phi, a lytic phage of Yersinia pestis, was isolated in China and is routinely used as a diagnostic phage for the identification of the plague pathogen. Yep-phi has an isometric hexagonal head containing dsDNA and a short non-contractile conical tail. In this study, we sequenced the Yep-phi genome (GenBank accession no. HQ333270) and performed proteomics analysis. The genome consists of 38 ,616 bp of DNA, including direct terminal repeats of 222 bp, and is predicted to contain 45 ORFs. Most structural proteins were identified by proteomics analysis. Compared with the three available genome sequences of lytic phages for Y. pestis, the phages could be divided into two subgroups. Yep-phi displays marked homology to the bacteriophages Berlin (GenBank accession no. AM183667) and Yepe2 (GenBank accession no. EU734170), and these comprise one subgroup. The other subgroup is represented by bacteriophage PhiA1122 (GenBank accession no. AY247822). Potential recombination was detected among the Yep-phi subgroup. PMID- 20943894 TI - Distribution of skinfold thickness and blood pressure among children and adolescents in Shandong, China. AB - This article reported the distribution of skinfold thickness (SFT) and blood pressure (BP) among children and adolescents in Shandong, China. A total of 8568 students (4333 boys and 4235 girls) aged 7-18 years participated in this study. Triceps and subscapular SFT and BP of all subjects were measured, the sum of Triceps and subscapular SFT (SSFT) was used as an indicator of the overall SFT. The overall prevalence of relative high BP was 24.07% for boys and 22.36% for girls. The prevalence of relative high BP was increasing with SSFT percentiles, this trend was obvious especially in upper percentiles of SSFT. The prevalence of relative high BP increased from 13.27% (boys) and 13.33% (girls) in <5th SSFT percentile group to 55.50% (boys) and 48.17% (girls) in >=95th SSFT percentile group, which increased by 3.2 and 2.6 times. There is a higher level of SSFT and higher prevalence of relative high BP among children and adolescents in Shandong, China. PMID- 20943895 TI - Deciphering the corelease of glutamate from dopaminergic terminals derived from the ventral tegmental area. PMID- 20943896 TI - Suppressing sensorimotor activity modulates the discrimination of auditory emotions but not speaker identity. AB - Our ability to recognize the emotions of others is a crucial feature of human social cognition. Functional neuroimaging studies indicate that activity in sensorimotor cortices is evoked during the perception of emotion. In the visual domain, right somatosensory cortex activity has been shown to be critical for facial emotion recognition. However, the importance of sensorimotor representations in modalities outside of vision remains unknown. Here we use continuous theta-burst transcranial magnetic stimulation (cTBS) to investigate whether neural activity in the right postcentral gyrus (rPoG) and right lateral premotor cortex (rPM) is involved in nonverbal auditory emotion recognition. Three groups of participants completed same-different tasks on auditory stimuli, discriminating between the emotion expressed and the speakers' identities, before and following cTBS targeted at rPoG, rPM, or the vertex (control site). A task selective deficit in auditory emotion discrimination was observed. Stimulation to rPoG and rPM resulted in a disruption of participants' abilities to discriminate emotion, but not identity, from vocal signals. These findings suggest that sensorimotor activity may be a modality-independent mechanism which aids emotion discrimination. PMID- 20943897 TI - Spike timing and information transmission at retinogeniculate synapses. AB - This study examines the rules governing the transfer of spikes between the retina and the lateral geniculate nucleus (LGN) with the goal of determining whether the most informative retinal spikes preferentially drive LGN responses and what role spike timing plays in the process. By recording from monosynaptically connected pairs of retinal ganglion cells and LGN neurons in vivo in the cat, we show that relayed spikes are more likely than nonrelayed spikes to be evoked by stimuli that match the receptive fields of the recorded cells and that an interspike interval-based mechanism contributes to the process. Relayed spikes are also more reliable in their timing and number where they often achieve the theoretical limit of minimum variance. As a result, relayed spikes carry more visual information per spike. Based on these results, we conclude that retinogeniculate processing increases sparseness in the neural code by selectively relaying the highest fidelity spikes to the visual cortex. PMID- 20943898 TI - Recoding of sensory information across the retinothalamic synapse. AB - The neural code that represents the world is transformed at each stage of a sensory pathway. These transformations enable downstream neurons to recode information they receive from earlier stages. Using the retinothalamic synapse as a model system, we developed a theoretical framework to identify stimulus features that are inherited, gained, or lost across stages. Specifically, we observed that thalamic spikes encode novel, emergent, temporal features not conveyed by single retinal spikes. Furthermore, we found that thalamic spikes are not only more informative than retinal ones, as expected, but also more independent. Next, we asked how thalamic spikes gain sensitivity to the emergent features. Explicitly, we found that the emergent features are encoded by retinal spike pairs and then recoded into independent thalamic spikes. Finally, we built a model of synaptic transmission that reproduced our observations. Thus, our results established a link between synaptic mechanisms and the recoding of sensory information. PMID- 20943899 TI - Phase entrainment of human delta oscillations can mediate the effects of expectation on reaction speed. AB - The more we anticipate a response to a predictable stimulus, the faster we react. This empirical observation has been confirmed and quantified by many investigators suggesting that the processing of behaviorally relevant stimuli is facilitated by probability-based confidence of anticipation. However, the exact neural mechanisms underlying this phenomenon are largely unknown. Here we show that performance changes related to different levels of expectancy originate in dynamic modulation of delta oscillation phase. Our results obtained in rhythmic auditory target detection tasks indicated significant entrainment of the EEG delta rhythm to the onset of the target tones with increasing phase synchronization at higher levels of predictability. Reaction times correlated with the phase of the delta band oscillation at target onset. The fastest reactions occurred during the delta phase that most commonly coincided with the target event in the high expectancy conditions. These results suggest that low frequency oscillations play a functional role in human anticipatory mechanisms, presumably by modulating synchronized rhythmic fluctuations in the excitability of large neuronal populations and by facilitating efficient task-related neuronal communication among brain areas responsible for sensory processing and response execution. PMID- 20943901 TI - Sonic hedgehog regulates discrete populations of astrocytes in the adult mouse forebrain. AB - Astrocytes are an essential component of the CNS, and recent evidence points to an increasing diversity of their functions. Identifying molecular pathways that mediate distinct astrocyte functions, is key to understanding how the nervous system operates in the intact and pathological states. In this study, we demonstrate that the Hedgehog (Hh) pathway, well known for its roles in the developing CNS, is active in astrocytes of the mature mouse forebrain in vivo. Using multiple genetic approaches, we show that regionally distinct subsets of astrocytes receive Hh signaling, indicating a molecular diversity between specific astrocyte populations. Furthermore, we identified neurons as a source of Sonic hedgehog (Shh) in the adult forebrain, suggesting that Shh signaling is involved in neuron-astrocyte communication. Attenuation of Shh signaling in postnatal astrocytes by targeted removal of Smoothened, an obligate Shh coreceptor, resulted in upregulation of GFAP and cellular hypertrophy specifically in astrocyte populations regulated by Shh signaling. Collectively, our findings demonstrate a role for neuron-derived Shh in regulating specific populations of differentiated astrocytes. PMID- 20943900 TI - Rescue of impaired fear extinction and normalization of cortico-amygdala circuit dysfunction in a genetic mouse model by dietary zinc restriction. AB - Fear extinction is impaired in neuropsychiatric disorders, including posttraumatic stress disorder. Identifying drugs that facilitate fear extinction in animal models provides leads for novel pharmacological treatments for these disorders. Zinc (Zn) is expressed in neurons in a cortico-amygdala circuit mediating fear extinction, and modulates neurotransmitter systems regulating extinction. We previously found that the 129S1/SvImJ mouse strain (S1) exhibited a profound impairment in fear extinction, coupled with abnormalities in the activation of the extinction circuit. Here, we tested the role of Zn in fear extinction in S1 and C57BL/6N reference strain (B6) by feeding the mice a Zn restricted diet (ZnR) and testing for fear extinction, as well as neuronal activation of the extinction circuit via quantification of the immediate-early genes c-Fos and Zif268. Results showed that (preconditioning or postconditioning) ZnR completely rescued deficient extinction learning and long-term extinction retrieval in S1 and expedited extinction learning in B6, without affecting fear acquisition or fear expression. The extinction-facilitating effects of ZnR were associated with the normalization of Zif268 and/or c-Fos expression in cortico amygdala regions of S1. Specifically, ZnR increased activity in infralimbic cortex, lateral and basolateral amygdala nuclei, and lateral central amygdala nucleus, and decreased activity in prelimbic and insular cortices and medial central amygdala nucleus. ZnR also increased activation in the main intercalated nucleus and decreased activation of the medial paracapsular intercalated mass in S1. Our findings reveal a novel role for Zn in fear extinction and further support the utility of the S1 model for identifying extinction facilitating drugs. PMID- 20943902 TI - Sound-induced enhancement of low-intensity vision: multisensory influences on human sensory-specific cortices and thalamic bodies relate to perceptual enhancement of visual detection sensitivity. AB - Combining information across modalities can affect sensory performance. We studied how co-occurring sounds modulate behavioral visual detection sensitivity (d'), and neural responses, for visual stimuli of higher or lower intensity. Co occurrence of a sound enhanced human detection sensitivity for lower- but not higher-intensity visual targets. Functional magnetic resonance imaging (fMRI) linked this to boosts in activity-levels for sensory-specific visual and auditory cortex, plus multisensory superior temporal sulcus (STS), specifically for a lower-intensity visual event when paired with a sound. Thalamic structures in visual and auditory pathways, the lateral and medial geniculate bodies, respectively (LGB, MGB), showed a similar pattern. Subject-by-subject psychophysical benefits correlated with corresponding fMRI signals in visual, auditory, and multisensory regions. We also analyzed differential "coupling" patterns of LGB and MGB with other regions in the different experimental conditions. Effective-connectivity analyses showed enhanced coupling of sensory specific thalamic bodies with the affected cortical sites during enhanced detection of lower-intensity visual events paired with sounds. Coupling strength between visual and auditory thalamus with cortical regions, including STS, covaried parametrically with the psychophysical benefit for this specific multisensory context. Our results indicate that multisensory enhancement of detection sensitivity for low-contrast visual stimuli by co-occurring sounds reflects a brain network involving not only established multisensory STS and sensory-specific cortex but also visual and auditory thalamus. PMID- 20943903 TI - Intact working memory for relational information after medial temporal lobe damage. AB - Working memory has traditionally been viewed as independent of the hippocampus and related medial temporal lobe structures. Yet memory-impaired patients with medial temporal lobe damage are sometimes impaired at remembering relational information (e.g., an object and its location) across delays as short as a few seconds. This observation has raised the possibility that medial temporal lobe structures are sometimes critical for maintaining relational information, regardless of whether the task depends on working or long-term memory. An alternative possibility is that these structures are critical for maintaining relational information only when the task exceeds working memory capacity and depends instead on long-term memory. To test these ideas, we drew on a method used previously in a classic study of digit span in patient HM that distinguished immediate memory from long-term memory. In two experiments, we assessed the ability of four patients with medial temporal lobe lesions to maintain varying numbers of object-location associations across a 1 s retention interval. In both experiments, the patients exhibited a similar pattern of performance. They performed similarly to controls when only a small number of object-location associations needed to be maintained, and they exhibited an abrupt discontinuity in performance with larger set sizes. This pattern of results supports the idea that maintenance of relational information in working memory is intact after damage to the hippocampus and related medial temporal lobe structures and that damage to these structures impairs performance only when the task depends on long term memory. PMID- 20943904 TI - Intrinsic plasticity complements long-term potentiation in parallel fiber input gain control in cerebellar Purkinje cells. AB - Synaptic gain control and information storage in neural networks are mediated by alterations in synaptic transmission, such as in long-term potentiation (LTP). Here, we show using both in vitro and in vivo recordings from the rat cerebellum that tetanization protocols for the induction of LTP at parallel fiber (PF)-to Purkinje cell synapses can also evoke increases in intrinsic excitability. This form of intrinsic plasticity shares with LTP a requirement for the activation of protein phosphatases 1, 2A, and 2B for induction. Purkinje cell intrinsic plasticity resembles CA1 hippocampal pyramidal cell intrinsic plasticity in that it requires activity of protein kinase A (PKA) and casein kinase 2 (CK2) and is mediated by a downregulation of SK-type calcium-sensitive K conductances. In addition, Purkinje cell intrinsic plasticity similarly results in enhanced spine calcium signaling. However, there are fundamental differences: first, while in the hippocampus increases in excitability result in a higher probability for LTP induction, intrinsic plasticity in Purkinje cells lowers the probability for subsequent LTP induction. Second, intrinsic plasticity raises the spontaneous spike frequency of Purkinje cells. The latter effect does not impair tonic spike firing in the target neurons of inhibitory Purkinje cell projections in the deep cerebellar nuclei, but lowers the Purkinje cell signal-to-noise ratio, thus reducing the PF readout. These observations suggest that intrinsic plasticity accompanies LTP of active PF synapses, while it reduces at weaker, nonpotentiated synapses the probability for subsequent potentiation and lowers the impact on the Purkinje cell output. PMID- 20943905 TI - Interdependent roles for accessory KChIP2, KChIP3, and KChIP4 subunits in the generation of Kv4-encoded IA channels in cortical pyramidal neurons. AB - The rapidly activating and inactivating voltage-dependent outward K(+) (Kv) current, I(A), is widely expressed in central and peripheral neurons. I(A) has long been recognized to play important roles in determining neuronal firing properties and regulating neuronal excitability. Previous work demonstrated that Kv4.2 and Kv4.3 alpha-subunits are the primary determinants of I(A) in mouse cortical pyramidal neurons. Accumulating evidence indicates that native neuronal Kv4 channels function in macromolecular protein complexes that contain accessory subunits and other regulatory molecules. The K(+) channel interacting proteins (KChIPs) are among the identified Kv4 channel accessory subunits and are thought to be important for the formation and functioning of neuronal Kv4 channel complexes. Molecular genetic, biochemical, and electrophysiological approaches were exploited in the experiments described here to examine directly the roles of KChIPs in the generation of functional Kv4-encoded I(A) channels. These combined experiments revealed that KChIP2, KChIP3, and KChIP4 are robustly expressed in adult mouse posterior (visual) cortex and that all three proteins coimmunoprecipitate with Kv4.2. In addition, in cortical pyramidal neurons from mice lacking KChIP3 (KChIP3(-/-)), mean I(A) densities were reduced modestly, whereas in mean I(A) densities in KChIP2(-/-) and WT neurons were not significantly different. Interestingly, in both KChIP3(-/-) and KChIP2(-/-) cortices, the expression levels of the other KChIPs (KChIP2 and 4 or KChIP3 and 4, respectively) were increased. In neurons expressing constructs to mediate simultaneous RNA interference-induced reductions in the expression of KChIP2, 3, and 4, I(A) densities were markedly reduced and Kv current remodeling was evident. PMID- 20943907 TI - Brain dynamics underlying training-induced improvement in suppressing inappropriate action. AB - Inhibitory control, a core component of executive functions, refers to our ability to suppress intended or ongoing cognitive or motor processes. Mostly based on Go/NoGo paradigms, a considerable amount of literature reports that inhibitory control of responses to "NoGo" stimuli is mediated by top-down mechanisms manifesting ~200 ms after stimulus onset within frontoparietal networks. However, whether inhibitory functions in humans can be trained and the supporting neurophysiological mechanisms remain unresolved. We addressed these issues by contrasting auditory evoked potentials (AEPs) to left-lateralized "Go" and right NoGo stimuli recorded at the beginning versus the end of 30 min of active auditory spatial Go/NoGo training, as well as during passive listening of the same stimuli before versus after the training session, generating two separate 2 * 2 within-subject designs. Training improved Go/NoGo proficiency. Response times to Go stimuli decreased. During active training, AEPs to NoGo, but not Go, stimuli modulated topographically with training 61-104 ms after stimulus onset, indicative of changes in the underlying brain network. Source estimations revealed that this modulation followed from decreased activity within left parietal cortices, which in turn predicted the extent of behavioral improvement. During passive listening, in contrast, effects were limited to topographic modulations of AEPs in response to Go stimuli over the 31-81 ms interval, mediated by decreased right anterior temporoparietal activity. We discuss our results in terms of the development of an automatic and bottom-up form of inhibitory control with training and a differential effect of Go/NoGo training during active executive control versus passive listening conditions. PMID- 20943906 TI - Haploinsufficiency in peptidylglycine alpha-amidating monooxygenase leads to altered synaptic transmission in the amygdala and impaired emotional responses. AB - The mammalian amygdala expresses various neuropeptides whose signaling has been implicated in emotionality. Many neuropeptides require amidation for full activation by peptidylglycine alpha-amidating monooxygenase (PAM), a transmembrane vesicular cuproenzyme and regulator of the secretory pathway. Mice heterozygous for the Pam gene (PAM(+/-)) exhibit physiological and behavioral abnormalities related to specific peptidergic pathways. In the present study, we evaluated emotionality and examined molecular and cellular responses that characterize neurophysiological differences in the PAM(+/-) amygdala. PAM(+/-) mice presented with anxiety-like behaviors in the zero maze that were alleviated by diazepam. PAM(+/-) animals were deficient in short- and long-term contextual and cued fear conditioning and required higher shock intensities to establish fear-potentiated startle than their wild-type littermates. Immunohistochemical analysis of the amygdala revealed PAM expression in pyramidal neurons and local interneurons that synthesize GABA. We performed whole-cell recordings of pyramidal neurons in the PAM(+/-) amygdala to elucidate neurophysiological correlates of the fear behavioral phenotypes. Consistent with these observations, thalamic afferent synapses in the PAM(+/-) lateral nucleus were deficient in long term potentiation. This deficit was apparent in the absence and presence of the GABA(A) receptor antagonist picrotoxin and was abolished when both GABA(A) and GABA(B) receptors were blocked. Both evoked and spontaneous excitatory signals were enhanced in the PAM(+/-) lateral nucleus. Phasic GABAergic signaling was also augmented in the PAM(+/-) amygdala, and this difference comprised activity independent and -dependent components. These physiological findings represent perturbations in the PAM(+/-) amygdala that may underlie the aberrant emotional responses in the intact animal. PMID- 20943908 TI - Prototypic seizure activity driven by mature hippocampal fast-spiking interneurons. AB - A variety of epileptic seizure models have shown that activation of glutamatergic pyramidal cells is usually required for rhythm generation and/or synchronization in hippocampal seizure-like oscillations in vitro. However, it still remains unclear whether GABAergic interneurons may be able to drive the seizure-like oscillations without glutamatergic transmission. Here, we found that electrical stimulation in rat hippocampal CA1 slices induced a putative prototype of seizure like oscillations ("prototypic afterdischarge," 1.8-3.8 Hz) in mature pyramidal cells and interneurons in the presence of ionotropic glutamate receptor antagonists. The prototypic afterdischarge was abolished by GABA(A) receptor antagonists or gap junction blockers, but not by a metabotropic glutamate receptor antagonist or a GABA(B) receptor antagonist. Gramicidin-perforated patch clamp and voltage-clamp recordings revealed that pyramidal cells were depolarized and frequently excited directly through excitatory GABAergic transmissions in each cycle of the prototypic afterdischarge. Interneurons that were actively spiking during the prototypic afterdischarge were mostly fast-spiking (FS) interneurons located in the strata oriens and pyramidale. Morphologically, these interneurons that might be "potential seizure drivers" included basket, chandelier, and bistratified cells. Furthermore, they received direct excitatory GABAergic input during the prototypic afterdischarge. The O-LM cells and most of the interneurons in the strata radiatum and lacunosum moleculare were not essential for the generation of prototypic afterdischarge. The GABA-mediated prototypic afterdischarge was observed later than the third postnatal week in the rat hippocampus. Our results suggest that an FS interneuron network alone can drive the prototypic form of electrically induced seizure-like oscillations through their excitatory GABAergic transmissions and presumably through gap junction-mediated communications. PMID- 20943909 TI - Glucocorticoids exacerbate lipopolysaccharide-induced signaling in the frontal cortex and hippocampus in a dose-dependent manner. AB - Although the anti-inflammatory actions of glucocorticoids (GCs) are well established, evidence has accumulated showing that proinflammatory GC effects can occur in the brain, in a poorly understood manner. Using electrophoretic mobility shift assay, real-time PCR, and immunoblotting, we investigated the ability of varying concentrations of corticosterone (CORT, the GC of rats) to modulate lipopolysaccharide (LPS)-induced activation of NF-kappaB (nuclear factor kappaB), expression of anti- and proinflammatory factors and of the MAP (mitogen-activated protein) kinase family [ERK (extracellular signal-regulated kinase), p38, and JNK/SAPK (c-Jun N-terminal protein kinase/stress-activated protein kinase)], and AKT. In the frontal cortex, elevated CORT levels were proinflammatory, exacerbating LPS effects on NF-kappaB, MAP kinases, and proinflammatory gene expression. Milder proinflammatory GCs effects occurred in the hippocampus. In the absence of LPS, elevated CORT levels increased basal activation of ERK1/2, p38, SAPK/JNK, and AKT in both regions. These findings suggest that GCs do not uniformly suppress neuroinflammation and can even enhance it at multiple levels in the pathway linking LPS exposure to inflammation. PMID- 20943910 TI - Attenuation of activity in an endogenous analgesia circuit by ongoing pain in the rat. AB - Analgesic efficacy varies depending on the pain syndrome being treated. One reason for this may be a differential effect of individual pain syndromes on the function of the endogenous pain control circuits at which these drugs act to produce analgesia. To test this hypothesis, we examined the effects of diverse (i.e., ongoing inflammatory, neuropathic, or chronic widespread) pain syndromes on analgesia induced by activation of an opioid-mediated, noxious stimulus induced endogenous pain control circuit. This circuit was activated by subdermal capsaicin injection at a site remote from the site of nociceptive testing. Analgesia was not affected by carrageenan-induced inflammatory pain or the early phase of oxaliplatin neuropathy (a complication of cancer chemotherapy). However, the duration of analgesia was markedly shorter in the late phase of oxaliplatin neuropathy and in alcoholic neuropathy. A model of fibromyalgia syndrome produced by chronic unpredictable stress and proinflammatory cytokines also shortened analgesia duration, but so did the same stress alone. Therefore, since chronic pain can activate neuroendocrine stress axes, we tested whether they are involved in the attenuation of analgesic duration induced by these pain syndromes. Rats in which the sympathoadrenal axis was ablated by adrenal medullectomy showed normal duration pain-induced analgesia in groups with either late-phase oxaliplatin neuropathy, alcoholic neuropathy, or exposure to sound stress. These results support the suggestion that pain syndromes can modulate activity in endogenous pain control circuits and that this effect is sympathoadrenal dependent. PMID- 20943911 TI - Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. AB - Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease. However, the underlying mechanisms are unclear. We found that female apoE4 knock-in (KI) mice had an age-dependent decrease in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits, as determined in the Morris water maze, in aged mice. Treating apoE4-KI mice with daily peritoneal injections of the GABA(A) receptor potentiator pentobarbital at 20 mg/kg for 4 weeks rescued the learning and memory deficits. In neurotoxic apoE4 fragment transgenic mice, hilar GABAergic interneuron loss was even more pronounced and also correlated with the extent of learning and memory deficits. Neurodegeneration and tauopathy occurred earliest in hilar interneurons in apoE4 fragment transgenic mice; eliminating endogenous Tau prevented hilar GABAergic interneuron loss and the learning and memory deficits. The GABA(A) receptor antagonist picrotoxin abolished this rescue, while pentobarbital rescued learning deficits in the presence of endogenous Tau. Thus, apoE4 causes age- and Tau dependent impairment of hilar GABAergic interneurons, leading to learning and memory deficits in mice. Consequently, reducing Tau and enhancing GABA signaling are potential strategies to treat or prevent apoE4-related Alzheimer's disease. PMID- 20943913 TI - Amyloid precursor protein cleavage-dependent and -independent axonal degeneration programs share a common nicotinamide mononucleotide adenylyltransferase 1 sensitive pathway. AB - Axonal degeneration is a hallmark of many debilitating neurological disorders and is thought to be regulated by mechanisms distinct from those governing cell body death. Recently, caspase 6 activation via amyloid precursor protein (APP) cleavage and activation of DR6 was discovered to induce axon degeneration after NGF withdrawal. We tested whether this pathway is involved in axonal degeneration caused by withdrawal of other trophic support, axotomy or vincristine exposure. Neurturin deprivation, like NGF withdrawal activated this APP/DR6/caspase 6 pathway and resulted in axonal degeneration, however, APP cleavage and caspase 6 activation were not involved in axonal degeneration induced by mechanical or toxic insults. However, loss of surface APP (sAPP) and caspase 6 activation were observed during axonal degeneration induced by dynactin 1(Dctn1) dysfunction, which disrupts axonal transport. Mutations in Dctn1 are associated with motor neuron disease and frontal temporal dementia, thus suggesting that the APP/caspase 6 pathway could be important in specific types of disease-associated axonal degeneration. The NGF deprivation paradigm, with its defined molecular pathway, was used to examine the context of Nmnat-mediated axonal protection. We found that although Nmnat blocks axonal degeneration after trophic factor withdrawal, it did not prevent loss of axon sAPP or caspase 6 activation within the axon, suggesting it acts downstream of caspase 6. These results indicate that diverse insults induce axonal degeneration via multiple pathways and that these degeneration signals converge on a common, Nmnat-sensitive program that is uniquely involved in axonal, but not cell body, degeneration. PMID- 20943912 TI - Spontaneous seizures and altered gene expression in GABA signaling pathways in a mind bomb mutant zebrafish. AB - Disruption of E3 ubiquitin ligase activity in immature zebrafish mind bomb mutants leads to a failure in Notch signaling, excessive numbers of neurons, and depletion of neural progenitor cells. This neurogenic phenotype is associated with defects in neural patterning and brain development. Because developmental brain abnormalities are recognized as an important feature of childhood neurological disorders such as epilepsy and autism, we determined whether zebrafish mutants with grossly abnormal brain structure exhibit spontaneous electrical activity that resembles the long-duration, high-amplitude multispike discharges reported in immature zebrafish exposed to convulsant drugs. Electrophysiological recordings from agar immobilized mind bomb mutants at 3 d postfertilization confirmed the occurrence of electrographic seizure activity; seizure-like behaviors were also noted during locomotion video tracking of freely behaving mutants. To identify genes differentially expressed in the mind bomb mutant and provide insight into molecular pathways that may mediate these epileptic phenotypes, a transcriptome analysis was performed using microarray. Interesting candidate genes were further analyzed using conventional reverse transcriptase-PCR and real-time quantitative PCR, as well as whole-mount in situ hybridization. Approximately 150 genes, some implicated in development, transcription, cell metabolism, and signal transduction, are differentially regulated, including downregulation of several genes necessary for GABA-mediated signaling. These findings identify a collection of gene transcripts that may be responsible for the abnormal electrical discharge and epileptic activities observed in a mind bomb zebrafish mutant. This work may have important implications for neurological and neurodevelopmental disorders associated with mutations in ubiquitin ligase activity. PMID- 20943914 TI - Comparisons of the dynamics of local field potential and multiunit activity signals in macaque visual cortex. AB - The local field potential (LFP) and multiunit activity (MUA) are extracellularly recorded signals that describe local neuronal network dynamics. In our experiments, the LFP and MUA, recorded from the same electrode in macaque primary visual cortex V1 in response to drifting grating visual stimuli, were evaluated on coarse timescales (~1-5 s) and fine timescales (<0.1 s). On coarse timescales, MUA and the LFP both produced sustained visual responses to optimal and non optimal oriented visual stimuli. The sustainedness of the two signals across the population of recording sites was correlated (correlation coefficient, ~0.4). At most recording sites, the MUA was at least as sustained as the LFP and significantly more sustained for optimal orientations. In previous literature, the blood oxygen level-dependent (BOLD) signal of functional magnetic resonance imaging studies was found to be more strongly correlated with the LFP than with the MUA as a result of the lack of sustained response in the MUA signal. Because we found that MUA was as sustained as the LFP, MUA may also be correlated with BOLD. On fine timescales, we computed the coherence between the LFP and MUA over the frequency range 10-150 Hz. The LFP and MUA were weakly but significantly coherent (~0.14) in the gamma band (20-90 Hz). The amount of gamma-band coherence was correlated with the power in the gamma band of the LFP. The data were consistent with the proposal that the LFP and MUA are generated in a noisy, resonant cortical network. PMID- 20943915 TI - Mitogen-activated protein kinase-activated protein kinase 2 (MK2) contributes to secondary damage after spinal cord injury. AB - The inflammatory response contributes importantly to secondary tissue damage and functional deficits after spinal cord injury (SCI). In this work, we identified mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAPK2 or MK2), a downstream substrate of p38 MAPK, as a potential target using microarray analysis of contused spinal cord tissue taken at the peak of the inflammatory response. There was increased expression and phosphorylation of MK2 after SCI, with phospho-MK2 expressed in microglia/macrophages, neurons and astrocytes. We examined the role of MK2 in spinal cord contusion injury using MK2(-/-) mice. These results show that locomotor recovery was significantly improved in MK2(-/-) mice, compared with wild-type controls. MK2(-/-) mice showed reduced neuron and myelin loss, and increased sparing of serotonergic fibers in the ventral horn caudal to the injury site. We also found differential expression of matrix metalloproteinase-2 and 9 in MK2(-/-) and wild-type mice after SCI. Significant reduction was also seen in the expression of proinflammatory cytokines and protein nitrosylation in the injured spinal cord of MK2(-/-) mice. Our previous work has shown that macrophages lacking MK2 have an anti-inflammatory phenotype. We now show that there is no difference in the number of macrophages in the injured spinal cord between the two mouse strains and little if any difference in their phagocytic capacity, suggesting that macrophages lacking MK2 have a beneficial phenotype. These findings suggest that a lack of MK2 can reduce tissue damage after SCI and improve locomotor recovery. MK2 may therefore be a useful target to treat acute SCI. PMID- 20943917 TI - A homolog of the vertebrate pituitary adenylate cyclase-activating polypeptide is both necessary and instructive for the rapid formation of associative memory in an invertebrate. AB - Similar to other invertebrate and vertebrate animals, cAMP-dependent signaling cascades are key components of long-term memory (LTM) formation in the snail Lymnaea stagnalis, an established experimental model for studying evolutionarily conserved molecular mechanisms of long-term associative memory. Although a great deal is already known about the signaling cascades activated by cAMP, the molecules involved in the learning-induced activation of adenylate cyclase (AC) in Lymnaea remained unknown. Using matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy in combination with biochemical and immunohistochemical methods, recently we have obtained evidence for the existence of a Lymnaea homolog of the vertebrate pituitary adenylate cyclase-activating polypeptide (PACAP) and for the AC-activating effect of PACAP in the Lymnaea nervous system. Here we first tested the hypothesis that PACAP plays an important role in the formation of robust LTM after single-trial classical food-reward conditioning. Application of the PACAP receptor antagonist PACAP6-38 around the time of single-trial training with amyl acetate and sucrose blocked associative LTM, suggesting that in this "strong" food-reward conditioning paradigm the activation of AC by PACAP was necessary for LTM to form. We found that in a "weak" multitrial food-reward conditioning paradigm, lip touch paired with sucrose, memory formation was also dependent on PACAP. Significantly, systemic application of PACAP at the beginning of multitrial tactile conditioning accelerated the formation of transcription-dependent memory. Our findings provide the first evidence to show that in the same nervous system PACAP is both necessary and instructive for fast and robust memory formation after reward classical conditioning. PMID- 20943916 TI - Cued spatial attention drives functionally relevant modulation of the mu rhythm in primary somatosensory cortex. AB - Cued spatial attention modulates functionally relevant alpha rhythms in visual cortices in humans. Here, we present evidence for analogous phenomena in primary somatosensory neocortex (SI). Using magnetoencephalography, we measured changes in the SI mu rhythm containing mu-alpha (7-14 Hz) and mu-beta (15-29 Hz) components. We found that cued attention impacted mu-alpha in the somatopically localized hand representation in SI, showing decreased power after attention was cued to the hand and increased power after attention was cued to the foot, with significant differences observed 500-1100 ms after cue. Mu-beta showed differences in a time window 800-850 ms after cue. The visual cue also drove an early evoked response beginning ~70 ms after cue with distinct peaks modulated with cued attention. Distinct components of the tactile stimulus-evoked response were also modulated with cued attention. Analysis of a second dataset showed that, on a trial-by-trial basis, tactile detection probabilities decreased linearly with prestimulus mu-alpha and mu-beta power. These results support the growing consensus that cue-induced alpha modulation is a functionally relevant sensory gating mechanism deployed by attention. Further, while cued attention had a weaker effect on the allocation of mu-beta, oscillations in this band also predicted tactile detection. PMID- 20943918 TI - REEP2 enhances sweet receptor function by recruitment to lipid rafts. AB - Heterologously expressed sensory receptors generally do not achieve the ligand sensitivity observed in vivo, and may require specific accessory proteins to ensure optimal function. We searched for taste cell-expressed receptor transporting protein (RTP) and receptor expression enhancing protein (REEP) family members that might serve as accessory molecules to enhance gustatory receptor function. We determined that REEP2 is an integral membrane protein expressed in taste cells, physically associates with both subunits of the type 1 taste receptor 2 and type 1 taste receptor 3 sweet receptor and specifically enhances responses to tastants of heterologously expressed sweet and bitter taste receptors. Downregulation of endogenously expressed REEP2 in the chemosensory enteroendocrine GLUTag cell line dramatically reduced sensitivity of endogenous sweet receptors. In contrast to the observation that RTP1, RTP2, and REEP1 enhance function of olfactory receptors by promoting their transit to the cell surface, we found that REEP2 does not increase cell surface expression of sweet receptors but instead alters their spatial organization. REEP2 recruits sweet receptors into lipid raft microdomains localized near the taste cell's apical region, thereby improving G-protein-coupled receptor signaling and promoting receptor access to tastants arriving through the apical taste pore. PMID- 20943919 TI - Membrane anchoring subunits specify selective regulation of RGS9.Gbeta5 GAP complex in photoreceptor neurons. AB - The RGS9.Gbeta5 complex is the key regulator of neuronal G-protein signaling and shows remarkable selectivity of subunit composition. In retinal photoreceptors, RGS9.Gbeta5 is bound to the membrane anchor R9AP and the complex regulates visual signaling. In the basal ganglia neurons, RGS9.Gbeta5 is instead associated with a homologous protein, R7BP, and regulates reward circuit. Switching this selective subunit composition of the complex in rod photoreceptors allowed us to study the molecular underpinning of signaling specificity in diverse G-protein pathways. We have found that both membrane anchoring subunits play a conserved role in regulating protein levels of RGS9.Gbeta5 and enhancing the ability of RGS.Gbeta5 complexes to stimulate GTPase activity of G proteins. However, notable differences exist in the subcellular targeting of alternatively configured complexes. Unlike R9AP, which relies on passive targeting mechanisms for the delivery to the outer segments of the photoreceptors, R7BP is excluded from this location and is instead specifically targeted to the plasma membrane. R7BP containing complexes could be rerouted to the outer segments, where they are capable of regulating the phototransduction cascade by the active targeting signals derived from rhodopsin. These findings illustrate the diversity of the G protein signaling regulation by RGS.Gbeta5 complexes achieved by differential recruitment of the membrane anchors. PMID- 20943920 TI - RBPJkappa-dependent signaling is essential for long-term maintenance of neural stem cells in the adult hippocampus. AB - The generation of new neurons from neural stem cells in the adult hippocampal dentate gyrus contributes to learning and mood regulation. To sustain hippocampal neurogenesis throughout life, maintenance of the neural stem cell pool has to be tightly controlled. We found that the Notch/RBPJkappa-signaling pathway is highly active in neural stem cells of the adult mouse hippocampus. Conditional inactivation of RBPJkappa in neural stem cells in vivo resulted in increased neuronal differentiation of neural stem cells in the adult hippocampus at an early time point and depletion of the Sox2-positive neural stem cell pool and suppression of hippocampal neurogenesis at a later time point. Moreover, RBPJkappa-deficient neural stem cells displayed impaired self-renewal in vitro and loss of expression of the transcription factor Sox2. Interestingly, we found that Notch signaling increases Sox2 promoter activity and Sox2 expression in adult neural stem cells. In addition, activated Notch and RBPJkappa were highly enriched on the Sox2 promoter in adult hippocampal neural stem cells, thus identifying Sox2 as a direct target of Notch/RBPJkappa signaling. Finally, we found that overexpression of Sox2 can rescue the self-renewal defect in RBPJkappa deficient neural stem cells. These results identify RBPJkappa-dependent pathways as essential regulators of adult neural stem cell maintenance and suggest that the actions of RBPJkappa are, at least in part, mediated by control of Sox2 expression. PMID- 20943921 TI - Mossy fiber long-term potentiation deficits in BACE1 knock-outs can be rescued by activation of alpha7 nicotinic acetylcholine receptors. AB - beta-Site amyloid precursor protein-cleaving enzyme 1 (BACE1)-the neuronal beta secretase responsible for producing beta-amyloid (Abeta) peptides-emerged as one of the key therapeutic targets of Alzheimer's disease (AD). Although complete ablation of the BACE1 gene prevents Abeta formation, we reported that BACE1 knock out mice display severe presynaptic deficits at mossy fiber (MF)-to-CA3 synapses in the hippocampus, a major locus of BACE1 expression. We also found that the deficits are likely due to abnormal presynaptic Ca(2+) regulation. Cholinergic system has been implicated in AD, in some cases involving Ca(2+)-permeable alpha7 nicotinic acetylcholine receptors (nAChRs). Here we report that brief application of nicotine, via alpha7-nAChRs, can restore MF long-term potentiation in BACE1 knock-outs. Our data suggest that activating alpha7-nAChRs can recover the presynaptic deficits in BACE1 knock-outs. PMID- 20943923 TI - Complex cells in the cat striate cortex have multiple disparity detectors in the three-dimensional binocular receptive fields. AB - Along the visual pathway, neurons generally become more specialized for signaling a limited subset of stimulus attributes and become more invariant to changes in the stimulus position within the receptive fields (RFs). One of the likely mechanisms underlying such invariance appears to be pooling of detectors located at different positions. Does such spatial pooling occur for disparity-selective neurons in primary visual cortex? To examine whether the three-dimensional (3D) binocular RFs are constructed by pooling detectors for binocular disparity, we investigated binocular interactions in the 3D space for neurons in the cat striate cortex. Approximately one-third of complex cells showed the spatial pooling of disparity detectors to a significant degree, whereas the majority of simple cells did not. The degree of spatial pooling of disparity detectors along the preferred orientation axis was generally larger than that along the axis orthogonal to the orientation axis. We then reconstructed 3D binocular RFs in their complete form and examined their structures. Disparity tuning curves were compared across positions along the orientation axis in the RFs. A small population of cells appeared to show a gradual shift of the preferred disparity along this axis, indicating that they can potentially signal inclination in the 3D space. However, the majority of cells exhibited a position-invariant disparity tuning. Finally, disparity tuning curves were examined for all oblique angles in addition to horizontal and vertical. Tunings were broadest along the orientation axis as the disparity energy model predicts. PMID- 20943922 TI - Mechanisms involved in systemic nicotine-induced glutamatergic synaptic plasticity on dopamine neurons in the ventral tegmental area. AB - Systemic exposure to nicotine induces glutamatergic synaptic plasticity on dopamine (DA) neurons in the ventral tegmental area (VTA), but mechanisms are largely unknown. Here, we report that single, systemic exposure in rats to nicotine (0.17 mg/kg free base) increases the ratio of DA neuronal currents mediated by AMPA relative to NMDA receptors (AMPA/NMDA ratio) assessed 24 h later, based on slice-patch recording. The AMPA/NMDA ratio increase is evident within 1 h and lasts for at least 72 h after nicotine exposure (and up to 8 d after repeated nicotine administration). This effect cannot be prevented by systemic injection of either alpha7-nAChR (nicotinic ACh receptor)-selective [methyllycaconitine (MLA)] or beta2*-nAChR-selective [mecamylamine (MEC)] antagonists but is prevented by coinjection of MLA and MEC. In either nAChR alpha7 or beta2 subunit knock-out mice, systemic exposure to nicotine still increases the AMPA/NMDA ratio. Preinjection in rats of a NMDA receptor antagonist MK-801((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate), but neither DA receptor antagonists [SCH-23390 (R-(+)-7-chloro-8-hydroxy-3-methyl 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) plus haloperidol] nor a calcineurin inhibitor (cyclosporine), prevents the nicotine-induced increase in AMPA/NMDA ratio. After systemic exposure to nicotine, glutamatergic (but not GABAergic) transmission onto rat VTA DA neuronal inputs is enhanced. Correspondingly, DA neuronal firing measured 24 h after nicotine exposure using extracellular single unit recording in vivo is significantly faster, and there is conversion of silent to active DA neurons. Collectively, these findings demonstrate that systemic nicotine acting via either alpha7- or beta2*-nAChRs increases presynaptic and postsynaptic glutamatergic function, and consequently initiates glutamatergic synaptic plasticity, which may be an important, early neuronal adaptation in nicotine reward and reinforcement. PMID- 20943924 TI - Analysis of the astray/robo2 zebrafish mutant reveals that degenerating tracts do not provide strong guidance cues for regenerating optic axons. AB - During formation of the optic projection in astray/robo2 mutant zebrafish, optic axons exhibit rostrocaudal pathfinding errors, ectopic midline crossing and increased terminal arbor size. Here we show that these errors persist into adulthood, even when robo2 function is conditionally reduced only during initial formation of the optic projection. Adult errors include massive ectopic optic tracts in the telencephalon. During optic nerve regeneration in astray/robo2 animals, these tracts are not repopulated and ectopic midline crossing is reduced compared with unlesioned mutants. This is despite a comparable macrophage/microglial response and upregulation of contactin1a in oligodendrocytes of entopic and ectopic tracts. However, other errors, such as expanded termination areas and ectopic growth into the tectum, were frequently recommitted by regenerating optic axons. Retinal ganglion cells with regenerating axons reexpress robo2 and expression of slit ligands is maintained in some areas of the adult optic pathway. However, slit expression is reduced rostral and caudal to the chiasm, compared with development and ubiquitous overexpression of Slit2 did not elicit major pathfinding phenotypes. This shows that (1) there is not an efficient correction mechanism for large-scale pathfinding errors of optic axons during development; (2) degenerating tracts do not provide a strong guidance cue for regenerating optic axons in the adult CNS, unlike the PNS; and (3) robo2 is less important for pathfinding of optic axons during regeneration than during development. PMID- 20943925 TI - Coupled noisy spiking neurons as velocity-controlled oscillators in a model of grid cell spatial firing. AB - One of the two primary classes of models of grid cell spatial firing uses interference between oscillators at dynamically modulated frequencies. Generally, these models are presented in terms of idealized oscillators (modeled as sinusoids), which differ from biological oscillators in multiple important ways. Here we show that two more realistic, noisy neural models (Izhikevich's simple model and a biophysical model of an entorhinal cortex stellate cell) can be successfully used as oscillators in a model of this type. When additive noise is included in the models such that uncoupled or sparsely coupled cells show realistic interspike interval variance, both synaptic and gap-junction coupling can synchronize networks of cells to produce comparatively less variable network level oscillations. We show that the frequency of these oscillatory networks can be controlled sufficiently well to produce stable grid cell spatial firing on the order of at least 2-5 min, despite the high noise level. Our results suggest that the basic principles of oscillatory interference models work with more realistic models of noisy neurons. Nevertheless, a number of simplifications were still made and future work should examine increasingly realistic models. PMID- 20943926 TI - Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. AB - Neurons in the brains of those with Alzheimer's disease (AD) and many frontotemporal dementias (FTDs) contain neurofibrillary tangles comprised of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs), and tau misfolding could lead to a loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, a possible therapeutic strategy for AD and related "tauopathies" is treatment with a MT-stabilizing anti cancer drug such as paclitaxel. However, paclitaxel and related taxanes have poor blood-brain barrier permeability and thus are unsuitable for diseases of the brain. We demonstrate here that the MT-stabilizing agent, epothilone D (EpoD), is brain-penetrant and we subsequently evaluated whether EpoD can compensate for tau loss-of-function in PS19 tau transgenic mice that develop forebrain tau inclusions, axonal degeneration and MT deficits. Treatment of 3-month-old male PS19 mice with low doses of EpoD once weekly for a 3 month period significantly improved CNS MT density and axonal integrity without inducing notable side effects. Moreover, EpoD treatment reduced cognitive deficits that were observed in the PS19 mice. These results suggest that certain brain-penetrant MT stabilizing agents might provide a viable therapeutic strategy for the treatment of AD and FTDs. PMID- 20943927 TI - Partial deficiency or short-term inhibition of 11beta-hydroxysteroid dehydrogenase type 1 improves cognitive function in aging mice. AB - 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates active glucocorticoids (GCs) from intrinsically inert 11-keto substrates inside cells, including neurons, thus amplifying steroid action. Excess GC action exerts deleterious effects on the hippocampus and causes impaired spatial memory, a key feature of age-related cognitive dysfunction. Mice with complete deficiency of 11beta-HSD1 are protected from spatial memory impairments with aging. Here, we tested whether lifelong or short-term decreases in 11beta-HSD1 activity are sufficient to alter cognitive function in aged mice. Aged (24 months old) heterozygous male 11beta-HSD1 knock-out mice, with ~60% reduction in hippocampal 11beta-reductase activity throughout life, were protected against spatial memory impairments in the Y-maze compared to age-matched congenic C57BL/6J controls. Pharmacological treatment of aged C57BL/6J mice with a selective 11beta-HSD1 inhibitor (UE1961) for 10 d improved spatial memory performance in the Y-maze (59% greater time in novel arm than vehicle control). These data support the use of selective 11beta-HSD1 inhibitors in the treatment of age-related cognitive impairments. PMID- 20943928 TI - Latent inputs improve estimates of neural encoding in motor cortex. AB - Typically, tuning curves in motor cortex are constructed by fitting the firing rate of a neuron as a function of some observed action, such as arm direction or movement speed. These tuning curves are then often interpreted causally as representing the firing rate as a function of the desired movement, or intent. This interpretation implicitly assumes that the motor command and the motor act are equivalent. However, any kind of perturbation, be it external, such as a visuomotor rotation, or internal, such as muscle fatigue, can create a difference between the motor intent and the action. How do we estimate the tuning curve under these conditions? Furthermore, it is well known that, during learning or adaptation, the relationship between neural firing and the observed movement can change. Does this change indicate a change in the inputs to the population, or a change in the way those inputs are processed? In this work, we present a method to infer the latent, unobserved inputs into the population of recorded neurons. Using data from nonhuman primates performing brain-computer interface experiments, we show that tuning curves based on these latent directions fit better than tuning curves based on actual movements. Finally, using data from a brain-computer interface learning experiment in which half of the units were decoded incorrectly, we demonstrate how this method might differentiate various aspects of motor adaptation. PMID- 20943929 TI - The Gli3 hypomorphic mutation Pdn causes selective impairment in the growth, patterning, and axon guidance capability of the lateral ganglionic eminence. AB - Previous studies have defined a requirement for Sonic hedgehog (Shh) signaling in patterning the ventral telencephalon, a major source of the neuronal diversity found in the mature telencephalon. The zinc finger transcription factor Gli3 is a critical component of the Shh signaling pathway and its loss causes major defects in telencephalic development. Gli3 is expressed in a graded manner along the dorsoventral axis of the telencephalon but it is unknown whether Gli3 expression levels are important for dorsoventral telencephalic patterning. To address this, we used the Gli3 hypomorphic mouse mutant Polydactyly Nagoya (Pdn). We show that in Pdn/Pdn embryos, the telencephalic expression of Gli3 remains graded, but Gli3 mRNA and protein levels are reduced, resulting in an upregulation of Shh expression and signaling. These changes mainly affect the development of the lateral ganglionic eminence (LGE), with some disorganization of the medial ganglionic eminence mantle zone. The pallial/subpallial boundary is shifted dorsally and the production of postmitotic neurons is reduced. Moreover, LGE pioneer neurons that guide corticofugal axons into the LGE do not form properly, delaying the entry of corticofugal axons into the ventral telencephalon. Pdn/Pdn mutants also show severe pathfinding defects of thalamocortical axons in the ventral telencephalon. Transplantation experiments demonstrate that the intrinsic ability of the Pdn ventral telencephalon to guide thalamocortical axons is compromised. We conclude that correct Gli3 levels are particularly important for the LGE's growth, patterning, and development of axon guidance capabilities. PMID- 20943930 TI - Slow degradation and aggregation in vitro of mutant GABAA receptor gamma2(Q351X) subunits associated with epilepsy. AB - The GABA(A) receptor gamma2 subunit nonsense mutation Q351X has been associated with the genetic epilepsy syndrome generalized epilepsy with febrile seizures plus, which includes a spectrum of seizures types from febrile seizures to Dravet syndrome. Although most genetic epilepsy syndromes are mild and remit with age, Dravet syndrome has a more severe clinical course with refractory seizures associated with developmental delay and cognitive impairment. The basis for the broad spectrum of seizure phenotypes is uncertain. We demonstrated previously that the GABA(A) receptor gamma2 subunit gene Q351X mutation suppressed biogenesis of wild-type partnering alpha1 and beta2 subunits in addition to its loss of function. Here we show that gamma2S(Q351X) subunits have an additional impairment of biogenesis. Mutant gamma2(Q351X) subunits were degraded more slowly than wild-type gamma2 subunits and formed SDS-resistant, high-molecular-mass complexes or aggregates in multiple cell types, including neurons. The half-life of gamma2S(Q351X) subunits was ~4 h, whereas that of gamma2S subunits was ~2 h. Mutant subunits formed complexes rapidly after synthesis onset. Using multiple truncated subunits, we demonstrated that aggregate formation was a general phenomenon for truncated gamma2S subunits and that their Cys-loop cysteines were involved in aggregate formation. Protein aggregation is a hallmark of neurodegenerative diseases, but the effects of the mutant gamma2S(Q351X) subunit aggregates on neuronal function and survival are unclear. Additional validation of the mutant subunit aggregation in vivo and determination of the involved signaling pathways will help reveal the pathological effects of these mutant subunit aggregates in the pathogenesis of genetic epilepsy syndromes. PMID- 20943931 TI - Clan mentality: evidence that the medial prefrontal cortex responds to close others. AB - Kinship, friendship alliances, and perceptions of others' beliefs guide social interactions and are central to cohesive group behavior. Under certain conditions, brain systems that involve regions along the frontal midline increase activity when inferences are drawn about others who share a similar view to one's own (similarity). A prominent hypothesis is that these regions contribute to social cognition by simulating the other person's perspective based on one's own experience. An alternative is that certain regions process the social relevance of the person (closeness) to oneself and contribute to the assessment akin to signals that govern behavioral approach responses. These alternatives were explored across four functional magnetic resonance imaging experiments (n = 98). Experiment 1 localized the target midline regions in the rostral anterior cingulate cortex and anterior medial prefrontal cortex by having participants make personal judgments. The two dimensions (similarity, closeness) were crossed in experiment 2 using actual friends of the participant and unknown others. Making judgments about oneself and friends resulted in increased midline response relative to unknown others regardless of whether the friends shared similar views as the participant. Experiment 3 revealed that similarity was not a factor even when close others were not included. Experiment 4 directly contrasted two extremes: participants made inferences about similar, unknown others and dissimilar friends. Judgments about the close others again increased blood oxygenation level-dependent response along the frontal midline. These results encourage further exploration of the idea that frontal systems linked with limbic circuits facilitate assessment of the relevance or personal significance in social contexts. PMID- 20943932 TI - Prospective cohort study of breast implants and the risk of connective-tissue diseases. AB - BACKGROUND: A 2000 meta-analysis indicated no overall association between breast implants and risk of connective-tissue diseases (CTDs). However, a large retrospective cohort study we previously conducted suggested, instead, a small increased risk of CTDs. Because of limitations inherent to the retrospective cohort study design, we sought clarification by conducting a prospective cohort study of the association of breast implants with CTD risk. METHODS: Participants were 23 847 US women (mean age 56.6 years), 3950 of whom had breast implants and 19 897 did not. Women reported their breast implant status at baseline in 2001 and were followed for a median of 3.63 years. During follow-up, women reported incident CTD, confirmed using a CTD screening questionnaire (CSQ) and medical records. RESULTS: In multivariate analyses, the rate ratios for self-reported CTD (113 vs 377 cases in the implanted and non-implanted group, respectively) were 1.60 [95% confidence interval (CI) 1.28-2.00], for CSQ-confirmed CTD (77 vs 226 cases), 1.80 (1.37-2.38) and for medical record confirmed CTD (21 vs 74 cases), 1.39 (0.82-2.35). CONCLUSIONS: Although this prospective cohort study represented a stronger design than the retrospective cohort study, the present data should still be viewed cautiously because of remaining methodological limitations, including the potential for differential self-reporting of CTD and CTD symptoms among women with and without breast implants, the difficulty of obtaining medical records for women reporting CTD and the low and possibly differential confirmation of self-reported disease against medical records. A reasonable conclusion is the lack of a large increase in CTD risk (e.g. >=2-fold) associated with breast implants. PMID- 20943933 TI - Child abuse in 28 developing and transitional countries--results from the Multiple Indicator Cluster Surveys. AB - BACKGROUND: Child abuse is a recognized public health and social problem worldwide. Using data from the Multiple Indicator Cluster Surveys (MICS) we aimed to (i) compare different forms of child abuse across countries and regions, and (ii) examine factors associated with different forms of child abuse. METHODS: Information on child abuse was available in 28 developing and transitional countries from the third round of the MICS conducted in 2005 and 2006 (n = 124 916 children aged between 2 and 14 years). We determined the prevalence of psychological, and moderate and severe physical abuse for the preceding month and examined correlates of different forms of child abuse with multilevel logistic regression analysis. RESULTS: A median of 83, 64 and 43% of children in the African region experienced psychological, and moderate and severe physical abuse, respectively. A considerably lower percentage of children in transitional countries experienced these forms of abuse (56, 46 and 9%, respectively). Parental attitudes towards corporal punishment were the strongest variable associated with all forms of child abuse. The risk of all forms of child abuse was also higher for male children, those living with many household members and in poorer families. CONCLUSIONS: Child abuse is a very common phenomenon in many of the countries examined. We found substantial variations in prevalence across countries and regions, with the highest prevalence in African countries. Population-based interventions (e.g. educational programmes) should be undertaken to increase public awareness of this problem. Actions on changing parental attitudes towards corporal punishment of children may help to prevent child abuse. The specific local situation in each country should be considered when selecting intervention strategies. PMID- 20943934 TI - Renal function and vasomotor activity in mice lacking the Cyp4a14 gene. AB - The production of 20-hydroxyeicosatetraenoic acid (20-HETE) in the kidney is thought to be involved in the control of renal vascular tone and tubular sodium and chloride reabsorption. Cytochrome (Cyp) P-450 enzymes of the Cyp4a family in the mouse, namely 4a10, -12 and 14, are involved in 20-HETE synthesis. Recent advances in the molecular genetics of the mouse have produced mice in which Cyp4a isoforms have been disrupted and the consequence of such an approach is examined. This study evaluated the effect of deletion of the Cyp4a14 gene on blood pressure, renal vascular responses and tubular function. When compared with the wild-type (WT) litter mates, systolic blood pressure was greater in Cyp4a14 null (KO) mice as were renal vascular responses to angiotensin II or phenyephrine, G protein-coupled receptor (GPCR) agonists, but not KCl, a non-GPCR agonist. Renal vascular responses to guanosine 5'-O-(gamma-thio)triphosphate, a non-hydrolyzable GTP analog, or NaF(4), an activator of G-proteins, were also enhanced. However, vasodilation to bradykinin or apocynin but not sodium nitroprusside was blunted in Cyp4a14 null (KO) kidneys. These changes in KO mice were accompanied by increased 20-HETE synthesis, reduced renal production of nitric oxide (NO), increased lipid hydroperoxides and increased apocynin-inhibitable vascular NADPH oxidase activity that was prevented by administration of NO synthase (NOS) inhibitor, suggesting endothelial nitric oxide synthase (eNOS) uncoupling. Cyp4a14 KO mice also exhibited a diminished capacity to excrete an acute sodium load (0.9% NaCl, 2.5 mL/kg). These data suggest that deletion of the Cyp4a gene conferred a prohypertensive status via mechanisms involving increased 20-HETE synthesis and eNOS uncoupling leading to increased oxidative stress, enhanced vasoconstriction but diminished vasodilation as well as a defect in the renal excretory capacity in Cyp4a14 KO mice. These mechanisms suggest that the Cyp4a14 deficient mouse may be a useful model for evaluation of NO/20-HETE interactions. PMID- 20943935 TI - In the nose of the beholder: are olfactory influences on human mate choice driven by variation in immune system genes or sex hormone levels? AB - The human leukocyte antigen (HLA) is the most polymorphic region of the genome, coding for proteins that mediate human immune response. This polymorphism may be maintained by balancing selection and certain populations show deviations from expected gene frequencies. Supporting this hypothesis, studies into olfactory preferences have suggested that females prefer the scent of males with dissimilar HLA to their own. However, it has also been proposed that androstenones play a role in female mate choice, and as these molecules inhibit the immune system, this has implications for the theory of HLA-driven mate preference. This review will critically analyze the findings of studies investigating olfactory preference in humans, and their implications for these two contrasting theories of mate choice. PMID- 20943936 TI - In the mood for adaptation: how affect regulates conflict-driven control. AB - Cognitive conflict plays an important role in tuning cognitive control to the situation at hand. On the basis of earlier findings demonstrating emotional modulations of conflict processing, we predicted that affective states may adaptively regulate goal-directed behavior that is driven by conflict. We tested this hypothesis by measuring conflict-driven control adaptations following experimental induction of four different mood states that could be differentiated along the dimensions of arousal and pleasure. After mood states were induced, 91 subjects performed a flanker task, which provided a measure of conflict adaptation. As predicted, pleasure level affected conflict adaptation: Less pleasure was associated with more conflict-driven control. Arousal level did not influence conflict adaptation. This study suggests that affect adaptively regulates cognitive control. Implications for future research and psychopathology are discussed. PMID- 20943937 TI - Culturally contingent situated cognition: influencing other people fosters analytic perception in the United States but not in Japan. AB - Interpersonal influence and interpersonal adjustment play crucial roles in structuring social interactions. However, not much is known about whether their consequences are culturally contingent. We hypothesized that in order to effectively influence others, people need to employ a perceptual style that serves their cultural imperative. Specifically, we predicted that in the United States, interpersonal influence fosters an analytic, context-independent perceptual style that helps people focus on their goal; however, in Japan, where the cultural imperative is to attend to other people and fit into social contexts, this pattern may be absent or reversed. In two studies, we tested this hypothesis by measuring interpersonal interactions (Study 1) and then by manipulating interpersonal interactions (Study 2). Overall, the findings support a culturally contingent situated-cognition approach, which highlights not only interpersonal underpinnings of perceptual styles but also the role that culture plays in ascribing meaning to interpersonal interactions. PMID- 20943938 TI - Border bias: the belief that state borders can protect against disasters. AB - In this research, we documented a bias in which people underestimate the potential risk of a disaster to a target location when the disaster spreads from a different state, but not when it spreads from an equally distant location within the same state. We term this the border bias. Following research on categorization, we propose that people consider locations within a state to be part of the same superordinate category, but consider locations in two different states to be parts of different superordinate categories. The border bias occurs because people apply state-based categorization to events that are not governed by human-made boundaries. Such categorization results in state borders being considered physical barriers that can keep disasters at bay. We demonstrated the border bias for different types of disasters (earthquake, environmental risk) and tested the underlying process in three studies. PMID- 20943939 TI - When in doubt, shout! paradoxical influences of doubt on proselytizing. AB - A seminal case study by Festinger found, paradoxically, that evidence that disconfirmed religious beliefs increased individuals' tendency to proselytize to others. Although this finding is renowned, surprisingly, it has never been subjected to experimental scrutiny and is open to multiple interpretations. We examined a general form of the question first posed by Festinger, namely, how does shaken confidence influence advocacy? Across three experiments, people whose confidence in closely held beliefs was undermined engaged in more advocacy of their beliefs (as measured by both advocacy effort and intention to advocate) than did people whose confidence was not undermined. The effect was attenuated when individuals affirmed their beliefs, and was moderated by both importance of the belief and open-mindedness of a message recipient. These findings not only have implications for the results of Festinger's seminal study, but also offer new insights into people's motives for advocating their beliefs. PMID- 20943940 TI - Neuronal gap junctions are required for NMDA receptor-mediated excitotoxicity: implications in ischemic stroke. AB - N-methyl-D-aspartate receptors (NMDARs) play an important role in cell survival versus cell death decisions during neuronal development, ischemia, trauma, and epilepsy. Coupling of neurons by electrical synapses (gap junctions) is high or increases in neuronal networks during all these conditions. In the developing CNS, neuronal gap junctions are critical for two different types of NMDAR dependent cell death. However, whether neuronal gap junctions play a role in NMDAR-dependent neuronal death in the mature CNS was not known. Using Fluoro-Jade B staining, we show that a single intraperitoneal administration of NMDA (100 mg/kg) to adult wild-type mice induces neurodegeneration in three forebrain regions, including rostral dentate gyrus. However, the NMDAR-mediated neuronal death is prevented by pharmacological blockade of neuronal gap junctions (with mefloquine, 30 mg/kg) and does not occur in mice lacking neuronal gap junction protein, connexin 36. Using Western blots, electrophysiology, calcium imaging, and gas chromatography-mass spectrometry in wild-type and connexin 36 knockout mice, we show that the reduced level of neuronal death in knockout animals is not caused by the reduced expression of NMDARs, activity of NMDARs, or permeability of the blood-brain barrier to NMDA. In wild-type animals, this neuronal death is not caused by upregulation of connexin 36 by NMDA. Finally, pharmacological and genetic inactivation of neuronal gap junctions in mice also dramatically reduces neuronal death caused by photothrombotic focal cerebral ischemia. The results indicate that neuronal gap junctions are required for NMDAR-dependent excitotoxicity and play a critical role in ischemic neuronal death. PMID- 20943941 TI - Role of neuronal synchrony in the generation of evoked EEG/MEG responses. AB - Evoked EEG/MEG responses are a primary real-time measure of perceptual and cognitive activity in the human brain, but their neuronal generator mechanisms are not yet fully understood. Arguments have been put forward in favor of either "phase-reset" of ongoing oscillations or "added-energy" models. Instead of advocating for one or the other model, here we show theoretically that the differentiation between these two generation mechanisms might not be possible if based solely on macroscopic EEG/MEG recordings. Using mathematical modeling, we show that a simultaneous phase reset of multiple oscillating neuronal (microscopic) sources contributing to EEG/MEG can produce evoked responses in agreement with both, the "added-energy" and the "phase-reset" model. We observe a smooth transition between the two models by just varying the strength of synchronization between the multiple microscopic sources. Consequently, because precise knowledge about the strength of microscopic ensemble synchronization is commonly not available in noninvasive EEG/MEG studies, they cannot, in principle, differentiate between the two mechanisms for macroscopic-evoked responses. PMID- 20943943 TI - Time course of information representation of macaque AIP neurons in hand manipulation task revealed by information analysis. AB - We used mutual information analysis of neuronal activity in the macaque anterior intraparietal area (AIP) to examine information processing during a hand manipulation task. The task was to reach-to-grasp a three-dimensional (3D) object after presentation of a go signal. Mutual information was calculated between the spike counts of individual neurons in 50-ms-wide time bins and six unique shape classifications or 15 one-versus-one classifications of these shapes. The spatiotemporal distribution of mutual information was visualized as a two dimensional image ("information map") to better observe global profiles of information representation. In addition, a nonnegative matrix factorization technique was applied for extracting its structure. Our major finding was that the time course of mutual information differed significantly according to different classes of task-related neurons. This strongly suggests that different classes of neurons were engaged in different information processing stages in executing the hand manipulation task. On the other hand, our analysis revealed the heterogeneous nature of information representation of AIP neurons. For example, "information latency" (or information onset) varied among individual neurons even in the same neuron class and the same shape classification. Further, some neurons changed "information preference" (i.e., shape classification with the largest amount of information) across different task periods. These suggest that neurons encode different information in the different task periods. Taking the present result together with previous findings, we used a Gantt chart to propose a hypothetical scheme of the dynamic interactions between different types of AIP neurons. PMID- 20943942 TI - Bilateral adaptation during locomotion following a unilaterally applied resistance to swing in nondisabled adults. AB - Human walking must be flexible enough to accommodate many contexts and goals. One form of this flexibility is locomotor adaptation: a practice-dependent alteration to walking occurring in response to some novel perturbing stimulus. Although studies have examined locomotor adaptation and its storage by the CNS in humans, it remains unclear whether altered movements occurring in the leg contralateral to a perturbation are caused by true practice-dependent adaptation or whether they are generated via feedback corrective mechanisms. To test this, we recorded leg kinematics and electromyography (EMG) from nondisabled adults as they walked on a treadmill before, during, and after a novel force was applied to one leg, which resisted its forward movement during swing phase. The perturbation produced kinematic changes to numerous walking parameters, including swing phase durations, step lengths, and hip angular excursions. Nearly all occurred bilaterally. Importantly, kinematic changes were gradually adjusted over a period of exposure to the perturbation and were associated with negative aftereffects on its removal, suggesting they were adjusted through a true motor adaptation process. In addition, increases in the EMG of both legs persisted even after the perturbation was removed, providing further evidence that the CNS made and stored changes to feedforward motor commands controlling each leg. Our results show evidence for a feedforward adaptation of walking involving the leg opposite a perturbation. This result may help support the application of locomotor adaptation paradigms in clinical rehabilitation interventions targeting recovery of symmetric walking patterns in a variety of patient populations. PMID- 20943944 TI - Handedness, dexterity, and motor cortical representations. AB - Motor system organization varies with handedness. However, previous work has focused almost exclusively on direction of handedness (right or left) as opposed to degree of handedness (strength). In the present study, we determined whether measures of interhemispheric interactions and degree of handedness are related to contra- and ipsilateral motor cortical representations. Participants completed a battery of handedness assessments including both handedness preference measures and behavioral measures of intermanual differences in dexterity, a computerized version of the Poffenberger paradigm (PP) to estimate interhemispheric transfer time (IHTT), and they underwent transcranial magnetic stimulation (TMS) mapping of both motor cortices while we recorded muscle activity from the first dorsal interosseous muscle bilaterally. A greater number of ipsilateral motor evoked potentials (iMEPs) were elicited in less lateralized individuals with the number of iMEPs correlated with IHTT. There were no relationships between handedness or lateralization of dexterity and symmetry of contralateral motor representations, although this symmetry was related to IHTT. Finally, IHTT was positively correlated with multiple measures of laterality and handedness. These findings demonstrate that degree of laterality of dexterity is related to the propensity for exhibiting iMEPs and the speed of interhemispheric interactions. However, it is not clear whether iMEPs are directly mediated via ipsilateral corticospinal projections or are transcallosally transmitted. PMID- 20943945 TI - A closed-loop human simulator for investigating the role of feedback control in brain-machine interfaces. AB - Neural prosthetic systems seek to improve the lives of severely disabled people by decoding neural activity into useful behavioral commands. These systems and their decoding algorithms are typically developed "offline," using neural activity previously gathered from a healthy animal, and the decoded movement is then compared with the true movement that accompanied the recorded neural activity. However, this offline design and testing may neglect important features of a real prosthesis, most notably the critical role of feedback control, which enables the user to adjust neural activity while using the prosthesis. We hypothesize that understanding and optimally designing high-performance decoders require an experimental platform where humans are in closed-loop with the various candidate decode systems and algorithms. It remains unexplored the extent to which the subject can, for a particular decode system, algorithm, or parameter, engage feedback and other strategies to improve decode performance. Closed-loop testing may suggest different choices than offline analyses. Here we ask if a healthy human subject, using a closed-loop neural prosthesis driven by synthetic neural activity, can inform system design. We use this online prosthesis simulator (OPS) to optimize "online" decode performance based on a key parameter of a current state-of-the-art decode algorithm, the bin width of a Kalman filter. First, we show that offline and online analyses indeed suggest different parameter choices. Previous literature and our offline analyses agree that neural activity should be analyzed in bins of 100- to 300-ms width. OPS analysis, which incorporates feedback control, suggests that much shorter bin widths (25-50 ms) yield higher decode performance. Second, we confirm this surprising finding using a closed-loop rhesus monkey prosthetic system. These findings illustrate the type of discovery made possible by the OPS, and so we hypothesize that this novel testing approach will help in the design of prosthetic systems that will translate well to human patients. PMID- 20943946 TI - Subset of thin spike cortical neurons preserve the peripheral encoding of stimulus onsets. AB - An important question in auditory neuroscience concerns how the neural representation of sound features changes from the periphery to the cortex. Here we focused on the encoding of sound onsets and we used a modeling approach to explore the degree to which auditory cortical neurons follow a similar envelope integration mechanism found at the auditory periphery. Our "forward" model was able to predict relatively accurately the timing of first spikes evoked by natural communication calls in the auditory cortex of awake, head-restrained mice, but only for a subset of cortical neurons. These neurons were systematically different in their encoding of the calls, exhibiting less call selectivity, shorter latency, greater precision, and more transient spiking compared with the same factors of their poorly predicted counterparts. Importantly, neurons that fell into this best-predicted group all had thin spike waveforms, suggestive of suspected interneurons conveying feedforward inhibition. Indeed, our population of call-excited thin spike neurons had significantly higher spontaneous rates and larger frequency tuning bandwidths than those of thick spike neurons. Thus the fidelity of our model's first spike predictions segregated neurons into one earlier responding subset, potentially dominated by suspected interneurons, which preserved a peripheral mechanism for encoding sound onsets and another longer latency subset that reflected higher, likely centrally constructed nonlinearities. These results therefore provide support for the hypothesis that physiologically distinct subclasses of neurons in the auditory cortex may contribute hierarchically to the representation of natural stimuli. PMID- 20943947 TI - Inhibitory and disinhibitory effects on I-wave facilitation in motor cortex. AB - A suprathreshold pulse of transcranial magnetic stimulation (TMS) delivered to human motor cortex results in a period of long-interval intracortical inhibition (LICI) followed by a briefer period of disinhibition (late cortical disinhibition [LCD]). Short-interval intracortical facilitation (SICF) is mediated by excitatory networks in the motor cortex responsible for the generation of the indirect (I-) wave volleys that are evoked by TMS at a periodicity of about 1.5 ms. Because the excitatory synaptic network responsible for SICF undergoes inhibitory regulation, we hypothesized that SICF will be modulated during periods of inhibition and disinhibition. In particular we were interested to know whether SICF was up-regulated during disinhibition, implying an increase in excitatory synaptic efficacy. We measured SICF, at a paired-pulse interval of 1.5 ms, at various times (100-300 ms) after a suprathreshold priming stimulus (PS) of sufficient strength to evoke LICI and LCD. We found that the strength of SICF was normal during LICI, but was increased during LCD by an average of 64%. SICF onset latency was reduced by one I-wave interval during LCD and was delayed by one I wave interval during LICI. We conclude that disinhibition, rather than inhibition, modulates the excitatory neuronal networks that underlie SICF, whereas the I-wave targeted is modified by the presence of both inhibition and disinhibition and that there is therefore a dissociation between the strength and site of SICF interaction. The increase in SICF during disinhibition further indicates that this is a promising period to investigate or modulate excitatory synaptic networks while they are less constrained by ongoing levels of inhibition. PMID- 20943948 TI - c-Src-mediated phosphorylation of NoxA1 and Tks4 induces the reactive oxygen species (ROS)-dependent formation of functional invadopodia in human colon cancer cells. AB - The NADPH oxidase family, consisting of Nox1-5 and Duox1-2, catalyzes the regulated formation of reactive oxygen species (ROS). Highly expressed in the colon, Nox1 needs the organizer subunit NoxO1 and the activator subunit NoxA1 for its activity. The tyrosine kinase c-Src is necessary for the formation of invadopodia, phosphotyrosine-rich structures which degrade the extracellular matrix (ECM). Many Src substrates are invadopodia components, including the novel Nox1 organizer Tks4 and Tks5 proteins. Nox1-dependent ROS generation is necessary for the maintenance of functional invadopodia in human colon cancer cells. However, the signals and the molecular machinery involved in the redox-dependent regulation of invadopodia formation remain unclear. Here, we show that the interaction of NoxA1 and Tks proteins is dependent on Src activity. Interestingly, the abolishment of Src-mediated phosphorylation of Tyr110 on NoxA1 and of Tyr508 on Tks4 blocks their binding and decreases Nox1-dependent ROS generation. The contemporary presence of Tks4 and NoxA1 unphosphorylable mutants blocks SrcYF-induced invadopodia formation and ECM degradation, while the overexpression of Tks4 and NoxA1 phosphomimetic mutants rescues this phenotype. Taken together, these results elucidate the role of c-Src activity on the formation of invadopodia and may provide insight into the mechanisms of tumor formation in colon cancers. PMID- 20943950 TI - Rubicon and PLEKHM1 negatively regulate the endocytic/autophagic pathway via a novel Rab7-binding domain. AB - The endocytic and autophagic pathways are involved in the membrane trafficking of exogenous and endogenous materials to lysosomes. However, the mechanisms that regulate these pathways are largely unknown. We previously reported that Rubicon, a Beclin 1-binding protein, negatively regulates both the autophagic and endocytic pathways by unidentified mechanisms. In this study, we performed database searches to identify potential Rubicon homologues that share the common C-terminal domain, termed the RH domain. One of them, PLEKHM1, the causative gene of osteopetrosis, also suppresses endocytic transport but not autophagosome maturation. Rubicon and PLEKHM1 specifically and directly interact with Rab7 via their RH domain, and this interaction is critical for their function. Furthermore, we show that Rubicon but not PLEKHM1 uniquely regulates membrane trafficking via simultaneously binding both Rab7 and PI3-kinase. PMID- 20943949 TI - AS160 associates with the Na+,K+-ATPase and mediates the adenosine monophosphate stimulated protein kinase-dependent regulation of sodium pump surface expression. AB - The Na(+),K(+)-ATPase is the major active transport protein found in the plasma membranes of most epithelial cell types. The regulation of Na(+),K(+)-ATPase activity involves a variety of mechanisms, including regulated endocytosis and recycling. Our efforts to identify novel Na(+),K(+)-ATPase binding partners revealed a direct association between the Na(+),K(+)-ATPase and AS160, a Rab GTPase-activating protein. In COS cells, coexpression of AS160 and Na(+),K(+) ATPase led to the intracellular retention of the sodium pump. We find that AS160 interacts with the large cytoplasmic NP domain of the alpha-subunit of the Na(+),K(+)-ATPase. Inhibition of the activity of the adenosine monophosphate stimulated protein kinase (AMPK) in Madin-Darby canine kidney cells through treatment with Compound C induces Na(+),K(+)-ATPase endocytosis. This effect of Compound C is prevented through the short hairpin RNA-mediated knockdown of AS160, demonstrating that AMPK and AS160 participate in a common pathway to modulate the cell surface expression of the Na(+),K(+)-ATPase. PMID- 20943951 TI - Arsenic-induced SUMO-dependent recruitment of RNF4 into PML nuclear bodies. AB - In acute promyelocytic leukemia (APL), the promyelocytic leukemia (PML) protein is fused to the retinoic acid receptor alpha (RAR). Arsenic is an effective treatment for this disease as it induces SUMO-dependent ubiquitin-mediated proteasomal degradation of the PML-RAR fusion protein. Here we analyze the nuclear trafficking dynamics of PML and its SUMO-dependent ubiquitin E3 ligase, RNF4 in response to arsenic. After administration of arsenic, PML immediately transits into nuclear bodies where it undergoes SUMO modification. This initial recruitment of PML into nuclear bodies is not dependent on RNF4, but RNF4 quickly follows PML into the nuclear bodies where it is responsible for ubiquitylation of SUMO-modified PML and its degradation by the proteasome. While arsenic restricts the mobility of PML, FRAP analysis indicates that RNF4 continues to rapidly shuttle into PML nuclear bodies in a SUMO-dependent manner. Under these conditions FRET studies indicate that RNF4 interacts with SUMO in PML bodies but not directly with PML. These studies indicate that arsenic induces the rapid reorganization of the cell nucleus by SUMO modification of nuclear body associated PML and uptake of the ubiquitin E3 ligase RNF4 leading to the ubiquitin-mediated degradation of PML. PMID- 20943952 TI - Cell death or survival promoted by alternative isoforms of ErbB4. AB - The significance of ErbB4 in tumor biology is poorly understood. The ERBB4 gene is alternatively spliced producing juxtamembrane (JM-a and JM-b) and cytoplasmic (CYT-1 and CYT-2) isoforms. Here, signaling via the two alternative ErbB4 JM isoforms (JM-a CYT-2 and JM-b CYT-2) was compared. Fibroblasts expressing ErbB4 JM-a demonstrated enhanced ErbB4 autophosphorylation, growth, and survival. In contrast, cells overexpressing ErbB4 JM-b underwent starvation-induced death. Both pro- and antisurvival responses to the two ErbB4 isoforms were sensitive to an ErbB kinase inhibitor. Platelet-derived growth factor receptor-alpha (PDGFRA) was identified as an ErbB4 target gene that was differentially regulated by the two ErbB4 isoforms. The soluble intracellular domain of ErbB4, released from the JM-a but not from the JM-b isoform, associated with the transcription factor AP-2 and promoted its potential to enhance PDGFRA transcription. Survival of cells expressing JM-a was suppressed by targeting either PDGFR-alpha or AP-2, whereas cells expressing JM-b were rescued from cell death by the PDGFR-alpha agonist, PDGF-BB. These findings indicate that two alternative ErbB4 isoforms may promote antagonistic cellular responses and suggest that pharmacological inhibition of ErbB4 kinase activity may lead to either suppression or promotion of cellular growth. PMID- 20943954 TI - Soy protein reduces serum cholesterol by both intrinsic and food displacement mechanisms. AB - The apparently smaller LDL cholesterol (LDL-C)-lowering effect of soy in recent studies has prompted the U.S. FDA to reexamine the heart health claim previously allowed for soy products. We therefore attempted to estimate the intrinsic and extrinsic (displacement) potential of soy in reducing LDL-C to determine whether the heart health claim for soy continues to be justified. The intrinsic effect of soy was derived from a meta-analysis using soy studies (20-133 g/d soy protein) included in the recent AHA Soy Advisory. The extrinsic effect of soy in displacing foods higher in saturated fat and cholesterol was estimated using predictive equations for LDL-C and NHANES III population survey data with the substitution of 13-58 g/d soy protein for animal protein foods. The meta-analysis of the AHA Soy Advisory data gave a mean LDL-C reduction of 0.17 mmol/L (n = 22; P < 0.0001) or 4.3% for soy, which was confirmed in 11 studies reporting balanced macronutrient profiles. The estimated displacement value of soy (13-58 g/d) using NHANES III population survey data was a 3.6-6.0% reduction in LDL-C due to displacement of saturated fats and cholesterol from animal foods. The LDL-C reduction attributable to the combined intrinsic and extrinsic effects of soy protein foods ranged from 7.9 to 10.3%. Thus, soy remains one of a few food components that reduces serum cholesterol (>4%) when added to the diet. PMID- 20943953 TI - Microautophagy of the nucleus coincides with a vacuolar diffusion barrier at nuclear-vacuolar junctions. AB - Nuclei bind yeast vacuoles via nucleus-vacuole (NV) junctions. Under nutrient restriction, NV junctions invaginate and release vesicles filled with nuclear material into vacuoles, resulting in piecemeal microautophagy of the nucleus (PMN). We show that the electrochemical gradient across the vacuolar membrane promotes invagination of NV junctions. Existing invaginations persist independently of the gradient, but final release of PMN vesicles requires again V ATPase activity. We find that NV junctions form a diffusion barrier on the vacuolar membrane that excludes V-ATPase but is enriched in the VTC complex and accessible to other membrane-integral proteins. V-ATPase exclusion depends on the NV junction proteins Nvj1p,Vac8p, and the electrochemical gradient. It also depends on factors of lipid metabolism, such as the oxysterol binding protein Osh1p and the enoyl-CoA reductase Tsc13p, which are enriched in NV junctions, and on Lag1p and Fen1p. Our observations suggest that NV junctions form in two separable steps: Nvj1p and Vac8p suffice to establish contact between the two membranes. The electrochemical potential and lipid-modifying enzymes are needed to establish the vacuolar diffusion barrier, invaginate NV junctions, and form PMN vesicles. PMID- 20943955 TI - Effects of fructo-oligosaccharide on DSS-induced colitis differ in mice fed nonpurified and purified diets. AB - We investigated whether feeding a purified compared with nonpurified diet supplemented with or without fructo-oligosaccharide (FOS; 50 g/kg diet) altered the response of C57BL/6 mice to DSS-induced diarrhea. In Expt. 1, we examined disease severity in mice receiving DSS (2% in drinking water) for 5 d. In Expt. 2, we measured cecal organic acid concentrations and fecal water-holding capacity (WHC). In Expts. 3 and 4, we tested whether polycarbophil calcium (PC), a water absorbing polymer, altered fecal WHC and disease severity. FOS exacerbated diarrhea and weight loss in mice fed the purified diet and reduced fecal bleeding in mice fed the nonpurified diet (P < 0.05). Without DSS administration, cecal acetate and butyrate concentrations were higher in mice fed the nonpurified diet than in mice fed the purified diet (P < 0.05). Fecal WHC was higher in mice fed the nonpurified diet than in mice fed the purified diet (P < 0.05). One day after starting DSS administration, cecal succinate concentrations were higher in mice fed the FOS-supplemented purified diet than in mice fed the other 3 diets, whereas SCFA concentrations were higher in mice fed the nonpurified diet than in mice fed the purified diet (P < 0.05). PC supplementation increased fecal WHC and prevented FOS exacerbation of diarrhea in mice fed the purified diet (P < 0.05). We conclude that the effects of FOS on DSS-induced diarrhea differ in mice fed the purified and nonpurified diets. The protective effect of nonpurified diet was associated with increased production of organic acids and WHC in the intestinal contents. PMID- 20943956 TI - Plasma zinc concentration responds rapidly to the initiation and discontinuation of short-term zinc supplementation in healthy men. AB - To assist with the evaluation of zinc (Zn) intervention programs, information is needed on the magnitude and velocity of response of plasma Zn concentration following changes in Zn intake. Our objective in this study was to measure plasma Zn concentration of healthy adult men before and after initiation and discontinuation of 1 of 2 dosages of Zn supplements or placebo. We conducted a randomized, double-blind, placebo-controlled trial in 58 apparently healthy males aged 19-54 y. Participants received 1 of 3 liquid supplements daily for 21 d: 10 or 20 mg Zn/d, as Zn sulfate, or placebo. Fasting plasma Zn concentrations were measured on 14 occasions before, during, and after supplementation. Data were analyzed using mixed-model ANCOVA. The plasma Zn concentration was related to day of study (P < 0.0001) and study group (P < 0.0001). Controlling for baseline concentrations, plasma Zn concentrations were consistently elevated above baseline by d 5 among individuals in both of the Zn-supplemented groups compared with those receiving placebo supplements, regardless of their initial plasma Zn concentration. There were no significant group-wise differences between those who received either 10 or 20 mg/d Zn. Plasma Zn concentrations of supplemented individuals declined following withdrawal of supplementation and within 2 wk no longer differed from those of the placebo group. Change in the plasma Zn concentration is a useful indicator to monitor compliance with, and possibly effectiveness of, Zn supplementation programs. To ensure accurate interpretation of the results, samples should be collected while the intervention is still in progress. PMID- 20943957 TI - Antifibrotic properties of c-Ski and its regulation of cardiac myofibroblast phenotype and contractility. AB - Cardiac myofibroblasts are key players in chronic remodeling of the cardiac extracellular matrix, which is mediated in part by elevated transforming growth factor-beta1 (TGF-beta1). The c-Ski proto-oncoprotein has been shown to modify TGF-beta1 post-receptor signaling through receptor-activated Smads (R-Smads); however, little is known about how c-Ski regulates fibroblast phenotype and function. We sought to elucidate the function of c-Ski in primary cardiac myofibroblasts using a c-Ski overexpression system. Cardiac myofibroblasts expressed three forms of c-Ski with the predominant band at 105 kDa, and adenoviral c-Ski treatment resulted in overexpression of 95-kDa c-Ski in cellular nuclei. Exogenous c-Ski led to significant inhibition of type I collagen secretion and myofibroblast contractility using two-dimensional semifloating gel contraction assay in both basal and with TGF-beta1 (10 ng/ml for 24 h) stimulation. Overexpressed c-Ski did not inhibit nuclear translocation of phosphorylated R-Smad2, despite their binding, as demonstrated by immunoprecipitation. Acute treatment of primary myofibroblasts with TGF-beta1 in vitro revealed a marked nuclear shuttling of c-Ski at 24 and 48 h following stimulation. Remarkably, overexpression of c-Ski led to a stepwise reduction of the myofibroblast marker alpha-smooth muscle actin with increasing multiplicity of infection, and these results indicate that 95-kDa c-Ski overexpression may effect a loss of the myofibroblastic phenotype. Furthermore, adenovirus (Ad) for hemagglutinin-tagged c-Ski infection led to a reduction in the number of myofibroblasts versus Ad-LacZ-infected and uninfected controls, due to induction of apoptosis. Finally, we observed a significant increase in 105-kDa c-Ski in the cytosolic fraction of cells of the infarct scar and adjacent remnant myocardium vs. noninfarcted controls. PMID- 20943958 TI - Cystathionine beta-synthase and cystathionine gamma-lyase double gene transfer ameliorate homocysteine-mediated mesangial inflammation through hydrogen sulfide generation. AB - Elevated level of homocysteine (Hcy) induces chronic inflammation in vascular bed, including glomerulus, and promotes glomerulosclerosis. In this study we investigated in vitro mechanism of Hcy-mediated monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) induction and determined the regulatory role of hydrogen sulfide (H2S) to ameliorate inflammation. Mouse glomerular mesangial cells (MCs) were incubated with Hcy (75 MUM) and supplemented with vehicle or with H2S (30 MUM, in the form of NaHS). Inflammatory molecules MCP-1 and MIP-2 were measured by ELISA. Cellular capability to generate H2S was measured by colorimetric chemical method. To enhance endogenous production of H2S and better clearance of Hcy, cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE) genes were delivered to the cells. Oxidative NAD(P)H p47(phox) was measured by Western blot analysis and immunostaining. Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase (JNK1/2) were measured by Western blot analysis. Our results demonstrated that Hcy upregulated inflammatory molecules MCP-1 and MIP-2, whereas endogenous production of H2S was attenuated. H2S treatment as well as CBS and CSE doubly cDNA overexpression markedly reduced Hcy-induced upregulation of MCP-1 and MIP-2. Hcy-induced upregulation of oxidative p47(phox) was attenuated by H2S supplementation and CBS/CSE overexpression as well. In addition to that we also detected Hcy-induced MCP-1 and MIP-2 induction was through phosphorylation of ERK1/2 and JNK1/2. Either H2S supplementation or CBS and CSE doubly cDNA overexpression attenuated Hcy-induced phosphorylation of these two signaling molecules and diminished MCP-1 and MIP-2 expressions. Similar results were obtained by inhibition of ERK1/2 and JNK1/2 using pharmacological and small interferring RNA (siRNA) blockers. We conclude that H2S plays a regulatory role in Hcy-induced mesangial inflammation and that ERK1/2 and JNK1/2 are two signaling pathways involved this process. PMID- 20943959 TI - Adipogenic and lipolytic effects of chronic glucocorticoid exposure. AB - Glucocorticoids have been proposed to be both adipogenic and lipolytic in action within adipose tissue, although it is unknown whether these actions can occur simultaneously. Here we investigate both the in vitro and in vivo effects of corticosterone (Cort) on adipose tissue metabolism. Cort increased 3T3-L1 preadipocyte differentiation in a concentration-dependent manner, but did not increase lipogenesis in adipocytes. Cort increased lipolysis within adipocytes in a concentration-dependent manner (maximum effect at 1-10 MUM). Surprisingly, removal of Cort further increased lipolytic rates (~320% above control, P < 0.05), indicating a residual effect on basal lipolysis. mRNA and protein expression of adipose triglyceride lipase and phosphorylated status of hormone sensitive lipase (Ser563/Ser660) were increased with 48 h of Cort treatment. To test these responses in vivo, Sprague-Dawley rats were subcutaneously implanted with wax pellets with/without Cort (300 mg). After 10 days, adipose depots were removed and cultured ex vivo. Both free fatty acids and glycerol concentrations were elevated in fed and fasting conditions in Cort-treated rats. Despite increased lipolysis, Cort rats had more visceral adiposity than sham rats (10.2 vs. 6.9 g/kg body wt, P < 0.05). Visceral adipocytes from Cort rats were smaller and more numerous than those in sham rats, suggesting that adipogenesis occurred through preadipocyte differentiation rather than adipocyte hypertrophy. Visceral, but not subcutaneous, adipocyte cultures from Cort-treated rats displayed a 1.5 fold increase in basal lipolytic rates compared with sham rats (P < 0.05). Taken together, our findings demonstrate that chronic glucocorticoid exposure stimulates both lipolysis and adipogenesis in visceral adipose tissue but favors adipogenesis primarily through preadipocyte differentiation. PMID- 20943961 TI - Effect of denervation-induced muscle disuse on mitochondrial protein import. AB - This study determined whether muscle disuse affects mitochondrial protein import and whether changes in protein import are related to mitochondrial content and function. Protein import was measured using a model of unilateral peroneal nerve denervation in rats for 3 (n = 10), 7 (n = 12), or 14 (n = 14) days. We compared the import of preproteins into the matrix of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria isolated from the denervated and the contralateral control tibialis anterior muscles. Denervation led to 50% and 29% reductions in protein import after 14 days of disuse in SS and IMF mitochondria, respectively. This was accompanied by significant decreases in mitochondrial state 3 respiration, muscle mass, and whole muscle cytochrome c oxidase activity. To investigate the mechanisms involved, we assessed disuse-related changes in 1) protein import machinery components and 2) mitochondrial function, reflected by respiration and reactive oxygen species (ROS) production. Denervation significantly reduced the expression of translocases localized in the inner membrane (Tim23), outer membrane (Tom20), and mitochondrial heat shock protein 70 (mtHsp70), especially in the SS subfraction. Denervation also resulted in elevated ROS generation, and exogenous ROS was found to markedly reduce protein import. Thus our data indicate that protein import kinetics are closely related to alterations in mitochondrial respiratory capacity (r = 0.95) and are negatively impacted by ROS. Deleterious changes in the protein import system likely facilitate the reduction in mitochondrial content and the increase in organelle dysfunction (i.e., increased ROS production and decreased respiration) during chronic disuse, which likely contribute to the activation of degradative pathways leading to muscle atrophy. PMID- 20943960 TI - Cathelicidin LL-37 peptide regulates endothelial cell stiffness and endothelial barrier permeability. AB - LL-37 peptide is a multifunctional host defense molecule essential for normal immune responses to infection or tissue injury. In this study we assess the impact of LL-37 on endothelial stiffness and barrier permeability. Fluorescence microscopy reveals membrane localization of LL-37 after its incubation with human umbilical vein endothelial cells (HUVECs). A concentration-dependent increase in stiffness was observed in HUVECs, bovine aortic endothelial cells (BAECs), human pulmonary microvascular endothelial cells, and mouse aorta upon LL-37 (0.5-5 MUM) addition. Stiffening of BAECs by LL-37 was blocked by P2X7 receptor antagonists and by the intracellular Ca2(+) chelator BAPTA-AM. Increased cellular stiffness correlated with a decrease in permeability of HUVEC cell monolayers after LL-37 addition compared with nontreated cells, which was similar to the effect observed upon treatment with sphingosine 1-phosphate, and both treatments increased F actin content in the cortical region of the cells. These results suggest that the antiinflammatory effect of LL-37 at the site of infection or injury involves an LL-37-mediated increase in cell stiffening that prevents increased pericellular permeability. Such a mechanism may help to maintain tissue fluid homeostasis. PMID- 20943962 TI - The nucleotides on the stem-loop RNA structure in the junction region of the hepatitis E virus genome are critical for virus replication. AB - The roles of conserved nucleotides on the stem-loop (SL) structure in the intergenic region of the hepatitis E virus (HEV) genome in virus replication were determined by using Huh7 cells transfected with HEV SL mutant replicons containing reporter genes. One or two nucleotide mutations of the AGA motif on the loop significantly reduced HEV replication, and three or more nucleotide mutations on the loop abolished HEV replication. Mutations on the stem and of the subgenome start sequence also significantly inhibited HEV replication. The results indicated that both the sequence and the SL structure in the junction region play important roles in HEV replication. PMID- 20943963 TI - NFAT and CREB regulate Kaposi's sarcoma-associated herpesvirus-induced cyclooxygenase 2 (COX-2). AB - COX-2 has been implicated in Kaposi's sarcoma-associated herpesvirus (KSHV) latency and pathogenesis (A. George Paul, N. Sharma-Walia, N. Kerur, C. White, and B. Chandran, Cancer Res. 70:3697-3708, 2010; P. P. Naranatt, H. H. Krishnan, S. R. Svojanovsky, C. Bloomer, S. Mathur, and B. Chandran, Cancer Res. 64:72-84, 2004; N. Sharma-Walia, A. G. Paul, V. Bottero, S. Sadagopan, M. V. Veettil, N. Kerur, and B. Chandran, PLoS Pathog. 6:e1000777, 2010; N. Sharma-Walia, H. Raghu, S. Sadagopan, R. Sivakumar, M. V. Veettil, P. P. Naranatt, M. M. Smith, and B. Chandran, J. Virol. 80:6534-6552, 2006). However, the precise regulatory mechanisms involved in COX-2 induction during KSHV infection have never been explored. Here, we identified cis-acting elements involved in the transcriptional regulation of COX-2 upon KSHV de novo infection. Promoter analysis using human COX-2 promoter deletion and mutation reporter constructs revealed that nuclear factor of activated T cells (NFAT) and the cyclic AMP (cAMP) response element (CRE) modulate KSHV-mediated transcriptional regulation of COX-2. Along with multiple KSHV-induced signaling pathways, infection-induced prostaglandin E(2) (PGE(2)) also augmented COX-2 transcription. Infection of endothelial cells markedly induced COX-2 expression via a cyclosporine A-sensitive, calcineurin/NFAT-dependent pathway. KSHV infection increased intracellular cAMP levels and activated protein kinase A (PKA), which phosphorylated the CRE-binding protein (CREB) at serine 133, which probably led to interaction with CRE in the COX-2 promoter, thereby enhancing COX-2 transcription. PKA selective inhibitor H 89 pretreatment strongly inhibited CREB serine 133, indicating the involvement of a cAMP-PKA-CREB-CRE loop in COX-2 transcriptional regulation. In contrast to phosphatidylinositol 3-kinase and protein kinase C, inhibition of FAK and Src effectively reduced KSHV infection-induced COX-2 transcription and protein levels. Collectively, our study indicates that mediation of COX-2 transcription upon KSHV infection is a paradigm of a complex regulatory milieu involving the interplay of multiple signal cascades and transcription factors. Intervention at each step of COX-2/PGE(2) induction can be used as a potential therapeutic target to treat KSHV-associated neoplasm and control inflammatory sequels of KSHV infection. PMID- 20943964 TI - Discovery and characterization of mammalian endogenous parvoviruses. AB - Public databases of nucleotide sequences contain exponentially increasing amounts of sequence data from mammalian genomes. Through the use of large-scale bioinformatic screening for sequences homologous to exogenous mammalian viruses, we found several sequences related to human and animal parvoviruses (PVs) in the Parvovirus and Dependovirus genera within genomes of several mammals, including rats, wallabies, opossums, guinea pigs, hedgehogs, African elephants, and European rabbits. However, phylogenetic analysis of these endogenous parvovirus (EnPV) sequences demonstrated substantial genetic divergence from exogenous mammalian PVs characterized to date. Entire nonstructural and capsid gene sequences of a novel EnPV were amplified and genetically characterized from rat (Rattus norvegicus) genomic DNA. Rat EnPV sequences were most closely related to members of the genus Parvovirus, with >70% and 65% amino acid identities to nonstructural and capsid proteins of canine parvovirus, respectively. Integration of EnPV into chromosome 5 of rats was confirmed by PCR cloning and sequence analysis of the viral and chromosomal junctions. Using inverse PCR, we determined that the rat genome contains a single copy of rat EnPV. Considering mammalian phylogeny, we estimate that EnPV integrated into the rat genome less than 30 million years ago. Comparative phylogenetic analysis done using all known representative exogenous parvovirus (ExPV) and EnPV sequences showed two major genetic groups of EnPVs, one genetically more similar to genus Parvovirus and the other genetically more similar to the genus Dependovirus. The full extent of the genetic diversity of parvoviruses that have undergone endogenization during evolution of mammals and other vertebrates will be recognized only once complete genomic sequences from a wider range of classes, orders, and species of animals become available. PMID- 20943965 TI - Identification of specific determinants of human APOBEC3F, APOBEC3C, and APOBEC3DE and African green monkey APOBEC3F that interact with HIV-1 Vif. AB - Human APOBEC3F (hA3F) and human APOBEC3G (hA3G) are potent anti-human immunodeficiency virus (anti-HIV) host factors that suppress viral replication by hypermutating the viral genome, inhibiting reverse transcription, and hindering integration. To overcome hA3F and hA3G, HIV-1 encodes Vif, which binds and targets these host proteins for proteasomal degradation. Previously, we reported that the hA3F-Vif interactions that lead to hA3F degradation are located in the region comprising amino acids 283 to 300. We have now performed mutational analysis of this region and found that the (289)EFLARH(294) amino acids contribute to hA3F-Vif binding and are critical for A3F's sensitivity to Vif. Mutants in which E289 is mutated significantly increase hA3F's ability to inhibit viral infectivity in the presence of Vif, and coimmunoprecipitation assays show that binding of Vif to the E289K mutant is decreased. We examined the role of the EFLARH sequence in other A3 proteins, including human A3C (hA3C), human A3DE (hA3DE), African green monkey A3F (agmA3F), and rhesus macaque A3F (rhA3F). hA3C, hA3DE, and agmA3F were all susceptible to degradation induced by HIV-1 Vif, while rhA3F was not. Mutagenesis of the glutamate in the EFLARH sites of hA3C, hA3DE, and agmA3F decreases the susceptibilities of these proteins to Vif-induced degradation. Together, these results indicate that the EFLARH region in hA3F, hA3C, hA3DE, and agmA3F interacts with HIV-1 Vif and that this interaction plays a role in the Vif-mediated proteasomal degradation of these A3 proteins. These studies identify a conserved region in 3 of 7 human A3 proteins that is critical for degradation mediated by HIV-1 Vif and provide structural insights into the hA3F-Vif interactions that could facilitate the development of a novel class of anti-HIV agents. PMID- 20943966 TI - Microevolution of canine influenza virus in shelters and its molecular epidemiology in the United States. AB - Canine influenza virus (CIV) emerged around 2000 when an equine influenza virus (EIV) was transmitted to dogs in Florida. After 2003, the canine virus was carried by infected greyhounds to various parts of the United States and then became established in several large animal shelters, where it has continued to circulate. To better understand the evolution of CIV since its emergence, and particularly its microevolution in spatially restricted populations, we examined multiple gene segments of CIV from dogs resident in two large animal shelters in New York City during the period 2006 to 2009. In particular, we focused on viruses circulating in the two shelters in 2008 and 2009, which we found shared a common ancestor. While viruses in each shelter were generally monophyletic, we observed some gene flow between them. These shelter sequences were compared to earlier CIV isolates. The shelter viruses differed in 1 to 6 amino acids in each gene segment compared to viruses isolated in Florida between 2003 and 2005 and in Colorado in 2006 and 2008. A comparison of the sequences of equine and canine viruses revealed amino acid replacements that distinguished the viruses from the two hosts, but no clear evidence of positive selection indicative of host adaptation was detected, suggesting that any host range adaptation in CIV occurred early in the emergence of this virus or even before it transferred to dogs. PMID- 20943967 TI - The early whole-blood transcriptional signature of dengue virus and features associated with progression to dengue shock syndrome in Vietnamese children and young adults. AB - Dengue is a pantropic public health problem. In children, dengue shock syndrome (DSS) is the most common life-threatening complication. The ability to predict which patients may develop DSS may improve triage and treatment. To this end, we conducted a nested case-control comparison of the early host transcriptional features in 24 DSS patients and 56 sex-, age-, and virus serotype-matched uncomplicated (UC) dengue patients. In the first instance, we defined the "early dengue" profile. The transcriptional signature in acute rather than convalescent samples (<=72 h post-illness onset) was defined by an overabundance of interferon inducible transcripts (31% of the 551 overabundant transcripts) and canonical gene ontology terms that included the following: response to virus, immune response, innate immune response, and inflammatory response. Pathway and network analyses identified STAT1, STAT2, STAT3, IRF7, IRF9, IRF1, CEBPB, and SP1 as key transcriptional factors mediating the early response. Strikingly, the only difference in the transcriptional signatures of early DSS and UC dengue cases was the greater abundance of several neutrophil-associated transcripts in patients who progressed to DSS, a finding supported by higher plasma concentrations of several canonical proteins associated with neutrophil degranulation (bactericidal/permeability-increasing protein [BPI], elastase 2 [ELA2], and defensin 1 alpha [DEF1A]). Elevated levels of neutrophil-associated transcripts were independent of the neutrophil count and also of the genotype of the infecting virus, as genome-length sequences of dengue virus serotype 1 (DENV-1) (n = 15) and DENV-2 (n = 3) sampled from DSS patients were phylogenetically indistinguishable from those sampled from uncomplicated dengue patients (32 DENV 1 and 9 DENV-2 sequences). Collectively, these data suggest a hitherto unrecognized association between neutrophil activation, pathogenesis, and the development of DSS and point to future strategies for guiding prognosis. PMID- 20943969 TI - Codon optimization of human parvovirus B19 capsid genes greatly increases their expression in nonpermissive cells. AB - Parvovirus B19 (B19V) is pathogenic for humans and has an extreme tropism for human erythroid progenitors. We report cell type-specific expression of the B19V capsid genes (VP1 and VP2) and greatly increased B19V capsid protein production in nonpermissive cells by codon optimization. Codon usage limitation, rather than promoter type and the 3' untranslated region of the capsid genes, appears to be a key factor in capsid protein production in nonpermissive cells. Moreover, B19 virus-like particles were successfully generated in nonpermissive cells by transient transfection of a plasmid carrying both codon-optimized VP1 and VP2 genes. PMID- 20943968 TI - Identification of basic amino acids at the N-terminal end of the core protein that are crucial for hepatitis C virus infectivity. AB - A major function of the hepatitis C virus (HCV) core protein is the interaction with genomic RNA to form the nucleocapsid, an essential component of the virus particle. Analyses to identify basic amino acid residues of HCV core protein, important for capsid assembly, were initially performed with a cell-free system, which did not indicate the importance of these residues for HCV infectivity. The development of a cell culture system for HCV (HCVcc) allows a more precise analysis of these core protein amino acids during the HCV life cycle. In the present study, we used a mutational analysis in the context of the HCVcc system to determine the role of the basic amino acid residues of the core protein in HCV infectivity. We focused our analysis on basic residues located in two clusters (cluster 1, amino acids [aa]6 to 23; cluster 2, aa 39 to 62) within the N terminal 62 amino acids of the HCV core protein. Our data indicate that basic residues of the first cluster have little impact on replication and are dispensable for infectivity. Furthermore, only four basic amino acids residues of the second cluster (R50, K51, R59, and R62) were essential for the production of infectious viral particles. Mutation of these residues did not interfere with core protein subcellular localization, core protein-RNA interaction, or core protein oligomerization. Moreover, these mutations had no effect on core protein envelopment by intracellular membranes. Together, these data indicate that R50, K51, R59, and R62 residues play a major role in the formation of infectious viral particles at a post-nucleocapsid assembly step. PMID- 20943970 TI - Physical interaction between the herpes simplex virus type 1 exonuclease, UL12, and the DNA double-strand break-sensing MRN complex. AB - The herpes simplex virus type 1 (HSV-1) alkaline nuclease, encoded by the UL12 gene, plays an important role in HSV-1 replication, as a UL12 null mutant displays a severe growth defect. The HSV-1 alkaline exonuclease UL12 interacts with the viral single-stranded DNA binding protein ICP8 and promotes strand exchange in vitro in conjunction with ICP8. We proposed that UL12 and ICP8 form a two-subunit recombinase reminiscent of the phage lambda Red alpha/beta recombination system and that the viral and cellular recombinases contribute to viral genome replication through a homologous recombination-dependent DNA replication mechanism. To test this hypothesis, we identified cellular interaction partners of UL12 by using coimmunoprecipitation. We report for the first time a specific interaction between UL12 and components of the cellular MRN complex, an important factor in the ATM-mediated homologous recombination repair (HRR) pathway. This interaction is detected early during infection and does not require viral DNA or other viral or cellular proteins. The region of UL12 responsible for the interaction has been mapped to the first 125 residues, and coimmunoprecipitation can be abolished by deletion of residues 100 to 126. These observations support the hypothesis that cellular and viral recombination factors work together to promote efficient HSV-1 growth. PMID- 20943971 TI - Roles of vaccinia virus genes E3L and K3L and host genes PKR and RNase L during intratracheal infection of C57BL/6 mice. AB - The importance of the 2'-5' oligoadenylate synthetase (OAS)/RNase L and double stranded RNA (dsRNA)-dependent protein kinase (PKR) pathways in host interferon induction resulting from virus infection in response to dsRNA has been well documented. In poxvirus infections, the interactions between the vaccinia virus (VV) genes E3L and K3L, which target RNase L and PKR, respectively, serve to prevent the induction of the dsRNA-dependent induced interferon response in cell culture. To determine the importance of these host genes in controlling VV infections, mouse single-gene knockouts of RNase L and PKR and double-knockout mice were studied following intratracheal infection with VV, VVDeltaK3L, or VVDeltaE3L. VV caused lethal disease in all mouse strains. The single-knockout animals were more susceptible than wild-type animals, while the RNase L(-/-) PKR( /-) mice were the most susceptible. VVDeltaE3L infections of wild-type mice were asymptomatic, demonstrating that E3L plays a critical role in controlling the host immune response. RNase L(-/-) mice showed no disease, whereas 20% of the PKR(-/-) mice succumbed at a dose of 10(8) PFU. Lethal disease was routinely observed in RNase L(-/-) PKR(-/-) mice inoculated with 10(8) PFU of VVDeltaE3L, with a distinct pathology. VVDeltaK3L infections exhibited no differences in virulence among any of the mouse constructs, suggesting that PKR is not the exclusive target of K3L. Surprisingly, VVDeltaK3L did not disseminate to other tissues from the lung. Hence, the cause of death in this model is respiratory disease. These results also suggest that an unanticipated role of the K3L gene is to facilitate virus dissemination. PMID- 20943972 TI - Interaction of poxvirus intracellular mature virion proteins with the TPR domain of kinesin light chain in live infected cells revealed by two-photon-induced fluorescence resonance energy transfer fluorescence lifetime imaging microscopy. AB - Using two-photon-induced fluorescence lifetime imaging microscopy, we corroborate an interaction (previously demonstrated by yeast two-hybrid domain analysis) of full-length vaccinia virus (VACV; an orthopoxvirus) A36 protein with the cellular microtubule motor protein kinesin. Quenching of enhanced green fluorescent protein (EGFP), fused to the C terminus of VACV A36, by monomeric red fluorescent protein (mDsRed), fused to the tetratricopeptide repeat (TPR) domain of kinesin, was observed in live chicken embryo fibroblasts infected with either modified vaccinia virus Ankara (MVA) or wild-type fowlpox virus (FWPV; an avipoxvirus), and the excited-state fluorescence lifetime of EGFP was reduced from 2.5 +/- 0.1 ns to 2.1 +/- 0.1 ns due to resonance energy transfer to mDsRed. FWPV does not encode an equivalent of intracellular enveloped virion surface protein A36, yet it is likely that this virus too must interact with kinesin to facilitate intracellular virion transport. To investigate possible interactions between innate FWPV proteins and kinesin, recombinant FWPVs expressing EGFP fused to the N termini of FWPV structural proteins Fpv140, Fpv168, Fpv191, and Fpv198 (equivalent to VACV H3, A4, p4c, and A34, respectively) were generated. EGFP fusions of intracellular mature virion (IMV) surface protein Fpv140 and type II membrane protein Fpv198 were quenched by mDsRed-TPR in recombinant FWPV-infected cells, indicating that these virion proteins are found within 10 nm of mDsRed TPR. In contrast, and as expected, EGFP fusions of the IMV core protein Fpv168 did not show any quenching. Interestingly, the p4c-like protein Fpv191, which demonstrates late association with preassembled IMV, also did not show any quenching. PMID- 20943973 TI - Cytoplasmic poly(A) binding proteins regulate telomerase activity and cell growth in human papillomavirus type 16 E6-expressing keratinocytes. AB - The high-risk human papillomavirus (HPV) E6 and E7 oncoproteins are critical to the immortalization of keratinocytes. HPV type 16 (HPV16) E6 interacts with endogenous proteins to activate hTERT, the catalytic subunit of telomerase, thus avoiding cellular senescence signals. NFX1-123, the longer splice variant of NFX1, interacts with HPV16 E6, as well as cytoplasmic poly(A) binding proteins 1 and 4 (PABPC1 and PABPC4). HPV16 E6 affects hTERT expression posttranscriptionally through NFX1-123, as NFX1-123 interacts with hTERT mRNA and stabilizes it, leading to greater telomerase activity. The PAM2 motif of NFX1 123, with which it binds PABPCs, is required for the posttranscriptional regulation of hTERT by HPV16 E6 and NFX1-123. There is increasing evidence that RNA and DNA viruses utilize RNA-processing proteins, and specifically PABPCs, in the normal virus life cycle, and there is also evidence that RNA-processing proteins are perturbed in cancers. Here, we show that PABPCs are critical in hTERT regulation by HPV16 E6. Although the amount and cellular localization of PABPCs were largely unchanged in cervical cancer cell lines with or without HPV16 and in human foreskin keratinocytes (HFKs) with or without HPV16 E6, knockdown of PABPCs decreased hTERT mRNA and telomerase activity and overexpression of PABPC4 increased these in HPV16 E6-expressing HFKs. In contrast, knockdown of PABPCs in C33A cells had no effect on hTERT mRNA or telomerase activity. Additionally, overexpression of PABPC4 and hTERT led to greater growth of cultured HPV16 E6 expressing HFKs. This is the first evidence that PABPCs have a targeted role in hTERT regulation leading to a growth advantage in cells expressing HPV16 E6. PMID- 20943974 TI - Nodavirus-induced membrane rearrangement in replication complex assembly requires replicase protein a, RNA templates, and polymerase activity. AB - Positive-strand RNA [(+)RNA] viruses invariably replicate their RNA genomes on modified intracellular membranes. In infected Drosophila cells, Flock House nodavirus (FHV) RNA replication complexes form on outer mitochondrial membranes inside ~50-nm, virus-induced spherular invaginations similar to RNA replication linked spherules induced by many (+)RNA viruses at various membranes. To better understand replication complex assembly, we studied the mechanisms of FHV spherule formation. FHV has two genomic RNAs; RNA1 encodes multifunctional RNA replication protein A and RNA interference suppressor protein B2, while RNA2 encodes the capsid proteins. Expressing genomic RNA1 without RNA2 induced mitochondrial spherules indistinguishable from those in FHV infection. RNA1 mutation showed that protein B2 was dispensable and that protein A was the only FHV protein required for spherule formation. However, expressing protein A alone only "zippered" together the surfaces of adjacent mitochondria, without inducing spherules. Thus, protein A is necessary but not sufficient for spherule formation. Coexpressing protein A plus a replication-competent FHV RNA template induced RNA replication in trans and membrane spherules. Moreover, spherules were not formed when replicatable FHV RNA templates were expressed with protein A bearing a single, polymerase-inactivating amino acid change or when wild-type protein A was expressed with a nonreplicatable FHV RNA template. Thus, unlike many (+)RNA viruses, the membrane-bounded compartments in which FHV RNA replication occurs are not induced solely by viral protein(s) but require viral RNA synthesis. In addition to replication complex assembly, the results have implications for nodavirus interaction with cell RNA silencing pathways and other aspects of virus control. PMID- 20943975 TI - Common inbred strains of the laboratory mouse that are susceptible to infection by mouse xenotropic gammaretroviruses and the human-derived retrovirus XMRV. AB - Laboratory mouse strains carry endogenous copies of the xenotropic mouse leukemia viruses (X-MLVs), named for their inability to infect cells of the laboratory mouse. This resistance to exogenous infection is due to a nonpermissive variant of the XPR1 gammaretrovirus receptor, a resistance that also limits in vivo expression of germ line X-MLV proviruses capable of producing infectious virus. Because laboratory mice vary widely in their proviral contents and in their virus expression patterns, we screened inbred strains for sequence and functional variants of the XPR1 receptor. We also typed inbred strains and wild mouse species for an endogenous provirus, Bxv1, that is capable of producing infectious X-MLV and that also contributes to the generation of pathogenic recombinant MLVs. We identified the active Bxv1 provirus in many common inbred strains and in some Japanese Mus molossinus mice but in none of the other wild mouse species that carry X-MLVs. Our screening for Xpr1 variants identified the permissive Xpr1(sxv) allele in 7 strains of laboratory mice, including a Bxv1-positive strain, F/St, which is characterized by lifelong X-MLV viremia. Cells from three strains carrying Xpr1(sxv), namely, SWR, SJL, and SIM.R, were shown to be infectable by X MLV and XMRV; these strains carry different alleles at Fv1 and vary in their sensitivities to specific X/P-MLV isolates and XMRV. Several strains with Xpr1(sxv) lack the active Bxv1 provirus or other endogenous X-MLVs and may provide a useful model system to evaluate the in vivo spread of these gammaretroviruses and their disease potential in their natural host. PMID- 20943976 TI - The C-terminal end of parainfluenza virus 5 NP protein is important for virus like particle production and M-NP protein interaction. AB - Enveloped virus particles are formed by budding from infected-cell membranes. For paramyxoviruses, viral matrix (M) proteins are key drivers of virus assembly and budding. However, other paramyxovirus proteins, including glycoproteins, nucleocapsid (NP or N) proteins, and C proteins, are also important for particle formation in some cases. To investigate the role of NP protein in parainfluenza virus 5 (PIV5) particle formation, NP protein truncation and substitution mutants were analyzed. Alterations near the C-terminal end of NP protein completely disrupted its virus-like particle (VLP) production function and significantly impaired M-NP protein interaction. Recombinant viruses with altered NP proteins were generated, and these viruses acquired second-site mutations. Recombinant viruses propagated in Vero cells acquired mutations that mainly affected components of the viral polymerase, while recombinant viruses propagated in MDBK cells acquired mutations that mainly affected the viral M protein. Two of the Vero-propagated viruses acquired the same mutation, V/P(S157F), found previously to be responsible for elevated viral gene expression induced by a well characterized variant of PIV5, P/V-CPI(-). Vero-propagated viruses caused elevated viral protein synthesis and spread rapidly through infected monolayers by direct cell-cell fusion, bypassing the need to bud infectious virions. Both Vero- and MDBK-propagated viruses exhibited infectivity defects and altered polypeptide composition, consistent with poor incorporation of viral ribonucleoprotein complexes (RNPs) into budding virions. Second-site mutations affecting M protein restored interaction with altered NP proteins in some cases and improved VLP production. These results suggest that multiple avenues are available to paramyxoviruses for overcoming defects in M-NP protein interaction. PMID- 20943977 TI - Interferon-induced cell membrane proteins, IFITM3 and tetherin, inhibit vesicular stomatitis virus infection via distinct mechanisms. AB - Tetherin and IFITM3 are recently identified interferon-induced cellular proteins that restrict infections by retroviruses and filoviruses and of influenza virus and flaviviruses, respectively. In our efforts to further explore their antiviral activities against other viruses and determine their antiviral mechanisms, we found that the two antiviral proteins potently inhibit the infection of vesicular stomatitis virus (VSV), a prototype member of the Rhabdoviridae family. Taking advantage of this well-studied virus infection system, we show that although both tetherin and IFITM3 are plasma membrane proteins, tetherin inhibits virion particle release from infected cells, while IFITM3 disrupts an early event after endocytosis of virion particles but before primary transcription of incoming viral genomes. Furthermore, we demonstrate that both the N-terminal 21 amino acid residues and C-terminal transmembrane region of IFITM3 are required for its antiviral activity. Collectively, our work sheds light on the mechanisms by which tetherin and IFITM3 restrict infection with rhabdoviruses and possibly other pathogenic viruses. PMID- 20943978 TI - Cationic lipid/DNA complex-adjuvanted influenza A virus vaccination induces robust cross-protective immunity. AB - Influenza A virus is a negative-strand segmented RNA virus in which antigenically distinct viral subtypes are defined by the hemagglutinin (HA) and neuraminidase (NA) major viral surface proteins. An ideal inactivated vaccine for influenza A virus would induce not only highly robust strain-specific humoral and T-cell immune responses but also cross-protective immunity in which an immune response to antigens from a particular viral subtype (e.g., H3N2) would protect against other viral subtypes (e.g., H1N1). Cross-protective immunity would help limit outbreaks from newly emerging antigenically novel strains. Here, we show in mice that the addition of cationic lipid/noncoding DNA complexes (CLDC) as adjuvant to whole inactivated influenza A virus vaccine induces significantly more robust adaptive immune responses both in quantity and quality than aluminum hydroxide (alum), which is currently the most widely used adjuvant in clinical human vaccination. CLDC-adjuvanted vaccine induced higher total influenza virus specific IgG, particularly for the IgG2a/c subclass. Higher levels of multicytokine-producing influenza virus-specific CD4 and CD8 T cells were induced by CLDC-adjuvanted vaccine than with alum-adjuvanted vaccine. Importantly, CLDC adjuvanted vaccine provided significant cross-protection from either a sublethal or lethal influenza A viral challenge with a different subtype than that used for vaccination. This superior cross-protection afforded by the CLDC adjuvant required CD8 T-cell recognition of viral peptides presented by classical major histocompatibility complex class I proteins. Together, these results suggest that CLDC has particular promise for vaccine strategies in which T cells play an important role and may offer new opportunities for more effective control of human influenza epidemics and pandemics by inactivated influenza virus vaccine. PMID- 20943980 TI - MyD88 signaling is indispensable for primary influenza A virus infection but dispensable for secondary infection. AB - Recent studies have revealed that innate immunity is involved in the development of adaptive immune responses; however, its role in protection is not clear. In order to elucidate the exact role of Toll-like receptor (TLR) or RIG-I-like receptor (RLR) signaling on immunogenicity and protective efficacy against influenza A virus infection (A/PR/8/34 [PR8]; H1N1), we adapted several innate signal-deficient mice (e.g., TRIF(-/-), MyD88(-/-), MyD88(-/-) TRIF(-/-), TLR3(-/ ) TLR7(-/-), and IPS-1(-/-)). In this study, we found that MyD88 signaling was required for recruitment of CD11b(+) granulocytes, production of early inflammatory cytokines, optimal proliferation of CD4 T cells, and production of Th1 cytokines by T cells. However, PR8 virus-specific IgG and IgA antibody levels in both systemic and mucosal compartments were normal in TLR- and RLR-deficient mice. To further assess the susceptibility of these mice to influenza virus infection, protective efficacy was determined after primary or secondary lethal challenge. We found that MyD88(-/-) and MyD88(-/-) TRIF(-/-) mice were more susceptible to primary influenza virus infection than the B6 mice but were fully protected against homologous (H1N1) and heterosubtypic (H5N2) secondary infection when primed with a nonlethal dose of PR8 virus. Taken together, these results show that MyD88 signaling plays an important role for resisting primary influenza virus infection but is dispensable for protection against a secondary lethal challenge. PMID- 20943982 TI - Determinants of strain-specific differences in efficiency of reovirus entry. AB - Cell entry of reovirus requires a series of ordered steps, which include conformational changes in outer capsid protein MU1 and its autocleavage. The MU1N fragment released as a consequence of these events interacts with host cell membranes and mediates their disruption, leading to delivery of the viral core into the cytoplasm. The prototype reovirus strains T1L and T3D exhibit differences in the efficiency of autocleavage, in the propensity to undergo conformational changes required for membrane penetration, and in the capacity for penetrating host cell membranes. To better understand how polymorphic differences in MU1 influence reovirus entry events, we generated recombinant viruses that express chimeric T1L-T3D MU1 proteins and characterized them for the capacity to efficiently complete each step required for membrane penetration. Our studies revealed two important functions for the central delta region of MU1. First, we found that MU1 autocleavage is regulated by the N-terminal portion of delta, which forms an alpha-helical pedestal structure. Second, we observed that the C terminal portion of delta, which forms a jelly-roll beta barrel structure, regulates membrane penetration by influencing the efficiency of ISVP* formation. Thus, our studies highlight the molecular basis for differences in the membrane penetration efficiency displayed by prototype reovirus strains and suggest that distinct portions of the reovirus delta domain influence different steps during entry. PMID- 20943983 TI - Quantitative and qualitative RNA-Seq-based evaluation of Epstein-Barr virus transcription in type I latency Burkitt's lymphoma cells. AB - RNA-seq provides a rich source of transcriptome information with high qualitative and quantitative value. Here, we provide a pipeline for Epstein-Barr virus (EBV) transcriptome analysis using RNA-seq and we apply it to two type I latency cell lines, Mutu I and Akata. This analysis revealed substantial average expression levels of many lytic genes in predominantly latent cell populations. The lytic transcripts BHLF1 and LF3 were expressed at levels greater than those for 98% of all cellular polyadenylated transcripts. Exon junction mapping accurately identified the Qp-derived EBNA1 splicing pattern, lytic gene splicing, and a complex splicing pattern within the BamHI A region. PMID- 20943984 TI - Structural basis of local, pH-dependent conformational changes in glycoprotein B from herpes simplex virus type 1. AB - Herpesviruses enter cells by membrane fusion either at the plasma membrane or in endosomes, depending on the cell type. Glycoprotein B (gB) is a conserved component of the multiprotein herpesvirus fusion machinery and functions as a fusion protein, with two internal fusion loops, FL1 and FL2. We determined the crystal structures of the ectodomains of two FL1 mutants of herpes simplex virus type 1 (HSV-1) gB to clarify whether their fusion-null phenotypes were due to global or local effects of the mutations on the structure of the gB ectodomain. Each mutant has a single point mutation of a hydrophobic residue in FL1 that eliminates the hydrophobic side chain. We found that neither mutation affected the conformation of FL1, although one mutation slightly altered the conformation of FL2, and we conclude that the fusion-null phenotype is due to the absence of a hydrophobic side chain at the mutated position. Because the ectodomains of the wild-type and the mutant forms of gB crystallized at both low and neutral pH, we were able to determine the effect of pH on gB conformation at the atomic level. For viruses that enter cells by endocytosis, the low pH of the endosome effects major conformational changes in their fusion proteins, thereby promoting fusion of the viral envelope with the endosomal membrane. We show here that upon exposure of gB to low pH, FL2 undergoes a major relocation, probably driven by protonation of a key histidine residue. Relocation of FL2, as well as additional small conformational changes in the gB ectodomain, helps explain previously noted changes in its antigenic and biochemical properties. However, no global pH dependent changes in gB structure were detected in either the wild-type or the mutant forms of gB. Thus, low pH causes local conformational changes in gB that are very different from the large-scale fusogenic conformational changes in other viral fusion proteins. We propose that these conformational changes, albeit modest, play an important functional role during endocytic entry of HSV. PMID- 20943985 TI - Fitness disadvantage of transitional intermediates contributes to dynamic change in the infecting-virus population during coreceptor switch in R5 simian/human immunodeficiency virus-infected macaques. AB - Fitness disadvantage of the transitional intermediates compared to the initial R5 viruses has been suggested to constitute one of the blockades to coreceptor switching, explaining the late appearance of X4 viruses. Using a simian model for human immunodeficiency virus type 1 (HIV-1) coreceptor switching, we demonstrate in this study that similar molecular evolutionary pathways to coreceptor switch occur in more than one R5 simian/human immunodeficiency virus (SHIV)(SF162P3N) infected macaque. In infected animals where multiple pathways for expansion or switch to CXCR4 coexist, fitness of the transitional intermediates in coreceptor usage efficiency influences their outgrowth and representation in the infecting virus population. Dualtropic and X4 viruses appear at different disease stages, but they have lower entry efficiency than the coexisting R5 strains, which may explain why they do not outcompete the R5 viruses. Similar observations were made in two infected macaques with coreceptor switch, providing in vivo evidence that fitness disadvantage is an obstacle to X4 emergence and expansion. PMID- 20943986 TI - Suppression of innate immune pathology by regulatory T cells during Influenza A virus infection of immunodeficient mice. AB - The viral infection of higher vertebrates elicits potent innate and adaptive host immunity. However, an excessive or inappropriate immune response also may lead to host pathology that often is more severe than the direct effects of viral replication. Therefore, several mechanisms exist that regulate the magnitude and class of the immune response. Here, we have examined the potential involvement of regulatory T (Treg) cells in limiting pathology induced by influenza A virus (IAV) infection. Using lymphocyte-deficient mice as hosts, we showed that Treg cell reconstitution resulted in a significant delay in weight loss and prolonged survival following infection. The adoptively transferred Treg cells did not affect the high rate of IAV replication in the lungs of lymphocyte-deficient hosts, and therefore their disease-ameliorating effect was mediated through the suppression of innate immune pathology. Mechanistically, Treg cells reduced the accumulation and altered the distribution of monocytes/macrophages in the lungs of IAV-infected hosts. This reduction in lung monocytosis was associated with a specific delay in monocyte chemotactic protein-2 (MCP-2) induction in the infected lungs. Nevertheless, Treg cells failed to prevent the eventual development of severe disease in lymphocyte-deficient hosts, which likely was caused by the ongoing IAV replication. Indeed, using T-cell-deficient mice, which mounted a T-cell-independent B cell response to IAV, we further showed that the combination of virus-neutralizing antibodies and transferred Treg cells led to the complete prevention of clinical disease following IAV infection. Taken together, these results suggested that innate immune pathology and virus-induced pathology are the two main contributors to pathogenesis during IAV infection. PMID- 20943987 TI - Ultrastructural analysis of virion formation and intraaxonal transport of herpes simplex virus type 1 in primary rat neurons. AB - After primary replication at the site of entry into the host, alphaherpesviruses infect and establish latency in neurons. To this end, they are transported within axons retrograde from the periphery to the cell body for replication and in an anterograde direction to synapses for infection of higher-order neurons or back to the periphery. Retrograde transport of incoming nucleocapsids is well documented. In contrast, there is still significant controversy on the mode of anterograde transport. By high-resolution transmission electron microscopy of primary neuronal cultures from embryonic rat superior cervical ganglia infected by pseudorabies virus (PrV), we observed the presence of enveloped virions in axons within vesicles supporting the "married model" of anterograde transport of complete virus particles within vesicles (C. Maresch, H. Granzow, A. Negatsch, B.G. Klupp, W. Fuchs, J.P. Teifke, and T.C. Mettenleiter, J. Virol. 84:5528-5539, 2010). We have now extended these analyses to the related human herpes simplex virus type 1 (HSV-1). We have demonstrated that in neurons infected by HSV-1 strains HFEM, 17+ or SC16, approximately 75% of virus particles observed intraaxonally or in growth cones late after infection constitute enveloped virions within vesicles, whereas approximately 25% present as naked capsids. In general, the number of HSV-1 particles in the axons was significantly less than that observed after PrV infection. PMID- 20943990 TI - Health status of Roma women in Spain. AB - BACKGROUND: The objective of the present study is to describe the health status of Roma women in Spain. Population-based health data have become available for this group, and we can now identify differences with non-Roma women. METHODS: Cross-sectional, epidemiological study from the 2006 Spanish National Health Survey and the first National Health Survey in the Romany population (2006). We analyzed 527 Spanish Roma women aged 16 years and over and 1054 Spanish non-Roma women, age and region matched. RESULTS: Our sample comprised 527 Spanish Roma women and 1054 Spanish non-Roma women. Roma women are more likely to suffer from obesity [odds ratio (OR) 1.91; 95% confidence interval (CI) 1.05-3.50], depression and migraine. Roma women have significantly higher values for alcohol consumption than non-Roma women (OR, 3.77; 95% CI, 2.32-6.13). The percentage of Roma women, who have had a smear test and a mammography, is significantly lower than that of non-Roma women. CONCLUSIONS: Our comparison showed that Spanish Roma women have a poorer health profile, worse lifestyles and more inequality in the use of health-care resources than non-Roma women, especially with respect to prevention. PMID- 20943988 TI - The matrix protein of vesicular stomatitis virus binds dynamin for efficient viral assembly. AB - Matrix proteins (M) direct the process of assembly and budding of viruses belonging to the Mononegavirales order. Using the two-hybrid system, the amino terminal part of vesicular stomatitis virus (VSV) M was shown to interact with dynamin pleckstrin homology domain. This interaction was confirmed by coimmunoprecipitation of both proteins in cells transfected by a plasmid encoding a c-myc-tagged dynamin and infected by VSV. A role for dynamin in the viral cycle (in addition to its role in virion endocytosis) was suggested by the fact that a late stage of the viral cycle was sensitive to dynasore. By alanine scanning, we identified a single mutation of M protein that abolished this interaction and reduced virus yield. The adaptation of mutant virus (M.L4A) occurred rapidly, allowing the isolation of revertants, among which the M protein, despite having an amino acid sequence distinct from that of the wild type, recovered a significant level of interaction with dynamin. This proved that the mutant phenotype was due to the loss of interaction between M and dynamin. The infectious cycle of the mutant virus M.L4A was blocked at a late stage, resulting in a quasi-absence of bullet-shaped viruses in the process of budding at the cell membrane. This was associated with an accumulation of nucleocapsids at the periphery of the cell and a different pattern of VSV glycoprotein localization. Finally, we showed that M-dynamin interaction affects clathrin-dependent endocytosis. Our study suggests that hijacking the endocytic pathway might be an important feature for enveloped virus assembly and budding at the plasma membrane. PMID- 20943989 TI - Cyclin T1/CDK9 interacts with influenza A virus polymerase and facilitates its association with cellular RNA polymerase II. AB - Influenza virus RNA-dependent RNA polymerase scavenges the 5' cap from host pre mRNA to prime viral transcription initiation. It is also well established that viral RNA-dependent RNA polymerase (vRNP) associates with cellular RNA polymerase II (Pol II), on which viral replication depends. Here we report that cyclin T1/CDK9 can interact with influenza virus polymerase and facilitate its association with cellular Pol II. The immunodepletion of cyclin T1/CDK9 totally abolished the association of vRNP with the C-terminal domain (CTD) Ser-2 phosphorylated form of RNA polymerase II. Further studies showed that overexpression of cyclin T1/CDK9 increased the transcription activity of vRNP, while knockdown of cyclin T1/CDK9 impaired viral replication. Our results suggest that cyclin T1/CDK9 serves as an adapter to mediate the interaction of vRNP and RNA Pol II and promote viral transcription. PMID- 20943991 TI - Excessive drinking and history of unemployment and cohabitation in Danish men born in 1953. AB - BACKGROUND: Few studies exist on social inequality of excessive drinking in Denmark and differences seem to be less pronounced than in other European countries. The aims of this study were to investigate how history of employment and cohabitation is associated with excessive drinking and to study interaction between both. METHODS: Birth-cohort study of 6112 Danish men born in 1953 with follow-up in 2004 on excessive drinking at age 51 years. RESULTS: Excessive drinking (between 22 and 35 units of alcohol per week) differed little depending on history of unemployment and cohabitation. Risk of very excessive drinking (drinking >35 units of alcohol per week) increased with number of job losses ranging from one job-loss [odds ratio (OR) 1.72, 95% confidence interval (CI) 1.39-2.14] to three or more job-losses (OR 2.48, 95% CI 1.75-3.52)--and duration of unemployment--ranging from 1 to 5 years (OR 1.34, 95% CI 1.11-1.63) to >=10 years (OR 4.16, CI 3.13-5-53). Very excessive drinking was also associated with number of broken partnerships-ranging from one broken partnership (OR 1.43, 95% CI 1.16-1.77) to three or more broken partnerships (OR 2.69, 95% CI 2.03-3.55)- and with living alone for >5 years--ranging from 6 to 9 years (OR 1.73, 95% CI 1.30-2.29) to >=10 years (OR 2.55, 95% CI 2.04-3.55). We found an interaction between the number of job-losses and of broken partnerships in relation to very excessive drinking. CONCLUSIONS: Very excessive drinking is related to number of job-losses, broken partnerships, living alone and duration of unemployment. PMID- 20943992 TI - Enforcement of regional bans on tobacco sales to minors in Switzerland--example of missed opportunity? AB - Tobacco control policies, aiming at reducing youth's access to tobacco, revealed positive outcomes and were implemented in most of the European countries. A naturalistic field study was conducted to assess retailer compliance with a regional ban forbidding selling tobacco products to youths under the age of 18 in a Swiss canton. Results revealed that, 20 months after implementation, the ban was respected by about one out of seven retailers and compliance did not improve significantly over the following 24-month period. Potentials for concrete improvements were observed and a call for stronger implementation at the regional and local levels was made. PMID- 20943993 TI - Health and the need for health promotion in hospital patients. AB - BACKGROUND: Integrated health promotion improves clinical outcomes after hospital treatment. The first step towards implementing evidence-based health promotion in hospitals is to estimate the need for health promoting activities directed at hospital patients. The aim of this study was to identify the distribution and association of individual health risk factors in a Norwegian hospital population and to estimate the need for health promotion in this population. METHODS: We used a validated documentation model (HPH-DATA Model) to identify the prevalence of patients with nutritional risk (measurements of waist and weight), self reported physical inactivity, daily smoking and hazardous drinking. We used logistic regression to describe the associations between health risk factors and demographic characteristics. RESULTS: Out of 10 included patients, 9 (N = 1522) had one or more health risk factors. In total 68% (N = 1026) were overweight, 44% (N = 660) at risk of under-nutrition, 38% (N = 574) physically inactive, 19% (N = 293) were daily smokers and 4% (N = 54) hazardous drinkers. We identified a new clinical relevant association between under-nutrition and smoking. The association between hazardous drinking and smoking was sustained. CONCLUSION: Nearly all patients included in this study had one or more health risk factors that could aggravate clinical outcomes. There is a significant need, and potential, for health-promoting interventions. Multi-factorial interventions may be frequently indicated and should be the subject of interventional studies. PMID- 20943994 TI - Mental health among the unemployed and the unemployment rate in the municipality. AB - BACKGROUND: Previous research has shown that unemployment experiences increase the risk of poor mental health and that this effect differs depending on individual characteristics. Relatively little is known, however, about how the unemployment rate and labour market conditions impact the relationship. This study investigates how municipal unemployment rates and vacancy rates affect mental health in a nationally representative longitudinal survey of initially unemployed Swedish respondents. METHODS: The study uses a nationally representative longitudinal survey of currently and recently unemployed people in Sweden, in which respondents were re-interviewed one year after the initial interview. Mental health was measured using the GHQ-12. The present article uses multilevel models (hierarchical linear models) to combine municipal-level information on unemployment levels and vacancy rates with individual-level control variables. RESULTS: Higher municipal vacancy rates improved mental health among the unemployed. However, no coherent effect of municipal unemployment rate on the relationship between unemployment and mental health was found. CONCLUSIONS: The effect of municipal vacancy rates can be understood in terms of the impact of perceived opportunity on the sense of life-course predictability. That there was no effect of municipal unemployment rate indicates that high local unemployment levels do not reduce the sense of shame and perceived stigma among the unemployed. Taken together, our findings would seem to present a rather bleak picture of the current dramatic labour market situation. The unemployed will be negatively affected by the extremely low demand for labour, while they will not be able to take comfort from their growing numbers. PMID- 20943995 TI - Social and behavioural characteristics of a sample of AIDS Help-Line users never tested for HIV in Italy. AB - BACKGROUND: We conducted an anonymous cross-sectional telephone survey among persons who had never undergone HIV testing to determine their socio-demographic characteristics, behaviour, risk perception and reasons for not being tested. METHODS: A questionnaire was administered to adult callers to the Italian National AIDS Help-Line who reported that they had never been tested for HIV. RESULTS: The study sample consisted of 539 individuals. The individual who does not undergo testing is young (median age 30 years), male (85.5%), unmarried (79.0%), employed (70.1%) and with a high educational level (81.6%). More than two-thirds of the respondents had little or no perception of risk. Among persons who had more than one sexual partner, 47.0% do not use a condom. When dividing the respondents into two groups (i.e. high risk and lower risk), the results showed that the proportion of respondents with a high risk was higher among women (73.1%), among persons >35 years (76.3%) and among persons with a low educational level (77.8%). Individuals who had hadbeen seen in health-care facilities also reported high-risk behaviour. CONCLUSIONS: The results indicate the socio demographic characteristics, behaviours, risk perception and reasons for not being tested among a sample of callers to Italy's National AIDS Help-Line, and they confirm the necessity of gearing prevention activities towards heterosexuals and young adults with a low perception of risk. PMID- 20943996 TI - Inhibition of matrix metalloproteinase-3 and -13 synthesis induced by IL-1beta in chondrocytes from mice lacking microsomal prostaglandin E synthase-1. AB - Joint destruction in arthritis is in part due to the induction of matrix metalloproteinase (MMP) expression and their inhibitors, especially MMP-13 and 3, which directly degrade the cartilage matrix. Although IL-1beta is considered as the main catabolic factor involved in MMP-13 and -3 expression, the role of PGE(2) remains controversial. The goal of this study was to determine the role of PGE(2) on MMP synthesis in articular chondrocytes using mice lacking microsomal PGE synthase-1 (mPGES-1), which catalyses the rate-limiting step of PGE(2) synthesis. MMP-3 and MMP-13 mRNA and protein expressions were assessed by real time RT-PCR, immunoblotting, and ELISA in primary cultures of articular chondrocytes from mice with genetic deletion of mPGES-1. IL-1beta-induced PGE(2) synthesis was dramatically reduced in mPGES-1(-/-) and mPGES-1(+/-) compared with mPGES-1(+/+) chondrocytes. A total of 10 ng/ml IL-1beta increased MMP-3 and MMP 13 mRNA, protein expression, and release in mPGES-1(+/+) chondrocytes in a time dependent manner. IL-1beta-induced MMP-3 and MMP-13 mRNA expression, protein expression, and release decreased in mPGES-1(-/-) and mPGES-1(+/-) chondrocytes compared with mPGES-1(+/+) chondrocytes from 8 up to 24 h. Otherwise, MMP inhibition was partially reversed by addition of 10 ng/ml PGE(2) in mPGES-1(-/-) chondrocytes. Finally, in mPGES-1(-/-) chondrocytes treated by forskolin, MMP-3 protein expression was significantly decreased compared with wild-type, suggesting that PGE(2) regulates MMP-3 expression via a signaling pathway dependent on cAMP. These results demonstrate that PGE(2) plays a key role in the induction of MMP-3 and MMP-13 in an inflammatory context. Therefore, mPGES-1 could be considered as a critical target to counteract cartilage degradation in arthritis. PMID- 20943997 TI - Polyinosinic-polycytidylic acid treatment of Friend retrovirus-infected mice improves functional properties of virus-specific T cells and prevents virus induced disease. AB - The induction of type I IFN is the most immediate host response to viral infections. Type I IFN has a direct antiviral activity mediated by antiviral enzymes, but it also modulates the function of cells of the adaptive immune system. Many viruses can suppress type I IFN production, and in retroviral infections, the initial type I IFN is weak. Thus, one strategy of immunotherapy in viral infection is the exogenous induction of type I IFN during acute viral infection by TLR ligands. Along these lines, the TLR3/MDA5 ligand polyinosinic polycytidylic acid [poly(I:C)] has already been used to treat viral infections. However, the immunological mechanisms underlying this successful therapy have not been defined until now. In this study, the Friend retrovirus (FV) mouse model was used to investigate the mode of action of poly(I:C) in antiretroviral immunotherapy. Postexposure, poly(I:C) treatment of FV-infected mice resulted in a significant reduction in viral loads and protection from virus-induced leukemia. This effect was IFN dependent because type I IFN receptor-deficient mice could not be protected by poly(I:C). The poly(I:C)-induced IFN response resulted in the expression of antiviral enzymes, which suppressed FV replication. Also, the virus-specific T cell response was augmented. Interestingly, it did not enhance the number of virus-specific CD4(+) and CD8(+) T cells, but rather the functional properties of these cells, such as cytokine production and cytotoxic activity. The results demonstrate a direct antiviral and immunomodulatory effect of poly(I:C) and, therefore, suggests its potential for clinical treatment of retroviral infections. PMID- 20943998 TI - Active immunization with amyloid-beta 1-42 impairs memory performance through TLR2/4-dependent activation of the innate immune system. AB - Active immunization with amyloid-beta (Abeta) peptide 1-42 reverses amyloid plaque deposition in the CNS of patients with Alzheimer's disease and in amyloid precursor protein transgenic mice. However, this treatment may also cause severe, life-threatening meningoencephalitis. Physiological responses to immunization with Abeta(1-42) are poorly understood. In this study, we characterized cognitive and immunological consequences of Abeta(1-42)/CFA immunization in C57BL/6 mice. In contrast to mice immunized with myelin oligodendrocyte glycoprotein (MOG)(35 55)/CFA or CFA alone, Abeta(1-42)/CFA immunization resulted in impaired exploratory activity, habituation learning, and spatial-learning abilities in the open field. As morphological substrate of this neurocognitive phenotype, we identified a disseminated, nonfocal immune cell infiltrate in the CNS of Abeta(1 42)/CFA-immunized animals. In contrast to MOG(35-55)/CFA and PBS/CFA controls, the majority of infiltrating cells in Abeta(1-42)/CFA-immunized mice were CD11b(+)CD14(+) and CD45(high), indicating their blood-borne monocyte/macrophage origin. Immunization with Abeta(1-42)/CFA was significantly more potent than immunization with MOG(35-55)/CFA or CFA alone in activating macrophages in the secondary lymphoid compartment and peripheral tissues. Studies with TLR2/4 deficient mice revealed that the TLR2/4 pathway mediated the Abeta(1-42) dependent proinflammatory cytokine release from cells of the innate immune system. In line with this, TLR2/4 knockout mice were protected from cognitive impairment upon immunization with Abeta(1-42)/CFA. Thus, this study identifies adjuvant effects of Abeta(1-42), which result in a clinically relevant neurocognitive phenotype highlighting potential risks of Abeta immunotherapy. PMID- 20943999 TI - Hydroxylase inhibition abrogates TNF-alpha-induced intestinal epithelial damage by hypoxia-inducible factor-1-dependent repression of FADD. AB - Hydroxylase inhibitors stabilize hypoxia-inducible factor-1 (HIF-1), which has barrier-protective activity in the gut. Because the inflammatory cytokine TNF alpha contributes to inflammatory bowel disease in part by compromising intestinal epithelial barrier integrity, hydroxylase inhibition may have beneficial effects in TNF-alpha-induced intestinal epithelial damage. The hydroxylase inhibitor dimethyloxalylglycin (DMOG) was tested in a murine model of TNF-alpha-driven chronic terminal ileitis. DMOG-treated mice experienced clinical benefit and showed clear attenuation of chronic intestinal inflammation compared with that of vehicle-treated littermates. Additional in vivo and in vitro experiments revealed that DMOG rapidly restored terminal ileal barrier function, at least in part through prevention of TNF-alpha-induced intestinal epithelial cell apoptosis. Subsequent transcriptional studies indicated that DMOG repressed Fas-associated death domain protein (FADD), a critical adaptor molecule in TNFR-1 mediated apoptosis, in an HIF-1alpha-dependent manner. Loss of this FADD repression by HIF-1alpha-targeting small interfering RNA significantly diminished the antiapoptotic action of DMOG. Additional molecular studies led to the discovery of a previously unappreciated HIF-1 binding site in the FADD promoter, which controls repression of FADD during hypoxia. As such, the results reported in this study allowed the identification of an innate mechanism that protects intestinal epithelial cells during (inflammatory) hypoxia, by direct modulation of death receptor signaling. Hydroxylase inhibition could represent a promising alternative treatment strategy for hypoxic inflammatory diseases, including inflammatory bowel disease. PMID- 20944000 TI - IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. AB - Experimental autoimmune encephalomyelitis (EAE) is a Th1 and Th17 cell-mediated autoimmune disease of the CNS. IDO and tryptophan metabolites have inhibitory effects on Th1 cells in EAE. For Th17 cells, IDO-mediated tryptophan deprivation and small molecule halofuginone-induced amino acid starvation response were shown to activate general control nonrepressed 2 (GCN2) kinase that directly or indirectly inhibits Th17 cell differentiation. However, it remains unclear whether IDO and tryptophan metabolites impact the Th17 cell response by mechanisms other than the GCN2 kinase pathway. In this article, we show that IDO deficient mice develop exacerbated EAE with enhanced encephalitogenic Th1 and Th17 cell responses and reduced regulatory T cell (Treg) responses. Administration of the downstream tryptophan metabolite 3-hydroxyanthranillic acid (3-HAA) enhanced the percentage of Tregs, inhibited Th1 and Th17 cells, and ameliorated EAE. We further demonstrate that Th17 cells are less sensitive to direct suppression by 3-HAA than are Th1 cells. 3-HAA treatment in vitro reduced IL-6 production by activated spleen cells and increased expression of TGF-beta in dendritic cells (DCs), which correlated with enhanced levels of Tregs, suggesting that 3-HAA-induced Tregs contribute to inhibition of Th17 cells. By using a DC-T cell coculture, we found that 3-HAA-treated DCs expressed higher levels of TGF beta and had properties to induce generation of Tregs from anti-CD3/anti-CD28 stimulated naive CD4(+) T cells. Thus, our data support the hypothesis that IDO induces the generation of Tregs via tryptophan metabolites, such as 3-HAA, which enhances TGF-beta expression from DCs and promotes Treg differentiation. PMID- 20944001 TI - Rapid T cell receptor delineation reveals clonal expansion limitation of the magnitude of the HIV-1-specific CD8+ T cell response. AB - TCRs mediate CTL specificity, but TCRs recognizing the same epitope often differ between persons due to their stochastic derivation. The role of this variability in the pathogenesis of virus infections and malignancies has been technically difficult to study. We apply an adaptation of TCR spectratyping to study HIV specific CTLs, defining the clonal breadth and sequences of epitope-specific TCRs from PBMCs without cellular sorting or molecular cloning. Examining 48 CTL responses in 12 persons reveals a mean of 4.5 +/- 2.7 clones per response, of both public and private clonotypes. The number of identified epitope-specific TCRs correlates with CTL frequency across epitopes, suggesting that clonal breadth limits the magnitude of the CTL response against HIV-1 in vivo. HLA A- and B-restricted CTLs are similar in their TCR breadth in this small cohort, preliminarily suggesting that qualitative differences may account for their disparate impacts on pathogenesis. Overall, these findings demonstrate that the magnitude of the CTL response in chronic HIV-1 infection is constrained by TCR clonal breadth, suggesting maximal expansion of CTLs in response to chronic antigenic stimulation. PMID- 20944002 TI - An intrinsic mechanism predisposes Foxp3-expressing regulatory T cells to Th2 conversion in vivo. AB - Naturally occurring regulatory T (nTreg) cells express Foxp3 and were originally discovered as immune suppressors critical for self-tolerance and immune homeostasis. Through yet-to-be-defined mechanisms, nTreg cells were recently shown to convert into proinflammatory cells. Particularly, attenuation of Foxp3 expression led to Th2 conversion of nTreg cells in vivo. In this paper, we demonstrated an nTreg-specific mechanism controlling their Th2 conversion. We found that wild-type nTreg cells expressing reduced levels of Foxp3 but not those expressing no Foxp3 produced the Th2 cytokine IL-4. Intriguingly, IL-4 production by converted nTreg cells is required for Th2 differentiation of coexisting naive CD4 T cells in vivo, suggesting that Th2 conversion of nTreg cells might be critical for directing Th2 immune responses. Th2 conversion of nTreg cells was not due to their inability to become Th1 cells, because IFN-gamma was produced by Foxp3-low-expressing cells when IL-4/STAT-6 signaling was abrogated. Surprisingly, however, unlike naive CD4 T cells whose IL-4 production is dependent on STAT-6, Foxp3-low-expressing cells generated IL-4 independent of STAT-6, indicating an intrinsic mechanism that favors nTreg-to-Th2 differentiation. Indeed, compared with naive CD4 T cells, nTreg expressed elevated levels of GATA-3 independent of STAT-6. And GATA-3 was required for nTreg-to-Th2 conversion. Foxp3 may account for this GATA-3 upregulation in nTreg cells, because ectopic expression of Foxp3 preferentially promoted GATA-3 but not T-bet expression. Thus, we have identified an intrinsic mechanism that imposes a Th2/Th1 imbalance and predisposes Foxp3-expressing cells to IL-4 production independent of STAT-6 signaling. PMID- 20944003 TI - A butyrophilin family member critically inhibits T cell activation. AB - The costimulatory molecules in the B7-CD28 families are important in the regulation of T cell activation and tolerance. The butyrophilin family of proteins shares sequence and structure homology with B7 family molecules; however, the function of the butyrophilin family in the immune system has not been defined. In this study, we performed an analysis on multiple butyrophilin molecules and found that butyrophilin-like (BTNL)1 molecule functions to dampen T cell activation. BTNL1 mRNA was broadly expressed, but its protein was only found in APCs and not T cells. The putative receptor for BTNL1 was found on activated T cells and APCs. Also, recombinant BTNL1 molecule inhibited T cell proliferation by arresting cell cycle progression. The administration of neutralizing Abs against BTNL1 provoked enhanced T cell activation and exacerbated disease in autoimmune and asthma mouse models. Therefore, BTNL1 is a critical inhibitory molecule for T cell activation and immune diseases. PMID- 20944004 TI - Dysregulation of inflammatory responses by chronic circadian disruption. AB - Circadian rhythms modulate nearly every mammalian physiological process. Chronic disruption of circadian timing in shift work or during chronic jet lag in animal models leads to a higher risk of several pathologies. Many of these conditions in both shift workers and experimental models share the common risk factor of inflammation. In this study, we show that experimentally induced circadian disruption altered innate immune responses. Endotoxemic shock induced by LPS was magnified, leading to hypothermia and death after four consecutive weekly 6-h phase advances of the light/dark schedule, with 89% mortality compared with 21% in unshifted control mice. This may be due to a heightened release of proinflammatory cytokines in response to LPS treatment in shifted animals. Isolated peritoneal macrophages harvested from shifted mice exhibited a similarly heightened response to LPS in vitro, indicating that these cells are a target for jet lag. Sleep deprivation and stress are known to alter immune function and are potential mediators of the effects we describe. However, polysomnographic recording in mice exposed to the shifting schedule revealed no sleep loss, and stress measures were not altered in shifted mice. In contrast, we observed altered or abolished rhythms in the expression of clock genes in the central clock, liver, thymus, and peritoneal macrophages in mice after chronic jet lag. We conclude that circadian disruption, but not sleep loss or stress, are associated with jet lag-related dysregulation of the innate immune system. Such immune changes might be a common mechanism for the myriad negative health effects of shift work. PMID- 20944005 TI - PRDM1/Blimp-1 controls effector cytokine production in human NK cells. AB - NK cells are major effectors of the innate immune response through cytolysis and bridge to the adaptive immune response through cytokine release. The mediators of activation are well studied; however, little is known about the mechanisms that restrain activation. In this report, we demonstrate that the transcriptional repressor PRDM1 (also known as Blimp-1 or PRDI-BF1) is a critical negative regulator of NK function. Three distinct PRDM1 isoforms are selectively induced in the CD56(dim) NK population in response to activation. PRDM1 coordinately suppresses the release of IFN-gamma, TNF-alpha, and TNF-beta through direct binding to multiple conserved regulatory regions. Ablation of PRDM1 expression leads to enhanced production of IFN-gamma and TNF-alpha but does not alter cytotoxicity, whereas overexpression blocks cytokine production. PRDM1 response elements are defined at the IFNG and TNF loci. Collectively, these data demonstrate a key role for PRDM1 in the negative regulation of NK activation and position PRDM1 as a common regulator of the adaptive and innate immune response. PMID- 20944006 TI - Generation of mucosal dendritic cells from bone marrow reveals a critical role of retinoic acid. AB - It is unknown how dendritic cells (DCs) become specialized as mucosal DCs and maintain intestinal homeostasis. We report that a subset of bone marrow cells freshly isolated from C57BL/6 mice express the retinoic acid (RA)-synthesizing enzyme aldehyde dehydrogenase family 1, subfamily A2 (ALDH1a2) and are capable of providing RA to DC precursors in the bone marrow microenvironment. RA induced bone marrow-derived DCs to express CCR9 and ALDH1a2 and conferred upon them mucosal DC functions, including induction of Foxp3(+) regulatory T cells, IgA secreting B cells, and gut-homing molecules. This response of DCs to RA was dependent on a narrow time window and stringent dose effect. RA promoted bone marrow-derived DC production of bioactive TGF-beta by inhibiting suppressor of cytokine signaling 3 expression and thereby enhancing STAT3 activation. These RA effects were evident in vivo, in that mucosal DCs from vitamin A-deficient mice had reduced mucosal DC function, namely failure to induce Foxp3(+) regulatory T cells. Furthermore, MyD88 signaling enhanced RA-educated DC ALDH1a2 expression and was required for optimal TGF-beta production. These data indicate that RA plays a critical role in the generation of mucosal DCs from bone marrow and in their functional activity. PMID- 20944007 TI - Temporal differences in the dependency on phosphoinositide-dependent kinase 1 distinguish the development of invariant Valpha14 NKT cells and conventional T cells. AB - This study uses two independent genetic strategies to explore the requirement for phosphoinositide-dependent kinase-1 (PDK1) in the development of mature T cell populations from CD4/CD8 double-positive thymocytes. The data show that CD4/CD8 double-positive thymocytes that do not express PDK1 or express a catalytically inactive PDK1 mutant fail to produce mature invariant Valpha14 NKT cells but can differentiate to conventional CD4, CD8, or regulatory T cell subsets in the thymus. The PDK1 requirement for Valpha14 NKT cell development reflects that these cells require the PDK1 substrate protein kinase B to meet the metabolic demands for proliferative expansion in response to IL-15 or AgR stimulation. There is also constitutive PDK1 signaling in conventional alpha/beta T cells that is not required for lineage commitment of these cells but fine-tunes the expression of coreceptors and adhesion molecules. Also, although PDK1 is dispensable for thymic development of conventional alpha/beta T cells, peripheral cells are reduced substantially. This reflects a PDK1 requirement for lymphopenia induced proliferation, a process necessary for initial population of the peripheral T cell niche in neonatal mice. PDK1 is thus indispensable for T cell developmental programs, but the timing of the PDK1 requirement is unique to different T cell subpopulations. PMID- 20944008 TI - PTPalpha activates Lyn and Fyn and suppresses Hck to negatively regulate FcepsilonRI-dependent mast cell activation and allergic responses. AB - Mast cell activation via FcepsilonRI involves activation of the Src family kinases (SFKs) Lyn, Fyn, and Hck that positively or, in the case of Lyn, negatively regulate cellular responses. Little is known of upstream activators of these SFKs in FcepsilonRI-dependent signaling. We investigated the role of receptor protein tyrosine phosphatase (PTP)alpha, a well-known activator of SFKs in diverse signaling systems, FcepsilonRI-mediated mast cell activation, and IgE dependent allergic responses in mice. PTPalpha(-/-) bone marrow-derived mast cells hyperdegranulate and exhibit increased cytokine and cysteinyl leukotriene secretion, and PTPalpha(-/-) mice display enhanced IgE-dependent anaphylaxis. At or proximal to FcepsilonRI, PTPalpha(-/-) cells have reduced IgE-dependent activation of Lyn and Fyn, as well as reduced FcepsilonRI and SHIP phosphorylation. In contrast, Hck and Syk activation is enhanced. Syk hyperactivation correlated with its increased phosphorylation at positive regulatory sites and defective phosphorylation at a negative regulatory site. Distal to FcepsilonRI, we observed increased activation of PI3K and MAPK pathways. These findings demonstrate that PTPalpha activates the FcepsilonRI coupled kinases Lyn and Fyn and suppresses Hck activity. Furthermore, the findings indicate that hyperactivation of PTPalpha(-/-) mast cells and enhanced IgE-dependent allergic responses of PTPalpha(-/-) mice are due to the ablated function of PTPalpha as a critical regulator of Lyn negative signaling. PMID- 20944009 TI - Notch ligand delta-like 4 regulates development and pathogenesis of allergic airway responses by modulating IL-2 production and Th2 immunity. AB - Activation of the canonical Notch pathways has been implicated in Th cell differentiation, but the role of specific Notch ligands in Th2-mediated allergic airway responses has not been completely elucidated. In this study, we show that delta-like ligand 4 (Dll4) was upregulated on dendritic cells in response to cockroach allergen. Blocking Dll4 in vivo during either the primary or secondary response enhanced allergen-induced pathogenic consequences including airway hyperresponsiveness and mucus production via increased Th2 cytokines. In vitro assays demonstrated that Dll4 regulates IL-2 in T cells from established Th2 responses as well as during primary stimulation. Notably, Dll4 blockade during the primary, but not the secondary, response increased IL-2 levels in lung and lymph node of allergic mice. The in vivo neutralization of Dll4 was associated with increased expansion and decreased apoptosis during the primary allergen sensitization. Moreover, Dll4-mediated Notch activation of T cells during primary stimulation in vitro increased apoptosis during the contraction/resting phase of the response, which could be rescued by exogenous IL-2. Consistent with the role for Dll4-mediated IL-2 regulation in overall T cell function, the frequency of IL 4-producing cells was also significantly altered by Dll4 both in vivo and in vitro. These data demonstrate a regulatory role of Dll4 both in initial Th2 differentiation and in Th2 cytokine production in established allergic responses. PMID- 20944010 TI - Slit2 regulates attractive eosinophil and repulsive neutrophil chemotaxis through differential srGAP1 expression during lung inflammation. AB - Directional migration of leukocytes is an essential step in leukocyte trafficking during inflammatory responses. However, the molecular mechanisms governing directional chemotaxis of leukocytes remain poorly understood. The Slit family of guidance cues has been implicated for inhibition of leuocyte migration. We report that Clara cells in the bronchial epithelium secreted Slit2, whereas eosinophils and neutrophils expressed its cell-surface receptor, Robo1. Compared to neutrophils, eosinophils exhibited a significantly lower level of Slit-Robo GTPase-activating protein 1 (srGAP1), leading to activation of Cdc42, recruitment of PI3K to Robo1, enhancment of eotaxin-induced eosinophil chemotaxis, and exaggeration of allergic airway inflammation. Notably, OVA sensitization elicited a Slit2 gradient at so-called bronchus-alveoli axis, with a higher level of Slit2 in the bronchial epithelium and a lower level in the alveolar tissue. Aerosol administration of rSlit2 accelerated eosinophil infiltration, whereas i.v. administered Slit2 reduced eosinophil deposition. In contrast, Slit2 inactivated Cdc42 and suppressed stromal cell-derived factor-1alpha-induced chemotaxis of neutrophils for inhibiting endotoxin-induced lung inflammation, which were reversed by blockade of srGAP1 binding to Robo1. These results indicate that the newly identified Slit2 gradient at the bronchus-alveoli axis induces attractive PI3K signaling in eosinophils and repulsive srGAP1 signaling in neutrophils through differential srGAP1 expression during lung inflammation. PMID- 20944011 TI - Hydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea. AB - Hydroxylases are oxygen-sensing enzymes that regulate cellular responses to hypoxia. Transepithelial Cl(-) secretion, the driving force for fluid secretion, is dependent on O(2) availability for generation of cellular energy. Here, we investigated the role of hydroxylases in regulating epithelial secretion and the potential for targeting these enzymes in treatment of diarrheal disorders. Ion transport was measured as short-circuit current changes across voltage-clamped monolayers of T(84) cells and mouse colon. The antidiarrheal efficacy of dimethyloxallyl glycine (DMOG) was tested in a mouse model of allergic disease. Hydroxylase inhibition with DMOG attenuated Ca(2+)- and cAMP-dependent secretory responses in voltage-clamped T(84) cells to 20.2 +/- 2.6 and 38.8 +/- 6.7% (n=16; P<=0.001) of those in control cells, respectively. Antisecretory actions of DMOG were time and concentration dependent, being maximal after 18 h of DMOG (1 mM) treatment. DMOG specifically inhibited Na(+)/K(+)-ATPase pump activity without altering its expression or membrane localization. In mice, DMOG inhibited agonist induced secretory responses ex vivo and prevented allergic diarrhea in vivo. In conclusion, hydroxylases are important regulators of epithelial Cl(-) and fluid secretion and present a promising target for development of new drugs to treat transport disorders. PMID- 20944012 TI - Functional redundancy of paralogs of an anaphase promoting complex/cyclosome subunit in Caenorhabditis elegans meiosis. AB - The anaphase promoting complex/cyclosome (APC/C) mediates the metaphase-to anaphase transition by instructing the ubiquitination and turnover of key proteins at this stage of the cell cycle. We have recovered a gain-of-function allele in an APC5 subunit of the anaphase promoting complex/cyclosome. This finding led us to investigate further the role of APC5 in Caenorhabditis elegans, which contains two APC5 paralogs. We have shown that these two paralogs, such-1 and gfi-3, are coexpressed in the germline but have nonoverlapping expression patterns in other tissues. Depletion of such-1 or gfi-3 alone does not have a notable effect on the meiotic divisions; however, codepletion of these two factors results in meiotic arrest. In sum, the two C. elegans APC5 paralogs have a redundant function during the meiotic divisions. PMID- 20944013 TI - Insulin/Insulin-like growth factor signaling controls non-Dauer developmental speed in the nematode Caenorhabditis elegans. AB - Identified as a major pathway controlling entry in the facultative dauer diapause stage, the DAF-2/Insulin receptor (InsR) signaling acts in multiple developmental and physiological regulation events in Caenorhabditis elegans. Here we identified a role of the insulin-like pathway in controlling developmental speed during the C. elegans second larval stage. This role relies on the canonical DAF-16/FOXO dependent branch of the insulin-like signaling and is largely independent of dauer formation. Our studies provide further evidence for broad conservation of insulin/insulin-like growth factor (IGF) functions in developmental speed control. PMID- 20944014 TI - Mutual antagonism between the anaphase promoting complex and the spindle assembly checkpoint contributes to mitotic timing in Caenorhabditis elegans. AB - The anaphase promoting complex/cyclosome (APC/C) triggers the separation of sister chromatids and exit from mitosis across eukaryotic evolution. The APC/C is inhibited by the spindle assembly checkpoint (SAC) until all chromosomes have achieved bipolar attachment, but whether the APC/C reciprocally regulates the SAC is less understood. Here, we report the characterization of a novel allele of the APC5 component SUCH-1 in Caenorhabditis elegans. We find that some such-1(t1668) embryos lack paternally contributed DNA and centrioles and assemble a monopolar spindle in the one-cell stage. Importantly, we show that mitosis is drastically prolonged in these embryos, as well as in embryos that are otherwise compromised for APC/C function and assemble a monopolar spindle. This increased duration of mitosis is dependent on the SAC, since inactivation of the SAC components MDF 1/MAD1 or MDF-2/MAD2 rescues proper timing in these embryos. Moreover, partial depletion of the E1 enzyme uba-1 significantly increases mitosis duration upon monopolar spindle assembly. Taken together, our findings raise the possibility that the APC/C negatively regulates the SAC and, therefore, that the SAC and the APC/C have a mutual antagonistic relationship in C. elegans embryos. PMID- 20944015 TI - Overlapping regulation of CenH3 localization and histone H3 turnover by CAF-1 and HIR proteins in Saccharomyces cerevisiae. AB - Accurate chromosome segregation is dependent on the centromere-specific histone H3 isoform known generally as CenH3, or as Cse4 in budding yeast. Cytological experiments have shown that Cse4 appears at extracentromeric loci in yeast cells deficient for both the CAF-1 and HIR histone H3/H4 deposition complexes, consistent with increased nondisjunction in these double mutant cells. Here, we examined molecular aspects of this Cse4 mislocalization. Genome-scale chromatin immunoprecipitation analyses demonstrated broader distribution of Cse4 outside of centromeres in cac1Delta hir1Delta double mutant cells that lack both CAF-1 and HIR complexes than in either single mutant. However, cytological localization showed that the essential inner kinetochore component Mif2 (CENP-C) was not recruited to extracentromeric Cse4 in cac1Delta hir1Delta double mutant cells. We also observed that rpb1-1 mutants displayed a modestly increased Cse4 half-life at nonpermissive temperatures, suggesting that turnover of Cse4 is partially dependent on Pol II transcription. We used genome-scale assays to demonstrate that the CAF-1 and HIR complexes independently stimulate replication-independent histone H3 turnover rates. We discuss ways in which altered histone exchange kinetics may affect eviction of Cse4 from noncentromeric loci. PMID- 20944016 TI - Intrinsic characteristics of neighboring DNA modulate transposable element activity in Drosophila melanogaster. AB - Identifying factors influencing transposable element activity is essential for understanding how these elements impact genomes and their evolution as well as for fully exploiting them as functional genomics tools and gene-therapy vectors. Using a genetics-based approach, the influence of genomic position on piggyBac mobility in Drosophila melanogaster was assessed while controlling for element structure, genetic background, and transposase concentration. The mobility of piggyBac elements varied over more than two orders of magnitude solely as a result of their locations within the genome. The influence of genomic position on element activities was independent of factors resulting in position-dependent transgene expression ("position effects"). Elements could be relocated to new genomic locations without altering their activity if >= 500 bp of genomic DNA originally flanking the element was also relocated. Local intrinsic factors within the neighboring DNA that determined the activity of piggyBac elements were portable not only within the genome but also when elements were moved to plasmids. The predicted bendability of the first 50 bp flanking the 5' and 3' termini of piggyBac elements could account for 60% of the variance in position dependent activity observed among elements. These results are significant because positional influences on transposable element activities will impact patterns of accumulation of elements within genomes. Manipulating and controlling the local sequence context of piggyBac elements could be a powerful, novel way of optimizing gene vector activity. PMID- 20944020 TI - Two languages, two personalities? Examining language effects on the expression of personality in a bilingual context. AB - The issue of whether personality changes as a function of language is controversial. The present research tested the cultural accommodation hypothesis by examining the impact of language use on personality as perceived by the self and by others. In Study 1, Hong Kong Chinese-English bilinguals responded to personality inventories in Chinese or English on perceived traits for themselves, typical native speakers of Chinese, and typical native speakers of English. Study 2 adopted a repeated measures design and collected data at three time points from written measures and actual conversations to examine whether bilinguals exhibited different patterns of personality, each associated with one of their two languages and the ethnicity of their interlocutors. Self-reports and behavioral observations confirmed the effects of perceived cultural norms, language priming, and interlocutor ethnicity on various personality dimensions. It is suggested that use of a second language accesses the perceived cultural norms of the group most associated with that language, especially its prototypic trait profiles, thus activating behavioral expressions of personality that are appropriate in the corresponding linguistic-social context. PMID- 20944018 TI - System-level analysis of genes and functions affecting survival during nutrient starvation in Saccharomyces cerevisiae. AB - An essential property of all cells is the ability to exit from active cell division and persist in a quiescent state. For single-celled microbes this primarily occurs in response to nutrient deprivation. We studied the genetic requirements for survival of Saccharomyces cerevisiae when starved for either of two nutrients: phosphate or leucine. We measured the survival of nearly all nonessential haploid null yeast mutants in mixed populations using a quantitative sequencing method that estimates the abundance of each mutant on the basis of frequency of unique molecular barcodes. Starvation for phosphate results in a population half-life of 337 hr whereas starvation for leucine results in a half life of 27.7 hr. To measure survival of individual mutants in each population we developed a statistical framework that accounts for the multiple sources of experimental variation. From the identities of the genes in which mutations strongly affect survival, we identify genetic evidence for several cellular processes affecting survival during nutrient starvation, including autophagy, chromatin remodeling, mRNA processing, and cytoskeleton function. In addition, we found evidence that mitochondrial and peroxisome function is required for survival. Our experimental and analytical methods represent an efficient and quantitative approach to characterizing genetic functions and networks with unprecedented resolution and identified genotype-by-environment interactions that have important implications for interpretation of studies of aging and quiescence in yeast. PMID- 20944024 TI - Advanced access appointments: Effects on family physician satisfaction, physicians' office income, and emergency department use. AB - OBJECTIVE: To examine the effects of advanced access (same-day physician appointments) on patient and provider satisfaction and to determine its association with other variables such as physician income and patient emergency department use. DESIGN: Patient satisfaction survey and semistructured interviews with physicians and support staff; analysis of physician medical insurance billings and patient emergency department visits. SETTING: Cape Breton, NS. PARTICIPANTS: Patients, physicians, and support staff of 3 comparable family physician practices that had not implemented advanced access and an established advanced access practice. MAIN OUTCOME MEASURES: Self-reported provider and patient satisfaction, physician office income, and patients' emergency department use. RESULTS: The key benefits of implementation of advanced access were an increase in provider and patient satisfaction levels, same or greater physician office income, and fewer less urgent (triage level 4) and nonurgent (triage level 5) emergency department visits by patients. CONCLUSION: Currently within the Central Cape Breton Region, 33% of patients wait 4 or more days for urgent appointments. Findings from this study can be used to enhance primary care physician practice redesign. This research supports many benefits of transitioning to an advanced access model of patient booking. PMID- 20944019 TI - Decoupling of host-symbiont-phage coadaptations following transfer between insect species. AB - Transferring endosymbiotic bacteria between different host species can perturb the coordinated regulation of the host and bacterial genomes. Here we use the most common maternally transmitted bacteria, Wolbachia pipientis, to test the consequences of host genetic background on infection densities and the processes underlying those changes in the parasitoid wasp genus Nasonia. Introgressing the genome of Nasonia giraulti into the infected cytoplasm of N. vitripennis causes a two-order-of-magnitude increase in bacterial loads in adults and a proliferation of the infection to somatic tissues. The host effect on W. pipientis distribution and densities is associated with a twofold decrease in densities of the temperate phage WO-B. Returning the bacteria from the new host species back to the resident host species restores the bacteria and phage to their native densities. To our knowledge, this is the first study to report a host-microbe genetic interaction that affects the densities of both W. pipientis and bacteriophage WO-B. The consequences of the increased bacterial density include a reduction in fecundity, an increase in levels of cytoplasmic incompatibility (CI), and unexpectedly, male to-female transfer of the bacteria to uninfected females and an increased acceptance of densely infected females to interspecific mates. While paternal inheritance of the W. pipientis was not observed, the high incidence of male-to female transfer in the introgressed background raises the possibility that paternal transmission could be more likely in hybrids where paternal leakage of other cytoplasmic elements is also known to occur. Taken together, these results establish a major change in W. pipientis densities and tissue tropism between closely related species and support a model in which phage WO, Wolbachia, and arthropods form a tripartite symbiotic association in which all three are integral to understanding the biology of this widespread endosymbiosis. PMID- 20944026 TI - Family practice registered nurses: The time has come. AB - OBJECTIVE: To provide a picture of the unique role and competencies of family practice registered nurses (FP-RNs). DESIGN: Case-study approach using interviews and focus groups. SETTING: Ontario. PARTICIPANTS: Seven FP-RNs identified as exemplary by family medicine and nursing peers. METHODS: An e-mail was sent to 9200 health care providers from nursing and family medicine, asking them to identify names of exemplary family practice nurses. Using a purposive sampling methodology, 7 exemplary FP-RNs were selected, taking into consideration the number of years in practice as a nurse, location of practice, length of practice as an FP-RN, and type of family practice. Individual interviews were held, and focus groups were organized with colleagues. Narratives were analyzed iteratively by the project team. MAIN FINDINGS: Four main themes emerged: The first theme relates to the relationship-centred approach to care delivered by FP-RNs, founded upon trust. The second theme highlights the FP-RN's unique skills in balancing the priorities of patients, colleagues, and the clinic as a whole. The third theme capitalizes on the nurses' commitment to advancing their learning to enhance their abilities to be FP-RNs. The fourth theme illuminates the perspectives shared by FP-RNs that family practice is uniquely different from acute care in the manner in which care is delivered. We draw attention to the approach and role of FP-RNs in Ontario. The 4 themes that emerged have striking similarities to stories shared by family physicians and to the evolutionary development of the discipline of family medicine. CONCLUSION: We believe the findings from this paper can help shape the role of the FP-RN within clinical practice and that they will propagate discussion among nursing educators to consider the necessary educational preparation required to develop the FP-RNs needed in this country. PMID- 20944025 TI - Interprofessional collaboration in family health teams: An Ontario-based study. AB - OBJECTIVE: To examine family health team (FHT) members' perspectives and experiences of interprofessional collaboration and perceived benefits. DESIGN: Qualitative case study using semistructured interviews. SETTING: Fourteen FHTs in urban and rural Ontario. PARTICIPANTS: Purposeful sample of the members of 14 FHTs, including family physicians, nurse practitioners, nurses, dietitians, social workers, pharmacists, and managers. METHODS: A multiple case-study approach involving 14 FHTs was employed. Thirty-two semistructured interviews were conducted and data were analyzed by employing an inductive thematic approach. A member-checking technique was also undertaken to enhance the validity of the findings. MAIN FINDINGS: Five main themes are reported: rethinking traditional roles and scopes of practice, management and leadership, time and space, interprofessional initiatives, and early perceptions of collaborative care. CONCLUSION: This study shows the importance of issues such as roles and scopes of practice, leadership, and space to effective team-based primary care, and provides a framework for understanding different types of interprofessional interventions used to support interprofessional collaboration. PMID- 20944027 TI - Physician, heal thyself: Survey of users of the Quebec Physicians Health Program. AB - OBJECTIVE: To document the opinions of the users of the Quebec Physicians Health Program (QPHP) about the services they received. DESIGN: Mailed questionnaire. SETTING: Quebec. PARTICIPANTS: A total of 126 physicians who used QPHP services between 1999 and 2004. MAIN OUTCOME MEASURES: Users' overall rating of the QPHP services, their opinions about the program, and whether their situations improved as a result of accessing QPHP services. RESULTS: Ninety-two of the 126 physicians surveyed returned their completed questionnaires, providing a response rate of 73%. Most respondents thought that the QPHP services were good or excellent (90%), most would use the program again (86%) or recommend it (96%), and most thought the Quebec physician associations and the College des medecins du Quebec should continue funding the QPHP (97%). Most respondents thought the service confidentiality was excellent (84%), as was staff professionalism (82%), and 62% thought the quality of the services they were referred to was excellent. However, only 57% believed their situations had improved with the help of the QPHP. CONCLUSION: The QPHP received good marks from its users. Given the effects of physician burnout on patients and on the health care system, it is not only a personal problem, but also a collective problem. Thus, actions are needed not only to set up programs like the QPHP for those suffering from burnout, but also to prevent these types of problems. Because family physicians are likely to be the first ones consulted by their physician patients in distress, they play a key role in acknowledging these problems and referring those colleagues to the appropriate help programs when needed. PMID- 20944029 TI - All my possessions for a moment of time. PMID- 20944031 TI - Asthma management in the real world: The perils of simplicity. PMID- 20944032 TI - Should medical journals carry pharmaceutical advertising?: YES. PMID- 20944017 TI - Contributions of flowering time genes to sunflower domestication and improvement. AB - Determining the identity and distribution of molecular changes leading to the evolution of modern crop species provides major insights into the timing and nature of historical forces involved in rapid phenotypic evolution. In this study, we employed an integrated candidate gene strategy to identify loci involved in the evolution of flowering time during early domestication and modern improvement of the sunflower (Helianthus annuus). Sunflower homologs of many genes with known functions in flowering time were isolated and cataloged. Then, colocalization with previously mapped quantitative trait loci (QTLs), expression, or protein sequence differences between wild and domesticated sunflower, and molecular evolutionary signatures of selective sweeps were applied as step-wise criteria for narrowing down an original pool of 30 candidates. This process led to the discovery that five paralogs in the flowering locus T/terminal flower 1 gene family experienced selective sweeps during the evolution of cultivated sunflower and may be the causal loci underlying flowering time QTLs. Our findings suggest that gene duplication fosters evolutionary innovation and that natural variation in both coding and regulatory sequences of these paralogs responded to a complex history of artificial selection on flowering time during the evolution of cultivated sunflower. PMID- 20944033 TI - Should medical journals carry pharmaceutical advertising?: NO. PMID- 20944034 TI - Gairdner was wrong. PMID- 20944035 TI - Foreskin management. PMID- 20944036 TI - Sensitive to emotional needs. PMID- 20944037 TI - Rebuttal: palivizumab for the prevention of respiratory syncytial virus infection. PMID- 20944038 TI - Empathy training a must for physicians. PMID- 20944039 TI - Prenatal genetic counseling in cross-cultural medicine: A framework for family physicians. AB - OBJECTIVE: To help family physicians practise effective genetic counseling and offer practical strategies for cross-cultural communication in the context of prenatal genetic counseling. SOURCES OF INFORMATION: PubMed and the Cochrane Database of Systematic Reviews were searched. Most evidence was level II and some was level III. MAIN MESSAGE: The values and beliefs of practitioners, no less than those of patients, are shaped by culture. In promoting a patient's best interest, the assumptions of both the patient and the provider must be held up for examination and discussed in the attempt to arrive at a consensus. Through the explicit discussion and formation of trust, the health professionals, patients, and family members who are involved can develop a shared understanding of appropriate therapeutic goals and methods. CONCLUSION: Reflecting on the cultural nature of biomedicine's ideas about risk, disability, and normality helps us to realize that there are many valid interpretations of what is in a patient's best interest. Self-reflection helps to ensure that respectful communication with the specific family and patient is the basis for health care decisions. Overall, this helps to improve the quality of care. PMID- 20944040 TI - Fish consumption in pregnancy and fetal risks of methylmercury toxicity. AB - QUESTION: Because I practise in a rural area with a large number of lakes, I have patients planning pregnancy who consume relatively large amounts of fish harvested by their families. What should be my advice to them? ANSWER: A recent Motherisk study has shown that fairly commonly these women's mercury levels exceed the threshold level for cognitive effects. Women should not consume excessive amounts of seafood in pregnancy (ie, no more than 2 weekly average size servings). Hair mercury level above 0.3 MUg/g indicates a potentially excessive body burden. PMID- 20944041 TI - Permethrin for scabies in children. AB - QUESTION: I frequently see children with scabies in my practice. A variety of medications are available to treat scabies. Permethrin is one of the most common medications used. Is permethrin a safe and effective option for children? ANSWER: Scabies is a common parasitic skin infection. It is highly prevalent in young children. Topical permethrin (5% cream) is a safe and effective scabicide in children. It is recommended as a first-line therapy for patients older than 2 months of age. Because there are theoretical concerns regarding percutaneous absorption of permethrin in infants younger than 2 months of age, guidelines recommend 7% sulfur preparation instead of permethrin. PMID- 20944042 TI - Anaphylaxis: A review and update. PMID- 20944043 TI - The autism-vaccine story: fiction and deception? PMID- 20944044 TI - Ocular side effects of bisphosphonates: A case report and literature review. PMID- 20944045 TI - Asthma management made too SIMPLE. PMID- 20944046 TI - Ophthaproblem: Can you identify this condition? 3. Abducent nerve palsy secondary to microvascular ischemia. PMID- 20944047 TI - Dermacase: Can you identify this condition? 4. Progressive pigmented purpuric dermatosis. PMID- 20944048 TI - Dart method: A technique for problem-free vaccinations. PMID- 20944049 TI - Postdated versus usual delayed antibiotic prescriptions in primary care: Reduction in antibiotic use for acute respiratory infections? AB - OBJECTIVE: To determine whether postdating delayed antibiotic prescriptions results in a further decrease (over usual delayed prescriptions) in antibiotic use. DESIGN: Randomized controlled trial. SETTING: A small rural town in Newfoundland and Labrador. PARTICIPANTS: A total of 149 consecutive adult primary care patients who presented with acute upper respiratory tract infections. INTERVENTION: Delayed prescriptions for patients who might require antibiotics were randomly dated either the day of the office visit (ie, the usual group) or 2 days later (ie, the postdated group). MAIN OUTCOME MEASURES: Whether or not the prescriptions were filled and the time it took for the patients to fill the prescriptions were noted by the 4 local pharmacies and relayed to the investigators. RESULTS: In total, 149 delayed antibiotic prescriptions were written, 1 per patient. Of the 74 usual delayed prescriptions given out, 32 (43.2%) were filled; of the 75 postdated delayed prescriptions given out, 33 (44.0%) were filled. Sixteen patients from each group filled their delayed prescriptions earlier than the recommended 48 hours. Statistical analyses-chi2 tests to compare the rates of antibiotic use between the 2 groups and t tests to compare the mean time to fill the prescription between the 2 groups-indicated that these results were not significant (P > .05). CONCLUSION: Although delayed prescriptions reduce the rate of antibiotic use, postdating the delayed prescription does not seem to lead to further reduction in use. PMID- 20944050 TI - [Copyright and right to know]. AB - Imagine that one of the texts published this month in the Canadian Family Physician (CFP) you are interested and want to send to a friend. Nothing more easy, is not it? You simply make a copy or import it and send the attached document. Although this document was protected, many ways you would have easy access to be saved under another format or by printing just as it appears on the screen. You could also ask the librarian for a hospital, university or medical association to which you belong, to the steps for you. In fact, nowadays, getting a paper published in the MFC or in another medical journal is relatively easy. PMID- 20944051 TI - Introducing Family Matters in CFP: Examinations. PMID- 20944052 TI - Masters of complexity: Celebrating the muddiness of family practice. PMID- 20944057 TI - A disease-relevant high-content screening assay to identify anti-inflammatory compounds for use in cystic fibrosis. AB - Chronic lung inflammation caused by bacterial pathogenesis through activation of nuclear factor kappa B (NFkappaB)-responsive proinflammatory genes is a major hurdle in the management of lung disease in cystic fibrosis (CF) patients. The authors generated a disease-relevant cell-based high-content screen to identify novel anti-inflammatory compounds for treating lung inflammation in CF. The human bronchial epithelial cell line KKLEB, harboring the most common form of mutation that causes CF, was modified to express an NFkappaB-responsive green fluorescent protein (GFP) reporter. After creation, the cell line was tested for its ability to respond to disease-relevant inflammatory stimuli elicited by treatment of cells with filtrates of Pseudomonas aeruginosa isolated from the airways of a CF patient. P. aeruginosa filtrates potently activated NFkappaB-responsive GFP reporter expression in cells. Subsequently, the assay was optimized for high throughput screening (HTS) through generation of a Z factor (~0.5) and by testing its tolerance to the commonly used solvents ethanol and DMSO. A pilot library of clinically approved compounds was screened for assay validation. Several compounds with known NFkappaB inhibitory activity were identified, including several steroidal compounds that have been clinically tested in CF. Thus, the assay can be used in a broader HTS campaign to find anti-inflammatory agents for use in CF. PMID- 20944056 TI - Translating the diabetes prevention program for Northern Plains Indian youth through community-based participatory research methods. AB - PURPOSE: The purpose of this study was to use a community-based participatory research (CBPR) approach to translate the original Diabetes Prevention Program (DPP) to be age and culturally specific for American Indian (AI) youth. METHODS: Tribally enrolled members on 2 Montana Indian reservations conducted focus groups and interviews to discuss community members' perspectives of factors that encouraged or were barriers to healthy diet and exercise behaviors in AI youth. In total, 31 community members, aged 10 to 68 years old, participated in 4 focus groups and 14 individual interviews. Participants were self-identified as elder, cultural expert, tribal health worker, educator, parent/guardian, youth, or school food service worker. Researchers analyzed transcripts based on inductive methods of grounded theory. RESULTS: Data analysis revealed translating the DPP to youth was contingent on the lessons incorporating cultural strategies for healthy behaviors in youth such as berry picking, gardening, horseback riding, and dancing; improving knowledge and access to healthy foods and physical activity for youth and their parents; having interactive, hands-on learning activities for healthy lifestyles in the DPP lessons; using a group format and tribal members to deliver the DPP lessons; and having tribal elders talk to youth about the importance of adopting healthy behaviors when they are young. CONCLUSIONS: A CBPR approach engaged community members to identify strategies inherent in their culture, tradition, and environment that could effectively translate the DPP to Montana Indian youth living in rural reservation communities. PMID- 20944058 TI - Ethical practice in sex offender assessment: consideration of actuarial and polygraph methods. AB - The current generation of community protection laws represents a shift in priorities that may see the individual rights of sex offenders compromised for the goal of public safety. At the center of many judicial decisions under these laws are the risk assessment reports provided by mental health practitioners. The widespread enactment of laws allowing for additional sanctions for sex offenders, and a burgeoning research literature regarding the methods used to assess risk have served to heighten rather than resolve the ethical concerns associated with professional practice in this area. This article examines ethical issues inherent in the use of two assessment methods commonly used with sex offenders in the correctional context, focusing on actuarial measures and polygraph tests. Properly conducted and adequately reported actuarial findings are considered to provide useful information of sufficient accuracy to inform rather than mislead judicial decision makers, although careful consideration must be given to the limitations of current measures in each individual case. Despite its increasing use, polygraph testing is considered controversial, with little consensus regarding its accuracy or appropriate applications. On the basis of the current state of the professional literature regarding the polygraph, its use with sex offenders raises unresolved ethical concerns. PMID- 20944055 TI - Implications of type 2 diabetes on adolescent reproductive health risk: an expert model. AB - PURPOSE: The purpose of this article was to summarize scientific knowledge from an expert panel on reproductive health among adolescents with type 2 diabetes (T2D). METHODS: Using a mental model approach, a panel of experts--representing perspectives on diabetes, adolescents, preconception counseling, and reproductive health--was convened to discuss reproductive health issues for female adolescents with T2D. RESULTS: Several critical issues emerged. Compared with adolescents with type 1 diabetes, (1) adolescents with T2D may perceive their disease as less severe and have less experience managing it, putting them at risk for complications; (2) T2D is more prevalent among African Americans, who may be less trusting of the medical establishment; (3) T2D is associated with obesity, and it is often difficult to change one's lifestyle within family environments practicing sedentary and dietary behaviors leading to obesity; (4) teens with T2D could be more fertile, because obesity is related to earlier puberty; (5) although obese teens with T2D have a higher risk of polycystic ovary syndrome, which is associated with infertility, treatment with metformin can increase fertility; and (6) women with type 2 diabetes are routinely transferred to insulin before or during pregnancy to allow more intensive management. CONCLUSIONS: Findings from the expert panel provide compelling reasons to provide early, developmentally appropriate, culturally sensitive preconception counseling for teens with T2D. PMID- 20944059 TI - The case of juvenile polygraphy as a clinical ethics dilemma. AB - Polygraph interrogations are used by half of all surveyed juvenile sex offender (JSO) treatment programs in the United States. This is a distinctive and controversial practice that is rarely if ever used with other juvenile delinquent populations, and that is rarely used or is banned from JSO treatment programs in other countries. Clinical polygraphy is an ethically sensitive issue because it involves mental health therapists in involuntary coercive interrogations of minors. This article reviews core mental health professional ethics principles for juveniles. JSO polygraphy is used as an illustrative issue for applying human rights principles to a practice in light of its benefits, risks, and available alternatives. PMID- 20944060 TI - The ethics of care and treatment of sex offenders. AB - The ethics of care acknowledges the importance of establishing and maintaining practices that help people to meet their needs, develop and protect basic capabilities for problem solving, emotional functioning, and social interaction, and avoid pain and suffering. In this article, we explore the contribution an ethics of care perspective can make to work with sex offenders. First, we briefly describe five classes of ethical problems evident in work with sex offenders. Second, the concept of care is defined and a justification for a version of care theory provided. Third, we apply the care ethical theory to ethical issues with sex offenders and demonstrate its value in responding to the five classes of problems outlined earlier. PMID- 20944061 TI - Nonenzymatic free radical-catalyzed generation of 15-deoxy-Delta(12,14) prostaglandin J2-like compounds (deoxy-J2-isoprostanes) in vivo. AB - 15-Deoxy-Delta(12,14)-prostaglandin J2 (15-d-PGJ2) is a reactive cyclopentenone eicosanoid generated from the dehydration of cyclooxygenase-derived prostaglandin D2 (PGD2). This compound possesses an alpha,beta-unsaturated carbonyl moiety that can readily adduct thiol-containing biomolecules such as glutathione and cysteine residues of proteins via the Michael addition. Due to its reactivity, 15-d-PGJ2 is thought to modulate inflammatory and apoptotic processes and is believed to be an endogenous ligand for peroxisome proliferator-activated receptor-gamma. However, the extent to which 15-d-PGJ2 is formed in vivo and the mechanisms that regulate its formation are unknown. Previously, we have reported the formation of PGD2 and PGJ2-like compounds, termed D2/J2-isoprostanes (D2/J2-IsoPs), produced in vivo by the free radical-catalyzed peroxidation of arachidonic acid (AA). Based on these findings, we investigated whether 15-d-PGJ2-like compounds are also formed via this nonenzymatic pathway. Here we report the generation of novel 15-d-PGJ2-like compounds, termed deoxy-J2-isoprostanes (deoxy-J2-IsoPs), in vivo, via the nonenzymatic peroxidation of AA. Levels of deoxy-J2-IsoPs increased 12 fold (6.4 +/- 1.1 ng/g liver) in rats after oxidant insult by CCl4 treatment, compared with basal levels (0.55 +/- 0.21 ng/g liver). These compounds may have important bioactivities in vivo under conditions associated with oxidant stress. PMID- 20944062 TI - The role of HDL in innate immunity. PMID- 20944063 TI - Inhibition of pathogen-induced apoptosis by a Coxiella burnetii type IV effector protein. AB - Coxiella burnetii and Legionella pneumophila are evolutionarily related pathogens with different intracellular infection strategies. C. burnetii persists within and is transmitted by mammalian hosts, whereas, L. pneumophila is found primarily in the environment associated with protozoan hosts. Although a type IV secretion system encoded by the defect in organelle trafficking (dot) and intracellular multiplication (icm) genes is a virulence determinant that remains highly conserved in both bacteria, the two pathogens encode a different array of effector proteins that are delivered into host cells by the Dot/Icm machinery. This difference suggests that adaptations to evolutionarily distinct hosts may be reflected in the effector protein repertoires displayed by these two pathogens. Here we provide evidence in support of this hypothesis. We show that a unique C. burnetii effector from the ankyrin repeat (Ank) family called AnkG interferes with the mammalian apoptosis pathway. AnkG was found to interact with the host protein gC1qR (p32). Either the addition of AnkG to the repertoire of L. pneumophila effector proteins or the silencing of p32 in mouse dendritic cells resulted in a gain of function that allowed intracellular replication of L. pneumophila in these normally restrictive mammalian host cells by preventing rapid pathogen-induced apoptosis. These data indicate that p32 regulates pathogen induced apoptosis and that AnkG functions to block this pathway. Thus, emergence of an effector protein that interferes with a proapoptotic signaling pathway directed against intracellular bacteria correlates with adaptation of a pathogen to mammalian hosts. PMID- 20944064 TI - The tryptophan photoproduct 6-formylindolo[3,2-b]carbazole helps genes jump. PMID- 20944065 TI - Molecular and regulatory properties of a public good shape the evolution of cooperation. AB - Public goods cooperation abounds in nature, occurring in organisms ranging from bacteria to humans. Although previous research focused on the behavioral and ecological conditions favoring cooperation, the question of whether the molecular and regulatory properties of the public good itself can influence selection for cooperation has received little attention. Using a metapopulation model, we show that extended molecular durability of a public good--allowing multiple reuse across generations--greatly reduces selection for cheating if (and only if) the production of the public good is facultatively regulated. To test the apparent synergy between public goods durability and facultative regulation, we examined the production of iron-scavenging pyoverdin molecules by the bacterium Pseudomonas aeruginosa, a cooperative behavior that is facultatively regulated in response to iron availability. We show that pyoverdin is a very durable public good and that extended durability significantly enhances fitness. Consistent with our model, we found that nonsiderophore-producing mutants (cheats) had a relative fitness advantage over siderophore producers (cooperators) when pyoverdin durability was low but not when durability was high. This was because cooperators facultatively reduced their investment in pyoverdin production when enough pyoverdin had accumulated in the media-a cost-saving strategy that minimized the ability of cheats to invade. These findings show how molecular properties of cooperative acts can shape the costs and benefits of cooperation. PMID- 20944066 TI - Teichoic acids are temporal and spatial regulators of peptidoglycan cross-linking in Staphylococcus aureus. AB - The cell wall of Staphylococcus aureus is characterized by an extremely high degree of cross-linking within its peptidoglycan (PGN). Penicillin-binding protein 4 (PBP4) is required for the synthesis of this highly cross-linked peptidoglycan. We found that wall teichoic acids, glycopolymers attached to the peptidoglycan and important for virulence in Gram-positive bacteria, act as temporal and spatial regulators of PGN metabolism, controlling the level of cross linking by regulating PBP4 localization. PBP4 normally localizes at the division septum, but in the absence of wall teichoic acids synthesis, it becomes dispersed throughout the entire cell membrane and is unable to function normally. As a consequence, the peptidoglycan of TagO null mutants, impaired in wall teichoic acid biosynthesis, has a decreased degree of cross-linking, which renders it more susceptible to the action of lysozyme, an enzyme produced by different host organisms as an initial defense against bacterial infection. PMID- 20944067 TI - Deconstructing thermodynamic parameters of a coupled system from site-specific observables. AB - Cooperative interactions mediate information transfer between structural domains of a protein molecule and are major determinants of protein function and modulation. The prevalent theories to understand the thermodynamic origins of cooperativity have been developed to reproduce the complex behavior of a global thermodynamic observable such as ligand binding or enzyme activity. However, in most cases the measurement of a single global observable cannot uniquely define all the terms that fully describe the energetics of the system. Here we establish a theoretical groundwork for analyzing protein thermodynamics using site-specific information. Our treatment involves extracting a site-specific parameter (defined as chi value) associated with a structural unit. We demonstrate that, under limiting conditions, the chi value is related to the direct interaction terms associated with the structural unit under observation and its intrinsic activation energy. We also introduce a site-specific interaction energy term (chi(diff)) that is a function of the direct interaction energy of that site with every other site in the system. When combined with site-directed mutagenesis and other molecular level perturbations, analyses of chi values of site-specific observables may provide valuable insights into protein thermodynamics and structure. PMID- 20944068 TI - CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adult mice. AB - Natural killer (NK) cells are granular lymphocytes that are generated from hematopoietic stem cells and play vital roles in the innate immune response against tumors and viral infection. Generation of NK cells is known to require several cytokines, including interleukin-15 (IL-15) and Fms-like tyrosine kinase 3 ligand, but not IL-2 or IL-7. Here we investigated the in vivo role of CXC chemokine ligand-12 (CXCL12) and its primary receptor CXCR4 in NK-cell development. The numbers of NK cells appeared normal in embryos lacking CXCL12 or CXCR4; however, the numbers of functional NK cells were severely reduced in the bone marrow, spleen, and peripheral blood from adult CXCR4 conditionally deficient mice compared with control animals, probably resulting from cell intrinsic CXCR4 deficiency. In culture, CXCL12 enhanced the generation of NK cells from lymphoid-primed multipotent progenitors and immature NK cells. In the bone marrow, expression of IL-15 mRNA was considerably higher in CXCL12-abundant reticular (CAR) cells than in other marrow cells, and most NK cells were in contact with the processes of CAR cells. Thus, CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adults, and CAR cells might function as a niche for NK cells in bone marrow. PMID- 20944069 TI - Transfusion-related acute lung injury: from bedside to bench and back. AB - Over the past 60 years, the transfusion medicine community has attained significant knowledge regarding transfusion-related acute lung injury (TRALI) through the bedside to bench and back to the bedside model. First, at the bedside, TRALI causes hypoxia and noncardiogenic pulmonary edema, typically within 6 hours of transfusion. Second, bedside studies showed a higher incidence in plasma and platelet products than in red blood cell products (the fatal TRALI incidence for plasma is 1:2-300 000 products; platelet, 1:3-400 000; red blood cells, 1:25 002 000), as well as an association with donor leukocyte antibodies (~ 80% of cases). Third, at the bench, antibody-dependent and antibody independent mechanisms have been described, requiring neutrophil and pulmonary endothelial cell activation. Antibodies, as well as alternate substances in blood products, result in neutrophil activation, which, in a susceptible patient, result in TRALI (2-hit hypothesis). Fourth, back to the bedside, policy changes based on results of these studies, such as minimizing use of plasma and platelet products from donors with leukocyte antibodies, have decreased the incidence of TRALI. Thus, steps to mitigate TRALI are in place, but a complete mechanistic understanding of the pathogenesis of TRALI and of which patients are at highest risk remains to be elucidated. PMID- 20944070 TI - Thrombospondin-1 is not the major activator of TGF-beta1 in thrombopoietin induced myelofibrosis. AB - Transforming growth factor-beta1 (TGF-beta1) is the most important cytokine involved in the promotion of myelofibrosis. Mechanisms leading to its local activation in the bone marrow environment remain unclear. As a recent study has highlighted the role of thrombospondin-1 (TSP-1) in platelet-derived TGF-beta1 activation, we investigated the role of TSP-1 in the TPO(high) murine model of myelofibrosis. Two groups of engrafted mice, WT TPO(high) and Tsp-1-null TPO(high), were constituted. All mice developed a similar myeloproliferative syndrome and an increase in total TGF-beta1 levels in the plasma and in extracellular fluids of marrow and spleen. Surprisingly, we were able to detect the active form of TGF-beta1 in Tsp-1-null TPO(high) mice. Accordingly, these mice developed marrow and spleen fibrosis, with intriguingly a higher grade than in WT TPO(high) mice. Our results show that TSP-1 is not the major activator of TGF-beta1 in TPO-induced myelofibrosis, suggesting the contribution of another mechanism in the megakaryocyte/platelet compartment. PMID- 20944071 TI - Aberrant global methylation patterns affect the molecular pathogenesis and prognosis of multiple myeloma. AB - We used genome-wide methylation microarrays to analyze differences in CpG methylation patterns in cells relevant to the pathogenesis of myeloma plasma cells (B cells, normal plasma cells, monoclonal gammopathy of undetermined significance [MGUS], presentation myeloma, and plasma cell leukemia). We show that methylation patterns in these cell types are capable of distinguishing nonmalignant from malignant cells and the main reason for this difference is hypomethylation of the genome at the transition from MGUS to presentation myeloma. In addition, gene-specific hypermethylation was evident at the myeloma stage. Differential methylation was also evident at the transition from myeloma to plasma cell leukemia with remethylation of the genome, particularly of genes involved in cell-cell signaling and cell adhesion, which may contribute to independence from the bone marrow microenvironment. There was a high degree of methylation variability within presentation myeloma samples, which was associated with cytogenetic differences between samples. More specifically, we found methylation subgroups were defined by translocations and hyperdiploidy, with t(4;14) myeloma having the greatest impact on DNA methylation. Two groups of hyperdiploid samples were identified, on the basis of unsupervised clustering, which had an impact on overall survival. Overall, DNA methylation changes significantly during disease progression and between cytogenetic subgroups. PMID- 20944072 TI - Delta-like ligand 4-Notch signaling regulates bone marrow-derived pericyte/vascular smooth muscle cell formation. AB - Delta-like ligand 4 (DLL4) is essential for the formation of mature vasculature. However, the role of DLL4-Notch signaling in pericyte/vascular smooth muscle cell (vSMC) development is poorly understood. We sought to determine whether DLL4 Notch signaling is involved in pericyte/vSMC formation in vitro and during vasculogenesis in vivo using 2 Ewing sarcoma mouse models. Inhibition of DLL4 with the antibody YW152F inhibited pericyte/vSMC marker expression by bone marrow (BM) cells in vitro. Conversely, transfection of 10T1/2 cells with the active domains of Notch receptors led to increased expression of pericyte/vSMC markers. Furthermore, the blood vessels of Ewing sarcoma tumors from mice treated with YW152F had reduced numbers of BM-derived pericytes/vSMCs, fewer open lumens, and were less functional than the vessels in tumors of control-treated mice. Tumor growth was also inhibited. These data demonstrate a specific role for DLL4 in the formation of BM-derived pericytes/vSMCs and indicate that DLL4 may be a novel therapeutic target for the inhibition of vasculogenesis. PMID- 20944073 TI - Langerhans cells are not required for graft-versus-host disease. AB - Graft-versus-host disease (GVHD) is initiated and maintained by antigen presenting cells (APCs) that prime alloreactive donor T cells. APCs are therefore attractive targets for GVHD prevention and treatment. APCs are diverse in phenotype and function, making understanding how APC subsets contribute to GVHD necessary for the development of APC-targeted therapies. Langerhans cells (LCs) have been shown to be sufficient to initiate skin GVHD in a major histocompatibility complex-mismatched model; however, their role when other host APC subsets are intact is unknown. To address this question, we used mice genetically engineered to be deficient in LCs by virtue of expression of diphtheria toxin A under the control of a BAC (bacterial artificial chromosome) transgenic hu-man Langerin locus. Neither CD8- nor CD4-mediated GVHD was diminished in recipients lacking LCs. Similarly, CD8- and CD4-mediated GVHD, including that in the skin, was unaffected if bone marrow came from donors that could not generate LCs, even though donor LCs engrafted in control mice. Engraftment of donor LCs after irradiation in wild-type hosts required donor T cells, with immunofluorescence revealing patches of donor and residual host LCs. Surprisingly, donor LC engraftment in Langerin-diphtheria toxin A (DTA) transgenic hosts was independent of donor T cells, suggesting that a Langerin(+) cell regulates repopulation of the LC compartment. PMID- 20944074 TI - Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. AB - OBJECTIVE: This study assessed the efficacy and safety of the neuronal potassium channel opener ezogabine (US adopted name; EZG)/retigabine (international nonproprietary name; RTG) as adjunctive therapy for refractory partial-onset seizures. METHODS: This was a multicenter, randomized, double-blind, placebo controlled trial in adults with >=4 partial-onset seizures per month receiving 1 to 3 antiepileptic drugs. EZG (RTG) or placebo, 3 times daily, was titrated to 600 or 900 mg/d over 4 weeks, and continued during a 12-week maintenance phase. Median percentage seizure reductions from baseline and responder rates (>=50% reduction in baseline seizure frequency) were assessed. RESULTS: The intention-to treat population comprised 538 patients (placebo, n = 179; 600 mg, n = 181; 900 mg, n = 178), 471 of whom (placebo, n = 164; 600 mg, n = 158; 900 mg, n = 149) entered the maintenance phase. Median percentage seizure reductions were greater in EZG (RTG)-treated patients (600 mg, 27.9%, p = 0.007; 900 mg, 39.9%, p < 0.001) compared with placebo (15.9%). Responder rates were higher in EZG (RTG) treated patients (600 mg, 38.6%, p < 0.001; 900 mg, 47.0%, p < 0.001) than with placebo (18.9%). Treatment discontinuations due to adverse events (AEs) were more likely with EZG (RTG) than with placebo (placebo, 8%; 600 mg, 17%, 900 mg, 26%). The most commonly reported (>10%) AEs in the placebo, EZG (RTG) 600 mg/d, and EZG (RTG) 900 mg/d groups were dizziness (7%, 17%, 26%), somnolence (10%, 14%, 26%), headache (15%, 11%, 17%), and fatigue (3%, 15%, 17%). CONCLUSIONS: In this dose ranging, placebo-controlled trial, adjunctive EZG (RTG) was effective and generally well tolerated in adults with refractory partial-onset seizures. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that adjunctive EZG/RTG reduces the occurrence of partial-onset seizures. PMID- 20944075 TI - Physical activity predicts gray matter volume in late adulthood: the Cardiovascular Health Study. AB - OBJECTIVES: Physical activity (PA) has been hypothesized to spare gray matter volume in late adulthood, but longitudinal data testing an association has been lacking. Here we tested whether PA would be associated with greater gray matter volume after a 9-year follow-up, a threshold could be identified for the amount of walking necessary to spare gray matter volume, and greater gray matter volume associated with PA would be associated with a reduced risk for cognitive impairment 13 years after the PA evaluation. METHODS: In 299 adults (mean age 78 years) from the Cardiovascular Health Cognition Study, we examined the association between gray matter volume, PA, and cognitive impairment. Physical activity was quantified as the number of blocks walked over 1 week. High resolution brain scans were acquired 9 years after the PA assessment on cognitively normal adults. White matter hyperintensities, ventricular grade, and other health variables at baseline were used as covariates. Clinical adjudication for cognitive impairment occurred 13 years after baseline. RESULTS: Walking amounts ranged from 0 to 300 blocks (mean 56.3; SD 69.7). Greater PA predicted greater volumes of frontal, occipital, entorhinal, and hippocampal regions 9 years later. Walking 72 blocks was necessary to detect increased gray matter volume but walking more than 72 blocks did not spare additional volume. Greater gray matter volume with PA reduced the risk for cognitive impairment 2-fold. CONCLUSION: Greater amounts of walking are associated with greater gray matter volume, which is in turn associated with a reduced risk of cognitive impairment. PMID- 20944076 TI - Extending high-frequency oscillation analysis to pediatric electrocorticography: ripple effect. PMID- 20944078 TI - Comparative effectiveness of prostate cancer treatments: evaluating statistical adjustments for confounding in observational data. AB - BACKGROUND: Using observational data to assess the relative effectiveness of alternative cancer treatments is limited by patient selection into treatment, which often biases interpretation of outcomes. We evaluated methods for addressing confounding in treatment and survival of patients with early-stage prostate cancer in observational data and compared findings with those from a benchmark randomized clinical trial. METHODS: We selected 14 302 early-stage prostate cancer patients who were aged 66-74 years and had been treated with radical prostatectomy or conservative management from linked Surveillance, Epidemiology, and End Results-Medicare data from January 1, 1995, through December 31, 2003. Eligibility criteria were similar to those from a clinical trial used to benchmark our analyses. Survival was measured through December 31, 2007, by use of Cox proportional hazards models. We compared results from the benchmark trial with results from models with observational data by use of traditional multivariable survival analysis, propensity score adjustment, and instrumental variable analysis. RESULTS: Prostate cancer patients receiving conservative management were more likely to be older, nonwhite, and single and to have more advanced disease than patients receiving radical prostatectomy. In a multivariable survival analysis, conservative management was associated with greater risk of prostate cancer-specific mortality (hazard ratio [HR] = 1.59, 95% confidence interval [CI] = 1.27 to 2.00) and all-cause mortality (HR = 1.47, 95% CI = 1.35 to 1.59) than radical prostatectomy. Propensity score adjustments resulted in similar patient characteristics across treatment groups, although survival results were similar to traditional multivariable survival analyses. Results for the same comparison from the instrumental variable approach, which theoretically equalizes both observed and unobserved patient characteristics across treatment groups, differed from the traditional multivariable and propensity score results but were consistent with findings from the subset of elderly patient with early-stage disease in the trial (ie, conservative management vs radical prostatectomy: for prostate cancer-specific mortality, HR = 0.73, 95% CI = 0.08 to 6.73; for all-cause mortality, HR = 1.09, 95% CI = 0.46 to 2.59). CONCLUSION: Instrumental variable analysis may be a useful technique in comparative effectiveness studies of cancer treatments if an acceptable instrument can be identified. PMID- 20944077 TI - Epidemiological study of anti-HPV16/18 seropositivity and subsequent risk of HPV16 and -18 infections. AB - BACKGROUND: Infection with human papillomavirus (HPV) 16 or HPV18 elicits an antibody response, but whether the elicited antibodies protect women against subsequent infection by a homologous HPV type compared with seronegative women is unknown. METHODS: Study participants were women aged 18-25 years at enrollment in the control group of the ongoing National Cancer Institute-sponsored, community based, randomized HPV16/18 Costa Rica Vaccine Trial. At enrollment, 2813 participants were negative for cervical HPV16 DNA and 2950 for HPV18 DNA. Women were interviewed regarding sociodemographic data and medical and health history. Medical and pelvic examinations were conducted for all consenting sexually experienced women. Serum samples taken at enrollment were tested for total HPV16/18 antibodies with a polyclonal enzyme-linked immunosorbent assay, and cervical specimens were tested for type-specific HPV DNA over 4 years of follow up. Using Poisson regression, we compared rate ratios of newly detected cervical HPV16 or HPV18 infection among homologous HPV-seropositive and HPV-seronegative women, adjusting for age, education, marital status, lifetime number of sexual partners, and smoking. RESULTS: There were 231 newly detected HPV16 infections during 5886 person-years among HPV16-seronegative women compared with 12 newly detected HPV16 infections during 581 person-years among HPV16-seropositive women with the highest HPV16 sero-levels. There were 136 newly detected HPV18 infections during 6352 person-years among HPV18-seronegative women compared with six new infections detected during 675 person-years among HPV18 seropositives with the highest sero-levels. After controlling for risk factors associated with newly detected HPV infection, having high HPV16 antibody titer at enrollment was associated with a reduced risk of subsequent HPV16 infection (women in the highest tertile of HPV16 antibody titers, adjusted rate ratio = 0.50, 95% confidence interval = 0.26 to 0.86 vs HPV16-seronegative women). Similarly, having high HPV18 antibody titer at enrollment was associated with a reduced risk of subsequent HPV18 infection (women in the highest tertile of HPV18 antibody titers, adjusted rate ratio = 0.36, 95% confidence interval = 0.14 to 0.76 vs HPV18-seronegative women). CONCLUSION: In this study population, having high antibody levels against HPV16 and HPV18 following natural infection was associated with reduced risk of subsequent HPV16 and HPV18 infections. PMID- 20944079 TI - Cancer pharmacogenomics and pharmacoepidemiology: setting a research agenda to accelerate translation. AB - Recent advances in genomic research have demonstrated a substantial role for genomic factors in predicting response to cancer therapies. Researchers in the fields of cancer pharmacogenomics and pharmacoepidemiology seek to understand why individuals respond differently to drug therapy, in terms of both adverse effects and treatment efficacy. To identify research priorities as well as the resources and infrastructure needed to advance these fields, the National Cancer Institute (NCI) sponsored a workshop titled "Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation" on July 21, 2009, in Bethesda, MD. In this commentary, we summarize and discuss five science-based recommendations and four infrastructure-based recommendations that were identified as a result of discussions held during this workshop. Key recommendations include 1) supporting the routine collection of germline and tumor biospecimens in NCI-sponsored clinical trials and in some observational and population-based studies; 2) incorporating pharmacogenomic markers into clinical trials; 3) addressing the ethical, legal, social, and biospecimen- and data-sharing implications of pharmacogenomic and pharmacoepidemiologic research; and 4) establishing partnerships across NCI, with other federal agencies, and with industry. Together, these recommendations will facilitate the discovery and validation of clinical, sociodemographic, lifestyle, and genomic markers related to cancer treatment response and adverse events, and they will improve both the speed and efficiency by which new pharmacogenomic and pharmacoepidemiologic information is translated into clinical practice. PMID- 20944080 TI - Preparation of the cortical reaction: maturation-dependent migration of SNARE proteins, clathrin, and complexin to the porcine oocyte's surface blocks membrane traffic until fertilization. AB - The cortical reaction is a calcium-dependent exocytotic process in which the content of secretory granules is released into the perivitellin space immediately after fertilization, which serves to prevent polyspermic fertilization. In this study, we investigated the involvement and the organization of SNARE (soluble N ethylmaleimide-sensitive factor attachment protein receptor) proteins in the docking and fusion of the cortical granule membrane with the oolemma in porcine oocytes. During meiotic maturation, secretory vesicles that were labeled with a granule-specific binding lectin, peanut agglutinin (PNA), migrated toward the oocyte's surface. This surface-orientated redistribution behavior was also observed for the oocyte-specific SNARE proteins SNAP23 and VAMP1 that colocalized with the PNA-labeled structures in the cortex area just under the oolemma and with the exclusive localization area of complexin (a trans-SNARE complex stabilizing protein). The coming together of these proteins serves to prevent the spontaneous secretion of the docked cortical granules and to prepare the oocyte's surface for the cortical reaction, which should probably be immediately compensated for by a clathrin-mediated endocytosis. In vitro fertilization resulted in the secretion of the cortical granule content and the concomitant release of complexin and clathrin into the oocyte's cytosol, and this is considered to stimulate the observed endocytosis of SNARE-containing membrane vesicles. PMID- 20944081 TI - Sertoli cell behaviors in developing testis cords and postnatal seminiferous tubules of the mouse. AB - Sertoli cells are the primary structural component of the fetal testis cords and postnatal seminiferous tubules. Live imaging technologies facilitate the visualization of cell morphologies and behaviors through developmental processes. A transgenic mouse line was generated using a fragment of the rat Gata4 gene to direct the expression of a dual-color fluorescent protein reporter in fetal and adult Sertoli cells. The reporter encoded a red fluorescent protein, monomeric Cherry (mCherry), fused to histone 2B and enhanced green fluorescent protein (EGFP) fused to a glycosylphosphatidylinositol sequence, with a self-cleaving 2A polypeptide separating the two fusion proteins. After translation, the red and green fluorescent proteins translocated to the nucleus and plasma membrane, respectively, of Sertoli cells. Transgene expression in testes was first detected by fluorescent microscopy around Embryonic Day 12.0. Sertoli cell division and migration were visualized during testis cord formation in organ culture. Initially, the Sertoli cells had mesenchyme-like morphologies and behaviors, but later, the cells migrated to the periphery of the testis cords to become epithelialized. In postnatal seminiferous tubules, Sertoli nuclei were evenly spaced when viewed from the external surface of tubules, and Sertoli cytoplasm and membranes were associated with germ cells basally in a rosette pattern. This mouse line was bred to previously described transgenic mouse lines expressing EGFP in Sertoli cytoplasm or a nuclear cyan fluorescent protein (Cerulean) and mCherry in plasma membranes of germ cells. This revealed the physical relationship between Sertoli and germ cells in developing testis cords and provided a novel perspective on Sertoli cell development. PMID- 20944082 TI - Release of free and conjugated forms of the putative pheromonal steroid 11-oxo etiocholanolone by reproductively mature male round goby (Neogobius melanostomus Pallas, 1814). AB - Previous studies of the round goby (Neogobius melanostomus Pallas, 1814), an invasive fish species in the Laurentian Great Lakes of North America, have shown that this species has the ability to both synthesize and smell steroids that have a 5 beta-reduced and 3 alpha-hydroxyl (5 beta,3 alpha) configuration. An enzyme linked immunoassay (EIA) for 3 alpha-hydroxy-5 beta-androstane-11,17-dione (11-O ETIO) has been used to show a substantial rise in the rate of release of immunoreactive compounds into the water when males are injected with salmon gonadotropin releasing hormone analogue. Similar increases were noted for 11 ketotestosterone and 17,20 beta-dihydroxypregn-4-en-3-one. Partitioning of the extracts between diethyl ether and water showed the presence of both free and conjugated immunoreactive 11-O-ETIO. Only conjugated immunoreactivity was found in urine (implying that free steroid is released via the gills). The identity of the conjugates was probed by using HPLC, EIA, and mass spectrometry and removal of sulfate and glucosiduronate groups. Immunoreactivity in the conjugated fraction was found to be due mainly to 3 alpha,17beta-dihydroxy-5 beta-androstan 11-one 17-sulfate. However, the evidence was also strong for the presence in water extracts of substantial amounts of 3 alpha-hydroxy-5 beta-androstane-11,17 dione 3-glucosiduronate (which could be detected only by EIA after removal of the glucosiduronate group with beta-glucuronidase). There were also small amounts of 3 alpha-hydroxy-5 beta-androstane-11,17-dione 3-sulfate and 3 alpha,17beta dihydroxy-5 beta-androstan-11-one 17-glucosiduronate. These studies give some idea of the types, amounts, and ratios of 11-O-ETIO derivatives that are released by reproductive N. melanostomus and will aid further research into the putative pheromonal roles of 5 beta,3 alpha-reduced androgens in this species. PMID- 20944083 TI - Cell-mediated transgenesis in rabbits: chimeric and nuclear transfer animals. AB - The ability to perform precise genetic engineering such as gene targeting in rabbits would benefit biomedical research by enabling, for example, the generation of genetically defined rabbit models of human diseases. This has so far not been possible because of the lack of functional rabbit embryonic stem cells and the high fetal and perinatal mortality associated with rabbit somatic cell nuclear transfer. We examined cultured pluripotent and multipotent cells for their ability to support the production of viable animals. Rabbit putative embryonic stem (ES) cells were derived and shown capable of in vitro and in vivo pluripotent differentiation. We report the first live born ES-derived rabbit chimera. Rabbit mesenchymal stem cells (MSCs) were derived from bone marrow, and multipotent differentiation was demonstrated in vitro. Nuclear transfer was carried out with both cell types, and embryo development was assessed in vitro and in vivo. Rabbit MSCs were markedly more successful than ES cells as nuclear donors. MSCs were transfected with fluorescent reporter gene constructs and assessed for nuclear transfer competence. Transfected MSCs supported development with similar efficiency as normal MSCs and resulted in the first live cloned rabbits from genetically manipulated MSCs. Reactivation of fluorescence reporter gene expression in reconstructed embryos was investigated as a means of identifying viable embryos in vitro but was not a reliable predictor. We also examined serial nuclear transfer as a means of rescuing dead animals. PMID- 20944084 TI - Techniques for culturing spermatogonial stem cells continue to improve. PMID- 20944085 TI - Protamine 3 shows evidence of weak, positive selection in mouse species (genus Mus)--but it is not a protamine. AB - Protamines are short and highly basic sperm-specific nuclear proteins that replace somatic histones during spermiogenesis in a process that is crucial for sperm formation and function. Many mammals have two protamine genes (PRM1 and PRM2) located in a gene cluster, which appears to evolve fast. Another gene in this cluster (designated protamine 3 [PRM3]) encodes a protein that is conserved among mammals but that does not seem to be involved in chromatin condensation. We have compared protein sequences and amino acid compositions of protamines in this gene cluster, searched for evidence of positive selection of PRM3, and examined whether sexual selection (sperm competition) may drive the evolution of the PRM3 gene. Nucleotide and amino acid analyses of mouse sequences revealed that PRM3 was very different from PRM1 and from both the precursor and the mature sequences of PRM2. Among 10 mouse species, PRM3 showed weak evidence of positive selection in two species, but there was no clear association with levels of sperm competition. In analyses from among mammalian species, no evidence of positive selection was found in PRM3. We conclude that PRM3 exhibits several clear differences from other protamines and, furthermore, that it cannot be regarded as a true protamine. PMID- 20944087 TI - Strategies for translational research in the United Kingdom. AB - In the United Kingdom, many foundations and institutions and the government have made substantial investments in translational research. We examine the structures that surround this support and consider some of the results of this prodigious push toward enhancing translational research pursuits and thus improved clinical medicine. PMID- 20944086 TI - Assessing the effect of the CLPG mutation on the microRNA catalog of skeletal muscle using high-throughput sequencing. AB - The callipyge phenotype is a monogenic muscular hypertrophy that is only expressed in heterozygous sheep receiving the CLPG mutation from their sire. The wild-type phenotype of CLPG/CLPG animals is thought to result from translational inhibition of paternally expressed DLK1 transcripts by maternally expressed miRNAs. To identify the miRNA responsible for this trans effect, we used high throughput sequencing to exhaustively catalog miRNAs expressed in skeletal muscle of sheep of the four CLPG genotypes. We have identified 747 miRNA species of which 110 map to the DLK1-GTL2 or callipyge domain. We demonstrate that the latter are imprinted and preferentially expressed from the maternal allele. We show that the CLPG mutation affects their level of expression in cis (~3.2-fold increase) as well as in trans (~1.8-fold increase). In CLPG/CLPG animals, miRNAs from the DLK1-GTL2 domain account for ~20% of miRNAs in skeletal muscle. We show that the CLPG genotype affects the levels of A-to-I editing of at least five pri miRNAs of the DLK1-GTL2 domain, but that levels of editing of mature miRNAs are always minor. We present suggestive evidence that the miRNAs from the domain target the ORF of DLK1, thereby causing the trans inhibition underlying polar overdominance. We highlight the limitations of high-throughput sequencing for digital gene expression profiling as a result of biased and inconsistent amplification of specific miRNAs. PMID- 20944088 TI - Network dynamics to evaluate performance of an academic institution. AB - Statistical assessments of performance are common in industry and for individual scientists, but the use of such measures to assess productivity in scientific organizations has lagged behind. The need for defined performance measures has grown as team science has begun to play a larger role in biomedical research, such as in the area of translational medicine. We used a metric, node degree over time, to measure the change in the rate of collaboration over the past five years within an organization, the University of Pennsylvania's Institute for Translational Medicine and Therapeutics (ITMAT). The number of collaborative papers and grants roughly doubled over the past five years among investigators within but not outside of ITMAT. Also, collaborations within institutions and departments were more frequent than those between them--an actionable area of improvement. PMID- 20944089 TI - A defined tuberculosis vaccine candidate boosts BCG and protects against multidrug-resistant Mycobacterium tuberculosis. AB - Despite the widespread use of the childhood vaccine against tuberculosis (TB), Mycobacterium bovis bacillus Calmette-Guerin (BCG), the disease remains a serious global health problem. A successful vaccine against TB that replaces or boosts BCG would include antigens that induce or recall the appropriate T cell responses. Four Mycobacterium tuberculosis (Mtb) antigens--including members of the virulence factor families PE/PPE and EsX or antigens associated with latency- were produced as a single recombinant fusion protein (ID93). When administered together with the adjuvant GLA-SE, a stable oil-in-water nanoemulsion, the fusion protein was immunogenic in mice, guinea pigs, and cynomolgus monkeys. In mice, this fusion protein-adjuvant combination induced polyfunctional CD4 T helper 1 cell responses characterized by antigen-specific interferon-gamma, tumor necrosis factor, and interleukin-2, as well as a reduction in the number of bacteria in the lungs of animals after they were subsequently infected with virulent or multidrug-resistant Mtb strains. Furthermore, boosting BCG-vaccinated guinea pigs with fusion peptide-adjuvant resulted in reduced pathology and fewer bacilli, and prevented the death of animals challenged with virulent Mtb. Finally, the fusion protein elicited polyfunctional effector CD4 and CD8 T cell responses in BCG vaccinated or Mtb-exposed human peripheral blood mononuclear cells. This study establishes that the protein subunit vaccine consisting of the fusion protein and adjuvant protects against TB and drug-resistant TB in animals and is a candidate for boosting the protective efficacy of the childhood BCG vaccine in humans. PMID- 20944091 TI - Multiple roles of the ERCC1-XPF endonuclease in DNA repair and resistance to anticancer drugs. AB - In this review, we focus on the discrepant roles of the DNA repair complex ERCC1/XPF in the prevention of cancer and in the resistance of cancer to chemotherapy. ERCC1/XPF is essential for nucleotide excision repair (NER) incising DNA 5' to the lesion. NER deficiency results in the skin cancer-prone inherited disease xeroderma pigmentosum (XP). The ERCC1/XPF complex is also involved in recombination, double strand break (DSB) and interstrand crosslink (ICL) repair cutting DNA overhangs around a lesion. In telomere maintenance ERCC1/XPF degrades 3' G-rich overhangs. In some types of cancer, high levels of ERCC1/XPF mRNA and protein correlate with poor overall survival and resistance to platinum-based chemotherapeutic treatments. Therefore, the ERCC1/XPF complex makes an attractive target for prediction of outcome for treatment in cancer patients as well as a novel drug target. PMID- 20944090 TI - PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. AB - PTEN (phosphatase and tensin homolog) loss of function is the most common genetic aberration in endometrioid endometrial carcinomas. In addition to its well described role in cell signaling, PTEN is involved in the maintenance of genomic stability. Loss of PTEN function causes defects in repair of DNA double-strand breaks by homologous recombination and, therefore, sensitizes cells to inhibition of the poly(adenosine diphosphate ribose) polymerase (PARP). Here, we determined the PTEN status of eight endometrioid endometrial carcinoma cell lines and correlated it with in vitro sensitivity to the PARP inhibitor KU0058948. PTEN deficient cells showed a significantly greater sensitivity to KU0058948 than the two endometrioid endometrial carcinoma cell lines with wild-type PTEN. The cell lines lacking PTEN expression were unable to elicit a homologous recombination damage response as assayed by RAD51 focus function (a marker of competent homologous recombination DNA repair) upon irradiation and treatment with PARP inhibitors. PTEN silencing in PTEN wild-type Hec-1b cells resulted in reduced RAD51 foci formation after DNA damage and increased sensitivity to PARP inhibition. PTEN reexpression in PTEN-null cell lines resulted in enhanced RAD51 foci formation and in relative resistance to KU0058948. Given that up to 80% of endometrioid endometrial cancers lack PTEN expression, our results suggest that PARP inhibitors may be therapeutically useful for a subset of endometrioid endometrial cancers. PMID- 20944092 TI - Medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and invention of boron tracedrugs as innovative future-architectural drugs. AB - We describe herein for the first time our medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and boron tracedrugs as newly emerging drug classes. A new area of antineoplastic drugs and treatments has recently focused on neoplastic cells of the tumor environment/microenvironment involving accessory cells. This tumor hypoxic environment is now considered as a major factor that influences not only the response to antineoplastic therapies but also the potential for malignant progression and metastasis. We review our medicinal electronomics bricolage design of hypoxia-targeting drugs, antiangiogenic hypoxic cell radiosensitizers, sugar-hybrid hypoxic cell radiosensitizers, and hypoxia-targeting 10B delivery agents, in which we design drug candidates based on their electronic structures obtained by molecular orbital calculations, not based solely on pharmacophore development. These drugs include an antiangiogenic hypoxic cell radiosensitizer TX-2036, a sugar-hybrid hypoxic cell radiosensitizer TX-2244, new hypoxia-targeting indoleamine 2,3 dioxygenase (IDO) inhibitors, and a hypoxia-targeting BNCT agent, BSH (sodium borocaptate-10B)-hypoxic cytotoxin tirapazamine (TPZ) hybrid drug TX-2100. We then discuss the concept of boron tracedrugs as a new drug class having broad potential in many areas. PMID- 20944093 TI - Weekly paclitaxel with intermittent imatinib mesylate (Gleevec): tolerance and activity in recurrent epithelial ovarian cancer. AB - OBJECTIVE: Imatinib mesylate (IM, Gleevec), a potent PDGF/PDGFR tyrosine kinase inhibitor, affects stroma and vascular endothelial cells. Our study sought to determine the safety and activity of paclitaxel with an intermittent schedule of IM. MATERIALS AND METHODS: rEOC patients previously treated with platinum/paclitaxel and <=2 regimens for recurrence were enrolled. Paclitaxel 80 mg/m2 was given on days 3, 10, 17 every 28 days and oral IM 300 mg bid on days 1 4, 8-11, and 13-18. RESULTS: Between 2007-2009, 14 patients enrolled, 12 were evaluable. Nine patients were on study at 12 weeks. Objective responses (by RECIST and/or CA125) occurred in 4 patients. There were no grade 4, and only four grade 3 toxic events: diarrhea, edema and 2 cases of neutropenia. Early study closure was due to sufficient safety information with preliminary encouraging efficacy results. CONCLUSION: This weekly paclitaxel regimen with intermittent IM is tolerable with anti-tumor activity, making it suitable as part of future studies. PMID- 20944094 TI - Transient metals enhance cytotoxicity of curcumin: potential involvement of the NF-kappaB and mTOR signaling pathways. AB - BACKGROUND/AIM: Curcumin has been recognized as a metal-binding compound and an anticancer agent, yet the involvement of metals in the anticancer action of curcumin remains unclear. The present study examined the role of transient metals in curcumin-induced cytotoxicity in cancer cells. MATERIALS AND METHODS: Metal binding activity and cytotoxicity of curcumin were examined in human cancer lines with cell viability assay, confocal microscopy, Western blot, and measurement of hydrogen peroxide generation. RESULTS: It was found that Cu (II) most significantly potentiated the cytotoxicity of curcumin among the metals tested. The combination of curcumin and Cu (II) did not generate reactive oxygen species and vitamin E did not block the cytotoxicity. Curcumin plus Cu (II) enhanced intracellular copper levels and potentiated curcumin-induced suppression of the nuclear factor kappa B (NF-kappaB) pathway, as well as alterations of mammalian target of rapamycin-raptor (mTOR) signaling. CONCLUSION: Transient metals enhance the cytotoxicity of curcumin, likely through targeting of the NF-kappaB and mTOR signaling pathways. PMID- 20944095 TI - Topoisomerase I deficiency results in chromosomal alterations in cervical cancer cells. AB - Human topoisomerase I has been suggested to be implicated in the maintenance of genomic stability via its ability to regulate genome topology during transcription and replication. In the present study, we demonstrate by whole genome array comparative genomic hybridization (aCGH) and fluorescence in situ hybridisation (FISH) analysis that topoisomerase I deficiency results in chromosome 5p gain in the cervical cancer cell line, HeLa-CCL2. In contrast, chromosome 5p copy number remained unaffected by topoisomerase I down-regulation in the non-cancer cell line HEK293T, as demonstrated by FISH analysis. Chromosome 5p gain is the most frequent genetic alteration in invasive cervical cancer, which leads to overexpression of genes involved in proliferation and occurs primarily at late stages in cancer development. The amplification of this region upon topoisomerase I down-regulation specifically in HeLa-CCL2 cells may indicate an important role of topoisomerase I in preventing malignant progression of precancerous lesions in the cervix. PMID- 20944096 TI - Assessment of V600E mutation of BRAF gene and rate of cell proliferation using fine-needle aspirates from metastatic melanomas. AB - BACKGROUND: metastatic melanomas are incurable by systemic treatment and it is therefore of the highest concern to develop new therapeutic regimens. RAF kinases play a key role in the RAS-RAF-MAPK signalling pathway which mediates cellular response to growth signals. An inhibitor of the RAS-RAF-MAPK cascade, sorafenib, has shown promising therapeutic results in treatment of several types of metastatic tumours. It can be hypothesized that metastatic melanomas with activating BRAF mutation may respond to RAF kinase-blocking therapy. The objective of the study was to analyze if the activating BRAF V600E mutation is present in metastatic melanomas. MATERIALS AND METHODS: Fine-needle aspirates from 44 metastatic melanomas were studied. The V600E mutation in exon 15 of the BRAF gene was selected for genotyping. A Taq-Man MGB biallelic discrimination system was used. Immunocytochemical assessment of the Ki-67 antigen was used to analyze the growth fraction of cells. RESULTS: Nearly 39% of metastatic melanomas had BRAF V600E mutation. Tumours with BRAF V600E mutation had a tendency to have a more aggressive clinical course. The growth fraction showed correlation with tumour progression. This study indicates that the V600E mutation is present in metastatic melanomas and occurs more often in sites without chronic sun exposure. Mutated tumours may have a more aggressive clinical course since such melanomas metastasize at an earlier stage. Determination of the BRAF mutation and the growth fraction of melanomas may add a prognostic value. CONCLUSION: A fraction of melanoma cases possess an activating BRAF mutation and may benefit from RAF kinase inhibitor treatment. Future studies are needed to confirm this hypothesis. PMID- 20944097 TI - Expression of dysadherin and cytokeratin as prognostic indicators of disease-free survival in patients with stage I NSCLC. AB - BACKGROUND: Adjuvant chemotherapy is required following the resection of aggressive NSCLC. It is therefore necessary to identify factors that accurately predict prognosis. MATERIALS AND METHODS: Tumor specimens were collected from 107 patients who underwent a complete resection for NSCLC from 1994-2000 in this Department. The expression of E-cadherin, dysadherin, and cytokeratin in stage I NSCLC specimens was analyzed by immunohistochemistry. RESULTS: Seventeen percent of tumors showed reduced E-cadherin immunostaining. Twenty-nine per cent of tumors showed dysadherin expression in over 50% of the cancer cells. Positive expression of cytokeratin was identified in 30 (28.0%) patients. The incidence of positive expression of dysadherin in females and elderly patients was higher than that in other patients. Cytokeratin immunoreactive tumor cells in lymph nodes were identified in 34 (28.0%) out of 107 patients. The incidence of positive expression of cytokeratin in T1 tumors was higher than that in T2 tumors. There was a significant inverse correlation between the expression of E-cadherin and dysadherin. The increased expression of cytokeratin was significantly associated with recurrence. Logistic regression models indicated that cytokeratin expression was an independent predictor of recurrence. The increased expression of dysadherin and cytokeratin had a significant impact on patient survival. Furthermore, tumors with an increased expression of dysadherin and a reduced expression of E-cadherin showed the worst prognosis. CONCLUSION: The detection of dysadherin in tumors and cytokeratin in the lymph nodes may be a potential significant indicator of a poor prognosis for patients who undergo complete resection of stage I NSCLC. PMID- 20944098 TI - The role of Akt activation in the response to chemotherapy in pancreatic cancer. AB - The PI3K/Akt signaling pathway is constitutively activated in some pancreatic cancers; when activated, it inhibits chemotherapy-mediated apoptosis. We examined whether Akt activity correlates with apoptotic resistance to chemotherapy in pancreatic cancer. MATERIALS AND METHODS: A panel of human pancreatic cancer cells was evaluated for basal Akt activity as well as response to three chemotherapies. Chemotherapy-induced cell death was evaluated following either up or down-regulation of Akt activity. Evaluation of phosphorylation of p21Cip/Waf1, a downstream target of Akt, was also evaluated. RESULTS: There was a broad distribution among pancreatic cancer cell lines by Akt activity, as well as sensitivity to the three chemotherapeutic agents with no apparent correlation. Phosphorylation of p21Cip/Waf1, but not change in total levels, correlated with the chemosensitizing effect of Akt inhibition to paclitaxel. CONCLUSIONS: Basal Akt activity does not appear to be a useful predictor for selection of pancreatic cancers in targeting Akt to broadly induce chemosensitivity. PMID- 20944099 TI - GFP-fluorescence-guided UVC irradiation inhibits melanoma growth and angiogenesis in nude mice. AB - Melanoma cell lines that stably express green fluorescent protein (GFP) and nude mice that ubiquitously express red fluorescent protein (RFP) have previously been developed to study tumor-host interaction by color-coded imaging. In the present study, the efficacy of fluorescence-guided ultraviolet C (UVC) irradiation on the growth of murine melanoma expressing GFP in the ear of RFP mice was determined using a non-invasive ear-tumor imaging model developed previously. The GFP expressing melanoma and RFP-expressing blood vessels from the transgenic mice expressing RFP used as hosts were readily visible using non-invasive imaging. The melanoma was treated under fluorescence guidance with UVC at 650 J/m2/minute for 3 minutes. The ears of the mice were observed before and 24 hours after irradiation with UVC. UVC inhibited melanoma growth and also damaged blood vessels in the tumor. Thus, UVC irradiation has a direct effect on melanoma growth as well as an anti-angiogenesis effect. This color-coded tumor-host model is useful for evaluation of treatment efficacy on melanoma growth and angiogenesis, which are readily discernable with non-invasive color-coded fluorescent protein imaging. These results suggest that fluorescence-guided UVC irradiation is a promising therapeutic strategy for melanoma. PMID- 20944102 TI - Evidence for a tumour suppressor function of SETD2 in human breast cancer: a new hypothesis. AB - BACKGROUND: SET domain containing protein 2 (SETD2) is a histone methyltransferase that is involved in transcriptional elongation. We previously demonstrated SETD2 to be a potential tumour suppressor gene in breast cancer. The aim of this study was to compare SETD2 expression in breast cancer with that in adjacent non-cancerous breast tissue (ANCT) in paired samples. A hypothesis is proposed that explains the mode of action of SETD2 as a tumour suppressor gene. MATERIALS AND METHODS: Paired samples of tumour and adjacent non-cancerous tissue (ANCT) from 25 patients were analysed. The levels of transcription of SETD2 were determined using quantitative polymerase chain reaction and normalized against cytokeratin 19. Immunohistochemical staining with appropriate antibodies against SETD2 protein was also performed in selected samples. RESULTS: Levels of SETD2 mRNA were significantly higher in ANCT when compared to those in tumour samples (p=0.01). Immunohistochemistry also demonstrated a higher protein expression in ANCT. CONCLUSION: This study offers further evidence that SETD2 behaves like a tumour suppressor gene. Our hypothesis links SETD2 mode of action with telomerase regulation through human telomerase reverse transcriptase (hTERT). Several studies have emphasised the importance of histone methylation of hTERT promotor in telomerase regulation. SETD2 function of histone methylation could be the missing link in this chain which could explain the potential tumour suppressor function of SETD2. PMID- 20944100 TI - NF-kappaB inhibitors from Brucea javanica exhibiting intracellular effects on reactive oxygen species. AB - AIM: Brucea javanica was studied to identify nuclear factor kappaB (NF-kappaB) inhibitors exhibiting reactive oxygen species (ROS) intracellular amplification. MATERIAL AND METHODS: Eight compounds were evaluated for selective cytotoxicity using HT-29, HeLa, and HL-60 cells, and in a NF-kappaB assay. Active compounds were then tested using ROS and mitochondria transmembrane potential (MTP) assays. NF-kappaB and nuclear factor activated T-cell (NFAT) translocation were also assessed using their respective whole cell assays. RESULTS: Bruceajavanone B, bruceantin, bruceine A, (-)-hydnocarpin, and chrysoeriol exhibited cytotoxic potential and NF-kappaB p65 inhibition. Chrysoeriol exhibited selective cytotoxicity against leukemia cells with greater potency and also showed an ability to up-regulate NFAT transcriptional pathways through the amplification of intracellular ROS, in the presence of H2O2, to a greater degree than bruceantin and bruceine. CONCLUSION: Chrysoeriol selectively kills leukemic cells and potentiates the amplification of ROS levels. Therefore, chrysoeriol could serve as a potential chemotherapeutic modifier for leukemia chemotherapy since leukemia cells have a higher susceptibility to elevated ROS levels. PMID- 20944101 TI - Maturation of tumor vasculature by interferon-beta disrupts the vascular niche of glioma stem cells. AB - BACKGROUND: The vascular niche necessary for cancer stem cell maintenance is a potential target for cancer therapy. MATERIALS AND METHODS: Human glioma xenografts were treated with IFN-beta delivered systemically via a liver targeted, adeno-associated viral vector. The vascular niche was examined with immunofluorescence for glioma stem cells, endothelial cells, and perivascular cells. RESULTS: Although IFN-beta was not directly toxic to glioma stem cells in vitro, IFN-beta decreased tumor size and the number of stem cells recovered in both heterotopic and orthotopic models. Treatment with IFN-beta increased perivascular cells investing the tumor vasculature (6-fold) distancing stem cells from endothelial cells. Additionally, vascular smooth muscle cells co-cultured between stem cells and endothelial cells decreased stem cell recovery. CONCLUSION: Continuous delivery of IFN-beta decreased the number of stem cells in glioma xenografts by disrupting the vascular niche through an increase in perivascular cells, which created a barrier between the glioma stem cells and the endothelial cells. PMID- 20944103 TI - Increased expression of macrophage migration inhibitory factor during progression to hypopharyngeal squamous cell carcinoma. AB - BACKGROUND/AIM: To examine the presence of macrophage migration inhibitory factor (MIF) quantitatively in relation to neoplastic progression of hypopharyngeal squamous cell carcinoma (HSCC). MATERIALS AND METHODS: The presence of MIF was analysed by quantitative immunohistochemistry in sections of 81 HSCCs, and compared to 15 specimens of tumour-free epithelia (TF_E), 29 low-grade dysplasias (Low_D) and 25 high-grade dysplasias (High_D). In parallel, MIF expression was studied using Western blotting on a series of 19 fresh biopsies. RESULTS: A significant increase in MIF staining intensity (mean optical density) was observed in carcinoma samples compared to TF_E (p<10(-6)), Low_D (p=0.0006) or High_D (p=0.0006). Immunohistochemical MIF positivity was significantly higher in HSCCs than in TF_E (p=0.00001) or Low_D (p=0.001). The percentage of MIF immunopositive cells (labelling index) significantly decreased in parallel with an apparent loss of histological differentiation (p=0.003). CONCLUSION: This study identified the presence of MIF as a parameter that positively correlates with neoplastic progression of HSCC and cell differentiation status. PMID- 20944104 TI - Efficacy of MDM2 inhibitor MI-219 against lung cancer cells alone or in combination with MDM2 knockdown, a XIAP inhibitor or etoposide. AB - The p53 tumor suppressor is negatively regulated by murine double minute 2 (MDM2), which binds to p53 and promotes p53 ubiquitination and degradation. MDM2 inhibitor-219 (MI-219), a small molecule MDM2 inhibitor, was recently reported to disrupt p53-MDM2 binding, leading to p53 activation and suppression of tumor cell growth both in vitro and in vivo. This study tested the efficacy of MI-219 against a panel of lung cancer cell lines alone or in combination with MDM2 knockdown, an X-linked inhibitor of apoptosis protein (XIAP) inhibitor, or a chemotherapeutic drug, etoposide. When acting alone, MI-219 selectively inhibited growth of wild-type (wt) p53-containing lung cancer cells by induction of G1 or G2 arrest in a p53-dependent manner, but had a minor effect on wt p53-bearing immortalized cells. MDM2 knockdown had a minimal effect on MI-219 induced growth suppression. Although MI-219 increased XIAP expression, blockage of XIAP via SM 164, a Smac mimetic compound, did not selectively enhance MI-219 cytotoxicity. Significantly, MI-219 sensitized lung cancer cells to etoposide-induced cell killing. This study revealed that, when acting alone, MI-219 selectively inhibits the growth of lung cancer cells harboring a wt p53. In combination, MI-219 induced cytotoxicity was not affected by MDM2 knockdown nor by a XIAP inhibitor, but MI-219 sensitized cancer cells to etoposide, suggesting MI-219 could serve as a chemosensitizing agent. PMID- 20944105 TI - Growth inhibitory and apoptosis-inducing effects of xanthohumol, a prenylated chalone present in hops, in human prostate cancer cells. AB - Promotion of apoptosis in cancer cells could potentially lead to the regression and improved prognosis of hormone-refractory prostate cancer. Xanthohumol (XN), a prenylated chalcone-derived from hops, has shown strong antitumorigenic activity towards diverse types of cancer cells. In the present study, the growth inhibitory and apoptosis-inducing activity of XN was tested in hormone-sensitive and hormone-refractory human prostate cancer cells lines. Cell growth/viability assay (MTS) demonstrated that prostate cancer cells are highly sensitive to XN at a concentration range of 20-40 MUM. The primary mode of tumor cell destruction was apoptosis as demonstrated by the binding of annexin V-FITC, cleavage of PARP 1, activation of procaspases -3, -8, and -9, mitochondrial depolarization and release of cytochrome c from mitochondria. Induction of apoptosis by XN was associated with the inhibition of prosurvival Akt, NF-kappaB and mTOR signaling proteins and NF-kappaB-regulated anti-apoptotic Bcl-2 and survivin. These studies provide a rationale for clinical evaluation of XN for the treatment of hormone refractory metastatic prostate cancer. PMID- 20944106 TI - Some considerations for the study of TGFbeta in medium of irradiated T98G cells: activation, release and consumption. AB - BACKGROUND: Transforming growth factor beta1 (TGFbeta1) has been proposed as a candidate for the transmission of radiation-induced bystander signals. AIM: To assess the influence that the presence of latent TGFbeta in the medium may have on the modulation of TGFbeta1 release and on its receptor (TGFbetaR2) expression after irradiation of glioblastoma cells or after treatment with medium collected from gamma-irradiated cells. MATERIALS AND METHODS: T98G cells cultured with a complete medium or a serum-free medium were irradiated with 0.25 and 1 Gy and the concentration of total TGFbeta1 was measured. RESULTS AND CONCLUSIONS: Irradiation of cells growing with a complete medium (i.e. a medium containing latent TGFbeta1, LTGFbeta1) caused a consistent dose-dependent decrease of the TGFbeta1 available in the medium. When LTGFbeta1 was not available in the medium (i.e. a medium without serum supplement), the levels of TGFbeta1 increased significantly. Changes in the pattern of expression of TGFbetaR2 were evident only when a serum-free medium was used. PMID- 20944107 TI - Effect of a neurokinin-1 receptor antagonist in a rat model of colitis-associated colon cancer. AB - AIM: The role of substance P and the neurokinin-1 receptor (NK-1R) in the transition from inflammation to dysplasia in inflammatory bowel disease is not clear. MATERIALS AND METHODS: Colitis-associated dysplasia was induced in Sprague Dawley rats by intracolonic, then systemic, administration of trinitrobenzene sulfonic acid. One group of animals received the NK-1R antagonist SR140333; the rest received vehicle. Colons were removed and analyzed for damage and expression of NK-1R downstream components. RESULTS: The NK-1R antagonist-treated animals had significantly reduced macroscopic and microscopic damage and decreased incidence of inflammatory bowel disease. Twice as many of these animals had a normal diagnosis in any region of the colon. A decrease in proliferation index, Cox-2 expression, and active Erk1/2 was found compared with the vehicle-treated group. In Caco-2 cells, Erk1/2 was activated by substance P and prostaglandin E2. CONCLUSION: A selective NK-1R antagonist may delay the development of further colonic damage, offering a potential treatment for patients with long-standing colitis. PMID- 20944108 TI - Sunitinib (SU11248) inhibits growth of human ovarian cancer in xenografted mice. AB - BACKGROUND: Treatment of ovarian cancer is still challenging especially in recurrent platinum refractory cases. Sunitinib is a multi tyrosine kinase inhibitor targeting receptors for vascular endothelial growth factor and platelet derived growth factor which play a role in tumor angiogenesis. It has been approved for the treatment of recurrent gastro intestinal stroma tumors and metastatic renal cancer. MATERIALS AND METHODS: In this study, sunitinib was tested for its effectiveness as a single agent in an ovarian cancer xenograft mouse model. Skov3 cells stably expressing firefly luciferase were injected into SCID beige mice. Mice received either 40 mg/kg bodyweight sunitinib or vehicle control. Tumor growth was monitored longitudinally by luciferase signal. RESULTS: Sunitinib significantly reduced tumor growth (p=0.0052) and peritoneal metastases, and was associated with a significantly reduced microvessel density count (p<0.001). CONCLUSION: These results suggest that clinical trials are warranted for the evaluation of sunitinib for treatment of patients with recurrent or advanced ovarian cancer. PMID- 20944109 TI - Sonodynamically induced cell damage using rose bengal derivative. AB - AIM: The ultrasonically induced effect of a tumor accumulative derivative of rose bengal (RB) on isolated tumor cells was investigated to clarify whether the RB derivative (RBD) maintains the sonosensitizing ability of RB. MATERIALS AND METHODS: Sarcoma 180 cells were suspended in air-saturated phosphate-buffered saline and were exposed to ultrasound in standing wave mode for up to 60 s in the presence and absence of RBD or RB. The viability of the cells was determined by the ability to exclude trypan blue. RESULTS: The ultrasonically induced cell damaging rate with 100 MUM RBD was one order of magnitude higher than that with the same concentration of RB. This increase was significantly inhibited by the active oxygen scavengers histidine, tryptophan and N-acetyl-L-cysteine. CONCLUSION: Chemical modification of RB to RBD for tumor accumulation significantly increased the sonodynamically induced antitumor effect of RB. PMID- 20944110 TI - Identification of up- and down-regulated proteins in gemcitabine-resistant pancreatic cancer cells using two-dimensional gel electrophoresis and mass spectrometry. AB - The prognosis of patients with pancreatic cancer is very poor because of late diagnosis and the lack of response to various therapies. Pancreatic cancer is generally resistant to chemotherapy and is highly fatal. Gemcitabine (GEM) appears to be the only effective agent for treatment of pancreatic cancer. However, a high level of inherent and acquired tumor resistance makes the clinical impact of GEM modest. Proteomic differential display analysis for GEM sensitive human pancreatic adenocarcinoma cell line KLM1 and GEM-resistant KLM1-R cells by using two-dimensional gel electrophoresis and liquid chromatography tandem mass spectrometry produced 33 protein spots. Of these, 23 were up regulated and 10 were down-regulated in KLM1-R compared to KLM1 cells. The up regulated proteins include acidic leucine-rich nuclear phosphoprotein 32 family member A, reticulocalbin-1, gamma-synuclein, microtubule-associated protein RP/EB family, sialic acid synthase, peptidyl-prolyl cis-trans isomerase A, far upstream element-binding protein 2 and catalase. The down-regulated proteins include far upstream element-binding protein 1, gamma-synuclein, galectin-1 and stathmin. Two spots of heat-shock protein 27 were up-regulated in KLM1-R cells. These results suggest an important complementary role for proteomics in the identification of proteins which may play a role in the poor response of pancreatic cancer to GEM. PMID- 20944111 TI - Influence of structural variations on biological activity of anti-PSMA scFv and immunotoxins targeting prostate cancer. AB - BACKGROUND: In this study, different variants of the anti-PSMA single-chain antibody fragment (scFv) D7 were cloned, varying in linker type, position of hexahistidine tags and VH-VL orientation. From these scFv, Pseudomonas exotoxin A based immunotoxins were constructed and their biological activities against prostate cancer cells were compared. MATERIALS AND METHODS: Binding of the constructs to PSMA-expressing prostate cancer cells was determined by flow cytometry. ADP-ribosyltransferase activity was analysed and cytotoxicity was measured with WST-1 assays. RESULTS: Different linker types did not influence the characteristics of the scFv or immunotoxins. The addition of an N-terminal hexahistidine-tag, however, resulted in decreased expression, binding and cytotoxicity. scFv in VH-VL orientation showed the highest expression and binding, whereas immunotoxins in VL-VH orientation exhibited the best binding and cytotoxicity. CONCLUSION: The present study showed how structure influences the characteristics of scFv and immunotoxins. It is therefore suggested that for each individual construct the optimal structure has to be determined separately. PMID- 20944112 TI - Autophagy inhibition enhances sulforaphane-induced apoptosis in human breast cancer cells. AB - AIM: Sulforaphane (SFN), which is present in cruciferous vegetables, induces growth arrest and/or cell death in cancer of various organs. The involvement of autophagy in the SFN-induced apoptotic death of human breast cancer cells was investigated. MATERIALS AND METHODS: Cell proliferation and viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue exclusion assay. Flow cytometry, immunofluorescence, electron microscopy, and Western blot analysis were used for detection of apoptosis and autophagy, and the role of autophagy was assessed using autophagy inhibitors. RESULTS: SFN dose- and time-dependently retarded the growth and induced cell death in MCF-7 and MDA-MB-231 human breast cancer cells. In MDA-MB 231 cells, 30 MUM SFN caused S and G2/M cell-cycle arrest associated with increased p21WAF1 and p27KIP1 levels and decreased cyclin A, cyclin B1 and CDC2 levels. Cell death was due to apoptosis with increased caspase-3 and lowered BCL 2 levels. In addition, the SFN-treated cells exhibited autophagy, as characterized by the appearance of autophagic vacuoles by electron microscopy, the accumulation of acidic vesicular organelles by flow cytometry, and the punctuate patterns of microtubule-associated protein 1 light chain 3 (LC3) by fluorescein microscopy. The levels of LC3-I and -II proteins (processed forms of LC3-I) and LC3 mRNA were increased. Treatment with autophagy inhibitor bafilomycin A1 (but not 3-methyladenine) with SFN significantly enhanced apoptosis, which was accompanied by increases in the level of BAX and the cleavage of caspase-3 and poly(ADP-ribose)polymerase (PARP)-1 and decreases in the mitochondrial membrane potential (DeltaPsim). CONCLUSION: These results indicate a cytoprotective role of autophagy against SFN-induced apoptosis and that the combination of SFN treatment with autophagy inhibition may be a promising strategy for breast cancer control. PMID- 20944113 TI - The effect of bevacizumab on tumour growth of malignant fibrous histiocytoma in an animal model. AB - BACKGROUND: Bevacizumab is a specific inhibitor of angiogenesis and a neutralising antibody against vascular endothelial growth factor (VEGF). The effect of bevacizumab was evaluated on malignant fibrous histiocytoma (MFH) in vivo using an animal model. MATERIALS AND METHODS: MFH cell line, NaraH, was implanted to athymic nude mice which were randomly divided into a treatment and a control group. The change in body weight and tumour volume were evaluated and immunohistochemical analysis was performed of microvessel density (MVD) and VEGF expression in the tumour tissue. RESULTS: Bevacizumab significantly induced inhibition of tumour growth, reducing tumour volume to 48% at the end of experiment. Intratumoural MVD was significantly decreased in the bevacizumab treatment group compared to the control group. A positive correlation was found between tumour volume and MVD. CONCLUSION: Bevacizumab suppressed MFH tumour growth by inhibiting tumoural angiogenesis. The current study suggests that bevacizumab may be a novel therapeutic agent for MFH. PMID- 20944114 TI - Novel anti-Tn single-chain Fv-Fc fusion proteins derived from immunized phage library and antibody Fc domain. AB - Tn[GalNAc(alpha1-3)-Ser/Thr] antigen, a tumor-associated carbohydrate antigen, is highly expressed in various tumors and an attractive candidate for cancer immunotherapy. The generation of an anti-Tn antibody is a first step toward the construction of new anticancer molecules. However, because of the simple and small conformation of the Tn molecule, it is difficult to generate an anti-Tn antibody for therapeutic use by conventional hybridoma technology. The purpose of this study was to isolate anti-Tn single-chain antibody fragments (scFv) by phage display technology from a novel immunised library, to attach an antibody constant region (Fc) and to convert them to scFv-Fc fusion proteins. The scFv-Fcs obtained here showed strict specificity against the Tn antigen and also showed antibody dependent cellular cytotoxicity. These results suggest a potential use of this antibody generating method by phage display and indicate the potential of Fc fusion proteins as therapeutic candidates. PMID- 20944115 TI - Jun amino-terminal kinase 1 activation promotes cell survival in ErbB2-positive breast cancer. AB - BACKGROUND: Downstream signaling is a key component of Her2/neu overexpression in human breast cancer. Major survival pathways downstream of Her2/neu include mitogen and stress activated protein kinases (ERK, JNK, p38). MATERIALS AND METHODS: MAPK protein expression was examined in mouse and human cancer tissue. MAPK expression was inhibited by genetic and pharmacologic methods in human breast cancer cell lines. The effects of MAPK inhibition on tumor formation in a preclinical model were determined. RESULTS: It was shown that tumors from MMTV neu mice expressed high levels of activated JNK1. Levels of this kinase were also highest in Her2/neu overexpressing human breast cancer cell lines. JNK1 inhibition specifically induced apoptosis in these lines. A JNK1 inhibitor also increased the latency period and decreased growth of MMTV-neu tumors by induction of apoptosis. JNK1 was preferentially activated in human breast cancer tissue overexpressing Her2/neu. CONCLUSION: JNK1 promotes cell survival in Her2/neu positive breast cancer. PMID- 20944116 TI - Human kallikrein 7 induces epithelial-mesenchymal transition-like changes in prostate carcinoma cells: a role in prostate cancer invasion and progression. AB - Human tissue kallikrein 7 (hK7), a chymotrypsin-like secreted serine protease, catalyzes the degradation of intercellular adhesive structures in the cornified layer of the skin, leading to desquamation. Thus, hK7 is implicated in cancer invasion and metastasis. Although hK7 is highly expressed in prostate tissues, its biological role in prostate cancer progression is poorly understood. In the current study, we established an hK7-expressing cell model for prostate tumors by stably transfecting prostate carcinoma 22RV1 and DU145 cells with an expression vector encoding hK7. We found that there were no obvious differences in cell proliferation between cells overexpressing hK7 and cells transfected with empty vector (p>0.05). Intriguingly, a Matrigel invasion assay revealed that hK7 remarkably increased the migration and invasion of prostate cancer cells (p<0.01). Furthermore, hK7 induced epithelial-mesenchymal transition-like changes in prostate carcinoma cells, as evidenced by scattered cellular growth, mesenchyma-like morphology, and up-regulated expression of vimentin, a mesenchymal marker. These novel findings suggest that hK7 plays an important role in mediating prostate cancer progression and that hK7 promotes invasion and metastasis, at least in part, through inducing the epithelial-mesenchymal transition of prostatic carcinoma cells. PMID- 20944117 TI - Cytoplasmic phospholipase A2 metabolites play a critical role in pulmonary tumor metastasis in mice. AB - BACKGROUND: Cytoplasmic PLA(2) (cPLA2) has been shown to be the major enzyme responsible for arachidonic acid (AA) release. Because of this key role of cPLA(2) in AA production, cPLA(2) involvement in tumorigenesis has been suggested. However, contradictory data are found in the literature. Additionally, little is known regarding the role of cPLA(2) in pulmonary tumor metastasis. MATERIALS AND METHODS: Tumor metastases were detected by lung colonization and angiogenesis was assayed as growth of blood vessels from subcutaneous tissue into an implanted matrigel of basement membrane. The matrix metalloproteinases (MMP) 2, and MMP-9 were detected by PCR with sequence-specific primers. RESULTS: In this study, the effects of inhibitors of cPLA2, 5-lipoxygenase (5-LO), and cyclooxygenase (COX)-2 on pulmonary metastasis formation by B16F10 melanoma cells were investigated. All of these inhibitors reduced B16F10 pulmonary metastasis formation in a dose-dependent manner. Importantly, cPLA2, and 5-LO, and COX-2 inhibitors reduced platelet-activating factor-induced angiogenesis in an in vivo mouse model employing Matrigel injected subcutaneously, and also reduced expression of MMP-2 and MMP-9 in the lungs. CONCLUSION: This study demonstrates that cPLA(2) metabolites play critical roles in tumor metastasis via the promotion, at least in part, of angiogenesis and MMP expression. PMID- 20944118 TI - Inhibitory effect of Cordyceps sinensis on experimental hepatic metastasis of melanoma by suppressing tumor cell invasion. AB - We investigated the anti-metastatic activity of a water extract of Cordyceps sinensis (WECS) using a model of mice injected with B16-F0 mouse melanoma cells into the spleen. WECS administered intraperitoneally reduced the number of metastatic surface nodules of B16-F0 cells in the liver of C57BL/6Cr mice in a dose-dependent manner, and significantly prolonged their survival. To identify the mechanism of the anti-metastatic effect of WECS, we examined its effects on hepatocyte growth factor (HGF)-accelerated invasion of B16-F0 cells using a chemo invasion assay in vitro. As a result, WECS reduced HGF-accelerated B16-F0 cell invasion in a concentration-dependent manner. These findings suggest that WECS exerts an anti-metastatic action, in part by inhibiting the HGF-accelerated tumor invasiveness of mouse melanoma cells. PMID- 20944119 TI - Frequency and role of HPV in the progression of epithelial dysplasia to oral cancer. AB - BACKGROUND: Human papillomavirus DNA (HPV DNA) and p16 and p53 protein expressions were investigated for their role in transforming dysplasia into squamous cell carcinoma of the oral cavity in a non-smoker and non-drinker patient group. MATERIALS AND METHODS: A total of 56 oral biopsies from non-smoker and non-drinker patients were analyzed. The specimens were grouped into three categories: group 1 included 31 cases of hyperplastic mucosa and mild dysplasia, group 2 included 14 cases of moderate and severe dysplasia, while group 3 comprised 11 cases of invasive squamous cell carcinomas. In all cases, immunohistochemical methods were performed to detect p16 and p53 protein expressions. The nested polymerase chain reaction for HPV (nested HPV-PCR) and the catalyzed signal-amplified colorimetric DNA in situ hybridization (CSAC-ISH) methods were applied for HPV DNA detection and typing of high-risk genotype. RESULTS: P16 protein, absent from all specimens of group 1, was especially noted in group 2 (92.86%) and in group3 (54.55%). Five out of 14 of group 2 cases (35.71%) and 3/11 (27.27%) of group 3 were HPV DNA positive. The HPVs detected were of both high-risk and low-risk genotype. The analysis of the relationship between HPV and p16 protein expression revealed that all the group 2 and 3 samples with HPV DNA, overexpressed p16 protein. CONCLUSION: The results suggest that HPV could be a molecular marker in group 2 and 3 specimens in non-smoker and non-drinker patients. The virus may play an etiological role in carcinogenesis in the oral cavity. The association between HPV and p16 overexpression suggests a molecular mechanism similar to that found in cervical cancer. PMID- 20944120 TI - MACC 1 as a marker for peritoneal-disseminated gastric carcinoma. AB - BACKGROUND: Recently, metastasis associated with the colon cancer 1 (MACC1) gene was identified by genome-wide search for differentially expressed genes in human colon cancer tissues and metastases. Previously, the MACC1 expression levels were examined in colorectal carcinomas and it was found that MACC1 expression showed significant correlation with peritoneal dissemination and higher stage of TNM classification. MATERIALS AND METHODS: In this study, MACC1 expression levels were analysed in 41 gastric cancer samples using quantitative real-time polymerase chain reaction (QRT-PCR). Results. Distribution of MACC1 expression scores in primary gastric carcinomas was between 0.01 and 4.36 (average +/- SD was 1.34 +/- 1.31). Subsequently, clinicopathological data were correlated with the MACC1 expression. It was found that MACC1 expression showed significant correlation with peritoneal dissemination (p=0.038). CONCLUSION: These results suggest that MACC1 is more frequently expressed in peritoneal-disseminated gastric carcinomas and may serve as a new parameter for the prognostic prediction of gastric cancer. PMID- 20944121 TI - Sporadic breast carcinomas with somatic BRCA1 gene deletions share genotype/phenotype features with familial breast carcinomas. AB - BACKGROUND: High frequencies of loss of heterozygosity (LOH) are found in familial breast carcinomas with BRCA mutations. Although LOH of BRCA1 does not coincide with somatic BRCA1 mutations, reduced BRCA1 protein expression and hypermethylation indicate the involvement of BRCA1 in sporadic carcinogenesis. To further investigate the role of BRCA we determined LOH of BRCA1 and correlated this with LOH in other breast cancer-associated regions. MATERIALS AND METHODS: A total of 105 sporadic breast carcinomas were analysed for LOH in the regions of BRCA1, BRCA2, TP53, Caveolin1, "putative BRCA3", PTEN, ATM and E-cadherin and correlated it with clinicopathological features. RESULTS: We found an overall increase of LOH in carcinomas with simultaneous LOH of BRCA1. Significantly higher LOH rates were detected in the regions of TP53 (80%: 34.7%; p<0.005), 8q21 (72.7%: 30.6%; p<0.010) and 10q22-23 (21.1%: 5.9%; p=0.043). Moreover, estrogen receptor-negative carcinomas revealed LOH of BRCA1 more frequently than estrogen receptor-positive carcinomas (39%: 12%; p=0.003). CONCLUSION: These data indicate that LOH of BRCA1 coincides with a defect of the DNA repair pathway. Therefore, LOH of BRCA1 determines a subgroup of sporadic breast carcinomas sharing genotype/phenotype features with familial breast carcinomas. PMID- 20944122 TI - Caveolin-1 and doxorubicin-induced P-glycoprotein modulate plasma cholesterol membrane accessibility in erythrolymphoblastic cell line. AB - AIM/ BACKGROUND: Various interactions between Caveolae membrane domains, multidrug resistance transporter P-glycoprotein (P-gp) and cholesterol have been suggested. We tested the assumption that anthracycline-induced P-gp and Caveolin 1 have correlated effects on cholesterol distribution in plasma membrane. MATERIALS AND METHODS: The present study was performed in four lymphoblastic K562 cell lines expressing none (KS), one (Cav and KR cells) or both P-gp and caveolin 1 proteins (CavKR cells). RESULTS: The CavKR cell line exhibits a significantly higher free cholesterol content than the other cell lines. Cholesterol distribution at the outer leaflet was distinct from the total cellular cholesterol by its accessibility to cholesterol oxidase (COase). When cells were ATP-deprived, cholesterol accessibility to oxidation was significantly delayed in CavKR cells. Caveolin-1 or P-gp expression did not induce detectable changes in membrane cholesterol accessibility to COase. CONCLUSION: Combination of functional P-gp, caveolae presence and lasting effect of anthracycline treatment appear determinant in free membrane cholesterol homeostasis and likely modulate cholesterol membrane order. PMID- 20944123 TI - TGF-beta1 antisense impacts the SMAD signalling system in fibroblasts from keloid scars. AB - AIM: To identify the effect of a TGF-beta1 antisense treatment of keloid fibroblasts on the SMAD signalling system. MATERIAL AND METHODS: In this cross sectional study, keloid and adjacent healthy tissue was harvested from 9 patients with keloid scars after otoplasty. Keloid fibroblasts were placed in monolayer cultures. Expression of SMAD2, -3, -4, -6, and SMURF2 were analysed by immunohistochemistry. Analysis of treatment with antisense oligonucleotides was conducted by immunohistochemistry, and RT-PCR. RESULTS: Immunohistochemical investigation demonstrated increased expression of SMAD2, -3 and -4, and decreased expression of SMURF2. TGF-beta1 antisense therapy significantly down regulated SMAD2 and SMAD4, up-regulated SMURF2 and showed no effect on SMAD3 and SMAD6. CONCLUSION: TGF-beta1 led to elevated levels of the SMAD signalling cascade, indicating an abnormal sensitivity of keloid-derived fibroblasts to this cytokine. Abrogation correlated with potential suppression of the fibro proliferative progress. There is growing evidence for an abnormal response to this cytokine in the intracellular signal transduction in keloid-derived fibroblasts. PMID- 20944124 TI - Down-regulation of heat-shock protein 70 (HSP-70) correlated with responsiveness to neoadjuvant aromatase inhibitor therapy in breast cancer patients. AB - BACKGROUND: Aromatase inhibitor (AI) has been established as an effective endocrine therapy in estrogen receptor (ER)-positive postmenopausal breast cancer patients. Our recent proteomic analysis demonstrated that ten proteins were significantly altered in their expression levels before and after the therapy in the patients receiving neoadjuvant AI. Among these newly identified proteins, heat-shock protein 70 (HSP-70) was the most significantly correlated with both clinical and pathological responses. Therefore, in this study, we further evaluated the significance of this HSP-70 alteration using immunohistochemistry. MATERIALS AND METHODS: A total of 32 patients treated with neoadjuvant exemestane or letrozole in whom pre- and post-treatment tumor tissues were available were included. Immunohistochemical evaluation of ER, progesterone receptor (PgR), Her 2, Ki-67 and HSP-70 was performed. Results obtained were compared to both clinical and biological responses of the patients. RESULTS: The majority of the patients responded to treatment (16 patients with partial response, 14 with stable disease and 2 with progressive disease). The means of ER, Ki-67 and HSP-70 were significantly different between treatment responders and non-responders. Decrement of HSP-70 and Ki-67 after AI treatment and pretreatment Ki-67 labeling index of >10% tumor cells were significantly associated with clinical responsiveness to AI treatment (p<0.0001). There was a significant positive correlation between changes of HSP-70 and Ki-67 before and after the therapy. CONCLUSION: Decrement of HSP-70 in breast carcinoma cells plays important roles in therapeutic mechanisms of AIs through suppressing tumor cell proliferation in breast cancer patients. PMID- 20944125 TI - Epstein-Barr virus-infected cell line TCC36B derived from B lymphocytes infiltrating renal pelvis urothelial carcinoma. AB - This study reports an initial analysis of an EBV-infected B cell line (TCC36B), established from an urothelial carcinoma (UC) lesion of the renal pelvis. MATERIALS AND METHODS: Cytofluorometric and G-banding analyses were performed for phenotyping and cytogenetics. PCR was used to detect EBV DNA, and sequence analysis to investigate mutations and deletions of the latent membrane protein (LMP)-1 gene of EBV. RESULTS: TCC36B cells proliferated in vitro and showed positivity for surface CD19, CD20, HLA-DR and IgG(lambda), indicating that they belong to B-cells. Cytogenetic analysis showed 46,XX with a unique clonal abnormality of dup(2)(p13p25). EBV DNA was detected in TCC36B cells. Sequence analysis revealed a 30-bp deletion and 7 point mutations on the LMP-1 gene in TCC36B cells. CONCLUSION: These results suggest the involvement of an EBV variant in the pathogenesis of UC. This cell line should thus facilitate further investigations on the aetiological role of EBV in urothelial cancer. PMID- 20944126 TI - KITENIN is associated with tumor progression in human gastric cancer. AB - BACKGROUND: KAI1 COOH-terminal interacting tetraspanin (KITENIN) promotes tumor cell migration, invasion and metastasis in colon, bladder, head and neck cancer. The aims of current study were to evaluate whether KITENIN affects tumor cell behavior in human gastric cancer cell line and to document the expression of KITENIN in a well-defined series of gastric tumors, including complete long-term follow-up, with special reference to patient prognosis. MATERIALS AND METHODS: To evaluate the impact of KITENIN knockdown on behavior of a human gastric cancer cell line, AGS, migration, invasion and proliferation assays using small interfering RNA were performed. The expression of activator protein-1 (AP-1) target genes and AP-1 transcriptional activity were evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and luciferase reporter assay. The expression of KITENIN and AP-1 target genes by RT-PCR and Western blotting or immunohistochemistry was also investigated in human gastric cancer tissues. RESULTS: The knockdown of KITENIN suppressed tumor cell migration, invasion and proliferation in AGS cells. The mRNA expression of matrix metalloproteinase-1 (MMP-1), MMP-3, cyclooxygenase-2 (COX-2), and CD44 was reduced by knockdown of KITENIN in AGS. AP-1 transcriptional activity was significantly decreased by knockdown of KITENIN in AGS cells. KITENIN expression was significantly increased in human cancer tissues at RNA and protein levels. Expression of MMP-1, MMP-3, COX-2 and CD44 were significantly increased in human gastric cancer tissues. Immunostaining of KITENIN was predominantly identified in the cytoplasm of cancer cells. Expression of KITENIN was significantly associated with tumor size, Lauren classification, depth of invasion, lymph node metastasis, tumor stage and poor survival. DISCUSSION: These results indicate that KITENIN plays an important role in human gastric cancer progression by AP-1 activation. PMID- 20944127 TI - Two multidrug-resistance (ABCB1) gene polymorphisms as prognostic parameters in women with ovarian cancer. AB - BACKGROUND: The transport protein P-glycoprotein, which is encoded by the multidrug-resistance ABCB1 gene, is crucially involved in the export of taxanes and other cytotoxic substances out of the cell. Treatment response to paclitaxel has been shown to correlate with ABCB1 gene polymorphisms. Data regarding the prognostic value of ABCB1 gene polymorphisms in ovarian cancer patients is conflicting. MATERIALS AND METHODS: The present study evaluates the association of two common ABCB1 gene polymorphisms, namely G2677T/A in exon 21 (rs2032582) and C3435T in exon 26 (rs1045642), and survival in 106 Caucasian women with ovarian cancer. RESULTS: The two ABCB1 gene polymorphisms (G2677T/A and C3435T) were associated neither with disease-free (p=0.8 and p=0.9, respectively) nor with overall survival (p=0.9 and p=0.9, respectively). Tumor stage (p=0.01; p=0.01) and residual tumor mass (p=0.005; p=0.01), but not tumor grade and age at diagnosis were associated with disease-free and overall survival, respectively, in a multivariate analysis. Haplotype analysis did not reveal any association between the combined effect of the two gene polymorphisms and survival. CONCLUSION: In the present study, ABCB1 G2677T/A and ABCB1 C3435T gene polymorphisms were not found to be associated with prognosis in Caucasian women with ovarian cancer. PMID- 20944128 TI - Optimized protocols for generation of cord blood-derived cytokine-induced killer/natural killer cells. AB - The efficacy of various combinations of stem cell factor (SCF), FLT3 ligand, interleukin (IL)-2, IL-7 and IL-15 to induce and expand cord blood-derived cytokine-induced killer (CIK) cells was investigated. There were three treatment groups: group A: SCF combined with IL-2, IL-7 and IL-15; group B: SCF, FLT3 ligand combined with IL-2, IL-7 and IL-15, and group C: IL-2, IL-7 and IL-15, the control group. Proliferation rates of CD3(+)CD56(+) CIK cells and CD3(-)CD56(+) natural killer (NK) cells were highest in group B; expansion of CIK cells increased 796.1 +/- 278.5-fold, and that of NK cells increased 36.6 +/- 3.5-fold. All expanded cord blood-derived CIK/NK cells showed cytotoxic activity against the K562 cell line. Interestingly, the cytotoxicity of group A was highest and significantly higher than that of other groups. These protocols might provide an alternative choice for CIK/NK cell expansion. PMID- 20944129 TI - Quercetin inhibits human DLD-1 colon cancer cell growth and polyamine biosynthesis. AB - BACKGROUND/AIM: Polyamines and ornithine decarboxylase are involved in cell growth and differentiation. The polyphenol quercetin may exert anti-tumour properties by influencing proliferation, differentiation, and apoptosis. The aim of the study was to investigate the effects of increasing concentrations of quercetin (from 0.1 to 100 MUM) on polyamine biosynthesis, cell proliferation, and apoptosis in the DLD-1 cells. MATERIALS AND METHODS: Polyamine levels and ornithine decarboxylase activity were evaluated by HPLC and radiometric technique, respectively. The proliferative response was estimated by 3-(4,5 dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide (MTT) test and [(3)H] thymidine incorporation in cell DNA. Apoptosis was investigated by DNA fragmentation. RESULTS: At concentrations >=50 MUM, quercetin significantly reduced ornithine decarboxylase activity, putrescine and spermidine levels compared to controls and cells treated with 0.1 MUM concentration. Quercetin concentrations >=70 MUM caused a significant reduction in the conversion of MTT tetrazolium salt and [(3)H]-thymidine incorporation. The same concentrations were needed to induce the apoptosis. CONCLUSION: The present study demonstrates that quercetin can affect growth of DLD-1 cells by both decreasing polyamine biosynthesis and inducing apoptosis. Due to the extensive dietary consumption of polyphenols, such as quercetin, the biological activity of these compounds deserves further investigation. PMID- 20944130 TI - Effect of inhibition of the ROCK isoform on RT2 malignant glioma cells. AB - BACKGROUND: Malignant glioma is one of the most intractable diseases in the human body. Rho-kinase (ROCK) is overexpressed and has been proposed as the main cause for the refractoriness of the disease. Since efficacious treatment is required, this study investigated the effect of inhibition of ROCK isoforms. MATERIALS AND METHODS: The short hairpin RNA transcription vector was transfected into the RT2 rat glioma cell line and the characteristics of the cells were investigated. The effect of nimustine hydrochloride (ACNU) anti-neoplastic agent on cells was also measured. RESULTS: Inhibition of ROCK isoforms did not alter cell growth. Cell cycle analysis revealed that ROCK1 down-regulation reduced the G(0) phase population and ROCK2 down-regulation reduced the G(2)/M phase population. When ROCK1-down-regulated cells were exposed to ACNU, they demonstrated susceptibility to the agent. CONCLUSION: The roles of ROCK1 and ROCK2 may be different in glioma cells. Furthermore, the combination of ROCK1 down-regulation and an anti neoplastic agent may be useful for the therapy of malignant glioma. PMID- 20944131 TI - Tumour-derived microvesicles (TMV) mimic the effect of tumour cells on monocyte subpopulations. AB - BACKGROUND: Monocytes/macrophages may be affected by tumour cells via cell-to cell contact, soluble factors and by tumour-derived microvesicles (TMV). Previous observations indicate that TMV interact with monocytes and alter their immunophenotype and activity. This study was designed to determine interactions of TMV with subpopulations (CD14(++)CD16(-) and CD14(+)CD16(++)) of human monocytes. METHODS: Engulfment of TMV by subsets of monocytes was analysed by flow cytometry. Moreover cytokine release and production of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI) by CD14(++)CD16(-) and CD14(+)CD16(++) cells after TMV stimulation was determined. RESULTS: It was found that TMV are engulfed more efficiently by CD14(++)CD16(-) than CD14(+)CD16(++) cells. TMV-activated CD14(++)CD16(-) cells produce more ROI and interleukin -10 (IL-10) than CD14(++)CD16(+). CD14(+)CD16(++) cells following TMV stimulation showed an increased release of tumour necrosis factor alpha, IL-12p40 and RNI. CONCLUSION: TMV significantly modulate biological activity of monocyte subsets with a pattern similar to tumour cells. Therefore, TMV mimic the activating effect of tumour cells on monocytes as assessed by release of cytokines, ROI and RNI. PMID- 20944132 TI - Expression of metalloproteinases MMP-2 and MMP-9 in sentinel lymph node and serum of patients with metastatic and non-metastatic breast cancer. AB - The objective of this study was to evaluate the expression of MMP-2 and MMP-9 in sentinel lymph node and serum of breast cancer patients in order to evaluate their clinical significance and usefulness as diagnostic tumour markers. Expression of MMP-2 and MMP-9 was performed on sentinel lymph node by immunohistochemistry while gelatine zymography was used to determinate the serum expression. The association of gelatinases with clinicopathological features, were analysed. Metastatic and non-metastatic breast cancer patients and 34 healthy women were involved. Gelatinases expression were significantly higher in metastatic breast cancer in comparison to non-metastatic cancer and the control group both in the sentinel lymph node and serum. Results showed a statistically significant correlation between MMP-2 or MMP-9 and cancer familiality, MMP-9 and CA 15.3 levels, and MMP-9 and grading. This study suggests a clinical utility of these proteolytic markers in malignant tumour, growth, invasion and metastasis in breast cancer. PMID- 20944133 TI - Differential expression of mTOR signalling components in drug resistance in ovarian cancer. AB - BACKGROUND/AIM: A limitation to successful cancer chemotherapy treatments is the acquisition of drug resistance. In advanced-stage ovarian cancer, the mammalian target of rapamycin (mTOR) pathway is up-regulated, and inhibition of this pathway increases chemosensitivity in ovarian carcinoma cell lines. In this study, the expression of DEPTOR, mTOR, RICTOR, RAPTOR and S6 kinases were investigated in SKOV-3 and PEO1 parental and the paclitaxel-resistant (TaxR) SKOV 3TaxR and PEO1TaxR cell lines. MATERIALS AND METHODS: RT-PCR, immunofluorescent analysis and Western blotting were carried out. RESULTS: Quantitative RT-PCR revealed significant up-regulation of DEPTOR in both paclitaxel-resistant cell lines. SKOV-3TaxR exhibited down-regulation of RICTOR, RAPTOR and mTOR, whereas PEO1-TaxR showed down-regulation of RAPTOR and up-regulation of RICTOR and mTOR. Semi-quantitative RT-PCR analysis revealed marked changes in the expression of p70S6K splice variants mRNA in PEO1TaxR. Moreover, the phosphorylation status of p70S6K at Ser371 appears to be cell-type specific. CONCLUSION: We hypothesize that mTOR signalling may play a role in mediating paclitaxel resistance in ovarian cancer. PMID- 20944134 TI - Decreased Srcasm expression in esophageal squamous cell carcinoma in a Chinese population. AB - BACKGROUND: Src-family tyrosine kinases (SFKs) play critical roles in regulating cellular differentiation and proliferation. Src-activating and signaling molecule (Srcasm) is a novel molecule that down-regulates SFK activity and promotes cell differentiation. The aim of this study was to determine whether Srcasm expression was altered in esophageal squamous epithelial carcinoma compared with normal epithelium in a Chinese population. MATERIALS AND METHODS: We examined Srcasm immunohistochemical staining in 30 cases in both normal esophageal epithelium and esophageal squamous cell carcinoma (SCC) from the same patient in formalin-fixed paraffin embedded tissue blocks. RESULTS: Srcasm protein expression levels are decreased in esophageal SCC compared to the esophageal normal epithelium. CONCLUSION: This pattern of Srcasm expression suggests that it may act as a negative regulator in esophageal SCC cell signaling. PMID- 20944135 TI - Prognostic relevance of the proliferation marker REPP86 for laryngeal cancer. AB - BACKGROUND: There is a clear correlation between proliferative activity and the biological behavior of cancer, which might have an impact on the patients' prognosis and consequences for the individual therapy concept. REPP86 (restrictedly expressed proliferation-associated protein 86) is a proliferation associated protein expressed in S-, G(2)- and M-phases of the cell cycle, regarded as a promising proliferation marker and has not yet been examined in squamous cell carcinoma of the larynx (SCCL). MATERIALS AND METHODS: REPP86 was analyzed retrospectively in 104 SCCL using the monoclonal antibody Ki-S2. Proliferative activity was correlated with tumor stage, histopathological grading, patients' survival and the results we recently published on Ki-67 staining in SCCL. Median follow-up time was 47 months. RESULTS: A significant correlation (p<0.05) between histopathological grading, N-status and proliferation activity was observed. The patient group consisting of low proliferating laryngeal cancer showed a statistically longer absolute (p<0.05) and relapse-free (p=0.001) 5-year survival time than the group with a high proliferating tumor. Compared to the Ki-67 staining results, the REPP86 antibody better predicts the relapse-free 5-year-survival. CONCLUSION: Our results indicate that REPP86 staining of SCCL with Ki-S2 is a helpful prognostic indicator for SCCL and better predicts the relapse-free survival than Ki-67 staining in SCCL. PMID- 20944136 TI - Houttuynia cordata Thunb extract inhibits cell growth and induces apoptosis in human primary colorectal cancer cells. AB - It is reported that Houttuynia cordata Thunb. (HCT), a traditional Chinese herbal medicine, has many biological properties such as antiviral, antibacterial and antileukemic activities. However, the molecular mechanisms of cytotoxicity and apoptosis in human primary colorectal cancer cells are not clear. In this study, whether HCT induced cytotoxicity in primary colorectal cancer cells obtained from three patients was investigated. The results indicated that HCT inhibited growth of cancer cells in a dose-dependent manner. After treatment with HCT (250 MUg/ml) for 24 h, cells exhibited chromatin condensation (an apoptotic characteristic). HCT increased reactive oxygen species (ROS) production and decreased the mitochondrial membrane potential (DeltaPsi(m)) in examined cells. Mitochondria dependent apoptotic signaling pathway was shown to be involved as determined by increase in the levels of cytochrome c, Apaf-1, and caspase-3 and -9. The decrease in the level of DeltaPsi(m) was associated with an increase in the BAX/BCL-2 ratio which led to activation of caspase-9 and -3. Based on our results, HCT induced apoptotic cell death in human primary colorectal cancer cells through a mitochondria-dependent signaling pathway. PMID- 20944137 TI - Increasing p53 protein sensitizes non-small cell lung cancer to paclitaxel and cisplatin in vitro. AB - AIM: To determine whether increasing p53 protein levels confers enhanced chemosensitivity in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Three NSCLC cell lines, with different endogenous p53 expression, were transfected with wild-type p53 (wt-p53) or CD-1 (truncated wt-p53) genes. Cells were subsequently treated with cisplatin (CDDP) or paclitaxel (PAX). Cell viability was measured using Alamar Blue Assay. RESULTS: Cells transfected with CD-1 expressed 13-38% higher levels of p53 protein compared to cells transfected with the wt-p53 gene, despite their baseline endogenous levels. CD-1-transfected cells also had higher cell death when treated with CDDP (p<0.05) or PAX, exhibiting 30-60% higher death rates than cells transfected with the wt-p53 gene and 130-160% higher than untransfected cells. A significant positive correlation between p53 protein concentration and cytotoxic response was demonstrated (R(2) for CDDP=0.823; R(2) for PAX=0.909; p<0.001). CONCLUSION: Increasing intracellular p53 protein concentrations can augment the effect of CDDP and PAX in NSCLC, despite the baseline level of p53 protein expression. PMID- 20944138 TI - Inhibition of heat-shock protein 27 expression eliminates drug resistance of osteosarcoma to zoledronic acid. AB - BACKGROUND: Although zoledronic acid (ZOL) has been reported to show anti-tumour effects on various malignant tumours, few studies have reported the molecular mechanisms of resistance to ZOL. MATERIALS AND METHODS: A drug-resistant cell line was developed by repeatedly treating human osteosarcoma cell line HOS with ZOL. Expression status of drug resistance-related molecules including ATP-binding cassette (ABC) and heat-shock protein 27 (HSP27) was confirmed in order to analyse molecular mechanisms of the drug resistance. RESULTS: Repeated treatment with ZOL induced drug resistance with down-regulation of apoptosis in the resistant cell line. Although ABC expression was down-regulated, up-regulation of HSP27 in the resistant cell line was confirmed. The resistance was overcome by HSP27 silencing. CONCLUSION: Resistance to ZOL in osteosarcoma cells may be induced by a molecular mechanism different from conventional efflux pump-based resistance. Up-regulation of HSP27 expression may play a role in the development of ZOL resistance in HOS cells. PMID- 20944139 TI - Significant association of methylenetetrahydrofolate reductase single nucleotide polymorphisms with prostate cancer susceptibility in taiwan. AB - Prostate cancer is the most common cause of cancer death in men and is a major health problem worldwide. Methylene tetrahydrofolate reductase (MTHFR) plays an important role in folate metabolism and is also an important source of DNA methylation and DNA synthesis (nucleotide synthesis). To assess the association and interaction of genotypic polymorphisms in MTHFR and lifestyle factors with prostate cancer in Taiwan, we investigated two well-known polymorphic variants of MTHFR, C677T (rs1801133) and A1298C (rs1801131), analyzed the association of specific genotypes with prostate cancer susceptibility, and discussed their joint effects with individual habits on prostate cancer risk. In total, 218 patients with prostate cancer and 436 healthy controls recruited from the China Medical Hospital in central Taiwan were genotyped for these polymorphisms with prostate cancer susceptibility. We found the MTHFR C677T but not the A1298C genotype was differently distributed between the prostate cancer and control groups. The T allele of MTHFR C677T conferred a significantly (p=0.0011) decreased risk of prostate cancer. As for the A1298C polymorphism, there was no difference in distribution between the prostate cancer and control groups. Gene interactions with smoking were significant for MTHFR C677T polymorphism. The MTHFR C677T CT and TT genotypes in association with smoking conferred a decreased risk of 0.501 (95% confidence interval=0.344-0.731) for prostate cancer. Our results provide the first evidence that the C allele of MTHFR C677T may be associated with the development of prostate cancer and may be a novel useful marker for primary prevention and anticancer intervention. PMID- 20944140 TI - Importance of miR-20a expression in prostate cancer tissue. AB - BACKGROUND: MicroRNAs (miRNAs), which are endogenously expressed regulatory noncoding RNAs, have an altered expression in tumor tissues. MiRNAs regulate cancer-related processes such as cell growth and tissue differentiation, and therefore, might function as oncogenes or tumor-suppressor genes. The aim of our study was to assess the expression of mir-20a, let-7a, miR-15a and miR-16 in prostate cancer (PCa) and benign prostatic hyperplasia (BPH) tissue and to investigate the relation between the expression of miRNAs and the clinicopathological features of PCa. PATIENTS AND METHODS: The study group comprised 138 patients: 85 patients with BPH and 53 patients with PCa. The total RNA was isolated from the tissue specimen core and miRNA expressions were quantified using a real-time RT-PCR method (TaqMan MicroRNA Assays). U6snRNA was used for the normalization of the miRNA expression. RESULTS: miR-20a expression was significantly higher in the group of patients with a Gleason score of 7-10 in comparison with the group of patients with a Gleason score of 0-6 (p=0.0082). We found no statistical differences in the miRNA expressions (mir-20a, let-7a, miR 15a and miR-16) in the PCa tissue samples in comparison with the BPH tissue samples. CONCLUSION: Our result shows that the more dedifferentiated PCa cells have a higher expression of miR-20a and this supports the oncogenic role of miR 20a in PCa carcinogenesis. The evaluation of miRNA expression could yield new information about PCa pathogenesis. PMID- 20944141 TI - Effect of Ha-rasval12 on nm23 expression, tumor formation and metastasis of the transformants, and immunomodulation in tumor-bearing mice. AB - Overexpression of the Ha-ras(val12) oncogene has frequently been detected in primary and metastatic carcinomas. NM23 is a metastasis inhibition factor and plays a suppressive role in metastasis in many types of cancer. In this study, a stable NIH/3T3 cell line harboring an inducible Ha-ras(val12) oncogene (designated as 7-4) and small interfering RNAs (siRNAs) were used to clarify the inverse correlation between nm23 and Ha-ras expression both in vitro and in vivo. A derivative 7-4/Z-3 cell line harboring a beta-galactosidase reporter gene was used to trace cell metastasis in a murine tumor model. The data presented here reveal that Ha-ras(val12) is able to cause cell morphological changes, induce tumor formation, and promote metastasis of tumor cells to the lungs. In mice with metastases, the immune surveillance against tumor formation was suppressed by Ha ras(val12) overexpression through an increase in T-reg cells and a decrease of cytotoxic T lymphocytes and natural killer cell populations. Our results suggest that the Ha-ras oncogene regulates morphogenesis, tumorigenesis, and metastasis through suppressing nm23 expression and modulation of immune cell function. PMID- 20944142 TI - Down-regulation of P-glycoprotein is associated with resistance to cisplatin and VP-16 in human lung cancer cell lines. AB - AIM: To investigate whether down-regulation of P-glycoprotein (P-gp) is correlated to resistance to cisplatin and VP-16 in four histopathological subtype cell lines of lung cancer (SK-MES-1, SPCA-1, NCI-H-460 and NCI-H-446). MATERIALS AND METHODS: After pretreatment with or without verapamil, the P-gp expression was examined by means of RT-PCR and immunofluorescence. Cell survival on treatment with cisplatin and VP-16 was determined by MTT assay. RESULTS: The expression of P-gp was clearly inhibited by verapamil in all four cell lines. Following pretreatment with verapamil, NCI-H-446 was more sensitive to cisplatin, while SPCA-1, NCI-H-460 and NCI-H-446 were more sensitive to VP-16 compared to the control. CONCLUSION: Down-regulation of P-gp is associated with intrinsic resistance to cisplatin in the NCI-H-446 and to VP-16 in SPCA-1, NCI-H-460 and NCI-H-446 cell lines. These findings indicate that down-regulation of P-gp may be helpful for the reversion of drug resistance in some lung cancer cell line subtypes. PMID- 20944144 TI - Comparison of the apoptosis-inducing capability of sulforaphane analogues in human colon cancer cells. AB - The anticancer activity of sulforaphane is known to be mediated at least partly by apoptosis induction and associated with the presence of the -N=C=S moiety. The present study explored how oxidation of sulphur in the side chain of sulforaphane affected apoptosis induction to provide the chemical basis of sulforaphane effects. Sulforaphane analogues containing oxidised sulphur (alyssin, sulforaphane, erysolin and alyssin sulfone) exerted a superior growth inhibitory effect compared with sulforaphane analogues with nonoxidised sulphur (erucin and berteroin) in human colon cancer cell lines. Furthermore, erysolin was a more potent inducer of reactive oxygen species (ROS) and apoptosis compared with erucin. Erysolin-induced ROS generation and subsequent apoptosis were inhibited by pretreatment with the antioxidant N-acetyl-cysteine. Erysolin induced caspase 8 activation, while blockade of caspsase 8 activation inhibited apoptosis induced by erysolin. Taken together, sulforaphane analogues with oxidised sulphur were the most efficient apoptosis inducers, likely due to high-level ROS induction. PMID- 20944143 TI - A Dihydroxy-pentamethoxyflavone from Gardenia obtusifolia suppresses proliferation and promotes apoptosis of tumor cells through modulation of multiple cell signaling pathways. AB - We sought to determine the molecular basis for the anticancer activities of 5,3' dihydroxy-3,6,7,8,4'-pentamethoxyflavone (DH-PMF), isolated from Gardenia obtusifolia traditionally used in Thailand for a variety of ailments. As little as 1 MUM DH-PMF inhibited the proliferation of prostate, colon, kidney, lung, head and neck, pancreas, breast, leukemia, and myeloma cancer cell lines. DH-PMF also suppressed the colony-forming ability of tumor cells, with 50% inhibition occurring at a dose less than 10 nM. DH-PMF induced G(2)/M and subG(1) cell cycle arrest, increased the levels of p21(WAF1/CIP1) and p27(KIP1), and reduced the expression of cyclin D1, CDC2, and c-MYC. Furthermore, DH-PMF inhibited AKT and glycogen synthase kinase 3 beta (GSK3beta) activation, reduced cell survival proteins, and induced apoptosis, as indicated by annexin V staining, TUNEL assay, and activation of caspase-8, -9 and -3. Overall, our results demonstrate that DH PMF induces suppression of cell proliferation through modulation of AKT-GSK3beta pathways and induction of cyclin-dependent kinase (CDK) inhibitors. PMID- 20944145 TI - A study of RET proto-oncogene polymorphisms in association with lung cancer risk in the Korean population. AB - BACKGROUND/AIM: This study examined whether the polymorphisms at the promoter region of RET gene are associated with the risk of lung cancer in the Korean population. PATIENTS AND METHODS: A total of 409 Korean lung cancer patients and 409 normal subjects were recruited. PCR-RFLP, SNaP Shot assay and logistic regression analyses were performed to characterize the association between polymorphisms of RET and lung cancer risk. RESULTS: Four SNPs (-1697 C>G, -1260 C>T, -719 C>T, -527 C>A) of RET were selected for large-scale genotyping. Statistical analyses revealed that novel -1260 C > T polymorphism and haplotype 3 (-1697G, -1260T, -719C, and -719C) were associated with the risk of lung cancer; specifically, there were significant associations within subgroups of males and smokers. CONCLUSION: These results demonstrated that this novel polymorphism of the RET gene is associated with an increased risk of lung cancer in the Korean population. PMID- 20944146 TI - Inhibition of growth and induction of alkaline phosphatase in colon cancer cells by flavonols and flavonol glycosides. AB - We observed previously that quercetin can increase the activity of the differentiation markers alkaline phosphatase and dipeptidyl peptidase in Caco-2 colon cancer cells. In the present work, we compared the effects of quercetin on cell proliferation and differentiation with the action of related flavonols and quercetin glycosides. Relative to the action of quercetin, effects on growth and enzyme activities did not always follow parallel trends but quercetin 3-glucoside was notably more potent in both respects while quercetin rutinoside was less active. Of the compounds examined, baicalein and myricetin caused the greatest production of hydrogen peroxide when incubated with the medium. Flavonols can have pro-oxidant effects, but our data suggested that this action was not the sole determinant of growth inhibitory or differentiating effects on Caco-2 cells. Our data indicated that effects of quercetin on colon cancer cell lines can be greatly affected by glycoside modification. PMID- 20944147 TI - The Wilms' tumor suppressor WT1 regulates expression of members of the epidermal growth factor receptor (EGFR) and estrogen receptor in acquired tamoxifen resistance. AB - BACKGROUND: In human breast cancer, a growth status switched from estrogen dependent to growth factor-dependent is a critical step during development of acquired tamoxifen resistance. However, the molecular mechanisms underlying this switch remain poorly understood. The Wilms' tumor suppressor gene, WT1, encodes a zinc-finger protein WT1 that functions as a transcription regulator. High levels of the WT1 expression have been associated with de novo tamoxifen resistance. The goal of this study was to investigate the function of WT1 in acquired tamoxifen resistance. MATERIALS AND METHODS: A stable tamoxifen-resistance cell line MCF7(TAM) was established by selecting ER-positive breast cancer MCF7 cells in a medium containing tamoxifen. Western blot, cell growth assay and shRNA method were used to examine the role of WT1 in acquired tamoxifen resistance. RESULTS: MCF7(TAM) cells expressed EGFR, HER2 and WT1 at higher levels compared to tamoxifen-sensitive parental MCF7 cells. MCF7(TAM) cells responded weakly to estrogen stimulation, grew rapidly in the absence of estrogen and were insensitive to tamoxifen. We also established stable cell lines from MCF7(TAM) cells to express shRNA specific for WT1, and found expression levels of the epidermal growth factor receptor (EGFR), HER2 and estrogen receptor (ER)-alpha to be down-regulated in MCF7(TAM) cells with knocked-down levels of WT1 expression. MCF7(TAM) cells with WT1 expression knocked-down by shRNA still retained tamoxifen insensitivity. CONCLUSION: Our results indicated that WT1 is involved in expressional regulation of the EGFR family members and ER-alpha during development of acquired tamoxifen resistance. PMID- 20944148 TI - Antiproliferative effect of LXR agonists T0901317 and 22(R)-hydroxycholesterol on multiple human cancer cell lines. AB - Previously, we and other groups reported that liver X receptor (LXR) agonists T0901317, 22(R)-hydroxycholesterol, and 24(S)-hydroxycholesterol suppressed the proliferation of prostate and breast cancer cells. In this study, we report that T0901317 and 22(R)-hydroxycholesterol treatment inhibited the proliferation of different progression stages of LNCaP human prostate cancer cells, as well as different commonly used human cancer cell lines. Cancer cell lines with higher LXRalpha mRNA expression were more sensitive to 22(R)-hydroxycholesterol-induced inhibition. T0901317 treatment decreased the percentage of the cell population in S-phase and caused G(1) cell cycle arrest. Overexpression of S-phase kinase associated protein 2 (Skp2) partially blocked the suppressive effect of T0901317 treatment. Modulating LXR signaling is therefore a potential adjuvant therapy for advanced prostate cancer and other types of cancer. PMID- 20944149 TI - Association study of cyclooxygenase 2 single nucleotide polymorphisms and childhood acute lymphoblastic leukemia in Taiwan. AB - AIM: The relationship between COX-2 gene and childhood leukemia risk is ambiguous. In this study, the association of genotypic polymorphisms in cyclooxygenase 2 (Cox-2) with childhood leukemia were investigated. MATERIALS AND METHODS: A total of 266 patients with childhood leukemia and 266 healthy controls recruited from the China Medical Hospital in central Taiwan were genotyped by PCR RFLP method. Six polymorphic variants of Cox-2 were investigated, including G 1195A, G-765C, T+8473C, intron 1, intron 5, and intron 6, and the associations of specific genotypes with susceptibility to childhood leukemia were analysed. RESULTS: The data showed that although there was no difference in the distribution for each genotype of Cox-2 G-1195A, G-765C, T+8473C, intron 1, intron 5, and intron 6, between the childhood leukemia and control groups (p>0.05), the analysis of combined effect for COX-2 G-765C and intron 6 showed that individuals with GC at G-765C and GG or AG+AA at intron 6 present a slightly higher potential for developing childhood leukemia than other groups. CONCLUSION: These findings suggest that the C allele of COX-2 G-765C may be responsible for childhood leukemia and may be useful in early detection of child leukemia. PMID- 20944150 TI - Synergistic cytotoxic effects of arsenic trioxide plus dithiothreitol on mice oral cancer cells. AB - The anti-tumor properties of arsenic trioxide have attracted extensive attention after successfully inducing apoptosis of acute promyelocytic leukemia cells. However, the therapeutic spectrum should not only be restricted to acute promyelocytic leukemia, but should also extend into other types of tumor cells. In this study, we aimed at investigating its potential application to clinical therapeutics in oral cancer. In this preclinical animal test, primarily cultured cells from the tumor sites and normal sites of a two-drug (200 MUg/ml 4 nitroquinoline 1-oxide (4NQO) plus 500 MUg/ml arecoline)-induced oral cancer C57BL/6J Narl mice model were examined for their viabilities after treatments of arsenic trioxide with/without other drugs. In this model, the mice were treated with 4NQO plus arecoline (NA) in their drinking water for eight weeks (8-w), and the drugs were withdrawn for another 10 or 20 weeks (18-w and 28-w, respectively). The results showed that 2 MUM of arsenic trioxide 24-h treatment suppressed the viabilities of cells primarily cultured from the tumor sites of 8 w, 18-w and 28-w NA-treated mice to 72.9%, 71.5% and 65.6%. However, it also suppressed the viabilities of cells from the sham-treated mice of 8-w, 18-w and 28-w to 76.8%, 73.4% and 75.7%, respectively. Therefore, 0.5 MUM of arsenic trioxide treatment for 24 h, which suppressed the viabilities of cells primarily cultured from the tumor sites of 28-w NA-treated and sham-treated mice to 15.6% and 9.1%, was examined for its synergistic effects on the two primarily cultured cell lines with other drugs. The results showed that 10-20 MUM dithiothreitol enhanced the cytotoxic effects of arsenic trioxide to 43.3~62.1%, better than those of 4 J/m(2) UVC, 20 MUM H(2)O(2) or 100 MUM buthionine sulfoximine (21.3%, 13.2%, and 14.2%, respectively). At the same time, 10-20 MUM dithiothreitol plus 0.5 MUM arsenic trioxide treatments caused only 12.3% and 15.2% of cell death in the control group. The cytotoxicity of dithiothreitol and arsenic trioxide combination on primarily cultured cells from this oral cancer model should be confirmed in human oral cancer cell lines before its application in clinical therapy, and the detailed mechanism is worth further investigation. PMID- 20944151 TI - The presence of P-glycoprotein in L1210 cells directly induces down-regulation of cell surface saccharide targets of concanavalin A. AB - Overexpression of P-glycoprotein (P-gp), a plasma membrane drug transporter (ABCB1, a member of the ABC transporter family), is the most prevalent cause of multidrug resistance in cancer tissues. Lectin concanavalin A (ConA) induces massive cell death of L1210 leukemia cells (S). Cell sublines of L1210 in which P gp overexpression was induced by selection with vincristine (R) or by stable transfection with a plasmid encoding full-length human P-gp (T) were less sensitive to ConA. Both P-gp-positive cell lines exhibited typical P-gp-mediated multidrug resistance. Resistance of R and T cells to ConA was associated with lower binding of ConA as compared to S cells when analysed by the following methods: (i) SDS PAGE and electroblotting of proteins in the crude membrane fraction followed by detection with biotinylated ConA and avidin-peroxidase, and (ii) fluorescent cytometry or confocal microscopy of the intact cells with surfaces labeled by FITC-ConA. These data indicated that the presence of P glycoprotein in L1210 cells independently of the mode of its expression induced down-regulation of cell surface saccharide targets of ConA. Therefore, this feature may be considered as a secondary cellular response to P-glycoprotein expression. PMID- 20944152 TI - Modulation of gemcitabine accumulation by DNA-damaging agents: mechanisms and specificity in an in vitro model. AB - Self-potentiation of the intracellular accumulation of gemcitabine accumulation occurs with repeated administration. Understanding the mechanism of this phenomena and its occurrence with other drugs is important for rational dosing of gemcitabine and design of gemcitabine combinations. The HCT116 cell line was used as a model of the in vivo findings to examine the effect of repeated gemcitabine exposure. HPLC analysis revealed a 10-fold increase in gemcitabine-triphosphate accumulation upon repeated gemcitabine exposure. The induction of accumulation was not associated with any changes in the dCK mRNA level. Comparable increases in gemcitabine-triphosphate were seen when the cells were pre-incubated with cytarabine and cisplatin. A lesser increase and no increase in GEM-TP were seen with oxaliplatin and 5'-azacytidine, respectively. In this model, induction of gemcitabine accumulation is likely to be mediated by post translational modification of dCK. The reduced effect of oxaliplatin compared to cisplatin is worthy of further study. PMID- 20944153 TI - Novel chemoradiosensitizers for cancer therapy. AB - Combined modality therapy using both chemotherapy and radiation has proved superior over radiation therapy alone for a variety of cancer types. While the locoregional control and survival benefits have been established, there is still much room for improvement both in terms of cancer control and normal tissue toxicity, i.e. the therapeutic ratio. Recently, the pace of research and development of both conventional cytotoxic and molecularly targeted radiosensitizers has been staggering. The aim of this paper is to bring the reader up to date on the clinical status of four promising new radiosensitizers: novel camptothecin analogs and inhibitors of poly(ADP-ribose) polymerase, histone deacetylase, and heat-shock protein 90. PMID- 20944154 TI - Active surveillance for low-risk prostate cancer. AB - Surgery, and radiation therapy remain the standard treatments for newly diagnosed prostate cancer patients. Nonetheless, these aggressive treatments are associated with decreased quality of life with altered sexual and urinary functions. Using modern risk stratification, several centers have gained significant experience in identifying patients with a low risk of prostate cancer progression and have adopted an active surveillance program with delayed, selective, or curative therapy. Interestingly, only limited numbers of patients under active surveillance require additional treatment. Recent data suggest that delayed treatment does not appear to alter the clinical outcome among those highly selected patients. A better understanding of the molecular determinants of prostate cancer behavior would not only enable healthcare professionals to identify which cases need aggressive treatment but, perhaps more importantly, would also indicate potential targets for the development of novel therapeutic strategies. PMID- 20944155 TI - The evolving role of radiofrequency ablation therapy of breast lesions. AB - BACKGROUND: The potential for radiofrequency ablation (RFA) therapy is an area of increasing interest in the context of breast conserving therapy for breast cancer. This non surgical technique potentially provides a non invasive, cosmetically pleasing result that is preferable to surgeon and patient. MATERIALS AND METHODS: A literature review was carried out facilitated by PubMed and Medline databases. Cross referencing of the obtained articles was used to identify other relevant studies. A total of 17 studies were reviewed. RESULTS: RFA is emerging as a promising treatment for breast cancer. Pilot and phase II studies have shown RFA to be effective at ablation with few complications or adverse effects experienced by patients. However, complete ablation of tumours is still not achieved in all patients. CONCLUSION: RFA represents a promising therapeutic modality for breast lesions. However, there is a clear need for further research and refinement of the procedure before it can be offered as a therapeutic alternative to surgical excision for operable breast cancer. PMID- 20944156 TI - p27kip1 Expression in non-small cell lung cancer is not an independent prognostic factor. AB - BACKGROUND: p27(Kip1) (p27) plays an important role in cancer cell cycle regulation. Recent evidence however, suggests that p27 may function as an oncogene rather than a tumour suppressor gene. PATIENTS AND METHODS: Ninety-two patients with previously untreated non-small cell lung cancer (NSCLC) were studied for the association between the immunohistochemical localization of p27 through a semi-quantitative method and time-to-progression (TTP) and overall survival (OS). RESULTS: The relationship between p27 H-Score and both TTP and OS was polynomial. Short TTP in patients with metastasis or whose tumors progressed during the eight-month period after diagnosis was statistically associated with overexpression of PIRH2 (p<0.001). In patients whose tumours progressed later, long TTP was associated with NSCLC of the non-adenocarcinoma type (p=0.027), p27 H-Score (p=0.032) and well-differentiated adenocarcinoma (p=0.047). None of the parameters correlated with duration of OS. CONCLUSIONS: This study showed that p27 H-Score may not appear to be an independent prognostic factor in patients with NSCLC. PMID- 20944157 TI - Gastric tumor from metastasis of breast cancer. AB - Metastatic tumours of the stomach have been reported to result from various types of cancer. Among them, gastric metastasis from breast cancer has been recognised in 0.3-18% patients (1-4). Here, a rare case of metastatic gastric tumour derived from breast carcinoma is reported. Gastric endoscopy confirmed a large, friable mass (approximately 5 cm in diameter) in the upper part of the gastric body. The mass within the stomach was difficult to distinguish from primary gastric cancer, although biopsies of this lesion revealed the characteristics of adenocarcinoma. In addition, immunohistochemistry showed the positive expression of mammaglobin. Taken together, the evidence pointed to metastasis of breast cancer to the stomach. The patient was treated with hormonal therapy (letrozole), and the size of the metastasis in the stomach was markedly reduced. Therefore, a gastric metastasis from breast cancer was diagnosed successfully using immunohistochemistry and unnecessary surgery was avoided. In conclusion, although gastric metastatic tumours derived from breast carcinoma are rare, their accurate pre-operative diagnosis and appropriate systemic treatment is essential. PMID- 20944158 TI - Immunological response after therapeutic vaccination with WT1 mRNA-loaded dendritic cells in end-stage endometrial carcinoma. AB - BACKGROUND: Wilms' tumour gene 1 (WT1), a highly ranked immunotherapeutic target, is expressed in uterine cancer and therefore WT1 immunotherapy may present an attractive treatment option. PATIENT AND METHODS: An HLA-A2.1-positive 46-year old woman with end-stage serous endometrial cancer received 4 weekly injections of WT1-RNA-loaded dendritic cells. Response was measured clinically (CT scan), biochemically (CA125) and immunologically (WT1-specific T cells). RESULTS: The patient showed WT1 positivity in 10% of tumour cells and diffusely in the intratumoural endothelial cells of the recurrent disease. After 2 injections, CA125 started to decrease and WT1-specific T-cells increased 2.5-fold. The treatment was feasible and there were no treatment-related side-effects. However, the patient, suffering from diffuse disease which became progressive again, died 8 months later. CONCLUSION: This is the first patient with a WT1-positive endometrial carcinoma, to receive immunotherapy with WT1-RNA-loaded dendritic cells, resulting in a vaccine-specific T cell response. PMID- 20944159 TI - Targeted therapy for Ewing's sarcoma: significance of heterogeneity. AB - BACKGROUND: Survival in Ewing's sarcoma (ES) is limited. Experience with insulin like growth factor targeting drugs, which require specific molecular tumour alterations, herald a major breakthrough. We screened for tumour heterogeneity within patients by DNA quantification. MATERIALS AND METHODS: DNA image cytometry (IC) was performed on 41 samples from 21 patients, evaluating if ploidy state remained constant over time and between different lesions within patients and the prognostic value of ploidy was assessed. RESULTS: DNA content varied over time and different ploidy states were found to coexist at a single timepoint. Non diploid DNA content was associated with shorter overall survival (median, 19 vs. 84 months, p=0.047). CONCLUSION: We encountered a change and heterogeneity of ploidy state. This implies that screening for targets on a single tumour sample is insufficient and may lead to under- or overtreatment. The fact that non diploid DNA content was associated with an adverse outcome confirms that this technique discriminates biologically different tumour clones. PMID- 20944160 TI - Importance of erythropoetin receptor expression in tumour tissue for the clinical course of breast cancer. AB - BACKGROUND: Adverse outcomes in breast cancer patients treated with recombinant human erythropoietin (rhEpo) have been linked to the expression of Epo-receptors (EpoR) in cancer cells, although limited data on the clinical significance of these observations are available. PATIENTS AND METHODS: Tissue samples from 107 patients with breast cancer who did not receive rhEpo and from 12 patients with benign lesions were retrospectively analysed for EpoR expression by RT-PCR and Western blot, and the results were correlated to clinical and demographic data. RESULTS: While EpoR levels were not linked to anaemia or inflammation, they were positively associated with progesterone and oestrogen receptor status. Patients with increased EpoR-mRNA expression had a higher local cancer recurrence rate (p=0.021), however, no significant difference in overall survival was observed. CONCLUSION: Since EpoR expression is associated with hormone receptor positivity and decreased locoregional disease control, this parameter characterises a specific cancer phenotype rather than being a negative predictor itself. PMID- 20944161 TI - Long-term survival in uterine clear cell carcinoma and uterine papillary serous carcinoma. AB - Uterine clear cell carcinoma (UCC) and uterine papillary serous carcinoma (UPSC) are rare entities that differ in clinical behavior from endometrial adenocarcinoma. Compared with endometrioid adenocarcinoma, they more often metastasize early and more commonly in the upper abdomen including the omentum. Treatment programs of UCC and UPSC at different stages vary and range from no adjuvant therapy in stage Ia to a wide variety of chemotherapies and radiotherapies in more advanced stages. This study presents the outcome of 109 patients with UCC or UPSC treated according to essentially the same treatment program from May 1993 to December 2004. Most patients were treated with a simple hysterectomy with no further adjuvant treatment. In stage Ia, 2/46 patients died of their disease and amongst all the stages, 30/109 patients died of their disease. These survival outcomes are comparable to or better than those presented previously. PMID- 20944162 TI - Pattern of failures and clinical outcome of patients with locally advanced cervical cancer treated with a tailored integrated therapeutic approach. AB - AIM: To review a tailored treatment with concurrent chemoradiotherapy (CT/RT) or neoadjuvant chemotherapy (NACT) followed by radical hysterectomy in locally advanced cervical cancer. PATIENTS AND METHODS: One hundred and four patients were treated with a tailored therapeutic approach. CT/RT was the standard treatment for patients with stage Ib2-IIb disease aged more than 70 years, or with high surgical risk, as well as for those with stage III-IV disease. NACT followed by radical hysterectomy was the treatment of choice for patients with stage Ib(2)-IIb disease, maximum age of 70 years and good performance status. RESULTS: For the 61 women who underwent CT/RT, 5-year disease-free (DFS) survival and 5-year overall survival (OS) were 62% and 71%, respectively. Patient outcome was associated with the clinical response to CT/RT (complete responders versus others: 5-year DFS, 81% versus 19%, p<0.001; 5-year OS, 84% versus 37%, p=0.001). For the 43 women who underwent NACT, 5-year DFS and 5-year OS were 66% and 75%, respectively. Patient outcome was associated with the pathological response to chemotherapy (optimal responders versus others: 5-year DFS, 89% versus 62%, p=0.03; 5-year OS, 90% versus 72%, p=0.05). CONCLUSION: Tailored treatments obtained satisfactory clinical outcomes in locally advanced cervical cancer. Optimal pathological response to NACT has been found to be a surrogate endpoint of OS. The identification of biological variables able to predict response to NACT is strongly warranted for an accurate selection of patients who may really benefit from chemosurgical treatment. PMID- 20944163 TI - Combination therapy with VP16 and ethinylestradiol for hormone-refractory prostate cancer: good response with tolerability. AB - OBJECTIVES: This study evaluated the safety profile and therapeutic value of a combination therapy of etoposide and ethinylestradiol, which is a novel treatment protocol for patients with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Patients were given etoposide (25 mg/day, daily) and ethinylestradiol (3 mg/day, daily) orally until disease progression or unacceptable toxicity. The response rate, survival and safety profiles were evaluated. RESULTS: Between 2003 and 2009, 61 patients were enrolled. In terms of PSA levels, >70% of patients showed a >50% reduction (complete response [CR] 51%, partial response 23%) and >90% showed a clinical response. Of 58 patients with measurable lesions, 24% (14/58) showed a CR, and most of these patients (13/14, 93%) survived without recurrence with median response duration of 28 months CONCLUSION: The regimen was tolerable, with a significant improvement in quality of life, and produced an effective response in patients with HRPC. PMID- 20944164 TI - Surface-bound TGF-beta1 on effusion-derived exosomes participates in maintenance of number and suppressive function of regulatory T-cells in malignant effusions. AB - BACKGROUND: This study analysed the contribution of malignant-effusion derived exosomes (Eff-Ex) to the number and function of regulatory T-cells (Treg) in malignant effusions. PATIENTS AND METHODS: Eff-Ex were collected from the malignant effusions of 24 cancer patients. Peripheral blood mononuclear cells (PBMCs) were co-cultured with different concentrations of Eff-Ex. FOXP3(+) CD4(+) T-cells were defined as Treg. Expression of molecules on Eff-Ex was determined by flow cytometric analysis. RESULTS: The number of Treg decreased daily in parallel with the FOXP3 expression level. Purified Eff-Ex prevented the decreases in both Treg number and FOXP3 expression levels in a dose-dependent manner. Pre-treatment of Eff-Ex with a neutralizing mAb against TGF-beta1 significantly reduced these effects and the suppressive function of Treg. CONCLUSION: Elimination of Eff-Ex or control of Eff-Ex expressing TGF-beta1 may be new therapeutic strategies in immunotherapy for advanced cancer patients with malignant effusions. PMID- 20944165 TI - Feasibility and efficacy of combination chemotherapy with S-1 and fractional Cisplatin for advanced gastric cancer. AB - BACKGROUND: There is a great need for effective outpatient chemotherapy for advanced gastric cancer in patients with good performance status. The present pilot study evaluated the use of combination chemotherapy with S-1 and fractional CDDP for unresectable-recurrent gastric cancer in an outpatient setting. PATIENTS AND METHODS: A total of 41 patients with unresectable or recurrent gastric cancer were treated with this combination chemotherapy. S-1 was administered orally every day on days 1-28 and CDDP was infused on days 1, 15, and 29. RESULTS: Thirty-six patients had measurable lesions and 19 patients had partial responses, resulting in an overall response rate of 52.8%. The median survival time was 494 days. There was no grade 4 haematological toxicity, no grade 3 or more non haematological toxicity, and no treatment-related death. CONCLUSION: This combination chemotherapy has no serious toxicities in patients with unresectable and recurrent gastric cancer and can be used effectively in an outpatient setting. PMID- 20944166 TI - A case of esophageal cancer showing complete remission of nephrotic syndrome after esophagectomy. AB - Nephrotic syndrome associated with a malignant tumor may remit following resection of the tumor. This report documents a case of esophageal cancer with concurrent nephrotic syndrome in which a surgical resection of the tumor resulted in a complete remission of nephrotic syndrome. A 78-year-old male patient noticed edema of his lower legs in February 2009 and was diagnosed with nephrotic syndrome. An endoscopic examination revealed an indented lesion with a nearly semiannular low elevation on the posterior wall of the esophagus at 31 to 34 cm from the upper incisors, and a diagnosis of esophageal cancer was made. A two stage operation was planned. In March 2009, a subtotal resection of the thoracic esophagus through a right thoracic approach and cervical external esophagostomy were performed, and in April 2009, antethoracic route esophagogastrostomy was performed. The urinary protein levels were negative by the 86th day of hospitalization, and the patient progressively improved and was discharged on the 91st hospital day. There has been no recurrence of esophageal cancer or relapse of nephrotic syndrome at 12 months following the operation. In esophageal cancer patients with nephrotic syndrome, surgical treatment should be undertaken because the remission of nephrotic syndrome may be expected following tumor resection. For this purpose, selecting the appropriate operative procedures and careful perioperative management, including nutritional management, are of profound importance. PMID- 20944167 TI - Desmoplastic small round cell tumour successfully treated with caffeine-assisted chemotherapy: a case report and review of the literature. AB - Desmoplastic small round cell tumour (DSRCT) is a rare tumour, usually arising in the abdominal cavity. DSRCT remains an aggressive malignancy, with a poor prognosis despite multi-modality treatments. In the published literature, there has been no patient who lived for three years or more without surgical excision. This report describes a case of DSRCT arising from the brachial plexus and successfully treated with caffeine-assisted chemotherapy. A 29-year-old male presented with pain and numbness in his left forearm. Radiological findings were suggestive of malignant tumour. Histology, immunohistochemical stain and fluorescence in situ hybridisation (FISH) results confirmed the diagnosis of DSRCT. He underwent caffeine-potentiated chemotherapy and the tumour disappeared. The tumour was not removed surgically as it was intertwined in the brachial plexus. Four years after the initial diagnosis, no local relapse and no distant metastases have been observed. Therefore, it is concluded that caffeine-assisted chemotherapy should be one of the treatment options for DSRCT. PMID- 20944168 TI - Dermatofibrosarcoma protuberans: a case series of 16 patients treated in a single institution with literature review. AB - BACKGROUND: Dermatofibrosarcoma protuberans is an uncommon skin tumour with a low to intermediate-grade of malignancy, characterized by progressive growth and a propensity for local recurrence. PATIENTS AND METHODS: A retrospective study of a series of 16 consecutive patients with dermatofibrosarcoma protuberans who were treated in the host Institution over the last seven years was performed, with special emphasis on the outcome and disease-free interval, as well as recurrence rate over a mean follow-up period of 43.65 months. RESULTS: The clinicopathological features and results were reviewed. The primary treatment consisted of wide local excision with or without radiotherapy on 13 patients with primary and 3 with recurrent disease, and all patients remained free of disease recurrence during the mean follow-up period. CONCLUSION: The results of this study and a review of the literature support the notion that aggressive, wide surgical resection with disease-free margins, with or without radiotherapy decreases local recurrences and offers an excellent probability of cure. The accumulated data also confirm that all patients with dermatofibrosarcoma protuberans should be followed up for an extended period, beyond the usual recommended 5-year follow-up, because late recurrences may occur. PMID- 20944169 TI - Re-irradiation of head and neck cancer-impact of total dose on outcome. AB - AIM: To evaluate the outcome of re-irradiation and to define favourable pre treatment characteristics. PATIENTS AND METHODS: seventy-five patients with locally recurrent head and neck cancer were treated with re-irradiation, either postoperatively or as definitive treatment, with and without chemotherapy. Mean time period between first and second series of irradiation was 19 months. Mean overall dose of re-irradiation was 46 Gy. Median follow-up was 8.7 months. RESULTS: Overall survival, loco-regional disease-free survival and metastasis free survival after two years were 23%, 24% and 77%, respectively. Higher overall doses of re-irradiation gave a statistically significant better outcome with regard to overall survival (p=0.018). CONCLUSION: For patients with locally recurrent head and neck cancer, re-irradiation is a feasible therapeutic option. The total dose at re-irradiation improves overall survival. Therefore, re irradiation with curative intent should only be applied if a sufficient total dose of >=46 Gy can be given. PMID- 20944170 TI - Evaluation of FDG-PET for detecting lymph node metastasis in uterine corpus cancer. AB - BACKGROUND: In order to decrease surgery-related morbidity, we evaluated the reliability of the evaluation of lymph node metastasis in patients with uterine corpus cancer by positron-emission tomography (PET) with 2-[(18)F]fluoro-2-deoxy D-glucose (FDG) before surgical staging. MATERIALS AND METHODS: Patients with newly diagnosed uterine corpus cancer scheduled for surgical staging, including lymphadenectomy, underwent PET imaging within 30 days before surgery. PET results and postoperative histopathology were compared for each patient and each nodal site. Sensitivity, specificity, positive and negative predictive value (PPV/NPV) as well as accuracy of FDG-PET in predicting nodal disease was determined by joined meta-analysis of the present data and the data available in the literature. RESULTS: Of 21 patients examined, 13 patients were eligible to enter this pilot study. Only one patient had lymph node metastasis, which was preoperatively detected by FDG-PET scan. Additionally, another patient was considered to have lymph node metastasis according to increased focal FDG uptake; however, all lymph nodes were free of malignant disease upon final pathology. In contrast, all other patients without lymph node metastasis upon final pathology showed negative preoperative FDG-PET scans. The meta-analysis yielded a sensitivity, specificity, PPV, NPV and accuracy of 0.53, 0.91, 0.57, 0.90 and 0.84, respectively. CONCLUSION: In patients with uterine corpus cancer, FDG-PET had an insufficient positive predictive value in detecting lymph node metastases, indicating that this method cannot replace surgical staging. However, due to its high NPV, FDG-PET might be beneficial in selected patients who are poor candidates for surgical staging. PMID- 20944171 TI - Complete response obtained by bortezomib plus dexamethasone in a patient with relapsed multiple myeloma with multiple plasmacytomas. AB - BACKGROUND: A case of relapsed multiple myeloma (MM) with multiple plasmacytomas of the parietal bone and the right orbit in which was achieved a complete response with bortezomib plus dexamethasone (BD) therapy is reported. A Japanese woman with Bench-Jones lambda-type MM who achieved a plateau phase with nine courses of melphalan plus prednisolone therapy complained of right exophthalmos and numbness around her mouth. Computed tomographic (CT) scan and T2-weighted magnetic resonance imaging showed tumours at the parietal bone and the right orbit. A tumour biopsy from the parietal bone revealed the histological morphology of a plasmacytoma. She was therefore diagnosed with relapsed MM with multiple plasmacytomas, and received BD therapy. A CT scan after the end of the second course of treatment revealed the disappearance of the plasmacytomas. At the end of the fifth course, no lambda light chain was detected by immunofixation of serum and urine, and the pathological plasma cells in bone marrow were fewer than 5%; therefore, she had achieved a complete response. The time to disease progression from the first course of BD therapy and the treatment-free interval were 400 days and 134 days, respectively. CONCLUSION: This case report indicates that bortezomib may be a promising agent for MM with multiple plasmacytomas. PMID- 20944172 TI - Functional results after giant cell tumor operation near knee joint and the cement radiolucent zone as indicator of recurrence. AB - BACKGROUND: Giant cell tumor of bone near the knee joints is a dilemma for the operating surgeon. Curettage and bone grafting have a high recurrence, whereas wide resection has a reduced recurrence rate with the compromise of limb function. MATERIALS AND METHODS: Thirty-eight patients with histologically proven giant cell tumor near the knee joint were treated. All patients were reviewed with regard to the operative method, recurrence rate, postoperative arthritis and functional results of the joint. In cases of cement filling, the radiolucent zone and the sclerotic rim were assessed as possible markers for recurrence. RESULTS: 14 male and 24 female patients were included in this study (mean age 28 years, range 13-56 years). All patients underwent surgery, 21 patients were treated with a bone cement filling and additional osteosynthesis after curettage. Seventeen patients were filled with cancellous bone or curettage alone. In the group with bone cement filling after curettage, the recurrence rate was 23.8%, whereas a recurrence rate of 52.9% was detected in the group with cancellous bone filling or curettage alone. The average time to recurrence was two years (5 months to 6 years). An increase of the radiolucent zone was seen in 80% of all patients with a recurrence. CONCLUSION: Cement filling after extensive curettage does not increase the recurrence rate and does not induce osteoarthritis, as long as the continuity of articular cartilage is maintained. Patients with giant cell tumor of bone near the knee joint can be treated satisfactorily with intralesional resection and bone cement packing. The extension of the radiolucent zone after bone cement filling is a reliable indicator for a possible local recurrence. PMID- 20944173 TI - The role of inflammation in patients with intraductal mucinous neoplasm of the pancreas and in those with pancreatic adenocarcinoma. AB - BACKGROUND: There are very few data regarding inflammation in patients with intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. AIM: To evaluate the circulating concentrations of placental growth factor (PlGF), transforming growth factor-alpha (TGF-alpha), transforming growth factor-beta1 (TGF-beta1), tumour necrosis factor receptor 1 (TNF-R1) and matrix metalloproteinase-2 (MMP-2) in patients with IPMNs and in those with pancreatic adenocarcinomas. PATIENTS AND METHODS: Sixty-nine patients were enrolled: 23 (33.3%) had IPMNs and 46 (66.7%) had histologically confirmed pancreatic adenocarcinomas. Thirteen healthy subjects were also studied. PlGF, TGF-alpha, TGF-beta1, TNF-R1 and MMP-2 were determined using commercially available kits. RESULTS: TNF-R1 (p=0.003) was the only protein significantly different among the three groups. CONCLUSION: Serum TNF-R1 was elevated in patients with IPMNs and in those with pancreatic adenocarcinomas, suggesting a high apoptotic activity in both groups of patients studied. PMID- 20944174 TI - Delayed elimination of methotrexate associated with co-administration of proton pump inhibitors. AB - AIM: We conducted a retrospective non-interventional cohort study to analyze the impact of proton pump inhibitors co-administration on methotrexate elimination in cancer patients receiving treatment protocol with the antifolate at high dose (>1 g/m(2) intravenously). PATIENTS AND METHODS: Between 2005 and 2008, 79 patients (mean age: 48.8 years; range: 16-76 years) were treated by high dose methotrexate for 197 cycles. RESULTS: Delayed methotrexate elimination (i.e., plasma concentration >15 MUmol/l at 24 h, >1.5 MUmol/l at 48 h and/or >0.15 MUmol/l at 72 h) occurred in 16% (32/197) of the cycles. The co-prescription of a proton pump inhibitor (pantoprazole, lansoprazole, omeprazole, esomeprazole) was found in 53% (17/32) of the courses with delayed elimination and in 15% (24/165) of the cycles without delayed elimination. We identified co-administration of proton pump inhibitors as a major risk factor for delayed elimination (odds ratio 6.66, 95% confidence interval 3.13, 14.17). CONCLUSION: Proton pump inhibitors should not be administered during methotrexate treatment. PMID- 20944175 TI - Randomized follow-up study of resected NSCLC patients: conventional versus 18F-DG coincidence imaging. AB - The aim of this study was to compare the utility of gamma camera using a coincidence detection system imaging (CDET) with 18-fluorodeoxyglucose to conventional imaging techniques in the detection of recurrence of non-small cell lung cancer. Sixty-nine patients were randomized into two groups for follow-up after surgery from October 2000 to December 2002. Each patient was evaluated every 6 months by conventional technique imaging in group A (n=33) or CDET imaging in group B (n=36) over two years. The direct costs of each procedure were evaluated. The major endpoint was the number of recurrences or new tumours detected. The two groups were similar. A total of 25 recurrences was detected (9 in group A and 16 in group B). Overall survival was similar in the two groups. CDET imaging was more expensive. CDET imaging provides earlier detection of recurrence, but does not modify survival outcome. Further studies are necessary to demonstrate the impact, if any, of 18-FDG imaging. PMID- 20944176 TI - Phase II study of neoadjuvant gemcitabine, pegylated liposomal doxorubicin, and docetaxel in locally advanced breast cancer. AB - AIM: This was a phase II study to assess the activity of a novel neoadjuvant regimen in locally-advanced breast cancer. PATIENTS AND METHODS: Fifty patients with histological confirmation of locally advanced breast cancer received treatment with gemcitabine 1000 mg/m(2) (day 1) followed by gemcitabine 800 mg/m(2) plus docetaxel 75 mg/m(2) plus pegylated liposomal doxorubicin (PLD) 30 mg/m(2) (day 8) every 3 weeks for at least 4 cycles, plus a final 2 additional cycles. Tumour size was T1 (n=2), T2 (n=32), T3 (n=14), T4 (n=2). All 50 patients underwent surgery. RESULTS: Clinical complete, partial and no response were observed in 13 (26%), 24 (48%) and 11 (22%) patients, respectively (overall response rate: 74%). The number of chemotherapy cycles was found to be an independent predictor of a pathologic complete response. CONCLUSION: The combination of gemcitabine-docetaxel-PLD can yield high tumour response rates in patients with locally-advanced breast cancer who undergo a full treatment of 6 cycles. PMID- 20944177 TI - Psychological response to cancer: role of 5-HTTLPR genetic polymorphism of serotonin transporter. AB - BACKGROUND: 5-HTTLPR genetic polymorphism of serotonin transporter (SERT) and stressful life events facilitate depression. The aim of this investigation was therefore to determine the correlations between SERT polymorphism and mental adjustment to cancer. PATIENTS AND METHODS: Breast cancer patients early after surgery, and subjects with various advanced tumours were recruited, evaluated using the Mini Mental Adjustment to Cancer Scale and Hospital Anxiety and Depression Scale (HADS), and genotyped. RESULTS: In early breast cancer patients (n=53), hopelessness-helplessness (HH) and anxious preoccupation (AP) significantly correlated with depression and anxiety; avoidance (AV) correlated with anxiety. Advanced cancer patients (n=73) displayed similar correlations, and a negative correlation of HADS depression with fighting spirit (FS) and AV. The stratification for 5-HTTLPR showed that early breast cancer carriers of the L/L variant displayed a significant correlation between HH and depression. CONCLUSION: Among early breast cancer patients, a specific set, characterized by their 5-HTTLPR variant, display differential correlations between HH and depression, with possible implications for treatment options. PMID- 20944178 TI - Efficacy of S-1 in patients with capecitabine-resistant breast cancer-Japan Breast Cancer Research Network (JBCRN) 04-1 trial. AB - BACKGROUND: S-1 is an orally administered fluorinated pyrimidine with high activity in metastatic breast carcinoma (MBC) and in chemotherapy-pretreated metastatic breast carcinoma. PATIENTS AND METHODS: Forty patients with MBC who did not respond to capecitabine-based chemo-therapy and then received S-1 were identified from our data base of records between 2006 and 2008. The clinico pathological data and outcomes of these patients were then reviewed. RESULTS: The overall response rate was 27.8%. The median survival was 19.2 months, and the median time to disease progression was 6.2 months. The most common treatment related adverse events (all grades) were hand-foot syndrome (15%), nausea (15%), vomiting (7.5%), disorder of taste (7.5%), and diarrhea (5%). However, the majority were mild to moderate in intensity, and only one patient experienced grade 3 (according to the National Cancer Institute of Canada Common Toxicity criteria) adverse events. Myelosuppression and alopecia were rare, and there were no reported treatment-related deaths. CONCLUSION: The results of the current study demonstrate that S-1 is an effective and well-tolerated treatment in patients with capecitabine-resistant MBC. In addition, it is a convenient, orally administered drug, which makes it an attractive agent for use in outpatient treatment. PMID- 20944179 TI - Optimal cutoff points of CYFRA21-1 for survival prediction in non-small cell lung cancer patients based on running statistical analysis. AB - PURPOSE: To determine pretreatment serum CYFRA21-1 levels as indicators of poor prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: 1,202 consecutive patients, diagnosed pathologically with NSCLC from January 1999 to December 2009, were entered in this study. To obtain optimal cutoff points of CYFRA21-1 for these endpoints, a running log-rank statistical method was applied. RESULTS: The cutoff level for the maximum log-rank statistical value of one-year survival in patients with NSCLC was 18.0 ng/ml. These results could be applied to patients with squamous cell carcinoma. In multivariate analysis, elevated (>18.0 ng/ml) levels of CYFRA21-1 was confirmed as being an unfavourable prognostic factor. CONCLUSION: CYFRA21-1 assay has a clinical significance for identifying patients with poor prognosis among those with early and advanced NSCLC. Elevated serum CYFRA21-1 levels at the time of diagnosis may be a useful noninvasive marker for identifying the risk of early death from NSCLC. PMID- 20944180 TI - Combined chemotherapy with gemcitabine and cisplatin for metastatic urothelial carcinomas in patients 80 years of age and over. AB - BACKGROUND: This retrospective study aimed to determine the efficacy and toxicity of a combined chemotherapeutic regimen of gemcitabine and cisplatin (GC) for the treatment of metastatic urothelial carcinomas (UCs) in patients 80 years of age and over. PATIENTS AND METHODS: Twelve patients who were at least 80 years old and had been diagnosed with metastatic UC were treated with GC. The patient cohort consisted of 9 men and 3 women, with a median age of 83 (range 80-84) years. The median follow-up was 54 (range 14-80) months. RESULTS: Five out of the 12 patients (42%) showed an objective response, with two achieving a clinically complete response and three a partial response with GC. The median time to progression was 6 months, and the median overall survival was 14 months. The grade 3 and 4 toxicities of the regimen were primarily hematological, including anemia (33%), neutropenia (58%), and thrombocytopenia (50%). No grade 3 or 4 non hematological toxicities were found. CONCLUSION: GC appears to be an effective and well-tolerated regimen for the treatment of metastatic UCs in very old patients. PMID- 20944181 TI - Autologous stem cell transplantation for patients with acute promyelocytic leukemia in second molecular remission. AB - Relapse still occurs in approximately 20-30% of patients with acute promyelocytic leukemia (APL) and, after achievement of second complete remission (CR), the optimal strategy is still controversial. We describe therapeutic results from a series of 13 patients autografted in second molecular remission (MR) by a molecular negative apheresis product. In all patients, the disease was confirmed at the molecular level and all had received the GIMEMA/AIDA protocol, achieving molecular remission at the end of consolidation. Relapse was hematological in 12 cases and molecular in one. After consolidation with chemotherapy, all patients achieved MR and received a further course plus granulocyte-colony stimulating factor as mobilizing therapy. A median of 7.6*10(6) (range 2.7-10) CD34-positive cells/kg were collected. In all cases, molecular evaluation of the apheresis product was negative for the promyelocytic leukemia/retinoic acid receptor alpha gene. No case of transplant-related mortality was recorded. No maintenance or consolidation therapy after autologous stem cell transplantation (ASCT) was given to any patient. After a median follow-up of 25 months from ASCT, 10 patients are alive in sustained MR, while two relapsed after ASCT and died in the setting of refractory disease; one patient achieved a third CR and is waiting for allogeneic SCT. These results suggest that ASCT performed with a molecularly negative graft in APL patients in second MR offers a valid chance for achieving a cure. Such an approach should also be considered in relapsed patients with an HLA-compatible donor, namely in those with a first CR lasting more than one year or in unfit or elderly individuals. PMID- 20944183 TI - Incidence, predictors and outcome of drug-eluting stent thrombosis in real-world practice. AB - BACKGROUND: Traditionally, stent thrombosis (STH) has been regarded as a complication of percutaneous coronary interventions during the first 30 post procedural days. However, delayed endothelialization associated with the implantation of drug-eluting stents (DES) may extend the risk of thrombosis beyond 30 days. Data are limited regarding the risks and the impact of this phenomenon outside clinical trials. OBJECTIVES: To evaluate the incidence, predictors and clinical outcomes of STH and premature discontinuation of thienopyridines after implantation of DES in real-world practice. METHODS: We prospectively collected data from consecutive unselected patients who underwent at least 1 DES implantation at our center from February 2006 until January 2007. The patients were followed by a phone interview or by collecting data from admission files over the course of 2 years after the implantation. Confirmed and suspected STH was defined as accepted in the medical literature. RESULTS: Three hundred fourteen patients were successfully treated with DES (436 lesions). At 20 +/- 6.7 months' follow up (median 22 months), 14 patients (4.4%) had STH (incidence density 2.7 cases/100 patients-years). Five patients had early thrombosis (0-30 days), 5 patients had late STH (31-360 days from the procedure) and 4 patients had very late STH (> 360 days). Five of the 14 patients with STH died (case fatality rate, 36%). In multivariant logistic regression analysis, history of a non-cardiac thrombotic event was a risk factor for STH (p = 0.006, odds ratio [OR] 7.7, confidence interval [CI] 1.8-32.9). Clopidogrel therapy lasting less than 3 months was an independent predictor of late and very late STH (p = 0.001, OR 10.8, CI 2.7-42.9). Independent predictors of early discontinuation of thienopyridines (<= 3 months) were Arab ethnic origin (p = 0.005, OR 19.2, CI 2.4-142), absence of cardiology follow up (p = 0.05, OR 4.7, CI 1-23.1) and absence of explanation about the clopidogrel importance at the time of hospital discharge (p = 0.001, OR 10.8, CI 2.7-42.9). CONCLUSIONS: The incidence of STH at 22- month follow up in real-world patients was substantially higher than the rate reported in previous clinical trials. Subsidizing the cost of thienopyridines, providing a clear explanation to the patient and encouraging cardiology follow up may prevent premature discontinuation of thienopyridines after implantation of DES and reduce the incidence of STH after DES implantation. PMID- 20944184 TI - Is implantation of drug-eluting stents a Faustian choice? PMID- 20944185 TI - The relative renal safety of iodixanol and low-osmolar contrast media in patients undergoing percutaneous coronary intervention. Insights from Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2). AB - Contrast-induced acute kidney injury (CI-AKI) is a common complication of percutaneous coronary intervention (PCI). Current guidelines support the use of iodixanol (Visipaque(r), GE Healthcare, Princeton, New Jersey) in patients at high risk for CI-AKI. Recent trials and meta-analyses have shown no difference in CI-AKI when iodixanol is compared to low-osmolar contrast media (LOCM). We evaluated the incidence of CI-AKI, in-hospital dialysis and in-hospital death in 58,957 patients who underwent PCI in 2007 and 2008 in a large regional consortium of 31 hospitals and who were treated with iodixanol (n = 17,814) or LOCM (n = 41,143). Propensity-matched analysis was performed to adjust for differences in baseline variables. Patients treated with iodixanol compared to those treated with LOCM were slightly older, had more medical comorbidities and a higher baseline creatinine (1.35 +/- 1.07 mg/dL versus 1.10 +/- 0.85 mg/dL; p < 0.0001). In propensity-matched, risk-adjusted models, there was no significant difference between iodixanol and LOCM in the risk of CIAKI (4.54% vs. 4.14%; p = 0.14), need for dialysis (0.37% vs. 0.43%; p = 0.35) or death (1.46% vs. 1.39%; p = 0.18). Among patients undergoing PCI, the use of iodixanol was more frequent in older patients with more comorbidities and worse baseline renal function. There was no difference in the adjusted risk of CI-AKI among patients treated with iodixanol compared with those treated with LOCM. PMID- 20944186 TI - Treatment and outcomes of nonagenarians with ST-elevation myocardial infarction. AB - There is no age limit for reperfusion therapy in the current guidelines for the treatment of patients with ST-elevation myocardial infarction (STEMI). Reperfusion therapy, although associated with better outcomes, is not always offered to the oldest patients. A retrospective analysis at our institution of all patients >= 90 years of age with a diagnosis of acute coronary syndrome at discharge from 2004 to 2008 identified 24 patients with STEMI. The majority of patients were Caucasian, females, hypertensive, with a low incidence of dementia and diabetes. Only 29% of patients presented to the hospital in less than 6 hours. Thirteen patients were treated with percutaneous coronary intervention (PCI) and 11 patients were treated medically. The in-hospital mortality was 23% in the PCI group and 36% in the medical therapy group. Kaplan-Meier analysis demonstrated a survival benefit favoring PCI, which disappeared when only patients presenting after 6 hours to the hospital were analyzed. PCI-treated patients had no procedure-associated complications and had a good prognosis if they survived to hospital discharge. PCI should be offered to nonagenarians presenting with STEMI. PMID- 20944187 TI - Primary angioplasty in the very elderly - how old is too old? PMID- 20944188 TI - Endothelial-cell-binding aptamer for coating of intracoronary stents. AB - Oligonucleotides capturing CD31 endothelial cells (= aptamer) were used for coating of intracoronary stents to improve endothelialization and vascular healing. METHODS: Three different coronary stents were implanted in 9 farm-raised swine: 1) cobalt-chromium stent (CC, control stent); 2) aminoparylene-coated stent (AP, polymer); and 3) aminoparylene- and aptamer-coated stent (AA). Stent length was 18 mm, stent diameter 3 mm. Animals were restudied after 6 weeks. Minimal lumen diameter (MLD) and late loss were determined by quantitative coronary angiography. Vessel lumen, intimal proliferation and restenosis were determined by histomorphometry. Disruption of the lamina elastica interna (LEI) and inflammatory reactions were assessed in all sections. RESULTS: The average MLD at baseline was 2.98 +/- 0.65 mm and at follow up 2.18 +/- 0.53 mm (p < 0.05, n = 27). Late loss and restenosis were smallest in CC and largest in AA (ns). Histomorphometry showed no significant differences between the three stents but there were inflammatory granulomas in 22% of all stents. A clear correlation between disruption of the LEI and inflammatory granulomas was observed. CONCLUSIONS: Stents coated with endothelial-cell-capturing aptamers show similar late loss and angiographic restenosis rates as uncoated cobalt-chromium stents. Neointimal proliferation was similar in all three stents suggesting comparable proliferative potentials. Inflammatory reactions were observed in 1 of 5 of all histologic sections. In the present study, no advantage of aptamer-coating on neointimal proliferation of intracoronary stents was found. PMID- 20944189 TI - Thrombus aspiration without additional ballooning or stenting to treat selected patients with ST-elevation myocardial infarction. AB - BACKGROUND: The use of thrombus aspiration during percutaneous coronary intervention (PCI) is recommended in patients with ST-elevation myocardial infarction (STEMI) undergoing mechanical revascularization. When thrombus aspiration is adopted, the standard technique includes, after mechanical thrombus extraction, angioplasty and/or stent implantation to eliminate residual stenosis. To date, no data are available concerning the use of thrombectomy alone without additional ballooning or stenting. METHODS AND RESULTS: We report the angiographic and clinical outcome of a series of selected STEMI patients undergoing mechanical reperfusion by thrombus aspiration without additional ballooning or stenting. Four patients out of 316 consecutive STEMI patients were managed by thrombus aspiration alone (1.3%). All patients had angiographic documentation of an occlusive large intracoronary thrombus in the infarct-related artery before intervention and complete restoration of coronary flow in the absence of critical coronary stenosis after thrombus aspiration. Three of these patients had a clinical contraindication to dual antiplatelet therapy, thus suggesting that to avoid stent implantation would be advisable. Angiographic reevaluation was performed before discharge in 3 patients confirming persistent patency of the infarct-related artery (in 1 case the residual stenosis was judged to require intravascular ultrasound evaluation and subsequent elective PCI with stent implantation). The thirty-day clinical course was uneventful in all patients. CONCLUSIONS: In selected patients with STEMI undergoing mechanical reperfusion, thrombus aspiration without additional ballooning or stenting may be successfully performed. Further studies are needed to assess the clinical relevance of this novel approach. PMID- 20944190 TI - Thrombus aspiration for restoring flow: stents for scaffolding? PMID- 20944191 TI - The GuideLiner "child" catheter for percutaneous coronary intervention - early clinical experience. AB - The failure to deliver a stent across the target lesion during percutaneous coronary intervention, especially in arteries with calcified tortuous anatomy, is often due to insufficient back-up support from the guiding catheter. Deep-vessel intubation with the guiding catheter may overcome this problem, but risks coronary dissection. The Heartrail II (Terumo, Japan) "five-in-six catheter system" (or "mother-and-child" catheter) comprises a flexible-tipped long 5 Fr catheter advanced through a standard 6 Fr guiding catheter to deeply intubate the target vessel, thus providing enough back-up support to enable stent delivery. Here we describe a newly developed "child" support catheter (The GuideLiner; Vascular Solutions, Inc., Minneapolis, Minnesota), report its successful use in a series of 4 difficult cases and discuss practical tips to optimize its performance. PMID- 20944192 TI - Anomalous origin of the three major coronary arteries from a single common ostium. AB - The prevalence of coronary anomalies is about 1.3% among patients who undergo coronary angiography. Although the majority of coronary artery anomalies are incidental findings and are not clinically significant, the interarterial course between the great vessels of the aberrant artery may be responsible for syncope, angina, arrhythmias or sudden death. There are only a few case reports in the literature that describe the origin of all coronary arteries from a single ostium. This type of anomaly has been seen in only 0.024-0.044% of the population. This is a first case where not only was there a common ostium of the left anterior descending artery and right coronary artery without a left main, but an absent left circumflex artery with blood supply of its territory by a posterolateral/marginal branch from the right posterior descending artery and conal branch. PMID- 20944193 TI - Temporary aortic occlusion to facilitate large-bore arterial closure. AB - Percutaneous closure of large-bore arterial sheaths remains a clinical challenge. We report a case of facilitated large-bore closure using a low-profile valvuloplasty balloon for aortic occlusion. This technique enhanced percutaneous closure device deployment and improved hemostasis during arteriotomy closure. PMID- 20944194 TI - Menstruation-associated spontaneous coronary artery dissection. AB - Eighty percent of all spontaneous coronary artery dissections occur in women. A third of these occur in pregnancy or post-partum period and a variation in hormonal levels is thought to play an etiologic role. It has been suggested that the menstrual period, a low-estrogen state, may be associated with spontaneous coronary artery dissections. We report a case of menstruation-associated spontaneous coronary artery dissection and review the available literature. PMID- 20944195 TI - A case of early drug-eluting stent fracture. AB - Although stent fracture following femoro-popliteal intervention is well recognized, coronary stent fracture represents an underrecognized entity. Its incidence is low but it represents an important clinical entity as it may complicate with stent thrombosis causing acute coronary syndromes, or may predispose to instent restenosis. Although coronary stent fracture may involve both bare metal stents (BMS) and drug-eluting stents (DES), a recent analysis of the literature indicates that reports of stent fracture have increased since DES was introduced. Furthermore, chronic stretch at specific vessel sites as bends may lead to late occurrence of fracture. We present the case of a patient with a non-ST-segment elevation acute coronary syndrome caused by the early fracture of an everolimus-eluting stent (Xience(r)) implanted only three days before. PMID- 20944196 TI - Acute streptococcal myocarditis presenting as acute ST-elevation myocardial infarction. AB - Acute streptococcal myocarditis is an uncommon diagnosis in the developed world. Its presentation masquerading as acute myocardial infarction is still uncommon. We describe a case of a young male presenting with a recent diagnosis of streptococcal pharyngitis followed by a classical presentation of post streptococcal myocarditis. This is an unusual presentation of acute rheumatic fever (ARF) masquerading as acute myocardial infarction, with a discussion on its diagnosis and management. PMID- 20944197 TI - Management of severe bilateral carotid artery stenosis concomitant to severely symptomatic coronary arterial disease requiring coronary artery bypass grafting: a case-based review. AB - Patients with significant carotid disease have an increased risk of stroke during coronary artery bypass grafting (CABG). However, due to its inherent risk and to the variety of mechanisms responsible for postoperative stroke, prophylactic carotid endarterectomy has an uncertain value, particularly in cases of asymptomatic unilateral carotid disease. In addition, the timing and sequence of coronary and carotid surgeries are controversial matters. Prophylactic carotid artery stenting is emerging as a potentially safer strategy. The major limitation of carotid stenting is the need for one month of dual antiplatelet therapy and the potential need to postpone CABG, which is not possible in patients with refractory unstable coronary syndromes. We describe the case of a patient with severe unstable coronary artery disease and bilateral carotid artery disease who was successfully managed with stenting of the most critical coronary lesion, staged bilateral carotid stenting, followed by CABG three weeks later. PMID- 20944198 TI - Successful retrieval of a broken intravascular ultrasound catheter tip in the coronary artery. AB - We report the successful retrieval of a broken intracoronary intravascular ultrasound (IVUS) catheter tip that was mostly invisible on fluoroscopy by using a snare catheter and pulling from distal to proximal. An 80-year-old male had presented with effort-related angina for one month. A coronary angiogram revealed severe stenosis of the proximal portion of the left anterior descending artery (LAD). Percutaneous coronary intervention (PCI) was planned for the lesion. During pre-procedural IVUS examination, the IVUS catheter fractured leaving the tip of the IVUS catheter inside the LAD. An attempt was made to remove the IVUS catheter tip by engaging the free proximal end of the tip with a loop snare. This attempt failed due to the free proximal end of the IVUS catheter tip being invisible on fluoroscopy. A loop snare was instead delivered distal to the IVUS catheter tip through a microcatheter, and the IVUS wire of the catheter tip was manipulated into the loop. The loop snare was then pulled back securely catching the IVUS catheter tip. The broken IVUS catheter tip was subsequently removed. This novel technique is effective for retrieving intracoronary foreign bodies. PMID- 20944199 TI - Late-presenting left internal mammary to great cardiac vein fistula treated with a vascular plug. AB - A 73-year-old patient, who underwent triple bypass surgery in another hospital in 1991 after suffering an acute myocardial infarction, was admitted to our institution after an episode of unstable angina. Evidence of a left internal mammary artery grafted to the great cardiac anterior interventricular vein (GCV), with Qp:Qs > 1.5:1, was demonstrated by angiography. We report the closure of said fistula using a percutaneous left radial artery access and the deployment of an Amplatzer vascular occlusion device via the antegrade approach. PMID- 20944200 TI - Rotational atherectomy in coronary dissection. AB - Rotational atherectomy is contraindicated in the presence of coronary dissection. Clinical scenarios of coronary dissection in which rotational atherectomy offers the only option are rare but can occur. This case study presents a challenging circumstance of an extensive coronary dissection resulting from failed angioplasty of a resistant and undilatable lesion. Rotational atherectomy was used as a last resort when the patient became clinically unstable. Standard technique of rotational atherectomy and additional technical considerations for this uncommon but potentially devastating scenario are discussed. PMID- 20944201 TI - AngioSculpt PTCA Balloon Catheter entrapment and detachment managed with stent jailing. AB - The AngioSculpt PTCA Scoring Balloon Catheter is an FDA-approved device for plaque modulation. We describe the first case of AngioSculpt EX catheter entrapment and detachment in the right coronary artery during PCI that was successfully managed with stent jailing of the entrapped balloon catheter and its shaft against the vessel wall. PMID- 20944202 TI - The JCSG high-throughput structural biology pipeline. AB - The Joint Center for Structural Genomics high-throughput structural biology pipeline has delivered more than 1000 structures to the community over the past ten years. The JCSG has made a significant contribution to the overall goal of the NIH Protein Structure Initiative (PSI) of expanding structural coverage of the protein universe, as well as making substantial inroads into structural coverage of an entire organism. Targets are processed through an extensive combination of bioinformatics and biophysical analyses to efficiently characterize and optimize each target prior to selection for structure determination. The pipeline uses parallel processing methods at almost every step in the process and can adapt to a wide range of protein targets from bacterial to human. The construction, expansion and optimization of the JCSG gene-to-structure pipeline over the years have resulted in many technological and methodological advances and developments. The vast number of targets and the enormous amounts of associated data processed through the multiple stages of the experimental pipeline required the development of variety of valuable resources that, wherever feasible, have been converted to free-access web-based tools and applications. PMID- 20944203 TI - TOPSAN: use of a collaborative environment for annotating, analyzing and disseminating data on JCSG and PSI structures. AB - The NIH Protein Structure Initiative centers, such as the Joint Center for Structural Genomics (JCSG), have developed highly efficient technological platforms that are capable of experimentally determining the three-dimensional structures of hundreds of proteins per year. However, the overwhelming majority of the almost 5000 protein structures determined by these centers have yet to be described in the peer-reviewed literature. In a high-throughput structural genomics environment, the process of structure determination occurs independently of any associated experimental characterization of function, which creates a challenge for the annotation and analysis of structures and the publication of these results. This challenge has been addressed by developing TOPSAN ('The Open Protein Structure Annotation Network'), which enables the generation of knowledge via collaborations among globally distributed contributors supported by automated amalgamation of available information. TOPSAN currently provides annotations for all protein structures determined by the JCSG in addition to preliminary annotations on a large number of structures from the other PSI production centers. TOPSAN-enabled collaborations have resulted in insightful structure function analysis for many proteins and have led to numerous peer-reviewed publications, as exemplified by the articles included in this issue of Acta Crystallographica Section F. PMID- 20944204 TI - DUFs: families in search of function. AB - Domains of unknown function (DUFs) are a large set of uncharacterized protein families that are found in the Pfam database. Here, the scale and growth of functionally uncharacterized families in biological databases are surveyed and the prospects for discovering their function are examined. In particular, the important role that structural genomics can play in identifying potential function is evaluated. PMID- 20944205 TI - Structure of the first representative of Pfam family PF09410 (DUF2006) reveals a structural signature of the calycin superfamily that suggests a role in lipid metabolism. AB - The first structural representative of the domain of unknown function DUF2006 family, also known as Pfam family PF09410, comprises a lipocalin-like fold with domain duplication. The finding of the calycin signature in the N-terminal domain, combined with remote sequence similarity to two other protein families (PF07143 and PF08622) implicated in isoprenoid metabolism and the oxidative stress response, support an involvement in lipid metabolism. Clusters of conserved residues that interact with ligand mimetics suggest that the binding and regulation sites map to the N-terminal domain and to the interdomain interface, respectively. PMID- 20944206 TI - The structure of SSO2064, the first representative of Pfam family PF01796, reveals a novel two-domain zinc-ribbon OB-fold architecture with a potential acyl CoA-binding role. AB - SSO2064 is the first structural representative of PF01796 (DUF35), a large prokaryotic family with a wide phylogenetic distribution. The structure reveals a novel two-domain architecture comprising an N-terminal, rubredoxin-like, zinc ribbon and a C-terminal, oligonucleotide/oligosaccharide-binding (OB) fold domain. Additional N-terminal helical segments may be involved in protein-protein interactions. Domain architectures, genomic context analysis and functional evidence from certain bacterial representatives of this family suggest that these proteins form a novel fatty-acid-binding component that is involved in the biosynthesis of lipids and polyketide antibiotics and that they possibly function as acyl-CoA-binding proteins. This structure has led to a re-evaluation of the DUF35 family, which has now been split into two entries in the latest Pfam release (v.24.0). PMID- 20944207 TI - Structure of the first representative of Pfam family PF04016 (DUF364) reveals enolase and Rossmann-like folds that combine to form a unique active site with a possible role in heavy-metal chelation. AB - The crystal structure of Dhaf4260 from Desulfitobacterium hafniense DCB-2 was determined by single-wavelength anomalous diffraction (SAD) to a resolution of 2.01 A using the semi-automated high-throughput pipeline of the Joint Center for Structural Genomics (JCSG) as part of the NIGMS Protein Structure Initiative (PSI). This protein structure is the first representative of the PF04016 (DUF364) Pfam family and reveals a novel combination of two well known domains (an enolase N-terminal-like fold followed by a Rossmann-like domain). Structural and bioinformatic analyses reveal partial similarities to Rossmann-like methyltransferases, with residues from the enolase-like fold combining to form a unique active site that is likely to be involved in the condensation or hydrolysis of molecules implicated in the synthesis of flavins, pterins or other siderophores. The genome context of Dhaf4260 and homologs additionally supports a role in heavy-metal chelation. PMID- 20944208 TI - The structure of the first representative of Pfam family PF09836 reveals a two domain organization and suggests involvement in transcriptional regulation. AB - Proteins with the DUF2063 domain constitute a new Pfam family, PF09836. The crystal structure of a member of this family, NGO1945 from Neisseria gonorrhoeae, has been determined and reveals that the N-terminal DUF2063 domain is likely to be a DNA-binding domain. In conjunction with the rest of the protein, NGO1945 is likely to be involved in transcriptional regulation, which is consistent with genomic neighborhood analysis. Of the 216 currently known proteins that contain a DUF2063 domain, the most significant sequence homologs of NGO1945 (~40-99% sequence identity) are from various Neisseria and Haemophilus species. As these are important human pathogens, NGO1945 represents an interesting candidate for further exploration via biochemical studies and possible therapeutic intervention. PMID- 20944210 TI - Structural classification of proteins and structural genomics: new insights into protein folding and evolution. AB - During the past decade, the Protein Structure Initiative (PSI) centres have become major contributors of new families, superfamilies and folds to the Structural Classification of Proteins (SCOP) database. The PSI results have increased the diversity of protein structural space and accelerated our understanding of it. This review article surveys a selection of protein structures determined by the Joint Center for Structural Genomics (JCSG). It presents previously undescribed beta-sheet architectures such as the double barrel and spiral beta-roll and discusses new examples of unusual topologies and peculiar structural features observed in proteins characterized by the JCSG and other Structural Genomics centres. PMID- 20944209 TI - Structures of the first representatives of Pfam family PF06684 (DUF1185) reveal a novel variant of the Bacillus chorismate mutase fold and suggest a role in amino acid metabolism. AB - The crystal structures of BB2672 and SPO0826 were determined to resolutions of 1.7 and 2.1 A by single-wavelength anomalous dispersion and multiple-wavelength anomalous dispersion, respectively, using the semi-automated high-throughput pipeline of the Joint Center for Structural Genomics (JCSG) as part of the NIGMS Protein Structure Initiative (PSI). These proteins are the first structural representatives of the PF06684 (DUF1185) Pfam family. Structural analysis revealed that both structures adopt a variant of the Bacillus chorismate mutase fold (BCM). The biological unit of both proteins is a hexamer and analysis of homologs indicates that the oligomer interface residues are highly conserved. The conformation of the critical regions for oligomerization appears to be dependent on pH or salt concentration, suggesting that this protein might be subject to environmental regulation. Structural similarities to BCM and genome-context analysis suggest a function in amino-acid synthesis. PMID- 20944211 TI - The structure of Jann_2411 (DUF1470) from Jannaschia sp. at 1.45 A resolution reveals a new fold (the ABATE domain) and suggests its possible role as a transcription regulator. AB - The crystal structure of Jann_2411 from Jannaschia sp. strain CCS1, a member of the Pfam PF07336 family classified as a domain of unknown function (DUF1470), was solved to a resolution of 1.45 A by multiple-wavelength anomalous dispersion (MAD). This protein is the first structural representative of the DUF1470 Pfam family. Structural analysis revealed a two-domain organization, with the N terminal domain presenting a new fold called the ABATE domain that may bind an as yet unknown ligand. The C-terminal domain forms a treble-clef zinc finger that is likely to be involved in DNA binding. Analysis of the Jann_2411 protein and the broader ABATE-domain family suggests a role as stress-induced transcriptional regulators. PMID- 20944212 TI - Structure of LP2179, the first representative of Pfam family PF08866, suggests a new fold with a role in amino-acid metabolism. AB - The structure of LP2179, a member of the PF08866 (DUF1831) family, suggests a novel alpha+beta fold comprising two beta-sheets packed against a single helix. A remote structural similarity to two other uncharacterized protein families specific to the Bacillus genus (PF08868 and PF08968), as well as to prokaryotic S adenosylmethionine decarboxylases, is consistent with a role in amino-acid metabolism. Genomic neighborhood analysis of LP2179 supports this functional assignment, which might also then be extended to PF08868 and PF08968. PMID- 20944213 TI - The structure of the first representative of Pfam family PF06475 reveals a new fold with possible involvement in glycolipid metabolism. AB - The crystal structure of PA1994 from Pseudomonas aeruginosa, a member of the Pfam PF06475 family classified as a domain of unknown function (DUF1089), reveals a novel fold comprising a 15-stranded beta-sheet wrapped around a single alpha helix that assembles into a tight dimeric arrangement. The remote structural similarity to lipoprotein localization factors, in addition to the presence of an acidic pocket that is conserved in DUF1089 homologs, phospholipid-binding and sugar-binding proteins, indicate a role for PA1994 and the DUF1089 family in glycolipid metabolism. Genome-context analysis lends further support to the involvement of this family of proteins in glycolipid metabolism and indicates possible activation of DUF1089 homologs under conditions of bacterial cell-wall stress or host-pathogen interactions. PMID- 20944214 TI - Structures of the first representatives of Pfam family PF06938 (DUF1285) reveal a new fold with repeated structural motifs and possible involvement in signal transduction. AB - The crystal structures of SPO0140 and Sbal_2486 were determined using the semiautomated high-throughput pipeline of the Joint Center for Structural Genomics (JCSG) as part of the NIGMS Protein Structure Initiative (PSI). The structures revealed a conserved core with domain duplication and a superficial similarity of the C-terminal domain to pleckstrin homology-like folds. The conservation of the domain interface indicates a potential binding site that is likely to involve a nucleotide-based ligand, with genome-context and gene-fusion analyses additionally supporting a role for this family in signal transduction, possibly during oxidative stress. PMID- 20944215 TI - New variants of known folds: do they bring new biology? AB - New distinct versions of known protein folds provide a powerful means of protein function prediction that complements sequence and genomic context analysis. These structures do not supplant direct biochemical experiments, but are indispensable for the complete characterization of proteins. PMID- 20944216 TI - Structure of an essential bacterial protein YeaZ (TM0874) from Thermotoga maritima at 2.5 A resolution. AB - YeaZ is involved in a protein network that is essential for bacteria. The crystal structure of YeaZ from Thermotoga maritima was determined to 2.5 A resolution. Although this protein belongs to a family of ancient actin-like ATPases, it appears that it has lost the ability to bind ATP since it lacks some key structural features that are important for interaction with ATP. A conserved surface was identified, supporting its role in the formation of protein complexes. PMID- 20944217 TI - Structure of a putative NTP pyrophosphohydrolase: YP_001813558.1 from Exiguobacterium sibiricum 255-15. AB - The crystal structure of a putative NTPase, YP_001813558.1 from Exiguobacterium sibiricum 255-15 (PF09934, DUF2166) was determined to 1.78 A resolution. YP_001813558.1 and its homologs (dimeric dUTPases, MazG proteins and HisE-encoded phosphoribosyl ATP pyrophosphohydrolases) form a superfamily of all-alpha-helical NTP pyrophosphatases. In dimeric dUTPase-like proteins, a central four-helix bundle forms the active site. However, in YP_001813558.1, an unexpected intertwined swapping of two of the helices that compose the conserved helix bundle results in a 'linked dimer' that has not previously been observed for this family. Interestingly, despite this novel mode of dimerization, the metal-binding site for divalent cations, such as magnesium, that are essential for NTPase activity is still conserved. Furthermore, the active-site residues that are involved in sugar binding of the NTPs are also conserved when compared with other alpha-helical NTPases, but those that recognize the nucleotide bases are not conserved, suggesting a different substrate specificity. PMID- 20944218 TI - Open and closed conformations of two SpoIIAA-like proteins (YP_749275.1 and YP_001095227.1) provide insights into membrane association and ligand binding. AB - The crystal structures of the proteins encoded by the YP_749275.1 and YP_001095227.1 genes from Shewanella frigidimarina and S. loihica, respectively, have been determined at 1.8 and 2.25 A resolution, respectively. These proteins are members of a novel family of bacterial proteins that adopt the alpha/beta SpoIIAA-like fold found in STAS and CRAL-TRIO domains. Despite sharing 54% sequence identity, these two proteins adopt distinct conformations arising from different dispositions of their alpha2 and alpha3 helices. In the 'open' conformation (YP_001095227.1), these helices are 15 A apart, leading to the creation of a deep nonpolar cavity. In the 'closed' structure (YP_749275.1), the helices partially unfold and rearrange, occluding the cavity and decreasing the solvent-exposed hydrophobic surface. These two complementary structures are reminiscent of the conformational switch in CRAL-TRIO carriers of hydrophobic compounds. It is suggested that both proteins may associate with the lipid bilayer in their 'open' monomeric state by inserting their amphiphilic helices, alpha2 and alpha3, into the lipid bilayer. These bacterial proteins may function as carriers of nonpolar substances or as interfacially activated enzymes. PMID- 20944219 TI - The structure of KPN03535 (gi|152972051), a novel putative lipoprotein from Klebsiella pneumoniae, reveals an OB-fold. AB - KPN03535 (gi|152972051) is a putative lipoprotein of unknown function that is secreted by Klebsiella pneumoniae MGH 78578. The crystal structure reveals that despite a lack of any detectable sequence similarity to known structures, it is a novel variant of the OB-fold and structurally similar to the bacterial Cpx pathway protein NlpE, single-stranded DNA-binding (SSB) proteins and toxins. K. pneumoniae MGH 78578 forms part of the normal human skin, mouth and gut flora and is an opportunistic pathogen that is linked to about 8% of all hospital-acquired infections in the USA. This structure provides the foundation for further investigations into this divergent member of the OB-fold family. PMID- 20944220 TI - Viewing the human microbiome through three-dimensional glasses: integrating structural and functional studies to better define the properties of myriad carbohydrate-active enzymes. AB - Recent studies have provided an unprecedented view of the trillions of microbes associated with the human body. The human microbiome harbors tremendous diversity at multiple levels: the species that colonize each individual and each body habitat; the genes that are found in each organism's genome; the expression of these genes and the interactions and activities of their protein products. The sources of this diversity are wide-ranging and reflect both environmental and host factors. A major challenge moving forward is defining the precise functions of members of various families of proteins represented in our microbiomes, including the highly diverse carbohydrate-active enzymes (CAZymes) involved in numerous biologically important chemical transformations, such as the degradation of complex dietary polysaccharides. Coupling metagenomic analyses to structural genomics initiatives and to biochemical and other functional assays of CAZymes will be essential for determining how these as well as other microbiome-encoded proteins operate to shape the properties of microbial communities and their human hosts. PMID- 20944221 TI - The structure of BVU2987 from Bacteroides vulgatus reveals a superfamily of bacterial periplasmic proteins with possible inhibitory function. AB - Proteins that contain the DUF2874 domain constitute a new Pfam family PF11396. Members of this family have predominantly been identified in microbes found in the human gut and oral cavity. The crystal structure of one member of this family, BVU2987 from Bacteroides vulgatus, has been determined, revealing a beta lactamase inhibitor protein-like structure with a tandem repeat of domains. Sequence analysis and structural comparisons reveal that BVU2987 and other DUF2874 proteins are related to beta-lactamase inhibitor protein, PepSY and SmpA_OmlA proteins and hence are likely to function as inhibitory proteins. PMID- 20944222 TI - Structure of BT_3984, a member of the SusD/RagB family of nutrient-binding molecules. AB - The crystal structure of the Bacteroides thetaiotaomicron protein BT_3984 was determined to a resolution of 1.7 A and was the first structure to be determined from the extensive SusD family of polysaccharide-binding proteins. SusD is an essential component of the sus operon that defines the paradigm for glycan utilization in dominant members of the human gut microbiota. Structural analysis of BT_3984 revealed an N-terminal region containing several tetratricopeptide repeats (TPRs), while the signature C-terminal region is less structured and contains extensive loop regions. Sequence and structure analysis of BT_3984 suggests the presence of binding interfaces for other proteins from the polysaccharide-utilization complex. PMID- 20944223 TI - A conserved fold for fimbrial components revealed by the crystal structure of a putative fimbrial assembly protein (BT1062) from Bacteroides thetaiotaomicron at 2.2 A resolution. AB - BT1062 from Bacteroides thetaiotaomicron is a homolog of Mfa2 (PGN0288 or PG0179), which is a component of the minor fimbriae in Porphyromonas gingivalis. The crystal structure of BT1062 revealed a conserved fold that is widely adopted by fimbrial components. PMID- 20944224 TI - Structure of Bacteroides thetaiotaomicron BT2081 at 2.05 A resolution: the first structural representative of a new protein family that may play a role in carbohydrate metabolism. AB - BT2081 from Bacteroides thetaiotaomicron (GenBank accession code NP_810994.1) is a member of a novel protein family consisting of over 160 members, most of which are found in the different classes of Bacteroidetes. Genome-context analysis lends support to the involvement of this family in carbohydrate metabolism, which plays a key role in B. thetaiotaomicron as a predominant bacterial symbiont in the human distal gut microbiome. The crystal structure of BT2081 at 2.05 A resolution represents the first structure from this new protein family. BT2081 consists of an N-terminal domain, which adopts a beta-sandwich immunoglobulin like fold, and a larger C-terminal domain with a beta-sandwich jelly-roll fold. Structural analyses reveal that both domains are similar to those found in various carbohydrate-active enzymes. The C-terminal beta-jelly-roll domain contains a potential carbohydrate-binding site that is highly conserved among BT2081 homologs and is situated in the same location as the carbohydrate-binding sites that are found in structurally similar glycoside hydrolases (GHs). However, in BT2081 this site is partially occluded by surrounding loops, which results in a deep solvent-accessible pocket rather than a shallower solvent-exposed cleft. PMID- 20944226 TI - Ligands in crystal structures that aid in functional characterization. AB - Liganded structures can be instrumental in assigning function to uncharacterized proteins by revealing active sites, conserved residues, binding motifs, and substrate specificity. This introduction provides an overview and commentary on the value of liganded structures emerging from the JCSG structural genomics initiative. PMID- 20944225 TI - Structure of a membrane-attack complex/perforin (MACPF) family protein from the human gut symbiont Bacteroides thetaiotaomicron. AB - Membrane-attack complex/perforin (MACPF) proteins are transmembrane pore-forming proteins that are important in both human immunity and the virulence of pathogens. Bacterial MACPFs are found in diverse bacterial species, including most human gut-associated Bacteroides species. The crystal structure of a bacterial MACPF-domain-containing protein BT_3439 (Bth-MACPF) from B. thetaiotaomicron, a predominant member of the mammalian intestinal microbiota, has been determined. Bth-MACPF contains a membrane-attack complex/perforin (MACPF) domain and two novel C-terminal domains that resemble ribonuclease H and interleukin 8, respectively. The entire protein adopts a flat crescent shape, characteristic of other MACPF proteins, that may be important for oligomerization. This Bth-MACPF structure provides new features and insights not observed in two previous MACPF structures. Genomic context analysis infers that Bth-MACPF may be involved in a novel protein-transport or nutrient-uptake system, suggesting an important role for these MACPF proteins, which were likely to have been inherited from eukaryotes via horizontal gene transfer, in the adaptation of commensal bacteria to the host environment. PMID- 20944227 TI - Ligands in PSI structures. AB - Approximately 65% of PSI structures report some type of ligand(s) that is bound in the crystal structure. Here, a description is given of how such ligands are handled and analyzed at the JCSG and a survey of the types, variety and frequency of ligands that are observed in the PSI structures is also compiled and analyzed, including illustrations of how these bound ligands have provided functional clues for annotation of proteins with little or no previous experimental characterization. Furthermore, a web server was developed as a tool to mine and analyze the PSI structures for bound ligands and other identifying features. PMID- 20944228 TI - The structure of Haemophilus influenzae prephenate dehydrogenase suggests unique features of bifunctional TyrA enzymes. AB - Chorismate mutase/prephenate dehydrogenase from Haemophilus influenzae Rd KW20 is a bifunctional enzyme that catalyzes the rearrangement of chorismate to prephenate and the NAD(P)(+)-dependent oxidative decarboxylation of prephenate to 4-hydroxyphenylpyruvate in tyrosine biosynthesis. The crystal structure of the prephenate dehydrogenase component (HinfPDH) of the TyrA protein from H. influenzae Rd KW20 in complex with the inhibitor tyrosine and cofactor NAD(+) has been determined to 2.0 A resolution. HinfPDH is a dimeric enzyme, with each monomer consisting of an N-terminal alpha/beta dinucleotide-binding domain and a C-terminal alpha-helical dimerization domain. The structure reveals key active site residues at the domain interface, including His200, Arg297 and Ser179 that are involved in catalysis and/or ligand binding and are highly conserved in TyrA proteins from all three kingdoms of life. Tyrosine is bound directly at the catalytic site, suggesting that it is a competitive inhibitor of HinfPDH. Comparisons with its structural homologues reveal important differences around the active site, including the absence of an alpha-beta motif in HinfPDH that is present in other TyrA proteins, such as Synechocystis sp. arogenate dehydrogenase. Residues from this motif are involved in discrimination between NADP(+) and NAD(+). The loop between beta5 and beta6 in the N-terminal domain is much shorter in HinfPDH and an extra helix is present at the C-terminus. Furthermore, HinfPDH adopts a more closed conformation compared with TyrA proteins that do not have tyrosine bound. This conformational change brings the substrate, cofactor and active-site residues into close proximity for catalysis. An ionic network consisting of Arg297 (a key residue for tyrosine binding), a water molecule, Asp206 (from the loop between beta5 and beta6) and Arg365' (from the additional C-terminal helix of the adjacent monomer) is observed that might be involved in gating the active site. PMID- 20944229 TI - Structure of a tryptophanyl-tRNA synthetase containing an iron-sulfur cluster. AB - A novel aminoacyl-tRNA synthetase that contains an iron-sulfur cluster in the tRNA anticodon-binding region and efficiently charges tRNA with tryptophan has been found in Thermotoga maritima. The crystal structure of TmTrpRS (tryptophanyl tRNA synthetase; TrpRS; EC 6.1.1.2) reveals an iron-sulfur [4Fe-4S] cluster bound to the tRNA anticodon-binding (TAB) domain and an L-tryptophan ligand in the active site. None of the other T. maritima aminoacyl-tRNA synthetases (AARSs) contain this [4Fe-4S] cluster-binding motif (C-x22-C-x6-C-x2-C). It is speculated that the iron-sulfur cluster contributes to the stability of TmTrpRS and could play a role in the recognition of the anticodon. PMID- 20944230 TI - Structures of three members of Pfam PF02663 (FmdE) implicated in microbial methanogenesis reveal a conserved alpha+beta core domain and an auxiliary C terminal treble-clef zinc finger. AB - Examination of the genomic context for members of the FmdE Pfam family (PF02663), such as the protein encoded by the fmdE gene from the methanogenic archaeon Methanobacterium thermoautotrophicum, indicates that 13 of them are co transcribed with genes encoding subunits of molybdenum formylmethanofuran dehydrogenase (EC 1.2.99.5), an enzyme that is involved in microbial methane production. Here, the first crystal structures from PF02663 are described, representing two bacterial and one archaeal species: B8FYU2_DESHY from the anaerobic dehalogenating bacterium Desulfitobacterium hafniense DCB-2, Q2LQ23_SYNAS from the syntrophic bacterium Syntrophus aciditrophicus SB and Q9HJ63_THEAC from the thermoacidophilic archaeon Thermoplasma acidophilum. Two of these proteins, Q9HJ63_THEAC and Q2LQ23_SYNAS, contain two domains: an N-terminal thioredoxin-like alpha+beta core domain (NTD) consisting of a five-stranded, mixed beta-sheet flanked by several alpha-helices and a C-terminal zinc-finger domain (CTD). B8FYU2_DESHY, on the other hand, is composed solely of the NTD. The CTD of Q9HJ63_THEAC and Q2LQ23_SYNAS is best characterized as a treble-clef zinc finger. Two significant structural differences between Q9HJ63_THEAC and Q2LQ23_SYNAS involve their metal binding. First, zinc is bound to the putative active site on the NTD of Q9HJ63_THEAC, but is absent from the NTD of Q2LQ23_SYNAS. Second, whereas the structure of the CTD of Q2LQ23_SYNAS shows four Cys side chains within coordination distance of the Zn atom, the structure of Q9HJ63_THEAC is atypical for a treble-cleft zinc finger in that three Cys side chains and an Asp side chain are within coordination distance of the zinc. PMID- 20944233 TI - NMR in a crystallography-based high-throughput protein structure-determination environment. AB - An introduction is provided to three papers which compare corresponding protein crystal and NMR solution structures determined by the Joint Center for Structural Genomics (JCSG). Special mention is made of the JCSG strategy for combined use of the two techniques, and of potential applications of the concept of 'reference crystal structures', which is introduced in the following three papers. PMID- 20944231 TI - Conformational changes associated with the binding of zinc acetate at the putative active site of XcTcmJ, a cupin from Xanthomonas campestris pv. campestris. AB - In the plant pathogen Xanthomonas campestris pv. campestris, the product of the tcmJ gene, XcTcmJ, encodes a protein belonging to the RmlC family of cupins. XcTcmJ was crystallized in a monoclinic space group (C2) in the presence of zinc acetate and the structure was determined to 1.6 A resolution. Previously, the apo structure has been reported in the absence of any bound metal ion [Chin et al. (2006), Proteins, 65, 1046-1050]. The most significant difference between the apo structure and the structure of XcTcmJ described here is a reorganization of the binding site for zinc acetate, which was most likely acquired from the crystallization solution. This site is located in the conserved metal ion-binding domain at the putative active site of XcTcmJ. In addition, an acetate was also bound within coordination distance of the zinc. In order to accommodate this binding, rearrangement of a conserved histidine ligand is required as well as several nearby residues within and around the putative active site. These observations indicate that binding of zinc serves a functional role in this cupin protein. PMID- 20944232 TI - Structure of the gamma-D-glutamyl-L-diamino acid endopeptidase YkfC from Bacillus cereus in complex with L-Ala-gamma-D-Glu: insights into substrate recognition by NlpC/P60 cysteine peptidases. AB - Dipeptidyl-peptidase VI from Bacillus sphaericus and YkfC from Bacillus subtilis have both previously been characterized as highly specific gamma-D-glutamyl-L diamino acid endopeptidases. The crystal structure of a YkfC ortholog from Bacillus cereus (BcYkfC) at 1.8 A resolution revealed that it contains two N terminal bacterial SH3 (SH3b) domains in addition to the C-terminal catalytic NlpC/P60 domain that is ubiquitous in the very large family of cell-wall-related cysteine peptidases. A bound reaction product (L-Ala-gamma-D-Glu) enabled the identification of conserved sequence and structural signatures for recognition of L-Ala and gamma-D-Glu and, therefore, provides a clear framework for understanding the substrate specificity observed in dipeptidyl-peptidase VI, YkfC and other NlpC/P60 domains in general. The first SH3b domain plays an important role in defining substrate specificity by contributing to the formation of the active site, such that only murein peptides with a free N-terminal alanine are allowed. A conserved tyrosine in the SH3b domain of the YkfC subfamily is correlated with the presence of a conserved acidic residue in the NlpC/P60 domain and both residues interact with the free amine group of the alanine. This structural feature allows the definition of a subfamily of NlpC/P60 enzymes with the same N-terminal substrate requirements, including a previously characterized cyanobacterial L-alanine-gamma-D-glutamate endopeptidase that contains the two key components (an NlpC/P60 domain attached to an SH3b domain) for assembly of a YkfC-like active site. PMID- 20944234 TI - NMR structure of the protein NP_247299.1: comparison with the crystal structure. AB - The NMR structure of the protein NP_247299.1 in solution at 313 K has been determined and is compared with the X-ray crystal structure, which was also solved in the Joint Center for Structural Genomics (JCSG) at 100 K and at 1.7 A resolution. Both structures were obtained using the current largely automated crystallographic and solution NMR methods used by the JCSG. This paper assesses the accuracy and precision of the results from these recently established automated approaches, aiming for quantitative statements about the location of structure variations that may arise from either one of the methods used or from the different environments in solution and in the crystal. To evaluate the possible impact of the different software used for the crystallographic and the NMR structure determinations and analysis, the concept is introduced of reference structures, which are computed using the NMR software with input of upper-limit distance constraints derived from the molecular models representing the results of the two structure determinations. The use of this new approach is explored to quantify global differences that arise from the different methods of structure determination and analysis versus those that represent interesting local variations or dynamics. The near-identity of the protein core in the NMR and crystal structures thus provided a basis for the identification of complementary information from the two different methods. It was thus observed that locally increased crystallographic B values correlate with dynamic structural polymorphisms in solution, including that the solution state of the protein involves a slow dynamic equilibrium on a time scale of milliseconds or slower between two ensembles of rapidly interchanging conformers that contain, respectively, the cis or trans form of the C-terminal proline and represent about 25 and 75% of the total protein. PMID- 20944235 TI - Comparison of NMR and crystal structures for the proteins TM1112 and TM1367. AB - The NMR structures of the TM1112 and TM1367 proteins from Thermotoga maritima in solution at 298 K were determined following a new protocol which uses the software package UNIO for extensive automation. The results obtained with this novel procedure were evaluated by comparison with the crystal structures solved by the JCSG at 100 K to 1.83 and 1.90 A resolution, respectively. In addition, the TM1112 solution structure was compared with an NMR structure solved by the NESG using a conventional largely interactive methodology. For both proteins, the newly determined NMR structure could be superimposed with the crystal structure with r.m.s.d. values of <1.0 A for the backbone heavy atoms, which provided a starting platform to investigate local structure variations, which may arise from either the methods used or from the different chemical environments in solution and in the crystal. Thereby, these comparative studies were further explored with the use of reference NMR and crystal structures, which were computed using the NMR software with input of upper-limit distance constraints derived from the molecular models that represent the results of structure determination by NMR and by X-ray diffraction, respectively. The results thus obtained show that NMR structure calculations with the new automated UNIO software used by the JCSG compare favorably with those from a more labor-intensive and time-intensive interactive procedure. An intriguing observation is that the 'bundles' of two TM1112 or three TM1367 molecules in the asymmetric unit of the crystal structures mimic the behavior of the bundles of 20 conformers used to represent the NMR solution structures when comparing global r.m.s.d. values calculated either for the polypeptide backbone, the core residues with solvent accessibility below 15% or all heavy atoms. PMID- 20944236 TI - Comparison of NMR and crystal structures highlights conformational isomerism in protein active sites. AB - The JCSG has recently developed a protocol for systematic comparisons of high quality crystal and NMR structures of proteins. In this paper, the extent to which this approach can provide function-related information on the two functionally annotated proteins TM1081, a Thermotoga maritima anti-sigma factor antagonist, and A2LD1 (gi:13879369), a mouse gamma-glutamylamine cyclotransferase, is explored. The NMR structures of the two proteins have been determined in solution at 313 and 298 K, respectively, using the current JCSG protocol based on the software package UNIO for extensive automation. The corresponding crystal structures were solved by the JCSG at 100 K and 1.6 A resolution and at 100 K and 1.9 A resolution, respectively. The NMR and crystal structures of the two proteins share the same overall molecular architectures. However, the precision of the structure determination along the amino-acid sequence varies over a significantly wider range in the NMR structures than in the crystal structures. Thereby, in each of the two NMR structures about 65% of the residues have displacements below the average and in both proteins the less well ordered residues include large parts of the active sites, in addition to some highly solvent-exposed surface areas. Whereas the latter show increased disorder in the crystal and in solution, the active-site regions display increased displacements only in the NMR structures, where they undergo local conformational exchange on the millisecond time scale that appears to be frozen in the crystals. These observations suggest that a search for molecular regions showing increased structural disorder and slow dynamic processes in solution while being well ordered in the corresponding crystal structure might be a valid initial step in the challenge of identifying putative active sites in functionally unannotated proteins with known three-dimensional structure. PMID- 20944237 TI - Structures of complexes of octahaem cytochrome c nitrite reductase from Thioalkalivibrio nitratireducens with sulfite and cyanide. AB - The structures of complexes of octahaem cytochrome c nitrite reductase from the bacterium Thioalkalivibrio nitratireducens (TvNiR) with the substrate sulfite (1.4 A resolution; R(cryst) = 0.126) and the inhibitor cyanide (1.55 A resolution; R(cryst) = 0.148) have been established. The complex with sulfite was prepared by the reduction of the protein crystal with sodium dithionite. The sulfite ion is bound to the iron ion of the catalytic haem through the S atom. The Fe-S distance is 2.24 A. The structure of the cyanide complex with full occupancy of the ligand site was established for the first time for cytochrome c nitrite reductases. The cyanide ion is bound to the catalytic haem iron through the C atom. The Fe-C distance is 1.91 A and the Fe-C-N angle is 171 degrees . The sulfite reductase activity of TvNiR was measured at different pH values. The activity is 0.02 umol of HS(-) per minute per milligram at pH 7.0; it decreases with increasing pH and is absent at pH 9.0. PMID- 20944238 TI - X-ray and molecular-dynamics studies on Mycobacterium leprae single-stranded DNA binding protein and comparison with other eubacterial SSB structures. AB - The crystal structures of two forms of Mycobacterium leprae single-stranded DNA binding protein (SSB) have been determined at 2.05 and 2.8 A resolution. Comparison of these structures with the structures of other eubacterial SSBs indicates considerable variation in their quaternary association, although the DNA-binding domains in all of them exhibit the same OB-fold. This variation has no linear correlation with sequence variation, but could be related to variation in protein stability. Molecular-dynamics simulations have been carried out on tetrameric molecules derived from the two forms and the prototype Escherichia coli SSB and the individual subunits of both proteins. Together, the X-ray studies and molecular-dynamics simulations yield information on the relatively rigid and flexible regions of the molecule and on the effect of oligomerization on flexibility. The simulations provide insight into the changes in subunit structure on oligomerization. They also provide insight into the stability and time evolution of the hydrogen bonds/water bridges that connect the two pairs of monomers in the tetramer. PMID- 20944239 TI - Crystallization of small proteins assisted by green fluorescent protein. AB - The generation of crystal lattice contacts by proteinaceous tags fused to target proteins is an attractive approach to aid in the crystallization of otherwise intractable proteins. Here, the use of green fluorescent protein (GFP) fusions for this purpose is demonstrated, using ubiquitin and the ubiquitin-binding motif (UBM) of Y-family polymerase iota as examples. The structure of the GFP-ubiquitin fusion protein revealed that the crystal lattice was formed by GFP moieties. Ubiquitin was accommodated in the lattice through interactions with the peripheral loops of GFP. However, in the GFP-UBM fusion crystal UBM formed extensive interactions with GFP and these interactions, together with UBM dimerization, mediated the crystal packing. Interestingly, the tyrosine residues that are involved in mediating crystal contacts in both GFP-ubiquitin and GFP-UBM crystals are arranged in a belt on the surface of the beta-barrel structure of GFP. Therefore, it is likely that GFP can assist in the crystallization of small proteins and of protein domains in general. PMID- 20944240 TI - Comparison of a nontoxic variant of Clostridium perfringens alpha-toxin with the toxic wild-type strain. AB - The alpha-toxin produced by Clostridium perfringens is one of the best-studied examples of a toxic phospholipase C. In this study, a nontoxic mutant protein from C. perfringens strain NCTC8237 in which Thr74 is substituted by isoleucine (T74I) has been characterized and is compared with the toxic wild-type protein. Thr74 is part of an exposed loop at the proposed membrane-interfacing surface of the toxin. The mutant protein had markedly reduced cytotoxic and myotoxic activities. However, this substitution did not significantly affect the catalytic activity towards water-soluble substrate or the overall three-dimensional structure of the protein. The data support the proposed role of the 70-90 loop in the recognition of membrane phospholipids. These findings also provide key evidence in support of the hypothesis that the hydrolysis of both phosphatidylcholine and sphingomyelin are required for the cytolytic and toxic activity of phospholipases. PMID- 20944241 TI - X-ray-induced deterioration of disulfide bridges at atomic resolution. AB - Overall and site-specific X-ray-induced damage to porcine pancreatic elastase was studied at atomic resolution at temperatures of 100 and 15 K. The experiments confirmed that irradiation causes small movements of protein domains and bound water molecules in protein crystals. These structural changes occur not only at 100 K but also at temperatures as low as 15 K. An investigation of the deterioration of disulfide bridges demonstrated the following. (i) A decrease in the occupancy of S(gamma) atoms and the appearance of new cysteine rotamers occur simultaneously. (ii) The occupancy decrease is observed for all S(gamma) atoms, while new rotamers arise for some of the cysteine residues; the appearance of new conformations correlates with the accessibility to solvent. (iii) The sum of the occupancies of the initial and new conformations of a cysteine residue is approximately equal to the occupancy of the second cysteine residue in the bridge. (iv) The most pronounced changes occur at doses below 1.4 * 10(7) Gy, with only small changes occurring at higher doses. Comparison of the radiation induced changes in an elastase crystal at 100 and 15 K suggested that the dose needed to induce a similar level of deterioration of the disulfide bonds and atomic displacements at 15 K to those seen at 100 K is more than two times higher. PMID- 20944242 TI - Glass transition in thaumatin crystals revealed through temperature-dependent radiation-sensitivity measurements. AB - The temperature-dependence of radiation damage to thaumatin crystals between T = 300 and 100 K is reported. The amount of damage for a given dose decreases sharply as the temperature decreases from 300 to 220 K and then decreases more gradually on further cooling below the protein-solvent glass transition. Two regimes of temperature-activated behavior were observed. At temperatures above ~200 K the activation energy of 18.0 kJ mol(-1) indicates that radiation damage is dominated by diffusive motions in the protein and solvent. At temperatures below ~200 K the activation energy is only 1.00 kJ mol(-1), which is of the order of the thermal energy. Similar activation energies describe the temperature dependence of radiation damage to a variety of solvent-free small-molecule organic crystals over the temperature range T = 300-80 K. It is suggested that radiation damage in this regime is vibrationally assisted and that the freezing out of amino-acid scale vibrations contributes to the very weak temperature dependence of radiation damage below ~80 K. Analysis using the radiation-damage model of Blake and Phillips [Blake & Phillips (1962), Biological Effects of Ionizing Radiation at the Molecular Level, pp. 183-191] indicates that large scale conformational and molecular motions are frozen out below T = 200 K but become increasingly prevalent and make an increasing contribution to damage at higher temperatures. Possible alternative mechanisms for radiation damage involving the formation of hydrogen-gas bubbles are discussed and discounted. These results have implications for mechanistic studies of proteins and for studies of the protein glass transition. They also suggest that data collection at T ? 220 K may provide a viable alternative for structure determination when cooling-induced disorder at T = 100 is excessive. PMID- 20944243 TI - Binding of flexible and constrained ligands to the Grb2 SH2 domain: structural effects of ligand preorganization. AB - Structures of the Grb2 SH2 domain complexed with a series of pseudopeptides containing flexible (benzyl succinate) and constrained (aryl cyclopropanedicarboxylate) replacements of the phosphotyrosine (pY) residue in tripeptides derived from Ac-pYXN-NH(2) (where X = V, I, E and Q) were elucidated by X-ray crystallography. Complexes of flexible/constrained pairs having the same pY + 1 amino acid were analyzed in order to ascertain what structural differences might be attributed to constraining the phosphotyrosine replacement. In this context, a given structural dissimilarity between complexes was considered to be significant if it was greater than the corresponding difference in complexes coexisting within the same asymmetric unit. The backbone atoms of the domain generally adopt a similar conformation and orientation relative to the ligands in the complexes of each flexible/constrained pair, although there are some significant differences in the relative orientations of several loop regions, most notably in the BC loop that forms part of the binding pocket for the phosphate group in the tyrosine replacements. These variations are greater in the set of complexes of constrained ligands than in the set of complexes of flexible ligands. The constrained ligands make more direct polar contacts to the domain than their flexible counterparts, whereas the more flexible ligand of each pair makes more single-water-mediated contacts to the domain; there was no correlation between the total number of protein-ligand contacts and whether the phosphotyrosine replacement of the ligand was preorganized. The observed differences in hydrophobic interactions between the complexes of each flexible/constrained ligand pair were generally similar to those observed upon comparing such contacts in coexisting complexes. The average adjusted B factors of the backbone atoms of the domain and loop regions are significantly greater in the complexes of constrained ligands than in the complexes of the corresponding flexible ligands, suggesting greater thermal motion in the crystalline state in the former complexes. There was no apparent correlation between variations in crystal packing and observed structural differences or similarities in the complexes of flexible and constrained ligands, but the possibility that crystal packing might result in structural variations cannot be rigorously excluded. Overall, it appears that there are more variations in the three-dimensional structure of the protein and the ligand in complexes of the constrained ligands than in those of their more flexible counterparts. PMID- 20944244 TI - The 2C putative helicase of echovirus 30 adopts a hexameric ring-shaped structure. AB - The 2C protein, which is an essential ATPase and one of the most conserved proteins across the Picornaviridae family, is an emerging antiviral target for which structural and functional characterization remain elusive. Based on a distant relationship to helicases of small DNA viruses, piconavirus 2C proteins have been predicted to unwind double-stranded RNAs. Here, a terminally extended variant of the 2C protein from echovirus 30 has been studied by means of enzymatic activity assays, transmission electron microscopy, atomic force microscopy and dynamic light scattering. The transmission electron-microscopy technique showed the existence of ring-shaped particles with ~12 nm external diameter. Image analysis revealed that these particles were hexameric and resembled those formed by superfamily 3 DNA virus helicases. PMID- 20944245 TI - Presidential address. PMID- 20944246 TI - Leprosy and MDT: eradication vs cure. PMID- 20944247 TI - Lack of antinuclear antibody in children with atopic dermatitis. AB - Antinuclear antibody (ANA) was assayed in 76 children with atopic dermatitis (AD) of which 46 were males and 30 females. Their ages ranged from 6 months to 12 years (mean 3.4 years). Age at onset of AD ranged from 2 months to 5.5 years (mean 1.9 years) and its duration ranged from 4 months to 4 years (mean 1.2 years). While facial lesions were present in 56 (73.3%) patients, 49 (64.5%) patients had predominant involvement of extensors. As per severity score designed by Rajka and Langerland, 31 (40.8%), 42 (55.3%) and 3 (3.9%) patients had mild, moderate and severe diseases respectively. History of photosensitivity was present in 6 (7.9%) patients. Serum samples were positive for ANA in a very low titre (1:20) in 2/6 patients with facial lesions. However LE cell, rheumatoid factor and C-reactive proteins were negative and serum complement levels were within normal limits. PMID- 20944248 TI - Pentoxifylline and ciprofloxacin in chronic folliculitis of legs. AB - Clinically diagnosed 38 patients of chronic superficial folliculitis were divided into 2 equal grops. Group I was given combination of ciprofloxacin and placebo for two weeks followed by placebo for another 4 weeks whereas patients in group II were given combination of ciprofloxacin and pentoxifylline for two weeks followed by pentoxifylline for 4 weeks. The combination of pentoxifylline with ciprofloxacin was found to be superior in initial response as well as prevention of reccurrence. PMID- 20944249 TI - Treatment of stable and recalcitrant depigmented skin conditions by autologous punch grafting. AB - Sixty cases of stable and refractory depigmented skin conditions which include local vitiligo, segmental vitiligo, chemical leucoderma, vitiligo vulgaris, post burn depigmentation etc constitute the study group. 39 of them were female and 21 male. Age ranged between 6 and 67 years. 1057 grafts were placed over 114 lesions and the cases were followed up to a period of 18 months. 70% to 100% repigmentation was observed in 56 lesions of 31 patients. Rate and extent of perigraft pigment spread was noted. Patients under PUVASOL showed a distinctly better response. Sequelae like cobble-stoning and polka-dotting were found to be disappearing with time or interference. PMID- 20944250 TI - A comparative study of liver function tests in patients of chronic liver disorders with and without cutaneous manifestations. AB - Forty six cases of chronic liver disorders with and without cutaneous manifestations were studied for abnormalities of liver function tests. 27 cases were associated with cutaneous manifestations and 19 cases without cutaneous manifestations. A higher serum bilirubin level was seen in all cases with cutaneous manifestations. Serum bilirubin was significantly high (P<0.05) in patients of chronic active hepatitis with cutaneous manifestations. Serum alkaline phosphatase and serum glutamic pyruvic transaminase (SGPT) levels were significantly high in chronic active hepatitis and alcoholic liver disease without cutaneous manifestations respectively. PMID- 20944251 TI - IgG subclasses in pemphigus vulgaris. AB - Direct immunofluorescence in perilesional skin of 13 pemphigus patients is studied for IgG subclasses. IgG1 and lgG4 were predominant subclasses deposited. No correlation of subclasses of IgG with clinical parameters were found. PMID- 20944252 TI - Extent and pattern of paediatric dermatoses in rural areas of central India. AB - A house to house study was done on 666 children aged 0-14 years in 5 villages of Wardha district in Maharastra (Central India). 346 children (51.95%) had one or more dermatoses. Infective dermatoses contributed 63.5% of all dermatoses, while noninfectious and nutritional deficiency dermatoses were responsibile for 21.2% and 15.2%, respectively. Pediculosis capitis was seen in 136 children (20.4%), followed by pyoderma in 107 (16.07%) and dematophytosis in 44 (6.61%). Scabies was found in only 6 and 4 cases of leprosy were also delected. Pityriasis alba, pityriasis capitis amond non-infectious; hair and skin changes among nutritional deficiency dermatoses were leading presentations. PMID- 20944253 TI - Topical coal tar alone and in combination with oral methotrexate in management of psoriasis : a retrospective analysis. AB - Thirty five patients admitted with psoriasis were analysed. 16 patients received 20% crude coal tar and 19 patients received 20% crude coal tar along with methotrexate in a weekly oral schedule (15mg/wk). After 4 weeks of therapy there was total clearence in 52.6% of the patients with combination therapy, whereas only 12.5% of the patients with conventional therapy achieved this. PMID- 20944254 TI - Pattern of skin diseases among civil population and armed forces personnel at Pune. AB - The pattern of skin disorders among 11393 civil and 8123 defence service personnel who attended out-patient department (OPD) from January 1989 to December 1994 is presented. Infective dermatoses were more common in civil population (41.2%) as compared to defence service personnel (36.3%). Fungal infection was common in both groups (15.1% and 17.2%) whereas parasitic infestations and pyoderma were more common in civil population (12.8% and 6.1%) as compared to service personnel (7.8% and 3.6%). Among non-infective dermatoses eczemas were more common in civil population (17.3%) as compared to Armed Forces personnel (11.7%), whereas papulosquamous disorders, pigmentary disorders, acne and alopecia were more common in Armed Forces personnel (13.5%, 13.4% 8.7% and 6.2%) as compared to civil population (10.8%, 10.1%, 6.4% and 4.1%). The incidence of other skin disorders did not differ much between the two groups. PMID- 20944255 TI - Lupus erythematosus panniculitis. AB - Lupus erythematosus panniculitis is a quite rare clinical entity characterised by one or several firm, asymptomatic, often fairly large subcutaneous nodules, as a manifestation of SLE or DLE. Two cases of lupus panniculitis, both female, are described here. Both of them had absence of typical lesions of SLE or DLE elsewhere in the body. Systemic symptoms were not present, antinuclear factor was positive in one case. Both showed typical lobular panniculitis on biospy and responded favourably to systemic chloroquine therapy. PMID- 20944256 TI - Cutaneous manifestations of HIV infection. AB - A total of 32 patients with HIV infection were examined for cutaneous manifestations from September 1994 to December 1995 in the Dermatology and Venereology Department of Wenlock District Hospital, Mangalore. Xerosis was the commonest skin manifestation (50%). Oropharyngeal candidiasis was an indicator of grave prognosis in 4 patients. Seborrhoeic dermatitis, seen is in 15.6%, presented in an atypical, extensive and rapidly evolving form. Infections were atypical, extensive and did not respond to conventional modalities of treatment. PMID- 20944257 TI - Erythroderma: a study of incidence and aetiopathogenesis. AB - Thirty cases of exfoliative dermatitis (22 male and 8 female) were selected at random for study. In addition to routine history and clinical examination, investigations like histopathology of skin and lymph nodes, peripheral blood smear for abnormal cells and bone marrow examinations were done. Aetiologically, the cases could be classified into 4 categories namely exfoliation in per existing dermatoses, drug-induced exfoliation, idiopathic exfoliation and exfoliation secondary to internal malignancy. Two cases showed abnormal monocytoid cells (sezary cells) in peripheral blood smear. PMID- 20944258 TI - Hereditary sensory and autonomic neuropathy type I. AB - Hereditary sensory and autonomic neuropathy (HSAN) type 1 is a rare hereditary neurological disorder. Two brothers aged 17 and 14 years had HSAN type 1 as both had big ulcers on feet, mutilation, dissociated anaesthesia, absent ankle jerks and normal hands. Probably these are first cases of HSAN type 1 in Indian literature. PMID- 20944259 TI - Papillon lefevre syndrome. AB - A 38-year-old Hindu female patient presented with palmoplantar keratoderma with premature fall of deciduous teeth. Clinical examination revealed diffuse hyperkeratosis of palms and soles. Upper incisor teeth were widely spaced and conical, while lower incisors were missing. X-ray was helpful in diagnosis. PMID- 20944260 TI - Proteus syndrome. AB - A 21/2-year-old male child born of a nonconsanguineous marriage with high parental age presented with macrodactyly, dysmorphic features, large disfiguring lipomas, small fibromas, a linear verrucous epidermal naevus and lymphangioma circumscriptum. X-ray of hand revealed macrodystrophia lipomatosa progressiva. A lipoma and lymphangioma circumscriptum were confirmed by histopathology. The cosmetically disfiguring lipomas were excised. This is the first case report from India with the characteristic macrodactyly. This could possibly be the first case of report of a mutational disorder following intake of carbimazole during pregnancy. PMID- 20944261 TI - Atypical dyskeratosis congenita. AB - Dyskeratosis congenita is a syndrome characterised mainly by pigmentation and atrophy of skin, nail dystrophy and oral leucoplakia. We report a patient who had features consistent with this syndrome including skin atrophy and pigmentation, oral leucoplakia, oesophageal stricture, but with normal finger and toe nails. Even though many variants have been described in the literature sparing of the nails as in our patient is extremely uncommon. PMID- 20944262 TI - Bilateral naevus of OTA. AB - Bilateral naevus of Ota is a rare condition. It is still more rare in males. Here is a report of such a case with review of literature. PMID- 20944263 TI - Porokeratosis of mibelli with a mucous membrane lesion. AB - Mucous membrane lesion of porokeratosis is a very vary rare occurrence. Here is a case report of such a case. PMID- 20944264 TI - Hereditary spherocytosis presenting as indolent leg ulcers. AB - Indolent leg ulcertation, which is the rarest manifestation of hereditary spherocytosis, started at the age of 5 years affecting a 15-year-old boy and his mother is reported. Review of literature showed very few reports from India and abroad. The response to oral folic acid was excellent. PMID- 20944265 TI - Pyoderma gangrenosum in HIV patient. AB - Pyoderma gangrenosum (PG) has previously been reported in very few patients with HIV infection. We describe here a 30-year-old housewife with HIV infection having multiple ulcerations over lower limbs characteristic of PG. PMID- 20944266 TI - Reliance on single dose therapy for gonococcal urethritis. AB - This case report is to highlight the shortfall of single dose therapy for acute uncomplicated gonococcal urethrits and its later effects. PMID- 20944268 TI - Hypomelanosis of Ito with rare neurological association. PMID- 20944267 TI - Thickening of peripheral nerves in neurofibromatosis. AB - A 14-year-old boy presented with multiple asymptomatic swellings all over the body. Cutaneous findings were classical for neurofibromatosis. Interesting and unusual finding was generalised thickening of peripheral nerve trunks. Biopsy from thickened nerve had features of neurofibromatosis. PMID- 20944269 TI - Pemphigus vulgaris with early eye involvement. PMID- 20944270 TI - Linear scleroderma with bilateral lesions, contractures and kyphoscoliosis. PMID- 20944271 TI - Lichen planus pemphigoides. PMID- 20944272 TI - Phenytoin hypersensitivity syndrome. PMID- 20944274 TI - Reactive perforating collagenosis. PMID- 20944273 TI - Blister beetle dermatitis in West Bengal. PMID- 20944275 TI - Griseofulvin therapy in acne vulgaris. PMID- 20944276 TI - Cetirizine induced urticaria. PMID- 20944277 TI - HIV seropositivity in STD patients. PMID- 20944278 TI - Editorial. PMID- 20944279 TI - Serum lipid profile in leprosy. AB - Serum lipids and lipoproteins were assessed in 40 patients of leprosy and 20 healthy controls (age & sex matched). The leprosy cases included 20 cases each of paucibacillary and multibacillary leprosy. PMID- 20944280 TI - Histopathological study of hyperkeratosis of palms and soles. AB - Clinically it is sometimes difficult to differentiate the various hyperkeratosis of palms and soles like psoriasis of palms and soles, pustulosis palmaris et plantaris, hyperkeratotic tinea and hyperkeratotic eczema. To differentiate amongst these conditions we have to take the help of histopathology. Here we are presenting the data of 292 cases of hyperkeratosis of palms & soles examined histologically by doing Haematoxylin and Eosin staining for the typical changes of the above mentioned conditions and PAS for the demonstration of the fungus in stratum corneum in cases of hyperkeratotic tinea. PMID- 20944281 TI - Hyperkeratosis of palms and soles : clinical study. AB - Typical lesions of hyperkeratosis of palms and soles do not create any problem but when slight variation is there it becomes difficult to diagnose and that changes the line of treatment. For that we have studied 300 fresh cases of hyperkeratosis of palms and soles which included 110 cases of hyperkeratotic eczema. 42 cases of hyperkeratotic tinea, 64 cases of psoriasis of palms and soles and 84 cases of pustulosis palmaris et plantaris (PPP). To reach the final diagnosis alongwith the detailed history, general physical examination and routine investigations, help was taken of special investigations like pus for culture and sensitivity, KOH smear examination of skin scrapings and nail cutting and culture on Sabouraud's dextrose agar medium. PMID- 20944282 TI - Bacterial culture and sensitivity in pemphigus. AB - Infection is the commonest cause of death in pemphigus and the commonest infection is Staphylococcus aureus bacteremia. In present study bacterial culture and sensitivity from the lesion was done in 25 patients of pemphigus vulgaris and accordingly antibiotics were given along with other treatment of pemphigus i.e. steroid, immunosuppressive drug etc. Most common pathogenic bacteria isolated was Staphylococcus aureus and it was sensitive to cloxacillin, erythromycin, cefotaxime and lincomycin. PMID- 20944283 TI - An immunological study of vitiligo. AB - Estimation of peripheral T lymphocytes T3, T4, T8 and NK cells was carried out in 30 cases of different clinical types of vitiligo by direct immunofluorescence technique. The cases were divided into two broad groups (1) Localised; and (2) Generalised. These cases were again divided into 3 groups as per duration of disease. Thirty healthy subjects served as control. Decrease in T3 and T4 and increase in T8 with decrease of T4/T8 ratio was seen in both localised and generalised variety. But the T4/T8 ratio was decreased to a greater extent in generalised variety. The NK cells showed significant increase in the generalised variety. As per disease T4/T8 ratio was reduced maximally in patients with disease duration less than one year. Of the generalised category NK cells were increased more in patients having disease duration more than 1 year. PMID- 20944284 TI - Vitiligo : a study of 998 cases attending KEM Hospital in Pune. AB - Background : Vitiligo is a condition of major social and cosmetic concern in India. An epidemiological study of large number of patients from India was indicated. PMID- 20944285 TI - Frictional pigmentary dermatoses : a clinical and histopathological study of 27 cases. AB - Twenty seven patients presenting with the complaint of pigmentary changes following friction were studied. Sixteen patients showed only pigmentary changes and 11 patients showed the presence of amyloid. PMID- 20944286 TI - Herpes zoster in patients with HIV infection. AB - Five hundred twenty seven HIV seropositive male cases were observed for herpes zoster for a period of five years. Overall incidence of herpes zoster in HIV infection was found to be 11.8%. Herpes zoster was presenting symptom in 50% cases. It developed in first year of follow up in 38.8% cases, in second and third year of follow up in 4.8% cases each and in fourth year in 1.6% case. Majority of cases (89%) were in age group of 20 - 40 years. Thoracic dermatome (68%) was commonest to get involved followed by cervical (14.5%), trigeminal (9.7%) and lumbosacral (8%). Among other associations of HIV seropositive herpes zoster cases 24.2% cases had tuberculosis and 4.8% cases had hepatitis B virus infection. The skin lesions of herpes zoster in majority of cases were bullous, haemorrhagic and necrotic. PMID- 20944287 TI - Primary cutaneous amyloidosis. AB - Three cases of primary cutaneous amyloidosis are reported. Family history was negative. Systemic involvement was ruled out. Histopathology was confirmed by congored stain. Patients responded to oral colchicine. PMID- 20944288 TI - Murray williams warts. AB - A case of eruptive acanthoma also known as Murray Williams warts is being reported in a 35-year old male following contact allergic dermatitis to air borne allergens. PMID- 20944289 TI - Neurofibroma occurring in patients with rheumatoid arthritis. AB - Two female patients suffering from rheumatoid arthritis presented with the complaint of papular skin lesions over the dorsal aspect of hands. Histopathological examination of papules showed the features of neurofibroma. PMID- 20944290 TI - Systemic sclerosis in a stone cutter. AB - Several occupational hazards especially exposure to silica have been implicated as eliciting factors for the development of scleroderma-like disorders. We here report a case of manual stone-cutter who developed progressive scleroderma, interstitial lung disease and decreased oesophageal motility after several years of exposure to silica dust. PMID- 20944291 TI - Acantholytic dyskeratotic epidermal naevus. AB - A 43-year old male presented with unilateral warty papular eruptions of 20 years duration, involving the left side of trunk, left upper and lower limbs. There were also whitish macules intermingled with them. Histological features were compatible with Darier's disease. There was no evidence of any family history or palmar pits and nail changes typical of Darier's disease. We are reporting this case as acantholytic dyskeratotic epidermal naevus representing a mosaic form of Darier's disease. PMID- 20944292 TI - Wells' syndrome. AB - Eosinophilic cellulitis/Wells' syndrome is a rare dermatosis with erythematous, urticarial plaques that become more indurated and eventually have grey blue discoloration. The histopathology is distinctive, with a diffuse infiltrate composed predominantly of eosinophils but admixed with lymphocytes, histicytes and occasionally multinucleated histiocytes. There is dermal edema with so called "flame figures" that is composed of collagen focally enveloped with aggregates of eosinophilic granules. These collagen fibres may be surrounded by palisading histiocyes. The course is variable with waxing and waning and eventual spontaneous resolution. PMID- 20944293 TI - Olmsted syndrome with hypotrichosis. AB - Olmsted syndrome is characterised by mutilating palmoplantar keratoderma with peri-orificial hyperkeratosis. We report the case of an 8-year old boy who presented with severe keratoderma of the soles since birth and of the palms from the age of 3 years. At 3 years of age hyperkeratotic plaques appeared on the elbows and knees. The child developed keratotic lesions at the angle of the mouth 1 year later. The child had sparse thin easily pluckable hair. Light and scanning electron microscopic examination of the hair revealed several hair shaft abnormalities. Though the psychomotor development of the child was normal till 1 year of age, thereafter the keratoderma had largely restricted the child's mobility. There was no history of hyperhidrosis and no dental abnormality was detected. The lesions had been unresponsive to keratolytics and had recurred after surgical removal. The patient was started on oral retinoids and topical keratolytics and had partially responded in 2 months. PMID- 20944294 TI - Milroy's disease. AB - A rare hereditary primary lymphoedema (Milroy's disease) affecting three generations of a family involving males only, starting at the age of 15 years is reported. PMID- 20944295 TI - Tarantula bite leads to death and gangrene. AB - Chilobrachys hardwikii-giant black hairy spider bite produced two deaths, one case of gangrene of the foot and urticarial rashes in another person in a remote village of Churulia 30 km from Asansol. PMID- 20944297 TI - Steatocystoma multiplex. PMID- 20944296 TI - Progressive nodular histiocytoma. AB - A 42-year-old male with progressive nodular histiocytoma is reported who presented with progressively increasing superficial reddish brown papules, deep cutaneous nodules and a pedunculated lesion with telangiectasia for the last 20 years. Histopathology revealed histiocytic, fibroblastic, and vascular proliferation, foam cells, occasional giant cells and iron deposit in the lesions. PMID- 20944298 TI - Dermatitic epidermal naevus. PMID- 20944299 TI - Erythema annulare centrifugum. PMID- 20944300 TI - Itching and immunity in malaria. PMID- 20944302 TI - Melkersson - rosenthal syndrome with geographical tongue. PMID- 20944301 TI - Granuloma multiforme. PMID- 20944303 TI - Allergic reaction to phorate-an organophosphorus compound. PMID- 20944304 TI - Metastatic cutaneous adenocarcinoma. PMID- 20944305 TI - Cortcosteroids : use in herpes zoster. PMID- 20944307 TI - New emerging drug regimens for leprosy. PMID- 20944306 TI - Atypical presentation of lichen planus. PMID- 20944308 TI - Pharmacokinetics and drug interactions of newer anti -leprosy drugs. PMID- 20944309 TI - Virology and immunology of HIV infection. PMID- 20944310 TI - Hand dermatitis in beauticians in India. AB - One hundred and sixty-one beauticians and hairdressers (146 women and 15 men) were examined for the presence of hand dermatitis and those with hand eczema were patch tested with a battery of antigens standardised for beauticians. Forty-two (26.1%) subjects were found to have hand dermatitis and of these, in 31 (69.3%) the patch tests were positive; the following antigens elicited a positive response; paraphenylene diamine (35.5%), rubber antigens (22.6%), nickel (22.6%), shampoos (12.9%), ammonium thioglycollate (9.7%), ammonium persulphate (3.2%), henna mixture (3.2%) and detergents (6.5%). In addition, irritant reaction was seen in 7; in 5 patients it was to shampoos and in 2 to ammonium persulphate. Of the 8 patients who, on questioning, had a history of atopy, 7 (87.5%) had hand eczema, while 1 (12.5%) did not, and this difference was statistically significant (p < 0.001), suggesting that beauticians with a history of atopy were more likely to develop hand eczema. PMID- 20944311 TI - Renal function status in leprosy. AB - 75 leprosy patients comprising of 47 males and 28 females ranging in age from 10 years to 75 years (mean 33.76 years) were studied. Duration of disease ranged from one month to 12 years. Thirty (40%) cases were in reaction. Renal involvement occurred in 53.66% of cases. 80% of type 2 reaction leprosy patients showed renal involvement as compared to 53% of type 1 reaction. 80% of leprosy cases with more than 3 years duration of disease showed renal involvement as compared to 46.6% of cases with less than 3 years duration of disease. 9% of cases showed reduction in one or both kidney size with loss of corticomedullary differentiation on USG. PMID- 20944312 TI - Oral fluconazole in tinea versicolor. AB - 25 patients with extensive tinea versicolor were treated with single oral dose of 400 mg of fluconazole. 25 patients returned for follow-up. Follow-up at 3 weeks, 6 weeks and 8 weeks showed 100% clinical cure rate and 92% mycological cure rate. No significant side effects were noticed. The majority of patients found the treatment effective, safe and convenient. PMID- 20944313 TI - Mycological study of tinea versicolor. AB - Mycological study of 100 cases of tinea versicolor was undertaken. Skin scrapings from 100 cases were subjected for culture in Sabouraud's dextrose agar, out of which 60 positive cultures (60%) were obtained. PMID- 20944314 TI - Comparative histopathology of scabies versus nodular scabies. AB - Comparative histopathology was studied in 25 cases of scabies versus 25 cases of nodular scabies which were selected from Dermato-Venereology out patients. Salient differences observed were that in scabies lifting of stratum corneum at places was seen in all 100% cases, spongiosis in 100%, spongiotic vesicles in 28%, burrows in 56%, mite in 40% and vasculitis in 28% whereas in nodular scabies acanthosis was seen in 100%, pseudo epitheliomatous hyperplasia in 8%, burrows in 48%, mite in 24% and vasculitis in 84%. In nodular scabies, dermal infiltrate in 32% cases was arranged as lymphoid follicles with admixture of plasma cells and eosinophils. PMID- 20944315 TI - Comparative biorelease study of fluticasone in combination with antibacterial (Neomycin) and or antifungal (coltrimazol, miconazole) agents by histamine percutaneous reaction method in healthy volunteers. AB - Fluticasone propionate is a novel, potent and topically active synthetic corticosteroid preparation with a much reduced potential, in relation to its anti inflammatory potency, for unwanted systemic side effects. It is indicated for the treatment of eczema, dermatitis etc. The objective of the present study was to evaluate and compare the biorelease of fluticassone with placebo (base formulation); its combination with antifungal (miconazole, clotrimazole) and / or antibacterial agents based on the attenuation of histamine induced wheal and flare reaction and flare intensity (on visual analouge scale) by McNemar test. In the present study, fluticasone alone and in combination with clotrimazole, miconazole and neomycin significantly reduced the wheal and flare response of histamine prick test. The flare intensity response was also significantly inhibited by these treatments. Furthermore, there was no difference in the anti inflammatory activity of various treatment groups. It may, therefore, be concluded that antibacterial (neomycin) and / or antifungal (miconazole, clotrimazole) agents in combination with steroid (fluticasone) do not alter the pharmacodynamic response of the latter. PMID- 20944316 TI - Skin manifestations of acromegaly - a study of 34 cases. AB - The common dermatological manifestations seen in 34 cases of acromegaly were changes in facial appearance, enlargement of hands and feet, intolerance to heat and sweating, carpal tunnel syndrome, hirsutism, acrochordons and acanthosis nigricans. The mean estimated age of onset was 32.8 years in males and 31.7 years in females, while the mean age at the time of diagnosis was 38.6 years and 36.1 years for males and females respectively, with a slight male preponderance noted. PMID- 20944317 TI - Secondary syphilis in HIV infection - a diagnostic dilemma. AB - A case of secondary syphilis in HIV infection is being reported. The patient presented with skin rash only. VDRL was found to be negative and HIV testing was positive. He was treated for secondary syphilis with clinical response. Blood VDRL test was subsequently reported as reactive. PMID- 20944318 TI - Malignant blue nevus. AB - Blue nevus represents an aberrant collection of functioning benign dermal melanocytes. Its malignant degeneration is rare and is regarded as a form of malignant melanoma. We report a case of 35-year old male with this rare condition whose primary lesion over left foot ulcerated and patient later succumbed to multiple metastases. PMID- 20944319 TI - Keratoderma hereditaria mutilans (vohwinkel's syndrome). AB - We report two cases of Vohwinkel's syndrome in son and mother presenting with a progressive palmoplantar keratoderma with 'honeycomb' appearance associated with constricting bands encircling digits of hands and feet along with keratotic plaques on dorsum of hands and feet. Both had associated sensorineural deafness. PMID- 20944320 TI - Schamberg's disease - an unusual presentation. AB - A 28-year-old man with typical lesions of Schamberg's progressive pigmented purpuric dermatosis involving his right forearm is reported here for its unusual localisation. PMID- 20944321 TI - Necrobiosis lipoidica mimicking cellulitis. AB - A 57-year-old obese patient presented with a 5 month history of tender, indurated, erythematous plaques with superficial ulceration on the right shin. The lesions closely mimicked cellulitis but were unresponsive to antibiotics. Though the patient was not a known diabetic, on investigations she was found to be a diabetic. Histology confirmed the diagnosis of necrobiosis lipoidica. This acutely inflammed presentation of necrobiosis lipoidica is extremely rare. PMID- 20944323 TI - An exaggerated manifestation of penile cancer: a report from Japan. AB - This report describes a Japanese case of penile carcinoma characterized by an extravagantly harsh clinical presentation. Report of penile cancer from Japan is extremely rare. PMID- 20944322 TI - Congenital familial acral vitiligo. AB - A 22-year-old female presented with vitiliginous lesions on her hands and feet since birth. Similar lesions at similar sites were present in 4 other family members. The trait appeared to have autosomal dominant inheritance with variable penetrance. PMID- 20944324 TI - Favus in a non-endemic area. AB - A typical case of favus of scalp in a 60-year-old female, resident of a village in district Udaipur (Rajasthan) is being reported for its rarity and occurrence in non-endemic zone. Some of the nails were also involved. Fungal hyphae were demonstrated in KOH examination from scalp and nails. Culture on Sabourauds agar medium grew Trichophyton violaceum. PMID- 20944325 TI - Extensive keloidal healing of pemphigus vulgaris. AB - Bullae of pemphigus vulgaris heal without scarring. We here report a patient of pemphigus vulgaris whose lesions healed with a one-month history of extensive flaccid bullae and uninfected erosions on the trunk and extremities along with superficial erosions in the oral mucosa. The clinical suspicion of pemphigus vulgaris was confirmed by histopathological and immunohistological examination. Pulse therapy with monthly parenteral dexamethasone and cyclophosphamide pulse was instituted. The cutaneous lesions on healing formed extensive keloidal scars despite high dose of monthly corticosteroid therapy. PMID- 20944327 TI - Stevens Johnson syndrome with keratitis following paracetamol injection. PMID- 20944326 TI - Quiz. PMID- 20944328 TI - "Fountain sign" in lichen planus hypertrophicus. PMID- 20944329 TI - Benign mucosal pemphigoid. PMID- 20944330 TI - Evaluation of efficacy of therapy for psoriasis : methodological issues. PMID- 20944331 TI - Systemic corticosteroids in toxic epidermal necrolysis. PMID- 20944332 TI - Genital ulcer and viral warts. PMID- 20944333 TI - Acrodermatitis enteropathica (CME). PMID- 20944334 TI - Methotrexate : Side effects and the role of folic acid supplementation in psoriasis - A study. AB - In 50 patients of psoriasis, side effects observed with methotrexate pulse were studied. Folic acid ameliorated majority of the side effects without compromising with the therapeutic efficacy of methotrexate. PMID- 20944335 TI - Radiological changes in psoriatic arthropathy. AB - Forty-one cases of psoriatic arthropathy (PA) were selected for the study. Biopsy, x rays of hands, feet, cervical and dorsolumbar spine, sacro-iliac joints and routine investigations were carried out. Clinical diagnosis of psoriasis was confirmed histopathologically. Radiological changes in order of frequency were most common in feet - 26/41, hands - 24/41, sacro-iliac joints -11/41, dorso lumbar spine - 4/41 and cervical spine - 3/41. Distinctive radiological changes were seen in psoriatic arthritis. PMID- 20944336 TI - K A P study on HIV / AIDS among first year MBBS students. AB - This Kap (Knowledge, Attitude, Practical) study was to assess the current level of knowledge among first year M.B.B.S. students about AIDS at the point of entry to medical course. One hundred and seventy-one students were given a pre-tested close ended questionnaire. Overall level of knowledge about AIDS was found to be 64.91%. Male students were found to have better knowledge regarding transmission and prevention of AIDS than female students. Misconceptions were found to exist regarding mode of transmission, prognosis and prevention. Awareness programmes should be initiated among M.B.B.S. students in the first year itself, so that, lacunae can be rectified. PMID- 20944337 TI - Paediatric HIV infection. AB - Four cases of HIV infection in children between one to eight years of age are reported. Three were males and the other one female. One child was horn to known HIV infected mother. The female child was victim of sexual abuse and had disseminated tuberculosis with syphilis and gonorrhoea. Other two children were having systemic as well as dermatological disorders for which HIV test was done and found positive. PMID- 20944338 TI - Cutaneous manifestations of diabetes mellitus. AB - 87 patients including 64 males and 24 females with diabetes mellitus and skin diseases were studied. The skin manifestations were common during the fifth decade of life. Maturity onset diabetes had increased incidence of skin disease. Incidence of skin disease was common in early diabetes. Infections both bacterial and fungal were seen in majority of patients. Specific cutaneous markers and metabolic changes were rare and seen in long standing diabetes. Infections were the common problems which recurred subsequently. PMID- 20944339 TI - Pagetoid melanoma. AB - A case of pagetoid melanoma is reported for its unusual site, larger size and presence of suprabasal lacunae in the histopathological study. PMID- 20944340 TI - Epidermodysplasia verruciformis. PMID- 20944341 TI - Mycetoma on an unusual site. PMID- 20944342 TI - Localised cutaneous blastomycosis. PMID- 20944343 TI - Punctate palmoplantar keratoderma (Buschke-Fischer). PMID- 20944344 TI - Conicidence of vitiligo and lichen planus. PMID- 20944345 TI - Tubero - eruptive xanthoma with hypothyroidism. PMID- 20944346 TI - Pachydermoperiostosis. PMID- 20944348 TI - Sea urchin granuloma. PMID- 20944347 TI - Genital herpes zoster with cutaneous dissemination. PMID- 20944349 TI - Larva currens - a marker of HIV infection. PMID- 20944350 TI - Pityriasis rosea in a 2-year-old child. PMID- 20944351 TI - Do you know? PMID- 20944352 TI - Psoriasis and diabetes in identical twins. PMID- 20944353 TI - Management of herpes zoster. PMID- 20944354 TI - Pyoderma gengrenosum treated with clofazimine. PMID- 20944356 TI - Sulfasalazine in psoriasis. PMID- 20944355 TI - Shield as topical ointment in herpes zoster. PMID- 20944357 TI - Psoralens. PMID- 20944358 TI - Approach To jaundice (CME). PMID- 20944359 TI - Punch grafting in vitiligo : Refinements and case selection. AB - Autogolous split thickness punch grafting is being increasingly used as an effective technique in the management of refractory vitiligo by dermatosurgeons as an office procedure. Refinements in the technique of punch grafting has been described with special attention to the junctional areas and graft interspaces. Based on the experience of 55 cases treated with this technique careful selection of patients and recipient sites has been suggested. PMID- 20944360 TI - A clinicopathological study of 50 cases of cutaneous tuberculosis in Jamnagar District. AB - A clinicopathological study of 50 cases of cutaneous tuberculosis was carried out. Majority of patients (30%) belonged to the age group 11-20 years. Male to female ratio was 3 : 2. In our study commonest type of cutaneous tuberculosis was lupus vulgaris (36%) followed by tuberculosis verrucosa cutis (32%) and scrofuloderma (28%). Face and neck were the commonest sites (36%) affected. All the patients showed significant response to antituberculosis treatment within a period of 9 months. PMID- 20944361 TI - Chronic folliculitis - A clinico-epidemiological study. AB - 50 male patients, diagnosed to have chronic folliculitis of legs (CFL), were included in a clinico epidemiological study. CFL affected predominantly young adults of the age group of 16 - 25 years. Severe pruritus was associated in 86% of patients with CFL, and this symptom preceded the onset of new lesions. Follicular papules were seen more often than pustules in 58% of patients. Staphylococcus aureus was isolated in 72.5%. The lesions were confined to both legs in 50%, extending upto thigh in 28% and in legs, thighs and forearms in 10% of individuals studied. PMID- 20944362 TI - Relapse in psoriasis after methotrexate. AB - 20 patients, 12 males and 8 females with chronic palque psoriasis, not responding to conventional therapy were treated with methotrexate (MTX) in the dose of 15 mg/week, 3 doses, 12th hourly apart, for 4 - 12 weeks. All the cases in which MTX was stopped after attaining remission and giving maintenance therapy of 5 mg/week for 8 weeks had relapsed within 6 weeks to 12 weeks. Premethotrexate or postmethotrexate laboratory investigations were within normal limits. No significant side effects were noted. PMID- 20944363 TI - Solitary mastocytoma in an adult. AB - A 24-year old female developed late onset solitary mastocytoma on the left forearm. She complained of intense pruritus off and on which was not associated with flushing of face and blister formation over the nodule. Darier's sign was positive. Excisional biopsy was done and histopathology confirmed the diagnosis. PMID- 20944364 TI - Acrokerato - elastoidosis of costa: Report of three cases. AB - Three cases of acrokeratoelastoidosis of Costa are reported. All the patients were females with marginal keratodermas composed of cornified papules, some of which were umbilicated, distributed along the borders of the hands and feet. A positive family history was present in all the cases. PMID- 20944365 TI - Pityriasis lichenoides chronica in association with Tubercular Lymphadenitis. AB - A patient with pityriasis lichenoides chronica (PLC) during the course of her skin disease developed tuberculosis of cervical lymph nodes. Anti-tuberculosis treatment resulted in remission of PLC. Mycobacterium tuberculosis could be one of the triggering agent in pityriasis lichenoides. PMID- 20944366 TI - Cervical canal stenosis masquerading as neuritis in a case of borderline tuberculoid leprosy. AB - A 40-year old male presented with typical features of leprosy borderline tuberculoid (BT) type. During the course of treatment, he developed neurological features which were initially attributed to neuritis. However, these features progressed despite antileprosy treatment. Detailed investigations revealed compressive myelopathy due to cervical canal stenosis. He was managed successfully with appropriate surgical treatment. PMID- 20944367 TI - Subcutaneous rhinosporidiosis. AB - A 50-year old fisherman presented with multiple polypoid cutaneous and globoid subcutaneous swellings of four years duration. There was history of surgical excision of a nasal polyp in the past. Aspiration cytology and histopathology confirmed the diagnosis of cutaneous and subcutaneous rhinosporidiosis. PMID- 20944368 TI - Unilateral Darier's disease. AB - A 60-year old house-wife presented with mildly pruritic, over crusted, greasy, follicular and non-follicular papules over the forehead, retroauricular region and abdomen on the right side. There were numerous discrete hypopigmented macules scattered over the mammary region, abdomen, thigh and leg on the right side. Histopathological study of one of the papules over the forearems showed features of acrokeratosis verruciformis of Hopf. PMID- 20944369 TI - Nodular malignant melanoma - Secondary to carcinoma rectum. AB - A 45-year female presented with a sudden eruption of multiple brownish black nodular lesions since 5 months over the face, trunk and extremities which were clinically diagnosed as a case of nodular malignant melanoma. Histopathologically, they revealed the secondaries from carcinoma rectum. PMID- 20944370 TI - Woolly hair nevus - Case report. AB - A case of woolly hair nevus with associated Mongolian spot is reported. PMID- 20944371 TI - Pyoderma gangrenosum treated with clofazimine. PMID- 20944372 TI - Peripheral T - lymphocyte count in Nodular Scabies. PMID- 20944373 TI - Varicella infection triggering psoriasis. PMID- 20944374 TI - Alopecia areata in a ten-week-old baby. PMID- 20944375 TI - Prostatitis. PMID- 20944376 TI - Enhanced Toxicity Potential of a Regimen on Addition of Doxorubicin in Combination Chemo-therapy. AB - A comparative study of cutaneous toxicities of two different commonly used combination chemotherapeutic regimens was conducted on 16 patients of non Hodgkin's lymphoma. The common drugs in the two regimens were cyclophosphamide, vincristine and prednisone. One of the regimens which was administered to 10 patients, included doxorubicin as an additional drug. This combination is preferred in high grade malignancy. However, the addition of doxorubicin resulted in enhanced severity and multiplicity of cutaneous manifestations. If it is possible to choose between two or more regimens for a given malignancy, the risk benefit ratio can be weighed to choose the appropriate and least toxic drugs. PMID- 20944377 TI - Dexamethasone - Cyclophosphamide pulse (DCP) therapy in Pemphigus. AB - Of the 37 patients enrolled for this treatment, 13 have been lost to follow up and 4 have died. Of the remaining 20, 8 are already in remission (40%), while 12 are still having active disease. Of the 8 patients who are now in remission, 1 is in phase II and taking monthly dexamethasone cyclophosphamide pulse and 50 mg cyclophosphamide daily while in 3 patients all the treatment has already been withdrawn (phase IV). All these patients are being followed up for any recurrence. The duration of remission has been more than 6 months in 7 patients (maximum 2 years). The chief side-effect observed was increased susceptibility to pyogenic and candidal infections of the skin and oral mucosa respectively. The other side-effects noted were generalized weakness and lethargy following DCP (1), irregular menstrual periods (1), amenorrhoea (1), general darkening of complexion (1), steroid psychosis (1), transient eosinophilia (1) and marked transient oligospermia. PMID- 20944378 TI - Psoriatic arthropathy : A clinical and biochemical study. AB - 39 psoriatic patients with arthropathy and a negative rheumatoid factor were analysed to find the types of arthropathy and psoriasis and also any associated bichemical changes which could indicate the risk of developing arthropathy. All 5 types of arthropathy were noted, though the asymmetrical mono or oligo articular type was the most common and psoriasis vulgaris with nail involvement was more commonly associated with arthropathy. A significant association between serum hypocalcemia and psoriatic arthropathy was observed. PMID- 20944379 TI - "Immunoperoxidase" an essential modality of immunohistochemistry. AB - The immunoperoxide (IP) technique can be used for the detection of immune deposits in various tissue pathologies. This article focusses on the standardization of the reagents anti IgG, anti IgA and anti C3C which are used to target these immune deposits. Lymph node tissue was used as substrate for standardization of anti IgG and anti IgM. For anti IgA, intestine was used while for anti C3C kidney tissue rapidly proliferating glomerulo nephritis - RPGN was utilized. Sensitivity of the technique was found to be high. Also the results on paraffin section were excellent and could be interpreted using simple light microscope. It is concluded that once standardization is achieved, IP can be used as an essential modality in the detection of immune deposits in a wide variety of immunologically mediated dermatologic disorders. PMID- 20944380 TI - Cutaneous horn overlying psoriasis. AB - A 32-year old man presented with erythematous papulosquamous lesions on the body with multiple horns of varying size and shape on scalp. PMID- 20944381 TI - Incontinentia pigmenti. AB - A case of incontinentia pigmenti, a rare genodermatosis is being reported from Kingdom of Saudi Arabia. PMID- 20944382 TI - Unusual presentation of T-cell lymphoma. AB - A 56-year old woman developed multiple papules, plaques and erythema - multiforme (EM) like lesions on palms, soles, abdomen, back, axillary and gluteal folds of one month duration. She also had erythematous plaques, painful necrotising ulcers and oro-genital ulcerations. Skin biopsy was suggestive of plaque stage of cutaneous T-cell lymphoma. PMID- 20944383 TI - Familial syringoma. AB - Three patients with a family history of syringomas seen over a 12-month period are reported. Familial syringomas may not be as rare as generally believed. PMID- 20944384 TI - Mycobacterium fortuitum in cutaneous infections. AB - Three cases of culture proven primary cutaneous infections caused by Mycobacterium fortuitum, a rapidly growing non tuberculous mycobacterium, are reported. The first case was treated with ciprofloxacin and the other two, with trimethoprim / sulphamethoxazole with an excellent outcome. PMID- 20944385 TI - Quiz. PMID- 20944386 TI - Tinea versicolor localized to dorsal surface of hands and feet - A rare presentation in childhood. PMID- 20944387 TI - A new effective topical therapy for aphthous stomatitis. PMID- 20944388 TI - Diffuse cutaneous mastocytosis without systemic involvement : Response to topical augmented betamethasone dipropionate under plastic occlusion. PMID- 20944389 TI - Lepromin response with dharmendra antigen in patients with leprosy. PMID- 20944390 TI - Smooth muscle hamartoma associated with bilateral becker's nevus. PMID- 20944391 TI - Yoga introducing as alternative medicine in some dermatological ailments. PMID- 20944392 TI - Widespread dissemination of warts in prexisting dermatoses. PMID- 20944393 TI - The effects of high hydrostatic pressure treatment on the flavor and color of grated ginger. AB - High hydrostatic pressure (HHP) was applied to grated ginger in order to inactivate quality-degrading enzymes in a non-thermal manner. The effects of HHP treatment on the flavor and the color of the grated ginger were investigated just after treatment and during storage. After HHP treatment (400 MPa, 5 min), geraniol dehydrogenase (GeDH) was inactivated to less than 5%, but the activity of polyphenol oxidase (PPO) was reduced only to 37%. Heat treatment (100 degrees C, 10 min) inactivated GeDH to 43% and PPO to about 10%. In storage, the reduction of geranial, neral, and citronellal to the corresponding alcohols was observed in the untreated and the heat-treated ginger, while it was not in the HHP-treated grated ginger. In the HHP-treated sample, terpene aldehydes almost disappeared without the formation of the corresponding alcohols. Browning was not observed immediately after HHP treatment, while it was complete in the heat treated sample. The color change during storage appeared to reflect the residual activity of PPO. PMID- 20944394 TI - Vba2p, a vacuolar membrane protein involved in basic amino acid transport in Schizosaccharomyces pombe. AB - A recent study filling the gap in the genome sequence in the left arm of chromosome 2 of Schizosaccharomyces pombe revealed a homolog of budding yeast Vba2p, a vacuolar transporter of basic amino acids. GFP-tagged Vba2p in fission yeast was localized to the vacuolar membrane. Upon disruption of vba2, the uptake of several amino acids, including lysine, histidine, and arginine, was impaired. A transient increase in lysine uptake under nitrogen starvation was lowered by this mutation. These findings suggest that Vba2p is involved in basic amino acid transport in S. pombe under diverse conditions. PMID- 20944395 TI - Identification of blue-light photoresponse genes in oyster mushroom mycelia. AB - Using the characteristics of light-emitting diodes, we studied the effects of light quality, light intensity, and repeated light-dark cycles on the growth of oyster mushroom mycelia. Blue-light stimulation suppressed growth in oyster mushroom mycelia, and this effect was remarkably dependent on light intensity. Random amplified polymorphic DNA differential display analysis enabled the identification for the first time of 15 upregulated and 13 downregulated genes induced by blue-light stimulation. On the basis of a homologous search using BLASTX and the Interpro database, the transcription products were analyzed to identify the putative proteins. In addition, by real-time PCR analysis, the time courses of the expression levels of eight of the genes identified were found to include intrinsic induction time. PMID- 20944396 TI - Azido-coronatine: a useful platform for "click chemistry"-mediated probe synthesis for bioorganic studies. AB - We report on the development of azide-coronatine as a useful platform for azide alkyne cycloaddition ("click chemistry")-mediated synthesis of molecular probes. (+)-Azido-coronatine was synthesized in 10 steps with 11% yield using improved synthesis of coronafacic acid, in which the highly exo-selective Diels-Alder reaction (endo:exo > 1:25) is the key step. Azido coronatine was as effective as the original coronatine in a stomatal opening assay, and was easily modified to a fluorescein isothiocyanate (FITC)-labeled probe with high yield. PMID- 20944397 TI - Characterization of a plant-specific gene induced by endoplasmic reticulum stress in Arabidopsis thaliana. AB - We have conducted transcriptome analysis and have identified a number of genes that are upregulated by treatment with the endoplasmic reticulum (ER) stress inducer tunicamycin. Here we focused on one particular gene of unknown function. This gene, designated tunicamycin induced 1 (TIN1), encodes an open reading frame consisting of 424 amino acids with a putative signal peptide. TIN1 orthologs are present in several plant species, including poplar, rice, and moss, but not in other organisms, including yeast and animals. Transcriptional induction of TIN1 by ER stress was regulated in part by AtbZIP60, a membrane-bound transcription factor activating many ER stress-responsive genes. In agreement with increases of TIN1 transcripts, the TIN1 protein accumulated in response to tunicamycin treatment. It was localized at the ER when fused with a fluorescent protein. These results represent a first step toward elucidating the molecular function of TIN1. PMID- 20944398 TI - A single oral administration of acetic acid increased energy expenditure in C57BL/6J mice. AB - We have reported that acetic acid (AcOH) intake suppresses body fat mass and up regulates the genes involved in fatty acid oxidation, but it is not clear whether the suppression of body fat mass by AcOH administration is due to an increase in energy expenditure (EE). In this study, we investigated to determine whether a single oral administration of AcOH would increase EE in C57BL/6J mice treated with 1.5% AcOH. The AcOH treatment group had significantly higher oxygen consumption (VO(2)), EE, and fat oxidation (FAT) than the water treatment group. These results suggest that a single administration of AcOH increases EE, resulting in suppression of body fat mass. PMID- 20944399 TI - Purification and characterization of aspartic protease derived from Sf9 insect cells. AB - An aspartic protease that is significantly produced by baculovirus-infected Spodoptera frugiperda Sf9 insect cells was purified to homogeneity from a growth medium. To monitor aspartic protease activity, an internally quenched fluoresce (IQF) substrate specific to cathepsin D was used. The purified aspartic protease showed a single protein band on SDS-PAGE with an apparent molecular mass of 40 kDa. The N-terminal amino acid sequence of the enzyme had a high homology to a Bombyx mori aspartic protease. The enzyme showed greatest affinity for the IQF substrate at pH 3.0 with a K(m) of 0.85 uM. The k(cat) and k(cat)/K(m) values were 13 s(-1) and 15 s(-1) uM(-1) respectively. Pepstatin A proved to be a potent competitive inhibitor with inhibitor constant, K(i), of 25 pM. PMID- 20944400 TI - Analysis of the eukaryotic community and metabolites found in clay wall material used in the construction of traditional Japanese buildings. AB - Clay wall (tsuchikabe in Japanese) material for Japanese traditional buildings is manufactured by fermenting a mixture of clay, sand, and rice straw. The aim of this study was to understand the fermentation process in order to gain insight into the ways waste biomass can be used to produce useful materials. In this study, in addition to Clostridium, we suggested that the family Nectriaceae and the Scutellinia sp. of fungi were important in degrading cell wall materials of rice straw, such as cellulose and/or lignin. The microorganisms in the clay wall material produced sulfur-containing inorganic compounds that may sulfurate minerals in clay particles, and polysaccharides that give viscosity to clay wall material, thus increasing workability for plastering, and possibly giving water resistance to the dried clay wall. PMID- 20944401 TI - Fast and reliable determination of voriconazole in human plasma by LC-APCI-MS/MS. AB - A fast and reliable liquid chromatography coupled with atmospheric pressure chemical ionization tandem mass spectrometry (LC-APCI-MS/MS) method was developed and validated for the quantification of voriconazole in human plasma. The proposed method was validated in a linear range of 50-10,000 ng/ml, and the total run time was 1.5 min. This method was successfully used to support routine therapeutic drug monitoring of voriconazole. PMID- 20944402 TI - Identification of a royal jelly glycoprotein that carries unique complex-type N glycans harboring the T-antigen (Galbeta1-3GalNAc) unit. AB - In this study, we identified a royal jelly glycoprotein (RJG) that carries a unique complex-type N-glycans harboring the T-antigen (Galbeta1-3GalNAc) unit. The amino acid sequence of the tryptic glycopeptide harboring the T-antigen unit was G-E-S-L-X-K (X might be glycosylated Asn), confirmed in the major royal jelly glycoprotein 1 (MRJP1), which is also expressed in the mushroom body of the honeybee brain. PMID- 20944403 TI - Analysis of a Clostridium josui cellulase gene cluster containing the man5A gene and characterization of recombinant Man5A. AB - A cellulase gene cluster of Clostridium josui was sequenced, and was found to encode 11 proteins responsible for cellulosome (cellulolytic complex) formation, viz., cipA, cel48A, cel8A, cel9A, cel9B, orfX, cel9C, cel9D, man5A, cel9E, and cel5B, in order from the upstream side. All the predicted enzymes had a dockerin module, suggesting that these proteins are members of the C. josui cellulosome. Among these genes, the man5A gene encoding beta-mannanase was expressed in Escherichia coli and the recombinant enzyme (rMan5A) was characterized. rMan5A showed strong activity toward carob galactomannan and low activity toward guar gum, suggesting that it prefers non-galactosylated mannan to galactomannan. This enzyme hydrolyzed ivory nut mannan to produce mainly mannotriose and larger mannooligosaccharides, and was not active toward mannotriose. An antiserum raised against the recombinant enzyme detected Man5A in the culture supernatants of C. josui, which was grown on either ball-milled cellulose or glucose as a carbon source. PMID- 20944404 TI - A role of TCP1 in the longitudinal elongation of leaves in Arabidopsis. AB - We clarified important roles of Arabidopsis TCP1, a member of the TEOSINTE BRANCHED1, CYCLOIDEA, and PCF (TCP) transcription factors, in the longitudinal elongation of petioles, rosette leaves and inflorescent stems. We found that the promoter of TCP1 was active in the cotyledonary petioles and the distal part of the expanding leaves, as well as the midrib region and the petiole. PMID- 20944405 TI - Non-reducing terminal fucose within N-linked glycan plays a significant role in the recognition of human milk lactoferrin by the 1CF11 monoclonal antibody. AB - We have recently demonstrated that the 1CF11 monoclonal antibody bound human milk lactoferrin (hLf) through the recognition of two distinct portions of the molecule, namely the N-glycan-relevant and -irrelevant structural elements. In this present study, we prepared four immunoreactive peptide fractions containing N-linked glycan from tryptic digests of reduced and alkylated hLf by using a concanavalin A lectin column and reverse-phase HPLC. Deglycosylation of these fractions and a competitive binding assay using fucosylated oligosaccharides revealed that the non-reducing terminal fucose residue in N-linked glycan(s) played a significant role in recognizing the N-glycan-relevant element in hLf by 1CF11. PMID- 20944406 TI - Estimated average daily intake of antioxidants from typical vegetables consumed in Japan: a preliminary study. AB - The hydrophilic antioxidant content of 23 vegetables commonly consumed in Japan was assessed by the hydrophilic oxygen radical absorbance capacity (H-ORAC) method to estimate the dietary intake of total antioxidants in Japan. The estimated average H-ORAC value for "typical vegetables" consumed in Japan was 594.3 umol Trolox equivalent (TE)/100 g. Hence, 2080 umol TE/d of hydrophilic antioxidants would be ingested when 350 g of vegetables a day are consumed. PMID- 20944407 TI - Antifungal activity of morinol B derivatives of tetrahydropyran sesquilignan. AB - The relationship between the structure of naturally occurring (7R,7'R,8R,8'R) morinol B and its antifungal activity was examined. 3-Demethoxy morinol B showed much higher activity than the natural compound. The activity of the 4-butoxy-3 demethoxy derivative was higher than that of 3-demethoxy morinol B. PMID- 20944408 TI - New polar constituents in the pupae of the silkworm Bombyx mori L. (II): developmental changes of the constituents. AB - A correlation between the quantitative changes in L-methionine analogs, the ratio of D-serine/L-serine during the pupal stage, and metamorphosis was observed. The glycoside appearing at low blood sugar values during the pupal stage was isolated and characterized as D-glucosyl-L-tyrosine. (1)H-NMR indicated the appearance and increase of this glycoside, and Mirrorcle Ray CV4 equipment was used to take X ray pictures of the pupal bodies. The results indicate that gamma-cyclic di-L glutamate and L-methionine sulfone might be concerned with ammonia assimilation in the pupae, and that D-glucosyl-L-tyrosine served as a switch for the fatty acid (pupal oil) dissimilation hybrid system. PMID- 20944409 TI - Synthesis of beta-D-fructopyranosyl-(2->6)-D-glucopyranose from D-glucose and D fructose by a thermal treatment. AB - The synthesis is reported of beta-D-fructopyranosyl-(2->6)-D-glucopyranose that had previously been isolated from a fermented plant extract as a new saccharide. A disaccharide was predominately formed from an equal amount of D-glucose and D fructose under melting conditions at 140 degrees C for 60 to 90 min. This saccharide was isolated from the reaction mixture by carbon-Celite column chromatography and preparative HPLC, and was confirmed to be beta-D fructopyranosyl-(2->6)-D-glucopyranose by TOF-MS and NMR analyses. PMID- 20944410 TI - Involvement of both the N-glycan-relevant and N-glycan-irrelevant structural elements in the recognition of human milk lactoferrin by the 1CF11 monoclonal antibody. AB - Monoclonal antibody 1CF11 has been suggested to specifically recognize a certain carbohydrate epitope shared by glycoproteins in human external secretions. We examined the effect of cleaving the polypeptide backbone and removing N-linked oligosaccharides on the reactivity with 1CF11 of human milk lactoferrin (hLf) to elucidate the structural features of the 1CF11 epitope. We reveal by treating hLF with trypsin and/or N-glycosidase that both the N-glycan-relevant and N-glycan irrelevant structural elements were involved in the recognition of hLf by 1CF11. PMID- 20944412 TI - Drosophila nucleostemin 2 proved essential for early eye development and cell survival. AB - Human nucleostemin (NS) is a nucleolar protein involved in cell-cycle progression and ribosomal biogenesis. While four NS orthologs have been reported in Drosophila melanogaster, their roles in development have yet to be determined. Here we describe evidence that Drosophila nucleostemin 2 (ns2) plays a significant role in early eye development and is essential for cell survival in vivo. PMID- 20944411 TI - The effects of methylglyoxal on glutathione S-transferase from Nicotiana tabacum. AB - Methylglyoxal (MG) is one of the aldehydes that accumulate in plants under environmental stress. Glutathione S-transferases (GSTs) play important roles, including detoxification, in the stress tolerance systems of plants. To determine the effects of MG, we characterized recombinant GST. MG decreased GST activity and thiol contents with increasing K(m). GST can serve as a target of MG modification, which is suppressed by application of reduced glutathione. PMID- 20944413 TI - Regulation of the violacein biosynthetic gene cluster by acylhomoserine lactone mediated quorum sensing in Chromobacterium violaceum ATCC 12472. AB - Chromobacterium violaceum produces the purple pigment violacein by quorum-sensing regulation. 20-bp of the lux box-like sequence was found upstream of vioA in C. violaceum ATCC 12472. CviR received C10-HSL and C6-HSL and activated the transcription of vioA in Escherichia coli. However, in strain ATCC 12472, C6-HSL inhibited both C10-HSL-mediated violacein production and the transcription of vioA. PMID- 20944414 TI - Preparation of protein transduction domain-fused peptidyl prolyl cis/trans isomerase Pin1. AB - The phenotypes of mice lacking peptidyl prolyl cis/trans isomerase Pin1 (Pin1(-/ )) indicated that deficient Pin1 might be related to a variety of diseases. We created TAT-Pin1, a fusion protein of human immunodeficiency virus 1 trans activator of transcription factor with Pin1. Treatment of HeLa cells with TAT Pin1 increased the ratio of the S phase. Moreover, TAT-Pin1 restored the proliferating function of Pin1(-/-) mouse embryonic fibroblasts which cannot restart proliferation after G0 arrest. These results indicate that TAT-Pin1 is useful in studying the functions of Pin1 and can be developed as a macromolecular drug for diseases related to Pin1 loss. PMID- 20944415 TI - The concentration of ethyl carbamate in commercial ume (Prunus mume) liqueur products and a method of reducing it. AB - The ethyl carbamate concentration of commercial ume liqueur products was studied, and a method of reducing it was examined from the viewpoint of antioxidation. The average ethyl carbamate concentration across 38 ume liqueur products was 0.12 mg/l (0.02-0.33 mg/l). When potassium metabisulfite was added to a concentration of 0-1,000 ppm during production, the generation of ethyl carbamate was reduced in a concentration-dependent manner, but when the amount of potassium metabisulfite added was below the maximum level allowed under the Japanese Food Sanitation Act, the reduction was only 27%. When ume liqueurs were produced under deoxygenated conditions created using an oxygen absorber, the ethyl carbamate concentration was reduced by up to 47% as compared with the control group, probably due mainly to a reduction in free hydrogen cyanide. When ume liqueur was produced in an oxygen atmosphere, the ethyl carbamate concentration increased by up to 50% as compared with the control group. Thus, oxygen may be involved in the generation of ethyl carbamate in ume liqueur production. PMID- 20944416 TI - Synthesis of (2RS,8R,10R)-YM-193221 and an improved approach to tyroscherin, bioactive natural compounds from Pseudallescheria sp. AB - Short-step syntheses of (2RS,8R,10R)-YM-193221 (1) and tyroscherin (2), which are biologically active compounds isolated from Pseudallescheria sp., were accomplished in six and eight steps from L-tyrosine. The relative stereochemistry of natural YM-193221 was determined to be 8R*,10R*. PMID- 20944417 TI - Genistein induced apoptotic cell death in adult T-cell leukemia cells through estrogen receptors. AB - Adult T-cell leukemia (ATL) occurs in human T-lymphotropic virus type I-infected individuals and is endemic to the southwestern area of Kyushu in Japan. Here, we found that nM levels of genistein and 17beta-estradiol had cytotoxic effects on ATL cells and activated caspase-3. The estrogen receptor antagonist ICI182780 negated the cytotoxic effect of genistein. In addition, G protein-coupled estrogen receptor agonist G-1 also had a cytotoxic effect on ATL cells. This is the first report suggesting that estrogen receptors are a molecular target for ATL therapy. PMID- 20944418 TI - Aspartyl aminopeptidase, encoded by an evolutionarily conserved syntenic gene, is colocalized with its cluster in secretory granules of pancreatic islet cells. AB - Aspartyl aminopeptidase (DAP), encoded by the DNPEP gene, is believed to be a cytosolic protein with high enzymatic activity in the neuroendocrine tissues. Bioinformatic analysis revealed that the genomic segment spanning the DNPEP gene is evolutionarily conserved from Caenorhabditis elegans to humans. In the present study, we sought to determine whether the expression of DAP is associated with its clustered genes when expressed in pancreatic islet cells. Using anti-DAP specific antibody in immunofluorescent stainings, we found that DAP was specifically expressed in islet alpha cells but not in exocrine acinar cells. Moreover, using electron microscopy, we found that DAP was associated with a lysosomal-like structure and secretory granules, suggesting that it plays an important role in post-translational processing and the secretion of hormones in islet cells. The identification and characterization of DNPEP syntenic genes confirm that conserved clustered genes can preferentially be expressed in the same signaling pathway. PMID- 20944419 TI - Proline and glycinebetaine ameliorated NaCl stress via scavenging of hydrogen peroxide and methylglyoxal but not superoxide or nitric oxide in tobacco cultured cells. AB - Efficient detoxification of the reactive oxygen species, nitric oxide (NO) and methylglyoxal (MG), provides protection against NaCl-induced damage in plants. To elucidate the protective mechanisms of proline and glycinebetaine (betaine) against NaCl stress, intracellular levels of hydrogen peroxide (H(2)O(2)), superoxide (O(2)(-)), NO, and MG were investigated in tobacco Bright Yellow-2 cells. The Levels of H(2)O(2), O(2)(-), NO and MG were higher in the short-term and long-term NaCl-stressed cells than in the non-stressed cells, whereas the O(2)(-) level was higher in the long-term stressed cells. Exogenous proline and betaine decreased the H(2)O(2) level in both the short-term and the long-term NaCl-stressed cells and the MG level in the long-term NaCl-stressed cells, but did not change the O(2)(-) or NO levels. Under salt stress, both proline and betaine increased the transcription levels of glutathione peroxidase, which can contribute to the reduction of H(2)O(2). In conclusion, proline and betaine mitigated salt stress via reduction of H(2)O(2) accumulation during short-term incubation and via reduction of the accumulation of H(2)O(2) and MG during long term incubation. PMID- 20944420 TI - A short period of mannitol stress but not LiCl stress led to global translational repression in plants. AB - In plant cells, high salinity stress induces rapid inhibition of general protein synthesis. In this study, we found that treatment with mannitol, but not lithium stress, led to rapid global translational repression, suggesting that a rapid response at the level of translation might be induced by the osmotic but not the ionic components of salinity stress. PMID- 20944421 TI - Artemisia princeps extract promoted glucose uptake in cultured L6 muscle cells via glucose transporter 4 translocation. AB - Artemisia princeps is a familiar plant as a food substance and medicinal herb. In this study, we evaluated the effects of an ethanol extract of A. princeps (APE) on glucose uptake in differentiated L6 muscle cells. Treatment with APE elevated deoxyglucose uptake, and translocation of the insulin-responsive glucose transporter (GLUT4) to the plasma membrane in L6 myotubes occurred. The PI3K inhibitor LY294002 attenuated glucose uptake induced by APE. Phosphorylation of the Ser(473) residue of Akt was not observed, but phosphorylation of PI3K, Akt (Thr(308)), and atypical PKC was. In addition, APE stimulated phosphorylation of AMP-activated protein kinase (AMPK) at a level similar to 5'-amino-5 imidazolecarboxamide-riboside (AICAR). These results indicate that APE stimulates glucose uptake by inducing GLUT4 translocation, which is in part mediated by combination of the PI3K-dependent atypical PKC pathway and AMPK pathways. PMID- 20944422 TI - Amelioration of oxygen and glucose deprivation-induced neuronal death by chloroform fraction of bay leaves (Laurus nobilis). AB - The purpose of this study was to determine whether the Laurus nobilis chloroform fraction (LNCF) protects against cerebral ischemia neuronal damage. Human neuroblastoma SH-SY5Y cells and brain slices from rats were subjected to oxygen and glucose deprivation (OGD), followed by reoxgenation with and without LNCF. The viabilities of SH-SY5Y cells and brain slices from the rats were 58.5+/-4.9% and 79.7+/-5.9% in the group subjected to OGD, and 80.4+/-0.4% and 97.2+/-1.9% at 4 ug/ml of LNCF, respectively. LNCF also significantly inhibited death-associated protein kinase (DAPK) dephosphorylation. Pretreatment with LNCF at 4 mg/kg significantly decreased infarct size by 79% of vehicle control in the middle cerebral artery occlusion (MCAO) in vivo model. LNCF is a neuroprotective drug candidate against cerebral ischemia neuronal damage. PMID- 20944423 TI - Preparation of optically active allothreonine by separating from a diastereoisomeric mixture with threonine. AB - A simple procedure is described to obtain D- and L-allothreonine (D- and L-aThr). A mixture of N-acetyl-D-allothreonine (Ac-D-aThr) and N-acetyl-L-threonine (Ac-L Thr) was converted to a mixture of their ammonium salts and then treated with ethanol to precipitate ammonium N-acetyl-L-threoninate (Ac-L-Thr.NH(3)) as the less-soluble diastereoisomeric salt. After separating Ac-L-Thr.NH(3) by filtration, Ac-D-aThr obtained from the filtrate was hydrolyzed in hydrochloric acid to give D-aThr of 80% de, recrystallized from water to give D-aThr of >99% de. L-aThr was obtained from a mixture of the ammonium salts of Ac-L-aThr and Ac D-Thr in a similar manner. PMID- 20944424 TI - 17beta-Estradiol increased the expression of daintain/AIF-1 in RAW264.7 macrophages. AB - We investigated the effect of 17beta-estradiol (E2) on the expression of daintain/AIF-1, a marker of activated macrophages, in RAW264.7. E2 upregulated the protein and mRNA levels of daintain/AIF-1 in similar manners under physiological concentrations of 10(-11) M to 10(-7) M. The application of ICI 182,780, an estrogen receptor (ER) antagonist, attenuated E2-induced daintain/AIF 1 production, suggesting the involvement of ER in this process. PMID- 20944425 TI - Anti-inflammatory and analgesic activities of SKLJI, a highly purified and injectable herbal extract of Lonicera japonica. AB - The parenteral route has many merits over the oral route, including greater predictability, reproducibility of absorption, and rapid drug action, but injectable phytomedicines are uncommon due to protein precipitating tannin and hemolytic saponin components. In this study, in an effort to develop a safe injectable analgesic phytomedicine, we prepared a tannin and saponin-free Lonicera japonica extract, SKLJI, through fractionation and column purification, and evaluated its anti-inflammatory and analgesic activities in in vivo experimental models of inflammation and pain. The removal of tannin and saponin resulted in loganin and sweroside-enriched SKLJI and it showed reduced hemolysis and protein precipitation. In efficacy tests, SKLJI inhibited croton oil- and arachidonic acid-induced ear edema, acetic acid-induced writhing, and carrageenan induced rat hind paw hyperalgesia. Inhibition of cylcooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and 5-lipoxyfenase (5-LO) activities by SKLJI appeared to be the mechanism underlying anti-inflammatory and analgesic efficacy. Loganin and sweroside also showed anti-inflammatory and analgesic activities, suggesting that they might be active principles in the efficacy of SKLJI. These results suggest that SKLJI is a viable candidate for a new anti inflammatory and analgesic phytomedicine that can be administered by the parenteral route. PMID- 20944426 TI - Effect of molecule branching and glycosidic linkage on the degradation of polydextrose by gut microbiota. AB - Polydextrose is a randomly linked complex glucose oligomer that is widely used as a sugar replacer, bulking agent, dietary fiber and prebiotic. Polydextrose is poorly utilized by the host and, during gastrointestinal transit, it is slowly degraded by intestinal microbes, although it is not known which parts of the complex molecule are preferred by the microbes. The microbial degradation of polydextrose was assessed by using a simulated model of colonic fermentation. The degradation products and their glycosidic linkages were measured by combined gas chromatography and mass spectrometry, and compared to those of intact polydextrose. Fermentation resulted in an increase in the relative abundance of non-branched molecules with a concomitant decrease in single-branched glucose molecules and a reduced total number of branching points. A detailed analysis showed a preponderance of 1,6 pyranose linkages. The results of this study demonstrate how intestinal microbes selectively degrade polydextrose, and provide an insight into the preferences of gut microbiota in the presence of different glycosidic linkages. PMID- 20944427 TI - Extension of the lifespan of Caenorhabditis elegans by the use of electrolyzed reduced water. AB - Electrolyzed reduced water (ERW) has attracted much attention because of its therapeutic effects. In the present study, a new culture medium, which we designated Water medium, was developed to elucidate the effects of ERW on the lifespan of Caenorhabditis elegans. Wild-type C. elegans had a significantly shorter lifespan in Water medium than in conventional S medium. However, worms cultured in ERW-Water medium exhibited a significantly extended lifespan (from 11% to 41%) compared with worms cultured in ultrapure water-Water medium. There was no difference between the lifespans of worms cultured in ERW-S medium and ultrapure water-S medium. Nematodes cultured in ultrapure water-Water medium showed significantly higher levels of reactive oxygen species than those cultured in ultrapure water-S medium. Moreover, ERW-Water medium significantly reduced the ROS accumulation induced in the worms by paraquat, suggesting that ERW-Water medium extends the longevity of nematodes at least partly by scavenging ROS. PMID- 20944428 TI - Genistein regulated serotonergic activity in the hippocampus of ovariectomized rats under forced swimming stress. AB - The mortality of individuals suffering from depression has been increasing, especially post-menopausal women; therefore, their care and treatment are important to maintain a high quality of life. In the present study, we evaluated the antidepressant-like effects of a major isoflavonoid, genistein (4',5,7 trihydroxyisoflavone), using a behavioral model of depression, the forced swimming test (FST), in ovariectomized rats. Daily administration of genistein to ovariectomized rats at a dosage of 10 mg/kg of body weight/d for 14 d significantly reduced the immobility time during the FST without changing motor dysfunction. On the other hand, a higher dosage, 100 mg/kg/d, did not have any effects on the immobility time compared with the vehicle control. Repeated administration of genistein at 10 mg/kg of body weight did not affect serotonergic activities in the hippocampus compared to the vehicle control in ovariectomized rats. A 5-min FST trial stimulated these activities. On the other hand, repeated pretreatment with genistein protected against changes in activity during the FST trial. These results suggest that daily consumption of genistein 10 mg/kg/d might have antidepressant-like effect on ovariectomized rats by regulating changes in serotonergic metabolism in the hippocampus under stressful conditions. PMID- 20944429 TI - Construction of a dominant negative form of human hypoxia-inducible factor 2alpha. AB - We constructed a dominant negative form of human hypoxia-inducible factor (HIF) 2alpha, HIF-2alphaDoN, which inhibited HIF transcriptional activity induced by hypoxia and by HIF-2alpha. HIF-2alphaDoN formed a complex with HIF-1beta and interacted with DNA containing hypoxia response elements (HREs). Thus, the complex appears to inhibit the binding of HIF-2 to HREs, and HIF-2alphaDoN might provide a useful therapeutic tool for HIF-2alpha-related diseases. PMID- 20944430 TI - Effects of Pro-Hyp, a collagen hydrolysate-derived peptide, on hyaluronic acid synthesis using in vitro cultured synovium cells and oral ingestion of collagen hydrolysates in a guinea pig model of osteoarthritis. AB - Proline-hydroxyproline (Pro-Hyp) stimulated hyaluronic acid production in cultured synovium cells. It was detected in guinea pig blood after oral ingestion of collagen hydrolysates. Oral administration of collagen hydrolysates increased the amount of proteoglycans in the epiphyses. It also reduced the morphological changes associated with osteoarthritic cartilage destruction of the knee joint. The results suggest that collagen hydrolysates have therapeutic potential for treatment of osteoarthritis. PMID- 20944431 TI - A detoxified extract of Rhus verniciflua Stokes upregulated the expression of BDNF and GDNF in the rat brain and the human dopaminergic cell line SH-SY5Y. AB - Rhus verniciflua Stokes (RVS) has traditionally been used as a food supplement and a traditional herbal medicine for centuries in Korea. This study attempted to evaluate the effects of RVS on the expression of Brain derived neurotrophic factor (BDNF) and Glial cell line-derived neurotrophic factor (GDNF) in SH-SY5Y cells and the rat brain. The results indicated that RVS is a potent inducer of Neurotrophic factor (NTF) production both in vitro and in vivo. Treatment with 10 ug/ml and 10 mg/kg RVS for 4 h of SH-SY5Y cells and rats yielded significant increases in BDNF and GDNF protein levels. We also detected BDNF and GDNF immunoreactive neurons in the rat brain. Both BDNF and GDNF-immunohistochemical staining was markedly enhanced in the animals treated with RVS. These results suggest that RVS serves as an ideal adjuvant in regard to regulating NTF expression, and can contribute to neuroprotection in neurodegenerative diseases. PMID- 20944432 TI - Effects of compressed hydrocarbon gases on the growth activity of Saccharomyces cerevisiae. AB - The inhibitory action of compressed hydrocarbon gases on the growth of the yeast Saccharomyces cerevisiae was investigated quantitatively by microcalorimetry. Both the 50% inhibitory pressure (IP(50)) and the minimum inhibitory pressure (MIP), which are regarded as indices of the toxicity of hydrocarbon gases, were determined from growth thermograms. Based on these values, the inhibitory potency of the hydrocarbon gases increased in the order methane << ethane < propane < i butane < n-butane. The toxicity of these hydrocarbon gases correlated to their hydrophobicity, suggesting that hydrocarbon gases interact with some hydrophobic regions of the cell membrane. In support of this, we found that UV absorbing materials at 260 nm were released from yeast cells exposed to compressed hydrocarbon gases. Additionally, scanning electron microscopy indicated that morphological changes occurred in these cells. PMID- 20944433 TI - Volatile attractants for the common bluebottle, Graphium sarpedon nipponum, from the host, Cinnamomum camphora. AB - Floral scent has been shown to elicit behavioral responses by butterflies which forage for flowers after receiving appropriate signals. In comparison with investigations about the role of floral scent, those of foliar odor are, however, very few. In this study, the foliar volatiles of Cinnamomum camphora (Lauraceae), which had been collected by air entrainment, exhibited activities toward Graphium sarpedon nipponum (Papilionidae) in both electrophysiological and behavioral tests. The volatiles were analyzed by capillary gas chromatography with electro antennographic detection (GC-EAD). Two electrophysiological active compounds were found which were determined as nonanal and decanal by using gas chromatography mass spectrometry (GC-MS). Female butterflies generally tend to show a greater EAG response than males to the headspace volatiles and EAG-active aldehydes. Two EAG-active aldehydes were found in attractant tests to be attractive to both sexes of the butterfly when treated individually. Although the difference between the sexes was not significant, the female butterflies' preference tended to be more active than that of the males. PMID- 20944434 TI - Dantrolene, a therapeutic agent for malignant hyperthermia, inhibits catecholaminergic polymorphic ventricular tachycardia in a RyR2(R2474S/+) knock in mouse model. AB - BACKGROUND: Dantrolene, a specific agent for the treatment of malignant hyperthermia, was found to inhibit Ca(2+) leak through not only the skeletal ryanodine receptor (RyR1), but also the cardiac ryanodine receptor (RyR2) by correcting the defective inter-domain interaction between N-terminal (1-619 amino acid) and central (2,000-2,500 amino acid) domains of RyRs. Here, the in vivo anti-arrhythmic effect of dantrolene in a human catecholaminergic polymorphic ventricular tachycardia (CPVT)-associated RyR2(R2474S/+) knock-in (KI) mouse model was investigated. METHODS AND RESULTS: ECG was monitored in KI mice (n=6) and wild-type (WT) mice (n=6), before and after an injection of epinephrine (1.0mg/kg) or on exercise using a treadmill. In all KI (but not WT) mice, bi directional ventricular tachycardia (VT) was induced after an injection of epinephrine or on exercise. Pre-treatment with dantrolene (for 7-10 days) significantly inhibited the inducible VT (P<0.01). In KI cardiomyocytes, Ca(2+) spark frequency (SpF; s(-1).100um(-1): 5.8+/-0.3, P<0.01) was much more increased after the addition of isoproterenol than in WT cardiomyocytes (SpF: 3.6+/-0.2). The increase in SpF seen in KI cardiomyocytes was attenuated by 1.0umol/L dantrolene (SpF: 3.6+/-0.5, P<0.01). CONCLUSIONS: Dantrolene prevents CPVT, presumably by inhibiting Ca(2+) leak through the RyR2. PMID- 20944435 TI - Association between circulating monocyte subsets and in-stent restenosis after coronary stent implantation in patients with ST-elevation myocardial infarction. AB - BACKGROUND: Recent studies have shown that monocytes in human peripheral blood are heterogeneous. The clinical significance of 2 distinct monocyte subsets as a marker of late in-stent restenosis (ISR) following implantation of bare-metal stents (BMSs) in patients with acute myocardial infarction (AMI) was examined. METHODS AND RESULTS: Seventy-one consecutive patients with AMI who underwent BMS implantation were enrolled in the study. Peripheral blood was collected 12 days after AMI onset. Two distinct monocyte subsets (CD14(+)CD16(-)CCR2(+) and CD14(+)CD16(+)CX3CR1(+)) were measured by flow cytometry. All patients underwent angiography at a scheduled follow up after 9 months. CD14(+)CD16(+)CX3CR1(+) monocyte subset counts were significantly higher in patients with restenosis than in patients without restenosis, whereas neither the total monocytes nor the CD14(+)CD16(-)CCR2(+) subset counts differed significantly between the 2 groups of patients. There was also a significant positive correlation between the CD14(+)CD16(+)CX3CR1(+) monocyte counts and angiographic late lumen loss. In multivariate analysis, the CD14(+)CD16(+)CX3CR1(+) monocyte count was an independent predictor for in-stent late lumen loss. CONCLUSIONS: CD14(+)CD16(+)CX3CR1(+) monocytes might have a role in ISR following coronary BMS implantation in patients with AMI. PMID- 20944436 TI - MRI is useful for diagnosis of H1N1 fulminant myocarditis. PMID- 20944437 TI - Paraoxonase 1 correlates with butyrylcholinesterase and gamma glutamyl transferase in workers chronically exposed to pesticides. AB - OBJECTIVES: Agricultural workers chronically exposed to complex mixtures of pesticides are at increased risk of acute and chronic toxicity of these compounds. Enzyme activities are among the biomarkers that may be used to detect the effects of pesticides before adverse clinical health effects occur. The aims of this study were to ascertain the relationships between paraoxonase 1 (PON1) and other serum enzymes and to investigate whether long-term exposure to pesticides affects these relationships in Tunisian agricultural workers. METHODS: The activities of butyrylcholinesterase (BChE), aminotransferases, gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in plasma from workers chronically exposed to pesticides using an Integra 400 plus(TM) system. PON1 activity was measured using konelab 30(TM) system. RESULTS: Significant increases in aminotransferases, CK, LDH and ALP activities were found in workers exposed to pesticides. However, BChE and PON1 activities were decreased significantly in these subjects. In addition, PON1 activity was positively correlated with both BChE and GGT activities in these workers. CONCLUSION: This study suggests that pesticides lead to alteration of serum enzymes and that chronic exposure to pesticides might contribute to explain the positive correlation between PON1 and GGT, perhaps in order to protect BChE and simultaneously induce detoxification of pesticides. PMID- 20944438 TI - Workplace bullying could play important roles in the relationships between job strain and symptoms of depression and sleep disturbance. AB - OBJECTIVE: The purpose of this study was to assess whether workplace bullying mediates between job strain, evaluated by the job demand-control model, and symptoms of depression and sleep disturbance. METHODS: The subjects in this cross sectional study were recruited from all the workers (N=2,634) at 50 organizations in Japan. Due to missing data, the numbers of subjects included in the analyses varied from 1,646 to 2,062 (response rates varied from 62.5% to 78.2%). Job strain and workplace social support, workplace bullying, depression, and sleep disturbance were assessed using the Japanese versions of the Job Content Questionnaire, the Negative Acts Questionnaire, the Center for Epidemiologic Studies Depression Scale, and the Pittsburgh Sleep Quality Index, respectively. Mediation analysis followed the approach outlined by Baron and Kenny. We quantitatively estimated the mediation effects and tested their significance after adjustment for various combinations of demographic variables and workplace social support. RESULTS: Total effects of job strain index on depression or sleep disturbance were all positive and significant (p<0.05) in both genders. Mediation effects of workplace bullying were also all positive and significant (p<0.05) in both genders. Even after adjustment for workplace social support, the mediation effects were decreased, especially in women, but remained significant (p<0.05). CONCLUSIONS: Workplace bullying seems to play important roles in the relationships of job strain with depression or sleep disturbance in both genders. PMID- 20944439 TI - Work and family stress is associated with menstrual disorders but not with fibrocystic changes: cross-sectional findings in Chinese working women. AB - OBJECTIVES: To explore the separate and combined effects of work and family stress on menstrual disorders and fibrocystic changes in Chinese working women. METHODS: Data were obtained from a cross-sectional study of 1,642 female railway workers. The Effort-Reward Imbalance Questionnaire and Family Stress Scale were used to measure work stress and family stress, respectively; the menstrual and breast conditions were evaluated by gynecologic interview and a medical examination. Multivariate log-binomial regression was performed to analyze the associations. RESULTS: Menstrual disorders were found in 59.3% of female workers, and 54.8% had fibrocystic changes. The risk of menstrual disorders was significantly elevated with respect to work and family stress. The highest risk was found in the group with combined exposure to both work and family stress (RR with 95% CI 1.33 (1.18-1.49)). No significant association between stress and fibrocystic changes was observed. CONCLUSIONS: Menstrual disorders were associated with stress from work and family life, but not fibrocystic changes, in working women. Tailored intervention measures reducing the burden of stressful psychosocial work and family environment are needed to improve women's reproductive well-being. PMID- 20944440 TI - DNA damage and decrease of cellular oxidase activity in piglet Sertoli cells exposed to arsanilic acid. AB - The study was designed to explore the toxic effects of arsanilic acid on piglet Sertoli cells. Sertoli cells were isolated from piglet testes using a two-step enzyme digestion followed by differential plating. Piglet Sertoli cells were cultured and classified into the following five groups: group A, the control without arsanilic acid treatment; group B, cultured with 5 uM arsanilic acid; group C, cultured with 50 uM arsanilic acid; group D, cultured with 0.5 mM arsanilic acid; and group E, cultured with 5 mM arsanilic acid. We found that Sertoli cell growth was inhibited by arsanilic acid at 0.5 mM compared with the control, group A. The oxidase activity of Sertoli cells was decreased by arsanilic acid at 0.5 mM as evidenced by the observations that arsanilic acid increased MDA content but decreased the SOD and GSH-Px activities of Sertoli cells. Moreover, 50 uM of arsanilic acid was observed to cause DNA damage in Sertoli cells. The results of our study suggest that exposure of Sertoli cells to arsanilic acid leads to induction of oxidative stress and inhibition of cell growth at a high concentration, while arsanilic acid causes DNA damage in Sertoli cells at a low concentration. PMID- 20944441 TI - Transplantation of adipose-derived stem cells promotes formation of prefabricated flap in a rat model. AB - Flap prefabrication is started with transposition of a vascular pedicle into a donor area that lacks an axial blood supply. Adipose-derived stem cells (ASCs) have been proven beneficial for promoting neovascularization and tissue regeneration in several animal models. Here we investigated the feasibility of applying ASCs as a novel strategy to promote flap prefabrication, which involves the processes of neovascularization and regeneration. Prefabricated flaps were performed by two-stage procedure in a rat model. At stage one, the right femoral vascular pedicle was dissected and embedded underneath the abdominal flap to form a man-made axial flap. At stage two, the prefabricated abdominal flap was elevated as an island flap based on the implanted femoral vessel. Ninety rats were randomly divided into 3 groups and received allogeneic ASCs, chondrocytes and phosphate-buffered saline (PBS), respectively during the first operation. Eighteen flaps of each group were harvested for vascular endothelial growth factor-A (VEGF-A) protein assay after the first surgery. The other flaps were processed for flap viability measurements by flap survival rate and capillary density after the second surgery. Results demonstrated that the ASCs treated group had higher survival percentage and capillary density of flap as compared with either PBS group or chondrocyte group. Furthermore, the ASC group had the highest level of in vivo VEGF-A among three groups, while the chondrocyte group had the lowest. These results indicate that ASCs are capable of promoting flap prefabrication, and its therapeutic potential is correlated with the angiogenic cytokines such as VEGF-A. PMID- 20944442 TI - Age-related decrease in inferior vena cava diameter measured with echocardiography. AB - The diameter of the inferior vena cava (IVC) measured with echocardiography is clinically used as a parameter to estimate right atrial pressure, which reflects dehydration or overhydration. Because elderly patients fall easily into dehydration, normal values for IVC diameters in elderly patients may be helpful for geriatric medicine. However, normal values of IVC diameter in relation to age have not been investigated. The purpose of this study was to elucidate age related changes in IVC diameter using echocardiography. Enrolled in the study were 200 patients (67 +/- 15 yrs: range 17-94 yrs) with cardiovascular risk factors but no overt cardiac diseases. IVC diameters throughout the respiratory cycle were measured as maximum and minimum IVC diameters (IVC(max), IVC(min)) using M-mode echocardiography. To assess IVC collapsibility, the respirophasic variation of IVC diameter was calculated as (IVC(max) - IVC(min))/(IVC(max)) *100. Maximum IVC diameter was decreased with advancing age (r = -0.221, p = 0.002). The respirophasic variation of the IVC diameter was increased with advancing age (r = 0.244, p = 0.001). Stepwise multiple regression analysis showed that age was an independent determinant for both maximum IVC diameter (beta coefficient = -0.249, p < 0.001) and respirophasic variation of the IVC diameter (beta coefficient = 0.268, p < 0.001). Age-related decrease in maximum IVC diameter and increase in the respirophasic IVC collapsibility may indicate the decrease in right atrial pressure in some elderly patients. Therefore, elderly patients with decreased maximum IVC and increased respirophasic IVC collapsibility may need prevention for dehydration. PMID- 20944443 TI - Duchenne muscular dystrophy in a female patient with a karyotype of 46,X,i(X)(q10). AB - Duchenne muscular dystrophy (DMD) is a severe recessive X-linked form of muscular dystrophy caused by mutations in the dystrophin gene and it affects males predominantly. Here we report a 4-year-old girl with DMD from a healthy family, in which her parents and sister have no DMD genotype. A PCR-based method of multiple ligation-dependent probe amplification (MLPA) analysis showed the deletion of exons 46 and 47 in the dystrophin gene, which led to loss of dystrophin function. No obvious phenotype of Turner syndrome was observed in this patient and cytogenetic analysis revealed that her karyotype is 46,X,i(X)(q10). In conclusion, we describe the first female patient with DMD who carries a de novo mutation of the dystrophin gene in one chromosome and isochromosome Xq, i(Xq), in another chromosome. PMID- 20944444 TI - Exploiting system fluctuations. Differential training in physical prevention and rehabilitation programs for health and exercise. AB - BACKGROUND: Traditional causal modeling of health interventions tends to be linear in nature and lacks multidisciplinarity. Consequently, strategies for exercise prescription in health maintenance are typically group based and focused on the role of a common optimal health status template toward which all individuals should aspire. MATERIALS AND METHODS: In this paper, we discuss inherent weaknesses of traditional methods and introduce an approach exercise training based on neurobiological system variability. The significance of neurobiological system variability in differential learning and training was highlighted. RESULTS: Our theoretical analysis revealed differential training as a method by which neurobiological system variability could be harnessed to facilitate health benefits of exercise training. It was observed that this approach emphasizes the importance of using individualized programs in rehabilitation and exercise, rather than group-based strategies to exercise prescription. CONCLUSION: Research is needed on potential benefits of differential training as an approach to physical rehabilitation and exercise prescription that could counteract psychological and physical effects of disease and illness in subelite populations. For example, enhancing the complexity and variability of movement patterns in exercise prescription programs might alleviate effects of depression in nonathletic populations and physical effects of repetitive strain injuries experienced by athletes in elite and developing sport programs. PMID- 20944445 TI - A dynamic systems approach to bimanual coordination in stroke: implications for rehabilitation and research. AB - During the last 30 years, the dynamic systems approach to coordination patterns contributed to shed new lights on the principles governing interlimb coordination, its dynamics, and its neural basis, predominantly in healthy people. In the present paper, we aim to show how these concepts could provide a theoretical and a methodological framework to address bimanual coordination dysfunction and rehabilitation in stroke patients. Compared to conventional approaches to research and rehabilitation in stroke, the one proposed in this paper is original since it seeks to assess and improve the impaired limb through (and in) coordination tasks. We concretely envisage a number of implications of the "dynamic systems" view to understand the behavioral consequences of intrinsic asymmetries (due to central nervous system injury) on bimanual dynamics in stroke and to identify how to exploit the central nervous system plasticity and self organizing properties for recovering more adaptive coordinated movements. We conclude that more interest should be accorded to bimanual coordination assessment and rehabilitation in stroke. In this respect, the dynamical systems approach provides interesting insights and valuable tools. Experimental and clinical studies are still needed in order to elaborate firm and founded guidelines for therapy. PMID- 20944446 TI - Motor control theories and their applications. AB - We describe several influential hypotheses in the field of motor control including the equilibrium-point (referent configuration) hypothesis, the uncontrolled manifold hypothesis, and the idea of synergies based on the principle of motor abundance. The equilibrium-point hypothesis is based on the idea of control with thresholds for activation of neuronal pools; it provides a framework for analysis of both voluntary and involuntary movements. In particular, control of a single muscle can be adequately described with changes in the threshold of motor unit recruitment during slow muscle stretch (threshold of the tonic stretch reflex). Unlike the ideas of internal models, the equilibrium-point hypothesis does not assume neural computations of mechanical variables. The uncontrolled manifold hypothesis is based on the dynamic system approach to movements; it offers a toolbox to analyze synergic changes within redundant sets of elements related to stabilization of potentially important performance variables. The referent configuration hypothesis and the principle of abundance can be naturally combined into a single coherent scheme of control of multi-element systems. A body of experimental data on healthy persons and patients with movement disorders are reviewed in support of the mentioned hypotheses. In particular, movement disorders associated with spasticity are considered as consequences of an impaired ability to shift threshold of the tonic stretch reflex within the whole normal range. Technical details and applications of the mentioned hypo-theses to studies of motor learning are described. We view the mentioned hypotheses as the most promising ones in the field of motor control, based on a solid physical and neurophysiological foundation. PMID- 20944447 TI - Linear and nonlinear heart rate dynamics in elderly inpatients. Relations with comorbidity and depression. AB - BACKGROUND: Hospitalization processes are known to increase depressive symptoms arising among elderly population. Meanwhile, dysregulation of cardiac autonomic function has been suggested to link depression and cardiovascular mortality. In this context, analysis of heart rate variability (HRV) is emerging as a powerful mortality risk stratifier clinical tool. The purpose of the study was to examine the relationship among HRV, depression, and comorbidity risk among an elderly inpatient population. MATERIAL AND METHODS: Twenty-six subjects (aged 78+/-9 years) were recruited from the Short-Term Stay Unit at the Hospital General de Alicante. Before joining a Physical Activity Program aimed to prevent functional impairment and after medical selection and written consent, inpatients were tested for heart rate variability, Yesavage Geriatric Depression Scale, and Charlson comorbidity index score. RESULTS: Men compared to women showed a significantly larger CCI score. Short-term scaling exponent (alpha(1)), derived from detrended fluctuation analysis, showed a negative correlation with Charlson comorbidity index. Conversely, a positive correlation was found between sample entropy (SampEn) and Yesavage Scale. CONCLUSIONS: On the one hand, fractal analysis of HRV confirms to be useful as a risk stratifier tool. On the other hand, SampEn is proposed to be reflecting a non-neurally generated complexity when accompanied with low values of alpha(1). Accordingly, in this regime, it would be indicative of a paradoxical gradual reduction in cardiac autonomic control, accentuated with the severity of depressive symptoms. PMID- 20944448 TI - Development and validation of a notational system to study the offensive process in football. AB - The most striking change within football development is the application of science to its problems and in particular the use of increasingly sophisticated technology that, supported by scientific data, allows us to establish a "code of reading" the reality of the game. Therefore, this study describes the process of the development and validation of an ad hoc system of categorization, which allows the different methods of offensive game in football and the interaction to be analyzed. Therefore, through an exploratory phase of the study, we identified 10 vertebrate criteria and the respective behaviors observed for each of these criteria. We heard a panel of five experts with the purpose of a content validation. The resulting instrument is characterized by a combination of field formats and systems of categories. The reliability of the instrument was calculated by the intraobserver agreement, and values above 0.95 for all criteria were achieved. Two FC Barcelona games were coded and analyzed, which allowed the detection of various T-patterns. The results show that the instrument serves the purpose for which it was developed and can provide important information for the understanding of game interaction in football. PMID- 20944449 TI - Capturing complex human behaviors in representative sports contexts with a single camera. AB - BACKGROUND AND OBJECTIVE: In the last years, several motion analysis methods have been developed without considering representative contexts for sports performance. The purpose of this paper was to explain and underscore a straightforward method to measure human behavior in these contexts. MATERIAL AND METHODS: Procedures combining manual video tracking (with TACTO device) and bidimensional reconstruction (through direct linear transformation) using a single camera were used in order to capture kinematic data required to compute collective variable(s) and control parameter(s). These procedures were applied to a 1vs1 association football task as an illustrative subphase of team sports and will be presented in a tutorial fashion. RESULTS: Preliminary analysis of distance and velocity data identified a collective variable (difference between the distance of the attacker and the defender to a target defensive area) and two nested control parameters (interpersonal distance and relative velocity). CONCLUSIONS: Findings demonstrated that the complementary use of TACTO software and direct linear transformation permit to capture and reconstruct complex human actions in their context in a low dimensional space (information reduction). PMID- 20944450 TI - Agility assessment in female futsal and soccer players. AB - Agility is the player's capability to perform rapid whole-body movement with change of velocity or direction in response to a stimulus. The aims of this study were as follows: 1) to assess the reliability of a reactive visual stimuli agility field test (RVS-T); and 2) to evaluate differences in RVS-T and planned (PVS-T) agility performances between female soccer and futsal players. MATERIAL AND METHODS: Sixty-six female players belonging to Italian teams of regional level were recruited to the study. The experimental apparatus consisted of four lighted spherical visual stimuli connected to a computer able to randomly generate three different sequences. Differences between RVS-T and PVS-T performances were calculated to evaluate the decision-making time (DMT) of players. RESULTS: The intraclass reliability coefficient for RVS-T was 0.80. Significant (P<0.05) differences emerged only for RVS-T (futsal, 17.3+/-0.5 s; soccer, 18.8+/-1.1 s) and DMT (futsal, 2.6+/-0.6 s; soccer, 4.1+/-1.2 s), whereas similar performances between groups resulted for PVS-T (futsal, 14.7+/-0.6 s; soccer, 14.6+/-0.6 s). CONCLUSIONS: The RVS-T proved to be a reliable tool to evaluate agility in field conditions. Futsal players showed better RVS-T and DMT performances with respect to soccer counterparts, probably due to the higher velocity of actions and faster decision-making of their sport. The lack of difference in PVS-T performances confirms the importance to evaluate agility capabilities of players in both planned and reactive conditions. PMID- 20944451 TI - Assessment of functional conditions of basketball and football players during the load by applying the model of integrated evaluation. AB - We consider the human body as an adaptable, complex, and dynamic system capable of organizing itself, though there is none, the only one, factor inside the system capable of doing this job. Making use of the computerized ECG analysis system "Kaunas-load" with parallel registration of ECG carrying out body motor characteristics, ABP, or other processes characterizing hemodynamics enable one to reveal and evaluate the synergistic aspects of essential systems of the human body what particularly extends the possibilities of functional diagnostics. The aim of the study was to determine the features of alterations in the functional condition of basketball and football players and nonathletes during the bicycle ergometry test by applying the model of evaluation of the functional condition of the human body. MATERIAL AND METHODS: The study population consisted of 266 healthy athletes and nonathletes. Groups of male basketball players, male football players, male nonathletes, female basketball players, and female nonathletes were studied. A computerized ECG analysis system "Kaunas-load" that is capable of both registering and analyzing the power developed by the subject and 12-lead ECG synchronically were used for evaluating the functional condition of the CVS. The subject did a computer-based bicycle ergometry test. The following ECG parameters at rest and throughout the load - HR, JT interval, and the deduced JT/RR ratio index that reflects the condition between regulatory and supplying systems - were evaluated. After measuring ABP, the pulse amplitude (S D) was evaluated. The pulse blood pressure ratio amplitude (S-D)/S that depicts the connection between the periphery and regulatory systems was also evaluated. Speeds of changes in physiological parameters during physical load were evaluated too. RESULTS: Heart rate and JT/RR ratio of athletes at the rest and during load were lower, and JT interval of rest was longer and became shorter more slowly during load, compared to that of healthy nonathletes. The pulse arterial blood pressure amplitude of men at rest and during load was higher than that of women. The pulse ABP amplitude of athletes was higher than that of nonathletes. The relative pulse ABP amplitude in the state of rest in the groups of men was higher than in groups of women. The relative pulse amplitude of female basketball players at rest and during load was higher than that of female nonathletes. Significant differences in the dynamics of speed of changes in HR, the pulse ABP amplitude, and the relative pulse ABP amplitude of male and female basketball players, male football players, as well as male and female nonathletes were observed. CONCLUSIONS: The newly deduced parameters, namely, speeds of changes in the parameters with changes in the phase of the load reflect very well peculiarities of functional condition of the human body during bicycle ergometry test. The sum total of those newly deduced parameters and customary parameters reveals new functional peculiarities of the human body. PMID- 20944452 TI - Functional state assessment on the dynamics of interparametric concatenations during exercise tests. AB - The aim of this study was to complement an analytical approach by new methodology of data sequences analysis of muscular and cardiovascular indices during the assessments of functional state. The participants of the study were 14 elite Greco-roman wrestlers and they underwent two exercise tests 30 squats per 45 s while 12-lead ECG was recorded continuously and 30-s vertical jumps test while the height, contact and flight times of each jump recorded. The parametric interactions parameters and their sequences analysis based on a mathematical method founded upon a matrix theory were applied. The obtained results enabled to identify dynamical changes of the independence of parameters or an opposite phenomenon - interaction. The dynamics of ECG or performance parameters did not allowed to find out the moments of critical changes during the exercising. The dynamics of concatenation between the time of push-off and the height of jumps while performing repeated jumps has a tendency to increase in the values of discriminant and the fluctuations at some point of jumping task comes on. Analysis of concatenation between ECG or muscle performance parameters allows distinguishing the individual peculiarities which could be in value of discriminant, in time of exercising before the fluctuations occurs, in character how the body behave as to compensate fatigue. It was concluded that assessment the dynamics of inter-parametric concatenation of physiological parameters based on the data sequences analysis provide a new approach in the field of functional state assessment allowing to reveal features of functional preparedness and fatigability during workloads. PMID- 20944453 TI - [Muscle crush injury and crush syndrome]. AB - Crush injury is defined as compression of extremities or other parts of the body that causes muscle breakdown (traumatic rhabdomyolysis). Systemic consequences of crush injuries are as follows: rhabdomyolysis, electrolyte and acid-base abnormalities, hypovolemia, and acute renal failure. Crush injuries are important injuries in disaster situations: earthquakes, hurricanes, mining and road traffic accidents, war, collapse of buildings, etc. In this review article, there are discussed about epidemiology of crush syndrome, risk factors, pathophysiology (mechanisms of muscle cell injury, release of substances from injured muscles, other consequences of reperfusion), clinical features, differential diagnosis, investigations, complications (acute renal failure, hypovolemic shock, hyperkalemia, infection, compartment syndrome), approach to treatment (adequate rehydration, a forced mannitol-alkaline diuresis, intravenous fluids, management of hyperkalemia, wound care, hyperbaric oxygen, etc.), prognosis, the mortality rate and prevention (timely support may reduce morbidity and mortality). PMID- 20944455 TI - Functional magnetic resonance imaging and estrogen effects on the brain: cautious interpretation of a BOLD finding. PMID- 20944487 TI - Pancreas is 25 years old!: the past, present, and future. PMID- 20944488 TI - 2010 American Pancreatic Association Presidential address: growth of pancreatology brings challenges and opportunities for the APA. PMID- 20944489 TI - Impact of methicillin-resistant Staphylococcus Aureus (MRSA) infection on patient outcome after pancreatoduodenectomy (PD)--a cause for concern? AB - OBJECTIVES: This study evaluated the impact of methicillin-resistant Staphylococcus aureus (MRSA) hospital-acquired infection on postoperative complications and patient outcome after pancreatoduodenectomy (PD). METHODS: Seventy-nine patients who underwent PD were monitored for hospital-acquired MRSA. The patients were grouped as (1) no MRSA infection, (2) skin colonization with MRSA, and (3) systemic MRSA infection. RESULTS: Forty (51%) of the 79 patients were MRSA positive during hospital admission. Fourteen of the 40 patients swabbed for MRSA were found positive (skin colonization), and 26 patients (33%) developed systemic MRSA infection after PD. The sites of MRSA infection included (1) abdominal drain fluid (16/26; 42%), (2) sputum (4/26; 15%), (3) blood cultures (2/26; 8%), and (4) combination of sites (9/26; 35%). The patients with systemic MRSA infection had a longer postoperative stay (31 vs 22 days; P = 0.005) and increased incidence of chest infections compared with MRSA-negative patients (14 vs 4; P = 0.02). Four of the 16 patients with MRSA-positive drain fluid had a postpancreatectomy hemorrhage compared with 3 of the 63 patients with no MRSA infection in drain fluid (P = 0.02). CONCLUSION: Of the 79 patients admitted for PD, 51% became colonized with MRSA infection. Systemic hospital-acquired MRSA infection in 33% was associated with prolonged postoperative stay, increased wound and chest infections, and increased risk of postoperative hemorrhage. PMID- 20944490 TI - Contribution of thymidylate synthase to gemcitabine therapy for advanced pancreatic cancer. AB - OBJECTIVES: Thymidylate synthase (TS) inhibitors activate human equilibrative nucleoside transporter 1. We evaluated the contribution of TS expression to determine a treatment method providing an effect from gemcitabine (GEM). METHODS: The expression of 5-fluorouracil (5-FU) and GEM metabolic factors (5-FU: TS, dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase; GEM: human equilibrative nucleoside transporter 1, deoxycytidine kinase, cytidine deaminase, 5'-nucleotidase) were studied in 7 pancreatic cancer cell lines by Western blotting, and drug resistance was evaluated by 3-[4,5-dimethylthiazol]-2,5 dephenyl tetrazolium bromide assay. The expression of 5-FU factors was observed immunohistochemically in resected pancreatic cancer specimens. RESULTS: Gemcitabine concentrations that inhibited colony formation by 50% correlated with TS protein expression (P = 0.0169). With a 5-FU non-growth-inhibiting dose, GEM concentrations that inhibited colony formation by 50% were significantly reduced by one fourth to one tenth. Knockout of TS expression by small interfering RNA decreased resistance to GEM in the cell lines (P = 0.0019). Immunohistochemically, TS expression related to disease-free survival time of patients treated with GEM (P = 0.0224). A high expression of 5-FU factors was detected: orotate phosphoribosyltransferase: differentiated cases (P = 0.0137), lower T factor (P = 0.0411); dihydropyrimidine dehydrogenase: nerve invasion (P = 0.0188), lymph node recurrence (P = 0.0253); TS, positive N factor (P = 0.0061). CONCLUSIONS: The expression of TS provides an alternative source of substrate for DNA synthesis and positively correlates with GEM resistance and shortened patient survival. PMID- 20944491 TI - Endoscopic ultrasound-guided fine-needle aspiration with liquid-based cytologic preparation in the diagnosis of primary pancreatic lymphoma. AB - OBJECTIVES: The diagnosis subtyping of lymphoma on specimens collected by endoscopic ultrasound fine-needle aspiration (EUS-FNA) can be extremely difficult. When a cytopathologist is available for the on-site evaluation, the diagnosis may be achieved by applying flow cytometric techniques. We describe our experience with immunocytochemistry (ICC) and molecular biology studies applied on EUS-FNA specimens processed with a liquid-based cytologic (LBC) preparation for the diagnosis of primary pancreatic lymphoma (PPL). METHODS: Three patients with a pancreatic mass underwent EUS-FNA. The collected specimens were processed with the ThinPrep method for the cytologic diagnosis and eventual additional investigations. RESULTS: A morphologic picture consistent with PPL was found on the LBC specimens of the 3 patients. Subsequent ICC and molecular biology studies for immunoglobulin heavy chain gene rearrangement established the diagnosis of pancreatic large B-cell non-Hodgkin lymphoma in 2 patients and a non-Hodgkin lymphoma with plasmoblastic/immunoblastic differentiation in the remaining one. CONCLUSIONS: An LBC preparation can be used to diagnose and subtype PPL by applying ICC and molecular biology techniques to specimens collected with EUS FNA. This method can be an additional processing method for EUS-FNA specimens in centers where on-site cytopathologist expertise is not available. PMID- 20944492 TI - Homocysteine and chronic pancreatitis. PMID- 20944496 TI - The changing face of Sheehan's syndrome. AB - Postpartum necrosis of the anterior pituitary gland is known as Sheehan's syndrome in honor of Harold Leeming Sheehan who characterized the syndrome as the consequence of ischemia after severe puerperal hemorrhage. With advancements of obstetrical care, Sheehan's syndrome has become uncommon except in developing countries. In many affected women, anterior pituitary dysfunction is not diagnosed for many years after the inciting delivery. This review emphasizes the long period of time that may elapse between the puerperal hemorrhage and the eventual diagnosis of hypopituitarism. The pathophysiology, epidemiology, clinical features and treatment of this disorder are discussed. PMID- 20944497 TI - Misidentification of Candida parapsilosis as C famata in a clinical case of vertebral osteomyelitis. AB - A case of vertebral osteomyelitis involving misidentification of Candida parapsilosis as C famata by the VITEK 2 compact is described. Species-specific primers were used in the polymerase chain reaction to correctly identify the clinical isolate. When uncommon species of Candida are reported using automated systems, heightened clinical suspicion is warranted. PMID- 20944498 TI - Reversible acute kidney injury caused by paroxysmal nocturnal hemoglobinuria. AB - The authors report a 57-year-old male patient who presented with diarrhea, darkened urine, jaundice and increased blood urea nitrogen and creatinine. Initially, his symptoms, which included hemolytic anemia, acute renal failure and low platelet count, seemed to be caused by renal injuries associated with thrombotic microangiopathy, hemolytic-uremic syndrome in particular. However, a renal biopsy indicated acute tubular necrosis and hemosiderin deposition. A CD55 and CD59 assay, Ham test and sugar-water hemolysis test confirmed the diagnosis of paroxysmal nocturnal hemoglobinuria. After fluid infusion, diuresis and urine alkalization, the patient gradually regained nearly normal renal function. This case illustrates that paroxysmal nocturnal hemoglobinuria may present with acute kidney injury when hemolysis, diarrhea and hemosiderin deposits in the renal tubular epithelial cells and renal tubules are present. Early diagnosis and treatment is crucial to prevent disease progression and irreversible chronic renal failure. PMID- 20944499 TI - Increasing threat of community-acquired methicillin-resistant Staphylococcus aureus. AB - INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a serious problem in the community. The objective of this prospective study was to report the frequency of community-acquired MRSA (CA-MRSA) isolates at King Fahd Hospital of the University in the Eastern Province of Saudi Arabia, to describe the spectrum of disease observed in patients infected with CA-MRSA and to study the antibiotic susceptibility profile. METHODS: Isolates of CA-MRSA from King Fahd Hospital of the University were reviewed prospectively during an 8-year period, from January 2001 to December 2008. RESULTS: The prevalence of CA-MRSA infections increased from 9.9 per 10,000 admissions in 2001 to 67 per 10,000 admissions in 2008 (P < 0.001). The number of CA-MRSA increased from 67 isolates in the first part of the study (2001-2004) to 176 cases in the second period of the study (2005-2008), and the percentage of CA-MRSA/of the total MRSA isolates rose from 20% in the first period to 59% in the second period of the study (P < 0.001). Soft tissue infections accounted for 198 (81%) of the 243 cases of CA MRSA infections and invasive infections in 14 (7%) patients. The antibiotic susceptibility pattern has also changed with increasing levels of resistance to erythromycin, tetracycline, clindamycin, ciprofloxacin and gentamicin. CONCLUSION: Continued emergence of MRSA in the community is a public-health problem that demands increased vigilance in the diagnosis and management of suspected and confirmed staphylococcal infections. PMID- 20944500 TI - Impact of estimated glomerular filtration rate after valve and combined valve and coronary surgery. AB - Preoperative renal impairment predicts postoperative mortality in patients undergoing cardiac surgery. We examined the impact of three equations for glomerular filtration rate (GFR) estimation on mortality. This is a retrospective, observational study on patients undergoing valve (n = 594) and combined valve and coronary procedures (n = 412). Glomerular filtration rate was estimated with modification in diet and renal disease (MDRD), Cockcroft-Gault (CG) equation, and Mayo-Clinic (MC) equation. Mean age was 65 +/- 11 years and mean logistic EuroSCORE was 9.0 [95% confidence interval (CI): 8.4-9.7]. Preoperative kidney dysfunction (eGFR <60 ml/min/1.73 m2) is associated with increased risk for mortality. Hazard ratios for 30-day mortality differed between eGFR equations [MC 2.6 (95% CI: 1.6-4.1); MDRD 2.9 (95% CI: 1.9-4.4); CG 3.9 (95% CI: 2.2-5.2)]. Discriminatory performance of GFR equations was comparable with logistic EuroSCORE, but CG and MC discriminated significantly better than MDRD. Median intensive care unit stay did not differ, but Bland-Altman plots showed considerable variation between eGFR equations, indicating that they cannot be used interchangeably. Substantial amount of agreement was achieved with CG and MDRD. Only one equation should be used in one institution. The bias between equations varied considerably. Impaired preoperative kidney dysfunction is associated with increased risk for mortality irrespective of the formula used. PMID- 20944501 TI - Implantation technique and early echocardiographic performance of newly designed stentless mitral bioprosthesis. AB - This article describes the implantation techniques of two new stentless mitral bioprosthesis and their early echocardiographic performance in 12 acute sheep model. The first stentless mitral bioprosthesis (stentless bileaflet valve [SBV]) was designed as a bileaflet valve with sewing ring to suture down to the native mitral annulus. The other one (SBV with chordae) has two chordae-like structures to be attached to the head of the native papillary muscles. Valvar performance and cardiac function were evaluated by epicardial echocardiography at postimplant (Rest) and during dobutamine (DOB) stimulation. Postimplant echocardiography revealed normal leaflet opening with a large orifice area and unrestricted leaflets motion. In both valves, leaflet closure showed no systolic anterior motion, prolapse, or tethering. Mitral regurgitation grade 2 or higher was not detected in any of the experiments. Transvalvar pressure gradients at Rest and DOB were 2.3 +/- 1.6 mm Hg and 2.5 +/- 2.2 mm Hg in SBV and 1.8 +/- 1.1 mm Hg and 2.3 +/- 1.2 mm Hg in SBV with chordae, respectively. Both stentless bioprosthesis showed reliable valve performance and preserved cardiac function in the acute phase. Further chronic study is needed to evaluate the reliability of implantation procedures, valvar performance, and biocompatibility. PMID- 20944502 TI - Effects of acute and repeated nicotine administration on delay discounting in Lewis and Fischer 344 rats. AB - Biological differences may underlie individual differences in impulsive behavior, such as choice for a smaller, more immediate reinforcer over a larger, more delayed reinforcer. Repeated exposure to drugs of abuse may have different effects on such behavior. To evaluate the acute and repeated effects of nicotine on impulsive choice, two strains of rats that have been shown to differ in impulsive choice were tested in a delay-discounting paradigm. Eight Lewis and eight Fischer 344 rats were allowed to choose between one food pellet delivered immediately and three food pellets delivered after a delay. The delay systematically increased in blocks of trials within each session, and the delay value at which the choice for the two alternatives was equal (i.e. the indifference point) was interpolated. Effects of nicotine (0.1-1.0 mg/kg, subcutaneous) on percent choice and indifference points were determined during the acute-testing phase and during the redetermination of effects of each dose after at least 30 sessions of repeated 1.0 mg/kg nicotine exposure. The Lewis rats had shorter indifference points (i.e. made fewer larger-reinforcer choices) compared with the Fischer 344 rats. Acute nicotine administration increased the mean larger-reinforcer choices at the 0.3 mg/kg dose in the Lewis rats and at the 1.0 mg/kg dose in the Fischer 344 rats. After repeated exposure to nicotine, indifference points returned to near-baseline (predrug) levels for both the strains. Strain differences were observed in the rates of delay discounting, and nicotine may decrease the impulsive choice acutely, but this effect does not seem to be long lasting. PMID- 20944505 TI - Effects of food insecurity on asthma outcomes in the pediatric emergency department. AB - OBJECTIVES: Food insecurity is associated with a wide variety of adverse health conditions in adults and children, but its relationship to asthma outcomes in children has not been described. The objectives of this study were to assess and characterize the food security status of an inner-city asthmatic population and to determine whether and to what extent household food insecurity is independently associated with negative clinical outcomes in children presenting to a pediatric emergency department (ED) with asthma exacerbations. METHODS: This study is a cross-sectional survey of a convenience sample of families of children presenting to an urban children's hospital ED for asthma exacerbations. Data were gathered through structured chart review and interview, including a published food insecurity questionnaire. RESULTS: A total of 127 families were enrolled, with a median patient age of 6.6 years. Of all families, 81% were black and 10% were white. Of these families, 35% met criteria for household food insecurity. 78% of food-insecure and 46% of food-secure households received food stamps. Of all food-insecure households, 67% reported never using food pantries or free community meals. 36% of food-insecure and 31% of food-secure patients lacked an adequate home supply of asthma medications. The overall admission rate was 37%; no significant difference was found in admission rate or length of stay. CONCLUSIONS: The rate of household food insecurity in families of asthmatic children presenting to an urban ED is high, with relatively low participation in a number of safety net programs. This study failed to demonstrate an association between household food insecurity and negative asthma outcomes. PMID- 20944504 TI - Psychopathology and disability in children with unexplained chest pain presenting to the pediatric emergency department. AB - OBJECTIVE: Chest pain is a common presentation in the pediatric emergency department (PED). In the majority of cases, no clear medical cause is found. Among adults with noncardiac chest pain, psychopathology including panic disorder is common. We assessed the likelihood and type of psychopathology as well as the health status of children and adolescents with unexplained chest pain who presented to the PED. METHODS: We performed a semistructured diagnostic interview of children 8 to 17 years old who presented to an urban, tertiary-care PED with a primary complaint of chest pain for which no medical cause was found. We used Diagnostic Statistical Manual of Mental Disorders, Fourth Edition criteria to diagnose psychopathology. We also assessed pain severity, extent of other somatic complaints, quality of life, and functional disability using standard, validated instruments. RESULTS: We enrolled 32 children with a mean age of 12.8 (SD, 2.9) years (range, 8-17 years); 47% were female. Twenty-six (81%) were diagnosed with a Diagnostic Statistical Manual of Mental Disorders, Fourth Edition anxiety disorder; 9 (28%) had full-criteria panic disorder. Quality of life was compromised in multiple domains, and children reported a range of functional disabilities due to chest pain. Other somatic symptoms, including other pain complaints, were commonly reported in this sample. CONCLUSION: Unexplained chest pain in the PED is frequently associated with potentially treatable anxiety disorders. Emergency physicians should consider the possibility of anxiety disorders in patients with medically unexplained chest pain. PMID- 20944503 TI - Reinforcing effects of d-amphetamine: influence of novel ratios on a progressive ratio schedule. AB - Progressive-ratio schedules are useful for studying the reinforcing effects of drugs. Earlier human laboratory studies showed that d-amphetamine significantly increased break points relative to placebo. However, the magnitude of the increase was modest, which may be attributable to rather high levels of placebo responding. We used novel response requirements in a modified progressive-ratio procedure and hypothesized that the altered range of response requirements would decrease responding for placebo and increase responding for d-amphetamine. Eight participants completed the study. The participants first sampled oral doses of d amphetamine (0, 8, 16, and 24 mg). In subsequent sessions, the participants were offered the opportunity to work for the sampled dose on a modified progressive ratio procedure with response requirements ranging from 400 to 1800 mouse clicks. A battery of participant-rated drug-effect questionnaires, a performance measure, and cardiovascular measures were included to more fully characterize the effects of d-amphetamine. Placebo maintained low levels of responding. The intermediate dose of d-amphetamine increased responding significantly above placebo levels. d Amphetamine produced prototypical subject-rated effects that were an orderly function of dose. These data suggest that the modified response requirements resulted in lower levels of placebo taking and a larger separation between the number of placebo and d-amphetamine capsules earned. PMID- 20944506 TI - Physician assessment of the likelihood of pneumonia in a pediatric emergency department. AB - BACKGROUND: The value of physical examination findings in the diagnosis of pneumonia in children may be limited, and the accuracy of physicians in predicting pneumonia is not known. OBJECTIVE: We sought to determine the correlation between physicians' assessment of the likelihood of pneumonia and radiographic presence of pneumonia. METHODS: Prospective observational study of children 21 years or younger presenting to a pediatric emergency department, who had a chest radiography performed for suspicion of pneumonia. Physicians recorded clinical findings and likelihood of pneumonia before obtaining the radiograph. Definite and probable pneumonia was defined by a radiologist's interpretation of the radiograph. RESULTS: Of 2071 children, 147 (7%) had definite radiographic pneumonia, whereas 321 (15%) had probable or definite pneumonia. Among patients perceived to be at lowest risk for pneumonia (<5% prediction), 4.3% (95% confidence interval [CI], 2.9%-5.7%) had definite pneumonia, and 10.0% (95% CI, 8.3%-12.5%) had probable or definite pneumonia. Among children perceived to be at highest risk for pneumonia (>75% prediction), 30.6% (95% CI, 15.5%-45.6%) had definite pneumonia, and 52.8% (95% CI, 37.7%-70.3%) had probable or definite pneumonia. Physicians' estimates of the likelihood of pneumonia were positively correlated with the rate of definite (Spearman rho = 0.15, P < 0.001) and probable or definite radiographic pneumonia (Spearman rho = 0.19, P < 0.001). CONCLUSIONS: With some overestimation, physicians' assessment of the likelihood of pneumonia correlates well with radiographic diagnosis of pneumonia. PMID- 20944507 TI - Emergency department utilization patterns and health care needs assessment among parents of Chinese American children in New York City. AB - A limited number of publications have addressed the health care needs of Chinese American children of recently immigrated parents. We administered a Chinese language survey to parents presenting to an urban pediatric emergency department (PED) in New York City and at community venues. The survey assessed demographics, access to health care, and utilization/expectations of the PED. Emergency Severity Index scores were recorded for emergency department patients. Three hundred fifteen families (54% in the PED) completed the survey. Of those completed in the PED, 79% sought emergency services because of pediatric referral or because their pediatrician's office was closed. Of our sickest patients with an Emergency Severity Index score of 3 or less, 28% of parents felt that the child was somewhat sick or not sick at all. Although the majority of our Chinese American families utilize the emergency department appropriately, 28% of the parents of our sickest patients did not appreciate the degree of illness of their children. PMID- 20944508 TI - "Be quick": a systems response to overcrowding in the pediatric emergency department. AB - OBJECTIVE: The purpose of this study was to evaluate the combined effects of focused system changes on several key measures of emergency department (ED) quality (length of stay, waiting time, rate of leaving without being seen, and patient satisfaction) in a children's hospital ED. METHODS: System-wide ED changes were made and implemented during a 6-month period. The combined changes are called "be quick"--BEQK. The components were bedside registration, the Bed ahead program, electronic medical records and tracking board, quick triage, and Kids Express. Three study periods were evaluated: before BEQK (2005) and the 2 periods after BEQK (2006 and 2007). RESULTS: The primary outcome measures, namely wait time, length of stay, and leaving without being seen rates, were all decreased during the 2 post-BEQK periods compared with the pre-BEQK period (2005). The mean waiting time was 46 minutes (95% confidence interval [CI], 39-53 minutes) in 2005 and this decreased to 22 minutes (95% CI, 21-23 minutes) and 14 minutes (95% CI, 13-15 minutes) in 2006 and 2007, respectively. The mean length of stay was 151 minutes (95% CI, 139-163 minutes) in 2005 and this decreased to 136 minutes (95% CI, 135-137 minutes) and 115 minutes (95% CI, 114-116 minutes) in 2006 and 2007, respectively. The rate of leaving without being seen was 2.45% of patient visits per month in 2005 and this decreased to 1.67% in 2006 and to 0.92% in 2007. CONCLUSIONS: In our pediatric ED, focused system changes significantly decreased wait time, leaving without being seen, and length of stay and improved patient satisfaction. PMID- 20944509 TI - Lights, camera, action... spotlight on trauma video review: an underutilized means of quality improvement and education. AB - BACKGROUND: Trauma video review (TVR) is an effective method of quality improvement and education. The objective of this study was to determine TVR practices in the United States and use of TVR for quality improvement and education. METHODS: Adult and pediatric trauma centers identified by the American College of Surgeons (n = 102) and the National Association of Children's Hospitals and Related Institutions (n = 24) were surveyed by telephone. Surveys included questions regarding program demographics, residency information, and past/present TVR practices. RESULTS: One hundred eight trauma centers (86%) were contacted, and 99% (107/108) completed surveys. Of the surveyed centers, 34% never used TVR; 37% previously used TVR and had discontinued at the time of the survey, with most reporting legal/privacy concerns; 20% were currently using TVR; and 9% were planning to use TVR in the future. Nineteen percent (14/73) of general trauma centers are using or planning to use TVR compared with 50% (17/34) of pediatric centers (P = 0.001). One hundred percent of current TVR programs report that TVR improves the trauma resuscitation process.Most pediatric emergency medicine (87%), emergency medicine (89%), and surgery (97%) trainees participate in trauma resuscitation at trauma centers. Fifty-two percent of centers using TVR report trainee attendance at TVR process/conference; 38% specifically use TVR for resident education. CONCLUSIONS: All current TVR programs report that it improves their trauma processes. More pediatric trauma centers report planning future TVR programs, but the implication of such plans remains unclear. Opportunities exist for expanded use of TVR for resident education. PMID- 20944510 TI - Laryngospasm during emergency department ketamine sedation: a case-control study. AB - OBJECTIVE: The objective of this study was to assess predictors of emergency department (ED) ketamine-associated laryngospasm using case-control techniques. METHODS: We performed a matched case-control analysis of a sample of 8282 ED ketamine sedations (including 22 occurrences of laryngospasm) assembled from 32 prior published series. We sequentially studied the association of each of 7 clinical variables with laryngospasm by assigning 4 controls to each case while matching for the remaining 6 variables. We then used univariate statistics and conditional logistic regression to analyze the matched sets. RESULTS: We found no statistical association of age, dose, oropharyngeal procedure, underlying physical illness, route, or coadministered anticholinergics with laryngospasm. Coadministered benzodiazepines showed a borderline association in the multivariate but not univariate analysis that was considered anomalous. CONCLUSIONS: This case-control analysis of the largest available sample of ED ketamine-associated laryngospasm did not demonstrate evidence of association with age, dose, or other clinical factors. Such laryngospasm seems to be idiosyncratic, and accordingly, clinicians administering ketamine must be prepared for its rapid identification and management. Given no evidence that they decrease the risk of laryngospasm, coadministered anticholinergics seem unnecessary. PMID- 20944511 TI - Feasibility of screening patients with nonpsychiatric complaints for suicide risk in a pediatric emergency department: a good time to talk? AB - OBJECTIVE: Screening children for suicide risk when they present to the emergency department (ED) with nonpsychiatric complaints could lead to better identification and treatment of high-risk youth. Before suicide screening protocols can be implemented for nonpsychiatric patients in pediatric EDs, it is essential to determine whether such efforts are feasible. METHODS: As part of an instrument validation study, ED patients (10-21 years old) with both psychiatric and nonpsychiatric presenting complaints were recruited to take part in suicide screening. Clinically significant suicidal thoughts, as measured by the Suicidal Ideation Questionnaire, and suicidal behaviors were assessed, as well as patient opinions about suicide screening. Recruitment rates for the study as well as impact on length of stay were assessed. RESULTS: Of the 266 patients and parents approached for the study, 159 (60%) agreed to participate. For patients entering the ED for nonpsychiatric reasons (n = 106), 5.7% (n = 6) reported previous suicidal behavior, and 5.7% (n = 6) reported clinically significant suicidal ideation. There were no significant differences for mean length of stay in the ED for nonpsychiatric patients with positive triggers and those who screened negative (means, 382 [SD, 198] and 393 [SD, 166] minutes, respectively; P = 0.80). Ninety-six percent of participants agreed that suicide screening should occur in the ED. CONCLUSIONS: Suicide screening of nonpsychiatric patients in the ED is feasible in terms of acceptability to parents, prevalence of suicidal thoughts and behaviors, practicality to ED flow, and patient opinion. Future endeavors should address brief screening tools validated on nonpsychiatric populations. PMID- 20944512 TI - Screening for developmental delay in high-risk users of an urban pediatric emergency department. AB - OBJECTIVE: To determine whether screening children in an urban pediatric emergency department (PED) would lead to identification of previously undiagnosed developmental delay. METHODS: This was a cross-sectional study of families presenting to an urban public hospital PED with children 6 to 36 months and no history of developmental delay. Children were screened for possible developmental delay using the Ages and Stages Questionnaire; parents completed an instrument that assesses 5 domains: communication, gross motor, fine motor, problem solving, and personal-social. Sociodemographic data were also obtained. RESULTS: One hundred thirty-eight children were enrolled, all accompanied by their mothers. Mean age of the children was 18.9 months; 51.5% were female; 56.8% of the mothers were high-school graduates; 59.9% were immigrants; 75.4% were Latino. Twenty-one percent did not have a regular source of primary care; 26.8% (95% confidence interval, 20.1%-34.8%) screened positive in at least 1 domain, with a trend toward the highest percentage of positive screens on the communication domain (z = 1.89, P = 0.059). In a simultaneous multiple logistic regression model including all predictor variables, child age of 12 to 30 months was associated with increased adjusted odds of positive screen (adjusted odds ratio, 8.4; 95% confidence interval, 1.4-48.9). Having a primary caregiver born in the United States was statistically significant for screening positive in at least 1 Ages and Stages Questionnaire domain (P = 0.03). CONCLUSIONS: Almost 30% of 6- to 36 month-old children presenting to an urban PED without prior developmental concerns screened positive for possible delay, suggesting the utility of performing routine developmental screening in the PED. Pediatric emergency department use alone may be an indication for screening. Further study is needed for feasibility of screening for delay in the PED. PMID- 20944513 TI - Responsibility: a guide for the foundation year doctor. PMID- 20944514 TI - The clinical examination of the thyroid gland. PMID- 20944515 TI - Radiology of acute skull and facial injuries. PMID- 20944516 TI - What is new in the third edition of the Foundation Programme Curriculum? PMID- 20944517 TI - A practical guide to undertaking out of programme experience in the United States of America. PMID- 20944518 TI - So you want to be ... a gastroenterologist. PMID- 20944519 TI - Cherry antioxidants: from farm to table. AB - The dietary consumption of fruits and vegetables is associated with a lower incidence of degenerative diseases such as cardiovascular disease and certain types of cancers. Most recent interest has focused on the bioactive phenolic compounds found in vegetable products. Sweet and sour cherries contain several antioxidants and polyphenols that possess many biological activities, such as antioxidant, anticancer and anti-inflammation properties. The review describes the effect of environment and other factors (such as production, handling and storage) on the nutritional properties of cherries, with particular attention to polyphenol compounds. Moreover the health benefits of cherries and their polyphenols against human diseases such as heart disease, cancers, diabetes are reviewed. PMID- 20944520 TI - Analysis of the chemical composition of the essential oil of Polygonum minus Huds. using two-dimensional gas chromatography-time-of-flight mass spectrometry (GC-TOF MS). AB - The essential oil in leaves of Polygonum minus Huds., a local aromatic plant, were identified by a pipeline of gas chromatography (GC) techniques coupled with mass-spectrometry (MS), flame ionization detector (FID) and two dimensional gas chromatography time of flight mass spectrometry (GC x GC-TOF MS). A total of 48 compounds with a good match and high probability values were identified using this technique. Meanwhile, 42 compounds were successfully identified in this study using GC-MS, a significantly larger number than in previous studies. GC-FID was used in determining the retention indices of chemical components in P. minus essential oil. The result also showed the efficiency and reliability were greatly improved when chemometric methods and retention indices were used in identification and quantification of chemical components in plant essential oil. PMID- 20944522 TI - The fungicidal terpenoids and essential oil from Litsea cubeba in Tibet. AB - A new C9 monoterpenoid acid (litseacubebic acid, 1) and a known monoterpene lactone (6R)-3,7-dimethyl-7-hydroxy-2-octen-6-olide (2), along with three known compounds--vanillic acid (3), trans-3,4,5-trimethoxylcinnamyl alcohol (4), and oxonantenine (5)--were isolated with bioassay-guided purification from the fruit extract of Litsea cubeba collected in Tibet. The structure of 1 was elucidated by MS, 1H-NMR, 13C-NMR, COSY, HSQC, HMBC, NOE spectral data as 2,6-dimethyl-6 hydroxy-2E,4E-hepta-2,4-diene acid. Additionally 33 compounds were identified from the essential oil of L. cubeba. The preliminary bioassay results showed that 1 and 2 have good fungicidal activities against Sclerotinia sclerotiorum, Thanatephorus cucumeris, Pseudocer-cospora musae and Colletotrichum gloeosporioides at the concentration of 588 and 272 MUM, and the essential oil has good fungicidal activities against T. cucumeris and S. sclerotiorum, with IC50 values of 115.58 and 151.25 MUg/mL, repectively. PMID- 20944523 TI - Multiple system atrophy. AB - Multiple system atrophy (MSA) is an adult-onset, progressive, neurodegenerative condition that has several different initial presentations. Ultimately affected patients develop parkinsonian features, autonomic dysfunction, cerebellar ataxia, and corticospinal deficits. Patients with MSA are often misdiagnosed as having Parkinson disease. This article discusses the epidemiology and pathophysiology of MSA, in addition to addressing clinical and diagnostic signs and symptoms, and the limited treatment options available to physicians. PMID- 20944521 TI - Potential of the dietary antioxidants resveratrol and curcumin in prevention and treatment of hematologic malignancies. AB - Despite considerable improvements in the tolerance and efficacy of novel chemotherapeutic agents, the mortality of hematological malignancies is still high due to therapy relapse, which is associated with bad prognosis. Dietary polyphenolic compounds are of growing interest as an alternative approach, especially in cancer treatment, as they have been proven to be safe and display strong antioxidant properties. Here, we provide evidence that both resveratrol and curcumin possess huge potential for application as both chemopreventive agents and anticancer drugs and might represent promising candidates for future treatment of leukemia. Both polyphenols are currently being tested in clinical trials. We describe the underlying mechanisms, but also focus on possible limitations and how they might be overcome in future clinical use--either by chemically synthesized derivatives or special formulations that improve bioavailability and pharmacokinetics. PMID- 20944525 TI - Essential tremor. AB - Essential tremor (ET) is one of the most common movement disorders. Although often considered a monosymptomatic disorder (postural and kinetic tremor), ET has more recently been considered a more heterogeneous syndrome, with motor and nonmotor features. The diagnosis is clinical and pharmacologic and surgical therapies exist. ET is frequently misdiagnosed as Parkinson disease or dystonia. The traditional notion of ET as a benign disorder has been challenged by those who view ET as a slowly progressive neurodegenerative disorder. PMID- 20944526 TI - Interface of sleep and neurologic disease. PMID- 20944527 TI - Gait dysfunction and cognition. PMID- 20944524 TI - An update on idiopathic intracranial hypertension. AB - Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology often encountered in neurologic practice. It produces nonlocalizing symptoms and signs of raised intracranial pressure and, when left untreated, can result in severe irreversible visual loss. It most commonly occurs in obese women of childbearing age, but it can also occur in children, men, nonobese adults, and older adults. Although it is frequently associated with obesity, it can be associated with other conditions, such as obstructive sleep apnea and transverse cerebral venous sinus stenoses. Recent identification of subgroups at high risk for irreversible visual loss, including black patients, men, and patients with fulminant forms of IIH, help guide the optimal management and follow-up. Ongoing studies of venous anatomy and physiology in IIH patients, as well as a recently begun randomized clinical treatment trial, should provide further insight into this common yet poorly understood syndrome. PMID- 20944528 TI - A patient with progressive weakness and cramping of right arm and both legs. Diagnosis: persistent, multifocal, partial conduction blocks (CB) of motor axons outside the common sites of nerve entrapment. AB - A 44-year-old man presented with a 1-year history of progressive muscle weakness and cramping. Neurophysiology study, along with clinical presentation, was diagnostic. The differential diagnosis, diagnostic testing, treatment, and prognosis of this rare disease are discussed. PMID- 20944529 TI - A patient with acute visual loss and transient neurologic symptoms. Diagnosis: an acute central retinal artery occlusion (CRAO) in the left eye with severe retinal ischemia. AB - A 73-year-old man presented with acute visual loss in his left eye associated with transient left upper extremity numbness. Diagnosis was made in the emergency room, where treatment strategies were discussed. PMID- 20944530 TI - Headache: occipital nerve involvement in headache. PMID- 20944533 TI - Serenoa repens in benign prostatic hypertrophy: analysis of 2 Italian studies. AB - AIM: Benign prostatic hypertrophy (BPH), which is characterized by a progressive swelling of the prostate causing symptoms of the lower urinary tract, is the second pathology as frequency among the diagnoses placed in men every year in Italy. The extract of Serenoa repens is an alternate therapeutic option to traditional drug therapies with a good profile of efficacy and safety for the management of the symptoms of BPH. The aim of this paper was to analyze systematically the results of two Italian studies carried out on patients with BPH treated with extract of serenoa repens (SABA. a product of Lampugnani Farmaceutici S.p.A.). METHODS: The studies were carried out on a total of 70 adult patients with diagnosis of benign prostatic hypertrophy. In one study the patients were treated with Serenoa repens 320 mg/day for 30 days; in the other study the patients received Serenoa repens 320 mg/day or Pygeum africanum (Tadenan) 4 capsules of 25 mg/day for 30 days. RESULTS: Both studies showed an improvement versus the baseline of about 50% of dysuria and pollakisuria, an about 50% increase in micturition rate with positive effects also in terms of reduction of the micturition rate and of prostate size. Also the tolerability profile was favorable. CONCLUSION: The extract of Serenoa repens (SABA Lampugnani Farmaceutici S.p.A.) administered at the dose of 320 mg/day to patients with benign prostatic hypertrophy, is effective in terms of improvement of the functional symptomatologic picture improvement and of the instrumental parameters with a good tolerability profile. PMID- 20944534 TI - Open partial nephrectomy with no clamping of the pedicule: a good surgical option in treatment of renal cancer. AB - AIM: The aim of the present work was to describe authors' surgical experience using the partial nephrectomy technique without intraoperatory pedicle clamping for masses even up to 4 cm of size. METHODS: The study enrolled 96 patients with an average age of 59.7 years, who underwent partial nephrectomy without pedicle clamping. The average dimensions of the masses treated were 3.7x3x3.8. In preoperative and in postoperative time creatinine, hemoglobine, hematocrit and platelets were monitored. The follow-up was of 1-3-6 months. At the third month postoperatively a renal US scan was performed, together with a control CT scan and at the sixth month of follow-up the patients underwent also a control Tc99/DMSA renal scintigraphy in back, front, oblique and right posterior oblique left rear projections. RESULTS: Surgery and anesthesia time have been respectively of 1 h 51 min e 2 h 30 min. In the postoperative time the average values were: creatinine 1.46 ng/mL (+/-0.45), hemoglobin: 11.25 g/dL (+/-1.6), hematocrit: 36.4 % (+/-3), platelets: 205 x 103 (+/-45 x 103). At follow-up at 1 3-6 months the average values were: creatinine 1.16 ng/dL (+/-0.66), hemoglobin 14.13 g/dL (+/-0.13), hematocrit 42.43% (+/-1.03), platelets 204 x 103 U/L (+/ 1.66 x103). After six months the renal function demonstrated intraparenchymal homogeneous distribution of the drug in all the patients, with a 7% of difference of relative uptake by the operated kidney than the healthy controlateral one. CONCLUSION: The partial nephrectomy without intraoperative pedicle clamping can be a good therapeutic option for the treatment of kidney cancer for masses even up to 4 cm of size. The follow-up should be longer to assess oncological results. PMID- 20944535 TI - Microscopic venous invasion is associated with disease free and cancer free survival in renal cell carcinoma. AB - AIM: The aim of this study was to investigate the significance of microscopic venous invasion (MVI) as a prognostic factor for patients with renal cell carcinoma (RCC). METHODS: The present study included 220 patients with non metastatic RCC who underwent radical nephrectomy (RN). MVI was defined by the presence of a cancer cell in blood vessels based on microscopic examination of hematoxylin-eosin stained specimens. The impact of MVI on disease progression and survival after 37 (6-190) months of median follow-up and its correlation with known clinicopathological features were studied. Survival analyses using Kaplan Meier and log-rank models for univariate comparisons and Cox proportional hazards model for multivariate analyses were performed. RESULTS: MVI was found in 68 patients (30.8%), and of these, 26 (38.2%) developed a tumor recurrence and 16 (23.5%) died of cancer progression, whereas only 18 (11.8%) of the remaining 152 patients without MVI presented with disease-recurrence and 8 (5.3%) died of cancer. In the multivariate analysis, MVI (P=0.014) Fuhrman's grade (P=0.028), and sarcomatoid differentiation (SD) (P=0.01) were the factors predicted a decreased disease-free survival (DFS). Meanwhile, MVI (P=0.04) and SD (P=0.029) were also found to be predictor of cancer specific survival (CSS) with necrosis (P=0.037) in multivariate analysis. CONCLUSION: The present study showed that MVI is associated with the vast majority of the adverse pathological features related with RCC. Furthermore, it was found to be an independent clinical prognostic factor for DFS and CSS. PMID- 20944536 TI - Overactive bladder syndrome: what is the role of evidence of detrusor overactivity in the cystometric study? AB - AIM: A prospective study was conducted on 62 female patients with overactive bladder syndrome, to check for differences in clinical profiles, subjective symptoms and urodynamic findings, between patients with or without cystometric evidence of detrusor overactivity (DO). Later both groups of women were assessed for the effect of an antimuscarinic agent, solifenacin succinate (SS), on the considered parameters. METHODS: Each patient underwent a full history, a physical examination, urinalysis and a urodynamic study. Provocative manoeuvres - cough, postural changes - were used when the cystometric study was performed. Hence two groups of patients were formed, divided according to the presence or absence of DO at the cystometric study: patients with overactive bladder syndrome (OAB) with DO (29), patients with OAB without DO (33). The two groups were compared before and after treatment with SS. RESULTS: When we compared the two groups, before treatment with SS, we saw statistically significant differences in just a few of the parameters assessed in the clinical profiles: patients with DO had a higher rate of constipation; whereas patients without DO had a higher rate of stress incontinence and a larger number of deliveries. Following treatment with SS, in both groups, significant differences were shown in subjective symptoms and urodynamic findings, with a reduction of the numbers of voids and incontinence episodes and an improved urge score. A significant increase in bladder capacity during the cystometric study was shown only in patients with DO. Whereas no statistically significant improvement was shown in patients without DO. Treatment with SS was connected with delayed involuntary detrusor contractions during cystometry and a reduction of their number and amplitude. Finally, SS did not produce any significant negative effects on detrusor function during voiding. CONCLUSION: The findings of this study suggest that it is important to conduct a urodynamic study in patients with OAB, to check for DO. In our experience, treatment with SS was shown to be effective only in patients with involuntary detrusor contractions at the cystometric study. PMID- 20944537 TI - SILS extraperitoneal radical prostatectomy. AB - AIM: This paper presents the surgical technique for video-laparoscopic extraperitoneal radical prostatectomy carried out through a single incision of 2.5 cm below the navel. METHODS: The technique involves the placement of a port of a new concept, the SILS-port, which has three channels through which you can insert instruments and camera. The study results were evaluated from the surgical, oncological and functional point of view. Ten patients undergoing prostatectomy were compared with the last 10 patients treated at our facilities with increasingly radical prostatectomy video-laparoscopic extraperitoneal, defined "conventional". RESULTS: There were no substantial differences between the two techniques, except for a modest lengthening of the operative time, at least initially. CONCLUSION: The results achieved with the adoption of this technique have shown its feasibility, security and undoubted advantages in terms of mini-invasiveness. PMID- 20944538 TI - Anterior urethroplasty and effects on sexual life: which is the best technique? AB - Established beliefs concerning outcomes following anterior urethral reconstruction are changing, both with regards to the genital cosmetics and to the impact on sexual activity. Today, the aim of stricture repair is not only to reinstate urinary function but also to safeguard sexual activity and guarantee genital cosmesis. A thorough evaluation of anterior urethroplasty results should include the sexual viewpoint which appears to play an important role in overall post-operative patient satisfaction. The most commonly reported sexual problems following anterior urethroplasty include: erectile and ejaculatory dysfunction, penile curvature or shortening, dissatisfaction with genital cosmetic appearance, sensorial impairment of glans. The prevalence of specific post-operative sexual problems may be related to the site of reconstruction (penile or bulbar) and to the technique of urethroplasty employed. In penile urethral reconstruction, the wide use of buccal mucosa grafts seems to excel the use of skin flaps which easily distort the cosmesis and elasticity of the penis. In bulbar reconstructions, graft augmentation techniques seem to impact less on sexual outcome than excision anastomotic techniques. Therefore, the policy of primarily indicating an excision anastomotic procedure, whenever possible, should come under scrutiny. Eventual sexual outcomes should be incorporated in the choice of the optimal anterior urethral reconstruction and in pre-operative patient counselling. PMID- 20944539 TI - Bladder cancer: a review of clinical management and prognostic factors. AB - Bladder cancer is a heterogeneous disease that offers a unique challenge for the patient and the physician as treatment paradigms are continually evolving. There are multiple factors that can influence how each individual is treated, including lymphovascular invasion, micropapillary histology, and p53 nuclear accumulation which have demonstrated a worse prognosis in patients with bladder cancer. They can influence the use of neoadjuvant and adjuvant chemotherapy, which in itself can affect the timing of extirpative surgery. This review will focus on the contemporary management and treatment of bladder cancer focusing on areas of clinical decision making. PMID- 20944540 TI - The use of new concepts in vascular physiology and pharmacology to improve hemodialysis access outcomes. AB - Greater insight into vascular pathophysiology and intimal hyperplasia has resulted in observational studies that suggest that interventions which decrease inflammatory mediators, improve endothelial function and inhibit smooth muscle migration and proliferation may be of benefit in improving hemodialysis vascular access survival. Longer dialysis times may also reduce inflammatory mediators and restore vascular sensitivity to endothelium dependent relaxation factor. In contrast, the common procedure of angioplasty is the experimental model to develop intimal hyperplasia and stenosis, while the efficacy of stents to prevent that stenosis in hemodialysis accesses remains controversial. Common drugs that interfere with metalloproteinases may prevent aneurysm formation while avoiding drugs that aid quorum sensing and using drugs that interfere with it may prevent biofilm infection in hemodialysis vascular catheters. Large prospective randomized studies will be needed to determine the true benefit. PMID- 20944541 TI - mTOR-inhibition in metastatic renal cell carcinoma. Focus on temsirolimus: a review. AB - The potent inhibitor of the mammalian target of rapamycin, temsirolimus, comprises for cell cycle, angiogenesis and proliferation and has proven beneficial in the treatment of advanced renal cell carcinoma (RCC). Temsirolimus is officially approved for first line therapy in high risk previously untreated mRCC patients. This review summarizes the current clinical role of temsirolimus in the treatment of advanced renal cell carcinoma with regard to pharmacological features, toxicity and tolerability. It particularily discusses quality of life issues as important outcome parameters in palliative treatment of patients with mRCC and gives an outlook on current clinical developments regarding possible future combining/ sequencing strategies of temsirolimus. PMID- 20944542 TI - Laparoendoscopic single-site surgery (LESS) prostatectomy--robotic and conventional approach. AB - This review deals with the preliminary advances in laparoendoscopic single-site surgery (LESS) as applied to prostate surgery including the simple and radical prostatectomy approaches both robot assisted and robot independent. It analyzed current publications based on animal models and human patients. The authors searched published reports in major urological meeting abstracts, Embase and Medline (1966 to 25 August 2008), with no language restrictions. Key word searches included: "prostate", "prostatectomy", "radical", "surgery", "robot", "da Vinci", "scarless", "scar free", "single port/trocar/incision", "intraumbilical", and "transumbilical", "natural orifice transluminal endoscopic surgery" (NOTES), "SILS", "OPUS" and "LESS". The role of LESS prostatectomy with or without robotic aid has been proven to be technically feasible; however, it is important to note that the approach has significant technical challenges. The da Vinci Surgical System allows some of these ergonomic challenges to be obviated with potentially reduced instrument clash, reduced surgeon and assistant fatigue and better precision with target tasking such as performing the vesicourethral anastomosis. Preliminary consensus regarding oncological control is not yet available on a large scale. Currently, no specific advantage of the LESS approach has been convincingly proven apart from the intuitive improvement in cosmesis. The development, and soon to be launched, flexible robotic platforms towards the end of 2010 will usher with it further refinements making the LESS approach to radical prostatectomy potentially more feasible ergonomically and could see the approach gain a more widespread acceptance. PMID- 20944543 TI - Current approaches to erectile dysfunction and testosterone deficiency. AB - Androgens are essential for the development of the penis and it is well known that testosterone play a critical role in the physiology of erectile function. From animal studies, testosterone insufficiency disrupts cellular-signaling pathways and induces pathologic alterations in penile tissues leading to erectile dysfunction. In human, the testosterone threshold for maintaining erection is low which explains the reason why some contracted men still have an erection due to the androgens produced by the adrenal gland. Testosterone alone can improve erectile function in hypogonadic patients. Associated with PDE5-I, testosterone supplementation is a treatment for the hypogonadic patients non responders to therapy. The article reviews the different aspects of the testosterone role in the pathophysiology of erection. PMID- 20944544 TI - Risk stratification for cardiac death in hemodialysis patients without obstructive coronary artery disease. AB - The incidence of cardiac death is higher among patients receiving dialysis compared with the general population. Although obstructive coronary artery disease is involved in cardiac deaths in the general population, deaths in hemodialysis patients occur in the apparent absence of obstructive coronary artery disease. To study this further, we prospectively enrolled 155 patients receiving hemodialysis after angiography had confirmed the absence of obstructive coronary lesions. All patients were examined by single-photon emission computed tomography using the iodinated fatty acid analog, BMIPP, the uptake of which was graded in 17 standard myocardial segments and assessed as summed scores. Insulin resistance was determined using the homeostasis model assessment index of insulin resistance (HOMA-IR). During a mean follow-up of 5.1 years, 42 patients died of cardiac events. Stepwise Cox hazard analysis associated cardiac death with reduced BMIPP uptake and increased insulin resistance. Patients were assigned to subgroups based on BMIPP summed scores and HOMA-IR cutoff values for cardiac death of 12 and 5.1, respectively, determined by receiver operating characteristic analysis. Cardiac death-free survival rates at 5 years were the lowest (32.2%) in the subgroup with both a summed score and assessment equal to or above the cutoff values compared with any other combination (52.9-98.7%) above, equal to, or below the thresholds. Thus, impaired myocardial fatty acid metabolism and insulin resistance may be associated with cardiac death among hemodialysis patients without obstructive coronary artery disease. PMID- 20944545 TI - Role of adipose tissue renin-angiotensin system in metabolic and inflammatory diseases associated with obesity. AB - Obesity is a leading cause of death worldwide because of its associated inflammatory disorders such as hypertension, cardiovascular and kidney diseases, dyslipidemia, glucose intolerance, and certain types of cancer. Adipose tissue expresses all components of the renin-angiotensin system necessary to generate angiotensin (Ang) peptides for local function. The angiotensin type 1 (AT1) and type 2 (AT2) receptors mediate the effect of Ang II and recent studies have shown that both receptors may modulate fat mass expansion through upregulation of adipose tissue lipogenesis (AT2) and downregulation of lipolysis (AT1). Thus, both receptors may have synergistic and additive effects to promote the storage of lipid in adipose tissue in response to the nutrient environment. The production of angiotensinogen (AGT) by adipose tissue in rodents also contributes to one third of the circulating AGT levels. Increased adipose tissue AGT production in the obese state may be responsible in part for the metabolic and inflammatory disorders associated with obesity. This supports the notion that besides the traditional role of Ang II produced by the liver in the control of blood pressure, Ang II produced by the adipose tissue may more accurately reflect the role of this hormone in the regulation of fat mass and associated disorders. PMID- 20944547 TI - Targeted inhibition of complement activation prevents features of preeclampsia in mice. AB - Preeclampsia is a major cause of maternal and neonatal morbidity and mortality. In mouse models, complement activation in the placenta is associated with abnormal placental development and miscarriage, and inhibiting complement prevents fetal injury. We mated two mouse strains, DBA/2 and CBA/J, expecting that the pregnancies might show features of preeclampsia and of immunologically mediated pregnancy loss. Along with placental dysfunction, these matings resulted in proteinuria, elevated BUN, fibrin deposition, and glomerular endotheliosis. We blocked placental complement activation throughout pregnancy by administering a single dose of the C3 inhibitor CR2-Crry given on day 5 of the pregnancy. This procedure specifically targets the sites of complement activation without inducing any systemic effects. Placental complement inhibition prevented oxidative stress and placental dysfunction, as well as proteinuria and renal pathologic features of preeclampsia. Thus, local blockade of complement activation at the maternal-fetal interface rescues preeclampsia in mice, and identifies new treatments. Hence, complement triggers a feed-forward cycle of placental damage, antiangiogenic factor production, and maternal vascular damage in patients. PMID- 20944548 TI - Secretin and body fluid homeostasis. AB - Body fluid homeostasis is critical for the survival of living organisms and hence is tightly controlled. From initial studies on the effects of secretin (SCT) on renal water reabsorption in the 1940s and recent investigations of its role in cardiovascular and neuroendocrine functions, it has now become increasingly clear that this peptide is an integral component of the homeostatic processes that maintain body fluid balance. This review, containing some of our recent findings of centrally expressed SCT on water intake, focuses on the actions of SCT in influencing the physiological, neuroendocrine, and cardiovascular processes that subserve body fluid homeostasis. PMID- 20944546 TI - Hyperphosphatemia-induced nanocrystals upregulate the expression of bone morphogenetic protein-2 and osteopontin genes in mouse smooth muscle cells in vitro. AB - Vascular calcification, which contributes to cardiovascular disease in patients with uremic hyperphosphatemia, is associated with vascular cell expression of osteogenic genes, including bone morphogenetic protein (BMP)-2 and osteopontin (OPN). High inorganic phosphate levels in vitro stimulate the osteogenic conversion of smooth muscle cells; however, the mechanism governing this is not clear. We found that high-phosphate medium increased the expression of BMP-2 and OPN in mouse smooth muscle cells in culture. However, this effect was lost in the presence of the mineralization inhibitor, pyrophosphate, suggesting a contribution of calcium phosphate crystals. Addition of 1-2 mmol/l phosphate alone to growth medium was sufficient to induce nanosized crystals after 1 day at 37 degrees C. Isolated crystals were about 160 nm in diameter and had a calcium to phosphate ratio of 1.35, consistent with the hydroxyapatite precursor octacalcium phosphate. Nanocrystal formation increased fourfold in the absence of serum, was blocked by fetuin-A, and was dependent on time and on the concentrations of phosphate and calcium. Purified synthetic hydroxyapatite nanocrystals and isolated high-phosphate-induced nanocrystals, but not nanocrystal-free high-phosphate medium, also induced BMP-2 and OPN. Thus, our results suggest that BMP-2 and OPN are induced by calcium phosphate nanocrystals, rather than soluble phosphate. This mechanism may contribute, in part, to hyperphosphatemia-related vascular cell differentiation and calcification. PMID- 20944549 TI - Defective glycosylation of alpha-dystroglycan contributes to podocyte flattening. AB - In addition to skeletal muscle and the nervous system, alpha-dystroglycan is found in the podocyte basal membrane, stabilizing these cells on the glomerular basement membrane. Fukutin, named after the gene responsible for Fukuyama-type congenital muscular dystrophy, is a putative glycosyltransferase required for the post-translational modification of alpha-dystroglycan. Chimeric mice targeted for both alleles of fukutin develop severe muscular dystrophy; however, these mice do not have proteinuria. Despite the lack of a functional renal defect, we evaluated glomerular structure and found minor abnormalities in the chimeric mice by light microscopy. Electron microscopy revealed flattening of podocyte foot processes, the number of which was significantly lower in the chimeric compared to wild-type mice. A monoclonal antibody against the laminin-binding carbohydrate residues of alpha-dystroglycan did not detect alpha-dystroglycan glycosylation in the glomeruli by immunoblotting or immunohistochemistry. In contrast, expression of the core alpha-dystroglycan protein was preserved. There was no statistical difference in dystroglycan mRNA expression or in the amount of nephrin and alpha3 integrin protein in the chimeric compared to the wild-type mice as judged by immunohistochemistry and real-time RT-PCR. Thus, our results indicate that appropriate glycosylation of alpha-dystroglycan has an important role in the maintenance of podocyte architecture. PMID- 20944550 TI - Chronic renal failure from lead: myth or evidence-based fact? AB - In this mini review, we would like to challenge the well-established 'fact' that lead exposure causes chronic renal failure (CRF). Even though only scarce evidence exists of the relationship between lead and renal failure, a World Health Organization Environmental Health Criteria document summarizes that 'Lead has been a very common cause of acute or chronic renal failure'. It is also written and cited in textbooks and numerous publications that chronic lead nephropathy causes a slowly progressive interstitial nephritis manifested by a reduced glomerular filtration rate, and that there is a growing consensus that lead contributes to hypertension in the general population. We will argue that, when published reports are carefully scrutinized, such statements on lead and CRF are not evidence based but are rather founded on a few narrative reports on lead exposed individuals and statistical associations between lead and serum creatinine (or urea) in a few population studies. We will, however, not argue that lead is not toxic and that lead does not cause other types of severe health effects where the evidence is unquestionable, but we do not believe that the kidneys are an early victim after lead exposure. PMID- 20944551 TI - Dicer regulates the development of nephrogenic and ureteric compartments in the mammalian kidney. AB - MicroRNAs (miRNAs) are a large and growing class of small, non-coding, regulatory RNAs that control gene expression predominantly at the post-transcriptional level. The production of most functional miRNAs depends on the enzymatic activity of Dicer, an RNase III class enzyme. To address the potential action of Dicer dependent miRNAs in mammalian kidney development, we conditionally ablated Dicer function within cells of nephron lineage and the ureteric bud-derived collecting duct system. Six2Cre-mediated removal of Dicer activity from the progenitors of the nephron epithelium led to elevated apoptosis and premature termination of nephrogenesis. Thus, Dicer action is important for maintaining the viability of this critical self-renewing progenitor pool and, consequently, development of a normal nephron complement. HoxB7Cre-mediated removal of Dicer function from the ureteric bud epithelium led to the development of renal cysts. This was preceded by excessive cell proliferation and apoptosis, and accompanied by disrupted ciliogenesis within the ureteric bud epithelium. Dicer removal also disrupted branching morphogenesis with the phenotype correlating with downregulation of Wnt11 and c-Ret expression at ureteric tips. Thus Dicer, and by inference Dicer dependent miRNA activity, have distinct regulatory roles within different components of the developing mouse kidney. Furthermore, an understanding of miRNA action may provide new insights into the etiology and pathogenesis of renal cyst based kidney disease. PMID- 20944552 TI - Patients with autosomal dominant polycystic kidney disease have elevated fibroblast growth factor 23 levels and a renal leak of phosphate. AB - Fibroblast growth factor 23 (FGF23) and parathyroid hormone blood levels rise following progressive loss of renal function. Here we measured parameters of phosphate metabolism in 100 patients with autosomal dominant polycystic kidney disease (ADPKD) in stage 1 or 2 of chronic kidney disease, 20 patients with non diabetic chronic kidney disease, and 26 with type 2 diabetes. Twenty healthy volunteers served as controls. The mean levels of FGF23 were significantly (4 fold) higher in ADPKD compared to non-diabetic and diabetic patients, and healthy volunteers. Mean serum phosphate levels were significantly lower in ADPKD patients compared to non-diabetic and diabetic patients, and the healthy volunteers. The prevalence of hypophosphatemia was 38, 25, 27, and 5% in ADPKD, non-diabetic and diabetic patients, and healthy volunteers, respectively. The tubular maximum of phosphate reabsorption per glomerular filtration rate was lowest in ADPKD patients with a significantly high positive correlation with serum phosphate levels. Estimated glomerular filtration rates were approximately 100 ml/min per 1.73 m2 in all groups and parathyroid hormone and vitamin D metabolite levels were in the normal range. Thus, FGF23 was substantially elevated in ADPKD patients compared to other CKD patients matched for glomerular filtration rate, and was associated with increased renal phosphate excretion. The mechanism for this anomaly will require further study. PMID- 20944553 TI - Cognitive and cortical plasticity deficits correlate with altered amyloid-beta CSF levels in multiple sclerosis. AB - Cognitive dysfunction is of frequent observation in multiple sclerosis (MS). It is associated with gray matter pathology, brain atrophy, and altered connectivity, and recent evidence showed that acute inflammation can exacerbate mental deficits independently of the primary functional system involved. In this study, we measured cerebrospinal fluid (CSF) levels of amyloid-beta(1-42) and tau protein in MS and in clinically isolated syndrome patients, as both proteins have been associated with cognitive decline in Alzheimer's disease (AD). In AD, amyloid-beta(1-42) accumulates in the brain as insoluble extracellular plaques, possibly explaining why soluble amyloid-beta(1-42) is reduced in the CSF of these patients. In our sample of MS patients, amyloid-beta(1-42) levels were significantly lower in patients cognitively impaired (CI) and were inversely correlated with the number of Gadolinium-enhancing (Gd+) lesions at the magnetic resonance imaging (MRI). Positive correlations between amyloid-beta(1-42) levels and measures of attention and concentration were also found. Furthermore, abnormal neuroplasticity of the cerebral cortex, explored with theta burst stimulation (TBS), was observed in CI patients, and a positive correlation was found between amyloid-beta(1-42) CSF contents and the magnitude of long-term potentiation-like effects induced by TBS. No correlation was conversely found between tau protein concentrations and MRI findings, cognitive parameters, and TBS effects in these patients. Together, our results indicate that in MS, central inflammation is able to alter amyloid-beta metabolism by reducing its concentration in the CSF and leading to impairment of synaptic plasticity and cognitive function. PMID- 20944554 TI - Electroconvulsive therapy alters dopamine signaling in the striatum of non-human primates. AB - Electroconvulsive therapy (ECT) is one of the most effective therapies for depression and has beneficial motor effects in parkinsonian patients. However, little is known about the mechanisms of therapeutic action of ECT for either condition. The aim of this work was to explore the impact of ECT on dopaminergic function in the striatum of non-human primates. Rhesus monkeys underwent a course of six ECT treatments under a human clinical protocol. Longitudinal effects on the dopaminergic nigrostriatal system were studied over 6 weeks using the in vivo capabilities of positron emission tomography (PET). PET scans were performed prior to the onset of ECT treatments and at 24-48 h, 8-10 days, and 6 weeks after the final ECT treatment. Early increases in dopamine transporter and vesicular monoamine transporter 2 binding returned to baseline levels by 6 weeks post-ECT. Transient increases in D1 receptor binding were also observed, whereas the binding potential to D2 receptors was unaltered. The increase in dopaminergic neurotransmission suggested by our results may account in part for the therapeutic effect of ECT in mood disorders and Parkinson's disease. PMID- 20944555 TI - Role of dopamine D1 receptors in the activation of nucleus accumbens extracellular signal-regulated kinase (ERK) by cocaine-paired contextual cues. AB - Exposure to drug-paired cues can trigger addicts to relapse into drug seeking. Although the molecular mechanisms underlying cue-elicited cocaine seeking are incompletely understood, the protein kinase extracellular signal-regulated kinase (ERK) is known to have an important role. Psychostimulants and their associated cues can activate ERK in medium spiny neurons of the nucleus accumbens core (AcbC). These medium spiny neurons can be classified according to their projections (to ventral pallidum and/or substantia nigra) and by their mRNA expression. The present experiments were designed to determine which distinct set of AcbC projection neurons expresses phosphorylated ERK (pERK) in response to cocaine-paired contextual cues. Combined use of the retrograde label Flurogold with immunohistochemical staining of pERK was used to show that the AcbC pERK accompanying preference for cocaine-paired contexts occurs in both the accumbens (Acb)-nigral and Acb-pallidal projections. The gene expression characteristics of the neurons expressing pERK in response to cocaine-paired cues was further investigated using combined in situ hybridization and immunocytochemistry to show that AcbC pERK+ cells correspond to D1, but not preproenkephalin, mRNA+ cells. Furthermore, intra-AcbC infusion of the D1-antagonist SCH23390 attenuated cue induced AcbC pERK expression. In aggregate, these results indicate that (i) the D1-expressing AcbC neurons evidence long-term plasticity related to drug-cue memories and (ii) local dopamine D1 receptors are necessary for the expression of cocaine-paired cue-induced pERK in these AcbC neurons. PMID- 20944556 TI - Mucosal administration of the B subunit of E. coli heat-labile enterotoxin promotes the development of Foxp3-expressing regulatory T cells. AB - Understanding the processes by which certain mucosal pathogens and their products induce regulatory T cells (Tregs) is important in determining mechanisms of pathogenicity and may point toward their use in treating immunological disorders. Accordingly, we have studied the events that follow mucosal administration of the B subunit of E. coli heat-labile enterotoxin (EtxB). EtxB modulates the response to co-administered antigens and can prevent autoimmune disease. Our data show that EtxB translocates across the nasal epithelium, modulating the expression of interleukin-10 (IL-10) and transforming growth factor-beta(1) (TGF-beta(1)). The modulated microenvironment drives an increase in Forkhead box P3 (Foxp3)-positive T cells, predominantly in the CD4(+)CD25(-) subset. Adoptive transfer experiments showed that enhanced Foxp3 expression was particularly evident in recently activated T cells by concomitant unrelated antigen challenge, and was both TGF beta(1) and IL-10 dependent. This ability to alter T-cell differentiation pathways following mucosal delivery explains how EtxB may modify mucosal immune environments and prevent unwanted pathologies. PMID- 20944557 TI - Adaptive immunity in the host-microbiota dialog. AB - The intestinal tract represents the largest mucosal surface and is a major site of multifaceted interactions between the host mucosal immune system and components of the intestinal microbiota. Host immune responses to the commensal microbiota are tightly controlled and, meanwhile, the microbiota actively shapes intestinal immune responses to itself. Appreciation of these interactions during health and disease may direct therapeutic approaches to a broad range of autoimmune and inflammatory disorders in humans. In this review, we will discuss findings on how the intestinal immune system, especially adaptive immune cells, helps accommodate the large number of resident bacteria, and in turn how the microbiota shapes intestinal immune responses to achieve mutualism. PMID- 20944558 TI - Interleukin-25 production is differently regulated by TNF-alpha and TGF-beta1 in the human gut. AB - An altered balance between effector and regulatory factors is supposed to sustain the tissue-damaging immune response in inflammatory bowel disease (IBD). We have recently shown that in IBD, there is a defective synthesis of the counter regulatory cytokine, interleukin (IL)-25. In this study we investigated factors that control IL-25 production in the gut. IBD patients produced less IL-25 when compared with normal controls. Stimulation of normal intestinal explants with tumor necrosis factor-alpha (TNF-alpha), but not interferon-gamma (IFN-gamma) or IL-21, reduced IL-25 synthesis. Consistently, IL-25 production was enhanced by anti-TNF-alpha both in vitro and in vivo. Upregulation of IL-25 was also seen in normal colonic explants stimulated with transforming growth factor-beta1 (TGF beta1). As in IBD, TGF-beta1 activity is abrogated by Smad7, we next assessed whether inhibition of Smad7 with an antisense oligonucleotide enhanced IL-25 expression. Knockdown of Smad7 was accompanied by an increase in IL-25 production. Data show that IL-25 production is differently regulated by TNF-alpha and TGF-beta1 in the human gut. PMID- 20944560 TI - Enrichment of clinical study populations. AB - Those who conduct clinical trials "enrich" study populations in a variety of ways in order to identify a population of patients in whom a drug effect, if present, is more likely to be demonstrable. The principal ways to do this are as follows: (i) practical enrichment, i.e., generally seeking to reduce noise (variability of measurement) and heterogeneity (by avoiding the enrollment of patients with other diseases and individuals in whom the disease disappears spontaneously), (ii) prognostic enrichment, i.e., finding patients who are likely to have the event of interest when enrolling for risk-reduction studies, and (iii) predictive enrichment, i.e., finding the individuals who are more likely to respond. Enrichment fits well into the growing interest in "individualization" of therapy but creates some tension with another trend, namely, the desire for "real-world studies" with less restrictive entry criteria and other requirements. PMID- 20944559 TI - Helicobacter hepaticus infection in mice: models for understanding lower bowel inflammation and cancer. AB - Pioneering work in the 1990s first linked a novel microaerobic bacterium, Helicobacter hepaticus, with chronic active hepatitis and inflammatory bowel disease in several murine models. Targeted H. hepaticus infection experiments subsequently demonstrated its ability to induce colitis, colorectal cancer, and extraintestinal diseases in a number of mouse strains with defects in immune function and/or regulation. H. hepaticus is now widely utilized as a model system to dissect how intestinal microbiota interact with the host to produce both inflammatory and tolerogenic responses. This model has been used to make important advances in understanding factors that regulate both acquired and innate immune response within the intestine. Further, it has been an effective tool to help define the function of regulatory T cells, including their ability to directly inhibit the innate inflammatory response to gut microbiota. The complete genomic sequence of H. hepaticus has advanced the identification of several virulence factors and aided in the elucidation of H. hepaticus pathogenesis. Delineating targets of H. hepaticus virulence factors could facilitate novel approaches to treating microbially induced lower bowel inflammatory diseases. PMID- 20944561 TI - Progress and prospects in treating postmenopausal vaginal atrophy. AB - Anatomically described as a "potential space," the vagina is a highly estrogen responsive organ, and its biology changes dramatically at menopause. After menopause, many women experience vaginal dryness and/or dyspareunia, which are caused primarily by regression of the vaginal epithelium.Unlike vasomotor symptoms, which typically resolve overtime, vaginal atrophy remains a persistent consequence of the menopausal transition. This article discusses current trends and potential future treatments that may improve choices for menopausal and postmenopausal women. PMID- 20944562 TI - Probabilistic risk analysis: improving early drug development decision making. AB - Model-based drug development (MBDD) is advocated by industry, academia, and regulatory agencies as a powerful tool to improve the efficiency of drug development. Clinical pharmacologists play key roles in implementing MBDD because of their ability to integrate mechanistic, preclinical, and clinical information, using quantitative approaches to address the complex questions arising during drug development. Use of probabilistic risk analysis (PRA) approaches (e.g., value of information, combining uncertain information, and modeling expert opinion) can improve the implementation of MBDD. PMID- 20944563 TI - Teetering on the brink. AB - The US Congress must authorize federal funding of human embryonic stem cell research. PMID- 20944564 TI - Geron trial resumes, but standards for stem cell trials remain elusive. PMID- 20944566 TI - US courts throw ES cell research into disarray. PMID- 20944567 TI - Roche backs Aileron's stapled peptides. PMID- 20944572 TI - Genzyme resumes shipping as Sanofi-aventis hovers. PMID- 20944573 TI - Cancer research fund launches biologics pilot plant. PMID- 20944575 TI - Monsanto relaxes restrictions on sharing seeds for research. PMID- 20944577 TI - Newsmaker: Constellation Pharmaceuticals. AB - Replete with investor funds, the Cambridge, Massachusetts-based epigenetics firm is taking aim at methylases anddemethylases linked to disease. PMID- 20944578 TI - Drug pipeline: Q310. PMID- 20944579 TI - Turning the tide in lung cancer. AB - Researchers are testing a slew of targeted therapeutic strategies in lung cancer. Signs are emerging that these therapies are gaining increasing traction in what has long been one of oncology's minefields. Malorye Allison investigates. PMID- 20944580 TI - At the heart of genetic testing. AB - Genetic testing for rare heart conditions might someday expand to more common cardiac ailments. Already there are signs testing is dramatically changing how some conditions are treated and doctors' definition of who a patient is. Stephen Strauss reports. PMID- 20944581 TI - Safe and effective synthetic biology. PMID- 20944582 TI - The regulatory bottleneck for biotech specialty crops. PMID- 20944583 TI - ProHits: integrated software for mass spectrometry-based interaction proteomics. PMID- 20944584 TI - More sizzle than fizzle. PMID- 20944585 TI - The path less costly. AB - When faced with a competitive threat, two companies took diametrically opposite approaches. Both were ultimately successful, but Genzyme's decision proved to be the cleaner and cheaper option. PMID- 20944586 TI - Faculty and employee ownership of inventions in Australia. AB - A recent Australian legal decision means that, unless faculty members are bound by an assignment or intellectual property policy, they may own inventions resulting from their research. PMID- 20944588 TI - Timing is everything in the human embryo. AB - A noninvasive imaging method for predicting how human embryos will develop may improve the success and safety of in vitro fertilization. PMID- 20944589 TI - Taking the measure of the methylome. AB - Two comparative studies from the International Human Epigenome Project find high concordance between different methods for measuring genomic methylation. PMID- 20944590 TI - Tracing cancer networks with phosphoproteomics. PMID- 20944592 TI - Making a mark. AB - High-throughput technologies are enabling epigenetic modifications to be mapped on a genome-wide scale, but whether such knowledge can be rapidly translated into biomedical applications remains unclear. PMID- 20944593 TI - Linking cell signaling and the epigenetic machinery. AB - One of the biggest gaps in our knowledge about epigenomes is how their interplay with cellular signaling influences development, adult cellular differentiation and disease. PMID- 20944594 TI - Tackling the epigenome: challenges and opportunities for collaboration. AB - What are the key considerations to take into account when large-scale epigenomics projects are being implemented? PMID- 20944595 TI - The NIH Roadmap Epigenomics Mapping Consortium. AB - The NIH Roadmap Epigenomics Mapping Consortium aims to produce a public resource of epigenomic maps for stem cells and primary ex vivo tissues selected to represent the normal counterparts of tissues and organ systems frequently involved in human disease. PMID- 20944596 TI - Epigenomics reveals a functional genome anatomy and a new approach to common disease. AB - Epigenomics provides the context for understanding the function of genome sequence, analogous to the functional anatomy of the human body provided by Vesalius a half-millennium ago. Much of the seemingly inconclusive genetic data related to common diseases could therefore become meaningful in an epigenomic context. PMID- 20944597 TI - Putting epigenome comparison into practice. AB - Comparative analysis of epigenomes offers new opportunities to understand cellular differentiation, mutation effects and disease processes. But the scale and heterogeneity of epigenetic data present numerous computational challenges. PMID- 20944598 TI - Epigenetic modifications and human disease. AB - Epigenetics is one of the most rapidly expanding fields in biology. The recent characterization of a human DNA methylome at single nucleotide resolution, the discovery of the CpG island shores, the finding of new histone variants and modifications, and the unveiling of genome-wide nucleosome positioning maps highlight the accelerating speed of discovery over the past two years. Increasing interest in epigenetics has been accompanied by technological breakthroughs that now make it possible to undertake large-scale epigenomic studies. These allow the mapping of epigenetic marks, such as DNA methylation, histone modifications and nucleosome positioning, which are critical for regulating gene and noncoding RNA expression. In turn, we are learning how aberrant placement of these epigenetic marks and mutations in the epigenetic machinery is involved in disease. Thus, a comprehensive understanding of epigenetic mechanisms, their interactions and alterations in health and disease, has become a priority in biomedical research. PMID- 20944599 TI - Epigenetic modifications as therapeutic targets. AB - Epigenetic modifications work in concert with genetic mechanisms to regulate transcriptional activity in normal tissues and are often dysregulated in disease. Although they are somatically heritable, modifications of DNA and histones are also reversible, making them good targets for therapeutic intervention. Epigenetic changes often precede disease pathology, making them valuable diagnostic indicators for disease risk or prognostic indicators for disease progression. Several inhibitors of histone deacetylation or DNA methylation are approved for hematological malignancies by the US Food and Drug Administration and have been in clinical use for several years. More recently, histone methylation and microRNA expression have gained attention as potential therapeutic targets. The presence of multiple epigenetic aberrations within malignant tissue and the abilities of cells to develop resistance suggest that epigenetic therapies are most beneficial when combined with other anticancer strategies, such as signal transduction inhibitors or cytotoxic treatments. A key challenge for future epigenetic therapies will be to develop inhibitors with specificity to particular regions of chromosomes, thereby potentially reducing side effects. PMID- 20944607 TI - Portfolio managing for scientists. PMID- 20944601 TI - Genomics tools for unraveling chromosome architecture. AB - The spatial organization of chromosomes inside the cell nucleus is still poorly understood. This organization is guided by intra- and interchromosomal contacts and by interactions of specific chromosomal loci with relatively fixed nuclear 'landmarks' such as the nuclear envelope and the nucleolus. Researchers have begun to use new molecular genome-wide mapping techniques to uncover both types of molecular interactions, providing insights into the fundamental principles of interphase chromosome folding. PMID- 20944609 TI - Science masterclass. PMID- 20944600 TI - Epigenetic modifications in pluripotent and differentiated cells. AB - Epigenetic modifications constitute a complex regulatory layer on top of the genome sequence. Pluripotent and differentiated cells provide a powerful system for investigating how the epigenetic code influences cellular fate. High throughput sequencing of these cell types has yielded DNA methylation maps at single-nucleotide resolution and many genome-wide chromatin maps. In parallel to epigenome mapping efforts, remarkable progress has been made in our ability to manipulate cell states; ectopic expression of transcription factors has been shown to override developmentally established epigenetic marks and to enable routine generation of induced pluripotent stem (iPS) cells. Despite these advances, many fundamental questions remain. The roles of epigenetic marks and, in particular, of epigenetic modifiers in development and in disease states are not well understood. Although iPS cells appear molecularly and functionally similar to embryonic stem cells, more genome-wide studies are needed to define the extent and functions of epigenetic remodeling during reprogramming. PMID- 20944610 TI - Anthropocene man. PMID- 20944611 TI - The family naturalist. PMID- 20944612 TI - Thinking in aeons. PMID- 20944613 TI - Working at the coal face. PMID- 20944614 TI - Timeline: Lindau and the zeitgeist. PMID- 20944615 TI - Life in science: Generation X-change. PMID- 20944616 TI - Science in the digital age. PMID- 20944617 TI - Introduction: Curiosity aroused. PMID- 20944618 TI - Event: Turning the tables. PMID- 20944619 TI - A runaway success. PMID- 20944620 TI - The joy of discovery. PMID- 20944621 TI - Science brick by brick. PMID- 20944622 TI - Nothing to fear from mistakes. PMID- 20944623 TI - The frontier physicist. PMID- 20944624 TI - Politics and prophecy. PMID- 20944625 TI - Pericytes are required for blood-brain barrier integrity during embryogenesis. AB - Vascular endothelial cells in the central nervous system (CNS) form a barrier that restricts the movement of molecules and ions between the blood and the brain. This blood-brain barrier (BBB) is crucial to ensure proper neuronal function and protect the CNS from injury and disease. Transplantation studies have demonstrated that the BBB is not intrinsic to the endothelial cells, but is induced by interactions with the neural cells. Owing to the close spatial relationship between astrocytes and endothelial cells, it has been hypothesized that astrocytes induce this critical barrier postnatally, but the timing of BBB formation has been controversial. Here we demonstrate that the barrier is formed during embryogenesis as endothelial cells invade the CNS and pericytes are recruited to the nascent vessels, over a week before astrocyte generation. Analysing mice with null and hypomorphic alleles of Pdgfrb, which have defects in pericyte generation, we demonstrate that pericytes are necessary for the formation of the BBB, and that absolute pericyte coverage determines relative vascular permeability. We demonstrate that pericytes regulate functional aspects of the BBB, including the formation of tight junctions and vesicle trafficking in CNS endothelial cells. Pericytes do not induce BBB-specific gene expression in CNS endothelial cells, but inhibit the expression of molecules that increase vascular permeability and CNS immune cell infiltration. These data indicate that pericyte-endothelial cell interactions are critical to regulate the BBB during development, and disruption of these interactions may lead to BBB dysfunction and neuroinflammation during CNS injury and disease. PMID- 20944626 TI - Single-molecule analysis of Mss116-mediated group II intron folding. AB - DEAD-box helicases are conserved enzymes involved in nearly all aspects of RNA metabolism, but their mechanisms of action remain unclear. Here, we investigated the mechanism of the DEAD-box protein Mss116 on its natural substrate, the group II intron ai5gamma. Group II introns are structurally complex catalytic RNAs considered evolutionarily related to the eukaryotic spliceosome, and an interesting paradigm for large RNA folding. We used single-molecule fluorescence to monitor the effect of Mss116 on folding dynamics of a minimal active construct, ai5gamma-D135. The data show that Mss116 stimulates dynamic sampling between states along the folding pathway, an effect previously observed only with high Mg(2+) concentrations. Furthermore, the data indicate that Mss116 promotes folding through discrete ATP-independent and ATP-dependent steps. We propose that Mss116 stimulates group II intron folding through a multi-step process that involves electrostatic stabilization of early intermediates and ATP hydrolysis during the final stages of native state assembly. PMID- 20944627 TI - Pericytes regulate the blood-brain barrier. AB - The blood-brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS). The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes, but the relative contribution of these different components to the BBB remains largely unknown. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB. PMID- 20944628 TI - Higher rates of sex evolve in spatially heterogeneous environments. AB - The evolution and maintenance of sexual reproduction has puzzled biologists for decades. Although this field is rich in hypotheses, experimental evidence is scarce. Some important experiments have demonstrated differences in evolutionary rates between sexual and asexual populations; other experiments have documented evolutionary changes in phenomena related to genetic mixing, such as recombination and selfing. However, direct experiments of the evolution of sex within populations are extremely rare (but see ref. 12). Here we use the rotifer, Brachionus calyciflorus, which is capable of both sexual and asexual reproduction, to test recent theory predicting that there is more opportunity for sex to evolve in spatially heterogeneous environments. Replicated experimental populations of rotifers were maintained in homogeneous environments, composed of either high- or low-quality food habitats, or in heterogeneous environments that consisted of a mix of the two habitats. For populations maintained in either type of homogeneous environment, the rate of sex evolves rapidly towards zero. In contrast, higher rates of sex evolve in populations experiencing spatially heterogeneous environments. The data indicate that the higher level of sex observed under heterogeneity is not due to sex being less costly or selection against sex being less efficient; rather sex is sufficiently advantageous in heterogeneous environments to overwhelm its inherent costs. Counter to some alternative theories for the evolution of sex, there is no evidence that genetic drift plays any part in the evolution of sex in these populations. PMID- 20944629 TI - Satellite phage TLCphi enables toxigenic conversion by CTX phage through dif site alteration. AB - Bacterial chromosomes often carry integrated genetic elements (for example plasmids, transposons, prophages and islands) whose precise function and contribution to the evolutionary fitness of the host bacterium are unknown. The CTXphi prophage, which encodes cholera toxin in Vibrio cholerae, is known to be adjacent to a chromosomally integrated element of unknown function termed the toxin-linked cryptic (TLC). Here we report the characterization of a TLC-related element that corresponds to the genome of a satellite filamentous phage (TLC Knphi1), which uses the morphogenesis genes of another filamentous phage (fs2phi) to form infectious TLC-Knphi1 phage particles. The TLC-Knphi1 phage genome carries a sequence similar to the dif recombination sequence, which functions in chromosome dimer resolution using XerC and XerD recombinases. The dif sequence is also exploited by lysogenic filamentous phages (for example CTXphi) for chromosomal integration of their genomes. Bacterial cells defective in the dimer resolution often show an aberrant filamentous cell morphology. We found that acquisition and chromosomal integration of the TLC-Knphi1 genome restored a perfect dif site and normal morphology to V. cholerae wild-type and mutant strains with dif(-) filamentation phenotypes. Furthermore, lysogeny of a dif(-) non-toxigenic V. cholerae with TLC-Knphi1 promoted its subsequent toxigenic conversion through integration of CTXphi into the restored dif site. These results reveal a remarkable level of cooperative interactions between multiple filamentous phages in the emergence of the bacterial pathogen that causes cholera. PMID- 20944630 TI - Fighting Babel with precise definitions of knowledge. PMID- 20944634 TI - New insights into the mechanism of narrow-band UVB therapy for psoriasis. PMID- 20944635 TI - Collapse of immune privilege in alopecia areata: coincidental or substantial? AB - Only indirect evidence supports the concept that a collapse of immune privilege (IP) in hair follicles leads to the development of alopecia areata (AA). In this issue, Kang et al. provide further evidence to support this theory, demonstrating downregulation of the expression of several genes important for the immunosuppressive environment in lesional and perilesional areas of AA. PMID- 20944636 TI - A nuclear function for plakophilin-1 in the DNA damage response? AB - Plakophilins are proteins of the desmosomal plaque. Based on the observation that plakophilins localize not only to desmosomes but also to the cytoplasm and nucleus, additional functions in cell signaling have been proposed. In this issue, Sobolik-Delmaire et al. address the nuclear function of Plakophilin-1. The authors show that Plakophilin-1 interacts with ssDNA in vitro and may have a function in protecting cells from DNA damage. PMID- 20944637 TI - IL-17: important for host defense, autoimmunity, and allergy? AB - In this issue, Milovanovic and colleagues present evidence that IL-17a enhances IgE production, although the precise mechanism remains unclear. Their initial finding was that higher numbers of IL-17a-producing CD4(+) T cells were observed after polyclonal stimulation in a largely airway allergic population. These data add to the evidence that atopic disorders such as asthma and, possibly, atopic dermatitis (AD) may have distinct immunologic phenotypes. The hope is that by characterizing the immunologic basis of these common diseases we will be able to understand the heterogeneity observed in natural history, response to treatments, susceptibility to infections, genetic risk factors, and associations with other atopic disorders. PMID- 20944638 TI - Comparison of angiotensin II type 1-receptor blockers to regress pressure overload-induced cardiac hypertrophy in mice. AB - Angiotensin II (AngII) type 1-receptor blockers (ARBs) have been effectively used not only in the treatment of hypertension but also in cardiac protection. However, whether and why there are differences in these effects still remain unclear. Here we compared the effects of five commonly used ARBs (Candesartan, Olmesartan, Losartan, Telmisartan and Valsartan) on pressure overload-induced cardiac hypertrophy in mice model. Pressure overload was produced by constriction of the transverse aorta (TAC) for 2 weeks, which induced a significant elevation of blood pressure; ARBs or saline was administered through a stomach tube; Cardiac hypertrophy was evaluated by transthoracic echocardiography, cardiac histology and specific gene expression analyses. Although all the five ARBs, which did not repress the elevation of left ventricular pressure after TAC, attenuated the development of cardiac hypertrophy in the wild-type mice, the degrees of regression by Candesartan, Olmesartan and Losartan tended to be larger than those by Telmisartan and Valsartan. Furthermore, in angiotensinogen-knockout mice lacking endogenous AngII, TAC-induced cardiac hypertrophy was regressed by Candesartan, Olmesartan and Losartan but not by Telmisartan and Valsartan administration. Our data suggest that Candesartan, Olmesartan and Losartan can effectively inhibit pressure overload-induced cardiac hypertrophy even in the absence of AngII, whereas Telmisartan and Valsartan could exert the inhibitory effects only in the presence of AngII. PMID- 20944639 TI - Marked cerebral atrophy is correlated with kidney dysfunction in nondisabled adults. AB - The relationship between kidney dysfunction, such as chronic kidney disease (CKD), and brain morphology has attracted increasing attention, but the association between kidney dysfunction and cerebral atrophy has yet to be determined. The purpose of this study was to clarify the relationship between kidney function and a substantial degree of cerebral atrophy. A total of 610 consecutive Japanese adults without neurological disorders who had undergone health screening tests of the brain were studied prospectively. Magnetic resonance imaging was performed using a 1.5-T scanner. Using a computer-assisted processing system, the percentage of cerebrum atrophy (%Cerebrum atrophy) was calculated as an index of cerebral atrophy. Atrophy was defined as >2 s.d.s below the mean %Cerebrum atrophy. The glomerular filtration rate (GFR) was estimated using the revised equations for estimated GFR from serum creatinine in Japan. Kidney function variables included the GFR value and the prevalence of subjects with GFR <60 ml min-1 per 1.73 m2. Cerebral atrophy was found in 25 (4.1%) cases. Univariate analysis showed that age, male sex, hypertension, each kidney function variable, white matter hyperintensities and lacunae were associated with cerebral atrophy. On logistic regression analysis, GFR (odds ratio (OR), 0.64; 95% confidence interval (CI), 0.42-0.98) and GFR <60 ml min-1 per 1.73 m2 (OR, 5.93; 95% CI, 1.82-19.27) were significantly associated with cerebral atrophy. On sub analysis, GFR <60 ml min-1 per 1.73 m2 was significantly associated with cortical atrophy (OR, 3.23; 95% CI, 1.15-9.11). Decreased GFR was significantly associated with cerebral atrophy, indicating that treatment of CKD may control age-related degenerative processes of the brain. PMID- 20944640 TI - Connective tissue growth factor induction in a pressure-overloaded heart ameliorated by the angiotensin II type 1 receptor blocker olmesartan. AB - Connective tissue growth factor (CTGF) is a secreted protein that regulates fibrosis. We hypothesized that CTGF is induced in a pressure-overloaded (PO) heart and that blocking the angiotensin II type 1 receptor would reduce CTGF expression. Accordingly, we administered olmesartan and compared its effects with other antihypertensive drugs in a PO heart. CTGF induction was determined in a rat PO model, and olmesartan, hydralazine or saline was continuously administered. The effects of olmesartan on CTGF induction, myocyte hypertrophy and fibrosis were evaluated. The effect of olmesartan on cardiac function was also examined in CTGF- and transforming growth factor-beta 1 (TGF-beta1)-infused rats. CTGF was increased in the PO heart 3 days after aortic banding and was markedly distributed around the perivascular fibrotic area. After 28 days, blood pressure was not significantly different in the olmesartan and hydralazine groups, but olmesartan treatment reduced CTGF distribution in PO hearts. Olmesartan was associated with a significantly reduced myocyte hypertrophy index (4.77+/-0.48 for olmesartan and 6.05+/-1.45 for saline, P<0.01), fibrosis area (32.0+/-15.5% compared with the saline group, P<0.05) and serum TGF-beta1 level (62.6+/-10.6 ng ml-1 for olmesartan and 84.4+/-7.2 ng ml-1 for hydralazine, P<0.05). In addition, cardiac function was significantly preserved in the olmesartan group compared with the saline group. Finally, olmesartan ameliorated the cardiac dysfunction in CTGF- and TGF-beta1-infused rats. Olmesartan attenuated CTGF induction, reduced perivascular fibrosis and ameliorated cardiac dysfunction in a PO heart. Our results provide insight into the beneficial effects of olmesartan on PO hearts, independent of blood-pressure lowering. PMID- 20944641 TI - ACE inhibitors in cardiac surgery: current studies and controversies. AB - Major complications associated with cardiac surgery are still common and carry great prognostic significance. Current medical interventions to prevent these cardiovascular complications include antiplatelet therapy, statins, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors. Both experimental studies and clinical trials have shown that ACE inhibitors hold promise as cardiovascular protective agents for cardiac surgery patients. Several lines of evidence support this hypothesis. First, long-term use of ACE inhibitors has been well established to provide cardiovascular protection and reduce ischemic events and complications, independent of their effect on heart function and blood pressure. Second, early ACE inhibitor therapy has been demonstrated to produce remarkable survival and heart function benefits in patients with acute myocardial infarction. Third, ACE blockage can prevent or delay the development or progression of renal disease at all stages, from subclinical microalbuminuria to end-stage renal disease. Nevertheless, perioperative studies of the effects of ACE inhibitors remain few and inconclusive. Results from recent clinical trials and observational studies are conflicting and raise more questions than answers. Further studies, both retrospective and larger-scale prospective studies, are critically needed to examine whether ACE inhibitors reduce mortality and major complications in patients undergoing cardiac surgery. PMID- 20944642 TI - A Japanese trichothiodystrophy patient with XPD mutations. AB - Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by sulfur-deficient brittle hair complicated with ichthyosis, physical and mental retardation, and proneness to infections. Approximately half of TTD patients exhibit cutaneous photosensitivity because of the defect of nucleotide excision repair. Three genes, XPB, XPD and TTDA, have been identified as causative genes of photosensitive TTD. These three genes are components of basal transcription factor IIH. Most TTD cases have been reported in Europe and North America. We report a severely affected Japanese TTD patient with XPD mutations. Interestingly, his father has ichthyotic skin. The alteration in the paternal allele was a nucleotide substitution leading to Arg-722 to Trp (R722W), as previously reported in TTD patients. The other alteration in the maternal allele was a novel 3-bp deletion at nucleotides 67-69, resulting in the deletion of Ser 23, which is located upstream of helicase motif I and is the closest to the N terminal end of XPD in reported mutations. The expression study showed that the two alterations were causative mutations for TTD. In Asia, it is likely that there are TTD patients who have not been diagnosed. PMID- 20944643 TI - Characterization of a mutation commonly associated with persistent stuttering: evidence for a founder mutation. AB - Stuttering is a disorder that affects the fluency of speech. It has been shown to have high heritability and has recently been linked to mutations in the GNPTAB gene. One such mutation, Glu1200Lys, has been repeatedly observed in unrelated families and individual cases. Eight unrelated individuals carrying this mutation were analyzed in an effort to distinguish whether these arise from repeated mutation at the same site, or whether they represent a founder mutation with a single origin. Results show that all 12 chromosomes carrying this mutation share a common haplotype in this region, indicating that it is a founder mutation. Further analysis estimated the age of this allele to be ~ 572 generations. Construction of a cladogram tracing the mutation through our study sample also supports the founder mutation hypothesis. PMID- 20944644 TI - Genotype-phenotype associations and human eye color. AB - Although eye color is usually modeled as a simple, Mendelian trait, further research and observation has indicated that eye color does not follow the classical paths of inheritance. Eye color phenotypes demonstrate both epistasis and incomplete dominance. Although there are about 16 different genes responsible for eye color, it is mostly attributed to two adjacent genes on chromosome 15, hect domain and RCC1-like domain-containing protein 2 (HERC2) and ocular albinism (that is, oculocutaneous albinism II (OCA2)). An intron in HERC2 contains the promoter region for OCA2, affecting its expression. Therefore, single-nucleotide polymorphisms in either of these two genes have a large role in the eye color of an individual. Furthermore, with all genetic expression, aberration also occurs. Some individuals may express two phenotypes--one in each eye--or a complete lack of pigmentation, ocular albinism. In addition, the evolutionary and population roles of the different expressions are significant. PMID- 20944645 TI - Identification of exonic cis-elements regulating the alternative splicing of scleroderma-associated lysyl hydroxylase 2 mRNA. PMID- 20944646 TI - siRNA knockdown of ribonucleotide reductase inhibits melanoma cell line proliferation alone or synergistically with temozolomide. AB - Systemically delivered small interfering RNA (siRNA) therapies for cancer have begun clinical development. The effects of siRNA-mediated knockdown of ribonucleotide reductase subunit-2 (RRM2), a rate-limiting enzyme in cell replication, were investigated in malignant melanoma, a cancer with a paucity of effective treatment options. A panel of human melanoma cell lines was transfected with siRNA to induce the knockdown of RRM2. Sequence-specific, siRNA-mediated inhibition of RRM2 effectively blocked cell proliferation and induced G1/S-phase cell cycle arrest. This effect was independent of the activating oncogenic mutations in the tested cell lines. Synergistic inhibition of melanoma cell proliferation was achieved using the combination of siRNA targeting RRM2 and temozolomide, an analog of the current standard of care for melanoma chemotherapy. In conclusion, siRNA-mediated RRM2 knockdown significantly inhibits proliferation of melanoma cell lines with different oncogenic mutations with synergistic enhancement in combination with temozolomide. PMID- 20944647 TI - Nevi, family history, and fair skin increase the risk of second primary melanoma. AB - Although risk factors for primary cutaneous melanoma are well defined, relatively little is known about predictors for second primary melanoma. Given the rising incidence of this cancer, coupled with improvements in survival, there is a prevalent and growing pool of patients at risk of second primary melanomas. To identify the predictors of second primary melanoma, we followed a cohort of 1,083 Queensland patients diagnosed with incident melanoma between 1982 and 1990 and who completed a baseline questionnaire. During a median follow-up of 16.5 years, 221 patients were diagnosed with at least one additional primary melanoma. In multivariate analyses, second primary melanomas were associated with high nevus count (hazard ratio (HR), 2.91; 95% confidence interval (CI) 1.94-4.35), high familial melanoma risk (HR, 2.12; 95% CI 1.34-3.36), fair skin (HR, 1.51; 95% CI 1.06-2.16), inability to tan (HR, 1.66; 95% CI 1.13-2.43), an in situ first primary melanoma (HR, 1.36; 95% CI 0.99-1.87), and male sex (HR, 1.49; 95% CI 1.12-2.00). Patients whose first primary was lentigo maligna melanoma (HR, 1.80; 95% CI 1.05-3.07) or nodular melanoma (HR, 2.13; 95% CI 1.21-3.74) had higher risks of subsequent primaries than patients whose first primary tumor was superficial spreading melanoma. These characteristics could be assessed in patients presenting with first primary melanoma to evaluate risk of developing a second primary. PMID- 20944648 TI - Effects of IGF-binding protein 5 in dysregulating the shape of human hair. AB - The hair follicle has a unique dynamic property to cyclically regenerate throughout life. Despite significant progress in hair structure and hair shape determination using animal models, the mechanisms controlling the architecture and the shape of the human hair remain largely unexplored. In this study, comparison of the genetic expression of several human genes, especially those involved in growth, development, and differentiation, between Caucasian curly hair and naturally straight hair was performed. Thereafter, analyses using human recombinant and lentiviral vector technologies were conducted to further dissect and elucidate a molecular mechanism that regulates hair growth and development, particularly in controlling the shape of the hair shaft. Overexpression of IGF binding protein 5 (IGFBP-5) in the human hair xenografts obtained from straight- and curly-haired individuals was found to result in the decreased expression of several extracellular matrix proteins and disassembly of adhesional junctions, resulting in twisted hair shafts as well as an unusual deposition of hair cuticle that may be derived from the disturbance of normal proliferation and differentiation. This study provides evidence that IGFBP-5 has an effect on human hair shape, and that lentiviral transduction regimen can be used for functional analysis of genes involved in human hair morphogenesis. PMID- 20944649 TI - Mechanical and metabolic injury to the skin barrier leads to increased expression of murine beta-defensin-1, -3, and -14. AB - Protection of the skin against microbiological infection is provided by the permeability barrier and by antimicrobial proteins. We asked whether the expression of murine beta-defensins (mBDs)-1, -3, and -14-orthologs of human beta defensins hBD-1, -2, and -3, respectively--is stimulated by mechanically/physicochemically (tape stripping or acetone treatment) or metabolically (essential fatty acid-deficient (EFAD) diet) induced skin barrier dysfunction. Both methods led to a moderate induction of mBD-1 and mBD-14 and a pronounced induction of mBD-3 mRNA. Protein expression of the mBDs was increased as shown by immunohistology and by western blotting. Artificial barrier repair by occlusion significantly reduced the increased expression of mBD-14 after mechanical injury and of all three mBDs in EFAD mice, supporting an interrelationship between permeability and the antimicrobial barrier. mBD-3 expression was stimulated in vitro by tumor necrosis factor-alpha (TNF-alpha), and a neutralizing anti-TNF-alpha antibody significantly reduced increased mBD-3 expression after barrier injury in mouse skin, indicating that induction of mBD-3 expression is mediated by cytokines. The expression of mBD-14 was stimulated by transforming growth factor-alpha and not by TNF-alpha. In summary, we demonstrated upregulation of mBD1, -3, and -14 after mechanically and metabolically induced skin barrier disruption, which may be an attempt to increase defense in the case of permeability barrier dysfunction. PMID- 20944650 TI - Risk factors for bullous pemphigoid in the elderly: a prospective case-control study. AB - A rise in the incidence of bullous pemphigoid (BP) was documented recently in Europe, and the main risk factors for BP remain unknown. We conducted a multicenter case-control study to evaluate risk factors for BP. We identified 201 incident BP cases and 345 controls individually matched for age, gender, center, and place of residence (home, nursing home, or extended-care facility). We used univariate and multivariate logistic regression analyses to compare drugs used for over 3 months, comorbidities, and physical and cognitive impairments between cases and controls. Mean age of BP patients was 84.2 (+/-8.7) years. Factors independently associated with BP by multivariate analysis were major cognitive impairment (odds ratio (OR), 2.19; 95% confidence interval (95% CI), 1.24-3.87), bedridden condition (OR, 2.19; 95% CI, 1.23-3.89), Parkinson's disease (OR, 2.16; 95% CI, 1.09-4.27), unipolar or bipolar disorder (OR, 5.25; 95% CI, 1.21-22.86), and chronic use of spironolactone (OR, 2.30; 95% CI, 1.20-4.46) or phenothiazines with aliphatic side chains (OR, 3.70; 95% CI, 1.21-11.34). Chronic analgesic use was associated with a lower risk of BP (OR, 0.49; 95% CI, 0.30-0.81). Thus, risk factors for BP include neurological disorders, particularly dementia and Parkinson's disease, psychiatric disorders (unipolar and bipolar disorders), bedridden condition, and chronic use of several drugs. PMID- 20944651 TI - Sun-induced nonsynonymous p53 mutations are extensively accumulated and tolerated in normal appearing human skin. AB - Here we demonstrate that intermittently sun-exposed human skin contains an extensive number of phenotypically intact cell compartments bearing missense and nonsense mutations in the p53 tumor suppressor gene. Deep sequencing of sun exposed and shielded microdissected skin from mid-life individuals revealed that persistent p53 mutations had accumulated in 14% of all epidermal cells, with no apparent signs of a growth advantage of the affected cell compartments. Furthermore, 6% of the mutated epidermal cells encoded a truncated protein. The abundance of these events, not taking into account intron mutations and mutations in other genes that also may have functional implications, suggests an extensive tolerance of human cells to severe genetic alterations caused by UV light, with an estimated annual rate of accumulation of ~35,000 new persistent protein altering p53 mutations in sun-exposed skin of a human individual. PMID- 20944652 TI - Activated Kras alters epidermal homeostasis of mouse skin, resulting in redundant skin and defective hair cycling. AB - Germline mutations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway are associated with genodermatoses, characterized by cutaneous, cardiac, and craniofacial defects, and cancer predisposition. Whereas activating mutations in HRAS are associated with the vast majority of patients with Costello syndrome, mutations in its paralog, KRAS, are rare. To better understand the disparity among RAS paralogs in human syndromes, we generated mice that activate a gain-of function Kras allele (Lox-Stop-Lox (LSL)-Kras(G12D)) in ectodermal tissue using two different Cre transgenic lines. Using Msx2-Cre or ligand-inducible keratin 15 (K15)-CrePR, the embryonic effects of activated Kras were bypassed and the effects of Kras(G12D) expression from its endogenous promoter were determined. We found that Kras(G12D) induced redundant skin, papillomas, shortened nails, and hair loss. Redundant skin was associated with basal keratinocyte hyperplasia and an increase in body surface area. Paradoxically, Kras(G12D) also prevented hair cycle activation. We find that Kras(G12D) blocks proliferation in the bulge region of the hair follicle, when activated through Msx2-Cre but not through K15 CrePR. These studies reveal that KRAS, although infrequently involved in RAS/MAPK syndromes, is capable of inducing multiple cutaneous features that grossly resemble human RAS/MAPK syndromes. PMID- 20944653 TI - Core outcome domains for controlled trials and clinical recordkeeping in eczema: international multiperspective Delphi consensus process. AB - There is wide variation in the use of outcome measures for eczema. We performed a three-stage web-based international Delphi exercise to develop consensus-based sets of core outcome domains for eczema for "controlled trials" and "clinical recordkeeping". A total of 57 individuals from four stakeholder groups (consumers, clinical experts, regulatory agency representatives, and journal editors) representing 13 countries were asked to rate the importance of 19 outcome domains for eczema and to choose which domains should be included in two core sets of outcomes. Forty-six individuals (81%) participated. Participants received standardized feedback, including the group median, interquartile range, and previous responses, and the assessment was repeated in two subsequent rounds. We defined consensus a priori if at least 60% of the members of at least three stakeholder groups, including consumers, recommended domain inclusion in the core set. Consensus was achieved for inclusion of symptoms, physician-assessed clinical signs, and a measurement for long-term control of flares in the core set of outcome domains for eczema trials. We recommend including these three core outcomes in future eczema trials in order to enhance clinical interpretability and to enable meta-analyses across different studies. For recordkeeping, consensus was reached to regularly monitor eczema symptoms in clinical practice. Future work is needed to select which existing or new scales should be used to measure the domains identified as relevant for the core set. PMID- 20944654 TI - The farnesyl transferase inhibitor lonafarnib inhibits mTOR signaling and enforces sorafenib-induced apoptosis in melanoma cells. AB - Farnesyl transferase inhibitors (FTIs) inhibit the farnesylation of proteins, including RAS and RHEB (Ras homolog enriched in brain). RAS signals to the RAF MEK-ERK (MAPK) and PI3K-AKT-mTOR (AKT) signaling pathways, which have a major role in melanoma progression. RHEB positively regulates mammalian target of rapamycin (mTOR). We investigated the effects of the FTI lonafarnib alone and in combination with MAPK (mitogen-activated protein kinase) or AKT (acutely transforming retrovirus AKT8 in rodent T-cell lymphoma) pathway inhibitors on proliferation, survival, and invasive tumor growth of melanoma cells. Lonafarnib alone did not sufficiently inhibit melanoma cell growth. Combinations of lonafarnib with AKT pathway inhibitors did not significantly increase melanoma cell growth inhibition. In contrast, combinations of lonafarnib with MAPK pathway inhibitors yielded additional growth-inhibiting effects. In particular, the combination of the FTI lonafarnib with the pan-RAF inhibitor sorafenib synergistically inhibited melanoma cell growth, significantly enhanced sorafenib induced apoptosis, and completely suppressed invasive tumor growth in monolayer and organotypic cultures, respectively. Apoptosis induction was associated with upregulation of the endoplasmic reticulum stress-related transcription factors p8 and CHOP (CAAT/enhancer binding protein (C/EBP) homologous protein), and downregulation of the antiapoptotic Bcl-2 (B-cell lymphoma-2) family protein Mcl 1(myeloid cell leukemia 1). Lonafarnib did not affect MAPK and AKT but did affect mTOR signaling. Together, these findings suggest that the FTI lonafarnib inhibits mTOR signaling and enforces sorafenib-induced apoptosis in melanoma cells and may therefore represent an effective alternative for melanoma treatment. PMID- 20944656 TI - Focusing on glaucoma progression and the clinical importance of progression rate measurement: a review. AB - PURPOSE: This review aims to provide guidance in managing glaucoma patients more effectively. It focuses on the importance of detecting progression and measuring its rate within the management of primary open-angle glaucoma today. Recent findings strongly indicate that continued monitoring of visual fields (VFs) and reassessment of target intraocular pressures (IOPs) depending on VF progression rates are mandatory in the management of glaucoma. METHODS: Data on glaucoma progression from older as well as most recent literature findings are summarized in this article. In addition, the article elaborates on the scientific content from a series of lectures given by experts in the field during several international symposia on 'rate of progression' in 2008. RESULTS: This review summarizes key findings on the natural history of glaucoma and known factors for disease progression. It highlights the visual function changes observed as glaucoma progresses and discusses disease impact on patients' quality of life. Findings support the need to obtain information on rate of progression and its importance for clinical management. Practical ways to measure rate of progression are given by new software options to help measure major parameters. Finally, on the basis of a patient's individual rate of progression therapeutic options are assessed, such as maximum medical therapy with fixed combinations. CONCLUSIONS: Estimating a patient's individual rate of VF progression by using newly developed analyses will be helpful to forecast the potential future development of the glaucoma. An individualized treatment approach then requires that in patients in whom the risk of becoming visually impaired or blind during their lifetime is higher, a more intensive medical IOP-lowering therapy such as fixed combinations can be considered as treatment option. PMID- 20944655 TI - RXRalpha ablation in epidermal keratinocytes enhances UVR-induced DNA damage, apoptosis, and proliferation of keratinocytes and melanocytes. AB - We show here that keratinocytic nuclear receptor retinoid X receptor-alpha (RXRalpha) regulates mouse keratinocyte and melanocyte homeostasis following acute UVR. Keratinocytic RXRalpha has a protective role in UVR-induced keratinocyte and melanocyte proliferation/differentiation, oxidative stress mediated DNA damage, and cellular apoptosis. We discovered that keratinocytic RXRalpha, in a cell-autonomous manner, regulates mitogenic growth responses in skin epidermis through secretion of heparin-binding EGF-like growth factor, GM CSF, IL-1alpha, and cyclooxygenase-2 and activation of mitogen-activated protein kinase pathways. We identified altered expression of several keratinocyte-derived mitogenic paracrine growth factors such as endothelin 1, hepatocyte growth factor, alpha-melanocyte stimulating hormone, stem cell factor, and fibroblast growth factor-2 in skin of mice lacking RXRalpha in epidermal keratinocytes (RXRalpha(ep-/-) mice), which in a non-cell-autonomous manner modulated melanocyte proliferation and activation after UVR. RXRalpha(ep-/-) mice represent a unique animal model in which UVR induces melanocyte proliferation/activation in both epidermis and dermis. Considered together, the results of our study suggest that RXR antagonists, together with inhibitors of cell proliferation, can be effective in preventing solar UVR-induced photocarcinogenesis. PMID- 20944657 TI - Replication of top markers of a genome-wide association study in multiple sclerosis in Spain. AB - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with presumed autoimmune origin, triggered by genetic and environmental risk factors. A recent genome-wide association study conducted on MS identified new biallelic markers outside the HLA (human leucocyte antigen) region involved in disease susceptibility: rs1109670 (DDEF2); rs1458175 (PDZRN4); rs1529316 and rs2049306 (CSMD1); rs16914086 (TBC1D2); rs1755289 (SH3GL2); rs1841770 (ZIC1); rs651477 (EN1); rs7607490 (TRIB2); rs397020 (C20orf46); rs908821 (SLC25A36); rs7672826 (MGC45800) and rs9523762 (GPC5). We aimed at replicating these top association signals in a Spanish cohort of 2863 MS patients and 2930 sex- and age matched controls. Only rs9523762 mapping in the GPC5 gene was significantly associated (G allele, P=1.6 * 10(-5); odds ratio (95% confidence interval)=1.23 (1.12-1.36)), supporting a role for this proteoglycan in MS predisposition. The independent replication of association signals to validate data generated by genome-wide association scans is a first step in the effort to improve patient care. PMID- 20944658 TI - Impact of type 2 diabetes on left ventricular geometry and diastolic function in hypertensive patients with chronic kidney disease. AB - Left ventricular hypertrophy (LVH) and diastolic dysfunction are very common in patients with chronic kidney disease (CKD). Aim of this study was to evaluate the impact of type 2 diabetes on LV geometry and diastolic function in hypertensive patients with CKD. We enrolled 288 Caucasian subjects with hypertension and CKD; of them, 112 had diabetes. Patients with cardiovascular (CV) diseases, glomerular filtration rate (GFR) >60 ml min(-1) per 1.73 m(2), dialysis treatment and other major non-CV diseases were excluded. All patients underwent routine biochemical analyses and echocardiographic examination with tissue Doppler imaging (TDI). Patients with diabetes had significantly higher LV wall thicknesses (P=0.0001), relative wall thickness (RWT) (P=0.0001) and left atrium volume index (P=0.03), when compared with patients without diabetes. Further, diabetic patients had very high prevalence of concentric LVH. Em, evaluated by TDI, was significantly lower in patients with diabetes (P=0.005). However, the difference lost statistical significance after correction by analysis of covariance for RWT. Multiple stepwise linear regression analysis showed that the variables independently associated with Em were: age (beta 0.364; P=0.0001), GFR (beta 0.101; P=0.019), and the presence of diabetes (beta 0.166; P=0.002). Our study showed that in hypertensive patients with CKD the presence of diabetes is associated with increased LV-wall thicknesses and concentric geometry; further, diabetes together with renal function (GFR) is associated with worse diastolic function, independently of potential confounders, such as age, gender, body mass index and blood pressure. PMID- 20944659 TI - The relationship between inflammation, obesity and risk for hypertension in the Multi-Ethnic Study of Atherosclerosis (MESA). AB - It has been suggested that inflammation is important in the aetiology of hypertension and that this may be most relevant among obese persons. To study this, we examined the independent relationships between obesity, inflammation related proteins (interleukin-6 (IL-6), C-reactive protein (CRP) and fibrinogen) and risk for hypertension in the Multi-Ethnic Study of Atherosclerosis (MESA). Hypertension status, defined as a blood pressure >=140/90 mm Hg or a history of hypertension and use of blood pressure medications, was determined at baseline and two subsequent exams over 5 years. Among 3543 non-hypertensives at baseline, 714 individuals developed incident hypertension by Exam 3. Cox proportional hazard models were used to determine the relationship between baseline levels of IL-6, CRP and fibrinogen and future risk of hypertension. One s.d. difference in baseline concentration of IL-6, CRP or fibrinogen was associated with 20-40% greater risk of incident hypertension. This risk was attenuated after accounting for other hypertension risk factors (hazard ratio (HR) IL-6: 1.13 (95% CI: 1.04 1.23); CRP: 1.11 (95% CI: 1.02-1.21); fibrinogen 1.0 (95% CI: 0.92-1.08)). Conversely, obesity was an independent risk factor for hypertension risk, minimally impacted by other covariates, including IL-6 and CRP (HR 1.72 (95% CI: 1.36-2.16)). IL-6 and CRP did not modify the relationship between obesity and hypertension, though an adjusted twofold greater risk was observed for obese individuals with a CRP >3 mg l-1 compared with CRP <1 mg l-1. The relationship between inflammation-related proteins and hypertension risk was predominantly explained by other hypertension risk factors. Obesity, independent of inflammation, remained a potent risk factor for future hypertension. PMID- 20944660 TI - SNP-by-fitness and SNP-by-BMI interactions from seven candidate genes and incident hypertension after 20 years of follow-up: the CARDIA Fitness Study. AB - The association of single nucleotide polymorphisms (SNPs) from seven candidate genes, including genotype-by-baseline fitness and genotype-by-baseline body mass index (BMI) interactions, with incident hypertension over 20 years was investigated in 2663 participants (1301 blacks, 1362 whites) of the Coronary Artery Risk Development in Young Adults Study (CARDIA). Baseline cardiorespiratory fitness was determined from duration of a modified Balke treadmill test. A total of 98 SNPs in blacks and 89 SNPs in whites from seven candidate genes were genotyped. Participants that became hypertensive (295 blacks and 146 whites) had significantly higher blood pressure and BMI (both races), and lower fitness (blacks only) at baseline than those who remained normotensive. Markers at the peroxisome proliferative activated receptor gamma coactivator 1alpha (PPARGC1A) and bradykinin beta2 receptor (BDKRB2) genes were nominally associated with greater risk of hypertension, although one marker each at the BDKRB2 and endothelial nitric oxide synthase-3 (NOS3) genes were nominally associated with lower risk. The association of baseline fitness with risk of hypertension was nominally modified by genotype at markers within the angiotensin converting enzyme, angiotensinogen, BDKRB2 and NOS3 genes in blacks and the BDKRB2, endothelin-1 and PPARGC1A genes in whites. BDKRB2 rs4900318 showed nominal interactions with baseline fitness on the risk of hypertension in both races. The association of baseline BMI with risk of hypertension was nominally modified by GNB3 rs2301339 genotype in whites. None of the above associations were statistically significant after correcting for multiple testing. We found that SNPs in these candidate genes did not modify the association between baseline fitness or BMI and risk of hypertension in CARDIA participants. PMID- 20944661 TI - Diabetic heart disease: the story continues. PMID- 20944663 TI - The dual role of the extracellular matrix in synaptic plasticity and homeostasis. AB - Recent studies have deepened our understanding of multiple mechanisms by which extracellular matrix (ECM) molecules regulate various aspects of synaptic plasticity and have strengthened a link between the ECM and learning and memory. New findings also support the view that the ECM is important for homeostatic processes, such as scaling of synaptic responses, metaplasticity and stabilization of synaptic connectivity. Activity-dependent modification of the ECM affects the formation of dendritic filopodia and the growth of dendritic spines. Thus, the ECM has a dual role as a promoter of structural and functional plasticity and as a degradable stabilizer of neural microcircuits. Both of these aspects are likely to be important for mental health. PMID- 20944662 TI - Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease. AB - Progressive loss of the ascending dopaminergic projection in the basal ganglia is a fundamental pathological feature of Parkinson's disease. Studies in animals and humans have identified spatially segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. In patients with Parkinson's disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour. These patients may therefore be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum. Thus, many of their behavioural difficulties may reflect a loss of normal automatic control owing to distorting output signals from habitual control circuits, which impede the expression of goal-directed action. PMID- 20944664 TI - Engineering the perfect (bacterial) cancer therapy. AB - Bacterial therapies possess many unique mechanisms for treating cancer that are unachievable with standard methods. Bacteria can specifically target tumours, actively penetrate tissue, are easily detected and can controllably induce cytotoxicity. Over the past decade, Salmonella, Clostridium and other genera have been shown to control tumour growth and promote survival in animal models. In this Innovation article I propose that synthetic biology techniques can be used to solve many of the key challenges that are associated with bacterial therapies, such as toxicity, stability and efficiency, and can be used to tune their beneficial features, allowing the engineering of 'perfect' cancer therapies. PMID- 20944665 TI - The genesis and evolution of high-grade serous ovarian cancer. AB - Germline mutation in either BRCA1 or BRCA2 is associated with an increased risk of ovarian cancer, particularly the most common invasive histotype - serous carcinoma. In addition, serous ovarian cancers have an unusually high frequency of other molecular events involving BRCA pathway dysfunction. Recent findings show a high frequency of TP53 mutation, chromosomal instability, distinct molecular subtypes and DNA copy number-driven changes in gene expression. These findings suggest a model in which homologous recombination repair deficiency initiates a cascade of molecular events that sculpt the evolution of high-grade serous ovarian cancer and dictate its response to therapy. PMID- 20944668 TI - Circadian rhythms: PARP1 feeds into clocks. PMID- 20944666 TI - Generating and navigating proteome maps using mass spectrometry. AB - Proteomes, the ensembles of all proteins expressed by cells or tissues, are typically analysed by mass spectrometry. Recent technical and computational advances have greatly increased the fraction of a proteome that can be identified and quantified in a single study. Current mass spectrometry-based proteomic strategies have the potential to reproducibly, accurately, quantitatively and comprehensively measure any protein or whole proteomes from cells and tissues at different states. Achieving these goals will require complete proteome maps and analytical strategies that use these maps as prior information and will greatly enhance the impact of proteomics on biological and clinical research. PMID- 20944669 TI - Protein degradation: time for trimming. PMID- 20944670 TI - Refined cytogenetic-risk categorization for overall and leukemia-free survival in primary myelofibrosis: a single center study of 433 patients. AB - We have previously identified sole +9, 13q- or 20q-, as 'favorable' and sole +8 or complex karyotype as 'unfavorable' cytogenetic abnormalities in primary myelofibrosis (PMF). In this study of 433 PMF patients, we describe additional sole abnormalities with favorable (chromosome 1 translocations/duplications) or unfavorable (-7/7q-) prognosis and also show that other sole or two abnormalities that do not include i(17q), -5/5q-, 12p-, inv(3) or 11q23 rearrangement are prognostically aligned with normal karyotype, which is prognostically favorable. These findings were incorporated into a refined two-tired cytogenetic-risk stratification: unfavorable and favorable karyotype. The respective 5-year survival rates were 8 and 51% (hazard ratio (HR): 3.1, 95% confidence interval (CI): 2.2-4.3; P<0.0001). Multivariable analysis confirmed the International Prognostic Scoring System (IPSS)-independent prognostic value of cytogenetic-risk categorization and also identified thrombocytopenia (platelets <100 * 10(9)/l) as another independent predictor of inferior survival (P<0.0001). A similar multivariable analysis showed that karyotype (P=0.001) and platelet count (P=0.04), but not IPSS (P=0.27), predicted leukemia-free survival; the 5-year leukemic transformation rates for unfavorable versus favorable karyotype were 46 and 7% (HR: 5.5, 95% CI: 2.5-12.0; P<0.0001). This study provides the rationale and necessary details for incorporating cytogenetic findings and platelet count in future prognostic models for PMF. PMID- 20944671 TI - Implementation of array based whole-genome high-resolution technologies confirms the absence of secondary copy-number alterations in MLL-AF4-positive infant ALL patients. PMID- 20944667 TI - Cellular strategies for controlling protein aggregation. AB - The aggregation of misfolded proteins is associated with the perturbation of cellular function, ageing and various human disorders. Mounting evidence suggests that protein aggregation is often part of the cellular response to an imbalanced protein homeostasis rather than an unspecific and uncontrolled dead-end pathway. It is a regulated process in cells from bacteria to humans, leading to the deposition of aggregates at specific sites. The sequestration of misfolded proteins in such a way is protective for cell function as it allows for their efficient solubilization and refolding or degradation by components of the protein quality-control network. The organized aggregation of misfolded proteins might also allow their asymmetric distribution to daughter cells during cell division. PMID- 20944672 TI - Low prevalence of IDH1 gene mutation in childhood AML in Italy. PMID- 20944674 TI - Complete remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post-transplant relapsed acute lymphoblastic leukemia. PMID- 20944673 TI - Follicular lymphoma cell niche: identification of a preeminent IL-4-dependent T(FH)-B cell axis. AB - Follicular lymphoma (FL) B cells contract tight connections with their microenvironment, which governs the pathogenesis and progression of the disease. Indeed, specific immune response gene signatures, obtained from whole biopsy samples, have been associated with patient survival. In this study, we performed gene expression profiling of purified B cell and non-B cell compartments obtained from FL and reactive lymph nodes. We identified 677 non-redundant genes defining the FL interface and involving 26 FL-specific functional networks. This approach highlighted an interleukin-4 (IL-4)-centered pathway associated with an activation of signal transducer and activator of transcription 6 (STAT6), which favors overexpression of IL-4-target genes. In addition, FL microenvironment was characterized by a strong enrichment in follicular helper T cells (T(FH)), as demonstrated through transcriptomic and flow cytometry analyses. The majority of phospho-STAT6(pos) B cells were located at the vicinity of cells expressing the programmed death 1 (PD-1) T(FH) marker. Moreover, purified FL-derived T(FH), expressed IL4 at very high levels compared with purified tonsil-derived T(FH) or non-T(FH) microenvironment. Altogether, our study demonstrated that tumor infiltrating T(FH) specifically express functional IL-4 in FL, creating an IL-4 dependent T(FH)-B cell axis. This cross talk could sustain FL pathogenesis and represent a new potential therapeutic target. PMID- 20944675 TI - The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the ALL-BFM 2000 protocol can be separated from FBXW7 loss of function. AB - Precursor T-cell acute lymphoblastic leukemia (T-ALL) remains an important challenge in pediatric oncology. Because of the particularly poor prognosis of relapses, it is vital to identify molecular risk factors allowing early and effective treatment stratification. Activating NOTCH1 mutations signify a favorable prognosis in patients treated on ALL-BFM protocols. We have now tested if NOTCH pathway activation at different steps has similar clinical effects and if multiple mutations in this pathway function synergistically. Analysis of a validation set of 151 T-ALL patients and of the total cohort of 301 patients confirms the low relapse rate generally and the overall favorable effect of activating NOTCH1 mutations. Subgroup analysis shows that the NOTCH1 effect in ALL-BFM is restricted to patients with rapid early treatment response. Inactivation of the ubiquitin ligase FBXW7 is associated with rapid early treatment response and synergizes with NOTCH1 receptor activation. However, the effect of FBXW7 inactivation is separable from NOTCH1 activation by not synergizing with NOTCH1 mutations in predicting favorable long-term outcome, which can probably be explained by the interaction of FBXW7 with other clients. Finally, the comparison with other European protocols suggests that the NOTCH effect is treatment dependent generally and may depend on the intensity of central nervous system-directed therapy specifically. PMID- 20944676 TI - Pre-transplant imatinib-based therapy improves the outcome of allogeneic hematopoietic stem cell transplantation for BCR-ABL-positive acute lymphoblastic leukemia. AB - A high complete remission (CR) rate has been reported in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib-based therapy. However, the overall effect of imatinib on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is undetermined. Between 2002 and 2005, 100 newly diagnosed adult patients with Ph+ALL were registered to a phase II study of imatinib-combined chemotherapy (Japan Adult Leukemia Study Group Ph+ALL202 study) and 97 patients achieved CR. We compared clinical outcomes of 51 patients who received allo-HSCT in their first CR (imatinib cohort) with those of 122 historical control patients in the pre-imatinib era (pre-imatinib cohort). The probability of overall survival at 3 years after allo-HSCT was 65% (95% confidence interval (CI), 49-78%) for the imatinib cohort and 44% (95% CI, 35-52%) for the pre-imatinib cohort. Multivariate analysis confirmed that this difference was statistically significant (adjusted hazard ratio, 0.44, P=0.005). Favorable outcomes of the imatinib cohort were also observed for disease-free survival (P=0.007) and relapse (P=0.002), but not for non-relapse mortality (P=0.265). Imatinib-based therapy is a potentially useful strategy for newly diagnosed patients with Ph+ALL, not only providing them more chance to receive allo-HSCT, but also improving the outcome of allo-HSCT. PMID- 20944677 TI - Immune reconstitution after haploidentical hematopoietic cell transplantation: impact of reduced intensity conditioning and CD3/CD19 depleted grafts. AB - Haploidentical hematopoietic cell transplantation (HHCT) using CD34 selected grafts is complicated by slow engraftment and immune reconstitution. Engraftment and immune reconstitution might be improved using CD3/CD19-depleted grafts and reduced intensity conditioning (RIC). We report on 28 patients after HHCT with CD3/CD19-depleted grafts using RIC, which were prospectively evaluated for engraftment and immune reconstitution. Engraftment was rapid with full chimerism reached on day +15 after HHCT. T-cell reconstitution was delayed with a median of 205 CD3+ cells/MUl, 70 CD3+CD4+ cells/MUl and 66 CD3+ CD8+ cells/MUl on day +100, respectively. A skewed T-cell receptor-Vbeta repertoire with oligoclonal T-cell expansions to day +100 and normalization after day +200 was observed. B-cell reconstitution was slow with a median of 100 CD19+ CD20+ cells/MUl on day +150. Natural killer (NK) cell engraftment was fast reaching normal values on day +20. An increased natural cytotoxicity receptor and NKG2A, but decreased NKG2D and KIR expressions were observed on NK cells until day +100. We observed a positive impact of donor lymphocyte infusions on immune reconstitution. In conclusion, after HHCT, using CD3/CD19-depleted grafts and RIC, T- and B-cell reconstitution is delayed, whereas NK-cell reconstitution occurs early and fast. PMID- 20944678 TI - Chemoproteomics-based kinome profiling and target deconvolution of clinical multi kinase inhibitors in primary chronic lymphocytic leukemia cells. AB - The pharmacological induction of apoptosis in neoplastic B cells presents a promising therapeutic avenue for the treatment of chronic lymphocytic leukemia (CLL). We profiled a panel of clinical multi-kinase inhibitors for their ability to induce apoptosis in primary CLL cells. Whereas inhibitors targeting a large number of receptor and intracellular tyrosine kinases including c-KIT, FLT3, BTK and SYK were comparatively inactive, the CDK inhibitors BMS-387032 and flavopiridol showed marked efficacy similar to staurosporine. Using the kinobeads proteomics method, kinase expression profiles and binding profiles of the inhibitors to target protein complexes were quantitatively monitored in CLL cells. The targets most potently affected were CDK9, cyclin T1, AFF3/4 and MLLT1, which may represent four subunits of a deregulated positive transcriptional elongation factor (p-TEFb) complex. Albeit with lower potency, both drugs also bound the basal transcription factor BTF2/TFIIH containing CDK7. Staurosporine and geldanamycin do not affect these targets and thus seem to exhibit a different mechanism of action. The data support a critical role of p-TEFb inhibitors in CLL that supports their future clinical development. PMID- 20944679 TI - Minimal doses of a sequence-optimized transgene mediate high-level and long-term EPO expression in vivo: challenging CpG-free gene design. AB - Advanced gene delivery techniques can be combined with rational gene design to further improve the efficiency of plasmid DNA (pDNA)-mediated transgene expression in vivo. Herein, we analyzed the influence of intragenic sequence modifications on transgene expression in vitro and in vivo using murine erythropoietin (mEPO) as a transgene model. A single electro-gene transfer of an RNA- and codon-optimized mEPOopt gene into skeletal muscle resulted in a 3- to 4 fold increase of mEPO production sustained for >1 year and triggered a significant increase in hematocrit and hemoglobin without causing adverse effects. mEPO expression and hematologic levels were significantly lower when using comparable amounts of the wild type (mEPOwt) gene and only marginal effects were induced by mEPODeltaCpG lacking intragenic CpG dinucleotides, even at high pDNA amounts. Corresponding with these observations, in vitro analysis of transfected cells revealed a 2- to 3-fold increased (mEPOopt) and 50% decreased (mEPODeltaCpG) erythropoietin expression compared with mEPOwt, respectively. RNA analyses demonstrated that the specific design of the transgene sequence influenced expression levels by modulating transcriptional activity and nuclear plus cytoplasmic RNA amounts rather than translation. In sum, whereas CpG depletion negatively interferes with efficient expression in postmitotic tissues, mEPOopt doses <0.5 MUg were sufficient to trigger optimal long-term hematologic effects encouraging the use of sequence-optimized transgenes to further reduce effective pDNA amounts. PMID- 20944680 TI - CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack. AB - Adoptive immunotherapy of cancer using chimeric antigen receptor (CAR)-engineered T cells with redirected specificity showed efficacy in recent trials. In preclinical models, 'second-generation' CARs with CD28 costimulatory domain in addition to CD3zeta performed superior in redirecting T-cell effector functions and survival. Whereas CD28 costimulation sustains physiological T-cell receptor (TCR)-CD3 activation of naive T cells, the impact of CD28 cosignalling on the threshold of CAR-mediated activation of pre-stimulated T cells without B7-CD28 recruitment remained unclear. Using CARs of different binding affinities, but same epitope specificity, we demonstrate that CD28 cosignalling neither lowered the antigen threshold nor the binding affinity for redirected T-cell activation. 'Affinity ceiling' above which increase in affinity does not increase T-cell activation was not altered. Accordingly, redirected tumor cell killing depended on the binding affinity but was likewise effective for CD3zeta and CD28-CD3zeta CARs. In contrast to CD3zeta, CD28-CD3zeta CAR-driven activation was not increased further by CD28-B7 engagement. However, CD28 cosignalling, which is required for interleukin-2 induction could not be replaced by high-affinity CD3zeta CAR binding or high-density antigen engagement. We conclude that CD28 CAR cosignalling does not alter the activation threshold but redirects T-cell effector functions. PMID- 20944681 TI - Development of murine leukemia virus-based retroviral vectors with a minimum possibility of cis-activation. AB - The possibility of insertional mutagenesis in retroviral gene therapy can be reduced by using a vector lacking the enhancer sequence present in the U3 of the long-terminal repeats. However, such vectors suffer from many pitfalls. We attempted to improve a murine leukemia virus-based retroviral vector containing the enhancer-free U3, first by making it easier to construct a producer line and then by introducing the cellular RPL10 promoter as an internal promoter. The reverse orientation of the expression cassette of the transgene was found to give higher transducing titer and higher-level gene expression. The deletion analysis revealed that the 54-bp-long sequence of U3 (34 and 20 bp present at 5' and 3' extreme ends, respectively) was sufficient for the functions of retroviral vectors. The data from the in vitro cell culture assay indicated that the final construct, ROK, containing all these features, had little cis-activation activity, even if it was placed right upstream from the RNA start site of the neighboring gene. Our data suggested that the newly developed vector might provide increased safety, while still producing high viral titer from a stable producer line and high-level gene expression in various target cells including human CD34(+) stem cells. PMID- 20944682 TI - Elevated seawater temperature causes a microbial shift on crustose coralline algae with implications for the recruitment of coral larvae. AB - Crustose coralline algae (CCA) are key reef-building primary producers that are known to induce the metamorphosis and recruitment of many species of coral larvae. Reef biofilms (particularly microorganisms associated with CCA) are also important as settlement cues for a variety of marine invertebrates, including corals. If rising sea surface temperatures (SSTs) affect CCA and/or their associated biofilms, this may in turn affect recruitment on coral reefs. Herein, we report that the CCA Neogoniolithon fosliei, and its associated microbial communities do not tolerate SSTs of 32 degrees C, only 2-4 degrees C above the mean maximum annual SST. After 7 days at 32 degrees C, the CCA exhibited clear signs of stress, including bleaching, a reduction in maximum quantum yield (F(v)/F(m)) and a large shift in microbial community structure. This shift at 32 degrees C involved an increase in Bacteroidetes and a reduction in Alphaproteobacteria, including the loss of the primary strain (with high-sequence similarity to a described coral symbiont). A recovery in F(v)/F(m) was observed in CCA exposed to 31 degrees C following 7 days of recovery (at 27 degrees C); however, CCA exposed to 32 degrees C did not recover during this time as evidenced by the rapid growth of endolithic green algae. A 50% reduction in the ability of N. fosliei to induce coral larval metamorphosis at 32 degrees C accompanied the changes in microbiology, pigmentation and photophysiology of the CCA. This is the first experimental evidence to demonstrate how thermal stress influences microbial associations on CCA with subsequent downstream impacts on coral recruitment, which is critical for reef regeneration and recovery from climate-related mortality events. PMID- 20944684 TI - Politics without the poison. PMID- 20944683 TI - High rates of denitrification and nitrate removal in cold seep sediments. AB - We measured denitrification and nitrate removal rates in cold seep sediments from the Gulf of Mexico. Heterotrophic potential denitrification rates were assayed in time-series incubations. Surficial sediments inhabited by Beggiatoa exhibited higher heterotrophic potential denitrification rates (32 MUM N reduced day(-1)) than did deeper sediments (11 MUM N reduced day(-1)). Nitrate removal rates were high in both sediment horizons. These nitrate removal rates translate into rapid turnover times (<1 day) for the nitrate pool, resulting in a faster turnover for the nitrate pool than for the sulfate pool. Together, these data underscore the rigorous nature of internal nitrogen cycling at cold seeps and the requirement for novel mechanisms to provide nitrate to the sediment microbial community. PMID- 20944685 TI - One backyard at a time. PMID- 20944686 TI - Probe retires to a place in the Sun. PMID- 20944687 TI - Publish your computer code: it is good enough. PMID- 20944700 TI - US midterm elections: Volatile forces shape US vote. PMID- 20944701 TI - US midterm elections: Deficit poses threat to science. PMID- 20944702 TI - US midterm elections: NIH prepares for loss of political champions. PMID- 20944703 TI - US midterm elections: A chilly season for climate crusaders. PMID- 20944704 TI - US midterm elections: Policy row launches NASA into limbo. PMID- 20944705 TI - US midterm elections: Opponents battle health-care research. PMID- 20944706 TI - Biodiversity hope faces extinction. PMID- 20944707 TI - Chemistry Nobel won by ... chemists. PMID- 20944708 TI - Cancer-gene testing ramps up. PMID- 20944709 TI - Global disease fund hit by cash crisis. PMID- 20944711 TI - Non-proliferation: A nuclear exchange. PMID- 20944710 TI - Science & politics: Speaking out about science. PMID- 20944712 TI - Computational science: ...Error. PMID- 20944713 TI - Biology without borders. PMID- 20944714 TI - A two-year plan for US science. PMID- 20944720 TI - Taxonomy: add a human touch too. PMID- 20944721 TI - Call to reshape university curricula. PMID- 20944722 TI - Science as a threat to far-right fringe. PMID- 20944723 TI - Alternative view of Serengeti road. PMID- 20944724 TI - Taxonomy: include social networking. PMID- 20944725 TI - Better governance to save rainforests. PMID- 20944726 TI - International, not 'campus', please. PMID- 20944727 TI - Reward quality not quantity. PMID- 20944728 TI - Left-handed DNA can be right. PMID- 20944729 TI - Basic science in Russia under threat. PMID- 20944730 TI - George C. Williams (1926-2010). PMID- 20944731 TI - Solar system: Accidental investigation. PMID- 20944732 TI - Immunology: Egocentric pre-T-cell receptors. PMID- 20944733 TI - Glaciology: Ice-sheet advance in Antarctica. PMID- 20944735 TI - Cancer: Oncogenes in context. PMID- 20944736 TI - Atmospheric chemistry: phase matters for aerosols. PMID- 20944737 TI - Sociology: political evolution. PMID- 20944739 TI - Rise and fall of political complexity in island South-East Asia and the Pacific. AB - There is disagreement about whether human political evolution has proceeded through a sequence of incremental increases in complexity, or whether larger, non sequential increases have occurred. The extent to which societies have decreased in complexity is also unclear. These debates have continued largely in the absence of rigorous, quantitative tests. We evaluated six competing models of political evolution in Austronesian-speaking societies using phylogenetic methods. Here we show that in the best-fitting model political complexity rises and falls in a sequence of small steps. This is closely followed by another model in which increases are sequential but decreases can be either sequential or in bigger drops. The results indicate that large, non-sequential jumps in political complexity have not occurred during the evolutionary history of these societies. This suggests that, despite the numerous contingent pathways of human history, there are regularities in cultural evolution that can be detected using computational phylogenetic methods. PMID- 20944741 TI - Gas accretion as the origin of chemical abundance gradients in distant galaxies. AB - It has recently been suggested that galaxies in the early Universe could have grown through the accretion of cold gas, and that this may have been the main driver of star formation and stellar mass growth. Because the cold gas is essentially primordial, it has a very low abundance of elements heavier than helium (referred to as metallicity). If funnelled to the centre of a galaxy, it will result in the central gas having an overall lower metallicity than gas further from the centre, because the gas further out has been enriched by supernovae and stellar winds, and not diluted by the primordial gas. Here we report chemical abundances across three rotationally supported star-forming galaxies at redshift z ~ 3, only 2 Gyr after the Big Bang. We find 'inverse' gradients, with the central, star-forming regions having lower metallicities than less active ones, which is opposite to what is seen in local galaxies. We conclude that the central gas has been diluted by the accretion of primordial gas, as predicted by 'cold flow' models. PMID- 20944740 TI - The Ndc80 kinetochore complex forms oligomeric arrays along microtubules. AB - The Ndc80 complex is a key site of regulated kinetochore-microtubule attachment (a process required for cell division), but the molecular mechanism underlying its function remains unknown. Here we present a subnanometre-resolution cryo electron microscopy reconstruction of the human Ndc80 complex bound to microtubules, sufficient for precise docking of crystal structures of the component proteins. We find that the Ndc80 complex binds the microtubule with a tubulin monomer repeat, recognizing alpha- and beta-tubulin at both intra- and inter-tubulin dimer interfaces in a manner that is sensitive to tubulin conformation. Furthermore, Ndc80 complexes self-associate along protofilaments through interactions mediated by the amino-terminal tail of the NDC80 protein, which is the site of phospho-regulation by Aurora B kinase. The complex's mode of interaction with the microtubule and its oligomerization suggest a mechanism by which Aurora B could regulate the stability of load-bearing kinetochore microtubule attachments. PMID- 20944742 TI - A collision in 2009 as the origin of the debris trail of asteroid P/2010 A2. AB - The peculiar object P/2010 A2 was discovered in January 2010 and given a cometary designation because of the presence of a trail of material, although there was no central condensation or coma. The appearance of this object, in an asteroidal orbit (small eccentricity and inclination) in the inner main asteroid belt attracted attention as a potential new member of the recently recognized class of main-belt comets. If confirmed, this new object would expand the range in heliocentric distance over which main-belt comets are found. Here we report observations of P/2010 A2 by the Rosetta spacecraft. We conclude that the trail arose from a single event, rather than a period of cometary activity, in agreement with independent results. The trail is made up of relatively large particles of millimetre to centimetre size that remain close to the parent asteroid. The shape of the trail can be explained by an initial impact ejecting large clumps of debris that disintegrated and dispersed almost immediately. We determine that this was an asteroid collision that occurred around 10 February 2009. PMID- 20944743 TI - A recent disruption of the main-belt asteroid P/2010 A2. AB - Most inner main-belt asteroids are primitive rock and metal bodies in orbit about the Sun between Mars and Jupiter. Disruption, through high-velocity collisions or rotational spin-up, is believed to be the primary mechanism for the production and destruction of small asteroids and a contributor to dust in the Sun's zodiacal cloud, while analogous collisions around other stars feed dust to their debris disks. Unfortunately, direct evidence about the mechanism or rate of disruption is lacking, owing to the rarity of the events. Here we report observations of P/2010 A2, a previously unknown inner-belt asteroid with a peculiar, comet-like morphology. The data reveal a nucleus of diameter approximately 120 metres with an associated tail of millimetre-sized dust particles. We conclude that it is most probably the remnant of a recent asteroidal disruption in February/March 2009, evolving slowly under the action of solar radiation pressure, in agreement with independent work. PMID- 20944744 TI - An amorphous solid state of biogenic secondary organic aerosol particles. AB - Secondary organic aerosol (SOA) particles are formed in the atmosphere from condensable oxidation products of anthropogenic and biogenic volatile organic compounds (VOCs). On a global scale, biogenic VOCs account for about 90% of VOC emissions and of SOA formation (90 billion kilograms of carbon per year). SOA particles can scatter radiation and act as cloud condensation or ice nuclei, and thereby influence the Earth's radiation balance and climate. They consist of a myriad of different compounds with varying physicochemical properties, and little information is available on the phase state of SOA particles. Gas-particle partitioning models usually assume that SOA particles are liquid, but here we present experimental evidence that they can be solid under ambient conditions. We investigated biogenic SOA particles formed from oxidation products of VOCs in plant chamber experiments and in boreal forests within a few hours after atmospheric nucleation events. On the basis of observed particle bouncing in an aerosol impactor and of electron microscopy we conclude that biogenic SOA particles can adopt an amorphous solid-most probably glassy-state. This amorphous solid state should provoke a rethinking of SOA processes because it may influence the partitioning of semi-volatile compounds, reduce the rate of heterogeneous chemical reactions, affect the particles' ability to accommodate water and act as cloud condensation or ice nuclei, and change the atmospheric lifetime of the particles. Thus, the results of this study challenge traditional views of the kinetics and thermodynamics of SOA formation and transformation in the atmosphere and their implications for air quality and climate. PMID- 20944745 TI - xnd-1 regulates the global recombination landscape in Caenorhabditis elegans. AB - Meiotic crossover (CO) recombination establishes physical linkages between homologous chromosomes that are required for their proper segregation into developing gametes, and promotes genetic diversity by shuffling genetic material between parental chromosomes. COs require the formation of double strand breaks (DSBs) to create the substrate for strand exchange. DSBs occur in small intervals called hotspots and significant variation in hotspot usage exists between and among individuals. This variation is thought to reflect differences in sequence identity and chromatin structure, DNA topology and/ or chromosome domain organization. Chromosomes show different frequencies of nondisjunction (NDJ), reflecting inherent differences in meiotic crossover control, yet the underlying basis of these differences remains elusive. Here we show that a novel chromatin factor, X non-disjunction factor 1 (xnd-1), is responsible for the global distribution of COs in C. elegans. xnd-1 is also required for formation of double strand breaks (DSBs) on the X, but surprisingly XND-1 protein is autosomally enriched. We show that xnd-1 functions independently of genes required for X chromosome-specific gene silencing, revealing a novel pathway that distinguishes the X from autosomes in the germ line, and further show that xnd-1 exerts its effects on COs, at least in part, by modulating levels of H2A lysine 5 acetylation. PMID- 20944746 TI - The structural basis for autonomous dimerization of the pre-T-cell antigen receptor. AB - The pre-T-cell antigen receptor (pre-TCR), expressed by immature thymocytes, has a pivotal role in early T-cell development, including TCR beta-selection, survival and proliferation of CD4(-)CD8(-) double-negative thymocytes, and subsequent alphabeta T-cell lineage differentiation. Whereas alphabetaTCR ligation by the peptide-loaded major histocompatibility complex initiates T-cell signalling, pre-TCR-induced signalling occurs by means of a ligand-independent dimerization event. The pre-TCR comprises an invariant alpha-chain (pre-Talpha) that pairs with any TCR beta-chain (TCRbeta) following successful TCR beta-gene rearrangement. Here we provide the basis of pre-Talpha-TCRbeta assembly and pre TCR dimerization. The pre-Talpha chain comprised a single immunoglobulin-like domain that is structurally distinct from the constant (C) domain of the TCR alpha-chain; nevertheless, the mode of association between pre-Talpha and TCRbeta mirrored that mediated by the Calpha-Cbeta domains of the alphabetaTCR. The pre TCR had a propensity to dimerize in solution, and the molecular envelope of the pre-TCR dimer correlated well with the observed head-to-tail pre-TCR dimer. This mode of pre-TCR dimerization enabled the pre-Talpha domain to interact with the variable (V) beta domain through residues that are highly conserved across the Vbeta and joining (J) beta gene families, thus mimicking the interactions at the core of the alphabetaTCR's Valpha-Vbeta interface. Disruption of this pre-Talpha Vbeta dimer interface abrogated pre-TCR dimerization in solution and impaired pre TCR expression on the cell surface. Accordingly, we provide a mechanism of pre TCR self-association that allows the pre-Talpha chain to simultaneously 'sample' the correct folding of both the V and C domains of any TCR beta-chain, regardless of its ultimate specificity, which represents a critical checkpoint in T-cell development. This unusual dual-chaperone-like sensing function of pre-Talpha represents a unique mechanism in nature whereby developmental quality control regulates the expression and signalling of an integral membrane receptor complex. PMID- 20944747 TI - Anthrax toxins cooperatively inhibit endocytic recycling by the Rab11/Sec15 exocyst. AB - Bacillus anthracis is the causative agent of anthrax in humans and other mammals. In lethal systemic anthrax, proliferating bacilli secrete large quantities of the toxins lethal factor (LF) and oedema factor (EF), leading to widespread vascular leakage and shock. Whereas host targets of LF (mitogen-activated protein-kinase kinases) and EF (cAMP-dependent processes) have been implicated in the initial phase of anthrax, less is understood about toxin action during the final stage of infection. Here we use Drosophila melanogaster to identify the Rab11/Sec15 exocyst, which acts at the last step of endocytic recycling, as a novel target of both EF and LF. EF reduces levels of apically localized Rab11 and indirectly blocks vesicle formation by its binding partner and effector Sec15 (Sec15-GFP), whereas LF acts more directly to reduce Sec15-GFP vesicles. Convergent effects of EF and LF on Rab11/Sec15 inhibit expression of and signalling by the Notch ligand Delta and reduce DE-cadherin levels at adherens junctions. In human endothelial cells, the two toxins act in a conserved fashion to block formation of Sec15 vesicles, inhibit Notch signalling, and reduce cadherin expression at adherens junctions. This coordinated disruption of the Rab11/Sec15 exocyst by anthrax toxins may contribute to toxin-dependent barrier disruption and vascular dysfunction during B. anthracis infection. PMID- 20944748 TI - Non-muscle myosin IIA is a functional entry receptor for herpes simplex virus-1. AB - Herpes simplex virus-1 (HSV-1), the prototype of the alpha-herpesvirus family, causes life-long infections in humans. Although generally associated with various mucocutaneous diseases, HSV-1 is also involved in lethal encephalitis. HSV-1 entry into host cells requires cellular receptors for both envelope glycoproteins B (gB) and D (gD). However, the gB receptors responsible for its broad host range in vitro and infection of critical targets in vivo remain unknown. Here we show that non-muscle myosin heavy chain IIA (NMHC-IIA), a subunit of non-muscle myosin IIA (NM-IIA), functions as an HSV-1 entry receptor by interacting with gB. A cell line that is relatively resistant to HSV-1 infection became highly susceptible to infection by this virus when NMHC-IIA was overexpressed. Antibody to NMHC-IIA blocked HSV-1 infection in naturally permissive target cells. Furthermore, knockdown of NMHC-IIA in the permissive cells inhibited HSV-1 infection as well as cell-cell fusion when gB, gD, gH and gL were coexpressed. Cell-surface expression of NMHC-IIA was markedly and rapidly induced during the initiation of HSV-1 entry. A specific inhibitor of myosin light chain kinase, which regulates NM-IIA by phosphorylation, reduced the redistribution of NMHC-IIA as well as HSV 1 infection in cell culture and in a murine model for herpes stromal keratitis. NMHC-IIA is ubiquitously expressed in various human tissues and cell types and, therefore, is implicated as a functional gB receptor that mediates broad HSV-1 infectivity both in vitro and in vivo. The identification of NMHC-IIA as an HSV-1 entry receptor and the involvement of NM-IIA regulation in HSV-1 infection provide an insight into HSV-1 entry and identify new targets for antiviral drug development. PMID- 20944749 TI - Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis. AB - Apoptotic cells release 'find-me' signals at the earliest stages of death to recruit phagocytes. The nucleotides ATP and UTP represent one class of find-me signals, but their mechanism of release is not known. Here, we identify the plasma membrane channel pannexin 1 (PANX1) as a mediator of find-me signal/nucleotide release from apoptotic cells. Pharmacological inhibition and siRNA-mediated knockdown of PANX1 led to decreased nucleotide release and monocyte recruitment by apoptotic cells. Conversely, PANX1 overexpression enhanced nucleotide release from apoptotic cells and phagocyte recruitment. Patch clamp recordings showed that PANX1 was basally inactive, and that induction of PANX1 currents occurred only during apoptosis. Mechanistically, PANX1 itself was a target of effector caspases (caspases 3 and 7), and a specific caspase-cleavage site within PANX1 was essential for PANX1 function during apoptosis. Expression of truncated PANX1 (at the putative caspase cleavage site) resulted in a constitutively open channel. PANX1 was also important for the 'selective' plasma membrane permeability of early apoptotic cells to specific dyes. Collectively, these data identify PANX1 as a plasma membrane channel mediating the regulated release of find-me signals and selective plasma membrane permeability during apoptosis, and a new mechanism of PANX1 activation by caspases. PMID- 20944751 TI - Retraction. Systemic signals regulate ageing and rejuvenation of blood stem cell niches. PMID- 20944750 TI - The proteasome antechamber maintains substrates in an unfolded state. AB - Eukaryotes and archaea use a protease called the proteasome that has an integral role in maintaining cellular function through the selective degradation of proteins. Proteolysis occurs in a barrel-shaped 20S core particle, which in Thermoplasma acidophilum is built from four stacked homoheptameric rings of subunits, alpha and beta, arranged alpha(7)beta(7)beta(7)alpha(7) (ref. 5). These rings form three interconnected cavities, including a pair of antechambers (formed by alpha(7)beta(7)) through which substrates are passed before degradation and a catalytic chamber (beta(7)beta(7)) where the peptide-bond hydrolysis reaction occurs. Although it is clear that substrates must be unfolded to enter through narrow, gated passageways (13 A in diameter) located on the alpha-rings, the structural and dynamical properties of substrates inside the proteasome antechamber remain unclear. Confinement in the antechamber might be expected to promote folding and thus impede proteolysis. Here we investigate the folding, stability and dynamics of three small protein substrates in the antechamber by methyl transverse-relaxation-optimized NMR spectroscopy. We show that these substrates interact actively with the antechamber walls and have drastically altered kinetic and equilibrium properties that maintain them in unstructured states so as to be accessible for hydrolysis. PMID- 20944753 TI - One hundred human pancreatic islet isolations at Baylor Research Institute. AB - The effectiveness of pancreatic islet isolation must be maximized to make islet cell transplantation (ICT) a standard therapy. We have performed 100 human islet isolations at Baylor Research Institute including islet isolations for research, for clinical allogeneic transplantation, and for autologous islet transplantation. In this study, we analyzed the results of these isolations. First, we assessed 79 islet isolations using brain-dead donors to determine variables associated with successful islet isolation. Univariate logistic regression analysis revealed that seven variables influenced the success of islet isolation for allogeneic ICT: cause of death, mechanism of death, techniques for pancreas procurement and preservation, heavy fatty infiltration, collagenase type, dilution time, and islet purification method. Multivariate regression analysis revealed that only the current isolation protocol, the Baylor Islet Isolation Method (BIIM)-with its four required elements of pancreas procurement by the team, pancreatic ductal injection, the two-layer method with perfluorocarbon, and density-adjusted density gradient purification-had a significant positive impact on successful islet isolation (P = 0.02). Second, we compared allogeneic and autologous ICT using the BIIM. There were no significant differences in islet yields between allogeneic and autologous ICT using the BIIM; total islet yield after purification was 628 +/- 84 * 10(3) IE in allogeneic ICT vs. 576 +/- 49 * 10(3) IE in autologous ICT (P = 0.59). This retrospective study revealed that the BIIM provided favorable outcomes for both autologous and allogeneic ICT. PMID- 20944754 TI - Changing epidemiology of trauma deaths leads to a bimodal distribution. AB - Injury mortality was classically described with a trimodal distribution, with immediate deaths at the scene, early deaths due to hemorrhage, and late deaths from organ failure. We hypothesized that the development of trauma systems has improved prehospital care, early resuscitation, and critical care and altered this pattern. This population-based study of all trauma deaths in an urban county with a mature trauma system reviewed data for 678 patients (median age, 33 years; 81% male; 43% gunshot, 20% motor vehicle crashes). Deaths were classified as immediate (scene), early (in hospital, <=4 hours from injury), or late (>4 hours after injury). Multinomial regression was used to identify independent predictors of immediate and early versus late deaths, adjusted for age, gender, race, intention, mechanism, toxicology, and cause of death. Results showed 416 (61%) immediate, 199 (29%) early, and 63 (10%) late deaths. Compared with the classical description, the percentage of immediate deaths remained unchanged, and early deaths occurred much earlier (median 52 vs 120 minutes). However, unlike the classic trimodal distribution, the late peak was greatly diminished. Intentional injuries, alcohol intoxication, asphyxia, and injuries to the head and chest were independent predictors of immediate death. Alcohol intoxication and injuries to the chest were predictors of early death, while pelvic fractures and blunt assaults were associated with late deaths. In conclusion, trauma deaths now have a predominantly bimodal distribution. Near elimination of the late peak likely represents advancements in resuscitation and critical care that have reduced organ failure. Further reductions in mortality will likely come from prevention of intentional injuries and injuries associated with alcohol intoxication. PMID- 20944755 TI - Postinjury employment as a surrogate for functional outcomes: a quality indicator for trauma systems. AB - Return to work may be easily monitored as a surrogate of long-term functional outcome for benchmarking and performance improvement of trauma systems. We hypothesized that employment rates among survivors of traumatic brain injury (TBI) decrease following injury and remain depressed for an extended period of time. Data were obtained from a statewide surveillance system of 3522 TBI patients (aged >15 years) who were discharged alive from acute care hospitals and followed yearly using telephone interviews (1996-1999). The study population consisted of patients with severe TBI (head abbreviated injury score 3, 4, or 5) and complete follow-up for 3 years postinjury (n = 572). Patients were mostly young males (43 +/- 19 years, 65% male) with blunt TBI (92%). The preinjury employment rate was 67%, which declined to 52% (P < 0.001) in the first year and slowly rose in subsequent years but never reached the preinjury level (54% in year 2, P < 0.001; 57% in year 3, P = 0.001). Increasing severity of TBI was associated with a lower employment rate. Patients who remained employed worked the same number of hours as they did before the injury (47.8 +/- 10.5 hours). Female employment rates rose similar to rates for males. However, women who were employed full-time before TBI were more likely to work part-time after TBI than men (50% vs 24%, P < 0.001). In conclusion, survivors of severe injury do not attain preinjury employment levels for several years. Once validated in other studies, postinjury employment may be used as an indicator to monitor functional outcomes in trauma registries. PMID- 20944756 TI - Central nervous system tuberculosis. AB - Central nervous system tuberculosis is a rare presentation of active tuberculosis and accounts for about 1% of cases (1). The three clinical categories include meningitis, intracranial tuberculomas, and spinal tuberculous arachnoiditis. We report a case of a young man who presented with active pulmonary tuberculosis in addition to tuberculous meningitis and the presence of numerous intracranial tuberculomas. PMID- 20944757 TI - Cardiac arrest due to torsades de pointes in a patient with complete heart block: the "R-on-T" phenomenon. PMID- 20944758 TI - Clostridium difficile-associated diarrhea in a tertiary care medical center. AB - This retrospective, case-control study aimed to identify variables associated with the incidence of Clostridium difficile-associated diarrhea (CDAD) in acute care facilities and to specifically identify the relationship of fluoroquinolones and acid suppressive agents in the development of CDAD. Seventy-one symptomatic patients positive for C. difficile toxin A or B hospitalized for at least 72 hours were compared with 142 control patients hospitalized for at least 72 hours who were not positive for C. difficile toxin A or B. Two controls were matched to one case patient for age within 5 years, unit of admission, and date of admission. The mean ages for cases and controls were 63.5 and 62.7 years, respectively. After adjusting for two confounding variables-hospital stay within 3 months and Charlson Comorbidity Index-conditional multiple logistic regression identified six risk factors for development of CDAD: gastrointestinal procedures within 60 days (odds ratio [OR] 9.1, P < 0.013), levofloxacin exposure (OR 8.2, P < 0.033), moxifloxacin exposure (OR 4.1, P < 0.026), imipenem exposure (OR 14.9, P < 0.014), laxative use (OR 20.2, P < 0.0001), and immunosuppressive use (OR 20.7, P < 0.034). The risk of CDAD after exposure to levofloxacin or moxifloxacin was not significantly different. Acid suppressive therapy was not a risk factor for CDAD development. PMID- 20944759 TI - Increased total heart rate variability and enhanced cardiac vagal autonomic activity in healthy humans with sinus bradycardia. AB - Sinus bradycardia can be defined as a sinus rhythm with a resting heart rate of 60 beats per minute or less. While it is assumed that increased autonomic parasympathetic activity is associated with sinus bradycardia, such an association has yet to be proven. The aims of this study were to compute a number of heart rate variability (HRV) parameters in healthy individuals with sinus bradycardia and determine whether there was a significant vagal component to sinus bradycardia. Forty-three healthy adults with normal sinus rhythm and 25 healthy adults with sinus bradycardia had an electrocardiogram recorded for 20 minutes, from which HRV indices were calculated. Results showed significant increases in SDNN (standard deviation of NN intervals) (P < 0.05), RMSDD (square root of the mean squared differences of successive NN intervals) (P < 0.05), and DFA32 (detrended fluctuation analysis) (P < 0.05) in bradycardic subjects compared with subjects with normal sinus rhythm. There were no significant differences in sympathetic frequency domain indices between the two groups. In conclusion, there were significant increases in total heart variability and increased parasympathetic drive in subjects with bradycardia. Clinically, bradycardia is likely to be cardioprotective in aging populations based upon these HRV findings. PMID- 20944760 TI - Joy shines more brightly engulfed in chaos: reflections on a mission trip to Haiti. PMID- 20944761 TI - H. L. Mencken and the four doctors: Osler, Halsted, Welch, and Kelly. PMID- 20944762 TI - Caroline Hampton Halsted: the first to use rubber gloves in the operating room. PMID- 20944763 TI - Doctors on display: the evolution of television's doctors. AB - Doctors have been portrayed on television for over 50 years. In that time, their character has undergone significant changes, evolving from caring but infallible supermen with smoldering good looks and impeccable bedside manners to drug addicted, sex-obsessed antiheroes. This article summarizes the major programs of the genre and explains the pattern of the TV doctors' character changes. Articulated over time in the many permutations of the doctor character is a complex, constant conversation between viewer and viewed representing public attitudes towards doctors, medicine, and science. PMID- 20944764 TI - Robert Arthur Kyle, MD: a conversation with the editor. PMID- 20944766 TI - Cancer caring. PMID- 20944765 TI - Current approaches to the recognition and treatment of alcohol withdrawal and delirium tremens: "old wine in new bottles" or "new wine in old bottles". PMID- 20944767 TI - Efficacy, safety, and tolerability of Desvenlafaxine 50 mg/d for the treatment of major depressive disorder:a systematic review of clinical trials. AB - OBJECTIVE: Desvenlafaxine is the third serotonin-norepinephrine reuptake inhibitor (SNRI) approved by the US Food and Drug Administration for major depressive disorder (MDD). This article summarizes data on the clinical pharmacology, efficacy, safety, and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) for MDD with a focus on the 50-mg/d therapeutic dose. Additionally, the article discusses clinical practice considerations and future directions in desvenlafaxine research. DATA SOURCES: Data relating to desvenlafaxine 50 mg/d were identified through searches of MEDLINE and publication databases of Pfizer for articles in English published before January 2009. Keywords were desvenlafaxine, O-desmethylvenlafaxine, ODV, and 50 mg. STUDY SELECTION: Three randomized, placebo- and/or active comparator-controlled, 8-week clinical trials reported the efficacy of desvenlafaxine 50 mg/d for the treatment of MDD. The third of these studies included a post hoc pooled analysis of data from all 3 of these trials. In addition, the search retrieved an article examining pooled data from 9 trials, including 50-mg data from 2 of the 3 retrieved trials. DATA SYNTHESIS: Desvenlafaxine is the major active metabolite of the SNRI venlafaxine. Significant improvements compared with placebo were observed on the primary efficacy measure (17-item Hamilton Depression Rating Scale total score) and most secondary measures in 2 of 3 clinical trials. An integrated analysis of registration data from 9 randomized, double-blind, placebo controlled, 8-week studies of desvenlafaxine (50 to 400 mg/d) for MDD demonstrated no evidence of greater efficacy with doses higher than 50 mg/d. Safety results indicate that desvenlafaxine treatment is generally safe and well tolerated; findings were consistent with those for the SNRI class. The 50-mg/d dose of desvenlafaxine was associated with low rates of discontinuation due to treatment-emergent adverse events, which were similar to placebo. CONCLUSIONS: Desvenlafaxine 50 mg/d has demonstrated efficacy, safety, and tolerability for the treatment of MDD in placebo-controlled trials. A long-term study is underway to further explore desvenlafaxine 50 mg/d for MDD. PMID- 20944768 TI - Mother cabrini and the anatomy of an illness. PMID- 20944769 TI - Nonadherence to medication in hypothyroidism: a case report. AB - This case report reviews the consequences of nonadherence to a hypothyroidism medication schedule and examines the complexity of hypothyroidism treatment. Both biologic and psychosocial aspects are discussed. The physician-patient relationship is a key to improving adherence, and medication alone is not sufficient to improve outcomes. It is essential for the physician to address and successfully manage the psychosocial factors involved as well. PMID- 20944770 TI - Attention-deficit/hyperactivity disorder in adults with bipolar disorder or major depressive disorder: results from the international mood disorders collaborative project. AB - OBJECTIVE: Relatively few studies have evaluated the clinical implications of lifetime attention-deficit/hyperactivity disorder (ADHD) in adults with bipolar disorder or major depressive disorder (MDD). Herein, we sought to determine the prevalence as well as the demographic and clinical correlates of lifetime ADHD in persons with a mood disorder. METHOD: The first 399 patients enrolled in the International Mood Disorders Collaborative Project (IMDCP) were evaluated for lifetime ADHD using the Mini-International Neuropsychiatric Interview-Plus (MINI Plus) as the primary instrument to derive current and lifetime DSM-IV diagnoses. All analyses of variables of interest were conducted utilizing the MINI-Plus, the Adult ADHD Self-Report Scale-v1.1, and the Wender Utah Rating Scale-Short Form. The effect of ADHD on clinical presentation, course of illness variables, comorbidity, anamnesis, treatment, and outcome are reported. The IMDCP is a joint initiative of the Mood Disorders Psychopharmacology Unit at the University Health Network, University of Toronto, Toronto, Ontario, Canada, and the Cleveland Clinic Center for Mood Disorders Treatment and Research at Lutheran Hospital, Cleveland, Ohio. All data for this study were procured between January 2008 and January 2009. RESULTS: The percentages of subjects with MDD or bipolar disorder meeting the DSM-IV criteria for lifetime adult ADHD were 5.4% and 17.6% (P < .001), respectively. Lifetime comorbid ADHD in both mood disorder populations was associated with earlier age at illness onset (MDD, P = .049; bipolar disorder, P = .005), a higher number of psychiatric comorbidities (eg, MDD and current panic disorder with agoraphobia [P = .002]; bipolar disorder and social phobia [P = .012]), and decreased quality of life (MDD, P = .018). CONCLUSIONS: The overarching findings herein are that the adult ADHD phenotype is commonly reported by individuals with MDD or bipolar disorder and is associated with a greater illness burden and complexity. PMID- 20944771 TI - Symptoms of depression in a Hispanic primary care population with and without chronic medical illnesses. AB - OBJECTIVE: To describe somatic and psychiatric symptoms reported by Hispanic primary care patients with and without depression and/or chronic medical illnesses. METHOD: Adult Hispanic patients (n = 104) in a Mobile Health Program in underserved southern Arizona participated in a survey conducted between September 2006 and February 2007 to obtain information about the somatic and psychiatric symptoms that they were experiencing. They were asked to rate the severity of their symptoms listed in the depression screen Personal Health Questionnaire-9 (PHQ-9), the Symptom Checklist-90-Revised (SCL-90-R), and 5 new symptoms described by patients in focus groups conducted in the first phase of the project. Patients were categorized as depressed if their PHQ-9 scores were 10 or above, and they were further categorized as having or not having chronic illnesses based on self-report. Analyses of variance were conducted for each SCL 90-R symptom dimension to compare across the 4 groups (group 1: not depressed and not medically ill; group 2: medically ill but not depressed; group 3: depressed but not medically ill; and group 4: depressed and medically ill). RESULTS: Patients with chronic medical illnesses comorbid with depression were found to report significantly more somatic symptoms than those with only chronic medical illnesses or depression alone (P <= .001). They also reported significantly more psychopathology than patients with depression alone (P <= .05 or better). CONCLUSIONS: Patients with medical illnesses comorbid with depression are more likely to exhibit psychopathology than patients with medical illnesses or depression alone. PMID- 20944772 TI - Increased self-report of obsessive-compulsive behaviors among hemodialysis patients: a case-control study. AB - BACKGROUND: Patients with end-stage renal insufficiency undergoing hemodialysis show important psychiatric morbidity, particularly increased depression and anxiety. Obsessive-compulsive symptoms, however, are much less frequently investigated. The purpose of the present study was thus to assess obsessive compulsive symptoms in hemodialysis patients. METHOD: Patients treated at an outpatient hospital hemodialysis unit (July 2007) were compared with controls on scores on the Maudsley Obsessional-Compulsive Inventory (MOCI) and its checking, cleaning, slowness, and doubting components as well as on measures of emotional (Beck Depression Inventory-Fast Screen), anxiety (Beck Anxiety Inventory), and cognitive (Trail Making Test) status. Student t tests, analyses of covariance, or nonparametric tests were used. Correlations were applied between behavioral outcomes and demographic, clinical, and laboratory data of patients. RESULTS: Patients showed more obsessive traits than controls on the MOCI total score (P < .001) and on the checking, cleaning, and doubting subscales. Significant differences between groups occurred also in Beck Depression and Anxiety Inventories (P <= .001). The MOCI total score did not correlate with marital status, education level, duration of hemodialysis, or the other psychological instrument scores in patients. By contrast, the MOCI total score was associated with the level of creatinine, and it showed an inverse correlation with the urea reduction ratio in patients (P < .05). CONCLUSIONS: Obsessive-compulsive symptoms may constitute an important aspect of the psychiatric profile of patients undergoing hemodialysis. Potential interpretation involves disease- and treatment associated factors or adaptive responses to emergence of otherwise uncontrollable stress. PMID- 20944773 TI - Multidisciplinary cognitive-behavioral therapy training for the veterans affairs primary care setting. AB - OBJECTIVE: Current research highlights the need to embed evidence-based psychotherapies such as cognitive-behavioral therapy (CBT) within primary care settings. Few studies have examined CBT training procedures, and no studies have examined the impact of CBT training in the primary care setting. The current study sought to describe and assess the feasibility and effectiveness of a focused CBT training program for a diverse sample of primary care mental health providers in the Department of Veterans Affairs (VA). METHOD: A multidisciplinary group of 28 mental health clinicians from 6 VA medical centers and 15 community based outpatient clinics received an intensive 11/2-day CBT workshop, held in Houston, Texas, in May 2008, including didactic presentations, expert modeling, and small-group role plays. CBT experts also provided biweekly follow-up group telephone consultation calls for participants over 12 weeks to aid in development of CBT skills. Participant program evaluation surveys and self-reported CBT knowledge, ability, and utilization were measured preworkshop, postworkshop, and 3 months postworkshop. Analyses compared mean change scores at baseline to those at 3-month follow-up. Wilcoxon signed rank tests were completed, and Cohen d effect-size calculations were also computed. RESULTS: Statistical analyses found that participant self-reported CBT knowledge (P < .01, effect size [ES] = 0.49) was significantly improved postworkshop and maintained at 3-month follow-up. Self reported abilities were also improved (P = .07, ES = 0.40). The potency of the training experience appeared to be enhanced by the multimodal nature of the program. CONCLUSION: Although challenges exist, focused and intensive training in CBT appears feasible for multidisciplinary mental health practitioners in the primary care setting. PMID- 20944775 TI - Functional quality of life in full versus partial posttraumatic stress disorder among veterans returning from Iraq and Afghanistan. AB - OBJECTIVE: This study assessed mental and health functioning in full versus partial posttraumatic stress disorder (PTSD) among newly returning veterans from Iraq (Operation Iraqi Freedom [OIF]) and Afghanistan (Operation Enduring Freedom [OEF]) who were referred by primary care providers for a behavioral health assessment and reported an emotional trauma. METHOD: Participants included OEF/OIF veterans receiving care in 2 veterans' affairs medical centers and affiliated community-based outpatient clinics who reported behavioral health issues to their primary care providers. All veterans underwent a clinical behavioral health assessment of Axis I disorders and functioning via telephone between June 2007 and April 2008. Functioning was measured using the 12-item Short-Form Health Survey (SF-12). Those reporting a previous emotional trauma were subsequently assessed for PTSD using the PTSD Patient Checklist (PCL). RESULTS: The final sample (N=201) was 88.1% male with a mean age of 34.2 years (SD=10.1). Individuals with full PTSD (n=120, 59.7%) reported worse mental health functioning compared to those with partial PTSD (n=37, 18.4%). Individuals with partial PTSD reported worse mental health functioning scores than the trauma exposed-only group (n=44, 21.9%). Compared to national norms, patients with partial PTSD reported mental health functioning scores that were worse than 75% of individuals within a similar age range. After controlling for other psychiatric factors, there was no difference between partial PTSD and the trauma only group. CONCLUSION: OEF/OIF veterans with partial PTSD referred for a behavioral health assessment may incur significant problems with functioning. These complaints may be better attributed to psychiatric comorbidity as opposed to symptoms specifically related to trauma. PMID- 20944774 TI - Evaluation of guideline-concordant care for bipolar disorder among privately insured youth. AB - OBJECTIVE: To describe and quantify the prevalence of treatments and services for youth with bipolar disorder and to assess whether concordance with treatment guidelines is associated with inpatient hospitalization and emergency department visits. METHOD: Insurance claims of 423 privately insured youth (ages 6-18) having prescription drug coverage and diagnosed with bipolar disorder were examined from the 2000-2001 Thomson Medstat MarketScan database, a national (US) dataset. Treatments and services were examined for the 6 months following the index bipolar disorder diagnosis, defined as the first diagnosis after a diagnosis-free period of 6 months. RESULTS: The majority of youth did not receive guideline-concordant care. Only 26% (n = 109) received a mood stabilizer or antipsychotic, as recommended, within 1 month of a bipolar diagnosis. Antidepressant monotherapy, which is contraindicated in therapeutic guidelines, was observed for 33% (n = 140) of youth. Less than 40% of youth received adjunctive psychotherapy. Guideline concordance was statistically significantly related to a lower likelihood of an inpatient hospitalization or an emergency department visit. CONCLUSIONS: Although deviation from guidelines may be warranted in some cases due to individual variation and patient complexity or patient and/or family preferences, these findings suggest that evidence-based guidelines are not followed in clinical practice. Incorporation of guideline concordant care may increase the likelihood of overall better quality of care and presage better long-term outcomes for youths diagnosed with bipolar disorder. PMID- 20944777 TI - Galantamine in the treatment of minor depression with mild to moderate Alzheimer's dementia in an elderly woman. PMID- 20944776 TI - Development and pilot study of a marketing strategy for primary care/internet based depression prevention intervention for adolescents (the CATCH-IT intervention). AB - BACKGROUND: Adolescent depression is both common and burdensome, and while evidence-based strategies have been developed to prevent adolescent depression, participation in such interventions remains extremely low, with less than 3% of at-risk individuals participating. To promote participation in evidence-based preventive strategies, a rigorous marketing strategy is needed to translate research into practice. OBJECTIVE: To develop and pilot a rigorous marketing strategy for engaging at-risk individuals with an Internet-based depression prevention intervention in primary care targeting key attitudes and beliefs. METHOD: A marketing design group was constituted to develop a marketing strategy based on the principles of targeting, positioning/competitor analysis, decision analysis, and promotion/distribution and incorporating contemporary models of behavior change. We evaluated the formative quality of the intervention and observed the fielding experience for prevention using a pilot study (observational) design. RESULTS: The marketing plan focused on "resiliency building" rather than "depression intervention" and was relayed by office staff and the Internet site. Twelve practices successfully implemented the intervention and recruited a diverse sample of adolescents with > 30% of all those with positive screens and > 80% of those eligible after phone assessment enrolling in the study with a cost of $58 per enrollee. Adolescent motivation for depression prevention (1-10 scale) increased from a baseline mean value of 7.45 (SD = 2.05) to 8.07 poststudy (SD = 1.33) (P = .048). CONCLUSIONS: Marketing strategies for preventive interventions for mental disorders can be developed and successfully introduced and marketed in primary care. PMID- 20944778 TI - Duloxetine May Improve Tourette's Syndrome: A Case Report. PMID- 20944779 TI - A motivational interviewing group to manage cardiometabolic risk on an inpatient psychiatry unit. PMID- 20944780 TI - Lamotrigine-induced vaginitis and dysuria in an adult woman with bipolar depression. PMID- 20944781 TI - Medically unexplainable somatic symptoms: a coat with many psychiatric colors. PMID- 20944782 TI - Osmotic release oral system (OROS) Methylphenidate-induced double incontinence: a case report. PMID- 20944783 TI - A case of suicidal thoughts with alprazolam. PMID- 20944784 TI - Ziprasidone-induced galactorrhea in an adolescent female: a case report. PMID- 20944785 TI - Acute relapse after successful vagus nerve stimulation therapy: a case report of last-resort ECT treatment. PMID- 20944786 TI - Northeastern Section AUA 62nd Annual Meeting * Pittsburgh, PA * September 22-26, 2010. PMID- 20944787 TI - 2010 NS-AUA Abstracts. PMID- 20944788 TI - 3.4 kb mitochondrial genome deletion serves as a surrogate predictive biomarker for prostate cancer in histopathologically benign biopsy cores. AB - Recently, we described a 3.4-kb mitochondrial genome deletion having significance for identifying malignant and benign prostate tissues (p < 0.001). This biomarker was also present in normal appearing tissue, in close proximity to a tumour indicating a "field effect." In the present study, we report 4 cases (3 malignant, 1 benign) which suggest that this field effect may occur before tumourigenesis; this effect may also identify the presence of a small tumour focus/foci, which are difficult to detect with single or multiple biopsy procedures. PMID- 20944789 TI - Vaginal entrapment of bathwater: a source of extra-urethral incontinence. AB - This report presents 2 cases of females (a prepubertal and a pre-menopausal female) with dribbling "incontinence" caused by vaginal entrapment of bathwater. In the first case, an 8-year-old girl presented with a history of bothersome wetness of her underwear, noted mainly in the morning. History revealed that she bathed almost nightly. She was instructed to shower or bath only, each for one week. The wetting occurred only after bathing. In the second case, a 39-year-old female, G2P2 with normal genitalia noted occasional, yet significant, dribbling into her underwear only after baths. She concluded this to be bathwater accumulating in her vagina, which she evacuates digitally. The differential diagnosis of dribbling incontinence in females of any age should include the extra-urethral cause of entrapped fluids of immersion. Although this condition may be rare, it is simple to rule out on history based on its temporal association with fluid immersion. Once diagnosed, the management is behavioural. PMID- 20944790 TI - Suprapubic cystostomy: a bizarre complication of catheter migration causing ureteric obstruction. AB - Suprapubic catheters are used routinely for bladder drainage; however, complications are commonly reported. These complications could be attributed to surgical technique or the catheter itself. Complications related to surgical technique can be controlled and reduced, but catheter-related complications are unavoidable and unpredictable. We report a rare catheter-related complication leading to obstruction of the ureter in a solitary kidney in a patient with neurogenic bladder and voiding dysfunction managed with suprapubic catheter drainage. PMID- 20944791 TI - A rare case of carcinoma cuniculatum of the penis in a 55-year-old. AB - Carcinoma cuniculatum of the penis is an extremely rare variant of squamous cell carcinoma characterized by an endophytic deeply branching and burrowing growth pattern. One documented case series demonstrated afflicted patients ranging in age from 73-83 years with the tumour located on the glans penis, coronal sulcus or foreskin. We report a case of a 55-year-old with disease located on the ventral aspect of the shaft of the penis. The tumour was invasive into the deep dermal connective tissue, comparatively superficial to all previous documented cases. He subsequently underwent a partial penectomy. The case is discussed with a brief review of the literature. PMID- 20944792 TI - Use of a novel parenchymal clamp for laparoscopic and open partial nephrectomy. AB - Increasing data advocates the wider use of partial nephrectomy for renal tumours amenable to this approach. We describe the initial North American use of a novel parenchymal clamp in an open and a laparoscopic partial nephrectomy. Initial results in 3 patients (2 open, 1 laparoscopic) demonstrate excellent preservation of renal function and good oncologic outcomes. Hilar dissection was avoided in all cases and the estimated blood loss was low. In our small series, we found this device to be a safe and useful adjunct to partial nephrectomy. PMID- 20944793 TI - Can radiotherapy be a viable salvage treatment option for the relapsed seminoma confined to the infra-diaphragm region recurring after primary chemotherapy for bulky stage II seminoma? AB - There has been a paucity of research describing a potential role of radiotherapy as salvage treatment for recurrent seminoma following primary chemotherapy for bulky stage IIC seminoma. We report a case of a bulky stage IIC seminoma relapsed in the pelvis after primary chemotherapy and surgery for post-chemotherapy residual mass, which was subsequently salvaged with radiotherapy. The patient has remained free of relapse at 3.7 years post-salvage radiotherapy. This case demonstrates that radiotherapy can be a salvage therapeutic option for recurrent seminoma following primary chemotherapy for bulky stage IIC seminoma, provided that the recurrent tumour is confined to a limited area of the infradiaphragmatic region. There is a need for further study to examine the potential role of radiotherapy as a salvage therapeutic tool for post-chemotherapy recurrent seminoma. PMID- 20944794 TI - Intravesical migration of an intrauterine device detected in a pregnant woman. AB - The intrauterine device (IUD) is common method of contraception among women because of its low cost and high efficacy. Perforations are possible; most perforations occur at the time of insertion, yet the complication can occur with a previously inserted IUD. Perforation of the bladder by an IUD is extremely rare. In this report, we present a case in which the IUD perforated the uterus and migrated to the bladder. At the time of the diagnosis, the patient was 8 weeks pregnant. PMID- 20944795 TI - Artificial urinary sphincter erosion: the role of corticosteroids in an unusual presentation. AB - Glucocorticosteroid use has proven beneficial for the management of many medical conditions. Unfortunately its anti-inflammatory properties also profoundly affect many aspects of wound healing. We present a case of an unusual presentation of an artificial urinary sphincter erosion in a patient treated with chronic high-dose steroids. PMID- 20944796 TI - Improving quality of care. PMID- 20944797 TI - CUA 2011 in Montreal. PMID- 20944798 TI - Vasectomy update 2010. PMID- 20944800 TI - Does the reflexive measurement of free PSA have a role in a tertiary cancer centre? AB - PURPOSE: The percent free prostate-specific antigen (PSA) may complement total PSA for prostate cancer screening, but is of no benefit for monitoring patients with previous prostate cancer diagnoses. At the Princess Margaret Hospital, a tertiary cancer centre in Toronto, Ontario, Canada, PSA values in the range 4 to 10 ng/mL prompt reflexive measurements of free PSA. We hypothesize that reflexive free PSA testing at tertiary cancer centres generates unnecessary costs as the test is often conducted on patients with previous diagnoses of prostate cancer. MATERIALS AND METHODS: We reviewed all reflexive free PSA measurements conducted on a random sample of 250 men in a 10-year period at our institution. We determined the clinical indications for the PSA tests which triggered reflexive free PSA measurements to estimate the proportion of free PSA tests that are not clinically indicated. RESULTS: We reviewed the 1099 reflexive free PSA measurements for the 250 subjects. Of these tests, 562 (51%) were triggered by PSA tests ordered for screening/early detection, and 537 (49%) for monitoring. CONCLUSIONS: Of all reflexive free PSA tests, 49% were unnecessary. We conducted 3022 free PSA tests, at a cost of $5.84 per test (Can$); the tests were performed in 2009 at this institution for a total cost of $17 648.48, about 49% of which ($8647.76) likely represents unnecessary annual costs. We suggest a trial of user selectable order sets allowing physicians to choose whether to include reflexive free PSA measurements on a case-by-case basis. This policy might improve the cost effectiveness of the PSA test at tertiary cancer centres. PMID- 20944799 TI - 2010 Update: Guidelines for the management of benign prostatic hyperplasia. PMID- 20944801 TI - Reflexive ordering of percent free PSA in patients: Do we need to ask the question? PMID- 20944802 TI - Cost analysis of two follow-up strategies for localized kidney cancer: a Canadian cohort comparison. AB - INTRODUCTION: The cost of surveillance strategies in patients after radical nephrectomy for localized primary renal cell carcinoma (RCC) has not been evaluated. We compared the costs of 2 different surveillance strategies, the new Canadian Urological Association (CUA) guidelines and the old strategy implemented in our institution. METHODS: Seventy-five patients who underwent radical nephrectomy for primary non-metastatic renal cancer were retrospectively reviewed. The direct cost of surveillance was determined and compared with the theoretical cost which would have been accrued using the CUA guidelines. RESULTS: Our mean follow-up was 31.1 (SD +/- 20.4) months. The overall and disease-free survival endpoints were 87.7% and 85.2%, respectively. Total medical costs were higher for our old institutional surveillance strategy than the CUA guidelines ($181 861 vs. $135 054). For the complete follow-up of 75 patients, a cost savings of $46 806 could have been achieved following the CUA guidelines (p = 0.002). Of recurrences, 7 of 8 were detected by routine screening, only 1 recurrence was identified by symptoms. The cost per recurrence detected in our old protocol was $9 812.92. The increased cost of our institution was due to more visits with basic testing, symptomatic investigation, and follow-up of imaging tests. The median percent cost attributable to these extra tests was 15% (range 0 to 59). CONCLUSION: Based on our results, we endorse the new CUA surveillance strategy in RCC follow-up as appropriate and cost effective in comparison with previous follow-up strategies used at our institution. PMID- 20944803 TI - Rational or rationing? Justifying follow-up after management of kidney cancer. PMID- 20944804 TI - Erratum. AB - [This corrects the article on p. 250 in vol. 4, PMID: 20694101.]. PMID- 20944805 TI - Renal and functional outcomes following cystectomy and neobladder reconstruction. AB - BACKGROUND: Orthotopic reconstruction following cystectomy has evolved in an attempt to restore anatomy and function to as close as possible to the preoperative state. We review the renal and functional outcomes of patients who underwent cystectomy and neobladder reconstruction at our institution. METHODS: Between December 2003 and October 2007, 31 patients underwent cystectomy with Studer neobladder reconstruction at the Ottawa Hospital, Ottawa, Ontario, Canada. Follow-up data were obtained regarding renal function (serum creatinine, MUmol/L), continence, urinary flow rates and post-void residual (PVR) at 3, 6 and 12 months after surgery. Change in creatinine from preoperative baseline was calculated and analyzed by student t-test to determine if there was a significant rise in creatinine. RESULTS: There was a statistically significant increase in creatinine from preoperative baseline, with an average increase of 17.3 MUmol/L, 21.8 MUmol/L and 26.3 MUmol/L at 3, 6 and 12 months, respectively. Six patients developed hydronephrosis. Excluding patients with hydronephrosis, there continued to be a statistically significant rise in creatinine with an average increase of 11.9 MUmol/L, 14.7 MUmol/L and 19.4 MUmol/L at 3, 6 and 12 months, respectively. At 1 year, daytime continence was achieved by 89% of patients; 70% were continent at night. INTERPRETATION: Orthotopic neobladders have excellent functional outcomes with low rates of incontinence, which improved throughout follow-up. A significant proportion of patients developed hydronephrosis, highlighting the need for close follow-up to prevent reversible renal deterioration. Creatinine increased during follow-up irrespective of the development of hydronephrosis, but the clinical significance is unknown. PMID- 20944806 TI - Functional outcomes after urinary diversion: The importance of long-term assessment. PMID- 20944807 TI - High-frequency jet ventilation is beneficial during shock wave lithotripsy utilizing a newer unit with a narrower focal zone. AB - INTRODUCTION: High-frequency jet ventilation (HFJV) during shock wave lithotripsy (SWL) has been reported using older lithotripsy units with larger focal zones. We investigated how HFJV affects the clinical parameters of SWL using a newer lithotripsy unit with a smaller focal zone. METHODS: We reviewed all patients who underwent SWL by a single surgeon (KVA) from July 2006 until December 2007 with the Siemens Lithostar Modularis (Siemens AG, Erlangen, Germany). Either HFJV or conventional anesthetic techniques were used based on the anesthesiologists' preference. Preoperative imaging was reviewed for stone size, number and location. Total operating room time, procedure time, number of shocks and total energy delivery were analyzed. Postoperative imaging was reviewed for stone-free rates. RESULTS: A total of 112 patients underwent SWL with 80 undergoing conventional anesthesia, and 32 with HFJV. Age, body mass index, preoperative stone size and number were not significantly different between the groups. The HFJV group required significantly less total shocks (3358 vs. 3754, p = 0.0015) and total energy (115.8 joules vs. 137.2 joules, p = 0.0015). Total operating room time, SWL procedure time and postoperative stone-free rates were not significantly different. CONCLUSIONS: Previous studies using older SWL units with larger focal zones have demonstrated that HFJV can be effective in reducing total shocks and total energy. Our data is consistent with these studies, but also shows benefit with newer units that have narrower focal zones. PMID- 20944809 TI - Laser ablation of the prostate: a safe effective treatment of obstructive benign prostatic disease. PMID- 20944808 TI - Residual renal function after partial or radical nephrectomy for renal cell carcinoma. AB - Renal cell carcinoma (RCC) is often detected incidentally and early. Currently, open partial nephrectomy and laparoscopic total nephrectomy form competing technologies. The former is invasive, but nephron-sparing; the other is considered less invasive but with more loss of renal mass. Traditionally, emphasis has been placed on oncologic outcomes. However, a patient with an excellent oncologic outcome may suffer from morbidity and mortality related to renal failure. Animal models with hypertension and diabetic renal disease indicate accelerated progression of pre-existing disease after nephrectomy. Patients with RCC are older and they have a high prevalence of diabetes and hypertension. The progression of renal failure may also be accelerated after a nephrectomy. Our analysis of the available literature indicates that renal outcomes in RCC patients after surgery are relatively poorly defined. A strategy to systematically evaluate the renal function of patients with RCC, with joint discussion between the nephrologist and the oncologic team, is strongly advocated. PMID- 20944810 TI - TURP in the new century: an analytical reappraisal in light of lasers. PMID- 20944811 TI - Gene therapy for muscular dystrophies: progress and challenges. AB - Muscular dystrophies are groups of inherited progressive diseases of the muscle caused by mutations of diverse genes related to normal muscle function. Although there is no current effective treatment for these devastating diseases, various molecular strategies have been developed to restore the expressions of the associated defective proteins. In preclinical animal models, both viral and nonviral vectors have been shown to deliver recombinant versions of defective genes. Antisense oligonucleotides have been shown to modify the splicing mechanism of mesenger ribonucleic acid to produce an internally deleted but partially functional dystrophin in an experimental model of Duchenne muscular dystrophy. In addition, chemicals can induce readthrough of the premature stop codon in nonsense mutations of the dystrophin gene. On the basis of these preclinical data, several experimental clinical trials are underway that aim to demonstrate efficacy in treating these devastating diseases. PMID- 20944812 TI - Cost-effectiveness of recombinant tissue plasminogen activator in the management of acute ischemic stroke: a systematic review. AB - BACKGROUND AND PURPOSE: This work was undertaken to review the current cost effectiveness analysis data on thrombolysis by intravenous (IV) therapy with recombinant tissue plasminogen activator (rtPA) for acute ischemic stroke. METHODS: PubMed was searched for articles published between 1995 and 2008. The cost-effectiveness analysis data from eight eligible studies were reviewed, paying particular attention to their modeling assumptions and the quality of the source data. RESULTS: THE REVIEWED STUDIES WERE FROM SIX COUNTRIES: USA (n=2), UK (n=2), Canada (n=1), Australia (n=1), Spain (n=1), and Denmark (n=1); most were performed from the healthcare-system and/or societal perspectives. IV rtPA was associated with an acceptable increase in short-term cost [range: US$ 36 236/patient; US$ 29,148-55,591/quality-adjusted life-years (QALYs)], and a net long-term cost saving that was higher from a societal perspective (range: -US$ 12,043 to -US$ 630/patient; -US$ 207,253 to -US$ 21,938/QALYs) than from a healthcare-system perspective (range: -US$ 5,811 to -US$ 5,415/patient; -US$ 41,137 to -US$ 4,662/QALYs). CONCLUSIONS: IV rtPA seems to be a cost-effective strategy for the management of acute ischemic stroke, and might reduce the associated healthcare costs as well as patients' disabilities. Further cost effectiveness research and the development of a public health strategy are warranted to optimize the use of rtPA in Korea. PMID- 20944813 TI - Melatonin Potentiates the Neuroprotective Properties of Resveratrol Against Beta Amyloid-Induced Neurodegeneration by Modulating AMP-Activated Protein Kinase Pathways. AB - BACKGROUND AND PURPOSE: Recent studies have demonstrated that resveratrol (RSV) reduces the incidence of age-related macular degeneration, Alzheimer's disease (AD), and stroke, while melatonin (MEL) supplementation reduces the progression of the cognitive impairment in AD patients. The purpose of this investigation was to assess whether the co-administration of MEL and RSV exerts synergistic effects on their neuroprotective properties against beta-amyloid (Abeta)-induced neuronal death. METHODS: The neuroprotective effects of co-treatment with MEL and RSV on Abeta1-42-induced cell death, was measured by MTT reduction assay. Abeta1-42 caused an increase in intracellular levels of reactive oxygen species (ROS), as assessed by H(2)-DCF-DA dye, and a reduction of total glutathione (GSH) levels and mitochondrial membrane potential, as assessed using monochlorobimane and rhodamine 123 fluorescence, respectively. Western blotting was used to investigate the intracellular signaling mechanism involved in these synergic effects. RESULTS: We treated a murine HT22 hippocampal cell line with MEL or RSV alone or with both simultaneously. MEL and RSV alone significantly attenuated ROS production, mitochondrial membrane-potential disruption and the neurotoxicity induced by Abeta1-42. They also restored the Abeta1-42-induced depletion of GSH, back to within its normal range and prevented the Abeta1-42-induced activation of glycogen synthase kinase 3beta (GSK3beta). However, co-treatment with MEL and RSV did not exert any significant synergistic effects on either the recovery of the Abeta1-42-induced depletion of GSH or on the inhibition of Abeta1-42-induced GSK3beta activation. Abeta1-42 treatment increased AMP-activated protein kinase (AMPK) activity, which is associated with subsequent neuronal death. We demonstrated that MEL and RSV treatment inhibited the phosphorylation of AMPK. CONCLUSIONS: Together, our results suggest that co-administration of MEL and RSV acts as an effective treatment for AD by attenuating Abeta1-42-induced oxidative stress and the AMPK-dependent pathway. PMID- 20944814 TI - Prehospital notification from the emergency medical service reduces the transfer and intra-hospital processing times for acute stroke patients. AB - BACKGROUND AND PURPOSE: There is little information available about the effects of Emergency Medical Service (EMS) hospital notification on transfer and intrahospital processing times in cases of acute ischemic stroke. METHODS: This study retrospectively investigated the real transfer and imaging processing times for cases of suspected acute stroke (AS) with EMS notification of a requirement for intravenous (IV) tissue-type plasminogen activator (t-PA) and for cases without notification. Also we compared the intra-hospital processing times for receiving t-PA between patients with and without EMS prehospital notification. RESULTS: Between December 2008 and August 2009, the EMS transported 102 patients with suspected AS to our stroke center. During the same period, 33 patients received IV t-PA without prehospital notification from the EMS. The mean real transfer time after the EMS call was 56.0+/-32.0 min. Patients with a transfer distance of more than 40 km could not be transported to our center within 60 min. Among the 102 patients, 55 were transferred via the EMS to our emergency room for IV t-PA. The positive predictive value for stroke (90.9% vs. 68.1%, p=0.005) was much higher and the real transfer time was much faster in patients with an EMS t PA call (47.7+/-23.1 min, p=0.004) than in those without one (56.3+/-32.4 min). The door-to-imaging time (17.8+/-11.0 min vs. 26.9+/-11.5 min, p=0.01) and door to-needle time (29.7+/-9.6 min vs. 42.1+/-18.1 min, p=0.01) were significantly shorter in the 18 patients for whom there was prehospital notification and who ultimately received t-PA than in those for whom there was no prehospital notification. CONCLUSIONS: Our results indicate that prehospital notification could enable the rapid dispatch of AS patients needing IV t-PA to a stroke centre. In addition, it could reduce intrahospital delays, particularly, imaging processing times. PMID- 20944815 TI - There is No Association between Cardiovascular Autonomic Dysfunction and Peripheral Neuropathy in Chronic Hemodialysis Patients. AB - BACKGROUND AND PURPOSE: The potential association between the severity of autonomic dysfunction and peripheral neuropathy has not been extensively investigated, with the few studies yielding inconsistent results. We evaluated the relationship between autonomic dysfunction and peripheral neuropathy in chronic hemodialysis patients in a cross-sectional study. METHODS: Cardiovascular autonomic function was assessed in 42 consecutive patients with chronic renal failure treated by hemodialysis, using a standardized battery of 5 cardiovascular reflex tests. Symptoms of autonomic dysfunction and of peripheral neuropathy were evaluated using the Autonomic Neuropathy Symptom Score (ANSS) and the Neuropathy Symptoms Score. Neurological deficits were assessed using the Neuropathy Disability Score. Conduction velocities along the sensory and motor fibers of the sural and peroneal nerves were measured. Thermal thresholds were documented using a standardized psychophysical technique. RESULTS: Parasympathetic and sympathetic dysfunction was prevalent in 50% and 28% of cases, respectively. Peripheral neuropathy was identified in 25 cases (60%). The prevalence of peripheral neuropathy did not differ between patients with impaired (55%) and normal (75%) autonomic function (p=0.297; Fisher's exact test). The electrophysiological parameters for peripheral nerve function, neuropathic symptoms, abnormal thermal thresholds, age, gender, and duration of dialysis did not differ significantly between patients with and without autonomic dysfunction. Patients with autonomic dysfunction were more likely to have an abnormal ANSS (p=0.048). The severity of autonomic dysfunction on electrophysiological testing was positively correlated with ANSS (r=0.213, p=0.036). CONCLUSIONS: The present data indicate that although cardiovascular autonomic dysfunction is prevalent among patients with chronic renal failure, it is not associated with the incidence of peripheral neuropathy. PMID- 20944816 TI - Behavioral changes as the earliest clinical manifestation of progressive supranuclear palsy. AB - BACKGROUND: The clinical and pathological heterogeneity of progressive supranuclear palsy (PSP) is well established. Even with a well-defined clinical phenotype and a thorough laboratory workup, PSP can be misdiagnosed, especially in its early stages. CASE REPORT: A 52-year-old woman, who we initially diagnosed with a behavioral variant of frontotemporal dementia developed parkinsonian features, which then progressed to gait instability and gaze abnormality. CONCLUSIONS: We report herein a pathologically confirmed case of PSP presenting with behavioral changes including agitation and irritability, which eventually led to the cardinal symptoms of progressive supranuclear palsy. PMID- 20944817 TI - Takotsubo cardiomyopathy following cerebral infarction involving the insular cortex. AB - BACKGROUND: Takotsubo cardiomyopathy is characterized by clinical features similar to those of acute myocardial ischemia, but without angiographic evidence of obstructive coronary artery disease. We present a patient with takotsubo cardiomyopathy following acute infarction involving the left insular cortex. CASE REPORT: A 52-year-old man was admitted with acute infarction of the left middle cerebral artery territory and acute chest pain. Acute myocardial infarction was suspected because of elevated serum troponin levels and hypokinesia of the left ventricle on echocardiography. However, a subsequent coronary angiography revealed no stenosis within the coronary arteries or ballooning of the apical left ventricle. CONCLUSIONS: We postulated that catecholamine imbalance due to the insular lesion could be responsible for these interesting features. PMID- 20944818 TI - Mononeuropathy multiplex in a patient with chronic active hepatitis B. AB - BACKGROUND: Mononeuropathy multiplex is a rare complication during the course of chronic hepatitis B, despite various neuropathies following acute hepatitis B having been reported previously. CASE REPORT: A 30-year-old man presented with sensorimotor symptoms in multiple peripheral nerves. The serological tests for hepatitis were consistent with chronic active hepatitis B. After treatment with oral prednisone combined with an antiviral agent, the sensory and motor symptoms improved and hepatitis B virus replication was reduced. CONCLUSIONS: We suggest that chronic immune-mediated neuropathy associated with hepatitis B virus infection should be considered in the differential diagnosis of patients with hepatitis B. PMID- 20944820 TI - Beyond the monthly seizure count. PMID- 20944819 TI - Epilepsy Care in Developing Countries: Part II of II. AB - Although 80% of people with epilepsy reside in resource poor, developing countries, epilepsy care in these regions remains limited and the majority of epilepsy patients go untreated. Cost-effective, sustainable epilepsy care services, delivering first-line antiepileptic drugs through established primary health care facilities, are needed to decrease these treatment gaps. Neurologists with local experience and knowledge of the culture, who are willing to serve as educators, policy advisors, and advocates, can make a difference. This is Part II of a two-part article. Part I reviewed the burden of epilepsy and the current state of resources for treatment in developing countries, while Part II will now discuss various aspects of care in these countries. PMID- 20944821 TI - Pharmacokinetic interactions with antiepileptic drugs: always the bad actor or simply misunderstood? PMID- 20944822 TI - Focal and generalized: both here and there. PMID- 20944824 TI - Axon sprouting and synaptic reorganization of GABAergic interneurons: a focused look at a general question. PMID- 20944823 TI - Primary and secondary mechanisms of epileptogenesis in the temporal lobe: there is a before and an after. AB - Extensive data involving several animal models of temporal lobe epilepsy highlight synaptic alterations that likely act synergistically during acquired epileptogenesis. Most of this research has utilized experimental models in which intense electrical activity in adult animals, primarily involving status epilepticus, causes variable neuronal death in the hippocampus and other temporal lobe structures. Neuronal death, including principal cells and specific interneurons, likely has several roles in epileptogenesis after brain injury. Both reduction of GABA-mediated inhibition from selective interneuron loss and the progressive formation of new recurrent excitatory circuits after death of principal neurons enhance excitability and promote seizures during the development of epilepsy. These epileptogenic circuits hypothetically continue to undergo secondary epileptogenesis, which involves further modifications that contribute to a progressive, albeit variable, increase in the frequency and severity of spontaneous recurrent seizures. PMID- 20944825 TI - Another Look at Early GABAergic Neurotransmission: Maybe It's Not So Exciting After All! PMID- 20944826 TI - Too much inhibition leads to excitation in absence epilepsy. PMID- 20944827 TI - Out of (Dis)order? The Dynamics of Seizure Initiation. PMID- 20944828 TI - Interictal spikes: memories forsaken. PMID- 20944834 TI - Acyclic diene metathesis: a versatile tool for the construction of defined polymer architectures. AB - Two decades have passed since the metathesis polymerisation of alpha,omega-dienes was successfully demonstrated by the group of Wagener and the term acyclic diene metathesis (ADMET) polymerisation was coined. Since then, the advances of metathesis chemistry have allowed to expand the scope of this versatile polymerisation reaction that nowadays finds applications in different fields, such as polymer, material, or medicinal chemistry. This critical review provides an insight into the historical aspects of ADMET and a detailed overview of the work done to date applying this versatile polymerisation reaction (221 references). PMID- 20944835 TI - Cobalt in NaBH4 hydrolysis. AB - Cobalt-catalyzed hydrolysis of sodium borohydride (NaBH(4)) has attracted great attention since the hydride is believed to be promising hydrogen storage material. Cobalt is an efficient metal catalyst and has already proven to be a potential alternative to noble metals. Nevertheless it is not stable. Indeed it transforms into a Co- and B-based material when on contact with NaBH(4). Through ex situ characterizations (e.g. ICP, XRD, XPS and SEM), the Co- and B-based material has been supposed to be either a cobalt boride Co(x)B (with x from 1 to 3) or a Co-B alloy. This contradiction is the topic of the present paper. Herein, the literature dedicated to the Co-catalyzed NaBH(4) hydrolysis is exhaustively surveyed. The results of the ex situ characterizations are largely discussed, for example that: (i) the ex situ characterized Co(x)B or Co-B might be different from the in situ formed Co- and B-based catalyst; (ii) there is no clear evidence of the formation of either Co(x)B or Co-B; (iii) the in situ formed catalyst would change in accordance with a cycle in the course of the hydrolysis; and (iv) in situ characterizations are clearly required but their setting up is a challenge. These conclusions, among others, are argued. PMID- 20944836 TI - PFOS or PreFOS? Are perfluorooctane sulfonate precursors (PreFOS) important determinants of human and environmental perfluorooctane sulfonate (PFOS) exposure? AB - The extent to which perfluorooctanesulfonate precursors (PreFOS) play a role in human or environmental exposure to perfluorooctanesulfonate (PFOS) is not well characterized. The diversity of manufactured PreFOS and its degradation products (e.g. C(8)F(17)SO(2)R and C(8)F(17)SO(2)NR'R'', where R is H or F, and R' and R'' are various) has made it difficult to track their fate. Temporal trends of PFOS in both humans and wildlife are discrepant, thus it is difficult to predict future exposure, and hypotheses about the role of PreFOS have been raised. Although abiotic degradation of commercially important PreFOS materials requires further research, current data suggest that the yield of PFOS is negligible or minor. On the other hand, in vivo biotransformation of PreFOS yields PFOS as the major metabolite, and >32% yields have been observed. In Canadians, exposure to PreFOS was equivalent or greater than direct PFOS exposure prior to 2002. In most ocean water, PFOS is dominant to PreFOS, but in the oceans east of Greenland there may be more PreFOS than PFOS, consistent with the fact that whales and humans in this region also show evidence of substantial PreFOS exposure. Quantitative assessments of PFOS body-burdens coming from PreFOS are complicated by the fact that PreFOS partitions to the cellular fraction of blood, thus biomonitoring in serum under predicts PreFOS relative to PFOS. Many unknowns exist that prevent accurate modelling, thus analytical methods that can distinguish directly manufactured PFOS, from PFOS that has been biotransformed from PreFOS, should be applied in future human and environmental monitoring. Two new source tracking principles are presented and applied to human serum. PMID- 20944838 TI - Are dopant-stabilized visible light-responsive photocatalysts efficient and stable? AB - Nitrogen and carbon codopants-stabilized hierarchical porous ZnS microspheres undergo an unexpected dynamic transformation into hollow microspheres when nitrogen and carbon are removed from the former. Thus, such a transformation is evidence for the unprecedented stability of non-metal doped visible light responsive photocatalysts. PMID- 20944837 TI - Controlled formation of calcium-phosphate-based hybrid mesocrystals by organic inorganic co-assembly. AB - An understanding of controlled formation of biomimetic mesocrystals is of great importance in materials chemistry and engineering. Here we report that organic inorganic hybrid plates and even mesocrystals can be conveniently synthesized using a one-pot reaction in a mixed system of protein (bovine serum albumin (BSA)), surfactant (sodium bis(2-ethylhexyl) sulfosuccinate (AOT)) and supersaturated calcium phosphate solution. The morphologies of calcium-phosphate based products are analogous to the general inorganic crystals but they have abnormal and interesting substructures. The hybrids are constructed by the alternate stacking of organic layer (thickness of 1.31 nm) and well-crystallized inorganic mineral layer (thickness of 2.13 nm) at the nanoscale. Their morphologies (spindle, rhomboid and round) and sizes (200 nm-2 MUm) can be tuned gradually by changing BSA, AOT and calcium phosphate concentrations. This modulation effect can be explained by a competition between the anisotropic and isotropic assembly of the ultrathin plate-like units. The anisotropic assembly confers mesocrystal characteristics on the hybrids while the round ones are the results of isotropic assembly. However, the basic lamellar organic-inorganic substructure remains unchanged during the hybrid formation, which is a key factor to ensure the self-assembly from molecule to micrometre scale. A morphological ternary diagram of BSA-AOT-calcium phosphate is used to describe this controlled formation process, providing a feasible strategy to prepare the required materials. This study highlights the cooperative effect of macromolecule (frame structure), small biomolecule (binding sites) and mineral phase (main component) on the generation and regulation of biomimetic hybrid mesocrystals. PMID- 20944839 TI - Simultaneous in situ generation of hydrogen peroxide and Fenton reaction over Pd Fe catalysts. AB - High mineralization degree of organic compounds can be achieved by a novel environmentally-friendly full heterogeneous Pd-Fe catalytic system, which involves in situ generation of hydrogen peroxide from formic acid and oxygen, and oxidation of organic compounds by Fenton process in a one-pot reaction. PMID- 20944840 TI - Preparation and characterization of lanthanide-azo-dye coordination polymers and polymer thin films via layer-by-layer depositions. AB - A series of tartrazine-lanthanide dye compounds has been synthesized and characterized. Structural studies reveal that the light rare-earth elements La, Ce, Pr and Nd form coordination compounds with tartrazine ligands in a 1:1 ratio and result in 1-D 'fish-bone' chain-like structures having uncoordinated organosulfonate groups on each side of the chain. However, reactions of tartrazine and heavy rare-earth elements Ho, Er, Tm and Yb, in the presence of auxiliary 1,10-phenanthroline, give new 1-D coordination polymers in which uncoordinated organosulfonate groups are located on the same side of the chains. The tartrazine ligands display similar but slightly different coordination modes in both types of structures and the 1,10-phenanthroline plays a vital role in the formation of heavy rare-earth dye compounds. Based on the knowledge of their structures, the light rare-earth dye compounds were utilized to assemble with positively-charged PEI into multilayer thin films by means of layer-by-layer depositions. The as-synthesized thin films showed enhanced stability and consistency on solid surfaces. PMID- 20944841 TI - Aptamer-barcode based immunoassay for the instantaneous derivatization chemiluminescence detection of IgE coupled to magnetic beads. AB - We report on a highly sensitive aptameric assay system for the determination of IgE, where a special chemiluminescence (CL) reagent, 3,4,5 trimethoxylphenylglyoxal (TMPG), acts as the signaling molecule and polystyrene beads as the amplification platform. Briefly, a "sandwich-type" detection strategy is employed in our design, where magnetic beads functionalized with a capture antibody were reacted with the target protein IgE, and then sandwiched with the aptamer-barcodes which were prepared by assembling polystyrene beads with IgE aptamer. The target immunoreaction event could be sensitively detected via an instantaneous derivatization reaction between TMPG and the guanine (G) nucleotides within the aptamer-barcodes to form an unstable CL intermediate for the generation of light. Further signal amplification is achieved by extending the G nucleotide-rich domain on the aptamer backbone for second amplification. Such simple amplified CL transduction allows the detection of IgE down to the 4.6 pM level, which is better than most previous aptameric methods for IgE detection. This new protocol also provides a good capability in discriminating IgE from nontarget proteins such as IgG, IgA, IgM, interferon and thrombin. The practical application of the proposed aptamer-barcode based immunoassay was successfully carried out for the determination of IgE in 20 human serum samples. It is straightforward to adapt this strategy to detect a spectrum of other proteins by using different aptamers, thus this method may offer a new direction in designing high-performance CL aptasensors for early diagnoses of diseases. PMID- 20944842 TI - Pd-catalysed regioselective C-H functionalisation of 2-pyrones. AB - A new synthetic methodology for the catalytic C-H functionalisation of 2-pyrones is described which proceeds regioselectively at the C3 position, mirroring the observed regioselectivity in 6pi-electrocyclisation/oxidative aromatisation reactions of related compounds. Insight into the reaction mechanism is provided, with support for a neutral palladium(II) pathway. Cationic palladium(II) complexes possessing 2-pyrones are unstable and readily undergo Pd(II)->P transfer at ambient temperature resulting in phosphonium salt formation (and Pd(0)L(n) species). PMID- 20944843 TI - Biocompatible glutathione capped gold clusters as one- and two-photon excitation fluorescence contrast agents for live cells imaging. AB - The one- and two-photon excitation emission properties of water soluble glutathione monolayer protected gold clusters were investigated. Strong two photon emission was observed from the gold clusters. The two-photon absorption cross section of these gold clusters in water was deduced from the z-scan measurement to be 189 740 GM, which is much higher compared to organic fluorescent dyes and quantum dots. These gold clusters also showed high photo stability. The MTT assay showed that these gold clusters have low toxicity even at high concentrations. We have successfully demonstrated their applications for both one and two-photon excitation live cell imaging. The exceptional properties of these gold clusters make them a promising alternative for one- and two-photon bio-imaging and other nonlinear optical applications. PMID- 20944844 TI - The Co-Au interface in bimetallic nanoparticles: a high resolution STEM study. AB - We report the formation of Au/Co nanoparticles and their characterization by aberration (Cs) corrected scanning transmission electron microscopy (STEM). The nanoparticles were synthesized by inert gas condensation, forming initially core shell and bimetallic crystals. However, after thermal treatment at normal atmospheric conditions, the Co nanoparticles changed their morphology into a fine layer forming a perfect interface with the gold. The ordering of the zone rich in Co presents a fcc arrangement matching the gold lattice. The atomic analysis on the interface and the comparison of the STEM images with numerical simulations corroborated the atomic substitution of gold by cobalt. PMID- 20944845 TI - Melamine sensing through riboflavin stabilized gold nanoparticles. AB - Melamine (M) sensing has been achieved through supramolecular assembly with riboflavin (R) via H-bonding in the platform of R stabilized gold nanoparticles (R-Au NPs), by colorimetric as well as UV-vis techniques. PMID- 20944846 TI - Confocal Raman microspectral imaging (CRMI) of murine stem cell colonies. AB - Confocal Raman micro-spectral imaging (CRMI) is a relatively novel technique for the construction of label-free images of biological entities, such as cells or tissue sections. This method utilizes thousands of spatially resolved Raman spectra, and sophisticated image analysis algorithms, to construct images which are based strictly on the inherent biochemical abundance contrast afforded by Raman microscopy. Here, we apply this methodology to monitor the very early communication processes that occur in a growing stem cell colony, yielding information on biochemical composition during development processes of the early stages of embryogenesis. PMID- 20944847 TI - Towards catenanes using pi-stacking interactions and their influence on the spin state of a bis(2,2':6',2"terpyridine)iron(II) domain. AB - The ligand 6,6"bis(4-methoxyphenyl)-4'-phenyl-2,2':6',2"terpyridine (2) has been prepared and characterized; deprotection using pyridinium chloride leads to the formation of 6,6"bis(4-hydroxyphenyl)-4'-phenyl-2,2':6',2"terpyridinium chloride ([H3]Cl). Treatment of the latter with 3-(2-(2-bromoethoxy)ethoxy)prop-1-ene under basic conditions yields ligand 4 containing pendant, alkene-terminated chains. Whereas direct complexation of 4 with ruthenium(II) proved problematical, the homoleptic complexes [Fe(2)(2)][PF(6)](2) and [Ru(2)(2)][PF(6)](2) were prepared in good to moderate yields. In the solid state, both complexes exhibit multiple face-to-face pi-stacking of arene and pyridine rings which influences the coordination geometry about the metal ion. Consequential weakening of the ligand field results in [Fe(2)(2)][PF(6)](2) being high-spin. Variable temperature solution (1)H NMR spectroscopic studies confirm the iron(ii) centre remains high-spin between 200 and 295 K. The paramagnetically shifted (1)H NMR spectrum exhibits signals in the range delta 109.7 to -66.5 ppm and has been fully assigned. Paramagnetic relaxation enhancement (PRE) has been used to correlate the observed proton line-widths to the distances of the protons from the metal centre and these are in good agreement with the Fe...H separations observed in the solid state. The [Fe(2)(2)](2+) ion undergoes two dynamic processes (i) rotation of the pendant phenyl rings which is fast on the NMR timescale at 200 K, and (ii) twisting and sliding of the aromatic rings of the tpy and anisyl units which interconverts the two enantiomers of [Fe(2)(2)](2+) at 295 K. PMID- 20944849 TI - Stability of thin film glasses of toluene and ethylbenzene formed by vapor deposition: an in situ nanocalorimetric study. AB - Vapor deposited thin films (~100 nm thickness) of toluene and ethylbenzene grown by physical vapor deposition show enhanced stability with respect to samples slowly cooled from the liquid at a rate of 5 K min(-1). The heat capacity is measured in situ immediately after growth from the vapor or after re-freezing from the supercooled liquid at various heating rates using quasi-adiabatic nanocalorimetry. Glasses obtained from the vapor have low enthalpies and large heat capacity overshoots that are shifted to high temperatures. The stability is maximized at growth temperatures in the vicinity of 0.8 T(g) for both molecules, although glasses of ethylbenzene show superior stabilization. Our data is consistent with previous results of larger organic molecules suggesting a generalized behavior on the stability of organic glasses grown from the vapor. In addition, we find that for the small molecules analyzed here, slowing the growth rate below 0.1 nm s(-1) does not result in increased thermodynamic stability. PMID- 20944848 TI - High electrochemiluminescence of a new water-soluble iridium(III) complex for determination of antibiotics. AB - A new water-soluble iridium(III) diimine complex with appended sugar was synthesized and characterized. The electrochemiluminescent behavior of the new complex in aqueous buffer was first studied and the ECL signal was found to be much higher than that of [Ru(bpy)(3)](2+) at a Pt working electrode. Tri-n propylamine (TPA) and antibiotics were determined by the ECL of the iridium(III) complex in aqueous buffer at the Pt electrode and the method was found to show good sensitivity and reproducibility. The new iridium(III) complex was found to display good solubility in aqueous solution and a strong ECL signal at the Pt electrode, which might open up the possibility of its application in analysis. PMID- 20944850 TI - A novel C-shaped, gold nanoparticle coated, embedded polymer waveguide for localized surface plasmon resonance based detection. AB - In this study, a novel embedded optical waveguide based sensor which utilizes localized surface plasmon resonance of gold nanoparticles coated on a C-shaped polymer waveguide is being reported. The sensor, as designed, can be used as an analysis chip for detection of minor variations in the refractive index of its microenvironment, which makes it suitable for wide scale use as an affinity biosensor. The C-shaped waveguide coupled with microfluidic channel was fabricated by single step patterning of SU8 on an oxidized silicon wafer. The absorbance due to the localized surface plasmon resonance (LSPR) of SU8 waveguide bound gold nano particle (GNP) was found to be linear with refractive index changes between 1.33 and 1.37. A GNP coated C-bent waveguide of 200 MU width with a bend radius of 1 mm gave rise to a sensitivity of ~5 DeltaA/RIU at 530 nm as compared to the ~2.5 DeltaA/RIU (refractive index units) of the same dimension bare C-bend SU8 waveguide. The resolution of the sensor probe was ~2 * 10(-4) RIU. PMID- 20944851 TI - Systematic prediction error correction: a novel strategy for maintaining the predictive abilities of multivariate calibration models. AB - The development of reliable multivariate calibration models for spectroscopic instruments in on-line/in-line monitoring of chemical and bio-chemical processes is generally difficult, time-consuming and costly. Therefore, it is preferable if calibration models can be used for an extended period, without the need to replace them. However, in many process applications, changes in the instrumental response (e.g. owing to a change of spectrometer) or variations in the measurement conditions (e.g. a change in temperature) can cause a multivariate calibration model to become invalid. In this contribution, a new method, systematic prediction error correction (SPEC), has been developed to maintain the predictive abilities of multivariate calibration models when e.g. the spectrometer or measurement conditions are altered. The performance of the method has been tested on two NIR data sets (one with changes in instrumental responses, the other with variations in experimental conditions) and the outcomes compared with those of some popular methods, i.e. global PLS, univariate slope and bias correction (SBC) and piecewise direct standardization (PDS). The results show that SPEC achieves satisfactory analyte predictions with significantly lower RMSEP values than global PLS and SBC for both data sets, even when only a few standardization samples are used. Furthermore, SPEC is simple to implement and requires less information than PDS, which offers advantages for applications with limited data. PMID- 20944852 TI - Design and synthesis of a novel three-hindered quadrant bisphosphine ligand and its application in asymmetric hydrogenation. AB - A novel three hindered quadrant bisphosphine ligand has been synthesized. The ligand shows excellent enantioselectivities and reactivities for rhodium catalyzed hydrogenations of various functionalized olefins. PMID- 20944853 TI - Optimum concentration gradient of the electrocatalyst, Nafion(r) and poly(tetrafluoroethylene) in a membrane-electrode-assembly for enhanced performance of direct methanol fuel cells. AB - A combinatorial library of membrane-electrode-assemblies (MEAs) which consisted of 27 different compositions was fabricated to optimize the multilayer structure of direct methanol fuel cells. Each spot consisted of three layers of ink and a gradient was generated by employing different concentrations of the three components (Pt catalyst, Nafion(r) and polytetrafluoroethylene (PTFE)) of each layer. For quick evaluation of the library, a high-throughput optical screening technique was employed for methanol electro-oxidation reaction (MOR) activity. The screening results revealed that gradient layers could lead to higher MOR activity than uniform layers. It was found that the MOR activity was higher when the concentrations of Pt catalyst and Nafion ionomer decreased downward from the top layer to the bottom layer. On the other hand, higher MOR activity was observed when PTFE concentration increased downward from the top to the bottom layer. PMID- 20944854 TI - Self-organized distribution of periodicity and chaos in an electrochemical oscillator. AB - We report a detailed numerical investigation of a prototype electrochemical oscillator, in terms of high-resolution phase diagrams for an experimentally relevant section of the control (parameter) space. The prototype model consists of a set of three autonomous ordinary differential equations which captures the general features of electrochemical oscillators characterized by a partially hidden negative differential resistance in an N-shaped current-voltage stationary curve. By computing Lyapunov exponents, we provide a detailed discrimination between chaotic and periodic phases of the electrochemical oscillator. Such phases reveal the existence of an intricate structure of domains of periodicity self-organized into a chaotic background. Shrimp-like periodic regions previously observed in other discrete and continuous systems were also observed here, which corroborate the universal nature of the occurrence of such structures. In addition, we have also found a structured period distribution within the order region. Finally we discuss the possible experimental realization of comparable phase diagrams. PMID- 20944855 TI - Synthesis, crystal and electronic structures of the new quaternary phases A5Cd2Sb5F (A = Sr, Ba, Eu), and Ba5Cd2Sb5O(x) (0.50.05). In the same way, no significant differences were found between materials, cavity types or operators (p>0.05). The ART approach was highly appropriate and effective in restorations involving two or more tooth surfaces, after 6 months. The results showed a promising performance of the ART technique with both materials. PMID- 20944875 TI - Comparative analysis of the visualization of small files using digital and conventional radiography. AB - The present work was designed to carry out a comparative analysis of the visualization of small files using digital and conventional radiographs. Forty maxillary molars inserted in human skulls were used; Maillefer K-files #06, #08, #10 and #15 were inserted in the mesiobuccal canals and measured at 0.5mm beyond and 1.5mm before the tip with 0.5-mm intervals, in order to allow five professionals to observe whether the files were at the limit, before or beyond the foramen when visualized on conventional radiographs taken on Insight Kodak film (Eastman Kodak, Rochester, NY, USA) and with the RVG digital system (Trophy). Based on the results obtained, the conclusions were: with the two systems it was possible to visualize #06 K-files in nearly 60% of the evaluated cases; for the others, #08, #10 and #15 K-files, visualization was higher with both radiographic systems, achieving 82% of correct visualization for #15 K-files with the conventional system. The differences between the results of the two systems studied - conventional (Insight film, Kodak F-speed) and last generation digital (RVG - Trophy) radiographs - were not statistically significant according to the Student's t test. PMID- 20944876 TI - Oral health of building construction workers: an epidemiological approach. AB - This cross-sectional study aimed at evaluating the oral health conditions of building construction workers from a city in the mid-west region of Sao Paulo, Brazil. This study involved 219 male subjects, aged 17 to 72. The definition of a random sample utilized the functional number of each worker as a criterion to the raffle, which took into account all 450 subjects registered in the Working Accidents Prevention Program. The examination of oral health conditions by DMFT index and need of treatment were carried out according to WHO criteria (1997). This paper reports the prevalence of caries according to age, occupation, and educational level. Among the 219 workers examined, the mean DMFT was 16.9. Amongst the younger workers (<25 years-old), 21.3 teeth showed no need of treatment, while the older ones showed increasing treatment needs (p<0.001). The DMFT values were 15.6 for the administrative duties and 21.7 for foremen and bricklayers, although the differences were not statistically significant. The DMFT index showed an increase with age for all groups (p<0.001). The self reported need of treatment was associated with a smaller DMFT for people that reported a positive response when compared with subjects that did not report these needs (p<0.05). These differences were statistically significant, as tested by ANOVA and Student t test. Among the building construction workers, in this study, important oral lesions were not observed, despite the daily exposition to some risk factors for oral cancer. PMID- 20944877 TI - Comparison of different methods for the occlusal dentine caries diagnosis. AB - The aim of this study was to compare the effectiveness of in-vitro methods for the occlusal dentine caries diagnosis. Thirty-eight sites were evaluated on third molars without macroscopic carious cavitation in adult individuals from the city of Barretos (SP), Brazil. Visual inspection (VI), endoscopic evaluation (AcuCam), visual inspection and blunt-tipped exploratory probes (Tactile), conventional bite-wing radiographs (CR), direct bite-wing digital radiograph (DR), and direct digital radiograph with contrast and brightness controled (DRbc) were used by five observers. In order to validate the data, the teeth were sectioned and histologically evaluated. The average sensitivity and specificity values of the methods were respectively:0,25 , 0,96 (VI); 0,15 , 0,92 (AcuCam); 0,17 , 0,95 (Tactile); 0,45 , 0,73 (CR); 0,33 , 0,80 (DR) and 0,35 , 0,84 (DRbc) , the effectiveness of clinical methods (VI, AcuCam and Tactile) as well as that of radiographic methods (CR, DR and DRbc) were comparatively similar. The clinical methods presented a smaller number of false-positive diagnosis than the radiographic methods. It was concluded that visual inspection is an important diagnostic method; conventional bite-wing and digital radiography aid the diagnosis and are equally efficient to diagnose carious lesions in the dentine of teeth without visible cavitation. PMID- 20944878 TI - Dental caries and dental fluorosis in 7-12-year-old schoolchildren in Catalao, Goias, Brazil. AB - INTRODUCTION: Over the last two decades, the prevalence of dental caries in children has decreased and the prevalence of dental fluorosis has increased. Knowledge on the epidemiologic conditions of a population is fundamental for the planning of health programs. OBJECTIVES: To determine the prevalence of dental caries and dental fluorosis among schoolchildren, in Catalao, Goias, Brazil. METHODS: A random sample of 432 schoolchildren aged 7-12-years old was obtained. WHO (1997) criteria for dental caries and fluorosis diagnosis were used. RESULTS: The DMFT indexes were 0.97; 1.20; 1.80; 1.62; 2.40 and 2.51 for 7, 8, 9, 10, 11 and 12 years old, respectively. Analysis of dental fluorosis for the same ages presented higher prevalence at 12 years old and for the female gender. The percentage of questionable dental fluorosis (Dean's classification) was 34.0%. Only 3% of the sample presented dental fluorosis with scores very mild, mild and moderate. CONCLUSIONS: The prevalence of caries in schoolchildren of Catalao, Goias, Brazil, was low. In average, private schools showed better results than public schools; however, all schools presented a low DMFT index. In this study, dental fluorosis is not a public health problem and has not damaged dental esthetics. PMID- 20944879 TI - Concentration and bioavailability of fluoride in mouthrinses prepared in dispensing pharmacies. AB - Considering the importance of medication quality control and that mouthrinses for dental caries prevention have commonly been prepared in dispensing pharmacies, this study assessed formulations containing 0.05% NaF acquired from 6 dispensing pharmacies in the city of Piracicaba, S.P. The mouthrinse formulations were purchased in 3 separate periods and coded from A to F. Fluoride ion (F-) concentration was determined in all formulations in the 3 periods, and in those acquired in the 3rd period, the bioavailability of fluoride with dental enamel with caries-like lesions and the pH of products were evaluated. A solution of 0.05% NaF and distilled deionized water were used, respectively, as positive and negative controls. In the bioavailability analysis, fluoride present in dental enamel was determined removing, by acid etching, two layers of enamel; fluoride in the acid extract was determined with a specific electrode. The mouthrinses prepared in 5 pharmacies presented a F- concentration close to the expected value, except for the product prepared in one of them, in which a mean of 0.01% NaF was found. All products were more efficient than the negative control (p<0.05) in terms of reactivity with dental enamel, but differences among them were observed with regard to the positive control (p<0.05). The data suggest that a quality control program should be implemented in dispensing pharmacies to guarantee the quality of fluoridated mouthrinses formulated. PMID- 20944880 TI - Bonding to densely sintered alumina- and glass infiltrated aluminum / zirconium based ceramics. AB - The objective of this study was to test two hypotheses: (1) silica coating affects the bond strength between ceramics and a resin cement; (2) bond strength is affected by the type of ceramic. Twelve blocks 5 x 6 x 8 mm of In-Ceram Zirconia (ZR) and twelve Procera AllCeram (PR) ceramics were made and duplicated in composite. Five blocks of each ceramic were treated as follows: (1) ZR + GB (laboratorial airborne particles abrasion with Al2O3 particles) + silane; (2) ZR + SC (chairside tribochemical silica coating system, Cojet); (3) PR + GB; (4) PR + SC. Two treated samples of ceramic were analyzed under SEM. The ceramic composite blocks were cemented with Panavia F and stored in 37oC distilled water for 7 days. They were then cut to produce bar specimens (n=30) with a bonding area of 0.6+/-0.1mm2. Specimens were loaded to failure under tension in a universal testing machine (1 mm/min). Bond strength (sigma) values were statistically analyzed using ANOVA (Two-way) and Tukey (alpha = 0.05). Mean sigma (MPa) and standard deviation were as follows: 1) 15.1 +/- 5.3; 2) 26.8 +/- 7.4; 3) 12.7 +/- 2.6; 4) 18.5 +/- 4.7. Silica coated surfaces showed statistically higher sigma than the same substrate treated with GB only. In addition, ZR (with vitreous phase) showed higher o than PR (without vitreous phase). PMID- 20944881 TI - Study of thermocycling effect on the bond strength between an aluminous ceramic and a resin cement. AB - This study evaluated the effect of thermocycling on the bond strength between Procera AllCeram (Nobel-Biocare) and a resin cement (Panavia F, Kuraray CO). Nine ceramic blocks with dimensions of 5x6x6mm were conditioned at one face with Rocatec System (Espe). After, they were luted with Panavia F to composite resin blocks (Clearfil AP-X, Kuraray CO). The nine groups formed by ceramic, cement and composite resin were split up obtaining 75 samples with dimensions of 12x1x1mm and adhesive surface presenting 1mm2+/-0.1mm2 of area. The samples were divided into 3 groups (n=25): G1 - 14 days in distilled water at 37oC; G2 - 6,000 cycles in water (5oC - 55oC - 30s); G3 - 12,000 cycles in water (5oC - 55oC - 30s). The samples were tested in a universal testing machine (EMIC) at a crosshead speed of 1mm/min. Data were analyzed by ANOVA and Tukey tests. The results indicated that mean values of rupture tension (MPa) of G1 (10.71 +/- 3.54) did not differ statistically (p <5%) from G2 (9.01 +/- 3.90), however there was statistical difference between G1 and G3 (7.28 +/- 3.00). It was concluded that thermocycling significantly reduced the bond strength values when samples were submitted to 12,000 cycles. PMID- 20944882 TI - Comparative analysis of pubertal growth spurt predictors: Martins and Sakima method and Grave and Brown method. AB - The aim of this study was to evaluate whether Martins and Sakima and Grave and Brown methods are useful for the study of pubertal growth spurt in children with cleft lip and palate. A total of 132 hand-wrist radiographs of patients from HRAC/USP aged 7 to 17 years old were analyzed, including girls and boys. Six radiographs of each age and gender were employed. These methods were applied to evaluating the stages of the hand-wrist ossification and epiphyseal formation, by graphic representation. The Martins and Sakima and the Grave and Brown methods revealed that the initial, peak and final stages of pubertal growth spurt occurred between 9 to 10, 12 and 15 years old, respectively, in the female gender. Similarly, in the male gender, both Martins and Sakima and Grave and Brown methods showed similar mean ages: 12, 14 and 16 years old for initial, peak and final stages of pubertal growth spurt, respectively. The Pearson's correlation test showed high and significant correlation (r = 0.99 and p < 0.001) between the methods investigated. In conclusion, the methods appeared to be highly and significantly correlated as regards the analysis of children with cleft lip and palate. Moreover, based on the literature and present results, it is possible to suggest that the two methods have shown similar pattern and may be used with equal efficiency for assessment of the pubertal growth spurt in children with cleft lip and palate. PMID- 20944883 TI - Evaluation of cast metallic posts reproduction according to its quantity and position inside the casting ring. AB - The aim of this study was the evaluation about the influence of the quantity and the localization of resin patterns to cast metallic posts in its diameter and length reproduction. Seventy-two patterns for posts were fabricated by using prefabricated FKG plastic posts and divided for casting in 3 groups: G1-small ring/4 patterns, G2- medium ring/6 patterns, G3- big ring/8 patterns. Half of the patterns of each group were placed on the right side of the ring midline and the other half, on the left side, in order to guide the ring inside of the centrifuge. Using the comparative microscope, measures of diameter and length in different places were obtained before and after casting. The results were submitted to statistic analysis (ANOVA two way and Tukey's test), to make possible these observations: 1 degrees ) the position of patterns didn't influenced the measured dimensions. 2 degrees ) the same happened with the quantity of patterns inside the ring. 3 degrees ) only the pins of group G3 have presented statistically significant diameter differences. In conclusion, 1 degrees ) the position of patterns inside the ring and its quantity did not result in significant changes in pins length and diameter. 2 degrees ) Although there were no significant length alterations, significant ones were observed in the diameters 3, 6, and 9mm of Group G3. PMID- 20944884 TI - Comparison of chemical composition of packable resin composites by scanning electron microscopy. AB - OBJECTIVES: the purpose of this study was to compare the chemical composition of four different shades (incisal/extra-light, A2, A3 and B3) of two packable resin composites (SOLITAIRE(r), and PRODIGY CONDENSABLE TM). METHODS AND MATERIALS: the specimens measured 4mm in diameter and 4mm in thickness. Five specimens were made for each shade of the materials. They were light cured for 40 seconds at a power of 600mW/cm2. Subsequently, the specimens were removed from the plates and ground to powder and then pressed into holes measuring 4mm in diameter in a Teflon matrix, using the plates of the same material as base and cover. Specimens were evaluated under SEM with an x-ray detector for the spectroscopic test by energy dispersing. RESULTS: the chemical components found in both materials were practically the same, but in different proportions. Carbon, Oxygen, Aluminum, Silica, Fluoride and Barium were found. CONCLUSIONS: the chemical composition of each same material varied according to each shade analyzed. PMID- 20944885 TI - Influence of the restoration quality on the success of pulpotomy treatment: a preliminary retrospective study. AB - The aim of this study was to evaluate the clinical status of pulpotomy treatment with calcium hydroxide and to correlate it with the quality of restoration of the treated teeth. Patients were retrieved from the files of the Operative Dentistry clinics (FOUFPel) between 1996 and 2000. Twenty-two patients were recalled, which had 23 teeth treated with pulpotomy due to exposure by caries. Seven anterior and 16 posterior teeth composed the evaluated group, being all restored with composite resin. The age varied from 15-50 years (mean 23.9) and the follow-up mean was 34.52 months. Clinical and radiographic examinations were performed to evaluate the clinical status of treatment. The criteria used, clinically favorable and failure, were based on the following clinical exams: pulp vitality; sensitivity; and periapical alterations. The quality of the restorations was based on the USPHS criteria. Pulpotomy treatment was ranked as clinically favorable in 10 teeth (43.5%), 4 in anterior and 6 in posterior teeth. Failure was verified in 13 teeth (56.5%), 4 anterior and 9 posterior. From the group clinically favorable, 90% of the restorations were ranked as clinically satisfactory, while only 10% were unsatisfactory. In the failure group, 77.8% of the restorations were classified was unsatisfactory and 22.2% were ranked as satisfactory. The statistical analysis (Fisher's exact test) demonstrated that there is a statistically significant association between the clinical status of pulpotomy and restoration quality (p<0.05). Within the limitation of the study, it was verified that the quality of restoration could influence the favorable clinical status of pulpotomized teeth. Randomized clinical trials are required to confirm these preliminary data. PMID- 20944886 TI - Evaluation of the surface of root canal walls after utilization of endodontic rotary systems: SEM study. AB - The objective of the present study was to determine, by scanning electron microscopy, the aspect of root canal walls after utilization of different rotary instrumentation systems for root canal preparation. Forty-two single-rooted and straight teeth were divided into six groups, whose root canals were prepared using the following rotary systems: groups 1 and 2 - Quantec; groups 3 and 4 - Pow-R; groups 5 and 6 - Profile. Irrigation was performed with 2.5% sodium hypochlorite solution in all groups, while only groups 2, 4 and 6 received a final flush with EDTA. Data were analyzed by non-parametric Kruskal-Wallis and Miller tests. Removal of the smear layer and other debris was more effective in the groups receiving EDTA as final irrigant. The Profile system showed the best cleaning, generating only a minimum smear layer, with a significant difference being observed compared to the Pow-R system (p<0.05), but no difference when compared with Quantec system. The final use of EDTA favored cleaner surfaces in all groups. PMID- 20944887 TI - Efficacy of three conditions of radiographic interpretation for assessment root canal length. AB - OBJECTIVE: To compare the efficacy of three conditions of image interpretation for radiographic root measurements and calculating the intra-observer reproducibility of the measurements. MATERIAL AND METHODS: Thirty intra-operative periapical radiographs of maxillary central and lateral incisors were measured, in mm, from the tip of the file to the radiographic apex, using a caliper. Three separate measurements were made of the 30 radiographs. The three measurements for each tooth were averaged and the mean used for further calculations. After a 12 day period, the measurements were repeated. The three experimental viewing conditions used: 1) standard viewbox without masking of background light around the radiograph and without magnification (Visual); 2) standard viewbox with use of a magnifying lens of 2.5x and with background light masked (Magnification); and 3) viewer device that restricts room lighting and enlarges the image by a magnifying lens of 1.75x (Viewer). The mean and standard deviation of the measurements were calculated and used for descriptive analysis. Two-way analysis of variance (ANOVA) was used to evaluate intra-observer and inter-method agreement of the measurements. The measurement error was estimated by Dalhberg's formula. RESULTS: The ANOVA showed no significant differences between measurement sessions, viewing methods, or interaction between observation session and method (p>0.05). The intra-observer measurement error was 0.02 mm for Visual and the Magnification methods and 0.01 mm for the Viewer. CONCLUSION: There does not seem to be any advantage in using viewbox masking or magnification for measuring the distance between the end of the endodontic file and the root apex in maxillary incisors. PMID- 20944888 TI - Evaluation of an IBAD thin-film process as an alternative method for surface incorporation of bioceramics on dental implants: a study in dogs. AB - Thin-film bioceramic coatings are potential alternatives to overcome the limitations provided by other commercially available coating techniques like PSHA, where variable bioceramic dissolution added to a metalloceramic weak link are process- inherent. The purpose of this investigation was to determine the overall and site specific (to 0.5 mm from implant surface) levels of osseoactivity around a thin-film (IBAD processed) coated titanium alloy implant versus a non surface modified (sand-blasted/acid etched) titanium alloy implant in a canine model. The surgical model comprised the proximal tibiae epiphyses with four implants placed in each limb remaining for 2 and 4 weeks in-vivo. 10 mg/Kg oxytetracycline was administered 48 hours prior to euthanization. The limbs were retrieved by sharp dissection, reduced to blocks, and subsequently nondecalcified processed for fluorescent microscopy. Micrographs (20x mag) were acquired around the implant perimeter and merged for overall biological response evaluations, and four micrographs (40x mag. subdivided in rectangles) were acquired along one of the implant sides for tetracycline labeled area fraction quantification. The results showed biocompatible and osseoconductive properties for the thin-film coated and uncoated titanium alloy implants. Tetracycline labeled area fraction analyses showed that the thin-film coated implants presented significantly higher overall and site specific osseoactivity levels at 2 and 4 weeks. The site specific osseoactivity values were significantly higher compared to overall values for control and thin-film coated implants at both times in-vivo. According to the results obtained in this study, thin-film coated implants enhanced biological response at the early implantation times evaluated. PMID- 20944889 TI - Effect of biomechanical preparation and calcium hydroxide pastes on the antisepsis of root canal systems in dogs. AB - In the endodontic treatment of root canals with necrotic pulps associated with periapical radiolucent areas, one of the main objectives of treatment consists in eliminating the microorganisms spread throughout the ramifications of the root canal system. The scope of this study was to evaluate the antiseptic efficacy of biomechanical preparation and two calcium hydroxide-based pastes, in dogs' teeth with experimentally induced chronic periapical lesions. After initial microbiological sampling, instrumentation of the root canals was undertaken using the conventional technique, using K type files used in conjunction with a solution of 5.25% sodium hypochlorite. After ninety-six hours, further microbiological sampling was undertaken and Calen/CPMC or Calasept pastes were applied for 15 and 30 days. Ninety six hours after the removal of the medication, the third microbiological sampling was undertaken and finally histomicrobiological analysis followed using Brown & Brenn staining. The results were analyzed using the Kruskall-Wallis test, with a level of significance established at 5% (p<0.05). It was shown that the biomechanical preparation significantly reduced the number of colony forming units of microorganisms in root canals. In contrast, there was no significant difference between the antiseptic action of long-term dressings over two periods of action, although 30 days produced a greater reduction in the quantity of microorganisms and of positive microbiological cultures. In histological sections of the four experimental groups, similar microbiological patterns were shown (p>0.05), characterized by an elevated incidence of cocci, bacilli and filaments, predominantly gram-positive, in root canals, secondary canals and accessories, apical cementoplasts and dentinal tubules, but with a low incidence of microorganisms in areas of cementum resorption and the periapical lesion. The biomechanical preparation and intracanal dressing based on calcium hydroxide were important in the antisepsis of the root canal; however, both procedures did not produce significant changes in the microbiological aspects of the root canal system. PMID- 20944890 TI - [Prevalence of HIV-1 subtypes in patients of an urban center in Southern Brazil]. AB - OBJECTIVE: To estimate the prevalence of HIV-1 subtypes and analyze factors associated. METHODS: A cross-sectional study was performed with a convenience sample of 80 adult HIV-positive patients, users of an AIDS/STD specialized service, in the city of Canoas, Southern Brazil, between July 2008 and January 2009. Determination of HIV subtypes was performed with the amplification of viral genome fragment, using polymerase chain reaction, followed by sequencing of the amplified fragments. Sociodemographic, clinical and behavioral variables were collected in a structured questionnaire. Univariate statistical analysis was performed, using chi-square test and Student's t-test. RESULTS: A higher prevalence of subtype C was found (43.8%; 95% CI: 32.9;54.6), followed by CRF31_BC (35.0%; 95% CI: 24.6;45.5) and subtypes B (18.8%; 95% CI: 10.2;27.3) and F (2.4%; 95% CI: 0;5.9). Other HIV-1 subtypes were not observed. Patients infected with CRF31_BC were diagnosed more recently than patients infected with subtype B (p<0.05). In addition, there was a higher frequency of co-infection with other viruses (hepatitis B and C and human T-lymphotropic viruses) in individuals with CRF31_BC, compared to other subtypes. With regard to sociodemographic aspects, there were no differences in the distribution of subtypes and recombinant forms, in terms of gender and sexual practices. CONCLUSIONS: Results obtained indicate a higher frequency of subtype C and CRF31_BC in this urban center of Southern Brazil, with possible different ways of transmission. PMID- 20944891 TI - Violent behavior in adolescents and parent-child cohabitation. AB - OBJECTIVE: To analyze the association between violent behavior in adolescents and parent-child cohabitation. METHODS: A population-based cross-sectional study with multiple-stage sampling was performed in the urban area of the city of Pelotas, Southern Brazil, in 2002. A total of 960 adolescents were interviewed using a self-applied questionnaire. The dependent variables (use of weapons and involvement in fights in the previous year were reported by adolescents) and the independent variable (parent-child cohabitation) were analyzed with the chi square test and prevalence ratios, adjusted for age, sex, socioeconomic level and reporting of alcohol, tobacco or illicit drug use, both recently and throughout life. RESULTS: Involvement in fights in the previous year was reported by 23% of participants and use of weapons by 9.6%. Prevalence ratios of occurrence of such behaviors was 1.38 (95% CI: 0.71; 2.68, p=0.34) for involvement in fights and 1.68 (95% CI: 1.06; 2.67, p=0.03) for use of weapons, including "adolescents living with the father, mother or both" as reference. CONCLUSIONS: Parent-child cohabitation must be considered in policies aimed at preventing the use of weapons by children and adolescents, although it is recommended that care should be taken not to stigmatize children and adolescents who do not live with their fathers and mothers. PMID- 20944892 TI - Brazilian Oral Health Policy: factors associated with comprehensiveness in health care. AB - OBJECTIVE: To analyze the factors associated with comprehensiveness in oral health care in Centers of Dental Specialists, according to the guiding principles of the Brazilian Oral Health Policy. METHODS: An exploratory cross-sectional study, based on an interview with 611 users of four specialized dental care centers, was performed in the state of Bahia, Northeastern Brazil, in 2008. The dependent variable was described as "comprehensiveness in oral health care", corresponding to having a primary dental care performed before specialized treatment or concomitantly with it. The main covariables referred to the level of coverage of the family health strategy in the city, users' sociodemographic characteristics, and organizational and geographic accessibility to the service, in addition to the type of specialized care required. RESULTS: Residents of the cities where the Family Healthcare Program had a coverage >50% were more likely to conclude their dental treatment (PR=2.03, 95% CI: 1.33;3.09), compared to those who lived in places with lower coverage. Individuals who sought endodontic treatment were more likely to receive comprehensive oral health care than users who were seeking other types of specialized care (PR=2.31, 95% CI: 1.67;3.19). Users with better geographic accessibility to specialized services (PR=1.22, 95% CI: 1.03;1.41), with a reference guide from primary care (PR=2.95, 95% CI: 1.82;4.78) and coming from primary health care services (PR=3.13, 95% CI: 1.70;5.77) were more likely to achieve comprehensiveness in oral health care than other users. CONCLUSIONS: Users with better geographic accessibility, lower age and need of endodontic services were more likely to receive comprehensive health care. Implementation of Centers of Dental Specialists in cities where primary healthcare is not adequately structured is not recommended, because secondary health care would meet the free demand and perform basic procedures, thus not fulfilling the expected principle of comprehensiveness. PMID- 20944893 TI - Policy analysis of the dengue control program in Mexico. AB - OBJECTIVE: To analyze municipal measures implemented to control the dengue epidemic, giving priority to the functions of intersectoral coordination, policy strengthening and community participation. METHODS: The observational study was performed in Morelos, Mexico in 2007. Data collected in interviews and direct observations were submitted to contents analysis and policy mapping. Policy Maker software was used to evaluate the values assigned to the stakeholders' performance (i.e., high, medium and low criteria) and to their role (actions undertaken for surveillance, control or management). A strategic analysis of opportunities and challenges regarding public policies and dengue control was conducted. RESULTS: The legal framework indicates that the approach to the dengue epidemic should be an intersectoral response. However, the burden of activities in terms of financial and human resources tends to fall on local health services, which contrasts with the contribution of other sectors (e.g., water and sanitation) that do not recognize their responsibilities. A high degree of operational feasibility links, in terms of optimization of resources and objectives fulfillment was detected, particularly among health authorities at state, jurisdictional and municipal levels. CONCLUSIONS: A multidisciplinary approach and strengthening of policy stewardship may allow a more efficient response to dengue outbreaks, sustained by intersectoral coordination and the active participation of the affected population. PMID- 20944894 TI - Lipid profile of schoolchildren from Recife, PE. AB - BACKGROUND: The occurrence of dyslipidemia is increasing in pediatric populations. Altered lipid profiles are related to a higher incidence of hypertension and atherosclerotic disease. OBJECTIVE: To evaluate the extent of dyslipidemia and investigate its association with overweight and abdominal obesity in adolescent students from Recife, Brazil. METHODS: Personal data, socioeconomic level, anthropometric measurements and lipid profile of 470 adolescents, aged 10 to 14 years, of both sexes, students at the Public School system in the city of Recife, state of Pernambuco, Brazil, were obtained. The statistical analysis was carried out using the Epi-info 6.04 and SPSS 13.0 software. The level of significance was set at 5%. RESULTS: The majority of the population was dyslipidemic (63.8%; 95%CI: 59.3 - 68.2), with hypoalphalipoproteinemia being the most prevalent dyslipidemia (56%; 95%CI: 51.3 60.5). Adolescents who were overweight or who had abdominal obesity presented higher levels of triglycerides and lower levels of HDL-cholesterol (p < 0.05). Levels of total cholesterol and fractions were not different between sexes. CONCLUSION: A high incidence of unfavorable lipid profile was shown in this series, demonstrating the necessity to measure the lipid profile as early as this age range. Healthy lifestyle measures should be encouraged in this population. PMID- 20944895 TI - Case 5/2010 - A seven-year-old girl with tetralogy of fallot and absent pulmonary valve. PMID- 20944896 TI - Pacemaker electrode misplaced in the left ventricle. AB - This study reports the case of an anomalous implantation of VVI pacemaker electrode in the left ventricle (LV) diagnosed during routine evaluation, two years after implantation. The patient is a 65-year-old woman with Chagas disease. Electrocardiogram (ECG) revealed a pattern of right branch block. Profile chest X ray showed electrode with posterior curvature path. In transthoracic echocardiography, the diagnosis revealed that the catheter penetrated the right atrium, crossed the atrial septum, descended through the left atrium and mitral valve orifice and deployed on the LV wall. The following related aspects are addressed: potential deployment routes, clinical, radiological, electrocardiographic and echocardiographic pictures, complications and treatment options. PMID- 20944897 TI - Infectious endocarditis due to Streptococcus bovis in a patient with colon carcinoma. AB - We report the case of a 66 year-old female patient with infectious endocarditis due to Streptococcus bovis and adenocarcinoma of the colon that developed acute aortic insufficiency. She was submitted to aortic valve replacement surgery and later to tumor resection (right hemicolectomy). It is important to emphasize the need for complementing the study of the colon, even in asymptomatic individuals, when infectious endocarditis due to S. bovis is diagnosed. PMID- 20944898 TI - Aspirin resistance: fact or fiction? AB - A meta-analysis of clinical studies of patients with cardiovascular disease demonstrated that the use of aspirin was associated with a 22% decrease in death rates and relevant ischemic vascular events. However, clinical studies demonstrated that patients that regularly took aspirin presented recurrence of cardiovascular events. Such observation led to the question whether, in some patients, the aspirin was not effective in blocking platelet aggregation and these patients were called unresponsive to aspirin or aspirin-resistant. The clinical aspirin resistance is characterized as the occurrence of cardiovascular events in patients during treatment with aspirin, whereas the laboratory resistance is defined as the persistence of platelet aggregation, documented by laboratory test, in patients regularly taking aspirin. Patients that are aspirin resistant presented, according to laboratory tests, on average 3.8 times more cardiovascular events when compared to non-resistant ones. PMID- 20944899 TI - Cardiovascular research: new model of collaborative training program. PMID- 20944900 TI - Cardiovascular risks of androgen deprivation therapy. AB - Prostate adenocarcinoma is the most common cancer type in the male sex after skin cancer. Among the several types of treatment for prostate cancer, the androgen deprivation therapy has been highly recommended in patients with metastatic or locally advanced disease, which probably results in increased survival. However, the androgen deprivation is the cause of several adverse effects. Complications such as osteoporosis, sexual dysfunction, gynecomastia, anemia and body composition alterations are well-known effects of the therapy. Recently, a number of metabolic complications have been described, such as increase in the abdominal circumference, insulin resistance, hyperglycemia, diabetes, dyslipidemia and metabolic syndrome, with a consequent increase in the risk of coronary events and cardiovascular mortality in this specific population. This update article presents a literature review carried out at MEDLINE database of all literature published in English from 1966 to June 2009, using the following key words: androgen deprivation therapy, androgen suppression therapy, hormone treatment, prostate cancer, metabolic syndrome and cardiovascular disease, with the objective of analyzing which would be the actual cardiovascular risks of androgen deprivation therapy, also called androgen suppression, in patients with prostate cancer. PMID- 20944901 TI - Is it only inflammation or infection as well? PMID- 20944902 TI - Adverse mucocutaneous reactions to chemotherapeutic agents: part I. AB - The local and systemic treatment of tumors can cause changes in the skin, mucous membranes, hair and nails. Accurate diagnosis and appropriate treatment of side effects require knowledge about the patterns of the most common adverse reactions to drugs the patient may be using. The dermatologist must be familiar with the manifestations of certain soft tissue neoplasms, as well as with the adverse mucocutaneous forms of cancer treatment. PMID- 20944903 TI - Agreement between dermatological diagnoses made by live examination compared to analysis of digital images. AB - BACKGROUND: Teledermatology is seldom used in Brazil, although some incipient initiatives have been implemented in the state of Amazonas. Further studies are still required to confirm the feasibility and efficacy of this diagnostic tool. OBJECTIVES: To evaluate the efficacy of an asynchronous method of teledermatology using simple, inexpensive technological resources. METHODS: One hundred and seventy-four patients were examined by four dermatologists, two clinic-based dermatologists, who diagnosed the patients following live examination (A1 and A2), and two consultant specialists in image dermatology, who reached diagnoses by examining images of the lesions and the patients' clinical histories (B1 and B2). The agreement between live examination and examination of images was evaluated. RESULTS: Agreement between the two live examiners (A1 and A2) with respect to the principal diagnosis was 83.3% compared to 81.0% between the physicians who diagnosed by examining images (B1 and B2). Agreement between the principal diagnosis established by live examination and that obtained from examining images ranged from 78.2% to 83.9%, CONCLUSION: Agreement between diagnoses of dermatological diseases reached following examination of digital images and those reached following live examination of the patient was excellent. PMID- 20944904 TI - Chromoblastomycosis: study of 27 cases and review of medical literature. AB - BACKGROUND: Chromoblastomycosis is a subcutaneous mycosis that occurs mainly in rural workers although is being more commonly found among people working in other sectors. The fungus penetrates the skin after its inoculation and the most frequently isolated agent is the Fonsecaea pedrosoi. OBJECTIVES: This study aims at evaluating patients suffering from chromoblastomycosis admitted into the Department of Dermatology of the University Hospital of the Faculty of Medicine of Sao Paulo State during the ten-year period from 1997 to 2007. METHODS: It is a retrospective study and the medical report cards of 27 Brazilian patients diagnosed as suffering from Chromoblastomycosis from 1997 to 2007 at the Dermatology Department of the Medical School, University of Sao Paulo were reviewed. The following items were analyzed: previous therapeutic approaches; treatment implemented by the group; length of time between the appearing of the lesion and diagnosis; age; gender; profession; origin; site of lesions; isolated agents found in culture and histopathology. RESULTS: Twenty two patients were from the state of Sao Paulo whereas the others came from the states of Bahia and Rondonia. 37% of them were rural workers. Men were more frequently infected (85%). Lesions were more commonly found on the lower limbs (59.2%). In 52% of the cases the isolated agent was the dematiaceous fungus Fonsecaea. pedrosoi. Biopsies showed sclerotic bodies in 92.5% of the cases. CONCLUSION: Data found are in accordance with medical literature on the subject. The disease had been previously studied in our institution in 1983 by Cuce et al. This present study is the second retrospective one about the characteristics of patients suffering from chromoblastmycosis which has been published in indexed medical literature in the state of Sao Paulo. PMID- 20944905 TI - Frequency of occupational contact dermatitis in an ambulatory of dermatologic allergy. AB - BACKGROUND: Occupational contact dermatitis (OCD) corresponds to 80% of the cases of skin diseases related to work. OBJECTIVES: To determine: the frequency of OCD in an ambulatory of allergy not specific for occupational dermatosis; the profile of these patients according to age, gender, color, profession, atopic history, duration and localization of the dermatosis; the diagnosed types of contact dermatitis; the main allergens and to compare the frequency of the main antigens with the results obtained from patients examined in the same period of time, without DCO. METHODS: During the three-year period from 2003 to 2006, 630 patients were examined and submitted to a battery of standardized contact patch tests and those who were diagnosed with OCD were selected. RESULTS: Sixty-nine out of the 630 patients were diagnosed with OCD. The average age was 44.5 years. Forty-eight patients (70%of the cases) presented the disease on the hands. The most prevalent activities of patients suffering from the disease were household tasks (39%) and building construction (33%). The allergic contact dermatitis (ACD) occurred in 48 cases which represent 70% of the total number of cases and irritant contact dermatitis in 21 cases corresponding to 30% of the total number of cases. The main allergens were potassium dichromate 28 (41%), nickel sulfate 16 (23%) and carba-mix 16 (23%). CONCLUSION: OCD was present in 10.9% of the patients. Concerning age the group in which the disease was more commonly found corresponded to the most productive group of the population. ACD corresponded to 48 cases, probably influenced by the long period of evolution of the dermatosis. Metal and rubber chemicals were the commonest allergens. PMID- 20944906 TI - Influence of climatic factors on the medical attentions of dermatologic diseases in a hospital of Lima, Peru. AB - BACKGROUND: Significant associations have been described between climatic factors and human health, which can occur in dermatologic diseases too. OBJECTIVE: To determine the influence of the climatic factors on the medical attentions of dermatologic diseases in a general hospital in Lima (Peru). PATIENTS AND METHODS: Observational study which was carried out in a national hospital between January 2004 and December 2007. The diagnoses were classified according to the ICD-10 system. The climate information was provided by the National Oceanographic and Atmospheric Administration from USA(NOAA). RESULTS: 3 294 patients were included in the study, the average age was 35.4 +/- 20.7 years old, and 53.2% were females. The "El Nino" phenomenon was associated with an increase in the prevalence of actinic keratosis (p=0.002), viral warts (p=0.001) and rosacea (p=0.014). The "La Nina" phenomenon was associated with a reduction in viral warts (p=0.026). Spring was associated with an increase of dermatitis (p=0.003), and summer was associated with an increase of benign neoplasms (p=0.049). CONCLUSION: The climatic variations influenced the occurrence of certain dermatologic diseases. The present study may represent an orientation guide to specialists and general practitioners identifying the most common dermatologic diagnoses and thus enabling better preparation to treat these cases in determined seasons of the year. PMID- 20944907 TI - Melanocytic nevi in a Brazilian community of predominantly Dutch descent (1999 2007). AB - BACKGROUNDS: Epidemiological studies have shown a significant relationship between melanocytic nevi and cutaneous melanoma. OBJECTIVE: To evaluate the development of melanocytic nevi in the pupils of a school composed primarily of children of Dutch descent and to assess the effect of environmental factors on these individuals whose phenotypic characteristics were similar to those of their ancestors. METHODS: In 1999 a cohort study was initiated to count the number of melanocytic nevi in 282 pupils of 3 to 17 years of age, 53.9% of whom were boys. Five years later a repeat exam was conducted in 148 students of 8 to 22 years of age, 49.3% of whom were males. The association between the age, skin phototype, eye color, hair color and ethnic group of the pupils and their parents and the presence of melanocytic nevi was analyzed at the beginning and at the end of the study. RESULTS: There was a significant increase in cases of melanocytic nevi and dysplastic nevi at the follow-up examination. The number of melanocytic nevi was greater in boys than in girls in both covered and exposed areas of skin. Likelihood analysis calculated using the odds ratio showed that boys were more likely to develop melanocytic nevi than girls and that the children of non-mixed and mixed race with lighter hair were more likely to develop melanocytic nevi than those of other ethnic groups and those with dark hair. Children with skin phototype I were more likely to develop melanocytic nevi in covered areas of skin compared to those with skin types II or III. CONCLUSIONS: These data show that individuals of Dutch descent were more likely to develop melanocytic nevi than individuals of other ethnic origins. PMID- 20944908 TI - Dermatosis due to plants (phytodermatosis). AB - Dermatosis caused by plants is relatively common and may occur by various pathogenic mechanisms. Dermatitis due to physical trauma, pharmacological action, irritation, sensitization, mediated by IgE and induced by light are described. Pseudophytodermatosis caused by plant-delivered elements is also described in the introduction to this work. PMID- 20944909 TI - Direct and indirect immunofluorescence. AB - Immunofluorescence is a valuable auxiliary diagnostic tool for autoimmune bullous diseases and inflammatory disorders, since their clinical and histopathologic findings may be inconclusive. It is a feasible laboratory method that requires experienced technicians and detects in situ and circulating immune deposits that may be involved in the pathogenesis of such skin diseases. PMID- 20944910 TI - Photodynamic therapy: a review of the literature and image documentation. AB - Photodynamic therapy (PDT) consists of a chemical reaction activated by light energy that is used to selectively destroy tissue. The reaction requires a photosensitizer in the target tissue, a light source and oxygen. The most extensively studied photosensitizing agents for PDT are 5-aminolevulinic acid for the treatment of actinic keratosis and methyl-aminolevulinate, which has been approved for the treatment of actinic keratosis, basal cell carcinoma and Bowen's disease. The light sources used in photodynamic therapy should emit light at wavelengths within the absorption spectrum of the photosensitizer used in PDT treatment. Light emitting diode (LED) lamps are indicated for the photodynamic treatment of nonmelanoma skin cancer. PDT should be considered as a therapeutic option, particularly in the case of patients with superficial, multiple or disseminated lesions and for immunosuppressed patients. More recently, PDT has been indicated for a wide range of dermatological conditions such as photo damaged skin, acne, hidradenitis, scleroderma, psoriasis, warts and leishmaniosis, among others. This article provides an extensive review of photodynamic therapy, its mechanisms, indications and results. PMID- 20944911 TI - Leucoderma syphiliticum: a rare expression of the secondary stage diagnosed by histopathology. AB - Biopsies are occasionally necessary to confirm the diagnosis of secondary-stage syphilis, currently achieved by clinico-serological correlation. However, histopathologic examination may offer clues that can lead to the diagnosis of the disease in previously unsuspected or unusual cases. We report the case of a 35 year-old male patient with vitiligo-like lesions for two years, whose diagnosis of syphilis was suggested only after histopathologic examination. Some microscopic aspects observed are discussed and compared to data from the literature. PMID- 20944912 TI - Subcutaneous phaeohyphomycosis on the scrotum caused by Exophiala jeanselmei: case report. AB - Subcutaneous phaeohyphomycosis is a disease caused by dematiaceous fungi that develops mainly in immunocompromised patients. Lesions are generally located on the lower limbs. The present report describes a case of phaeohyphomycosis in an immunocompetent patient in whom a subcutaneous abscess was located in an unusual site, on the left hemiscrotum. The abscess was treated successfully with oral fluconazole associated with surgical excision. PMID- 20944913 TI - Intravenous immunoglobulin for treatment of severe acquired bullous epidermolysis refractory to conventional immunosuppressive therapy. AB - Acquired bullous epidermolysis is a chronic and rare bullous subepidermal disease. It usually begins in adulthood and its etiology is unknown although it is associated with antibodies against type VII collagen. There are spontaneous and trauma induced formation of blisters that may cause serious complications. Treatment is disappointing and difficult. Apart from conventional therapy with systemic corticosteroid, new therapeutic modalities such as intravenous immunoglobulin are currently being used. This report highlights the extremely difficult clinical management of this rare disease and the important improvement provided by intravenous immunoglobulin. PMID- 20944914 TI - Lymphogranuloma venereum: "a clinical and histopathological chameleon?". AB - Lymphogranuloma venereum is an infection caused by a variety of the bacterium Chlamydia trachomatis. Both genital and extragenital manifestations of the disease can cause serious differential diagnostic difficulties, indirectly leading to progression and dissemination of the infection. This work describes cases of patients with lymphogranuloma venereum showing atypical clinical and/or histopathological findings. It also focuses on alternative therapeutic approaches, such as surgical excision at stage 1, that may lead to a positive outcome. It is not completely clear whether histopathological findings of lymphogranuloma venereum can reveal progression or changes in the course of the disease over time, as is the case in other diseases. We conclude that both clinical and histopathological observations in a larger number of patients are needed in order to further evaluate the findings presented in this article. PMID- 20944915 TI - Reed nevus (pigmented spindle-cell nevus): a report of three cases with distinct dermoscopic patterns. AB - Reed nevus or pigmented spindle-cell nevus may mimic cutaneous melanoma; however, its dermoscopic and histopathological characteristics are different. This case report describes three patients with distinct clinical, dermoscopic and histopathological presentations, which were correlated to enable a differential diagnosis to be made between melanoma and Spitz nevus. PMID- 20944916 TI - Keratosis follicularis spinulosa decalvans: case report. AB - Keratosis follicularis spinulosa decalvans is a rare disease, with genetic transmission either X-linked or sporadic, characterized by follicular hyperkeratosis and cicatricial alopecia. The disease usually begins in early childhood exacerbating throughout adolescence. The therapies are somewhat effective, with frustrating treatment when there are changes which are predominantly cicatricial. It is reported a case of child with intense cicatricial alopecia, with precocious changes (already present at birth) that rapidly evolved to diffuse cicatricial alopecia on the scalp, which has limited the treatment, with disappointing results. PMID- 20944917 TI - Secondary Ekbom syndrome to organic disorder: report of three cases. AB - The Ekbom syndrome, also known as delusion of parasitosis or acarophobia is an obsessive phobic state in which the patient thinks, imagines or believes that his or her skin is infested by parasites. In the hallucinatory state, he/she removes parts of the skin, identifying them as parasites. It can be primary or secondary to other organic or psychiatric diseases. Generally speaking these patients take a long time to seek for medical support and the dermatologist is almost always the first physician to see them. Here we describe three patients with delusional parasitosis associated with organic disorders. PMID- 20944918 TI - Photodynamic therapy for treatment of multiple lesions on the scalp in nevoid basal cell carcinoma syndrome: case report. AB - Photodynamic therapy is an effective alternative for the treatment of non melanoma skin cancer, selectively destroying the neoplastic cells through the use of photosensitizer substances that are irradiated with a source of light of adequate wave length. Nevoid Basal Cell Carcinoma Syndrome is a genodermatosis characterized by multiples basal cell carcinomas occurring at an early age, compelling patients to various surgeries, some of them disfiguring. The aim of this article is to show the excellent result of the treatment of multiple basal cell carcinomas on the scalp of a patient suffering from Nevoid Basal Cell Carcinoma Syndrome. PMID- 20944919 TI - Treatment of human papillomavirus in childhood with imiquimod 5% cream. AB - In children, lesions caused by the human papillomavirus (HPV) constitute a significant epidemiological issue and a therapeutic dilemma, particularly in the case of anogenital warts. The treatment of anogenital warts in children is a challenge, since standard treatments are generally painful and require the patient to be anesthetized. Imiquimod, a topical immune response modifier, constitutes an alternative therapeutic agent for the treatment of HPV. The present report describes four cases in which treatment with topically applied imiquimod 5% cream was implemented with successful results. PMID- 20944920 TI - Spitz nevus: a case report and the use of dermoscopy. AB - The Spitz nevus is a benign melanocytic lesion with clinical and histopathological features similar to those of melanoma. It was first described in 1948 but great controversy still remains today with respect to its diagnosis and management. The use of dermoscopy may increase diagnostic accuracy. In Spitz nevus, the most common dermoscopic finding is a starburst-like pattern, followed by globular and atypical patterns. Diagnosis must be confirmed by histopathology, particularly in atypical cases. PMID- 20944921 TI - Tinea pseudoimbricata caused by M. gypseum associated to crusted scabies. AB - Tinea pseudoimbricata is related to T. tonsurans and T. rubrum and crusted scabies is a highly contagious dermatosis caused by excessive proliferation of S. scabiei var. hominis. We described a case of a 21-year-old patient, seronegative for HIV, with both skin diseases. The occurrence of these dermatosis simultaneously in immunocompetent patients is very rare. PMID- 20944922 TI - Case for diagnosis. AB - Lichen nitidus is a rare dermatosis, characterized by round, skin-colored papules whose size varies between 1-2 mm and are generally asymptomatic. It does not have predilection for gender or race, affecting mainly children and young adults. Its clinical course is unpredictable, but most cases tend to spontaneously regress years after the onset of the disease. Lesions are often localized, but rare reports of disseminated disease exist. PMID- 20944923 TI - Case for diagnosis. AB - Since the first reports and descriptions of AIDS in the early 1980s, herpetic infection has been considered as one of the most prevalent and opportunistic aids related infections in patients with retroviral diseases Infection by Herpes simplex type 2 (HSV-2), the etiologic agent responsible for 60% to 90% of the cases of genital herpes, is very common among patients suffering from AIDS. Herpes simplex type 2 infection may cause severe and prolonged (over a period of time of one month) mucocutaneous onset of the disease, being characterized as an aids defining clinical condition. PMID- 20944924 TI - High voltage electrical stimulation as an alternative treatment for chronic ulcers of the lower limbs. AB - High voltage electrical stimulation has been recommended as a means of accelerating the wound healing process. The effects of high voltage electrical stimulation were evaluated in the treatment of three volunteers with chronic ulcers of the lower limbs. After fifteen weeks of treatment, a reduction was found in the area of all the ulcers, suggesting that high voltage electric stimulation is an effective therapeutic option for chronic ulcers. PMID- 20944925 TI - Leukoderma punctata following topical PUVAsol treatment. AB - Two adolescent females and a girl, all with clinically diagnosed vitiligo, were treated with 0.2% 8-methoxypsoralen cream followed by exposure to solar ultraviolet light. One year later, they developed hypopigmented and achromic spots on the areas affected by the vitiligo. Biopsy of skin tissue taken from one of these cases showed a marked reduction in melanin. Clinical and histological findings point to a diagnosis of leukoderma punctata. PMID- 20944926 TI - Do you know this syndrome? Ectrodactyly - ectodermal dysplasia - cleft lip/palate(EEC) syndrome. AB - Ectrodactyly - ectodermal dysplasia - cleft lip/palate syndrome (EEC) is a rare autosomal dominant genetic disorder, with variable expression and penetrance. This congenital disorder is associated either with a mutation in chromosome 7 or with a translocation between chromosomes 7 and 9, reflected primarily in the abnormalities listed in its name. This case report describes a 35-year-old male with syndromic stigmata since birth and no cleft lip/palate. Four relatives are also affected by the condition. PMID- 20944927 TI - Treatment of hidradenitis suppurativa with infliximab. PMID- 20944931 TI - Microbial keratitis in the elderly: a 32-year review. AB - PURPOSE: To describe the demographic characteristics, associated factors and causative agents of infectious keratitis in the elderly in a tertiary referral center in Sao Paulo, Brazil. METHODS: A retrospective review of all patients aged 60 years and over with a presumptive diagnosis of infectious keratitis who had material collected for microbiological analysis, between the years 1975 and 2007 (32-year span). RESULTS: From a total of 7,060 age-independent cases of microbial keratitis, 1,545 cases in the elderly were reviewed, which had a mean age of 71.0 +/- 7.8 years, ranging from 60 to 101 years. There were 707 males (45.6%) and 838 females (54.3%). Associated factors were: past ocular surgery (25.1%), ocular trauma (7.2%) and contact lens use (3.0%). Bacterioscopy was positive in 40.5% of cases. Culture positivity for any agent was 53.5% (bacteria 47.0%, fungi 6.1%, Acanthamoeba 0.4%). The most frequent bacteria were the gram-positive cocci (mostly coagulase-negative Staphylococci) and gram-negative bacilli (mostly the genera Pseudomonas, Moraxella and Proteus), while the most frequent fungi were the filamentous (mostly the genus Fusarium). CONCLUSIONS: This study represents a large series of microbial keratitis in the elderly in a single referral center. The most important factor associated with this condition in the elderly was past ocular surgery. The most frequent causative agents were bacteria, especially gram positive cocci and gram-negative bacilli. PMID- 20944932 TI - Simulated cup/disc ratio: a tool for ophthalmologists. AB - PURPOSE: To evaluate and compare the observers' ability to measure simulations of cup/disc ratios (CDR) as concentric and non-concentric circles. METHODS: In a prospective, random, and masked setting, 43 images representing the CDR spectrum from 0.2 to 0.9 for vertical and horizontal CDR measurements were developed and presented on a computer screen to 171 participants. RESULTS: There were satisfactory agreements according to the kappa coefficient (0.755 and 0.730 for horizontal and vertical cup disc ratios, respectively) and Lin's concordance correlation (R=0.88 and R=0.86 for horizontal and vertical measurements, respectively). However, very poor agreement was found for intermediate CDR values. The worst agreement occurred when the CDR was between 0.4 and 0.6 for both the horizontal and vertical values. The kappa coefficient was 0.37 and 0.39 for 0.4 CDR (horizontal and vertical, respectively), 0.39 and 0.38 for 0.5 CDR (horizontal and vertical, respectively) and 0.45 and 0.41 for 0.6 CDR (horizontal and vertical, respectively). CONCLUSION: Despite a good general agreement between the gold standard and the participants' responses, the absolute agreement for intermediate CDR values was very poor for both horizontal and vertical values. PMID- 20944933 TI - Wavefront-guided refractive surgery results of training-surgeons. AB - PURPOSE: To assess clinical outcomes and changes on higher-order aberrations (HOA) after wavefront-guided laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) for correction of myopia and myopic astigmatism performed by training-surgeons. METHODS: One hundred and seventy patients had customized LASIK (207 eyes) and PRK (103 eyes) performed by surgeons in-training using the LADARVision 4000 (Alcon, Fort Worth, TX). Preoperative and 1, 3, 6 and 12 months postoperative data of spherical equivalent (SE), best spectacle corrected visual acuity (BSCVA) and uncorrected visual acuity (UCVA) were analysed. Wavefront changes were determined using the LADARWave Hartmann-Shack wavefront aberrometer and the pupil size was scaled for 6.5 mm. RESULTS: The mean SE in the LASIK group was -3.04 +/-1.07 D and in the PRK group was -1.60 +/- 0.59 D. At 1-year follow-up, (80.6%) (LASIK) and (66.7%) (PRK) were within +/- 0.50 D of the intended refraction. The UCVA was 20/20 or better in (58.1%) (LASIK) and (66.7%) (PRK) of the operated eyes. A statistically significant positive correlation was found between achieved versus attempted refractive correction in both groups: LASIK (r=0.975, P<0.0005) and PRK (r=0.943, P<0.005). The higher order aberrations (HO) RMS and coma did not changed significantly in the PRK group between preoperative and 1-year follow-up. In the LASIK group the HO RMS and coma changed between preoperative and 1-month postoperative but remained statistically unchanged during 1-year follow-up. The spherical aberration showed statistically significant changes in both groups. CONCLUSIONS: Wavefront-guided LASIK and photorefractive keratectomy performed by training-surgeons were found to be similarly effective, predictable and stable. PMID- 20944934 TI - Distribution of spontaneous inter-blink interval in repeated measurements with and without topical ocular anesthesia. AB - PURPOSE: To determine if the distribution of inter-blink time intervals is constant with repeated measurements with and without topical ocular anesthesia. METHODS: Inter-blink time was measured in 15 normal subjects ranging from 19 to 32 years (mean +/- SD= 23.9 +/- 3.20) with the magnetic search coil technique on 3 different occasions, the last one with topical ocular anesthesia. RESULTS: One way analysis of variance for repeated measurements showed that topical anesthesia significantly reduced the blink rate (blinks per minute), which was constant in the first two measurements (F=8.27, p=0.0015. First measurement: mean +/- SD= 13.7 +/- 7.8; second measurement: 13.1 +/- 8.5 SD; with topical anesthesia: = 7.2 +/- 4.6). However, distributions shape was not affected when the blink rate was reduced. The three distributions followed a Log Normal pattern, which means that the time interval between blinks was symmetrical when the time logarithm was considered. CONCLUSIONS: Topical ocular anesthesia reduces the rate of spontaneous blinking, but does not change the distribution of inter-blink time interval. PMID- 20944935 TI - Ability of corneal biomechanical metrics and anterior segment data in the differentiation of keratoconus and healthy corneas. AB - PURPOSE: To evaluate the sensitivity, specificity, and test accuracy of corneal biomechanical metrics and anterior segment data in differentiating keratoconus from healthy corneas. METHODS: Comparative case series. Patients with and without keratoconus (gender and age-matched) were submitted for complete eye examinations including corneal hysteresis (CH) and corneal resistance factor (CRF) as measured by the Ocular Response Analyzer and anterior segment data as gathered through Pentacam assessments. The anterior segment data measurement included average central keratometric readings (K-Ave), corneal astigmatism (CA), central corneal thickness (CCT), anterior chamber depth (AC depth) and corneal volume (CV). All parameters were assessed, compared and analyzed. A receiver operating characteristic (ROC) curve was used to identify the best cutoff point by which to maximize the sensitivity and specificity of discriminating keratoconus from normal corneas for each data category. RESULTS: Seventy seven eyes from forty three patients (24 male, 19 female) with keratoconus and eighty six eyes from forty three (24 male, 19 female) healthy controls were enrolled. ROC curve analysis showed poor overall predictive accuracy for all studied parameters in differentiating keratoconus from normal corneas. The highest sensitivity (79.2%) was obtained for both AC depth and CH (cutoff points 3.22 mm and 9.39 mmHg respectively). The best specificity (89.5%) and test accuracy (80.34%) were obtained for CA (cutoff point of 2.2 D). CONCLUSION: When considered together, studied parameters showed statistical differences between groups. However, when considered independently they presented low sensitivity, specificity and test accuracy in differentiating keratoconus from healthy corneas. PMID- 20944936 TI - [Intravitreal injection of ketorolac tromethamine in patients with diabetic macular edema refractory to retinal photocoagulation]. AB - PURPOSE: To evaluate the effect of a single dose of intravitreous injection of ketorolac tromethamine (500 ug/0.1 ml) in patients with diabetic macular edema refractory to retinal photocoagulation. METHODS: Prospective study. Twenty patients with bilateral diabetic macular edema and ETDRS best-corrected visual acuity between 20/50 and 20/200 were selected. Patients who had other ocular diseases or previous eye surgery were excluded. Preservative-free ketorolac tromethamine was injected intravitreally (500 ug in 0.1 ml) in 20 eyes; fellow eyes served as controls. Ophthalmic examinations included ETDRS best-corrected visual acuity, measurement of intraocular pressure and optical coherence tomography. The examinations were performed preoperatively, 1 week and 1 month postoperatively. RESULTS: A statistically significant increase in visual acuity over time in the treated eye compared with the fellow eye was noted (p=0.039). There were no statistically significant differences in the assessment of intraocular pressure (p=0.99), foveal thickness (p=0.86) and macular volume (p=0.23) during the period. CONCLUSION: Patients with diabetic macular edema refractory to photocoagulation showed improvement in visual acuity over a one month period with a statistically significant difference when compared with the control eye. There were no statistically significant differences in intraocular pressure, foveolar thickness and macular volume between the treated and control eyes. PMID- 20944937 TI - [Prevalence of pterygium in Botucatu city - Sao Paulo State, Brazil]. AB - PURPOSE: To evaluate the prevalence of pterygium in a population-based sample at Botucatu City - Sao Paulo State, Brazil. METHODS: A population-based cross sectional study with randomized clustered sampling of households was conducted in the urban area of the Botucatu City - Sao Paulo State, Brazil and 85.1% of the intended sample was evaluated. All participants were submitted to ophthalmologic examination and the data were statistically analyzed. RESULTS: The prevalence of pterygium lesion in Botucatu City was 8.12% (7.0% < CI < 9.2%), affecting mainly males (10.4% males X 6.5% females - 8.5% < CI < 12.3% for males and 5.1% < CI < 7.8% for females) with 49.6 +/- 14.9 years old in average; 32.18% of the pterygium carriers aged between 40 and 50 years. CONCLUSIONS: The prevalence of pterygium at Botucatu is 8.12%, affecting most frequently 40-50 year-old males. PMID- 20944938 TI - Importance of intraocular pressure measurement at 6:00 a.m. in bed and in darkness in suspected and glaucomatous patients. AB - PURPOSE: To assess the importance of intraocular pressure measurement obtained at 6:00 a.m. in bed and darkness for the diagnosis and intraocular pressure control of primary open-angle glaucoma. METHODS: Retrospective analysis of the daily curve of intraocular pressure of suspects and glaucomatous patients under treatment. Suspects were classified as intraocular pressure values ranging from 19 to 24 mmHg in isolated measurements and/or cup/disc ratio > 0.7 in one or both eyes and/or asymmetry of cup/disc ratio > 0.3 and a normal visual field. Each daily curve of intraocular pressure comprised five to seven IOP measurements with Goldmann applanation tonometer at 9:00 a.m., 12:00 p.m., 3:00 and/or 6:00 and 10:00 p.m. and/or 12:00 a.m. and in the following day morning at 6:00 a.m. in supine position in bed and in darkness with Perkins tonometer before the patient had stood up. Only the daily curves of intraocular pressure that presented an intraocular pressure peak (difference between the higher and the lesser intraocular pressure value) >6 mmHg were analyzed. In these daily curves, the average intraocular pressure and the standard deviation were calculated. The average intraocular pressure and standard deviation values were compared with the normal superior limits: average + two standard deviation of average intraocular pressure and standard deviation of intraocular pressure daily curve from normal patients of the same age group. Daily curves were considered abnormal when their average intraocular pressure and standard deviation values were above the normal superior limits. Secondary and congenital glaucoma were excluded. RESULTS: Daily curves of intraocular pressure of 565 eyes were analyzed; 361 suspected eyes and 204 eyes with primary open-angle glaucoma. In suspects, 64.3% presented an intraocular pressure peak at 6:00 a.m. in bed. In primary open-angle glaucoma, 68.6% presented an intraocular pressure peak at 6:00 a.m. in bed. In 5.3% of the suspects and in 5.9% of primary open-angle glaucoma patients, the daily curve of intraocular pressure profile was inverted (lesser intraocular pressure at 6:00 a.m.). CONCLUSION: Intraocular pressure peaks at 6:00 a.m. were responsible for the diagnosis of preperimetric glaucoma in 64.3% of suspects and revealed inadequate intraocular pressure control in 68.6% of eyes with primary open-angle glaucoma. The daily curve of intraocular pressure including the intraocular pressure measurement at 6:00 a.m. in bed and in darkness is of vital importance in doubtful cases in order to confirm the diagnosis of preperimetric glaucoma in suspects as well as for the adequate intraocular pressure evaluation of antiglaucomatous treatment. PMID- 20944939 TI - [Conjunctival autologous transplantation using fibrin glue in primary pterygium]. AB - PURPOSE: To assess the rate of recurrence and complications after primary pterygium removal with conjunctival autograft using fibrin tissue adhesive. Secondarily, to compare these results with a retrospective series that underwent the same surgery using sutures. METHODS: A hundred and six eyes of 100 patients who underwent surgery with fibrin glue were prospectively studied, while 58 eyes of 51 patients who underwent surgery with sutures were retrospectively evaluated. Data included: age, gender, eye involved, location, grade and pterygium invasion and post-operative complications. Patients were followed for at least 5 months. RESULTS: Among 106 eyes undergoing surgery with fibrin glue, 12 (11.3%) had recurrence, including 4 (3.8%) conjunctival and 8 (7.5%) corneal. Mean age was statistically inferior in the recurrence cases compared to others (mean of 34.6 vs. 43.7; P=0.033). The time for recurrence ranged from 1.6 to 13.1 months (mean of 4.4). Among the corneal recurrences, 2 eyes had invasion beyond the limbus of up to 0.5 mm and 6 eyes from 0.6 to 1.0 mm. No eye underwent reoperation. Other complications included: transitory granuloma formation in 3 cases, partial graft detachment or slippage in 3 and dellen in 1. In the suture group, 15 eyes (25.9%) had recurrence, including 8 conjunctival (13.8%) and 7 (12.1%) corneal. The time for recurrence ranged from 0.7 to 9.7 months (mean 4.5 months). The conjunctival recurrence rate was statistically inferior in the glue group compared to the suture (P=0.023), however no statistically significant difference was observed in relation to corneal recurrence (P=0.232). CONCLUSION: The use of fibrin glue as an alternative to sutures in pterygium surgery was associated with good results and few complications. Despite a decrease in conjunctival recurrence rates, this technique does not appear to significantly decrease corneal recurrences. PMID- 20944940 TI - Factors affecting the variability of the Heidelberg Retina Tomograph III measurements in newly diagnosed glaucoma patients. AB - PURPOSE: To determine factors associated with the test-retest variability of optic nerve head (ONH) topography measurements with confocal scanning laser ophthalmoscopy (CSLO) in newly diagnosed glaucomatous patients. METHODS: Consecutive patients with newly diagnosed primary open-angle glaucoma were prospectively enrolled. Patients presenting with any ocular disease other than glaucoma were excluded. All patients underwent CSLO using the Heidelberg Retina Tomograph III (HRT-III) in one randomly selected eye (three consecutive scans; performed by the same examiner). For each Heidelberg Retina Tomograph III parameter, repeatability was assessed using within subject standard deviation (Sw) and coefficient of variation (CVw), repeatability coefficient (RC) and intraclass correlation coefficient (ICC). Scatter plots and regression lines were constructed to identify which factors influenced test-retest measurement variability. RESULTS: A total of 32 patients were included (mean age, 65.4 +/- 13.8 years). Most patients were female (65%) and white (50%). Among all Heidelberg Retina Tomograph III parameters evaluated, rim area and mean cup depth had the best measurement repeatability. Vertical cup-to-disc ratio (CDR, as determined by optic disc stereophotograph examination) was significantly associated (R2=0.21, p<0.01) with test-retest measurement variability. Eyes with larger CDR showed less variable measurements. Other factors, including age, disc area, central corneal thickness and intraocular pressure were not significant (p>0.14). CONCLUSION: Heidelberg Retina Tomograph III showed good test-retest repeatability for all ONH topographic measurements, mainly for rim area and mean cup depth. Test-retest repeatability seemed to improve with increasing CDR. These findings suggest that HRT-III topographic measurements should be cautiously interpreted when evaluating longitudinally glaucoma patients with early structural damage (small CDR). PMID- 20944941 TI - [Prevalence and spatial distribution of trachoma among schoolchildren in Botucatu, Sao Paulo - Brazil]. AB - PURPOSE: To assess the prevalence of trachoma in schoolchildren of Botucatu/ SP Brazil and its spatial distribution. METHODS: Cross-sectional study in children aged from 7 to 14 years, who attended elementary schools in Botucatu/SP in November/2005. The sample size was estimated in 2,092 children, considering the 11.2% historic prevalence of trachoma, accepting an estimation error of 10% and confidence level of 95%. The sample was random, weighted and increased by 20%, because of the possible occurrence of losses. The total number of children examined was 2,692. The diagnosis was clinical, based on WHO guidelines. For the evaluation of spatial data, the CartaLinx program (v1.2) was used, and the school demand sectors digitized according to the planning divisions of the Department of Education. The data were statistically analyzed, and the analysis of the spatial structure of events calculated using the Geode program. RESULTS: The prevalence of trachoma in schoolchildren of Botucatu was 2.9% and there were cases of follicular trachoma. The exploratory spatial analysis failed to reject the null hypothesis of randomness (R= -0.45, p>0.05), with no significant demand sectors. The analysis for the Thiessen polygons also showed that the overall pattern was random (I= -0.07, p=0.49). However, local indicators pointed to a group of low low type for a polygon to the north of the urban area. CONCLUSION: The prevalence of trachoma in schoolchildren in Botucatu was 2.9%. The analysis of the spatial distribution did not reveal areas of greater clustering of cases. Although the overall pattern of the disease does not reproduce the socio-economic conditions of the population, the lower prevalence of trachoma was found in areas of lower social vulnerability. PMID- 20944942 TI - Interchangeability between Placido disc and Scheimpflug system: quantitative and qualitative analysis. AB - PURPOSE: Many systems try to replace Placido disc-based topographers, such as those based in Scheimpflug principles. The purpose of this study is to check if they are interchangeable. METHODS: Quantitative analysis evaluated data obtained from EyeSys and Pentacam, i.e. simulated keratometric values, in addition to flattest and steepest keratometric values. Sixty-three maps from each device (EyeSys scale=0.5 D; Pentacam scale= 0.25 D) were used for the comparison. Qualitative analysis selected 10 EyeSys and 15 Pentacam topographies used in the quantitative evaluation. Aspheric, keratoconus suspects (KS) and established keratoconus corneas were included. Four groups (children [CH], non-physicians adults [AD], residents in ophthalmology [OP] and refractive surgeons [RS]) were asked to match the topographies belonging to the same eye. RESULTS: Analysis showed that the parameters are correlated; however they are not clinically similar. In the qualitative analysis, the percent of correct matches increased when KS was removed. CH group was statistically different from every group in these comparisons. When only KS was considered, CH vs. OP, CH vs. RS and AD vs. RS remained statistically different. AD vs. OP showed no relevant difference in any comparison. CONCLUSIONS: The systems are not fully interchangeable, yet they are correlated. Practitioners who are adapting to Pentacam should use the 0.25 D scale maps and transform formulas that use EyeSys parameters. Only with persistent training may the topographies be properly matched; KS corneas are more difficult to be correctly paired. PMID- 20944943 TI - [Peter's anomaly, clinical and therapeutic aspects: case report]. AB - Peter's anomaly consists in the most common congenital corneal opacity related to a malformation of the anterior segment of the eye. Its main characteristics are central leukoma and iridocorneal adherences at the area affected by the leukoma. It can be identified isolated or in association with other ocular or systemic abnormalities, and the prognostic tend to be worse in the latter cases. The etiology of Peter's anomaly remains uncertain, but the most likely causes are related to genetic, infectious, traumatic and toxic factors. A range of possible treatment strategies exists, though the effectiveness of each of them depends on how the disease occurs and whether it is identified in early or advanced stages - the earlier the diagnosis, the higher the possibility of a successful intervention, given that precocious treatments are more likely to result in a good development of the vision. This work reports a case of Peter's anomaly that was diagnosed in an advanced stage, discussing the characteristics of the case and treatment possibilities. PMID- 20944944 TI - [Secondary glaucoma following carotid cavernous fistula resolved after fistula's embolization: case report]. AB - Spontaneous carotid cavernous fistulas are a rare entity occurring more frequently in middle aged women. The authors report a case of a spontaneous carotid cavernous fistula in an elderly woman resulting in glaucoma of hard management. After surgical embolization of the fistula, the symptoms regressed and the intraocular pressure moved back to regular levels. PMID- 20944945 TI - [Treatment of radiation retinopathy with intravitreal injection of bevacizumab (Avastin(r)): case report]. AB - PURPOSE: To report a case of radiation retinopathy treatment with intravitreal injection of bevacizumab (Avastin(r)) in a patient undergoing radiotherapy for lymphoma in the right orbit. Patient of 55 years-old male, diabetic, diagnosed with an orbital MALT lymphoma three years ago, treated with local radiotherapy (dose: 35Gy) two years ago, complaining of reduced visual acuity of the right eye for about four months. During the ophthalmologic evaluation, he had an exam suggestive of radiation retinopathy. Macular thickness at the optical coherence tomography was 480 um. Patient was referred to intravitreal injection (0.05 ml) of bevacizumab (Avastin(r)) in the right eye, showing reduction of macular edema and mild improvement of visual acuity. In this case, the treatment of radiation retinopathy with intravitreal injection of bevacizumab (Avastin(r)) was relatively useful, with mild improvement of visual acuity due to the regression of macular edema. PMID- 20944946 TI - [Inflammatory Brown syndrome: case report]. AB - Brown syndrome fits the group of restrictive strabismus and is caused by a movement limitation of the superior oblique tendon through the trochlea. It is characterized by parallelism in the primary gaze position, limitation or absence of elevation in adduction, frequent depression of the eye in adduction with anisotropy in V-pattern and positive passive duction in the elevation in adduction. It is called inflammatory Brown syndrome, a secondary disorder, which main causes are local inflammation in the orbit and inflammatory diseases such as rheumatoid arthritis and tenosynovitis. A case of a 44 year-old patient, male, complaining of binocular vertical diplopia due to recurring dextroversion is reported. It was diagnosed as inflammatory Brown syndrome of uncertain etiology, confirmed by magnetic nuclear resonance, and with spontaneous resolution. PMID- 20944947 TI - [Monocular surgery for large-angle esotropias: review and new paradigms]. AB - The primitive strabismus surgeries, myotomies and tenotomies, were performed simply by sectioning the muscle or its tendon without any suture. Such surgeries were usually performed in just one eye both in small and in large angles with not really predictable results. In 1922, Jameson introduced a new surgery technique using sutures and fixing the sectioned muscle to the sclera, increasing surgery predictability. For the esotropias he carried out no more than 5 mm recession of the medial rectus, which became a rule for the surgeons who followed him, which made it impossible from then on to correct large-angle esotropias with a monocular surgery. Rodriguez-Vasquez, in 1974, exceeded the 5 mm parameter by proposing large recessions of the medial recti (6 to 9 mm) to treat the Ciancia syndrome with good results. The authors revised the literature year after year with the purpose of comparing the several works and concluded that monocular recession-resection surgery may be a feasible option for the surgical treatment of large-angle esotropias. PMID- 20944948 TI - [Ocular complications of chloroquine and derivatives therapy]. AB - INTRODUCTION: Byproducts of 4-aminoquinolones are being used since its industrialization in the treatment of malaria, rheumatic and dermatologic diseases. These drugs present systemic and ocular adverse events. Systemic adverse reactions affect the gastrointestinal, nervous and skeletal muscular systems and the skin. Ocular adverse reactions are: photophobia, cornea verticillata, poliosis, cataract, extraocular muscle palsy, anterior uveitis, toxic maculopathy and optical neuritis. PURPOSE: Bibliography review of complications due to the use of chloroquine and its derivatives. To analyze the current practice and propedeutics' evolution. To suggest practical managements for early toxicity signs. METHODS: Bibliographic review through research on MEDLINE, PUBMED, LILACS and SciELO database. DISCUSSION: All exams that can be used to screen ocular adverse reactions are described, such as: complete ophthalmologic exam, with emphasis on biomicroscopy and indirect binocular ophthalmoscopy, computerized visual field, Amsler grid testing and color vision testing, electrophysiological exams, polarimetry and optical coherence tomography. A description of maculopathy is presented, focusing on epidemiology, risk factors, histopathology and propedeutics. Chemical structure and the differences between 4-aminoquinolone derivatives are described. CONCLUSION: All patients using chloroquine and its derivatives must be followed-up and documented since the beginning of the therapy until they reach a cumulative dose above 100 grams. The higher the cumulative dose, the more we must be concerned with patient follow-up. PMID- 20944949 TI - [Recommendations for the management of pulmonary thromboembolism, 2010]. AB - Pulmonary thromboembolism and deep vein thrombosis together constitute a condition designated venous thromboembolism. Despite the advances, the morbidity and the mortality attributed to this condition are still high, because the patients present with more complex diseases, are submitted to a greater number of invasive procedures and survive longer. Although there are various international guidelines available, we decided to write these recommendations for their application in medical practice in Brazil. These recommendations are based on the best evidence in the literature and the opinion of the advisory committee. This document is only a tool for use in the management of patients. Although the recommendations it contains can be applied to most situations, physicians should adapt its content depending on their local context and on a case-by-case basis. Pulmonary thromboembolism is diagnosed by evaluating pre-test clinical probability (scores) together with the results of imaging studies, the current method of choice being CT angiography. Stratification of the risk for an unfavorable outcome is fundamental. Hemodynamic instability is the most important predictor. Low-risk patients should be treated with heparin, commonly low molecular-weight heparins. High-risk patients require intensive monitoring and, in some cases, thrombolytic therapy. In the long term, patients should receive anticoagulants for at least three months. The decision to prolong this treatment is made based on the presence of risk factors for the recurrence of the condition and the probability of bleeding. Prophylaxis is highly effective and should be widely used in clinical and surgical patients alike, according to their risk group. Finally, we include recommendations regarding the prevention, diagnosis and treatment of pulmonary thromboembolism. PMID- 20944971 TI - [Epidemiology of sleep-disordered breathing]. AB - The principal types of sleep-disordered breathing--snoring and obstructive sleep apnea syndrome--are highly prevalent in the general population, although it is believed that the majority of cases continue to go undiagnosed. We should be aware of the principal risk factors that favor the onset of these disorders, such as male gender, obesity, aging and craniofacial features. Similarly, systemic arterial hypertension, cardiovascular diseases and metabolic disorders should alert us to the possibility of obstructive sleep apnea syndrome. PMID- 20944972 TI - [Pathophysiology of sleep-disordered breathing]. AB - Sleep is a phase during which the respiratory system undergoes major changes. These changes lead to greater vulnerability and a greater risk of abnormalities, even in normal individuals. In the transition from wakefulness to sleep, there is commonly an increase in upper airway resistance and impairment of various protective responses and reflexes, which are efficient in promoting and maintaining upper airway patency during wakefulness. In individuals who present risk factors, such as anatomical abnormalities in the upper airway, these sleep related changes cannot be efficaciously compensated, which increases the chances that sleep-disordered breathing will occur. Sleep-disordered breathing is characterized by a reduction in the size of upper airways, although the degree of the reduction varies. This reduction has multifactorial causes, which include anatomical abnormalities in the upper airway, alterations in the neuromuscular response and impairment of receptors in the upper airway. Upper airway functional and anatomical changes are likely to have genetic components, and, therefore, individuals exposed to certain environmental factors, such as allergies, have a greater chance of developing sleep-disordered breathing. PMID- 20944973 TI - [Obstructive sleep apnea syndrome: clinical history and physical examination]. AB - Although obstructive sleep apnea syndrome is a common disease, it often goes undiagnosed. The signs and symptoms of the syndrome are mostly subjective. Therefore, snoring, daytime sleepiness, fatigue, dejection and mood changes should raise the suspicion of obstructive sleep apnea syndrome. Scales and tables that have good sensitivity and include the most relevant clinical symptoms and physical examination results can suggest a diagnosis of obstructive sleep apnea syndrome. The diagnosis is confirmed by polysomnography, which is considered the gold standard method. PMID- 20944974 TI - [Genetic aspects of obstructive sleep apnea syndrome]. AB - The physiopathology of obstructive sleep apnea syndrome (OSAS) results from the interaction between genetic and environmental factors. The principal risk factors are obesity and age. Other relevant risk factors are craniofacial abnormalities, hypothyroidism and menopause, as well as the use of alcohol and sedatives. By virtue of its association with factors such as HLA levels, obesity, genetic syndromes, ethnicity, excessive sleepiness, alterations in ventilatory control and expression of inflammatory mediators, OSAS has been related to heritability. This chapter addresses the genetic and phenotypic variability of the disease, showing its relevance in the understanding of the physiopathology and clinical evaluation of OSAS. PMID- 20944975 TI - [Snoring: diagnostic criteria and treatment]. AB - Snoring is a significant problem with social and medical manifestations. After snoring has been confirmed, other nocturnal respiratory diseases should be excluded so that the appropriate treatment can be instituted. This chapter addresses the current management of snoring and its treatment. PMID- 20944976 TI - [Diagnostic criteria and treatment for sleep-disordered breathing: RERA]. AB - In polysomnography, RERA is defined as a respiratory parameter that indicates an arousal associated with a respiratory event and an increase in respiratory effort. Initially, RERA was described by means of esophageal manometry for the evaluation of respiratory effort. This greater respiratory effort occurs as a response to an increase in upper airway resistance, which is a factor present in the pathophysiology of sleep-disordered breathing, such as obstructive sleep apnea syndrome and upper airway resistance syndrome. Later, the use of a nasal pressure cannula was reported to be a reliable means of identifying airflow limitation and one that is more sensitive than is a thermistor. In addition, the nasal pressure cannula method has been used as a surrogate for esophageal manometry in the identification of periods in which upper airway resistance increases. Consequently, the American Academy of Sleep Medicine recommend the use of either method for the identification of RERA, which is defined by the flattening of the inspiratory curve, characteristic of airflow limitation. Although RERA has been identified and evaluated in current medical practice, it has yet to be standardized. Therefore, it is recommended that polysomnographic reports indicate which abnormal respiratory events were taken into consideration in the evaluation of the severity of sleep-disordered breathing. PMID- 20944977 TI - [Diagnostic criteria and treatment for sleep-disordered breathing: obstructive sleep apnea syndrome]. AB - In this chapter, the principal approaches to the diagnosis and treatment of patients with obstructive sleep apnea syndrome (OSAS) are presented. The diagnosis should be carried out by the taking of a thorough clinical history and by physical examination. For diagnostic confirmation, it is necessary to perform supervised overnight polysomnography. For patients in whom clinical suspicion is high, a simplified home study can be an alternative. The treatment of OSAS requires general measures and the use of positive pressure devices. In moderate and severe cases, CPAP is the method of choice, whereas oral appliances can be used in mild cases. Surgical procedures are recommended when anatomical alterations are evident or as an auxiliary method in combination with other types of treatment. PMID- 20944978 TI - [Consequences of untreated snoring]. AB - In some studies, snoring has been associated with an increased risk of hypertension, ischemic heart disease and stroke. Although the mechanisms involved in these associations are unknown, they are probably mediated by obstructive sleep apnea. Nevertheless, most snorers do not have sleep apnea. Whether snoring itself increases the risk of cardiovascular disease remains controversial. PMID- 20944979 TI - [Cognitive impairment in obstructive sleep apnea syndrome]. AB - Cognitive and performance impairment is well established in patients with obstructive sleep apnea syndrome (OSAS), having a significant impact on the quality of life and the risk of accidents in these individuals. The severity of the impairment correlates with that of the OSAS, which explains the apparent discrepancy between studies using patients from sleep clinics and population based studies in terms of the reported frequency and severity of such impairment. Cognitive processing, sustained attention, executive functioning, and memory have all been reported to be impaired in OSAS. However, the causal mechanisms of these deficits have not been entirely clarified, and the relative contribution of intermittent hypoxia and sleep disruption in OSAS is particularly controversial. The potential effect of daytime sleepiness on the performance of these patients on various cognitive tests has yet to be determined, as does that of common comorbidities, such as diabetes, systemic arterial hypertension, cardiovascular disease, and obesity. There is compelling evidence that CPAP treatment can improve performance and cognition, particularly in mild to moderate cases, although further studies on the long-term impact of this type of treatment are still needed. PMID- 20944980 TI - [Cardiovascular consequences of obstructive sleep apnea syndrome]. AB - Obstructive sleep apnea syndrome (OSAS) is a common condition associated with various cardiovascular diseases, including systemic arterial hypertension, atrial fibrillation, and atherosclerosis. The association between OSAS and cardiovascular disease has been related to the overlapping of risk factors, including obesity, having a sedentary lifestyle, being male, and being older. However, there is mounting evidence that OSAS can also independently contribute to the development and progression of various cardiovascular diseases. The mechanisms by which OSAS can affect the cardiovascular system are multiple, including the activation of the sympathetic nervous system, systemic inflammation, insulin resistance, and oxidative stress. There is also evidence that the treatment of OSAS with CPAP can reduce arterial blood pressure, early signs of atherosclerosis, the risk of atrial fibrillation recurrence, and mortality (principally mortality due to stroke or acute myocardial infarction) in patients with severe OSAS. PMID- 20944981 TI - [Metabolic consequences of untreated obstructive sleep apnea syndrome]. AB - There is a recognized association between obstructive sleep apnea syndrome and metabolic syndrome, designated syndrome Z. The criteria for metabolic syndrome include at least three of the following factors: central obesity (waist circumference >= 102 cm for males and >= 88 cm for females); triglycerides >= 150 mg/dL; HDL cholesterol < 40 mg/dL for males and < 50 mg/dL for females; arterial blood pressure >= 130/85 mmHg; and fasting glucose >= 100 mg/dL. Central obesity is associated with OSAS and metabolic syndrome, and there is evidence that obstructive sleep apnea is an independent risk factor for obesity, glucose intolerance and insulin resistance. The implied mechanisms result from the activation of the sympathetic nervous system and of the hypothalamus-hypophysis adrenal axis; activation of pro-inflammatory markers, such as IL-6 and TNF-alpha; and the reduction in adiponectin levels, principally triggered by intermittent hypoxemia related to apnea. Despite such evidence, the results are controversial regarding the benefits of treating sleep apnea with CPAP in the presence of these metabolic alterations. In addition, the few studies that have addressed sleep apnea as a risk factor for dyslipidemia have presented conflicting results. Population-based, longitudinal controlled studies are necessary in order to elucidate the interaction between sleep apnea and metabolic consequences so that these individuals are properly treated. PMID- 20944982 TI - [Sleep hypoventilation]. AB - Sleep hypoventilation is seen in patients with neuromuscular disease, as well as in those with obesity hypoventilation syndrome (OHS), which is defined as the combination of obesity, chronic hypercapnia, and hypoxemia during wakefulness that is aggravated during sleep. In 90% of cases, OHS is accompanied by obstructive sleep apnea. The diagnosis of OHS is based on hypoventilation and pulmonary hypertension that cannot be explained by alterations in pulmonary function. The mortality of patients with OHS is greater than is that of obese patients without hypoventilation. The principal neuromuscular diseases associated with OHS are the muscular dystrophies. The progression to chronic respiratory failure results from respiratory muscle weakness and impaired airway secretion clearance, causing atelectasis and pneumonia. With a decrease of greater than 50% in respiratory muscle strength, there is a reduction in VC. Cough peak flow < 160 L/min is associated with impaired airway secretion clearance, and values near 270 L/min indicate the need for assisted cough techniques. Obstructive sleep apnea usually worsens sleep hypoventilation. Noninvasive ventilation during sleep can improve survival, symptoms, and hypoventilation during wakefulness, as well as being able to improve pulmonary function in patients with neuromuscular disease. Patients with OHS can require oxygen therapy. PMID- 20944983 TI - [Sleep and chronic lung diseases: diffuse interstitial lung diseases, bronchial asthma, and COPD]. AB - Chronic lung diseases can be aggravated by various factors and comorbidities, including sleep-disordered breathing. Although changes in the quality of life of patients with chronic lung disease are usually related to daytime variables, the physiological changes in sleep impair the quality of sleep and interfere with the natural history of the disease. Alterations in sleep architecture appear to be a common mechanism in these diseases. During sleep, the upper and lower airways are more interconnected: changes in upper airway resistance during sleep are added to the severe resistive alterations in the lower airways due to asthma and COPD. In addition, there are complex mechanical and ventilatory interactions. The recognition of these interactions allows better assessment of the exacerbations and the progression of chronic lung diseases. PMID- 20944984 TI - [Obstructive sleep apnea in children]. AB - Childhood obstructive sleep apnea syndrome (OSAS) is characterized by recurrent episodes of partial or complete upper airway obstruction during sleep. The disease encompasses a continuum from primary snoring (a benign condition without physiological alterations or associated complications) to increased upper airway resistance, obstructive hypoventilation and OSAS. The prevalence of snoring is high, ranging from 1.5% to 15%, depending on how it is defined. Based on parent reported questionnaires and complementary tests, the prevalence of OSAS is 1-4%. This syndrome is more common in boys, overweight children, of African ancestry, with a history of atopy and prematurity. The most common symptoms are snoring that is frequent and loud; family-reported apnea; and restless sleep. The physical examination should assess growth status, signs of chronic upper airway obstruction, and craniofacial malformations. Overnight polysomnography is the gold standard test for the diagnosis and for the determination of the appropriate positive pressure level, as well as for postsurgical treatment evaluation. Intermittent hypoxia and multiple arousals resulting from obstructive events contribute to the well-described cardiovascular, neurocognitive, and behavioral consequences in pediatric patients with OSAS. Although the main treatment for OSAS in children is adenotonsillectomy, treatment with CPAP or Bilevel is becoming more widely used in the pediatric population. PMID- 20944985 TI - Immunological and parasitological parameters after treatment with dexamethasone in murine Schistosoma mansoni. AB - This work aimed to evaluate the effect of diphenyl dimethyl bicarboxylate (DDB) and dexamethasone alone and in combination with praziquantel on various parasitological, immunological and pathological parameters reflecting disease severity and morbidity in murine schistosomiasis. DDB and dexamethasone had no effect on worm burden but altered tissue egg distribution. This indicates that, under the schedule used, neither drug interfered with the development of adult worms or oviposition, but both can modulate liver pathology. Dexamethasone resulted in a greater reduction in granuloma size than did DDB. Dexamethasone treated mice also showed lower levels of serum gamma interferon (IFN-gamma), interleukin-12 (IL-12) and IL-4, together with higher IL-10 levels, than infected untreated control animals. These data suggest that dexamethasone is a convenient and promising coadjuvant agent that results in decreased morbidity in murine schistosomiasis. PMID- 20944986 TI - Low and high-dose intradermal infection with Leishmania major and Leishmania amazonensis in C57BL/6 mice. AB - A model of skin infection with Leishmania amazonensis with low doses of parasites is compared to infection with high doses of L. amazonensis and low and high doses of Leishmania major. C57BL/6 mice were infected with 103 or 10(6) parasites in the ear and the outcome of infection was assessed. The appearance of lesions in mice infected with 103 parasites was delayed compared to mice infected with 10(6) Leishmania and parasites were detectable at the infection site before lesions became apparent. Mice infected with L. amazonensis displayed persistent lesions, whereas infection with L. major spontaneously healed in all groups, although lymphocytes persisted at the site of infection after healing. Macrophages persisted only in L. amazonensis-infected mice. High-dose L. amazonensis-infected mice produced lower levels of IFN-gamma and TNF than mice infected with L. major. No correlation between the persistence of parasites and IL-10 levels and the production of nitric oxide or urea by macrophages was found. We conclude that infection with low doses of L. amazonensis in the dermis changes the course of infection by delaying the appearance of lesions. However, low-dose infection does not change the outcomes of susceptibility and cytokine production described for subcutaneous infection with high numbers of parasites. PMID- 20944987 TI - The benefits of using selenium in the treatment of Chagas disease: prevention of right ventricle chamber dilatation and reversion of Trypanosoma cruzi-induced acute and chronic cardiomyopathy in mice. AB - Cardiac damage is a frequent manifestation of Chagas disease, which is caused by the parasite Trypanosoma cruzi. Selenium (Se) is an essential micronutrient, the deficiency of which has been implicated in the development of cardiomyopathy. Our group has previously demonstrated that Se supplementation prevents myocardial damage during acute T. cruzi infection in mice. In this study, we analyzed the effect of Se treatment in cases of T. cruzi infection using prevention and reversion schemes. In the Se prevention scheme, mice were given Se supplements (2 ppm) starting two weeks prior to inoculation with T. cruzi(Brazil strain) and continuing until 120 days post-infection (dpi). In the Se reversion scheme, mice were treated with Se (4 ppm) for 100 days, starting at 160 dpi. Dilatation of the right ventricle was observed in the infected control group at both phases of T. cruzi infection, but it was not observed in the infected group that received Se treatment. Surviving infected mice that were submitted to the Se reversion scheme presented normal P wave values and reduced inflammation of the pericardium. These data indicate that Se treatment prevents right ventricular chamber increase and thus can be proposed as an adjuvant therapy for cardiac alterations already established by T. cruzi infection. PMID- 20944988 TI - Residual effect of a micro-encapsulated formulation of organophosphates and piriproxifen on the mortality of deltamethrin resistant Triatoma infestans populations in rural houses of the Bolivian Chaco region. AB - The Bolivian Chaco is part of the endemic region of Chagas disease and an area where pyrethroid resistant Triatoma infestans (Hemiptera: Reduviidae) populations has been reported. The World Health Organization identified these resistant populations as an important focus for research. The objective of this study was to evaluate the residual effect of a micro-encapsulated formulation containing organophosphate active ingredients and a juvenile hormone analogue (Inesfly 5A IGR) on the mortality of T. infestans. Studies took place in rural houses of the Bolivian Chaco that were treated up to 34 months before and evaluated the susceptibility to pyrethroids of the offspring of field collected insects. Thirty houses were randomly selected within three communities to carry out wall bio assays with T. infestans nymphs. Mortality was recorded 24, 48 and 72 h after wall contact. Eggs laid by females collected in the area were used to obtain first-instar nymphs and carry out pyrethroid susceptibility tests. The wall bio assays showed that the micro-encapsulated insecticide eliminates T. infestans populations and produces detectable mortality of insects exposed to walls treated 34 months prior to the tests. The discriminant dose of deltamethrin (0.01 mg/mL) showed 65% nymph survival, whereas at the highest tested dose (1.0 mg/mL) 14% of the nymphs survived. These results show that Inesfly 5A IGR is an appropriate tool for the elimination of intradomestic and peridomestic populations of T. infestans resistant to pyrethroids. PMID- 20944989 TI - IgG and IgM western blot assay for diagnosis of congenital toxoplasmosis. AB - The aim of this study was to evaluate the utility of western blot (WB) analysis as a diagnostic tool for congenital toxoplasmosis in 215 newborn infants. The children were submitted to clinical examinations to assess macular, neurological and hearing signals. The WB results obtained were compared to the persistence of IgG antibodies at the end of 12 months, which is regarded as the "gold standard" diagnosis of congenital toxoplasmosis. Association between the WB results and the clinical signs presented by the infants was also assessed. Of the 215 children, 177 had a confirmed congenital toxoplasmosis diagnosis and 38 were uninfected. IgG-WB showed a sensitivity of 73.5% and a specificity of 97.4%. IgM-WB showed a sensitivity of 54.8% and a specificity of 94.7%. The IgG-WB and IgM-WB combination increased the sensitivity to 86.5%. The IgM-WB-positive children had a 1.4-fold greater risk of presenting active macular lesions than did those that were IgM-WB-negative. This study showed that the WB assay is a useful tool to confirm a diagnosis of congenital toxoplasmosis and that the IgM-WB-positive results can indicate active macular lesions in newborn infants. PMID- 20944990 TI - Phylogeny, ultrastructure, histopathology and prevalence of Myxobolus oliveirai sp. nov., a parasite of Brycon hilarii (Characidae) in the Pantanal wetland, Brazil. AB - This paper presents the morphological, histological and ultrastructural characteristics of Myxobolus oliveirai sp. nov., a parasite of the gill filaments in Brycon hilarii from the Brazilian Pantanal. Out of 216 B. hilariispecimens examined (126 wild and 90 cultivated), 38.1% of wild specimens (n = 48) were infected. The parasites form elongated plasmodia primarily in the tip of gill filaments, reaching about 3 mm in length. A thorough comparison with all the Myxobolus species described from South American hosts, as well as nearly all the Myxobolus species described so far is provided. Partial sequencing of the 18S rDNA gene revealed a total of 1,527 bp. The Myxobolus species parasite of B. hilarii did not match any of the Myxozoa available in GenBank. In the phylogenetic analysis, M. oliveirai sp. nov. composed a monophyletic group with eight other species: five species of Myxobolus parasites of mugilid fishes, two parasites of pangasiid and one of centrarchid. Infection prevalence values of the parasite revealed no significant differences between wet and dry seasons or between males and females. The importance of the infection to the farming of the host species is emphasized. PMID- 20944991 TI - Hepatitis B genotype G and high frequency of lamivudine-resistance mutations among human immunodeficiency virus/hepatitis B virus co-infected patients in Brazil. AB - In this study, we evaluated the hepatitis B virus (HBV) genotype distribution and HBV genomic mutations among a group of human immunodeficiency virus-HBV co infected patients from an AIDS outpatient clinic in Sao Paulo. HBV serological markers were detected by commercially available enzyme immunoassay kits. HBV DNA was detected using in-house nested polymerase chain reaction and quantified by Cobas Amplicor. HBV genotypes and mutations in the basal core promoter (BCP)/pre core/core regions and surface/polymerase genes were determined by sequencing. Among the 59 patients included in this study, 55 reported prior use of lamivudine (LAM) or tenofovir. HBV DNA was detected in 16/22 patients, with a genotype distribution of A (n = 12,75%), G (n = 2,13%), D (n = 1,6%) and F (n = 1,6%). The sequence data of the two patients infected with genotype G strongly suggested co infection with genotype A. In 10 patients with viremia, LAM-resistance mutations in the polymerase gene (rtL180M + rtM204V and rtV173L + rtL180M + rtM204V) were found, accompanied by changes in the envelope gene (sI195M, sW196L and sI195M/sE164D). Mutations in the BCP and pre-core regions were identified in four patients. In conclusion, genotype G, which is rarely seen in Brazil, was observed in the group of patients included in our study. A high prevalence of mutations associated with LAM-resistance and mutations associated with anti-HBs resistance were also found among these patients. PMID- 20944992 TI - Genotyping of Mycobacterium tuberculosis isolates from a low-endemic setting in northwestern state of Parana in Southern Brazil. AB - The purpose of this study was to provide information about the genetic diversity and prevalent genotype of Mycobacterium tuberculosis in a low-endemic setting in northwestern state of Parana in Southern Brazil. We employed spoligotyping and mycobacterial interspersed repetitive units-variable number tandem repeat (MIRU VNTR) techniques to genotype M. tuberculos isisolates from patients with pulmonary tuberculosis (TB). The 93 isolates analyzed by spoligotyping were divided into 36 different patterns, 30 of which were described in the SITVIT database. Latin American and Mediterranean, Haarlem and T families were responsible for 26.9%, 17.2% and 11.8% of TB cases, respectively. From the 84 isolates analyzed by MIRU-VNTR, 58 shared a unique pattern and the remaining 26 belonged to nine clusters. The MIRU loci 40, 23, 10 and 16 were the most discriminatory. A combination of MIRU-VNTR and spoligotyping resulted in 85.7% discriminatory power (Hunter-Gaston index = 0.995). Thus, combining spoligotyping and MIRU-VNTR typing proved to be most useful for epidemiological study in this low-endemic setting in Southern Brazil. The current study demonstrated that there is significant diversity in circulating strains in the city of Maringa and the surrounding regions, with no single genotype of M. tuberculosis predominating. PMID- 20944993 TI - Expression of bacterial virulence factors and cytokines during in vitro macrophage infection by enteroinvasive Escherichia coli and Shigella flexneri: a comparative study. AB - Enteroinvasive Escherichia coli (EIEC) and Shigella spp cause bacillary dysentery in humans by invading and multiplying within epithelial cells of the colonic mucosa. Although EIEC and Shigella share many genetic and biochemical similarities, the illness caused by Shigella is more severe. Thus, genomic and structure-function molecular studies on the biological interactions of these invasive enterobacteria with eukaryotic cells have focused on Shigella rather than EIEC. Here we comparatively studied the interactions of EIEC and of Shigella flexneri with cultured J774 macrophage-like cells. We evaluated several phenotypes: (i) bacterial escape from macrophages after phagocytosis, (ii) macrophage death induced by EIEC and S. flexneri, (iii) macrophage cytokine expression in response to infection and (iv) expression of plasmidial (pINV) virulence genes. The results showed that S. flexneri caused macrophage killing earlier and more intensely than EIEC. Both pathogens induced significant macrophage production of TNF, IL-1 and IL-10 after 7 h of infection. Transcription levels of the gene invasion plasmid antigen-C were lower in EIEC than in S. flexneri throughout the course of the infection; this could explain the diminished virulence of EIEC compared to S. flexneri. PMID- 20944994 TI - Description of Sergentomyia (Parrotomyia) rectangulata sp. nov. (Diptera: Psychodidae: Phlebotominae) from southern India. AB - Both sexes of Sergentomyia (Parrotomyia) rectangulata sp. nov. from southern India are described with illustrations. The specimens were collected in tree holes, termite mounds, cattle sheds and mud-walled, thatched roof human dwellings in rural areas. Our findings reveal similarity with Sergentomyia (Parrotomyia) modii Lewis. PMID- 20944995 TI - Detection of Leishmania infantum in naturally infected Lutzomyia longipalpis (Diptera: Psychodidae: Phlebotominae) and Canis familiaris in Misiones, Argentina: the first report of a PCR-RFLP and sequencing-based confirmation assay. AB - In this study, a genotypification of Leishmania was performed using polimerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing techniques to identify species of Leishmania parasites in phlebotomine sand flies and dogs naturally infected. Between January-February of 2009, CDC light traps were used to collect insect samples from 13 capture sites in the municipality of Posadas, which is located in the province of Misiones of Argentina. Sand flies identified as Lutzomyia longipalpis were grouped into 28 separate pools for molecular biological analysis. Canine samples were taken from lymph node aspirates of two symptomatic stray animals that had been positively diagnosed with canine visceral leishmaniasis. One vector pool of 10 sand flies (1 out of the 28 pools tested) and both of the canine samples tested positively for Leishmania infantum by PCR and RFLP analysis. PCR products were confirmed by sequencing and showed a maximum identity with L. infantum. Given that infection was detected in one out of the 28 pools and that at least one infected insect was infected, it was possible to infer an infection rate at least of 0.47% for Lu. longipalpis among the analyzed samples. These results contribute to incriminate Lu. longipalpis as the vector of L. infantum in the municipality of Posadas, where cases of the disease in humans and dogs have been reported since 2005. PMID- 20944996 TI - Socioepidemiological screening of serologically ineligible blood donors due to Chagas disease for the definition of inconclusive cases. AB - Epidemiological screening combined with serological tests has become an important tool at blood banks for the characterization of donors with or without Trypanosoma cruzi infection. Thus, the objective of the present study was to describe the sociodemographic and epidemiological characteristics of blood donors with non-negative serology for T. cruzito determine possible risk factors associated with serological ineligibility. Sociodemographic and epidemiological data were collected by analysis of patient histories and interviews. The data were analyzed descriptively using absolute and relative frequencies and odds ratio (OR) evaluation. The frequency of serological ineligibility was 0.28%, with a predominance of inconclusive reactions (52%) and seropositivity among first time donors (OR = 607), donors older than 30 years (OR = 3.7), females (OR = 1.9), donors from risk areas (OR = 4) and subjects living in rural areas (OR = 1.7). The risk of seropositivity was higher among donors who had contact with the triatomine vector (OR = 11.7) and those with a family history of Chagas disease (OR = 4.8). The results demonstrate the value of detailed clinical epidemiological screening as an auxiliary tool for serological definition that, together with more specific and more sensitive laboratory methods, will guarantee a higher efficacy in the selection of donors at blood centres. PMID- 20944997 TI - Molecular characterization of Echinococcus granulosus from Peru by sequencing of the mitochondrial cytochrome C oxidase subunit 1 gene. AB - Echinococcus granulosus, the etiologic agent of cystic echinococcosis (CE) in humans and other animal species, is distributed worldwide. Ten intra-specific variants, or genotypes (G1-G10), have been defined based on genetic diversity. To determine the genotypes present in endemic areas of Peru, samples were collected from cattle (44), sheep (41) and humans (14) from Junin, Puno Huancavelica, Cusco, Arequipa and Ayacucho. DNA was extracted from protoscolex and/or germinal layers derived from 99 E. granulosus isolates and used as templates to amplify the mitochondrial cytochrome C oxidase subunit 1 gene. The resulting polymerase chain reaction products were sequenced and further examined by sequence analysis. All isolates, independent of the host, exhibited the G1 genotype. Phylogenetic analysis showed that three isolates from Ayacucho shared the same cluster with microvariant G1(4). The G1 genotype is considered the most widespread and infectious form of E. granulosus worldwide and our results confirm that the same patterns apply to this country. Therefore, these findings should be taken into consideration in developing prevention strategies and control programs for CE in Peru. PMID- 20944998 TI - Immune response to Leishmania (Leishmania) chagasi infection is reduced in malnourished BALB/c mice. AB - Protein-energy malnutrition and micronutrient deficiencies may down-regulate immune response and increase morbidity and mortality due to infection. In this study, a murine model was used to study the effects of protein, iron and zinc deficiencies on the immune response to Leishmania (Leishmania) chagasi infection. Mice were initially fed a standard diet or with a diet containing 3% casein but deficient in zinc and iron. After malnutrition was established, mice were inoculated with L. chagasi and sacrificed four weeks later in order to evaluate liver and spleen parasite loads and serum biochemical parameters. Significant decreases in liver and spleen weight, an increase in the parasite loads in these organs and decreases in serum protein and glucose concentrations in malnourished animals were observed. Furthermore, the production of interferon-gamma by spleen cells from infected malnourished mice stimulated by Leishmania antigen was significantly lower compared with that in control diet mice. These data suggest that malnutrition alters the immune response to L. chagasi infection in the BALB/c model and, in association with the effects on biochemical and anatomical parameters of the host, favored increases in the parasite loads in the spleens and livers of these animals. PMID- 20944999 TI - Antigenic extracts of Leishmania braziliensis and Leishmania amazonensis associated with saponin partially protects BALB/c mice against Leishmania chagasi infection by suppressing IL-10 and IL-4 production. AB - This study evaluated two vaccine candidates for their effectiveness in protecting BALB/c mice against Leishmania chagasi infection. These immunogenic preparations were composed of Leishmania amazonensis or Leishmania braziliensis antigenic extracts in association with saponin adjuvant. Mice were given three subcutaneous doses of one of these vaccine candidates weekly for three weeks and four weeks later challenged with promastigotes of L. chagasi by intravenous injection. We observed that both vaccine candidates induced a significant reduction in the parasite load of the liver, while the L. amazonensis antigenic extract also stimulated a reduction in spleen parasite load. This protection was associated with a suppression of both interleukin (IL)-10 and IL-4 cytokines by spleen cells in response to L. chagasi antigen. No change was detected in the production of IFN-gamma. Our data show that these immunogenic preparations reduce the type 2 immune response leading to the control of parasite replication. PMID- 20945000 TI - Nested PCR to detect and distinguish the sympatric filarial species Onchocerca volvulus, Mansonella ozzardi and Mansonella perstans in the Amazon Region. AB - We present filaria-nested polymerase chain reaction (PCR), which is based on amplification of first internal transcribed spacer rDNA to distinguish three parasitic filarial species (Onchocerca volvulus, Mansonella ozzardi and Mansonella perstans) that can be found in the Amazon Region. Nested PCR-based identifications yielded the same results as those utilizing morphological characters. Nested PCR is highly sensitive and specific and it detects low-level infections in both humans and vectors. No cross-amplifications were observed with various other blood parasites and no false-positive results were obtained with the nested PCR. The method works efficiently with whole-blood, blood-spot and skin biopsy samples. Our method may thus be suitable for assessing the efficacy of filaria control programmes in Amazonia by recording parasite infections in both the human host and the vector. By specifically differentiating the major sympatric species of filaria, this technique could also enhance epidemiological research in the region. PMID- 20945001 TI - Serologic evidence of the recent circulation of Saint Louis encephalitis virus and high prevalence of equine encephalitis viruses in horses in the Nhecolandia sub-region in South Pantanal, Central-West Brazil. AB - As in humans, sub-clinical infection by arboviruses in domestic animals is common; however, its detection only occurs during epizootics and the silent circulation of some arboviruses may remain undetected. The objective of the present paper was to assess the current circulation of arboviruses in the Nhecolandia sub-region of South Pantanal, Brazil. Sera from a total of 135 horses, of which 75 were immunized with bivalent vaccine composed of inactive Eastern equine encephalitis virus (EEEV) and Western equine encephalitis virus(WEEV) and 60 were unvaccinated, were submitted to thorough viral isolation, reverse transcriptase polymerase chain reaction (RT-PCR) and neutralization tests for Saint Louis encephalitis virus (SLEV), EEEV, WEEV and Mayaro virus (MAYV). No virus was isolated and viral nucleic-acid detection by RT-PCR was also negative. Nevertheless, the prevalence of neutralizing antibodies in horses older than seven months was 43.7% for SLEV in equines regardless of vaccine status, and 36.4% for WEEV and 47.7% for EEEV in unvaccinated horses. There was no evidence of MAYV infections. The serologic evidence of circulation of arboviruses responsible for equine and human encephalitis, without recent official reports of clinical infections in the area, suggests that the Nhecolandia sub-region in South Pantanal is an important area for detection of silent activity of arboviruses in Brazil. PMID- 20945002 TI - Differential tissue tropism of Trypanosoma cruzi strains: an in vitro study. AB - We have previously demonstrated selection favoring the JG strain of Trypanosoma cruzi in hearts of BALB/c mice that were chronically infected with an equal mixture of the monoclonal JG strain and a clone of the Colombian strain, Col1.7G2. To evaluate whether cell invasion efficiency drives this selection, we infected primary cultures of BALB/c cardiomyocytes using these same T. cruzi populations. Contrary to expectation, Col1.7G2 parasites invaded heart cell cultures in higher numbers than JG parasites; however, intracellular multiplication of JG parasites was more efficient than that of Col1.7G2 parasites. This phenomenon was only observed for cardiomyocytes and not for cultured Vero cells. Double infections (Col1.7G2 + JG) showed similar results. Even though invasion might influence tissue selection, our data strongly suggest that intracellular development is important to determine parasite tissue tropism. PMID- 20945003 TI - High prevalence of drug-resistant tuberculosis and other mycobacteria among HIV infected patients in Brazil: a systematic review. AB - There is a little-noticed trend involving human immunodeficiency virus (HIV) infected patients suspected of having tuberculosis: the triple-treatment regimen recommended in Brazil for years has been potentially ineffective in over 30% of the cases. This proportion may be attributable to drug resistance (to at least 1 drug) and/or to infection with non-tuberculous mycobacteria. This evidence was not disclosed in official statistics, but arose from a systematic review of a few regional studies in which the diagnosis was reliably confirmed by mycobacterial culture. This paper clarifies that there has long been ample evidence for the potential benefits of a four-drug regimen for co-infected patients in Brazil and it reinforces the need for determining the species and drug susceptibility in all positive cultures from HIV-positive patients. PMID- 20945004 TI - Three years of accomplishments at CNPq. PMID- 20945005 TI - Assessment of global motor performance and gross and fine motor skills of infants attending day care centers. AB - OBJECTIVE: To analyze the global motor performance and the gross and fine motor skills of infants attending two public child care centers full-time. METHODS: This was a longitudinal study that included 30 infants assessed at 12 and 17 months of age with the Motor Scale of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). This scale allows the analysis of global motor performance, fine and gross motor performance, and the discrepancy between them. The Wilcoxon test and Spearman's correlation coefficient were used. RESULTS: Most of the participants showed global motor performance within the normal range, but below the reference mean at 12 and 17 months, with 30% classified as having "suspected delays" in at least one of the assessments. Gross motor development was poorer than fine motor development at 12 and at 17 months of age, with great discrepancy between these two subtests in the second assessment. A clear individual variability was observed in fine motor skills, with weak linear correlation between the first and the second assessment of this subtest. A lower individual variability was found in the gross motor skills and global motor performance with positive moderate correlation between assessments. Considering both performance measurements obtained at 12 and 17 months of age, four infants were identified as having a "possible delay in motor development". CONCLUSIONS: The study showed the need for closer attention to the motor development of children who attend day care centers during the first 17 months of life, with special attention to gross motor skills (which are considered an integral part of the child's overall development) and to children with suspected delays in two consecutive assessments. PMID- 20945006 TI - Determination of the power-duration relationship in upper-limb exercises. AB - OBJECTIVES: To determine the power-duration relationship in upper limb exercises and to investigate the relationships between parameters derived from this function with physiological indicators of aerobic fitness. METHODS: Ten healthy men (26.2 +/- 2.3 years, 75.0 +/- 11.8 kg, 178.2 +/- 11.5 cm and 15.0 +/- 5.7% body fat) performed a ramped test on an arm cycle ergometer with increments of 20 W/min. Subsequently, five tests with constant load were performed until exhaustion, with 70, 80, 90, 95 and 100% difference between VT1 and VO2peak. The critical power (CP) was obtained by means of linearization of the power-duration function. RESULTS: The power-duration relationship was described using an adjusted function (r=0.98 +/- 0.02). The VO2 at CP (2.66 +/- 0.62 l/min) was higher than VT1 (1.62 +/- 0.38 l/min) and VT2 (2.36 +/- 0.59 l/min), but lower than VO2peak (3.06 +/- 0.62 l/min). The CP workload (103.0 +/- 26 W) was significantly different from VT1 (69.5 +/- 21 W) and VO2peak workloads (151.0 +/- 26.3), but was no different of VT2 (103.5 +/- 30.8 W). The association between critical power and aerobic condition indexes were always significant when expressed as VO2 (0.73 to 0.78, p<0.05) and in W (0.83 to 0.91, p<0.05). Determination of CP in upper-limb dynamic exercises is simple and inexpensive, and can be used by physical therapists for prescribing and evaluating upper-limb training programs. CONCLUSIONS: The power-duration relationship in upper-limb exercises can be described by a hyperbolic function and it is associated with physiological indicators of aerobic fitness. PMID- 20945007 TI - [Access to pulmonary rehabilitation programs within the public healthcare service]. PMID- 20945009 TI - [Breast cancer: a future challenge for health systems in developing countries]. PMID- 20945010 TI - [Maternal complications following endoscopic surgeries in fetal Medicine]. AB - PURPOSE: To describe the maternal complications due to therapeutic endoscopic procedures in fetal Medicine performed at an university center in Brazil. METHODS: Retrospective observational study including patients treated from April 2007 to May 2010 who underwent laser ablation of placental vessels (LAPV) for severe twin-twin transfusion syndrome (TTTS); fetal tracheal occlusion (FETO) and endoscopic removal of tracheal balloon in cases of severe congenital diaphragmatic hernia (CDH); LAPV with or without bipolar coagulation of the umbilical cord in cases of twin reversed arterial perfusion (TRAP) sequence. The main variables described for each disease/type of surgery were maternal complications and neonatal survival (discharge from nursery). RESULTS: Fifty-six patients underwent 70 procedures: Severe TTTS (34 patients; 34 surgeries); severe CDH (16 patients; 30 surgeries), and TRAP sequence (6 patients; 6 surgeries). Among 34 women who underwent LAPV for TTTS, two (2/34=5.9%) experienced amniotic fluid leakage to the peritoneal cavity and seven (7/34=20.6%) miscarried after the procedure. Survival of at least one twin was 64.7% (22/34). Among 30 interventions performed in cases of CDH, there was amniotic fluid leakage into the maternal peritoneal cavity in one patient (1/30=3.3%) and premature preterm rupture of membranes after three (3/30=30%) fetoscopies for removal of the tracheal balloon. Infant survival with discharge from nursery was 43.8% (7/16). Among six cases of TRAP sequence, there was bleeding into the peritoneal cavity after surgery in one patient (1/6=16.7%) and neonatal survival with discharge from nursery was 50% (3/6). CONCLUSIONS: In agreement with the available data in literature, at our center, the benefits related to therapeutic endoscopic interventions for TTTS, CDH and TRAP sequence seem to overcome the risks of maternal complications, which were rarely considered severe. PMID- 20945011 TI - [Levels of alpha-tocopherol in maternal serum and colostrum of adolescents and adults]. AB - PURPOSE: To assess the alpha-tocopherol concentration in the serum and colostrum of adolescent and adult mothers and to determine the nutritional adequacy of vitamin E in the colostrum offered to infants. METHODS: In total, 72 pregnant women participated in the study, 25 adolescents and 47 adults. An amount of 5 mL of blood and 2 mL of colostrum were collected under fasting conditions for the analysis of alpha-tocopherol levels. The samples were analyzed by means of high performance liquid chromatography. Nutritional adequacy of colostrum for vitamin E was calculated as the product of the estimated volume of milk intake by the concentration of alpha-tocopherol in colostrum and by direct comparison of this product with the reference value for nutrient intake (4 mg/day). RESULTS: The levels of alpha-tocopherol in the serum of adolescents and adults were 30.8 +/- 9.8 and 34.1 +/- 9.5 umol/L (mean +/- SD), respectively, and in colostrum, the adolescents showed a concentration of 32.9 +/- 15.8 umol/L and the adults, a concentration of 30.4 +/- 18.0 umol/L. No significant difference was found between concentrations of alpha-tocopherol in serum or in colostrum between adolescents and adults. CONCLUSIONS: Both adolescents and adult women had a satisfactory vitamin E nutritional status reflected in the colostrum, whose values were able to meet the nutritional requirements of infants, suggesting that the maternal age does not influence the levels of alpha-tocopherol in human colostrum. PMID- 20945012 TI - [Validation of the International Consultation on Incontinence Questionnaire Overactive Bladder (ICIQ-OAB) for Portuguese]. AB - PURPOSE: To translate, culturally adapt and validate the questionnaire "International Consultation on Incontinence Questionnaire Overactive Bladder" (ICIQ-OAB) for the Portuguese Language. METHODS: Two Brazilian translators acquainted with the objectives of this research translated the ICIQ-OAB into Portuguese and both translations were back-translated by two other native English speaking translators. The differences between the versions were brought to agreement and pre-tested in a pilot study. The final version of the ICIQ-OAB was applied together with the previously translated and tested version of the International Consultation on Incontinence Questionnaire - Short Form (ICIQ-SF) in 142 male and female patients with irritative urinary symptoms. For the validation of the ICIQ-OAB the following psychometric features were evaluated: reliability (internal consistency and test-retest) and validity of the survey. The retest was performed four weeks after the first interview. RESULTS: The reliability of the instrument was demonstrated through the Cronbach alpha Coefficient, with a general result of 0.7. The test-retest corroborated the stability of the instrument through the intraclass correlation coefficient and presented a result of 0.91 and 0.95 when compared to both the ICIQ-OAB and ICIQ SF, respectively. When the instruments were compared by the Pearson correlation coefficient the result was 0.7 (p=0.0001), that confirms the validity of the study criterion. The concurrent validity was evaluated by the correlation between some clinical and sociodemographic variants and the ICIQ-OAB score. CONCLUSION: The culturally adapted version of the ICIQ-OAB translated into Brazilian Portuguese presented satisfactory reliability and survey validity and was considered valid for the evaluation of irritative urinary symptoms of Brazilian patients of both genders. PMID- 20945013 TI - [Serum markers of oxidative stress in infertile women with endometriosis]. AB - PURPOSE: to compare serum markers of oxidative stress between infertile patients with and without endometriosis and to assess the association of these markers with disease staging. METHODS: this was a prospective study conducted on 112 consecutive infertile, non-obese patients younger than 39 years, divided into two groups: Endometriosis (n=48, 26 with minimal and mild endometriosis - Stage I/II, and 22 with moderate and severe endometriosis - Stage III/IV) and Control (n=64, with tubal and/or male factor infertility). Blood samples were collected during the early follicular phase of the menstrual cycle for the analysis of serum malondialdehyde, glutathione and total hydroxyperoxide levels by spectrophotometry and of vitamin E by high performance liquid chromatography. The results were compared between the endometriosis and control groups, stage I/II endometriosis and control, stage III/IV endometriosis and control, and between the two endometriosis subgroups. The level of significance was set at 5% (p < 0.05) in all analyses. RESULTS: vitamin E and glutathione levels were lower in the serum of infertile women with moderate/severe endometriosis (21.7 +/- 6.0 mMol/L and 159.6 +/- 77.2 nMol/g protein, respectively) compared to women with minimal and mild endometriosis (28.3 +/- 14.4 mMol/L and 199.6 +/- 56.1 nMol/g protein, respectively). Total hydroxyperoxide levels were significantly higher in the endometriosis group (8.9 +/- 1.8 uMol/g protein) than in the Control Group (8.0 +/- 2 uMol/g protein) and among patients with stage III/IV disease (9.7 +/- 2.3 uMol/g protein) compared to patients with stage I/II disease (8.2 +/- 1.0 uMol/g protein). No significant differences in serum malondialdehyde levels were observed between groups. CONCLUSIONS: we demonstrated a positive association between infertility related to endometriosis, advanced disease stage and increased serum hydroxyperoxide levels, suggesting an increased production of reactive species in women with endometriosis. These data, taken together with the reduction of serum vitamin E and glutathione levels, suggest the occurrence of systemic oxidative stress in women with infertility associated with endometriosis. The reproductive and metabolic implications of oxidative stress should be assessed in future studies. PMID- 20945014 TI - [Is there any change in the cell adhesion method mediated by e-cadherin in cervical neoplasia of HIV-infected patients?]. AB - PURPOSE: to evaluate the expression of E-cadherin in cervical lesions of patients suffering from HIV infection. METHODS: we conducted a study with 77 patients with cervical HPV infection, 40 of them were HIV seropositive and 37 HIV seronegative who underwent colposcopy and a biopsy of the cervix. The material obtained by biopsy of the cervix was sent for histopathologic and immunohistochemical study. Sections were obtained and mounted on silanized slides and examined by an observer who was blind to patient serology. E-cadherin antibody, clone NHC-38 diluted 1:400 (DAKO) and the Novolink polymer system (Novocastra) were used. The expression of E-cadherin was determined on the epithelial cell membrane based on the extent of the stained area. The chi2 test with Yates correction or the Fisher's Exact test was used for comparison of the proportion in univariate analysis. All the variables with p<0.25 were included in the logistic regression model, called initial model. The analyses were carried out using the SPSS software, with the level of significance set at 5%. RESULTS: the expression of E cadherin was observed in up to the internal 1/3 of the epithelium in 59.3% of cases and in up to 2/3 of the epithelium in 11.1% of cases, but in 29.6% of cases the expression was identified throughout the thickness of the epithelium in HIV seronegative patients. In contrast, in HIV-seropositive patients, 45.9% showed expression up to 1/3 of the epithelium, 13.5% showed expression in up to 2/3 of the epithelium, and 40.5% showed expression throughout the thickness of the epithelium. E-cadherin expression did not differ between groups (p=0.5). However, the multivariate analysis identified a significant association between high-grade cervical injury and E-cadherin expression in 2/3 and 3/3 of the epithelium (p=0.001; chi2=36.9). CONCLUSIONS: the expression of E-cadherin in the epithelial cell membrane is not associated with infection by the human immunodeficiency virus, but with the degree of intraepithelial cervical injury. PMID- 20945015 TI - [A borderline ovarian tumor in inguinal canal: case report]. AB - The symptoms of ovarian tumor are not specific and a rare presentation of the tumor is as the content of an inguinal hernia. We reported a case of an 82-year old woman, diagnosed with breast cancer and with a concomitant hypoecoic adnexal mass at the ecographic exam. The patient was treated with conservative breast surgery and laparotomy. A cystic-solid ovarian lesion was found inside the right inguinal canal. Frozen-section examination was negative for malignancy, and the anatomopathological analysis revealed a borderline ovarian tumor. PMID- 20945016 TI - [Current aspects on diagnosis and treatment of endometriosis]. AB - Endometriosis is characterized by the presence of endometrial tissue, localized outside the uterine cavity, such as peritoneal surface, ovaries, and rectum vaginal septum. The prevalence is about 6 to 10%. Concerning the etiopathogenesis, the retrograde menstruation theory is accepted, although disruption in endometrial molecular biology seems to be fundamental to the development of endometriosis ectopic focuses. Women with endometriosis may be asymptomatic or may present complaints of dysmenorrhea, dispareunia, chronic pelvic pain and/or infertility. Although the definitive diagnosis of endometriosis needs a surgical intervention, mainly by laparoscopy, many findings obtained by physicalexamination and imaging and laboratory tests can predict, with a high degree of reliability, that the patient has endometriosis. The most common current treatments include surgery, ovarian suppression therapy or both. Pharmacological treatments that do not inhibit ovarian function are under investigation. PMID- 20945017 TI - What are the principles that should guide mental health policies in countries of low and middle income? PMID- 20945018 TI - Principles that should guide mental health policies in low-and middle-income countries. PMID- 20945019 TI - [First national survey on patterns of alcohol consumption in the Brazilian population]. PMID- 20945020 TI - [The newer sedative-hypnotics]. AB - There has been a search for more effective and safe hypnotic drugs in the last decades. Zolpidem, zaleplon, zopiclone, eszopiclone (the z-drugs) and indiplon are GABA-A modulators which bind selectively alpha1 subunits, thus, exhibiting similar mechanisms of action, although recent evidence suggests that eszopiclone is not as selective for alpha1 subunit as zolpidem is. Ramelteon and tasimelteon are new chrono-hypnotic agents, selective for melatonin MT1 and MT2 receptors. On the other hand, the consumption of sedative antidepressant drugs is significantly increasing for the treatment of insomnia, in the last years. As an experimental drug, eplivanserin is being tested as a potent antagonist of serotonin 2-A receptors (ASTAR) with a potential use in sleep maintenance difficulty. Another recent pharmacological agent for insomnia is almorexant, which new mechanism of action involves antagonism of hypocretinergic system, thus inducing sleep. Finally we also discuss the potential role of other gabaergic drugs for insomnia. PMID- 20945021 TI - [Brazilian guidelines for the treatment of narcolepsy]. AB - This manuscript contains the conclusion of the consensus meeting of the Brazilian Sleep Association with Brazilian sleep specialists on the treatment of narcolepsy based on the review of medical literature from 1980 to 2010. The manuscript objectives were to reinforce the use of agents evaluated in randomized placebo controlled trials and to issue consensus opinions on the use of other available medications as well as to inform about safety and adverse effects of these medications. Management of narcolepsy relies on several classes of drugs, namely, stimulants for excessive sleepiness, antidepressants for cataplexy and hypnotics for disturbed nocturnal sleep. Behavioral measures are likewise valuable and universally recommended. All therapeutic trials were analyzed according to their class of evidence. Recommendations concerning the treatment of each single symptom of narcolepsy as well as general recommendations were made. Modafinil is the first-line pharmacological treatment of excessive sleepiness. Second-line choices for the treatment of excessive sleepiness are slow-release metylphenidate followed by mazindol. The first-line treatments of cataplexy are the antidepressants, reboxetine, clomipramine, venlafaxine, desvenlafaxine or high doses of selective serotonin reuptake inibitors antidepressants. As for disturbed nocturnal sleep the best option is still hypnotics. Antidepressants and hypnotics are used to treat hypnagogic hallucinations and sleep paralysis. PMID- 20945022 TI - Electroconvulsive therapy (ECT) effective for psychotic recrudescence and suicidality after varenicline adjunctive therapy for smoking cessation in a schizoaffective patient. PMID- 20945023 TI - [Edimburg Postpartum Depression Scale: factorial analyses and development of six items version]. PMID- 20945024 TI - Clozapine treatment for schizophrenia-related polydipsia. PMID- 20945025 TI - [Out-of-body experience as a possible symptom of panic disorder]. PMID- 20945026 TI - [Necrophilia: a rare paraphilia]. PMID- 20945027 TI - Sleep-terror in a child evolving into sleepwalking in adolescence: case report with the patient's point of view. PMID- 20945028 TI - Positive association between MET allele (BDNF Val66Met polymorphism) and obsessive-compulsive disorder. PMID- 20945029 TI - Amphetamine, catatonic depression, and heart transplant: a case report. PMID- 20945033 TI - Effect of hyperoxia on the intestinal IgA secretory component in neonatal rats and on intestinal epithelial cells in vitro. AB - Oxygen therapy is essential for the treatment of some neonatal critical care conditions but its extrapulmonary effects have not been adequately investigated. We therefore studied the effects of various oxygen concentrations on intestinal epithelial cell function. In order to assess the effects of hyperoxia on the intestinal immunological barrier, we studied two physiological changes in neonatal rats exposed to hyperoxia: the change in intestinal IgA secretory component (SC, an important component of SIgA) and changes in intestinal epithelial cells. Immunohistochemistry and Western blot were used to detect changes in the intestinal tissue SC of neonatal rats. To detect intestinal epithelial cell growth, cells were counted, and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) and Giemsa staining were used to assess cell survival. Immunohistochemistry was used to determine SC expression. The expression of intestinal SC in neonatal rats under hyperoxic conditions was notably increased compared with rats inhaling room air (P < 0.01). In vitro, 40% O2 was beneficial for cell growth. However, 60% O2 and 90% O2 induced rapid cell death. Also, 40% O2 induced expression of SC by intestinal epithelial cells, whereas 60% O2 did not; however, 90% O2 limited the ability of intestinal epithelial cells to express SC. In vivo and in vitro, moderate hyperoxia brought about increases in intestinal SC. This would be expected to bring about an increase in intestinal SIgA. High levels of SC and SIgA would serve to benefit hyperoxia-exposed individuals by helping to maintain optimal conditions in the intestinal tract. PMID- 20945034 TI - In vivo fluctuation of Tax, Foxp3, CTLA-4, and GITR mRNA expression in CD4(+)CD25(+) T cells of patients with human T-lymphotropic virus type 1 associated myelopathy. AB - HTLV-1 Tax expression exerts an inhibitory effect on the Foxp3 transcription factor in CD4(+)CD25(+) T-regulatory cells (Treg). For a better understanding of the role of Tax mRNA in the gene expression of cellular markers we measured Tax, Foxp3, CTLA-4, GITR, TGF-beta, and IL-10 mRNA in Treg cells of 50 patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP; 27 women and 23 men; mean age: 56.7 years). The control group consisted of 23 non-infected subjects (12 women and 11 men) with a mean age of 51.3 years. Real-time PCR was used to measure mRNA of Tax proteins and several cellular markers of Treg function. Determinations revealed a high level of Tax mRNA in HAM/TSP (124.35 copies/100 CD4(+)CD25(+) T cells). Foxp3, GITR, and CTLA 4 mRNA levels were lower in HAM/TSP patients (mean +/- SD, 22.07 +/- 0.78, 9.63 +/- 0.36, and 4.54 +/- 0.39, respectively) than in non-infected controls (47.15 +/- 12.94, 22.14 +/- 1.91, and 21.07 +/- 2.31). Both groups had similar levels of TGF-beta and IL-10. An inverse relationship was found between Tax levels and Foxp3, CTLA-4, and GITR levels. Conversely, there was a direct correlation between levels of Foxp3, GITR, and CTLA-4. Disease severity and evolution time did not correlate with Tax or Foxp3 levels. The present results suggest that Tax and Foxp3 mRNA vary with the same degree of disease severity in HAM/TSP patients. Tax fluctuations may affect CTLA-4 and GITR expression via the Foxp3 pathway, causing virus-induced dysfunction of CD4(+)CD25(+) T cells in HAM/TSP patients. PMID- 20945035 TI - Ovariectomy does not affect the cardiac sympathovagal balance of female SHR but estradiol does. AB - The low incidence of cardiovascular diseases, including hypertension, in premenopausal women has led to the conclusion that ovarian hormones may have a protective effect on the cardiovascular system. We evaluated the effects of ovariectomy and/or estradiol on sympathovagal balance and heart rate variability (HRV) in female spontaneously hypertensive rats (SHR) with tachycardia and compared them to Wistar rats (12 weeks old; N = 8-12). Ovariectomy (OVX) and/or estradiol (10 ug/kg) did not affect basal arterial pressure in either rat strain, but estradiol increased basal heart rate (HR) in OVX SHR (454 +/- 18 vs 377 +/- 9 bpm). HR changes elicited by methylatropine and propranolol were used to evaluate the sympathovagal balance. Ovariectomy did not affect the cardiac sympathovagal balance of any group, while estradiol increased sympathetic tone in OVX SHR (120 +/- 8 vs 56 +/- 10 bpm) and sham-operated Wistar rats (57 +/- 7 vs 28 +/- 4 bpm), and decreased the parasympathetic tone only in OVX SHR (26 +/- 7 vs 37 +/- 5 bpm). HRV was studied in the frequency domain (Fast Fourier Transformation). Spectra of HR series were examined at low frequency (LF: 0.2-0.75 Hz) and high frequency (HF: 0.75-3 Hz) bands. The power of LF, as well as the LF/HF ratio, was not affected by ovariectomy, but estradiol increased both LF (29 +/- 4 vs 18 +/- 3 nu in Wistar sham-operated, 26 +/- 5 vs 15 +/- 3 nu in Wistar OVX, 50 +/- 3 vs 38 +/- 4 nu in SHR sham-operated, and 51 +/- 3 vs 42 +/- 3 nu in SHR OVX) and LF/HF (0.48 +/- 0.08 vs 0.23 +/- 0.03 nu in Wistar sham-operated, 0.41 +/- 0.14 vs 0.19 +/- 0.05 nu in Wistar OVX, 0.98 +/- 0.11 vs 0.63 +/- 0.11 nu in SHR sham operated, and 1.10 +/- 0.11 vs 0.78 +/- 0.1 nu in SHR OVX). Thus, we suggest that ovariectomy did not affect the cardiac sympathovagal balance of SHR or Wistar rats, while estradiol increased the sympathetic modulation of HR. PMID- 20945036 TI - Effects of isoflavone on the learning and memory of women in menopause: a double blind placebo-controlled study. AB - Hormone decline is common to all women during aging and, associated with other factors, leads to cognitive impairment. Its replacement enhances cognitive performance, but not all women present a clinical and family or personal history that justifies its use, mainly women with a history of cancer. The aim of this study was to determine whether a daily oral dose of 80 mg of isoflavone extract for 4 months can produce benefits in women with low hormone levels, contributing to improvement in cognitive aspects. The sample comprised 50- to 65-year-old women whose menstruation had ceased at least 1 year before and who had not undergone hormone replacement. The volunteers were allocated to two groups of 19 individuals each, i.e., isoflavone and placebo. There was a weak correlation between menopause duration and low performance in the capacity to manipulate information (central executive). We observed an increase in the capacity to integrate information in the group treated with isoflavone, but no improvement in the capacity to form new memories. We did not observe differences between groups in terms of signs and symptoms suggestive of depression according to the Geriatric Depression Scale. Our results point to a possible beneficial effect of isoflavone on some abilities of the central executive. These effects could also contribute to minimizing the impact of memory impairment. Further research based on controlled clinical trials is necessary to reach consistent conclusions. PMID- 20945037 TI - Prognosis of colorectal cancer with liver metastasis: value of a prognostic index. AB - The objective of the present study was to explore the factors related to the prognosis of colorectal cancer (CRC) and to establish a prognostic model for the selection of patients who might benefit from hepatic resection for metastatic CRC. A total of 293 patients undergoing liver resection for metastatic CRC (172 males and 80 females ranging in age from 26 to 80 years) were selected and clinical, pathological and outcome data were examined in this retrospective study. The prognostic index (PI) of the patients was calculated on the basis of results of multivariate analysis. Patients were stratified into different groups, with survival curves projected according to PI. The 1-, 3-, and 5-year overall survival rates were 58.3, 26.4, and 11.3%, respectively. Univariate analysis indicated that degree of primary tumor differentiation, resection margin, preoperative carcinoembryonic antigen (CEA) level, number of liver metastases, and resection of liver metastases were associated with prognosis (P < 0.05). In multivariate analysis, the last three factors were found to be independent prognostic factors. The resection of liver metastases was a favorable factor. Patients were classified into three groups according to PI, which differed significantly in survival rate (P < 0.05). The individual survival rate was evaluated based on PI. Resection of hepatic colorectal metastases may produce long-term survival and cure. The proposed PI was easy to use, was highly predictive of patient outcome, and permitted categorization of patients into treatment groups. PMID- 20945038 TI - Lipopolysaccharide-induced dental pulp cell apoptosis and the expression of Bax and Bcl-2 in vitro. AB - Lipopolysaccharide exerts many effects on many cell lines, including cytokine secretion, and cell apoptosis and necrosis. We investigated the in vitro effects of lipopolysaccharide on apoptosis of cultured human dental pulp cells and the expression of Bcl-2 and Bax. Dental pulp cells showed morphologies typical of apoptosis after exposure to lipopolysaccharide. Flow cytometry showed that the rate of apoptosis of human dental pulp cells increased with increasing lipopolysaccharide concentration. Compared with controls, lipopolysaccharide promoted pulp cell apoptosis (P < 0.05) from 0.1 to 100 MUg/mL but not at 0.01 MUg/mL. Cell apoptosis was statistically higher after exposure to lipopolysaccharide for 3 days compared with 1 day, but no difference was observed between 3 and 5 days. Immunohistochemistry showed that expression of Bax and Bcl 2 was enhanced by lipopolysaccharide at high concentrations, but no evident expression was observed at low concentrations (0.01 and 0.1 MUg/mL) or in the control groups. In conclusion, lipopolysaccharide induced dental pulp cell apoptosis in a dose-dependent manner, but apoptosis did not increase with treatment duration. The expression of the apoptosis regulatory proteins Bax and Bcl-2 was also up-regulated in pulp cells after exposure to a high concentration of lipopolysaccharide. PMID- 20945039 TI - Reproducibility of heart rate variability parameters measured in healthy subjects at rest and after a postural change maneuver. AB - Heart rate variability (HRV) provides important information about cardiac autonomic modulation. Since it is a noninvasive and inexpensive method, HRV has been used to evaluate several parameters of cardiovascular health. However, the internal reproducibility of this method has been challenged in some studies. Our aim was to determine the intra-individual reproducibility of HRV parameters in short-term recordings obtained in supine and orthostatic positions. Electrocardiographic (ECG) recordings were obtained from 30 healthy subjects (20 49 years, 14 men) using a digital apparatus (sampling ratio = 250 Hz). ECG was recorded for 10 min in the supine position and for 10 min in the orthostatic position. The procedure was repeated 2-3 h later. Time and frequency domain analyses were performed. Frequency domain included low (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.4 Hz) bands. Power spectral analysis was performed by the autoregressive method and model order was set at 16. Intra-subject agreement was assessed by linear regression analysis, test of difference in variances and limits of agreement. Most HRV measures (pNN50, RMSSD, LF, HF, and LF/HF ratio) were reproducible independent of body position. Better correlation indexes (r > 0.6) were obtained in the orthostatic position. Bland-Altman plots revealed that most values were inside the agreement limits, indicating concordance between measures. Only SDNN and NNv in the supine position were not reproducible. Our results showed reproducibility of HRV parameters when recorded in the same individual with a short time between two exams. The increased sympathetic activity occurring in the orthostatic position probably facilitates reproducibility of the HRV indexes. PMID- 20945040 TI - The pacemaker functions of visceral interstitial cells of Cajal. AB - Interstitial cells of Cajal (ICCs) are located in most parts of the digestive system. Although they have been found over 100 years, their functions began to be unravelled only recently. ICCs are considered as pacemaker cells which elicit spontaneous rhythmic electric activity termed "basic electrical rhythm" or "slow waves" in gastrointestinal tract. Moreover, they also mediate neurotransmission from neurons to smooth muscle in gastrointestinal tract. ICC-like cells also exist in other visceral smooth muscles, such as urinary tract, genital system and vascular smooth muscle. In this paper we review the progress of research about the functions of visceral ICCs. PMID- 20945041 TI - [Glucagon-like peptide 1: a novel therapeutic strategy for Alzheimer's disease]. AB - There is a close correlation between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) in the course of pathophysiological processes. The neuroprotective action of glucagon-like peptide 1 (GLP-1), a latest drug for clinical treatment of T2DM, is being more deeply investigated at present, and a novel therapeutic strategy for AD with GLP-1 has been proposed boldly. This review mainly discussed the correlation of pathogenesis between T2DM and AD, the synthesis and secretion of GLP-1, the distribution and physiological effects of GLP-1 receptor in the brain, and the progresses on the study of GLP-1 in the treatment of AD. PMID- 20945042 TI - Inhibitory effects of purified antibody against alpha-1 repeat (117-137) on Na(+) Ca(2+) exchange and L-type Ca(2+) currents in rat cardiomyocytes. AB - Considering that alpha-1 repeat region may be involved in the ion binding and translocation of Na(+)-Ca(2+) exchanger (NCX), it is possible that the antibodies against NCX alpha-1 repeat may have a crucial action on NCX activity. The aim of the present study is to investigate the effect of antibody against alpha-1 repeat (117-137), designated as alpha-1(117-137), on NCX activity. The antibody against the synthesized alpha-1(117-137) was prepared and affinity-purified. Whole-cell patch clamp technique was used to study the change of Na(+)-Ca(2+) exchange current (I(Na/Ca)) in adult rat cardiomyocytes. To evaluate the functional specificity of this antibody, its effects on L-type Ca(2+) current (I(Ca,L)), voltage-gated Na(+) current (I(Na)) and delayed rectifier K(+) current (I(K)) were also observed. The amino acid sequences of alpha-1(117-137) in NCX and residues 1 076-1 096 within L-type Ca(2+) channel were compared using EMBOSS Pairwise Alignment Algorithms. The results showed that outward and inward I(Na/Ca) were decreased by the antibody against alpha-1(117-137) dose-dependently in the concentration range from 10 to 160 nmol/L, with IC(50) values of 18.9 nmol/L and 22.4 nmol/L, respectively. Meanwhile, the antibody also decreased I(Ca,L) in a concentration-dependent manner with IC(50) of 22.7 nmol/L. No obvious effects of the antibody on I(Na) and I(K) were observed. Moreover, comparison of the amino acid sequences showed there was 23.8% sequence similarity between NCX alpha-1(117-137) and residues 1 076-1 096 within L-type Ca(2+) channel. These results suggest that antibody against alpha-1(117-137) is a blocking antibody to NCX and can also decrease I(Ca,L) in a concentration dependent manner, while it does not have obvious effects on I(Na) and I(K). PMID- 20945043 TI - [Calpain mediates cardiac troponin I degradation in tail-suspended rats]. AB - The aim of the present study was to investigate the expressions of calpain and calpastatin in the myocardium of simulated weightlessness rats, and to elucidate the underlying mechanism of cardiac troponin I (cTnI) degradations. Tail suspended (SUS) rats were used as a simulated weightlessness model on the ground. The myocardium of rats was homogenized, and the expressions of calpain-1, calpain 2, calpastatin and cTnI were analyzed by Western blotting technique. Calpastatin expression was significantly decreased in 2- and 4-week SUS groups compared with that in the synchronous controls (P<0.05). Calpain-2 expression was slightly decreased, whereas calpain-1 expression was unaltered in SUS groups. However, calpain-1/calpastatin and calpain-2/calpastatin ratios were increased after tail suspension, being significantly higher in 2- and 4-week SUS groups than those in the synchronous controls (P<0.05, P<0.01). Cardiac TnI degradation was significantly increased after tail-suspension (P<0.01), but cTnI degradation in both SUS and control groups was significantly inhibited by a non-specific inhibitor of calpain, PD150606 (P<0.01). These results suggest that an increase in calpain activity may enhance cTnI degradation in the myocardium of tail suspended rats. PMID- 20945044 TI - [Comparison of electrophysiological properties of vascular smooth muscle cells in different arterioles in guinea pig]. AB - Arterioles are major contributors to the control of systemic blood pressure and local blood flow. In this study, we compared electrophysiological properties of vascular smooth muscle cells (VSMCs) in anterior inferior cerebellar artery (AICA), mesenteric artery (MA) and spiral modiolar artery (SMA) by intracellular microelectrode recording and whole-cell patch clamp recording techniques. Results were shown as below: (1) Intracellular microelectrode recordings were made from VSMCs in AICA, MA and SMA with resting potentials of (-68+/-1.8) (n=65), (-71+/ 2.4) (n=80) and (-66+/-2.9) mV (n=58), respectively. There was no significant difference in resting potentials among arterioles. (2) The membrane capacitance and membrane conductance in situ cells were much larger than those in dispersed smooth muscle cells by whole-cell recording techniques, and there was significant difference among arterioles, which were in the order: MA>AICA>SMA. After application of gap junction blocker 2-APB (100 MUmol/L), the membrane capacitance and membrane conductance in situ cells were very close with those in single smooth muscle cells. (3) The I/V relation of whole-cell current of dissociated smooth muscle cells (AICA, MA and SMA) showed a prominent outward rectification, and the currents were substantially inhibited by 1 mmol/L 4-AP or 10 mmol/L TEA. When the command voltage was +40 mV, the current densities of VSMCs in AICA, MA and SMA were (26+/-2.0), (24+/-1.7) and (18+/-1.3) pA/pF respectively. SMA showed significant difference in the current density from AICA and MA respectively. These results suggest that the electrophysiological properties of coupling strength of gap junction and current density of smooth muscle cells are different among arterioles in the guinea pig. PMID- 20945045 TI - [PPARgamma signal transduction pathway in the foam cell formation induced by visfatin]. AB - The aim of the present study was to investigate the role of peroxisome proliferator-activated receptor gamma (PPARgamma) signal transduction pathway in the expression of ATP binding cassette transporter A1 (ABCA1) and acyl CoA:cholesterol acyltransferase 1 (ACAT1) induced by visfatin and to discuss the mechanism of foam cell formation induced by visfatin. THP-1 monocytes were induced into macrophages by 160 nmol/L phorbol myristate acetate (PMA) for 48 h, and then the macrophages were exposed to visfatin and PPARgamma activator rosiglitazone, respectively. The expressions of PPARgamma, ABCA1 and ACAT1 mRNA and protein were determined by RT-PCR and Western blot respectively. The contents of total cholesterol (TC) and free cholesterol (FC) were detected by enzyme fluorescence analysis. The content of cholesterol ester (CE) was calculated by the difference between TC and FC. The results showed that visfatin decreased the mRNA and protein expressions of PPARgamma and ABCA1, increased the mRNA and protein expressions of ACAT1, and increased the contents of FC and CE in a concentration-dependent manner. These above effects of visfatin were inhibited by rosiglitazone in a concentration-dependent manner. These results suggest that visfatin may down-regulate the ABCA1 expression and up-regulate the ACAT1 expression via PPARgamma signal transduction pathway, which decreases the outflow of FC, increases the content of CE, and then induces foam cell formation. PMID- 20945046 TI - [Oxidized low density lipoprotein induces macrophage endoplasmic reticulum stress via CD36.]. AB - The purpose of the present study is to explore the effect of oxidized low density lipoprotein (ox-LDL) on the induction of endoplasmic reticulum stress (ERS) and the underlying mechanisms in ox-LDL-induced macrophage foam-forming process. RAW264.7 macrophages were cultured in DMEM medium containing 10% fetal bovine serum, and then treated with ox-LDL (25, 50 and 100 mg/L), anti-CD36 monoclonal antibody+ox-LDL and tunicamycin (TM), respectively. After incubation for 24 h, the cells were collected. The cellular lipid accumulation was showed by oil red O staining and the content of cellular total cholesterol was quantified by enzymatic colorimetry. The expression of glucose-regulated protein 94 (GRP94), a molecular marker of ERS, was determined by immunocytochemistry assay. The levels of GRP94 protein, phosphorylated inositol-requiring enzyme 1 (p-IRE1) and X box binding protein 1 (XBP1) in RAW264.7 cells were detected by Western blotting. The results indicated that after incubation with ox-LDL (25, 50 and 100 mg/L) for 24 h, a large amount of lipid droplets were found in the cytoplasm, and the contents of cellular total cholesterol were increased by 2.1, 2.8 and 3.1 folds compared with the control, respectively. Anti-CD36 antibody decreased markedly the cellular lipid accumulation induced by ox-LDL at 100 mg/L. Both ox-LDL and TM, a specific ERS inducer, could up-regulate the protein expression of GRP94 in a dose dependent manner. Furthermore, p-IRE1 and XBP1, two key components of the unfolded protein response, were also significantly induced by the treatment with ox-LDL. The up-regulations of the three proteins induced by ox-LDL were inhibited significantly when the macrophages were pre-incubated with anti-CD36 antibody. These results suggest that ox-LDL may induce ERS in a dose-dependent way and subsequently activate the unfolded protein response signaling pathway in RAW264.7 macrophages, which is potentially mediated by scavenger receptor CD36. PMID- 20945047 TI - [BK(Ca) channel agonist NS1619 and Kv channel antagonist 4-AP on the facial mechanical pain threshold in a rat model of chronic constriction injury of the infraorbital nerve]. AB - Trigeminal neuralgia is a paroxysmal disorder with severely disabling facial pain and thus continues to be a real therapeutic challenge. At present there are few effective drugs for treatment of this pain. The present study was aimed to explore the involvement of BK(Ca) channels and Kv channels in the mechanical allodynia in a rat model of trigeminal neuropathic pain. Here the effectiveness of drug target injection at the trigeminal ganglion through the infraorbital foramen was first evaluated by immunofluorescence and animal behavior test. Trigeminal neuropathic pain model was established by chronic constriction injury of the infraorbital nerve (ION-CCI) in rats. BK(Ca) channel agonist and Kv channel antagonist were administered into the trigeminal ganglion in ION-CCI rats and sham rats by the above target injection method, and the facial mechanical pain threshold was measured. The results showed that the drug could accurately reach the trigeminal ganglion by target injection which was more effective than that by the normal injection around infraorbital foramen. Rats suffered significant mechanical allodynia in the whisker pad of the operated side from 6 d to 42 d after ION-CCI. BK(Ca) channel agonist NS1619 significantly and dose dependently attenuated the facial mechanical allodynia and increased the facial mechanical pain threshold in ION-CCI rats 15 d after operation. Kv antagonist 4 AP was able to reduce the threshold in ION-CCI rats when facial mechanical threshold was partly recovered and relatively stable on the 35th day after operation. These results suggest that BK(Ca) channel agonist NS1619 and Kv channel antagonist 4-AP can significantly affect the rats' facial mechanical pain threshold after ION-CCI. Activation of BK(Ca) channels may be related to the depression of the primary afferent neurons in trigeminal neuropathic pain pathways. Activation of Kv channels may exert a tonic inhibition on the trigeminal neuropathic pain. PMID- 20945048 TI - [Difference in properties of spontaneous electric activities of visceral nociceptive neurons in bilateral anterior cingulate gyrus of cats]. AB - The aim of the present study is to explore the role of anterior cingulate gyrus (ACG) in bilateral cerebral cortex in visceral nociceptive sensation. Electrical stimulation of greater splanchnic nerve (GSN) was used as visceral nociceptive stimulus, and intracellular recording techniques in vivo was used to record and analyze the responses to stimuli and spontaneous electric activities of the neurons in the bilateral ACG. According to the responses to electrical stimulation of GSN, the neurons in the bilateral ACG were divided into GSN stimulus-relative neurons (GSRNs) and GSN-stimulus-irrelative ones. According to the characteristics of the evoked responses to electrical stimulation of the GSN, GSRNs could be further classified into visceral nociceptive neurons (VNNs) and non-visceral nociceptive neurons (NVNNs). VNNs included specific visceral nociceptive neurons (SVNNs) and non-specific visceral nociceptive neurons (NSVNNs). The results showed that the percentage of GSRNs in the contralateral ACG (38.18%) was significantly higher than that in the ipsilateral ACG (29.49%, P<0.01), suggesting although GSN afferent fibers project to bilateral ACG, they mainly project to the contralateral ACG. Compared with ipsilateral ACG, contralateral ACG possessed lower proportion of SVNNs and higher proportion of NSVNNs (P<0.01). The absolute values of resting potentials (RP) of GSRNs, VNNs, NVNNs and SVNNs in ipsilateral ACG were less than those of corresponding neurons in contralateral ACG. However, there were no significant differences in the absolute values of RP of NSVNNs between ipsilateral and contralateral ACG. There were no significant differences in modes, frequencies and amplitudes of spontaneous electric activities of VNNs and NVNNs between ipsilateral and contralateral ACG. Additionally, the percentage of neurons having spontaneous electric activities from VNNs was significantly higher than that from NVNNs, which indicated that the excitability of VNNs was higher than that of the NVNNs in bilateral ACG. These results suggest that the patterns and degrees of the responses to nociceptive GSN-stimulation of the ipsilateral and contralateral ACG are different, thus providing new experimental data for the asymmetry of functions of the bilateral brain. PMID- 20945049 TI - [Relation between fat mass, fat free mass and ventilatory function in children and adolescents]. AB - The aim of the present study was to evaluate the relation between fat mass (FM), fat free mass (FFM) and ventilatory function in children and adolescents. 1 174 healthy children and adolescents (583 males and 591 females) aged 10-18 years were selected from Heilongjiang Province through random sampling by means of questionnaire and physical examination, and measured for height, weight, waist to hip ratio (WHR), FM, FFM and ventilatory function. The data were analyzed by means of independent-samples t test, Pearson correlation analysis and multi factors regression analysis. Regardless of sex, an independent positive correlation was found (P<0.001) between age and FFM index (FFMI). FM index (FMI) correlated negatively with age in males (P<0.001), but positively with age in females (P<0.001). Regardless of sex, FFMI correlated positively with forced vital capacity (FVC), forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), forced expiratory flow at 25% of forced vital capacity (FEF25%), FEF50%, and maximal mid-expiratory flow (MMEF) (P<0.05), while negatively with FEV1/FVC (P<0.01). FFMI was correlated positively with FEF75% in males (P<0.05), but not correlated in females. In males, FMI correlated negatively with FEV1, FEV1/FVC, PEF, FEF25%, FEF50%, FEF75% and MMEF (P<0.05), but not correlated with FVC. No correlation was found between the ventilatory function indices and FMI in females. Except FEV1/FVC and FEF75% in males, the effect of FFMI in predicting ventilatory function was higher than FMI regardless of sex. Moreover, the predicting effect of FFMI was higher in males than that in females. Growth spurt of lung function occurred in the ages of 12-15 years in males, while in the ages of 12, 13 and 18 years in females. During the period of growth spurt of lung function, regardless of sex, the effect of FFMI in predicting the lung function was higher than that of age. In conclusion, regardless of sex, FFMI correlates positively with ventilatory function, as a reflection of muscle mass. The effect of FFM in predicting ventilatory function is higher in males than that in females. FM correlates negatively with ventilatory function in males, but not in females. The rapid growth of height and FFM are possibly the main reasons for growth spurt of lung function. PMID- 20945050 TI - [Involvement of metallothionein in the protection of lung ischemic preconditioning]. AB - The aim of the present study was to investigate whether metallothionein was involved in the protection of lung ischemic preconditioning (IP) against lung ischemia-reperfusion (I/R) injury. Adult male Sprague-Dawley rats were randomly divided into 3 groups based upon the intervention (n=8): control group (C), lung I/R group (I/R), lung I/R+IP group (IP). At the end of the experiment, the content of metallothionein was tested in lung tissue. Blood specimens collected from the arteria carotis were tested for the contents of malondialdehyde (MDA), the activities of superoxide dismutase (SOD) and myeloperoxidase (MPO). The pneumocyte apoptosis index (AI) was determined by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL). Ultrastructural changes of lung tissue were observed by using transmission electron microscope. The results showed that in I/R group, the content of metallothionein was decreased (P<0.05), the content of MDA and MPO activity were increased (P<0.01), and SOD activity was decreased (P<0.01), compared with those in control group. IP treatment significantly increased the content of metallothionein (P<0.01), attenuated the MDA level (P<0.05) and MPO activity (P<0.01), and improved SOD activity (P<0.01) in blood serum. The number of TUNEL-positive cells in IP group was significantly reduced compared with that in I/R group (P<0.01). There were abnormal ultrastructural changes in I/R group, which were markedly reversed in IP group. In conclusion, IP may protect lung against I/R injury by inducing the expression of metallothionein. PMID- 20945051 TI - [Sound duration and sound pattern affect the recovery cycles of inferior collicular neurons in leaf-nosed bat, Hipposideros armiger]. AB - The effects of sound duration and sound pattern on the recovery cycles of inferior collicular (IC) neurons in constant frequency-frequency modulation (CF FM) bats were explored in this study. Five leaf-nosed bats, Hipposideros armiger (4 males, 1 female, 43-50 g body weight), were used as subjects. The extracellular responses of IC neurons to paired sound stimuli with different duration and patterns were recorded, and the recovery was counted as the ratio of the second response to the first response. Totally, 169 sound-sensitive IC neurons were recorded in the experiment. According to the interpulse interval (IPI) of paired sounds when neurons reached 50% recovery (50% IPI), the recovery cycles of these IC neurons were classified into 3 types: fast recovery (F, the 50% IPI was less than 15 ms), short recovery (S, the 50% IPI was between 15.1 and 30 ms) and long recovery (L, the 50% IPI was more than 30 ms). When paired CF stimuli with 2 ms duration was used, the ratio of F neurons was 32.3%, and it decreased to 18.1% and 18.2% respectively when 5 and 7 ms CF stimuli were used. The ratios of S and L neurons were 41.5%, 33.7%, 29.1% and 26.2%, 48.2%, 52.7% respectively when 2, 5 and 7 ms CF stimuli were used. The average 50% IPI determined after stimulation with paired 2 ms, 5 ms and 7 ms CF sounds were (30.2 +/- 27.6), (39.9 +/- 29.1) and (49.4 +/- 34.7) ms, respectively, and the difference among them was significant (P< 0.01). When the stimuli of paired 2 ms CF sounds were shifted to paired 2 ms FM sounds, the proportion of F, S and L neurons changed from 32.3%, 41.5%, 26.2% to 47.7%, 24.6%, 27.7%, respectively, and the average 50% IPI decreased from (30.2 +/- 27.6) to (23.9 +/- 19.0) ms (P< 0.05, n = 65). When paired 5+2 ms CF-FM pulses were used instead of 7 ms CF sounds, the proportion of F, S and L neurons changed from 18.2%, 29.1%, 52.7% to 29.1%, 27.3%, 43.6%, respectively, and the average 50% IPI decreased from (49.4 +/- 34.7) to (36.3 +/- 29.4) ms (P< 0.05, n = 55). All these results suggest that the CF and FM components in echolocation signal of CF-FM bats play different roles during bats' hunting and preying on. The FM component of CF-FM signal presenting in the terminal phase can increase the number of F type neurons and decrease the recovery cycles of IC neurons for processing high repetition echo information, which ensures the bat to analyze the target range and surface texture more accurately. PMID- 20945052 TI - The current management of delusional parasitosis and dermatitis artefacta. AB - Psychocutaneous disorders involve a unique and somewhat difficult patient population, whose treatment requires the use of drugs unusual to the dermatologist and a significant investment of the clinician's time. This paper describes an effective interpersonal approach and appropriate drug therapy for patients with delusional disorders and dermatitis artefacta, as well as outlines the expectable course and prognosis in each. PMID- 20945053 TI - Nanodermatology: a glimpse of caution just beyond the horizon - part II. AB - Nanotechnology is a relatively new branch of engineering and medicine that is making rapid inroads in dermatology. Nanotechnology applies the unique properties of matter on the nanoscale (1000 nm and smaller) for the purposeful design of new materials. Dermatology is already one of the leading beneficiaries of nanotechnology. In Part I of this series, we discussed the benefits of nanotechnology in dermatology. In Part II, we discuss some of the risks. Matter on the nanoscale has the potential for significant chemical volatility, which carries with it an increased risk of cellular and tissue damage. This article summarizes some of the theoretical safety concerns regarding nanotechnology and offers suggestions for addressing them. PMID- 20945054 TI - [Prehospital airway management of laryngeal tubes. Should the laryngeal tube S with gastric drain tube be preferred in emergency medicine?]. AB - Laryngeal tubes (LT) are increasingly being used for emergency airway management. This article reports on two patients in whom out-of-hospital intubation with a single-lumen LT was associated with massive pulmonary aspiration in one patient and gastric overinflation in the other. In both cases peak inspiratory pressures exceeded the LT leak pressure of approximately 35 mbar. This resulted in gastric inflation and decreased pulmonary compliance and increased inspiratory pressure further, thereby creating a vicious circle. It is therefore recommended that laryngeal tube suction (LTS) should be used in all cases of emergency airway management and a gastric drain tube be inserted through the dedicated second lumen. Apart from gastric overinflation, incorrect LT/LTS placement must be detected and immediately corrected, e.g. in cases of difficult or impossible gastric tube placement, permanent drainage of air from the gastric tube, decreasing minute ventilation or an ascending capnography curve. PMID- 20945055 TI - [Dithiols as chelators. A cause of bullous skin reactions]. AB - Chelation therapy with (RS)-2,3-Bis(sulfonyl)propane-1-sulfonic acid (DMPS) after an occupational lead exposure led to the development of a severe bullous drug eruption. Skin tests and histology/immunohistology of the test reactions indicated a T-cell-mediated immune response against DMPS. Metal-binding thiol groups as in DMPS are chemically highly reactive and therefore effectively mediate the development of immunogenic hapten (DMPS)-protein complexes. Therefore, the pharmacological effects and sensitization potential of dithiols are tightly connected. Cross-reactivity of DMPS to other chelators like D penicillamine is possible; the indications for chelation therapy should be weighed carefully. PMID- 20945056 TI - [Unusual cause of abdominal lymphomas]. AB - A 72 year old HIV-negative patient without relevant immunosuppression presented with abdominal lymphomas and inflammatory signs in the colon. Mycobacterium intracellulare was grown from colonic biopsies and stool. There was no sign of malignancy or chronic inflammatory bowel disease. We diagnosed an atypical, gastrointestinal mycobacteriosis und treated the patient accordingly. This led to a good response. PMID- 20945057 TI - [Lymphogranuloma venereum. An old disease in a new dress]. AB - Lymphogranuloma venereum is a sexually transmitted disease caused by Chlamydia trachomatis, serotypes L1, L2 and L3. The classical clinical manifestation is a painful inguinal lymphadenopathy, resulting without treatment in severe complications. Over the last years, however, the emergence of massive ulcerative proctitis has been observed, especially in men who have sex with men. Because the clinical symptoms are unspecific, Chlamydia trachomatis should actively be looked for. Reliable and rapid molecular tests have now been established to diagnose lymphogranuloma venereum. The therapeutic recommendation is tetracycline for 3 weeks. We present 5 cases to illustrate this disease. PMID- 20945058 TI - [Gastroenteritis with fever, headache and rash after travelling in India]. AB - A 63-year-old patient presented to our emergency unit two days after returning from India suffering from watery diarrhea, nausea, fever and headache. On admission we found a maculopapular rash on his trunk and forehead. Laboratory findings revealed a leuko-thrombopenia and elevated levels of CRP and procalcitonin. We started treatment with ciprofloxacin. After 48 hours of treatment the diarrhea subsided, whereas the rush on his trunk increased. Under the suspicion of rickettsial fever we started doxycycline 200 mg/d. Because of an incipient pneumonia we added ceftriaxon. The patient improved rapidly and the laboratory abnormalities resolved. Serological investigations revealed a significant increase of specific antibodies against Rickettsia typhi. In conclusion, headache with fever and maculopapular rash after traveling to endemic countries should rise suspicion for murine typhus. PMID- 20945059 TI - [Pyrosequencing in uro-oncology: applications in prostate cancer]. AB - Changes in the methylation pattern in particular gene promoters as well as genetic sequence mutations play an important role in carcinogenesis. Molecular methods like pyrosequencing provide the specific analysis of these epigenetic and genetic modifications. In this review the relevance of these alterations for prostate cancer and the function of pyrosequencing will be described and explained on the basis of a search of the PubMed literature database. At present, in uro-oncology only a few studies outlining methylation in prostate cancer and pyrosequencing have been published. Nevertheless, it becomes evident that epigenetic mechanisms as well as specific gene sequence alterations have an impact on the carcinogenesis of prostate cancer and knowledge of these factors might open perspectives in diagnostic approaches of the future. PMID- 20945060 TI - [Social gradient of PSA screening? 8 years follow up from the cancer registry of the tumor center in Regensburg]. AB - BACKGROUND: Prostate cancer is the most frequent male cancer. In Germany most tumors are detected by PSA testing. Data on the long-term survival of patients with localized early prostate carcinoma are insufficient. We examined the relative survival of the patients with organ-defined prostate cancer (TNM T1 2N0M0, UICC I-II) compared to the standardized age-adjusted rates of the normal male population. METHODS: Epidemiological and clinical data from 4,124 patients with prostate cancer diagnosed from 1998 to 2007 were extracted from the cancer registry of the tumor center in Regensburg; 2,087 patients suffered from localized early cancer. Kaplan-Meier analysis was used to estimate the overall survival rates in the patient cohorts irrespective of primary cancer therapy. These rates were adjusted for the expected survival rates in a comparable set of individuals from the general population. RESULTS: Eight years after diagnosis, patients with stage I and II localized prostate cancer had an approximately 10% relative increase in survival compared with the normal male population. This relative increase in survival was already observed 3 years after diagnosis. CONCLUSION: Patients with stage I-II localized prostate cancer have improved survival compared with the normal male population. This finding cannot be explained solely by the administration of prostate cancer treatments, which do not affect survival until 8-10 years after treatment, suggesting that men who participate in PSA testing may have a better overall health status. Another hypothesis may be a social gradient of PSA testing in Germany. PMID- 20945061 TI - [Primary diffuse neurofibroma of the urinary bladder: a rare case report and review of the literature]. AB - Diffuse neurofibromas are benign mesenchymal tumours with nerve sheath differentiation. Only a few cases have been reported in the urinary bladder. We present a well-documented case report of a 62-year-old man presenting with gross haematuria and histopathological confirmation of a diffuse neurofibroma. We further reviewed the current literature with regard to clinical features and treatment options. PMID- 20945062 TI - Dissipation of oxaziclomefone and residue analysis in rice, soil and water under field conditions. AB - The analytical method for the residue analysis of a novel herbicide, oxaziclomefone, and its dissipation in soil, water, rice plants and husked rice in rice fields at GAP (Good Agricultural Practices) conditions were studied. Oxaziclomefone residues were determined by GC-NPD. Mean recoveries ranged from 84.4 to 108.2% with relative standard deviations (RSDs) of 2.4 to 17.2% at three different spiking levels for each different matrix. The limits of quantification (LOQ) were found to be 0.01 mg/kg in soil, water, rice plants and husked rice and 0.02 mg/kg in rice hull. The mean half-lives of oxaziclomefone residues in water, soil and rice plants were 11.3, 37 and 4.4 days, respectively. At harvest, soil, straw, rice hull and husked rice samples were found to contain oxaziclomefone below the maximum residue level (0.1 mg/kg) set by Japan and Korea. Following the recommended application method, this herbicide is therefore safe to apply to rice fields. PMID- 20945063 TI - Pre-ramus passage of inside-out transobturator sling. AB - Groin pain after transobturator tape is not uncommon. Differential diagnosis and treatment strategies are becoming elaborated in the literature. A patient presented with partial improvement in her stress incontinence and persistent groin and vulvar discomfort for 3 months after "inside-out" transobturator tape. The sling was removed secondary to malposition anterior to the inferior pubic ramus, i.e., a trans-vulvar passage. Her vulvar and groin complaints resolved. Recommendations are made to facilitate the "inside to out" transobturator dissection and trocar passage to prevent this complication. PMID- 20945065 TI - The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. AB - RATIONALE: Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic-like effects in rodents and humans after systemic administration. Previous results from our group showed that CBD injection into the bed nucleus of the stria terminalis (BNST) attenuates conditioned aversive responses. The aim of this study was to further investigate the role of this region on the anxiolytic effects of the CBD. Moreover, considering that CBD can activate 5-HT1A receptors, we also verified a possible involvement of these receptors in those effects. METHODS: Male Wistar rats received injections of CBD (15, 30, or 60 nmol) into the BNST and were exposed to the elevated plus-maze (EPM) or to the Vogel conflict test (VCT), two widely used animal models of anxiety. RESULTS: CBD increased open arms exploration in the EPM as well as the number of punished licks in the VCT, suggesting an anxiolytic-like effect. The drug did not change the number of entries into the enclosed arms of the EPM nor interfered with water consumption or nociceptive threshold, discarding potential confounding factors in the two tests. Moreover, pretreatment with the 5-HT1A receptor antagonist WAY100635 (0.37 nmol) blocked the effects of CBD in both models. CONCLUSIONS: These results give further support to the proposal that BNST is involved in the anxiolytic-like effects of CBD observed after systemic administration, probably by facilitating local 5-HT1A receptor-mediated neurotransmission. PMID- 20945064 TI - Correlates and predictors of patient satisfaction with drug therapy and combined drug therapy and behavioral training for urgency urinary incontinence in women. AB - INTRODUCTION AND HYPOTHESIS: The goal was to identify correlates of patient satisfaction with drug and behavioral treatments for urge-predominant incontinence, which may help tailor treatments to improve satisfaction. METHODS: Planned secondary analysis of a multi-center, clinical trial randomizing 307 women to 10 weeks of tolterodine alone or combined with behavioral training. Satisfaction was measured using the Patient Satisfaction Question (PSQ). Potential correlates included baseline demographics, incontinence characteristics and prior treatments, history and physical parameters, expectations of treatment success, and outcome variables including the Global Perception of Improvement (GPI) and Urogenital Distress Inventory (UDI). RESULTS: After multivariable analysis, every 10-point increase in UDI change score increased odds of satisfaction by 11% (OR 1.11; 1.04-1.19). Odds of satisfaction increased among women reporting "much better" on the GPI (OR 13.8; 4.94-38.60). CONCLUSIONS: Treatment satisfaction for women with urge-predominant incontinence was associated with patient-related outcomes reflecting impression of improvement and bother from incontinence-related symptoms. PMID- 20945066 TI - TPH1 is associated with major depressive disorder but not with SSRI/SNRI response in Taiwanese patients. AB - RATIONALE: Tryptophan hydroxylase 1 (TPH1), which encodes the rate-limiting enzyme tryptophan hydroxylase in the biosynthesis of serotonin, is a candidate gene in the development and treatment response of major depressive disorder (MDD); however, its actual role is uncertain. OBJECTIVES: We aimed to compare the allele frequencies of TPH1 in MDD patients and healthy controls in Taiwan, and also to investigate the association between TPH1 A218C and treatment response to either fluoxetine or venlafaxine in a Taiwanese population with MDD. METHODS: One hundred five healthy controls and 115 outpatients diagnosed with MDD were recruited and genotyped for the TPH1 218A/C (rs1800532) polymorphism. Patients were randomized into either the fluoxetine or venlafaxine treatment group. The 21 item Hamilton rating scale for depression (HAM-D) was administered to evaluate depressive symptoms at baseline and bi-weekly over 6 weeks of treatment. RESULTS: The TPH1 218A/C allele frequencies differed significantly between healthy controls and MDD patients in Taiwan, with a higher prevalence of the A allele in the patient group (p = 0.025). The odds ratio of the A allele to the C allele was 0.507 for the subjects with MDD. There was no significant correlation between the percentage change in HAM-D score and either TPH1 218A/C genotype or TPH1 allele frequencies. CONCLUSIONS: This study indicated that the TPH1 218A/C genotype and allele frequencies differed between the Taiwanese healthy controls and MDD patients but could not be used to predict treatment outcome in Taiwanese MDD patients. Further research with larger sample sizes is needed to confirm the role of TPH1 218A/C. PMID- 20945067 TI - Maximum diameter measurements of aortic aneurysms on axial CT images after endovascular aneurysm repair: sufficient for follow-up? AB - PURPOSE: To assess the accuracy of maximum diameter measurements of aortic aneurysms after endovascular aneurysm repair (EVAR) on axial computed tomographic (CT) images in comparison to maximum diameter measurements perpendicular to the intravascular centerline for follow-up by using three-dimensional (3D) volume measurements as the reference standard. MATERIALS AND METHODS: Forty-nine consecutive patients (73 +/- 7.5 years, range 51-88 years), who underwent EVAR of an infrarenal aortic aneurysm were retrospectively included. Two blinded readers twice independently measured the maximum aneurysm diameter on axial CT images performed at discharge, and at 1 and 2 years after intervention. The maximum diameter perpendicular to the centerline was automatically measured. Volumes of the aortic aneurysms were calculated by dedicated semiautomated 3D segmentation software (3surgery, 3mensio, the Netherlands). Changes in diameter of 0.5 cm and in volume of 10% were considered clinically significant. Intra- and interobserver agreements were calculated by intraclass correlations (ICC) in a random effects analysis of variance. The two unidimensional measurement methods were correlated to the reference standard. RESULTS: Intra- and interobserver agreements for maximum aneurysm diameter measurements were excellent (ICC = 0.98 and ICC = 0.96, respectively). There was an excellent correlation between maximum aneurysm diameters measured on axial CT images and 3D volume measurements (r = 0.93, P < 0.001) as well as between maximum diameter measurements perpendicular to the centerline and 3D volume measurements (r = 0.93, P < 0.001). CONCLUSION: Measurements of maximum aneurysm diameters on axial CT images are an accurate, reliable, and robust method for follow-up after EVAR and can be used in daily routine. PMID- 20945068 TI - Occlusion of an intraosseous arteriovenous malformation with percutaneous injection of polymethylmethacrylate. AB - Primary intraosseous arteriovenous malformations are rare. Many minimally invasive procedures can be considered preoperative steps and/or definitive treatment. The case reported regards a young woman with a voluminous arteriovenous extratroncular infiltrating malformation of the humerus. She underwent several treatments, but none of them was completely occlusive. The last treatment consisted of direct percutaneous puncture of the intraosseous alteration and injection of polymethylmethacrylate (PMMA), which is normally used in percutaneous vertebroplasty. We obtained complete occlusion of the humerus lytic lesion. To the best of our knowledge, this represents the first case of intraosseous AVM treated by percutaneous injection of PMMA. PMID- 20945069 TI - State of psychiatry in Germany. AB - Psychiatry in Germany is characterized by high relevance both individually and socioeconomically, and by the burden caused by mental disorders as lifelong diseases. This is comparable to most industrialized countries in the world. For Germany, the role of psychiatry in Nazi-Germany has to be critically discussed and still remains incompletely researched. Another more current focus has to be directed to attracting the most promising young students to the discipline. Psychiatry promises to profit especially from new approaches that combine scientific and clinical expertise in education and professional career. PMID- 20945070 TI - Differential expression of presynaptic genes in a rat model of postnatal hypoxia: relevance to schizophrenia. AB - Obstetric complications play a role in the pathophysiology of schizophrenia. However, the biological consequences during neurodevelopment until adulthood are unknown. Microarrays have been used for expression profiling in four brain regions of a rat model of neonatal hypoxia as a common factor of obstetric complications. Animals were repeatedly exposed to chronic hypoxia from postnatal (PD) day 4 through day 8 and killed at the age of 150 days. Additional groups of rats were treated with clozapine from PD 120-150. Self-spotted chips containing 340 cDNAs related to the glutamate system ("glutamate chips") were used. The data show differential (up and down) regulations of numerous genes in frontal (FR), temporal (TE) and parietal cortex (PAR), and in caudate putamen (CPU), but evidently many more genes are upregulated in frontal and temporal cortex, whereas in parietal cortex the majority of genes are downregulated. Because of their primary presynaptic occurrence, five differentially expressed genes (CPX1, NPY, NRXN1, SNAP-25, and STX1A) have been selected for comparisons with clozapine treated animals by qRT-PCR. Complexin 1 is upregulated in FR and TE cortex but unchanged in PAR by hypoxic treatment. Clozapine downregulates it in FR but upregulates it in PAR cortex. Similarly, syntaxin 1A was upregulated in FR, but downregulated in TE and unchanged in PAR cortex, whereas clozapine downregulated it in FR but upregulated it in PAR cortex. Hence, hypoxia alters gene expression regionally specific, which is in agreement with reports on differentially expressed presynaptic genes in schizophrenia. Chronic clozapine treatment may contribute to normalize synaptic connectivity. PMID- 20945071 TI - Dietary intake of vitamin D during adolescence and risk of multiple sclerosis. AB - Adolescence may be an important etiological period in the development of multiple sclerosis (MS), and studies suggest that adequate vitamin D nutrition is protective. Here, the authors examined whether dietary intake of vitamin D during adolescence decreases the risk of MS in adulthood. In 1986 in the Nurses' Health Study and in 1998 in the Nurses' Health Study II (NHSII), women completed a food frequency questionnaire regarding their dietary intake during adolescence. From this, daily intake of vitamin D was calculated. Adolescent diet was available for 379 incident MS cases confirmed over the combined 44 years of follow-up in both cohorts, and for 67 prevalent cases in the NHSII who had MS at baseline (1989). Cox proportional hazards models were used to calculate relative risk estimates and 95% confidence intervals. Total vitamin D intake during adolescence was not associated with MS risk. Intake of >= 400 IU/day of vitamin D from multivitamins was associated with a non-statistically significant reduced risk (RR compared to no intake = 0.73, 95% CI: 0.50-1.07, P = 0.11), whereas intake of whole milk, an important source of dietary vitamin D, was associated with an increased risk. The possibility of opposite effects of vitamin D and milk intake on MS risk should be considered in future studies. PMID- 20945072 TI - Neurogenic transdifferentiation of human adipose-derived stem cells? A critical protocol reevaluation with special emphasis on cell proliferation and cell cycle alterations. AB - Adipose-derived stem cells (ASCs) are reported to display multilineage differentiation potential, including neuroectodermal pathways. The aim of the present study was to critically re-evaluate the potential neurogenic (trans )differentiation capacity of ASCs using a neurogenic induction protocol based on the combination of isobutylmethylxanthine (IBMX), indomethacin and insulin. ASCs isolated from lipo-aspirate samples of five healthy female donors were characterized and potential neurogenic (trans-)differentiation was assessed by means of immunohistochemistry and gene expression analyses. Cell proliferation and cell cycle alterations were studied, and the expression of CREB/ATF transcription factors was analyzed. ASCs expressed CD59, CD90 and CD105, and were tested negative for CD34 and CD45. Under neurogenic induction, ASCs adopted a characteristic morphology comparable to neur(on)al progenitors and expressed musashi1, beta-III-tubulin and nestin. Gene expression analyses revealed an increased expression of beta-III-tubulin, GFAP, vimentin and BDNF, as well as SOX4 in induced ASCs. Cell proliferation was significantly reduced under neurogenic induction; cell cycle analyses showed a G2-cell cycle arrest accompanied by differential expression of key regulators of cell cycle progression. Differential expression of CREB/ATF transcription factors could be observed on neurogenic induction, pointing to a decisive role of the cAMP CREB/ATF system. Our findings may point to a potential neurogenic (trans )differentiation of ASCs into early neur(on)al progenitors, but do not present definite evidence for it. Especially, the adoption of a neural progenitor cell like morphology must not automatically be misinterpreted as a specific characteristic of a respective (trans-)differentiation process, as this may as well be caused by alterations of cell cycle progression. PMID- 20945073 TI - Propionate-induced epithelial K(+) and Cl(-)/HCO3(-) secretion and free fatty acid receptor 2 (FFA2, GPR43) expression in the guinea pig distal colon. AB - Propionate, a fermented product in the lumen of the large intestine, is a short chain fatty acid (SCFA) known to have a variety of localized physiological and pathophysiological functions (e.g., luminal fluid secretion and anti-inflammatory response). In the present study, we investigated propionate-induced transepithelial ion transport and the expression of SCFA receptor, free fatty acid receptor 2 (FFA2, otherwise known as GPR43) in the guinea pig distal colon utilizing the Ussing chamber technique and immunohistochemistry. The addition of propionate to the luminal bathing solution concentration-dependently induced transient K(+) and Cl(-) and/or bicarbonate secretion within approximately 30 s and long-lasting Cl(-) secretion for approximately 60 min was first identified in the present study. The transient anion secretion was tetrodotoxin (TTX)-sensitive and mediated through the cholinergic (both nicotinic and muscarinic) neural pathway, but the transient K(+) and long-lasting Cl(-) secretion were due to TTX insensitive mechanism. Immunohistochemistry studies showed that some chromogranin A-immunoreactive enteroendocrine cells were also immunoreactive for FFA2 but not colocalized with 5-hydroxytryptamine. In conclusion, the propionate-induced secretion consisted of the neural and non-neural three-phase secretory manner possibly mediated by the stimulation of FFA2 expressed by enteroendocrine cells. PMID- 20945075 TI - The ILAR-East Africa initiative: current needs and progress in the globalization of rheumatology. AB - In early 2009, the International League of Associations for Rheumatology (ILAR) funded a program known as the "East Africa Initiative." The long-term goal of this program is to unite the international rheumatology community to aid in enhancing clinical rheumatology services in an area that carries 25% of the world's disease burden but has only 2% of the world's human resources for health. This paper provides an overview of the rationale and progress to date of this collaborative effort toward the globalization of rheumatology. PMID- 20945074 TI - Cell-based therapy for stroke. AB - Current treatments for stroke, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window. However, the regeneration of the brain after damage is still active days even weeks after stroke occurs, which might provide a second window for treatment. Cell-based therapy can be categorized into two strategies. One is transplantation of exogenous cells into the injured brain to replace the lost cells or support the remaining cells. The other strategy is to enhance the proliferation, differentiation, migration of endogenous stem or progenitor cells. Recent development in adult stem cell research and advancement in the induction of pluripotent stem cells from somatic adult cells provide a tremendous opportunity for transplantation therapy. Understanding the mechanisms and regulations involved in the endogenous neurogenesis will also help develop novel therapeutic interventions to promote neurogenesis and functional recovery in stroke. This review describes up-to-date progresses in cell-based therapy for the treatment of stroke. PMID- 20945076 TI - Plasma asymmetric dimethylarginine (ADMA) levels and atherosclerotic disease in ankylosing spondylitis: a cross-sectional study. AB - Conclusive data about the prevalence of endothelial dysfunction and atherosclerotic process in ankylosing spondylitis (AS) patients with respect to the general population are lacking. Elevated plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been reported in clinical conditions associated with endothelial dysfunction and atherosclerotic disease. We performed a cross-sectional study to evaluate plasma ADMA levels and atherosclerotic disease in AS patients. Seventeen consecutive AS patients free of any cardiovascular disease and 17 healthy controls [strictly matched for sex, age (+/-5 years) and atherosclerotic risk factors] were recruited. Plasma ADMA levels were assessed by capillary electrophoresis. Common carotid artery intima-media thickness (CCA-IMT), flow-mediated dilatation (FMD) and arterial stiffness (aS) were registered as surrogate markers of atherosclerotic disease. Plasma ADMA levels appeared significantly (p = 0.001) higher in AS patients (0.65 +/- 0.10 MUmoli/L) than in the control subjects (0.54 +/- 0.07 MUmoli/L) while no statistically significant differences between AS and controls were demonstrated in CCA-IMT, FMD, and aS. AS patients showed increased plasma ADMA levels with respect to control subjects. On the contrary, we were not able to document a significant difference in atherosclerotic process between patients and controls. PMID- 20945077 TI - Authentication and self-correction in sequential MRI slices. AB - One of the new challenges of Information Technology in the medical world is the protection and authentication of a variety of digital medical files, datasets, and images. In this work, the ability of magnetic resonance imaging (MRI) slice sequences to hide digital data is investigated and more specifically the case that the hidden data are the regions of interest (ROI) of the MRI slices. The regions of non-interest (RONI) are used as cover. The hiding capacity of the whole sequence is taken into account. Any ROI-targeted tampering attempt can be detected, and the original image can be self-restored (under certain conditions) by extracting the ROI from the RONI. PMID- 20945078 TI - Epidemiology of salmonellosis in garden birds in England and Wales, 1993 to 2003. AB - Salmonellosis has been reported as an important cause of mortality of garden birds in several countries, including Norway and Scotland. We investigated the frequency of the disease in garden birds submitted for postmortem examination by members of the public in England and Wales between 1993 and 2003, inclusive. We found salmonellosis to be the most frequent cause of death due to infectious disease in the garden birds submitted. This disease was confirmed in 7 of the 45 bird species that were examined postmortem, with the greenfinch (Carduelis chloris) and the house sparrow (Passer domesticus) most frequently affected. Salmonella Typhimurium definitive phage type (DT) 40, DT56 variant(v), and DT160 accounted for the majority of isolates. Salmonellosis incidents chiefly occurred in the English Midlands, the English/Welsh border region, and southern England. Variation in the temporal and spatial distribution of the phage types occurred over the study period. While birds were examined throughout the year, there was a marked winter seasonality in salmonellosis. A significant sex bias was observed in affected greenfinches, with males more frequently diagnosed with salmonellosis than females. No sex bias was observed for other affected species. Further research is required to determine if salmonellosis is an important constraint to the populations of affected species and if disease outbreaks are driven by human factors, such as provisioning. PMID- 20945079 TI - Optical CO2 sensing with ionic liquid doped electrospun nanofibers. AB - The first use of electrospun nanofibrous materials as highly responsive fluorescence quenching-based optical CO(2) sensors is reported. Poly(methyl methacrylate) and ethyl cellulose were used as polymeric materials. Sensing slides were fabricated by electrospinning technique. A fiber-optic bundle was used for the gas detection. CO(2) sensors based on the change in the fluorescence signal intensity of ion pair form of 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS). The sensor slides showed high sensitivities due to the high surface area to-volume ratio of the nanofibrous membrane structures. The preliminary results of Stern-Volmer analysis show that the sensitivities of electrospun nanofibrous membranes to detect CO(2) are 24 to 120 fold higher than those of the thin film based sensors. The response times of the sensing reagents were short and the signal changes were fully reversible. The stability of ion pair form of HPTS in the employed matrix materials was excellent and when stored in the ambient air of the laboratory there was no significant drift in signal intensity after 7 months. Our stability tests are still in progress. PMID- 20945080 TI - Unusual excited state characteristics of 6-aminobenzothiazole with beta cyclodextrin. AB - The interaction between 6-aminobenzothiazole (6ABT) and beta-cyclodextrin (beta CDx) has been investigated in solution and solid state. The stoichiometry and binding constants of the complex between 6ABT and beta-CDx in solution have been determined by steady state and time-resolved fluorescence spectroscopy. Fluorescence intensity of neutral form decreases during complexation which is contrary to the usual observation. This is explained by hydrogen bonding interaction between lone pair of nitrogen with OH groups of beta-CDx. The FT-IR spectral study and SEM images of solid complex confirmed the formation of inclusion complex. Excited state acidity constants for 6ABT have been determined in aqueous and beta-CDx medium and discussed. PMID- 20945081 TI - Molecular geometry optimization, two-photon absorption and electrochemistry of new diphenylethylene derivatives linking with benzophenone moiety through ether covalent bond. AB - This paper presents the molecular geometry optimization, two-photon absorption and electrochemistry of new dyes containing benzophenone part, including 4-(p benzoyl-benzyloxy)yl-4'-nitro-diphenylethylene (C1), 4-[N-methyl-N-(2-(p-benzoyl benzyloxy)yl-ethyl]-4'-nitro-diphenylethylene (C2), 4-[N-ethyl-N-(2-(p-benzoyl benzyloxy)yl-ethyl]-4'-nitro-diphenylethylene (C3), and 4-N, N-bis[(2-(p-benzoyl benzyloxy)yl-ethyl]-4'-nitro-diphenyl ethylene (C4). The molecular structural parameters show that the coplanarity of diphenylethylene moiety is diminished in the excited state for C1, while it is enhanced for C2, C3 and C4. The electron density distribution of frontier orbital suggests that the derivatives exhibit (pi, pi) transition with internal charge transfer character, and the extent of charge transfer of C2, C3 and C4 is larger than that of C1. The derivatives display remarkable two-photon absorption (TPA) induced up-converted emission under 800 nm Ti: Sapphire femtosecond laser excitation. The maximal TPA emission wavelength of C2, C3 and C4 is red-shifted with respect to that of C1. TPA cross sections of C2, C3 and C4 are larger than those of C1. The cyclic voltammograms and the fluorescence lifetimes of the derivatives were determined and discussed. PMID- 20945082 TI - The role of community in pediatric injury. AB - Cultural variations between communities may impact injury rates, especially among children. We conducted a retrospective study of three communities in Israel using data from the Israel National Trauma Registry (1998-2007). Pediatric injury hospitalization rates in urban communities with varied levels of socio-economic status (low, medium, and high) were compared for all injuries and cause-specific injuries. Age-standardized and age-specific rates were calculated. Age standardized injury hospitalization rates were lowest for the low socio-economic status (SES) community (299.7, 95% confidence interval [CI] 289.8-309.6) compared to the medium SES (658.2, 95% CI 629.1-687.3) and high SES (443.7, 95% CI 422.2 465.3) communities. Similar rates were observed for injuries from falls, transportation, accidental striking and intentional causes. For example, rate ratios for falls were 149.1 (95% CI 142.0-156.2), 340.8 (95% CI 319.5-362.1) and 245.7 (229.9-261.5) in the low, medium and high SES communities, respectively. Deviations from these overall trends were noted, however, for pedestrian injuries and burns that were relatively higher in the low SES community and injuries from motorized vehicles that were greater among children living in the high SES community. These results suggest that strong social capital is associated with reduced pediatric injury risks regardless of community wealth. However, targeted interventions for reducing injuries in at-risk populations that rely solely on injury rates may omit culturally distinct communities and overlook their uneven burden to the trauma care system. PMID- 20945083 TI - A role for accessory genes rI.-1 and rI.1 in the regulation of lysis inhibition by bacteriophage T4. AB - Lysis inhibition (LIN) is a known feature of the T-even family of bacteriophages. Despite its historical role in the development of modern molecular genetics, many aspects of this phenomenon remain mostly unexplained. The key element of LIN is an interaction between two phage-encoded proteins, the T holin and the RI antiholin. This interaction is stabilized by RIII. In this report, we demonstrate the results of genetic experiments which suggest a synergistic action of two accessory proteins of bacteriophage T4, RI.-1, and RI.1 with RIII in the regulation of LIN. PMID- 20945084 TI - Should sexual desire and arousal disorders in women be merged? PMID- 20945085 TI - Artists' advance: decreased upper alpha power while drawing in artists compared with non-artists. AB - Brain mechanisms associated with artistic talents or skills are still not well understood. This exploratory study investigated differences in brain activity of artists and non-artists while drawing previously presented perspective line drawings from memory and completing other drawing-related tasks. Electroencephalography (EEG) data were analyzed for power in the frequency domain by means of a Fast Fourier Transform (FFT). Low Resolution Brain Electromagnetic Tomography (LORETA) was applied to localize emerging significances. During drawing and related tasks, decreased power was seen in artists compared to non artists mainly in upper alpha frequency ranges. Decreased alpha power is often associated with an increase in cognitive functioning and may reflect enhanced semantic memory performance and object recognition processes in artists. These assumptions are supported by the behavioral data assessed in this study and complement previous findings showing increased parietal activations in non artists compared to artists while drawing. However, due to the exploratory nature of the analysis, additional confirmatory studies will be needed. PMID- 20945086 TI - "Overcoming breast cancer drug resistance with mTOR inhibitors". Could it be a myth or a real possibility in the short-term future? AB - The mTOR pathway is pivotal not only in tumorigenesis but also in chemotherapy and hormonal drug sensitivity. It is clear that improvements in using new targeted therapies are required to improve breast cancer (BC) outcome. Nevertheless, to achieve this, new molecular biomarkers are required to define the potential sensitivity or resistance of cancer cells. By targeting the mTOR pathway, several critical central transduction pathways that sustain BC are abrogated (HER-2/Neu and the estrogen receptor pathway). Thus, the compounds that inhibit mTOR have a double mechanism of toxicity on BC cells when used in combination with a currently used drug: (1) overcoming primary drug resistance and (2) restoring sensitivity when resistance arises after long-term exposure. This review covers the utility of inhibitors of the mTOR pathway in BC and emphasizes the new paradigm of close symbiosis between oncology and molecular biology to better profiling and treating BC with a targeted approach. In particular, we focused on the new drug RAD001 (Everolimus) due to the great results from preclinical and clinical trials make it the most hopeful compound among mTOR inhibitors for the treatment of BC. PMID- 20945087 TI - Pure flat epithelial atypia (DIN 1a) on core needle biopsy: study of 60 biopsies with follow-up surgical excision. AB - Flat epithelial atypia (FEA) is recognized as a precursor of breast cancer and its management (surgical excision or intensive follow-up) remains unclear after diagnosis on core needle biopsy (CNB). The aim of this study was to determine the underestimation rate of pure FEA on CNB and clinical, radiological, and pathological factors of underestimation. 4,062 CNBs from 5 breast cancer centers, performed over a 5-year period, were evaluated. A CNB diagnosis of pure FEA was made in 60 cases (1.5%) (the presence of atypical ductal hyperplasia, lobular neoplasia, radial scars, phyllodes tumor, papillary lesions, ductal carcinoma in situ or invasive carcinoma at CNB were exclusion criteria), and subsequent surgical excision was systematically performed. The histological diagnosis was retrospectively reviewed using standardized criteria and the precise terminology of the World Health Organization by two pathologist physicians. At surgical excision, 6 (10%) ductal carcinoma in situ and 2 (3%) invasive carcinoma were diagnosed. The total underestimation rate was 13%. FEA was associated with atypical ductal hyperplasia in 10 (17%) cases and with lobular neoplasia in 2 (3%) at final pathology. Residual FEA was found in 14 (23%) cases. No clinical, radiological or pathological factors were significantly associated with underestimation. Our data highlight the importance of recognizing and diagnosing FEA in core needle biopsies. Thus, the presence of FEA on CNB, even in isolation, warrants follow-up excision. PMID- 20945088 TI - Should breast conservation be offered to young women with breast cancer? PMID- 20945089 TI - Molecular classification of breast phyllodes tumors: validation of the histologic grading scheme and insights into malignant progression. AB - Phyllodes tumors of the breast are rare fibroepithelial neoplasms with a potential for recurrence. Current histological classification is not always predictive of clinical behavior. The aim of this study was to identify genetic changes associated with the development of borderline and malignant phyllodes tumors in an Asian population, and to assess if genetic data supported the categorization of these tumors into the existing three grades of benign, borderline, and malignant. Expression profiling of 21 phyllodes tumors (6 benign, 10 borderline, 5 malignant) was performed using Affymetrix U133Plus 2.0 GeneChips((r)). Gene expression among benign, borderline, and malignant tumors was compared and a 29 gene list was able to classify them according to their histologic grade. Among these 29 genes are those responsible for matrix formation, cell adhesion, epidermis formation, and cell proliferation. Comparative genomic microarray analysis showed that the most common chromosomal alteration associated with borderline and malignant tumors was 1q gain, and an increasing number of chromosomal changes was noted with increasing histological grade. Upregulation of HOXB13 was seen in malignant relative to borderline phyllodes tumors and further investigated by immunohistochemistry in a corresponding set of formalin-fixed, paraffin-embedded tumors. HOXB13 protein overexpression was found to be correlated with stromal hypercellularity and atypia (P = 0.03, P = 0.039, respectively) and may be implicated in the development of malignant phyllodes tumors. PMID- 20945090 TI - The benefits of discussing adjuvant therapies one at a time instead of all at once. AB - Breast cancer patients must often decide between multiple adjuvant therapy options to prevent cancer recurrence. Standard practice, as implemented in current decision support tools, is to present information about all options simultaneously, but psychology research suggests that sequential decision processes might improve decision making. We tested whether asking women to consider hormonal therapy and chemotherapy separately would improve women's risk knowledge and/or affect treatment intentions. We conducted an Internet administered experimental survey of a demographically diverse sample of 1,781 women ages 40-74. Participants were randomized to experience a standard, comprehensive decision process versus sequential (one at a time) decisions regarding adjuvant therapy options for a hypothetical breast cancer patient with an estrogen receptor-positive (ER+) tumor. We assessed comprehension of key statistics, perceptions of treatment effectiveness, and perceived interest in adjuvant chemotherapy, as well as participants' numeracy levels. When participants made sequential decisions, they demonstrated greater comprehension of decision-relevant risk statistics, as compared to when they made decisions all at once (all P's < 0.001). Among higher-numeracy participants, those making sequential decisions were less interested in chemotherapy (P < 0.001). Lower numeracy participants who considered all options simultaneously were insensitive to the degree of risk reduction, but those who made sequential decisions were sensitive (P = 0.03). In conclusion, presenting adjuvant therapy options sequentially improves women's comprehension of incremental treatment benefit and increases less numerate women's sensitivity to the magnitude of the achievable risk reduction over standard, all at once approaches. Sequential approaches to adjuvant therapy decisions may reduce use of chemotherapy among those at low risk for recurrence. PMID- 20945091 TI - Adjuvant dose-dense doxorubicin plus cyclophosphamide followed by dose-dense nab paclitaxel is safe in women with early-stage breast cancer: a pilot study. AB - Every-2-week (dose-dense) adjuvant doxorubicin (A) plus cyclophosphamide (C) followed by paclitaxel is a safe and effective adjuvant chemotherapy regimen. Every-3-week nab-paclitaxel is safe and more effective at 50% higher dose than every-3-week paclitaxel in metastatic breast cancer (BC). This study evaluated the safety of adjuvant dose-dense AC followed by dose-dense nab-paclitaxel for early-stage BC. Women with operable, histologically confirmed BC received four cycles of dose-dense A 60 mg/m(2) plus C 600 mg/m(2) with pegfilgrastim, followed by dose-dense 260 mg/m(2) nab-paclitaxel (with pegfilgrastim given as needed). Endpoints were adverse events (AEs), including myelosuppression. Patients with neuropathy were followed until symptom improvement to grade <= 1. Thirty women received four cycles of dose-dense AC with no unanticipated AEs, one withdrew after AC therapy. Of 29 women who began nab-paclitaxel therapy, 27 received all the four doses (mean cumulative dose, 959 mg/m(2)); one discontinued nab paclitaxel after two doses due to unacceptable AEs. Four patients had a grade 3 nab-paclitaxel-related neuropathy (no grade 4 event). Of 29 patients, 34% received pegfilgrastim during nab-paclitaxel therapy and 31% had a nab-paclitaxel treatment delay, mainly due to hematologic toxicity. Based on the Kaplan-Meier probability estimates, the percentage of patients having <= 1 grade neuropathy at the end of treatment, 2, and 8 months after treatment were 59, 79, and 97%. Administering adjuvant dose-dense AC followed by 260 mg/m(2) dose-dense nab paclitaxel was feasible in women with early-stage BC, with manageable AEs. Most patients had <= 1 grade neuropathy 2 months after treatment completion. PMID- 20945092 TI - A transposon insertion single-gene knockout library and new ordered cosmid library for the model organism Streptomyces coelicolor A3(2). AB - A simple and high-throughput transposon mediated mutagenesis system employing in vitro shuttle transposon mutagenesis has been used to systematically mutagenise the Streptomyces coelicolor genome. To achieve the highest coverage, a new ordered cosmid library was also constructed. Individual cosmids from both the existing and new libraries were disrupted using the Tn5-based mini-transposon Tn5062. A total of 35,358 insertions were sequenced resulting in the disruption of 6,482 genes (83% of the predicted open reading frames). Complete information for both the newly generated cosmids as well as all the insertions has been uploaded onto a central database, StrepDB ( http://strepdb.streptomyces.org.uk/ ). All insertions, new cosmids and a range of transposon exchange cassettes are available for study of individual gene function. PMID- 20945093 TI - The increase in balloon size to over 15 mm does not affect the development of pancreatitis after endoscopic papillary large balloon dilatation for bile duct stone removal. AB - BACKGROUND: Endoscopic papillary large balloon dilatation (EPLBD) after endoscopic sphincterotomy (EST) has recently become widely used for common bile duct (CBD) stone removal, but many clinicians remain concerned about post procedural pancreatitis with increasing the balloon size to over 15 mm. AIMS: We aimed to evaluate the safety and efficacy of EPLBD with a relatively large balloon (15-20 mm) after EST and to evaluate the factors related to post-EPLBD pancreatitis. METHODS: A retrospective review was undertaken of the endoscopic database of 101 patients with CBD stones who underwent EPLBD using a larger balloon size of over 15 mm (15-20 mm). Clinical parameters, endoscopic data, and outcomes were analyzed. RESULTS: The mean age of the subjects was 69 years. All patients had a dilated CBD of over 11 mm (mean = 22.6 mm). The mean size of balloon used in EPLBD was 17.1 +/- 1.9 mm (range 15-20 mm). Mechanical lithotripsy was required in seven patients (6.9%). The rate of complete stone removal in the first session was 92.1%. Post-procedural pancreatitis developed in five cases (5.4%), but none were graded as severe. The smaller dilatation of the CBD, longer cannulation time, and longer time for stone removal were associated with post-procedural pancreatitis, but larger size of balloon did not affect the development of post-EPLBD pancreatitis. CONCLUSIONS: EPLBD with a large balloon of over 15 mm with EST is an effective and safe procedure with a very low probability of severe post-procedural pancreatitis. Post-EPLBD pancreatitis was not associated with larger balloon size, but was associated with longer procedure time and smaller dilatation of the CBD. PMID- 20945094 TI - Predictive algorithms: uses and limitations. PMID- 20945095 TI - Methotrexate for primary biliary cirrhosis: who is to be trusted? PMID- 20945096 TI - Lung diffusion capacity in early cirrhosis: is lung diffusion capacity a predictor of esophageal varices and ascites? AB - BACKGROUND: Varices and ascites are clinical manifestations of hyperdynamic circulation syndrome originating from increased nitric oxide in cirrhosis. Research was conducted in order to find any correlation between lung diffusion capacity and the presence of varices and ascites in cirrhosis. METHODS: The study was conducted on a total of 120 subjects. Tests for pulmonary function, including carbon monoxide diffusing capacity (DLCO) and fractional exhaled nitric oxide (FENO), were performed. RESULTS: DLCO/alveolar ventilation (VA) values were lower in cirrhosis and chronic liver disease groups than in the control group (3.79 vs. 4.5 vs. 5.1 ml/mmHg/min, p<0.001). DLCO/VA showed a negative correlation with the Child score and the MELD score (r=-0.3 vs. r=-0.41). In patients with varices, the DLCO/VA value was 3.75 ml/mmHg/min, which was lower than the 4.12 ml/mmHg/min observed in patients without varices (p=0.029). FENO levels were higher in the chronic liver disease and liver cirrhosis groups than in the control group. FENO and DLCO showed a negative correlation (r=-0.25, p=0.006). The frequency of significant varix and decompensation were higher in the high FeNO group. CONCLUSIONS: Lung diffusion capacity decreased according to the disease's severity in early cirrhosis, and showed a good correlation with esophageal varices and ascites. PMID- 20945097 TI - Psychiatric Patient Assaults and the Staff Victims: An Introduction. AB - This brief paper presents an introductory overview of three papers on psychiatric patient assailants. The papers include the characteristics of patient assailants, precipitants to such assaults, and the characteristics of the staff victims of these assaults. The flexibility of the Assaulted Staff Action Program (ASAP) to address staff victims' post-incident psychological needs is discussed. PMID- 20945098 TI - Assessing cultural perspectives on healthcare quality. AB - This study explores cultural differences in perceptions of quality of care and examines whether existing surveys, such as the Consumer Assessment of Healthcare Providers and Systems (CAHPS((r))) questionnaires, adequately capture conceptions of healthcare quality among members of racial/ethnic minority groups. Eight focus groups with African Americans, Asian Indians, Latinos, and whites were organized into two 45-minute segments. In one segment, participants rated the quality of care depicted in a video; in the other they discussed the concept of "healthcare quality." We found that members of racial/ethnic minority groups are more likely than whites to identify cultural competency and providing a holistic approach to care as important to healthcare quality. Neither of these concepts is currently included in the core CAHPS((r)) questionnaire. The CAHPS((r)) and other quality surveys may not accurately capture concepts of healthcare quality that members of racial/ethnic minority groups deem most important. PMID- 20945099 TI - Binge drinking among male Mexican immigrants in Rural North Carolina. AB - While it is clear that alcohol use among immigrants from Mexico has serious consequences, limited data exist on the correlates of this behavior for Mexican immigrants residing in rural, traditionally non-Hispanic settings. A cross sectional survey with an outreach approach was used to target 173 male Mexican immigrants in rural eastern North Carolina. Questionnaires including demographics, pre and post immigration alcohol use, acculturation, stress, social support, and depressive symptoms were administered through oral interview by trained bilingual interpreters. Results show a higher prevalence of binge drinking in the study sample compared to rate of alcohol use by Hispanics in the United States. Relationships were identified between Pre-immigration alcohol use, lower perceived social support, socialization within one's own cultural group, and binge drinking. These findings provide a preliminary basis in the development of interventions to address the problem of binge drinking in this population. Further exploration of the interaction between social isolation and social support is also needed. PMID- 20945100 TI - Health, well-being, and social indicators among monks, prisoners, and other adult members of an Open University Cohort in Thailand. AB - This study has brought together two seemingly socially extreme population subgroups to compare their health and social well-being. These groups had in common restricted living arrangements and aspirational enrollment. As well, they are part of the population-based Thai Cohort Study (TCS) of 87,134 adult Open University students residing throughout the country. Analysis was restricted to men aged 20-39 years resulting in 711 monks, 195 prisoners and 29,713 other cohort members. For physical health, we have found certain conditions such as tuberculosis or malaria much more common among prisoners, while goiter and liver diseases were more common among monks. This could be due to prison living arrangements for the former and region of residence for the latter. For other social outcomes, lower trust, higher economic stress and lower personal well being was noted for prisoners compared to other groups. Findings here with regard to spirituality and religion are encouraging with almost no difference reported between prisoners and other cohort members implying that trust-building and other social intervention for prisoners could be activated through prevalent religious beliefs and practices and with continuing support from Thai prison authorities. PMID- 20945101 TI - Time for a new budget allocation model for hospital care in Stockholm? AB - In Stockholm County Council (SLL), budgets for hospital care have been allocated to geographically responsible authorities for a long time. This hospital care includes all publicly financed specialist care, also privately owned hospitals, except private practitioner care. The old needs-index model, a 6D capitation matrix based on demography and socio-economy, was generated on linked individual data for 1994-96. In this paper the power of the old allocation model is evaluated by the use of new data for 2006. The analysis shows that most of the socioeconomic variables have lost their descriptive power in 10 years. Using a methodical search we also find an improved need-based allocation model for hospital care using the new data for 2006. By focusing on costly diagnoses, where the descriptive power has increased between 1996 and 2006, and by using some new socioeconomic variables, and by relying on birth and death prognoses, we are able to generate a matrix model with much higher coefficients-of-determinations in 1 year predictions. In addition, a more careful modelling of multi-morbidity, part of-the-year inhabitants, episode definition and cost transformation is developed. The area-level cost residuals of registered versus predicted costs show stable signs over the years, indicating unexplained systematics. For the reduction of the residuals, accepting proven inpatient diagnoses but not the full costs, a mixed capitation/fee-for-service strategy is discussed. Once equivalent (e.g. full-year) observations are determined, the link between background and consumption is not on individual-level but on cell-level, as in current resource allocation studies in the United Kingdom. PMID- 20945102 TI - Pituicytoma in a patient with Cushing's disease: case report and review of the literature. AB - Pituicytoma is an exceptionally rare low-grade glioma (WHO grade I) of the neurohypophysis and infundibulum. We are reporting the case of a 48-year-old man who presented with severe Cushing's syndrome. Endocrinological evaluation unequivocally confirmed pituitary-dependent Cushing's syndrome (=Cushing's disease). Cranial MR-imaging displayed a conspicuous area in the dorsal and basal pituitary gland and a minimal bulging of the pituitary gland paramedian of the pituitary stalk on the right side. Transsphenoidal inspection revealed a small tumor in the basal and dorsal pituitary gland. Surprisingly, the definite postoperative histopathological diagnosis of the removed tumor was pituicytoma and not pituitary adenoma. Hence, the microadenoma responsible for Cushing's disease was not yet removed and persistent hypercortisolism necessitated transsphenoidal re-operation. During re-operation, hemihypophysectomy was performed on the right side. The non-tumorous specimen of the adeno-hypophysis showed signs of Crooke's hyalinization consistent with Cushing's disease. Undetectable postoperative ACTH- and cortisol levels provided clear evidence that the underlying ACTH-source was successfully removed during re-operation. Coincidence of pituicytoma and pituitary-dependent Cushing's disease has not previously been reported. PMID- 20945103 TI - Domain view: a web tool for protein domain visualization and analysis. AB - The identification of sequence-based protein domains and their boundaries is often a prelude to structure determination. An accurate prediction of disordered regions, secondary structures and low complexity segments of target protein sequences can improve the efficiency of selection in structural genomics and also aid in design of constructs for directed structural biology studies. At the Center for Eukaryotic Structural Genomics (CESG) we have developed DomainView, a web tool to visualize and analyze predicted protein domains, disordered regions, secondary structures and low complexity segments of target protein sequences for selection of experimental protein structure attempts. DomainView consists of a relational database and a web graphical-user interface. The database was developed based on MySQL, which stores data from target protein sequences and their domains, disordered regions, secondary structures and low complexity segments. The program of the web user interface is a Perl CGI script. When a user searches for a target protein sequence, the script displays the combinational information about the domains and other features of that target sequence graphically on a web page by querying the database. The graphical representation for each feature is linked to a web page showing more detailed annotation information or to a new window directly running the corresponding prediction program to show further information about that feature. PMID- 20945104 TI - Diagnostic value of BRAF(V600E) mutation analysis of thyroid nodules according to ultrasonographic features and the time of aspiration. AB - BACKGROUND: We investigated the diagnostic value of the BRAF(V600E) mutation of thyroid nodules according to ultrasonography (US) features and the time of BRAF(V600E) mutation analysis. METHODS: A total of 304 nodules in 295 patients (mean age, 49.4 years) were included. Thyroid nodules were classified as suspicious or probably benign on US. Group 1 (n = 168) included nodules with BRAF(V600E) mutation analysis at the time of the initial US-guided fine needle aspiration biopsy (US-FNAB) and group 2 (n = 136) included nodules with analysis at the time of the repeat US-FNAB. The frequency of malignancy and the BRAF(V600E) mutation were compared between suspicious and probably benign nodules on US and between groups 1 and 2. RESULTS: Of 304 nodules, 113 were malignant and 59 (52.2%) had the BRAF(V600E) mutation. Also, 58 of 196 nodules suspicious on US (29.6%) had the BRAF(V600E) mutation, whereas 1 of 108 (0.9%) probably benign nodules had the BRAF(V600E) mutation (P value <.0001). The BRAF(V600E) mutation was more frequently found in nodules suspicious on US than those probably benign in both groups 1 and 2 (P value <.0001 and .0058, respectively). Preoperative detection of the BRAF(V600E) mutation led surgeons to perform surgery in 5.8% of 103 nodules with benign and nondiagnostic results on cytology in group 1 and 1% of 98 nodules in group 2 without treatment delay. CONCLUSIONS: The BRAF(V600E) mutation analysis was a useful adjunctive diagnostic tool, especially in nodules suspicious on US, and was more effective if performed at the time of the initial US-FNAB. PMID- 20945105 TI - The feasibility of N stage of the 7th edition TNM for gastric cancer. PMID- 20945106 TI - TNM: it is time to consider further expanding both the M stage as well as the R stage. PMID- 20945107 TI - Prognostic factors after surgical resection for intrahepatic, hilar, and distal cholangiocarcinoma. AB - BACKGROUND: The prognosis of patients with cholangiocarcinoma is unsatisfactory. Therefore, evaluation of prognostic factors and establishment of new therapeutic strategies are needed to improve their long-term survival. The aim of this study was to identify useful prognostic factors for patients with intrahepatic, hilar, and distal cholangiocarcinoma. MATERIALS AND METHODS: Records of 127 patients with cholangiocarcinoma (21 with intrahepatic cholangiocarcinoma, 50 with hilar cholangiocarcinoma, and 56 with distal cholangiocarcinoma) who underwent surgical resection were reviewed retrospectively. Relationships between survival and clinicopathological factors including patient demographics and tumor characteristics were evaluated using univariate and multivariate analysis. RESULTS: For all 127 patients, overall 1-, 3-, 5-year survival rates were 80, 51, and 40%, respectively. Univariate analysis revealed that adjuvant chemotherapy (P = .049), tumor differentiation (P = .014), lymph node metastasis (P < .001), surgical margin status (P < .001), UICC pT factor (P < .001), and UICC stage (P < .001) were associated significantly with survival. UICC pT factor (P = .007), adjuvant chemotherapy (P = .009), surgical margin status (P = .012), and lymph node metastasis (P = .014) remained independently associated with long-term survival by multivariate analysis. The 5-year survival rates of patients with or without positive surgical margins were 13 and 49%, respectively. The 5-year survival rates of patients treated with or without adjuvant chemotherapy were 47 and 36%, respectively. CONCLUSIONS: R0 resection and adjuvant chemotherapy may be mandatory to achieve long-term survival for patients with cholangiocarcinoma. PMID- 20945108 TI - Health and oral health care needs and health care-seeking behavior among homeless injection drug users in San Francisco. AB - Few existing studies have examined health and oral health needs and treatment seeking behavior among the homeless and injection drug users (IDUs). This paper describes the prevalence and correlates of health and oral health care needs and treatment-seeking behaviors in homeless IDUs recruited in San Francisco, California, from 2003 to 2005 (N = 340). We examined sociodemographic characteristics, drug use patterns, HIV status via oral fluid testing, physical health using the Short Form 12 Physical Component Score, self-reported needs for physical and oral health care, and the self-reported frequency of seeking medical and oral health care. The sample had a lower health status as compared to the general population and reported a frequent need for physical and oral health care. In bivariate analysis, being in methadone treatment was associated with care-seeking behavior. In addition, being enrolled in Medi-Cal, California's state Medicaid program, was associated with greater odds of seeking physical and oral health care. Methamphetamine use was not associated with higher odds of needing oral health care as compared to people who reported using other illicit drugs. Homeless IDUs in San Francisco have a large burden of unmet health and oral health needs. Recent cuts in Medi-Cal's adult dental coverage may result in a greater burden of oral health care which will need to be provided by emergency departments and neighborhood dental clinics. PMID- 20945109 TI - Food security and nutritional outcomes among urban poor orphans in Nairobi, Kenya. AB - The study examines the relationship between orphanhood status and nutritional status and food security among children living in the rapidly growing and uniquely vulnerable slum settlements in Nairobi, Kenya. The study was conducted between January and June 2007 among children aged 6-14 years, living in informal settlements of Nairobi, Kenya. Anthropometric measurements were taken using standard procedures and z scores generated using the NCHS/WHO reference. Data on food security were collected through separate interviews with children and their caregivers, and used to generate a composite food security score. Multiple regression analysis was done to determine factors related to vulnerability with regards to food security and nutritional outcomes. The results show that orphans were more vulnerable to food insecurity than non-orphans and that paternal orphans were the most vulnerable orphan group. However, these effects were not significant for nutritional status, which measures long-term food deficiencies. The results also show that the most vulnerable children are boys, those living in households with lowest socioeconomic status, with many dependants, and female headed and headed by adults with low human capital (low education). This study provides useful insights to inform policies and practice to identify target groups and intervention programs to improve the welfare of orphans and vulnerable children living in urban poor communities. PMID- 20945110 TI - Work in cancer survivors: a model for practice and research. AB - INTRODUCTION: As with other illnesses, several variables can impact the transition back to the workplace, long-term work productivity, or job retention among cancer survivors. We developed a model related to work and cancer based in part on the general area of work disability and the specific literature on cancer survivors and work. METHODS: A systematic search of the literature on work and cancer was conducted to determine whether an evidence base existed to support the proposed model. RESULTS: Forty-five papers met the review criteria. The percentage of studies that addressed modifiable categories included in the proposed model was: health and well-being (20%), symptoms (16%), function (24%), work demands (9%), work environment (18%), and policy, procedures, and economic factors (16%). Return to work was the most common work outcome studied although problems with productivity and retention are reported in the general cancer and work literature. Wide variation in definition of cancer survivor was reported and breast cancer survivors were studied most often. Each of the categories in the model has some empirical support. DISCUSSION: The model considers the health, functional status in relation to demands, work environment, and policy, procedures, and financial factors. The model allows the clinician and survivor to consider factors that can be addressed by the health care provider, survivor, and workplace. Implications for Cancer Survivors. This model provides a framework to aid in conceptualizing problems related to work. PMID- 20945112 TI - Adherence, placebo effects, and mortality. PMID- 20945113 TI - Online social networking by patients with diabetes: a qualitative evaluation of communication with Facebook. AB - BACKGROUND: Several disease-specific information exchanges now exist on Facebook and other online social networking sites. These new sources of knowledge, support, and engagement have become important for patients living with chronic disease, yet the quality and content of the information provided in these digital arenas are poorly understood. OBJECTIVE: To qualitatively evaluate the content of communication in Facebook communities dedicated to diabetes. DESIGN: We identified the 15 largest Facebook groups focused on diabetes management. For each group, we downloaded the 15 most recent "wall posts" and the 15 most recent discussion topics from the 10 largest groups. PATIENTS: Four hundred eighty unique users were identified in a series of 690 comments from wall posts and discussion topics. MAIN MEASURES: Posts were abstracted and aggregated into a database. Two investigators evaluated the posts, developed a thematic coding scheme, and applied codes to the data. KEY RESULTS: Patients with diabetes, family members, and their friends use Facebook to share personal clinical information, to request disease-specific guidance and feedback, and to receive emotional support. Approximately two-thirds of posts included unsolicited sharing of diabetes management strategies, over 13% of posts provided specific feedback to information requested by other users, and almost 29% of posts featured an effort by the poster to provide emotional support to others as members of a community. Approximately 27% of posts featured some type of promotional activity, generally presented as testimonials advertising non-FDA approved, "natural" products. Clinically inaccurate recommendations were infrequent, but were usually associated with promotion of a specific product or service. Thirteen percent of posts contained requests for personal information from Facebook participants. CONCLUSIONS: Facebook provides a forum for reporting personal experiences, asking questions, and receiving direct feedback for people living with diabetes. However, promotional activity and personal data collection are also common, with no accountability or checks for authenticity. PMID- 20945114 TI - Improving blood pressure control: results of home-based post-acute care interventions. AB - BACKGROUND: Blood pressure (BP) control remains elusive for many Americans. Although home health nurses are uniquely positioned to help vulnerable individuals achieve BP control, hypertension (HTN) management has not been a high priority in post-acute care. OBJECTIVE: To examine the effects of two home-based interventions designed to improve BP outcomes among high-risk African-American patients. DESIGN: Cluster randomized controlled trial. PARTICIPANTS: A total of 845 newly admitted patients with uncontrolled HTN (JNC7 stages 1 or 2). INTERVENTIONS: The "basic" intervention delivered key HTN information to clinicians and patients, and a home BP monitor to patients, while the patients received usual post-acute care. The "augmented" intervention provided more intensive and extensive HTN information, monitoring and feedback for 3 months beyond the index home care admission. MEASURES: Primary: BP control. Secondary: reductions in mmHG SBP and DBP, improvements in proportions improving JNC7 stage or achieving clinically meaningful reductions in SBP and DBP. METHODS: Multivariate regression models. KEY RESULTS: The basic intervention produced no significant BP improvements; the augmented intervention significantly improved stage 2 patients' outcomes. Among stage 2 patients, the augmented intervention increased BP control by 8.7 percentage points relative to usual care (8.9% vs. 17.6%; p=0.01), yielded an 8.3 mmHG relative reduction in SBP (p=0.01), and increased the proportion achieving at least a 20 mmHG reduction in SBP by 16.4 percentage points (p=0.01). CONCLUSION: Among stage 2 patients, a nurse-led intervention providing additional HTN medication review and patient self management support during the 3-month post-acute care period yielded significant improvements in 3-month BP control, plus improvements in secondary BP outcomes. PMID- 20945115 TI - CEA is an independent prognostic indicator that is associated with reduced survival and liver metastases in SCLC. AB - Small-cell lung cancer (SCLC) is classified into two stages, limited-stage small cell lung cancer (LS-SCLC) and extensive-stage small-cell lung cancer (ES-SCLC), with ES-SCLC being associated with reduced survival. However, disease stage alone is not a very precise predictor of survival time. The aim of this study is to search for a prognostic indicator that can be used in conjunction with the staging system in SCLC. We performed a prospective analysis of 116 patients with SCLC undergoing standard chemotherapy with or without radiotherapy. Expression levels of 12 tumor markers were measured at the time of diagnosis by a commercial protein chip system, and patients were followed up for a maximum of 54 weeks. CEA was the most frequently detected tumor marker in SCLC, with 32.8% of samples scoring positive, and was also the only marker that correlated with overall survival. The average survival time was 16.78 months for patients with CEA below 5 ng/ml and 11.4 months for patients with CEA above 5 ng/ml (P < 0.001). In contrast, no association was found between tumor stage and overall survival. CEA expression was independent of tumor stage (P = 0.930). CEA is an independent prognostic factor that can be used in conjunction with disease stage in SCLC. PMID- 20945116 TI - Left ventricular dysfunction and cerebral infarction from vasospasm after subarachnoid hemorrhage. AB - BACKGROUND: Although neurogenic stunned myocardium (NSM) after aneurysmal subarachnoid hemorrhage (SAH) is well described, its clinical significance remains poorly defined. We investigated the influence of left ventricular (LV) dysfunction and cerebral vasospasm on cerebral infarction, serious cardiovascular events, and functional outcome after SAH. METHODS: Of the 481 patients enrolled in the University Columbia SAH Outcomes Project between 10/96 and 05/02, we analyzed a subset of 119 patients with at least one echocardiogram, serial transcranial Doppler (TCD) data, and with no prior history of cardiac disease. LV dysfunction was defined as an ejection fraction <40% on echocardiography. Infarction from vasospasm was adjudicated by the study team after comprehensive review of all clinical and imaging data. Functional outcome was assessed at 15 and 90 days with the modified Rankin Scale (mRS). RESULTS: Eleven percent of patients had LV dysfunction (N = 13). Younger age, hydrocephalus, and complete filling of the quadrigeminal and fourth ventricles were associated with LV dysfunction (all P < 0.05). Despite a similar frequency of pre-existing hypertension, 0% of patients with LV dysfunction reported taking antihypertensive medication, compared to 35% of those without (P = 0.009). There was a significant association between LV dysfunction and infarction from vasospasm after adjusting for clinical grade, age, and peak TCD flow velocity (P = 0.03). Patients with LV dysfunction also had higher rates of hypotension requiring vasopressors (P = 0.001) and pulmonary edema (P = 0.002). However, there was no association between LV dysfunction and outcome at 14 days after adjustment for established prognostic variables. CONCLUSIONS: LV dysfunction after SAH increases the risk of cerebral infarction from vasospasm, hypotension, and pulmonary edema, but with aggressive ICU support does not affect short-term survival or functional outcome. Antihypertensive medication may confer cardioprotection and reduce the risk of catecholamine-mediated injury after SAH. PMID- 20945117 TI - Central nervous system involvement in Hodgkin's lymphoma. AB - Central nervous system involvement in Hodgkin's lymphoma is extremely rare. We report three cases who had a relapse from the disease involving CNS. The most frequent causes are skull contiguity, meningeal invasion and via the hematogenous route. It is frequent that the association between Epstein-Barr Virus and Hodgkin's lymphoma, and a biopsy for confirmation, is always required. Diagnostic imaging tests like CT and MRI are useful. The standard treatment remains holocraneal radiotherapy combined with chemotherapy. PMID- 20945118 TI - Sonographic assessment of hyoid bone movement during swallowing: a study of normal adults with advancing age. AB - Our aim in this study was to evaluate hyoid bone movement trajectories and the age-related changes during swallowing in healthy subjects by ultrasonography. Data were obtained from 30 healthy volunteers (15 men, 15 women) in three age groups (20-39, 40-59, 60-79 years). The subjects were examined while sitting in an upright position, with the back against a wall to control movement. The transducer was placed in a longitudinal scan above the larynx. The subjects were then given 5 mL of mineral water. The water bolus was held in their mouth until they were forced to do a rapid swallow. The imaging was repeated five times for averaging. The movement was divided into 4 phases: slowly ascending phase (A-B, Elevation); rapidly ascending phase (B-C, Anterior); temporary pause phase (position of maximum rise, Remain); and rapidly and slowly descending shifts toward the resting position phase (C-D, Return). We easily visualized the hyoid bone trajectory by using ultrasonography. In all cases, ultrasonographic analysis of the hyoid bone was confirmed to have a similar trajectory, as determined with videofluoroscopy. The average swallowing duration measurements increased with age. The measurement of the maximally elevated point of the hyoid bone decreased with age. The movement of the hyoid bone during swallowing can be visualized by US. The trajectory of the hyoid bone in sagittal section indicated the capability of swallowing, and may detect some anomalies in swallowing. PMID- 20945119 TI - Artesunate inhibiting angiogenesis induced by human myeloma RPMI8226 cells. AB - Multiple myeloma (MM) remains an incurable plasma cell disorder to date; therefore, new biologically target-based therapies are in urgent demand. Our previous studies showed that the antimalarial artesunate (ART) possessed anti myeloma effect by inhibiting proliferation and inducing apoptosis of myeloma cells. The present study evaluated the effect of ART on human myeloma cell induced angiogenesis and elucidated its mechanism. The human umbilical vein endothelial cells (HUVECs) migration test, aortic sprouting in fibrin gel in vitro and chicken chorioallantoic membrane (CAM) neovascularization in vivo model were used to examine the effect of ART on angiogenesis induced by human myeloma cells. The results showed that ART could inhibit HUVECs migration, even at a lower concentration (3 MUmol/l, P < 0.01, compared with the result of control group), and suppress efficiently the angiogenic ability of myeloma RPMI8226 cells in a dose-dependent pattern (3-12 MUmol/l, P < 0.05). The levels of VEGF and Ang 1 in the conditioned medium (CM) were quantified by enzyme-linked immunosorbent assay (ELISA). The results confirmed that 3 MUmol/l ART could significantly decrease VEGF and Ang-1 secretion by RPMI8226 cells (P < 0.05), which correlated well with the reduction of angiogenesis induced by myeloma RPMI8226 cells. The present study also showed that ART downregulated the expression of VEGF and Ang-1 in RPMI8226 cells and reduced the activation of extracellular signal-regulated kinase 1 (ERK1) as well. Therefore, ART can block ERK1/2 activation, downregulate VEGF and Ang-1 expression and inhibit angiogenesis induced by human multiple myeloma RPMI8226 cells. Combined with our previous published data, results from the present study indicate that ART possesses potential anti-myeloma effect. PMID- 20945120 TI - Increased antibiotic release from a bone cement containing bacterial cellulose. AB - BACKGROUND: Major disadvantages of antibiotic bone cements include limited drug release and reduced strength resulting from the addition of high doses of antibiotics. Bacterial cellulose, a three-dimensional hydrophilic mesh, may retain antibiotics and release them gradually. We hypothesized that the addition of cellulose to antibiotic bone cement would improve mechanical strength and antibiotic release. QUESTIONS/PURPOSES: We therefore examined the mechanical strength and antibiotic release of cellulose antibiotic cement. METHODS: A high dose of antibiotics (5 g per 40 g cement powder) was incorporated into bacterial cellulose and then mixed with bone cement. We compared the compression strength, fracture toughness, fatigue life, and elution kinetics of this formulation with those of plain cement and a traditional antibiotic cement. RESULTS: The average values for compression strength, fracture toughness, and fatigue life of the cellulose antibiotic cement were 97%, 97%, and 78% of the values obtained for plain cement, respectively. The corresponding values for the traditional antibiotic cement were 79%, 82%, and 17%, respectively. The cumulative elution over 35 days was 129% greater from the cellulose antibiotic cement than from the traditional antibiotic cement. CONCLUSIONS: With a high dose of antibiotics, incorporating cellulose into the bone cement prevented compression and fracture fragility, improved fatigue life, and increased antibiotic elution. CLINICAL RELEVANCE: Antibiotic cements containing cellulose may have applications in clinical situations that require high levels of antibiotic release and preservation of the mechanical properties of the cement. PMID- 20945121 TI - Patients with cervical metastasis and neoplastic pachymeningitis are less likely to improve neurologically after surgery. AB - BACKGROUND: Although many patients with cervical spine metastases are treated surgically, it is unknown whether certain subsets achieve better pain relief and improvement of neurologic function. QUESTIONS/PURPOSES: (1) Does tumor removal with reconstruction improve the neurologic status? (2) Is any subset of patients more likely to have neurological recovery from palliative surgery? (3) What is the rate of surgery-related complications? PATIENTS AND METHODS: We retrospectively reviewed 46 patients who had palliative surgery for metastatic solid tumor metastases of the subaxial cervical spine. Indications were neurologic deficits, life expectancy longer than 6 months, and a Karnofsky Performance Score of 50 to 70. Surgery consisted of anterior tumor removal and reconstruction with titanium mesh cages and/or tricortical iliac crest allograft plus plate fixation or of a combined procedure with adjunctive posterior decompression and stabilization with lateral mass screw fixation. Postoperatively, neurologic Frankel score grade, Karnofsky Performance Score, and complications were recorded. RESULTS: Five of 18 nonambulatory patients (Frankel B/C) became ambulatory again (Frankel D). No patients were Frankel Grade E preoperatively, whereas 19 of 46 gained Frankel Grade E after surgery. One patient worsened neurologically and died 4 months after surgery. Patients with neoplastic pachymeningitis had less neurologic recovery than those without. Complications included dural tears (three), wound infection (three), and tumor relapse at the same or an adjacent level (four). Two of these four patients had instrumentation-related complications. CONCLUSIONS: Surgery improved clinical and neurologic status according to Frankel score; patients with neoplastic pachymeningitis are likely to experience less neurologic recovery. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20945122 TI - Metatarsal length does not correlate with maximal peak pressure and maximal force. AB - BACKGROUND: Primary metatarsalgia of the lesser metatarsals is common and caused by mechanical overload of the affected metatarsal heads. Increased metatarsal length generally is believed to be a factor in the development of primary metatarsalgia. However, there is no clear biomechanical evidence supporting this theory. QUESTIONS/PURPOSES: We asked whether metatarsal length correlated with plantar-loading parameters under the corresponding metatarsal heads. PATIENTS AND METHODS: We prospectively followed two groups of patients 46 (51 feet) with and 45 (51 feet) without metatarsalgia. Each foot was physically examined and underwent standardized full-weightbearing radiography and dynamic pedobarography to assess maximal peak pressure and maximal force under the first, second, and third metatarsal heads. We correlated the relative length of the first and third metatarsals with the corresponding two plantar-loading parameters. We compared maximal peak pressure and maximal force in patients with metatarsalgia with those of symptom-free patients. RESULTS: The relative length of the first and third metatarsals did not correlate (r < 0.13) with the maximal peak pressure or maximal force under the corresponding metatarsal heads. Maximal force under the first metatarsal head was decreased in the metatarsalgia group. There was no difference in maximal peak pressure between the metatarsalgia and nonmetatarsalgia groups. CONCLUSIONS: Relative metatarsal length had no influence on plantar-loading parameters. Shortening of a symptomatic ray to decrease plantar-loading parameters cannot be supported from a biomechanical rationale. PMID- 20945123 TI - THA after acetabular fracture fixation: is frozen section necessary? AB - BACKGROUND: Infection is uncommon after THA performed for failed acetabular fracture repair, despite a high reported incidence of culture-positive fixation implants. The use of frozen section analysis at the time of THA after acetabular fracture fixation surgery is unknown. QUESTIONS/PURPOSES: We asked whether frozen section analysis predicted occult infection after THA performed after acetabular fracture repair. METHODS: We retrospectively reviewed the charts of 43 of 49 patients with prior acetabular fracture fixation who had intraoperative frozen section and culture data from a conversion THA between 2002 and 2010. The average age of patients at fracture was 53 years; conversion was performed after an average of 553 days (median, 369 days; range, 51-2951 days). Five patients had an infection after acetabular fracture surgery (three deep, two superficial). At conversion we obtained an average of three frozen section specimens per patient; 10 specimens in eight patients contained greater than 10 polymorphonuclear cells/high-power field. The minimum followup was 51 days (median, 256 days; range, 51-2085 days). RESULTS: Five patients had positive intraoperative cultures, three of whom had a positive frozen section. All patients who had prior deep infection developed positive intraoperative cultures. The sensitivity, specificity, positive predictive value, and negative predictive value of frozen section analysis were 0.60, 0.87, 0.38, and 0.94, respectively. CONCLUSION: Infection complicating THA after acetabular fracture repair is uncommon. A history of deep infection complicating the acetabular fracture surgery was the strongest predictor of infection. Frozen section analysis has a high specificity and negative predictive value. LEVEL OF EVIDENCE: Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20945125 TI - Overview of human cytochrome P450 networks in chemical space. PMID- 20945126 TI - In vivo electron spin resonance: An effective new tool for reactive oxygen species/reactive nitrogen species measurement. AB - Reactive oxygen species are regarded as important factors in the initiation and progression of many diseases. Therefore, measurement of redox status would be helpful in understanding the "Redox Navigation" of such diseases. Because electron spin resonance (ESR) shows good signal responses to nitroxyl radical and various redox-related species, such as oxygen radicals and antioxidants, the in vivo ESR/nitroxyl probe technique can provide useful information on real-time redox status in a living body. ESR spectrometers for in vivo measurements can be operated at lower frequencies (approximately 3.5 GHz, 1 GHz, 700 MHz, and 300 MHz) than usual (9-10 GHz). Several types of resonators were also designed to minimize the dielectric loss of electromagnetic waves caused by water in animal bodies. In vivo ESR spectroscopy and its imaging have been used to analyze radical generation, redox status, partial pressure of oxygen and other conditions in various diseases. In addition, ESR has been used to analyze injury models related to oxidative stresses, such as nitroxyl radicals. The application of in vivo ESR for diseases related to oxidative injuries currently being investigated and the accumulation of basic data for therapy is ongoing. Recent progress in the instrumentation for in vivo ESR spectroscopy and its application to the life sciences are reviewed, because measurement of redox status in vivo is considered necessary to understand the initiation and progression of diseases. PMID- 20945124 TI - Direct left atrial pressure monitoring in severe heart failure: long-term sensor performance. AB - We report the stability, accuracy, and development history of a new left atrial pressure (LAP) sensing system in ambulatory heart failure (HF) patients. A total of 84 patients with advanced HF underwent percutaneous transseptal implantation of the pressure sensor. Quarterly noninvasive calibration by modified Valsalva maneuver was achieved in all patients, and 96.5% of calibration sessions were successful with a reproducibility of 1.2 mmHg. Absolute sensor drift was maximal after 3 months at 4.7 mmHg (95% CI, 3.2-6.2 mmHg) and remained stable through 48 months. LAP was highly correlated with simultaneous pulmonary wedge pressure at 3 and 12 months (r = 0.98, average difference of 0.8 +/- 4.0 mmHg). Freedom from device failure was 95% (n = 37) at 2 years and 88% (n = 12) at 4 years. Causes of failure were identified and mitigated with 100% freedom from device failure and less severe anomalies in the last 41 consecutive patients (p = 0.005). Accurate and reliable LAP measurement using a chronic implanted monitoring system is safe and feasible in patients with advanced heart failure. PMID- 20945127 TI - Preparation of 2R, 3S, 2'R-nadolol enantiomer using S-(-)-menthyl chloroformate as a chiral derivatizing reagent. AB - Stereoisomers of nadolol were derivatized with S-(-)-menthyl chloroformate((-) MCF) forming their diastereomers, RSR-nadolol-(-)-MCF, SRS-nadolol-(-)-MCF, RRS nadolol-(-)-MCF and SSRnadolol-(-)-MCF. Diastereomeric mixture were then chromatographically resolved by preparative HPLC (JAIGEL-ODS-BP-L, 500 * 25 mm column) eluted with methanol-water (84:16, v/v) at flow rate 2.5 mL/min. RSR nadolol-(-)-MCF diastereomer was hydrolyzed with 5% LiOH at 80 degrees C for 48 h, and the decomposed mixture was further purified by semi-preparative HPLC. The purity and final yield of RSR-nadolol were 99.97% and 12.95%, respectively. PMID- 20945128 TI - Inhibition of DNA topoisomerases I and II and cytotoxicity of compounds from Ulmus davidiana var. japonica. AB - Twenty five compounds including ten triterpenes (1-3, 5-11), six flavonoids (12 15, 24, 25), five lignans (17, 18, 21-23), two butenyl clohexnone glycosides (19 20), one fructofuranoside (16) and one fatty acid (4) were isolated from the roots of Ulmus davidiana var. japonica. The structures of those compounds were identified by comparing their physicochemical and spectral data with those of published in literatures. All the compounds were evaluated for DNA topoisomerase inhibitory activities and cytotoxicities. Among the purified compounds, 4 and 19 showed more potent inhibitory acitivities (IC(50): 39 and 19 MUM, respectively) than camptothecin, as the positive control (IC(50): 46 MUM) against topoisomerase I. Compounds, 4, 10, 12, 19, 24 and 25 showed strong inhibitory activities toward DNA topoisomerase II (IC(50): 0.1, 0.52, 0.47, 0.42, 0.17 MUM and 17 nM, respectively), which were more potent than that of etoposide as positive control (IC(50): 20 MUM). In A549 cell line, 5 and 6 showed cytotoxicities (IC(50): 4 MUM and 3 MUM, respectively, with IC(50) of camptothecin as positive control: 10.3 MUM). In the HepG2 cell line, 3, 5 and 7 showed cytotoxicity (IC(50): 4, 3 and 4 MUM, respectively, with IC(50) of camptothecin: 0.3 MUM). Compounds 6, 12 and 23 showed cytotoxicities in the HT-29 cell line (IC(50): 19, 19 and 15 MUM, respectively, with IC(50) of camptothecin: 2 MUM). PMID- 20945129 TI - Scopoletin from the flower buds of Magnolia fargesii inhibits protein glycation, aldose reductase, and cataractogenesis ex vivo. AB - Five compounds previously known structures, scopoletin (1), northalifoline (2), stigmast-4-en-3-one (3), tiliroside (4), and oplopanone (5) were obtained from the flower buds of Magnolia fargesii using chromatographic separation methods. The structures of 1-5 were identified by the interpretation of their spectroscopic data including 1D- and 2D-NMR as well as by comparison with reported values. Three compounds 1-3 were found from M. fargesii for the first time in this study. All the isolates (1-5) were subjected to in vitro bioassays to evaluate the inhibitory activity on advanced glycation end products formation and rat lens aldose reductase (RLAR). Compound 1 showed a remarkable inhibitory activity on advanced glycation end products formation with IC(50) value of 2.93 MUM (aminoguanidine: 961 MUM), and showed a significant RLAR inhibitory activity with IC(50) value of 22.5 MUM (3.3-tetramethyleneglutaric acid: 28.7 MUM). Compound 4 exhibited potent inhibitory activity against RLAR (IC(50) = 14.9 MUM). In the further experiment ex vivo, cataractogenesis of rat lenses induced with xylose was significantly inhibited by compound 1 treatment. PMID- 20945130 TI - The occurrence of 15-keto-prostaglandins in the red alga Gracilaria verrucosa. AB - New 15-keto-prostaglandins (1-4) were isolated from the MeOH extract of the red alga, Gracilaria verrucosa. Their structures were determined to be prostaglandin B congeners (1-3) and a prostaglandin E congener (4) based on the NMR and MS data. Prostaglandins with a C-15 keto function are rare from natural sources. The presence of these metabolites in the alga is notable because 15-keto prostaglandins (15-keto-PGs) are considered to be the metabolic products of regular prostaglandins in mammals. The occurrence of different prostaglandins in this alga might be due to the existence of different oxidative enzymes, as previously mentioned for oxygenated fatty acids of the red alga Gracilariopsis lemaneiformis. The antiinflammatory activity of these prostaglandins was examined by evaluating their inhibitory effects on nitric oxide production in lipopolysaccharide (LPS)-activated RAW264.7 murine macrophage cells. These prostaglandins showed weak activity on nitric oxide production. PMID- 20945131 TI - Inhibition of melanogenesis by piceid isolated from Polygonum cuspidatum. AB - Piceid (5,4'-dihydroxystilbene-3-O-beta-D-glucopyranoside) is one of the stilbenes found in Polygonum cuspidatum. Previous studies have shown that this compound has little effect on tyrosinase inhibition when compared with other stilbenes in a cell-free tyrosinase assay. Furthermore, its role for melanogenesis in melanocytes is relatively unknown. In melanocytes, piceid inhibits tyrosinase activity and melanin production in a concentration-dependent manner. To explore the action of piceid on melanogenesis, we studied its effect on several key cellular enzymes and a transcriptional factor known to be involved in melanogenesis, including: tyrosinase, tyrosinase-related protein 1, tyrosinase related protein 2, and microphthalmia-associated transcription factor. Interestingly, the effects of piceid on hypopigmentation and inhibition of tyrosinase activity were better than those of arbutin, which is well known to inhibit melanin formation in melanocytes. In addition, piceid suppressed the mRNA and protein expression of the aforementioned enzymes and transcriptional factor in a concentration-dependent manner. In this regards, our results showed that piceid represents a safe and new candidate for a skin-lightening agent. PMID- 20945132 TI - Anti-listerial compounds from Asari Radix. AB - Asari Radix, the roots of Asarum heterotropoides F. Maekawa var. manshuricum F. Maekawa or A. sieboldii F. Maekawa, has traditionally been used for the treatment of various infectious diseases. Since its MeOH extract inhibited the growth of Listeria monocytogenes in a preliminary test, the aim of this study was to isolate and identify the anti-listerial compounds from the plant. Activity-guided fractionation led to the isolation of seven compounds 1-7 from the MeOH extract, and their chemical structures were identified by comparison of the spectroscopic data with those in the literature. Compounds 1-7 exhibited inhibitory activity against all five tested strains of L. monocytogenes with diameter of inhibition zones ranging from 7 to 11 mm in the agar disc diffusion method. Compounds 1-3 and 7 demonstrated potent antimicrobial effects on the L. monocytogenes strains, with MICs between 62.5 and 125 MUg/mL. This is the first report that AR possesses inhibitory activity against L. monocytogenes. PMID- 20945133 TI - Structural implication in cytotoxic effects of sterols from Sellaginella tamariscina. AB - A bioassay-guided fractionation of the CH(2)Cl(2) extract of Selaginella tamariscina yielded six sterols 1-6 such as (4alpha, 5alpha)-4, 14 dimethylcholest-8-en-3-one (1), ergosta-4, 6, 8(14), 22-tetraene-3-one (2), ergosterol endoperoxide (3), 7beta-hydroxycholesterol (4), 7beta hydroxysitosterol (5), and 7alpha-hydroxysitosterol (6). The structures of isolated compounds were determined using spectroscopic methods. Among these isolates, compounds 2-5 showed potent cytotoxicity against five human tumor cells, while compounds 1 and 6 did not. In the case of compounds 1 and 2, 3-oxo sterol derivatives, compound 1 was inactive, but compound 2 showed potent cytotoxicity. In addition, compound 5 exhibited potent cytotxicity, but, compound 6 which is the 7-epimer of compound 5 was weakly active against tumor cell lines. Therefore, in the case of oxysterol derivatives, the cytotoxicity appeared to be affected by the structural differences, i.e. the configuration of hydroxyl group and the number of conjugated double bond. Taken all together, the present study isolated six sterols from S. tamariscina for the first time based on a bioassay guided fractionation and indicated that isolated oxysterols could exhibit the cytotoxic effects against tumor cells, suggesting that S. tamariscina might be a promising candidate for the development of anticancer agents. PMID- 20945134 TI - Identification of marker compounds in herbal drugs on TLC with DART-MS. AB - This study was conducted to provide a more versatile and specific information on Thin Layer Chromatographic (TLC) analysis of medicinal plants. TLC plates developed with the extract of herbal medicines were analyzed with direct analysis in real time (DART) ion source. Three well known herbal drugs were extracted and developed on a silica-coated TLC plate with the conditions pre-established in Korean Pharmacopoeia IX. The developed plate was placed between the DART ion source and TOF-MS analyzer to get real time mass spectra from the bands on the TLC plate directly. The marker coumarin compounds, decursin and decursinol were successfully identified from the TLC plate developed with Angelicae gigantis radix, along with alkaloid compounds of rutaecarpine and evodiamine from Evodiae fructus, and lignan molecules of gomisin A, N, and schisandrin from Schisandrae fructus. This hyphenation system of TLC and DART-MS could provide unique and specific information on the major constituents of crude plant drug on TLC through uncovering high resolution mass number of each band on the TLC plate directly in real time. PMID- 20945135 TI - Cytochrome P450 networks in chemical space. AB - A global analysis of the chemical space of cytochrome P450 enzymes in humans has not been achieved despite its great importance for drug metabolism and drug-drug interactions. We analyzed the global characteristics of cytochrome P450s by building several networks at the family, subfamily, and gene levels from information on P450 substrates, inducers, and inhibitors. These networks provide insight into the relationship of cytochrome P450 isoforms on the metabolism of drugs, changes in drug activity, and the promiscuous properties of each cytochrome P450 enzyme. From the networks, we analyzed the centrality of nodes and measured the strength of correlations between two nodes by drawing promiscuity maps. In addition, heat maps were generated to cluster cytochrome P450s by their similarity within three chemical spaces (substrates, inducers, and inhibitors). We observed the intra-linking and interlinking connections between three chemical spaces, the relative correlations of a given cytochrome P450 isoform with other isoforms, and the similarity of the metabolizing ability and changing pattern by chemicals. These results provide a global view of the relationship and similarity of cytochrome P450s on various chemical spaces at various levels. The measures of the strength of connection between two cytochrome P450s and the heat-map information could be used to predict drug-drug interactions, perform phylogenetic analyses, and further understand cooperative properties of these enzymes. PMID- 20945136 TI - Formulation and evaluation of an alternative triglyceride-free propofol microemulsion. AB - A new triglyceride-free propofol microemulsion for intravenous injection was formulated using nonionic surfactants, poloxamers and polyethylene glycol 660 hydroxystearate. The aim of this investigation was to evaluate the formulation for storage stability, antimicrobial activity, toxicity and preclinical efficacy. The results were compared to the characteristics obtained for the most commonly used formulation of propofol (Diprivan(r)). The mean particle diameter of the microemulsion was less than 100 nm so that it could be readily sterilized using a 0.22 MUm membrane at room temperature. The microemulsion formulation demonstrated enhanced stability compared to the marketed macroemulsion formulation. In a stress storage condition, it was physicochemically stable for at least 40 months. This new formulation showed higher antimicrobial activity, lower risk of hyperlipidemia and better tolerability than Diprivan(r). In preclinical studies, the efficacy and pharmacokinetic profile of the microemulsion were similar to those of Diprivan(r). Nevertheless, the administration of the microemulsion caused considerably low histamine release compared to the macroemulsion. Based on these results, the newly developed microemulsion of propofol appeared to have several advantages and, thus, could be an alternative to the fat macroemulsions of propofol. PMID- 20945137 TI - Quantification of a novel PPARgamma partial agonist (S)-2-ethoxy-3-(4-{3-methyl-5 [4-(3-methyl-isoxazol-5-yl)-phenyl]thiophen-2-ylmethoxy}-phenyl)-propionic acid (PAM-1616) in rat plasma using liquid chromatography-tandem mass spectrometry. AB - (S)-2-Ethoxy-3-(4-{3-methyl-5-[4-(3-methyl-isoxazol-5-yl)-phenyl]thiophen-2 ylmethoxy}-phenyl)-propionic acid (PAM-1616) is a novel peroxisome proliferators activated receptor gamma (PPARgamma) partial agonist with excellent antihyperglycemic activity. It is a promising new drug candidate for the treatment of type-2 diabetes with reduced possibility of edema in vitro/in vivo. In order to evaluate the pharmacokinetics of PAM-1616, a reliable, selective and sensitive highperformance liquid chromatography/electrospray ionization tandem mass spectrometry was developed for the quantification of PAM-1616 in rat plasma. The analytes were extracted from rat plasma with ethyl acetate, separated on an Atlantis dC(18) column with a mobile phase of 75% acetonitrile in 10 mM ammonium formate (pH 4.5), and detected by tandem mass spectrometry in the selective reaction monitoring mode. The calibration curve was linear (r (2) = 0.999) over the concentration range of 0.05-20.0 MUg/mL and the lower limit of quantification was 0.05 MUg/mL. The coefficient of variation and relative error at four QC levels were 1.8% to 14.3% and -10.0% to 6.5%, respectively. The present method was successfully applied to the pharmacokinetic study of PAM-1616 after intravenous administration of PAM-1616 potassium at a dose of 1 mg/kg in rats. PMID- 20945138 TI - Effects of prednisolone on the pharmacokinetics of loratadine after oral and intravenous administration of loratadine in rats. AB - The present study aims to investigate the effects of prednisolone on the pharmacokinetics of orally and intravenously administered loratadine in rats. A single dose of loratadine was administered orally (4 mg/kg) and intravenously (1 mg/kg) in the presence or absence of prednisolone (0.2 or 0.8 mg/kg). Compared to the oral control group, prednisolone (0.2 mg/kg, p < 0.05; 0.8 mg/kg, p < 0.01) significantly increased the area under the plasma concentrationtime curve of orally administered loratadine by 54.0-96.4%. After oral administration, the peak plasma concentration of loratadine was significantly (0.2 mg/kg, p < 0.05; 0.8 mg/kg, p < 0.01) increased by 20.9-65.3% in the presence of prednisolone. Consequently, the relative bioavailability of loratadine was increased by 1.54- to 1.96-fold. Compared to the intravenous control group, the presence of prednisolone significantly (0.8 mg/kg, p < 0.05) increased the area under the plasma concentration-time curve of loratadine. Prednisolone enhanced the oral bioavailability of loratadine in this study. The enhanced bioavailability of loratadine may be due to inhibition both cytochrome P450 3A4-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or liver by the presence of prednisolone. PMID- 20945139 TI - Novel combinational treatment of cisplatin with cyclophilin A inhibitors in human heptocellular carcinomas. AB - The fungal cyclic peptide cyclosporin A (CsA) and fungal macrolide compound sanglifehrin A (SFA) have been developed as immunosuppressive drugs and both bind to cyclophilin A (CypA). CypA has been reported to be upregulated in diverse human cancers including hepatocellular carcinomas (HCC). CypA overexpression induces resistance to hypoxia and chemotherapeutic agents such as cisplatin in cancer cells. In this report, it was shown that CsA or SFA can synergistically increase apoptotic cell death in HCC cells, when combined with cisplatin. The increased cytotoxicity was accompanied by enhanced oxidative stress. The effects of CsA and SFA were due to inhibition of CypA activity. It was also shown that CsA and SFA abrogate cisplatin resistance as well as protection against hypoxia that is provided by CypA overexpression. Importantly, the synergistic effect of CsA or SFA with cisplatin was shown even in p53 defective Hep3B cells. Finally, overexpression of CypA was observed in human HCC tissues. In conclusion, CsA or SFA synergistically enhances cisplatin-induced apoptosis in HCC cells including the p53-defective Hep3B. PMID- 20945140 TI - Drug synergism of antihypertensive action in combination of telmisartan with lercanidipine in spontaneous hypertensive rats. AB - To examine drug synergism between angiotensin II AT1-receptor blocker and Ca(2+) channel blocker for lowering blood pressure (BP), telmisartan and lercanidipine were orally injected into to telemetered-spontaneous hypertensive rats and BP was monitored. The highest doses of both drugs (7.66 mg/kg of telmisartan and 1.92 mg/kg of lercanidipine) were clinically relevant at 80 and 20 mg human equivalent doses, respectively, and denoted as dose 1. After constructing the dose-response curve using 0 (vehicle-treated control), 1/16, 1/8, 1/4, 1/2 and 1 doses, all possible combinations of both drugs were tested. Drug synergism in combination therapy of telmisartan with lercanidipine was assessed by calculating the interaction index (gamma) as evaluated by gamma < 1. We found statistically significant drug synergism in the investigated (telmisartan: lercandipine) combinations of (1/8:1/4), (1/4:1) and (1/8:1). Our results suggest that the combination therapy of telmisartan and lercanidipine at lower doses are effective in lowering BP, and also reduce side effects caused by maximal doses of each drug. Therefore, drug combination of AT1-receptor blocker with Ca(2+) channel blocker is a clinically important tool for the management of hypertension and hypertension-related cardiovascular risks. PMID- 20945141 TI - Direct enantiomer separation of thyroxine in pharmaceuticals using crown ether type chiral stationary phase. AB - Thyroxine is the tyrosine based hormone produced by the thyroid gland, containing a chiral center in its molecular structure. Synthetic thyroxine is commercially available to treat thyroid dysfunctions, but only a few direct analytical methods to determine its optical purity have been reported. This study attempted to find an optimized liquid chromatographic condition for direct enantiomer separation on crown ether type chiral stationary phase. Among various mobile phases tested, 100% methanol solution containing 10 mM H(2)SO(4) was found to be most appropriate. This chromatographic method was validated and applied to measure the optical purity of six different L-thyroxine products from three domestic pharmaceutical companies and four commercially available D- and L-thyroxine reagents. The chromatographic results showed that every pharmaceutical product had quite high optical purity of above 97% (all but one were higher than 99%) while two of four thyroxine reagents demonstrated relatively higher enantiomer impurity (5-6%). PMID- 20945142 TI - Hypocholesterolemic effect of sonication-killed Bifidobacterium longum isolated from healthy adult Koreans in high cholesterol fed rats. AB - We have previously reported that live Bifidobacterium longum SPM1207, a strain isolated from healthy adult Koreans, significantly reduced serum cholesterol in broth and rat. We here examined the effect of oral administration of sonication killed B. longum SPM1207 on serum cholesterol in rats in order to investigate whether this killed strain could be utilized as a potent probiotics for human and animals. Dietary treatments consisted of 3 treatment groups of 24 rats each randomly assigned to either normal diet, high cholesterol diet and saline (HCS), or high cholesterol diet and sonication-killed B. longum SPM1207 (HCKB) for 3 weeks. Although HDL-cholesterol levels in the serum were not significantly (p > 0.05) different between HCKB rats and HCS rats, total and LDL-cholesterol levels in the serum were significantly (p < 0.05) less increased in HCKB (total: 177.71 mg/dL, LDL-: 60.50 mg/dL) rats when compared to HCS (total: 237.17 mg/dL, LDL-: 71.50 mg/dL) rats. AI was significantly (p < 0.05) lower in HCKB (4.95 mg/dL) rats when compared to HCS (9.22 mg/dL) rats. Body weight increase and relative liver weight were significantly (p < 0.05) lower in HCKB rats when compared to HCS rats. Over the time, high cholesterol diet caused dry feces accompanied by decreased fecal water content (66.00 to 61.94%) but sonication-killed B. longum SPM1207 administration increased fecal water content (71.58 to 74.25%). The results in the current study provide evidence that the sonication-killed cells of B. logum SPM1207 isolated from healthy adult Koreans have a greater potential to be used as a cholesterol-lowering agent. Furthermore, the current study suggest that this killed specific strain may play role in part in blocking the body weight increase and relieving or eliminating constipation. PMID- 20945143 TI - Mistletoe lectin transport by M-cells in follicle-associated epithelium (FAE) and IL-12 secretion in dendritic cells situated below FAE in vitro. AB - A galactose- and N-acetyl-D-galactosamine-specific lectin (Viscum album L. var. coloratum agglutinin, VCA), which is known for its anti-tumor activity, was isolated from Korean mistletoe. Mistletoe preparations have been given subcutaneously because of the unstability and poor absorption in the GI tract. In this study, we investigated the effect of incubation time and glucose on the VCA transport across the in vitro model of human FAE (follicle-associated epithelium) by two different cell models: Caco-2 cell monolayers mimicking human enterocytes and a model of the human FAE which is mainly composed of M-cells and enterocytes. As a result, the VCA transport across the FAE monolayer cells was higher and faster than the transport across the Caco-2 monolayer cells, and glucose increased VCA transport across both monolayer cells. In addition, IL-12 was secreted from myeloid DC1 and lymphoid DC2.4 cells which were co-treated simultaneously with LPS and VCA. Furthermore, the FAE model associated with underlying immune cells was established and VCA was added to the inserts apically. There was a greater IL-12 secretion in dendritic cells situated below FAE monolayer than Caco-2 monolayer. The results from this study provide important insight into the possible oral application of mistletoe on anti-tumor therapeutics. PMID- 20945144 TI - Activation of LXRalpha induces lipogenesis in HaCaT cells. AB - The oxysterol nuclear receptors, LXRalpha (liver X receptor alpha; NR1H3) and LXRbeta (NR1H2), coordinately regulate the expression of genes involved in lipid metabolism, anti-inflammation, and cholesterol transport. Previous studies have demonstrated that ligands of LXRalpha are important in the maintenance of the normal epidermal barrier function and keratinocyte differentiation. In this study, we examined whether LXRalpha and its ligands regulate lipid synthesis in HaCaT cells, a spontaneously transformed human keratinocyte cell line. When HaCaT cells were treated with the LXRalpha ligand TO901317, lipid droplets accumulated in the majority of cells, which were stained by Oil Red O. A luciferase reporter construct containing the LXR response element was activated about fourfold in HaCaT cells by TO901317 treatment, suggesting that LXR has a role in lipid synthesis in these cells. The expression of LXRalpha target genes, such as those encoding sterol regulatory binding protein and fatty acid synthase, were induced time dependently by TO901317, as measured by RT-PCR and western blotting. The expression of PPAR-alpha, -beta, and -gamma which regulate lipid metabolism, was also increased by TO901317 treatment. In contrast, TO901317 reduced the lipopolysaccharide-induced expression of cyclooxygenase 2 and inducible nitric oxide synthase in HaCaT cells. These results indicate that LXRalpha activation leads to lipogenesis in keratinocytes, which may enhance the epidermal barrier function of the skin. PMID- 20945145 TI - Support vector machine based classification of 3-dimensional protein physicochemical environments for automated function annotation. AB - The knowledge of protein functions as well as structures is critical for drug discovery and development. The FEATURE system developed at Stanford is an effective tool for characterizing and classifying local environments in proteins. FEATURE utilizes vectors of a fixed dimension to represent the physicochemical properties around a residue. Functional sites and non-sites are identified by classifying such vectors using the Naive Bayes classifier. In this paper, we improve the FEATURE framework in several ways so that it can be more flexible, robust and accurate. The new tool can handle vectors of a user-specified dimension and can suppress noise effectively, with little loss of important signals, by employing dimensionality reduction. Furthermore, our approach utilizes the support vector machine for a more accurate classification. According to the results of our thorough experiments, the proposed new approach outperformed the original tool by 20.13% and 13.42% with respect to true and false positive rates, respectively. PMID- 20945146 TI - [Physical aspects of different tomosynthesis systems]. AB - Digital breast tomosynthesis (DBT) is a new image processing technique based on digital mammography technology. Image slices of the stationary compressed breast are reconstructed from multiple images taken at different angles of the X-ray tube at the same time. The main goal is to achieve a similar radiation dose exposure as common encountered in traditional digital mammography. One of the key advantages of DBT is that lesions are less likely to be hidden amongst normal tissues as they are in traditional digital mammography. This way the quality of diagnosis can be improved, especially for dense breasts. Current DBT implementations from several manufacturers differ in certain features such as scanning angle, number of projections, scanning time, pixel size, reconstruction methods and type of tube movement. A comparison and description of these different characteristics as well as a discussion on the proposed number of imaging planes and related radiation dose requirements are given. PMID- 20945147 TI - [New information on high risk breast screening]. AB - Women with an elevated risk for breast cancer require intensified screening beginning at an early age. Such high risk screening differs considerably from screening in the general population. After an expert has evaluated the exact risk a breast MRI examination should be offered at least once a year and beginning latest at the age of 30 depending on the patients risk category. Complementary mammograms should not be performed before the age of 35. An additional ultrasound examination is no longer recommended. To ensure a high sensitivity and specificity high risk screening should be performed only at a nationally or regionally approved and audited service. Adequate knowledge about the phenotypical characteristics of familial breast cancer is essential. Besides the common malignant phenotypes, benign morphologies (round or oval shape and smooth margins) as well as a low prevalence of calcifications have been described. Using MRI benign contrast media kinetics as well as non-solid lesions with focal, regional and segmental enhancement can often be visualized. PMID- 20945148 TI - [Perspectives of the digital mammography platform]. AB - In Europe one out of every nine women suffers from breast cancer during her lifetime. Since the introduction of mammography screening programs more breast cancers are being diagnosed when they are still small and early stage cancers with a favourable prognosis. The introduction of digital mammography systems has led to a continuous reduction of breast cancer mortality especially in specific patient subgroups. Furthermore, the digital mammography platform enables the development of new, innovative breast imaging methods to increase sensitivity and decrease breast cancer mortality. This digital mammography platform includes digital breast tomosynthesis, digital contrast medium mammography and digital contrast medium breast tomosynthesis as well as fused data sets from digital mammography with ultrasound or MRI. The following article summarizes these new applications, describes the strengths of the digital platform and illustrates the potential advantages of an improved breast cancer diagnosis by digital mammography. PMID- 20945149 TI - Oral bisphosphonates and risk of ischemic stroke: a case-control study. AB - Bisphosphonates have been associated with an increased risk of atrial fibrillation and may thus be associated with an increased risk of ischemic stroke. This would have substantial clinical and public health implications. We found no evidence of an association between bisphosphonate use and risk of ischemic stroke. INTRODUCTION: Bisphosphonates have been associated with an increased risk of atrial fibrillation in some studies and may be associated with an increased risk of ischemic stroke. However, data regarding these possibilities are limited. METHODS: We conducted a population-based case-control study of 6,257 female cases of ischemic stroke and 31,285 age- and gender-matched population controls. Data on bisphosphonate use, other medication use, comorbidity, and ischemic stroke were obtained from medical databases. Current bisphosphonate use was defined as at least one redeemed prescription within 90 days before diagnosis/index date. We estimated the odds ratio (OR) of ischemic stroke among users and nonusers of bisphosphonates using conditional logistic regression, controlling for potential confounding factors. RESULTS: One hundred eighty-two (2.9%) cases and 901 (2.9%) controls were current users of bisphosphonates. Etidronate and alendronate were prescribed with similar frequency among cases and controls. The adjusted OR of ischemic stroke for bisphosphonate users compared with nonusers was 0.97 (95% confidence interval [CI], 0.82-1.15). New and continuing bisphosphonate users had adjusted ORs for ischemic stroke of 1.16 (95% CI, 0.69-1.96) and 0.97 (95% CI, 0.81-1.16), respectively. Excluding patients with known atrial fibrillation/flutter yielded an OR of 1.00 (95% CI, 0.85-1.19). The OR for ischemic stroke was 0.59 (95% CI, 0.32-1.09) among patients with a history of previous hospitalization for cardiovascular disease and 1.07 (95% CI, 0.88-1.18) among those without (P < 0.001). The OR for former users was 1.23 (95% CI, 1.01-1.49). CONCLUSION: We found no evidence of an association of oral bisphosphonate use with the risk of ischemic stroke. PMID- 20945150 TI - Distal femoral varus osteotomy: problems associated with the lateral open-wedge technique. AB - INTRODUCTION: Varisation osteotomies on the distal femur are an established treatment method for valgus osteoarthritis of the knee in younger patients. Osteotomy can be done in a lateral open-wedge or medial closed-wedge manner. METHOD: We retrospectively studied 14 patients treated by the lateral open-wedge technique, fixed with the Tomofix plate, with a mean duration of follow-up of 45 +/- 3.4 months. RESULTS: We observed often delayed osteotomy healing after 3, 6 and 12 months, no secondary dislocations, and frequent troublesome irritation due to the plate being on the iliotibial band. However, outcome was satisfactory once the osteotomy healed and the plate was removed. CONCLUSION: Based on the often slow healing of the osteotomy and frequent irritation due to the plate, this procedure has been abandoned by the authors, and the medial closing-wedge osteotomy adopted as the alternative treatment. PMID- 20945151 TI - Influence of training status and exercise modality on pulmonary O2 uptake kinetics in pubertal girls. AB - The influence of training status on the oxygen uptake (VO2) response to heavy intensity exercise in pubertal girls has not previously been investigated. We hypothesised that whilst training status-related adaptations would be evident in the VO2, heart rate (HR) and deoxyhaemoglobin ([HHb]) kinetics of pubertal swimmers during both lower and upper body exercise, they would be more pronounced during upper body exercise. Eight swim-trained (T; 14.2 +/- 0.7 years) and eight untrained (UT; 14.5 +/- 1.3 years) girls completed a number of constant-work-rate transitions on cycle and upper body ergometers at 40% of the difference between the gas exchange threshold and peak VO2. The phase II VO2 time constant (tau) was significantly shorter in the trained girls during both cycle (T: 21 +/- 6 vs. UT: 35 +/- 11 s; P < 0.01) and upper body exercise (T: 29 +/- 8 vs. UT: 44 +/- 8 s; P < 0.01). The VO2 slow component was not influenced by training status. The [HHb] tau was significantly shorter in the trained girls during both cycle (T: 12 +/- 2 vs. UT: 20 +/- 6 s; P < 0.01) and upper body exercise (T: 13 +/- 3 vs. UT: 21 +/- 7 s; P < 0.01), as was the HR tau (cycle, T: 36 +/- 5 vs. UT: 53 +/- 9 s; upper body, T: 32 +/- 3 vs. UT: 43 +/- 2; P < 0.01). This study suggests that both central and peripheral factors contribute to the faster VO2 kinetics in the trained girls and that differences are evident in both lower and upper body exercise. PMID- 20945152 TI - Optically active: microwave-assisted synthesis and characterization of L-lysine derived poly (amide-imide)s. AB - L-lysine hydrochloride was transformed to ethyl L-lysine dihydrochloride. This salt was reacted with trimellitic anhydride to yield the corresponding diacid (1). Microwave-assisted polycondensation results a series of novel Poly (amide imide)s (PAI (a-i)). These polymers have inherent viscosities in the range of 0.23-0.66 dl g(-1), display optical activity from +8.02 to +15.11 (as there is no obvious regioselectivity between alpha and epsilon amino groups of the chiral diacid during the polymerization step then random orientation of diacid moieties along the polymer backbone can be predicted and the concept of "tacticity" cannot be addressed in this research), and are readily soluble in polar aprotic solvents. They start to decompose (T (10%)) above 362 degrees C and display glass transition temperatures at 119-153 degrees C. All of the above polymers were fully characterized by UV, FT-IR and (1)H NMR spectroscopy, elemental analysis, thermogravimetric analyses, DSC, inherent viscosity measurement and specific rotation. PMID- 20945154 TI - Application of Bayesian classifier for the diagnosis of dental pain. AB - Toothache is the most common symptom encountered in dental practice. It is subjective and hence, there is a possibility of under or over diagnosis of oral pathologies where patients present with only toothache. Addressing the issue, the paper proposes a methodology to develop a Bayesian classifier for diagnosing some common dental diseases (D = 10) using a set of 14 pain parameters (P = 14). A questionnaire is developed using these variables and filled up by ten dentists (n = 10) with various levels of expertise. Each questionnaire is consisted of 40 real-world cases. Total 14*10*10 combinations of data are hence collected. The reliability of the data (P and D sets) has been tested by measuring (Cronbach's alpha). One-way ANOVA has been used to note the intra and intergroup mean differences. Multiple linear regressions are used for extracting the significant predictors among P and D sets as well as finding the goodness of the model fit. A naive Bayesian classifier (NBC) is then designed initially that predicts either presence/absence of diseases given a set of pain parameters. The most informative and highest quality datasheet is used for training of NBC and the remaining sheets are used for testing the performance of the classifier. Hill climbing algorithm is used to design a Learned Bayes' classifier (LBC), which learns the conditional probability table (CPT) entries optimally. The developed LBC showed an average accuracy of 72%, which is clinically encouraging to the dentists. PMID- 20945153 TI - Physicochemical selectivity of the BBB microenvironment governing passive diffusion--matching with a porcine brain lipid extract artificial membrane permeability model. AB - PURPOSE: To mimic the physicochemical selectivity of the blood-brain barrier (BBB) and to predict its passive permeability using a PAMPA model based on porcine brain lipid extract (PBLE 10%w/v in alkane). METHODS: Three PAMPA (BD pre coated and PBLE with 2 different lipid volumes) models were tested with 108 drugs. Abraham solvation descriptors were used to interpret the in vitro-in vivo correlation with 282 in situ brain perfusion measurements, spanning over 5 orders of magnitude. An in combo PAMPA model was developed from combining measured PAMPA permeability with one H-bond descriptor. RESULTS: The in combo PAMPA predicted 93% of the variance of 197 largely efflux-inhibited in situ permeability training set. The model was cross-validated by the "leave-many-out" procedure, with q(2) = 0.92 +/- 0.03. The PAMPA models indicated the presence of paramembrane water channels. Only the PBLE-based PAMPA-BBB model with sufficient lipid to fill all the internal pore space of the filter showed a wide dynamic range window, selectivity coefficient near 1, and was suitable for predicting BBB permeability. CONCLUSION: BBB permeability can be predicted by in combo PAMPA. Its speed and substantially lower cost, compared to in vivo measurements, make it an attractive first-pass screening method for BBB passive permeability. PMID- 20945155 TI - Developing spatial frequency biases for face recognition in autism and Williams syndrome. AB - The current study investigated whether contrasting face recognition abilities in autism and Williams syndrome could be explained by different spatial frequency biases over developmental time. Typically-developing children and groups with Williams syndrome and autism were asked to recognise faces in which low, middle and high spatial frequency bands were masked. All three groups demonstrated a gradual specialisation toward the mid-band. However, while the use of high spatial frequencies decreased in control and autism groups over development, the Williams syndrome group did not display a bias toward this band at any point. These data demonstrate that typical outcomes can be achieved through atypical developmental processes, and confirm the importance of cross-syndrome studies in the investigation of developmental disorders. PMID- 20945156 TI - Sex partying among gay men in Sydney, Melbourne and Brisbane, Australia. AB - Group sex is relatively common among gay men, and is a likely risk factor for infection with HIV and other sexually transmissible infections (STI). The 5,432 participants in the 2008 Gay Community Periodic Survey in Sydney, Melbourne and Brisbane, Australia, were asked about their participation in group sex. Nearly half (44.0%) of those who reported sex with casual male partners in the previous 6 months also reported engaging in group sex. Among other factors, using drugs odds ratios (OR) and confidence intervals (CI) (OR = 1.89, CI = 1.61-2.21), being HIV-positive (OR = 1.62, CI = 1.13-2.32), and engaging in anal intercourse, both with a condom (OR = 3.03, CI = 2.46-3.73) and without a condom (OR = 5.68, CI = 4.53-7.12) were independently associated with having engaged in group sex. This study suggests that gay men who engage in group sex represent an important priority for targeted HIV and STI prevention activities and research. PMID- 20945157 TI - Individual- and family-level psychosocial correlates of HIV risk behavior among youth in rural Kenya. AB - Associations between individual- and family-level psychosocial factors and sexual behavior were examined among 325 adolescents ages 10-18 in rural Kenya. History of sexual activity was reported by 51% of males and 30% of females. Among those reporting sex within the past year, 64% of males and 32% of females had multiple partners; 85% of males and 54% of females reported not using a condom at last sex. Multivariate logistic regression modeling demonstrated sexually active adolescents were significantly more likely to be older, male, more accepting of risky behavior, and have greater perceived HIV risk, caregiver social support, social support related to HIV, and emotional problems. Youths reporting high-risk behavior (unprotected sex or multiple partners) were significantly more likely to be younger, male, and have lower sex-related self-efficacy, lower caregiver monitoring, and more externalizing problems. Future studies should evaluate HIV prevention interventions targeting improvements in mental health and family relationships. PMID- 20945158 TI - Provision of HIV counseling and testing services at five community-based organizations among young men of color who have sex with men. AB - In the context of monitoring and improving CDC-funded HIV prevention programs, we describe HIV tests and infections, provision of results, previous HIV tests, and risk behaviors for young (aged 13-29) men of color who have sex with men who received HIV tests at five community-based organizations. Of 1,723 tests provided, 2.1% were positive and 75.7% of positives were previously unaware of their infection. The highest positivity rate was among men aged 25-29 (4.7%). Thirty-four percent of tests were provided to men who were tested for the first time. Over half the tests (53.2%) were provided to men who reported sex with a person of unknown HIV status, and 34% to men who reported sex with an anonymous partner. Continued and more focused prevention efforts are needed to reach and test young men of color who have sex with men and to identify previously undiagnosed HIV infections among this target population. PMID- 20945159 TI - Dynamic assessment of baroreflex control of heart rate during induction of propofol anesthesia using a point process method. AB - In this article, we present a point process method to assess dynamic baroreflex sensitivity (BRS) by estimating the baroreflex gain as focal component of a simplified closed-loop model of the cardiovascular system. Specifically, an inverse Gaussian probability distribution is used to model the heartbeat interval, whereas the instantaneous mean is identified by linear and bilinear bivariate regressions on both the previous R-R intervals (RR) and blood pressure (BP) beat-to-beat measures. The instantaneous baroreflex gain is estimated as the feedback branch of the loop with a point-process filter, while the RR-->BP feedforward transfer function representing heart contractility and vasculature effects is simultaneously estimated by a recursive least-squares filter. These two closed-loop gains provide a direct assessment of baroreflex control of heart rate (HR). In addition, the dynamic coherence, cross bispectrum, and their power ratio can also be estimated. All statistical indices provide a valuable quantitative assessment of the interaction between heartbeat dynamics and hemodynamics. To illustrate the application, we have applied the proposed point process model to experimental recordings from 11 healthy subjects in order to monitor cardiovascular regulation under propofol anesthesia. We present quantitative results during transient periods, as well as statistical analyses on steady-state epochs before and after propofol administration. Our findings validate the ability of the algorithm to provide a reliable and fast-tracking assessment of BRS, and show a clear overall reduction in baroreflex gain from the baseline period to the start of propofol anesthesia, confirming that instantaneous evaluation of arterial baroreflex control of HR may yield important implications in clinical practice, particularly during anesthesia and in postoperative care. PMID- 20945160 TI - Presenteeism in college students: reliability and validity of the Presenteeism Scale for Students. AB - OBJECTIVE: Presenteeism is the impaired work performance due to health problems. We aimed to develop a Presenteeism Scale for Students (PSS), and to reveal the existence of presenteeism among students. METHODS: Students (n = 5,701) in 4 national universities in Japan were recruited via the school-based health examination. Moreover, 122 students participated in a 2-week interval test-retest to examine the reliability and criterion-related validity of the PSS. RESULTS: Of the students, 59.2% indicated some health problems. Allergy was most prevalent health problems, affecting 35.7% of the whole students. Students with emotional problems had higher degree of presenteeism than those with the other problems. The Cronbach's alpha of the work impairment score of the PSS was 0.90. The Spearman's coefficient for the test-retest score was 0.80 (P < 0.001). Regarding criterion-related validity, Spearman's coefficient between the work impairment score of the PSS and summary score of the SF-36 was -0.60 (P < 0.001). CONCLUSIONS: These findings suggest that the PSS can be expected to be useful for assessment of students with presenteeism. Furthermore, we found that the majority of students have some health problems, and proposed that the issue of presenteeism on campus should be addressed. PMID- 20945161 TI - Scientific imperatives, clinical implications, and theoretical underpinnings for the investigation of the relationship between genetic variables and patient reported quality-of-life outcomes. AB - OBJECTIVES: There is emerging evidence for a genetic basis of patient-reported quality-of-life (QOL) outcomes that can ultimately be incorporated into clinical research and practice. Objectives are (1) to provide arguments for the timeliness of investigating the genetic basis of QOL given the scientific advances in genetics and patient-reported QOL research; (2) to describe the clinical implications of such investigations; (3) to present a theoretical foundation for investigating the genetic underpinnings of QOL; and (4) to describe a series of papers resulting from the GENEQOL Consortium that was established to move this work forward. METHODS: Discussion of scientific advances based on relevant literature. RESULTS: In genetics, technological advances allow for increases in speed and efficiency and decreases in costs in exploring the genetic underpinnings of disease processes, drug metabolism, treatment response, and survival. In patient-based research, advances yield empirically based and stringent approaches to measurement that are scientifically robust. Insights into the genetic basis of QOL will ultimately allow early identification of patients susceptible to QOL deficits and to target care. The Wilson and Cleary model for patient-reported outcomes was refined by incorporating the genetic underpinnings of QOL. CONCLUSIONS: This series of papers provides a path for QOL and genetics researchers to work together to move this field forward and to unravel the intricate interplay of the genetic underpinnings of patient-reported QOL outcomes. The ultimate result will be a greater understanding of the process relating disease, patient, and doctor that will have the potential to lead to improved survival, QOL, and health services delivery. PMID- 20945162 TI - Patient-reported outcomes in clinical trials of inhaled asthma medications: systematic review and research needs. AB - PURPOSE: To assess the diversity, application, analysis and interpretation of patient-reported outcomes (PROs) in asthma clinical trials. METHODS: We critically appraised the use of asthma-specific PROs in 87 randomised controlled trials (RCTs) of inhaled asthma medications published during 1985-2006. RESULTS: A total of 79 RCTs reported PROs, of which 78 (99%) assessed symptom scores and seven (9%) assessed asthma quality of life scores. Only eight (10%) used validated instruments and five (6%) provided clinical interpretation of scores. Due to heterogeneity in the reporting of symptom measures, it is not possible to determine how many discrete symptom assessment instruments have been used. Only 26 (33%) of the RCTs that measured symptom scores reported the scores for follow up. Limited improvement occurred over time: fewer than 30% of the RCTs used validated PRO measures in any individual year. CONCLUSION: Numerous validated PRO instruments are available but it is unclear why few are used in asthma clinical trials. Problems include poor reporting, and uncritical analysis and interpretation of PRO scores. Research needs include identifying and recommending a set of PROs for use in asthma clinical research and providing guidance for researchers on the application, analysis and interpretation of PRO measures in clinical trials. PMID- 20945163 TI - Aging and movement errors when lifting and lowering light loads. AB - The purpose was to determine the influence of movement variability and level of muscle activation on the accuracy of targeted movements performed with the index finger by young and older adults. Twelve young (27.4 +/- 4.4 years) and 12 older adults (74.5 +/- 8.9 years) attempted to match the end position of an index finger movement to a target position when lifting and lowering a light load (10% of the maximum). Visual feedback was provided after each trial. Movement error was calculated as the absolute distance from the target. Movement variability was quantified as the standard deviation of finger acceleration and the variability of end position across trials. The EMG activity of first dorsal interosseus (FDI) and second palmar interosseus (SPI) muscles was measured with intramuscular electrodes. Older adults exhibited greater spatial and temporal errors and greater variability in finger acceleration and end position during both the lifting and lowering tasks. Older adults lifted the load by activating FDI less but SPI the same as young adults, whereas they lowered the load by activating SPI less and FDI the same as young adults. In addition, older adults exhibited lower variability across trials in SPI activation when lifting the load and lower variability for FDI activation when lowering the load. The findings demonstrate that the decrease in spatial and temporal accuracy observed in older adults when lifting and lowering a light load to a target position was due to greater movement variability and differences in antagonistic muscle activity. PMID- 20945164 TI - Are incisionless fundoplication procedures a safer alternative to the laparoscopic nissen for the treatment of chronic gastroesophageal reflux disease? PMID- 20945165 TI - Mouse ataxin-3 functional knock-out model. AB - Spinocerebellar ataxia 3 (SCA3) is a genetic disorder resulting from the expansion of the CAG repeats in the ATXN3 gene. The pathogenesis of SCA3 is based on the toxic function of the mutant ataxin-3 protein, but the exact mechanism of the disease remains elusive. Various types of transgenic mouse models explore different aspects of SCA3 pathogenesis, but a knock-in humanized mouse has not yet been created. The initial aim of this study was to generate an ataxin-3 humanized mouse model using a knock-in strategy. The human cDNA for ataxin-3 containing 69 CAG repeats was cloned from SCA3 patient and introduced into the mouse ataxin-3 locus at exon 2, deleting it along with exon 3 and intron 2. Although the human transgene was inserted correctly, the resulting mice acquired the knock-out properties and did not express ataxin-3 protein in any analyzed tissues, as confirmed by western blot and immunohistochemistry. Analyses of RNA expression revealed that the entire locus consisting of human and mouse exons was expressed and alternatively spliced. We detected mRNA isoforms composed of exon 1 spliced with mouse exon 4 or with human exon 7. After applying 37 PCR cycles, we also detected a very low level of the correct exon 1/exon 2 isoform. Additionally, we confirmed by bioinformatic analysis that the structure and power of the splicing site between mouse intron 1 and human exon 2 (the targeted locus) was not changed compared with the native mouse locus. We hypothesized that these splicing aberrations result from the deletion of further splicing sites and the presence of a strong splicing site in exon 4, which was confirmed by bioinformatic analysis. In summary, we created a functional ataxin-3 knock-out mouse model that is viable and fertile and does not present a reduced life span. Our work provides new insights into the splicing characteristics of the Atxn3 gene and provides useful information for future attempts to create knock-in SCA3 models. PMID- 20945166 TI - Improved albendazole dissolution rate in pluronic 188 solid dispersions. AB - Solids dispersions (SDs) have been proposed as an alternative to improve the dissolution rate of low solubility drugs. SDs containing albendazole (ABZ; 5, 10, 25, and 50% w/w) and Pluronic 188 (P 188) as hydrophilic carrier were formulated. The obtained SDs were assessed in comparison to physical mixtures (PMs). Drug polymer interactions in solid state were investigated using Fourier-transform infrared spectroscopy, scanning electron microscopy, and X-ray diffraction analysis. No chemical interaction was found between ABZ and poloxamer. The dissolution profiles indicated that ABZ incorporated in SDs and PMs was rapidly released, reaching rapidly the steady state. Increased dissolution rates are usually observed at the highest polymer proportions. However, an opposite effect for SDs as well as for PMs was observed in the assays described here. The systems with the lowest P 188 percentages (SD4, SD3; PM4, PM3) tended to be more effective in increasing the ABZ dissolution rate. Such a result can be attributed to the fact that concentrated aqueous solutions of Poloxamer may form thermo reversible gels. The physical-mechanical properties indicated that SDs possess improved flow and compacting properties compared to PMs. Thus, ABZ SDs would be more convenient for solid dosage form design and manufacture. PMID- 20945168 TI - The cognitive neuroscience of face processing: an introduction. PMID- 20945167 TI - Value of coronary CTA in patients with known or suspected CAD and non-diagnostic initial myocardial perfusion testing: current evidence and clinical considerations. PMID- 20945169 TI - Effect of image orientation and size on object recognition: responses of single units in the macaque monkey temporal cortex. AB - This study examined how cells in the temporal cortex code orientation and size of a complex object. The study focused on cells selectively responsive to the sight of the head and body but unresponsive to control stimuli. The majority of cells tested (19/26, 73%) were selectively responsive to a particular orientation in the picture plane of the static whole body stimulus, 7/26 cells showed generalisation responding to all orientations (three cells with orientation tuning superimposed on a generalised response). Of all cells sensitive to orientation, the majority (15/22, 68%) were tuned to the upright image. The majority of cells tested (81%, 13/16) were selective for stimulus size. The remaining cells (3/16) showed generalisation across four-fold decrease in size from life-sized. All size-sensitive cells were tuned to life-sized stimuli with decreasing responses to stimuli reduced from life-size. These results do not support previous suggestions that cells responsive to the head and body are selective to view but generalise across orientation and size. Here, extensive selectivity for size and orientation is reported. It is suggested that object orientation and size-specific responses might be pooled to obtain cell responses that generalise across size and orientation. The results suggest that experience affects neuronal coding of objects in that cells become tuned to views, orientation, and image sizes that are commonly experienced. Models of object recognition are discussed. PMID- 20945170 TI - Structural encoding and identification in face processing: erp evidence for separate mechanisms. AB - The present study had two aims. The first aim was to explore the possible top down effect of face-recognition and/or face-identification processes on the formation of structural representation of faces, as indexed by the N170 ERP component. The second aim was to examine possible ERP manifestations of face identification processes as an initial step for assessing their time course and functional neuroanatomy. Identical N170 potentials were elicited by famous and unfamiliar faces in Experiment 1, when both were irrelevant to the task, suggesting that face familiarity does not affect structural encoding processes. Small but significant differences were observed, however, during later-occurring epochs of the ERPs. In Experiment 2 the participants were instructed to count occasionally occurring portraits of famous politicians while rejecting faces of famous people who were not politicians and faces of unfamiliar people. Although an attempt to identify each face was required, no differences were found in the N170 elicited by faces of unfamiliar people and faces of familiar non politicians. Famous faces, however, elicited a negative potential that was significantly larger than that elicited by unfamiliar faces between about 250 and 500msec from stimulus onset. This negative component was tentatively identified as an N400 analogue elicited by faces. Both the absence of an effect of familiarity on the N170 and the familiarity face-N400 effect were replicated in Experiment 3, in which the participants made speeded button-press responses in each trial, distinguishing among faces of politicians and faces of famous and unfamiliar non-politicians. In addition, ERP components later than the N400 were found to be associated with the speed of the response but not with face familiarity. We concluded that (1) although reflected by the N170, the structural encoding mechanism is not influenced by the face recognition and identification processes, and (2) the negative component modulated by face familiarity is associated with the semantic activity involved in the identification of familiar faces. PMID- 20945171 TI - Models of face recognition and delusional misidentification: a critical review. AB - The "two-route model of face recognition" proposed by Bauer (1984) and adopted by Ellis and Young (1990), has become a widely accepted model in studies of face processing disorders, including both prosopagnosia and the delusional misidentification syndromes. We review the origin and application of the two route model of face recognition in examining both the neuroanatomical pathways and the cognitive pathways to face recognition. With respect to the neuroanatomy, we conclude that face recognition is subserved by a single pathway, the ventral visual pathway, as there is no evidence to suggest that the dorsal visual pathway is capable of visual recognition or of providing an affective response to familiar stimuli. We demonstrate how operation of the ventral visual pathway and its connections to the amygdala can parsimoniously account for the findings in the literature on prosopagnosia and delusional misidentification syndromes. In addition, we propose a cognitive model of face processing stemming from the work of Bruce and Young (1986). Our model involves two pathways subsequent to the system responsible for face recognition: one pathway to a system containing semantic and biographical information about the seen face, and a second pathway to a system responsible for the generation of an affective response to faces that are familiar. We demonstrate how this cognitive model can explain the dissociations between overt and covert recognition observed in prosopagnosia and the Capgras delusion. PMID- 20945172 TI - Facial expression recognition by people with mobius syndrome. AB - We present an investigation of facial expression recognition by three people (BC, LP, and NC) with Mobius syndrome, a congenital disorder producing facial paralysis. The participants were asked to identify the emotion displayed in 10 examples of facial expressions associated with each of 6 basic emotions from the Ekman and Friesen (1976) series. None of the three people with Mobius syndrome was significantly impaired on this task. On a second test of facial expression recognition using computer-morphed facial expressions, NC showed a statistically significant impairment, BC a borderline deficit, and LP was unimpaired. However, even when impairments were found, people with Mobius syndrome still recognised many of the facial expressions shown to them. The recognition of facial expressions by people who have never been able to produce such signals on their own faces demonstrates that the ability to produce facial expressions is not a necessary prerequisite of their recognition. PMID- 20945173 TI - Structural encoding precludes recognition of face parts in prosopagnosia. AB - The extent and the impact of spared processing of facial stimuli in the prosopagnosic patient LH is examined using the inversion effect and the face context effect. Our study asked how the deficit in individual face recognition is related to two perceptual abilities that are spared in this patient but between which there is interference when both are applied to the face stimulus, i.e. structural encoding of the face and parts-based matching procedures. Three experiments studied this relationship with task demands and stimulus properties designed to trigger the parts-based processes. In the first experiment, human and animal faces are presented upright or inverted with good performance only for the inverted condition. In Experiment 2 normals show a clear face context effect (matching of upright faces easier than scrambled or inverted ones) in the full face matching task whereas in the parts matching task the face superiority effect disappears. In contrast, LH shows a face inferiority effect when matching full faces but also when matching an isolated face part to a face part in a full face context. The results show that structural encoding of the face overrules parts based procedures that could otherwise be helpful to tell individual faces apart. PMID- 20945174 TI - Attentional modulations of event-related brain potentials sensitive to faces. AB - Event-related brain potentials (ERPs) were recorded in response to centrally and peripherally presented faces and chairs under conditions where one stimulus category was attended and the other unattended. It was studied whether selective attention affects ERP components sensitive to the presence of faces. When compared with chairs, faces elicited larger N1 amplitudes at lateral temporal electrodes and a midline positivity in the same latency range. The latter effect was only found for central faces. Attention to centrally presented faces was reflected in enhanced posterior N1 amplitudes. This effect may be related to an attentional modulation of processing within face-specific brain areas. It was not elicited by chairs or peripheral faces. Beyond 200msec post-stimulus, a category unspecific attentional negativity was found at all recording sites for centrally and peripherally presented face and nonface stimuli. PMID- 20945175 TI - Early commitment of neural substrates for face recognition. AB - We present evidence of a striking failure of plasticity in the neural substrates of face recognition, which suggests that the distinction between faces and other objects, and the localisation of faces relative to other objects, is fully determined prior to any postnatal experience. A boy who sustained brain damage at 1 day of age has the classic lesions and behavioural profile of adult-acquired prosopagnosia. He has profoundly impaired face recognition, whereas his recognition of objects is much less impaired. This implies that the human genome contains sufficiently explicit information about faces and nonface objects, or visual features by which they can be distinguished, that experience with these categories is not necessary for their functional delineation and differential brain localisation. PMID- 20945176 TI - Is face recognition not so unique after all? AB - In monkeys, a number of different neocortical as well as limbic structures have cell populations that respond preferentially to face stimuli. Face selectivity is also differentiated within itself: Cells in the inferior temporal and prefrontal cortex tend to respond to facial identity, others in the upper bank of the superior temporal sulcus to gaze directions, and yet another population in the amygdala to facial expression. The great majority of these cells are sensitive to the entire configuration of a face. Changing the spatial arrangement of the facial features greatly diminishes the neurons' response. It would appear, then, that an entire neural network for faces exists which contains units highly selective to complex configurations and that respond to different aspects of the object "face." Given the vital importance of face recognition in primates, this may not come as a surprise. But are faces the only objects represented in this way? Behavioural work in humans suggests that nonface objects may be processed like faces if subjects are required to discriminate between visually similar exemplars and acquire sufficient expertise in doing so. Recent neuroimaging studies in humans indicate that level of categorisation and expertise interact to produce the specialisation for faces in the middle fusiform gyrus. Here we discuss some new evidence in the monkey suggesting that any arbitrary homogeneous class of artificial objects-which the animal has to individually learn, remember, and recognise again and again from among a large number of distractors sharing a number of common features with the target-can induce configurational selectivity in the response of neurons in the visual system. For all of the animals tested, the neurons from which we recorded were located in the anterior inferotemporal cortex. However, as we have only recorded from the posterior and anterior ventrolateral temporal lobe, other cells with a similar selectivity for the same objects may also exist in areas of the medial temporal lobe or in the limbic structures of the same "expert" monkeys. It seems that the encoding scheme used for faces may also be employed for other classes with similar properties. Thus, regarding their neural encoding, faces are not "special" but rather the "default special" class in the primate recognition system. PMID- 20945177 TI - Does visual subordinate-level categorisation engage the functionally defined fusiform face area? AB - Functional magnetic resonance imaging was used to compare brain activation associated with basic-level (e.g. bird) and subordinate-level (e.g. eagle) processing for both visual and semantic judgements. We localised the putative face area for 11 subjects, who also performed visual matching judgements for pictures and aurally presented words. The middle fusiform and occipital gyri were recruited for subordinate minus basic visual judgements, reflecting additional perceptual processing. When the face area was localised individually for each subject, analyses in the middle fusiform gyri revealed that subordinate-level processing activated the individuals face area. We propose that what is unique about the way faces engage this region is the focal spatial distribution of the activation rather than the recruitment of the face per se. Eight subjects also performed semantic judgements on aurally presented basic- and subordinate-level words. The parahippocampal gyri were more activated for subordinate-level than basic-level semantic judgements. Finally, the left posterior inferior temporal gyrus was activated for subordinate-level judgements, both visual and semantic, as well as during passive viewing of faces. PMID- 20945178 TI - Age-related changes in the neural correlates of degraded and nondegraded face processing. AB - In order to explore the neural correlates of age-related changes in visual perception of faces, positron emission tomographic scans were obtained on young and old adults while they were engaged in tasks of nondegraded and degraded face matching. Old adults were less accurate than were young adults across all face matching conditions, although the age difference was greatly reduced when degraded performance was adjusted for nondegraded performance. The interaction of age and degree of degradation on performance measures was not significant. Brain activity patterns during nondegraded face matching were similar in the two groups with some differences in parietal and prestriate cortices (greater activity in young adults) and in prefrontal cortex, thalamus, and hippocampus (greater activity in old adults). Increases in activity related to increasing degradation of the faces were seen mainly in prefrontal cortices in both age groups. Despite this similarity in the brain response to face degradation, there were striking differences between groups in the correlations between brain activity and degraded task performance. Different regions of extrastriate cortex were positively correlated with behavioural measures in the two groups (fusiform gyrus in the young adults and posterior occipital regions in old adults). In addition two areas where older adults showed greater activity during nondegraded face matching, thalamus and hippocampus, also showed positive correlations with behaviour during the degraded tasks in this group, but not in the young group. Thus, although the elderly are not more vulnerable to the effects of increasing face degradation, the brain systems involved in carrying out these visual discriminations in young and old adults are not the same. These results are consistent with the idea of functional plasticity in face processing over the life span. PMID- 20945179 TI - Localised face processing by the human prefrontal cortex: face-selective intracerebral potentials and post-lesion deficits. AB - The patient described in the companion paper by Vignal, Chauvel, and Halgren (this issue) was studied with event related potentials (ERPs) recorded directly within the brain substance, as well as with neuropsychological tests before and after therapeutic cortectomy. Large ERPs were evoked in the prefrontal cortex to faces, as compared to sensory controls and words. The largest such ERPs were highly localised to the same right anterior inferior prefrontal site where direct electrical stimulation resulted in face hallucinations. Face-selective ERPs were also evoked in the right prefrontal sites that had shown projected activity during face hallucinations, and near the right anterior superior temporal sulcus. Selective responses began about 150msec after face onset. Words, but not faces or sensory controls, evoked large ERPs in distinct locations, mainly in the left hemisphere. A successful surgical therapy was performed by removing the cortex surrounding the right prefrontal site where face-selective responses were recorded and where face hallucinations were evoked by stimulation. This cortectomy resulted in a severe deficit in the recognition of emotional facial expressions, especially fear. No change was noted, however, in the recall of emotional words, or other tasks. The current results provide strong support for the early, specific, and sustained involvement of a multi-focal network in the right inferior fronto-temporal cortex in face-processing. PMID- 20945180 TI - Super face-inversion effects for isolated internal or external features, and for fractured faces. AB - Two experiments were conducted to determine the contributions of the face and object systems to the recognition of upright and inverted faces. In Experiment 1, CK, a person with object agnosia and normal recognition of upright faces, and 12 controls attempted to identify faces when presented with upright or inverted versions of the whole face, or with only their internal or external features. CK recognised as many upright whole faces as controls and the performance of both dropped slightly in the upright, internal feature condition. CK's recognition, however, was impaired in the upright, external condition, and severely impaired in the inverted whole condition, whereas control performance was equivalent in the two, and only somewhat worse than in the upright whole condition. Recognition in the inverted internal and external condition was extremely poor for all participants, leading to a super-inversion effect. This super-inversion effect suggested that recognition depends on more than just piecemeal identification of individual features. Experiment 2 was conducted to determine whether relational information is needed even for the identification of inverted faces. Twelve controls were required to identify whole and fractured faces in the upright and inverted orientation. The fractured faces had all the parts in the canonical order (eyes above nose above mouth) but they were separated by gaps, thereby altering the spatial relation among them. Recognition of inverted fractured faces was much worse than recognition of upright fractured faces and inverted whole faces, producing yet another super-inversion effect. The deficit in the inverted fractured condition was equal to the combined drop in performance in the other two conditions, indicating that the effects of inversion and fracturing are additive. On the basis of these results, we proposed that the face system forms holistic representations of faces based on orientation-specific global configurations primarily of internal features. When this information is unavailable, as when viewing inverted or fractured faces, the object system is needed to integrate information about individual features, which themselves may be orientation-specific, with information about the local or categorical relations among them into an object-system counterpart of the face-system representation. The creation of the facial counterpart by the object system and the consequent identification by the face system involves an exchange of information between the two systems according to an interactive activation model. PMID- 20945181 TI - Erps evoked by viewing facial movements. AB - Human neuroimaging and event-related potential (ERP) studies suggest that ventral and lateral temporo-occipital cortex is sensitive to static faces and face parts. Recent fMRI data also show activation by facial movements. In this study we recorded from 22 posterior scalp locations in 20 normal right-handed males to assess ERPs evoked by viewing: (1) moving eyes and mouths in the context of a face; (2) moving and static eyes with and without facial context. N170 and P350 peak amplitude and latency data were analysed. N170 is an ERP previously shown to be preferentially responsive to face and eye stimuli, and P350 immediately follows N170. Major results were: (1) N170 was significantly larger over the bilateral temporal scalp to viewing opening mouths relative to closing mouths, and to eye aversion relative to eyes gazing at the observer; (2) at a focal region over the right inferior temporal scalp, N170 was significantly earlier to mouth opening relative to closing, and to eye aversion relative to eyes gazing at the observer; (3) the focal ERP effect of eye aversion occurred independent of facial context; (4) these differences cannot be attributable to movement per se, as they did not occur in a control condition in which checks moved in comparable areas of the visual field; (5) isolated static eyes produced N170s that were not significantly different from N170s to static full faces over the right inferior temporal scalp, unlike in the left hemisphere where face N170s were significantly larger than eye N170s; (6) unlike N170, P350 exhibited nonspecific changes as a function of stimulus movement. These results suggest that: (1) bilateral temporal cortex forms part of a system sensitive to biological motion, of which facial movements form an important subset; (2) there may be a specialised system for facial gesture analysis that provides input for neuronal circuitry dealing with social attention and the actions of others. PMID- 20945182 TI - Prosopamnesia: a selective impairment in face learning. AB - The structures required for new learning, and those required for the representation of what has been learned, are believed to be distinct. This counterintuitive division of labour when considered alongside the localised nature of knowledge representation for at least some stimulus domains, implies that circumscribed new learning impairments should occasionally be found as a result of disconnection between learning mechanisms and domain-specific representations. We describe the most narrowly circumscribed new learning deficit so far reported, consisting of a selective new learning impairment for faces, which we term "prosopamnesia." Logically, a diagnosis of prosopamnesia requires preserved face perception, preserved memory for material other than faces (including visual material), and preserved recognition of faces known premorbidly. We describe a patient who meets these criteria, thus supporting the division of labour between neural systems for learning and neural systems for knowledge representation, as well as providing further support for segregated face representation in cortex. PMID- 20945183 TI - Response properties of the human fusiform face area. AB - We used functional magnetic resonance imaging to study the response properties of the human fusiform face area (FFA: Kanwisher, McDermott, & Chun, 1997) to a variety of face-like stimuli in order to clarify the functional role of this region. FFA responses were found to be (1) equally strong for cat, cartoon and human faces despite very different image properties, (2) equally strong for entire human faces and faces with eyes occluded but weaker for eyes shown alone, (3) equal for front and profile views of human heads, but declining in strength as faces rotated away from view, and (4) weakest for nonface objects and houses. These results indicate that generalisation of the FFA response across very different face types cannot be explained in terms of a specific response to a salient facial feature such as the eyes or a more general response to heads. Instead, the FFA appears to be optimally tuned to the broad category of faces. PMID- 20945184 TI - Localised face processing by the human prefrontal cortex: stimulation-evoked hallucinations of faces. AB - Left and right prefrontal, premotor, and anterior temporal sites were stereotaxically implanted in order to direct surgical therapy for epilepsy. Direct electrical stimulation of the right anterior inferior frontal gyrus resulted in face-related hallucinations and illusions. When the patient was viewing a blank background, stimulation induced the experience of a rapid succession of faces. When the patient was viewing a real face, stimulation induced a series of modifications to that face. Effective stimulations induced afterdischarges that remained localised to right ventrolateral prefrontal cortex (VLPFC). Stimulation of other frontal and anterior temporal sites, bilaterally, induced no face-related hallucinations or illusions. This result supports a contribution of right VLPFC to face processing, and is consistent with models wherein it activates representations in working or declarative memories. PMID- 20945185 TI - Contention scheduling and the control of routine activities. AB - The control of routine action is a complex process subject both to minor lapses in normals and to more severe breakdown following certain forms of neurological damage. A number of recent empirical studies (e.g. Humphreys & Ford, 1998; Schwartz et al., 1991, 1995, 1998) have examined the details of breakdown in certain classes of patient, and attempted to relate the findings to existing psychological theory. This paper complements those studies by presenting a computational model of the selection of routine actions based on competitive activation within a hierarchically organised network of action schemas (cf. Norman & Shallice, 1980, 1986). Simulations are reported which demonstrate that the model is capable of organised sequential action selection in a complex naturalistic domain. It is further demonstrated that, after lesioning, the model exhibits behaviour qualitatively equivalent to that observed by Schwartz et al., in their action disorganisation syndrome patients. PMID- 20945186 TI - Biased attentional shifts associated with unilateral left neglect. AB - Data are reported on the ability of a patient with unilateral left neglect to detect the presence of a gap in broken lines. Although there were some deficits in her left field in baseline conditions, more striking was the asymmetry in the effects of attentional cueing. Ipsilesional cues facilitated detection at far right locations most strongly. Contralesional cues facilitated detection at near left locations, but particularly when cues appeared on the far left. The results are interpreted in terms of biases in the lateral shifting of attention, with attention tending to overshoot to the right and undershoot to the left. The effects arise even when attentional engagement rather than disengagement is stressed. PMID- 20945187 TI - Loss of stored knowledge of object structure: implications for "category specific" deficits. AB - Following a right-hemisphere lesion, the patient SM had impaired object recognition, with good elementary visual abilities, and could derive information about object structure. He was also impaired on all tasks tapping stored structural knowledge, even when tested in the verbal modality. This suggests that SM has a disorder affecting stored knowledge of object structure, though he remains able to assemble novel structural descriptions. His object recognition ability also appeared significantly worse for non-living things. By contrast, existing models relating to stored knowledge would predict that SM would show greater impairment with living things. We argue that SM's deficit reflects the loss of a type of structural knowledge that relates to the "within-item structural diversity" of items. It is argued that living things show less structural variation than objects in the natural world, and might arguably be easier to recognise, because the image of the to-be-recognised object would be similar to the stored representation. Hence, a deficit affecting this aspect of stored knowledge would differentially impact upon non-living things. This argument receives confirming independent support from the finding that normal subjects ratings for the within-item structural diversity of visual stimuli are (unlike other "critical" variables) significant predictors of SM's naming performance. PMID- 20945188 TI - A double dissociation between linguistic and perceptual representations of spatial relationships. AB - This paper explores from a neuropsychological perspective the relation between the meanings of English locative prepositions (e.g., in, on, above, below) and the kinds of representations that are used for many visuospatial processes such as recognising, drawing, and constructing spatially complex objects. One possibility that has been proposed by some psycholinguists is that the meanings of prepositions are the same as the representations used in these other processes. An alternative possibility, which has been proposed by a different group of researchers, is that the relation is more distant such that the meanings of prepositions constitute language-specific semantic structures that are distinct from the representations that underlie many visuospatial abilities. Here we report a detailed assessment of the linguistic as well as perceptual and cognitive representations of spatial relationships in two brain-damaged subjects. Four tests were administered that involve both the production and comprehension of English locative prepositions. In addition, four standardised neuropsychological tests that probe high-level nonlinguistic visuospatial perception and cognition were administered. Case 1 was significantly impaired on all of the preposition tests but was normal on all of the visuospatial tests. In striking contrast, Case 2 was normal on all of the preposition tests but was significantly impaired on all of the visuospatial tests. The subjects also had entirely different brain lesions: Case 1 had a left-hemisphere lesion in the frontoparietal region, and Case 2 had a right-hemisphere lesion in the frontoparietal and temporal regions. Together, the results constitute a "double dissociation," suggesting that the preposition tests and the visuospatial tests require cognitively and neurally distinct mechanisms that can be disrupted independently of each other. We interpret the data as supporting the second possibility described-namely, that the meanings of locative prepositions may be language-specific semantic structures that are separate from the mental representations underlying many other kinds of high-level nonlinguistic visuospatial abilities. PMID- 20945189 TI - Role of the right prefrontal cortex in ill-structured planning. AB - We tested an architect with a lesion to the right prefrontal cortex in a real world architectural design/planning task that required him to develop a new design for our lab space and compared his performance to an age- and education matched architect. The patient understood the task and even observed that "this is a very simple problem." His sophisticated architectural knowledge base was still intact and he used it quite skilfully during the problem structuring phase. However, the patient's problem-solving behaviour differed from the control's behaviour in the following ways: (1) he was unable to make the transition from problem structuring to problem solving; (2) as a result preliminary design did not start until two thirds of the way into the session; (3) the preliminary design phase was minimal and erratic, consisting of three independently generated fragments; (4) there was no progression or lateral development of these fragments; (5) there was no carry-over of abstract information into the preliminary design or later phases, and (6) the patient did not make it to the detailing phase. This suggests that the key to understanding our patient's deficit is to understand the cognitive processes and mechanisms involved in the preliminary design phase. We appeal to a theory of design problem solving (Goel, 1995) that associates cognitive processes involved in preliminary design with "lateral" state transformations and argues that "ill-structured" representational and computational systems are necessary to support these transformations. We conclude that the neural basis of this system is selectively damaged in our patient. PMID- 20945190 TI - Gogi aphasia or semantic dementia? Simulating and assessing poor verbal comprehension in a case of progressive fluent aphasia. AB - Many patients with progressive fluent aphasia present with poor verbal comprehension and profound word-finding difficulties in the context of much better picture comprehension and object use. The Japanese term Gogi (literally "word-meaning") aphasia matches this behavioural pattern. The alternative label of semantic dementia is most often used for these patients and this term emphasises a generalised degradation of conceptual knowledge that encompasses both verbal and nonverbal comprehension. The study presented here investigates whether progressive fluent aphasia has a functional impairment limited to the verbal domain (Gogi aphasia) or more widespread involvement of all conceptual knowledge (semantic dementia). We report data collected from a patient with progressive fluent aphasia, IW, who presented with profound word-finding difficulties and relatively poor word comprehension. The predictions of three theoretical interpretations of this pattern are investigated in a series of experimental tasks. We argue that IW's poor verbal comprehension and anomia cannot easily be explained as an impairment to either a semantic lexicon or a modality-specific verbal semantic system. Instead we favour an explanation in terms of a single impairment to a unitary semantic system within a framework that emphasises the underlying differences in the mapping between surface form and meaning, for words and pictures. We demonstrate how IW's pattern of data can be replicated in an implemented connectionist network that includes a systematic mapping for pictures but an arbitrary relationship for words. We conclude that although Gogi aphasia may be an accurate clinical description of the most striking features observed in progressive fluent aphasia, the disorder is primarily a progressive loss of conceptual knowledge-it is semantic dementia. PMID- 20945191 TI - METHODOLOGICAL ISSUES CONFRONTING PET AND fMRI STUDIES OF COGNITIVE FUNCTION. PMID- 20945192 TI - Selective deficit for people's names following left temporal damage: an impairment of domain-specific conceptual knowledge. AB - As a consequence of a head trauma, APA presented with selective anomia for the names of familiar people, in the absence of comparable disorders for common names and other proper names. Face recognition was normal; and naming performance was unaffected by stimulus and response types. Selective proper name anomia was not due to effects of frequency of usage or of age of acquisition, or to selective memory/learning deficits for the names of people. Even though APA was able to provide at least some information on many celebrities whom she failed to name, she was clearly impaired in all tasks that required full conceptual information on the same people (but she performed flawlessly in similar tasks that involved common names). This pattern of performance indicates that in our subject the inability to name familiar persons results from damage to conceptual information. It is argued that detailed analyses of conceptual knowledge are necessary before it is concluded that a subject with proper name anomia suffers from a purely output disorder, as opposed to a conceptual disorder. The behaviour observed in APA is consistent with the domain-specific hypothesis of conceptual organisation (Caramazza & Shelton, 1998), and in this framework can be explained by assuming selective damage to knowledge of conspecifics. The anatomo-clinical correlates of our subject's disorder are discussed with reference to recent hypotheses on the neural structures representing knowledge of familiar people. PMID- 20945193 TI - The selective impairment of the phonological output buffer. AB - A single case study is presented of a patient, LT, with a reproduction conduction aphasic pattern of performance on word reproduction tasks; thus he made substitutions, insertions, deletions, and transpositions in reading, writing, and repetition of words and nonwords, as well as in sentence production, and in spoken and written picture and action naming. Further analyses revealed that there was no effect of semantic or syntactic structure on performance, and that reading was slightly better than repetition and writing. Finally, the observed effects of lexicality, length, and word frequency were similar to those found in other phonological output buffer patients. Overall, the pattern observed fits the characteristics typical of phonological output buffer patients, as characterised by Caramazza, Miceli, and Villa (1986). We discuss the implications of these results for understanding the role of the output phonological buffer in neuropsychological and computational models of writing, reading, and repetition. From the perspective of LT's performance, the hypothesis suggested by Caramazza et al. (1986), and that of Hartley and Houghton (1996), that word production in reading and repetition uses an additional route to access articulatory or phoneme level representations from the phonological output lexicon, is unnecessary; instead, word-nonword differences in other patients can be attributed to resource demand differences between the two types of stimuli. LT's preserved span fit with the assumption that two phonological buffers exist, one for input and the other for output. Results from a word repetition experiment, in which word syllable structure was manipulated, are in conflict with one further noncentral aspect of the Hartley and Houghton's model, which otherwise fits the results well. PMID- 20945194 TI - Neuropsychological evidence distinguishing object selection from action (effector) selection. AB - We report two sets of data on object and action selection in a patient, ES, with an impaired ability to make task-based actions to objects. In simple action tasks, ES often made familiar actions to objects rather than the action appropriate to the task rule. We show that, despite having impaired selection of action, ES was able to select the target for action (based on salient perceptual differences). Relatively good object selection occurred even when the distractor had a stronger learned response than the target. In addition we show that distractors close to the path of action to a target can compete for, but are rejected from, selection along with any concurrently activated response. Suppression of an activated response improved performance, when the response would have been inappropriate to the task. PMID- 20945195 TI - Calculating without reading: unsuspected residual abilities in pure alexia. AB - In pure alexic patients, clear-cut dissociations between impaired naming and preserved comprehension abilities can be found in the domain of number processing (Cohen & Dehaene, 1995). In the present study, we report a novel case of pure alexia with striking preservation of some calculation abilities. The patient was fully able to decide which of two numbers was the larger, or whether a number was odd or even, even with 2-digit numerals for which she made close to 90% reading errors. In arithmetic the patient, though unable to read aloud correctly the operands of visually presented problems, could still produce verbally the exact result of the very same problems. For instance, when presented visually with the subtraction problem 8 - 6, the patient read the problem aloud as "five minus four", but nevertheless produced the correct result "two." Such capacities for "calculating without reading" were observed in subtraction, addition, and division tasks, but not in multiplication tasks. We discuss how both the existence of residual abilities and the pattern of dissociations between operation types can be explained by current theories of the cerebral substrates of number processing (Dehaene & Cohen, 1995). PMID- 20945196 TI - Focal retrograde amnesia and the attribution of causality: An exceptionally critical view. AB - A detailed critique of the literature on focal retrograde amnesia is provided. Some of the cases commonly cited in this literature had, in fact, severely impaired anterograde memory, most often involving visuospatial material. Other cases showed poor anterograde memory in more moderate or subtle form, begging the question of whether "like" had really been compared with "like" across the retrograde and anterograde domains: there may be alternative explanations for the observed patterns of performance. One suggestion is that these patients suffer an impairment of long-term consolidation, an attractive hypothesis but one which requires much more rigorous testing than has occurred to date and which implies that the underlying problem is not specific to retrograde memory. Moreover, within the literature on cases of focal retrograde amnesia, differing patterns of performance on tests of autobiographical memory or remote semantic knowledge have been reported, and sometimes these may have reflected factors other than the sites of lesions. Many of the most convincing cases in this literature have been those in whom there was an initially severe anterograde amnesia as well as an extensive retrograde loss: in these cases, the critical issue is what determines differential patterns of recovery across these domains-it is likely that both physiological and psychological factors are important. A second, somewhat different, group are patients with semantic dementia, who show a pronounced recency effect in remote memory but, in these cases, the most parsimonious explanation may be in terms of predominantly semantic/linguistic and/or strategic factors. A third group are those with transient epileptic amnesia but, in these cases, the memory gaps may reflect past (anterograde) ictal activity. A fourth group are those in whom psychogenic factors may well be relevant. Although it is difficult to "prove" psychological causation, the logical difficulties in attributing causation where brain lesions are either very subtle or multiple have been considerably underestimated in the neuropsychological literature. Given these problems, in uncertain or equivocal cases, it is as critical to present the relevant psychological data for the reader to evaluate as it is to provide the pertinent memory test scores: this is underemphasised in many of the studies reviewed. Publication of cases in the absence of such data may lead to faulty clinical, neuropsychological, and cognitive conclusions. Abbreviations : AA: anterograde amnesia; AMI: Autobiographical Memory Interview; PTA: posttraumatic amnesia; RA: retrograde amnesia; RMT: Recognition Memory Test; TEA: transient epileptic amnesia; TGA: transient global amnesia; WMS: Wechsler Memory Scale. PMID- 20945197 TI - Focal retrograde amnesia and the attribution of causality: An exceptionally benign commentary. AB - Kopelman offers an invaluable and comprehensive review of empirical and theoretical issues relating to focal retrograde amnesia and related conditions. He makes two main points: (1) That many of the published cases of focal retrograde amnesia in fact showed significant anterograde memory impairment, and thus should strictly not be classified as cases of focal retrograde amnesia; (2) that there are hazards in attributing causality in patients with retrograde amnesia, especially those with a major autobiographical component. In the case of his first point, I suggest that his observations are a matter of interpretation, essentially revolving around the defining criteria for the selection of memories to be compared and for regarding one set of memories as "disproportionately impaired" compared to the other. With regard to the second point, however, I largely concur with his observations, adding some reservations of my own. I conclude that although some patients with focal retrograde amnesia may represent a diagnostic dilemma when it comes to attributing causality, those who are shown to have a clear neural basis to their memory loss provide an avenue for exploring the brain's plasticity in accommodating the formation of new memories despite the loss of equivalent old memories. PMID- 20945198 TI - Comments on focal retrograde amnesia and the attribution of causality: An exceptionally benign commentary by Narinder Kapur. PMID- 20945199 TI - Consonant-vowel encoding and orthosyllables in a case of acquired dysgraphia. AB - An acquired dysgraphic patient - BA - is described who produces a large proportion of nonword responses. It is shown that single letter substitutions tend to preserve consonant-vowel status and that the majority of errors are orthographically legal. It is shown that these constraints do not arise from an application of phoneme-to-grapheme conversion procedures, since these skills are severely impaired in BA. They also do not arise from frequency-sensitive bigram/trigram units since her responses do not contain bigrams/trigrams that are higher in frequency than the target. It is suggested that BA's results support the notion of consonant-vowel encoding and syllable-like units in orthography. They do not, however, support the notion that orthographic syllables can be ranked according to complexity since no effects of syllabic complexity were found. This latter finding is consistent with previous results reported in English-speaking dysgraphic patients. PMID- 20945200 TI - Grammatical class in lexical production and morhpological processing: Evidence from a case of fluent aphasia. AB - We present the case of a fluent aphasic patient who is impaired at producing nouns relative to verbs in picture naming, sentence completion, and sentence generation tasks, but is better at both producing and comprehending concrete nouns than abstract nouns. Moreover, he displays a selective difficulty in producing the plural forms of some nouns and pseudowords presented as nouns, but was able to produce the phonologically identical third-person singular forms of corresponding verb homonyms and of the same pseudowords presented as verbs. This pattern of performance casts doubt on the hypothesis that grammatical class effects are always epiphenomena of more general semantic impairments that affect the naming of actions or of concrete objects, and suggests that these effects may arise instead from damage to syntactic processes pertaining specifically to the grammatical properties of words. We also discuss the implications of such damage for models of morphological processing. PMID- 20945201 TI - The "living things" impairment and the nature of semantic memory organisation: An experimental study using PI-release and semantic cues. AB - The present paper evaluated categorical and featural proposals of memory organisation, for explaining the living/nonliving things dissociation observed in semantic memory. The experimental study used the Release from Proactive Interference (PI-release) paradigm. Normal subjects were tested with this task using word vs. picture stimuli in a standard taxonomical PI-release condition (i.e., nonliving to living things) and in a cue condition with attributes that run opposite to the taxonomical shift. Experiments 1 and 2 cued functional attributes (means of transportation; dangerousness), and experiments 3 and 4 cued perceptual attributes (size; number of legs). The overall pattern of PI-release emphasizes the role of functional attributes and the role of structural processing to semantic processing. Implications for the different proposals presented, including possible alternative accounts of the results, are also discussed. PMID- 20945202 TI - Sparing of country and nationality names in a case of modality-specific oral output impairment: Implications for theories of speech production. AB - This paper describes a patient (BF) with Pick's disease who presented with a modality-specific category preservation. In the oral output modality (oral naming and reading aloud) she presented with a selective sparing of country and nationality names in the context of severe impairment affecting a wide variety of common and proper nouns. In the written output modality (written naming and writing to dictation) her deficits were restricted only to proper nouns (except country names). Her written production of common nouns is virtually intact. Semantic errors were present only in the oral output modality. It is argued that this evidence is seriously problematic for the dual-stage models of lexical production and for the hypothesis of obligatory phonological mediation. It is concluded that: (1) access to words' modality-specific lexical information need not to be mediated by the selection of a modality-neutral level of lexical representation (lemma); (2) orthographical lexical forms can indeed be independently accessed for production without the mediating role of phonology. The possible distinct neuronal structures underpinning country and nationality names categories are discussed. PMID- 20945203 TI - The computation of occluded contours in visual agnosia: Evidence for early computation prior to shape binding and figure-ground coding. AB - We examined whether an agnosic patient with a deficit in early visual processing, HJA, completed occluded contours. We used matching tasks with stimuli composed of three superimposed or occluded shapes. Experiments 2 and 6 required superimposed or occluded shapes to be discriminated from distractors in which the position of one shape was changed. HJA was selectively impaired with occluded relative to superimposed shapes. His performance was affected by the spatial separation of the occluded contours rather than the area of the occluded surface. Experiments 3 and 5 required HJA to discriminate the central shape. Making occluded contours easier to compute (by reducing their spatial separation) facilitated discrimination of a central occluded shape (in the background), although it impaired discrimination of a central occluding shape (in the foreground). Free choice shape judgements made to the central shape (Experiment 2) showed that HJA used both real and completed contours to segment foreground shapes inappropriately. When asked to copy overlapping shapes (Experiment 4), HJA drew in the occluded parts as if real contours were present, at least on some occasions. These drawings and a task requiring discrimination between real and occluded contours (Experiment 7), showed a tendency to continue contours inappropriately, an insensitiviy to junctions, and impaired integration of contours into more global shapes. The results suggest that occluded contours can be computed early on in visual processing, probably at the level where long-range mechanisms group collinear contour segments together. Our control experiment shows that HJA is not impaired in collinear contour grouping. These mechanisms are prior to processes in which contours are bound to shapes and in which foregroundbackground relationships between shapes are resolved. In visual agnosia, occluded contours can be computed even when there is impairment of both binding of contours to shapes and the computation of foreground-background relations in overlapping shapes. PMID- 20945204 TI - Discourse processing in women with fragile x syndrome: evidence for a deficit establishing coherence. AB - The language phenotype in individuals with fragile X syndrome (FXS) and its relation to the molecular genetics of the disorder was investigated. Previous research has focused on describing deviance in conversational speech, and has not yet examined component discourse skills. The ability of women with FXS to use coherence to select endings to humorous and straightforward passages was evaluated, and the relation of this with neuropsychological measures of working memory, executive functions, and molecular measures of the syndrome were also evaluated. Three groups of nonretarded women were examined: (a) 14 women with FXS who carry the full mutation; (b) 25 women who carry the premutation; and (c) 16 women without the fragile X mutation. The results indicated that subjects with the full mutation showed a dramatic deficit in selecting appropriate endings to jokes relative to stories, even though the jokes were identical to the stories except for their endings. The coherence deficit found in the jokes task for women with the full mutation was found to correlate strongly with the X activation ratio, and to a neuropsychological measure of working memory. The full mutation subjects' coherence deficit is discussed in terms of the additional demand to hold information in memory and shift set. PMID- 20945205 TI - Backward pattern masking of familiar and unfamiliar materials in disabled and normal readers. AB - A discrimination task involving backward pattern masking was designed to investigate differences between disabled and normal readers in text perception. Masking was observed for both groups with unfamiliar Japanese materials, but disabled readers were less sensitive in discriminating than were normal readers. The same result was obtained with Roman letters, despite the high familiarity of materials to both groups, and with nonwords and words. A significant interaction between group and stimulus onset asynchrony, indicating that disabled readers recovered from masking at a slower rate than normal readers, was found only with nonwords. Visual factors alone could not have mediated group differences. A subgroup of disabled readers, formed on the basis of susceptiblity to masking, showed evidence of a deficit in rate of visual processing. The results are likely due to differences in the quality of representations of visual information used in discrimination and in word recognition. PMID- 20945206 TI - A case of prevailing deficit of nonliving categories or a case of prevailing sparing of living categories? AB - We describe a new case of semantic deficit in which nonliving categories are disproportionately impaired. PL, a woman affected by progressive degeneration of the left temporal lobe, was examined twice, at a distance of 1 year. The deficit was first apparent on naming and on a verbal semantic questionnaire, but a year later nonliving categories were disproportionately affected also on verbal comprehension (word/picture matching task). Body parts and musical instruments were also investigated: the former was the best preserved category, whereas the latter was the most severely affected. Considering all categories, functional and perceptual information was not differently affected, but there was a trend toward a worse score for nonliving category functional questions. Discussing the current hypotheses on the genesis of category dissociations, we conclude that nonliving categories might not be a true domain, and that their impairment could simply derive from the relative sparing of the domains of the living categories, for which separate cognitive and anatomical representations can be better postulated. Finally, we discuss the problems raised by published cases in an attempt to find a consistent anatomical substrate for category dissociations. PMID- 20945207 TI - Are there orthographic impairments in phonological dyslexia? AB - Two hypotheses have been advanced concerning the basis of acquired phonological dyslexia. According to the dual-route model, the pattern derives from impaired grapheme-phoneme conversion. According to the phonological impairment hypothesis, it derives from impaired representation and use of phonology. Effects of graphemic complexity and visual similarity observed in studies by Howard and Best (1996), orthographic effects on phoneme counting (Berndt, Haendiges, Mitchum, & Wayland, 1996), and data from patient LB (Derouesne & Beauvois, 1985) have been taken as evidence for an orthographic impairment in phonological dyslexia and therefore against the impaired phonology hypothesis (Coltheart, 1996). We present a computational simulation, results of two behavioral studies, and a critical analysis of the MJ and LB data, which suggest that the "orthographic" deficits in such patients arise from phonological impairments that interact with orthographic properties of stimuli. PMID- 20945208 TI - Memory for single items, word pairs, and temporal order of different kinds in a patient with selective hippocampal lesions. AB - One kind of between-list and two kinds of within-list temporal order memory were examined in a patient with selective bilateral hippocampal lesions. This damage disrupted memory for all three kinds of temporal order memory, but left item and word pair recognition relatively intact. These findings are inconsistent with claims that (1) hippocampal lesions, like those of the medial temporal lobe (MTL) cortex, disrupt item and word pair recognition, and that (2) hippocampal lesions disrupt temporal order memory and item recognition to the same degree. Not only was word pair recognition intact in the patient, but further evidence indicates that her recognition of other associations between items of the same kind is also spared so retrieval of such associations cannot be sufficient to support within list temporal order recognition. Rather, as other evidence indicates that the patient is impaired at recognition of associations between different kinds of information, within-list (and possibly between-list) temporal order memory may be impaired by hippocampal lesions because it critically depends on retrieving associations between different kinds of information. PMID- 20945209 TI - Prototypicality, distinctiveness, and intercorrelation: Analyses of the semantic attributes of living and nonliving concepts. AB - Many cognitive psychological, computational, and neuropsychological approaches to the organisation of semantic memory have incorporated the idea that concepts are, at least partly, represented in terms of their fine-grained features. We asked 20 normal volunteers to provide properties of 64 concrete items, drawn from living and nonliving categories, by completing simple sentence stems (e.g., an owl is __, has __, can__). At a later date, the same participants rated the same concepts for prototypicality and familiarity. The features generated were classified as to type of knowledge (sensory, functional, or encyclopaedic), and also quantified with regard to both dominance (the number of participants specifying that property for that concept) and distinctiveness (the proportion of exemplars within a conceptual category of which that feature was considered characteristic). The results demonstrate that rated prototypicality is related to both the familiarity of the concept and its distance from the average of the exemplars within the same category (the category centroid). The feature database was also used to replicate, resolve, and extend a variety of previous observations on the structure of semantic representations. Specifically, the results of our analyses (1) resolve two conflicting claims regarding the relative ratio of sensory to other kinds of attributes in living vs. nonliving concepts; (2) offer new information regarding the types of features-across different domains-that distinguish concepts from their category coordinates; and (3) corroborate some previous claims of higher intercorrelations between features of living things than those of artefacts. PMID- 20945210 TI - The real-object advantage in agnosia: Evidence for a role of surface and depth information in object recognition. AB - We examine the factors that lead to the identification advantage for real objects over line drawings in agnosia. In a single case study we show that identification is improved when shading cues can be used to guide the segmentation of objects into their parts. In addition we demonstrate that depth information, conveyed both by binocular disparity cues and by head movements, also facilitates object segmentation. The data indicate that information about depth and surface shading can contribute to object recognition in cases where edge-based object coding is impaired. PMID- 20945211 TI - Dissociable components of short-term memory and their relation to long-term learning. AB - Short-term memory (STM) includes dissociable phonological and semantic components (R.C. Martin, 1993). Previous findings indicate that phonological STM capacity supports learning of novel phonological forms, such as new vocabulary (e.g., Baddeley, Gathercole, & Papagno, 1998). It was hypothesised that semantic STM capacity would support the learning of novel semantic information. Five aphasic patients were tested who demonstrated deficits in the short-term retention of either phonological or semantic information. Four of the five patients demonstrated learning deficits in a paired associate paradigm that corresponded to their STM deficits. One patient with a severe deficit in phonological STM but a better-preserved ability to retain semantic information showed better learning of new semantic information than new phonological information. Three patients with a greater deficit in semantic than phonological STM showed the reverse. A fifth patient with a severe semantic STM deficit failed to show learning for either type of material. Results suggest that the semantic and phonological components of STM are essential for the long-term learning of corresponding representations in long-term memory. PMID- 20945212 TI - Shifting attention to different levels within global-local stimuli: A study of normal participants and a patient with temporal-parietal lobe damage. AB - Shifts of attention to different levels of global-local stimuli were examined in normal participants and a patient with right temporal-parietal lobe damage. Global-local stimuli were presented in sequential couplets and the target could either be at the same global-local level or the target could change levels within each couplet. Normal participants were faster to respond to the second stimulus when the target remained at the same level compared to when it changed levels. This level-shifting effect appeared to be independent of any perceptual- or identity/response-based priming, and did not appear to be due to the size of the stimuli per se. In contrast, the patient did not display any level-shifting effects when the target appeared at the global level, whereas he did display this effect when the target appeared at the local level. These results suggest that the right temporal-parietal lobe may be involved in activating attentional weights to the different levels of global-local stimuli. These results also indicate that intra-stimulus attentional shifts are mediated by different neurocognitive mechanisms than are spatial attentional shifts. PMID- 20945213 TI - Early concepts of tactile object recognition: An historical synopsis and appraisal of Josef Gerstmann's Reine taktile Agnosie (1918). PMID- 20945214 TI - Pure tactile agnosia. PMID- 20945215 TI - Calculating without reading? Comments on Cohen and Dehaene (2000). AB - Cohen and Dehaene (Cognitive Neuropsychology, 2000, Vol. 17, pp. 563-583) reported the case of a pure alexic patient who preserved some calculation abilities despite severely impaired Arabic numeral reading. They argued that these residual abilities and the general pattern of performance of the patient can be fully explained within their anatomo-functional triple-code model. Here, we show how the lack of specification of the assumed architecture, the failure to provide sufficiently detailed data, and the absence of adequate refutation of alternative accounts make this study unsuitable for constraining theories of numerical cognition. PMID- 20945216 TI - Occam's razor is not a Swiss-army knife: A reply to Pillon and Pesenti. PMID- 20945217 TI - Specialised structural descriptions for human body parts: Evidence from autotopagnosia. AB - Previous accounts of autotopagnosia (e.g., Ogden, 1985; Pick, 1908; Semenza, 1988) propose that the disorder is attributable to deficits in "mental images," visual body schema, or semantic representations. A recent account (Sirigu, Grafman, Bressler, & Sunderland, 1991b) posits deficits in visual structural descriptions of the human body and its parts, in the context of spared semantic and proprioceptivespatio-motor body representations, but provides no evidence bearing on the nature or format of the putatively damaged representation. We report data from a man with autotopagnosia consequent to lefthemisphere brain damage which bear directly on the nature of the representation impaired in the disorder. The subject, GL, is unable to localise body parts on himself or others, whether cued by verbal or visual input. In contrast, he uses body parts precisely in reaching and grasping tasks, correctly matches items of clothing to body parts, and localises the parts of animals and man-made objects without error. We also demonstrate that GL is unable to match pictured or real human body parts across shifts in orientation or changes in visual appearance, but can perform analogous matching tasks with animal body parts and man-made object parts. The data extend the account of Sirigu et al. (1991b) in suggesting that human body part localisation depends upon structural descriptions of human (but not animal) bodies that enable viewpoint-independent body part recognition and participate in the calculation of equivalence between the body parts of self and others across transformations in orientation. PMID- 20945218 TI - Allograph errors and impaired access to graphic motor codes in a case of unilateral agraphia of the dominant left hand. AB - This paper describes the case of a unilateral agraphic patient (GG) who makes letter substitutions only when writing letters and words with his dominant left hand. Accuracy is significantly greater when he is writing with his right hand and when he is asked to spell words orally. GG also makes case errors when writing letters, and will sometimes write words in mixed case. However, these allograph errors occur regardless of which hand he is using to write. In terms of cognitive models of peripheral dysgraphia (e.g., Ellis, 1988), it appears that he has an allograph level impairment that affects writing with both hands, and a separate problem in accessing graphic motor patterns that disrupts writing with the left hand only. In previous studies of left-handed patients with unilateral agraphia (Zesiger & Mayer, 1992; Zesiger, Pegna, & Rilliet, 1994), it has been suggested that allographic knowledge used for writing with both hands is stored exclusively in the left hemisphere, but that graphic motor patterns are represented separately in each hemisphere. The pattern of performance demonstrated by GG strongly supports such a conclusion. PMID- 20945219 TI - Evidence for scripts in semantic dementia: Implications for theories of semantic memory. AB - This paper presents evidence that the breakdown of semantic memory in semantic dementia reveals the influence of two properties of script theory (Schank, 1982; Schank & Abelson, 1977). First, the physical and personal context of specific scripts supports meaning for words, objects, and locations that are involved in the script. Second, meaning is updated or transformed by a dynamic memory system that learns continuously from personal experience. In severe cases, semantic dementia exposes the basic level of this learning system from which all knowledge normally develops. It will be argued that the evidence supports a theory of semantic memory that represents meaning in a continuum of levels of meaning from the most specific and context-bound to the most generalisable and context-free. This contrasts with current theories of semantic memory that represent meaning as a collection of abstracted properties entirely removed from the context of events and activities. PMID- 20945220 TI - The emergence of jargon in progressive fluent dysgraphia: The widening gap between target and response. AB - This paper presents a long-term follow-up study of a dysgraphic patient reported in an earlier paper (Graham, Patterson, & Hodges, 1997). FM developed "jargon dysgraphia": In writing to dictation, she fluently produced well-formed written output consisting of pronounceable neologisms which, over time, bore a progressively weaker resemblance to the target words (e.g., scribe -> SCRIPE, January 1992; -> SRIME, November, 1994; -> BRINCE, August, 1996; -> MEATH, November, 1997). Although this spelling disorder has been (rarely) reported in patients with stable brain lesions, this is the first time that it has been documented in the context of progressive disease, a situation that provided a unique opportunity to document its characteristics at different stages. Longitudinal results from a spelling-to-dictation task showed that FM was, for a time, able to activate at least partial orthographic information, even after her overall accuracy (assessed in terms of the number of words spelled completely correctly) had reached the floor. For example, her error responses were correlated in length with the targets, and contained a larger than chance number of letters that overlapped between target and response. Ultimately, FM's spelling responses had no detectable similarity with the targets, although they remained word-like in that they were pronounceable and contained few illegal letter combinations. PMID- 20945221 TI - Compensatory coding of body part location in autotopagnosia: Evidence for extrinsic egocentric coding. AB - We report a patient with autotopagnosia (JD) who was unable to code the position of body parts relative to each other and who failed to update the position of body parts after passive movements. JD's performance in Studies 1-4 suggest that her ability to code the dynamic location of body parts with respect to each other ("intrinsic egocentric" spatial coding) was impaired, and that she employed a compensatory strategy by means of which the location of body parts was computed with respect to objects in the environment ("extrinsic egocentric" spatial coding). Studies 5-8 suggest that JD's ability to update hand position information was impaired after passive relative to active movements of her arm. For example, she was impaired in reaching to a target after passive but not active movements of her hand. Taken together, these findings extend previously reported functions of extrinsic egocentric coding to the localisation of body parts and demonstrate a possible dissociation between body part localisation dependent upon proprioceptive and efference copy information. PMID- 20945222 TI - Deep dysphasia: Further evidence on the relationship between phonological short term memory and language processing impairments. AB - We report a cognitive investigation of a case of deep dysphasia appearing in the context of primary progressive aphasia. Over a period of 5 years, patient CO presented progressive difficulties in word finding and in oral comprehension, while nonverbal cognitive functions remained preserved. As in other deep dysphasic patients, CO's repetition performance showed marked imageability and lexicality effects, and semantic paraphasias. The same effects were observed in writing-to-dictation. Regularisation errors occurred in word reading. CO's short term memory span was less than two words. A cognitive analysis of language processing revealed difficulties in phoneme identification and rhyme judgement, in detecting grammatical class for orally presented words, and in oral and written naming. The interpretation of CO's deep dysphasic symptoms within interactive models of language processing confirmed the importance of a phonological short-term storage impairment as an explanatory factor of deep dysphasia. PMID- 20945223 TI - Dissociations among functional subsystems governing melody recognition after right-hemisphere damage. AB - This study describes an amateur musician, KB, who became amusic following a right hemisphere stroke. A series of assessments conducted post-stroke revealed that KB functioned in the normal range for most verbal skills. However, compared with controls matched in age and music training, KB showed severe loss of pitch and rhythmic processing abilities. His ability to recognise and identify familiar instrumental melodies was also lost. Despite these deficits, KB performed remarkably well when asked to recognise and identify familiar song melodies presented without accompanying lyrics. This dissociation between the ability to recognise/identify song vs. instrumental melodies was replicated across different sets of musical materials, including newly learned melodies. Analyses of the acoustical and musical features of song and instrumental melodies discounted an explanation of the dissociation based on these features alone. Rather, the results suggest a functional dissociation resulting from a focal brain lesion. We propose that, in the case of song melodies, there remains sufficient activation in KB's melody analysis system to coactivate an intact representation of both associative information and the lyrics in the speech lexicon, making recognition and identification possible. In the case of instrumental melodies, no such associative processes exist; thus recognition and identification do not occur. PMID- 20945224 TI - C rossmodal agnosia for familiar people as a consequence of right infero polar temporal atrophy. AB - A 60-year-old, right-handed woman, with no focal brain lesions, suffered from a progressive impairment in recognising people of personal relevance and public figures familiar to her in the premorbid period. The patient did not suffer from general cognitive deterioration. There was no ecological or clear psychometric evidence of visuoperceptual or visuospatial deficits. Her defective person recognition was not overcome by extra-facial (e.g., observing animated people in their usual surroundings) or extra-visual information (e.g., listening to the voice). Moreover, presenting the correct name in the presence of an unrecognised familiar person failed to prompt her familiarity judgement, or retrieval of the relevant biographical knowledge. The patient also had some recognition difficulties with famous buildings and songs as well as with some common objects. It is argued that the patient's difficulty in identifying familiar people was the consequence of progressive loss of stored exemplars of familiar persons and perhaps also of some other "unique items" (famous songs and monuments) in an independent subsystem of semantics that we term "exemplar semantics." We discuss the associative (semantic) nature and specificity of the deficit in person knowledge, the possible top-down negative influences of the loss of exemplars in the person recognition system, and the link between the disorders and the right/left temporal lobe. PMID- 20945225 TI - Lexical recovery from extinction: Interactions between visual form and stored knowledge modulate visual selection. AB - The effects of lexical knowledge on extinction were examined in a patient with bilateral parietal lesions and left extinction under double simultaneous stimulation: GK. GK was bilaterally presented with two letters that could form either a word or a nonword. In Experiments 1-3, the task was to identify each letter. GK showed better identification of left-side letters in words than in nonwords, whilst the identification of left-side letters in nonwords was worse than that of single letters presented in the same spatial positions (i.e., there was a word superiority effect under conditions in which extinction occurred). This lexical effect on completely correct responses tended to be larger for words with lower-case letters (Experiments 2 and 3) than for words with upper-case letters (Experiment 1). Different results arose when detection was measured. When letters could group by proximity and common contrast polarity, no word superiority effect was apparent. However, a word superiority effect re-emerged when low-level grouping was reduced by using letters with opposite contrast polarity (one white and one black on a grey background). The results are discussed in terms of the impact of different factors on selection in detection and identification tasks, and in terms of the modulatory roles of familiar form and stored knowledge on visual selection. PMID- 20945226 TI - Neuropsychological evidence for a topographical learning mechanism in parahippocampal cortex. AB - The Parahippocampal Place Area (PPA; Epstein & Kanwisher, 1998) is a region within posterior parahippocampal cortex that responds selectively to visual stimuli that convey information about the layout of local space. Here we describe two patients who suffered damage to the PPA after vascular incidents. Both subsequently exhibited memory problems for topographical materials and were unable to navigate unassisted in unfamiliar environments. Performance on a continuous n-back visual memory test was significantly lower for novel scene-like stimuli than for novel object-like stimuli. In contrast, performance was normal on a famous landmark recognition task and on two perceptual tasks that required on-line analysis of scene geometry. Both patients were able to produce accurate maps of premorbidly learned places but were unable to produce accurate maps of new places. These results converge with previous neuroimaging work to demonstrate that the PPA (1) is selectively involved in processing information about the geometry of surrounding space, and (2) may play a more critical role in the encoding of this information into memory than in the initial perceptual processing, recognition, or recall of this information. PMID- 20945227 TI - Visual crowding and category specific deficits for pictorial stimuli: A neural network model. AB - This paper describes a series of modular neural network simulations of visual object processing. In a departure from much previous work in this domain, the model described here comprises both supervised and unsupervised modules and processes real pictorial representations of items from different object categories. The unsupervised module carries out bottom-up encoding of visual stimuli, thereby developing a "perceptual" representation of each presented picture. The supervised component then classifies each perceptual representation according to a target semantic category. Model performance was assessed (1) during learning, (2) under generalisation to novel instances, and (3) after lesion damage at different stages of processing. Strong category effects were observed throughout the different experiments, with living things and musical instruments eliciting greater recognition failures relative to other categories. This pattern derives from within-category similarity effects at the level of perceptual representation and our data support the view that visual crowding can be a potentially important factor in the emergence of some category-specific impairments. The data also accord with the cascade model of object recognition, since increased competition between perceptual representations resulted in category-specific impairments even when the locus of damage was within the semantic component of the model. Some strengths and limitations of this modelling approach are discussed and the results are evaluated against some other accounts of category-specific recognition failure. PMID- 20945228 TI - A peripheral reading deficit under conditions of diffuse visual attention. AB - We report a single case study of a patient, FL, who has a peripheral dyslexia with symptoms resembling attentional dyslexia. FL demonstrated impaired identification of letters within strings, and better identification of words than their constituent letters. We found that FL was impaired at both letter counting and same-case letter matching with letter strings, and his matching and naming performance were strongly affected by letter spacing. The effects of these visual variables on performance suggest an early locus to FL's deficit. We propose that letter identification was disrupted by abnormal lateral masking and poor location coding within words. These peripheral processing deficits were reduced when the task required focused attention on the central letter location. Nevertheless, even with impaired letter coding, word representations could be accessed to some degree, via supra-letter units. We discuss the implications of the data for understanding normal reading. PMID- 20945229 TI - Neglect dyslexia with a stimulus-centred deficit and without visuospatial neglect. AB - This paper reports a single case of ipsilesional left neglect dyslexia and interprets it according to the three-level model of visual word recognition proposed by Caramazza and Hillis (1990). The three levels reflect a progression from the physical stimulus to an abstract representation of a word. RR was not impaired at the first, retinocentric, level, which represents the individual features of letters within a word according to the location of the word in the visual field: She made the same number of errors to words presented in her left visual field as in her right visual field. A deficit at this level should also mean the patient neglects all stimuli. This did not occur with RR: She did not neglect when naming the items in rows of objects and rows of geometric symbols. In addition, although she displayed significant neglect dyslexia when making visual matching judgements on pairs of words and nonwords, she did not do so to pairs of nonsense letter shapes, shapes which display the same level of visual complexity as letters in words. RR was not impaired at the third, graphemic, level, which represents the ordinal positions of letters within a word: She continued to neglect the leftmost (spatial) letter of words presented in mirror reversed orientation and she did not neglect in oral spelling. By elimination, these results suggest RR's deficit affects a spatial reference frame where the representational space is bounded by the stimulus: A stimulus-centred level of representation. We define five characteristics of a stimulus-centred deficit, as manifest in RR. First, it is not the case that neglect dyslexia occurs because the remaining letters in a string attract or capture attention away from the leftmost letter(s). Second, the deficit is continuous across the letter string. Third, perceptually significant features, such as spaces, define potential words. Fourth, the whole, rather than part, of a letter is neglected. Fifth, category information is preserved. It is concluded that the Caramazza-Hillis model accounts well for RR's data, although we conclude that neglect dyslexia can be present when a more general visuospatial neglect is absent. PMID- 20945230 TI - A form of ideational apraxia as a delective deficit of contention scheduling. AB - In this paper we studied three brain-damaged patients: the first two, DR and FG, had limb apraxia whilst the third was a control patient (WH2) with an executive function disorder but without limb apraxia. DR and FG were impaired in carrying out everyday actions, whilst they maintained the ability to sequence photographs representing those same activities. The failure in the action production task was not caused by visual agnosia for objects, as the patients could recognise them from sight. Nor was it produced by a loss of knowledge about their functions (De Renzi & Lucchelli, 1988), as DR and FG could identify objects from descriptions of their use. WH2's pattern of performance doubly dissociated from that of the apraxic patients, namely spared action production on the multiple object test, but faulty sequencing of photographs. WH2's difficulties in sequencing photographs were not due to a failure to understand the task, as she could sequence stimuli other than actions (e.g., shapes and numbers). Nor were the differences due to a loss of knowledge about the actions, since she could perform and identify them from photographs. These results show that the kind of apraxia observed in DR and FG is not produced by a degraded action sequence representation (Lehmkuhl & Poeck, 1981; Poeck & Lehmkuhl, 1980). We interpreted our results within a contention scheduling model (Cooper & Shallice, 2000; Norman & Shallice, 1986). PMID- 20945231 TI - Influence of Competing Distractors on Response Selection in Huntington's Disease and Parkinson's Disease. AB - Current theories of the basal ganglia suggest a functional role in filtering stimuli that are competing for response selection. We hypothesised that damage to the basal ganglia, as occurs in Huntington's disease (HD) and Parkinson's disease (PD), may alter the effects of distractors on this filtering process. Fourteen HD subjects, 16 PD subjects, and age-matched healthy controls performed an ignored repetition test of negative priming. Negative priming was defined as a significant time cost in responding to a target that shared features with the distractor from the previous trial. Results indicated that whereas healthy controls and PD subjects showed normal negative priming, HD subjects failed to show negative priming. The results indicate that disruption to cells in the neostriatum, but not necessarily to cells in the substantia nigra, may affect selective attention by altering the influence of distractor stimuli competing for action. PMID- 20945232 TI - A neural basis for the retrieval of words for actions. AB - Although much has been learned in recent years about the neural basis for retrieving words denoting concrete entities, the neural basis for retrieving words denoting actions remains poorly understood. We addressed this issue by testing two specific anatomical hypotheses. (1) Naming of actions depends not only on the classical implementation structures of the left frontal operculum, but also on mediational structures located in left premotor/prefrontal areas. (2) The neural systems subserving naming of actions and naming of concrete entities are segregated. The study used the lesion method and involved 75 subjects with focal, stable lesions in the left or right hemispheres, whose magnetic resonance data were analysed with a three-dimensional reconstruction method. The experimental tasks were standardised procedures for measuring action and object naming. The findings offered partial support for the hypotheses, in that: (1) lesions related to impaired action naming overlapped maximally in the left frontal operculum and in the underlying white matter and anterior insula; and (2) lesions of the left anterior temporal and inferotemporal regions, which produce impairments in naming of concrete entities, did not cause action naming deficits. A follow-up analysis indicated that action naming impairments, especially when they were disproportionate relative to concrete entity naming impairments, were not only associated with premotor/prefrontal lesions, but also with lesions of the left mesial occipital cortex and of the paraventricular white matter underneath the supramarginal and posterior temporal regions. PMID- 20945233 TI - Letter position dyslexia. AB - Many word-reading models assume that the early stages of reading involve a separate process of letter position encoding. However, neuropsychological evidence for the existence and selectivity of this function has been rather indirect, coming mainly from position preservation in migrations between words in attentional dyslexia, and from nonselective reading deficits. No pure demonstration of selective impairment of letter position function has yet been made. In this paper two Hebrew-speaking acquired dyslexic patients with occipito parietal lesions are presented who suffer from a highly selective deficit to letter position encoding. As a result of this deficit, they predominantly make errors of letter migration within words (such as reading "broad" for "board") in a wide variety of tasks: oral reading, lexical decision, same-different decision, and letter location. The deficit is specific to orthographic material, and is manifested mainly in medial letter positions. The implications of the findings to models of reading and attention are discussed. PMID- 20945234 TI - Phonological activation in pure alexia. AB - Pure alexia is a reading impairment in which patients appear to read letter-by letter. This disorder is typically accounted for in terms of a peripheral deficit that occurs early on in the reading system, prior to the activation of orthographic word representations. The peripheral interpretation of pure alexia has recently been challenged by the phonological deficit hypothesis, which claims that a postlexical disconnection between orthographic and phonological information contributes to or is responsible for the disorder. Because this hypothesis was mainly supported by data from a single patient (IH), who also has surface dyslexia, the present study re-examined this hypothesis with another pure alexic patient (EL). In contrast to patient IH, EL did not show any evidence of a phonological deficit. Her pattern of performance in naming was not qualitatively different from that of normal readers; she appeared to be reading via a mode of processing resulting in strong serial and lexical effects, a pattern often observed in normal individuals reading unfamiliar stimuli. The present results do not obviously support the phonological hypothesis and are more consistent with peripheral interpretations of pure alexia. The peripheral and the phonological accounts of pure alexia are discussed in light of two current models of visual word recognition. PMID- 20945235 TI - A case study of acquired dyslexia and dysgraphia in cantonese: evidence for nonsemantic pathways for reading and writing chinese. AB - We report a Cantonese-speaking brain-damaged patient, CML, who demonstrates better oral reading than oral naming and better writing to dictation than written naming. Such dissociations are taken as evidence for nonsemantic routes for the production of spoken and written Chinese words. The occurrence of tonal errors in CML's reading aloud informs us about the structure of phonological representations. We propose that it is a nonlinear structure, similar to that which has been proposed in tonal phonology of Chinese. Specific impairment to these representations may lead to a dissociation between segmental and suprasegmental information. Finally, the similarity of CML's neologistic responses in oral and written naming, and her production of tonal errors in writing to dictation and written naming, favour the mediated version of the nonsemantic pathway for writing more than the unmediated pathway. PMID- 20945236 TI - Implementing dementia care models in primary care settings: The Aging Brain Care Medical Home. AB - OBJECTIVES: The purpose of this article is to describe our experience in implementing a primary care-based dementia and depression care program focused on providing collaborative care for dementia and late-life depression. METHODS: Capitalizing on the substantial interest in the US on the patient-centered medical home concept, the Aging Brain Care Medical Home targets older adults with dementia and/or late-life depression in the primary care setting. We describe a structured set of activities that laid the foundation for a new partnership with the primary care practice and the lessons learned in implementing this new care model. We also provide a description of the core components of this innovative memory care program. RESULTS: Findings from three recent randomized clinical trials provided the rationale and basic components for implementing the new memory care program. We used the reflective adaptive process as a relationship building framework that recognizes primary care practices as complex adaptive systems. This framework allows for local adaptation of the protocols and procedures developed in the clinical trials. Tailored care for individual patients is facilitated through a care manager working in collaboration with a primary care physician and supported by specialists in a memory care clinic as well as by information technology resources. CONCLUSIONS: We have successfully overcome many system-level barriers in implementing a collaborative care program for dementia and depression in primary care. Spontaneous adoption of new models of care is unlikely without specific attention to the complexities and resource constraints of health care systems. PMID- 20945237 TI - Priming effects from young-old to very old age on a word-stem completion task: minimizing explicit contamination. AB - We investigated the size of repetition priming effects from young-old to very old age using a newly developed Word-Stem Completion (WSC) task. Retrospectively, we examined the role of explicit, intentional retrieval strategies in priming. We constructed our task by taking factors into account that were known to complicate the measurement of significant and valid priming effects. Within our sample of 170 cognitively healthy elderly persons of 55-94 years old, we found no effects on priming of age, gender, education, intelligence, cognitive status, memory complaints, or depressive symptoms. Participants that subsequent to task administration reported awareness of the study-test relationship obtained higher priming scores. However, analysis of stem-completion times showed that explicit contamination during the task was unlikely. The results suggest that WSC priming is age-invariant up to very old age. This task with increased validity might contribute to the differentiation with Alzheimer's disease by improving specificity of assessment. PMID- 20945238 TI - War exposure and post-traumatic stress as predictors of Portuguese colonial war veterans' physical health. AB - The relationship between war exposure and post-traumatic stress disorder (PTSD) has been largely investigated but the impact of the combat experience on physical health has only recently merited attention. The authors investigated the relationship between war exposure and psychological and physical health among 350 Portuguese colonial war veterans. The role of current PTSD symptoms as a mediator of these relationships was also investigated. The results showed that 39% of the veterans met criteria for current PTSD diagnosis and psychological distress was present in half of the sample. Pain, fatigue, and sleep problems were the most reported physical symptoms and mental health and gastro-intestinal problems, the most reported illnesses. Combat exposure variables were significant predictors of current health. The results indicated that veterans with higher exposure to war trauma maintained higher current levels of psychological distress and presented more physical health problems and physical symptoms than those less exposed. Mediation analyses showed that current PTSD was a full mediator of the relationship between war exposure and physical health outcomes. PMID- 20945239 TI - Superior estimation abilities in two autistic spectrum children. AB - Anecdotal reports of superior estimation abilities in autistic individuals (e.g., Sacks, 1985) have never been confirmed empirically. We present here case studies of 2 children with autistic spectrum diagnoses and report remarkable abilities in estimation for several quantifiable dimensions. K.T. and G.T. were tested at 9 years of age for estimation of rank, numerosity, time, weight, length, surface, distance, and precise enumeration for small numbers. Their performances were compared to those of 6 age- and IQ- matched comparison children. K.T. demonstrated a superior level of performance in estimating rank (e.g., which set has larger numerosity?) but his performance in other tasks was average. G.T. displayed outstanding performance in estimating numerosity, time, weight, surface, length, and distance, with average performance in other tasks. These results show that certain autistic spectrum individuals may develop superior and highly specialized abilities in estimation. We discuss these findings in relation to the role of "veridical mapping" in the development of special ability (Mottron, Dawson, & Soulieres, 2009; Mottron, Dawson, Soulieres, Hubert, & Burack, 2006a). Veridical mapping is the detection of isomorphism within a code, between two codes, or between one code and isomorphic elements of the world. Within this framework, it is proposed that estimation abilities, like absolute pitch, rely on the ability to map a verbal code with a specific magnitude of a psychophysical dimension. PMID- 20945240 TI - Effects of individual characteristics and school environment on cigarette smoking among students ages 13-15: A multilevel analysis of the 2007 Global Youth Tobacco Survey (GYTS) data from Vietnam. AB - This paper aims to estimate the prevalence of cigarette smoking among students in Vietnam ages 13-15 and examines its relationship with compositional and contextual factors. The data used in this paper were obtained from the 2007 Global Youth Tobacco Survey conducted in nine provinces in Vietnam. A multilevel logistic regression model was applied to analyse the association between the current incidence of cigarette smoking and factors on both the individual and school level. The prevalence of cigarette smoking among students was 3.3% overall. The prevalence of smoking among male students (5.9%) was higher than that among females (1.2%). Parental smoking was a significant risk factor for smoking among the students. Having a friend who smoked was the strongest predictor of smoking status among the study subjects. We have demonstrated that school-level factors appeared to impact the prevalence of cigarette smoking among students ages 13-15. This paper highlights the importance of utilising an extensive range of actions to prevent students from using tobacco in Vietnam. These actions should include providing specific curricula for students that address both individual characteristics and the school environment. Further, prevention programmes should also target both parental- and peer-smoking issues. PMID- 20945241 TI - Influence of coexisting contaminants on the sorption of 17beta-estradiol by marine sediments. AB - The adsorption behavior of 17beta-estradiol (E2) on marine sediments treated by different methods was investigated in the presence of bisphenol A (BPA), dibutyl phthalate (DBP), cationic surfactant cetyltrimethylammonium bromide (CTAB), nonionic surfactant polyoxyethylene (80) sorbitan esters (Tween 80) and anionic surfactant sodium dodecylbenzene sulfonate (SDBS). Four sets of experiments were conducted to determine the adsorption isotherms of E2 with coexisting contaminants, to explore the effects of concentrations and types of coexisting contaminants on the E2 adsorption capacity, and to examine the influence of pH on E2 adsorption on the sediments. The adsorption behavior of E2 to marine sediments without the addition of surfactant mainly related to organic carbon content of sediments and fitted well with the Freundlich model. The presence of CTAB or Tween 80 enhanced the adsorption capacity of E2 of marine sediments. In contrast, the presence of BPA, DBP and SDBS inhibited the adsorption capacity of E2. The pH value of the solution could influence the adsorption behavior of E2 of the marine sediments. A decline in pH values was beneficial to the adsorption of E2 with the addition of surfactants. PMID- 20945242 TI - Nitrogen removal of anammox cultures under different enrichment conditions. AB - Anammox bacteria in sludge from an anoxic tank of a municipal wastewater treatment plant at Nongkhaem, Bangkok, Thailand were enriched in two sequencing batch reactors (SBRs; SBR-1 and SBR-2), under different conditions. SBR-1 was open to the atmosphere, while SBR-2 was closed and flushed with a mixture of 95% argon and 5% CO(2) during the fill period in order to provide strict anaerobic conditions. The specific nitrogen removal rates of SBR-1 and SBR-2 were 0.43 g N/g VSS-d and 2.59 g N/g VSS-d, respectively. Denaturing gradient gel electrophoresis (DGGE) analyses showed differences in band patterns among the Nongkhaem sludge and the two enrichment cultures. Based on fluorescent in situ hybridization (FISH), the anammox bacteria in both systems were either "Candidatus Brocadia anammoxidans" or "Candidatus Kuenenia stuttgartiensis". The results from this study demonstrate the potential of alternative anammox systems for nitrogen removal and provide information on the microbial communities of anammox cultures under different enrichment conditions. PMID- 20945243 TI - Where's the dust? Characterizing locations of azinphos-methyl residues in house and vehicle dust among farmworkers with young children. AB - Organophosphate pesticides are commonly used in the United States, and farmworkers are at risk for chronic exposure. Using data from a community randomized trial to interrupt the take-home pathway of pesticide exposure, we examined the association between floor surface type (smooth floor, thin carpet, and thick carpet) and rooms in which dust samples were collected (living room vs. non-living room) and concentrations of azinphos-methyl residues in home environments. We also examined the association between vehicle type (truck, auto, or other) and footwell floor surfaces (carpeted, smooth surface, or no mat) and concentrations of azinphos-methyl in vehicle dust samples. Dust samples were collected from 203 and 179 households and vehicles, respectively. All households had at least one child aged 2-6. Vehicle dust samples were collected from footwells of the vehicle used for commuting to and from work. A total of 183 samples were collected from living rooms, and 20 were collected from other rooms in the home. Forty-two samples were collected from thick carpets, 130 from thin carpets, and 27 from smooth floor surfaces. Thick and thin carpets had a significantly greater dust mass than smooth floor surfaces (6.0 g/m(2) for thick carpets, 7.8 g/m(2) for thin carpets, and 1.5 g/m(2) for smooth surfaces). Of the 179 vehicle samples, 113 were from cars, 34 from trucks, and 32 from other vehicles. Vehicles with no mats had a significantly higher mass of dust (21.3 g) than those with hard mats (9.3 g) but did not differ from vehicles with plush mats (12.0 g). Further research is needed to characterize the environment in which children may be exposed to pesticides. PMID- 20945244 TI - Community-based applications to enhance road safety. AB - Road safety plays an increasing role in communities throughout the entire world. According to estimates, road accidents will have moved from ninth to third in the worldwide ranking of burden of disease by 2020. This theme issue is dedicated to community-based applications that have the aim to enhance road safety. Although various interventions will be demonstrated, this issue provides by no means an exhaustive overview of community-based applications. The applications presented in this issue are predominantly meant to stimulate ideas and discussion on what can be done to enhance road safety. PMID- 20945245 TI - Fear patterns: a new approach to designing road safety advertisements. AB - This research studies fear patterns within fear appeal anti-speeding television commercials. A pattern of fear is the sequence of fear arousal and fear reduction, if any, that is felt by the viewing audience when exposed to a fear appeal advertisement. Many road safety advertisers use fear appeals, such as "shock" advertising, that result in fear arousal, leaving the viewer feeling extremely tense. The moment-to-moment reactions of young drivers to 12 road safety commercials are gauged using a dynamic, temporal measure of fear. The fear patterns generated from each ad are analyzed and a new perspective on creating fear appeal road safety advertisements, with an emphasis on fear-relief, fear partial relief, and fear-only patterns, is discussed. PMID- 20945246 TI - Observed seat belt use in Kumasi Metropolis, Ghana. AB - We conducted an observational survey of seat belt use to determine the use rate of drivers and front-right passengers of vehicles in Kumasi, Ghana. Unobtrusive observations of seat belt use were made at 41 locations composed of signalized intersections and roundabouts where vehicles come to a halt or slow down considerably. The overall driver seat belt use rate was 17.6% compared to 4.9% for front-right passengers. Driver belt use was 33.2% for private cars, 9.0% for taxis, 8.3% for minibus (trotro), 13.1% for large buses and 9.7% for trucks. Overall seat belt use was higher for female drivers than for male drivers (44.8% versus 16.4%, p < .001), was lowest within the Central Business District (CBD) compared to the outskirts of the city (16.3% versus 21.0%, p < .001) and seat belt use rate increased with age. Passengers belted more often if drivers were belted, but about three-quarters of male passengers and 70-80% of female passengers were unbelted even when drivers were belted. In conclusion, the seat belt use rate was generally low in Kumasi, Ghana, and it is a function of occupant seating position, gender, vehicle type and usage, age group, and location setting. The results provide important preliminary data about seat belt use, particularly among male drivers and commercial vehicle occupant population. The study also suggests the need to develop effective strategies and programs that address low seat belt use in Ghana. PMID- 20945247 TI - Investigating road safety issues and deaf people in the United kingdom: an empirical study and recommendations for good practice. AB - Very little research has been carried out in the United Kingdom or other countries on the views and experiences of deaf people on road safety and other aspects of travel. Historically, there has been little specific attention to either the issue of road safety for deaf people or more general travel issues affecting deaf people. Deaf-specific support, guidance, or advice on road safety from the police or other agencies has been sparse. This has led to a situation where support for deaf pedestrians, drivers, and other deaf road users has been developed on an ad-hoc basis, and available measures have not been uniformly adopted across the United Kingdom. Furthermore, although the United Kingdom police force has aimed to provide some support to deaf and hard of hearing people, this has mainly concentrated on communications support in the form of note-taking, interpreters, and video-based information. This article aims to fill the gap in knowledge of road safety issues for deaf and hard of hearing people by reporting empirical research carried out with deaf people in the United Kingdom and making recommendations to improve their road safety. PMID- 20945248 TI - Evaluation of a community-based intervention to enhance road safety. AB - A total of 300 motorists were recruited at public places to answer a self-report questionnaire on a new community-based intervention to enhance road safety. The intervention consisted of a speed-displaying device that was mounted next to the road and was visible to both motorists and the public. The device gives feedback about the current speed of the motorist. The majority of motorists believed these devices influenced compliance with the speed limit. They indicated they approached locations with these devices more slowly than similar locations without such devices. Moreover, they slowed down if they were going faster than the speed limit. They also said that their reaction to the devices was not influenced by whether they were driving in a community where they had friends or in a community where nobody knew them. These results were consistent across gender, age, levels of education, and professions. PMID- 20945249 TI - Road safety and deaf people: the role of the police. AB - The ability to travel safely and independently is very important for participation in many aspects of modern life and the police have an important role in maintaining safety on the roads. Although people with hearing impairments form a significant percentage of the population in the United Kingdom (estimated at 1 in 7 by the Royal National Institute of Deaf People), there has been little research on how the police ensure the road safety of deaf and hearing impaired people. This article discusses an investigation into existing police practice in providing support and training to police officers on interacting with deaf people in situations that could have an effect on road safety. It makes recommendations for improving existing practice. PMID- 20945250 TI - Motivating motorists to voluntarily slow down. AB - It is estimated that by 2020 road accidents will rise from ninth to third place in the worldwide ranking of the burden of disease. Traffic calming can reduce road accidents; however, many motorists do not adhere to speed limits. We report on an intervention that can influence many motorists at dangerous sites, where accidents are likely to occur (e.g., near playgrounds, schools). The intervention is a speed-displaying device mounted next to the road (visible to both motorists and the public). Our findings indicate that the device is associated with a significant speed reduction relative to the control condition. PMID- 20945251 TI - Altered movement patterns but not muscle recruitment in moderately trained triathletes during running after cycling. AB - Previous studies have shown that cycling can directly influence neuromuscular control during subsequent running in some highly trained triathletes, despite these triathletes' years of practice of the cycle-run transition. The aim of this study was to determine whether cycling has the same direct influence on neuromuscular control during running in moderately trained triathletes. Fifteen moderately trained triathletes participated. Kinematics of the pelvis and lower limbs and recruitment of 11 leg and thigh muscles were compared between a control run (no prior exercise) and a 30 min run that was preceded by a 15 min cycle (transition run). Muscle recruitment was different between control and transition runs in only one of 15 triathletes (<7%). Changes in joint position (mean difference of 3 degrees ) were evident in five triathletes, which persisted beyond 5 min of running in one triathlete. Our findings suggest that some moderately trained triathletes have difficulty reproducing their pre-cycling movement patterns for running initially after cycling, but cycling appears to have little influence on running muscle recruitment in moderately trained triathletes. PMID- 20945252 TI - Too impulsive for implementation intentions? Evidence that impulsivity moderates the effectiveness of an implementation intention intervention. AB - OBJECTIVE: The reported research explored whether impulsivity moderated the effectiveness of an implementation intention prompt to increase fruit and vegetable consumption. DESIGN: The study employed a prospective experimental design. At Time 1, participants completed a measure of impulsivity. At Time 2, participants in the experimental condition formed implementation intentions to increase their fruit and vegetable intake by two extra portions daily over the following 7 days. Participants in the control condition performed an equivalent neutral task. At Time 3, participants reported their fruit and vegetable consumption over the preceding 7 days. RESULTS: The impulsivity dimension urgency moderated the effectiveness of the implementation intention intervention. Implementation intention formation only prompted fruit and vegetable consumption amongst those with low levels of urgency. Implementation intention formation did not increase consumption amongst those high in urgency. CONCLUSION: The findings suggest that implementation intention interventions may fail to promote goal attainment for those high in impulsivity. PMID- 20945253 TI - Can the onset of type 2 diabetes be delayed by a group-based lifestyle intervention? A randomised control trial. AB - This study was a randomised control trial with a waiting control group. It was designed to evaluate the effectiveness of a 6-month, group-based diabetes prevention programme, The Healthy Living Course and assess whether participation in the programme led to changes in modifiable risk factors for type 2 diabetes among an already at-risk pre-diabetic population. Individuals designated at risk for diabetes by their general practitioners (GPs) were screened using an Oral Glucose Tolerance Test. Volunteers (N = 307) with pre-diabetes were assigned to an intervention or wait-control group in the ratio of approximately 2 : 1. The sample was pre-tested on biochemical, anthropometric and self-report behavioural, cognitive and mood variables and post-tested either at the end of the educational/support-based lifestyle programme or the end of the wait period. The intervention group significantly improved their diabetes knowledge, motivation to change, positive affect, healthy eating and activity levels and showed significantly greater reductions in weight, body mass index, waist circumference, diastolic blood pressure and fasting plasma glucose in comparison with controls. The intervention group also changed their diagnostic status from pre-diabetes to non-diabetes at a greater rate than the wait group (43% vs. 26%) who received standard care from their GPs. PMID- 20945254 TI - 'You can spend your life dying or you can spend your life living': identity transition in people who are HIV-positive. AB - This article examines, through the lenses of HIV-positive people, the unique phenomenon of identity transition. This research proposes that life-changing illnesses, such as HIV, are an undesired 'possession' that people accept to varying degrees, which we refer to as 'ownership'. While illnesses, such as HIV compel individuals to undergo a transformation process that usually begins with a deep feeling of detachment, and then proceeds to acceptance of their illness, and to feeling empowered and in control of their HIV status and lives, this process is very complex and non-linear as it involves many iterative progressions in identity transition. These transitions are highly individualistic; however, the underlying theme is that the more positive trajectories were those of people who focus on their new lives, living with HIV (i.e. taking ownership of their illness), rather than focusing on what they have lost when they became HIV positive. The findings demonstrate that identity transition is a result of the ways that individuals rework, negotiate and transform their roles, actions and behaviours through their active engagement with support mechanisms. This study suggests that it is vital to promote positive interactions with support mechanisms to ensure that those with HIV view themselves positively. PMID- 20945255 TI - The role of cognitive, emotional and personality factors in the experience of fatigue in a university and community sample. AB - The aim of this study was to investigate the contribution of cognitive, emotional and personality factors to the experience of fatigue severity in healthy adult individuals. Specifically, the study examined whether fatigue catastrophising and emotional distress mediated the relationships between neuroticism, general irrational and rational thoughts to fatigue severity. One hundred and eighty nine university students and community volunteers completed self-report questionnaires assessing fatigue catastrophising and symptom severity, neuroticism, general rational and irrational thoughts and emotional distress. A series of correlational and path analyses were conducted to test the study hypotheses. Neuroticism and more general negative, irrational cognitions were associated with elevated fatigue catastrophising and fatigue severity, whereas more adaptive, rational cognitions were related to lower fatigue catastrophising and fatigue severity. Both elevated fatigue catastrophising and emotional distress uniquely and simultaneously mediated the relationships between irrational and rational cognitions and neuroticism to fatigue severity. These findings demonstrate that cognitions play a role in fatigue severity. The results have implications in the assessment and treatment of fatigue disturbances in the general community. PMID- 20945257 TI - A journal of a journal: The founding editor's perspective on The American Journal of Bioethics. PMID- 20945256 TI - Dysfunctions in brain networks supporting empathy: an fMRI study in adults with autism spectrum disorders. AB - The present study aimed at identifying dysfunctions in brain networks that may underlie disturbed empathic behavior in autism spectrum disorders (ASD). During functional magnetic resonance imaging, subjects were asked to identify the emotional state observed in a facial stimulus (other-task) or to evaluate their own emotional response (self-task). Behaviorally, ASD subjects performed equally to the control group during the other-task, but showed less emotionally congruent responses in the self-task. Activations in brain regions related to theory of mind were observed in both groups. Activations of the medial prefrontal cortex (MPFC) were located in dorsal subregions in ASD subjects and in ventral areas in control subjects. During the self-task, ASD subjects activated an additional network of frontal and inferior temporal areas. Frontal areas previously associated with the human mirror system were activated in both tasks in control subjects, while ASD subjects recruited these areas during the self-task only. Activations in the ventral MPFC may provide the basis for one's "emotional bond" with other persons' emotions. Such atypical patterns of activation may underlie disturbed empathy in individuals with ASD. Subjects with ASD may use an atypical cognitive strategy to gain access to their own emotional state in response to other people's emotions. PMID- 20945258 TI - The history of the American Journal of Bioethics. PMID- 20945259 TI - The American Journal of Bioethics today. PMID- 20945260 TI - An open letter to institutional review boards considering Northfield Laboratories' PolyHeme(r) trial. AB - At the time of this writing, a widely publicized, waived-consent trial is underway. Sponsored by Northfield Laboratories, Inc. (Evanston, IL) the trial is intended to evaluate the emergency use of PolyHeme(r), an oxygen-carrying resuscitative fluid that might prevent deaths from uncontrolled bleeding. The protocol allows patients in hemorrhagic shock to be randomized between PolyHeme(r) and saline in the field and, still without consent, randomized between PolyHeme(r) and blood after arrival at an emergency department. The Federal regulations that govern the waiver of consent restrict its applicability to circumstances where proven, satisfactory treatments are unavailable. Blood-the standard treatment for hemorrhagic shock-is not available in ambulances but is available in hospitals. The authors argue that the in-hospital stage of the study fails to meet ethical and regulatory standards. PMID- 20945261 TI - Americans should not be on a game show in U.S. emergency rooms and ambulances. PMID- 20945262 TI - All gifts large and small: toward an understanding of the ethics of pharmaceutical industry gift-giving. AB - Much attention has been focused in recent years on the ethical acceptability of physicians receiving gifts from drug companies. Professional guidelines recognize industry gifts as a conflict of interest and establish thresholds prohibiting the exchange of large gifts while expressly allowing for the exchange of small gifts such as pens, note pads, and coffee. Considerable evidence from the social sciences suggests that gifts of negligible value can influence the behavior of the recipient in ways the recipient does not always realize. Policies and guidelines that rely on arbitrary value limits for gift-giving or receipt should be reevaluated. PMID- 20945263 TI - PhRMA's Code on Interactions with Healthcare Professionals. PMID- 20945264 TI - Rethinking research ethics. AB - Contemporary research ethics policies started with reflection on the atrocities perpetrated upon concentration camp inmates by Nazi doctors. Apparently, as a consequence of that experience, the policies that now guide human subject research focus on the protection of human subjects by making informed consent the centerpiece of regulatory attention. I take the choice of context for policy design, the initial prioritization of informed consent, and several associated conceptual missteps, to have set research ethics off in the wrong direction. The aim of this paper is to sort out these confusions and their implications and to offer instead a straightforward framework for considering the ethical conduct of human subject research. In the course of this discussion I clarify different senses of autonomy that have been confounded and present more intelligible justifications for informed consent. I also take issue with several of the now accepted dogmas that govern research ethics. These include: the primacy of informed consent, the protection of the vulnerable, the substitution of beneficence for research's social purpose, and the introduction of an untenable distinction between innovation and research. PMID- 20945265 TI - "Rethinking research ethics," again: Casuistry, phronesis, and the continuing challenges of human research. PMID- 20945266 TI - Emerging neurotechnologies for lie-detection: promises and perils. AB - Detection of deception and confirmation of truth telling with conventional polygraphy raised a host of technical and ethical issues. Recently, newer methods of recording electromagnetic signals from the brain show promise in permitting the detection of deception or truth telling. Some are even being promoted as more accurate than conventional polygraphy. While the new technologies raise issues of personal privacy, acceptable forensic application, and other social issues, the focus of this paper is the technical limitations of the developing technology. Those limitations include the measurement validity of the new technologies, which remains largely unknown. Another set of questions pertains to the psychological paradigms used to model or constrain the target behavior. Finally, there is little standardization in the field, and the vulnerability of the techniques to countermeasures is unknown. Premature application of these technologies outside of research settings should be resisted, and the social conversation about the appropriate parameters of its civil, forensic, and security use should begin. PMID- 20945267 TI - Emerging neurotechnologies for lie-detection: where are we now? An appraisal of Wolpe, Foster and Langleben's "Emerging neurotechnologies for lie-detection: promise and perils" five years later. PMID- 20945268 TI - Audiovisual speech from emotionally expressive and lateralized faces. AB - Emotional expression and how it is lateralized across the two sides of the face may influence how we detect audiovisual speech. To investigate how these components interact we conducted experiments comparing the perception of sentences expressed with happy, sad, and neutral emotions. In addition we isolated the facial asymmetries for affective and speech processing by independently testing the two sides of a talker's face. These asymmetrical differences were exaggerated using dynamic facial chimeras in which left- or right-face halves were paired with their mirror image during speech production. Results suggest that there are facial asymmetries in audiovisual speech such that the right side of the face and right-facial chimeras supported better speech perception than their left-face counterparts. Affective information was also found to be critical in that happy expressions tended to improve speech performance on both sides of the face relative to all other emotions, whereas sad emotions generally inhibited visual speech information, particularly from the left side of the face. The results suggest that approach information may facilitate visual and auditory speech detection. PMID- 20945269 TI - [Dialectical behavior therapy for posttraumatic stress disorder in survivors of childhood sexual abuse]. AB - So far, no specifically tailored and empirically evaluated psychological treatment program exists, which is tailored for adult survivors with posttraumatic stress disorder (PTSD) after childhood sexual abuse. At the Central Institute of Mental Health, Mannheim we developed Dialectical Behavioral Therapy for PTSD (DBT-PTSD) as a residential intensive program, which is specifically tailored to the needs of these patients and which is acceptable as well as tolerable for patients and therapists. The treatment program is mainly based on the principles and methods of Dialectical Behavior Therapy according to M. Linehan and integrates methods of traumafocused cognitive-behavioural therapy. An overview is given on the treatment rational, the dynamic hierarchy of treatment focusses and the interventions used. In the internet version of this article treatment application is exemplified in a case study. PMID- 20945270 TI - Pioglitazone has direct effects on insulin sensitivity and intracellular lipid content in L6 skeletal muscle cells. AB - Using L6 skeletal muscle cell line, rendered insulin resistant by incubation with triglyceride-rich lipoproteins (TGRLs), we sought to answer the question whether pioglitazone has direct effects on this cell line. Incubation of L6 cells with TGRLs led to an increase in the intramyocellular triglyceride content. Moreover, TGRLs led to a reduction in insulin-stimulated glycogen content and GSK-3 phosphorylation. All these changes induced by TGRLs could be antagonized by incubation of L6 cells with pioglitazone. The PPAR-gamma antagonist GW9662 reversed the pioglitazone effects. We conclude that pioglitazone has direct insulin-sensitizing effects on the L6 skeletal muscle cell line, which are paralleled by a reduction in intramyocellular triglyceride accumulation. PMID- 20945271 TI - Metformin can activate imidazoline I-2 receptors to lower plasma glucose in type 1-like diabetic rats. AB - Metformin is widely used in clinic for handling the diabetic disorders. However, action mechanisms of metformin remain obscure. It has recently been indicated that guanidinium derivatives are ligands to activate type-2 imidazoline receptors (I-2 receptors) that can improve diabetes through increment in skeletal muscle glucose uptake. Also, activation of I-2 receptors can increase the release of beta-endorphin in diabetic animals. Because metformin is a guanidinium derivative, we were interested in the effect of metformin on I-2 receptors. In the present study, the marked blood glucose-lowering action of metformin in streptozotocin-induced type-1 like diabetes rats was blocked by specific I-2 receptor antagonist, BU224, in a dose-dependent manner. Also, the increase of beta-endorphin release by metformin was blocked by BU224 in same manner. A specific competition between metformin and BU224 was observed in isolated adrenal medulla. Otherwise, amiloride at the dose sufficient to block I-2A receptor abolished the metformin-induced beta-endorphin release, but only the blood glucose-lowering action of metformin was markedly reduced. In addition, the blood glucose-lowering action of metformin in bilateral adrenalectomized rats was diminished by amiloride at higher doses. These results suggest that metformin might activate imidazoline I-2 receptors while I-2A receptors link the increase of beta-endorphin release and I-2B receptors couple to the other actions for lowering of blood glucose in type-1 like diabetic rats. PMID- 20945272 TI - A promoter polymorphism in the liver-specific fatty acid transport protein 5 is associated with features of the metabolic syndrome and steatosis. AB - The fatty acid transport protein 5 (FATP5) is exclusively expressed in the liver and is involved in hepatic lipid and bile metabolism. We investigated whether a variation in the FATP5 promoter (rs56225452) is associated with hepatic steatosis and further features of the metabolic syndrome. A total of 716 male subjects from the Metabolic Intervention Cohort Kiel (MICK) and 103 male subjects with histologically proved nonalcoholic fatty liver disease (NAFLD) were genotyped for this FATP5 polymorphism rs56225452 and phenotyped for features of the metabolic syndrome. In the MICK cohort, ALT activities, postprandial insulin, and triglyceride concentrations were higher in subjects carrying the rare A-allele compared to GG homozygotes. Accordingly, the insulin sensitivity index determined after a mixed meal and standardized glucose load was lower in A-allele carriers. NAFLD cases carrying allele A were presented with also higher ALT activities. In NAFLD subjects, the association of BMI with the degree of steatosis and glucose concentration differed across FATP5 promoter polymorphism. The FATP5 promoter polymorphism rs56225452 is associated with higher ALT activity, insulin resistance, and dyslipidemia in the general population. The impact of the BMI on the severity of steatosis in NAFLD cases seems to depend on the FATP5 polymorphism. PMID- 20945273 TI - Cervical scrapes levels of insulin-like growth factor-II and insulin-like growth factor binding protein 3 in women with squamous intraepithelial lesions and cervical cancer. AB - A growing number of studies have demonstrated an association between serum levels of insulin-like growth factors (IGFs) and IGF binding protein-3 (IGFBP-3) and increased risk for various cancers. The aim of this study was to evaluate the relationship between levels of IGF-II or IGFBP-3 in cervical scrapes with cervical cancer and precancerous lesions: low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL). 4 groups of cases were examined: LSIL (n=20), HSIL (n=28), cervical cancer (n=45), and controls (n=51). Control subjects were women with normal, HPV DNA-negative Papanicolau (Pap) test. IGF-II and IGFBP-3 levels in cervical scrapes were measured by ELISA. Results show that median protein levels of IGF-II were significantly lower in cervical cancer cases vs. controls (446.5 ng/mg vs. 1,168.6 ng/mg, p<0.001). Significantly higher values of IGFBP-3 were found in HSIL vs. controls (median: 549.5 ng/mg vs. 216 ng/mg; p=0.018), and were not affected by HR HPV infection, meanwhile no significant differences were observed in IGFBP-3 levels between LSIL or cervical cancer as compared to controls. These data suggests that the progression to cervical cancer is associated with alterations in the IGF system and not affected by HR HPV infection. More studies are needed to understand the possible role of IGFBP-3 in cervical carcinogenesis. PMID- 20945274 TI - Sleeping sickness pathogen (Trypanosoma brucei) and natural products: therapeutic targets and screening systems. AB - Trypanosoma brucei is the causative agent of human African trypanosomiasis (sleeping sickness) which is fatal if left untreated. This disease occurs in 36 African countries, south of the Sahara, where 60 million people are at risk of acquiring infection. The current chemotherapy relies on only four drugs, three of which were developed more than 60 years ago. These drugs have many limitations, ranging from oral inabsorption, acute toxicities, short duration of action and the emergence of trypanosomal resistance. Despite decades of use of most of the current trypanocides, little is known about their mode of action. That being said, African trypanosomes continue to be among the most extensively studied parasitic protists to date. Many of their intriguing biological features have been well documented and can be viewed as attractive targets for antitrypanosomal chemotherapy. A considerable number of natural products with diverse molecular structures have revealed antiparasitic potency in the laboratory and represent interesting lead compounds for the development of new and urgently needed antiparasitics. The major validated drug targets in T. brucei are discussed with particular emphasis on those known to be attacked by natural compounds. PMID- 20945275 TI - Effects of astragaloside IV on IFN-gamma level and prolonged airway dysfunction in a murine model of chronic asthma. AB - Astragaloside IV (AST) is the main active constituent of Radix Astragali, a Chinese herb traditionally used to prevent asthma attack from chronic asthma patients. Its efficacy and action mechanisms in asthma attack prevention remain nonetheless to be further explored. In this study, chronic asthma was induced exposing ovalbumin (OVA) sensitized mice to repeated OVA challenges twice every two weeks for 12 weeks. Mice were treated with AST for 4 weeks just after the final challenge. In this murine model of chronic asthma, the airway dysfunction and remodeling remained severe and was accompanied with suppression of the IFN gamma level in the bronchoalveolar lavage fluid (BALF) even four weeks after the final challenge, indicating that the airway structural changes continued to develop even after interruption of OVA challenges. However, after AST treatment, the airway hyperresponsiveness was sharply relieved, accompanied by the reduction of collagen deposition and mucus production, meanwhile the inflammatory cells were decreased but the IFN-gamma level increased in BALF. In conclusion, AST could prevent the development of chronic asthma, thus reducing asthma attacks. Our results indicated that it should be used as a supplementary therapy on preventing asthma attacks from chronic asthma patients. PMID- 20945276 TI - The anti-immobility effect of hyperoside on the forced swimming test in rats is mediated by the D2-like receptors activation. AB - The crude extracts of HYPERICUM species native to South Brazil showed analgesic and antidepressant-like effects in rodents. The chemical characterization of these species revealed that they are rich in flavonoids and phloroglucinol derivatives. In the present study a detailed investigation was performed on the activities of hyperoside (HYP), a common flavonoid in the genus HYPERICUM. Hyperoside was obtained from the aerial parts of H. CAPRIFOLIATUM by chromatographic procedures. Mice treated with single doses (10, 20 and 40 mg/kg i.p.) did not present signs of toxicity or weight loss. At 20 and 40 mg/kg i.p. the mice exploratory behavior in the open field test was reduced. At 20 mg/kg i. p. the pentobarbital sleeping time increased, but not the sleeping latency. No activity was found on the hot-plate (10 and 20 mg/kg i.p.) or in the acetic acid induced writhing test (20 and 40 mg/kg p.o.). Nevertheless, an antidepressant like effect in the forced swimming test in mice and rats was observed (HYP 10 and 20 mg/kg i.p. in mice; HYP 1.8 mg/kg/day p.o. in rats). The antidepressant-like effect in rats was prevented by the administration of sulpiride (50 mg/kg i.p.) a D2 antagonist. In conclusion, hyperoside was found to present a depressor effect on the central nervous system as well as an antidepressant-like effect in rodents which is, at least in part, mediated by the dopaminergic system. PMID- 20945277 TI - Protoflavonoids from ferns impair centrosomal integrity of tumor cells. AB - Six protoflavonoids, including two new compounds, were isolated during a large scale screening of fern extracts for original interaction with mitosis. The new compounds isolated from PHEGOPTERIS decursive-pinnata and EQUISETUM fluviatile were 2',3'-dihydroprotogenkwanone (1) and 2',3'-dihydro-2'-hydroxyprotoapigenone (2). Known compounds were: protoapigenone, protogenkwanone, protoapigenin, and 4' O- beta-D-glucopyranosyl protoapigenin. They showed a cytotoxic activity against HeLa cells at a micromolar level. IC50 values were 2 uM for compound 1 > 10 uM for compound 2, and respectively 2.4, 0.6, > 10 uM for the known compounds. Their cytotoxic effects were associated with phenotypic changes never observed before and characterized by the loss of centrosomal gamma-tubulin labelling in both mitotic and interphasic cells. PMID- 20945278 TI - The posterior thigh flap for ischial pressure sores. PMID- 20945279 TI - Using a punch biopsy to fashion an arteriotomy for end-to-side anastomosis. PMID- 20945280 TI - The utility of multidetector-row computed tomography angiography for evaluating perforators of fibular osteocutaneous flaps. AB - Multidetector-row computed tomography angiography (MDCTA) can be used to visualize small vessels and has been used to search for perforators in deep inferior epigastric artery perforator flaps and anterolateral thigh flaps. Fibula osteocutaneous flaps are often used for mandibular reconstruction, but questions remain about the reliability of these flaps and the variety of their perforators. Eight patients who were candidates for mandibular or pedal reconstruction with a fibula osteocutaneous flap were prospectively evaluated with MDCTA and Doppler sonography. We evaluated the number, position, and course of perforators with MDCTA. The perforators were classified, and intraoperative findings were compared with those of Doppler sonography and MDCTA. MDCTA accurately identified the perforators and showed a satisfactory concordance with intraoperative findings. The high spatial resolution of MDCTA allows the perforators' origin, course, and type to be precisely described. Eighteen vessels were identified with MDCTA, and on average, 2.3 vessels were identified in the leg of each patient. The rate of concordance with operative findings was 87.5% for MDCTA. With MDCTA, flap perforators can be accurately evaluated before surgery in a manner not possible with traditional angiography or Doppler sonography. Reliable perforators can be chosen, and detailed operative plans can be made. PMID- 20945281 TI - Sutured attachment of the implantable Doppler probe cuff for large or complex pedicles in free tissue transfer. AB - The Cook-Swartz implantable Doppler probe (Cook Medical((r)), Cook Ireland Ltd., Limerick, Ireland) has evolved as a useful option for postoperative free flap monitoring. For placement, the probe either is left unattached around the venous pedicle or is secured. In our experience with over 300 applications, we typically secure the cuff with two small microclips, or use fibrin glue. These techniques require redundant silicone cuff for apposition; however, we have encountered some vessels that are of sufficiently large diameter as to not provide enough cuff to employ these methods. The first technique comprises the application of two interrupted sutures through the cuff ends to mimic the technique of microclips. The sutures can be tightened to the desired tension and can be used in cases where the cuff ends are not in direct apposition. A second technique is to excise a segment of silicone cuff and either clip or suture the excised segment to the cuff ends, effectively elongating the cuff diameter. All four techniques (nonattachment, microclip fixation, suture fixation, silicone cuff elongation) have been used effectively, and none have resulted in any complications. Of note, the technique of nonattachment was associated with an increased rate of false positive results, as migration away from the vessel was postulated to have occurred. There are a range of techniques for attachment of the implantable Doppler probe, and each contributes to the range of options for cuff attachment in difficult cases, with each technique worthwhile in particular settings. PMID- 20945282 TI - Factors influencing successful outcome in the arteriovenous loop model: a retrospective study of 612 loop operations. AB - The arteriovenous (AV) loop is a complex model and requires advanced microsurgical skills. After several years of studies including characterization of the physiological and molecular phenomena behind the process of neovascularization, we would like to evaluate our experience from a microsurgical point of view. The AV loop operation was performed in 612 male Lewis rats. Species, surgeon, previous microsurgical skills, solid or soft consistency of matrix, weeks from implantation to explantation, experience, and practice of surgeon as well length of operation and outcome (patent versus thrombosed) upon evaluation were analyzed for each loop operation. Previous microsurgical skills, matrix, and explantation interval were not significant predictors. There was a significant correlation of experience, practice, and individual performance of microsurgical technicians with the rate of thrombosis and duration of the procedure. Experimental microsurgical operations on animals are best performed by especially trained technicians, rather than microsurgeons working parallel to their clinical activities. The AV loop is an excellent model in the arena of translational technologies, but due to its complexity is unsuitable for screening purposes. Experience and practice are both significant predictors of successful outcome. Possible applications of the model for research purposes are discussed. PMID- 20945283 TI - Effect of bilateral median nerve excision on sciatic functional index in rat: an applicable animal model for autologous nerve grafting. AB - Autologous nerve graft is still the treatment of choice in peripheral nerve injury when end-to-end nerve repair is not possible. The sciatic nerve is the most widely used nerve in rat experimental studies. To assess the possibility of using the rat median nerve as a delayed animal autologous nerve graft model in nerve regeneration studies, the effect of median nerve excision on the sciatic functional index (SFI) was evaluated. Thirty rats were distributed into three equal groups: in the sciatic and median nerve excision (SMNE) group, 10 mm of the right sciatic nerve was excised and 5 mm of both median nerves were excised a week later; in the median nerve excision (MNE) group, 5 mm of both median nerves were excised (both sciatic nerves remained intact); in the control group, no intervention was performed. SFI was calculated before and after each intervention. There was no significant difference between mean SFI values calculated before and after median nerve excision in SMNE (-86.8 versus -88.4, P = 0.61) and MNE groups (-3.9 versus -3.3, P = 0.93). Therefore, it may be suggested that median nerve excision does not affect SFI measurements in intact and/or completely injured sciatic nerve, which may propose the median nerve as an autologous donor nerve graft model in rats. PMID- 20945284 TI - Pedicled sensate composite calcaneal flap to achieve full weight-bearing surface in midshaft leg amputations: case report. AB - Of the possible levels of amputation, transtibial amputations result in functionally excellent outcomes. However, in contrast to hind foot amputations, such as Syme and especially Boyd amputation, acute or late complications related to the amputated stump are frequent with the various described techniques. The aim of this study was to describe a hind foot (including the calcaneum and fat pad) pedicled sensate flap with a surface that allowed full terminal weight bearing in transtibial amputations in adults. One male patient, 66 years old with schizophrenia and chronic distal tibial osteomyelitis, underwent a leg amputation with sensate composite calcaneal flap construction. The stump was painless and able to bear total terminal weight at 12 weeks. Calcaneum tibial fusion was observed at 12-week postoperative follow-up. A below-knee prosthesis was adapted in 12 weeks, and at the 1-year follow-up, the patient was completely satisfied with the functional performance of his stump. The flap described provides proprioceptive feedback with the best bone and skin to support weight bearing. Another advantage is the possibility to use the same prosthesis commonly used in Boyd or Syme amputation due a longer arm leverage, which also allows full terminal weight-bearing. In the current study, a transtibial amputation covered with a pedicled sensate plantar flap preserving the calcaneum was proposed. In theory, the anatomic structures spared in this technique provide a strong full weight-bearing terminal surface of the stump that will last a lifetime. PMID- 20945285 TI - The use of massive allograft with intramedullary fibular graft for intercalary reconstruction after resection of tibial malignancy. AB - Reconstruction after intercalary excision of tibia malignancy is challenging. The combined use of a vascularized fibular flap and allograft can provide a reliable reconstructive option. Eight patients underwent reconstruction with an allograft and vascularized fibula following tibia malignancy resection. Patients were examined clinically and radiographically. The average age of patients was 16.5 years. The mean follow-up time was 38.4 months. Contralateral free fibula flap was used in three patients and ipsilateral pedicle fibula in five. The average length of defect was 11.8 cm and of fibula flap was 15.9 cm. Primary union was achieved in seven patients. The average time for bone union was 5.8 months at fibula-tibia junction and 14.1 months at allograft-tibia junction. Five patients had 10 complications. The Musculoskeletal Tumor Society average score was 90.8% at final follow-up. Intramedullary fibular flap in combination with massive allografts provide an excellent option for reconstruction of large bony defects after tibial malignancy extirpation. Ipsilateral pedicle fibula transportation had the advantages of short operation time and avoidance of donor site complications compared with the contralateral free fibula transfer. PMID- 20945286 TI - Assessment of processed porcine extracellular matrix as a protective barrier in a rabbit nerve wrap model. AB - Nerve wrapping can improve outcomes by protecting nerves in a scarred tissue bed. Autologous tissue wraps have shown good results, but there are limitations associated with harvesting and availability. Extracellular matrix (ECM) derived from porcine small intestinal submucosa offers an attractive off-the-shelf option. This study evaluated this material as a nerve wrap. The sciatic nerves of 18 New Zealand rabbits were exposed and then wrapped, while the contralateral side served as sham control. Presence and quality of adhesions, motor conduction velocity (MCV), and histology were evaluated at 1, 2, and 6 months ( N = 6 animals per time point). The quality, extent, tenacity, and overall impression of adhesions were not different from control at any time point ( P = 0.18 to 0.99). MCV was also not statistically different from control (1 month, P = 0.35; 2 months, P = 0.20; 6 months, P = 0.83). Histology demonstrated that wrapped nerves were healthy in terms of myelination, density, and vascularity compared with controls. Vascularization and incorporation of the ECM material could be visualized at explants. All assessments supported the feasibility and safety of this material as a nerve wrap. Its ability to function as a protective barrier has strong implications for clinical use in trauma and/or recurrent compression neuropathies. PMID- 20945287 TI - Nerve endoneurial microstructure facilitates uniform distribution of regenerative fibers: a post hoc comparison of midgraft nerve fiber densities. AB - Despite their inferiority to nerve autograft, clinical alternatives are commonly used for reconstruction of peripheral nerve injuries because of their convenient off-the-shelf availability. Previously, our group compared isografts with NeuraGen((r)) (Integra, Plainsboro, NJ) nerve guides, which are a commercially available type I collagen conduit and processed rat allografts comparable to Avance((r)) (AxoGen, Alachua, FL) human decellularized allograft product. From this study, qualitative observations were made of distinct differences in the pattern of regenerating fibers within conduits, acellular allografts, and isografts. In the current post hoc analysis, these observations were quantified. Using nerve density, we statistically compared the differential pattern of regenerating axon fibers within grafts and conduit. The conduits exhibited a consistent decrease in midgraft density when compared with the isograft and acellularized allografts at two gap lengths (14 mm and 28 mm) and time points (12 and 22 weeks). The decrease in density was accompanied by clustered distribution of nerve fibers in conduits, which contrasted the evenly distributed regeneration seen in processed allografts and isografts. We hypothesize that the lack of endoneurial microstructure of conduits results in the clustering regenerating fibers, and that the presence of microstructure in the acellularized allograft and isografts facilitates even distribution of regenerating fibers. PMID- 20945288 TI - A minimally invasive technique for burying free flaps and grafts. AB - The placement of large-volume flaps and grafts into a subcutaneous pocket often requires extensive incisions for accurate placement. We describe a technique that allows for the precise, atraumatic placement of these tissues through minimal incisions. No unusual or expensive surgical instrumentation is required, and the technique is easy to learn. We have found the technique especially useful in the augmentation of severe facial atrophy. PMID- 20945289 TI - [Leiomyosarcoma of the inferior vena cava]. PMID- 20945291 TI - MRI assessment of chronic pancreatitis. AB - Magnetic resonance imaging (MRI) plays an important role in the assessment of chronic pancreatitis. By standard MRI techniques, decreased parenchymal signal on T1-weighted fat-suppressed images and delayed gradual enhancement on serial contrast enhanced images represent fibrotic changes caused by chronic inflammation. Magnetic resonance cholangiopancreaticography (MRCP) can reveal ductal changes, including side branch ectasias, that are related to tissue fibrosis and destruction. The exocrine function of the gland and an increased number of side branch ectasias can be evaluated with secretin-stimulated MRCP. Diffusion weighted imaging is an emerging technology that can complement standard MRI to assess the parenchymal changes associated with chronic pancreatitis. The same technique can also quantify the parenchymal response to secretin stimulation. This article reviews standard imaging techniques and new advancements in MRI technology as they relate to the assessment of chronic pancreatitis. PMID- 20945292 TI - Dual-energy CT revisited with multidetector CT: review of principles and clinical applications. AB - Although dual-energy CT (DECT) was first conceived in the 1970s, it was not widely used for CT indications. Recently, the simultaneous acquisition of volumetric dual-energy data has been introduced using multidetector CT (MDCT) with two X-ray tubes and rapid kVp switching (gemstone spectral imaging). Two major advantages of DECT are material decomposition by acquiring two image series with different kVp and the elimination of misregistration artifacts. Hounsfield unit measurements by DECT are not absolute and can change depending on the kVp used for an acquisition. Typically, a combination of 80/140 kVp is used for DECT, but for some applications, 100/140 kVp is preferred. In this study, we summarized the clinical applications of DECT and included images that were acquired using the dual-source CT and rapid kVp switching. In general, unenhanced images can be avoided by using DECT for body and neurological applications; iodine can be removed from the image, and a virtual, non-contrast (water) image can be obtained. Neuroradiological applications allow for the removal of bone and calcium from the carotid and brain CT angiography. Thorax applications include perfusion imaging in patients with pulmonary thromboemboli and other chest diseases, xenon ventilation-perfusion imaging and solitary nodule characterization. Cardiac applications include dual-energy cardiac perfusion, viability and cardiac iron detection. The removal of calcific plaques from arteries, bone removal and aortic stent graft evaluation may be achieved in the vascular system. Abdominal applications include the detection and characterization of liver and pancreas masses, the diagnosis of steatosis and iron overload, DECT colonoscopy and CT cholangiography. Urinary system applications are urinary calculi characterization (uric acid vs. non-uric acid), renal cyst characterization and mass characterization. Musculoskeletal applications permit the differentiation of gout from pseudogout and a reduction of metal artifacts. Recent introduction of iterative reconstruction techniques can increase the use of DECT techniques; the use of dual energy in patients with a high BMI is limited due to noise and the radiation dose. DECT may be a good alternative to PET-CT. Iodine map images can quantify iodine uptake, and this approach may be more effective than obtaining non-contrast and post-contrast images for the diagnosis of a solid mass. Thus, computer-aided detection may be used more effectively in CT applications. DECT is a promising technique with potential clinical applications. PMID- 20945293 TI - Redefining readmission risk factors for general medicine patients. AB - BACKGROUND: Readmissions are costly both financially for our healthcare system and emotionally for our patients. Identifying factors that increase risk for readmissions may be helpful to focus resources to optimize the discharge process and reduce avoidable readmissions. OBJECTIVE: To identify factors associated with readmission within 30 days for general medicine patients. METHODS: We performed a retrospective observational study of an administrative database at an urban 550 bed tertiary care academic medical center. Cohort patients were discharged from the general medicine service over a 2-year period from June 1, 2006, to May 31, 2008. Clinical, operational, and sociodemographic factors were evaluated for association with readmission. RESULTS: Our cohort included 10,359 consecutive admissions (6805 patients) discharged from the general medicine service. The 30 day readmission rate was 17.0%. In multivariate analysis, factors associated with readmission included black race (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.24-1.65), inpatient use of narcotics (1.33; 1.16-1.53) and corticosteroids (1.24; 1.09-1.42), and the disease states of cancer (with metastasis 1.61; 1.33-1.95; without metastasis 1.95; 1.54-2.47), renal failure (1.19; 1.05-1.36), congestive heart failure (1.30; 1.09-1.56), and weight loss (1.26; 1.09-1.47). Medicaid payer status (1.15; 0.97-1.36) had a trend toward readmission. CONCLUSION: Readmission of general medicine patients within 30 days is common and associated with several easily identifiable clinical and nonclinical factors. Identification of these risk factors can allow providers to target interventions to reduce potentially avoidable readmissions. PMID- 20945294 TI - Recurrent readmissions in medical patients: a prospective study. AB - BACKGROUND: Hospital readmissions are common and costly. A recent previous hospitalization preceding the index admission is a marker of increased risk of future readmission. OBJECTIVES: To identify factors associated with an increased risk of recurrent readmission in medical patients with 2 or more hospitalizations in the past 6 months. DESIGN: Prospective cohort study. SETTING: Australian teaching hospital acute medical wards, February 2006-February 2007. PARTICIPANTS: 142 inpatients aged >= 50 years with a previous hospitalization <= 6 months preceding the index admission. Patients from residential care, with terminal illness, or with serious cognitive or language difficulties were excluded. VARIABLES OF INTEREST: Demographics, previous hospitalizations, diagnosis, comorbidities and nutritional status were recorded in hospital. Participants were assessed at home within 2 weeks of hospital discharge using validated questionnaires for cognition, literacy, activities of daily living (ADL)/instrumental activities of daily living (IADL) function, depression, anxiety, alcohol use, medication adherence, social support, and financial status. MAIN OUTCOME MEASURE: Unplanned readmission to the study hospital within 6 months. RESULTS: A total of 55 participants (38.7%) had a further unplanned hospital admission within 6 months. In multivariate analysis, chronic disease (adjusted odds ratio [OR] 3.4; 95% confidence interval [CI], 1.3-9.3, P = 0.002), depressive symptoms (adjusted OR, 3.0; 95% CI, 1.3-6.8, P = 0.01), and underweight (adjusted OR, 12.7; 95% CI, 2.3-70.7, P = 0.004) were significant predictors of readmission after adjusting for age, length of stay and functional status. CONCLUSIONS: In this high-risk patient group, multiple chronic conditions are common and predict increased risk of readmission. Post-hospital interventions should consider targeting nutritional and mood status in this population. PMID- 20945295 TI - Detection of metabolites using high-performance liquid chromatography and mass spectrometry. AB - This unit provides a discussion of high-pressure liquid chromatography atmospheric pressure ionization mass spectrometry (LC-API-MS) for separation, detection, and identification of products from xenobiotic metabolism. It includes an introduction and important technical information for electrospray and atmospheric pressure chemical ionization methods as well as scan modes. Emphasis has been placed on each method as related to phase I and phase II metabolite identification and there are listings of specific applications (and references) to reduce method development time. PMID- 20945296 TI - Measurement of aryl and alcohol sulfotransferase activity. AB - Two methods are presented for determining the catalytic activity of aryl and alcohol sulfotransferases. The first assay is a simple and rapid procedure that is based on the extraction of a paired ion formed between the product organic sulfate and methylene blue. The second method employs HPLC analysis of the substrate-dependent formation of PAP, an assay that is particularly useful when the sulfuric acid ester product is chemically unstable. PMID- 20945297 TI - Assays for the classification of two types of esterases: carboxylic ester hydrolases and phosphoric triester hydrolases. AB - Assays for the Classification of Two Types of Esterases: Carboxylic Ester Hydrolase and Phosphoric Triester Hydrolase (Douglas D. Anspaugh and Michael Roe, North Carolina State University, Raleigh, North Carolina). This unit describes assays that quantitate two types of esterase the carboxylic ester hydrolases and the phosphoric triester hydrolases. Carboxylic ester hydrolases include the B esterases, which are inhibited by organophosphorus compounds. Among the phosphoric triester hydrolases is aryldialkylphosphatase, which has been called A esterase or paraoxonase due to its ability to oxidize paraoxon and other organophosphates. These assays are colorimetric and miniaturized for rapid simultaneous testing of multiple, small-volume samples in a microtiter plate format. There is also a discussion of the history of esterase nomenclature and the reasons why this large group of enzymes is so difficult to classify. PMID- 20945298 TI - Measuring the activity of arylamine N-acetyltransferase (NAT). AB - This unit describes methods for measuring the activity of arylamine N acetyltransferases (NAT). Genetic polymorphisms in NAT 1 and NAT 2 have been associated with susceptibility to aromatic amines carcinogens and effects of therapeutic drugs. Evaluation of the activities associated with substrates of NATs is helpful in elucidating the contribution of these enzymes to the pharmacologic and toxicologic effects of arylamines and hydrazines. PMID- 20945299 TI - Measurement of carboxylesterase (CES) activities. AB - Measurement of Carboxylesterase (CES) Activities (Masakiyo Hosokawa, Chiba University, Chiba, Japan and Tetsuo Satoh, Biomedical Research Institute, Chiba, Japan). Mammalian carboxyesterase (CES) efficiently catalyzes the hydrolysis of a variety of ester- and amide-containing chemicals. CES is involved in detoxification or metabolic activation of various drugs, environmental toxicants, and carcinogens. This unit contains three protocols for measuring CES activities. PMID- 20945300 TI - Analysis of the aryl hydrocarbon receptor (AhR) signal transduction pathway. AB - Analysis of the Ah Receptor Signal Transduction Pathway (Michael S. Denison, Jane M. Rohers, S. Renee Rushing. Carol L. Jones, Selwyna C. Tetangico, and Sharon Heath-Pagliuso, University of California, Davis, California).The protocols in this unit will allow researchers to detect the Ah receptor and characterize its functional activities (i.e., ligand binding, transformation and DNA binding, and gene expression) in their biological test system and to use these methods to detect chemical and biochemical events that affect this signaling system. PMID- 20945301 TI - Measurements of flavin-containing monooxygenase (FMO) activities. AB - Measurement of Flavin-Containing Monooxygenase (FMO) Activities (Randy L. Rose, North Carolina State University, Raleigh, North Carolina). This unit describes methods used for measuring the presence of flavin-containing monooxygenases using NADPH oxygenation and methamizole oxidation. Methods are also provided to determine the relative contributions of FMO versus cytochrome P450 from microsomes. PMID- 20945302 TI - Techniques for measuring the activity of carboxylic acid:CoA ligase and acyl CoA:amino acid N-acyltransferase: the amino acid conjugation pathway. AB - A wide variety of xenobiotic carboxylic acids are metabolized to their amino acid conjugates via a pathway that exists primarily in liver and kidney. This conjugation occurs in a two-step pathway catalyzed by two distinct types of enzymes, ligases and transferases. Measurements of acyl-CoA ligase activity include monitoring the rate of appearance of AMP or PPi, or the CoA adduct. N acyltransferases catalyze formation of an amino acid conjugate from the CoA activated intermediate, releasing CoA. This reaction is monitored by following the release of free CoA or the disappearance of the acyl-CoA adduct. PMID- 20945303 TI - Determination of paraoxonase 1 status and genotypes at specific polymorphic sites. AB - The procedures for determining paraoxonase (PON1) status and for determining PON1 genotypes for polymorphisms in coding and important regulatory regions are described. PON1 status is determined by a functional two-substrate analysis of plasma PON1 activities. Differences in catalytic efficiency of the PON1192Q and PON1192R alloforms result in the clear separation of all three phenotypes at position 192 (Q/Q, Q/R, R/R) and at the same time, the two-substrate analysis indicates activity levels of PON1. Because the enzyme activity levels are as important as the polymorphic genotypes, this two-substrate analysis of PON1 status provides the most relevant information for investigating the association of PON1 genetics with susceptibilities to disease, organophosphorus insecticide sensitivity, and pharmacokinetic status of drug metabolism. Genotyping of polymorphic sites alone fails to provide this important information but can be useful for gene frequency determination and forensic analysis. Analytical procedures for determining PON1 status and genotypes are described. PMID- 20945304 TI - Human cytochrome P450: metabolism of testosterone by CYP3A4 and inhibition by ketoconazole. AB - This unit describes methods for measuring CYP3A4 activity using testosterone as a specific substrate, and for measuring CYP3A4 inhibition using ketoconazole as a selective inhibitor of testosterone oxidation. CYP3A4 is one of the most important and most abundant drug-metabolizing CYP isoforms in human liver microsomes (~40% of total CYP), and it has the broadest substrate specificity. It is important to determine whether CYP3A4 is involved in its metabolism. PMID- 20945305 TI - Modification of polydivinylbenzene microspheres by a hydrobromination/click chemistry protocol and their protein-adsorption properties. AB - Hydrophobic- and/or hydrophilic-polymer-grafted PDVB microspheres are synthesized by the combination of hydrobromination and click-chemistry processes. The modified-PDVB microspheres and the intermediates at various stages of synthesis are characterized using GPC, 1H NMR and FTIR spectroscopy and TGA analysis. Use of the microspheres as a support matrix for reversible protein immobilization via adsorption is investigated. The system parameters such as the adsorption conditions (i.e., enzyme concentration, medium pH) and desorption are studied and evaluated with regards to the biocatalytic activity and adsorption capacity. PMID- 20945306 TI - Hydrophobic polyphenylalanine-grafted hyperbranched polyethylenimine and its in vitro gene transfection. AB - A series of amphiphilic multi-armed PPn copolymers were prepared by ROP of Phe NCA with PEI-25k as a macroinitiator. The particle size of the PPn/DNA complexes was about 100 nm and the zeta potentials were below 20 mV. An MTT assay demonstrated that all the PPn copolymers had lower cytotoxicity compared to PEI 25k. In vitro gene transfection studies were also conducted in HeLa, 293 and CT 26 cells. The optimal quantity of hydrophobic phenylalanine segments in PP80 led to higher transfection efficiency in various cell lines based on this study. The results indicate that PP80 was the best candidate for gene delivery among these PPn copolymers. PMID- 20945307 TI - Effect of chronic hypoxia on pulmonary artery blood velocity in rats as assessed by electrocardiography-triggered three-dimensional time-resolved MR angiography. AB - Pulmonary arterial hypertension (PAH) is a severe disease that leads to increased pulmonary vascular resistance and right heart failure. Noninvasive methods are needed to detect changes in the pulmonary artery circulation during PAH establishment and/or treatment. Pulmonary blood flow velocity can be evaluated by dynamic MR angiography, although the relevance of such data in the context of PAH remains to be demonstrated. A novel dynamic MR angiography technique was used in this work to measure blood flow velocity in the pulmonary arteries of the same living animals, before and after the establishment of chronic hypoxia-induced PAH. Chronic hypoxia decreased significantly the blood flow velocity (43.8 +/- 4.9 vs 24.3 +/- 8.7 cm/s) on electrocardiography-triggered time-resolved angiograms. In parallel, chronic hypoxia-induced PAH was confirmed from invasive measurements of the mean pulmonary arterial pressure (32.1 +/- 4.8 vs 12.5 +/- 2.2 mmHg) and the ratio of the right ventricle weight to the left ventricle plus septum weight (Fulton index: 0.54 +/- 0.06 vs 0.27 +/- 0.04). This study demonstrates the potential interest of dynamic MR angiography for the investigation of experimental models and for the evaluation of treatment efficacy. PMID- 20945308 TI - Mechanism of the catalytic deperoxidation of tert-butylhydroperoxide with cobalt(II) acetylacetonate. AB - The Co(II)/Co(III)-induced decomposition of hydroperoxides is an important reaction in many industrial processes and is referred to as deperoxidation. In the first step of the so-called Haber-Weiss cycle, alkoxyl radicals and Co(III) OH species are generated upon the reaction of the Co(II) ion with ROOH. The catalytic cycle is closed upon the regeneration of the Co(II) ion through the reaction of the Co(III)-OH species with a second ROOH molecule, thus producing one equivalent of the peroxyl radicals. Herein, the deperoxidation of tert butylhydroperoxide by dissolved cobalt(II) acetylacetonate is studied by using UV/Vis spectroscopy in situ with a noninteracting solvent, namely, cyclohexane. Kinetic information extracted from experiments, together with quantum-chemical calculations, led to new mechanistic hypotheses. Even under anaerobic conditions, the Haber-Weiss cycle initiates a radical-chain destruction of ROOH propagated by both alkoxyl and peroxyl radicals. This chain mechanism rationalizes the high deperoxidation rates, which are directly proportional to the cobalt concentration up to approximately 75 MUM at 333 K. However, at higher cobalt concentrations, a remarkable decrease of the rate is observed. The hypothesis put forward herein is that this remarkable autoinhibition effect could be explained by the hitherto overlooked chain termination of two Co(III)--OH species. The direct competition between the first-order Haber-Weiss initiation and the second-order termination can indeed explain this peculiar kinetic behavior of this homogeneous deperoxidation system. PMID- 20945309 TI - Photochemical synthesis of intensely luminescent isocyano rhenium(I) complexes with readily tunable structural features. AB - A new class of readily tunable isocyano rhenium(I) diimine luminophores, cis,cis [Re(CO)(2)(CNR)(2)(N-N)](+) (R=2,4,6-Cl(3)C(6)H(2), 4-ClC(6)H(4), 4-Br-2,6 (CH(3))(2)C(6)H(2), 2,6-(CH(3))(2)C(6)H(3), 4-[(CH(3))(2)N]C(6)H(4), 4 (C(6)H(5))C(6)H(4), 4-nBuC(6)H(4), tBu), has been synthesized in high yield by a highly selective photochemical substitution reaction. These complexes were characterized by (1)H NMR and IR spectroscopy, mass spectrometry, and elemental analysis. The X-ray crystal structures of one of the complexes and one of the precursor complexes for the photosubstitution reaction were also determined. As the isocyanide ligands are readily tunable, complexes with excellent solubility in benzene or other nonpolar solvents could be designed through slight modification of the isocyanide ligands with a short nBu substituent. With the characteristic strong infrared absorptions of the carbonyl (C=O) and isocyanide (C=N) stretches as well as the high solubility of the reactant and product in benzene, which is the solvent for the photoreaction, the photosubstitution reaction of [Re(CO)(3)(nBuC(6)H(4)NC)(2)Br] with 4,4'-di-tert-butyl-2,2' bipyridine was also studied by in situ IR spectroscopy. The photophysical and electrochemical properties of these complexes were also investigated. Except for the complex with [(CH(3))(2)N]C(6)H(4)NC ligands, all complexes displayed intense luminescence with quantum yields of up to 0.37 in degassed CH(2)Cl(2) solution at room temperature. These emissions were assigned as the phosphorescence derived from the metal-to-ligand charge transfer [dpi(Re)->pi*(N-N)] excited state. The emissive excited states of these complexes have also been characterized by transient absorption spectroscopic studies. The capability of tuning the emissive excited-state energy through the modification of the isocyanide ligands could be reflected by the significant shifting of the phosphorescence from 530 to 620 nm with the same phenanthroline ligand. PMID- 20945310 TI - Neutralization of a sec-ammonium group unusually stabilized by the "rotaxane effect": synthesis, structure, and dynamic nature of a "free" sec-amine/crown ether-type rotaxane. AB - A fifteen-year riddle has been settled: neutralization, the most popular chemical event, of a crown ether/sec-ammonium salt-type rotaxane has been achieved and a completely nonionic crown ether/sec-amine-type rotaxane isolated. A [2]rotaxane was prepared as a typical substrate from a mixture of dibenzo[24]crown-8 ether (DB24C8) and sec-ammonium hexafluorophosphate (PF(6)) with a terminal hydroxy group through end-capping with 3,5-dimethylbenzoic anhydride in the presence of tributylphosphane as a catalyst in 90% yield. A couple of approaches to the neutralization of the ammonium rotaxane were investigated to isolate the free sec amine-type rotaxane by decreasing the degree of thermodynamic and kinetic stabilities. One approach was the counteranion-exchange method in which the soft counterion PF(6)(-) was replaced with the fluoride anion by mixing with tetrabutylammonium fluoride, thus decreasing the cationic character of the ammonium moiety. Subsequent simple washing with a base allowed us to isolate the free sec-amine-type rotaxane in a quantitative yield. The other approach was a synthesis based on a protection/deprotection protocol. The acylation of the sec ammonium moiety with 2,2,2-trichloroethyl chloroformate gave an N-carbamated rotaxane that could be deprotected by treating with zinc in acetic acid to afford the corresponding free sec-amine-type rotaxane in a quantitative yield. The structure of the free sec-amine-type rotaxane was fully confirmed by spectral and analytical data. The generality of the counteranion-exchange method was also confirmed through the neutralization of a bisammonium-type [3]rotaxane. The mechanism was studied from the proposed potential-energy diagram of the rotaxanes with special emphasis on the role of the PF(6)(-) counterion. PMID- 20945311 TI - Crystallization-controlled dynamic self-assembly and an on/off switch for equilibration using boronic ester formation. AB - Macrocyclic boronic esters of different sizes can be prepared selectively from the same starting diboronic acid and 1,2-diol by means of an interesting dynamic self-assembly phenomena. More specifically, two kinds of macrocyclic boronic esters could be formed diastereoselectively and nearly quantitatively under neutral conditions by the addition of an appropriate guest molecule that acts as a template. Although a mixture of tetrol 1 and di(boronic acid) 2 in methanol gave only insoluble polymeric boronic esters, a soluble macrocyclic boronic ester, homo-[2+2], was obtained selectively in the presence of toluene as a guest molecule. Furthermore, when benzene was employed as a guest molecule, the selective formation of another macrocyclic boronic ester, hetero-[3+3], occurred. Interestingly, each of these macrocycles could be converted into the other in the presence of methanol and the appropriate guest molecule; however, under aprotic conditions, guest molecules encaged by the macrocyclic boronic ester could be exchanged without affecting its structure. Thus the presence or absence of a protic solvent could be used as a regulator to switch on or off the dynamic equilibrium of the system. In addition, investigation of the effect of reaction time, direct observation of the reaction mixture by NMR spectroscopy, and carrying out the reaction using optically active tetrol suggested that precipitation plays an essentially important role in the selective formation of the macrocyclic boronic esters. Thus, although both of [2+2] and [3+3] were present as solutes in the reaction mixture, the type of added guest molecule induced the selective precipitation of only one form of macrocyclic boronic ester, hence displacing the equilibrium of the system. PMID- 20945312 TI - Organocatalysts for the controlled "immortal" ring-opening polymerization of six membered-ring cyclic carbonates: a metal-free, green process. AB - Six-membered cyclic carbonates, namely trimethylene carbonate (TMC), 3,3 dimethoxytrimethylene carbonate (DMTMC) and 3-benzyloxytrimethylene carbonate (BTMC), undergo controlled "immortal" ring-opening polymerization (iROP) under mild conditions (bulk, 60-150 degrees C), by using organocatalysts, including an amine [4-N,N-dimethylaminopyridine (DMAP)], a guanidine [1,5,7-triazabicyclo [4.4.0]dec-5-ene (TBD)], or a phosphazene [2-tert-butylimino-2-diethylamino-1,3 dimethylperhydro-1,3,2-diazaphosphorine (BEMP)], in the presence of an alcohol [benzyl alcohol (BnOH), 1,3-propanediol (PPD), glycerol (GLY)] that acts as both a co-initiator and a chain-transfer agent. Remarkably, such organocatalysts remain highly active in the iROP of technical-grade, unpurified TMC. Under optimized conditions, as much as 100,000 equivalents of TMC were fully converted by as little as 10 ppm of BEMP with the simultaneous growth of as many as 200 polymer chains, allowing the preparation of high molar mass poly(trimethylene carbonate)s (up to 45,800 g mol(-1)). These catalyst systems enable among the highest activities (TOF=55,800 h(-1)) and productivities (TON=95,000) ever reported for the ROP of TMC. PMID- 20945313 TI - Surface passivation-induced strong ferromagnetism of zinc oxide nanowires. PMID- 20945314 TI - X-ray fluorescence investigation of ordered intermetallic phases as electrocatalysts towards the oxidation of small organic molecules. AB - The composition of ordered intermetallic nanoparticles (PtBi and PtPb) has been quantitatively studied by in situ X-ray fluorescence (XRF) during active electrochemical control in solutions of supporting electrolyte and small organic molecules (SOMs). Because the Pt L(beta1,2) lines and the Bi L(alpha1,2) lines are only separated by 200 eV, an energy-dispersive detector and a multiple channel analyzer (MCA) were used to record the major fluorescent emission lines from these two elements. The molar ratios of platinum to the less-noble elements (Bi, Pb) in the nanoparticles dramatically changed as a function of the applied upper limit potentials (E(ulp)) in cyclic voltammetric (CV) characterization. Similar to previous investigations for bulk intermetallic surfaces, the less noble elements leached out from the surfaces of the intermetallic nanoparticles. For PtBi nanoparticles, the ratios of fluorescence intensities of Pt/Bi in the samples were 0.42, 0.96, and 1.36 for E(ulp)=+0.40, +0.80, and 1.20 V, respectively, while cycling the potential from -0.20 V to the E(ulp) value for 10 cycles. The leaching-out process of the less-noble elements occurred at more negative E(ulp) values than expected. After cycling to relatively positive E(ulp) values, nonuniform PtM (M=Bi of Pb) nanoparticles formed with a Pt-rich shell and intermetallic PtM core. When the supporting solutions contained active fuel molecules in addition to the intermetallic nanoparticles (formic acid for PtBi, formic acid and methanol for PtPb), kinetic stabilization effects were observed for E(ulp)=+0.80 V, in a way similar to the response of the bulk materials. It was of great importance to quantitatively explore the change in composition and structure of the intermetallic nanoparticles under active electrochemical control. More importantly, this approach represents a simple, universal, and multifunctional method for the study of multi-element nanoparticles as electrocatalysts. This is, to our knowledge, the first report of nondestructive, quantitative characterization of bimetallic or multi-elemental nanoparticles electrocatalysts under active electrochemical control. PMID- 20945315 TI - Short-peptide-based hydrogel: a template for the in situ synthesis of fluorescent silver nanoclusters by using sunlight. AB - N-terminally Fmoc-protected dipeptide, Fmoc-Val-Asp-OH, forms a transparent, stable hydrogel with a minimum gelation concentration of 0.2% w/v. The gelation property of the hydrogel was investigated by using methods such as transmission electron microscopy, field-emission scanning electron microscopy, atomic force microscopy and Fourier transform infrared spectroscopy. The silver-ion encapsulating hydrogel can efficiently and spontaneously produce fluorescent silver nanoclusters under sunlight at physiological pH (7.46) by using a green chemistry approach. Interestingly, in the absence of any conventional reducing agent but in the presence of sunlight, silver ions were reduced by the carboxylate group of a gelator peptide that contains an aspartic acid residue. These clusters were investigated by using UV/Vis spectroscopy, photoluminescence spectroscopy, high-resolution transmission electron microscopy (HR-TEM), atomic force microscopy (AFM) and X-ray diffraction (XRD) studies. Mass spectrometric analysis shows the presence of a few atoms in nanoclusters containing only Ag(2). The reported fluorescent Ag nanoclusters show excellent optical properties, including a very narrow emission profile and large Stokes shift (>100 nm). The reported fluorescent Ag nanoclusters within hydrogel are very stable even after 6 months storage in the dark at 4 degrees C. The as-prepared hydrogel-nanocluster conjugate could have applications in antibacterial preparations, bioimaging and other purposes. PMID- 20945316 TI - Partial agonists and subunit selectivity at NMDA receptors. AB - Subunit-selective ligands for glutamate receptors remains an area of interest as glutamate is the major excitatory neurotransmitter in the brain and involved in a number of diseased states in the central nervous system (CNS). Few subtype selective ligands are known, especially among the N-methyl-D-aspartic acid (NMDA) receptor class. Development of these ligands seems to be a difficult task because of the conserved region in the binding site of the NMDA receptor subunits. A few scaffolds have been developed showing potential to differentiate between the NMDA receptors. PMID- 20945317 TI - The role of epigenetic transcription repression and DNA methyltransferases in cancer. AB - Epigenetic alterations such as DNA methylation have been implicated in the development and progression of various cancers. DNA methylation consists of the reversible addition of a methyl group to the carbon 5 position of cytosine in CpG dinucleotides and is considered essential for normal embryonic development. However, global genomic hypomethylation and aberrant hypermethylation of regulatory regions of tumor suppressor genes have been associated with chromosomal instability and transcription repression, respectively, providing neoplastic cells with a selective advantage. DNA methyltransferases are the enzymes responsible for the addition of methyl groups to CpG dinucleotides, which, together with histone modifiers, initiate the events necessary for transcription repression to occur. It has been demonstrated that increased expression of DNA methyltransferases may contribute to tumor progression through methylation-mediated gene inactivation in various human cancers. Given their importance, this article reviews the main epigenetic mechanisms for regulating transcription and its implications in cancer development. PMID- 20945318 TI - The effects of body mass index on complications and survival outcomes in patients with cervical carcinoma undergoing curative chemoradiation therapy. AB - BACKGROUND: The effect of body mass index (BMI) on treatment outcomes for patients with locally advanced cervical carcinoma who receive definitive chemoradiation is unclear. METHODS: The cohort in this study included all patients with cervical carcinoma (n = 404) who had stage IB(1) disease and positive lymph nodes or stage >=IB(2) disease and received treatment at the authors' facility between January 1998 and January 2008. The mean follow-up was 47.2 months. BMI was calculated using the National Institute of Health online calculator. BMI categories were created according to the World Health Organization classification system. Primary outcomes were overall survival, disease-free survival, and complication rate. Univariate and multivariate analyses were performed. Kaplan-Meier survival curves were generated and compared using Cox proportional hazard models. RESULTS: On multivariate analysis, compared with normal weight (BMI 18.5-24.9 kg/m(2) ), a BMI <18.5 kg/m(2) was associated with decreased overall survival (hazard ratio, 2.37; 95% confidence interval, 1.28-4.38; P < .01). The 5-year overall survival rate was 33%, 60%, and 68% for a of BMI <18.5 kg/m(2) , a BMI from 18.5 kg/m(2) to 24.9 kg/m(2) , and a BMI >24.9 kg/m(2) , respectively. A BMI <18.5 kg/m(2) was associated with increased risk of grade 3 or 4 complications compared with a BMI >24.9 kg/m(2) (radiation enteritis: 16.7% vs 13.6%, respectively; P = .03; fistula: 11.1% vs 8.8%, respectively; P = .05; bowel obstruction: 33.3% vs 4.4%, respectively; P < .001; lymphedema: 5.6% vs 1.2%, respectively; P = .02). CONCLUSIONS: Underweight patients (BMI <18.5 kg/m(2) ) with locally advanced cervical cancer had diminished overall survival and more complications than normal weight and obese patients. PMID- 20945319 TI - Local, regional, and systemic recurrence rates in patients undergoing skin sparing mastectomy compared with conventional mastectomy. AB - BACKGROUND: Although the use of SSM is becoming more common, there are few data on long-term, local-regional, and distant recurrence rates after treatment. The purpose of this study was to examine the rates of local, regional, and systemic recurrence, and survival in breast cancer patients who underwent skin-sparing mastectomy (SSM) or conventional mastectomy (CM) at our institution. METHODS: Patients with stage 0 to III unilateral breast cancer who underwent total mastectomy at our center from 2000 to 2005 were included in this study. Kaplan Meier curves were calculated, and the log-rank test was used to evaluate the differences between overall and disease-free survival rates in the 2 groups. RESULTS: Of 1810 patients, 799 (44.1%) underwent SSM and 1011 (55.9%) underwent CM. Patients who underwent CM were older (58.3 vs 49.3 years, P<.0001) and were more likely to have stage IIB or III disease (53.0% vs 31.8%, P<.0001). Significantly more patients in the CM group received neoadjuvant chemotherapy and adjuvant radiation therapy (P<.0001). At a median follow-up of 53 months, 119 patients (6.6%) had local, regional, or systemic recurrences. The local, regional, and systemic recurrence rates did not differ significantly between the SSM and CM groups. After adjusting for clinical TNM stage and age, disease-free survival rates between the SSM and CM groups did not differ significantly. CONCLUSIONS: SSM is an acceptable treatment option for patients who are candidates for immediate breast reconstruction. Local-regional recurrence rates are similar to those of patients undergoing CM. Cancer 2011. (c) 2010 American Cancer Society. PMID- 20945320 TI - International staging system and metaphase cytogenetic abnormalities in the era of gene expression profiling data in multiple myeloma treated with total therapy 2 and 3 protocols. AB - BACKGROUND: Myeloma survival varies markedly with International Staging System classification, presence of cytogenetic abnormalities, and, especially, gene expression profiling-based risk and delTP53 status, whose collective impact has not been examined in the context of specific therapies. METHODS: The authors examined overall survival (OS), event-free survival (EFS), and complete response duration (CRD) in Total Therapy 2 with randomization to a control or thalidomide arm and in Total Therapy 3 with added bortezomib. Among 612 patients with complete data sets, multivariate analyses were used to investigate the relative contributions to OS, EFS, and CRD of International Staging System stage, cytogenetic abnormalities, and gene expression profiling-derived risk and delTP53 status, in the context of the 3 Total Therapy regimens. RESULTS: Whereas gene expression profiling risk segregated outcomes within all 3 International Staging System stages, International Staging System 3 conferred inferior prognosis only in low-risk myeloma, whereas the grave prognosis of high-risk disease was International Staging System-independent. After adjusting for gene expression profiling-defined high risk and delTP53 in multivariate analysis, International Staging System 3 and cytogenetic abnormalities both retained independent adverse implications for OS, EFS, and CRD. Among the 86% with low-risk disease, cytogenetic abnormalities and delTP53 both affected all 3 endpoints negatively, whereas the International Staging System 3 effect was limited to OS. Total Therapy 3 improved survival outcomes beyond results obtained with Total Therapy 2. CONCLUSIONS: In the genomic era, standard laboratory variables, such as International Staging System stage and presence of cytogenetic abnormalities, continue to impact survival after adjusting for gene expression profiling risk and delTP53 status, providing a basis for stratification in our current practice of gene expression profiling risk-based treatment assignment. PMID- 20945321 TI - Long-term outcomes in the second-line treatment of chronic myeloid leukemia: a review of tyrosine kinase inhibitors. AB - Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative neoplasm. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph), which results in the synthesis of the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) fusion oncoprotein, a constitutively active tyrosine kinase. The introduction of imatinib, a tyrosine kinase inhibitor (TKI) that is specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). For patients with CML, failure on standard-dose imatinib therapy (400 mg daily), imatinib dose escalation (600-800 mg daily) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients who experience drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutation status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historic response, adverse-event tolerance, and risk factors. PMID- 20945322 TI - A higher degree of methylation of the HPV 16 E6 gene is associated with a lower likelihood of being diagnosed with cervical intraepithelial neoplasia. AB - BACKGROUND: Although HPV 16 is the most common HPV genotype associated with cancerous lesions of the cervix, only a fraction of HPV 16 infected women are diagnosed with precancerous lesions of the cervix. Therefore, molecular changes in HPV 16, rather than infections per se, may serve as better screening or diagnostic biomarkers. The purpose of the study was to evaluate whether methylation status of specific regions of the HPV E6 gene promoter and enhancer is independently associated with the likelihood of being diagnosed with higher grades of cervical intraepithelial neoplasia (CIN 2+). METHODS: The study included 75 HPV 16-positive women diagnosed with CIN 2+ or <=CIN 1. Pyrosequencing technology was applied to quantify methylation at 6 cytosine guanine dinucleotide (CpG) sites of the HPV 16 E6 promoter and enhancer. CIN 2+ (yes/no) was the dependent variable in logistic regression models that specified the degree of methylation of the CpG sites of the HPV 16 E6 gene as the primary independent predictors. All models were adjusted for demographic, lifestyle, known risk factors for cervical cancer, and circulating concentrations of "cancer protective" micronutrients. RESULTS: The odds of being diagnosed with CIN 2+ were 79% lower when the degree of methylation of the HPV 16 enhancer and promoter sites was >=9.5% (OR = 0.21; 95% CI, 0.06-0.79; P = .02). CONCLUSIONS: Results suggested that CpG methylation is independently involved in the biology of HPV 16 as well as in the development of higher grades of CIN. PMID- 20945323 TI - Subcutaneous or intravenous administration of romiplostim in thrombocytopenic patients with lower risk myelodysplastic syndromes. AB - BACKGROUND: Romiplostim is a peptibody protein that augments thrombopoiesis by activating the thrombopoietin receptor. METHODS: In this phase 2, multicenter, open-label study, 28 thrombocytopenic patients with lower risk myelodysplastic syndromes (MDS) were assigned to receive romiplostim 750 MUg administered subcutaneously either weekly or biweekly or administered as biweekly intravenous injections for 8 weeks. Patients also could enter a 1-year study extension phase. RESULTS: At least 1 adverse event was observed in 93% of patients. The most common adverse events were fatigue and headache (18% for both, and 5 events were grade 3 or 4. There was 1 serious treatment-related adverse event in the biweekly intravenous cohort (hypersensitivity). This hypersensitivity resolved without discontinuation of study treatment. No patients developed neutralizing antibodies or bone marrow fibrosis. Of the patients who completed 8 weeks of treatment, 57% had a complete platelet response, an additional 8% had a major platelet response, and 61% did not require a platelet transfusion during this period. Weekly subcutaneous injections achieved the highest mean trough concentrations. CONCLUSIONS: The safety and efficacy profiles of romiplostim in this study suggested that weekly subcutaneous administration of 750 MUg romiplostim is an appropriate starting dose for future clinical studies in patients with MDS and thrombocytopenia. PMID- 20945324 TI - Radiofrequency ablation as an adjunct to systemic chemotherapy for colorectal pulmonary metastases. PMID- 20945326 TI - Concordance in histological and biological parameters between first and second primary breast cancers. AB - BACKGROUND: Women with breast cancer are more likely to have a second breast cancer than women in the general population are to have a primary cancer. However, the biological relationship between primary and second breast cancers is not clear. METHODS: A total of 30,617 patients diagnosed with bilateral breast cancers between 1990 and 2007 were identified through 17 cancer registries of the Surveillance, Epidemiology, and End Results program. Logistic regression with odds ratios (ORs) and 95% confidence intervals (CIs) was used to model strength of association in hormone receptor status, grade, and histology between 2 cancers. RESULTS: There was a strong association in estrogen receptor status between 2 bilateral tumors (OR, 7.64; 95% CI, 7.00-8.35). The strength of association in estrogen receptor status depended on the time interval between the first and second tumors and age at diagnosis. The OR was 25.9 for synchronous tumors (within 1 month) and 3.69 for metachronous tumors separated by >=10 years. The strength of association was stronger in patients whose first cancer was diagnosed before age 50 (OR, 11.7) versus after age 50 (OR, 5.71). A similar pattern was observed for progesterone receptor, grade, and histological type, but with relatively weaker association. CONCLUSIONS: The strong concordance in hormone receptor status of primary and second breast cancers suggests that 2 breast cancers arise in a common milieu and that tumor subtypes are predetermined in the early stage of breast carcinogenesis. PMID- 20945327 TI - Methylation of the candidate biomarker TCF21 is very frequent across a spectrum of early-stage nonsmall cell lung cancers. AB - BACKGROUND: The transcription factor TCF21 is involved in mesenchymal-to epithelial differentiation and was shown to be aberrantly hypermethylated in lung and head and neck cancers. Because of its reported high frequency of hypermethylation in lung cancer, further characterization of the stages and types of nonsmall cell lung cancer (NSCLC) that are hypermethylated and the frequency of hypermethylation and associated "second hits" were assessed. METHODS: TCF21 promoter hypermethylation in 105 NSCLC including various stages and histologies in smokers and nonsmokers was determined. In addition, TCF21 loss of heterozygosity and mutational status were examined. Twenty-two cancer cell lines from varied tissue origins were also assayed. The NSCLC results were validated and expanded by examining TCF21 immunohistochemical expression on a tissue microarray containing 300 NSCLC cases. RESULTS: Overall, 81% of NSCLC samples showed TCF21 promoter hypermethylation, and 84% showed decreased TCF21 protein expression. Multivariate analysis showed that TCF21 expression, although below normal in both histologies, was lower in adenocarcinoma than in squamous cell carcinoma and was not independently correlated with sex, smoking, and EGFR mutation status or with clinical outcome. Cell lines from other cancer types also showed frequent TCF21 promoter hypermethylation. CONCLUSIONS: Hypermethylation and decreased expression of TCF21 were tumor specific and very frequent in all NSCLCs, even early-stage disease, thus making TCF21 a potential candidate methylation biomarker for early-stage NSCLC screening. TCF21 hypermethylation in a variety of tumor cell lines suggests it may also be a valuable methylation biomarker in other tumor types. PMID- 20945328 TI - Fine-needle aspiration cytopathology--an accurate diagnostic modality in mammary carcinoma with osteoclast-like giant cells: a study of 8 consecutive cases. AB - BACKGROUND: Invasive ductal carcinoma with osteoclast-like giant cells (OGCs) is a very rare breast tumor the main characteristic of which is the presence of multinucleated cells of histiocytic nature. METHODS: The authors report a study of 8 consecutive cases of fine-needle aspiration cytopathology (FNAC) of breast nodules in which OGCs and malignant epithelial cells were associated and diagnosed as mammary carcinoma with OGCs. These cases were selected over a period of 5 years from more than 6000 patients who were examined during a weekly, single day, multidisciplinary breast clinic. The corresponding biopsies and surgical specimens were examined histologically in an immunohistochemical study using a histiocytic marker (cluster of differentiation 68 [CD68]). RESULTS: Conventional histologic analysis made it possible to diagnose 5 of the 8 cases as mammary carcinoma with OGCs; whereas, in the other 3 cases, OGCs were not detected without the help of immunohistochemistry. CONCLUSIONS: FNAC appeared to be a very efficient way to diagnose breast carcinoma with OGCs, because it detected forms with only a few OGCs that usually are not observed at histologic diagnosis. Consequently, the current results indicated that mammary carcinoma with OGCs may be more frequent than reported previously. PMID- 20945329 TI - Experience with standardized thyroid fine-needle aspiration reporting categories: follow-up data from 529 cases with "indeterminate" or "atypical" reports. AB - BACKGROUND.: A significant number of thyroid fine-needle aspiration cytology (FNAC) cases yield inconclusive results. The recent National Cancer Institute guidelines and those published by other societies are important contributions to standardizing the diagnostic approach. Nevertheless, there are significant issues in the application of guidelines and the evaluation of their clinical efficacy. Data from individual departments can be useful in demonstrating the role of standardized reporting. METHODS.: The authors followed 529 consecutive cases with inconclusive thyroid FNA results that were analyzed in a single laboratory in Western Australia. In that laboratory, standardized reporting in categories has been in place for a decade, and inconclusive cases have been subdivided into indeterminate and atypical groups. Follow-up data was obtained for 341 indeterminate cases (17.2% of total thyroid FNA accessions) and for 188 atypical cases (9.5% of accessions). RESULTS.: In total, 127 nodules with atypical results (67.6%) underwent surgical excision compared with 131 nodules with indeterminate results (38.4%; P < .0001). In 96 excised nodules with atypical results (75.6%), the excised specimens were identified as neoplastic compared with 61 excised nodules with indeterminate results (46.6%; P < .0001). In addition, 31 excised nodules with atypical results (24.4%) had a malignancy proven compared with 17 excised nodules with indeterminate results (13%; P < .05). In addition, 51 of 82 repeat FNAs (62.2%) among patients who had indeterminate results yielded a more specific diagnosis compared with 2 of 9 repeat FNAs (22.2%) among patients who had atypical results (P < .05). CONCLUSIONS.: The routine subcategorization of patients who had inconclusive thyroid FNA reports into indeterminate and atypical groups resulted in statistically significant differences in the likelihood of neoplasia and malignancy. Patients who had indeterminate results were more likely to benefit from repeat FNAC than patients who had atypical results. The current results indicated that patients who fall into these 2 categories are likely to benefit from different clinical management protocols. Cancer Cancer Cytopathol 2010. (c) 2010 American Cancer Society. PMID- 20945330 TI - Phosphorylation of Sox2 cooperates in reprogramming to pluripotent stem cells. AB - Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by transduction of reprogramming factors, including Oct4, Sox2, Klf4, and c-Myc. A coordinated network of these factors was suggested to confer a pluripotency of iPSCs. Together with Oct4, Sox2 plays a major role as a master regulator in ESCs. However, the underlying mechanisms by which Sox2 contributes to self-renewal or reprogramming processes remain to be determined. Here, we provide new evidence for a phosphorylation-based regulation of Sox2 activity. Akt directly interacts with Sox2 and promotes its stabilization through phosphorylation at Thr118, which enhances the transcriptional activity of Sox2 in ESCs. Moreover, phosphorylation of Sox2 cooperates in the reprogramming of mouse embryonic fibroblasts by enabling more efficient induction of iPSCs. Overall, our studies provide new insights into the regulatory mechanism of Sox2 in ESCs and also provide a direct link between phosphorylation events and somatic cell reprogramming. PMID- 20945331 TI - Irradiation enhances the tumor tropism and therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand-secreting human umbilical cord blood-derived mesenchymal stem cells in glioma therapy. AB - Irradiation is a standard therapy for gliomas and many other cancers. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for cancer gene therapy. Here, we show that tumor irradiation enhances the tumor tropism of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) and the therapeutic effect of TRAIL delivered by UCB-MSCs. The sequential treatment with irradiation followed by TRAIL secreting UCB-MSCs (MSC-TRAIL) synergistically enhanced apoptosis in either TRAIL sensitive or TRAIL-resistant glioma cells by upregulating the death receptor 5 and by inducing caspase activation. Migration assays showed greater MSC migration toward irradiated glioma cells and the tumor site in glioma-bearing mice compared with unirradiated tumors. Irradiated glioma cells had increased expression of interleukin-8 (IL-8), which leads to the upregulation of the IL-8 receptor on MSCs. This upregulation, which is involved in the migratory capacity of UCB-MSCs, was confirmed by siRNA inhibition and an antibody-neutralizing assay. In vivo survival experiments in orthotopic xenografted mice showed that MSC-based TRAIL gene delivery to irradiated tumors had greater therapeutic efficacy than a single treatment. These results suggest that clinically relevant tumor irradiation increases the therapeutic efficacy of MSC-TRAIL by increasing tropism of MSCs and TRAIL-induced apoptosis, which may be a more useful strategy for cancer gene therapy. PMID- 20945332 TI - Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. AB - Recent in vivo studies indicate that mesenchymal stem cells (MSCs) may have beneficial effects in the treatment of sepsis induced by bacterial infection. Administration of MSCs in these studies improved survival and enhanced bacterial clearance. The primary objective of this study was to test the hypothesis that human MSCs possessed intrinsic antimicrobial properties. We studied the effect of human MSCs derived from bone marrow on the bacterial growth of Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) bacteria. MSCs as well as their conditioned medium (CM) demonstrated marked inhibition of bacterial growth in comparison with control medium or normal human lung fibroblasts (NHLF). Analysis of expression of major antimicrobial peptides indicated that one of the factors responsible for the antimicrobial activity of MSC CM against Gram-negative bacteria was the human cathelicidin antimicrobial peptide, hCAP-18/LL-37. Both m-RNA and protein expression data showed that the expression of LL-37 in MSCs increased after bacterial challenge. Using an in vivo mouse model of E. coli pneumonia, intratracheal administration of MSCs reduced bacterial growth (in colony-forming unit) in the lung homogenates and in the bronchoalveolar lavage (BAL) fluid, and administration of MSCs simultaneously with a neutralizing antibody to LL-37 resulted in a decrease in bacterial clearance. In addition, the BAL itself from MSC-treated mice had a greater antimicrobial activity in comparison with the BAL of phosphate buffered saline (PBS)-treated mice. Human bone marrow-derived MSCs possess direct antimicrobial activity, which is mediated in part by the secretion of human cathelicidin hCAP-18/ LL-37. PMID- 20945333 TI - Trends in survival for patients with metastatic soft-tissue sarcoma. AB - BACKGROUND: The objective of this study was to determine whether the overall survival of patients with metastatic soft tissue sarcoma (STS) has improved over the last 20 years. METHODS: In total, 1024 patients who had synchronous metastatic (SM) STS or metachronous metastatic (MM) STS diagnosed between 1987 and 2006 were included prospectively in the French Sarcoma Group database after central histologic review. Four periods of diagnosis of metastatic disease were defined: P1, from 1987 to 1991 (n = 208); P2, from 1992 to 1996 (n = 287); P3, from 1997 to 2001 (n = 285); and P4, from 2002 to 2006 (n = 244). Patient characteristics were analyzed as prognostic factors by using a Cox model. RESULTS: The proportion of patients with SM, the interval between diagnosis and MM, and the clinical characteristics of the patients were similar across the 4 periods. Although there was no significant difference in the median overall survival (OS) from P1 through P2 (P1, 12.3 months; 95% confidence interval [CI], 9.9-14.7 months; P2, 11.4 months; 95% CI, 9-13.9 months), significant improvements were observed in the later periods (P3, 15 months; 95% CI, 11.8-18.2 months; P4, 18 months; 95% CI, 15.3-20.7 months; P = .029; log-rank test). The 2 year OS rate also increased throughout the study period from 28.1% during P1 to 38.7% during P4. On multivariate analysis, period of diagnosis, age, histologic subtype, time to metastatic recurrence, French Federation of Cancer Centers Sarcoma Group grade, and the number of metastatic sites were independent prognostic factors for OS. CONCLUSIONS: The current analysis revealed that the median OS of patients with metastatic STS had improved by 50% during the last 20 years. These data should be considered in the interpretation of results from ongoing and future STS trials. PMID- 20945334 TI - The severity of osteogenesis imperfecta: a comparison to the relative free energy differences of collagen model peptides. AB - Molecular dynamics simulations were carried out to calculate free energy differences between the folded and unfolded states of wild type and mutant collagen model peptides. The calculated stability of the collagen models was compared with the severity of osteogenesis imperfecta. Free energy differences of Gly -> Xaa (Xaa: Ser, Cys, Glu, and Asp) mutations between the wild type and the mutants at position 15 of the model peptide were 3.8, 4.2, 5.6, and 8.8 kcal/mol, respectively. The corresponding free energy differences of a second Gly mutation at the same position in different chains were, on average, 1.3, 1.5, 2.9, and 5.4 kcal/mol, respectively. Free energy simulations were also performed to estimate the relative stability between an oxidized form and a reduced form of the mutants containing two Cys residues, which indicated that the mutant of the collagen-like peptide containing an intramolecular disulfide bond was more stable than the mutant containing one Cys residue but less stable than the wild type. The calculated free energy differences between an oxidized and a reduced form of the mutants containing two Cys residues are 0.8 and 2.6 kcal/mol for the disulfide bonds between Chains A and B and between Chains A and C, respectively. PMID- 20945335 TI - The crystal structure of cobalt-substituted pseudoazurin from Alcaligenes faecalis. AB - The Cu(II) center at the active site of the blue copper protein pseudoazurin from Alcaligenes faecalis has been substituted by Co(II) via denaturing of the protein, chelation and removal of copper by EDTA and refolding of the apo protein, followed by addition of an aqueous solution of CoCl(2). Sitting drop vapour diffusion experiments produced green hexagonal crystals, which belong to space group P6(5), with unit cell dimensions a = b = 50.03, c = 98.80 A. Diffraction data, collected at 291 K on a copper rotating anode X-ray source, were phased by the anomalous signal of the cobalt atom. The structure was built automatically, fitted manually and subsequently refined to 1.86 A resolution. The Co-substituted protein exhibits similar overall geometry to the native structure with copper. Cobalt binds more strongly to the axial Met86-Sdelta and retains the tetrahedral arrangement with the four ligand atoms, His40-Ndelta(1), Cys78 Sgamma, His81-Ndelta(1), and 86Met-Sdelta, although the structure is less distorted than the native copper protein. The structure reported herein, is the first crystallographic structure of a Co(II)-substituted pseudoazurin. PMID- 20945336 TI - Imaging of apoptosis in the heart with nanoparticle technology. AB - Apoptosis plays an important role in the loss of cardiomyocytes in both ischemic injury and heart failure. Pioneering work with single photon emission computed tomography imaging of (99)Tc-annexin showed that cell death in the heart could be imaged in vivo. Over the last 5 years a significant amount of experience with annexin-labeled magnetic nanoparticles, principally AnxCLIO-Cy5.5, has also been gained. Here, we review the experience with AnxCLIO-Cy5.5 in the heart and compare this experience to that of earlier studies with (99)Tc-annexin. The imaging of apoptosis with AnxCLIO-Cy5.5 provides valuable insights not only into molecular imaging in the heart but, more broadly, into the use of nanoparticle technology for molecular imaging in general. PMID- 20945337 TI - TIEG1 negatively controls the myoblast pool indispensable for fusion during myogenic differentiation of C2C12 cells. AB - The transforming growth factor (TGF)-beta inducible early gene (TIEG)-1 is implicated in the control of cell proliferation, differentiation, and apoptosis in some cell types. Since TIEG1 functioning may be associated with TGF-beta, a suppressor of myogenesis, TIEG1 is also likely to be involved in myogenesis. Therefore, we investigated the function of TIEG1 during myogenic differentiation in vitro using the murine myoblasts cell line, C2C12. TIEG1 expression increased during differentiation of C2C12 cells. Constitutive expression of TIEG1 reduced survival and decreased myotube formation. Conversely, knocking down TIEG1 expression increased the number of viable cells during differentiation, and accelerated myoblast fusion into multinucleated myotubes. However, expression of the myogenic differentiation marker, myogenin, remained unaffected by TIEG1 knockdown. The mechanism underlying these events was investigated by focusing on the regulation of myoblast numbers after induction of differentiation. The knockdown of TIEG1 led to changes in cell cycle status and inhibition of apoptosis during the initial stages of differentiation. Microarray and real-time PCR analyses showed that the regulators of cell cycle progression were highly expressed in TIEG1 knockdown cells. Therefore, TIEG1 is a negative regulator of the myoblast pool that causes inhibition of myotube formation during myogenic differentiation. PMID- 20945339 TI - The relationship between baseline health and longitudinal costs of hospital use. AB - In this paper, we investigate the relationship between baseline health and costs of hospital use over a period of eight years. We combine cross-sectional survey data with information from the Dutch national hospital register. Four different indicators of health (self-perceived health, long-term impairments, ADL limitations and comorbidity) are considered. We find that for ages 50 to 70, differences in hospital costs between good health and bad health are substantial and persist during the whole time period. However, for higher ages expected hospital costs for individuals in bad health decline rapidly and become lower than those for people in good health after about six to seven years. The higher mortality rate among people in bad health is the primary cause here. Our results are confirmed for all four health indicators. We conclude that relying on better health to contain healthcare expenditures is too optimistic, and the interaction between health and mortality should be taken into account when projecting healthcare costs. Healthy ageing is important, but more for health gains than for cost savings. PMID- 20945340 TI - Family income and child cognitive and behavioural development in the United Kingdom: does money matter? AB - This study investigates the extent to which family income is associated with an extensive range of child cognitive and behavioural outcomes in a cohort of almost 19 000 British children born between 2000 and 2001. Merging the economists' and developmental psychologists' approaches, it also attempts to identify the main mechanisms through which family economic resources translate into better developmental outcomes for children. The relative and joint relevance of three groups of mediating factors (parental stress, parental investment and other family-related pathways), identified from the recent economic and psychological literature, are examined both in a cross-sectional ('mopping-up' approach) and in a panel data (fixed effects models) context. Results indicate a weak or absent direct effect of family economic resources on child development after controlling for potential mediating mechanisms. The study also identifies key mediating factors (e.g. maternal depression, a cognitively stimulating home environment, parenting practices and length of breastfeeding) that could be targeted by government initiatives in order to effectively improve children's intellectual development and behaviour beyond what income redistribution can achieve. PMID- 20945341 TI - The Hippo pathway in biological control and cancer development. AB - The Hippo pathway is an evolutionally conserved protein kinase cascade involved in regulating organ size in vivo and cell contact inhibition in vitro by governing cell proliferation and apoptosis. Deregulation of the Hippo pathway is linked to cancer development. Its first core kinase Warts was identified in Drosophila more than 15 years ago, but it gained much attention when other core components of the pathway were identified 8 years later. Major discoveries of the pathway were made during past several years. The core kinase components Hippo, Salvador, Warts, and Mats in the fly and Mst1/2, WW45, Lats1/2, and Mob1 in mammals phosphorylate and inactivate downstream transcriptional co-activators Yorkie in the fly, Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in mammals, respectively. Phosphorylated Yorkie, YAP, and TAZ are sequestered in the cytoplasm by interaction with 14-3-3 proteins. Here we review recent progresses of this pathway by focusing on how these proteins communicate with each other and how loss of regulation results in cancers. PMID- 20945342 TI - Cell surface N-glycans-mediated isolation of mouse neural stem cells. AB - The isolation of neural stem cells (NSCs) has been hampered by the lack of valid cell-surface antigens on NSCs, and novel valuable markers have been proposed. Glycan (oligosaccharide chain) is a potential candidate as a marker to isolate NSCs, because the species and the combination order of saccharides in glycan generate remarkable structural diversity and specificity. At present, the expression of hundreds of glycoconjugates with glycans have been found in the NSCs; however, just a few glycan-epitopes have been identified as valuable cell surface markers. This review focused on the isolation of NSC using glycoprotein, especially complex type N-glycans. The cell-surface N-glycan-mediated isolation of NSCs is therefore expected to provide a comprehensive understanding of the biologic characteristics of NSCs in the brain, and thereby help to develop novel strategies in the field of regenerative medicine. PMID- 20945343 TI - PINCH: More than just an adaptor protein in cellular response. AB - Particularly interesting new cysteine-histidine-rich protein (PINCH) is a LIM domain-only adaptor protein involved in protein recruitment, subsequent assembly of multi-protein complexes, and subcellular localization of these complexes. PINCH is developmentally regulated and its expression is critical for proper cytoskeletal organization and extracellular matrix adhesion. Although PINCH has no catalytic abilities, the PIP (PINCH-ILK-parvin) complex serves as a link between integrins and components of growth factor receptor kinase and GTPase signaling pathways. Accordingly, PINCH-mediated signaling induces cell migration, spreading, and survival. Further research on the signaling cascades affected by PINCH is key to appreciating its biological significance in cell fate and systems maintenance, as the developmental functions of PINCH may extend to disease states and the cellular response to damage. PINCH is implicated in a diverse array of diseases including renal failure, cardiomyopathy, nervous system degeneration and demyelination, and tumorigenesis. This review presents evidence for PINCH's structural and functional importance in normal cellular processes and in pathogenesis. The current data for PINCH expression in nervous system disease is substantial, but due to the complex and ubiquitous nature of this protein, our understanding of its function in pathology remains unclear. In this review, an overview of studies identifying PINCH binding partners, their molecular interactions, and the potentially overlapping role(s) of PINCH in cancer and in nervous system diseases will be discussed. Many questions remain regarding PINCH's role in cells. What induces cell-specific PINCH expression? How does PINCH expression contribute to cell fate in the central nervous system? More broadly, is PINCH expression in disease a good thing? Clarifying the ambiguous functions of PINCH expression in the central nervous system and other systems is important to understand more clearly signaling events both in health and disease. PMID- 20945344 TI - Nestin (+) stem cells independently contribute to neural remodelling of the ischemic heart. AB - Recent studies have revealed the existence of multipotent nestin-immunoreactive cells in the adult mammalian heart. These cells were recruited to infarct site following ischemic injury and differentiated to a vascular lineage leading to de novo blood vessel formation. Here, we show that a sub-population of cardiac resident nestin((+)) cells can further differentiate to a neuronal-like fate in vivo following myocardial infarction. In the ischemically damaged rat heart, neurofilament-M((+)) fibres were detected innervating the peri-infarct/infarct region and the preponderance of these fibres were physically associated with processes emanating from nestin((+)) cells. One week after isogenic heterotopic cardiac transplantation, the beating transplanted rat heart was devoid of neurofilament-M((+)) fibre staining. The superimposition of an ischemic insult to the transplanted heart led to the de novo synthesis of neurofilament-M((+)) fibres by cardiac resident nestin((+)) cells. Nerve growth factor infusion and the exposure of normal rats to intermittent hypoxia significantly increased the density of neurofilament-M((+)) fibres in the heart. However, these newly formed neurofilament-M((+)) fibres were not physically associated with nestin((+)) processes. These data highlight a novel paradigm of reparative fibrosis as a subpopulation of cardiac resident nestin((+)) cells directly contributed to neural remodelling of the peri-infarct/infarct region of the ischemically damaged rat heart via the de novo synthesis of neurofilament-M fibres. PMID- 20945345 TI - Fibroblast cytoskeletal remodeling contributes to connective tissue tension. AB - The visco-elastic behavior of connective tissue is generally attributed to the material properties of the extracellular matrix rather than cellular activity. We have previously shown that fibroblasts within areolar connective tissue exhibit dynamic cytoskeletal remodeling within minutes in response to tissue stretch ex vivo and in vivo. Here, we tested the hypothesis that fibroblasts, through this cytoskeletal remodeling, actively contribute to the visco-elastic behavior of the whole tissue. We measured significantly increased tissue tension when cellular function was broadly inhibited by sodium azide and when cytoskeletal dynamics were compromised by disrupting microtubules (with colchicine) or actomyosin contractility (via Rho kinase inhibition). These treatments led to a decrease in cell body cross-sectional area and cell field perimeter (obtained by joining the end of all of a fibroblast's processes). Suppressing lamellipodia formation by inhibiting Rac-1 decreased cell body cross-sectional area but did not affect cell field perimeter or tissue tension. Thus, by changing shape, fibroblasts can dynamically modulate the visco-elastic behavior of areolar connective tissue through Rho-dependent cytoskeletal mechanisms. These results have broad implications for our understanding of the dynamic interplay of forces between fibroblasts and their surrounding matrix, as well as for the neural, vascular, and immune cell populations residing within connective tissue. PMID- 20945346 TI - Constitutive overexpression of Id-1 in mammary glands of transgenic mice results in precocious and increased formation of terminal end buds, enhanced alveologenesis, delayed involution. AB - Inhibitor of differentiation-1 (Id-1) has been shown to play an essential role in cell proliferation, invasion, migration, and anti-apoptosis. However, the effect of Id-1 in mammary gland development remains unknown. Here, we generated MMTV-Id 1 transgenic mice to study the role of Id-1 in mammary gland development. In virgin mice, Id-1 overexpression led to precocious development and delayed regression of terminal end buds (TEBs) compared with wild-type mice. The number of BrdU-positive cells and the expression of Wnt signaling molecules, beta catenin and cyclin D1, which regulate ductal extension and TEB formation in virgin, were statistically higher in Id-1 transgenic mice than in wild-type mice. Id-1 also had an effect on the formation and proliferation of lobuloalveolar structures during early and mid-pregnancy. Id-1 transgenic mice had more lobulated and prominent alveolar budding than wild-type mice and had significantly greater counts of lobuloalveolar structures in early pregnancy. The expression of BrdU, beta-catenin, and cyclin D1 was also predominantly increased in Id-1 transgenic mice. Moreover, Id-1 transgenic mice showed delayed involution. Id-1 regulated the expression levels of anti-apoptotic Bcl-2 and pro apoptotic Bax, and resulted in delay of apoptotic peak during postlactational involution. We also found that Id-1 was able to modulate expression of the regulators of Wnt/beta-catenin signaling such as phospho-Akt, BMP2, FGF3, and RAR beta in tubuloalveolar development of mammary glands. Taken together, our results suggest that Id-1 plays a pivotal role in mammary gland development through Wnt signaling-mediated acceleration of precocity and alveologenesis and Bcl-2 family members-mediated delay of involution. PMID- 20945347 TI - Mechanisms of transforming growth factor beta induced cell cycle arrest in palate development. AB - Immaculate and complete palatal seam disintegration, which takes place at the last phase of palate development, is essential for normal palate development. And in absence of palatal midline epithelial seam (MES) disintegration, cleft palate may arise. It has been established that transforming growth factor (TGF) beta induces both epithelial mesenchymal transition (EMT) and/or apoptosis during MES disintegration. It is likely that MES might cease cell cycle to facilitate cellular changes prior to undergoing transformation or apoptosis, which has never been studied before. This study was designed to explore whether TGFbeta, which is crucial for palatal MES disintegration, is capable of inducing cell cycle arrest. We studied the effects of TGFbeta1 and TGFbeta3, potent negative regulators of the cell cycle, on p15ink4b activity in MES cells. We surprisingly found that TGFbeta1, but not TGFbeta3, plays a major role in activation of the p15ink4b gene. In contrast, following successful cell cycle arrest by TGFbeta1, it is TGFbeta3 but not TGFbeta1 that causes later cellular morphogenesis, such as EMT and apoptosis. Since TGFbeta signaling activates Smads, we analyzed the roles of three Smad binding elements (SBEs) on the p15ink4b mouse promoter by site specific mutagenesis and found that these binding sites are functional. The ChIP assay demonstrated that TGFbeta1, not TGFbeta3, promotes Smad4 binding to two 5' terminal SBEs but not the 3' terminal site. Thus, TGFbeta1 and TGFbeta3 play separate yet complimentary roles in achieving cell cycle arrest and EMT/apoptosis and cell cycle arrest is a prerequisite for later cellular changes. PMID- 20945348 TI - Control of lung development by latent TGF-beta binding proteins. AB - The latent TGF-beta binding proteins (LTBP-1 -3, and -4) assist in the secretion and localization of latent TGF-beta molecules. Ltbp3(-/-) and Ltbp4S(-/-) mice have distinct phenotypes and only in the lungs does deficiency of either Ltbp-3 or Ltbp-4 cause developmental abnormalities. To determine if these two LTBPs have additional common functions, we generated mice deficient for both Ltbp-3 and Ltbp 4S. The only novel defect in Ltbp3(-/-);Ltbp4S(-/-) mice was an early lethality compared to mice with single mutations. In addition lung abnormalities were exacerbated and the terminal air sac septation defect was more severe in Ltbp3(-/ );Ltbp4S(-/-) mice than in Ltbp4S(-/-) mice. Decreased cellularity of Ltbp3(-/ );Ltbp4S(-/-) lungs was correlated with higher rate of apoptosis in newborn lungs of Ltbp3(-/-);Ltbp4S(-/-) animals compared to WT, Ltbp3(-/-), and Ltbp4S(-/-) mice. No differences in the maturation of the major lung cell types were discerned between the single and double mutant mice. However, the distribution of type 2 cells and myofibroblasts was abnormal, and myofibroblast segregation in some areas might be an indication of early fibrosis. We also observed differences in ECM composition between Ltbp3(-/-);Ltbp4S(-/-) and Ltbp4S(-/-) lungs after birth, reflected in decreased incorporation of fibrillin-1 and -2 in Ltbp3(-/ );Ltbp4S(-/-) matrix. The function of the lungs of Ltbp3(-/-);Ltbp4S(-/-) mice after the first week of life was potentially further compromised by macrophage infiltration, as proteases secreted from macrophages might exacerbate developmental emphysema. Together these data indicate that LTBP-3 and -4 perform partially overlapping functions only in the lungs. PMID- 20945349 TI - Defining quality of care in rheumatology: the American College of Rheumatology white paper on quality measurement. PMID- 20945350 TI - Urinary 8-OHdG elevations in a partial lesion rat model of Parkinson's disease correlate with behavioral symptoms and nigrostriatal dopaminergic depletion. AB - Increased oxidative stress contributes to pathogenesis of Parkinson's disease (PD). 8-hydroxy-2'-deoxyguanosine (8-OHdG) is the oxidation product most frequently measured as an indicator of oxidative DNA damage. Several studies have shown increased 8-OHdG in PD patients. There are few basic laboratory data examining 8-OHdG levels in animal models of PD. In this study, we utilized hemiparkinsonian model of rats induced by intrastriatal injection of 6 hydroxydopamine (6-OHDA). The urinary 8-OHdG level was measured in relation to behavioral and pathological deficits arising from 6-OHDA-induced neurotoxic effects on the nigrostriatal dopaminergic pathway. All rats were subjected to a series of behavioral tests for 42 days after 6-OHDA injection. We collected urine samples with subsequent measurement of 8-OHdG level using ELISA kits. For immunohistochemical evaluation, tyrosine hydroxylase (TH) staining was performed. Significant increments in urinary 8-OHdG level were observed continuously from day 7 until day 35 compared to control group, which showed a trend of elevation as early as day 3. Such elevated urinary 8-OHdG level significantly correlated with all of the behavioral deficits measured here, suggesting that urinary 8-OHdG level provides a good index of severity of parkinsonism. Urinary 8-OHdG level also had a significant positive correlation with the survival rate of dopaminergic fibers or neurons, advancing the concept that oxidative stress during the early phase of 6-OHDA neurotoxicity may correspond to disease progression closely approximating neuronal degeneration in the nigrostriatal dopaminergic system. The present results demonstrate that alterations in urinary 8-OHdG level closely approximate onset and disease progression in PD. PMID- 20945351 TI - Novel thiopurine methyltransferase variant TPMT*28 results in a misdiagnosis of TPMT deficiency. PMID- 20945352 TI - An ex vivo imaging pipeline for producing high-quality and high-resolution diffusion-weighted imaging datasets. AB - Diffusion tensor (DT) imaging and related multifiber reconstruction algorithms allow the study of in vivo microstructure and, by means of tractography, structural connectivity. Although reconstruction algorithms are promising imaging tools, high-quality diffusion-weighted imaging (DWI) datasets for verification and validation of postprocessing and analysis methods are lacking. Clinical in vivo DWI is limited by, for example, physiological noise and low signal-to-noise ratio. Here, we performed a series of DWI measurements on postmortem pig brains, which resemble the human brain in neuroanatomical complexity, to establish an ex vivo imaging pipeline for generating high-quality DWI datasets. Perfusion fixation ensured that tissue characteristics were comparable to in vivo conditions. There were three main results: (i) heat conduction and unstable tissue mechanics accounted for time-varying artefacts in the DWI dataset, which were present for up to 15 h after positioning brain tissue in the scanner; (ii) using fitted DT, q-ball, and persistent angular structure magnetic resonance imaging algorithms, any b-value between ~2,000 and ~8,000 s/mm(2) , with an optimal value around 4,000 s/mm(2) , allowed for consistent reconstruction of fiber directions; (iii) diffusivity measures in the postmortem brain tissue were stable over a 3-year period. On the basis of these results, we established an optimized ex vivo pipeline for high-quality and high-resolution DWI. The pipeline produces DWI data sets with a high level of tissue structure detail showing for example two parallel horizontal rims in the cerebral cortex and multiple rims in the hippocampus. We conclude that high-quality ex vivo DWI can be used to validate fiber reconstruction algorithms and to complement histological studies. PMID- 20945353 TI - Lack of association between stretch-activated and volume-activated Cl- currents in hepatocellular carcinoma cells. AB - Stretch-activated chloride currents (I(Cl,SA) ) have been considered to be a component of volume-activated chloride currents (I(Cl,vol) ) for some time. This is due to a similarity in biophysical and pharmacological properties that involve a membrane curvature-induced mechanism and rearrangement of the cytoskeleton induced by cell swelling or membrane stretch. In the present study, we demonstrated that current density, along with the time taken from the activation of currents to the peak, were significantly different between the two currents, in highly metastatic human hepatocellular carcinoma cells. In addition, the activation of I(Cl,vol) or I(Cl,SA), induced maximally by hypotonic solutions or membrane stretch, respectively, did not affect the following activation of the other one. Moreover, neither inhibition of I(Cl,vol) by sh-ClC-3 transfection, nor functional blocking of I(Cl,vol) by intracellular dialysis of anti-ClC-3 antibody had an effect on the activation and properties of I(Cl,SA). Collectively, our results suggest that I(Cl,SA) is different from I(Cl,vol) in activation mechanism and/or in molecular entity responsible for formation of the currents. ClC-3 is involved in the activation of I(Cl,vol), but not of I(Cl,SA). PMID- 20945354 TI - The relationship between the Wnt/beta-catenin and TGF-beta/BMP signals in the intervertebral disc cell. AB - Degeneration of the lumbar intervertebral disc (IVD) is a cause of low back pain. In osteoarthritis patients, an increase in beta-catenin accumulation has been reported. However, the molecular mechanisms involved in IVD remain unclear. In the present study, we examined the relationship of Wnt/beta-catenin and transforming growth factor-beta (TGF-beta)/bone morphogenetic protein (BMP) signals in the IVDs. We found that treatment of nucleus pulposus (NP) cells with the Wnt/beta-catenin activator lithium chloride (LiCl) results in the increased expression of beta-catenin mRNA and protein, and cell proliferation is decreased due to the activation of the Wnt/beta-catenin signals through the suppression of c-myc and cyclin-D1. In addition, T-cell-specific transcription factor (TCF) promoter activity was found to increase the following stimulation with LiCl alone, and was further increased when BMP2 was added, in comparison to the control group. We further observed the effects of treatment with PD98059, a specific inhibitor of the mitogen-activated protein kinase pathway, on TCF promoter activity in NP cells. These effects were largely attenuated by PD98059. Moreover, when transfected IVDs were co-transfected with R-Smad expression plasmids, there was a significant decrease in TCF reporter activity. We thereafter evaluated the effects of increased Wnt/beta-catenin activity on the transcriptional activity of the Smad binding element (SBE). As a result, LiCl suppressed the activity of SBE reporter activity. The present study demonstrates for the first time that there are opposing effects between the Wnt/beta-catenin and TGF-beta/BMP signals in IVDs, which is consistent with the Wnt/beta-catenin signals contributing to the pathogenesis of IVD degeneration. PMID- 20945355 TI - Substance P stimulates the recovery of bone marrow after the irradiation. AB - The therapeutic use of ionizing radiation (e.g., X-rays and gamma-rays) needs to inflict minimal damage on non-target tissue. Recent studies have shown that substance P (SP) mediates multiple activities in various cell types, including cell proliferation, anti-apoptotic responses, and inflammatory processes. The present study investigated the effects of SP on gamma-irradiated bone marrow stem cells (BMSCs). In mouse bone marrow extracts, SP prolonged activation of Erk1/2 and enhanced Bcl-2 expression, but attenuated the activation of apoptotic molecules (e.g., p38 and cleaved caspase-3) and down-regulated Bax. We also observed that SP-decreased apoptotic cell death and stimulated cell proliferation in gamma-irradiated mouse bone marrow tissues through TUNEL assay and PCNA analysis. To determine how SP affects bone marrow stem cell populations, mouse bone marrow cells were isolated and colony-forming unit (CFU) of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) was estimated. SP-pretreated ones showed higher CFUs of MSC and HSC than untreated ones. Furthermore, when SP was pretreated in cultured human MSC, it significantly decreased apoptotic cells at 48 and 72 h after gamma-irradiation. Compared with untreated cells, SP-treated human MSCs showed reduced cleavage of apoptotic molecules such as caspase-8, -9, 3, and poly ADP-ribose polymerase (PARP). Thus, our results suggest that SP alleviates gamma-radiation-induced damage to mouse BMSCs and human MSCs via regulation of the apoptotic pathway. PMID- 20945356 TI - Impact of oxidation on protein therapeutics: conformational dynamics of intact and oxidized acid-beta-glucocerebrosidase at near-physiological pH. AB - The solution dynamics of an enzyme acid-beta-glucocerebrosidase (GCase) probed at a physiologically relevant (lysosomal) pH by hydrogen/deuterium exchange mass spectrometry (HDX-MS) reveals very uneven distribution of backbone amide protection across the polypeptide chain. Highly mobile segments are observed even within the catalytic cavity alongside highly protective segments, highlighting the importance of the balance between conformational stability and flexibility for enzymatic activity. Forced oxidation of GCase that resulted in a 40-60% reduction in in vitro biological activity affects the stability of some key structural elements within the catalytic site. These changes in dynamics occur on a longer time scale that is irrelevant for catalysis, effectively ruling out loss of structure in the catalytic site as a major factor contributing to the reduction of the catalytic activity. Oxidation also leads to noticeable destabilization of conformation in remote protein segments on a much larger scale, which is likely to increase the aggregation propensity of GCase and affect its bioavailability. Therefore, it appears that oxidation exerts its negative impact on the biological activity of GCase indirectly, primarily through accelerated aggregation and impaired trafficking. PMID- 20945357 TI - TEV protease-facilitated stoichiometric delivery of multiple genes using a single expression vector. AB - Delivery and expression of multiple genes is an important requirement in a range of applications such as the engineering of synthetic signaling pathways and the induction of pluripotent stem cells. However, conventional approaches are often inefficient, nonstoichiometric and may limit the maximum number of genes that can be simultaneously expressed. We here describe a versatile approach for multiple gene delivery using a single expression vector by mimicking the protein expression strategy of RNA viruses. This was accomplished by first expressing the genes together with TEV protease as a single fusion protein, then proteolytically self-cleaving the fusion protein into functional components. To demonstrate this method in E. coli cells, we analyzed the translation products using SDS-PAGE and showed that the fusion protein was efficiently cleaved into its components, which can then be purified individually or as a binding complex. To demonstrate this method in mammalian cells, we designed a differential localization scheme and used live cell imaging to observe the distinctive subcellular targeting of the processed products. We also showed that the stoichiometry of the processed products was consistent and corresponded with the frequency of appearance of their genes on the expression vector. In summary, the efficient expression and separation of up to three genes was achieved in both E. coli and mammalian cells using a single TEV protease self-processing vector. PMID- 20945358 TI - Structural and thermodynamic analysis of the GFP:GFP-nanobody complex. AB - The green fluorescent protein (GFP)-nanobody is a single-chain VHH antibody domain developed with specific binding activity against GFP and is emerging as a powerful tool for isolation and cellular engineering of fluorescent protein fusions in many different fields of biological research. Using X-ray crystallography and isothermal titration calorimetry, we determine the molecular details of GFP:GFP-nanobody complex formation and explain the basis of high affinity and at the same time high specificity of protein binding. Although the GFP-nanobody can also bind YFP, it cannot bind the closely related CFP or other fluorescent proteins from the mFruit series. CFP differs from GFP only within the central chromophore and at one surface amino acid position, which lies in the binding interface. Using this information, we have engineered a CFP variant (I146N) that is also able to bind the GFP-nanobody with high affinity, thus extending the toolbox of genetically encoded fluorescent probes that can be isolated using the GFP-nanobody. PMID- 20945359 TI - Preparation of a highly translocation-competent proOmpA/SecB complex. AB - Methods for reproducibly preparing highly translocation-competent proOmpA were developed. Only a competent form of proOmpA was sorted out from incompetent one using SecB, a translocation-dedicated chaperone, as a probe. Trypsin digestion revealed that the incompetent form of proOmpA was partially folded at its N terminus, consistent with the jamming of proOmpA within translocon. Although the incompetent form of proOmpA was not active as to topology inversion of SecG, the isolated proOmpA/SecB complex had recovered the ability of SecG inversion. These results let us prepare a proOmpA/SecB complex both in vivo and in vitro that is highly translocation-competent. E. coli cells harboring a plasmid, in which ompA and secB were encoded as a synthetic operon, accumulated the proOmpA/SecB complex in the cytosol. The complex, purified by means of a His tag attached to SecB, was found to be translocation-competent as revealed by the occurrence of SecG inversion, although the signal peptide of proOmpA was sensitive to proteolytic digestion. ProOmpA, in vitro synthesized by means of a continuous exchange cell free system in the presence of SecB-His, was purified as a complex with SecB, which was active as to SecG inversion as well. PMID- 20945360 TI - Rapid exploration of the folding topology of helical membrane proteins using paramagnetic perturbation. AB - An understanding of the folding states of alpha-helical membrane proteins in detergent systems is important for functional and structural studies of these proteins. Here, we present a rapid and simple method for identification of the folding topology and assembly of transmembrane helices using paramagnetic perturbation in nuclear magnetic resonance spectroscopy. By monitoring the perturbation of signals from glycine residues located at specific sites, the folding topology and the assembly of transmembrane helices of membrane proteins were easily identified without time-consuming backbone assignment. This method is validated with Mistic (membrane-integrating sequence for translation of integral membrane protein constructs) of known structure as a reference protein. The folding topologies of two bacterial histidine kinase membrane proteins (SCO3062 and YbdK) were investigated by this method in dodecyl phosphocholine (DPC) micelles. Combing with analytical ultracentrifugation, we identified that the transmembrane domain of YbdK is present as a parallel dimer in DPC micelle. In contrast, the interaction of transmembrane domain of SCO3062 is not maintained in DPC micelle due to disruption of native structure of the periplasmic domain by DPC micelle. PMID- 20945361 TI - Mass spectrometry-based clinical proteomics: head-and-neck cancer biomarkers and drug-targets discovery. AB - Mass spectrometry (MS)-based proteomics is a rapidly developing technology for both qualitative and quantitative analyses of proteins, and investigations into protein posttranslational modifications, subcellular localization, and interactions. Recent advancements in MS have made tremendous impact on the throughput and comprehensiveness of cancer proteomics, paving the way to unraveling deregulated cellular pathway networks in human malignancies. In turn, this knowledge is rapidly being translated into the discovery of novel potential cancer markers (PCMs) and targets for molecular therapeutics. Head-and-neck cancer is one of the most morbid human malignancies with an overall poor prognosis and severely compromised quality of life. Early detection and novel therapeutic strategies are urgently needed for more effective disease management. The characterizations of protein profiles of head-and-neck cancers and non malignant tissues, with unprecedented sensitivity and precision, are providing technology platforms for identification of novel PCMs and drug targets. Importantly, low-abundance proteins are being identified and characterized, not only from the tumor tissues, but also from bodily fluids (plasma, saliva, and urine) in a high-throughput and unbiased manner. This review is a critical appraisal of recent advances in MS-based proteomic technologies and platforms for facilitating the discovery of biomarkers and novel drug targets in head-and-neck cancer. A major challenge in the discovery and verification of these cancer biomarkers is the typically limited availability of well-characterized and adequately stored clinical samples in tumor and sera banks, collected using recommended procedures, and with detailed information on clinical, pathological parameters, and follow-up. Most biomarker discovery studies use limited number of clinical samples and verification of cancer markers in large number of samples is beyond the scope of a single laboratory. The validation of these potential markers in large sample cohorts in multicentric studies is needed for their translation from the bench to the bedside. PMID- 20945362 TI - Depressive symptoms and executive functioning in stroke patients: a follow-up study. AB - BACKGROUND: Cognitive and emotional sequellae are commonly observed in stroke patients and these symptoms often co-occur. Diagnosis can be difficult since symptoms of depression and executive dysfunction overlap. OBJECTIVE: To study the longitudinal relationship between depressive symptoms and executive dysfunction in stroke patients. METHODS: The study comprises of 116 first-ever stroke patients who were followed-up for 2 years and who were assessed for emotional and cognitive sequellae after 1, 6, 12, and 24 months. Emotional disturbances were evaluated using the SCL-90 depression subscale. Executive functions were assessed using compound scores of a combination of the interference scores of the Stroop Colour Word Test and the Concept Shifting Test. RESULTS: Twenty-five patients suffered from both depressive symptoms and executive dysfunction, 28 patients were depressed with no signs of executive dysfunction, and 13 patients showed executive dysfunction with no depressive symptoms. Patients with executive dysfunction had higher mean SCL-90-D scores compared to patients with no executive dysfunction (30.9 (SD 11.7) versus 26.2 (SD 11.1, p = 0.037). Depressive symptoms were predictive for executive dysfunction in a regression analysis corrected for age, sex, and diabetes mellitus but not after additional correction for pre-existent brain damage and other vascular risk factors. After 2 years 66.6 and 53.3% of patients with both depressive symptoms and executive dysfunction at baseline still had depressive symptoms and executive dysfunctions respectively and had worse prognostic outcome than patients with depressive symptoms or executive dysfunction alone. CONCLUSIONS: Symptoms of depression and executive dysfunction are highly prevalent in stroke patients and often co-occur. These patients are more at risk for poor stroke outcome, chronic depression, and cognitive deterioration. PMID- 20945363 TI - Underutilization of therapy for hepatocellular carcinoma in the medicare population. AB - BACKGROUND: The incidence of hepatocellular carcinoma (HCC) is increasing in the United States, and the care of these patients remains highly specialized and complex. Multiple treatment options are available for HCC but their use and effectiveness remain unknown. METHODS: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data, 8730 patients who were diagnosed with HCC between 1991 and 2005 were identified. Therapy included surgical resection (8.7%), liver transplantation (1.4%), ablation (3.6%), or transarterial chemoembolization (16%). Patients who received no or palliative-only treatment were grouped together (NoTx; 70.3%). Patient, disease, and tumor factors were examined as determinants of therapy. RESULTS: HCC is increasing in the Medicare population. The median age at diagnosis was 75.1 years and 73.6% of patients were coded as white, 17.2% as Asian, 8.3% as black, and 0.9% as other race. The rate of therapy increased over time, but only 29.7% of patients overall underwent therapy. In patients with early stage HCC, only 43.1% underwent therapy. In the NoTx group, 49.4% did not have cirrhosis, 36.0% had tumors that measured <5 cm, and 39.8% were diagnosed with stage I or II disease when variables were complete. The use of therapy for all HCC patients increased over time, correlating with a commensurate increase in median survival. In multivariate regression analysis, patients who received any modality of treatment achieved significant benefit compared with the NoTx group (odds ratio, 0.41; 95% confidence interval, 0.39 0.43). CONCLUSIONS: In the Medicare population, HCC patients who received therapy experienced a substantial survival advantage over their nonoperative peers (NoTx). Despite evidence that many patients had favorable biological characteristics, <30% of patients diagnosed with HCC received any treatment. PMID- 20945364 TI - Exhaustive exercise increases inflammatory response via Toll like receptor-4 and NF-kappaBp65 pathway in rat adipose tissue. AB - Cytokines (IL-6, IL-10, and TNF-alpha) are increased after exhaustive exercise in the retroperitoneal adipose tissue (RPAT) and mesenteric adipose tissue (MEAT). An exhaustive acute exercise protocol induces inflammation in adipose tissue that lasts 6 h after the exercise has ended. It is well-established that this protocol increases circulating plasma levels of non-esterified fatty acids (NEFAs) and lipopolysaccharides (LPS), compounds that are important in stimulating signaling via toll like receptor-4 (TLR-4) in different type cells. In the present study, we investigated the regulation of TLR-4 and DNA-binding of nuclear factor kappaBp65 (NF-kappaBp65) in different depots of adipose tissue in rats after exhaustive exercise. Rats were killed by decapitation immediately (E0 group, n=6), 2 (E2 group, n=6), and 6 h (E6 group, n=6) after the exhaustive exercise, which consisted of running on a treadmill (approximately 70% V(O2max) ) for 50 min and then running at an elevated rate that increased at 1 m/min, until exhaustion. The control group (C group, n=6) was not subjected to exercise. In RPAT, TLR-4, MYD-88, and IkBalpha increased in the E2 group after exercise. MYD 88 and TRAF6 remained increased in the E6 group in comparison with the control group. DNA-binding of NF-kappaBp65 was not altered. In MEAT, TLR-4, MYD-88, TRAF6, and DNA-binding of NF-kappaBp65 were increased only in the E6 group. In conclusion, we have shown that increases in pro-inflammatory cytokines in adipose tissue pads after exhaustive exercise may be mediated via TLR-4 signaling, leading to increases in NF-kappaBp65 binding to DNA in MEAT. PMID- 20945365 TI - Regulation of PIP5K activity by Arf6 and its physiological significance. AB - The phospholipid kinase phosphatidylinositol 4-phosphate 5-kinase (PIP5K) catalyzes the phosphorylation of the membrane phospholipid phosphatidylinositol 4 phosphate to generate the pleiotropic phospholipid phosphatidylinositol 4,5 bisphosphate [PI(4,5)P(2) ]. To date, three mammalian PIP5K isozymes, alpha, beta, and gamma, and several splicing variants of the gamma isozyme have been identified. These PIP5K isozymes and PIP5Kgamma variants play critical roles in various cellular functions through their product PI(4,5)P(2) . The small GTPase Arf6 is one of the key activators of PIP5K. Increasing evidence suggests that PIP5K functions as a downstream effector of Arf6 to regulate a wide variety of cellular functions, such as exocytosis, endocytosis, endosomal recycling, membrane ruffle formation, immune response, and bacterial invasion. In this review, we place our focus on the recent advances in Arf6/PIP5K signaling and its linkage to cellular functions. PMID- 20945366 TI - The roles of pathogen small RNAs. AB - Regulatory small RNAs (sRNAs), also known as non-coding RNA, are not translated into proteins and widespread in prokaryotes and eukaryotes. sRNAs involve in multiple fundamental cellular events. They are emerging regulatory elements that are gaining momentum. Knowledge of sRNA largely originates from eukaryotes. Prokaryotic sRNAs, particularly those of pathogen are only recently explored. The main types, function, and methodology to predict pathogen sRNAs are summarized in this review. Special focus is sRNAs regulating pathogen gene expression, particularly that of Mycobacterium tuberculosis, which is hitherto the most successful pathogen afflicting mankind. PMID- 20945367 TI - Identification of heat shock protein 5, calnexin and integral membrane protein 2B as Adam7-interacting membrane proteins in mouse sperm. AB - In mammals, sperm acquire their motility and ability to fertilize eggs in the epididymis. This maturation process involves the acquisition of particular proteins from the epididymis. One such secretory protein specifically expressed in the epididymis is Adam7 (a disintegrin and metalloprotease 7). Previous studies have shown that Adam7 that resides in an intracellular compartment of epididymal cells is transferred to sperm membranes, where its levels are dependent on the expression of Adam2 and Adam3, which have critical roles in fertilization. Here, using a proteomics approach based on mass spectrometry, we identified proteins that interact with Adam7 in sperm membranes. This analysis revealed that Adam7 forms complexes with calnexin (Canx), heat shock protein 5 (Hspa5), and integral membrane protein 2B (Itm2b). Canx and Hspa5 are molecular chaperones, and Itm2b is a type II integral membrane protein implicated in neurodegeneration. The interaction of Adam7 with these proteins was confirmed by immunoprecipitation-Western blot analysis. We found that Adam7 and Itm2b are located in detergent-resistant regions known to be highly correlated with membrane lipid rafts. We further found that the association of Adam7 with Itm2b is remarkably promoted during sperm capacitation owing to a conformational change of Adam7 that occurs in concert with the capacitation process. Thus, our results suggest that Adam7 functions in fertilization through the formation of a chaperone complex and enhanced association with Itm2b during capacitation in sperm. PMID- 20945368 TI - Human embryonic stem cell proliferation and differentiation as parameters to evaluate developmental toxicity. AB - In vitro models based on embryonic stem cells (ESC) are highly promising for improvement of predictive toxicology screening in humans. After the successful validation of embryonic stem cell test (EST) in 2001; concerns have been raised on the usage of mouse ESC and also the morphological evaluation of beating cell clusters. This requires specialized skill-sets and is highly prone to misjudgement and false positive results. To overcome these limitations, we undertook the present study incorporating improvisations over the conventional EST. Here, we explored the potential of a human ESC (hESC)-based assay to evaluate the potential toxicity of penicillin-G, caffeine, and hydroxyurea. Drug treatment inhibited hESC adhesion and substantially altered the morphology and viability (~ 50%) of embryoid bodies (EBs). Flow cytometry analysis not only showed a significant increase of apoptotic cells in the highest doses but also induced a diverse pattern in DNA content and cell cycle distribution relative to control. Both semi-quantitative and quantitative RT-PCR studies revealed a selective down regulation of markers associated with stemness (Nanog, Rex1, SOX 2, and hTERT); cardiac mesoderm (Cripto1, MEF-2C, and Brachyury); hepatic endoderm (AFP, HNF-3beta, HNF-4alpha, GATA-4, and SOX-17); and neuroectoderm (Nestin, SOX-1, NURR1, NEFH, Synaptophysin, TH, and Olig2) in a drug as well as dose dependent manner indicating abnormal differentiation. Furthermore, a decrease in the expression of AFP and GFAP proteins followed by a dose-dependent reduction in the levels of hCG-beta, progesterone-II, and estradiol hormones was demonstrated by immunocytochemistry and ECLIA, respectively. This new and unique approach comprising of DNA cell cycle analysis, germ layer-specific marker expression and hormone levels as endpoints might offer a clinically relevant and commercially viable alternative for predicting in vivo developmental toxicity. PMID- 20945369 TI - Toll-like receptors expressed by dermal fibroblasts contribute to hypertrophic scarring. AB - Hypertrophic scar (HTS), a fibroproliferative disorder (FPD), complicates burn wound healing. Although the pathogenesis is not understood, prolonged inflammation is a known contributing factor. Emerging evidence suggests that fibroblasts regulate immune/inflammatory responses through toll-like receptor 4 (TLR4) activated by lipopolysaccharide (LPS) through adaptor molecules, leading to nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen activated protein kinases activation, cytokine gene transcription and co stimulatory molecule expression resulting in inflammation. This study explored the possible role of TLR4 in HTS formation. Paired normal and HTS tissue from burn patients was collected and dermal fibroblasts isolated and cultured. Immunohistochemical analysis of tissues demonstrated increased TLR4 staining in HTS tissue. Quantitative RT-PCR of three pairs of fibroblasts demonstrated mRNA levels for TLR4 and its legend myeloid differentiation factor 88 (MyD88) in HTS fibroblasts were increased significantly compared with normal fibroblasts. Flow cytometry showed increased TLR4 expression in HTS fibroblasts compared with normal. ELISA demonstrated protein levels for prostaglandin E2, interleukin (IL) 6, IL-8 and monocyte chemotactic protein-1 (MCP-1) were significantly increased in HTS fibroblasts compared to normal. When paired normal and HTS fibroblasts were stimulated with LPS, significant increases in mRNA and protein levels for MyD88, IL-6, IL-8, and MCP-1 were detected. However, when transfected with MyD88 small interfering RNA (siRNA), then stimulated with LPS, a significant decrease in mRNA and protein levels for these molecules compared to only LPS-stimulated fibroblasts was detected. In comparison, a scramble siRNA transfection did not affect mRNA or protein levels for these molecules. Results demonstrate LPS stimulates proinflammatory cytokine expression in dermal fibroblasts and MyD88 siRNA eliminates the expression. Therefore, controlling inflammation and manipulating TLR signaling in skin cells may result in novel treatment strategies for HTS and other FPD. PMID- 20945370 TI - Differential role of Rho GTPases in intestinal epithelial barrier regulation in vitro. AB - Maintenance of intestinal epithelial barrier functions is crucial to prevent systemic contamination by microbes that penetrate from the gut lumen. GTPases of the Rho-family such as RhoA, Rac1, and Cdc42 are known to be critically involved in the regulation of intestinal epithelial barrier functions. However, it is still unclear whether inactivation or activation of these GTPases exerts barrier protection or not. We tested the effects of Rho GTPase activities on intestinal epithelial barrier functions by using the bacterial toxins cytotoxic necrotizing factor 1 (CNF-1), toxin B, C3 transferase (C3 TF), and lethal toxin (LT) in an in vitro model of the intestinal epithelial barrier. Incubation of cell monolayers with CNF-1 for 3 h induced exclusive activation of RhoA whereas Rac1 and Cdc42 activities were unchanged. As revealed by FITC-dextran flux and measurements of transepithelial electrical resistance (TER) intestinal epithelial permeability was significantly increased under these conditions. Inhibition of Rho kinase via Y27632 blocked barrier destabilization of CNF-1 after 3 h. In contrast, after 24 h of incubation with CNF-1 only Rac1 and Cdc42 but not RhoA were activated which resulted in intestinal epithelial barrier stabilization. Toxin B to inactivate RhoA, Rac1, and Cdc42 as well as Rac1 inhibitor LT increased intestinal epithelial permeability. Similar effects were observed after inhibition of RhoA/Rho kinase signaling by C3 TF or Y27632. Taken together, these data demonstrate that both activation and inactivation of RhoA signaling increased paracellular permeability whereas activation of Rac1 and Cdc42 correlated with stabilized barrier functions. PMID- 20945371 TI - Divalent metal transporter 1 is a hypoxia-inducible gene. AB - Our recent study revealed a high correlation between the expression of hypoxia inducible factor-1 (HIF-1) alpha and divalent metal transporter 1 (DMT1) in HepG2 cells treated with chemical or physical hypoxia. We therefore speculated that DMT1 might be one of the target genes of HIF-1. Here, we characterized the DMT1 exon1B promoter region and identified a functional hypoxia response element (HRE, 5'-TCAGTACCTAACGTGGCGCCACGGC-3') harboring a binding site for HIF-1. We demonstrated that hypoxia-dependent activation of a luciferase reporter gene in transfected HepG2 cells is mediated by a fragment of human DMT1 exon1B promoter containing the putative HRE sequence. We also showed that the HIF-1 binding site (HBS) is in DMT1 exon1B promoter with the core sequence of HRE (5'-ACGTG-3') at 327 to -323 relative to the transcription start site of the human DMT1 exon1B gene. The mutation of this sequence prevented stimulation of luciferase activity. Electrophoretic mobility shift assays revealed that the HRE sequence found in the DMT1 gene promoter was bound by HIF-1. In addition, we provide evidence that hypoxia could significantly increase ferrous uptake, while the silencing of total DMT1 by RNA interference down-regulates DMT1 expression and ferrous uptake in HepG2 cells. We conclude that DMT1 is a hypoxia-inducible gene. PMID- 20945372 TI - FTS (fused toes homolog) a novel oncoprotein involved in uterine cervical carcinogenesis and a potential diagnostic marker for cervical cancer. AB - The high incidence and fatality rate of uterine cervical cancer warrant effective diagnostic and therapeutic target identification for this disease. Here, we have found a novel oncoprotein FTS (Fused Toes Homolog), which is involved in cervical cancer pathogenesis. Immunohistochemical analysis of human cervical biopsy samples revealed that the expression of FTS is absent in normal cervical epithelium but progressively overexpressed in human cervical intraneoplastic lesions (CIN-I to CIN-III), this characteristic phenomenon put this protein, a potential diagnostic marker for the screening of early neoplastic changes of cervix. Using FTS-specific small hairpin RNA (shRNA) in cervical cancer cells, we determined a specific role for FTS protein in, cervical neoplasia. Targeted stable knock down of FTS in HeLa cells led to the growth inhibition, cell-cycle arrest, and apoptosis with concurrent increase in p21 protein. FTS effectively represses the p21 mRNA expression in dual luciferase assay which indicates that p21 is transcriptionally regulated by this oncoprotein which in turn affect the regular cell-cycle process and its components. Consistent with this we found a reciprocal association between these proteins in early cervical neoplastic tissues. These data unraveled the involvement of new oncoprotein FTS in cervical cancer which plays a central role in carcinogenesis. Targeted inhibition of FTS lead to the shutdown of key elemental characteristics of cervical cancer and could lead to an effective therapeutic strategy for cervical cancer. PMID- 20945374 TI - Cell growing density affects the structural and functional properties of Caco-2 differentiated monolayer. AB - The human intestinal Caco-2 cell line has been extensively used as a model of the intestinal barrier. However, it is widely reported in literature that culture related conditions, as well as the different Caco-2 cell lines utilized in different laboratories, often lead to problems of reproducibility making difficult to compare results. We developed a new cell-maintenance protocol in which Caco-2 cells were subcultured at 50% of confluence instead of 80% of confluence, as usually suggested. Using this new protocol, Caco-2 cells retained a higher proliferation potential resulting in a cell population, which, on reaching confluence, was able to differentiate almost synchronously, forming a more homogeneous and polarized cell monolayer, as compared to that obtained using a high cell growing density. This comparison has been done by analyzing the gene expression and the structural characteristics of the 21-days differentiated monolayers by microarrays hybridization and by confocal microscopy. We then investigated if these differences could also modify the effects of toxicants on 21-days-differentiated cells. We analyzed the 2 h-acute toxicity of CuCl(2) in terms of actin depolymerization and metallothionein 2A (MT2A) and heat shock protein 70 (HSPA1A) genes induction. Copper treatment resulted in different levels of actin depolymerization and gene expression induction in relationship with culture protocol, the low-density growing cells showing a more homogeneous and stronger response. Our results suggest that cell growing density could influence a number of morphological and physiological properties of differentiated Caco-2 cells and these effects must be taken in account when these cells are used as intestinal model. PMID- 20945373 TI - Vasodilator-stimulated phosphoprotein deficiency potentiates PAR-1-induced increase in endothelial permeability in mouse lungs. AB - Vasodilator-stimulated phosphoprotein (VASP) is implicated in the protection of the endothelial barrier in vitro and in vivo. The function of VASP in thrombin signaling in the endothelial cells (ECs) is not known. For the first time we studied the effects of VASP deficiency on EC permeability and pulmonary vascular permeability in response to thrombin receptor stimulation. We provided the evidence that VASP deficiency potentiates the increase in endothelial permeability induced by activation of thrombin receptor in cultured human umbilical vein endothelial cells (HUVECs) and isolated mouse lungs. Using transendothelial resistance measurement, we showed that siRNA-mediated VASP downregulation in HUVECs leads to a potentiation of thrombin- and protease activated receptor 1 (PAR-1) agonist-induced increase in endothelial permeability. Compared to control cells, VASP-deficient HUVECs had delayed endothelial junctional reassembly and abrogated VE-cadherin cytoskeletal anchoring in the recovery phase after thrombin stimulation, as demonstrated by immunofluorescence studies and cell fractionation analysis, respectively. Measurement of the capillary filtration coefficient in isolated mouse lungs demonstrated that VASP(-/-) mice have increased microvascular permeability in response to infusion with PAR-1 agonist compared to wild type mice. Lack of VASP led to decreased Rac1 activation both in VASP-deficient HUVECs after thrombin stimulation and VASP(-/-) mouse lungs after PAR-1 agonist infusion, indicating that VASP effects on thrombin signaling may be correlated with changes in Rac1 activity. This study demonstrates that VASP may play critical and complex role in the regulation of thrombin-dependent disruption of the endothelial barrier function. PMID- 20945375 TI - The inhibitory effect of ginsan on TGF-beta mediated fibrotic process. AB - Transforming growth factor-beta (TGF-beta) plays a central role in the development of fibrosis by stimulating extracellular matrix accumulation, and signals either directly or indirectly through types I, II, and III (TbetaRI, II, and III) TGF-beta receptor complexes. Ginsan, a polysaccharide extracted from Panax ginseng, has multiple immunomodulatory effects. Here, we examine whether ginsan regulates the fibrogenic process by interfering with TGF-beta signaling pathways. TGF-beta treatment of murine or human normal lung fibroblasts enhanced the levels of several fibrotic markers, including smooth muscle alpha actin (alpha-SMA), collagen-1, and fibronectin. Interestingly, ginsan treatment either before or after TGF-beta administration led to significant reductions in all of alpha-SMA, collagen-1, and fibronectin expression levels. Ginsan not only inhibited phosphorylation of Smad2 and Smad3, but also attenuated pERK and pAKT signaling induced by TGF-beta. Moreover, ginsan restored TbetaRIII protein expression, which was significantly downregulated by TGF-beta, but reduced TbetaRI and TbetaRII protein levels. In a murine model of bleomycin (BLM)-induced pulmonary fibrosis, ginsan significantly suppressed accumulation of collagen, alpha-SMA, and TGF-beta. These data collectively suggest that ginsan acts as an effective anti-fibrotic agent in the treatment of pulmonary fibrosis by blocking multiple TGF-beta signaling pathways. PMID- 20945376 TI - The role of electrical signals in murine corneal wound re-epithelialization. AB - Ion flow from intact tissue into epithelial wound sites results in lateral electric currents that may represent a major driver of wound healing cell migration. Use of applied electric fields (EF) to promote wound healing is the basis of Medicare-approved electric stimulation therapy. This study investigated the roles for EFs in wound re-epithelialization, using the Pax6(+/-) mouse model of the human ocular surface abnormality aniridic keratopathy (in which wound healing and corneal epithelial cell migration are disrupted). Both wild-type (WT) and Pax6(+/-) corneal epithelial cells showed increased migration speeds in response to applied EFs in vitro. However, only Pax6(+/+) cells demonstrated consistent directional galvanotaxis towards the cathode, with activation of pSrc signaling, polarized to the leading edges of cells. In vivo, the epithelial wound site normally represents a cathode, but 43% of Pax6(+/-) corneas exhibited reversed endogenous wound-induced currents (the wound was an anode). These corneas healed at the same rate as WT. Surprisingly, epithelial migration did not correlate with direction or magnitude of endogenous currents for WT or mutant corneas. Furthermore, during healing in vivo, no polarization of pSrc was observed. We found little evidence that Src-dependent mechanisms of cell migration, observed in response to applied EFs in vitro, normally exist in vivo. It is concluded that endogenous EFs do not drive long-term directionality of sustained healing migration in this mouse corneal epithelial model. Ion flow from wounds may nevertheless represent an important component of wound signaling initiation. PMID- 20945377 TI - PET translates neurophysiology into images: A review to stimulate a network between neuroimaging and basic research. AB - In the last decades there has been a progressive advance in the development of techniques able to explore in humans neurophysiologic and neurochemical processes. Positron emission tomography (PET) is a very powerful technique allowing to study a quite variable range of physiological and biochemical processes in the healthy subjects and in diseases. Apart from its capacity to provide pathophysiological information, PET is also important for the objective assessment of therapeutic efficacy. Initial studies were performed measuring cerebral metabolic rate for glucose (CMRglc) and cerebral blood flow (CBF), representing an indirect index of synaptic activity. The advent of receptor tracers allowed measuring other important physiological parameters, such as receptor occupancy, and endogenous release. In neuropsychiatric disorders, as Alzheimer disease, schizophrenia, epilepsy and Huntington disease, PET has been useful to elaborate hypothesis of the pathogenesis, to relate symptoms to biological variables and to study individuals at increased risk. The new concepts of neurovascular unit and default network, preferentially active at rest, can significantly change the approach of PET, with images reflecting a complex scenario, not merely limited to neural activity, but involving the activity of the entire neurovascular unit and the multifunctional role of astrocytes. To detect dysfunction of the dialog between glutamatergic neurons and astrocytes could lead to a better understanding of altered functional brain images. In this direction a professional network between PET researchers and basic scientists, could give a determinant improvement in the capability to understand the complex physiological and pathophysiological cerebral world. PMID- 20945379 TI - Potential role of follicle-stimulating hormone (FSH) and transforming growth factor (TGFbeta1) in the regulation of ovarian angiogenesis. AB - Angiogenesis occurs during ovarian follicle development and luteinization. Pituitary secreted FSH was reported to stimulate the expression of endothelial mitogen VEGF in granulosa cells. And, intraovarian cytokine transforming growth factor (TGF)beta1 is known to facilitate FSH-induced differentiation of ovarian granulosa cells. This intrigues us to investigate the potential role of FSH and TGFbeta1 regulation of granulosa cell function in relation to ovarian angiogenesis. Granulosa cells were isolated from gonadotropin-primed immature rats and treated once with FSH and/or TGFbeta1 for 48 h, and the angiogenic potential of conditioned media (granulosa cell culture conditioned media; GCCM) was determined using an in vitro assay with aortic ring embedded in collagen gel and immunoblotting. FSH and TGFbeta1 increased the secreted angiogenic activity in granulosa cells (FSH + TGFbeta1 > FSH ~ TGFbeta1 >control) that was partly attributed to the increased secretion of pro-angiogenic factors VEGF and PDGF-B. This is further supported by the evidence that pre-treatment with inhibitor of VEGF receptor-2 (Ki8751) or PDGF receptor (AG1296) throughout or only during the first 2-day aortic ring culture period suppressed microvessel growth in GCCM treated groups, and also inhibited the FSH + TGFbeta1-GCCM-stimulated release of matrix remodeling-associated gelatinase activities. Interestingly, pre-treatment of AG1296 at late stage suppressed GCCM-induced microvessel growth and stability with demise of endothelial and mural cells. Together, we provide original findings that both FSH and TGFbeta1 increased the secretion of VEGF and PDGF-B, and that in turn up-regulated the angiogenic activity in rat ovarian granulosa cells. This implicates that FSH and TGFbeta1 play important roles in regulation of ovarian angiogenesis during follicle development. PMID- 20945378 TI - Mechanistic insights into reprogramming to induced pluripotency. AB - Induced pluripotent stem (iPS) cells can be generated from various embryonic and adult cell types upon expression of a set of few transcription factors, most commonly consisting of Oct4, Sox2, cMyc, and Klf4, following a strategy originally published by Takahashi and Yamanaka (Takahashi and Yamanaka, 2006, Cell 126: 663-676). Since iPS cells are molecularly and functionally similar to embryonic stem (ES) cells, they provide a source of patient-specific pluripotent cells for regenerative medicine and disease modeling, and therefore have generated enormous scientific and public interest. The generation of iPS cells also presents a powerful tool for dissecting mechanisms that stabilize the differentiated state and are required for the establishment of pluripotency. In this review, we discuss our current view of the molecular mechanisms underlying transcription factor-mediated reprogramming to induced pluripotency. PMID- 20945380 TI - Peptidoglycan induces interleukin-6 expression through the TLR2 receptor, JNK, c Jun, and AP-1 pathways in microglia. AB - We recently reported that peptidoglycan (PGN), a cell wall component of the Gram positive bacterium, induces NF-kappaB activation and microglia activation. However, PGN-regulated AP-1 activation and cytokine expression in microglia remains unclear. This study investigated how PGN influences the signaling pathway involved in IL-6 production in microglia. IL-6 mRNA and protein level up regulation were increased by PGN in a concentration- and time-dependent manner. In addition, PGN increased toll-like receptor-2 (TLR2) expression, but not TLR4 receptor up-regulation. Administration of TLR2 siRNA or TLR2 neutralized antibody effectively inhibited PGN-induced IL-6 expression. In contrast, PGN-induced IL-6 mRNA and protein up-regulation were attenuated by the SAPK/JNK (c-Jun N-terminal kinases) inhibitor SP600125. Treatment of microglia with PGN increased levels of JNK phosphorylation and c-Jun phosphorylation, and up-regulated of JNK kinase activity. Treatment of microglia with AP-1 inhibitors (Tanshinone IIA and curcumin) effectively reduced PGN-induced IL-6 expression. PGN also significantly increased c-Fos and phospho-c-Jun translocation to nucleus. In line with this, PGN also increased AP-1-DNA complexes formation, as determined by the electrophoretic mobility shift assay. Furthermore, PGN also increased IL-6 transcription activity determined by transfection with IL-6 promoter construct plasmid. Co-transfection with dominant negative mutant of JNK (DN-JNK), or treatment with SP600125, curcumin, or Tanshinone IIA effectively antagonized PGN increased IL-6 transcription activity. Our data demonstrate that PGN-induced IL-6 expression is mediated by AP-1 activation through the TLR2 and JNK/c-Jun pathways in microglia. PMID- 20945381 TI - Oncoprotein Cot1 represses kinase suppressors of Ras1/2 and 1,25-dihydroxyvitamin D3-induced differentiation of human acute myeloid leukemia cells. AB - Metabolites and derivatives of vitamin D are well-known inducers of monocytic differentiation, but the mechanistic basis for their action is not fully elucidated. Here we show that the product of protooncogene Cot1 represses the monocytic phenotype in human acute myeloid leukemia (AML) cells induced to differentiate by 1,25-dihydroxyvitamin D(3) (1,25D), even though the expression of cellular Cot1 increases early in the process of 1,25D-induced differentiation. Interestingly, the expression of the two members of the Kinase Suppressor of Ras (KSR) family of molecular scaffolds, known to be positive regulators of Ras signaling and of 1,25D-induced differentiation, increases in parallel with Cot1 in 1,25D-treated cells. However, KSR1/2 are negatively regulated by Cot1, as determined by transfection of siCot1, and confirmed by a reverse effect of ectopic expression of Cot1. The effect of Cot1 in AML cells appears to be cell type specific, as previous reports in other cell types found KSR-2 to be a negative regulator of Cot1, a reverse relationship. Also in contrast to findings in other cells, in AML cells Cot1 exerts negative control on the MAP kinase pathways, since siCot1 increases the levels of activated Raf1, p90RSK, JNK1, c jun, and p38, though not of MEK/ERK. These findings have implications for therapy of AML, since in AML cells active MAPKs hasten cell differentiation, and specific pharmacological inhibitors of Cot1 kinase activity have recently became available, thus making Cot1 a "druggable" target. PMID- 20945382 TI - Involvement of membrane type 1-matrix metalloproteinase (MT1-MMP) in RAGE activation signaling pathways. AB - An advanced glycation end products (AGE)/a receptor for AGE (RAGE) axis plays a key role in diabetic vascular complications. Membrane type 1-matrix metalloproteinase (MT1-MMP) has been shown to function not only as a proteolytic enzyme but also as a signaling molecule. In this study, we investigated the role of MT1-MMP in the AGE/RAGE-triggered signaling pathways in cultured rabbit smooth muscle cells (SMCs) and the molecular interaction between RAGE and MT1-MMP in vitro and in vivo. In SMCs, AGE-activated Rac1 and p47(phox) within 1 min, NADPH oxidase activity and reactive oxygen species (ROS) generation within 5 min, and NF-kappaB phosphorylation within 15 min, thereby inducing redox-sensitive molecular expression. Silencing of RAGE by small-interfering RNA (siRNA) blocked the AGE-induced signaling pathways. AGE-induced geranylgeranyl transferase I (GGTase I) activity, Rac1.p47(phox) activation, NADPH oxidase activity, ROS generation, and molecular expression were also markedly attenuated by silencing of MT1-MMP. An inhibitor of GGTase I mimicked the effects of MT1-MMP-specific siRNA. Fluorescent immunohistochemistry revealed that MT1-MMP was partially co localized with RAGE in SMCs, and RAGE was found to form a complex with MT1-MMP in both cultured SMCs and the aortae of diabetic rats by immunoprecipitation. Furthermore, MT1-MMP and RAGE formed a complex in the aortic atherosclerotic lesions of hyperlipidemic rabbits. We show that MT1-MMP plays a crucial role in RAGE-activated NADPH oxidase-dependent signaling pathways and forms a complex with RAGE in the vasculature, thus suggesting that MT1-MMP may be a novel therapeutic target for diabetic vascular complications. PMID- 20945383 TI - Role of Smad2/3 and p38 MAP kinase in TGF-beta1-induced epithelial-mesenchymal transition of pulmonary epithelial cells. AB - Idiopathic pulmonary fibrosis is characterized by myofibroblast accumulation, extracellular matrix (ECM) remodeling, and excessive collagen deposition. ECM producing myofibroblasts may originate from epithelial cells through epithelial to mesenchymal transition (EMT). TGF-beta1 is an inducer of EMT in pulmonary epithelial cells in vitro and in vivo, though the mechanisms are unclear. We hypothesized that TGF-beta1 induced EMT through Smad-dependent and -independent processes. To test this hypothesis, we studied the roles and mechanisms of TGF beta1-induced Smad and p38 mitogen-activated protein kinase (MAPK) signaling in EMT-related changes in pulmonary epithelial cells. Exposure of pulmonary epithelial 1HAEo(-) cells to TGF-beta1 resulted in morphological and molecular changes of EMT over a 96-h period; loss of cell-cell contact, cell elongation, down-regulation of E-cadherin, up-regulation of fibronectin, and up-regulation of collagen I. Both Smad2/3 and p38 MAPK signaling pathways were activated by TGF beta1. However, neither Smad2/3 nor p38 MAPK were required for the down regulation of E-cadherin, yet p38 MAPK was associated with fibronectin up regulation. Both Smad2/3 and p38 MAPK had a role in regulation of TGF-beta1 induced collagen expression. Furthermore, these data demonstrate that Smads and p38 MAPK differentially regulate EMT-related changes in pulmonary epithelial cells. PMID- 20945384 TI - CXCL5/ENA78 increased cell migration and epithelial-to-mesenchymal transition of hormone-independent prostate cancer by early growth response-1/snail signaling pathway. AB - Prostate cancers that are resistant to hormone therapy are more invasive and have greater ability to spread to other organs than androgen-dependent prostate cancers. Furthermore, this type of prostate cancer is also highly resistant to current forms of chemotherapy. This study analyzed CXCL5/ENA78, which is highly expressed in androgen-independent prostate cancers, and is responsible for cell migration and epithelial-to-mesenchymal transition in two androgen-independent prostate cancer cell lines. Inducement of PC-3 and DU145 cancer progression by CXCL5/ENA78 is associated with increased Raf/MEK/ERK activation, and the upregulation of early growth response-1 (Egr-1) and Snail. Blockade of Egr-1 decreased Snail upregulation and cell migration, indicating that Egr-1 is required in CXCL5/ENA78-mediated Snail enhancement and cell migration. In addition, Egr-1 siRNA also decreased the effect of CXCL5/ENA78 on p27 inhibition, Cdk4 induction and cell proliferation, suggesting Egr-1 is also involved in CXCL5/ENA78-mediated cell growth. Moreover, blocking ERK1/2 by siRNA suppressed CXCL5/ENA78-induced Egr-1 enhancement, cell migration, and proliferation. Our study suggests that inhibition of CXCL5/ENA78-mediated ERK/Egr-1/Snail signaling is an attractive therapeutic target for androgen-independent prostate cancer. PMID- 20945385 TI - Leptin increases motility and integrin up-regulation in human prostate cancer cells. AB - Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to distant organs. Leptin, an adipocyte-derived cytokine that is closely associated with obesity, has recently been shown to be involved in carcinogenesis and cancer progression. The aim of this study was to investigate whether leptin is associated with the motility of prostate cancer cells. We found that leptin increased the migration of human prostate cancer cells and expression of alphavbeta3 integrin on these cells. Leptin-mediated migration and increased integrin expression were attenuated by OBRl receptor antisense oligonucleotide (ODN). Activation of insulin receptor substrate (IRS 1), phosphatidylinositol 3-kinase (PI3K), Akt, and NF-kappaB pathways after leptin treatment was demonstrated. Furthermore, leptin-induced integrin expression and migration activity were inhibited by specific inhibitors; small interfering RNAs (siRNAs); and mutants of the IRS-1, PI3K, Akt, and NF-kappaB cascades. Therefore, this study shows that leptin stimulates the migration of human prostate cancer cells, one of the mechanisms underlying leptin-directed migration was transcriptional up-regulation of alphavbeta3 integrin expression through the OBR1/IRS-1/PI3K/Akt/NF-kappaB signal transduction pathway. PMID- 20945386 TI - Analysis of dynamic tyrosine phosphoproteome in LFA-1 triggered migrating T cells. AB - The ordered, directional migration of T-lymphocytes is a key process during immune surveillance and response. This requires cell adhesion to the high endothelial venules or to the extracellular matrix by a series of surface receptor/ligand interactions involving adhesion molecules of the integrin family including lymphocyte function associated molecule-1 (LFA-1) and intercellular adhesion molecules (ICAMs). Reversible protein phosphorylation is emerging as a key player in the regulation of biological functions with tyrosine phosphorylation playing a crucial role in signal transduction. Thus, the study of this type of post-translational modification at the proteomic level has great biological significance. In this work, phospho-enriched cell lysates from LFA-1 triggered migrating human T-cells were subjected to immunoaffinity purification of tyrosine phosphorylated proteins, mass spectrometric, and bioinformatic analysis. In addition to the identification of several well-documented proteins, the analysis suggested involvement of a number of new and novel proteins in LFA-1 induced T-cell migration. This dataset expands the list of the signaling components of the LFA-1 induced phosphotyrosine protein complexes in migrating T cells that will be extremely useful in the study of their specific roles within LFA-1 associated signaling pathways. Identification of proteins previously not reported in the context of LFA-1 stimulated signal transduction might provide new insights into understanding the LFA-1 signaling networks and aid in the search for new potential therapeutic targets. PMID- 20945387 TI - Testosterone attenuates morpho-functional alterations by 2-methoxyestradiol exposure and induces differentiation in C6 cells. AB - 2-Methoxyestradiol (2ME) is a cytotoxic drug that interacts with tubulin and alters microtubule dynamics. It has been reported that testosterone (T) has a neuroprotective effect against oxidative stress and induces differentiation in mouse C1300 neuroblastoma cells. Here, we investigated the ability of T to attenuate the cytotoxic effects of 2ME and to induce cell differentiation in an immortalized rat glial cell line, known as C6. C6 cells were exposed for 5 days to 5 uM 2ME, 50 nM T, or both. We evaluated the morphological changes, growth rate, vitality, catalase activity, and glial fibrillary acidic protein (GFAP) immunoreactivity in control and treated C6 cells. Western blot analyses were used to quantify expression of tyrosinated tubulin (Tyr-Tub), acetylated tubulin (Acet Tub), total alpha-tubulin (TOT-Tub), and GFAP. After 2ME exposure, the cells displayed a globular, shrunken shape, and retraction or absence of cytoplasmic processes; moreover, 2ME treatment significantly decreased cell growth, cell viability, catalase activity, and expression of both Tyr-Tub and Acet-Tub. However, when T was added, the cells exhibited a glial-like shape, elongated cell processes, and enhanced cell growth, cell vitality, catalase activity, and GFAP immunoreactivity. Densitometric values of Tyr-Tub, Acet-Tub, and GFAP increased significantly when T was present, while Tot-Tub values were unaltered. These results indicate that, in C6 cells, T: (i) attenuated the morpho-functional changes caused by 2ME exposure; (ii) induced glial differentiation; and (iii) exerted a direct action on the microtubule system. PMID- 20945388 TI - 5-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3,7-dimethoxy-4H-chromen-4-one (MSF-2) suppresses fMLP-mediated respiratory burst in human neutrophils by inhibiting phosphatidylinositol 3-kinase activity. AB - Respiratory burst mediates crucial bactericidal mechanism in neutrophils. However, undesirable respiratory burst leads to pathological inflammation and tissue damage. This study investigates the effect and the underlying mechanism of 5-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3,7-dimethoxy-4H-chromen-4-one (MSF-2), a lignan extracted from the fruit of Melicope Semecarprifolia, on fMLP-induced respiratory burst in human neutrophils and suggests a possible therapeutic approach to ameliorate disease associated with neutrophil hyperactivation. MSF-2 inhibited fMLP-induced neutrophil superoxide anion production, cathepsin G release and migration in human neutrophils isolated from healthy volunteers, reflecting inhibition of phosphatidylinositol 3-kinase (PI3K) activation. Specifically, PI3K/AKT activation results in migration, degranulation and superoxide anion production in neutrophils. MSF-2 suppresses PI3K activation and phosphatidylinositol (3,4,5)-trisphosphate (PIP3) production, and consequently inhibits downstream activation of PDK1 and AKT. Further, PI3K also stimulates respiratory burst via PLC-dependent elevation of intracellular calcium. MSF-2 reduces fMLP-mediated PLCgamma2 activation and intracellular calcium accumulation notably through extracellular calcium influx in a PI3K and PLC-dependent manner. However, MSF-2 is not a competitive or allosteric antagonist of fMLP. Additionally, in an in vivo study, MSF-2 prevents fMLP-induced neutrophil infiltration and inflammation in mice. In conclusion, MSF-2 opposes fMLP-mediated neutrophil activation and inflammation by inhibiting PI3K activation and subsequent activation of AKT and PLCgamma2. PMID- 20945389 TI - Embryonal carcinoma cell induction of miRNA and mRNA changes in co-cultured prostate stromal fibromuscular cells. AB - The prostate stromal mesenchyme controls organ-specific development. In cancer, the stromal compartment shows altered gene expression compared to non-cancer. The lineage relationship between cancer-associated stromal cells and normal tissue stromal cells is not known. Nor is the cause underlying the expression difference. Previously, the embryonal carcinoma (EC) cell line, NCCIT, was used by us to study the stromal induction property. In the current study, stromal cells from non-cancer (NP) and cancer (CP) were isolated from tissue specimens and co-cultured with NCCIT cells in a trans-well format to preclude heterotypic cell contact. After 3 days, the stromal cells were analyzed by gene arrays for microRNA (miRNA) and mRNA expression. In co-culture, NCCIT cells were found to alter the miRNA and mRNA expression of NP stromal cells to one like that of CP stromal cells. In contrast, NCCIT had no significant effect on the gene expression of CP stromal cells. We conclude that the gene expression changes in stromal cells can be induced by diffusible factors synthesized by EC cells, and suggest that cancer-associated stromal cells represent a more primitive or less differentiated stromal cell type. PMID- 20945390 TI - Protein kinase Ciota expression and oncogenic signaling mechanisms in cancer. AB - Accumulating evidence demonstrates that PKCiota is an oncogene and prognostic marker that is frequently targeted for genetic alteration in many major forms of human cancer. Functional data demonstrate that PKCiota is required for the transformed phenotype of lung, pancreatic, ovarian, prostate, colon, and brain cancer cells. Future studies will be required to determine whether PKCiota is also an oncogene in the many other cancer types that also overexpress PKCiota. Studies of PKCiota using genetically defined models of tumorigenesis have revealed a critical role for PKCiota in multiple stages of tumorigenesis, including tumor initiation, progression, and metastasis. Recent studies in a genetic model of lung adenocarcinoma suggest a role for PKCiota in transformation of lung cancer stem cells. These studies have important implications for the therapeutic use of aurothiomalate (ATM), a highly selective PKCiota signaling inhibitor currently undergoing clinical evaluation. Significant progress has been made in determining the molecular mechanisms by which PKCiota drives the transformed phenotype, particularly the central role played by the oncogenic PKCiota-Par6 complex in transformed growth and invasion, and of several PKCiota dependent survival pathways in chemo-resistance. Future studies will be required to determine the composition and dynamics of the PKCiota-Par6 complex, and the mechanisms by which oncogenic signaling through this complex is regulated. Likewise, a better understanding of the critical downstream effectors of PKCiota in various human tumor types holds promise for identifying novel prognostic and surrogate markers of oncogenic PKCiota activity that may be clinically useful in ongoing clinical trials of ATM. PMID- 20945391 TI - Live cell imaging of the cancer-related transcription factor RUNX2 during mitotic progression. AB - The nuclear matrix bound transcription factor RUNX2 is a lineage-specific developmental regulator that is linked to cancer. We have previously shown that RUNX2 controls transcription of both RNA polymerase II genes and RNA polymerase I dependent ribosomal RNA genes. RUNX2 is epigenetically retained through mitosis on both classes of target genes in condensed chromosomes. We have used fluorescence recovery after photobleaching to measure the relative binding kinetics of enhanced green fluorescent protein (EGFP)-RUNX2 at transcription sites in the nucleus and nucleoli during interphase, as well as on mitotic chromosomes. RUNX2 becomes more strongly bound as cells go from interphase through prophase, with a doubling of the most tightly bound "immobile fraction." RUNX2 exchange then becomes much more facile during metaphase to telophase. During interphase the less tightly bound pool of RUNX2 exchanges more slowly at nucleoli than at subnuclear foci, and the non-exchanging immobile fraction is greater in nucleoli. These results are consistent with a model in which the molecular mechanism of RUNX2 binding is different at protein-coding and ribosomal RNA genes. The binding interactions of RUNX2 change as cells go through mitosis, with binding affinity increasing as chromosomes condense and then decreasing through subsequent mitotic phases. The increased binding affinity of RUNX2 at mitotic chromosomes may reflect its epigenetic function in "bookmarking" of target genes in cancer cells. PMID- 20945392 TI - A comprehensive characterization study of human bone marrow mscs with an emphasis on molecular and ultrastructural properties. AB - Human bone marrow-derived mesenchymal stem cells (hBM-MSCs) continue to draw attention of researchers in the fields of basic science and medicine due to their indispensible regenerative, reparative, angiogenic, anti-apoptotic, and immunosuppressive properties, all of which collectively point out their enormous therapeutic potential. There is still, however, a need for further investigation of their characteristics to broaden their field of use and learn much more about how to control their fate and improve their therapeutic effectiveness. hBM-MSCs were extensively characterized in terms of their growth characteristics, genetic stability, and differentiation capability to the mesodermal and ectodermal cell lineages; a special emphasis was given to their phenotypic and ultrastructural properties. Expression of embryonic stem cell markers Oct4, Rex-1, FoxD-3, Sox2, and Nanog was shown with real-time PCR. Transmission electron microscopy revealed the ultrastructural characteristics of hBM-MSCs; they had pale, irregularly shaped and large euchromatic nuclei, and two distinct areas in their cytoplasm: an intensely stained inner zone rich in mitochondria and rough endoplasmic reticulum (rER) with dilated cisternae and a relatively peripheral zone poor in organelles. hBM-MSCs expressed adipogenic (adipophilin and PPARgamma), myogenic (desmin, myogenin, alpha-SMA), neurogenic (gamma-enolase, MAP2a,b, c-fos, nestin, NF-H, NF-L, GFAP, beta3-tubulin), osteogenic (osteonectin, osteocalcin, osteopontin, Runx-2, type I collagen), and chondrogenic (type II collagen, SOX9) markers either at RNA or protein level even under basal conditions, without any stimulation towards differentiation. The differentiation potential of hBM-MSCs to adipogenic, osteogenic, and neurogenic lineages was shown by using the relevant differentiation factors. PMID- 20945393 TI - Protein acetylation within the cellular response to radiation. AB - Post-translational protein modification represents a fundamental tool within the control of protein functions. While phosphorylation is the longest known of these modifications, several more were identified. Among these, acetylation was originally discovered as an important modification of histones within the process of transcription. Later it was revealed that histone acetylation also plays a crucial role in DNA repair, and that histones are not the only target for transient acetylation within these processes. Although there is no doubt that protein acetylation is essential, its function and even more its regulation is still not fully elucidated. Here we will discuss how protein acetylation occurs within the cellular response to radiation, a well characterized DNA-damaging environmental stressor and further want to draw the attention to open questions within the field of protein acetylation. PMID- 20945394 TI - On the role of subtype selective adenosine receptor agonists during proliferation and osteogenic differentiation of human primary bone marrow stromal cells. AB - Purines are important modulators of bone cell biology. ATP is metabolized into adenosine by human primary osteoblast cells (HPOC); due to very low activity of adenosine deaminase, the nucleoside is the end product of the ecto-nucleotidase cascade. We, therefore, investigated the expression and function of adenosine receptor subtypes (A(1) , A(2A) , A(2B) , and A(3) ) during proliferation and osteogenic differentiation of HPOC. Adenosine A(1) (CPA), A(2A) (CGS21680C), A(2B) (NECA), and A(3) (2-Cl-IB-MECA) receptor agonists concentration-dependently increased HPOC proliferation. Agonist-induced HPOC proliferation was prevented by their selective antagonists, DPCPX, SCH442416, PSB603, and MRS1191. CPA and NECA facilitated osteogenic differentiation measured by increases in alkaline phosphatase (ALP) activity. This contrasts with the effect of CGS21680C which delayed HPOC differentiation; 2-Cl-IB-MECA was devoid of effect. Blockade of the A(2B) receptor with PSB603 prevented osteogenic differentiation by NECA. In the presence of the A(1) antagonist, DPCPX, CPA reduced ALP activity at 21 and 28 days in culture. At the same time points, blockade of A(2A) receptors with SCH442416 transformed the inhibitory effect of CGS21680C into facilitation. Inhibition of adenosine uptake with dipyridamole caused a net increase in osteogenic differentiation. The presence of all subtypes of adenosine receptors on HPOC was confirmed by immunocytochemistry. Data show that adenosine is an important regulator of osteogenic cell differentiation through the activation of subtype-specific receptors. The most abundant A(2B) receptor seems to have a consistent role in cell differentiation, which may be balanced through the relative strengths of A(1) or A(2A) receptors determining whether osteoblasts are driven into proliferation or differentiation. PMID- 20945395 TI - Retinoic acid receptor-mediated signaling protects cardiomyocytes from hyperglycemia induced apoptosis: role of the renin-angiotensin system. AB - Diabetes mellitus (DM) is a primary risk factor for cardiovascular diseases and heart failure. Activation of the retinoic acid receptor (RAR) and retinoid X receptor (RXR) has an anti-diabetic effect; but, a role in diabetic cardiomyopathy remains unclear. Using neonatal and adult cardiomyocytes, we determined the role of RAR and RXR in hyperglycemia-induced apoptosis and expression of renin-angiotensin system (RAS) components. Decreased nuclear expression of RARalpha and RXRalpha, activation of apoptotic signaling and cell apoptosis was observed in high glucose (HG) treated neonatal and adult cardiomyocytes and diabetic hearts in Zucker diabetic fatty (ZDF) rats. HG induced apoptosis and reactive oxygen species (ROS) generation was prevented by both RAR and RXR agonists. Silencing expression of RARalpha and RXRalpha, by small interference RNA, promoted apoptosis under normal conditions and significantly enhanced HG-induced apoptosis, indicating that RARalpha and RXRalpha are required in regulating cell apoptotic signaling. Blocking angiotensin type 1 receptor (AT(1) R); but, not AT(2) R, attenuated HG-induced apoptosis and ROS generation. Moreover, HG induced gene expression of angiotensinogen, renin, AT(1) R, and angiotensin II (Ang II) synthesis were inhibited by RARalpha agonists and promoted by silencing RARalpha. Activation of RXRalpha, downregulated the expression of AT(1) R; and RXRalpha silencing accelerated HG induced expression of angiotensinogen and Ang II synthesis, whereas there was no significant effect on renin gene expression. These results indicate that reduction in the expression of RARalpha and RXRalpha has an important role in hyperglycemia mediated apoptosis and expression of RAS components. Activation of RAR/RXR signaling protects cardiomyocytes from hyperglycemia, by reducing oxidative stress and inhibition of the RAS. PMID- 20945396 TI - G-protein coupled receptor kinase 5 mediates lipopolysaccharide-induced NFkappaB activation in primary macrophages and modulates inflammation in vivo in mice. AB - G-protein coupled receptor kinase-5 (GRK5) is a serine/threonine kinase discovered for its role in the regulation of G-protein coupled receptor signaling. Recent studies have shown that GRK5 is also an important regulator of signaling pathways stimulated by non-GPCRs. This study was undertaken to determine the physiological role of GRK5 in Toll-like receptor-4-induced inflammatory signaling pathways in vivo and in vitro. Using mice genetically deficient in GRK5 (GRK5(-/-) ) we demonstrate here that GRK5 is an important positive regulator of lipopolysaccharide (LPS, a TLR4 agonist)-induced inflammatory cytokine and chemokine production in vivo. Consistent with this role, LPS-induced neutrophil infiltration in the lungs (assessed by myeloperoxidase activity) was markedly attenuated in the GRK5(-/-) mice compared to the GRK5(+/+) mice. Similar to the in vivo studies, primary macrophages from GRK5(-/-) mice showed attenuated cytokine production in response to LPS. Our results also identify TLR4-induced NFkappaB pathway in macrophages to be selectively regulated by GRK5. LPS-induced IkappaBalpha phosphorylation, NFkappaB p65 nuclear translocation, and NFkappaB binding were markedly attenuated in GRK5( /-) macrophages. Together, our findings demonstrate that GRK5 is a positive regulator of TLR4-induced IkappaBalpha-NFkappaB pathway as well as a key modulator of LPS-induced inflammatory response. PMID- 20945397 TI - Neutrophil differentiation from human-induced pluripotent stem cells. AB - Induced pluripotent stem (iPS) cells are of potential value not only for regenerative medicine, but also for disease investigation. The present study describes the development of a neutrophil differentiation system from human iPS cells (hiPSCs) and the analysis of neutrophil function and differentiation. The culture system used consisted of the transfer of hiPSCs onto OP9 cells and their culture with vascular endothelial growth factor (VEGF). After 10 days, TRA 1 85(+) CD34(+) VEGF receptor-2 (VEGFR-2)(high) cells were sorted and co-cultured with OP9 cells in the presence of hematopoietic cytokines for 30 days. Floating cells were collected and subjected to morphological and functional analysis. These hiPSC-derived neutrophils were similar to peripheral blood mature neutrophils in morphology, contained functional neutrophil specific granules, and were equipped with the basic functions such as phagocytosis, superoxide production, and chemotaxis. In the process of differentiation, myeloid cells appeared sequentially from immature myeloblasts to mature segmented neutrophils. Expression patterns of surface antigen, transcription factors, and granule proteins during differentiation were also similar to those of granulopoiesis in normal bone marrow. In conclusion, differentiation of mature neutrophils from hiPSCs was successfully induced in a similar process to normal granulopoiesis using an OP9 co-culture system. This system may be applied to elucidate the pathogenesis of various hematological diseases that affect neutrophils. PMID- 20945398 TI - Gene profiling reveals hydrogen sulphide recruits death signaling via the N methyl-D-aspartate receptor identifying commonalities with excitotoxicity. AB - Recently the role of hydrogen sulphide (H(2) S) as a gasotransmitter stimulated wide interest owing to its involvement in Alzheimer's disease and ischemic stroke. Previously we demonstrated the importance of functional ionotropic glutamate receptors (GluRs) by neurons is critical for H(2) S-mediated dose- and time-dependent injury. Moreover N-methyl-D-aspartate receptor (NMDAR) antagonists abolished the consequences of H(2) S-induced neuronal death. This study focuses on deciphering the downstream effects activation of NMDAR on H(2) S-mediated neuronal injury by analyzing the time-course of global gene profiling (5, 15, and 24 h) to provide a comprehensive description of the recruitment of NMDAR-mediated signaling. Microarray analyses were performed on RNA from cultured mouse primary cortical neurons treated with 200 uM sodium hydrosulphide (NaHS) or NMDA over a time-course of 5-24 h. Data were validated via real-time PCR, western blotting, and global proteomic analysis. A substantial overlap of 1649 genes, accounting for over 80% of NMDA global gene profile present in that of H(2) S and over 50% vice versa, was observed. Within these commonly occurring genes, the percentage of transcriptional consistency at each time-point ranged from 81 to 97%. Gene families involved included those related to cell death, endoplasmic reticulum stress, calcium homeostasis, cell cycle, heat shock proteins, and chaperones. Examination of genes exclusive to H(2) S-mediated injury (43%) revealed extensive dysfunction of the ubiquitin-proteasome system. These data form a foundation for the development of screening platforms and define targets for intervention in H(2) S neuropathologies where NMDAR-activated signaling cascades played a substantial role. PMID- 20945399 TI - Dicer is required for the formation of white but not brown adipose tissue. AB - Dicer, an enzyme involved in microRNA maturation, is required for proper embryo gastrulation and tissue morphogenesis during mammalian development. Using primary cultures of fibroblasts and pre-adipocytes, we have previously shown that Dicer is essential for early stages of adipogenic cell differentiation. In this study, we have utilized Dicer-conditional mice to explore a role for Dicer and microRNA biogenesis in the terminal differentiation of adipocytes in vivo and in the formation of white and brown adipose tissue. Deletion of Dicer in differentiated adipocytes in Dicer-conditional, aP2-Cre transgenic mice reduced the level of various adipogenic-associated transcripts and inhibited lipogenesis in white adipocytes, resulting in a severe depletion of white adipose tissue in mice. In contrast, Dicer was not required in vivo for lipogenesis in brown adipose or for brown fat formation. However, Dicer deletion in brown adipose did decrease the expression of genes involved in thermoregulation. The results of our study provide genetic evidence of a role for microRNA molecules in regulating adipogenesis and reveal distinct requirements for Dicer in the formation of white and brown adipose tissue. PMID- 20945400 TI - Raloxifene induces cell death and inhibits proliferation through multiple signaling pathways in prostate cancer cells expressing different levels of estrogen receptor alpha and beta. AB - Raloxifene (RAL), a selective estrogen receptor (ER) modulator (SERM) seems to induce apoptosis in both androgen-dependent and -independent prostate cell (PC) lines via activation of ERbeta and an antagonistic effect on ERalpha. In this study, we evaluated the effects of RAL on epithelial PC growth using the two following in vitro models: the androgen-dependent cell line EPN which expressed both ERs; and a stabilized epithelial cell line derived from a prostate cancer specimen (CPEC), which expressed low levels of ERbeta and lacked ERalpha. In EPN cells, there was an increase in the pre-G1 apoptotic peak and a reduction in the S phase of the cell cycle with G0/G1 arrest after E2 or RAL treatment; bcl-2 mRNA and Bcl-2 protein levels were significantly reduced, while activated caspase-3 and Par-4 levels increased significantly after either E2 or RAL treatment; in addition, c-myc transcript was inhibited after 10(-6) M RAL treatment. A dose dependent increase of metallothionein II gene RNA level was also induced by RAL in EPN. In CPEC, there was only a weak apoptotic peak associated with caspase-3 activation and Par-4 increase after either E2 or RAL treatment; while c-myc transcript level increased. RAL induced a rapid but transient phosphorylation of ERK 1/2 in EPN cells but generated a sustained effect in CPEC. These findings suggest that RAL effects on PC growth control in vitro are cell-specific, depending on ERbeta or ERbeta/ERalpha relative expression levels. Moreover, this study demonstrated that RAL affected both transcriptional regulation and non genomic signals, which resulted in the modulation of multiple signaling pathways of apoptosis and of cell cycle progression. PMID- 20945401 TI - MicroRNA-24 regulates the processing of latent TGFbeta1 during cyclic mechanical stress in human trabecular meshwork cells through direct targeting of FURIN. AB - Cyclic mechanical stress (CMS) leads to alterations of cellular functions in the trabecular meshwork (TM), including the up-regulation of transforming growth factor beta 1 (TGFbeta1), that can potentially contribute to the pathogenesis of glaucoma. Although microRNAs (miRNAs) are known to play important roles in many biological functions, little is known about their potential involvement in the cellular responses elicited by mechanical stress. Here we analyzed changes in miRNA expression induced by CMS, and examined the possible role of miR-24 in the response of human TM cells to CMS. CMS induced the expression of miR-24 that led to the down regulation of the subtilisin-like proprotein convertase FURIN, which is known to play a major role in the processing of TGFbeta1. FURIN was confirmed as a novel target of miR-24 by 3' UTR luciferase assay and western blot. Overexpression of miR-24 resulted in a significant decrease in activated TGFbeta1. This effect was mimicked by down regulation of FURIN by siRNA. Conversely, inhibition of miR-24 expression with a specific antagomir led to a small but significant increase in TGFbeta1. Furthermore, the increase in active TGFbeta1 induced by CMS in HTM cells was prevented by miR-24. Altogether, our results suggest that miRNAs might contribute to the regulation of responses to CMS in TM cells. Specifically, miR-24 might play an important role in modulating the induction of TGFbeta1 mediated by CMS through direct targeting of FURIN. PMID- 20945402 TI - Effective targeting of prostate cancer by lymphocytes redirected by a PSMA * CD3 bispecific single-chain diabody. AB - BACKGROUND: For redirecting T-lymphocytes to induce prostate cancer cell lysis, we constructed a novel bispecific single-chain (bsc) diabody directed to the prostate specific membrane antigen (PSMA) and the T-cell receptor (TCR) associated CD3 molecule on T-cells. METHODS: The PSMA * CD3 bsc diabody was generated from an anti-CD3 single chain Fv fragment (scFv) and the anti-PSMA scFv D7. It was expressed in E. coli and purified from the periplasmic extract and culture supernatant by immobilized metal affinity chromatography (IMAC). The binding properties were tested on PSMA-expressing prostate cancer cells and PSMA negative cell lines as well as on Jurkat cells by flow cytometry. For in vitro functional analysis, a cell viability test (WST-1) was used and activation of T cells was determined by measuring the surface marker expression of CD25 and CD69. For in vivo evaluation, the diabody was administered in combination with human peripheral blood lymphocytes (Ly) in a C4-2 xenograft-SCID mouse model. RESULTS: Specific binding of the PSMA * CD3 bsc diabody both to CD3-positive Jurkat cells and PSMA-expressing C4-2 cells was shown by flow cytometry. In vitro, the PSMA * CD3 bsc diabody proved to be a potent agent for retargeting CD4+ and CD8+ human lymphocytes to lyse C4-2 prostate cancer cells. Treatment of SCID mice bearing C4 2 tumor xenografts with the diabody and human lymphocytes efficiently inhibited tumor growth. CONCLUSIONS: The PSMA * CD3 bsc diabody bears a high potential for the immunotherapy of prostate cancer. PMID- 20945403 TI - LHRH antagonist Cetrorelix reduces prostate size and gene expression of proinflammatory cytokines and growth factors in a rat model of benign prostatic hyperplasia. AB - BACKGROUND: Recent findings suggest that BPH has an inflammatory component. Clinical trials have documented that therapy with LHRH antagonist Cetrorelix causes a marked and prolonged improvement in LUTS in men with symptomatic BPH. We investigated the mechanism of action and effect of Cetrorelix in a rat model of BPH. METHODS: Adult male Wistar rats were used. BPH was induced in rats by subcutaneous injections of TE 2 mg/day for 4 weeks. Control animals received injections of corn oil. After induction of BPH, rats received depot Cetrorelix pamoate at the doses of 0.625, 1.25, and 12.5 mg/kg on days 1 and 22 and TE control rats received vehicle injections. Whole prostates were weighed and processed for RNA and protein. Real-time RT-PCR assays for numerous inflammatory cytokines and growth factors were performed. Quantitative analyses of prostatic LHRH receptor, LHRH, androgen receptor (AR) and 5alpha-reductase 2 were done by real-time RT-PCR and immunoblotting; serum DHT, LH, PSA, and IGF-1 by immunoassays. RESULTS: mRNA levels for inflammatory cytokines IFN-gamma, IL-3, IL 4, IL-5, IL-6, IL-8, IL-13, IL-15, and IL-17 and for growth factors EGF, FGF-2, FGF-7, FGF-8, FGF-14, TGF-beta1, and VEGF-A were significantly reduced by Cetrorelix 0.625 mg/kg (P < 0.05). Prostate weights were also significantly lowered by any dose of Cetrorelix. CONCLUSIONS: This study suggests that Cetrorelix reduces various inflammatory cytokines and growth factors in rat prostate and, at doses which do not induce castration levels of testosterone, can lower prostate weights. Our findings shed light on the mechanism of action of LHRH antagonists in BPH. PMID- 20945405 TI - Immunoreactivity of the salivary protein statherin in human male accessory sex glands. AB - BACKGROUND: Statherin is a small phosphoprotein chiefly studied for its protective roles towards teeth and oral tissues. Although generally considered as exclusively secreted by salivary glands, circumstantial evidences suggested that other tissues also produce it. This article first demonstrates statherin immunoreactivity in human prostate and seminal vesicles. METHODS: Surgical samples of prostate and seminal vesicles were fixed in a mixture of paraformaldehyde and glutaraldehyde, and embedded in Epon resin without previous osmication. Ultrathin sections were treated for the intracellular localization of statherin by means of an immunogold staining method. RESULTS: Reactive statherin was revealed in secreting cells of both seminal vesicle and prostate epithelia: labeling was found in secretory granules of seminal vesicle cells and in cytoplasmic vesicles of prostatic cells. CONCLUSIONS: The different staining patterns suggested that the two glands secrete statherin through different pathways. Prostate 71:671-674, 2011. (c) 2010 Wiley-Liss, Inc. PMID- 20945404 TI - Fine-mapping of prostate cancer aggressiveness loci on chromosome 7q22-35. AB - BACKGROUND: Deciphering the genetic basis of prostate cancer aggressiveness could provide valuable information for the screening and treatment of this common but complex disease. We previously detected linkage between a broad region on chromosome 7q22-35 and Gleason score-a strong predictor of prostate cancer aggressiveness. To further clarify this finding and focus on the potentially causative gene, we undertook a fine-mapping study across the 7q22-35 region. METHODS: Our study population encompassed 698 siblings diagnosed with prostate cancer. 3,072 single nucleotide polymorphisms (SNPs) spanning the chromosome 7q22 35 region were genotyped using the Illumina GoldenGate assay. The impact of SNPs on Gleason scores were evaluated using affected sibling pair linkage and family based association tests. RESULTS: We confirmed the previous linkage signal and narrowed the 7q22-35 prostate cancer aggressiveness locus to a 370 kb region. Centered under the linkage peak is the gene KLRG2 (killer cell lectin-like receptor subfamily G, member 2). Association tests indicated that the potentially functional non-synonymous SNP rs17160911 in KLRG2 was significantly associated with Gleason score (P = 0.0007). CONCLUSIONS: These findings suggest that genetic variants in the gene KLRG2 may affect Gleason score at diagnosis and hence the aggressiveness of prostate cancer. PMID- 20945406 TI - Internal prostatic architecture on transrectal ultrasonography predicts future prostatic growth: natural history of prostatic hyperplasia in a 15-year longitudinal community-based study. AB - BACKGROUND: From 1992 to 1993, we conducted a cross-sectional community-based study to clarify the prevalence of benign prostatic hyperplasia in Japanese men aged 40-79. Based on the results, we hypothesized that the internal prostatic architecture (IPA) on transrectal ultrasonography (TRUS) would predict future prostatic growth. We investigated the changes in prostate volume (PV) over time and validated our hypothesis on predictors for future prostatic growth. METHODS: Of 319 participants in the initial study, the PV of 104 men was evaluated by TRUS with approximately a 15-year follow-up in the current study. We categorized prostates into three groups based on the IPA: group 1, invisible transition zone (TZ); group 2, visible TZ with an unclear border; and group 3, visible TZ with a clear border. RESULTS: Overall PV significantly increased from 17.4 ml to 23.9 ml (P < 0.001). The median PV changes by age decade (40s, 50s, 60s, and 70s) were 5.5, 5.6, 8.6, and 11.1 ml, respectively. Those by baseline PV < 20 ml, 20 25 ml, and >= 25 ml were 5.3, 9.8, and 14.7 ml, respectively. Those by baseline IPA for group 1, group 2, and group 3 were 4.7, 6.5, and 17.3 ml, respectively. Multiple linear regression analysis indicated that PV (P = 0.027) and the IPA (P < 0.001) at baseline were independent predictors for future prostatic growth. CONCLUSIONS: This was the first study by longitudinal community based study that the PV in Japanese men increased during 15 years. The IPA on TRUS is useful for predicting future prostatic growth. PMID- 20945407 TI - Gastrin-releasing peptide: predictor of castration-resistant prostate cancer? AB - BACKGROUND: Neuroendocrine (NE) cells of the prostate are known to be androgen independent and NE peptides like gastrin-releasing peptide (GRP) or neuron specific enolase (NSE) can stimulate growth in a paracrine manner, and this is thought to be one of the escape mechanisms in castration-resistant prostate cancer (CRPCa). In a longitudinal study, we investigated the development of the NE serum factors GRP, NSE, and chromogranin A and their correlation with prostate specific androgen (PSA) during hormonal treatment. MATERIALS AND METHODS: Thirty two patients, with histology-proven, localized or metastatic prostatic carcinoma (PCa), who were undergoing therapy with LHRH analogue or a combination of LHRH analog and peripheral androgen blockade, took part in the study. In addition, eight healthy volunteers were each tested twice for serum GRP to elicit a "physiological" standard value. Blood samples were taken periodically from each patient within an 18-month time frame. RESULTS: We defined the standard value for GRP in the healthy participants as 0.852 ng/ml (mean + 2 SD) and observed that the GRP values for patients with PCa were significantly higher (P = 0.034). There was a positive correlation between PSA and GRP in patients with biochemical failure. CgA correlated with PSA development in the CRPCa patients. NSE values rose steadily over the study period, but with no correlation to PSA. CONCLUSION: Our data confirm that NE factors are elevated during hormonal treatment of prostate cancer. GRP is higher in PCa patients undergoing androgen deprivation therapy and is possibly involved in the initiation of hormonal escape in PCa. PMID- 20945409 TI - Maternal plasma polychlorinated biphenyl levels in cynomolgus monkeys (Macaca fascicularis) affect infant social skills in mother-infant interaction. AB - Polychlorinated biphenyls (PCBs) are endocrine disrupting chemicals that disturb normal development of embryonic brains. In the present study, we evaluated the relationship between maternal plasma PCB concentration and infant behavioral characteristics in mother-infant interactions. We grouped 20 pregnant cynomolgus monkeys (Macaca fascicularis) into higher and lower PCB exposure groups; monkeys in the higher PCB group had PCB concentrations above 15 pg/g, which is representative of natural exposure levels. Maternal PCB concentration correlated negatively with infant behaviors (approach, look, proximity, locomotion) at the age of 6 months (p < .05), when an increase in these behaviors should normally occur. These results suggest that maternal PCB exposure may affect the development of infant social behavior in cynomolgus monkeys. Furthermore, this study provides primate evidence to support observations of associations between behavioral and learning disabilities and prenatal exposure to PCBs in humans. PMID- 20945410 TI - Age-related changes in visual recognition memory during infancy and early childhood. AB - Age-related changes in long-term memory during infancy and early childhood were examined using the Visual Recognition Memory (VRM) procedure. Independent groups of 1-, 2-, 3-, and 4-year-olds were familiarized with a visual stimulus and were tested either immediately or after a delay that ranged from 24 hr to 6 months. Although all age groups exhibited a significant novelty preference when tested immediately after familiarization, clear age-related differences emerged over longer retention intervals. We conclude that age-related increases in basic retention are a fundamental aspect of mammalian memory development and, in humans, these increases may play a vital role in the offset of childhood amnesia. PMID- 20945408 TI - Parental division of labor, coordination, and the effects of family structure on parenting in monogamous prairie voles (Microtus ochrogaster). AB - Family relationships help shape species-typical social and emotional development, but our understanding of how this shaping occurs is still relatively limited. Prairie voles are a socially monogamous and biparental species that is well situated to complement traditional animal models, such as rats and mice, in investigating the effects of family experience. In this series of studies, we aimed to test hypotheses relating to how prairie vole families function under undisturbed, standard laboratory conditions. In the first study, we compared the parental behavior of primiparous biparental (BP) and single-mother (SM) prairie vole family units for 12 postnatal days and then tested for sex differences, behavioral coordination, and family structure effects. Under BP conditions, nest attendance was coordinated and shared equally by both sexes, while pup-directed and partner-directed licking and grooming (LG) were coordinated in a sex and social-context-dependent manner. Contrary to our expectations, SMs showed no evidence of strong parental compensation in response to the lack of the father, indicating a minimal effect of family structure on maternal behavior but a large effect on pup care. In the second study, we examined the effects of these BP and SM rearing conditions on family dynamics in the next generation and found that SM reared adult parents exhibited lower rates of pup-directed LG in comparison to BP reared counterparts. Situated in the context of human family dynamics and psychology, these results suggest that the study in prairie voles may help improve our understanding of family systems and how perturbations to these systems can affect adults and offspring. PMID- 20945411 TI - Application of microchip CGE for the analysis of PEG-modified recombinant human granulocyte-colony stimulating factors. AB - The purpose of this study was to evaluate the microchip CGE (MCGE) for the analysis of PEG-modified granulocyte-colony stimulating factor (PEG-G-CSF) prepared with PEG-aldehydes. The unmodified and PEG-modified G-CSFs were analyzed by Protein 80 and 230 Labchips on the Agilent 2100 Bioanalyzer. The MCGE allowed size-based separation and quantitation of PEG-G-CSF. The Protein 80 Labchip was useful for PEG-5K-G-CSF, while the Protein 230 Labchip was more suitable for PEG 20K-G-CSF. The MCGE was also used to monitor a search for optimal PEG modification (PEGylation) conditions to produce mono-PEG-G-CSF. This study demonstrates the usefulness of MCGE for monitoring and optimizing the PEGylation of G-CSF with the advantages of speed, minimal sample consumption, and automatic quantitation. PMID- 20945412 TI - Manipulating particles in microfluidics by floating electrodes. AB - Various particle manipulations including enrichment, movement, trapping, separation, and focusing by floating electrodes attached to the bottom wall of a straight microchannel under an imposed DC electric field have been experimentally demonstrated. In contrast to a dielectric microchannel possessing a nearly uniform surface charge (or zeta potential), the metal strip (floating electrode) is polarized under the imposed electric field, resulting in a nonuniform distribution of the induced surface charge with a zero net surface charge along the floating electrode's surface, and accordingly induced-charge electroosmotic flow near the metal strip. The induced induced-charge electroosmotic flow can be regulated by controlling the strength of the imposed electric field and affects both the hydrodynamic field and the particle's motion. By using a single floating electrode, charged particles could be locally concentrated in a section of the channel or in an end-reservoir and move toward either the anode or the cathode by controlling the strength of the imposed electric field. By using double floating electrodes, negatively charged particles could be concentrated between the floating electrodes, subsequently squeezed to a stream flowing in the center region of the microchannel toward the cathodic reservoir, which can be used to focus particles. PMID- 20945413 TI - Simple determination of azasetron in rat plasma by column-switching high performance liquid chromatography. AB - For the quantification of azasetron in rat plasma samples, a column-switching HPLC method was developed and validated. Following dilution of plasma samples with mobile phase A (17 mM potassium phosphate buffer (pH 3.0)) and simple protein precipitation by addition of perchloric acid (60%), the mixture was directly injected onto the pre-column. After endogenous plasma substances were eluted to waste, the analyte was transferred to the trap column by switching the system. Then, the analyte was back-flushed to the analytical column for separation with mobile phase B (a 22:78 v/v mixture of acetonitrile and 17 mM potassium phosphate buffer (pH 3.0)) and detected at 250 nm using a photodiode array detector. A linear standard curve was obtained in the concentration range of 10-800 ng/mL with the correlation coefficient (r) of 0.9998. The intra- and inter-day precision and accuracy values for azasetron were in the ranges of 0.3 12.9% and 89.7-101.4%, respectively. The method was valid in terms of specificity, precision, and accuracy. In addition, this efficient analytical method was successfully applied to determine plasma concentrations of azasetron following oral administration of azasetron at a dose of 4.0 mg/kg to rats. PMID- 20945414 TI - Inhibition of all-trans-retinoic acid-induced proteasome activation potentiates the differentiating effect of retinoid in acute myeloid leukemia cells. AB - All-trans retinoic acid (ATRA) is nowadays considered to be the sole efficient agent for differentiation-based therapy in leukemia; however, the mechanisms of ATRA's biological effects remain largely unknown. Here we first reported that ATRA-induced myeloid leukemia differentiation was accompanied with the increased level of ubiquitin-protein conjugates and the upregulation of proteasome activity. To explore the functional role of the activated proteasome in retinoic acid (RA) signaling, the effects of proteasome inhibitors on RA-induced cell differentiation were determined. Our results demonstrated that inhibition of ATRA elevated proteasome activity obviously promoted the myeloid maturation program triggered by ATRA, suggesting that the overactivated proteasome is not beneficial for ATRA's effects. Further studies demonstrated that the synergistic differentiating effects of ATRA and proteasome inhibitors might be associated with the protection of retinoic acid receptor alpha (RARalpha) from degradation by the ubiquitin-proteasome pathway (UPP). Moreover, the accumulated RARalpha was able to enhance the transcription of its target gene, which might also contribute to the enhanced differentiation of leukemia cells. Together, by linking the UPP to ATRA-dependent signaling, our data provide a novel insight into studying the mechanisms of ATRA-elicited cellular effects and imply the possibility of combination of ATRA and proteasome inhibitors in leukemia therapy. PMID- 20945415 TI - Regulation of FGF-2 by an endogenous antisense RNA: effects on cell adhesion and cell-cycle progression. AB - Fibroblast growth factor (FGF-2) and its endogenous antisense RNA FGF antisense (FGF-AS) have been implicated in cancer progression and correlated with clinical outcomes of cancer patients. We previously reported that elevated FGF-AS expression is associated with reduced tumor recurrence and improved survival rates in patients with FGF-2-dependent esophageal adenocarcinoma. In the present study we examined the effect of siRNA knockdown of each transcript on the expression of its complementary partner RNA, and consequent changes in cellular phenotype and behavior. FGF-AS and FGF-2 were inversely expressed in a cell-cycle dependent manner and siRNA-mediated knockdown of either FGF-AS or FGF-2 resulted in upregulation of the complementary transcript and protein. siRNA-mediated knockdown of FGF-AS was associated with a dramatic increase in cell-substratum adhesion and marked changes in the expression of a number of genes encoding adhesion molecules. Microarray analysis and RT-PCR analysis also revealed antithetical effects of FGF-2 and FGF-AS siRNA knockdown on the expression of a number of cell-cycle-related genes, including SKP2, SESTRIN-3, EIF4BP2, CDC27, and P190RhoGAP (P190). Cell-cycle analysis following siRNA-mediated knockdown of FGF-AS or FGF-2 indicate that both factors are involved in control of transition through the G1 and G2 boundaries, affecting cell-cycle progression, proliferation, and apoptosis. Finally, siRNA knockdown of FGF-AS resulted in a significant increase in invasion activity. These data indicate that regulatory interactions between FGF-AS and FGF-2 are involved in control of cell adhesion, cell-cycle progression, and invasion, providing a possible explanation for the protective effects of FGF-AS expression observed in FGF-2-dependent cancers. PMID- 20945417 TI - Association of angiotensin I converting enzyme (insertion/deletion) and angiotensin II type 1 receptor (A1166C) polymorphisms with breast cancer prognostic factors in Iranian population. AB - It has been indicated that renin-angiotensin system (RAS) has role in various steps of cancer progression. The presence of RAS components has been shown in normal and breast cancer tissue. insertion/deletion (I/D) is one of angiotensin I converting enzyme (ACE) polymorphisms and A1166C is one of angiotensin II type-1 receptor (AT1R) polymorphisms which have been associated with various diseases such as cardiovascular diseases. In the present study, we aimed to substantiate the putative significance of ACE and AT1R on breast cancer biology by investigating the influence of their gene polymorphisms on breast cancer progression. The I/D and A1166C polymorphisms were evaluated by using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), respectively in 70 breast cancer patients diagnosed with invasive breast cancer and 70 healthy women. Breast cancer prognostic factors were obtained from medical and pathology reports of patients. There was no significant difference between cases and controls for ACE (I/D) (P = 0.15) and AT1R (A1166C) genotypes (P = 0.86). In breast cancer patients, when DD genotype was used as reference group, the combination of II and ID genotypes was associated with increased HER-2 expression (P = 0.020; OR, 4.58; 95% CI, 1.26-16.60). Also, when AA genotype was used as reference group, the AC genotype was associated with higher tumor TNM stage (P = 0.024; OR, 4.66; 95% CI, 1.18-18.35). This is the first study indicating that ACE (I/D) polymorphism is associated with HER-2 expression and AT1R (A1166C) polymorphism is associated with tumor TNM stage in breast cancer patients. PMID- 20945416 TI - Loss of tyrosine phosphatase-dependent inhibition promotes activation of tyrosine kinase c-Src in detached pancreatic cells. AB - Despite an intense focus on novel therapeutic strategies, pancreatic adenocarcinoma remains one of the deadliest human malignancies. The frequent and rapid mortality associated with pancreatic cancer may be attributed to several factors, including late diagnosis, rapid tumor invasion into surrounding tissues, and formation of distant metastases. Both local invasion and metastasis require disruption of tumor cell contacts with the extracellular matrix. Detachment of normal cells from the extracellular matrix leads to a form of programmed cell death termed anoikis. Pancreatic cancer cells avert anoikis by activation of signaling pathways that allow for adhesion-independent survival. In the present studies, cellular signaling pathways activated in detached pancreatic cancer cells were examined. We demonstrate a rapid and robust activation of Src kinase in detached pancreatic cancer cells, relative to adherent. Src autophosphorylation rapidly returned to baseline levels upon reattachment to tissue culture plastic, in the presence or absence of specific extracellular matrix proteins. Treatment of pancreatic cancer cells with tyrosine phosphatase inhibitors increased steady-state Src autophosphorylation in adherent cells and abrogated the detachment-induced increase in Src autophosphorylation. Src was found to co-immunoprecipitate with the Src homology 2 (SH2) domain containing protein tyrosine phosphatase (SHP-2) in pancreatic cancer cells, suggesting that SHP-2 may participate in regulation of Src autophosphorylation in adherent cells. Src family kinase (SFK) dependent increases in Akt and Jun N-terminal kinase (JNK) phosphorylation were observed in detached cells, indicating the potential for Src-dependent activation of survival and stress pathways in pancreatic cancer cells that have detached from the extracellular matrix. PMID- 20945423 TI - Coordination-insertion copolymerization of polar vinyl monomers by palladium catalysts. AB - Random incorporation of polar functional groups into polyolefins and polyketones along with the precise control of incorporation ratios and polymer microstructures is one of the most significant challenges in polymer chemistry. For such a purpose, late-transition-metal complexes are often employed as a catalyst for the copolymerization of polar vinyl monomers, because of their high functional group compatibility. This account describes our contribution to the development of coordination-insertion copolymerization of polar vinyl monomers by palladium catalysts. In particular, the use of palladium/phosphine-sulfonate catalysts enables to incorporate various polar vinyl monomers into polyolefins and polyketones. PMID- 20945425 TI - Special focus on top-down proteomics. PMID- 20945426 TI - A low-bandgap diketopyrrolopyrrole-benzothiadiazole-based copolymer for high mobility ambipolar organic thin-film transistors. PMID- 20945429 TI - Androgen hypersensitivity in prostate cancer: molecular perspectives on androgen deprivation therapy strategies. AB - Androgen deprivation therapy is initially successful in treating advanced prostate cancer. However, after a period of time tumors inevitably recur. Improved understanding of the various biochemical causes of resistance to hormonal therapy is of crucial importance for developing more effective therapeutic strategies in this cohort of patients. This review discusses the preclinical evidence for androgen hypersensitivity (AH), as a mechanism by which tumors become hormone-refractory (HR). We propose that the growth of some such tumors may be not only stimulated by, but also dependent on low hormone levels, and furthermore, that normal hormone concentrations can have an inhibitory effect on growth. The incidence and importance of AH merits further investigation both in preclinical studies and during clinical trials of intermittent androgen withdrawal or testosterone replacement. We suggest that a subset of HR prostate cancer patients who have androgen-hypersensitive tumors could be particularly amenable to these treatments. Finally, potential approaches for developing biomarkers to identify such patients are explored. PMID- 20945431 TI - Instability of syllable repetition as a marker of disease progression in Parkinson's disease: a longitudinal study. AB - Parkinsonian speakers show a tendency to articulatory acceleration and have difficulties to keep the steady pace of repeated syllables. The aim of this study was to analyse the stability of motor speech performance based upon a syllable repetition paradigm during the course of disease to find a potential marker of disease progression in Parkinson's disease (PD). 58 patients with PD and 35 controls were tested and re-tested after at least 12 months (mean: 33.40/range: 12-88). In the PD group, motor impairment was similar at first and second visit. Participants had to repeat the syllable /pa/ in a self chosen steady pace. Percental coefficient of variance (COV) of interval length was measured for description of pace stability throughout the performance. Percental pace acceleration (%PA) was based upon a comparison of the speed of syllable repetition in the first and second half of the task. Patients with PD showed a significant elevation of COV and %PA indicating an instability of syllable repetition and a tendency to pace acceleration in the course of performing. Furthermore, in the PD group, COV and %PA showed a significant deterioration from first to second examination. Instability of steady syllable repetition in PD shows characteristic changes during the course of the disease, but no correlation with general motor impairment. Therefore, the underlying mechanism may be independent from dopaminergic deficits. The potential role of impaired syllable repetition as a marker of non-dopaminergic disease progression in PD needs validation by further studies. PMID- 20945430 TI - Differential genetic susceptibility in diphasic and peak-dose dyskinesias in Parkinson's disease. AB - To examine whether there is a differential genetic susceptibility in the diphasic and peak-dose forms of levodopa-induced dyskinesias (LID) in patients with Parkinson's disease (PD). The study cohort comprised 503 unrelated Korean PD patients who were treated with levodopa and had a disease duration of at least 5 years. The presence of LID was identified during a routine follow-up and special care was taken to separate the two distinct forms of LID into diphasic and peak dose dyskinesias (PDSK). Genotyping was performed in the 503 patients and in 559 healthy controls to search for polymorphisms of DRD3 p.S9G, DRD2 Taq1A, GRIN2B c.2664C>T, c.366C>G, c.-200T>G, and the promoter region of SLC6A4. A total of 229 patients expressed LID (peak-dose in 205, diphasic in 57, and both in 33). The presence of diphasic dyskinesia (DDSK) was exclusively associated with the DRD3 p.S9G variant after adjusting for gender, age at PD onset, Hoehn & Yahr stage, and duration of levodopa treatment. Carrying the AA genotype was likely to shorten the onset of DDSK according to the duration of levodopa therapy (P = 0.02). The presence of PDSK was not significantly associated with any of the six genetic variants studied. There may be a genetic susceptibility in the development of DDSK in PD patients on chronic levodopa therapy, and its underlying pathophysiological mechanism might be distinct from that of PDSK. PMID- 20945433 TI - Oral high-calorie, low-protein supplements in a Parkinson's disease patient: a case report. PMID- 20945432 TI - Central oscillators in a patient with neuropathic tremor: evidence from intraoperative local field potential recordings. AB - Present pathophysiological concepts of neuropathic tremor assume mistimed and defective afferent input resulting in deregulation of cerebello-thalamo-cortical motor networks. Here, we provide direct evidence of central tremor processing in a 76-year-old female who underwent bilateral deep brain stimulation of the ventral intermedial nucleus of the thalamus (Vim-DBS) because of neuropathic tremor associated with IgM paraproteinemia. Electrophysiological recordings of EEG and EMG were performed in three perioperative sessions: (1) preoperatively, (2) intraoperatively, and (3) 4 days after surgery in both rest and postural tremor conditions. Tremor-related synchronization (coherence) between motor cortex (M1) and muscles (M. extensor digitorum, M. flexor digitorum) was assessed, and additional intraoperative local field potential (LFP) recordings from Vim allowed comprehensive coherence mapping in thalamo-cortico-muscular networks. Directionality of information flow was determined by directed transfer function (DTF) and phase analyses. Stimulation effects on tremor and corticomuscular coherence were assessed and the patient was followed for 12 months on clinical outcome measures (Tremor Rating Scale, CADET-Score). Vim-DBS reduced tremor (59%) and improved motor functionality in daily activities (31%, CADET-A) after 12 months. Intraoperative recordings demonstrated significant coherence in the tremor frequency (4 Hz) between M1 and contralateral muscle, Vim and ipsilateral M1, Vim and contralateral muscle, but not between Vim and contralateral M1. Information flow was directed from M1 to Vim and bidirectional between M1 and muscle and between Vim and muscle, respectively. Corticomuscular coherence at tremor frequency was completely suppressed by Vim-DBS. Our case study demonstrates central oscillators underlying neuropathic tremor and implies a strong pathophysiological rationale for Vim-DBS. PMID- 20945434 TI - Nonmotor symptoms are independently associated with impaired health-related quality of life in Chinese patients with Parkinson's disease. AB - We performed a cross-sectional study of 82 Chinese patients with Parkinson's disease (PD) enrolled during an 18-month period using a clinical interview to assess the prevalence of nonmotor symptoms (NMS), the association with disease severity and motor status, and the impact on patients' health-related quality of life (Hr-QoL). The patients' NMS, Hr-QoL, disease severity, and motor status were assessed by the Nonmotor Symptoms Scale (NMSS), the 39-item Parkinson's Disease Questionnaire (PDQ-39), the modified Hoehn and Yahr staging scale (H&Y) and the Unified Parkinson's Disease Rating Scale part III (UPDRS III), respectively. We found that 100% of patients with PD presented with NMS. The NMSS significantly correlated with disease duration (Spearman's r(S) = 0.276, P = 0.012), H&Y (r(S) = 0.230, P = 0.038), and UPDRS III (r(S) = 0.350, P = 0.001). Similarly, the PDQ 39 SI significantly associated with the disease duration (r(S) = 0.258, P = 0.019), H&Y (r(S) = 0.340, P = 0.002), and UPDRS III (r(S) = 0.453, P < 0.001). NMS domains that influenced the PDQ-39 SI were sleep/fatigue, mood, gastrointestinal, urinary, and miscellaneous symptoms. This strongly suggested that the five domains played a key role in the manifestation of Hr-QoL. NMSS explains more of the variability in Hr-QoL than UPDRS III, when both are the model (stepwise multiple linear regression analysis R2 change, 47.8% vs. 5.87%, respectively). Therefore, these findings demonstrate that NMS are independently and negatively associated with Hr-QoL in PD and that improving NMS should be viewed as an important part in the management of PD. PMID- 20945435 TI - Putaminal, but not nigral alterations, characterize hemiparkinsonism-hemiatrophy syndrome: a case report. PMID- 20945436 TI - Contact-active antimicrobial and potentially self-polishing coatings based on cellulose. AB - A contact-active antimicrobial coating is described that is only degraded in the presence of cellulase, which is an extracellular enzyme of numerous microbial strains. Antimicrobial DDA was grafted to a cellulose backbone via a polymeric spacer. The antimicrobial activity of the coatings, their biodegradability and their self-polishing potential were investigated. It was found that all coatings were antimicrobially active against Staphylococcus aureus. Coatings with high DS and long polymeric spacers degraded in water, while coatings with low DS and short spacers were not hydrolyzed even in the presence of cellulase. One coating was found to be selectively degradable by cellulase and recovered most of its antimicrobial activity after overloading and subsequent treatment with cellulase. PMID- 20945437 TI - The transforming growth factor-beta (TGF-beta) mediates acquisition of a mesenchymal stem cell-like phenotype in human liver cells. AB - Transforming growth factor-beta (TGF-beta) mediates several and sometime opposite effects in epithelial cells, inducing growth inhibition, and apoptosis but also promoting an epithelial to mesenchymal transition (EMT) process, which enhances cell migration and invasion. TGF-beta plays relevant roles in different liver pathologies; however, very few is known about its specific signaling and cellular effects in human primary hepatocytes. Here we show that TGF-beta inhibits proliferation and induces pro-apoptotic genes (such as BMF or BIM) in primary cultures of human fetal hepatocytes (HFH), but also up-regulates anti-apoptotic genes, such as BCL-XL and XIAP. Inhibition of the epidermal growth factor receptor (EGFR), using gefitinib, abrogates the increase in the expression of the anti-apoptotic genes and significantly enhances cell death. Simultaneously, TGF beta is able to induce an EMT process in HFH, coincident with Snail up-regulation and a decrease in E-cadherin levels, cells showing mesenchymal proteins and reorganization of the actin cytoskeleton in stress fibers. Interestingly, these cells show loss of expression of specific hepatic genes and increased expression of stem cell markers. Chronic treatment with TGF-beta allows selection of a population of mesenchymal cells with a de-differentiated phenotype, reminiscent of progenitor-like cells. Process is reversible and the mesenchymal stem-like cells re-differentiate to hepatocytes under controlled experimental conditions. In summary, we show for the first time that human hepatocytes may respond to TGF beta inducing different signals, some of them might contribute to tumor suppression (growth inhibition and apoptosis), but others should mediate liver tumor progression and invasion (EMT and acquisition of a stem-like phenotype). PMID- 20945438 TI - Reprogramming the pluripotent cell cycle: restoration of an abbreviated G1 phase in human induced pluripotent stem (iPS) cells. AB - Induced pluripotent stem (iPS) cells derived from terminally differentiated human fibroblasts are reprogrammed to possess stem cell like properties. However, the extent to which iPS cells exhibit unique properties of the human embryonic stem (hES) cell cycle remains to be established. hES cells are characterized by an abbreviated G1 phase (~ 2.5 h) and accelerated organization of subnuclear domains that mediate the assembly of regulatory machinery for histone gene expression [i.e., histone locus bodies (HLBs)]. We therefore examined cell cycle parameters of iPS cells in comparison to hES cells. Analysis of DNA synthesis [5-bromo-2' deoxy-uridine (BrdU) incorporation], cell cycle distribution (FACS analysis and Ki67 staining) and subnuclear organization of HLBs [immunofluorescence microscopy and fluorescence in situ hybridization (FISH)] revealed that human iPS cells have a short G1 phase (~ 2.5 h) and an abbreviated cell cycle (16-18 h). Furthermore, HLBs are formed and reorganized rapidly after mitosis (within 1.5-2 h). Thus, reprogrammed iPS cells have cell cycle kinetics and dynamic subnuclear organization of regulatory machinery that are principal properties of pluripotent hES cells. Our findings support the concept that the abbreviated cell cycle of hES and iPS cells is functionally linked to pluripotency. PMID- 20945440 TI - Asymmetric reduction of beta-ketoesters and chiral beta-iminoesters: impact of a alpha-quaternary stereocenter. AB - Diastereomeric reduction of nonactivated, hindered beta-keto and chiral beta iminoesters are described. The influence of a alpha-stereocontrolled center on the efficiency and stereoselectivity of the reduction was studied. Reaction conditions were optimized to synthesize beta-hydroxy- and beta-aminoesters in good yields. In the case of chiral beta-iminoesters, influence of matched/mismatched diastereomeric pairs has been assessed. PMID- 20945441 TI - Double-CO3(2-) centered [Co(II)5] wheel and modeling of its magnetic properties. AB - A high-spin Co(II) cluster with a rare pentagonal molecular structure and formula [Co(5)(CO(3))(2)(bpp)(5)]ClO(4) (1; Hbpp is 2,6-bis(phenyliminomethyl)-4 methylphenolate) has been synthesized and characterized by single-crystal X-ray diffraction. This topology arises from fusing five [Co(2)(bpp)] moieties in a cyclic manner around two CO(3)(2-) central ligands, resulting in propeller-like configuration. The irregular coordination of the carbonate ions to the metal centers results in a combination of coordination numbers (CNs) of the Co(II) ions of five and six. The bulk magnetization of this complicated magnetically exchanged system has been modeled successfully by employing a matrix diagonalization technique. For this, the combination of S=3/2 ions (CN=5) with ions exhibiting strong spin-orbit coupling (CN=6) has been considered and a perturbative approach to handle the data in the whole studied range of temperatures (2-300 K) yielding parameters of g and D (for the five-coordinate Co(II) ions), of A, kappa, lambda, and Delta (for the metals with spin-orbit coupling) and of the exchange constants J. The agreement with results from DFT calculations, also presented here, is remarkable. PMID- 20945439 TI - Racial disparity in death from colorectal cancer: does vitamin D deficiency contribute? AB - BACKGROUND: The reasons blacks have higher mortality rates from colorectal cancer (CRC) than non-Hispanic whites are not fully understood. Blacks have higher rates of vitamin D deficiency than non-Hispanic whites, and vitamin D deficiency has been associated with CRC. The authors of this report investigated the association of vitamin D deficiency with excess risk for CRC mortality for blacks in the Third National Health and Nutrition Examination Survey (NHANES III) that was conducted from 1988 to 1994. METHODS: The association between serum 25(OH)D levels and CRC mortality and its contribution to elevated risk among blacks were studied using baseline data from NHANES III and CRC mortality data through 2006 from the National Death Index. By using survival models, the adjusted risk of death from CRC for African Americans was examined with and without adjusting for vitamin D deficiency, which was defined as an 25(OH)D level <20 ng/dL. RESULTS: Black race (hazard ratio [HR], 2.03; 95% confidence interval [95% CI], 1.04 3.95), age (HR, 1.12; 95% CI, 1.09-1.15), not having health insurance (HR, 2.45; 95% CI, 1.12-5.36), and a history of CRC (HR, 7.22; 95% CI, 2.12-24.6) predicted CRC mortality. When added to the model, vitamin D deficiency was associated significantly with CRC mortality (HR, 2.11; 95% CI, 1.11-4.00), and the effect of race was decreased (HR, 1.60; 95% CI, 0.87-2.93); the 40% attenuation was statistically significant (F(1) (,49) = 4.85; P = .03). Similar results were observed when participants who had a history of CRC were excluded from the analysis. CONCLUSIONS: The current findings were consistent with the hypothesis that vitamin D deficiency contributes to excess African-American mortality from CRC. Cancer 2011. PMID- 20945442 TI - Cyclopropylamines from N,N-dialkylcarboxamides and Grignard reagents in the presence of titanium tetraisopropoxide or methyltitanium triisopropoxide. AB - Thirty-three different N,N-dialkyl- and N-alkyl-N-phosphorylalkyl-substituted carboxamides 9-17 were treated with unsubstituted as well as with 2-alkyl-, 2,2 dialkyl-, and 3-alkenyl-substituted ethylmagnesium bromides 6 in the presence of stoichiometric amounts of titanium tetraisopropoxide or methyltitanium triisopropoxide to furnish substituted cyclopropylamines 20-25 in 20-98% yield, depending on the substituents with no (1:1) to excellent (>25:1) diastereoselectivities. Generally higher yields (up to 98%) of the cyclopropylamines 20-28 without loss of the diastereoselectivity were obtained with methyltitanium triisopropoxide as the titanium mediator. Under these conditions, even dioxolane-protected ketones and halogen-substituted and chiral as well as achiral alkyloxyalkyl-substituted carboxamides could be converted to the correspondingly substituted cyclopropylamines with unsubstituted as well as phenyl- and a variety of alkyl-substituted ethylmagnesium bromides in addition to numerous heteroatom-containing (e.g., halogen-, trityloxy-, tetrahydropyranyloxy substituted) Grignard reagents (62 examples altogether). The transformation of N,N-diformylalkylamines 54 with ethylmagnesium bromide in the presence of methyltitanium triisopropoxide to N,N-dicyclopropyl-N-alkylamines 55 can be brought about in up to 82% yield (6 examples). An asymmetric variant of the titanium-mediated cyclopropanation of N,N-dialkylcarboxamides has been developed by applying chiral titanium mediators generated from stoichiometric amounts of titanium tetraisopropoxide and chiral diamino or diol ligands, respectively. The most efficient chiral mediators turned out to be titanium bistaddolates that provided the corresponding cyclopropylamines with enantiomeric excesses (ee) of up to 84%. Evaluation of several silyl-based additives revealed that the reaction can also efficiently be carried out with substoichiometric amounts (down to 25 mol%) of the titanium reagent, as long as 2-aryl- or 2-ethenyl-substituted ethylmagnesium halides are used and a concomitant slight decrease in yields is accepted. The newly developed methodology was successfully applied for the preparation of analogues with cyclopropylamine moieties of known drugs and natural products such as the nicotine metabolite (S)-Cotinine as well as the insecticides Dinotefuran and Imidacloprid. PMID- 20945443 TI - Smart macrocyclic molecules: induced fit and ultrafast self-sorting inclusion behavior through dynamic covalent chemistry. AB - A family of macrocycles with oligo(ethylene glycol) chains, 4O, 5O, and 6O, was developed to construct a series of new incorporated macrocycles through dynamic covalent chemistry. These flexible macrocycles exhibited excellent "self-sorting" abilities with diamine compounds, which depended on the "induced-fit" rule. For instance, the host macrocycles underwent conformational modulation to accommodate the diamine guests, affording [1+1] intramolecular addition compounds regardless of the flexibility of the diamine. These macrocycles folded themselves to fit various diamines with different chain length through modulation of the flexible polyether chain, and afforded intramolecular condensation products. However, if the chain of the diamine was too long and rigid, oligomers or polymers were obtained from the mixture of the macromolecule and the diamine. All results demonstrated that inclusion compounds involving conformationally suitable aromatic diamines were thermodynamically favorable candidates in the mixture due to the restriction of the macrocycle size. Furthermore, kinetic and thermodynamic studies of self-sorting behaviors of both mixed 4O-5O and 4O-6O systems were investigated in detail. Finally, theoretical calculations were also employed to further understand such self-sorting behavior, and indicated that the large enthalpy change of H(2)NArArNH(2)@4O is the driving force for the sorting behavior. Our system may provide a model to further understand the principle of biomolecules with high specificity due only to their conformational self adjusting ability. PMID- 20945444 TI - Intermediate states on the way to edge-sharing BO4 tetrahedra in M6B22O39.H2O (M=Fe, Co). AB - The new borates Fe(II)(6)B(22)O(39).H(2)O (colourless) and Co(II)(6)B(22)O(39).H(2)O (dichroic: red/bluish) were synthesised under the high pressure/high-temperature conditions of 6 GPa and 880 degrees C (Fe)/950 degrees C (Co) in a Walker-type multi-anvil apparatus. The compounds crystallise in the orthorhombic space group Pmn2(1) (Z=2) with the lattice parameters a=771.9(2), b=823.4(2), c=1768.0(4) pm, V=1.1237(4) nm(3), R(1)=0.0476, wR(2)=0.0902 (all data) for Fe(6)B(22)O(39).H(2)O and a=770.1(2), b=817.6(2), c=1746.9(4) pm, V=1.0999(4) nm(3), R(1)=0.0513, wR(2)=0.0939 (all data) for Co(6)B(22)O(39).H(2)O. The new structure type of M(6)B(22)O(39).H(2)O (M=Fe, Co) is built up from corner-sharing BO(4) tetrahedra and BO(3) groups, the latter being distorted and close to BO(4) tetrahedra if additional oxygen atoms of the neighbouring BO(4) tetrahedra are considered in the coordination sphere. This situation can be regarded as an intermediate state in the formation of edge sharing tetrahedra. The structure consists of corrugated multiple layers interconnected by BO(3)/BO(4) groups to form Z-shaped channels. Inside these channels, iron and cobalt show octahedral (M1, M3, M4, M5) and strongly distorted tetrahedral (M2, M6) coordination by oxygen atoms. Co(II)(6)B(22)O(39).H(2)O is dichroic and the low symmetry of the chromophore [Co(II)O(4)] is reflected by the polarised absorption spectra (Delta(t)=4650 cm(-1), B=878 cm(-1)). PMID- 20945445 TI - Development of versatile and silver-free protocols for gold(I) catalysis. AB - The use of a versatile N-heterocyclic carbene (NHC) gold(I) hydroxide precatalyst, [Au(OH)(IPr)], (IPr=N,N'-bis(2,6-diisopropylphenyl)imidazol-2 ylidene) permits the in situ generation of the [Au(IPr)](+) ion by simple addition of a Bronsted acid. This cationic entity is believed to be the active species in numerous catalytic reactions. (1)H NMR studies in several solvent media of the in situ generation of this [Au(IPr)](+) ion also reveal the formation of a dinuclear gold hydroxide intermediate [{Au(IPr)}(2)(MU-OH)], which is fully characterized and was tested in gold(I) catalysis. PMID- 20945446 TI - Synthesis of 2-arylacrylates from pyruvate by tosylhydrazide-promoted Pd catalyzed coupling with aryl halides. PMID- 20945447 TI - Synthesis and enhanced H2 adsorption properties of a mesoporous nanocrystal of MOF-5: controlling nano-/mesostructures of MOFs to improve their H2 heat of adsorption. PMID- 20945448 TI - Bulk and surface structure and high-temperature thermoelectric properties of inverse clathrate-III in the Si-P-Te system. AB - The creation of thermoelectric materials for waste heat recovery and direct solar energy conversion is a challenge that forces the development of compounds that combine appreciable thermoelectric figure-of-merit with high thermal and chemical stability. Here we propose a new candidate for high-temperature thermoelectric materials, the type-III Si(172-x)P(x)Te(y) cationic clathrate, in which the framework is composed of partially ordered silicon and phosphorus atoms, whereas tellurium atoms occupy guest positions. We show that the utmost stability of this clathrate (up to 1500 K) in air is ensured by the formation of a nanosized layer of phosphorus-doped silica on the surface, which prevents further oxidation and degradation. As-cast (non-optimized) Si-P-Te clathrates display rather high values of the thermoelectric figure-of-merit (ZT=0.24-0.36) in the temperature range of 700-1100 K. These ZT values are comparable to the best values achieved for the properly doped transition-metal-oxide materials. The methods of the thermoelectric efficiency optimization are discussed. PMID- 20945449 TI - A novel soluble In(I) precursor for Pn ligand coordination chemistry. PMID- 20945450 TI - Nanocrystal-based time-temperature indicators. PMID- 20945451 TI - Protease activation of split green fluorescent protein. PMID- 20945452 TI - Hydrogen sulfide adsorption on MOFs and MOF/graphite oxide composites. AB - Composites of a copper-based metal-organic framework (MOF) and graphite oxide (GO) were tested for hydrogen sulfide removal at ambient conditions. In order to understand the mechanisms of adsorption, the initial and exhausted samples were analyzed by various techniques including X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetric analyses, and sorption of nitrogen. Compared to the parent materials, an enhancement in hydrogen sulfide adsorption was found. It was the result of physical adsorption of water and H(2)S in the pore space formed at the interface between the MOF units and the graphene layers where the dispersive forces are the strongest. Besides physisorption, reactive adsorption was found as the main mechanism of retention. H(2)S molecules bind to the copper centers of the MOF. They progressively react with the MOF units resulting in the formation of copper sulfide. This leads to the collapse of the MOF structure. Water enhances adsorption in the composites as it allows the dissolution of hydrogen sulfide. PMID- 20945453 TI - Synthesis of a room-temperature-stable dimeric copper(I) hydride. PMID- 20945454 TI - Is bisphenol A a weak carcinogen like the natural estrogens and diethylstilbestrol? AB - Bisphenol A (BPA) displays weak estrogenic properties and could be a weak carcinogen by a mechanism similar to that of estrone (E(1)), estradiol (E(2)) and the synthetic estrogen diethylstilbestrol, a human carcinogen. A wide variety of scientific evidence supports the hypothesis that certain estrogen metabolites, predominantly catechol estrogen-3,4-quinones, react with DNA to cause mutations that can lead to the initiation of cancer. One of the major pathways of estrogen metabolism leads to the 4-catechol estrogens, 4-OHE(1)(E(2)), which are oxidized to their quinones, E(1)(E(2))-3,4-Q. The quinones react with DNA to form predominantly the depurinating adducts 4-OHE(1)(E(2))-1-N3Ade and 4-OHE(1)(E(2)) 1-N7Gua. This process constitutes the predominant pathway in the initiation of cancer by estrogens. One pathway of BPA metabolism is hydroxylation of one of its symmetric benzene rings to form its catechol, 3-OHBPA. Subsequent oxidation to BPA-3,4-quinone would lead to reaction with DNA to form predominantly the depurinating adducts 3-OHBPA-6-N3Ade and 3-OHBPA-6-N7Gua. The resulting apurinic sites in the DNA could generate mutations in critical genes that can initiate human cancers. The catechol of BPA may also alter expression of estrogen activating and deactivating enzymes, and/or compete with methoxylation of 4 OHE(1)(E(2)) by catechol-O-methyltransferase, thereby unbalancing the metabolism of estrogens to increase formation of E(1)(E(2))-3,4-Q and the depurinating estrogen-DNA adducts leading to cancer initiation. Thus, exposure to BPA could increase the risk of developing cancer by direct and/or indirect mechanisms. Knowledge of these mechanisms would allow us to begin to understand how BPA may act as a weak carcinogen and would be useful for regulating its use. PMID- 20945455 TI - Specific replication factors are targeted by different genotoxic agents to inhibit replication. AB - When mammalian cells experience DNA damaging stress, they block DNA replication to avoid erroneous replication of the damaged template. The cells that are unable to respond to DNA damage continue faulty DNA replication that results in incorporation of genomic lesions. To understand the regulation of replication machinery during stress, systemic studies have been carried out but they have been restricted to the evaluation of the mRNA levels and therefore have not been able to identify post-transcriptional changes, vital for immediate blocking of the progressing DNA replication. We have recently discovered that an essential replication factor is downregulated by radiation stress. In this study, we have carried out a systematic evaluation of protein levels of entire replication apparatus after different types of DNA damage. We report that, independent of the status of p53 and retinoblastoma protein, mammalian cells choose targets that are essential for prereplication, preinitiation, and elongation phases of replication. We imposed different kinds of stress to discern whether similar or unique responses are invoked, and we propose a model for inhibition of replication machinery in which mammalian cells target specific essential replication factors based on the experienced stress. PMID- 20945456 TI - A reverse phase HPLC method for the separation of two stereo isomers of 2-[4 (methylsulfonyl)phenyl]-3-(3(R)-oxocyclopentyl)propanoic acid. AB - This study describes successful method development and separation of two stereo isomers of 2-[4-(methylsulfonyl)phenyl]-3-(3(R)-oxocyclopentyl)propanoic acid by reverse phase high-performance liquid chromatography. Baseline resolution was achieved on a J'sphere-ODS-H80 (150 mm * 4.6 mm, 4 MUm) column using mobile phase consisting of 0.05% triflouroacetic acid in water-acetonitrile (85:15, v/v) at a flow rate of 1.0 ml/min. The detection was carried out at 228 nm. The title compound, in turn, can be obtained by C-alkylation of methyl 2-[4 (methylthio)phenyl]acetate with 2(S)-iodomethyl-8,8-dimethyl-6,10 dioxaspiro[4.5]decane followed by consecutive hydrolysis and oxidation. The partially validated analytical method (system suitability, peak homogeneity, linearity, precision, robustness, and solution stability) has limit of detection and limit of quantification, 0.15 and 0.50 MUg/ml respectively. Alternatively, the new method is being routinely utilized to monitor epimerization of alpha carbon of the propanoic acid in the title compound by crystallization-induced dynamic resolution. PMID- 20945457 TI - Purification, characterization and functional expression of a new peptide with an analgesic effect from Chinese scorpion Buthus martensii Karsch (BmK AGP-SYPU1). AB - In this study, a new peptide named BmK AGP-SYPU1 with an analgesic effect was purified from the venom of Chinese scorpion Buthus martensi Karsch (BmK) through a four-step chromatographic process. The mouse twisting test was used to identify the target peptides in every separation step. The purified BmK AGP-SYPU1 was further qualified by RP-HPLC and HPCE. The molecular mass determined by the MALDI 4800-TOF/TOF MS for BmK AGP-SYPU1 was 7544 Da. Its primary structure of the N terminal was obtained using Edman degradation. The gene sequence of BmK AGP-SYPU1 was cloned from the cDNA pool and genomic of scorpion glands, respectively, and then expressed in Escherichia coli. The sequence determination showed that BmK AGP-SYPU1 was composed of 66 amino acid residues with a new primary structure. The metal chelating affinity column and cation exchange chromatography were used to purify the recombinant BmK AGP-SYPU1. Consequently, the native and recombinant BmK AGP-SYPU1 showed similar analgesic effects on mice as assayed using a mouse twisting model. These results suggested that BmK AGP-SYPU1 is a new analgesic component found in the Chinese scorpion Buthus martensi Karsch. PMID- 20945458 TI - Purine analog for the prevention of postoperative recurrence of Crohn's disease: is it really better? PMID- 20945459 TI - Sensitivity and workload for manual and automated gynecologic screening: best current estimates. AB - Sensitivity for screening gynecologic cytology appears to be correlated with workload, but data in the literature is limited. We gathered all known published data that included independently estimated measures of sensitivity and workload, for manual and automated screening, including individual cytotechnologist (CT) and laboratory data. We then attempted to synthesize the best estimates of sensitivity with workload volume. While this interpretation is limited by the scarcity of collected data and the few assumptions needed to combine the data, our results suggest that manual and automated screening correlate differently with workload. Manual screening was directly related to total workload volume, appeared to reach near 100% sensitivity for some individual CTs at workloads of ~30 slides/day, and decreased to below 80% sensitivity at ~70 slides /day. Most CTs performed at a higher sensitivity than the laboratory averages, but a small subset of CTs had significantly lower sensitivities with similar workload volumes. Sensitivity of automated screening, on the other hand, was more closely correlated with epithelial cell abnormality (ECA)-adjusted workload (ECA * total slides/day). While these results are preliminary and additional studies are warranted to confirm them, our results may be useful in monitoring workload limits in gynecologic cytology. PMID- 20945460 TI - An overview of the legislation and light microscopy for detection of processed animal proteins in feeds. AB - From the first cases of bovine spongiform encephalopathy (BSE) among cattle in the United Kingdom in 1986, the route of infection of BSE is generally believed by means of feeds containing low level of processed animal proteins (PAPs). Therefore, many feed bans and alternative and complementary techniques were resulted for the BSE safeguards in the world. Now the feed bans are expected to develop into a "species to species" ban, which requires the corresponding species specific identification methods. Currently, banned PAPs can be detected by various methods as light microscopy, polymerase chain reaction, enzyme-linked immunosorbent assay, near infrared spectroscopy, and near infrared microscopy. Light microscopy as described in the recent Commission Regulation EC/152/2009 is the only official method for the detection and characterization of PAPs in feed in the European Union. It is able to detect the presence of constituents of animal origin in feed at the level of 1 g/kg with hardly any false negative. Nevertheless, light microscopy has the limitation of lack of species specificity. This article presents a review of legislations on the use of PAPs in feedstuff, the detection details of animal proteins by light microscopy, and also presents and discusses the analysis procedure and expected development of the technique. PMID- 20945461 TI - Effects of ultramorphological changes on adhesion to lased dentin-Scanning electron microscopy and transmission electron microscopy analysis. AB - Dentin irradiation with erbium lasers has been reported to alter the composite resin bond to this treated surface. There is still a lack of studies reporting the effect of erbium lasers on dentin organic content and elucidating how laser treatment could interfere in the quality of the resin-dentin interface. This study aimed to evaluate the effect of erbium laser irradiation on dentin morphology and microtensile bond strength (MUTBS) of an adhesive to dentin. Seventy-two dentin disks were divided into nine groups (n = 8): G1-Control (600 grit SiC paper); Er:YAG groups: G2- 250 mJ/4 Hz; G3- 200 mJ/4 Hz; G4- 180 mJ/10 Hz; G5- 160 mJ/10 Hz; Er,Cr:YSGG groups: G6- 2 W/20 Hz; G7- 2.5 W/20 Hz; G8- 3 W/20 Hz; G9- 4 W/20 Hz. Specimens were processed for cross-sectional analysis by scanning electron microscopy (SEM) (n = 3), transmission electron microscopy (TEM) (n = 2), and adhesive interface (n = 3). Forty-five dentin samples (n = 5) were restored and submitted to MUTBS testing. ANOVA (alpha = 5%) revealed that G1 presented the highest MUTBS values and irradiated groups did not differ from each other. TEM micrographs showed a superficial layer of denatured collagen fibrils. For SEM micrographs, it was possible to verify the laser effects extending to dentin subsurface presenting a rough aspect. Cross-sectional dentin micrographs of this hybridized surface revealed a pattern of modified tags with ringlike structures around it. This in vitro study showed that erbium laser irradiation interacts with the dental hard tissue resulting in a specific morphological pattern of dentin and collagen fibrils that negatively affected the bond strength to composite resin. PMID- 20945462 TI - Immunohistochemical and immunochemical characterization of the distribution of leptin-like proteins in the gastroenteric tract of two teleosts (Dicentrarchus labrax and Carassius auratus L.) with different feeding habits. AB - Leptin is a modulator of food intake and energy homeostasis both in mammals and in some species of nonmammals vertebrates. In this study, we reported for the first time, using an immunohistochemical and immunochemical approach, the presence and distribution of immunoreactivity to leptin-like protein in the gastroenteric tract of Dicentrarchus labrax (bass) and Carassius auratus (goldfish), two teleostean species with different feeding and different adaptative morphological organization of the gastroenteric tract. Bass stomach showed intense immunoreactivity to leptin-like protein in all regions, with immunoreactive cells located at the base of the mucosal plicae and at the apical margin of the gastric crypts. Immunoreactive fibers and neuronal cells were observed close to vascular structures in the pyloric region. In bass and goldfish intestine, rare immunoreactive cells were observed along the mucosal epithelium mostly at the base or the apex of intestinal folds in the proximal and medium intestine; numerous immunoreactive nerve fibers in the circular and longitudinal layers of the tunica muscolaris as well as in the myenteric plexus were observed. Western blot analysis recognized a ~15 kDa signal with a similar expression pattern for goldfish and sea bass. Our results could contribute to confirm the evolutive conservation of leptin-like proteins and their probably precocious functional diversification in fish. PMID- 20945463 TI - Histological and ultrastructural study of the intracellular behavior of indium in the testicular tissues. AB - Indium, a IIIA group element of the periodic chart, has many medical uses for diagnostic and clinical investigations in humans. This element is also used in industry and in nuclear fields where released streams can contaminate environment. Consequently, indium can reach humans mainly by natural ways. In this work, we attempted to study the incidence of this element on the food intake and body and testicle weights of rat, as well as the histological and the ultrastructural consequences of its presence in testicles using conventional transmission electron microscopy. Our study showed that this element induced a significant decrease in the food intake and body and testicles weights and caused necrosis and vacuolization in germinal cells. The ultrastructural observations showed the presence of electron-dense deposits characteristic of indium in the lysosomes of Leydig and Sertoli cells as well as sufferance in mitochondria of indium-treated rats. Despite the role of lysosome in the protection of living cells, by sequestration and concentration of indium in testicle cells under insoluble form, it is probable that this element has noxious effects on food intake and body and testicles weight and induces necrosis on seminal tissues of treated rats. PMID- 20945464 TI - Analytic differential approach for robust registration of rat brain histological images. AB - Image registration is an important topic in medical image analysis. It is usually used to reconstruct 3D structure of tissues from a series of microscopic images. However, a variety of inherent factors may result in great differences between acquired slices during imaging even if they are adjacent. The common differences include the color difference and geometry discrepancy, which make the registration problem a difficult challenge. In this study, we propose a robust registration method to automatically reconstruct 3D volume data of the rat brain. It mainly consists of three procedures, including multiscale wavelet-based feature extraction, analytic robust point matching (ARPM), and registration refinement with feature-based modified Levenberg-Marquardt algorithm (FMLM). The product of gradient moduli in multi-scales is used to decide if extracted feature points are true according to the characteristic that features could exist in multiscale. The ARPM registration algorithm is proposed to speedily accomplish the registration of two point sets with different size by simultaneously evaluating the spatial correspondence and geometrical transformation. In addition, a FMLM method is also proposed to further refine registration results and achieve subpixel accuracy. The FMLM method converges much faster than most other methods due to its feature-based and nonlinear characteristic. The performance of proposed method is evaluated by comparing it with well-known thin plate spline robust point matching (TPS-RPM) algorithm. The results indicate that ARPM-FMLM algorithm is a robust and fast method in image registration. PMID- 20945465 TI - Histochemical analysis of the root tuber of Polygonum multiflorum Thunb. (Fam. Polygonaceae). AB - Authentication is the first priority in quality evaluation of Chinese herbal medicines (CHMs). The most commonly used authentication methods are morphological identification and microscopic identification. Unfortunately, these two methods cannot provide the chemical information needed to assess the quality of CHMs. In this study, a combination of fluorescence microscopy and high performance liquid chromatography-mass spectrometry (HPLC-MS) was used to analyze the chemical profiles of the tissues of the raw root tubers of Polygonum multiflorum Thunb. The results showed that the cork cells, cortex, and vessels in transverse sections of the raw root tuber of P. multiflorum fluoresced differently. Further analysis by HPLC-MS revealed that anthraquinones are mainly distributed in the cortex, and 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucopyranoside could be found in all tissues of the raw root tubers of P. multiflorum with its relative content as cork > cortex > xylem of allotype vascular bundles > xylem of central vascular bundles. Moreover, the fluorescence characteristics of the tissues from the steamed root tuber of P. multiflorum were compared and showed different fluorescence from those of raw material. From these results, it can be deduced that the root tuber of P. multiflorum with a broader cortex and fewer vascular bundles visible in a transverse section should be of better quality. The different fluorescence characteristics can be used to differentiate raw root tubers of P. multiflorum from those that have been steamed. PMID- 20945466 TI - Automated image analysis for tracking cargo transport in axons. AB - The dynamics of cargo movement in axons encodes crucial information about the underlying regulatory mechanisms of the axonal transport process in neurons, a central problem in understanding many neurodegenerative diseases. Quantitative analysis of cargo dynamics in axons usually includes three steps: (1) acquiring time-lapse image series, (2) localizing individual cargos at each time step, and (3) constructing dynamic trajectories for kinetic analysis. Currently, the later two steps are usually carried out with substantial human intervention. This article presents a method of automatic image analysis aiming for constructing cargo trajectories with higher data processing throughput, better spatial resolution, and minimal human intervention. The method is based on novel applications of several algorithms including 2D kymograph construction, seed points detection, trajectory curve tracing, back-projection to extract spatial information, and position refining using a 2D Gaussian fitting. This method is sufficiently robust for usage on images with low signal-to-noise ratio, such as those from single molecule experiments. The method was experimentally validated by tracking the axonal transport of quantum dot and DiI fluorophore-labeled vesicles in dorsal root ganglia neurons. PMID- 20945467 TI - Intensive insulin management of inpatient hyperglycemia: where are we? PMID- 20945468 TI - A comparison study of continuous insulin infusion protocols in the medical intensive care unit: computer-guided vs. standard column-based algorithms. AB - PURPOSE: To compare the safety and efficacy of continuous insulin infusion (CII) via a computer-guided and a standard paper form protocol in a medical intensive care unit (ICU). METHODS: Multicenter randomized trial of 153 ICU patients randomized to CII using the Glucommander (n = 77) or a standard paper protocol (n = 76). Both protocols used glulisine insulin and targeted blood glucose (BG) between 80 mg/dL and 120 mg/dL. RESULTS: The Glucommander resulted in a lower mean BG value (103 +/- 8.8 mg/dL vs. 117 +/- 16.5 mg/dL, P < 0.001) and in a shorter time to reach BG target (4.8 +/- 2.8 vs.7.8 hours +/- 9.1 hours, P < 0.01), and once at target resulted in a higher percentage of BG readings within target (71.0 +/- 17.0% vs. 51.3 +/- 19.7%, P < 0.001) than the standard protocol. Mean insulin infusion rate in the Glucommander was similar to the standard protocol (P = 0.12). The percentages of patients with >=1 episode of BG <40 mg/dL and <60 mg/dL were 3.9% and 42.9% in the Glucommander and 5.6% and 31.9% in the standard, respectively [P = not significant (NS)]. Repeated measures analyses show that the probabilities of BG reading <40 mg/dL or <60 mg/dL were not significantly different between groups (P = 0.969, P = 0.084) after accounting for within-patient correlations with or without adjusting for time effect. There were no differences between groups in the length of hospital stay (P = 0.704), ICU stay (P = 0.145), or inhospital mortality (P = 0.561). CONCLUSION: Both treatment algorithms resulted in significant improvement in glycemic control in critically ill patients in the medical ICU. The computer-based algorithm resulted in tighter glycemic control without an increased risk of hypoglycemic events compared to the standard paper protocol. PMID- 20945469 TI - Maintaining glycemic control when transitioning from infusion insulin: a protocol driven, multidisciplinary approach. AB - BACKGROUND: An observational pilot study of 41 medical and surgical intensive care patients on infusion insulin at our own institution found that glycemic control rapidly deteriorated within 48 hours of stopping infusion insulin. This prompted the design and testing of a transition protocol. METHODS: The transition protocol identified appropriate patients for subcutaneous (SC) insulin along with the insulin dose and schedule. A pharmacist-hospitalist improvement team offered protocol guidance but adherence was left to the discretion of the provider. The primary endpoints were mean blood glucose the first and second day after stopping the insulin infusion and the number of patients with hypoglycemia (41-70 mg/dL) and severe hypoglycemia (<40 mg/dL) during the 48-hour transition. Secondary endpoints include severe hyperglycemia (>300 mg/dL), length of stay (LOS), re initiation of the infusion insulin, day-weighted glucose mean 12 days following transition for patients with diabetes, and identification of a new diagnosis of diabetes. RESULTS: Patients with diabetes transitioned by protocol (n = 33) had better glycemic control than those (n = 39) transitioned without the protocol (Day 1 population glucose mean of 168 mg/dL vs. 211 mg/dL [P<0.001], Day 2 means of 176 mg/dL vs 218 mg/dL [P<0.001]). Severe hypoglycemia occurred once in each group. There were 14 patients newly diagnosed with diabetes based on an A1c >=6%. Patients with stress hyperglycemia maintained good glycemic control with correctional insulin only. CONCLUSION: Protocol adherence improved glycemic control, reduced unnecessary use of insulin, and identified patients with previously undiagnosed diabetes, without any increase in hypoglycemia. PMID- 20945470 TI - Unplanned transfers to the intensive care unit: the role of the shock index. AB - BACKGROUND: Unplanned (unexpected) transfers to the intensive care unit (ICU) are typically preceded by physiologic instability. However, trends toward instability may be subtle and not accurately reflected by changes in vital signs. The shock index (SI) (heart rate/systolic blood pressure as an indicator of left ventricular function, reference value of 0.54) may be a simple alternative means to predict clinical deterioration. OBJECTIVE: To assess the association of the SI with unplanned ICU transfers. DESIGN: Retrospective case-control study. SETTING: Academic medical center. PATIENTS: Fifty consecutive general medical patients with unplanned ICU transfers between 2003 and 2004 and 50 matched controls admitted to the same general medical unit between 2002 and 2004. MEASUREMENTS: Demographic data and vital signs abstracted from chart review. RESULTS: The SI was associated with unplanned ICU transfer at values of 0.85 or greater (P < 0.02; odds ratio, 3.0) and there was a significant difference between the median of worst shock indices of cases and controls (0.87 vs. 0.72; P < 0.005). There was no significant difference in age, race, admission ward, or Charlson Comorbidity Index, but hospital stay for cases was significantly longer (mean [standard deviation, SD], 14.8 [9.7] days vs. 5.7 [6.3] days; P < 0.001). CONCLUSIONS: SI is associated with unplanned transfers to the ICU from general medical units at values of 0.85 or greater. Future studies will determine whether SI is more accurate than simple vital signs as an indicator of clinical decline. If so, it may be a useful trigger to activate medical emergency or rapid response teams (RRTs). PMID- 20945471 TI - Accuracy of bedside physical examination in distinguishing categories of shock: a pilot study. AB - HYPOTHESIS: Selected elements of a simple physical examination algorithm accurately predict categories of shock. SETTING: A 350-bed community teaching hospital. METHODS: Resident trainees who manage all critically ill and medically unstable patients were instructed to document capillary refill, (palpated) pulse volume, skin temperature, jugular venous pressure (JVP) and lung examination in all patients with prolonged (>30 minutes hypotension <90 mmHg). Treatment was determined by house officers guided by attending physicians of record. All cases were retrospectively reviewed by a senior clinician who applied consensus criteria/definitions to categorize shock as septic, cardiogenic or hypovolemic. Operating characteristics of examination findings for predicting categories of shock were computed. RESULTS: A total of 68 patients, averaging 71 +/- 16 years, were studied. A total of 37 patients were diagnosed with septic shock, 18 with cardiogenic shock of and 13 with hypovolemic shock. Capillary refill and skin temperature predicted septic shock with sensitivity of 89%, specificity of 68%, positive predictive value (PPV) of 77%, negative predictive value (NPV) of 84%, and overall accuracy of 79%. Presence of JVP >7 cmH(2)O was more accurate than bilateral pulmonary crackles (>1/3 from bases) in predicting cardiogenic shock for low-output patients with sensitivity of 82%, specificity of 79%, PPV of 75%, NPV of 85%, and overall accuracy of 80%. Using just skin temperature and JVP, the bedside approach correctly diagnosed 52/68 cases (overall accuracy = 76%). CONCLUSIONS: Simple bedside clinical examination findings correctly predict categories of shock in a majority of cases. PMID- 20945474 TI - Unforgettable? PMID- 20945473 TI - Making inpatient medication reconciliation patient centered, clinically relevant and implementable: a consensus statement on key principles and necessary first steps. AB - Medication errors and adverse events caused by them are common during and after a hospitalization. The impact of these events on patient welfare and the financial burden, both to the patient and the healthcare system, are significant. In 2005, The Joint Commission put forth medication reconciliation as National Patient Safety Goal (NPSG) No. 8 in an effort to minimize adverse events caused during these types of care transitions. However, the meaningful and systematic implementation of medication reconciliation, as expressed through NPSG No. 8, proved to be extraordinarily difficult for healthcare institutions around the country. Given the importance of accurate and complete medication reconciliation for patient safety occurring across the continuum of care, the Society of Hospital Medicine convened a stakeholder conference in 2009 to begin to identify and address: (1) barriers to implementation; (2) opportunities to identify best practices surrounding medication reconciliation; (3) the role of partnerships among traditional healthcare sites and nonclinical and other community-based organizations; and (4) metrics for measuring the processes involved in medication reconciliation and their impact on preventing harm to patients. The focus of the conference was oriented toward medication reconciliation for a hospitalized patient population; however, many of the themes and concepts derived would also apply to other care settings. This paper highlights the key domains needing to be addressed and suggests first steps toward doing so. An overarching principle derived at the conference is that medication reconciliation should not be viewed as an accreditation function. It must, first and foremost, be recognized as an important element of patient safety. From this principle, the participants identified ten key areas requiring further attention in order to move medication reconciliation toward this focus. 1 There is need for a uniformly acceptable and accepted definition of what constitutes a medication and what processes are encompassed by reconciliation. Clarifying these terms is critical to ensuring more uniform impact of medication reconciliation. 2 The varying roles of the multidisciplinary participants in the reconciliation process must be clearly defined. These role definitions should include those of the patient and family/caregiver and must occur locally, taking into account the need for flexibility in design given the varying structures and resources at healthcare sites. 3 Measures of the reconciliation processes must be clinically meaningful (i.e., of defined benefit to the patient) and derived through consultation with stakeholder groups. Those measures to be reported for national benchmarking and accreditation should be limited in number and clinically meaningful. 4 While a comprehensive reconciliation system is needed across the continuum of care, a phased approach to implementation, allowing it to start slowly and be tailored to local organizational structures and work flows, will increase the chances of successful organizational uptake. 5 Developing mechanisms for prospectively and proactively identifying patients at risk for medication-related adverse events and failed reconciliation is needed. Such an alert system would help maintain vigilance toward these patient safety issues and help focus additional resources on high risk patients. 6 Given the diversity in medication reconciliation practices, research aimed at identifying effective processes is important and should be funded with national resources. Funding should include varying sites of care (e.g., urban and rural, academic and nonacademic, etc.). 7 Strategies for medication reconciliation-both successes and key lessons learned from unsuccessful efforts-should be widely disseminated. 8 A personal health record that is integrated and easily transferable between sites of care is needed to facilitate successful medication reconciliation. 9 Partnerships between healthcare organizations and community-based organizations create opportunities to reinforce medication safety principles outside the traditional clinician patient relationship. Leveraging the influence of these organizations and other social networking platforms may augment population-based understanding of their importance and role in medication safety. 10 Aligning healthcare payment structures with medication safety goals is critical to ensure allocation of adequate resources to design and implement effective medication reconciliation processes. Medication reconciliation is complex and made more complicated by the disjointed nature of the American healthcare system. Addressing these ten points with an overarching goal of focusing on patient safety rather than accreditation should result in improvements in medication reconciliation and the health of patients. PMID- 20945475 TI - It starts with a dog scratch. PMID- 20945476 TI - Postcards from our students--reflections on professionalism and ethics. PMID- 20945477 TI - Wear behavior and in vitro cytotoxicity of wear debris generated from hydroxyapatite-carbon nanotube composite coating. AB - This work evaluates the effect of carbon nanotube (CNT) addition to plasma sprayed hydroxyapatite (HA) coating on its tribological behavior, biocompatibility of the coating, and cytotoxicity of CNT-containing wear debris. Biological response of the CNT-containing wear debris is critical for osteoblasts, the bone-forming cells, and macrophages, the cells that clear up wear debris from blood stream. The addition of 4 wt % CNTs to HA coating reduces the volume of wear debris generation by 80% because of the improved elastic modulus and fracture toughness. CNT reinforcement has a pronounced effect on the particle size in the wear debris and subsequent biological response. There was a slight increase in the numbers and viability of osteoblasts grown on HA-CNT compared with HA alone. The cytotoxic effect of HA and HA-CNT debris to macrophages and osteoblasts was similar, demonstrating that loose CNT does not pose a problem to these cells. PMID- 20945478 TI - Self-cleaving purification tags re-engineered for rapid Topo(r) cloning. AB - In this work, our previously reported DeltaI-CM and DeltaI(G)-CM mutant inteins were rationally re-engineered to be compatible with Invitrogen's Topo(r) cloning system. The resulting new inteins include the vaccinia virus topoisomerase I DNA recognition sequence TCCTT at their 3' ends, making them compatible with the highly convenient one-step Topo(r) cloning method. Addition of the Topo(r) recognition sequence resulted in an altered amino acid sequence at the C-termini of the inteins, changing their final five residues from VVVHN to VLVHN. Despite this change, these modified inteins retained their self-cleaving function, and continue to exhibit pH and temperature-sensitive cleaving characteristics as required for their use in generating self-cleaving affinity tags. Although the C terminal modification decreased the intein cleavage rate under optimal conditions, cleavage can typically be completed within several hours at pH 6.5 and 37 degrees C. In particular, the modified DeltaI(GT)-CM intein is compatible with both the Topo(r) and Gateway(r) methods simultaneously, allowing fast parallel construction of multiple expression vectors with varying combinations of target proteins, self-cleaving affinity tags and promoters. These newly engineered inteins increase the functionality of intein-mediated technology, making it possible to explore a large number of combinations between target genes, self-cleaving affinity tags and expression hosts in a fast and efficient manner. PMID- 20945479 TI - Diffusion properties of bacteriophages through agarose gel membrane. AB - A simple two-chamber diffusion method was developed to study the diffusion properties of bacteriophages (phages). The apparent diffusion coefficients (D(app)) of Myoviridae phage T4 and filamentous phage fNEL were investigated, and the diffusion of the phages was found to be much slower than the diffusion of three antibiotics, ciprofloxacin, penicillin G, and tetracycline. D(app) of T4 and fNEL in water through filter paper were calculated to be 2.8 x 10-11 m2/s and 6.8 x 10-12 m2/s, respectively, and D(app) of fNEL through agarose gel membrane, an artificial biofilm, was also calculated to be smaller than that of T4. In addition, D(app) of phages through agarose gel was dependent on agarose concentration due to the similar size of phage and agarose gel mesh. We concluded that D(app) of phages through an artificial biofilm is dependent on both phage morphology and biofilm density, and suggest the use of this method to study diffusion properties through real biofilms. PMID- 20945480 TI - Metabolic flux analysis of embryonic stem cells using three distinct differentiation protocols and comparison to gene expression patterns. AB - Metabolic flux analysis (MFA) was performed on mouse embryonic stem cells cultured under three distinct differentiation conditions: classical embryoid body formation (EB), and on surfaces coated with either gelatin (GEL) or matrigel (MAT). MFA was based on 15 metabolic reactions and eight transport steps, and was carried out based on measurements of four substrates and/or metabolites: glucose, lactate, glutamine, and glutamate. Fluxes representing biomass production remained fairly constant for all three culture conditions with at most a 40% variation. In contrast, major temporal variations, up to 500%, were observed for all other major central metabolic fluxes across all culture conditions. Fluxes were compared to gene-expression patterns measured by microarray analysis. Particularly interesting is the correlation between the metabolic fluxes with expression patterns of the corresponding genes of the pyruvate to lactate reaction, whereby the genes for several isoforms of the lactate dehydrogenase enzyme were examined. The patterns of this flux were notably different in the EB cultures compared to the GEL and MAT cultures and reflected differences in oxygen and nutrient transport in EB vs. the GEL and MAT cultures. Another novel finding of this study is an event occurring between Days 4 and 5 of differentiation, which was identified by a notable change in both the metabolic fluxes and gene expression patterns. This suggests that metabolic patterns can be used as effective beacons of changes in differentiating stem cells. Overall, and qualitatively, core metabolic fluxes, under the three culture conditions examined, correlated well with gene-expression patterns. PMID- 20945481 TI - Expression and purification of an antitumor-analgesic peptide from the venom of Mesobuthus martensii Karsch by small ubiquitin-related modifier fusion in Escherichia coli. AB - To prevent protein aggregation, some proteins are usually expressed as fusion proteins from which target proteins can be released by proteolytic or chemical reagents. In this report, small ubiquitin-related modifier (SUMO) linked with a hexa-histidine tag was used as a fusion partner for the antitumor-analgesic peptide from the venom of Buthus martensii (Karsch) scorpion (AGAP). The optimal expression level of the soluble fusion protein, SUMO-AGAP, was up to 40% of the total cellular protein. The fusion protein was purified by Ni-NTA affinity chromatography and cleaved by a SUMO-specific protease (Ulp1) to obtain the recombinant AGAP (rAGAP), which was further purified by Ni-NTA affinity chromatography. The purified final product was >95% pure by SDS-PAGE stained with Coomassie brilliant blue R-250. Mass spectroscopic analysis indicated the protein to be 7142.63 Dalton, which equaled the theoretically expected mass. N-terminal sequencing of rAGAP showed the sequence corresponded to the native protein. MTT assay indicated the rAGAP could significantly inhibit the proliferation of Jurkat and Hut 78 T lymphoma cell lines. The further writhing experiment showed that the rAGAP had an intensive analgesic effect. The expression strategy presented in this study allows convenient high yield and easy purification of the rAGAP with native sequences. PMID- 20945482 TI - Economic impact of total solids loading on enzymatic hydrolysis of dilute acid pretreated corn stover. AB - In process integration studies of the biomass-to-ethanol conversion process, it is necessary to understand how cellulose conversion yields vary as a function of solids and enzyme loading and other key operating variables. The impact of solids loading on enzymatic cellulose hydrolysis of dilute acid pretreated corn stover slurry was determined using an experimental response surface design methodology. From the experimental work, an empirical correlation was obtained that expresses monomeric glucose yield from enzymatic cellulose hydrolysis as a function of solids loading, enzyme loading, and temperature. This correlation was used in a technoeconomic model to study the impact of solids loading on ethanol production economics. The empirical correlation was used to provide a more realistic assessment of process cost by accounting for changes in cellulose conversion yields at different solids and enzyme loadings as well as enzyme cost. As long as enzymatic cellulose conversion drops off at higher total solids loading (due to end-product inhibition or other factors), there is an optimum value for the total solids loading that minimizes the ethanol production cost. The optimum total solids loading shifts to higher values as enzyme cost decreases. PMID- 20945483 TI - Recombinant Candida rugosa lipase 2 from Pichia pastoris: immobilization and use as biocatalyst in a stereoselective reaction. AB - The characterization of the recombinant Candida rugosa Lip2 (r-Lip2) isoenzyme obtained from fed-batch cultures of Pichia pastoris under PAOX promoter was carried out, determining the optimal pH and temperature as well as their catalytic performance in both hydrolysis and synthesis reactions comparing with purified native Lip2 (n-Lip2) previously determined. The substrate specificity of r-Lip2 in hydrolysis reactions was determined with a series of triacylglycerols and p-nitrophenyl esters of variable acyl chain length. r-Lip2 showed the maximum specificity for both substrates towards medium-chain esters (C-8), similar behavior was observed with n-Lip2. However, significant differences were observed towards unsaturated substrates (triolein) or short-chain esters. A statistical design applied to study the effect of pH and temperature on lipase stability shown that r-Lip2, like n-Lip2, was more sensitive to pH than temperature changes. Nevertheless, the overall stability of soluble r-Lip2 was lower than soluble n-Lip2. The stability of r-lip2 was significantly improved by immobilization onto EP100, an excellent support for lipases with yields around 95% for offered lipolytic activity lower than 600 AU/mL. Finally, immobilized r Lip2 was tested in the resolution of ibuprofen in isooctane by means of enantioselective esterification using 1-butanol as esterifying agent. r-Lip2 showed a better performance in terms of enantiomeric excess (74%) and enatiomeric factor (96%) than n-Lip2 (56 and 80%, respectively) for the same conversion (40%). Thus, r-Lip2 should be considered a good and pure biocatalyst, easy to produce and with a remaining activity of ca. 90% after one reaction cycle when immobilized on EP100. PMID- 20945484 TI - Microfluidic reactor for continuous cultivation of Saccharomyces cerevisiae. AB - A diffusion-based microreactor system operated with a reaction volume of 8 MUL is presented and characterized to intensify the process understanding in microscale cultivations. Its potential as screening tool for biological processes is evaluated. The advantage of the designed microbioreactor is the use for the continuous cultivation mode by integrating online measurement technique for dissolved oxygen (DO) and optical density (OD). A further advantage is the broaden application for biological systems. The bioreactor geometry was chosen to achieve homogeneous flow during continuous process operation. The device consisted of a microstructured top layer made of poly(dimethylsiloxane) (PDMS), which was designed and fabricated using UV-depth and soft lithography assembled with a glass bottom. CFD simulation data used for geometry design were verified via microparticle-image-velocimetry (MUPIV). In the used microreactor geometry no concentration gradients occurred along the entire reaction volume because of rapid diffusive mixing, the homogeneous medium flow inside the growth chamber of the microreactor could be realized. Undesirable bubble formation before and during operation was reduced by using degassed medium as well as moistened and moderate incident air flow above the gas permeable PDMS membrane. Because of this a passive oxygen supply of the culture medium in the device is ensured by diffusion through the PDMS membrane. The oxygen supply itself was monitored online via integrated DO sensors based on a fluorescent dye complex. An adequate overall volumetric oxygen transfer coefficient K(L)a as well as mechanical stability of the device were accomplished for a membrane thickness of 300 MUm. Experimental investigations considering measurements of OD (online) and several metabolite concentrations (offline) in a modified Verduyn medium. The used model organism Saccharomyces cerevisiae DSM 2155 tended to strong reactor wall growth resembling a biofilm. PMID- 20945485 TI - Characterization of a nutrient feed precipitate from an E. coli fermentation process. AB - Metalloproteins require soluble metal ions such as zinc to properly fold into their native and active state to maintain stability and biological activity. When protein products are produced during microbial fermentations, metals are made available to the metalloproteins via nutrient supplements. During the production at the manufacturing-scale of a recombinant product that required zinc as a cofactor, an insoluble precipitate formed in the preparation tank after steam sterilization of the nutrient feed containing methionine, glycerophosphate, and zinc sulfate (MGZ). The precipitated nutrient feed was believed to be the cause for not enough zinc delivered to the production fermentor, leading to poor product assembly and stabilization. This article explores several analytical techniques such as capillary zone electrophoresis, inductively coupled plasma and phosphate molybdate assays to identify and quantify the composition of the precipitate. Our results show that the glycerophosphate component of the combined MGZ nutrient feed contains inorganic phosphate, which precipitates zinc from the feed media. PMID- 20945486 TI - Removal of heavy metals from water effluents using supermacroporous metal chelating cryogels. AB - Applications of IDA in, for example, immobilized metal ion affinity chromatography for purification of His-tagged proteins are well recognized. The use of IDA as an efficient chelating adsorbent for environmental separations, that is, for the capture of heavy metals, is not studied. Adsorbents based on supermacroporous gels (cryogels) bearing metal chelating functionalities (IDA residues and ligand derived from derivatization of epoxy-cryogel with tris(2 aminoethyl)amine followed by the treatment with bromoacetic acid (defined as TBA ligand)) have been prepared and evaluated on capture of heavy metal ions. The cryogels were prepared in plastic carriers, resulting in desired mechanical stability and named as macroporous gel particles (MGPs). Sorption and desorption experiments for different metals (Cu2+, Zn2+, Cd2+, and Ni2+ with IDA adsorbent and Cu2+ and Zn2+ with TBA adsorbent) were carried out in batch and monolithic modes, respectively. Obtained capacities with Cu2+ were 74 MUmol/mL (TBA) and 19 MUmol/mL gel (IDA). The metal removal was higher for pH values between pH 3 and 5. Both adsorbents showed improved sorption at lower temperatures (10 degrees C) than at higher (40 degrees C) and the adsorption significantly dropped for the TBA adsorbent and Zn2+ at 40 degrees C. Desorption of Cu2+ by using 1 M HCl and 0.1 M EDTA was successful for the IDA adsorbent whereas the desorption with the TBA adsorbent needs further attention. The result of this work has demonstrated that MGPs are potential treatment alternatives within the field of environmental separations and the removal of heavy metals from water effluents. PMID- 20945487 TI - Evaluation of alternatives for human lysozyme purification from transgenic rice: impact of phytic acid and buffer. AB - Producing economically competitive recombinant human lysozyme from transgenic rice demands an inexpensive purification process for nonpharmaceutical applications. Human lysozyme is a basic protein, and thus, cation exchange chromatography was the selected method for lysozyme purification. Similar to other protein production systems, the identification of critical impurities in the rice extract was important for the development of an efficient purification process. Previous adsorption data indicated that phytic acid was probably responsible for an unacceptably low cation exchange adsorption capacity. In this study, we confirm that reducing phytic acid concentration improves lysozyme binding capacity and investigate alternative process conditions that reduce phytic acid interference. Compared with the previous best process, the adsorption capacity of human lysozyme was increased from 8.6 to 19.7 mg/mL when rice extract was treated with phytase to degrade phytic acid. Using tris buffer to adjust pH 4.5 extract to pH 6 before adsorption reduced phytic acid interference by minimizing phytic acid-lysozyme interactions, eliminated the need for phytase treatment, and increased the binding capacity to 25 mg/mL. Another method of reducing phytic acid concentration was to extract human lysozyme from rice flour at pH 10 with 50 mM NaCl in 50 mM sodium carbonate buffer. A similar binding capacity (25.5 mg/mL) was achieved from pH 10 extract that was clarified by acidic precipitation and adjusted to pH 6 for adsorption. Lysozyme purities ranged from 95 to 98% for all three processing methods. The tris-mediated purification was the most efficient of the alternatives considered. PMID- 20945488 TI - Evaluation of cell disruption effects on primary recovery of antibody fragments using microscale bioprocessing techniques. AB - Intracellular antibody Fab' fragments periplasmically expressed in Escherichia coli require the release of Fab' from the cells before initial product recovery. This work demonstrates the utility of microscale bioprocessing techniques to evaluate the influence of different cell disruption operations on subsequent solid-liquid separation and product recovery. Initially, the industrial method of Fab' release by thermochemical extraction was established experimentally at the microwell scale and was observed to yield Fab' release consistent with the larger scale process. The influence of two further cell disruption operations, homogenization and sonication, on subsequent Fab' recovery by microfiltration was also examined. The results showed that the heat-extracted cells give better dead end microfiltration performance in terms of permeate flux and specific cake resistance. In contrast, the cell suspensions prepared by homogenization and sonication showed more efficient product release but with lower product purity and poorer microfiltration performance. Having established the various microscale methods the linked sequence was automated on the deck of a laboratory robotic platform and used to show how different conditions during thermochemical extraction impacted on the optimal performance of the linked unit operations. The results illustrate the power of microscale techniques to evaluate crucial unit operation interactions in a bioprocess sequence using only microliter volumes of feed. PMID- 20945489 TI - Monoclonal antibody purification using cationic polyelectrolytes: an alternative to column chromatography. AB - The potential of cationic polyelectrolytes to precipitate host cell and process related impurities was investigated, to replace one or more chromatography steps in monoclonal antibody purification. The impact of antibody isoelectric point, solution properties (pH and ionic strength), and polyelectrolyte properties (structure, molecular weight and pK(a)) on the degree of precipitation was studied. At neutral pH, increasing solution ionic strength impeded the ionic interaction between the polyelectrolyte and impurities, reducing impurity precipitation. Increasing polyelectrolyte molecular weight and pK(a) enabled precipitation of impurities at higher ionic strength. PoIy(arginine) was selected as the preferred polyelectrolyte in unconditioned cell culture fluid. PoIy(arginine) precipitation achieved consistent host cell protein clearance and antibody recovery for multiple antibodies across a wider range of polyelectrolyte concentrations. Poly(arginine) precipitation was evaluated as a flocculant and as a functional replacement for anion exchange chromatography in an antibody purification process. Upstream treatment of cell culture fluid with poly(arginine) resulted in flocculation of solids (cells and cell debris), and antibody recovery and impurity clearance (host cell proteins, DNA and insulin) comparable to the downstream anion exchange chromatography step. PMID- 20945490 TI - A simple apparatus for measuring cell settling velocity. AB - Accurate cell settling velocity determination is critical for perfusion culture using a gravity settler for cell retention. We have developed a simple apparatus (a "settling column") for measuring settling velocity and have validated the procedure with 15-MUm polystyrene particles with known physical properties. The measured settling velocity of the polystyrene particles is within 4% of the value obtained using the traditional Stokes' law approach. The settling velocities of three hybridoma cell lines were measured, resulting in up to twofold variation among cell lines, and the values decreased as the cell culture aged. The settling velocities of the nonviable cells were 33-50% less than the corresponding viable cells. The significant variation of settling velocities among cell populations and growth phases confirms the necessity of routine measurement of this property during long-term perfusion culture. PMID- 20945491 TI - Combining high-throughput screening of caspase activity with anti-apoptosis genes for development of robust CHO production cell lines. AB - A set of anti-apoptotic genes were over-expressed, either singly or in combination, in an effort to develop robust Chinese Hamster Ovary host cell lines suitable for manufacturing biotherapeutics. High-throughput screening of caspase 3/7 activity enabled a rapid selection of transfectants with reduced caspase activity relative to the host cell line. Transfectants with reduced caspase 3/7 activity were then tested for improved integrated viable cell count (IVCC), a function of peak viable cell density and longevity. The maximal level of improvement in IVCC could be achieved by over-expression of either single anti apoptotic genes, e.g., Bcl-2Delta (a mutated variant of Bcl-2) or Bcl-XL, or a combination of two or three anti-apoptotic genes, e.g., E1B-19K, Aven, and XIAPDelta. These cell lines yielded higher transient antibody production and a greater number of stable clones with high antibody yields. In a 5 L fed-batch bioreactor system, BDelta31-1, a stable clone expressing Bcl-2Delta, had a product titer that was 180% as compared to an optimal clone (Con-1) from the control cell line. Although lactate accumulated to more than 5 g/L in the control culture, its concentration was reduced in the anti-apoptotic BDelta31-1 cultures to below 1 g/L, confirming our earlier findings that cells over-expressing anti apoptotic genes consume the lactate that would otherwise accumulate as a by product in the culture medium. To the best of our knowledge, this is the first study to use the high throughput caspase screening method to identify CHO host cell lines with superior anti-apoptotic characteristics. PMID- 20945493 TI - Investigation of beta-glucans binding to human/mouse dectin-1 and associated immunomodulatory effects on two monocyte/macrophage cell lines. AB - Dectin-1, a specific pattern recognition receptor for beta-1,3/beta-1,6-glucans, is expressed mainly on phagocytes. Human dectin-1 (hDectin-1) and mouse dectin-1 (mDectin-1) were separately expressed on HEK293 cell surfaces for examination of the binding abilities of a synthetic particulate beta-glucan (pbetaG), a product extracted from Saccharomyces cerevisiae, in this study. The binding of zymosan FITC to hDectin-1 and mDectin-1 was inhibited by pbetaG at similar concentrations for 50% inhibition of binding (IC50). However, the kinetics of the time course and dose response to zymosan stimulation observed for U937 and J774A.1 differed. Superoxide anion production was increased in U937 but reduced in J774A.1 when cells were treated with pbetaG, zymosan, or laminarin, whereas ovalbumin endocytosis was enhanced in U937 and J774A.1 treated either with pbetaG, zymosan, laminarin, or barley-glucan. These results indicate that the binding affinity of pbetaG to hDectin-1 is similar to the binding affinity to mDectin-1, and that stimulation by pbetaG as well as various forms of beta-1,3-glucans on U937 and J774A.1 resulted in upregulation of cell activity and ovalbumin endocytosis. Additionally, other coreceptors on U937 and J774A.1 may be involved in directing different responses to superoxide anion production in these two types of cells. These results will likely contribute to further investigations on identifying the biological forms of beta-glucans capable of binding its specific receptor as the effective immunomodulators. PMID- 20945492 TI - Scaffold stiffness affects the contractile function of three-dimensional engineered cardiac constructs. AB - We investigated the effects of the initial stiffness of a three-dimensional elastomer scaffold--highly porous poly(glycerol sebacate)--on functional assembly of cardiomyocytes cultured with perfusion for 8 days. The polymer elasticity varied with the extent of polymer cross-links, resulting in three different stiffness groups, with compressive modulus of 2.35 +/- 0.03 (low), 5.28 +/- 0.36 (medium), and 5.99 +/- 0.40 (high) kPa. Laminin coating improved the efficiency of cell seeding (from 59 +/- 15 to 90 +/- 21%), resulting in markedly increased final cell density, construct contractility, and matrix deposition, likely because of enhanced cell interaction and spreading on scaffold surfaces. Compact tissue was formed in the low and medium stiffness groups, but not in the high stiffness group. In particular, the low stiffness group exhibited the greatest contraction amplitude in response to electric field pacing, and had the highest compressive modulus at the end of culture. A mathematical model was developed to establish a correlation between the contractile amplitude and the cell distribution within the scaffold. Taken together, our findings suggest that the contractile function of engineered cardiac constructs positively correlates with low compressive stiffness of the scaffold. PMID- 20945494 TI - Maximizing productivity of CHO cell-based fed-batch culture using chemically defined media conditions and typical manufacturing equipment. AB - A highly productive chemically defined fed-batch process was developed to maximize titer and volumetric productivity for Chinese hamster ovary cell-based recombinant protein manufacturing. Two cell lines producing a recombinant antibody (cell line A) and an Fc-fusion protein (cell line B) were used for development. Both processes achieved product titers of 10 g/L on day 18 under chemically defined conditions. For cell line B, the use of plant derived hydrolysates combined with the optimized chemically defined medium increased the titer to 13 g/L. Volumetric productivities were increased from a base line of about 200 mg/L/d to about 500 mg/L/d under chemically defined conditions and as high as 700 mg/L/d with cell line B using plant derived hydrolysates. Peak cell densities reached greater than 20E6 vc/mL, and cell viabilities were maintained above 80% on day 18 without the use of antiapoptotic genes or temperature shift. A rapid compound screening method was developed to effectively test positive factors within 72 h. Peak volumetric oxygen uptake rates (OUR) more than tripled from the baseline condition. Oxygen demand continued to increase after maximum cell density was reached with a maximal OUR of 3.7 mmol/L/h. The new process format was scaled up and verified at 100 L pilot scale using reactor equipment of similar configuration as used at manufacturing scale. PMID- 20945495 TI - Thermal stability of carbonic anhydrase immobilized within polyurethane foam. AB - Thermal stability of carbonic anhydrase (CA) immobilized within polyurethane (PU) foam was investigated. The catalytic activity of the enzyme was estimated by using p-nitrophenyl acetate (p-NPA) as the substrate in tris buffer containing 10% acetonitrile. The immobilized CA was stable during the repeatable washings and stability tests over 45 days stored in tris buffer at ambient conditions indicating that the CA was covalently attached to the polyurethane (PU) foam by crosslinking. The immobilized CA was found to be 98% stable below 50 degrees C, whereas a drastic decrease was seen at temperatures between 50 and 60 degrees C. The optimum temperature for the immobilized CA was found to be 45 degrees C and it lost its activity completely at 60 degrees C. Thermal deactivation energies for the free and immobilized CA were estimated to be 29 and 86 kcal/mol, respectively. The association of unfolded CA with the polymeric backbone chains of the PU foam was also addressed. It was concluded that the immobilized CA was highly stable at temperatures less than 50 degrees C and could be used in biomimetic CO2 sequestration processes. PMID- 20945496 TI - Monitoring oxygen uptake in 3D tissue engineering scaffolds by phosphorescence quenching microscopy. AB - Measuring oxygen concentration in three-dimensional cultures, without interfering with cellular activities, is a fundamental request of tissue engineering research. Among the other techniques, it has been demonstrated that phosphorescence quenching microscopy (PQM) represents a valid tool for the detection of oxygen concentration in 3D environments. Indeed, it is not invasive, with high spatial and temporal resolution, and, once calibrated, it is not affected by the presence of extracellular matrix components and other environmental factors. In this work, a description of the PQM experimental set up for oxygen measurements in solutions and 3D polymer-based cellular constructs is provided. Moreover, the advantage and the limits in the use of this technique are critically discussed to provide a technical note for future applications. PMID- 20945497 TI - Altered prostate epithelial development and IGF-1 signal in mice lacking the androgen receptor in stromal smooth muscle cells. AB - BACKGROUND: Androgens and the androgen receptor (AR) play critical roles in the prostate development via mesenchymal-epithelial interactions. Smooth muscle cells (SMC), differentiated from mesenchyme, are one of the basic components of the prostate stroma. However, the roles of smooth muscle AR in prostate development are still obscure. METHODS: We established the smooth muscle selective AR knockout (SM-ARKO) mouse model using the Cre-loxP system, and confirmed the ARKO efficiency at RNA, DNA and protein levels. Then, we observed the prostate morphology changes, and determined the epithelial proliferation, apoptosis, and differentiation. We also knocked down the AR in a prostate smooth muscle cell line (PS-1) to confirm the in vivo findings and to probe the mechanism. RESULTS: The AR was selectively and efficiently knocked out in the anterior prostates of SM-ARKO mouse. The SM-ARKO prostates have defects with loss of infolding structures, and decrease of epithelial proliferation, but with little change of apoptosis and differentiation. The mechanism studies showed that IGF-1 expression level decreased in the SM-ARKO prostates and AR-knockdown PS-1 cells. The decreased IGF-1 expression might contribute to the defective development of SM ARKO prostates. CONCLUSIONS: The AR in SMCs plays important roles in the prostate development via the regulation of IGF-1 signal. PMID- 20945498 TI - AMACR polymorphisms, dietary intake of red meat and dairy and prostate cancer risk. AB - BACKGROUND: Alpha-methylacyl CoA racemase (AMACR) is an enzyme involved in fatty acids metabolism. One of AMACRs primary substrates, phytanic acid, is principally obtained from dietary red meat/dairy, which are associated with prostate cancer (PCa) risk. AMACR is also a tumor tissue biomarker over-expressed in PCa. In this study, we explored the potential relationship between AMACR polymorphisms, red meat/dairy intake, and PCa risk. METHODS: Caucasian participants from two population-based PCa case-control studies were included. AMACR single nucleotide polymorphisms (SNPs) were selected to capture variation across the gene and regulatory regions. Red meat and dairy intake was determined from food frequency questionnaires. The odds ratio (OR) of PCa (overall and by disease aggressiveness) was estimated by logistic and polytomous regression. Potential interactions between genotypes and dietary exposures were evaluated. RESULTS: Data from 1,309 cases and 1,267 controls were analyzed. Carriers of the variant T allele (rs2287939) had an OR of 0.81 (95% CI 0.68-0.97) for less aggressive PCa, but no alteration in risk for more aggressive PCa. Red meat consumption was positively associated with PCa risk, and the association was stronger for more aggressive disease (lowest vs. highest tertile OR=1.55, 95% CI 1.10-2.20). No effect modification of AMACR polymorphisms by either dietary red meat or dairy intake on PCa risk was observed. CONCLUSIONS: PCa risk varied by level of red meat intake and by one AMACR SNP, but there was no evidence for gene-environment interaction. These findings suggest that the effects of AMACR polymorphisms and red meat and dairy on PCa risk are independent. PMID- 20945499 TI - Comment on "Androgen-hypersensitive preclinical model of prostate cancer" by Kawata et al. PMID- 20945500 TI - The anterior gradient 2 (AGR2) gene is overexpressed in prostate cancer and may be useful as a urine sediment marker for prostate cancer detection. AB - BACKGROUND: AGR2 is a member of the endoplasmatic reticulum protein disulphide isomerase gene family implicated in tumor metastasis. Its expression pattern, function, and utility as a marker remains to be further investigated. METHODS: Using real-time RT-PCR and immunohistochemistry, changes of expression in different tumor stages were explored in microdissected tumor samples. AGR2 transcript level in urine sediments was scrutinized for suitability as a tumor marker. AGR2 androgen regulation and function were analyzed in cellular prostate cancer models. RESULTS: AGR2 is highly expressed in prostate cancer compared to benign tissue in particular also in low-grade tumors and PIN lesions. AGR2 transcripts were detected in urine sediments of patients undergoing prostate biopsy with significantly higher levels in tumor patients. The urine AGR2/PSA transcript ratio allowed much better discrimination between cancer and benign patients than serum total PSA or %freePSA. Prostate tumor cells express and secrete variable amounts of AGR2 protein, the highest level was found in PC3 cells. In androgen receptor-positive cell lines AGR2 is upregulated by androgens. Increased expression enhanced the migratory and invasive potential but decreased growth and proliferation in vitro and in vivo. CONCLUSION: AGR2 enhances the invasion phenotype of prostate cancer cells while at the same time attenuating cell-cycle progression. This function, its expression pattern and the increased level of AGR transcripts in urine sediments of prostate cancer patients call for further exploration as a prostate cancer marker and a modulator of tumor growth and invasion. PMID- 20945501 TI - Androgen regulation of micro-RNAs in prostate cancer. AB - BACKGROUND: Androgens play a critical role in the growth of both androgen dependent and castration-resistant prostate cancer (CRPC). Only a few micro-RNAs (miRNAs) have been suggested to be androgen regulated. We aim to identify androgen regulated miRNAs. METHODS: We utilized LNCaP derived model, we have established, and which overexpresses the androgen receptor (AR), the VCaP cell line, and 13 intact-castrated prostate cancer (PC) xenograft pairs, as well as clinical specimens of untreated (PC) and CRPC. The expression of miRNAs was analyzed by microarrays and quantitative RT-PCR (Q-RT-PCR). Transfection of pre miR-141 and anti-miR-141 was also used. RESULTS: Seventeen miRNAs were > 1.5-fold up- or downregulated upon dihydrotestosterone (DHT) treatment in the cell lines, and 42 after castration in the AR-positive xenografts. Only four miRNAs (miR-10a, miR-141, miR-150*, and miR-1225-5p) showed similar androgen regulation in both cell lines and xenografts. Of those, miR-141 was found to be expressed more in PC and CRPC compared to benign prostate hyperplasia. Additionally, the overexpression of miR-141 enhanced growth of parental LNCaP cells while inhibition of miR-141 by anti-miR-141 suppressed the growth of the LNCaP subline overexpressing AR. CONCLUSIONS: Only a few miRNAs were found to be androgen regulated in both cell lines and xenografts models. Of those, the expression of miR-141 was upregulated in cancer. The ectopic overexpression of miR-141 increased growth of LNCaP cell suggesting it may contribute to the progression of PC. PMID- 20945502 TI - Evidence of epithelial to mesenchymal transition associated with increased tumorigenic potential in an immortalized normal prostate epithelial cell line. AB - BACKGROUND: The majority of established human prostate cancer cell lines are derived from metastatic lesions and are already tumorigenic in vivo, therefore immortalized normal prostate cell lines may provide a more relevant model to unveil the mechanisms associated with cancer progression and metastasis. METHODS: PZ-HPV-7, an immortalized human prostate epithelial cell line was used to generate xenograft tumors in mice. A subline designated HPV-PZ-7T was subsequently derived from the subrenal capsule xenograft of a nude mouse. These cells were further characterized using karyotyping, immunofluorescence, qRT-PCR, Western blotting, and three-dimensional cultures in Matrigel. RESULTS: The PZ-HPV 7 cell line possesses a typical epithelial morphology, expresses basal cell markers, and is capable of forming web-like structures with evidence of budding on Matrigel. PZ-HPV-7 is non-tumorigenic in immunocompromised mice by either subcutaneous injection or subrenal grafting. In contrast, the PZ-HPV-7T cells, derived from a xenograft tumor induced by co-inoculation with matrigel using subrenal grafting, possess a mesenchymal phenotype as well as luminal cell markers and are highly tumorigenic and metastatic in nude mice. Functionally and biochemically, the PZ-HPV-7T subline appears to have undergone an epithelial-to mesenchymal transition (EMT) from the parental PZ-HPV-7 line. CONCLUSION: We have developed a novel EMT model using an immortalized normal prostate epithelial cell line and generated a new prostate cancer cell line, PZ-HPV-7T, which may represent an excellent system to study mechanisms associated with prostate cancer progression and metastasis. PMID- 20945503 TI - Unveiling the methylation status of CpG dinucleotides in the substituted segment of the human p53 knock-in (Hupki) mouse genome. AB - Methylated cytosines within CpG dinucleotides (mCpGs) along the DNA-binding domain of the TP53 tumor suppressor gene (exons ~5-8) are the single most significant mutational target in human cancers. The human p53 knock-in (Hupki) mouse model was constructed using gene-targeting technology to create a mouse strain that harbors human wild-type TP53 DNA sequences spanning exons 4-9 in both copies of the mouse p53 gene. To date, however, the methylation status of cytosines within CpGs in the substituted segment of the Hupki mouse genome has not been determined. This lack of information deserves special attention because DNA methylation in mammals, which occurs almost exclusively within CpG dinucleotides, is a dynamic process throughout developmental stages and may vary among different species. Here, we have investigated the status of CpG methylation in the substituted segment of the Hupki mouse genome, and compared it to the methylation profile of the corresponding segment in the human genome using the combined bisulfite-restriction analysis and sodium bisulfite genomic sequencing. We found that all cytosines within CpGs of the TP53 DNA-binding domain, on both the coding and noncoding strands, were heavily methylated in Hupki fibroblasts, as they were in human fibroblasts. This is in keeping with the fully methylated status of TP53 CpGs that is known to prevail in adult human tissues. The remarkably similar patterns of cytosine methylation within CpG dinucleotides in Hupki cells and human cells further validates the suitability of mutagenesis assays in Hupki cells for experimental induction of TP53 mutations that have been observed in human tumors. PMID- 20945504 TI - Benfluorex and valvular heart disease: a cohort study of a million people with diabetes mellitus. AB - PURPOSE: To evaluate and quantify in diabetic patients treated with benfluorex in France, a fenfluramine-derivated product, a possible increase in risk of valvular heart disease, previously suggested by several published case reports. METHODS: This was a French comparative cohort study using data from two large national linked databases, health insurance system (SNIIRAM) and hospitalization (PMSI). Patients aged 40-69 years with reimbursement for oral antidiabetic and/or insulin in 2006 were eligible. Exposed patients were defined as patients with at least one benfluorex reimbursement in 2006. Selected admission diagnoses of interest in 2007 and 2008 PMSI databases were valvular insufficiency for any cause, mitral insufficiency, aortic insufficiency, and valvular replacement surgery with cardiopulmonary bypass. Relative risks (RR) were adjusted on gender, age, and history of chronic cardiovascular disease. RESULTS: A total of 1,048173 diabetic patients were included, with 43,044 (4.1%) exposed to benfluorex. The risk of hospitalization in 2007 and 2008 for any cardiac valvular insufficiency was higher in the benfluorex group: crude RR=2.9 [95% confidence interval 2.2-3.7] and adjusted RR=3.1 [2.4-4.0], with a lower risk for patients with lower cumulative dose of benfluorex. Adjusted RR for mitral insufficiency and aortic insufficiency admissions were 2.5 [1.9-3.7] and 4.4 [3.0-6.6], respectively. Adjusted RR for valvular replacement surgery was 3.9 [2.6-6.1]. CONCLUSIONS: Benfluorex in diabetic patients was significantly associated with hospitalization for valvular heart disease in the 2 years following benfluorex exposure. Linkage between SNIIRAM and PMSI databases is in France a valuable tool to quantify the risk of serious adverse drug reactions. PMID- 20945505 TI - Methods for drug safety signal detection in longitudinal observational databases: LGPS and LEOPARD. AB - PURPOSE: There is a growing interest in using longitudinal observational databases for drug safety signal detection, but most of the existing statistical methods are tailored towards spontaneous reporting. Here a sequential set of methods for detecting and filtering drug safety signals in longitudinal databases is presented. METHOD: Longitudinal GPS (LGPS) is a modification of the Gamma Poisson Shrinker (GPS) that uses person time rather than case counts for the estimation of the expected number of events. Longitudinal Evaluation of Observational Profiles of Adverse events Related to Drugs (LEOPARD) is a method that can be used to automatically discard false drug-event associations caused by protopathic bias or misclassification of the dates of the adverse events by comparing prior event prescription rates to post event prescription rates. LEOPARD can generate a single test statistic, or a visualization that can be used for more qualitative information on the relationship between drug and event. Both methods were evaluated using data simulated using the Observational medical dataset SIMulator (OSIM), including the dataset used in the Observational Medical Outcomes Partnership (OMOP) cup, a recent public competition for signal detection methods. The Mean Average Precision (MAP) was used for performance measurement. RESULTS: On the OMOP cup data, LGPS achieved a MAP of 0.245, and the combination of LGPS and LEOPARD achieved a MAP of 0.260, the highest score in the competition. CONCLUSIONS: The sequential use of LGPS and LEOPARD have proven to be a useful novel set of methods for drug safety signal detection on longitudinal health records. PMID- 20945506 TI - Changes in volatile compounds upon aging and drying in oolong tea production. AB - BACKGROUND: Long-term storage (aging) with periodic drying of fresh oolong tea gives rise to so-called old oolong tea. Alteration of aroma compounds is expected when a fresh oolong tea is converted into an old one, as the two teas smell drastically different. The aim of this study was to compare the volatile compounds in fresh and old oolong teas. RESULTS: Significant differences were observed between the volatile compounds in fresh and old oolong teas. This observation suggested that long straight chains of alcohols and acids were putatively decomposed while shorter-chain acids, their amide derivatives and many nitrogen-containing compounds were generated during the tea conversion processes. The overall patterns of volatile compounds observed in five different preparations of old oolong tea were fundamentally identical. This consensus pattern was different from that observed in oolong tea either stored for more than 10 years without drying or prepared at relatively low temperatures and short baking time. CONCLUSION: Characteristic aroma nitrogen-containing compounds, including N-ethylsuccinimide, 2-acetylpyrrole, 2-formylpyrrole and 3-pyridinol, were consistently found in the examined old oolong teas. These compounds might be regarded as typical constituents at least for a certain kind of old oolong tea. PMID- 20945507 TI - Ultrasound-enhanced mass transfer in Halal compared with non-Halal chicken. AB - BACKGROUND: Halal foods are often perceived as wholesome products that are specially selected and processed to achieve the highest standards of quality. In this study, dye penetration from an aqueous solution of methylene blue (1 mol L( 1)) was used as a model for the marination process of Halal and non-Halal chicken breast. RESULTS: The effect of dye penetration was evaluated by three techniques: (1) the mass of methylene blue solution in the samples was quantified by mass gain, (2) the amount of dye absorbed was determined by spectroscopy and (3) the penetration distance of dye inside the samples was measured. For non-Halal meat, ultrasound increased the amount of dye inside the samples by 6 and 13% after 15 and 30 min respectively. The effect on Halal meat was much more pronounced, with an increase in dye uptake of over 60% being observed for both time periods. CONCLUSION: Dye penetration is an indication of meat permeability and so can be used as an estimate of marinading of meat. Thus the use of high-power ultrasound has potential in poultry-processing methods, in particular that of Halal chicken marination. PMID- 20945508 TI - Chemical composition, antioxidant and antibacterial properties of the essential oils of Etlingera elatior and Cinnamomum pubescens Kochummen. AB - BACKGROUND: Plant essential oils are widely used as fragrances and flavours. Therefore, the essential oils from the leaves of Cinnamomum pubescens Kochummen (CP) and the whole plant of Etlingera elatior (EE) were investigated for their antioxidant, antibacterial and phytochemical properties. RESULTS: CP and EE were found to contain appreciable levels of total phenolic contents (50.6 and 33.41 g kg(-1) as gallic acid equivalent) and total flavonoid contents (205.6 and 244.8 g kg(-1) as rutin equivalent), respectively. DPPH free radical scavenging activity of CP is superior to EE (P < 0.05) showing IC(50) of 77.2 and 995.1 ug mL(-1), respectively. Methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis, Pseudomonas aeruginosa and Salmonella choleraesuis were tested against CP and EE. Only MRSA was the most susceptible bacteria to CP. GC/MS studies resulted in the identification of 79 and 73 compounds in CP and EE, respectively. The most abundant components of EE included beta-pinene (24.92%) and 1-dodecene (24.31%). While the major compound in CP were 1,6-octadien-3-ol,3,7-dimethyl (11.55%), cinnamaldehyde (56.15%) and 1-phenyl-propane-2,2-diol diethanoate (11.38%). CONCLUSION: This study suggests that the essential oils from Cinnamomum pubescens Kochummen and Etlingera elatior could be potentially used as a new source of natural antioxidant and antibacterial in the food and pharmaceutical industries. PMID- 20945509 TI - Effects of alkylresorcinols on volume and structure of yeast-leavened bread. AB - BACKGROUND: Alkylresorcinols (AR) are amphiphilic phenolic compounds found in high amounts in wheat, durum wheat and rye, with different homologue composition for each cereal. The effect of different amounts of added AR from these cereals on bread volume, height, porosity and microstructure was studied. Breads with added rye bran (with high levels of AR) or acetone-extracted rye bran (with low levels of AR) were also baked, as well as breads with finely milled forms of each of these brans. RESULTS: Breads with high amounts of added AR, irrespective of AR homologue composition, had a lower volume, a more compact structure and an adverse microstructure compared with breads with no or low levels of added AR. AR were also shown to inhibit the activity of baker's yeast. There was no difference in bread volume and porosity between bread baked with rye bran and acetone extracted rye bran or with brans of different particle size. CONCLUSION: Irrespective of homologue composition, AR had a negative effect on wheat bread properties when added in high amounts as purified extracts from wheat, durum wheat and rye. Natural levels of AR in rye bran, however, did not affect the volume and porosity of yeast-leavened wheat breads. PMID- 20945510 TI - Rheological properties of patatin gels compared with beta-lactoglobulin, ovalbumin, and glycinin. AB - BACKGROUND: The thermal unfolding and rheological properties of patatin gels were compared with those of commonly used proteins (beta-lactoglobulin, ovalbumin, glycinin). RESULTS: A significant difference between these proteins was observed in both the denaturation temperature (59 degrees C for patatin; about 20 degrees C lower than the other proteins) and the onset temperature of gel formation (50-60 degrees C, compared to 70-85 degrees C for the other proteins). At low ionic strength the minimal concentration was only 6% (w/v) for patatin, compared to 8-11% for the other proteins. This effect was attributed to the relatively high exposed hydrophobicity of patatin as determined by hydrophobic interaction chromatography. For gels compared at 'iso-strength', the frequency dependence was found to be close to identical, while small differences were observed in the strain at fracture. CONCLUSIONS: Patatin was found to form gels with comparable small-deformational rheological properties as typical food proteins. In addition, at concentrations where the elastic modulus was similar for all proteins, the frequency and strain dependence were also comparable. From this it is concluded that patatin is a promising protein to be used in food applications as a gelling agent. PMID- 20945511 TI - Effect of preheating temperature on the microstructure of walleye pollack surimi gels under the inhibition of the polymerisation and degradation of myosin heavy chain. AB - BACKGROUND: The physical attribute of heat-induced gel texture is highly dependent on the microstructure of the gel. In this study the microstructures of walleye pollack surimi gels preheated at various temperatures with and without inhibitors (ethylenediamine-N,N,N',N'-tetraacetic acid, iodoacetamide and leupeptin) were observed with a natural scanning electron microscope. RESULTS: Without inhibitors, gels preheated at 30 degrees C showed a fine and uniform network structure together with the highest polymerisation of myosin heavy chain (MHC) and the highest gel strength. At 60 degrees C, gels exhibited a broken, disrupted and loose cluster-like structure together with the highest degradation of MHC and the lowest gel strength. Under the inhibition of polymerisation and degradation of MHC a fine network was observed up to 40 degrees C during preheating. However, after a second step of heating at 80 degrees C the microstructures were disrupted and resembled each other regardless of the preheating temperature. CONCLUSION: Heat-induced gel formation is related to the polymerisation and degradation of MHC and the microstructure of the gel during preheating. Gelation occurred during setting even under the inhibitory condition, and the formation of covalent bonding by transglutaminase is not essential to the formation of a three-dimensional network during setting but is essential to the gel strength enhancement effect of setting by subsequent heating at 80 degrees C. PMID- 20945512 TI - Insecticidal and repellency activity of essential oil of Eucalyptus sp. against Sitophilus zeamais Motschulsky (Coleoptera, Curculionidae). AB - BACKGROUND: The objective of this work was to evaluate the insecticidal and repellent effect of essential oils of Eucalyptus dunnii, E. saligna, E. benthamii, E. globulus and E. viminalis in the control of Sitophilus zeamais in maize grains. RESULTS: The essential oils chemical composition showed that the E. benthamii presents the cis-ocimene (56.88%) as major compound. Results permitted us to verify that the evaluated species presented different insecticidal action under Sitophilus zeamais. About 100% of mortality was achieved with doses of 65, 100 and 400 microL for E. dunnii, E. saligna and E. benthamii, respectively. After regression analysis the LD(50) values were calculated and E. dunnii was shown to be the most efficient (25.03 microL), followed by E. saligna (37.93 microL) and E. benthamii (121.09 microL). Using the previously calculated LD(50) values, the repellency activity was calculated, allowing us to conclude that all species presented significant values in terms of this important parameter. CONCLUSION: The essential oil of Eucalyptus sp. presented insecticidal and repellency against Sitophilus zeamais Motschulsky (Coleoptera, Curculionidae). Although from an economic point of view synthetic chemicals are still more frequently used as repellents, natural products (essential oils) have the potential to provide efficient and safer repellents for humans and the environment. PMID- 20945513 TI - Simultaneous detection of deoxynivalenol and zearalenone by dual-label time resolved fluorescence immunoassay. AB - BACKGROUND: The health risks of deoxynivalenol (DON) and zearalenone (ZEN) necessitate the development of analytical methods for widespread food and feed screening. We sought to establish a rapid, economic and sensitive dual-label time resolved fluoroimmunoassay (TRFIA) to detect DON and ZEN simultaneously. Eu(3+)- and Sm(3+)-labelled antibodies were used, as lanthanides are more stable and have narrower emission spectra than most fluorescent dyes. RESULTS: The limit of detection was 0.0194 ng mL(-1) for DON (range: 0.0194-100 ng mL(-1)) and 0.37 ng mL(-1) for ZEN (range: 0.37-50 ng mL(-1)). DON recovery in spiked cereal samples was 88-107%, and for ZEN was 83-108%, with both intra- and inter-assay coefficients of variation (CVs) less than 5%. The dual-label TRFIA results correlated well with ELISA results (correlation coefficients: 0.9733 for DON and 0.9784 for ZEN). CONCLUSION: The dual-label TRFIA is a simple, fast and sensitive method for high-throughput screening of DON and ZEN in food and feedstuff. PMID- 20945514 TI - Chemical composition and antioxidant and antimicrobial activities of essential oil of Allium sphaerocephalon L. subsp. sphaerocephalon (Liliaceae) inflorescences. AB - BACKGROUND: Allium sphaerocephalon is a wild-growing plant commonly used as an onion substitute. In this study the essential oil obtained from A. sphaerocephalon subsp. sphaerocephalon inflorescences was analysed by gas chromatography and gas chromatography/mass spectrometry and also evaluated for in vitro antioxidant and antimicrobial activities. The obtained results are reported for the first time and discussed with respect to the sulfur compounds detected in the essential oil. RESULTS: Ninty-one compounds were identified, representing 91.6% (w/w) of the total oil. Major constituents of the analysed sample were shyobunol (15.3%), beta-caryophyllene (8.1%), alpha-cadinol (7.8%), 3,5-diethyl 1,2,4-trithiolane (isomer II, 5.9%) and delta-cadinene (5.2%). The diluted oil had an antioxidant capacity of 160 000 +/- 111 micromol alpha-tocopherol acetate equivalents g(-1). Its antimicrobial activity was evaluated against five bacterial and two fungal strains using the broth microdilution assay. Among the micro-organisms tested, the most susceptible strains were Pseudomonas aeruginosa (minimal inhibitory/bactericidal concentration = 0.08/2.5 mg mL(-1)) and Aspergillus niger (minimal inhibitory/fungicidal concentration = 0.31/0.63 mg mL( 1)). CONCLUSION: The results showed that the examined species had strong antioxidant and antimicrobial properties and are in accordance with the popular use of plants belonging to the genus Allium in traditional medicine, emphasising the necessity of further detailed study of the active principles in Allium species. PMID- 20945515 TI - Human activity recognition based on Evolving Fuzzy Systems. AB - Environments equipped with intelligent sensors can be of much help if they can recognize the actions or activities of their users. If this activity recognition is done automatically, it can be very useful for different tasks such as future action prediction, remote health monitoring, or interventions. Although there are several approaches for recognizing activities, most of them do not consider the changes in how a human performs a specific activity. We present an automated approach to recognize daily activities from the sensor readings of an intelligent home environment. However, as the way to perform an activity is usually not fixed but it changes and evolves, we propose an activity recognition method based on Evolving Fuzzy Systems. PMID- 20945516 TI - Variable selection in nonlinear modeling based on RBF networks and evolutionary computation. AB - In this paper a novel variable selection method based on Radial Basis Function (RBF) neural networks and genetic algorithms is presented. The fuzzy means algorithm is utilized as the training method for the RBF networks, due to its inherent speed, the deterministic approach of selecting the hidden node centers and the fact that it involves only a single tuning parameter. The trade-off between the accuracy and parsimony of the produced model is handled by using Final Prediction Error criterion, based on the RBF training and validation errors, as a fitness function of the proposed genetic algorithm. The tuning parameter required by the fuzzy means algorithm is treated as a free variable by the genetic algorithm. The proposed method was tested in benchmark data sets stemming from the scientific communities of time-series prediction and medicinal chemistry and produced promising results. PMID- 20945517 TI - Designing boosting ensemble of relational fuzzy systems. AB - A method frequently used in classification systems for improving classification accuracy is to combine outputs of several classifiers. Among various types of classifiers, fuzzy ones are tempting because of using intelligible fuzzy if-then rules. In the paper we build an AdaBoost ensemble of relational neuro-fuzzy classifiers. Relational fuzzy systems bond input and output fuzzy linguistic values by a binary relation; thus, fuzzy rules have additional, comparing to traditional fuzzy systems, weights - elements of a fuzzy relation matrix. Thanks to this the system is better adjustable to data during learning. In the paper an ensemble of relational fuzzy systems is proposed. The problem is that such an ensemble contains separate rule bases which cannot be directly merged. As systems are separate, we cannot treat fuzzy rules coming from different systems as rules from the same (single) system. In the paper, the problem is addressed by a novel design of fuzzy systems constituting the ensemble, resulting in normalization of individual rule bases during learning. The method described in the paper is tested on several known benchmarks and compared with other machine learning solutions from the literature. PMID- 20945518 TI - An online self-organizing scheme for Parsimonious and Accurate Fuzzy Neural Networks. AB - In this paper, an online self-organizing scheme for Parsimonious and Accurate Fuzzy Neural Networks (PAFNN), and a novel structure learning algorithm incorporating a pruning strategy into novel growth criteria are presented. The proposed growing procedure without pruning not only simplifies the online learning process but also facilitates the formation of a more parsimonious fuzzy neural network. By virtue of optimal parameter identification, high performance and accuracy can be obtained. The learning phase of the PAFNN involves two stages, namely structure learning and parameter learning. In structure learning, the PAFNN starts with no hidden neurons and parsimoniously generates new hidden units according to the proposed growth criteria as learning proceeds. In parameter learning, parameters in premises and consequents of fuzzy rules, regardless of whether they are newly created or already in existence, are updated by the extended Kalman filter (EKF) method and the linear least squares (LLS) algorithm, respectively. This parameter adjustment paradigm enables optimization of parameters in each learning epoch so that high performance can be achieved. The effectiveness and superiority of the PAFNN paradigm are demonstrated by comparing the proposed method with state-of-the-art methods. Simulation results on various benchmark problems in the areas of function approximation, nonlinear dynamic system identification and chaotic time-series prediction demonstrate that the proposed PAFNN algorithm can achieve more parsimonious network structure, higher approximation accuracy and better generalization simultaneously. PMID- 20945519 TI - Fuzzy regression modeling for tool performance prediction and degradation detection. AB - In this paper, the viability of using Fuzzy-Rule-Based Regression Modeling (FRM) algorithm for tool performance and degradation detection is investigated. The FRM is developed based on a multi-layered fuzzy-rule-based hybrid system with Multiple Regression Models (MRM) embedded into a fuzzy logic inference engine that employs Self Organizing Maps (SOM) for clustering. The FRM converts a complex nonlinear problem to a simplified linear format in order to further increase the accuracy in prediction and rate of convergence. The efficacy of the proposed FRM is tested through a case study - namely to predict the remaining useful life of a ball nose milling cutter during a dry machining process of hardened tool steel with a hardness of 52-54 HRc. A comparative study is further made between four predictive models using the same set of experimental data. It is shown that the FRM is superior as compared with conventional MRM, Back Propagation Neural Networks (BPNN) and Radial Basis Function Networks (RBFN) in terms of prediction accuracy and learning speed. PMID- 20945520 TI - Backpropagation through time training of a neuro-fuzzy controller. AB - The paper considers gradient training of fuzzy logic controller (FLC) presented in the form of neural network structure. The proposed neuro-fuzzy structure allows keeping linguistic meaning of fuzzy rule base. Its main adjustable parameters are shape determining parameters of the linguistic variables fuzzy values as well as that of the used as intersection operator parameterized T-norm. The backpropagation through time method was applied to train neuro-FLC for a highly non-linear plant (a biotechnological process). The obtained results are discussed with respect to adjustable parameters rationality. Conclusions are made with respect to the appropriate intersection operations too. PMID- 20945521 TI - Automated nonlinear system modeling with multiple fuzzy neural networks and kernel smoothing. AB - This paper, presents a novel identification approach using fuzzy neural networks. It focuses on structure and parameters uncertainties which have been widely explored in the literatures. The main contribution of this paper is that an integrated analytic framework is proposed for automated structure selection and parameter identification. A kernel smoothing technique is used to generate a model structure automatically in a fixed time interval. To cope with structural change, a hysteresis strategy is proposed to guarantee finite times switching and desired performance. PMID- 20945522 TI - Why cell phone conversations distract drivers. PMID- 20945523 TI - Physics of DNA: unravelling hidden abilities encoded in the structure of 'the most important molecule'. AB - A comprehensive article "Structure and Interactions of Biological Helices", published in 2007 in Reviews of Modern Physics, overviewed various aspects of the effect of DNA structure on DNA-DNA interactions in solution and related phenomena, with a thorough analysis of the theory of these effects. Here, an updated qualitative account of this area is presented without any sophisticated 'algebra'. It overviews the basic principles of the structure-specific interactions between double-stranded DNA and focuses on the physics behind several related properties encoded in the structure of DNA. Among them are (i) DNA condensation and aptitude to pack into small compartments of cells or viral capcids, (ii) the structure of DNA mesophases, and (iii) the ability of homologous genes to recognize each other prior to recombination from a distance. Highlighted are some of latest developments of the theory, including the shape of the 'recognition well'. The article ends with a brief discussion of the first experimental evidence of the protein-free homology recognition in a 'test tube'. PMID- 20945524 TI - Commentary on Turgay ST and Khorshid L (2010). Effectiveness of the auscultatory and pH methods in predicting feeding tube placement. Journal of Clinical Nursing 19, 1553-1559. PMID- 20945526 TI - Re: Time of decline in sexual function after external beam radiotherapy for prostate cancer. PMID- 20945525 TI - Clinical report-the pediatrician's role in child maltreatment prevention. AB - It is the pediatrician's role to promote the child's well-being and to help parents raise healthy, well-adjusted children. Pediatricians, therefore, can play an important role in the prevention of child maltreatment. Previous clinical reports and policy statements from the American Academy of Pediatrics have focused on improving the identification and management of child maltreatment. This clinical report outlines how the pediatrician can help to strengthen families and promote safe, stable, nurturing relationships with the aim of preventing maltreatment. After describing some of the triggers and factors that place children at risk for maltreatment, the report describes how pediatricians can identify family strengths, recognize risk factors, provide helpful guidance, and refer families to programs and other resources with the goal of strengthening families, preventing child maltreatment, and enhancing child development. PMID- 20945527 TI - Novel aspects of heat shock factors. PMID- 20945528 TI - The heat shock factor family and adaptation to proteotoxic stress. AB - The heat shock response was originally characterized as the induction of a set of major heat shock proteins encoded by heat shock genes. Because heat shock proteins act as molecular chaperones that facilitate protein folding and suppress protein aggregation, this response plays a major role in maintaining protein homeostasis. The heat shock response is regulated mainly at the level of transcription by heat shock factors (HSFs) in eukaryotes. HSF1 is a master regulator of the heat shock genes in mammalian cells, as is HSF3 in avian cells. HSFs play a significant role in suppressing protein misfolding in cells and in ameliorating the progression of Caenorhabditis elegans, Drosophila and mouse models of protein-misfolding disorders, by inducing the expression of heat shock genes. Recently, numerous HSF target genes were identified, such as the classical heat shock genes and other heat-inducible genes, called nonclassical heat shock genes in this study. Importance of the expression of the nonclassical heat shock genes was evidenced by the fact that mouse HSF3 and chicken HSF1 play a substantial role in the protection of cells from heat shock without inducing classical heat shock genes. Furthermore, HSF2 and HSF4, as well as HSF1, shown to have roles in development, were also revealed to be necessary for the expression of certain nonclassical heat shock genes. Thus, the heat shock response regulated by the HSF family should consist of the induction of classical as well as of nonclassical heat shock genes, both of which might be required to maintain protein homeostasis. PMID- 20945529 TI - Regulation of the members of the mammalian heat shock factor family. AB - Regulation of gene expression is fundamental in all living organisms and is facilitated by transcription factors, the single largest group of proteins in humans. For cell- and stimulus-specific gene regulation, strict control of the transcription factors themselves is crucial. Heat shock factors are a family of transcription factors best known as master regulators of induced gene expression during the heat shock response. This evolutionary conserved cellular stress response is characterized by massive production of heat shock proteins, which function as cytoprotective molecular chaperones against various proteotoxic stresses. In addition to promoting cell survival under stressful conditions, heat shock factors are involved in the regulation of life span and progression of cancer and they are also important for developmental processes such as gametogenesis, neurogenesis and maintenance of sensory organs. Here, we review the regulatory mechanisms steering the activities of the mammalian heat shock factors 1-4. PMID- 20945530 TI - Novel aspects of heat shock factors: DNA recognition, chromatin modulation and gene expression. AB - Heat shock factor (HSF) is an evolutionarily conserved stress-response regulator that activates the transcription of heat shock protein genes, whose products maintain protein homeostasis under normal physiological conditions, as well as under conditions of stress. The promoter regions of the target genes contain a heat shock element consisting of multiple inverted repeats of the pentanucleotide sequence nGAAn. A single HSF of yeast can bind to heat shock elements that differ in the configuration of the nGAAn units and can regulate the transcription of various genes that function not only in stress resistance, but also in a broad range of biological processes. Mammalian cells have four HSF family members involved in different, but in some cases similar, biological functions, including stress resistance, cell differentiation and development. Mammalian HSF family members exhibit differential specificity for different types of heat shock elements, which, together with cell type-specific expression of HSFs is important in determining the target genes of each HSF. This minireview focuses on the molecular mechanisms of DNA recognition, chromatin modulation and gene expression by yeast and mammalian HSFs. PMID- 20945531 TI - Roles of heat shock factors in gametogenesis and development. AB - Heat shock factors form a family of transcription factors (four in mammals), which were named according to the first discovery of their activation by heat shock. As a result of the universality and robustness of their response to heat shock, the stress-dependent activation of heat shock factor became a 'paradigm': by binding to conserved DNA sequences (heat shock elements), heat shock factors trigger the expression of genes encoding heat shock proteins that function as molecular chaperones, contributing to establish a cytoprotective state to various proteotoxic stress and in several pathological conditions. Besides their roles in the stress response, heat shock factors perform crucial roles during gametogenesis and development in physiological conditions. First, during these process, in stress conditions, they are either proactive for survival or, conversely, for apoptotic process, allowing elimination or, inversely, protection of certain cell populations in a way that prevents the formation of damaged gametes and secure future reproductive success. Second, heat shock factors display subtle interplay in a tissue- and stage-specific manner, in regulating very specific sets of heat shock genes, but also many other genes encoding growth factors or involved in cytoskeletal dynamics. Third, they act not only by their classical transcription factor activities, but are necessary for the establishment of chromatin structure and, likely, genome stability. Finally, in contrast to the heat shock gene paradigm, heat shock elements bound by heat shock factors in developmental process turn out to be extremely dispersed in the genome, which is susceptible to lead to the future definition of 'developmental heat shock element'. PMID- 20945532 TI - The Promyelocytic Leukemia Zinc Finger (PLZF ) gene is a novel transcriptional target of the CCAAT-Displacement-protein (CUX1) repressor. AB - The CCAAT-Displacement-Protein (CUX1) can transcriptionally repress sucrase isomaltase gene expression, a specific product of enterocytes that becomes re expressed during human colonic polyposis. Little is known of the gene repertoire that is directly affected by CUX1 in the intestinal epithelial context. This article identifies the Promyelocytic Leukemia Zinc Finger (PLZF) gene as a transcriptional target for the CUX1 repressor. CUX1 interacts in vivo with multiple DNA-binding sites in the 5'-UTR and promoter of the PLZF gene in colorectal cancer cells, a region that is functionally targeted by CUX1 in cotransfection assays. PLZF was found to be induced in colorectal cancer cell lines, correlating with a low detectable level of CUX1, a pattern that was reversed in normal human colonocytes. Reduction of p200CUX1 expression by RNAi in the Caco-2/15 cell line increased PLZF gene transcript expression. Because of the implication of Plzf in the regulation of stem cell maintenance, as well as Wnt and Ras signaling, in other systems, our observations suggest that the novel genetic relationship between CUX1 and PLZF could be of relevance to human diseases, such as leukemia, and open up a new field of investigation for the implication of these regulators during intestinal polyposis and cancer. PMID- 20945533 TI - Cell death-inducing DFF45-like effector, a lipid droplet-associated protein, might be involved in the differentiation of human adipocytes. AB - Cell death-inducing DFF45-like effector (CIDE) family proteins, including cell death-inducing DFF45-like effector A (CIDEA), cell death-inducing DFF45-like effector B (CIDEB) and cell death-inducing DFF45-like effector C (CIDEC) [fat specific protein of 27 kDa in rodent (FSP27) in rodents], were originally identified by their sequence homology to the N-terminal region of DNA fragmentation factor DFF40/45. Recent reports have revealed that CIDE family proteins play important roles in lipid metabolism. Several studies involving knockdown mice revealed that FSP27 is a lipid droplet-targeting protein that can promote the formation of lipid droplets. However, the detailed roles of human CIDEC in the differentiation of human adipocytes remain unknown. In the present study, we found that the expression of CIDEC increased during the differentiation of fetal adipose tissues, but decreased during the de-differentiation of adipocytic tumors, suggesting that the expression of CIDEC should be positively correlated with the differentiation of adipocytes. Furthermore, we verified that human CIDEC was localized on the surface of lipid droplets. Using human primary pre-adipocytes, we confirmed that the expression of CIDEC was elevated during the differentiation of pre-adipocytes, and knockdown of CIDEC in human primary pre adipocytes resulted in differentiation defects. These data demonstrate that CIDEC is essential for the differentiation of adipose tissue. Together with regulating adipocyte lipid metabolism, CIDEC should be a potential target for regulating adipocyte differentiation and reducing fat cell mass. PMID- 20945534 TI - Botswana gets boost in AIDS funding. PMID- 20945535 TI - Phase 3 study results released for telaprevir and HCV. PMID- 20945536 TI - Black AIDS Institute launches treatment and care advocacy network. PMID- 20945537 TI - Almotriptan: a review of 10 years' clinical experience. AB - Almotriptan, a serotonin 5-HT 1B/1D agonist, was developed for the acute treatment of migraine with or without aura and has been available for 10 years. This article evaluates the wealth of experience that has been obtained with almotriptan, including large randomized clinical trials (RCTs) and post-marketing studies that more closely reflect everyday clinical practice. Initial RCTs required patients to take almotriptan when migraine pain was of moderate or severe intensity, and found that 12.5 mg provided optimal outcomes for both pain relief and tolerability. Almotriptan effectively improved 2-h pain-relief, reduced migraine-associated symptoms and demonstrated low recurrence rates. These findings were also shown in patient subgroups, such as adolescents and menstrual migraineurs. A secondary finding in these trials was that patients who took almotriptan early, when the pain was still mild, achieved better outcomes. This prompted the initiation of studies designed to assess the effect of almotriptan in early intervention. Open-label trials reported improvements in pain-free end points (2 h, 24 h), and subsequent RCTs confirmed these findings. Pharmacovigilance data from more than 100 million tablets dispensed worldwide have confirmed that almotriptan is associated with a low occurrence of adverse effects, which, in clinical trials, has been shown to be similar to that observed with placebo. The clinical evidence obtained and comparisons made over a decade of use have demonstrated that almotriptan is one of the more effective and fast acting triptans available, with a placebo-like tolerability profile. This suggests that almotriptan is an excellent choice for patients requiring specific acute migraine treatment. PMID- 20945538 TI - Multimodality intraoperative MRI for brain tumor surgery. AB - Intraoperative MRI has already fundamentally changed the way current brain tumor surgery is performed. The ability to integrate high-field MRI into the operating room has allowed intraoperative MRI to emerge as an important adjunct to CNS tumor treatment. Furthermore, the ability of MRI to successfully couple with molecular imaging (PET and/or optical imaging), neuroendoscopy and therapeutic devices, such as focused ultrasound, will allow it to emerge as an important image-guidance modality for improving brain tumor therapy and outcomes. PMID- 20945539 TI - Crystalline nanoporous metal oxide thin films by post-synthetic hydrothermal transformation: SnO2 and TiO2. AB - Nanostructured and nanoporous metal oxide thin films are rarely accessible by standard synthetic approaches but highly desired for many applications, e.g. as electrodes, transparent conducting coatings, sensors or surface catalysts. Template based sol-gel chemistry combined with post-synthetic hydrothermal treatment allows now the synthesis of nanocrystalline mesostructured porous thin films of metal oxides, e.g. tin oxide and titania. Even in cases where the crystallization cannot be induced highly stable thin films can be achieved, e.g. niobium oxide thin films. We demonstrate how the size of the nanocrystallites influences and stabilizes the mesostructure at temperatures as low as 100 C and thereby in the case of titania or tin dioxide even prevents it from deterioration at higher temperatures up to 400-600 C. PMID- 20945540 TI - Rationale for the treatment of mild hyperglycemia during pregnancy. PMID- 20945541 TI - Excision arthroplasty of the hip joint in dogs and cats. Clinical, radiographic, and gait analysis findings from the Department of Surgery, Veterinary Faculty of the Ludwig-Maximilians-University of Munich, Germany. 1997. AB - From 1978 to 1989, 132 dogs and 51 cats underwent femoral head and neck ostectomy at the Department of Veterinary Surgery, Ludwig-Maximilians University, Munich, Germany. Clinical and radiographic re-evaluations were carried out an average of four years postoperatively in 81 (44%) of the animals, and gait analysis was also done in 17. The functional results were rated good in 38% of patients, satisfactory in 20%, and poor in 42%. However 96% of the owners were satisfied with the results. Kinetic and kinematic measurements showed that although femoral head and neck resection alleviated pain, it resulted in functional deficits in small as well as large breed dogs. These deficits were not visible during rapid movement. PMID- 20945542 TI - Real-time lung ultrasound for the diagnosis of alveolar consolidation and interstitial syndrome in the emergency department. AB - During the last few years, a growing number of studies have shown the accuracy of lung ultrasound in the diagnosis of pulmonary diseases. The latest developments in lung ultrasound are not because of technological advance, but are based on new applications and discovering the meanings of sonographic artifacts. Real-time sonography of the lung in the emergency department saves time and cost, providing immediate information to the clinician, relying on very easy-to-acquire data. The bedside sonographic recognition of pulmonary diseases practically guides management and reduces the amount of negative radiologic image testings. This review describes some innovative practical applications of B-mode lung ultrasound in the diagnosis of alveolar consolidations and interstitial syndrome in the emergency department. PMID- 20945543 TI - Comments on the Tri-Council for Nursing's recent policy statement. PMID- 20945544 TI - Crystallographic identification of an unusual homoleptic palladium citrate [Na(OH2)6].{[Na3(OH2)8]3[NaPd3(C6H4O7)3]2}.(H2O) stabilised by intermetallic aggregation with sodium and heavy hydration. AB - A rare precious metal binary citrate represented by palladium in the form of a water-rich Na-Pd intermetallic aggregate has been isolated and crystallographically characterised. It shows a penta-anionic [NaPd3(citrate)3]5- core balanced by [Na3]3+ and Na+ hydrates in a 3-D coordination network stabilised exclusively by citrate bridges and fortified by extensive H-bonding. PMID- 20945545 TI - Re: Survival benefit of radical prostatectomy in lymph node-positive patients with prostate cancer. PMID- 20945546 TI - Re: Testicular microlithiasis and carcinoma in situ: overview and proposed clinical guideline. PMID- 20945547 TI - Re: Penile sonographic and clinical characteristics in men with Peyronie's disease. PMID- 20945548 TI - Re: Early sacral neuromodulation prevents urinary incontinence after complete spinal cord injury. PMID- 20945549 TI - Re: MicroRNA regulation of oncolytic herpes simplex virus-1 for selective killing of prostate cancer cells. PMID- 20945550 TI - Metal nanowire grating patterns. AB - Metal nanowire patterning in the form of grating structures has been carried out using a wide range of lithography techniques, and many hybrid methods derived from them. The challenge is to achieve sub-100 nm linewidths with controllable spacing and thickness over large areas of substrates with high throughput. In particular, the patterns with linewidth and spacing of a few tens of nm offer properties of great interest in optoelectronics and plasmonics. Crossbar grating structures--two gratings patterned perpendicular to each other--will play an important role as ultra-high density electrode grids in memristive devices for non-volatile memory. PMID- 20945551 TI - Patient information page. Continuous glucose monitoring. PMID- 20945552 TI - Conflict of interest in diabetes research. PMID- 20945582 TI - Nutrition and fertility. PMID- 20945583 TI - On call. I'm 53 years old, and I only need glasses for reading. Recently though I've seen tiny black specs that move around in random directions. My eyes are not red, watery, or painful, but I'm worried that I may have the start of an eye disease. PMID- 20945584 TI - Abstracts of the 7th International Conference on Frontotemporal Dementias. October 6-8, 2010. Indianapolis, Indiana, USA. PMID- 20945585 TI - Delivering on a promise. Interviewed by Kristie Nybo. PMID- 20945586 TI - Promise and pitfalls of the cancer biomarker search. PMID- 20945588 TI - Role of extra-pulmonary factors - depression, muscle weakness, health-related quality of life - in COPD evolution. PMID- 20945589 TI - [Editorial comment on: Laparoscopic radical cystectomy. Where do we stand?]. PMID- 20945590 TI - [Dismantling cliches about immigration and health]. PMID- 20945591 TI - Urachal adenocarcinoma with late brain metastases. AB - OBJECTIVE: To describe a case of urachal adenocarcinoma with late brain metastases in a sixty one year old man who presented abdominal discomfort and hematuria during six months. METHODS: The clinical suspicion was bladder tumor and diagnostic studies were performed (urinary cytology, cystoscopy, abdominal ultrasound and abdominopelvic CT scan). Surgical treatment was performed. RESULTS: Negative urinary cytology. Cystoscopy showed a lesion with infiltration of the bladder dome. Ultrasound and CT scan showed a five centimeter rounded lesion, with intermediate density, internal echoes and calcifications on the anterior supravesical middle line, that infiltrated the bladder. The extension study had not findings. Partial cystectomy and lymphadenectomy were performed. The histopathologic diagnosis was mucin-secreting urachal adenocarcinoma. After five years without disease the patient suffered lung and brain metastases. CONCLUSIONS: Urachal adenocarcinoma is a tumor which must be distinguished of primary bladder adeno-carcinoma. The mucing-secreting adenocarcinoma can be associated with calcifications that can be demostrated on imaging studies. Late metastases without signs of local recurrence (after five years without disease) are an infrequent clinical-pathologic finding. PMID- 20945592 TI - Bladder schistosomiasis: case report and bibliographic review. AB - OBJECTIVE: To report a new case of bladder schistosomiasis. METHODS: A 21-year old patient came to our consultation with gross hematuria several weeks before, existing reddish lesions in the cystoscopy that suggested the existence of an atypical bladder tumor. RESULTS: After intense blood and urine test, ultrasonography and intravenous urography, transurethral resection of bladder was performed and the diagnosis on histological examination was bladder schistosomiasis. CONCLUSIONS: Given the high prevalence of schistosomiasis in the sub-Saharan countries and later clinical epidemiologic implications, the appearance of macro or microscopic hematuria in black race immigrants, or even any urinary symptoms, it is necessary a complete evaluation, at least with a parasitological analysis (being the bilharziasis the most probably reason). The patients who have suffered severe urinary schistosomiasis must complete long-term follow-up to prevent bladder carcinoma. PMID- 20945593 TI - Stuttering priapism: case report and bibliographic review. AB - OBJECTIVE: To review the presentation, physiopathology, diagnosis and therapeutic alternatives of stuttering priapism with the contribution of a new clinical case. METHODS: A 25 year old man, studied in another center for recurrent episodes of priapism for about 18 months. These episodes occur daily, significantly interfering with patient's quality of life. RESULTS: Initially he was treated with Bicalutamide 50mg/24h with no improvement. Blood test, penile Doppler ultrasound and selective arteriography of pudendal arteries showed no abnormalities. Tadalafil 5mg/24h was given for two months without response. Subsequently were treated with Diazepam 10 mg/24h and Terbutaline 5 mg/24h allowing control of the disease, remaining asymptomatic at present. CONCLUSIONS: Stuttering priapism is a rare form of presentation of this disease, caused by an alteration in the regulatory mechanisms of erection mediated by 5PDE and cGMP. Several drugs have been proposed in treatment with variable effectiveness, though there is no series long enough to recommend either as first choice. The use of inhibitors 5PDE so long, has been used successfully by some groups. Knowledge of these alternatives is important for the treatment of this complex and unusual pathology. PMID- 20945594 TI - Images in urology. Crossed fused renal ectopia with massive vesicoureteral reflux. PMID- 20945595 TI - Images in urology. Inguinoscrotal bladder hernia: multidetector CT scan reconstruction. PMID- 20945596 TI - Jobs, yes. But what about safe patient care? PMID- 20945597 TI - Impaired nursing practice and the law in Michigan. PMID- 20945598 TI - Ascension Health defies Catholic teachings. PMID- 20945599 TI - ULP filed for ignoring nurses input. Nurses march for the Lapeer community. PMID- 20945600 TI - A lift team that really works! PMID- 20945601 TI - Local allergic rhinitis: concept, clinical manifestations, and diagnostic approach. AB - Local allergic rhinitis is a newly described type of rhinitis involving nasal production of specific immunoglobulin (slg) E antibodies in the absence of atopy. It can affect patients previously diagnosed with non-allergic rhinitis. Evidence for this entity is supported by clinical symptoms, local production of slgE, a type 2 helperT cell inflammatory pattern in nasal secretions during natural exposure to aeroallergens, and a positive response to nasal allergen provocation with local nasal production of slgE to aeroallergens, tryptase, and eosinophil cationic protein (ECP). Based on these new findings, an advanced diagnostic approach is proposed in patients with symptoms suggestive of allergic rhinitis but negative results in skin prick test and serum slgE determination. Detection of local slgE in nasal secretions during natural exposure to aeorallergens and a positive nasal allergen provocation test with local production of tryptase, ECP, and slgE are useful for detecting patients with local allergic rhinitis. PMID- 20945602 TI - Correlation between common variable immunodeficiency clinical phenotypes and parental consanguinity in children and adults. AB - BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous group of disorders with a wide range of clinical manifestations and immunological findings, which could possibly form the basis for classification into different phenotypes. OBJECTIVES: This study was performed to distinguish between different clinical phenotypes in Iranian patients with CVID and compare complications and prognosis between these subgroups. METHODS: Ninety-three CVID patients were classified according to 5 clinical phenotypes: infections only (n=42), polyclonal lymphocytic infiltration (n=35), autoimmunity (n=10), malignancy (n=10), and enteropathy (n=9). The patients were further categorized into 4 groups based on age of diagnosis (cutoff, 13 years) and parental consanguinity. RESULTS: Grouping of patients showed that CVID children with parental consanguinity was the most frequent group (51%), followed by CVID children without parental consanguinity (21%), CVID adults without parental consanguinity (21%), and CVID adults with parental consanguinity (7%). There were significant associations between the group of CVID children with parental consanguinity and the polyclonal lymphocytic infiltration (P=.011) and enteropathy (P=.048) phenotypes. This group also had a higher mortality rate than other groups (P=.014). High serum levels of immunoglobulin M (IgM) at the time of diagnosis were associated with the eventual development of autoimmunity (P=.023). The adjusted odds ratio (OR) for mortality in all phenotypes showed that mortality was significantly increased in patients with the polyclonal lymphocytic infiltration phenotype (Mantel-Haenszel OR=5.3, CI=3.42-6.2). CONCLUSIONS: Parameters such as parental consanguinity and early onset of disease could describe a subgroup of CVID patients characterized by more complications, poorer prognosis, and a need for greater medical care and attention. PMID- 20945603 TI - Evidence of bacterial biofilms in nasal polyposis. AB - INTRODUCTION: The pathogeny of chronic rhinosinusitis with nasal polyposis (CRS/NP) has not been elucidated. Bacterial exotoxins have been implicated in many inflammatory chronic diseases, such as chronic otitis, chronic tonsillitis, cholesteatomas, and more recently CRS/NP. We propose that the bacteria in CRS/NP are not only present in a planktonic state, but also occur in microbial communities as biofilms. OBJECTIVE: To determine and characterize the presence of biofilms in CRS/NP. METHODS: We performed a prospective study in 12 patients undergoing endoscopic sinus surgery for nasal polyposis. Ten patients without CRS/NP who underwent septoplasty were included as a control group. Tissue samples were obtained from the inferior turbinate mucosae. The bacteria were isolated and typified and the material was examined in vitro using a spectrophotometer, and in vivo using optical microscopy and confocal scanning laser microscopy. RESULTS: Moderate to high in vitro biofilm-forming capacity was detected in 9 out of 12 patients with CRS/NP (mean [SD] optical density values of between 0.284 [0.017] and 3.337 [0.029]). The microorganisms isolated were Staphylococcus (5 patients), Streptococcus viridans, Pseudomonas aeruginosa, Enterococcus faecalis and Streptococcus viridans/Corynebacterium. Biofilms were demonstrated in vivo in 2 patients and no biofilm structures were evident in any of the controls. CONCLUSION: This study demonstrates the presence of bacterial biofilms in patients with CRS/NP. This chronic inflammatory factor might contribute to nasal mucosa damage, increased inflammatory cells in tissue, and the subsequent hyperplasic process. PMID- 20945604 TI - Usefulness of a short course of oral prednisone in antihistamine-resistant chronic urticaria: a retrospective analysis. AB - BACKGROUND: The effectiveness of corticosteroids in antihistamine-resistant chronic urticaria (CU) is widely accepted although large studies on their use in this disease are lacking. OBJECTIVE: To assess the proportion of patients with antihistamine-resistant CU that respond to a course of corticosteroids. METHODS: We studied 750 adult patients with CU and prescribed a course of oral corticosteroids (starting with prednisone 25 mg/day for 3 days) to those who reported little or partial response to antihistamine treatment. The corticosteroid treatment was considered effective if it resulted in long-term control of the disease with antihistamines only. Patients showing a temporary response were offered a second course of prednisone, at the end of which temporary responders and nonresponders were offered ciclosporin therapy for 3 months. RESULTS: A total of 660 patients (88%) (male/female, 194/556) responded to antihistamine treatment. In 40/86 patients (47%), prednisone induced remission of the disease and subsequent control with antihistamines at licensed doses only. Thirty-five patients responded well but relapsed when prednisone doses were tapered or shortly after withdrawal. In all responders, the effect was appreciable as early as the day after the first 25 mg dose. In 8/23 temporary responders, a second course of prednisone induced remission of the disease; the other 15 patients responded well but only temporarily. CONCLUSIONS: A single short course of prednisone induced remission in nearly 50% of patients with CU, and a second course induced remission in a further 9%. Less than 15% of patients did not respond at all to this treatment. PMID- 20945605 TI - Intestinal lamina propria TcRgammadelta+ lymphocytes selectively express IL-10 and IL-17. AB - BACKGROUND: The characteristics and roles of gut lymphocytes have been only partly elucidated, in particular with regard to activation patterns. OBJECTIVES: To characterize lymphocytes from various parts of the gut and examine their activation pattern as a network. METHODS: Lymphocytes were isolated from the epithelium, the lamina propria, Peyer's patches, mesenteric lymph nodes, the spleen, and peripheral blood of naive mice. They were then characterized for T cell phenotype, T cell receptors (TcRs), activation markers, and cytokine production. RESULTS: The results showed a gradient of cells with an increasing proportion of TcRgammadelta+, CD8alphaalpha+ cells towards the gut lumen, with the highest number found in intraepithelial lymphocytes. These cells, together with lamina propria lymphocytes (LPLs) were also characterized by a memory-like phenotype (CD25- CD45RB(low) and CD44(high)) and CD69 expression. CD8+ TcRgammadelta+ LPLs produced IL-10 and IL-17, while TcRalphabeta+ LPLs were FoxP3 positive. CONCLUSIONS: Gut lymphocytes express various receptors and cytokines according to their location. These specific features suggest a differential function for gut lymphocytes depending on their location. PMID- 20945606 TI - Rhinitis and its association with asthma in patients under 14 years of age treated in allergy departments in Spain. AB - BACKGROUND: Allergic rhinitis is the most frequent chronic allergic disease in children, and may be an important risk factor for the subsequent development of asthma. OBJECTIVE: To describe the characteristics of patients younger than 14 years of age presenting with rhinitis and the possible association with asthma. METHODS: We carried out a prospective, observational, descriptive, cross sectional epidemiologic study (Alergologica 2005) of 917 patients under the age of 14 consulting for the first time in allergy departments in Spain. RESULTS: Rhinitis was diagnosed in 42.5% of the children. The association between asthma and rhinitis was significantly higher in children than in adults (44.9% vs 35.5%; P<.05). Time from onset of rhinitis was significantly associated with the development of asthma (2.97 vs 2.06 years; P<.0001). Allergy was the most frequent cause of rhinitis in children with and without asthma. Allergy to epithelia and fungi was more frequent in children with rhinitis and asthma than in children with rhinitis alone. We found no differences in the frequency of treatment with immunotherapy between children with and without asthma. CONCLUSION: Rhinitis was frequently associated with asthma in children consulting for the first time at allergy departments. Time since onset of rhinitis and sensitivity to epithelia and fungi were associated with the development of asthma. PMID- 20945607 TI - Involvement of lipid transfer proteins in saffron hypersensitivity: molecular cloning of the potential allergens. AB - BACKGROUND: Lipid transfer proteins (LTPs) are relevant allergens, and have recently been proposed as model plant allergens from fruit, vegetables, seeds, and pollens. However, no LTP spice allergen has been characterized to date. OBJECTIVES: To identify and isolate saffron LTPs and to explore their relevance in saffron allergy. METHODS: Six patients with rhinitis and positive skin prick test (SPT) results to saffron extract were selected. Two recombinant LTPs from saffron were isolated, cloned into pPIC9 plasmid, and produced in Pichia pastoris. Immunoglobulin (Ig) E immunodetection and enzyme-linked immunosorbent assays were performed with the 2 purified allergens and with the major peach allergen Pru p 3. RESULTS: Full cDNA corresponding to 2 saffron LTP variants was isolated and expressed in P pastoris. The molecular weight of rCro s 3.01 and rCro s 3.02 was 9.15 kDa and 9.55 kDa, respectively. The sequences obtained had a 47% identity with each other and 51% and 43% with Pru p 3. Both proteins were recognized by anti-Pru p 3 antibodies. Specific IgE to the purified allergens was found in 50% of patients for rCro s 3.01 and 33% for rCro s 3.02 and Pru p 3 in the saffron-allergic patients. CONCLUSIONS: Our results indicated that rCro s 3.01 and rCro s 3.02 are minor allergens of saffron, at least in the study patients. To our knowledge, this is the first report on the implication of LTPs in spice allergy. PMID- 20945608 TI - Altered immunoglobulin A and M levels associated with changes in BAFF and APRIL after administration of intravenous immunoglobulin to treat Kawasaki disease. AB - BACKGROUND: Kawasaki disease (KD) is an acute vasculitis of unknown etiology. Immunoregulatory abnormalities have been thought to contribute to its pathogenesis. Although treatment with intravenous immunoglobulin (IVIG) effectively prevents significant cardiac morbidity, the mechanism by which IVIG produces an effect in KD has yet to be fully elucidated. OBJECTIVE: To investigate the effects of IVIG on the immune system of patients with KD. PATIENTS AND METHODS: Eleven patients with KD (mean [SD] age, 2.2 [1.5] years) were enrolled in this prospective study and treated with high-dose IVIG therapy (2 g/kg in 1 or 2 infusions) during the acute phase of the disease. We examined immunological changes, with special reference to Ig levels and 2 previously unassessed cytokines: B cell-activating factor belonging to the tumor necrosis factor family (BAFF), and a proliferation-inducing ligand (APRIL). RESULTS: Clinical symptoms disappeared quickly in all cases, with no coronary artery abnormalities. IgA and IgM levels responded more rapidly than previously reported and reached a peak between the 3rd and 10th day after the start of IVIG treatment. The mean (SD) BAFF level was high before IVIG treatment (3234 [1904] pg/mL) and decreased significantly (1085 [257] pg/mL) after IVIG treatment, whereas the mean (SD) APRIL level before IVIG treatment (18.0 [10.0] ng/mL) rose significantly (120.6 [41.2] ng/mL). A significant inverse correlation between BAFF and APRIL was observed in patients with KD. CONCLUSIONS: These results suggest that IVIG may affect the pathogenesis of KD through alteration of BAFF/APRIL. PMID- 20945609 TI - Assessment of the bronchodilation test by visual analog scale in the selection of patients with rhinitis for screening spirometry. AB - BACKGROUND: The nose and bronchi are closely linked, and rhinitis often precedes the onset of asthma. Bronchial obstruction is a characteristic of asthma, and demonstration of its reversibility is a key element in diagnosis. However, reversibility testing requires a spirometer, which is rarely available in the doctor's office. Visual analog scales (VAS) are frequently used in daily practice. OBJECTIVE: This study evaluated the suitability of a VAS for assessing bronchodilation in patients with persistent allergic rhinitis as a means of selecting candidates for screening spirometry. METHODS: We evaluated 120 patients with moderate to severe persistent allergic rhinitis. All patients underwent a clinical examination, skin prick test, spirometry, bronchodilation test, and VAS. RESULTS: Patients with rhinitis showed significantly increased forced expiratory volume in the first second (FEV1) after the bronchodilation test (median, 11.5%). Positive results were observed in 60%, and VAS values increased (>30%) after the test. There was a significant relationship between deltaVAS and deltaFEV1 (P<.0001; r=0.482). CONCLUSION: This preliminary study shows that patients with moderate to severe persistent allergic rhinitis often experience an increase in FEV1 after the bronchodilation test. VAS assessment of the test might be useful when selecting candidates for spirometry for possible bronchial involvement. PMID- 20945610 TI - Allergen-specific immunoglobulin E in the skin and nasal mucosa of symptomatic and asymptomatic children sensitized to aeroallergens. AB - BACKGROUND: Asymptomatic sensitization is confirmed by a positive response to skin prick tests (SPT) with allergens in the absence of clinical symptoms of allergy. This is a common observation for which no convincing explanation has been provided.We investigated the extent to which the presence of specific immunoglobulin (Ig) E in the nasal mucosa accounts for the occurrence of symptoms. METHODS: The study population comprised 192 patients with positive SPT results to aeroallergens: 111 had symptomatic allergic rhinitis and 81 were totally asymptomatic. All patients underwent measurement of nasal specific IgE using a validated technique (nasal IgE test). RESULTS: A family history of atopy was significantly more frequent in symptomatic patients than in asymptomatic patients (P<.0001). The result of the nasal IgE test was positive in 77.5% of symptomatic patients and in only 13.6% of asymptomatic patients (P<.0001). With regard to individual allergens, there was no association between clinical symptoms and a positive response to SPT, although there was a strong association between symptoms and individual allergens tested for nasal IgE. In symptomatic patients, there was only a slight correlation between SPT and nasal tests with allergens. CONCLUSION: These findings suggest that the absence of specific IgE in the nasal mucosa may explain the absence of symptoms in most sensitized subjects and pave the way for further study of the behavior of mucosal IgE in asymptomatic and symptomatic subjects. PMID- 20945611 TI - Uterine contractions: an unusual side effect of venom immunotherapy. AB - Venom immunotherapy (VIT) is an efficient treatment modality for preventing further sting-induced anaphylactic reactions in patients with Hymenoptera venom allergy. The main side effects of VIT include local and systemic allergic reactions with a variable risk of up to 46%. We report the case of a woman who experienced rapid-onset hypocalcemia and regular uterine contractions on 3 occasions within 30 minutes of receiving Apis mellifera VIT. To the best of our knowledge, this is the first report of uterine contractions as a side effect of VIT. The importance of this event is clear, as VIT has now been approved for pregnant women. We provide recommendations to physicians using this modality. PMID- 20945612 TI - Use of the lymphocyte transformation test in the diagnosis of DRESS syndrome induced by ceftriaxone and piperacillin-tazobactam: two case reports. AB - Drug-related rash with eosinophilia and systemic symptoms (DRESS) syndrome, or drug-induced hypersensitivity syndrome (DIHS), is a life-threatening multiorgan systemic reaction characterized by rash, fever, lymphadenopathy, hepatitis, and leukocytosis with eosinophilia. Aromatic anticonvulsant drugs and allopurinol have been reported to be the most frequent eliciting agents. Our search of the literature revealed only 2 cases induced by piperacillin and 1 case by ceftriaxone.We present 2 cases of DRESS syndrome induced by the beta-lactam drugs ceftriaxone and piperacillin-tazobactam. An allergological workup including skin prick test, intradermal tests, patch tests, and lymphocyte transformation test (LTT) was performed. LTT was shown to be a useful technique in both cases to help to identify the drugs involved. PMID- 20945613 TI - Multiple acute parasitization by Anisakis simplex. AB - Hypersensitivity to Anisakis is an increasingly prominent medical problem throughout the world, due to a better understanding of diseases induced by parasites and to modern culinary habits of eating raw or undercooked fish. We describe the case of a patient who presented epigastric pain, wheals, erythema, and pruritus 3 hours after the ingestion of fish. More than 200 larvae were obtained by endoscopy. However, the patient only developed an immune response with specific immunoglobulin E and eosinophilia peaking at day 18 and decreasing during the 17-month follow-up. Only eosinophilia reached normal limits. PMID- 20945615 TI - Cold urticaria: its importance in the operating room. PMID- 20945614 TI - Ataxia-telangiectasia in a patient presenting with hyper-immunoglobulin M syndrome. AB - Ataxia-telangiectasia (AT) and hyper-immunoglobulin M (HIGM) syndrome are both primary immunodeficiency diseases caused by different genetic defects. While a small proportion of AT patients have increased serum immunoglobulin (Ig) M concentrations during the course of a disease, a high level of IgM at onset is rare. We report the case of an 8-year-old girl who had experienced recurrent respiratory infection, cutaneous abscesses, and hepatosplenomegaly since the age of 2 years. She was diagnosed with HIGM based on the results of immunological studies, including low IgG and IgA levels and raised serum IgM concentrations. However, at the age of 4 years, a neurological examination revealed gait disturbance and telangiectatic lesions on the conjunctiva; therefore, a diagnosis of AT was suggested. In spite of regular intravenous immunoglobulin infusions and antimicrobial prophylaxis, the patient experienced several episodes of respiratory infection and eventually died of respiratory failure at the age of 8 years. Further molecular analysis revealed a novel homozygous missense mutation in exon 53 (c.8250C>T, p.2622Ala>Val) of the ATM gene. Patients with AT and the HIGM phenotype may not develop clinical characteristics of AT for some time. While patients with AT and increased serum IgM levels could have a considerably more severe disease course and a shorter survival, IgM levels could be considered a prognostic factor. PMID- 20945616 TI - Desensitization protocol administered successfully with interferon-alpha 2a in a child with chronic hepatitis B infection. PMID- 20945617 TI - Omalizumab: a potential new therapeutic approach for aspirin-exacerbated respiratory disease. PMID- 20945618 TI - Deflazacort: a possible alternative in corticosteroid allergy. PMID- 20945619 TI - Omalizumab in severe allergic asthma: efficacy assessment by comparison of symptom score and peak expiratory flow values before and after therapy. PMID- 20945620 TI - Self-injectable adrenaline devices: is training necessary? PMID- 20945621 TI - Food allergy due to olive. PMID- 20945622 TI - Comparison of seronegative and seropositive rheumatoid arthritis with regard to some clinical characteristics. AB - The aim of this study is to establish a scientific comparative analysis between seronegative and seropositive rheumatoid arthritis (RA), with regard to some clinical characteristics. The studied group consisted of RA seronegative patients with titters lower then 1:64 defined by Rose-Waaler test, while the control group consisted of RA seropositive patients with titters of 1:64 or higher. Examinees all belonged to the 2nd and 3rd functional classes according to ARA criteria, were between 25-60 years of age (Xb = 49.96), with disease duration between 1-27 years (Xbox = 6.41). In the disease onset most frequently affected joints were metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joint of the hands, almost equally represented with regard to sero-status and sex. During the examination seropositive patients showed a higher presence of inflamation of peripheral joints of hand and foot, but only the presence of PIP of the hands was statistically significant (chi2 = 15.63, p < 0.01). Knees, talocrural joints and elbows were more frequently affected in seropositive patients, whereas humeroscapular, coxofemoral and sacroiliacal joints were more frequently affected in seronegative patients, but without significant statistical difference with regard to sero-status. The presence of affected PIP of the hands (chi2 = 9.96, p < 0.01) and knees (chi2 = 4.17, p < 0.05) with regard to sex was statistically significant in seropositive female patients, as well as the presence of atacked PIP of the hands (chi2 = 6.08, p < 0.05), and cervical vertebrae (chi2 = 6.00, p < 0.05) in seropositive male patients. There were some differences between groups with regard to sex in metatarsophalangealjoints (MTP), PIP of the foot, and other joints, but without any statistical significance. In both subsets statistically significant domination was found in affected second (chi2 = 20.85, p < 0.01) and third (chi2 = 15.70, p < 0.01) fingers of the PIP level of hands and third finger (chi2 = 6.52, p < 0.05) of the MCP level. The mentioned parameters did not show a significant statistical difference with regard to sero-status and sex. Majority of patients had 1-4 deformities. Seropositive group had prevalent knee contractures, e.g. the eversion of the foot, while seronegative group had more "swan neck" deformities. The mentioned parameters did not show a significant statistical difference with regard to sero-status and sex. Longer duration of the disease resulted in an increased number of deformities, and this difference was statistically significant (t = 5.92, p < 0.01). Linear correlation between these two parameters resulted as high positive in general (r = 0.49, p < 0.01) and for groups separately, but without significant statistical difference with regard to sero-status. Duration of the disease with regard to the type of deformities was different in both subsets: in case of the longer duration of the disease "buttonhole" was prevalent with statistically significant difference in seropositive patients (t = 2.10, p < 0.05), whereas "fibular deviation" was prevalent in seronegative patients (t = 2.64, p < 0.01). PMID- 20945623 TI - Dermatoglyphics of digitopalmar complex in forty male patients affected by rheumatoid arthritis--quantitative analysis. AB - Quantitative analysis of digitopalmar ridge count was performed in forty male patients with rheumatoid arthritis to evaluation of genetic factors in that disease. Twenty five variables (ridge count on each of ten fingers, their sum on five and ten fingers, four traits on each palm, i. e. ridge count between a-b, b c and c-d triradii, their sum on each and both palm and at angle on two palms and their bilateral sum) were determined. The data thus obtained were compared with digitopalmar prints of 200 healthy men who served as a control group. A significant difference from the control group was found in eight variables. Ridge count was increased on the first and fifth finger bilaterally, on the fourth right finger tip, and their sum on each, and both fists. Accordingly, a polygenic system identical in some loci to the polygenic system predisposing to rheumatoid arthritis susceptibility might be found responsible for the dermatoglyphic pattern development. That means that they could used, and that is the aim of this study, as a diagnostic tool in rheumatic diseases. PMID- 20945625 TI - In the firing line: NHS white paper promises deep cuts in number of senior staff posts. PMID- 20945627 TI - Working in a new financial landscape. PMID- 20945628 TI - In excellent e-health. PMID- 20945629 TI - Creative care: the role of the arts in hospital. AB - Hospital patients often experience many different art forms, from the simple placing of sculpture in hospital grounds to the involvement of patients and staff in exhibitions, performances or workshops. In this article, the author refers to the work of Royal Brompton & Harefield Arts to improve the wellbeing of patients and staff at Royal Brompton Hospital, in Chelsea, London, and Harefield Hospital, near Uxbridge, Middlesex, which together form the Royal Brompton & Harefield NHS Foundation Trust, the largest specialist heart and lung centre in the U.K. PMID- 20945630 TI - Using a template to coach yourself and others. AB - Coaches question, inspire, motivate and support other people to change their lives. In doing so, they need enthusiasm and accountability, and the ability to set goals and create action plans. This article explains how to combine these qualities, and the techniques discussed in previous articles in this series, to create great coaching results. PMID- 20945631 TI - Work-based learning and the role of managers. AB - Healthcare policy makers have advocated the introduction of work-based learning (WBL) methods to help improve care. Some healthcare professionals and academics do not support WBL, however, possibly because they experienced, and value, traditional learning methods. This article reports on one of the findings of a longitudinal evaluation of WBL among registered nurses and highlights the pivotal role that managers play in supporting WBL. PMID- 20945632 TI - Experiences of overseas nurses recruited to the NHS. AB - Overseas staff have been described as the 'saviours of British nursing' and it has been mooted that some healthcare organisations, particularly in the independent sector, would cease to function without them (Buchan 2003). This article discusses a review of the experiences of migrant nurses who came to the U.K. between 1995 and 2007, focusing on the implications of its findings for senior nurses and managers. It also makes recommendations for the future recruitment and retention of internationally recruited nurses. PMID- 20945633 TI - Doing the job I love. PMID- 20945634 TI - Comparison of racemic ketamine versus (S+) ketamine when combined with midazolam for anesthesia of Callithrix jacchus and Callithrix penicillata. AB - Ten common marmosets (Callithrix jacchus) and 10 black-tufted marmosets (Callithrix penicillata) were immobilized to compare the anesthetic effects of racemic ketamine and (S+) ketamine in combination with midazolam. The animals were distributed into four groups: five common marmosets (group CJR) and five black-tufted marmosets (group CPR) received 9.8 +/- 1.4 mg/kg of racemic ketamine, and five common marmosets (group CJS) and five black-tufted marmosets (group CPS) received 10.4 +/- 1.6 mg/kg of (S+) ketamine. All groups received similar dosages of midazolam (1.0 +/- 0.15 mg/kg). During immobilization, heart rates, respiratory rates, rectal temperatures, and muscle relaxation scores were recorded at 5, 10, and 20 min after initial injection. Quality of induction and quality of recovery were evaluated in each marmoset by recording physical reactions including withdrawal reflexes, involuntary movements, salivation, compulsive licking, catalepsy, and ataxia. There were no significant differences in the induction, immobilization, and recovery times between the four groups. Similarly, there were no significant differences between groups in heart rates, respiratory rates, or body temperatures, although there was a significant decrease in respiratory rates over time in group CPR. In addition, the CJR and CPS groups showed significant decreases over time in rectal temperature. Muscle relaxation was more profound in the CPR group than in the other groups. Compulsive licking, involuntary movements, salivation, and withdrawal reflexes were observed more frequently in animals given S(+) ketamine; but in general, racemic ketamine and S(+) ketamine had similar effects in all callitrichines. Further studies are required to confirm that S(+) ketamine has different potency in these species. PMID- 20945635 TI - Surgical implantation of a cardiac resynchronization therapy device in a western lowland gorilla (Gorilla gorilla gorilla) with fibrosing cardiomyopathy. AB - A 24-yr-old, male western lowland gorilla (Gorilla gorilla gorilla) was diagnosed in March of 2003 with congestive heart failure (CHF). Transesophageal and transthoracic echocardiography demonstrated global left and right ventricular hypokinesia with a left ventricular ejection fraction of 0.20. At the time of diagnosis, the animal exhibited symptoms and signs of CHF with minimal exertion (New York Heart Association class III). Over a 16-mo period, the severity of CHF progressed to class IV (resting signs and symptoms) despite angiotensin converting enzyme inhibition, beta-blockers, and diuretics. Because of intractable CHF and a QRS duration that was markedly prolonged compared with the normal range for this species, a cardiac resynchronization therapy (CRT) device was implanted using implantation techniques based on human surgical procedures. Placement of the right ventricular, right atrial, and left ventricular leads and pulse generator were accomplished in 5.5 hr. Telemetry of the device postoperatively via wand or remote radio frequency has allowed for noninvasive programming and interrogation. The clinical improvement in CHF with this therapy was immediate and dramatic for this animal. Six months after CRT device implantation, the device leads became dislodged during an altercation with another gorilla, with the rapid development of CHF upon cessation of biventricular pacing. A second procedure to replace the leads returned the gorilla to his previous level of activity. In 2007, the pulse generator was electively replaced for battery depletion with a device capable of remote radiofrequency programming and interrogation. CRT implantation, although requiring specialized equipment and surgical skill, appears to be a viable option for treatment of dilated cardiomyopathy in gorillas. PMID- 20945636 TI - Changes in serum calcium, phosphorus, and magnesium levels in captive ruminants affected by diet manipulation. AB - A combination of low serum calcium (Ca), high serum phosphorus (P), and low serum magnesium (Mg) has been observed in individual captive ruminants, primarily affecting kudu (Tragelaphus strepsiceros), eland (Taurotragus oryx), nyala (Tragelaphus angasii), bongo (Tragelaphus eurycerus), and giraffe (Giraffa camelopardalis). These mineral abnormalities have been associated with chronic laminitis, acute tetany, seizures, and death. Underlying rumen disease secondary to feeding highly fermentable carbohydrates was suspected to be contributing to the mineral deficiencies, and diet changes that decreased the amount of starch fed were implemented in 2003. Serum chemistry values from before and after the diet change were compared. The most notable improvement after the diet change was a decrease in mean serum P. Statistically significant decreases in mean serum P were observed for the kudu (102.1-66.4 ppm), eland (73.3-58.4 ppm), and bongo (92.1-64.2 ppm; P < 0.05). Although not statistically significant, mean serum P levels also decreased for nyala (99.3-86.8 ppm) and giraffe (82.6-68.7 ppm). Significant increases in mean serum Mg were also observed for kudu (15.9-17.9 ppm) and eland (17.1-19.7 ppm). A trend toward increased serum Mg was also observed in nyala, bongo, and giraffe after the diet change. No significant changes in mean serum Ca were observed in any of the five species evaluated, and Ca was within normal ranges for domestic ruminants. The mean Ca:P ratio increased to greater than one in every species after the diet change, with kudu, eland, and bongo showing a statistically significant change. The results of this study indicate that the diet change had a generally positive effect on serum P and Mg levels. PMID- 20945637 TI - Ultrasonographic anatomy of the Asian elephant (Elephas maximus) eye. AB - Bilateral transpalpebral ultrasonography was performed on 53 captive Asian elephants (Elephas maximus) in order to describe the normal ultrasonographic appearance and measurements of the Asian elephant eye. Transpalpebral ultrasonography was performed using a portable ultrasound unit and a 4-7-MHz broadband curvilinear transducer on animals housed at seven institutions in the United Kingdom and in Sri Lanka. Both males and females were included in the study and ages ranged from 14 mo to 65 yr. Ultrasonic examinations were conducted on unsedated animals, without the use of topical or local anesthesia. The ultrasonographic appearance of the globe and intraocular structures of the Asian elephant eye is similar to that in other species. Biometry measurements recorded for adult (n=41) and juvenile (n=10) Asian elephants were: axial length, 3.44 +/- 0.21 cm and 3.18 +/- 0.19 cm (mean +/- SD); equatorial diameter, 3.88 +/- 0.32 cm and 3.60 +/- 0.24 cm; corneal thickness, 0.17 +/- 0.02 cm and 0.16 +/- 0.02 cm; anterior segment depth, 0.45 +/- 0.08 cm and 0.36 +/- 0.07 cm; lens diameter, 1.90 +/- 0.14 cm and 1.75 +/- 0.19 cm; lens depth, 1.01 +/- 0.12 cm and 0.94 +/- 0.10 cm, and posterior segment depth, 1.82 +/- 0.17 cm and 1.72 +/- 0.15 cm, respectively. Multiple linear regression analysis indicated a significant relationship between the explanatory variables (age, sex, and height) and the dependent variables (axial length, equatorial diameter, corneal thickness, anterior segment depth, lens diameter, and lens depth). The main finding of this statistical test was that the globe increases in size as the animal ages. Transpalpebral ultrasonography was found to be an effective and practical imaging modality in the evaluation of the Asian elephant eye, without the need for chemical restraint. PMID- 20945638 TI - Pharmacokinetics and intramuscular bioavailability of a single dose of butorphanol in Asian elephants (Elephas maximus). AB - Captive Asian elephants (Elephas maximus) are susceptible to lameness resulting from foot and joint pain, including chronic arthritis. In the past, opioid analgesics, such as butorphanol, have been used clinically for pain management. However, dosages used in treating elephants were often extrapolated from data in horses, with no pharmacokinetic information on the specific agents used in elephant species. In this pharmacokinetic study, six adult captive Asian elephants (5 female, 1 male castrate) were administered a 0.015 mg/kg dose of butorphanol by both i.v. and i.m. routes. A complete crossover design was used with a 3-wk washout period between treatments. Serial blood samples were collected immediately prior to butorphanol administration and at 5, 10, 20, and 40 min and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 24 h after administration. The butorphanol analysis was performed using a validated liquid chromatography-mass spectrophotometric assay with a limit of quantitation of 0.025 ng/ml. The mean Cmax after i.m. administration was 7.9 ng/ml, with a corresponding Tmax, of 40 min and t(1/3), of 7.1 h. After i.v. administration, the mean Vd(ss) was 1.4 L/kg and the mean Cl(p) was 0.26 L/kg/h. Mean i.m. bioavailability was 37%. The results indicate that butorphanol used at 0.015 mg/kg i.m. or i.v. could be useful in elephants when given for pain control. PMID- 20945639 TI - The normal electrocardiogram of conscious golden eagles (Aquila chrysaetos). AB - The aim of this study was to describe the normal electrocardiographic patterns and values in conscious golden eagles (Aquila chrysaetos). The standard bipolar and augmented unipolar limb leads' electrocardiograms were recorded in the golden eagles. The waveforms were analyzed in all leads at 50 mm/sec and at 10 mm = 1 mV to determine P, PR (segment and interval), QRS, ST, and QT durations and P, net QRS complex, and T amplitudes. The polarity of each waveform was tabulated in all leads. The mean electrical axis for the frontal plane was calculated using standard bipolar leads II and III. The mean heart rate was 346.7 +/- 14.29 beats/min. The P wave was predominantly positive in standard bipolar leads I and II and augmented unipolar limb leads aVL and aVF. The dominant pattern ofwaveforms of the QRS complexes were QS in leads I, II, III, and aVF, whereas in leads aVR and aVL, the pattern was always R. The T wave was slightly positive in leads I, II, and aVF. The average value of the heart mean electrical axis was 85.9 +/- 7.50 degrees. Establishment of normal electrocardiogram values will facilitate a better understanding of electrocardiographic changes seen in many avian diseases. PMID- 20945640 TI - Hematologic values of captive Acadian redfish (Sebastes fasciatus). AB - The Acadian redfish (Sebastes fasciatus) is a popular display animal in public aquaria and an important fisheries resource, but hematologic values for this species have not been reported. This study investigated hematocrit, leucocyte counts, and leucocyte differential counts for 29 captive Acadian redfish collected in 2006 and 2008. All fish were judged to be in good health based on behavior, appetite, physical examination, skin cytology, and gill biopsy. Fish were anesthetized with tricaine methanesulfonate (MS-222) for blood collection from the ventral coccygeal vasculature. In 2008, MS-222 was buffered with sodium bicarbonate. Hematocrit values ranged from 27% to 45% (mean = 33% in 2006, mean = 31% in 2008). Leucocyte counts ranged from 670 to 35,000 cells/microl (mean = 6430 cells/microl in 2006, and 13,130 cells/microl in 2008). Lymphocytes were the most numerous of the leucocytes, followed by neutrophils and monocytes. Eosinophils and basophils were not seen. Fish weights were significantly greater in 2006, whereas total leucocyte counts, lymphocyte counts, and monocyte counts were significantly greater in 2008. Differences in leucogram values between the two groups may have been due to differences in size, age, anesthetic method, or other undetected factors. This is the first report of leucogram values for a species of the family Scorpaenidae. In general, values were similar to those of other teleosts, in which leucocyte counts can be quite variable. PMID- 20945641 TI - Environmental and physiological factors contributing to outbreaks of cryptosporidium in Coquerel's sifaka (Propithecus coquereli) at the Duke Lemur Center: 1999-2007. AB - This population-based, retrospective study examined the susceptibility of a prosimian primate, Coquerel's sifaka (Propithecus coquereli), to Cryptosporidium spp. over a 9-yr period from 1999 to 2007 at the Duke Lemur Center (DLC) located in Durham, North Carolina. The investigation examined potential epidemiologic risk factors that could be correlated to infectious outbreaks at the center, such as prevalence, signalment (species, age, and sex), seasonality of occurrence, recurrence rate, family lineage, parturition, clinical signs, and concurrent diseases or health conditions. Findings included Propithecus spp. being the only lemur species at the DLC showing clinical signs of infection, with age being an important factor in susceptibility, and showing a strong correlation between temperature and seasonality with shedding of Cryptosporidium oocysts. These findings present new information regarding cryptosporidiosis in captive prosimians. PMID- 20945642 TI - Comparison of systemic cytokine levels in Mycobacterium spp. seropositive and seronegative Asian elephants (Elephas maximus). AB - Mycobacterium spp. infection is an important health concern for Asian elephant (Elephas maximus) populations worldwide. The disease is of particular concern considering its potential to affect not only the individual animal but also herd and public health. Although elephant tuberculosis susceptibility is poorly understood, immune function alterations are central to disease pathogenesis in other species and probably affect outcome of mycobacterial infections in elephants. Measurement of immune mediator (cytokine) levels within blood samples can provide information regarding immune function that may elucidate disease susceptibility. For this study, mRNA levels of interleukin (IL)-2, IL-4, IL-10, and IL-12; interferon (IFN)-gamma; tumor necrosis factor (TNF)-alpha; and transforming growth factor (TGF)-beta were measured using elephant-specific, real time reverse transcription-polymerase chain reaction (RT-PCR) assays in RNA preserved whole blood samples from 106 Asian elephants, 15% of which were Mycobacterium tuberculosis complex seropositive. The Elephant TB STAT-PAK (Chembio Diagnostics, Inc., Medford, New York 11763, USA), a novel lateral flow antibody detection assay developed for specific use in elephants, was used to determine serologic status for the study. Seropositive animals had higher levels of TNF-alpha and lower levels of TGF-beta than seronegative animals; these differences between groups were statistically significant when levels were analyzed as categorical variables. Trends toward higher levels of IFN-gamma and IL-4 and slightly lower levels of IL-10 and IL-12 were noted in the seropositive group, although differences between groups were not statistically significant. Presence of other inflammatory conditions was found to be a significant confounding variable in the analysis of the relationship between tuberculosis status and TNF-alpha levels, necessitating its inclusion in statistical models. Age and sex were not found to significantly affect the relationship between tuberculosis status and any of the cytokines measured. Interleukin-2 levels were below the sensitivity of the real-time RT-PCR assay irrespective of tuberculosis status. These findings provide a foundation for future research into the immunopathogenesis of elephant tuberculosis. PMID- 20945643 TI - A comparison of oral and topical vitamin A supplementation in African foam nesting frogs (Chiromantis xerampelina). AB - Vitamin A is essential for a variety of functions, including cellular differentiation, morphogenesis, growth, vision, immune response, and reproduction. A captive population of African foam-nesting frogs (Chiromantis xerampelina) with a known history of vitamin A deficiency had higher than expected incidence of sudden death, bacterial osteomyelitis, and stunted growth. Due to the high prevalence and untreatable nature of the diseases in the population, euthanasia of the population was recommended. Before euthanasia, the population was entered into a study to compare oral dietary supplementation of vitamin A to topical treatment with water-miscible vitamin A palmitate (AQUASOL A Parenteral, Mayne Pharma Inc., Paramus, New Jersey 07652, U.S.A.). Eighty-four frogs, weighing 2-7 g, were divided into a control and three treatment groups of 21 frogs per group, with normalized weight distribution. The control group received standard daily nutrition of crickets dusted with a supplement containing 342,000 international units (IU) vitamin A/kg. The treatment groups consisted of oral supplementation with crickets dusted with a fortified supplement containing 822,510 IU vitamin A/kg; topical vitamin A palmitate 50 IU every other day; and topical vitamin A palmitate 50 IU once a week. After 30 days, all frogs were euthanized, and 12 frogs from each group were analyzed for whole-body vitamin A levels. The control and treatment groups 1, 2, and 3 had average whole-body vitamin A levels of 1371.4 IU/kg (SE 284.4), 908.7 IU/kg (SE 186.5), 6385.9 IU/kg (SE 675.9), and 3521.8 IU/kg (SE 575.1), respectively. These results suggest that oral supplementation using a product high in vitamin A may be ineffective at raising whole-body vitamin A levels above those achieved with standard nutrition. Topical administration of vitamin A on an every other day and once a week dosing schedule achieved levels 4.5- and 2.5-fold higher than standard nutrition, respectively. PMID- 20945644 TI - Ophthalmic examination findings in a captive colony of western gray kangaroos (Macropus fuliginosus). AB - Complete ophthalmic examination of a mob of western gray kangaroos (Macropus fuliginosus) was performed under chemical restraint. Examination included intraocular pressure (IOP) measurement by rebound and applanation tonometry, fluorescein staining, corneal diameter measurement, slit-lamp biomicroscopy and indirect funduscopy. The corneal diameters had a mean of 19.52 mm, SD 2.16 mm, 95% confidence interval (CI) 18.71-20.32 mm. Ocular abnormalities were noted in 4/8 (50%) of examined kangaroos. Intraocular pressure as estimated by rebound tonometry was 9.00 mm Hg with a 25-75% quartile range of 6.5-10.75 mm Hg and a minimum-maximum range of 5.00-23.00 mm Hg. Intraocular pressure as estimated by applanation tonometry was 11.50 mm Hg with a 25-75% quartile range of 10.00-17.00 mm Hg and a minimum-maximum range of 9.00-20.00 mm Hg. This is the first report of ocular examination findings in a mob of captive western gray kangaroos and provides ranges and values for tonometry and corneal diameter. PMID- 20945645 TI - First seropositive cases of Coxiella burnetii in red deer populations in the southwest Iberian peninsula. AB - The aim of this study was to evaluate the seroprevalence of Coxiella burnetii in different red deer populations and to investigate role of red deer densities, livestock, and habitat on seroprevalence. The serosurvey revealed 5 positive cases out of 137 sera (3.64%) that occurred in two of the three study areas. This study documents the first cases of Coxiella burnetii in red deer in the southwest Iberian peninsula. A relationship between deer density and Coxiella seroprevalence was not found. Results revealed that indirect transmission through ticks between livestock and red deer might be associated with higher prevalence. The timing of shelter area usage may influence the contact between ticks and red deer by favoring transmission. Coxiella burnetii in red deer may be associated with infertility or early abortions with reabsorption. Further research is needed to evaluate its epidemiology and effect on the disease dynamics of red deer in the southwest Iberian peninsula. PMID- 20945646 TI - Surveillance of rabies prevalence and bite protocols in captive mammals in American zoos. AB - A national survey questionnaire was conducted in 32 zoos throughout 17 U.S. states between February and May 2008. The questionnaire consisted of six questions that evaluated rabies prevalence on zoo grounds; captive mammalian bites among zoo visitors and personnel; and the outcome of each incident. The survey was completed by zoo staff after review of their most recent bite incident reports. Rabies was documented, albeit minimally, on zoo grounds in both wild and collection animals. The information collected documented that mammalian bites occur commonly. An average of 9.1 bite incidents per zoo involving zoo visitors were reported in the last 5 yr, compared to an average of 7.5 bite incidents per zoo involving personnel within the last 5 yr. Zoo personnel had a larger variety of mammals inflicting bites of greater injury severity, with an average rating 3.83 out of 5. While victim profile and severity of the wound differed between visitor and personnel bites, the majority of bites were not reported to the local health department. Lack of reporting may be due to low rabies risk, fear of media involvement, and an unknown conclusion for the offending animal. Animals involved in reported attacks had an average quarantine of 47.5 days when the bite involved a zoo visitor versus an average quarantine of 18 days when the bite involved personnel. These results demonstrate the need for a standardized protocol following a bite incident, including cooperation with the local health department, as necessary. PMID- 20945647 TI - Cross matching of blood in carcharhiniform, lamniform, and orectolobiform sharks. AB - The transfusion of whole blood in elasmobranchs could provide cardiovascular support following hemorrhage. Since donor and recipient compatibility is not known, a technique was established to allow cross matching of red blood cells and serum in sharks. Cross matching was carried out among 19 individuals from seven species: the nurse shark (Ginglymostoma cirratum), sandbar shark (Carcharhinus plumbeus), sandtiger shark (Carcharias taurus), white-spotted bamboo shark (Chiloscyllium plagiosum), brown-banded bamboo shark (Chiloscyllium punctatum), zebra shark (Stegostoma fasciatum), and spotted wobbegong (Orectolobus maculatus). Negative cross-matches showed no agglutination or hemolysis, suggesting that donor and recipient would be compatible. Cross-matches between conspecifics were all negative (sandbar, sandtiger, nurse, and white-spotted bamboo sharks). All cross-matches between sandbar and sandtiger sharks were also negative. Positive crossmatches consisted of agglutination or hemolysis of red blood cells, suggesting that the donor and recipient would be incompatible. Strong positive reactions occurred, for example, with red blood cells from sandtiger and sandbar sharks and serum from nurse sharks. Cross matching should be carried out in elasmobranchs prior to any blood transfusion. PMID- 20945648 TI - Effects of compounding on pharmacokinetics of itraconazole in black-footed penguins (Spheniscus demersus). AB - Itraconazole is used to treat and prevent aspergillosis in captive penguin colonies. Although commercial formulations of itraconazole are available, compounding is sometimes performed to decrease cost or to provide a different concentration of the drug. Using a two-way crossover design, the pharmacokinetics of both a commercially available oral itraconazole solution and a compounded oral itraconazole solution were compared in six black-footed penguins (Spheniscus demersus). Each itraconazole formulation was administered orally in frozen-thawed capelin at 7 mg/kg. Plasma itraconazole concentrations at time 0 (pretreatment), 20 and 40 min post-drug administration, and 1, 2, 4, 6, 8, and 12 hr post-drug administration were determined using reverse-phase high-performance liquid chromatography. Drug concentrations were analyzed using standard pharmacokinetic methods. Plasma clearance of the commercial itraconazole solution was more rapid than the clearance published for other species, possibly warranting more frequent dosing in black-footed penguins. Absorption of itraconazole, as determined by peak concentration and area under the curve, was significantly higher for the commercial formulation when compared to the compounded formulation, likely as a result of the presence of cyclodextrin, a carrier compound shown to improve oral absorption, in the commercial formulation. Extrapolating dosing regimens for compounded itraconazole formulations from regimens determined for commercial formulations warrants caution as a result of the significant differences in pharmacokinetics. PMID- 20945649 TI - Generalized demodecosis in three sibling, juvenile rock hyraxes (Procavia capensis). AB - One female and two male 4-mo-old, sibling rock hyraxes (Procavia capensis) presented with severe generalized dermatitis characterized by nonpruritic, nonalopecic, mildly encrusted, focally, ulcerated pustular nodules. The dorsum, limbs, and dorsal cranium were most severely affected. Skin scrapings, histopathology, and scanning electron microscopy revealed the presence of various life stages of a novel Demodex sp. As a result of the generalized nature of infestation, treatment began with ivermectin and then changed to doramectin, at a dose of 0.6 mg/kg s.c. every 7 days. Weekly skin scrapings and intermittent blood work, including serum protein electrophoresis, were used to evaluate treatment response. Complete resolution, as determined by two consecutive negative skin scrapings, was noted in all three hyraxes within 10-14 wk. PMID- 20945650 TI - Cystoscopic guided removal of ectopic eggs from the urinary bladder of the Florida cooter turtle (Pseudemys floridana floridana). AB - Three gravid, female, wild Florida cooter turtles (Pseudemys floridana floridana) were evaluated and treated by the North Carolina State University College of Veterinary Medicine Turtle Rescue Team as a result of traumatic injuries or infection. As part of medical management, oviposition was induced using oxytocin, which was only partially effective. In all three cases, ectopic eggs were subsequently identified in the urinary bladder by ultrasound and were successfully removed via a minimally invasive cystoscopic-guided technique. One of the three turtles died within several days of the procedure, and necropsy revealed granulomatous bacterial cystitis. It is hypothesized that these complications were likely due to the length of time between induction with oxytocin and the identification and removal of the ectopic egg. PMID- 20945651 TI - Epizootic hemorrhagic disease outbreak in a captive facility housing white-tailed deer (Odocoileus virginianus), bison (Bison bison), elk (Cervus elaphus), cattle (Bos taurus), and goats (Capra hircus) in Colorado, U.S.A. AB - An ungulate research facility in Fort Collins, Colorado, U.S.A., experienced mortality in white-tailed deer (Odocoileus virginianus) because of epizootic hemorrhagic disease virus (EHDV) infection from 20 August 2007 through 26 September 2007. Epizootic hemorrhagic disease virus (EHDV) was detected by reverse transcriptase polymerase chain reaction and virus isolation from the spleen and lung tissues of two white-tailed deer. Virus neutralization tests were performed on pre- and postoutbreak sera from other species maintained in the same facility, including bison (Bison bison), elk (Cervus elaphus), domestic cattle (Bos taurus), and domestic goats (Capra hircus), as well as postoutbreak sera from the surviving white-tailed deer. Serum samples that represented all species in the facility neutralized EHDV-1 and EHDV-2 either before or after the outbreak. The animals that neutralized EHDV-1 did not neutralize EHDV-2. No clinical signs attributable to EHDV infection were noted in any of the species other than the deer during the outbreak. Although experimental EHDV infections have been reported in bison and elk, natural exposures have not been previously documented in these species in North America. The roles that elk, bison, cattle, and goats might play in the epidemiology of EHDV in a close-contact multispecies situation remain unknown. PMID- 20945652 TI - Ultrasound-guided vascular catheterization in loggerhead sea turtles (Caretta caretta). AB - In this study, the authors describe a simple, nontraumatic procedure for ultrasound-guided placement and maintenance ofjugular and cephalic vein catheterization. The ultrasound scans were performed with a GE Logiq 400 machine connected to a multifrequency (7-11 MHz) linear-array transducer. To find the cephalic vein, longitudinal and transverse color-Doppler ultrasonographic scans were made of the dorsal surface of the flipper. To find the jugular vein, scans of the midline of the lateral surface of the neck were performed. Once the vein had been located, a 16- to 22-gauge 51-mm needle catheter was inserted into the skin beneath the ultrasound probe, inclined at 15-25 degrees to the skin surface. The successful insertion of the catheter inside the vein was monitored by ultrasound. The authors believe that the procedure described offers a good option for fashioning a simple, nontraumatic, and durable vascular access in sea turtles compared with previously described techniques. Caretta caretta, cephalic vein, jugular vein, ultrasonography, vascular catheterization. PMID- 20945653 TI - Gastroesophageal intussusception in a leopard (Panthera pardus). AB - An 8-yr-old male leopard (Panthera pardus) was presented with a 4-day history of lethargy, vomiting, and anorexia. Thoracic and abdominal radiographs revealed a soft-tissue mass cranial to the diaphragm and atypical appearance of the gastric fundus. Esophagoscopy revealed gastric mucosa in the lumen of the esophagus, which confirmed gastroesophageal intussusception. An exploratory celiotomy with manual reduction of the intussusception was performed. Reduction was verified by intraoperative esophagoscopy and gastroscopy. An incisional fundic gastropexy to the left abdominal wall was performed to reduce the chance of a recurrence of the intussusception. No postoperative complications related to the surgery were observed, and the animal resumed eating within 48 hr of surgery. A subsequent recurrence of clinical signs was not noted by the owner. PMID- 20945654 TI - Successful treatment of acute systemic anaphylaxis in a western lowland gorilla (Gorilla gorilla gorilla). AB - This brief communication describes the successful treatment of acute systemic anaphylaxis in a wild-born but captive infant western lowland gorilla (Gorilla gorilla gorilla) in the Republic of Congo. The infant demonstrated signs of acute respiratory distress, lingual swelling, and reaction to intradermal tuberculin, given 55 hr earlier. Details of the treatment with steroids, anesthetic induction, and i.v. epinephrine are all reported, and potential antigens that may have initiated the anaphylactic shock are discussed. PMID- 20945655 TI - Staphylococcus aureus mastitis in a white-eared opossum (Didelphis albiventris) in the Atlantic Forest of northeast Brazil. AB - This is the first brief communication of clinical mastitis caused by Staphylococcus aureus occurring in a white-eared opossum (Didelphis albiventris) captured in a remnant of the Atlantic Forest in northeast Brazil. The bacterium was cultured from a milk sample by using sheep blood and Levine agars. Phenotyping of S aureus was performed with coagulase biochemical tests, DNase agar, mannitol agar, and anaerobic glucose and mannitol fermentation. PMID- 20945656 TI - Lafora's-like disease in a fennec fox (Vulpes zerda). AB - A 6-yr-old captive-born female fennec fox (Vulpes zerda) had a history of multiple seizures and was treated with diazepam and phenobarbital therapy. Despite medical treatment, the seizures continued. They were intermittent and progressive, resulting in neurologic deficits and death of the animal within 6 mo of onset of the clinical signs. At necropsy, the animal was in good nutritional condition, and no gross lesions were noted in the brain. Histologically, amphophilic to basophilic, periodic acid-Schiff (PAS) positive, diastase resistant inclusions were present in the brain, heart, and liver. Ultrastructurally, the inclusions were variably electron dense, fibrillary to occasionally granular, and non-membrane bound. The clinical, histologic, and ultrastructural findings were consistent with Lafora's disease, which in humans is a rare, fatal, autosomal recessive hereditary neurometabolic disorder characterized by progressive myoclonic epilepsy. This is the first report of Lafora's-like disease in a fennec fox. PMID- 20945657 TI - Application of the laryngeal mask airway for anesthesia in three chimpanzees and one gibbon. AB - Three pediatric chimpanzees and one pediatric gibbon were anesthetized for routine physical examination. Anesthesia was maintained with inhalant delivered via a laryngeal mask airway (LMA). The LMA was easy to insert, provided adequate control of the airway for ventilation, and caused no tracheal stimulation. No complications were observed. As compared with a face mask, the LMA has the advantage of a more secure airway; the ability to effectively ventilate the patient; less dead space, which leads to lower rebreathing of carbon dioxide; and less exposure of personnel to waste gases. As compared with an endotracheal tube, the LMA causes less airway trauma, is easier to place, and is less stimulating to the patient. The LMA should be considered for use in fasted non-human primates presented for procedures lasting less than 60 min where high peak inspiratory pressures are not needed. PMID- 20945658 TI - Pituitary cystadenoma, enterolipidosis, and cutaneous mycosis in an Everglades ratsnake (Elaphe obsoleta rossalleni). AB - An 11-yr-old captive-born male Everglades ratsnake (Elaphe obsoleta rosalleni) presented with dysecdysis, hyperkeratosis, and inappetance. Two skin biopsies demonstrated a diffuse hyperkeratosis with both a bacterial and fungal epidermitis. Fusarium oxysporum was cultured from both biopsies and considered an opportunistic infection rather than a primary pathogen. Medical management was unsuccessful, and the snake was euthanized. Histologic findings included a pituitary cystadenoma arising from the pars intermedia, severe intestinal lipidosis, generalized epidermal hyperkeratosis, and lesions consistent with sepsis. It is hypothesized that endocrine derangements from the pituitary tumor may have caused the skin and intestinal lesions. PMID- 20945659 TI - Vasculitis secondary to presumptive leptospirosis treated with long-term corticosteroids in a captive lesser kudu (Tragelaphus imberbis australis). AB - A 2-yr-old female lesser kudu (Tragelaphus imberbis australis) was presented for lethargy. Empirical antibiotic treatment appeared to improve its clinical signs, although no etiology for the symptoms was determined. The kudu again presented with lethargy, diffusely swollen limbs, and subcutaneous ecchymoses of 1 day's duration after completion of the initial therapy. Vasculitis secondary to presumptive leptospirosis infection was diagnosed based on a skin biopsy and decreasing paired serologic titers for Leptospira grippotyphosa. The vasculitis was responsive to intramuscular antibiotic therapy and dexamethasone treatment. This case provides evidence that corticosteroids can be used in ruminants at moderate doses for chronic treatment without clinically relevant detrimental effects. PMID- 20945660 TI - Diagnosis and treatment of vitiligo in a sub-adult eastern black rhinoceros (Diceros bicornis michaeli). AB - A captive-born female sub-adult Eastern black rhinoceros (Diceros bicornis michaeli) developed areas of non-ulcerated, non-pruritic depigmentation around the nares at 2 yr of age. Over the subsequent 18 mo, the symmetrical multifocal depigmented macules increased in size and distribution to include facial fold crypts, interdigital skin, lips, nares, palmar carpi, ventral abdomen, ventral mandible, axillae, lateral brachium and antebrachium, lateral thighs, ventral tail, and perineal region with an estimated 15% of the skin affected. Facial fold skin biopsies revealed multifocal hypopigmentation with melanin incontinence and mild perivascular lymphohistiocytic dermatitis. The gross appearance and histologic lesions were consistent with vitiligo. Treatment with UV-B narrowband phototherapy was performed on the lateral thighs, lateral elbows, palmar carpi, and rostral maxilla for a period of 12 mo. Significant repigmentation of the treatment areas was achieved. PMID- 20945661 TI - Granulomatous pneumonia in a captive freshwater crocodile (Crocodylus johnstoni) caused by Mycobacterium szulgai. AB - A 25-yr-old male freshwater crocodile (Crocodylus johnstoni) was diagnosed with pulmonary mycobacteriosis caused by Mycobacterium szulgai. Necropsy revealed fibrinous exudate in the right pleural cavity and white miliary nodules in the right lung lobe. Histopathologic examination revealed well-demarcated granulomas consisting of multinucleated giant cells and epithelioid cells surrounded by fibrous connective tissue. Atypically, lymphocytes had accumulated in the outer region of fibrous connective tissue. Mycobacterial infection was confirmed by nested polymerase chain reaction targeting the hsp65 gene and by Fite's method for detection of acid-fast bacilli within formalin-fixed, paraffin-embedded lung tissue. Sequence analysis of the DNA amplicon revealed that the species of mycobacterium shared 98% homology with the gene encoding the hsp65 gene of M. szulgai. This is the first report of M. szulgai as the causative agent of mycobacteriosis in a reptile. PMID- 20945662 TI - Elodontoma in captive southern red-backed voles (Myodes gapperi). AB - Five southern red-backed voles (Myodes gapperi) of the first generation of a wild caught breeding colony were presented with lesions at the maxillary incisors consistent with elodontoma. The affected animals had a history of chronic weight loss, were >16 months of age, and were siblings. Radiographs of the head showed multiglobular to irregularly outlined mineral opacity masses at the apices of the maxillary incisors. On necropsy, maxillary incisor teeth were not grossly visible, and a gingival ulceration was observed at the expected site of eruption. Microscopically, the apical region of the maxillary incisors was thickened or replaced by irregular dental tissue masses consistent with elodontoma. This is the first report to describe elodontoma in red-backed voles. PMID- 20945663 TI - Surgical repair of a cleft palate in an American bison (Bison bison). AB - A 4-mo-old bison (Bison bison) was evaluated and treated at a university veterinary hospital for a cleft defect in the hard and soft palate. Using a mandibular symphysiotomy approach, the palatal defect was repaired with a Z plasty pattern in the soft palate and mucoperiosteal flaps in the hard palate. A small area of dehiscence in the rostral aspect of the hard palate, and aspiration pneumonia, were complications, but the bison calf recovered with medical management. Even though this surgical procedure has a high potential for complications, the described technique allowed return to normal feeding and resolution of the aspiration pneumonia by 14 mo postsurgery. PMID- 20945664 TI - Comparison of thiafenantil-xylazine and carfentanil-xylazine for immobilization of gemsbok (Oryx gazella). AB - This study compared immobilization of gemsbok (Oryx gazella) using thiafentanil xylazine (TX) versus carfentanil-xylazine (CX). Twelve adult gemsboks were divided into two groups, TX and CX. Each group received either 6 mg thiafentanil (0.036 microg/kg (0.032-0.040 microg/kg) and 20 mg xylazine (TX) or 3.6 mg carfentanil (0.021 mg/kg [DOSAGE ERROR CORRECTED] (0.017-0.024 mg/kg) [DOSAGE ERROR CORRECTED] and 20 mg xylazine (CX). Once handled, physiologic measurements were taken every 5 min for 20 min. There were few physiologic differences between the groups, although TX gemsboks were more hypertensive. Quality of induction, quality of recovery, depth of anesthesia, and muscle relaxation were subjectively assessed. Although TX gemsboks showed a trend for more-rapid induction and recovery postantagonist administration, this difference was not statistically significant. Similarly, there was a trend for TX animals to have smoother inductions and improved immobilization quality, but only the quality of induction was significantly different. These trends suggest that TX is preferable to CX when anesthetizing adult gemsboks. PMID- 20945665 TI - Seroprevalence of Toxoplasma gondhi antibodies in captive wild mammals and birds in Brazil. AB - In this study, serum samples of 203 animals from different locations, from zoos and breeding facilities from the north and northeast regions of Brazil, were analyzed for the presence of anti-Toxoplasma gondii antibodies by the modified agglutination test (MAT) with a cutoff of 1:25. Of the sampled animals, 184 were adult mammals of both sexes and 19 were birds. Antibodies were found in 61 of 184 mammals, and no association between sex and age of the animals and the presence of T. gondii antibodies was observed (P < 0.05). Anti-T gondii antibodies were not found in birds. Toxoplasma gondii was detected in Brazilian tapir (Tapirus terrestris) for the first time. PMID- 20945666 TI - When oncology nurses are just a call away. PMID- 20945667 TI - Telephone triage. Interview by Jennifer K Mitchell. AB - As the care of patients with cancer has shifted from the inpatient arena to the outpatient setting, the traditional role of outpatient oncology nurses has also changed. Outpatient oncology nurses must not only be knowledgeable about disease processes and care of patients in the clinic, but they must also be skilled in telephone nursing triage. PMID- 20945668 TI - What resources do you use for telephone nursing triage? PMID- 20945669 TI - Nursing's role in the management of healthcare-associated infections. PMID- 20945670 TI - Strategies for breaking bad news to patients with cancer. PMID- 20945671 TI - ACSM releases new guidelines for physical activity for patients with cancer. PMID- 20945672 TI - Is children's universal access to dental coverage just around the corner? PMID- 20945675 TI - The ABCDiet program: evaluation of project outcomes. PMID- 20945676 TI - Implementing the ABCDiet program: a school nurse's perspective. PMID- 20945677 TI - Minority nurse educators. Thomas Edison State College School of Nursing launches nation's first free online database of minority nurse educators. PMID- 20945678 TI - Why we screen children's vision in school. PMID- 20945679 TI - Helping students cope with diabetes: the role of the school nurse. PMID- 20945680 TI - My view: Give Kids a Smile. Where did we go wrong? PMID- 20945681 TI - My view: Give Kids a Smile. Success! PMID- 20945682 TI - My view: Give Kids a Smile. A model worth trying. PMID- 20945683 TI - Born to smile. PMID- 20945684 TI - They don't teach THAT in dental school! PMID- 20945685 TI - Oral cancer awareness. PMID- 20945686 TI - The assessment of nursing caries and its relationship to high caries in the permanent dentition. 1992. PMID- 20945687 TI - The "bone-less" bone graft: The use of bone morphogenic protein-2 in jaw reconstruction. AB - A growth factor known as Bone Morphogenic Protein has through recombinant technology been made available to dentists as a "bone-less" bone graft. This recombinant human bone morphogenic protein-2 is placed on an absorbable collagen sponge carrier and delivered to a site of bone deficiency. This material will induce new osteoblasts to form from mesenchymal stem cells in the surrounding recipient site. This eliminates the need for an autogenous bone graft and its inherent surgical morbidity. The new bone formed is of the same quality and quantity as that produced by autogenous grafting. Dentists should be familiar with alternative techniques of bone grafting in contemporary practice. PMID- 20945688 TI - Meet your new IDA President, Dr. Martin R. Szakaly. Interview by Kelly Jones Sharp. PMID- 20945689 TI - Mirror, mirror: Remaining true to our patients, our profession AND ourselves. PMID- 20945690 TI - Smilematters. Patient fact sheet: Want a healthy body? Start with a healthy mouth! PMID- 20945691 TI - Getting the word out. PMID- 20945692 TI - Debt collection practices: what's legal? What isn't? PMID- 20945693 TI - The ADA unveils a strong, new strategic plan. PMID- 20945694 TI - My pay records are being audited! Is my hygienist to blame? PMID- 20945695 TI - Reporting suspected adult abuse. PMID- 20945696 TI - The CLASS Act: the government's new long-term care program. PMID- 20945697 TI - Nicely done! The power of genuine compliments. PMID- 20945698 TI - New MDA TV ads are on the air! Four new commercials emphasize dental appointments, MDA members. PMID- 20945699 TI - UDM School of Dentistry: back to basics. PMID- 20945700 TI - U-M School of Dentistry: new and exciting changes. PMID- 20945701 TI - General dentists and periodontal referrals. AB - Questionnaire data were collected from 160 MDA members. The data showed that 16 percent of the respondents had not made a periodontal referral during the last month, 67 percent had made one to five referrals, 7 percent between six and 10 referrals, and 10 percent referred more than 10 patients. The number of referrals did not differ as a function of patients' disease characteristics or dentists' periodontal treatment patterns. They were affected by considerations of practice characteristics and patient's oral hygiene efforts. In conclusion, general dentists differ greatly in the number of periodontal referrals they make. Referral frequencies were not affected by diagnostic considerations or treatment patterns. PMID- 20945702 TI - Osteochondritis dissecans of the elbow. PMID- 20945703 TI - Clinically-relevant anatomy and physical examination of the persistently painful shoulder. PMID- 20945704 TI - Shoulder instability in the young athlete. AB - Shoulder instability is common in young athletes due to acute and repetitive trauma, as well as overuse in athletes with generalized ligamentous laxity. In overhead athletes, instability may present as impingement or rotator cuff tenderness. Fortunately, most symptomatic instability can be treatedwith rehabilitation. In athletes with recurrent symptomatic instability despite conservative treatment, surgical stabilization can restore function and allow return to sport. PMID- 20945705 TI - Essential knee examination. PMID- 20945706 TI - Knee injuries in athletes. PMID- 20945707 TI - Vitamin D: extent of deficiency, effect on muscle function, bone health, performance, and injury prevention. AB - Vitamin D deficiencyis increasingly being identified in children, adolescents, and adults. Primary production of the active form of vitamin D occurs via a photolytic reaction induced by ultraviolet radiation B. Vitamin D has important effects on bone and muscle as well as on the immune system. Isolation ofa vitamin D receptor on muscle cells has been accompanied by studies showing receptor polymorphisms and age-related functional changeswhich have an effect on muscle performance. Insufficient levels havebeen associated with increased risk of stress fractures, decreased muscle performance, and increased sick days. Although there is still debate about the appropriate levels of vitamin D, studies have suggested a minimal level of 32 ng/ml. Supplementation serves as an inexpensive option associated with reduction in both morbidity and financial costs. PMID- 20945708 TI - Rowing injuries. PMID- 20945709 TI - How physicians are managing concussions in Connecticut. PMID- 20945710 TI - Sports: a positive cultural force. PMID- 20945711 TI - The Committee on the Medical Aspects of Sports. PMID- 20945713 TI - The game. PMID- 20945712 TI - Broken necks: a study of their present-day mortality and other pertinent data. 1960. PMID- 20945714 TI - A sporting challenge. PMID- 20945716 TI - Playing safe. PMID- 20945715 TI - 21,528 miles and counting. PMID- 20945717 TI - Iron supplements. PMID- 20945718 TI - Comments on 'The worst doctor in the worst clinic'. PMID- 20945719 TI - 'The flu'. PMID- 20945720 TI - Seasonal influenza in primary care settings: review for primary care physicians. AB - CONTEXT: Influenza is a common and significant respiratory pathogen in primary medical care. Better understanding of influenza epidemiology, clinical characteristics, prevention, and management is essential for effective ambulatory care. EVIDENCE ACQUISITION: Review of the current literature was performed through PubMed queries and based on the authors' background and experience with influenza. In addition, summary data were presented from existing surveillance of influenza in Wisconsin. RESULTS: Seasonal influenza presents in annual epidemics with significant features of fever and cough. Prevention can be achieved through avoidance, influenza vaccine, and chemoprophylaxis. Diagnoses can be made on clinical grounds when appropriately supported by public health surveillance. Other diagnostic methods have limited use in primary care. Antiviral medications can have significant effects on illness course if started early, but may be limited by resistance. CONCLUSIONS: Influenza is commonly prevented, diagnosed, and treated in the primary care arena. A combined approach to influenza response requires background knowledge on influenza epidemiology, prevention, diagnosis, and management, coupled with up-to-date information based on public health surveillance. PMID- 20945721 TI - Epidemiologic and clinical features among patients hospitalized in Wisconsin with 2009 H1N1 influenza A virus infections, April to August 2009. AB - BACKGROUND: During April 15 through July 23, 2009, Wisconsin reported the most confirmed and probable cases of 2009 influenza A (H1N1) virus (2009 H1N1) infection in the United States. Preliminary reports suggest that 2009 H1N1 infection disproportionately affected minority populations. METHODS: Prospective surveillance among all acute care hospitals in Wisconsin to detect patients hospitalized at least 24 hours with confirmed 2009 H1N1 infection during April 23 through August 15, 2009. RESULTS: During the study interval, 252 patients were hospitalized and 11 (4%) died. Statewide hospitalization rates by age, sex, and race/ethnicity categories were highest among patients aged <1 year (21.6/100,000), females (4.9/100,000), and African Americans (36.3/100,000). The median age was 28 years: Hispanics (median age=16 years) and African Americans (24 years) were younger than non-Hispanic whites (37 years) and Asians (38 years). African Americans were more likely to have a hematologic condition and be morbidly obese (BMI > or = 40 kg/m2), and less likely to be admitted to an intensive care unit compared to other race/ethnicity groups (P<0.05). Hispanics and non-Hispanic whites were more likely to have cancer, be non-morbidly obese (BMI 30-39.9 kg/m2 or BMI percentile > or = 95%), and be hospitalized for >5 days compared to African Americans and Asians (P<0.05). There were no significant racial/ethnic differences in time from illness onset to admission or receipt of antiviral therapy, need for mechanical ventilation, acute respiratory distress syndrome, or death. CONCLUSIONS: The first wave of the 2009 H1N1 pandemic in Wisconsin disproportionately affected hospitalized patients who were African Americans, Asians, and Hispanics compared to non-Hispanic whites. Preventive measures focused on these populations may reduce morbidity associated with 2009 H1N1 infection. PMID- 20945722 TI - Influenza-related viral myocarditis. AB - Seasonal influenza outbreak is responsible for significant morbidity and mortality around the world. The disease can be severe, leading to rapid worsening of breathing and culminating in death. The pulmonary manifestations are prominent and may mask the involvement of other organs, such as the heart. This paper will discuss the incidence, clinical manifestations, and management of viral myocarditis in a modest attempt to heighten awareness of acute viral myocarditis for early recognition and prompt management during seasonal episodes of influenza infection. PMID- 20945723 TI - The usefulness of health care databases in Wisconsin for identifying Hmong patients with cancer. AB - OBJECTIVES: The Wisconsin Cancer Reporting System (WCRS) collects data on cancer diagnoses in the state of Wisconsin. California and Minnesota cancer registries have reported that Hmong have higher rates of certain cancers than the general population. WCRS collaborated with the Wisconsin Comprehensive Cancer Control Program (WCCCP) and Wisconsin United Coalition of Mutual Assistance Associations (WUCMAA) to investigate the reporting of cancer cases in the Hmong population by medical facilities. METHODS: WCRS, WCCCP, and WUCMAA conducted a mail survey of facilities in 12 Wisconsin counties where Hmong populations reside. RESULTS: The survey found that <30% of facilities collected Hmong as a demographic category or identified cancer patients as Hmong; most facilities reported Hmong patients only as Asian. A training webcast was developed for facilities to reinforce WCRS reporting requirements and to elucidate the Hmong culture. A pamphlet for Hmong patients was developed to explain the importance of self identification for more racially representative cancer data in Wisconsin. PMID- 20945724 TI - Cardiac computed tomography and quadricuspid aortic valve: a case report. AB - A quadricuspid aortic valve is rare and often incidentally found by echocardiography, surgically, or on post mortem examination. Aortic regurgitation is common and if severe enough can lead to symptoms of dyspnea. We report a case of a quadricuspid aortic valve, which was found by cardiac multidetector computed tomography during a pre-operative assessment for severe aortic regurgitation. PMID- 20945725 TI - 'SWINEUPDATE': Using EMR charting tools as a clinical decision support tool during the H1N1 outbreak. PMID- 20945726 TI - A summer in research on newborn screening. PMID- 20945727 TI - Barriers to research in rural Wisconsin. PMID- 20945728 TI - WHITEC: the Wisconsin Health Information Technology Center. PMID- 20945729 TI - Birthday reflections for family medicine at the University of Wisconsin. PMID- 20945730 TI - Five things every physician needs to know about freebies and discounts. PMID- 20945731 TI - Immortal beloved and beleaguered: towards the integration of the law on assisted death and the scientific pursuit of life extension. PMID- 20945732 TI - President's message. PMID- 20945733 TI - Conflicts of interest in research: is clinical decision-making compromised? An opinion paper. AB - Lack of transparency in funded research can compromise clinical decision-making in an evidence-based practice. Transparency can be defined as full disclosure of all financial assistance and support to authors and investigators. There is a perception that ethical principles are eroding and that research data can be biased due to conflicts of interest. These research outcomes biased or not, are used for clinical decision-making in the evidence-based practice. One suggested solution to this common ethical dilemma is to continue the dialogue on transparency in research and to create oversight bodies which include representatives from business and industry, private practice, academia, and research. There is increasing evidence of the need for more ethics education at all levels. PMID- 20945734 TI - Fluoride varnish: the top choice for professionally applied fluoride. AB - Although various modes of delivery for professionally applied fluoride exist, one form has emerged that combines caries prevention efficacy with safety and versatility. The American Dental Association Council on Scientific Affairs recommends fluoride varnish as the only professionally applied fluoride for moderate to high risk patients of all age groups. In addition to demonstrating effectiveness equivalent to fluoride gels, fluoride varnish provides improved safety and acceptability. Furthermore, fluoride varnish has shown promise in preventing dental caries in special groups, such as orthodontic patients and the elderly. PMID- 20945735 TI - Texas Medicaid...TDA dentists making a difference. PMID- 20945736 TI - Sound advice. How to leverage your telephone's on-hold feature to build loyalty and enhance patient experience. PMID- 20945737 TI - Oral and maxillofacial pathology case of the month. Neurosarcoidosis. PMID- 20945738 TI - Technology--an old guy's view. PMID- 20945740 TI - Clinical comparison of bur- and laser-prepared minimally invasive occlusal resin composite restorations: two-year follow-up. AB - This study evaluated the two-year clinical performance of two minimally invasive cavity preparation techniques, bur and laser, in Class I occlusal resin composite restorations. Twenty-seven patients, each having at least one pair of occlusal caries, were enrolled in this study. For each patient, one of the cavities was prepared with a diamond bur, and the other was prepared with Er, Cr:YSGG laser. The cavities were restored with a nanofilled flowable resin composite, Grandio Flow, using an etch-and-rinse adhesive, Solobond M. A total of 108 restorations were placed in molars by a single operator. The restorations were evaluated according to modified Cvar/Ryge criteria. The evaluations were performed at baseline, 6, 12, 18 and 24 months after initial placement by two calibrated operators. The Chi-square and Fisher's exact test were used for statistical analysis. All the patients were available during all evaluated periods, resulting in a recall rate of 100%. The retention rates of the restorations at 24 months were 98.1% for bur and 100% for the laser-prepared group. After 24 months, 5.6% of the bur-prepared and 7.4% of the laser-prepared restorations were rated Bravo in marginal discoloration (p > 0.05). Bur-prepared (9.3%) and laser-prepared (13%) restorations were rated Bravo in marginal adaptation (p > 0.05). There were no significant differences between the two cavity preparation techniques regarding the evaluated parameters (p > 0.05). Both cavity preparation techniques performed equally, with excellent outcomes after a 24-month period. PMID- 20945739 TI - Rubber dam use during routine operative dentistry procedures: findings from the Dental PBRN. AB - Rubber dam use during operative dentistry procedures has been quantified based on questionnaires completed by dentists. However, based on the knowledge of the authors of the current study, there are no reports based on use during actual clinical procedures other than in dental materials studies and none based on routine care. The objectives of the current study were to: 1) quantify how commonly the rubber dam is used during operative dentistry procedures; 2) test the hypothesis that certain dentist, restoration and patient-level factors are associated with its use. A total of 229 dentist practitioner-investigators in The Dental Practice-Based Research Network (DPBRN) participated. DPBRN comprises five regions of the USA: Alabama/Mississippi, Florida/Georgia, Minnesota, Permanente Dental Associates and Scandinavia. Practitioner-investigators collected data on 9,890 consecutive restorations done in previously unrestored tooth surfaces from 5,810 patients. Most dentists (63%) did not use a rubber dam for any restoration in this study. A rubber dam was used for only 12% of restorations, 83% of which were used in one DPBRN region. With regions accounted for, no other dentist characteristics were significant. A multi-level multiple logistic regression of rubber dam use was done with restoration and patient-level variables modeled simultaneously. In this multi-variable context, these restoration-level characteristics were statistically significant: tooth-arch type, restoration classification and reason for placing the restoration. These patient-level characteristics were statistically significant: ethnicity, dental insurance and age. These results, obtained from actual clinical procedures rather than questionnaires, document a low prevalence of usage of the rubber dam during operative dentistry procedures. Usage varied with certain dentist, restoration and patient-level characteristics. PMID- 20945741 TI - Influence of storage conditions of adhesive vials on dentin bond strength. AB - This study was carried out to examine the effect of storage conditions of adhesive vials on the dentin bond strength of single-step self-etch adhesive systems. The adhesive/resin composite combinations used were: Absolute 2/Ceram.X(AB), Adper Prompt L-Pop/Filtek Supreme(AP), Bond Force/Estelite sigma Quick(BF), Clearfil tri-S Bond/Clearfil AP-X(CT) and G-Bond/Gradia Direct(GB). Vials of adhesives were stored at 5 degrees C, 23 degrees C or 40 degrees C. Specimens for the dentin bond strength tests were made after 0, 1, 2, 3, 4, 5 and 6 months. Labial bovine mandibular incisor dentin was wet ground with #600 SiC. The adhesives were applied according to the manufacturer's instructions. After adhesive light irradiation, resin composite cylinders were created (4 mm x 2 mm) and polymerized (n = 10). Samples were stored in 37 degrees C distilled water for 24 hours, then shear tested at a crosshead speed of 1.0 mm/minute. ANOVA and Dunnet tests were performed at a significance level of 0.05. Scanning electron microscopic (SEM) observations of the dentin surfaces were made. Bond strengths varied, with storage conditions ranging from 2.2 +/- 1.4 to 9.3 +/- 2.4 MPa for AB, 4.5 +/- 1.5 to 13.3 +/- 2.7 MPa for AP, 5.1 +/- 1.9 to 5.1 +/- 1.9 MPa for BF, 7.7 +/- 1.9 to 19.7 +/- 2.0 MPa for CT and 7.4 +/- 1.3 to 15.7 +/- 2.8 MPa for GB. With longer storage periods and higher temperatures, significant decreases in bond strength were found for all the adhesives. From SEM observation, the etching effect of the adhesives was weakened and the remaining smear layer was observed. The data suggests that the storage conditions of adhesive vials significantly affects the bond strengths of single-application self-etch adhesive systems. PMID- 20945742 TI - Activation mode effects on the shear bond strength of dual-cured resin cements. AB - OBJECTIVES: This study evaluated the immediate (10-minute) and delayed (24-hour) bond strength of dual-cured resin cements that are light-activated either immediately or delayed (after five minutes) or chemically-activated only. MATERIALS AND METHODS: Three dual-cured resin cements were evaluated: RelyX ARC, Panavia F and Enforce. Cylinders of resin cement were built up over resin composite blocks following the manufacturers' instructions for each luting agent. The cements were mixed, inserted into the molds and light-activated either immediately or after five minutes (delayed light activation). When no light activation was performed, the materials were protected from light exposure until testing. Half of the samples were tested at 10 minutes; the remaining samples were stored at 100% relative humidity for 24 hours when they were then tested (n = 10). Data were submitted to three-way ANOVA and post-hoc Tukey's tests (alpha = 0.05). The failure mode was evaluated under SEM. RESULTS: RelyX ARC presented the highest values of shear bond strength, followed by Enforce. Panavia F showed the lowest values. Both immediate and delayed light activation caused the cements to present the highest means of shear bond strength. There was an improvement in bond strength after 24 hours of storage. CONCLUSIONS: RelyX ARC produced the highest bond strength, which was improved by light activation and storage for 24 hours. PMID- 20945743 TI - Effect of adhesives and thermocycling on the shear bond strength of a nano composite to coronal and root dentin. AB - OBJECTIVES: To evaluate the effects of "etch & rinse" vs "self-etch" adhesives and thermocycling on the shear bond strength (SBS) of a nano-composite to coronal and root dentin. MATERIALS AND METHODS: FIFTY-SIX EXTRACTED HUMAN MOLARS WERE mounted and ground to expose coronal and root dentin surfaces and were randomly divided into two groups according to adhesive system: SE--a two-step self-etch adhesive (Adper SE Plus, 3M ESPE) and ER-an etch & rinse adhesive (Adper Single Bond 2, 3M ESPE). The adhesives were applied to the coronal and root dentin of the mounted teeth. A nano-composite (Filtek Supreme XT, 3M ESPE) was applied to both dentin surfaces. The bonded specimens were stored in distilled water at 37 degrees C for 24 hours. Half of the bonded specimens were tested for SBS in a universal testing machine without thermocycling. The remaining specimens were thermocycled (500 cycles between 5 degrees C and 55 degrees C) prior to SBS testing. Two specimens from each group were kept for Scanning Electron Microscope evaluations of the adhesive interfaces. Failure modes were determined under a stereomicroscope. The mean SBS value of each group was calculated, and the results were subjected to ANOVA, Duncan test and Paired samples t-test (p = 0.05). RESULTS: Thermocycling did not affect the SBS of coronal dentin for either adhesive. However, it affected the SBS of SE in root dentin (p < 0.05). The two different dentin substrates did not exhibit a significant difference except for higher values in root dentin with the SE group without thermocycling. The greatest number of cohesive failures was observed in root dentin with SE adhesive; however, the failure modes were mainly adhesive for the other groups. CONCLUSION: The SE adhesive exhibited higher SBS values than the ER adhesive in root dentin. Thermocycling did not affect the SBS in coronal dentin for either adhesive but it decreased the SBS of SE in root dentin. PMID- 20945744 TI - Fracture resistance of endodontically-treated teeth: effect of combination bleaching and an antioxidant. AB - This in vitro study assessed the fracture resistance of endodontically-treated teeth undergoing combination bleaching with 38% and 9.5% hydrogen peroxide gels as in-office and at-home bleaching techniques, respectively. In addition, the effect of an antioxidizing agent, sodium ascorbate, was investigated. METHODS AND MATERIALS: Sixty maxillary premolars were endodontically-treated, received a glass ionomer barrier as a mechanical seal and were embedded in acrylic resin up to the cemento-enamel junction. The specimens were divided into four groups (n = 15) as follows: G I: no bleaching, access cavity restored with resin composite (negative control); G II: bleached for three weeks daily using 9.5% hydrogen peroxide for two hours and three sessions of in-office bleaching using 38% hydrogen peroxide every seven days, then restored (positive control); G III: bleached similar to G II and restored after one week; G IV: bleached similar to G II, along with the use of an antioxidizing agent for 24 hours, then restored. In each in-office and at-home bleaching session, the whitening gels were applied to the buccal surface of the tooth and placed inside the pulp chamber (inside/outside bleaching technique). Finally, the specimens underwent fracture resistance testing; the data were analyzed using ANOVA and Scheffe's test (alpha = 0.05). RESULTS: Significant differences were observed among the study groups (p < 0.05). Groups I and II demonstrated the highest and lowest fracture resistance, respectively. The samples that were not bleached (Group I) and the 10% sodium ascorbate gel group (Group IV) demonstrated significantly higher fracture resistance than the positive control group (p < 0.05). No significant differences were found between Groups III and II (p > 0.05). CONCLUSION: Within the limitations of the current study, it can be concluded that the fracture resistance of endodontically-treated teeth decreases after combination bleaching. The use of sodium ascorbate can reverse decreased fracture resistance. PMID- 20945745 TI - Removal of enamel caries with an air abrasion powder. AB - This study compared the efficiency of air abrasion on enamel caries with selective enamel powder (SEP) or with alumina powder and a negative and positive control group. Ninety-three extracted molars with non-cavitated incipient enamel lesions were selected. After embedding the roots in resin, each lesion was sectioned perpendicular to the surface and photographed. Each lesion was classified microscopically as having or not having dentin involvement. The lesions were distributed into four groups with an equal number of enamel caries with or without dentin involvement. Each group was treated differently: Group 1 had SEP abrasion, Group 2 had alumina abrasion, Group 3 had sodium bicarbonate abrasion (negative control) and Group 4 had bur treatment (positive control). The surface was rephotographed after treatment. Superimposition of the photographs identified areas of "correct-excavation," "under-excavation" and "over excavation." There were no statistical differences between lesions treated with or without dentin involvement for Groups 2 through 4. However, in the SEP group, all measured areas were significantly influenced by dentin involvement. In pairwise comparisons, no statistical differences were found between the alumina and bur groups. The SEP group, however, showed statistically significant differences for each area compared to the alumina group in enamel caries without dentin involvement. SEP performed as well as alumina and bur in lesions with dentin involvement. SEP is different in its ablative properties toward caries with dentin involvement or no dentin involvement. In terms of dental treatment, SEP seems to have a diagnostic potential for enamel lesions before operative intervention in patients with high caries risk. PMID- 20945746 TI - Microtensile bond strength of one- and two-step self-etching adhesives on sclerotic dentin: the effects of thermocycling. AB - This study evaluated the effects of thermocycling on the microtensile bond strength (microTBS) of one- and two-step self-etch adhesives (SEAs) to sclerotic dentin. Two adhesives, Clearfil S3 Bond (S3), a one-step self-etch adhesive (1 SEA), and Clearfil SE Bond (SE), a two-step self-etch adhesive (2-SEA), were applied on cervical lesions in human premolars with sclerotic or normal dentin. After adhesive application, the lesions were restored and built up using a resin composite (Clearfil AP-X). After 24 hours in water storage, the restored teeth were sectioned into 0.7 x 0.7 mm composite-dentin beams. The beams were then aged with 0, 5,000 or 10,000 thermocycles. The use of two adhesives, two substrate types and three thermocycling regimens yielded 12 experimental groups of 14-19 beams each. The beams were subsequently subjected to microTBS testing at a crosshead speed of 1 mm/minute and statistical analyses were computed with three way ANOVA and Tukey's post hoc test at p < 0.05. Three-way ANOVA showed statistically significant effects on bonding effectiveness by lesion type, adhesive system, thermocycling or combinations of the adhesive system and thermocycling (p < 0.05). With sclerotic dentin, although S3 and SE provided comparable microTBS after 24 hours of water storage, S3 showed significantly lower microTBS than SE after thermocycling (p < 0.05). Regardless of lesion type, the microTBS for S3 decreased significantly after 5,000 or 10,000 thermocycles, while the microTBS for SE showed a significant decrease only after 10,000 thermocycles. Regardless of the extent of thermocycling, the microTBS values for either SE or S3 bonded to sclerotic dentin were significantly lower than to normal dentin (p < 0.05). The results suggested that thermocycling had a significant negative effect on the bond strength of the two SEAs tested. In contrast to 2-SEA, 1-SEA might not be a good choice for sclerotic dentin when seeking durability of the resin-dentin bond. PMID- 20945747 TI - Microleakage of posterior composite restorations lined with self-adhesive resin cements. AB - PURPOSE: This study determined the microleakage of Class II composite restorations lined with self-adhesive resin-cements as bonding agents. METHODS: Forty-five caries-free extracted molars were sterilized, mounted in acrylic bases and divided into five equal groups according to the adhesive used: RXU (RelyX Unicem, self-adhesive resin-cement, 3M ESPE), BRZ (Breeze, self-adhesive resin cement, Pentron Clinical Technologies), MON (Monocem, self-adhesive resin-cement, Shofu), PAN (Panavia-F-2.0, resin-cement with self-etch primer, Kuraray) and SBMP (Scotchbond Multi-Purpose, total-etch three-step adhesive, 3M ESPE). Class II MOD cavities were prepared with gingival floors located on dentin at one side and on enamel on the other. The bonding agent SBMP, used according to the manufacturer's directions, or a thin layer of resin cement, was applied on all cavity walls and cavosurface margins. Filtek Z250 (3M ESPE) was used to restore cavities in all groups. The specimens were subjected to 1,000 thermocycles between 5 degrees C and 55 degrees C. All tooth surfaces were sealed with nail-varnish to within 1 mm from the restoration margins. The specimens were immersed in 2% fuchsine red solution for 24 hours at 37 degrees C. The teeth were then sectioned mesiodistally and dye penetration was assessed according to a five-point scale. Data were statistically analyzed with the Chi-square test (p < 0.05). RESULTS: Microleakage scores revealed that, on enamel margins, the SBMP group had significantly less microleakage than the RXU and BRZ groups, which, in turn, had significantly less microleakage than the MON and PAN groups; whereas on dentin margins, the RXU and BRZ groups had significantly less microleakage than the SBMP, MON and PAN groups. CONCLUSIONS: This in-vitro study showed that, when two self-adhesive resin-cements (RXU & BRZ) were used as liners in Class II composite restorations, they resulted in low microleakage scores as compared to the two other cements at both the enamel and dentin cavosurface margins. PMID- 20945748 TI - In vitro detection of secondary caries associated with composite restorations on approximal surfaces using laser fluorescence. AB - This study evaluated the performance of the DIAGNOdent pen laser fluorescence device (LFpen) in comparison with visual examination (VE), bitewing radiographs (BW) and visual examination combined with bitewing radiographs (VEBW) in detecting secondary approximal caries associated with composite restorations. In total, 60 approximal surfaces from 43 permanent molars with composite restorations were assessed twice by two examiners using the LFpen, VE, BW and VEBW. After histological preparation and hardness measurements, the sample was assigned to either a crown or root caries group, depending on the location of the lesions as the gold standard. For crown caries at D1, the highest values of specificity and sensitivity were observed for the LFpen at a cutoff value of 18 (1.00) and for the VEBW (0.89). At D3 (cutoff of 30), the LFpen showed the highest values of sensitivity and specificity. For root caries, the LFpen and VEBW showed the highest values of specificity (0.54), sensitivity (0.81) and accuracy (0.69). The Spearman rank correlation coefficients for crown/root caries with histology were 0.54/0.37 (LFpen), 0.29/0.10 (BW), 0.29/0.18 (VE) and 0.23/0.37 (VEBW). For the LFpen, the ICC varied from 0.80 (interexaminer) to 0.97 (intraexaminer B); the kappa value was 0.19 for BW and 0.35 for VE (interexaminer). Intraexaminer kappa values for BW were 0.25 (A) and 0.29 (B), and those for VE were 0.31 (A) and 0.32 (B). The LFpen device exhibited a performance comparable to that of conventional methods but with higher interexaminer reproducibility. Therefore, the LFpen should be considered an auxiliary method for the detection of secondary approximal caries associated with composite restorations. PMID- 20945749 TI - The influence of bonding agents on the decision to replace composite restorations. AB - This in vitro study evaluated the validity of the decision to replace of a restoration based upon the radiolucent zone beneath a resin composite. MATERIALS AND METHODS: Class II cavities were prepared on the approximal surfaces of 40 molars. The teeth were divided into four groups. Clearfil SE Bond, PQ1 or Single Bond was applied in the experimental groups. No bonding agent was used in the control group. Following the restorations, digital radiographs were obtained and independently evaluated by two oral radiologists and two specialists in restorative dentistry to determine the need for replacement. The coronal portions of the teeth were then sectioned and the interfaces between the restorations and cavity walls were examined using an optical light microscope. Possible adhesive pooling and voids were examined under a light microscope. Inter-examiner reliability was evaluated with the Cohen's kappa (kappa) test. Sensitivity, specificity and negative and positive predictive values were calculated. Kruskal Wallis, followed by the Mann-Whitney U-test, determined differences among the pooling thicknesses of the different adhesives. RESULTS: Various sensitivity and specificity degrees were obtained from the groups in which different adhesive systems were used. The PQ1 adhesive system was the best for identifying well adapted restorations with the highest true non-replacement diagnosis (TND = 0.70). Clearfil SE Bond had the highest false positive scores. Adhesive pooling was significantly different in the experimental groups of the current study (p < 0.05). CONCLUSION: Replacement decisions for a resin composite restoration based upon digital images frequently resulted in false-positive or negative decisions. PMID- 20945750 TI - Degree of conversion of luting resins around ceramic inlays in natural deep cavities: a micro-Raman spectroscopy analysis. AB - This study evaluated the degree of conversion (%DC) of luting agents around ceramic inlays placed in deep natural cavities. Thirty-six cylindrical Class I cavities (diameter = 4 mm, depth = 4 mm) were prepared in freshly extracted human teeth and randomly divided according to the luting materials used for luting CAD/CAM fabricated inlays (Empress CAD). The dual-cure resin cements Clearfil Esthetic Cement and Variolink II Low and the light-cure composites Grandio Flow and Grandio were luted using the total-etch technique. The self-adhesive dual cure cements RelyX Unicem and Maxcem Elite were used as recommended by the manufacturer. All of the restorations were photo-activated using a quartz halogen unit (Elipar TriLight; 750 mW/cm2) for 40 seconds. After 24 hour dry-storage in the dark, all the teeth were vertically sectioned into two halves (n = 12 per group) using a slow-speed diamond-saw in the bucco-vestibular direction under constant water lubrication to avoid specimen heating. The DC of the luting materials was measured by vibrational spectroscopy using a micro-Raman spectrometer at depths of 1, 3 and 4 mm on each side of the tooth halves (n = 24). Disc-shaped samples were produced for measurement of the maximum %DC of each material. Two-way ANOVA and the Student-Newman-Keuls post-hoc test were used in the statistical analysis (alpha = 0.05). All the materials showed no statistical differences in degree of conversion at all tested depths, except for Grandio Flow and Maxcem Elite. Dual-cure and light-cure luting materials showed polymerization homogeneity around ceramic inlays, although dual-cure conventional resin cements tended to show an overall higher conversion. PMID- 20945751 TI - Clinical use of a sectional matrix and ring. PMID- 20945752 TI - Mounting partially edentulous casts. PMID- 20945753 TI - Direct effects of habitat area on interaction diversity in pollination webs. AB - Island biogeography theory predicts that species richness increases with habitat area and declines with isolation. We expand this framework to address changes in the number of links and species in pollination webs from 12 isolated hills, ranging in area from tens to thousands of hectares, immersed in the agriculture matrix of the Argentine Pampas. We also studied whether total interaction frequency is partitioned more evenly among individual links in richer webs. Our results reveal a direct effect of area on the number of links and species present in each pollination web. However, link richness increased twofold faster than species richness with area. These area effects were not confounded by sampling effort or correlated incidence of exotic species, despite widespread habitat disturbance. Habitat proximity, an inverse measure of isolation, had a marginally significant influence on link but not on species richness. Increased link number was associated with decreasing dominance by any particular interaction and increasing interaction evenness. Despite the strong area effect, a rich pollination web sampled from a small, protected sierra suggests that simple conservation measures, such as reduced grazing and fire suppression, may effectively preserve much local interaction diversity. PMID- 20945754 TI - Shifts in phenotypic plasticity constrain the value of seabirds as ecological indicators of marine ecosystems. AB - Marine ecosystems are critically challenged by human activities, urgently calling for better management practices. It has been proposed that conspicuous top predators such as seabirds may be used as ecological indicators. This approach requires intimate knowledge of relationships connecting seabird parameters to other ecosystem components (i.e., population plasticity, underlined by individual reaction norms), information which remains scarce. Furthermore, if seabirds are to be used as long-term indicators, the strength of the average plastic response in a studied population has to be sustained through time and space. This second aspect has so far been startlingly neglected, although previous studies underline shifts in the plasticity of seabird traits and detail the tools allowing an evolutionary and ecological study of plasticity in bird populations. Building upon these advances, we argue that gradual or sudden spatiotemporal changes in seabird phenotypic plasticity should not be neglected when designing monitoring schemes. We conclude that seabirds are best used as qualitative sentinels, rather than as quantitative indicators. PMID- 20945755 TI - Spearfishing to depletion: evidence from temperate reef fishes in Chile. AB - Unreliable and data-poor marine fishery landings can lead to a lack of regulatory action in fisheries management. Here we use official Chilean landing reports and non-conventional indicators, such as fishers' perceptions and spearfishing competition results, to provide evidence of reef fishes depletions caused by unregulated spearfishing. Results show that the three largest and most emblematic reef fishes targeted mainly by spearfishers (> 98% of landings) [Graus nigra (vieja negra), Semicossyphus darwini (sheephead or pejeperro), and Medialuna ancietae (acha)] show signs of depletion in terms of abundance and size and that overall the catches of reef fishes have shifted from large carnivore species toward smaller-sized omnivore and herbivore species. Information from two snorkeling speargun world championships (1971 and 2004, Iquique, Chile) and from fishers' perceptions shows the mean size of reef fish to be declining. Although the ecological consequences of reef fish depletion are not fully understood in Chile, evidence of spearfishing depleting temperate reef fishes must be explicitly included in policy debates. This would involve bans or strong restrictions on the use of SCUBA and hookah diving gear for spearfishing, and minimum size limits. It may also involve academic and policy discussions regarding conservation and fisheries management synergies within networks of no take and territorial user-rights fisheries areas, as a strategy for the sustainable management of temperate and tropical reef fisheries. PMID- 20945756 TI - Contrasting changes in taxonomic vs. functional diversity of tropical fish communities after habitat degradation. AB - Human activities have strong impacts on ecosystem functioning through their effect on abiotic factors and on biodiversity. There is also growing evidence that species functional traits link changes in species composition and shifts in ecosystem processes. Hence, it appears to be of utmost importance to quantify modifications in the functional structure of species communities after human disturbance in addition to changes in taxonomic structure. Despite this fact, there is still little consensus on the actual impacts of human-mediated habitat alteration on the components of biodiversity, which include species functional traits. Therefore, we studied changes in taxonomic diversity (richness and evenness), in functional diversity, and in functional specialization of estuarine fish communities facing drastic environmental and habitat alterations. The Terminos Lagoon (Gulf of Mexico) is a tropical estuary of primary concern for its biodiversity, its habitats, and its resource supply, which have been severely impacted by human activities. Fish communities were sampled in four zones of the Terminos Lagoon 18 years apart (1980 and 1998). Two functions performed by fish (food acquisition and locomotion) were studied through the measurement of 16 functional traits. Functional diversity of fish communities was quantified using three independent components: richness, evenness, and divergence. Additionally, we measured the degree of functional specialization in fish communities. We used a null model to compare the functional and the taxonomic structure of fish communities between 1980 and 1998. Among the four largest zones studied, three did not show strong functional changes. In the northern part of the lagoon, we found an increase in fish richness but a significant decrease of functional divergence and functional specialization. We explain this result by a decline of specialized species (i.e., those with particular combinations of traits), while newly occurring species are redundant with those already present. The species that decreased in abundance have functional traits linked to seagrass habitats that regressed consecutively to increasing eutrophication. The paradox found in our study highlights the need for a multifaceted approach in the assessment of biodiversity changes in communities under pressure. PMID- 20945757 TI - Decision analysis for designing marine protected areas for multiple species with uncertain fishery status. AB - Marine protected areas (MPAs) are growing in popularity as a conservation tool, and there are increasing calls for additional MPAs. Meta-analyses indicate that most MPAs successfully meet the minimal goal of increasing biomass inside the MPA, while some do not, leaving open the important question of what makes MPAs successful. An often-overlooked aspect of this problem is that the success of fishery management outside MPA boundaries (i.e., whether a population is overfished) affects how well MPAs meet both conservation goals (e.g., increased biomass) and economic goals (e.g., minimal negative effects on fishery yield). Using a simple example of a system with homogeneous habitat and periodically spaced MPAs, we show that, as area in MPAs increases, (1) conservation value (biomass) may initially be zero, implying no benefit, then at some point increases monotonically; and (2) fishery yield may be zero, then increases monotonically to a maximum beyond which further increase in MPA area causes yield to decline. Importantly, the points at which these changes in slope occur vary among species and depend on management outside MPAs. Decision makers considering the effects of a potential system of MPAs on multiple species are confronted by a number of such cost-benefit curves, and it is usually impossible to maximize benefits and minimize costs for all species. Moreover, the precise shape of each curve is unknown due to uncertainty regarding the fishery status of each species. Here we describe a decision-analytic approach that incorporates existing information on fishery stock status to present decision makers with the range of likely outcomes of MPA implementation. To summarize results from many species whose overfishing status is uncertain, our decision-analysis approach involves weighted averages over both overfishing uncertainty and species. In an example from an MPA decision process in California, USA, an optimistic projection of future fishery management success led to recommendation of fewer and smaller MPAs than that derived from a more pessimistic projection of future management success. This example illustrates how information on fishery status can be used to project potential outcomes of MPA implementation within a decision analysis framework and highlights the need for better population information. PMID- 20945758 TI - Least-cost control of agricultural nutrient contributions to the Gulf of Mexico hypoxic zone. AB - In 2008, the hypoxic zone in the Gulf of Mexico, measuring 20 720 km2, was one of the two largest reported since measurement of the zone began in 1985. The extent of the hypoxic zone is related to nitrogen and phosphorous loadings originating on agricultural fields in the upper Midwest. This study combines the tools of evolutionary computation with a water quality model and cost data to develop a trade-off frontier for the Upper Mississippi River Basin specifying the least cost of achieving nutrient reductions and the location of the agricultural conservation practices needed. The frontier allows policymakers and stakeholders to explicitly see the trade-offs between cost and nutrient reductions. For example, the cost of reducing annual nitrate-N loadings by 30% is estimated to be US$1.4 billion/year, with a concomitant 36% reduction in P and the cost of reducing annual P loadings by 30% is estimated to be US$370 million/year, with a concomitant 9% reduction in nitrate-N. PMID- 20945759 TI - Wetland response to sedimentation and nitrogen loading: diversification and inhibition of nitrogen-fixing microbes. AB - Anthropogenic inputs of nutrients and sediment simultaneously impact coastal ecosystems, such as wetlands, especially during storms. Independent and combined effects of sediment and ammonium nitrate loading on nitrogen fixation rates and diversity of microbes that fix nitrogen (diazotrophs) were tested via field manipulations in Spartina foliosa and unvegetated zones at Tijuana Estuary (California, USA). This estuary is subject to episodic nitrogen enrichment and sedimentation associated with rain-driven flooding and slope instabilities, the latter of which may worsen as the Triple Border Fence is constructed along the U.S.-Mexico border. Responses of diazotrophs were assessed over 17 days using acetylene reduction assays and genetic fingerprinting (terminal restriction fragment length polymorphism [T-RFLP]) of nifH, which codes for dinitrogenase reductase. Sulfate-reducing bacteria performed approximately 70% of nitrogen fixation in Spartina foliosa rhizospheres in the absence of nitrogen loading, based on sodium molybdate inhibitions in the laboratory. Following nutrient additions, richness (number of T-RFs [terminal restriction fragments]) and evenness (relative T-RF fluorescence) of diazotrophs in surface sediments increased, but nitrogen fixation rates decreased significantly within 17 days. These responses illustrate, within a microbial community, conformance to a more general ecological pattern of high function among assemblages of low diversity. Diazotroph community composition (T-RF profiles) and rhizosphere diversity were not affected. Pore water ammonium concentrations were higher and more persistent for 17 days in plots receiving sediment additions (1 cm deep), suggesting that recovery of diazotroph functions may be delayed by the combination of sediment and nutrient inputs. Nitrogen fixation constitutes a mechanism for rapid transfer of fixed N to S. foliosa roots and a variety of primary consumers (within 3 and 8 days, respectively), as determined via 15N2 enrichment studies with in situ microcosms of intact marsh sediment. Thus, long-term declines in nitrogen fixation rates in response to increasingly frequent nutrient loading and sedimentation may potentially alter nitrogen sources for vascular plants as well as trophic pathways in wetland ecosystems. PMID- 20945760 TI - Looking deeper into the soil: biophysical controls and seasonal lags of soil CO2 production and efflux. AB - We seek to understand how biophysical factors such as soil temperature (Ts), soil moisture (theta), and gross primary production (GPP) influence CO2 fluxes across terrestrial ecosystems. Recent advancements in automated measurements and remote sensing approaches have provided time series in which lags and relationships among variables can be explored. The purpose of this study is to present new applications of continuous measurements of soil CO2 efflux (F0) and soil CO2 concentrations measurements. Here we explore how variation in Ts, theta, and GPP (derived from NASA's moderate-resolution imaging spectroradiometer [MODIS]) influence F0 and soil CO2 production (Ps). We focused on seasonal variation and used continuous measurements at a daily timescale across four vegetation types at 13 study sites to quantify: (1) differences in seasonal lags between soil CO2 fluxes and Ts, theta, and GPP and (2) interactions and relationships between CO2 fluxes with Ts, theta, and GPP. Mean annual Ts did not explain annual F0 and Ps among vegetation types, but GPP explained 73% and 30% of the variation, respectively. We found evidence that lags between soil CO2 fluxes and Ts or GPP provide insights into the role of plant phenology and information relevant about possible timing of controls of autotrophic and heterotrophic processes. The influences of biophysical factors that regulate daily F0 and Ps are different among vegetation types, but GPP is a dominant variable for explaining soil CO2 fluxes. The emergence of long-term automated soil CO2 flux measurement networks provides a unique opportunity for extended investigations into F0 and Ps processes in the near future. PMID- 20945762 TI - Spatial and temporal corroboration of a fire-scar-based fire history in a frequently burned ponderosa pine forest. AB - Fire scars are used widely to reconstruct historical fire regime parameters in forests around the world. Because fire scars provide incomplete records of past fire occurrence at discrete points in space, inferences must be made to reconstruct fire frequency and extent across landscapes using spatial networks of fire-scar samples. Assessing the relative accuracy of fire-scar fire history reconstructions has been hampered due to a lack of empirical comparisons with independent fire history data sources. We carried out such a comparison in a 2780 ha ponderosa pine forest on Mica Mountain in southern Arizona (USA) for the time period 1937-2000. Using documentary records of fire perimeter maps and ignition locations, we compared reconstructions of key spatial and temporal fire regime parameters developed from documentary fire maps and independently collected fire scar data (n = 60 plots). We found that fire-scar data provided spatially representative and complete inventories of all major fire years (> 100 ha) in the study area but failed to detect most small fires. There was a strong linear relationship between the percentage of samples recording fire scars in a given year (i.e., fire-scar synchrony) and total area burned for that year (y = 0.0003x + 0.0087, r2 = 0.96). There was also strong spatial coherence between cumulative fire frequency maps interpolated from fire-scar data and ground-mapped fire perimeters. Widely reported fire frequency summary statistics varied little between fire history data sets: fire-scar natural fire rotations (NFR) differed by < 3 yr from documentary records (29.6 yr); mean fire return intervals (MFI) for large-fire years (i.e., > or = 25% of study area burned) were identical between data sets (25.5 yr); fire-scar MFIs for all fire years differed by 1.2 yr from documentary records. The known seasonal timing of past fires based on documentary records was furthermore reconstructed accurately by observing intra annual ring position of fire scars and using knowledge of tree-ring growth phenology in the Southwest. Our results demonstrate clearly that representative landscape-scale fire histories can be reconstructed accurately from spatially distributed fire-scar samples. PMID- 20945761 TI - On the differential advantages of evergreenness and deciduousness in mediterranean oak woodlands: a flux perspective. AB - We assessed the differential advantages of deciduousness and evergreenness by examining 26 site-years of carbon dioxide, water vapor, and energy flux measurements from five comparable oak woodlands in France, Italy, Portugal, and California (USA). On average, the evergreen and deciduous oak woodlands assimilated and respired similar amounts of carbon while using similar amounts of water. These results suggest that evergreen and deciduous woodlands have specific, and similar, ecological costs in mediterranean climates, and that both leaf habits are able to meet these costs. What are the mechanisms behind these findings? Deciduous oaks compensated for having a shorter growing season by attaining a greater capacity to assimilate carbon for a given amount of intercepted solar radiation during the well-watered spring period; at saturating light levels, deciduous oaks gained carbon at six times the rate of evergreen oaks. Otherwise, the two leaf habits experienced similar efficiencies in carbon use (the change in carbon respired per change in carbon assimilated), water use (the change in carbon assimilation per change in water evaporated), and rainfall use (the change in evaporation per change in rainfall). Overall, leaf area index, rather than leaf habit, was the significant factor in determining the absolute magnitude of carbon gained and water lost by each evergreen and deciduous oak woodland over an annual interval; the closed canopies assimilated and respired more carbon and transpired more water than the open canopies. Both deciduous and evergreen mediterranean oaks survive in their seasonally hot/dry, wet/ cool native range by ensuring that actual evaporation is less than the supply of water. This feat is accomplished by adjusting the leaf area index to reduce total water loss at the landscape scale, by down-regulating photosynthesis, respiration, and stomatal conductance with progressive seasonal soil water deficits, and by extending their root systems to tap groundwater. PMID- 20945763 TI - Managing the matrix: decadal responses of eucalypt-dominated savanna to ambient fire regimes. AB - Much of our understanding of the response of savanna systems to fire disturbance relies on observations derived from manipulative fire plot studies. Equivocal findings from both recent Australian and African savanna fire plot assessments have significant implications for informing conservation management and reliable estimation of biomass stocks and dynamics. Influential northern Australian replicated fire plot studies include the 24-year plot-scale Munmarlary and the five-year catchment-scale Kapalga, mesic savanna (> 1000 mm/yr of rainfall) experiments in present-day Kakadu National Park. At Munmarlary, under low-to moderate-intensity fire treatments, woody vegetation dominated by mature eucalypts was found to be structurally stable. At Kapalga, substantial declines in woody biomass were observed under more intense fire treatments, and modeling assessments implicate early-season fires as having adverse effects on longer-term tree recruitment. Given these contrasting perspectives, here we take advantage of a landscape-scale fire response monitoring program established on three major northern Australian conservation reserves (Kakadu, Litchfield, and Nitmiluk National Parks). Using statistical modeling we assess the decadal effects of ambient fire regime parameters (fire frequency, severity, seasonality, time since fire) on 32 vegetation structure components and abundance of 21 tree and 16 grass species from 122 monitoring plots. Over the study period the mean annual frequency of burning of plots was 0.53, comprising mostly early-dry-season, low severity fires. Structural and species responses were variable but often substantial, notably resulting in stem recruitment and declines in juveniles, but only weakly explained by fire regime and habitat variables. Modeling of these observations under three realistic scenarios (increased fire severity under projected worsening climate change; modest and significant reductions in fire frequency to meet conservation criteria) indicates that all scenarios have positive and negative structural implications. Effecting significant regional fire regime change (e.g., reduction in frequency and size of severe fires) is demonstrably feasible, but it incurs risks and potentially some undesirable structural consequences. Given recent Australian and African experience, the generality and application of landscape-scale implications derived from manipulative fire assessments (including variable grazing and browsing regimes) in savanna require more critical assessment. PMID- 20945764 TI - Quantifying fire severity, carbon, and nitrogen emissions in Alaska's boreal forest. AB - The boreal region stores a large proportion of the world's terrestrial carbon (C) and is subject to high-intensity, stand-replacing wildfires that release C and nitrogen (N) stored in biomass and soils through combustion. While severity and extent of fires drives overall emissions, methods for accurately estimating fire severity are poorly tested in this unique region where organic soil combustion is responsible for a large proportion of total emissions. We tested a method using adventitious roots on black spruce trees (Picea mariana) in combination with canopy allometry to reconstruct prefire organic soil layers and canopy biomass in boreal black spruce forests of Alaska (USA), thus providing a basis for more accurately quantifying fire severity levels. We calibrated this adventitious-root height method in unburned spruce stands and then tested it by comparing our biomass and soils estimates reconstructed in burned stands with actual prefire stand measurements. We applied this approach to 38 black spruce stands burned in 2004 in Alaska, where we measured organic soil and stand characteristics and estimated the amount of soil and canopy biomass, as well as C and N pools, consumed by fire. These high-intensity quantitative estimates of severity were significantly correlated to a semiquantitative visual rapid assessment tool, the composite burn index (CBI). This index has proved useful for assessing fire severity in forests in the western United States but has not yet been widely tested in the boreal forest. From our study, we conclude that using postfire measurements of adventitious roots on black spruce trees in combination with soils and tree data can be used to reconstruct prefire organic soil depths and biomass pools, providing accurate estimates of fire severity and emissions. Furthermore, using our quantitative reconstruction we show that CBI is a reasonably good predictor of biomass and soil C loss at these sites, and it shows promise for rapidly estimating fire severity across a wide range of boreal black spruce forest types, especially where the use of high-intensity measurements may be limited by cost and time. PMID- 20945765 TI - Effect of forest clear-cutting on subtropical bryophyte communities in waterfalls, on dripping walls, and along streams. AB - Forested freshwater ecosystems worldwide are threatened by a number of anthropogenic disturbances, such as water pollution and canalization. Transient or permanent deforestation can also be a serious threat to organisms in forested watersheds, but its effects on different types of freshwater systems has been little studied. We investigated lotic bryophyte communities on rock and soil in subtropical cloud laurel forests on La Gomera Island in the Canary Islands, Spain, and asked whether the response to forest clear-cutting varied among the communities associated with dripping walls, streams, and waterfalls. We compared three successional forest stages: ancient forests (> 250 years), young forests (20-50 years after clear-cutting), and open stands (5-15 years after clear cutting). In each of 56 study sites we sampled general vegetation and substrate data in a 0.01-ha plot and took composition data of bryophyte species in 3 + 3 subplots of 1 x 1 m. The general pattern of decline in species richness and change in species composition after forest clear-cutting was stronger for streamside assemblages compared to assemblages on dripping walls and in waterfalls. The change in species numbers on rocks was larger than that on soils, because a guild of species growing on soil (but not on rocks) were favored by disturbance and thus increased in the disturbed sites. Most of the sensitive species could be classified as typical laurel forest species. Mosses were generally more tolerant to forest clear-cutting than were liverworts. We suggest that streamsides are more sensitive to disturbance than waterfalls and dripping walls because of a larger variation in microclimate before than after clear cutting and because they are more easily invaded by early-successional species (both bryophytes and highly competitive vascular plants). We propose that special care should be taken along small streams within disturbed watersheds if bryophyte assemblages and threatened species should be protected. The susceptibility to anthropogenic pressures is probably rather high in ecosystems that do not regularly experience large-scale stand-replacing disturbances, especially on oceanic islands because of isolation and a small total habitat area for focal organisms. PMID- 20945766 TI - Favorable fragmentation: river reservoirs can impede downstream expansion of riparian weeds. AB - River valleys represent biologically rich corridors characterized by natural disturbances that create moist and barren sites suitable for colonization by native riparian plants, and also by weeds. Dams and reservoirs interrupt the longitudinal corridors and we hypothesized that this could restrict downstream weed expansion. To consider this "reservoir impediment" hypothesis we assessed the occurrences and abundances of weeds along a 315-km river valley corridor that commenced with an unimpounded reach of the Snake River and extended through Brownlee, Oxbow, and Hells Canyon reservoirs and dams, and downstream along the Snake River. Sampling along 206 belt transects with 3610 quadrats revealed 16 noxious and four invasive weed species. Ten weeds were upland plants, with Canada thistle (Cirsium arvense) restricted to the upstream reaches, where field morning glory (Convolvulus arvensis) was also more common. In contrast, St. John's wort (Hypericum perforatum) was more abundant below the dams, and medusahead wildrye (Taeniatherum caput-medusae) occurred primarily along the reservoirs. All seven riparian species were abundant in the upstream zones but sparse or absent below the dams. This pattern was observed for the facultative riparian species, poison hemlock (Conium maculatum) and perennial pepperweed (Lepidium latifolium), the obligate riparian, yellow nut sedge (Cyperus esculentus), the invasive perennial, reed canary grass (Phalaris arundinacea), and three invasive riparian trees, Russian olive (Elaeagnus angustifolia), false indigo (Amorpha fruticosa), and tamarisk (Tamarix spp.). The hydrophyte purple loosestrife (Lythrum salicaria) was also restricted to the upstream zone. These longitudinal patterns indicate that the reservoirs have impeded the downstream expansion of riparian weeds, and this may especially result from the repetitive draw-down and refilling of Brownlee Reservoir that imposes a lethal combination of drought and flood stress. The dams and reservoirs may also interrupt hydrochory, the downstream flow of seeds and clonal fragments. We thus conclude that with some operational patterns, dams and reservoirs can impede the downstream expansion of riparian weeds. PMID- 20945767 TI - Floral and nesting resources, habitat structure, and fire influence bee distribution across an open-forest gradient. AB - Given bees' central effect on vegetation communities, it is important to understand how and why bee distributions vary across ecological gradients. We examined how plant community composition, plant diversity, nesting suitability, canopy cover, land use, and fire history affected bee distribution across an open forest gradient in northwest Indiana, USA, a gradient similar to the historic Midwest United States landscape mosaic. When considered with the other predictors, plant community composition was not a significant predictor of bee community composition. Bee abundance was negatively related to canopy cover and positively to recent fire frequency, bee richness was positively related to plant richness and abundance of potential nesting resources, and bee community composition was significantly related to plant richness, soil characteristics potentially related to nesting suitability, and canopy cover. Thus, bee abundance was predicted by a different set of environmental characteristics than was bee species richness, and bee community composition was predicted, in large part, by a combination of the significant predictors of bee abundance and richness. Differences in bee community composition along the woody vegetation gradient were correlated with relative abundance of oligolectic, or diet specialist, bees. Because oligoleges were rarer than diet generalists and were associated with open habitats, their populations may be especially affected by degradation of open habitats. More habitat-specialist bees were documented for open and forest/scrub habitats than for savanna/woodland habitats, consistent with bees responding to habitats of intermediate woody vegetation density, such as savannas, as ecotones rather than as distinct habitat types. Similarity of bee community composition, similarity of bee abundance, and similarity of bee richness between sites were not significantly related to proximity of sites to each other. Nestedness analysis indicated that species composition in species-poor sites was not merely a subset of species composition at richer sites. The lack of significant proximity or nestedness effects suggests that factors at a small spatial scale strongly influence bees' use of sites. The findings indicate that patterns of plant diversity, nesting resource availability, recent fire, and habitat shading, present at the scale of a few hundred meters, are key determinants of bee community patterns in the mosaic open-savanna-forest landscape. PMID- 20945768 TI - Identifying signature of chemical applications on indigenous and invasive nontarget arthropod communities in vineyards. AB - Communities of arthropods providing ecosystem services (e.g., pest control, pollination, and soil nutrient cycling) to agricultural production systems are influenced by pesticide inputs, yet the impact of pesticide applications on nontarget organisms is normally evaluated through standardized sets of laboratory tests involving individual pesticides applied to a few representative species. By combining season-long pesticide applications of various insecticides and fungicides into a metric based on the International Organization for Biological and Integrated Control (IOBC) toxicity ratings, we evaluate season-long pesticide impacts on communities of indigenous and exotic arthropods across 61 vineyards assessed for an entire growing season. The composition of arthropod communities, identified mostly at the family level, but in some cases at the species level, was altered depending on season-long pesticide use. Numbers of mostly indigenous parasitoids, predatory mites, and coccinellids in the canopy, as well as carabid/tenebrionid beetles and some spider families on the ground, were decreased at higher cumulative pesticide metric scores. In contrast, numbers of one invasive millipede species (Ommatoiulus moreletti Lucas, Julida: Julidae) increased under higher cumulative pesticide metric scores. These changing community patterns were detected despite the absence of broad-spectrum insecticide applications in the vineyards. Pesticide effects were mostly due to indoxacarb and sulphur, applied as a fungicide. The reduction of beneficial arthropods and increase in an invasive herbivorous millipede under high cumulative pesticide metric scores highlights the need to manage nontarget season long pesticide impacts in vineyards. A cumulative pesticide metric, based on IOBC toxicity ratings, provides a way of assessing overall toxicity effects, giving managers a means to estimate and consider potential negative season-long pesticide impacts on ecosystem services provided through arthropod communities. PMID- 20945769 TI - Water table response to an experimental alley farming trial: dissecting the spatial and temporal structure of the data. AB - Clearing vegetation for traditional agriculture diminishes native habitat and reduces plant transpiration, leading to increased groundwater recharge and onset of dryland salinization due to rising groundwater and mobilization of salt stores in the soil profile. This change in hydrology and salinity can also negatively affect biodiversity in many semiarid regions. Alternating native perennial tree belts with mono-species agriculture within the tree belt alleys is one possible system that can provide recharge control and recover some of the ecosystem services of degraded agricultural landscapes. To assess the effect of this agroforestry technique on groundwater levels, an alley farming trial was established in 1995, incorporating different combinations of belt width, alley width, and revegetation density. Transects of piezometers within each design have been monitored from October 1995 to January 2008. The data set consisted of 70 piezometers monitored on 39 dates. Two trends were observed within the raw data: An increase in water table depth with time and an increase in the range of depths monitored at the site were clearly discernible. However, simple hydrograph analysis of the data has proved unsuccessful at distinguishing the effect of the tree belts on the water table morphology. The statistical techniques employed in this paper to show the effect of the experiment on the water table were variation partitioning, principal coordinates of neighbor matrices (PCNM), and canonical redundancy analysis (RDA). The environmental variables (alley farming design, distance of piezometer from the tree belt, and percentage vegetation cover including edge effect) explained 20-30% of the variation of the transformed and detrended data for the entire site. The spatial PCNM variables explained a further 20-30% of the variation. Partitioning of the site into a northern and southern block increased the proportion of explained variation for the plots in the northern block. The spatial PCNM variables and vegetation cover remained the most significant variables. The PCNM analysis revealed no spatial pattern that could be attributed to the trial. The high proportion of unexplained variation may be due to site variables that have not been considered in this study. PMID- 20945770 TI - Conserving biodiversity in production landscapes. AB - Alternative land uses make different contributions to the conservation of biodiversity and have different implementation and management costs. Conservation planning analyses to date have generally assumed that land is either protected or unprotected, and that the unprotected portion does not contribute to conservation goals. We develop and apply a new planning approach that explicitly accounts for the contribution of a diverse range of land uses to achieving conservation goals. Using East Kalimantan (Indonesian Borneo) as a case study, we prioritize investments in alternative conservation strategies and account for the relative contribution of land uses ranging from production forest to well-managed protected areas. We employ data on the distribution of mammals and assign species specific conservation targets to achieve equitable protection by accounting for life history characteristics and home range sizes. The relative sensitivity of each species to forest degradation determines the contribution of each land use to achieving targets. We compare the cost effectiveness of our approach to a plan that considers only the contribution of protected areas to biodiversity conservation, and to a plan that assumes that the cost of conservation is represented by only the opportunity costs of conservation to the timber industry. Our preliminary results will require further development and substantial stakeholder engagement prior to implementation; nonetheless we reveal that, by accounting for the contribution of unprotected land, we can obtain more refined estimates of the costs of conservation. Using traditional planning approaches would overestimate the cost of achieving the conservation targets by an order of magnitude. Our approach reveals not only where to invest, but which strategies to invest in, in order to effectively and efficiently conserve biodiversity. PMID- 20945771 TI - Rapid ecosystem recovery from diffuse pollution after the Great Irish Famine. AB - Remarkably little is known about the effectiveness or rates of recovery of aquatic ecosystems from reductions in human-associated pressures at landscape scales. The retention of anthropogenic contaminants within ecosystems can retard rates of recovery considerably, while the trajectories of recovery processes vary with the extent of disturbance and the resilience of biotic assemblages. The Great Irish Famine of 1845-1850 comprised one of the most significant human disasters of the 19th century, causing the death of approximately one million people and the emigration of a further two million from the country between 1845 and 1855. We found, through analysis of detailed historical census data combined with paleolimnological investigation of sedimentary nutrient concentrations, stable isotope ratios, and diatom assemblages, that the trophic level of Lough Carra, a largely shallow calcareous lake in the west of Ireland with no urban areas or point sources of any significance in its catchment, reduced considerably during and immediately after the Great Famine, shifting to new equilibria within just 2-10 years. Our results demonstrate that the reduction of human pressures from diffuse sources at landscape scales can result in the rapid and monotonic recovery of aquatic ecosystems. Moreover, the recovery of ecosystems from diffuse pollution need not necessarily take longer than recovery from pollution from point sources. PMID- 20945772 TI - Variation in delta13C and delta15N diet-vibrissae trophic discrimination factors in a wild population of California sea otters. AB - The ability to quantify dietary inputs using stable isotope data depends on accurate estimates of isotopic differences between a consumer (c) and its diet (d), commonly referred to as trophic discrimination factors (TDFs) and denoted by delta(c-d). At present, TDFs are available for only a few mammals and are usually derived in captive settings. The magnitude of TDFs and the degree to which they vary in wild populations is unknown. We determined delta13C and delta15N TDFs for vibrissae (i.e., whiskers), a tissue that is rapidly becoming an informative isotopic substrate for ecologists, of a wild population of sea otters for which individual diet has been quantified through extensive observational study. This is one of the very few studies that report TDFs for free-living wild animals feeding on natural diets. Trophic discrimination factors of 2.2 per thousand +/- 0.7 per thousand for delta13C and 3.5 per thousand +/- 0.6 per thousand for delta15N (mean +/- SD) were similar to those reported for captive carnivores, and variation in individual delta13C TDFs was negatively but significantly related to sea urchin consumption. This pattern may relate to the lipid-rich diet consumed by most sea otters in this population and suggests that it may not be appropriate to lipid-extract prey samples when using the isotopic composition of keratinaceous tissues to examine diet in consumers that frequently consume lipid rich foods, such as many marine mammals and seabirds. We suggest that inherent variation in TDFs should be included in isotopically based estimates of trophic level, food chain length, and mixing models used to quantify dietary inputs in wild populations; this practice will further define the capabilities and limitations of isotopic approaches in ecological studies. PMID- 20945773 TI - Population-specific vital rate contributions influence management of an endangered ungulate. AB - To develop effective management strategies for the recovery of threatened and endangered species, it is critical to identify those vital rates (survival and reproductive parameters) responsible for poor population performance and those whose increase will most efficiently change a population's trajectory. In actual application, however, approaches identifying key vital rates are often limited by inadequate demographic data, by unrealistic assumptions of asymptotic population dynamics, and of equal, infinitesimal changes in mean vital rates. We evaluated the consequences of these limitations in an analysis of vital rates most important in the dynamics of federally endangered Sierra Nevada bighorn sheep (Ovis canadensis sierrae). Based on data collected from 1980 to 2007, we estimated vital rates in three isolated populations, accounting for sampling error, variance, and covariance. We used analytical sensitivity analysis, life stage simulation analysis, and a novel non-asymptotic simulation approach to (1) identify vital rates that should be targeted for subspecies recovery; (2) assess vital rate patterns of endangered bighorn sheep relative to other ungulate populations; (3) evaluate the performance of asymptotic vs. non-asymptotic models for meeting short-term management objectives; and (4) simulate management scenarios for boosting bighorn sheep population growth rates. We found wide spatial and temporal variation in bighorn sheep vital rates, causing rates to vary in their importance to different populations. As a result, Sierra Nevada bighorn sheep exhibited population-specific dynamics that did not follow theoretical expectations or those observed in other ungulates. Our study suggests that vital rate inferences from large, increasing, or healthy populations may not be applicable to those that are small, declining, or endangered. We also found that, while asymptotic approaches were generally applicable to bighorn sheep conservation planning; our non-asymptotic population models yielded unexpected results of importance to managers. Finally, extreme differences in the dynamics of individual bighorn sheep populations imply that effective management strategies for endangered species recovery may often need to be population specific. PMID- 20945774 TI - Flaws and pitfalls in the chemical analysis of feathers: bad news-good news for avian chemoecology and toxicology. AB - Ecologists have frequently used biochemical assays as proxies for processes or phenomena too difficult to explore by traditional means of investigation. Feathers have been subjected to a number of chemical analyses to study such things as their elemental composition, contaminants, and hormones. The reliance on standard methodology of using concentrations to express quantities of chemical substances is seriously problematic because it creates artifacts by ignoring the physiology of feathers. Some elements and compounds are incorporated into the feather as part of the very building blocks of the keratin. However, others that are less functionally important to feathers (but not necessarily to the bird) enter the developing cells in proportion to their abundance in the bloodstream; in other words, feathers are merely receptacles, and deposition of chemicals is time dependent. In the latter case, one that applies to much of the work done on feather chemistry, data expressed as concentrations are meaningless because the varying mass across the feather alters concentrations in a way that has no biological significance. I discuss this problem and various pitfalls in the chemical analysis of feathers, and offer solutions that ultimately will offer a better understanding of the mechanisms influencing feather composition and, thus, the ecological patterns and processes they were meant to study. PMID- 20945775 TI - Recreation-induced changes in boreal bird communities in protected areas. AB - The impacts of human-induced disturbance on birds have been studied in growing extent, but there are relatively few studies about the effects of recreation on forest bird communities in protected areas. In this paper, the relative importance of recreation as well as environmental variables on bird communities in Oulanka National Park, in northeastern Finland, was investigated using general additive models (GAM). Bird data collected using the line transect method along hiking trails and in undisturbed control areas were related to number of visits, area of tourism infrastructure, and habitat variables. We further examined the impact of spatial autocorrelation by calculating an autocovariate term for GAMs. Our results indicate that number of visits affects the occurrence and composition of bird communities, but it had no impact on total species richness. Open-cup nesters breeding on the ground showed strongest negative response to visitor pressure, whereas the open-cup nesters nesting in trees and shrubs were more tolerant. For cavity-nesting species, recreation had no significant impact. The contribution of the number of visits was generally low also in models in which it was selected, and the occurrence of birds was mainly determined by habitat characteristics of the area. However, our results show that the recreation induced disturbance with relatively low visitor pressure can have negative impacts on some bird species and groups of species and should be considered in management of protected areas with recreational activities. PMID- 20945776 TI - High incidence of glomerulonephritis associated with inclusion body hepatitis in broiler chickens: routine histopathology and histomorphometric studies. AB - During the routine histologic evaluation of an outbreak of inclusion body hepatitis (IBH) in Mississippi broilers, a high incidence of renal enlargement and glomerulonephropathy was observed in the birds presenting classic hepatic pathology. Characteristic intranuclear adenoviral inclusion bodies were demonstrated in the livers of these birds, and fowl adenovirus was identified by viral isolation and by PCR. The glomerular lesions were consistent with proliferative or membranoproliferative forms of glomerulonephritis. Histomorphometric evaluations were performed to generate a more quantitative analysis of altered glomerular size and cellularity, to detect statistically significant borderline changes, and to get a clearer insight into the incidence of the glomerular alterations. Marked increases in both the average glomerular size (area) and the total glomerular cellularity were observed for the affected glomeruli relative to normal controls. The average glomerular area values for normal glomeruli in the peripheral subcapsular cortical and central cortical kidney regions were 1791 microm2 and 5302 microm2, respectively. In contrast, glomerular measurements for kidneys exhibiting glomerulonephritis by routine histopathology, had average values for the two regions of 4429 microm2 and 11,063 microm2. The average glomerular cell counts for the two regions in controls were 44 and 107 cells/ glomeruli, while averages for birds with glomerulonephritis were 85 and 193 cells/glomeruli. The proportion of IBH-associated glomeruli greater than two standard deviations above the mean glomerular size of the normal controls was 52% for the central region and 62% for the peripheral region. PMID- 20945777 TI - Forensic investigation of a 1986 outbreak of osteopetrosis in commercial brown layers reveals a novel avian leukosis virus-related genome. AB - Avian leukosis virus (ALV) is known to cause several neoplastic conditions in chickens, such as B-cell lymphomas, myelocytomas, erythroblastosis, and other types of neoplasia including osteopetrosis. We describe herein the identification of unique ALV-related proviral DNA sequences in an archived chicken bone affected with osteopetrosis. The osteopetrotic bone was obtained from an affected 46-week old brown layer during an outbreak of osteopetrosis in Costa Rica in 1986. Analysis of proviral DNA in the 23-year-old osteopetrotic bone revealed unique exogenous ALV-related sequences that were named CR-1986 (Costa Rica, 1986). The 5' and 3' long terminal repeats (LTR) in the proviral DNA were identical to each other. The U3 regions in the LTRs were most similar to equivalent sequences in ALV-J, while U5 was identical to known endogenous ALV-E sequences. The predicted CR-1986 envelope protein was most similar to the envelope of myeloblastosis associated virus type 1 (MAV-1), although the percentage of amino acid sequence similarity to MAV-1 was low (90.4%). The variable and hypervariable regions of gp85 displayed several mutations compared to representative strains of ALV. The gp37 (transmembrane or TM) envelope protein showed three leucine to serine mutations that may represent important changes in the conformation of this protein, a finding that is currently being investigated. Several recombination events may have contributed to the emergence of CR-1986 because each analyzed segment was similar to a different ALV. CR-1986 may represent a unique ALV based on distinctive characteristics of its predicted envelope protein in comparison to previously reported ALVs. PMID- 20945778 TI - Detection of avian nephritis virus in Australian chicken flocks. AB - Avian nephritis virus (ANV) is thought to infect poultry flocks worldwide, but no confirmed case has been reported in Australia. The first such case is described in this study. Cases of young chickens with clinical signs of dehydration and diarrhea were submitted to our laboratory and histopathology detected interstitial nephritis. Vaccine strains of infectious bronchitis virus were detected in some of these cases but were not considered to be the causative agent. A total of seven fresh submissions from broiler chicken flocks were collected at 8-11 days of age. Degenerate PCR primers were designed based on published ANV polymerase gene sequences and used to analyze historic cases as well as the fresh submissions. Six of the seven fresh submissions, and one historic case, were positive for ANV with nucleotide sequencing confirming these results. These results establish ANV as an infectious pathogen circulating in Australian poultry. PMID- 20945779 TI - Ornithobacterium rhinotracheale North American field isolates express a hemolysin like protein. AB - Ornithobacterium rhinotracheale is a gram-negative bacterium responsible for the sporadic outbreaks of airsacculitis in poultry, accounting for millions of dollars in losses to the poultry industry annually. Although the organism was originally classified as non-beta-hemolytic, recent North American field isolates of O. rhinotracheale obtained from pneumonic lungs and air sacs indicated hemolytic activity on blood agar plates upon extended incubation for 48 hr at room temperature in air after initial incubation at 37 C for 48 hr under 7.5% CO2. This report characterizes the beta-hemolytic activity of O. rhinotracheale isolates by using in vitro kinetic hemolysis assays with sheep red blood cells, western blotting with leukotoxin-specific monoclonal antibodies, and isobaric tagging and relative and absolute quantitative (iTRAQ) analysis of O. rhinotracheale outer membrane protein digest preparations. The kinetic analyses of the hemolytic activity with red blood cells indicated that the protein is a pore former. iTRAQ analysis with membrane preparations revealed four peptides with homology to Mannheimia haemolytica leukotoxin and two peptides with homology to Actinobacillus actinoacetemcomitans leukotoxin. This is the first report that North American field isolates of O. rhinotracheale may express a hemolysin-like activity. PMID- 20945780 TI - Comparison of Eimeria species distribution and salinomycin resistance in commercial broiler operations utilizing different coccidiosis control strategies. AB - The purpose of the present study was to evaluate the species composition and salinomycin sensitivity of Eimeria oocysts isolated from commercial broiler farms that differed by means of coccidiosis control (anticoccidial drugs [ACD] vs. live oocyst vaccines [VAC]). A comparison of Eimeria species composition and salinomycin sensitivity was also made before and after a producer switched from salinomycin to live oocyst vaccines. In general, no significant difference was observed in the concentration of Eimeria spp. oocysts in litter from VAC utilizing farms compared to litter from ACD-utilizing farms. Application of PCR based methods to detect coccidia found that Eimeria species distribution in litter from VAC operations more closely resembled the species composition in the live oocyst vaccines. Drug sensitivity testing found that Eimeria oocysts from VAC operations displayed greater salinomycin sensitivity as measured by weight gain and feed conversion efficiency compared to oocysts from ACD farms. These findings provide additional evidence for the usefulness of live oocyst vaccines to restore ionophore sensitivity in poultry operations that contain an ionophore resistant population of Eimeria spp. oocysts. PMID- 20945781 TI - Survey of biosecurity protocols and practices adopted by growers on commercial poultry farms in Georgia, U. S. A. AB - The integrated commercial poultry system is a highly connected network in which routine activities keep farms within a geographic area in constant contact. Consequently, biosecurity practices designed to minimize the transmission of infectious diseases between and within farms are an important component of modern flock health programs. A survey of Georgia poultry growers was conducted in order to assess the level of adoption of standard biosecurity measures by farm personnel and visitors. The results showed that compliance with recommended biosecurity practices did not significantly vary by company, farm size, or number of farms owned by the same grower. However, biosecurity was higher in the northern part of the state, where the density of farms is higher, and where there was an ongoing outbreak of infectious laryngotracheitis at the time of the study. The survey found that growers place more emphasis on biosecurity measures targeting farm visitors than those targeting farm personnel. Most growers reported that all visitors to the farm were required to wear shoe covers, although visitors were not typically required to park outside the farm entrance or to wash tires on their vehicles. No visitor type was reportedly excluded from poultry houses during grow out on all farms. The results highlight the need to evaluate the comparative efficacy of specific biosecurity measures in order to set priorities and attain feasible rates of implementation of targeted biosecurity practices. PMID- 20945782 TI - Selected blood chemistry and gas reference ranges for broiler breeders using the i-STAT handheld clinical analyzer. AB - Selected blood chemistry and gas reference ranges for clinically healthy broiler breeder hens were established using CG8+ cartridges in an i-STAT handheld point of-care clinical analyzer. Samples from 165 hens (25-36 wk of age), representing three broiler breeder strains reared by four integrators, were evaluated. A standardized sampling technique was developed to minimize instrument error readings. The following reference ranges and means, respectively, were determined: sodium (141.6-152.6, 147.1 [mmol/L]), potassium (4.1-5.7, 4.9 [mmol/L]), ionized calcium (1.20-1.73, 1.47 [mmol/L]), glucose (207.2-260.7, 234.0 [mg/dl]), hematocrit (21.3-30.8, 26.1 [% packed cell volume]), hemoglobin (7.3-10.5, 8.9 [g/dl]), pH (7.28-7.57, 7.42), carbon dioxide partial pressure (25.9-49.5, 37.7 [mm Hg]), oxygen partial pressure (32.0-60.5, 46.2 [mm Hg]), bicarbonate (18.9-30.3, 24.6 [mmol/L]), total carbon dioxide (19.9-31.5, 25.7 [mmol/L]), base excess (-6.8 to 7.2, 0.2), and oxygen saturation (70.6-93.3, 82.0 [%]). Wide ranges in blood gases and base excess occurred in all strains. Cobb strain hens had significantly lower glucose and higher partial and saturated oxygen values compared with two Ross strains. Significant differences in several blood parameters were found among different integrators and in older postpeak production birds. The i-STAT handheld point-of-care clinical analyzer provides rapid, relatively low cost, blood chemistry values that are useful for investigating broiler breeder flock diseases of unknown or uncertain etiology, especially those suspected of having a metabolic cause. PMID- 20945783 TI - Detection of DNA of Histomonas meleagridis and Tetratrichomonas gallinarum in German poultry flocks between 2004 and 2008. AB - Between 2004 and 2008, 338 samples from 156 German turkey, chicken, and peacock flocks with suspected histomonosis (histomoniasis) were sent to the Institute for Poultry Diseases of the Free University Berlin. Most samples were from ceca or livers; the other samples were organ pools or were taken from other organs or the environment. In 108 samples from 65 flocks, histomonal DNA was detected by polymerase chain reaction (PCR). Tetratrichomonas gallinarum DNA was found in 5.3% of investigated samples from flocks infected with Histomonas meleagridis and in 27.4% of investigated samples from flocks that were not infected with H. meleagridis. For subtyping of the strains, the C-profiling method, a method used to analyze the internal transcribed spacer-1 (ITS-1) of the rRNA gene, was modified to be more specific for H. meleagridis. Results showed the presence of more than the three subtypes described so far. There was no clear correlation between the subtype and the host. By C-profiling the clonal cultures, heterogeneous ITS-1 sequences were shown to probably result from intragenomic differences between rRNA genes. PMID- 20945784 TI - Retrospective study of myocarditis associated with reovirus in turkeys. AB - The myocarditis associated with reovirus in commercial turkeys was studied retrospectively. Fifty-two cases were identified between 1991 and 2009. The lesions occurred in four different poultry companies in California and affected male and female turkeys with an average age of 19 days. Increased mortality in the turkey flocks ranged from 0.35% to 3% per week in 47 cases. Reovirus was isolated from the heart in 14 out of 19 cases. Twenty-four out of 28 birds from nine cases had low vitamin E levels in the liver ranging from 0.29 to 2.5 ppm (normal 3.0 to > or = 15 ppm). Transmission electron microscopy of the heart revealed degenerative changes in the myocardial cells. Reovirus has been suggested as a probable etiology of this condition. Vitamin E deficiency might also contribute to the development of the lesions. PMID- 20945785 TI - Unusual biphasic disease in domestic pigeons (Columba livia f. domestica) following experimental infection with Sarcocystis calchasi. AB - A novel Sarcocystis species has recently been reported in the domestic pigeon (Columba livia f. domestica) as intermediate host, causing severe central nervous signs similar to Paramyxovirus-1 or Salmonella Typhimurium var. cop. infection. Transmission of the parasite via the northern goshawk (Accipiter gentilis) as definitive host has been established. Experimental infection of domestic pigeons with sporocysts excreted by experimentally infected northern goshawks reproduced the natural infection in the pigeon, proving the causative role of the parasite in the disease. Here, we describe in greater detail the course of the fulminant biphasic disease depending on the infectious dose. Pigeons infected with 10(3) or 10(4) sporocysts showed clinical signs of polyuria and apathy around 10-11 days postinfection (dpi) and sudden neurological signs 51-57 dpi as a second phase of disease. Pigeons infected with higher doses died within 7-12 dpi, also showing polyuria and apathy but without nervous signs. At necropsy, livers and spleens had multifocal necroses and infestations with parasitic stages, namely, schizonts. Moreover, lesions and schizonts were also found in the lung, bone marrow, and next to blood vessels in the connective tissue of various organs. Pigeons infected with 102 sporocysts remained symptomless until 58-65 dpi, when sudden central nervous signs occurred. Major histopathologic findings of pigeons with neurological signs were encephalitis and myositis of virtually every skeletal muscle with high infestations of sarcocysts. Only mild myocarditis and very few cysts were found in the heart muscles. Importantly, a sentinel pigeon developed identical lesions when compared to those of low-dose infected pigeons, suggesting a risk of mechanical transmission of sporocysts from freshly infected to uninfected pigeons in a flock. By contrast, chickens failed to develop any clinical signs or pathologic lesions in the same experiment. The findings further characterize the new highly pathogenic disease in domestic pigeons, which clinically mimics paramyxovirosis and salmonellosis in both phases of the disease and exclude chickens as further intermediate host species. PMID- 20945786 TI - The effect of the time interval between exposures on the susceptibility of chickens to superinfection with Marek's disease virus. AB - Marek's disease virus (MDV) is ubiquitous within commercial poultry flocks because current vaccines do not prevent MDV infection or transmission. In order for newly-evolved MDV strains to become established within a flock, it seems inevitable that any new strain would need to infect and replicate in chickens previously infected with resident MDV strains. This phenomenon is difficult to detect and there is no clear evidence that it is even possible. Four experiments were performed to demonstrate superinfection and evaluate the effect of time between challenges on the effect of superinfection with the use of two pairs of fully virulent MDV strains that could be discriminated by novel technology: 1) JM/102W and rMd5//38CVI, and 2) rMd5 and rMd5//38CVI. Feather follicle epithelium (FFE), spleen, and tumor samples were collected at single or multiple time points from the same bird to determine the frequency and distribution of each virus present following superinfection, with the use of pyrosequencing and immunohistochemistry. Superinfection was observed in 82 of 149 (55%) FFE samples following short-interval challenge (24 hr) compared to only 6 of 121 (5%) samples following long-interval challenge (13 days), indicating a strong influence of challenge interval. In cases where the first inoculated virus was weak or delayed, the second inoculated virus was detected in 42 of 95 (44%) birds. In tumors from dually challenged birds, the second virus was again present much more often following short-interval challenge (68%) compared to long-interval challenge (11%). Virus mixtures in tumors were less common compared to those in FFE samples. Vaccination with turkey herpesvirus had no significant effect on the virus frequency for either virus pair or challenge time interval, suggesting these conclusions may be applicable to vaccinated chickens in the field. These studies demonstrated superinfection for the first time with two fully virulent MDV strains and suggest that short-interval challenge exposure and/or weak initial exposures may be important factors leading to superinfection--a prerequisite for the establishment of a second virus strain in the population. This model system should be useful to elucidate this important phenomenon further. PMID- 20945788 TI - Optimized necrotic enteritis model producing clinical and subclinical infection of Clostridium perfringens in broiler chickens. AB - In this study we assessed the roles of Eimeria infection and dietary manipulation (feeding a diet with a high level of fishmeal) in an Australian necrotic enteritis (NE) challenge model in broiler chickens. An experiment was designed to test the hypothesis that Eimeria infection and dietary manipulation, i.e., inclusion of fishmeal in the diet, are necessary to induce NE experimentally. The results showed that the combination of Eimeria administration and fishmeal feeding had a significant effect on induction of clinical and subclinical Clostridium perfringens infection. The majority of the mortality that occurred during the second week of the trial was due to an NE outbreak following the C. perfringens challenge. The mortality rate of the birds was 12.00% for the high fishmeal (HFM; 500 g/kg) group and 9.33% for the low-fishmeal (LFM; 250 g/kg) group when the birds were subjected to C. perfringens and Eimeria. Fishmeal alone did not induce significant mortality in birds challenged only with C. perfringens but showed a significantly higher C. perfringens count than the non-fishmeal (NFM) control group. Eimeria administration had a significant effect on NE related mortality but did not have an effect on the C. perfringens count. In accordance with the time course of bird mortality, it can be determined that of the 3 successive days of oral gavage with C. perfringens, the first inoculation was essential for inducing NE, but the third had no additional effect on NE related mortality. Also, reducing the fishmeal level from 500 to 250 g/kg had no negative impact on the reproducibility of the model. It may be concluded that NE can be consistently induced under experimental conditions by feeding broilers a diet containing 250 g/kg fishmeal, using a single inoculation with low numbers of Eimeria, administering one or two oral C. perfringens inoculations, and maintaining appropriate ambient temperatures and diets. PMID- 20945787 TI - Pathogenesis of two strains of avian paramyxovirus serotype 2, Yucaipa and Bangor, in chickens and turkeys. AB - Nine serologic types of avian paramyxovirus (APMV) have been recognized. Newcastle disease virus (APMV-1) is the most extensively characterized virus, while relatively little information is available for the other APMV serotypes. In the present study, we examined the pathogenicity of two strains of APMV-2, Yucaipa and Bangor, in 9-day-old embryonated chicken eggs, 1-day-old specific pathogen-free (SPF) chicks, and 4-wk-old SPF chickens and turkeys. The mean death time in 9-day-old embryonated chicken eggs was more than 168 hr for both strains, and their intracerebral pathogenicity index (ICPI) was zero, indicating that these viruses are nonpathogenic in chickens. When inoculated intracerebrally in 1 day-old chicks, neither strain caused disease or replicated detectably in the brain. This suggests that the zero ICPI value of APMV-2 reflects the inability of the virus to grow in neural cells. Groups of twelve 4-wk-old SPF chickens and turkeys were inoculated oculonasally with either strain, and three birds per group were euthanatized on days 2, 4, 6, and 14 postinoculation for analysis. There were no overt clinical signs of illnesses, although all birds seroconverted by day 6. The viruses were isolated predominantly from the respiratory and alimentary tracts. Immunohistochemistry studies also showed the presence of a large amount of viral antigens in epithelial linings of respiratory and alimentary tracts. There also was evidence of systemic spread even though the cleavage site of the viral fusion glycoprotein does not contain the canonical furin protease cleavage site. PMID- 20945789 TI - Phylogenetic analysis of six isolates of beak and feather disease virus from African grey parrots in Portugal. AB - Beak and feather disease virus (BFDV), a member of the genus Circovirus, was detected in six dead African grey parrots (Psittacus erithacus) in Portugal. The complete nucleotide sequences of these six BFDVs (PT05, PT08, PT08-2, PT08-3, PT09, and PT09-2) were determined and analyzed. The seven open reading frames (ORFs) described for other BFDVs were detected in all strains, except for PT05 and PT08, in which ORFs 4 and 7 are absent. Bayesian inference of phylogeny based on complete genomes of BFDVs isolated in Portugal and 32 other BFDVs found in other parts of the world revealed that PT05 is included in lineage IV, whereas the others form a new proposed genotype lineage IX. The nucleotide diversity ranged from 2% to 12% between the BFDV strains isolated in Portugal and other BFDVs found worldwide. PMID- 20945790 TI - Comparison of Campylobacter levels in crops and ceca of broilers at slaughter. AB - A considerable fraction of the poultry carcasses becomes contaminated with Campylobacter by cross-contamination from the digestive tract of colonized broilers at slaughter. Campylobacter in the crop may serve as a possible source of cross-contamination, because the crop may contain high numbers of Campylobacter and is more likely to rupture during the slaughtering process than intestines. In this study, the correlation between Campylobacter colonization levels in crop and cecum was assessed in 48 broilers of 31 days of age. In addition, the effect of drinking water supplemented with 0.2% volatile fatty acid (VFA) on these Campylobacter colonization levels was studied. No correlation between crop and cecal colonization levels was found (p = 0.09; P = 0.71), indicating that future studies on cross-contamination should include an examination of not only cecal colonization levels but also crop colonization levels. Supplementation of drinking water with VFA did not result in a significant reduction of colonization levels in either the crop (P = 0.50) or the ceca (P = 0.92), indicating that this is not an effective measure to reduce cross contamination at slaughter. PMID- 20945791 TI - Molecular characterization of avian paramyxovirus type 1 (Newcastle disease) viruses isolated from pigeons between 2000 and 2008 in Slovenia. AB - Fourteen avian paramyxovirus type 1 (APMV-1; Newcastle disease) viruses isolated from dead free-living and domestic pigeons in Slovenia between 2000 and 2008 were analyzed by a molecular characterization of a part of the fusion protein gene, which included the region encoding the fusion protein cleavage site. Phylogenetic analysis indicated that the Slovene pigeon paramyxovirus type 1 (PPMV-1) viruses do not cluster together but instead are divided into two groups--4bi and 4bii--of sublineage 4b. Nine Slovenian strains were placed in group 4bii. Five other strains clustered together with PPMV-1 from group 4bi. The sequence of the fusion protein cleavage site of all Slovenian strains was typical for pathogenic APMV-1. The 112RRQKRF117 motif was present in the strains from group 4bii, whereas strains from group 4bi displayed the 112GRQKRF117 motif. PMID- 20945792 TI - Preliminary molecular characterization of a fowl poxvirus isolate in Grenada. AB - Two 1-mo-old local breed chickens, with gross lesions in the skin of the head region suspected to be fowl poxvirus infection, were submitted to the Diagnostic Laboratory of the School of Veterinary Medicine, Grenada, West Indies. Cutaneous lesions were collected from these birds for virus isolation, histopathologic diagnosis, and molecular analysis. Fowl poxvirus infection was confirmed by virus isolation in chicken embryo and by histopathology. Molecular characterization of the fowl poxvirus was conducted by PCR amplification of selected genomic fragments and by nucleotide sequencing. Integration of reticuloendotheliosis virus fragments into the fowl poxvirus genome was confirmed by PCR and DNA sequencing. This is the first report from the Caribbean region on the preliminary molecular characterization of a fowl poxvirus isolate. PMID- 20945793 TI - Surveillance and identification of influenza A viruses in wild aquatic birds in the Crimea, Ukraine (2006-2008). AB - The ecology of avian influenza (AI) viruses in wild aquatic birds of Asia is poorly understood, especially for the H5N1 high pathogenicity AI (HPAI) viruses. From March 2006 through November 2008, 20 AI viruses were isolated in the Crimea region of Ukraine with an overall frequency of virus recovery of 3.3%. All the viruses were isolated from three species of dabbling ducks: mallard (Anas platyrhynchos), wigeon (Anas penelope), and garganey (Anas querquedula), making the frequency of virus recovery for dabbling ducks 6.3%. The viruses were predominantly isolated during the fall sampling period. All viruses were genetically and antigenically characterized. No H5N1 HPAI viruses were isolated, but other HA and NA subtypes were identified including H3N1 (2), H3N6 (3), H3N8 (4), H4N6 (6), H5N2 (3), H7N8 (1), and H10N6 (1) subtypes. All isolates were of low pathogenicity, as determined by the intravenous pathogenicity index of 0.00. For H5N2 and H7N8 isolates, the HA gene was sequenced and the phylogenetic analysis revealed possible ecologic connections of the Crimea region with AI viruses from Siberia and Europe. No influenza A isolates were recovered from other Anseriformes (diving ducks [two species of pochards] and graylag geese), Columbiformes (collared doves), Gruiformes (coot), and Galliformes (gray partridges). PMID- 20945794 TI - Potential of low pathogenicity avian influenza viruses of wild bird origin to establish experimental infections in turkeys and chickens. AB - The potential of low pathogenicity (LP) avian influenza virus (AIV) isolates of wild bird origin to establish infection in commercial turkeys and broiler chickens was studied. Isolates, representing subtypes H5N1, H7N3, H6N2, and H3N6, were recovered in 2005 and 2006 from waterfowl and shorebirds in the Delmarva Peninsula region of the east coast of the United States. The LP AIV isolates were not pathogenic for 2-wk-old meat-type turkeys and broiler chickens. No mortality, clinical signs, or gross lesions were observed following intratracheal and conjunctival sac routes of exposures with 10(6.0) EID50 (embryo infectious dose) per bird. Isolates resulting in an established infection based on virus isolation were: A/mallard/Maryland/1159/ 2006 (H5N1) in the upper respiratory tract of turkeys; A/mallard/Delaware/418/2005 (H7N3) in the upper respiratory and intestinal tracts of turkeys and chickens; and A/shorebird environment/Delaware/251/2005 (H3N6) in the upper respiratory and intestinal tracts of chickens. Infections were also confirmed by production of AIV-specific serum antibodies detected by hemagglutination inhibition. PMID- 20945795 TI - Identification of Avibacterium paragallinarum serovar B-1 from severe infectious coryza outbreaks in Panama. AB - The isolation and identification of Avibacterium paragallinarum serovar B-1 from severe infectious coryza outbreaks in broiler breeders in Panama is reported for the first time. Infectious coryza was absent for over a decade in the breeder farms area. Disease outbreaks were characterized by an up to 45% drop in egg production and increased mortality. Use of a commercial trivalent bacterin and a strengthened biosecurity program prevented outbreaks in susceptible flocks in the farm. PMID- 20945796 TI - Articular aspergillosis of hip joints in turkeys. AB - Aspergillosis is an important cause of morbidity and mortality in birds. Turkey poults are known to be particularly susceptible to fungal infection. Although the respiratory tract is the most commonly affected, dissemination can occur into virtually any organ. Here, we report an unusual outbreak of articular aspergillosis in a flock of meat turkeys with clinical signs of lameness. Between 7 and 11 weeks of age, turkeys had severe granulomatous osteoarthritis of the hip joints with necrosis of the femur head. Fungal morphology and PCR amplification and sequencing of the first ITS1-5.8S-ITS2 rDNA region identified Aspergillus fumigatus as the infectious agent. Concurrently, Staphylococcus spp. was isolated from the hip joints, which may have promoted the tropism of the fungus. Mild respiratory tract aspergillosis was observed in only one case. The findings suggest that fungal arthritis may present a specific disease entity in turkeys and should be considered as further cause of lameness in turkeys. PMID- 20945797 TI - Cryptosporidium avian genotype III as a possible causative agent of chronic vomiting in peach-faced lovebirds (Agapornis roseicollis). AB - In the present study, Cryptosporidium oocysts were found, by light microscopy, in 37 fecal samples of peach-faced lovebirds (Agapornis roseicollis). Cryptosporidium avian genotype III was isolated in 13 of the 37 infected birds by sequence analysis of the small subunit ribosomal RNA and the actin genes. All of the birds showed chronic vomiting and weight loss with enlargement of isthmi, narrowed proventricular lumens, and thickened proventricular walls radiographically. Cryptosporidium parasites were found only in the ductal epithelium of the proventricular glands in three of the tissue samples provided for necropsy. To date, there have been no reports concerning the pathogenicity, nor the location, of avian genotype III in avian hosts. Our report confirms, for the first time, the presence of avian genotype III in peach-faced lovebirds in Japan and also reveals the location in the avian host. PMID- 20945798 TI - A chronicle of serologic response in commercial layer chickens to vaccination with commercial F strain Mycoplasma gallisepticum vaccine. AB - Vaccination of multi-age layer operations, wherein one million plus commercial layer chickens are housed, has been spurious until the development of a self propelled, constant-speed spray vaccinator. Still, even with its use, live Mycoplasma gallisepticum (MG) vaccinations have been questionable in terms of seroconversion. Using the vaccinator as a research tool over the past 5 yr, factors have been elucidated which impact seroconversion to one live MG vaccine in particular, the F strain of MG (FMG). These factors include the type of nozzle used to spray the vaccine, the temperature of the water used to rehydrate and administer the vaccine, and the pH and osmolarity of the fluid used to apply the vaccine. In the present study, one farm was monitored for its seroconversion rates over 4 1/2 yr, during which time the FMG vaccination protocol was amended as factors were identified that enhanced seroconversion rates. The results of this study showed that implementation and inclusion of the optimized factors into the vaccination protocol for FMG enhanced seroconversion rates because they went from an initial 50%-55% positive seroconversion rate to a consistent 100% positive seroconversion rate over the 56-mo study period. PMID- 20945799 TI - An unusual case of coccidiosis in laboratory-reared pheasants resulting from a breach in biosecurity. AB - An outbreak of coccidiosis in laboratory-reared Chinese ring-necked pheasants (Phasianus colchicus) resulted in high morbidity and moderate mortality. The outbreak was associated with a breach in biosecurity caused by the cleaning of a sewer line with a mechanical device, resulting in extensive splattering of fecal material throughout the "clean room" where birds were held prior to use in coccidiosis experiments. Mortality and morbidity in the affected birds were seen exactly 5 days after the incident, after birds had been moved to another room for experimental use, corresponding closely with the known prepatent or preclinical period of Eimeria phasiani and Eimeria colchici. Gross lesions in the affected birds varied from dehydration to intestinal and ventricular hemorrhage. Microscopic examination confirmed a diagnosis of severe intestinal coccidiosis. This report underscores the ease of contamination of experimental birds leading to coccidiosis outbreaks during breaches of management and biosecurity. PMID- 20945800 TI - Isolation of highly pathogenic avian influenza H5N1 from table eggs after vaccinal break in commercial layer flock. AB - In May 2009, during routine monitoring of a commercial layer flock of about 87,000 birds kept in cages in 4 different houses that had been vaccinated 3 times with an inactivated H5N1 vaccine at weeks 1, 7, and 16, highly pathogenic avian influenza (HPAI) virus of subtype H5N1 was isolated and detected by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in tracheal and cloacal swabs collected from houses 3 and 4; 7 days after onset of clinical signs, there was an increase in mortality accompanied by a decrease in egg production and egg quality. In addition, using RT-PCR, the viral RNA could be detected from albumin and eggshell as well. Seven days after the onset of the clinical signs, the hemagglutination inhibition (HI) titers in the affected houses were 3.2 and 1.9 log2. In the other two houses, there were no clinical signs, and all tested samples were negative using virus isolation and real-time RT-PCR. The HI titers were 6.6 and 7.0 log2 in nonaffected houses. The isolated virus from egg albumin showed high nucleotides and amino-acid identities and clustered with viruses from recently H5N1-confirmed human infections and poultry from different places in Egypt. Moreover, several amino-acid substitutions of viral H5 protein were observed. The vaccinal break seems to be associated with immune escape mutants and/or improper vaccination. The role of contaminated eggs as a source of infection and as a vehicle for spread of the virus should be considered in area with avian influenza outbreaks. PMID- 20945801 TI - Pathology and microbiology of dermal squamous cell carcinoma in young brown chickens reared on reused litter. AB - Dermal squamous cell carcinoma (DSCC) was found in young brown chicken flocks reared on reused litter in Japan. DSCC was often detected at slaughter from April 2007 to March 2009, especially in June and July 2007. No DSCC was observed in the broiler chickens on the farms. Twelve 11-wk-old brown chickens with DSCC were investigated pathologically and microbiologically. Various degrees of crater-like skin lesions were found on the back, waist, neck, legs, abdomen, and wings of the carcasses. The feather follicles were enlarged. The feather follicular epithelial cells proliferated, and the squamous cells proliferated neoplastically in association with collagen fibers and fibroblasts in the dermis under the feather follicular epithelium. "Keratin pearl" structures were often seen in the dermis. Immunohistochemically, the keratin antigen was positive in the neoplastically proliferated squamous cells in the dermis. Avian leukosis virus antigens could not be found in the neoplastic squamous cells in the dermis. Ultrastructurally, no viral agents could be detected in the skin with DSCC. Virologically, reverse transcription-polymerase chain reactions of the skin with DSCC for fowlpox virus and avian leukosis virus were negative. No viruses could be isolated from the skin with DSCC. This study suggests that the chicken breed, reused litter, and season may be associated with the incidence of DSCC in brown chickens. PMID- 20945802 TI - Safety, permanency, and well-being revisited. PMID- 20945803 TI - Reforming child welfare: an integrated approach. AB - Throughout the 1990s, child welfare systems were exposed to intense pressure. As a result, most systems have undertaken processes of reform and change. This article discusses the strategic development of New Zealand's service system in child welfare. A partnership between managerial discipline and professional leadership has been critical in the service system reform. With respect to management, a strong vision, a culture of high performance, and greater organizational stability and confidence provided the platform on which professional reforms could be established-including the knowledge framework, the service model, the practice package, and staff support. The managerial efforts that have provided the platform for the professional reforms are discussed, followed by an exploration of the professional reform package. PMID- 20945804 TI - Effect of child protective services system factors on child maltreatment rereporting. AB - This study examined how child protective services (CPS) systems respond to initial and subsequent reports in the context of child maltreatment rereporting and to what extent CPS system factors are associated with the risk of rereporting after controlling for abuse type and child and family factors. This study followed 67,243 families who were reported to the CPS agencies in seven counties in Florida for child abuse and neglect over a period of 5.4 years and found that 14,218 families had one or more child maltreatment rereports. Key findings include that CPS system factors were significantly different from initial report to subsequent reports. Five CPS system factors, reporting source, contact by CPS workers, investigative level at intake, postinvestigation services, and duration ofCPS involvement were significantly associated with the risk of child maltreatment rereporting. Multivariate analyses found that CPS system factors were substantially different for three categories ofrereporting, unsubstantiated rereports, substantiated rereports, and recurrence reports. Interpretations and implications for practice are discussed. PMID- 20945805 TI - Comparing differential responses within child protective services: a longitudinal examination. AB - This study examines the efficacy of a family differential response program to lower rates of (1) reentry into child protective services (CPS) and (2) child removal. Data were collected over 20 months from one region of British Columbia, Canada. Comparisons between family development response (FDR) and cases assigned to regular investigation (INV) suggest that FDR does not decrease recidivism to CPS. However, fewer children in the FDR group were removed than children in the INV group. PMID- 20945806 TI - Let's help caregivers and children in informal kinship care: de facto custodian legislation. AB - Caregivers in informal kinship care encounter numerous difficulties when lacking a legal relationship with the children in their care. The de facto custodian guardianship, a concept that is relatively unknown in social work, provides an additional legal option to caregivers by allowing them to present their caregiving history during custody hearings. This article introduces the significance of the de facto concept and provides detailed information on its components and limitations. Recommendations are forwarded for social education and practice. PMID- 20945807 TI - Understanding caregiving patterns, motivations, and resource needs of subsidized family, friend, and neighbor child care providers. AB - Family, friend, and neighbor (FFN) caregivers play important roles in delivering subsidized noncustodial child care. Yet, little is known about these noncustodial caregivers. This article profiles the caregiving experiences, motivations, and resource needs of these providers, based on a survey of 301 randomly selected FFN providers in one state. Kecommendations are offered for strengthening public supports to enhance the quality of this form of caregiving. PMID- 20945808 TI - Vulnerable infants program of Rhode Island: promoting permanency for substance exposed infants. AB - The Vulnerable Infants Program of Rhode Island is a care coordination program to promote permanency for substance-exposed infants by addressing parental needs and increasing collaboration among social service agencies. Over the first four years of the program, there was a decrease in time spent in the newborn nursery beyond medical necessity and identification of permanent placements by 12 months for 84% of infants, with the majority of infants (78%) placed with biological parents or relatives. PMID- 20945809 TI - Occupational burnout levels in emergency medicine--a nationwide study and analysis. AB - INTRODUCTION: The specificity of the emergency medical act strongly manifests itself on account of a wide series of psycho-traumatizing factors augmented both by the vulnerable situation of the patient and the paroxysmal state of the act. Also, it has been recognized that the physical solicitation and distress levels are the highest among all medical specialties, this being a valuable marker for establishing the quality of the medical act. MATERIAL AND METHODS: We have surveyed a total of 4725 emergency medical workers with the MBI-HSS instrument, receiving 4693 valid surveys (99.32% response rate). Professional categories included Emergency Department doctors (M-EMD), ambulance doctors (M-AMB), ED doctors with field work in emergency and resuscitation (including mobile intensive care units and airborne intensive care units) (D-SMU), medical nurses in Emergency Departments (N-EMD), medical nurses in the ambulance service (N AMB), ED medical nurses with field activity in emergency and resuscitation (N SMU), ambulance drivers (DRV) and paramedic (EMT). The n values for every category of subjects and percentage of system coverage (table 3) shows that we have covered an estimated total of 29.94% of the Romanian emergency medical field workers. RESULTS: MBI-HSS results show a moderate to high level of occupational stress for the surveyed subjects. The average values for the three parameters, corresponding to the entire Romanian emergency medical field were 1.41 for EE, 0.99 for DP and 4.47 for PA (95% CI). Average results stratified by professional category show higher EE average values (v) for the M-SMU (v=2.01, 95%CI) and M EMD (v=2.21, 95% CI) groups corresponding to higher DP values for the same groups (vM-EMD=1.41 and vM-SMU=1.22, 95% CI). PA values for these groups are below average, corresponding to an increased risk factor for high degrees of burnout. Calculated PA values are 4.30 for the M-EMD group and 4.20 for the M-SMU group. CONCLUSIONS: Of all surveyed groups, our study shows a high risk of burnout consisting of high emotional exhaustion (EE) and high depersonalization (DP) values for Emergency Department doctors, Emergency, and Resuscitation Service doctors (M-SMU). Possible explanations for this might be linked to high patient flow, Emergency Department crowding, long work hours and individual parameters such as coping mechanisms, social development and work environment. PMID- 20945810 TI - Quality of life of post-stroke patients and their caregivers. AB - With improvements in health care, more people survive stroke but many have to cope with the physical, psychological, social and functional sequelae, resulting in increased personal and public costs. Cerebral stroke causes a significant deterioration of the patient's functioning and worsening of her/his quality of life. Long-term disability caused by stroke is a common problem in all countries and its incidence increases markedly with advancing age. The assessment of the Quality of Life could be as well the evaluator of sequelae of stroke as an indicator of the effectiveness of the post-stroke rehabilitation. In this review article, the contemporary state of art in assessment of the post-stroke Quality of Life has been presented. The emphasis was placed on participation in terms of personal factors and environmental factors of post-stroke persons and their caregivers. PMID- 20945811 TI - The brain--the organ of the psychic (the lesions/ the defense mechanisms). AB - The article is based on the Leopold Szondi theory (March 11, 1893 - January 24, 1986), who was a Hungarian psychiatrist. He is known for the psychological tool that bears his name, the Szondi test. He developed a form of depth psychology that had some prominence in Europe in the mid-20th century, but has been ignored for the most part), the study seeks to correlate the szondian test results with the imagistic ones on a wide-range pathology. In the Neurosurgery Department, patients are investigated using modern exploration methods (MRI, CTscan, and computed EEG, etc.) in order to identify possible somatic lesions. The study's subjects selected during 2000-2004 from the patients admitted and investigated for neurosurgical conditions; they were divided into two subgroups, based on whether the organic lesions were or were not present (the independent variable). The exclusion criterion was a lesion due to external causes. Statistically meaningful there are seven types of Ego profiles, in relation with the lesion: the archaic ego [0 -], the inhibited ego [- +], the adaptive ego [- -], the narcissist ego [+ +], the identified ego [+/- 0], the fugitive ego [+/- -] and the possessed ego [0 +]. The nexus in the destiny's analysis description highlights the dialectic between the Ego's functions and the drived dangers when facing the demands of the concrete reality. PMID- 20945812 TI - Confocal scanning laser ophthalmoscopy in glaucoma diagnosis and management. AB - The early diagnosis and detection of progression are two key-elements in the actual management of glaucoma. The current opinion in clinical practice is to quantify the structural damage for a better follow-up of the patient and the standardization of the results. The present review is a concise survey of literature covering the period of 1990-2010, documenting the evidence-based role of confocal scanning laser ophthalmoscopy in glaucoma diagnosis and management. PMID- 20945813 TI - Deficiencies of proteins C, S and antithrombin and factor V Leiden and the risk of ischemic strokes. AB - Although hypercoagulable states are most often associated with venous thromboses, arterial thromboses are reported in protein C, protein S, antithrombin deficient patients and in those with factor V Leiden, components of hereditary thrombophilia. Because these arterial thromboses (peripheral artery disease, myocardial infarction, and cerebral infarction) mostly affect young persons, aged below 45 years, it is important to test and treat these thrombophilic defects. Because the relation thrombophilia--arterial thromboses is still under debate, due to conflicting data, this article is a review of studies published in literature regarding the implication of the above-mentioned thrombophilic defects in cerebral infarcts. PMID- 20945814 TI - Intervention of the occlusion relations in the appearance of the modifications in sagittal and transversal plan in the anomalies of the class III angle. AB - During the development of the neuronic and visceral cranium, an important number of factors, not only genetic, but also functional, led to the apparition of some different aspects of growing at the level of each section: the basis of the cranium, the basis of the maxillary, dental alveolus, dental arch. All these "aggravating" or "compensatory" changes are added to the level of the occlusion plan, leading to the establishment of the occlusion relations in the three plans. From now on, the occlusion will directly influence the development at the level of the above-described sections. PMID- 20945815 TI - Right ventricular myocardial infarction and pulmonary embolism differential diagnosis--a challenge for the clinician. AB - It is frequently recognized in medical literature as well as in daily clinical practice that right ventricular myocardial infarction and pulmonary embolism are two of the most challenging clinical pictures to differentiate in cardiology and the treatment, often chosen upon a mixture of clinical suspicion criteria subsequently confirmed by other diagnostic methods, can lead to therapeutic success. Differential diagnosis is often difficult due to similar clinical picture, unspecific electrocardiographic changes and unspecific biological markers. It is very important to know the risk factors and the associated comorbidities for these two clinical entities in order to be able to interpret them contextually. In most cases the diagnosis key is the clinical suspicion. Usually in evaluating these cases we are in the position of choosing more complex diagnostic procedures, most likely not available in Emergency Department. In conclusion it is expected from the clinician to use the available methods with a thorough approach to details but in the same time considering the whole clinical picture. PMID- 20945816 TI - Molecular basis of vascular events following spinal cord injury. AB - The aim of this article is to analyze the effects of the molecular basis of vascular events following spinal cord injury and their contribution in pathogenesis. First of all, we reviewed the anatomy of spinal cord vessels. The pathophysiology of spinal cord injuries revealed two types of pathogenic mechanisms. The primary event, the mechanic trauma, results in a disruption of neural and vascular structures into the spinal cord. It is followed by secondary pathogenesis that leads to the progression of the initial lesion. We reviewed vascular responses following spinal cord injury, focusing on both primary and secondary events. The intraparenchymal hemorrhage is a direct consequence of trauma; it has a typical pattem of distribution into the contused spinal cord, inside the gray matter and, it is radially extended into the white matter. The intraparenchymal hemorrhage is restricted to the dorsal columns, into adjacent rostral and caudal spinal segments. Distribution of chronic lesions overlaps the pattern of the early intraparenchymal hemorrhage. We described the mechanisms of action, role, induction and distribution of the heme oxygenase isoenzymes 1 and 2. Posttraumatic inflammatory response contributes to secondary pathogenesis. We analyzed the types of cells participating in the inflammatory response, the moment of appearance after the injury, the decrease in number, and the nature of their actions. The disruption of the blood-spinal cord barrier is biphasic. It exposes the spinal cord to inflammatory cells and to toxic effects of other molecules. Endothelin 1 mediates oxidative stress into the spinal cord through the modulation of spinal cord blood flow. The role of matrix metalloproteinases in blood-spinal cord barrier disruption, inflammation, and angiogenesis are reviewed. PMID- 20945817 TI - Integrative emphases on intimate, intrinsic propensity/pathological processes- causes of self recovery limits and also, subtle related targets for neuroprotectionl pleiotropicity/multimodal actions, by accessible therapeutic approaches--in spinal cord injuries. AB - BACKGROUND: The last two decades have come up with some important progresses in the genetic, immune, histochemical and bio (nano)-technological domains, that have provided new insight into cellular/molecular mechanisms, occurring in the central nervous system (CNS)--including in spinal cord-injuries. METHODS: In previous works, emerging from our theoretical and practical endeavors in the field, we have thoroughly described the principal intimate propensity and the pathophysiological processes--representing intrinsic limitations for self recovery after SCI, and, at the same time, subtle targets for neuroprotection/recovery--and reviewed the main related worldwide-published reports. The aim of this paper is to emphasize the connections between such main aspects and some feasible integrative solutions, including the ones for clinical practice. RESULTS: Consequently, we stress upon some therapeutic suggestions regarding this subject matter by systematizing the most up to date and efficient ones--obviously, within major limits, according to the very low capacities of CNS/ spinal cord (SC) to post-injury self preserve and recover. Moreover, we also talk about accessible drugs, respectively those being already in clinical use (but at present, mainly used to treat other conditions, including the neurological ones) and hence, with relatively well known, determined effects and/or respectively, restrictions. DISCUSSIONS: The recent advances in the knowledge on the basic components of the afore mentioned CNS/ SC propensity for self destroying and inefficient endogenous repair mechanisms in the actual new context, will hopefully be, from now on, more effectively correlated with revolutionary--mostly still experimental--treatments, especially by using stem cells within tissue engineering, including, if needed, more advanced/courageous approaches, based on somatic cell nuclear transfer (SCNT). CONCLUSIONS: This paper contains the scientific motivated highlighting of some already available drugs, "neuroprotective" (and not only) properties too, which enable practitioners with (although not yet capable to cure--but anyway) more efficient therapeutic means, to approach the extremely difficult and still painfully disappointing domain, of spinal cord injury (SCI). PMID- 20945818 TI - Vascular dysfunctions following spinal cord injury. AB - The aim of this article is to analyze the vascular dysfunctions occurring after spinal cord injury (SCI). Vascular dysfunctions are common complications of SCI. Cardiovascular disturbances are the leading causes of morbidity and mortality in both acute and chronic stages of SCI. Neuroanatomy and physiology of autonomic nervous system, sympathetic and parasympathetic, is reviewed. SCI implies disruption of descendent pathways from central centers to spinal sympathetic neurons, originating in intermediolateral nuclei of T1-L2 cord segments. Loss of supraspinal control over sympathetic nervous system results in reduced overall sympathetic activity below the level of injury and unopposed parasympathetic outflow through intact vagal nerve. SCI associates significant vascular dysfunction. Spinal shock occurs during the acute phase following SCI and it is a transitory suspension of function and reflexes below the level of the injury. Neurogenic shock, part of spinal shock, consists of severe arterial hypotension and bradycardia. Autonomic dysreflexia appears during the chronic phase, after spinal shock resolution, and it is a life-threatening syndrome of massive imbalanced reflex sympathetic discharge occurring in patients with SCI above the splanchnic sympathetic outflow (T5-T6). Arterial hypotension with orthostatic hypotension occurs in both acute and chronic phases. The etiology is multifactorial. We described a few factors influencing the orthostatic hypotension occurrence in SCI: sympathetic nervous system dysfunction, low plasma catecholamine levels, rennin-angiotensin-aldosterone activity, peripheral alpha adrenoceptor hyperresponsiveness, impaired function of baroreceptors, hyponatremia and low plasmatic volume, cardiovascular deconditioning, morphologic changes in sympathetic neurons, plasticity within spinal circuits, and motor deficit leading to loss of skeletal muscle pumping activity. Additional associated cardiovascular concerns in SCI, such as deep vein thrombosis and long term risk for coronary heart disease and systemic atherosclerosis are also described. Proper prophylaxis, including non-pharmacologic and pharmacological strategies, diminishes the occurrence of the vascular dysfunction following SCI. Each vascular disturbance requires a specific treatment. PMID- 20945819 TI - Complementary treatment with oral pidotimod plus vitamin C after laser vaporization for female genital warts: a prospective study. AB - This is a prospective study to assess a complementary treatment for genital warts after laser vaporization. 62 patients were enrolled in two randomized groups: Al: laser vaporization alone. A2: laser vaporization, followed with Pidotimod plus vitamin C for 2 1/2 months. The latter treatment shortened the time of warts remission and marginally decreased the rate of the warts' recurrence: 81% versus 67% (N.S.). Despite the non-significant difference, this complementary treatment seems to have some efficiency. PMID- 20945820 TI - Nonoperative management of high degree hepatic trauma in the patient with risk factors for failure: have we gone too far? AB - BACKGROUND: Nonoperative management (NOM) of liver trauma is currently rather the rule than the exception. However, the current evidence presents subgroups of patients at higher risk for NOM failure. These patients must be treated more cautiously regarding the NOM approach. METHOD: A case report of 3 polytrauma patients (Injury Severity Score > 17) with high-degree liver trauma managed nonoperatively. RESULTS: The first case presented is the one of a polytrauma patient with degree IV liver injury and impaired mental status. It was a high risk for NOM failure because there was an angiographically hemostasis. The second case is one of a polytrauma patient who became hemodynamically stable after the administration of 2000 ml of fluid intravenously. There was a nonoperative approach with angiography and embolization of degree IV liver injury. Despite the success of the nonoperative treatment, there was an important hepatic necrosis following embolization. The third case is one of a polytrauma patient with a degree IV hepatic injury. Success was accomplished in NOM without an angiography. CONCLUSIONS: Nonoperative management of liver injuries can be applied safely even in high degree hepatic trauma. In hemodynamically metastable patients or impaired mental status patients, the nonoperative approach can be applied successfully, but the trauma surgeon must be very cautious. PMID- 20945821 TI - Cerebrolysin adjuvant treatment in Broca's aphasics following first acute ischemic stroke of the left middle cerebral artery. AB - BACKGROUND: The aim of our study was to assess the efficacy of Cerebrolysin administration in Broca's aphasics with acute ischemic stroke. METHODS: We registered 2212 consecutive Broca's aphasics following an acute ischemic stroke admitted in four departments of neurology in Romania, between September 2005 and September 2009. Language was evaluated with the Romanian version of the Western Aphasia Battery (WAB). The following inclusion criteria were used for this study: age 20-75 years, admission in the hospital within 12 hours from the onset of the symptoms, diagnosis of first acute left middle cerebral artery (MCA) ischemic stroke, presence of large artery disease (LAD) stroke, a NIHSS score of 5-22 points, and a therapeutic time window within 72 h. Fifty two patients were treated with Cerebrolysin (Cerebrolysin group) as an adjunctive treatment. A placebo group, which received saline infusions (n=104 patients) were matched to the NIHSS and WAB scores, gender and age of the Cerebrolysin group at baseline. We assessed spontaneous speech (SS), comprehension (C), repetition (R), naming (N), and Aphasia Quotient (AQ) scores of the two groups in an open label design, over 90 days, the mRS scores and mortality. RESULTS: The Cerebrolysin and the placebo groups had similar age (66 +/- 8 versus 65 +/- 8 years) and sex ratio (14/38 versus 30/74). The mean AQ scores and the mean subscores for 3 subtests of WAB (SS, R, N) were similar at baseline and improved in the Cerebrolysin group significantly (p < 0.05) over placebo group at all study time points. The mRS score at 90 days was also lower in the Cerebrolysin group than in the placebo group. Cerebrolysin and placebo were both tolerated and safe, and no difference in the mortality rate was seen (3.8% in each group). CONCLUSION: Cerebrolysin is effective for the treatment of Broca's aphasics with a first acute ischemic stroke of the left MCA territory. PMID- 20945822 TI - Giant adrenal cyst: case study. AB - One of the rarest situations regarding an adrenal incidentaloma is an adrenal cyst. We present the case of a 61-year-old male patient diagnosed with peritonitis. During surgery, a right adrenal tumor of 2 cm is discovered. The patient was referred to endocrinology. 6 months later the diameter of the tumor is 7 times bigger than the initial stage. It has no secretory phenotype, except for the small increase of serum aldosterone and the 24-h 17-ketosteroids. Open right adrenalectomy is performed and a cyst of 15 cm is removed. The evolution after surgery is good. The pathological exam reveals an adrenal cyst with calcifications and osteoid metaplasia. The immunohistochemistry showed a positive reaction for CD34 and ACT in the vessels and VIM in the stroma. The adrenal cysts are not frequent and represent a challenge regarding the preoperative diagnostic and surgical procedure of resection. The pathological exam highlights the major aspects. PMID- 20945823 TI - Locally aggressive colonic and rectal cancer--clinical trial. AB - This clinical trial studies local invasions from primary colonic and rectal cancers (urinary bladder, abdominal wall, small bowls, uterus, vagina, stomach, bile tract, spleen, duodenum, pancreas, ureters, kidneys), with or without undiscovered metastasis. Primary locally aggressive colonic and rectal cancers include tumors that are staged T4N1-2Mx on diagnosis, and are often associated with a lower prognosis than earlier cancers. Diagnosis is based on thorough clinical evaluation, imagistic support: abdominal XR with contrast (barium enema), colonoscopy, abdominal and pelvic ultrasound exam, endoscopic endolumenal ultrasound exam, abdominal and pelvic CT/IRM with contrast (administrated both orally and intravenously), PET Scan, and intra-operatory confirmation. The primary symptom was pain. Locally aggressive colonic and rectal cancers, primary or secondary, can extend to any visceral or parietal structure. The ability to perform a total resection is based upon anatomical localization and on the fixation of other organs to the lesion. Identifying the anatomical extension provides a better appreciation of the purpose of the tumoral resection. Radical nuanced surgery is the base of treatment of the locally aggressive colon-rectal cancer. The studies have shown that in certain localizations of the colon-rectal cancer, the locally aggressive forms can be better controlled by using multimodal therapy, including radiotherapy, either external or guided intraoperatory radiotherapy and chemotherapy with much better results. PMID- 20945825 TI - Trends of rheumatoid arthritis monitorization in Romania. AB - BACKGROUND: rheumatoid arthritis (RA) is associated with the loss of overall functionality, which leads to substantial economic losses. Second line agents used in RA treatment require careful monitorization in terms of efficiency and tolerability. OBJECTIVE: trends, predictive factors and characteristics of clinical, biological and radiological RA monitorization in a cross sectional observational cohort study, conducted on over 206 patients in Romania, with a 12 months follow up (December 2007 - December 2008). METHOD: Cases were recruited from the south-west region of the country, covering a geographical area of 23 counties. Patients were invited to complete three sets of interviews (collected by post) in a consent letter, containing self reported questionnaires, at 6 months intervals: an original questionnaire (which included quantitative self reported of pain, disease activity and fatigue on visual analogue scale-VAS), Health Assessment Questionnaire-HAQ-Disability and Discomfort Scales and EUROQOL EQ-5D, validated in Romanian (obtaining a user agreement by authors of the original version). RESULTS: analysis was carried out in SPSS 10. The cohort enrolled 206 patients, with the average age of 54.90 +/- 12.67 years, 66% urban, 86.4% women, 29.1% professionally active, 48.5% graduates of primary education. The average disease duration after diagnosis of RA was of 9.40 +/- 8.87 years. The duration of the treatment reported at baseline was of 2.70 +/- 2.64 years. Most patients followed a program of monthly monitoring at a general practitioner (GP) (41.7% at baseline and 37.1% to 12 months). Visits to the rheumatologist followed a monthly regimen (32.3% at baseline and 31.7% to 12 months) or a 2 months interval (19.4% at baseline and 29.6% to 12 months, p = 0.000). Biological monitoring was quarterly (39.6% and 53.2% at 12 months; p = 0.000) or at 2 months interval (26.2% at baseline and 16.7% to 12 months, p = 0.000). X-ray monitoring lacked in over half the cases in a year of disease progression (63.3% at 6 months and 62.2% at 12 months), although it sums between 1 and 3 radiographs to one third of the cases (36.8%), CONCLUSION: generally, in our country, there is a lack of aggregation in the dispensarization algorithm of patients with RA; consequently, the decision is awarded to the human factor. Under these circumstances, some patients are over evaluated. Promoting a dispensarization guide for RA patients could induce benefits both clinically and economically. Therefore, we submit a proposal of recommendations as a guideline for clinical, biological and radiological monitoring, according to the phase and stage of RA. PMID- 20945824 TI - The impact of hepatitis viruses on chronic lymphoproliferative disorders- preliminary results. AB - The aim of this study is to analyze a group of patients with chronic lymphoproliferative disorders associated with B, C, D hepatitis viral infection. This group of chronic lymphoproliferative disordered patients with associated hepatitis viral infection has been diagnosed and monitored in the Hematology Department of the University Emergency Hospital of Bucharest, between December 2007 and January 2009. Our study is meant to observe the influence of the viral infection on clinical and biological evolution of the enrolled patients. The diagnosis of the chronic lymphoproliferative disorder was based on the bone marrow/ lymph node biopsy and flow-cytometry analysis. The positive diagnosis for hepatitis viral infection was established by ELISA serological tests and viremia was performed by TaqMan method at INBI "Matei Bals" Bucharest. The analyzed group is made up of 41 patients, 25/41 (60.97%) females and 16/41 (39.02%) males, with ages: 20-50 years old--6/41 (14.63%), 51-70 years old--23/41 (56.09%) and over 71 years old--12/41 (29.26%) patients. The histological types of CLD: B-cell non Hodgkin's lymphoma--in 28/41 (68.29%) patients, T-cell non-Hodgkin's lymphoma- 2/41 (4.87%) patients, Hodgkin's lymphoma--2/41 (4.87%), chronic lymphocytic leukemia--7/41 (17.07%), Waldenstrom disease--2/41 (4.87%) patients. Regarding the type of CLD, 19/41 (46.34%) of the patients have an aggressive type of CLD and 22/41 (53.65%) a non-aggressive type of CLD. The hepatitis viral infection distribution in our patients: 14/41 (34.14%) have HBV infection, 24/41 (58.53%) have HCV infection, double/triple association of viral infection was found in 3/41 (7.31%) patients. Within HBV infection subgroup 9/14 (64.28%) patients have an aggressive type of CLD and 5/14 (35,71%) patients have a non-aggressive type, whereas within the group with HCV infection we found a different distribution: 9/24 (37,5%) patients with aggressive type and 15/24 (62.5%) with non-aggressive type of CLD. The clinical parameters monitored were: B signs were present in 19/41 (43.34%) patients, the superficial or profound adenopathies--were found in 29/41 (70,73%) patients, hepatomegaly--in 38/41 (92,68%) patients, splenomegaly- in 21/41 (51.21%) patients, extra-nodal involvements in 10/41 (24,39%) patients and most frequent in the non-aggressive type of CLD--6/10 (60%) patients. The hematological and biochemical parameters were: the presence of anemia and thrombocytopenia--found in a small number of patients; lymphocytosis--positive in 33/41 (80.48%) patients, most with HCV infection and non-aggressive type of disease, the presence of autoimmune hemolytic anemia--in 4/41 (9.75%) patients, cryoglobulins--8/41 (19.51%) patients, all with HCV infection; also the liver function was monitored. Antiviral therapy was administered to 12/41 (29.26%) patients--Lamivudine to 8/41 (19.51%) patients and Ribavirine/Interferon to 4/41 (9.75%) patients. Chemotherapy was given in 32/41 (78%) patients. Monoclonal antibodies anti CD20 (Rituximab) therapy was associated in 6/41 (14.63%) patients. CONCLUSIONS: A high incidence in female sex of over 50 years old was noticed. A strong association between B-cell chronic lymphoproliferative disorders and hepatitis viral infection B, C, D was revealed, the most frequent being the C hepatitis virus, associated with the non-aggressive type of CLD, extra-nodal involvement, splenomegaly, lymphocytosis, cryoglobulins, cytolysis and colestasis. The clinical and biological disease history will be monitored during chemotherapy and antiviral treatment. PMID- 20945826 TI - Investigation of subarachnoid haemorrhage: does the buck stop with CT? AB - BACKGROUND AND AIM: In patients suspected of having a subarachnoid haemorrhage (SAH), a normal CT should be followed by lumbar puncture (LP) to detect xanthochromia. We studied the practice of performing a LP following a normal CT in patients with a clinical suspicion of SAH in a District General Hospital. We aimed to assess whether patients were being fully investigated for SAH and whether standards were being met. METHODS: This was a prospective study aiming to improve the patient's care by implementing the best practice. We initially recorded CT and LP results of patients with suspected SAH (phase 1) and presented the results to the referring clinicians. After a period of time, data was re collected to study any change in practice (phase 2). RESULTS: In phase 1, 36 of 61 patients (59.0%) with a normal CT had a subsequent LP compared to 67/104 (64.4%) in the second phase (p = 0.51). In the first phase, xanthochromia was detected in 1 of 36 patients (2.8%) who had a LP following a normal CT, compared to 1 of 67 patients (1.5%) in the second phase (p = 1.0). CONCLUSION: Approximately a third of patients with symptoms of SAH in both study periods did not undergo LP following a normal CT scan. This is an important finding, as it is known that a normal CT does not exclude the diagnosis of SAH and by not proceeding to LP, patients have not been fully investigated for a SAH. PMID- 20945827 TI - Influence of personalized therapeutic approach on quality of life and psychiatric comorbidity in patients with advanced colonic cancer requiring palliative care. AB - Personalized medical care has been consistently proven in literature as contributing to the maintenance of psychological balance and quality of life in patients suffering from chronic conditions. However, limited research has investigated the role of personalized approach in improving these parameters in patients with advanced incurable diseases. The scope of this paper was to investigate the possible impact of personalized care condition in advanced colon cancer patients, requiring palliative care. 60 patients (32 M, 28 F) (mean age 64.6) suffering from this disease were randomly assigned to a standard or to a personalized care condition. The latest implied (a) frequent (at least 2 monthly) meetings with the doctor, (b) possibility to be involved in treatment decisions, (c) more information given about diagnosis and prognosis and (d) psychological support provided to the patient and his/her family members, to deal better with daily problems and needs. The design of the study was prospective and consisted of two successive evaluations of quality of life (SF-36 questionnaire) and anxiety and depression (HAD test). Cancer patients pertaining to the personalized treatment approach had both superior quality of life scores (p < 0.05) and lower anxiety (p < 0,01) and depression (p < 0.05) than the control group. A more detailed analysis showed significant differences of vitality and social functioning for subjects pertaining to the study group (p < 0.05), as well as a lower ratio between latent and manifest anxiety (p < 0,01). These results argue in favor of the benefits of a personalized treatment approach for patients with advanced incurable diseases. PMID- 20945828 TI - Pharmaceutical industry in Syria. AB - The aim of this article is to present the development of the pharmaceutical industry in Syria using national and international public data sources. At the end of the 80ies, the pharmaceutical industry in Syria was very poor, covering 6% of the national needs. In less than 20 years, with the government support in terms of legal frame and strategic political engagement, the Syrian pharmaceutical industry finally covered almost 90% of the national needs, in terms of drugs, and exported drugs in around 52 Arabian countries. Beyond covering the local market, the main added values of this huge development consisted in exporting drugs in amount of 150 million dollars per year and providing jobs for 17000 Syrian people, out of which around 85% are women. Strong and weak points of the pharmaceutical sector are taken into consideration in the article and further interventions to support a sustainable development are proposed by the author. PMID- 20945829 TI - FastANOVA: an Efficient Algorithm for Genome-Wide Association Study. AB - Studying the association between quantitative phenotype (such as height or weight) and single nucleotide polymorphisms (SNPs) is an important problem in biology. To understand underlying mechanisms of complex phenotypes, it is often necessary to consider joint genetic effects across multiple SNPs. ANOVA (analysis of variance) test is routinely used in association study. Important findings from studying gene-gene (SNP-pair) interactions are appearing in the literature. However, the number of SNPs can be up to millions. Evaluating joint effects of SNPs is a challenging task even for SNP-pairs. Moreover, with large number of SNPs correlated, permutation procedure is preferred over simple Bonferroni correction for properly controlling family-wise error rate and retaining mapping power, which dramatically increases the computational cost of association study.In this paper, we study the problem of finding SNP-pairs that have significant associations with a given quantitative phenotype. We propose an efficient algorithm, FastANOVA, for performing ANOVA tests on SNP-pairs in a batch mode, which also supports large permutation test. We derive an upper bound of SNP-pair ANOVA test, which can be expressed as the sum of two terms. The first term is based on single-SNP ANOVA test. The second term is based on the SNPs and independent of any phenotype permutation. Furthermore, SNP-pairs can be organized into groups, each of which shares a common upper bound. This allows for maximum reuse of intermediate computation, efficient upper bound estimation, and effective SNP-pair pruning. Consequently, FastANOVA only needs to perform the ANOVA test on a small number of candidate SNP-pairs without the risk of missing any significant ones. Extensive experiments demonstrate that FastANOVA is orders of magnitude faster than the brute-force implementation of ANOVA tests on all SNP pairs. PMID- 20945830 TI - Drying of organic solvents: quantitative evaluation of the efficiency of several desiccants. AB - Various commonly used organic solvents were dried with several different drying agents. A glovebox-bound coulometric Karl Fischer apparatus with a two compartment measuring cell was used to determine the efficiency of the drying process. Recommendations are made relating to optimum drying agents/conditions that can be used to rapidly and reliably generate solvents with low residual water content by means of commonly available materials found in most synthesis laboratories. The practical method provides for safer handling and drying of solvents than methods calling for the use of reactive metals, metal hydrides, or solvent distillation. PMID- 20945831 TI - Distribution of r.p in atomic systems. AB - We present formulas for computing the probability distribution of the posmom s = r . p in atoms, when the electronic wave function is expanded in a single particle Gaussian basis. We study the posmom density, S(s), for the electrons in the ground states of 36 lightest atoms (H-Kr) and construct an empirical model for the contribution of each atomic orbital to the total S(s). The posmom density provides unique insight into types of trajectories electrons may follow, complementing existing spectroscopic techniques that provide information about where electrons are (X-ray crystallography) or where they go (Compton spectroscopy). These, a priori, predictions of the quantum mechanically observable posmom density provide an challenging target for future experimental work. PMID- 20945832 TI - Platform for establishing interlaboratory reproducibility of selected reaction monitoring-based mass spectrometry peptide assays. AB - Mass spectrometry (MS) is an attractive alternative to quantification of proteins by immunoassays, particularly for protein biomarkers of clinical relevance. Reliable quantification requires that the MS-based assays are robust, selective, and reproducible. Thus, the development of standardized protocols is essential to introduce MS into clinical research laboratories. The aim of this study was to establish a complete workflow for assessing the transferability and reproducibility of selected reaction monitoring (SRM) assays between clinical research laboratories. Four independent laboratories in North America, using identical triple-quadrupole mass spectrometers (Quantum Ultra, Thermo), were provided with standard protocols and instrumentation settings to analyze unknown samples and internal standards in a digested plasma matrix to quantify 51 peptides from 39 human proteins using a multiplexed SRM assay. The interlaboratory coefficient of variation (CV) was less than 10% for 25 of 39 peptides quantified (12 peptides were not quantified based upon hydrophobicity) and exhibited CVs less than 20% for the remaining peptides. In this report, we demonstrate that previously developed research platforms for SRM assays can be improved and optimized for deployment in clinical research environments. PMID- 20945833 TI - High-performance isotope labeling for profiling carboxylic acid-containing metabolites in biofluids by mass spectrometry. AB - We have developed a new isotope labeling method, based on the use of isotope coded p-dimethylaminophenacyl (DmPA) bromide as a reagent, combined with liquid chromatography-mass spectrometry (LC-MS) for high-performance metabolome analysis with a focus on profiling carboxylic acid-containing metabolites. Derivatization is simple, fast (1 h plus 30 min for quenching the reaction), and applicable to a wide range of carboxylic acids with a high yield and little or no side reaction products. This labeling method is demonstrated to be not only effective in introducing an isotope tag for accurate metabolite quantification but also improving the chromatographic retention of the metabolites in reversed-phase (RP) LC, enhancing ESI efficiency by 2-4 orders of magnitude, and facilitating the identification of metabolite peaks in LC-MS. In triplicate experiments of a 1:1 ratio of (13)C-/(12)C-DmPA labeled human urine, we were able to detect 2671, 2546, and 2820 ion pairs from metabolites containing one or more carboxylic acid groups. PMID- 20945835 TI - Coordination chemistry in the solid state: reactivity of manganese and cadmium chlorides with imidazole and pyrazole and their hydrochlorides. AB - Crystalline coordination compounds [MnCl(2)(Hpz)(2)] 3, [CdCl(2)(Hpz)(2)] 5, [MnCl(2)(Him)(2)] 9, and [CdCl(2)(Him)(2)] 13 (Him = imidazole; Hpz = pyrazole) can be synthesized in solid state reactions by grinding together the appropriate metal chloride and 2 equiv of the neutral ligand. Similarly, grinding together the metal chlorides with the ligand hydrochloride salts produces the halometallate salts [H(2)pz][MnCl(3)(OH(2))] 1, [H(2)pz][CdCl(4)] 4, [H(2)im](6)[MnCl(6)][MnCl(4)] 8, and [H(2)im](6)[CdCl(6)][CdCl(4)] 11. In contrast, reacting the metal chloride salt with the ligand in concentrated HCl solution yields a second set of salts [H(2)pz][MnCl(3)] 2, [H(2)im][MnCl(3)(OH(2))(2)] 7, and [H(2)im][CdCl(3)(OH(2))].H(2)O 12. Compound 5 can be partly dehydrochlorinated by grinding with KOH to form an impure sample of the pyrazolate compound [Cd(pz)(2)] 6, while recrystallizing 9 from ethanol yielded crystals of solvated [Mn(4)Cl(8)(Him)(8)] 10. The crystal structure determinations of 1, 2, 4, 11, and 12 are reported. PMID- 20945834 TI - Improvement of enzyme properties with a two-step immobilizaton process on novel heterofunctional supports. AB - Novel heterofunctional glyoxyl-agarose supports were prepared. These supports contain a high concentration of groups (such as quaternary ammonium groups, carboxyl groups, and metal chelates) that are capable of adsorbing proteins, physically or chemically, at neutral pH as well as a high concentration of glyoxyl groups that are unable to immobilize covalently proteins at neutral pH. By using these supports, a two-step immobilization protocol was developed. In the first step, enzymes were adsorbed at pH 7.0 through adsorption of surface regions, which are complementary to the adsorbing groups on the support, and in the second step, the immobilized derivatives were incubated under alkaline conditions to promote an intramolecular multipoint covalent attachment between the glyoxyl groups on the support and the amino groups on the enzyme surface. These new derivatives were compared with those obtained on a monofunctional glyoxyl support at pH 10, in which the region with the greatest number of lysine residues participates in the first immobilization step. In some cases, multipoint immobilization on heterofunctional supports was much more efficient than what was achieved on the monofunctional support. For example, derivatives of tannase from Lactobacillus plantarum on an amino-glyoxyl heterofunctional support were 20-fold more stable than the best derivative on a monofunctional glyoxyl support. Derivatives of lipase from Geobacillus thermocatenulatus (BTL2) on the amino glyoxyl supports were two times more active and four times more enantioselective than the corresponding monofunctional glyoxyl support derivative. PMID- 20945836 TI - An unusual 3D entangled Co(II) coordination polymer directed by ferromagnetic molecular building block. AB - A fascinating 3D entangled metal-organic framework, namely, {[Co(2)(bcp)(2)].3H(2)O}(n) (1), was obtained through the solvothermal generation of flexible and long dicarboxylate (bcp) and metal salt. The crystal structure contains a 1D metal chain with bcp ligands wrapped around it in a wavy line and features an unusual entangled topological net. Furthermore, the magnetic behavior of 1 was also studied and indicated the existence of ferromagnetic interaction and long-range ordering character. PMID- 20945837 TI - Asymmetric bromolactonization using amino-thiocarbamate catalyst. AB - A novel amino-thiocarbamate-catalyzed bromolactonization of unsaturated carboxylic acids has been developed. The scope of the reaction is evidenced by 22 examples of gamma-lactones with up to 99% yield and 93% ee. The protocol was applied in the enantioselective synthesis of the key intermediates of VLA-4 antagonists. PMID- 20945838 TI - Structural analysis, spectroscopic, and magnetic properties of the 1D triple bridged compounds [M(dca)2(bpa)] (M = Mn, Fe, Co, Zn; dca = dicyanamide; bpa = 1,2-bis(4-pyridyl)ethane) and the 3D [Ni(dca)(bpa)2]dca.6H2O. AB - The family of compounds [Mn(dca)(2)(bpa)] (1), [Fe(dca)(2)(bpa)] (2), [Co(dca)(2)(bpa)] (3), [Zn(dca)(2)(bpa)] (4), and [Ni(dca)(bpa)(2)]dca.6H(2)O (5), with dca = dicyanamide and bpa = 1,2-bis(4-pyridyl)ethane, has been synthesized. These compounds have been characterized by single crystal (1, 2, 4, and 5) and powder X-ray diffraction (3), by Fourier transform infrared (FTIR), UV vis, and electron paramagnetic resonance (EPR) spectroscopies, and by magnetic measurements. Compound 1 crystallizes in the monoclinic C2/c space group, Z = 4, with a = 16.757(6), b = 9.692(3), and c = 13.073(4) A, and beta = 123.02(2) degrees ; Compound 2 crystallizes in the monoclinic C2/c space group, Z = 4, with a = 16.588(5), b = 9.661(3), c = 12.970(5) A, and beta = 123.16(3) degrees ; Compound 4 crystallizes in the monoclinic C2/c space group, Z = 4, with a = 16.519(2), b = 9.643(2), c = 12.943(2) A, and beta = 123.15(1) degrees ; Compound 5 crystallizes in the monoclinic C2/c space group, Z = 4, with a = 18.504(4), b = 19.802(3), and c = 8.6570(18) A, and beta = 99.74(2) degrees . The compounds 1-4 are isostructural and show a one dimensional (1D) disposition, with the metal(II) ions bridged by double MU(1,5) dca ligands and unusually by a third bridge consisting of the bpa ligand, which adopts a very low torsion angle to accommodate in the structure. This kind of structure is unusual, even considering the voluminous bpa bridge. The compound 5 shows a 3D structure with layers of Ni bpa joined by single dca bridges. Magnetic susceptibility measurements show antiferromagnetic couplings, increasing for 1-3. Compound 5 shows very slight antiferromagnetic interactions. PMID- 20945839 TI - Reductive side of water splitting in artificial photosynthesis: new homogeneous photosystems of great activity and mechanistic insight. AB - Rhodamine photosensitizers (PSs) substituting S or Se for O in the xanthene ring give turnover numbers (TONs) as high as 9000 for the generation of hydrogen via the reduction of water using [Co(III)(dmgH)(2)(py)Cl] (where dmgH = dimethylglyoximate and py = pyridine) as the catalyst and triethanolamine as the sacrificial electron donor. The turnover frequencies were 0, 1700, and 5500 mol H(2)/mol PS/h for O, S, and Se derivatives, respectively (Phi(H(2)) = 0%, 12.2%, and 32.8%, respectively), which correlates well with relative triplet yields estimated from quantum yields for singlet oxygen generation. Phosphorescence from the excited PS was quenched by the sacrificial electron donor. Fluorescence lifetimes were similar for the O- and S-containing rhodamines (~2.6 ns) and shorter for the Se analog (~0.1 ns). These data suggest a reaction pathway involving reductive quenching of the triplet excited state of the PS giving the reduced PS(-) that then transfers an electron to the Co catalyst. The longer lived triplet state is necessary for effective bimolecular electron transfer. While the cobalt/rhodamine/triethanolamine system gives unprecedented yields of hydrogen for the photoreduction of water, mechanistic insights regarding the overall reaction pathway as well as system degradation offer significant guidance to developing even more stable and efficient photocatalytic systems. PMID- 20945840 TI - Hexa boron-dipyrromethene cyclotriphosphazenes: synthesis, crystal structure, and photophysical properties. AB - We have synthesized four examples of a cyclotriphosphazene ring appended with six boron-dipyrromethene dyes N(3)P(3)(BODIPY)(6) by adopting two different methods. In method I, 1 equiv of N(3)P(3)Cl(6) was treated with 6 equiv of meso-(o- or m- or p-hydroxyphenyl)boron-dipyrromethene in tetrahydrofuran (THF) in the presence of cesium carbonate. This afforded N(3)P(3)(BODIPY)(6) in yields ranging from 80 to 90%. In method II, we first prepared hexakis(p formylphenoxy)cyclotriphosphazene N(3)P(3)(CHO)(6) by treating 1 equiv of N(3)P(3)Cl(6) with 6 equiv of 4-hydroxybenzaldehyde in the presence of cesium carbonate in THF. In the second step, N(3)P(3)(CHO)(6) was condensed with excess of pyrrole in the presence of catalytic amount of trifluoroacetic acid (TFA) in CH(2)Cl(2) at room temperature and afforded hexakis(p-phenoxy dipyrromethane)cyclotriphosphazene. In the last step, the hexakis(p-phenoxy dipyrromethane)cyclotriphosphazene was first oxidized with 6 equiv of DDQ in CH(2)Cl(2) at room temperature for 1 h followed by neutralization with triethylamine and further reaction with excess BF(3).Et(2)O afforded the target N(3)P(3)(BODIPY)(6) in 16% yield. The route II was used only for the synthesis of one target compound whereas the route I was used for the synthesis of all four target compounds. The four compounds were characterized by mass, NMR, absorption, electrochemical, and fluorescence techniques. The crystal structure solved for one of the compounds revealed that the P(3)N(3) ring is slightly puckered and the six substituents were not interacting with each other and attained pseudo-axial and pseudo-equatorial positions. The photophysical studies in five different solvents indicated that the compounds exhibit large Stokes' shifts unlike reference monomeric BODIPYs indicating that the compounds are promising for fluorescence bioassays. The quantum yields and lifetimes of compounds 1-4 depends on the type of BODIPY unit attached to the cyclotriphosphazene ring. PMID- 20945841 TI - Synthesis, structure, and solution properties of [(mim-TASN)FeCl2]+ and its MU oxo derivative. AB - A series of iron(III) complexes based on the tetradentate ligand 4-((1-methyl-1H imidazol-2-yl)methyl)-1-thia-4,7-diazacyclononane (L) has been synthesized, and their solution properties investigated. Addition of FeCl(3) to methanol solutions of L yields [LFeCl(2)]FeCl(4) as a dark red solid. X-ray crystallographic analysis reveals a pseudo-octahedral environment around iron(III) with the three nitrogen donors of L coordinated facially. Ion exchange reactions with NaPF(6) in methanol facilitate chloride exchange resulting in a different diastereomer for the [LFeCl(2)](+) cation. X-ray analysis of [LFeCl(2)]PF(6) finds meridional coordination of the three nitrogen donors of L. Electrochemical studies of [LFeCl(2)](+) in acetonitrile display a single Fe(III)/(II) reduction potential at -280 mV versus ferrocenium/ferrocene. In methanol, a broad cathodic wave is observed because of partial exchange of one chloride for methoxide with half potentials of -170 mV and -440 mV for [LFeCl(2)](+/0) and [LFeCl(OCH(3))](+/0), respectively. The equilibrium constants for chloride exchange are 7 * 10(-4) M( 1) for Fe(III) and 2 * 10(-8) M(-1) for Fe(II). In aqueous solutions chloride exchange yields three accessible complexes as a function of pH. Strongly acidic conditions yield the aqua complex [LFeCl(OH(2))](2+) with a measured pK(a) of 3.8 +/- 0.1. Under mildly acidic conditions, the MU-OH complex [(LFeCl)(2)(OH)](3+) with a pK(a) of 6.1 +/- 0.3 is obtained. The MU-oxo complex [(LFeCl)(2)(O)](2+) is favored under basic conditions. The diiron Fe(III)/Fe(III) complexes [(LFeCl)(2)(OH)](3+) and [(LFeCl)(2)(O)](2+) can be reduced by one electron to the mixed valence Fe(III)/Fe(II) derivatives at -170 mV and -390 mV, respectively. From pH dependent voltammetric studies, the pK(a) of the mixed valent MU-OH complex [(LFeCl)(2)(OH)](2+) is calculated at 10.3. PMID- 20945842 TI - Remembrances of self-assemblies past. AB - Research on four types of self-assemblies (micelles, coacervates, gels, and vesicles) is discussed via a particular investigative methodology (in order of appearance): kinetics, dynamic NMR, PGSE-NMR, double-(13)C labeling, molecular dynamics computations, phase diagrams, cryo-HRSEM, rheology, light/electron microscopy, electrophoretic mobility, electroformation, confocal microscopy, and calorimetry. The emphasis here is on how a given method, each in its own special way, illuminates a complex system. PMID- 20945843 TI - A chemical bond theory of quantum size effects of semiconductor clusters. AB - Size dependence effects in semiconductor clusters have been a subject of extensive studies for the last two decades. However, it is still difficult to employ the existing theoretical models to give reliable results of energies for clusters in the whole nanometer region. Here we offer a new theoretical method for the quantum size effects based on the idea that the energy gap shift of the cluster arises from the sum of the surface effect shift and quantum effect shift parts. We express the effects through algebraic relations rather than through variational solutions of the wave equation, without the use of any special adjustable parameter. Results reveal for the first time that the shape of the energy gap shift curve is dominated by the surface energy shift. Our method can also predict quantitatively the size dependence of dielectric constant. The new theoretical findings in the ultrasmall (<1 nm) anatase TiO(2) and the silicon clusters cannot be explained using previous theories. PMID- 20945844 TI - Novel nonvolatile memory with multibit storage based on a ZnO nanowire transistor. AB - We demonstrate a room temperature processed ferroelectric (FE) nonvolatile memory based on a ZnO nanowire (NW) FET where the NW channel is coated with FE nanoparticles. A single device exhibits excellent memory characteristics with the large modulation in channel conductance between ON and OFF states exceeding 10(4), a long retention time of over 4 * 10(4) s, and multibit memory storage ability. Our findings provide a viable way to create new functional high-density nonvolatile memory devices compatible with simple processing techniques at low temperature for flexible devices made on plastic substrates. PMID- 20945845 TI - Large integrated absorption enhancement in plasmonic solar cells by combining metallic gratings and antireflection coatings. AB - We describe an ultrathin solar cell architecture that combines the benefits of both plasmonic photovoltaics and traditional antireflection coatings. Spatially resolved electron generation rates are used to determine the total integrated current improvement under AM1.5G solar illumination, which can reach a factor of 1.8. The frequency-dependent absorption is found to strongly correlate with the occupation of optical modes within the structure, and the improved absorption is mainly attributed to improved coupling to guided modes rather than localized resonant modes. PMID- 20945846 TI - Effective strain in helical rippled carbon nanotubes: a unifying concept for understanding electromechanical response. AB - Despite its importance, little is known about how complex deformation modes alter the intrinsic electronic states of carbon nanotubes. Here we consider the rippling deformation mode characterized by helicoidal furrows and ridges and elucidate that a new intralayer strain effect rather than the known bilayer coupling and sigma-pi orbital mixing effects dominates its gapping. When an effective shear strain is used, it is possible to link both the electrical and the mechanical response of the complex rippled morphology to the known behavior of cylindrical tubes. In combination with objective molecular dynamics, this concept may be useful for understanding the electromechanical characteristics of large scale carbon nanotube assemblies and other individual nanoscale forms of carbon. PMID- 20945847 TI - Quinonoid-bridged chair-shaped dirhenium(I) metallacycles: synthesis, characterization, and spectroelectrochemical studies. AB - Self-assembled, chair-shaped dirhenium(I) macrocyclic compounds featuring the two different bis-chelating quinone dianions (1, L = dhnq(2-); 2, L = dhaq(2-); H(2)dhnq = 6,11-dihydroxy-5,12-naphthacenedione; H(2)dhaq = 1,4-dihydroxy-9,10 anthraquinone) that interface with two fac-Re(CO)(3) cores and a ditopic semirigid N-donor 1,4-bis(5,6-dimethylbenzimidazol-1-ylmethyl)naphthalene (L' = p NBimM) ligand coordinated to the remaining orthogonal site were prepared in high yields. Their structures were confirmed by single-crystal X-ray diffraction analysis. Electrochemical assessments, using cyclic voltammetry (CV) and UV-vis NIR spectroelectrochemistry (SEC), revealed the existence of two well-separated, single-electron quinone ligand-centered, reversibly accessible 0, -1, and -2 redox states. Among the two singly reduced radical complexes, the symmetrically bridged quinone complex 1(*-), showed a strong absorption in the NIR regions, which was not observed for the neutral and doubly reduced states, analogous to that of the free dhnq(3*-) quinone. In contrast, when 2 was reduced to 2(*-), a broad signal at 866 nm was observed, very similar to the reduced dhaq(3*-) quinone. This difference in spectral behavior in the singly reduced states is likely due to the annealed benzene ring in 1 and dhnq(2-) because of its symmetrical pi-electron system, which is perturbed to a lesser degree compared to asymmetric 2 and dhaq(2-). Reduction to 1(*-) produces a small but not negligible g factor anisotropy (Deltag = 0.024) in the electron spin resonance (ESR) signal, indicative of a very small metal-centered spin (5%), but 2(*-) shows a g value in the expected range for organic radicals (no detectable Deltag). Thus, the combined investigations reveal that the singly reduced metallacycles are best described as being highly stable, noncommunicating, localized, quinonoid-centered radical complexes, [(CO)(3)Re(I)(MU-L(3*-))(MU-L')Re(I)(CO)(3)](*-). PMID- 20945848 TI - Raman scattering at pure graphene zigzag edges. AB - Theory has predicted rich and very distinct physics for graphene devices with boundaries that follow either the armchair or the zigzag crystallographic directions. A prerequisite to disclose this physics in experiment is to be able to produce devices with boundaries of pure chirality. Exfoliated flakes frequently exhibit corners with an odd multiple of 30 degrees , which raised expectations that their boundaries follow pure zigzag and armchair directions. The predicted Raman behavior at such crystallographic edges however failed to confirm pure edge chirality. Here, we perform confocal Raman spectroscopy on hexagonal holes obtained after the anisotropic etching of prepatterned pits using carbothermal decomposition of SiO(2). The boundaries of the hexagonal holes are aligned along the zigzag crystallographic direction and leave hardly any signature in the Raman map indicating unprecedented purity of the edge chirality. This work offers the first opportunity to experimentally confirm the validity of the Raman theory for graphene edges. PMID- 20945849 TI - Intramolecular hydroamination of dithioketene acetals: an easy route to cyclic amino acid derivatives. AB - Catalytic intramolecular hydroamination of dithioketene acetals was developed for the synthesis of cyclic amino acid derivatives. Triggered by the addition of a catalytical amount of n-BuLi, the reaction proceeds to give proline and pipecolic acid derivatives in excellent yields and diastereoselectivity. PMID- 20945850 TI - Catalytic acylation of amines with aldehydes or aldoximes. AB - The simple nickel salt NiCl(2).6H(2)O catalyzes the coupling of aldoximes with amines to give secondary or tertiary amide products. The aldoxime can be prepared in situ from the corresponding aldehyde. The use of (18)O-labeled oximes has allowed insight into the mechanism of this reaction. PMID- 20945851 TI - Practical synthesis of a renin inhibitor via a diastereoselective Dieckmann cyclization. AB - A scalable synthesis of a potent renin inhibitor (1) is described. The absolute stereochemistry is set via an unprecedented diastereoselective Dieckmann cyclization directed by a remote chiral protecting group. This transformation enables preparation of chiral 1,3-[3.3.1]-diazabicyclononenes by desymmetrization of alkyl-esters, with selectivities ranging from 4 to 17:1. PMID- 20945852 TI - A case of fast photocyclization: the model of a downhill ladder reaction pathway for the bichromophoric phototrigger 3',5'-dimethoxybenzoin acetate. AB - A downhill ladder reaction pathway for the bichromophoric phototrigger 3',5' dimethoxybenzoin acetate was mapped using ab initio multiconfigurational methods. These computational results explicitly describe a case of fast photocyclization that overcomes two small barriers (<5.0 kcal/mol) and undergoes three internal conversions (ICs) via efficient nonadiabatic relay of conical intersections among long and short distance charge transfer excited states as well as the npi* excited and ground states. This novel reaction pathway is a consequence of the interaction of the two chromophores. PMID- 20945853 TI - Stereoselective synthesis of 2,3,6-trisubstituted tetrahydropyridines via Tf(2)O mediated Grob fragmentation: access to indolizidines (-)-209I and (-)-223J. AB - Herein we describe the gamma-amino hydroxide Grob fragmentation of the aza bicyclo[2.2.2]octene 1 using triflic anhydride as the activating agent. The resulting dihydropyridinium ion can react with a wide variety of Grignard reagents, giving access to 2,3,6-trisubstituted tetrahydropyridines (2) with high regio- and stereoselectivities. This methodology has been applied to the short synthesis of natural indolizidines (-)-209I (3) and (-)-223J (4). PMID- 20945854 TI - Influence of surface charge on wetting kinetics. AB - The wettability of a titania surface, partially covered with octadecyltrihydrosilane, has been investigated as a function of solution pH. The results show that surface charge affects both static wettability and wetting kinetics. The static contact angle decreases above and below the point of zero charge of the titania surface in a Lippman-like manner as the pH is altered. The dependence of dynamic contact angle on velocity is also affected by pH. The molecular-kinetic theory (MKT) is used to interpret the dynamic contact angle data. The frequency of molecular displacement kappa(0) strongly varies with surface charge, whereas the mean molecular displacement length lambda is essentially unaffected. There is an exponential dependence of contact-line friction upon work of adhesion, which is varied simply by altering the pH. PMID- 20945855 TI - Single boryl isomerization in silyl-bridged photochromic diboryl dyes. AB - Silyl-bridged dimers of a ppy-BMes(2) (ppy = 2-phenylpyridine, Mes = mesityl) photochrome were found to undergo photochromic switching involving a single boryl unit only. A through-space intramolecular energy transfer was found to be responsible for the single-chromophore isomerization phenomenon and fluorescence quenching. Steric congestion in the diboryl molecules was found to have an impact on photoisomerization quantum efficiency. PMID- 20945856 TI - Oxadisilole fused triptycene and extended triptycene: precursors of triptycyne and extended triptycyne. AB - With benzobisoxadisilole 1 as a 1,4-benzdiyne equivalent, oxadisilole fused triptycene 5 and extended triptycene 6 were synthesized. Triptycenes 5 and 6 are new precursors of triptycyne 7 and extended triptycyne 8 respectively via the phenyliodination/fluoride induced elimination protocol. Using these two arynes, a series of triptycene derivatives were synthesized. PMID- 20945858 TI - P[N(i-Bu)CH(2)CH(2)](3)N: nonionic Lewis base for promoting the room-temperature synthesis of alpha,beta-unsaturated esters, fluorides, ketones, and nitriles using Wadsworth-Emmons phosphonates. AB - The bicyclic triaminophosphine P(RNCH(2)CH(2))(3)N (R = i-Bu, 1c) serves as an effective promoter for the room-temperature stereoselective synthesis of alpha,beta-unsaturated esters, fluorides, and nitriles from a wide array of aromatic, aliphatic, heterocyclic, and cyclic aldehydes and ketones, using a range of Wadsworth-Emmons (WE) phosphonates. Among the analogues of 1c [R = Me (1a), i-Pr (1b), Bn (1d)], 1a and 1b performed well, although longer reaction times were involved, and 1d led to poorer yields than 1c. Functionalities such as cyano, chloro, bromo, methoxy, amino, ester, and nitro were well tolerated. We were able to isolate and characterize (by X-ray means; see above) the reactive WE intermediate species formed from 2b and 1c. PMID- 20945857 TI - Metalated aziridines for cross-coupling with aryl and alkenyl halides via palladium catalysis. AB - The palladium-catalyzed coupling of an aziridinylzinc chloride intermediate with alkenyl and aryl halides has been demonstrated. The method provides products with retention of aziridine stereochemistry. The utility of the coupling procedure is illustrated in the synthesis of structures related to l-furanomycin. PMID- 20945859 TI - Energetics of association in poly(lactic acid)-based hydrogels with crystalline and nanoparticle-polymer junctions. AB - We report the energetics of association in polymeric gels with two types of junction points: crystalline hydrophobic junctions and polymer-nanoparticle junctions. Time-temperature superposition (TTS) of small-amplitude oscillatory rheological measurements was used to probe crystalline poly(L-lactide) (PLLA) based gels with and without added laponite nanoparticles. For associative polymer gels, the activation energy derived from the TTS shift factors is generally accepted as the associative strength or energy needed to break a junction point. Our systems were found to obey TTS over a wide temperature range of 15-70 degrees C. For systems with no added nanoparticles, two distinct behaviors were seen, with a transition occurring at a temperature close to the glass transition temperature of PLLA, T(g). Above T(g), the activation energy was similar to the PLLA crystallization enthalpy, suggesting that the activation energy is related to the energy needed to pull a PLLA chain out of the crystalline domain. Below T(g), the activation energy is expected to be the energy required to increase mobility of the polymer chains and soften the glassy regions of the PLLA core. Similar behavior was seen in the nanocomposite gels with added laponite; however, the added clay appears to reduce the average value of the activation enthalpy. This confirms our SAXS results and suggests that laponite particles are participating in the network structure. PMID- 20945860 TI - Aromatic C-methyltransferases with antipodal stereoselectivity for structurally diverse phenolic amino acids catalyze the methylation step in the biosynthesis of the actinomycin chromophore. AB - The actinomycin biosynthetic gene cluster of Streptomyces chrysomallus harbors two paralogous genes, acmI and acmL, encoding methyltransferases. To unveil their suspected role in the formation of 3-hydroxy-4-methyl-anthranilic acid (4-MHA), the building block of the actinomycin chromophore, each gene was expressed in Escherichia coli. Testing the resulting ~40 kDa His(6)-tagged proteins with compounds of biogenetic relevance as substrates and S-adenosyl-l-methionine revealed that each exclusively methylated 3-hydroxykynurenine (3-HK) with formation of 3-hydroxy-4-methylkynurenine (4-MHK) identified by its in vitro conversion to 4-MHA with hydroxykynureninase. AcmI and AcmL methylate also hydroxyphenyl-amino propanoic acids such as p-tyrosine, m-tyrosine, or 3,4 dihydroxy-l-phenylalanine (DOPA) but at a lower rate than 3-HK. The presence of the alpha-amino group was necessary for substrate recognition. Phenolic acids with shorter chains such as 4-hydoxyphenyl-l-glycine (HPG), 3-hydroxybenzoic acid (3-HB), or 3-hydroxyanthranilic acid (3-HA) gave no product. Both enzymes were stereospecific for the optical configuration at alpha-C with unprecedented antipodal selectivity for the d-enantiomer of 3-HK and the l-enantiomer of p tyrosine or m-tyrosine. AcmI and AcmL show sequence similarity to various C- and O-methyltransferases from bacteria. Phylogenetic analysis places them into the clade of C-methyltransferases comprising among others orthologues involved in 4 MHA formation of other biosynthesis systems and methyltransferases putatively involved in the C-methylation of tyrosine. Remarkably, computational remodelling of AcmI and AcmL structures revealed significant similarity with the 3-D structures of type 1 O-methyltransferases from plants such as caffeic acid O methyltransferase (COMT) and other phenylpropanoid methyltransferases. The relevance of 3-HK or 3-HA methylation in the actinomycin biosynthesis pathways of different actinomycetes is discussed. PMID- 20945861 TI - Experimental and theoretical evidence of a persistent radical-cation dimer generated during the electrooxidation of an N-glucosamine-pyrrole derivative. AB - The results of the electrochemical characterization by cyclic voltammetry of 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-2-(pyrro-1-yl)-beta-d-glucopyranose (Py GSATA) are presented. This compound was analyzed in acetonitrile containing 0.1 M tetrabutylammonium perchlorate, using a platinum disk electrode as the working electrode. Py-GSATA showed two irreversible oxidation signals, the first at 1.24 and the second at 1.54 V vs Fc(+)/Fc. After successive cyclic voltammetry, under different experimental conditions, it was shown that it is not possible to electropolymerize this pyrrole derivative. Surprisingly, the bulk anodic electrolysis of Py-GSATA generated a single electroactive soluble product with an electrochemical cathodic signal located at -0.35 V vs Fc(+)/Fc. Mass spectrometry of the solution showed the presence of a dimeric species of the parent compound. ESR spectroscopy of the electrolysis solution showed a persistent radical species stable at least for 6 months (4 degrees C). UV-vis spectroscopy was consistent with low chain cation-radical oligomers. In order to propose an explanation to the dimer cation stability in solution, molecular modeling using a B3LYP/6-31+G** level of theory was used to analyze the stability and feasibility of the electrogenerated species. PMID- 20945862 TI - The Journal of Chemical Documentation and the Journal of Chemical Information and Computer Sciences: publication and citation statistics. PMID- 20945863 TI - Solid phase synthesis of aromatic oligoamides: application to helical water soluble foldamers. AB - Synthetic helical aromatic amide foldamers and in particular those based on quinolines have recently attracted much interest due to their capacity to adopt bioinspired folded conformations that are highly stable and predictable. Additionally, the introduction of water-solubilizing side chains has allowed to evidence promising biological activities. It has also created the need for methods that may allow the parallel synthesis and screening of oligomers. Here, we describe the application of solid phase synthesis to speed up oligomer preparation and allow the introduction of various side chains. The synthesis of quinoline-based monomers bearing protected side chains is described along with conditions for activation, coupling, and deprotection on solid phase, followed by resin cleavage, side-chain deprotection, and HPLC purification. Oligomers having up to 8 units were thus synthesized. We found that solid phase synthesis is notably improved upon reducing resin loading and by applying microwave irradiation. We also demonstrate that the introduction of monomers bearing benzylic amines such as 6-aminomethyl-2-pyridinecarboxylic acid within the sequences of oligoquinolines make it possible to achieve couplings using a standard peptide coupling agent and constitute an interesting alternative to the use of acid chloride activation required by quinoline residues. The synthesis of a tetradecameric sequence was thus smoothly carried out. NMR solution structural studies show that these alternate aminomethyl-pyridine residues do not perturb the canonical helix folding of quinoline monomers in protic solvents, contrary to what was previously observed in nonprotic solvents. PMID- 20945864 TI - A highly diastereoselective synthesis of alpha-hydroxy-beta-amino acid derivatives via a Lewis acid catalyzed three-component condensation reaction. AB - A very efficient three-component synthesis of a series of syn alpha-hydroxy-beta amino esters, obtained in high diastereoselection and yield, was realized starting from an aldehyde, benzylamine, and the ketene silyl acetals derived from Ley's lactones. The synthetic protocol was optimized and the above compounds were obtained without the isolation of intermediates. The origin of the observed diastereoselection was investigated through a computational model of the key reaction step. PMID- 20945865 TI - A generalized formulation of ion-pi electron interactions: role of the nonelectrostatic component and probe of the potential parameter transferability. AB - The intermolecular potentials for hexafluorobenzene (HFBz) and 1,3,5 trifluorobenzene (TFBz) interacting with alkali (M(+); M = Li, Na, K, Rb, Cs) and halogen (X(-); X = F, Cl, Br, I) ions are provided as a combination of electrostatic and nonelectrostatic terms. The ion-HFBz and ion-TFBz electrostatic components are formulated as a sum of Coulombic potentials associated with the interactions between the ion charge and point charges on the molecular frame, whose distributions are consistent with the permanent quadrupole moment of HFBz and TFBz, respectively. The corresponding nonelectrostatic components are represented as a sum of effective potential functions, each one having a specific physical meaning, related to ion-molecular bond pair interactions. In the present paper, we test the transferability of the ion-bond potential parameters. Moreover, the powerfulness of the model is analyzed by comparing predicted binding energies and equilibrium geometries for the family of M(+)-HFBz, X(-) HFBz, M(+)-TFBz, and X(-)-TFBz systems with available ab initio results. PMID- 20945866 TI - Aptamers as affinity reagents in an integrated electrophoretic lab-on-a-chip platform. AB - Nucleic acid based affinity reagents (e.g., aptamers) offer several possible advantages over antibodies as specific recognition elements in biochemical assays. Besides offering improved cost and stability, aptamers are ideal for rapid electrophoretic analysis due to their low molecular weight and high negative charge. While aptamers have proven well-suited for affinity-shift electrophoretic analysis, demonstrating a fully integrated aptamer-based assay platform represents an important achievement toward low-cost point-of-care analysis, particularly for remote or resource poor settings where cost and ambient stability of reagents is a key consideration. Here we perform and evaluate the suitability of aptamer-based affinity assays for two clinically relevant target analytes (IgE using a known aptamer and NF-kappaB using a thio modified aptamer) in an integrated electrophoretic gel-shift platform. Key steps of (i) mixing sample with aptamer, (ii) buffer exchange, and (iii) preconcentration of sample were successfully integrated on-chip upstream of a fluorescence-based gel-shift analysis step. This approach, utilizing a size exclusion membrane optimized here for aptamer retention and preconcentration with sample, enables automated sample-to-answer for trace analytes in 10 min or less. We addressed notable nonspecific interference from serum proteins by adding similar nucleic acid competitors to suppress such interactions with the aptamer. Nanomolar sensitivities were demonstrated and integrated preconcentration of sample provides an important means of further improving detection sensitivities. Aptamers proved superior in many respects to antibody reagents, particularly with regard to speed and resolution of gel-shifts associated with specific binding to target. PMID- 20945867 TI - Stabilization of lead sulfide nanoparticles by polyamines in aqueous solutions. A structural study of the dispersions. AB - Lead sulfide (PbS) nanoparticles have been synthesized in aqueous solutions by a reaction between inorganic lead salts and sodium sulfide and stabilized using the cationic polyelectrolytes branched poly(ethylenimine) (PEI), poly(allylamine hydrochloride) (PAH), and poly(diallyldimethylammonium chloride) (PDDA). The structures of the polyamine-stabilized nanoparticle dispersions were examined in detail using UV-vis spectroscopy, small-angle X-ray scattering (SAXS), static and dynamic electrophoretic mobility measurements, and transmission electron microscopy (TEM). Considerable differences were found between the stabilizing efficiencies of these polyelectrolytes, which cannot be attributed to their charge densities or their persistence lengths. Small monodisperse nanoparticles of PbS with a tight stabilizing shell were consistently found only when PEI was used as a stabilizer even at high pH values, although its charge density is then very low. The excellence of PEI as a stabilizer is mainly due to the extensive branching of the chains and the presence of uncharged secondary and tertiary amine groups, which apparently serve as good anchoring points at the nanoparticle surfaces. None of the polyelectrolytes examined here provide long-term protection of the nanoparticles toward oxidation by air, showing that a need for more complex multipurpose stabilizers exists for aqueous PbS dispersions. PMID- 20945868 TI - Direct detection and quantification of methylation in nucleic acid sequences using high-resolution melting analysis. AB - High-resolution melting (HRM) analysis exploits the reduced thermal stability of DNA fragments that contain base mismatches to detect single nucleotide polymorphisms (SNPs). However, the capacity of HRM to reveal other features of DNA chemistry remains unexplored. DNA methylation plays a key role in regulating gene expression and is essential for normal development in many higher organisms. The presence of methylated bases perturbs the double-stranded DNA structure, although its effect on DNA thermal stability is largely unknown. Here, we reveal that methylated DNA has enhanced thermal stability and is sufficiently divergent from nonmethylated DNA to allow detection and quantification by HRM analysis. This approach reliably distinguishes between sequence-identical DNA differing only in the methylation of one base. The method also provides accurate discrimination between mixes of methylated and nonmethylated DNAs, allowing discrimination between DNA that is 1% and 0% methylated and also between 97.5% and 100% methylated. Thus, the method provides a new means of adjusting thermal optima for DNA hybridization and PCR-based techniques and to empirically measure the impact of DNA methylation marks on the thermostability of regulatory regions. In the longer term, it could enable the development of new techniques to quantify methylated DNA. PMID- 20945869 TI - A searchable map of PubChem. AB - The database PubChem was classified using 42 integer value descriptors of molecular structure, here called molecular quantum numbers (MQNs), which count atoms and bond types, polar groups, and topological features. Principal component analysis of the MQN data set shows that PubChem compounds occupy a partially filled elliptical cone in the (PC1,PC2,PC3) space whose axis is the first principal component PC1 (65% variability) representing molecular size, and the ellipse axes are PC2 (18% variability, representing structural flexibility) and PC3 (7% variability, representing polarity). A visual overview of PubChem is provided by color-coded representations of the (PC2,PC3) plane. The MQNs form a scalar fingerprint which can be used to measure the similarity between pairs of molecules and enable ligand-based virtual screening, as illustrated for the enrichment of bioactives from the DUD data set from PubChem. An MQN-annotated version of PubChem with an MQN-similarity search tool is available at www.gdb.unibe.ch . PMID- 20945870 TI - Microwave synthesis of noncentrosymmetric BaTiO3 truncated nanocubes for charge storage applications. AB - Truncated nanocubes of barium titanate (BT) were synthesized using a rapid, facile microwave-assisted hydrothermal route. Stoichiometric composition of pellets of nanocube BT powders was prepared by two-stage microwave process. Characterization by powder XRD, Rietveld refinement, SEM, TEM, and dielectric and polarization measurements was performed. X-ray diffraction revealed a polymorphic transformation from cubic Pm3m to tetragonal P4mm after 15 min of microwave irradiation, arising from titanium displacement along the c-axis. Secondary electron images were examined for nanocube BT synthesis and annealed at different timings. Transmission electron microscopy showed a narrow particle size distribution with an average size of 70 +/- 9 nm. The remanence and saturation polarization were 15.5 +/- 1.6 and 19.3 +/- 1.2 MUC/cm(2), respectively. A charge storage density of 925 +/- 47 nF/cm(2) was obtained; Pt/BT/Pt multilayer ceramic capacitor stack had an average leakage current density of 5.78 +/- 0.46 * 10(-8) A/cm(2) at +/-2 V. The significance of this study shows an inexpensive and facile processing platform for synthesis of high-k dielectric for charge storage applications. PMID- 20945871 TI - Increased mass transport at lithographically defined 3-D porous carbon electrodes. AB - Increased mass transport due to hemispherical diffusion is observed to occur in 3D porous carbon electrodes defined by interferometric lithography. Enhanced catalytic methanol oxidation, after modifying the porous carbon with palladium nanoparticles, and uncharacteristically uniform conducting polymer deposition into the structures are demonstrated. Both examples result in two regions of hierarchical porosity that can be created to maximize surface area, via nanostructuring, within the extended porous network, while taking advantage of hemispherical diffusion through the open pores. PMID- 20945872 TI - From water clustering to osmotic coefficients. AB - Water activity is an important macroscopic property of aerosol particles and droplets in the atmosphere as well as aqueous solutions in many other fields of physical chemistry. This study focuses on relating water activity, described using osmotic coefficients, to the microscopic water structure in systems of atmospheric relevance, namely, aqueous solutions of each of the four electrolytes: NaCl, (NH(4))(2)SO(4), NH(4)Cl, and Na(2)SO(4). The osmotic coefficients of these compounds, as reported in literature based on thermodynamic measurements, decrease as a function of molality for dilute solutions and increase as a function of molality for concentrated solutions. At an intermediate molality, a minimum value of the osmotic coefficient is observed. We explain this behavior by describing osmotic coefficients as the product of two concentration dependent effects: incomplete electrolyte dissociation and variations in the microphysical water structure. The degree of dissociation in electrolyte solutions can be obtained directly from literature or derived from reported pK values, and in this work the water structure is quantified using low-wavenumber Raman spectroscopy. We use the band at 180 cm(-1) in Raman spectra of aqueous electrolyte solutions, which has been assigned to the displacement of the central oxygen atom in a tetrahedral hydrogen bonding environment composed of five H(2)O units. The abundance of such translationally restricted water molecules is essential in describing the local microphysical structure of water, and the height of the band is used to estimate the amount of such translationally restricted water molecules in solution. We were able to qualitatively reproduce and explain literature values of osmotic coefficients for the four studied electrolytes. Our results indicate that the effect of electrolyte dissociation, which decreases as a function of molality, dominates in dilute solutions, whereas changes in water structure are more significant at higher concentrations. PMID- 20945873 TI - Colorimetric assay for S-adenosylhomocysteine hydrolase activity and inhibition using fluorosurfactant-capped gold nanoparticles. AB - This study reports a simple colorimetric method for the sensitive detection of S adenosylhomocysteine hydrolase (SAHH) activity and inhibition using fluorosurfactant-capped gold nanoparticles (FSN-AuNPs). FSN stabilizes the AuNPs against conditions of high ionic strength, and FSN-AuNPs are merely aggregated in the presence of homocysteine (HCys) and cysteine. Because of this feature, FSN AuNPs were found to be dispersed in the presence of S-adenosylhomocysteine (SAH) that lacks a free thiol group. After SAHH catalyzed the hydrolysis of SAH, the produced HCys molecules were bound to the surface of AuNPs through the formation of Au-S bonds. As a result, the nanoparticle (NP) aggregation occurred through electrostatic attraction between each HCys-attached AuNP. This approach had a minimum detectable concentration of 100 units/L (~6 nM). Additionally, because adenosine analogs are capable of inhibiting SAHH activity, the addition of adenosine analogs to a solution containing SAH and SAHH resulted in the suppression of hydrolyzed SAH-induced NP aggregation. Adenosine analogs exhibited the following trend in the half-maximal inhibitory concentrations: adenosine > adenosine monophosphate > adenosine diphosphate ~ adenosine triphosphate. We have demonstrated that the combination of SAHH inhibition and FSN-AuNPs can be utilized for the selective detection of adenosine. PMID- 20945874 TI - Effect of pH on anisotropic gelation of DNA induced by aluminum cations. AB - To investigate the effects of pH on the structure and the properties of DNA anisotropic gels and their growth process, we have observed the morphology of DNA anisotropic gel films prepared from DNA solutions with various initial pH, and measured the pH dependences of the shrinking ratio, the birefringence, and the relaxation modulus of the gel as well as the time courses of the gel front and pH change front lines. The gel films prepared from DNA solutions with high pH have inhomogeneous macroscopic structure, large shrinking ratio, and high optical anisotropy whereas those prepared from DNA solutions with low pH have homogeneous macroscopic structure, small shrinking ratio, and low optical anisotropy. The difference observed at different pH is attributed to the difference in the interaction between DNA molecules and aluminum cations. The time courses of the gel front and pH-change front lines were analyzed with theories based on assumptions for each condition. Both two-stage dynamics observed under high initial pH and one-stage dynamics under low initial pH were explained consistently with the theories. PMID- 20945875 TI - Analyzing the topology of active sites: on the prediction of pockets and subpockets. AB - Automated prediction of protein active sites is essential for large-scale protein function prediction, classification, and druggability estimates. In this work, we present DoGSite, a new structure-based method to predict active sites in proteins based on a Difference of Gaussian (DoG) approach which originates from image processing. In contrast to existing methods, DoGSite splits predicted pockets into subpockets, revealing a refined description of the topology of active sites. DoGSite correctly predicts binding pockets for over 92% of the PDBBind and the scPDB data set, being in line with the best-performing methods available. In 63% of the PDBBind data set the detected pockets can be subdivided into smaller subpockets. The cocrystallized ligand is contained in exactly one subpocket in 87% of the predictions. Furthermore, we introduce a more precise prediction performance measure by taking the pairwise ligand and pocket coverage into account. In 90% of the cases DoGSite predicts a pocket that contains at least half of the ligand. In 70% of the cases additionally more than a quarter of the respective pocket itself is covered by the cocrystallized ligand. Consideration of subpockets produces an increase in coverage yielding a success rate of 83% for the latter measure. PMID- 20945876 TI - Gas phase electrodeposition: a programmable multimaterial deposition method for combinatorial nanostructured device discovery. AB - This article reports and applies a recently discovered programmable multimaterial deposition process to the formation and combinatorial improvement of 3D nanostructured devices. The gas-phase deposition process produces charged <5 nm particles of silver, tungsten, and platinum and uses externally biased electrodes to control the material flux and to turn deposition ON/OFF in selected domains. Domains host nanostructured dielectrics to define arrays of electrodynamic 10 * nanolenses to further control the flux to form <100 nm resolution deposits. The unique feature of the process is that material type, amount, and sequence can be altered from one domain to the next leading to different types of nanostructures including multimaterial bridges, interconnects, or nanowire arrays with 20 nm positional accuracy. These features enable combinatorial nanostructured materials and device discovery. As a first demonstration, we produce and identify in a combinatorial way 3D nanostructured electrode designs that improve light scattering, absorption, and minority carrier extraction of bulk heterojunction photovoltaic cells. Photovoltaic cells from domains with long and dense nanowire arrays improve the relative power conversion efficiency by 47% when compared to flat domains on the same substrate. PMID- 20945877 TI - Importance of the nature of alpha-substituents in pyrrolidine organocatalysts in asymmetric Michael additions. AB - The fundamental factors contributing toward the stereoselectivity in organocatalyzed asymmetric Michael reaction between aldehydes (propanal and 3 phenyl propanal) and methyl vinyl ketone (MVK) are established by using density functional theory methods. Three of the most commonly employed alpha-substituted pyrrolidine organocatalysts are examined. Several key stereochemical modes of addition between (i) a model enamine or (ii) pyrrolidine enamines derived from aldehydes and secondary amine to MVK are examined. Among these possibilities, the addition of (E)-enamine to cis-MVK is found to have a lower activation barrier. The stereochemical outcome of the reaction is reported on the basis of the relative energies between pertinent diastereomeric transition states. Moderate selectivity is predicted for the reaction involving pyrrolidine catalysts I and II, which carry relatively less bulky alpha-substituents dimethylmethoxymethyl and diphenylmethyl, respectively. On the other hand, high selectivity is computed in the case of catalyst III having a sufficiently large alpha-substituent (diarylmethoxymethyl or diphenylprolinol methyl ether). The enantiomeric excess in the case of 3-phenyl propanal is found to be much higher as compared to that with unsubstituted propanal, suggesting potential for improvement in stereoselectivity by substrate modifications. The computed enantiomeric excess is found to be in reasonable agreement with the reported experimental stereoselectivities. A detailed investigation on the geometries of the crucial transition states reveals that apart from steric interactions between the alpha substituent and MVK, various other factors such as orbital interactions and weak stabilizing hydrogen-bonding interactions play a vital role in stereoselectivity. The results serve to establish the importance of cumulative effects of various stabilizing and destabilizing interactions at the transition state as responsible for the stereochemical outcome of the reaction. The limitations of commonly employed qualitative propositions, relying on the steric protection of one of the prochiral faces of enamines offered by the bulky alpha-substituent, are presented. PMID- 20945878 TI - Dip-pen nanolithography of electrical contacts to single graphene flakes. AB - This study evaluates an alternative to electron-beam lithography for fabricating nanoscale graphene devices. Dip-pen nanolithography is used for defining monolayer graphene flakes and for patterning of gold electrodes through writing of an alkylthiol on thin films of gold evaporated onto graphene flakes. A wet gold etching step was used to form the individual devices. The sheet resistances of these monolayer graphene devices are comparable to reported literature values. This alternative technique for making electrical contact to 2D nanostructures provides a platform for fundamental studies of nanomaterial properties. The merits of using dip-pen nanolithography include lack of electron-beam irradiation damage and targeted patterning of individual devices with imaging and writing conducted in the same instrument under ambient conditions. PMID- 20945879 TI - Strong dependence of mechanical properties on fiber diameter for polymer-nanotube composite fibers: differentiating defect from orientation effects. AB - We have prepared polyvinylalcohol-SWNT fibers with diameters from ~1 to 15 MUm by coagulation spinning. When normalized to nanotube volume fraction, V(f), both fiber modulus, Y, and strength, sigma(B), scale strongly with fiber diameter, D: Y/V(f) ? D(-1.55) and sigma(B)/V(f) ? D(-1.75). We show that much of this dependence is attributable to correlation between V(f) and D due to details of the spinning process: V(f) ? D(0.93). However, by carrying out Weibull failure analysis and measuring the orientation distribution of the nanotubes, we show that the rest of the diameter dependence is due to a combination of defect and orientation effects. For a given nanotube volume fraction, the fiber strength scales as sigma(B) ? D(-0.29)D(-0.64), with the first and second terms representing the defect and orientation contributions, respectively. The orientation term is present and dominates for fibers of diameter between 4 and 50 MUm. By preparing fibers with low diameter (1-2 MUm), we have obtained mean mechanical properties as high as Y = 244 GPa and sigma(B) = 2.9 GPa. PMID- 20945880 TI - Parallel scanning near-field photolithography: the snomipede. AB - The "Millipede", developed by Binnig and co-workers (Bining, G. K.; et al. IBM J. Res. Devel. 2000, 44, 323.), elegantly solves the problem of the serial nature of scanning probe lithography processes, by deploying massive parallelism. Here we fuse the "Millipede" concept with scanning near-field photolithography to yield a "Snomipede" that is capable of executing parallel chemical transformations at high resolution over macroscopic areas. Our prototype has sixteen probes that are separately controllable using a methodology that is, in principle, scalable to much larger arrays. Light beams generated by a spatial modulator or a zone plate array are coupled to arrays of cantilever probes with hollow, pyramidal tips. We demonstrate selective photodeprotection of nitrophenylpropyloxycarbonyl-protected aminosiloxane monolayers on silicon dioxide and subsequent growth of nanostructured polymer brushes by atom-transfer radical polymerization, and the fabrication of 70 nm structures in photoresist by a Snomipede probe array immersed under water. Such approaches offer a powerful means of integrating the top-down and bottom-up fabrication paradigms, facilitating the reactive processing of materials at nanometer resolution over macroscopic areas. PMID- 20945881 TI - Structural stability of tandemly occurring noncanonical basepairs within double helical fragments: molecular dynamics studies of functional RNA. AB - Noncanonical basepairs have gained importance over the past few years because of their various functions in RNA biochemistry. These basepairs appear quite frequently in different double helical stems also, but whether they are stabilized by contextual pressure or act as seeds of folding is not yet clear. We have used all-atom molecular dynamics simulations to characterize the stability and functional features of a few noncanonical basepairs within two RNA double helical fragments obtained from ribosome crystal structures. It is anticipated that the noncanonical basepairs would open up spontaneously if they had appeared due to contextual pressure. However, we have found from MD simulations that the noncanonical basepairs occurring in tandem at the central regions of double helical stretches are quite stable. Analysis of basepairing parameters carried out in terms of H-bonding edge-specific axis system indicates that dynamics of the noncanonical basepairs are very similar to those of the canonical ones. The stacking parameters for dinucleotide steps consisting of noncanonical basepairs are rather unusual, but the variability patterns indicate their significant stability. The stacking free-energy values as presumed from the distributions of structural parameters also appear to be similar for both canonical and noncanonical basepair steps. PMID- 20945882 TI - Magnetic assembly of nonmagnetic particles into photonic crystal structures. AB - We report the rapid formation of photonic crystal structures by assembly of uniform nonmagnetic colloidal particles in ferrofluids using external magnetic fields. Magnetic manipulation of nonmagnetic particles with size down to a few hundred nanometers, suitable building blocks for producing photonic crystals with band gaps located in the visible regime, has been difficult due to their weak magnetic dipole moment. Increasing the dipole moment of magnetic holes has been limited by the instability of ferrofluids toward aggregation at high concentration or under strong magnetic field. By taking advantage of the superior stability of highly surface-charged magnetite nanocrystal-based ferrofluids, in this paper we have been able to successfully assemble 185 nm nonmagnetic polymer beads into photonic crystal structures, from 1D chains to 3D assemblies as determined by the interplay of magnetic dipole force and packing force. In a strong magnetic field with large field gradient, 3D photonic crystals with high reflectance (83%) in the visible range can be rapidly produced within several minutes, making this general strategy promising for fast creation of large-area photonic crystals using nonmagnetic particles as building blocks. PMID- 20945883 TI - Confirmatory analysis of continuous erythropoietin receptor activator and erythropoietin analogues in equine plasma by LC-MS for doping control. AB - Continuous erythropoietin receptor activator (CERA) is the third generation of recombinant human erythropoietin (rhEPO) medication that retains the effect of promoting red blood cell production but has longer duration of action in the body. CERA, rhEPO, and darbepoetin alpha (DPO) can be misused to enhance performance in both human and equine athletes. To deter such misuse, a very selective and sensitive liquid chromatography-tandem mass spectrometric (LC MS/MS) method has now been developed for identification of CERA, rhEPO, and DPO in equine plasma. The method employs a new signature tryptic peptide, T8 ((54)MEVGQQAVEVWQGLALLSEAVLR(76), common to the three proteins), and improved immunoaffinity extraction. The analytes were extracted by anti-rhEPO antibodies from plasma samples that were pretreated with polyethylene glycol (PEG) 6000. The extracted analytes were digested by trypsin and analyzed by LC-MS/MS. The limit of identification was 0.5 ng/mL for CERA, 0.2 ng/mL for rhEPO, and 0.1 ng/mL for DPO in equine plasma; the limit of detection was 0.3 ng/mL for CERA, 0.1 ng/mL for rhEPO, and 0.05 ng/mL for DPO. Specificity of the method was assessed via BLAST and SEQUEST protein database searches, and the T8 is extremely specific at both peptide and product ion levels for the identification of CERA, rhEPO, and DPO. This method was successful in identifying CERA and DPO in plasma samples collected from research horses post the drug administrations. It provides a useful tool in the fight against blood doping with CERA, rhEPO, and DPO in racehorses. Additionally, the following two technical approaches adopted in this study may also be helpful in protein identifications and biomarker discoveries in a broad scope: precipitating plasma proteins with PEG 6000 to improve immunoaffinity extraction efficiency of the target proteins and making a large and more lipophilic peptide detectable at low concentrations by increasing its solubility in the sample solvent. PMID- 20945884 TI - Composition-tunable optical properties of colloidal IV-VI quantum dots, composed of core/shell heterostructures with alloy components. AB - Colloidal quantum dots (CQDs) attract worldwide scientific and technological attention due to the ability to engineer their optical properties by the variation of their size. However, several important applications, such as biological tagging and photovoltaic cells, impose a limit on their size yet demand tunability and thermal stability of the optical band edge. This work introduces a new class of heterostructures, composed of PbSe or PbSe(y)S(1-y) cores, coated by PbS or PbSe(x)S(1-x) shells, with different core-radius/shell width division, with a radial gradient composition (with 0 < y < 1, 0 < x < 1), which offer a control of the band edge properties by varying the CQDs' composition. Continuous-wave and transient photoluminescence measurements over a wide temperature range (1.4-300 K) revealed a distinct behavior of the heterostructures with respect to that of pure PbSe cores: (i) increase of the emission quantum yield; (ii) red-shift of the absorption edge but a decrease of the emission Stokes shift; (iii) alleviation of a dark exciton recombination, viz., a reduction of an exchange interaction; (iv) tuning of the radiative lifetime with shell width and composition; (v) reduction of the band edge temperature coefficient, dE/dT, viz., induction of thermal stability. The k.p envelope function calculation, considering abrupt or smooth alloying continuation of the potential at the core-shell interface, revealed a delocalization of the hole wave function over the entire volume of the CQDs, as a partial explanation for the marked tunability, nonetheless preserving a desired size. PMID- 20945885 TI - New unsymmetrical bolaamphiphiles: synthesis, assembly with DNA, and application for gene delivery. AB - The success in gene therapy relies strongly on new efficient gene delivery vectors. Nonviral vectors based on lipids and polymers constitute an important alternative to the viral vectors. However, the key problem with these vectors is the poor structural control of their DNA complexes. In the present work, following new design we synthesized unsymmetrical bolaamphiphiles, molecules bearing neutral sugar (gluconic acid) and dicationic ornithine head groups connected by different long hydrophobic spacers. Within this design, a positively charged headgroup is expected to bind DNA, the hydrophobic spacer is to drive the formation of a monolayer membrane shell around DNA, while the neutral group is to be exposed outside of the complex. Our fluorescence and gel electrophoresis data showed that self-assembly of bolas and their interaction with DNA depend strongly on the bola structure. The size of bola/DNA complexes (bolaplexes) estimated from dynamic light scattering data was ~100 nm at low N/P (cationic nitrogen/DNA phosphate molar ratio), while at higher N/Ps it was significantly larger due to neutralization of their surface charge. Atomic force microscopy studies revealed nanostructural rod-shaped or spherical morphology of the bolaplexes. Transfection efficiency of the bolaplexes in vitro was significant when either DOPE or chloroquine were used as helping agents, suggesting that the key barrier for their internalization is the endosomal escape. Finally, all bolas showed low cytotoxicity (cell viability >80%). The present results show that bolas are prospective candidates for construction of nonviral gene delivery vectors. We believe that further optimization of polar head groups and a hydrophobic spacer in the bolas will lead to vectors with controlled small size and high transfection efficiency. PMID- 20945886 TI - How donor-bridge-acceptor energetics influence electron tunneling dynamics and their distance dependences. AB - Long-range electron transfer may occur via two fundamentally different mechanisms depending on the combination of electron donor, acceptor, and the bridging medium between the two redox partners. Activating the so-called hopping mechanism requires matching the energy levels of the donor and the bridge. If electrons from the donor can thermodynamically access bridge-localized redox states, the bridge may be temporarily reduced before the electron is forwarded to the acceptor. As a result, electron transfer rates may demonstrate an extremely shallow dependence on distance. When transient reduction of the bridging medium is thermodynamically impossible, a tunneling mechanism that exponentially depends on distance becomes important for electron transport. Fifty years ago, superexchange theory had already predicted that electron transfer rates should be affected by donor-bridge-acceptor energetics even in the tunneling regime, in which the energy gap (Deltaepsilon) is too large for electrons to hop from the donor onto the bridge. However, because electron tunneling rates depend on many parameters and the influence of donor-bridge energy gaps is difficult to distinguish from other influences, direct experimental support for the theoretical prediction has been difficult to find. Because of remarkable progress, particularly in the past couple of years, researchers have finally found direct evidence for the long-sought but elusive tunneling-energy gap effect. After a brief introduction to the theory of the tunneling mechanism, this Account discusses recent experimental results describing the importance of the tunneling-energy gap. Experimental studies in this area usually combine synthetic chemistry with electrochemical investigations and time-resolved (optical) spectroscopy. For example, we present a case study of hole tunneling through synthetic DNA hairpins, in which different donor-acceptor couples attached to the same hairpins resulted in tunneling rates with significantly different dependences on distance. Recent systematic studies of conjugated molecular bridges have demonstrated the same result: The distance decay constant (beta), which describes the steepness of the exponential decrease of charge tunneling rates with increasing donor-acceptor distance, is not a property of the bridge alone; rather it is a sensitive function of the entire donor-bridge-acceptor (D-b A) combination. In selected cases, researchers have found a quantitative relationship between the experimentally determined distance decay constant (beta) and the magnitude of the tunneling-energy gap (Deltaepsilon). The rates and efficiencies of charge transfer reactions occurring over long distances are of pivotal importance in light-to-chemical energy conversion and molecular electronics. Tunneling-energy gap effects play an intriguing role in the formation of long-lived charge-separated states after photoexcitation: The kinetic stabilization of these charge-separated states frequently exploits the inverted driving-force effect. Recent studies indicate that tunneling-energy gap effects can differentiate the distance dependences of energy-storing charge separation reactions from those of energy-wasting charge-recombination processes. Thus, the exploitation of tunneling-energy gap effects may provide an additional way to obtain long-lived charge-separated states. PMID- 20945887 TI - Nickel-catalyzed hydrosilylation/cyclization of difluoro-substituted 1,6-enynes. AB - Ni-catalyzed hydrosilylative cyclization of difluoro-substituted 1,6-enynes can be carried out. The presence of a geminal-difluoromethylene group at an alkene terminus in enynes is essential for the reaction to proceed. PMID- 20945888 TI - Computational design of a self-assembling beta-peptide oligomer. AB - The first computationally designed self-assembling oligomer consisting of exclusively beta-amino acids (betaAAs) is presented. The packing of a beta-3(14) helix into coiled-coils of varying stoichiometries as a function of amino acid sequence is examined. beta-Peptides with hVal repeating every third residue in the sequence appeared to have a strong propensity to pack into hexameric bundles. The designed sequence was synthesized and characterized with CD spectroscopy, NMR, and analytical ultracentrifugation, suggesting that the peptide adopts a well-folded hexameric structure. PMID- 20945889 TI - From conventional to microphotochemistry: photodecarboxylation reactions involving phthalimides. AB - A series of acetone-sensitized photodecarboxylation reactions involving phthalimides have been investigated using conventional and microphotochemistry. Both, intra- and intermolecular transformations were compared. In all cases examined, the reactions performed in microreactors were superior in terms of conversions or isolated yields. These findings unambiguously prove the advantage of microphotochemistry over conventional photochemical techniques. PMID- 20945890 TI - Applying the input-output method to account for water footprint and virtual water trade in the Haihe River basin in China. AB - The virtual water strategy which advocates importing water intensive products and exporting products with low water intensity is gradually accepted as one of the options for solving water crisis in severely water scarce regions. However, if we count the virtual water embodied in imported products as the water saved for a region, we might overestimate the saving by including the virtual water that is later re-exported in association with the proceeded products made from the originally imported products. This problem can be avoided by accounting for the saved water through calculating water footprint (WF) in domestic final consumptive products. In this paper, an input-output analysis (IOA) based on the water footprint accounting framework is built to account for WF and virtual water trade of final consumptive products in the water stressed Haihe River basin in China for the year 1997, 2000, and 2002. The input-output transaction tables of the three years are constructed. The results show WF of 46.57, 44.52, and 42.71 billion m(3) for the three years, respectively. These volumes are higher than the water used directly in the corresponding years in the basin. A WF intensity (WFI) indicator is then used to assess if the economic activities in the basin are consistent with the virtual water strategy. The temporal change of the WFI is also decomposed by the index number analysis method. The results showed that the basin was silently importing virtual water through the trade of raw and processed food commodities under the background of the whole economic circulation. PMID- 20945891 TI - Effect of dissolved organic carbon on sorption of pyrethroids to sediments. AB - Despite their strong hydrophobicity, recent studies showed widespread occurrence of pyrethroid in downstream surface waters bodies. In this work, the effect of dissolved organic carbon (DOC) on the sorption and desorption of pyrethroids in sediment was evaluated to understand the role of DOC in facilitating pyrethroid transport. Presence of DOC from three sources at 38 +/- 2 mg L-1 in the aqueous phase decreased pesticide sorption to a sediment by 1.7 to 38.9 times and increased their desorption by 1.2 to 41.4 times. The effect on pyrethroid sorption to the sediment was linear. In addition, interactions between DOC and pyrethroids, when taking place prior to the contact with sediment, decreased sorption of some pyrethroids even further, implying that DOC-pyrethroid complexs were relatively stable in solution. DOC sources with higher contents of carboxylic and phenolic groups were found to have a higher potential to associate with pyrethroids. The DOC-water partition coefficients (K(DOC)) obtained by solid phase microextraction measurement were significantly correlated (P < 0.01) with K(d) values measured for the sediment. These results provide evidence that DOC increases the distribution of pyrethroids from the sediment to the solution phase and plays an important role in mobilizing pyrethroids in runoff and surface streams. PMID- 20945892 TI - Coupling the Petasis condensation to an iron(III) chloride-promoted cascade provides a short synthesis of Relenza congeners. AB - Iron(III) chloride hexahydrate promotes a cascade of transformations on a Petasis condensation product that sets up the right dihydropyran precursors of valuable Relenza congeners. PMID- 20945893 TI - Control of electronic structure of graphene by various dopants and their effects on a nanogenerator. AB - It is essential to control the electronic structure of graphene in order to apply graphene films for use in electrodes. We have introduced chemical dopants that modulate the electronic properties of few-layer graphene films synthesized by chemical vapor deposition. The work function, sheet carrier density, mobility, and sheet resistance of these films were systematically modulated by the reduction potential values of dopants. We further demonstrated that the power generation of a nanogenerator was strongly influenced by the choice of a graphene electrode with a modified work function. The off-current was well quenched in graphene films with high work functions (Au-doped) due to the formation of high Schottky barrier heights, whereas leakage current was observed in graphene films with low work functions (viologen-doped), due to nearly ohmic contact. PMID- 20945894 TI - C-H bond functionalization in the synthesis of fused 1,2,3-triazoles. AB - A highly modular approach to fused 1,2,3-triazoles has been developed featuring a one-pot procedure combining copper(I) catalyzed azide-alkyne cycloaddition and palladium-catalyzed C-H bond functionalization. A class of structurally unique heterocycles was synthesized in good yields. PMID- 20945895 TI - Tailoring enzyme-rich environmental DNA clones: a source of enzymes for generating libraries of unnatural natural products. AB - A detailed bioinformatics analysis of six glycopeptide biosynthetic gene clusters isolated from soil environmental DNA (eDNA) megalibraries indicates that a subset of these gene clusters contains collections of tailoring enzymes that are predicted to result in the production of new glycopeptide congeners. In particular, sulfotransferases appear in eDNA-derived gene clusters at a much higher frequency than would be predicted from the characterization of glycopeptides from cultured Actinomycetes . Enzymes found on tailoring-enzyme rich eDNA clones associated with these six gene clusters were used to produce a series of new sulfated glycopeptide derivatives in both in vitro and in vivo derivatization studies. The derivatization of known natural products with eDNA derived tailoring enzymes is likely to be a broadly applicable strategy for generating libraries of new natural product variants. PMID- 20945896 TI - Amphiphilic polyethylenes leading to surfactant-free thermoresponsive nanoparticles. AB - Linear copolymers of ethylene and acrylic acid (PEAA) were prepared by catalytic polymerization of ethylene and tert-butyl acrylate followed by hydrolysis of the ester groups. The copolymers contained COOH groups inserted into the crystalline unit cell with formation of intramolecular hydrogen-bonds, as established on the basis of differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD) studies. A solvent-exchange protocol, with no added surfactant, converted a solution in tetrahydrofuran of a PEAA sample containing 12 mol % of acrylic acid (AA) into a colloidally stable aqueous suspension of nanoparticles. Transmission electron microscopy (TEM), dynamic light scattering (DLS), and high sensitivity differential scanning calorimetry (HS-DSC) were used to characterize the nanoparticles. They are single crystals of elongated shape with a polar radius of 49 nm (sigma = 15 nm) and an equatorial radius of 9 nm (sigma = 3 nm) stabilized in aqueous media via carboxylate groups located preferentially on the particle/water interface. The PEAA (AA: 12 mol %) nanoparticles dispersed in aqueous media exhibited a remarkable reversible thermoresponsive behavior upon heating/cooling from 25 to 80 degrees C. PMID- 20945897 TI - Restricted guest tumbling in phosphorylated self-assembled capsules. AB - ABii diphosphonatocavitands self-assemble in chloroform solution to form dimeric molecular capsules. The molecular capsules can incarcerate an N-methylpyridinium or N-methylpicolinium guest. We have demonstrated that the supramolecular assembly acts as a molecular rotor as a result of the restricted motion of the guest inside the molecular cavity. In the solid state, X-ray diffraction analysis of the free host showed that two cavitands interact through strong hydrogen bonds to give the supramolecular self-assembled capsule. The solid-state structure of the N-methylpicolinium complex is comparable to that of the free host and indicates that the guest is not a prerequisite for the formation of the capsule. DOSY NMR studies provided a definitive argument for the formation of the free and complexed supramolecular capsule in CDCl(3) solution. In solution, the tumbling of the N-methylpyridinium and N-methylpicolinium guests about the equatorial axes of the host can be frozen and differs by the respective energy barriers, with the larger picolinium substrate having a larger value (DeltaG(++) = 69.7 kJ mol(-1)) than the shorter pyridinium guest (DeltaG(++) = 44.8 kJ mol(-1)). This behavior corresponds to the restricted rotation of a rotator in a supramolecular rotor. PMID- 20945898 TI - Palladium-catalyzed regio-, diastereo-, and enantioselective allylic alkylation of acylsilanes with monosubstituted allyl substrates. AB - Acylsilanes as a new type of "hard" carbon prenucleophile reacted with monosubstituted allyl reagents under Pd-catalyzed asymmetric allylic alkylation reaction conditions to provide products with high regio-, diastereo-, and enantioselectivities. The usefulness of the protocol has been demonstrated by the ready conversion of the allylated products into the corresponding alcohols, esters, and ketones with retention of stereochemistry as well as by the enantioselective synthesis of cis-3-ethyl-4-phenylpiperidine and cinnamomumolide. PMID- 20945899 TI - Growth of metal-organic frameworks on polymer surfaces. AB - Polymer substrates have been functionalized with a MOF material (MIL-47) synthesized directly on polyacrylonitrile using in situ microwave irradiation. The growth of MIL-47 on these substrates was studied as a function of microwave irradiation time using scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The conversion of nitrile to carboxylic acid groups on the PAN surface was necessary for the growth of MIL-47 on the substrate. MIL-47 crystals grew over time at the expense of a related disordered precursor phase, which lacks the long-range order of MIL-47. This work paves the way for the development of a new class of hybrid MOF-polymer materials that will extend the applications of MOFs to fields such as membrane separations, filtration, and protective textiles. PMID- 20945900 TI - De novo design and molecular assembly of a transmembrane diporphyrin-binding protein complex. AB - The de novo design of membrane proteins remains difficult despite recent advances in understanding the factors that drive membrane protein folding and association. We have designed a membrane protein PRIME (PoRphyrins In MEmbrane) that positions two non-natural iron diphenylporphyrins (Fe(III)DPP's) sufficiently close to provide a multicentered pathway for transmembrane electron transfer. Computational methods previously used for the design of multiporphyrin water soluble helical proteins were extended to this membrane target. Four helices were arranged in a D(2)-symmetrical bundle to bind two Fe(II/III) diphenylporphyrins in a bis-His geometry further stabilized by second-shell hydrogen bonds. UV-vis absorbance, CD spectroscopy, analytical ultracentrifugation, redox potentiometry, and EPR demonstrate that PRIME binds the cofactor with high affinity and specificity in the expected geometry. PMID- 20945901 TI - Incorporation of furan into low band-gap polymers for efficient solar cells. AB - The design, synthesis, and characterization of the first examples of furan containing low band-gap polymers, PDPP2FT and PDPP3F, with substantial power conversion efficiencies in organic solar cells are reported. Inserting furan moieties in the backbone of the conjugated polymers enables the use of relatively small solubilizing side chains because of the significant contribution of the furan rings to overall polymer solubility in common organic solvents. Bulk heterojunction solar cells fabricated from furan-containing polymers and PC(71)BM as the acceptor showed power conversion efficiencies reaching 5.0%. PMID- 20945902 TI - Synthesis of phototrappable shape-shifting molecules for adaptive guest binding. AB - We have designed and synthesized oligosubstituted bullvalenes 1 and 2 as adaptive molecules that can change their shapes in order to bind tightly to a suitable guest. By incorporation of a photolabile o-nitroveratryloxycarbonate (NVOC) group into bullvalenes 1 and 2, tightly binding species can be selectively isolated from a population of hundreds of interconverting structural isomers. Spontaneous strain-assisted Cope rearrangements allow these shape-shifting molecules to exist in a dynamic equilibrium of configurationally distinct valence isomers, as revealed by dynamic NMR and HPLC studies. When NVOC bullvalenes 1 and 2 were exposed to UV light, the cleavage of the NVOC group resulted in a mixture of static isomers of the corresponding bullvalone. Binding studies of NVOC bisporphyrin bullvalene 1 demonstrated that the dynamic isomeric equilibrium shifted in the presence of C(60), favoring configurations with more favorable binding affinities. Irradiation of a mixture of 1 and C(60) with UV light and isolation of the major static isomer yielded an isomer of bisporphyrin bullvalone with a binding affinity for C(60) that was ~2 times larger than that of the nonadapted isomer bisporphyrin bullvalone 41. PMID- 20945903 TI - Pyridine-functionalized single-walled carbon nanotubes as gelators for poly(acrylic acid) hydrogels. AB - Pyridine-functionalized single-walled carbon nanotubes (SWNTs) are prepared from the addition of a pyridine diazonium salt to nanotubes. The location and distribution of the functional groups is determined by atomic force microscopy using electrostatic interactions with gold nanoparticles. The pyridine functionalized SWNTs are able to act as cross-linkers and hydrogen bond to poly(acrylic acid) to form SWNT hydrogels. The pyridine-functionalized SWNTs are further characterized using Raman, FTIR, UV/vis-NIR, and X-ray photoelectron spectroscopy and thermogravimetric analysis-mass spectrometry. PMID- 20945904 TI - A systems approach to controlling supramolecular architecture and emergent solution properties via host-guest complexation in water. AB - The assembly behavior of aryl/alkyl imidazolium ionic liquid salts in aqueous solution has been investigated. These salts undergo self-assembly into one dimensional stacks via hydrophobic and pi-pi interactions upon increasing concentration, which led to a substantial increase in the solution viscosity in water. Addition of the macrocyclic host molecules cucurbit[n]urils (CB[n]) were found to effectively alter the supramolecular assemblies, as evidenced from the dramatic increase (by CB[7]) and decrease (by CB[8]) in solution viscosity and aggregation size in water, on account of the different binding stoichiometries, 1:1 complexation with CB[7] and 2:1 complexation with CB[8]. Furthermore, the aggregate architectures were controllably modified by competitive guests for the CB[n] hosts. This complex supramolecular systems approach has tremendous implications in the fields of molecular sensor design, nonlinear viscosity modification, and controlled release of target molecules from a defined supramolecular scaffold in water. PMID- 20945905 TI - Design, synthesis, crystal structures, and antimicrobial activity of sulfonamide boronic acids as beta-lactamase inhibitors. AB - We investigated a series of sulfonamide boronic acids that resulted from the merging of two unrelated AmpC beta-lactamase inhibitor series. The new boronic acids differed in the replacement of the canonical carboxamide, found in all penicillin and cephalosporin antibiotics, with a sulfonamide. Surprisingly, these sulfonamides had a highly distinct structure-activity relationship from the previously explored carboxamides, high ligand efficiencies (up to 0.91), and K(i) values down to 25 nM and up to 23 times better for smaller analogues. Conversely, K(i) values were 10-20 times worse for larger molecules than in the carboxamide congener series. X-ray crystal structures (1.6-1.8 A) of AmpC with three of the new sulfonamides suggest that this altered structure-activity relationship results from the different geometry and polarity of the sulfonamide versus the carboxamide. The most potent inhibitor reversed beta-lactamase-mediated resistance to third generation cephalosporins, lowering their minimum inhibitory concentrations up to 32-fold in cell culture. PMID- 20945906 TI - Diaryldiamines with dual inhibition of the histamine H(3) receptor and the norepinephrine transporter and the efficacy of 4-(3-(methylamino)-1-phenylpropyl) 6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-ol in pain. AB - A series of compounds was designed as dual inhibitors of the H(3) receptor and the norepinephrine transporter. Compound 5 (rNET K(i) = 14 nM; rH(3)R K(i) = 37 nM) was found to be efficacious in a rat model of osteoarthritic pain. PMID- 20945907 TI - Synthetic analogues of the microtubule-stabilizing sponge alkaloid ceratamine A are more active than the natural product. AB - Desbromoceratamine A (3) exhibits significantly less potent activity than the natural product ceratamine A (1) in a cell-based assay for antimitotic activity. Synthesis of the ceratamine A analogue 4 has shown that replacing the bromine atoms in the natural product with methyl groups generates an analogue that is more active than natural ceratamine A (1). Further enhancement of the antimitotic activity of the ceratamine pharmacophore has been achieved in the synthetic analogue 33, which has both bromine atoms replaced with methyl groups and an additional methyl substituent on the amino nitrogen at C-2. An efficient synthetic route has been developed to 33 that should enable the first in vivo evaluation of the new ceratamine microtubule-stabilizing pharmacophore and has provided several additional analogues for structure-activity relationship evaluation. PMID- 20945909 TI - Rheology and structure formation in diluted mixed particle-surfactant systems. AB - In the present work, we focus on the bulk rheology of mixtures consisting of surfactant modified silica nanoparticles in water. Depending on the ratio of surfactant and nanoparticle concentrations, significant modifications in the measured rheology are evidenced. A domain where the dispersions behave like viscoelastic media is observed. Outside this domain, the dispersions exhibit viscous properties. The changes in the bulk rheology characteristics are discussed in terms of interaction effects between the surfactant and the particles. The results obtained are seen in the context of diluted emulsions' properties and characteristics. PMID- 20945908 TI - Poly[(5-methyl-5-allyloxycarbonyl-trimethylene carbonate)-co-(5,5-dimethyl trimethylene carbonate)] with grafted polyethylenimine as biodegradable polycations for efficient gene delivery. AB - In this paper, biodegradable polycations based on polycarbonates with grafted polyethylenimine (PEI) were synthesized as a nonviral vector for gene delivery. Immobilized porcine pancreas lipase (IPPL) was employed to perform the copolymerization of 5-methyl-5-allyloxy carbonyl-trimethylenecarbonate (MAC) with 5,5-dimethyl-trimethylene carbonate (DTC). The DTC molar percent X was equal to 6.7, 12.5, and 45.4, respectively. The resulting copolymers with different compositions (P(MAC-co-DTCx) underwent additional allyl epoxidation and thereby grafted by low molecular weight PEI1800. The MWs of P(MAC-co-DTCx)-g-PEI, measured by GPC-MALLS, were 219800, 179100, and 51700 g/mol with polydispersities of 1.5, 1.4, and 1.2, respectively. Physicochemical properties of these vectors were characterized and the DNA loading was evaluated. P(MAC-co-DTCx)-g-PEI could form nanosized particles (less than 100 nm) with pDNA. The three P(MAC-co-DTCx)-g PEI/DNA polyplexes had similar buffer capabilities that were better than that of PEI25K and PMAC-g-PEI. Despite a slightly lower DNA binding ability, the PEI grafted polycarbonates, especially P(MAC-co-DTC45.4)-g-PEI, presented apparently low cytotoxicity and much higher gene transfection efficiency in comparison with PEI25K in 293T cells. Moreover, preincubation of P(MAC-co-DTC6.7)-g-PEI showed a quickly weakening DNA binding capacity, while a suitable degradation rate of vectors would facilitate the efficient release of pDNA from polyplexes after cellular uptake and also reduce cell cytotoxicity. The results of this study demonstrated the promise of P(MAC-co-DTCx)-g-PEI copolymers for efficient gene delivery. PMID- 20945910 TI - Adsorption kinetics of catalase to thin films of carbon nanotubes. AB - The adsorption conditions used to immobilize catalase onto thin films of carbon nanotubes were investigated to elucidate the conditions that produced films with maximum amounts of active catalase. The adsorption kinetics were monitored by spectroscopic ellipsometry, and the immobilized catalase films were then assayed for catalytic activity. The development of a volumetric optical model used to interpret the ellipsometric data is discussed. According to the results herein discussed, not only the adsorbed amount but also the initial adsorption rates determine the final catalytic activity of the adsorbed layer. The results described in this paper have direct implications on the rational design and analytical performance of enzymatic biosensors. PMID- 20945911 TI - Semiconductor quantum dots and quantum dot arrays and applications of multiple exciton generation to third-generation photovoltaic solar cells. PMID- 20945912 TI - Metabolism and toxicity of menthofuran in rat liver slices and in rats. AB - Menthofuran is a monoterpene present in mint plants that is oxidized by mammalian cytochrome P450 (CYP) to hepatotoxic metabolites. Evidence has been presented that p-cresol and other unusual oxidative products are metabolites of menthofuran in rats and that p-cresol may be responsible in part for the hepatotoxicity caused by menthofuran [ Madyastha, K. M. and Raj, C. P. (1992) Drug Metab. Dispos. 20, 295 - 301]. In the present study, several oxidative metabolites of menthofuran were characterized in rat and human liver microsomes and in rat liver slices exposed to cytotoxic concentrations of menthofuran. Metabolites that were identified were monohydroxylation products of the furanyl and cyclohexyl groups, mintlactones and hydroxymintlactones, a reactive gamma-ketoenal, and a glutathione conjugate. A similar spectrum of metabolites was found in urine 24 h after the administration of hepatotoxic doses of menthofuran to rats. In no case was p-cresol (or any of the other reported unusual oxidative metabolites of menthofuran) detected above background concentrations that were well below concentrations of p-cresol that cause cytotoxicity in rat liver slices. Thus, the major metabolites responsible for the hepatotoxic effects of menthofuran appear to be a gamma-ketoenal and/or epoxides formed by oxidation of the furan ring. PMID- 20945913 TI - SIRT3 substrate specificity determined by peptide arrays and machine learning. AB - Accumulating evidence suggests that reversible protein acetylation may be a major regulatory mechanism that rivals phosphorylation. With the recent cataloging of thousands of acetylation sites on hundreds of proteins comes the challenge of identifying the acetyltransferases and deacetylases that regulate acetylation levels. Sirtuins are a conserved family of NAD(+)-dependent protein deacetylases that are implicated in genome maintenance, metabolism, cell survival, and lifespan. SIRT3 is the dominant protein deacetylase in mitochondria, and emerging evidence suggests that SIRT3 may control major pathways by deacetylation of central metabolic enzymes. Here, to identify potential SIRT3 substrates, we have developed an unbiased screening strategy that involves a novel acetyl-lysine analogue (thiotrifluoroacetyl-lysine), SPOT-peptide libraries, machine learning, and kinetic validation. SPOT peptide libraries based on known and potential mitochondrial acetyl-lysine sites were screened for SIRT3 binding and then analyzed using machine learning to establish binding trends. These trends were then applied to the mitochondrial proteome as a whole to predict binding affinity of all lysine sites within human mitochondria. Machine learning prediction of SIRT3 binding correlated with steady-state kinetic k(cat)/K(m) values for 24 acetyl-lysine peptides that possessed a broad range of predicted binding. Thus, SPOT peptide-binding screens and machine learning prediction provides an accurate and efficient method to evaluate sirtuin substrate specificity from a relatively small learning set. These analyses suggest potential SIRT3 substrates involved in several metabolic pathways such as the urea cycle, ATP synthesis, and fatty acid oxidation. PMID- 20945914 TI - Design, synthesis, and development of novel guaianolide-endoperoxides as potential antimalarial agents. AB - Design and synthesis of a guaianolide-endoperoxide (thaperoxide) 3 was pursued as a new antimalarial lead which was found to be noncytotoxic as compared to the natural product lead thapsigargin 2. Several analogues of 3 were successfully synthesized and found to be comparable to derivatives of artemisinin 1 in in vitro antimalarial assay. Among the synthesized compounds, 22 showed excellent in vitro potency against the cultured parasites (W2 IC(50) = 13 nM) without apparent cytotoxicity. Furthermore, SAR trends in thaperoxide analogues are presented and explained with the help of docking studies in the homology model of PfSERCA(PfATP6). PMID- 20945915 TI - Diastereoselective synthesis of aryloxy phosphoramidate prodrugs of 3'-deoxy 2',3'-didehydrothymidine monophosphate. AB - The first diastereoselective synthesis of aryloxy phosphoramidate prodrugs of 3' deoxy-2',3'-didehydrothymidine monophosphate (d4TMP) is reported. In our approach, (S)-4-isopropylthiazolidine-2-thione 1 was used as a chiral auxiliary to introduce the stereochemistry at the phosphorus atom. In the last step of the developed reaction sequence, the nucleoside analogue d4T was introduced to a stereochemically pure phosphordiamidate which led to the formation of the almost diastereomerically pure phosphoramidate prodrugs 8a-d (>=95% de). As expected, the individually prepared diastereomers of the phosphoramidate prodrugs showed significant differences in the antiviral activity. Moreover, the difference was strongly dependent on the aryl substituent attached to the phosphoramidate moiety. PMID- 20945917 TI - Patterning of polystyrene by scanning electrochemical microscopy. Biological applications to cell adhesion. AB - Polystyrene surfaces may be patterned by Ag(II), NO(3)(*), and OH(*) electrogenerated at the tip of a scanning electrochemical microscope. These electrogenerated reagents lead to local surface oxidation of the polymer. The most efficient surface treatment is obtained with Ag(II). The patterns are evidenced by XPS and IR and also by the surface wettability contrast between the hydrophobic virgin surface and the hydrophilic pattern. Such Ag(II) treatment of a polystyrene Petri dish generates discriminative surfaces able to promote or disfavor the adhesion of proteins and also the adhesion and growth of adherent cells. The process is also successfully applied to a cyclo-olefin copolymer and should be suitable to pattern any hydrogenated polymer. PMID- 20945916 TI - The nonribosomal peptide synthetase enzyme DdaD tethers N(beta)-fumaramoyl-l-2,3 diaminopropionate for Fe(II)/alpha-ketoglutarate-dependent epoxidation by DdaC during dapdiamide antibiotic biosynthesis. AB - The gene cluster from Pantoea agglomerans responsible for biosynthesis of the dapdiamide antibiotics encodes an adenylation-thiolation didomain protein, DdaD, and an Fe(II)/alpha-ketoglutarate-dependent dioxygenase homologue, DdaC. Here we show that DdaD, a nonribosomal peptide synthetase module, activates and sequesters N(beta)-fumaramoyl-l-2,3-diaminopropionate as a covalently tethered thioester for subsequent oxidative modification of the fumaramoyl group. DdaC catalyzes Fe(II)- and alpha-ketoglutarate-dependent epoxidation of the covalently bound N(beta)-fumaramoyl-l-2,3-diaminopropionyl-S-DdaD species to generate N(beta)-epoxysuccinamoyl-DAP (DAP = 2,3-diaminopropionate) in thioester linkage to DdaD. After hydrolytic release, N(beta)-epoxysuccinamoyl-DAP can be ligated to l-valine by the ATP-dependent ligase DdaF to form the natural antibiotic N(beta) epoxysuccinamoyl-DAP-Val. PMID- 20945919 TI - Simultaneous quantification of cardiolipin, bis(monoacylglycero)phosphate and their precursors by hydrophilic interaction LC-MS/MS including correction of isotopic overlap. AB - Cardiolipin (CL) and bis(monoacylglycero)phosphate (BMP) are unique lipid structures with important biological roles for mitochondrial integrity and endolysosomal degradation, respectively. They are synthesized from common precursors, phosphatidylglycerol (PG) and phosphatidic acid (PA). Here we present a rapid method for the simultaneous quantification of BMP, CL, PG, and PA using hydrophilic interaction chromatography coupled with electrospray ionization tandem mass spectrometry (HILIC-MS/MS). HILIC provides coelution of lipid species and their internal standards required for accurate quantification. Coelution leads to isotope overlap of lipid species which was successfully corrected. This assay was validated in mouse heart tissue and primary human skin fibroblasts. It shows reproducibility and limits of detection sufficient for biomarker studies contributing to basic research on BMP and CL metabolism. PMID- 20945920 TI - In-plane parallel scanning: a microarray technology for point-of-care testing. AB - A new microarray technology is described for rapid, inexpensive, multiplex diagnostics assays. Referred to as "in-plane parallel scanning" (IPPS), this technology replaces expensive laser scanning with a grid of 100-MUm-wide waveguides embedded in the chip's substrate, enabling real-time quantification of molecular complex formation on the chip's surface. Compared to conventional microarray technology, IPPS has advantages of shorter assay time and lower instrument cost and complexity so that the platform can potentially be used in point-of-care (POC) settings. Two different chip formats are described: a low density microarray with 10 sensing wells (IPPS-10) and a medium-density one with 100 sensing wells (IPPS-100). Performance was evaluated in two different proof-of principle immunoassays: interleukin-1beta (IL-1beta) and Clostridium difficile toxin A. The two assays gave similar limits of detection of 0.67 and 0.94 pM, respectively. A saturation kinetics model described the sensor response with apparent dissociation constants of 511 pM for IL-1beta and 6.47 nM for C. difficile toxin A toxoid. The multiplexing capabilities of the IPPS technology were also demonstrated in a multiplex assay for both analytes on the same IPPS-10 chip. Based on these results, the IPPS technology holds promise for translating diagnostic microarrays into near-patient environments. PMID- 20945921 TI - Metabolite identification in Synechococcus sp. PCC 7002 using untargeted stable isotope assisted metabolite profiling. AB - Metabolite profiling using mass spectrometry provides an attractive approach for the interrogation of cellular metabolic capabilities. Untargeted metabolite profiling has the potential to identify numerous novel metabolites; however, de novo identification of metabolites from spectral features remains a challenge. Here we present an integrated workflow for metabolite identification using uniform stable isotope labeling. Metabolite profiling of cell and growth media extracts of unlabeled control, (15)N, and (13)C-labeled cultures of the cyanobacterium, Synechococcus sp. PCC 7002 was performed using normal phase liquid chromatography coupled to mass spectrometry (LC-MS). Visualization of three-way comparisons of raw data sets highlighted characteristic labeling patterns for metabolites of biological origin allowing exhaustive identification of corresponding spectral features. Additionally, unambiguous assignment of chemical formulas was greatly facilitated by the use of stable isotope labeling. Chemical formulas of metabolites responsible for redundant spectral features were determined and fragmentation (MS/MS) spectra for these metabolites were collected. Analysis of acquired MS/MS spectra against spectral database records led to the identification of a number of metabolites absent not only from the reconstructed draft metabolic network of Synechococcus sp. PCC 7002 but not included in databases of metabolism (MetaCyc or KEGG). PMID- 20945922 TI - Raman enhancement on graphene: adsorbed and intercalated molecular species. AB - Strong Raman scattering is observed from iodine anions adsorbed at ca. 3% coverage on single layer graphene. In addition, the Raman signal from just one bromine intercalation layer inside three and four layer thick graphenes is observed. We analyze and model the intramolecular electronic, charge-transfer, and multiple reflection electromagnetic mechanisms responsible for this unusual sensitivity. Graphene is an excellent Raman substrate for adsorbed species showing intramolecular electronic resonance, because graphene efficiently quenches interfering excited-state luminescence. The Raman sensitivity for adsorbed and intercalated molecular species is highest for single layer graphene and decreases with increasing thickness. These phenomena are compared with surface enhanced Raman spectroscopy field enhancement and "chemical" Raman processes in aggregated Ag particles and on flat, highly reflective metal surfaces. The Raman spectra of adsorbed bromine layers are not observed, despite significant charge transfer to graphene. Charge transfer from adsorbed bromine is about one-half of charge transfer from intercalated bromine. We attribute the large Raman signal for both adsorbed iodine and intercalated bromine species to intramolecular electronic resonance enhancement. The signal evolution with varying graphene thickness is explained by multiple reflection electromagnetic calculations. PMID- 20945923 TI - Transparent organic p-dopant in carbon nanotubes: bis(trifluoromethanesulfonyl)imide. AB - We propose bis(trifluoromethanesulfonyl)imide [(CF(3)SO(2))(2)N](-) (TFSI) as a transparent strong electron-withdrawing p-type dopant in carbon nanotubes (CNTs). The conventional p-dopant, AuCl(3), has several drawbacks, such as hygroscopic effect, formation of Au clusters, decrease in transmittance, and high cost in spite of the significant increase in conductivity. TFSI is converted from bis(trifluoromethanesulfonyl)amine (TFSA) by accepting electrons from CNTs, subsequently losing a proton as a characteristic of a Bronsted acid, and has an inductive effect from atoms with high electronegativity, such as halogen, oxygen, and nitrogen. TFSI produced a similar improvement in conductivity to AuCl(3), while maintaining high thermal stability, and no appreciable change in transmittance with no cluster formation. The effectiveness of TFSI was compared with that of other derivatives. PMID- 20945924 TI - Moire superstructures of graphene on faceted nickel islands. AB - Using scanning tunneling microscopy and spectroscopy, in combination with density functional theory calculations, we investigated the morphology and electronic structure of monolayer graphene grown on the (111) and (110) facets of three dimensional nickel islands on highly oriented pyrolytic graphite substrate. We observed graphene domains exhibiting hexagonal and striped moire patterns with periodicities of 22 and 12 A, respectively, on (111) and (110) facets of the Ni islands. Graphene domains are also observed to grow, as single crystals, across adjacent facets and over facet boundaries. Scanning tunneling spectroscopy data indicate that the graphene layers are metallic on both Ni(111) and Ni(110), in agreement with the calculations. We attribute this behavior to a strong hybridization between the d-bands on Ni and the pi-bands of carbon. Our findings point to the possibility of preparing large-area epitaxial graphene layers even on polycrystalline Ni substrates. PMID- 20945925 TI - Physiologically based pharmacokinetic modeling of nanoparticles. AB - Rapid expansion of nanoparticle research demands new technologies that will enable better interpretation of experimental data and assistance in the rational design of future nanoparticles. The use of physiologically based pharmacokinetic (PBPK) models may serve as powerful tools to meet these needs. PBPK models have been successfully applied for the study of the absorption, distribution, metabolism, and excretion (ADME) of small molecules, such as drugs. Preliminary application of PBPK models to nanoparticles illustrated their potential usefulness for nanoparticle ADME research. However, due to the differences between nanoparticles and small molecules, modifications are needed to build appropriate PBPK models for nanoparticles. This review is divided into two sections, with the first discussing nanoparticle ADME research, emphasizing the interaction of nanoparticles with living systems, including transportation kinetics across biobarriers. In the second section, the basic principles of PBPK model development are introduced, and research pertaining to PBPK models of nanoparticles is reviewed. Factors that need to be considered for developing PBPK models for nanoparticles are also discussed. Finally, perspective applications of nanoparticle PBPK models are summarized. PMID- 20945926 TI - Standardless atom counting in scanning transmission electron microscopy. AB - We demonstrate that high-angle annular dark-field imaging in scanning transmission electron microscopy allows for quantification of the number and location of all atoms in a three-dimensional, crystalline, arbitrarily shaped specimen without the need for a calibration standard. We show that the method also provides for an approach to directly measure the finite effective source size of a scanning transmission electron microscope. PMID- 20945927 TI - Fabrication and evaluation of solution-processed reduced graphene oxide electrodes for p- and n-channel bottom-contact organic thin-film transistors. AB - Reduced graphene oxide (RGO) is an electrically conductive carbon-based nanomaterial that has recently attracted attention as a potential electrode for organic electronics. Here we evaluate several solution-based methods for fabricating RGO bottom-contact (BC) electrodes for organic thin-film transistors (OTFTs), demonstrate functional p- and n-channel devices with such electrodes, and compare their electrical performance with analogous devices containing gold electrodes. We show that the morphology of organic semiconductor films deposited on RGO electrodes is similar to that observed in the channel region of the devices and that devices fabricated with RGO electrodes have lower contact resistances compared to those fabricated with gold contacts. Although the conductivity of RGO is poor compared to that of gold, RGO is still an enticing electrode material for organic electronic devices possibly owing to the retention of desirable morphological features, lower contact resistance, lower cost, and solution processability. PMID- 20945928 TI - Synthesis of visible-light responsive graphene oxide/TiO(2) composites with p/n heterojunction. AB - Graphene oxide/TiO(2) composites were prepared by using TiCl(3) and graphene oxide as reactants. The concentration of graphene oxide in starting solution played an important role in photoelectronic and photocatalytic performance of graphene oxide/TiO(2) composites. Either a p-type or n-type semiconductor was formed by graphene oxide in graphene oxide/TiO(2) composites. These semiconductors could be excited by visible light with wavelengths longer than 510 nm and acted as sensitizer in graphene oxide/TiO(2) composites. Visible-light driven photocatalytic performance of graphene oxide/TiO(2) composites in degradation of methyl orange was also studied. Crystalline quality and chemical states of carbon elements from graphene oxide in graphene oxide/TiO(2) composites depended on the concentration of graphene oxide in the starting solution. This study shows a possible way to fabricate graphene oxide/semiconductor composites with different properties by using a tunable semiconductor conductivity type of graphene oxide. PMID- 20945929 TI - Local gate effect of mechanically deformed crossed carbon nanotube junction. AB - In this work, we have demonstrated that the local deformation at the crossed carbon nanotube (CNT) junctions can introduce significant tunable local gate effect under ambient environment. Atomic force microscope (AFM) manipulation of the local deformation yielded a variation in transconductance that was retained after removing the AFM tip. Application of a large source-drain voltage and pressing the CNT junction above a threshold pressure can respectively erase and recover the transconductance modulation reversibly. The local gate effect is found to be independent of the length of the crossed CNT and attributed to the charges residing at the deformed junctions due to formation of localized states. The number of localized charges is estimated to be in the range of 10(2) to 10(3). These results may find potential applications in electromechanical sensors and could have important implications for designing nonvolatile devices based on crossed CNT junctions. PMID- 20945930 TI - A characterization of the Raman modes in a J-aggregate-forming dye: a comparison between theory and experiment. AB - J-Aggregates are a class of organic molecules that possess several interesting characteristics that make them attractive for a range of organic-based optoelectronic devices. We present experimental and computer-simulation studies of the Raman-active vibrational modes in the J-aggregate-forming dye 5,6-dichloro 2-[[5,6-dichloro-1-ethyl-3-(4-sulfobutyl)benzimidazol-2-ylidene]propenyl]-1-ethyl 3-(4-sulfobutyl)benzimidazolium hydroxide, sodium salt, inner salt. The molecular monomer and dimer are analyzed computationally and the Raman mode energies extracted. There is a good agreement between the energies of the theoretical and experimental Raman modes. Experimentally, an enhancement is seen in the intensity of two low frequency modes upon aggregation of the dye. This is attributed to aggregation-enhanced Raman scattering. An enhancement is also observed in certain modes of the calculated spectra upon changing from a monomer to dimeric arrangement. A link is suggested between the Raman-active vibrational modes of the molecule, and a time-dependent electronic coupling present over several molecules. PMID- 20945931 TI - Evidence for cobalt-cobalt bond homolysis and wavelength-dependent CO loss in (MU2-alkyne)Co2(CO)6 complexes. AB - Time-resolved infrared spectroscopy was used to probe the photochemistry of three (MU(2)-alkyne)Co(2)(CO)(6) complexes. The data indicate the formation of a triplet diradical species, with lifetimes in the range 38-71 ps. Theoretical calculations support these experimental findings. No evidence for the CO loss species, (MU(2)-alkyne)Co(2)(CO)(5), was observed, and this is rationalized by the low quantum yield for this process at the excitation wavelengths used. PMID- 20945932 TI - Air-stable ambipolar field-effect transistors and complementary logic circuits from solution-processed n/p polymer heterojunctions. AB - We demonstrate the use of n/p polymer/polymer heterojunctions deposited by sequential solution processing to fabricate ambipolar field-effect transistors and complementary logic circuits. Electron and hole mobilities in the transistors were ~0.001-0.01 cm(2)/(V s) in air without encapsulation. Complementary circuits integrating multiple ambipolar transistors into NOT, NAND, and NOR gates were fabricated and shown to exhibit sharp signal switching with a high voltage gain. PMID- 20945933 TI - Investigating photoinduced charge transfer in carbon nanotube-perylene-quantum dot hybrid nanocomposites. AB - In this study, we investigate photophysical and photoinduced current responses of a nanocomposite which consists of multiwalled carbon nanotubes (CNTs), thiol derivative perylene compound (ETPTCDI), and cadmium selenide quantum dots (QDs). These QDs as well as the ETPTCDI harvest photons and transfer their excited electrons or holes to CNTs to complete the circuit. Both QDs and ETPTCDI contribute charges to the carbon nanotubes, which increased the overall photon harvest efficiency of the nanocomposite. Herein, we investigate through a series of photophysical photoluminescence quenching studies the charge transfer between donors (QDs and ETPTCDI) and acceptor (CNTs). The incorporation of ETPTCDI into the nanocomposite significantly increases the adhesion between QDs and CNTs through bonding between QDs and thiol groups on ETPTCDI and pi-pi interactions between ETPTCDI and CNTs. Thus, ETPTCDI acted as a molecular linker between QDs and CNTs. Furthermore, a significant increase (>5 times) in the Stern-Volmer constant, K(sv), for QD emission after addition of ETPTCDI-tagged CNTs clearly indicates a large enhancement in the adhesion between CNTs and QDs. The nanocomposite shows a ~2-4-fold increase in the photoconductivity when exposed to AM1.5 solar-simulated light. The damage to the nanocomposite from the intensity of the solar-simulated light is also investigated. The proposed nanocomposite has the potential for photovoltaic applications such as being the active component in a hybrid bulk heterojunction solar cell. PMID- 20945934 TI - Classification of genus Pseudomonas by MALDI-TOF MS based on ribosomal protein coding in S10-spc-alpha operon at strain level. AB - We have proposed a rapid phylogenetic classification at the strain level by MALDI TOF MS using ribosomal protein matching profiling. In this study, the S10-spc alpha operon, encoding half of the ribosomal subunit proteins and highly conserved in eubacterial genomes, was selected for construction of the ribosomal protein database as biomarkers for bacterial identification by MALDI-TOF MS analysis to establish a more reliable phylogenetic classification. Our method revealed that the 14 reliable and reproducible ribosomal subunit proteins with less than m/z 15,000, except for L14, coded in the S10-spc-alpha operon were significantly useful biomarkers for bacterial classification at species and strain levels by MALDI-TOF MS analysis of genus Pseudomonas strains. The obtained phylogenetic tree was consisted with that based on genetic sequence (gyrB). Since S10-spc-alpha operons of genus Pseudomonas strains were sequenced using specific primers designed based on nucleotide sequences of genome-sequenced strains, the ribosomal subunit proteins encoded in S10-spc-alpha operon were suitable biomarkers for construction and correction of the database. MALDI-TOF MS analysis using these 14 selected ribosomal proteins is a rapid, efficient, and versatile bacterial identification method with the validation procedure for the obtained results. PMID- 20945935 TI - Dietary pectin regulates the levels of inflammatory cytokines and immunoglobulins in interleukin-10 knockout mice. AB - Pectin has protective, anti-inflammatory effects on inflammatory bowel disease (IBD), but the exact mechanism is unknown. Therefore, we investigated the immunological effect of dietary pectin in IL-10(-/-) mice, a murine model for IBD. Cytokine expression, CD4(+) and CD8(+) T cell populations, and immunoglobulin secretion were observed in three groups of mice: normal (BALb/c), IL-10(-/-), and IL-10(-/-) treated with pectin. Pectin treatment reduced expression of TNF-alpha and GATA-3, an important transcription factor for the Th2 immune response. These mice also expressed lower levels of IgE in the spleen and Peyer's patches (PP) and lower IgG and IgM expression in PP. Interestingly, IL-10 deficiency resulted in lower CD4(+) and CD8(+) populations in the spleen, mesenteric lymph node (MLN), and PP; however, pectin counteracted these declines in the MLN and PP. Therefore, dietary pectin downregulates the inflammatory response in the colon by moderating the production of proinflammatory cytokines and immunoglobulins. PMID- 20945936 TI - Comparative study of polymeric stabilizers for magnetite nanoparticles using ATRP. AB - A series of polyelectrolytes with controlled molecular weight, a narrow chain length distribution, and systematic structural differences were synthesized using atom-transfer radical polymerization and investigated as stabilizers for magnetite nanoparticles in aqueous suspensions. Structural differences include the degree of polymerization, the chain architecture, and the identity of the charged functional unit. The synthesized polymers are sulfonated poly(2 hydroxyethyl methacrylate), a block copolymer of the former with poly(n-butyl methacrylate), poly(sodium styrene sulfonate), poly(sodium acrylate), and poly(sodium vinylphosphonate). The colloidal stability is assessed by measuring the fraction of particles, based on turbidity, that sediment after a period of time at increasing ionic strength. Sedimentation results are complimented by dynamic light scattering determinations of the hydrodynamic diameter of the particles that remain suspended. When adsorption and sedimentation are conducted at high pH, poly(sodium acrylate) and poly(sodium vinylphosphonate) yield the most stable suspensions because of their strong coordinative interactions with the iron oxide surface. At low pH, the polymers that retain pendant negative charges (each of the sulfonated polymers) yield high stable fractions at all ionic strengths investigated up to 100 mM (NaCl), whereas polyelectrolytes that become protonated with decreasing pH, poly(sodium acrylate) and poly(sodium vinylphosphonate), lose their stabilizing capacity even at low ionic strengths. The chain-length distribution profoundly alters a polymer's stabilization tendencies. Two poly(sodium acrylate) samples with the same number-average molecular weight but widely different chain-length distributions proved to have opposite tendencies, with the polydisperse sample being a good stabilizer and the low polydispersity one being a strong flocculant. This investigation provides guidelines for the design of polymeric stabilizers for magnetite nanoparticles according to the pH and ionic strength of the intended application. PMID- 20945937 TI - Doxorubicin-induced thymus senescence. AB - Doxorubicin (DOX) is an anticancer drug used for the treatment of solid tumors. The ability of DOX to treat cancer is not specific to cancer cells; some of the cells that are normal may also become targets of DOX, thereby altering the normal cellular functions and eventual cell loss. DOX effects have been studied in detail in heart because of its ability to cause cardiomyopathy. The exact mechanism of DOX-induced cardiomyopathy is not completely understood. One of organs that can be affected by DOX is thymus. DOX treatment leads to degeneration of thymus; however, since thymus undergoes age-dependent degeneration, researchers have understudied the effect of DOX on thymus. In the present investigation, we studied the effects of DOX on thymus, an organ that is important for the T-cell maturation. DOX treatment led to loss of cortical cells, decrease lymphopoiesis and increased the number of Hassells corpuscles, a marker of thymus aging. Proteomics analysis led to identification of a number of thymic proteins whose expression are altered by in vivo DOX treatment. Taken together, these results are consistent with the notion that DOX-treatment leads to thymic senescence. PMID- 20945941 TI - The regulation of factor IXa by supersulfated low molecular weight heparin. AB - Supersulfated low molecular weight heparin (ssLMWH) inhibits the intrinsic tenase (factor IXa-factor VIIIa) complex in an antithrombin-independent manner. Recombinant factor IXa with alanine substitutions in the protease domain (K126A, N129A, K132A, R165A, R170A, N178A, R233A) was assessed with regard to heparin affinity in solution and ability to regulate protease activity within the factor IXa-phospholipid (PL) and intrinsic tenase complexes. In a soluble binding assay, factor IXa K126A, K132A, and R233A dramatically (10-20-fold) reduced ssLMWH affinity, while factor IXa N129A and R165A moderately (5-fold) reduced affinity relative to wild type. In the factor IXa-PL complex, binding affinity for ssLMWH was increased 4-fold, and factor X activation was inhibited with a potency 7-fold higher than predicted for wild-type protease-ssLMWH affinity in solution. In the intrinsic tenase complex, ssLMWH inhibited factor X activation with a 4-fold decrease in potency relative to wild-type factor IXa-PL. The mutations increased resistance to inhibition by ssLMWH in a similar fashion for both enzyme complexes (R233A > K126A > K132A/R165A > N129A/N178A/wild type) except for factor IXa R170A. This protease had ssLMWH affinity and potency for the factor IXa-PL complex similar to wild-type protease but was moderately resistant (6-fold) to inhibition in the intrinsic tenase complex based on increased cofactor affinity. These results are consistent with conformational regulation of the heparin binding exosite and macromolecular substrate catalysis by factor IXa. An extensive overlap exists between the heparin and factor VIIIa binding sites on the protease domain, with residues K126 and R233 dominating the heparin interaction and R165 dominating the cofactor interaction. PMID- 20945942 TI - Using iTRAQ combined with tandem affinity purification to enhance low-abundance proteins associated with somatically mutated EGFR core complexes in lung cancer. AB - In this study, we report a novel use for the iTRAQ reagent combined with a peptide mass inclusion list to enhance the signal of low-abundance proteins during analysis by mass spectrometry. C-tagged-SH-EGFR was retrovirally transduced into two mutant lung cancer cell lines (HCC827 and PC9), and the core protein complexes were enriched by tandem affinity purification. Tryptically digested peptides were derivatized with iTRAQ and analyzed by higher-energy collision-induced dissociation mass spectrometry. The data revealed that UBS3B is a member of the EGFR core complex in the HCC827 cell line, which was not apparent by standard, unbiased one-dimensional shotgun analysis and collision-induced dissociation. The expression level of UBS3B, however, was 6-10 times lower than that observed in the PC9 cell line. Thus, using iTRAQ in this fashion allows the identification of low-abundance interactors when combined with samples where the same protein has a higher abundance. Ultimately, this approach may uncover proteins that were previously unknown or only suspected as members of core protein complexes. PMID- 20945943 TI - Two-dimensional differential in gel electrophoresis (2D-DIGE) analysis of grape berry proteome during postharvest withering. AB - The practice of postharvest withering is commonly used to correct quality traits and sugar concentration of high quality wines. To date, changes in the metabolome during the berry maturation process have been well documented; however, the biological events which occur at the protein level have yet to be fully investigated. To gain insight into the postharvest withering process, we studied the protein expression profiles of grape (Corvina variety) berry development focusing on withering utilizing a two-dimensional differential in gel electrophoresis (2D-DIGE) proteomics approach. Comparative analysis revealed changes in the abundance of numerous soluble proteins during the maturation and withering processes. On a total of 870 detected spots, 90 proteins were differentially expressed during berry ripening/withering and 72 were identified by MS/MS analysis. The majority of these proteins were related to stress and defense activity (30%), energy and primary metabolism (25%), cytoskeleton remodelling (7%), and secondary metabolism (5%). Moreover, this study demonstrates an active modulation of metabolic pathways throughout the slow dehydration process, including de novo protein synthesis in response to the stress condition and further evolution of physiological processes originated during ripening. These data represent an important insight into the withering process in terms of both Vitis germplasm characterization and knowledge which can assist quality improvement. PMID- 20945944 TI - Safety of gadoterate meglumine (Gd-DOTA) as a contrast agent for magnetic resonance imaging: results of a post-marketing surveillance study in Japan. AB - BACKGROUND: Safety is a primary concern with contrast agents used for MRI. If precautions could be taken before the repeated administration of gadolinium-based contrast media, then the awareness and management of adverse reactions would be more efficient. OBJECTIVES: To assess the safety and efficacy of gadoterate meglumine (Gd-DOTA) [Magnescope(r) in Japan, Dotarem(r) in other countries], a gadolinium-based contrast agent, in patients undergoing imaging of the brain/spinal cord and/or trunk/limbs, and to identify factors associated with the onset of adverse reactions. METHODS: The study ran for 4 years and included 3444 cases. The study was conducted before it became known that gadolinium-based contrast agents could trigger the development of nephrogenic systemic fibrosis. Patients for whom the contrast agent was indicated and who underwent imaging of the brain/spinal cord and/or trunk/limbs by MRI were enrolled. There were 1300 inpatients who were followed up during hospitalization (for several days), and 2144 outpatients who were followed up for at least 2 hours on-site. After Gd-DOTA administration, 13 patient baseline characteristics were used to explore factors that might predict a greater likelihood of acute non-renal adverse reactions. The physician's appraisal of the efficacy of Gd-DOTA was also assessed. RESULTS: A total of 40 adverse reactions were recorded in 32 patients, giving an overall incidence of adverse reactions of 0.93%. Gastrointestinal disorders were the most commonly reported adverse reactions (0.49%). Most adverse reactions reported were of mild intensity and no serious adverse reactions were reported. This study found that statistically significant risk factors for adverse reactions were general patient condition, liver disorder, kidney disorder, health complications, concomitant treatments, and Gd-DOTA dose (although the incidence of adverse reactions was not dose dependent). In the majority of cases (99.53%), the efficacy of Gd-DOTA was rated as 'effective' or 'very effective'; only the presence of kidney disorder was associated with a significantly greater likelihood of Gd-DOTA inefficacy. CONCLUSION: Overall, this post-marketing surveillance study did not reveal any untoward or unexpected findings concerning the safety or efficacy of Gd-DOTA. The low incidence of adverse reactions (<1%) and the absence of serious adverse reactions reported during the survey period showed that Gd-DOTA was very well tolerated. The use of Gd-DOTA as an MRI enhancing contrast medium in the clinical practice setting appears to be safe and effective. PMID- 20945945 TI - Effects of leukotriene receptor antagonists on peripheral eosinophil counts and serum IgE levels in children with food allergy. AB - BACKGROUND: Although the efficacy of leukotriene receptor antagonists (LTRAs) for bronchial asthma is already established, their effect on food allergy remains unclear. OBJECTIVE: To investigate the efficacy of LTRAs in children with food allergy. METHODS: This retrospective study examined 65 children with food allergy who were aged between 3 and 36 months (mean 14 +/- 9.6 months) from 2005 to 2008. Thirty-two children were treated as a dietary control group by avoiding any antigenic foods to which they had previously experienced adverse reactions. The remaining 33 children, designated the LTRA group, were treated with pranlukast (7 mg/kg bodyweight/day) in addition to maintaining dietary control. Clinical symptoms and laboratory data before and after 1 year of treatment were compared between the groups. RESULTS: Allergic symptoms improved in both the dietary controlled and LTRA groups, and there was no significant difference observed in the clinical parameters examined between the groups after the 1-year trial. Peripheral eosinophil count, serum IgE, interleukin (IL)-4, IL-5, IL-6, and eosinophil cationic protein (ECP) levels in children with food allergy were above standardized values in both groups. Although both the dietary controlled and LTRA groups showed a decreased eosinophil count (-273 +/- 232 vs -595 +/- 295/MUL; p < 0.05 and p < 0.001, respectively), only children treated with LTRA showed a significant decrease in serum IgE (-73.5 +/- 115 IU/mL; p < 0.01); conversely, the control group exhibited a significant increase in serum IgE (+159 +/- 138 IU/mL; p < 0.01). Furthermore, the LTRA group also showed a significant decrease in serum IL-4 (54.5 +/- 31.0 to 27.3 +/- 10.1 pg/mL), IL-5 (6.7 +/- 5.2 to 5.0 +/ 0.4 pg/mL), and ECP (45.4 +/- 15.0 to 15.0 +/- 9.8 MUg/L) levels (p < 0.05 for each). CONCLUSION: Early intervention with LTRAs may be effective in regulating eosinophil count and serum IgE, IL-4, IL-5, and ECP levels. These data support the potential effectiveness of LTRAs in young children with food allergy to prevent further allergic development. PMID- 20945947 TI - Ridaforolimus. AB - Ridaforolimus (AP23573; MK 8669) is an analog of sirolimus and a small molecule inhibitor of the mammalian target of rapamycin for the treatment of cancer. Both intravenous and oral formulations of the compound are being tested in clinical trials for the treatment of soft-tissue and bone sarcomas. It is in phase III development for sarcoma in the EU and US, and phase II for breast cancer, endometrial cancer, non-small cell lung cancer, and prostate cancer in the US and other markets in the world. This review discusses the key development milestones and therapeutic trials of this drug. PMID- 20945946 TI - Effects of edaravone on muscle atrophy and locomotor function in patients with ischemic stroke: a randomized controlled pilot study. AB - BACKGROUND AND OBJECTIVE: Stroke patients with severe leg paralysis are often bedridden in the acute and subacute phase, which increases the risk of disuse muscle atrophy in the chronic phase. The evidence to date indicates that oxidative stress plays an important role in the mechanism of disuse muscle atrophy. Therefore, the aim of this study was to determine if long-term radical scavenger treatment with edaravone following an acute stroke prevents the progression of disuse muscle atrophy and improves leg locomotor function in the chronic phase. METHODS: This randomized controlled pilot study was conducted at 19 acute stroke and rehabilitation centers across Japan. Forty-seven ischemic stroke patients with at least leg motor weakness admitted within 24 hours of onset were randomly assigned to receive continuous intravenous infusions of edaravone 30 mg twice daily for 3 days (short-term group) or 10-14 days (long term group). The primary endpoints of the study included the degree of leg disuse muscle atrophy, as measured by the percentage change from baseline in femoral muscle circumference 15 cm above the knee, and the improvement in leg locomotor function, as assessed by the maximum walking speed over 10 m, 3 months after the onset of stroke. RESULTS: Three-month follow-up was completed by a total of 41 patients (21 in the short-term group and 20 in the long-term group). On admission, there was no significant difference in the severity of stroke or the grade of leg paresis between the two treatment groups. The grade of disuse muscle atrophy and incidence of gait impairment 3 weeks after stroke onset were also similar between the short- and long-term groups. However, disuse muscle atrophy of the paretic and non-paretic legs was significantly less severe in the long term versus the short-term treatment group (3.6 +/- 5.9% and 1.5 +/- 6.0% vs 8.3 +/- 5.2% and 5.7 +/- 6.4%; p < 0.01 and p < 0.05) 3 months after stroke onset. Additionally, the maximum walking speed over a distance of 10 m was significantly greater in the long-term group (98 +/- 67 vs 54 +/- 55 cm/sec; p < 0.05). CONCLUSION: Edaravone treatment for up to 14 days suppresses the progression of disuse muscle atrophy and improves leg locomotor function to a greater extent than shorter-term treatment in acute stroke patients. This suggests that the management of stroke may be improved with long-term edaravone therapy by providing myoprotective effects that ameliorate functional outcome in the chronic phase. PMID- 20945948 TI - Telaprevir. AB - Telaprevir (LY 570310; LY-570310; LY570310; MP 424; MP-424; VX 950; VX-950) is an orally administered peptidomimetic inhibitor of the hepatitis C virus (HCV) protease NS3/4A. It is being developed by Vertex Pharmaceuticals and its licensees for the treatment of HCV infections and has recently been submitted to the US FDA for approval. As the first ever HCV protease inhibitor in phase III development, it is being studied in trials in combination therapy with pegylated interferon alfa-2a and ribavirin in Europe, the US, Australia, Canada, and Puerto Rico in treatment-naive and treatment-experienced patients with HCV genotype 1 infection. Phase III trials of telaprevir as combination therapy are also in progress in Japan. This review discusses the key development milestones and therapeutic trials of this drug to date. PMID- 20945949 TI - Boceprevir. AB - Boceprevir (SCH 503034; SCH-503034) is a peptidomimetic NS3/4A serine protease inhibitor, representing a new class of hepatitis C virus (HCV) inhibitors. It is being developed by Merck & Co. as part of a combination therapy regimen for the treatment of HCV infections. In two phase III trials, the HCV RESPOND-2 and HCV SPRINT-2 trials, the primary endpoints were met. Phase III development continues in the US, Europe, and Canada. This review looks at the key development milestones and therapeutic trials of this drug. PMID- 20945950 TI - Influence of dietary sesamin, a bioactive compound on fatty acids and expression of some lipid regulating genes in Baltic Atlantic salmon (Salmo salar L.) juveniles. AB - The effects of inclusion of sesamin / episesamin in Baltic Atlantic salmon (Salmo salar L.) diets based on vegetable oils were studied. The study was designed as a dose response study with two control diets, one diet based on fish oil (FO) and one diet based on a mixture of linseed and sunflower oil (6:4 by vol.) (MO). As experimental diets three different levels of inclusion of sesamin / episesamin (hereafter named sesamin) to the MO based diet and one diet based on sesame oil and linseed oil (SesO) (1:1 by vol.) were used. The dietary oils were mirrored in the fatty acid profile of the white muscle. Sesamin significantly decreased the levels of 18:3n-3 in the white muscle phospholipid (PL) fraction of all groups fed sesamin, no significant differences were found in the triacylglycerol fraction (TAG). Slightly increased levels of docosahexaenoic acid (22:6n-3, DHA) in PL and TAG were found in some of the sesamin fed groups. Sesamin significantly affected the expression of peroxisome proliferator-activated receptor alpha, scavenger receptor type B and hormone sensitive lipase, in agreement with previous studies on rainbow trout (Oncorhynchus mykiss) and Atlantic salmon (Salmo salar L.) hepatocytes published by our group. No significant effects on toxicological response measured as ethoxyresorufin O-deethylase activity was found. The total cytochrome P450 enzymes were significantly higher in MO 0.29 and SesO group. The amount of alpha- and gamma-tocopherols in liver and the amount of gamma-tocopherol in white muscle were significantly lower in fish fed the FO diet compared to the MO diet, but no difference after inclusion of sesamin was found in this study. Increased inclusion of sesamin increased the levels of sesamin and episesamin in the liver, but did not affect the amounts in white muscle. PMID- 20945951 TI - Fatty acid transfer from sow to piglet differs for different polyunsaturated fatty acids (PUFA). AB - Polyunsaturated fatty acids (PUFA) are essential for the development of the nervous system in animals. It is known that pigs are good models for human in many aspects. The aim of the study was to investigate how fat content and FA composition in sows' diet influence FA composition in brain of newborn and in liver and brain of one-day-old piglets, respectively. High fat (6 %) feeds were designed with regard to saturated or polyunsaturated fat content and n-6/n-3 ratio by adding either oats rich in linoleic acid (LA) or linseed oil rich in alpha-linolenic acid (ALA). The ratio n-6/n-3 PUFA was 11 in all three diets (the low fat (3 %), high fat saturated and high fat oats diet), while the ratio in the linseed oil diet was 2. Increased proportion of ALA in the diet increased ALA and eicosapentaenoic acid (EPA) in piglets' neutral and polar liver lipids and the long chain PUFA, EPA, docosapentaenoic and docosahexaenoic acid in piglet brain. The results suggest that transport of n-3 PUFA from sow to piglet was higher via milk than via bloodstream in the uterus and that increased content of ALA in sows' feed led to an increased accumulation of n-3 FA in piglets' liver and brain. PMID- 20945952 TI - FTO variant, energy intake, physical activity and basal metabolic rate in Caucasians. The HAPIEE study. AB - The FTO gene variants are the most important genetic determinants of body weight and obesity known so far, but the mechanism of their effect remains unclear. We have analyzed FTO rs17817449 variant (G>T in first intron) in 6024 adults aged 45 69 years to assess the potential mediating role of diet and physical activity. Diet was assessed by a 140-item food frequency questionnaire. Physical activity was measured by hours spent during a typical week by sport, walking and other activities outside of work requiring heavy and medium physical activity. Basal metabolic rate was calculated according Schofield formula. The FTO variant was significantly associated with body mass index (means in GG, GT and TT carriers were 28.7, 28.2 and 27.8 kg/m(2), p<0.001) and basal metabolic rate (BMR) (means in GG, GT and TT were 1603, 1588 and 1576 kcal per day, respectively, p<0.008) but it was not associated with physical activity, total energy intake or with energy intakes from fat, carbohydrates, proteins or alcohol. Results were essentially similar in men and women and the adjustment for physical activity or dietary energy intake did not reduce the effect of the FTO polymorphism. Means of BMR per kg of body weight was lowest in GG carriers (20.09, 20.21 for GT and 20.30 for TT, p<0.006) and this effect was more pronounced in females. These results suggest that the effect of the FTO rs17817449 variant on BMI in Caucasian adults is not mediated by energy intake or physical activity, but some effect on BMR per kg of body weight is possible. PMID- 20945953 TI - Body mass index change in females after short-time life style intervention is not dependent on the FTO polymorphisms. AB - Variants within the FTO gene are important determinants of body mass index (BMI), but their role in determination of BMI changes after combined dietary/physical activity intervention is unclear. We have analyzed 107 unrelated overweight non diabetic Czech females (BMI over 27.5 kg/m(2), age 49.2+/-12.3 years). FTO variants rs17817449 (first intron) and rs17818902 (third intron) were genotyped. The life style modification program (10 weeks) consisted of an age-matched reduction of energy intake and exercise program (aerobic exercise 4 times a week, 60 min each). The mean BMI before intervention was 32.8+/-4.2 kg/m(2) and the mean achieved weight loss was 4.8+/-3.5 kg (5.3+/-3.5 %, max. -15.5 kg, min. +2.0 kg, p<0.01). No significant association between BMI decrease and FTO variants was found. Also waist-to-hip ratio, body composition (body fat, water, active tissue), lipid parameters (total, LDL and HDL cholesterol, triglycerides) glucose and hsCRP changes were independent on FTO variants. FTO variants rs17817449 and rs17818902 are not associated with BMI changes after combined short time dietary/physical activity intervention in overweight females. PMID- 20945954 TI - A new non-uremic rat model of long-term peritoneal dialysis. AB - Together with the development of peritoneal dialysis (PD), appropriate animal models play an important role in the investigation of physiological, pathophysiological and clinical aspects of PD. However, there is still not an ideal experimental PD animal model. In this study, 45 Sprague-Dawley rats were divided into three groups. Group 1 (n=15) was receiving daily peritoneal injection through the catheter connected to the abdominal cavity, using PD solution containing 3.86 % D-glucose. Group 2 (n=15) was receiving daily peritoneal injection of 0.9 % physiological saline through a catheter. Group 3 (n=15), which was subjected to sham operation, served as controls. Our results showed that WBC counts in peritoneal effluent of Group 1 were slightly higher than those of Group 2 and control group, respectively (p<0.05). However, there was no episode of infection in any group. In addition, there was no significant difference in neutrophils fractions among these three groups. Hematoxylin-eosin and Masson's trichrome staining demonstrated a dramatic increase in thickness of the mesothelium-to-muscle layer of peritoneum exposed to high glucose (Group 1) compared to Group 2 and controls (p<0.01). These data indicated that we established a novel rat model of PD with a modified catheter insertion method. This model is more practical, easy to operate, not too expensive and it will facilitate the investigate of long-term effects of PD. PMID- 20945955 TI - Association of eNOS gene polymorphisms T-786C and G894T with blood pressure variability in man. AB - The aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) T-786C and G894T in the gene encoding eNOS with blood pressure variability (BPV) in man. Blood pressure was recorded beat-to-beat at rest three times in periods of one week (5 min, Finapres, breathing at 0.33 Hz) in 152 subjects (19-24 years). Systolic (SBPV(0.1r)/SBPV(0.1a)) and diastolic (DBPV(0.1r)/DBPV(0.1a)) blood pressure variabilities in relative (r.u.) and absolute (mm Hg(2)/Hz) units were determined by the spectral method as spectral power at the frequency of 0.1 Hz. Genotypes of both polymorphisms were detected using polymerase chain reaction and restriction analysis using enzymes Msp I and Ban II. Significant differences were observed in BPV among genotypes of T-786C SNP (p<0.05; Kruskal-Wallis), and among haplotypes of both SNPs (p<0.05; Kruskal Wallis) as well. In T-786C SNP, carriers of less frequent allele (CC homozygotes and TC heterozygotes) showed significantly greater SBPV(0.1r) and SBPV(0.1a) compared to TT homozygotes (Mann-Whitney; p<0.05). The G894T variant showed no significant differences, but, both SNPs were in linkage disequilibrium (D'=0.37; p<0.01). Carriers of haplotype CT/CT (CC homozygotes of -786C/T and TT homozygotes of G894T) displayed significantly greater SBPV(0.1r), SBPV(0.1a) and DBPV(0.1a) compared to carriers of other haplotype combinations (Kruskal-Wallis; p=0.015, p=0.048, and p=0.026, respectively). In conclusion, the haplotype formed by less frequent alleles of both eNOS variants was associated with increased systolic and diastolic BPV in this study. PMID- 20945956 TI - Defective Ca(2+) handling proteins regulation during heart failure. AB - Abnormal release of Ca(2+) from sarcoplasmic reticulum (SR) via the cardiac ryanodine receptor (RyR2) may contribute to contractile dysfunction in heart failure (HF). We previously demonstrated that RyR2 macromolecular complexes from HF rat were significantly more depleted of FK506 binding protein (FKBP12.6). Here we assessed expression of key Ca(2+) handling proteins and measured SR Ca(2+) content in control and HF rat myocytes. Direct measurements of SR Ca(2+) content in permeabilized cardiac myocytes demonstrated that SR luminal [Ca(2+)] is markedly lowered in HF (HF: DeltaF/F(0) = 26.4+/-1.8, n=12; control: DeltaF/F(0) = 49.2+/-2.9, n=10; P<0.01). Furthermore, we demonstrated that the expression of RyR2 associated proteins (including calmodulin, sorcin, calsequestrin, protein phosphatase 1, protein phosphatase 2A), Ca(2+) ATPase (SERCA2a), PLB phosphorylation at Ser16 (PLB-S16), PLB phosphorylation at Thr17 (PLB-T17), L type Ca(2+) channel (Cav1.2) and Na(+)- Ca(2+) exchanger (NCX) were significantly reduced in rat HF. Our results suggest that systolic SR reduced Ca(2+) release and diastolic SR Ca(2+) leak (due to defective protein-protein interaction between RyR2 and its associated proteins) along with reduced SR Ca(2+) uptake (due to down-regulation of SERCA2a, PLB-S16 and PLB-T17), abnormal Ca(2+) extrusion (due to down-regulation of NCX) and defective Ca(2+) -induced Ca(2+) release (due to down-regulation of Cav1.2) could contribute to HF. PMID- 20945957 TI - Phosphodiesterases inhibition enhances the effect of glucagon on cardiac automaticity in the isolated right ventricle of the rat. AB - We evaluated the effect of glucagon on cardiac automaticity as well as the possible role of cyclic nucleotide phosphodiesterases (PDE) in regulating this effect. Concentration response curves for glucagon in the absence and in the presence of the non-selective PDE inhibitor IBMX were performed in the isolated right ventricle of the rat. We found that glucagon produces only a minor increase of ventricular automaticity (11.0+/-4.1, n=5) when compared to the full agonist of beta-adrenoceptor isoproterenol (182.2+/-25.3, n=7). However, IBMX enhances the maximal efficacy of glucagon on cardiac automaticity (11.0+/-4.1, in the absence and 45.3+/-3.2 in the presence of IBMX, n=5, P<0.05). These results indicate that PDE blunts proarrhythmic effects of glucagon in rat myocardium. PMID- 20945958 TI - Insulin resistance and vitamin D deficiency in patients with chronic kidney disease stage 2-3. AB - Vitamin D status and the relationship between serum 25(OH) vitamin D concentrations and the components of insulin resistance were examined in 120 patients with chronic kidney disease stage 2 and 3. Insulin sensitivity/resistance was calculated by the quantitative insulin sensitivity check index (QUICKI). In this analysis, the prevalence of insulin resistance was 42 %. Only 17 % of patients had serum 25(OH) vitamin D concentration in the recommended range (>/=30 ng/ml), 42 % suffered from vitamin D insufficiency and 41 % had moderate vitamin D deficiency. Insulin resistance significantly correlated with serum 25(OH)D and 1,25(OH)(2)D concentrations, renal function and protein excretion rate. Our results support the increasing evidence that vitamin D deficiency may be one of the factors participating in the development of insulin resistance already in the early stages of chronic kidney disease. PMID- 20945959 TI - In situ assessment of the brain microcirculation in mechanically-ventilated rabbits using sidestream dark-field (SDF) imaging. AB - Assessment of the cerebral microcirculation by on-line visualization has been impossible for a long time. Sidestream dark-field (SDF) imaging is a relatively new method allowing direct visualization of cerebral surface layer microcirculation using hand-held probe for direct contact with target tissue. The aim of this study was to elucidate the feasibility of studying the cerebral microcirculation in situ by SDF imaging and to assess the basic cerebral microcirculatory parameters in mechanically ventilated rabbits. Images were obtained using SDF imaging from the surface of the brain via craniotomy. Clear high contrast SDF images were successfully obtained. Total small-vessel density was 14.6+/-1.8 mm/mm(2), total all-vessel density was 17.9+/-1.7 mm/mm(2), DeBacker score was 12.0+/-1.6 mm(-1) and microvascular flow index was 3.0+/-0.0. This method seems to be applicable in animal studies with possibility to use SDF imaging also intraoperatively, providing unique opportunity to study cerebral microcirculation during various experimental and clinical settings. PMID- 20945960 TI - Adiponectin inhibits spontaneous and catecholamine-induced lipolysis in human adipocytes of non-obese subjects through AMPK-dependent mechanisms. AB - Adiponectin is an adipokine increasing glucose and fatty acid metabolism and improving insulin sensitivity. The aim of this study was to investigate the role of adiponectin in the regulation of adipocyte lipolysis. Human adipocytes isolated from biopsies obtained during surgical operations from 16 non-obese and 17 obese subjects were incubated with 1) human adiponectin (20 microg/ml) or 2) 0.5 mM AICAR - activator of AMPK (adenosine monophosphate activated protein kinase). Following these incubations, isoprenaline was added (10(-6) M) to investigate the influence of adiponectin and AICAR on catecholamine-induced lipolysis. Glycerol concentration was measured as lipolysis marker. We observed that adiponectin suppressed spontaneous lipolysis by 21 % and isoprenaline induced lipolysis by 14 % in non-obese subjects. These effects were not detectable in obese individuals, but statistically significant differences in the effect of adiponectin between obese and non-obese were not revealed by two way ANOVA test. The inhibitory effect of AICAR and adiponectin on lipolysis was reversed by Compound C. Our results suggest, that adiponectin in physiological concentrations inhibits spontaneous as well as catecholamine-induced lipolysis. This effect might be lower in obese individuals and this regulation seems to involve AMPK. PMID- 20945961 TI - Changes of plasma obestatin, ghrelin and NPY in anorexia and bulimia nervosa patients before and after a high-carbohydrate breakfast. AB - Peptides ghrelin, obestatin and neuropeptide Y (NPY) play an important role in regulation of energy homeostasis, the imbalance of which is associated with eating disorders anorexia (AN) and bulimia nervosa (BN). The changes in ghrelin, obestatin and NPY plasma levels were investigated in AN and BN patients after administration of a high-carbohydrate breakfast (1604 kJ). Eight AN women (aged 25.4+/-1.9, BMI: 15.8+/-0.5), thirteen BN women (aged 22.0+/-1.05, BMI: 20.1+/ 0.41) and eleven healthy women (aged 25.1+/-1.16, BMI: 20.9+/-0.40) were recruited for the study. We demonstrated increased fasting ghrelin in AN, but not in BN patients, while fasting obestatin and NPY were increased in both AN and BN patients compared to the controls. Administration of high-carbohydrate breakfast induced a similar relative decrease in ghrelin and obestatin plasma levels in all groups, while NPY remained increased in postprandial period in both patient groups. Ghrelin/obestatin ratio was lower in AN and BN compared to the controls. In conclusions, increased plasma levels of fasting NPY and its unchanged levels after breakfast indicate that NPY is an important marker of eating disorders AN and BN. Different fasting ghrelin and obestatin levels in AN and BN could demonstrate their diverse functions in appetite and eating suppression. PMID- 20945962 TI - Heart rate, body temperature and physical activity are variously affected during insulin treatment in alloxan-induced type 1 diabetic rat. AB - Diabetes mellitus is associated with a variety of cardiovascular complications including impaired cardiac muscle function. The effects of insulin treatment on heart rate, body temperature and physical activity in the alloxan (ALX)-induced diabetic rat were investigated using in vivo biotelemetry techniques. The electrocardiogram, physical activity and body temperature were recorded in vivo with a biotelemetry system for 10 days before ALX treatment, for 20 days following administration of ALX (120 mg/kg) and thereafter, for 15 days whilst rats received daily insulin. Heart rate declined rapidly after administration of ALX. Pre-ALX heart rate was 321+/-9 beats per minute, falling to 285+/-12 beats per minute 15-20 days after ALX and recovering to 331+/-10 beats per minute 5-10 days after commencement of insulin. Heart rate variability declined and PQ, QRS and QT intervals were prolonged after administration of ALX. Physical activity and body temperature declined after administration of ALX. Pre-ALX body temperature was 37.6+/-0.1 degrees C, falling to 37.3+/-0.1 degrees C 15-20 days after ALX and recovering to 37.8+/-0.1 degrees C 5-10 days after commencement insulin. ALX-induced diabetes is associated with disturbances in heart rhythm, physical activity and body temperature that are variously affected during insulin treatment. PMID- 20945963 TI - Difference in angiotensinogen haplotype frequencies between chronic heart failure and advanced atherosclerosis patients - new prognostic factor? AB - Numerous association studies have been involved in studying the angiotensinogen (AGT) variants, AGT plasma levels and relations to cardiovascular diseases, such as hypertension, myocardial infarction, coronary heart disease. To investigate a role of AGT G(-6)A and M235T genetic variants for chronic heart failure (CHF) and advanced atherosclerosis (AA), a total of 240 patients with CHF and 200 patients with AA of the Czech origin were evaluated for the study. The study shows the role of polymorphism AGT G(-6)A in genetic background among advanced atherosclerosis patients and chronic heart failure patients (Pg=0.001). This difference was also observed in comparison of AA patients with subgroup of CHF with dilated cardiomyopathy (Pg=0.02; Pa=0.009), and ischemic heart disease (Pg=0.007). The greatest difference between triple-vessel disease and chronic heart failure groups was observed in frequency of GT haplotype (P<0.001) and GGMT associated genotype (P<0.001). Retrospectively, we found the same trend when the subgroups of CHF were compared to AA group (AA vs. IHD with CHF P<0.001; AA vs. DCM P<0.001). These results suggest AGT genetic variants as a risk factor for chronic heart failure compared to advanced atherosclerosis disease without heart failure, with a strong difference between IHD patients and chronic heart failure patients with ischemic heart disease, especially in haplotypes and associated genotypes. PMID- 20945964 TI - Relationship between high aortic pulse pressure and extension of coronary atherosclerosis in males. AB - A high pulse pressure (PP) is a marker of increased artery stiffness and represents a well-established independent predictor for cardiovascular morbidity and mortality. The objective of the research was to determine whether invasively measured central aortic PP was related to the presence and severity of coronary artery disease. In total 1075 consecutive stable male patients undergoing diagnostic coronary angiography with a preserved left ventricular function were included. Diseased coronary vessel (DCV) was defined by the presence of >50 % stenosis. Men were divided into 3 groups according to the increased value of PP. The average PP in the tertiles was 47.8+/-7.1 vs. 67.0+/-4.9 vs. 91.3+/-12.8 mm Hg (p<0.01). The significant differences of DCV was found among tertiles (1.51+/ 1.11 vs 1.80+/-1.04 vs. 1.99+/-0.98 DCV, p<0.01). Aortic PP together with age and hyperlipoproteinemia were found as factors with an independent relationship to DCV according to multivariate linear regression. In conclusions the increased value of aortic PP in the male population is independently connected with more severe atherosclerosis evaluated by the significant number of DCV. PMID- 20945965 TI - Effects of organophosphate insecticides on mechanical properties of rat aorta. AB - The present study was carried out to search whether organophosphate pesticides affect the mechanical properties of the thoracic aorta. Wistar female rats (aged 6-8 weeks) were assigned randomly to a control group and groups treated with either dichlorvos or chlorpyriphos for 90 days at a dose of 5 mg/kg/day. After that period, animals were killed and thoracic aorta strips in longitudinal direction were isolated. The stress, strain and elastic modulus were obtained from the strips. Our results showed that chronic administration of chlorpyriphos and dichlorvos caused downward shift of the stress-strain relations compared to the control curve. The elastic modulus-stress curve revealed distinct characteristics in the low and high stress regions. A power function was used to simulate the low stress region while a line was fit to the high stress region. Curve fitting procedure illustrated that both pesticides influenced mainly the high stress region, but they had diverse effects at the low stress region. The results also imply that chlorpyriphos and dichlorvos decrease the strength of the aorta and therefore might influence the response of the aorta to mechanical loading induced by blood pressure. PMID- 20945966 TI - The interaction of osteoblasts with bone-implant materials: 1. The effect of physicochemical surface properties of implant materials. AB - This comparative study of various surface treatments of commercially available implant materials is intended as guidance for orientation among particular surface treatment methods in term of the cell reaction of normal human osteoblasts and blood coagulation. The influence of physicochemical surface parameters such as roughness, surface free energy and wettability on the response of human osteoblasts in the immediate vicinity of implants and on the blood coagulation was studied. The osteoblast proliferation was monitored and the expression of tissue mediators (TNF-alpha, IL-8, MMP-1, bone alkaline phosphatase, VCAM-1, TGF-beta) was evaluated after the cell cultivation onto a wide range of commercially available materials (titanium and Ti6Al4V alloy with various surface treatments, CrCoMo alloy, zirconium oxide ceramics, polyethylene and carbon/carbon composite). The formation of a blood clot was investigated on the samples immersed in a freshly drawn whole rabbit blood using scanning electron microscope. The surfaces with an increased osteoblast proliferation exhibited particularly higher surface roughness (here R(a) 3.5 microm) followed by a high polar part of the surface free energy whereas the effect of wettability played a minor role. The surface roughness was also the main factor regulating the blood coagulation. The blood clot formation analysis showed a rapid coagulum formation on the rough titanium-based surfaces. The titanium with an etching treatment was considered as the most suitable candidate for healing into the bone tissue due to high osteoblast proliferation, the highest production of osteogenesis markers and low production of inflammatory cytokines and due to the most intensive blood clot formation. PMID- 20945967 TI - Characterization of the capillary network in skeletal muscles from 3D data. AB - In this review we present immunohistochemical methods for visualization of capillaries and muscle fibres in thick muscle sections. Special attention is paid to the procedures that preserve good morphology. Applying confocal microscopy and virtual 3D stereological grids, or tracing of capillaries in virtual reality, length of capillaries within a muscle volume or length of capillaries adjacent to a muscle fibre per fibre length, fibre surface area or fibre volume can be evaluated by an unbiased approach. Moreover, 3D models of capillaries and muscle fibres can be produced. Comparison of the developed methods with counting capillary profiles from 2D sections is discussed and the reader is warned that counting capillary profiles from 2D sections can underestimate the capillary length by as much as 75 percent. Application of the described 3D methodology is illustrated by the anatomical remodelling of capillarity during acute denervation and early reinnervation in the rat soleus and extensor digitorum longus muscles. PMID- 20945968 TI - Serotonin receptors - from molecular biology to clinical applications. AB - Serotonin (5-hydroxytryptamine) is an ubiquitary monoamine acting as one of the neurotransmitters at synapses of nerve cells. Serotonin acts through several receptor types and subtypes. The profusion of 5-HT receptors should eventually allow a better understanding of the different and complex processes in which serotonin is involved. Its role is expected in the etiology of several diseases, including depression, schizophrenia, anxiety and panic disorders, migraine, hypertension, pulmonary hypertension, eating disorders, vomiting and irritable bowel syndromes. In the past 20 years, seven distinct families of 5-HT receptors have been identified and various subpopulations have been described for several of them. Increasing number of 5-HT receptors has made it difficult to unravel the role of 5-HT receptor subpopulations due to the lack of suitable selective agents. The present review describes the different populations and nomenclature of recently discovered 5-HT receptors and their pharmacological relevance. PMID- 20945969 TI - Complexation/encapsulation of green tea polyphenols in mixed calcium carbonate and phosphate micro-particles. AB - We used a double-jet mixer to encapsulate water-soluble polyphenols, green tea extract (GTE), with calcium-based inorganic materials. The device mixed calcium chloride solutions with a solution of carbonate and phosphate in the presence of a GTE solution, and formed micro-particles which capture the GTE molecules. The micro-particles were analysed by liquid chromatography coupled to tandem mass spectroscopy to determine the encapsulation yield and loading of the different GTE components. We established correlations between (1) the efficiency of the GTE encapsulation and the composition of the mixed anion solutions and (2) the protonation degree of the ions and the molar ratio of calcium cations and carbonate/phosphate anions. An optimal and reproducible GTE loading of about 40% with an encapsulation yield of 65% was observed for a carbonate/phosphate molar composition of 4 : 1. In addition, our experimental results showed that the process is selective and favours the encapsulation of gallated species which form stronger complexes with calcium cations. PMID- 20945970 TI - Effects of tremella-alginate-liposome encapsulation on oral delivery of inactivated H5N3 vaccine. AB - In this study, we evaluated a system for oral vaccine delivery, consisting of liposomes coated first with a layer of tremella and then with an outer layer of acid-induced alginate. In vitro release studies showed that the triple layer of alginate-tremella-liposomes was more resistant to an acidic pH and modulated the release profiles at an alkaline pH. Transepithelial electrical resistance (TEER) studies revealed that liposomes or tremella-coated liposomes were able to open tight junctions of the Caco-2 cell monolayer. In mice, although serum immunoglobulin G (IgG) was not expected to increase and haemagglutination inhibition showed that antibody levels were still too low to provide sufficient protection, alginate-tremella-liposomes encapsulated virus-induced intestinal secretory immunoglobulin A (s-IgA) production to provide protection against virus infection. In conclusion, an oral virus vaccine entrapped in alginate-tremella liposomes improved the mucosal antiviral s-IgA response. This system may have potential use as a carrier for oral vaccine delivery. PMID- 20945971 TI - High throughput surface characterization: A review of a new tool for screening prospective biomedical material arrays. AB - The application of high throughput surface characterization (HTSC) to the analysis of polymeric biomaterial libraries is an important advancement for the discovery and development of new biomedical materials and is the focus of this review. The potential for HTSC to identify structure/activity relationships for large libraries of materials can be utilized to accelerate materials discovery as well as providing insight into the underlying biological-material interactions. Furthermore, the correlations identified between surface chemical structure and cellular behavior could not have been predicted by a rational design approach based simply on review of bulk structure, which demonstrates the importance of HTSC in the assessment of cell-material and cell-biomolecular interactions that are dependent on surface properties. PMID- 20945972 TI - Protective effects of clioquinol on human neuronal-like cells: a new formulation of clioquinol-loaded PLGA microspheres for Alzheimer's disease. AB - BACKGROUND: Clioquinol (CQ), a metal chelator, has gained renewed attention due to its ability to modulate metal homeostasis in neurodegenerative disorders such as Alzheimer's disease. PURPOSE: To investigate the protective effects of a wide range of concentrations of CQ on two human neuroblastoma cell lines (IMR-32 and SKN-AS) and to develop and characterize a new controlled release system of CQ consisting of biodegradable microspheres. RESULTS: H(2)O(2) (400 MUM) adequately induced death cell in IMR-32 and SKN-AS cell lines thereby resulting in a useful model for neuroprotective studies. CQ (20-50 MUM) induced a potent and robust protective effect against peroxide-mediated oxidative stress in human neuronal like cells (SKN-AS) determined by both MTT and flow cytometry (cell viability). These results were also confirmed by means of reactive oxygen species (ROS) production. Biodegradable poly(dl-lactic-co-glycolic acid) (PLGA) resomers assayed for microspheres preparation were PLGA-502 and PLGA-502H. Optimization by using an experimental design resulted in a formulation prepared with CQ (112 mg) and PLGA-502H (400 mg). With this formulation, mean encapsulation efficiency of 82.37% +/- 6.67% and, zero-order release rate of 58 +/- 3ug CQ/day/10 mg microspheres between Days 10 and 35 were obtained. CONCLUSION: We have developed a promising formulation for the treatment of Alzheimer's disease. PMID- 20945973 TI - A single-incision laparoscopic hepatectomy for hepatocellular carcinoma: initial experience in a Japanese patient. AB - Minimally invasive approaches for small liver tumors are desirable. We describe a single-incision laparoscopic hepatectomy (SILH) using total laparoscopic surgery (TLS) technique. SILH was performed to remove a solitary 2-cm hepatocellular carcinoma located at segment 3. The technique included a one-inch skin incision with three ports (one 12 mm and two of 5 mm each). The liver was sealed and dissected by three different devices: Harmonic scalpel, TissueLink sealing dissector, and Endoclip. Operation time was 70 minutes and blood loss was trivial. The patient required no analgesia postoperatively and walked unaided the next day. Various aspects of the procedure were not different from TLS. SILH is a safe procedure with several advantages. The procedure is promising as minimally invasive liver surgery. PMID- 20945974 TI - Single incision endoscopic surgery for lumbar hernia. AB - Single Incision Endoscopic Surgery (SIES) has emerged as a less invasive surgery among laparoscopic surgeries, and this approach for incisional hernia was reported recently. This is the first report of SIES for an incisional lumbar hernia. A 66-year-old Japanese woman was referred to our institution because of a left flank hernia that developed after left iliac crest bone harvesting. A 20-mm incision was created on the left side of the umbilicus and all three trocars (12, 5, and 5 mm) were inserted into the incision. The hernial defect was 14 * 9 cm and was repaired with intraperitoneal onlay mesh and a prosthetic graft. The postoperative course was uneventful. SIES for lumbar hernia offers a safe and effective outcome equivalent compared to laparoscopic surgery. In addition, SIES is less invasive and has a cosmetic benefit. PMID- 20945975 TI - Prospective risk of stillbirth in monochorionic-diamniotic twin gestations: a population based study. AB - OBJECTIVE: To calculate a population-based prospective risk of fetal death in monochorionic-diamniotic twins. STUDY DESIGN: We evaluated 387 monochorionic diamniotic twin pregnancies that were followed and delivered after 24 weeks in Slovenia during the period 1997-2007. Surveillance was not standardized. The prospective risk of fetal death was calculated as the total number of deaths after the beginning of the gestational period divided by the number of continuing pregnancies at or beyond that period. RESULTS: Fetal death rate was 32 of 774 fetuses (4.1%; 95% confidence interval (CI), 3.0%-5.9%); the prospective risk of stillbirth per pregnancy after 33 weeks of gestation was 6.2% (95% CI, 4.2% 9.1%). CONCLUSION: The Slovenian population-based prospective risk of fetal death in monochorionic-diamniotic pregnancies that remained undelivered after 33 weeks' gestation is higher than previously reported from hospital-based studies. PMID- 20945977 TI - Biomarker research in Parkinson's disease: objective measures needed for patient stratification in future cause-directed trials. PMID- 20945976 TI - A discrete affinity-driven elevation of ZAP-70 kinase activity initiates negative selection. AB - CONTEXT: Although ZAP-70 is required for T-cell development, it's unclear how this kinase controls both positive and negative selection. OBJECTIVE AND METHODS: Using OT-I pre-selection thymocytes and a panel of peptide major histocompatibility complex (pMHC) ligands of defined affinity, the recruitment, phosphorylation and activity of ZAP-70 was determined at the interface with antigen-presenting cells (APCs). RESULTS: pMHC ligands promoting negative selection induce a discrete elevation of ZAP-70 recruitment, phosphorylation and enzymatic activity in the thymocyte:APCs interface. DISCUSSION: The quantity of ZAP-70 kinase activity per cell is a key parameter controlling the fate of a developing thymocyte since partial inhibition of ZAP-70 kinase activity converted negative into positive selection. Surprisingly, the amount of ZAP-70 enzymatic activity observed during negative selection is not controlled by differential phosphorylation of the ZAP-70 protein but rather by the total amount of T-cell receptor and co-associated ZAP-70 recruited to the thymocyte:APC interface. CONCLUSIONS: These data provide evidence that a burst of ZAP-70 activity initiates the signaling pathways for negative selection. PMID- 20945978 TI - Imaging dopamine transporters in Parkinson's disease. AB - The dopamine transporter (DAT) is responsible for clearance of dopamine from the synaptic cleft after its release. Imaging DAT availability provides a measure of dopamine terminal function and a method for detecting striatal dopamine deficiency states present in idiopathic Parkinson's disease and atypical neurodegenerative Parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy. DAT imaging with PET or single photon emission computed tomography can be used to support a diagnosis of dopamine-deficient parkinsonism in cases where this is suspected and rationalize the use of dopaminergic agents as therapy. It can also detect subclinical dopaminergic dysfunction when present in subjects at risk of Parkinson's disease, such as relatives of patients, susceptibility gene mutation carriers, and subjects with late-onset hyposmia or sleep disorders. Finally, the presence of normal DAT availability on imaging can help exclude nondopamine-deficient syndromes, such as dystonic and severe essential tremors, drug-induced and psychogenic parkinsonism that, on occasion, mimic Parkinson's disease. PMID- 20945979 TI - Olfaction as a biomarker in Parkinson's disease. AB - Olfactory dysfunction in Parkinson's disease is common and of interest, both as a clinical finding and potential biomarker. In this article, we discuss studies characterizing the olfactory deficit in Parkinson's disease and pathological analysis that suggests the olfactory system is a likely induction site of the neurodegenerative process. These studies have enabled research to explore the potential of olfactory dysfunction as a key component in early diagnostic strategies, as a biomarker for diagnostic purposes, a predictor of clinical outcomes and a potential therapy-independent marker of disease progression. PMID- 20945980 TI - Problems associated with fluid biomarkers for Parkinson's disease. AB - This article focuses on biochemical markers that may be used in the diagnostics of Parkinson's disease and associated disorders, and to identify early cases and stratify patients into subgroups. We present an updated account of some currently available candidate fluid biomarkers, and discuss their diagnostic performance and limitations. We also discuss some of the general problems with Parkinson's disease biomarkers and possible ways of moving forward. It may be concluded that a diagnostically useful fluid biomarker for Parkinson's disease is yet to be identified. However, some interesting candidates exist and may prove useful in the future, alone or when analyzed together in patterns. PMID- 20945981 TI - Quantification of alpha-synuclein in cerebrospinal fluid as a biomarker candidate: review of the literature and considerations for future studies. AB - The pursuit of laboratory tests that allow for the reliable and inexpensive identification of subjects with parkinsonism represents a hot topic in translational neuroscience. This unmet need affects the counseling of presymptomatic, at-risk subjects and delays the accurate diagnosis of already symptomatic individuals. The absence of validated markers that are closely linked to the pathological disease process also compromises the objective monitoring of therapeutic interventions in clinical trials. Typical Parkinson's disease represents a heterogenous syndrome (but the majority of patients suffer from neurodegeneration) that is linked to the misprocessing of alpha-synuclein (alpha Syn). The identification of alpha-Syn as a bona fide constituent of human cerebrospinal fluid and its quantification in early cross-sectional studies represent the beginning of a new chapter in Parkinson's disease research. It will determine what role, if any, cerebrospinal fluid alpha-Syn plays as a biomarker candidate in Lewy inclusion-positive forms of parkinsonism. This article focuses on the progress that has been made in seven recently published papers and highlights the challenges that lie ahead. We also provide specific information regarding standardized operating procedures for cerebrospinal fluid collection in PD biomarker research efforts. PMID- 20945983 TI - Autosomal recessive mutations in the development of Parkinson's disease. AB - Although Parkinson's disease was long considered a nongenetic disorder, it is now clear that there are multiple predisposing genes, and that the disorder can exhibit either Mendelian or non-Mendelian modes of inheritance. The identification of several of these genes has provided important insights into the pathogenesis of this common complex disorder. This article presents an overview of the genes associated with autosomal recessive Parkinson's disease, including Parkin (PARK2), PINK1 (PARK6), DJ1 (PARK7) and ATP13A2 (PARK9). Recently, it was recognized that mutations in the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are associated with an increased incidence of parkinsonism. While Gaucher disease is an autosomal recessive inherited disorder, patients with Parkinson's disease can be Gaucher heterozygotes or homozygotes. Elucidating the basis for this association may shed light on new disease mechanisms that contribute to the development of parkinsonism. PMID- 20945982 TI - Urate: a novel biomarker of Parkinson's disease risk, diagnosis and prognosis. AB - A growing number of studies have correlated higher urate levels with a lower risk of developing Parkinson's disease (PD) and with a favorable rate of disease progression, indicating that urate could be an important biomarker of the pathophysiology underlying PD. Dietary and genetic determinants of urate have also been linked to a reduced risk or delayed onset of PD. Based on the known antioxidant and metal complexing properties of urate, together with evidence for oxidative stress as a contributor to neurodegeneration in PD, urate may serve as an endogenous neuroprotectant that helps reduce the risk and rate of the disease. In this article we review the convergent biological, epidemiological and clinical data that identify urate as a promising biomarker of the risk, diagnosis and prognosis of PD. PMID- 20945984 TI - Biomarkers in Parkinson's disease: a funder's perspective. AB - Therapeutic development in Parkinson's disease is hampered by the paucity of well validated biomarkers that can assist with diagnosis and/or tracking the progression of the disease. Since its inception, the Michael J Fox Foundation for Parkinson's Research has invested heavily in biomarker research and continues to prioritize discovery and development efforts. This article summarizes the history and evolution of the Michael J Fox Foundation's role in supporting biomarker research and lays out the current challenges in successfully developing markers that can be used to test therapies, while also providing a vision of future funding efforts in Parkinson's disease biomarkers. PMID- 20945985 TI - Biomarkers in Parkinson's disease: a venture capitalist's perspective. AB - The emergence of biomarkers linking disease and treatment effects in a clear manner presents an opportunity to change the current drug development paradigm, which could lead to more cost-efficient and higher-quality clinical trials. This has raised the hopes of venture capital investors, who may be able to better navigate the stormy and risky sea of early-stage life science investments, to find a way out of the current funding crisis for novel, nonvalidated drugs and their clinical development. The following survey paints a snapshot of the current perception of biomarkers as a paradigm changer in the eyes of the venture capital community. PMID- 20945986 TI - Identification of novel genetic markers and improved treatment options for diabetic kidney disease. PMID- 20945987 TI - Apoptosis in nonalcoholic steatohepatitis with normal aminotransferase values: zooming in on cytokeratin 18 fragments. PMID- 20945989 TI - Vascular dysfunction biomarkers are elevated in children with HIV. PMID- 20945990 TI - Cytokine patterns after therapy with Avonex(r), Rebif(r), Betaferon(r) and CinnoVexTM in relapsing-remitting multiple sclerosis in Iranian patients. AB - AIM: Several lines of evidence exist which suggest that changes in the expression of circulating cytokines are linked to the development or reoccurrence of multiple sclerosis (MS). This study aimed to evaluate the serum levels of relevant cytokines after therapy with IFN-beta formulations in MS patients. MATERIALS & METHODS: In this study, blood samples were collected from 70 MS patients undergoing four different types of IFN-beta formulation treatment and 100 healthy controls. After 24 months of treatment, the serum levels of IL-17A, IL-12, IFN-gamma and IL-10 in patients and healthy controls were analyzed by ELISA. RESULTS: Our results demonstrated that serum levels of IL-17A were significantly higher in patients treated with CinnoVexTM and Avonex(r) when compared with healthy controls. Serum levels of IL-10 were significantly decreased after therapy with CinnoVex, whereas serum levels of IFN-beta were elevated. No difference in serum levels of IL-12 were detected between patients and controls. CONCLUSION: Results of our study suggest that CinnoVex and Avonex modulate the immune system less than Rebif(r) and Betaferon(r) in MS patients, and an elevated dose of CinnoVex and Avonex may be required for better regulation of the immune system in MS patients. PMID- 20945992 TI - The need for noninvasive biomarkers for drug safety in neonatal circulation. AB - The new EU Pediatric Drug Regulation covers the development of new drugs to include studies in children and newborn babies. An important part of the evaluation of a new drug will be data on efficacy and safety related to short term and possible long-term effects. Owing to the special circumstances of studying drugs, especially in newborn babies, new, preferably noninvasive, biomarkers are required that can be used for assessment and monitoring in this vulnerable patient population. Feedback from expert groups and public stakeholders should be taken into account when introducing biomarkers into the study design. New noninvasive biomarkers for monitoring cardiovascular circulation in newborns will be used to illustrate an example of their practical use and implementation. PMID- 20945994 TI - Efficacy and safety profiles of manidipine compared with amlodipine: a meta analysis of head-to-head trials. AB - Abstract The aim of this meta-analysis was to compare the efficacy and safety profile of manidipine 20 mg with that of amlodipine 10 mg. A systematic research of quantitative data produced or published between 1995 and 2009 was performed. Head-to-head randomized controlled trials (RCTs) of 12 months minimum duration reporting comparative efficacy (changes in systolic and diastolic blood pressure) and safety (total adverse events and ankle oedema), were included. Four high quality RCTs, accounting for 838 patients (436 received manidipine and 402 received amlodipine) were included. The efficacy of manidipine and amlodipine was statistically equivalent: effect size for DBP = -0.08 (p = 0.22) and SBP = -0.01 (p = 0.83). The global safety of manidipine was significantly better than amlodipine: the relative risk (RR) for adverse event was 0.69 (0.56-0.85), and particularly for ankle oedema RR was 0.35 (0.22-0.54). Publication bias was not significant and the robustness of the analyses was good. These data suggest a better efficacy/safety ratio of manidipine over amlodipine. PMID- 20945991 TI - miRNAs as biomarkers for management of patients with colorectal cancer. AB - miRNAs serve as micromanagers, negatively regulating gene expression. Since altered miRNA expression is implicated in the pathobiology of various cancers, including colorectal cancers (CRCs), these molecules serve as potential therapeutic targets. Manipulation of miRNAs may offer an alternative therapy for chemo- and radio-resistant CRCs. For CRC patients, miRNA expression patterns can be used for diagnosis, and to predict prognosis and efficacy of therapy. This article describes the methodological approaches for miRNA measurement, their function in the pathobiology of CRCs and their potential clinical utility. PMID- 20945995 TI - The impact of previous or concomitant IFN therapy on deferiprone-induced agranulocytosis and neutropenia: a retrospective study. AB - OBJECTIVE: Although IFN therapy is known to cause neutropenia, data on the risk of deferiprone (DFP)-induced haematological complications in patients receiving IFN are lacking. RESEARCH DESIGN AND METHODS: This was a retrospective single centre study to assess the association between exposure to IFN for hepatitis C virus treatment and haematological side effects of DFP therapy in patients with thalassemia major and intermedia using a large database spanning 2001 - 2008. During observation time, a total of 66 patients, including 63 affected by thalassemia major and 3 by thalassemia intermedia, were treated with chelation DFP-based regimens. A subset of 25 patients was treated at least for 3 months also with IFN (6 were cotreated and 19 were pretreated). RESULTS: Overall, the incidence of neutropenia and agranulocytosis was 9.83 and 1.14/100 patient/year, respectively. Receipt of IFN was significantly associated with increased risk of haematological complications of DFP therapy: among patients receiving IFN, 48 and 12% experienced at least one episode of neutropenia and agranulocytosis, respectively. CONCLUSIONS: These results suggest that IFN therapy may increase the risk of complications of DFP-based iron chelation therapy in patients with thalassemia. Further research is needed to assess whether the association observed in this retrospective single-centre observational study is due to IFN or other factors. PMID- 20945996 TI - Diagnosis and cause of death in a neonatal intensive care unit--how important is autopsy? AB - OBJECTIVES: To characterize mortality in a tertiary referral Neonatal Intensive Care Unit (NICU) in Portugal and evaluate the concordance between ante-mortem and post-mortem diagnoses. METHODS: Retrospective review of the clinical and pathological records of infants who died in five consecutive years was done. Pathological findings and clinical diagnoses were compared and classified according to general concordance and to modified Goldman classification. RESULTS: During the referred period, 1938 patients were admitted to the NICU, with a mortality rate of 5.7% (110 patients). The median of age at death was 10.5 days and the most frequent causes of death were congenital malformations and prematurity with its complications. Autopsy was performed in 53 patients resulting in a 48.2% overall autopsy rate. There was complete agreement between pathological and clinical diagnoses in 18 cases (34%) and additional findings were identified in 22 cases; in 13 cases (24.5%), the diagnosis was revised or established by pathology. Five autopsies revealed information relevant for genetic counseling. CONCLUSION: Despite the high agreement rate between clinical and pathological diagnoses, autopsy frequently added important data, including several cases in which it established the diagnosis or provided information relevant for parental counseling regarding future pregnancies. PMID- 20945997 TI - Editorial: introduction to special section on the national fragile X survey. PMID- 20945998 TI - Using a parent survey to advance knowledge about the nature and consequences of fragile X syndrome. AB - Understanding the nature and consequences of intellectual and developmental disabilities is challenging, especially when the condition is rare, affected individuals are geographically dispersed, and/or resource constraints limit large scale studies involving direct assessment. Surveys provide an alternative methodology for gathering information but must be carefully designed and interpreted in light of obvious limitations. In this paper we discuss the potential of surveys in understanding a disabling condition; delineate characteristics of successful survey research; describe a survey of families of individuals with fragile X syndrome; and synthesize major findings. The survey has provided new information about the nature and consequences of fragile X syndrome in a cost-effective fashion, suggesting that survey methodology has a useful place in creating new knowledge about intellectual and developmental disabilities. PMID- 20945999 TI - Seizures in fragile X syndrome: characteristics and comorbid diagnoses. AB - A national survey of caregivers of individuals with fragile X syndrome addressed characteristics of epilepsy and co-occurring conditions. Of the 1,394 individuals (1,090 males and 304 females) with the full mutation, 14% of males and 6% of females reported seizures. Seizures were more often partial, began between ages 4 and 10 years, and were infrequent and easily treated. Similar characteristics and patterns were seen in medical chart review data from a large clinic cohort of patients with fragile X syndrome. National survey data showed that autism was significantly associated with seizures as a co-occurring condition. Although seizures in fragile X syndrome are typically not severe and easily treated with medications, they appear to be associated with developmental–behavioral comorbidity that impacts function. PMID- 20946000 TI - Self-injurious behavior and fragile X syndrome: findings from the national fragile X survey. AB - We used National Fragile X Survey data in order to examine reported self injurious behavior (SIB) to (a) generate lifetime and point prevalence estimates, (b) document detailed features of SIB (frequency, types, location, severity) in relation to gender, and (c) compare comorbid conditions between matched pairs (SIB vs. no SIB). Results indicate significant gender differences in frequency, topography, and location of SIB as well as sleep difficulties, comorbid conditions, pain sensitivity, and seizures. Matched pair comparisons (SIB vs. no SIB) revealed differences for males in sensory and attention problems, hyperactivity, aggression, autism, and anxiety and for females, in autism, attention, and anxiety. These results further clarify gender differences as well as comorbidity patterns between children with fragile X syndrome with and without SIB. PMID- 20946001 TI - Obesity, food selectivity, and physical activity in individuals with fragile X syndrome. AB - National survey data from 884 families were used to examine the overall health of children and adults with fragile X syndrome. Results indicate the rate of obesity in adults with fragile X syndrome is similar to the general population (~30%). Male children with fragile X syndrome, however, had higher rates of obesity (31%) when compared with typically developing same-aged peers (18%). Both males and females displayed food selectivity, especially with regard to texture. Physical activity levels for children were higher than for adults, but neither group met recommended levels. Several cognitive and behavioral characteristics, food selectivity, and physical activity were related to overall health and body mass index. Continued monitoring of the health status of individuals with fragile X syndrome is recommended. PMID- 20946002 TI - Adaptation and psychometric properties of the Spanish version of the Supports Intensity Scale (SIS). AB - The Supports Intensity Scale (SIS) is used to determine the profile and intensity of the supports needed by a person to participate successfully in major life activities. With its publication into 13 languages, a need has arisen to document its reliability and validity across language and cultural groups. Here we explain the adaptation and the validation process of the SIS on a Spanish sample of 885 people with intellectual disability. Results of the study are discussed in terms of the reliability and validity of the SIS on the Spanish sample and its efficacy for multiple uses in Spain. PMID- 20946003 TI - Effectiveness of a novel community-based early intervention model for children with autistic spectrum disorder. AB - The Nova Scotia early intensive behavior intervention model -NS EIBI ( Bryson et al., 2007 ) for children with autistic spectrum disorders was designed to be feasible and sustainable in community settings. It combines parent training and naturalistic one-to-one behavior intervention employing Pivotal Response Treatment - PRT (R. Koegel & Koegel, 2006 ). We followed 45 children (33 males, mean baseline age = 50 months) for 12months. Mean gains of 14.9 and 19.5 months were observed on expressive and receptive language measures, respectively, for children with an IQ of 50 or more at baseline versus 6.1 and 8.4 months for children with IQs less than 50. Behavior problems decreased significantly over the 1-year treatment for both groups, but autism symptoms decreased only for those with an IQ of 50 or more. PMID- 20946005 TI - Assessing the impact of musculoskeletal health conditions using the International Classification of Functioning, Disability and Health. AB - PURPOSE: To propose the joint use of the International Classification of Diseases (ICD) and the International Classification of Functioning, Disability and Health (ICF) and to illustrate this proposal using musculoskeletal (MSK) conditions. METHOD: In light of the MSK conditions as classified in the ICD, categories from existing ICF core sets for MSK conditions were pooled to specify functioning. Another approach was to consider other categories from measures or instruments already linked in the literature. RESULTS: ICF Categories have been pooled from six core sets for MSK conditions, two specific care settings, one MSK clinical trial setting and eight instrument linkage papers. CONCLUSIONS: The ICD-ICF joint use would be able to capture the impact of a health condition by taking into account the disease and functioning status which would facilitate clinical care. Therefore, there is reasonable ground to demonstrate the operational linkage and complementary role of the ICD and the ICF in the context of the ICD revision. PMID- 20946006 TI - Preparation and evaluation of tributyrin emulsion as a potent anti-cancer agent against melanoma. AB - Histone deacetylase inhibitors such as butyrate are known to exhibit anti-cancer activities in a wide range of cancer including melanoma. In spite of these potencies, butyrate is not practically used for cancer treatment due to its rapid metabolism and very short plasma half-life. Tributyrin, a triglyceride analog of butyrate, can act as a pro-drug of butyrate after being cleaved by intracellular enzymes. The present study sought to investigate a possibility to develop tributyrin emulsion as a potent anti-cancer agent against melanoma. Mixture of Tween80 and 1, 2-dimyristoyl-sn-glycero-3-phosphocholine as a surfactant to disperse tributyrin produced homogeneous emulsions with nanometer sizes, even without a harsh homogenization procedure. Tributyrin emulsion was more potent than butyrate in inhibiting the growth of B16-F10 melanoma cells. Accumulation of cells at sub G(0)/G(1) phase and the DNA fragmentation induced by tributyrin emulsion treatment revealed that tributyrin emulsion inhibited the growth of B16 F10 cells by inducing apoptosis. Treatment with tributyrin emulsion suppressed the colony formation of melanoma cells in a dose-dependent manner. Furthermore, after intraperitoneal administration into mice, tributyrin emulsion inhibited the formation of tumor colonies in the lung following intravenous injection of melanoma cells. Taken together, our data suggests that tributyrin emulsion may be developed as a potent anti-cancer agent against melanoma. PMID- 20946007 TI - Association between plasma leptin levels and diabetes mellitus. AB - BACKGROUND: Leptin is an important adipose tissue-derived hormone that has been shown to be involved in pathophysiological mechanisms related to cardiovascular disease and diabetes. However, few studies have examined the association between plasma leptin and diabetes mellitus in humans. Also, it is not clear if this association is present among women as well as in men. Therefore, we examined the association between plasma leptin levels and diabetes mellitus in a representative multiethnic sample of U.S. adults. METHODS: We examined the 1988 1994 third National Health and Nutrition Examination Survey (NHANES III) participants >20 years of age (n = 5,599, 54.7% women). Plasma leptin levels were categorized into quartiles (women, <7.68 fg/L, 7.68-13.18 fg/L, 13.19-21.70 fg/L, >21.70 fg/L; men, <2.64 fg/L, 2.64-4.36 fg/L, 4.37-7.12 fg/L, >7.12 fg/L). Diabetes mellitus was defined as fasting glucose >=126 mg/dL, non-fasting glucose >=200 mg/dL or use of oral hypoglycemic medication or insulin (n = 395). RESULTS: Higher plasma leptin levels were initially found to be associated with diabetes mellitus after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, hypertension, serum cholesterol and C-reactive protein [odds ratio (OR), 3.79; confidence interval (CI), 2.05-7.00; P trend <0.0001). However, when we additionally adjusted for body mass index (BMI), the association between plasma leptin levels and diabetes mellitus disappeared in both men (OR, 1.07; CI, 0.59-1.94; P trend = 0.5004) and women (OR, 0.86; CI, 0.49-1.51; P trend = 0.2819). CONCLUSION: Higher plasma leptin levels are not independently associated with diabetes mellitus after adjustment for BMI. The null association was evident both in women as well as in men. PMID- 20946008 TI - Fetuin-A does not explain ethnic disparity in cardiometabolic risk factors and subclinical atherosclerosis between Hispanics and non-Hispanic whites. AB - BACKGROUND: Fetuin-A has been associated with insulin resistance and inversely related with vascular calcification. The present study evaluated whether serum fetuin-A explains the ethnic disparity in the subclinical atherosclerosis and risk for diabetes between healthy Hispanic and non-Hispanic white (NHW) subjects. METHODS: Fetuin-A was measured in serum of 76 age-matched healthy males (41 NHW, 35 Hispanics). Body mass index, blood pressure, serum lipoprotein cholesterol and triglyceride levels, coronary artery calcium (CAC), fasting glucose and insulin concentrations, and plasma glucose levels 2 h after a 75-g oral glucose tolerance test were measured in all participants. Insulin resistance was estimated using the homeostasis model assessment (HOMA). RESULTS: Fasting insulin, fasting and 2 h serum glucose, and HOMA values were all significantly higher in Hispanics (p < 0.05 for all), yet CAC trended lower and the prevalence of very high CAC (>400 Agatston score) was lower (P = 0.03). There was no statistically significant difference in serum fetuin-A when comparing Hispanics and NHW (P = 0.12). Furthermore, there was no correlation between fetuin-A levels and CAC (P = 0.9). CONCLUSIONS: Serum fetuin-A concentration was not associated with measures of insulin resistance or with preclinical atherosclerosis in Hispanics and NHW. These data indicate that the disparity in prevalence of insulin resistance, type 2 diabetes, and subclinical atherosclerosis between Hispanics and NHW does not appear attributable to differences in fetuin-A concentrations. PMID- 20946009 TI - Assessing the impact of health conditions using the ICF. AB - PURPOSE: People may suffer from diseases and a variety of health conditions, but a full understanding of the experience of their health condition also requires comprehensive information about the impact of the disease or the health condition on the person. This article operationalises the impacts of health conditions as classified in the International Classification of Diseases (ICD) in terms of the concept of functioning as found in the International Classification of Functioning, Disability and Health (ICF). It identifies a set of ICF categories as the functioning properties - to describe the impact of health conditions generically across health conditions to be jointly used with the ICD. METHOD: The ICF categories to characterise the functioning properties of any health condition have been selected from three main generic health profile instruments: The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0), the World Health Survey (WHS) Questionnaire and a list of candidate categories of the generic ICF core set. RESULTS: A set of ICF categories to describe the impact of a health condition is presented according to specific functioning domains. CONCLUSIONS: The joint use of the ICD and the ICF through the list of functioning properties and in the context of ICD-11 development captures the valuable synergy of the two classifications. It enhances patient management, intervention design and the reporting of health. It also enables us to distinguish severity of disease from its impacts. The ICD-ICF joint use creates a shared formal representation across the continuum of care for health information system implementation. PMID- 20946010 TI - Review of studies on the effect of bile acid sequestrants in patients with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) and prediabetes (or patients at risk for diabetes) have been increasing in epidemic proportions. Dyslipidemia and hypertension are cardiovascular risk factors frequently associated with diabetes and prediabetes. Bile acid sequestrants (BAS) were initially approved for the treatment of elevated low-density lipoprotein cholesterol (LDL-C), but they were subsequently found to have a glucose-lowering effect as well. Colesevelam hydrochloride (HCl), a BAS, has been approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM based on several studies that used it as an addition to sulfonylurea-based, metformin-based, and insulin-based therapies. Colesevelam HCl has not been approved for use for glycemic control in type 1 diabetes or for treating diabetic ketoacidosis and has not been studied in T2DM as monotherapy or in combination with dipeptidyl peptidase 4 inhibitors, or extensively with thiazolidinediones. A recent study has examined the combination of colesevelam HCl and metformin as an initial therapy for treatment-naive patients with T2DM. Another recent study, which looked at colesevelam for the treatment of dyslipidemia of prediabetes, raised the possibility of the use of colesevelam therapy for both dyslipidemia and hyperglycemia of T2DM. This article reviews and summarizes the recent clinical studies regarding colesevelam as therapy for both diabetes and dyslipidemia. This dual mechanism of action is an attractive feature for the treatment of diabetes. PMID- 20946011 TI - PNA-based antisense oligonucleotides for micrornas inhibition in the absence of a transfection reagent. AB - MicroRNAs (miRNAs) are noncoding RNAs approximately 22 nucleotides in length that play a major role in the regulation of important biological processes, including cellular development, differentiation, and apoptosis. Antisense oligonucleotides against miRNAs are useful tools for studying the biological mechanisms and therapeutic targets of miRNAs. Various antisense oligonucleotides chemistries, including peptide nucleic acids (PNAs), have been developed to enhance nuclease resistance and affinity and specificity for miRNA targets. PNAs have a greater specificity and affinity for DNA and RNA than do natural nucleic acids, and they are resistant to nucleases-an essential property of an miRNA inhibitor that will be exposed to cellular nucleases. However, the main limiting factor in the use of PNAs is their reduced penetration into cells. Recently, several cell-penetrating peptides (CPPs) have been investigated as a means to overcome the limited penetration of PNAs. Here, we evaluated the ability of 11 CPPs to transport PNAs inside cells in the absence of transfection reagents and then investigated the ability of these CPPs to inhibit miRNAs. Of the 11 CPPs tested, Tat-modified conjugated PNA showed the most effective penetration into cells in the absence of transfection reagents and most effectively inhibited miRNAs. Our data demonstrate that Tat-modified-conjugated CPP is the most suitable for supporting PNA-mediated miRNA inhibition. PMID- 20946013 TI - Investigation of validity of model for estimating shear force applied to buttocks in elderly people with kyphosis while sitting comfortably on a chair. AB - PURPOSE: The purpose of the present study was to investigate the validity of a model for estimating shear force on the buttocks of elderly people with kyphosis. METHOD: The subjects with kyphosis were 10 elderly people in a facility providing health care services for the elderly. The shear force was measured using a force plate and, simultaneously, the position of the resultant centre of mass of the upper body and the inclination angle of the trunk were measured. The estimated shear force was calculated by substituting these values in the model. RESULTS: The average value of the measured shear force was 8.4 SD 1.4 [%BW], and the average value of the estimated shear force was 5.8 SD 1.0 [%BW]. Although there was a significant difference between these two values (p < 0.01), there was a strong positive correlation between them (r = 0.786, p < 0.01). The regression line between the two values was y = 1.097x + 1.96, where x = estimated value, y = measured value. CONCLUSIONS: These results suggest that the estimated shear force was close to the measured shear force and thus is approximately known by substituting the calculated values for the linear regression. PMID- 20946012 TI - Intracellular traffic of oligodeoxynucleotides in and out of the nucleus: effect of exportins and DNA structure. AB - The delivery of oligodeoxynucleotides (ODNs) into cells is widely utilized for antisense, antigene, aptamer, and similar approaches to regulate gene and protein activities based upon the ODNs' sequence-specific recognition. Short pieces of DNA can also be generated in biological processes, for example, after degradation of viral or bacterial DNA. However, the mechanisms that regulate intracellular trafficking and localization of ODNs are not fully understood. Here we study the effects of major transporters of microRNA, exportin-1 (Exp1) and exportin-5 (Exp5), on the transport of single-stranded ODNs in and out of the nucleus. For this, we employed a fluorescent microscopy-based assay to quantitatively measure the redistribution of ODNs between the nucleus and cytoplasm of live cells. By measuring the fluorescent signal of the nuclei we observed that after delivery into cells via cationic liposomes ODNs rapidly accumulated inside nuclei. However, after removal of the ODN/liposome containing media, we found re localization of ODNs from the nuclei to cytoplasm of the cells over the time course of several hours. Downregulation of the Exp5 gene by siRNA resulted in a slight increase of ODN uptake into the nucleus, but the kinetics of ODN efflux to the cytoplasm was not affected. Inhibition of Exp1 with leptomycin B somewhat slowed down the clearance of ODNs from the nucleus; however, within 6 hours most of the ODN were still being cleared form the nucleus. ODNs that could form intramolecular G-quadruplex structures behaved differently. They also accumulated in nuclei, although at a lesser extent than unstructured ODN, but they remained there for up to 20 hours after transfection, causing significant cell death. We conclude that Exp1 and Exp5 are not the major transporters of our ODNs out of the nucleus, and that the transport of ODNs is strongly affected by their secondary structure. PMID- 20946014 TI - Safety assessment of a calcium-potassium salt of (-)-hydroxycitric acid. AB - The safety of Garcinia cambogiaextract, its active ingredient (-)-hydroxycitric acid (HCA), and the marketed weight management formula, Super CitriMax((r)) (HCA SX), is supported by numerous in vitro and animal experimental studies as well as several clinical studies. HCA-SX has been shown to reduce appetite, inhibit fat synthesis, and decrease body weight. A series of toxicological tests including acute, short-term, and sub-chronic studies as well as teratogenicity/reproduction and genotoxicity studies were performed on HCA-SX. In the acute oral toxicity study, administration of a single dose of 5,000 mg/kg of HCA-SX did not reveal any significant changes for all examined tissues. Following the high dose safety testing, there were no remarkable changes or differences observed in any of the experimental conditions monitored. There were no macroscopic abnormalities for any examined tissues at scheduled necropsies. On the basis of these findings, the consumption of HCA-SX at dose level of up to 4667 mg/day is considered safe. PMID- 20946015 TI - Evaluation of Moon-tang on allergic reactions. AB - Moon-tang (M-tang) is a traditional Korean medicine that has been used for the treatment of various allergic disorders. However, the precise antiallergic effect and mechanism of it remain unknown. To figure out accurately the effect of M-tang on mast cell-mediated allergic reactions, we measured parameters including changes in the compound 48/80-induced systemic anaphylaxis, ear-swelling response, histamine release, passive cutaneous anaphylaxis (PCA), and tumor necrosis factor (TNF)-alpha secretion and expression, which related to allergic inflammatory reaction. The oral administration of M-tang inhibited systemic anaphylaxis and ear-swelling response in mice. M-tang suppressed the PCA and histamine release. In addition, M-tang and its active component, beta-eudesmol, inhibited the TNF-alpha production and expression in activated mast cells. These results suggest that M-tang may be a beneficial applicability as a candidate for an antiallergic agent. PMID- 20946016 TI - Pluripotent hybrid cells contribute to extraembryonic as well as embryonic tissues. AB - The restricted gene expression of a differentiated cell can be reversed by forming hybrid with embryonic stem cells (ESCs). The resulting hybrid cells showed not only an ESC-specific marker expression but also a differentiation potential similar to the pluripotent fusion partner. Here, we evaluated whether the tetraploid fusion hybrid cells have a unique differentiation potential compared with diploid pluripotent cells. The first Oct4-GFP-positive cells were observed at day 2 following fusion between ESCs and neurosphere cells (OG2(+/ )/ROSA26(+/-)). Reprogramming efficiency was as high as 94.5% at passage 5 and 96.4% at passage 13. We have found that the tetraploid hybrid cells could form chimera with contribution to placenta after blastocyst injection. This result indicates that the tetraploid pluripotent fusion hybrid cells have wide range of differentiation potential. Therefore, we suggest that once the somatic cells are reprogrammed by fusion with ESCs, the tetraploid hybrid cells contributed to the extraembryonic as well as embryonic tissues. PMID- 20946017 TI - Exploring new applications for Rhodiola rosea: can we improve the quality of life of patients with short-term hypothyroidism induced by hormone withdrawal? AB - Patients treated for differentiated thyroid cancer (DTC) are subjected to periodic surveillance that includes serum thyroglobulin measurements followed by radioiodine administrations for diagnostic and therapeutic purposes if necessary. Both procedures require adequately elevated blood levels of thyroid-stimulating hormone (TSH), which can be achieved by two approaches: parenteral administration of recombinant human TSH (rhTSH) or stopping thyroid hormone replacement until optimal levels of endogenous TSH are achieved. Although rhTSH administration does not require hormone withdrawal, it is not inexpensive and carries the risk of secondary effects. The latter option is simpler but induces a profound state of hypothyroidism, which results in physical and mental complaints that may interfere severely with the patient's activities of daily living. Rhodiola rosea is a popular plant in traditional medical systems in Eastern Europe and Asia with a reputation for stimulating the nervous system, decreasing depression, enhancing work performance, and eliminating fatigue, all features of clinical hypothyroidism. Investigators have also suggested additional benefits such as cardioprotection or even tumor growth inhibition. Here, we propose R. rosea as a viable alternative treatment for the symptoms of short-term hypothyroidism in patients with DTC who require hormone withdrawal. PMID- 20946018 TI - Lethal/severe osteogenesis imperfecta in a large family: a novel homozygous LEPRE1 mutation and bone histological findings. AB - We report a large consanguineous Turkish family in which multiple individuals are affected with autosomal recessive lethal or severe osteogenesis imperfecta (OI) due to a novel homozygous LEPRE1 mutation. In one affected individual histological studies of bone tissue were performed, which may indicate that the histology of LEPRE1 -associated OI is indistinguishable from COL1A1/2 -, CRTAP -, and PPIB -related OI. PMID- 20946019 TI - Comparative study of the efficacy of ascorbic acid, quercetin, and thiamine for reversing ethanol-induced toxicity. AB - This study compares the curative effect of three antioxidants-ascorbic acid, quercetin, and thiamine-on ethanol-induced toxicity in rats. Administration of ethanol at a dose of 4 g/kg of body weight/day for 90 days initiated chronic alcohol-induced oxidative stress as shown by increased malondialdehyde level and DNA fragmentation in liver and brain. Ethanol administration also led to a decrease in DNA content. Activities of toxicity marker enzymes-alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltranspeptidase-in liver and serum increased progressively upon ethanol administration. After ethanol administration for 90 days, the efficacy of antioxidant treatment of the alcohol-induced toxicity was studied by supplementing ascorbic acid (200 mg/100 g of body weight/day), quercetin (50 mg/kg of body weight/day), and thiamine (25 mg/kg of body weight/day) for 30 days. These groups were compared with the abstention group (not treated with ethanol). All the alterations induced by alcohol were reduced significantly by the supplementation of antioxidants and also with abstention. The regression by antioxidants was greater that of abstention. Antioxidants significantly reduced the oxidative stress induced by ethanol intoxication, increased membrane integrity, and also increased organ regeneration. Ascorbic acid was shown to be more effective than quercetin and thiamine in treating both hepatotoxicity and neurotoxicity induced by alcohol administration. This may be due to the higher antioxidant potential of ascorbic acid in physiological conditions. PMID- 20946020 TI - Ameliorating effects of L-carnitine on diabetic podocyte injury. AB - High glucose levels can change podocyte gene expression and subsequently induce podocyte damage through altered glucose metabolism. l-Carnitine is known to play a beneficial role in diabetes; however, there are no studies on the effects of l carnitine on podocyte alteration under high glucose conditions. This study investigated whether l-carnitine can attenuate diabetic podocyte injury through the prevention of loss of slit diaphragm proteins. The l-carnitine treatment group showed increased glucose uptakes compared to the control group, suggesting that glucose utilization in the podocytes was increased by l-carnitine. l Carnitine treatment also prevented decreased mRNA expressions of nephrin and podocin in the high glucose-stimulated podocytes. However, mRNA expressions of CD2AP and alpha-actinin-4 were not significantly changed by the high glucose conditions. When these data are taken together, l-carnitine can increase glucose uptake in podocytes under high glucose conditions, and its mechanism may be at least partly related to the up-regulation of nephrin and podocin. Our results help clarify the beneficial effects of l-carnitine in diabetic nephropathy. PMID- 20946021 TI - Resveratrol arrests cell cycle and induces apoptosis in human hepatocellular carcinoma Huh-7 cells. AB - Resveratrol has been shown to possess anticancer, anti-aging, anti-inflammatory, antimicrobial, and neuroprotective activities. In this study, we examined the antiproliferative properties of resveratrol and its molecular mechanism(s) of action in Huh-7 cells, a new human hepatoma cell line system for hepatitis C virus. Results showed that resveratrol significantly inhibited Huh-7 cell proliferation (50% inhibitory concentration = 22.4 MUg/mL) and effectively induced cell cycle arrest and apoptosis. It up-regulated p21/WAF1 expression in a p53-independent manner, but the expressions of cyclin E, cyclin A, and cyclin dependent kinase 2 were down-regulated. It also caused an increase in the ratio of pro-apoptotic/anti-apoptotic protein, which was associated with the mitochondrial membrane depolarization and the increase in caspase activity. Resveratrol showed no effect on Fas, Fas ligand, extracellular signal regulated kinase (ERK) 1/2, and p38 expression but down-regulated phospho-ERK and phospho p38 expression. In addition, resveratrol was noted to trigger autophagic cell death through the increased expression of autophagy-related Atg5, Atg7, Atg9, and Atg12 proteins. These results suggest that resveratrol could be an important chemoprevention agent for hepatoma of hepatitis C virus infection. PMID- 20946022 TI - Preparation of carotenoids and chlorophylls from Gynostemma pentaphyllum (Thunb.) Makino and their antiproliferation effect on hepatoma cell. AB - A preparative column chromatographic method for isolation of carotenoids and chlorophylls from Gynostemma pentaphyllum, a traditional Chinese herb, was developed to evaluate their antiproliferative effects on the hepatoma cell Hep3B. An open column containing 70 g of magnesium oxide-diatomaceous earth (1:2.5, wt/wt) was used to elute carotenoid with 2% ethanol in ethyl acetate and chlorophyll with 50% ethanol in acetone. After high-performance liquid chromatography-mass spectrometry analysis, the carotenoid fraction was composed of all-trans- and cis-isomers of lutein, alpha-carotene, and beta-carotene as well as epoxy-containing carotenoids, while the chlorophyll fraction consisted of chlorophylls a and b and their derivatives. Both carotenoid and chlorophyll fractions as well as lutein and chlorophyll a standards at 50-100 MUg/mL were effective against Hep3B cells with a dose-dependent response with the following order: carotenoid fraction > chlorophyll fraction > lutein > chlorophyll a. For all treatments, the cell cycle was arrested in the G0/G1 phase, with Hep3B cells undergoing necrosis or apoptosis. PMID- 20946023 TI - A time to act. PMID- 20946024 TI - Retired biomeds find time for new hobbies, old interests. PMID- 20946028 TI - Biomeds find their volunteer spirit at home and abroad. PMID- 20946031 TI - Technology trends. Texas Intruments, University collaboration on computer power. PMID- 20946032 TI - First, do no harm: making infusion pumps safer. PMID- 20946033 TI - Foundation shines a light on patient safety. Interview by BI&T. PMID- 20946034 TI - Cat got your tongue? Tips on being a better public speaker. PMID- 20946035 TI - Biodesign: the process of innovating medical technologies. PMID- 20946036 TI - Budget model can help department take control of its financial future. PMID- 20946037 TI - Formal agreement brings seamless clinical engineering, IT coordination. PMID- 20946038 TI - Dollars and 'Sense' get a handle on managing service costs. PMID- 20946040 TI - Can we talk? Good communication is key to effective service. PMID- 20946039 TI - Electrophoresis. PMID- 20946041 TI - Feeling some budget pain? Make the most of your PM program. PMID- 20946042 TI - ACR ultrasound accreditation: how does that impact equipment maintenance? PMID- 20946043 TI - Back to basics: understanding operating systems and network operating systems. PMID- 20946044 TI - Venezuela makes medical IT a national priority. PMID- 20946045 TI - Non-hospital owned medical equipment poses challenge. PMID- 20946046 TI - Routine monitoring is critical to patient care. PMID- 20946047 TI - Manufacturers face 'adjustment' challenge in home market. PMID- 20946048 TI - A systems-oriented approach to auditing the design controls process. PMID- 20946049 TI - The growing move toward clinical systems engineering. PMID- 20946050 TI - Microcontroller-based system for estimate of calcium in serum samples. AB - In this study, a microcontroller-based control unit was designed and constructed for the estimation of serum calcium in blood samples. The proposed optoelectronic instrument used a red light emitting diode (LED) as a light source and photodiode as a sensor. The performance of the system was compared with that of a commercial instrument in measuring calcium ion. The quantitative analysis of calcium in a catalyst using arsenazo III as colorimetric reagent was used to test the device. The calibration curve for calcium binding with arsenazo III was drawn to check the range of linearity, which was between 0.1 to 4.5 mM L-1. The limit of detection (LOD) is 0.05 mM L-1. Absorbance changes over the pH range of 2-12 were determined to optimize the assay, with maximum absorption at pH 9.0. Interferences in absorbance from monovalent (K+ and Na+) and divalent (Mg2+) cations were also studied. The results show that the system works successfully. PMID- 20946051 TI - Help us make infusion systems safer. PMID- 20946052 TI - Gaucher disease with prenatal onset and perinatal death due to compound heterozygosity for the missense R131C and null Rec Nci I GBA mutations. AB - Gaucher disease is an autosomal recessive disorder resulting from deficient activity of the lysosomal enzyme glucocerebrosidase (GBA, E.C.3.2.1.45). Three clinical forms of Gaucher disease have been described: type 1, nonneuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic (OMIM 230800, 230900, 231000). Over the past decade, recognition of a distinct, perinatal lethal form of Gaucher disease (PLGD) has led researchers and clinicians to evaluate Gaucher disease in the differential diagnosis of congenital ichthyosis and nonimmune hydrops fetalis. To date, more than 30 cases of PLGD have been genotyped and reported. It has been observed that homozygosity for recombinant GBA alleles, which are fundamentally null alleles, leads to early lethality, usually in utero or during the 1st few days of life, whereas genotypes involving a recombinant allele and a missense mutation may be less detrimental. Here, we report a case of Gaucher disease with prenatal onset and death within hours of birth, likely due to compound heterozygosity for the GBA Rec Nci I null allele and a R131C missense mutation. In view of the patient's severe clinical course, and based on reviews of other PLGD cases, we postulate that a missense mutation that abruptly disrupts the structure/function of GBA, in combination with a null allele, may result in early lethality in patients with PLGD. We also speculate that R131C is an extremely severe mutation that has occurred more than once in different populations and, in either the homozygous form or heterozygous with another severe mutation, will result in a poor prognosis. PMID- 20946053 TI - Influence of musical expertise on segmental and tonal processing in Mandarin Chinese. AB - A same-different task was used to test the hypothesis that musical expertise improves the discrimination of tonal and segmental (consonant, vowel) variations in a tone language, Mandarin Chinese. Two four-word sequences (prime and target) were presented to French musicians and nonmusicians unfamiliar with Mandarin, and event-related brain potentials were recorded. Musicians detected both tonal and segmental variations more accurately than nonmusicians. Moreover, tonal variations were associated with higher error rate than segmental variations and elicited an increased N2/N3 component that developed 100 msec earlier in musicians than in nonmusicians. Finally, musicians also showed enhanced P3b components to both tonal and segmental variations. These results clearly show that musical expertise influenced the perceptual processing as well as the categorization of linguistic contrasts in a foreign language. They show positive music-to-language transfer effects and open new perspectives for the learning of tone languages. PMID- 20946054 TI - The corollary discharge in humans is related to synchronous neural oscillations. AB - How do animals distinguish between sensations coming from external sources and those resulting from their own actions? A corollary discharge system has evolved that involves the transmission of a copy of motor commands to sensory cortex, where the expected sensation is generated. Through this mechanism, sensations are tagged as coming from self, and responsiveness to them is minimized. The present study investigated whether neural phase synchrony between motor command and auditory cortical areas is related to the suppression of the auditory cortical response. We recorded electrocorticograms from the human brain during a vocalizing/listening task. Neural phase synchrony between Broca's area and auditory cortex in the gamma band (35 to ~50 Hz) in the 50-msec time window preceding speech onset was greater during vocalizing than during listening to a playback of the same spoken sounds. Because prespeech neural synchrony was correlated (r = -.83, p = .006), with the subsequent suppression of the auditory cortical response to the spoken sound, we hypothesize that phase synchrony in the gamma band between Broca's area and auditory cortex is the neural instantiation of the transmission of a copy of motor commands. We suggest that neural phase synchrony of gamma frequencies may contribute to transmission of corollary discharges in humans. PMID- 20946055 TI - Binding under conflict conditions: state-space analysis of multivariate EEG synchronization. AB - Real-world objects are often endowed with features that violate Gestalt principles. In our experiment, we examined the neural correlates of binding under conflict conditions in terms of the binding-by-synchronization hypothesis. We presented an ambiguous stimulus ("diamond illusion") to 12 observers. The display consisted of four oblique gratings drifting within circular apertures. Its interpretation fluctuates between bound ("diamond") and unbound (component gratings) percepts. To model a situation in which Gestalt-driven analysis contradicts the perceptually explicit bound interpretation, we modified the original diamond (OD) stimulus by speeding up one grating. Using OD and modified diamond (MD) stimuli, we managed to dissociate the neural correlates of Gestalt related (OD vs. MD) and perception-related (bound vs. unbound) factors. Their interaction was expected to reveal the neural networks synchronized specifically in the conflict situation. The synchronization topography of EEG was analyzed with the multivariate S-estimator technique. We found that good Gestalt (OD vs. MD) was associated with a higher posterior synchronization in the beta-gamma band. The effect of perception manifested itself as reciprocal modulations over the posterior and anterior regions (theta/beta-gamma bands). Specifically, higher posterior and lower anterior synchronization supported the bound percept, and the opposite was true for the unbound percept. The interaction showed that binding under challenging perceptual conditions is sustained by enhanced parietal synchronization. We argue that this distributed pattern of synchronization relates to the processes of multistage integration ranging from early grouping operations in the visual areas to maintaining representations in the frontal networks of sensory memory. PMID- 20946056 TI - Making mirrors: premotor cortex stimulation enhances mirror and counter-mirror motor facilitation. AB - Mirror neurons fire during both the performance of an action and the observation of the same action being performed by another. These neurons have been recorded in ventral premotor and inferior parietal cortex in the macaque, but human brain imaging studies suggest that areas responding to the observation and performance of actions are more widespread. We used paired-pulse TMS to test whether dorsal as well as ventral premotor cortex is involved in producing mirror motor facilitation effects. Stimulation of premotor cortex enhanced mirror motor facilitation and also enhanced the effects of counter-mirror training. No differences were found between the two premotor areas. These results support an associative account of mirror neuron properties, whereby multiple regions that process both sensory and motor information have the potential to contribute to mirror effects. PMID- 20946057 TI - Harming kin to save strangers: further evidence for abnormally utilitarian moral judgments after ventromedial prefrontal damage. AB - The ventromedial PFC (vmPFC) has been implicated as a critical neural substrate mediating the influence of emotion on moral reasoning. It has been shown that the vmPFC is especially important for making moral judgments about "high-conflict" moral dilemmas involving direct personal actions, that is, scenarios that pit compelling utilitarian considerations of aggregate welfare against the highly emotionally aversive act of directly causing harm to others [Koenigs, M., Young, L., Adolphs, R., Tranel, D., Cushman, F., Hauser, M., et al. Damage to the prefrontal cortex increases utilitarian moral judgments. Nature, 446, 908-911, 2007]. The current study was designed to elucidate further the role of the vmPFC in high-conflict moral judgments, including those that involve indirect personal actions, such as indirectly causing harm to one's kin to save a group of strangers. We found that patients with vmPFC lesions were more likely than brain damaged and healthy comparison participants to endorse utilitarian outcomes on high-conflict dilemmas regardless of whether the dilemmas (1) entailed direct versus indirect personal harms and (2) were presented from the Self versus Other perspective. In addition, all groups were more likely to endorse utilitarian outcomes in the Other perspective as compared with the Self perspective. These results provide important extensions of previous work, and the findings align with the proposal that the vmPFC is critical for reasoning about moral dilemmas in which anticipating the social-emotional consequences of an action (e.g., guilt or remorse) is crucial for normal moral judgments [Greene, J. D. Why are VMPFC patients more utilitarian?: A dual-process theory of moral judgment explains. Trends in Cognitive Sciences, 11, 322-323, 2007; Koenigs, M., Young, L., Adolphs, R., Tranel, D., Cushman, F., Hauser, M., et al. Damage to the prefrontal cortex increases utilitarian moral judgments. Nature, 446, 908-911, 2007]. PMID- 20946058 TI - Effects of emotional preferences on value-based decision-making are mediated by mentalizing and not reward networks. AB - Real-world decision-making often involves social considerations. Consequently, the social value of stimuli can induce preferences in choice behavior. However, it is unknown how financial and social values are integrated in the brain. Here, we investigated how smiling and angry face stimuli interacted with financial reward feedback in a stochastically rewarded decision-making task. Subjects reliably preferred the smiling faces despite equivalent reward feedback, demonstrating a socially driven bias. We fit a Bayesian reinforcement learning model to factor the effects of financial rewards and emotion preferences in individual subjects, and regressed model predictions on the trial-by-trial fMRI signal. Activity in the subcallosal cingulate and the ventral striatum, both involved in reward learning, correlated with financial reward feedback, whereas the differential contribution of social value activated dorsal temporo-parietal junction and dorsal anterior cingulate cortex, previously proposed as components of a mentalizing network. We conclude that the impact of social stimuli on value based decision processes is mediated by effects in brain regions partially separable from classical reward circuitry. PMID- 20946059 TI - Dissociable neural systems supporting knowledge about human character and appearance in ourselves and others. AB - Functional neuroimaging has identified a neural system comprising posterior cingulate (pCC) and medial prefrontal (mPFC) cortices that appears to mediate self-referential thought. It is unclear whether the two components of this system mediate similar or different psychological processes, and how specific this system is for self relative to others. In an fMRI study, we compared brain responses for evaluation of character (e.g., honest) versus appearance (e.g., svelte) for oneself, one's mother (a close other), and President Bush (a distant other). There was a double dissociation between dorsal mPFC, which was more engaged for character than appearance judgments, and pCC, which was more engaged for appearance than character judgments. A ventral region of mPFC was engaged for judgments involving one's own character and appearance, and one's mother's character, but not her appearance. A follow-up behavioral study indicated that participants rate their own character and appearance, and their mother's character, but not her appearance, as important in their self-concept. This suggests that ventral mPFC activation reflects its role in processing information relevant to the self, but not limited to the self. Thus, specific neural systems mediate specific aspects of thinking about character and appearance in oneself and in others. PMID- 20946060 TI - Transcranial direct current stimulation improves word retrieval in healthy and nonfluent aphasic subjects. AB - A number of studies have shown that modulating cortical activity by means of transcranial direct current stimulation (tDCS) affects performances of both healthy and brain-damaged subjects. In this study, we investigated the potential of tDCS to enhance associative verbal learning in 10 healthy individuals and to improve word retrieval deficits in three patients with stroke-induced aphasia. In healthy individuals, tDCS (20 min, 1 mA) was applied over Wernicke's area (position CP5 of the International 10-20 EEG System) while they learned 20 new "words" (legal nonwords arbitrarily assigned to 20 different pictures). The healthy subjects participated in a randomized counterbalanced double-blind procedure in which they were subjected to one session of anodic tDCS over left Wernicke's area, one sham session over this location and one session of anodic tDCS stimulating the right occipito-parietal area. Each experimental session was performed during a different week (over three consecutive weeks) with 6 days of intersession interval. Over 2 weeks, three aphasic subjects participated in a randomized double-blind experiment involving intensive language training for their anomic difficulties in two tDCS conditions. Each subject participated in five consecutive daily sessions of anodic tDCS (20 min, 1 mA) and sham stimulation over Wernicke's area while they performed a picture-naming task. By the end of each week, anodic tDCS had significantly improved their accuracy on the picture-naming task. Both normal subjects and aphasic patients also had shorter naming latencies during anodic tDCS than during sham condition. At two follow-ups (1 and 3 weeks after the end of treatment), performed only in two aphasic subjects, response accuracy and reaction times were still significantly better in the anodic than in the sham condition, suggesting a long-term effect on recovery of their anomic disturbances. PMID- 20946061 TI - Ex-vivo ureteral spatulation during laparoscopic pyeloplasty: a novel approach to a difficult problem. AB - Ureteral spatulation and performance of the anastamosis to the renal pelvis are the most important and often technically demanding and time consuming steps in performing a laparoscopic pyeloplasty. We describe a novel ex-vivo technique of ureteral spatulation and placement of the apical anastamotic sutures. This technique is especially helpful in challenging cases where optimal angles may not be viable via pure laparoscopic technique. The technique was performed on six patients, five pediatric and one adult without any immediate complications or long-term stricture or anastamotic disruption. PMID- 20946062 TI - Long-term results after computed-tomography-guided percutaneous radiofrequency ablation for small renal tumors. AB - PURPOSE: To present the long-term results and to identify possible risk factors for recurrence after radiofrequency ablation (RFA) for renal tumors. PATIENTS AND METHODS: Thirty-one patients with a total of 39 renal tumors ranging from 1.3 to 7.5 cm (mean size 3.1 cm) were treated with RFA using a Rita Medical System model 1500 RF generator attached to a 15-gauge Starburst XL probe under percutaneous CT scan guidance. The average patient age was 61.4 years (range 37-86 y). Indications for RFA were bilateral tumors, presence of serious comorbidities, a high risk of development of additional renal-cell carcinomas, marginal renal function, and patient preference. No tumor was biopsied before treatment; therefore, only local control success rates could be provided. Recurrence was defined as enhancement or lesion enlargement on follow-up CT scan. Statistical analysis was performed to identify possible risk factors for recurrence. Parameters tested were age, sex, and number of ablation sessions, tumor size, location, multiplicity, body mass index, and American Society of Anesthesiologists score. RESULTS: Initial ablation success rate was 90% and with repeated treatment, a success rate of complete ablation reached 97%. Average follow-up was 61.2 months (range 36-84 mos). Recurrence was seen in four tumors. The risk factor associated with recurrence was tumor size exceeding 4 cm (P < 0.01, relative risk [RR] = 3.31). Overall 3- and 5-year tumor control rate was 92% and 89%, respectively. Tumor size was also predictive for recurrence in the subgroup of 17 patients followed for more than 5 years (P = 0.02, RR = 3.15). Tumor control rate for this subgroup was 90%. CONCLUSIONS: According to our results, larger tumor size was prognostic for recurrence after RFA for renal tumors. This treatment seems to demonstrate excellent tumor control long-term results, comparable to those achieved by nephron-sparing surgery in a selected group of patients. PMID- 20946064 TI - Awareness of heart disease among female college students. AB - OBJECTIVE: Awareness of heart disease as the leading cause of death in women has increased over the past 10 years, but little is known about the awareness level of college students. This study evaluated the level of awareness and knowledge of heart disease in women among college students. METHODS AND RESULTS: Using a cross sectional design, a sample of 320 women from a private university was queried. A 13-item survey assessed demographic information and awareness of cardiovascular disease (CVD). The mean age was 23 years; the majority were single and of Hispanic ethnicity. Almost one third believed breast cancer was the greatest problem facing women. One half recognized CVD as the leading cause of death among women. Students aged 18-24 years were significantly less likely to identify heart disease/heart attack as the leading cause of death in women compared with students aged 25-34 years. Significant ethnic differences in perceptions of risk were found. Family history and obesity were seen as major contributors to CVD; less than a fourth ever discussed CVD with their healthcare provider. Information was gained primarily from television, magazines, and the Internet. Exercise and maintenance of healthy blood pressure were viewed as priorities in prevention of CVD. CONCLUSIONS: Results add to the body of research on CVD risk and the need for intervention to increase awareness and knowledge of heart disease risk among younger and ethnically diverse young women and raises questions about the role of colleges and universities in promotion of student health. Colleges and universities may provide the last opportunity to reach youth as a group to affect lifestyle changes. PMID- 20946066 TI - Guiding clinical care through evidence-free zones. PMID- 20946065 TI - High levels of antibody to panton-valentine leukocidin are not associated with resistance to Staphylococcus aureus-associated skin and soft-tissue infection. AB - BACKGROUND: Community-associated methicillin-resistant Staphylococcus aureus (CA MRSA) expressing Panton-Valentine leukocidin (PVL) causes severe skin and soft tissue infection (SSTI), necrotizing pneumonia, and other invasive infections. The PVL toxin has been implicated as a virulence factor, and antibody to a component of this toxin is under investigation as a vaccine candidate. The role of PVL in pathogenesis remains controversial, and it is unknown whether human serum antibody to PVL modulates infection. METHODS: We determined antibody levels to PVL in serum samples from children aged 0-18 years presenting with polymerase chain reaction-confirmed, PVL-positive MRSA-associated SSTI (with or without prior MRSA infection or SSTI), PVL-positive MRSA invasive infection, and PVL negative MRSA infection, as well as uninfected control subjects. We also measured antibody-mediated neutralization of PVL-induced lysis of human polymorphonuclear cells. RESULTS: Antibody to PVL was present in healthy children reaching adult levels by 4-6 years, with a nadir at 3-11 months likely due to loss of maternal antibody. Children with a primary PVL-positive MRSA infection had moderate levels of antibody to PVL that increased after infection. Children with prior MRSA infection or SSTI had high levels of antibody to PVL after the onset of PVL positive MRSA infection. There was no increase in antibody to PVL in this population's serum samples after the onset of infection. Serum samples from children with PVL-positive MRSA-associated SSTIs, particularly those with prior MRSA infection or SSTI, and convalescent-phase serum samples from children with invasive PVL-positive MRSA infection potently inhibited PVL-induced lysis of polymorphonuclear cells. CONCLUSIONS: Neutralizing antibody to PVL does not protect children against primary or recurrent CA-MRSA-associated SSTI. PMID- 20946067 TI - Quality and strength of evidence of the Infectious Diseases Society of America clinical practice guidelines. AB - OBJECTIVE: To describe the distribution and temporal trends of the quality and strength of evidence supporting recommendations in the Infectious Diseases Society of America (IDSA) clinical practice guidelines. METHODS: Guidelines either issued or endorsed by IDSA from March 1994 to July 2009 were evaluated using the IDSA-US Public Health Service Grading System. In this system, the letters A-E signify the strength of the recommendation, and numerals I-III indicate the quality of evidence supporting these recommendations. The distribution of the guideline recommendations among strength of recommendation and quality of evidence classes was quantified. Temporal changes between the first and current guideline version were evaluated. RESULTS: Approximately one half (median, 50.0%; interquartile range [IQR], 38.1%-58.6%) of the recommendations in the current guidelines are supported by level III evidence (derived from expert opinion). Evidence from observational studies (level II) supports 31% of recommendations (median, 30.9%; IQR, 23.3%-43.2%), whereas evidence based on >= 1 randomized clinical trial (level I) constitutes 16% of the recommendations (median, 15.8%; IQR, 5.8%-28.3%). The strength of recommendation was mainly distributed among classes A (median, 41.5%; IQR, 28.7%-55.6%) and B (median, 40.3%; IQR, 27.1%-47.9%). Among guidelines with >= 1 revised version, the recommendations moved proportionately toward more level I evidence (+12.4%). Consequently, there was a proportional increase in class A recommendations (+11.1%) with a decrease in class C recommendations (-23.5%). CONCLUSIONS: The IDSA guideline recommendations are primarily based on low-quality evidence derived from nonrandomized studies or expert opinion. These findings highlight the limitations of current clinical infectious diseases research that can provide high-quality evidence. There is an urgent need to support high-quality research to strengthen the evidence available for the formulation of guidelines. PMID- 20946068 TI - Phosphorylation events catalyzed by major cell signaling proteins differ in response to thermal and osmotic stress among native (Mytilus californianus and Mytilus trossulus) and invasive (Mytilus galloprovincialis) species of mussels. AB - Sharp environmental gradients encountered within the intertidal zone have driven the evolution of physiological adaptations that allow its inhabitants to maintain cellular function in the presence of fluctuating abiotic factors. These adaptations are mediated by gene-regulatory networks that, despite their inherent complexity, must remain evolvable and capable of responding to different selection pressures associated with specific ecological niches. Phosphorylation events catalyzed by cell-signaling enzymes represent a parsimonious mechanism to integrate new functional or regulatory properties into these gene-regulatory networks. In this study, proteins phosphorylated on consensus sequences for protein kinases A, B, and C; cyclin-dependent kinases; and mitogen-activated protein kinases, as well as the abundance of phosphorylated stress-activated protein kinase (phospho-SAPK/JNK), were quantified in order to ascertain whether phosphorylation events are divergent among native (Mytilus californianus and Mytilus trossulus) and invasive (Mytilus galloprovincialis) species of mussels that differ in their tolerance toward environmental stress. Abundances of phosphorylated substrate proteins for each of the major signaling proteins that were investigated, as well as the abundance of phospho-SAPK/JNK, differed both within and between species during thermal and osmotic stress. These data suggest that modulating protein function via phosphorylation may be an important mechanism to integrate novel properties into stress-regulatory networks. In turn, differential phosphorylation during environmental stress may contribute to species-specific tolerances toward abiotic stress, interspecies dynamics, and biogeographic patterns in Mytilus congeners. PMID- 20946069 TI - Differing perspectives of sputum and its expectoration: a qualitative study involving patients with cystic fibrosis and physiotherapists. AB - Sputum specimens are frequently requested from individuals with chronic suppurative conditions such as cystic fibrosis (CF). For a proportion of people, expectorating sputum can be difficult. Our goal was to explore the potential barriers and facilitators to expectorating sputum from the perspective of those with CF and physiotherapists involved in their care. Eighteen interviews were conducted with people who have CF and three focus groups with physiotherapists. Data were recorded, transcribed verbatim, and analysed using a framework approach. Variation emerged in perceptions between physiotherapists and people with CF in terms of sputum's impact on everyday life and the importance of its role in managing the condition. These differences were reflected in the following themes: (1) seepage of bodily boundaries, (2) discrediting nature of sputum, (3) embodied representation of chronic illness, and (4) non-production as a decisional balance. Differing views between participants could have arisen from the personal nature of sputum for people with CF, whilst physiotherapists may see sputum specimens as a necessary part of holistic management of this condition. Education could assist individuals in overcoming some of the barriers associated with expectorating, but physiotherapists may have to individualise the collection of sputum, recognising not everyone will be at ease with this procedure. PMID- 20946070 TI - Student perceptions of a community engagement experience: exploration of reflections on social responsibility and professional formation. AB - Physical therapy educators are challenged to emphasize the importance of social responsibility as a vital curricular element of professional development. Through reflection, students are able to identify core values, beliefs, and attitudes as part of the professional development process. The purpose of this study was to explore student perceptions and values of a community engagement experience based upon frequency of participation. This qualitative research report investigated student perceptions of the community experience following participation. Data collection tools included an open-ended questionnaire and focus group interviews. Comparisons were made across data for participants who engaged in the activity one time versus multiple times. Data analysis revealed participation in the community engagement experience had a positive impact on most participants. One time only participants demonstrated increased self-awareness, contemplating change, and capacity to serve while more than one time participants described a deeper understanding of community, impact on others, and professional transformation. Student involvement in community engagement activities combined with structured reflection provided meaningful insight into participants' personal beliefs. The results suggest incorporation of community-based learning experiences into academic curriculum may be beneficial in the students' preliminary understanding of social responsibility. PMID- 20946071 TI - Promoting physical activity for people with neurological disability: perspectives and experiences of physiotherapists. AB - Both New Zealand and Sweden have health and disability policies that promote recreational exercise within society for people with disability. Despite these policies, levels of physical activity by people with disability in these countries are low. Physiotherapists are equipped to assist people with disabling conditions into physical activity. This qualitative study explored the perspectives and experiences of physiotherapists in New Zealand and Sweden toward promoting physically active recreation for adults with chronic neurological conditions. Nine physiotherapists who worked with adults with neurological disability in a range of long-term rehabilitation and community (home) health services were interviewed and the data analysed for themes. The physiotherapists described innovative and resourceful expertise to assist patients to be physically active. However, they perceived a lack of support for their work from within the health system and a lack of knowledge of disability issues within the recreational arena, both of which they perceived hindered their promotion of physical activity for people with neurological disability. Physiotherapists feel unable to fully support health and disability policies for the promotion of physically active recreation for people with neurological conditions, because of perceived constraints from within the recreational arena and their own health systems. If these constraints were addressed, then physiotherapists could be better agents to promote physical activity for people with neurological conditions. PMID- 20946073 TI - Wildlife operations in Gulf soon to enter new phase. PMID- 20946074 TI - Discussion continues on foreign veterinary school accreditation. PMID- 20946075 TI - What is your diagnosis? Ameloblastic fibroma. PMID- 20946076 TI - What is your diagnosis? Diagnosis: Colonic volvulus. PMID- 20946077 TI - Pathology in practice. Diagnosis: Multicentric plasma cell tumor (multiple myeloma [MM]). PMID- 20946078 TI - Animal behavior case of the month. Diagnoses: Territorial aggression, fearful behavior, and generalized anxiety. PMID- 20946079 TI - Employment of female and male graduates of US veterinary medical colleges, 2010. PMID- 20946080 TI - Evaluation of treatment with a combination of azathioprine and prednisone in dogs with meningoencephalomyelitis of undetermined etiology: 40 cases (2000-2007). AB - OBJECTIVE: To evaluate outcome of treatment with a combination of azathioprine and prednisone in dogs with meningoencephalomyelitis of undetermined etiology (MUE). DESIGN: Retrospective case series. ANIMALS: 40 dogs. PROCEDURES: Medical records of dogs with MUE treated with prednisone and azathioprine were evaluated with regard to response, survival, and adverse effects. RESULTS: All dogs improved during treatment. Twenty-four (60%) dogs had a complete response (resolution of clinical signs), and the other 16 (40%) dogs had a partial response (improvement but not resolution of signs). Most dogs that achieved a complete response remained neurologically normal. Six dogs remained stable after a partial response. Eleven dogs had a relapse of clinical signs. Twenty dogs died during the study period, 18 survived, and 2 were lost to follow-up monitoring. Median survival time was 1,834 days (range, 50 to 2,469 days). Survival time was significantly longer for dogs that had a complete response than for those that did not. Survival time was significantly shorter for dogs that relapsed than for those that did not. The most common adverse effects included weight gain, thinning of the hair, and elevated activities of liver enzymes, all of which may have been attributed to concurrent corticosteroid administration. Less common adverse effects included diabetes mellitus, keratoconjunctivitis sicca, mammary gland adenoma, lymphoma, and hepatic masses. CONCLUSIONS AND CLINICAL RELEVANCE: Azathioprine appeared to be a safe and potentially effective adjunct to prednisone for treatment of dogs with MUE. Prospective, double-blinded, controlled studies with histologic confirmation are warranted to substantiate these findings. PMID- 20946081 TI - Biological behavior of oral and perioral mast cell tumors in dogs: 44 cases (1996 2006). AB - OBJECTIVE: To describe clinical outcome of dogs with mast cell tumors (MCTs) arising from the oral mucosa, oral mucocutaneous junction, or perioral region of the muzzle and evaluate the potential role of the chemokine receptor type 7 (CCR7) in the biological behavior of these tumors. DESIGN: Retrospective case series. ANIMALS: 44 dogs with MCTs of the oral mucosa (n=14), oral mucocutaneous junction (19), or perioral region of the muzzle (11). PROCEDURES: Medical records were reviewed for information on signalment, regional metastasis, treatments, cause of death, and survival time. Twenty of the 44 cases had stored histologic samples available for immunohistochemical staining for CCR7 RESULTS: For all dogs, median survival time was 52 months. Twenty-six (59%) dogs had regional lymph node metastasis on admission. Median survival time for dogs with lymph node metastasis was 14 months, whereas median survival time was not reached for dogs without lymph node metastasis. Intensity of staining for CCR7 was not significantly associated with the presence of regional lymph node metastasis or survival time. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that in dogs with MCTs arising from the oral mucosa, oral mucocutaneous junction, or perioral region of the muzzle, the presence of regional lymph node metastasis at the time of diagnosis was a negative prognostic factor. However, prolonged survival times could be achieved with treatment. In addition, CCR7 expression in the primary tumor was not significantly associated with the presence of regional lymph node metastasis or survival time. PMID- 20946082 TI - Distensible superficial venous orbital malformations involving the lower eyelid in two horses. AB - CASE DESCRIPTION: 2 horses were examined because of vascular masses involving the lower eyelid. CLINICAL FINDINGS: Both horses had a unilateral, fluctuant mass involving the lower eyelid. For horse 1, the mass had been present since birth and had slowly increased in size over time. The mass also changed in size in response to various environmental stimuli, alterations in the position of the horse's head, and digital obstruction of superficial vessels adjacent to the mass. Horse 2 was brought to the hospital for euthanasia, and no historical or antemor-tem data were available. A combination of contrast angiography, Doppler ultrasonography, surgical exploration, and blood gas analysis (horse 1) and postmortem and histologic examination (horse 2) were used to determine that the masses consisted of non-neoplastic distended venous channels with anastomoses to the inferior lateral palpebral and angularis oculi veins (both horses) as well as the facial vein (horse 2). Histologic examination (horse 2) revealed large, endothelial cell-lined, blood-filled spaces within the deep dermis consistent with a distensible superficial venous orbital malformation. TREATMENT AND OUTCOME: Horse 1 underwent surgical exploration and ligation of the vascular malformation. Six months after surgery, the mass was markedly reduced in size, and size of the mass was static regardless of head position or environmental stimuli. CLINICAL RELEVANCE: Thorough preoperative planning with Doppler ultrasonography, contrast angiography, and blood gas analysis is recommended when attempting surgical correction of these malformations in horses. Surgical ligation can result in a successful cosmetic and functional outcome. PMID- 20946083 TI - Comparison of passive transfer of immunity in neonatal dairy calves fed colostrum or bovine serum-based colostrum replacement and colostrum supplement products. AB - OBJECTIVE: To compare serum total protein (sTP) and serum IgG (sIgG) concentrations In neonatal calves administered colostrum or a bovine serum-based colostrum replacement (CR) product followed by a bovine serum-based colostrum supplement (CS) product. DESIGN: Randomized controlled clinical trial. ANIMALS: 18 Jersey and 269 Holstein neonatal heifer calves. PROCEDURES: 141 calves were given 4 L of colostrum in 1 or 2 feedings (first or only feeding was provided<=2 hours after birth; when applicable, a second feeding was provided between 2 and 12 hours after birth). Other calves (n=146) were fed 2 L of a CR product<=2 hours after birth and then 2 L of a CS product between 2 and 12 hours after birth. Concentrations of sTP and sIgG were measured 1 to 7 days after birth. Data from cohorts on individual farms and for all farms were analyzed. RESULTS: Mean sTP and sIgG concentrations differed significantly between feeding groups. In calves fed colostrum and calves fed CR and CS products, mean+/-SD sTP concentration was 5.58+/-0.67 g/dL and 5.26+/-0.54 g/dL, respectively, and mean sIgG concentration was 1,868+/-854 mg/dL and 1,320+/-620 mg/dL, respectively. The percentage of calves that had failure of passive transfer of immunity (ie, sIgG concentrations<1,000 mg/dL) was not significantly different between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that sequential feeding of bovine serum-based CR and CS products to neonatal calves is an alternative to feeding colostrum for achieving passive transfer of immunity. PMID- 20946084 TI - Investigation of a bluetongue disease epizootic caused by bluetongue virus serotype 17 in sheep in Wyoming. AB - OBJECTIVE: To characterize a 2007 bluetongue disease (BT) epizootic caused by bluetongue virus (BTV) serotype 17 in sheep in the Big Horn Basin of Wyoming. DESIGN: Cross-sectional study. ANIMALS: 1,359 sheep from ranches in Wyoming and Montana. PROCEDURES: Information on clinical signs and history of BT in sheep was obtained from ranchers and attending veterinarians. At 3 to 6 months after the 2007 BT epizootic, blood samples were collected from rams, ewes, and lambs within and outside the Big Horn Basin; blood samples were also collected from lambs born in the spring of 2008. Sera were tested for anti-BTV antibodies by use of a competitive ELISA to determine the seroprevalence of BTV in sheep and to measure antibody titers. Virus isolation and reverse transcriptase PCR assays were used to determine long-term presence of the infectious virus or viral genetic material in RBCs of sheep. RESULTS: The percentage of sheep seropositive for BTV closely matched morbidity of sheep within flocks, indicating few subclinical infections. Flocks separated by as little as 1 mile had substantial variation in infection rate. Rams were infected at a higher rate than ewes. There was no evidence of BTV successfully overwintering in the area. CONCLUSIONS AND CLINICAL RELEVANCE: This epizootic appears to be a new intrusion of BTV into a naive population of sheep previously protected geographically by the mountains surrounding the Big Horn Basin. Rams may have a higher infection rate as a result of increased vector biting opportunity because of the large surface area of the scrotum. PMID- 20946085 TI - Refractory asthma coexisting with a double aortic arch: a case report and literature review. AB - Asthma that is poorly controlled despite adequate treatment should be investigated for medication compliance, treatment adherence, environmental control, asthma mimics, and comorbidities especially in infants and young children. Here, the case of a 2-year-old child with refractory asthma coexisting with a double aortic arch is reported. PMID- 20946086 TI - Temozolomide for adult brain stem glioblastoma: case report of a long-term survivor. AB - Brain stem gliomas are rare intracranial tumors, especially in adults. Malignant or high-grade brain stem gliomas are usually associated with a very poor prognosis. This case report documents an adolescent harboring brain stem glioblastoma who had complete radiological response to temozolomide after partial tumor resection and survived for more than 3 years. Radiological and pathological findings are described. To the best of our knowledge, no similar cases have been reported in the literature. PMID- 20946087 TI - An interspecies extrapolation of the pharmacokinetics of telavancin, a rapidly bactericidal, concentration-dependent antibiotic. AB - Telavancin is an intravenous lipoglycopeptide antibiotic active against many Gram positive pathogens via inhibition of bacterial cell wall synthesis and disruption of bacterial membrane function. Non-compartmental pharmacokinetic parameters of telavancin (clearance [Cl], steady-state volume of distribution [Vss], area under the concentration curve [AUC], and elimination half-life [t(1/2)]) were determined for five preclinical species (mice, rats, rabbits, dogs, and monkeys). Interspecies scaling was applied to predict the corresponding parameters in humans and compare retrospectively with observed values. Plasma concentrations of single doses of telavancin declined monoexponentially in all species with half lives between 1.2 and 2.4 h. The pharmacokinetics of telavancin was demonstrated to be dose-proportional in rabbits and gender-independent in monkeys. Application of the simple allometric equation (Y = aW(b)) resulted in a good correlation between predicted and observed values of Vss in humans. Application of a modified allometric equation that includes brain weight (Cl * BW = aW(b)) resulted in a good correlation between predicted and observed values of Cl, AUC, and t(1/2) in humans. These data suggest that interspecies scaling may be useful to predict pharmacokinetic parameters of telavancin in humans. PMID- 20946088 TI - Differential effect of genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP) and organic anion-transporting polypeptide 1B1 (OATP1B1) on the uptake of HMG-CoA reductase inhibitors. AB - The purpose of this study was to investigate the effect of genetic variations in organic anion-transporting polypeptide 1B1 (OATP1B1) and Na(+)/taurocholate co transporting polypeptide (NTCP) on the uptake of various statins having different affinities for these transporters. The functional activities and simultaneous expression of NTCP and OATP1B1 were confirmed by the uptake of taurocholate and estrone-3-sulphate as representative substrates for NTCP and OATP1B1, respectively, and by an immunofluorescence analysis. The substrate specificities of NTCP and OATP1B1 for statins and the effects of genetic variations on the uptake of rosuvastatin, pitavastatin, and atorvastatin were measured. Based on the K(m) values and intrinsic clearances of the three statins, pitavastatin was taken up more efficiently than rosuvastatin and atorvastatin by OATP1B1. Consequently, the cellular accumulation of pitavastatin was modulated according to the genetic variation of OATP1B1 (OATP1B1*15), rather than NTCP*2. In contrast, NTCP*2 displayed greater transport of atorvastatin and rosuvastatin, compared with NTCP wild type. Thus, the measurements of decreased rosuvastatin and atorvastatin transport by OATP1B1*15 were confounded by the presence of NTCP and its genetic variant, NTCP*2. In conclusion, the functional consequences of genetic variants of NTCP and OATP1B1 may be different for various statins, depending on the substrate specificity of the OATP1B1 and NTCP transporters. PMID- 20946089 TI - Novel CRTH2 antagonists: a review of patents from 2006 to 2009. AB - IMPORTANCE OF THE FIELD: The receptor CRTH2 (also known as DP2) is an important mediator of the inflammatory effects of prostaglandin D2 and has attracted much attention as a therapeutic target for the treatment of conditions such as asthma, COPD, allergic rhinitis and atopic dermatitis. AREAS COVERED IN THIS REVIEW: The validation of CRTH2 as a therapeutic target and the early antagonists are summarized, CRTH2 antagonists published in the patent literature from 2006 to 2009 are comprehensively covered and a general update on the recent progress in the development of CRTH2 antagonists for the treatment of inflammatory diseases is provided. WHAT THE READER WILL GAIN: Insight into the validation of CRTH2 as a therapeutic target, a comprehensive overview of the development of new CRTH2 ligands between 2006 and 2009, and a general overview of the state of the art. TAKE HOME MESSAGE: Many diverse potent CRTH2 antagonists are now available, and several are in or on the way into the clinic. It is still early to draw final conclusions, but preliminary results give reason for optimism, and the prospect that we will see new CRTH2 antagonists reaching the market for the treatment of asthma, rhinitis, atopic dermatitis and/or COPD seems good. PMID- 20946090 TI - Preparation and the influencing factors of cetirizine hydrochloride microemulsion. AB - We constructed pseudo-ternary phase diagrams to obtain the area of water-in-oil (w/o) microemulsion formation, prepared cetirizine hydrochloride microemulsion, and evaluated its quality. The w/o microemulsion had been formulated using span80 as surfactant, alcohol as co-surfactant, and oleinic acid as oil. Pseudo-ternary phase diagrams were constructed to evaluate the phase behavior of the w/o microemulsion. The properties, including appearance, particle size, and stability, were determined. The stable w/o microemulsion could be prepared using span80/ alcohol/ oleinic acid/ water (1.2/ 4.8/ 2/ 2). The w/o microemulsion is a new carrier for hydrosoluble drugs, which are easy to prepare with consistent quality. PMID- 20946091 TI - Tumor vasculature as target for therapeutic intervention. AB - IMPORTANCE OF THE FIELD: Solid tumors rely on efficient oxygen and nutrients transport for their growth, development and survival. Many tumors can stimulate new blood vessel formation. Because this angiogenic vasculature is aberrant from normal host vasculature, several strategies have been explored that specifically target tumor blood vessels. AREAS COVERED IN THIS REVIEW: Over the past decade, many molecules that act on tumor vasculature have been identified. They can be divided into three groups based on their mechanism of action: i) antiangiogenic molecules cause tumor growth arrest; ii) vasoactive agents induce hyperabnormalization of the tumor vasculature, improving conventional drug accumulation in the tumor; iii) vascular disrupting agents that cause blood vessel congestion, resulting in massive secondary tumor cell necrosis. Many investigational drugs from these classes are currently being evaluated to assess their role in tumor therapy. WHAT THE READER WILL GAIN: The underlying principle of each of the strategies is discussed, and the (pre)clinical results of the investigational drugs in this class are highlighted. TAKE HOME MESSAGE: To fully exploit the therapeutic potential of these drugs, it appears necessary to combine them with conventional anticancer agents, improve their selectivity for tumor vasculature, and develop biomarkers that predict the tumor sensitivity for these vascular strategies. PMID- 20946092 TI - Barriers and facilitators for adherence to antiretroviral therapy in Papua New Guinea. AB - Papua New Guinea (PNG) is in a phase of scaling up access to antiretroviral therapy (ART), and adherence to the newly available drug therapy is becoming an important issue. This paper examines adherence to ART in a sample of 374 HIV positive people in six provinces in PNG. Participants were recruited to the study using non-probability sampling. Sixty-two % of participants reported complete adherence (no missed or late doses in the past week) and 79% reported not missing any doses in the last week. Revival church members were significantly more likely to report having missing a treatment dose(s) (66%). Those living in the Highlands and those attending Catholic health clinics were significantly more likely to be adherent to their treatment. Age, gender, marital status, education level and employment type did not show significant association with treatment adherence. Adherence rates in PNG are not alarming, indicating that people with HIV can adhere to treatment despite the challenges of living in PNG. PMID- 20946093 TI - Cofactors for HIV-1 incidence during pregnancy and postpartum period. AB - OBJECTIVES: to estimate HIV-1 incidence and cofactors for HIV-1 incidence during pregnancy and postpartum. DESIGN: retrospective study among women who were HIV seronegative during pregnancy. METHODS: mothers accompanying their infants for routine 6-week immunizations at 6 maternal child health clinics in Nairobi and Western Kenya were tested for HIV-1 after completing a questionnaire that included assessment of sociodemographics, obstetric history and HIV-1 risk perception. RESULTS: of 2,135 mothers who had tested HIV-1 seronegative antenatally, 2,035 (95.3%) accepted HIV-1 re-testing at 6 weeks postpartum. Of these, 53 (2.6%) were HIV-1 seropositive yielding an estimated HIV-1 incidence of 6.8 (95% CI: 5.1-8.8) per 100 woman-years). Mothers who seroconverted were more likely to be employed (45.3% vs 29.0%, p=0.01), married (96.2 vs 86.6%, p=0.04) and from a higher HIV-1 prevalence region (60.4% in Western Kenya vs 28.8% in Nairobi, p<0.001). Among married women, those in polygamous relationship were significantly more likely to seroconvert (19.6% vs 6.7%, p<0.001). In multivariate analysis, region and employment independently predicted seroconversion. CONCLUSIONS: repeat HIV-1 testing in early postpartum was highly acceptable and resulted in detection of substantial HIV-1 incidence during pregnancy and postpartum period. Within prevention of mother-to-child HIV-1 transmission programs strategic approaches to prevent maternal HIV-1 acquisition during pregnancy are urgently needed. PMID- 20946094 TI - Effects of plant extracts on HIV-1 protease. AB - Acquired immunodeficiency syndrome (AIDS) is one of the most important public health problems, affecting many people every day. This syndrome is caused by the human immunodeficiency virus (HIV) and the HIV-1 protease plays an essential role by promoting virus maturation and thus infecting new cells. The HIV-1 protease is one of the main targets for anti-HIV drug therapy. The present work is a literature survey of plant extracts whose activity has been studied on HIV-1 protease. Here we list 275 species of medicinal plants, distributed in 99 families, with their place of origin, part used, type of extract, concentration and activity. We aim with this work to provide data that could be used in the research and development of new therapeutic agents for AIDS treatment. PMID- 20946095 TI - The impact of HAART on HPV-related cervical disease. AB - PURPOSE OF REVIEW: highly active antiretroviral therapy (HAART) has had an unequivocally positive impact on morbidity and mortality in HIV-infected individuals. These benefits have clearly extended to some HIV-related malignancies, including Kaposi's sarcoma and non-Hodgkin's lymphoma. The impact of HAART on cervical cancer, however, remains uncertain. The objective of this review is to summarize the last ten years of registry-based and clinical research into the impact of HAART on human papillomavirus (HPV) related cervical disease. RELEVANT FINDINGS: compared to their HIV-uninfected counterparts, HIV-infected women have an increased prevalence of HPV infection, increased risk of progression of HPV-related cervical disease, and an increased risk of invasive cervical cancer. While the partial immune reconstitution afforded by HAART might be expected to decrease susceptibility to HPV infection and cervical disease, the local effects of improved immunosurveillance on the cervix are uncertain and the increased longevity of patients on HAART may increase risk of exposure to HPV and provide the time required for progression of cervical disease. Registry-based evidence has been consistent in identifying the lack of decrease in cervical cancer incidence in the HAART era. Clinical research on the subject, however, has produced conflicting evidence with regards to both the effect of HAART on HPV infection and its impact on cervical disease progression/regression. SUMMARY: the incidence of cervical cancer has not decreased in the HAART-era. Furthermore, clinical research has not shown a clear benefit of HAART in decreasing HPV related cervical disease in HIV-infected women. A better understanding of this subject will have an impact on cervical disease surveillance practices. PMID- 20946097 TI - Etravirine in the treatment of HIV-1: a clinical overview for healthcare professionals. AB - Current HIV treatment guidelines emphasize the importance of using an active antiretroviral therapy regimen that produces full virologic suppression and immunologic competence, while at the same time providing patients with a favorable safety profile and limited risk for development of drug resistance. Etravirine (TMC125), a recently approved, non-nucleoside reverse transcriptase inhibitor (NNRTI), has shown durable, superior virologic efficacy over placebo in the Phase III, randomized, double-blind DUET trials in 1,203 treatment experienced, NNRTI-resistant, HIV-1-infected patients. Statistical significance of responses with etravirine over placebo was maintained through Week 24, 48 and 96, regardless of baseline demographics, baseline disease characteristics or the background regimen used. Etravirine has demonstrated a favorable safety and tolerability profile; the incidence of treatment-emergent adverse events was comparable with placebo in the DUET trials, with the exception of rash. The tolerability profile of etravirine also appears to be favorable in terms of neuropsychiatric and hepatic side effects. The pharmacokinetic profile of twice daily etravirine minimizes the potential for clinically relevant drug-drug interactions and allows for its use in combination with a wide range of other agents. In addition, etravirine has a high genetic barrier to the development of resistance, further enhancing potential benefit in patients infected with NNRTI resistant virus. The clinical efficacy and favorable safety profile of etravirine, together with its pharmacokinetic profile and high genetic barrier to resistance, make it a valuable treatment option for a wide range of treatment experienced HIV-1-infected patients. PMID- 20946098 TI - Chemistry and reactivity of acyl glucuronides. AB - This review presents a survey of acyl glucuronides (AGs) from the perspective of a synthetic medicinal chemist. After a brief introduction to the biogenesis of AGs and current attitudes of the pharmaceutical industry towards them, the importance of the availability of pure synthetic AGs as probe molecules is stressed. Current synthetic methods including the selective acylation method and enzymatic procedures are discussed with actual drug examples. The major reaction pathways of AGs, acyl migration and direct acyl transfer, are then examined with consideration of both in vitro and in vivo situations. Both the aglycone and the carbohydrate residue are shown to be important in determining the reactivity of AGs, especially the alpha-substitution in aryl acetates and propionates and aryl substitution in benzoates. The significance of these effects for important drugs such as the NSAIDs diclofenac and ibuprofen is noted. Appropriate models of the reactivity of AGs with proteins are presented, from short model peptides to body proteins, and examples where AGs clearly interact with protein in vivo (e. g. mycophenolic acid) are presented. Recent results with AGs in plasma, where half lives differ significantly from their values in aqueous buffer, show the importance of considering the external medium especially when other hydrolytic enzymes are present. Finally, the importance of considering the reactivity of acyl thioesters-which may be formed directly or via AGs as intermediates- is also stressed. This pathway may lead to different protein reactivity than shown for AGs themselves, including interference with the glutathione pathway as shown for NSAID-like carboxylic acids. PMID- 20946099 TI - Drug-S-acyl-glutathione thioesters: synthesis, bioanalytical properties, chemical reactivity, biological formation and degradation. AB - Carboxylic acid-containing drugs can be metabolized to chemically-reactive acyl glucuronide, S-acyl-CoA thioester, and/or intermediate acyl-adenylate metabolites that are capable of transacylating the cysteinyl-thiol of glutathione (GSH) resulting in the formation of drug-S-acyl-GSH thioesters detected in-vivo in bile and in-vitro in hepatocytes. Authentic S-acyl-GSH thioesters of carboxylic acids can be readily synthesized by modifying the cysteinyl-thiol group of GSH with an applicable acylating reagent. Bionanalytical characterization of S-acyl-GSH derivatives has demonstrated enhanced extraction efficiency from biological samples when formic acid is included in appropriate extraction solvents, and that tandem mass spectrometry of S-acyl-GSH conjugates results in fragmentation producing a common MH+-147 Da product ion. Chemical reactivity comparisons have shown that S-acyl-CoA thioester and acyl-adenylate conjugates are more reactive than their corresponding 1-beta-O-acyl glucuronides toward the transacylation of GSH forming S-acyl-GSH thioesters. S-Acyl-GSH thioester derivatives are also chemically-reactive electrophiles capable of transacylating biological nucleophiles. Glutathione S-transferases (GSTs) weakly catalyze S-acyl-GSH conjugate formation from S-acyl-CoA, acyl-adenylate, and 1-beta-O-acyl glucuronide substrates; however purified-GSTs have also been shown to hydrolyze S acyl-GSH thioesters. Mechanistic in vitro studies in hepatocytes have revealed the primary importance of the S-acyl-CoA formation pathway leading to S-acyl-GSH adduct formation. In addition to being hydrolytically-unstable in hepatocytes and plasma, S-acyl-GSH thioesters undergo gamma-glutamyltranspeptidase-mediated cleavage of the gamma-glutamyl-group leading to N-acyl-cysteinylglycine amide linked products. In summary, S-acyl GSH thioesters are indicators of reactive transacylating metabolite formation produced from the biotransformation of carboxylic acids, but since they are also chemically-reactive, perhaps these derivatives can contribute to covalent binding to tissue proteins and potential toxicity. PMID- 20946100 TI - The C-terminal basic residues contribute to the chemical- and voltage-dependent activation of TRPA1. AB - The ankyrin transient receptor potential channel TRPA1 is a non-selective cationic channel that is expressed by sensory neurons, where it can be activated by pungent chemicals, such as AITC (allyl isothiocyanate), cinnamon or allicin, by deep cooling (<18 degrees C) or highly depolarizing voltages (>+100 mV). From the cytoplasmic side, this channel can be regulated by negatively charged ligands such as phosphoinositides or inorganic polyphosphates, most likely through an interaction with as yet unidentified positively charged domain(s). In the present study, we mutated 27 basic residues along the C-terminal tail of TRPA1, trying to explore their role in AITC- and voltage-dependent gating. In the proximal part of the C-terminus, the function-affecting mutations were at Lys969, Arg975, Lys988 and Lys989. A second significant region was found in the predicted helix, centred around Lys1048 and Lys1052, in which single alanine mutations completely abolished AITC- and voltage-dependent activation. In the distal portion of the C terminus, the charge neutralizations K1092A and R1099A reduced the AITC sensitivity, and, in the latter mutant, increased the voltage-induced steady state responses. Taken together, our findings identify basic residues in the C terminus that are strongly involved in TRPA1 voltage and chemical sensitivity, and some of them may represent possible interaction sites for negatively charged molecules that are generally considered to modulate TRPA1. PMID- 20946101 TI - Snapin deficiency is associated with developmental defects of the central nervous system. AB - The autophagy-lysosomal pathway is an intracellular degradation process essential for maintaining neuronal homoeostasis. Defects in this pathway have been directly linked to a growing number of neurodegenerative disorders. We recently revealed that Snapin plays a critical role in co-ordinating dynein-driven retrograde transport and late endosomal-lysosomal trafficking, thus maintaining efficient autophagy-lysosomal function. Deleting snapin in neurons impairs lysosomal proteolysis and reduces the clearance of autolysosomes. The role of the autophagy lysosomal system in neuronal development is, however, largely uncharacterized. Here, we report that snapin deficiency leads to developmental defects in the central nervous system. Embryonic snapin-/- mouse brain showed reduced cortical plates and intermediate zone cell density, increased apoptotic death in the cortex and third ventricle, enhanced membrane-bound LC3-II staining associated with autophagic vacuoles and an accumulation of polyubiquitinated proteins in the cortex and hippocampus. Thus our results provide in vivo evidence for the essential role of late endocytic transport and autophagy-lysosomal function in maintaining neuronal survival and development of the mammalian central nervous system. In addition, our study supports the existence of a functional interplay between the autophagy-lysosome and ubiquitin-proteasome systems in the protein quality-control process. PMID- 20946102 TI - Differentiation of temporomandibular joint synovial mesenchymal stem cells into neuronal cells in vitro: an in vitro study. AB - SMSCs (synovial mesenchymal stem cells) isolated from TMJs (temporomandibular joints) were induced to proliferate and differentiate in vitro by bFGF (basic fibroblast growth factor) and explore the potential of SMSC differentiation into neuronal cells. In this study, the cultured SMSCs were derived from the TMJ synovial membrane of condylar hyperplasia patients and were amplified with the indicated concentration of FCS (fetal calf serum) and DMEM (Dulbecco's modified Eagle's medium) in vitro. bFGF (25 ng/ml) was applied to induced synovial cells differentiated into neuronal cells. Inverted microscopy, scanning electron microscopy, immunocytochemical and RT-PCR were used for checking the change of the induced cells. Morphology was mostly spindle; a small part was of a polygon. The undifferentiated SMSCs showed the fibroblast-like morphology; however, most of the differentiated cells were in the shape of a spindle and the rest were polygonal. Furthermore, being induced by bFGF, SMSCs can be found to be a unique long extension from the cell body under the scanning electron microscope. RT-PCR and immunocytochemical analysis was made to confirm nestin (neural stem cell marker) and NF-L (neurofilament-light or neurofilament 68-kDa mature nerve cell marker) expression in SMSCs. SMSCs can differentiate into neuronal cells when induced by bFGF. The bFGF-induced SMSCs not only changed into neural-like cells but also expressed specific markers. PMID- 20946103 TI - Urotensin-2 promotes collagen synthesis via ERK1/2-dependent and ERK1/2 independent TGF-beta1 in neonatal cardiac fibroblasts. AB - U2 (urotensin-2) is the most potent vasoconstrictor in mammals which is involved in cardiac remodelling, including cardiac hypertrophy and cardiac fibrosis. Although the cellular mechanisms of the U2-induced vasoconstriction have been extensively studied, the signalling pathways involved in U2-induced TGF-beta1 (transforming growth factor-beta1) expression and collagen synthesis remain unclear. In this study, we show that U2 promoted collagen synthesis and ERK1/2 (extracellular signal-regulated kinase 1/2) activation in neonatal cardiac fibroblasts. The U2-induced collagen synthesis and TGF-beta1 production were significantly but not completely inhibited by blocking ERK1/2. Both ERK1/2 inhibitor and TGF-beta1 antibody could separately inhibit U2-induced collagen synthesis, and the synergistic inhibition effect was observed by blocking ERK1/2 and TGF-beta1 simultaneously. These data suggest that U2 promotes collagen synthesis via ERK1/2-dependent and independent TGF-beta1 pathway in neonatal cardiac fibroblasts. PMID- 20946104 TI - Myogenic differentiation of mesenchymal stem cells co-cultured with primary myoblasts. AB - TE (tissue engineering) of skeletal muscle is a promising method to reconstruct loss of muscle tissue. This study evaluates MSCs (mesenchymal stem cells) as new cell source for this application. As a new approach to differentiate the MSCs towards the myogenic lineage, co-cultivation with primary myoblasts has been developed and the myogenic potential of GFP (green fluorescent protein) transduced rat MSC co-cultured with primary rat myoblasts was assessed by ICC (immunocytochemistry). Myogenic potential of MSC was analysed by ICC, FACS and qPCR (quantitative PCR). MSC-myoblast fusion phenomena leading to hybrid myotubes were evaluated using a novel method to evaluate myotube fusion ratios based on phase contrast and fluorescence microscopy. Furthermore, MSC constitutively expressed the myogenic markers MEF2 (myogenic enhancer factor 2) and alpha sarcomeric actin, and MEF2 expression was up-regulated upon co-cultivation with primary myoblasts and the addition of myogenic medium supplements. Significantly higher numbers of MSC nuclei were involved in myotube formations when bFGF (basic fibroblast growth factor) and dexamethasone were added to co-cultures. In summary, we have determined optimal co-culture conditions for MSC myogenic differentiation up to myotube formations as a promising step towards applicability of MSC as a cell source for skeletal muscle TE as well as other muscle cell-based therapies. PMID- 20946105 TI - Protein pattern of Xenopus laevis embryos grown in simulated microgravity. AB - Numerous studies indicate that microgravity affects cell growth and differentiation in many living organisms, and various processes are modified when cells are placed under conditions of weightlessness. However, until now, there is no coherent explanation for these observations, and little information is available concerning the biomolecules involved. Our aim has been to investigate the protein pattern of Xenopus laevis embryos exposed to simulated microgravity during the first 6 days of development. A proteomic approach was applied to compare the protein profiles of Xenopus embryos developed in simulated microgravity and in normal conditions. Attention was focused on embryos that do not present visible malformations in order to investigate if weightlessness has effects at protein level in the absence of macroscopic alterations. The data presented strongly suggest that some of the major components of the cytoskeleton vary in such conditions. Three major findings are described for the first time: (i) the expression of important factors involved in the organization and stabilization of the cytoskeleton, such as Arp (actin-related protein) 3 and stathmin, is heavily affected by microgravity; (ii) the amount of the two major cytoskeletal proteins, actin and tubulin, do not change in such conditions; however, (iii) an increase in the tyrosine nitration of these two proteins can be detected. The data suggest that, in the absence of morphological alterations, simulated microgravity affects the intracellular movement system of cells by altering cytoskeletal proteins heavily involved in the regulation of cytoskeleton remodelling. PMID- 20946106 TI - Generation of mesenchymal stem cell from human umbilical cord tissue using a combination enzymatic and mechanical disassociation method. AB - MSCs (mesenchymal stem cells) promise a great potential for regenerative medicine due to their unique properties of self-renewal, high plasticity, modulation of immune response and the flexibility for genetic modification. Therefore, the increasing demand for cellular therapy necessitates a larger-scale production of MSC; however, the technical and ethical issues had put a halt on it. To date, studies have shown that MSC could be derived from human UC (umbilical cord), which is once considered as clinical waste. We have compared the two conventional methods which are classic enzymatic digestion and explant method with our newly tailored enzymatic-mechanical disassociation method to generate UC-MSC. The generated UC-MSCs from the methods above were characterized based on their immunophenotyping, early embryonic transcription factors expression and mesodermal differentiation ability. Our results show that enzymatic-mechanical disassociation method increase the initial nucleated cell yield greatly (approximately 160-fold) and maximized the successful rate of UC-MSC generation. Enzymatic-mechanical disassociation-derived UC-MSC exhibited fibroblastic morphology and surface markers expression of CD105, CD73, CD29, CD90 and MHC class I. Furthermore, these cells constitutively express early embryonic transcription factors (Nanog, Oct-4, Sox-2 and Rex-1), as confirmed by RT-PCR, indicating their multipotency and high self-renewal capacity. They are also capable of differentiating into osteoblasts and adipocytes when given an appropriate induction. The present study demonstrates a new and efficient approach in generating MSC from UC, hence serving as ideal alternative source of mesenchymal stem cell for clinical and research use. PMID- 20946107 TI - Was the C282Y mutation an Irish Gaelic mutation that the Vikings helped disseminate? HLA haplotype observations of hemochromatosis from the west coast of Sweden. AB - The HLA-related hemochromatosis mutation C282Y is thought to have originated in Ireland in a person with HLA-A3-B14 and was spread by Vikings. Irish people with two HLA-A3 alleles had a high risk of hemochromatosis. In this study, from west Sweden, we wanted to test these hypotheses. METHODS: HFE mutations in controls, bone marrow donors with HLA-A3/A3 and patients with hemochromatosis. HLA haplotypes, extended haplotype analysis and pedigree studies. RESULTS: The allelic C282Y frequency 0.04, (CI 0.01-0.07) was lower (P < 0.001) in Sweden than in Ireland 0.10 (CI 0.08-0.11), and Swedish bone marrow donors with HLA-A3/A3 (n = 77) had a low risk of hemochromatosis. HLA haplotypes available from 239/262 (91.5%) proband patients homozygous for C282Y showed a dominance of A3-B7 and A3 B14 both in linkage disequilibrium with controls (P < 0.001). Pedigree studies extended into the 17th century supported a local founder effect of A3-B14 in the county of Bohuslan. The A3-B14 haplotype may well be the original and A3-B7 the result of centromeric recombinations. The haplotype diversity and recombination events were not different from a Celtic series. These findings do not support the hypothesis of the C282Y mutation being of an Irish Celtic origin. CONCLUSIONS: The C282Y frequency shows a west to east decline from Ireland through the north of Europe. Vikings may have been involved in the spread of C282Y, but the mutation is probably older and may have been spread in Europe by earlier seafarers. PMID- 20946108 TI - Enhancer of Zeste 2 (EZH2) is up-regulated in malignant gliomas and in glioma stem-like cells. AB - AIMS: Proteins of the Polycomb repressive complex 2 (PRC2) are epigenetic gene silencers and are involved in tumour development. Their oncogenic function might be associated with their role in stem cell maintenance. The histone methyltransferase Enhancer of Zeste 2 (EZH2) is a key member of PRC2 function: we have investigated its expression and function in gliomas. METHODS: EZH2 expression was studied in grade II-IV gliomas and in glioma stem-like cells (GSC) by quantitative PCR and immunohistochemistry. Effects of EZH2 down-regulation were analysed by treating GSC with the histone deacetylase (HDAC) inhibitor suberoylanide hydroxamic acid (SAHA) and by shRNA. RESULTS: DNA microarray analysis showed that EZH2 is highly expressed in murine and human GSC. Real-time PCR on gliomas of different grade (n = 66) indicated that EZH2 is more expressed in glioblastoma multiforme (GBM) than in low-grade gliomas (P = 0.0013). This was confirmed by immunohistochemistry on an independent set of 106 gliomas. Treatment with SAHA caused significant up-regulation of PRC2 predicted target genes, GSC disruption and decreased expression of EZH2 and of the stem cell marker CD133. Inhibition of EZH2 expression by shRNA was associated with a significant decrease of glioma proliferation. CONCLUSION: The data suggest that EZH2 plays a role in glioma progression and encourage the therapeutic targeting of these malignancies by HDAC inhibitors. PMID- 20946109 TI - Estimation of the dissociation rate of unlabelled ligand-receptor complexes by a 'two-step' competition binding approach. AB - BACKGROUND AND PURPOSE: Because the in vivo effectiveness of ligands may also be determined by the rate by which they dissociate from their target receptors, drug candidates are being increasingly screened for this kinetic property. The dissociation rate of unlabelled ligand-receptor complexes can be estimated indirectly from their ability to slow the association of subsequently added radioligand molecules. EXPERIMENTAL APPROACH: We used the 'two-step competition' binding approach consisting of pre-incubating the receptor preparation with a wide range of ligand concentrations, washing off free ligand molecules, adding radioligand and monitoring its receptor binding after a fixed time. Based on the rationale that binding of both ligands is mutually exclusive and that they bind according to the law of mass action to a single class of sites, the unlabelled ligand's dissociation rate can be estimated from the upward shift that the competition curve experiences after washing. KEY RESULTS: The relevance of the 'two-step competition' approach was explored by computer simulations and by comparing the dissociation behaviour of unlabelled D(2) dopamine and CB(1) cannabinoid receptor antagonists in this and alternative approaches. Besides providing satisfactory estimations of dissociation rates, the method also detects the ability of the unlabelled ligand molecules to be released from 'sinks' such as the cell membrane. CONCLUSIONS AND IMPLICATIONS: As the 'two-step competition' requires rapid intermediate washing steps and needs radioligand binding to be measured at only one time point, this approach is particularly suited for binding studies on intact plated cells. LINKED ARTICLES: This article is part of a themed section on Analytical Receptor Pharmacology in Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2010.161.issue-6. PMID- 20946110 TI - Bone scan images reveal increased osteoblastic function after bortezomib treatment in patients with multiple myeloma. AB - Osteolytic lesions with activated osteoclast (OC) and suppressed osteoblast (OB) activity are characteristics of myeloma bone lesion. Recently, it has been shown that bortezomib treatment enhances OB function. To evaluate the effect of bortezomib on myeloma bone lesions, we performed bone scans, where increased uptake of the radiopharmaceutical by OBs is associated with re-building activity. Bortezomib treatment markedly enhanced bone metabolic activity and increased alkaline phosphatase levels, and decreased monoclonal protein levels. These findings suggest that bortezomib has potent anti-myeloma activity and bone protecting effects, with enhanced OB function. PMID- 20946111 TI - Role of immune molecules in the establishment and plasticity of glutamatergic synapses. AB - An increasing number of studies support an unexpected role for immune molecules in regulating healthy brain functions during development and in adulthood. Here we review the roles of specific immune molecules (including cytokines, components of the complement cascade, and members of the major histocompatibility complex class I family and their receptors) in the formation and plasticity of glutamatergic synapses. These findings add a new dimension to our understanding of neural-immune interactions, and suggest novel molecular mechanisms that may underlie the modification of glutamatergic synapses in both normal and pathological states. PMID- 20946112 TI - Differential roles for CaM kinases in mediating excitation-morphogenesis coupling during formation and maturation of neuronal circuits. AB - Ca(2+) -regulated reorganization of actin cytoskeleton is one of the key cell biological events that critically regulate neuronal morphogenesis during circuit formation, spinogenesis during synapse development, and activity-dependent structural plasticity at mature synapses. However, it remains unclear as to what extent the underlying Ca(2+) signaling processes are shared or segregated. Here, we present evidence from the literature that collectively begins to suggest that distinct calmodulin-dependent protein kinase (CaMK) isoforms are differentially expressed in time and in subcellular space, and thus may be selectively activated and engaged by distinct upstream stimuli; each CaMK isoform, in turn, couples to related, but separate, cytoskeletal and transcriptional regulatory pathways, dependent on its abundance or physical proximity with either the upstream or downstream signaling complexes. These signal transduction characteristics provide the basis for better understanding the role of excitation-morphogenesis coupling via multiple CaMKs during neuronal circuit and synapse formation. PMID- 20946113 TI - Mitochondrial trafficking and the provision of energy and calcium buffering at excitatory synapses. AB - Neuronal postsynaptic currents consume most of the brain's energy supply. Delineating how neurons control the distribution, morphology and function of the energy-producing mitochondria that fuel synaptic communication is therefore important for our understanding of nervous system function and pathology. Here we review recent insights into the molecular mechanisms that control activity dependent regulation of mitochondrial trafficking, morphology and activity at excitatory synapses. We also consider some implications of this regulation for synaptic function and plasticity and discuss how this may contribute to synaptic dysfunction and signalling in neurological disease, with a focus on Alzheimer's disease. PMID- 20946114 TI - Regulation of AMPA receptors by transmembrane accessory proteins. AB - Regulating the number and function of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptors located at the postsynaptic density is a key mechanism underlying synaptic strength and plasticity. Thus, an active area of investigation is the discovery of accessory proteins that regulate AMPA receptor trafficking and biophysical properties. One decade ago, pioneering studies identified the transmembrane protein stargazin as a critical regulator of synaptic targeting of AMPA receptors in cerebellar granule neurons. Stargazin related family members called TARPs (transmembrane AMPA receptor regulatory proteins) are now recognized as essential auxiliary subunits for AMPA receptors that control both receptor trafficking and channel gating properties in a wide variety of neuronal cell types. Recent studies have identified a diverse array of additional accessory transmembrane proteins with distinct and overlapping functions compared with TARPs. Coupled with the wide variety of established cytoplasmic AMPA receptor accessory proteins, it is clear that AMPA receptor regulation encompasses a previously unrecognized diversity of molecular mechanisms. PMID- 20946115 TI - Working together to improve the care of older people: a new framework for collaboration. AB - AIM: This paper is a report of a study identifying the care issues experienced by older people in the acute setting that could be improved through a collaborative approach to action. BACKGROUND: Actively involving consumers in the governance of healthcare organizations is viewed positively, although there is less agreement on how to do this. Co-operative inquiry is a useful approach to involve consumers and clinicians in structured dialogue about understanding and changing care, whereas traditional quality improvement methodologies are often singular in their dimensions of change. METHOD: Using a co-operative inquiry approach, five workshops were facilitated over a 4-month period in 2008 with four volunteer older people, four clinicians and three facilitators (n=11). All participants were actively involved in generating ideas and actions using a range of facilitation techniques and data collection methods. FINDINGS: There was increased awareness, understanding and acceptance of clinicians' and consumers' experiences and expectations of care. The complexity behind changing so-called simple care (providing warm drinks, appetizing food), which were the key concerns for consumers, relied on the active management and broader transformation of the system, including teamwork, communication processes and organizational and individual values and beliefs. CONCLUSION: Consumers and clinicians put different emphasis on perspectives related to improving care of older people in the acute hospital setting. The disconnect between what consumers viewed as 'simple' organizational behaviours to change and what the clinicians viewed as complex, led to a recognition that the approach to organizational change needs to be reconceptualized. PMID- 20946116 TI - CH05-10, a novel indinavir analog, is a broad-spectrum antitumor agent that induces cell cycle arrest, apoptosis, endoplasmic reticulum stress and autophagy. AB - Indinavir, a human immunodeficiency virus (HIV) protease inhibitor, inhibits the growth of tumor cells in vivo but does not show any cytotoxicity against cancer cells in vitro. To optimize the anticancer activity of indinavir, two novel analogs, CH05-0 and CH05-10, were synthesized. CH05-10 was much more cytotoxic than indinavir and had similar cytotoxicity to nelfinavir, the one with the best anticancer activities among all HIV protease inhibitors examined. For 14 cell lines representing 10 different types of human malignancies, the 50% inhibitory concentration (IC(50)) values of CH05-10 are in the range of 4.64-38.87 MUM. Further detailed studies using the lung cancer cell line A549 as the model system showed that the effect of CH05-10 on the A549 cell line is both time- and dose dependent. The CH05-10 treatment not only induced cell cycle arrest at G(1) and caused caspase-dependent apoptosis, but also resulted in caspase-independent death via the induction of endoplasmic reticulum stress and unfolded protein response. These findings demonstrate that CH05-10, a novel indinavir analog, is a potent anticancer agent with pleiotropic effects. PMID- 20946118 TI - Review: The neuropathology of drug abuse. AB - Drug abuse represents a significant health issue. The major substances abused include cannabis, opiates, cocaine, amphetamine, methamphetamine and 'ecstasy'. Alterations of intracellular messenger pathways, transcription factors and immediate early genes within the brain reward system seem to be fundamentally important for the development of addiction and chronic drug abuse. Genetic risk factors and changes in gene expression associated with drug abuse are still poorly understood. Besides cardiovascular complications, psychiatric and neurologic symptoms are the most common manifestations of drug toxicity. A broad spectrum of changes affecting the central nervous system is seen in drug abusers. The major findings result from the consequences of ischaemia and cerebrovascular diseases. Except for a few observations of vasculitis, the aetiology of these cerebrovascular accidents is not fully understood. The abuse of amphetamine, methamphetamine and MDMA has been related to neurotoxicity in human long-term abusers and to the risk of developing Parkinson's disease. However, whether such neurotoxicity occurs remain to be established. Systematic histological, immunohistochemical and morphometric investigations have shown profound morphological alterations in the brains of polydrug abusers. The major findings comprise neuronal loss, neurodegenerative alterations, a reduction of glial fibrillary acidic protein-immunopositive astrocytes, widespread axonal damage with concomitant microglial activation as well as reactive and degenerative changes of the cerebral microvasculature. These observations demonstrate that drugs of abuse initiate a cascade of interacting toxic, vascular and hypoxic factors, which finally result in widespread disturbances within the complex network of central nervous system cell-to-cell interactions. PMID- 20946117 TI - Connective tissue growth factor enhances the migration of gastric cancer through downregulation of E-cadherin via the NF-kappaB pathway. AB - Local invasion and distant metastasis are difficult problems for surgical intervention and treatment in gastric cancer. Connective tissue growth factor (CTGF/CCN2) was considered to have an important role in this process. In this study, we demonstrated that expression of CTGF was significantly upregulated in clinical tissue samples of gastric carcinoma (GC) samples. Forced expression of CTGF in AGS GC cells promoted their migration in culture and significantly increased tumor metastasis in nude mice, whereas RNA interference-mediated knockdown of CTGF in GC cells significantly inhibited cell migration in vitro. We disclose that CTGF downregulated the expression of E-cadherin through activation of the nuclear factor-kappaappa B (NF-kappaB) pathway. The effects of CTGF in GC cells were abolished by dominant negative IkappaappaB. Collectively, these data reported here demonstrate CTGF could modulate the NF-kappaappaB pathway and perhaps be a promising therapeutic target for gastric cancer invasion and metastasis. PMID- 20946120 TI - Anticipatory nausea among ambulatory cancer patients undergoing chemotherapy: prevalence, associated factors, and impact on quality of life. AB - The purposes of this study were to investigate the prevalence of anticipatory nausea (AN), its associated factors, and its impact on quality of life (QOL) among ambulatory cancer patients receiving chemotherapy. Patients were randomly selected to participate in this study, and were asked to complete the Morrow Assessment of Nausea and Emesis scale, the Hospital Anxiety and Depression Scale, the Short-form Supportive Care Needs Survey questionnaire, and the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. Complete data were available for 214 patients. A total of 10.3% of the patients experienced very mild to severe AN. The presence of AN was significantly associated with most domains of the investigated patients' outcome, including psychological distress and perceived needs, with the exception of the health system and information domain of patients' needs, and the physical functioning domain of QOL. Anticipatory nausea was also associated with QOL even after adjustments for age, sex, performance status, and psychological distress. The prevalence of AN in ambulatory cancer patients who receive chemotherapy may not be as high as previously reported. However, given its potentially significant impact on relevant outcome, including QOL, AN should not be neglected in current clinical oncology practice. (Cancer Sci 2010; 101: 2596-2660). PMID- 20946119 TI - Suppression of antibody-mediated arthritis in mice by Fab fragments of the mediating antibodies. AB - BACKGROUND AND PURPOSE: Fab fragments (Fabs) of antibodies maintain the ability to bind specific antigens, but lack the binding site for complement as well as the site for binding to receptors on effector cells, such as macrophages that play an important role in inflammation. In the present study, we investigated whether Fabs specific for ovalbumin (OVA) were specifically able to suppress anti OVA antibody-mediated arthritis (AOA-MA) in mice. EXPERIMENTAL APPROACH: AOA-MA was induced by i.v. injection of purified anti-OVA antibodies into naive mice followed by intra-articular (left ankle) challenge with the antigen. Anti-OVA Fabs prepared by digestion of anti-OVA antibodies with papain were injected i.v. immediately after administration of the intact antibodies. Normal Fabs were used as a control. Arthritis was assessed by thickness of the joints (caliper) and by histology of paw sections, stained with haematoxylin and eosin. KEY RESULTS: AOA MA was markedly suppressed by anti-OVA Fabs, but not by control Fabs. Histologically, mice treated with control Fabs showed marked oedema of synovial tissues with a large number of inflammatory cells including neutrophils, whereas animals given anti-OVA Fabs had mild oedema of the synovium and sparse infiltration of such cells. The antigen-specific suppression of joint inflammation by anti-OVA Fabs was associated with reduced consumption of complement. In vitro studies showed that anti-OVA Fabs significantly blocked the binding of intact anti-OVA antibodies to OVA. CONCLUSIONS AND IMPLICATIONS: Antibody-mediated arthritis appears to be specifically down-regulated by Fabs that competitively inhibit the binding of antibodies to antigens. PMID- 20946121 TI - Runx2 in human breast carcinoma: its potential roles in cancer progression. AB - Runx2 has been proposed as one of the pivotal factors in the process of osteogenesis and metastasis in human malignancies including breast cancer, but its details have not been evaluated. Therefore, in this study, we evaluated its expression in human breast cancer using immunohistochemistry. One hundred and thirty-seven formalin-fixed and paraffin-embedded breast cancer specimens were used in this analysis of immunohistochemical study. Immunoreactivity was evaluated using the labeling index (LI). Runx2 immunoreactivity was detected in both carcinoma and stromal cells, as well as non-pathological ductal cells. The nuclear LI of Runx2 in carcinoma cells was associated with the clinical stage, histological grade and HER2 status of the patients examined. In addition, among the patients not associated with distant metastasis, those with high Runx2 LI demonstrated a significantly worse clinical outcome than those with a low LI. This was more pronounced in the group of estrogen receptor (ER)-negative cases. In addition, both univariate and multivariate analyses demonstrated that the Runx2 LI in breast carcinoma cells turned out an independent prognostic factor. Results of our present study demonstrated that Runx2 plays very important roles in the progression of breast cancer, especially in those of ER-negative cases. PMID- 20946122 TI - Removal of autologous activated CD4-positive T lymphocytes also results in increased colony-forming units in patients with low and intermediate-1 risk myelodysplastic syndromes. AB - Autologous activated CD4(+) T lymphocytes (CD4(+) /CCR5(+) double-positive cells) that derived from BMNCs of patients with low and intermediate-1 risk myelodysplastic syndrome were depleted or added to in vitro cultures. The BMNCs depleted of CD4(+) /CCR5(+) T cells exhibited significantly increased numbers of colony-forming units (CFUs). Conversely, the bone marrow mononuclear cells cultures with a fourfold augmentation of CD4(+) /CCR5(+) T lymphocytes exhibited no colonies in cultures in vitro. The apoptotic index (AI) of colony cells was decreased compared with that of preculture counterparts. After depletion of CD4(+) /CCR5(+) in vitro cultures, the clonal cells increased in patients with chromosome 5q- or 20q- abnormalities but remained unchanged in patients with trisomy 8. In addition, after removal of CD4(+) /CCR5(+) T cells, the number of CFUs was increased in those patients with a higher number of BM Th1 (CD4(+) / IFN gamma(+) ) cells, hypocellularity, or bearing the DR15 allele. We concluded that the selective removal of autologous activated CD4(+) T cells can increase the generation of CFUs. However, whether the increased CFUs consisted of cells derived from residual normal hemopoiesis or clonal hemopoiesis remains unknown. PMID- 20946124 TI - Bradykinin and B2 receptor antagonism in rat and human articular chondrocytes. AB - BACKGROUND AND PURPOSE: In osteoarthritis (OA), bradykinin (BK) is known to contribute to pain and synovitis, but not to cartilage degradation. Here, we investigated effects of BK and its antagonists on chondrocytes, cells involved in cartilage homeostasis. EXPERIMENTAL APPROACH: BK receptor density and affinities of BK, its analogues and antagonists were measured in cultured human and rat chondrocytes by radioligand binding. Effects of BK were assessed by accumulation of inositol phosphates (IP) and release of interleukin (IL)-6 and IL-8. KEY RESULTS: Density of [3H]-BK binding sites was higher (13-30-fold) and BK evoked a greater (48-fold) IP production, in human than in rat chondrocytes. The BK B2 receptor antagonists MEN16132 and icatibant displayed similar binding affinity. MEN16132 was 40-fold more potent than icatibant in the IP assay. In human chondrocytes, BK increased release (over 24 h) of IL-6 and IL-8, effects blocked by MEN16132 but not by the B1 receptor antagonist Lys-[Leu8][desArg9]BK. BK induced release of IL-6, but not of IL-8, was partially inhibited by indomethacin (10 uM) and nordihydroguaiaretic acid (10 uM). Antagonists for the prostanoid EP receptors (AH6809 10 uM; L-798,196, 200 nM; L-161,982, 1 uM) were ineffective. Dexamethasone (100 nM) partially inhibited release of both IL-6 and IL-8. Inhibitors of intracellular downstream signalling pathways (SB203580 10 uM; PD98059, 30 uM; SP600125, 30 uM; BAY-117085, 5 uM) indicated the involvement of p38 MAPK and the activation of NF-kappaB. CONCLUSION AND IMPLICATIONS: BK mediated inflammatory changes and cartilage degradation and B2 receptor blockade would, therefore, be a potential treatment for OA. PMID- 20946125 TI - Saliva and serum lacosamide concentrations in patients with epilepsy. AB - PURPOSE: Lacosamide is a new antiepileptic drug that has a novel mechanism of action, linear pharmacokinetics, and proven efficacy in the adjunctive treatment of partial-onset seizures. We ascertained the relationship between serum and saliva lacosamide concentrations so as to determine whether saliva may be a useful alternative to serum for therapeutic drug monitoring. METHODS: Blood samples were obtained from 98 people with intractable epilepsy (51 male; mean age 43 +/- 12; range 19-76 years) prescribed lacosamide as adjunctive therapy. For 48 patients, concurrent saliva samples were also collected. Lacosamide concentrations in serum (free and total) and in saliva were determined by high performance liquid chromatography (HPLC). RESULTS: Linear regression analysis showed a good correlation between lacosamide dose and both total (r(2) = 0.825; n = 32) and free (r(2) = 0.815; n = 29) serum concentrations, and lacosamide serum total and free concentrations were linearly related (r(2) = 0.721; n = 97). There was also a good correlation between saliva lacosamide and both total (r(2) = 0.842; n = 49) and free (r(2) = 0.828; n = 47) serum lacosamide concentrations. Based on the saliva data, the protein binding of lacosamide in serum is calculated to be 87 +/- 4% and is comparable to the value calculated by direct measurement of the free and total lacosamide concentration in serum (91 +/- 4%). DISCUSSION: These data support the use of saliva as a viable alternative to serum for monitoring lacosamide therapy in patients with epilepsy. PMID- 20946126 TI - Spontaneous and evoked high-frequency oscillations in the tetanus toxin model of epilepsy. AB - PURPOSE: High-frequency oscillations (HFOs) are an emerging biomarker for epileptic tissue. Yet the mechanism by which HFOs are produced is unknown, and their rarity makes them difficult to study. Our objective was to examine the occurrence of HFOs in relation to action potentials (APs) and the effect of microstimulation in the tetanus toxin (TT) model of epilepsy, a nonlesional model with a short latency to spontaneous seizures. METHODS: Rats were injected with TT into dorsal hippocampus and implanted with a 16-channel (8 * 2) multielectrode array, one row each in CA3 and CA1. After onset of spontaneous seizures (3-9 days), recordings were begun of APs and local field potentials, analyzed for the occurrence of interictal spikes and HFOs. Recordings were made during microstimulation of each electrode using customized, open-source software. RESULTS: Population bursts of APs during interictal spikes were phase-locked with HFOs, which were observable almost exclusively with high-amplitude interictal spikes. Furthermore, HFOs could reliably be produced by microstimulation of the hippocampus, providing evidence that these oscillations can be controlled temporally by external means. DISCUSSION: We show for the first time the occurrence of HFOs in the TT epilepsy model, an attractive preparation for their experimental investigation and, importantly, one with a different etiology than that of status models, providing further evidence of the generality of HFOs. The ability to provoke HFOs with microstimulation may prove useful for better understanding of HFOs by directly evoking them in the lab, and designing high throughput techniques for presurgical localization of the epileptic focus. PMID- 20946127 TI - 18Fluoroethyl-L-tyrosine-PET in long-term epilepsy associated glioneuronal tumors. AB - PURPOSE: Long-term epilepsy associated tumors (LEATs) are a frequent cause of drug-resistant partial epilepsy. A reliable tumor diagnosis has an important impact on therapeutic strategies and prognosis in patients with epilepsy, but often is difficult by magnetic resonance imaging (MRI) only. Herein we analyzed a large LEAT cohort investigated by 18fluoroethyl-L-tyrosine-positron emission tomography (FET-PET). METHODS: Thirty-six patients with chronic partial epilepsy and a LEAT-suspect MRI lesion were analyzed by FET-PET using visual inspection and quantitative analysis of standard uptake values (SUV). PET results were correlated with clinical and histopathologic data. RESULTS: FET-PET study was positive in 22 of 36 analyzed lesions and in 14 of 22 histologically verified LEAT lesions. The precise World Health Organization (WHO) tumoral entity was not predicted by FET-PET. Notably, FET uptake correlated strikingly with age at epilepsy onset (p = 0.001). Further correlations were seen for age at surgery (p = 0.007) and gadolinium-contrast enhancement on MRI (p < 0.05). DISCUSSION: FET PET is a helpful tool for LEAT diagnosis, particularly when MRI readings are ambiguous. FET uptake, which is likely mediated by the l-amino acid transporter (LAT) family, might indicate a principally important biologic property of certain LEATs, since LAT molecules also are involved in cell growth regulation. PMID- 20946128 TI - Anatomofunctional organization of the insular cortex: a study using intracerebral electrical stimulation in epileptic patients. AB - PURPOSE: Different lines of evidence suggest that the insular cortex has many important functional roles. Direct electrical stimulation (ES) of the human insular cortex during surgical procedures for epilepsy, functional imaging techniques, and lesion studies also occasionally induces clinical responses. METHODS: In this study, we evaluated 25 patients with drug-refractory focal epilepsy by stereotactically implanting at least one electrode into the insular cortex using an oblique approach (transfrontal or transparietal). One hundred twenty-eight insular sites (each situated between two contiguous contacts within the same electrode) were examined within the gyral substructures. We located each stimulation site by fusing preimplantation three-dimensional (3D) magnetic resonance imaging (MRI) images with the postimplantation 3D computed tomography (CT) scans that revealed the electrode contacts. RESULTS: Sixty-seven stimulations induced at least one clinical response. Stimulation from within the insular cortex evoked 83 responses, without evidence of afterdischarge in the insular or extrainsular regions. We classified the principal responses as sensory (paresthesias and localized warm sensations), motor, pain, auditory, oropharyngeal, speech disturbances (including speech arrest and reduced voice intensity) and neurovegetative phenomena, such as facial reddening, generalized sensations of warmth or cold, hypogastric sensations, anxiety attacks, respiratory accelerations, sensations of rotation, and nausea. CONCLUSIONS: These findings may indicate a functional specificity for the insular gyri and show the need for exploring this structure during invasive presurgical evaluation of epileptic patients according to seizure manifestations. PMID- 20946129 TI - Multiple time scales of adaptation in the auditory system as revealed by human evoked potentials. AB - Single neurons in the primary auditory cortex of the cat show faster adaptation time constants to short- than long-term stimulus history. This ability to encode the complex past auditory stimulation in multiple time scales would enable the auditory system to generate expectations of the incoming stimuli. Here, we tested whether large neural populations exhibit this ability as well, by recording human auditory evoked potentials (AEP) to pure tones in a sequence embedding short- and long-term aspects of stimulus history. Our results yielded dynamic amplitude modulations of the P2 AEP to stimulus repetition spanning from milliseconds to tens of seconds concurrently, as well as amplitude modulations of the mismatch negativity AEP to regularity violations. A simple linear model of expectancy accounting for both short- and long-term stimulus history described our results, paralleling the behavior of neurons in the primary auditory cortex. PMID- 20946130 TI - After the P3: late executive processes in stimulus categorization. AB - Two experiments examined the hypothesis that dual systems of stimulus evaluation for categorization can be observed in event-related potentials: one whose duration is indexed by the latency of the P3 component, and a second evident in a later frontal potential. Subjects categorized artificial animals by a "two out of three" rule. Stimuli with two visual features of their own category and one feature of a different category (i.e., near the boundary between categories) elicited very prolonged reaction times as compared to stimuli with three features from a single category. This response time (RT) delay was not accompanied by a delayed P3, suggesting that the P3 indexed only a first pass of stimulus evaluation. The near-boundary stimuli elicited more positive potentials than far boundary stimuli at prefrontal and frontotemporal sites, suggesting that a secondary stage of stimulus evaluation was triggered when detection of single features or simple conjunctions was insufficient to support a correct decision. The frontal potential that was sensitive to categorization difficulty was of opposite polarity to frontal potentials previously observed in manipulations of working memory. The roles of frontal executive processes in categorization and memory tasks are discussed. PMID- 20946131 TI - Host plant secondary metabolite profiling shows a complex, strain-dependent response of maize to plant growth-promoting rhizobacteria of the genus Azospirillum. AB - Most Azospirillum plant growth-promoting rhizobacteria (PGPR) benefit plant growth through source effects related to free nitrogen fixation and/or phytohormone production, but little is known about their potential effects on plant physiology. These effects were assessed by comparing the early impacts of three Azospirillum inoculant strains on secondary metabolite profiles of two different maize (Zea mays) cultivars. After 10d of growth in nonsterile soil, maize methanolic extracts were analyzed by reverse-phase high-performance liquid chromatography (RP-HPLC) and secondary metabolites identified by liquid chromatography/mass spectrometry (LC/MS) and nuclear magnetic resonance (NMR). Seed inoculation resulted in increased shoot biomass (and also root biomass with one strain) of hybrid PR37Y15 but had no stimulatory effect on hybrid DK315. In parallel, Azospirillum inoculation led to major qualitative and quantitative modifications of the contents of secondary metabolites, especially benzoxazinoids, in the maize plants. These modifications depended on the PGPR strain*plant cultivar combination. Thus, Azospirillum inoculation resulted in early, strain-dependent modifications in the biosynthetic pathways of benzoxazine derivatives in maize in compatible interactions. This is the first study documenting a PGPR effect on plant secondary metabolite profiles, and suggests the establishment of complex interactions between Azospirillum PGPR and maize. PMID- 20946132 TI - Endoscopic management of suspected esophageal foreign body in adults. AB - Foreign bodies should not be allowed to remain in the esophagus beyond 24 hours after presentation. However, some patients with esophageal foreign body ingestion do not come to the hospital immediately and may delay medical intervention from the time of ingestion. The aim of this study was to investigate the outcomes of adults with suspected esophageal foreign body ingestion according to the time of ingestion and types of foreign bodies. A total of 326 adult patients (151 men and 175 women) were analyzed, and divided into two groups according to the time period: within or beyond 24 hours from ingestion to endoscopic intervention. A total of 172 patients (52.7%) were found to have ingested foreign bodies; 73.5% were removed smoothly, 10.3% were treated by push technique and 16.0% with failed retrieval received alternative treatments. A higher proportion of patients in the beyond-24 hours group suffered from odynophagia (25.9 vs. 12.9%, P < 0.05). Negative identification of esophageal foreign bodies was more frequent in the beyond-24 hours group (67 vs. 40.2%, P < 0.05), but these patients showed higher proportions of esophageal ulcers (21.1 vs. 7.2%, P < 0.05). The beyond-24 hours group also showed a significantly higher rate of foreign bodies in the lower esophagus (40.0 vs. 15.3%, P < 0.05). Patients with esophageal food bolus impaction had significant delayed endoscopic intervention, longer therapeutic endoscopic time, higher proportions of esophageal cancer, stricture and fewer complications. Endoscopic intervention within 24 hours from the time of ingestion should be considered early in adults, because delaying intervention may produce more symptomatic esophageal ulcerations with odynophagia. PMID- 20946133 TI - Immunonutrition in patients undergoing esophageal cancer resection. AB - Specialized nutritional support containing immunonutrients such as arginine, omega-3 fatty acids, and ribonucleic acid significantly reduces the incidence of postoperative infective complications and hospital length of stay in elective surgery patients. However, immunonutrition use is not standard practice in esophago-gastric units internationally. This review provides a clinical update regarding the use of immunonutrition in patients undergoing major gastrointestinal surgery and, in particular, esophageal cancer resection, and provides direction for future collaborative research. A review of MEDLINE and Cochrane Library databases was conducted for randomized controlled trials or meta analyses. A recent meta-analysis demonstrated that preoperative immunonutrition use significantly reduces hospital length of stay and the incidence of postoperative complications in patients undergoing major elective surgery, particularly for gastrointestinal malignancies. Only three small randomized controlled trials have evaluated immunonutrition use in patients exclusively undergoing esophageal cancer surgery. These were unable to determine whether immune-enhancing formulae positively influence key clinical outcomes such as mortality, hospital and intensive care unit length of stay, and postoperative morbidity in this patient group. Currently, there is insufficient evidence to recommend routine use of immunonutrition in patients undergoing esophageal cancer surgery. Future collaborative research should evaluate whether: (i) immunonutrition use positively influences key clinical outcomes in this population; (ii) these patients benefit from preoperative supplementation with an immune-enhancing formula or whether they require postoperative continuation (perioperative approach) to combat their risk of complications after surgery; and (iii) these formulae can be used safely in those patients who develop sepsis. PMID- 20946134 TI - Metabolic syndrome is associated with gastroesophageal reflux disease based on a 24-hour ambulatory pH monitoring. AB - Several studies have focused on the relationship between metabolic syndrome and gastroesophageal reflux disease (GERD). They were based on GERD complications, whereas little is known about the association between metabolic syndrome and objectively measured esophageal acid exposure. The aim of our study was to assess the relationship between metabolic syndrome and GERD based on a 24-hour pH testing. It was a cross-sectional study including 100 consecutive patients who underwent a 24-hour pH-metry monitoring and were assessed for the five metabolic syndrome components as well as for body mass index (BMI). Among the 100 patients, 54 had a pathological acid GERD. The 46 GERD-free patients represented control group. Sex distribution was comparable between both groups but GERD patients were older than controls (44.59 vs. 37.63 years, P= 0.006) and more often obese or with overweight (83.3 vs. 60.9%, P= 0.01). Frequency of metabolic syndrome as a whole entity was higher among patients with GERD than those without GERD (50 vs. 19.56%; P= 0.002) with a crude odds ratio of 4.11 (95% confidence interval: 1.66 10.14). Multivariate regression analysis showed that metabolic syndrome as well as an age >= 30 years were independent factors associated to GERD but not BMI and sex. Abnormal waist circumference and fasting glucose level >= 100 mg/L were the only independent factors among the five components of metabolic syndrome. Metabolic syndrome but not BMI was an independent factor associated to GERD. These results confirm the hypothesis that central obesity is associated to GERD. PMID- 20946135 TI - Therapeutic strategy for the treatment of postoperative recurrence of esophageal squamous cell carcinoma: clinical efficacy of radiotherapy. AB - We investigated the effectiveness of chemoradiotherapy for the treatment of lymph node recurrence and hematogenous metastasis after esophagectomy for esophageal squamous cell carcinoma. Between 2001 and 2006, 216 patients with thoracic esophageal squamous cell carcinoma had curative esophagectomy. Of those, 23 with lymph node recurrence received chemoradiotherapy (50.0-68.8 Gy). In addition, five patients had isolated recurrences in a distant organ and received chemoradiotherapy (50.0-60.0 Gy). We analyzed outcomes from the radiotherapy for recurrent esophageal cancer. The 1-, 2-, and 5-year survival rates after recurrence for the 23 patients whose lymph node recurrence was treated with chemoradiotherapy were 52, 31, and 24%, respectively, and the median survival time was 13 months. Among the five patients with recurrent tumors in a distant organ, chemoradiotherapy produced a complete response in two patients, a partial response in one patient, and stable disease in two patients, giving an effectiveness rate of 60% (complete response + partial response). Chemoradiotherapy has a beneficial prognostic effect in patients with lymph node recurrence of esophageal squamous cell carcinoma. Chemoradiotherapy for a metastatic tumor in a distant organ may be the treatment of choice in cases where systemic chemotherapy has proven ineffective. PMID- 20946136 TI - Fluticasone propionate for treatment of esophageal lichen planus. A case series. AB - Esophageal lichen planus is a rare condition, and although the majority of cases occur in conjunction with lichen planus at other sites, the endoscopic features are often misinterpreted resulting in a delay in diagnosis. We report a series of five patients presenting to our unit between 2005 and 2009. All five patients were female and presented with dysphagia. Endoscopy demonstrated proximal esophageal stricturing in four patients. Characteristic histological findings were found in four patients. Lichen planus was diagnosed at other sites, and preceded gastrointestinal symptoms, in all patients; five had oral involvement, two had genital involvement, and one had dermal involvement. All patients received proton pump inhibitor therapy without demonstrable benefit. Administration of oral fluticasone proprionate resulted in symptomatic improvement in three patients. PMID- 20946137 TI - Synergism between maggot excretions and antibiotics. AB - Maggots are successfully used to treat severe, infected wounds. This study investigated whether maggot excretions/secretions influence the antibacterial activity of different antibiotics. Minimal inhibitory concentrations and minimal bactericidal concentrations (MBC) were determined of gentamicin and flucloxacillin for Staphylococcus aureus, of penicillin for Streptococcus pyogenes, of amoxicillin and vancomycin for Enterococcus faecalis, of gentamicin for Enterobacter cloacae, and of gentamicin, tobramycin, and ciprofloxacin for Pseudomonas aeruginosa by checkerboard titration. A range of concentrations of antibiotics in combination with excretions/secretions was examined to investigate the potential of maggot excretions/secretions to affect antibacterial activity. The results showed a dose-dependent increase of the antibacterial effect of gentamicin in the presence of excretions/secretions on S. aureus. Minimal concentrations and MBC of gentamicin decreased, respectively, 64- and 32-fold. The MBC of flucloxacillin and excretions/secretions against S. aureus were also decreased. The other antibiotic and excretions/secretions combinations exerted an indifferent effect. Excretions/secretions alone did not have any antibacterial effect. The synergism between gentamicin and maggot excretions/secretions could be of direct importance in clinical practice, because it could allow the use of lower doses of gentamicin and thus minimize the risk of gentamicin-related side effects. PMID- 20946138 TI - Human amniotic fluid stimulates the proliferation of human fetal and adult skin fibroblasts: the roles of bFGF and PDGF and of the ERK and Akt signaling pathways. AB - Fetuses and adults follow different repair strategies for the healing of skin wounds. Experimental evidence indicates that this most probably reflects the intrinsic characteristics of fetal tissue, although environmental factors may also contribute to this phenomenon. Accordingly, the aim of the present study was to investigate the effect of the in utero environment, i.e., amniotic fluid, on one of the major parameters of wound healing, namely cell proliferation, and especially its effect on cultures of both human fetal and adult skin fibroblasts. We found that second trimester human amniotic fluid is a potent stimulant of DNA synthesis and proliferation of cells from both developmental stages. This effect is due to the presence of growth factors, especially basic fibroblast growth factor and platelet-derived growth factor, because inhibitors of their respective receptor kinases and specific neutralizing antibodies can significantly inhibit cell proliferation. Furthermore, we found that this mitogenic effect is mediated through the activation of the MEK/ERK and the PI3K/Akt signaling pathways. Interestingly, we have not observed any significant differences between fetal and adult fibroblasts in their response to amniotic fluid, indicating that cells from both developmental stages respond equally to this complex mixture of regulatory molecules. PMID- 20946139 TI - Mathematical modeling of venous ulcer healing rates after implantation of keratinocytes: New ways to predict the efficacy of wound healing after regenerative methods. AB - The treatment of patients with leg ulcers is both time consuming as well as costly. We found predictable and objective parameters with a mathematical model, which will help to assess wound healing in an individual. The basic principle of our mathematic model is that cells of the neoepithelium are under the influence of different stress factors. We identified correlations between the parameters of our equation and the ulcer area and ulcer duration, based on wound size reduction by a new epithelial layer, and we estimated the survival rates of the transplanted keratinocytes. Our model is consistent with our clinical data and seems applicable for analogous situations, e.g., transplantations of cells to wounds. By this method, we are able to compare qualitatively different treatments and different materials for wound healing even in small groups of patients in an objective way. PMID- 20946140 TI - Macroscale spatial variation in chronic wound microbiota: a cross-sectional study. AB - Controlling for sample site is considered to be an important aspect of chronic wound microbiological investigations; yet, macroscale spatial variation in wound microbiota has not been well characterized. A total of 31 curette samples were collected at the leading edge, opposing leading edge, and/or center of 13 chronic wounds. Bacterial community composition was characterized using a combination of 16S rRNA gene-based pyrosequencing; heat map display; hierarchical clustering; nonmetric multidimensional scaling; and permutation multivariate analysis of variance. A total of 58 bacterial families and 91 bacterial genera were characterized among the 13 wounds. While substantial macroscale spatial variation was observed among the wounds, bacterial communities at different sites within individual wounds were significantly more similar than those in different wounds (p=0.001). Our results support the prevalent opinion that controlling for sample site may improve the quality of wound microbiota studies; however, the significant similarity in bacterial communities from different sites within individual wounds indicates that studies failing to control for sampling site should not be disregarded based solely on this criterion. A composite sample from multiple sites across the surface of individual wounds may provide the most robust characterization of wound microbiota. PMID- 20946142 TI - Expression of WAVEs, the WASP (Wiskott-Aldrich syndrome protein) family of verprolin homologous proteins in human wound tissues and the biological influence on human keratinocytes. AB - WAVEs (Wiskott-Aldrich syndrome protein family verprolin homologs) regulate actin polymerization and influence cellular motility. Here, we investigated the pattern of expression of WAVE-1, WAVE-2, and WAVE-3, in a cohort of human wound tissues together with normal skins and evaluated the role of these molecules in the reepithelialization and migration of keratinocytes. It was shown that there was a significant reduction of the WAVE-3 transcripts in chronic wound tissues, when compared with normal skin and acute wound tissue (p=0.002). Marginal reduction of the WAVE-1 and WAVE-2 transcripts in chronic wounds were also seen. Immunohistochemical analysis showed a significant reduction of all three WAVE proteins in chronic wound tissues in comparison with the acute. We created in vitro cell models using keratinocytes in which we overexpressed WAVE-2, and knocked down the expression of WAVE-1 and WAVE-3. Using ECIS assay, it was shown that knocking down WAVE-3 had a significant effect on the migration and reepithelialization of keratinocytes and that overexpression of WAVE-2 also increased the migration of keratinocytes. We further demonstrated that the impact of WAVE on cell migration was independent upon the PLCg and ERK pathways, but in the downstream requires PI3K pathway and ROCK pathways. In conclusion, the WAVE family proteins are essential for the reepithelialization of keratinocytes. Aberrant expression of WAVEs is linked to the healing process of clinical wounds and loss of WAVE-3 is a particular indicator of an abnormally healing wound. The WAVE proteins have a significant predicative and therapeutic value in wound healing. PMID- 20946141 TI - The effectiveness of the Australian Medical Sheepskin for the prevention of pressure ulcers in somatic nursing home patients: a prospective multicenter randomized-controlled trial (ISRCTN17553857). AB - A multicenter prospective randomized clinical trial was undertaken to investigate the effectiveness of the Australian Medical Sheepskin (AMS) in the prevention of sacral pressure ulcers in somatic nursing home patients. Patients were randomized at admission and were then followed daily for 30 days. The experimental group received usual care plus an AMS as a layer on the mattress within ultimately 48 hours after admission; the control group received usual care only. Usual care was all the care that nursing wards normally applied for pressure ulcer prevention without any further standardization for this study. A total of 588 patients were randomized (293 control and 295 experimental group) and the data of 543 patients could be analyzed (272 from the control and 271 from the experimental group). The incidence of sacral pressure ulcers grade 1 or higher was significantly lower in the experimental group than in the control group (8.9% vs. 14.7%). In a multilevel analysis on the incidence of pressure ulcers adjusted for Braden risk score, age, and gender, it shows an odds ratio of 0.53 (95% confidence interval: 0.29-0.95), meaning a significant protective effect of the AMS. These results are in line with the results of two earlier trials on the AMS in hospital patients. The majority of patients in our trial that used an AMS rated it positively, but one-third found the sheepskin too warm. We conclude that the AMS is an effective aid in the prevention of sacral pressure ulcers in nursing home patients. PMID- 20946143 TI - Mechanisms of improved wound healing in Murphy Roths Large (MRL) mice after skin transplantation. AB - Scars arise in the late phase of wound healing and are characterized by fibroplasia. Previous controversial studies have discussed the regenerative wound healing capacity of Murphy Roths Large (MRL) mice. The aim of this study was to investigate the mechanisms of improved wound healing in a skin transplantation model. Skin grafts from MRL and haplotypically identical B10.BR mice were cross transplanted. At day 10, B10.BR and MRL grafts on B10.BR recipients deposited collagen and showed severe apoptosis. Grafts of MRL recipients were not affected by such alterations and showed an enhanced healing progress. They were characterized by higher partial pressure of tissue oxygen, increased microcirculation, exceptionally intense neovascularization, and a blunted inflammatory response. This phenotype was accompanied by increased vascular endothelial growth factor expression, augmented by enhanced signal transducer and activator of transcription 3 (STAT3) phosphorylation. These effects were combined with a decreased STAT1 expression and phosphorylation. STAT1 pattern variation was associated with decreased Smad7 levels. Furthermore, MRL recipients showed improved stem cell recruitment to the wound area. The basic accelerated wound healing mechanism in MRL mice found in this skin transplantation model is improved engraftment; this is based on enhanced neovascularization and reduced inflammation. These effects are most likely due to higher vascular endothelial growth factor levels and changes in the STAT/Smad signal pathway, which may enhance transforming growth factor-beta signaling, reducing proinflammatory responses. PMID- 20946144 TI - Accelerated wound healing mediated by activation of Toll-like receptor 9. AB - Wound healing is mediated through complex interactions between circulating immune cells and local epithelial and endothelial cells. Elements of the innate immune system are triggered when Toll-like receptors (TLR) are stimulated by their cognate ligands, and previous studies suggest that such interactions can accelerate wound healing. This work examines the effect of treating excisional skin biopsies with immunostimulatory CpG oligodeoxynucleotides (ODN) that trigger via TLR9. Results indicate that CpG (but not control) ODN accelerate wound closure and reduce the total wound area exposed over time by >40% (p<0.01). TLR9 knockout mice, a strain unresponsive to the immunomodulatory effects of CpG stimulation, are unresponsive to ODN treatment and exhibit a general delay in healing when compared with wild-type mice. CpG ODN administration promoted the influx of macrophages to the wound site and increased the production of vascular endothelial growth factor, expediting neovascularization of the wound bed (p<0.01 for both parameters). Stimulation via TLR9 thus represents a novel strategy to accelerate wound healing. PMID- 20946145 TI - Comparison of rectal and tympanic core body temperature measurement in adult Guyanese squirrel monkeys (Saimiri sciureus sciureus). AB - BACKGROUND: Measuring core body temperature in a manner that is safe for animals and veterinary personnel is an important part of a physical examination. For nonhuman primates, this can involve increased restraint, additional stress, as well as the use of anesthetics and their deleterious effects on body temperature measurements. The purpose of this study was to compare two non-invasive methods of infrared tympanic thermometry to standard rectal thermometry in adult squirrel monkeys. METHODS: Tympanic temperatures were collected from 37 squirrel monkeys and compared to rectal temperatures using a human and veterinary infrared tympanic thermometer. RESULTS: Compared with rectal temperature measurements, the human tympanic thermometer readings were not significantly different, while the veterinary tympanic thermometer measurements were significantly higher (P<0.05). There were no differences between sexes. CONCLUSIONS: The tympanic thermometer designed for use in humans can be used in adult squirrel monkeys as an alternative to rectal thermometry for assessing core body temperature. PMID- 20946147 TI - How do continence nurses address sexual function and a history of sexual abuse in daily practice? Results of a pilot study. AB - INTRODUCTION: There is a strong association between urological complaints, sexual dysfunction, and history of sexual abuse (SA), and it is unknown whether urological continence nurses integrate this knowledge in their daily practice. AIM: To evaluate how, in their daily practice, Dutch urological continence nurses address sexual dysfunction and possible SA. METHODS: An anonymous 19-item questionnaire was distributed among all Dutch urinary continence nurses visiting their yearly congress. MAIN OUTCOME MEASURES: The survey results. RESULTS: The response rate was 48.9% (93/190). Of the respondents, 11.8% did not ask their female patients about sexual function; 37.6% asked only rarely; 44.1% asked often; and 6.5% always asked. Sexual functioning in males was not evaluated by the majority of the nurses (13.2% never, and 46.2% rarely). A minority of continence nurses asked males about sexual functioning (36.3% often and 4.3% always). Important reasons for not asking were insufficient knowledge of how to adequately ask males (38.9%) and females (47.8%) about sexual problems, and because nurses assumed the urologist had addressed this issue (48.1% asking males, 39.1% asking females). Younger nurses found it particularly difficult to raise sexual issues with both male and female patients (P=0.001 and P=0.003, respectively). Screening for sexual dysfunction was stated to be important by almost all nurses (65.2% "quite important," and 31.5% "very important"). Within their patient population, both male and female, 28% of the nurses never asked about SA and 49.5% asked only rarely. CONCLUSION: Dutch urological incontinence nurses acknowledge the importance of sexual problems in their patient population, but asking about this issue was not part of routine care. The main reasons for not asking, according to the nurses' responses, were that they had insufficient knowledge and that they assumed the urologist had already asked about sexual problems. PMID- 20946146 TI - Species diversity and relative abundance of lactic acid bacteria in the milk of rhesus monkeys (Macaca mulatta). AB - BACKGROUND: Mother's milk is a source of bacteria that influences the development of the infant commensal gut microbiota. To date, the species diversity and relative abundance of lactic acid bacteria in the milk of non-human primates have not been described. METHODS: Milk samples were aseptically obtained from 54 female rhesus monkeys (Macaca mulatta) at peak lactation. Following GM17 and MRS agar plating, single bacterial colonies were isolated based on difference in morphotypes, then grouped based on whole-cell protein profiles on SDS-PAGE. Bacterial DNA was isolated and the sequence the 16S rRNA gene was analyzed. RESULTS: A total of 106 strains of 19 distinct bacterial species, belonging to five genera, Bacillus, Enterococcus, Lactobacillus, Pediococcus, and Streptococcus, were identified. CONCLUSIONS: Maternal gut and oral commensal bacteria may be translocated to the mammary gland during lactation and present in milk. This pathway can be an important source of commensal bacteria to the infant gut and oral cavity. PMID- 20946148 TI - A multi-stage multi-design strategy provides strong evidence that the BAI3 locus is associated with early-onset venous thromboembolism. AB - BACKGROUND: Factor VIII (FVIII) and von Willebrand factor (VWF) are two known quantitative risk factors for venous thromboembolism (VTE). OBJECTIVES: To identify new loci that could contribute to VTE susceptibility and to modulating FVIII and/or VWF levels. PATIENTS/METHODS: A pedigree linkage analysis was first performed in five extended French-Canadian families, including 253 individuals, to identify genomic regions linked to FVIII or VWF levels. Identified regions were further explored using 'in silico' genome-wide association studies (GWAS) data on VTE (419 patients and 1228 controls), and two independent case-control studies (MARTHA and FARIVE) for VTE, gathering 1166 early-onset patients and 1408 healthy individuals. Single nucleotide polymorphisms (SNPs) associated with VTE risk were further investigated in relation to plasma levels of FVIII and VWF in a cohort of 108 healthy nuclear families. RESULTS: Four main linkage regions were identified, among which the well-characterized ABO locus, the recently identified STAB 2 gene, and a third one, on chromosome 6q13-14, harbouring four non redundant SNPs, associated with VTE at P < 10(-4) in the GWAS dataset. The association of one of these SNPs, rs9363864, with VTE was further replicated in the MARTHA and FARIVE studies. The rs9363864-AA genotype was associated with a lower risk for VTE (OR = 0.58 [0.42-0.80], P = 0.0005) but mainly in non-carriers of the FV Leiden mutation. This genotype was further found to be associated with the lowest levels of FVIII (P = 0.006) and VWF (P = 0.001). CONCLUSIONS: The BAI3 locus where the rs9363864 maps is a new candidate for VTE risk. PMID- 20946149 TI - Assessing the utility of diagnostic criteria: a multisite study on gender identity disorder. AB - INTRODUCTION: Studies involving patients with gender identity disorder (GID) are inconsistent with regard to outcomes and often difficult to compare because of the vague descriptions of the diagnostic process. A multisite study is needed to scrutinize the utility and generality of different aspects of the diagnostic criteria for GID. AIM: To investigate the way in which the diagnosis-specific Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision criteria for GID were used to reach a psychiatric diagnosis in four European countries: the Netherlands (Amsterdam), Norway (Oslo), Germany (Hamburg), and Belgium (Ghent). The main goal was to compare item (symptom) characteristics across countries. METHODS: The current study included all new applicants to the four GID clinics who were seen between January 2007 and March 2009, were at least 16 years of age at their first visit, and had completed the diagnostic assessment (N = 214, mean age = 32 +/- 12.2 years). Mokken scale analysis, a form of Nonparametric Item Response Theory (NIRT) was performed. MAIN OUTCOME MEASURES: Operationalization and quantification of the core criteria A and B resulted in a 23-item score sheet that was filled out by the participating clinicians after they had made a diagnosis. RESULTS: We found that, when ordering the 23 items according to their means for each country separately, the rank ordering was similar among the four countries for 21 of the items. Furthermore, only one scale emerged, which combined criteria A and B when all data were analyzed together. CONCLUSIONS: Our results indicate that patients' symptoms were interpreted in a similar fashion in all four countries. However, we did not find support for the treatment of A and B as two separate criteria. We recommend the use of NIRT in future studies, especially in studies with small sample sizes and/or with data that show a poor fit to parametric IRT models. PMID- 20946150 TI - Revising the International Index of Erectile Function--letter to the editor regarding "IIEF-15: unsuitable for assessing erectile function of young men?". PMID- 20946151 TI - For: Fibrinogen concentrate for management of bleeding. PMID- 20946152 TI - Factor V Leiden as a risk factor for preterm birth--a population-based nested case-control study. AB - BACKGROUND: Preterm birth is a major cause of neonatal morbidity and mortality, occurring in 5-13% of deliveries in developed countries. Genetic thrombophilia can theoretically contribute to the induction of preterm delivery, but the role of thrombophilia as risk factor is unclear. OBJECTIVES: To assess factor V Leiden, FII G20210A and other selected inherited and acquired variables as risk factors for preterm birth. PATIENTS/METHODS: We performed a population-based nested case-control study of 100,000 consecutive pregnancies in Finland. Cases and controls were identified by combining national registers. Clinical data were obtained from medical records and standardized questionnaires. We studied 324 cases with preterm delivery at or after 22 and before 37 completed weeks of gestation, and 752 controls. RESULTS: FV Leiden was associated with a 2.4-fold risk (95% confidence interval [CI] 1.3-4.6) of preterm birth in all pregnancies, and a 2.6-fold risk (95% CI 1.4-5.1) in singleton pregnancies. FV Leiden was especially associated with late preterm birth at or after 32 weeks of pregnancy, with an odds ratio (OR) of 2.9 (95% CI 1.5-5.6) in all pregnancies and an OR of 3.1 (95% CI 1.6-6.2) in singleton pregnancies. FII G20210A was not associated with preterm birth. Twin pregnancy (OR 12.0, 95% CI 6.0-24.1) and a history of venous thrombosis (OR 3.8, 95% CI 1.4-9.8) were associated with increased risk. High educational level and modest overweight (body mass index 25-29.9 kg m(-2) ) had protective effects. CONCLUSIONS: Maternal carriage of FV Leiden was associated with increased risk of late but not early preterm birth. FII G20120A was not associated with preterm birth. PMID- 20946153 TI - Effects of Behcet's disease on sexual function and psychological status of male patients. AB - INTRODUCTION: There are no studies on the sexual function of male patients with Behcet's disease (BD), but it is probable that male sexual dysfunction may be seen in this chronic condition. AIM: The aim of this study was to assess the effect of BD on male sexual function and psychiatric status, and to examine the relationship between sexual function and depression in this population. METHODS: Patients with a diagnosis of BD for at least one year were included in the study. The patients' age, educational level, and duration of disease were recorded. A healthy control group was selected with highly similar characteristics to the patient group. The sexual functions of the patient and the control groups were assessed using the International Index of Erectile Functions (IIEF), and their emotional status was evaluated using the Beck Depression Inventory (BDI). MAIN OUTCOME MEASURES: The results of the questionnaires in patient and control groups were compared. The relationship between the clinical findings and questionnaire scores was assessed in the patient group. RESULTS: Forty-two patients with BD and 42 healthy individuals were included in the study. The mean subscale scores of the IIEF for erectile function were significantly lower in the patient group compared to the control group (P < 0.001). The IIEF score was not related to active skin findings, active oral ulcers, active genital ulcers, eye involvement, or medication for BD, but it was related with history of arthritis. The BDI and IIEF scores were negatively correlated in the patient group. CONCLUSION: BD has a negative impact on men's psychological state and sexual function. We recommend that depression and sexual dysfunction be investigated and treated while assessing patients with BD. PMID- 20946154 TI - Contraceptive use among low-income urban married women in India. AB - INTRODUCTION: The reports of a rise in contraceptive practices have not been matched by a similar decrease in population, so there is a need to look into the causes of this discrepancy. AIM: To obtain information from low-income urban married women regarding their contraceptive knowledge, practices, and utilization of the services. MAIN OUTCOME MEASURE: Percentage of low-income urban married women using contraception, different types of contraception used, influence of education on choice of contraception. METHODS: All nonpregnant married women between the ages of 18 and 45 years, belonging to low-income groups were selected for study. Statistical analysis was done using EPI Info ver-5.0. Chi square test was used to test the significance of data. RESULTS: Contraceptive use among these women was 52%; the most common method was tubal ligation. Educated women used spacing methods more often than uneducated women. Women had adequate awareness regarding type of contraceptives available but had no idea about the timing of starting contraception after delivery and about emergency contraception. CONCLUSION: The low-income urban population is aware of the importance of limiting the family size and has family planning facilities yet has less contraceptive usage because of low level of education, increased rate of discontinuation, and lack of proper knowledge of the use of contraception. PMID- 20946155 TI - Thirteen novel VKORC1 mutations associated with oral anticoagulant resistance: insights into improved patient diagnosis and treatment. AB - BACKGROUND: Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) is the molecular target of oral anticoagulants. Mutations in VKORC1 cause partial or total coumarin resistance. OBJECTIVES: To identify new VKORC1 oral anticoagulant (OAC) resistance (OACR) mutations and compare the severity of patient phenotypes across different mutations and prescribed OAC drugs. PATIENTS/METHODS: Six hundred and twenty-six individuals exhibiting partial or complete coumarin resistance were analyzed by VKORC1 gene sequencing and CYP2C9 haplotyping. RESULTS: We identified 13 patients, each with a different, novel human VKORC1 heterozygous mutation associated with an OACR phenotype. These mutations result in amino acid substitutions: Ala26->Thr, His28->Gln, Asp36->Gly, Ser52->Trp, Ser56->Phe, Trp59->Leu, Trp59->Cys, Val66->Gly, Gly71->Ala, Asn77->Ser, Asn77 >Tyr, Ile123->Asn, and Tyr139->His. Ten additional patients each had one of three previously reported VKORC1 mutations (Val29->Leu, Asp36->Tyr, and Val66->Met). Genotyping of frequent VKORC1 and CYP2C9 polymorphisms in these patients revealed a predominant association with combined non-VKORC1*2 and wild-type CYP2C9 haplotypes. Additionally, data for OAC dosage and the associated measured International Normalized Ratio (INR) demonstrate that OAC therapy is often discontinued by physicians, although stable therapeutic INR levels may be reached at higher OAC dosages. Bioinformatic analysis of VKORC1 homologous protein sequences indicated that most mutations cluster into protein sequence segments predicted to be localized in the lumenal loop or at the endoplasmic reticulum membrane-lumen interface. CONCLUSIONS: OACR mutations of VKORC1 predispose afflicted patients to high OAC dosage requirements, for which stable, therapeutic INRs can sometimes be attained. PMID- 20946156 TI - Psychometric properties of the Spanish version of the Changes in Sexual Functioning Questionnaire Short-Form (CSFQ-14) in patients with severe mental disorders. AB - INTRODUCTION: Sexual dysfunction in patients with severe mental disorders is often underestimated or overlooked by psychiatrists. A brief and valid self report instrument for assessing sexual functioning may well contribute to changing this situation. AIMS: To validate the Short Form of the Changes in Sexual Functioning Questionnaire (CSFQ-14) in Spanish patients with severe mental disorders. METHODS: Naturalistic, cross-sectional, multicenter, validation study. Eighty-nine patients with schizophrenia and 82 with bipolar disorder were evaluated using the CSFQ-14, the Visual Analogue Scale for Sexual Functioning Satisfaction (VAS-SFS), and the Clinical Global Impression-Severity scales for mental disorders (CGI-S) and for Sexual Dysfunction (CGI-SSD). MAIN OUTCOME MEASURES: The 14-item Changes in Sexual Functioning Questionnaire. RESULTS: Internal reliability (Cronbach's alpha) = 0.90. Construct validity = 3 principal components, of which the first, arousal-orgasm, explained 46.4% of the total variance. Convergent validity: Pearson correlation coefficients between CSFQ-14 and VAS-SFS = 0.33 (P < 0.01) and between CSFQ-14 and CGI-SDS = -0.71 (P < 0.01). Discriminant validity: The CSFQ-14 was able to discriminate among patients with no, mild, moderate, and severe sexual dysfunction according to CGI-SDS scores, both in males (P < 0.001) and females (P < 0.001). In males, the area under the curve (AUC) was 0.833 and a cutoff point of 49 provided a sensitivity of 92.9% and a specificity of 59.5%. In females, the AUC was 0.834 and a cutoff point of 43 provided a sensitivity of 91.9% and a specificity of 62.5%. CONCLUSION: The Spanish version of the CSFQ-14 is a reliable and valid instrument for assessing sexual functioning in patients with severe mental disorders. As a brief, self rated instrument, the CSFQ-14 scale seems to be appropriate for use in everyday clinical practice as a means of identifying and monitoring changes in sexual functioning. PMID- 20946158 TI - Exposure to mother's pregnancy and lactation in infancy is associated with sexual attraction to pregnancy and lactation in adulthood. AB - INTRODUCTION: Several theories, including psychodynamic theories, sexual imprinting and early conditioning have been formulated to explain sexual development. Empirical data, however, remain insufficient for a thorough evaluation of these theories. AIM: In this study, we test the hypothesis that a critical period exists for the acquisition of sexual preferences, as suggested by empirical findings in birds and mammals (sexual imprinting). METHODS: An Internet questionnaire was used. MAIN OUTCOME MEASURES: We gather data from individuals with a sexual preference for pregnant and/or lactating women, under the hypothesis that pregnancy or lactation may become sexually attractive in adulthood following an exposure to pregnant or lactating women in infancy. RESULTS: We find that these preferences are more common in older siblings, i.e., in individuals who have been exposed to more maternal pregnancy and lactation. This result is independent of respondent and sibling sex. In addition, only maternal pregnancies and lactations experienced between 1.5 and 5 years of age are associated with the preferences. CONCLUSIONS: We discuss our findings in relation to theories of sexual development and to earlier reports of birth order effects on sexual behavior. We suggest that this age range may constitute a sensitive period for the acquisition of sexual preferences. PMID- 20946159 TI - Mental- and physical-health indicators and sexually explicit media use behavior by adults. AB - INTRODUCTION: Converging evidence from culturally diverse contexts indicates that sexually explicit media use behavior (SEMB; i.e., pornography consumption) is associated with risky sexual health perceptions and behaviors, many that involve high risks of HIV/STD transmission. AIM: Essentially unexplored, and the focus here, are potential relationships between SEMB and nonsexual mental- and physical health indicators. MAIN OUTCOME MEASURE: Variability in six continuously measured health indicators (depressive symptoms, mental- and physical-health diminished days, health status, quality of life, and body mass index) was examined across two levels (users, nonusers) of SEMB. METHODS: A sample of 559 Seattle-Tacoma Internet-using adults was surveyed in 2006. Multivariate general linear models parameterized in a SEMB by respondent gender (2 * 2) factorial design were computed incorporating adjustments for several demographics. RESULTS: SEMB was reported by 36.7% (n = 205) of the sample. Most SEMB users (78%) were men. After adjusting for demographics, SEMB users, compared to nonusers, reported greater depressive symptoms, poorer quality of life, more mental- and physical-health diminished days, and lower health status. CONCLUSIONS: The findings show that mental- and physical-health indicators vary significantly across SEMB, suggesting the value of incorporating these factors in future research and programmatic endeavors. In particular, the findings suggest that evidence-based sexual health promotion strategies simultaneously addressing individuals' SEMB and their mental health needs might be a useful approach to improve mental health and address preventable sexual health outcomes associated with SEMB. PMID- 20946157 TI - Efficacy and safety of once weekly subcutaneous idrabiotaparinux in the treatment of patients with symptomatic deep venous thrombosis. AB - BACKGROUND: Idraparinux, a long acting inhibitor of factor (F) Xa, is as effective as standard anticoagulant therapy for patients with symptomatic deep venous thrombosis. We investigated the potential use of the biotinylated molecule, idrabiotaparinux. Biotinylation enables reversal of the anticoagulant effect. METHODS: We performed a randomized double-blind trial in 757 patients with symptomatic deep venous thrombosis, comparing equimolar doses of idrabiotaparinux (3 mg) with idraparinux (2.5 mg), both given subcutaneously, once weekly for 6 months. Inhibition of FXa activity was measured at days 15, 36, 57, 92 and 183. The efficacy outcome was recurrent venous thromboembolism. The safety outcomes were clinically relevant bleeding and death. RESULTS: Inhibition of FXa was similar in the two treatment groups at each time point of measurement. Recurrent venous thromboembolism during the 6-month treatment period occurred in nine of 386 patients (2.3%) in the idrabiotaparinux group and in 12 of 371 patients (3.2%) in the idraparinux group, a difference of - 0.9% (95% confidence interval, -3.2-1.4%). The incidence of clinically relevant bleeding was 5.2% in the idrabiotaparinux group and 7.3% in the idraparinux group (P = 0.29), a difference of - 2.1% (95% confidence interval, -5.6-1.4%). Six patients (1.6%) who received idrabiotaparinux died, compared with 12 patients (3.2%) given idraparinux, a difference of - 1.7% (95% confidence interval, -3.9-0.5%). CONCLUSIONS: Idrabiotaparinux has a similar time course of FXa inhibition, efficacy and safety to idraparinux for the treatment of deep venous thrombosis. PMID- 20946160 TI - In vitro and in vivo animal models in priapism research. AB - INTRODUCTION: Priapism is an enigmatic yet devastating clinical phenomenon. In the last two decades, the use of various animal models to study this disorder has dramatically advanced our understanding of this mysterious disorder. AIM: This report reviews various animal models used to study ischemic priapism and informs basic science researchers the broad view of priapism research. METHODS: Retrospective review of pertinent literature from the last two decades via PubMed search using the keywords "ischemic priapism" and "priapism model." MAIN OUTCOME MEASURES: Findings on the animal models used in ischemic priapism research and its advantages and limitations. RESULTS: In vitro and in vivo animal models varying from dogs, cats, rabbits, rats to mice were used in priapism research. In vitro models included: (i) corpora cavernosa smooth muscle (CCSM) strip in organ bath; (ii) corporal tissue binding assay; (iii) CCSM cell culture under hypoxia/anoxia. In vivo models could be categorized as: (i) pharmacologically induced by corpus cavernosum medicine injection; (ii) ventilation induced by tidal volume control; (iii) mechanical induced by a constrictor band placed around the base of the penis combined with induced erection; (iv) genetic engineered by intracorporal gene transfer, transgenic, or gene knock-out. CONCLUSIONS: The ischemic priapism animal models are shifting from pharmaceutically or mechanically induced to genetically engineered. The knowledge generated by those models is enhancing our understanding and management of this clinical challenge. PMID- 20946161 TI - Men with mild erectile dysfunction benefit from sildenafil treatment. AB - INTRODUCTION: Sildenafil treatment has not been evaluated in a double-blind, placebo-controlled (DBPC) trial specific to men with mild erectile dysfunction (ED), defined by a 22-25 score on the International Index of Erectile Function erectile function domain (IIEF-EF). AIM: To assess sildenafil efficacy in sexually dissatisfied men with mild ED. MAIN OUTCOME MEASURES: Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), IIEF, Quality of Erection Questionnaire (QEQ), Erection Hardness Score (EHS 4=completely hard/fully rigid), general efficacy questions (GEQs), event log questions (hardness sufficient for penetration, duration sufficient for successful intercourse, ejaculation/orgasm, and second erection within 24 hours), and analog scales (erection firmness, reliability, and maintenance, and general sexual performance). METHODS: Eight-week DBPC flexible-dose (25, 50, or 100 mg) trial with 6-week, open-label (OL) extension. RESULTS: One hundred and seventy-six men were randomized (mean+/-standard deviation: age, 50+/-12 year; ED duration, 3.5+/ 3.2 year). Most had organic or mixed ED. For sildenafil vs. placebo, 66% vs. 89% titrated to 100 mg and efficacy at DBPC end was better, including the EDITS Index score (least squares mean [standard error], 80.3 [2.3] vs. 62.1 [2.5]; P<0.0001); treatment satisfaction (EDITS Index score >50 in 89% vs. 63%; P=0.0001); no ED (IIEF-EF >=26 in 58% vs. 39%; P<0.05); GEQs (>=4.9-fold greater odds of improved erections and ability to have sexual intercourse); and EHS 4 (47.2% vs. 25.2% of occasions; P<0.0001). At OL end, 93% of men were satisfied (EDITS Index score>50), 77% had no ED, and >=89% were GEQ responders; mean scores on IIEF domains, the QEQ, and analog scales were >80% of the maximum; 60% of occasions had EHS 4; and event log responses were positive on >80% of occasions, except for second erections (41.9%). Headache, nasal congestion, and flushing, mostly mild to moderate, were the most common adverse events. CONCLUSION: Men with mild ED derive substantial benefit from sildenafil treatment. PMID- 20946162 TI - Early versus late rehabilitation of erectile function after nerve-sparing radical cystoprostatectomy: a prospective randomized study. AB - INTRODUCTION: Pharmacological rehabilitation of erectile function (EF) after nerve-sparing radical prostatectomy was repeatedly advocated. AIM: To compare early vs. late penile rehabilitation in patients with nerve-sparing (NS) radical cystoprostatectomy based on a prospective randomized trial. METHODS: Eighteen patients without spontaneous erection 8 weeks after NS radical cystoprostatectomy were randomly divided into two groups; group I and II who started the erectogenic therapy at the 2nd and 6th month postoperatively, respectively. The pharmacological therapy constitutes of sildenafil citrate twice weekly to be shifted to intracavernosal injection (ICI) of prostaglandin E1 (PGE1) if not responding. The treatment continued for 6 months in both groups. MAIN OUTCOME MEASURES: The EF status was evaluated before and at the end of the treatment by International Index of Erectile Function questionnaire and penile Doppler ultrasonography (PDU). RESULTS: Six out of nine patients recovered unassisted erection after treatment in group I compared to three out of nine patients in group II. Two patients in group I and three patients in group II were maintained on sildenafil therapy on demand basis. The remaining four patients were dependent on ICI of PGE1. At final evaluation, a significant improvement was found in the EF, the intercourse satisfaction and overall satisfaction domains (P = 0.02, 0.03, and 0.02, respectively) in group I compared with group II. Regarding PDU findings, significant improvement in end-diastolic velocity was elicited in the early rehabilitation group compared with the pretreatment value (P = 0.03) with no significant difference between both groups. CONCLUSION: Early compared with delayed erectile rehabilitation brings forward the natural healing time of potency and maintains nerve-assisted erection. PMID- 20946163 TI - Infection rates of rifampin/gentamicin-coated Titan Coloplast penile implants. Comparison with Inhibizone-impregnated AMS penile implants. AB - INTRODUCTION: It is a common practice to soak Titan((r)) Coloplast penile implants in antibiotic solution prior to implantation. Experience with Inhibizone impregnation suggests that rifampin coating significantly reduces infection rates of penile implant surgery. In this article we describe the results of coating Titan Coloplast penile implants with rifampin/gentamicin solution. AIM: To compare infection rates of Titan((r)) Coloplast penile implants coated with vancomycin/gentamycin, rifampin/gentamicin, and Inhibizone-impregnated American Medical Systems (AMS) penile implants. METHODS: Chart review was done for all Mentor/Coloplast and AMS implant surgeries performed at our center between the dates January 1, 2002 and February 8, 2010. Infection rates for Titan((r)) Coloplast penile implants coated with vancomycin/gentamycin, rifampin/gentamicin, and Inhibizone-impregnated (AMS) penile implants were compared. MAIN OUTCOME MEASURES: Infection rates for penile implants coated with different antibiotics. RESULTS: Infection rates for Titan((r)) Coloplast penile implants coated with vancomycin/gentamycin and Inhibizone-impregnated (AMS) penile implants was 4.4% and 1.3%, respectively (P = 0.05). None of the rifampin/gentamicin-coated Titan((r)) Coloplast penile implants have developed infection. Rifampin is the common antibiotic both in rifampin/gentamicin-coated Coloplast implants and Inhibizone((r)) . The infection rate in this combined rifampin/gentamicin-coated Titan Coloplast implants and Inhibizone-coated AMS implants group was 0.63% (P = 0.03). CONCLUSION: Both rifampin/gentamicin-coated Titan((r)) Coloplast penile implants and Inhibizone-impregnated (AMS) penile implants appear to have lower infection rates compared with vancomycin/gentamycin-coated Titan((r)) Coloplast penile implants The present study does not suggest superiority of rifampin/gentamicin-coated Titan((r)) Coloplast penile implants or Inhibizone impregnated (AMS) penile implants but we strongly suggest that all Titan((r)) Coloplast penile implants should be coated with rifampin/gentamicin solution. PMID- 20946164 TI - TNF receptor-associated factor 4 (TRAF4) is a novel binding partner of glycoprotein Ib and glycoprotein VI in human platelets. AB - BACKGROUND: Reactive oxygen species generation is one consequence of ligand engagement of platelet glycoprotein (GP) receptors GPIb-IX-V and GPVI, which bind VWF/collagen and initiate thrombosis at arterial shear; however, the precise molecular mechanism coupling redox pathway activation to engagement of these receptors is unknown. OBJECTIVE: The objective of this study was to identify novel binding partners for GPIb-IX-V and GPVI that could provide a potential link between redox pathways and early platelet signaling events. METHODS AND RESULTS: Using protein array analysis and affinity-binding assays, we demonstrated that the orphan TNF receptor-associated factor (TRAF) family member, TRAF4, selectively binds cytoplasmic sequences of GPIbbeta and GPVI. TRAF4, p47(phox) [of the NADPH oxidase (Nox2) enzyme complex] and other redox relevant signaling proteins such as Hic-5, co-immunoprecipitate with GPIb/GPVI from human platelet lysates whilst MBP-TRAF4 or MBP-p47(phox) fusion proteins specifically pull-down GPIb/GPVI. GPIb- or GPVI-selective agonists induce phosphorylation of the TRAF4 associated proteins, Hic-5 and Pyk2, with phosphorylation attenuated by Nox2 inhibition. CONCLUSION: These results describe the first direct association of TRAF4 with a receptor, and identify a novel binding partner for GPIb-IX-V and GPVI, providing a potential link between these platelet receptors and downstream TRAF4/Nox2-dependent redox pathways. PMID- 20946165 TI - Effect of corticotropin-releasing factor receptor antagonist on psychologically suppressed masculine sexual behavior in rats. AB - INTRODUCTION: Corticotropin-releasing factor (CRF) coordinates various responses of the body to stress, and CRF receptors are important targets of treatment for stress-related disorders. AIM: To investigate the effect of a nonselective CRF receptor antagonist, astressin, on suppression of masculine sexual behavior by psychological stress in rats. METHODS: First, we investigated the influence of psychological stress, induced 2 hours per day for three consecutive days, on sexual behavior. Then, rats were divided into 4 groups: a control group, an astressin administration group (A), a psychological stress loading group (PS), and a psychological stress loading and astressin administration group (PS + A). The rats were exposed to sham or psychological stress for three consecutive days. After the last stress loading, the rats were injected with vehicle or astressin, and their sexual behavior was observed. We also measured serum levels of adrenocorticotropic hormone (ACTH). MAIN OUTCOME MEASURE: The effects of astressin on sexual behavior and serum levels of ACTH in rats affected by psychological stress were determined. RESULTS: Sexual behavior was reduced after psychological stress loading. The PS rats had significantly longer mount, intromission, and ejaculation latencies and lower ejaculation frequency than did the control, A, and PS + A rats. The intromission latency and ejaculation frequency in the PS + A rats did not achieve the level observed in the controls. There was no significant difference in these parameters between the control and A rats. Serum ACTH levels were significantly lower in PS + A rats than in PS rats. CONCLUSIONS: Psychologically suppressed masculine sexual behavior could be partially recovered with astressin administration in rats. These data provide a rationale for the further study of CRF receptor antagonists as novel agents for treating psychological sexual disorders. PMID- 20946166 TI - Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. AB - INTRODUCTION: Rivaroxaban is an oral direct factor Xa inhibitor developed for prophylaxis and treatment of thromboembolic disorders. Laboratory monitoring is not necessary but the dose-dependent effects on common reagents and assay procedures are largely unknown. OBJECTIVES: To investigate the effect of rivaroxaban on commonly used coagulation assays. MATERIALS AND METHODS: Rivaroxaban was added to plasma from healthy subjects in the concentration range 0-1000 MUg L(-1) and analyzed using different reagents for activated partial thromboplastin time (APTT), prothrombin time (PT), antithrombin, fibrinogen and activated protein C (APC) resistance assays. RESULTS: At an expected peak concentration of rivaroxaban in clinical use, the APTTs were almost invariably prolonged but at lower concentrations the effect was weak. The concentration needed to double the APTT varied between 389 +/- 106 and 617 +/- 149 MUg L(-1) for different reagents. The PT assays showed a marked degree of difference. In general, the Quick PT type assays were more sensitive compared with the Owren type PT assays. The results from antithrombin assays were dependent on the type of reagent, with the Xa-based assay being sensitive for rivaroxaban with an estimated increase of 0.09 IU mL(-1) per 100 MUg L(-1) rivaroxaban. There were only minor effects on fibrinogen assays based on thrombin reagents. The APTT based assay for APC resistance is affected in a dose-dependent manner whereas an assay based on the activation of coagulation at the prothrombinase level was unaffected. CONCLUSIONS: Different assays, and even different reagents within an assay group, display variable effects by therapeutic concentrations of rivaroxaban. PMID- 20946167 TI - Plasma glutathione peroxidase in pediatric stroke families. AB - BACKGROUND/OBJECTIVES: Promoter polymorphisms in the plasma glutathione peroxidase gene (GPX3), which encodes a major antioxidant enzyme implicated in post-translational modification of fibrinogen, have been implicated as risk factors for arterial ischemic stroke (AIS) and cerebral sinovenous thrombosis (CSVT) in young adults. However, the contribution of these polymorphisms could not be confirmed by other studies. PATIENTS/METHODS: The aim of the present study was to investigate the association of three haplotype-tagging single-nucleotide polymorphisms (htSNPs) in GPX3 in a large family-based study sample comprising 268 nuclear families with different pediatric AIS subtypes, i.e. arteriopathy stroke (AS) and thromboembolic stroke (TS). In addition, an independent study sample comprising 154 nuclear families of pediatric CSVT was investigated. Single point and haplotype association was assessed with the transmission disequilibrium test implemented in haploview. RESULTS: Single-point analysis revealed that the G allele of htSNP rs8177412 was significantly overtransmitted to affected AS children (T/U = 25 : 11, chi(2) = 5.54, P = 0.019), but not to affected TS children (T/U = 49 : 40, chi(2) = 0.91, P = 0.34). The corresponding GG haplotype (H2: frequency 0.18) was also significantly overtransmitted to AS children (T/U = 23 : 11, chi(2) = 4.28, P= 0.03), but not to TS children or in children with CSVT. These results remained significant following 10,000 bootstrap permutations. Our findings indicate that genetic variants of GPX3 are risk factors for AS, but not for thromboembolic AIS or CSVT, in children. CONCLUSIONS: Our results further highlight the need to analyze the contribution of genetic variants to pediatric AS, TS or CSVT separately, as these subcategories probably result from different combinations of risk-conferring and protective genetic variations. PMID- 20946168 TI - Investigation of the neural target level of hyperthyroidism in premature ejaculation in a rat model of pharmacologically induced ejaculation. AB - INTRODUCTION: Association between hyperthyroidism and premature ejaculation was demonstrated in clinical studies. AIM: The aim of this study is to determine the target level of changes on ejaculatory physiology under hyperthyroid states. METHODS: p-Chloroamphetamine (PCA)-induced pharmacologic ejaculation model with 24 male Wistar rats was used in the study. Subcutaneous injection of L-thyroxine for 14 days was performed to induce hyperthyroidism. At the end of the injection period, thyroid hormone status was evaluated by serum thyroid-stimulating hormone measurements in all rats. At the beginning of the operations, complete spinal transections (tx) at the T8-T9 level were performed to half of the L-thyroxine injected and control group rats. Thus, experimental groups were constructed as follows: Group 1--control-spinal intact (n=6), group 2-control-spinal tx (n=6), group 3-hyperthyroid-spinal intact (n=6), and group 4-hyperthyroid-spinal tx (n=6). Ejaculatory responses were recorded before and 30 minutes after intraperitoneal administration of 5 mg/kg PCA. MAIN OUTCOME MEASURES: During the operations, seminal vesicle (SV) catheterization and bulbospongiosus (BS) muscle dissections were performed in all rats to demonstrate SV pressure (SVP) BS electromyographic (EMG) activity changes. RESULTS: Following PCA administration SVP tonic amplitude, SV phasic contraction (SVPC) frequency, SVPC maximal amplitude, and BS EMG area under curve values were higher in hyperthyroid intact rats than in control intact rats. The time interval between PCA administration and first ejaculation of hyperthyroid intact rats were significantly shorter than control intact rats (261 +/- 7.30 seconds vs. 426 +/- 49.6 seconds, P=0.008). All of the changes in the ejaculatory parameters that were induced by hyperthyroidism were completely resolved after spinal transections at the T8-T9 level in group 4. CONCLUSION: In this study, we confirmed the recent data that hyperthyroidism affects both the emission and expulsion phases of ejaculation. The changes that were induced by hyperthyroidism on ejaculatory physiology probably take place in the supraspinal centers above T8 level. PMID- 20946169 TI - Coloplast titan inflatable penile prosthesis with one-touch release pump: review of 100 cases and comparison with genesis pump. AB - INTRODUCTION: In 2008 Coloplast Corporation modified their Titan inflatable penile prosthesis (IPP) with a new One-Touch Release (OTR) pump, in an attempt to facilitate device deflation. There is currently little published data concerning this new pump. AIM: The aim of this pilot study was to assess initial patient and physician experience with the Titan OTR pump. METHODS: Retrospective chart review was used to assess the functionality and surgeon experience with 100 consecutive patients implanted with a Titan OTR pump, compared with 100 prior consecutive patients implanted with a Titan Genesis pump. MAIN OUTCOME MEASURES: The ease of implantation of the OTR pump, the number of required postoperative inflate/deflate teaching visits, and OTR pump functionality were assessed and compared with that of the prior Genesis pump. RESULTS: The mean length of follow up in the Genesis group (N = 100) was 20.8 months, and mean length of follow-up in the OTR group (N = 100) was 8.4 months. There was one device infection in each group. The average number of postoperative teaching sessions needed to teach the patient how to operate the device was 1.87 in the Genesis group, and 1.19 in the OTR group (P < 0.001). The range of teaching visits was 1-5 in the Genesis group, and 1-3 in the OTR group (P < 0.001). No pump malfunctions were seen in either group. Subjectively, the OTR pump was just as easy to implant as the Genesis pump. In addition, the OTR pump was subjectively easier for the surgeon and the patient to deflate, and just as easy to inflate, compared with the Genesis pump. CONCLUSIONS: This pilot study revealed that the OTR pump functioned as specified by the manufacturer. With short-term follow-up, no pump malfunctions were detected. The OTR pump was associated with a statistically significant reduction in the number of postoperative teaching sessions required for the patient to properly operate the device. It was subjectively just as easy to implant and inflate, and easier to deflate, compared with the Genesis pump. PMID- 20946170 TI - Increased cavernous expression of transforming growth factor-beta1 and activation of the Smad signaling pathway affects erectile dysfunction in men with spinal cord injury. AB - INTRODUCTION: Transforming growth factor-beta1 (TGF-beta1) is implicated in bladder fibrosis after spinal cord injury (SCI) and in the fibrosis in the corpus cavernosum tissue after cavernous nerve injury. AIM: We investigated the differential expression of TGF-beta1 and the Smad transcription factor, the key molecule for the initiation of TGF-beta-mediated fibrosis, in cavernous tissue from SCI patients. METHODS: After obtaining informed consent and approval from the patients and our institutional review board, we enrolled 5 patients with psychogenic erectile dysfunction (ED) (mean age 36.8 years; range 20-50 years) and 10 patients with neurogenic ED from SCI (mean age 38.8 years; range 18-50 years). Cavernous tissues were obtained by percutaneous biopsy and stained with Masson trichrome, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL), or antibodies to TGF-beta1 and phospho Smad2. MAIN OUTCOME MEASURES: Semi-quantitative analysis of TGF-beta1 and phospho Smad2 was performed, and the numbers of apoptotic cells were counted. We also quantified the cavernous collagen area with the use of an image analyzer system. RESULTS: The expression of TGF-beta1 and phospho-Smad2 protein was significantly higher in the SCI group than in the psychogenic group. The TUNEL assay revealed a higher apoptotic index in the SCI group than in the psychogenic group. Higher TGF beta1 and phospho-Smad2 expression and more apoptotic cells were noted mainly in endothelial cells, smooth muscle cells, and fibroblasts of the SCI group. Double labeling of cavernous tissue with TUNEL and antibody to phospho-Smad2 revealed that most TUNEL-positive cells showed immunoreactivity to phospho-Smad2 staining. Cavernous collagen content was significantly greater in the SCI group than in the psychogenic group. CONCLUSION: Upregulation of TGF-beta1 and activation of the Smad signaling pathway may play important roles in SCI-induced cavernous fibrosis and deterioration of erectile function, which warrants early pharmacological intervention to protect erectile tissue from irreversible damage. PMID- 20946171 TI - Focusing "hot" or focusing "cool": attentional mechanisms in sexual arousal in men and women. AB - INTRODUCTION: Knowledge about the regulation of sexual emotion may add to the understanding of sexual problems such as diminished sexual desire and hypersexuality. AIM: To investigate the regulation of sexual arousal by means of attentional focus in healthy sexually functional men and women. METHOD: Using a habituation design with attentional strategies, it was investigated whether a focus on hot, emotional information of sexual stimuli would sustain or amplify sexual responses, whereas a focus on cool, cognitive information would weaken sexual responses. MAIN OUTCOME MEASURES: Genital response (in women measured by vaginal photoplethysmography assessing vaginal pulse amplitude, and in men measured by mechanical penile strain gauge assessing penile circumference) and subjective report of sexual arousal and absorption. RESULTS: Attenuation of sexual feelings by attentional focus was observed, with stronger sexual feelings under the hot focus condition than under the cool focus condition. Also, sexual feelings diminished during repeated erotic stimulation, and increased with the introduction of novel stimulation, indicating habituation and novelty effects. Contrary to the expectations, the hot attentional focus did not preclude habituation of sexual arousal. CONCLUSIONS: Attentional focus has substantial regulatory effects on subjective sexual arousal. Taking a participant and emotion oriented focus rather than a spectator and stimulus-oriented focus while viewing erotic stimuli, enhances feelings of sexual arousal. Implications for the treatment of hypoactive sexual desire, sexual arousal disorder, and hypersexuality are discussed, as well as future directions for studying regulation of sexual emotion. PMID- 20946172 TI - Disulfide bond reduction of von Willebrand factor by ADAMTS-13. AB - BACKGROUND: von Willebrand factor (VWF) released from endothelial cells is rich in ultra-large (UL) multimers that are intrinsically active in binding platelets, whereas plasma-type VWF multimers require shear stress to be activated. This functional difference may be attributed to thiols exposed on the surface of plasma-type VWF multimers, but not on ULVWF multimers. Shear stress induces the exposed thiols to form disulfide bonds between laterally apposed plasma-type VWF multimers, leading to enhanced VWF binding to platelets. OBJECTIVES: We tested a hypothesis that ADAMTS-13 has a disulfide bond reducing activity that regulates shear-induced thiol-disulfide exchange of VWF. METHODS: Thiol blocking agents and active thiol bead capturing were used to identify and locate this activity, along with truncated ADAMTS-13 mutants. RESULTS: ADAMTS-13 contains a disulfide bond reducing activity that primarily targets disulfide bonds in plasma-type VWF multimers induced by high shear stress or formed with thiol beads, but not disulfide bonds in native multimeric structures. Cysteine thiols targeted by this activity are in the VWF C-domain and are known to participate in shear-induced thiol-disulfide exchange. ADAMTS-13 contains cysteine thiols that remain exposed after being subjected to hydrodynamic forces. Blocking these active thiols eliminates this reducing activity and moderately decreases ADAMTS-13 activity in cleaving ULVWF strings anchored to endothelial cells under flow conditions, but not under static conditions. This activity is located in this C-terminal region of ADAMTS-13. CONCLUSIONS: This novel disulfide-bond-reducing activity of ADAMTS 13 may prevent covalent lateral association and increased platelet adherence of plasma-type VWF multimers induced by high fluid shear stress. PMID- 20946173 TI - Vascular modifications of the clitoris induced by topic nitric oxide donor gel- preliminary study. AB - INTRODUCTION: The clitoral blood flow increase is dependent of nitric oxide (NO) and it occurs due to sexual arousal. Female sexual disorder mechanisms are poorly understood and NO therapeutic role in this scenario is to be determined. AIM: To assess topic NO donor S-nitrosoglutationa (GSNO) gel-100 uM effect on clitoral blood flow in healthy women. METHODS: Forty healthy women were double-blinded randomized for Group 1, GSNO gel, n=20 and Group 2, placebo gel, n=20. All patients underwent Doppler ultrasound test in the clitoral artery. Hemodynamic analysis consisted of: systolic peak speed, diastolic speed, and vase resistance rate. Ten random patients were analyzed regarding sexual function after two double-blinded placebo and NO donor gel periods of 30 days. MAIN OUTCOME MEASURES: To consider female sexual dysfunction treatment through local NO dependent pathway. RESULTS: Mean age was 31 years (20-39) and mean female sexual function index score 31.5 (26-34). Group 1: The mean and standard deviation baseline and 15 minutes after the application of the GSNO gel systolic (11.7+/ 2.1 cm/second to 15.9+/-2.4 cm/second) and diastolic speeds (2.7+/-0.3 cm/second to 4.2+/-0.4 cm/second) and resistance (0.71+/-0.04 to 1.38+/-0.06) were significantly increased (P=0.002) (P=0.043), and (P=0.005), respectively. No local or systemic adverse effect was observed in women or in their sexual partners and the sexual function presented a slightly insignificant improvement (P=0.065), although eight of 10 women could subjectively identify the GSNO gel as the preferred and most pleasant between both tried. Group 2 presented no significant differences at baseline and 15 minutes after the application of the placebo gel, P>0.05. CONCLUSION: The topic GSNO gel increased significantly the clitoral blood flow and could be considered therapeutically in selected cases of female sexual dysfunction warranting further investigation. PMID- 20946174 TI - Comments on "Squamous cell carcinoma at the site of a Prince Albert's piercing". PMID- 20946175 TI - The effects of anti-TNF-alpha antibody on hyperprolactinemia-related suppression of hCG-induced testosterone release in male rats. AB - INTRODUCTION: Hyperprolactinemia (hyperPRL)-related hypogonadism or suppression of human chorionic gonadotropin (hCG)-induced testosterone (T) release is hypothesized to be mediated by a testicular interstitial macrophage and tumor necrosis factor alpha (TNF-alpha)-involved blockage. AIM: To test if the lower T response after hCG challenge in the hyperPRL rats is reversed by administrating anti-TNF-alpha antibody (Ab). METHODS: HyperPRL was induced by allografting two anterior pituitary (AP) glands per rat. Control rats were grafted with similar amount of cerebral cortex. The testicular interstitial cells (TIC) were isolated from the testis 6 weeks after grafting. TIC was treated with anti-TNF-alpha Ab with or without hCG. The other groups of rats received intra-testicular or intra muscular anti-TNF-alpha Ab 7 days before in vitro study. The TIC isolated from each testis was incubated and T release with or without hCG challenge were measured. MAIN OUTCOME MEASURES: Prolactin (PRL) and T were measured by radioimmunoassay. TNF-alpha was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: When low dose of anti-TNF-alpha Ab was administered to the TIC incubation, the effects of PRL-related suppression of hCG-stimulated T release were not significant. While a higher dose of anti-TNF-alpha Ab almost abolished the suppressive effects of PRL to hCG-stimulated T release. Prior intra testicular or intra-muscular administration of anti-TNF-alpha Ab reversed the suppressive effects of AP grafting on TIC's T release. This was demonstrated in groups with anti-TNF-alpha Ab injection both 7 and 1 day prior to TIC incubations. CONCLUSIONS: The data support the hypothesis that the suppression of hCG-induced T release associated with hyperPRL is through a TNF-alpha-mediated mechanism to suppress the Leydig cells. The effect of anti-TNF-alpha Ab is durable for at least 7 days. Besides intra-testicular injection, there might be other ways available for administrating Ab. Anti-TNF-alpha Ab has a potential therapeutic application on hyperPRL-induced hypogonadism or suppression of hCG induced T release. PMID- 20946176 TI - Tenderness as measured by pressure pain thresholds extends beyond the pelvis in chronic pelvic pain syndrome in men. AB - INTRODUCTION: Urological Chronic Pelvic Pain Syndrome (UCPPS) in men is a common complaint, and causes significant impairment in quality of life. Until recently, the focus of research has primarily been on pain symptoms or underlying prostate pathology. However, new clinical phenotyping demonstrates pelvic tenderness to be an important component of UCPPS. Unfortunately, mechanisms underlying tenderness remain to be understood, and tenderness itself has not been well quantified. AIM: To validate the use of pressure pain thresholds as a method of measuring tenderness in UCPPS and to demonstrate that tenderness extends beyond the pelvis. METHODS: Fifty-five men diagnosed with UCPPS and 46 healthy controls were recruited through referrals and advertisements. Each participant filled out questionnaires and was assessed by a structured interview. In addition, all UCPPS men underwent urological assessment. MAIN OUTCOME MEASURES: Demographic information was collected as well as the National Institutes of Health-Chronic Prostatitis Symptom Index. Using a digital algometer, pressure pain thresholds on 10 genito-pelvic and one control site (deltoid) were measured. The four-glass test was used for all UCPPS men. RESULTS: UCPPS men had reliably lower pain thresholds compared to controls in all locations, including the deltoid. UCPPS men also demonstrated consistently lower overall pain thresholds regardless of location. Furthermore, pressure pain thresholds were able to correctly distinguish patients from controls 77% of the time. Prostate infection did not influence pain thresholds. CONCLUSIONS: Lower pelvic and nonpelvic thresholds suggest the involvement of a central mechanism in UCPPS. Overall, the data confirm the move away from a prostate-based view of UCPPS. This is supported by the failure to find threshold differences related to prostate infection. Pressure pain thresholds appear to be a promising method of assessing tenderness in UCPPS. PMID- 20946177 TI - Melatonin plasma levels during sexual arousal and orgasm in males. PMID- 20946178 TI - Laboratory diagnosis of von Willebrand disease: results from a prospective and blind study in 32 laboratories worldwide using lyophilized plasmas. PMID- 20946179 TI - Invasive Streptococcus pneumoniae trigger platelet activation via Toll-like receptor 2. AB - BACKGROUND: Sepsis is the most common manifestation of invasive pneumococcal disease and is characterized by a severe systemic inflammatory state that leads to circulatory compromise or end organ malperfusion or dysfunction. Patients suffering from sepsis often display low platelet counts characterized by thrombocytopenia as a result of platelet activation. OBJECTIVE: To investigate the mechanism through which platelets become activated in sepsis upon binding to Streptococcus pneumoniae. PATIENTS AND METHODS: We determined S. pneumoniae inducible platelet reactivity using light transmission aggregometry. Dense granule secretion was measured by luminometry using a luciferin/luciferase assay. RESULTS: Streptococcus pneumoniae induced platelet aggregation in a strain dependent manner. Induction of aggregation was not attributable to capsule serotype, as unencapsulated strains also induced platelet aggregation. Platelet aggregation was not associated with pneumolysin toxin, as a pneumolysin-deficient mutant of S. pneumoniae induced aggregation equally as well as the parent strain. Platelet aggregation also occurred in the absence of plasma proteins or antibody, and was GPIIbIIIa dependent but aspirin independent. Toll-like receptor 2 (TLR2) is present on platelets and acts as a receptor for gram-positive bacterial lipoteichoic acid and peptidoglycan. Inhibition of TLR2 but not TLR4 (also present on platelets) completely abolished platelet aggregation. S. pneumoniae induced platelet aggregation resulted in activation of the PI3kinase/RAP1 pathway, leading to integrin GPIIbIIIa activation and dense granule release. CONCLUSIONS: Our results demonstrate a novel interaction between S. pneumoniae and TLR2, which results in platelet activation that is likely to contribute to the thrombotic complications of sepsis. PMID- 20946180 TI - Molecular weight fibrinogen variants alter gene expression and functional characteristics of human endothelial cells. AB - BACKGROUND: Fibrin is a temporary matrix that not only seals a wound, but also provides a temporary matrix structure for invading cells during wound healing. Two naturally occurring fibrinogen variants, high molecular weight (HMW) and low molecular weight (LMW) fibrinogen, display different properties in supporting angiogenesis in vivo and in vitro. OBJECTIVES: This study was aimed at investigating the functional characteristics and molecular mechanisms of human microvascular endothelial cells (HMVECs) cultured on HMW and LMW fibrin matrices. METHODS AND RESULTS: HMVECs on HMW fibrin matrices showed increased proliferation and tube formation as compared with their counterparts on unfractionated and LMW fibrin. Degradation of HMW fibrin was markedly enhanced by the presence of HMVECs, that of LMW fibrin was enhanced only slightly. However, the expression levels of fibrinolysis-regulating proteins and integrins were similar. Subsequent microarray analysis revealed that the expression of 377 genes differed significantly between HMVECs cultured on HMW fibrin and those cultured on LMW fibrin. Among these genes, UNC5B, DLL4 and the DLL4-Notch downstream targets Hey1, Hey2 and Hes1 showed increased expression in HMVECs on LMW fibrin. However, pharmacologic and genetic (DLL4 small interfering RNA) inhibition of DLL4-Notch signaling blunted rather than enhanced proliferation and tube formation by HMVECs on both fibrin variants. CONCLUSIONS: Heterogeneity in naturally occurring fibrinogen strongly influences endothelial cell proliferation and tube formation, and causes alterations in gene expression, including that of DLL4-Notch. The higher fibrinolytic sensitivity of HMW fibrin in the presence of HMVECs contributes to increased tube formation. Although the expression of DLL4-Notch was altered, it did not explain the enhanced tube formation in HMW fibrin. This study provides new perspectives for biological and tissue engineering applications. PMID- 20946181 TI - Is extensive screening for cancer in idiopathic venous thromboembolism warranted? AB - BACKGROUND: Patients with a first episode of idiopathic venous thromboembolism (IVTE) have an estimated 10% incidence of cancer within 12 months after diagnosis. However, the utility of screening for cancer in this population is controversial. METHODS: In this prospective concurrently controlled cohort study, limited and extensive cancer screening strategies were compared. All 630 patients underwent baseline screening consisting of history, physical examination, basic laboratory tests and chest X-ray. In the extensive screening group abdominal and chest CT scan and mammography were added. Outcomes were incidence and curability of cancer, and cancer-related and overall mortality. RESULTS: In 12 of the 342 (3.5%) patients in the extensive screening group malignancy was diagnosed at baseline compared with 2.4% (seven of 288 patients) in the limited screening group. Extensive screening detected six additional cancers (2.0%; 95% CI, 0.74 4.3), of which three were potentially curable. During a median 2.5 years of follow-up, cancer was diagnosed in 3.7% and 5.0% in the extensive and limited screening groups, respectively. In the extensive screening group 26 patients (7.6%) died compared with 24 (8.3%) in the limited screening group; adjusted hazard ratio 1.22 (95% CI, 0.69-2.22). Of these deaths 17 (5.0%) in the extensive screening group and 8 (2.8%) in the limited screening group were cancer related; adjusted hazard ratio 1.79 (95% CI, 0.74-4.35). CONCLUSIONS: The low yield of extensive screening and lack of survival benefit do not support routine screening for cancer with abdominal and chest CT scan and mammography in patients with a first episode of IVTE. PMID- 20946182 TI - Estimating the effect of medication adherence on health outcomes among patients with type 2 diabetes--an application of marginal structural models. AB - OBJECTIVE: We applied marginal structural models (MSMs) to estimate the effects of medication adherence with hypoglycemics on reducing the risk of microvascular complications in type 2 diabetic patients. METHODS: A retrospective longitudinal cohort study for type 2 diabetes patients was conducted using the California Medicaid claims database (1995-2002). Medication adherence and multiple time varying confounders were measured quarterly over a maximum of 7.5 years follow up. Cox regression models and MSMs results on the effect of compliance were compared. RESULTS: Of 4708 eligible patients, 2644 (56.2%) experienced microvascular complications during the follow-up period. After controlling for baseline covariates, standard Cox models estimated that adherence was associated with increased risk of complication with hazard ratio (HR) of 1.09 (95% confidence interval (CI): 1.00, 1.18). With adjustment of time-varying confounders as exogenous variables, the HR was 0.96 (0.88, 1.04). Using the MSM technique, the HR was 0.76 (95% bootstrap CI: 0.60, 0.92), indicating a significant benefit of medication adherence with hypoglycemics on the reduction of microvascular complications. This result contrasts with the negative results obtained in the hazard model, and is more consistent with prior clinical trial results CONCLUSION: Unlike conventional models, MSMs estimated that higher medication adherence may result in reduced risk of microvascular complications among patients with type 2 diabetes. PMID- 20946183 TI - Unexpected suppression of anti-Fya and prevention of hemolytic disease of the fetus and newborn after administration of Rh immune globulin. AB - BACKGROUND: Rh immune globulin (RhIG) has been used successfully for many years for the antenatal suppression of anti-D in D- mothers carrying D+ babies to prevent hemolytic disease of the fetus and newborn. Although the mechanism of RhIG-induced immunosuppression remains unknown, a recent report (TRANSFUSION 2006;46:1316-22) has shown that women receiving RhIG produce elevated levels of transforming growth factor (TGF)beta-1, a powerful immunosuppressant cytokine. It was suggested that induction of TGFbeta-1 and immunosuppression may be independent of cognate antigen recognition by RhIG. Herein, we present a description of a mother and baby that supports this hypothesis. STUDY DESIGN AND METHODS: Red blood cells and serum were analyzed using saline-tube indirect antiglobulin test methods. RhIG (RhoGAM) was administered after each amniocentesis performed at 28, 31, and 36 weeks' gestation. RESULTS: A group A, D (cde), K+, Fy(a-b+), MNs, Jk(a+b+) mother with no detectable anti-D had an anti Fy(a) titer of 4096 before RhIG but only 256 after RhIG. Mother gave birth to a group O, D-(cde), Fy(a+b+) healthy baby boy having a weak-positive direct antiglobulin test with anti-Fy(a) eluted from his cells and the titer in the cord serum was 4. CONCLUSION: This case demonstrates the potential immunosuppressive properties of RhIG for down regulation of a possible clinically significant alloantibody, not anti-D, where no D+ antigen is in the circulation of the mother. The case illustrates the potential utility for using RhIG to modulate antibody levels in situations other than for classical suppression of anti-D production. Although the mechanism in this case is unknown, TGFbeta-1-mediated or antibody-mediated immunosuppression to soluble nonparticulate antigens are possible mechanisms. PMID- 20946184 TI - Recent trends and geographic patterns of the burden of disease attributable to smoking. AB - PURPOSE: Quality-adjusted life-years (QALYs) use a single number to provide an assessment of the overall health burden of diseases associated both with mortality and morbidity. This study examined the trend and geographic variation of the burden of smoking by calculating smoking-related QALYs lost from 1993 to 2008 for the US adults and individual states. METHODS: Population health-related quality of life scores were estimated from the 1993 to 2008 Behavioral Risk Factor Surveillance System. The smoking-related QALYs lost are the sum of QALYs lost due to morbidity and future QALYs lost in expected life years due to premature deaths (mortality). RESULTS: From 1993 to 2008, the percent of US adults who smoked declined from 22.7% to 18.5%, but the smoking-related QALYs lost were relatively stable at 0.0438 QALYs lost per population. Although smoking contributed more QALYs lost for men (0.0535) than for women (0.0339), smoking related QALYs lost decreased by 2.5% for men but increased by 12.6% for women. Kentucky, Oklahoma, Mississippi, West Virginia, and Tennessee had the most smoking-related QALYs lost wheras Utah, California, Connecticut, Minnesota, and Hawaii had the least QALYs lost. The state tobacco tax rate was strongly and negatively associated with both the percent smoked (r = -0.60) and QALYs lost (r = -0.54), as well as the percentage change in both. CONCLUSIONS: This analysis quantified the overall burden of smoking for the nation and individual states from 1993 to 2008. Such data might assist in providing specified quantitative targets for the Healthy People 2020 smoking-related health objectives and for tracking changes on a yearly basis. PMID- 20946185 TI - Economic evaluations alongside effectiveness trials. PMID- 20946186 TI - Association of Doberman hepatitis to canine major histocompatibility complex II. AB - Doberman hepatitis (DH) is a chronic and progressive inflammatory liver disease that mainly affects female dogs. The high incidence of chronic hepatitis in Dobermans is suggestive of a genetic predisposition. DH is characterized by mononuclear cell infiltration and copper accumulation in the liver and major histocompatibility complex (MHC) class II antigen expression in the hepatocytes. In dogs, the MHC is referred to as the dog leukocyte antigen (DLA) system. In this study, the potential role of DLA genes in DH was investigated by sequence based typing in the exon 2 of DLA-DRB1, -DQA1 and -DQB1. The case group comprised 37 Dobermans with subclinical or clinical DH. The control group consisted of 37 healthy Dobermans, with normal liver enzyme values and without immunosuppressive medication. The control dogs were over 10 years old to include dogs with the lowest genetic risk of DH. Our results indicate that Dobermans with homozygous DLA-DRB1*00601/DQA1*00401/DQB1*01303 [odds ratio (OR) = 14.9, confidence limit (CL) = 3.1-71.7, P < 0.00005], especially with homozygosity for DLA-DRB1*00601 (P < 0.0005), are susceptible to DH. The DQ heterodimer DLA-DQA1*00901/DQB1*00101 and the allele DLA-DRB1*01501 appear to confer protection against DH (P < 0.001). Allele and haplotype frequencies were compared using chi-squared statistics. The disease shows a complex pattern of inheritance, but the observed DLA class II association with DH suggests a role for the immune system in the development of the disease. PMID- 20946187 TI - Methods for the collection of resource use data within clinical trials: a systematic review of studies funded by the UK Health Technology Assessment program. AB - BACKGROUND: The UK Health Technology Assessment (HTA) program funds trials that address issues of clinical and cost-effectiveness to meet the needs of the National Health Service (NHS). The objective of this review was to systematically assess the methods of resource use data collection and costing; and to produce a best practice guide for data capture within economic analyses alongside clinical trials. METHODS: All 100 HTA-funded primary research papers published to June 2009 were reviewed for the health economic methods employed. Data were extracted and summarized by: health technology assessed, costing perspective adopted, evidence of planning and piloting, data collection method, frequency of data collection, and sources of unit cost data. RESULTS: Ninety-five studies were identified as having conducted an economic analysis, of which 85 recorded patient level resource use. The review identified important differences in how data are collected. These included: a priori evidence of analysts having identified important cost drivers; the piloting and validation of patient-completed resource use questionnaires; choice of costing perspective; and frequency of data collection. Areas of commonality included: the extensive use of routine medical records and reliance on patient recall; and the use of standard sources of unit costs. CONCLUSION: Economic data collection is variable, even among a homogeneous selection of trials designed to meet the needs of a common organization (NHS). Areas for improvement have been identified, and based on our findings and related reviews and guidelines, a checklist is proposed for good practice relating to economic data collection within clinical trials. PMID- 20946188 TI - The use of sirolimus as a rescue therapy in pediatric intestinal transplant recipients. AB - To review our experience with SRL as a second-line therapy in our series of 45 SBTx recipients (1997-2009). Retrospective review of five children converted to SRL: 3 M/2 F; median of three yr old (range 20 months-18 yr); rescue indications, adverse events with SRL, resolution of tacrolimus-related side effects, incidence of rejection, PTLD, or GVHD were summarized. Tacrolimus was discontinued (average 13 months after transplant) because of refractory hemolytic anemia in four patients with decreased renal function and because of advanced renal failure and unclear neutropenia in one. PTLD and GVHD had been previously diagnosed in two. Tacrolimus-related side effects disappeared in all five although other immunosuppressants and splenectomy were used simultaneously or later in most of them. Adverse events reported after the conversion were infections (tuberculosis and Pneumocystis carinii in two) and mild hypertriglyceridemia. No rejection, GVHD, or PTLD episode was observed. Four patients are alive with excellent quality of life (median follow-up 18 months). Sirolimus is a safe rescue therapy in SBTx children when tacrolimus is not well tolerated. Renal function and hematologic disorders seem to improve, although other simultaneous strategies could be also involved. Further studies could demonstrate its efficacy as a first line treatment. PMID- 20946190 TI - The amino acid variation of HLA-A*02:182 in a highly conserved region is predicted to be functionally similar to HLA-A*02:01:01:01 allele. AB - We here describe the identification of the novel human leukocyte antigen allele HLA-A*02:182 which has been detected in a potential bone marrow donor. The new allele differs from the sequence of HLA-A*02:01:01:01 only by a non-synonymous nucleotide exchange of Guanin (G) -> Cytosin (C) at position 199 in exon 3 replacing amino acid (AA) Arginine (Arg, R) by Threonine (Thr, T) in codon 157. Since the HLA-A*02:01:01:01 allele differs from A*02:182 only at AA position 157, it is assumed that the protein structures of these alleles are highly similar. A mismatch between HLA-A*02:01:01:01 and HLA-A*02:182 is predicted to have a very low allogeneic potential in hematopoietic stem cell transplantation. PMID- 20946193 TI - Novel major histocompatibility complex class I alleles extracted from two rhesus macaque populations. AB - We report here the novel Mamu-A and -B alleles that were detected in two groups of rhesus monkeys. PMID- 20946191 TI - Cognitive and adaptive functioning after liver transplantation for maple syrup urine disease: a case series. AB - MSUD is a complex metabolic disorder that has been associated with central nervous system damage, developmental delays, and neurocognitive deficits. Although liver transplantation provides a metabolic cure for MSUD, changes in cognitive and adaptive functioning following transplantation have not been investigated. In this report, we present data from 14 patients who completed cognitive and adaptive functioning testing pre- and one yr and/or three yr post liver transplantation. Findings show either no significant change (n=8) or improvement (n=5) in IQ scores pre- to post-liver transplantation. Greater variability was observed in adaptive functioning scores, but the majority of patients evidenced no significant change (n=8) in adaptive scores. In general, findings indicate that liver transplantation minimizes the likelihood of additional central nervous system damage, providing an opportunity for possible stabilization or improvement in neurocognitive functioning. PMID- 20946192 TI - Tertiary excess of fibroblast growth factor 23 and hypophosphatemia following kidney transplantation. AB - Hypophosphatemia caused by inappropriate urinary phosphate wasting is a frequent metabolic complication of the early period following kidney transplantation. Although previously considered to be caused by tertiary hyperparathyroidism, recent evidence suggests a primary role for persistently elevated circulating levels of the phosphorus-regulating hormone, FGF23. In the setting of a healthy renal allograft, markedly increased FGF23 levels from the dialysis period induce renal phosphate wasting and inhibition of calcitriol production, which contribute to hypophosphatemia. While such tertiary FGF23 excess and resultant hypophosphatemia typically abates within the first few weeks to months post transplant, some recipients manifest persistent renal phosphate wasting. Furthermore, increased FGF23 levels have been associated with increased risk of kidney disease progression, cardiovascular disease, and death outside of the transplant setting. Whether tertiary FGF23 excess is associated with adverse transplant outcomes is unknown. In this article, we review the physiology of FGF23, summarize its relationship with hypophosphatemia after kidney transplantation, and speculate on its potential impact on long-term outcomes of renal allograft recipients. PMID- 20946194 TI - Use of the donor bladder trigone to facilitate pediatric en bloc kidney transplantation. AB - We performed three cases of donor bladder trigone facilitated transplantation using pediatric en bloc kidneys into adult recipients. The donors were aged 11, 21, and 23 months; two of the donors were male, and the other was a female. In each case, the donor bladder was removed and the trigone was fashioned into a patch that contained both ureters, which was attached to the recipient anterior bladder wall. The recipients of the two male donor transplants healed and have normal voiding with no evidence of vesico-ureteral reflux. At 14 and 12 months, they have a creatinine of 1.2 and 1.0 mg/dL. The recipient of the female donor transplant developed a pelvic abscess, which necessitated reconstruction of the donor ureters and patch. She is now nine months with a creatinine of 1.2 mg/dL and voiding well. The use of the donor bladder trigone to facilitate pediatric en bloc transplantation can be carried out safely using the male donor urinary tract. However, the use of a female donor for this procedure may be a special circumstance requiring increased attention to sterilize the small donor introitus and avoiding devascularization of the bladder trigone that is adherent to the anterior vaginal wall. PMID- 20946195 TI - A simple method for establishing concordance between short-tandem-repeat allele frequency databases. AB - BACKGROUND: Current paternity and forensic accreditation standards do not require concordance to be established between short-tandem-repeat allele frequency databases representing the same population. The current statistical methods for evaluating databases do not establish concordance. Although acceptable under current forensic statistical methods, databases representing the same population may have sufficient variation to influence the outcome of a nondirect relationship testing result (i.e., siblingship). Hence there is a need for a quantitative method to determine concordance between databases. STUDY DESIGN AND METHODS: Local allele frequency databases were generated for major US ethnic groups. Statistical analysis was performed as recommended by international forensic standards. A new method was developed and used for evaluating concordance between the locally developed and published databases. Smaller deviation values signify greater concordance between compared databases. The results were quantitatively confirmed against data obtained from a multidimensional scaling analysis system (SPSS, SPSS, Inc.). RESULTS: The locally developed database deviated from the mean of the published data by approximately 0.1073 for Caucasians, 0.1341 for US Hispanics, and 0.1287 for African Americans. Upon pairwise comparison, the published databases deviated from one another by 0.1210 in US Caucasians, 0.1457 in US Hispanics, and 0.1228 in African Americans. The local database was observed to be more concordant to published databases than some of the published data to themselves. CONCLUSION: The developed database was shown to be concordant with four previously published databases using the new method. The results were confirmed by comparison to qualitative data obtained from the multidimensional scaling analysis system. PMID- 20946196 TI - Identification of a new HLA-A*02 allele, HLA-A*02:230, using polymerase chain reaction sequence-based typing in a Chinese individual. AB - Nucleotide sequence of HLA-A*02:230 allele was different from that of HLA A*02:03:01 by a single nucleotide substitution at codon 139 (GCA > ACA), resulting in one amino acid change (Ala to Thr). PMID- 20946197 TI - Reduction in plasma transfusion after enforcement of transfusion guidelines. AB - BACKGROUND: The majority of fresh-frozen plasma (FFP) is transfused in the United States in the management of acquired bleeding disorders. The prothrombin time (PT), and its derivative the international normalized ratio (INR), is the most common test used to detect the presence and gauge the severity of these disorders. Observation studies have shown that the PT correlates poorly with clinical bleeding and that transfusion of plasma often achieves no measurable change in the INR nor is of any known clinical benefit. STUDY DESIGN AND METHODS: Data on FFP and red blood cell transfusions and measures of hospital activity and mortality were collected over a 12-year period. The first 3 years were baseline years, the next 3 years were physician education years, and in the last 6 years all requests for FFP were screened. Orders were discouraged if the INR was less than 2.0 in the absence of active bleeding and the use of vitamin K was encouraged if the patient was taking warfarin. RESULTS: This program ultimately resulted in an approximate 80% reduction in transfused FFP using the average of the baseline years compared to the average of the last 3 years (157 +/- 19 units FFP/1000 discharges vs. 30 +/- 15, p < 0.01, respectively). Overall, hospital activity remained largely unchanged or increased. No unexpected bleeding was reported, which was attributed to a failure to transfuse FFP, and inpatient mortality rate decreased during these 12 years. CONCLUSIONS: A program of engagement and interdiction using evidence-based guidelines can successfully decrease the use of FFP without any observable increase in unexpected bleeding. PMID- 20946198 TI - Human T-lymphotropic virus antibody screening of blood donors: rates of false positive results and evaluation of a potential donor reentry algorithm. AB - BACKGROUND: Blood donor screening with enzyme immunoassays (EIAs) for antibodies to human T-lymphotropic virus (HTLV)-I, and later to HTLV-I/II, has led to the unnecessary deferral of tens of thousands of individuals. The licensure of the Abbott PRISM HTLV-I/HTLV-II chemiluminescent immunoassay (ChLIA) may permit the reinstatement of historically deferred donors. STUDY DESIGN AND METHODS: The efficacy of a reentry algorithm involving a follow-up sample from EIA-deferred donors testing HTLV-I/II ChLIA nonreactive was evaluated using 386 serologic confirmed-positive samples archived since the inception of anti-HTLV donor screening. Reactivity of the 386 samples by the ChLIA, when coupled with the package insert sensitivity data, may be used to demonstrate efficacy of the reentry algorithm. Donor incidence was also examined from 2008 through 2009 to evaluate changes to the existing HTLV screening policy. RESULTS: From January 1, 1995, to April 28, 2008, a total of 64,052 donors to the American Red Cross were deferred solely because of HTLV EIA false positivity, representing more than 130,000 US donors. HTLV ChLIA identified 386 confirmed-positive donations from 386 randomly selected donors representing reactivity to both the bioMerieux and the Abbott HTLV-I/II EIAs (95% confidence interval [CI], 99.2%-100%); both EIAs have since been discontinued. This is comparable to the detection of 843 of 843 confirmed-positive samples during the ChLIA clinical trials (95% CI, 99.48% 100%). Incident HTLV infections occurred primarily among female repeat donors during 2008 throughout 2009. CONCLUSIONS: Donors testing falsely positive by historic EIAs since 1988 should be considered for reinstatement if a contemporary sample tests ChLIA nonreactive. Changes to the existing screening algorithm seem unlikely since new HTLV infections were detected among repeat donors. PMID- 20946199 TI - Transfusion-transmissible viral infections among US military recipients of whole blood and platelets during Operation Enduring Freedom and Operation Iraqi Freedom. AB - BACKGROUND: Current US military clinical practice guidelines permit emergency transfusions of non-Food and Drug Administration (FDA)-compliant freshly collected blood products in theaters of war. This investigation aimed to characterize the risks of transfusion-transmitted infections (TTIs) associated with battlefield transfusions of non-FDA-compliant blood products. STUDY DESIGN AND METHODS: US Service members who received emergency transfusion products in Iraq and Afghanistan (March 1, 2002-September 30, 2007) were tested for hepatitis C virus (HCV), human immunodeficiency virus (HIV), and hepatitis B virus (HBV) infections using reposed pre- and posttransfusion sera. Selected regions of viral genomes from epidemiologically linked infected recipients and their donors were sequenced and compared. RESULTS: Of 761 US Service members who received emergency transfusion products, 475 were tested for HCV, 472 for HIV, and 469 for HBV. One transfusion-transmitted HCV infection (incidence rate of 2.1/1000 persons) was identified. The pretransfusion numbers (prevalence per 1000 persons) were HCV four (8/1000), HIV-zero (0/1000), chronic HBV-two (4 /1000), and naturally immune (antibody to HBV core antigen)-nine (19/1000). CONCLUSION: One HCV TTI was determined to be associated with emergency blood product use. The pretransfusion HCV and HBV prevalence in transfusion recipients, themselves members of the potential donor population, indicates better characterization of the deployed force's actual donor population, and further investigations of the TTI prevalence in these donors are needed. These data will inform countermeasure development and clinical decision making. PMID- 20946200 TI - Randomized comparative study of group versus individual cognitive behavioural therapy for obsessive compulsive disorder. AB - OBJECTIVE: The primary aim of the study was to compare the effectiveness of group and individual cognitive behaviour therapy (CBT) for obsessive compulsive disorder (OCD). METHOD: One hundred and ten out-patients with OCD were randomly assigned to 15 sessions of either group CBT or individual CBT. Outcome measures were administered before and after treatment, as well as at 6- and 12-month follow-ups. The study was supplemented by a meta-analysis of accomplished comparative studies of group vs. individual CBT for OCD. RESULTS: Large and stable pre-post effect sizes were found for both treatment conditions in the study (d = 1.06-1.24 on the Yale-Brown Obsessive Compulsive Scale). There were no significant between-group differences in outcome at any data point (ds= -0.13 to 0.15). The meta-analysis of four accomplished comparative studies (including the present one) found a between-group mean effect size of (d= 0.15 favouring individual over group CBT at posttreatment (95% confidence interval, -0.12, 0.42). CONCLUSION: The results of this study suggest that OCD can be treated effectively with a group format of CBT, thus sparing some therapist resources, although the four accomplished comparative studies do not rule out the possibility of a small superiority of individually conducted CBT. PMID- 20946201 TI - A comparison of washed and volume-reduced platelets with respect to platelet activation, aggregation, and plasma protein removal. AB - BACKGROUND: Washed or volume-reduced platelets (PLTs) are occasionally requested for patients with a history of allergic or anaphylactic transfusion reactions. However, conclusive data are not available as to which method is more suitable. STUDY DESIGN AND METHODS: A direct comparison of saline-washed and volume-reduced PLTs was performed by splitting 11 units of 6-day-old apheresis PLT units. PLT activation, aggregation, plasma protein, and PLT count were determined before and after each procedure. To assess whether washing using neutral, calcium-free Ringer's acetate (NRA) would better preserve PLT function, 8 additional units of apheresis PLTs were split and were washed in saline or NRA. RESULTS: Saline washing resulted in significantly increased number of activated, P-selectin expressing PLTs compared to volume reduction (24.2% vs. 10.3%, p = 0.001). Aggregation was also significantly reduced (-40.6% vs. -0.8%, p = 0.004). Plasma protein removal was significantly better for saline-washed than volume-reduced PLTs (96% vs. 51.1%, p < 0.001). PLT recovery was not significantly different for saline-washed versus volume-reduced PLTs (70.5% vs. 80.7%, p = 0.079). There was no difference between washing in saline or NRA with regard to PLT activation and loss of aggregation. CONCLUSIONS: PLT washing with saline or NRA significantly increases PLT activation and decreases PLT aggregability. On the other hand, volume reduction does not adequately remove plasma proteins. Therefore, PLT washing should be reserved for patients with a history of severe allergic or anaphylactic transfusion reactions. We suggest that fresher PLTs be selected to improve the functionality of washed PLTs. PMID- 20946202 TI - The role of child sexual abuse in the etiology of suicide and non-suicidal self injury. AB - OBJECTIVE: To address the best available scientific evidence on the role of child sexual abuse in the etiology of suicide and non-suicidal self-injury. METHOD: Seven databases were searched, supplemented with hand-search of reference lists from retrieved papers. The author and a psychiatrist independently evaluated the eligibility of all studies identified, abstracted data, and assessed study quality. Disagreements were resolved by consensus. RESULTS: Four reviews, including about 65,851 subjects from 177 studies, were analyzed. There is evidence that child sexual abuse is a statistically significant, although general and non-specific, risk factor for suicide and non-suicidal self-injury. The relationship ranges from small to medium in magnitude and is moderated by sample source and size. Certain biological and psychosocial variables, such as serotonin hypoactivity and genes, family dysfunction, other forms of maltreatment, and some personality traits and psychiatric disorders, may either act independently or interact with child sexual abuse to promote suicide and non-suicidal self-injury in abuse victims, with child sexual abuse conferring additional risk, either as a 'distal' and indirect cause or as a 'proximal' and direct cause. CONCLUSION: Child sexual abuse should be considered one of the several risk factors for suicide and non-suicidal self-injury and included in multifactorial etiological models. PMID- 20946203 TI - Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies. AB - OBJECTIVE: Zuclopenthixol pharmacokinetics is incompletely characterised. We investigated potential interactions mediated through cytochrome P450 enzymes. METHOD: In vitro, we examined the impact of CYP2D6 and CYP3A4 inhibitors on zuclopenthixol metabolism in microsomes from six human livers. Subsequently, we compared dose-corrected serum zuclopenthixol concentrations in 923 samples from a therapeutic drug monitoring database from patients prescribed oral (n = 490) or injected (n = 423) zuclopenthixol alone or with fluoxetine, paroxetine, levomepromazine or carbamazepine. RESULTS: In vitro fluoxetine, paroxetine, ketoconazole and quinidine all significantly inhibited zuclopenthixol metabolism. Ketoconazole and quinidine together abolished zuclopenthixol disappearance. Clinically, dose-corrected oral zuclopenthixol serum concentrations increased significantly, after adjustment, by 93%, 78% and 46% during co-treatment with fluoxetine, paroxetine and levomepromazine and decreased 67% with carbamazepine. Carbamazepine caused dose-dependent reductions in the oral zuclopenthixol concentration-dose ratio (P < 0.001), fluoxetine (P < 0.001) and paroxetine (P = 0.011) dose-dependent increases and levomepromazine an increase related to its serum concentration (P < 0.001). Results for injected zuclopenthixol were similar but not all reached statistical significance. CONCLUSION: The In vitro study suggests zuclopenthixol is metabolised primarily by CYP2D6 and CYP3A4. The clinical study supports this, demonstrating the impact of co-prescribed inhibitors or inducers. Guidelines should incorporate these interactions noting the potential for zuclopenthixol-related toxicity or treatment failure. PMID- 20946204 TI - Acute kidney injury requiring dialysis secondary to adenovirus nephritis in renal transplant recipient. AB - Disseminated adenoviral infection is a serious problem, especially in an immunocompromised host. The disease carries a mortality rate reaching as high as 80%. It is seen most frequently in bone marrow transplant recipients, where it causes pneumonia and disseminated disease. In solid organ transplant recipients it causes graft infection. We report the case of a renal transplant recipient with disseminated adenoviral infection and acute kidney failure requiring dialysis. Reduction of immunosuppression and 1 dose of cidofovir were associated with resolution of viremia and viruria and return of kidney function to near baseline. PMID- 20946205 TI - Safety of dental implant surgery in patients undergoing anticoagulation therapy: a prospective case-control study. AB - OBJECTIVES: Several studies have described oral surgical procedures in patients receiving anticoagulant therapy, but no prospective studies on dental implant surgery during anticoagulant treatment are currently available, and only a limited number of case reports refer to endosseous dental implant treatment in these patients. In the setting of oral surgery, it has been suggested that anticoagulant treatment is not required when the International Normalized Ratio (INR) is <4 and local haemostatic measures are applied. The purpose of this preliminary study was to evaluate the incidence of bleeding complications following surgical implant therapy in a group of 50 consecutive patients receiving oral anticoagulant therapy (warfarin) without interruption or modifications to their therapy (group A). MATERIALS AND METHODS: One hundred and nine otherwise healthy patients comparable for age, sex, extent and site of the implant surgical procedure formed the control group (group B). In both groups, a standard protocol of local haemostasis, including non-reabsorbable sutures and compressive gauzes soaked with tranexamic acid, was applied. Surgeons, blind to the group allocation, performed all the procedures in an outpatient setting. RESULTS: Two and three late-bleeding complications were reported in group A and group B, respectively, without significant difference in the bleeding risk (relative risk = 1.45; P= 0.65; 95% confidence interval 0.2506-8.4271). These complications were managed using a compressive gauze soaked with tranexamic acid at the site of the surgical wound. CONCLUSION: According to our preliminary results, local haemostasis in dental implant surgery is able to prevent bleeding complications in patients on oral anticoagulants, allowing these surgical procedures to be performed on an outpatient basis. PMID- 20946206 TI - Retrospective study of two biochemical markers for the risk assessment of oral bisphosphonate-related osteonecrosis of the jaws: can they be utilized as risk markers? AB - PURPOSE: the purpose of this retrospective study was to examine the possibility of utilizing serum C-terminal telopeptide cross-link of type I collagen (s-CTX) and serum osteocalcin (s-OC) as risk markers for oral bisphosphonate-related osteonecrosis of the jaws (BRONJ). PATIENTS AND METHODS: the s-CTX values and the s-OC values were measured from 23 patients (one male, 22 females) diagnosed with BRONJ using clinical and radiographic examinations. The two biochemical markers were evaluated during a regular checkup for osteoporosis management. For the control group of s-CTX study, s-CTX values were obtained from 61 independently recruited postmenopausal women who have been on bisphosphonate therapy for >6 months. The s-CTX values of the ONJ group and the control group were compared. Because of retrospective nature of this study, the control group for s-OC study could not be established. A single sample t-test was performed for the s-OC value from the ONJ group. RESULT: twenty-three ONJ patients had taken alendronate for osteoporosis treatment, and the s-CTX testing results were low levels of 10-192 pg/ml (mean: 93.2 +/- 49.4 pg/ml). Mean of s-CTX of the control (n=61) was 125 +/ 85.7 pg/ml. The duration of BP therapy ranged between 1 and 10 years (4.82 +/- 2.6). The s-OC level was estimated between 0.2 and 5.4 ng/ml (1.91 +/- 1.51 ng/ml). The mean s-CTX value of the control group was higher but without significance (P=0.12). The s-OC values of the ONJ group were significantly lower than the lowest value of the reference range (P<0.001). CONCLUSION: as a result of the s-CTX and s-OC testings at the diagnosis of BRONJ, the values of the two markers were decreased. The decrease of the s-OC values implies a problem during the bone-formation process. Therefore, we can assume that in this patient group, invasive dental surgery contributes to an increase in the risk of BRONJ incidence. This result may imply that, during bisphosphonate therapy, simultaneous consideration of s-CTX showing inhibition of bone resorption and s OC indicating the degree of bone formation might be a set of risk markers assessing risk prediction for BRONJ before invasive dental surgery. PMID- 20946207 TI - Progress and trends in patients' mindset on dental implants. II: implant acceptance, patient-perceived costs and patient satisfaction. AB - OBJECTIVES: compared with widespread investigations on dental implant survival and biologic parameters, patient-based outcomes of implant dentistry have been neglected for years and are now becoming more popular. The aim of this representative opinion poll was to assess the up-to-date patients' mindset on dental implants and draw comparisons with the results published in 2003. MATERIAL AND METHODS: one thousand adults - representative for the Austrian population - were presented with a total of 16 questionnaire items regarding acceptance and subjectively perceived costs of dental implant treatment as well as patient satisfaction with implant-supported rehabilitation. RESULTS: the implant acceptance rate was 56%, while 23% of the interviewees decidedly rejected implant treatment (same rate as in 2003), especially those over 50 years of age. Only 5% had themselves undergone implant treatment and 22% reported to know someone fitted with implants. The estimated costs of implant treatment were significantly higher than those in 2003, and three-quarters felt that the prize was too high and that the sick fund or social security agencies should bear them. Satisfaction scores were significantly higher among interviewees wearing implant-supported rehabilitations compared with those with conventional fixed or removable dentures. CONCLUSIONS: little has changed in patients' attitude toward dental implants compared with the representative opinion poll in 2003. Neither implant acceptance nor implant prevalence in the Austrian population demonstrated upward trends. Professional public relations efforts are indicated to drop resentments and increase patient acceptance of dental implants as a treatment modality. PMID- 20946209 TI - Antral computerized tomography pre-operative evaluation: relationship between mucosal thickening and maxillary sinus function. AB - OBJECTIVES: to assess the correlation between maxillary sinus inferior mucosal thickening and sinus outflow obstruction. MATERIAL AND METHODS: the study included 280 computerized tomography (CT) scans (560 maxillary sinuses). CT aimed to assess sinusitis; trauma to the face and intubated patients were excluded. Mucosal thickening was graded as < 5 mm (1), < 10 mm (2), < 15 mm (3), < 20 mm (4) and > 20 mm (5), and classified by appearance as normal, rounded, circumferential, irregular, or complete. Maxillary sinus outflow was classified as patent or obstructed. RESULTS: mucosal thickening was found in 36.1% of the maxillary sinuses, graded as 31.2% (1), 34.2% (2), 12.9% (3), 5.4% (4) and 16.3% (5), and classified as rounded (11.8%), irregular (10.4%), circumferential (8.8%) and complete (5.2%). Sinus outflow was obstructed in 15% of the scans. Mucosal thickening of < 5 mm (11.1%), < 10 mm (36.2%) and > 10 mm (74.3%) was associated with sinus obstruction (P<0.0001). Rounded (6.1%), circumferential (55.2%), irregular (38.8%) and complete (100%) mucosal appearances were associated with sinus obstruction (P<0.001). When statistically combined, a substantial risk for sinus obstruction was observed with irregular mucosal appearance of > 5 mm (56.5% for grade 2 up to 82.6% for grades 3-5) and circumferential appearance (21.4% for grade 1 up to 100% for grades 3-5). A low risk for obstruction was found with the rounded appearance (mean 6.1%). CONCLUSIONS: irregular (> 5 mm), circumferential and complete mucosal appearance are associated with an increased risk for sinus outflow obstruction and an ENT consultation is recommended. A rounded mucosal appearance of any grade is associated with a low risk for sinus obstruction. Routine CT scans, including the maxillary sinus ostium, are recommended. PMID- 20946208 TI - Improvement in the osteoblastic cellular response to a commercial collagen membrane and demineralized freeze-dried bone by an amino acid derivative: an in vitro study. AB - PURPOSE: The objectives of this in vitro study were (1) to determine whether a commercially available collagen membrane (CM) or human demineralized freeze-dried bone (DFDB) particles adversely affected viability or function in cultured osteoblasts through oxidative stress, and, if so, (2) to determine whether N acetyl cysteine (NAC) successfully prevented loss of viability and dysfunction in osteoblasts. MATERIALS AND METHODS: Rat calvaria-derived osteoblasts were seeded onto polystyrene and commercially available CM (Cytoplast (r)) or DFDB (DynaGraft TM) with or without pretreatment with NAC solution. The osteoblastic response was evaluated using a flow cytometric cell viability assay, measurement of attached viable cell number, quantification of reactive oxygen species (ROS) and alkaline phosphatase (ALP) staining. RESULTS: The percentage of viable cells on CM was <50% at 24 h after seeding. However, this increased to 70% by pretreatment with NAC. The numbers of attached osteoblasts on DFDB remained at 60% the level of that on polystyrene at 24 h after seeding, but increased to up to 90% the level of that on polystyrene with NAC pretreatment. Although collagen materials increased intracellular ROS generation 1.5-5 times that with polystyrene, this was significantly reduced by NAC pretreatment. The percentage of the ALP-positive area was consistently 7% or less on CM and DFDB at days 7 and 14, which was restored by NAC pretreatment up to 60% or more. CONCLUSIONS: Commercially available CM and DFDB impaired osteoblastic viability and function and markedly increased intracellular ROS, indicating an oxidative stress-mediated negative impact on osteoblasts. Pretreatment with NAC substantially alleviated these cytotoxic effects. PMID- 20946210 TI - The effect of oestrogen and alendronate therapies on postmenopausal bone loss around osseointegrated titanium implants. AB - OBJECTIVES: This study evaluated the influence of oestrogen deficiency and its therapies on bone tissue around osseointegrated implants. METHODS: Implants were placed in 66 female rats tibiae. The animals were assigned into five groups: control (CTL), sham, ovariectomy (OVX), oestrogen (EST), and alendronate (ALE). While CTL was sacrificed 60 days after implant placement, other groups were subjected to ovariectomy or sham surgery according to group and euthanized after 90 days. Blood and urine samples were collected at sacrifice day for osteocalcin (OCN) and deoxypyridinoline (DPD) quantification. Densitometry of femur and lumbar vertebrae was performed in order to evaluate rats' skeletal impairment. Non-decalcified sections were referred to fluorescent and light microscopy for analyses of mineral apposition rate (MAR), eroded and osteoclastic surfaces, bone to-implant contact (BIC), and bone area fraction occupancy (BAFO). RESULTS: Results from the OVX group showed significantly lower bone mineral density (BMD), BIC, BAFO, and MAR, while OCN, deoxipiridinoline, eroded surface and ostecoclastic surface were increased compared with the other groups of the study. ALE reduced OCN and DPD concentrations, MAR, osteoclastic and eroded surfaces, and no difference was in BIC and BAFO relative to SHAM. EST and CTL showed similar results to SHAM for measurements. CONCLUSIONS: Oestrogen deficiency exerted a negative influence on bone tissue around implants, while oestrogen replacement therapy and alendronate were effective against its effects. Although alendronate therapy maintained the quantity of bone around implants, studies evaluating bone turnover kinetics are warranted. PMID- 20946212 TI - Service improvement in health care. PMID- 20946211 TI - Osseointegration and stability of a modified sand-blasted acid-etched implant: an experimental pilot study in sheep. AB - OBJECTIVE: The aim of this pilot study was to compare the early-term osseointegration characteristics of standard (SLA) and modified sand-blasted and acid-etched (modSLA) implants in an experimental animal model. MATERIAL AND METHODS: A total of 30 SLA and modSLA implants were placed to the tibiae of three sheep and the insertion torque value (ITV) and resonance frequency analysis (RFA) measurements were performed. RFA measurement was repeated on 3 and 6 weeks healed implants after which the animals were sacrificed for histomorphometric analysis. Bone-to-implant contact was assessed on the non-decalcified sections. Six weeks healed implants were also subjected to the reverse torque test (RTT). Results were analyzed by the Friedman test, Kruskal-Wallis test and Spearman rank correlation test. RESULTS: All implants reached to a strong primary stability with a mean 36.13 +/- 2.47 and 35.47 +/- 2.85 N/cm ITV. In the surgical stage, RFA values for SLA and modSLA implants were found to be 72.27 +/- 3.17 and 71.6 +/- 2.87, respectively. After 3 weeks of healing, mean BIC% (80.64 +/- 13.89%) and RFA value (76.8 +/- 1.14) of modSLA implants were significantly higher (P=0.0002) than that of SLA implants (64.39 +/- 21.2 BIC% and 74.2 +/- 4.76 RFA). However, no statistically significant difference between SLA and modSLA implants was recorded after 6 weeks of healing. Both implants revealed similar results in the RTT test (115.2 +/- 4.14 and 117 +/- 4.47 N/cm for SLA and modSLA implants, respectively). No correlation was found between RFA and BIC%. CONCLUSION: Within the limits of this pilot study, it can be concluded that modSLA implants achieve a higher bone contact and stability at earlier time points when compared with SLA implants. PMID- 20946213 TI - Creating an improvement culture for enhanced patient safety: service improvement learning in pre-registration education. AB - AIM: The present study reports a descriptive survey of nursing students' experience of service improvement learning in the university and practice setting. BACKGROUND: Opportunities to develop service improvement capabilities were embedded into pre-registration programmes at a university in the Northwest of England to ensure future nurses have key skills for the workplace. METHODS: A cross-sectional survey designed to capture key aspects of students' experience was completed by nursing students (n = 148) who had undertaken a service improvement project in the practice setting. RESULTS: Work organizations in which a service improvement project was undertaken were receptive to students' efforts. Students reported increased confidence to undertake service improvement and service improvement capabilities were perceived to be important to future career development and employment prospects. CONCLUSION: Service improvement learning in pre-registration education appears to be acceptable, effective and valued by students. Further research to identify the impact upon future professional practice and patient outcomes would enhance understanding of this developing area. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse Managers can play an active role in creating a service culture in which innovation and improvement can flourish to enhance patient outcomes, experience and safety. PMID- 20946214 TI - The hidden contribution of the health care assistant: a survey-based exploration of support to their role in caring for the acutely ill patient in the general ward setting. AB - AIM: To examine the feelings, support and feedback available to health care assistants (HCA) when caring for acutely ill ward patients. BACKGROUND: The role of the HCA continues to evolve with increased responsibility for patient care. Contextual issues that affect their contribution to acute care management of the ward patient have been given limited attention. METHODS: A survey of HCAs (n = 131) was conducted within two district general hospitals. RESULTS: There were a number of emotions and stressors associated with the care of acutely ill patients. While normal hierarchical systems were in place in order to obtain help HCAs additionally bypassed these normal channels. Support mechanisms included registered nurses, ward doctors, peers and family. Feedback regarding performance was limited. CONCLUSION: HCAs play a significant role in the care of the acutely ill patient. Feedback mechanisms need to be developed and associated emotions recognized. IMPLICATIONS FOR NURSING MANAGEMENT: HCAs support needs to be more evident and clinical feedback mechanisms need to be reviewed in order to improve care delivery. PMID- 20946215 TI - Structural empowerment and patient safety culture among registered nurses working in adult critical care units. AB - AIM: The aim of the present study was to examine the relationship between structural empowerment and patient safety culture among staff level Registered Nurses (RNs) within adult critical care units (ACCU). BACKGROUND: There is literature to support the value of RNs' structurally empowered work environments and emerging literature towards patient safety culture; the link between empowerment and patient safety culture is being discovered. METHODS: A sample of 257 RNs, working within adult critical care of a tertiary hospital in the United States, was surveyed. Instruments included a background data sheet, the Conditions of Workplace Effectiveness and the Hospital Survey on Patient Safety Culture. RESULTS: Structural empowerment and patient safety culture were significantly correlated. As structural empowerment increased so did the RNs' perception of patient safety culture. CONCLUSION: To foster patient safety culture, nurse leaders should consider providing structurally empowering work environments for RNs. IMPLICATIONS FOR NURSING MANAGEMENT: This study contributes to the body of knowledge linking structural empowerment and patient safety culture. Results link structurally empowered RNs and increased patient safety culture, essential elements in delivering efficient, competent, quality care. They inform nursing management of key factors in the nurses' environment that promote safe patient care environments. PMID- 20946216 TI - Factors contributing to nurse job satisfaction in the acute hospital setting: a review of recent literature. AB - AIM: To explore and discuss from recent literature the common factors contributing to nurse job satisfaction in the acute hospital setting. BACKGROUND: Nursing dissatisfaction is linked to high rates of nurses leaving the profession, poor morale, poor patient outcomes and increased financial expenditure. Understanding factors that contribute to job satisfaction could increase nurse retention. EVALUATION: A literature search from January 2004 to March 2009 was conducted using the keywords nursing, (dis)satisfaction, job (dis)satisfaction to identify factors contributing to satisfaction for nurses working in acute hospital settings. KEY ISSUES: This review identified 44 factors in three clusters (intra-, inter- and extra-personal). Job satisfaction for nurses in acute hospitals can be influenced by a combination of any or all of these factors. Important factors included coping strategies, autonomy, co-worker interaction, direct patient care, organizational policies, resource adequacy and educational opportunities. CONCLUSIONS: Research suggests that job satisfaction is a complex and multifactorial phenomenon. Collaboration between individual nurses, their managers and others is crucial to increase nursing satisfaction with their job. IMPLICATIONS FOR NURSING MANAGEMENT: Recognition and regular reviewing by nurse managers of factors that contribute to job satisfaction for nurses working in acute care areas is pivotal to the retention of valued staff. PMID- 20946217 TI - Transformational leadership and shared governance: an action study. AB - AIMS: The present study demonstrates the practical relevance of the concepts of transformational leadership as a Director of Nursing working with structure (shared governance) and active processes, informed by action research, to achieve the incremental breakthroughs associated with culture change in nursing. BACKGROUND: Responding to the context of a decade of health reforms in a New Zealand tertiary hospital, the leadership challenge, as a Director of Nursing, was to find ways of transforming the nursing workforce. How could nursing evolve from a relatively disempowered position within the organization (impact of the reforms) and reshape to achieve effectiveness within the new organizational culture? METHODS: Interwoven with transformational leadership are action processes progressively moving forward through cycles of reconnaissance, planning, implementation and evaluation. The principles of shared governance 'partnership', 'equity', 'accountability' and 'ownership' underpin and work synchronically with the active processes in advancing the effectiveness of nursing. It is leadership for and in action. This study is descriptive and exploratory overall, and more specifically it uses reflective practice and self reporting as methods. RESULTS: The outcomes of transformational leadership are evident in a confident, competent and committed nursing workforce which embraces continuous learning and expresses a professional respect for each other. CONCLUSIONS: The practical inter-weaving of the concepts of transformational leadership, shared governance and action processes provide a framework for sustainable change processes both at a unit and organizational level. IMPLICATIONS FOR NURSING MANAGEMENT: It is the interplay between the three concepts that generates a process of creative innovation, questioning and challenging existing structures to try and reach a new level of excellence through the participation and valuing of nurses and nursing practice. PMID- 20946218 TI - Supportive leadership in Swedish community night nursing. AB - AIM: The aim of the present study was to examine the support night nurses' give to staff in community night nursing. BACKGROUND: Studies have shown that support given to staff is one of night registered nurses' (RNs') experiences of the meaning of caring. This support, that community RNs display for staff in night time care, is sparsely described. METHODS: All community night-duty nurses in a medium-sized municipal in Sweden participated in the present study. Thematic content analysis was used to analyse data from observations. RESULTS: The support given by RNs to staff is described using three themes: (1) a conditional supporting stance, (2) preparing propitious conditions for caring and (3) confidence in the abilities of individual staff members and adaptation to their individual needs. The results reveal that RNs consider support to staff in terms of nursing leadership. CONCLUSIONS: Out of 'concern for the staff' the RNs try to be there for them, which corresponds to nursing leadership. Such concern also arises from the RNs' awareness that by giving support to staff this affects the staffs' caring for older people. IMPLICATIONS FOR NURSING MANAGEMENT: The current municipal social care organization of community nursing of older people in which RNs have extensive responsibilities with insufficient control, is a working condition with a risk for decreased quality of care and a high risk for work related stress syndrome. PMID- 20946219 TI - The Nursing and Midwifery Content Audit Tool (NMCAT): a short nursing documentation audit tool. AB - BACKGROUND: The Nursing and Midwifery Content Audit Tool (NMCAT) was developed to monitor the quality of nursing documentation. METHODS: A health care record audit was conducted on 200 records. Using a time-sampling approach, recent nursing documentation was examined. Inter-rater reliability was determined at 85% agreement between two raters. RESULTS: The NMCAT criteria relating to the recording of the patients' health status, use of objective information and logical presentation were met to a high level. The patients' response to treatment or nursing interventions including medications requires attention. The recording of events immediately after they have occurred was limited. The structure of the sentences and language used, restricted the readability of the documentation. The widespread use of local abbreviations, often connected together to form the text, was problematic. CONCLUSIONS: The present study provides new audit solutions based on time-sampling approaches and focused evidence-based criteria. The use of language support software and writing coaches to improve the presentation of nursing documentation is recommended. IMPLICATIONS FOR NURSING MANAGEMENT: The NMCAT is a time-efficient tool available to managers for monitoring the quality of nursing documentation, either at a unit level or across health facilities to demonstrate compliance with quality standards. PMID- 20946220 TI - Multigenerational workforce issues and their implications for leadership in nursing. AB - AIM(S): With many countries facing current or impending nursing shortages, considering the impact of the multigenerational workforce, their needs and behaviours may impact on efforts to recruit and retain nurses. BACKGROUND: As the nursing workforce changes, with ageing nurses, an increased demand for nursing care and an ageing population, greater emphasis is placed on an understanding of the workforce's needs and the differences highlighted by various generational groups. EVALUATION: Offered is a literature review and definitions of the four different generational groups evident in the current nursing workforce. These are offered as an insight into the different needs and attitudes that multigenerational groups bring to the nursing workforce. KEY ISSUE(S): Making the most of the multigenerational workforce and offering recommendations for meeting their unique challenges. CONCLUSIONS: Understanding the different generational groups may allow nursing leaders and managers to consider what drives, motivates or hinders nurses from different generations. IMPLICATIONS: Recruiting and retaining a workforce increasingly made up of nurses from many generational groups is a challenge that can be tackled with a deeper understanding of each of the commonly identified generational groups. PMID- 20946221 TI - Nurses' role in medication safety. AB - AIM: To explore the nurse's role in the process of medication management and identify the challenges associated with safe medication management in contemporary clinical practice. BACKGROUND: Medication errors have been a long standing factor affecting consumer safety. The nursing profession has been identified as essential to the promotion of patient safety. EVALUATION: A review of literature on medication errors and the use of electronic prescribing in medication errors. KEY ISSUES: Medication management requires a multidisciplinary approach and interdisciplinary communication is essential to reduce medication errors. Information technologies can help to reduce some medication errors through eradication of transcription and dosing errors. Nurses must play a major role in the design of computerized medication systems to ensure a smooth transition to such as system. CONCLUSION: The nurses' roles in medication management cannot be over-emphasized. This is particularly true when designing a computerized medication system. IMPLICATION FOR NURSING MANAGEMENT: The adoption of safety measures during decision making that parallel those of the aviation industry safety procedures can provide some strategies to prevent medication error. Innovations in information technology offer potential mechanisms to avert adverse events in medication management for nurses. PMID- 20946223 TI - Scientific information, journal impact factors and editorial policy. PMID- 20946222 TI - Meta-analysis of the reliability and validity of the Anticipated Turnover Scale across studies of registered nurses in the United States. AB - BACKGROUND: Globally, there are serious human and financial costs associated with registered nurse (RN) turnover. Anticipating turnover before turnover occurs is important to prevent costly and unnecessary turnover. Using a reliable and valid measure of anticipated turnover is essential to credible healthcare research on which nursing policy decisions are based. This meta-analysis provides a systematic way to determine the legitimacy of the use of the Anticipated Turnover Scale (ATS) in RN workforce research. AIMS: The aims of this meta-analysis were to determine the consistency of reliability estimates and evidence of construct validity of ATS scores across studies of RNs in the US. A secondary purpose was to evaluate variability in reliability and validity according to study quality, century within which studies were conducted and whether studies were published or unpublished. METHODS: Search strategies included accessing computerized databases, emailing researchers, consulting experts, footnote-chasing and accessing unpublished reports. Two independent reviewers examined studies according to inclusion criteria and quality. Consensus was reached on selected studies and quality ratings. RESULTS: Overall mean weighted effect size (MWES) of reliability from 12 studies was 0.89. Overall MWES of validity correlating the ATS and four job satisfaction measures for seven studies was -0.53. There was variability in reliability according to quality of studies. CONCLUSION: The ATS demonstrated excellent reliability and construct validity across studies of RNs in the US. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing management should consider the ATS in research on prevention of RN turnover. PMID- 20946224 TI - Steroids in thyroid eye disease. PMID- 20946225 TI - Low-level vagosympathetic nerve stimulation inhibits atrial fibrillation inducibility: direct evidence by neural recordings from intrinsic cardiac ganglia. AB - INTRODUCTION: We hypothesized that low-level vagosympathetic stimulation (LL-VNS) can suppress atrial fibrillation (AF) by inhibiting the activity of the intrinsic cardiac autonomic nervous system (ICANS). METHODS AND RESULTS: Wire electrodes inserted into both vagosympathetic trunks allowed LL-VNS at 10% or 50% below the voltage required to slow the sinus rate or atrioventricular conduction. Multielectrode catheters were attached to atria, atrial appendages and all pulmonary veins. Electrical stimulation at the anterior right and superior left ganglionated plexi (ARGP, SLGP) was used to simulate a hyperactive state of the ICANS. Effective refractory period (ERP) and window of vulnerability (WOV) for AF were determined at baseline and during ARGP+SLGP stimulation in the presence or absence of LL-VNS. Neural activity was recorded from the ARGP or SLGP. ARGP+SLGP stimulation induced shortening of ERP, increase of ERP dispersion and increase of AF inducibility (WOV), all of which were suppressed by LL-VNS (10% or 50% below threshold) at all tested sites. Sham LL-VNS failed to induce these changes. The effects of LL-VNS were mediated by inhibition of the ICANS, as evidenced by (1) LL-VNS suppression of the ability of the ARGP stimulation to slow the sinus rate, (2) the frequency and amplitude of the neural activity recorded from the ARGP or SLGP was markedly suppressed by LL-VNS, and (3) the spatial gradient of the ERP and WOV from the PV-atrial junction toward the atrial appendage was eliminated by LL-VNS. CONCLUSIONS: LL-VNS suppressed AF inducibility by inhibiting the neural activity of major GP within the ICANS. PMID- 20946226 TI - Temporal associations between thoracic volume overload and malignant ventricular arrhythmias: a study of intrathoracic impedance. AB - BACKGROUND: Acute exacerbations of heart failure (HF) are believed to trigger malignant ventricular arrhythmias, but the temporal association between fluid accumulation and ventricular arrhythmias has not been evaluated in an objective manner. We hypothesized that increased intrathoracic fluid accumulation in patients with HF, as measured by an index of intrathoracic impedance, is associated with an increased risk of ventricular arrhythmias. METHODS AND RESULTS: We analyzed interrogations in a cohort of 96 patients with left ventricular dysfunction (EF <= 35%) with devices that monitor intrathoracic impedance (OptiVol fluid index). Treated episodes of ventricular tachycardia or fibrillation (VT/VF) were adjudicated and stratified according to predetermined fluid index thresholds (OptiVol indices of 15, 30, 45, 60 Omega-days). VT/VF episodes occurred in 16 patients (17%). VT/VF was more common on days when the fluid index was elevated using threshold values of 15, 30, and 45 Omega-days (P = 0.006, 0.04, 0.02, respectively). There were no differences in the percent of time above any threshold between patients with and without VT/VF. CONCLUSIONS: In patients with HF who develop VT/VF, volume overload, as detected by an index incorporating changes in intrathoracic impedance, was temporally associated with malignant ventricular tachyarrhythmias. PMID- 20946228 TI - An alternative method of assessing bidirectional block for atrial flutter. AB - BACKGROUND: The success of cavotricuspid (CTI) ablation depends on the achievement of bidirectional block. Previous investigators have shown that right ventricular (RV) pacing can replace proximal coronary sinus (pCS) pacing in assessing clockwise CTI conduction block. OBJECTIVE: We sought to assess bidirectional conduction using antegrade (A-V) and retrograde (V-A) conduction times in the absence of coronary sinus (CS) pacing. METHODS: Counterclockwise CTI conduction block was evaluated using conduction time to the QRS from 2 pacing sites (immediately lateral and further lateral to the CTI). This was compared to the conduction time to the pCS with pacing from the same 2 lateral points. This was measured prior to ablation in 7 patients and 41 patients following ablation. To evaluate clockwise CTI conduction block we measured the conduction time to the 2 lateral sites during RV pacing and pCS pacing. This was measured in 7 patients prior to ablation and 16 patients following successful ablation. RESULTS: The abbreviated technique correctly indicated the presence or absence of bidirectional block in all patients. Furthermore, conduction times as assessed by the 2 methods correlated well both before and after creation of bidirectional block (correlation coefficients prior to ablation: clockwise direction r = 0.92, P = 0.0036; counterclockwise direction r = 0.86, P = 0.0132; after ablation: clockwise direction r = 0.82, P = 0.0001; counterclockwise direction r = 0.91, P < 0.0001). CONCLUSION: Bidirectional CTI conduction block can be successfully demonstrated using A-V and V-A conduction without the need for CS pacing. Patients need, however, to have intact A-V and V-A AV nodal conduction. PMID- 20946227 TI - Statin therapy for the prevention of atrial fibrillation trial (SToP AF trial). AB - BACKGROUND: Inflammation and oxidative stress are associated with atrial fibrillation (AF). Statins have antioxidant and anti-inflammatory properties. We tested if atorvastatin reduced AF recurrence after DC cardioversion (CV) by modifying systemic oxidative stress and inflammation (NCT00252967). METHODS AND RESULTS: In a randomized, double-blinded, placebo-controlled trial, patients with atrial fibrillation/flutter (AF) were randomized to receive either atorvastatin 80 mg (n = 33) or placebo (n = 31) before CV. Treatment was continued for 12 months or until AF recurred. Serum oxidative stress markers (ratios of oxidized to reduced glutathione and cysteine, derivatives of reactive oxygen species, isoprostanes) and inflammatory markers (high-sensitivity C- reactive protein [hs CRP], interleukin-6 [IL-6], interleukin-1beta[IL-1beta], tumor necrosis factor alpha [TNFalpha]) were measured at baseline and on follow-up. AF recurred in 22 (66.7%) of atorvastatin and 26 (83.9%) of placebo group (P = 0.2). The adjusted hazard ratio of having recurrence on atorvastatin versus on placebo was 0.99 (95% CI: 0.98-1.01, P = 0.3). There was no significant difference in the time to recurrence using Kaplan-Meier survival estimates (median [IR]: 29 [2-145] days versus 22 [7-70] days, P = 0.9). Although no significant effect was seen on oxidative stress, 2 of 4 inflammatory markers, IL-6 (adjusted OR: 0.59, 95% CI: 0.35-0.97, P = 0.04) and hs-CRP (adjusted OR: 0.59, 95% CI: 0.37-0.95, P = 0.03) were significantly lowered with atorvastatin. Cholesterol levels significantly decreased with atorvastatin (P = 0.03). CONCLUSIONS: High-dose atorvastatin did not reduce the recurrence of AF after CV. It reduced selective markers of inflammation without affecting systemic oxidative stress. Failure of atorvastatin to prevent AF recurrence may be due to its failure to affect oxidative stress. PMID- 20946230 TI - Posttraumatic left ventricular tachycardia arising from the anterior papillary muscle in an otherwise healthy child. AB - After being struck by a car at the age of 7, an otherwise healthy boy developed recalcitrant, albeit hemodynamically, well-tolerated ventricular tachycardia. An electrophysiological study with 3-dimensional electroanatomic mapping was performed under transesophageal echocardiographic guidance at 10 years of age. Nonautomatic focal ventricular tachycardia was mapped to the left anterolateral papillary muscle, where it was successfully ablated. To our knowledge, this report represents the first description of papillary muscle ventricular tachycardia in a child, and of blunt thoracic trauma as a potential trigger. PMID- 20946229 TI - Different patterns of atrial remodeling after catheter ablation of chronic atrial fibrillation. AB - BACKGROUND: Multiple remodeling patterns have been observed after catheter ablation of atrial fibrillation (AF). OBJECTIVE: We aimed to clarify the electrical/structural properties associated with recurrences after ablation of chronic AF. METHODS: After a stepwise ablation procedure in 120 consecutive patients with persistent/long-lasting persistent AF, 36 had a recurrence of AF (Group 1/Group 2: recurrence with paroxysmal/persistent AF, n = 16/20). RESULTS: During the first procedure, the left atrial (LA) bipolar voltage did not differ between the 2 groups, and the LA volume was smaller in Group 1 than in Group 2 and it was the only factor predicting the recurrent types (P = 0.009, OR = 1.04). In the second procedure, the bipolar voltage of the global left atrium increased (1.33 +/- 0.11 mV vs 1.76 +/- 0.16 mV, P = 0.001) in Group 1 and decreased (1.31 +/- 0.14 mV vs 0.90 +/- 0.12 mV, P = 0.01) in Group 2, when compared with that of the first procedure. The LA low-voltage area (<0.5 mV) decreased in Group 1, and increased in Group 2. The LA volume (90 +/- 8 cm(3) vs 72 +/- 8 cm(3), P = 0.002) decreased in the second procedure in Group 1. It remained the same in Group 2. The right atrial substrates did not change between the procedures. After a follow up of 27 +/- 3 months, all patients in Group 1 and 14 patients in Group 2 remained in sinus rhythm (P = 0.02). CONCLUSION: A better outcome with reverse electrical and structural remodeling occurred after the ablation of chronic AF when the recurrence was paroxysmal AF. Progressive electrical remodeling without any structural remodeling developed in those with a recurrence involving persistent AF. PMID- 20946231 TI - Tissue-specific variability in human epicardial impedance. AB - INTRODUCTION: Epicardial ablation can be employed to treat ventricular tachycardia. Voltage attenuation in regions of fat can mimic epicardial scar, limiting its specificity. Ablation over fat may not be as effective. Prior animal data have shown that infarcted myocardium has lower impedance than normal, and human bioimpedance studies suggest peripheral fat displays higher impedance. Therefore, we tested the hypothesis that human epicardial fat has higher impedance than myocardium when measured with standard ablation tools. METHODS: Patients undergoing elective surgery for coronary artery or valve disease were enrolled. A reference patch was placed on the patients' back between the scapulae and connected to a standard RF generator (Stockert, GmBH, Germany). Impedance was measured by passing a 1 MUA, 50 kHz current from the catheter tip to the patch. After sternotomy but before initiation of cardiopulmonary bypass, an ablation catheter (Celsius, Biosense Webster, Diamond Bar, CA, USA) was placed onto the epicardial surface in ventricular regions visually identified as fat or myocardium. At each site, impedance was recorded from the generator. RESULTS: A total of 37 (7 patients) points were sampled. Impedance was significantly higher in regions of fat versus normal muscle (697 Omega vs. 301 Omega; P = 0.01). Moreover, normal sites from the LV had higher impedance than from the RV (381 Omega vs. 271 Omega; P = 0.01). CONCLUSIONS: Human epicardial fat has higher tissue impedance than normal muscle. Using epicardial impedance and voltage mapping in conjunction may improve differentiation of arrhythmia substrate from epicardial fat and improve the efficacy of epicardial ablation. PMID- 20946232 TI - Contributions of a hemodynamic sensor embedded in an atrial lead in a porcine model. AB - INTRODUCTION: Preliminary studies have revealed a high correlation between peak endocardial acceleration (PEA) measured with a sensor embedded in a ventricular lead and human cardiac contractility. In this study we assessed (1) the contributions made by measurements of PEA1, an index of ventricular systolic contraction, from the right atrium, and (2) the feasibility of recording a fourth component of PEA (PEA4), coincident with atrial contraction and corresponding to the phonocardiographic fourth heart sound. METHODS: We placed a PEA sensor embedded at the tip of a right atrial lead in 9 pigs. A 7F Millar catheter tip micromanometer was introduced into the left ventricular (LV) cavity to measure dP/dt(max). Myocardial contractility was increased by infusion of dobutamine and depressed by the infusion of esmolol. We searched, during VDD pacing, for PEA4 following atrial systole, while gradually lengthening the atrioventricular delay. Ventricular fibrillation was then triggered by rapid stimulation. RESULTS: The changes in PEA1 were correlated with the changes in LV dP/dt(max) (r = 0.91; P < 0.001). A low-frequency component of the endocardial signal (PEA4) was visible approximately 50 milliseconds after the atrial electrogram in all experiments. Following the induction of ventricular fibrillation, PEA4 remained visible on the endocardial recording, simultaneous with the sensed atrial electrogram. CONCLUSIONS: This study confirms the merit of embedding a PEA sensor in an atrial lead. The exploitation of the information provided by the PEA1 signal remains pertinent and the possibility to record an additional PEA4 component offers the perspective of new clinical applications. PMID- 20946233 TI - Insecticide-treated bed nets in rural Bangladesh: their potential role in the visceral leishmaniasis elimination programme. AB - OBJECTIVE: To analyse the feasibility, acceptability and effectiveness of insecticide-treated bed nets with slow-release insecticides (KO Tab 123) as an option for kala-azar vector management in Bangladesh. METHODS: Intervention study involving an insecticide dipping programme through village health workers supervised by public health officers covering 6967 households in Mymensingh and 8287 in Rajshahi district. In a subsample of households, sandfly densities at baseline, 1, 12 and 18 months were measured with CDC light traps both in intervention and control areas. Bioassays were performed for determining the bioavailability of the insecticide and tests of chemical residues in the treated bed nets were undertaken. Satisfaction surveys and direct observation of use of treated bed net use were conducted. RESULTS: The dipping programme was feasible with the help of communities and public health staff, was well accepted, reached a coverage of 98.2% and 96.2% in the two study sites within 4 weeks and was effective in terms of a significant reduction in sandfly densities (approximately 60%) for a period of 18 months. Bioassay results were satisfactory (>80% sandfly mortality) and the average chemical content of the treated bed nets was sufficient for killing sand flies at the end of the observation period. CONCLUSION: Bed nets treated with slow-release insecticides can be an important complementary measure for sandfly control in the visceral leishmaniasis elimination programme. PMID- 20946234 TI - Sound stimulation modulates high-threshold K(+) currents in mouse auditory brainstem neurons. AB - The auditory system provides a valuable experimental model to investigate the role of sensory activity in regulating neuronal membrane properties. In this study, we have investigated the role of activity directly by measuring changes in medial nucleus of the trapezoid body (MNTB) neurons in normal hearing mice subjected to 1-h sound stimulation. Broadband (4-12 kHz) chirps were used to activate MNTB neurons tonotopically restricted to the lateral MNTB, as confirmed by c-Fos-immunoreactivity. Following 1-h sound stimulation a substantial increase in Kv3.1b-immunoreactivity was measured in the lateral region of the MNTB, which lasted for 2 h before returning to control levels. Electrophysiological patch clamp recordings in brainstem slices revealed an increase in high-threshold potassium currents in the lateral MNTB of sound-stimulated mice. Current-clamp and dynamic-clamp experiments showed that MNTB cells from the sound-stimulated mice were able to maintain briefer action potentials during high-frequency firing than cells from control mice. These results provide evidence that acoustically driven auditory activity can selectively regulate high-threshold potassium currents in the MNTB of normal hearing mice, likely due to an increased membrane expression of Kv3.1b channels. PMID- 20946235 TI - Investigating object representations during change detection in human extrastriate cortex. AB - Detecting a change in a visual stimulus is particularly difficult when it is accompanied by a visual disruption such as a saccade or flicker. In order to say whether a stimulus has changed across such a disruption, some neural trace must persist. Here we investigated whether two different regions of the human extrastriate visual cortex contain neuronal populations encoding such a trace. Participants viewed a stimulus that included various objects and a short blank period (flicker) made it difficult to distinguish whether an object in the stimulus had changed or not. By applying transcranial magnetic stimulation (TMS) during the visual disruption we show that the lateral occipital (LO) cortex, but not the occipital face area, contains a sustained representation of a visual stimulus. TMS over LO improved the sensitivity and response bias for detecting changes by selectively reducing false alarms. We suggest that TMS enhanced the initial object representation and thus boosted neural events associated with object repetition. Our findings show that neuronal signals in the human LO cortex carry a sustained neural trace that is necessary for detecting the repetition of a stimulus. PMID- 20946236 TI - Successful treatment of disseminated mixed invasive fungal infection after hematopoietic stem cell transplantation for severe aplastic anemia. AB - Concomitant infections are frequent and usually the causes of death in patients with severe AA. HSCT can restore hematopoiesis in AA, but it is usually life threatening when patients simultaneously have an IFI. Mixed IFIs have been reported on rare occasions. The exact diagnosis of IFIs is difficult because of low fungus culture rate, difficultly obtaining tissue specimens in severely immunocompromised patients or those with bleeding tendencies. Otherwise, treatment with anti-fungal drugs alone for DMIFI was always lethal in previous reports. Surgical resection is crucial for invasive zygomycosis, but severe pancytopenia and bleeding tendency make therapy difficult. Herein, we report that with a combination of aggressive anti-fungal drugs, HSCT, and surgery, we successfully treated a 10-yr-old boy with severe AA and pulmonary zygomycosis before HSCT and disseminated mixed invasive zygomycosis and aspergillosis after HSCT. PMID- 20946237 TI - No effect of systemic isocapnic hypoxia on alpha-adrenergic vasoconstrictor responsiveness in human skin. AB - Hypoxia impairs body temperature regulation and abolishes the decline in skin temperature associated with cold exposure, suggesting that cutaneous vasoconstriction is impaired. AIM: The purpose of this study was to test the hypothesis that cutaneous vasoconstriction to intradermal tyramine, an index of post-junctional vasoconstrictor responsiveness, is reduced during hypoxia. METHODS: Twelve subjects (six males, six females) had three microdialysis fibres placed in the ventral forearm. Fibres received either lactated ringers, 5 mm yohimbine (alpha-adrenergic blockade), or 10.5 MUm BIBP-3226 (to antagonize neuropeptide Y Y(1) receptors). Skin blood flow was assessed at each site (laser Doppler flowmetry) and cutaneous vascular conductance (CVC) was calculated (red blood cell flux/mean arterial pressure) and scaled to baseline. Vasoconstrictor responses to tyramine (173 MUm) were tested during normoxia and steady-state isocapnic hypoxia (SaO(2) = 80%) in random order. RESULTS: During normoxia, tyramine reduced CVC by 56.0+/-5.6 and 50.3+/-8.0% in control and BIBP-3226 sites (both P<0.05 vs. pre-tyramine; P=0.445 between sites) whereas CVC in the yohimbine site did not change (P=0.398 vs. pre-tyramine). During isocapnic hypoxia, tyramine reduced CVC by 55.9+/-5.1 and 54.2+/-5.4% in control and BIBP 3226 sites (both P<0.05 vs. pre-tyramine; P=0.814 between sites) whereas CVC was unchanged in the yohimbine site (P=0.732 vs. pre-tyramine). Isocapnic hypoxia did not affect vasoconstrictor responses at any site (all P>0.05 vs. normoxia). CONCLUSION: We conclude that post-junctional alpha-adrenergic vasoconstrictor responsiveness is not affected by hypoxia in non-acral skin. PMID- 20946238 TI - Physiological factors influencing capillary growth. AB - (1) Angiogenesis (growth of new capillaries from an existing capillary bed) may result from a mismatch in microvascular supply and metabolic demand (metabolic error signal). Krogh examined the distribution and number of capillaries to explore the correlation between O(2) delivery and O(2) consumption. Subsequently, the heterogeneity in angiogenic response within a muscle has been shown to reflect either differences in fibre type composition or mechanical load. However, local control leads to targetted angiogenesis in the vicinity of glycolytic fibre types following muscle stimulation, or oxidative fibres following endurance training, while heterogeneity of capillary spacing is maintained during ontogenetic growth. (2) Despite limited microscopy resolution and lack of specific markers, Krogh's interest in the structure of the capillary wall paved the way for understanding the mechanisms of capillary growth. Angiogenesis may be influenced by the response of perivascular or stromal cells (fibroblasts, macrophages and pericytes) to altered activity, likely acting as a source for chemical signals modulating capillary growth such as vascular endothelial growth factor. In addition, haemodynamic factors such as shear stress and muscle stretch play a significant role in adaptive remodelling of the microcirculation. (3) Most indices of capillarity are highly dependent on fibre size, resulting in possible bias because of scaling. To examine the consequences of capillary distribution, it is therefore helpful to quantify the area of tissue supplied by individual capillaries. This allows the spatial limitations inherent in most models of tissue oxygenation to be overcome generating an alternative approach to Krogh's tissue cylinder, the capillary domain, to improve descriptions of intracellular oxygen diffusion. PMID- 20946240 TI - Etiology of chronic leg ulcers in 31,619 patients in Germany analyzed by an expert survey. AB - BACKGROUND: The etiology of chronic leg ulcers is heterogenous and they exhibit quite different healing rates depending on the underlying cause. Although the prevalence and incidence of chronic leg ulcers appear to be increasing, data on these patients in Germany are lacking. PATIENTS AND METHODS: Altogether 100 German wound care professionals were asked to complete a questionnaire regarding the diagnosis and etiology of their patients with chronic leg ulcers. RESULTS: We received the data on 31,619 patients. In these patients, venous insufficiency was the dominating causative factor in 47.6 % and arterial insufficiency in 14.5 %, 17.6 % of ulcers were due to combined arterial and venous insufficiency. Rarer causes included vasculitis (5.1 %), exogenous factors (3.8 %), pyoderma gangrenosum (3.0 %), infection (1.4 %), neoplasia (1.1 %), calciphylaxis (1.1 %) and drug-induced (1.1 %). The used diagnostic methods used varied widely between the medical and surgical specialties. CONCLUSIONS: Even though the results of our study cannot claim to be a representative overview, they demonstrate clearly that next to known etiologies, e. g. chronic venous insufficiency or peripheral arterial insufficiency, which are relevant in 79.7 % of all patients a multitude of other causes exist, which are responsible in 20.3 % of all patients for the development of chronic leg ulcers. PMID- 20946241 TI - Review: sporadic cerebral amyloid angiopathy. AB - Cerebral amyloid angiopathy (CAA) may result from focal to widespread amyloid beta protein (Abeta) deposition within leptomeningeal and intracortical cerebral blood vessels. In addition, pericapillary Abeta refers to Abeta depositions in the glia limitans and adjacent neuropil, whereas in capillary CAA Abeta depositions are present in the capillary wall. CAA may cause lobar intracerebral haemorrhages and microbleeds. Hypoperfusion and reduced vascular autoregulation due to CAA might cause infarcts and white matter lesions. CAA thus causes vascular lesions that potentially lead to (vascular) dementia and may further contribute to dementia by impeding the clearance of solutes out of the brain and transport of nutrients across the blood brain barrier. Severe CAA is an independent risk factor for cognitive decline. The clinical diagnosis of CAA is based on the assessment of associated cerebrovascular lesions. In addition, perivascular spaces in the white matter and reduced concentrations of both Abeta(40) and Abeta(42) in cerebrospinal fluid may prove to be suggestive for CAA. Transgenic mouse models that overexpress human Abeta precursor protein show parenchymal Abeta and CAA, thus corroborating the current concept of CAA pathogenesis: neuronal Abeta enters the perivascular drainage pathway and may accumulate in vessel walls due to increased amounts and/or decreased clearance of Abeta, respectively. We suggest that pericapillary Abeta represents early impairment of the perivascular drainage pathway while capillary CAA is associated with decreased transendothelial clearance of Abeta. CAA plays an important role in the multimorbid condition of the ageing brain but its contribution to neurodegeneration remains to be elucidated. PMID- 20946239 TI - Transcellular and paracellular pathways of transepithelial fluid secretion in Malpighian (renal) tubules of the yellow fever mosquito Aedes aegypti. AB - Isolated Malpighian tubules of the yellow fever mosquito secrete NaCl and KCl from the peritubular bath to the tubule lumen via active transport of Na(+) and K(+) by principal cells. Lumen-positive transepithelial voltages are the result. The counter-ion Cl(-) follows passively by electrodiffusion through the paracellular pathway. Water follows by osmosis, but specific routes for water across the epithelium are unknown. Remarkably, the transepithelial secretion of NaCl, KCl and water is driven by a H(+) V-ATPase located in the apical brush border membrane of principal cells and not the canonical Na(+), K(+) -ATPase. A hypothetical cation/H(+) exchanger moves Na(+) and K(+) from the cytoplasm to the tubule lumen. Also remarkable is the dynamic regulation of the paracellular permeability with switch-like speed which mediates in part the post-blood-meal diuresis in mosquitoes. For example, the blood meal the female mosquito takes to nourish her eggs triggers the release of kinin diuretic peptides that (i) increases the Cl(-) conductance of the paracellular pathway and (ii) assembles V(1) and V(0) complexes to activate the H(+) V-ATPase and cation/H(+) exchange close by. Thus, transcellular and paracellular pathways are both stimulated to quickly rid the mosquito of the unwanted salts and water of the blood meal. Stellate cells of the tubule appear to serve a metabolic support role, exporting the HCO(3)(-) generated during stimulated transport activity. Septate junctions define the properties of the paracellular pathway in Malpighian tubules, but the proteins responsible for the permselectivity and barrier functions of the septate junction are unknown. PMID- 20946242 TI - Review: molecular pathogenesis of blood-brain barrier breakdown in acute brain injury. AB - Historically, the blood-brain barrier (BBB) was considered to be at the level of cerebral endothelium. Currently, the interaction of endothelium with other components of the vessel wall and with neurones and glial cells is considered to constitute a functional unit, termed the neurovascular unit that maintains cerebral homeostasis in steady states and brain injury. The emphasis of this review is on cerebral endothelium, the best-studied component of the neurovascular unit, and its permeability mechanisms in health and acute brain injury. Major advances have been made in unravelling the molecular structure of caveolae and tight junctions, both of which are components of the structural barrier to the entry of plasma proteins into brain. Time course studies suggest that caveolar changes precede junctional changes in acute brain injury. Additional factors modulating BBB permeability in acute brain injury are matrix metalloproteinases-2 and 9 and angiogenic factors, the most notable being vascular endothelial growth factor-A and angiopoietins (Ang) 1 and 2. Vascular endothelial growth factor-A and Ang2 have emerged as potent inducers of BBB breakdown while Ang1 is a potent anti-leakage factor. These factors have the potential to modulate permeability in acute brain injury and this is an area of ongoing research. Overall, a combination of haemodynamic, structural and molecular alterations affecting brain endothelium results in BBB breakdown in acute brain injury. PMID- 20946243 TI - Expression of delta-toxin by Staphylococcus aureus mediates escape from phago endosomes of human epithelial and endothelial cells in the presence of beta toxin. AB - Staphylococcus aureus is able to invade non-professional phagocytes by interaction of staphylococcal adhesins with extracellular proteins of mammalian cells and eventually resides in acidified phago-endosomes. Some staphylococcal strains have been shown to subsequently escape from this compartment. A functional agr quorum-sensing system is needed for phagosomal escape. However, the nature of this agr dependency as well as the toxins involved in disruption of the phagosomal membrane are unknown. Using a novel technique to detect vesicular escape of S. aureus, we identified staphylococcal virulence factors involved in phagosomal escape. Here we show that a synergistic activity of the cytolytic peptide, staphylococcal delta-toxin and the sphingomyelinase beta-toxin enable the phagosomal escape of staphylococci in human epithelial as well as in endothelial cells. The agr dependency of this process can be directly explained by the location of the structural gene for delta-toxin within the agr effector RNAIII. PMID- 20946245 TI - Novel interactions of a microbial superantigen with TLR2 and TLR4 differentially regulate IL-17 and Th17-associated cytokines. AB - Mycoplasma arthritidis, an inflammatory murine pathogen, secretes a potent superantigen, Mycoplasma arthritidis mitogen (MAM) that contributes to toxic shock, arthritis and skin necrosis. Previously we showed that MAM induced type 2 T-cell cytokines in mice that express functional TLR2 and TLR4, but type 1 cytokines in mice that lack TLR4 function. We show here that IL-17, pSTAT3 and retinoid-related orphan nuclear receptorgammat are rapidly expressed in wild-type C3H/HeSnJ (TLR2+/4+) mice but are significantly delayed in mutant C3H/HeJ (TLR2+/4-) mice. This marked kinetic difference was associated with a high level of IL-6 in TLR2+/4+ mice versus high levels of IL-1beta and TNFalpha in TLR2+/4- mice. Also antibodies to IL-6 and IL-23, suppressed IL-17 responses to MAM in TLR2+/4+ mice whereas anti-IL-1beta, but not anti-TNFalpha, enhanced IL-17 in TLR2+/4- mice. Antibody blocking of TLR4 in TLR2+/4+ mice decreased IL-17 and IL 6 but not IL-23. In addition both IL-17 and IL-6 but not IL-23 were elevated in TLR2 KO mice versus wild-type TLR2+/4+ mice given MAM. We conclude that the MAM interaction with TLR2 versus TLR4 leads to distinct cytokine pathways mediated primarily by IL-1beta or IL-6/IL-17 signalling respectively. Our findings suggest that the differential interaction of MAM with different TLRs might play an important role in disease outcomes by M. arthritidis. PMID- 20946244 TI - Role of CypA and Hsp90 in membrane translocation mediated by anthrax protective antigen. AB - Bacillus anthracis lethal toxin consists of the protective antigen (PA) and the metalloprotease lethal factor (LF). During cellular uptake PA forms pores in membranes of endosomes, and unfolded LF translocates through the pores into the cytosol. We have investigated whether host cell chaperones facilitate translocation of LF and the fusion protein LF(N)DTA. LF(N) mediates uptake of LF(N)DTA into the cytosol, where DTA, the catalytic domain of diphtheria toxin, ADP-ribosylates elongation factor-2, allowing for detection of small amounts of translocated LF(N)DTA. Cyclosporin A, which inhibits peptidyl-prolyl cis/trans isomerase activity of cyclophilins, and radicicol, which inhibits Hsp90 activity, prevented uptake of LF(N)DTA into the cytosol of CHO-K1 cells and protected cells from intoxication by LF(N)DTA/PA. Both inhibitors, as well as an antibody against cyclophilin A blocked the release of active LF(N)DTA from endosomal vesicles into the cytosol in vitro. In contrast, the inhibitors did not inhibit cellular uptake of LF. In vitro, cyclophilin A and Hsp90 bound to LF(N)DTA and DTA but not to LF, implying that DTA determines this interaction. In conclusion, cyclophilin A and Hsp90 facilitate translocation of LF(N)DTA, but not of LF, across endosomal membranes, and thus they function selectively in promoting translocation of certain proteins, but not of others. PMID- 20946246 TI - Profile and competences for the graduating European dentist - update 2009. AB - This paper presents the profile and competences for the European Dentist as approved by the General Assembly of the Association for Dental Education in Europe at its annual meeting held in Helsinki in August 2009. A new taskforce was convened to update the previous document published in 2005. The updated document was then sent to all European Dental Schools, ministries of health, national dental associations and dental specialty associations or societies in Europe. The feedback received was used to improve the document. European dental schools are expected to adhere to the profile and the 17 major competences but the supporting competences may vary in detail between schools. The document will be reviewed once again in 5 years time. Feedback to the newly published document is welcomed and all dental educators are encouraged to draw upon the content of the paper to assist them in harmonising the curriculum throughout Europe with the aim of improving the quality of the dental curriculum. PMID- 20946247 TI - OSCEs in Japanese postgraduate clinical training Hiroshima experience 2000-2009. AB - BACKGROUND: Hiroshima University Hospital used the Objective Structured Clinical Examination (OSCE) as a formative and summative assessment tool to evaluate trainees' competence. AIM: To reflect on Hiroshima University Hospital experience of OSCEs in postgraduate training in terms of OSCE structure and trainees' perception of the OSCE they attended. METHODS: A total 27 OSCEs implemented in Hiroshima University Hospital from 2000 to 2009 were examined. The OSCE in postgraduate training, Hiroshima University Hospital, was influenced by many factors from organisational and pedagogical perspectives, and changed to meet social and curriculum needs. At each OSCE, all examinees were required to answer an anonymous questionnaire, which consisted of ten checklists, just after their experience of OSCE. RESULTS: Five hundred and forty trainees who attended each OSCE were required to answer a questionnaire and 510 were returned (94.4%). In the comparison between formative and summative OSCEs, the number of trainees who answered "the OSCE is meaningful" in formative OSCE was significantly higher than that in summative OSCE (P < 0.001). In the comparison between before and after the 2006/2007 academic year, trainees who indicated that OSCEs were meaningful increased after 2006/2007 (P < 0.05), and trainees who felt they were evaluated appropriately by these OSCEs increased after 2006/2007 (P < 0.01). CONCLUSION: Trainees viewed OSCEs positively and appreciated their effectiveness from a pedagogical perspective, and OSCE positively affected the trainees' approach to learning. A ten-year process of OSCE change has helped with educational reforms because of its adaptability. Flexible attitudes to change are necessary for stakeholders to achieve the desired reforms. PMID- 20946248 TI - A generic consensus assessment of undergraduate competence in forceps exodontia in the United Kingdom. AB - The assessment of competence in clinical skills has become more frequent in published healthcare curricula and syllabuses recently. There are agreed mechanisms for the assessment of competence in the post-graduate environment, but no consensus within the undergraduate curriculum. This paper seeks to develop an agreed generic checklist for the assessment of competence in forceps exodontia. MATERIALS AND METHODS: A modified Delphi process was undertaken with representatives from all UK dental schools (n = 13) to develop a generic checklist for the assessment of competence in forceps exodontia. A content analysis of the assessments employed by each school was used to help discussion and inform the Delphi process. RESULTS: Seven schools currently employ a summative assessment of competence in forceps exodontia, with the majority employing a structured clinical objective test (n = 6). From the seven assessments, there were a total of 29 putative items and 10 putative domains identified for a generic checklist. These were reduced to five domains and 19 items through the content analysis and Delphi process, and a generic overarching checklist was created. CONCLUSION: Using this generic checklist, it may now be possible to pool data inter-institution to perform more powerful analyses on how our students obtain, or fail to obtain competence in forceps exodontia. PMID- 20946249 TI - Admission systems to dental school in Europe: a closer look at Flanders. AB - Dental education in Europe faces enormous challenges. One deals with the admission to dental school. Although admission procedures vary considerably across Europe, a characteristic of some systems is that the same procedure is used across students who will ultimately pursue different majors (medical or dental). This is based on the assumptions that there is no significant difference in these students' scores and that the requirements for medicine and dentistry are equal. This study examines these assumptions in the admission exam 'Medical and Dental Studies' in Flanders. Students who pass may choose whether they start medical or dental education. Over an 8-year period (2000-2007), admission exam scores of students starting medicine (n = 4492) were compared to those of students starting dentistry (n = 547). Second, the validity of this exam is examined for both medical and dental education. It was found that students starting dentistry had a significantly lower total score on the admission exam than students starting medicine. Differences were especially striking for the cognitive part of the admission exam. For both medical and dental students, the admission exam score was a valid predictor of academic grades in the first 3 years, although correlations were lower for dental education. These results have implications for admission procedures in countries where the same system is used for both majors. The findings that students who have a lower score choose dental education and that the validity of the exam is slightly lower for dentistry, raise questions about using the same admission exam for two obviously different majors. PMID- 20946250 TI - Description and evaluation of a new approach on pre-clinical implant dentistry education based on an innovative simulation model. AB - INTRODUCTION: Predominantly theoretical courses are employed to teach German dental students in implant dentistry at pre-clinical stage. As implant dentistry is an important part of the clinical treatment spectra, practical implementation of this field at an early stage of education seems to be appropriate. By a newly developed interdisciplinary implant dentistry course, students should assess an improved competence level as well as first practical experiences in the field of implant dentistry at the pre-clinical stage of their education. MATERIALS AND METHODS: Interdisciplinary implant dentistry education was integrated in the final pre-clinical course Phantom II at the Department of Prosthodontics, LMU, Munich. In total 120 pre-clinical students participated at the implant dentistry education course. After theoretical introduction into implant surgery and implant prosthetics, 30 simulation units were employed for the practical training of the participants. All important treatment steps were carried out by the students under instruction by the supervisors, including interdisciplinary planning, the use of the drilling template, the template guided insertion of two implants, as well as the integration of two ball attachments into a pre-existing full denture. After the course participants were asked by questionnaire about the quality of the course and their personal opinion. RESULTS: The course received an extraordinary positive feedback. In total 108 students evaluated the course with the overall grade of 1.68 according to the German school-mark system (1 = excellent, 6 = unsatisfactory). Also the single parts of the course were voted constantly positively. CONCLUSION: The aim of this first interdisciplinary course for pre-clinical students was to enhance competence level and practical implementation of implant dentistry at an early stage of education. Participants' comments and suggestions on the questionnaires demonstrated the positive response and the general interest in this form of dental education, as well as the demand for further development of training in this field. PMID- 20946251 TI - Participation in continuing professional development by dental practitioners in Victoria, Australia in 2007. AB - BACKGROUND: Mandatory continuing professional development (CPD) was introduced in 2005 in Victoria, Australia to ensure that dental practitioners maintained their skills, knowledge and kept up-to-date with current topics in dentistry. The aim of this study was to investigate the participation, impact on practice and attitudes of Victorian dentists and dental specialists to CPD activities since the commencement of mandatory CPD. METHODS: A cross-sectional survey of a random sample of registered dentists and dental specialists (n = 895) was conducted from May to August 2008 using an anonymous, postal, self-administered questionnaire. RESULTS: The response rate was 66%. More than three quarters of practitioners believed mandatory CPD is a reasonable requirement for continued registration. Dentists reported attending an average of 30.9 h of certifiable clinical CPD whilst specialists attended an average of 33.2 h of certifiable clinical CPD over a 12-month period. Nearly three quarters of respondents reported changing their practice as a result of CPD activities, whilst one quarter attended CPD mainly to meet the mandatory requirements. CONCLUSIONS: Overall there was a positive attitude towards mandatory CPD and a high level of participation in CPD activities by Victorian dentists and specialists in 2007, although nearly half of the respondents attended <20 h of certified clinical CPD during 2007. A number of barriers exist, particularly for rural and female practitioners in accessing CPD, and further research is required to examine the benefits derived from mandatory CPD. PMID- 20946252 TI - Dental nurses as trainers and assessors: vocational dental trainer attitudes. AB - AIM: To explore the attitudes of vocational dental trainers (VDTs) working in general dental practice to the role of dental nurses as trainers and assessors of trainee dental nurses (tDNs), vocational dental practitioners (VDPs) and vocational dental hygienist/therapists (VDHTs). METHOD: This research was conducted within the context of the development of a training and assessment qualification for dental nurses. A survey was sent to all 148 VDTs in Scotland. The survey assessed VDT attitudes as to the appropriateness of dental nurses to train and assess tDNs, VDPs, VDHTs with regard to their clinical, communication based and administrative duties. The three sets of attitudes for tDNS, VDPS and VDHTs were assessed on a five-point Likert scale ranging from 1 (strongly disagree) to 5 (strongly agree). The data were subjected to one way and repeated measures of ANOVA. RESULTS: A total of 126 VDTs responded giving an 85% response rate. For clinical, communication-based and administrative activities, VDTs had significantly greater mean scores for the appropriateness of DNs to train [F(1,57) = 45.69, P < 0.001] and assess [F(1,57) = 76.94, P < 0.001] tDNs compared with VDPs and VDHTs. CONCLUSION: Vocational dental trainers felt it was more appropriate for DNs to train and assess tDNs' clinical, communication-based and administrative activities compared with VDPs and VDHTs. Over 80% of dental trainers, however, indicated there would be benefit to their practice in having a dental nurse educated in the principles and application of training and assessment. PMID- 20946253 TI - Differences in the perception of seven behaviour-modifying techniques in paediatric dentistry by undergraduate students using lecturing and video sequences for teaching. AB - Whilst preparing undergraduate students for a clinical course in paediatric dentistry, four consecutive classes (n = 107) were divided into two groups. Seven behaviour-modifying techniques were introduced: systematic desensitization, operant conditioning, modelling, Tell, Show, Do-principle, substitution, change of roles and the active involvement of the patient. The behaviour-modifying techniques that had been taught to group one (n = 57) through lecturing were taught to group two (n = 50) through video sequences and vice versa in the following semester. Immediately after the presentations, students were asked by means of a questionnaire about their perceptions of ease of using the different techniques and their intention for clinical application of each technique. After completion of the clinical course, they were asked about which behaviour modifying techniques they had actually used when dealing with patients. Concerning the perception of ease of using the different techniques, there were considerable differences for six of the seven techniques (P < 0.05). Whilst some techniques seemed more difficult to apply clinically after lecturing, others seemed more difficult after video-based teaching. Concerning the intention for clinical application and the actual clinical application, there were higher percentages for all techniques taught after video-based teaching. However, the differences were significant only for two techniques in each case (P < 0.05). It is concluded that the use of video based teaching enhances the intention for application and the actual clinical application only for a limited number of behaviour-modifying techniques. PMID- 20946254 TI - Cis-acting allelic variation in MUC5B mRNA expression is associated with different promoter haplotypes. AB - Mucins play a critical role in protecting and clearing the airways of noxious materials. Genetic variation that influences this environmental response is likely to affect respiratory disease susceptibility. It has been reported previously that variation in the promoter of MUC5B, the gene that encodes one of the two major gel-forming mucins (MUC5B) of the mucus of the respiratory tract, is associated with susceptibility to diffuse panbronchiolitis, and that a genetic difference in promoter activity can be detected in vitro. The aim of this study was to determine whether this genetic difference in promoter activity can be detected in vivo. Here, we undertake RNA transcript expression studies, making use of human fetal tissue to explore constitutive differences. We compare in vivo transcript expression levels in heterozygotes and use the Bayesian method, PHASE to associate exonic simple nucleotide polymorphisms (SNPs) with promoter SNPs to generate haplotypes. We successfully show haplotypic differences in MUC5B expression in vivo. This genetic variation should be taken into account in future studies on MUC5B in respiratory disease. PMID- 20946255 TI - A novel polymorphic AP-1 binding element of the GFAP promoter is associated with different allelic transcriptional activities. AB - The Glial Fibrillary Acidic Protein (GFAP) gene encodes a cytoskeletal protein belonging to the intermediate filament family whose expression is considered as a marker of astrocytes differentiation. GFAP expression, shown to be upregulated as a consequence of brain gliosis, depends on hormones, growth factors, cytokine, and transcription factors and, among these latters, activator protein 1 (AP-1) has been demonstrated to play a crucial role. In this study, we have focused on a 2.2 kb sequence of the regulatory region located upstream of the GFAP gene, searching in a panel of control individuals for single-nucleotide polymorphisms (SNPs) that could modulate GFAP transcription. Among four SNPs of the GFAP promoter whose alleles have been predicted by in silico analysis to induce differences in the pattern of binding transcription factors, we have identified a new AP-1 binding site lying at -250 bp upstream from the GFAP transcriptional start site. The two alleles of this polymorphic locus have shown to bind the AP-1 complex to different extents, thus promoting variable transcriptional activities of the GFAP promoter. Therefore, these SNP alleles may, among others, mediate the effects of GFAP mutations, thus explaining the phenotypic heterogeneity of Alexander disease. PMID- 20946256 TI - Assessment of genetic ancestry and population substructure in Costa Rica by analysis of individuals with a familial history of mental disorder. AB - The population of Costa Rica has been considered valuable for locating susceptibility genes of complex disorders because of historical events and a gradual admixture process. We present an assessment of 426 unrelated individuals with a familial history of mental disorder and with ancestors born in the Central Valley, genotyped at 730 microsatellites to evaluate genetic diversity, ancestry, and substructure at the general and regional population levels using quantitative methods. Low population substructure was found. Estimated mean ancestry proportions were 54%, 32%, and 13% for European, Amerindian, and African components, respectively, with some regional variation. The F(ST) values obtained confirm the largest genetic similarity to Europeans. Subdivision of the Amerindians into individual populations revealed strong similarity to Chibchan groups. Analysis of the African ancestry showed high similarity to West and Central African populations. Gene ancestries from other African areas were also detected, probably resulting from ancestral admixture within Africa prior to colonial times. Our analyses show, in an ethnohistorical-genetic context, that gene flow and admixture are important components of Costa Rican population history. The results confirm the need to consider the particular regional genetic structure, the effects of genetic drift and the ancestry when designing and interpreting investigations of genetic traits in this population. PMID- 20946257 TI - Detecting gene duplications in the human lineage. AB - Gene duplications represent an important class of evolutionary events that is likely to have contributed to the unique human phenotype in the short evolutionary time since the human-chimpanzee divergence. With the availability of both human and chimpanzee genome drafts in high coverage re-sequencing assemblies and the high annotation quality of most human genes, it should now be possible to identify all human lineage-specific gene duplication events (human inparalogues) and a few pioneering studies have attempted to do that. However, the different levels of coverage in the human and chimpanzee's genomes assemblies, and the differing levels of gene annotation, have led to problematic assumptions and oversimplifications in the algorithms and the datasets used to detect human lineage-specific gene duplications. In this study, we have developed a set of bioinformatic tools to overcome a number of the conceptual problems that are prevalent in previous studies and have collected a reliable and representative set of human inparalogues. PMID- 20946258 TI - Simvastatin inhibits glucose-stimulated vascular smooth muscle cell migration involving increased expression of RhoB and a block of Ras/Akt signal. AB - BACKGROUND: Diabetic patients are at high risk to develop atherosclerotic cardiovascular disease and have a higher restenotic rate after percutaneous coronary intervention (PCI). Statins improve cardiovascular outcome and reduce restenosis after PCI by inhibiting proliferation and migration of vascular smooth muscle cells (VSMCs). But the effect of statins on diabetes without dyslipidemia was still not fully understood. Our previous study has demonstrated that simvastatin inhibits VSMC proliferation in high glucose status without dyslipidemia, inducing a G0/G1 phase cell cycle growth arrest by acting on multiple steps upstream of pRb, including inhibition of CDK2/4 expression and upregulation of p53, p21, p16, and p27. METHOD: Following our previous study, we investigated the mechanism of simvastatin inhibition of VSMC migration in a diabetes-like model (A7r5 cells under high glucose conditions without dyslipidemia). RESULTS: Under high glucose conditions, simvastatin dose dependently inhibited VSMC migration, decreased PI3K/Akt pathway activity, reduced c-Raf and Ras expression, increased RhoB but not RhoA, Rac1, and Cdc2 expression, dose-dependently inhibited MMP-2, but not MMP-9, activity, and dose dependently inhibited NF-kappaB activity. CONCLUSION: The inhibition of VSMC migration under high glucose conditions was via two different pathways. The first pathway is mevalonate-related but not RhoA protein-related and involves suppression of Ras and PI3K/Akt signals. The second pathway is not mevalonate related and involves increasing RhoB expression directly. PMID- 20946260 TI - Extracellular protease expression in Microsporum gypseum complex, its regulation and keratinolytic potential. AB - Two soil isolates of Microsporum gypseum were studied for the production of extracellular proteases. Both the strains secreted protease on glucose-gelatin medium. The enzyme activity peaked on day 15 at 28 degrees C. Asparagine repressed protease yield. Sugars caused catabolite repression of protease formation. Protease activities of both the isolates were significantly affected by incubation period, culture media and carbohydrates used. Both the strains grew on the skin bait and caused a gravimetrically measurable loss of the substrate. Despite less pronounced differences in the keratinase levels, great variations occurred in the amount of keratin degraded by two isolates. Keratinase production as well as loss in substrate mass was better in glucose-lacking flasks than those containing the sugar. Although the rate of keratin degradation was independent of enzyme production, statistically positive correlations were recorded between loss in substrate mass: yielded dry mycelial weight and substrate degradation: keratinase levels. PMID- 20946259 TI - Cell cycle arrest induced by the bacterial adenylate cyclase toxins from Bacillus anthracis and Bordetella pertussis. AB - Bacillus anthracis oedema toxin (ET) and Bordetella pertussis adenylate cyclase toxin (ACT) enter host cells and produce cAMP. To understand the cellular consequences, we exposed J774 cells to these toxins at ng ml(-1) (pM) concentrations, then followed cell number and changes in cell signalling pathways. Under these conditions, both toxins produce a concentration-dependent inhibition of cell proliferation without cytotoxicity. ET and ACT increase the proportion of cells in G(1) /G(0) and reduce S phase, such that a single addition of ET or ACT inhibits cell division for 3-6 days. Treatment with ET or ACT produces striking changes in proteins controlling cell cycle, including virtual elimination of phosphorylated ERK 1/2 and Cyclin D1 and increases in phospho-CREB and p27(Kip1) . Importantly, PD98059, a MEK inhibitor, elicits a comparable reduction in Cyclin D1 to that produced by the toxins and blocks proliferation. These data show that non-lethal concentrations of ET and ACT impose a prolonged block on the proliferation of J774 cells by impairment of the progression from G(1) /G(0) to S phase in a process involving cAMP-mediated increases in phospho CREB and p27(Kip1) and reductions in phospho-ERK 1/2 and Cyclin D1. This phenomenon represents a new mechanism by which these toxins affect host cells. PMID- 20946262 TI - Would sir like to see the wine list? PMID- 20946261 TI - Attainment of Canadian and European guidelines' lipid targets with atorvastatin plus ezetimibe vs. doubling the dose of atorvastatin. AB - BACKGROUND: Canadian and European treatment guidelines identify low-density lipoprotein cholesterol (LDL-C) as a primary treatment target for hypercholesterolaemia. OBJECTIVES: This post hoc analysis compared ezetimibe 10 mg (ezetimibe) added to atorvastatin vs. doubling the atorvastatin dose on achievement of the 2009 Canadian Cardiovascular Society (CCS) and the 2007 Joint European Prevention Guidelines primary and optional secondary lipid targets and high-sensitivity C-reactive protein (hs-CRP) levels. METHODS: After stabilisation on atorvastatin, hypercholesterolaemic patients at moderately high risk (MHR) for coronary heart disease (CHD) not at LDL-C < 2.6 mmol/l were randomised to atorvastatin 20 mg vs. doubling their atorvastatin dose to 40 mg; and patients at high risk (HR) for CHD not at LDL-C < 1.8 mmol/l were randomised to atorvastatin 40 mg plus ezetimibe vs. doubling their atorvastatin dose to 80 mg for 6 weeks. RESULTS: When treated with atorvastatin plus ezetimibe, MHR and HR patients had greater attainment of LDL-C, most lipids and lipoproteins and/or hs-CRP targets compared with doubling their atorvastatin dose. More MHR and HR patients achieved dual targets of LDL-C and: Apolipoprotein (Apo) B, total cholesterol (total-C), total-C/high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, Apo B/Apo A-I or hs-CRP with ezetimibe + atorvastatin treatment compared with doubling their atorvastatin dose. CONCLUSIONS: These results demonstrated greater achievement of single/dual treatment targets as set by Canadian and European treatment guidelines with ezetimibe added to atorvastatin 20 mg or 40 mg compared with doubling the atorvastatin dose to 40 mg or 80 mg in MHR and HR patients, respectively. PMID- 20946263 TI - Female sexual dysfunction: a reality not a myth. PMID- 20946264 TI - Insights from the new European Society of Cardiology guidelines for the medical management of atrial fibrillation. PMID- 20946265 TI - Ouabain - the insulin of the heart. PMID- 20946266 TI - Prevention of dementia by ACE inhibitors and angiotensin receptor blockers - potential but not proven. PMID- 20946267 TI - Doctors take on the state: championing patients' right to pain treatment. PMID- 20946268 TI - Characteristics of patients prescribed sitagliptin and other oral antihyperglycaemic agents in a large US claims database. AB - BACKGROUND AND AIMS: Non-randomised comparative studies of pharmacological agents can be biased because of differences in baseline demographics, medical history and health status of patients prescribed different therapies. Characteristics of patients with type 2 diabetes mellitus (T2DM) taking sitagliptin were compared with patients taking other oral antihyperglycaemic agents (OAHA) in a large US insurance claims database. MATERIALS AND METHODS: Using the United Health Care database, we identified T2DM patients with at least one OAHA prescription, and at least 1 year prior enrollment. Patients were classified into subcohorts including sitagliptin or other OAHA, add-on to monotherapy, and triple or more therapy. Comorbidities 12 months before the first OAHA prescription in study window were based on ICD-9 diagnostic codes and NDC codes for prescriptions. RESULTS: Prevalence of comorbidities was consistently higher for patients with sitagliptin prescriptions across most comorbidities (p < 0.05 for 20 of 30 assessed comorbidities). Overall, baseline differences were apparent (p < 0.0001) for retinopathy (5.7% vs. 3.4%), renal failure (5.1% vs. 2.6%), proteinuria (2.8% vs. 2.0%), hypertension (76.9% vs. 68.2%), congestive heart failure (3.4% vs. 2.6%), myocardial infarction (18.0% vs. 14.4%) and chronic neurological conditions (8.1% vs. 6.6%). Differences were most pronounced for initial monotherapy subcohorts. A higher proportion of sitagliptin users had prescriptions for cardiovascular medication (84.2% vs. 74.9%). CONCLUSION: Sitagliptin users had higher proportions of comorbidities and greater use of prescription medications and physician visits. Researchers should be aware that sitagliptin is prescribed to patients with seemingly worse health status. Ability to analyse observational, non-randomised studies may be limited by substantial differences in patient characteristics between different treatments. PMID- 20946269 TI - A comparison of intermediate and long-acting insulins in people with type 2 diabetes starting insulin: an observational database study. AB - AIMS: Insulin is normally added to oral glucose-lowering drugs in people with type 2 diabetes when glycaemic control becomes suboptimal. We evaluated outcomes in people starting insulin therapy with neutral protamine Hagedorn (NPH), detemir, glargine or premixed insulins. METHODS: Insulin-naive people with type 2 diabetes (n = 8009), >= 35 years old, HbA(1c) >= 6.5% and begun on NPH (n = 1463), detemir (n = 357), glargine (n = 2197) or premix (n = 3992), were identified from a UK database of primary care records (The Health Improvement Network). Unadjusted and multivariate-adjusted analyses were conducted, with persistence of insulin therapy assessed by survival analysis. RESULTS: In the study population (n = 4337), baseline HbA(1c) was 9.5 +/- 1.6%, falling to 8.4 +/ 1.5% over 12 months (change -1.1 +/- 1.8%, p < 0.001). Compared with NPH, people taking detemir, glargine and premix had an adjusted reduction in HbA(1c) from baseline, of 0.00% (p = 0.99), 0.19% (p < 0.001) and 0.03% (p = 0.51). Body weight increased by 2.8 kg overall (p < 0.001), and by 2.3, 1.7, 1.9, and 3.3 kg on NPH, detemir, glargine and premix (p < 0.001 for all groups); insulin dose at 12 months was 0.70 (overall), 0.64, 0.61, 0.56 and 0.76 U/kg/day. After 36 months, 57% of people on NPH, 67% on glargine and 83% on premix remained on their initially prescribed insulin. DISCUSSION AND CONCLUSION: In routine clinical practice, people with type 2 diabetes commenced on NPH experienced a modest disadvantage in glycaemic control after 12 months compared with other insulins. When comparing the insulins, glargine achieved best HbA(1c) reduction, while premix showed greatest weight gain and the highest dose requirement, but had the best persistence of therapy. PMID- 20946270 TI - Exploring the needs and expectations of women presenting for hysterosalpingogram examination following a period of subfertility: a qualitative study. AB - AIMS: This study examines women's experience of healthcare following the referral for hysterosalpingography (HSG) after a period of subfertility. These otherwise fit and healthy women enter the healthcare system and their only problem is a failure to become pregnant. They find themselves trying to negotiate a system designed for sick people. Previous research in this field consists mainly of studies comparing HSG to other diagnostic studies. The study aims to address the underlying issues that women have at the start of their subfertility investigations. METHODS: This qualitative study uses grounded theory methodology. Interviews with women were undertaken immediately prior to their HSG examination. Ten women were interviewed using 12 core questions. Each woman had a diagnosis of primary subfertility. Each was asked how they were coping with the uncertainty of their fertility. They were asked about their expectations of the HSG examination, the importance of HSG and what methods were available to them to reduce any anxiety experienced. Data analysis was undertaken after each interview. RESULTS: Presently, HSG is seen by healthcare providers as a routine outpatient examination at the start of subfertility investigations. In contrast to this, it was discovered at interview that HSG was seen by the women as a defining moment that would signpost their future treatment options to become pregnant. Women reported receiving little support from health care providers, and that written information given did not fulfil all of their needs. Often written information alone heightened anxiety, and this written information needs to be tailored to a specific set of circumstances. The literature review noted that anxiety can lead to mental health issues, but that properly focused, correctly given, timely information can reduce anxiety. CONCLUSIONS: The implications of the findings are that if anxiety relating to treatment at this early stage can be managed effectively, it could minimise the possible physical and emotional trauma to the woman as her subfertility journey continues, thus at the same time preventing future anxiety related illness. PMID- 20946271 TI - Pelvic floor dysfunction: a scoping study exploring current service provision in the UK, interprofessional collaboration and future management priorities. AB - OBJECTIVE: Pelvic floor dysfunction (PFD) has a significant socioeconomic and healthcare cost. This study aimed to investigate current service provision for PFD in the UK, highlighting any gaps and areas for improvement to inform future service improvement. METHODS: A three-phase design comprised a scoping literature review, consultation survey with frontline practitioners from four key professional groups and an overarching synthesis. An interpretative analytical framework was informed by the concepts of interdisciplinary and interprofessional collaboration. RESULTS: Empirical evidence on PFD service provision is limited. No overarching strategic approach to PFD as a single clinical entity in the UK was identified. Two hundred and forty-three medical, nursing and physiotherapy practitioners from different clinical subspecialties participated in the survey. Access and availability to services, models of delivery and individual practice vary widely within and across the disciplines. Time restrictions, mixed professional attitudes, lack of standardisation and low investment priority were identified as major barriers to optimal service provision. Five overlapping areas for improvement are highlighted: access and availability, team working and collaboration, funding and investment, education, training and research, public and professional awareness. CONCLUSIONS: Current services are characterised by a fragmented approach with asynchronous delivery, limited investment and poor interprofessional integration. An improved service delivery model has the potential to improve outcomes through better interdisciplinary collaboration and efficient use of resources. PMID- 20946272 TI - The effectiveness of the '2-week wait' referral service for colorectal cancer. AB - INTRODUCTION: The UK government target expects all suspected cancer patients to be seen within 2 weeks of referral made by general practitioners. This has significant impact on the workload for colorectal surgeons. The aim of this study was to investigate the effectiveness of this colorectal service. METHOD: A retrospective study of all patients referred to a 2-week wait colorectal clinic over a 12-month period was assessed, documenting diagnosis and staging. Comparison of patients diagnosed with colorectal cancer (CRC) presenting via other routes in the same period was made. RESULTS: Over the 12-month period, all 1100 patients were seen in the 2-week wait clinic; 938 (85%) patients fulfilled the referral criteria, but only 81 (7.3%) were diagnosed with cancer. Conversely, 136 CRC patients presented to the surgeons via urgent referrals (n = 86), emergency (n = 13), routine colorectal clinic (n = 19) and bowel screening (n = 18). The 2-week cohort had more advanced staging than those referred by standard letter and pilot screening. Cancers in the symptomatic population are predominantly Dukes' B and Dukes' C whereas in pilot screening group predominantly Dukes' A. CONCLUSION: The effectiveness of 2-week wait referral was poor, confirming its lack of validity. Further work is required to offer primary care stricter inclusion and exclusion referral criteria. PMID- 20946273 TI - A two-millimetre free margin from invasive tumour minimises residual disease in breast-conserving surgery. AB - AIMS: In breast-conserving surgery, the width of free margin around a tumour to ensure adequate excision is controversial. The aim of this study was first to evaluate the frequency of residual disease in wider excision specimens in patients who undergo further surgery because of close margins of < 5 mm. Secondly, the ability of demographic and tumour-related factors to predict the close margins was appraised. PATIENTS AND METHODS: Three-hundred-and-three patients were included in the study. Patients undergoing wider excision were assessed for the presence of residual disease, and this was tested for association with the width of the initial free margin. Various factors were studied for association with close or involved margins by univariate analysis. RESULTS: Fifty-three per cent of patients were eligible for re-excision based on the need for a 5-mm clearance. With a free margin of 2 mm or more from invasive tumour, the probability of finding residual disease was 2.4%. The probability of residual disease was higher for ductal carcinoma in situ (DCIS) and did not decline with increasing the free margin width. Tumour size, lobular cancer type, vascular invasion and nodal involvement were associated with close margins. CONCLUSIONS: We suggest that a free margin of 2 mm from invasive tumour is adequate to minimise residual disease, whereas the equivalent free margin for DCIS remains unclear. Patients with large tumours and lobular cancer type should be counselled at the time of first surgery concerning the higher risk of further excision and mastectomy. PMID- 20946274 TI - The impact of tramadol and dihydrocodeine treatment on quality of life of patients with cancer pain. AB - BACKGROUND: Tramadol and dihydrocodeine (DHC) are analgesics of step 2 WHO analgesic ladder (opioids for mild to moderate pain, weak opioids) frequently used in the treatment of cancer pain of moderate intensity. The aim of the study was to assess the impact of tramadol and DHC treatment on quality of life (QL) and performance status (PS) of patients with cancer pain. PATIENTS AND METHODS: Randomised, cross-over, clinical study of 40 opioid-naive patients with nociceptive cancer pain who received tramadol or DHC controlled release tablets for 7 days, and then drugs were switched and administered for another 7 days. Pain was assessed by visual analogue scale (VAS), QL by EORTC QLQ C 30, and PS by Eastern Cooperative Oncology Group (ECOG) and Karnofsky. RESULTS: From 40 patients recruited, 30 completed the study. DHC treatment provided better analgesia (VAS). In QL functional scales, better emotional functioning in tramadol group and better global QL and cognitive functioning in DHC group were observed. In symptom scales, less fatigue, pain and sleep disturbances, less nausea and vomiting and better appetite in DHC group were noted. In tramadol group, less constipation and less financial problems were observed. No differences in dyspnoea and diarrhoea were noted. ECOG and Karnofsky PS were low and did not differ between tramadol and DHC groups. CONCLUSIONS: Dihydrocodeine treatment was associated with better global QL, cognitive functioning, analgesia and appetite, less fatigue, sleep disturbances, nausea and vomiting. Tramadol therapy was connected with better emotional functioning, less constipation and financial problems. PS deteriorated in both tramadol and DHC groups. PMID- 20946275 TI - Maternal and perinatal outcomes amongst haemoglobinopathy carriers: a systematic review. AB - With the introduction of screening programmes for haemoglobinopathies (HbP), more women will be aware of their HbP status. The genetic risk for women who are carriers of HbP is well known. However, midwives and obstetricians need to know whether there are other risks involved in the pregnancies of women who are carriers of HbP. The objective of this study was to investigate the hypothesis that being a carrier of HbP has no consequences for the health of pregnant women and the outcome of their pregnancies. A systematic search was carried out until August 2008 in the Cochrane Library, Medline, EMBASE and CINAHL databases. All references were inspected to identify further studies. The authors of key publications were contacted for any unpublished research. Selection of studies was made on the basis of the following criteria: Cohort and case-control studies, pregnant women with a singleton pregnancy, exposure: HbAS or thalassaemia minor and the following outcomes: urinary tract infection (UTI), anaemia, (pre )eclampsia, gestational diabetes, premature labour, low birth weight, intrauterine growth retardation, miscarriage, neonatal death, low Apgar score, neural tube defects. Quality assessment and data extraction were carried out by two researchers. A total of 780 subjects were identified of which nine were included in the study. A protective effect of sickle cell trait was found for premature birth, low Apgar score and perinatal mortality rate. No significant effect was found for low birth weight, growth retardation, UTI or high blood pressure. The risk of anaemia and bacteriuria was increased. In conclusion, the risks amongst pregnant HbP carriers are low. Midwives and obstetricians need to be aware of the risk of anaemia and UTI. PMID- 20946276 TI - Biomarkers of opiate use. AB - The interpretation of toxicological findings is critical for the thorough investigation of the use and abuse of psychoactive substances. A positive analytical result for a sample taken could usually result in criminal proceedings and a punitive outcome for the defendant whose sample was analysed. The detection of markers of illicit opiate misuse is important both in the management of substance misuse and in the postmortem identification of illicit opiate use. The aim of this study was to emphasise the role of opiate biomarkers available at the laboratory and in the clinical environment. Urine remains the biological tool of choice for qualitative detection of illicit drug use in a clinical setting, while quantitative accuracy remains strictly the domain of blood. Accurate interpretation of the screening tests within a clinical setting alongside other relevant information remains the key to the usefulness of any test. Moreover, the finding of a morphine/codeine concentration ratio in blood exceeding unity is a strong evidence that the person had used heroin, as opposed to having taken a prescription analgesic drug containing codeine. PMID- 20946277 TI - The marriage of true minds: the partner of the ICD patient as a new focus for study. PMID- 20946278 TI - The anatomy and physiology of the sinoatrial node--a contemporary review. AB - The sinoatrial node is the primary pacemaker of the heart. Nodal dysfunction with aging, heart failure, atrial fibrillation, and even endurance athletic training can lead to a wide variety of pathological clinical syndromes. Recent work utilizing molecular markers to map the extent of the node, along with the delineation of a novel paranodal area intermediate in characteristics between the node and the surrounding atrial muscle, has shown that pacemaker tissue is more widely spread in the right atrium than previously appreciated. This can explain the phenomenon of a "wandering pacemaker" and concomitant changes in the P-wave morphology. Extensive knowledge now exists regarding the molecular architecture of the node (in particular, the expression of ion channels) and how this relates to pacemaking. This review is an up-to-date summary of the current state of our appreciation of the above topics. PMID- 20946279 TI - Effect of substance abuse on defibrillation threshold in patients with implantable cardioverter-defibrillator. AB - BACKGROUND: The use of recreational drugs has been observed to have deleterious effects on the heart. The aim of our study was to evaluate the effect of substance abuse on the defibrillation threshold (DFT) in patients with implantable cardioverter-defibrillators (ICDs). METHODS: A retrospective analysis was conducted on patients who had undergone ICD placement at a tertiary university medical center in Detroit, Michigan. Subjects were identified based on self-reported drug use and placed into one of the three groups: controls, cocaine, and other illicit drugs. Due to a disparity in race among groups, the main analysis on DFT value was conducted on African-American patients only. Furthermore, exploratory analyses were conducted to investigate the effects of marijuana use and race on DFT values. RESULTS: A history of cocaine use (n = 17) significantly increases DFT among African Americans (17.3 +/- 8 Joule [J] vs 12.5 +/- 5 J in cases vs controls, P < 0.05), while previous use of marijuana does not significantly influence DFT. African-American patients with a history of illicit drug use had indications for ICD implantation at an earlier age and that within the control (nondrug using) group; African Americans (n = 73) had higher DFT compared to Caucasians (n = 32), (14.5 +/- 0.5 J vs 9.7 +/- 0.6 J, P < 0.05). CONCLUSIONS: A history of cocaine use in African Americans with ICD is a risk factor for high DFT and race itself (being African American) may be a risk for high DFT. Use of high-energy ICDs and other DFT lowering techniques may be considered for patients who have used or continue to use cocaine or in whom DFT testing cannot be performed at the time of implantation. PMID- 20946280 TI - Miniaturization of a magnetically levitated axial flow blood pump. AB - This article introduces a unique miniaturization process of a magnetically levitated axial flow blood pump from a functional prototype to a pump suitable for animal trials. Through COMSOL three-dimensional finite element analysis and experimental verification, the hybrid magnetic bearings of the pump have been miniaturized, the axial spacing between magnetic components has been reduced, and excess material in mechanical components of the pump was reduced. Experimental results show that the pump performance was virtually unchanged and the smaller size resulted in the successful acute pump implantation in calves. PMID- 20946281 TI - A highly accurate and consistent microfluidic viscometer for continuous blood viscosity measurement. AB - A high-precision microfluidic viscometer with a microfluidic channel array composed of 100 indicating channels is demonstrated in this study. The relative viscosity of the sample fluid could be measured by simply counting the number of the indicating channels occupied by the sample and the reference fluids. Using lumped parameter modeling, an analytical solution of the relative viscosity is derived. In order to evaluate the performance of the developed microfluidic viscometer, the viscosity values obtained by the microfluidic viscometer are compared with the ones obtained by a conventional viscometer. In Newtonian fluid (sodium dodecyl sulfate [SDS] solution) tests, the normalized differences in the viscosities measured by two methods are less than 2.5%. In non-Newtonian fluid (whole blood, 45% hematocrit) tests at various shear rates, the viscosities measured by two methods are evaluated by a regression analysis via power law (). The k values for both the microfluidic viscometer and the conventional viscometer are 12.953 and 13.175, respectively; the n values are 0.797 and 0.807, respectively. The normalized differences in two parameters measured by two methods are less than 2%. Thus, it could be concluded that the microfluidic viscometer developed in this study is capable of measuring viscosity of both Newtonian fluid (SDS solution) and non-Newtonian fluid (whole blood) with a relatively high accuracy in a continuous and near real-time fashion. Furthermore, the viscometer could be potentially employed in cardiopulmonary bypass procedures by continuously monitoring viscosity changes due to blood damages and hemodilution. PMID- 20946282 TI - Evaluation of HL-20 roller pump and Rotaflow centrifugal pump on perfusion quality and gaseous microemboli delivery. AB - The purpose of this study was to compare the HL-20 roller pump (Jostra USA, Austin, TX, USA) and Rotaflow centrifugal pump (Jostra USA) on hemodynamic energy production and gaseous microemboli (GME) delivery in a simulated neonatal cardiopulmonary bypass (CPB) circuit under nonpulsatile perfusion. This study employed a simulated model of the pediatric CPB including a Jostra HL-20 heart lung machine (or a Rotaflow centrifugal pump), a Capiox BabyRX05 oxygenator (Terumo Corporation, Tokyo, Japan), a Capiox pediatric arterial filter (Terumo Corporation), and 1/4-inch tubing. The total volume of the experimental system was 700mL (500mL for the circuit and 200mL for the pseudo neonatal patient). The hematocrit was maintained at 30% using human blood. At the beginning of each trial, a 5mL bolus of air was injected into the venous line. Both GME data and pressure values were recorded at postpump and postoxygenator sites. All the experiments were conducted under nonpulsatile perfusion at three flow rates (500, 750, and 1000mL/min) and three blood temperatures (35, 30, and 25 degrees C). As n=6 for each setup, a total of 108 trials were done. The total number of GME increased as temperature decreased from 35 degrees C to 25 degrees C in the trials using the HL-20 roller pump while the opposite effect occurred when using the Rotaflow centrifugal pump. At a given temperature, total GME counts increased with increasing flow rates for both pumps. Results indicated the Rotaflow centrifugal pump delivered significantly fewer microemboli compared to the HL-20 roller pump, especially under high flow rates. Less than 10% of total microemboli were larger than 40um in size and the majority of GME were in the 0-20um class in all trials. Postpump total hemodynamic energy (THE) increased with increasing flow rates and decreasing temperatures in both circuits using these two pumps. The HL-20 roller pump delivered more THE than the Rotaflow centrifugal pump at all tested flow rates and temperature conditions. Results suggest the HL-20 roller pump delivers more GME than the Rotaflow centrifugal pump but produces more hemodynamic energy under nonpulsatile perfusion mode. PMID- 20946283 TI - Electrophysiological differences between the epicardium and the endocardium of the left atrium. AB - BACKGROUND: Electrophysiological properties of the atrial endocardium compared to epicardium are not well understood. The purpose of this study was to compare the electrophysiological properties and vulnerability to arrhythmia induction from these regions. METHODS AND RESULTS: Transseptal endocardial and percutaneous epicardial mapping were performed in a porcine model (n = 7). Two opposing 4-mm electrophysiological catheters were positioned endocardially and epicardially. A circular mapping catheter (CMC) was positioned at the ostium of the common inferior pulmonary vein (CIPV) recording left atrial (LA)-PV potentials. Endocardial and epicardial effective refractory periods (ERPs) at two basic cycle lengths (CLs) of 600 and 400 ms were recorded from four anatomic locations (CIPV, LA appendage, right superior PV, and LA posterior wall). Atrial repetitive response (ARR) induction was also tested from endocardial and epicardial sites. Overall, 254 ERP measurements (mean 36.3 per animal) and 84 induction attempts (mean 12 per animal) were performed. The ERP was significantly shorter in the epicardium compared to the endocardium at basic CL of 400 ms (P = 0.006) but not at CL of 600 ms (P = 0.2). In addition, only the epicardium demonstrated ERP shortening when the CL of the basic drive was shortened (P = 0.03). ARR could be induced more often from the epicardium (P = 0.002) and fibrillatory activity with epicardial/endocardial dissociation was recorded (n = 3). Also, the earliest PV activation site on the CMC was noted to be different in 16.5% of cases during epicardial and endocardial pacing. CONCLUSION: The electrophysiological characteristics of the atrial epicardium are different from the endocardium with a shorter ERP and more frequent ARR induction by programed stimulation. PMID- 20946284 TI - Percutaneous closure and "push-pull" technique to repair arterial lead and sheath placement complicating cardiac resynchronization therapy. AB - We present a case of inadvertent subclavian arterial puncture and lead placement to the left ventricle in a patient undergoing cardiac resynchronization therapy. We describe the use of a "push-pull" technique within an arterial setting to allow removal of the lead, while maintaining access through the same puncture to allow an arterial-closure device to then seal the artery at this site. As a result of this percutaneous approach, the patient avoided the need for a vascular surgical procedure. PMID- 20946285 TI - Prevalence and persistence of depression in patients with implantable cardioverter defibrillator: a 2-year longitudinal study. AB - BACKGROUND: It is unclear whether depression persists in patients with implantable cardioverter defibrillators (ICDs). We evaluated the prevalence and persistence of depression in ICD patients over a 2-year period. METHODS: The study included 90 consecutively hospitalized patients. Patients underlying heart disease was 24% coronary artery disease, 29% idiopathic dilated cardiomyopathy, 24% hypertrophic cardiomyopathy, 13% idiopathic VF/long QT syndrome and miscellaneous conditions 11%. A secondary indication for ICD implantation was present in 20 patients. All patients completed the Zung Self-Rating Depression Scale (SDS) at study baseline and at the their routine follow-up visit 2 years after the baseline questionnaire. Delivery of ICD therapies was tracked throughout the 2 years. RESULTS: Depression, indicated by a Zung SDS index score exceeding 60, was present in 29 (32%) of patients at study baseline. Depression was present in 11/51 (21%) patients scheduled to undergo ICD implantation, 2/2 (100%) patients whose device was upgraded to a CRT-D, 3/14 (21%) patients who had undergone pulse generator replacement, 7/14 (50%) patients who experienced electrical storm and 6/9 (66%) patients hospitalized with acute decompensated heart failure. NYHA functional class III was significantly associated with depression at baseline (HR 6.7, 95% CI 1.68-27.2, p = 0.0007). No differences were noted for female gender, demographics, beta-blocker use, or LVEF <=35% (p = ns). Depression was present in 25 (28%) of patients at 2 years follow-up, persisting in 21 (72%) of patients whose Zung SDS scores were elevated at baseline. The median time from ICD shock therapy to completion of the 2 year questionnaire was 9 months (range, 1-22). Patients who were depressed (9/25, 36%) experienced more shocks than non-depressed patients (6/65, 9%) after 2 years (p = 0.002). CONCLUSIONS: Depression is not uncommon among patients who meet criteria for ICD implantation and persists over time particularly when functional status is impaired. Depression is associated with a higher incidence shock therapy. PMID- 20946286 TI - Clinical predictors of conduction disease progression in type I myotonic muscular dystrophy. AB - BACKGROUND: Patients with type I myotonic muscular dystrophy (DM1) are at risk for sudden death due to atrioventricular conduction block. We sought to characterize the trends and predictors of time-dependent electrocardiographic (ECG) variations in patients with DM1. METHODS: Seventy patients with DM1 underwent standard electrocardiography at first evaluation and routine and symptom prompted follow-up. Individual variations in ECG conduction intervals were assessed using spaghetti plots. Clinical predictors of conduction disease progression were assessed using multivariate random effects regression models of panel data clustered by patient and adjusted for heart rate. RESULTS: Substantial individual variability was noted in time-dependent changes in PR, QRS, and QTc intervals of patients with DM1. Changes in the QTc interval were closely associated with prolongation of the QRS interval. Age, the presence of paroxysmal atrial flutter or fibrillation, and the number of cytosine-thymine-guanine (CTG) repeats were independent positive predictors of time-dependent PR and QRS prolongation during long-term follow-up. Female sex was negatively associated with PR prolongation but positively associated with QTc prolongation. Lower left ventricular ejection fraction was associated with greater QRS interval progression during long-term follow-up but was not predictive of PR interval progression. CONCLUSIONS: Patients with DM1 can develop rapid changes in cardiac conduction intervals. Paroxysmal atrial flutter or fibrillation, older age, and larger CTG expansions predict greater time-dependent PR and QRS interval prolongation and warrant particular attention in the arrhythmic evaluation of this high risk patient subset. PMID- 20946287 TI - Altered left ventricular contraction pattern during right ventricular pacing: assessment using real-time three-dimensional echocardiography. AB - BACKGROUND: Chronic right ventricular apical (RVA) pacing has been associated with increased risk of heart failure and adverse outcome. The acute effects of RVA pacing on three-dimensional (3D) ventricular function and mechanical dyssynchrony are not well known. We performed a real-time 3D echocardiographic (RT3DE) study to assess global and regional left ventricular function during RVA pacing. METHODS: Twenty-six patients with implanted cardiac devices and normal intrinsic atrioventricular conduction were included in the study. RT3DE was performed during intrinsic sinus rhythm and during RVA pacing. Quantification of global and regional left ventricular function was performed offline by time volume analysis of 16 myocardial segments. Time to reach minimum regional volume was calculated for each segment as a percentage of the cardiac cycle. The systolic dyssynchrony index (SDI) was defined as the standard deviation of these time periods. Longitudinal function was assessed by time-volume analysis of apical, midventricular, and basal segments. RESULTS: During RVA pacing, a reversed apical-to-basal longitudinal contraction sequence was observed in 58% of all patients. RVA pacing was associated with increased left ventricular (LV) dyssynchrony (SDI increase from 4.4 +/- 2.2% to 6.3 +/- 2.4%, P = 0.001) and reduced LV ejection fraction (decrease from 53 +/- 13% to 47 +/- 14%, P = 0.05). CONCLUSION: RT3DE assessment of LV function provides evidence that pacing from the RVA results in acute alterations in LV contraction sequence and increased LV dyssynchrony. Further studies are warranted to assess the potential of RT3DE to identify patients who might be at increased risk of pacing-induced heart failure or who might benefit from alternate-site or multisite pacing. PMID- 20946288 TI - Transplantation of liver organoids in the omentum and kidney. AB - Liver organoids were reconstructed by mouse-immortalized hepatocytes and nonparenchymal cells (sinusoidal endothelial cells and hepatic stellate cells) in a radial-flow bioreactor (RFB). A biodegradable apatite-fiber scaffold (AFS) was used as a scaffold packed in the RFB, which enables three-dimensional cell cultures. The organoids cocultured in the RFB showed a liver-like structure with high-density layers of hepatocytes and the formation of vessel-like structures. A liver organoid consisting of three cocultured cells was transplanted under the kidney capsule (kidney group) or into the omentum (omentum group) using BALB/c nude mice. Transplanted liver organoids survived in the kidney or omentum. The expression of mRNAs of albumin, connexin 26 and 32, hepatocyte nuclear factor 4alpha, and glucose-6-phosphatase was increased in both groups at 8 weeks after transplantation in comparison to the pretransplant status. Tyrosine aminotransferase appeared only in the omentum group. The results suggested that the functions of liver organoids differed depending on the transplanted site in the recipient animals. PMID- 20946290 TI - Trends of temporary pacemaker implant and underlying disease substrate. AB - BACKGROUND: To evaluate contemporary trends of clinical characteristics, etiologies, and underlying diseases, and their relationship between different bradyarrhythmias in patients undergoing temporary pacemakers (TPMs). METHODS: This study included 509 patients (77 +/- 11 year, 74% males) with symptomatic bradyarrhythmias requiring TPMs between 2002 and 2008. Demographics, electrocardiographic indications, etiologies, underlying diseases, and the outcome of permanent pacemaker (PPM) implants within 30 days were analyzed. RESULTS: Atrioventricular conduction dysfunction (AVCD) (64.0%) dominated in all bradyarrhythmias, with idiopathic degeneration (61%) as its major etiology. Antiarrhythmic drug (38%) was the leading cause in sinoatrial node dysfunction (SAND). There was an increasing trend in AVCD, while a decreasing trend in SAND. Regarding etiologies for TPM, an increasing trend was found in idiopathic degeneration, whereas a decreasing trend in acute coronary syndrome (ACS). Idiopathic degeneration had an odds ratio (OR) of 1.9 for AVCD (P = 0.001), whereas electrolyte/acid-base disturbances (OR = 3.7, P = 0.001), beta-blockers (OR = 2.4, P = 0.002), and chronic renal disease (OR = 1.9, P = 0.01) were associated with SAND. Patients with intrinsic etiologies for TPM had a high incidence of PPM implantation within 30 days than those with extrinsic causes (67.5% vs 3.8%, P < 0.0001) CONCLUSION: Increasing trends in patients requiring TPMs were observed in the elderly patients and those with AVCD and idiopathic degeneration, while decreasing trends were observed in those with SAND and ACS. Idiopathic degeneration was associated with AVCD, whereas extrinsic etiologies were related to SAND. Patients with intrinsic etiologies had a higher incidence of PPM implantation than those with extrinsic factors for TPM. PMID- 20946289 TI - Spironolactone therapy is associated with reduced ventricular tachycardia rate in patients with cardiomyopathy. AB - INTRODUCTION: Multiple pharmacological therapies currently in prevalent clinical use for cardiac diseases have antifibrotic properties. Spironolactone, a potent antifibrotic agent, is currently used for advanced heart failure. Therapies such as HMG-CoA reductase inhibitors (statins) and angiotensin-converting enzyme inhibitors (ACEi) also have antifibrotic properties. However, the effect of these medications on the ventricular arrhythmia phenotype is currently unknown. Therefore, we set out to define the ventricular arrhythmia rates in patients actively treated with such therapies. METHODS AND RESULTS: We retrospectively evaluated the ventricular tachycardia (VT) rates in patients with structural heart disease actively treated with therapies with antifibrotic properties. VT rates were significantly diminished in patients treated with spironolactone (158 +/- 26 beats per minute [bpm], n = 21) compared to patients on no medications (205 +/- 22 bpm, n = 13) or those who were on similar heart-failure therapies but not on spironolactone (186 +/- 32 bpm, n = 82). In addition, we observed that VT rates showed a significant trend toward lower rates in patients receiving either statins or ACEi, compared to patients on no medical therapy. In multivariate analysis, spironolactone therapy was identified as the single most significant variable for reduced VT rate. CONCLUSION: Use of spironolactone in patients with heart failure is associated with reduced VT rate. Similar but less-significant reductions in VT rates were observed with use of other pharmacological agents with antifibrotic properties, such as statins and ACEi. Our findings, at least in part, could account for reduction in sudden cardiac death rates documented with use of these therapies. PMID- 20946291 TI - Failure of transvenous ICD to terminate ventricular fibrillation in a patient with left ventricular noncompaction and polycystic kidneys. AB - Implantable cardioverter defibrillator (ICD) testing in patients with left ventricular noncompaction (LVNC) at the time of implantation and potential difficulties with ventricular fibrillation (VF) induction/termination in LVNC patients are often not stated in the literature. This report describes the failure of transvenous implantation of an ICD in a 40-year-old patient with LVNC and polycystic kidneys. A high defibrillation threshold (DFT) prevented termination of ICD-induced VF. This case suggests that DFT testing should be considered in any LVNC patient during ICD implantation. The association of LVNC and polycystic kidneys is also discussed. PMID- 20946292 TI - A Narrow QRS-Complex Supraventricular Rhythm with 1:1 VA Relationship: What is the Mechanism? PMID- 20946293 TI - Repair of bone defect in caprine tibia using a laminated scaffold with bone marrow stromal cells loaded poly (L-lactic acid)/beta-tricalcium phosphate. AB - Repair of bone defects of a critical size encounters many problems, and many efforts aim to build a porous scaffold loading bone marrow stromal cells (BMSCs) or bone morphogenetic protein (BMP2) to quickly repair bone defects. In this paper, a laminated scaffold was designed and tested for the repair of bone defects in a caprine tibia. Beta-tricalcium phosphate (beta-TCP) and poly (L lactic acid) (PLLA) were fabricated to a sandwich structured composite that was then rolled up to form a cylindrical shaped, porous scaffold. The porosity and bending strength of the PLLA/beta-TCP laminated scaffold were around 70% and 1.7 MPa, respectively. Results from in vitro experiments showed that the pH value of the scaffold in water fluctuated between 4.9 and 7.0 during its degradation. When exposed to the simulated body fluid, the scaffold lost its strength after 11 weeks of degradation. After implantation in Chinese caprines' diaphyseal defects with loaded allogeneic BMSCs, the scaffold sped up the bone repair without collapse of the scaffold and the unwanted inflammatory response, and then rapidly degraded and finally disappeared at 12 weeks. Gross examinations and pullout tests showed that the experimental caprines walked normally and the implanted leg could be heavily loaded. X-ray examinations and histological analyses showed new bone tissues formed with similar structures to normal ones. It is suggested that the novel PLLA/beta-TCP laminated scaffold with BMSCs loading can regenerate new bones quickly. PMID- 20946294 TI - Hemodiafiltration with online regeneration of ultrafiltrate: effect on heme oxygenase-1 and inducible subunit of nitric oxide synthase and implication for oxidative stress and inflammation. AB - Hemodiafiltration with regeneration of ultrafiltrate (HFR) has a positive impact on inflammation and oxidative stress (OxSt), risk factors for cardiovascular disease (CVD), the most common cause of excess morbidity and mortality for end stage renal disease (ESRD) patients. However, studies have been of limited duration. This study extends our previous study of HFR effects by evaluating the effect on mononuclear cell protein expression of heme-oxygenase-1 (HO-1), induced by OxSt, and inducible subunit of nitric oxide synthase (iNOS), and plasma level of interleukin-1beta (Il-1beta) and oxidized low-density lipoproteins (OxLDL), marker of OxSt, for a 12-month period. Fourteen ESRD patients stable on hemodialysis over a period of at least 2 years and on conventional bicarbonate dialysis were switched to be treated with HFR. Blood samples were collected at baseline, after 3, 6, 9 and 12 months. HO-1 and iNOS protein expression were evaluated by Western blot, OxLDL by enzyme-linked immunosorbent assay (ELISA), and Il-1beta by enzyme amplified sensitivity immumoassay assay. HFR significantly increased HO-1 at the 9 and 12 months (ANOVA = P < 0.00001): 0.17 +/- 0.11 (baseline) versus 0.48 +/- 0.20, P < 0.043 and 0.59 +/- 0.32, P < 0.004, respectively. Il-1beta declined (ANOVA = P < 0.0001) since the 3 months from 169.92 +/- 92.39 pg/mL (baseline) to 39.03 +/- 10.01 (12 months), P < 0.0001. HFR also reduced plasma OxLDL: 475.4 +/- 110.8 ng/mL (baseline) versus 393.1 +/- 101.9 ng/mL (12 months), P < 0.04. iNOS showed no changes upon HFR treatment. These results together with our previous results indicate that HFR improves OxSt and inflammation. Given the strong relationships between OxSt and inflammation with CVD, their reduction might provide a beneficial impact by reducing the risk of atherosclerotic CVD in dialysis patients. PMID- 20946295 TI - Comparison of two platelet activation markers using flow cytometry after in vitro shear stress exposure of whole human blood. AB - Platelet activation is the initiating step to thromboembolic complications in blood-contacting medical devices. Currently, there are no widely accepted testing protocols or relevant metrics to assess platelet activation during the in vitro evaluation of new medical devices. In this article, two commonly used platelet activation marker antibodies, CD62P (platelet surface P-selectin) and PAC1 (activated GP IIb/IIIa), were evaluated using flow cytometry. Anticoagulant citrate dextrose solution A (ACDA) and heparin anticoagulated human blood from healthy donors were separately exposed to shear stresses of 0, 10, 15, and 20 Pa for 120 s using a cone-plate rheometer model, and immediately mixed with the platelet marker antibodies for analysis. To monitor for changes in platelet reactivity between donors and over time, blood samples were also evaluated after exposure to 0, 2, and 20 uM of adenosine diphosphate (ADP). Following ADP stimulation, the percentage of both CD62P and PAC1 positive platelets increased in a dose dependent fashion, even 8 h after the blood was collected. After shear stress stimulation, both CD62P and PAC1 positive platelets increased significantly at shear stress levels of 15 and 20 Pa when ACDA was used as the anticoagulant. However, for heparinized blood, the PAC1 positive platelets decreased with increasing shear stress, while the CD62P positive platelets increased. Besides the anticoagulant effect, the platelet staining buffer also impacted PAC1 response, but had little effect on CD62P positive platelets. These data suggest that CD62P is a more reliable marker compared with PAC1 for measuring shear-dependent platelet activation and it has the potential for use during in vitro medical device testing. PMID- 20946296 TI - Level of alcohol response is not a risk factor for alcohol dependence. PMID- 20946298 TI - Emotional distress in partners of patients with an implantable cardioverter defibrillator: a systematic review and recommendations for future research. AB - Both patients with an implantable cardioverter defibrillator (ICD) and their partners face challenges when adapting to the ICD. Distress is a burden on its own for partners but may also affect well being and health of patients. This review provides a systematic overview of the literature on psychological distress in partners of ICD patients and recommendations for future research. PubMed and PsycInfo were searched in March 2010 using a priori defined search terms. This search and the additional hand search resulted in 22 studies, of which 13 were quantitative and eight qualitative. Sample sizes in quantitative studies varied considerably from 10 to 196 partners, with only six of 13 studies including >50 partners. Partner levels of distress were at least on par with patient levels. The majority of large-scale studies suggested that partner distress levels decrease in the first year postimplantation. Most studies reported no impact of ICD shocks on distress levels or quality of life in partners. ICD indication as well as comorbid conditions, age, and the psychological profile of the partner were related to distress and quality of life. Domains of concern emerging from qualitative studies were related to care of the ICD patient, helplessness and uncertainties related to shocks, role changes, sexual activities, overprotectiveness, and driving. Partner levels of distress may be as high as that of ICD patients. Research with large samples is needed to further investigate the course and determinants of partner distress and the influence that partner distress may have on patient health outcomes. PMID- 20946299 TI - Effects of low intensity pulsed ultrasound on rat Schwann cells metabolism. AB - The effects of low intensity pulsed ultrasound to tenocytes and osteocytes are well understood and applied clinically. However, its effects on cultured Schwann cells are still not well elucidated. This study was designed to elucidate the effects of low intensity pulsed ultrasound on cultured Schwann cells and their possible molecular mechanism. Schwann cells were harvested from sciatic nerves of 3-day-old Sprague-Dawley rats. Low intensity pulsed ultrasound stimulator (frequency: 1 MHz, duration: 2 min, duty cycle: 20%, total treatment time: 3 min) was applied to three different culture conditions: regular culture medium containing 0, 5, or 10% fetal bovine serum. The viability, damage, and differentiation of Schwann cells were examined; gene expression was also analyzed. In the presence of 0.3 W/cm(2) pulsed ultrasound stimulation, increases in cell viability and decreases in cell apoptosis were observed in the serum deprivation group; in this culture condition, interleukin-1, tumor necrosis factor-alpha, and protein zero genes expression were downregulated and Desert Hedgehog transcripts gene expression was upregulated. We concluded that intervention with low intensity pulsed ultrasound could promote Schwann cell proliferation, prevent cell death, and keep adequate phenotype presentation for peripheral nerve recovery. The low intensity pulsed ultrasound stimulation to an injured nerve site could be applied as early as possible especially when the microenvironment is almost serum-free to obtain the most benefit. PMID- 20946297 TI - Pregnenolone and ganaxolone reduce operant ethanol self-administration in alcohol preferring p rats. AB - BACKGROUND: Neuroactive steroids modulate ethanol intake in several self administration models with variable effects. The purpose of this work was to examine the effects of the long-acting synthetic GABAergic neurosteroid ganaxolone and the endogenous neurosteroid pregnenolone, a precursor of all GABAergic neuroactive steroids, on the maintenance of ethanol self-administration in an animal model of elevated drinking-the alcohol-preferring (P) rats. METHODS: P rats were trained to self-administer ethanol (15% v/v) versus water on a concurrent schedule of reinforcement, and the effects of ganaxolone (0 to 30 mg/kg, subcutaneous [SC]) and pregnenolone (0 to 75 mg/kg, intraperitoneal [IP]) were evaluated on the maintenance of ethanol self-administration. After completion of self-administration testing, doses of the neuroactive steroids that altered ethanol self-administration were assessed on spontaneous locomotor activity. Finally, the effect of pregnenolone administration on cerebral cortical levels of the GABAergic neuroactive steroid (3alpha,5alpha)-3-hydroxypregnan-20 one (allopregnanolone, 3alpha,5alpha-THP) was determined in both ethanol experienced and ethanol-inexperienced P rats because pregnenolone is a precursor of these steroids. RESULTS: Ganaxolone produced a dose-dependent biphasic effect on ethanol reinforcement, as the lowest dose (1 mg/kg) increased and the highest dose (30 mg/kg) decreased ethanol-reinforced responding. However, the highest ganaxolone dose also produced a nonspecific reduction in locomotor activity. Pregnenolone treatment significantly reduced ethanol self-administration (50 and 75 mg/kg), without altering locomotor activity. Pregnenolone (50 mg/kg) produced a significant increase in cerebral cortical allopregnanolone levels. This increase was observed in the self-administration trained animals, but not in ethanol-naive P rats. CONCLUSIONS: These results indicate that pregnenolone dose dependently reduces operant ethanol self-administration in P rats without locomotor impairment, suggesting that it may have potential as a novel therapeutic for reducing chronic alcohol drinking in individuals that abuse alcohol. PMID- 20946300 TI - Clinical and electrophysiological profile of Brugada syndrome in the Tunisian population. AB - BACKGROUND: Most clinical studies of the clinical profile of Brugada syndrome (BS) have been conducted in either Asia, Europe, or America and their applicability to North African populations is largely unknown. The aim of the study was to analyze the clinical profile of BS in Tunisian patients. METHODS: The clinical and follow-up data of 24 patients (22 men, mean age: 40.8 +/- 13.7 years) were collected since 2002. Baseline characteristics, morbidity, and mortality data were obtained from medical records. RESULTS: One patient (4.16%) survived sudden cardiac death (SCD), four patients (16.3%) had syncope, and 19 patients (79.1%) were asymptomatic. Eleven patients (45.8%) had a family history of SCD. Twenty patients showed a spontaneous coved-type ST-segment elevation on electrocardiogram and after medical challenge on the four remnants. An electrophysiological study was performed in 15 of 24 patients (62.5%), during which ventricular fibrillation was induced in six patients (40%); three of the six patients were previously asymptomatic. An implantable cardioverter defibrillator (ICD) was implanted in 14 patients (58.3%). After a mean follow-up of 26 +/- 21 months, one patient died from a noncardiac cause and one patient (with a history of aborted SCD) received an appropriate shock from his ICD. None of the asymptomatic and noninducible patients experienced a cardiac event. CONCLUSIONS: BS is present in the North African population and is probably under recognized. Tunisian patients with BS share with their western and Asiatic counterparts similar clinical profile. PMID- 20946301 TI - Radiofrequency ablation of a left accessory pathway unmasks classic Chagas' disease ECG pattern. AB - In patients with chronic Chagas' cardiomyopathy, there are forms of the disease that affect the electrical conduction system almost exclusively. The most common disorders include right bundle branch block alone or in association with left anterior fascicular block. We present an unusual case of a patient with Chagas' cardiomyopathy in association with a preexcitation syndrome. PMID- 20946302 TI - Atypical initiation of endless-loop, pacemaker-mediated tachycardia. PMID- 20946303 TI - Permanent pacing for late-onset atrioventricular block in patients with heart transplantation: a single center experience. AB - INTRODUCTION: The incidence, mechanisms, clinical associations, and outcomes in patients with late-onset (>3 months) atrioventricular (AV) block following heart transplantation are not well known. This study will characterize late-onset AV block following cardiac transplantation. METHODS: We retrospectively reviewed our databases to identify patients who required pacemakers for late-onset AV block postheart and heart-lung transplantation from January 1990 to December 2007. Orthotopic heart and heart-lung transplantation were separately analyzed. RESULTS: This study included 588 adults who received cardiac transplants over a 17-year period at our center (519 orthotopic, 64 heart-lung transplants, and five heterotopic heart transplants). Of the 519 patients with orthotopic heart transplant, 39 required pacing (7.5%), 17 (3.3%) within 3 months posttransplant, 11 (2.1%) for late-onset sinus node dysfunction (SND), 11 (2.1%) for late-onset AV block. Also, five patients (7.8%) out of 64 heart-lung transplants required pacemakers, two (3.1%) for late-onset SND, three (4.7%) for late-onset AV block. None of the five patients who underwent heterotopic transplant required cardiac pacing prior to or posttransplant. CONCLUSIONS: Late-onset AV block occurs in 2.4% of patients with orthotopic heart transplant or heart-lung transplant. AV block is predominantly intermittent and, often, does not progress to permanent AV block. There are no predictable factors for its onset. PMID- 20946304 TI - Monitoring of diabetic foot syndrome treatment: some new perspectives. AB - Diabetic foot syndrome (DFS) is one of the major complications of diabetes, and it can lead to foot amputations. It is very important to assure good medical care for diabetic patients not only during their stay at hospital but also at home. Telecare can be one good solution for extending medical care to patients' homes. There are some reports regarding the application of new technologies in this field. The standard current model of telecare of DFS includes experts at hospital who conduct clinical examinations and decision making at a distance, in close cooperation with a visiting nurse and the patient. In the present paper a new paradigm of the DFS's telecare is introduced, which eliminates the visiting nurse. The designed and developed TeleDiaFoS system consists of a traditional database and mobile patient's module (PM) allowing for documentation of the foot images as well as the results of blood glucose and blood pressure measurements taken by the patient himself at home. A 2-year validation of the TeleDiaFoS system on 10 DFS patients (3 months each) proved its usefulness and led to acceptance of this type of technical support by patients and physicians. The designed and developed system and proposed sterilization procedure of the PM have been found to be easy to use by the patient at home. PMID- 20946305 TI - Explant culture: an efficient method to isolate adipose-derived stromal cells for tissue engineering. AB - Enzymatic digestion, the commonly used method of adipose-derived stromal cells isolation, is time consuming and expensive, especially when applied to large volumes of tissue. In the present study, the characteristics of the cells obtained by adipose tissue explant culture were studied. We found that adipose tissue fragments could adhere onto the growth surface of flasks in a very short time after plating and that fibroblast-like cells migrated from the explants and reached confluence. Morphologic analysis and surface markers expression suggested the mesenchymal origin of the cells derived from adipose tissue explants. After in vitro expansion these cells were successfully induced into adipogenic, osteogenic, and chondrogenic lineages, which demonstrated their multipotency. The high growth rate and colony-forming efficiency of explant-derived cells were similar to those of cells obtained by digestion. Furthermore, explant culture gave higher yield of cells than digestion method after primary culture. The experiment of ectopic adipogenesis in nude mice suggested the prospects for tissue engineering of these cells. In conclusion, we obtained multipotent stromal cells from adipose tissue by explant culture, and this method was simple, time saving, and gave a high yield of cells. Therefore, explant culture can be used as an effective way to isolate adipose-derived stromal cells for tissue engineering. PMID- 20946307 TI - Increased heterogenity of ventricular repolarization in obese nonhypertensive children. AB - OBJECTIVE: Obese children, without arterial hypertension, may be a unique clinical opportunity to evaluate the effect of obesity, per se, on ventricular repolarization, excluding the influence of possible comorbidities. The QTc dispersion (QTc-d), JTc dispersion (JTc-d), and transmural dispersion of repolarization (TDR) have been suggested to be electrocardiographic indexes reflecting the physiological variability of regional ventricular repolarization. The aim of our study is to define the effects of obesity on the ventricular repolarization in obese children who have no other clinically appreciable cause of heart disease. METHODS: The study involved 70 subjects (48 male, 22 female), with a mean age (+/- standard deviation) of 13 +/- 2 years. A total of 35 individuals were obese (Group A: 24 male, 11 female, mean body mass index [BMI] of 38.2 +/- 5.8 kg/m(2) ), and 35 participants were healthy lean children (Group C: 24 male, 11 female, mean BMI of 22.3 +/- 0.3 kg/m(2) ). Heart rate; QRS duration; maximum and minimum QT interval; and QTc-d, JTc-d, and TDR measurement were performed. RESULTS: Compared with the healthy control group, obese children presented increased values of the QTc-d, JTc-d, and TDR (31.1 +/- 10.6 vs 46.2 +/ 15.3 ms, P < 0.003; 29.8 +/- 8.5 vs 40.1 +/- 10.3 ms, P < 0.04; 83.2 +/- 13.5 vs 100.7 +/- 16.3 ms, P < 0.05). A statistically significant correlation was found between the values of QTc-d, insulin serum concentration (r = 0.46, P = 0.04), and homeostasis model assessment of insulin resistance (r = 0.34, P = 0.03). CONCLUSIONS: Our data suggest that obese nonhypertensive children have an increased ventricular repolarization heterogeneity in relation to controls. PMID- 20946306 TI - The nicotinic acetylcholine receptor partial agonist varenicline increases the ataxic and sedative-hypnotic effects of acute ethanol administration in C57BL/6J mice. AB - BACKGROUND: The costs associated with alcohol abuse are staggering, therefore much effort has been put into developing new pharmacologic strategies to decrease alcohol abuse. Recently, the nicotinic acetylcholine receptor (nAChR) partial agonist varenicline has been shown to decrease ethanol consumption in both humans and animal models. METHODS: We examined the effects of varenicline on the ataxic and sedative-hypnotic effects of ethanol. First, varenicline was administered prior to placement in a locomotor activity chamber to determine whether varenicline influenced baseline locomotor activity. To determine the effect of nicotinic modulation on ethanol-induced motor incoordination, varenicline was administered 30 minutes prior to an acute ethanol injection and then mice were tested on the balance beam, dowel test, or fixed-speed rotarod. To examine ethanol's sedative-hypnotic effects, varenicline was administered 30 minutes prior to 4 g/kg ethanol and the duration of loss of righting reflex (LORR) was measured. RESULTS: Varenicline markedly reduced baseline locomotor activity in C57BL/6J mice. Varenicline increased ethanol-induced ataxia when measured on the balance beam and dowel test but had no effect when measured on the fixed-speed rotarod. Pretreatment with varenicline increased the duration of LORR. CONCLUSIONS: These data provide evidence that nAChRs may be involved in the ataxic and sedative effects of ethanol. It is possible that one mechanism that could contribute to the ability of varenicline to decrease ethanol consumption may be through increasing negative behavioral effects of alcohol. PMID- 20946309 TI - Long-term follow-up data of coronary sinus stenting for the stabilization of the left ventricular leads. AB - BACKGROUND: Cardiac resynchronization therapy has been increasingly used for patients with heart failure. However, unstable and dislocated coronary sinus leads reduce the effectiveness of this important intervention. AIM: To examine the long-term effects of coronary sinus side branch stenting on sensing and pacing parameters of the left ventricular leads. METHODS: A total of eight patients (six males; two females; mean age, 56.6 +/- 14.4 years) whose coronary sinus lead dislocated during the procedure were included in the study. Targeted coronary sinus side branch stenting was performed to stabilize the leads. Sensing and pacing parameters including lead impedance, capture threshold, and R-wave amplitude were measured at implantation, first month, sixth month, and every 6 month period. RESULTS: Mean follow-up period was 30.4 +/- 7.4 months. At the time of implantation, lead impedance, capture threshold, and R-wave amplitude were 656 +/- 162 Omega, 1.1 +/- 0.5 V, and 13.0 +/- 6.8 mV, respectively. No statistically significant mean lead impedance, capture threshold, and R-wave amplitude differences were observed between at the time of implantation and at the time of last follow-up (697 +/- 164 Omega, 1.1 +/- 0.5 V, 12.8 +/- 6.9 mV, respectively). CONCLUSION: In this long-term study, coronary sinus side branch stenting for the stabilization of dislocated leads seems to be effective. PMID- 20946310 TI - Predictors of mortality in patients with Chagas' cardiomyopathy and ventricular tachycardia not treated with implantable cardioverter-defibrillators. AB - BACKGROUND: The natural history of the arrhythmogenic form of Chagas' heart disease is not fully understood. METHODS: We assessed the outcome of 56 patients with Chagas' cardiomyopathy ([31 men]; mean age of 55 years; mean left ventricular ejection fraction [LVEF] 42%) presenting with either sustained ventricular tachycardia (VT) or nonsustained VT (NSVT), before therapy with implantable cardioverter-defibrillator was available at our center. RESULTS: Over a mean follow-up of 38 +/- 16 months (range, 1-61 months), 16 patients (29%) died, 11 due to sudden cardiac death (SCD), and five from progressive heart failure. Survivors and nonsurvivors had comparable baseline characteristics, except for a lower LVEF (46 +/- 7% vs 31 +/- 9%, P < 0.001) and a higher New York Heart Association class (P = 0.003) in those who died during follow-up. Receiver operator characteristic curve analysis showed that an LVEF cutoff value of 38% had the best accuracy for predicting all-cause mortality and an LVEF cutoff value of 40% had the best accuracy for prediction of SCD. Using the multivariate Cox regression analysis, LVEF < 40% was the only predictor of all-cause mortality (hazard ratio [HR] 12.22, 95% confidence interval [CI] 3.46-43.17, P = 0.0001) and SCD (HR 6.58, 95% CI 1.74-24.88, P = 0.005). CONCLUSIONS: Patients with Chagas' cardiomyopathy presenting with either sustained VT or NSVT run a major risk for mortality when had concomitant severe or even moderate LV systolic dysfunction. PMID- 20946311 TI - Pacing within the ischemic area significantly decreases the left ventricular ejection fraction during experimental acute myocardial infarction. AB - BACKGROUND: The aim of this study was to examine the effects on left ventricular (LV) function of LV apical or/and lateral wall pacing during an experimental acute myocardial infarction. METHODS: In 12 anesthetized pigs, epicardial LV pacing at the apex or lateral wall, or at both sites simultaneously, was performed before and after left anterior descending (LAD) ligation. Data concerning LV function were obtained by two-dimensional echo during spontaneous sinus rhythm (SR) and during pacing before and 15, 45, 60, and 90 minutes after LAD ligation. RESULTS: Before ligation of the LAD, pacing at the lateral wall (48.04 +/- 6.25%) or both sites (45.71 +/- 6.31%) reduced the LV ejection fraction (EF) significantly (P < 0.01) in comparison to SR (55.44 +/- 4.10%). However, during pacing at the apex (50.19 +/- 6.50%), the reduction was not significant. After LAD ligation, the EF during lateral pacing (43.02 +/- 7.71%) was significantly higher than during apical pacing (38.78 +/- 8.26%, P < 0.04) but was not significantly different from that during dual-site pacing (41.65 +/- 8.69%). CONCLUSIONS: Pacing within the ischemic LV apical zone after LAD ligation impairs left ventricular ejection fraction, as compared with pacing the nonischemic LV lateral wall, and should therefore be avoided in clinical settings where the LV pacing site may be chosen. PMID- 20946312 TI - Possibility of skin epithelial cell transdifferentiation in tracheal reconstruction. AB - In tissue engineering, injured tissue is normally reconstructed with cells obtained from that tissue itself. However, it is difficult to obtain cells for reconstruction of the trachea because of its shape and limited accessibility. Therefore, other cell sources having similar form and function or stem cells are used for tracheal reconstruction. In a previous study, we used autologous skin epithelial cells and successfully reconstructed canine tracheas. We found that the tracheal epithelial layer was completely covered with ciliated cells, which is a remarkable finding because skin and tracheal epithelial cells originate from different germinal layers and have very different forms. In this study, to elucidate the origin of the ciliated cells, we identified the stem cell contents of skin epithelial cells on primary culture, marked the skin epithelial cells with PKH26 dye, and transplanted them onto canine tracheas. After 5 months, we identified PKH26 fluorescence on the tracheal epithelial layers, especially over the tracheal cartilages. Consequently, we demonstrated that transplanted autologous skin epithelial stem cells can remain viable on the trachea for a few months and can transdifferentiate into tracheal epithelial cells and chondrocytes. PMID- 20946313 TI - Monitoring photochemical pathogen inactivation treatment using amotosalen and ultraviolet-A light: evaluation of an indicator label. PMID- 20946315 TI - Reproductive tract vasculature of the female emu (dromaius novaehollandiae). AB - The arterial supply of the ovary and oviduct is provided by the ovarian artery, cranial oviductal artery, accessory cranial oviductal artery, middle oviductal artery, caudal oviductal artery and the medial and lateral vaginal arteries. These arteries supply various regions of the oviduct and are branches of either the left cranial renal artery, left external iliac artery, left middle renal artery, left lateral caudal artery or the left pudendal artery. The veins that drain the reproductive tract are satellite vessels to each artery that supplied the tract. PMID- 20946314 TI - Phase I/II study of the pharmacokinetics, safety and efficacy of S-1 in patients with advanced hepatocellular carcinoma. AB - S-1, an oral fluoropyrimidine derivative, has been shown to be clinically effective against various solid tumors, and preclinical studies have demonstrated activity against hepatocellular carcinoma. We conducted a phase I/II study in patients with advanced hepatocellular carcinoma to examine the pharmacokinetics, recommended dose, safety and efficacy of S-1. In phase I, the administered dose of S-1 was approximately 64 mg/m(2) per day in three patients (level 1) and approximately 80 mg/m(2) per day in six patients (level 2). There was no dose limiting toxicity at level 1, but two patients had dose-limiting toxicity at level 2 (grade 3 anorexia and grade 2 rash requiring eight or more consecutive days of rest). The recommended dose was finally estimated to be 80 mg/m(2) per day. There were no significant differences in the pharmacokinetics of S-1 between patients with Child-Pugh A and those with B. In phase II, five of 23 patients (21.7%) had partial responses. The median progression-free survival and overall survival were 3.7 and 16.6 months, respectively. The most common toxicities of grade 3 or 4 were elevated serum aspartate aminotransferase levels, hypochromia and thrombocytopenia. In conclusion, S-1 showed an acceptable toxicity profile and promising antitumor activity for hepatocellular carcinoma, warranting further evaluation in randomized clinical trials. PMID- 20946316 TI - Adrenal glands of slaughtered bulls, heifers and cows: a histological study. AB - The study involved histological and immunohistochemical examinations of the adrenal glands of healthy slaughtered cattle. Glands of 13 bulls, 10 heifers and 10 cows were examined. The following histological findings were observed: Unequal thickness of connective capsule and nodular formations of the zona glomerulosa (ZG), eosinophilic granules in cells of the ZG, globoid arrangement of the zona fasciculata, nodules or pegs of cortical tissue in the medulla, mutual interlacing of superficial and deep zones of the medulla, proliferation of cortical or medullary cells into the blood vessels wall situated in the medulla and focal inflammatory infiltrates. Cortical cells and noradrenalin-secreting (N) cells in the medulla expressed cytoplasmic positivity of S100 protein. Both adrenalin (A) cells and N cells were positive in synaptophysin. The majority of the cells in the cortex and in the medulla displayed were positive for chromogranin A. Electron microscopy showed structureless, electrondense particles of varying size and shape, mostly displaying the having mostly character of secretory granules. PMID- 20946317 TI - Quantitative trait loci for resistance to fish pasteurellosis in gilthead sea bream (Sparus aurata). AB - Fish pasteurellosis is a bacterial disease causing important losses in farmed fish, including gilthead sea bream, a teleost fish of great relevance in marine aquaculture. We report in this study a QTL analysis for resistance to fish pasteurellosis in this species. An experimental population of 500 offspring originating from eight sires and six dams in a single mass-spawning event was subjected to a disease challenge with Photobacterium damselae subsp. piscicida (Phdp), the causative agent of fish pasteurellosis. A total of 151 microsatellite loci were genotyped in the experimental population, and half-sib regression QTL analysis was carried out on two continuous traits, body length at time of death and survival, and for two binary traits, survival at day 7 and survival at day 15, when the highest peaks of mortality were observed. Two significant QTLs were detected for disease resistance. The first one was located on linkage group LG3 affecting late survival (survival at day 15). The second one, for overall survival, was located on LG21, which allowed us to highlight a potential marker (Id13) linked to disease resistance. A significant QTL was also found for body length at death on LG6 explaining 5-8% of the phenotypic variation. PMID- 20946318 TI - Marathon of eponyms: 14 Noonan syndrome. AB - The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology, oral and maxillofacial radiology and oral and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognised relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarises data about Noonan syndrome. PMID- 20946319 TI - Diannexin reduces no-reflow after reperfusion in rabbits with large ischemic myocardial risk zones. AB - INTRODUCTION AND AIMS: In patients with ST-segment elevation myocardial infarction who receive percutaneous coronary intervention and stenting, a large zone with no-reflow is associated with adverse outcomes. During myocardial ischemia/reperfusion, phosphatidylserine (PS) translocates to the surface of endothelial cells triggering attachment of platelets and leukocytes, thus impairing microvascular blood flow. Diannexin, a recombinant dimer of the endogenous human annexin V protein, binds PS and thus inhibits the adverse effects of PS. It has been shown to attenuate postischemic reperfusion injury in several experimental models. We speculated that Diannexin would reduce no-reflow in the heart after coronary artery occlusion (CAO) and reperfusion. Rabbits received: (1) Diannexin 5 min pre-CAO (diannexin pre ischemia [DPI], 400 MUg/kg, n = 17), or (2) Diannexin 5 min pre-coronary reperfusion (diannexin pre reperfusion [DPR], 400 MUg/kg, n = 20), or (3) saline (Cont, n = 18), with 30 min CAO and 3 h reperfusion. In a secondary analysis, rabbits were divided into two groups based on the overall average risk zone size of 29% of the left ventricle (LV): small (<29% of LV) and large (>29% of LV). RESULTS: Overall, risk zones and infarct size, and the no-reflow zone were similar in all groups. In hearts with large risk zones the no-reflow area was significantly smaller in both drug treated groups (DPI, 22 +/- 5% and DPR, 22 +/- 3% vs. control 40 +/- 3%, P < 0.006), the hemorrhagic areas were significantly smaller, and infarct size was reduced at the P < 0.06 level compared with control. In animals with small risk zones there were no significant differences. Diannexin treatment did not affect hemodynamics or LV function. CONCLUSION: Diannexin was cardioprotective in rabbits with a severe ischemic insult. This is important, because large infarcts accompanied by no-reflow in humans are associated with increased complications. In animals with small risk zones, no significant drug effect was observed. PMID- 20946320 TI - TREK-1 K(+) channels in the cardiovascular system: their significance and potential as a therapeutic target. AB - Potassium (K(+) ) channels are important in cardiovascular disease both as drug targets and as a cause of underlying pathology. Voltage-dependent K(+) (K(V) ) channels are inhibited by the class III antiarrhythmic agents. Certain vasodilators work by opening K(+) channels in vascular smooth muscle cells (VSMCs), and K(+) channel activation may also be a route to improving endothelial function. The two-pore domain K(+) (K(2P) ) channels form a group of 15 known channels with an expanding list of functions in the cardiovascular system. One of these K(2P) channels, TREK-1, is the focus of this review. TREK-1 channel activity is tightly regulated by intracellular and extracellular pH, membrane stretch, polyunsaturated fatty acids (PUFAs), temperature, and receptor coupled second messenger systems. TREK-1 channels are also activated by volatile anesthetics and some neuroprotectant agents, and they are inhibited by selective serotonin reuptake inhibitors (SSRIs) as well as amide local anesthetics. Some of the clinical cardiovascular effects and side effects of these drugs may be through their actions on TREK-1 channels. It has recently been suggested that TREK-1 channels have a role in mechano-electrical coupling in the heart. They also seem important in the vascular responses to PUFAs, and this may underlie some of the beneficial cardiovascular effects of the essential dietary fatty acids. Development of selective TREK-1 openers and inhibitors may provide promising routes for intervention in cardiovascular diseases. PMID- 20946321 TI - Unfractionated heparin during elective PCI: fixed dose or weight adjusted? AB - INTRODUCTION: To assess two different dosing strategies of unfractionated heparin (UFH) during elective percutaneous coronary intervention (PCI). AIMS: The optimal dose of heparin during elective PCI in patients with stable angina is unknown. Existing guidelines are based on limited data. We interrogated data from the PCI database. Patients with stable angina undergoing planned transradial PCI for uncomplicated single lesions were included. The main endpoint was troponin I release. We compared a fixed heparin dose (3000 U) UFH to a weight-adjusted dose. RESULTS: Of 698 patients 244 (35.0%) received fixed dose (3000 U) and 454 (65.0%) 70 U/kg weight-adjusted UFH. There was no significant difference in median troponin between the fixed dose and the weight-adjusted groups; 0.17 ng/mL versus 0.14; P= 0.21. The proportion of troponin positive patients was similar in both groups (61.9% in the fixed dose group vs. 58.1%; P= 0.37). There were no deaths or major ischemic events during hospitalization. There was no bleeding requiring transfusion or delaying hospital discharge. CONCLUSION: In conclusion, this retrospective observational study of elective transradial PCI demonstrated that a reduced, fixed dose of periprocedural heparin was associated with similar postprocedural troponin levels when compared to a standard weight-adjusted regime. Our study further questions the optimal dose of heparin required during elective PCI and suggests a need for further trials. PMID- 20946322 TI - Cardiac cell therapies: the next generation. AB - Although significant advances have been made in terms of pharmacological, catheter-based, and surgical palliation, heart failure remains a fatal disease. As a curative concept, regenerative medicine aims at the restoration of the physiologic cellular composition of diseased organs. So far, clinical cardiac regeneration attempts have only been moderately successful, but a better understanding of myocardial cell homeostasis and somatic as well as embryonic stem cell biology has opened the door for the development of more potent therapeutic cardiac regeneration strategies. Accumulating evidence indicates that the postnatal mammalian heart retains a pool of tissue-specific progenitor cells and is also repopulated by cells from extracardiac sources. However, this intrinsic myocardial regeneration potential clearly needs to be augmented by either manipulation of the cell cycle of differentiated cells, activation of resident cardiac progenitor cells, and/or the transplantation of exogenous cells. This review summarizes the recent developments in cardiac regenerative medicine, many of which may find their way into the clinical setting in the foreseeable future. PMID- 20946323 TI - The potential for clinical use of cannabinoids in treatment of cardiovascular diseases. AB - Cannabinoids, the constituents of the marijuana plant and their analogs, have not only neurobehavioral but also cardiovascular effects. Great advances in the last couple of decades have led to better understanding of the physiological effects of the cannabinoids and of their role in various cardiovascular pathologies. The potential therapeutic use of cannabinoids in various cardiac diseases, such as ischemic injury, heart failure, and cardiac arrhythmias, has been studied in animal models. The purpose of this article is to review the physiological cardiovascular properties of cannabinoids and to summarize the knowledge related to their potential therapeutic use. PMID- 20946324 TI - Disruption of coronary vasomotor function: the coronary spasm syndrome. AB - Abnormal coronary vasoconstriction, or coronary spasm, can be the result of several factors, including local and neuroendocrine aberrations. It can manifest clinically as a coronary syndrome and plays an important role in the genesis of myocardial ischemia. Over the past half century, coronary angiography allowed the in vivo demonstration of spasm in patients who fit the initial clinical description of the condition as reported by Prinzmetal et al. Several clinical, basic, and more recently, genetic studies have provided insight into the pathogenesis, manifestations, and therapy of this condition. It is not uncommonly encountered in patients with coronary syndromes and absence of clearly pathologic lesions on angiography. Provocation tests utilizing pharmacologic and nonpharmacologic stimuli combined with imaging (echocardiography or coronary angiography) can help make the correct diagnosis. The use of calcium channel blockers and long-acting nitrates is currently considered standard of care and the overall prognosis appears to be good. The recent discovery of genetic abnormalities predisposing to abnormal spasm of the coronaries has stimulated interest in the development of targeted therapies for the management of this condition. PMID- 20946325 TI - MicroRNA-based therapeutic approaches in the cardiovascular system. AB - MicroRNAs (miRNAs) are endogenous small ribonucleotides that participate in the orchestration of the genome by regulating target messenger RNA translation. MiRNAs control physiological processes and misexpression of miRNAs is pathogenically involved in many diseases including cardiovascular diseases. Normalization of miRNA expression and thus downstream target networks may have enormous therapeutic chances but also risks. We here highlight and discuss recent advances in the development and use of miRNA therapeutics to target miRNAs in vivo that may translate into novel therapeutic strategies for cardiovascular diseases in the future. PMID- 20946326 TI - Focal and panretinal photocoagulation with a navigated laser (NAVILAS(r)). PMID- 20946327 TI - Histomorphometry of the circular peripapillary arterial ring of Zinn-Haller in normal eyes and eyes with secondary angle-closure glaucoma. AB - PURPOSE: To examine the location and size of the peripapillary arterial circle of Zinn-Haller (PACZH) and its associations with other eye measures in normal eyes and eyes with secondary angle-closure glaucoma. METHODS: The study included 29 human globes enucleated because of malignant choroidal melanoma (n = 19) (control group) or because of secondary angle-closure glaucoma (n=10). Anterior-posterior histological sections were morphometrically evaluated. RESULTS: The PACZH was present in all eyes. The glaucoma group and the control group did not vary significantly in the distance from the PACZH to Bruch's membrane (297 +/- 67 versus 270 +/- 67 MUm; p = 0.29), optic disc border (281 +/- 103 versus 391 +/- 170 MUm; p=0.07), optic disc centre (1059 +/- 191 versus 978 +/- 205MUm; p = 0.30) and retrobulbar cerebrospinal fluid space (173 +/- 58 versus 172 +/- 81 MUm; p = 0.97) nor in the minimal PACZH diameter (39+/- 18 versus 36 +/- 18 MUm; p = 0.74) and maximal PACZH diameter (78 +/-37 versus 65 +/- 25 MUm; p = 0.36). The PACZH location, measured as distance from Bruch's membrane, disc border, disc centre and cerebrospinal fluid space, was not significantly associated with axial length (p > 0.39), horizontal globe diameter (p > 0.17) and vertical globe diameter (p > 0.22). Both diameters were statistically independent of axial length (p = 0.72 and p = 0.58, respectively), horizontal globe diameter (p = 0.60 and p = 0.41, respectively) and vertical globe diameter (p = 0.64 and p = 0.52, respectively). All parameters were statistically independent of age (p > 0.10) and gender (p > 0.10). CONCLUSIONS: The PACZH was present in all human eyes examined and did not vary significantly in location and diameter between eyes with secondary angle-closure glaucoma and nonglaucomatous eyes, nor between myopic versus hyperopic eyes. PMID- 20946328 TI - Intravitreal bevacizumab for perifoveal telangiectasia. PMID- 20946329 TI - Verteporfin photodynamic therapy of six eyes with retinal capillary haemangioma. AB - PURPOSE: Single-centre consecutive interventional case series by retrospective chart review to evaluate the efficacy of verteporfin (VisudyneTM) photodynamic therapy (PDT) of retinal capillary haemangioma (RCH). METHODS: Following an initial period of observation, six eyes of five patients with RCH (juxtapapillary 3 and extrapapillary (EP) 3) received 1-3 sessions of standard verteporfin PDT upon the development of progressive vision-threatening complications. Four of the five patients had von Hippel-Lindau (VHL) disease. Follow-up included documentation of best-corrected Snellen visual acuity (BCVA), tumour regression, and presence or absence of subretinal fluid (SRF) and/or lipid exudation as assessed by dilated fundus examination (DFE), fundus photos, and optical coherence tomography (OCT). These parameters were documented at 1 week, 1 month, and 3 months following each PDT session and up to 32 months following the first PDT. RESULTS: All eyes showed favourable response to PDT as defined by tumour regression or stabilization as well as improvement of SRF and lipid exudation. BCVA improved or stabilized in three eyes. Three eyes required PDT retreatment for recurrent SRF. Epiretinal membrane (ERM) worsened in three eyes, requiring vitreoretinal surgery at a median of 6 months following PDT. CONCLUSIONS: PDT is a moderately effective treatment for juxtapapillary and EP RCH. In this series, PDT resulted in tumour regression or stabilization as well as in the improvement of SRF and lipid exudation in all cases. However, stabilization or improvement of visual acuity was observed in only 50 per cent of the cases. The treatment benefits may be limited by pre-existing macular changes and worsening of ERM. A larger prospective study is necessary to validate these findings. PMID- 20946330 TI - Corneal endothelial cells 6-7 years following cataract surgery in patients with pseudoexfoliation syndrome. AB - PURPOSE: To assess the condition of the corneal endothelium an extended period after cataract surgery in eyes with and without pseudoexfoliation syndrome (PES). METHODS: Forty-six patients with PES who underwent cataract surgery in the Eye Department, Oslo University Hospital, in 2001 and 2002 were enrolled and compared to 101 matched controls without PES who had surgery in the same period. They were re-examined 6-7 years following surgery with measurements taken of corneal endothelial cell density (ECD), pleomorphism, polymegathism and corneal thickness. RESULTS: Mean ECD was 2024 +/- 371 cells/mm(2) in eyes with PES and 2144 +/- 365 cells/mm(2) in eyes without PES. The difference was not statistically significant. No significant difference in polymegathism and pleomorphism was noted. Mean corneal thickness was 543 and 547 MUm in eyes with and without PES, respectively (not statistically significant). The presence of glaucoma in pseudoexfoliative eyes was not associated with endothelial cell changes. CONCLUSION: Six to 7 years following cataract surgery, no statistically significant differences were established in ECD, pleomorphism, polymegathism and corneal thickness in eyes with and without PES. No clinical signs of corneal decompensation were noted amongst the participants. PMID- 20946331 TI - Recurrent choroidal melanoma after brachytherapy in an eye with scleral calcification. PMID- 20946332 TI - Intravitreal triamcinolone, bevacizumab and pegaptanib for occult choroidal neovascularization. AB - PURPOSE: To evaluate best-corrected visual acuity (BCVA) and foveal thickness (FT) changes in occult subfoveal choroidal neovascularization (CNV) from age related macular degeneration (AMD) after intravitreal bevacizumab (IVB, 1.25 mg/0.05 ml), pegaptanib (IVP, 0.3 mg/0.09 ml) and triamcinolone acetonide (IVTA, 4 mg/0.1 ml) injected on an as needed basis. METHODS: Retrospective, interventional, comparative study. BCVA (Early Treatment Diabetic Retinopathy Study LogMAR) and FT by optical coherence tomography (OCT) were evaluated during 12 months from first treatment. Patients were retreated if signs of neovascular activity were still present on angiography or OCT. RESULTS: Forty-eight eyes received IVB, 43 eyes received IVP, 52 eyes received IVTA. BCVA and FT at baseline were 1.22 +/- 0.49 LogMAR and 410.2 +/- 41.83 MUm in the IVB group, 1.25 +/- 0.43 LogMAR and 452.3 +/- 44.83 MUm in the IVP group and 1.31 +/- 0.4 LogMAR and 456.6 +/- 48.27 MUm in the IVTA group. BCVA and FT improved in the three groups during follow-up. A significantly greater improvement of BCVA was present at month-3, month-6 and at month-12 in the IVB and IVP groups (p = 0.01). Improvement of FT was greater in the IVTA group at month-3 (p = 0.02), while it was greater in the anti-Vascular Endothelial Growth Factor (VEGF) groups at month 6 and month-12 (p = 0.01). A postoperative increase of intraocular pressure was detected in 9/52 (17.3%) eyes treated with IVTA, and in two cases it was resistant to topical therapy. CONCLUSION: Intravitreal injection of anti-VEGF drugs administered on an as needed basis for AMD-related occult CNVs provided functional and anatomic improvement during 12 months of follow-up. PMID- 20946333 TI - Increased electroretinogram a-wave amplitude after intravitreal bevacizumab injection for neovascular age-related macular degeneration. AB - PURPOSE: To assess the effect of bevacizumab (Avastin), a vascular endothelial growth factor inhibitor, on retinal function by full-field electroretinography (ERG) in patients with neovascular age-related macular degeneration (AMD). DESIGN: A prospective, nonrandomized, controlled interventional clinical trial. METHODS: Twelve patients (aged 50)85) with neovascular AMD each received one unilateral intravitreal injection of bevacizumab 1.25 mg/ 0.05 ml as part of the standard management for choroidal neovascular AMD. Before and 1 month after injection, all patients underwent bilateral full-field ERG scanning by a masked technician according to the ISCEV protocol, and their wave amplitudes were recorded. Untreated eyes served as controls. Scotopic responses were recorded at four incremental light intensities and photopic responses at two incremental light intensities. Changes in ERG-amplitude responses were calculated. Repeated measures ANOVA was used for data analysis. RESULTS: Mean pre- and postinjection differences in a-wave amplitudes between the incremental light intensities in injected eyes were significantly higher than in controls (15.92 versus 1.33 lV for scotopic responses and 4.97 versus )1.06 lV for photopic responses; p = 0.057 and p = 0.01, respectively). Mean b-wave amplitudes in injected eyes were significantly higher than in controls for photopic responses (p = 0.048), but for scotopic responses, the difference between treated and untreated eyes was not significant (p = 0.23). CONCLUSIONS: Intravitreally injected bevacizumab improves both rod and cone functioning in patients with neovascular AMD, as demonstrated by the increase in the ERG a-wave responses of these patients. Other measured ERG parameters yielded no significant photoreceptor toxicity. PMID- 20946334 TI - Changes in respiratory disorder parameters during the night in patients with obstructive sleep apnoea. AB - BACKGROUND AND OBJECTIVE: Patients with OSA frequently experience cardiovascular events, especially late at night. This phenomenon raises the possibility that respiratory disorders are progressively aggravated during the course of nocturnal sleep. To test this hypothesis, we investigated the changes in respiratory disorder parameters occurring during the night in patients with OSA, in the supine position and in all sleep positions. METHODS: Thirty consecutive patients with OSA were enrolled in the study and categorized into those with moderate OSA (n = 12; AHI <40 events/h) and those with severe OSA (n=18; AHI >=40 events/h). To identify the time during the sleep period at which changes in respiratory disorder parameters were most pronounced, AHI, mean duration of apnoea and average SaO(2) were assessed during the early, middle and late segments of sleep, in the supine position and in all sleep positions. RESULTS: AHI decreased significantly with time during the course of the total sleep period, and especially during non-rapid eye movement (NREM) sleep. In the group with severe OSA, prolongation of the mean duration of apnoea and the decrease in average SaO2 were also significant in the late segment of sleep in the supine position, especially during NREM sleep. CONCLUSIONS: In patients with severe OSA, there was progressive prolongation of the mean duration of apnoea late at night and this was associated with aggravation of hypoxia in the supine position during NREM sleep. This phenomenon may contribute to the remarkable rise in blood pressure early in the morning, possibly increasing the vulnerability of these patients to cardiovascular events. PMID- 20946336 TI - Comparison of Fcgamma receptor expression on neutrophils with procalcitonin for the diagnosis of sepsis in critically ill patients. AB - BACKGROUND AND OBJECTIVE: The expression of Fc receptors for IgG (FcgammaRs) on neutrophils, including CD16, CD32 and CD64, may be modulated in response to sepsis. We investigated the expression of FcgammaRs on neutrophils and procalcitonin (PCT) as biomarkers of sepsis among critically ill patients. METHODS: This prospective study was conducted in a 24-bed respiratory intensive care unit between July 2007 and June 2008. Critically ill patients requiring mechanical ventilation were enrolled and categorized into three groups: those with systemic inflammatory response syndrome (SIRS), those with severe sepsis and those with septic shock. Expression of FcgammaRs on neutrophils was quantitatively measured by flow cytometry immediately after enrolment of the patient. Serum PCT levels were also measured. Receiver operating characteristic (ROC) curves were used to evaluate the performance of FcgammaR expression and PCT as biomarkers of sepsis. RESULTS: Sixty-six patients were enrolled, including 11 with SIRS, 31 with severe sepsis and 24 with septic shock. Nineteen healthy volunteers served as normal controls. CD64 was upregulated, CD16 was downregulated and CD32 remained unchanged during sepsis. CD64 expression and the ratio of CD64/CD16 increased significantly with the severity of sepsis. However, serum PCT levels were not significantly different between SIRS and severe sepsis patients. CD64, CD64/CD16 and PCT all significantly predicted sepsis, septic shock and bacteraemia. As assessed using ROC curves, CD64 was better than PCT for differentiating SIRS from severe sepsis and septic shock. CD64 and CD64/CD16 were associated with mortality. CONCLUSIONS: CD64 and CD16 were differentially modulated by sepsis. CD64, CD64/CD16 and PCT may be biomarkers of sepsis. CD64 was better than PCT for identifying patients who required treatment with antibiotics. PMID- 20946337 TI - Heart rate recovery after six-minute walk test predicts pulmonary hypertension in patients with idiopathic pulmonary fibrosis. AB - BACKGROUND AND OBJECTIVE: In patients with IPF, we sought to validate that abnormal heart rate recovery at 1 min (HRR1) after six-minute walk test (6MWT) predicts mortality and to explore the relationship between abnormal HRR1 and pulmonary hypertension (PH). METHODS: We identified IPF patients who performed a 6MWT as part of their clinical evaluation between 2006 and 2009 and were followed to lung transplantation or death. Right heart catheterization (RHC) data were collated and analysed for the subgroup who had this procedure. RESULTS: There were 160 subjects who qualified for the survival analysis, and those with an abnormal HRR1 had worse survival than subjects with normal HRR1 (log-rank P = 0.01). Eighty-two subjects had a right heart catheter (RHC); among them, abnormal HRR1 was associated with RHC-confirmed PH (chi(2) = 4.83, P = 0.03) and had a sensitivity, specificity, positive predictive value and negative predictive value of 52%, 74%, 41% and 82%, respectively, for PH. In bivariate and multivariable analyses, abnormal HRR1 appeared to be the strongest predictor of RHC-confirmed PH (odds ratio (OR) = 4.0, 95% CI: 1.17-13.69, P = 0.02 in the multivariable analysis). CONCLUSIONS: This study adds to data that support the validity of abnormal HRR1 as a predictor of mortality and of RHC-confirmed PH in IPF. Research is needed to further investigate the link between abnormal HRR1 and PH and to elucidate heart-lung interactions at work during exercise and recovery in patients with IPF. PMID- 20946338 TI - Extrapulmonary involvement in patients with sarcoidosis in Turkey. AB - BACKGROUND AND OBJECTIVE: Extrapulmonary sarcoidosis is common, and is almost always associated with concomitant thoracic involvement. Extrapulmonary manifestations vary on the basis of gender, age at presentation and ethnicity. The aim of this study was to investigate extrapulmonary involvement in patients with sarcoidosis in Turkey. METHODS: This study was conducted by Turkish Thoracic Society Clinical Problems Study Group. New cases of sarcoidosis between 1 June 2004 and 31 May 2006 were recorded on electronic case record forms sent to all potential investigators and information about extrapulmonary involvement was collected. RESULTS: One hundred and nineteen of 293 patients (83 female, 36 male, mean age = 45 +/- 12 years) had extrapulmonary involvement in this study (40.6%). The median time to diagnosis was 6 months and this was longer than patients with just thoracic sarcoidosis (P = 0.001). Extrapulmonary symptoms were present in 181 (61.8%) patients, and skin lesions, arthralgia and back pain were the commonest (33.4%, 20.8% and 16.4%, respectively). Incidence of organ involvement was independent of age with the exception of ocular involvement, which was higher in those under the age of 40 years (P = 0.007). CONCLUSIONS: Skin and peripheral lymph node involvement were the most common sites of extrapulmonary involvement and ocular involvement was more common in those under the age of 40 years in patients with sarcoidosis in a Turkish population. PMID- 20946339 TI - Association between the tumour necrosis factor-alpha-308G/A polymorphism and chronic obstructive pulmonary disease: an update. AB - BACKGROUND AND OBJECTIVE: Previous studies have suggested that the -308A allele in the tumour necrosis factor-alpha (TNF-alpha) gene promoter (rs1800629) may be a potential risk factor for COPD. However, more recent findings have been inconsistent. In the present study, a meta-analysis was performed to assess the association between the TNF-alpha-308G/A single nucleotide polymorphism (SNP) and the risk of COPD. METHODS: Published studies were retrieved from PubMed, EMBASE and other databases. All studies assessing the association between the TNF-alpha 308G/A SNP and the risk of COPD were assessed. Pooled ORs with 95% CIs were calculated. RESULTS: In the 36 studies that met the inclusion criteria, 4975 patients and 6518 control subjects had been genotyped. The overall results showed that the association between the TNF-alpha-308G/A SNP and the risk of COPD was statistically significant for Asians (OR = 2.36, 95% CI: 1.84-3.02, P < 0.0001) but not for Caucasians (OR = 1.07, 95% CI: 0.91-1.25, P = 0.438). As smoking is one of the most important risk factors for COPD, a second meta-analysis that included only smokers (3018 patients and 2749 control subjects) was performed. This analysis confirmed that the association between the TNF-alpha-308G/A SNP and COPD was statistically significant for Asians (OR = 1.72, 95% CI: 1.14-2.61, P = 0.011) but not for Caucasians (OR = 1.16, 95% CI: 0.86-1.56, P = 0.33). CONCLUSIONS: This meta-analysis suggests that the TNF-alpha-308A genotype is associated with an increased risk of COPD in Asian but not Caucasian populations. Further studies are necessary to evaluate the relationship between TNF-alpha polymorphisms and the risk of COPD. PMID- 20946335 TI - Severe pandemic (H1N1)v influenza A infection: report on the first deaths in Spain. AB - BACKGROUND AND OBJECTIVE: The impact of pandemic influenza A (H1N1)v infection is still unknown but it is associated with a high case-fatality rate. METHODS: This was a prospective, observational, multicentre study conducted in 144 Spanish intensive care units. Demographic and clinical data were reviewed for all cases of pandemic influenza A (H1N1)v infection reported from 23 June 2009 through 11 February 2010 and confirmed by reverse transcriptase PCR assay. RESULTS: Out of 872 cases reported by statewide surveillance, data for the first 131 deceased patients were analysed. Thirty-seven patients (28.2%) died within the first 14 days. The median age of these patients was 46 years (interquartile range 35-58) and 60.3% were male. Twenty-eight patients (21.4%) did not present with any comorbidities on admission. Forty-six per cent of patients were reported to be obese and 22 (16.8%) had COPD. The vast majority of the patients (72.5%) had viral pneumonia; 95.4% of these had bilateral patchy alveolar opacities (predominantly basal), affecting three or four quadrants. One hundred and fifteen patients (87.8%) developed multi-organ dysfunction syndrome. Ninety-seven patients (74%) required vasopressor drugs, 37 (27.2%) received renal replacement therapy, and 47 (35.1%) received intravenous corticosteroids on admission to the intensive care unit. Only 68 patients (51.9%) received empirical antiviral treatment. CONCLUSIONS: One-third of patients with pandemic influenza A (H1N1)v infection died within the first two weeks and these were young patients, with rapidly progressive viral pneumonia as the primary cause of admission. Obese patients were at high risk but one in four patients did not present with any risk factors on admission. Only half the patients received empirical antiviral therapy and this was administered late. PMID- 20946340 TI - Severe pandemic H1N1 2009 influenza A infection: are we ready to move on? PMID- 20946341 TI - Recurrence of choroidal neovascular membrane after autologous transplantation of RPE and choroid for neovascular AMD. PMID- 20946342 TI - Performance of time-domain and spectral-domain Optical Coherence Tomography for glaucoma screening. AB - PURPOSE: To investigate the measures of validity for selective or population screening of the time-domain Stratus and the spectral-domain Cirrus Optical Coherence Tomography (OCT) imaging techniques in a population-based sample and in clinical glaucoma patients at different stages of glaucoma. PATIENTS AND METHODS: A random sample of 307 subjects living in two rural areas in southern Sweden, and a random sample of 394 clinical glaucoma patients were selected. A large battery of examinations, including Stratus and Cirrus OCT was performed. OCT retinal nerve fibre layer (RNFL) thickness analyses for average thickness, quadrant and clock-hour sectors were compared with normative significance limits available in the instruments. RESULTS: The population-based sample included 129 healthy and nine glaucoma subjects, and the sample of clinical glaucoma patients included 138 patients. Specificity and positive predictive values were generally better with Stratus than for Cirrus, and sensitivity was generally better with Cirrus. With the average RNFL thickness parameter, Stratus reached 100% specificity and a positive predictive value of 100% and 68% sensitivity in the whole group of the clinical glaucoma patients, but sensitivity was only 28% among the earliest stage glaucoma patients. Sensitivity increased considerably when relying on the quadrant sector parameter, while specificity decreased only marginally. CONCLUSION: Stratus, with high specificity and positive predictive values, seemed to be best of choice for screening purposes, while Cirrus, with high sensitivity, was the better choice for early detection. PMID- 20946343 TI - Improvement of cardio-ankle vascular index by glimepiride in type 2 diabetic patients. AB - AIMS: Glimepiride, a third generation sulfonylurea (SU), is known to have extrapancreatic effects, but its vascular effect is unclear. We investigated the efficacy of glimepiride in improving arterial stiffness assessed by cardio-ankle vascular index (CAVI) in type 2 diabetic patients, compared with glibenclamide, a conventional SU. METHODS: Forty type 2 diabetic patients were randomly assigned to two groups. One group was administered glimepiride 1.5 mg/day, and the other group was administered glibenclamide 1.25 mg/day for 6 months. RESULTS: No significant difference in hypoglycaemic effect was observed between two groups. CAVI significantly decreased only in glimepiride group (9.4 +/- 1.4->8.9 +/- 0.8, p < 0.05). Decrease in CAVI was greater in glimepiride group than in glibenclamide group (-0.50 +/- 0.98 vs. -0.04 +/- 0.57, p = 0.048). Urinary 8 hydroxy-2'-deoxyguanosine (8-OHdG) decreased in glimepiride group and increased in glibenclamide group, and the changes were significantly different between groups (-1.5 +/- 3.5 vs. + 1.8 +/- 3.6, p = 0.009); whereas serum lipoprotein lipase mass increased in glibenclamide group and decreased in glibenclamide group, and the changes tended to be different between groups (+ 2.1 +/- 19.1 vs. 7.4 +/- 19.2, p = 0.096). Change in urinary 8-OHdG was a significant independent predictor for change in CAVI in all subjects. CONCLUSIONS: These results suggest that glimepiride improves CAVI compared with glibenclamide. Reduced oxidative stress and improved insulin resistance may contribute to the improvement of CAVI by glimerpiride. PMID- 20946344 TI - A retrospective study of 889 injured permanent teeth. AB - The aim of this study was to investigate pre-injury factors, causes of dental injuries and healing complications after traumatic injuries to permanent teeth. The analysed sample comprised 889 permanent teeth of 384 patients, who were treated in the Dentistry Department in Faculty Hospital in Pilsen. Enamel-dentin fractures [233 teeth (26.2%)] and lateral luxations [207 teeth (23.3%)] were the most frequent injuries. The age of the patients at the time of injury varied between 7 and 65 years. Predominantly, children were affected [587 injured teeth (66.0%)]. The most frequent causes of injuries in patients older than 11 years were various sport activities, predominantly bicycling. Pulp necrosis was observed in 239 teeth (26.9%). It was the most frequent post-traumatic complication in all types of dental traumas. Teeth with a completed root formation demonstrated a higher prevalence of pulp necrosis than teeth with an incomplete root formation in all types of luxation injuries. External root resorption was observed in 144 teeth. The rate of inflammatory resorption differed between the various types of luxation injuries (extrusive luxation 5.6%, lateral luxation 11.6%, intrusive luxation 33.3%). Following avulsion and replantation, active inflammatory resorptions were diagnosed in 13 (26.5%) of 49 replanted teeth and ankylosis/replacement resorptions were observed in 21 (42.9%) of 49 replanted teeth. After avulsion, primarily, immature teeth were affected by these complications. Within the observation period of 5 years, 39 teeth (4.4%) had to be removed (16 teeth with root fractures, 19 avulsed and replanted teeth, 3 luxated teeth, 1 tooth with crown-root fracture). PMID- 20946345 TI - Effect of HBSS storage time on human periodontal ligament fibroblast viability. AB - Hank's balanced salt solution (HBSS) is recommended for the storage of avulsed teeth. The objective of this study was to evaluate if the HBSS storage time influences its ability to maintain the viability of human periodontal ligament fibroblasts (PDLF) by the analysis of cell metabolic function using MTT assay. PDLF were kept at 20 degrees C for 3, 6, 24, 48, 72, 96 and 120 h in recently prepared HBSS (HBSS), HBSS stored for 6 months (HBSS 6 M), HBSS stored for 12 months (HBSS 12 M), and in Save-A-Tooth system's HBSS (Save). Minimum essential medium (MEM) at 37 degrees C and tap water at 20 degrees C served as positive and negative controls, respectively. Cell viability was determined by the tetrazolium salt-based colorimetric (MTT) assay. Data were statistically analyzed by the Kruskal-Wallis and Scheffe tests (alpha = 5%). Starting with the 6 h time-point, HBSS was significantly more effective than HBSS 6 M, HBSS 12 M and Save in maintaining cell viability. HBSS 6 M effectiveness was similar to that of HBSS 12 M for up to 48 h, becoming higher at 72 h. In conclusion, the storage time of HBSS had a negative influence on its ability to maintain PDLF viability. PMID- 20946346 TI - Resolution of a titanium implant fracture after a recurrent trauma. AB - Post-traumatic complications occasionally lead to tooth loss as well as the need for future implants. However, rehabilitation with endosseous osseointegrated implants does not protect the patient from the risk of suffering a new trauma. Implant fracture and the damage of the hexagon are post-traumatic complications that guide the clinician to preparing a more intricate treatment plan. The authors present a clinical case of a recurrent trauma of maxillary implant fracture. The treatment plan was to remove the implants followed by autogenous bone grafting to correct the defect. Two titanium implants were replaced, followed by connective tissue graft after allowing complete the healing process of the bone graft to occur. In the postoperative period of 6 months, satisfactory results have been shown as regards soft and hard tissues wound healing. PMID- 20946347 TI - Inactivation of the STT7 gene protects PsaF-deficient Chlamydomonas reinhardtii cells from oxidative stress under high light. AB - Photosystem I (PSI) utilizes light energy to excite electrons for the reduction of NADP(+) , and like photosystem II, it is sensitive to excess light. When PSI is excited and unable to be reduced by the electron transport chain, the special pair of chlorophyll molecules, P700(+) , will take electrons from neighboring sources leading to cellular damage. A Chlamydomonas reinhardtii mutant, which is defective in the production of the PsaF subunit of PSI, provides an ideal platform for studying the processes involved in protecting PSI from excess light. This strain dies following the exposure to high light (HL) because of photo oxidative damage. We used a second-site suppressor screen to identify genes involved in protecting PsaF-deficient PSI from excess light. In doing so, we demonstrated that the absence of the STT7 protein, which is required for LHCII phosphorylation and the process of state transitions suppresses the psaF HL lethal phenotype. On the basis of chlorophyll fluorescence measurements, the psaF mutant has a more reduced plastoquinone pool at a given photosynthetic photon flux density than the wild-type cells. Under these conditions the process of state transitions will become active, resulting in the transfer of phosphorylated LHCII proteins to PSI, further increasing the excitation of PSI. However, in the psaF stt7 double mutant, the LHCII proteins will not be transferred to PSI, and thus the level of PSI excitation will remain lower. This study provides clear genetic evidence that the HL-lethal phenotype of the psaF mutant is because of PSI overexciation. PMID- 20946348 TI - Characterization of the programmed cell death induced by metabolic products of Alternaria alternata in tobacco BY-2 cells. AB - Alternaria alternata has received considerable attention in current literature and most of the studies are focused on its pathogenic effects on plant chloroplasts, but little is known about the characteristics of programmed cell death (PCD) induced by metabolic products (MP) of A. alternata, the effects of the MP on mitochondrial respiration and its relation to PCD. The purpose of this study was to explore the mechanism of MP-induced PCD in non-green tobacco BY-2 cells and to explore the role of mitochondrial inhibitory processes in the PCD of tobacco BY-2 cells. MP treatment led to significant cell death that was proven to be PCD by the concurrent cytoplasm shrinkage, chromatin condensation and DNA laddering observed in the cells. Moreover, MP treatment resulted in the overproduction of reactive oxygen species (ROS), rapid ATP depletion and a respiratory decline in the tobacco BY-2 cells. It was concluded that the direct inhibition of the mitochondrial electron transport chain (ETC), alternative pathway (AOX) capacity and catalase (CAT) activity by the MP might be the main contributors to the MP-induced ROS burst observed in tobacco BY-2 cells. The addition of adenosine together with the MP significantly inhibited ATP depletion without preventing PCD; however, when the cells were treated with the MP plus CAT, ROS overproduction was blocked and PCD did not occur. The data presented here demonstrate that the ROS burst played an important role in MP-induced PCD in the tobacco BY-2 cells. PMID- 20946349 TI - Phenotypic approach to the management of the chronic prostatitis/chronic pelvic pain syndrome. AB - * Our traditional approach to managing the chronic prostatitis (CP) syndromes has not been very successful for many of our patients. * Our developing understanding of CP/chronic pelvic pain syndrome (CP/CPPS) as a heterogeneous syndrome rather than a homogenous disease has allowed us to develop treatment strategies based on individual patient characteristics. * By considering each patient as a unique individual and tailoring treatments to a specific patient's clinical 'phenotype' we improve our therapeutic outcomes. PMID- 20946350 TI - Interstitial cystitis: a negative ongoing situation? PMID- 20946351 TI - Robot-assisted intracorporeal ileal conduit 'Marionette' technique. PMID- 20946352 TI - Human faecal microbiota display variable patterns of glycerol metabolism. AB - Significant amounts of glycerol reach the colon microbiota daily through the diet and/or by in situ microbial production or release from desquamated epithelial cells. Some gut microorganisms may anaerobically reduce glycerol to 1,3 propanediol (1,3-PDO), with 3-hydroxypropanal as an intermediate. Accumulation of the latter intermediate may result in the formation of reuterin, which is known for its biological activity (e.g. antimicrobial properties). To date, glycerol metabolism in mixed cultures from the human colon has received little attention. Using in vitro batch incubations of faeces from 10 human individuals, we demonstrated that glycerol addition (140 mM) significantly affects the metabolism and composition of the microbial community. About a third of the samples exhibited rapid glycerol conversion, yielding proportionally higher levels of acetate and 1,3-PDO. In contrast, a slower glycerol metabolism resulted in higher levels of propionate. Furthermore, rapid glycerol metabolism correlated with significant shifts in the Lactobacillus-Enterococcus community, which were not observed in slower glycerol-metabolizing samples. As the conversion of glycerol to 1,3-PDO is a highly reducing process, we infer that the glycerol metabolism may act as an effective hydrogen sink. Given the importance of hydrogen-consuming processes in the gut, this work suggests that glycerol may have potential as a tool for modulating fermentation kinetics and profiles in the gastrointestinal tract. PMID- 20946353 TI - Receptor-mediated ER export of human MHC class I molecules is regulated by the C terminal single amino acid. AB - Major histocompatibility complex class I (MHC-I) molecules bind antigens in the endoplasmic reticulum (ER) and deliver them to the cell surface for immune surveillance of viruses and tumors. Whereas key steps of MHC-I assembly and its acquisition of peptides in the ER are relatively well defined, little is known about how MHC-I molecules leave the ER for cell surface expression. Here, we show that ER export of human classical MHC-I molecules (HLA-A/-B/-C) is regulated by their C-terminal single amino acid, valine or alanine. These amino acids, conserved in nearly all known human MHC-I alleles, serve as the ER export signal by binding to the Sec23/24 complex, a structural component of coat protein complex II (COPII) vesicles that mediate ER-to-Golgi trafficking. Together, our results strongly suggest that ER export of human classical MHC-I molecules can occur via a receptor-mediated process dictated by a highly conserved ER export signal. PMID- 20946354 TI - Anthrolysin O and fermentation products mediate the toxicity of Bacillus anthracis to lung epithelial cells under microaerobic conditions. AB - Bacillus anthracis generates virulence factors such as lethal and edema toxins, capsule, and hemolytic proteins under conditions of reduced oxygenation. Here, we report on the acute cytotoxicity of culture supernatants (Sups) of six nonencapsulated B. anthracis strains grown till the stationary phase under static microaerobic conditions. Human small airway epithelial, umbilical vein endothelial, Caco-2, and Hep-G2 cells were found to be susceptible. Sups displayed a reduction of pH to 5.3-5.5, indicating the onset of acid anaerobic fermentation; however, low pH itself was not a major factor of toxicity. The pore forming hemolysin, anthrolysin O (ALO), contributed to the toxicity in a concentration-dependent manner. Its effect was found to be synergistic with a metabolic product of B. anthracis, succinic acid. Cells exposed to Sups demonstrated cytoplasmic membrane blebbing, increased permeability, loss of ATP, mitochondrial membrane potential collapse, and arrest of cell respiration. The toxicity was reduced by inhibition of ALO by cholesterol, decomposition of reactive oxygen species, and inhibition of mitochondrial succinate dehydrogenase. Cell death appears to be caused by an acute primary membrane permeabilization by ALO, followed by a burst of reactive radicals from the mitochondria fuelled by the succinate, which is generated by bacteria in the hypoxic environment. This mechanism of metabolic toxicity is relevant to the late-stage conditions of hypoxia and acidosis found in anthrax patients and might operate at anatomical locations of the host deprived from oxygen supply. PMID- 20946356 TI - Mitochondrial diseases and the role of the yeast models. AB - Nowadays, mitochondrial diseases are recognized and studied with much attention and they cannot be considered anymore as 'rare diseases'. Yeast has been an instrumental organism to understand the genetic and molecular aspects of the many roles of mitochondria within the cells. Thanks to the general conservation of mitochondrial genes and pathways between human and yeast, it can also be used to model some diseases. In this review, we focus on the most recent topics, exemplifying those for which yeast models have been especially valuable. PMID- 20946355 TI - Association study in eating disorders: TPH2 associates with anorexia nervosa and self-induced vomiting. AB - Twin studies suggest that genetic factors play a substantial role in anorexia nervosa (AN) and self-induced vomiting (SV), a key symptom that is shared among different types of eating disorders (EDs). We investigated the association of 25 single nucleotide polymorphisms (SNPs), capturing 71-91% of the common variance in candidate genes, stathmin (STMN1), serotonin receptor 1D (HTR1D), tryptophan hydroxylase 2 (TPH2) and brain-derived neurotrophic factor (BDNF), with AN and EDs characterized by regular SV. The first allele frequencies of all the SNPs were compared between a Dutch case group (182 AN, 149 EDs characterized by SV) and 607 controls. Associations rendering P-values < 0.05 from this initial study were then tested for replication in a meta-analysis with two additional independent ED case-control samples, together providing 887 AN cases, 306 cases with an ED characterized by SV and 1914 controls. A significant effect for the minor C-allele of tryptophan hydroxylase 2 rs1473473 was observed for both AN [odds ratio (OR) = 1.30, 95% CI 1.08-1.57, P < 0.003] and EDs characterized by SV (OR = 1.52, 95% CI 1.28-2.04, P < 0.006). In the combined case group, a dominant effect was observed for rs1473473 (OR = 1.38, 95% CI 1.16-1.64, P < 0.0003). The meta-analysis revealed that the tryptophan hydroxylase 2 polymorphism rs1473473 was associated with a higher risk for AN, EDs characterized by SV and for the combined group. PMID- 20946357 TI - Electronic tuning of ruthenium complexes by 8-quinolate ligands. AB - A series of Ru(II) complexes were synthesized with the deprotonated forms of the ligands 8-hydroxyquinoline (quo(-)) and 5-NO(2)-8-hydroxyquinoline (5-NO(2)-quo( )) as analogs to the prototypical complex [Ru(bpy)(3)](2+) (bpy = 2,2' bipyridine). Electrochemistry, spectroscopy and density functional theory calculations were utilized to investigate the electronic tuning of the occupied t(2g)-type orbitals of the metal center with variation in the ligation sphere. The maximum of the lowest energy absorption of complexes containing one, two and three 8-quinolate ligands progressively redshifts from 452 nm in [Ru(bpy)(3)](2+) to 510 nm in [Ru(bpy)(2)(quo)](+), 515 nm in [Ru(bpy)(quo)(2)] and 540 nm in [Ru(quo)(3)](-) in water. This bathochromic shift results from the increase in energy of the occupied t(2g)-type orbital across the series afforded by coordination of each subsequent quo(-) ligand to the Ru(II) center. Time dependent density functional theory calculations along with electrochemical analysis reveals that the lowest energy transition has contributions in the highest occupied molecular orbital from both the quo(-) ligand and the metal, such that the lowest energy transition is not from an orbital that is purely metal-centered in character as in [Ru(bpy)(3)](2+). PMID- 20946359 TI - A new method to quantify the application thickness of sunscreen on skin. AB - Proper application of sunscreen is essential as an effective public health strategy for skin cancer prevention. Insufficient application is common among sunbathers, results in decreased sun protection and may therefore lead to increased UV damage of the skin. However, no objective measure of sunscreen application thickness (SAT) is currently available for field-based use. We present a method to detect SAT on human skin for determining the amount of sunscreen applied and thus enabling comparisons to manufacturer recommendations. Using a skin swabbing method and subsequent spectrophotometric analysis, we were able to determine SAT on human skin. A swabbing method was used to derive SAT on skin (in mg sunscreen per cm(2) of skin area) through the concentration absorption relationship of sunscreen determined in laboratory experiments. Analysis differentiated SATs between 0.25 and 4 mg cm(-2) and showed a small but significant decrease in concentration over time postapplication. A field study was performed, in which the heterogeneity of sunscreen application could be investigated. The proposed method is a low cost, noninvasive method for the determination of SAT on skin and it can be used as a valid tool in field- and population-based studies. PMID- 20946360 TI - Peculiar properties of photoinduced hydroxylaminolysis in different bacteriorhodopsin-based media using O-substituted hydroxylamines. AB - The process of photoinduced hydroxylaminolysis has been re-examined in different bacteriorhodopsin (BR)-based media using O-substituted hydroxylamines, in particular, O-(4-nitrobenzyl) hydroxylamine hydrochloride (NBHA), O-(2,3,4,5,6 pentafluorobenzyl) hydroxylamine hydrochloride (FBHA) and O-(t-butyl) hydroxylamine hydrochloride (BHA). Both wild type (WT) and D96N BR-based gelatine films and gels were studied. The expected increase in the bleaching rate of BR in gelatin films by using O-substituted hydroxylamines in place of HA was not achieved. On the other hand, it was shown that in gels HA derivatives NBHA and FBHA (as against HA itself) do provide about three- to four-fold higher bleaching rate. By contrast to that in films, D96N BR in gels demonstrates more effective bleaching as compared to WT BR. The plausible interpretation for the results is discussed in frames of reduced mobilities of large-sized molecules of O substituted hydroxylamines in dehydrated media. FBHA- or NBHA-modified gels possess higher photosensitivity both with D96N and WT BR (as compared with that for HA-modified gels) and offer a potentiality for application as an irreversible recording medium. As anticipated, it is specifically D96N BR gel modified with FBHA that may present a promising medium suitable for write-once recording thus extending the range of recording materials in the optical processing field. PMID- 20946358 TI - Oral feeding of pomegranate fruit extract inhibits early biomarkers of UVB radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis. AB - Pomegranate from the plant Punica granatum L. possesses strong antioxidant and anti-inflammatory properties. Recently, we have demonstrated that treatment of normal human epidermal keratinocytes with pomegranate fruit extract (PFE) inhibited UVB-mediated activation of nuclear factor kappa B (NF-kappaB) and mitogen activated protein kinases pathways. Here, we evaluated the effect of PFE on early biomarkers of photocarcinogenesis employing SKH-1 hairless mice. PFE was provided in drinking water (0.2%, wt/vol) to SKH-1 hairless mice for 14 days before a single UVB (180 mJ cm(-2)) irradiation. We found that oral feeding of PFE inhibited UVB-induced: (1) skin edema; (2) hyperplasia; (3) infiltration of leukocytes; (4) lipid peroxidation; (5) hydrogen peroxide generation; (6) ornithine decarboxylase (ODC) activity; and (7) ODC, cyclooxygenase-2 and proliferating cell nuclear antigen protein expression. Oral feeding of PFE enhanced repair of UVB-mediated formation of cyclobutane pyrimidine dimers (CPDs) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). Importantly, PFE treatment further enhanced UVB-mediated increase in tumor suppressor p53 and cyclin kinase inhibitor p21. Furthermore, oral feeding of PFE inhibited UVB-mediated: (1) nuclear translocation of NF-kappaB; (2) activation of IKKalpha; and (3) phosphorylation and degradation of IkappaBalpha. Taken together, we provide evidence that oral feeding of PFE to mice affords substantial protection from the adverse effects of UVB radiation via modulation in early biomarkers of photocarcinogenesis and provide suggestion for its photochemopreventive potential. PMID- 20946362 TI - Challenges of long-term nutrition intervention studies on cognition: discordance between observational and intervention studies of vitamin B12 and cognition. AB - Conducting long-term nutrition intervention studies on cognition can be challenging. The gaps in current methodology are addressed via a case study of the relationship between vitamin B(12) and cognition in people aged 60 and older. There is robust evidence from many observational studies, both cross-sectional and longitudinal, showing that a deficit of the vitamin is associated with poor or declining cognition in this age group, but supplementation of the vitamin in trials does not bring about improved cognition. The evidence from observational studies as well as clinical trials is reviewed here, and the potential difficulties in conducting long-term nutritional intervention studies in this area are highlighted. PMID- 20946361 TI - Proteomic identification of cathepsin B and nucleophosmin as novel UVA-targets in human skin fibroblasts. AB - Solar UVA exposure plays a causative role in skin photoaging and photocarcinogenesis. Here, we describe the proteomic identification of novel UVA targets in human dermal fibroblasts following a two-dimensional-difference-gel electrophoresis (2D-DIGE) approach. Fibroblasts were exposed to noncytotoxic doses of UVA or left untreated, and total protein extracts underwent CyDye labeling followed by 2D-DIGE/mass-spectrometric identification of differentially expressed proteins, confirmed independently by immunodetection. The protein displaying the most pronounced UVA-induced upregulation was identified as the nucleolar protein nucleophosmin. The protein undergoing the most pronounced UVA induced downregulation was identified as cathepsin B, a lysosomal cysteine protease displaying loss of enzymatic activity and altered maturation after cellular UVA exposure. Extensive lysosomal accumulation of lipofuscin-like autofluorescence and osmiophilic material occurred in UVA-exposed fibroblasts as detected by confocal fluorescence microscopy and transmission electron microscopy, respectively. Array analysis indicated UVA-induced upregulation of oxidative stress response gene expression, and UVA-induced loss of cathepsin B enzymatic activity in fibroblasts was suppressed by antioxidant intervention. Pharmacological cathepsin B inhibition using CA074Me mimicked UVA-induced accumulation of lysosomal autofluorescence and deficient cathepsin B maturation. Taken together, these data support the hypothesis that cathepsin B is a crucial target of UVA-induced photo-oxidative stress causatively involved in dermal photodamage through the impairment of lysosomal removal of lipofuscin. PMID- 20946363 TI - Design considerations in long-term intervention studies for the prevention of cognitive decline or dementia. AB - The results of randomized controlled trials of nutritional interventions aimed at preventing cognitive decline or dementia in older people have been largely disappointing. A reasonable argument can be made that this is at least in part because the design of primary prevention trials in older people is not straightforward and that the complexities of such trials are not readily apparent and commonly remain not fully recognized. This article analyzes some of the difficulties associated with identifying and enrolling study participants in long term prevention trials, with available data from three large, recently published trials used as examples. This analysis also serves to identify examples of good practice and areas for further research. Randomized controlled trials remain the single most important tool in the epidemiological arsenal for identifying the effects of specific interventions, but consideration of critically important design features is essential. PMID- 20946364 TI - Nutrition and cognition: meeting the challenge to obtain credible and evidence based facts. AB - Nutrition provides a practical and appealing approach to cognitive enhancement, including the modulation of long-term cognitive processes such as neurodevelopment and neurodegeneration. An abundance of promising nutritional influences on cognition have been identified, but many long-term effects remain to be confirmed by data from randomized controlled trials (RCTs). The current article provides a general outline of various factors that hamper the demonstration of causal long-term nutritional effects on cognition by RCTs and advocates the development of methodological solutions to enable substantiation in future RCTs. PMID- 20946365 TI - Evaluation of techniques to identify beneficial effects of nutrition and natural products on cognitive function. AB - This article considers the appropriate selection of cognitive tasks for research into the effects of nutrition and natural products on mental performance. It is recommended that tests appropriate to the domains of the cognitive function under investigation be used, and a set of criteria is provided to enable researchers to select appropriate tests and test systems for their research purposes. Research in this field is generally performed to establish whether products can produce beneficial effects on cognitive function, including optimizing development in pediatric populations, reversing existing cognitive deficits, preventing age related declines, counteracting fatigue-based impairment, or simply improving performance above normal levels. The requirements of tests for these purposes are detailed, and evidence is presented that properly developed cognitive test procedures can be used in a range of normal and clinical populations, even in large, long-term studies and in a variety of cultures and languages. PMID- 20946366 TI - A primer for brain imaging: a tool for evidence-based studies of nutrition? AB - Nutrition affects brain structure and function throughout life. Nutritional scientists and practitioners are interested in gathering evidence clarifying which of the micro- or macronutrients may affect particular aspects of brain functioning at a given period of the life cycle and in identifying possible brain mechanisms underlying such effects. This article provides a primer on brain imaging techniques suitable for the assessment of the structure and function of the human brain, focusing on noninvasive techniques such as structural and functional magnetic resonance imaging, electroencephalography, and magnetoencephalography. The article concludes with a few suggestions regarding the choice of a particular imaging tool in observational studies and randomized controlled trials investigating nutritional effects on the human brain. PMID- 20946367 TI - Nutrigenomics: where are we with genetic and epigenetic markers for disposition and susceptibility? AB - The revelation of the human genome has enabled scientists to assess the disposition and response of an organism to an environmental stimulus; transcriptomics, proteomics, and metabonomics can each generate such holistic views. Nutrigenomic techniques help researchers elucidate individual responses to nutritional interventions holistically and help with the design of personalized diets adapted to individual needs. Human genetics has revealed insights into health and disease susceptibility and can help differentiate responders from nonresponders in dietary interventions, but the predictive power of single nucleotide polymorphisms in disease susceptibility genes has so far been limited in terms of helping to foresee a health trajectory. Epigenetics encompasses alterations of genetic material that do not affect the DNA nucleotide sequence; these include DNA methylation patterns, chromatin structure, histone codes, and non-coding small RNAs. DNA methylation is modified particularly around the time of birth; therefore, early-life nutrition may affect health outcomes later in life. PMID- 20946368 TI - Case study on iron in mental development--in memory of John Beard (1947-2009). AB - Iron deficiency (ID) anemia is associated with poor neurocognitive development in infants and children. Depending on the stage of development at the time of deficiency, these adverse effects may be reversible. Recent investigations using sensitive measurements have confirmed that the deposition of iron in the brain varies according to brain region and age, and that dopamine-dependent behaviors are among the core deficits in ID. Dr John Beard (1947-2009) has been one of the leading scientists and pioneers in the area of iron and child development. His legacy to this area of science will grow through the continuation of his work by his co-workers and colleagues. PMID- 20946369 TI - Summary and discussion: Methodologies to assess long-term effects of nutrition on brain function. AB - The objective of the workshop titled "Methodologies to assess long-term effects of nutrition and brain function", which took place on November 12-13, 2009, in Brussels, Belgium, was to obtain an overview of the current knowledge of science in the field of cognitive performance assessment and to identify knowledge gaps and opportunities related to nutritional approaches to improving brain function and cognitive performance. It is known that methodologies should be assessed according to biological relevance, sensitivity, and feasibility. An overview of these issues in terms of neurodevelopment and neurodegeneration over the lifespan was discussed at the workshop by Professor David Benton. This was followed by talks on intervention trials conducted with B vitamins and folic acid (C McCracken) and on trial designs used for some long-term intervention studies in large populations (Alan Dangour). Once the scene was set, solutions and an overview of potentially useful outcome measures, including imaging (T Paus), biomarkers (N Coley), genetic markers (M Kussmann), and cognitive testing (K Wesnes), were discussed. To conclude, a case study of iron deficiency (S Osendarp) was presented. Some of the highlights of the talks are briefly summarized here. PMID- 20946370 TI - Neurodevelopment and neurodegeneration: are there critical stages for nutritional intervention? AB - Rather than being an inevitable consequence of age, cognitive decline can occur with marked variation among individuals. In this context, nutrition is one factor that is believed to be influential. When considering the potential role of diet, two factors need to be considered. First, cognitive or brain reserve is said to decrease the incidence of dementia; that is, it has been suggested that those with larger brains and better intellectual functioning have a greater capacity to resist the effects of the biological changes that define dementia. As such, the adequacy of nutrition before birth and in the early formative years may have long term consequences. Second, shrinkage of the brain begins in young adulthood, suggesting that any insidious influence of diet will take place from that time onward over a period of many decades. The marked decline in the weight of the brain associated with advanced dementia suggests it will be easier to slow that decline than to repair the brain. If this model is accurate, diet is influential throughout the entire lifespan, and this has substantial methodological implications for the study of the topic. PMID- 20946371 TI - Mutation surfing and the evolution of dispersal during range expansions. AB - A growing body of empirical evidence demonstrates that at an expanding front, there can be strong selection for greater dispersal propensity, whereas recent theory indicates that mutations occurring towards the front of a spatially expanding population can sometimes 'surf' to high frequency and spatial extent. Here, we consider the potential interplay between these two processes: what role may mutation surfing play in determining the course of dispersal evolution and how might dispersal evolution itself influence mutation surfing? Using an individual-based coupled-map lattice model, we first run simulations to determine the fate of dispersal mutants that occur at an expanding front. Our results highlight that mutants that have a slightly higher dispersal propensity than the wild type always have a higher survival probability than those mutants with a dispersal propensity lower than, or very similar to, the wild type. However, it is not always the case that mutants with very high dispersal propensity have the greatest survival probability. When dispersal mortality is high, mutants of intermediate dispersal survive most often. Interestingly, the rate of dispersal that ultimately evolves at an expanding front is often substantially higher than that which confers a novel mutant with the greatest probability of survival. Second, we run a model in which we allow dispersal to evolve over the course of a range expansion and ask how the fate of a neutral or nonneutral mutant depends upon when and where during the expansion it arises. These simulations highlight that the success of a neutral mutant depends upon the dispersal genotypes that it is associated with. An important consequence of this is that novel mutants that arise at the front of an expansion, and survive, typically end up being associated with more dispersive genotypes than the wild type. These results offer some new insights into causes and the consequences of dispersal evolution during range expansions, and the methodology we have employed can be readily extended to explore the evolutionary dynamics of other life history characteristics. PMID- 20946372 TI - Micromorphometry and cellular characteristics of the canine cervical intervertebral discs. AB - BACKGROUND: Dogs have a high prevalence of disc-associated cervical spinal cord disorders. Despite this, there are no descriptions of the micromorphometry or cellular characteristics of canine cervical intervertebral discs. HYPOTHESIS/OBJECTIVES: To compare micromorphometric and cellular characteristics at 4 disc regions (outer annulus [OA], inner annulus [IA], transitional zone [TZ], nucleus pulposus [NP]). We hypothesized that measurements would differ between chondrodystrophic (CH) and nonchondrodystrophic (NCH) dogs. ANIMALS: Six CH dogs and 6 NCH dogs, under 3 years old. METHODS: Histologic sections of all cervical discs from each dog were examined. Micromorphometric variables included relative ratio of ventral to dorsal annulus fibrosus (AF), number and mean width of AF fibers, and relative percentage of NP. Cellular variables included cell density, morphology, and grouping. RESULTS: The NP from CH dogs was smaller, more rounded, and more dorsally located compared with that from NCH dogs. The NP occupied a greater proportion of the disc in NCH dogs compared with CH dogs (27.7 versus 15.8%; P<.001). The ratio of ventral to dorsal AF was approximately 3:1 in the CH group and 2:1 in the NCH group. Cellular variables were region dependent. Cell density was 2.4-fold higher in the OA compared with the NP. Approximately 50 of NP cells and 4.5% of OA cells occurred in groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Micromorphometric variables differed by CH status. Cellular variables differed by disc region. Our findings potentially can explain the high incidence of intervertebral disc extrusions in CH dogs compared with NCH dogs. PMID- 20946373 TI - Association of admission plasma D-dimer concentration with diagnosis and outcome in horses with colic. AB - BACKGROUND: Coagulopathies detected in horses with gastrointestinal problems seem to be associated with poor outcome. Plasma D-Dimer concentration is a sensitive test for assessing coagulopathies. HYPOTHESIS: Plasma D-Dimer concentration tested on admission is related to diagnosis and outcome in horses with colic. ANIMALS: Four hundred and ninety three horses referred for evaluation of abdominal pain. METHODS: Prospective observational clinical study. Horses were grouped according to diagnosis (medical and surgical intestinal obstructions, ischemic disorders with and without intestinal resection, enteritis, peritonitis), outcome (survivors, nonsurvivors), and number of coagulopathies (normal profile, 1 or 2 coagulopathies, subclinical disseminated intravascular coagulation [DIC]). Blood samples were collected on admission and plasma D-Dimer concentration, clotting times (PT and aPTT), and antithrombin activity were determined. Positive likelihood ratios (LR+) were calculated for evaluation of D Dimer cut-off values, which were later tested in a logistic regression model. RESULTS: Horses with enteritis or peritonitis had significantly (P<.001) higher plasma D-Dimer concentrations and more severe coagulopathies on admission than horses with other diagnoses. Nonsurvivors also had significantly (P<.001) higher plasma D-Dimer concentrations at presentation than did survivors, and those horses with subclinical DIC on presentation had an odds ratio (OR) 8.6 (95% confidence interval [CI], 3.3-22.5, P<.001) for nonsurvival. Finally, D-Dimer concentrations>4,000 ng/mL had a LR+ of 5.9 and an OR 8.8 (95% CI, 4.5-17.1, P<.001) for nonsurvival. CONCLUSION AND CLINICAL IMPORTANCE: Plasma D-Dimer concentration measured on admission can be used to facilitate diagnosis and outcome prediction in horses with colic. A potential cut-off value for nonsurvival was found at approximately 4,000 ng/mL. PMID- 20946374 TI - The unstable dynamics of multiple alternative reproductive tactics. AB - Although negative frequency-dependent fitness is argued to allow the stable coexistence of two alternative reproductive types (such as resource defenders and reproductive parasites), no existing theory has considered a third strategy where resource defenders invest differentially in defence against reproductive parasites. Here, we present the results of a three-strategy game, where reproductive parasites interact with two resource defenders: 'Susceptibles' defend more resources but lose more reproductive success to parasites. 'Immunes' lose less to parasites, but immunity carries a reproductive cost. We show that the inclusion of a third strategy dramatically changes the evolutionary dynamics, such that for a wide range of parameter values, our model predicts the continuous sequential invasion of the three strategies instead of stable coexistence. Our results therefore limit the generality of the prediction that frequency-dependent fitness necessarily allows alternative reproductive tactics to coexist at equilibrium and may also explain the observed dynamics of some multiple-strategy systems. PMID- 20946375 TI - Dual-channel heterodyne microscope: new functions. AB - Quantitative assessment of critical dimensions of sub-wavelength structures, dark field and bright-field modes of operation, recognition of nonpatterned anisotropic surfaces, and three-dimensional profiling of opaque and transparent samples are the new features of a super-resolution dual-channel heterodyne microscope that was introduced in a previous publication in this journal. The aforementioned modes of operation can be activated by simple rotation of a polarizer or insertion of a polarization-separating prism. Various experimental results are presented, demonstrating new performance capabilities of the heterodyne microscope. PMID- 20946376 TI - Stereology of isolated objects with the invariator. AB - The invariator is a new stereological design to generate motion invariant test lines in three dimensions on an isotropic plane through a fixed point. The theory has been published recently. The purpose of this paper is to illustrate the application of the invariator on a group of rat brains to estimate brain volume and external surface area. Each brain was first split into its two hemispheres and then embedded into a ball filled with agar following a configuration named the antithetic isector, with the idea of reducing the error variance. After rolling the ball at random it was scanned by magnetic resonance imaging into a stack of parallel systematic sections: this is the isotropic Cavalieri design which, combined with the antithetic isector idea, proves to be very accurate. The invariator used only an equatorial section of the ball, and in the present case the coefficient of error of the volume and surface area estimators of an individual brain was about 30%. As it is design unbiased, the invariator may prove its strength mainly to estimate population means. PMID- 20946377 TI - Optimized sample preparation for high-resolution AFM characterization of fixed human cells. AB - Atomic force microscopy enables the simultaneous acquisition of high-resolution topographical and biophysical data allowing integrated analysis of cell surfaces during development and pathogenesis, and, critically, can link molecular and biophysical events. Here we used atomic force microscopy to analyse endometrial epithelial cells and neuronally differentiated P19 cells. Optimized reproducible sample preparation techniques enabled micro- and nanoscale multi-parameter analysis. Comparative analysis using atomic force microscopy and scanning electron microscopy demonstrated the utility of atomic force microscopy for examining tissue morphology, and its ability to generate data allowing differentiation of cells from different origins to be monitored. At low resolution atomic force microscopy produced topographic data complementary to scanning electron microscopy images, whilst at high resolution atomic force microscopy captured novel cell surface structural detail for both epithelial and neuronal cell types. Analysis of surface roughness provided biophysical data which enabled qualitative and quantitative differences between samples to be measured. This study provides an important optimization of sample preparation enabling more generalized atomic force microscopy utilization for cellular analysis required for advanced cell surface morphological studies. PMID- 20946378 TI - 3D volumes constructed from pixel-based images by digitally clearing plant and animal tissue. AB - Construction of three-dimensional volumes from a series of two-dimensional images has been restricted by the limited capacity to decrease the opacity of tissue. The use of commercial software that allows colour-keying and manipulation of two dimensional images in true three-dimensional space allowed us to construct three dimensional volumes from pixel-based images of stained plant and animal tissue without generating vector information. We present three-dimensional volumes of (1) the crown of an oat plant showing internal responses to a freezing treatment, (2) a sample of a hepatocellular carcinoma from a woodchuck liver that had been heat-treated with computer-guided radiofrequency ablation to induce necrosis in the central portion of the tumour, and (3) several features of a sample of mouse lung. The technique is well suited to images from large sections (greater than 1 mm) generated from paraffin-embedded tissues. It is widely applicable, having potential to recover three-dimensional information at virtually any resolution inherent in images generated by light microscopy, computer tomography, magnetic resonance imaging or electron microscopy. PMID- 20946379 TI - LR White sections as slot grid support films for transmission electron microscopy. AB - The utility of LR White sections as slot grid support films for the examination of thin resin-embedded tissue sections by transmission electron microscopy was investigated and compared with traditional formvar-carbon films. Throughout a variety of staining procedures, which involved the use of organic solvent, oxidizing agents, strong acid and prolonged incubation, LR White support films remained intact and the attached tissue sections remained adherent. By contrast, complete loss of formvar-carbon support films occurred in 25% of preparations during routine staining with aqueous reagents. This loss increased to 62% following staining with either alcoholic or oxidizing and acidic stains, and to 66% following prolonged (immunohistochemical) staining. Tissue contrast, ultrastructural detail and immunohistochemical staining intensity were comparable between sections on the two types of support film. The use of LR White sections as support films for slot grids represents a quick, cheap, simple and robust alternative to traditional support films and, furthermore, requires no carbon coating. PMID- 20946380 TI - Nanomechanical characterization of skin and skin cream. AB - The mechanical properties of skin are an important characteristic of its resistance to damage and important indicators of pathological situations. Skin care products are the most common method to improve skin health and create a smooth, soft, and elastic perception by altering the mechanical properties of skin. It is of interest to study how skin cream affects the mechanical properties of skin. It also can help to quantify the effectiveness of cosmetic products. In this study, we present a systematic study of the mechanical properties of virgin skin and cream-treated skin. In nanoscratch measurements, the scratch wear tracks were generated at various loads using an atomic force microscope. Hardness and elastic moduli were measured using a nanoindenter. The in situ tensile properties of virgin skin and cream-treated skin were measured using a custom-built tensile stage that attaches to the atomic force microscope. Compared with virgin skin, cream-treated skin exhibits better scratch resistance up to a normal load of 15 MUN. The indentation hardness and elastic modulus of cream-treated skin are lower than that of virgin skin, indicating that the skin cream moistens and softens the skin surface. In the stretching experiments, the elastic modulus is lower and ultimate strain is higher than that of virgin skin, indicating skin cream can improve the tensile response of skin. Mechanisms for the observed trends are discussed. PMID- 20946381 TI - Investigation of porous asphalt microstructure using optical and electron microscopy. AB - Direct observations of porous asphalt concrete samples in their natural state using optical and electron microscopy techniques led to useful information regarding the microstructure of two mixes and indicated a relationship between microstructure and in situ performance. This paper presents evidence that suboptimal microstructure can lead to premature failure thus making a first step in defining well or suboptimal performing pavements with a bottom-up approach (microstructure). Laboratory and field compaction produce different samples in terms of the microstructure. Laboratory compaction using the gyratory method has produced more microcracks in mineral aggregates after the binder had cooled. Well performing mixes used polymer-modified binders, had a more homogeneous void structure with fewer elongated voids and better interlocking of the aggregates. Furthermore, well-performing mixes showed better distribution of the mastic and better coverage of the aggregates with bitumen. Low vacuum scanning electron microscopy showed that styrene butadiene styrene polymer modification in binder exists in the form of discontinuous globules and not continuous networks. A reduction in the polymer phase was observed as a result of aging and in-service use. PMID- 20946382 TI - Automated focusing in bright-field microscopy for tuberculosis detection. AB - Automated microscopy to detect Mycobacterium tuberculosis in sputum smear slides would enable laboratories in countries with a high tuberculosis burden to cope efficiently with large numbers of smears. Focusing is a core component of automated microscopy, and successful autofocusing depends on selection of an appropriate focus algorithm for a specific task. We examined autofocusing algorithms for bright-field microscopy of Ziehl-Neelsen stained sputum smears. Six focus measures, defined in the spatial domain, were examined with respect to accuracy, execution time, range, full width at half maximum of the peak and the presence of local maxima. Curve fitting around an estimate of the focal plane was found to produce good results and is therefore an acceptable strategy to reduce the number of images captured for focusing and the processing time. Vollath's F4 measure performed best for full z-stacks, with a mean difference of 0.27 MUm between manually and automatically determined focal positions, whereas it is jointly ranked best with the Brenner gradient for curve fitting. PMID- 20946383 TI - Digital stain separation for histological images. AB - It is often desirable to perform digital image analyses on sections prepared for human interpretation, e.g. nuclear chromatin texture analysis or three dimensional reconstructions using sections requiring human delineation of structures of interest. Unfortunately such analyses are often more effective using stains with less complex contrast. Here an automated selective 'de staining' method for digital images is presented. The method separates an image into its red, green and blue and hue, saturation and intensity components. A mask of stained tissue is prepared by automatic percentile thresholding. A single weighted inverted colour channel is then added to each of the three primary colour channels separately by an iterative algorithm that adjusts the weights to give minimum variance within the mask. The modified red, green and blue channels are then recombined. This method is automatic requiring no pre-definition of stain colours or special hardware. The method is demonstrated to 'de-stain' nuclei in haematoxylin and eosin (H&E) sections (and a separate haematoxylin image can be derived from this). An image of isolated brown reaction product is produced with immunoperoxidase preparations counterstained with haematoxylin. Furthermore trichrome (haematoxylin van Gieson, picrosirius red) and other common stains may be separated into their components with modifications of the same algorithm. Although other methods for colour separation do exist (e.g. spectral pathology and colour deconvolution) these require special apparatus or precise calibration and foreknowledge of pure dye colour spectra. The present method of digital stain separation is fully automatic with no such prerequisites. PMID- 20946384 TI - Scaling of swim speed in breath-hold divers. AB - 1. Breath-hold divers are widely assumed to descend and ascend at the speed that minimizes energy expenditure per distance travelled (the cost of transport (COT)) to maximize foraging duration at depth. However, measuring COT with captive animals is difficult, and empirical support for this hypothesis is sparse. 2. We examined the scaling relationship of swim speed in free-ranging diving birds, mammals and turtles (37 species; mass range, 0.5-90,000 kg) with phylogenetically informed statistical methods and derived the theoretical prediction for the allometric exponent under the COT hypothesis by constructing a biomechanical model. 3. Swim speed significantly increased with mass, despite considerable variations around the scaling line. The allometric exponent (0.09) was statistically consistent with the theoretical prediction (0.05) of the COT hypothesis. 4. Our finding suggests a previously unrecognized advantage of size in divers: larger animals swim faster and thus could travel longer distance, search larger volume of water for prey and exploit a greater range of depths during a given dive duration. 5. Furthermore, as predicted from the model, endotherms (birds and mammals) swam faster than ectotherms (turtles) for their size, suggesting that metabolic power production limits swim speed. Among endotherms, birds swam faster than mammals, which cannot be explained by the model. Reynolds numbers of small birds (<2 kg) were close to the lower limit of turbulent flow (~ 3 * 10(5) ), and they swam fast possibly to avoid the increased drag associated with flow transition. PMID- 20946385 TI - Development of a qPCR assay for specific quantification of Botrytis cinerea on grapes. AB - The aim of this study was to develop a system for rapid and accurate real-time quantitative PCR (qPCR) identification and quantification of Botrytis cinerea, one of the major pathogens present on grapes. The intergenic spacer (IGS) region of the nuclear ribosomal DNA was used to specifically detect and quantify B. cinerea. A standard curve was established to quantify this fungus. The qPCR reaction was based on the simultaneous detection of a specific IGS sequence and also contained an internal amplification control to compensate for variations in DNA extraction and the various compounds from grapes that inhibit PCR. In these conditions, the assay had high efficiency (97%), and the limit of detection was estimated to be 6.3 pg DNA (corresponding to 540 spores). Our method was applied to assess the effects of various treatment strategies against Botrytis in the vineyard. Our qPCR assay proved to be rapid, selective and sensitive and may be used to monitor Botrytis infection in vineyards. PMID- 20946386 TI - Identification of the J and K genes in the bacteriophage Mu genome sequence. AB - Bacteriophage Mu was the first transposable phage to be discovered and still serves as the model for a large family of related transposable phages and prophages. The Mu genome sequence is known (NC-000929.1 GI:9633494), but not all of the genes have been assigned to the ORFs in the genome sequence. For this paper, we have sequenced an approximately 3-kb DNA region containing four predicted ORFs, Mup35-Mup38, from lysogens containing amber mutant prophages defective in either the J or the K gene. Amber mutations in prophages with J gene mutations mapped to the Mup36 ORF, and those in the K gene were found in Mup37, identifying the ORFs corresponding to these genes. PMID- 20946387 TI - Replacing Luer connectors: still work in progress. PMID- 20946388 TI - Malignant hyperthermia in India. PMID- 20946389 TI - NCEPOD - so what? PMID- 20946390 TI - A simulation-based evaluation of two proposed alternatives to Luer devices for use in neuraxial anaesthesia. AB - The National Patient Safety Agency has issued a Patient Safety Alert with the aim of eliminating Luer connectors from equipment for lumbar puncture and subarachnoid injections by 1 April 2011, and from all neuraxial and regional anaesthesia equipment in 2013. B-link (UK) Ltd and InterVene Ltd have produced non-Luer connectors for neuraxial devices: the Neurax and Spinalok respectively. Using an adult spinal simulator, 59 experienced clinicians performed neuraxial procedures using these devices and reported on specific performance characteristics and overall usability. Cross-connectivity between non-Luer and Luer connectors was also examined. The median (IQR [range]) overall assessment scores (0-10 scale) of usability for the standard, Neurax and Spinalok systems were 8 (8-9 [7-10]), 6 (5-7 [0-8]) and 7 (6-8 [1-9]) for spinal procedures and 8 (8-9 [6-10]), 7 (5-8 [1-9]) and 4 (3-6 [0-9]) for epidural procedures, respectively. Both study systems scored significantly lower than standard equipment for overall performance of spinal and epidural procedures, although the performance of non-Luer devices was mostly rated 'adequate' or better. Both non Luer connectors could cross-connect with one or more Luer connectors. Following feedback to the manufacturers, both systems have been modified and cross connectivity apparently has been eliminated. Our results indicate that clinicians may not find non-Luer devices immediately 'user-friendly'. More importantly, some cross-connectivity with Luer devices was possible. Our findings illustrate that introducing equipment that is fully compliant with the National Patient Safety Agency alert poses a significant challenge to manufacturers and clinicians. We conclude that before introducing any non-Luer device into widespread use, independent, formal evaluation should be carried out. PMID- 20946391 TI - Murphy P. A fibre-optic endoscope used for nasal intubation. Anaesthesia 1967; 22: 489-91. PMID- 20946392 TI - A rare case of malignant hyperthermia in the Indian subcontinent. PMID- 20946393 TI - Rapid sequence obstetric spinal anaesthesia. PMID- 20946394 TI - Not again! The non-cycling blood pressure cuff. PMID- 20946396 TI - Rapid sequence spinal anaesthesia: a trainee's viewpoint. PMID- 20946398 TI - Rapid sequence spinal anaesthesia: are we being serious? PMID- 20946399 TI - The learning curve for videolaryngoscopy. PMID- 20946401 TI - Instillagel, lipid rescue and the Medicines and Healthcare products Regulatory Agency. PMID- 20946402 TI - Lighting during ultrasound-guided regional anaesthesia. PMID- 20946403 TI - Intravenous lipid emulsion in propranolol [corrected] overdose. PMID- 20946404 TI - An unusual complication of arterial catheter removal. PMID- 20946405 TI - Unusual complication of a McCoy bladed laryngoscope. PMID- 20946406 TI - Aura-i laryngeal mask as a conduit for elective fibreoptic intubation. PMID- 20946407 TI - Genetic variation of the HIV-1 integrase region in newly diagnosed anti retroviral drug-naive patients with HIV/AIDS in Korea. AB - The survival time of HIV/AIDS patients in Korea has increased since HAART (highly active anti-retroviral therapy) was introduced. However, the occurrence of drug resistant strains requires new anti-retroviral drugs, one of which, an integrase inhibitor (INI), was approved by the US Food and Drug Administration (FDA) in 2007. INIs have been used for therapy in many countries and are about to be employed in Korea. Therefore, it is important to identify basic mutant variants prior to the introduction of INIs in order to estimate their efficacy. To monitor potential drug-resistant INI mutations in Korean HIV/AIDS patients, the polymorphism of the int gene was investigated together with the pol gene using a genotypic assay for 75 randomly selected Korean HIV-1 patients newly diagnosed in 2007. The drug-resistant mutation sequences were analysed using the Stanford HIV DB and the International AIDS Society resistance testing-USA panel (IAS-USA). Seventy strains of Korean subtype B were compared with foreign subtype-B strains, and there were no significantly different variants of the int gene region in the study population. Major mutation sites in the integrase (E92Q, F121Y, G140A/S, Y143C/R, Q148H/R/K and N155H) were not detected, and only a few minor mutation sites (L74M, V151I, E157Q, V165I, I203M, S230N and D232N) were identified in 21 strains (28%). Resistance due to mutations in the pol gene was observed in a single strain (1.3%) resistant to protease inhibitors (PIs) and in four strains (5.3%) resistant to reverse transcriptase inhibitors (RTIs). In summary, this demonstrates that INIs will be susceptible to drug naive HIV/AIDS patients in Korea. PMID- 20946408 TI - Mortality in enterococcal bloodstream infections increases with inappropriate antimicrobial therapy. AB - Enterococcus species are common in nosocomial bloodstream infections and their incidence is rising. Although well recognized in several serious bacterial infections, the influence of appropriate antimicrobial therapy in enterococcal bacteraemia has not been fully settled. The aim of the study was to determine whether administration of inappropriate antibiotics in enterococcal bacteraemia is an independent risk factor for mortality, among other known and suspected risk factors. We conducted a cohort study of E. faecalis/faecium bacteraemia during a 3-year period at a single tertiary care hospital in Denmark. Patients with growth of non-enterococcus co-pathogens apart from the enterococcal bacteraemia were also included, as were patients with repeated enterococcal bacteraemia. Time to appropriate antimicrobial therapy was counted from the first episode. Appropriate antibiotic therapy was defined as any therapy with documented clinical effect, in vitro activity and a minimum treatment length of 6 days. Multivariate regression models were built to determine the independent risk factors for mortality. We included 196 patients with enterococcal bacteraemia. Appropriate antibiotics for at least 6 days were administered in 146 of these (74%). Thirty-day mortality was 26%. Multivariate logistic regression identified independent predictors of 30-day all-cause mortality: appropriate antimicrobial therapy for >= 6 days (odds ratio for mortality 0.33, 0.14-0.79), ICU admission (4.2, 1.7-10), thrombocytopenia (3.9, 1.6-9.3), chronic liver failure (3.3, 1.1-10) and age >= 60 years (2.2, 0.99-5.0). Antibiotics not appropriately covering enterococci are frequently administered empirically in suspected bloodstream infections. Inappropriate antibiotic therapy was an independent risk factor for mortality in enterococcal bacteraemia. PMID- 20946409 TI - Clarithromycin and amikacin vs. clarithromycin and moxifloxacin for the treatment of post-acupuncture cutaneous infections due to Mycobacterium abscessus: a prospective observational study. AB - An outbreak of post-acupuncture cutaneous infections due to Mycobacterium abscessus occurred in Ansan, Korea, from November 2007 through to May 2008. During this time a prospective, observational, non-randomized study was conducted involving 52 patients that were diagnosed with cutaneous M. abscessus infection. We compared the clinical response between patients treated with clarithromycin plus amikacin regimen and those treated with clarithromycin plus moxifloxacin regimens with regard to time to resolution of the cutaneous lesions. Among the 52 study patients, 33 were treated with clarithromycin plus amikacin, and 19 were treated with clarithromycin plus moxifloxacin. The baseline characteristics for the treatment groups were not significantly different, except for initial surgical excision (n = 27 vs. 6, respectively, p = 0.001). The median time (weeks) to resolution of the lesions in the clarithromycin plus moxifloxacin treated subjects was significantly shorter than that in the clarithromycin plus amikacin-treated subjects (17 +/- 1.1 vs. 20 +/- 0.9, respectively, p = 0.017). With adjustments for age, location of lesions, prior incision and drainage, and excision during medical therapy, clarithromycin plus moxifloxacin-treated subjects were more likely to have resolved lesions (hazard ratio, 0.387; 95% confidence interval, 0.165-0.907; p = 0.029). The frequency of drug-related adverse events in the two treatment groups was not significantly different (n = 18 vs. 14, respectively; p = 0.240). The most common adverse event was gastrointestinal discomfort. The results of our study showed that the combination regimen of clarithromycin and moxifloxacin resulted in a better clinical response than a regimen of clarithromycin plus amikacin when used for treatment of cutaneous M. abscessus infection. PMID- 20946410 TI - Tsukamurella tyrosinosolvens and Rhizobium radiobacter sepsis presenting with septic pulmonary emboli. AB - Septic pulmonary embolism (SPE) is an uncommon, but life-threatening event that is usually associated with extrapulmonary infections. We report the first case of bilateral SPE secondary to a central venous catheter-related bloodstream infection involving pathogens commonly considered environmental contaminants: Tsukamurella tyrosinosolvens and Rhizobium radiobacter. Empirical levofloxacin treatment was confirmed by in vitro susceptibility data and produced prompt clinical improvement, but removal of the infected line proved indispensable for eradication of the infection. Laboratory personnel should be aware of the pathogenic potential of these environmental organisms, particularly in immunocompromised hosts with indwelling catheters. PMID- 20946411 TI - Improved clinical laboratory identification of human pathogenic yeasts by matrix assisted laser desorption ionization time-of-flight mass spectrometry. AB - The key to therapeutic success with yeast infections is an early onset of antifungal treatment with an appropriate drug regimen. To do this, yeast species identification is necessary, but conventional biochemical and morphological approaches are time-consuming. The recent arrival of biophysical methods, such as matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), in routine diagnostic laboratories holds the promise of significantly speeding up this process. In this study, two commercially available MALDI-TOF MS species identification systems were evaluated for application in clinical diagnostics, using a geographically diverse collection of 1192 clinical yeast and yeast-like isolates. The results were compared with those of the classical differentiation scheme based on microscopic and biochemical characteristics. For 95.1% of the isolates, all three procedures consistently gave the correct species identification, but the rate of misclassification was greatly reduced in both MALDI-TOF MS systems. Furthermore, several closely related species (e.g. Candida orthopsilosis/metapsilosis/parapsilosis or Candida glabrata/bracarensis) could be resolved by both MALDI-TOF MS systems, but not by the biochemical approach. A significant advantage of MALDI-TOF MS over biochemistry in the recognition of isolates novel to the system was observed. Although both MALDI-TOF MS systems employed different approaches in the database structure and showed different susceptibilities to errors in database entries, these were negligible in terms of clinical usefulness. The time-saving benefit of MALDI-TOF MS over biochemical identification will substantially improve fungal diagnostics and patient treatment. PMID- 20946412 TI - Prolonged viral shedding in pandemic influenza A(H1N1): clinical significance and viral load analysis in hospitalized patients. AB - The clinical significance of prolonged viral shedding (PVS) and viral load (VL) dynamics has not been sufficiently assessed in hospitalized patients with pandemic 2009 influenza A(H1N1). We performed a prospective study of adults with confirmed influenza A(H1N1) virus infection admitted to our hospital from 20 September 2009 to 31 December 2009. Consecutive nasopharyngeal swabs were collected every 2 days during the first week after diagnosis, and then every week or until viral detection was negative. Relative VL was measured on the basis of haemagglutinin and RNaseP gene analysis. PVS was defined as positive detection of influenza A(H1N1) virus by real-time RT-PCR at day 7 after diagnosis. We studied 64 patients: 16 (25%) presented PVS. The factors associated with PVS were admission to the intensive-care unit (69% vs. 33%, p 0.02), purulent expectoration (75% vs. 44%, p 0.04), higher dosage of oseltamivir (62.5% vs. 27%, p 0.016), corticosteroid treatment (50% vs. 21%, p 0.05), mechanical ventilation (MV) (50% vs. 12.5%, p 0.004), and longer stay (34 vs. 7 median days, p 0.003). Multivariate analysis revealed the factors independently associated with PVS to be immunosuppression (OR 5.15; 95% CI 1.2-22.2; p 0.03) and the need for MV (OR 11.7; 95% CI 2.5-54.4; p 0.002). VL at diagnosis correlated negatively with age and septic shock. VL dynamics of patients with acute respiratory distress syndrome and/or mortality were very different from those of other patients. PVS was detected in 25% of hospitalized patients with pandemic 2009 influenza A(H1N1) and was strongly associated with immunosuppression and the need for MV. Diagnostic VL and viral clearance varied with the clinical course. PMID- 20946413 TI - Real-time PCR assay-based strategy for differentiation between active Pneumocystis jirovecii pneumonia and colonization in immunocompromised patients. AB - Diagnosis of pneumocystosis usually relies on microscopic demonstration of Pneumocystis jirovecii in respiratory samples. Conventional PCR can detect low levels of P. jirovecii DNA but cannot differentiate active pneumonia from colonization. In this study, we used a new real-time quantitative PCR (qPCR) assay to identify and discriminate these entities. One hundred and sixty-three bronchoalveolar lavage fluids and 115 induced sputa were prospectively obtained from 238 consecutive immunocompromised patients presenting signs of pneumonia. Each patient was classified as having a high or a low probability of P. jirovecii pneumonia according to clinical and radiological presentation. Samples were processed by microscopy and by a qPCR assay amplifying the P. jirovecii mitochondrial large-subunit rRNA gene; qPCR results were expressed as trophic form equivalents (TFEq)/mL by reference to a standard curve obtained from numbered suspensions of trophic forms. From 21 samples obtained from 16 patients with a high probability of P. jirovecii pneumonia, 21 were positive by qPCR whereas only 16 were positive by microscopy. Fungal load ranged from 134 to 1.73 * 10(6) TFEq/mL. Among 257 specimens sampled from 222 patients with a low probability of P. jirovecii pneumonia, 222 were negative by both techniques but 35 were positive by qPCR (0.1-1840 TFEq/mL), suggesting P. jirovecii colonization. Two cut-off values of 120 and 1900 TFEq/mL were proposed to discriminate active pneumonia from colonization, with a grey zone between them. In conclusion, this qPCR assay discriminates active pneumonia from colonization. This is particularly relevant for patient management, especially in non-human immunodeficiency virus (HIV)-infected immunocompromised patients, who often present low-burden P. jirovecii infections that are not diagnosed microscopically. PMID- 20946414 TI - Severe outcome of influenza A/H1N1/09v infection associated with 222G/N polymorphisms in the haemagglutinin: a multicentre study. AB - In a multicentre study, influenza A/H1N1/09v 222G/N variants were more frequently detected in patients admitted to the intensive-care unit for invasive mechanical ventilation or extracorporeal membrane oxygenation (10/23; 43.5%) than in patients hospitalized in other units (2/27; 7.4%) and community patients (0/81; 0.0%) (p <0.01). A significantly higher virus load (p 0.02) in the lower vs the upper respiratory tract was observed. Predominance of 222G/N variants in the lower respiratory tract (40% of total virus population) vs the upper respiratory tract (10%) was shown by clonal analysis of haemagglutinin sequences in paired nasal swab and bronchoalveolar lavage samples. The time from illness onset to sampling was significantly longer in patients with severe infection vs community patients (p <0.001). It was concluded that the 222G/N variants showed increased virulence; mutant variants were probably selected in individual patients; and the longer duration of illness might have favoured the emergence of adaptive mutations through multiple replication cycles. PMID- 20946415 TI - Mixed infection with Beijing and non-Beijing strains in pulmonary tuberculosis in Taiwan: prevalence, risk factors, and dominant strain. AB - Patients with pulmonary tuberculosis (TB) can be simultaneously infected with different strains of Mycobacterium tuberculosis (mixed infection). We investigated the prevalence and risk factors of mixed infection by Beijing and non-Beijing strains in pulmonary TB patients in Taiwan. We developed a quantitative PCR method to simultaneously detect the presence of Beijing and non Beijing strains. A total of 868 pretreatment samples (from 868 patients), including 563 sputum samples smear-positive for acid-fast bacilli and 305 liquid medium samples culture-positive for mycobacteria, were tested. Medical records of patients with culture-confirmed pulmonary TB were reviewed. The detection limit of our quantitative PCR method was five copies of target sequences. With mycobacterial culture result as the reference standard, the sensitivity and specificity of our quantitative PCR method were 95% and 98%, respectively. M. tuberculosis strains were isolated in 466 samples, of which 231 (49.6%) were infected with a Beijing strain. Another 14 patients (3.0%) had mixed infection, with the Beijing strain being the dominant strain in 13 (93%). Age <25 years with pulmonary cavities was associated with mixed infection. In patients infected with non-Beijing strains, the bacterial load of non-Beijing strains was lower among those with mixed infection than among those without. Our quantitative PCR method was accurate in detecting Beijing and non-Beijing strains in smear-positive sputum and culture-positive liquid medium samples. Mixed infection was present in pulmonary TB patients (3.0%), especially in those aged <25 years with pulmonary cavities. Beijing strains seem to be more dominant than non-Beijing strains in patients with mixed infection. PMID- 20946416 TI - Neurochemical profile of the developing mouse cortex determined by in vivo 1H NMR spectroscopy at 14.1 T and the effect of recurrent anaesthesia. AB - The neurochemical profile of the cortex develops in a region and time specific manner, which can be distorted by psychiatric and other neurological pathologies. Pre-clinical studies often involve experimental mouse models. In this study, we determined the neurochemical profile of C57BL/6 mice in a longitudinal study design to provide a reference frame for the normal developing mouse cortex. Using in vivo proton NMR spectroscopy at 14 T, we measured the concentrations of 18 metabolites in the anterior and posterior cortex on postnatal days (P) 10, 20, 30, 60 and 90. Cortical development was marked by alterations of highly concentrated metabolites, such as N-acetylaspartate, glutamate, taurine and creatine. Regional specificity was represented by early variations in the concentration of glutamine, aspartate and choline. In adult animals, regional concentration differences were found for N-acetylaspartate, creatine and myo inositol. In this study, animals were exposed to recurrent isoflurane anaesthesia. Additional experiments showed that the latter was devoid of major effects on behaviour or cortical neurochemical profile. In conclusion, the high sensitivity and reproducibility of the measurements achieved at 14 T allowed us to identify developmental variations of cortical areas within the mouse cortex. PMID- 20946417 TI - A residue close to alpha1 loop F disrupts modulation of GABAA receptors by benzodiazepines while their binding is maintained. AB - Benzodiazepines act at the major isoforms of GABA type A receptors where they potentiate the current evoked by the agonist GABA. The underlying mechanism of this potentiation is poorly understood, but hypothesized to be related to the mechanism that links agonist binding to channel opening in these ligand activated ion channels. The loop F of the alpha(1) and the beta(2) subunit have been implicated in channel gating, and loop F of the gamma(2) subunit in the modulation by benzodiazepines. We have identified the conservative point mutation Y168F located N-terminally of loop F in the alpha(1) subunit that fails to affect agonist properties. Interestingly, it disrupts modulation by benzodiazepines, but leaves high affinity binding to the benzodiazepine binding site intact. Modulation by barbiturates and neurosteroids is also unaffected. Residue alpha(1) Y168 is not located either near the binding pockets for GABA, or for benzodiazepines, or close to the loop F of the gamma(2) subunit. Our results support the fact, that broader regions of ligand gated receptors are conformationally affected by the binding of benzodiazepines. We infer that also broader regions could contribute to signaling from GABA agonist binding to channel opening. PMID- 20946418 TI - A seed high-lysine trait is negatively associated with the TCA cycle and slows down Arabidopsis seed germination. AB - * Lysine is a nutritionally important essential amino acid, but significant elevation of its levels in Arabidopsis seeds, by enhancing its synthesis and blocking its catabolism, causes a retardation of germination. Here, we hypothesized that this negative effect is associated with changes in primary metabolism and gene expression programs that are essential for early germination. * Seeds at different stages of germination sensu stricto of the seed-high-lysine genotype were subjected to detailed analysis of primary metabolism, using GC-MS, as well as microarray analysis and two-dimensional, isoelectric focusing, sodium dodecylsulfate polyacrylamide gel electrophoresis, to detect storage protein mobilization. * Our results exposed a major negative effect of the seed-specific increased lysine synthesis and knockout of its catabolism on the levels of a number of TCA cycle metabolites. This metabolic alteration also influences significantly the transcriptome, primarily attenuating the boost of specific transcriptional programs that are essential for seedling establishment, such as the onset of photosynthesis, as well as the turnover of specific transcriptional programs associated with seed embryonic traits. * Our results indicate that catabolism of the aspartic acid family of amino acids is an important contributor to the energy status of plants, and hence to the onset of autotrophic growth associated processes during germination. PMID- 20946419 TI - Stable isotope labelling and zinc distribution in grains studied by laser ablation ICP-MS in an ear culture system reveals zinc transport barriers during grain filling in wheat. AB - Zinc (Zn) deficiency has been recognized as a potential risk for human health in many developing regions where staple food with low micronutrient density represents a major proportion of the diet. The success of strategies to increase Zn content in the edible part of crops requires better understanding of Zn transport to, and distribution within, the grains. The transfer of Zn from the growth medium to wheat (Triticum aestivum) grains in an ear culture system was investigated by using the stable Zn isotope (70) Zn, and the spatial distribution of Zn within the grains was studied by laser ablation-inductively coupled plasma mass spectrometry (LA-ICP-MS). Zinc was readily transported in the stem up to the rachis. More Zn accumulated in the stem when higher amounts of Zn were supplied to the medium. Once Zn was transported into the grain, Zn accumulated particularly in the crease vascular tissue. The gradient of (70) Zn concentration between crease vascular tissue, aleurone layer and endosperm demonstrates that Zn is distributed within grain through the crease phloem. These results suggest that two barriers of Zn transport into wheat grains may exist: between the stem tissue rachis and the grain, and the maternal and filial tissues in the grain. PMID- 20946420 TI - Association between nonsynonymous mutations of starch synthase IIa and starch quality in rice (Oryza sativa). AB - Starch quality is one of the most important agronomic traits in Asian rice, Oryza sativa. Starch synthase IIa (SsIIa) is a major candidate gene for starch quality variation. Within SsIIa, three nonsynonymous mutations in exon 8 have been shown to affect enzyme activity when expressed in Escherichia coli. To search for the variation in SsIIa that is responsible for starch quality variation in rice, we sequenced the SsIIa exon 8 region and measured starch quality as starch disintegration in alkali for 289 accessions of cultivated rice and 57 accessions of its wild ancestor, Oryza rufipogon. A general linear model and nested clade analysis were used to identify the associations between the three nonsynonymous single nucleotide polymorphisms (SNPs) and starch quality. Among the three nonsynonymous SNPs, we found strong evidence of association at one nucleotide site ('SNP 3'), corresponding to a Leu/Phe replacement at codon 781. A second SNP, corresponding to a Val/Met replacement at codon 737, could potentially show an association with increased sample sizes. Variation in SsIIa enzyme activity is associated with the cohesiveness of rice grains when cooked, and our findings are consistent with selection for more cohesive grains during the domestication of tropical japonica rice. PMID- 20946421 TI - Nursing-sensitive benchmarks for hospitals to gauge high-reliability performance. AB - Benchmarking expedites the quest for best practices and is crucial to hospitals' effective, reliable, and superior performance. Comparative performance data are used by accrediting and regulatory bodies to evaluate performance and by consumers in making decisions on where to seek healthcare. Nursing-sensitive quality measures affirmed by the National Quality Forum are now used in public reporting and pay-for-performance in addition to traditional medical outcome metrics. This report provides hospital nursing-sensitive benchmarks from medical/surgical, critical care, and step-down units drawn from 196 hospitals during six quarters in 2007 and 2008. Outcome measures include pressure ulcer prevalence rates and fall/falls with injury rates. Additional indicators that describe nursing care (nurse staffing care hours, skill mix, nurse/patient ratios, workload intensity, voluntary turnover, and use of sitters) and patient descriptors (age, gender, and diagnosis description) were also included. Specific benchmarks are provided using the 10th and the 90th percentiles, as well as quartiles to allow hospitals an opportunity to understand comparative performance with specificity. The purpose of this article is to provide hospitals not currently participating in comparative benchmarking databases with nursing sensitive data from the Collaborative Alliance for Nursing Outcomes for use in performance improvement processes. PMID- 20946422 TI - The utilization of six sigma and statistical process control techniques in surgical quality improvement. AB - Surgeons have been slow to incorporate industrial reliability techniques. Process control methods were applied to surgeon waiting time between cases, and to length of stay (LOS) after colon surgery. Waiting times between surgeries were evaluated by auditing the operating room records of a single hospital over a 1-month period. The medical records of 628 patients undergoing colon surgery over a 5 year period were reviewed. The average surgeon wait time between cases was 53 min, and the busiest surgeon spent 291/2 hr in 1 month waiting between surgeries. Process control charting demonstrated poor overall control of the room turnover process. Average LOS after colon resection also demonstrated very poor control. Mean LOS was 10 days. Weibull's conditional analysis revealed a conditional LOS of 9.83 days. Serious process management problems were identified in both analyses. These process issues are both expensive and adversely affect the quality of service offered by the institution. Process control mechanisms were suggested or implemented to improve these surgical processes. Industrial reliability and quality management tools can easily and effectively identify process control problems that occur on surgical services. PMID- 20946423 TI - Development of a concept map to convey understanding of patient and family centered care. AB - Even though the expression "Patient and Family-Centered Care (PFCC)" is widely used, there remains a lack of clarity regarding how the fundamental tenets of PFCC fit with our current model of healthcare. The purpose of this manuscript was to describe the first step in developing an organizational understanding of the operational construct for PFCC utilizing a concept map and the fundamental concept mapping learning theories. The overall goals were to build a more robust organization-wide understanding of the basic PFCC tenets guided by the philosophy of concept mapping. The long-range aspirations of this process are to improve safety and quality of life by incorporating the PFCC philosophy in the career development path of our students and healthcare professionals. PMID- 20946425 TI - Development and implementation of a hospital-acquired pressure ulcer incidence tracking system and algorithm. AB - Hospital-acquired pressure ulcers (HAPUs) are a national concern due to patient morbidity, treatment cost, and reimbursement issues. Stages III and IV pressure ulcers (PUs) that occur during hospitalization are among the conditions considered preventable by the Centers for Medicare and Medicaid Services (CMS). Harborview Medical Center (HMC), located in Seattle, WA, is a Level 1 trauma/burn center and safety net hospital serving diverse populations. HMC is committed to providing excellence in care including optimal skin care and PU prevention to people from all walks of life. At HMC a new system for monitoring daily PU incidence, completing monthly multidisciplinary intensive reviews on HAPUs, and application of an algorithm used to determine if HAPUs were avoidable was developed and implemented. This system has assisted HMC in addressing PU tracking, prevention, compliance with regulatory mandates and has improved skin related outcomes. PMID- 20946424 TI - Transforming mental healthcare in the Veterans Health Administration: a model for measuring performance to improve access, quality, and outcomes. AB - In this paper we present the conceptual framework and research design of a national evaluation of the quality of mental healthcare provided to veterans by the Veterans Health Administration, and present results on the reported availability of evidence-based practices. We used the Donabedian paradigm to design a longitudinal evaluation of the quality of mental healthcare. To evaluate the structure of care we used a combination of survey and administrative data and designed a web-based facility survey to examine the availability and characteristics of 12 evidence-based practices and other mental health services. We identified 138 unique facilities that provided mental healthcare to 783,280 veterans. With the exception of opiate substitution therapies, every evidence based practice was reported in at least one location in each service network. We use maps to estimate the maximum number of veterans that might benefit from expanding the availability of an evidence-based practice. We demonstrate the feasibility of overcoming several major challenges typically associated with measuring the quality of healthcare systems. This framework for evaluation of mental healthcare delivery provides a model upon which other stakeholders can continue to build and expand. PMID- 20946426 TI - The concentration of hospital care for black veterans in Veterans Affairs hospitals: implications for clinical outcomes. AB - Where minorities receive their care may contribute to disparities in care, yet, the racial concentration of care in the Veterans Health Administration is largely unknown. We sought to better understand which Veterans Affairs (VA) hospitals treat Black veterans and whether location of care impacted disparities. We assessed differences in mortality rates between Black and White veterans across 150 VA hospitals for any of six conditions (acute myocardial infarction, hip fracture, stroke, congestive heart failure, gastrointestinal hemorrhage, and pneumonia) between 1996 and 2002. Just 9 out of 150 VA hospitals (6% of all VA hospitals) cared for nearly 30% of Black veterans, and 42 hospitals (28% of all VA hospitals) cared for more than 75% of Black veterans. While our findings show that overall mortality rates were comparable between minority-serving and non minority-serving hospitals for four conditions, mortality rates were higher in minority-serving hospitals for acute myocardial infarction (AMI) and pneumonia. The ratio of mortality rates for Blacks compared with Whites was comparable across all VA hospitals. In contrast to the private sector, there is little variation in the degree of racial disparities in 30-day mortality across VA hospitals, although higher mortality among patients with AMI and pneumonia requires further investigation. PMID- 20946427 TI - Improving the effectiveness of fecal occult blood testing in a primary care clinic by direct colonoscopy referral for positive tests. AB - Fecal occult blood testing (FOBT) is recommended by national guidelines for colorectal cancer (CRC) screening and has been shown to reduce both the incidence and mortality of CRC. FOBT screening is a complex process and little is known concerning the best methods for implementing FOBT screening in primary care clinics. The purpose of this study was to determine if direct gastroenterology (GI) service notification of all positive FOBT results in improved time for provider response and colonoscopy. The secondary aims were to determine to what extent implementation of FOBT screening was appropriate in a large primary care clinic and correlate this with findings from colonoscopy. Data were collected prospectively following implementation of a direct referral strategy and compared with two retrospective time periods during which the ordering practitioners were responsible for follow-up of all positive FOBT. Implementation of immediate GI referral of positive tests eliminated improper and neglected follow-up, and resulted in shorter delays in provider response time and colonoscopy completion. Inappropriate use of FOBT was observed in 49% of patients, indicating that further interventions in primary care clinics to improve the quality of FOBT screening are necessary. PMID- 20946428 TI - A diffusion tensor magnetic resonance imaging study of corpus callosum from adult patients with migraine complicated with depressive/anxious disorder. AB - OBJECTIVE: The aim of this study was to investigate the possible microstructural abnormalities of the corpus callosum (CC) in adult patients with migraine without aura complicated with depressive/anxious disorder. BACKGROUND: Emotional disorders, especially depression and anxiety, are with relatively higher incidence in migraine population. However, the mechanism of migraine complicated with depressive/anxious disorder remains unclear. METHODS: Diffusion tensor magnetic resonance imaging was carried out in 12 adult patients with simple migraine (without aura and without depressive/anxious disorder) (S-M group), 12 adult patients with complicated migraine (without aura but complicated with depressive/anxious disorder) (Co-M group), and 12 age- and sex-matched healthy subjects (Control group). Fractional anisotropy (FA) and apparent diffusion coefficient were measured at genu, body, and splenium of the CC, respectively. RESULTS: There were significant differences in FA values at all locations of the CC among the 3 groups. The FA values from both the SM and Co-M groups were significantly lower than the control (P < .05 and P < .01, respectively). The FA values from Co-M group were significantly lower than the SM group (P < .01). The apparent diffusion coefficient values of the above regions had no significant differences among these groups (P > .05). There were negative correlations between FA value of genu of the CC and disease course as well as FA value of genu and body of the CC and headache frequency (P < .05). Negative correlations were also found between FA values at all locations of the CC and Hamilton anxiety and Hamilton depression scores (both P < .05). CONCLUSIONS: There might be an integrity change of neurofibrotic microstructures existing as a possible neuroanatomical basis in the CC of migraine patients complicated with depressive/anxious disorder. PMID- 20946429 TI - The effects of oral contraceptives on detection and pain thresholds as well as headache intensity during menstrual cycle in migraine. AB - BACKGROUND: Clinically, oral contraceptives (OC) can influence pain in both migraine headache and temporomandibular pain disorders. Estrogen as an ingredient of OC might be a responsible factor for these observations. We conducted the present study to test whether OC are able to alter the severity of headache attacks as well as the detection or pain thresholds over the course of the menstrual cycle in patients with migraine. METHODS: Thirteen healthy and regularly menstruating women and 26 migraineurs (13 using OC and 13 not using OC) were studied on the days 1, 4, 14, and 22 of their menstrual cycle. In all participants, saliva was collected first for determination of estrogen on each study day. Then, detection thresholds (warmth, cold, electrical current) and pain thresholds (cold, heat, pressure, electrical current) were assessed. Migraineurs were asked for headache attacks occurring in a period of 24 hours before testing and to estimate pain intensity on a verbal rating scale. RESULTS: On day 4 of the menstrual cycle, migraineurs using OC suffered significantly more from severe migraine attacks than migraineurs not taking OC. With respect to detection and pain thresholds, no effects of OC could be observed as concerning the differences between migraineurs with or without OC medication. On day 22, the severity of migraine headache was significantly related with the pain thresholds for pressure and electrical current, suggesting paradoxically more severe headache attacks in patients presenting with higher pain thresholds. Healthy volunteers disclosed higher salivary estrogen levels than migraineurs and migraineurs not using OC higher concentrations than migraineurs using OC throughout the menstrual cycle. CONCLUSIONS: In this study, the use of OC intensified migraine (however only at the end of menstruation) however had no influence on detection and pain thresholds in migraineurs. Possible reasons for this dissociation will be discussed. PMID- 20946430 TI - Prevalence and impact of headache and migraine among secondary school students in Nigeria. AB - BACKGROUND: A cross-sectional descriptive study to determine the overall, age and gender specific prevalence, trigger factors and impact of headache and migraine on quality of life of students attending secondary schools in Benin City, Nigeria. METHODS: Six secondary schools were randomly selected from which students were randomly selected. A self-administered questionnaire was used to screen those with frequent headache, defined as at least 2 episodes of headache unrelated to fever or any underlying disease within the last 12 months or at least 1 episode in the last 6 months preceding the date questionnaire was administered. Another questionnaire based on the ICHD-2 criteria for diagnosis of migraine was then administered to those with frequent headaches. Data analysis was with SPSS 13.0 for Windows. RESULTS: One thousand six hundred and seventy nine students aged 11-18 years were recruited. The overall prevalence of headache was 19.5%. The prevalence of migraine was 13.5%. Migraine was more common in girls than in boys at all ages. The most common trigger factors included emotional stress, sunlight or bright light, sleep deprivation, and hunger. Inability to participate in outdoor activities, household chores, and school absenteeism were the common impacts on the quality of life of among 76.8% of the migraineurs. CONCLUSION: Migraine is common and underdiagnosed among secondary school students in Benin City, Nigeria, and negatively impacts on the quality of life including school absenteeism. PMID- 20946431 TI - Time delay from onset to diagnosis of migraine. AB - OBJECTIVE: To investigate the factors involved in the delayed diagnosis of migraine without aura among patients attending a tertiary center for headache diagnosis and management. METHODS: Two hundred consecutive patients were divided into 3 groups according to the time elapsed from the first clinical manifestations and the diagnosis of migraine at our center. RESULTS: The interval was <1 year in 16.5% of patients (n = 33); from 1 to 5 years in 30% (n = 60); and >5 years in 53.5% (n = 107). Younger age at migraine onset and a lower level of education were significantly associated with a longer time to diagnosis (P = .01 and P = .0001, respectively). Longer delays were significantly associated with a larger number of specialists consulted (P < .05). CONCLUSION: Our findings suggest an insufficient awareness of the diagnostic criteria of migraine by non specialist physicians, who often prescribe expensive and unnecessary diagnostic investigations that do not alleviate patients' symptoms while wasting health care resources. PMID- 20946433 TI - Central pain modulation and scalp tenderness in frequent episodic tension-type headache. AB - OBJECTIVE: To determine whether the inhibitory effect of acute limb pain on pain to mechanical stimulation of the forehead is compromised in individuals with frequent episodes of tension-type headache. BACKGROUND: Central pain modulation processes are disrupted in patients with chronic tension-type headache. This deficit in pain modulation might be a predisposing characteristic that increases vulnerability to tension-type headache and to symptoms such as scalp tenderness, or could be a feature that develops secondarily during attacks and that persists for a few days afterward. To distinguish between these 2 possibilities in the present study, inhibitory pain control was investigated in participants with episodic rather than chronic tension-type headache. METHODS: Pressure-pain thresholds and sensitivity to sharpness in the forehead were measured in 34 individuals with 1-10 episodes of tension-type headache per month and in 32 controls before and after immersion of their hand in painfully cold water. RESULTS: Before the cold pressor test, pressure-pain thresholds and sensitivity to the sharp stimulus were similar in both groups. Mild headache developed and pressure-pain thresholds in the forehead decreased from 631 +/- 178 g to 579 +/- 196 g (mean +/- SD) after the cold water immersion in the episodic tension-type headache group (P < .05). However, sharpness ratings did not change (mean rating 3.2 +/- 1.4 on a 0-10 scale). In contrast, headache did not develop, pressure pain thresholds did not change, and sharpness ratings decreased from 3.0 +/- 1.3 to 2.3 +/- 1.1 after the immersion in controls (P < .01). CONCLUSIONS: These findings suggest that endogenous pain modulation processes are compromised in individuals with frequent episodic tension-type headache. This deficit could increase vulnerability to scalp tenderness and recurrent episodes of headache. PMID- 20946432 TI - Association between intimate partner violence, migraine and probable migraine. AB - OBJECTIVE: Intimate partner violence (IPV) among women is a global public health problem. The association between childhood maltreatment and migraine is well established, but not the association between IPV and migraine. The aim of this cross-sectional study was to evaluate the relationship between type and severity of IPV and migraine in a large cohort of Peruvian women. METHODS: Women who delivered singleton infants (n = 2066) at the Instituto Nacional Materno Perinatal, Lima, Peru were interviewed during their postpartum hospital stay. Participants were queried about their lifetime experiences with headaches and migraine, and with physical and sexual violence. The International Classification of Headache Disorders (ICHD-2) diagnostic criteria were used to classify participants according to their migraine status. Questions on physical and sexual violence were adapted from the protocol of Demographic Health Survey Questionnaires and Modules: Domestic Violence Module and the World Health Organization (WHO) Multi-Country Study on Violence against Women. Depressive symptoms were assessed using a modified version of the Patient Health Questionnaire-9. Logistic regression was used to estimate multivariate adjusted odds ratios (aOR) and 95% confidence intervals (CI). RESULTS: Compared with women without a history of violence, women with experiences of lifetime physical or sexual violence (aOR = 1.44, 95% CI 1.19-1.75), physical violence only (aOR = 1.36, 95% CI 1.10-1.68), sexual violence only (aOR = 1.76, 95% CI 0.97-3.21), and both physical and sexual violence (aOR = 1.61, 95% CI 1.12-2.31) had increased odds of any migraine after adjusting for maternal age, parity, and access to basic foods. There was no gradient of increased odds of any migraine with severity of physical violence. The relationship between IPV and any migraine was strongest among women with moderate to severe levels of depressive symptoms. The odds of any migraine was increased 2.25-fold (95% CI 1.75-2.28) among abused women who also had moderate to severe levels of depressive symptomology compared with women who were not abused and had none or mild levels of depressive symptomology. Associations from sensitivity analyze that segregated women according to probable migraine (ICHD-2 category 1.6.1) and migraine (ICHD-2 category 1.1) diagnoses were of similar magnitudes as those reported here for women with any migraine diagnoses. IPV, particularly sexual violence, appears to be a risk factor for migraine. CONCLUSION: Our findings suggest the potential importance of considering a history of violence among migraineurs. PMID- 20946434 TI - MTHFR 677C>T polymorphism and cluster headache. AB - BACKGROUND: An association between the 677C>T polymorphism (rs1801133) in the methylenetetrahydrofolate reductase gene (MTHFR) and cluster headache is plausible, but has not been investigated. OBJECTIVE: To investigate this association among Caucasians. METHODS: Case-control study among 147 cluster headache patients and 599 population-based age- and gender-matched controls. Cluster headache was diagnosed according to the criteria of the International Headache Society. Genotypes of the MTHFR 677C>T polymorphism were detected by restriction fragment length polymorphism analysis. We used logistic regression analysis to investigate the association between cluster headache and genotypes with additive, dominant, and recessive models. We considered a Bonferroni corrected P value <.004 as significant. RESULTS: Mean age at study entry among patients was 44.9 years (SD 11.4), of whom 76.2% were men. The genotype distribution among controls and patients was in Hardy-Weinberg equilibrium. The genotype and allele distribution did not differ between patients with any cluster headache and controls. We also did not find an association when assuming additive, dominant or recessive genetic models. When we looked at subgroups, the effect estimates suggested an increased risk for chronic cluster headache (dominant model: odds ratio = 2.82; 99.6% confidence interval = 0.72-11.07; P = .03). CONCLUSIONS: Data from our case-control study do not indicate an association between genotypes of the MTHFR 677C>T polymorphism and cluster headache overall. Subgroup analyses suggested that carriers of the MTHFR 677T allele may have an increased risk for chronic cluster headache. This may be regarded as hypothesis-generating and should be further investigated in independent studies. PMID- 20946435 TI - Migraine and patent foramen ovale: the secret in the bubbles? PMID- 20946436 TI - A practice guide for continuous opioid therapy for refractory daily headache. PMID- 20946437 TI - Caffeine protects against increased risk-taking propensity during severe sleep deprivation. AB - Previous research suggests that sleep deprivation is associated with declines in metabolic activity within brain regions important for judgement and impulse control, yet previous studies have reported inconsistent findings regarding the effects of sleep loss and caffeine on risk-taking. In this study, 25 healthy adults (21 men, four women) completed the Balloon Analog Risk Task (BART) and Evaluation of Risks (EVAR) scale at regular intervals to examine behavioral and self-reported risk-taking propensity during 75 h of continuous sleep deprivation. Participants received either four double-blind administrations of 200 mg caffeine (n=12) or indistinguishable placebo (n=13) gum bi-hourly during each of the 3 nights of sleep deprivation. No significant effects of drug group or sleep deprivation were evident on the BART or EVAR when measured at 51 h of wakefulness. However, by 75 h, the placebo group showed a significant increase in risk-taking behavior on the cost-benefit ratio and total number of exploded balloons on the BART, whereas the caffeine group remained at baseline levels. On the EVAR, several factors of self-reported risk-taking propensity, including total risk, impulsivity and risk/thrill seeking, were reduced among subjects receiving caffeine across the 3 days of sleep deprivation, but remained at baseline levels for the placebo group. These results suggest that 3 nights of total sleep deprivation led to a significant increase in behavioral risk-taking but not self-reported perception of risk-propensity. Overnight caffeine prevented this increase in risky behavior. PMID- 20946438 TI - Sleep deprivation impairs contextual fear conditioning and attenuates subsequent behavioural, endocrine and neuronal responses. AB - Sleep deprivation (SD) affects hippocampus-dependent memory formation. Several studies in rodents have shown that brief SD immediately following a mild foot shock impairs consolidation of contextual fear memory as reflected in a reduced behavioural freezing response during re-exposure to the shock context later. In the first part of this study, we examined whether this reduced freezing response is accompanied by an attenuated fear-induced activation of the hypothalamic pituitary-adrenal (HPA) axis. Results show that 6h of SD immediately following the initial shock results in a diminished adrenal corticosterone (CORT) response upon re-exposure to the shock context the next day. In the second part, we established whether the attenuated freezing response in SD animals is associated with reduced activation of relevant brain areas known to be involved in the retrieval and expression of fear memory. Immunohistochemical analysis of brain slices showed that the normal increase in phosphorylation of the transcription factor 3',5'-cyclic AMP response-element binding protein (CREB) upon re-exposure to the shock context was reduced in SD animals in the CA1 region of the hippocampus and in the amygdala. In conclusion, brief SD impairs the consolidation of contextual fear memory. Upon re-exposure to the context, this is reflected in a diminished behavioural freezing response, an attenuated HPA axis response and a reduction of the normal increase of phosphorylated CREB expression in the hippocampus and amygdala. PMID- 20946439 TI - Induction of antibacterial activity in larvae of the blowfly Lucilia sericata by an infected environment. AB - Maggot debridement therapy (MDT) is a method for the treatment of intractable, infected and necrotic wounds. In MDT, sterile larvae of Lucilia sericata Meigen (Diptera: Calliphoridae) are applied to infected wounds, where they exert antibacterial effects. Once the larvae are placed in the wound, they are no longer germ-free. This study analysed the influence of infected environments on larval antibacterial activities. Sterile larvae were mixed in a test tube containing a bacterial suspension of Staphylococcus aureus or Pseudomonas aeruginosa, transferred to liver puree agar, and incubated at 25 degrees C for set periods. To collect the larval extracts, the incubated larvae were transferred to a test tube containing phosphate buffered saline (PBS), cut into multiple pieces with scissors, and centrifuged. The supernatant was used to test antibacterial activities. The results showed that infected larvae had better antibacterial capacities than sterile larvae. Antibacterial activities were induced by pretreatment with a single bacterial species, S. aureus or P. aeruginosa, within 24 h and 12 h, respectively, and disappeared after 36 h. The activities were effective against S. aureus, but not against P. aeruginosa. This natural infection model is very similar to the clinical wound context in MDT and will be a powerful tool with which to study the antibacterial activities of L. sericata larvae in MDT. PMID- 20946440 TI - Conventional progesterone receptors (PR) B and PRA are expressed in human spermatozoa and may be involved in the pathophysiology of varicocoele: a role for progesterone in metabolism. AB - The physiological roles of intracellular progesterone (PRG) receptors (PRs) have been studied intensively in female mammals, while their functions in male are scarce. Conventional PRs were evidenced in our study by Western blotting, concomitantly in healthy spermatozoa and in oligoasthenoteratozoospermic samples without and with varicocoele. Transmission electron microscopy revealed the presence of the PRs on the membrane as well as in the nucleus, mitochondria and flagellum. A reduced expression of the PRs was observed only in varicocoele spermatozoa. Responses to PRG treatment on cholesterol efflux, tyrosine phosphorylation, src and Akt activities, acrosin activity and acrosome reaction in varicocoele spermatozoa were reduced or absent. To further investigate PRG significance in human male gamete, we focused its action on lipid and glucose metabolism. The evaluation of the triglycerides content, lipase and acyl-CoA dehydrogenase activities suggests that PRG through the PRs exerts a lipolytic effect on human spermatozoa. An increase in glucose-6-phosphate dehydrogenase activity was also obtained, evidencing a role for PRG on glucose metabolism. In 'varicocoele' spermatozoa, the PRG did not induce energy consumption. The action of PRs on sperm metabolism is a novel finding that renews the importance of PRG in male fertility. Our results showed that varicocoele may lead to male factor infertility by a mechanism involving a decreased PR expression in human spermatozoa that evidences a detrimental effect on spermatozoa at the molecular level, going beyond the abnormal sperm morphology described to date. PMID- 20946441 TI - Evaluation of the possible influence of hepatitis C virus and liver fibrosis on HIV type 1 immunological and virological outcomes. AB - OBJECTIVES: The aim of the study was to evaluate the possible effect of hepatitis C virus (HCV) coinfection on the viroimmunological outcomes of HIV-1 infection. METHODS: A cross-sectional study of 805 patients with active HCV infection receiving or not receiving antiretroviral therapy (ART) was carried out. RESULTS: A number of parameters were significantly associated with undetectable HIV-1 viral load in univariate analyses, such as age, toxic habits, CD4 cell count, liver test results, HCV viral load and ART. However, only current ART (P<0.0001), CD4 cell count (P<0.0001), age (P=0.004) and current injecting drug use (P=0.02) were independently associated with undetectable viral load in multivariate analysis. None of the many HCV- and liver fibrosis-related parameters analysed showed a significant association with HIV-1 viral load or CD4 cell count in multivariate analyses, with the exception of the annual fibrosis progression index which almost reached statistical significance in the subgroup of ART untreated patients (P=0.06) and was inversely predictive of CD4 cell count in the whole group (P=0.007). However, its relative weight was modest, as it only explained 0.8% of the total variability in CD4 cell count. CONCLUSIONS: HCV related parameters did not significantly affect virological and immunological outcomes of HIV-1 infection in ART-treated and untreated patients. In contrast, liver fibrosis, as measured using the annual fibrosis progression index, was inversely associated with CD4 cell count, although its weight was relatively small. Therefore, HCV- and liver fibrosis-related factors do not seem appreciably to influence these outcomes from a practical viewpoint in ART-naive patients, nor impair CD4 and HIV-1 viral load responses to ART. PMID- 20946442 TI - The nature and impact of collaboration and integrated service delivery for pregnant women, children and families. AB - AIM: This paper explores the impact of models of integrated services for pregnant women, children and families and the nature of collaboration between midwives, child and family health nurses and general practitioners. BACKGROUND: Increasingly, maternity and child health services are establishing integrated service models to meet the needs of pregnant women, children and families particularly those vulnerable to poor outcomes. Little is known about the nature of collaboration between professionals or the impact of service integration across universal health services. DESIGN: Discursive paper. METHODS: A literature search was conducted using a range of databases and combinations of relevant keywords to identify papers reporting the process, and/or outcomes of collaboration and integrated models of care. RESULTS: There is limited literature describing models of collaboration or reporting outcomes. Several whole-of government and community-based integrated service models have been trialled with varying success. Effective communication mechanisms and professional relationships and boundaries are key concerns. Liaison positions, multidisciplinary teams and service co-location have been adopted to communicate information, facilitate transition of care from one service or professional to another and to build working relationships. CONCLUSIONS: Currently, collaboration between universal health services predominantly reflects initiatives to move services from the level of coexistence to models of cooperation and coordination. RELEVANCE TO CLINICAL PRACTICE: Integrated service models are changing the way professionals are working. Collaboration requires knowledge of the roles and responsibilities of colleagues and skill in communicating effectively with a diverse range of professionals to establish care pathways with referral and feedback mechanisms that generate collegial respect and trust. PMID- 20946443 TI - Sudden cardiac death among people with diabetes: preventive measures documented in their medical records. AB - AIMS: The purpose of this study was to examine how prevention of complications for people with diabetes mellitus had been conducted, as described in their medical records, focusing particularly on sudden cardiac death. A further aim was to compare the documentation with guidelines for diabetes care. BACKGROUND: Diabetes mellitus is associated with an increased risk of cardiovascular disease, death and sudden cardiac death. About half of those affected by sudden cardiac death are assumed to have had one or more risk factors for cardiovascular disease that could have been treated effectively resulting in a reduced risk of sudden death. DESIGN: Survey. METHOD: Fifty-six people diagnosed with diabetes mellitus, who had died of a sudden cardiac arrest between the years 2003-2005, from the Northern Sweden MONICA myocardial registry were included. These people's medical records were examined with regard to documentation of the care given during the year prior to the person's sudden cardiac death. RESULTS: The qualitative content analysis resulted in four categories: individualised goals for diabetes care; prevention of complications; self-care; and factors which may affect ability to adhere to treatment. The quantitative analysis showed that few people with diabetes mellitus achieved goals for metabolic control, compared with those set in guidelines for diabetes mellitus care. CONCLUSION: To prevent complications for people with diabetes mellitus, it is a challenge for nurses and physicians to involve people with diabetes mellitus in their own care to improve the prognosis. RELEVANCE TO CLINICAL PRACTICE: Examination of medical records of people with diabetes mellitus showed that documentation could be more informative and systematic. It is important to achieve better adherence to treatment and to increase people's understanding of their illness. PMID- 20946444 TI - The effectiveness of structured discharge education on maternal confidence, caring knowledge and growth of premature newborns. AB - AIMS: The aim of this study is to evaluate the effectiveness of structured discharge education on maternal confidence and caring knowledge and the growth of premature newborns. BACKGROUND: Parents of premature newborns are usually confronted with great difficulties in caring for their babies after discharge. Building maternal confidence and caring knowledge can help mothers reduce such difficulties of caring for their babies after discharge from hospital. DESIGN: Randomised controlled trial. METHODS: Mothers with premature babies were randomly assigned into experimental (n=29) and control groups (n=30) at a medical centre in southern Taiwan. The mothers of both groups had received a questionnaire concerning maternal confidence and caring knowledge at pretest. After the pretest, a structured discharged education programme was provided to the mothers of the experimental group. The control group only received traditional discharge education. Mothers of experimental and control groups again received the questionnaire of maternal confidence and caring knowledge at the day before discharge and one month after discharge. At that time, the body height and body weight of newborns were measured and recorded. RESULTS: Maternal confidence and caring knowledge of mothers in the experimental group were significantly higher than those of the control group at the day before discharge; however, there were no significant differences between the two groups one month after discharge. Using repeated anova analysis, the time * group interaction was significant for maternal confidence and caring knowledge, indicating that the groups differed significantly in changes in maternal confidence and caring knowledge over the three time points. CONCLUSIONS: Structured discharge education on mothers could significantly increase maternal confidence and caring knowledge at the day before discharge. Furthermore, structured discharge education could significantly increase the percentage of growth on body height of premature newborns. RELEVANCE TO CLINICAL PRACTICE: The results could help clinical nurses design appropriate discharge education programmes for mothers of premature newborns. PMID- 20946445 TI - GYNOTEL: telephone advice to gynaecological surgical patients after discharge. AB - AIMS AND OBJECTIVES: To investigate in surgical gynaecological patients the types of health problems arising or persisting up to six weeks after discharge and the effectiveness of telephone advice. BACKGROUND: The decreasing length of hospital stay has increased the need for specific instructions about the postdischarge period. Telephone advice could be a valuable tool to address this problem. To our knowledge, postdischarge health problems and the value of telephone advice have not been investigated among gynaecological patients. DESIGN: Randomised controlled trial. METHODS: Gynaecological patients expected to stay in the ward longer than 24 hour were invited to participate. A pilot study showed that wound healing, pain, mobility, urination, defecation and vaginal bleeding were the most common health problems postdischarge. Based on that information, guidelines were formulated that were used by trained nurses to give telephone advice to the intervention group (n=235), in addition to the usual care. The control group of gynaecological patients (n=233) received usual care only. RESULTS: Of all 468 participants, about 50% were operated for general gynaecology. At discharge, wound pain (56%), mobility problems (54%) and constipation (27%) were the most frequently mentioned problems in both groups. Participants who completely followed the advice with regard to wound healing (p=0.02), pain (p=0.01), vaginal bleeding (p=0.03) and mobility (p=0.04) experienced greater improvement than participants who did not follow, or only partly followed, the advice. CONCLUSIONS: The telephone advice appears to make a significant contribution to help gynaecological surgical patients to solve or reduce their postdischarge health problems. RELEVANCE TO CLINICAL PRACTICE: The positive effect of such advice can be interpreted as an improvement in the quality of life of the postoperative gynaecological patient. PMID- 20946446 TI - Concurrent analysis: towards generalisable qualitative research. AB - AIMS AND OBJECTIVES: This study develops an original method of qualitative analysis coherent with its interpretivist principles. The objective is to increase the likelihood of achieving generalisability and so improve the chance of the findings being translated into practice. BACKGROUND: Good qualitative research depends on coherent analysis of different types of data. The limitations of existing methodologies are first discussed to justify the need for a novel approach. To illustrate this approach, primary evidence is presented using the new methodology. The primary evidence consists of a constructivist grounded theory of how mental health nurses with prescribing authority integrate prescribing into practice. This theory is built concurrently from interviews, reflective accounts and case study data from the literature. DESIGN: Concurrent analysis. METHOD: Ten research articles and 13 semi-structured interviews were sampled purposively and then theoretically and analysed concurrently using constructivist grounded theory. RESULTS: A theory of the process of becoming competent in mental health nurse prescribing was generated through this process. This theory was validated by 32 practising mental health nurse prescribers as an accurate representation of their experience. CONCLUSIONS: The methodology generated a coherent and generalisable theory. It is therefore claimed that concurrent analysis engenders consistent and iterative treatment of different sources of qualitative data in a manageable manner. This process supports facilitation of the highest standard of qualitative research. RELEVANCE TO CLINICAL PRACTICE: Concurrent analysis removes the artificial delineation of relevant literature from other forms of constructed data. This gives researchers clear direction to treat qualitative data consistently raising the chances of generalisability of the findings. Raising the generalisability of qualitative research will increase its chances of informing clinical practice. PMID- 20946447 TI - Development and implementation of a bereavement follow-up intervention for grieving fathers: an action research. AB - AIMS AND OBJECTIVES: The aim is to present the development and implementation of a bereavement follow-up intervention for grieving fathers. The development and implementation process and components of the intervention are presented. BACKGROUND: There is a lack of research into fathers' grief and bereavement support for them after the death of a child. Promotion of evidence-based nursing requires transparent development and implementation of nursing interventions and models to be able to repeat, evaluate their effectiveness and redevelop them. DESIGN: Phases of action research were used when developing and implementing the intervention. METHODS: Results of the baseline study of father's grief and social support, the study of current bereavement support and the literature review were combined using triangulation. RESULTS: In this action research, the development of a bereavement follow-up intervention for grieving fathers began with the planning phase that included a baseline study about fathers' grief and social support, a study of current bereavement support systems in Finnish university hospitals and a systematic review of literature on the topic area and collaboration with a panel of experts. The developed bereavement follow-up intervention included three complementary components: support package, peer supporters' contact and health care personnel's contact. Implementation of the intervention included the development of a programme to be used in nursing practice, intervention training for programme implementers and intervention implementation. CONCLUSIONS: Developing and implementing an intervention is a complex, demanding and long-term process. The planning required theoretical knowledge as well as understanding the experiences of fathers, nursing practice and collaboration with those who implemented the intervention. RELEVANCE TO CLINICAL PRACTICE: New information about the fathers' grief and bereavement follow-up support is described. The model developed is evidence-based and can be applied in nursing care where grieving fathers and families are met. PMID- 20946448 TI - Estimation of disease severity in the NHS cervical screening programme. Part I: artificial cut-off points and semi-quantitative solutions. AB - OBJECTIVE: Current cytology and histology classifications are based on ordered categories and have a strong emphasis on providing information that decides a woman's management rather than the best estimate of disease severity. This two part paper explores the use of a quantitative approach to both cytology and histology disease severity measurements. METHODS: In Part I the problem of artificial cut-off points is discussed and a simple semi-quantitative solution to the problem is proposed. This closely relates to the revised British Society for Clinical Cytology (BSCC) terminology. The estimates of disease severity are designed as extensions of the existing methods, with an emphasis on probability rather than certainty, as a more natural way of approaching the problem. Borderline changes are treated as categorical variables, but koilocytosis, mild, moderate and severe dyskaryosis, and ?invasive as quasi-continuous and the disease severity estimated as a grade number (GN) with any value between 0-4 and the margin of error as a calculated grade range (CGR). RESULTS: As an example, if the reader is unsure between moderate dyskaryosis (HSIL favouring CIN2) and mild dyskaryosis (LSIL favouring CIN1) they can register this uncertainty as a probability, such as 60%/40% moderate/mild. With 2 and 1 as the mid-points of the grade numbers for moderate and mild dyskaryosis the GN value is ((60 * 2)+(40 * 1))/100 = 1.6. The CGR is 1.5 - 0.4 to 1.5 + 0.6 = 1.1 to 2.1. The GN (CGR) estimate of disease severity is therefore 1.6 (1.1-2.1). In a similar manner the disease severity from all slides showing koilocytosis or dyskaryosis can be estimated as a number between 0 and 4 with an associated error. Histology can be treated in a similar way. CONCLUSIONS: This semi-quantitative approach provides a framework more suitable for research and audit of disease severity estimates. It avoids the paradox inherent in the current systems using artificial cut-points to produce categories whereby increasing agreement can only be achieved by losing information. PMID- 20946449 TI - Estimation of disease severity in the NHS cervical screening programme. Part II: quantitative methods of estimating disease severity and progression potential. AB - OBJECTIVE: This is the second of a two-part paper exploring the use of a more quantitative approach to both cytology and histology disease severity measurements. In Part I the problem of artificial cut-off points was discussed and a semi-quantitative solution to the problem proposed. In Part II quantitative methods are proposed that are used to predict the estimated progression probability (EPP) to invasive cancer. METHODS: Based on models derived from published data the grade number (GN) is related to the EPP to invasive cancer over the next 10 years for both cytology (CEPP) and histology (HEPP) using a look up table. CEPP and HEPP are then adjusted by other factors such as age, persistence, HPV result, number of cells and lesion size to obtain the adjusted CEPP and HEPP (ACEPP and (AHEPP). The two factors can be combined to produce an adjusted weighted estimated progression potential using the formula AWEPP ?((ACEPP + AHEPP)/2) * AHEPP) using a two to one bias in favour of the histology. RESULTS: As an example of the methodology consider a slide estimated as showing a 60% probability of moderate dyskaryosis (HSIL favouring CIN2) and 40% probability of mild dyskaryosis (LSIL favouring CIN1). The GN number would be 1.6 (as described in Part I) and the EPP over the next 10 years 0.78%. For a woman aged 52 years (correction factor *2.0) with a second mildly dyskaryotic smear (correction factor *1.25) and >50 dyskaryotic cells (correction factor 1.5) the ACEPP would be 0.78 * 2.00 * 1.25 * 1.5 = 2.9%. If the HEPP on histology was 50:50 between CIN1 and CIN2, the AHEPP can be calculated as 1.4%. The AWEPP would be ?((2.9 + 1.4)/2 * 1.4) = 1.7%. The final estimate of disease progression potential based on both cytology and histology is 1.7% over 10 years. CONCLUSIONS: These quantitative approaches based on adjusted and weighted EPP provide a framework suitable for research, audit and comparison between screening centres, and for tailoring criteria for colposcopy referral and treatment. Further research is required to improve the estimates given in the paper. PMID- 20946450 TI - Oesophageal varices in cirrhotic patients: from variceal screening to primary prophylaxis of the first oesophageal variceal bleeding. AB - Bleeding from oesophageal varices is still a lethal complication in cirrhotic patients with portal hypertension. Approximately 5-10% of patients with cirrhosis will develop oesophageal varices per year, and about 25-30% of cirrhotic patients with oesophageal varices and without previous variceal haemorrhage will bleed from ruptured varices. To date, data on preventing the formation/growth of oesophageal varices (preprimary prophylaxis) are conflicting, with insufficient evidence to use beta-blockers. There is evidence for the need for primary prophylaxis, and both beta-blockers and endoscopic variceal ligation have shown the same efficacy in preventing first bleeding, but which one to prefer is still controversial. The present article reviews the established and potential therapeutic strategies for preventing the development and rupture of oesophageal varices. PMID- 20946451 TI - A review of abdominal organ transplantation in cystic fibrosis. AB - With advances in medical treatments, patients with CF are having improved quality of life and living longer. Although pulmonary disease is still the leading cause of morbidity and mortality, this longevity has allowed for the development of other organ dysfunction, mainly liver and pancreas. This review discusses the abdominal organ complications and the role of abdominal organ transplantation in CF. Liver failure and portal hypertension complications are the most common indicators for liver transplantation in CF, and five-yr survival for isolated liver transplantation is >80%. Deficiency of pancreatic enzymes is almost universal and up to 40% of patients with CF can develop insulin-dependent diabetes, although the role of pancreas transplantation is less clear and needs further research. Finally, the need for lung transplantation should always be assessed and considered in combination with liver transplantation on a case-by case basis. PMID- 20946452 TI - Quantifying human susceptibility to contact sensitization; risk assessments now and in the future. AB - Assessment and quantification of the risk that a chemical will induce allergic contact sensitization presently depend heavily on background data from animal tests. Following the banning of animal testing of chemicals used in cosmetics and personal products in Europe after 2013, alternative approaches will be required. The chemical properties likely to make a given compound a sensitizer can be determined in vitro with reasonable certainty, but confirmation that it is a sensitizer comes only from in vivo exposure to it. Assessment of the sensitization risks involves consideration of how much of the compound will be applied to skin, for how long, and at which sites. However, the in vivo interactions of the chemical with the skin, with regard to its permeability, and biochemical and immune defences, cannot be predicted from a theoretical position. The xenobiotic-metabolizing enzymes and antioxidant defences may degrade chemicals or may generate potentially immunogenic haptens. Many factors can modify the skin and the immune response, including sex, race, age, genetic programming of epidermal permeability, and/or antioxidant and drug-metabolizing pathways. The only certain way to evaluate whether a chemical will sensitize is in vivo exposure, and the nature of the hazard is revealed by determination of the dose-response relationship. This review shows there is still a serious gap in our understanding of the biological factors and variables involved in conferring resistance or susceptibility to the development of allergic sensitization by chemicals. We are not yet in a position to predict sensitization by chemicals from a theoretical starting point. PMID- 20946453 TI - Fragrance mix I patch test reactions in 5006 consecutive dermatitis patients tested simultaneously with TRUE Test(r) and Trolab(r) test material. AB - BACKGROUND: The prevalence of contact allergy to fragrance mix (FM) I varies from study to study, depending on factors such as test population, patch test material, and technique. OBJECTIVES: To compare the outcome of routine patch testing with FM I TRUE Test and FM I Trolab. MATERIALS AND METHODS: A total of 5006 consecutive eczema patients were patch tested with both patch test materials according to the International Contact Dermatitis Research Group. RESULTS: A total of 9.9% patients tested had a positive reaction to one of the FM I mixes; 4.4% to FM I TRUE Test, 9.3% to FM I Trolab, and 3.7% to both (P < 0.0001). Patients with a stronger reaction to FM I TRUE Test almost all reacted to FM I Trolab, whereas the reverse situation showed a lower association. Clinical relevance of a positive patch test reaction to FM I TRUE Test was found in 73.0%, and clinical relevance of a positive patch test reaction to FM I Trolab was found in 64.3%; 68.4% of the patients with a positive reaction to FM I TRUE Test and 54.3% with a positive reaction to FM I Trolab were positive to one or more of the eight constituents of the mix. LIMITATIONS: The study is retrospective, and supplementary testing with FM components in patients with a positive reaction to the mixes was performed in a selected group of patients. Determination of clinical relevance may be biased. CONCLUSIONS: From this study, we cannot conclude which of the two FM I test preparations is the best for diagnostic purposes. Inclusion of both FM I tests in the baseline series to obtain a graded degree of FM I allergy for the individual patient is one option. Prospective controlled patch test studies with FM I patch test material are recommended. PMID- 20946454 TI - Patch testing with fragrance mix II: results of the IVDK 2005-2008. AB - BACKGROUND: The fragrance mix (FM I), established in 1977, detects the majority, but not all cases of contact allergy to fragrances. Based on European research 2002/2003, fragrance mix II (FM II) was developed to supplement FM I. In 2005, the German Contact Dermatitis Research Group (DKG) added FM II to their baseline series. OBJECTIVES: To evaluate reactions to FM II and its constituents in routine patch testing. METHODS: Retrospective data analysis of the Information Network of Departments of Dermatology (IVDK), 2005-2008, of patch test results with FM II and its constituents. RESULTS: A total of 35 633 patients were patch tested with FM II as part of the DKG baseline series. Of these, 1742 (4.9%) reacted positively. Concomitant reactions to FM I were observed in 41.9% of the patients reacting to FM II. In 367 FM II-positive patients, a full breakdown test of the mix was performed. Of these, 47.7% reacted to hydroxyisohexyl 3 cyclohexene carboxaldehyde, 16.1% to citral, 11.4% to farnesol, 3.8% to hexyl cinnamal, 2.7% to coumarin, and 2.5% to citronellol. CONCLUSIONS: FM II is an important screening and diagnostic tool to detect fragrance allergy. Hydroxyisohexyl 3-cyclohexene carboxaldehyde is the most important fragrance allergen in FM II. PMID- 20946455 TI - Fragrance mix II in the baseline series contributes significantly to detection of fragrance allergy. AB - BACKGROUND: Fragrance mix II (FM II) is a relatively new screening marker for fragrance contact allergy. It was introduced in the patch test baseline series in Denmark in 2005 and contains six different fragrance chemicals commonly present in cosmetic products and which are known allergens. AIM: To investigate the diagnostic contribution of including FM II in the baseline series by comparing it with other screening markers of fragrance allergy: fragrance mix I (FM I), Myroxylon pereirae and hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC). METHOD: Retrospective study of 12 302 patients consecutively patch tested with FM II by members of the Danish Contact Dermatitis Group 2005-2008. RESULTS: FM II gave a positive patch test in 553 patients (4.5%), and in 72.2% of these patients the reaction was judged to be clinically relevant. FM II ranked second in detecting fragrance allergy, after FM I. If FM II had not been included as a screening marker in the baseline series, 15.6% (n = 202) of individuals with fragrance allergy would not have been identified by the other fragrance screening markers (FM I, M. pereirae or HICC). CONCLUSION: FM II contributes substantially to detecting fragrance allergy. It ranked second among the fragrance screening markers tested in the baseline series and detects individuals with an allergy who otherwise would not have been identified. PMID- 20946456 TI - Contact allergy to essential oils: current patch test results (2000-2008) from the Information Network of Departments of Dermatology (IVDK). AB - BACKGROUND: Essential oils are used in perfumery and in products for aromatherapy or balneotherapy. Previous studies have shown some to be important contact sensitizers. A practical diagnostic approach, based on the results of a large, central European network and other evidence, is needed. METHODS: Data of the Information Network of Departments of Dermatology (IVDK; www.ivdk.org) on all patients patch tested between January 2000 and December 2008 with essential oils were retrospectively analysed. RESULTS: 15 682 patients of 84 716 consulting in the period had been tested with at least one essential oil, and 637 reacted positively to at least one of the essential oils, most commonly to ylang-ylang oil (I and II) (3.1% as weighted mean of positive tests in special series and consecutive testing), lemongrass oil (1.8%), jasmine absolute (1.6%), sandalwood oil and clove oil (1.5% each). Cross-reactivity between distillate and main allergen, if available, was marked. CONCLUSIONS: Patch testing the important essential oils should be considered in patients with a suggestive history. Additionally, culprit products brought in by the patient should be tested, closing a diagnostic gap by (i) including those other essential oils not included in the commercial test series and (ii) providing a means of testing with the oxidized substances to which the patient had actually been exposed. PMID- 20946457 TI - Comparison of three different techniques for application of water solutions to Finn Chambers(r). AB - BACKGROUND: With regard to contact allergy, the dose of a sensitizer per unit skin area is an important factor for both sensitization and elicitation, and therefore a known amount/volume of test preparation should be applied at patch testing. OBJECTIVES: To compare three different techniques for the application of aqueous solutions to Finn Chambers, in order to determine the precision and accuracy of each technique when the recommended 15 ul volume is applied. METHODS: Four technicians applied formaldehyde 1.0% aq. (wt/vol) and methylchloroisothiazolinone/methylisothiazolinone 200 ppm (wt/vol) in sets of 10 onto Finn Chambers, with three different techniques: (i) micro-pipetting; (ii) dripping the solutions; and (iii) dripping the solutions followed by removal of excess solution with a soft tissue. Assessment of the variations was performed with the use of descriptive data. The ability to apply the exact amount was assessed by Fisher's exact test by categorizing each application as in or out of the range 12-18 ul. RESULTS/CONCLUSIONS: The micro-pipette technique had the best accuracy and precision, as well as the lowest inter-individual variation. The technique in which excess solution was removed had good precision, but failed in the application of the defined amount, i.e. 15 ul. PMID- 20946458 TI - Flare-up of dermatitis following patch testing is more common in polysensitized patients. PMID- 20946459 TI - Occupational allergic contact dermatitis caused by N-(3-aminopropyl)-N dodecylpropane-1,3-diamine in a surface disinfectant. PMID- 20946460 TI - Contact sensitization to textile dyes in a self-selected population and a dermatological referral population in Beijing. PMID- 20946461 TI - Occupational cobalt-allergic contact dermatitis resulting from polyester resin. PMID- 20946462 TI - Fixed drug eruption caused by amoxicillin-clavulanic acid. PMID- 20946463 TI - Occupational allergy to cinnamal in a baker. PMID- 20946464 TI - Allergic contact stomatitis caused by a polyether dental impression material. PMID- 20946465 TI - Effect of air transport on acrylate/methacrylate allergens in syringes and IQ chambers. PMID- 20946466 TI - Late patch test reaction to Disperse Orange 1 not related to active sensitization. PMID- 20946467 TI - Second allogeneic hematopoietic stem cell transplantation: a treatment for graft failure. AB - We evaluated the results in 20 recent patients treated with a second hematopoietic stem cell transplantation (HSCT) after graft failure (GF). There were 10 children <18 yr of age. Ten patients had a non-malignant disease, and the other 10 had a malignant disease. In most of the transplantations, fludarabine based reduced intensity conditioning (RIC) was given. Bone marrow was given to 11 patients, peripheral blood system cell (PBSC) in seven and cord blood to two patients. For the second transplantation (n = 20), a new donor was used in nine cases, while the initial donor was used in 11 transplants. Eight patients (40%) suffered from a second GF. Five of these patients were treated with a third HSCT. The probability of survival was 65% one yr and 60% three yr after the second HSCT. No difference in survival was found between patients transplanted with a new donor (56%) compared to those using the original donor (64%). The three-yr survival was 70% for children compared to 50% for adults (p = ns). Patients with a non-malignant disorder showed a three-yr survival of 90% compared to 20% in patients with a malignant disease (p = 0.005). We concluded that re transplantation using RIC is a valid option for GF, especially in patients with non-malignant disorders. PMID- 20946468 TI - Liver transplantation for children with Wilson disease: comparison of outcomes between children and adults. AB - Liver transplantation (LT) is lifesaving for patients with Wilson disease (WD) presenting with fulminant hepatic failure (FHF) or chronic liver disease (CLD) unresponsive to treatment. AIM: To determine the outcome of LT in pediatric and adult patients with WD. METHODS: United Network for Organ Sharing data on LT from 1987 to 2008 were analyzed. Outcomes were compared for patients requiring LT for FHF and CLD after 2002. Multivariate logistic regression was used to determine risk factors for death and graft loss. RESULTS: Of 90,867 patients transplanted between 1987 and 2008, 170 children and 400 adults had WD. The one- and five-yr patient survival of children was 90.1% and 89% compared to 88.3% and 86% for adults, p = 0.53, 0.34. After 2002, 103 (41 children) were transplanted for FHF and 67 (10 children) for CLD. One- and five-yr patient survival was higher in children transplanted for CLD compared to FHF; 100%, 100% vs. 90%, 87.5% respectively, p = 0.30, 0.32. One- and five-yr patient survival was higher in adults transplanted for CLD compared to FHF; 94.7%, 90.1% vs. 90.3%, 89.7%, respectively, p = 0.36, 0.88. Encephalopathy, partial graft, and ventilator use were risk factors for death by logistic regression. CONCLUSION: LT is an excellent treatment option for patients with WD. Patients transplanted for CLD had higher patient survival rates than patients with FHF. PMID- 20946469 TI - Kidney transplantation in the morbidly obese: complicated but still better than dialysis. AB - Obese patients are denied renal transplantation in many centers. We report results regarding obesity from a new transplant program (1999 through 2007). Six hundred and forty-two patients were transplanted: 439 patients with BMI < 30 (Group 1), 109 patients with BMI 30.1-34.9 (Group 2), and 89 patients with BMI > 35 (Group 3). Follow-up was at least one yr. Medical and surgical management was performed by the same team throughout the study period. There were no demographic differences between groups except for increased diabetes in Groups 2 and 3. Actuarial graft and patient survivals were not statistically different between groups. Group 3 patients had numerical trends toward more delayed graft function and lower graft survivals but these did not reach statistical significance. Biopsy-proven rejections did not differ between groups. Wound infections were statistically significant in Groups 2 and 3 compared to Group 1 (p < 0.01). Despite increased wound infection rates with increased BMI, transplanting patients with morbid obesity results in better survival for individual patients than dialysis. Thus, there is no a priori ethical reason for treating obese ESRD patients differently from those with other comorbidities. PMID- 20946470 TI - Granulovacuolar degeneration (GVD) bodies of Alzheimer's disease (AD) resemble late-stage autophagic organelles. AB - AIMS: Granulovacuolar degeneration involves the accumulation of large, double membrane-bound bodies within certain neurones during the course of Alzheimer's disease (AD) and other adult-onset dementias. Because of the two-layer membrane morphology, it has been proposed that the bodies are related to autophagic organelles. The aim of this study was to test this hypothesis, and determine the approximate stage at which the pathway stalls in AD. METHODS: Spatial colocalization of autophagic and endocytic markers with casein kinase 1 delta, a marker for granulovacuolar degeneration (GVD) bodies, was evaluated in hippocampal sections prepared from post mortem Braak stage IV and V AD cases using double-label confocal fluorescence microscopy. RESULTS: GVD bodies colocalized weakly with early-stage autophagy markers LC3 and p62, but strongly with late-stage marker lysosome-associated membrane protein 1 (LAMP1), which decorated their surrounding membranes. GVD bodies also colocalized strongly with charged multivesicular body protein 2B (CHMP2B), which colocalized with the core granule, but less strongly with lysosomal marker cathepsin D. CONCLUSIONS: The resultant immunohistochemical signature suggests that granulovacuolar degeneration bodies (GVBs) do contain late-stage autophagic markers, and accumulate at the nexus of autophagic and endocytic pathways. The data further suggest that failure to complete autolysosome formation may be an important correlate of GVB accumulation. PMID- 20946472 TI - Review: leucocyte-endothelial cell crosstalk at the blood-brain barrier: a prerequisite for successful immune cell entry to the brain. AB - Leucocyte migration into the central nervous system is a key stage in the development of multiple sclerosis. While much has been learnt regarding the sequential steps of leucocyte capture, adhesion and migration across the vasculature, the molecular basis of leucocyte extravasation is only just being unravelled. It is now recognized that bidirectional crosstalk between the immune cell and endothelium is an essential element in mediating diapedesis during both normal immune surveillance and under inflammatory conditions. The induction of various signalling networks, through engagement of cell surface molecules such as integrins on the leucocyte and immunoglobulin superfamily cell adhesion molecules on the endothelial cell, play a major role in determining the pattern and route of leucocyte emigration. In this review we discuss the extent of our knowledge regarding leucocyte migration across the blood-brain barrier and in particular the endothelial cell signalling pathways contributing to this process. PMID- 20946471 TI - Review: cerebral microvascular pathology in ageing and neurodegeneration. AB - This review of age-related brain microvascular pathologies focuses on topics studied by this laboratory, including anatomy of the blood supply, tortuous vessels, venous collagenosis, capillary remnants, vascular density and microembolic brain injury. Our studies feature thick sections, large blocks embedded in celloidin, and vascular staining by alkaline phosphatase. This permits study of the vascular network in three dimensions, and the differentiation of afferent from efferent vessels. Current evidence suggests that there is decreased vascular density in ageing, Alzheimer's disease and leukoaraiosis, and cerebrovascular dysfunction precedes and accompanies cognitive dysfunction and neurodegeneration. A decline in cerebrovascular angiogenesis may inhibit recovery from hypoxia-induced capillary loss. Cerebral blood flow is inhibited by tortuous arterioles and deposition of excessive collagen in veins and venules. Misery perfusion due to capillary loss appears to occur before cell loss in leukoaraiosis, and cerebral blood flow is also reduced in the normal appearing white matter. Hypoperfusion occurs early in Alzheimer's disease, inducing white matter lesions and correlating with dementia. In vascular dementia, cholinergic reductions are correlated with cognitive impairment, and cholinesterase inhibitors have some benefit. Most lipid microemboli from cardiac surgery pass through the brain in a few days, but some remain for weeks. They can cause what appears to be a type of vascular dementia years after surgery. Donepezil has shown some benefit. Emboli, such as clots, cholesterol crystals and microspheres can be extruded through the walls of cerebral vessels, but there is no evidence yet that lipid emboli undergo such extravasation. PMID- 20946473 TI - Carvedilol protects tubular epithelial cells from ischemia-reperfusion injury by inhibiting oxidative stress. AB - OBJECTIVES: Renal ischemia-reperfusion injury (IRI), leading to acute kidney injury, is a frequent complication with renal transplantation and it is associated with graft function. Its pathogenesis involves ischemia, vascular congestion and reactive oxygen metabolites. Carvedilol is an antihypertensive drug with potent anti-oxidant properties. In this study we investigated the protective effects of carvedilol in a rat renal IRI model. METHODS: Twenty-four rats were randomized into sham, untreated control and carvedilol (2 mg/kg 30 min before surgery and 12 hr after reperfusion) treatment groups and were subjected to 60 min of left renal ischemia followed by reperfusion at 24, 48, 96 and 168 hr. RESULTS: Treatment with carvedilol significantly decreased plasma creatinine levels after IRI (up to 168 hr) compared to controls (P < 0.001), suggesting an improvement in renal function. Histopathological analysis revealed decreased IRI induced damage in kidneys from carvedilol-treated rats. A significant increase in the expression levels of Cu/Zn superoxide dismutase and reduction of 8 hydroxydeoxyguanosine and apoptosis levels (P < 0.005) suggested a protective effect after treatment with carvedilol. CONCLUSIONS: Our findings suggest that carvedilol ameliorates IRI resulting in improved renal function. PMID- 20946474 TI - Proteolytic activation of heparin-binding EGF-like growth factor by membrane-type matrix metalloproteinase-1 in ovarian carcinoma cells. AB - Increased expression of heparin-binding EGF-like growth factor (HB-EGF) and membrane-type matrix metalloproteinase-1 (MT1-MMP) is frequently associated with various types of malignant tumor. HB EGF-like growth factor has been reported to promote the malignant progression of ovarian carcinoma. Based on this finding, inhibition of HB-EGF activity with CRM197 is now under phase I clinical evaluation. On the other hand, MT1-MMP expressed in ovarian carcinoma cells is thought to promote invasion and growth of tumor cells by degrading the extracellular matrix. However, we recently demonstrated that co-expression of MT1 MMP and HB-EGF in gastric carcinoma cells leads to cleavage of HB-EGF within its N-terminal heparin-binding region, converting it into a potent heparin independent growth factor. In this study, we evaluated the importance of regulation of HB-EGF by MT1-MMP in clinical samples of ovarian carcinoma. We detected co-expression of HB-EGF and MT1-MMP in clear cell ovarian carcinoma tissues, particularly at the invasion front and in tumor cells that had disseminated into the ascites, whereas HB-EGF alone was expressed in non-invasive borderline ovarian tumor tissue. Furthermore, a soluble HB-EGF fragment that corresponds to that processed by MT1-MMP was detected in malignant ascites obtained from patients with metastatic ovarian carcinoma. Ovarian carcinoma cells that express MT1-MMP and HB-EGF exhibited enhanced cell growth in a 3D-collagen matrix and anchorage-independent growth in suspension. These results indicate that MT1-MMP co-expressed with HB-EGF in ovarian carcinoma cells potentiates the activity of HB-EGF to promote invasive tumor growth and spreading in vivo. PMID- 20946475 TI - Increase of oxidant-related triglycerides and phosphatidylcholines in serum and small intestinal mucosa during development of intestinal polyp formation in Min mice. AB - Recent epidemiological studies have shown a positive association of a high-fat diet with the risk of colon cancer. Indeed, increments in the serum levels of triglycerides (TG) and cholesterols are positively related with colon carcinogenesis. We previously reported that an age-dependent hyperlipidemic state is characteristic of Min mice, an animal model for human familial adenomatous polyposis (FAP). However, qualitative and quantitative changes of lipid metabolism are poorly understood in this state. Here, we provide detailed analysis of serum lipids in Min mice using reverse-phased liquid chromatography/electrospray ionization mass spectrometry (RPLC/ESI-MS). We also demonstrate local analysis of lipid droplets in the villi of the small intestine using laser capture microdissection and a sensitive chip-based nanoESI-MS system. As a result, oxidized phosphatidylcholines (PC) such as aldehyde and carboxylic acid types were increased, even at an early stage of intestinal polyp formation in serum. In addition, hydroperoxidizable TG precursors containing linoleic acid (18:2n-6) were deposited at the tip of the villi with aging, and these hydroperoxidized TG were also increased in serum. Meanwhile, increments of the oxidizable TG precursors in serum and small intestinal mucosa were suppressed by treatment with pitavastatin, a novel third generation lipophilic statin. These results suggest that quantitative and qualitative lipid changes such as hydroperoxidizable TG precursors are important in the course of intestinal polyp formation and oxidative stress might lead to the development of intestinal polyp formation in Min mice. PMID- 20946476 TI - The effectiveness of self-directed learning in health professions education: a systematic review. AB - OBJECTIVES: Given the continuous advances in the biomedical sciences, health care professionals need to develop the skills necessary for life-long learning. Self directed learning (SDL) is suggested as the methodology of choice in this context. The purpose of this systematic review is to determine the effectiveness of SDL in improving learning outcomes in health professionals. METHODS: We searched MEDLINE, EMBASE, ERIC and PsycINFO through to August 2009. Eligible studies were comparative and evaluated the effect of SDL interventions on learning outcomes in the domains of knowledge, skills and attitudes. Two reviewers working independently selected studies and extracted data. Standardised mean difference (SMD) and 95% confidence intervals (95% CIs) were estimated from each study and pooled using random-effects meta-analysis. RESULTS: The final analysis included 59 studies that enrolled 8011 learners. Twenty-five studies (42%) were randomised. The overall methodological quality of the studies was moderate. Compared with traditional teaching methods, SDL was associated with a moderate increase in the knowledge domain (SMD 0.45, 95% CI 0.23-0.67), a trivial and non-statistically significant increase in the skills domain (SMD 0.05, 95% CI 0.05 to 0.22), and a non-significant increase in the attitudes domain (SMD 0.39, 95% CI-0.03 to 0.81). Heterogeneity was significant in all analyses. When learners were involved in choosing learning resources, SDL was more effective. Advanced learners seemed to benefit more from SDL. CONCLUSIONS: Moderate quality evidence suggests that SDL in health professions education is associated with moderate improvement in the knowledge domain compared with traditional teaching methods and may be as effective in the skills and attitudes domains. PMID- 20946477 TI - Has the UK Clinical Aptitude Test improved medical student selection? AB - OBJECTIVES: In 2006, the United Kingdom Clinical Aptitude Test (UKCAT) was introduced as a new medical school admissions tool. The aim of this cohort study was to determine whether the UKCAT has made any improvements to the way medical students are selected. METHODS: Regression analysis was performed in order to study the ability of previous school type and gender to predict UKCAT, personal statement or interview scores in two cohorts of accepted students. The ability of admissions scores and demographic data to predict performance on knowledge and skills examinations was also studied. RESULTS: Previous school type was not a significant predictor of either interview or UKCAT scores amongst students who had been accepted onto the programme (n = 307). However, it was a significant predictor of personal statement score, with students from independent and grammar schools performing better than students from state-maintained schools. Previous school type, personal statements and interviews were not significant predictors of knowledge examination performance. UKCAT scores were significant predictors of knowledge examination performance for all but one examination administered in the first 2 years of medical school. Admissions data explained very little about performance on skills (objective structured clinical examinations [OSCEs]) assessments. CONCLUSIONS: The use of personal statements as a basis for selection results in a bias towards students from independent and grammar schools. However, no evidence was found to suggest that students accepted from these schools perform any better than students from maintained schools on Year 1 and 2 medical school examinations. Previous school type did not predict interview or UKCAT scores of accepted students. UKCAT scores are predictive of Year 1 and 2 examination performance at this medical school, whereas interview scores are not. The results of this study challenge claims made by other authors that aptitude tests do not have a place in medical school selection in the UK. PMID- 20946478 TI - Equity in interviews: do personal characteristics impact on admission interview scores? AB - CONTEXT: Research indicates that some social groups are disadvantaged by medical school selection systems. The stage(s) of a selection process at which this occurs is unknown, but at interview, when applicant and interviewer are face-to face, there is potential for social bias to occur. METHODS: We performed a detailed audit of the interview process for a single-entry year to a large UK medical school. Our audit included investigating the personal characteristics of both interviewees and interviewers to find out whether any of these factors, including the degree of social matching between individual pairs of interviewees and interviewers, influenced the interview scores awarded. RESULTS: A total of 320 interviewers interviewed 734 applicants, providing complete data for 2007 interviewer-interviewee interactions. The reliability of the interview process was estimated using generalisability theory at 0.82-0.87. For both interviewers and interviewees, gender, ethnic background, socio-economic group and type of school attended had no influence on the interview scores awarded or achieved. Staff and student interviewer marks did not differ significantly. Although numbers in each group of staff interviewers were too small for formal statistical analysis, there were no obvious differences in marks awarded between different medical specialties or between interviewers with varying amounts of interviewing experience. CONCLUSIONS: Our data provide reassurance that the interview does not seem to be the stage of selection at which some social groups are disadvantaged. These results support the continued involvement of senior medical students in the interview process. Despite the lack of evidence that an interview is useful for predicting future academic or clinical success, most medical schools continue to use interviews as a fundamental component of their selection process. Our study has shown that at least this arguably misplaced reliance upon interviewing is not introducing further social bias into the selection system. PMID- 20946479 TI - Intersections of creativity in the evaluation of the Wilson Centre Fellowship Programme. AB - OBJECTIVES: Comprehensive programme evaluation frameworks are increasingly important to inform the development of sophisticated programmes that educate the next generation of health professions education researchers. This paper highlights an innovative process undertaken by the Wilson Centre for Research in Education to evaluate its fellowship programme. This process incorporates the principles of programme theory and a framework drawn from the field of organisational development. METHODS: During the iterative and dynamic process of articulating the programme's theory, a hidden tension between structured and unstructured components of the fellowship programme was unearthed. This necessitated a secondary process beyond traditional programme evaluations involving the use of a method called 'Polarity Management(r)'. RESULTS: The use of this model allowed the team to identify priority actions for balancing both the structured and unstructured components, along with indicators which can serve as an early warning system to alert observers to any imbalance between the components. DISCUSSION: Lessons learned and implications for other health education programming and the practice of programme evaluation are discussed. PMID- 20946480 TI - An ethnographic study of attending rounds in general paediatrics: understanding the ritual. AB - OBJECTIVES: Teaching at the bedside during attending rounds is considered to be fundamental to medical education. We conducted an ethnographic case study to investigate such teaching in general paediatrics as a social phenomenon and to explore change over time in both the meaning of rounds and the context in which rounds take place. METHODS: We conducted a case study from January to August 2006 on a 22-bed general paediatric unit in an urban children's hospital and focused our observation on interns, senior residents and attending physicians. We observed the medical team during its normal activities on the study unit and conducted semi-structured interviews with a sample of attendings, interns and senior residents. We compiled a list of codes that emerged from patterns in the data and constructed a rich description of rounds according to the principles of inductive analysis. RESULTS: Four themes emerged from the data: (i) attending rounds are a pervasive and routine part of clinical education; (ii) interns, senior residents and attending physicians hold assumptions about what should happen on rounds; (iii) tension exists between interns', senior residents' and attending physicians' assumptions about bedside teaching during rounds and the reality imposed by contextual factors, and (iv) bedside teaching during rounds is impacted, but not prohibited, by contextual factors. CONCLUSIONS: Our case study provides evidence that bedside teaching during rounds is a pedagogical ideal entrenched in medical education. Participants readily acknowledged teaching at the bedside during rounds as something they perceived should happen, although, in actuality, it was infrequently achieved. This study revealed a telling inconsistency in language and behaviour: 'bedside rounds' was embedded in the participants' ordinary language, but the activity was not necessarily part of their ordinary behaviour. We propose that the practice of bedside teaching is best explained as a ritual. Considering bedside teaching as a ritual helps to explain why rounds are sacrosanct and helps to develop more appropriate expectations for rounds. PMID- 20946483 TI - A novel method of defining the core objectives of a specialty undergraduate curriculum. PMID- 20946484 TI - Student involvement in the development of integrated curricula. PMID- 20946485 TI - Using appreciative inquiry on learning styles to facilitate student learning. PMID- 20946486 TI - Pause 2 Learn: developing self-regulated learning. PMID- 20946487 TI - Virtual histology in the classroom and beyond. PMID- 20946488 TI - The power of the latte: sustaining leaders of change. PMID- 20946489 TI - Safety science meets basic science in problem-based learning. PMID- 20946490 TI - Virtual microscopy as a teaching tool adjuvant to traditional microscopy. PMID- 20946491 TI - Sorting chromosomes as a software-based exercise. PMID- 20946492 TI - Integrating surface anatomy learning with clinical skills training. PMID- 20946493 TI - Training surgeons to teach anatomy: an innovative approach. PMID- 20946494 TI - Description and validation of a novel programme for theatre-based surgical education. PMID- 20946495 TI - Communication skills for interviewing hearing-impaired patients. PMID- 20946496 TI - PBL.2.0: blended learning for an interactive, problem-based pedagogy. PMID- 20946497 TI - Students overlook information in the electronic health record. PMID- 20946498 TI - 'Speed dating' workshop to pair interns and researchers. PMID- 20946499 TI - A procedural teaching tree to aid resident doctor peer-teachers. PMID- 20946500 TI - A novel module for obstetrics and gynaecology resident doctor education. PMID- 20946501 TI - Community-based cervical cancer prevention in the Western Amazon. PMID- 20946502 TI - Teaching community-based palliative care to medical students. PMID- 20946503 TI - Identification of social determinants of health components for teaching: a pilot process. PMID- 20946504 TI - Medical students working with nurses. PMID- 20946505 TI - Exploring chronic pain with patients: medicine meets art. PMID- 20946506 TI - A clerkship essay requirement addressing challenges in medicine. PMID- 20946507 TI - Strengthening medical documentation skills through a focused writing course. PMID- 20946508 TI - A new course for a new curriculum. PMID- 20946509 TI - Clerkship-based reflective writing: a rubric for feedback. PMID- 20946510 TI - Using peer feedback in a formative objective structured clinical examination. PMID- 20946511 TI - Student peer evaluation using a remote response system. PMID- 20946512 TI - Supporting doctors who are experiencing difficulties. PMID- 20946514 TI - Desensitisation of medical students towards the dying. PMID- 20946515 TI - Tackling the spectrum of transition: what can be done in pediatric settings? AB - Transition to adulthood is a complicated process for children with special health care needs. During adolescence, patients must begin to assume responsibility for their medical care as family member's transition health care management from caregivers to patients. At some specific point, patients will also transfer out of pediatrics to adult-oriented services. We present a compilation of manuscripts that describe, study, and offer solutions for these two related challenges as faced by pediatric transplant recipients. PMID- 20946516 TI - PLUTO first report. AB - The PLUTO is a registry developed by an international collaboration of the Liver Tumors Strategy Group (SIOPEL) of the SIOP. Although the number of patients collected in PLUTO to date is too small to add any analytic power to the existing literature, this new registry has great promise. It has been created to clarify issues regarding the role of liver transplantation in the treatment of children with unresectable liver tumors. By reviewing the results to date, we hope we can motivate more centers to participate, enroll patients, complete data entry, and boost the potential impact of the collaborative effort. To achieve this goal, a large number of patients are needed, which requires an intensified international collaboration. Pediatric oncologists, pediatric surgical oncologists, and pediatric liver transplant surgeons are all encouraged to participate and contribute. This is a preliminary glimpse of what we hope to be a series of interim reports over the next decade from the steering committee to help guide therapy in this very challenging group of children. PMID- 20946517 TI - Outcome of pediatric renal transplantation in north India. AB - We report our experience and long-term outcome of pediatric renal transplantation at a referral center in New Delhi. During 1995-2008, 45 transplants were performed in 43 patients at a mean age of 13.3 +/- 4.0 (range 3.8-18) yr. The chief causes for ESRD were reflux nephropathy, obstructive uropathy, vasculitis, renal dysplasia, and focal segmental glomerulosclerosis. Most (91.1%) donors were living related. Post-transplant immunosuppression comprised prednisolone, a calcineurin inhibitor and azathioprine or MMF. AR and CR were seen in 14 (31.1%) and 12 (26.7%) allografts, respectively. Predictors of CR were unsatisfactory compliance and multiple episodes of AR (p = 0.002 each). Urinary infections (n = 13), septicemia (4), tuberculosis (4), CMV disease (7), viral hepatitis (7), and pneumonia (3) were important causes of morbidity. Two patients each had lymphoproliferative disease and new-onset diabetes. There were eight (17.8%) graft losses and six (14%) deaths. The one-, five- and 10-yr graft survivals were 91.1%, 80.4% and 75.1%, respectively; the mean graft survival was 119.4 +/- 8.38 months. The respective patient survivals were 95.3%, 87.9%, and 76.9% at one-, five- and 10 yr. Our results affirm that despite scarcity of resources and frequent infections, long-term outcomes of pediatric renal transplantation are highly satisfactory. PMID- 20946518 TI - Enhanced resolution of interstitial fibrosis in pediatric renal allograft biopsies using image analysis of trichrome stain. AB - The Banff classification is ill suited to detect subtle histologic progression in renal allografts. We present image analysis methodology to precisely quantify IF in pediatric renal allograft biopsies routinely stained with MT. The mean area %IF was determined in 105 pediatric renal allograft biopsies. Associations between %IF or Banff ci scores and estimated GFR were determined using GEE modeling. Logistic regression was used to estimate IF progression. Percent IF (mean +/- s.d.) was 6.83% +/- 3.94, 10.39 +/- 5.23%, and 20.53 +/- 8.74 in patients with ci0, ci1, and ci2, respectively. The difference in %IF between biopsies with ci0, ci1, and ci2 was not proportionately incremental: compared to ci2, ci0 had 67% less IF (p < 0.0001), while ci1 had 48% less IF (p < 0.0001). AR had no impact on the precision of %IF measurements. Each 0.5% decrement in %IF was associated with a 1 mL/min per 1.73 m2 increase in GFR (p < 0.004). Histologic progression was demonstrated by increasing %IF values (p < 0.0001) and could be estimated by IF = 2.61 * (months) + 6.43. This readily adaptable methodology may be used for the longitudinal assessment of IF in pediatric protocol renal allograft biopsies. PMID- 20946519 TI - Use of tissue microarrays and immunohistochemistry to standardize the diagnosis of gastrointestinal stromal tumors. AB - We assessed the concordance among seven general pathologists with respect to histologic diagnosis and interpretation of c-kit proto-oncogene (KIT) and platelet-derived growth factor receptor alpha (PDGFRA) immunostaining of 36 cases of primary spindle-cell tumor, predominantly of the gastrointestinal tract, mesentery, and retroperitoneum, based on review of a tissue microarray (TMA) subjected to immunohistochemistry with antibodies to KIT/CD117, PDGFRA, vimentin, desmin, smooth muscle action, CD34, and S-100 protein. Tumors included 20 molecularly analyzed gastrointestinal stromal tumors (GISTs), 4 leiomyosarcomas, 4 schwannomas, 4 desmoid-type fibromatoses, and 4 solitary fibrous tumors. The mean overall concordance with original diagnosis for each histologic type was 91.1%, with a mean kappa value of 0.91. With respect to PDGFRA immunostaining, the four GISTs with PDGFRA mutation were interpreted as cytoplasm positive, but the 16 GISTs with c-kit mutation were interpreted as weak or positive. These results indicate that the overall concordance with original diagnosis in mesenchymal tumors with the use of immunohistochemical panels is high, despite the use of TMAs. To some extent, PDGFRA immunophenotyping may be useful in GISTs with PDGFRA mutation, but it was not highly reproducible or specific. Therefore, in KIT-negative or weakly positive GISTs, mutation analysis will be required. PMID- 20946520 TI - Expression of phosphorylated Akt in patients with small cell carcinoma of the lung indicates good prognosis. AB - Patients with pulmonary small cell carcinoma are well known to have a poor prognosis. However, predictors of prognosis and treatment outcome have not been reported for this type of cancer. We examined whether excision repair cross complementation group 1 (ERCC1), phosphorylated Akt (p-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), and the uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) genetic polymorphism were useful indicators of prognosis in cases of small cell carcinoma of the lung. We investigated 45 patients with advanced small cell lung cancer who received chemotherapy with irinotecan combined with cisplatin or carboplatin. Staining results showed that 12 of 45 cases (27%) were positive for p-Akt, while 18 (40%) were positive for p-mTOR and 16 (36%) were positive for ERCC1. As for UGT1A1, more than one polymorphism was found in 30 cases (67%). There was a significant relationship observed between the expressions of p-Akt and p-mTOR (P= 0.0006). Univariate analysis indicated a significantly better survival rate for patients positive for p-Akt or p-mTOR, while multivariate analysis using a Cox test showed p-Akt to be the strongest prognostic factor. Our results indicate that p-Akt is a reliable prognostic factor in patients with small cell carcinoma of the lung. PMID- 20946521 TI - Using immunofluorescent digital slide technology to quantify protein expression in archival paraffin-embedded tissue sections. AB - Molecularly targeted therapies require an adequate assessment of molecular expression in cancer. Immunofluorescent staining is a better method to quantify protein expression than immunohistochemistry (IHC), although the latter is currently used to score human epidermal growth factor receptor 2 (HER2) and steroid receptors. The quantification of signal intensity in IHC is still controversial. The advanced technology of virtual slides permits digitizing a whole slide image of immunofluorescence for a few minutes. We have established fluorescence-based, immunofluorescent quantification digital slides (IQD), a method widely applicable in routine practice. The IQD were made by scanning images of formalin-fixed, paraffin-embedded sections and contained, not only morphological information obtained from hematoxylin-counterstains, but also immunofluorescent signals. Assessing protein expression on IQD was carried out using the original image analysis software and was compared with the IHC score (HER2 and steroid receptors). There was a statistically significant correlation between the IQD and IHC scores. In addition, we compared IQD scores of groups classified by IHC scores. The IHC intermediate-expression groups were not statistically different from the high, or negative-expression groups. Immunofluorescent quantification digital slides may help pathologists to assess molecular expression in cancer tissue, and resolve the issue of scoring the intensity of brown signal on IHC slides. PMID- 20946522 TI - Frequent expression of the breast differentiation antigen NY-BR-1 in mammary and extramammary Paget's disease. AB - While mammary Paget's disease (MPD) is clearly linked to breast cancer, the histogenesis of extramammary Paget's disease (EMPD) is controversial. Recently NY BR-1, a differentiation antigen expressed in the breast and in skin adnexal structures was identified. Its protein expression is restricted to normal and neoplastic breast epithelium and to adnexal tumors of the skin. In this study, we examine NY-BR-1 expression by immunohistochemistry in 24 MPD cases with synchronous ductal carcinoma in situ or invasive breast cancer. Results were compared with 26 cases of EMPD of men (n= 4) and women (n= 22) as well as in apoeccrine glands of the axilla and mammary-like glands of the anogenital region. We found NY-BR-1 positivity in 18 of 24 MPD (75%) and in 21 of 26 EMPD (80.8%). All apoeccrine glands of the axilla and mammary-like glands of the anogenital region were NY-BR-1-positive. NY-BR-1 expression is a common finding in MPD and in EMPD. When considering the diagnosis of Paget's disease, NY-BR-1 is a useful diagnostic marker. Furthermore NY-BR-1 positivity in apoeccrine glands of the axilla and anogenital region suggests a potential histogenetic link between these structures and Paget's disease. PMID- 20946523 TI - Correlation of pathological grade and tumor stage of urothelial carcinomas with CD109 expression. AB - Bladder cancer is one of the most common malignant diseases. Since a high-rate of recurrence is a serious problem for early stage urothelial carcinomas, new strategies for the management of recurrent urothelial carcinomas have been explored. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein and is expressed in various cancer tissues, mainly squamous cell carcinomas. CD109 negatively controls transforming growth factor (TGF)-beta/Smad signaling in vitro. In this study, we analyzed the clinical significance of CD109 expression in bladder cancer using immunohistochemistry. Of 156 urothelial carcinoma tissues, 69.9% were positive for CD109, whereas CD109 was not expressed in seven normal bladder epithelia. CD109 expression was significantly higher in non-muscle invasive (pTa+pT1) or low-grade (G1+G2) tumors than in muscle-invasive (pT2-4) or high-grade (G3) tumors, and was associated with cancer-specific survival. Simultaneous immunostaining of CD109 and phosphorylated Smad2 showed an inverse immunoreactivity relationship between the two, suggesting that CD109 inhibits TGF beta/Smad signaling in tumor tissues. Interestingly, CD109 was found to be highly expressed in the basal layer of non-invasive urothelial carcinomas, and the expression pattern was similar to that of CD44, a marker of cancer stem cells. These findings suggest that CD109 is involved in bladder tumorigenesis and is a potential target for cancer immunotherapy. PMID- 20946524 TI - Medullary ray injury in renal allografts. AB - Non-immune injury leading to interstitial fibrosis and tubular atrophy (IF/TA) in renal allografts has various etiologies, but pathological means of verification have yet to be developed. Medullary ray injury (MRI) is a pathological feature of many non-immune injuries inducing IF/TA and pathological determination of calcineurin inhibitor (CNI) toxicity proceeding to striped fibrosis. We investigated the contribution of CNI toxicity to MRI and other non-immune etiologies related to IF/TA. In this study MRI is defined as fibrosis and inflammation localized exclusively to the medullary ray. Thirty-six protocol biopsies showing MRI were analyzed and classified histopathologically as following: MRI related to CNI toxicity; chronic obstruction or reflux nephropathy; and acute or chronic pyelonephritis. The etiology of MRI was CNI toxicity (n= 16, 44.4%), chronic obstruction (n= 13, 36.1%), acute or chronic pyelonephritis (n= 2, 5.6%), and other (n= 5, 13.9%). We performed cystography in seven cases of MRI related to chronic obstruction or reflux nephropathy and six cases showing vesicoureteral reflux. The ci+ct score showed significant progression after one year in 30 of the 36 cases (1.53 +/- 1.04 vs. 3.03 +/- 1.13, P < 0.01). MRI has various etiologies and may also predict changes in urological complications. The classification of MRI may be useful to determine the non-immune etiology leading to IF/TA. PMID- 20946525 TI - Hepatoid adenocarcinoma of the stomach with multi-nucleated giant cell proliferation in a 100-year-old man. AB - Few cases of gastric carcinoma with infiltrating multi-nucleated giant cells (MGCs) have been reported, and giant cells infiltrating the gastric carcinoma were previously described as osteoclast-like giant cells (OGCs). However, hepatoid adenocarcinomas have never been reported previously, and the present case is extremely rare. A 100-year-old Japanese man with gastralgia was found to have a mass in his gastric body. Histological examination showed a poorly differentiated adenocarcinoma with infiltration of MGCs. Vascular and lymphatic invasion were noted but there were no metastases. Almost all the tumor comprised cells with hepatoid-like features. The MGCs proliferated, with infiltration of lymphoid cells. A few MGCs contained mucous material in their cytoplasm, indicating these were foreign-body giant cells. Immunohistochemically, the hepatoid-like components were positive for AFP, and staining with polyclonal antibodies against carcinoembryonic antigen (CEA) showed the canalicular pattern. We concluded that this component was hepatoid adenocarcinoma. The MGCs were positive for CD68, and surrounding infiltrating lymphoid cells were diffusely positive for CD3. Infiltration of MGCs in gastric cancer may represent a cellular immune response against gastric cancer invasion. Further studies are required to elucidate the etiology of MGCs in gastric cancer. PMID- 20946526 TI - Acute fibrinous and organizing pneumonia in systemic lupus erythematosus: a case report and review of the literature. AB - Pulmonary manifestations of systemic lupus erythematosus (SLE) typically include pleuritis, alveolar hemorrhage, and infectious pneumonia due to immunosuppression with less common entities including bronchiolitis, interstitial pneumonia, and pulmonary fibrosis. More rare manifestations include organizing pneumonia (OP) and diffuse alveolar damage (DAD). A similar but distinct entity of acute fibrinous and organizing pneumonia (AFOP), characterized by intra-alveolar fibrin deposition and associated organizing pneumonia, has been reported in association with connective tissue disorders, but has not been described in association with SLE. Reported herein is a patient with SLE and accompanying antiphospholipid syndrome with recent pulmonary embolism, persistent respiratory symptomology, and persistent radiographic abnormalities who underwent lung biopsy displaying features of AFOP. This case in conjunction with previous literature indicates that AFOP can be a manifestation of connective tissue disease including SLE and may be an underreported variant of medical lung disease due to overlap in histological characteristics with OP and DAD. PMID- 20946527 TI - Odontogenic myxofibroma with HMGA2 overexpression and HMGA2 rearrangement. AB - Odontogenic myxofibromas are variants of odontogenic myxomas that contain considerable amounts of collagen fibers in the myxoid stroma. Cytogenetic studies of odontogenic myxomas/myxofibromas have rarely been reported. This report describes the first case of an odontogenic myxofibroma presenting with HMGA2 protein overexpression and HMGA2 rearrangement in a 40-year-old woman. A 2.7-cm tumor in the premolar region of the right mandible was curettaged. There was no evidence of recurrence or metastasis at 12 months after the surgery. Histological examination revealed that the tumor comprised spindle or stellate cells with mild nuclear pleomorphism, abundant myxoid matrix and partly dense collagen fibers. Mitotic figures were rarely observed. Immunohistochemically, the tumor cells were diffusely positive for vimentin and HMGA2. Less than 1% of the tumor cells were positive for Ki-67. We detected split signals by interphase fluorescence in situ hybridization (FISH) in paraffin sections using HMGA2 break-apart probes. The breaks were certainly located within or near the HMGA2 gene. No rearrangement of the FUS gene was detected by FISH, implying discrimination from low-grade fibromyxoid sarcoma. It is suggested that HMGA2 rearrangement and HMGA2 protein overexpression may be associated with the tumorigenesis of odontogenic myxomas/myxofibromas, similar to the case for many other benign mesenchymal tumors. PMID- 20946528 TI - Deglycosylation of puerarin and other aromatic C-glucosides by a newly isolated human intestinal bacterium. AB - The human intestinal microbiota may influence the fate of bioactive polyphenols, such as the isoflavone puerarin (daidzein 8-C-glucoside), following their oral intake. Faecal suspensions from 19 healthy subjects were tested for their ability to C-deglycosylate puerarin. Only one of these catalysed this reaction. A rod shaped Gram-positive bacterium, strain CG19-1, capable of deglycosylating puerarin to daidzein was isolated from the corresponding suspension. However, the strictly anaerobic isolate was unable to utilize puerarin as sole carbon and energy source nor any of the tested carbohydrates. Comparative 16S rRNA gene sequence analysis indicated that strain CG19-1 is a new species of the Lachnospiraceae. Strain CG19-1 also converted other aromatic C-glucosides in addition to puerarin. The xanthone C-glucoside mangiferin was deglycosylated to norathyriol. The flavone C-glucosides homoorientin and vitexin were degraded to 3 (3,4-dihydroxyphenyl)propionic acid via luteolin and 3-(4-hydroxyphenyl)propionic acid respectively. In addition, strain CG19-1 converted flavonoid O-glucosides, but at rates that were lower than those of the C-glucosides tested. The isolate deglycosylated the isoflavone O-glucosides daidzin and genistin to daidzein and genistein respectively. Several O-glucosides of the flavones luteolin and apigenin undergoing deglycosylation were subsequently cleaved to 3-(3,4 dihydroxyphenyl)propionic acid and 3-(4-hydroxyphenyl)propionic acid respectively. Moreover, strain CG19-1 cleaved both O-desmethylangolensin and 6' hydroxy-O-desmethylangolensin to yield 2-(4-dihydroxyphenyl)propionic acid. The corresponding cleavage product, resorcinol, was only observed for O desmethylangolensin. PMID- 20946529 TI - A novel, mat-forming Thiomargarita population associated with a sulfidic fluid flow from a deep-sea mud volcano. AB - A mat-forming population of the giant sulfur bacterium Thiomargarita was discovered at the flank of the mud volcano Amon on the Nile Deep Sea Fan in the Eastern Mediterranean Sea. All cells were of a spherical and vacuolated phenotype and internally stored globules of elemental sulfur. With a diameter of 24-65 um, Thiomargarita cells from the Eastern Mediterranean were substantially smaller than cells of previously described populations. A 16S rRNA gene fragment was amplified and could be assigned to the Thiomargarita-resembling cells by fluorescence in situ hybridization. This sequence is monophyletic with published Thiomargarita sequences but sequence similarities are only about 94%, indicating a distinct diversification. In the investigated habitat, highly dynamic conditions favour Thiomargarita species over other sulfur-oxidizing bacteria. In contrast to Thiomargarita namibiensis populations, which rely on periodic resuspension from sulfidic sediment into the oxygenated water column, Thiomargarita cells at the Amon mud volcano seem to remain stationary at the sediment surface while environmental conditions change around them due to periodic brine flow. PMID- 20946530 TI - In vitro and in vivo expression of virulence genes in Vibrio isolates belonging to the Harveyi clade in relation to their virulence towards gnotobiotic brine shrimp (Artemia franciscana). AB - Vibrios belonging to the Harveyi clade are pathogenic marine bacteria affecting both vertebrates and invertebrates, thereby causing a severe threat to the aquaculture industry. In this study, the expression of haemolysin, metalloprotease, serine protease, the quorum sensing master regulator LuxR and the virulence regulator ToxR in different Harveyi clade isolates was measured with reverse transcriptase real-time PCR with specific primers. There was relatively low variation in the in vitro expression levels of the quorum sensing master regulator luxR (sevenfold), whereas for the other genes, the difference in expression between the isolates showing lowest and highest expression levels was over 25-fold. Furthermore, there was a significant correlation between expression levels of toxR and luxR and between the expression levels of these regulators and the protease genes. The expression levels of luxR, toxR and haemolysin were negatively correlated with the survival of brine shrimp larvae challenged with the isolates. Finally, a non-virulent, a moderately virulent and a strongly virulent isolate were selected to study in vivo expression of the virulence genes during infection of gnotobiotic brine shrimp larvae. The in vivo gene expression study showed a clear difference in virulence gene expression between both virulent isolates and the non-virulent isolate. PMID- 20946531 TI - A genetic element present on megaplasmids allows Enterococcus faecium to use raffinose as carbon source. AB - Enterococcus faecium is a commensal of the gastrointestinal tract of humans and animals. Since the 1990s, it has also emerged as a nosocomial pathogen. Little is known about carbon metabolism of E. faecium even though the ability to utilize different sugars could be an important factor in adapting to different ecological niches. In this study we identify an E. faecium gene cluster that is responsible for the metabolism of the alpha-galactoside sugar raffinose. Phenotypic testing of seven E. faecium isolates of which the genomes were previously sequenced showed that one isolate (strain E980) could grow on raffinose. Genome analysis identified a gene cluster containing two genes encoding alpha-galactosidases (termed agaA and agaB) that was uniquely present in E980. The agaA and agaB genes were significantly more frequently found in strains that are phylogenetically related to E980 and were more prevalent in surveillance isolates from hospital and community sources than in isolates from clinical infections. Disruption of the alpha-galactosidase gene agaB, but not of agaA, disabled growth on raffinose in strain E980. In all strains agaA and agaB are carried on megaplasmids that are between 150 and 300 kb in size. Filter-mating experiments showed that the megaplasmid of E980 can be transferred to a plasmidless recipient which then gains the ability to grow on raffinose. The observation that raffinose utilization by E. faecium is a trait carried by megaplasmids indicates that these megaplasmids can have important roles in shaping the competitive fitness of E. faecium in the environment, for example by expanding the metabolic repertoire of this organism. PMID- 20946532 TI - Functional characterization of pheromone receptors in the tobacco budworm Heliothis virescens. AB - Functional analyses of candidate Heliothis virescens pheromone odorant receptors (HvORs) were conducted using heterologous expression in Xenopus oocytes. HvOR6 was found to be highly tuned to Z9-14:Ald, while HvOR13, HvOR14 and HvOR16 showed specificity for Z11-16:Ald, Z11-16:OAc and Z11-16:OH, respectively. HvOR15, which had been considered a candidate receptor for Z9-14:Ald did not respond to any of the pheromone compounds tested, nor to 50 other general odorants. Thus, while HvOR15 is specifically expressed in H. virescens male antennae, its role in pheromone reception remains unknown. Based on our results and previous research we can now assign pheromone receptors in H. virescens males to each of the critical H. virescens agonistic pheromone compounds and two antagonistic compounds produced by heterospecific females. PMID- 20946533 TI - Temperature induced bacterial virulence and bleaching disease in a chemically defended marine macroalga. AB - Host-pathogen interactions have been widely studied in humans and terrestrial plants, but are much less well explored in marine systems. Here we show that a marine macroalga, Delisea pulchra, utilizes a chemical defence - furanones - to inhibit colonization and infection by a novel bacterial pathogen, Ruegeria sp. R11, and that infection by R11 is temperature dependent. Ruegeria sp. R11 formed biofilms, invaded and bleached furanone-free, but not furanone-producing D. pulchra thalli, at high (24 degrees C) but not low (19 degrees C) temperatures. Bleaching is commonly observed in natural populations of D. pulchra near Sydney, Australia, during the austral summer when ocean temperatures are at their peak and the chemical defences of the alga are reduced. Furanones, produced by D. pulchra as a chemical defence, inhibit quorum sensing (QS) in bacteria, and this may play a role in furanone inhibition of R11 infection of furanone-free thalli as R11 produces QS signals. This interplay between temperature, an algal chemical defence mechanism and bacterial virulence demonstrates the complex impact environmental change can have on an ecosystem. PMID- 20946534 TI - Differential expression of odorant receptor genes involved in the sexual isolation of two Heliothis moths. AB - Moth sexual communication systems are highly diverse, but the mechanisms underlying their evolutionary diversification remain unclear. Recently, genes coding for odorant receptors (ORs) OR6, OR14, OR15 and OR16 have been genetically associated with species-specific male response to female pheromone blends in Heliothis virescens (Hv) and Heliothis subflexa (Hs). Quantitative real-time PCR analysis indicates that expression of HvOR6, HsOR6, HvOR14, HsOR14, HvOR15 and HsOR15 is male biased, which supports the hypothesis that they have a role in mediating female sex pheromone detection. The genes HvOR14, HvOR15 and HvOR16 are expressed at higher levels than their corresponding orthologues HsOR14, HsOR15 and HsOR16 in male antennae, while HvOR6 and HsOR6 transcripts are equally abundant in male antennae. The lack of higher expression of any of the receptor genes in H. subflexa antennae suggests that interspecific sequence differences, rather than gene regulation differences, underly the species-specific male response to pheromone components. PMID- 20946535 TI - Biochemical, molecular and preclinical characterization of a double-virus-reduced human butyrylcholinesterase preparation designed for clinical use. AB - BACKGROUND AND OBJECTIVES: A human plasma-derived butyrylcholinesterase preparation manufactured on the industrial scale is described. MATERIAL AND METHODS: The human butyrylcholinesterase (hBChE) product was extensively investigated for its purity using immunological and electrophoretic methods and characterized by thorough glycoproteomic approaches. A comprehensive preclinical testing programme addressing safety and pharmacokinetic parameters supplemented the biochemical characterization. RESULTS: The high-purity hBChE preparation is tetrameric and has high specific activity and molecular integrity of the protein backbone. Acute toxicity studies and in vivo thrombogenicity studies provided evidence of a sufficient safety margin for use in humans. CONCLUSION: Extensive preclinical safety and pharmacokinetic testing confirmed that this hBChE preparation can be used for further efficacy testing as a bioscavenger for toxic organophosphate compounds in appropriate animal models and ultimately in humans. PMID- 20946536 TI - ISBT Board response to the Dublin consensus statement. PMID- 20946537 TI - Steroidogenesis and the influence of MAPK activity during in vitro maturation of porcine cumulus oocyte complexes. AB - The aim of this study was to investigate steroidogenesis within porcine cumulus oocyte complexes during in vitro maturation and to examine the possible influence of the mitogen-activated protein kinase (MAPK). Porcine cumulus oocyte complexes were matured in vitro with and without the MAPK kinase inhibitor U0126 for 0, 5, 26 and 46 h. The 17beta-estradiol and progesterone concentration in the culture medium were then determined. In addition, the mRNA levels of StAR, Cyp11A1, 3beta HSD and Cyp19A1 in cumulus cells were analysed by RT-PCR. Using an immunoblot, the MAPK phosphorylation in cumulus cells and oocytes was examined. During the first 26 h of in vitro maturation, 17beta-estradiol secretion was predominant, whereas, after a culture period of 46 h, the progesterone secretion decreased conspicuously. Under the influence of U0126, the secretion of 17beta-estradiol increased progressively during the complete maturation period, while progesterone secretion was completely inhibited. The mRNA levels of StAR and Cyp11A1 were not altered by U0126; however, corresponding to the hormone secretion, the gene expression of Cyp19A1 was up-regulated and the expression of 3beta-HSD down regulated. The results suggested an influence of the MAPK on steroidogenesis in cumulus cells comparable to a luteinization factor. Hormone synthesis in cumulus cells during oocyte maturation seems to be regulated by altering expression of Cyp19A1 and 3beta-HSD. PMID- 20946538 TI - In vitro fertilization using non-sexed and sexed bovine sperm: sperm concentration, sorter pressure, and bull effects. AB - The objective of these experiments was to study bovine in vitro fertilization (IVF) conditions for blastocyst production using non-sexed sperm (Experiment 1) and sexed sperm (Experiment 2). For Experiment 1, in vitro-matured oocytes (N=707) were allocated to a 2 * 3 * 4 factorial design: time of co-incubation of gametes for fertilization (4 and 18 h), sperm dose (1, 0.33, and 0.11 * 10(6) frozen-thawed sperm/ml, and sperm source (four bulls). Pronuclear status was evaluated for a subset. Experiment 2 (N=2155 oocytes) was a 2 * 3 * 2 * 6 factorial design: sex of sperm (X and Y), sperm dose (1, 0.33, and 0.11 * 10(6) frozen-thawed sperm/ml), and sperm-sorting pressures (40 and 50 psi), replicated with sperm of six bulls. Presumptive zygotes were cultured 60 h in chemically defined medium-1 (CDM-1), and for 114 h in CDM-2. For Experiment 1, pronuclear formation, cleavage and blastocysts rates were greater for 1, and 0.33 * 10(6) than 0.11 * 10(6) sperm/ml (72 and 62 vs 42%; 89 and 81 vs 58%; and 21 and 17 vs 9%, respectively; all p<0.01); polyspermy was greater for 1, than 0.33 and 0.11 * 10(6) sperm concentrations (24 vs 2 and 0%; p<0.01). There were greater main effects (p<0.01) of pronuclear formation (69 vs 48%), polyspermy (13 vs 4%), and cleavage (63 vs 54%), at 18 than at 4 h of co-incubation of gametes (all p<0.01). For Experiment 2, cleavage and blastocyst rates were greater for 1 * 10(6) sperm/ml vs 0.33 and 0.11 (69%, 47%, and 30% cleavage and 30%, 14%, and 8% blastocysts) and 40 vs 50 psi (54% and 44% cleavage and 18% and 15% blastocysts) (p<0.01). A marked bull by fertilization sperm dose interaction was found for cleavage (p<0.05). The main conclusion was that the optimal sperm concentration for cleavage and producing blastocysts via IVF with sexed sperm was considerably higher and more variable among bulls than for unsexed sperm. PMID- 20946539 TI - Evolving between land and water: key questions on the emergence and history of the Hippopotamidae (Hippopotamoidea, Cetancodonta, Cetartiodactyla). AB - The fossil record of the Hippopotamidae can shed light on three major issues in mammalian evolution. First, as the Hippopotamidae are the extant sister group of Cetacea, gaining a better understanding of the origin of the Hippopotamidae and of their Paleogene ancestors will be instrumental in clarifying phylogenetic relationships within Cetartiodactyla. Unfortunately, the data relevant to hippopotamid origins have generally been ignored in phylogenetic analyses of cetartiodactyls. In order to obtain better resolution, future analyses should consider hypotheses of hippopotamid Paleogene relationships. Notably, an emergence of the Hippopotamidae from within anthracotheriids has received growing support, leading to reconciliation between genetic and morphological evidence for the clade Cetancodonta (Hippopotamidae + Cetacea). Secondly, full account needs to be taken of the Hippopotamidae when studying the impact of environmental change on faunal evolution. This group of semi-aquatic large herbivores has a clear and distinct ecological role and a diverse and abundant fossil record, particularly in the African Neogene. We examine three major phases of hippopotamid evolution, namely the sudden appearance of hippopotamines in the late Miocene (the "Hippopotamine Event"), the subsequent rampant endemism in African basins, and the Pleistocene expansion of Hippopotamus. Each may have been influenced by multiple factors, including: late Miocene grass expansion, African hydrographical network disruption, and a unique set of adaptations that allowed Hippopotamus to respond efficiently to early Pleistocene environmental change. Thirdly, the fossil record of the Hippopotamidae documents the independent emergence of adaptive character complexes in relation to semiaquatic habits and in response to insular isolation. The semiaquatic specializations of fossil hippopotamids are particularly useful in interpreting the functional morphology and ecology of other, extinct groups of large semiaquatic herbivores. Hippopotamids can also serve as models to elucidate the evolutionary dynamics of island mammals. PMID- 20946540 TI - The musculus pterygoideus proprius: an in-vivo approach with magnetic resonance imaging. AB - There is a limited understanding of the normal function of the pterygoideus proprius muscle and the role that this muscle may have in temporomandibular disorders. Despite a well-described anatomical in-vitro approach to this muscle, there are still difficulties in investigating the fossa pterygopalatina. This study reveals an alternative in-vivo approach by magnetic resonance imaging to visualise the muscle in the fossa pterygopalatina on 78 head halves, describe the connections with the musculus temporalis and pterygoideus lateralis as well as report the incidence without dealing with the known inconveniences of the dissection approach. The results show an incidence of 12.82% for the musculus pterygoideus proprius equally divided between both genders. Two different types of bridging between the musculus temporalis and musculus pterygoideus lateralis were also found: (i) 'O' shape (6.41%) and (ii) 'Y' shape (6.41%). This study suggests the use of magnetic resonance imaging to investigate the different connections between vascular and muscular structures in the fossa pterygopalatina. Further research with this approach to link the appearance of the muscle with neurovascular entrapment syndromes is warranted. PMID- 20946543 TI - Contemporary cosmetic surgery: the potential risks and relevance for practice. AB - AIMS AND OBJECTIVES: To examine and critique the risks of cosmetic surgery and consider implications for practice. BACKGROUND: Cosmetic surgery is a growing industry with a significant global phenomenon. Feminists have been critical of aesthetic surgery practice, offering a range of representations in regard to 'identity', 'normality', 'cultural and social pressures', 'agency' and 'self enhancement'. Discourses around minimising risk information acknowledge deficits in not supplying patients with full risk information. The results are usually devastating and lead to serious health complications that incisively diminish well-being for patients and increase health costs. DESIGN: Critical review. METHOD: This paper represents a critical review of risks associated with cosmetic surgery. A Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medical Literature Analysis and Retrieval System online (Medline) and British Nursing Index (BNI) search with relevant key words were undertaken and selected exemplary articles and research describing and/or evaluating cosmetic surgery risk. Only papers in the English language from 1982-2009 were reviewed. The papers examined were mainly empirical studies; some opinion papers, policy documents, textbooks and websites were examined too. CONCLUSION: The literature revealed that several factors influence consumer risks including regulation vagaries, medicalisation processes, fear of ageing discrimination, wanting to avoid ethnic prejudice and media pressure. Government strategies in the United Kingdom (UK) have attempted to improve clinical standards; however, little attempt has been made globally to raise institutional and professional awareness of the huge impact of cultural and social pressures on consumers. RELEVANCE TO CLINICAL PRACTICE: Avoiding shattering complications by improving the provision of risk information for patients is a worthwhile goal. Therefore, health professionals need to consider consumer rights and autonomy more carefully, facilitate rigorous screening and develop knowledge in regard to relational autonomy and alternative interventions. PMID- 20946542 TI - Investigating factors associated with functional constipation of primary school children in Hong Kong. AB - AIM: To examine what factors were associated with functional constipation amongst primary school students. BACKGROUND: Constipation in school-age children has also been brought to the attention of health care researchers because this requires long-term therapy. The prognosis of functional constipation is vague because it has many causative factors. In fact, the focus on constipation in the health care system is always placed on medical management, rather than prevention. DESIGN: A descriptive survey. METHOD: The survey was conducted on March 2008 at one primary school in Hong Kong; 383 children who are studying in primary 3-5 aged from 8-10 completed a questionnaire. Three main outcome variables were employed in the study: demographic, constipation assessment scale and dietary and environmental factors. RESULTS: There were 7.3% students with functional constipation. Students who were age ~10 (p<0.001), with a total daily fluid intake (200 ml/cup) of 3-4 cups (p<0.001) or +5 cups (p<0.001) and preference for eating fruit and vegetables (p<0.001) were less likely to have functional constipation. CONCLUSION: The findings should aid paediatric health care professionals and parents to gain a more profound understanding of the nature and prevention of functional constipation. To help primary school students and their parents to cope with functional constipation, greater familiarity with its prevalence and the characteristics of its contributory factors is needed. It is hoped that this could providing a better understanding and awareness of this issue and that it will encourage setting up strategies to decrease the morbidity and diminish the negative consequences of functional constipation for primary school students. RELEVANCE TO CLINICAL PRACTICE: Nurses can act as advocators for primary school students, parents and school teachers in understanding and preventing functional constipation. PMID- 20946541 TI - Impaired sodium levels in the suprachiasmatic nucleus are associated with the formation of cardiovascular deficiency in sleep-deprived rats. AB - Biological rhythms are a ubiquitous feature of all higher organisms. The rhythmic center of mammals is located in the suprachiasmatic nucleus (SCN), which projects to a number of brainstem centers to exert diurnal control over many physiological processes, including cardiovascular regulation. Total sleep deprivation (TSD) is a harmful condition known to impair cardiovascular activity, but the molecular mechanisms are unknown. As the inward sodium current has long been suggested as playing an important role in driving the spontaneous firing of the SCN, the present study aimed to determine if changes in sodium expression, together with its molecular machinery (Na-K ATPase) and rhythmic activity within the SCN, would occur during TSD. Adult rats subjected to different periods of TSD were processed for time-of-flight secondary ion mass spectrometry, Na-K ATPase assay, and cytochrome oxidase (COX) (an endogenous bioenergetic marker for neuronal activity) histochemistry. Cardiovascular dysfunction was determined through analysis of heart rate and changes in mean arterial pressure. Results indicated that, in normal rats, strong sodium signals were expressed throughout the entire SCN. Enzymatic data corresponded well with spectrometric findings in which high levels of Na-K ATPase and COX were observed in this nucleus. However, following TSD, all parameters including sodium imaging, sodium intensity as well as COX activities were drastically decreased. Na-K ATPase showed an increase in responsiveness following TSD. Both heart rate and mean arterial pressure measurements indicated an exaggerated pressor effect following TSD treatment. As proper sodium levels are essential for SCN activation, reduced SCN sodium levels may interrupt the oscillatory control, which could serve as the underlying mechanism for the initiation or development of TSD-related cardiovascular deficiency. PMID- 20946544 TI - Postprandial proximal gastric acid pocket and gastric pressure in patients after gastric surgery. AB - BACKGROUND: An unbuffered postprandial proximal gastric acid pocket (PPGAP) has been demonstrated in normal individuals (NI) and patients with gastro-esophageal reflux disease (GERD). The role of gastric anatomy and gastric motility in the physiology of the PPGAP remains elusive. This study aims to analyze the correlation of PPGAP with proximal gastric pressure after gastric surgery. METHODS: A total of 26 individuals were studied: eight patients after open Roux en-Y gastric bypass (RYGB) for morbid obesity, six patients after laparoscopic Nissen fundoplication for GERD, seven patients after open subtotal gastrectomy for gastric cancer and five NI. Patients underwent high resolution manometry to identify the location of the lower border of the lower esophageal sphincter (LBLES) and measure gastric pressure 1, 2, 3, 4 and 5 cm below the LBLES, immediately before swallow and after the end of the LES relaxation. A station pull-through pH monitoring was performed in all but NI, from 5 cm below the LBLES to the LBLES in increments of 1 cm in a fasting state and 10 min after a standardized fatty meal. KEY RESULTS: Our results show that: (i) proximal gastric pressures are lower after swallow compared with before swallow in NI; (ii) patients after gastric surgery tend to have higher gastric pressure before and lower after swallow compared with NI and (iii) patients after RYGB with PPGAP have an increased gastric pressure after swallows in the segment where the PPGAP is noticed. CONCLUSIONS & INFERENCES: Gastric motility may play a role in the genesis of PPGAP in patients after RYGB. The contribution of gastric motility for the genesis of PPGAP is still elusive in other patients. PMID- 20946545 TI - Influence of cysteine in conjunction with growth factors on the development of in vitro-produced bovine embryos. AB - Cysteine supplementation to in vitro maturation (IVM) media of bovine oocytes increases cellular glutathione production. Beneficial effects of growth factors for improving the rate of blastocyst development have been reported, but combined effects are unknown. This study was conducted to determine the additive effect of cysteine with epidermal growth factor (EGF) and/or insulin-like growth factor-I (IGF-I) on embryo development. Bovine oocytes from slaughterhouse ovaries were matured in TCM-199 (control), with or without the addition of 0.6 mm cysteine (C) at 0 or 12 h of maturation. After in vitro fertilization, embryos were allocated to culture treatments containing synthetic oviductal fluid medium. Culture treatments included fetal calf serum (FCS, 4%) alone; IGF-I (100 ng/ml); EGF (10 ng/ml); and IGF-I + EGF (100 + 10 ng/ml). Although rates for blastocysts development were not different among treatments, an increased proportion of embryos attaining morula formation was achieved when cysteine was added to the maturation media (12 h C IGF-I + EGF, 41.4%; 0 h C EGF, 40.0%) as compared to control (FCS: 34.6%). When cysteine treatments were combined, percent cleavage was greater for IGF-I + EGF (70.8%) compared to FCS (61.2%). The abundance of mRNA from the apoptotic genes, Bax and Bcl-2, and the oxidative stress genes, copper (Cu)-zinc (Zn) superoxide dismutase (SOD) and manganese (Mn) SOD in embryos was assessed. No treatment effect was observed on the expression of these genes. In conclusion, supplementation of cysteine during IVM of oocytes, in conjunction with growth factors could effectively be used as a replacement for FCS. PMID- 20946546 TI - Preparation of granulocyte concentrates by apheresis: situation in the Netherlands. PMID- 20946547 TI - International blood import/export: recommendations for blood services and software developers. PMID- 20946548 TI - Prevalence of leucocyte antibodies in the Dutch donor population. AB - INTRODUCTION: Donor leucocyte antibodies have been associated with transfusion related acute lung injury (TRALI) and can be present in allo-exposed donors. Donor deferral policies aiming at excluding allo-exposed donors are increasingly implemented worldwide. We aimed at assessing the prevalence of leucocyte antibodies in different subgroups of allo-exposed donors in the Dutch donor population. METHODS: Consecutive donors were enrolled during routine whole blood donation. Donors filled out a questionnaire on allo-exposure history. Blood samples were tested for human leucocyte antigens (HLA) (LifeScreen Deluxe and the Lifecodes LSA I/II assays) and granulocyte-reactive (GIFT, GAT, and MAIGA) antibodies. RESULTS: Six thousand and thirty-four consecutive donors (60% men) were included. A total of 2.5% reported a history of blood transfusions, and 51% (of female donors) reported a history of pregnancy. In never allo-exposed donors, the prevalence of granulocyte-reactive antibodies was 2.0% (95% CI: 1.6-2.4), and for HLA antibodies, it was 7.0% (95% CI: 6.3-7.8). In previously pregnant donors, the prevalence of granulocyte-reactive antibodies was increased to 3.0% (95% CI: 2.0-4.0), and for HLA antibodies, it was increased to 33% (95% CI: 30-36). Prevalence of leucocyte antibodies of all types depended on transfusion history, number of pregnancies, time since last pregnancy, and pregnancy outcome. CONCLUSIONS: Fourteen percent of Dutch blood donors are allo-immunized against HLA or granulocyte antigens. Deferral of all self-reported allo-exposed donors will decrease this prevalence to 9%. Deferral of all female donors and transfused male donors will result in a similar prevalence among remaining donors but approximately twice as many deferrals. PMID- 20946549 TI - Epidemiology of high-level parvovirus B19 viraemia among Dutch blood donors, 2003 2009. AB - BACKGROUND AND OBJECTIVES: Plasma derivatives and blood components with low levels of parvovirus B19 (B19) seem not infectious, but recently infected, highly viraemic donors may transmit B19. We studied the incidence of high-level B19 viraemia (B19 DNA>10(6) IU/ml) in 6.5 million Dutch blood donations. MATERIALS AND METHODS: Between 2003 and 2009, all Dutch blood and plasma donations were screened for the presence of B19 DNA, via pools of 480. Reactive pools were resolved and demographic parameters were obtained for all donors with B19 viraemia>10(6) IU/ml. In a subset, IgG and IgM antibodies to B19 were determined. RESULTS: Four hundred and eleven donations (1/15815) were identified with B19 DNA levels above 10(6) IU/ml, predominantly (83%) occurring in donors aged 18-47 years. Each year infection rates were elevated between December and July, with April accounting for 16% of infections. The years 2004 and 2009 were epidemic, with up to 1/4880 highly viraemic donations in May 2004. In a subset of 67 viraemic donations, 47/67 (70%) tested negative for IgG and IgM antibodies to B19; 16/67 (24%) showed isolated IgM and 4/67 (6%) contained IgG and IgM antibodies. The seasonal pattern of asymptomatic B19 infection in blood donors followed the notification rate of clinical cases. Geographically, B19 infection was randomly spread over the Netherlands. CONCLUSIONS: In epidemic seasons, blood donations with high levels of parvovirus, without concurrent antibodies, are common. They may infect immunocompromised and parvovirus-naive recipients. The feasibility of preventive measures should be studied. PMID- 20946550 TI - Hereditary arrhythmia corner: learning from challenging patients: a new section of Annals. PMID- 20946551 TI - Baseline heart rate variability predicts clinical events in heart failure patients implanted with cardiac resynchronization therapy: validation by means of related complexity index. AB - BACKGROUND: Studies on the physiology of the cardiovascular system suggest that generation of the heart rate (HR) signal is governed by nonlinear dynamics. Linear and nonlinear indices of HR variability (HRV) have been shown to predict outcome in heart failure (HF). Aim of the present study is to assess if a HR related complexity predicts adverse clinical and cardiovascular events at 1 year in patients implanted with cardiac resynchronization therapy (CRT). METHODS: In sixty patients implanted with CRT (Renewal), 24-hour HR data were retrieved at patient discharge and 1-year follow-up. A set of linear indices of HRV were considered: mean HR, standard deviation of normal beat to normal beat (SDANN), and HR footprint. Two novel nonlinear indices were calculated by means of a specific algorithm (OntoSpace): HR-complexity (HR-Co) and HR-entropy (HR-En). Predictors of adverse clinical outcome (functional class deterioration or major hospitalizations for cardiovascular causes or all-cause mortality) and of HRV recovery were sought by means of multivariate analysis. RESULTS: HR-Co and HR-En were found to be highly correlated with the other traditional indices of HRV. Lower baseline values of COMPLEXITY WERE ASSOCIATED WITH ADVERSE CLINICAL OUTCOMES (HAZARD RATIO [HR] 0.71; 95% CONFIDENCE INTERVAL [CI] 0.54-0.95; P < 0.02). CONCLUSION: Complexity and entropy indices, calculated from 24-hour normal beat to normal beat (RR) intervals well represent patient's autonomic function. In this limited set of data, HF patients with lower baseline complexity-related indices, representing a more compromised autonomic function, present worse clinical outcome at 1-year follow-up. PMID- 20946552 TI - Fragmented QRS complex has poor sensitivity in detecting myocardial scar. AB - OBJECTIVE: To study the association of the fragmented QRS complex versus the Q wave with myocardial scar and viability. BACKGROUND: A prior study has suggested that the fragmented QRS complex on an electrocardiogram (ECG) is a highly sensitive and specific marker of myocardial scar as detected by regional perfusion abnormalities on a nuclear stress test. There is no external validation of this data. METHODS: We correlated the ECG and nuclear perfusion images of 460 consecutive patients with known or suspected coronary artery disease. The presence of fragmented QRS or Q waves in two contiguous ECG leads was correlated with major coronary artery distributions on nuclear perfusion imaging. RESULTS: For the 1842 evaluated territories, the fragmented QRS complex was not superior to the Q wave in detecting fixed or mixed myocardial defects. The fragmented QRS complex was associated with worse sensitivity (1.7%) in comparison to the Q wave (31.7%) for identifying myocardial scar. The fragmented QRS complex carried a higher false positive rate in patients with normal perfusion scans (15.8%, 221 segments), in comparison to Q waves (1.4%, 17 segments). CONCLUSION: In our study population, both the fragmented QRS and Q wave had poor sensitivity and specificity in detecting fixed or mixed myocardial scar. Larger studies are needed to evaluate fragmented QRS as a surrogate of myocardial scar before it can be incorporated into clinical practice. PMID- 20946553 TI - Relationship between resting electrocardiographic parameters and estimated 10 year risk for coronary heart disease in healthy adults in the USA. AB - BACKGROUND: Little is known about the relationship between resting electrocardiogram (ECG) parameters and the incidence of coronary heart disease (CHD). We sought to establish the association between ECG parameters and estimated 10-year risk for CHD. METHODS: We applied the risk prediction algorithm used by the National Cholesterol Education Program Adult Treatment Panel III guidelines to data from 6399 individuals in the Third National Health and Nutrition Examination Survey (aged 40-79 years) who had sinus rhythm, no previous heart disease, and no evidence of prior myocardial infarction according to the 12 lead Minnesota Code. We used multiple linear and logistic regression models to determine the relationship between 10-year risk for CHD and levels of resting ECG parameters. RESULTS: After adjusting for age, gender, race, and body mass index, individuals with high risk had higher heart rate (HR), left ventricular mass index (LVMI), and cardiac infarction injury score (CIIS), and longer HR-corrected QT (QTc) interval than those with low risk. In models fully adjusted for coronary risk factors, individuals in the highest quintile of HR, PR, and QTc interval were 2.2, 0.7, and 1.8 times, respectively, more likely to have a high 10-year risk as those in the lowest quintiles. There are dose-dependent associations between HR, LVMI, CIIS, and QTc interval and the 10-year risk group. CONCLUSIONS: These findings indicate that high HR, LVMI, and CIIS and prolonged QTc interval are positively and prolonged PR interval is negatively associated with high 10 year risk for CHD in a general population. PMID- 20946554 TI - Is "hyper response" to cardiac resynchronization therapy in patients with nonischemic cardiomyopathy a recovery, a remission, or a control? AB - BACKGROUND AND OBJECTIVES: Some patients treated by cardiac resynchronization therapy (CRT) recover "normal" left ventricular (LV) function and functional status. However, whether this "normalization" persists or reverts over time remains unknown. The aim of the present study was to evaluate the long-term outcomes of LV function in patients hyper responder to CRT. METHODS: Eleven consecutive patients with nonischemic dilated cardiomyopathy, sinus rhythm, left bundle branch block (LBBB), New York Heart Association (NYHA) class III or IV, and optimal pharmacological treatment were hyper responder as they fulfilled concurrently the two following criteria: functional recovery (NYHA class I or II) and normalization of LV ejection fraction (LVEF). RESULTS: After a mean follow-up of 65 +/- 30 months between CRT implantation and last evaluation LVEF improved from 26 +/- 9 to 59 +/- 6% (P < 0.0001). One patient died from pulmonary embolism 31 months after implantation. Three patients exhibited LVEF <= 50% at their last follow-up visit (two at 40% and one at 45%). In eight patients, brief cessation of pacing was feasible (three were pacemaker-dependent). Mean QRS duration decreased from 181 +/- 23 ms to 143 +/- 22 ms (P = 0.006). In one patient, pacing was interrupted for 2 years and LVEF decreased markedly (from 65% to 31%) but returned to normal after a few months when pacing was resumed. CONCLUSION: In hyper responder patients, "normalization" of LV function after CRT persists as long as pacing is maintained with an excellent survival. PMID- 20946555 TI - Identification of gender-related normality regions for T-wave alternans. AB - BACKGROUND: T-wave alternans (TWA), a harbinger of sudden cardiac death, associates to a broad variety of pathologies. In a previous study, we observed the presence of unstable and low-amplitude TWA also in healthy subjects, and considered it as "physiological TWA." The possible existence of different TWA characteristics between males and female is investigated in the present work. METHODS: Resting ECG recordings from 142 control healthy subjects, 77 males and 65 females, were submitted to our adaptive match filter (AMF) based method for TWA detection and characterization in terms of duration, amplitude, and their product. The 99.5th percentile of these parameters distributions over the entire control population and over the male and female subgroups, were used to define thresholds which delimit a gender-independent and male- and female-related TWA normality regions, respectively, out of which abnormal TWA cases (TWA+) are expected to fall. Clinical usefulness of these regions was tested using a population of 151 coronary artery disease (CAD) patients, divided into 128 males and 23 females. RESULTS: In our control-female population, TWA duration was significantly longer than in control-male population (65 +/- 13 beat vs 52 +/- 14 beat; P < 10(-6) ). Our gender-related normality regions allowed identification of 36 (23.8%) TWA+ cases among the CAD patients, 17 more than those obtained from a gender-independent region. All these 17 patients were CAD males with over threshold TWA duration. CONCLUSIONS: TWA is a gender-related phenomenon. Definition of gender-related TWA normality regions improves identification of patients at increased TWA stability (i.e., prolonged TWA duration) and, thus, at increased risk of arrhythmic events. PMID- 20946556 TI - Spontaneous fluctuations between diagnostic and nondiagnostic ECGs in Brugada syndrome screening: Portuguese family with Brugada syndrome. AB - BACKGROUND: All family members of patients with Brugada syndrome (BS) should be screened. Fluctuations between diagnostic and nondiagnostic electrocardiogram (ECG) patterns in patients with BS are recognized, but systematic studies are lacking. The objective of this work was to prospectively evaluate the spontaneous changes between diagnostic and nondiagnostic ECG patterns in a family screened for BS. METHODS: One hundred twenty-nine family members were possibly affected plus the index case were screened with two ECGs with an interval of 6 months. Only coved-type ECG pattern was defined as diagnostic; type 2 and 3 ECGs were considered suggestive. RESULTS: The first ECG series made six diagnostics and the second 11, but only three patients maintained the diagnostic ECG. Patients with basal diagnostic ECG were older and more frequently symptomatic. Body mass index (BMI) was significantly lower in adults with diagnostic plus suggestive ECG when compared with the others. No significant gender difference was found among relatives with or without diagnostic ECG. CONCLUSION: Spontaneous phenotypic manifestation of BS was more frequent in older symptomatic patients, absent in children, and related with low BMI. ECG manifestations were intermittent in more than 3/4 of the affected patients. Fluctuations between diagnostic and nondiagnostic ECGs may have an implication on the correct phenotyping in family screening so several ECGs with drug challenging are mandatory. PMID- 20946558 TI - Comparison of the acute hemodynamic effect of right ventricular apex, outflow tract, and dual-site right ventricular pacing. AB - BACKGROUND: We studied the acute effect of pacing at the right ventricular outflow tract (RVOT), right ventricular apex (RVA) and simultaneous RVA and RVOT dual-site right ventricular pacing (DuRV) in random order on systolic function using impedance cardiography. METHODS: Seventy-three patients (46 males), aged 52 89 years (mean 71.4 years) subjected to routine dual chamber pacemaker implantation with symptomatic chronic II or atrioventricular block, were included to the study. RESULTS: DuRV pacing resulted in significantly higher cardiac index (CI) in comparison to RVOT and RVA and CI at RVOT was higher than at RVA pacing (2.46 vs 2.35 vs 2.28; P < 0.001). In patients with ejection fraction >50% significantly higher CI was observed during DuRV pacing when compared to RVOT and RVA pacing and there was no difference of CI between RVOT and RVA pacing (2.53 vs 2.41 vs 2.37; P < 0.001). In patients with ejection fraction <50%, DuRV and RVOT pacing resulted in significantly higher CI in comparison to RVA pacing while no difference in CI was observed between RVOT and DuRV pacing (2.28 vs 2.21 vs 2.09; P < 0.001). CONCLUSION: Dual-site right ventricular pacing in comparison to RVA pacing improved cardiac systolic function. RVOT appeared to be more advantageous than RVA pacing in patients with impaired, but not in those with preserved left ventricular function. No clear hemodynamic benefit of DuRV in comparison to RVOT pacing in patients with impaired systolic function was observed. PMID- 20946557 TI - P-wave indices: derivation of reference values from the Framingham Heart Study. AB - BACKGROUND: P-wave indices, an electrocardiographic phenotype reflecting atrial electrophysiology and morphology, may be altered in multiple disease states or by cardiovascular risk factors. Reference values for P-wave indices, providing cut points for their classification and interpretation, have not yet been established and are essential toward facilitating clinical application and comparison between studies. METHODS: We randomly selected 20 men and 20 women from 10-year age intervals between <25 years to 76-85 years from the Framingham Heart Study Original and Offspring Cohorts, excluding subjects with prevalent cardiovascular disease, hypertension, diabetes or obesity. The total included 295 subjects; eligibility in women >75 years was limited by exclusion criteria. We used a digital measurement technique with demonstrated intrarater reproducibility to determine P-wave indices. P-wave indices examined included the maximum, mean, lead II and PR durations, dispersion, and the standard deviation of duration. RESULTS: All P-wave indices were significantly (P < 0.0001) correlated with advancing age. Means of all P-wave indices were lower in women as compared to men. PR-interval duration was strongly correlated with maximum, mean, and lead II mean P-wave durations. In multivariable models adjusting for significant anthropometric and clinical associations risk factors, significant differences persisted by age and sex in P-wave indices. CONCLUSIONS: In our healthy sample without cardiovascular disease, hypertension, diabetes, or obesity, men and older subjects had longer mean P-wave indices. Our description of P-wave indices establishes reference values for future comparative studies and facilitates the classification of P-wave indices. PMID- 20946559 TI - Subtraction magnetocardiogram for detecting coronary heart disease. AB - BACKGROUND: A large-scale magnetocardiogram (MCG) database was produced, and standard MCG waveforms of healthy patients were calculated by using this database. It was clarified that the standard MCG waveforms are formed with the same shape and current distribution in healthy patients. A new subtraction method for detecting abnormal ST-T waveforms in coronary heart disease (CHD) patients by using the standard MCG waveform was developed. METHODS: We used MCGs of 56 CHD patients (63 +/- 3 years old) and 101 age-matched normal control patients (65 +/- 5 years old). To construct a subtracted ST-T waveform, we used standard MCG waveforms produced from 464 normal MCGs (male: 268, female: 196). The standard MCG waveforms were subtracted from each subject's measured MCGs, which were shortened or lengthened and normalized to adjust to the data length and magnitude of the standard waveform. We evaluated the maximum amplitude and maximum current arrow magnitude of the subtracted ST-T waveform. RESULTS: The maximum magnetic field, maximum magnitude of current arrows, and maximum magnitude of total current vector increased according to the number of coronary artery lesions. The sensitivity and specificity of detecting CHD and normal control patients were 74.6% and 84.1%, respectively. CONCLUSIONS: The subtraction MCG method can be used to detect CHD with high accuracy, namely, sensitivity of 74.6% and specificity of 84.1% (in the case of maximum amplitude of total current vector). Furthermore, the subtraction MCG magnitude and its current distribution can reflect the expanse of the ischemic lesion area and the progress from ischemia to myocardial infarction. PMID- 20946560 TI - Electrocardiographic clues to identify nonresponders to cardiac resynchronization therapy. AB - BACKGROUND: The aim of cardiac resynchronization therapy (CRT) is to restore myocardial electromechanical synchrony. Achieving this in patients with chronic severe heart failure due to poor left ventricular (LV) systolic function and cardiac dyssynchrony on optimal medical therapy, is associated with improved clinical performance and outcomes. Up to one-third of patients undergoing CRT do not benefit from implantation. Ensuring LV capture is essential and can be at times difficult to confirm. METHODS: Described herein, are six patients who underwent biventricular pacemaker implantation but failed to experience an improvement in LV systolic function or functional capacity. RESULTS: In each case, the 12-lead electrocardiogram (ECG) was helpful in unmasking loss of LV capture in patients who were presumed to have biventricular pacing. CONCLUSIONS: Despite the technical wizardry behind CRT and patient system analyzers, the surface ECG should continue to be an invaluable tool for evaluating patients who have undergone CRT. PMID- 20946561 TI - The year of 2009 in electrocardiology. PMID- 20946562 TI - "Awakenings": electrocardiographic findings in central sleep apnea. AB - Central sleep apnea is an important but frequently missed clinical diagnosis. The purpose of this clinical case series is to demonstrate that in a subset of patients with central sleep apnea, inpatient telemetry ECG recordings may reveal a consistent relationship between changes in sinus rate, AV conduction, and the presence and rate of respiratory artifact that should raise the clinical suspicion of central sleep apnea. In the three presented cases, marked sinus bradycardia or AV block was followed by the simultaneous occurrence of abrupt acceleration of heart rate and the appearance of rapid micro-oscillations consistent with respiratory artifact. These changes suggested central sleep apnea characterized by bradycardia during the apneic spells followed by awakening of the breathing center and postvagal tachycardia. In each case, central sleep apnea was confirmed by visual observation of the patient, documentation of arterial desaturations during episodes of bradycardia, and in two, by a subsequent sleep study. Physicians should be aware of the potential and significance of these electrocardiographic disturbances in patients with central sleep apnea. PMID- 20946563 TI - To change a dogma can be very difficult. PMID- 20946564 TI - Health Belief Model Scale for Cervical Cancer and Pap Smear Test: psychometric testing. AB - AIM: This study is a report of the development and psychometric testing of the Health Belief Model Scale for Cervical Cancer and the Pap Smear Test. BACKGROUND: While the Champion Health Belief Model scales have been tested extensively for breast cancer and screening for this, evaluation of these scales in explaining the beliefs of women with regard to cervical cancer and the Pap Smear Test has only received limited attention. METHODS: This methodological research was carried out in Turkey in 2007. The data were collected with 237 randomly selected women who met the criteria for inclusion and agreed to participate in this study. The Champion Health Belief Model scales were translated into Turkish, adapted for cervical cancer, validated by professional experts, translated back into English and pilot-tested. FINDINGS: Factor analysis yielded five factors: Pap smear benefits and health motivation, Pap smear barriers, seriousness, susceptibility and health motivation. Cronbach's alpha reliability coefficients for the five subscales ranged from 0.62 to 0.86, and test-retest reliability coefficients ranged from 0.79 to 0.87 for the subscales. CONCLUSION: The Health Belief Model Scale for Cervical Cancer and the Pap Smear Test was found to be a valid and reliable tool in assessing the women's health beliefs. Understanding the beliefs of women in respect of cervical cancer and the Pap Smear Test will help healthcare professionals to develop more effective cervical cancer screening programmes. PMID- 20946565 TI - Nursing and healthcare students' experiences and use of e-learning in higher education. AB - AIM: This paper presents research on nursing and healthcare students' experiences and use of e-learning. BACKGROUND: The inception of e-learning in higher education is supported by a policy background and technological developments, yet little is known of student experience and use in the United Kingdom. METHODS: Conducted in 2007 and 2008, this study employed a mixed methods approach. An initial quantitative questionnaire was completed by 25 Higher Education Institutions and nine case study sites were visited. In the sites 41 students took part in focus groups and 35 staff were interviewed. FINDINGS: Twenty-four Higher Education Institutions used a virtual learning environment and all respondents used e-learning to enable access to course materials and web-based learning resources. Three main themes were identified from student interviews, 'Pedagogic use'; 'Factors inhibiting use' and 'Facilitating factors to engagement'. Student's main engagement with e-learning was at an instructivist level and as a support to existing face-to-face modes of delivery. Student use of Web 2.0 was limited, although a number were using social software at home. Limited computer access, computing skills, technical issues and poor peer commitment affected use. Motivation and relevance to the course and practice, in addition to an appreciation of the potential for student-centred and flexible learning, facilitated use. CONCLUSION: There is scope to broaden the use of e learning that would engage students in the social construction of knowledge. In addition, experiences of e-learning use could be improved if factors adversely affecting engagement were addressed. PMID- 20946566 TI - Attitudes of paediatric intensive care nurses to development of a nurse practitioner role for critical care transport. AB - AIM: This paper is a report of a descriptive study of the attitudes and opinions of nurses before and after the introduction of independent Retrieval Nurse Practitioners into a critical care transport service for children. BACKGROUND: Little is known about nurses' attitudes to advanced practice roles, particularly when these function as part of a team in a high-risk, remote setting (distant to the base hospital). Increasing knowledge in this area may give insight into ways of improving team working and enhancing quality of patient care. METHOD: A qualitative questionnaire was sent to nurses pre- (June 2006) and post- (July 2007) retrieval nurse practitioner introduction. Questionnaires were analysed using an adapted phenomenological method. FINDINGS: The response rates were 62% (2006) and 48% (2007). The main themes that emerged included fear, communication, trust, team working, role conflict, role division and role boundaries. In the first survey, most nurses anticipated difficulties during retrieval with retrieval nurse practitioners and felt anxious about the prospect of being part of a team with an independent retrieval nurse practitioner. However, by the second survey (after retrieval nurse practitioner introduction), the majority reported confidence in the retrieval nurse practitioners' knowledge and skills. CONCLUSION: This advanced practice development has been a challenge for the nurses and the retrieval nurse practitioners, but initial anxieties and fears of a host of anticipated problems have been largely dispelled as enhanced communication and team working were reported. PMID- 20946567 TI - Living with advanced Parkinson's disease: a constant struggle with unpredictability. AB - AIM: This paper is a report of an exploration of patients' lifeworld and way of managing life with advanced Parkinson's disease prior to Deep Brain Stimulation and what they expect from life following this treatment. BACKGROUND: Parkinson's disease is a progressive neurodegenerative disease, which is initially well treated with L-dopa. Living with Parkinson's disease means living with the experience of continuous loss of independence and self-esteem and unpredictable ON/OFF phenomena. Thus, in the advanced stage of the disease, treatment with Deep Brain Stimulation may become relevant. METHOD: Eleven patients eligible for Deep Brain Stimulation were interviewed prior to treatment. Data were collected in 2007 and analysed according to the hermeneutic phenomenological methodology of van Manen, using the four existentials as analytic tools. FINDINGS: Living with advanced Parkinson's disease can be described as the experience of living with and managing unpredictability. The disease gradually took over, and participants had to struggle with unpredictability on a daily basis. Themes in relation to this were: The body - setting the agenda, Always a struggle to be on time, Living in dependence and compromise - being a burden, and Living with restrained space and changes in social life. CONCLUSION: Parkinson's disease leads to profound bodily restrictions. Living with an unpredictable body affects all aspects of life, and nurses need to be aware of the impact the disease has on the entire lifeworld, and how this may affect the way treatment is perceived. PMID- 20946568 TI - Care-based ethical reasoning among first-year nursing and social services students. AB - AIM: This paper is a report of a study conducted to describe nursing and social services students' ethical reasoning at the start of their studies. BACKGROUND: Gilligan argued that there are two modes of moral reasoning - the ethic of justice, focusing on individuals' rights, and the ethic of care, focusing on responsibilities in relationships. Recent research has established the ethic of care as a developmental phenomenon. It has been widely argued that the ethic of care is crucial for nursing, but there has been little international research in this area. METHOD: Participants were first-year nursing and social services students in Finland (N =112). Their care-based moral reasoning was measured using the Ethic of Care Interview, and their ethical reasoning on an abortion-related dilemma was analysed by content analysis. Expressed ethical codes and principles were calculated according to levels. The data were collected over a 5-month period in 2007-2008. FINDINGS: Students' level of care reasoning was varied. Their current level of care reasoning was reflected in their responses to the ethical dilemma. Ethical reasoning at each level and its specific premises constituted a distinct entity. Use of the principle of self-determination was positively related to levels of care development. Care-based moral reasoning constitutes the bedrock for ethical reasoning among these novice students. CONCLUSION: Educators should be sensitive to the variation in students' current developmental levels in care reasoning. Reflective discussion on real-life ethical conflicts should be an explicit part of education and clinical practice in caring professions. PMID- 20946569 TI - Factors interfering with the microflora on hands: a regression analysis of samples from 465 healthcare workers. AB - AIMS: This paper is a report of a study of the impact of finger rings, wrist watches, nail polish, length of fingernails, hand lotion, gender and occupation on hand microbiology of healthcare workers. BACKGROUND: The impact of the above mentioned variables on hand microbiology of healthcare workers is not well defined. Large scale studies suitable for multivariate analysis are needed to elucidate their role. METHODS: Both hands of 465 Norwegian healthcare workers were sampled by the glove juice method during two study periods (2004 and 2007), and examined for total number of bacteria and presence of Staphylococcus aureus, Enterobacteriacea and non-fermentative Gram-negative rods. Multiple regression analysis was performed. RESULTS: The use of a wrist watch was associated with an enhanced total bacterial count on hands compared to hands without a watch [(B) 3.25 (95% CI: 1.73-6.07), P <0.001], while the use of one plain finger ring increased the carriage rate of Enterobacteriaceae [odds ratio 2.71 (95% CI: 1.42 5.20), P = 0.003]. The carriage rate of Staphylococcus aureus was enhanced with fingernails longer than 2 mm [odds ratio 2.17 (95% CI: 1.29-3.66), P = 0.004] and after recent use of hand lotion [odds ratio 22.52 (95% CI: 4.05-125.30), P < 0.001]. No effect of nail polish was observed. We found an association between occupation and carriage rate of S. aureus and Enterobacteriaceae. CONCLUSIONS: Health care workers should remove finger rings and watches at work. Fingernails should be shorter than 2 mm, nail polish may be used. PMID- 20946570 TI - Paediatric nurses' identification of violence against children. AB - AIM: This paper is a report of an evaluation of paediatric nurses' assessment and diagnostic skills and interventions used for child maltreatment. BACKGROUND: The use of violence against children occurs in all environments worldwide. Therefore, broader theoretical and practical knowledge related to this issue is needed in health care to facilitate more accurate identification of child maltreatment in order to instigate implementation of appropriate care for these children. METHODS: The study was based on cross-sectional data obtained with a convenience sample of 160 Registered Nurses employed at paediatric wards at two large cities in Poland (response rate 80%). Data collection took place between December 2005 and March 2006. The research tool was a questionnaire form designed on the basis of international literature concerning battered child syndrome. RESULTS: Battered child syndrome seems to be a relatively common phenomenon, as a great majority of participants (86.25%) had encountered it in their practice. The form of child maltreatment which was most often mentioned (by 30.00% of participants) was neglect. Almost three-quarters of the nurses (61.25%; n = 98) said that they had been involved in providing care for a maltreated child. CONCLUSION: Nurses should work with maltreated children on an individualized basis, combined with interdisciplinary cooperation with specialists from related disciplines concerned with the issue. There appears to be a need for specialized training for nurses to increase their competence in working with maltreated children and their families. PMID- 20946571 TI - Patients' experiences of day surgery: a Parsonian analysis. AB - AIM: The aim of the study was to explore patients' experiences of day surgery using a sociological framework of analysis. BACKGROUND: Although day surgery has increased globally in the last 20 years, little applied sociological research has been undertaken in this area. METHOD: The Glaserian methodology of Grounded Theory was used. Semi-structured interviews were conducted with 145 patients and 100 carers on three occasions from 2004 to 2006. Analysis of the data involved line-by-line analysis, compilation of key words and phrases (codes) and constant comparison of the codes until core categories were identified. FINDINGS: A major category to emerge from the data was the ambiguity presented to patients in relation to the sick role. Of concern to patients was society's attitudes, which seem to deny to day surgery patients full entitlement to the privileges associated with the sick role. Day surgery patients wanted to feel comfortable in a role that was socially acceptable--the sick role. However, many patients actively resisted this role, and this could have implications for recovery. A large number of patients wished for a limited ascription of the sick role, whilst a minority actively sought to acquire this role. CONCLUSION: The importance of nurses in providing supportive, psychological care, and ensuring patient and carer understanding of what day surgery entails cannot be overstated. Day surgery personnel should teach that day surgery is not minor surgery and that recovery times may be protracted, during which patients will need support. PMID- 20946572 TI - Long-term prophylaxis of hereditary angioedema with androgen derivates: a critical appraisal and potential alternatives. AB - Androgen derivatives are regarded as standard in the long-term prophylaxis of swelling attacks in patients with hereditary angioedema (HAE). Because of their relatively slow onset of action, they are not suitable for acute therapy. Long term prophylaxis with androgen derivatives must be regarded critically, especially on account of their androgenic and anabolic effects, some of which are severe. The risk of adverse events increases with the daily dose and the duration of treatment. Thus, treatment always calls for close monitoring of patients with regard to potential adverse events. In addition, androgens are subject to numerous contraindications and they show interactions with a large number of other drugs. Off-label use, doping issues, clarification of reimbursement and the need to import the androgen derivatives, which are no longer marketed in Germany, result in additional effort for the treating physician in terms of logistics and time involved. In symptomatic treatment of acute attacks the intravenous substitution of C1-INH and - since 2008 - subcutaneous administration of icatibant are available. The two substances are well tolerated and their effect occurs rapidly and, when the diagnosis has been confirmed, reliably. In the light of these two treatment options for controlling acute attacks, prophylactic treatment of HAE patients with androgen derivatives such as danazol should be reassessed. Patients might benefit from a dose reduction or the withdrawal of androgen prophylaxis and attacks can be controlled with demand-oriented acute treatment using C1-INH or icatibant. PMID- 20946573 TI - Mendelian genetics of rare--and not so rare--cancers. AB - Mendelian genetics forms the basis for gene-informed risk assessment and management for the patient and family, and should be at the very foundation of 21st century personalization of healthcare. Yet this is an underutilized commodity. Identification and characterization of germline mutations in the RET proto-oncogene, encoding a receptor tyrosine kinase, as causing >90% of multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominant disorder characterized by medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism, heralded the era of evidence-based molecular diagnosis, predictive testing, genetic counseling, gene-informed cancer risk assessment, and preventative medicine. Since then, many syndromic endocrine neoplasias have proven to fall under this clinically utile and actionable model, such as those caused by mutations in RET, VHL, or SDHB-D. The familial risk associated with epithelial (nonmedullary) thyroid carcinoma is among the highest of all solid tumors, yet only a few highly penetrant heritable epithelial thyroid cancer syndrome exist. This is illustrated by Cowden syndrome, a difficult-to-recognize autosomal dominant disorder characterized by breast, thyroid, and other cancers, caused by germline mutations in PTEN, encoding a phosphatase, and minorly, SDHB/SDHD variants. PMID- 20946574 TI - Epidemiology and risk factors for osteonecrosis of the jaw in cancer patients. AB - Osteonecrosis of the jaw (ONJ), previously an entity associated with radiation therapy to the head and neck, has been observed in patients treated with bisphosphonates. Patients with metastatic breast cancer and myelomatous bone disease, commonly treated with high-potency nitrogen-containing bisphosphonates for a prolonged period of time, have the greatest risk of ONJ development. The reported frequency of ONJ ranges from 0.6% to 6.2% in breast cancer and from 1.7% to 15% in patients with multiple myeloma. Osteonecrosis of the jaw has also been observed in patients with other cancers such as prostate cancer and in benign bone disorders such as osteoporosis and Paget's disease in which the incidence is low. Risk factors associated with the development of ONJ include dental extractions, length of bisphosphonate treatment, and the type of bisphosphonate used. In this review, we summarize the reported incidence and risk factors associated with ONJ. PMID- 20946575 TI - Bisphosphonate use in conditions other than osteoporosis. AB - Bisphosphonates are the gold standard of treatment of postmenopausal osteoporosis, male osteoporosis, and steroid-induced osteoporosis. They have potential use in multiple musculoskeletal conditions other than osteoporosis and have also been shown to treat Paget's disease of the bone and osteogenesis imperfecta. Bisphophonates may have potential use in periprosthetic bone loss, osteonecrosis of the hip, fibrous dysplasia, and calcinosis in juvenile dermatomyositis. PMID- 20946576 TI - The interface between veterinary and human antibiotic use. AB - The identification and early development of novel antimicrobial agents for use in veterinary medicine is subject to many of the same business and technical challenges as those found in antimicrobial agent use for human infectious disease. However, as awareness that some of the antimicrobial classes used in veterinary medicine are the same as used in human medicine, concern by multiple stakeholders has increased that this nonhuman use might be contributing to the problem of antimicrobial resistance to pathogens in humans, particularly with regard to food-borne diseases, such as salmonellosis and campylobacteriosis. Consequently, the interface between veterinary and human antibiotic use and resistance, especially with respect to human microbial food safety, has begun to redirect the industry pipeline of novel antimicrobial agents to be commercialized for use in veterinary medicine. PMID- 20946577 TI - Biochemical markers of bone turnover in osteonecrosis of the jaw in patients with osteoporosis and advanced cancer involving the bone. AB - Osteonecrosis of the jaw (ONJ) has been hypothesized to result in part from a relative "oversuppression" of normal physiologic bone remodeling at the jaw brought about by bisphosphonate therapy. Biochemical markers of bone turnover give readily measurable information on integrated systemic bone remodeling activity, as measured by blood and urine assays. The intra- and interassay variability of most currently available assays is less than 10%, although many biological factors can influence levels of bone turnover markers. Bone turnover markers may show a dynamic response to changes in clinical status for a given disease state. Elevated bone turnover on and off treatment appears to predict adverse clinical consequences in both osteoporosis and cancer. Bisphosphonates effectively decrease the level of the bone turnover markers with a pattern depending on the marker, the bisphosphonate, the dose regimen, and the disease. However, long-term (10-year) treatment with bisphosphonates for osteoporosis does not appear to result in a progressive decline in bone turnover, as measured by markers and bone histology. The effects of long-term (greater than 2 years) treatment with monthly intravenous bisphosphonates on bone turnover markers in cancer are unknown. Discontinuation of bisphosphonate therapy appears to allow a recovery of bone turnover, which is related to the bisphosphonate, the duration of therapy, and the disease being treated. At this time, data are limited with regard to the utility of bone turnover markers in assessing risk for ONJ and whether bone marker-directed bisphosphonate holidays would be useful in prevention or treatment of ONJ. PMID- 20946578 TI - Immunomodulators as adjuvants for vaccines and antimicrobial therapy. AB - A highly effective strategy for combating infectious diseases is to enhance host defenses using immunomodulators, either preventatively, through vaccination, or therapeutically. The effectiveness of many vaccines currently in use is due in part to adjuvants, molecules that have little immunogenicity by themselves but which help enhance and appropriately skew the immune response to an antigen. The development of new vaccines necessitates the development of new types of adjuvants to ensure an appropriate immune response. Herein, we review commonly used vaccine adjuvants and discuss promising adjuvant candidates. We also discuss various other immunomodulators (namely cytokines, Toll-like receptor agonists, and host defense peptides) that are, or have potential to be, useful for antimicrobial therapies that exert their effects by boosting host immune responses rather than targeting pathogens directly. PMID- 20946579 TI - Use of bisphosphonates in the management of postmenopausal osteoporosis. AB - Bisphosphonates are widely used in the treatment of postmenopausal osteoporosis. They decrease the rate of bone turnover, maintain or improve structural and material properties of bone, and increase bone mineral density and thereby decrease the risk of fractures. Available potent bisphosphonates can be given to patients by different dosing regimens that range from daily oral administration to yearly intravenous infusions. Controlled studies, extending to 10 years of continuous treatment, provide information about long-term efficacy and safety and can help in the planning of long-term treatment strategies. Selection of bisphosphonates for the treatment of individuals should be based on a careful review of efficacy data, a risk profile of the bisphosphonate, and values and preferences of the patient. PMID- 20946580 TI - Bisphosphonate-related osteonecrosis of the jaw: an overview. AB - Bisphosphonates are widely used in the management of metastatic disease to bone and in diseases of altered bone turnover. Recently, multiple-case series and retrospective studies have established a relationship between necrotic bone lesions localized to the jaw and the use of chronic bisphosphonate therapy. This condition has been named bisphosphonate-related osteonecrosis of the jaw (BRONJ). To evaluate the potential risks associated with this new and emerging complication, stage-specific management strategies and guidelines have been developed. In view of the widespread use of chronic bisphosphonate therapy, the observation of an associated risk of osteonecrosis of the jaw should alert practitioners to monitor for this previously unrecognized complication and to reevaluate the indications for and the duration of bisphosphonate therapy in patients with osteopenia/osteoporosis and cancer. Morbidity associated with BRONJ might be prevented or reduced by implementing prevention strategies and establishing early diagnostic procedures. The current widespread use of bisphosphonates as an inhibitor of bone resorption is directly attributable to their efficacy in improving the quality of life for patients with metastatic bone cancer, osteoporosis, and Paget's disease. PMID- 20946581 TI - The use of bisphosphonates in cancer treatment. AB - Bone metastases result in considerable morbidity and exert complex demands on health care resources. Additionally, for many patients, metastatic bone disease is a chronic condition affecting quality of life and independence over years rather than months. The bisphosphonates, notably zoledronic acid, have been shown to reduce skeletal morbidity in multiple myeloma, as well as a wide range of solid tumors affecting bone, by 30-50%. Quite appropriately, the bisphosphonates are increasingly used alongside anticancer treatments to prevent skeletal complications and relieve bone pain. In addition, they are increasingly used to prevent cancer treatment-induced bone loss and show promise in the adjuvant setting to prevent metastasis from breast cancer. PMID- 20946582 TI - Non-invasive management of non-melanoma skin cancer in patients with cancer predisposition genodermatosis: a role for confocal microscopy and photodynamic therapy. AB - BACKGROUND: Patients with genodermatosis such as Gorlin syndrome (GS) and Xeroderma pigmentosum (XP) require a close follow-up for early diagnosis and treatment of skin cancer. We aimed to evaluate the efficacy of methyl aminolevulinate (MAL) photodynamic therapy (PDT) in basal cell carcinomas (BCCs) from patients with GS and XP, and to determine the utility of reflectance confocal microscopy (RCM) in the diagnosis and the evaluation of therapeutic response. PATIENTS AND METHODS: We included four patients with GS and two siblings with XP. Single or multiple lesions in localized areas were treated with 1-3 cycles of MAL PDT. RCM was performed before and 3 months after the treatment in target lesions in all the patients. Patients were followed up for 3 years. RESULTS: In XP patients, we treated 13 pigmented BCCs on the face. All the lesions responded to the treatment and six lesions showed a complete clinical clearing. In GS patients, facial or trunk areas with multiple BCCs were treated (up to 200). Complete clinical remission was obtained in 25-67% of the lesions. Some nodular and pigmented lesions failed to achieve a complete remission. RCM could identify already described confocal features for BCC. Tumour remissions could be assessed by this technique. CONCLUSIONS: Methyl-aminolevulinate PDT may be useful for the treatment of superficial BCC in GS and XP. In some nodular lesions, PDT may complement surgery reducing tumour size. RCM may be regarded in the future as a complementary technique in BCC for the diagnosis and post treatment assessment to non-invasive therapeutic modalities. PMID- 20946583 TI - UVB 308-nm excimer light and bath PUVA: combination therapy is very effective in the treatment of prurigo nodularis. AB - BACKGROUND: Prurigo nodularis (PN) is a chronic inflammatory skin disease with nodular itching lesions. UV therapy--both PUVA and NUVB--are known to clear up PN temporarily due to the antipruritic effect of UV light. However, relapse after treatment is common in PN, which means that either long-term therapy is necessary or the treatment protocols have to be optimized to minimize side-effects. OBJECTIVE: The aim of this study was to evaluate the effect that combining bath PUVA and targeted UVB 308 nm excimer radiation has on recalcitrant nodular prurigo. METHODS: In a prospective trial, 22 patients with PN were treated with either PUVA alone or with a combination of PUVA and excimer UVB. The end point was complete or almost complete remission of PN. RESULTS: Adding a 308-nm excimer UVB to the treatment of the pruritic nodules sped up the healing process; 30% less PUVA radiation was needed. CONCLUSION: The combination of PUVA and excimer UVB in PN appears to be very efficacious. Reducing psoralen UVA doses by 30% offered long-term benefits in phototherapy of chronic recalcitrant diseases like PN. PMID- 20946584 TI - Are port wines stains a feature of tuberous sclerosis? AB - BACKGROUND: Tuberous sclerosis complex is a multisystem inherited disorder characterized by the development of tumour-like growths in brain, skin and other organs. Although cutaneous vascular anomalies are not considered a common manifestation, we have encountered co-occurrence of port wine stains and tuberous sclerosis. OBJECTIVE: To assess the prevalence of port wine stain in patients with previously diagnosed tuberous sclerosis. METHODS: All cases diagnosed with tuberous sclerosis at two tertiary care centres from 2000 to 2009 were reviewed. Cases with clinically documented port wine stains were included for evaluation. RESULTS: Of 24 patients diagnosed with tuberous sclerosis, three (12.5%) had clinically evident port wine stains. The prevalence of port wine stains in this series of tuberous sclerosis patients was significantly higher than the 0.3% prevalence of port wine stain in the general population. CONCLUSION: Port wine stain rate in this population was significantly greater than the expected rate. Further studies are needed to assess the frequency of port wine stains in tuberous sclerosis and to clarify whether the finding should be added to the list of cutaneous features of tuberous sclerosis. PMID- 20946585 TI - Patients with profuse hair shedding may reveal anagen hair dystrophy: a diagnostic clue of alopecia areata incognita. AB - BACKGROUND: Several patients, especially women, seek advice because of hair loss. They may be diagnosed clinically as having telogen effluvium (TE) or androgenetic alopecia (AGA), but histopathology may reveal that a proportion of them have in fact alopecia areata incognita (AAI). OBJECTIVES: To detect dystrophic anagen hairs in such patients. METHODS: We studied 1932 patients with hair loss and no signs of classical alopecia areata. They were submitted to the modified wash test (which counts the total number of telogen hairs lost and the percentage of vellus hairs) and divided into patients having pure TE (403), patients with AGA+TE (1235) and patients with pure AGA (294). Dystrophic hairs were detected with a low magnification microscope. RESULTS: Dystrophic hairs were observed in 13 patients with TE (3.2%), in 54 with AGA+TE (4.4%) and in none with AGA. In addition, 7 patients with TE and 32 with AGA+TE developed small patches of alopecia areata in 6 to 9 weeks. No patches developed in patients with AGA. CONCLUSIONS: The presence of dystrophic hairs and the development of patches of alopecia areata (and their absence in pure AGA) provide a first evidence of the possibility that within the heterogenous condition named TE some patients have in fact AAI. PMID- 20946587 TI - Ecological differentiation in xylem cavitation resistance is associated with stem and leaf structural traits. AB - Cavitation resistance is a critical determinant of drought tolerance in tropical tree species, but little is known of its association with life history strategies, particularly for seasonal dry forests, a system critically driven by variation in water availability. We analysed vulnerability curves for saplings of 13 tropical dry forest tree species differing in life history and leaf phenology. We examined how vulnerability to cavitation (P50) related to dry season leaf water potentials and stem and leaf traits. P50-values ranged from -0.8 to -6.2 MPa, with pioneers on average 38% more vulnerable to cavitation than shade tolerants. Vulnerability to cavitation was related to structural traits conferring tissue stress vulnerability, being negatively correlated with wood density, and surprisingly maximum vessel length. Vulnerability to cavitation was negatively related to the Huber-value and leaf dry matter content, and positively with leaf size. It was not related to SLA. We found a strong trade-off between cavitation resistance and hydraulic efficiency. Most species in the field were operating at leaf water potentials well above their P50, but pioneers and deciduous species had smaller hydraulic safety margins than shade-tolerants and evergreens. A trade-off between hydraulic safety and efficiency underlies ecological differentiation across these tropical dry forest tree species. PMID- 20946586 TI - ppGpp is the major source of growth rate control in E. coli. AB - It is widely accepted that the DNA, RNA and protein content of Enterobacteriaceae is regulated as a function of exponential growth rates; macromolecular content increases with faster growth regardless of specific composition of the growth medium. This phenomenon, called growth rate control, primarily involves regulation of ribosomal RNA and ribosomal protein synthesis. However, it was uncertain whether the global regulator ppGpp is the major determinant for growth rate control. Therefore, here we re-evaluate the effect of ppGpp on macromolecular content for different balanced growth rates in defined media. We find that when ppGpp is absent, RNA/protein and RNA/DNA ratios are equivalent in fast and slow growing cells. Moreover, slow growing ppGpp-deficient cells with increased RNA content, display a normal ribosomal subunit composition although polysome content is reduced when compared with fast growing wild-type cells. From this we conclude that growth rate control does not occur in the absence of ppGpp. Also, artificial elevation of ppGpp or introduction of stringent RNA polymerase mutants in ppGpp-deficient cells restores this control. We believe these findings strongly argue in favour of ppGpp and against redundant regulation of growth rate control by other factors in Escherichia coli and other enteric bacteria. PMID- 20946588 TI - Glycinebetaine protects plants against abiotic stress: mechanisms and biotechnological applications. AB - Various compatible solutes enable plants to tolerate abiotic stress, and glycinebetaine (GB) is one of the most-studied among such solutes. Early research on GB focused on the maintenance of cellular osmotic potential in plant cells. Subsequent genetically engineered synthesis of GB-biosynthetic enzymes and studies of transgenic plants demonstrated that accumulation of GB increases tolerance of plants to various abiotic stresses at all stages of their life cycle. Such GB-accumulating plants exhibit various advantageous traits, such as enlarged fruits and flowers and/or increased seed number under non-stress conditions. However, levels of GB in transgenic GB-accumulating plants are relatively low being, generally, in the millimolar range. Nonetheless, these low levels of GB confer considerable tolerance to various stresses, without necessarily contributing significantly to cellular osmotic potential. Moreover, low levels of GB, applied exogenously or generated by transgenes for GB biosynthesis, can induce the expression of certain stress-responsive genes, including those for enzymes that scavenge reactive oxygen species. Thus, transgenic approaches that increase tolerance to abiotic stress have enhanced our understanding of mechanisms that protect plants against such stress. PMID- 20946589 TI - Cryptogein, a fungal elicitor, remodels the phenylpropanoid metabolism of tobacco cell suspension cultures in a calcium-dependent manner. AB - Plant cells use calcium-based signalling pathways to transduce biotic and/or abiotic stimuli into adaptive responses. However, little is known about the coupling between calcium signalling, transcriptional regulation and the downstream biochemical processes. To understand these relationships better, we challenged tobacco BY-2 cells with cryptogein and evaluated how calcium transients (monitored through the calcium sensor aequorin) impact (1) transcript levels of phenylpropanoid genes (assessed by RT-qPCR); and (2) derived-phenolic compounds (analysed by mass spectrometry). Most genes of the phenylpropanoid pathway were up-regulated by cryptogein and cell wall-bound phenolic compounds accumulated (mainly 5-hydroxyferulic acid). The accumulation of both transcripts and phenolics was calcium-dependent. The transcriptional regulation of phenylpropanoid genes was correlated in a non-linear manner with stimulus intensity and with components of the cryptogein-induced calcium signature. In addition, calmodulin inhibitors increased the sensitivity of cells to low concentrations of cryptogein. These results led us to propose a model of coupling between the cryptogein signal, calcium signalling and the transcriptional response, exerting control of transcription through the coordinated action of two decoding modules exerting opposite effects. PMID- 20946590 TI - A young clade repeating an old pattern: diversity in Nothonotus darters (Teleostei: Percidae) endemic to the Cumberland River. AB - Hypotheses of diversification in eastern North American freshwater fishes have focused primarily on allopatric distributions of species between disjunct highland areas and major river systems. However, these hypotheses do not fully explain the rich diversity of species within highland regions and river systems. Relatively old diversification events at small geographic scales have been observed in the Barcheek Darter subclade that occurs in the Cumberland River drainage (CRD) in Kentucky and Tennessee, United States of America, but it is unknown if this pattern is consistent in other darter subclades. We explored phylogeographic diversity in two species of Nothonotus darters, N. microlepidus and N. sanguifluus, endemic to the CRD to compare phylogenetic patterns between Barcheek Darters and species of Nothonotus. We collected sequence data for a mitochondrial gene (cytb) and three nuclear genes (MLL, S7 and RAG1) from 19 N. microlepidus and 35 N. sanguifluus specimens. Gene trees were estimated using maximum likelihood and Bayesian methods, and a 'species tree' was inferred using a Bayesian method. These trees indicate that species diversity in Nothonotus is underestimated. Five distinct lineages were evident, despite retained ancestral polymorphism and unsampled extirpated populations. Comparison of chronograms for Barcheek Darters and Nothonotus revealed that microendemism resulting from species diversification at small geographic scales in the CRD is a consistent pattern in both old and young darter subclades. Our analyses reveal that geographic isolating mechanisms that result in similar phylogeographic patterns in the CRD are persistent through long expanses of evolutionary time. PMID- 20946591 TI - 12th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI) Bethesda, MD, USA. 26-27 April, 2010. Abstracts. PMID- 20946592 TI - Proceedings of the 2010 MidSouth Computational Biology and Bioinformatics Society (MCBIOS) conference. PMID- 20946593 TI - Evaluation of gene expression data generated from expired Affymetrix GeneChip(r) microarrays using MAQC reference RNA samples. AB - BACKGROUND: The Affymetrix GeneChip(r) system is a commonly used platform for microarray analysis but the technology is inherently expensive. Unfortunately, changes in experimental planning and execution, such as the unavailability of previously anticipated samples or a shift in research focus, may render significant numbers of pre-purchased GeneChip(r) microarrays unprocessed before their manufacturer's expiration dates. Researchers and microarray core facilities wonder whether expired microarrays are still useful for gene expression analysis. In addition, it was not clear whether the two human reference RNA samples established by the MAQC project in 2005 still maintained their transcriptome integrity over a period of four years. Experiments were conducted to answer these questions. RESULTS: Microarray data were generated in 2009 in three replicates for each of the two MAQC samples with either expired Affymetrix U133A or unexpired U133Plus2 microarrays. These results were compared with data obtained in 2005 on the U133Plus2 microarray. The percentage of overlap between the lists of differentially expressed genes (DEGs) from U133Plus2 microarray data generated in 2009 and in 2005 was 97.44%. While there was some degree of fold change compression in the expired U133A microarrays, the percentage of overlap between the lists of DEGs from the expired and unexpired microarrays was as high as 96.99%. Moreover, the microarray data generated using the expired U133A microarrays in 2009 were highly concordant with microarray and TaqMan(r) data generated by the MAQC project in 2005. CONCLUSIONS: Our results demonstrated that microarray data generated using U133A microarrays, which were more than four years past the manufacturer's expiration date, were highly specific and consistent with those from unexpired microarrays in identifying DEGs despite some appreciable fold change compression and decrease in sensitivity. Our data also suggested that the MAQC reference RNA samples, stored at -80 degrees C, were stable over a time frame of at least four years. PMID- 20946594 TI - Mixed reality simulation of rasping procedure in artificial cervical disc replacement (ACDR) surgery. AB - BACKGROUND: Until quite recently spinal disorder problems in the U.S. have been operated by fusing cervical vertebrae instead of replacement of the cervical disc with an artificial disc. Cervical disc replacement is a recently approved procedure in the U.S. It is one of the most challenging surgical procedures in the medical field due to the deficiencies in available diagnostic tools and insufficient number of surgical practices For physicians and surgical instrument developers, it is critical to understand how to successfully deploy the new artificial disc replacement systems. Without proper understanding and practice of the deployment procedure, it is possible to injure the vertebral body. Mixed reality (MR) and virtual reality (VR) surgical simulators are becoming an indispensable part of physicians' training, since they offer a risk free training environment. In this study, MR simulation framework and intricacies involved in the development of a MR simulator for the rasping procedure in artificial cervical disc replacement (ACDR) surgery are investigated. The major components that make up the MR surgical simulator with motion tracking system are addressed. FINDINGS: A mixed reality surgical simulator that targets rasping procedure in the artificial cervical disc replacement surgery with a VICON motion tracking system was developed. There were several challenges in the development of MR surgical simulator. First, the assembly of different hardware components for surgical simulation development that involves knowledge and application of interdisciplinary fields such as signal processing, computer vision and graphics, along with the design and placements of sensors etc . Second challenge was the creation of a physically correct model of the rasping procedure in order to attain critical forces. This challenge was handled with finite element modeling. The third challenge was minimization of error in mapping movements of an actor in real model to a virtual model in a process called registration. This issue was overcome by a two-way (virtual object to real domain and real domain to virtual object) semi-automatic registration method. CONCLUSIONS: The applicability of the VICON MR setting for the ACDR surgical simulator is demonstrated. The main stream problems encountered in MR surgical simulator development are addressed. First, an effective environment for MR surgical development is constructed. Second, the strain and the stress intensities and critical forces are simulated under the various rasp instrument loadings with impacts that are applied on intervertebral surfaces of the anterior vertebrae throughout the rasping procedure. Third, two approaches are introduced to solve the registration problem in MR setting. Results show that our system creates an effective environment for surgical simulation development and solves tedious and time-consuming registration problems caused by misalignments. Further, the MR ACDR surgery simulator was tested by 5 different physicians who found that the MR simulator is effective enough to teach the anatomical details of cervical discs and to grasp the basics of the ACDR surgery and rasping procedure. PMID- 20946595 TI - Enzyme structure dynamics of xylanase I from Trichoderma longibrachiatum. AB - BACKGROUND: Enzyme dynamics has recently been shown to be crucial for structure function relationship. Among various structure dynamics analysis platforms, HDX (hydrogen deuterium exchange) mass spectrometry stands out as an efficient and high-throughput way to analyze protein dynamics upon ligand binding. Despite the potential, limited research has employed the HDX mass spec platform to probe regional structure dynamics of enzymes. In particular, the technique has never been used for analyzing cell wall degrading enzymes. We hereby used xylanase as a model to explore the potential of HDX mass spectrometry for studying cell wall degrading enzymes. RESULTS: HDX mass spectrometry revealed significant intrinsic dynamics for the xylanase enzyme. Different regions of the enzymes are differentially stabilized in the apo enzyme. The comparison of substrate-binding enzymes revealed that xylohexaose can significantly stabilize the enzyme. Several regions including those near the reaction centres were significantly stabilized during the xylohexaose binding. As compared to xylohexaose, xylan induced relatively less protection in the enzyme, which may be due to the insolubility of the substrate. The structure relevance of the enzyme dynamics was discussed with reference to the three dimensional structure of the enzyme. HDX mass spectrometry revealed strong dynamics-function relevance and such relevance can be explored for the future enzyme improvement. CONCLUSION: Ligand-binding can lead to the significant stabilization at both regional and global level for enzymes like xylanase. HDX mass spectrometry is a powerful high-throughput platform to identify the key regions protected during the ligand binding and to explore the molecular mechanisms of the enzyme function. The HDX mass spectrometry analysis of cell wall degrading enzymes has provided a novel platform to guide the rational design of enzymes. PMID- 20946596 TI - Quail Genomics: a knowledgebase for Northern bobwhite. AB - BACKGROUND: The Quail Genomics knowledgebase (http://www.quailgenomics.info) has been initiated to share and develop functional genomic data for Northern bobwhite (Colinus virginianus). This web-based platform has been designed to allow researchers to perform analysis and curate genomic information for this non-model species that has little supporting information in GenBank. DESCRIPTION: A multi tissue, normalized cDNA library generated for Northern bobwhite was sequenced using 454 Life Sciences next generation sequencing. The Quail Genomics knowledgebase represents the 478,142 raw ESTs generated from the sequencing effort in addition to assembled nucleotide and protein sequences including 21,980 unigenes annotated with meta-data. A normalized MySQL relational database was established to provide comprehensive search parameters where meta-data can be retrieved using functional and structural information annotation such as gene name, pathways and protein domain. Additionally, blast hit cutoff levels and microarray expression data are available for batch searches. A Gene Ontology (GO) browser from Amigo is locally hosted providing 8,825 unigenes that are putative orthologs to chicken genes. In an effort to address over abundance of Northern bobwhite unigenes (71,384) caused by non-overlapping contigs and singletons, we have built a pipeline that generates scaffolds/supercontigs by aligning partial sequence fragments against the indexed protein database of chicken to build longer sequences that can be visualized in a web browser. CONCLUSION: Our effort provides a central repository for storage and a platform for functional interrogation of the Northern bobwhite sequences providing comprehensive GO annotations, meta-data and a scaffold building pipeline. The Quail Genomics knowledgebase will be integrated with Japanese quail (Coturnix coturnix) data in future builds and incorporate a broader platform for these avian species. PMID- 20946597 TI - Discovering gene functional relationships using FAUN (Feature Annotation Using Nonnegative matrix factorization). AB - BACKGROUND: Searching the enormous amount of information available in biomedical literature to extract novel functional relationships among genes remains a challenge in the field of bioinformatics. While numerous (software) tools have been developed to extract and identify gene relationships from biological databases, few effectively deal with extracting new (or implied) gene relationships, a process which is useful in interpretation of discovery-oriented genome-wide experiments. RESULTS: In this study, we develop a Web-based bioinformatics software environment called FAUN or Feature Annotation Using Nonnegative matrix factorization (NMF) to facilitate both the discovery and classification of functional relationships among genes. Both the computational complexity and parameterization of NMF for processing gene sets are discussed. FAUN is tested on three manually constructed gene document collections. Its utility and performance as a knowledge discovery tool is demonstrated using a set of genes associated with Autism. CONCLUSIONS: FAUN not only assists researchers to use biomedical literature efficiently, but also provides utilities for knowledge discovery. This Web-based software environment may be useful for the validation and analysis of functional associations in gene subsets identified by high-throughput experiments. PMID- 20946598 TI - Next generation models for storage and representation of microbial biological annotation. AB - BACKGROUND: Traditional genome annotation systems were developed in a very different computing era, one where the World Wide Web was just emerging. Consequently, these systems are built as centralized black boxes focused on generating high quality annotation submissions to GenBank/EMBL supported by expert manual curation. The exponential growth of sequence data drives a growing need for increasingly higher quality and automatically generated annotation. Typical annotation pipelines utilize traditional database technologies, clustered computing resources, Perl, C, and UNIX file systems to process raw sequence data, identify genes, and predict and categorize gene function. These technologies tightly couple the annotation software system to hardware and third party software (e.g. relational database systems and schemas). This makes annotation systems hard to reproduce, inflexible to modification over time, difficult to assess, difficult to partition across multiple geographic sites, and difficult to understand for those who are not domain experts. These systems are not readily open to scrutiny and therefore not scientifically tractable. The advent of Semantic Web standards such as Resource Description Framework (RDF) and OWL Web Ontology Language (OWL) enables us to construct systems that address these challenges in a new comprehensive way. RESULTS: Here, we develop a framework for linking traditional data to OWL-based ontologies in genome annotation. We show how data standards can decouple hardware and third party software tools from annotation pipelines, thereby making annotation pipelines easier to reproduce and assess. An illustrative example shows how TURTLE (Terse RDF Triple Language) can be used as a human readable, but also semantically-aware, equivalent to GenBank/EMBL files. CONCLUSIONS: The power of this approach lies in its ability to assemble annotation data from multiple databases across multiple locations into a representation that is understandable to researchers. In this way, all researchers, experimental and computational, will more easily understand the informatics processes constructing genome annotation and ultimately be able to help improve the systems that produce them. PMID- 20946599 TI - HPIDB--a unified resource for host-pathogen interactions. AB - BACKGROUND: Protein-protein interactions (PPIs) play a crucial role in initiating infection in a host-pathogen system. Identification of these PPIs is important for understanding the underlying biological mechanism of infection and identifying putative drug targets. Database resources for studying host-pathogen systems are scarce and are either host specific or dedicated to specific pathogens. RESULTS: Here we describe "HPIDB" a host-pathogen PPI database, which will serve as a unified resource for host-pathogen interactions. Specifically, HPIDB integrates experimental PPIs from several public databases into a single, non-redundant web accessible resource. The database can be searched with a variety of options such as sequence identifiers, symbol, taxonomy, publication, author, or interaction type. The output is provided in a tab delimited text file format that is compatible with Cytoscape, an open source resource for PPI visualization. HPIDB allows the user to search protein sequences using BLASTP to retrieve homologous host/pathogen sequences. For high-throughput analysis, the user can search multiple protein sequences at a time using BLASTP and obtain results in tabular and sequence alignment formats. The taxonomic categorization of proteins (bacterial, viral, fungi, etc.) involved in PPI enables the user to perform category specific BLASTP searches. In addition, a new tool is introduced, which allows searching for homologous host-pathogen interactions in the HPIDB database. CONCLUSIONS: HPIDB is a unified, comprehensive resource for host pathogen PPIs. The user interface provides new features and tools helpful for studying host-pathogen interactions. HPIDB can be accessed at http://agbase.msstate.edu/hpi/main.html. PMID- 20946600 TI - Promoter prediction in E. coli based on SIDD profiles and Artificial Neural Networks. AB - BACKGROUND: One of the major challenges in biology is the correct identification of promoter regions. Computational methods based on motif searching have been the traditional approach taken. Recent studies have shown that DNA structural properties, such as curvature, stacking energy, and stress-induced duplex destabilization (SIDD) are useful in promoter prediction, as well. In this paper, the currently used SIDD energy threshold method is compared to the proposed artificial neural network (ANN) approach for finding promoters based on SIDD profile data. RESULTS: When compared to the SIDD threshold prediction method, artificial neural networks showed noticeable improvements for precision, recall, and F-score over a range of values. The maximal F-score for the ANN classifier was 62.3 and 56.8 for the threshold-based classifier. CONCLUSIONS: Artificial neural networks were used to predict promoters based on SIDD profile data. Results using this technique were an improvement over the previous SIDD threshold approach. Over a wide range of precision-recall values, artificial neural networks were more capable of identifying distinctive characteristics of promoter regions than threshold based methods. PMID- 20946601 TI - Phylometrics: a pipeline for inferring phylogenetic trees from a sequence relationship network perspective. AB - BACKGROUND: Comparative sequence analysis of the 16S rRNA gene is frequently used to characterize the microbial diversity of environmental samples. However, sequence similarities do not always imply functional or evolutionary relatedness due to many factors, including unequal rates of change and convergence. Thus, relying on top BLASTN hits for phylogenetic studies may misrepresent the diversity of these constituents. Furthermore, attempts to circumvent this issue by including a large number of BLASTN hits per sequence in one tree to explore their relatedness presents other problems. For instance, the multiple sequence alignment will be poor and computationally costly if not relying on manual alignment, and it may be difficult to derive meaningful relationships from the resulting tree. Analyzing sequence relationship networks within collective BLASTN results, however, reveal sequences that are closely related despite low rank. RESULTS: We have developed a web application, Phylometrics, that relies on networks of collective BLASTN results (rather than single BLASTN hits) to facilitate the process of building phylogenetic trees in an automated, high throughput fashion while offering novel tools to find sequences that are of significant phylogenetic interest with minimal human involvement. The application, which can be installed locally in a laboratory or hosted remotely, utilizes a simple wizard-style format to guide the user through the pipeline without necessitating a background in programming. Furthermore, Phylometrics implements an independent job queuing system that enables users to continue to use the system while jobs are run with little or no degradation in performance. CONCLUSIONS: Phylometrics provides a novel data mining method to screen supplied DNA sequences and to identify sequences that are of significant phylogenetic interest using powerful analytical tools. Sequences that are identified as being similar to a number of supplied sequences may provide key insights into their functional or evolutionary relatedness. Users require the same basic computer skills as for navigating most internet applications. PMID- 20946602 TI - Time lagged information theoretic approaches to the reverse engineering of gene regulatory networks. AB - BACKGROUND: A number of models and algorithms have been proposed in the past for gene regulatory network (GRN) inference; however, none of them address the effects of the size of time-series microarray expression data in terms of the number of time-points. In this paper, we study this problem by analyzing the behaviour of three algorithms based on information theory and dynamic Bayesian network (DBN) models. These algorithms were implemented on different sizes of data generated by synthetic networks. Experiments show that the inference accuracy of these algorithms reaches a saturation point after a specific data size brought about by a saturation in the pair-wise mutual information (MI) metric; hence there is a theoretical limit on the inference accuracy of information theory based schemes that depends on the number of time points of micro-array data used to infer GRNs. This illustrates the fact that MI might not be the best metric to use for GRN inference algorithms. To circumvent the limitations of the MI metric, we introduce a new method of computing time lags between any pair of genes and present the pair-wise time lagged Mutual Information (TLMI) and time lagged Conditional Mutual Information (TLCMI) metrics. Next we use these new metrics to propose novel GRN inference schemes which provides higher inference accuracy based on the precision and recall parameters. RESULTS: It was observed that beyond a certain number of time-points (i.e., a specific size) of micro-array data, the performance of the algorithms measured in terms of the recall-to-precision ratio saturated due to the saturation in the calculated pair-wise MI metric with increasing data size. The proposed algorithms were compared to existing approaches on four different biological networks. The resulting networks were evaluated based on the benchmark precision and recall metrics and the results favour our approach. CONCLUSIONS: To alleviate the effects of data size on information theory based GRN inference algorithms, novel time lag based information theoretic approaches to infer gene regulatory networks have been proposed. The results show that the time lags of regulatory effects between any pair of genes play an important role in GRN inference schemes. PMID- 20946603 TI - Applying internal coordinate mechanics to model the interactions between 8R lipoxygenase and its substrate. AB - BACKGROUND: Lipoxygenases (LOX) play pivotal roles in the biosynthesis of leukotrienes and other biologically active potent signalling compounds. Developing inhibitors for LOX is of high interest to researchers. Modelling the interactions between LOX and its substrate arachidonic acid is critical for developing LOX specific inhibitors. Currently, there are no LOX-substrate structures. Recently, the structure of a coral LOX, 8R-LOX, which is 41% sequence identical to the human 5-LOX was solved to 1.85A resolution. This structure provides a foundation for modelling enzyme-substrate interactions. METHODS: In this research, we applied a computational method, Internal Coordinate Mechanics (ICM), to model the interactions between 8R-LOX and its substrate arachidonic acid. Docking arachidonic acid to 8R-LOX was performed. The most favoured docked ligand conformations were retained. We compared the results of our simulation with a proposed model and concluded that the binding pocket identified in this study agrees with the proposed model partially. RESULTS: The results showed that the conformation of arachidonic acid docked into the ICM-identified docking site has less energy than that docked into the manually defined docking site for pseudo wild type 8R-LOX. The mutation at I805 resulted in no docking pocket found near Fe atom. The energy of the arachidonic acid conformation docked into the manually defined docking site is higher in mutant 8R-LOX than in wild type 8R LOX. The arachidonic acid conformations are not productive conformations. CONCLUSIONS: We concluded that, for the wild type 8R-LOX, the conformation of arachidonic acid docked into the ICM-identified docking site is more stable than that docked into the manually defined docking site. Mutation affects the structure of the putative active site pocket of 8R-LOX, and leads no docking pockets around the catalytic Fe atom. The docking simulation in a mutant 8R-LOX demonstrated that the structural change due to the mutation impacts the enzyme activity. Further research and analysis is required to obtain the 8R-LOX substrate model. PMID- 20946604 TI - A framework for automated enrichment of functionally significant inverted repeats in whole genomes. AB - BACKGROUND: RNA transcripts from genomic sequences showing dyad symmetry typically adopt hairpin-like, cloverleaf, or similar structures that act as recognition sites for proteins. Such structures often are the precursors of non coding RNA (ncRNA) sequences like microRNA (miRNA) and small-interfering RNA (siRNA) that have recently garnered more functional significance than in the past. Genomic DNA contains hundreds of thousands of such inverted repeats (IRs) with varying degrees of symmetry. But by collecting statistically significant information from a known set of ncRNA, we can sort these IRs into those that are likely to be functional. RESULTS: A novel method was developed to scan genomic DNA for partially symmetric inverted repeats and the resulting set was further refined to match miRNA precursors (pre-miRNA) with respect to their density of symmetry, statistical probability of the symmetry, length of stems in the predicted hairpin secondary structure, and the GC content of the stems. This method was applied on the Arabidopsis thaliana genome and validated against the set of 190 known Arabidopsis pre-miRNA in the miRBase database. A preliminary scan for IRs identified 186 of the known pre-miRNA but with 714700 pre-miRNA candidates. This large number of IRs was further refined to 483908 candidates with 183 pre-miRNA identified and further still to 165371 candidates with 171 pre miRNA identified (i.e. with 90% of the known pre-miRNA retained). CONCLUSIONS: 165371 candidates for potentially functional miRNA is still too large a set to warrant wet lab analyses, such as northern blotting, on all of them. Hence additional filters are needed to further refine the number of candidates while still retaining most of the known miRNA. These include detection of promoters and terminators, homology analyses, location of candidate relative to coding regions, and better secondary structure prediction algorithms. The software developed is designed to easily accommodate such additional filters with a minimal experience in Perl. PMID- 20946605 TI - A predictive model for secondary RNA structure using graph theory and a neural network. AB - BACKGROUND: Determining the secondary structure of RNA from the primary structure is a challenging computational problem. A number of algorithms have been developed to predict the secondary structure from the primary structure. It is agreed that there is still room for improvement in each of these approaches. In this work we build a predictive model for secondary RNA structure using a graph theoretic tree representation of secondary RNA structure. We model the bonding of two RNA secondary structures to form a larger secondary structure with a graph operation we call merge. We consider all combinatorial possibilities using all possible tree inputs, both those that are RNA-like in structure and those that are not. The resulting data from each tree merge operation is represented by a vector. We use these vectors as input values for a neural network and train the network to recognize a tree as RNA-like or not, based on the merge data vector. The network estimates the probability of a tree being RNA-like. RESULTS: The network correctly assigned a high probability of RNA-likeness to trees previously identified as RNA-like and a low probability of RNA-likeness to those classified as not RNA-like. We then used the neural network to predict the RNA-likeness of the unclassified trees. CONCLUSIONS: There are a number of secondary RNA structure prediction algorithms available online. These programs are based on finding the secondary structure with the lowest total free energy. In this work, we create a predictive tool for secondary RNA structures using graph-theoretic values as input for a neural network. The use of a graph operation to theoretically describe the bonding of secondary RNA is novel and is an entirely different approach to the prediction of secondary RNA structures. Our method correctly predicted trees to be RNA-like or not RNA-like for all known cases. In addition, our results convey a measure of likelihood that a tree is RNA-like or not RNA-like. Given that the majority of secondary RNA folding algorithms return more than one possible outcome, our method provides a means of determining the best or most likely structures among all of the possible outcomes. PMID- 20946606 TI - Comparative genome analysis of PHB gene family reveals deep evolutionary origins and diverse gene function. AB - BACKGROUND: PHB (Prohibitin) gene family is involved in a variety of functions important for different biological processes. PHB genes are ubiquitously present in divergent species from prokaryotes to eukaryotes. Human PHB genes have been found to be associated with various diseases. Recent studies by our group and others have shown diverse function of PHB genes in plants for development, senescence, defence, and others. Despite the importance of the PHB gene family, no comprehensive gene family analysis has been carried to evaluate the relatedness of PHB genes across different species. In order to better guide the gene function analysis and understand the evolution of the PHB gene family, we therefore carried out the comparative genome analysis of the PHB genes across different kingdoms. RESULTS: The relatedness, motif distribution, and intron/exon distribution all indicated that PHB genes is a relatively conserved gene family. The PHB genes can be classified into 5 classes and each class have a very deep evolutionary origin. The PHB genes within the class maintained the same motif patterns during the evolution. With Arabidopsis as the model species, we found that PHB gene intron/exon structure and domains are also conserved during the evolution. Despite being a conserved gene family, various gene duplication events led to the expansion of the PHB genes. Both segmental and tandem gene duplication were involved in Arabidopsis PHB gene family expansion. However, segmental duplication is predominant in Arabidopsis. Moreover, most of the duplicated genes experienced neofunctionalization. The results highlighted that PHB genes might be involved in important functions so that the duplicated genes are under the evolutionary pressure to derive new function. CONCLUSION: PHB gene family is a conserved gene family and accounts for diverse but important biological functions based on the similar molecular mechanisms. The highly diverse biological function indicated that more research needs to be carried out to dissect the PHB gene function. The conserved gene evolution indicated that the study in the model species can be translated to human and mammalian studies. PMID- 20946607 TI - Lesion detection in demoscopy images with novel density-based and active contour approaches. AB - BACKGROUND: Dermoscopy is one of the major imaging modalities used in the diagnosis of melanoma and other pigmented skin lesions. Automated assessment tools for dermoscopy images have become an important field of research mainly because of inter- and intra-observer variations in human interpretation. One of the most important steps in dermoscopy image analysis is the detection of lesion borders, since many other features, such as asymmetry, border irregularity, and abrupt border cutoff, rely on the boundary of the lesion. RESULTS: To automate the process of delineating the lesions, we employed Active Contour Model (ACM) and boundary-driven density-based clustering (BD-DBSCAN) algorithms on 50 dermoscopy images, which also have ground truths to be used for quantitative comparison. We have observed that ACM and BD-DBSCAN have the same border error of 6.6% on all images. To address noisy images, BD-DBSCAN can perform better delineation than ACM. However, when used with optimum parameters, ACM outperforms BD-DBSCAN, since ACM has a higher recall ratio. CONCLUSION: We successfully proposed two new frameworks to delineate suspicious lesions with i) an ACM integrated approach with sharpening and ii) a fast boundary-driven density-based clustering technique. ACM shrinks a curve toward the boundary of the lesion. To guide the evolution, the model employs the exact solution 27 of a specific form of the Geometric Heat Partial Differential Equation 28. To make ACM advance through noisy images, an improvement of the model's boundary condition is under consideration. BD-DBSCAN improves regular density-based algorithm to select query points intelligently. PMID- 20946608 TI - Dynamics of protofibril elongation and association involved in Abeta42 peptide aggregation in Alzheimer's disease. AB - BACKGROUND: The aggregates of a protein called, 'Abeta' found in brains of Alzheimer's patients are strongly believed to be the cause for neuronal death and cognitive decline. Among the different forms of Abeta aggregates, smaller aggregates called 'soluble oligomers' are increasingly believed to be the primary neurotoxic species responsible for early synaptic dysfunction. Since it is well known that the Abeta aggregation is a nucleation dependent process, it is widely believed that the toxic oligomers are intermediates to fibril formation, or what we call the 'on-pathway' products. Modeling of Abeta aggregation has been of intense investigation during the last decade. However, precise understanding of the process, pre-nucleation events in particular, are not yet known. Most of these models are based on curve-fitting and overlook the molecular-level biophysics involved in the aggregation pathway. Hence, such models are not reusable, and fail to predict the system dynamics in the presence of other competing pathways. RESULTS: In this paper, we present a molecular-level simulation model for understanding the dynamics of the amyloid-beta (Abeta) peptide aggregation process involved in Alzheimer's disease (AD). The proposed chemical kinetic theory based approach is generic and can model most nucleation dependent protein aggregation systems that cause a variety of neurodegenerative diseases. We discuss the challenges in estimating all the rate constants involved in the aggregation process towards fibril formation and propose a divide and conquer strategy by dissecting the pathway into three biophysically distinct stages: 1) pre-nucleation stage 2) post-nucleation stage and 3) protofibril elongation stage. We next focus on estimating the rate constants involved in the protofibril elongation stages for Abeta42 supported by in vitro experimental data. This elongation stage is further characterized by elongation due to oligomer additions and lateral association of protofibrils (13) and to properly validate the rate constants involved in these phases we have presented three distinct reaction models. We also present a novel scheme for mapping the fluorescence sensitivity and dynamic light scattering based in vitro experimental plots to estimates of concentration variation with time. Finally, we discuss how these rate constants will be incorporated into the overall simulation of the aggregation process to identify the parameters involved in the complete Abeta pathway in a bid to understand its dynamics. CONCLUSIONS: We have presented an instance of the top-down modeling paradigm where the biophysical system is approximated by a set of reactions for each of the stages that have been modeled. In this paper, we have only reported the kinetic rate constants of the fibril elongation stage that were validated by in vitro biophysical analyses. The kinetic parameters reported in the paper should be at least accurate upto the first two decimal places of the estimate. We sincerely believe that our top-down models and kinetic parameters will be able to accurately model the biophysical phenomenon of Abeta protein aggregation and identify the nucleation mass and rate constants of all the stages involved in the pathway. Our model is also reusable and will serve as the basis for making computational predictions on the system dynamics with the incorporation of other competing pathways introduced by lipids and fatty acids. PMID- 20946609 TI - Integrated database for identifying candidate genes for Aspergillus flavus resistance in maize. AB - BACKGROUND: Aspergillus flavus Link:Fr, an opportunistic fungus that produces aflatoxin, is pathogenic to maize and other oilseed crops. Aflatoxin is a potent carcinogen, and its presence markedly reduces the value of grain. Understanding and enhancing host resistance to A. flavus infection and/or subsequent aflatoxin accumulation is generally considered an efficient means of reducing grain losses to aflatoxin. Different proteomic, genomic and genetic studies of maize (Zea mays L.) have generated large data sets with the goal of identifying genes responsible for conferring resistance to A. flavus, or aflatoxin. RESULTS: In order to maximize the usage of different data sets in new studies, including association mapping, we have constructed a relational database with web interface integrating the results of gene expression, proteomic (both gel-based and shotgun), Quantitative Trait Loci (QTL) genetic mapping studies, and sequence data from the literature to facilitate selection of candidate genes for continued investigation. The Corn Fungal Resistance Associated Sequences Database (CFRAS DB) (http://agbase.msstate.edu/) was created with the main goal of identifying genes important to aflatoxin resistance. CFRAS-DB is implemented using MySQL as the relational database management system running on a Linux server, using an Apache web server, and Perl CGI scripts as the web interface. The database and the associated web-based interface allow researchers to examine many lines of evidence (e.g. microarray, proteomics, QTL studies, SNP data) to assess the potential role of a gene or group of genes in the response of different maize lines to A. flavus infection and subsequent production of aflatoxin by the fungus. CONCLUSIONS: CFRAS-DB provides the first opportunity to integrate data pertaining to the problem of A. flavus and aflatoxin resistance in maize in one resource and to support queries across different datasets. The web-based interface gives researchers different query options for mining the database across different types of experiments. The database is publically available at http://agbase.msstate.edu. PMID- 20946610 TI - Analysis of density based and fuzzy c-means clustering methods on lesion border extraction in dermoscopy images. AB - BACKGROUND: Computer-aided segmentation and border detection in dermoscopic images is one of the core components of diagnostic procedures and therapeutic interventions for skin cancer. Automated assessment tools for dermoscopy images have become an important research field mainly because of inter- and intra observer variations in human interpretation. In this study, we compare two approaches for automatic border detection in dermoscopy images: density based clustering (DBSCAN) and Fuzzy C-Means (FCM) clustering algorithms. In the first approach, if there exists enough density--greater than certain number of points- around a point, then either a new cluster is formed around the point or an existing cluster grows by including the point and its neighbors. In the second approach FCM clustering is used. This approach has the ability to assign one data point into more than one cluster. RESULTS: Each approach is examined on a set of 100 dermoscopy images whose manually drawn borders by a dermatologist are used as the ground truth. Error rates; false positives and false negatives along with true positives and true negatives are quantified by comparing results with manually determined borders from a dermatologist. The assessments obtained from both methods are quantitatively analyzed over three accuracy measures: border error, precision, and recall. CONCLUSION: As well as low border error, high precision and recall, visual outcome showed that the DBSCAN effectively delineated targeted lesion, and has bright future; however, the FCM had poor performance especially in border error metric. PMID- 20946611 TI - Constructing non-stationary Dynamic Bayesian Networks with a flexible lag choosing mechanism. AB - BACKGROUND: Dynamic Bayesian Networks (DBNs) are widely used in regulatory network structure inference with gene expression data. Current methods assumed that the underlying stochastic processes that generate the gene expression data are stationary. The assumption is not realistic in certain applications where the intrinsic regulatory networks are subject to changes for adapting to internal or external stimuli. RESULTS: In this paper we investigate a novel non-stationary DBNs method with a potential regulator detection technique and a flexible lag choosing mechanism. We apply the approach for the gene regulatory network inference on three non-stationary time series data. For the Macrophages and Arabidopsis data sets with the reference networks, our method shows better network structure prediction accuracy. For the Drosophila data set, our approach converges faster and shows a better prediction accuracy on transition times. In addition, our reconstructed regulatory networks on the Drosophila data not only share a lot of similarities with the predictions of the work of other researchers but also provide many new structural information for further investigation. CONCLUSIONS: Compared with recent proposed non-stationary DBNs methods, our approach has better structure prediction accuracy By detecting potential regulators, our method reduces the size of the search space, hence may speed up the convergence of MCMC sampling. PMID- 20946612 TI - IView: introgression library visualization and query tool. AB - BACKGROUND: An introgression library is a family of near-isogenic lines in a common genetic background, each of which carries one or more genomic regions contributed by a donor genome. Near-isogenic lines are powerful genetic resources for the analysis of phenotypic variation and are important for map-base cloning genes underlying mutations and traits. With many thousands of distinct genotypes, querying introgression libraries for lines of interest is an issue. RESULTS: We have created IView, a tool to graphically display and query near-isogenic line libraries for specific introgressions. This tool incorporates a web interface for displaying the location and extent of introgressions. Each genetic marker is associated with a position on a reference map. Users can search for introgressions using marker names, or chromosome number and map positions. This search results in a display of lines carrying an introgression at the specified position. Upon selecting one of the lines, color-coded introgressions on all chromosomes of the line are displayed graphically.The source code for IView can be downloaded from http://xrl.us/iview. CONCLUSIONS: IView will be useful for those wanting to make introgression data from their stock of germplasm searchable. PMID- 20946613 TI - GOModeler--a tool for hypothesis-testing of functional genomics datasets. AB - BACKGROUND: Functional genomics technologies that measure genome expression at a global scale are accelerating biological knowledge discovery. Generating these high throughput datasets is relatively easy compared to the downstream functional modelling necessary for elucidating the molecular mechanisms that govern the biology under investigation. A number of publicly available 'discovery-based' computational tools use the computationally amenable Gene Ontology (GO) for hypothesis generation. However, there are few tools that support hypothesis-based testing using the GO and none that support testing with user defined hypothesis terms.Here, we present GOModeler, a tool that enables researchers to conduct hypothesis-based testing of high throughput datasets using the GO. GOModeler summarizes the overall effect of a user defined gene/protein differential expression dataset on specific GO hypothesis terms selected by the user to describe a biological experiment. The design of the tool allows the user to complement the functional information in the GO with his/her domain specific expertise for comprehensive hypothesis testing. RESULTS: GOModeler tests the relevance of the hypothesis terms chosen by the user for the input gene dataset by providing the individual effects of the genes on the hypothesis terms and the overall effect of the entire dataset on each of the hypothesis terms. It matches the GO identifiers (ids) of the genes with the GO ids of the hypothesis terms and parses the names of those ids that match to assign effects. We demonstrate the capabilities of GOModeler with a dataset of nine differentially expressed cytokine genes and compare the results to those obtained through manual analysis of the dataset by an immunologist. The direction of overall effects on all hypothesis terms except one was consistent with the results obtained by manual analysis. The tool's editing capability enables the user to augment the information extracted. GOModeler is available as a part of the AgBase tool suite (http://www.agbase.msstate.edu). CONCLUSIONS: GOModeler allows hypothesis driven analysis of high throughput datasets using the GO. Using this tool, researchers can quickly evaluate the overall effect of quantitative expression changes of gene set on specific biological processes of interest. The results are provided in both tabular and graphical formats. PMID- 20946614 TI - Assessing constancy of substitution rates in viruses over evolutionary time. AB - BACKGROUND: Phylogenetic analyses reveal probable patterns of divergence of present day organisms from common ancestors. The points of divergence of lineages can be dated if a corresponding historical or fossil record exists. For many species, in particular viruses, such records are rare. Recently, Bayesian phylogenetic analysis using sequences from closely related organisms isolated at different times have been used to calibrate divergences. Phylogenetic analyses depend on the assumption that the average substitution rates that can be calculated from the data apply throughout the course of evolution. RESULTS: The present study tests this crucial assumption by charting the kinds of substitutions observed between pairs of sequences with different levels of total substitutions. Datasets of aligned sequences, both viral and non-viral, were assembled. For each pair of sequences in an aligned set, the distribution of nucleotide interchanges and the total number of changes were calculated. Data were binned according to total numbers of changes and plotted. The accumulation of the six possible interchange types in retroelements as a function of distance followed closely the expected hyperbolic relationship. For other datasets, however, significant deviations from this relationship were noted. A rapid initial accumulation of transition interchanges was frequent among the datasets and anomalous changes occurred at specific divergence levels. CONCLUSIONS: The accumulation profiles suggested that substantial changes in frequencies of types of substitutions occur over the course of evolution and that such changes should be considered in evaluating and dating viral phylogenies. PMID- 20946615 TI - An FDA bioinformatics tool for microbial genomics research on molecular characterization of bacterial foodborne pathogens using microarrays. AB - BACKGROUND: Advances in microbial genomics and bioinformatics are offering greater insights into the emergence and spread of foodborne pathogens in outbreak scenarios. The Food and Drug Administration (FDA) has developed a genomics tool, ArrayTrackTM, which provides extensive functionalities to manage, analyze, and interpret genomic data for mammalian species. ArrayTrackTM has been widely adopted by the research community and used for pharmacogenomics data review in the FDA's Voluntary Genomics Data Submission program. RESULTS: ArrayTrackTM has been extended to manage and analyze genomics data from bacterial pathogens of human, animal, and food origin. It was populated with bioinformatics data from public databases such as NCBI, Swiss-Prot, KEGG Pathway, and Gene Ontology to facilitate pathogen detection and characterization. ArrayTrackTM's data processing and visualization tools were enhanced with analysis capabilities designed specifically for microbial genomics including flag-based hierarchical clustering analysis (HCA), flag concordance heat maps, and mixed scatter plots. These specific functionalities were evaluated on data generated from a custom Affymetrix array (FDA-ECSG) previously developed within the FDA. The FDA-ECSG array represents 32 complete genomes of Escherichia coli and Shigella. The new functions were also used to analyze microarray data focusing on antimicrobial resistance genes from Salmonella isolates in a poultry production environment using a universal antimicrobial resistance microarray developed by the United States Department of Agriculture (USDA). CONCLUSION: The application of ArrayTrackTM to different microarray platforms demonstrates its utility in microbial genomics research, and thus will improve the capabilities of the FDA to rapidly identify foodborne bacteria and their genetic traits (e.g., antimicrobial resistance, virulence, etc.) during outbreak investigations. ArrayTrackTM is free to use and available to public, private, and academic researchers at http://www.fda.gov/ArrayTrack. PMID- 20946616 TI - The EDKB: an established knowledge base for endocrine disrupting chemicals. AB - BACKGROUND: Endocrine disruptors (EDs) and their broad range of potential adverse effects in humans and other animals have been a concern for nearly two decades. Many putative EDs are widely used in commercial products regulated by the Food and Drug Administration (FDA) such as food packaging materials, ingredients of cosmetics, medical and dental devices, and drugs. The Endocrine Disruptor Knowledge Base (EDKB) project was initiated in the mid 1990's by the FDA as a resource for the study of EDs. The EDKB database, a component of the project, contains data across multiple assay types for chemicals across a broad structural diversity. This paper demonstrates the utility of EDKB database, an integral part of the EDKB project, for understanding and prioritizing EDs for testing. RESULTS: The EDKB database currently contains 3,257 records of over 1,800 EDs from different assays including estrogen receptor binding, androgen receptor binding, uterotropic activity, cell proliferation, and reporter gene assays. Information for each compound such as chemical structure, assay type, potency, etc. is organized to enable efficient searching. A user-friendly interface provides rapid navigation, Boolean searches on EDs, and both spreadsheet and graphical displays for viewing results. The search engine implemented in the EDKB database enables searching by one or more of the following fields: chemical structure (including exact search and similarity search), name, molecular formula, CAS registration number, experiment source, molecular weight, etc. The data can be cross-linked to other publicly available and related databases including TOXNET, Cactus, ChemIDplus, ChemACX, Chem Finder, and NCI DTP. CONCLUSION: The EDKB database enables scientists and regulatory reviewers to quickly access ED data from multiple assays for specific or similar compounds. The data have been used to categorize chemicals according to potential risks for endocrine activity, thus providing a basis for prioritizing chemicals for more definitive but expensive testing. The EDKB database is publicly available and can be found online at http://edkb.fda.gov/webstart/edkb/index.html. PMID- 20946617 TI - Two new ArrayTrack libraries for personalized biomedical research. AB - BACKGROUND: Recent advances in high-throughput genotyping technology are paving the way for research in personalized medicine and nutrition. However, most of the genetic markers identified from association studies account for a small contribution to the total risk/benefit of the studied phenotypic trait. Testing whether the candidate genes identified by association studies are causal is critically important to the development of personalized medicine and nutrition. An efficient data mining strategy and a set of sophisticated tools are necessary to help better understand and utilize the findings from genetic association studies. DESCRIPTION: SNP (single nucleotide polymorphism) and QTL (quantitative trait locus) libraries were constructed and incorporated into ArrayTrack, with user-friendly interfaces and powerful search features. Data from several public repositories were collected in the SNP and QTL libraries and connected to other domain libraries (genes, proteins, metabolites, and pathways) in ArrayTrack. Linking the data sets within ArrayTrack allows searching of SNP and QTL data as well as their relationships to other biological molecules. The SNP library includes approximately 15 million human SNPs and their annotations, while the QTL library contains publically available QTLs identified in mouse, rat, and human. The QTL library was developed for finding the overlap between the map position of a candidate or metabolic gene and QTLs from these species. Two use cases were included to demonstrate the utility of these tools. The SNP and QTL libraries are freely available to the public through ArrayTrack at http://www.fda.gov/ArrayTrack. CONCLUSIONS: These libraries developed in ArrayTrack contain comprehensive information on SNPs and QTLs and are further cross-linked to other libraries. Connecting domain specific knowledge is a cornerstone of systems biology strategies and allows for a better understanding of the genetic and biological context of the findings from genetic association studies. PMID- 20946618 TI - PEPPI: a peptidomic database of human protein isoforms for proteomics experiments. AB - BACKGROUND: Protein isoform generation, which may derive from alternative splicing, genetic polymorphism, and posttranslational modification, is an essential source of achieving molecular diversity by eukaryotic cells. Previous studies have shown that protein isoforms play critical roles in disease diagnosis, risk assessment, sub-typing, prognosis, and treatment outcome predictions. Understanding the types, presence, and abundance of different protein isoforms in different cellular and physiological conditions is a major task in functional proteomics, and may pave ways to molecular biomarker discovery of human diseases. In tandem mass spectrometry (MS/MS) based proteomics analysis, peptide peaks with exact matches to protein sequence records in the proteomics database may be identified with mass spectrometry (MS) search software. However, due to limited annotation and poor coverage of protein isoforms in proteomics databases, high throughput protein isoform identifications, particularly those arising from alternative splicing and genetic polymorphism, have not been possible. RESULTS: Therefore, we present the PEPtidomics Protein Isoform Database (PEPPI, http://bio.informatics.iupui.edu/peppi), a comprehensive database of computationally-synthesized human peptides that can identify protein isoforms derived from either alternatively spliced mRNA transcripts or SNP variations. We collected genome, pre-mRNA alternative splicing and SNP information from Ensembl. We synthesized in silico isoform transcripts that cover all exons and theoretically possible junctions of exons and introns, as well as all their variations derived from known SNPs. With three case studies, we further demonstrated that the database can help researchers discover and characterize new protein isoform biomarkers from experimental proteomics data. CONCLUSIONS: We developed a new tool for the proteomics community to characterize protein isoforms from MS-based proteomics experiments. By cataloguing each peptide configurations in the PEPPI database, users can study genetic variations and alternative splicing events at the proteome level. They can also batch-download peptide sequences in FASTA format to search for MS/MS spectra derived from human samples. The database can help generate novel hypotheses on molecular risk factors and molecular mechanisms of complex diseases, leading to identification of potentially highly specific protein isoform biomarkers. PMID- 20946619 TI - Identification of diagnostic subnetwork markers for cancer in human protein protein interaction network. AB - BACKGROUND: Finding reliable gene markers for accurate disease classification is very challenging due to a number of reasons, including the small sample size of typical clinical data, high noise in gene expression measurements, and the heterogeneity across patients. In fact, gene markers identified in independent studies often do not coincide with each other, suggesting that many of the predicted markers may have no biological significance and may be simply artifacts of the analyzed dataset. To find more reliable and reproducible diagnostic markers, several studies proposed to analyze the gene expression data at the level of groups of functionally related genes, such as pathways. Studies have shown that pathway markers tend to be more robust and yield more accurate classification results. One practical problem of the pathway-based approach is the limited coverage of genes by currently known pathways. As a result, potentially important genes that play critical roles in cancer development may be excluded. To overcome this problem, we propose a novel method for identifying reliable subnetwork markers in a human protein-protein interaction (PPI) network. RESULTS: In this method, we overlay the gene expression data with the PPI network and look for the most discriminative linear paths that consist of discriminative genes that are highly correlated to each other. The overlapping linear paths are then optimally combined into subnetworks that can potentially serve as effective diagnostic markers. We tested our method on two independent large-scale breast cancer datasets and compared the effectiveness and reproducibility of the identified subnetwork markers with gene-based and pathway-based markers. We also compared the proposed method with an existing subnetwork-based method. CONCLUSIONS: The proposed method can efficiently find reliable subnetwork markers that outperform the gene-based and pathway-based markers in terms of discriminative power, reproducibility and classification performance. Subnetwork markers found by our method are highly enriched in common GO terms, and they can more accurately classify breast cancer metastasis compared to markers found by a previous method. PMID- 20946620 TI - Analysis of Bovine Viral Diarrhea Viruses-infected monocytes: identification of cytopathic and non-cytopathic biotype differences. AB - BACKGROUND: Bovine Viral Diarrhea Virus (BVDV) infection is widespread in cattle worldwide, causing important economic losses. Pathogenesis of the disease caused by BVDV is complex, as each BVDV strain has two biotypes: non-cytopathic (ncp) and cytopathic (cp). BVDV can cause a persistent latent infection and immune suppression if animals are infected with an ncp biotype during early gestation, followed by a subsequent infection of the cp biotype. The molecular mechanisms that underscore the complex disease etiology leading to immune suppression in cattle caused by BVDV are not well understood. RESULTS: Using proteomics, we evaluated the effect of cp and ncp BVDV infection of bovine monocytes to determine their role in viral immune suppression and uncontrolled inflammation. Proteins were isolated by differential detergent fractionation and identified by 2D-LC ESI MS/MS. We identified 137 and 228 significantly altered bovine proteins due to ncp and cp BVDV infection, respectively. Functional analysis of these proteins using the Gene Ontology (GO) showed multiple under- and over- represented GO functions in molecular function, biological process and cellular component between the two BVDV biotypes. Analysis of the top immunological pathways affected by BVDV infection revealed that pathways representing macropinocytosis signalling, virus entry via endocytic pathway, integrin signalling and primary immunodeficiency signalling were identified only in ncp BVDV-infected monocytes. In contrast, pathways like actin cytoskeleton signalling, RhoA signalling, clathrin-mediated endocytosis signalling and interferon signalling were identified only in cp BDVD-infected cells. Of the six common pathways involved in cp and ncp BVDV infection, acute phase response signalling was the most significant for both BVDV biotypes. Although, most shared altered host proteins between both BVDV biotypes showed the same type of change, integrin alpha 2b (ITGA2B) and integrin beta 3 (ITGB3) were down- regulated by ncp BVDV and up- regulated by cp BVDV infection. CONCLUSIONS: This study shows that, as we expected, there are significant functional differences in the host proteins that respond to cp or ncp BVDV infection. The combined use of GO and systems biology network modelling facilitated a better understanding of host pathogen interactions. PMID- 20946621 TI - Efficacy of a multimodal physiotherapy treatment program for hip osteoarthritis: a randomised placebo-controlled trial protocol. AB - BACKGROUND: Hip osteoarthritis (OA) is a common condition leading to pain, disability and reduced quality of life. There is currently limited evidence to support the use of conservative, non-pharmacological treatments for hip OA. Exercise and manual therapy have both shown promise and are typically used together by physiotherapists to manage painful hip OA. The aim of this randomised controlled trial is to compare the efficacy of a physiotherapy treatment program with placebo treatment in reducing pain and improving physical function. METHODS: The trial will be conducted at the University of Melbourne Centre for Health, Exercise and Sports Medicine. 128 participants with hip pain greater or equal to 40/100 on visual analogue scale (VAS) and evidence of OA on x-ray will be recruited. Treatment will be provided by eight community physiotherapists in the Melbourne metropolitan region. The active physiotherapy treatment will comprise a semi-structured program of manual therapy and exercise plus education and advice. The placebo treatment will consist of sham ultrasound and the application of non therapeutic gel. The participants and the study assessor will be blinded to the treatment allocation. Primary outcomes will be pain measured by VAS and physical function recorded on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) immediately after the 12 week intervention. Participants will also be followed up at 36 weeks post baseline. CONCLUSIONS: The trial design has important strengths of reproducibility and reflecting contemporary physiotherapy practice. The findings from this randomised trial will provide evidence for the efficacy of a physiotherapy program for painful hip OA. PMID- 20946622 TI - Curcumin supplementation could improve diabetes-induced endothelial dysfunction associated with decreased vascular superoxide production and PKC inhibition. AB - BACKGROUND: Curcumin, an Asian spice and food-coloring agent, is known for its anti-oxidant properties. We propose that curcumin can improve diabetes-induced endothelial dysfunction through superoxide reduction. METHODS: Diabetes (DM) was induced in rats by streptozotocin (STZ). Daily curcumin oral feeding was started six weeks after the STZ injection. Twelve weeks after STZ injection, mesenteric arteriolar responses were recorded in real time using intravital fluorescence videomicroscopy. Superoxide and vascular protein kinase C (PKC-betaII) were examined by hydroethidine and immunofluorescence, respectively. RESULTS: The dilatory response to acetylcholine (ACh) significantly decreased in DM arterioles as compared to control arterioles. There was no difference among groups when sodium nitroprusside (SNP) was used. ACh responses were significantly improved by both low and high doses (30 and 300 mg/kg, respectively) of curcumin supplementation. An oxygen radical-sensitive fluorescent probe, hydroethidine, was used to detect intracellular superoxide anion (O2?-) production. O2?- production was markedly increased in DM arterioles, but it was significantly reduced by supplementation of either low or high doses of curcumin. In addition, with a high dose of curcumin, diabetes-induced vascular PKC-betaII expression was diminished. CONCLUSION: Therefore, it is suggested that curcumin supplementation could improve diabetes-induced endothelial dysfunction significantly in relation to its potential to decrease superoxide production and PKC inhibition. PMID- 20946623 TI - Changing trends in intestinal parasitic infections among long-term-residents and settled immigrants in Qatar. AB - BACKGROUND: The rapid socio-economic development in Qatar in the last two decades has encouraged a mass influx of immigrant workers, the majority of whom originate from countries with low socio-economic levels, inadequate medical care and many are known to carry patent intestinal helminth and protozoan infections on arrival in Qatar. Some eventually acquire residency status but little is known about whether they continue to harbour infections. METHODS: We examined 9208 hospital records of stool samples that had been analysed for the presence of intestinal helminth and protozoan ova/cysts, over the period 2005-2008, of subjects from 28 nationalities, but resident in Qatar and therefore not recent arrivals in the country. RESULTS: Overall 10.2% of subjects were infected with at least one species, 2.6% with helminths and 8.0% with protozoan species. Although hookworms, Ascaris lumbricoides, Trichuris trichiura and Hymenolepis nana were observed, the majority of helminth infections (69%) were caused by hookworms, and these were largely aggregated among 20.0-39.9 year-old male subjects from Nepal. The remaining cases of helminth infection were mostly among Asian immigrants. Protozoan infections were more uniformly spread across immigrants from different regions when prevalence was calculated on combined data, but this disguised three quite contrasting underlying patterns for 3 taxa of intestinal protozoa. Blastocystis hominis, Giardia duodenalis and non-pathogenic amoebae were all acquired in childhood, but whereas prevalence of B. hominis rose to a plateau and then even further among the elderly, prevalence of G. duodenalis fell markedly in children aged 10 and older, and stayed low (< 2%) gradually falling even further in the elderly. In contrast the prevalence of non-pathogenic amoebae (Entamoeba coli, E. hartmanni, Endolimax nana and Iodamoeba buetschlii) peaked in the 30.0 39.9 age group and only then dropped to very low values among the oldest subjects examined. A worrying trend in respect of both helminth and protozoan parasites was the increase in prevalence over the period 2005-2008, in helminth infections prevalence increasing 2-3 fold by 2008, and in protozoan infections by 1.5-2.0 fold. CONCLUSIONS: We suggest that helminth infections are probably acquired abroad when immigrants visit their home villages, whilst protozoan infections are reinforced by transmission in Qatar, possibly in the poorer areas of the state where immigrant workers live. We discuss the significance of these findings and emphasize that they have clear implications for the health authorities. PMID- 20946624 TI - Development and evaluation of an immunochromatographic strip test based on the recombinant UL51 protein for detecting antibody against duck enteritis virus. AB - BACKGROUND: Duck enteritis virus (DEV) infection causes substantial economic losses to the worldwide duck-producing areas. The monitoring of DEV-specific antibodies is a key to evaluate the effect of DEV vaccine and develop rational immunization programs. Thus, in this study, an immunochromatographic strip (ICS) test was developed for detecting DEV serum antibodies. RESULTS: The ICS test is based on membrane chromatography, and uses both the purified recombinant UL51 protein conjugated with colloidal gold and goat anti-rabbit IgG conjugated with colloidal gold as tracers, the purified recombinant UL51 protein as the capture reagent at the test line, and rabbit IgG as the capture reagent at the control line. The specificity of the ICS was evaluated by sera against DEV, Duck hepatitis virus (DHV), Riemerella anatipestifer (RA), Duck E. coli, Muscovy duck parvovirus (MPV), or Duck Influenza viruses (DIV). Only sera against DEV showed the strong positive results. In order to determine the sensitivity of the ICS, anti-DEV serum diluted serially was tested, and the minimum detection limit of 1:128 was obtained. The ICS components, which are provided in a sealed package, require no refrigeration and are stable for 12 months. To evaluate the effect of the ICS, 110 duck serum samples collected from several non-immune duck flocks were simultaneously tested by the ICS test, enzyme-linked immunosorbent assay (ELISA) and neutralization test (NT). The results showed that the sensitivity of the ICS test was almost consistent with ELISA and much higher than NT, has low cost, and is rapid (15 min) and easy to perform with no requirement of specialized equipment, reagent or technicians. CONCLUSIONS: In this work, we successfully developed a simple and rapid ICS test for detecting DEV serum antibodies for the first time. The ICS test was high specific and sensitive for the rapid detection of anti-DEV antibodies, and has great potential to be used for the serological surveillance of DEV infection in the field. PMID- 20946625 TI - Decreased Toll-like receptor 8 expression and lower TNF-alpha synthesis in infants with acute RSV infection. AB - BACKGROUND: Toll-like receptors (TLRs) are part of the innate immune system, able to recognize pathogen-associated molecular patterns and activate immune system upon pathogen challenge. Respiratory syncytial virus (RSV) is a RNA virus particularly detrimental in infancy. It could cause severe lower respiratory tract disease and recurrent infections related to inadequate development of anti viral immunity. The reason could be inadequate multiple TLRs engagement, including TLR8 in recognition of single-stranded viral RNA and diminished synthesis of inflammatory mediators due to a lower expression. METHODS: Intracellular TLR8 expression in peripheral blood monocytes from RSV-infected infants was profiled and compared to healthy adults and age matched controls. Whether the observed difference in TLR8 expression is a transitory effect, infants in convalescent phase (4-6 weeks later) were retested. Specific TLR8 mediated TNF-alpha production in monocytes during an acute and convalescent phase was analyzed. RESULTS: RSV-infected and healthy infants had lower percentage of TLR8-expressing monocytes than healthy adults whereas decreased of TLR8 protein levels were detected only for RSV-infected infant group. Lower protein levels of TLR8 in monocytes from RSV-infected infants, compared to healthy infants, negatively correlated with respiratory frequency and resulted in lower TNF-alpha synthesis upon a specific TLR8 stimulation. In the convalescent phase, levels of TLR8 increased, accompanied by increased TNF-alpha synthesis compared to acute infection. CONCLUSIONS: Lower TLR8 expression observed in monocytes, during an acute RSV infection, might have a dampening impact on early anti-viral cytokine production necessary to control RSV replication, and subsequently initiate an adaptive Th1 type immune response leading to severe disease in infected infants. PMID- 20946626 TI - Dent's disease. AB - Dent's disease is a renal tubular disorder characterized by manifestations of proximal tubule dysfunction, including low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. These features are generally found in males only, and may be present in early childhood, whereas female carriers may show a milder phenotype. Prevalence is unknown; the disorder has been reported in around 250 families to date. Complications such as rickets or osteomalacia may occur. The disease is caused by mutations in either the CLCN5 (Dent disease 1) or OCRL1 (Dent disease 2) genes that are located on chromosome Xp11.22 and Xq25, respectively. CLCN5 encodes the electrogenic Cl-/H(+) exchanger ClC-5, which belongs to the CLC family of Cl- channels/transporters. OCRL1 encodes a phosphatidylinositol bisphosphate (PIP2) 5 phosphatase and mutations are also associated with Lowe Syndrome. The phenotype of Dent's disease is explained by the predominant expression of ClC-5 in the proximal tubule segments of the kidney. No genotype-phenotype correlation has been described thus far, and there is considerable intra-familial variability in disease severity. A few patients with Dent's disease do not harbour mutations in CLCN5 and OCRL1, pointing to the involvement of other genes. Diagnosis is based on the presence of all three of the following criteria: low-molecular-weight proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, kidney stones, hematuria, hypophosphatemia or renal insufficiency. Molecular genetic testing confirms the diagnosis. The differential diagnosis includes other causes of generalized dysfunction of the proximal tubules (renal Fanconi syndrome), hereditary, acquired, or caused by exogenous substances. Antenatal diagnosis and pre-implantation genetic testing is not advised. The care of patients with Dent's disease is supportive, focusing on the treatment of hypercalciuria and the prevention of nephrolithiasis. The vital prognosis is good in the majority of patients. Progression to end-stage renal failure occurs between the 3rd and 5th decades of life in 30-80% of affected males. PMID- 20946627 TI - Anti-HIV-1 activity of salivary MUC5B and MUC7 mucins from HIV patients with different CD4 counts. AB - BACKGROUND: We have previously shown that MUC5B and MUC7 mucins from saliva of HIV negative individuals inhibit HIV-1 activity by 100% in an in vitro assay. The purpose of this subsequent study was to investigate whether MUC5B and MUC7 from saliva of HIV patients or with full blown AIDS had a similar inhibitory activity against the virus. METHODS: Salivary MUC5B and MUC7 from HIV patients with different CD4 counts (< 200, 200-400 and > 400) were incubated with HIV-1 prior to infection of the human T lymphoblastoid cell line (CEM SS cells). Cells were then cultured and viral replication was measured by a qualitative p24 antigen assay. The size, charge and immunoreactivity of mucins from HIV negative and positive individuals was also analysed by SDS-PAGE, Western blot and ELISA respectively. RESULTS: It was shown that irrespective of their CD4 counts both MUC5B and MUC7 from HIV patients, unlike the MUC5B and MUC7 from HIV negative individuals, did not inhibit HIV-1 activity. Size, charge and immunoreactivity differences between the mucins from HIV negative and positive individuals and among the mucins from HIV patients of different CD4 count was observed by SDS PAGE, Western blot and ELISA. CONCLUSIONS: Purified salivary mucins from HIV positive patients do not inhibit the AIDS virus in an in vitro assay. Although the reason for the inability of mucins from infected individuals to inhibit the virus is not known, it is likely that there is an alteration of the glycosylation pattern, and therefore of charge of mucin, in HIV positive patients. The ability to inhibit the virus by aggregation by sugar chains is thus diminished. PMID- 20946628 TI - The utility of clinical care pathways in determining perinatal outcomes for women with one previous caesarean section; a retrospective service evaluation. AB - BACKGROUND: The rising rates of primary caesarean section have resulted in a larger obstetric population with scarred uteri. Subsequent pregnancies in these women are risk-prone and may complicate. Besides ensuring standardised management, care pathways could be used to evaluate for perinatal outcomes in these high risk pregnancies. We aim to demonstrate the use of a care pathway for vaginal birth after caesarean section as a service evaluation tool to determine perinatal outcomes. METHODS: A retrospective service evaluation by review of delivery case notes and records was undertaken at the Aga Khan University Hospital, Nairobi, Kenya between January 2008 and December 2009. Women with >=2 previous caesarean sections, previous classical caesarean section, multiple gestation, breech presentation, severe pre-eclampsia, transverse lie, placenta praevia, conditions requiring induction of labour and incomplete records were excluded. Outcome measures included the proportion of eligible women who opted for test of scar (ToS), success rate of vaginal birth after caesarean section (VBAC); proportion on women opting for elective repeat caesarean section (ERCS) and their perinatal outcomes. RESULTS: A total of 215 women with one previous caesarean section were followed up using a standard care pathway. The median parity (minimum-maximum) was 1.01234. The other demographic characteristics were comparable. Only 44.6% of eligible mothers opted to have a ToS. The success rate for VBAC was 49.4% with the commonest (31.8%) reason for failure being protracted active phase of labour. Maternal morbidity was comparable for the failed and successful VBAC group. The incidence of hemorrhage was 2.3% and 4.4% for the successful and failed VBAC groups respectively. The proportion of babies with acidotic arterial PH (< 7.10) was 3.1% and 22.2% among the successful and failed VBAC groups respectively. No perinatal mortality was reported. CONCLUSIONS: Besides ensuring standardised management, care pathways could be objective audit and service evaluation tools for determining perinatal outcomes. PMID- 20946629 TI - Spermine oxidase (SMO) activity in breast tumor tissues and biochemical analysis of the anticancer spermine analogues BENSpm and CPENSpm. AB - BACKGROUND: Polyamine metabolism has a critical role in cell death and proliferation representing a potential target for intervention in breast cancer (BC). This study investigates the expression of spermine oxidase (SMO) and its prognostic significance in BC. Biochemical analysis of Spm analogues BENSpm and CPENSpm, utilized in anticancer therapy, was also carried out to test their property in silico and in vitro on the recombinant SMO enzyme. METHODS: BC tissue samples were analyzed for SMO transcript level and SMO activity. Student's t test was applied to evaluate the significance of the differences in value observed in T and NT samples. The structure modeling analysis of BENSpm and CPENSpm complexes formed with the SMO enzyme and their inhibitory activity, assayed by in vitro experiments, were examined. RESULTS: Both the expression level of SMO mRNA and SMO enzyme activity were significantly lower in BC samples compared to NT samples. The modeling of BENSpm and CPENSpm complexes formed with SMO and their inhibition properties showed that both were good inhibitors. CONCLUSIONS: This study shows that underexpression of SMO is a negative marker in BC. The SMO induction is a remarkable chemotherapeutical target. The BENSpm and CPENSpm are efficient SMO inhibitors. The inhibition properties shown by these analogues could explain their poor positive outcomes in Phases I and II of clinical trials. PMID- 20946630 TI - 17-allyamino-17-demethoxygeldanamycin treatment results in a magnetic resonance spectroscopy-detectable elevation in choline-containing metabolites associated with increased expression of choline transporter SLC44A1 and phospholipase A2. AB - INTRODUCTION: 17-allyamino-17-demethoxygeldanamycin (17-AAG), a small molecule inhibitor of Hsp90, is currently in clinical trials in breast cancer. However, 17 AAG treatment often results in inhibition of tumor growth rather than shrinkage, making detection of response a challenge. Magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) are noninvasive imaging methods than can be used to monitor metabolic biomarkers of drug-target modulation. This study set out to examine the MRS-detectable metabolic consequences of Hsp90 inhibition in a breast cancer model. METHODS: MCF-7 breast cancer cells were investigated, and MRS studies were performed both on live cells and on cell extracts. (31)P and (1)H MRS were used to determine total cellular metabolite concentrations and (13)C MRS was used to probe the metabolism of [1,2-(13)C]-choline. To explain the MRS metabolic findings, microarray and RT-PCR were used to analyze gene expression, and in vitro activity assays were performed to determine changes in enzymatic activity following 17-AAG treatment. RESULTS: Treatment of MCF-7 cells with 17 AAG for 48 hours caused a significant increase in intracellular levels of choline (to 266 +/- 18% of control, P = 0.05) and phosphocholine (PC; to 181 +/- 10% of control, P = 0.001) associated with an increase in expression of choline transporter SLC44A1 and an elevation in the de novo synthesis of PC. We also detected an increase in intracellular levels of glycerophosphocholine (GPC; to 176 +/- 38% of control, P = 0.03) associated with an increase in PLA2 expression and activity. CONCLUSIONS: This study determined that in the MCF-7 breast cancer model inhibition of Hsp90 by 17-AAG results in a significant MRS-detectable increase in choline, PC and GPC, which is likely due to an increase in choline transport into the cell and phospholipase activation. (1)H MRSI can be used in the clinical setting to detect levels of total choline-containing metabolite (t Cho, composed of intracellular choline, PC and GPC). As Hsp90 inhibitors enter routine clinical use, t-Cho could thus provide an easily detectable, noninvasive metabolic biomarker of Hsp90 inhibition in breast cancer patients. PMID- 20946631 TI - Open lung approach associated with high-frequency oscillatory or low tidal volume mechanical ventilation improves respiratory function and minimizes lung injury in healthy and injured rats. AB - INTRODUCTION: To test the hypothesis that open lung (OL) ventilatory strategies using high-frequency oscillatory ventilation (HFOV) or controlled mechanical ventilation (CMV) compared to CMV with lower positive end-expiratory pressure (PEEP) improve respiratory function while minimizing lung injury as well as systemic inflammation, a prospective randomized study was performed at a university animal laboratory using three different lung conditions. METHODS: Seventy-eight adult male Wistar rats were randomly assigned to three groups: (1) uninjured (UI), (2) saline washout (SW), and (3) intraperitoneal/intravenous Escherichia coli lipopolysaccharide (LPS)-induced lung injury. Within each group, animals were further randomized to (1) OL with HFOV, (2) OL with CMV with "best" PEEP set according to the minimal static elastance of the respiratory system (BP CMV), and (3) CMV with low PEEP (LP-CMV). They were then ventilated for 6 hours. HFOV was set with mean airway pressure (PmeanHFOV) at 2 cm H2O above the mean airway pressure recorded at BP-CMV (PmeanBP-CMV) following a recruitment manoeuvre. Six animals served as unventilated controls (C). Gas-exchange, respiratory system mechanics, lung histology, plasma cytokines, as well as cytokines and types I and III procollagen (PCI and PCIII) mRNA expression in lung tissue were measured. RESULTS: We found that (1) in both SW and LPS, HFOV and BP CMV improved gas exchange and mechanics with lower lung injury compared to LP CMV, (2) in SW; HFOV yielded better oxygenation than BP-CMV; (3) in SW, interleukin (IL)-6 mRNA expression was lower during BP-CMV and HFOV compared to LP-CMV, while in LPS inflammatory response was independent of the ventilatory mode; and (4) PCIII mRNA expression decreased in all groups and ventilatory modes, with the decrease being highest in LPS. CONCLUSIONS: Open lung ventilatory strategies associated with HFOV or BP-CMV improved respiratory function and minimized lung injury compared to LP-CMV. Therefore, HFOV with PmeanHFOV set 2 cm H2O above the PmeanBP-CMV following a recruitment manoeuvre is as beneficial as BP-CMV. PMID- 20946632 TI - Dramatic and sustained increase in HIV-testing rates among antenatal attendees in Eastern Uganda after a policy change from voluntary counselling and testing to routine counselling and testing for HIV: a retrospective analysis of hospital records, 2002-2009. AB - BACKGROUND: The burden of mother-to-child transmission of HIV in Uganda is high. The aim of this paper is to describe the experience of the first 7 years of the prevention of mother- to- child transmission of HIV (PMTCT) programme in Mbale Regional Hospital, Eastern Uganda, with particular reference to the lessons learnt in changing from voluntary counselling and testing (VCT) to routine counselling and testing (RCT) for HIV testing in antenatal services. METHODS: The study was a retrospective analysis of the PMTCT records of Mbale Regional Referral Hospital, Uganda, from May 2002 to April 2009. The data on HIV testing of pregnant women and their male partners was extracted from the reports and registers using a standardized data extraction form, and data was analysed using descriptive statistics. Permission to conduct the study was obtained from School of Medicine, Makerere University College of Health Sciences; Uganda National Council of Science and Technology, and Mbale Hospital. RESULTS: A total of 54 429 new antenatal (ANC) attendees and 469 male-partners accessed antenatal services at Mbale Regional Referral Hospital. There was a sustained, significant increase in HIV testing among new ANC attendees from 22% during the VCT period to 88% during the RCT period (p = 0.002), while among male partners, HIV testing increased from 88% to 100% (p = 0.010) However, the overall number of male partners who tested for HIV remained very low despite the change from VCT to RCT approach in HIV testing. CONCLUSIONS: Routine offer of antenatal HIV testing dramatically increased HIV testing in pregnant women and their partners in Uganda. Our findings call for further strengthening of the policy for routine HIV testing in antenatal clinics. Our study also showed that male partner HIV testing in antenatal clinics is low and this area needs further work through research and innovative interventions in order to improve male partner involvement. PMID- 20946633 TI - Association between intratumoral lymphatic microvessel density (LMVD) and clinicopathologic features in endometrial cancer: a retrospective cohort study. AB - BACKGROUND: Lymph node metastasis in endometrial cancer significantly decreases survival rate. Few data on the influence of intratumoral lymphatic microvessel density (LMVD) on survival in endometrial cancer are available. Our aim was to assess the intratumoral LMVD of endometrial carcinomas and to investigate its association with classical pathological factors, lymph node metastasis and survival. METHODS: Fifty-seven patients with endometrial carcinoma diagnosed between 2000 and 2008 underwent complete surgical staging and evaluation of intratumoral LMVD and other histologic variables. Lymphatic microvessels were identified by immunohistochemical staining using monoclonal antibody against human podoplanin (clone D2-40) and evaluated by counting the number of immunostained lymphatic vessels in 10 hot spot areas at 400* magnification. The LMVD was expressed by the mean number of vessels in these 10 hot spot microscopic fields. We next investigated the association of LMVD with the clinicopathologic findings and prognosis. RESULTS: The mean number of lymphatic vessels counted in all cases ranged between 0 and 4.7. The median value of mean LMVD was 0.5, and defined the cut-off for low and high LMVD. We identified low intratumoral LMVD in 27 (47.4%) patients and high LMVD in 30 (52.6%) patients. High intratumoral LMVD was associated with lesser miometrial and adnaexal infiltration, lesser cervical and peritoneal involvement, and fewer fatal cases. Although there was lower lymph node involvement among cases with high LMVD, the difference did not reach significance. No association was seen between LMVD and FIGO staging, histological type, or vascular invasion. On the other hand, low intratumoral LMVD was associated with poor outcome. Seventy-five percent of deaths occurred in patients with low intratumoral LMVD. CONCLUSION: Our results show association of high intratumoral LMVD with features related to more localized disease and better outcome. We discuss the role of lymphangiogenesis as an early event in the endometrial carcinogenesis. PMID- 20946634 TI - The reduction of intoxication and disorder in premises licensed to serve alcohol: an exploratory randomised controlled trial. AB - BACKGROUND: Licensed premises offer a valuable point of intervention to reduce alcohol-related harm. OBJECTIVE: To describe the research design for an exploratory trial examining the feasibility and acceptability of a premises-level intervention designed to reduce severe intoxication and related disorder. The study also aims to assess the feasibility of a potential future large scale effectiveness trial and provide information on key trial design parameters including inclusion criteria, premises recruitment methods, strategies to implement the intervention and trial design, outcome measures, data collection methods and intra-cluster correlations. DESIGN: A randomised controlled trial in licensed premises that had experienced at least one assault in the year preceding the intervention, documented in police or hospital Emergency Department (ED) records. Premises were recruited from four study areas by piloting four recruitment strategies of varying intensity. Thirty two licensed premises were grouped into matched pairs to reduce potential bias and randomly allocated to the control or intervention condition. The study included a nested process evaluation to provide information on intervention acceptability and implementation. Outcome measures included police-recorded violent incidents, assault-related attendances at each premises' local ED and patron Breath Alcohol Concentration assessed on exiting and entering study premises. RESULTS: The most successful recruitment method involved local police licensing officers and yielded a 100% success rate. Police-records of violence provided the most appropriate source of data about disorder at the premises level. CONCLUSION: The methodology of an exploratory trial is presented and despite challenges presented by the study environment it is argued an exploratory trial is warranted. Initial investigations in recruitment methods suggest that study premises should be recruited with the assistance of police officers. Police data were of sufficient quality to identify disorder and street surveys are a feasible method for measuring intoxication at the individual level. TRIAL REGISTRATION: UKCRN 7090; ISRCTN: 80875696. FUNDING: Medical Research Council (G0701758) to Simon Moore, Simon Murphy, Laurence Moore and Jonathan Shepherd. PMID- 20946636 TI - Variation in mode of physical activity by ethnicity and time since immigration: a cross-sectional analysis. AB - BACKGROUND: Physical activity (PA) levels are known to be significantly lower in ethnic minority and immigrant groups living in North America and Europe compared to the general population. While there has been an increase in the number of interventions targeting these groups, little is known about their preferred modes of PA. METHODS: Using three cycles of the Canadian Community Health Survey (cycles 1.1, 2.1, 3.1; 2000-2005, n = 400,055) this investigation determined PA preferences by self-ascribed ethnicity (White, South Asian, South-East Asian, Blacks, Latin American, West Asian, Aboriginal persons and Other) and explored variation in PA preference across time since immigration categories (non immigrant, established immigrant [> 10 years], and recent immigrant [<= 10 years]). PA preferences over the past three months were collapsed into eight categories: walking, endurance, recreation, sports, conventional exercise, active commuting, and no PA. Logistic regression models were used to estimate the odds of participating in each PA across ethnicity and time since immigration compared to Whites and non-immigrants, respectively. RESULTS: Compared to Whites, all other ethnic groups were more likely to report no PA and were less likely to engage in walking, with the exception of Aboriginal persons (OR: 1.25, CI: 1.16 1.34). Further, all ethnic groups including Aboriginal persons were less likely to engage in endurance, recreation, and sport activities, but more likely to have an active commute compared to Whites. Recent and established immigrants were more likely to have an active commute and no PA, but a lower likelihood of walking, sports, endurance, and recreation activities than non-immigrants. CONCLUSION: Ethnic minority groups and immigrants in Canada tend to participate in conventional forms of exercise compared to Whites and non-immigrants and are less likely to engage in endurance exercise, recreation activities, and sports. Health promotion initiatives targeting ethnic and immigrant groups at high-risk for physical inactivity and chronic disease should consider mode of PA preference in intervention development. PMID- 20946635 TI - Global transcript profiling of transgenic plants constitutively overexpressing the RNA-binding protein AtGRP7. AB - BACKGROUND: The clock-controlled RNA-binding protein AtGRP7 influences circadian oscillations of its own transcript at the post-transcriptional level. To identify additional targets that are regulated by AtGRP7, transcript profiles of transgenic plants constitutively overexpressing AtGRP7 (AtGRP7-ox) and wild type plants were compared. RESULTS: Approximately 1.4% of the transcripts represented on the Affymetrix ATH1 microarray showed changes in steady-state abundance upon AtGRP7 overexpression. One third of the differentially expressed genes are controlled by the circadian clock, and they show a distinct bias of their phase: The up-regulated genes preferentially peak around dawn, roughly opposite to the AtGRP7 peak abundance whereas the down-regulated genes preferentially peak at the end of the day. Further, transcripts responsive to abiotic and biotic stimuli were enriched among AtGRP7 targets. Transcripts encoding the pathogenesis-related PR1 and PR2 proteins were elevated in AtGRP7-ox plants but not in plants overexpressing AtGRP7 with a point mutation in the RNA-binding domain, indicating that the regulation involves RNA binding activity of AtGRP7. Gene set enrichment analysis uncovered components involved in ribosome function and RNA metabolism among groups of genes upregulated in AtGRP7-ox plants, consistent with its role in post-transcriptional regulation. CONCLUSION: Apart from regulating a suite of circadian transcripts in a time-of-day dependent manner AtGRP7, both directly and indirectly, affects other transcripts including transcripts responsive to abiotic and biotic stimuli. This suggests a regulatory role of AtGRP7 in the output of the endogenous clock and a complex network of transcripts responsive to external stimuli downstream of the AtGRP7 autoregulatory circuit. PMID- 20946637 TI - Data structures and compression algorithms for high-throughput sequencing technologies. AB - BACKGROUND: High-throughput sequencing (HTS) technologies play important roles in the life sciences by allowing the rapid parallel sequencing of very large numbers of relatively short nucleotide sequences, in applications ranging from genome sequencing and resequencing to digital microarrays and ChIP-Seq experiments. As experiments scale up, HTS technologies create new bioinformatics challenges for the storage and sharing of HTS data. RESULTS: We develop data structures and compression algorithms for HTS data. A processing stage maps short sequences to a reference genome or a large table of sequences. Then the integers representing the short sequence absolute or relative addresses, their length, and the substitutions they may contain are compressed and stored using various entropy coding algorithms, including both old and new fixed codes (e.g Golomb, Elias Gamma, MOV) and variable codes (e.g. Huffman). The general methodology is illustrated and applied to several HTS data sets. Results show that the information contained in HTS files can be compressed by a factor of 10 or more, depending on the statistical properties of the data sets and various other choices and constraints. Our algorithms fair well against general purpose compression programs such as gzip, bzip2 and 7zip; timing results show that our algorithms are consistently faster than the best general purpose compression programs. CONCLUSIONS: It is not likely that exactly one encoding strategy will be optimal for all types of HTS data. Different experimental conditions are going to generate various data distributions whereby one encoding strategy can be more effective than another. We have implemented some of our encoding algorithms into the software package GenCompress which is available upon request from the authors. With the advent of HTS technology and increasingly new experimental protocols for using the technology, sequence databases are expected to continue rising in size. The methodology we have proposed is general, and these advanced compression techniques should allow researchers to manage and share their HTS data in a more timely fashion. PMID- 20946639 TI - PCR and serology find no association between xenotropic murine leukemia virus related virus (XMRV) and autism. AB - Xenotropic murine leukemia virus-related virus (XMRV) is a retrovirus implicated in prostate cancer and chronic fatigue syndrome (CFS). Press releases have suggested that it could contribute to autism spectrum disorder (ASD). In this study we used two PCR assays and one antibody assay to screen 25 blood samples from autistic children born to mothers with CFS and from 20 mixed controls including family members of the children assayed, people with fibromyalgia and people with chronic Lyme disease. Using a real-time PCR assay, we screened an additional 48 South Carolina autism disorder samples, 96 Italian ASD samples, 61 South Carolina ASD samples and 184 healthy controls. Despite having the ability to detect low copy number XMRV DNA in a large background of cellular DNA, none of the PCR assays found any evidence of XMRV infection in blood cells from patients or controls. Further, no anti-XMRV antibodies were detected, ruling out possible low level or abortive infections in blood or in other reservoirs. These results imply that XMRV is not associated with autism. PMID- 20946638 TI - Exercise counteracts fatty liver disease in rats fed on fructose-rich diet. AB - BACKGROUND: This study aimed to analyze the effects of exercise at the aerobic/anaerobic transition on the markers of non-alcoholic fatty liver disease (NAFLD), insulin sensitivity and the blood chemistry of rats kept on a fructose rich diet. METHODS: We separated 48 Wistar rats into two groups according to diet: a control group (balanced diet AIN-93 G) and a fructose-rich diet group (60% fructose). The animals were tested for maximal lactate-steady state (MLSS) in order to identify the aerobic/anaerobic metabolic transition during swimming exercises at 28 and 90 days of age. One third of the animals of each group were submitted to swimming training at an intensity equivalent to the individual MLSS for 1 hours/day, 5 days/week from 28 to 120 days (early protocol). Another third were submitted to the training from 90 to 120 days (late protocol), and the others remained sedentary. The main assays performed included an insulin tolerance test (ITT) and tests of serum alanine aminotransferase [ALT] and aspartate aminotransferase [AST] activities, serum triglyceride concentrations [TG] and liver total lipid concentrations. RESULTS: The fructose-fed rats showed decreased insulin sensitivity, and the late-exercise training protocol counteracted this alteration. There was no difference between the groups in levels of serum ALT, whereas AST and liver lipids increased in the fructose-fed sedentary group when compared with the other groups. Serum triglycerides concentrations were higher in the fructose-fed trained groups when compared with the corresponding control group. CONCLUSIONS: The late-training protocol was effective in restoring insulin sensitivity to acceptable standards. Considering the markers here evaluated, both training protocols were successful in preventing the emergence of non-alcoholic fatty liver status disease. PMID- 20946640 TI - Reduction of freezing of gait in Parkinson's disease by repetitive robot-assisted treadmill training: a pilot study. AB - BACKGROUND: Parkinson's disease is a chronic, neurodegenerative disease characterized by gait abnormalities. Freezing of gait (FOG), an episodic inability to generate effective stepping, is reported as one of the most disabling and distressing parkinsonian symptoms. While there are no specific therapies to treat FOG, some external physical cues may alleviate these types of motor disruptions. The purpose of this study was to examine the potential effect of continuous physical cueing using robot-assisted sensorimotor gait training on reducing FOG episodes and improving gait. METHODS: Four individuals with Parkinson's disease and FOG symptoms received ten 30-minute sessions of robot assisted gait training (Lokomat) to facilitate repetitive, rhythmic, and alternating bilateral lower extremity movements. Outcomes included the FOG Questionnaire, a clinician-rated video FOG score, spatiotemporal measures of gait, and the Parkinson's Disease Questionnaire-39 quality of life measure. RESULTS: All participants showed a reduction in FOG both by self-report and clinician-rated scoring upon completion of training. Improvements were also observed in gait velocity, stride length, rhythmicity, and coordination. CONCLUSIONS: This pilot study suggests that robot-assisted gait training may be a feasible and effective method of reducing FOG and improving gait. Videotaped scoring of FOG has the potential advantage of providing additional data to complement FOG self-report. PMID- 20946641 TI - Expression proteomics of UPF1 knockdown in HeLa cells reveals autoregulation of hnRNP A2/B1 mediated by alternative splicing resulting in nonsense-mediated mRNA decay. AB - BACKGROUND: In addition to acting as an RNA quality control pathway, nonsense mediated mRNA decay (NMD) plays roles in regulating normal gene expression. In particular, the extent to which alternative splicing is coupled to NMD and the roles of NMD in regulating uORF containing transcripts have been a matter of debate. RESULTS: In order to achieve a greater understanding of NMD regulated gene expression we used 2D-DiGE proteomics technology to examine the changes in protein expression induced in HeLa cells by UPF1 knockdown. QPCR based validation of the corresponding mRNAs, in response to both UPF1 knockdown and cycloheximide treatment, identified 17 bona fide NMD targets. Most of these were associated with bioinformatically predicted NMD activating features, predominantly upstream open reading frames (uORFs). Strikingly, however, the majority of transcripts up regulated by UPF1 knockdown were either insensitive to, or even down-regulated by, cycloheximide treatment. Furthermore, the mRNA abundance of several down regulated proteins failed to change upon UPF1 knockdown, indicating that UPF1's role in regulating mRNA and protein abundance is more complex than previously appreciated. Among the bona fide NMD targets, we identified a highly conserved AS NMD event within the 3' UTR of the HNRNPA2B1 gene. Overexpression of GFP tagged hnRNP A2 resulted in a decrease in endogenous hnRNP A2 and B1 mRNA with a concurrent increase in the NMD sensitive isoforms. CONCLUSIONS: Despite the large number of changes in protein expression upon UPF1 knockdown, a relatively small fraction of them can be directly attributed to the action of NMD on the corresponding mRNA. From amongst these we have identified a conserved AS-NMD event within HNRNPA2B1 that appears to mediate autoregulation of HNRNPA2B1 expression levels. PMID- 20946642 TI - Comparative analysis of acute and chronic corticosteroid pharmacogenomic effects in rat liver: transcriptional dynamics and regulatory structures. AB - BACKGROUND: Comprehensively understanding corticosteroid pharmacogenomic effects is an essential step towards an insight into the underlying molecular mechanisms for both beneficial and detrimental clinical effects. Nevertheless, even in a single tissue different methods of corticosteroid administration can induce different patterns of expression and regulatory control structures. Therefore, rich in vivo datasets of pharmacological time-series with two dosing regimens sampled from rat liver are examined for temporal patterns of changes in gene expression and their regulatory commonalities. RESULTS: The study addresses two issues, including (1) identifying significant transcriptional modules coupled with dynamic expression patterns and (2) predicting relevant common transcriptional controls to better understand the underlying mechanisms of corticosteroid adverse effects. Following the orientation of meta-analysis, an extended computational approach that explores the concept of agreement matrix from consensus clustering has been proposed with the aims of identifying gene clusters that share common expression patterns across multiple dosing regimens as well as handling challenges in the analysis of microarray data from heterogeneous sources, e.g. different platforms and time-grids in this study. Six significant transcriptional modules coupled with typical patterns of expression have been identified. Functional analysis reveals that virtually all enriched functions (gene ontologies, pathways) in these modules are shown to be related to metabolic processes, implying the importance of these modules in adverse effects under the administration of corticosteroids. Relevant putative transcriptional regulators (e.g. RXRF, FKHD, SP1F) are also predicted to provide another source of information towards better understanding the complexities of expression patterns and the underlying regulatory mechanisms of those modules. CONCLUSIONS: We have proposed a framework to identify significant coexpressed clusters of genes across multiple conditions experimented from different microarray platforms, time-grids, and also tissues if applicable. Analysis on rich in vivo datasets of corticosteroid time-series yielded significant insights into the pharmacogenomic effects of corticosteroids, especially the relevance to metabolic side-effects. This has been illustrated through enriched metabolic functions in those transcriptional modules and the presence of GRE binding motifs in those enriched pathways, providing significant modules for further analysis on pharmacogenomic corticosteroid effects. PMID- 20946643 TI - Turning a blind eye: the mobilization of radiology services in resource-poor regions. AB - While primary care, obstetrical, and surgical services have started to expand in the world's poorest regions, there is only sparse literature on the essential support systems that are required to make these operations function. Diagnostic imaging is critical to effective rural healthcare delivery, yet it has been severely neglected by the academic, public, and private sectors. Currently, a large portion of the world's population lacks access to any form of diagnostic imaging. In this paper we argue that two primary imaging modalities--diagnostic ultrasound and X-Ray--are ideal for rural healthcare services and should be scaled-up in a rapid and standardized manner. Such machines, if designed for resource-poor settings, should a) be robust in harsh environmental conditions, b) function reliably in environments with unstable electricity, c) minimize radiation dangers to staff and patients, d) be operable by non-specialist providers, and e) produce high-quality images required for accurate diagnosis. Few manufacturers are producing ultrasound and X-Ray machines that meet the specifications needed for rural healthcare delivery in resource-poor regions. A coordinated effort is required to create demand sufficient for manufacturers to produce the desired machines and to ensure that the programs operating them are safe, effective, and financially feasible. PMID- 20946644 TI - Congenital myelomeningocele - do we have to change our management? AB - BACKGROUND: Eagerly awaiting the results of the Management of Myelomeningocele Study (MOMS) and with an increasing interest in setting up intrauterine myelomeningocele repair (IUMR), the optimal management of patients suffering from congenital myelomeningocele (MMC) has become a matter of debate again. We performed a cross-sectional study at our referral-center for MMC to determine the outcome for our expectantly managed patients. MATERIALS AND METHODS: A computed chart review at our institution revealed 70 patients suffering from MMC. Forty three patients were eligible for the study and analyzed further. A retrospective analysis was performed only in patients that underwent MMC repair within the first two days of life and were seen at our outpatient clinic between 2008 and 2009 for a regular multidisciplinary follow-up. Data were collected on: gestational age (GA) and weight at birth, age at shunt placement and shunt status after the first year of life, radiological evidence for Arnold-Chiari malformation (ACM) and tethered cord (TC), need for surgery for TC, bladder function, lower leg function and educational level. Data were compared to published results for IUMR and to studies of historical controls. RESULTS: Patients were born with MMC between 1979 and 2009 and are now 13.3 +/- 8.9 (mean +/- SD) years of age. At birth, mean GA was 37.8 +/- 2.3 weeks and mean weight was 2921.3 +/- 760.3 g, both significantly higher than in IUMR patients. Shunt placement in our cohort was required in 69.8% at a mean age of 16.0 +/- 10.7 days, which was less frequent than for historical controls. Amongst our cohort, radiological observations showed 57.1% had ACM II and 41.9% had TC. Only two of our patients underwent a surgical correction for TC. Clean intermittent catheterization was performed in 69.7% of our patients, 56.4% were (assisted) walkers and 64.1% attended regular classes, both comparable to historical controls. CONCLUSIONS: With a close and interdisciplinary management by pediatric surgeons, neurologists and urologists, the long-term outcome of patients suffering from MMC can currently be considered satisfactory. With respect to the known drawbacks of fetal interventions for mother and child, especially preterm delivery, the results of the MOMS trial should be awaited with caution before proceeding with a complex intervention like IUMR. PMID- 20946645 TI - Inhibitory effect of small interfering RNA on dengue virus replication in mosquito cells. AB - BACKGROUND: Dengue viruses (DENs) are the wildest transmitted mosquito-borne pathogens throughout tropical and sub-tropical regions worldwide. Infection with DENs can cause severe flu-like illness and potentially fatal hemorrhagic fever. Although RNA interference triggered by long-length dsRNA was considered a potent antiviral pathway in the mosquito, only limited studies of the value of small interfering RNA (siRNA) have been conducted. RESULTS: A 21 nt siRNA targeting the membrane glycoprotein precursor gene of DEN-1 was synthesized and transfected into mosquito C6/36 cells followed by challenge with DEN. The stability of the siRNA in cells was monitored by flow cytometry. The antiviral effect of siRNA was evaluated by measurement of cell survival rate using the MTT method and viral RNA was quantitated with real-time RT-PCR. The presence of cells containing siRNA at 0.25, 1, 3, 5, 7 days after transfection were 66.0%, 52.1%, 32.0%, 13.5% and 8.9%, respectively. After 7 days incubation with DEN, there was reduced cytopathic effect, increased cell survival rate (76.9 +/- 4.5% vs 23.6 +/- 14.6%) and reduced viral RNA copies (Ct value 19.91 +/- 0.63 vs 14.56 +/- 0.39) detected in transfected C6/36 cells. CONCLUSIONS: Our data showed that synthetic siRNA against the DEN-1 membrane glycoprotein precursor gene effectively inhibited DEN 1 viral RNA replication and increased C6/36 cell survival rate. siRNA may offer a potential new strategy for prevention and treatment of DEN infection. PMID- 20946646 TI - Treatment of euvolemic hyponatremia in the intensive care unit by urea. AB - INTRODUCTION: Hyponatremia in the intensive care unit (ICU) is most commonly related to inappropriate secretion of antidiuretic hormone (SIADH). Fluid restriction is difficult to apply in these patients. We wanted to report the treatment of hyponatremia with urea in these patients. METHODS: Two groups of patients are reported. The first one is represented by a retrospective study of 50 consecutive patients with mild hyponatremia treated with urea. The second group is presented by a series of 35 consecutive patients with severe hyponatremia acquired outside the hospital (<= 115 mEq/L) who where treated by isotonic saline and urea (0.5 to 1 g/kg/day), administered usually by gastric tube. RESULTS: In the first group with mild hyponatremia (128 +/- 4 mEq/L) the serum sodium (SNa) increased to a mean value of 135 +/- 4 mEq/L (P < 0.001) after two days of urea therapy (46 +/- 25 g/day), despite a large fluid intake (> 2 L/day). The mean duration of urea therapy was six days (from 2 to 42 days). Six patients developed hyponatremia again once the urea was stopped, which necessitated its reintroduction. Six patients developed hypernatremia (maximum value 155 mEq/L). In the second group, SNa increased from 111 +/- 3 mEq/L to 122 +/- 4 mEq/L in one day (P < 0.001). All the patients with neurological symptoms made a rapid recovery. No side effects were observed. CONCLUSIONS: These data show that urea is a simple and inexpensive therapy to treat euvolemic hyponatremia in the ICU. PMID- 20946647 TI - Rapid induction of autoantibodies during ARDS and septic shock. AB - BACKGROUND: Little is known about the induction of humoral responses directed against human autoantigens during acute inflammation. We utilized a highly sensitive antibody profiling technology to study autoantibodies in patients with acute respiratory distress syndrome (ARDS) and severe sepsis, conditions characterized by intensive immune activation leading to multiple organ dysfunction. METHODS: Using Luciferase Immunoprecipitation Systems (LIPS), a cohort of control, ARDS and sepsis patients were tested for antibodies to a panel of autoantigens. Autoantibody titers greater than the mean plus 3 SD of the 24 control samples were used to identify seropositive samples. Available longitudinal samples from different seropositive ARDS and sepsis patient samples, starting from within the first two days after admission to the intensive care, were then analyzed for changes in autoantibody over time. RESULTS: From screening patient plasma, 57% of ARDS and 46% of septic patients without ARDS demonstrated at least one statistically significant elevated autoantibody compared to the controls. Frequent high titer antibodies were detected against a spectrum of autoantigens including potassium channel regulator, gastric ATPase, glutamic decarboxylase-65 and several cytokines. Analysis of serial samples revealed that several seropositive patients had low autoantibodies at early time points that often rose precipitously and peaked between days 7-14. Further, the use of therapeutic doses of corticosteroids did not diminish the rise in autoantibody titers. In some cases, the patient autoantibody titers remained elevated through the last serum sample collected. CONCLUSION: The rapid induction of autoantibodies in ARDS and severe sepsis suggests that ongoing systemic inflammation and associated tissue destruction mediate the break in tolerance against these self proteins. PMID- 20946649 TI - 10 years of Malaria Journal: how did Open Access change publication patterns? PMID- 20946648 TI - Macrophages may promote cancer growth via a GM-CSF/HB-EGF paracrine loop that is enhanced by CXCL12. AB - BACKGROUND: Increased numbers of tumour-associated macrophages correlate with shortened survival in some cancers. The molecular bases of this correlation are not thoroughly understood. Events triggered by CXCL12 may play a part, as CXCL12 drives the migration of both CXCR4-positive cancer cells and macrophages and may promote a molecular crosstalk between them. RESULTS: Samples of HER1-positive colon cancer metastases in liver, a tissue with high expression of CXCL12, were analysed by immunohistochemistry. In all of the patient biopsies, CD68-positive tumour-associated macrophages presented a mixed CXCL10 (M1)/CD163 (M2) pattern, expressed CXCR4, GM-CSF and HB-EGF, and some stained positive for CXCL12. Cancer cells stained positive for CXCR4, CXCL12, HER1, HER4 and GM-CSF. Regulatory interactions among these proteins were validated via experiments in vitro involving crosstalk between human mononuclear phagocytes and the cell lines DLD-1 (human colon adenocarcinoma) and HeLa (human cervical carcinoma), which express the above-mentioned ligand/receptor repertoire. CXCL12 induced mononuclear phagocytes to release HB-EGF, which activated HER1 and triggered anti-apoptotic and proliferative signals in cancer cells. The cancer cells then proliferated and released GM-CSF, which in turn activated mononuclear phagocytes and induced them to release more HB-EGF. Blockade of GM-CSF with neutralising antibodies or siRNA suppressed this loop. CONCLUSIONS: CXCL12-driven stimulation of cancer cells and macrophages may elicit and reinforce a GM-CSF/HB-EGF paracrine loop, whereby macrophages contribute to cancer survival and expansion. The involvement of mixed M1/M2 GM-CSF-stimulated macrophages in a tumour-promoting loop may challenge the paradigm of tumour-favouring macrophages as polarized M2 mononuclear phagocytes. PMID- 20946650 TI - Lipoprotein biosynthesis as a target for anti-Wolbachia treatment of filarial nematodes. AB - BACKGROUND: Lymphatic filariasis and onchocerciasis are debilitating diseases caused by filarial nematodes. Disease pathogenesis is induced by inflammatory responses following the death of the parasite. Wolbachia endosymbionts of filariae are potent inducers of innate and adaptive inflammation and bacterial lipoproteins have been identified as the ligands that bind toll-like receptors (TLR) 2 and TLR6. Lipoproteins are important structural and functional components of bacteria and therefore enzymes involved in Wolbachia lipoprotein biosynthesis are potential chemotherapeutic targets. RESULTS: Globomycin, a signal peptidase II (LspA) inhibitor, has activity against Gram-negative bacteria and a putative lspA gene has been identified from the Wolbachia genome of Brugia malayi (wBm). The amino acids required for function are strictly conserved and functionality was verified by complementation tests in a temperature-sensitive Escherichia coli lspA mutant. Also, transformation of wild type E. coli with Wolbachia lspA conferred significant globomycin resistance. A cell-based screen has been developed utilizing a Wolbachia-containing Aedes albopictus cell line to assay novel compounds active against Wolbachia. Globomycin was screened using this assay, which resulted in a dose-dependent reduction in Wolbachia load. Furthermore, globomycin was also effective in reducing the motility and viability of adult B. malayi in vitro. CONCLUSIONS: These studies validate lipoprotein biosynthesis as a target in an organism for which no genetic tools are available. Further studies to evaluate drugs targeting this pathway are underway as part of the A-WOL drug discovery and development program. PMID- 20946651 TI - The addition of a goal-based motivational interview to standardised treatment as usual to reduce dropouts in a service for patients with personality disorder: a feasibility study. AB - BACKGROUND: Rates of non-completion of treatments for personality disorder are high and there are indications that those who do not complete treatment have worse outcomes than those who do. Improving both cost-efficiency and client welfare require attention to engaging people with personality disorder in treatment. A motivational interview, based on the Personal Concerns Inventory, may have the ability to enhance engagement and retention in therapy. Here, we report the protocol for a feasibility study for a randomised controlled trial (RCT). METHODS: All referrals accepted to the psychological service of Nottinghamshire Healthcare NHS Trust's outpatient service for people with personality disorder are eligible for inclusion. Consenting participants are randomised to receive the Personal Concerns Inventory interview plus treatment as usual or treatment as usual only. We aim to recruit 100 participants over 11/2 years. A randomised controlled trial will be considered feasible if 1 the recruitment rate to the project is 54% of all referrals (95% CI 54-64), 2 80% of clients find the intervention acceptable in terms of its practicability and usefulness (95% CI 80-91), and 3 80% of therapists report finding the intervention helpful (95% CI 80-100). In a full-scale randomised controlled trial, the primary outcome measure will be completion of treatment i.e., entry into and completion of >= 75% of sessions offered. Therefore, information will be collected on recruitment rates, attendance at therapy sessions, and completion of treatment. The feasibility of examining the processes of engagement will be tested by assessing the value, coherence, and attainability of goals pre treatment, and engagement in treatment. The costs associated with the intervention will be calculated, and the feasibility of calculating the cost benefits of the intervention will be tested. The views of clients and therapists on the intervention, collected using semi-structured interviews, will be analysed using thematic analysis. DISCUSSION: The Personal Concerns Interview as a preparation for treatment of people with personality has the potential to maximise treatment uptake, reduce unfilled places in treatment programmes, and prevent group treatments faltering through non-attendance. Most importantly, it has the potential to improve patient outcomes, helping them to function better and reduce hospitalisation. TRIAL REGISTRATION: ClinicalTrials.Gov.UK Identifier- NCT01132976. PMID- 20946652 TI - Transcriptomic and functional analysis of the Anopheles gambiae salivary gland in relation to blood feeding. AB - BACKGROUND: The Anopheles gambiae salivary glands play a major role in malaria transmission and express a variety of bioactive components that facilitate blood feeding by preventing platelet aggregation, blood clotting, vasodilatation, and inflammatory and other reactions at the probing site on the vertebrate host. RESULTS: We have performed a global transcriptome analysis of the A. gambiae salivary gland response to blood-feeding, to identify candidate genes that are involved in hematophagy. A total of 4,978 genes were found to be transcribed in this tissue. A comparison of salivary gland transcriptomes prior to and after blood-feeding identified 52 and 41 transcripts that were significantly up regulated and down-regulated, respectively. Ten genes were further selected to assess their role in the blood-feeding process using RNAi-mediated gene silencing methodology. Depletion of the salivary gland genes encoding D7L2, anophelin, peroxidase, the SG2 precursor, and a 5'nucleotidase gene significantly increased probing time of A. gambiae mosquitoes and thereby their capacity to blood-feed. CONCLUSIONS: The salivary gland transcriptome comprises approximately 38% of the total mosquito transcriptome and a small proportion of it is dynamically changing already at two hours in response to blood feeding. A better understanding of the salivary gland transcriptome and its function can contribute to the development of pathogen transmission control strategies and the identification of medically relevant bioactive compounds. PMID- 20946653 TI - Systematic identification of conserved motif modules in the human genome. AB - BACKGROUND: The identification of motif modules, groups of multiple motifs frequently occurring in DNA sequences, is one of the most important tasks necessary for annotating the human genome. Current approaches to identifying motif modules are often restricted to searches within promoter regions or rely on multiple genome alignments. However, the promoter regions only account for a limited number of locations where transcription factor binding sites can occur, and multiple genome alignments often cannot align binding sites with their true counterparts because of the short and degenerative nature of these transcription factor binding sites. RESULTS: To identify motif modules systematically, we developed a computational method for the entire non-coding regions around human genes that does not rely upon the use of multiple genome alignments. First, we selected orthologous DNA blocks approximately 1-kilobase in length based on discontiguous sequence similarity. Next, we scanned the conserved segments in these blocks using known motifs in the TRANSFAC database. Finally, a frequent pattern mining technique was applied to identify motif modules within these blocks. In total, with a false discovery rate cutoff of 0.05, we predicted 3,161,839 motif modules, 90.8% of which are supported by various forms of functional evidence. Compared with experimental data from 14 ChIP-seq experiments, on average, our methods predicted 69.6% of the ChIP-seq peaks with TFBSs of multiple TFs. Our findings also show that many motif modules have distance preference and order preference among the motifs, which further supports the functionality of these predictions. CONCLUSIONS: Our work provides a large scale prediction of motif modules in mammals, which will facilitate the understanding of gene regulation in a systematic way. PMID- 20946654 TI - Disease-specific definitions of vitamin D deficiency need to be established in autoimmune and non-autoimmune chronic diseases: a retrospective comparison of three chronic diseases. AB - INTRODUCTION: We compared the odds of vitamin D deficiency in three chronic diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 2 diabetes (T2DM), adjusting for medications, demographics, and laboratory parameters, common to all three diseases. We also designed multivariate models to determine whether different factors are associated with vitamin D deficiency in different racial/ethnic groups. METHODS: We identified all patients with non overlapping diagnoses of SLE, RA, and T2DM, with 25-hydroxyvitamin D (25OHD) levels measured between 2000 and 2009. Vitamin D deficiency was defined as 25OHD levels <20 ng/ml, based on previously established definitions. Race/ethnicity was analyzed as African-American non-Hispanic (African-American), Hispanic non African-American (Hispanic), and Other based on self report. RESULTS: We included 3,914 patients in the final analysis: 123 SLE, 100 RA, and 3,691 T2DM. Among African-Americans the frequency of vitamin D deficiency was 59% in SLE, 47% in RA, and 67% in T2DM. Among Hispanics the frequency of vitamin D deficiency was 67% in SLE, 50% in RA, and 59% in T2DM. Compared with the SLE group, the adjusted odds ratio of vitamin D deficiency was 1.1, 95% CI (0.62, 2.1) in the RA group, and 2.0, 95% CI (1.3, 3.1) in the T2DM group. In the multivariate analysis, older age, higher serum calcium and bisphosphonate therapy were associated with a lower odds of vitamin D deficiency in all three racial/ethnic groups: 1,330 African American, 1,257 Hispanic, and 1,100 Other. T2DM, serum creatinine, and vitamin D supplementation were associated with vitamin D deficiency in some, but not all, racial/ethnic groups. CONCLUSIONS: Vitamin D deficiency is highly prevalent in our patients with SLE, RA, and T2DM. While the odds of vitamin D deficiency are similar in RA and SLE patients in a multivariate analysis, T2DM patients have much higher odds of being vitamin D deficient. Different demographic and laboratory factors may be associated with vitamin D deficiency within different racial/ethnic groups. Therefore, disease-specific and race/ethnicity-specific definitions of vitamin D deficiency need to be established in future studies in order to define goals of vitamin D replacement in patients with autoimmune and non-autoimmune chronic diseases. PMID- 20946655 TI - The impact of highly active antiretroviral therapy on prevalence and incidence of cervical human papillomavirus infections in HIV-positive adolescents. AB - BACKGROUND: The implementation of highly active antiretroviral therapy (HAART) among HIV-positive patients results in immune reconstitution, slower progression of HIV disease, and a decrease in the occurrence of opportunistic infections. However, the impact of HAART on cervical human papillomavirus (HPV) infection, clearance, and persistence in high-risk adolescents remains controversial. METHODS: HIV-positive and high-risk HIV-negative female adolescents were enrolled in the Reaching for Excellence in Adolescent Care and Health (REACH) longitudinal cohort study. At each semi-annual clinical visit, cervical lavage samples were tested for 30 HPV types. Type-specific and carcinogenic risk-specific HPV prevalence and incidence were compared in 373 eligible participants: 146 HIV negative female adolescents with a median follow-up of 721.5 [IQR: 483-1301] days and 227 HIV-positive female adolescents. Of the 227 HIV-positive participants, a fixed set (n = 100) were examined both before and after HAART initiation; 70 were examined only before HAART initiation; and 57 were examined only after HAART initiation, with overall median follow-up of 271 [IQR: 86.5-473] and 427.25 [IQR: 200-871] days respectively for before and after HAART initiation. RESULTS: Of the 373 eligible participants, 262 (70%) were infected with at least one type of HPV at baseline, and 78 of the remaining 111 (70%) became infected with at least one type of HPV by the end of the study. Overall, the incidence and prevalence of HPV types 58, 53/66, 68/70, and 31/33/35 were much higher than the established carcinogenic and HPV vaccine types 16 and 18, especially in HIV-positive females both before and after HAART initiation. Baseline prevalence for individual high risk HPV types ranged, depending on type, from 0.7-10%, 1-17%, and 1-18% in the HIV-negative group, the HIV-positive before HAART initiation group, and the HIV positive after HAART initiation group, respectively. Likewise, the incidence ranged, depending on HPV type, from 0.64-9.83 cases/100 PY, 3.00-12.80 cases/100 PY, and 1.49-17.05 cases/100 PY in the three groups, respectively. The patterns of each HPV type infection, clearance, and persistence did not differ considerably before or after the introduction of HAART and were clearly independent of CD4+ change within the short post-HAART follow-up period. CONCLUSIONS: HAART did not immediately affect the incidence of type-specific HPV infections within a short-period follow-up; however, future studies are warranted in larger populations to evaluate HAART's impact over longer periods. PMID- 20946656 TI - Absorption of silicon from artesian aquifer water and its impact on bone health in postmenopausal women: a 12 week pilot study. AB - BACKGROUND: Decreased bone mineral density and osteoporosis in postmenopausal women represents a growing source of physical limitations and financial concerns in our aging population. While appropriate medical treatments such as bisphosphonate drugs and hormone replacement therapy exist, they are associated with serious side effects such as osteonecrosis of the jaw or increased cardiovascular risk. In addition to calcium and vitamin D supplementation, previous studies have demonstrated a beneficial effect of dietary silicon on bone health. This study evaluated the absorption of silicon from bottled artesian aquifer water and its effect on markers of bone metabolism. METHODS: Seventeen postmenopausal women with low bone mass, but without osteopenia or osteoporosis as determined by dual x-ray absorptiometry (DEXA) were randomized to drink one liter daily of either purified water of low-silicon content (PW) or silicon-rich artesian aquifer water (SW) (86 mg/L silica) for 12 weeks. Urinary silicon and serum markers of bone metabolism were measured at baseline and after 12 weeks and analyzed with two-sided t-tests with p < 0.05 defined as significant. RESULTS: The urinary silicon level increased significantly from 0.016 +/- 0.010 mg/mg creatinine at baseline to 0.037 +/- 0.014 mg/mg creatinine at week 12 in the SW group (p = 0.003), but there was no change for the PW group (0.010 +/- 0.004 mg/mg creatinine at baseline vs. 0.009 +/- 0.006 mg/mg creatinine at week 12, p = 0.679). The urinary silicon for the SW group was significantly higher in the silicon-rich water group compared to the purified water group (p < 0.01). NTx, a urinary marker of bone resorption did not change during the study and was not affected by the silicon water supplementation. No significant change was observed in the serum markers of bone formation compared to baseline measurements for either group. CONCLUSIONS: These findings indicate that bottled water from artesian aquifers is a safe and effective way of providing easily absorbed dietary silicon to the body. Although the silicon did not affect bone turnover markers in the short-term, the mineral's potential as an alternative prevention or treatment to drug therapy for osteoporosis warrants further longer-term investigation in the future. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01067508. PMID- 20946658 TI - Collaborative research between clinicians and researchers: a multiple case study of implementation. AB - BACKGROUND: Bottom-up, clinician-conceived and directed clinical intervention research, coupled with collaboration from researcher experts, is conceptually endorsed by the participatory research movement. This report presents the findings of an evaluation of a program in the Veterans Health Administration meant to encourage clinician-driven research by providing resources believed to be critical. The evaluation focused on the extent to which funded projects: maintained integrity to their original proposals; were methodologically rigorous; were characterized by collaboration between partners; and resulted in sustained clinical impact. METHODS: Researchers used quantitative (survey and archival) and qualitative (focus group) data to evaluate the implementation, evaluation, and sustainability of four clinical demonstration projects at four sites. Fourteen research center mentors and seventeen clinician researchers evaluated the level of collaboration using a six-dimensional model of participatory research. RESULTS: Results yielded mixed findings. Qualitative and quantitative data suggested that although the process was collaborative, clinicians' prior research experience was critical to the quality of the projects. Several challenges were common across sites, including subject recruitment, administrative support and logistics, and subsequent dissemination. Only one intervention achieved lasting clinical effect beyond the active project period. Qualitative analyses identified barriers and facilitators and suggested areas to improve sustainability. CONCLUSIONS: Evaluation results suggest that this participatory research venture was successful in achieving clinician-directed collaboration, but did not produce sustainable interventions due to such implementation problems as lack of resources and administrative support. PMID- 20946657 TI - Nitrates in drinking water and methemoglobin levels in pregnancy: a longitudinal study. AB - BACKGROUND: Private water systems are more likely to have nitrate levels above the maximum contaminant level (MCL). Pregnant women are considered vulnerable to the effects of exposure to high levels of nitrates in drinking water due to their altered physiological states. The level of methemoglobin in the blood is the biomarker often used in research for assessing exposure to nitrates. The objective of this study was to assess methemoglobin levels and examine how various factors affected methemoglobin levels during pregnancy. We also examined whether differences in water use practices existed among pregnant women based on household drinking water source of private vs. public supply. METHODS: A longitudinal study of 357 pregnant women was conducted. Longitudinal regression models were used to examine changes and predictors of the change in methemoglobin levels over the period of gestation. RESULTS: Pregnant women showed a decrease in methemoglobin levels with increasing gestation although <1% had levels above the physiologic normal of 2% methemoglobin, regardless of the source of their drinking water. The multivariable analyses did not show a statistically significant association between methemoglobin levels and the estimated nitrate intake from tap water among pregnant women around 36 weeks gestation (beta = 0.046, p = 0.986). Four women had tap water nitrate levels above the MCL of 10 mg/L. At enrollment, a greater proportion of women who reported using water treatment devices were private wells users (66%) compared to public system users (46%) (p < 0.0001). Also, a greater proportion of private well users (27%) compared to public system users (13%) were using devices capable of removing nitrate from water (p < 0.0001). CONCLUSION: Pregnant women potentially exposed to nitrate levels primarily below the MCL for drinking water were unlikely to show methemoglobin levels above the physiologic normal. Water use practices such as the use of treatment devices to remove nitrates varied according to water source and should be considered in the assessment of exposure to nitrates in future studies. PMID- 20946659 TI - Conservative management of post-appendicectomy intra-abdominal abscesses. AB - PURPOSE: Appendicitis is the most common abdominal inflammatory process in children which were sometimes followed by complications including intra-abdominal abscess. This later needs classically a surgical drainage. We evaluated the efficacy of antibiotic treatment and surgical drainage. METHODS: Hospital records of children treated in our unit for intra-abdominal post appendectomy abscesses over a 6 years period were reviewed retrospectively. RESULTS: This study investigates a series of 14 children from 2 to 13 years of age with one or many abscesses after appendectomy, treated between 2002 and 2007. Seven underwent surgery and the others were treated with triple antibiotherapy. The two groups were comparable. For the 7 patients who receive medical treatment alone, it was considered efficient in 6 cases (85%) with clinical, biological and radiological recovery of the abscess. There was one failure (14%). The duration of hospitalization from the day of diagnosis of intra-abdominal abscess was approximately 10.28 days (range 7 to 14 days). In the other group, the efficacy of treatment was considered satisfactory in all cases. The duration of hospitalization was about 13 days (range: 9 to 20). CONCLUSION: Compared to surgical drainage, antibiotic management of intra-abdominal abscesses was a no invasive treatment with shorter hospitalization. PMID- 20946660 TI - Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an Alzheimer's disease model mouse. AB - BACKGROUND: Alzheimer's Disease (AD) is the most common of the conformational neurodegenerative disorders characterized by the conversion of a normal biological protein into a beta-sheet-rich pathological isoform. In AD the normal soluble Abeta (sAbeta) forms oligomers and fibrils which assemble into neuritic plaques. The most toxic form of Abeta is thought to be oligomeric. A recent study reveals the cellular prion protein, PrPC, to be a receptor for Abeta oligomers. Abeta oligomers suppress LTP signal in murine hippocampal slices but activity remains when pretreated with the PrP monoclonal anti-PrP antibody, 6D11. We hypothesized that targeting of PrPC to prevent Abeta oligomer-related cognitive deficits is a potentially novel therapeutic approach. APP/PS1 transgenic mice aged 8 months were intraperitoneally (i.p.) injected with 1 mg 6D11 for 5 days/week for 2 weeks. Two wild-type control groups were given either the same 6D11 injections or vehicle solution. Additional groups of APP/PS1 transgenic mice were given either i.p. injections of vehicle solution or the same dose of mouse IgG over the same period. The mice were then subjected to cognitive behavioral testing using a radial arm maze, over a period of 10 days. At the conclusion of behavioral testing, animals were sacrificed and brain tissue was analyzed biochemically or immunohistochemically for the levels of amyloid plaques, PrPC, synaptophysin, Abeta40/42 and Abeta oligomers. RESULTS: Behavioral testing showed a marked decrease in errors in 6D11 treated APP/PS1 Tg mice compared with the non 6D11 treated Tg groups (p < 0.0001). 6D11 treated APP/PS1 Tg mice behaved the same as wild-type controls indicating a recovery in cognitive learning, even after this short term 6D11 treatment. Brain tissue analysis from both treated and vehicle treated APP/PS1 groups indicate no significant differences in amyloid plaque burden, Abeta40/42, PrPC or Abeta oligomer levels. 6D11 treated APP/PS1 Tg mice had significantly greater synaptophysin immunoreactivity in the dentate gyrus molecular layer of the hippocampus compared to vehicle treated APP/PS1 Tg mice (p < 0.05). CONCLUSIONS: Even short term treatment with monoclonal antibodies such as 6D11 or other compounds which block the binding of Abeta oligomers to PrPC can be used to treat cognitive deficits in aged AD transgenic mice. PMID- 20946661 TI - Three-dimensional in vitro follicle growth: overview of culture models, biomaterials, design parameters and future directions. AB - In vitro ovarian follicle culture is a new frontier in assisted reproductive technology with tremendous potential, especially for fertility preservation. Folliculogenesis within the ovary is a complex process requiring interaction between somatic cell components and the oocyte. Conventional two-dimensional culture on tissue culture substrata impedes spherical growth and preservation of the spatial arrangements between oocyte and surrounding granulosa cells. Granulosa cell attachment and migration can leave the oocyte naked and unable to complete the maturation process. Recognition of the importance of spatial arrangements between cells has spurred research in to three-dimensional culture system. Such systems may be vital when dealing with human primordial follicles that may require as long as three months in culture. In the present work we review pertinent aspects of in vitro follicle maturation, with an emphasis on tissue-engineering solutions for maintaining the follicular unit during the culture interval. We focus primarily on presenting the various 3-dimensional culture systems that have been applied for in vitro maturation of follicle:oocyte complexes. We also try to present an overview of outcomes with various biomaterials and animal models and also the limitations of the existing systems. PMID- 20946662 TI - The dynamics of risk perceptions and precautionary behavior in response to 2009 (H1N1) pandemic influenza. AB - BACKGROUND: The trajectory of an infectious disease outbreak is affected by the behavior of individuals, and the behavior is often related to individuals' risk perception. We assessed temporal changes and geographical differences in risk perceptions and precautionary behaviors in response to H1N1 influenza. METHODS: 1,290 US adults completed an online survey on risk perceptions, interests in pharmaceutical interventions (preventive intervention and curative intervention), and engagement in precautionary activities (information seeking activities and taking quarantine measures) in response to H1N1 influenza between April 28 and May 27 2009. Associations of risk perceptions and precautionary behaviors with respondents' sex, age, and household size were analyzed. Linear and quadratic time trends were assessed by regression analyses. Geographic differences in risk perception and precautionary behaviors were evaluated. Predictors of willingness to take pharmaceutical intervention were analyzed. RESULTS: Respondents from larger households reported stronger interest in taking medications and engaged in more precautionary activities, as would be normatively predicted. Perceived risk increased over time, whereas interest in pharmaceutical preventive interventions and the engagement in some precautionary activities decreased over time. Respondents who live in states with higher H1N1 incidence per population perceived a higher likelihood of influenza infection, but did not express greater interests in pharmaceutical interventions, nor did they engage in a higher degree of precautionary activities. Perceived likelihood of influenza infection, willingness to take medications and engagement in information seeking activities were higher for women than men. CONCLUSIONS: Perceived risk of infection and precautionary behavior can be dynamic in time, and differ by demographic characteristics and geographical locations. These patterns will likely influence the effectiveness of disease control measures. PMID- 20946663 TI - Treatment combining RU486 and Ad5IL-12 vector attenuates the growth of experimentally formed prostate tumors and induces changes in the sentinel lymph nodes of mice. AB - BACKGROUND: Tumor immune responses are first generated and metastases often begin in tumor sentinel lymph nodes (TSLN). Therefore, it is important to promote tumor immunity within this microenvironment. Mifepristone (RU486) treatment can interfere with cortisol signaling that can lead to suppression of tumor immunity. Here, we assessed whether treatment with RU486 in conjunction with an intratumor injection of Ad5IL-12 vector (a recombinant adenovirus expressing IL-12) could impact the TSLN microenvironment and prostate cancer progression. METHODS: The human PC3, LNCaP or murine TRAMP-C1 prostate cancer cell lines were used to generate subcutaneous tumors in NOD.scid and C57BL/6 mice, respectively. Adjuvant effects of RU486 were looked for in combination therapy with intratumor injections (IT) of Ad5IL-12 vector in comparison to PBS, DL70-3 vector, DL70-3 + RU486, RU486 and Ad5IL-12 vector treatment controls. Changes in tumor growth, cell cytotoxic activity and populations of CD4+/FoxP3+ T regulatory cells (Treg) in the TSLN were evaluated. RESULTS: Treatment of human PC3 prostate xenograft or TRAMP-C1 tumors with combination Ad5IL-12 vector and RU486 produced significantly better therapeutic efficacy in comparison to controls. In addition, we found that combination therapy increased the capacity of TSLN lymphocytes to produce Granzyme B in response to tumor cell targets. Finally, combination therapy tended towards decreases of CD4+/FoxP3+ T regulatory cell populations to be found in the TSLN. CONCLUSION: Inclusion of RU486 may serve as a useful adjuvant when combined with proinflammatory tumor killing agents by enhancement of the immune response and alteration of the TSLN microenvironment. PMID- 20946664 TI - MMP-1 is a (pre-)invasive factor in Barrett-associated esophageal adenocarcinomas and is associated with positive lymph node status. AB - BACKGROUND: Esophageal adenocarcinomas (EACs) arise due to gastroesophageal reflux, with Barrett's esophagus (BE) regarded as precancerous lesion. Matrix metalloproteinases (MMPs) might play a role during the multistep carcinogenetic process. METHODS: Expression of MMP-1 and -13 was analyzed in esophageal cancer (n = 41 EAC with BE, n = 19 EAC without BE, and n = 10 esophageal squamous-cell carcinomas, ESCC), furthermore in BE without intraepithelial neoplasia (IN) (n = 18), and the cell line OE-33. MMP-1 was co-labelled with Ki-67 (proliferation), Cdx-2 (marker for intestinal metaplasia, BE) and analyzed on mRNA level. MMP-1 staining results were correlated with clinicopathological parameters. RESULTS: On protein level, MMP-1 expression was found in 39 of 41 (95%) EAC with BE, in 19 of 19 (100%) EAC without BE, in 6 of 10 (60%) ESCC, and in 10 of 18 (56%) BE without IN. No expression of MMP-13 was found in these specimens. Quantification showed 48% MMP-1 positive cells in EAC with BE, compared to 35% in adjacent BE (p < 0.05), 44% in EAC without BE, 32% in ESCC, and 4% in BE without IN. Immunofluorescence double staining experiments revealed increased MMP-1 expressing in proliferating cells (MMP-1+/Ki-67+) (r = 0.943 for BE and r = 0.811 for EAC). On mRNA-level, expression of MMP-1 was significantly higher in EAC compared to BE (p = 0.01) and confirmed immunohistochemical staining results. High MMP-1 levels were associated with lymph node metastases but not with poorer survival (p = 0.307). CONCLUSIONS: Our findings suggest that MMP-1 plays a role as preinvasive factor in BE-associated EAC. Expression of MMP-1 in proliferating BE and EAC cells suggest malignant proliferation following the clonal expansion model. PMID- 20946665 TI - A multigene predictor of metastatic outcome in early stage hormone receptor negative and triple-negative breast cancer. AB - INTRODUCTION: Various multigene predictors of breast cancer clinical outcome have been commercialized, but proved to be prognostic only for hormone receptor (HR) subsets overexpressing estrogen or progesterone receptors. Hormone receptor negative (HRneg) breast cancers, particularly those lacking HER2/ErbB2 overexpression and known as triple-negative (Tneg) cases, are heterogeneous and generally aggressive breast cancer subsets in need of prognostic subclassification, since most early stage HRneg and Tneg breast cancer patients are cured with conservative treatment yet invariably receive aggressive adjuvant chemotherapy. METHODS: An unbiased search for genes predictive of distant metastatic relapse was undertaken using a training cohort of 199 node-negative, adjuvant treatment naive HRneg (including 154 Tneg) breast cancer cases curated from three public microarray datasets. Prognostic gene candidates were subsequently validated using a different cohort of 75 node-negative, adjuvant naive HRneg cases curated from three additional datasets. The HRneg/Tneg gene signature was prognostically compared with eight other previously reported gene signatures, and evaluated for cancer network associations by two commercial pathway analysis programs. RESULTS: A novel set of 14 prognostic gene candidates were identified as outcome predictors: CXCL13, CLIC5, RGS4, RPS28, RFX7, EXOC7, HAPLN1, ZNF3, SSX3, HRBL, PRRG3, ABO, PRTN3, MATN1. A composite HRneg/Tneg gene signature index proved more accurate than any individual candidate gene or other reported multigene predictors in identifying cases likely to remain free of metastatic relapse. Significant positive correlations between the HRneg/Tneg index and three independent immune-related signatures (STAT1, IFN, and IR) were observed, as were consistent negative associations between the three immune related signatures and five other proliferation module-containing signatures (MS 14, ONCO-RS, GGI, CSR/wound and NKI-70). Network analysis identified 8 genes within the HRneg/Tneg signature as being functionally linked to immune/inflammatory chemokine regulation. CONCLUSIONS: A multigene HRneg/Tneg signature linked to immune/inflammatory cytokine regulation was identified from pooled expression microarray data and shown to be superior to other reported gene signatures in predicting the metastatic outcome of early stage and conservatively managed HRneg and Tneg breast cancer. Further validation of this prognostic signature may lead to new therapeutic insights and spare many newly diagnosed breast cancer patients the need for aggressive adjuvant chemotherapy. PMID- 20946666 TI - Progranulin modulates zebrafish motoneuron development in vivo and rescues truncation defects associated with knockdown of Survival motor neuron 1. AB - BACKGROUND: Progranulin (PGRN) encoded by the GRN gene, is a secreted glycoprotein growth factor that has been implicated in many physiological and pathophysiological processes. PGRN haploinsufficiency caused by autosomal dominant mutations within the GRN gene leads to progressive neuronal atrophy in the form of frontotemporal lobar degeneration (FTLD). This form of the disease is associated with neuronal inclusions that bear the ubiquitinated TAR DNA Binding Protein-43 (TDP-43) molecular signature (FTLD-U). The neurotrophic properties of PGRN in vitro have recently been reported but the role of PGRN in neurons is not well understood. Here we document the neuronal expression and functions of PGRN in spinal cord motoneuron (MN) maturation and branching in vivo using zebrafish, a well established model of vertebrate embryonic development. RESULTS: Whole mount in situ hybridization and immunohistochemical analyses of zebrafish embryos revealed that zfPGRN-A is expressed within the peripheral and central nervous systems including the caudal primary (CaP) MNs within the spinal cord. Knockdown of zfPGRN-A mRNA translation mediated by antisense morpholino oligonucleotides disrupted normal CaP MN development resulting in both truncated MNs and inappropriate early branching. Ectopic over-expression of zfPGRN-A mRNA resulted in increased MN branching and rescued the truncation defects brought about by knockdown of zfPGRN-A expression. The ability of PGRN to interact with established MN developmental pathways was tested. PGRN over-expression was found to reverse the truncation defect resulting from knockdown of Survival of motor neuron 1 (smn1). This is involved in small ribonucleoprotein biogenesis RNA processing, mutations of which cause Spinal Muscular Atrophy (SMA) in humans. It did not reverse the MN defects caused by interfering with the neuronal guidance pathway by knockdown of expression of NRP-1, a semaphorin co-receptor. CONCLUSIONS: Expression of PGRN within MNs and the observed phenotypes resulting from mRNA knockdown and over-expression are consistent with a role in the regulation of spinal cord MN development and branching. This study presents the first in vivo demonstration of the neurotrophic properties of PGRN and suggests possible future therapeutic applications in the treatment of neurodegenerative diseases. PMID- 20946667 TI - Cellular and vaccine therapeutic approaches for gliomas. AB - Despite new additions to the standard of care therapy for high grade primary malignant brain tumors, the prognosis for patients with this disease is still poor. A small contingent of clinical researchers are focusing their efforts on testing the safety, feasibility and efficacy of experimental active and passive immunotherapy approaches for gliomas and are primarily conducting Phase I and II clinical trials. Few trials have advanced to the Phase III arena. Here we provide an overview of the cellular therapies and vaccine trials currently open for patient accrual obtained from a search of http://www.clinicaltrials.gov. The search was refined with terms that would identify the Phase I, II and III immunotherapy trials open for adult glioma patient accrual in the United States. From the list, those that are currently open for patient accrual are discussed in this review. A variety of adoptive immunotherapy trials using ex vivo activated effector cell preparations, cell-based and non-cell-based vaccines, and several combination passive and active immunotherapy approaches are discussed. PMID- 20946668 TI - Synergistic epigenetic reactivation of estrogen receptor-alpha (ERalpha) by combined green tea polyphenol and histone deacetylase inhibitor in ERalpha negative breast cancer cells. AB - BACKGROUND: The status of estrogen receptor-alpha (ERalpha) is critical to the clinical prognosis and therapeutic approach in breast cancer. ERalpha-negative breast cancer is clinically aggressive and has a poor prognosis because of the lack of hormone target-directed therapies. Previous studies have shown that epigenetic regulation plays a major role in ERalpha silencing in human breast cancer cells. Dietary green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), is believed to be an anticancer agent in part through its regulation of epigenetic processes. RESULTS: In our current studies, we found that EGCG can reactivate ERalpha expression in ERalpha-negative MDA-MB-231 breast cancer cells. Combination studies using EGCG with the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), revealed a synergistic effect of reactivation of ERalpha expression in ERalpha-negative breast cancer cells. Reactivation of ERalpha expression by EGCG and TSA treatment was found to sensitize ERalpha-dependent cellular responses to activator 17beta-estradiol (E2) and antagonist tamoxifen in ERalpha-negative breast cancer cells. We also found that EGCG can lead to remodeling of the chromatin structure of the ERalpha promoter by altering histone acetylation and methylation status thereby resulting in ERalpha reactivation. A decreased binding of the transcription repressor complex, Rb/p130-E2F4/5-HDAC1 SUV39H1-DNMT1, in the regulatory region of the ERalpha promoter also contributes to ERalpha transcriptional activation through treatment with EGCG and/or TSA. CONCLUSIONS: Collectively, these studies show that green tea EGCG can restore ERalpha expression by regulating epigenetic mechanisms, and this effect is enhanced when combined with an HDAC inhibitor. This study will facilitate more effective uses of combination approaches in breast cancer therapy and will help to explore more effective chemotherapeutic strategies toward hormone-resistant breast cancer. PMID- 20946670 TI - Data-driven approach for creating synthetic electronic medical records. AB - BACKGROUND: New algorithms for disease outbreak detection are being developed to take advantage of full electronic medical records (EMRs) that contain a wealth of patient information. However, due to privacy concerns, even anonymized EMRs cannot be shared among researchers, resulting in great difficulty in comparing the effectiveness of these algorithms. To bridge the gap between novel bio surveillance algorithms operating on full EMRs and the lack of non-identifiable EMR data, a method for generating complete and synthetic EMRs was developed. METHODS: This paper describes a novel methodology for generating complete synthetic EMRs both for an outbreak illness of interest (tularemia) and for background records. The method developed has three major steps: 1) synthetic patient identity and basic information generation; 2) identification of care patterns that the synthetic patients would receive based on the information present in real EMR data for similar health problems; 3) adaptation of these care patterns to the synthetic patient population. RESULTS: We generated EMRs, including visit records, clinical activity, laboratory orders/results and radiology orders/results for 203 synthetic tularemia outbreak patients. Validation of the records by a medical expert revealed problems in 19% of the records; these were subsequently corrected. We also generated background EMRs for over 3000 patients in the 4-11 yr age group. Validation of those records by a medical expert revealed problems in fewer than 3% of these background patient EMRs and the errors were subsequently rectified. CONCLUSIONS: A data-driven method was developed for generating fully synthetic EMRs. The method is general and can be applied to any data set that has similar data elements (such as laboratory and radiology orders and results, clinical activity, prescription orders). The pilot synthetic outbreak records were for tularemia but our approach may be adapted to other infectious diseases. The pilot synthetic background records were in the 4-11 year old age group. The adaptations that must be made to the algorithms to produce synthetic background EMRs for other age groups are indicated. PMID- 20946669 TI - Moderate performance of serum S100A12, in distinguishing inflammatory bowel disease from irritable bowel syndrome. AB - BACKGROUND: S100A12, a calcium-binding proinflammatory protein secreted by granulocytes, has been associated with different diseases of inflammatory origin, including inflammatory bowel disease (IBD). In this study, the utility of serum S100A12, in discriminating IBD from irritable bowel syndrome (IBS), was tested. METHODS: S100A12 serum levels were determined in 64 patients with ulcerative colitis (UC), 64 with Crohn's disease (CD) and 73 with IBS, by means of an enzyme linked immunosorbent assay. S100A12 serum levels were evaluated with respect to the levels of known inflammatory markers and patients' characteristics. RESULTS: The median values of serum S100A12 levels were 68.2 ng/mL (range: 43.4-147.4) in UC, 70 ng/mL (41.4-169.8) in CD and 43.4 ng/mL (34.4-74.4) in IBS patients. UC and CD patients had significantly higher serum S100A12 levels compared to IBS patients (P = 0.001 for both comparisons). Moreover, a cut-off for serum S100A12 levels of 54.4 ng/mL could predict both UC and CD with a 66.7% sensitivity and a 64.4% specificity. The area under curve was estimated at 0.67 with a 95% confidence interval of 0.60-0.75 (P < 0.001). Considering standard activity indices, higher serum S100A12 levels in active compared to inactive IBD were observed, although the recorded difference did not reach statistical significance. C-reactive protein (CRP) and serum amyloid A (SAA) levels, showed a statistically significant positive correlation with S100A12 (r = 0.39, P = 0.001 and r = 0.23, P = 0.02 respectively). CONCLUSIONS: Increased levels of circulating S100A12 are found in IBD, compared to IBS. When used to distinguish IBD from IBS adult patients, serum S100A12 levels exhibit moderate performance. On the other hand, serum S100A12 may serve as an inflammatory marker in IBD, since it is well correlated with CRP and SAA. PMID- 20946671 TI - HLA B27 allele types in homogeneous groups of juvenile idiopathic arthritis patients in Latvia. AB - Juvenile idiopathic arthritis (JIA) is a heterogeneous condition and therapeutic strategies vary in different JIA types. The routinely accepted practice to start with Sulphasalazine (SS) as the first line treatment in patients with HLA B27 positive JIA proves to be ineffective in a large proportion of children. OBJECTIVE: to investigate HLA B27 positive JIA patients clinical characteristics, determined HLA B27 allele types and their connection with antirheumatic treatment in homogenous patient groups. MATERIALS AND METHODS: 56 patients diagnosed with JIA and observed over the period 2006 to 2009 included in the study. HLAB27 allele types were determined using PCR method. RESULTS: In HLA B27 positive JIA patients mean disease onset was 12.34 +/- 3.3 years. Most common (44%) JIA type was enthesitis related arthritis. Positive response to the treatment with SS was found in 32% of patients, Methotrexate (MTX) - in 43%, combined treatment - SS with MTX was effective in 12.5%. 12.5% of patients required combination MTX with Enbrel.Eight HLA B27 allele types were found in JIA patients in Latvia: *2702, *2703, *2704, *2705, *2710, *2715, *2717, *2728. The most common was *2705 - in 55% of cases. Among all the patients enthesitis related arthritis most commonly occurred in patients with HLAB*2705 allele (OR = 2.01, p < 0.02), oligoarthritis in patients with *2710 allele (OR = 3.0, p < 0.04) and polyarthritis with *2717 allele (OR = 3.0, p < 0.05). In patients with *2705 allele effective treatment was MTX (OR = 1.13, p < 0.03) and MTX with SS (OR = 2.02, p < 0.05), but in patients having *2703 allele - MTX with Enbrel (OR = 2.94, p < 0.02). CONCLUSIONS: There are 8 different HLA B27 alleles in JIA patients in Latvia and the most common is *2705, but in order to assert them to be disease associated alleles, more extensive studies are needed, including control group of HLA B27 positive healthy individuals. Standard treatment approach with SS proves to be unsatisfactory in the majority of JIA patients. To improve children's quality of life achieving rapid disease control, the first line treatment in HLA B27 positive patients should be MTX. In order to start with the most appropriate drug it is necessary to determine HLAB 27 type at the onset of disease. PMID- 20946672 TI - Comparison of methods for the detection of biofilm production in coagulase negative staphylococci. AB - BACKGROUND: The ability of biofilm formation seems to play an essential role in the virulence of coagulase-negative staphylococci (CNS). The most clearly characterized component of staphylococcal biofilms is the polysaccharide intercellular adhesin (PIA) encoded by the icaADBC operon. Biofilm production was studied in 80 coagulase-negative staphylococci (CNS) strains isolated from clinical specimens of newborns with infection hospitalized at the Neonatal Unit of the University Hospital, Faculty of Medicine of Botucatu, and in 20 isolates obtained from the nares of healthy individuals without signs of infection. The objective was to compare three phenotypic methods with the detection of the icaA, icaD and icaC genes by PCR. FINDINGS: Among the 100 CNS isolates studied, 82% tested positive by PCR, 82% by the tube test, 81% by the TCP assay, and 73% by the CRA method. Using PCR as a reference, the tube test showed the best correlation with detection of the ica genes, presenting high sensitivity and specificity. CONCLUSIONS: The tube adherence test can be indicated for the routine detection of biofilm production in CNS because of its easy application and low cost and because it guarantees reliable results with excellent sensitivity and specificity. PMID- 20946673 TI - Intensity modulated radiotherapy (IMRT) in the management of locally advanced oropharyngeal squamous cell carcinomata (SCC): disease control and functional outcome using the therapy outcome measure (TOM) score--report from a single U.K. institution. AB - INTRODUCTION: This paper evaluates tumour control and toxicity especially in relation to swallowing dysfunction in those patients with locally advanced oropharyngeal squamous cell carcinoma who have undergone either primary chemo radiation or post-operative parotid sparing IMRT. The TOM scoring system was used to assess dysphagia. METHODS: All patients with locally advanced (stage 3/4) squamous cell oropharyngeal cancer and who required either primary or post operative RT were identified. Toxicity was recorded prospectively. The TOM score (0-5 where 5 indicates that the patient is able to eat a normal diet and 0-2 varying degrees of enteral feeding dependency), weights and trismus was recorded immediately prior to and following radiotherapy. RESULTS: 24 patients were identified between 1/2003 and 11/2007. Median weight loss during radiotherapy was 9 kg. All but one patient had a gastrostomy (RIG) tube inserted prophylactically. With a mean follow-up of 37.1 months, 62.5% of pts had a TOM score of 5, 12.5% scored 3, 8% scored and 17% scored 0-2. For those patients whose swallowing function did recover, it took on average 8.7 months. 15% patients experienced trismus secondary to radiotherapy. 2 year overall survival was 92% and disease specific survival 96%. CONCLUSION: Excellent disease control with intensified schedules of radiotherapy with IMRT has been achieved in this patient population. Intermediate toxicity is significant but with longer follow-up, dysphagia continues to improve with 75% of patients not requiring any form of enteral or oral supplementation. PMID- 20946674 TI - A prospective randomized trial of content expertise versus process expertise in small group teaching. AB - BACKGROUND: Effective teaching requires an understanding of both what (content knowledge) and how (process knowledge) to teach. While previous studies involving medical students have compared preceptors with greater or lesser content knowledge, it is unclear whether process expertise can compensate for deficient content expertise. Therefore, the objective of our study was to compare the effect of preceptors with process expertise to those with content expertise on medical students' learning outcomes in a structured small group environment. METHODS: One hundred and fifty-one first year medical students were randomized to 11 groups for the small group component of the Cardiovascular-Respiratory course at the University of Calgary. Each group was then block randomized to one of three streams for the entire course: tutoring exclusively by physicians with content expertise (n = 5), tutoring exclusively by physicians with process expertise (n = 3), and tutoring by content experts for 11 sessions and process experts for 10 sessions (n = 3). After each of the 21 small group sessions, students evaluated their preceptors' teaching with a standardized instrument. Students' knowledge acquisition was assessed by an end-of-course multiple choice (EOC-MCQ) examination. RESULTS: Students rated the process experts significantly higher on each of the instrument's 15 items, including the overall rating. Students' mean score (+/-SD) on the EOC-MCQ exam was 76.1% (8.1) for groups taught by content experts, 78.2% (7.8) for the combination group and 79.5% (9.2) for process expert groups (p = 0.11). By linear regression student performance was higher if they had been taught by process experts (regression coefficient 2.7 [0.1, 5.4], p < .05), but not content experts (p = .09). CONCLUSIONS: When preceptors are physicians, content expertise is not a prerequisite to teach first year medical students within a structured small group environment; preceptors with process expertise result in at least equivalent, if not superior, student outcomes in this setting. PMID- 20946675 TI - The activation of CD14, TLR4, and TLR2 by mmLDL induces IL-1beta, IL-6, and IL-10 secretion in human monocytes and macrophages. AB - Atherosclerosis is considered a chronic inflammatory disease in which monocytes and macrophages are critical. These cells express CD14, toll-like receptor (TLR) 2, and TLR4 on their surfaces, are activated by minimally modified low-density lipoprotein (mmLDL) and are capable of secreting pro-inflammatory cytokines. The aim of this research was thus to demonstrate that the activation of CD14, TLR2, and TLR4 by mmLDL induces the secretion of cytokines. METHODS: Human monocytes and macrophages were incubated with monoclonal antibodies specific for CD14, TLR4, and TLR2 prior to stimulation with mmLDL. Cytokine secretion was then compared to that observed upon mmLDL stimulation in untreated cells. RESULTS: Stimulation with mmLDL induced the secretion of pro-inflammatory cytokines. Blocking CD14 in monocytes inhibited secretion of interleukin (IL)-1beta (72%), IL-6 (58%) and IL-10 (63%), and blocking TLR4 inhibited secretion of IL-1beta by 67%, IL-6 by 63% and IL-10 by 60%. Blocking both receptors inhibited secretion of IL-1beta by 73%, IL-6 by 69% and IL-10 by 63%. Furthermore, blocking TLR2 inhibited secretion of IL-1beta by 65%, IL-6 by 62% and IL-10 by 75%. In macrophages, we found similar results: blocking CD14 inhibited secretion of IL 1beta by 59%, IL-6 by 52% and IL-10 by 65%; blocking TLR4 inhibited secretion of IL-1beta by 53%, IL-6 by 63% and IL-10 by 61%; and blocking both receptors inhibited secretion of IL-1beta by 69%, IL-6 by 67% and IL-10 by 65%. Blocking TLR2 in macrophages inhibited secretion of IL-1beta by 57%, IL-6 by 40% and IL-10 by 72%. CONCLUSION: Our study demonstrates that CD14, TLR4, and TLR2 participate in the immune response against mmLDL by inducing the production of pro inflammatory cytokines in both monocytes and macrophages. These findings suggest that the activation of these receptors by mmLDL contributes to the inflammatory process of atherosclerosis. PMID- 20946676 TI - Preconception care for diabetic women for improving maternal and fetal outcomes: a systematic review and meta-analysis. AB - BACKGROUND: Preexisting diabetes mellitus is associated with increased risk for maternal and fetal adverse outcomes. Despite improvement in the access and quality of antenatal care recent population based studies demonstrating increased congenital abnormalities and perinatal mortality in diabetic mothers as compared to the background population. This systematic review was carried out to evaluate the effectiveness and safety of preconception care in improving maternal and fetal outcomes for women with preexisting diabetes mellitus. METHODS: We searched the following databases, MEDLINE, EMBASE, WEB OF SCIENCE, Cochrane Library, including the CENTRAL register of controlled trials and CINHAL up to December 2009, without language restriction, for any preconception care aiming at health promotion, glycemic control and screening and treatment of diabetes complications in women of reproductive age group with type I or type II diabetes. Study design were trials (randomized and non-randomized), cohort and case-control studies. Of the 1612 title scanned 44 full papers were retrieved of those 24 were included in this review. Twelve cohort studies at low and medium risk of bias, with 2502 women, were included in the meta-analysis. RESULTS: Meta-analysis suggested that preconception care is effective in reducing congenital malformation, RR 0.25 (95% CI 0.15-0.42), NNT17 (95% CI 14-24), preterm delivery, RR 0.70 (95% CI 0.55 0.90), NNT = 8 (95% CI 5-23) and perinatal mortality RR 0.35 (95% CI 0.15-0.82), NNT = 32 (95% CI 19-109). Preconception care lowers HbA1c in the first trimester of pregnancy by an average of 2.43% (95% CI 2.27-2.58). Women who received preconception care booked earlier for antenatal care by an average of 1.32 weeks (95% CI 1.23-1.40). CONCLUSION: Preconception care is effective in reducing diabetes related congenital malformations, preterm delivery and maternal hyperglycemia in the first trimester of pregnancy. PMID- 20946677 TI - GIST suture-line recurrence at a gastrojejunal anastomosis 8 years after gastrectomy: can GIST ever be described as truly benign? A case report. AB - We present the case of a 71 year old man with recurrence of a Gastro Intestinal Stromal Tumour (GIST) at the gastrojejunal anastomosis eight years following partial gastrectomy for a very small primary gastric GIST. He presented acutely on both occasions with haemodynamic shock secondary to massive haematemesis. During his initial presentation in 2001, an emergency laparotomy was performed, demonstrating a pre-pyloric ulcerative lesion. The histopathology was in keeping with a diagnosis of a gastric GIST with a <2 cm tumour, with <5 mitosis per 50/HPF, no signs of necrosis and invasion limited to the mucosa. Eight years later the same patient presented with a similar clinical picture of haemodynamic instability secondary to haematemesis. Emergency endoscopy showed an irregularly shaped elevated lesion on the gastrojejunostomy line suggestive of recurrence. He subsequently underwent completion gastrectomy and the histology revealed a 0.8 cm GIST tumour composed of spindle cells with <5 mitosis per 50/HPF, tumor invasion into the submucosa and positive expression of c-kit and SMA. The patient remains recurrence free 18 months post surgery. The literature suggests that tumour size, mitotic rate and tumour site are the most important predictive factors of recurrence. Additional features such as the presence of necrosis, local tumour invasion and positive resection margins, can also influence recurrence rates. In this case the lesion was a gastric GIST, very small (<2 cm), had low proliferation rate (<5 mitosis/HPF), lacked necrosis and was limited to the mucosa. Recurrence of such a primary GIST at the anastomotic line, eight years after initial resection has never been demonstrated among review of several thousand primary GISTs. This case highlights how even the most innocent GISTs can never be described as truly benign. PMID- 20946679 TI - The trainees' perspective on developing an end-of-grant knowledge translation plan. AB - BACKGROUND: Knowledge translation (KT) is a rapidly growing field that is becoming an integral part of research protocols. METHODS: This meeting report describes one group's experience at the 2009 KT Canada Summer Institute in developing an end-of-grant KT plan for a randomized control trial proposal. RESULTS: Included is a discussion of the process, challenges, and recommendations from the trainee's perspective in developing an end-of-grant KT plan. CONCLUSION: New researchers should consider developing an end-of-grant KT plan with strategies that move beyond passive dissemination to incorporate innovative means of collaboration with the end user to craft the message, package the information, and share the research findings with end users. PMID- 20946678 TI - Determinants of research use in clinical decision making among physical therapists providing services post-stroke: a cross-sectional study. AB - BACKGROUND: Despite evidence of the benefits of research use in post-acute stroke rehabilitation where compliance with clinical practice guidelines has been associated with functional recovery and patient satisfaction, the rate of reliance on the research literature in clinical decision making among physical therapists is low. More research examining factors that motivate physical therapists to consider research findings in neurological practice is needed to inform efforts to intervene. The objective of this study was to identify practitioner, organizational, and research characteristics associated with research use among physical therapists providing services post-stroke. METHODS: A cross-sectional mail survey of physical therapists providing services to people with stroke in Ontario, Canada was conducted. The survey questionnaire contained items to evaluate practitioner and organizational characteristics and perceptions of research considered to influence evidence-based practice (EBP), as well as the frequency of using research evidence in clinical decision making in a typical month. Ordinal regression was used to identify factors associated with research use. RESULTS: The percentage of respondents reporting research use in clinical decision making 0 to 1, 2 to 5, or 6+ times in a typical month was 33.8%, 52.9%, and 13.3%, respectively (n = 263). Academic preparation in the principles of EBP, research participation, service as a clinical instructor, self-efficacy to implement EBP, a positive attitude towards research, perceived organizational support of research use, and Internet access to bibliographic databases at work were each associated with research use and placed in the final regression model. In the final model (n = 244), academic preparation in EBP, EBP self-efficacy, agreement that research findings are useful, and research participation each remained significantly associated with research use after adjusting for the effects of the other variables in the model. CONCLUSIONS: A third of therapists rarely use research evidence in clinical decision making. Education in the principles of EBP, EBP self-efficacy, a positive attitude towards research, and involvement in research at work may promote research use in neurological physical therapy practice. Future research is needed to confirm these findings and to determine the type of research participation that may promote research use. PMID- 20946680 TI - Home-based music therapy--a systematic overview of settings and conditions for an innovative service in healthcare. AB - BACKGROUND: Almost every Western healthcare system is changing to make their services more centered around out-patient care. In particular, long-term or geriatric patients who have been discharged from the hospital often require home based care and therapy. Therefore, several programs have been developed to continue the therapeutic process and manage the special needs of patients after discharge from hospital. Music therapy has also moved into this field of healthcare service by providing home-based music therapy (HBMT) programs. This article reviews and summarizes the settings and conditions of HBMT for the first time. METHODS: The following databases were used to find articles on home-based music therapy: AMED, CAIRSS, EMBASE, MEDLINE, PsychINFO, and PSYNDEX. The search terms were "home-based music therapy" and "mobile music therapy". Included articles were analyzed with respect to participants as well as conditions and settings of HBMT. Furthermore, the date of publication, main outcomes, and the design and quality of the studies were investigated. RESULTS: A total of 20 international publications, 11 clinical studies and nine reports from practice, mainly from the United States (n = 8), were finally included in the qualitative synthesis. Six studies had a randomized controlled design and included a total of 507 patients. The vast majority of clients of HBMT are elderly patients living at home and people who need hospice and palliative care. Although settings were heterogeneous, music listening programs played a predominant role with the aim to reduce symptoms like depression and pain, or to improve quality of life and the relationship between patients and caregivers as primary endpoints. CONCLUSIONS: We were able to show that HBMT is an innovative service for future healthcare delivery. It fits with the changing healthcare system and its conditions but also meets the therapeutic needs of the increasing number of elderly and severely impaired people. Apart from music therapists, patients and their families HBMT is also interesting as a blueprint for home based care for other groups of caregivers. PMID- 20946681 TI - Maternal health care professionals' perspectives on the provision and use of antenatal and delivery care: a qualitative descriptive study in rural Vietnam. AB - BACKGROUND: High quality maternal health care is an important tool to reduce maternal and neonatal mortality. Services offered should be evidence based and adapted to the local setting. This qualitative descriptive study explored the perspectives and experiences of midwives, assistant physicians and medical doctors on the content and quality of maternal health care in rural Vietnam. METHOD: The study was performed in a rural district in northern Vietnam. Four focus group discussions with health care professionals at primary health care level were conducted. The data was analysed using qualitative manifest and latent content analysis. RESULT: Two main themes emerged: "Contextual conditions for maternal health care" and "Balancing between possibilities and constraints". Contextual conditions influenced both pregnant women's use of maternal health care and health care professionals' performance. The study participants stated that women's uses of maternal health care were influenced by economical constraints and cultural norms that impeded their autonomy in relation to childbearing. Structural constraints within the health care system included inadequate financing of the primary health care, resulting in lack of human resources, professional re-training and adequate equipment. CONCLUSION: Contextual conditions strongly influenced the performance and interaction between pregnant women and health care professionals within antenatal care and delivery care in a rural district of Vietnam. Although Vietnam is performing comparatively well in terms of low maternal and child mortality figures, this study revealed midwives' and other health care professionals' perceived difficulties in their daily work. It seemed maternal health care was under-resourced in terms of staff, equipment and continuing education activities. The cultural setting in Vietnam constituting a strong patriarchal society and prevailing Confucian norms limits women's autonomy and reduce their possibility to make independent decisions about their own reproductive health. This issue should be further addressed by policy makers. Strategies to reduce inequities in maternal health care for pregnant women are needed. The quality of client-provider interaction and management of pregnancy may be strengthened by education, human resources, re-training and provision of essential equipment. PMID- 20946682 TI - Efficacy of c-Met inhibitor for advanced prostate cancer. AB - BACKGROUND: Aberrant expression of HGF/SF and its receptor, c-Met, often correlates with advanced prostate cancer. Our previous study showed that expression of c-Met in prostate cancer cells was increased after attenuation of androgen receptor (AR) signalling. This suggested that current androgen ablation therapy for prostate cancer activates c-Met expression and may contribute to development of more aggressive, castration resistant prostate cancer (CRPC). Therefore, we directly assessed the efficacy of c-Met inhibition during androgen ablation on the growth and progression of prostate cancer. METHODS: We tested two c-Met small molecule inhibitors, PHA-665752 and PF-2341066, for anti proliferative activity by MTS assay and cell proliferation assay on human prostate cancer cell lines with different levels of androgen sensitivity. We also used renal subcapsular and castrated orthotopic xenograft mouse models to assess the effect of the inhibitors on prostate tumor formation and progression. RESULTS: We demonstrated a dose-dependent inhibitory effect of PHA-665752 and PF 2341066 on the proliferation of human prostate cancer cells and the phosphorylation of c-Met. The effect on cell proliferation was stronger in androgen insensitive cells. The c-Met inhibitor, PF-2341066, significantly reduced growth of prostate tumor cells in the renal subcapsular mouse model and the castrated orthotopic mouse model. The effect on cell proliferation was greater following castration. CONCLUSIONS: The c-Met inhibitors demonstrated anti proliferative efficacy when combined with androgen ablation therapy for advanced prostate cancer. PMID- 20946683 TI - Integrating the markers Pan I and haemoglobin with the genetic linkage map of Atlantic cod (Gadus morhua). AB - BACKGROUND: Haemoglobin (Hb) and pantophysin (Pan I) markers have been used intensively in population studies of Atlantic cod (Gadus morhua) and in the analysis of traits such as temperature tolerance, growth characteristics and sexual maturation. We used an Illumina GoldenGate panel and the KASPar SNP genotyping system to analyse SNPs in three Atlantic cod families, one of which was polymorphic at the Hb beta1 locus, and to generate a genetic linkage map integrating Pan I and multiple Hb loci. FINDINGS: Data generated allowed the mapping of nine Hb loci, the Pan I locus, and other 122 SNPs onto an existing linkage genetic map for Atlantic cod. Four Hb genes (i.e. alpha1, alpha4, beta1 and beta5) have been mapped on linkage group (LG) 2 while the other five (i.e. alpha2, alpha3, beta2, beta3 and beta4) were placed on LG18. Pan I was mapped on LG 1 using a newly developed KASPar assay for a SNP variable only in Pan IA allelic variants. The new linkage genetic map presented here comprises 1046 SNPs distributed between 23 linkage groups, with a length of 1145.6 cM. A map produced by forcing additional loci, resulting in a reduced goodness-of-fit for mapped markers, allowed the mapping of a total of 1300 SNPs. Finally, we compared our genetic linkage map data with the genetic linkage map data produced by a different group and identified 29 shared SNPs distributed on 10 different linkage groups. CONCLUSIONS: The genetic linkage map presented here incorporates the marker Pan I, together with multiple Hb loci, and integrates genetic linkage data produced by two different research groups. This represents a useful resource to further explore if Pan I and Hbs or other genes underlie quantitative trait loci (QTL) for temperature sensitivity/tolerance or other phenotypes. PMID- 20946684 TI - Short sleep duration and obesity among Australian children. AB - BACKGROUND: There is limited information on sleep duration and obesity among Australian children. The objective of the study is to cross-sectionally examine the relationship between sleep duration and obesity in Australian children aged 5 to 15 years. METHODS: Data were collected using the South Australian Monitoring and Surveillance System between January 2004 and December 2008. Each month a representative random sample of South Australians are selected from the Electronic White Pages with interviews conducted using Computer Assisted Telephone Interviewing (CATI). Within each household, the person who was last to have a birthday was selected for interview. Parents reported the number of hours their children slept each day. Obesity was defined according to the International Obesity Task Force (IOTF) definition based on BMI calculated from reported body weight and height. RESULTS: Overall, parents of 3495 children aged 5-15 years (mean 10.7 years, 50.3% boys) were interviewed. The prevalence of obesity was 7.7% (8.9% in boys, 6.6% in girls). In multivariate analysis after adjusting for sociodemographic variables, intake of fruit and vegetables, physical activity and inactivity, the odds ratio (OR) for obesity comparing sleeping <9 hours with >=10 hours was 2.23 (95% CI 1.04-4.76) among boys, 1.70(0.78-3.73) among girls, and 1.97(1.15-3.38) in both genders. The association between short sleep (<9 hours) and obesity was stronger in the younger age group. No significant association between short sleep and obesity was found among children aged 13-15. There was also an additive interaction between short sleep and low level of physical activity. CONCLUSION: Short sleep duration is associated with increased obesity in children especially among younger age groups and boys. PMID- 20946685 TI - Effect of standing posture during whole body vibration training on muscle morphology and function in older adults: a randomised controlled trial. AB - BACKGROUND: Whole body vibration (WBV) is a novel modality of exercise shown to improve musculoskeletal function. This study aims to examine the effects of standing posture during low magnitude WBV training on muscle function and muscle morphology in older adults. METHODS: Nineteen men and women (50-80 years) were recruited to a three month randomised controlled trial and allocated to one of three groups: WBV with flexed knees (FK), WBV with locked knees (LK), or sham WBV with flexed knees (CON). Exposure was intermittent (1 min WBV:1 min rest) for 20 min, three times per week for 13 weeks. Measurements were taken at baseline and at three months. Primary outcomes included upper and lower body muscle function (strength, power and velocity). Secondary outcomes were muscle morphology, balance, habitual and maximal gait velocity, stair climb power, and chair stand performance. RESULTS: Sixteen subjects completed the study. Relative (%) upper body contraction velocity improved significantly after WBV with FK compared to LK (FK 16.0%, LK -7.6%, CON 4.7, p = 0.01). Relative upper body strength (LK 15.1%, p = 0.02; FK 12.1%, p = 0.04; CON 4.7%) increased significantly following WBV compared to control. Absolute (p = 0.05) and relative (p = 0.03) lower leg strength significantly improved with both standing postures (LK 14.4%; FK 10.7%; CON 1.3%). Only the LK group differed significantly from CON in relative leg strength gains (p = 0.02). Potentially clinically meaningful but statistically non-significant improvements in lower leg muscle cross-sectional area (LK 3.7 cm2, FK 2.4 cm2, CON 2.2 cm2 p = 0.13) were observed after WBV with LK compared to the other groups. No significant effects of WBV on any functional performance tests were observed. CONCLUSIONS: Our results suggest that WBV may improve muscle strength and contraction velocity in some muscle groups in older adults. However, hypothesised differential adaptation to standing posture (FK > LK) was observed only for upper body contraction velocity, making recommendations regarding this prescriptive element inconclusive. The efficacy, mechanism of action and long term feasibility of WBV for musculoskeletal health in older adults warrants continued investigation in robustly designed, sufficiently powered future studies. TRIAL REGISTRATION: ACTRN12609000353291. PMID- 20946686 TI - Self-medication with antibiotics for the treatment of menstrual symptoms in Southwest Nigeria: a cross-sectional study. AB - BACKGROUND: Self-medication with antibiotics is an important factor contributing to the development of bacterial antibiotic resistance. The purpose of this study was to evaluate the prevalence of self-medication with antibiotics for the treatment of menstrual symptoms among university women in Southwest Nigeria. METHODS: A cross-sectional survey was administered to female undergraduate and graduate students (n = 706) at four universities in Southwest Nigeria in 2008. The universities were selected by convenience and the study samples within each university were randomly selected cluster samples. The survey was self administered and included questions pertaining to menstrual symptoms, analgesic and antibiotic use patterns, and demographics. Data were analyzed using descriptive statistics and logistic regression. RESULTS: The response rate was 95.4%. Eighty-six percent (95% CI: 83-88%) of participants experienced menstrual symptoms, and 39% (95% CI: 36-43%) reported using analgesics to treat them. Overall, 24% (95% CI: 21-27%) of participants reported self-medicated use of antibiotics to treat the following menstrual symptoms: cramps, bloating, heavy bleeding, headaches, pimples/acne, moodiness, tender breasts, backache, joint and muscle pain. Factors associated with this usage were: lower levels of education (Odds Ratio (OR): 2.8, 95% CI: 1.1-7.1, p-value: 0.03); non-science major (OR: 1.58, 95% CI: 1.03-2.50, p-value: 0.04); usage of analgesics (OR: 3.17, 95% CI: 2.07-4.86, p-value: <0.001); and mild to extreme heavy bleeding (OR: 1.64, 95% CI: 1.01-2.67, p-value: 0.05) and pimples/acne (OR: 1.57, 95% CI: 0.98-2.54, p value: 0.06). Ampicillin, tetracycline, ciprofloxacin and metronidazole were used to treat the most symptoms. Doctors or nurses (6%, 95% CI: 4-7%), friends (6%, 95% CI: 4-7%) and family members (7%, 95% CI: 5-8%) were most likely to recommend the use of antibiotics for menstrual symptoms, while these drugs were most often obtained from local chemists or pharmacists (10.2%, 95% CI: 8-12%). CONCLUSIONS: This is the first formal study to report that approximately 1 out of 4 university women surveyed in Southwest Nigeria self-medicate with antibiotics to treat menstrual symptoms. This practice could provide monthly, low-dose exposures to antibiotics among users. Further studies are necessary to evaluate the impacts of self-medication on student health. PMID- 20946687 TI - Kruppel-like factor 4, a novel transcription factor regulates microglial activation and subsequent neuroinflammation. AB - BACKGROUND: Activation of microglia, the resident macrophages of the central nervous system (CNS), is the hallmark of neuroinflammation in neurodegenerative diseases and other pathological conditions associated with CNS infection. The activation of microglia is often associated with bystander neuronal death. Nuclear factor-kappaB (NF-kappaB) is one of the important transcription factors known to be associated with microglial activation which upregulates the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (Cox-2) and other pro-inflammatory cytokines. Recent studies have focused on the role of Kruppel-like factor 4 (Klf4), one of the zinc-finger transcription factors, in mediating inflammation. However, these studies were limited to peripheral system and its role in CNS is not understood. Our studies focused on the possible role of Klf4 in mediating CNS inflammation. METHODS: For in vitro studies, mouse microglial BV-2 cell lines were treated with 500 ng/ml Salmonella enterica lipopolysacchride (LPS). Brain tissues were isolated from BALB/c mice administered with 5 mg/kg body weight of LPS. Expressions of Klf4, Cox-2, iNOS and pNF-kappaB were evaluated using western blotting, quantitative real time PCR, and reverse transcriptase polymerase chain reactions (RT-PCRs). Klf4 knockdown was carried out using SiRNA specific for Klf4 mRNA and luciferase assays and electromobility shift assay (EMSA) were performed to study the interaction of Klf4 to iNOS promoter elements in vitro. Co-immunoprecipitation of Klf4 and pNF kappaB was done in order to study a possible interaction between the two transcription factors. RESULTS: LPS stimulation increased Klf4 expression in microglial cells in a time- and dose-dependent manner. Knockdown of Klf4 resulted in decreased levels of the pro-inflammatory cytokines TNF-alpha, MCP-1 and IL-6, along with a significant decrease in iNOS and Cox-2 expression. NO production also decreased as a result of Klf4 knockdown. We found that Klf4 can potentially interact with pNF-kappaB and is important for iNOS and Cox-2 promoter activity in vitro. CONCLUSIONS: These studies demonstrate the role of Klf4 in microglia in mediating neuroinflammation in response to the bacterial endotoxin LPS. PMID- 20946688 TI - Triple negativity and young age as prognostic factors in lymph node-negative invasive ductal carcinoma of 1 cm or less. AB - BACKGROUND: Whether a systemic adjuvant treatment is needed is an area of controversy in patients with node-negative early breast cancer with tumor size of <=1 cm, including T1mic. METHODS: We performed a retrospective analysis of clinical and pathology data of all consecutive patients with node-negative T1mic, T1a, and T1b invasive ductal carcinoma who received surgery between Jan 2000 and Dec 2006. The recurrence free survival (RFS) and risk factors for recurrence were identified. RESULTS: Out of 3889 patients diagnosed with breast cancer, 375 patients were enrolled (T1mic:120, T1a:93, T1b:162). Median age at diagnosis was 49. After a median follow up of 60.8 months, 12 patients developed recurrences (T1mic:4 (3.3%), T1a:2 (2.2%), T1b:6 (3.7%)), with a five-year cumulative RFS rate of 97.2%. Distant recurrence was identified in three patients. Age younger than 35 years (HR 4.91; 95% CI 1.014-23.763, p = 0.048) and triple negative disease (HR 4.93; 95% CI 1.312-18.519, p = 0.018) were significantly associated with a higher rate of recurrence. HER2 overexpression, Ki-67, and p53 status did not affect RFS. CONCLUSIONS: Prognosis of node-negative breast cancer with T1mic, T1a and T1b is excellent, but patients under 35 years of age or with triple negative disease have a relatively high risk of recurrence. PMID- 20946689 TI - Changing malaria intervention coverage, transmission and hospitalization in Kenya. AB - BACKGROUND: Reports of declining incidence of malaria disease burden across several countries in Africa suggest that the epidemiology of malaria across the continent is in transition. Whether this transition is directly related to the scaling of intervention coverage remains a moot point. METHODS: Paediatric admission data from eight Kenyan hospitals and their catchments have been assembled across two three-year time periods: September 2003 to August 2006 (pre scaled intervention) and September 2006 to August 2009 (post-scaled intervention). Interrupted time series (ITS) models were developed adjusting for variations in rainfall and hospital use by surrounding communities to show changes in malaria hospitalization over the two periods. The temporal changes in factors that might explain changes in disease incidence were examined sequentially for each hospital setting, compared between hospital settings and ranked according to plausible explanatory factors. RESULTS: In six out of eight sites there was a decline in Malaria admission rates with declines between 18% and 69%. At two sites malaria admissions rates increased by 55% and 35%. Results from the ITS models indicate that before scaled intervention in September 2006, there was a significant month-to-month decline in the mean malaria admission rates at four hospitals (trend P < 0.05). At the point of scaled intervention, the estimated mean admission rates for malaria was significantly less at four sites compared to the pre-scaled period baseline. Following scaled intervention there was a significant change in the month-to-month trend in the mean malaria admission rates in some but not all of the sites. Plausibility assessment of possible drivers of change pre- versus post-scaled intervention showed inconsistent patterns however, allowing for the increase in rainfall in the second period, there is a suggestion that starting transmission intensity and the scale of change in ITN coverage might explain some but not all of the variation in effect size. At most sites where declines between observation periods were documented admission rates were changing before free mass ITN distribution and prior to the implementation of ACT across Kenya. CONCLUSION: This study provides evidence of significant within and between location heterogeneity in temporal trends of malaria disease burden. Plausible drivers for changing disease incidence suggest a complex combination of mechanisms, not easily measured retrospectively. PMID- 20946690 TI - What do first-time mothers worry about? A study of usage patterns and content of calls made to a postpartum support telephone hotline. AB - BACKGROUND: Telephone hotlines designed to address common concerns in the early postpartum could be a useful resource for parents. Our aim was to test the feasibility of using a telephone as an intervention in a randomized controlled trial. We also aimed to test to use of algorithms to address parental concerns through a telephone hotline. METHODS: Healthy first-time mothers were recruited from postpartum wards of hospitals throughout Lebanon. Participants were given the number of a 24-hour telephone hotline that they could access for the first four months after delivery. Calls were answered by a midwife using algorithms developed by the study team whenever possible. Callers with medical complaints were referred to their physicians. Call patterns and content were recorded and analyzed. RESULTS: Eighty-four of the 353 women enrolled (24%) used the hotline. Sixty percent of the women who used the service called more than once, and all callers reported they were satisfied with the service. The midwife received an average of three calls per day and most calls occurred during the first four weeks postpartum. Our algorithms were used to answer questions in 62.8% of calls and 18.6% of calls required referral to a physician. Of the questions related to mothers, 66% were about breastfeeding. Sixty percent of questions related to the infant were about routine care and 23% were about excessive crying. CONCLUSIONS: Utilization of a telephone hotline service for postpartum support is highest in the first four weeks postpartum. Most questions are related to breastfeeding, routine newborn care, and management of a fussy infant. It is feasible to test a telephone hotline as an intervention in a randomized controlled trial. Algorithms can be developed to provide standardized answers to the most common questions. PMID- 20946691 TI - Genetic structure of the oak wilt vector beetle Platypus quercivorus: inferences toward the process of damaged area expansion. AB - BACKGROUND: The ambrosia beetle, Platypus quercivorus, is the vector of oak wilt, one of the most serious forest diseases in Japan. Population genetics approaches have made great progress toward studying the population dynamics of pests, especially for estimating dispersal. Knowledge of the genetic structuring of the beetle populations should reveal their population history. Using five highly polymorphic microsatellite loci, 605 individuals from 14 sampling sites were assessed to infer the ongoing gene flow among populations as well as the processes of expansion of damaged areas. RESULTS: Population differentiation (FST = 0.047, G'ST = 0.167) was moderate and two major clusters were detected by several methods, dividing the samples into north-eastern and south-western populations, a similar genetic divergence was reported in host oak trees. Within the north-eastern populations, the subgroups mostly corresponded to differences in the collection period. The genetic characteristics of the population might have changed after 2 years due to the mixing of individuals between populations with enhanced migration related to population outbreaks. Because isolation by distance was detected for whole populations and also within the north-eastern populations, migration was considered to be limited between neighbouring populations, and most populations were suggested to be in genetic equilibrium of genetic drift and gene flow. Recent bottlenecks were found in some populations with no geographical bias; however, they were all from newly emerged oak wilt forests. The emergence of oak wilt should have induced intense fluctuations in the beetle population size. CONCLUSIONS: Because the genetic boundaries coincide, we suggest that the geographical structuring of the beetle was formed by co evolution with the host species. Our findings indicate the oak wilt expansion process. PMID- 20946692 TI - Piperonyl butoxide enhances triclabendazole action against triclabendazole resistant Fasciola hepatica. AB - A study has been carried out to determine whether the action of triclabendazole (TCBZ) against the liver fluke, Fasciola hepatica is altered by inhibition of the cytochrome P450 (CYP 450)-mediated drug metabolism pathway. The Oberon TCBZ resistant and Cullompton TCBZ-susceptible fluke isolates were used for these experiments, the basic design of which is given in the paper by Devine et al. (2010a). Piperonyl butoxide (PB) was the CYP P450 inhibitor used. Morphological changes resulting from drug treatment and following metabolic inhibition were assessed by means of transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ susceptible than TCBZ-resistant isolate. However, co-incubation with PB+TCBZ, but more particularly PB+TCBZ.SO, led to greater changes to the TCBZ-resistant isolate than with each drug on its own, with blebbing of the apical plasma membrane, severe swelling of the basal infolds and their associated mucopolysaccharide masses in the syncytium and flooding in the internal tissues. Golgi complexes were greatly reduced or absent in the tegumental cells and the synthesis and production of secretory bodies were badly disrupted. The mitochondria were swollen throughout the tegumental system and the somatic muscle blocks were disrupted. With the TCBZ-susceptible Cullompton isolate, there was a limited increase in drug action following co-incubation with PB. The results provide evidence that the condition of a TCBZ-resistant fluke can be altered by inhibition of drug metabolism. Moreover, they support the concept that altered drug metabolism contributes to the mechanism of resistance to TCBZ. PMID- 20946694 TI - A mechanistic model of developing immunity to Teladorsagia circumcincta infection in lambs. AB - Acquired immunity influences the severity of parasitic disease, but modelling the effects of acquired immunity in helminth infections has proved challenging. This may be due to a lack of suitable immunological data, or to the perceived complexity of modelling the immune response. We have developed a model of T. circumcincta infection in domestic sheep that incorporates the effects of acquired immunity on parasite establishment and fecundity. A large data set from commercially managed populations of Scottish Blackface sheep was used, which included relationships between IgA activity and worm length, and between worm length and fecundity. Use was also made of a recently published meta-analysis of parasite establishment rates. This realistic but simple model of nematode infection emulates observed patterns of faecal egg counts. The end-of-season faecal egg counts are remarkably robust to perturbations in the majority of the parameters, possibly because of priming of the immune system early in the season, reducing parasite establishment and growth and, therefore, faecal egg counts. Lowering the amount of early infection leads to higher end-of-season egg counts. The periparturient rise in egg counts in ewes appears to have an important role in supplying infection for the priming of the immune response. This feedback in the immune priming suggests that nematode infections may be difficult to eliminate. PMID- 20946693 TI - Acquired immune heterogeneity and its sources in human helminth infection. AB - Similarities in the immunobiology of different parasitic worm infections indicate that co-evolution of humans and helminths has shaped a common anti-helminth immune response. However, recent in vitro and immuno-epidemiological studies highlight fundamental differences and plasticity within host-helminth interactions. The 'trade-off' between immunity and immunopathology inherent in host immune responses occurs on a background of genetic polymorphism, variable exposure patterns and infection history. For the parasite, variation in life cycle and antigen expression can influence the effector responses directed against them. This is particularly apparent when comparing gastrointestinal and tissue-dwelling helminths. Furthermore, insights into the impact of anti helminthic treatment and co-infection on acquired immunity suggest that immune heterogeneity arises not from hosts and parasites in isolation, but also from the environment in which immune responses develop. Large-scale differences observed in the epidemiology of human helminthiases are a product of complex host-parasite environment interactions which, given potential for exposure to parasite antigens in utero, can arise even before a parasite interacts with its human host. This review summarizes key differences identified in human acquired immune responses to nematode and trematode infections of public health importance and explores the factors contributing to these variations. PMID- 20946695 TI - Variation within and among host species in engorgement of larval trombiculid mites. AB - We recovered larval trombiculid mites (i.e. chiggers), vectors of scrub typhus, from small mammal hosts in Taiwan, and compared the relative degree of engorgement (RDE) of the dominant chigger (Leptotrombidium imphalum) from different hosts. Naturally occurring chiggers recovered from Rattus losea and Bandicota indica were 1.4x and 1.3x as engorged as those from Apodemus agrarius. Within each host species, RDE was negatively related to chigger loads, but was mostly unrelated to gender or to body or reproductive condition of hosts. We documented significant variation in chigger engorgement both within and among host species; to the extent that RDE is a proxy for fitness, this contradicts predictions of the Ideal Free Distribution (IFD) that the per capita fitness of vectors should be similar among hosts. Failure to meet predictions of the IFD may reflect the limited mobility of chiggers, which consequently must be less selective in the hosts on which they feed. Further disease control efforts should consider vector feeding success in addition to vector abundance and may be able to capitalize on the unsuitability of certain hosts in supporting disease vectors. PMID- 20946696 TI - Phylogenetic position of Sphaerospora testicularis and Latyspora scomberomori n. gen. n. sp. (Myxozoa) within the marine urinary clade. AB - An amendment of the family Sinuolineidae (Myxosporea) is proposed in order to include a newly described genus Latyspora n. gen. The type species Latyspora scomberomori n. gen. n. sp. is a coelozoic parasite in the kidney tubules of Scomberomorus guttatus. In addition to the morphological and molecular characterization of L. scomberomori n. gen. n. sp., we also present novel SSU rDNA data on Sphaerospora testicularis, a serious parasite of Dicentrarchus labrax. Performed phylogenetic analyses revealed that both species cluster within the marine urinary clade encompassing the representatives with a shared insertion within their V4 SSU rRNA region and grouping according to the shape of their spores' sutural line and their similar tissue tropism in the host. Sphaerospora testicularis is the closest relative to Parvicapsula minibicornis within the Parvicapsula subclade and L. scomberomori n. gen. n. sp. is the basal species of the Zschokkella subclade. The phylogenetic position of S. testicularis, outwith the basal Sphaerospora sensu stricto clade, and its morphology suggest it being a non-typical Sphaerospora. The sequence data provided on S. testicularis can help in future revisions of the strongly polyphyletic genus Sphaerospora. We recommend re-sequencing of several sphaerosporids as an essential step before such taxonomic changes are accomplished. PMID- 20946697 TI - First description of monogenean parasites in Lake Tanganyika: the cichlid Simochromis diagramma (Teleostei, Cichlidae) harbours a high diversity of Gyrodactylus species (Platyhelminthes, Monogenea). AB - Lake Tanganyika harbours the most diverse endemic cichlid fish assemblage of Africa, but its monogenean fish parasites have not been investigated. Here we report, for the first time, on the Gyrodactylus parasites in this hotspot of fish biodiversity. Haptor morphometrics and nuclear ribosomal DNA sequences revealed 3 new species on Zambian Simochromis diagramma: Gyrodactylus sturmbaueri n. sp., G. thysi n. sp. and G. zimbae n. sp. Their distinct morphology and strong genetic differentiation suggest that they belong to distant lineages within the genus Gyrodactylus, and phylogenetic reconstructions suggest affinities with other genera of gyrodactylids. Additional U-shaped haptoral plates in G. thysi n. sp. and a second large spine-like structure in the male copulatory organ of G. zimbae seem to represent new features for the genus. Such large diversity on a single host species can probably be explained by host-switching events during the course of evolution, in agreement with the generally accepted concept that ecological transfer is an important aspect of gyrodactylid speciation. Additional parasitological surveys on other host species, covering a broader phylogenetic and geographical range, should clarify the evolutionary history of Gyrodactylidae on cichlids in the African Great Lake and other parts of Africa. PMID- 20946698 TI - Cytological and molecular description of Hamiltosporidium tvaerminnensis gen. et sp. nov., a microsporidian parasite of Daphnia magna, and establishment of Hamiltosporidium magnivora comb. nov. AB - We describe the new microsporidium Hamiltosporidium tvaerminnensis gen. et sp. nov. with an emphasis on its ultrastructural characteristics and phylogenetic position as inferred from the sequence data of SSU rDNA, alpha- and beta-tubulin. This parasite was previously identified as Octosporea bayeri Jirovec, 1936 and has become a model system to study the ecology, epidemiology, evolution and genomics of microsporidia - host interactions. Here, we present evidence that shows its differences from O. bayeri. Hamiltosporidium tvaerminnensis exclusively infects the adipose tissue, the ovaries and the hypodermis of Daphnia magna and is found only in host populations located in coastal rock pool populations in Finland and Sweden. Merogonial stages of H. tvaerminnensis have isolated nuclei; merozoites are formed by binary fission or by the cleaving of a plasmodium with a small number of nuclei. A sporogonial plasmodium with isolated nuclei yields 8 sporoblasts. Elongated spores are generated by the most finger-like plasmodia. The mature spores are polymorphic in shape and size. Most spores are pyriform (4.9-5.6*2.2-2.3 MUm) and have their polar filament arranged in 12-13 coils. A second, elongated spore type (6.8-12.0*1.6-2.1 MUm) is rod-shaped with blunt ends and measures 6.8-12.0*1.6-2.1 MUm. The envelope of the sporophorous vesicle is thin and fragile, formed at the beginning of the sporogony. Cytological and molecular comparisons with Flabelliforma magnivora, a parasite infecting the same tissues in the same host species, reveal that these two species are very closely related, yet distinct. Moreover, both cytological and molecular data indicate that these species are quite distant from F. montana, the type species of the genus Flabelliforma. We therefore propose that F. magnivora also be placed in Hamiltosporidium gen. nov. PMID- 20946699 TI - The melatonergic agonist and clinically active antidepressant, agomelatine, is a neutral antagonist at 5-HT(2C) receptors. AB - The novel antidepressant, agomelatine, behaves as an agonist at melatonergic receptors, and as an antagonist at edited, human serotonin2C(VSV) receptors [h5 HT2C(VSV)Rs]. However, its actions at constitutively active 5-HT2CRs have yet to be characterized, an issue addressed herein. At unedited h5-HT2C(INI)Rs expressed in HEK-293 cells, 5-HT enhanced [35S]GTPgammaS binding to Galphaq, whereas the inverse agonists SB206,553 and S32006 inhibited binding and, by analogy to the neutral antagonist, SB242,084, agomelatine exerted no effect alone. Mirroring these observations, 5-HT stimulated, whereas SB206,553 and S32006 inhibited, [3H]inositol phosphate formation. Both the agonist actions of 5-HT and the inverse agonist actions of SB206,553 and S32006 were abolished by agomelatine and SB242,084. As demonstrated by bioluminescence resonance energy transfer, 5-HT enhanced, whereas SB206,553 and S32006 decreased, association of 'h5-HT2C(INI) Rluc-tagged' receptors with yellow-fluorescence-protein-coupled beta-arrestin2. These actions of 5-HT, SB206,553 and S32006 were prevented by agomelatine and SB242,084 were ineffective alone. As shown by ELISA and confocal microscopy, prolonged (18 h) exposure to SB206,553 or S32006 enhanced cell surface expression of N-terminal Flag-tagged h5-HT2C(INI)Rs: these effects were blocked by agomelatine and SB242,084, which were inactive alone. Finally, following pre exposure to SB206,553 or S32006 for 18 h, 5-HT triggered 5-HT2CR-mediated elevations in cytosolic Ca2+ in primary cultures of mice cortical neurons. Agomelatine and SB242,084, inactive alone, prevented these actions of SB206,553 and S32006. In conclusion, agomelatine behaves as a neutral antagonist at constitutively active h5-HT2C(INI)Rs and native, cortical 5-HT2CRs. It will be of interest to determine whether the neutral antagonist properties of agomelatine are related to its favourable clinical profile of antidepressant properties with few side-effects and no discontinuation syndrome. PMID- 20946700 TI - New electrostatic phase plate for phase-contrast transmission electron microscopy and its application for wave-function reconstruction. AB - A promising novel type of electrostatic phase plate for transmission electron microscopy (TEM) is presented. The phase plate consists of a single microcoaxial cable-like rod with its electrode exposed to the undiffracted electrons. The emerging field is used to shift the phase of the undiffracted electrons with respect to diffracted electrons. The design overcomes the drawback of the spatial frequency-blocking ring electrode of the Boersch phase plate. First, experimental phase-contrast images are presented for PbSe and Pt nanoparticles with clearly varying phase contrast, which depends on the applied voltage and resulting phase shift of the unscattered electrons. With the new phase-plate design, we show for the first time the reconstruction of an object wave function based on a series of only three experimental phase-contrast TEM images obtained with an electrostatic phase plate. PMID- 20946701 TI - Colocalization analysis in fluorescence micrographs: verification of a more accurate calculation of pearson's correlation coefficient. AB - One of the most routine uses of fluorescence microscopy is colocalization, i.e., the demonstration of a relationship between pairs of biological molecules. Frequently this is presented simplistically by the use of overlays of red and green images, with areas of yellow indicating colocalization of the molecules. Colocalization data are rarely quantified and can be misleading. Our results from both synthetic and biological datasets demonstrate that the generation of Pearson's correlation coefficient between pairs of images can overestimate positive correlation and fail to demonstrate negative correlation. We have demonstrated that the calculation of a thresholded Pearson's correlation coefficient using only intensity values over a determined threshold in both channels produces numerical values that more accurately describe both synthetic datasets and biological examples. Its use will bring clarity and accuracy to colocalization studies using fluorescent microscopy. PMID- 20946702 TI - Sleep in dementia and caregiving--assessment and treatment implications: a review. AB - BACKGROUND: The increasing prevalence of dementia will precipitate a significant burden in terms of the costs of caring for people with dementia over the next 30 years; sleep disturbances in dementia are an important factor contributing to this burden. METHODS: We reviewed sleep disturbances in people with dementia and their carers and describe the various diagnostic, assessment and treatment strategies available to physicians in the management of this clinically significant problem. RESULTS: Sleep disturbances in people with dementia and their carers (i) are highly prevalent; (ii) impact significantly on quality of life of both people with dementia and their carers; (iii) increase the rate of cognitive decline; and (iv) accelerate the breakdown of community-based care. The training of physicians in the assessment and treatment of sleep disturbances in dementia and caregiving is scant despite a wide range of assessment strategies and treatment approaches, which comprise both pharmacological (including hypnotic/sedative medications) and non-pharmacological approaches (including: environmental; psychobehavioral; exercise and activity; and multi-component interventions). Specific diagnostic criteria for sleep disturbances in people with dementia and their carers remain lacking despite established criteria for general insomnia. Further to this, proposed changes to diagnostic criteria for DSM-V do not include a specific focus for the diagnosis and management of sleep disturbances in people with dementia or their carers. CONCLUSIONS: This review suggests that the improved training of physicians to meet the needs of these vulnerable groups of older people is a priority, especially in the context of a rapidly increasing demand for accurate, early diagnosis and efficient management of sleep disturbance in these groups. PMID- 20946703 TI - Kana Pick-out Test and brain perfusion imaging in Alzheimer's disease. AB - BACKGROUND: The Kana Pick-out Test (KPT), which was developed in Japan, is suitable for evaluating frontal lobe function and screening for mild dementia. However, the neural substrates involved remain to be elucidated. The aim of the present study was to identify the regional perfusion patterns in the brain associated with performance scores on the KPT in patients with mild Alzheimer's disease (AD), using brain perfusion assessed by single photon emission computed tomography (SPECT). METHODS: Twenty AD patients with high scores on the KPT and 20 age- and sex-matched AD patients with low scores were selected from 227 consecutive Japanese patients of the Memory Clinic of Okayama University Hospital. All 40 subjects underwent brain SPECT with 99mTc-ethylcysteinate dimer, and the SPECT images were analyzed by Statistical Parametric Mapping. RESULTS: With the exception of KPT scores, no significant differences were found between high and low scoring groups with respect to Addenbrooke's Cognitive Examination scores, Mini-mental State Examination scores, or the depression score of the Neuropsychiatric Inventory subscale. Compared to patients with high scores on the KPT, AD patients with low scores on the KPT showed significant hypoperfusion in the left subgenual cingulate gyrus (SGC) extending to the right SGC. CONCLUSIONS: Our results suggest that functional activity of the SGC is closely related to scores on the KPT. KPT might be a promising strategy to use in detecting early stages of AD with low SGC function. PMID- 20946704 TI - A review of the effectiveness of memory interventions in mild cognitive impairment (MCI). AB - BACKGROUND: Mild cognitive impairment (MCI) is commonly associated with memory impairment. There have been a number of studies attempting to ameliorate this through memory interventions including memory rehabilitation and training. The current paper reviews the evidence for the effectiveness of such interventions in enhancing learning of specific information, their impact on untrained material, compensation for memory impairment and improving everyday functioning. METHODS: The literature was systematically searched for studies focusing on interventions targeting memory impairment in MCI using relevant search terms. Studies were screened for inclusion or exclusion using a priori criteria and, once identified, studies were examined for quality using pre-specified criteria. RESULTS: A total of 226 studies were identified in the search, ten of which were included in the final review. Only one study was an RCT of "adequate" methodology. It was tentatively suggested that people with MCI can learn specific information, although there was little evidence to suggest that memory training can generalize. There was some limited evidence of ability to learn to compensate for memory difficulties and contradictory findings regarding improvement in everyday life. CONCLUSIONS: The poor methodological quality of the included studies implies that the ability to draw conclusions is limited. MCI is a controversial concept and there is a need for good quality trials examining the efficacy of memory interventions. There are some indications that memory impairment in MCI might best be targeted by interventions developing compensatory strategies and targeting the learning of specific information relevant to the individual. PMID- 20946705 TI - Attributional intervention for depression in two people with multiple sclerosis (MS): single case design. AB - BACKGROUND: Depression is common in those with MS. The hopelessness theory of depression, emphasizing the role of attributional style, is supported in this population. Cognitive behaviour therapy (CBT) that can affect attributional style can reduce depression in people who have MS. AIMS: The present study aimed to consider whether changing attributional style would reduce depression in two people with MS, thereby supporting the importance of this component of CBT with this population. METHOD: Two female participants with MS were offered a 5-session intervention designed to alter attributional style. The study followed an ABA design. Attributional style and depressive symptoms were the principal measures considered. Negative life events and MS related stresses were also monitored. RESULTS: The intervention appeared effective for one of the participants, with predicted changes in attributional style and sizeable reductions in depressive symptoms from pre- to post-treatment that were sustained at 3-month follow-up. Improvement was still evident at 6 months, although with some reduction of effect. The intervention was less successful for the other participant who declined further treatment after three sessions. CONCLUSIONS: Some support for the hopelessness theory of depression was found, indicating its relevance to CBT interventions for those who have MS and depression. PMID- 20946706 TI - Socio-economic, demographic, lifestyle and health characteristics associated with consumption of fatty-sweetened and fatty-salted foods in middle-aged French adults. AB - Few studies have specifically focused on characteristics associated with consumption of combined fatty-salted and fatty-sweetened foods, whereas their identification could be useful for defining effective public health measures. The aim of the present study was to investigate the association between demographic, socio-economic, lifestyle and health characteristics and consumption of these types of food in a general sample of French adults. Dietary intake was assessed using a minimum of six 24 h dietary records collected over a 2-year period in 6240 subjects aged 35-60 years who participated in the Supplementation en VItamines Mineraux et AntioXydants cohort study. Associations of individual characteristics with high and intermediate consumption of fatty-sweetened and fatty-salted foods were assessed using multivariate polytomic logistic regression models. Risk of moderate or high consumption of fatty-salted foods decreased with increasing age. Current smokers, drinkers, individuals with overweight and with hypertension were more likely to consume moderate or high amounts of such foods. Risk of moderate or high consumption of fatty-sweetened foods decreased with increasing age. Women, individuals living as a couple, moderate drinkers and persons with low or medium physical activity level were more likely to consume moderate or high amounts of such foods. Lower educated subjects, current smokers, heavy drinkers and individuals with severe hypertriacylglycerolaemia were less likely to have moderate or high consumption. Consumption of fatty-sweetened and fatty-salted foods varied according to demographic, lifestyle and health characteristics. Common unhealthy behaviours such as smoking, low physical activity and alcohol drinking, associated with high consumption of these food groups, may help to effectively target public health efforts. PMID- 20946707 TI - Confabulation in Alzheimer's disease and amnesia: a qualitative account and a new taxonomy. AB - Clinical and experimental observation have shown that patients who confabulate, especially but not exclusively when provoked by specific questions, retrieve personal habits, repeated events or over-learned information and mistake them for actually experienced, specific, unique events. Accordingly, the aim of this study is to characterize and quantify the relative contribution of this type of confabulation, which we refer to as Habits Confabulation (HC), to confabulations produced by 10 mild Alzheimer's disease (AD) patients and 8 confabulating amnesics (CA) of various etiologies. On the Confabulation Battery (Dalla Barba, 1993a, Dalla Barba & Decaix, 2009), a set of questions involving the retrieval of various kinds of semantic and episodic information, patients produced a total of 424 confabulation. HC accounted for 42% and 62% of confabulations in AD patients and CA, respectively. This result indicates that, regardless the clinical diagnosis, the brain pathology or their lesion's site, confabulation largely reflects the individuals' tendency to consider habits, routines, and over-learned information as unique episodes. These results are discussed in the framework of the Memory Consciousness and Temporality Theory (Dalla Barba, 2002). PMID- 20946708 TI - Everyday memory: self-perception and structural brain correlates in a healthy elderly population. AB - Mapping the cerebral structural correlates of age-related cognitive decline is a growing area of research. The aim of the present study was to investigate the relationship between healthy elderly's perceived memory functioning in daily life, neuropsychological test performance on a standardized test on verbal memory, and cortical thickness and subcortical volumes in brain regions implicated in memory networks, including the medial temporal lobe (MTL). Eighty three healthy and cognitively well-functioning volunteers aged 60-85 years underwent MRI scans, Everyday Memory Questionnaire (EMQ), and neuropsychological assessment. Both self-perceived memory in daily life related to attention and executive functions and an objective measure of verbal recall (CVLT) were, independently, associated with thickness of the left MTL. The two cognitive variables were uncorrelated, and including both measures in the model nearly doubled the amount of explained variance on MTL thickness. This suggests that measures of perceived everyday memory might substantially inform and supplement studies investigating the relationships between neuropsychological test performance and brain morphology. The results are consistent with a bigger-is better relationship in the MTL and suggest that EMQ and neuropsychological test performance have detectable and comparable structural correlates in a region critically involved in memory functions in the well-functioning elderly. PMID- 20946709 TI - Retrieval practice: a simple strategy for improving memory after traumatic brain injury. AB - Memory impairment is common following traumatic brain injury (TBI), but interventions to improve memory in persons with TBI have been ineffective. Retrieval practice is a robust memory strategy among healthy undergraduates, whereby practice retrieving information shortly after it is presented leads to better delayed recall than simple restudy. In a verbal paired associate paradigm, we investigated the effect of retrieval practice relative to massed and spaced restudy on delayed recall in 14 persons with chronic memory impairment following a TBI and 14 age-matched healthy controls. A significant learning condition (massed restudy, spaced restudy, retrieval practice) by group (TBI, healthy) interaction emerged, whereby only healthy controls benefited from spaced restudy (i.e., distributed learning) over massed restudy, but both groups greatly benefited from retrieval practice over massed and spaced restudy. That is, retrieval practice greatly improves memory in persons with TBI, even when other mnemonic strategies (e.g., distributed learning) are less effective. PMID- 20946711 TI - Preface to the Canadian Health Measures Survey results - oral health statistics, 2007-2009. PMID- 20946712 TI - The public health implications of assisted reproductive technologies. AB - OBJECTIVE: The public health implications of Assisted Reproductive Technologies (ART) are largely unknown by researchers and policy makers alike. Outcomes need to be considered, not just as clinical issues, but in terms of effect on public health. METHODS: Using a qualitative key informant process involving interviews with selected professionals and a review of the medical literature, eight general themes of public health issues associated with ART were identified, and are discussed. RECOMMENDATIONS: Short and long-term health outcomes of women undergoing ART procedures, and of their offspring, need to be considered, as do the epidemiological risks associated with donated gametes and the effect on health services of multiple and preterm births, both produced in higher rates by ART. A national surveillance system and greater inter-jurisdictional communication are important strategies for addressing these evolving concerns. PMID- 20946713 TI - Autism spectrum disorders, maternal characteristics and obstetric complications among singletons born in Alberta, Canada. AB - OBJECTIVE: To determine whether certain maternal characteristics and obstetric complications are associated with increased risk of autism spectrum disorders (ASD) in children. METHODS: Provincial delivery records identified the cohort of 218 890 singleton live births in Alberta, Canada,between January 1, 1998, and December 31, 2004. These were followed-up for ASD via ICD-9 diagnostic codes assigned by physician billing until March 31, 2008. Maternal and obstetric risk factors were also extracted from PDR. RESULTS: Prevalence and incidence of ASD in Alberta are in line with those reported elsewhere and suggest recent increases in rate of diagnosis and/or incidence. Boys have 5-fold higher prevalence than girls. The peak age of diagnosis occurs at age 3 years. Relative risk modelling indicates that the risk of ASD is elevated among children of older mothers and those who experience specific pregnancy and birth complications. CONCLUSION: Certain maternal characteristics and obstetric complications are associated with ASD in children. We identified lower rates of ASD and later age at diagnosis among children of Aboriginal mothers that requires further research. PMID- 20946714 TI - An investigation of cancer incidence in a First Nations community in Alberta, Canada, 1995-2006. AB - OBJECTIVE: To determine colorectal and overall cancer incidence as part of a three-pronged investigation in response to the concerns of a First Nations community in Alberta, Canada, located close to sulfur-rich natural gas installations, and to determine whether the incidence of cancers observed in this reserve was higher than expected. METHODS: A population dataset with information identifying First Nations status and band affiliation was linked to the Alberta Cancer Registry to determine cancer incidence cases between 1995 and 2006 for on- and off-reserve study populations. Using indirect standardized incidence ratios, observed cancer incidence cases for the study populations were compared with cases expected based on three separate reference populations. RESULTS: Observed colorectal and overall cancer incidence cases within the First Nations community were not higher than expected. Cervical cancer incidence cases, however, were higher than expected for on- and off-reserve populations; public health measures designed to address this risk have been implemented and on-going surveillance of cancer incidence in the community will be maintained. PMID- 20946715 TI - Myocardial infarction and the validation of physician billing and hospitalization data using electronic medical records. AB - OBJECTIVE: Population-based identification of patients with a myocardial infarction is limited to patients presenting to hospital with an acute event. We set out to determine if adding physician billing data to hospital discharge data would result in an accurate capture of patients who have had a myocardial infarction. METHODS: We performed a retrospective chart abstraction of 969 randomly selected adult patients using data abstracted from primary care physicians on an electronic medical record in Ontario, Canada, as the reference standard. RESULTS: An algorithm of 3 physician billings in a one-year period with at least one being by a specialist or within a hospital or emergency room plus one hospital discharge abstract performed with a sensitivity of 80.4% (95% CI: 69.5-91.3), specificity of 98.0% (95% CI: 97.1-98.9), positive predictive value of 69.5% (95% CI: 57.7-81.2), negative predictive value of 98.9% (95% CI: 98.2% to 99.6%) and kappa statistic of 0.73 (95% CI: 0.63-0.83). CONCLUSION: Using a combination of hospital discharge abstracts and physician billing data may be the best way of assessing trends of MI occurrence over time since it increases the capture of MI beyond those patients who have been hospitalized. PMID- 20946716 TI - Meals and snacks consumed by young Quebecers. PMID- 20946717 TI - Attention deficit hyperactivity disorder and eating disorders. AB - Attention deficit hyperactivity disorder (ADHD) is a common child diagnosis with frequent comorbidities (Quinn, 2008). According to present studies eating disorders may represent one of them (Mikami et al., 2008). Several studies reported ADHD relation to the higher predisposition to obesity (Altafas, 2002), higher values of signs of overnutrition, as body mass index (Waring and Lapane, 2008) or higher value of fat (Ptacek et al., 2009a, c). These characteristics are considered to be directly related to the disorder. They can be caused by impulsivity and probable specific feeding customs of ADHD patients. The presence of eating disorders in ADHD patients could partially explain previously described growth and weight changes. PMID- 20946718 TI - Effect of the single-dose of nicotine-administration on the brain bioelectrical activity and on behaviour in immature 12-day-old rats. AB - A variety of current studies is concentrated on the effect of short-term or long term administration of nicotine in humans and in animals. The aim of this study was to investigate the effect of nicotine after a single administration in two different doses on the brain bioelectrical activity and on behaviour and motor activity in young, immature rats. Male Wistar albino rats, 12-day-old, were used in the experiment. Two groups were administrated by one intraperitoneal (i.p.) injection of nicotine in two various doses. The last (the third) group, which was given one i.p. saline injection, served as a control group. The group with lower dose of nicotine (0.75 mg/kg body weight) showed only mild alteration of the electrocorticogram (ECoG), and no behavioural or motor changes. In the second group (with higher dose of nicotine--1.00 mg/kg), epileptiform discharges manifested in about 50% of animals. Those animals showed also changes in motor activity (tremor of hindlimbs), but only slightly expressed within the time when epileptiform changes occurred in the ECoG. Routine behaviour and locomotion was observed only in a part of animals. In the third group (control group) no changes in bioelectrical activity, in behaviour or in motor activity were observed. We conclude that even a single dose of nicotine can evoke alteration in the ECoG, in behaviour and in motor activity of immature rats. On the other hand, the quantity, quality and length of ECoG abnormalities as well as parameters of behaviour were closely related to the dose of nicotine. PMID- 20946719 TI - Reactivity of Langerhans cells after application of different chemicals--an ultrastructural analysis. AB - The goal of this study was to investigate changes in epidermal Langerhans cells after application of different chemicals (acetone, 60% alcohol, 5% nickel sulphate, iodisole, and 0.1% 2,4-dinitrochlorobenzene) on the skin of volunteers. The skin of eight volunteers was treated with acetone, 60% alcohol, iodisol, 5% nickel sulphate, and 0.1% 2,4-dinitrochlorobenzene (DNCB). After application of DNCB, Langerhans cells (LCs) showed increased accumulation of Birbeck granules (Bgs). Alcohol and nickel sulphate caused alternative changes, mainly cytoplasmic vacuolation, in LCs. Nickel sulphate was even responsible for the disappearance of dendrites. Both chemicals have cytotoxic effects on LCs: cytoplasmic organelles and Bgs disappear and subsequently, the antigen-presenting activity of epidermal LCs is inhibited. We did not found any morphological changes in LCs after application of acetone. PMID- 20946720 TI - Size exclusion chromatography as a tool for evaluation of fragmentation pattern of gastric mucins under non-degrading conditions. AB - Gastric mucins are high molecular weight extracellular glycoproteins that play a major role in the protection of the gastrointestinal tract and besides that they are also involved in many disease processes. In the present study, size exclusion chromatography under non-degrading conditions was used to study the fragmentation pattern of native gastric mucins. The samples of gastric mucins of different origin obtained by an extraction of gastric mucosa with Tris-HCl buffer, pH 7.3 were separated using size exclusion chromatography on Sephadex G-100. While samples of rat gastric mucins are characterized by the presence of only high molecular weight fraction of glycoproteins, fragmented mucin components in non denaturated samples were observed in canine and human gastric mucins. Differences in the fragmentation pattern were observed in patients with ulcer diseases and gastric cancer. Degradation products of mucins were also detected using polyacrylamide gel electrophoresis in the presence of SDS. PMID- 20946721 TI - Retrospective analysis of the results of high-dose chemotherapy with the support of autologous blood stem cells in patients with multiple myeloma. The experience of a single centre. AB - Despite new medical products introduced in multiple myeloma therapy, autologous stem cell transplant (ASCT) remains a standard procedure in younger patients with symptomatic disease. We analyzed a group of 190 patients who underwent ASCT at our clinic for multiple myeloma as primary therapy in years 1995-2008. The total number of transplants performed in this group was 291. 110 patients underwent one ASCT, 59 patients had double transplant, out of which 51 patients underwent tandem transplant, 21 patients underwent triple ASCT, out of which 15 patients were transplanted front-line throughout a clinical trial and 6 patients underwent follow-up transplants due to disease progression. The assessment of the best therapeutic effect of ASCT showed the total rates of patients with complete remission--22%, very good partial remission (VGPR)--8%, partial remission--63%, stabilized disease--6% and progression--1%. The transplant related mortality (TRM) was 4.1%. With the median follow-up of surviving patients 2.6 years, the median progression-free survival (PFS) and overall survival (OS) were 21 and 54 months, respectively; the likelihood of a 7-year overall survival was 28%. Comparing tandem versus single transplants, there was a significant increase in the median PFS (25.8 versus 20.8 months, respectively); however, there was no difference in overall survivals. The IVE mobilization regimen was found to be more efficacious for PBPC collection than high-dosed cyclophosphamide. PMID- 20946722 TI - Effect of long-term treatment on subjective problems of patients with common thyroid gland disorders in the Czech Republic. AB - In this study, a total of 364 patients of the Endocrinology outpatient clinic who had undergone thyreopathy treatment of various lengths were investigated. The objective of the study was to find out the consequences of thyroid gland disorder on a person's life, and whether the treatment length has any effect on subjective problems of patients. Common problems reported by patients were evaluated; the final number of such "common problems" in the final stage of the research was 56. In order to achieve better orientation in the processing of results, the patient described types of disorders were classified according to the patients' own opinions into the following groups: eufunctional thyroid gland, inflammation, hypothyroidism, hyperthyroidism, tumour and surgery. The fact is that in the first year of treatment, almost half of all patients with a thyroid gland disorder experienced some problems caused by the disease. It is not a favourable finding that in the upcoming years, i.e. from 2 to 10 years, the number of those with problems will increase to as much as 61%. The period of treatment between 11 and 15 years means a decrease in the occurrence of problems to 50%, but with the number of patients with problems increasing, their number becomes even higher than that in the period of 2 to 10 years. Influence of aging processes should be also taken into account. PMID- 20946723 TI - Segmental costovertebral anomaly presenting with horn-like appearance in the chest. AB - Several types of abnormalities of the ribs have been reported. Many of these anomalies usually result in the correct diagnosis thanks to the characteristic radiological appearances. But some of the anomalies are rare and it is important to recognize and get accustomed to differing appearances of these osseous abnormalities in order to differentiate the pathological processes and to diagnose the syndromes which may accompany rib anomalies. The localized costovertebral anomaly with horn-like appearance, which has not yet been described in literature, is presented in this paper. PMID- 20946724 TI - Symptomatic severe tricuspid insufficiency as a late complication of pulmonary balloon valvuloplasty. AB - The authors describe an unusual case of a young adult patient with symptomatic tricuspid valve insufficiency as a late consequence of pulmonary valve balloon dilatation in childhood. Patient was successfully treated by tricuspid valve repair with neo-chordae implantation and a ring plasty. Two years after the operation the patient, an active sportsman, is asymptomatic with trace tricuspid regurgitation on the echo examination. PMID- 20946736 TI - Predictors of drug-use patterns in maltreated children and matched controls followed up into middle adulthood. AB - OBJECTIVE: This study examines whether child abuse; child neglect; demographic, family and social, behavioral, economic, and neighborhood risk; and protective factors predict different drug-use patterns into middle adulthood. METHOD: Using a prospective cohort design, individuals with documented cases of childhood physical and sexual abuse and neglect (processed during 1967-1971) and a matched control group were followed into middle adulthood. Participants completed in person interviews in 1989-1995 (average age 29), 2000-2002 (average age 39.5), and 2003-2004 (average age 41). The sample for this study included 374 women and 332 men. RESULTS: Four patterns of drug use were revealed: (a) abstinence and low use (34%), (b) adolescent and young adult limited use (31%), (c) chronic persistent use (29%), and (d) late use (7%). The chronic-persistent pattern was associated with being male, parental substance-use problems, involvement in crime, and neighborhood problems. The late-use pattern was significantly associated with childhood neglect and being Black, when other risk factors were controlled; bivariate analyses also indicated associations with female gender, lower income, and greater neighborhood disadvantage. CONCLUSIONS: This study revealed two patterns of drug use involving substance use and substance-related problems in middle adulthood that are associated with different sets of risk factors. Further research is needed to understand the late-drug-use pattern, which appears to disproportionately involve low-income Black women with histories of childhood neglect. These individuals may be missed in efforts to prevent or reduce drug use among youths. PMID- 20946737 TI - Posttraumatic stress disorder and alcohol dependence in young women. AB - OBJECTIVE: The aim of the current study is to characterize the relationship between posttraumatic stress disorder (PTSD) and alcohol dependence (AD) in women, distinguishing PTSD-specific influences on AD from the contribution of co occurring psychiatric conditions and from the influences of trauma more generally. METHOD: Trauma histories and DSM-IV lifetime diagnoses, including PTSD and AD, were obtained via telephone interview from 3,768 female twins. Based on PTSD status and trauma history, participants were categorized as no trauma (43.7%), trauma without PTSD (52.6%), or trauma with PTSD (3.7%). Cox proportional hazards regression analyses were conducted using trauma/PTSD status to predict AD, first adjusting only for ethnicity and parental problem drinking, then including conduct disorder, major depressive disorder, regular smoking, and cannabis abuse. RESULTS: Before accounting for psychiatric covariates, elevated rates of AD were evident in both trauma-exposed groups, but those with PTSD were at significantly greater risk for AD than those without PTSD. This distinction was no longer statistically significant when psychiatric covariates were included in the model, but both trauma-exposed groups continued to show elevated odds of developing AD compared with the no trauma group. CONCLUSIONS: The elevated rates of AD in women who have experienced trauma are not accounted for in full by psychiatric conditions that commonly co-occur with AD and trauma exposure. The greater likelihood of developing AD in the subset of trauma-exposed individuals who develop PTSD may reflect higher levels of distress and/ or higher rates of psychopathology associated with traumas that lead to PTSD rather than PTSD specific influences. PMID- 20946738 TI - Subpopulations of older foster youths with differential risk of diagnosis for alcohol abuse or dependence. AB - OBJECTIVE: Distinctive combinations of factors are likely to be associated with serious alcohol problems among adolescents about to emancipate from the foster care system and face the difficult transition to independent adulthood. This study identifies particular subpopulations of older foster youths that differ markedly in the probability of a lifetime diagnosis for alcohol abuse or dependence. METHOD: Classification and regression tree (CART) analysis was applied to a large, representative sample (N = 732) of individuals, 17 years of age or older, placed in the child welfare system for more than 1 year. CART evaluated two exploratory sets of variables for optimal splits into groups distinguished from each other on the criterion of lifetime alcohol-use disorder diagnosis. RESULTS: Each classification tree yielded four terminal groups with different rates of lifetime alcohol-use disorder diagnosis. Notable groups in the first tree included one characterized by high levels of both delinquency and violence exposure (53% diagnosed) and another that featured lower delinquency but an independent-living placement (21% diagnosed). Notable groups in the second tree included African American adolescents (only 8% diagnosed), White adolescents not close to caregivers (40% diagnosed), and White adolescents closer to caregivers but with a history of psychological abuse (36% diagnosed). CONCLUSIONS: Analyses incorporating variables that could be comorbid with or symptomatic of alcohol problems, such as delinquency, yielded classifications potentially useful for assessment and service planning. Analyses without such variables identified other factors, such as quality of caregiving relationships and maltreatment, associated with serious alcohol problems, suggesting opportunities for prevention or intervention. PMID- 20946739 TI - Following problem drinkers over eleven years: understanding changes in alcohol consumption. AB - OBJECTIVE: Much of what we know about the course of alcohol consumption in problem and dependent drinkers comes from studies of in-treatment populations. Less is known about the natural course of alcohol consumption among such drinkers in the general population and what predicts how much they drink. METHOD: This study examined alcohol consumption over the course of 11 years in a randomly selected sample of 672 problem and dependent drinkers from a single, heterogeneous U.S. county. RESULTS: Alcohol consumption declined and leveled off over time but did not decrease to the average general U.S. population level. Several indicators of ongoing problems with drinking are associated with high levels of drinking over time: having a heavy-drinking network, receiving suggestions to do something about one's drinking, and going to treatment. Factors associated with less drinking include having contact with community agencies and going to Alcoholics Anonymous (AA). CONCLUSIONS: Results suggest that problem and dependent drinkers continue to drink at an elevated level over the course of years. Gatekeepers, family members, and policymakers should encourage and facilitate contact with social service agencies and with AA for problem drinkers. Suggestions from others to do something about one's drinking and seeking specialty care occur more often in those with more severe problems and do not appear to be linked to less drinking over time. PMID- 20946740 TI - Network support as a prognostic indicator of drinking outcomes: the COMBINE Study. AB - OBJECTIVE: To increase understanding of the interrelationship between a patient's social network and patient drinking, the Important People and Activities (IPA) instrument was developed. To meet the aims of the COMBINE (Combining Medications and Behavioral Interventions) Study, the IPA was modified to create the Important People Inventory (IPI), which was used to measure the contextual influence of the patient's social network on patient outcomes and treatment effects. The aims of the present article were to describe the IPI and its differences from the IPA and to test the relationship of network support as measured by the IPI in predicting drinking during and following treatment. METHOD: Alcohol-dependent patients (N = 1,373) seeking outpatient treatment in the COMBINE randomized clinical trial were administered the IPI before treatment. Six network constructs were tested for predicting patient drinking. RESULTS: As unique effects, alcohol-specific support, as measured by network drinking and opposition to patient drinking, is predictive of patient abstinent days during and following treatment and heavy drinking days following treatment. Other measures of network support have variable relationships to patient drinking at different phases: Some are predictive of patient drinking during treatment but diminish, whereas others are unrelated to drinking during treatment but become increasingly predictive of drinking as time from treatment increases. CONCLUSIONS: The IPI is a useful instrument for describing network support of alcohol-use disorder patients entering treatment. Measures of alcohol-specific support are prognostic of drinking outcomes. The patient's network support should be systematically assessed prior to tailored treatment planning. PMID- 20946741 TI - Romantic relationship status changes and substance use among 18- to 20-year-olds. AB - OBJECTIVE: Changes in romantic relationship status are common in emerging adulthood and may be linked to changes in substance use. This study tested the hypothesis that entry into relationships or transitioning to a more committed status leads to decreases in substance use and that dissolution of relationships or transitioning to a less committed status results in increases in substance use. METHOD: Data were from a community sample of 939 individuals. Substance use (heavy drinking, marijuana use, and cigarette smoking) and relationship status (single, in a romantic relationship but not cohabiting, cohabiting, or married) were assessed at the beginning and end of three 6-month intervals between the ages of 18 and 20 years. Models were estimated to assess the association between transitions in relationship status and substance use, adjusting for prior levels of use. RESULTS: There were increases in heavy drinking, marijuana use, and cigarette smoking associated with dissolution of a romantic relationship, as well as increases in marijuana use and cigarette smoking associated with switching partners within a 6-month interval. Mediation analyses found some support for increases in both depressive symptoms and exposure to substance-using peers partially accounting for these associations. Decreases in substance use were not found for individuals entering into a new relationship or transitioning to a more committed relationship status. In fact, cigarette smoking increased among those who went from being single to being in a romantic relationship compared with those whose relationship status did not change. CONCLUSIONS: Emerging adults who experience dissolution of romantic relationships or quickly move from one relationship to another experience increased substance use. Both depressive symptoms and changes in peer environments may partially account for these changes in use. PMID- 20946742 TI - DSM-IV alcohol abuse due to hazardous use: a less severe form of abuse? AB - OBJECTIVE: A majority of individuals that meet criteria for alcohol abuse based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV), do so by endorsing the hazardous use criterion. We used a large, nationally representative data set to investigate whether alcohol abuse due to hazardous use is distinct from abuse attributable to other abuse criteria and whether abuse due to hazardous use is a less severe form of alcohol abuse. METHOD: Two waves of data, collected 3 years apart, from 34,653 individuals who participated in the National Epidemiological Survey on Alcohol and Related Conditions were used. Logistic regression was used to compare those with alcohol abuse due to hazardous use and those with alcohol abuse due to other criteria across several sociodemographic and psychiatric correlates at Wave 1 and across alcohol-related outcomes at the 3-year follow-up. Those with a lifetime history of alcohol dependence at Wave 1 were excluded. RESULTS: Abuse due to hazardous use was more commonly noted in older individuals, those not living below the poverty line, and those without nicotine dependence and was more likely to be noted in White participants. Abuse due to hazardous use was also associated with lower rates of problematic drinking, alcohol dependence, and help seeking at 3-year follow-up. CONCLUSIONS: Individuals endorsing hazardous use are at greater risk than those endorsing no abuse criteria, but abuse due to hazardous use may represent a less severe form of alcohol-use disorders. This is troubling, because current DSM conceptualizations allow for endorsement of hazardous use to denote alcohol-use disorders. Future classifications may wish to consider a higher threshold for alcohol-use disorders, particularly when hazardous use is endorsed. PMID- 20946744 TI - Patterns of alcohol-dependence symptoms using a latent empirical approach: associations with treatment usage and other correlates. AB - OBJECTIVE: The aim of this study was to understand the variation in response to alcohol use by identifying classes of alcohol users based on alcohol-dependence symptoms and to compare these classes across demographic characteristics, abuse symptoms, and treatment usage. METHOD: Data from combined 2002-2005 National Survey on Drug Use and Health identified 110,742 past-year alcohol users, age 18 years or older. Latent class analysis defined classes based on observed clustering of alcohol-dependence symptoms based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Chi-square statistics were used to test differences in sociodemographic and alcohol-abuse characteristics across classes. Multivariable latent class regressions were used to compare treatment usage across classes. RESULTS: The four-class model had the best overall fit and identified classes that differed quantitatively and qualitatively, with 2.3% of the users in the most-severe class and 83.8% in the least-severe/ not-affected class. These classes differed in a number of demographic characteristics and alcohol-abuse symptoms. All individuals in the most severe class met DSM-IV criteria for alcohol dependence; 80% of this class had alcohol-abuse symptoms. Twenty-six percent of the moderate and 50% of the moderate-high class met dependence criteria. Approximately 19% of the most-severe class and less than 5% of the moderate and moderate-high class received treatment for alcohol in the past year. CONCLUSIONS: This study demonstrates that meeting dependence criteria only partially captures variations in responses to severity of alcohol problems. Although individuals in the most-severe class were more likely to perceive need and receive treatment, the percentage of individuals receiving treatment was low. PMID- 20946743 TI - Three (or more) alcohol-dependence symptoms but not clustered in the same 12 months: diagnostic orphans from a longitudinal perspective. AB - OBJECTIVE: The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), currently uses a polythetic classification system for defining alcohol use disorders (AUD; alcohol abuse and dependence). This classification results in individuals who are subthreshold for an official AUD diagnosis but still endorse one or two criteria of dependence: so-called "diagnostic orphans." To our knowledge, however, there has been no attention given to diagnostic orphans from a lifetime perspective. The goal of the current article was to compare various diagnostic groups based on lifetime reports of abuse and dependence symptoms on a range of outcomes. METHOD: Data taken from the National Epidemiological Survey of Alcohol and Related Conditions study were used to form seven mutually exclusive diagnostic groups based on lifetime abuse and dependence symptomatology. RESULTS: Diagnostic groups that experienced extensive dependence symptoms, regardless of past-12-month clustering (i.e., formal diagnostic criteria), tended to exhibit poorer outcomes compared with participants that met formal lifetime diagnosis for an AUD through abuse alone. It is notable that a significant group of individuals who failed to meet formal lifetime AUD diagnosis, but who endorsed a number of dependence symptoms, consistently demonstrated more problematic outcomes on a range of measures compared with individuals who never reported dependence symptoms but who were formally diagnosed with lifetime AUD through alcohol abuse. CONCLUSIONS: DSM-IV lifetime diagnostic criteria may exclude individuals with a history of extensive dependence symptomatology. Implications regarding lifetime diagnosis conceptualization are discussed. PMID- 20946745 TI - Sleep quality and alcohol-use disorders in a select population of young-adult Mexican Americans. AB - OBJECTIVE: Adult male Hispanics, particularly those born in the United States, are more likely to drink frequently and to consume larger quantities of alcohol than Whites or Blacks. Because alcohol and other substance-use disorders are frequently associated with disturbances in sleep, this study investigated measures of sleep quality and substance use disorders in a select sample of young adult Mexican Americans. METHOD: Diagnoses of alcohol-use disorders and other psychiatric disorders (based on the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised), results from the Pittsburgh Sleep Quality Index (PSQI), family history of alcohol dependence, and measures of acculturation stress were obtained from 294 Mexican American young adults, ages 18-30, who were literate in English and were residing legally in San Diego County. RESULTS: Lifetime diagnoses of alcohol-use disorders, family history of alcohol dependence, acculturation stress, and lifetime diagnoses of major depressive disorder were all correlated with significantly poorer quality sleep as indexed by the global score on the PSQI. Regression analyses also revealed that gender was correlated with habitual bedtime, whereas drug dependence (cannabis, stimulants, and/or opiates) was significantly correlated with how long it took to fall asleep, major depressive disorder with the number of hours spent sleeping a night, and anxiety disorders and major depressive disorder with waking up in the early morning or middle of the night. CONCLUSIONS: These data suggest that alcohol-use disorders are significantly associated with poorer quality of sleep in this population of young adults and that substance-use disorders may affect different aspects of sleep than anxiety and depressive disorders do. These findings may be helpful in designing prevention and intervention programs for alcohol-use disorders in this high-risk population. PMID- 20946746 TI - Learning and memory performances in adolescent users of alcohol and marijuana: interactive effects. AB - OBJECTIVE: Lifetime alcohol hangover and withdrawal symptoms in youth have been shown to predict poorer recall of verbal and nonverbal information, as well as reduced visuospatial skills. Some evidence has suggested that negative effects of alcohol on the brain may be buffered in part by potential neuroprotective properties of cannabinoids. We hypothesized that a history of more alcohol hangover symptoms would predict worse performances on measures of verbal and visual memory, and that this relationship would be moderated by marijuana involvement. METHOD: Participants were 130 adolescents (65 with histories of heavy marijuana use, and 65 non-marijuana-using controls), ranging in age from 15.7 to 19.1 years. Neuropsychological tests for visual and verbal memory and interviews assessing lifetime and recent substance use, hangover/withdrawal symptoms, and abuse and dependence criteria were administered. RESULTS: Regression models revealed that greater alcohol hangover symptoms predicted worse verbal learning (p < .05) and memory (p < .05) (California Verbal Learning Test, Second Edition) scores for non-marijuana users, but alcohol hangover symptoms were not linked to performance among marijuana users. Alcohol hangover symptoms did not predict visual memory in either group. CONCLUSIONS: Results confirm previous studies linking adolescent heavy drinking to reduced verbal learning and memory performance. However, this relationship is not seen in adolescents with similar levels of alcohol involvement who also are heavy users of marijuana. PMID- 20946747 TI - Perceived norms for drinking in the transition from high school to college and beyond. AB - OBJECTIVE: We evaluated selection and socialization processes associated with perceived descriptive norms and drinking from high school through the first 2 years of college. METHOD: Participants (n = 2,247; 61.6% female) completed measures of high school drinking and descriptive drinking norms for their social group and the typical student at the university they were entering, as well as alcohol use and social-group norms through their sophomore year of college. We conducted structural equation models by gender and ethnicity to test high school drinking and drinking norms as predictors of collegiate drinking and social-group norms. RESULTS: Perceptions of typical-college-student drinking during high school predicted freshman-year drinking for men but not women and for White but not Asian or Hispanic students. High school social-group norms predicted freshman drinking for White but not Asian or Hispanic students, whereas freshman social group norms predicted sophomore drinking for all participants. CONCLUSIONS: Selection and socialization processes co-occur during this transitional time. Heavy drinkers in high school who perceive their friends to be heavy drinkers select into college social groups with perceived heavy drinking. Men and White students who perceive heavy drinking by the typical college student tend to drink heavily in college and choose social groups with perceived heavy drinking. These results support the importance of interventions that are tailored to the individual and that target perceptions of typical-college-student and social group drinking before entering college for Whites and men but after matriculation for women, Asian, and Hispanic students. PMID- 20946748 TI - Direct and indirect effects of injunctive norms on marijuana use: the role of reference groups. AB - OBJECTIVE: Little work has evaluated the relationship between injunctive norms and marijuana use. This study sought to establish whether misperceptions exist between perceived injunctive norms of typical college students and the actual approval level of the students. We also examined respondents' perceptions of which groups (typical student, close friends, and parents) were the most and least approving of marijuana. These variables were then applied to an explanatory model to assess their relationships with marijuana use. METHOD: Participants were 3,753 students (61% female) randomly recruited from two West Coast campuses. Participants were asked about their own marijuana use and their own approval toward marijuana. Injunctive norms were assessed by asking respondents about their perceptions of how much other reference groups approved of marijuana. RESULTS: Students overestimated the extent to which the typical student approves of marijuana use. A path model showed that perceived approval of both close friends and parents predicted actual/self-approval, which in turn was most predictive of personal marijuana use. Perceptions of typical-student and close friends' approval also directly predicted one's own use, whereas the path from parental approval to marijuana use was fully mediated by one's own approval. CONCLUSIONS: Findings suggest that perceived injunctive norms may function differently with respect to marijuana use than they do with respect to alcohol use and raise questions about how to incorporate social-normative information into marijuana interventions. PMID- 20946749 TI - Establishments licensed to serve alcohol and their contribution to police recorded crime in Australia: further opportunities for harm reduction. AB - OBJECTIVE: Although strategies exist to minimize alcohol-related harms associated with establishments licensed to serve alcohol, such establishments are associated with a disproportionate level of harm. To date, understanding the association between such establishments and alcohol-related harms, and hence the opportunities for reducing harm, has been limited by inadequate information regarding incidents of alcohol-related crime. To address this deficiency, this study was undertaken to describe the association between such establishments and incidents of crime using enhanced police-recorded, alcohol-related crime intelligence. METHOD: A descriptive analysis was undertaken of intoxicated people who had last consumed alcohol in establishments licensed to serve alcohol (841 bars, 551 licensed social clubs, 11 nightclubs, and 18 other locations) preceding their involvement in police-recorded incidents of violence, disorder, or motor vehicle crashes. The study area encompassed 21 nonmetropolitan police commands in the state of New South Wales, Australia. RESULTS: Among intoxicated persons involved in incidents of violence, disorder, or motor vehicle crashes, the risk of being recorded as having last consumed alcohol in a bar or nightclub before the incident was at least twice that of licensed social clubs and other establishments. Approximately 20% of establishments accounted for 80% of intoxicated persons involved in such incidents, and 6% of establishments were in the top 20% of establishments for all three offense types. CONCLUSIONS: The disproportionate burden of alcohol-related crime associated with establishments licensed to serve alcohol may be reduced if harm-reduction strategies address the specific risks posed by bars and nightclubs, and individual high-risk establishments. PMID- 20946750 TI - Prescription drug misuse among antisocial youths. AB - OBJECTIVE: The aim of this study was to describe the prevalence and correlates of nonmedical prescription drug misuse (PDM) in a state population of youths in residential care for antisocial behavior. METHOD: Interviews assessing substance use, psychiatric symptoms, antisocial traits/behavior, and traumatic life experiences were conducted with 723 Missouri youths. Participants were predominantly male (87.0%), averaged 15.5 (SD = 1.2) years of age, and constituted 97.7% of the service population sampled. RESULTS: Overall, 314 youths (43.4%) reported lifetime PDM; 33.7%, 32.0%, and 11.2% had misused prescription opioids, tranquilizers, and barbiturates, respectively. Prescription drug misusers were significantly older, and larger proportions were girls, were White, and resided in small towns, compared with non-prescription drug misusers. Prescription drug misusers evidenced significantly more varied, frequent, and problematic psychoactive drug use; evidenced higher levels of distressing psychiatric symptoms; and were nearly twice as likely to have been diagnosed with a psychiatric disorder, compared with non-prescription drug misusers. Traumatic life events, experiences of criminal victimization, and suicidal ideation were significantly more prevalent in the histories of prescription drug misusers, compared with non-prescription drug misusers. In multiple logistic regression models, older age; White racial status; prior inhalant, marijuana, and LSD (lysergic acid diethylamide) use; residence in a small town; and impulsivity were associated with increased risk for PDM. CONCLUSIONS: Adolescents in residential care for antisocial behavior have high rates of PDM, as well as comorbid psychiatric and behavioral problems. Youths served in institutional settings should be routinely screened and treated for PDM and co-occurring disorders. PMID- 20946751 TI - Differential alcohol expectancies based on type of alcoholic beverage consumed. AB - OBJECTIVE: Expectancies regarding the global effects of alcohol are influential aspects of drinking behavior that can vary by type of beverage consumed. Lacking in the research literature is a thorough investigation of how expected effects and subjective evaluations of specific positive (e.g., increased sociability, relaxation) and specific negative (e.g., impairment, aggression) expectancy effects vary by different types of alcoholic beverages. METHOD: The present between-subjects study used a sample of 498 young adults randomized to complete a measure of alcohol expectancies based on one of three alcohol-type conditions (beer, wine, distilled spirits). Participants also indicated the typical amount consumed of the beverage. Separate multivariate analysis of variance tests were run to determine if differences existed among the three conditions for positive and negative expected effects and subjective evaluations. RESULTS: Findings suggested that individuals may expect different effects from consuming different types of alcoholic beverages. Participants expressed more agreement that wine would have relaxation effects and rated this effect more positively. Participants expressed more disagreement that beer or shots would have effects on sexuality and rated sexuality effects more positively for wine. Participants reported less agreement that wine would have impairing effects, as well as more disagreement that wine would affect risk, aggression, and self-perception. Impairing effects of wine were also viewed less negatively than other condition beverages. CONCLUSIONS: Findings suggest that individuals may hold different beliefs about the effects of wine, compared with beer and shots of distilled spirits. Research and interventions targeting general alcohol expectancies may miss important between-beverage differences in perceived effects and subjective evaluations regarding alcohol's effects. PMID- 20946752 TI - Indirect effect of social support for drinking on drinking outcomes: the role of motivation. AB - OBJECTIVE: This study tested an integrated relapse model drawing hypotheses from both interpersonal and intra-individual relapse models. It was hypothesized that the relationships between alcohol-specific social support (support for drinking and support for not drinking) and drinking outcomes would be partially mediated by motivation. METHOD: Participants were 158 women with alcohol use disorders participating in two linked randomized controlled trials. One trial compared standard individual cognitive behavioral therapy (CBT) for alcohol use disorders with female-specific CBT for alcohol use disorders; the other compared alcohol behavioral couple therapy with blended individual CBT and alcohol behavioral couple therapy. Measures included the Important People Interview to measure social-support variables, the Timeline Followback to measure drinking variables, and the Stages of Change Readiness and Treatment Eagerness Scale to measure motivation. RESULTS: Results of structural equation modeling suggested a mediational role of motivation in the relationship between support for drinking and drinking frequency. Individuals with more network support for drinking at baseline had less motivation for abstinence at the end of treatment, which predicted drinking frequency over the 6 months after treatment. The indirect effect of baseline support for drinking on 6-month follow-up drinking frequency was statistically significant. A similar, although only marginally significant, pattern was found for the relationship between support for not drinking and drinking frequency. Individuals with more social network for not drinking at baseline had more motivation at the end of treatment at the trend level, which in turn predicted 6-month follow-up drinking frequency. The indirect effect of baseline support for not drinking on 6-month follow-up drinking frequency trended toward significance. CONCLUSIONS: This study offers preliminary evidence that motivation is one mechanism by which abstinence-specific social support affects treatment outcome. PMID- 20946755 TI - Benefit and risks of trivalent 2010 seasonal influenza vaccine in Australian children. PMID- 20946753 TI - Gender differences in family formation behavior: the effects of adolescent substance use. AB - OBJECTIVE: This study extended previous research on the association of substance use with family formation behavior by assessing the effects of the type and extent of adolescent substance use in a competing risks model. Substance use was expected to increase the likelihood of nonmarital family formation overall and differently by gender. METHOD: Longitudinal data from home interviews with the 14 to 16-year-old respondents to the first wave of the National Longitudinal Survey of Youth 1979 (N = 4,011) were used in multinomial logistic regressions estimating the odds that first cohabitation, parenthood, or remaining single occurred before first marriage among five types of substance users compared with nonusers. Full sample analysis preceded separate analyses of women (n = 1,946) and men (n = 2,065). RESULTS: Illegal drug use and concurrent substance use increased the likelihood that cohabitation, as opposed to marriage, was the first family type. Concurrent use of three types of substances had the largest effect on family formation behavior. The effects of singular marijuana use mattered only for men. The effects of substance use on parenthood as the first family type were significant only for women and increased the likelihood that marriage occurred first. CONCLUSIONS: The effects of substance use depended on the type(s) of substance(s) used, singular or concurrent use, and gender. Previous research regarding cohabitation was supported and extended. Assumptions that substance use leads to teenage or unwed parenthood based on the relationship of substance use to pregnancy or its predictors should be re-examined. PMID- 20946756 TI - Characteristics of reoffending accommodation sites in Europe with clusters of Legionnaires disease, 2003-2007. AB - Between 2003 and 2007, 21% (n=100/477) of accommodation sites linked to clusters of two or more cases of Legionnaires' disease that were investigated by the European Surveillance Scheme for Travel-Associated Legionnaires' Disease (EWGLINET) went on to be associated with at least one further case, despite reporting that satisfactory control measures had been implemented at the time the cluster was first detected. This paper examines these sites (termed reoffenders) in order to determine whether they share any characteristics that may have contributed to the reoffence. All investigations conducted at cluster sites between 2003 and 2007 were included in the analysis, giving a total of 615 investigations conducted at 477 sites. Every country that investigated more than three cluster sites had to deal with at least one reoffence, and one site reoffended five times. The cases involved in the cluster that stayed elsewhere during their incubation periods could be used to help assess the probability of exposure, and therefore the risk, posed by particular cluster sites. A more extensive investigation and control regime may be needed in some instances to better control the risk of Legionnaires' disease at an accommodation site. PMID- 20946757 TI - Seroprevalence of 2009 pandemic influenza A(H1N1) virus in Australian blood donors, October - December 2009. AB - Assessment of the severity of disease due to the 2009 pandemic influenza A(H1N1) in Australian states and territories has been hampered by the absence of denominator data on population exposure. We compared antibody reactivity to the pandemic virus using haemagglutination inhibition assays performed on plasma specimens taken from healthy adult blood donors (older than 16 years) before and after the influenza pandemic that occurred during the southern hemisphere winter. Pre-influenza season samples (April - May 2009, n=496) were taken from donation collection centres in North Queensland (in Cairns and Townsville); post-outbreak specimens (October - November 2009, n=779) were from donors at seven centres in five states. Using a threshold antibody titre of 40 as a marker of recent infection, we observed an increase in the influenza-seropositive proportion of donors from 12% to 22%, not dissimilar to recent reports of influenza A(H1N1) specific immunity in adults from the United Kingdom. No significant differences in seroprevalence were observed between Australian states, although the ability to detect minor variations was limited by the sample size. On the basis of these figures and national reporting data, we estimate that approximately 0.23% of all individuals in Australia exposed to the pandemic virus required hospitalisation and 0.01% died. The low seroprevalence reported here suggests that some degree of prior immunity to the virus, perhaps mediated by broadly reactive T-cell responses to conserved influenza viral antigens, limited transmission among adults and thus constrained the pandemic in Australia. PMID- 20946758 TI - Spotlight on measles 2010: An ongoing measles outbreak in the district of Neamt, Romania, August - September 2010. AB - We report an outbreak of measles that has been ongoing in the district of Neamt, Romania, since 22 August 2010. As of 21 September, 17 of 21 suspected cases have been laboratory-confirmed and there was one measles-related fatality. PMID- 20946759 TI - Dengue virus infection in a traveller returning from Croatia to Germany. AB - Dengue virus (DENV) is endemic in south-east Asia and Central to South America. In August 2010, a DENV infection was diagnosed in a German traveller returning from a trip to Croatia in south-east Europe. The patient presented with fever and other typical symptoms of DENV-infection. Virological investigation revealed the presence of DENV-specific IgM, a rise in DENV-specific IgG and the presence of DENV NS1 antigen in the patient's blood. PMID- 20946762 TI - Nucleotide analog interference mapping. AB - Nucleotide analog interference mapping (NAIM) is a powerful chemogenetic technique that rapidly identifies chemical groups essential for RNA function. Using a series of phosphorothioate-tagged nucleotide analogs, each carrying different modifications of nucleobase or backbone functionalities, it is possible to simultaneously, yet individually, assess the contribution of particular functional groups to an RNA's activity at every position within the molecule. In contrast to traditional mutagenesis, which modifies RNA on the nucleobase level, the smallest mutable unit in a NAIM analysis is a single atom, providing a detailed description of interactions at critical nucleotides. Because the method introduces modified nucleotides by in vitro transcription, NAIM offers a straightforward and efficient approach to study any RNA that has a selectable function, and it can be applied to RNAs of nearly any length. PMID- 20946763 TI - Hydroxyl-radical footprinting to probe equilibrium changes in RNA tertiary structure. AB - Hydroxyl-radical footprinting utilizes the ability of a highly reactive species to nonspecifically cleave the solvent accessible regions of a nucleic acid backbone. Thus, changes in a nucleic acids structure can be probed either as a function of time or of a reagent's concentration. When combined with techniques that allow single nucleotide resolution of the resulting fragments, footprinting experiments provide richly detailed information about local changes in tertiary structure of a nucleic acid accompanying its folding or ligand binding. In this chapter, we present two protocols of equilibrium hydroxyl-radical footprinting based on peroxidative and oxidative Fenton chemistry and discuss how to adjust the Fenton reagent concentrations for a specific experimental condition. We also discuss the choice of the techniques to separate the reaction products and specifics of the data analysis for equilibrium footprinting experiments. Protocols addressing the use of peroxidative Fenton chemistry for time-resolved studies have been published [Schlatterer and Brenowitz, 2009. Methods; Shcherbakova and Brenowitz, 2008. Nat. Protoc.3(2), 288-302; Shcherbakova et al., 2006. Nucleic Acids Res.34(6), e48; Shcherbakova et al., 2007. Methods Cell Biol.84, 589-615]. PMID- 20946764 TI - Rapid quantification and analysis of kinetic *OH radical footprinting data using SAFA. AB - The use of highly reactive chemical species to probe the structure and dynamics of nucleic acids is greatly simplified by software that enables rapid quantification of the gel images that result from these experiments. Semiautomated footprinting analysis (SAFA) allows a user to quickly and reproducibly quantify a chemical footprinting gel image through a series of steps that rectify, assign, and integrate the relative band intensities. The output of this procedure is raw band intensities that report on the relative reactivity of each nucleotide with the chemical probe. We describe here how to obtain these raw band intensities using SAFA and the subsequent normalization and analysis procedures required to process these data. In particular, we focus on analyzing time-resolved hydroxyl radical ((*)OH) data, which we use to monitor the kinetics of folding of a large RNA (the L-21 T. thermophila group I intron). Exposing the RNA to bursts of (*)OH radicals at specific time points during the folding process monitors the time progress of the reaction. Specifically, we identify protected (nucleotides that become inaccessible to the (*)OH radical probe when folded) and invariant (nucleotides with constant accessibility to the (*)OH probe) residues that we use for monitoring and normalization of the data. With this analysis, we obtain time-progress curves from which we determine kinetic rates of folding. We also report on a data visualization tool implemented in SAFA that allows users to map data onto a secondary structure diagram. PMID- 20946766 TI - Metal ion-based RNA cleavage as a structural probe. AB - It is well established that many metal ions accelerate the spontaneous degradation of RNA. This property has been exploited in several ways to garner information about RNA structure, especially in regards to the location of site specifically bound metal ions, the presence of defined structural motifs, and the occurrence of conformational changes in structured RNAs. In this chapter, we review this information, briefly giving strengths and limitations for each of these approaches. Finally, we provide a general protocol to perform metal ion mediated cleavage of RNA. PMID- 20946765 TI - High-throughput SHAPE and hydroxyl radical analysis of RNA structure and ribonucleoprotein assembly. AB - RNA folds to form complex structures vital to many cellular functions. Proteins facilitate RNA folding at both the secondary and tertiary structure levels. An absolute prerequisite for understanding RNA folding and ribonucleoprotein (RNP) assembly reactions is a complete understanding of the RNA structure at each stage of the folding or assembly process. Here we provide a guide for comprehensive and high-throughput analysis of RNA secondary and tertiary structure using SHAPE and hydroxyl radical footprinting. As an example of the strong and sometimes surprising conclusions that can emerge from high-throughput analysis of RNA folding and RNP assembly, we summarize the structure of the bI3 group I intron RNA in four distinct states. Dramatic structural rearrangements occur in both secondary and tertiary structure as the RNA folds from the free state to the active, six-component, RNP complex. As high-throughput and high-resolution approaches are applied broadly to large protein-RNA complexes, other proteins previously viewed as making simple contributions to RNA folding are also likely to be found to exert multifaceted, long-range, cooperative, and nonadditive effects on RNA folding. These protein-induced contributions add another level of control, and potential regulatory function, in RNP complexes. PMID- 20946767 TI - 2'-amino-modified ribonucleotides as probes for local interactions within RNA. AB - The 2'-hydroxyl group plays an integral role in RNA structure and catalysis. This ubiquitous component of the RNA backbone can participate in multiple interactions essential for RNA function, such as hydrogen bonding and metal ion coordination, but the multifunctional nature of the 2'-hydroxyl renders identification of these interactions a significant challenge. By virtue of their versatile physicochemical properties, such as distinct metal coordination preferences, hydrogen bonding properties, and ability to be protonated, 2'-amino-2' deoxyribonucleotides can serve as tools for probing local interactions involving 2'-hydroxyl groups within RNA. The 2'-amino group can also serve as a chemoselective site for covalent modification, permitting the introduction of probes for investigation of RNA structure and dynamics. In this chapter, we describe the use of 2'-aminonucleotides for investigation of local interactions within RNA, focusing on interactions involving 2'-hydroxyl groups required for RNA structure, function, and catalysis. PMID- 20946769 TI - Chemical probing of RNA and RNA/protein complexes. AB - Chemical probing is widely used as a rapid approach for assessing RNA structure, folding, and function. In this chapter, we outline procedures for handling and using chemicals commonly used to probe nucleic acids. Detailed experimental conditions and design for footprinting and modification interference are presented herein. Protocols for RNA extraction, normalization, primer extension, and data evaluation are also provided. The methods described are designed to aid in the study of large RNAs, but with slight modifications are applicable to smaller RNAs. PMID- 20946768 TI - RNA crosslinking methods. AB - RNA-RNA crosslinking provides a rapid means of obtaining evidence for the proximity of functional groups in structurally complex RNAs and ribonucleoproteins. Such evidence can be used to provide a physical context for interpreting structural information from other biochemical and biophysical methods and for the design of further experiments. The identification of crosslinks that accurately reflect the native conformation of the RNA of interest is strongly dependent on the position of the crosslinking agent, the conditions of the crosslinking reaction, and the method for mapping the crosslink position. Here, we provide an overview of protocols and experimental considerations for RNA RNA crosslinking with the most commonly used long- and short-range photoaffinity reagents. Specifically, we describe the merits and strategies for random and site specific incorporation of these reagents into RNA, the crosslinking reaction and isolation of crosslinked products, the mapping crosslinked sites, and assessment of the crosslinking data. PMID- 20946770 TI - RNA folding during transcription: protocols and studies. AB - RNA folds during transcription in the cell. Compared to most in vitro studies where the focus is generally on Mg(2+)-initiated refolding of fully synthesized transcripts, cotranscriptional RNA folding studies better replicate how RNA folds in a cellular environment. Unique aspects of cotranscriptional folding include the 5'- to 3'-polarity of RNA, the transcriptional speed, pausing properties of the RNA polymerase, the effect of the transcriptional complex and associated factors, and the effect of RNA-binding proteins. Identifying strategic pause sites can reveal insights on the folding pathway of the nascent transcript. Structural mapping of the paused transcription complexes identifies important folding intermediates along these pathways. Oligohybridization assays and the appearance of the catalytic activity of a ribozyme either in trans or in cis can be used to monitor cotranscriptional folding under a wide range of conditions. In our laboratory, these methodologies have been applied to study the folding of three highly conserved RNAs (RNase P, SRP, and tmRNA), several circularly permuted forms of a bacterial RNase P RNA, a riboswitch (thiM), and an aptamer activated ribozyme (glmS). PMID- 20946772 TI - Probing RNA structure within living cells. AB - RNA folding is the most fundamental process underlying RNA function. RNA structure and associated folding paradigms have been intensively studied in vitro. However, in vivo RNA structure formation has only been explored to a limited extent. To determine the influence of the cellular environment, which differs significantly from the in vitro refolding conditions, on RNA architecture, we have applied a chemical probing technique to assess the structure of catalytic RNAs in living cells. This method is based on the fact that chemicals like dimethyl sulfate readily penetrate cells and modify specific atoms of RNA bases (N1-A, N3-C), provided that these positions are solvent accessible. By mapping the modified residues, one gains substantial information on the architecture of the target RNA on the secondary and tertiary structure level. This method also allows exploration of interactions of the target RNA with ligands such as proteins, metabolites, or other RNA molecules and associated conformational changes. In brief, in vivo chemical probing is a powerful tool to investigate RNA structure in its natural environment and can be easily adapted to study RNAs in different cell types. PMID- 20946771 TI - Catalytic activity as a probe of native RNA folding. AB - As RNAs fold to functional structures, they traverse complex energy landscapes that include many partially folded and misfolded intermediates. For structured RNAs that possess catalytic activity, this activity can provide a powerful means of monitoring folding that is complementary to biophysical approaches. RNA catalysis can be used to track accumulation of the native RNA specifically and quantitatively, readily distinguishing the native structure from intermediates that resemble it and may not be differentiated by other approaches. Here, we outline how to design and interpret experiments using catalytic activity to monitor RNA folding, and we summarize adaptations of the method that have been used to probe aspects of folding well beyond determination of the folding rates. PMID- 20946774 TI - Determination of intracellular RNA folding rates using self-cleaving RNAs. AB - We have developed a system that relies on RNA self-cleavage to report quantitatively on assembly of RNA structures in vivo. Self-cleaving RNA sequences are inserted into mRNAs or snoRNAs and expressed in yeast under the control of a regulated promoter. Chimeric RNAs that contain self-cleaving ribozymes turn over faster than chimeric RNAs that contain a mutationally inactivated ribozyme by an amount that reflects the rate at which the ribozyme folds and self-cleaves. A key feature of this system is the choice of assay conditions that selectively monitor intracellular assembly and self-cleavage by suppressing further ribozyme activity during the analysis. PMID- 20946773 TI - Structural analysis of RNA in living cells by in vivo synchrotron X-ray footprinting. AB - Chemical footprinting methods are widely used to probe the solution structures of nucleic acids and their complexes. Among the many available modifying reagents, hydroxyl radical is exceptional in its ability to provide nucleotide-level information on the solvent accessibility of the nucleic acid backbone. Until recently, hydroxyl radical footprinting has been limited to in vitro experiments. We describe the use of synchrotron X-radiation to generate hydroxyl radicals within cells for effective footprinting of RNA-protein complexes in vivo. This technique gives results that are consistent with in vitro footprinting experiments, with differences reflecting apparent structural changes to the RNA in vivo. PMID- 20946775 TI - Separation of RNA phosphorothioate oligonucleotides by HPLC. AB - Phosphorothioate oligonucleotides are indispensable tools for probing nucleic acid structure and function and for the design of antisense therapeutics. Many applications involving phosphorothioates require site- and stereospecific substitution of individual pro-R(P) or pro-S(P) nonbridging oxygens. However, the traditional approach to phosphorothioate synthesis produces a mixture of R(P) and S(P) diastereomers that must be separated prior to use. High-performance liquid chromatography (HPLC) has proven to be a versatile method for effecting this separation, with both reversed phase (RP) and strong anion exchange (SAX) protocols yielding favorable results. In this chapter, we present several examples of successful separations of RNA phosphorothioate diastereomers by HPLC. We also report the use of complementary DNA oligonucleotides for the separation of poorly resolved phosphorothioate RNAs. PMID- 20946776 TI - Use of phosphorothioates to identify sites of metal-ion binding in RNA. AB - Single atom substitutions provide an exceptional opportunity to investigate RNA structure and function. Replacing a phosphoryl oxygen with a sulfur represents one of the most common and powerful single atom substitutions and can be used to determine the sites of metal-ion binding. Using functional assays of ribozyme catalysis, based on pre-steady-state kinetics, it is possible to extend this analysis to the transition state, capturing ligands for catalytic metal ions in this fleeting state. In conjunction with data determined from X-ray crystallography, this technique can provide a picture of the environment surrounding catalytic metal ions in both the ground state and the transition state at atomic resolution. Here, we describe the principles of such analysis, explain limitations of the method, and provide a practical example based on our results with the Tetrahymena group I ribozyme. PMID- 20946777 TI - EPR methods to study specific metal-ion binding sites in RNA. AB - The properties of metal-ion interactions with RNA can be explored by spectroscopic methods. In this chapter, we describe the use of paramagnetic Mn(2+) ions and electron paramagnetic resonance (EPR)-based techniques to monitor the association of Mn(2+) with RNA and related nucleotides. Solution EPR methods are used to determine the numbers of Mn(2+) ions associating with RNA. For RNA poised with a single-bound Mn(2+), low-temperature EPR characteristics provide information about the asymmetry of the Mn(2+) coordination site. To identify the RNA groups coordinating to the Mn(2+) ion, ENDOR (electron nuclear double resonance) and ESEEM (electron spin echo envelope modulation) methods are applied. Both continuous-wave (CW) and electron spin echo (ESE)-detected ENDOR methods are described. This chapter includes practical details for RNA sample preparation, including isotope substitution and cryoprotection, and an overview of data acquisition and analysis methods used in these techniques, as well as examples from the current literature. PMID- 20946778 TI - Optical melting measurements of nucleic acid thermodynamics. AB - Optical melting experiments provide measurements of thermodynamic parameters for nucleic acids. These thermodynamic parameters are widely used in RNA structure prediction programs and DNA primer design software. This review briefly summarizes the theory and underlying assumptions of the method and provides practical details for instrument calibration, experimental design, and data interpretation. PMID- 20946779 TI - Analyzing RNA and DNA folding using temperature gradient gel electrophoresis (TGGE) with application to in vitro selections. AB - Gel electrophoresis is a ubiquitous separation technique in nucleic acid biochemistry. Denaturing gel electrophoresis separates nucleic acids on the basis of length, while native gel electrophoresis separates nucleic acids on the basis of both shape and length. Temperature gradient gel electrophoresis (TGGE), in which a temperature gradient is present across the gel, combines the advantages of denaturing and native gel electrophoresis by having native gel-like properties at low temperatures and denaturing gel-like properties at high temperatures. We describe here the techniques of perpendicular and parallel TGGE and some of their applications. Isolation of stable and unstable RNA and DNA sequences from combinatorial libraries is accomplished with TGGE-SELEX, while thermodynamic characterization of an RNA tertiary motif is performed by perpendicular TGGE melts. Specific examples are chosen from the literature to illustrate the methods. TGGE provides a powerful biophysical approach for analyzing RNA and DNA that complements more traditional methodologies. PMID- 20946780 TI - Studying RNA-RNA and RNA-protein interactions by isothermal titration calorimetry. AB - Isothermal Titration Calorimetry (ITC) provides a sensitive and accurate means by which to study the thermodynamics of RNA folding, RNA binding to small molecules, and RNA-protein interactions. The advent of extremely sensitive instrumentation and the increasing availability of ITC in shared facilities have made it increasingly valuable as a tool for RNA biochemistry. As an isothermal measurement, it allows analysis at a defined temperature, distinguishing it from thermal melting approaches (UV melting and differential scanning calorimetry, for instance) that provide thermodynamic information specific to the melting temperature. Residual structures at low temperature in the unfolded state and heat capacity changes lead to potential differences between thermodynamic values measured by ITC and those derived from melting studies. This article describes how ITC can be put to use in the study of RNA biochemistry. PMID- 20946782 TI - Large-scale native preparation of in vitro transcribed RNA. AB - Biophysical studies of RNA require concentrated samples that are chemically and structurally homogeneous. Historically, the most widely used methods for preparing these samples involve in vitro transcription, denaturation of the RNA, purification based on size, and subsequent refolding. These methods are useful but are inherently slow and do not guarantee that the RNA is properly folded. Possible mis-folding is of particular concern with large, complexly folded RNAs. To address these problems, we have developed methods for purifying in vitro transcribed RNAs in their native, folded states. These methods also have the advantage of being rapid and readily scaled to virtually any size RNA or transcription amount. Two methods are presented: the first is an affinity chromatography approach and the second is a weak ion-exchange chromatography approach. Both use equipment and materials readily available to almost any lab and hence should provide flexibility for those seeking alternate approaches to large-scale purification of RNA in the folded state. PMID- 20946783 TI - Assembly of complex RNAs by splinted ligation. AB - Mechanistic studies of RNA enzymes (ribozymes) and ribonucleoprotein (RNP) complexes such as the ribosome and telomerase, often seek to characterize RNA structural features, either dynamic or static, and relate these properties to specific catalytic functions. Many experimental techniques that probe RNA structure-function relationships rely upon site-specific incorporation of chemically modified ribonucleotides into the RNA of interest, often in the form of chemical cross-linkers to probe for sites of protein-RNA interaction or small organic fluorophores to measure dynamic structural properties of RNAs. The ability to arbitrarily modify any RNA molecule has been greatly enabled by modern RNA synthesis techniques; however, there remains a practical size limitation (~70 bases). Consequently, experimental approaches involving specific chemical modifications of larger RNAs require the use of RNA ligation methods. The aim of this chapter is to describe a general approach for covalently joining multiple site-specifically modified RNA fragments, drawing from our fluorescence-based structural studies of telomerase RNA as an example. PMID- 20946784 TI - Methods of site-specific labeling of RNA with fluorescent dyes. AB - Single molecule fluorescence techniques offer unique insights into mechanisms of conformational changes of RNA. Knowing how to make fluorescently labeled RNA molecules and understanding potential limitations of different labeling strategies is essential for successful implementation of single molecule fluorescence techniques. This chapter offers a step by step overview of the process of obtaining RNA constructs ready for single molecule measurements. Several alternative methods are described for each step, and ways of troubleshooting the most common problems, in particular, splinted RNA ligation, are suggested. PMID- 20946785 TI - Fluorophore labeling to monitor tRNA dynamics. AB - Transfer RNA (tRNA) molecules mediate translation of the nucleic acid genetic code into the amino acid building blocks of proteins, thus ensuring the survivability of cells. The dynamic properties of tRNA molecules are crucial to their functions in both activity and specificity. This chapter summarizes two methods that have been recently developed or improved upon previous protocols to introduce fluorophores to site-specific positions in tRNA. One method enables incorporation of fluorophores carrying a primary amine (such as proflavin or rhodamine) to dihydrouridine (D) residues in the tRNA tertiary core, and a second method enables incorporation of pyrroloC and 2-aminopurine to positions 75 and 76, respectively, of the CCA sequence at the 3' end. These site-specific fluorophore labeling methods utilize tRNA transcripts as the substrates to provide the versatility with both wild-type and mutant sequences for examining their motions in space and time during the process of decoding genetic information. PMID- 20946787 TI - Strategies in RNA crystallography. AB - A number of RNAs ranging from small helices to large megadalton ribonucleoprotein complexes have been solved to atomic resolution using X-ray crystallography. As with proteins, RNA crystallography involves a number of screening trials in which the concentration of macromolecule, precipitant, salt, and temperature are varied, an approach known as searching "condition space." In contrast to proteins, the nature of base pairing in nucleic acids creates predictable secondary structure that facilitates the rational design of RNA variants, allowing "sequence space" to be screened in parallel. This chapter reviews RNA specific techniques and considerations for RNA crystallography and presents a complete workflow used by our laboratory for solving RNA structures starting with initial library construction, methods to investigate and improve RNA crystal quality, and finally phase determination and structure solution. PMID- 20946786 TI - Use of deoxyribozymes in RNA research. AB - Since their first identification by in vitro selection in 1994, deoxyribozymes have been developed to catalyze a variety of chemical reactions. The first DNA catalyzed reaction was cleavage of a ribonucleotide linkage within an oligonucleotide substrate. In subsequent years, growing collections of deoxyribozymes have been developed for several reactions that have practical utility for RNA research. These deoxyribozymes are useful for site-specific RNA cleavage as well as ligation to form linear, branched, and lariat RNA products. An application related to RNA ligation is deoxyribozyme-catalyzed labeling of RNA (DECAL), which is used to attach a biophysical tag to a desired RNA sequence at a specific position. With current achievements and likely future developments, deoxyribozymes are a useful contributor to the toolbox of RNA research methods. PMID- 20946788 TI - Comparative gel electrophoresis analysis of helical junctions in RNA. AB - Comparative gel electrophoresis provides information on the relative angles subtended between helical arms at a branchpoint in RNA. It is based upon the comparison of electrophoretic mobility in polyacrylamide gels of species containing two long arms, with the remaining one(s) being significantly shorter. Although the method currently lacks a really well-established basis of physical theory, it is very powerful, yet simple to apply. It has had a number of significant successes in RNA, DNA and DNA-protein complexes, and in all cases to date the results have stood the test of time and eventual comparison with crystallographic analysis. PMID- 20946789 TI - The structure and folding of branched RNA analyzed by fluorescence resonance energy transfer. AB - Fluorescence resonance energy transfer (FRET) is a spectroscopic means of obtaining distance information over a range up to ~80A in solution. It is based on the dipolar coupling between the electronic transition moments of a donor and acceptor fluorophore attached at known positions on the RNA species of interest. It can be applied in ensembles of molecules, either by steady-state fluorescence or by lifetime measurements, but it is also very appropriate for single-molecule studies. In addition to the provision of distance information, recent studies have emphasized the orientation dependence of energy transfer. PMID- 20946790 TI - Analysis of RNA folding by native polyacrylamide gel electrophoresis. AB - Polyacrylamide gel electrophoresis under native conditions (native PAGE) is a well-established and versatile method for probing nucleic acid conformation and nucleic acid-protein interactions. Native PAGE has been used to measure RNA folding equilibria and kinetics under a wide variety of conditions. Advantages of this method are its adaptability, absolute determination of reaction endpoints, and direct analysis of conformational hetereogeneity within a sample. Native PAGE is also useful for resolving ligand-induced structural changes. PMID- 20946791 TI - Using analytical ultracentrifugation (AUC) to measure global conformational changes accompanying equilibrium tertiary folding of RNA molecules. AB - Analytical ultracentrifugation (AUC) is a powerful technique to determine the global conformational changes in RNA molecules mediated by cations or small molecule ligands. Although most of the developments in the field of AUC have been centered on studies involving protein molecules, the experimental methods as well as the analytical approaches have been successfully adapted and applied to the study of a variety of RNA molecules ranging from small riboswitches to large ribozymes. Most often AUC studies are performed in conjunction with other structural probing techniques that provide complementary information on local changes in the solvent accessibilities at specific regions within RNA molecules. This chapter provides a brief theoretical background, working knowledge of instrumentation, practical considerations for experimental setup, and guidelines for data analysis procedures to enable the design, execution, and interpretation of sedimentation velocity experiments that detect changes in the global dimensions of an RNA molecule during its equilibrium folding. PMID- 20946792 TI - Use of small angle X-ray scattering (SAXS) to characterize conformational states of functional RNAs. AB - Small-angle X-ray scattering (SAXS) is emerging as an important technique to characterize the structure of RNA molecules. While lower in resolution than X-ray crystallography or NMR spectroscopy, SAXS has the great advantage to have virtually no molecular weight limitations and does not require crystallization. In addition, SAXS can be readily applied under a large range of solution conditions, allowing to monitor RNA folding, ligand binding, and to characterize partially folded intermediates. Here, we review how the development of SAXS as a structural technique is driven by advances in computer algorithms that allow to reconstruct low-resolution electron density maps ab initio from scattering profiles. In addition, we delineate how these low-resolution models can be used in free energy electrostatics calculations. Finally, we discuss how one can exploit the hierarchical nature of RNA folding by combining the low resolution, global information provided by SAXS with local information on RNA structure, from either experiments or state-of-the-art RNA structure prediction algorithms, to further increase the resolution and quality of models obtained from SAXS. PMID- 20946793 TI - Time-resolved X-ray scattering and RNA folding. AB - Time-resolved small-angle X-ray scattering (SAXS) reports changes in the global conformation of macromolecules and is thus a valuable probe of structural transitions like RNA folding. Time-resolved SAXS has been applied to study folding of the Tetrahymena ribozyme. This chapter describes the methods that enable acquisition and analysis of time-resolved SAXS data and insights into RNA folding gained from these studies. PMID- 20946794 TI - 2-aminopurine as a probe of RNA conformational transitions. AB - 2-aminopurine (2AP) is a fluorescent nucleobase that provides the means to probe structure and dynamics of RNA molecules. Because 2AP can base pair with Uridine, it can replace normal A:U pairs without substantial deformation of duplexes. It is best used as a probe of ostensibly single-stranded regions: its fluorescence intensity reports on base stacking and its fluorescence decay lifetimes report on its conformational dynamics. Three examples of its use are described here, illustrating how 2AP fluorescence has been used to probe RNA folding and hairpin loop dynamics. PMID- 20946795 TI - Fluorescence polarization anisotropy to measure RNA dynamics. AB - RNA requires helical motion to fold and carry out its function. As RNA helical motion occurs on the nanosecond timescale, the timescale probed by fluorescence dyes, fluorescence polarization anisotropy (FPA) is a simple, yet powerful, technique to study helical dynamics in RNA. With the recent development of several fluorescent base analogs that have a nanosecond timescale lifetime in a duplex, FPA has begun to be used for characterizing RNA dynamics. Using the probe 6-methylisoxanthopterin (6-MI) as an example, we describe the procedure for carrying out FPA experiments on model oligonucleotide systems and in a complex RNA, the Tetrahymena group I intron. For smaller RNA systems, isolating the motion of the target helix from the overall tumbling of the whole RNA system is necessary, and nucleic acids binding proteins can be incorporated into the RNA system to increase the overall size of the system, slow the overall tumbling, and thereby reduce the anisotropy contribution from the overall tumbling to negligible. The procedure for incorporating one such protein, the Lac Repressor, is given as an example. PMID- 20946796 TI - Studying RNA using site-directed spin-labeling and continuous-wave electron paramagnetic resonance spectroscopy. AB - In site-directed spin-labeling (SDSL), a stable nitroxide radical is attached to a specific location within a macromolecule and electron paramagnetic resonance (EPR) spectroscopy is used to interrogate the local environment surrounding the nitroxide. The SDSL strategy enables probing site-specific structural and dynamic features of RNA in solution without being limited by the size of the molecule, thus serving as a unique tool in biophysical studies of RNA. This chapter describes the use of continuous-wave (cw)-EPR to study dynamic features of RNAs as well as to monitor interactions between them. Various approaches for attaching nitroxide spin labels to nucleic acids are described, followed by detailed descriptions of cw-EPR spectral acquisition and processing procedures. Specific examples are subsequently used to illustrate analysis of EPR spectra, showing how information regarding the parent RNA can be extracted. PMID- 20946797 TI - Mapping global folds of oligonucleotides by pulsed electron-electron double resonance. AB - The understanding of structure-dynamics-function relationships in oligonucleotides or oligonucleotide/protein complexes calls for biophysical methods that can resolve the structure and dynamics of such systems on the critical nanometer length scale. A modern electron paramagnetic resonance (EPR) method called pulsed electron-electron double resonance (PELDOR or DEER) has been shown to reliably and precisely provide distances and distance distributions in the range of 1.5-8nm. In addition, recent experiments proved that a PELDOR experiment also contains information on the orientation of labels, enables easy separation of coupling mechanisms and allows for counting the number of monomers in complexes. This chapter briefly summarizes the theory, describes how to perform and analyze such experiments and discusses the limitations. PMID- 20946798 TI - Laser-induced temperature jump infrared measurements of RNA folding. AB - Probing a sample using infrared spectroscopy following a laser-induced temperature jump is a powerful method to monitor fast relaxation kinetics. Here, we describe how this approach is used to study the kinetics of RNA folding. We begin with a concise summary of the infrared spectral properties of RNA in the 1500-1800cm(-1) region. The infrared transitions in this region are directly related to the double bond stretching vibrations and ring modes of the nucleotide bases. When RNA undergoes a conformational change, the local environments of the nucleotides are altered. Consequently, the changes in the corresponding infrared spectrum are associated with the structural changes. Experimentally, temperature is used to systematically vary the RNA structure. When a short laser pulse is used to produce a rapid temperature increase in the sample, the structural changes that ensue can be followed in real time. In this contribution, we discuss experimental methods including sample preparation, instrumentation, and data analysis. We conclude with several experimental examples that highlight usefulness of the technique. PMID- 20946799 TI - Probing nucleic acid-ion interactions with buffer exchange-atomic emission spectroscopy. AB - The ion atmosphere of nucleic acids directly affects measured biochemical and biophysical properties. However, study of the ion atmosphere is difficult due to its diffuse and dynamic nature. Standard techniques available have significant limitations in sensitivity, specificity, and directness of the assays. Buffer exchange-atomic emission spectroscopy (BE-AES) was developed to overcome many of the limitations of previously available techniques. This technique can provide a complete accounting of all ions constituting the ionic atmosphere of a nucleic acid at thermodynamic equilibrium. Although initially developed for the study of the ion atmosphere of nucleic acids, BE-AES has also been applied to study site bound ions in RNA and protein. PMID- 20946800 TI - Using anomalous small angle X-ray scattering to probe the ion atmosphere around nucleic acids. AB - Anomalous small angle X-ray scattering (ASAXS) exploits contrast variation methods to highlight the scattering from one elemental component in a multielement sample, such as one ion species in an ion-DNA system. The ASAXS method has been applied to measure ions condensed around short nucleic acid duplexes. This chapter, which briefly describes the origin of the ASAXS signal, focuses on the experimental methods required to carry out these measurements and the interpretation of the anomalous signals. PMID- 20946801 TI - Simulations of RNA interactions with monovalent ions. AB - RNA folding and binding reactions are mediated by interactions with ions that make up the surrounding aqueous electrolytic milieu. Although Mg(2+) ions are often implicated as being crucial for RNA folding, it is known that folding is feasible in high concentrations of monovalent alkali-halide salts. Experiments have yielded important information regarding the salt dependence of RNA stability. Recent work has shown that molecular simulations based on explicit representations of solvent molecules and monovalent ions can also provide useful insights regarding the ionic atmospheres around model RNA systems. These insights can help rationalize intriguing observations regarding the dependence of RNA stability on cation type providing one pays attention to important considerations that go into the proper design of molecular simulations. These issues are discussed in detail and the methods are applied to an A-form RNA and B-form DNA sequence. The results of these simulations are compared to previous work on a kissing-loop system with analogous sequence. In particular, ionic atmospheres obtained from molecular simulations are compared to those obtained using the nonlinear Poisson Boltzmann model for continuum electrostatics for these three different nucleic acid systems. The comparisons indicate reasonable agreement in terms of coarse-grained observables such as the numbers of counterions accumulated around the solutes. However, details of the ionic atmospheres, captured in terms of spatial free energy density profiles, are quite different between the two approaches. These comparisons suggest the need for improvements in continuum models to capture sequence-specific effects, ion-ion correlation, and the effects of partial dehydration of ions. PMID- 20946802 TI - Ion-RNA interactions thermodynamic analysis of the effects of mono- and divalent ions on RNA conformational equilibria. AB - RNA secondary and tertiary structures are strongly stabilized by added salts, and a quantitative thermodynamic analysis of the relevant ion-RNA interactions is an important aspect of the RNA folding problem. Because of long-range electrostatic forces, an RNA perturbs the distribution of both cations and anions throughout a large volume. Binding formalisms that require a distinction between "bound" and "free" ions become problematic in such situations. A more fundamental thermodynamic framework is developed here, based on preferential interaction coefficients; linkage equations derived from this framework provide a model-free description of the "uptake" or "release" of cations and anions that accompany an RNA conformational transition. Formulas appropriate for analyzing the dependence of RNA stability on either mono- or divalent salt concentration are presented and their application to experimental data is illustrated. Two example datasets are analyzed with respect to the monovalent salt dependence of tertiary structure formation in different RNAs, and three different experimental methods for quantitating the "uptake" of Mg(2+) ions are applied to the folding of a riboswitch RNA. Advantages and limitations of each method are discussed. PMID- 20946803 TI - Predicting electrostatic forces in RNA folding. AB - Metal ion-mediated electrostatic interactions are critical to RNA folding. Although considerable progress has been made in mechanistic studies, the problem of accurate predictions for the ion effects in RNA folding remains unsolved, mainly due to the complexity of several potentially important issues such as ion correlation and dehydration effects. In this chapter, after giving a brief overview of the experimental findings and theoretical approaches, we focus on a recently developed new model, the tightly bound ion (TBI) model, for ion electrostatics in RNA folding. The model is unique because it can treat ion correlation and fluctuation effects for realistic RNA 3D structures. For monovalent ion (such as Na(+)) solutions, where ion correlation is weak, TBI and the Poisson-Boltzmann (PB) theory give the same results and the results agree with the experimental data. For multivalent ion (such as Mg(2+)) solutions, where ion correlation can be strong, however, TBI gives much improved predictions than the PB. Moreover, the model suggests an ion correlation-induced mechanism for the unusual efficiency of Mg(2+) ions in the stabilization of RNA tertiary folds. In this chapter, after introducing the theoretical framework of the TBI model, we will describe how to apply the model to predict ion-binding properties and ion dependent folding stabilities. PMID- 20946804 TI - Analysis of gene function using DNA microarrays. AB - This chapter provides a guide to analyzing gene function using DNA microarrays. First, I discuss the design and interpretation of experiments where gene expression levels in mutant and wild-type strains are compared. I then provide a detailed description of the protocols for isolating mRNA from yeast cells, converting the RNA into dye-labeled cDNA, and hybridizing these samples to a microarray. Finally, I discuss methods for washing, scanning, and analyzing the arrays. Emphasis is placed on describing approaches and techniques that help to minimize the artifacts and noise that so often plague microarray data. PMID- 20946805 TI - An introduction to microarray data analysis and visualization. AB - Microarray experiments offer a potential wealth of information but also present a significant data analysis challenge. A typical microarray data analysis project involves many interconnected manipulations of the raw experimental values, and each stage of the analysis challenges the experimenter to make decisions regarding the proper selection and usage of a variety of statistical techniques. In this chapter, we will provide an overview of each of the major stages of a typical yeast microarray project. We will focus on providing a solid conceptual foundation to help the reader better understand each of these steps, will highlight useful software tools, and will suggest best practices where applicable. PMID- 20946806 TI - Genome-wide approaches to monitor pre-mRNA splicing. AB - Pre-mRNA processing is an essential control-point in the gene expression pathway of eukaryotic organisms. The budding yeast Saccharomyces cerevisiae offers a powerful opportunity to examine the regulation of this pathway. In this chapter, we will describe methods that have been developed in our lab and others to examine pre-mRNA splicing from a genome-wide perspective in yeast. Our goal is to provide all of the necessary information--from microarray design to experimental setup to data analysis--to facilitate the widespread use of this technology. PMID- 20946807 TI - ChIP-Seq using high-throughput DNA sequencing for genome-wide identification of transcription factor binding sites. AB - Much of eukaryotic gene regulation is mediated by binding of transcription factors near or within their target genes. Transcription factor binding sites (TFBS) are often identified globally using chromatin immunoprecipitation (ChIP) in which specific protein-DNA interactions are isolated using an antibody against the factor of interest. Coupling ChIP with high-throughput DNA sequencing allows identification of TFBS in a direct, unbiased fashion; this technique is termed ChIP-Sequencing (ChIP-Seq). In this chapter, we describe the yeast ChIP-Seq procedure, including the protocols for ChIP, input DNA preparation, and Illumina DNA sequencing library preparation. Descriptions of Illumina sequencing and data processing and analysis are also included. The use of multiplex short-read sequencing (i.e., barcoding) enables the analysis of many ChIP samples simultaneously, which is especially valuable for organisms with small genomes such as yeast. PMID- 20946808 TI - Genome-wide mapping of nucleosomes in yeast. AB - The packaging of eukaryotic genomes into chromatin has wide-ranging influences on all DNA-templated processes, from DNA repair to transcriptional regulation. The repeating subunit of chromatin is the nucleosome, which comprises 147 bp of DNA wrapped around an octamer of proteins. Positioning of nucleosomes relative to underlying DNA is a key factor in the regulation of gene transcription by chromatin, as DNA sequences between nucleosomes are more accessible to regulatory factors than are DNA sequences within nucleosomes. Here, I describe protocols for mapping nucleosome positions across the yeast genome. PMID- 20946809 TI - Genome-wide translational profiling by ribosome footprinting. AB - We present a detailed protocol for ribosome profiling, an approach that we developed to make comprehensive and quantitative measurements of translation in yeast. In this technique, ribosome positions are determined from their nuclease footprint on their mRNA template and the footprints are quantified by deep sequencing. Ribosome profiling has already enabled highly reproducible measurements of translational control. Because this technique reports on the exact position of ribosomes, it also revealed the presence of ribosomes on upstream open reading frames and demonstrated that ribosome density was higher near the beginning of protein-coding genes. Here, we describe nuclease digestion conditions that produce uniform ~28 nucleotide (nt) protected fragments of mRNA templates that indicate the exact position of translating ribosomes. We also give a protocol for converting these RNA fragments into a DNA library that can be sequenced using the Illumina Genome Analyzer. Unbiased conversion of anonymous, small RNAs into a sequencing library is challenging, and we discuss standards that played a key role in optimizing library generation. Finally, we discuss how deep sequencing data can be used to quantify gene expression at the level of translation. PMID- 20946810 TI - Synthetic genetic array (SGA) analysis in Saccharomyces cerevisiae and Schizosaccharomyces pombe. AB - A genetic interaction occurs when the combination of two mutations leads to an unexpected phenotype. Screens for synthetic genetic interactions have been used extensively to identify genes whose products are functionally related. In particular, synthetic lethal genetic interactions often identify genes that buffer one another or impinge on the same essential pathway. For the yeast Saccharomyces cerevisiae, we developed a method termed synthetic genetic array (SGA) analysis, which offers an efficient approach for the systematic construction of double mutants and enables a global analysis of synthetic genetic interactions. In a typical SGA screen, a query mutation is crossed to an ordered array of ~5000 viable gene deletion mutants (representing ~80% of all yeast genes) such that meiotic progeny harboring both mutations can be scored for fitness defects. This approach can be extended to all ~6000 genes through the use of yeast arrays containing mutants carrying conditional or hypomorphic alleles of essential genes. Estimating the fitness for the two single mutants and their corresponding double mutant enables a quantitative measurement of genetic interactions, distinguishing negative (synthetic lethal) and positive (within pathway and suppression) interactions. The profile of genetic interactions represents a rich phenotypic signature for each gene and clustering genetic interaction profiles group genes into functionally relevant pathways and complexes. This array-based approach automates yeast genetic analysis in general and can be easily adapted for a number of different genetic screens or combined with high-content screening systems to quantify the activity of specific reporters in genome-wide sets of single or more complex multiple mutant backgrounds. Comparison of genetic and chemical-genetic interaction profiles offers the potential to link bioactive compounds to their targets. Finally, we also developed an SGA system for the fission yeast Schizosaccharomyces pombe, providing another model system for comparative analysis of genetic networks and testing the conservation of genetic networks over millions of years of evolution. PMID- 20946811 TI - Making temperature-sensitive mutants. AB - The study of temperature-sensitive (Ts) mutant phenotypes is fundamental to gene identification and for dissecting essential gene function. In this chapter, we describe two "shuffling" methods for producing Ts mutants using a combination of PCR, in vivo recombination, and transformation of diploid strains heterozygous for a knockout of the desired mutation. The main difference between the two methods is the type of strain produced. In the "plasmid" version, the product is a knockout mutant carrying a centromeric plasmid carrying the Ts mutant. In the "chromosomal" version, The Ts alleles are integrated directly into the endogenous locus, albeit not in an entirely native configuration. Both variations have their strengths and weaknesses, which are discussed here. PMID- 20946813 TI - Exploring gene function and drug action using chemogenomic dosage assays. AB - In this chapter, we describe a series of genome-wide, cell-based assays that provide a solid basis for understanding drug-gene interactions, gene function, and for defining the mechanism of action of small molecules. Each of these assays takes advantage of the ability to grow complex pools competitively and to use high-density microarrays that report the results of such screens. The assays described here take advantage of alterations in gene dosage of Saccharomyces cerevisiae, and include HIP (haploinsufficiency profiling), HOP (homozygous profiling), and MSP (multicopy suppression profiling) as genetic tools to understand gene function and drug mechanism. The common experimental theme is that, in each assay, strains are pooled and screened in parallel to investigate the relative contribution of each gene product to sensitivity or resistance to a drug or environmental perturbation across the genome in a single assay. Further, the compendium of results from these screens can inform large-scale network analysis of genetic function, gene-gene interactions, and mechanism of drug action. PMID- 20946812 TI - Quantitative genetic interaction mapping using the E-MAP approach. AB - Genetic interactions represent the degree to which the presence of one mutation modulates the phenotype of a second mutation. In recent years, approaches for measuring genetic interactions systematically and quantitatively have proven to be effective tools for unbiased characterization of gene function and have provided valuable data for analyses of evolution. Here, we present protocols for systematic measurement of genetic interactions with respect to organismal growth rate for two yeast species. PMID- 20946814 TI - Yeast expression proteomics by high-resolution mass spectrometry. AB - Comprehensive analysis of yeast as a model system requires to reliably determine its composition. Systematic approaches to globally determine the abundance of RNAs have existed for more than a decade and measurements of mRNAs are widely used as proxies for detecting changes in protein abundance. In contrast, methodologies to globally quantitate proteins are only recently becoming available. Such experiments are essential as proteins mediate the majority of biological processes and their abundance does not always correlate well with changes in gene expression. Particularly translational and post-translational controls contribute majorly to regulation of protein abundance, for example in heat shock stress response. The development of new sample preparation methods, high-resolution mass spectrometry and novel bioinfomatic tools close this gap and allow the global quantitation of the yeast proteome under different conditions. Here, we provide background information on proteomics by mass-spectrometry and describe the practice of a comprehensive yeast proteome analysis. PMID- 20946815 TI - High-quality binary interactome mapping. AB - Physical interactions mediated by proteins are critical for most cellular functions and altogether form a complex macromolecular "interactome" network. Systematic mapping of protein-protein, protein-DNA, protein-RNA, and protein metabolite interactions at the scale of the whole proteome can advance understanding of interactome networks with applications ranging from single protein functional characterization to discoveries on local and global systems properties. Since the early efforts at mapping protein-protein interactome networks a decade ago, the field has progressed rapidly giving rise to a growing number of interactome maps produced using high-throughput implementations of either binary protein-protein interaction assays or co-complex protein association methods. Although high-throughput methods are often thought to necessarily produce lower quality information than low-throughput experiments, we have recently demonstrated that proteome-scale interactome datasets can be produced with equal or superior quality than that observed in literature-curated datasets derived from large numbers of small-scale experiments. In addition to performing all experimental steps thoroughly and including all necessary controls and quality standards, careful verification of all interacting pairs and validation tests using independent, orthogonal assays are crucial to ensure the release of interactome maps of the highest possible quality. This chapter describes a high-quality, high-throughput binary protein-protein interactome mapping pipeline that includes these features. PMID- 20946816 TI - Quantitative analysis of protein phosphorylation on a system-wide scale by mass spectrometry-based proteomics. AB - Systems biology at the molecular level is concerned with networks of interacting molecules, their structure, and dynamic response to perturbations that give rise to systems' properties that determine measurable, macroscopic phenotypes. At any time, in any cell, multiple types of molecular networks are concurrently active. One of the most important known regulatory systems in eukaryotic cells is reversible protein phosphorylation catalyzed by protein kinases and phosphatases, respectively. Therefore, it is essential to understand and eventually model the protein phosphorylation-mediated informational fluxes in cells from sensors and signaling systems to effector molecules, to comprehensively analyze the dynamic system of kinases/phosphatases and their substrates and to determine the basic rules of information processing in cells. In this chapter, we describe the protocols necessary to comprehensively and quantitatively measure the phosphorylation-modulated informational networks in cells. The pipeline relies on the selective, quantitative isolation of phosphopeptides generated by the tryptic digestion of complex protein mixtures and their subsequent mass spectrometric and computational analysis. We believe that the protocols and data processing tools described in this chapter will be a valuable resource for biologists interested in the analysis of protein phosphorylation-based signal transduction. PMID- 20946817 TI - A toolkit of protein-fragment complementation assays for studying and dissecting large-scale and dynamic protein-protein interactions in living cells. AB - Protein-fragment complementation assays (PCAs) are a family of assays for detecting protein-protein interactions (PPIs) that have been developed to provide simple and direct ways to study PPIs in any living cell, multicellular organism or in vitro. PCAs can be used to detect PPI between proteins of any molecular weight and expressed at their endogenous levels. Proteins are expressed in their appropriate cellular compartments and can undergo any posttranslational modification or degradation that, barring effects of the PCA fragment fusion, they would normally undergo. Applications of PCAs in yeast have been limited until recently, simply because appropriate expression plasmids or cassettes had not been developed. However, we have now developed and reported on several PCAs in Saccharomyces cerevisiae that cover the gamut of applications one could envision for studying any aspect of PPIs. Here, we present detailed protocols for large-scale analysis of PPIs with the survival-selection dihydrofolate reductase (DHFR) reporter PCA and a new PCA based on a yeast cytosine deaminase reporter that allows for both survival and death selection. This PCA should prove a powerful way to dissect PPIs. We then present a method to study spatial localization and dynamics of PPIs based on fluorescent protein reporter PCAs and finally, two luciferase reporter PCAs that have proved useful for studies of dynamics of PPIs. PMID- 20946818 TI - Yeast lipid analysis and quantification by mass spectrometry. AB - The systematic and quantitative analysis of the different lipid species within a cell or an organism has recently become possible and the general approach has been termed "lipidomics." Traditional methods of identification and quantification of lipid species were laborious processes and it was necessary to use a wide variety of techniques to analyse the different lipid species, especially concerning the assigning of particular acyl chain lengths, hydroxylations, and desaturations to the diverse lipid species. While it is still not possible to quantitatively analyze all lipid species in one fell swoop, great progress has been made with the intensive use of quantitative mass spectrometry approaches. It is now relatively simple to quantify most of the lipid species, including all of the major ones, in a yeast cell. Different degrees of sophistication of mass spectrometric analysis exist and the available techniques and instrumentation are evolving rapidly. Therefore, we have decided to present robust, simple methods to quantify the major yeast lipids by mass spectrometry that should be accessible to anyone who has access to a standard mass spectrometry equipment. The methods to identify and quantify yeast glycerophospholipids and sphingolipids involve electrospray ionization mass spectrometry using fragmentation to characterize the lipid species. A simplified gas chromatographic method is used to quantify the major sterols that occur in wild-type yeast cells and ergosterol biosynthesis mutants. PMID- 20946819 TI - Mass spectrometry-based metabolomics of yeast. AB - Driven by the advent of metabolomics, recent years have seen renewed interest in the investigation of yeast metabolism. Here we provide a practical guide to metabolomic analysis of yeast using liquid chromatography-mass spectrometry (LC MS). We begin with background on LC-MS and its utility in studying yeast metabolism. We then describe key issues involved at each step of a typical yeast metabolomics experiment: in experimental design, cell culture, metabolite extraction, LC-MS, and data processing and analysis. Throughout, we highlight interdependencies between the steps that are relevant to developing an integrated workflow which effectively leverages LC-MS to reveal yeast biology. PMID- 20946820 TI - Imaging single mRNA molecules in yeast. AB - Yeast cells in an isogenic population do not all display the same phenotypes. To study such variation within a population of cells, we need to perform measurements on each individual cell instead of measurements that average out the behavior of a cell over the entire population. Here, we provide the basic concepts and a step-by-step protocol for a recently developed technique enabling one such measurement: fluorescence in situ hybridization that renders single mRNA molecule visible in individual fixed cells. PMID- 20946821 TI - Reconstructing gene histories in Ascomycota fungi. AB - Whole-genome sequencing allows researchers to study evolution through the lens of comparative genomics. Several landmark studies in yeast have showcased the utility of this approach for identifying functional elements, tracing the evolution of gene regulatory sites, and the revelation of an ancestral whole genome duplication event. Such studies first require an accurate and comprehensive mapping of all orthologous loci across all species. In this chapter, we present a computational framework for systematic reconstruction of all gene orthology relations across multiple yeast species. We then discuss how to use the resulting genome- and species-wide catalogue of gene phylogenies to study the histories of gene duplications and losses from a functional genomics perspective. We show how these methods allowed us to uncover the functional constraints underlying gene duplications and losses within Ascomycota fungi, and to highlight the importance and limitations of these evolutionary processes. The analytical framework we present here is generalizable and scalable, and can be applied to an array of comparative genomics needs. PMID- 20946822 TI - Experimental evolution in yeast: a practical guide. AB - Experimental evolution refers to a broad range of studies in which selection pressures are applied to populations. In some applications, particular traits are desired, while in others the subject of study is the mechanisms of evolution or the different modes of behavior between systems. This chapter will explore the range of studies falling under the experimental evolution umbrella, and their relative merits for different types of applications. Practical aspects of experimental evolution will also be discussed, including commercial suppliers, analysis methods, and best laboratory practices. PMID- 20946823 TI - Enhancing stress resistance and production phenotypes through transcriptome engineering. AB - As Saccharomyces cerevisiae is engineered further as a microbial factory for industrially relevant but potentially cytotoxic molecules such as ethanol, issues of cell viability arise that threaten to place a biological limit on output capacity and/or the use of less refined production conditions. Evidence suggests that one naturally evolved mode of survival in deleterious environments involves the complex, multigenic interplay between disparate stress response and homeostasis mechanisms. Rational engineering of such resistance would require a systems-level understanding of cellular behavior that is, in general, not yet available. To circumvent this limitation, we have developed a phenotype discovery approach termed global transcription machinery engineering (gTME) that allows for the generation and selection of nonphysiological traits. We alter gene expression on a genome-wide scale by selecting for dominant mutations in a randomly mutagenized general transcription factor. The gene encoding the mutated transcription factor resides on a plasmid in a strain carrying the unaltered chromosomal allele. Thus, although the dominant mutations may destroy the essential function of the plasmid-borne variant, alteration of the transcriptome with minimal perturbation to normal cellular processes is possible via the presence of the native genomic allele. Achieving a phenotype of interest involves the construction and diversity evaluation of yeast libraries harboring random sequence variants of a chosen transcription factor and the subsequent selection and validation of mutant strains. We describe the rationale and procedures associated with each step in the context of generating strains possessing enhanced ethanol tolerance. PMID- 20946824 TI - Visualizing yeast chromosomes and nuclear architecture. AB - We describe here optimized protocols for tagging genomic DNA sequences with bacterial operator sites to enable visualization of specific loci in living budding yeast cells. Quantitative methods for the analysis of locus position relative to the nuclear center or nuclear pores, the analysis of chromatin dynamics and the relative position of tagged loci to other nuclear landmarks are described. Methods for accurate immunolocalization of nuclear proteins without loss of three-dimensional structure, in combination with fluorescence in situ hybridization, are also presented. These methods allow a robust analysis of subnuclear organization of both proteins and DNA in intact yeast cells. PMID- 20946825 TI - Quantitative localization of chromosomal loci by immunofluorescence. AB - DNA within the yeast nucleus is spatially organized. Yeast telomeres cluster together at the nuclear periphery, centromeres cluster together near the spindle pole body, and both the rDNA repeats and tRNA genes cluster within the nucleolus. Furthermore, the localization of individual genes to subnuclear compartments can change with changes in transcriptional status. As such, yeast researchers interested in understanding nuclear events may need to determine the subnuclear localization of parts of the genome. This chapter describes a straightforward quantitative approach using immunofluorescence and confocal microscopy to localize chromosomal loci with respect to well characterized nuclear landmarks. PMID- 20946826 TI - Spinning-disk confocal microscopy of yeast. AB - Spinning-disk confocal microscopy is an imaging technique that combines the out of-focus light rejection of confocal microscopy with the high sensitivity of wide field microscopy. Because of its unique features, it is well suited to high resolution imaging of yeast and other small cells. Elimination of out-of-focus light significantly improves the image contrast and signal-to-noise ratio, making it easier to resolve and quantitate small, dim structures in the cell. These features make spinning-disk confocal microscopy an excellent technique for studying protein localization and dynamics in yeast. In this review, I describe the rationale behind using spinning-disk confocal imaging for yeast, hardware considerations when assembling a spinning-disk confocal scope, and methods for strain preparation and imaging. In particular, I discuss choices of objective lens and camera, choice of fluorescent proteins for tagging yeast genes, and methods for sample preparation. PMID- 20946827 TI - Correlative GFP-immunoelectron microscopy in yeast. AB - Correlative light and electron microscopy represents the ultimate goal for the visualization of cell biological processes. In theory, it is possible to combine the strengths of both methods, that is, the live-cell imaging of the movement of GFP-tagged proteins captured by fluorescence microscopy with an image of the fine structural context surrounding the tagged protein imaged and localized by immunoelectron microscopy. In practice, inherent technical limitations of the two individual methods and their combination make the technique very complex to handle. Here, we present a high-pressure freezing and freeze-substitution protocol which fulfills the key criterion for correlative microscopy, namely, the ability to achieve excellent visibility of fine structures without disrupting the antigens recognized by the immunolabeling protocol. This is achieved by a fixative-free freeze-substitution and low-temperature embedding. PMID- 20946828 TI - Analyzing P-bodies and stress granules in Saccharomyces cerevisiae. AB - Eukaryotic cells contain at least two types of cytoplasmic RNA-protein (RNP) granules that contain nontranslating mRNAs. One such RNP granule is a P-body, which contains translationally inactive mRNAs and proteins involved in mRNA degradation and translation repression. A second such RNP granule is a stress granule which also contains mRNAs, some RNA binding proteins and several translation initiation factors, suggesting these granules contain mRNAs stalled in translation initiation. In this chapter, we describe methods to analyze P bodies and stress granules in Saccharomyces cerevisiae, including procedures to determine if a protein or mRNA can accumulate in either granule, if an environmental perturbation or mutation affects granule size and number, and granule quantification methods. PMID- 20946829 TI - Analyzing mRNA expression using single mRNA resolution fluorescent in situ hybridization. AB - As the product of transcription and the blueprint for translation, mRNA is the main intermediate product of the gene expression pathway. The ability to accurately determine mRNA levels is, therefore, a major requirement when studying gene expression. mRNA is also a target of different regulatory steps, occurring in different subcellular compartments. To understand the different steps of gene expression regulation, it is therefore essential to analyze mRNA in the context of a single cell, maintaining spatial information. Here, we describe a stepwise protocol for fluorescent in situ hybridization (FISH) that allows detection of individual mRNAs in single yeast cells. This method allows quantitative analysis of mRNA expression in single cells, permitting "absolute" quantification by simply counting mRNAs. It further allows us to study many aspects of mRNA metabolism, from transcription to processing, localization, and mRNA degradation. PMID- 20946830 TI - The use of in vitro assays to measure endoplasmic reticulum-associated degradation. AB - Approximately one-third of all newly translated polypeptides interact with the endoplasmic reticulum (ER), an event that is essential to target these nascent proteins to distinct compartments within the cell or to the extracellular milieu. Thus, the ER houses molecular chaperones that augment the folding of this diverse group of macromolecules. The ER also houses the enzymes that catalyze a multitude of posttranslational modifications. If, however, proteins misfold or are improperly modified in the ER they are proteolyzed via a process known as ER associated degradation (ERAD). During ERAD, substrates are selected by molecular chaperones and chaperone-like proteins. They are then delivered to the cytoplasmic proteasome and hydrolyzed. In most cases, delivery and proteasome targeting require the covalent attachment of ubiquitin. The discovery and underlying mechanisms of the ERAD pathway have been aided by the development of in vitro assays that employ components derived from the yeast, Saccharomyces cerevisiae. These assays recapitulate the selection of ERAD substrates, the "retrotranslocation" of selected polypeptides from the ER into the cytoplasm, and the proteasome-mediated degradation of the substrate. The ubiquitination of integral membrane ERAD substrates has also been reconstituted. PMID- 20946831 TI - A protein transformation protocol for introducing yeast prion particles into yeast. AB - A range of methods for transforming organisms with nucleic acids has been established. However, techniques for introducing proteins, or particularly protein aggregates, into cells are less developed. Here, we introduce a highly efficient protocol for introducing protein aggregates such as prions into yeast. The protein transformation protocol allows one to infect yeast with amyloid fibers of recombinant fragments (Sup-NM) of Sup35p, the protein determinant of the yeast prion state [PSI+], or in vivo Sup35p prions. Infectivity is dependent on the concentration of Sup-NM fibers and approaches approximately 100% at high Sup-NM concentrations. We also describe a method to create distinct conformations of Sup-NM amyloids. Using the protein transformation protocol, infection of yeast with different Sup-NM amyloid conformations leads to distinct [PSI+] strains. This protein transformation procedure is readily adaptable to other prion proteins and makes it possible to bridge in vitro and in vivo studies and greatly helps to elucidate the principles of prion inheritance. PMID- 20946832 TI - Overexpression and purification of integral membrane proteins in yeast. AB - The budding yeast Saccharomyces cerevisiae is a viable system for the overexpression and functional analysis of eukaryotic integral membrane proteins (IMPs). In this chapter we describe a general protocol for the initial cloning, transformation, overexpression, and subsequent purification of a putative IMP and discuss critical optimization steps and approaches. Since expression and purification are often the two predominant hurdles one will face in studying this difficult class of biological macromolecules the intent is to outline the general workflow while providing insights based upon our collective experience. These insights should facilitate tailoring of the outlined protocol to individual IMPs and expression or purification routines. PMID- 20946833 TI - Biochemical, cell biological, and genetic assays to analyze amyloid and prion aggregation in yeast. AB - Protein aggregates are associated with a variety of debilitating human diseases, but they can have functional roles as well. Both pathological and nonpathological protein aggregates display tremendous diversity, with substantial differences in aggregate size, morphology, and structure. Among the different aggregation types, amyloids are particularly remarkable, because of their high degree of order and their ability to form self-perpetuating conformational states. Amyloids form the structural basis for a group of proteins called prions, which have the ability to generate new phenotypes by a simple switch in protein conformation that does not involve changes in the sequence of the DNA. Although protein aggregates are notoriously difficult to study, recent technological developments and, in particular, the use of yeast prions as model systems, have been very instrumental in understanding fundamental aspects of aggregation. Here, we provide a range of biochemical, cell biological and yeast genetic methods that are currently used in our laboratory to study protein aggregation and the formation of amyloids and prions. PMID- 20946834 TI - Genetics and molecular biology in Candida albicans. AB - Candida albicans is an opportunistic fungal pathogen of humans. Although a normal part of our gastrointestinal flora, C. albicans has the ability to colonize nearly every human tissue and organ, causing serious, invasive infections. In this chapter we describe current methodologies used in molecular genetic studies of this organism. These techniques include rapid sequential gene disruption, DNA transformation, RNA isolation, epitope tagging, and chromatin immunoprecipitation. The ease of these techniques, combined with the high-quality C. albicans genome sequences now available, have greatly facilitated research into this important pathogen. Candida albicans is a normal resident of the human gastrointestinal tract; it is also the most common fungal pathogen of humans, causing both mucosal and systemic infections, particularly in immune compromised patients. C. albicans and Saccharomyces cerevisiae last shared a common ancestor more than 900 million years ago; in terms of conserved coding sequences, the two species are approximately as divergent as fish and humans. Although C. albicans and S. cerevisiae share certain core features, they also exhibit many significant differences. This is not surprising as C. albicans has the ability to survive in nearly every niche of a mammalian host, a property not shared by S. cerevisiae. Research into C. albicans is important in its own right, particularly with regards to its ability to cause disease in humans; in addition, comparison with S. cerevisiae can reveal important insights into evolutionary processes. Many of the methodologies developed for use in S. cerevisiae have been adapted for C. albicans, and we describe some of the most common. Although alternative procedures are described in the literature, we have found those described below to be the most convenient. Because the C. albicans parasexual cycle is cumbersome to use in the laboratory, genetics in this organism has been based almost entirely on directed mutations. Because the organism is diploid, creating a deletion mutant requires two rounds of gene disruption. We describe a rapid method for creating sequential disruptions, one which can be scaled up to create large collections of C. albicans deletion mutants. We also describe a series of additional techniques including DNA transformation, mRNA isolation, epitope tagging, and chromatin immunoprecipitation (ChIP). The ease of these techniques, combined with the high-quality C. albicans genome sequences now available, has greatly increased the quality and pace of research into this important pathogen. PMID- 20946835 TI - Molecular genetics of Schizosaccharomyces pombe. AB - In this chapter we present basic protocols for the use of Schizosaccharomyces pombe, commonly known as fission yeast, in molecular biology and genetics research. Fission yeast is an increasingly popular model organism for the study of biological pathways because of its genetic tractability and as a model for metazoan biology. It provides an alternative and complimentary approach to Saccharomyces cerevisiae for addressing questions of cell biology, physiology, genetics, and genomics/proteomics. We include details and considerations for growing fission yeast, information on crosses and genetics, gene targeting and transformation, cell synchrony and analysis, and molecular biology protocols. PMID- 20946836 TI - Applying genetics and molecular biology to the study of the human pathogen Cryptococcus neoformans. AB - The basidiomycete yeast Crytococcus neoformans is a prominent human pathogen. It primarily infects immunocompromised individuals producing a meningoencephalitis that is lethal if untreated. Recent advances in its genetics and molecular biology have made it a model system for understanding both the Basidiomycota phylum and mechanisms of fungal pathogenesis. The relative ease of experimental manipulation coupled with the development of murine models for human disease allow for powerful studies in the mechanisms of virulence and host responses. This chapter introduces the organism and its life cycle and then provides detailed step-by-step protocols for culture, manipulation of the genome, analysis of nucleic acids and proteins, and assessment of virulence and expression of virulence factors. PMID- 20946837 TI - The fungal genome initiative and lessons learned from genome sequencing. AB - The sequence of Saccharomyces cerevisiae enabled systematic genome-wide experimental approaches, demonstrating the power of having the complete genome of an organism. The rapid impact of these methods on research in yeast mobilized an effort to expand genomic resources for other fungi. The "fungal genome initiative" represents an organized genome sequencing effort to promote comparative and evolutionary studies across the fungal kingdom. Through such an approach, scientists can not only better understand specific organisms but also illuminate the shared and unique aspects of fungal biology that underlie the importance of fungi in biomedical research, health, food production, and industry. To date, assembled genomes for over 100 fungi are available in public databases, and many more sequencing projects are underway. Here, we discuss both examples of findings from comparative analysis of fungal sequences, with a specific emphasis on yeast genomes, and on the analytical approaches taken to mine fungal genomes. New sequencing methods are accelerating comparative studies of fungi by reducing the cost and difficulty of sequencing. This has driven more common use of sequencing applications, such as to study genome-wide variation in populations or to deeply profile RNA transcripts. These and further technological innovations will continue to be piloted in yeasts and other fungi, and will expand the applications of sequencing to study fungal biology. PMID- 20946838 TI - Ultradian metabolic cycles in yeast. AB - Budding yeast are capable of displaying various modes of oscillatory behavior. Such cycles can occur with a period ranging from 1 min up to many hours, depending on the growth and culturing conditions used to observe them. This chapter discusses the robust oscillations in oxygen consumption exhibited by high density yeast cell populations during continuous, glucose-limited growth in a chemostat. These ultradian metabolic cycles offer a view of the life of yeast cells under a challenging, nutrient-poor growth environment and might represent useful systems to interrogate a variety of fundamental metabolic and regulatory processes. PMID- 20946839 TI - Characterizing cross-talk in vivo avoiding pitfalls and overinterpretation. AB - Cross-talk between noncognate histidine kinases and response regulators has been widely reported in vitro and, in specific mutant backgrounds and conditions, in vivo. However, in most cases there is little evidence supporting a physiological role of cross-talk. Indeed, histidine kinases and response regulators show remarkable specificity for their cognate partners. In vivo studies of cross-talk have the potential to establish mechanisms that control specificity and, if the cross-talk is observable in wild-type strains, may reveal new levels of cross regulation. However such studies can be complicated by effects of other regulatory circuits and by the inactivation of mechanisms that would otherwise suppress cross-talk. It is thus easy to mis- or overinterpret the significance of such studies. We address potential complications associated with measuring cross talk and discuss some methods for identifying and unmasking sources of cross-talk in cells using transcriptional reporters and in vivo DNA-binding assays. PMID- 20946840 TI - Inference of direct residue contacts in two-component signaling. AB - Since the onset of the genomic era more than 1000 bacterial genomes have been sequenced and several fold more are expected to be completed in the near future. These genome sequences supply a wealth of information that can be exploited by statistical methods to gain significant insights into cellular processes. In Volume 422 of Methods in Enzymology we described a covariance-based method, which was able to identify coevolving residue pairs between the ubiquitous bacterial two-component signal transduction proteins, the sensor kinase and the response regulator. Such residue position pairs supply interaction specificity in the light of highly amplified but structurally conserved two-component systems in a typical bacterium and are enriched with interaction surface residue pairings. In this chapter we describe an extended version of this method, termed "direct coupling analysis" (DCA), which greatly enhances the predictive power of traditional covariance analysis. DCA introduces a statistical inference step to covariance analysis, which allows to distinguish coevolution patterns introduced by direct correlations between two-residue positions, from those patterns that arise via indirect correlations, that is, correlations that are introduced by covariance with other residues in the respective proteins. This method was shown to reliably identify residue positions in spatial proximity within a protein or at the interface between two interaction partners. It is the goal of this chapter to allow an experienced programmer to reproduce our techniques and results so that DCA can soon be applied to new targets. PMID- 20946841 TI - Computational modeling of phosphotransfer complexes in two-component signaling. AB - Two-component signal transduction systems enable cells in bacteria, fungi, and plants to react to extracellular stimuli. A sensor histidine kinase (SK) detects such stimuli with its sensor domains and transduces the input signals to a response regulator (RR) by trans-phosphorylation. This trans-phosphorylation reaction requires the formation of a complex formed by the two interacting proteins. The complex is stabilized by transient interactions. The nature of the transient interactions makes it challenging for experimental techniques to gain structural information. X-ray crystallography requires stable crystals, which are difficult to grow and stabilize. Similarly, the mere size of these systems proves problematic for NMR. Theoretical methods can, however, complement existing data. The statistical direct coupling analysis presented in the previous chapter reveals the interacting residues at the contact interface of the SK/RR pair. This information can be combined with the structures of the individual proteins in molecular dynamical simulation to generate structural models of the complex. The general approach, referred to as MAGMA, was tested on the sporulation phosphorelay phosphotransfer complex, the Spo0B/Spo0F pair, delivering crystal resolution accuracy. The MAGMA method is described here in a step-by-step explanation. The developed parameters are transferrable to other SK/RR systems. PMID- 20946842 TI - Kinetic studies of the yeast His-Asp phosphorelay signaling pathway. AB - For both prokaryotic and eukaryotic His-Asp phosphorelay signaling pathways, the rates of protein phosphorylation and dephosphorylation determine the stimulus-to response time frame. Thus, kinetic studies of phosphoryl group transfer between signaling partners are important for gaining a full understanding of how the system is regulated. In many cases, the phosphotransfer reactions are too fast for rates to be determined by manual experimentation. Rapid quench flow techniques thus provide a powerful method for studying rapid reactions that occur in the millisecond time frame. In this chapter, we describe experimental design and procedures for kinetic characterization of the yeast SLN1-YPD1-SSK1 osmoregulatory phosphorelay system using a rapid quench flow kinetic instrument. PMID- 20946843 TI - Purification of MBP-EnvZ fusion proteins using an automated system. AB - Bacteria use two-component signal transduction systems to detect and respond to environmental changes. These systems have been studied systematically in Escherichia coli as a model organism. Most of the signal transduction systems present in E. coli are conserved in related pathogenic bacteria; however, differences in regulation by these systems have been reported from one bacterial species to another [Oropeza, R., and Calva, E. (2009). The cysteine 354 and 277 residues of Salmonella enterica serovar Typhi EnvZ are determinants of autophosphorylation and OmpR phosphorylation. FEMS Microbiol. Lett.292, 282-290]. Our laboratory has been interested in studying the OmpR/EnvZ two-component system in S. enterica. In S. enterica serovar Typhi (Typhi), it regulates the expression of the porin genes, namely ompC, ompF, ompS1, and ompS2. OmpR proteins are identical between E. coli and Typhi, but several differences exist between the EnvZ proteins. To define whether some differences in porin regulation are due to changes on EnvZ, we decided to overexpress and purify E. coli, Typhi, and S. enterica serovar Typhimurium (Typhimurium) EnvZ proteins fused to the maltose binding protein (MBP) as a purification tag. Differences in the autophosphorylation level of these proteins were evidenced. Hence, considering the differences at the amino acid level between E. coli and Typhi EnvZ proteins, several mutations were introduced in the Typhi EnvZ protein in order to try to find the amino acids affecting the enzymatic activity of the protein. We found that Cys354 plays an important role in defining the enzymatic activity of this histidine kinase. Here, we report the automated purification of a collection of MBP-EnvZ fusions using a mini-chromatography commercial system, but adapting an amylose affinity column packed by ourselves. PMID- 20946844 TI - Measurement of response regulator autodephosphorylation rates spanning six orders of magnitude. AB - Two-component regulatory systems, comprising sensor kinase and response regulator proteins, carry out signal transduction in prokaryotic and eukaryotic microorganisms, as well as plants. Response regulators act as phosphorylation mediated switches, turning on and off cellular responses to environmental stimuli. Self-catalyzed dephosphorylation is an important determinant of the duration of the response regulator activated state. Reported response regulator autodephosphorylation rates vary over almost a million-fold range, consistent with control of biological processes that occur on widely different timescales. We describe general considerations for the design and execution of in vitro assays to measure the autodephosphorylation rates of purified response regulator proteins, as well as specific methods that utilize loss of 32P, changes in fluorescence, or release of inorganic phosphate. The advantages and disadvantages of different methods are discussed, including suitability for different timescales. In addition to outlining established methods, an assay modification is proposed to measure fast autodephosphorylation rates with radioactivity, and optimization of the fluorescence/pH jump method is described. PMID- 20946845 TI - Transmembrane receptor chimeras to probe HAMP domain function. AB - HAMP domains are the central signal converters in bacterial chemotaxis receptors and chemosensory histidine kinases. They link the signal input modules in these proteins, that is, the ligand-binding domains, to the output modules, for example, the histidine kinase domain. A similar architecture is present in the adenylyl cyclase (AC) Rv3645 from Mycobacterium tuberculosis, where a HAMP domain is positioned between the N-terminal membrane anchor and the C-terminal catalytic domain. Because the activity of the catalytic domain responds to alterations in the HAMP domain, a method has been developed which uses the catalytic domain of Rv3645 as a reporter to probe the HAMP domain function of diverse bacterial proteins. A strategy for construction of chimeras between a variety of HAMP domains and the catalytic domain of the AC Rv3645 is described. The enzymes are overexpressed in Escherichia coli and purified by Ni2+-affinity chromatography. AC activity of the chimeras is determined by a radiotracer method published earlier in the series. Results of the mutagenesis of the HAMP domain from the Af1503 protein of Archeoglobus fulgidus are shown as an example for the successful application of the method. PMID- 20946846 TI - Light-activated bacterial LOV-domain histidine kinases. AB - Bacteria rely on two-component signaling systems in their adaptive responses to environmental changes. Typically, the two-component system consists of a sensory histidine kinase that signals by transferring a phosphoryl group to a secondary response regulator that ultimately relays the signal to the cell. Some of these sensors use PAS (Per-Arnt-Sin) domains. A new member of the PAS super family is the LOV (light, oxygen, voltage) domain, a 10-kDa flavoprotein that functions as a light-sensory module in plant, algal, fungal, and bacterial blue-light receptors. Putative LOV domains have been identified in the genomes of many higher and lower eukaryotes, plants, eubacteria, archaebacteria, and particularly in genes coding for histidine kinases (LOV-histidine kinases, LOV-HKs) of plant and animal pathogenic bacteria, including Brucella. We describe here biochemical, photochemical, and biophysical methodology to purify these enzymes and to characterize their light-activation process. PMID- 20946847 TI - Characterization of bacteriophytochromes from photosynthetic bacteria: histidine kinase signaling triggered by light and redox sensing. AB - Bacteria detect environmental changes, thanks to two-component signal transduction systems, composed, in general, of a sensor coupled to a histidine kinase and a DNA binding response regulator. Anoxygenic photosynthetic bacteria like Rhodopseudomonas (Rps.) palustris, possess a highly versatile metabolism and can grow via photosynthesis using light energy or via respiration through oxygen consumption. For photosynthetic bacteria, detecting changes in light quality or quantity, or in oxygen concentration, is therefore of prime importance for adjusting their metabolism for optimal development. A central role is played by bacteriophytochromes for light detection and initiation of regulatory responses. The switch of these chromoproteins between two photointerconvertible forms is the first event in the light-regulated cascade. This chapter describes in vitro and in vivo methods that have been successfully used to investigate the bacteriophytochrome dependent light regulation pathways, in several strains of Rps. palustris and Bradyrhizobium. These approaches range from biochemical and biophysical methods to genetic techniques. Such multiple approaches are indispensable for understanding these complex light-regulated pathway. In a first step, bacteriophytochromes and associated response regulators are overexpressed in Escherichia coli and purified. The spectral and kinetic properties of the two photointerconvertible forms of the purified bacteriophytochromes are then determined by biophysical approaches. Original spectral and kinetic properties found in some of the bacteriophytochromes that we studied necessitated the development of new methods for computing the spectra of the pure forms and the photoconversion yields. In vitro biochemical approaches help to assess the histidine kinase activity of bacteriophytochromes depending on light conditions, the phosphotransfer to response regulators and their affinity to promoter DNA sequences. Finally, gene inactivation tests the importance of specific genes in photosynthesis regulation under particular light and oxygen tension growth conditions. The methods described in this chapter are not restricted to the study of the light-transduction pathways of Rps. palustris and Bradyrhizobium strains but are applicable to the understanding of any bacterial light-regulatory system. PMID- 20946848 TI - Biophysical assays for protein interactions in the Wsp sensory system and biofilm formation. AB - Many signal transduction and regulatory events are mediated by a change in oligomeric state upon posttranslational modification or ligand binding. Hence, the characterization of proteins and protein complexes with respect to their size and shape is crucial for elucidating the molecular mechanisms that control their activities. Commonly used methods for the determination of molecular weights of biological polymers such as standard size-exclusion chromatography or analytical ultracentrifugation have been applied successfully but have some limitations. Static multiangle light scattering presents an attractive alternative approach for absolute molecular weight measurements in solution. We review the biophysical principles, advantages, and pitfalls of some popular methods for determining the quaternary structure of proteins, using the response regulator diguanylate cyclase WspR from Pseudomonas and FimX, a protein involved in Pseudomonas aeruginosa twitching motility, as examples. PMID- 20946849 TI - High-throughput screening of bacterial protein localization. AB - The ever-increasing number of sequenced genomes and subsequent sequence-based analysis has provided tremendous insight into cellular processes; however, the ability to experimentally manipulate this genomic information in the laboratory requires the development of new high-throughput methods. To translate this genomic information into information on protein function, molecular and cell biological techniques are required. One strategy to gain insight into protein function is to observe where each specific protein is subcellularly localized. We have developed a pipeline of methods that allows rapid, efficient, and scalable gene cloning, imaging, and image analysis. This work focuses on a high-throughput screen of the Caulobacter crescentus proteome to identify proteins with unique subcellular localization patterns. The cloning, imaging, and image analysis techniques described here are applicable to any organism of interest. PMID- 20946850 TI - In vitro and in vivo analysis of the ArcB/A redox signaling pathway. AB - The Arc (anoxic redox control) two-component system (TCS) is a complex signal transduction system that plays an important role in regulating energy metabolism at the level of transcription in bacteria. This system comprises the ArcB protein, a hybrid membrane-associated sensor kinase, and the ArcA protein, a typical response regulator. Under anoxic growth conditions, ArcB autophosphorylates and transphosphorylates ArcA via a His->Asp->His->Asp phosphorelay. Under aerobic conditions, the ArcB kinase activity is silenced by the oxidation of two cytosol-located redox-active cysteine residues that participate in intermolecular disulfide bond formation. Under such conditions, ArcB acts as a phosphatase that catalyzes the dephosphorylation of ArcA-P and thereby releasing its transcriptional regulation. This chapter describes general in vitro and in vivo assays and strategies that have been used to characterize the ArcB/A two-component signal transduction system, which could, also, be applied to most other TCS. PMID- 20946851 TI - Potassium sensing histidine kinase in Bacillus subtilis. AB - The soil-dwelling organism Bacillus subtilis is able to form multicellular aggregates known as biofilms. It was recently reported that the process of biofilm formation is activated in response to the presence of various, structurally diverse small-molecule natural products. All of these small-molecule natural products made pores in the membrane of the bacterium, causing the leakage of potassium cations from the cytoplasm of the cell. The potassium cation leakage was sensed by the membrane histidine kinase KinC, triggering the genetic pathway to the production of the extracellular matrix that holds cells within the biofilm. This chapter presents the methodology used to characterize the leakage of cytoplasmic potassium as the signal that induces biofilm formation in B. subtilis via activation of KinC. Development of novel techniques to monitor activation of gene expression in microbial populations led us to discover the differentiation of a subpopulation of cells specialized to produce the matrix that holds all cells together within the biofilm. This phenomenon of cell differentiation was previously missed by conventional techniques used to monitor transcriptional gene expression. PMID- 20946852 TI - Two-component systems and regulation of developmental progression in Myxococcus xanthus. AB - Myxococcus xanthus is a prokaryotic model system for multicellular development and cell differentiation. Two-component signal transduction genes are abundant in this organism and the majority is likely organized into complex signaling pathways. This chapter describes in vivo genetic and in vitro biochemical methods used to define signal transduction systems in M. xanthus. We also describe a series of phenotypic analyses utilized to define how a specific set of atypical histidine kinases (HKs) influence progression through the complex developmental program. PMID- 20946853 TI - Two-component signaling to the stress MAP kinase cascade in fission yeast. AB - In the fission yeast Schizosaccharomyces pombe, the Mak2/3 sensor histidine kinases (HKs), the Mpr1 histidine-containing phosphotransfer (HPt) protein, and the Mcs4 response regulator (RR) constitute a multistep phosphorelay, which is connected to a stress-activated mitogen-activated protein kinase (MAPK) cascade. This hybrid signaling pathway senses H2O2 and transmits the stress signal by sequential phosphorylation of the component proteins, whose physical interactions play crucial roles to attain eventual activation of Spc1 MAPK. This chapter describes methodological details of the copurification assays in S. pombe cell lysate to detect the physical interactions between the Mpr1 HPt and Mcs4 RR proteins and between Mcs4 and the MAPK kinase kinases (MAPKKKs) of the Spc1 cascade. Unexpectedly, we found that the glycolytic enzyme glyceraldehyde-3 phosphate dehydrogenase (GAPDH) encoded by tdh1+ is involved in the H2O2 signaling process, and its association with Mcs4 and MAPKKKs in cell lysate is also detectable by copurification assays. In response to H2O2, the catalytic cysteine residue of Tdh1 GAPDH is subjected to S-thiolation, of which detection protocol is described as well. PMID- 20946854 TI - Genetic and biochemical analysis of the SLN1 pathway in Saccharomyces cerevisiae. AB - The histidine kinase-based signal transduction pathway was first uncovered in bacteria and is a prominent form of regulation in prokaryotes. However, this type of signal transduction is not unique to prokaryotes; over the last decade two component signal transduction pathways have been identified and characterized in diverse eukaryotes, from unicellular yeasts to multicellular land plants. A number of small but important differences have been noted in the architecture and function of eukaryotic pathways. Because of the powerful genetic approaches and facile molecular analysis associated with the yeast system, the SLN1 osmotic response pathway in Saccharomyces cerevisiae is particularly useful as a eukaryotic pathway model. This chapter provides an overview of genetic and biochemical methods that have been important in elucidating the stimulus-response events that underlie this pathway and in understanding the details of a eukaryotic His-Asp phosphorelay. PMID- 20946855 TI - Analysis of mitogen-activated protein kinase phosphorylation in response to stimulation of histidine kinase signaling pathways in Neurospora. AB - In eukaryotes, two-component regulatory systems have been demonstrated to regulate phosphorylation of mitogen-activated protein kinases (MAPKs). Here, we describe a method implementing preparation of a protein extract under denaturing conditions, followed by Western analysis using MAPK antibodies that can be used to observe the effects of components of two-component signaling pathways or other proteins on the phosphorylation status of MAPKs. The protein extraction method presented may also be used to concentrate cellular proteins for additional applications, such as metabolic labeling or analysis of other posttranslational modifications. PMID- 20946856 TI - Biochemical characterization of plant hormone cytokinin-receptor histidine kinases using microorganisms. AB - Results of recent studies on the model higher plant Arabidopsis thaliana have led us to learn about the generality and versatility of two-component systems (TCS) in eukaryotes. In the plant, TCS are crucially involved in certain signal transduction mechanisms underlying the regulation of plant development in response to a subset of plant hormones, namely, cytokinin and ethylene. Results of extensive plant genomics revealed that these hormone-responsive TCS are evolutionarily conserved in many other plants, including mosses, grasses, crops, and trees. In particular, the conserved cytokinin-responsive TCS is typical in the sense that the signaling pathway consists of cytokinin-receptor histidine kinases (HK), histidine-containing phosphotransfer (HPt) factors, and downstream phosphoaccepting response regulators (RR), which together act as His-to-Asp multistep phosphorelay components, and which together modulate the downstream network of cytokinin-responsive gene regulation. The ethylene-responsive TCS is atypical in that ethylene-receptor HKs appear to directly interact with the downstream mitogen-activated protein kinase (MAPK) cascade. The ethylene responsive HKs have already been introduced in the previous edition of Methods in Enzymology [Schaller, G. E., and Binder, B. M. (2007). Biochemical characterization of plant ethylene receptors following transgenic expression in yeast. Methods Enzymol. 422, 270-287]. Hence, here we focus on the cytokinin receptor HKs, which are capable of functioning in microorganisms, such as Escherichia coli and Saccharomyces cerevisiae. Some versatile protocols useful for analyzing plant TCS factors by employing these microorganisms will be introduced. PMID- 20946857 TI - Characterization of pseudo-response regulators in plants. AB - A small family of clock-regulated pseudo-response regulators (PRRs) plays a number of critical roles in the function of the plant circadian clock. The regulation of the PRRs is complex and entails both transcriptional and posttranslational regulation. PRR proteins engage in a number of important protein-protein interactions, some of which are modulated by modifications including phosphorylation. PRR stability is also tightly controlled. This chapter provides methods for studying both the PRR genes and their encoded proteins. PMID- 20946858 TI - Reversible histidine phosphorylation in mammalian cells: a teeter-totter formed by nucleoside diphosphate kinase and protein histidine phosphatase 1. AB - Regulation of protein phosphorylation by kinases and phosphatases is involved in many signaling pathways in mammalian cells. In contrast to prokaryotes and lower eukaryotes a role for the reversible phosphorylation of histidine residues is just emerging. The beta subunit of heterotrimeric G proteins, the metabolic enzyme adenosine 5'-triphosphate-citrate lyase (ACL), and the Ca2+-activated K+ channel KCa3.1 have been identified as targets for nucleoside diphosphate kinase (NDPK) acting as protein histidine kinase and the so far only identified mammalian protein histidine phosphatase (PHPT-1). Herein, we describe the analysis of the phosphorylation and dephosphorylation of histidine residues by NDPK and PHPT-1. In addition, experimental protocols for studying the consequences of heterotrimeric G protein activation via NDPK/Gbetagamma mediated phosphorelay, the regulation of ACL activity and of KCa3.1 conductivity by histidine phosphorylation will be presented. PMID- 20946859 TI - Histidine phosphorylation in histones and in other mammalian proteins. AB - The investigation of protein histidine phosphorylation has required the development of a number of methods that differ from traditional methods of phosphoprotein analysis that were developed to study phosphorylation of serine, threonine, and tyrosine, which are, unlike phosphohistidine, acid-stable. The investigation of histidine phosphorylation is further complicated by the fact that in mammalian proteins, phosphorylation appears to occur at either 1-N or 3-N positions of the imidazole ring, depending on the source of the kinase. In this review, we describe methods developed for phosphoamino acid analysis to detect phosphohistidine, including the determination of the isoform present, using chromatographic and mass spectrometric analysis of phosphoprotein hydrolysates and 1H- and 31P NMR analysis of intact phosphoproteins and phosphopeptides. We also describe methods for the assay of protein histidine kinase activity, including a quantitative assay of alkali-stable, acid-labile protein phosphorylation, and an in-gel kinase assay applied to histidine kinases. Most of the detailed descriptions of methods are as they are applied in our laboratory to the investigation of histone H4 phosphorylation and histone H4 histidine kinases, but which can be applied to the phosphorylation of any proteins and to any such histidine kinases. PMID- 20946860 TI - Influenza antigen-sparing by immune stimulation with Gram-positive enhancer matrix (GEM) particles. AB - Gram-positive enhancer matrix (GEM) particles, produced from non-genetically modified Lactococcus lactis bacteria have an inherent immunostimulatory activity. It was investigated whether co-administration of GEM particles can reduce the amount of influenza subunit vaccine (HA) necessary to protect mice from viral infection. Decreasing HA amounts of 5, 1, 0.2 and 0.04MUg admixed with GEM particles were tested in intramuscular immunizations. Combinations of GEM and seasonal HA (A/Wisconsin/67/2005 [H3N2]) induced significantly higher systemic and better Th1/Th2-type balanced immune responses than HA alone. Addition of GEM to 0.04MUg HA resulted in similar HI titers as 1-5MUg non-adjuvanted HA. To test the protective efficacy of the adjuvanted combination, mice were immunized with influenza subunit vaccine A/PR/8/34 (H1N1) and then challenged with live virus (A/PR/8/34). Mice immunized with 1MUg HA+GEM showed undetectable virus titers in the lungs 5 days after challenge, whereas mice immunized with 1MUg HA alone showed detectable levels of virus in the lungs. Interestingly, mice vaccinated with the 0.04MUg HA+GEM vaccine demonstrated reduced lung virus titers and a reduction in weight that was similar as that in mice vaccinated with 1MUg non adjuvanted HA. These results indicate that the use of GEM as immunostimulant allows for a strong reduction in the antigen dose as compared to the benchmark vaccine by using GEM particles. Thus, addition of GEM can strongly potentiate immunogenicity of influenza subunit vaccine both quantitatively and qualitatively. PMID- 20946861 TI - Herpes zoster: Burden of disease in France. AB - This work provides estimates of HZ incidence and HZ-related hospitalization and mortality rates in France, where no immunization programme has been implemented. Herpes zoster data was obtained from the Sentinelles surveillance general practitioners (GPs) network, the PMSI Data processing centre for hospital discharges and from the French National Mortality Database (INSERM CepiDC). The yearly HZ incidence rate averaged 382 cases per 100,000 inhabitants (95% CI 364 405) and exponentially increased with age. The annual rates of hospitalizations and mortality due to HZ varied from 4.14+/-0.32 to 14.42+/-0.39 and from 0.11+/ 0.03 to 0.29+/-0.04 per 100,000 inhabitants, respectively, depending on whether HZ was coded in a 'primary' or 'primary or associated' diagnosis. One or more factors of immunodepression occurred in 43.4% of hospitalized cases and in 21.6% HZ-related deaths. PMID- 20946863 TI - Quantitative high-resolution melting analysis for detecting adulterations. AB - Admixtures of different plant species are a common problem in raw materials for medicinal use. Two exemplary assays were developed to admixtures in Helleborus niger with high-resolution melting analysis. HRM proved to be a very sensitive tool in detecting admixtures, able to detect a ratio of 1:1000 with unknown species, and of 1:200,000 with Veratrum nigrum. The example proves the ability of HRM for quantification in multiplex PCR. The method is not limited to detecting adulterations. It can also be used to quantify a specific target by integrating a second amplicon in the assay as internal standard. PMID- 20946862 TI - Characterization of mycolic acids from the pathogen Rhodococcus equi by tandem mass spectrometry with electrospray ionization. AB - We describe a simple tandem mass spectrometric approach toward structural characterization of mycolic acids, the long-chain alpha-alkyl-beta-hydroxy fatty acids unique to mycobacteria and related taxa. On collisionally activated dissociation in a linear ion trap or tandem quadrupole mass spectrometer, the [M H](-) ions of mycolic acid generated by electrospray ionization undergo dissociation to eliminate the meroaldehyde residue, leading to formation of carboxylate anions containing alpha-alkyl chains. The structural information from these fragment ions affords structural assignment of the mycolic acids, including the lengths of the meromycolate chain and the alpha-branch. This study revealed that the mycolic acids isolated from pathogenic Rhodococcus equi 103 contained a series of homologous ions having C(30) to C(50) chain with 0-2 double bonds. The alpha-branch ranged from C(10) to C(18) with 0 to 1 double bond, in which 16:0 and 14:0 are the most prominent, whereas the meromycolate chain ranged from C(14) to C(34) with 0 to 2 double bonds. The major molecular species consisted of more than 3 isomers that differ by the lengths of the alpha-branch or meromycolate chain, and up to 10 isobaric isomers were identified for some minor ions. We also employed tandem quadrupole mass spectrometry with precursor ion and neutral loss scans for profiling mycolic acid with specific structure in mixtures. The tandem spectra obtained from precursor ion scans of m/z 255 (16:0-carboxylate anion) and m/z 227 (14:0-carboxylate anion) may provide a simple specific means for classification of Rhodococci species, whereas tandem spectra from neutral loss of meroaldehyde residue scans provided a simple approach to reveal the mycolic acid molecules with specific meromycolate chain in mixtures. PMID- 20946864 TI - Self-dissociative primers for nucleic acid amplification and detection based on DNA quadruplexes with intrinsic fluorescence. AB - We have developed a new method, quadruplex priming amplification, to greatly simplify nucleic acid amplification and real-time quantification assays. The method relies on specifically designed guanine-rich primers, which after polymerase elongation are capable of spontaneous dissociation from target sites and forming DNA quadruplex. The quadruplex is characterized by significantly more favorable thermodynamics than the corresponding DNA duplexes. As a result, target sequences are accessible for the next round of priming and DNA amplification proceeds under isothermal conditions with improved product yield. In addition, the quadruplex formation is accompanied by an increase in intrinsic fluorescence of the primers, allowing simple and accurate detection of product DNA. PMID- 20946865 TI - A high-performance liquid chromatography-based fluorometric method for assaying serine hydroxymethyltransferase toward serine formation. AB - A high-performance liquid chromatography (HPLC)-based fluorometric method for measuring serine hydroxymethyltransferase (SHMT) activity toward formation of serine and (6S)-H(4)PteGlu(n) has been developed. In this method, serine formed by SHMT activity is reacted with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) to form the fluorescent adduct NBD-serine. The fluorescent assay components are then separated by reversed-phase chromatography, and NBD-serine is quantified by comparison with standards. This method was used to determine the K(m) and k(cat) values for 5,10-CH(2)-H(4)PteGlu(5) of an SHMT from Arabidopsis thaliana. These data represent the first determination of kinetic parameters for (6S)-5,10-CH(2) H(4)PteGlu(5) for an SHMT from any organism. PMID- 20946866 TI - Discontinuous pH gradient-mediated separation of TiO2-enriched phosphopeptides. AB - Global profiling of phosphoproteomes has proven to be a great challenge due to the relatively low stoichiometry of protein phosphorylation and poor ionization efficiency in mass spectrometers. Effective, physiologically relevant, phosphoproteome research relies on the efficient phosphopeptide enrichment from complex samples. Immobilized metal affinity chromatography and titanium dioxide chromatography can greatly assist selective phosphopeptide enrichment. However, the complexity of resultant enriched samples is often still high, suggesting that further separation of enriched phosphopeptides is required. We have developed a pH gradient elution technique for enhanced phosphopeptide identification in conjunction with titanium dioxide chromatography. Using this process, we demonstrated its superiority to the traditional "one-pot" strategies for differential protein identification. Our technique generated a highly specific separation of phosphopeptides by an applied pH gradient between 9.2 and 11.3. The most efficient elution range for high-resolution phosphopeptide separation was between pHs 9.2 and 9.4. High-resolution separation of multiply phosphorylated peptides was primarily achieved using elution ranges greater than pH 9.4. Investigation of phosphopeptide sequences identified in each pH fraction indicated that phosphopeptides with phosphorylated residues proximal to acidic residues, including glutamic acid, aspartic acid, and other phosphorylated residues, were preferentially eluted at higher pH values. PMID- 20946867 TI - A novel bifunctional europium chelate applied in quantitative determination of human immunoglobin G using time-resolved fluoroimmunoassay. AB - The authors demonstrate herein a novel time-resolved fluoroimmunoassay (TRFIA) protocol for quantification of human IgG with the new bifunctional chelate Eu(TTA)3(5-NH2-phen) (ETNP) labeling the goat anti-human IgG. The immunoassay was conducted by following the typical procedure for sandwich-type immunoreactions. Goat anti-human IgG was immobilized on aldehyde-modified glass slides. The human IgG analyte was first captured by the primary antibody and then sandwiched by a secondary antibody labeled with the chelate ETNP. The experimental procedure was simple to follow and gave desirable levels of sensitivity and low limits of detection. To the best of our knowledge, this is the first application of the new chelate, ETNP, in an immunoassay. In comparison to typical organic, fluorescent compounds and other lanthanide fluorescent chelates used in immunoassay, the detection sensitivity of our method using ETNP chelate in the solid phase was greatly improved and a concentration of human IgG about 5 MUg/L could be detected under optimal conditions. The main result of this work shows that the new chelate ETNP can be applied as a powerful fluorescent labeling material for constructing ultrasensitive TRFIAs. The detection of human IgG, using ETNP as the chelate, is a model example of the effectiveness of this immunoassay. Many other types of antigen-antibody immunoassays should be possible using the protocol described herein. PMID- 20946868 TI - Purification, characterization and inhibition of sterol C24-methyltransferase from Candida albicans. AB - Solubilized sterol C24-methyltransferase (24-SMT) was purified to homogeneity from a cell extract of the yeast Candida albicans (Ca) by anion exchange chromatography, gel permeation chromatography and fast performance liquid chromatography using a Mono Q column. The purified enzyme has an apparent molecular mass of 178 kDa on gel permeation chromatography and 43 kDa on SDS/PAGE, indicating that it is composed of four identical subunits. The substrate requirement of the native enzyme has an optimal specificity for zymosterol with associated kinetic constants of K(m) 50 MUM and k(cat) of 0.01 s 1. The product of the enzyme incubated with zymosterol was fecosterol. Inhibition of the catalyst was observed with substrate analogs designed as transition state analogs (25-azalanosterol, K(i)=54 nM and 24 (R,S),25-epiminolanosterol, K(i)=11 nM) or as mechanism-based inactivators (26,27-dehydrozymosterol, K(i) 9 MUM) and k(inact)=0.03 min-1) of the C24-methylation reaction. Product analogs ergosterol and fecosterol, but neither cholesterol nor sitosterol, inhibited activity affording K(i) values of 20 and 72 MUM, respectively. Ammonium and thia analogs of the intermediates of the sterol C24-methyl reaction sequence were effective growth inhibitors exhibiting IC(50) values that ranged from 3 to 20 MUM. PMID- 20946869 TI - A novel hemerythrin DNase from the nitrogen-fixing cyanobacterium Anabaena sp. strain PCC7120. AB - The open reading frame alr3199 of the nitrogen-fixing cyanobacterium, Anabaena sp. strain PCC7120 was cloned and overexpressed in Escherichia coli. Purified recombinant Alr3199 protein was found to be a functionally active deoxyribonuclease with novel features, such as (1) no homology to typical DNases (2) a Ca2(+)-dependent Nickase activity (3) presence of a di-hemerythrin domain, and (4) requirement of Fe2(+) conjugated to hemerythrin domains for optimal activity. Both the DNase and Nickase activities were found to be associated with the N-terminal non-hemerythrin region, but were modulated by Fe2(+) conjugated to the C-terminal hemerythrin region. This is the first report of a hemerythrin protein with DNase activity, tentatively designated as 'HE-DNase', and with a possible role in stress-induced DNA damage/repair in Anabaena. PMID- 20946870 TI - Ischemia-induced angiogenesis is impaired in aminopeptidase A deficient mice via down-regulation of HIF-1alpha. AB - Aminopeptidase A (APA; EC 3.4.11.7) is a transmembrane metalloprotease with several functions in tumor angiogenesis. To investigate the role of APA in the process of ischemia-induced angiogenesis, we evaluated the cellular angiogenic responses under hypoxic conditions and the process of perfusion recovery in the hindlimb ischemia model of APA-deficient (APA-KO; C57Bl6/J strain) mice. Western blotting of endothelial cells (ECs) isolated from the aorta of APA-KO mice revealed that the accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) protein in response to hypoxic challenge was blunted. Regarding the proteasomal ubiquitination, a proteasome inhibitor MG-132 restored the reduced accumulation of HIF-1alpha in ECs from APA-KO mice similar to control mice under hypoxic conditions. These were associated with decreased growth factor secretion and capillary formation in APA-KO mice. In the hindlimb ischemia model, perfusion recovery in APA-KO mice was decreased in accordance with a significantly lower capillary density at 2weeks. Regarding vasculogenesis, no differences were observed in cell populations and distribution patterns between wild type and APA KO mice in relation to endothelial progenitor cells. Our results suggested that Ischemia-induced angiogenesis is impaired in APA-KO mice partly through decreased HIF-1alpha stability by proteasomal degradation and subsequent suppression of HIF 1alpha-driven target protein expression such as growth factors. APA is a functional target for ischemia-induced angiogenesis. PMID- 20946871 TI - A role for tumor protein TPD52 phosphorylation in endo-membrane trafficking during cytokinesis. AB - Tumor protein D52 is expressed at high levels in exocrine cells containing large secretory granules where it regulates Ca(2+)-dependent protein secretion; however, D52 expression is also highly induced in multiple cancers. The present study investigated a role for the Ca(2+)-dependent phosphorylation of D52 at the single major phospho-acceptor site serine 136 on cell division. Ectopic expression of wild type D52 (D52wt) and the phosphomutants serine 136/alanine (S136A) or serine 136/glutamate (S136/E) resulted in significant multinucleation of cells. D52wt and S136/E each resulted in a greater than 2-fold increase in multinucleated cells compared to plasmid-transfected controls whereas the S136/A phospho-null mutant caused a 9-fold increase in multinucleation at 48h post transfection. Electron microscopy revealed D52 expression induced a marked accumulation of vesicles along the mid-line between nuclei where the final stages of cell abscission normally occurs. Supporting this, D52wt strongly colocalized on vesicular structures containing the endosomal regulatory protein vesicle associated membrane protein 8 (VAMP 8) and this colocalization significantly increased with elevations in cellular Ca(2+). As VAMP 8 is known to be necessary for the endo-membrane fusion reactions that mediate the final stages of cytokinesis, these data indicate that D52 expression and phosphorylation at serine 136 play an important role in supporting the Ca(2+)-dependent membrane trafficking events necessary for cytokinesis in rapidly proliferating cancer cells. PMID- 20946872 TI - Novel role of specific Tudor domains in Tudor-Aubergine protein complex assembly and distribution during Drosophila oogenesis. AB - Germ cells give rise to the next generation and contain ribonucleoprotein particles, germ granules. In these granules, Piwi protein Aubergine has been shown to interact with Tudor protein in Drosophila. Tudor protein has 11 Tudor domains and it has been unclear to what extent all these domains are involved in the interaction with Aubergine. Here we present direct biochemical evidence that Tudor-Aubergine interaction surface is composed of different Tudor domains including those that have not been previously implicated in Aubergine recognition. Furthermore, we show that specific single Tudor domains determine localization of Tudor complex to different sites in ovarian germ cells. Our data suggest that multiple Tudor domains of germline proteins from various species are redundantly used for interaction with the same protein partner during germline development. PMID- 20946873 TI - Site-specific protein backbone and side-chain NMR chemical shift and relaxation analysis of human vinexin SH3 domain using a genetically encoded 15N/19F-labeled unnatural amino acid. AB - SH3 is a ubiquitous domain mediating protein-protein interactions. Recent solution NMR structural studies have shown that a proline-rich peptide is capable of binding to the human vinexin SH3 domain. Here, an orthogonal amber tRNA/tRNA synthetase pair for (15)N/(19)F-trifluoromethyl-phenylalanine ((15)N/(19)F-tfmF) has been applied to achieve site-specific labeling of SH3 at three different sites. One-dimensional solution NMR spectra of backbone amide ((15)N)(1)H and side-chain (19)F were obtained for SH3 with three different site-specific labels. Site-specific backbone amide ((15)N)(1)H and side-chain (19)F chemical shift and relaxation analysis of SH3 in the absence or presence of a peptide ligand demonstrated different internal motions upon ligand binding at the three different sites. This site-specific NMR analysis might be very useful for studying large-sized proteins or protein complexes. PMID- 20946874 TI - PlexinA1 interacts with PTK7 and is required for neural crest migration. AB - Members of the plexin protein family are known regulators of axon guidance, but recent data indicate that they have broader functions in the regulation of embryonic morphogenesis. Here we provide further evidence of this by showing that PlexinA1 is expressed in Xenopus neural crest cells and is required for their migration. PlexinA1 expression is detected in migrating cranial neural crest cells and knockdown of PlexinA1 expression using Morpholino oligonucleotides inhibits neural crest migration. PlexinA1 likely affects neural crest migration by interaction with PTK7, a regulator of planar cell polarity that is required for neural crest migration. PlexinA1 and PTK7 interact in immunoprecipitation assays and show phenotypic interaction in co-injection experiments. Considering that plexins and PTK7 have been shown to genetically interact in Drosophila axon guidance and chick cardiac morphogenesis, our data suggest that this interaction is evolutionary conserved and may be relevant for a broad range of morphogenetic events including the migration of neural crest cells in Xenopus laevis. PMID- 20946875 TI - Intersectin 1 forms complexes with SGIP1 and Reps1 in clathrin-coated pits. AB - Intersectin 1 (ITSN1) is an evolutionarily conserved adaptor protein involved in clathrin-mediated endocytosis, cellular signaling and cytoskeleton rearrangement. ITSN1 gene is located on human chromosome 21 in Down syndrome critical region. Several studies confirmed role of ITSN1 in Down syndrome phenotype. Here we report the identification of novel interconnections in the interaction network of this endocytic adaptor. We show that the membrane-deforming protein SGIP1 (Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1) and the signaling adaptor Reps1 (RalBP associated Eps15-homology domain protein) interact with ITSN1 in vivo. Both interactions are mediated by the SH3 domains of ITSN1 and proline-rich motifs of protein partners. Moreover complexes comprising SGIP1, Reps1 and ITSN1 have been identified. We also identified new interactions between SGIP1, Reps1 and the BAR (Bin/amphiphysin/Rvs) domain-containing protein amphiphysin 1. Immunofluorescent data have demonstrated colocalization of ITSN1 with the newly identified protein partners in clathrin-coated pits. These findings expand the role of ITSN1 as a scaffolding molecule bringing together components of endocytic complexes. PMID- 20946876 TI - Regulatory light chains modulate in vitro actin motility driven by skeletal heavy meromyosin. AB - Phosphorylation and Ca(2+)-Mg(2+) exchange on the regulatory light chains (RLCs) of skeletal myosin modulate muscle contraction. However, the relation between the mechanisms for the effects of phosphorylation and metal ion exchange are not clear. We propose that modulation of skeletal muscle contraction by phosphorylation of the myosin regulatory light chains (RLCs) is mediated by altered electrostatic interactions between myosin heads/necks and the negatively charged thick filament backbone. Our study, using the in vitro motility assay, showed actin motility on hydrophilic negatively charged surfaces only over the HMM with phosphorylated RLCs both in the presence and absence of Ca(2+). In contrast, good actin motility was observed on silanized surfaces (low charge density), independent of RLC phosphorylation status but with markedly lower velocity in the presence of Ca(2+). The data suggest that Ca(2+)-binding to, and phosphorylation of, the RLCs affect the actomyosin interaction by independent molecular mechanisms. The phosphorylation effects depend on hydrophobicity and charge density of the underlying surface. Such findings might be exploited for control of actomyosin based transportation of cargoes in lab-on-a chip applications, e.g. local and temporary stopping of actin sliding on hydrophilic areas along a nanosized track. PMID- 20946877 TI - The new HNO donor, 1-nitrosocyclohexyl acetate, increases contractile force in normal and beta-adrenergically desensitized ventricular myocytes. AB - Contractile dysfunction and diminished response to beta-adrenergic agonists are characteristics for failing hearts. Chemically donated nitroxyl (HNO) improves contractility in failing hearts and thus may have therapeutic potential. Yet, there is a need for pharmacologically suitable donors. In this study we tested whether the pure and long acting HNO donor, 1-nitrosocyclohexyl acetate (NCA), affects contractile force in normal and pathological ventricular myocytes (VMs) as well as in isolated hearts. VMs were isolated from mice either subjected to isoprenaline-infusion (ISO; 30 MUg/g per day) or to vehicle (0.9% NaCl) for 5 days. Sarcomere shortening and Ca2+ transients were simultaneously measured using the IonOptix system. Force of contraction of isolated hearts was measured by a Langendorff-perfusion system. NCA increased peak sarcomere shortening by+40-200% in a concentration-dependent manner (EC50 ~55 MUM). Efficacy and potency did not differ between normal and chronic ISO VMs, despite the fact that the latter displayed a markedly diminished inotropic response to acute beta-adrenergic stimulation with ISO (1 MUM). NCA (60 MUM) increased peak sarcomere shortening and Ca2+ transient amplitude by ~200% and ~120%, respectively, suggesting effects on both myofilament Ca2+ sensitivity and sarcoplasmic reticulum (SR) Ca2+ cycling. Importantly, NCA did not affect diastolic Ca2+ or SR Ca2+ content, as assessed by rapid caffeine application. NCA (45 MUM) increased force of contraction by 30% in isolated hearts. In conclusion, NCA increased contractile force in normal and beta-adrenergically desensitized VMs as well as in isolated mouse hearts. This profile warrants further investigations of this HNO donor in the context of heart failure. PMID- 20946878 TI - Tyrosine phosphatase TpbA controls rugose colony formation in Pseudomonas aeruginosa by dephosphorylating diguanylate cyclase TpbB. AB - Tyrosine phosphatase TpbA in Pseudomonas aeruginosa PA14 is a negative regulator of the diguanylate cyclase TpbB. Inactivation of TpbA caused rugose colony morphology which is related to cell persistence in clinical infections. We show here that TpbA is a dual specific tyrosine phosphatase, that TpbB is phosphorylated, and that TpbA controls phosphorylation of TpbB at both Tyr and Ser/Thr residues in vivo as detected by Western blot analysis. In addition, TpbB is demonstrated to be a substrate of TpbA in vitro using purified enzymes. Thus, TpbA controls the rugose morphology in P. aeruginosa by dephosphorylating TpbB. PMID- 20946879 TI - Functional characterization of the zebrafish WHSC1-related gene, a homolog of human NSD2. AB - Methylation of specific lysine residues of histone H3 and H4 has been reported to be important in the structuring of chromatin and for the transcription of certain genes. Proteins with SET domains have been shown to methylate specific lysine residues of histone H3 and H4. We isolated a SET domain-containing gene from the zebrafish (Danio rerio). The gene has the highest sequence similarity to human NSD2, also known as Wolf-Hirschhorn syndrome candidate 1 or WHSC1, and therefore, was named DrWhsc1. DrWhsc1 mRNA is expressed in various tissues with the highest level in testis. Morpholino oligonucleotides for the DrWhsc1 gene affected early embryogenesis in zebrafish, such as endbrain enlargement, abnormal cartilage, marked reduction of bone, and incomplete motor neuron formation. Such developmental abnormalities are also observed in Wolf-Hirschhorn syndrome patients and Whsc1-deficient mice. In addition, suppression of the DrWhsc1 gene or defect in the SET domain of DrWhsc1 resulted in impairment of di-methylation of histone H3K36 at early embryogenesis. These results indicate that DrWhsc1 is a functional homolog of WHSC1 and that the SET domain of DrWhsc1 is essential for di-methylation of histone H3K36 in zebrafish. PMID- 20946880 TI - Rosuvastatin reduces microglia in the brain of wild type and ApoE knockout mice on a high cholesterol diet; implications for prevention of stroke and AD. AB - We have previously shown that a high cholesterol (HC) diet results in increases in microglia load and levels of the pro-inflammatory cytokine interleukin-6 (IL 6) in the brains of wild type (WT) and apolipoprotein E knockout (ApoE-/-) mice. In the present investigation, we analyzed whether treatment with rosuvastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, would prevent the increases in inflammatory microglia and IL-6 levels in the brain and plasma of WT and ApoE-/- mice. We report that a HC diet resulted in an increased microglia load in the brains of WT and ApoE-/- mice, in support of our previous study. Treatment with rosuvastatin significantly decreased the microglia load in the brains of WT and ApoE-/- mice on a HC diet. Rosuvastatin treatment resulted in lowered plasma IL-6 levels in WT mice on a HC diet. However, in the present study the number of IL-6 positive cells in the brain was not significantly affected by a HC diet. A recent clinical study has shown that rosuvastatin reduces risk of ischemic stroke in patients with high plasma levels of the inflammatory marker C-reactive protein by 50%. The results from our study show that rosuvastatin reduces inflammatory cells in the brain. This finding is essential for furthering the prevention and treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and stroke. PMID- 20946881 TI - IDH1 and IDH2 mutations are frequent in Chinese patients with acute myeloid leukemia but rare in other types of hematological disorders. AB - Frequent mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) have been identified in gliomas and acute myeloid leukemia (AML). Our aim is to assess whether IDH mutations were presented in Chinese patients with various hematological disorders. In this study, we screened the IDH1 and IDH2 mutations in a cohort of 456 Chinese patients with various hematological malignancies and disorders. We found three missense (p.R132C, p.R132G, and p.I99M; occurred in five patients) and one silent mutation (c.315C>T; occurred in two patients) in the IDH1 gene and two missense mutations (p.R140Q and p.R172K; occurred in four AML patients) and one silent mutation (c.435G>A) in the IDH2 gene. Except for one non-Hodgkin lymphoma (NHL) patient harboring IDH1 mutation p.R132C, all IDH1 and IDH2 missense mutations were observed in patients with AML. Intriguingly, the IDH2 mutation p.R140Q and novel IDH1 mutation p.I99M co-occurred in a 75-year-old patient with AML developed from myelodysplastic syndromes (MDS). The frequency of IDH1 and IDH2 missense mutations in Chinese AML patients reached 5.9% and 8.3%, respectively. Our results supported the recent findings that IDH gene mutations were common in AML. Conversely, IDH mutations were rather rare in Chinese patients with other types of hematological disorders. PMID- 20946882 TI - Interaction of Sp1 zinc finger with transport factor in the nuclear localization of transcription factor Sp1. AB - Transcription factor Sp1 is localized in the nucleus and regulates the expression of many cellular genes, but the nuclear transport mechanism of Sp1 is not well understood. In this study, we revealed that GST-fused Sp1 protein bound to endogenous importin alpha in HeLa cells via the Sp1 zinc finger domains, which comprise the DNA binding domain of Sp1. It was found that the Sp1 zinc finger domains directly interacted with a wide range of importin alpha including the armadillo (arm) repeat domain and the C-terminal acidic domain. Furthermore, it turned out that all three zinc fingers of Sp1 are essential for binding to importin alpha. Taken together, these results suggest that the Sp1 zinc finger domains play an essential role as a NLS and Sp1 can be transported into the nucleus in an importin-dependent manner even though it possesses no classical NLSs. PMID- 20946883 TI - One residue substitution in PcyA leads to unexpected changes in tetrapyrrole substrate binding. AB - Phycocyanobilin:ferredoxin oxidoreductase (PcyA) catalyzes the sequential reduction of the vinyl group of the D-ring and A-ring of biliverdin IXalpha (BV), using reducing equivalents provided by ferredoxin. This reaction produces phycocyanobilin, a pigment used for light-harvesting and light-sensing in red algae and cyanobacteria. The crystal structure of PcyA-BV reveals that BV is specifically bound in the PcyA active pocket through extensive hydrophobic and hydrophilic interactions. During the course of a mutational study of PcyA, we observed that mutation of the V225 position, apart from the processing sites, conferred an unusual property on PcyA; V225D mutant protein could bind BV and its analog BV13, but these complexes showed a distinct UV-vis absorption spectrum from that of the wild-type PcyA-BV complex. The crystal structures of BV- and BV13-bound forms of V225D protein revealed that gross structural changes occurred near the substrate-binding pocket, and that the BV/BV13 binding manner in the pocket was dramatically altered. Protein folding in V225D-BV/BV13 was more similar to that of substrate-free PcyA than that in PcyA-BV; the "induced-fit" did not occur when BV/BV13 was bound to the V225D protein. The unexpected structural change presented here provides a cautionary note about interpreting functional data derived from a mutated protein in the absence of its exact structure. PMID- 20946884 TI - Effect of collagen I and fibronectin on the adhesion, elasticity and cytoskeletal organization of prostate cancer cells. AB - Despite of intensive research efforts, the precise mechanism of prostate cancer metastasis in bone is still not fully understood. Several studies have suggested that specific matrix production by the bone cells, such as collagen I, supports cancer cell invasion. The aim of this study was to investigate the effect of collagen I (COL1) and fibronectin (FN) on cell adhesion, cell elasticity and cytoskeletal organization of prostate cancer cells. Two cell lines, bone marrow- (PC3) and lymph node-derived (LNCaP) were cultivated on COL1 and FN (control protein). By using a quantitative adhesion assay and time-lapse analysis, it was found that PC3, but not LNCaP, adhered strongly and were more spread on COL1. Next, PC3 and LNCaP were evaluated by atomic force microscopy (AFM) and flatness shape factor and cellular Young's modulus were calculated. The shape analysis revealed that PC3 were significantly flatter when grown on COL1 in comparison to LNCaP. In general, PC3 were also significantly stiffer than LNCaP and furthermore, their stiffness increased upon interaction with COL1. Since cell stiffness is strongly dependent on actin organization, phalloidin-based actin staining was performed and revealed that, of the two cell types as well as the two different matrix proteins, only PC3 grown on COL1 formed robust actin cytoskeleton. In conclusion, our study showed that PC3 cells have a strong affinity towards COL1. On this matrix protein, the cells adhered strongly and underwent a specific cell flattening. Moreover, with the establishment of PC3 contact to COL1 a significant increase of PC3 stiffness was observed due to a profound cytoskeletal rearrangement. PMID- 20946885 TI - Crystal structure of glutamate-1-semialdehyde aminotransferase from Bacillus subtilis with bound pyridoxamine-5'-phosphate. AB - Glutamate-1-semialdehyde aminotransferase (GSA-AT), also named glutamate-1 semialdehyde aminomutase (GSAM), a pyridoxamine-5'-phosphate (PMP)/pyridoxal-5' phosphate (PLP) dependent enzyme, catalyses the transamination of the substrate glutamate-1-semialdehyde (GSA) to the product 5-Aminolevulinic acid (ALA) by an unusual intramolecular exchange of amino and oxo groups within the catalytic intermediate 4,5-diaminovalerate (DAVA). This paper presents the crystal structure of GSA-AT from Bacillus subtilis (GSA-ATBsu) in its PMP-bound form at 2.3A resolution. The structure was determined by molecular replacement using the Synechococcus GSAM (GSAMSyn) structure as a search model. Unlike the previous reported GSAM/GSA-AT structures, GSA-ATBsu is a symmetric homodimer in the PMP bound form, which shows the structural symmetry at the gating loop region with open state, as well as identical cofactor (PMP) binding in each monomer. This observation of PMP in combination with an "open" lid supports one characteristic feature for this enzyme, as the catalyzed reaction is believed to be initiated by PMP. Furthermore, the symmetry of GSA-ATBsu structure challenges the previously proposed negative cooperativity between monomers of this enzyme. PMID- 20946886 TI - PRIMA-1 cytotoxicity correlates with nucleolar localization and degradation of mutant p53 in breast cancer cells. AB - PRIMA-1 has been identified as a compound that restores the transactivation function to mutant p53 and induces apoptosis in cells expressing mutant p53. Studies on subcellular distribution of the mutant p53 protein upon treatment with PRIMA-1Met, a methylated form of PRIMA-1, have suggested that redistribution of mutant p53 to nucleoli may play a role in PRIMA-1 induced apoptosis. Here, we specifically investigated the influence of PRIMA-1 on cellular localization of mutated p53-R280K endogenously expressed in tumour cells. By using immunofluorescence staining, we found a strong nucleolar redistribution of mutant p53 following PRIMA-1 treatment. This subcellular localization was associated to p53 degradation via ubiquitylation. When cells were treated with adriamycin, neither nucleolar redistribution nor mutant p53 down modulation and degradation were observed. Interestingly, cells where p53-R280K was silenced were more sensitive to PRIMA-1 than the parental ones. These results indicate that in some cellular context, the cell sensitivity to PRIMA-1 could depend on the abolition of a gain-of-function activity of the mutated p53, through a protein degradation pathway specifically induced by this compound. PMID- 20946887 TI - Th1 cells promote neurite outgrowth from cortical neurons via a mechanism dependent on semaphorins. AB - The roles of T lymphocytes in the central nervous system (CNS) are diverse; their roles in the injured CNS have been reported to be both detrimental and advantageous. Hence, an investigation of the effects of specific subsets of T cells on neurons may provide an insight into the interaction between the nervous system and the immune system. In the present study, we demonstrate that a specific subset of T lymphocytes enhanced neurite outgrowth in vitro. When cultured T helper type 1 (Th1) cells were co-cultured with cortical neurons, neurite outgrowth from neurons was enhanced; however, the same was not observed when Th2 or naive T cells were used. We observed that the promotion of neurite outgrowth by Th1 cells was completely inhibited by anti-interferon gamma (IFN gamma) neutralizing antibody, but that IFN-gamma did not directly promote neurite growth. Furthermore, experiments using knockout mice revealed that semaphorin 4A (Sema4A) but not Sema7A was required for the effect produced by Th1 cells. These results demonstrate that Sema4A and IFN-gamma expressed in Th1 cells play a critical role in enhancing neurite outgrowth from cortical neurons. PMID- 20946888 TI - Extracellular high dosages of adenosine triphosphate induce inflammatory response and insulin resistance in rat adipocytes. AB - Adenosine triphosphate (ATP), an important signaling molecule, participates in various pathophysiological processes via the activation of purinergic-receptors. Recent studies have shown that the expression and function of purinergic receptors (P2-receptors) could be altered in diabetic or hyperinsulinemia conditions. To characterize the effect of ATP on insulin signaling, we treated primary rat adipocytes with varied concentrations of ATP. The pre-treatment led to impaired insulin signaling, i.e., blunted phosphorylation in Insulin Receptor Substrate-1 (IRS-1) tyrosine and Protein Kinase B (PKB) Ser473 in response to insulin treatment, when ATP concentration reached 1mM. We then observed that ATP dose-dependently reduced the level of IkappaB, a negative regulator of inflammatory response. Consistently, IRS-1 Ser307 phosphorylation in response to insulin treatment, a site for inflammatory pathway to interfere insulin signaling, was enhanced by ATP. Furthermore, effects of ATP on insulin signaling and IkappaB content were blocked by P2-receptor inhibition. Finally, insulin stimulated glucose uptake was impaired by ATP in adipocytes but not in the L6 muscle cells. This study therefore shows for the first time the involvement of ATP-evoked P2-receptor activation in mediating the inflammatory response and the generation of insulin resistance in adipocytes. PMID- 20946889 TI - Malformation of the human superior olive in autistic spectrum disorders. AB - Autistic spectrum disorders (ASD) comprise a continuum of psychosocial disorders clinically characterized by social difficulties, impaired communication skills and repetitive behavioral patterns. Despite the prevalence of ASD, the neurobiology of this disorder is poorly understood. However, abnormalities in neuronal morphology, cell number and connectivity have been described throughout the autistic brain. Further, there is ample evidence that auditory dysfunction is a common feature of autism. Our preliminary investigation of neuronal morphology in the auditory brainstem of individuals with ASD focused on the medial superior olive (MSO) and revealed that neurons in this region were significantly smaller and rounder than in controls. In this report, we expand our investigation to examine all nuclei within the human superior olivary complex (SOC), an important auditory brainstem center. We examine neuronal morphology and neuronal number in four control (average age=15 years) and 9 autistic brains (average age=15 years). This detailed investigation supports our previous descriptions of the MSO, and also reveals significant dysmorphology in five other SOC nuclei. Moreover, we provide evidence of a consistent and significant decrease in the number of SOC neurons in the autistic brain. Our studies implicate an extensive malformation of the auditory brainstem in the hearing and language difficulties in individuals with ASD. The results from this investigation suggest that neonatal testing of auditory function may aid in the identification of individuals with ASD earlier than presently possible. PMID- 20946891 TI - Recent advances in the study on capsaicinoids and capsinoids. AB - Chili peppers are the major source of nature capsaicinoids, which consist of capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin, etc. Capsaicinoids are found to exert multiple pharmacological and physiological effects including the activities of analgesia, anticancer, anti inflammation, antioxidant and anti-obesity. Therefore, capsaicinoids may have the potential value in clinic for pain relief, cancer prevention and weight loss. In addition, capsaicinoids also display the benefits on cardiovascular and gastrointestinal system. It has been shown that capsaicinoids are potential agonists of capsaicin receptor or transient receptor potential vanilloid subfamily member 1 (TRPV1). They could exert the effects not only through the receptor-dependent pathway but also through the receptor-independent one. CH-19 Sweet peppers are the source of nature capsinoids, which share similar structure with capsaicinoids and consist of capsiate, dihydrocapsiate, and nordihydrocapsiate, etc, Comparing with capsaicinoids, capsinoids are less pungent and easily broken down in the normal aqueous conditions. So far, it has been found that capsinoids possess the biological properties of antitumor, antioxidant and anti-obesity. Since capsinoids are less toxic than capsaicinoids, therefore, capsinoids may have the advantages over capsaicinoids in clinical applications such as cancer prevention and weight loss. PMID- 20946890 TI - Quantitative analysis of AMPA receptor subunit composition in addiction-related brain regions. AB - The subunit composition of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) is an important determinant of AMPAR biophysical properties and trafficking. To date, AMPAR subunit composition has been quantitatively evaluated only for the hippocampus, where different experimental approaches have yielded different results. Here, we used quantitative co-immunoprecipitation to characterize GluA1-3 associations in the adult rat nucleus accumbens, dorsal striatum, prefrontal cortex, and hippocampus, and blue native electrophoresis (BNE) to study GluA1-3 assembly state. In all brain regions, co immunoprecipitation experiments showed that ~90% of GluA1 was associated with GluA2 or GluA3 (most was GluA1A2). All regions contained a small number of GluA1A3 receptors. Homomeric GluA1 receptors may also exist. More than half of the GluA2 (53%-65% depending on the region) was not associated with GluA1. However, this represents an over-estimate of the percent of GluA2 present in GluA2A3 receptors, based on BNE results demonstrating that the majority of GluA2 exists as dimers, rather than functional tetrameric receptors. Relatively more GluA1 was present in tetramers. Together with other findings, our results suggest a dominant role for GluA1A2 receptors in all brain regions examined. They also help explain why different results for hippocampal AMPAR subunit composition were obtained using co-immunoprecipitation, which assesses the total cellular pool of AMPARs including partially assembled AMPARs in intracellular compartments, and electrophysiological approaches, which can selectively assess tetrameric (functional) AMPARs on the cell surface. PMID- 20946892 TI - A novel synthetic compound PHID (8-Phenyl-6a, 7, 8, 9, 9a, 10-hexahydro-6H isoindolo [5, 6-g] quinoxaline-7, 9-dione) protects SH-SY5Y cells against MPP(+) induced cytotoxicity through inhibition of reactive oxygen species generation and JNK signaling. AB - 1-Methyl-4-phenylpyridinium ion (MPP(+)), a neurotoxin selective to dopaminergic neurons and an inhibitor of mitochondrial complex I, has been widely used as an etiologic model of Parkinson's disease. In this study, we investigated the protective effects of a novel synthetic compound, 8-Phenyl-6a,7,8,9,9a,10 hexahydro-6H-isoindolo[5,6-g]quinoxaline-7,9-dione (PHID), on MPP(+)-induced cytotoxicity in SH-SY5Y cells. MPP(+) induced apoptosis characterized by generation of reactive oxygen species, caspase-3 activation, poly ADP ribose polymerase proteolysis and increase in Bax/Bcl-2 ratio were blocked by PHID in a dose-dependent fashion. Furthermore, MPP(+)-mediated activation of stress activated protein kinase/c-Jun N-terminal kinase (JNK) was also inhibited by PHID in a dose-dependent manner. The results indicate that PHID protects against MPP(+)-induced apoptosis by blocking reactive oxygen species stimulation and JNK signaling pathways in SH-SY5Y cells, implicating the novel compound in the prevention of progressive neurodegenerative diseases such as Parkinson's disease. PMID- 20946893 TI - Effects of adolescent social isolation on the expression of brain-derived neurotrophic factors in the forebrain. AB - Adolescence is a critical period for the development of neural plasticity. Social isolation is an important animal model for various neurodevelopmental disorders. Brain derived neurotrophic factor (BDNF) mediates many important brain functions such as neural plasticity, and aberrations in its expression have been implicated in many brain disorders. However, to date there have been few reports of effects of adolescent social isolation on BDNF expression in adult animals. In the present study, we subjected weaning Sprague Dawley rats to a four-week early adolescence social isolation procedure followed by four-week standard housing until adulthood for molecular assays. BDNF protein levels in several key forebrain regions relevant to brain development were investigated using immunohistochemistry, including frontal and cingulate cortex as well as hippocampus. Our results show that adolescent social isolation significantly increased BDNF protein expression in the medial prefrontal cortex and all three sub-fields of the hippocampus, including CA1, CA2/3 and dentate gyrus. This study advances the use of adolescent social isolation as an animal model for studying neurobiological underpinnings of various neurodevelopmental disorders. PMID- 20946894 TI - Suppression of ovalbumin-induced Th2-driven airway inflammation by beta sitosterol in a guinea pig model of asthma. AB - In the present study, the efficacy of beta-sitosterol isolated from an n-butanol extract of the seeds of the plant Moringa oleifera (Moringaceae) was examined against ovalbumin-induced airway inflammation in guinea pigs. All animals (except group I) were sensitized subcutaneously and challenged with aerosolized 0.5% ovalbumin. The test drugs, beta-sitosterol (2.5mg/kg) or dexamethasone (2.5mg/kg), were administered to the animals (p.o.) prior to challenge with ovalbumin. During the experimental period (on days 18, 21, 24 and 29), a bronchoconstriction test (0.25% acetylcholine for 30s) was performed and lung function parameters (tidal volume and respiration rate) were measured for each animal. On day 30, blood and bronchoalveolar lavaged fluid were collected to assess cellular content, and serum was collected for cytokine assays. Lung tissue was utilized for a histamine assay and for histopathology. beta-sitosterol significantly increased the tidal volume (V(t)) and decreased the respiration rate (f) of sensitized and challenged guinea pigs to the level of non-sensitized control guinea pigs and lowered both the total and differential cell counts, particularly eosinophils and neutrophils, in blood and bronchoalveolar lavaged fluid. Furthermore, beta-sitosterol treatment suppressed the increase in cytokine levels (TNFalpha, IL-4 and IL-5), with the exception of IL-6, in serum and in bronchoalveolar lavaged fluid detected in model control animals. Moreover, treatment with beta-sitosterol protected against airway inflammation in lung tissue histopathology. beta-sitosterol possesses anti-asthmatic actions that might be mediated by inhibiting the cellular responses and subsequent release/synthesis of Th2 cytokines. This compound may have therapeutic potential in allergic asthma. PMID- 20946895 TI - What has gene expression profiling taught us about glaucoma? AB - The availability in recent years of new cellular and animal models, as well as advances in genomic and related technologies, have made possible important advances in our understanding of the cellular and molecular events that mediate retinal ganglion cell dysfunction and death in glaucoma. In this review, we briefly summarize the methodology and results of a number of genome-wide expression studies that have been performed to study the retina and optic nerve head in glaucoma. PMID- 20946896 TI - Clinical application of adult olfactory bulb ensheathing glia for nervous system repair. AB - The ability of adult olfactory bulb ensheathing glia (OB-OEG) to promote histological and functional neural repair has been broadly documented. Pre clinical studies show that beneficial effects of adult OB-OEG are repeatable in the same type of spinal cord injury initially tested, in other spinal cord and CNS injury models, in different species and after the administration of these cells in different forms (either alone or in combination with other cells, drugs, products or devices). These studies demonstrate the reproducibility, robustness, fundamental nature and relevance of the findings. Therefore, the use of adult OB OEG for spinal cord injury repair meets the scientific criteria established by the International Campaign for Cures of Spinal Cord Injury Paralysis (ICCP) for the translation to human application. Because there is so much heterogeneity in the way adult OEG is administered, each of these different OEG-based therapies must be individually categorized to determine whether they fulfill the requisites dictated by the consolidated regulatory body to be considered or not as a medicine. In the case they do, in Europe, they shall be subjected to the Regulatory European Framework for Advanced Therapy Medicinal Products and the European Clinical Trials Directive (Directives 2001/20/EC and 2009/120/EC). After a deep analysis of the European Regulation we have concluded that grafts consisting of suspensions of purified adult OEG, to be used for the promotion of axonal regeneration in the CNS, do not comply with the definition of Medicinal Product provided by the European Medicines Agency. In contrast, experimental therapies using OEG in combination with other cell types, drugs, products or devices, or genetically-modified OEG fall under the definitions of Medicinal Product. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair. PMID- 20946898 TI - Recommendations for the validation of flow cytometric testing during drug development: II assays. AB - Flow cytometry-based assays serve as valuable tools for various aspects of the drug development process ranging from target discovery and characterization to evaluation of responses in a clinical setting. The integrity of the samples and the appropriate selection and characterization of the reagents used in these assays are in themselves challenging. These concerns taken together with the flow based technology makes the validation of flow cytometry assays a challenging effort. Therefore, apart from summarizing the role of flow cytometry technology in various stages of drug development, this manuscript focuses on recommendations for the validation of methods applying flow cytometry. Information is also provided on the relevant validation parameters for different types of flow cytometry assays to guide the users of this platform. Together, the recommendations and the information on regulatory guidelines provided in this manuscript represent the consensus of all the authors and can assist the flow cytometry user in implementing the appropriate method validation strategies. PMID- 20946897 TI - Lack of genetic structure among Eurasian populations of the tick Ixodesricinus contrasts with marked divergence from north-African populations. AB - Host-parasite interactions may select for significant novel mutations with major evolutionary consequences for both partners. In poor active dispersers such as ticks, their population structures are shaped by their host movements. Here, we use population genetics and phylogeography to investigate the evolutionary history of the most common tick in Europe, Ixodes ricinus, a vector of pathogenic agents causing diseases in humans and animals. Two mitochondrial and four nuclear genes were sequenced for 60 individuals collected on four geographical scales (local, regional, Eurasian and western Palearctic scales). The overall level of nucleotide diversity was low and the variability did not differ at the local, regional or Eurasian scales but increased two fold for the western Palearctic scale. Moreover, the phylogenetic trees indicated an absence of genetic structure among Eurasian ticks, contrasting with a strong differentiation of the north African ticks which formed a divergent clade. The homogeneity in Eurasian ticks may be explained by gene flows due to passive dispersal of ticks by hosts within a continuous population and recent range expansion of I. ricinus as shown by the fit of the observed frequency distribution of numbers of mismatches between pairwise sequences with the demographic expansion model (Harpending raggedness index, P=0.74). The genetic divergence of the north-African populations could be explained by genetic drift in these small populations that are geographically isolated and/or selection pressures due to different ecological conditions (seasonal activity, pathogenic agents and hosts communities). The consequences of these results on the epidemiology of vector-borne diseases are discussed. PMID- 20946899 TI - Current NHLBI perspectives on translational heart failure research. PMID- 20946900 TI - Structure and mechanism of the magnesium-independent aromatic prenyltransferase CloQ from the clorobiocin biosynthetic pathway. AB - CloQ is an aromatic prenyltransferase from the clorobiocin biosynthetic pathway of Streptomyces roseochromogenes var. oscitans. It is involved in the synthesis of the prenylated hydroxybenzoate moiety of the antibiotic, specifically catalyzing the attachment of a dimethylallyl moiety to 4-hydroxyphenylpyruvate. Herein, we report the crystal structure of CloQ and use it as a framework for interpreting biochemical data from both wild-type and variant proteins. CloQ belongs to the aromatic prenyltransferase family, which is characterized by an unusual core fold comprising five consecutive alphaalphabetabeta elements that form a central 10-stranded anti-parallel beta-barrel. The latter delineates a solvent-accessible cavity where substrates bind and catalysis takes place. This cavity has well-defined polar and nonpolar regions, which have distinct roles in substrate binding and facilitate a Friedel-Crafts-type mechanism. We propose that the juxtaposition of five positively charged residues in the polar region circumvents the necessity for a Mg(2+), which, by contrast, is a strict requirement for the majority of prenyltransferases characterized to date. Our structure of CloQ complexed with 4-hydroxyphenylpyruvate reveals the formation of a covalent link between the substrate and Cys215 to yield a thiohemiketal species. Through site-directed mutagenesis, we show that this link is not essential for enzyme activity in vitro. Furthermore, we demonstrate that CloQ will accept alternative substrates and, therefore, has the capacity to generate a range of prenylated compounds. Since prenylation is thought to enhance the bioactivity of many natural products, CloQ offers considerable promise as a biocatalyst for the chemoenzymatic synthesis of novel compounds with therapeutic potential. PMID- 20946901 TI - Modelling cell lineage using a meta-Boolean tree model with a relation to gene regulatory networks. AB - A cell lineage is the ancestral relationship between a group of cells that originate from a single founder cell. For example, in the embryo of the nematode Caenorhabditis elegans an invariant cell lineage has been traced, and with this information at hand it is possible to theoretically model the emergence of different cell types in the lineage, starting from the single fertilized egg. In this report we outline a modelling technique for cell lineage trees, which can be used for the C. elegans embryonic cell lineage but also extended to other lineages. The model takes into account both cell-intrinsic (transcription factor based) and -extrinsic (extracellular) factors as well as synergies within and between these two types of factors. The model can faithfully recapitulate the entire C. elegans cell lineage, but is also general, i.e., it can be applied to describe any cell lineage. We show that synergy between factors, as well as the use of extrinsic factors, drastically reduce the number of regulatory factors needed for recapitulating the lineage. The model gives indications regarding co variation of factors, number of involved genes and where in the cell lineage tree that asymmetry might be controlled by external influence. Furthermore, the model is able to emulate other (Boolean, discrete and differential-equation-based) models. As an example, we show that the model can be translated to the language of a previous linear sigmoid-limited concentration-based model (Geard and Wiles, 2005). This means that this latter model also can exhibit synergy effects, and also that the cumbersome iterative technique for parameter estimation previously used is no longer needed. In conclusion, the proposed model is general and simple to use, can be mapped onto other models to extend and simplify their use, and can also be used to indicate where synergy and external influence would reduce the complexity of the regulatory process. PMID- 20946902 TI - Life history and mating systems select for male biased parasitism mediated through natural selection and ecological feedbacks. AB - tlsb-1%Males are often the 'sicker' sex with male biased parasitism found in a taxonomically diverse range of species. There is considerable interest in the processes that could underlie the evolution of sex-biased parasitism. Mating system differences along with differences in lifespan may play a key role. We examine whether these factors are likely to lead to male-biased parasitism through natural selection taking into account the critical role that ecological feedbacks play in the evolution of defence. We use a host-parasite model with two sexes and the techniques of adaptive dynamics to investigate how mating system and sexual differences in competitive ability and longevity can select for a bias in the rates of parasitism. Male-biased parasitism is selected for when males have a shorter average lifespan or when males are subject to greater competition for resources. Male-biased parasitism evolves as a consequence of sexual differences in life-history that produce a greater proportion of susceptible females than males and therefore reduce the cost of avoiding parasitism in males. Different mating systems such as monogamy, polygyny or polyandry did not produce a bias in parasitism through these ecological feedbacks but may accentuate an existing bias. PMID- 20946903 TI - A mathematical synthesis of niche and neutral theories in community ecology. AB - The debate between niche-based and neutral community theories centers around the question of which forces shape predominantly ecological communities. Niche theory attributes a central role to niche differences between species, which generate a difference between the strength of intra- and interspecific interactions. Neutral theory attributes a central role to migration processes and demographic stochasticity. One possibility to bridge these two theories is to combine them in a common mathematical framework. Here we propose a mathematical model that integrates the two perspectives. From a niche-based perspective, our model can be interpreted as a Lotka-Volterra model with symmetric interactions in which we introduce immigration and demographic stochasticity. From a neutral perspective, it can be interpreted as Hubbell's local community model in which we introduce a difference between intra- and interspecific interactions. We investigate the stationary species abundance distribution and other community properties as functions of the interaction coefficient, the immigration rate and the strength of demographic stochasticity. PMID- 20946904 TI - A mechanochemical 3D continuum model for smooth muscle contraction under finite strains. AB - This paper presents a modelling framework in which the mechanochemical properties of smooth muscle cells may be studied. The activation of smooth muscles is considered in a three-dimensional continuum model which is key to realistically capture the function of hollow organs such as blood vessels. On the basis of a general thermodynamical framework the mechanical and chemical phases are specialized in order to quantify the coupled mechanochemical process. A free energy function is proposed as the sum of a mechanical energy stored in the passive tissue, a coupling between the mechanical and chemical kinetics and an energy related purely to the chemical kinetics and the calcium ion concentration. For the chemical phase it is shown that the cross-bridge model of Hai and Murphy [1988. Am. J. Physiol. Cell Physiol. 254, C99-C106] is included in the developed evolution law as a special case. In order to show the specific features and the potential of the proposed continuum model a uniaxial extension test of a tissue strip is analysed in detail and the related kinematics and stress-stretch relations are derived. Parameter studies point to coupling phenomena; in particular the tissue response is analysed in terms of the calcium ion level. The model for smooth muscle contraction may significantly contribute to current modelling efforts of smooth muscle tissue responses. PMID- 20946905 TI - Control of constraint forces and trajectories in a rich sensory and actuation environment. AB - A simple control strategy is proposed and applied to a class of non-linear systems that have abundant sensory and actuation channels as in living systems. The main objective is the independent control of constrained trajectories of motion, and control of the corresponding constraint forces. The peripheral controller is a proportional, derivative and integral (PID) controller. A central controller produces, via pattern generators, reference signals that are the desired constrained position and velocity trajectories, and the desired constraint forces. The basic tenet of the this hybrid control strategy is the use of two mechanisms: 1. linear state and force feedback, and 2. non-linear constraint velocity feedback - sliding mode feedback. The first mechanism can be envisioned as a high gain feedback systems. The high gain attribute imitates the agonist-antagonist co-activation in natural systems. The strategy is applied to the control of the force and trajectory of a two-segment thigh-leg planar biped leg with a mass-less foot cranking a pedal that is analogous to a bicycle pedal. Five computational experiments are presented to show the effectiveness of the strategy and the performance of the controller. The findings of this paper are applicable to the design of orthoses and prostheses to supplement functional electrical stimulation for support purposes in the spinally injured cases. PMID- 20946906 TI - Visual search performance in the autism spectrum II: the radial frequency search task with additional segmentation cues. AB - The Embedded Figures Test (EFT) requires detecting a shape within a complex background and individuals with autism or high Autism-spectrum Quotient (AQ) scores are faster and more accurate on this task than controls. This research aimed to uncover the visual processes producing this difference. Previously we developed a search task using radial frequency (RF) patterns with controllable amounts of target/distracter overlap on which high AQ participants showed more efficient search than low AQ observers. The current study extended the design of this search task by adding two lines which traverse the display on random paths sometimes intersecting target/distracters, other times passing between them. As with the EFT, these lines segment and group the display in ways that are task irrelevant. We tested two new groups of observers and found that while RF search was slowed by the addition of segmenting lines for both groups, the high AQ group retained a consistent search advantage (reflected in a shallower gradient for reaction time as a function of set size) over the low AQ group. Further, the high AQ group were significantly faster and more accurate on the EFT compared to the low AQ group. That is, the results from the present RF search task demonstrate that segmentation and grouping created by intersecting lines does not further differentiate the groups and is therefore unlikely to be a critical factor underlying the EFT performance difference. However, once again, we found that superior EFT performance was associated with shallower gradients on the RF search task. PMID- 20946907 TI - Group differences in anterior hippocampal volume and in the retrieval of spatial and temporal context memory in healthy young versus older adults. AB - The ability to retrieve temporal and spatial context information from memory declines with healthy aging. The hippocampus (HC) has been shown to be associated with successful encoding and retrieval of spatio-temporal context, versus item recognition information (Davachi, Mitchell, & Wagner, 2003; Nadel, Samsonovich, Ryan, & Moscovitch, 2000; Ross & Slotnick, 2008). Aging has been linked to volume reduction in the HC (Bouchard, Malykhin, Martin, Hanstock, Emery, Fisher, & Camicioli, 2008; Malykhin, Bouchard, Camicioli, & Coupland, 2008; Raz et al., 2005). As such, age-associated reductions in anterior HC volume may contribute to the context memory deficits observed in older adults. In the current MRI study we investigated whether item recognition, spatial context and temporal context memory performance would be predicted by regional volumes in HC head (HH), body (HB) and tail (HT) volumes, using within group multiple regression analyses in a sample of 19 healthy young (mean age 24.3) and 20 older adults (mean age 67.7). We further examined between age-group differences in the volumes of the same HC sub-regions. Multiple regression analyses revealed that in younger adults both spatial and temporal context retrieval performance was predicted by anterior HC volume. Older age was associated with significant volume reductions in HH and HB, but not HT; and with reduced ability to retrieve spatial and temporal contextual details from episodic memory. However, HC volumes did not predict context retrieval performance in older adults. We conclude that individual differences in anterior, not posterior, HC volumes predict context memory performance in young adults. With age there may be a posterior-to-anterior shift from using HC-related processes, due to HC volume loss, to employing the prefrontal cortex to aid in the performance of cognitively demanding context memory tasks. However, due to concomitant changes in the prefrontal system with age, there are limits to compensation in the aging brain. PMID- 20946908 TI - Experience with activity based anorexia enhances conditioned taste aversion learning in rats. AB - Activity based anorexia (ABA) is a model that mimics the self-starvation and hyperactivity features of anorexia nervosa (AN). This study investigated whether a history of ABA will enhance food avoidance learning and retard its extinction in female rats. We compared the acquisition and extinction of a conditioned taste aversion (CTA) in naive (ad lib with no access to RW), ABA, and pair-fed to the food intake of ABA (with access to a locked RW) female Sprague-Dawley rats. The CTA conditioning was conducted after the ABA and pair-fed rats had recovered to their pre-food restriction body weights. For the CTA learning, 0.3M sucrose consumption was followed by low doses LiCl (0.009M or 0.018M at 1.33ml/100g of body weight, IP) injection. The results revealed that the ABA rats acquired an aversion to sucrose significantly sooner than the naive controls. Furthermore, they completely avoided sucrose while the naive and pair-fed controls still sampled it by the end of 10 conditioning trials. When extinction was assessed by 1-bottle and 2-bottle tests, the ABA rats extinguished more slowly than the controls. However, the differences in sucrose aversion extinction between the ABA and control rats were only significant in the 1-bottle test. These data suggest that experience with AN-like behaviors results in an acquired aversion to a preferred food sooner and a longer retention of the negative food associations. These findings have implications for understanding the persistence of aberrant eating behaviors in eating disorders. PMID- 20946909 TI - Combination therapy with andrographolide and d-penicillamine enhanced therapeutic advantage over monotherapy with d-penicillamine in attenuating fibrogenic response and cell death in the periportal zone of liver in rats during copper toxicosis. AB - Long treatment regime with d-penicillamine is needed before it can exert clinically meaningful benefits in the treatment of copper toxicosis. The consequence of long-term d-penicillamine treatment is associated with numerous side effects. The limitations of d-penicillamine monotherapy prompted us to search for more effective treatment strategies that could decrease the duration of d-penicillamine therapy. The present study was designed to evaluate the therapeutic potential of d-penicillamine in combination with another hepatoprotective drug, andrographolide in treatment of copper toxicosis in rats. d-penicillamine treatment led to the excretion of copper through urine. Addition of andrographolide to d-penicillamine regime appeared to increase protection of liver by increasing the biliary excretion of copper and reduction in cholestatic injury. The early removal of the causative agent copper during combination treatment was the most effective therapeutic intervention that contributed to the early rectification of fibrosis in liver. Combination treatment reduced Kupffer cells accumulation and TNFalpha production in liver of copper exposed rats. In particular, andrographolide mediated the anti-inflammatory effect by inhibiting the cytokine production. However, another possible mechanism of cytoprotection of andrographolide was decreasing mitochondrial production of superoxide anions that resulted in better restoration of mitochondrial dysfunction during combination therapy than monotherapy. Furthermore, ROS inhibition by combination regimen resulted in significant decline in activation of caspase cascade. Inhibition of caspases attenuated apoptosis of hepatocytes, induced by chronic copper exposure. In summary, this study suggested that added benefit of combination treatment over use of either agent alone in alleviating the hepatotoxicity and fibrosis associated with copper toxicosis. PMID- 20946910 TI - Atorvastatin acts synergistically with N-acetyl cysteine to provide therapeutic advantage against Fas-activated erythrocyte apoptosis during chronic arsenic exposure in rats. AB - Arsenic is an environmental toxicant that reduces the lifespan of circulating erythrocytes during chronic exposure. Our previous studies had indicated involvement of hypercholesterolemia and reactive oxygen species (ROS) in arsenic induced apoptotic death of erythrocytes. In this study, we have shown an effective recovery from arsenic-induced death signaling in erythrocytes in response to treatment with atorvastatin (ATV) and N-acetyl cysteine (NAC) in rats. Our results emphasized on the importance of cholesterol in the promotion of ROS-mediated Fas signaling in red cells. Arsenic-induced activation of caspase 3 was associated with phosphatidylserine exposure on the cell surface and microvesiculation of erythrocyte membrane. Administration of NAC in combination with ATV, proved to be more effective than either of the drugs alone towards the rectification of arsenic-mediated disorganization of membrane structural integrity, and this could be linked with decreased ROS accumulation through reduced glutathione (GSH) repletion along with cholesterol depletion. Moreover, activation of caspase 3 was capable of promoting aggregation of band 3 with subsequent binding of autologous IgG and opsonization by C3b that led to phagocytosis of the exposed cells by the macrophages. NAC-ATV treatment successfully amended these events and restored lifespan of erythrocytes from the exposed animals almost to the control level. This work helped us to identify intracellular membrane cholesterol enrichment and GSH depletion as the key regulatory points in arsenic-mediated erythrocyte destruction and suggested a therapeutic strategy against Fas-activated cell death related to enhanced cholesterol and accumulation of ROS. PMID- 20946911 TI - Palytoxin toxicology: animal studies. AB - Palytoxin and its derivatives have been implicated in toxic events in humans following ingestion or inhalation, and many studies on the toxicities of these substances to animals, via various routes of administration, have been described. In this report, the toxicity of palytoxin to animals has been reviewed, with comments on possible mechanisms of action. Information required for the risk assessment of palytoxin and its derivatives is by no means complete, and recommendations for further studies, which may better inform regulatory decisions regarding these substances, are also discussed. PMID- 20946912 TI - Cyanobacterial cytotoxicity versus toxicity to brine shrimp Artemia salina. AB - Heterocytous cyanobacteria from various habitats were screened for toxicity to brine shrimp Artemia salina and the murine lymphoblastic cell line Sp/2 in order to compare these two testing models for evaluation of risk posed by cyanobacteria to human health. Methanol extracts of biomass and cultivation media were tested for toxicity and selected extracts were fractionated to determine the active fraction. We found a significant toxic effect to A. salina and to Sp/2 cells in 5.2% and 31% of studied extracts, respectively. Only 8.6% of the tested strains were highly toxic to both A. salina and the Sp/2 cell line, and only two of the tested strains were toxic to A. salina and not to the murine cell line. Therefore, it is likely that the toxic effect of cyanobacterial secondary metabolites mostly targets basal metabolic pathways present in mammal cells and so is not manifested in A. salina. We conclude that it is insufficient to monitor cytotoxicity of cyanobacteria using only the brine shrimp bioassay as was usual in the past, since cytotoxicity is a more frequent feature in cyanobacteria in comparison with toxicity to A. salina. A. salina toxicity test should not be used when estimating the possible health risk for humans. We suggest that in vitro mammal cells be used for these purposes. PMID- 20946913 TI - Effect of ionic liquids on the structure, stability and activity of two related alpha-amylases. AB - Ionic liquids are recognized as green solvents for carbohydrates dissolution. However, only a limited number of studies have been carried out to investigate their effect on carbohydrate hydrolyzing enzymes. We have investigated the influence of two water miscible ionic liquids on the activity, stability and structure of two related alpha-amylases from Bacillus amyloliquefaciens and Bacillus lichiniformis. Upon changes in ionic liquids concentrations, both enzymes activity and stability were reduced. Associated thermodynamic and conformational changes were observed using differential scanning calorimetry and fluorescence techniques. Thermal denaturation was accompanied by aggregation in both aqueous buffer and [BMIm][Cl] but [HMIm][Cl] significantly suppressed aggregation. PMID- 20946914 TI - Evidence for GABAergic inhibitory deficits in major depressive disorder. AB - Converging evidence suggests that deficits in gamma-aminobutyric acid (GABA) functioning are implicated in the pathophysiology of major depressive disorder (MDD). This is highlighted by research investigating cortical inhibition (CI), a process whereby GABAergic interneurons selectively attenuate pyramidal neurons. Transcranial magnetic stimulation (TMS) paradigms evaluate this marker of neuronal inhibitory activity in the cortex. This review will examine the neuroanatomic and neurophysiological evidence from neuroimaging, molecular, treatment, and TMS studies linking dysfunctional GABAergic neurotransmission to MDD. PMID- 20946916 TI - Immunohistochemical analysis of HLDA9 Workshop antibodies against cell-surface molecules in reactive and neoplastic lymphoid tissues. AB - The study of human leukocyte antigens, predominantly by monoclonal antibody (mAb) techniques, has become a fundamental part of basic research and clinical investigation. In particular, mAbs have allowed a more precise phenotypic dissection of lymphocyte subsets and have increased our understanding of the mechanisms that regulate humoral immunity and tumour transformation. In the present study we have investigated the expression, in both reactive and neoplastic lymphoid tissues, of a panel of HLDA9 mAbs (TRAIL-R2 (CD262), CCR6 (CD196), HVEM (CD270), Galectin-3 and BAFF-R (CD268)) capable of recognizing their target molecules in paraffin-embedded tissue sections. A series of reactive lymphoid tissues and B and T cell lymphomas (151 cases) were studied, using whole sections and tissue microarrays (T.M.A.). The most interesting results were obtained from the Galectin-3 study. In human lymphomas our data are consistent with the results previously described that showed that Galectin-3 is expressed in anaplastic large cell lymphoma (ALCL). Moreover, we provide additional information of Galetin-3 expression in other lymphoma types. In T cell lymphomas, Galectin-3 was strongly expressed by a significant number of peripheral (PTCL 12/43) and cutaneous T cell lymphomas (CTCL 6/24) while in B cell lymphoma only a small proportion of follicular (FL 2/10) and diffuse large B cell lymphomas (DLBCL 3/10) were positives. Our study encourage further investigations into the potential role that TRAIL-R2, CD196, HVEM, Galectin-3 and BAFF-R proteins may play in lymphocyte development and differentiation, but also constitute an additional tool for the study of lymphoid subpopulations and lymphoproliferative disorders. PMID- 20946915 TI - Biomarkers of manganese intoxication. AB - Manganese (Mn), upon absorption, is primarily sequestered in tissue and intracellular compartments. For this reason, blood Mn concentration does not always accurately reflect Mn concentration in the targeted tissue, particularly in the brain. The discrepancy between Mn concentrations in tissue or intracellular components means that blood Mn is a poor biomarker of Mn exposure or toxicity under many conditions and that other biomarkers must be established. For group comparisons of active workers, blood Mn has some utility for distinguishing exposed from unexposed subjects, although the large variability in mean values renders it insensitive for discriminating one individual from the rest of the study population. Mn exposure is known to alter iron (Fe) homeostasis. The Mn/Fe ratio (MIR) in plasma or erythrocytes reflects not only steady-state concentrations of Mn or Fe in tested individuals, but also a biological response (altered Fe homeostasis) to Mn exposure. Recent human studies support the potential value for using MIR to distinguish individuals with Mn exposure. Additionally, magnetic resonance imaging (MRI), in combination with noninvasive assessment of gamma-aminobutyric acid (GABA) by magnetic resonance spectroscopy (MRS), provides convincing evidence of Mn exposure, even without clinical symptoms of Mn intoxication. For subjects with long-term, low-dose Mn exposure or for those exposed in the past but not the present, neither blood Mn nor MRI provides a confident distinction for Mn exposure or intoxication. While plasma or erythrocyte MIR is more likely a sensitive measure, the cut-off values for MIR among the general population need to be further tested and established. Considering the large accumulation of Mn in bone, developing an X-ray fluorescence spectroscopy or neutron-based spectroscopy method may create yet another novel non-invasive tool for assessing Mn exposure and toxicity. PMID- 20946917 TI - Susceptibility to experimental autoimmune encephalomyelitis is associated with altered B-cell subsets distribution and decreased serum BAFF levels. AB - B cells possess the ability to regulate either pathogenic or protective events in several autoimmune diseases such as multiple sclerosis (MS) and its experimental model, experimental autoimmune encephalomyelitis (EAE). Given the extensive use of B-cell-targeting treatments, it appears crucial to more precisely define the dual role of B cells in the progression of the disease. In the present study, we explored the impact of EAE induction on the distribution of potential regulatory B-cell subsets (CD5(+) B1a, marginal zone and transitional 2 B cells) over critical time points in the relapsing-remitting EAE model, SJL/J (H2s). The same approach was carried out in B10.S mice that are resistant to EAE induction, (H2s). The comparative data obtained from these experiments showed that the homeostasis of the regulatory B-cell subsets is altered during the EAE preclinical and acute phases. These observations were associated with a distortion of the BAFF response. All these data suggest the existence of a close relationship between B-cell homeostasis, BAFF response and the susceptibility to develop EAE. PMID- 20946919 TI - WITHDRAWN: Inhibition by toltrazuril of the recombinant cyclophilin ETCYP21 of Eimeria tenella. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 20946918 TI - Evaluation of an immunoglobulin M-specific capture enzyme-linked immunosorbent assay for rapid diagnosis of dengue infection. AB - Various assays have been developed to diagnose dengue virus infection, relying on techniques from the fields of serology and molecular biology. Many of these assays have been successful, but there is still an urgent need for accurate, simple and rapid diagnostic assays to diagnose dengue virus infection and to assist in patient management. Using a panel of well-characterized sera and a collection of retrospective samples obtained during the dengue epidemics that occurred in Belem, Brazil, between 2002 and 2009, a modified immunoglobulin M specific capture enzyme-linked immunosorbent assay (Rapid-MAC-ELISA) was evaluated and compared with the "gold standard" MAC-ELISA, in order to assess the specificity, sensitivity, stability, reproducibility and cost-effectiveness of this new assay. These results demonstrated that the Rapid-MAC-ELISA is comparable to the MAC-ELISA in terms of sensitivity and specificity and is highly reproducible; additionally, it is easily performed, less expensive than other available formats and can be completed within three hours. Furthermore, the Rapid MAC-ELISA can be used for the diagnosis of dengue virus infections in resource limited areas where dengue is endemic. PMID- 20946920 TI - Peptide dendrimers as efficient and biocompatible gene delivery vectors: Synthesis and in vitro characterization. AB - We report the synthesis and characterization of different generations of dendritic poly(l-lysine) vectors, and their use for in vitro gene transfection. Gel retardation assay revealed that the dendrimers could form complexes with plasmid DNAs (pDNAs), evident from the inhibition of the migration of pDNA at the N/P ratios of 0.5, 1 and 2 by G3, G4 and G5 dendritic generations, respectively. DNase I assay revealed the protection of pDNA acquired from the complexation with dendrimers from nuclease-catalyzed degradation, with the protection capacity of G5 being even stronger than poly(ethyleneimine) (PEI). Atomic force microscopy (AFM) revealed that all 4 generations of dendrimer/DNA complexes studied were of similar particle sizes within 100-200nm. Zeta potential measurements showed that as the N/P ratio increased from 1 to 25, all dendrimer/pDNA complexes gradually changed from negative to positive charges. The higher generations tended to produce the greater positive potentials, indicating a stronger potency of the complexes to interact with negatively charged cell membranes. In vitro and in vivo cytotoxicity evaluations showed good biocompatibility of the dendrimers and their complexes over the different N/P ratios studied. In vitro gene transfection revealed higher efficiency of G5 than other dendrimers and insensitive variation to the presence of serum. Given its similar transfection efficiency to PEI but lower toxicity to cultured cells, dendrimer G5 could be a better candidate for gene delivery. PMID- 20946921 TI - A LDL-masked liposomal-doxorubicin reverses drug resistance in human cancer cells. AB - Doxorubicin is one of the most employed anticancer drugs, but its efficacy is limited by the onset of adverse effects such as drug resistance, due to the drug efflux via P-glycoprotein (Pgp). Several factors are associated to a high Pgp activity, including the amount of cholesterol in plasma membrane, which is essential to maintain the pump function. In this work we started from the following observations: 1) the drug-resistant colon cancer HT29-dx cells had a higher content of cholesterol in plasma membrane than drug-sensitive HT29 cells and a higher activity of Pgp, which was decreased by the cholesterol-lowering agent beta-methyl-cyclodextrin; 2) HT29-dx cells showed a higher synthesis of endogenous cholesterol and a higher expression of the low-density lipoprotein receptor (LDLR); 3) the anti-cholesterolemic drug simvastatin reduced the cholesterol synthesis, increased the synthesis of LDLR and lowered the Pgp activity in resistant cells. In order to circumvent drug resistance we designed a new liposomal doxorubicin, conjugated with a recombinant LDLR-binding peptide from human apoB100: this LDL-masked doxorubicin ("apo-Lipodox") was efficiently internalized by a LDLR-driven endocytosis and induced cytotoxic effects in HT29 dx cells, reversing their drug resistance. Its efficacy was further increased by simvastatin, which up-regulates the LDLR levels and contemporarily reduces the Pgp activity, thus increasing the liposomes uptake and limiting the drug efflux. We propose that the association of liposomal doxorubicin and statins may be a future promising strategy to reverse drug-resistance in human cancer cells. PMID- 20946922 TI - Maltose- and maltotriose-modified, hyperbranched poly(ethylene imine)s (OM-PEIs): Physicochemical and biological properties of DNA and siRNA complexes. AB - Polycationic non-viral polymers are widely employed as delivery platforms of plasmid DNA, or of small interfering RNAs (siRNAs) for the induction of RNA interference (RNAi). Among those, poly(ethylene imine)s (PEIs) take a prominent position due to their relatively high efficacy; however, their biodistribution profiles upon systemic delivery and their toxicity pose limitations which can be addressed by the introduction of PEI modifications. In this paper, we systematically analyse physicochemical and biological properties of DNA and siRNA complexes prepared from a set of maltose-, maltotriose- or maltoheptaose-modified hyperbranched PEIs (termed (oligo-)maltose-modified PEIs; OM-PEIs). We show that pH-dependent charge densities of the OM-PEIs correlate with the structure and degree of grafting, and the length of the oligomaltose. Decreased zeta potentials of OM-PEI-based complexes and changes in the thermodynamics of DNA complex formation are observed, while the complex sizes are largely unaffected by maltose grafting and the presence of serum proteins. Furthermore, although complexation efficacies of siRNAs are not altered, complex stabilities are markedly increased in OM-PEI complexes. DNA complex uptake and transfection kinetics are slowed down upon maltose-grafting of the PEI which can be attributed to decreased zeta potentials, and alterations in the uptake mechanisms (clathrin-dependent/clathrin independent endocytosis) are observed. Independent of the maltose architecture, DNA and siRNA complexes based on maltose-grafted PEI show considerably lower cytotoxicity as compared to PEI complexes. While maltose grafting generally leads to reduced in vitro transfection efficacies, this effect is less profound in some OM-PEI/siRNA complexes as compared to OM-PEI/DNA complexes. Importantly, upon their systemic application in vivo, OM-PEI/siRNA complexes show marked differences in the siRNA biodistribution profile with e.g. substantially decreased siRNA levels in the liver and increased siRNA levels in the muscle. Taken together, we demonstrate that OM-PEI complexes show structure-dependent physicochemical and biological properties and may represent promising, tailor made platforms for the delivery of siRNAs, particularly for in vivo applications. PMID- 20946923 TI - Hydrocortisone nanosuspensions for ophthalmic delivery: A comparative study between microfluidic nanoprecipitation and wet milling. AB - Recently, drug nanosuspensions have shown a potential for ophthalmic delivery. In this study, a hydrocortisone (HC) nanosuspension (NS) was developed using microfluidic nanoprecipitation as a recent, simple and cost-effective bottom-up technique of drug nanonization. For comparison, a second HC NS was prepared by top-down wet milling procedures. The produced nanosuspensions were characterized for particle size, shape and zeta potential. HC nanosuspensions of approximately 300nm particle size were produced by adjusting experimental conditions of the two processing techniques. Results of X-ray diffraction and differential scanning calorimetry revealed that HC maintained the crystalline structure upon milling, while predominant amorphous particles were generated after precipitation. Ocular bioavailability of HC nanosuspensions was assessed in albino rabbits using HC solution as a control. A sustained drug action was maintained up to 9h for the nanosuspensions compared to 5h for the drug solution. The precipitated and milled NS achieved comparable AUC(0-9h) values of 28.06+/-4.08 and 30.95+/-2.2, respectively, that were significantly (P<0.05) higher than that of HC solution (15.86+/-2.7). After 2 months storage at room temperature, the milled HC NS showed good stability with no discernable changes in particle size, whereas the particle size of the precipitated HC NS increased to 440nm. PMID- 20946924 TI - PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights. AB - Salmon calcitonin (sCT) was conjugated via cysteine-1 to novel comb-shaped end functionalised (poly(PEG) methyl ether methacrylate) (sCT-P) polymers, to yield conjugates of total molecular weights (MW) inclusive of sCT: 6.5, 9.5, 23 and 40kDa. The conjugates were characterised by HPLC and their in vitro and in vivo bioactivity was measured by cAMP assay on human T47D cells and following intravenous (i.v.) injection to rats, respectively. Stability against endopeptidases, rat serum and liver homogenates was assessed. There were linear and exponential relationships between conjugate MW with potency and efficacy respectively, however the largest MW conjugate still retained 70% of E(max) and an EC(50) of 3.7nM. In vivo, while free sCT and the conjugates reduced serum [calcium] to a maximum of 15-30% over 240 min, the half-life (T(1/2)) was increased and the area under the curve (AUC) was extended in proportion to conjugate MW. Likewise, the polymer conferred protection on sCT against attack by trypsin, chymotrypsin, elastase, rat serum and liver homogenates, with the best protection afforded by sCT-P (40kDa). Mathematical modelling accurately predicted the MW relationships to in vitro efficacy, potency, in vivo PK and enzymatic stability. With a significant increase in T(1/2) for sCT, the 40kDa MW comb shaped PEG conjugate of sCT may have potential as a long-acting injectable formulation. PMID- 20946926 TI - Information processing of food pictures in binge eating disorder. AB - Previous research has yielded evidence of attentional biases for food-related cues in binge eating disorder (BED) using behavioural measures such as the Stroop and dot probe paradigm. Being a more direct measure of attentional processing, the present study used event related potentials (ERPs) to test reactivity to high caloric and low caloric food pictures in women with BED compared to overweight healthy female controls (HC). In order to detect a possible motivational ambivalence, self-report and psychophysiological measures of the sympathetic and parasympathetic response system were assessed additionally. The main results yielded evidence that in women with BED high caloric food pictures elicit larger long latency ERPs compared to HC. By contrast, no such group difference was found for low caloric food pictures. Peripheral measures did not yield any group differences with respect to the processing of the caloric value of food. The results suggest that for women with BED, high caloric food may have high motivational properties and consume large parts of attentional resources. In the context of an environment in which high caloric food is omnipresent, such an abnormal processing may be relevant for the maintenance of the disorder. PMID- 20946925 TI - Targeted renal therapies through microbubbles and ultrasound. AB - Microbubbles and ultrasound enhance the cellular uptake of drugs (including gene constructs) into the kidney. Microbubble induced modifications to the size selectivity of the filtration capacity of the kidney may enable drugs to enter previously inaccessible compartments of the kidney. So far, negative renal side effects such as capillary bleeding have been reported only in rats, with no apparent damage in larger models such as pigs and rabbits. Although local delivery is accomplished by applying ultrasound only to the target area, efficient delivery using conventional microbubbles has depended on the combined injection of both drugs and microbubbles directly into the renal artery. Conjugation of antibodies to the shell of microbubbles allows for the specific accumulation of microbubbles in the target tissue after intravenous injection. This exciting approach opens new possibilities for both drug delivery and diagnostic ultrasound imaging in the kidney. PMID- 20946927 TI - Structure-function analysis of helix 8 of human calcitonin receptor-like receptor within the adrenomedullin 1 receptor. AB - Adrenomedullin 1 (AM(1)) receptor is a heterodimer composed of calcitonin receptor-like receptor (CLR) - a family B G protein-coupled receptor (GPCR) - and receptor activity-modifying protein 2 (RAMP2). Both family A and family B GPCRs possess an eighth helix (helix 8) in the proximal portion of their C-terminal tails; however, little is known about the function of helix 8 in family B GPCRs. We therefore investigated the structure-function relationship of human (h)CLR helix 8, which extends from Glu430 to Trp439, by separately transfecting nine point mutants into HEK-293 cells stably expressing hRAMP2. Glu430, Val431, Arg437 and Trp439 are all conserved among family B GPCRs. Flow cytometric analysis revealed that Arg437Ala or Trp438Ala mutation significantly reduced cell surface expression of the receptor complex, leading to a ~20% reduction in specific (125)I-AM binding but little change in their IC(50) values. Both mutants showed 6 8-fold higher EC(50) values for AM-induced cAMP production and ~50% reductions in their maximum responses. Glu430Ala mutation also reduced AM signaling by ~45%, but surface expression and (125)I-AM binding were nearly the same as with wild type CLR. Surprisingly, Glu430Ala and Val431Ala mutations significantly enhanced AM-induced internalization of the mutant receptor complexes. Taken together, these findings suggest that within hCLR helix 8, Glu430 is crucial for Gs coupling, and Arg437 and Trp439 are involved in both cell surface expression of the hAM(1) receptor and Gs coupling. Moreover, the Glu430-Val431 sequence may participate in the negative regulation of hAM(1) receptor internalization, which is not dependent on Gs coupling. PMID- 20946928 TI - Computational studies of protegrin antimicrobial peptides: a review. AB - Antimicrobial peptides (AMPs) are small, naturally occurring peptides that exhibit strong antibacterial properties generally believed to be a result of selective bacterial membrane disruption. As a result, there has been significant interest in the development of therapeutic antibiotics based on AMPs; however, the poor understanding of the fundamental mechanism of action of these peptides has largely hampered such efforts. We present a summary of computational and theoretical investigations of protegrin, a particularly potent peptide that is both an excellent model for the mechanism of action of AMPs and a promising therapeutic candidate. Experimental investigations have shed light on many of the key steps in the action of protegrin: protegrin monomers are known to dimerize in various lipid environments; protegrin peptides interact strongly with lipid bilayer membranes, particularly anionic lipids; protegrins have been shown to form pores in lipid bilayers, which results in uncontrolled ion transport and may be a key factor in bacterial death. In this work, we present a comprehensive review of the computational and theoretical studies that have complemented and extended the information obtained from experimental work with protegrins, as well as a brief survey of the experimental biophysical studies that are most pertinent to such computational work. We show that a consistent, mechanistic description of the bactericidal mechanism of action of protegrins is emerging, and briefly outline areas where the current understanding is deficient. We hope that the research reviewed herein offers compelling evidence of the benefits of computational investigations of protegrins and other AMPs, as well as providing a useful guide to future work in this area. PMID- 20946929 TI - Inhibition of LPS-induced apoptosis in differentiated-PC12 cells by new triazine derivatives through NF-kappaB-mediated suppression of COX-2. AB - Anti-inflammatory therapy approaches have been in the focus of attention in the treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). In this study, we examined the role of new 1,2,4-triazine derivatives against cytotoxicity exerted by lipopolysaccharide (LPS) in differentiated rat pheochromocytoma (PC12) cell line. Our results indicated that LPS-induced cell death can be inhibited in the presence of some of these compounds, as measured by MTT test, acridine orange/ethidium bromide staining and caspase-3 expression assay. We further showed that these compounds exert their protective effects through the inhibition of LPS-induced generation of nitric oxide and reactive oxygen species. Triazine derivatives inhibited LPS-induced nuclear translocation of nuclear factor- kappaB, a known regulator of a host of genes involved in specific stress and inflammatory responses. Pretreatment of PC12 cells with triazine derivatives also suppressed LPS-induced cyclooxygenase-2 expression while up-regulated heat shock protein-70 (Hsp-70). Moreover, the treatment of brain diseases is limited by the insufficiency in delivering therapeutic drugs into brain relating to highly limited transport of compounds through blood-brain barrier (BBB). Using a reliable model based on the artificial neural network, we indicated that these compounds are capable of penetrating BBB and may be useful agents for preventing neuroinflammatory diseases like AD. PMID- 20946930 TI - Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats: role of serotonin synthesis. AB - We have investigated effects of continuous SSRI administration and abrupt discontinuation on biochemical and behavioral indices of rat brain serotonin function, and attempted to identify underlying mechanisms. Biochemistry of serotonin was assessed with brain tissue assays and microdialysis; behavior was assessed as the acoustic startle reflex. Long-term SSRI administration to rats reduced the content of 5-HT and its main metabolite shortly after inhibition of 5 HT synthesis in many brain areas with more than 50%. Turnover was not appreciably decreased, but significantly increased within 48h of drug discontinuation. The microdialysis experiments indicate that neuronal release of 5-HT depends strongly on new synthesis and emphasize the role of 5-HT(1B) receptors in the regulation of these processes. Discontinuation of the SSRI rapidly increased behavioral reactivity to the external stimulus. Additional startle experiments suggest that the increased reactivity is more likely related to the reduced extracellular 5-HT levels than to impaired synthesis. The combination of the marked reduction of serotonin content and limited synthesis may destabilize brain serotonin transmission during long-term SSRI treatment. These combined effects may compromise the efficacy of an SSRI therapy and facilitate behavioral changes following non-compliance. PMID- 20946931 TI - Acute oral, pulmonary and intravenous toxicity/pathogenicity testing of a new formulation of Bacillus thuringiensis var israelensis SH-14 in rats. AB - During the last decades, efforts are being made to develop microbial insecticides as biological control agents. Bacillus thuringiensis has been one of the most consistent and significant biopesticides for using on crops as an insecticidal spray. The aim of this study was to assess and to compare the pathogenicity of a new formulation of B.thuringiensis var israelensis SH-14 in rats through oral, intranasal and intravenous single dosing. Through 21 days after administration, clinical examinations were performed daily, and body weight gain was evaluated. Clearance was estimated by means of collection of feces or examination of lungs and blood, and infectivity was evaluated enumerating microorganisms from organs of Bti SH-14 treated animals sacrificed at intervals. Gross necropsy of animals was performed at interim or final sacrifice. There were no treatment-related mortalities, and no evidence of pathogenicity or treatment related toxicity, although in the intravenous study, the microorganism was capable of achieving persistence in organs after administration, and the Bti SH-14 treated animals developed skin ulcerations and hemorrhages at the injection site. It could be concluded that the tested microorganism was not toxic or pathogenic to rats via oral or intranasal route, although it was capable of achieving persistence in organs after intravenous administration, eliciting local effects at the injection site. PMID- 20946932 TI - 7,8-didehydrocimigenol from Cimicifugae rhizoma inhibits TNF-alpha-induced VCAM-1 but not ICAM-1expression through upregulation of PPAR-gamma in human endothelial cells. AB - Activators of PPAR have been demonstrated to inhibit the induction of VCAM-1 but not ICAM-1 in human endothelial cells (EC). During the screening of anti inflammatory activity of traditional herbs, we found 7,8-didehydrocimigenol (7,8 DHC), one of active triterpenoids of Cimicifugae rhizoma (C. rhizoma) increases PPAR-gamma expression in EC in a time- and dose-dependent manner. Therefore, we asked whether 7,8-DHC selectively inhibits the expression of VCAM-1 but not ICAM 1 in TNF-alpha-activated EC via upregulation of PPAR-gamma. Treatment with 7,8 DHC or PPAR-gamma agonists (GW1929, troglitazone) inhibited the expression of VCAM-1 but not ICAM-1. Furthermore, the selective inhibition of VCAM-1 expression was inhibited by PPAR-gamma antagonist, GW9662, or siPPAR-gamma-transfected cells. 7,8-DHC significantly inhibited NF-kB activity via inhibition of phosphorylation of IkB and it also inhibited phosphorylation of ERK1/2 and Akt but not PKC. Finally, attachment of monocytes (U937) to EC by TNF-alpha was significantly reduced by 7,8-DHC. These results indicate that upregualtion of PPAR-gamma by 7,8-DHC in EC inhibits NF-kB activity of TNF-alpha-activated EC which leads to selective inhibition of VCAM-1 expression. In addition, ERK1/2 and Akt signal pathways are involved in differential regulation by 7,8-DHC. We concluded that 7,8-DHC can be used for the treatment of cardiovascular disorders such as atherosclerosis. PMID- 20946933 TI - Subchronic oral toxicity assessment of N-acetyl-L-aspartic acid in rats. AB - We investigated the systemic effects of subchronic dietary exposure to NAA in Sprague Dawley(r) rats. NAA was added to the diet at different concentrations to deliver target doses of 100, 250 and 500 mg/kg of body weight/day and was administered for 90 consecutive days. All rats (10/sex/group) survived until scheduled sacrifice. No diet-related differences in body weights, feed consumption and efficiency, clinical signs, or ophthalmologic findings were observed. No biologically significant differences or adverse effects were observed in functional observation battery (FOB) and motor activity evaluations, hematology, coagulation, clinical chemistry, urinalysis, organ weights, or gross pathology evaluations that were attributable to dietary exposure to NAA. Treatment-related increased incidence and degree of acinar cell hypertrophy in salivary glands was observed in both male and female rats in the high dose group. Because there was no evidence of injury or cytotoxicity to the salivary glands, this finding was not considered to be an adverse effect. Based on these results and the actual average doses consumed, the no-observed-adverse-effect-levels (NOAEL) for systemic toxicity from subchronic dietary exposure to NAA were 451.6 and 490.8 mg/kg of body weight/day for male and female Sprague Dawley(r) rats, respectively. PMID- 20946935 TI - Perceived parental support predicts enhanced late positive event-related brain potentials to parent faces. AB - This study examined event-related brain potentials in college students viewing facial pictures of their parents, celebrities, and strangers in the context of a guessing task. A temporal principal component analysis of data obtained from midline electrode sites was used to extract a component reflecting the mid- to late-positive deflection observed between 200 and 500ms following stimulus onset. Parent faces elicited enhanced positivity compared to celebrity and stranger faces suggesting greater attention allocation to parent faces. In addition, greater perceived parental support predicted larger factor scores to parent faces relative to non-parent faces. Greater perceived negative interaction with parent, however, attenuated this relationship. PMID- 20946936 TI - The effects of acupuncture (PC6) on chronic mild stress-induced memory loss. AB - A previous study reported that the PC6 acupuncture point can alleviate chronic mild stress (CMS)-induced anxiety [17]. Following the previous study, this study examined the effects of the PC6 acupuncture point on CMS-induced memory loss. The memory storage and acetylcholinesterase (AchE) activity in the hippocampus were measured, respectively, using a passive avoidance test (PAT) and AchE immunohistochemistry. In the PAT (retention test), the CMS group showed a markedly lower latency time than the control (post (72h): P<0.01, post (96h): P<0.05, post (120h): P<0.001). However, acupuncture at PC6 significantly recovered the impairment of memory compared to the CMS group (post (120h): P<0.001). Exposure to CMS also significantly decreased the AchE activity in the hippocampus compared to the control rats. Acupuncture stimulation at the PC6 point on the pericardium channels (3min), but not at other points (TE5), produced memory improvements and an increase in AchE reactivity in the hippocampus compared to the CMS group. These results show that the acupuncture point is effective in restoring the CMS-related biochemical and behavioral impairments, such as learning and memory. PMID- 20946937 TI - Neural stem cells differentiation ability of human umbilical cord mesenchymal stromal cells is not altered by cryopreservation. AB - Human umbilical mesenchymal stem cells (HUMSCs) have potential therapeutic use in the recovery of central nervous system injury for their ability to differentiate into neural stem cells. However, for transformed HUMSCs to be constantly available for use during surgery a reliable method of cell storage is necessary. The present study aimed to determine whether a simple method of cryopreservation by slow cooling with Me(2)SO had an effect on the proliferation, secretion and differentiation capacities of HUMSCs. These results demonstrate that cryopreservation has no effect on the phenotype, cell cycle, cell proliferation and the ability to secret neurotrophins. Non-cryopreserved and cryopreserved HUMSCs showed the similar ability to differentiate into neural stem-like cells. There results show that cryopreservation by slow cooling with Me(2)SO is effective to retain the proliferation and neural differentiation ability of HUMSCs, cryopreserved HUMSCs maybe very useful for future clinical applications in neural regenerative medicine. PMID- 20946934 TI - Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Due to its high prevalence, MS is the leading cause of non-traumatic neurological disability in young adults in the United States and Europe. The clinical disease course is variable and starts with reversible episodes of neurological disability in the third or fourth decade of life. This transforms into a disease of continuous and irreversible neurological decline by the sixth or seventh decade. Available therapies for MS patients have little benefit for patients who enter this irreversible phase of the disease. It is well established that irreversible loss of axons and neurons are the major cause of the irreversible and progressive neurological decline that most MS patients endure. This review discusses the etiology, mechanisms and progress made in determining the cause of axonal and neuronal loss in MS. PMID- 20946938 TI - Indirubin-3'-oxime inhibits inflammatory activation of rat brain microglia. AB - Microglial cells play critical roles in the immune and inflammatory responses of the brain. Under pathological conditions, the activation of microglia helps to restore brain homeostasis. However, chronic microglial activation endangers neuronal survival through the release of various proinflammatory and neurotoxic factors. As such, regulators of microglial activation have been considered as potential therapeutic candidates to reduce the risk of neurodegeneration associated with neurodegenerative diseases, including Alzheimer's and, Parkinson's diseases. Indirubin-3'-oxime, a potent inhibitor of cyclin-dependent kinases and glycogen synthase kinase-3beta, has been shown to have neuroprotective potential. The specific aim of this study was to examine the efficacy of indirubin-3'-oxime in the repression of microglial activation. Indirubin-3'-oxime was shown to effectively inhibit lipopolysaccharide (LPS) induced nitric oxide release from cultured rat brain microglia. This compound reduced the LPS-stimulated productions of tumor necrosis factor-alpha, interleukin-1beta, prostaglandin E(2), and intracellular reactive oxygen species and also effectively reduced LPS-elicited NF-kappaB activation. In organotypic hippocampal slice cultures, indirubin-3'-oxime blocked LPS-related hippocampal cell death. These results suggest that indirubin-3'-oxime provides neuroprotection by reducing the productions of various neurotoxic molecules in activated microglia. PMID- 20946939 TI - Chronic ethanol ingestion, type 2 diabetes mellitus, and brain-derived neurotrophic factor (BDNF) in rats. AB - Chronic alcohol consumption contributes to the development of type 2 diabetes mellitus (T2DM) while decreasing the level of brain-derived neurotrophic factor (BDNF). BDNF may be an important regulator of glucose metabolism, so it may be associated with an increased risk for T2DM in alcoholism. We evaluated the association of chronic heavy alcohol exposure, T2DM and BDNF level. Ten week-old type 2 diabetic OLETF rats and non-diabetic LETO rats of similar weight were used. The rats were randomized by weight into four treatment groups: (1) OLETF Ethanol (O-E, n=13), (2) OLETF-Control (O-C, n=15), (3) LETO-Ethanol (L-E, n=11), and (4) LETO-Control (L-C, n=14). The ethanol groups were fed an isocaloric liquid diet containing ethanol while the control groups were fed with the same diet containing maltose-dextran over a 6-week period using a pair-feeding control model in order to regulate different caloric ingestion. After 6 weeks of feeding, an Intraperitoneal Glucose Tolerance Test (IP-GTT) was performed and BDNF levels were analyzed. Prior to IP-GTT, the mean glucose levels in the O-E, O-C, L-E, and L-C groups were 90.38+/-12.84, 102.13+/-5.04, 95.18+/-6.43, and 102.36+/ 4.43mg/dL, respectively. Thirty minutes after intraperitoneal injection, the mean glucose levels were 262.62+/-63.77, 229.07+/-51.30, 163.45+/-26.63, and 156.64+/ 34.42mg/dL, respectively; the increased amount of the mean glucose level in the O E group was significantly higher than that in the O-C group (p<0.05). One hundred twenty minutes after intraperitoneal injection, the mean glucose levels were 167.38+/-45.37, 121.20+/-18.54, 106.73+/-6.94, and 104.57+/-9.49mg/dL, respectively; the increased amount of the mean glucose level in the O-E group was significantly higher than that in the O-C group (p<0.01). The difference in mean glucose levels between the O-E group and O-C group was still significant even after adjusting for time (p<0.05). Mean BDNF levels were 405.95+/-326.16, 618.23+/-462.15, 749.18+/-599.93, and 1172.00+/-839.17pg/mL, respectively; mean BDNF level in the O-E group was significantly lower than the L-C group (p<0.05). In conclusion, the results of the present study suggest that chronic heavy alcohol ingestion may aggravate T2DM and may possibly lower BDNF level. PMID- 20946940 TI - Association of variants within APOE, SORL1, RUNX1, BACE1 and ALDH18A1 with dementia in Alzheimer's disease in subjects with Down syndrome. AB - BACKGROUND: Down syndrome (DS) is caused by either complete or partial triplication of chromosome 21, affecting approximately 1/1000 live births, and it is widely accepted that individuals with DS are more likely to develop dementia of Alzheimer's disease (DAD) compared with the general population. Many studies have investigated genetic susceptibility to AD in the general population, resulting in a number of potential candidate genes that may influence the development of DAD. The majority of these variants, however, have not been investigated in subjects with DS. AIM: The aim of this study was to determine whether genetic variants previously associated with AD in the general population, were also associated with DAD in individuals with DS. METHODS: Genotyping of 43 SNPs within 28 genes was undertaken in 187 individuals with Down syndrome with and without dementia of Alzheimer's disease, using the SNPlex platform. RESULTS: Significant associations of SNPs in five genes with DAD in DS were found, namely APOE, SORL1, BACE1, RUNX1 and ALDH18A1. As expected, the most strongly associated SNP was the APOE E4 rs429358 variant (HR=2.47 [1.58, 3.87], p=7.52*10(-5)), although variants within the more recently implicated SORL1 and RUNX1 genes were also strongly associated with DAD in DS (HR=0.54 [0.37, 0.80], p=0.002 and HR=1.61 [1.15, 2.26], p=0.006 respectively). CONCLUSIONS: Our study demonstrates that a number of variants previously associated with AD in the general population are also associated with DAD in DS. To enable us to determine whether these variants, as well as other more recently revealed AD susceptibility variants, truly contribute to the development of DAD in DS, further multi-centre collaborative studies comprising large number of individuals with DS are needed. PMID- 20946941 TI - Lack of vasopressin does not prevent the behavioural and endocrine changes induced by chronic unpredictable stress. AB - Vasopressin (VP) plays an important role in hypothalamo-pituitary-adrenal (HPA) axis regulation and in stress-related disorders. Our previous studies confirmed the role of VP in acute situations, where VP-deficient Brattleboro rats had less depression-like behaviour compared to animals that express VP. In this study, we test the hypothesis that VP-deficient rats are more resistant to the development of chronic HPA axis hyperactivity and depression-like symptoms after chronic unpredictable stress (CUS). Male VP-deficient Brattleboro rats were compared to their heterozygous littermates (controls). CUS consisted of different mild stimuli for 5 weeks. Elevated plus maze and forced swim test were used for behavioural characterization, while organs and blood for HPA axis parameters were collected at the end of the experiment. In controls, CUS resulted in the development of chronic stress state characterized by typical somatic (body weight reduction, thymus involution) and endocrine changes (resting plasma ACTH and corticosterone elevation and POMC mRNA elevation in anterior lobe of the pituitary). Floating time in the forced swim test was enhanced together with reduced open arm entries on elevated plus maze and a reduction in daily food intake. Unexpectedly, the lack of VP did not alter the effect of CUS on the somatic and behavioural measures, but only prevented CUS-induced corticosterone changes. In conclusion, lifelong VP-deficiency has a positive effect on corticosterone elevation following CUS but does not affect the behavioural consequences of CUS. It is likely that the interplay of several related factors, rather than an alteration in a single neuropeptide, modulates behaviour and disease pathogenesis. PMID- 20946942 TI - Identification of three tomato flower and fruit MADS-box proteins with a putative histone deacetylase binding domain. AB - MADS-box transcription factors play crucial roles in organ and cell differentiation in organisms ranging from yeast to humans. Most of the work on plant MADS-box proteins focused on their roles in floral development whereas less information is available on their function in fruit maturation. We cloned three distinct tomato cDNAs using a RT-PCR approach, encoding LeMADS1, LeMADS5 and LeMADS6 factors and whose mRNAs mostly accumulate in tomato flowers and fruits. Phylogeny analysis indicates that LeMADS1, 5 and 6 belong to the MEF2-like family. When transiently expressed in tobacco leaves or in human cells, LeMADS1, 5 and 6 are targeted to the cell nucleus. As the endogenous target genes of these putative transcription factors are unknown, the transcriptional activity of these proteins was characterized in a heterologous system and we showed that, when fused to a Gal4-DNA-binding domain, they repress the transcription of heterologous reporter genes. Since histone deacetylases control MEF2 transcriptional activity and since a putative histone deacetylase binding site was present in LeMADS1, 5 and 6, we tested the potential interaction between these factors and HDAC5 deacetylase. Surprisingly, in this heterologous system, LeMADS1, 5 and 6 interacted with HDAC5 N-terminal region. Our data suggest that, like mammalian MEF2A, plant MADS-box transcriptional activity might be regulated by enzymes controlling chromatin acetylation. PMID- 20946943 TI - Differential gene expression activity among species-specific polypyrimidine/polypurine motifs in mu opioid receptor gene promoters. AB - The mu opioid receptor (MOR) is the principle molecular target of opioid analgesics. An appropriate understanding of MOR gene expression across species is critical for understanding its analgesic functions in humans. Here, we undertake a cross-species analysis of the polymorphic polypyrimidine/polypurine (PPy/u) motif, a key enhancer of MOR gene expression. The mouse PPy/u motif is highly homologous to those of rat (67%) and human (83%), but drives reporter gene expression tenfold and fivefold more effectively than those of rat and human, respectively. Circular dichroism profiles of PPy/u oligonucleotides from different species showed that they are primarily different in structure. Conformational studies of reporter plasmids using confocal Raman spectra, S1 nuclease and restriction enzymes demonstrated that the structural difference is the result of changes in the phosphodiester backbone. Furthermore, these conformational disparities produce differences in torsional stress, as shown by topoisomerase II relaxation and activation of different levels of gene expression under hypertonic conditions. This study demonstrates that homologous PPy/u motifs adopt unique species-specific conformations with different mechanisms and activities for gene expression. We further discuss how structural aspects of transcription regulatory elements, rather than the sequence itself, are significant when studying functional gene expression regulatory elements. PMID- 20946944 TI - A novel combined approach to detect androgenic activities with yeast based assays in Schizosaccharomyces pombe and Saccharomyces cerevisiae. AB - We describe the construction and validation of novel test systems for detecting androgenic activities using a combination of the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. By applying the reporter enhanced Green Fluorescent Protein (EGFP) the incubation time could be reduced to only 24h if compared to the classical beta-galactosidase reporter (48 h). Both yeast systems were validated by analyzing the effects of seven androgens as well as five anti androgens. One androgen (stanozolol) could be detected ten times more sensitive in S. cerevisiae than in S. pombe. Three of the five anti-androgenic substances showed no or only a slight effect in both yeast assays. The other two anti androgens could be detected much better in S. pombe. Additionally, we could show that both yeast assays tolerated 10% urine within the media and still were capable to detect dihydrotestosterone at a concentration of 10(-8)M suggesting the use of the assays for applied doping pre-screening. In summary, the novel androgen-sensitive yeast assays have a large potential for various applications, e.g. as pre-screening in doping analysis or cattle feeding. A combination of both assays, exploiting these two phylogenetic very different yeasts, allows detection of the activity of a wide range of androgenic substances. PMID- 20946945 TI - Electrical field imaging as a means to predict the loudness of monopolar and tripolar stimuli in cochlear implant patients. AB - Tripolar and other electrode configurations that use simultaneous stimulation inside the cochlea have been tested to reduce channel interactions compared to the monopolar stimulation conventionally used in cochlear implant systems. However, these "focused" configurations require increased current levels to achieve sufficient loudness. In this study, we investigate whether highly accurate recordings of the intracochlear electrical field set up by monopolar and tripolar configurations correlate to their effect on loudness. We related the intra-scalar potential distribution to behavioral loudness, by introducing a free parameter (alpha) which parameterizes the degree to which the potential field peak set up inside the scala tympani is still present at the location of the targeted neural tissue. Loudness balancing was performed on four levels between behavioral threshold and the most comfortable loudness level in a group of 10 experienced Advanced Bionics cochlear implant users. The effect of the amount of focusing on loudness was well explained by alpha per subject location along the basilar membrane. We found that alpha was unaffected by presentation level. Moreover, the ratios between the monopolar and tripolar currents, balanced for equal loudness, were approximately the same for all presentation levels. This suggests a linear loudness growth with increasing current level and that the equal peak hypothesis may predict the loudness of threshold as well as at supra threshold levels. These results suggest that advanced electrical field imaging, complemented with limited psychophysical testing, more specifically at only one presentation level, enables estimation of the loudness growth of complex electrode configurations. PMID- 20946946 TI - Proteomic analysis of the regulatory function of DSF-dependent quorum sensing in Xanthomonas oryzae pv. oryzicola. AB - Xanthomonas oryzae pv. oryzicola (Xoc), which caused bacterial leaf streak in rice, is a bacterial pathogen limited to the apoplast of the mesophyll tissue. The rpfF that encodes diffusible signal factor (DSF) synthase, played a key role in the virulence of many plant pathogenic bacteria. In this study, the rpf gene cluster was cloned, and the rpfF was deleted in Xoc. It was observed that the rpfF mutant lost the ability to produce DSF molecular, and exhibited a significant reduction of virulence in rice compared to the wild-type strain. Furthermore, the mutation of rpfF impaired EPS production, and led to Xoc cell aggregation. To analyze the differences of proteome expression between Xoc wild type and rpfF mutant, a comparative proteome analysis was performed by two dimensional gel electrophoresis (2-DE). The results clearly revealed that 48 protein spots were differentially expressed above the threshold ratio of 1.5. Among them, 18 proteins were identified by MS, which were involved in nitrogen transfer, protein folding, elimination of superoxide radicals and flagellar formation. Our results indicated that DSF might play an important role in virulence and growth of Xoc by mediating expression of proteins. PMID- 20946947 TI - Precision-Cut Liver Slices of Salmo salar as a tool to investigate the oxidative impact of CYP1A-mediated PCB 126 and 3-methylcholanthrene metabolism. AB - Fish isolated cell systems have long been used to predict in vivo toxicity of man made chemicals. In present study, we tested the suitability of Precision-Cut Liver Slices (PCLS) as an alternative to these models that allows the evaluation of a global tissue response to toxicants, to investigate oxidative stress response to cytochrome P450 1A (CYP1A) induction in fish liver. PCLS of Salmo salar were exposed for 21 h to increasing doses of 3-methylcholanthrene (3-MC) and Polychlorobiphenyl 126 (PCB 126). 3-MC (25 MUM) strongly induced CYP1A transcription. In dose-response analysis (25-100 MUM), EROD activity was strongly increased at intermediate 3-MC concentrations. We found the counter-intuitive decline of EROD at the highest 3-MC doses to result from reversible competition with ethoxyresorufin. No increases of H(2)O(2) production, antioxidant enzymes activities or oxidative damage to lipids were found with 3-MC treatments. PCLS subjected to PCB 126 (2-200 nM) showed increased contamination levels and a parallel increased CYP1A mRNA synthesis and EROD activity. H(2)O(2) production tended to increase but no oxidative damage to lipids was found. As antioxidant enzymes activities declined at the highest PCB 126 dose, it is suggested that longer incubation periods could be required to generate oxidative stress in PCLS. PMID- 20946948 TI - The pro-apoptotic effect of hydroquinone in human neutrophils and eosinophils. AB - Hydroquinone (HQ) is a benzene metabolite that is involved in hematopoiesis via its accumulation into bone marrow. HQ also acts as a toxic agent that influences various immune responses. Both neutrophils and eosinophils function as important leukocytes in immunological regulation and immune diseases. In this study, we examined the toxic effects of HQ on the apoptosis of human neutrophils and eosinophils isolated from the blood of healthy donors. HQ markedly increased the apoptosis of neutrophils and eosinophils in a concentration- and a time-dependent manner. The pro-apoptotic effect is involved in activation of caspase 9 and caspase 3. Reactive oxygen species (ROS) production was enhanced after HQ treatment in a dose-dependent manner. In addition, HQ upregulated the release of IL-8 and MCP-1 from neutrophils and eosinophils, respectively. Taken together, the results of this study demonstrated that HQ strongly induces the apoptosis of neutrophils and eosinophils through the caspase 9/3-dependent pathway and the increased ROS production. HQ exerts a cytotoxic effect in human neutrophils and eosinophils and may impair the regulation of immune responses. PMID- 20946949 TI - Effect of chromium and cobalt ions on phase I and phase II enzymatic activities in vitro in freshly isolated rat hepatocytes. AB - The effect of in vitro exposure to the metal ions (chromium (VI) and cobalt (II)) on phase I and phase II enzymatic activities in freshly isolated rat hepatocytes is reported. Concentrations of metal ions used reflect those reported in the livers of cadavers that had worn metal-on-metal hip implants. To assess the effect of exposure to metal ions on enzymatic activities of phase I metabolic reactions the hydroxylations of testosterone were measured, and the phase II reactions measured were glucuronidation and sulfation. No effect was observed in the formation of the testosterone metabolites measured in the presence of either ion, Cr (VI) inhibited both glucuronidation and sulfation of 7-hydroxycoumarin (7 HC) and 1-naphthol, while Co inhibited only the glucuronidation of 7-HC and 1 naphthol. ATP levels were reduced in freshly isolated rat hepatocytes treated with Cr (VI) compared with control hepatocytes with no metal treatment. Cr (VI) probably inhibits the formation of 3'-phosphoadenosine 5'-phosphosulfate (PAPS), the high energy co-factor of sulfation, by reducing the availability of ATP and also by acting as a substrate analog and competing with sulfate for ATP sulfurylase. High concentrations of these metal ions in the livers of patients with loose or worn metal implants may act synergistically, and have consequences for the metabolism of xenobiotics. PMID- 20946950 TI - Effects of acute and repeated administration of Staphylococcal enterotoxin A on Morris water maze learning, corticosterone and hippocampal IL-1beta and TNFalpha. AB - Staphylococcal enterotoxin A (SEA) is a bacterial superantigen that induces pronounced T cell expansion and cytokine production. In addition, SEA activates the HPA axis and forebrain regions relevant to cognitive functions. Since learning-related cognitive changes have not been assessed in response to SEA, spatial learning in the Morris water maze (MWM) was determined in male C57BL/6J mice subjected to acute or repeated injections of 5MUg SEA or Saline. Injections were given 2h prior to 4-5days of hidden platform sessions. Animals were then rested for 1month and given retraining without further injections. In addition, splenic IL-1beta, IL-2 and TNFalpha, plasma corticosterone, and hippocampal IL 1beta and TNFalpha were measured after the regimen of treatment used in the behavioral experiments. The results showed no learning impairment following acute or repeated SEA challenge. Moreover, when retested 1month later, and without further injections, the SEA group showed more rapid relearning of the MWM. This suggested that coincidental superantigenic T cell activation and training served to promote long-term improvement in recovery of learning. Furthermore, repeated SEA challenge continued to drive increases in plasma corticosterone, but with a compensatory reduction in hippocampal IL-1beta. However, while hippocampal TNFalpha was reduced after acute and repeated SEA treatment, this was not statistically significant. In view of the importance of modest glucocorticoid elevations and hippocampal IL-1beta in promoting contextual learning, the data point to the hypothesis that SEA promotes long-term plasticity by restraining disruptive increases in hippocampal IL-1beta, and possibly TNFalpha, during learning. PMID- 20946952 TI - Beta-arrestins as regulators of signal termination and transduction: how do they determine what to scaffold? AB - Over the last decade beta-arrestins have emerged as pleiotropic scaffold proteins, capable of mediating numerous diverse responses to multiple agonists. Most well characterized are the G-protein-coupled receptor (GPCR) stimulated beta arrestin signals, which are sometimes synergistic with, and sometimes independent of, heterotrimeric G-protein signals. beta-arrestin signaling involves the recruitment of downstream signaling moieties to beta-arrestins; in many cases specific sites of interaction between beta-arrestins and the downstream target have been identified. As more information unfolds about the nature of beta arrestin scaffolding interactions, it is evident that these proteins are capable of adopting multiple conformations which in turn reveal a specific set of interacting domains. Recruitment of beta-arrestin to a specific GPCR can promote formation of a specific subset of available beta-arrestin scaffolds, allowing for a higher level of specificity to given agonists. This review discusses recent advances in beta-arrestin signaling, discussing the molecular details of a subset of known beta-arrestin scaffolds and the significance of specific binding interactions on the ultimate cellular response. PMID- 20946951 TI - Degree of modification of Ro60 by the lipid peroxidation by-product 4-hydroxy-2 nonenal may differentially induce Sjogren syndrome or systemic lupus erythematosus in BALB/c mice. AB - Our previous work showed that immunization of rabbits with 4-hydroxy-2-nonenal modified Ro60 (HNE-Ro60) accelerates autoimmunity. We extended this model into mice, hypothesizing that the severity of autoimmunity would be dependent on the degree of HNE modification of Ro60. Five groups of BALB/c mice (10/group) were used. Group I was immunized with Ro60. Groups II to IV were immunized with Ro60 modified with 0.4 mM (low), 2 mM (medium), and 10 mM (high) HNE, respectively. Group V controls received Freund's adjuvant. A rapid abrogation of tolerance to Ro60/La antigens occurred in mice immunized with HNE-modified Ro60, especially in the low and medium HNE-Ro60 groups. Lymphocytic infiltration and significantly high decrement in salivary flow (37%) compared to controls was observed only in the high HNE-Ro60 group, suggesting induction of a Sjogren syndrome-like condition in this group. Anti-dsDNA occurred only in mice immunized with medium HNE-Ro60. This group did not have a significant decrement in salivary flow, suggesting induction of a systemic lupus erythematosus-like manifestation in this group. Significantly high antibodies to Ro60 were found in saliva of mice in the low and medium HNE-Ro60 and the Ro60 groups, as well as anti-HNE Ro60 in the low and medium HNE-Ro60 groups. Understanding the mechanism of this differential induction may help discriminate between these two autoimmune diseases. PMID- 20946953 TI - Expression of Galpha(z) in C2C12 cells restrains myogenic differentiation. AB - The recent identification of Galpha(z) expression in C2C12 myoblasts and its demonstrated interaction with the transcription factor Eya2 inferred an unanticipated role of Galpha(z) in muscle development. In the present study, endogenous Galpha(z) mRNA and protein expressions in C2C12 cells increased upon commencement of myogenesis and peaked at around 4-6days after induction but were undetectable in adult skeletal muscle. Surprisingly, stable expression of recombinant Galpha(z) in C2C12 myoblasts strongly suppressed myotube formation upon serum deprivation, and the constitutively active mutant Galpha(z)QL exerted more pronounced effects. Transcriptional activities of reporter genes responsive to early (MyoD, MEF2 and myogenin) and late (muscle creatine kinase and myosin heavy chain) myogenic markers were reduced by transiently expressed Galpha(z)QL. Membrane attachment of Galpha(z) was apparently required for the suppressive effects because a fatty acylation-deficient Galpha(z) mutant could not inhibit myogenin expression. Introduction of siRNA against Galpha(z) enhanced myogenin driven luciferase activity and increased myosin heavy chain expression. Immunostaining of C2C12 cells over-expressing Galpha(z) showed delayed nuclear expression of myogenin and severe myotube deformation. Galpha(z) expression was accompanied by reduced levels of Rock2, RhoA and RhoGAP, enhanced expression of Rnd3, and a reduction of serum-responsive factor-driven reporter activity. These results support a novel role of Galpha(z) in restraining myogenic differentiation through the disruption of Rho signaling. PMID- 20946954 TI - Regulation of Protein Kinase C function by phosphorylation on conserved and non conserved sites. AB - Protein Kinase C (PKC) is a family of serine/threonine kinases whose function is influenced by phosphorylation. In particular, three conserved phosphorylation sites known as the activation-loop, the turn-motif and the hydrophobic-motif play important roles in controlling the catalytic activity, stability and intracellular localisation of the enzyme. Prevailing models of PKC phosphorylation suggest that phosphorylation of these sites occurs shortly following synthesis and that these modifications are required for the processing of newly-transcribed PKC to the mature (but still inactive) form; phosphorylation is therefore a priming event that enables catalytic activation in response to lipid second messengers. However, many studies have also demonstrated inducible phosphorylation of PKC isoforms at these sites following stimulation, highlighting that our understanding of PKC phosphorylation and its impact on enzymatic function is incomplete. Furthermore, inducible phosphorylation at these sites is often interpreted as catalytic activation, which could be misleading for some isoforms. Recent studies that include systems-wide phosphoproteomic profiling of cells has revealed a host of additional (and in many cases non conserved) phosphorylation sites on PKC family members that influence their function. Many of these may in fact be more suitable than previously described sites as surrogate markers of catalytic activation. Here we discuss the role of phosphorylation in controlling PKC function and outline our current understanding of the mechanisms that regulate these phosphorylation sites. PMID- 20946955 TI - Synergy in ERK activation by cytokine receptors and tyrosine kinase growth factor receptors. AB - Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) signal through EGF and PDGF receptors, which are important receptor tyrosine kinases (RTKs). Growth hormone (GH) and prolactin (PRL) are four helical bundle peptide hormones that signal via GHR and PRLR, members of the cytokine receptor superfamily. In this study, we examine crosstalk between signaling pathways emanating from these disparate receptor groups (RTKs and cytokine receptors). We find that GH and EGF specifically synergize for activation of ERK in murine preadipocytes. The locus of this synergy resides at the level of MEK activation, but not above this level (i.e., not at the level of EGFR, SHC, or Raf activation). Furthermore, dephosphorylation of the scaffold protein, KSR, at a critical serine residue is also synergistically promoted by GH and EGF, suggesting that GH sensitizes these cells to EGF-induced ERK activation by augmenting the actions of KSR in facilitating MEK-ERK activation. Similarly specific synergy in ERK activation is also detected in human T47D breast cancer cells by cotreatment with PRL and PDGF. This synergy also resides at the level of MEK activation. Consistent with this synergy, PRL and PDGF also synergized for c fos-dependent transactivation of a luciferase reporter gene in T47D cells, indicating that events downstream of ERK activation reflect this signaling synergy. Important conceptual and physiological implications of these findings are discussed. PMID- 20946956 TI - Temporal lobe epilepsy induces intrinsic alterations in Na channel gating in layer II medial entorhinal cortex neurons. AB - Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy involving the limbic structures of the temporal lobe. Layer II neurons of the entorhinal cortex (EC) form the major excitatory input into the hippocampus via the perforant path and consist of non-stellate and stellate neurons. These neurons are spared and hyper-excitable in TLE. The basis for the hyper-excitability is likely multifactorial and may include alterations in intrinsic properties. In a rat model of TLE, medial EC (mEC) non-stellate and stellate neurons had significantly higher action potential (AP) firing frequencies than in control. The increase remained in the presence of synaptic blockers, suggesting intrinsic mechanisms. Since sodium (Na) channels play a critical role in AP generation and conduction we sought to determine if Na channel gating parameters and expression levels were altered in TLE. Na channel currents recorded from isolated mEC TLE neurons revealed increased Na channel conductances, depolarizing shifts in inactivation parameters and larger persistent (I(NaP)) and resurgent (I(NaR)) Na currents. Immunofluorescence experiments revealed increased staining of Na(v)1.6 within the axon initial segment and Na(v)1.2 within the cell bodies of mEC TLE neurons. These studies provide support for additional intrinsic alterations within mEC layer II neurons in TLE and implicate alterations in Na channel activity and expression, in part, for establishing the profound increase in intrinsic membrane excitability of mEC layer II neurons in TLE. These intrinsic changes, together with changes in the synaptic network, could support seizure activity in TLE. PMID- 20946958 TI - Is 2+2=4? Meta-analyses of brain areas needed for numbers and calculations. AB - Most of us use numbers daily for counting, estimating quantities or formal mathematics, yet despite their importance our understanding of the brain correlates of these processes is still evolving. A neurofunctional model of mental arithmetic, proposed more than a decade ago, stimulated a substantial body of research in this area. Using quantitative meta-analyses of fMRI studies we identified brain regions concordant among studies that used number and calculation tasks. These tasks elicited activity in a set of common regions such as the inferior parietal lobule; however, the regions in which they differed were most notable, such as distinct areas of prefrontal cortices for specific arithmetic operations. Given the current knowledge, we propose an updated topographical brain atlas of mental arithmetic with improved interpretative power. PMID- 20946957 TI - The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. AB - A growing body of literature highlights the cross-talk between tumor cells and the surrounding peri-tumoral stroma as a key modulator of the processes of hepatocarcinogenesis, epithelial mesenchymal transition (EMT), tumor invasion and metastasis. The tumor microenvironment can be broadly classified into cellular and non-cellular components. The major cellular components include hepatic stellate cells, fibroblasts, immune, and endothelial cells. These cell types produce the non-cellular components of the tumor stroma, including extracellular matrix (ECM) proteins, proteolytic enzymes, growth factors and inflammatory cytokines. The non-cellular component of the tumor stroma modulates hepatocellular carcinoma (HCC) biology by effects on cancer signaling pathways in tumor cells and on tumor invasion and metastasis. Global gene expression profiling of HCC has revealed that the tumor microenvironment is an important component in the biologic and prognostic classification of HCC. There are substantial efforts underway to develop novel drugs targeting tumor-stromal interactions. In this review, we discuss the current knowledge about the role of the tumor microenvironment in pathogenesis of HCC, the role of the tumor microenvironment in the classification of HCC and efforts to develop treatments targeting the tumor microenvironment. PMID- 20946959 TI - Cognitive state and connectivity effects of the genome-wide significant psychosis variant in ZNF804A. AB - Alterations of connectivity are central to the systems-level pathophysiology of schizophrenia. One of the best-established genome-wide significant risk variants for this highly heritable disorder, the rs1344706 single nucleotide polymorphism in ZNF804A, was recently shown to modulate connectivity in healthy carriers during working memory (WM) in a pattern mirroring that which was found in overt disease. However, it was unclear whether this finding is specific to WM or if it is present regardless of cognitive state. Therefore, we examined genotype effects on connectivity in healthy carriers during rest and an emotion processing task without WM component. 111 healthy German subjects performed a battery of functional imaging tasks. Functional connectivity with the right dorsolateral prefrontal cortex during rest and an implicit emotion recognition task was determined using the seed voxel method and compared to results during WM. During rest and during the emotional task, a pattern of reduced interhemispheric prefrontal connectivity with increasing number of rs1344706 risk alleles could be seen that was close to identical to that during WM, suggesting a state independent influence of the genetic variant on interhemispheric processing, possibly through structural effects. By contrast, the abnormal prefronto hippocampal connectivity was only seen during the WM task, indicating a degree of task specificity in agreement with prior results in patients with schizophrenia. Our findings confirm a key role for disturbed functional connectivity in the genetic risk architecture of schizophrenia and identify cognitive state-dependent and independent components with regard to WM function. PMID- 20946960 TI - Cognitive versus automatic mechanisms of mood induction differentially activate left and right amygdala. AB - The amygdala plays a key role in emotional processing. The specific contribution of the amygdala during the experience of one's own emotion, however, remains controversial and requires clarification. There is a long-standing debate on hemispheric lateralization of emotional processes, yet few studies to date directly investigated differential activation patterns for the left and right amygdala. Limited evidence supports right amygdala involvement in automatic processes of emotion and left amygdala involvement in conscious and cognitively controlled emotion processing. The present study investigated differential contributions of the left and right amygdala to cognitive and automatic mechanisms of mood induction. Using functional magnetic resonance imaging (fMRI), we examined hemispheric amygdala responses during two mood induction paradigms: a purely visual method presenting face stimuli and an audiovisual method using faces and music. Amygdala responses in 30 subjects (16 females) showed differences in lateralization patterns depending on the processing mode. The left amygdala exhibited comparable activation levels for both methods. The right amygdala, in contrast, showed increased activity only for the audiovisual condition and this activity was increasing over time. The left amygdala showed augmented activity with higher intensity ratings of negative emotional valence. These results support a left-lateralized cognitive and intentional control of mood and a right-sided more automatic induction of emotion that relies less on explicit reflection processes. The modulation of the left amygdala responses by subjective experience may reflect individual differences in the cognitive effort used to induce the mood. Thus, the central role of the amygdala may not be restricted to the perception of emotion in others but also extend into processes involved in regulation of mood. PMID- 20946961 TI - Functional asymmetries in the representation of noise-vocoded speech. AB - It is generally accepted that, while speech is processed bilaterally in auditory cortical areas, complementary analyses of the speech signal are carried out across the hemispheres. However, the Asymmetric Sampling in Time (AST) model (Poeppel, 2003) suggests that there is functional asymmetry due to different time scales of temporal integration in each hemisphere. The right hemisphere preferentially processes slow modulations commensurate with the theta frequency band (~4-8 Hz), whereas the left hemisphere is more sensitive to fast temporal modulations in the gamma frequency range (~25-50 Hz). Here we examined the perception of noise-vocoded, i.e. spectrally-degraded, words. Magnetoencephalography (MEG) beamformer analyses were used to determine where and how noise-vocoded speech is represented in terms of changes in power resulting from neuronal activity. The outputs of beamformer spatial filters were used to delineate the temporal dynamics of these changes in power. Beamformer analyses localised low-frequency "delta" (1-4 Hz) and "theta" (3-6 Hz) changes in total power to the left hemisphere and high-frequency "gamma" (60-80 Hz, 80-100 Hz) changes in total power to the right hemisphere. Time-frequency analyses confirmed the frequency content and timing of changes in power in the left and right hemispheres. Together the beamformer and time-frequency analyses demonstrate a functional asymmetry in the representation of noise-vocoded words that is inconsistent with the AST model, at least in brain areas outside of primary auditory cortex. PMID- 20946962 TI - Attention to aversive emotion and specific activation of the right insula and right somatosensory cortex. AB - The evaluation of emotional stimuli is based on different levels of information processing, ranging from rather automatic processes to focused attention to the emotional relevance of stimuli. The role of specific brain areas for these processes is a matter of debate. In this event-related fMRI study, we varied the information processing mode of participants exposed to aversive and neutral pictures. Based on four different tasks, participants' attentional focus onto the emotional quality of the stimuli and the own emotional involvement was increased systematically across tasks. Regardless of task, stronger activation to threatening vs. neutral pictures was found in several regions such as the amygdala, anterior insula, anterior cingulate cortex, primary somatosensory cortex and medial prefrontal cortex. However, there was a parametric increase of activation with increasing attention to one's own emotion specifically in the right posterior insula and right primary and secondary somatosensory cortex, i.e. in areas implicated in self-awareness of a person's own body. These findings are in accordance with theories suggesting a crucial role of the perception of bodily states for emotional experiences. PMID- 20946963 TI - Lost in thoughts: neural markers of low alertness during mind wandering. AB - During concentration tasks, spontaneous attention shifts occurs towards self centered matters. Little is known about the brain oscillatory activity underlying these mental phenomena. We recorded 128-channels electroencephalographic activity from 12 subjects performing a breath-counting task. Subjects were instructed to press a button whenever, based on their introspective experience, they realized their attention had drifted away from the task. Theta (4-7 Hz) and delta (2-3.5 Hz) EEG activity increased during mind wandering whereas alpha (9-11 Hz) and beta (15-30 Hz) decreased. A passive auditory oddball protocol was presented to the subjects to test brain-evoked responses to perceptual stimuli during mind wandering. Mismatch negativity evoked at 100 ms after oddball stimuli onset decreased during mind wandering whereas the brain-evoked responses at 200 ms after stimuli onset increased. Spectral analyses and evoked related potential results suggest decreased alertness and sensory processing during mind wandering. To our knowledge, our experiment is one of the first neuro-imaging studies that relies purely on subjects' introspective judgment, and shows that such judgment may be used to contrast different brain activity patterns. PMID- 20946964 TI - Meta-analytic evidence for common and distinct neural networks associated with directly experienced pain and empathy for pain. AB - A growing body of evidence suggests that empathy for pain is underpinned by neural structures that are also involved in the direct experience of pain. In order to assess the consistency of this finding, an image-based meta-analysis of nine independent functional magnetic resonance imaging (fMRI) investigations and a coordinate-based meta-analysis of 32 studies that had investigated empathy for pain using fMRI were conducted. The results indicate that a core network consisting of bilateral anterior insular cortex and medial/anterior cingulate cortex is associated with empathy for pain. Activation in these areas overlaps with activation during directly experienced pain, and we link their involvement to representing global feeling states and the guidance of adaptive behavior for both self- and other-related experiences. Moreover, the image-based analysis demonstrates that depending on the type of experimental paradigm this core network was co-activated with distinct brain regions: While viewing pictures of body parts in painful situations recruited areas underpinning action understanding (inferior parietal/ventral premotor cortices) to a stronger extent, eliciting empathy by means of abstract visual information about the other's affective state more strongly engaged areas associated with inferring and representing mental states of self and other (precuneus, ventral medial prefrontal cortex, superior temporal cortex, and temporo-parietal junction). In addition, only the picture-based paradigms activated somatosensory areas, indicating that previous discrepancies concerning somatosensory activity during empathy for pain might have resulted from differences in experimental paradigms. We conclude that social neuroscience paradigms provide reliable and accurate insights into complex social phenomena such as empathy and that meta-analyses of previous studies are a valuable tool in this endeavor. PMID- 20946967 TI - The role and impact of quantitative discovery pathology. AB - The decision to advance an early-stage compound into formal preclinical testing depends on confidence in mechanism, efficacy and toxicity profiles. A substantial percentage of this confidence comes from histopathology interpretation, as the local tissue environment contains strong signals of both efficacy and toxicity. Accessing this tissue information is made difficult by biological variability across organs and tissues, an insufficient pool of pathology experts working in discovery, and the high subjectivity and individual isolation of microscope-based observations. This article describes how whole-slide imaging and quantitative analysis by trained pathologists are improving early-stage decision-making. PMID- 20946965 TI - Treatment with GM-CSF secreting myeloid leukemia cell vaccine prior to autologous BMT improves the survival of leukemia-challenged mice. AB - Vaccination with irradiated autologous tumor cells, engineered to secrete granulocyte macrophage-colony stimulating factor (GM-CSF) (GM tumor), can generate potent antitumor effects when combined with autologous bone marrow transplantation (BMT). That notwithstanding, the post-BMT milieu, characterized by marked cytopenia, can pose a challenge to the implementation of vaccine immunotherapies. To bypass this problem, partial post-BMT immune reconstitution has been allowed to develop prior to vaccination. However, delaying vaccination can also potentially allow the expansion of residual tumor cells. Other approaches have used reinfusion of "primed" autologous lymphocytes and multiple administrations of GM tumor cells, which required the processing of large amounts of tumor. Utilizing the MMB3.19 murine myeloid leukemia model, we tested whether a single dose of GM tumor cells, 7 days prior to syngeneic BMT, could be a curative treatment in MMB3.19-challenged recipient mice. This vaccination protocol significantly improved survival of mice by eliciting long-lasting host immune responses that survived lethal irradiation, and were even protective against post-BMT tumor rechallenge. Furthermore, we demonstrated that mature donor lymphocytes can also play a limited role in mounting the antitumor response, but our pre-BMT vaccination strategy obviated the need for either established de novo immune reconstitution or the use of multiple post-BMT immunizations. PMID- 20946966 TI - Clofarabine +/- fludarabine with once daily i.v. busulfan as pretransplant conditioning therapy for advanced myeloid leukemia and MDS. AB - Although a combination of i.v. busulfan (Bu) and fludarabine (Flu) is a safe, reduced-toxicity conditioning program for acute myelogenous leukemia/myelodysplastic syndromes (AML/MDS), recurrent leukemia posttransplantation remains a problem. To enhance the conditioning regimen's antileukemic effect, we decided to supplant Flu with clofarabine (Clo), and assayed the interactions of these nucleoside analogs alone and in combination with Bu in Bu-resistant human cell lines in vitro. We found pronounced synergy between each nucleoside and the alkylator but even more enhanced cytotoxic synergy when the nucleoside analogs were combined prior to exposing the cells to Bu. We then designed a 4-arm clinical trial in patients with myeloid leukemia undergoing allogeneic stem cell transplantation (allo-SCT). Patients were adaptively randomized as follows: Arm I-Clo:Flu 10:30 mg/m(2), Arm II-20:20 mg/m(2), Arm III-30:10 mg/m(2), and Arm IV-single-agent Clo at 40 mg/m(2). The nucleoside analog(s) were/was infused over 1 hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily area under the curve (AUC) of 6000 MUMol-min +/- 10%. Fifty-one patients have been enrolled with a minimum follow-up exceeding 100 days. There were 32 males and 19 females, with a median age of 45 years (range: 6-59). Nine patients had chronic myeloid leukemia (CML) (BC: 2, second AP: 3, and tyrosine-kinase inhibitor refractory first chronic phase [CP]: 4). Forty-two patients had AML: 14 were induction failures, 8 in first chemotherapy-refractory relapse, 7 in untreated relapse, 3 in second or subsequent relapse, 4 were in second complete remission (CR), and 3 in second CR without platelet recovery (CRp), 2 were in high-risk CR1. Finally, 1 patient was in first CRp. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and mini-methorexate (MTX), and those who had an unrelated or 1 antigen-mismatched donor received low-dose rabbit-ATG (ThymoglobulinTM). All patients engrafted. Forty-one patients had active leukemia at the time of transplant, and 35 achieved CR (85%). Twenty of the 42 AML patients and 5 of 9 CML patients are alive with a projected median overall survival (OS) of 23 months. Marrow and blood (T cell) chimerism studies at day +100 revealed that both in the lower-dose Clo groups (groups 1+2) and the higher dose Clo groups (groups 3+4), the patients had a median of 100% donor (T cell) derived DNA. There has been no secondary graft failure. In the first 100 days, 1 patient died of pneumonia, and 1 of liver GVHD. We conclude that (1) Clo +/- Flu with i.v. Bu as pretransplant conditioning is safe in high-risk myeloid leukemia patients; (2) clofarabine is sufficiently immunosuppressive to support allo-SCT in myeloid leukemia; and (3) the median OS of 23 months in this high-risk patient population is encouraging. Additional studies to evaluate the antileukemic efficacy of Clo +/- Flu with i.v. Bu as pretransplant conditioning therapy are warranted. PMID- 20946968 TI - Synergic effect of metronidazole and pyrantel pamoate on Giardia lamblia. AB - Giardia lamblia is a pathogenic protozoan presenting as the main characteristic, the trophozoite capacity to adhere in host intestinal epithelium, infecting mammals, including humans. The clinical treatment of this disease is based on metronidazole (Mz) that acts as an alternative electron acceptor, and its reduction promotes DNA impairment. In veterinary treatment, one of the best options is pyrantel pamoate (Pm), which the mode of action has not elucidated yet. Different strategies for Giardia treatment have been explored to avoid side effects to the host. In this context, the efficiency of treatment combining drugs raise as an interesting alternative for protozoan diseases. Here, we evaluated in vitro synergic effect of Mz and Pm on trophozoites and on its adherence to IEC-6 cells. The treatment with Mz or Pm was effective on trophozoites, with IC(50)/24h values of 5.3+/-0.9 MUM and 13.8+/-1.4 MUM, respectively. The treatment of trophozoites with different combinations of Mz and Pm were also evaluated, as showed by fractional inhibitory concentration index (FICI) under 0.5 in all conditions tested, corresponding to the synergic effect. This synergic activity was also observed when the combinations of 5.3 MUM Mz+0.4 MUM Pm and 13.8 MUM Pm+0.1 MUM Mz induced a remarkable reduction in % adhesion (85-90% and 52-59%, respectively) and in number of adhered parasites per 100 cells. The low cytotoxicity to the host cells of the combinations, associated to the strong synergic potential of the combination, encourage us to further investigate its effect in in vivo models. PMID- 20946969 TI - Luminescence targeting and imaging using a nanoscale generation 3 dendrimer in an in vivo colorectal metastatic rat model. AB - Surgery is currently the best approach for treating either primary or metastatic hepatic malignancies. Because only 20% of hepatic cancers are operable in patients, several types of regional therapy (RT) are emerging as alternate treatment modalities. However, RTs can have their own limitations at controlling tumor growth or may lack the ability to detect such metastases. Additional strategies can be implemented to enhance their efficacy. An animal model of hepatic metastases coupled with a gastroduodenal artery (GDA) cannulation technique may provide a site to apply such therapies. In our study, splenic injections were performed with CC531 adenocarcinoma cells, which generated metastatic hepatic tumors in WAG/RijHsd rats. Cannulation of GDA was achieved via a polyethylene catheter. Infusion of generation 3 polyamidoamine 4-amino-1,8 naphthalimide dendrimer containing 8 europium ions (Eu-G3P4A18N) via the GDA resulted in luminescence of the hepatic metastatic nodules. Imaging of the metastatic hepatic nodules was obtained with the help of a cooled charge coupled device (CCD) camera. FROM THE CLINICAL EDITOR: Hepatic malignancies represent a major therapeutic challenge, despite the available surgical and oncologic treatment modalities. In this paper, an animal model of hepatic adenocarcinoma is used in demonstrating successful targeting of spleen metastases with generation 3 polyamidoamine 4-amino-1,8-naphthalimide dendrimer containing 8 europium ions (Eu G3P4A18N) for luminescence imaging. PMID- 20946970 TI - Next-generation sequencing of the Trichinella murrelli mitochondrial genome allows comprehensive comparison of its divergence from the principal agent of human trichinellosis, Trichinella spiralis. AB - The mitochondrial genome's non-recombinant mode of inheritance and relatively rapid rate of evolution has promoted its use as a marker for studying the biogeographic history and evolutionary interrelationships among many metazoan species. A modest portion of the mitochondrial genome has been defined for 12 species and genotypes of parasites in the genus Trichinella, but its adequacy in representing the mitochondrial genome as a whole remains unclear, as the complete coding sequence has been characterized only for Trichinella spiralis. Here, we sought to comprehensively describe the extent and nature of divergence between the mitochondrial genomes of T. spiralis (which poses the most appreciable zoonotic risk owing to its capacity to establish persistent infections in domestic pigs) and Trichinella murrelli (which is the most prevalent species in North American wildlife hosts, but which poses relatively little risk to the safety of pork). Next generation sequencing methodologies and scaffold and de novo assembly strategies were employed. The entire protein-coding region was sequenced (13,917 bp), along with a portion of the highly repetitive non-coding region (1524 bp) of the mitochondrial genome of T. murrelli with a combined average read depth of 250 reads. The accuracy of base calling, estimated from coding region sequence was found to exceed 99.3%. Genome content and gene order was not found to be significantly different from that of T. spiralis. An overall inter-species sequence divergence of 9.5% was estimated. Significant variation was identified when the amount of variation between species at each gene is compared to the average amount of variation between species across the coding region. Next generation sequencing is a highly effective means to obtain previously unknown mitochondrial genome sequence. Particular to parasites, the extremely deep coverage achieved through this method allows for the detection of sequence heterogeneity between the multiple individuals that necessarily comprise such templates. PMID- 20946971 TI - Mitochondrial DNA origins of the Latvian clefting population. AB - Latvia has one of the highest prevalence of isolated cleft lip with or without cleft palate (CL/P) in Europe. To clarify the genetic origins of the Latvian cleft population and establish a method for genetic mapping, mitochondrial DNA variation was studied in a population affected with clefting. One-hundred and seven subjects and 351 samples from unrelated healthy volunteers representing four anthropologically, archaeologically and ethno-linguistically different regions of Latvia were selected. The case group showed a higher frequency of haplogroups U4 (p=0.02) and U5 (p=0.0003) than in non-U haplogroups. We hypothesize that U4 and U5 mtDNA haplotype carriers may also carry susceptibility genes for clefts. Future studies will take into consideration these definitions based on mtDNA haplotypes when analyzing genetic variations and their possible contribution to CL/P susceptibility. PMID- 20946972 TI - Impact of cellular senescence signature on ageing research. AB - Cellular senescence as the state of permanent inhibition of cell proliferation is a tumour-suppressive mechanism. However, due to the associated secretory phenotype senescence can also contribute to cancer and possibly other age-related diseases, such as obesity, diabetes, atherosclerosis and Alzheimer's disease. There are two major mechanisms of cellular senescence; replicative senescence depends on telomere erosion or dysfunction whilst stress-induced premature senescence (SIPS) is telomere-independent and also includes oncogene-induced senescence (OIS). The senescence phenotype is characterised by altered cellular morphology, increased activity for senescence-associated-beta-galactosidase (SA beta-GAL), increased formation of senescence-associated heterochromatin foci (SAHF) and promyelocytic leukemia protein nuclear bodies (PML NBs), permanent DNA damage, chromosomal instability and an inflammatory secretome. Some of these markers have been identified in cells from age-related pathologies. However, to improve our understanding of the contribution of cellular senescence to organismal ageing and age-related disease, it is imperative to define an unequivocal signature of cellular senescence that is functionally connected with normal and pathological ageing. Herein, we describe the processes leading to senescence, and the current biomarkers of cellular senescence, with particular emphasis on the causal role of DNA damage responses involved in the process. We highlight the gaps in our knowledge both of the processes leading to senescence, and the signature of cellular senescence both in vitro and in vivo. A well defined set of senescence biomarkers for ageing and age-related disease would have a strong impact on the diagnosis, staging and predicted outcomes of age related disease, providing the basis for a pharmacological intervention to postpone ageing and age-related disease. PMID- 20946973 TI - Magnetic resonance spectroscopy studies of the glutamatergic system in mood disorders: a pathway to diagnosis, novel therapeutics, and personalized medicine? PMID- 20946974 TI - Can single genes matter in a polygenic world? PMID- 20946975 TI - Insider influence on ErbB activity. AB - The receptor tyrosine kinase ErbB is activated by ligand-induced dimerization, leading to transphosphorylation of the cytoplasmic kinase domains. Bill et al. (2010) now demonstrate that transphosphorylation can be modulated from within the cell by the cytoplasmic protein cytohesin, providing new insights into ErbB dependent processes during normal development and cancer. PMID- 20946976 TI - Chromatin in multicolor. AB - Chromatin consists of DNA and a large number of associated proteins. Filion et al. (2010) provide a genome-wide analysis of the location of 53 chromatin proteins in Drosophila, revealing important principles underlying chromatin regulation and providing colorful insights into their organization. PMID- 20946977 TI - The Myc connection: ES cells and cancer. AB - Gene profiling experiments have revealed similarities between cancer and embryonic stem (ES) cells. Kim et al. (2010) dissect the gene expression signature of ES cells into three functional modules and find that the Myc module, including genes targeted by Myc-interacting proteins, accounts for most of the similarity between ES and cancer cells. PMID- 20946978 TI - Emerging role of ISG15 in antiviral immunity. AB - Cells express a plethora of interferon-stimulated genes (ISGs) in response to viral infection. Among these is ISG15, a ubiquitin-like protein (UBL) that can be covalently attached to both host and viral proteins. Here we review recent advances toward understanding the role and mechanism of ISG15 modification in antiviral defense. PMID- 20946979 TI - Biological applications of protein splicing. AB - Protein splicing is a naturally occurring process in which a protein editor, called an intein, performs a molecular disappearing act by cutting itself out of a host protein in a traceless manner. In the two decades since its discovery, protein splicing has been harnessed for the development of several protein engineering methods. Collectively, these technologies help bridge the fields of chemistry and biology, allowing hitherto impossible manipulations of protein covalent structure. These tools and their application are the subject of this Primer. PMID- 20946980 TI - Cytohesins are cytoplasmic ErbB receptor activators. AB - Signaling by ErbB receptors requires the activation of their cytoplasmic kinase domains, which is initiated by ligand binding to the receptor ectodomains. Cytoplasmic factors contributing to the activation are unknown. Here we identify members of the cytohesin protein family as such factors. Cytohesin inhibition decreased ErbB receptor autophosphorylation and signaling, whereas cytohesin overexpression stimulated receptor activation. Monitoring epidermal growth factor receptor (EGFR) conformation by anisotropy microscopy together with cell-free reconstitution of cytohesin-dependent receptor autophosphorylation indicate that cytohesins facilitate conformational rearrangements in the intracellular domains of dimerized receptors. Consistent with cytohesins playing a prominent role in ErbB receptor signaling, we found that cytohesin overexpression correlated with EGF signaling pathway activation in human lung adenocarcinomas. Chemical inhibition of cytohesins resulted in reduced proliferation of EGFR-dependent lung cancer cells in vitro and in vivo. Our results establish cytohesins as cytoplasmic conformational activators of ErbB receptors that are of pathophysiological relevance. PMID- 20946981 TI - The solution structure of the ADAR2 dsRBM-RNA complex reveals a sequence-specific readout of the minor groove. AB - Sequence-dependent recognition of dsDNA-binding proteins is well understood, yet sequence-specific recognition of dsRNA by proteins remains largely unknown, despite their importance in RNA maturation pathways. Adenosine deaminases that act on RNA (ADARs) recode genomic information by the site-selective deamination of adenosine. Here, we report the solution structure of the ADAR2 double-stranded RNA-binding motifs (dsRBMs) bound to a stem-loop pre-mRNA encoding the R/G editing site of GluR-2. The structure provides a molecular basis for how dsRBMs recognize the shape, and also more surprisingly, the sequence of the dsRNA. The unexpected direct readout of the RNA primary sequence by dsRBMs is achieved via the minor groove of the dsRNA and this recognition is critical for both editing and binding affinity at the R/G site of GluR-2. More generally, our findings suggest a solution to the sequence-specific paradox faced by many dsRBM containing proteins that are involved in post-transcriptional regulation of gene expression. PMID- 20946982 TI - Exon junction complex subunits are required to splice Drosophila MAP kinase, a large heterochromatic gene. AB - The exon junction complex (EJC) is assembled on spliced mRNAs upstream of exon exon junctions and can regulate their subsequent translation, localization, or degradation. We isolated mutations in Drosophila mago nashi (mago), which encodes a core EJC subunit, based on their unexpectedly specific effects on photoreceptor differentiation. Loss of Mago prevents epidermal growth factor receptor signaling, due to a large reduction in MAPK mRNA levels. MAPK expression also requires the EJC subunits Y14 and eIF4AIII and EJC-associated splicing factors. Mago depletion does not affect the transcription or stability of MAPK mRNA but alters its splicing pattern. MAPK expression from an exogenous promoter requires Mago only when the template includes introns. MAPK is the primary functional target of mago in eye development; in cultured cells, Mago knockdown disproportionately affects other large genes located in heterochromatin. These data support a nuclear role for EJC components in splicing a specific subset of introns. PMID- 20946983 TI - The exon junction complex controls the splicing of MAPK and other long intron containing transcripts in Drosophila. AB - Signaling pathways are controlled by a vast array of posttranslational mechanisms. By contrast, little is known regarding the mechanisms that regulate the expression of their core components. We conducted an RNAi screen in Drosophila for factors modulating RAS/MAPK signaling and identified the Exon Junction Complex (EJC) as a key element of this pathway. The EJC binds the exon exon junctions of mRNAs and thus far, has been linked exclusively to postsplicing events. Here, we report that the EJC is required for proper splicing of mapk transcripts by a mechanism that apparently controls exon definition. Moreover, whole transcriptome and RT-PCR analyses of EJC-depleted cells revealed that the splicing of long intron-containing genes, which includes mapk, is sensitive to EJC activity. These results identify a role for the EJC in the splicing of a subset of transcripts and suggest that RAS/MAPK signaling depends on the regulation of MAPK levels by the EJC. PMID- 20946984 TI - Patronin regulates the microtubule network by protecting microtubule minus ends. AB - Tubulin assembles into microtubule polymers that have distinct plus and minus ends. Most microtubule plus ends in living cells are dynamic; the transitions between growth and shrinkage are regulated by assembly-promoting and destabilizing proteins. In contrast, minus ends are generally not dynamic, suggesting their stabilization by some unknown protein. Here, we have identified Patronin (also known as ssp4) as a protein that stabilizes microtubule minus ends in Drosophila S2 cells. In the absence of Patronin, minus ends lose subunits through the actions of the Kinesin-13 microtubule depolymerase, leading to a sparse interphase microtubule array and short, disorganized mitotic spindles. In vitro, the selective binding of purified Patronin to microtubule minus ends is sufficient to protect them against Kinesin-13-induced depolymerization. We propose that Patronin caps and stabilizes microtubule minus ends, an activity that serves a critical role in the organization of the microtubule cytoskeleton. PMID- 20946985 TI - Structural basis for actin assembly, activation of ATP hydrolysis, and delayed phosphate release. AB - Assembled actin filaments support cellular signaling, intracellular trafficking, and cytokinesis. ATP hydrolysis triggered by actin assembly provides the structural cues for filament turnover in vivo. Here, we present the cryo-electron microscopic (cryo-EM) structure of filamentous actin (F-actin) in the presence of phosphate, with the visualization of some alpha-helical backbones and large side chains. A complete atomic model based on the EM map identified intermolecular interactions mediated by bound magnesium and phosphate ions. Comparison of the F actin model with G-actin monomer crystal structures reveals a critical role for bending of the conserved proline-rich loop in triggering phosphate release following ATP hydrolysis. Crystal structures of G-actin show that mutations in this loop trap the catalytic site in two intermediate states of the ATPase cycle. The combined structural information allows us to propose a detailed molecular mechanism for the biochemical events, including actin polymerization and ATPase activation, critical for actin filament dynamics. PMID- 20946986 TI - Nuclear size is regulated by importin alpha and Ntf2 in Xenopus. AB - The size of the nucleus varies among different cell types, species, and disease states, but mechanisms of nuclear size regulation are poorly understood. We investigated nuclear scaling in the pseudotetraploid frog Xenopus laevis and its smaller diploid relative Xenopus tropicalis, which contains smaller cells and nuclei. Nuclear scaling was recapitulated in vitro using egg extracts, demonstrating that titratable cytoplasmic factors determine nuclear size to a greater extent than DNA content. Nuclear import rates correlated with nuclear size, and varying the concentrations of two transport factors, importin alpha and Ntf2, was sufficient to account for nuclear scaling between the two species. Both factors modulated lamin B3 import, with importin alpha increasing overall import rates and Ntf2 reducing import based on cargo size. Importin alpha also contributes to nuclear size changes during early X. laevis development. Thus, nuclear transport mechanisms are physiological regulators of both interspecies and developmental nuclear scaling. PMID- 20946987 TI - TGF-beta and insulin signaling regulate reproductive aging via oocyte and germline quality maintenance. AB - Reproductive cessation is perhaps the earliest aging phenotype that humans experience. Similarly, reproduction of Caenorhabditis elegans ceases in mid adulthood. Although somatic aging has been studied in both worms and humans, mechanisms regulating reproductive aging are not yet understood. Here, we show that TGF-beta Sma/Mab and Insulin/IGF-1 signaling regulate C. elegans reproductive aging by modulating multiple aspects of the reproductive process, including embryo integrity, oocyte fertilizability, chromosome segregation fidelity, DNA damage resistance, and oocyte and germline morphology. TGF-beta activity regulates reproductive span and germline/oocyte quality noncell autonomously and is temporally and transcriptionally separable from its regulation of growth. Chromosome segregation, cell cycle, and DNA damage response genes are upregulated in TGF-beta mutant oocytes, decline in aged mammalian oocytes, and are critical for oocyte quality maintenance. Our data suggest that C. elegans and humans share many aspects of reproductive aging, including the correlation between reproductive aging and declining oocyte quality and mechanisms determining oocyte quality. PMID- 20946989 TI - SnapShot: network motifs. PMID- 20946988 TI - A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. AB - c-Myc (Myc) is an important transcriptional regulator in embryonic stem (ES) cells, somatic cell reprogramming, and cancer. Here, we identify a Myc-centered regulatory network in ES cells by combining protein-protein and protein-DNA interaction studies and show that Myc interacts with the NuA4 complex, a regulator of ES cell identity. In combination with regulatory network information, we define three ES cell modules (Core, Polycomb, and Myc) and show that the modules are functionally separable, illustrating that the overall ES cell transcription program is composed of distinct units. With these modules as an analytical tool, we have reassessed the hypothesis linking an ES cell signature with cancer or cancer stem cells. We find that the Myc module, independent of the Core module, is active in various cancers and predicts cancer outcome. The apparent similarity of cancer and ES cell signatures reflects, in large part, the pervasive nature of Myc regulatory networks. PMID- 20946990 TI - A pilot randomized controlled trial of the Yoga of Awareness program in the management of fibromyalgia. AB - A mounting body of literature recommends that treatment for fibromyalgia (FM) encompass medications, exercise and improvement of coping skills. However, there is a significant gap in determining an effective counterpart to pharmacotherapy that incorporates both exercise and coping. The aim of this randomized controlled trial was to evaluate the effects of a comprehensive yoga intervention on FM symptoms and coping. A sample of 53 female FM patients were randomized to the 8 week Yoga of Awareness program (gentle poses, meditation, breathing exercises, yoga-based coping instructions, group discussions) or to wait-listed standard care. Data were analyzed by intention to treat. At post-treatment, women assigned to the yoga program showed significantly greater improvements on standardized measures of FM symptoms and functioning, including pain, fatigue, and mood, and in pain catastrophizing, acceptance, and other coping strategies. This pilot study provides promising support for the potential benefits of a yoga program for women with FM. PMID- 20946991 TI - Ruptured aneurysm of the sinus of valsalva demonstrated by 3-dimensional echocardiography. PMID- 20946992 TI - Stent thrombosis. AB - Intense investigation continues on the pathobiology of stent thrombosis (ST) because of its morbidity and mortality. Because little advance has been made in outcomes following ST, ongoing research is focused on further understanding predictive factors as well as ST frequency and timing in various patient subsets, depending upon whether a drug-eluting stent or bare-metal stent has been implanted. Although the preventive role of antiplatelet therapies remains unchallenged, new data on genomics and variability in response to antiplatelet therapy, as well as the effects of novel therapeutic agents and duration of therapy, have become available. The goal remains identification of patients at particularly increased risk of ST so that optimal prevention strategies can be developed and employed. PMID- 20946993 TI - Long-term outcomes after stenting versus coronary artery bypass grafting for unprotected left main coronary artery disease: 10-year results of bare-metal stents and 5-year results of drug-eluting stents from the ASAN-MAIN (ASAN Medical Center-Left MAIN Revascularization) Registry. AB - OBJECTIVES: This study sought to evaluate the long-term safety and effectiveness of percutaneous coronary intervention (PCI), as compared with coronary artery bypass grafting (CABG), for unprotected left main coronary artery (LMCA) disease. BACKGROUND: Data on the long-term (beyond 5-year) comparative results of treatment of unprotected LMCA disease with stent implantation or CABG are limited. METHODS: We performed a 10-year clinical follow-up of 350 patients with unprotected LMCA disease who underwent PCI with bare-metal stents (BMS) (n = 100) or CABG (n = 250) from January 1995 to April 1999, and 5-year clinical follow-up of 395 patients with unprotected LMCA disease who underwent PCI with drug-eluting stents (DES) (n = 176) or CABG (n = 219) from January 2003 to May 2004. The primary safety end points were all-cause mortality and the composite of death, Q wave myocardial infarction (MI), or stroke, and the primary efficacy end point was target vessel revascularization (TVR). RESULTS: In the 10-year follow-up cohort of BMS and concurrent CABG, the adjusted risks of death (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.44 to 1.50; p = 0.50) and the composite of death, Q-wave MI, or stroke (HR: 0.92; 95% CI: 0.55 to 1.53; p = 0.74) were similar between the 2 groups. The rate of TVR was significantly higher in the group that received BMS (HR: 10.34; 95% CI: 4.61 to 23.18; p < 0.001). In the 5-year follow-up cohort of DES and concurrent CABG, there was no significant difference in the adjusted risk of death (HR: 0.83; 95% CI: 0.34 to 2.07; p = 0.70) or the risk of the composite outcome (HR: 0.91; 95% CI: 0.45 to 1.83; p = 0.79). The rates of TVR were also higher in the DES group than the CABG group (HR: 6.22; 95% CI: 2.26 to 17.14; p < 0.001). CONCLUSIONS: For the treatment of unprotected LMCA disease, PCI with stent implantation showed similar long-term mortality and rates of death, Q-wave MI, or stroke. However, stenting, even with DES, was associated with higher rates of repeat revascularization than was CABG. PMID- 20946994 TI - Prior aspirin use and outcomes in acute coronary syndromes. AB - OBJECTIVES: The purpose of this study was to determine whether patients taking aspirin before an acute coronary syndrome (ACS) are at higher risk of recurrent events or mortality. BACKGROUND: Controversy exists whether prior aspirin use is an independent predictor of worse outcomes in patients who experience an ACS. METHODS: We evaluated 66,443 ACS patients from a merged database of previous Thrombolysis in Myocardial Infarction trials. We evaluated the differences in ACS type, total mortality, and the composite end point of death, myocardial infarction (MI), recurrent ischemia, or stroke between prior aspirin and nonprior aspirin users. We used multivariate analysis to control for differences in baseline characteristics. RESULTS: Prior aspirin users (n = 17,839) were older (63 years vs. 59 years) and had more coronary risk factors and evidence of coronary artery disease (MI, angina, prior intervention) than nonprior aspirin users (n = 48,604) (all p < 0.0001). Prior aspirin use was associated with less severe types of ACS at presentation (e.g., unstable angina > non-ST-segment elevation MI > ST-segment elevation MI) than their nonaspirin user counterparts (p < 0.0001). After multivariate analysis, there was no difference in total mortality between prior aspirin users and nonaspirin users at day 30 (odds ratio [OR]: 1.01; 95% confidence interval [CI]: 0.90 to 1.13) or by the last follow-up visit (mean 328 days) (hazard ratio: 1.03; 95% CI: 0.95 to 1.11). Prior aspirin use was modestly associated with recurrent MI (OR: 1.26; 95% CI: 1.12 to 1.43) and the composite end point (OR: 1.16; 95% CI: 1.08 to 1.24). CONCLUSIONS: Prior aspirin use was associated with more comorbidities and coronary disease and a higher risk of recurrent MI, but not mortality. As such, it should best be considered a marker of a patient population at high risk for recurrent adverse events after ACS. PMID- 20946995 TI - Optical mapping of the isolated coronary-perfused human sinus node. AB - OBJECTIVES: We sought to confirm our hypothesis that the human sinoatrial node (SAN) is functionally insulated from the surrounding atrial myocardium except for several exit pathways that electrically bridge the nodal tissue and atrial myocardium. BACKGROUND: The site of origin and pattern of excitation within the human SAN has not been directly mapped. METHODS: The SAN was optically mapped in coronary-perfused preparations from nonfailing human hearts (n = 4, age 54 +/- 15 years) using the dye Di-4-ANBDQBS and blebbistatin. The SAN 3-dimensional structure was reconstructed using histology. RESULTS: Optical recordings from the SAN had diastolic depolarization and multiple upstroke components, which corresponded to the separate excitations of the SAN and atrial layers. Excitation originated in the middle of the SAN (66 +/- 17 beats/min), and then spread slowly (1 to 18 cm/s) and anisotropically. After a 82 +/- 17 ms conduction delay within the SAN, the atrial myocardium was excited via superior, middle, and/or inferior sinoatrial conduction pathways. Atrial excitation was initiated 9.4 +/- 4.2 mm from the leading pacemaker site. The oval 14.3 +/- 1.5 mm * 6.7 +/- 1.6 mm * 1.0 +/- 0.2 mm SAN structure was functionally insulated from the atrium by connective tissue, fat, and coronary arteries, except for these pathways. CONCLUSIONS: These data demonstrated for the first time, to our knowledge, the location of the leading SAN pacemaker site, the pattern of excitation within the human SAN, and the conduction pathways into the right atrium. The existence of these pathways explains why, even during normal sinus rhythm, atrial breakthroughs could arise from a region parallel to the crista terminalis that is significantly larger (26.1 +/- 7.9 mm) than the area of the anatomically defined SAN. PMID- 20946996 TI - The tell-tale heart (now, optically mapped). PMID- 20946997 TI - Coronary risk stratification, discrimination, and reclassification improvement based on quantification of subclinical coronary atherosclerosis: the Heinz Nixdorf Recall study. AB - OBJECTIVES: The purpose of this study was to determine net reclassification improvement (NRI) and improved risk prediction based on coronary artery calcification (CAC) scoring in comparison with traditional risk factors. BACKGROUND: CAC as a sign of subclinical coronary atherosclerosis can noninvasively be detected by CT and has been suggested to predict coronary events. METHODS: In 4,129 subjects from the HNR (Heinz Nixdorf Recall) study (age 45 to 75 years, 53% female) without overt coronary artery disease at baseline, traditional risk factors and CAC scores were measured. Their risk was categorized into low, intermediate, and high according to the Framingham Risk Score (FRS) and National Cholesterol Education Panel Adult Treatment Panel (ATP) III guidelines, and the reclassification rate based on CAC results was calculated. RESULTS: After 5 years of follow-up, 93 coronary deaths and nonfatal myocardial infarctions occurred (cumulative risk 2.3%; 95% confidence interval: 1.8% to 2.8%). Reclassifying intermediate (defined as 10% to 20% and 6% to 20%) risk subjects with CAC <100 to the low-risk category and with CAC >=400 to the high-risk category yielded an NRI of 21.7% (p = 0.0002) and 30.6% (p < 0.0001) for the FRS, respectively. Integrated discrimination improvement using FRS variables and CAC was 1.52% (p < 0.0001). Adding CAC scores to the FRS and National Cholesterol Education Panel ATP III categories improved the area under the curve from 0.681 to 0.749 (p < 0.003) and from 0.653 to 0.755 (p = 0.0001), respectively. CONCLUSIONS: CAC scoring results in a high reclassification rate in the intermediate-risk cohort, demonstrating the benefit of imaging of subclinical coronary atherosclerosis. Our study supports its application, especially in carefully selected individuals with intermediate risk. PMID- 20946998 TI - Coronary calcium score improves classification of coronary heart disease risk in the elderly: the Rotterdam study. AB - OBJECTIVES: The purpose of this study was to examine the effect of coronary artery calcium (CAC) on the classification of 10-year hard coronary heart disease (CHD) risk and to empirically derive cut-off values of the calcium score for a general population of elderly patients. BACKGROUND: Although CAC scoring has been found to improve CHD risk prediction, there are limited data on its impact in clinical practice. METHODS: The study comprised 2,028 asymptomatic participants (age 69.6 +/- 6.2 years) from the Rotterdam Study. During a median follow-up of 9.2 years, 135 hard coronary events occurred. Persons were classified into low (<10%), intermediate (10% to 20%), and high (>20%) 10-year coronary risk categories based on a Framingham refitted risk model. In a second step, the model was extended by CAC, and reclassification percentages were calculated. Cutoff values of CAC for persons in the intermediate-risk category were empirically derived based on 10-year hard CHD risk. RESULTS: Reclassification by means of CAC scoring was most substantial in persons initially classified as intermediate risk. In this group, 52% of men and women were reclassified, all into more accurate risk categories. CAC values above 615 or below 50 Agatston units were found appropriate to reclassify persons into high or low risk, respectively. CONCLUSIONS: In a general population of elderly patients at intermediate CHD risk, CAC scoring is a powerful method to reclassify persons into more appropriate risk categories. Empirically derived CAC cutoff values at which persons at intermediate risk reclassified to either high or low risk were 615 and 50 Agatston units, respectively. PMID- 20946999 TI - Coronary artery calcification, an improvement in risk classification: need for reappraisal? PMID- 20947000 TI - Doxycycline attenuates protein aggregation in cardiomyocytes and improves survival of a mouse model of cardiac proteinopathy. AB - OBJECTIVES: The goal of this pre-clinical study was to assess the therapeutic efficacy of doxycycline (Doxy) for desmin-related cardiomyopathy (DRC) and to elucidate the potential mechanisms involved. BACKGROUND: DRC, exemplifying cardiac proteinopathy, is characterized by intrasarcoplasmic protein aggregation and cardiac insufficiency. No effective treatment for DRC is available presently. Doxy was shown to attenuate aberrant intranuclear aggregation and toxicity of misfolded proteins in noncardiac cells and animal models of other proteinopathies. METHODS: Mice and cultured neonatal rat cardiomyocytes with transgenic (TG) expression of a human DRC-linked missense mutation R120G of alphaB-crystallin (CryAB(R120G)) were used for testing the effect of Doxy. Doxy was administered via drinking water (6 mg/ml) initiated at 8 or 16 weeks of age. RESULTS: Doxy treatment initiated at 16 weeks of age significantly delayed the premature death of CryAB(R120G) TG mice, with a median lifespan of 30.4 weeks (placebo group, 25 weeks; p < 0.01). In another cohort of CryAB(R120G) TG mice, Doxy treatment initiated at 8 weeks of age significantly attenuated cardiac hypertrophy in 1 month. Further investigation revealed that Doxy significantly reduced the abundance of CryAB-positive microscopic aggregates, detergent resistant CryAB oligomers, and total ubiquitinated proteins in CryAB(R120G) TG hearts. In cell culture, Doxy treatment dose-dependently suppressed the formation of both microscopic protein aggregates and detergent-resistant soluble CryAB(R120G) oligomers and reversed the up-regulation of p62 protein induced by adenovirus-mediated CryAB(R120G) expression. CONCLUSIONS: Doxy suppresses CryAB(R120G)-induced aberrant protein aggregation in cardiomyocytes and prolongs CryAB(R120G)-based DRC mouse survival. PMID- 20947001 TI - Protein quality control in heart disease: using established drugs to target novel mechanisms. PMID- 20947002 TI - Hope and hype. PMID- 20947003 TI - Sleep-disordered breathing, hypertension, and obesity in retired National Football League players. PMID- 20947004 TI - Electrocardiographic criteria in Takotsubo cardiomyopathy and race differences: Asians versus Caucasians. PMID- 20947006 TI - Opening up the group II chaperonins. AB - A new study in this issue of Structure (Huo et al., 2010) reports the crystal structure of a group II chaperonin in the open state, providing unprecedented levels of detail for the domain movements that result from ATP hydrolysis and a clearer picture of the protein folding mechanism mediated by chaperonins. PMID- 20947007 TI - The talin FERM domain is not so FERM. AB - The structure of the head domain of talin, an intracellular activator of integrin membrane adhesion receptors, has been solved by Elliott et al. (2010). A FERM domain can be identified in the head from sequence comparisons but, rather than having a compact structure of three subdomains, it has linear arrangement of four subdomains. PMID- 20947008 TI - DEEP Insights through the DEP Domain. AB - In this issue, Yu et al. (2010) provide a crystal structure for the bipartite interface between the MU2 subunit of the adaptor protein AP-2 complex and Dishevelled, a key component for Wnt signaling. PMID- 20947009 TI - Dynamics of nuclear receptors. AB - The dynamic properties of VDR LBD and full-length VDR/RXRalpha heterodimer in the presence and absence of ligands were investigated by hydrogen/deuterium exchange mass spectrometry (Zhang et al., 2010a). The results beautifully complement X-ray crystal structure data. PMID- 20947010 TI - Repeat recognition. AB - CUG-binding protein 1 (CUGBP1) is a ubiquitous RNA-binding protein implicated in altered RNA metabolism linked to myotonic dystrophy type 1. Crystal structures of the RRM domains in complex with cognate RNAs (Teplova et al., 2010) reveal molecular details for the selectivity of CUGBP1 toward GU-rich mRNA elements. PMID- 20947011 TI - The NPC-transporter, a ghost in the machine. AB - Yeast FG nucleoporins are intrinsically disordered proteins that contain cohesive molten globular regions and repulsive extended-coil regions. When placed along the central axis of the NPC, FG nups may self-assemble to create a novel transport channel that provides a series of docking sites for karyopherin-cargo complexes (Yamada et al., 2010). PMID- 20947012 TI - Transient protein-protein interactions: structural, functional, and network properties. AB - Transient interactions, which involve protein interactions that are formed and broken easily, are important in many aspects of cellular function. Here we describe structural and functional properties of transient interactions between globular domains and between globular domains, short peptides, and disordered regions. The importance of posttranslational modifications in transient interactions is also considered. We review techniques used in the detection of the different types of transient protein-protein interactions. We also look at the role of transient interactions within protein-protein interaction networks and consider their contribution to different aspects of these networks. PMID- 20947013 TI - Biology of amyloid: structure, function, and regulation. AB - Amyloids are highly ordered cross-beta sheet protein aggregates associated with many diseases including Alzheimer's disease, but also with biological functions such as hormone storage. The cross-beta sheet entity comprising an indefinitely repeating intermolecular beta sheet motif is unique among protein folds. It grows by recruitment of the corresponding amyloid protein, while its repetitiveness can translate what would be a nonspecific activity as monomer into a potent one through cooperativity. Furthermore, the one-dimensional crystal-like repeat in the amyloid provides a structural framework for polymorphisms. This review summarizes the recent high-resolution structural studies of amyloid fibrils in light of their biological activities. We discuss how the unique properties of amyloids gives rise to many activities and further speculate about currently undocumented biological roles for the amyloid entity. In particular, we propose that amyloids could have existed in a prebiotic world, and may have been the first functional protein fold in living cells. PMID- 20947014 TI - Workshop on molecular animation. AB - From February 25 to 26, 2010, in San Francisco, the Resource for Biocomputing, Visualization, and Informatics (RBVI) and the National Center for Macromolecular Imaging (NCMI) hosted a molecular animation workshop for 21 structural biologists, molecular animators, and creators of molecular visualization software. Molecular animation aims to visualize scientific understanding of biomolecular processes and structures. The primary goal of the workshop was to identify the necessary tools for producing high-quality molecular animations, understanding complex molecular and cellular structures, creating publication supplementary materials and conference presentations, and teaching science to students and the public. Another use of molecular animation emerged in the workshop: helping to focus scientific inquiry about the motions of molecules and enhancing informal communication within and between laboratories. PMID- 20947015 TI - The protein circular dichroism data bank, a Web-based site for access to circular dichroism spectroscopic data. AB - The Protein Circular Dichroism Data Bank (PCDDB) is a newly released resource for structural biology. It is a web-accessible (http://pcddb.cryst.bbk.ac.uk) data bank for circular dichroism (CD) and synchrotron radiation circular dichroism (SRCD) spectra and their associated experimental and secondary metadata, with links to protein sequence and structure data banks. It is designed to provide a public repository for CD spectroscopic data on macromolecules, to parallel the Protein Data Bank (PDB) for crystallographic, electron microscopic, and nuclear magnetic resonance spectroscopic data. Similarly to the PDB, it includes validation checking procedures to ensure good practice and the integrity of the deposited data. This paper reports on the first public release of the PCDDB, which provides access to spectral data that comprise standard reference datasets. PMID- 20947016 TI - Crystal structure of group II chaperonin in the open state. AB - Thermosomes are group II chaperonins responsible for protein refolding in an ATP dependent manner. Little is known regarding the conformational changes of thermosomes during their functional cycle due to a lack of high-resolution structure in the open state. Here, we report the first complete crystal structure of thermosome (rATcpnbeta) in the open state from Acidianus tengchongensis. There is a ~30 degrees rotation of the apical and lid domains compared with the previous closed structure. Besides, the structure reveals a conspicuous hydrophobic patch in the lid domain, and residues locating in this patch are conserved across species. Both the closed and open forms of rATcpnbeta were also reconstructed by electron microscopy (EM). Structural fitting revealed the detailed conformational change from the open to the closed state. Structural comparison as well as protease K digestion indicated only ATP binding without hydrolysis does not induce chamber closure of thermosome. PMID- 20947017 TI - The structure of the talin/integrin complex at a lipid bilayer: an NMR and MD simulation study. AB - Integrins are cell surface receptors crucial for cell migration and adhesion. They are activated by interactions of the talin head domain with the membrane surface and the integrin beta cytoplasmic tail. Here, we use coarse-grained molecular dynamic simulations and nuclear magnetic resonance spectroscopy to elucidate the membrane-binding surfaces of the talin head (F2-F3) domain. In particular, we show that mutations in the four basic residues (K258E, K274E, R276E, and K280E) in the F2 binding surface reduce the affinity of the F2-F3 for the membrane and modify its orientation relative to the bilayer. Our results highlight the key role of anionic lipids in talin/membrane interactions. Simulation of the F2-F3 in complex with the alpha/beta transmembrane dimer reveals information for its orientation relative to the membrane. Our studies suggest that the perturbed orientation of talin relative to the membrane in the F2 mutant would be expected to in turn perturb talin/integrin interactions. PMID- 20947018 TI - The Structure of the talin head reveals a novel extended conformation of the FERM domain. AB - FERM domains are found in a diverse superfamily of signaling and adaptor proteins at membrane interfaces. They typically consist of three separately folded domains (F1, F2, F3) in a compact cloverleaf structure. The crystal structure of the N terminal head of the integrin-associated cytoskeletal protein talin reported here reveals a novel FERM domain with a linear domain arrangement, plus an additional domain F0 packed against F1. While F3 binds beta-integrin tails, basic residues in F1 and F2 are required for membrane association and for integrin activation. We show that these same residues are also required for cell spreading and focal adhesion assembly in cells. We suggest that the extended conformation of the talin head allows simultaneous binding to integrins via F3 and to PtdIns(4,5)P2 enriched microdomains via basic residues distributed along one surface of the talin head, and that these multiple interactions are required to stabilize integrins in the activated state. PMID- 20947019 TI - Cryo-EM analysis reveals new insights into the mechanism of action of pyruvate carboxylase. AB - Pyruvate carboxylase (PC) is a conserved multifunctional enzyme linked to important metabolic diseases. PC homotetramer is arranged in two layers with two opposing monomers per layer. Cryo-EM explores the conformational variability of PC in the presence of different substrates. The results demonstrate that the biotin-carboxyl carrier protein (BCCP) domain localizes near the biotin carboxylase (BC) domain of its own monomer and travels to the carboxyltransferase (CT) domain of the opposite monomer. All density maps show noticeable conformational differences between layers, mainly for the BCCP and BC domains. This asymmetry may be indicative of a coordination mechanism where monomers from different layers catalyze the BC and CT reactions consecutively. A conformational change of the PC tetramerization (PT) domain suggests a new functional role in communication. A long-range communication pathway between subunits in different layers, via interacting PT-PT and BC-BC domains, may be responsible for the cooperativity of PC from Staphylococcus aureus. PMID- 20947020 TI - Structural analysis of the interaction between Dishevelled2 and clathrin AP-2 adaptor, a critical step in noncanonical Wnt signaling. AB - Wnt association with its receptor, Frizzled (Fz), and recruitment by the latter of an adaptor, Dishevelled (Dvl), initiates signaling through at least two distinct pathways ("canonical" and "noncanonical"). Endocytosis and compartmentalization help determine the signaling outcome. Our previous work has shown that Dvl2 links at least one Frizzled family member (Fz4) to clathrin mediated endocytosis by interacting with the MU2 subunit of the AP-2 clathrin adaptor, through both a classical endocytic tyrosine motif and a so-called "DEP domain." We report here the crystal structure of a chimeric protein that mimics the Dvl2-MU2 complex. The DEP domain binds at one end of the elongated, C terminal domain of MU2. This domain:domain interface shows that parts of the MU2 surface distinct from the tyrosine-motif site can help recruit specific receptors or adaptors into a clathrin coated pit. Mutation of residues at the DEP-MU2 contact or in the tyrosine motif reduce affinity of Dvl2 for MU2 and block efficient internalization of Fz4 in response to ligation by Wnt5a. The crystal structure has thus allowed us to identify the specific interaction that leads to Frizzled uptake and to downstream, noncanonical signaling events. PMID- 20947021 TI - Hydrogen/deuterium exchange reveals distinct agonist/partial agonist receptor dynamics within vitamin D receptor/retinoid X receptor heterodimer. AB - Regulation of nuclear receptor (NR) activity is driven by alterations in the conformational dynamics of the receptor upon ligand binding. Previously, we demonstrated that hydrogen/deuterium exchange (HDX) can be applied to determine novel mechanism of action of PPARgamma ligands and in predicting tissue specificity of selective estrogen receptor modulators. Here, we applied HDX to probe the conformational dynamics of the ligand binding domain (LBD) of the vitamin D receptor (VDR) upon binding its natural ligand 1alpha,25 dihydroxyvitamin D3 (1,25D3), and two analogs, alfacalcidol and ED-71. Comparison of HDX profiles from ligands in complex with the LBD with full-length receptor bound to its cognate receptor retinoid X receptor (RXR) revealed unique receptor dynamics that could not be inferred from static crystal structures. These results demonstrate that ligands modulate the dynamics of the heterodimer interface as well as provide insight into the role of AF-2 dynamics in the action of VDR partial agonists. PMID- 20947022 TI - Structural basis for ligand recognition and activation of RAGE. AB - The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor involved in inflammatory processes and is associated with diabetic complications, tumor outgrowth, and neurodegenerative disorders. RAGE induces cellular signaling events upon binding of a variety of ligands, such as glycated proteins, amyloid-beta, HMGB1, and S100 proteins. The X-ray crystal structure of the VC1 ligand-binding region of the human RAGE ectodomain was determined at 1.85 A resolution. The VC1 ligand-binding surface was mapped onto the structure from titrations with S100B monitored by heteronuclear NMR spectroscopy. These NMR chemical shift perturbations were used as input for restrained docking calculations to generate a model for the VC1-S100B complex. Together, the arrangement of VC1 molecules in the crystal and complementary biochemical studies suggest a role for self-association in RAGE function. Our results enhance understanding of the functional outcomes of S100 protein binding to RAGE and provide insight into mechanistic models for how the receptor is activated. PMID- 20947023 TI - Structural insight into serine protease Rv3671c that Protects M. tuberculosis from oxidative and acidic stress. AB - Rv3671c, a putative serine protease, is crucial for persistence of Mycobacterium tuberculosis in the hostile environment of the phagosome. We show that Rv3671c is required for M. tuberculosis resistance to oxidative stress in addition to its role in protection from acidification. Structural and biochemical analyses demonstrate that the periplasmic domain of Rv3671c is a functional serine protease of the chymotrypsin family and, remarkably, that its activity increases on oxidation. High-resolution crystal structures of this protease in an active strained state and in an inactive relaxed state reveal that a solvent-exposed disulfide bond controls the protease activity by constraining two distant regions of Rv3671c and stabilizing it in the catalytically active conformation. In vitro biochemical studies confirm that activation of the protease in an oxidative environment is dependent on this reversible disulfide bond. These results suggest that the disulfide bond modulates activity of Rv3671c depending on the oxidative environment in vivo. PMID- 20947025 TI - Solution NMR investigation of the CD95/FADD homotypic death domain complex suggests lack of engagement of the CD95 C terminus. AB - We have addressed complex formation between the death domain (DD) of the death receptor CD95 (Fas/APO-1) with the DD of immediate adaptor protein FADD using nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and size exclusion chromatography with in-line light scattering. We find complexation to be independent of the C-terminal 12 residues of CD95 and insensitive to mutation of residues that engage in the high-order clustering of CD95-DD molecules in a recently reported crystal structure obtained at pH 4. Differential NMR linewidths indicate that the C-terminal region of the CD95 chains remains in a disordered state and (13)C-methyl TROSY data are consistent with a lack of high degree of symmetry for the complex. The overall molecular mass of the complex is inconsistent with that in the crystal structure, and the complex dissociates at pH 4. We discuss these findings using sequence analysis of CD95 orthologs and the effect of FADD mutations on the interaction with CD95. PMID- 20947024 TI - Structural insights into RNA recognition by the alternate-splicing regulator CUG binding protein 1. AB - CUG-binding protein 1 (CUGBP1) regulates multiple aspects of nuclear and cytoplasmic mRNA processing, with implications for onset of myotonic dystrophy. CUGBP1 harbors three RRM domains and preferentially targets UGU-rich mRNA elements. We describe crystal structures of CUGBP1 RRM1 and tandem RRM1/2 domains bound to RNAs containing tandem UGU(U/G) elements. Both RRM1 in RRM1-RNA and RRM2 in RRM1/2-RNA complexes use similar principles to target UGU(U/G) elements, with recognition mediated by face-to-edge stacking and water-mediated hydrogen-bonding networks. The UG step adopts a left-handed Z-RNA conformation, with the syn guanine recognized through Hoogsteen edge-protein backbone hydrogen-bonding interactions. NMR studies on the RRM1/2-RNA complex establish that both RRM domains target tandem UGUU motifs in solution, whereas filter-binding assays identify a preference for recognition of GU over AU or GC steps. We discuss the implications of CUGBP1-mediated targeting and sequestration of UGU(U/G) elements on pre-mRNA alternative-splicing regulation, translational regulation, and mRNA decay. PMID- 20947026 TI - Neurosurgery Clinics of North America. Minimally invasive intracranial surgery. Preface. PMID- 20947027 TI - The concept of minimally invasive neurosurgery. AB - Applying the concept of keyhole techniques to neurosurgery has divided the neurosurgical community. This should never have happened because keyhole refers to a philosophy not a size. This philosophy stems from a desire to minimize collateral damage without compromising the intended goal of surgery. The revolution received its impetus from technological advances in pre- and intraoperative navigation, use of surgical-friendly anesthetic agents, lower profile instruments, the introduction of hemostatic agents, and better visualization. If a smaller craniotomy compromises the goal of surgery, then the approach should be re-evaluated and modified to achieve minimal collateral damage and maximal efficacy. PMID- 20947028 TI - Application of technology for minimally invasive neurosurgery. AB - Minimally invasive neurosurgery has developed from technological innovations, including endoscopy, instrumentation, neuroimaging, stereotaxy, and others. This article highlights current technologies for minimally invasive cranial neurosurgery. PMID- 20947029 TI - Transcranial minimally invasive neurosurgery for tumors. AB - This article considers common minimally invasive craniotomy approaches and the role of neuroendoscopy in the removal of extra-axial and intra-axial brain tumors, excluding those of the ventricle. The use of a keyhole craniotomy combined with a carefully selected trajectory can help avoid the disadvantages associated with a standard craniotomy. However, the decision to use endoscopy must be individualized based on the patient and tumor. Endoscopy can also be used as a surgical adjunct to improve tumor resection and to help protect neurovascular structures. Complications associated with minimally invasive tumor neurosurgery have been similar to those associated with conventional neurosurgical approaches, and available outcomes are promising. PMID- 20947030 TI - Minimally invasive surgery (endonasal) for anterior fossa and sellar tumors. AB - The primary goal of any surgical approach is to adequately visualize and treat the pathologic condition with minimal disruption to adjacent normal anatomy. The work of several researchers has revealed the promise of minimally invasive endonasal neurosurgery and paved the way for broader applications of the technology. This article discusses the current state of minimally invasive endonasal techniques to address the pathologic conditions of the anterior cranial fossa and parasellar region. PMID- 20947031 TI - Expanded endonasal approaches to middle cranial fossa and posterior fossa tumors. AB - Skull base lesions that involve the middle and posterior cerebral fossae have been historically managed through extensive transcranial approaches. The development of endoscopic endonasal techniques during the past decade has made possible a vast array of alternative routes to the ventral skull base, providing the ability to expose lesions in difficult-to-access regions of the cranial base in a less invasive manner. In this review, the authors detail the endoscopic surgical anatomy and the operative nuances of the expanded endoscopic endonasal approaches to tumors of the middle and posterior cranial fossae. These techniques offer excellent exposure of the targeted regions yielding optimal resections, while avoiding the morbidity associated with transcranial surgical approaches. PMID- 20947032 TI - Reconstruction of dural defects of the endonasal skull base. AB - Endonasal, endoscopic approaches to the cranial base have undergone significant technique refinement over the past decade. Repair of the resultant defects remains perhaps the most important concern with these approaches; however, recent advances suggest that with careful attention to the closure, these procedures can be done with acceptable rates of morbidity. In this review, the authors discuss known techniques for the repair of endonasal defects, and provide some insight based on their experience. PMID- 20947033 TI - Making the transition from microsurgery to endoscopic trans-sphenoidal pituitary neurosurgery. AB - This article reviews the published experience of others and introduces the authors' insights into the development of an endoscopic pituitary program. While initially challenging, this transition to endoscopic trans-sphenoidal pituitary surgery can yield rewards in the form of superior visualization and potentially more complete tumor resections. With increasing cumulative experience with the endoscopic transsphenoidal technique for pituitary surgery, the improved visualization and less steep learning curve will facilitate more widespread acceptance of endoscopic pituitary surgery as a valid alternative to the trans septal trans-sphenoidal microscopic approach to pituitary tumors. If not a complete alternative, endoscopic-assisted pituitary surgery will also become more widespread, as endoscopy can easily supplement standard microscopic approaches to pituitary tumors. As transnasal endoscopic approaches to the skull base are increasingly refined in technology and skill, additional applications of this technology may permit skull base approaches through the planum sphenoidale and tuberculum sellae for the removal of giant suprasellar macroadenomas that may otherwise require an open craniotomy for surgical management. The collaboration between otolaryngologists and neurosurgeons is important for further developing successful endoscopic trans-sphenoidal pituitary surgery and improving care for patients. Objective evidence is needed to validate whether the improved visualization results in superior patient outcomes and reduced clinical complications, and if this technique can be reasonably taught in a controlled, supervised setting in residency training programs. Additional outcomes data are needed to evaluate long-term outcomes and define the boundaries of endoscopic trans-sphenoidal pituitary surgery. PMID- 20947034 TI - Minimally invasive neurosurgery for cerebrospinal fluid disorders. AB - This article focuses on minimally invasive approaches used to address disorders of cerebrospinal fluid (CSF) circulation. The author covers the primary CSF disorders that are amenable to minimally invasive treatment, including aqueductal stenosis, fourth ventricular outlet obstruction (including Chiari malformation), isolated lateral ventricle, isolated fourth ventricle, multiloculated hydrocephalus, arachnoid cysts, and tumors that block CSF flow. General approaches to evaluating disorders of CSF circulation, including detailed imaging studies, are discussed. Approaches to minimally invasive management of such disorders are described in general, and for each specific entity. For each procedure, indications, surgical technique, and known outcomes are detailed. Specific complications as well as strategies for their avoidance and management are addressed. Lastly, future directions and the need for structured outcome studies are discussed. PMID- 20947035 TI - Minimally invasive neurosurgery for vascular lesions. AB - Intracranial vascular lesions are known to affect 2% to 4% of the population, predisposing those affected to a lifetime risk of hemorrhagic stroke, ischemia, focal neurologic deficits, or epileptic seizures. These lesions constitute a heterogeneous group, with different lesion types characterized by distinct biologic mechanisms of pathogenesis and progression. In this article, the minimally invasive management of intracranial aneurysms, arteriovenous malformations including arteriovenous fistulas, and cavernous malformations are discussed. PMID- 20947036 TI - Minimally invasive surgery for movement disorders. AB - Movement disorders surgery, particularly deep brain stimulation (DBS), is already a minimally invasive procedure. However, new innovations in the delivery devices for DBS electrodes, new methods for target localization, and alternatives to implanted hardware are all strategies that can make movement disorders surgery less invasive. Frameless DBS techniques can increase patient comfort and shorten operative time. Interventional magnetic resonance imaging can further reduce operative time, and allows DBS placement to be done with a patient asleep and usually with a single brain penetration. Finally, gene transfer eliminates the need for implanted hardware or batteries and simplifies postoperative care. PMID- 20947037 TI - Complication avoidance in minimally invasive neurosurgery. AB - Although minimally invasive neurosurgery (MIN) holds the potential for reducing the approach-related impact on normal brain, bone, and soft tissues, which must be manipulated in more conventional transcranial microneurosurgery, the techniques necessary to perform minimally invasive, yet maximally effective neurosurgery place significant demands on the surgeon because in many ways the more limited exposure creates a number of unique ways these operations can go wrong. Safe and effective MIN requires the conscious institution of specific alterations to the surgeon's usual operative case flow, which are designed to make specific well-known mistakes impossible or at least very unlikely. Thus, it is important for the aspiring MIN surgeons to learn from the mistakes of their predecessors and to institute patterns of behavior that prevent a repetition of these mistakes. This article provides practical information regarding known pitfalls in intraventricular and transcranial neuroendoscopic surgeries and practical methods to reduce the incidence of these complications to the lowest rate possible. PMID- 20947041 TI - Ex vivo evaluation of coronary atherosclerotic plaques: characterization with dual-source CT in comparison with histopathology. AB - BACKGROUND: Identification and differentiation of coronary atherosclerotic plaques may improve risk stratification for incident coronary events. OBJECTIVE: We investigated the ability of dual-source computed tomography (CT) to depict and characterize atherosclerotic coronary plaques. METHODS: Contrast-enhanced CT was performed in 25 human heart specimens with a total of 322 histologically determined plaques. Coronary plaques were classified on CT as (1) noncalcified, mixed, or calcified and (2) by CT attenuation values. Atherosclerotic plaques were histopathologically characterized according to the Stary classification. RESULTS: CT detected 79% (245/322) of all plaques. Lesions missed by CT were generally early lesions, type I (n = 31), type II (n = 38), or type III (n = 8), according to Stary. CT detected 29% of early (Stary I-III) and 100% of advanced (Stary IV-VIII) plaques. Plaque classification as noncalcified was sensitive (100%) and specific (72%) for early, whereas classification as mixed/calcified was sensitive (92%, 89%) and specific (100%) for advanced plaques. Calcified plaques on CT were detected with high sensitivity (80%) and specificity (95%). Other subtypes were not distinguishable with CT according to the presence or absence of calcification. CT density was significantly higher for advanced (306 +/- 470 HU) than for early (42 +/- 14 HU; P < 0.01) plaques. The mean CT density value of type VII plaques (512 +/- 349 HU) was significantly higher than those of other plaques (34-101 HU; P < 0.001). CONCLUSIONS: CT reliably depicts advanced coronary plaques and allows for the differentiation between early and advanced plaques. PMID- 20947042 TI - Coronary calcium test phantom containing true CaHA microspheres for evaluation of advanced CT calcium scoring methods. AB - BACKGROUND: Test phantoms with simulated micro-calcifications of true calcium hydroxyapatite (CaHA) density were not available to validate advanced calcium scoring methods or plaque density measurements. OBJECTIVES: We evaluated a coronary calcium scoring (CCS) test phantom containing very small CaHA microspheres and validated a new scoring method for measurements of plaque densities. METHODS: The semianthropomorphic CCS phantom was constructed with CaHA microspheres (volumes, 0.05-3.1 mm(3)) with the approximate density of biologic calcifications. QRM and CCS phantoms were scored with a new calibrated and automated calcium scoring method (N-vivo; Image Analysis). The densities of the microspheres and 609 individual patient plaques were measured. RESULTS: The range of measured densities of the CaHA microspheres was approximately equivalent to that measured in the patient coronary calcifications. The smallest microspheres scored with the calibrated/automated and the Agatston methods had volumes of 0.075 mm(3) and 0.27 mm(3), respectively. The standard deviations of the mass scores of the microspheres ranged from 0.02 to 0.17 mg with regression slope of 0.962 and R(2) = 0.997. The relationship of measured density to measured mass of the patient plaques was similar to that of the microspheres, suggesting that vascular calcifications are CaHA density. CONCLUSIONS: The CaHA microspheres of the CCS test phantom were found to be representative in density and size of coronary calcifications. The measurements show that CT calcium scoring underestimates plaque density and greatly overestimates volume. The heterogeneity of calcium concentration densities measured in the patient plaques was due largely to CT scanner measurement errors. PMID- 20947043 TI - Pre-procedural planning for percutaneous atrial septal defect closure: transesophageal echocardiography compared with cardiac computed tomographic angiography. AB - BACKGROUND: The safety and efficacy of percutaneous closure of atrial septal defects (ASDs) is determined by several variables, including defect size, presence of adequate rim tissue, relationship to other cardiac structures, and associated congenital anomalies. OBJECTIVE: We sought to determine the accuracy of computed tomographic angiography (CTA) in predicting a defect's size compared with pre-procedural transesophageal echocardiography (TEE) and to the current "gold standard" balloon sizing by intracardiac echocardiography (ICE). METHODS: Thirty-five consecutive patients referred for possible percutaneous closure of suspected secundum ASD were evaluated with gated multislice CTA after initial TEE screening. Axial and sagittal image planes of the ASD from the CTA multiplanar reformation (MPR) images were used to measure the defect size and surface area. RESULTS: Of the 35 patients with secundum-type ASDs, 5 subjects had disqualifying anatomy by CTA and 2 had an unsuccessful closure, resulting in a procedural success rate of 93%. Measurement of defect area by gated MPR images provided the strongest correlate to ICE balloon size. In large ASDs, TEE was less well correlated to the maximum defect size and identification of the inferior/inferoposterior rims than CTA. CONCLUSIONS: Cardiac CTA is an accurate and useful technique for pre-procedural assessment of ASDs and may be superior to conventional TEE in large defects that have deficient inferior rims. PMID- 20947044 TI - Natural history of left ventricular mechanics in transplanted hearts: relationships with clinical variables and genetic expression profiles of allograft rejection. AB - OBJECTIVES: The aim of this study was to explore the temporal evolution of left ventricular (LV) mechanics in relation to clinical variables and genetic expression profiles implicated in cardiac allograft function. BACKGROUND: Considerable uncertainty exists regarding the range and determinants of variability in LV systolic performance in transplanted hearts (TXH). METHODS: Fifty-one patients (mean age 53 +/- 12 years; 37 men) underwent serial assessment of echocardiograms, cardiac catheterization, gene expression profiles, and endomyocardial biopsy data within 2 weeks and at 3, 6, 12, and 24 months after transplantation. Two-dimensional speckle-tracking data were compared between patients with TXH and 37 controls (including 12 post-coronary artery bypass patients). Post-transplantation mortality and hospitalizations were recorded with a median follow-up period of 944 days. RESULTS: Global longitudinal strain (LS) and radial strain remained attenuated in patients with TXH at all time points (p < 0.001 and p = 0.005), independent of clinical rejection episodes. Failure to improve global LS at 3 months (>= 1 SD) was associated with higher incidence of death and cardiac events (hazard ratio: 5.92; 95% confidence interval: 1.96 to 17.91; p = 0.049). Multivariate analysis revealed gene expression score as the only independent predictor of global LS (R(2) = 0.53, p = 0.005), with SEMA7A gene expression having the highest correlation with global LS (r = -0.84, p < 0.001). CONCLUSIONS: Speckle tracking-derived LV strains are helpful in estimating the burden of LV dysfunction in patients with TXH that evolves independent of biopsy-detected cellular rejection. Failure to improve global LS at 3 months after transplantation is associated with a higher incidence of death and cardiac events. Serial changes in LV mechanics correlate with peripheral blood gene expression profiles and may affect the clinical assessment of long term prognosis in patients with TXH. PMID- 20947045 TI - The impact of endurance exercise training on left ventricular torsion. AB - OBJECTIVES: We sought to examine the effect of endurance exercise training (EET) on peak systolic left ventricular torsion (LVT) and peak early diastolic untwisting rate (UTR). BACKGROUND: Left ventricular (LV) structural adaptations to EET have been well characterized. LVT, a recognized marker of LV function in numerous cardiac diseases, has recently been investigated in the setting of exercise. However, longitudinal data characterizing the impact of sustained exercise training on LVT have not been reported. METHODS: A prospective, longitudinal study design examined the impact of a 90-day period of training on LV twist mechanics in university male rowers (n = 15, mean age 18.6 +/- 0.5 years). Conventional LV structural measurements, LV apical and basal rotation, peak systolic LVT, and peak early diastolic UTR were measured by 2-dimensional and speckle tracking echocardiography before and after the EET study period. RESULTS: Participants experienced LV eccentric hypertrophy, characterized by increased LV end-diastolic volume (80.8 +/- 8.7 ml/m(2) vs. 91.3 +/- 8.0 ml/m(2), p < 0.001) and LV mass (101.3 +/- 11.4 g/m(2) vs. 115.7 +/- 12.6 g/m(2), p = 0.001). There was a significant increase in peak systolic apical rotation (8.9 +/ 4.2 degrees vs. 12.7 +/- 3.9 degrees , p = 0.002) but no change in basal rotation. This translated into a highly significant increase in peak systolic LVT after EET (14.1 +/- 5.0 degrees vs. 18.0 +/- 3.6 degrees , p = 0.002). The impact of EET on LV twist mechanics was not confined to ventricular systole, as peak early diastolic UTR (-110.6 +/- 41.8 degrees /s vs. -148.0 +/- 29.8 degrees /s, p = 0.003) and the percentage of untwisting that occurred by the end of isovolumic relaxation (31.2 +/- 12.0% vs. 39.9 +/- 14.9%, p = 0.04) increased. CONCLUSIONS: Participation in EET was associated with significant changes in LV twist mechanics characterized by increased apical rotation, LVT, and UTR. These findings suggest that LVT and UTR augmentation may be an important and previously unrecognized component of exercise-induced cardiac remodeling. PMID- 20947046 TI - Comparison of the extent and severity of myocardial perfusion defects measured by CT coronary angiography and SPECT myocardial perfusion imaging. AB - OBJECTIVES: We compared electrocardiogram-gated computed tomography (CT) myocardial perfusion imaging (MPI) based on quantification of the extent and severity of perfusion abnormalities to that measured with single-photon emission computed tomography (SPECT) MPI. BACKGROUND: Contrast-enhanced CT-MPI has been used for the identification of myocardial ischemia. METHODS: We performed CT-MPI during intravenous adenosine infusion in 30 patients with perfusion abnormalities on rest/adenosine stress SPECT-MPI acquired within 60 days (18 stress-rest CT-MPI and 12 stress CT-MPI only). The extent and severity of perfusion defects on SPECT MPI were assessed on a 5-point scale in a standard 17-segment model, and total perfusion deficit (TPD) was quantified by automated software. The extent and severity of perfusion defects on CT-MPI was visually assessed by 2 observers using the same grading scale and expressed as summed stress score and summed rest score; visually quantified TPD was given by summed stress score/(maximal score of 68) and summed rest score/68. The magnitude of perfusion abnormality on CT-MPI in regions of the myocardium was defined. RESULTS: On a per-segment basis, there was good agreement between CT-MPI and SPECT-MPI with a kappa of 0.71 (p < 0.0001) for detection of stress perfusion abnormalities. Automated TPD on SPECT-MPI was similar to visual TPD from CT-MPI (p = 0.65 stress TPD, and p = 0.12 ischemic TPD stress-rest) with excellent agreement (bias = -0.3 for stress TPD, and bias = 1.2 for ischemic TPD) on Bland-Altman analysis. Software-based quantification of the magnitude of stress perfusion deficit and ischemia on CT-MPI were similar to that for automated TPD measured by SPECT (p = 0.88 stress, and p = 0.48 ischemia), with minimal bias (bias = 0.6, and bias = 1.2). CONCLUSIONS: Stress and reversible myocardial perfusion deficit measured by CT-MPI using a visual semiquantitative approach and a visually guided software-based approach show strong similarity with SPECT-MPI, suggesting that CT-MPI-based assessment of myocardial perfusion defects may be of clinical and prognostic value. PMID- 20947047 TI - Extent of thoracic aortic atheroma burden and long-term mortality after cardiothoracic surgery: a computed tomography study. AB - OBJECTIVES: We hypothesized that the extent of aortic atheroma of the entire thoracic aorta, determined by pre-operative multidetector-row computed tomographic angiography (MDCTA), is associated with long-term mortality following nonaortic cardiothoracic surgery. BACKGROUND: In patients evaluated for cardiothoracic surgery, presence of severe aortic atheroma is associated with adverse short- and long-term post-operative outcome. However, the relationship between aortic plaque burden and mortality remains unknown. METHODS: We reviewed clinical and imaging data from all patients who underwent electrocardiographic gated contrast-enhanced MDCTA prior to coronary bypass or valvular heart surgery at our institution between 2002 and 2008. MDCTA studies were analyzed for thickness and circumferential extent of aortic atheroma in 5 segments of the thoracic aorta. A semiquantitative total plaque-burden score (TPBS) was calculated by assigning a score of 1 to 3 to plaque thickness and to circumferential plaque extent. When combined, this resulted in a score of 0 to 6 for each of the 5 segments and, hence, an overall score from 0 to 30. The primary end point was all-cause mortality during long-term follow-up. RESULTS: A total of 862 patients (71% men, 67.8 years) were included and followed over a mean period of 25 +/- 16 months. The mean TPBS was 8.6 (SD: +/-6.0). The TPBS was a statistically significant predictor of mortality (p < 0.0001) while controlling for baseline demographics, cardiovascular risk factors, and type of surgery including reoperative status. The estimated hazard ratio for TPBS was 1.08 (95% confidence interval: 1.045 to 1.12). Other independent predictors of mortality were glomerular filtration rate (p = 0.015), type of surgery (p = 0.007), and peripheral artery disease (p = 0.03). CONCLUSIONS: Extent of thoracic aortic atheroma burden is independently associated with increased long-term mortality in patients following cardiothoracic surgery. Although our data do not provide definitive evidence, they suggest a relationship to the systemic atherosclerotic disease process and, therefore, have important implications for secondary prevention in post-operative rehabilitation programs. PMID- 20947048 TI - Prognostic value of global MR myocardial perfusion imaging in women with suspected myocardial ischemia and no obstructive coronary disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study. AB - OBJECTIVES: The purpose of this study was to assess the prognostic value of global magnetic resonance (MR) myocardial perfusion imaging (MPI) in women with suspected myocardial ischemia and no obstructive (stenosis <50%) coronary artery disease (CAD). BACKGROUND: The prognostic value of global MR-MPI in women without obstructive CAD remains unknown. METHODS: Women (n = 100, mean age 57 +/- 11 years, age range 31 to 76 years), with symptoms of myocardial ischemia and with no obstructive CAD, as assessed by coronary angiography, underwent MR-MPI and standard functional assessment. During follow-up (34 +/- 16 months), time to first adverse event (death, myocardial infarction, or hospitalization for worsening anginal symptoms) was analyzed using global MPI and left ventricular ejection fraction (EF) data. RESULTS: Adverse events occurred in 23 (23%) women. Using univariable Cox proportional hazards regression modeling, variables found to be predictive of adverse events were global MR-MPI average uptake slope (p < 0.05), the ratio of MR-MPI peak signal amplitude to uptake slope (p < 0.05), and EF (p < 0.05). Two multivariable Cox models were formed, 1 using variables that were performance site dependent: ratio of MR-MPI peak amplitude to uptake slope together with EF (chi square: 13, p < 0.005); and a model using variables that were performance site independent: MR-MPI slope and EF (chi square: 12, p < 0.005). Each of the 2 multivariable models remained predictive of adverse events after adjustment for age, disease history, and Framingham risk score. For each of the Cox models, patients were categorized as high risk if they were in the upper quartile of the model and as not high risk otherwise. Kaplan-Meier analysis of time to event was performed for high risk versus not high risk for site-dependent (log rank: 15.2, p < 0.001) and site-independent (log rank: 13.0, p < 001) models. CONCLUSIONS: Among women with suspected myocardial ischemia and no obstructive CAD, MR-MPI-determined global measurements of normalized uptake slope and peak signal uptake, together with global functional assessment of EF, appear to predict prognosis. PMID- 20947049 TI - CMR predictors of mitral regurgitation in mitral valve prolapse. AB - OBJECTIVES: We sought to assess the correlation between mitral valve characteristics and severity of mitral regurgitation (MR) in subjects with mitral valve prolapse (MVP) undergoing cardiac magnetic resonance (CMR) imaging. BACKGROUND: Compared with extensive echocardiographic studies, CMR predictors of MVP-related MR are unknown. The severity of MR at the time of diagnosis has prognostic implication for patients; therefore, the identification of determinants of MR and its progression may be important for risk stratification, follow-up recommendations, and surgical decision making. METHODS: Seventy-one MVP patients (age 54 +/- 11 years, 58% males, left ventricular [LV] ejection fraction 65 +/- 5%) underwent cine CMR to assess annular dimensions, maximum systolic anterior and posterior leaflet displacement, papillary muscle (PM) distance to coaptation point and prolapsed leaflets, as well as diastolic anterior and posterior leaflet thickness and length, and LV volumes and mass. Velocity-encoded CMR was used to obtain aortic outflow and to quantify MR volume. RESULTS: Using multiple linear regression analysis including all variables, LV mass (p < 0.001), anterior leaflet length (p = 0.006), and posterior displacement (p = 0.01) were the best determinants of MR volume with a model-adjusted R(2) = 0.6. When the analysis was restricted to valvular characteristics, MR volume correlated with anterior mitral leaflet length (p < 0.001), posterior mitral leaflet displacement (p = 0.003), posterior leaflet thickness (p = 0.008), and the presence of flail (p = 0.005) with a model-adjusted R(2) = 0.5. We also demonstrated acceptable intraobserver and interobserver variability in these measurements. CONCLUSIONS: Anterior leaflet length, posterior leaflet displacement, posterior leaflet thickness, and the presence of flail are the best CMR valvular determinants of MVP-related MR. The acceptable intraobserver and interobserver variability of our measurements confirms the role of CMR as an imaging modality for assessment of MVP patients with significant MR. PMID- 20947050 TI - To MR or not to MR: is that the question? PMID- 20947051 TI - The role of echocardiography and other imaging modalities in patients with left ventricular assist devices. AB - Recent advances in the field of left ventricular device support have led to an increased use of left ventricular assist devices (LVADs) in patients with end stage heart disease. The primary imaging modality to monitor patients with LVADs has been echocardiography. The purpose of this review is to highlight the clinical role of echo and other noninvasive imaging modalities in the assessment of cardiac structure and function in patients with pulsatile and continuous flow LVADs. In addition, we discuss the role of imaging with emphasis on echo to detect LVAD dysfunction and device related complications. PMID- 20947052 TI - The year in coronary artery disease. AB - Imaging plays a central role in the diagnosis and management of coronary artery disease. Imaging is used for the detection of underlying coronary artery stenoses in patients with stable or chronic chest pain, for the assessment of myocardial scar and viability, for assessing prognosis, or for predicting complications. Echocardiography, nuclear imaging, cardiac magnetic resonance, and-more recently computed tomography are powerful tools to provide answers to these questions. New technology, new contrast agents, and newly developed imaging protocols widen the applicability and increase accuracy of these imaging modalities, and new clinical studies provide information on their diagnostic potential and their therapeutic as well as prognostic value. The relative strengths and weaknesses of the different imaging modalities influence the selection of the most appropriate imaging approach in different clinical scenarios. This article outlines some of the most important developments of the past 12 months in the field of echocardiography, nuclear imaging, cardiac magnetic resonance, and computed tomography as they pertain to coronary artery disease. PMID- 20947053 TI - Myocardial perfusion imaging in hypertrophic cardiomyopathy. PMID- 20947054 TI - Large LV aneurysm and multiple diverticula in a patient with normal coronary arteries: another form of cardiomyopathy? PMID- 20947055 TI - Correlating multimodality imaging and pathological validation in heart failure. PMID- 20947056 TI - 3D TEE and systolic anterior motion in hypertrophic cardiomyopathy. PMID- 20947058 TI - Diagnosis of patent foramen ovale. PMID- 20947059 TI - On fishing expeditions, laws of fishing, and good fishermen.... PMID- 20947060 TI - [Cochlear implant complications and failures]. AB - INTRODUCTION: Cochlear implantation is a relatively safe surgery performed on profound bilateral hearing loss patients. Its surgical indications have increased and the age of implantation has decreased over the last years. As with any other surgery, it presents complications; device failure is one of the most important, given its potential risk for the need to explant and reimplant the device. OBJECTIVE: To evaluate cochlear implant complications, determine possible causes and discuss medical and surgical management. MATERIAL AND METHODS: A retrospective study of cochlear implants was performed. A total of 246 implants over an eleven-year period were evaluated. The sample consisted of 123 implants in patients younger than 10 years old, and 123 in those older than 10 years old; there were 138 males and 108 females. The devices implanted were 129 Advance Bionics, 95 MED-El, and 22 Cochlear. Complications and device failures were analysed. RESULTS: A total of 28 complications were reported, which corresponds to 11.38% of all implants. Seven minor complications and 21 mayor complications were found. Device Failure was the most frequent complication, reported in 6.5% of all implants, and it was more frequent among children less than 10 years old. CONCLUSIONS: Cochlear implant surgery has a low complication rate. Complications are usually resolved easily, but device failure continues to be a problem. It is important to keep studying the causes of such failure to find possible solutions that can lead to lowering and resolving its appearance. PMID- 20947061 TI - Participatory ergonomics in design processes: the role of boundary objects. AB - The aim of this paper is to introduce the concept of boundary objects in order to better understand the role of objects in participatory ergonomics (PE) design processes. The research question is: What characterizes boundary objects in PE processes? Based on two case studies, we identify eight characteristics of boundary objects and their use, which make them particularly useful in PE design processes. These characteristics go beyond the object itself and extend into the context of their use. We argue that the selection of boundary objects in PE processes is of great importance, since different objects enable workers' participation and collaborative design in different ways. The framework developed may serve to provide criteria to guide practitioners and intervention researchers in the selection of objects to facilitate a PE process. The paper concludes with a list of recommendations for ergonomic practitioners that are based on the framework. PMID- 20947062 TI - Errors in landmarking and the evaluation of the accuracy of traditional and 3D anthropometry. AB - Body dimensions are based on landmarks of the body, but the magnitude of error in landmark determination is not well known. Therefore, a study was performed in which 40 subjects were marked five times in total by one highly skilled marker and a novice marker. Immediately after marking, a skilled measurer determined 34 body dimensions that were based on the mark locations. Intra- and inter-observer errors in landmarking of 35 landmarks, as well as those in 34 body dimensions were quantified. The error in landmarking was defined as the distance between two marks made on the same landmark by the same marker (intra-observer error) or by two different markers (inter-observer error). To make the first mark invisible when the second mark was made, the first mark was made using an invisible ink pen under black light. Landmarks with large intra-observer errors also had large inter-observer errors. Errors in body dimensions were smaller than landmarking errors in 23 measurements, which suggested that the magnitude of landmarking error would be underestimated from errors in body dimensions. In 15 body dimensions, measurements based on marks made by two different markers were not comparable according to the ISO 20685 criterion. Examination of body dimensions and landmarks with large inter-observer errors suggested that reducing inter observer landmarking errors was necessary to reduce inter-observer measurement errors, and that a possible solution was to explicitly define landmarks with large errors in more detail so that anthropometrists can pinpoint them on the skin. Quantitative data on the intra- and inter-observer landmarking errors in the present study may be useful as a reference when evaluating and comparing the performance of software for calculating landmark locations for 3D anthropometry. PMID- 20947063 TI - Analysis of visual acuity and motion resolvability as measures for optimal visual perception of the workspace. AB - For working tasks with high visual demand, ergonomic design of the working stations requires defining criteria for comparative evaluation and analysis of the visual perceptibility in different regions of the workspace. This paper provides kinematic models of visual acuity and motion resolvability as adopted measures of visual perceptibility of the workspace. The proposed models have been examined through two sets of experiments. The first experiment is designed to compare the models outputs with those from experiments. Time measurements of the participants' response to visual events are employed for calculation of the perceptibility measures. The overall comparison results show similar patterns and moderate statistical errors of the measured and kinematically modeled values of the parameters. In the second experiment, the proposed set of visual perceptibility measures are examined for a simulated industrial task of inserting electronic chips into slots of a working table, resembling a fine assembly line of transponders manufacturing. The results from ANOVA tests for the visual acuity and the motion resolvability justify the postures adopted by the participants using visual perceptibility measures for completing the insertion tasks. PMID- 20947064 TI - Inflammatory responses in two commonly used rat models for experimental tooth movement: comparison with ligature-induced periodontitis. AB - OBJECTIVE: To compare two often used rat models for experimental tooth movement, namely the elastic band, and the coil spring model. They were compared with a silk-ligature-induced periodontitis model. DESIGN: Thirty six, 6-weeks-old rats were used. In a split mouth design four experimental conditions were allocated by permutation: (1) insertion of an orthodontic elastic band between the maxillary first and the second molar, (2) placement of a silk ligature around the cervix of the upper second molar, (3) a 10cN NiTi coil spring for mesial movement of the three maxillary molars as one block, and (4) Control. After 1, 3, and 5 days, rats were killed and immunohistochemical staining for ED1, cathepsin K, and MMP9 was performed. RESULTS: A time-dependent increase in the inflammatory infiltration of the interdental papilla was found in the elastic band and the ligature model, but not in the spring model. The disruption of the epithelium of the interdental papilla and the transseptal fibers was less severe in the spring group than in the other two experimental groups. All three experimental groups showed a time-dependent resorption of the interdental bony septum. However, this started faster and was more severe in the elastic band and the ligature than in the spring group. The numbers of cathepsin K+ and MMP9+ cells were higher in the elastic band and the ligature group than in the spring group. CONCLUSIONS: Elastic bands yield similar periodontal effects as ligatures. The spring model is to be preferred for experimental tooth movement studies. PMID- 20947065 TI - Altered function and connectivity of the medial frontal cortex in pediatric obsessive-compulsive disorder. AB - BACKGROUND: Exaggerated concern for correct performance has been linked to hyperactivity of the medial frontal cortex (MFC) in adult obsessive-compulsive disorder (OCD), but the role of the MFC during the early course of illness remains poorly understood. We tested whether hyperactive MFC-based performance monitoring function relates to altered MFC connectivity within task control and default mode networks in pediatric patients. METHODS: Eighteen pairs of OCD and matched healthy youth underwent functional magnetic resonance imaging during performance monitoring and at rest. Task-related hyperactivations in the posterior and ventral MFC were used as seeds for connectivity analyses during task and resting state. RESULTS: In posterior MFC, patients showed greater activation of dorsal anterior cingulate cortex (dACC) than control subjects, with greater activation predicting worse performance. In ventral MFC, control subjects exhibited deactivation, whereas patients activated this region. Compared with control subjects, patients showed increased dACC-ventral MFC connectivity during task and decreased dACC-right anterior operculum and ventral MFC-posterior cingulate connectivity during rest. CONCLUSIONS: Excessive activation and increased interactions of posterior and ventral MFC during performance monitoring may combine with reduced resting state connectivity of these regions within networks for task control and default mode to reflect early markers of OCD. Alteration of reciprocal interactions between these networks could potentiate the intrusion of ventral MFC-based affectively laden, self-referential thoughts, while disrupting posterior MFC-based performance-monitoring function in young patients. PMID- 20947066 TI - Is ecstasy an "empathogen"? Effects of +/-3,4-methylenedioxymethamphetamine on prosocial feelings and identification of emotional states in others. AB - BACKGROUND: Users of +/-3,4-methylenedioxymethamphetamine (MDMA), "ecstasy," report that the drug produces unusual psychological effects, including increased empathy and prosocial feelings. These "empathogenic" effects are cited as reasons for recreational ecstasy use and also form the basis for the proposed use of MDMA in psychotherapy. However, they have yet to be characterized in controlled studies. Here, we investigate effects of MDMA on an important social cognitive capacity, the identification of emotional expression in others, and on socially relevant mood states. METHODS: Over four sessions, healthy ecstasy-using volunteers (n = 21) received MDMA (.75, 1.5 mg/kg), methamphetamine (METH) (20 mg), and placebo under double-blind, randomized conditions. They completed self report ratings of relevant affective states and undertook tasks in which they identified emotions from images of faces, pictures of eyes, and vocal cues. RESULTS: MDMA (1.5 mg/kg) significantly increased ratings of feeling "loving" and "friendly", and MDMA (.75 mg/kg) increased "loneliness". Both MDMA (1.5 mg/kg) and METH increased "playfulness"; only METH increased "sociability". MDMA (1.5 mg/kg) robustly decreased accuracy of facial fear recognition relative to placebo. CONCLUSIONS: The drug MDMA increased "empathogenic" feelings but reduced accurate identification of threat-related facial emotional signals in others, findings consistent with increased social approach behavior rather than empathy. This effect of MDMA on social cognition has implications for both recreational and therapeutic use. In recreational users, acute drug effects might alter social risk-taking while intoxicated. Socioemotional processing alterations such as those documented here might underlie possible psychotherapeutic benefits of this drug; further investigation of such mechanisms could inform treatment design to maximize active components of MDMA-assisted psychotherapy. PMID- 20947067 TI - Impaired emotional-like behavior and serotonergic function during protracted abstinence from chronic morphine. AB - BACKGROUND: Opiate abuse is a chronic relapsing disorder, and maintaining prolonged abstinence remains a major challenge. Protracted abstinence is characterized by lowered mood, and clinical studies show elevated comorbidity between addiction and depressive disorders. At present, their relationship remains unclear and has been little studied in animal models. Here we investigated emotional alterations during protracted abstinence, in mice with a history of chronic morphine exposure. METHODS: C57BL6J mice were exposed to a chronic intermittent escalating morphine regimen (20-100 mg/kg). Physical dependence (naloxone-precipitated withdrawal), despair-related behaviors (tail suspension test), and social behaviors were examined after 1 or 4 weeks of abstinence. Stress hormones and forebrain bioamine levels were analyzed at the end of morphine regimen and after 4 weeks of abstinence. Finally, we examined the effects of chronic fluoxetine during abstinence on morphine-induced behavioral deficits. RESULTS: Acute naloxone-induced withdrawal was clearly measurable after 1 week, and became undetectable after 4 weeks. In contrast, social and despair related behaviors were unchanged after 1 week, but low sociability and despair like behavior became significant after 4 weeks. Chronic morphine regimen increased both corticosterone levels and forebrain serotonin turnover, but only serotonergic activity in the dorsal raphe remained impaired after 4 weeks. Remarkably, chronic fluoxetine prevented depressive-like behavioral deficits in 4 week abstinent mice. CONCLUSIONS: During protracted abstinence, the immediate consequences of morphine exposure attenuate, whereas fluoxetine-sensitive emotional alterations strengthen with time. Our study establishes a direct link between morphine abstinence and depressive-like symptoms and strongly suggests that serotonin dysfunction represents a main mechanism contributing to mood disorders in opiate abstinence. PMID- 20947068 TI - Exploring the impact of ketamine on the experience of illusory body ownership. AB - BACKGROUND: Our sense of body ownership is profound and familiar, yet it may be misleading. In the rubber-hand illusion, synchronous tactile and visual stimulation lead to the experience that a rubber hand is actually one's own. This illusion is stronger in schizophrenia. Given the evidence that ketamine, a noncompetitive N-methyl-D-aspartate antagonist reproduces symptoms of schizophrenia, we sought to determine whether the rubber-hand illusion is augmented by ketamine. METHODS: We studied 15 healthy volunteers in a within subjects placebo-controlled study. All volunteers carried out two versions of the rubber-hand task, each under both placebo and ketamine infusions. In one task, they saw a rubber hand being stroked in synchrony with tactile stimulation of their real, hidden hand. In the other, stroking of the real and rubber hands was asynchronous. We recorded subjective changes in sense of ownership, as well as participants' ability to localize their hidden hand. RESULTS: Ketamine was associated with significant increases in subjective measures of the illusion and in hand mislocalization. Although asynchronous visuotactile stimulation attenuates the strength of the illusion during both placebo and ketamine, there remained a significant illusory effect during asynchronous visuotactile stimulation under ketamine compared with placebo. The strength of the illusion during asynchronous visuotactile stimulation correlated with other subjective effects of the drug. CONCLUSIONS: Ketamine mimics the perturbed sense of body ownership seen in schizophrenia, suggesting that it produces a comparable alteration in integration of information across sensory domains and in the subjective and behavioral consequences of such integration. PMID- 20947069 TI - A recombinant alpha-(2->3)-sialyltransferase with an extremely broad acceptor substrate specificity from Photobacterium sp. JT-ISH-224 can transfer N acetylneuraminic acid to inositols. AB - We confirmed that a recombinant alpha-(2->3)-sialyltransferase cloned from Photobacterium sp. JT-ISH-224 recognizes inositols having a structure corresponding to the C-3 and C-4 of a galactopyranoside moiety, such as epi-, 1d chiro, myo-, and muco-inositol, as acceptor substrates, and that the enzyme can transfer N-acetylneuraminic acid (Neu5Ac) from cytidine 5'-monophospho-N acetylneuraminic acid (CMP-Neu5Ac) to them. After purifying the reaction products, the structures were confirmed by use of NMR spectroscopy and mass spectrometry. From these results, it was clearly shown that the alpha-(2->3) sialyltransferase from Photobacterium sp. JT-ISH-224 recognizes acceptor substrates through the cis-diol structure corresponding to the 3- and 4-position of the galactopyranoside moiety. PMID- 20947071 TI - Cascading influences on the production of speech: evidence from articulation. AB - Recent investigations have supported the suggestion that phonological speech errors may reflect the simultaneous activation of more than one phonemic representation. This presents a challenge for speech error evidence which is based on the assumption of well-formedness, because we may continue to perceive well-formed errors, even when they are not produced. To address this issue, we present two tongue-twister experiments in which the articulation of onset consonants is quantified and compared to baseline measures from cases where there is no phonemic competition. We report three measure of articulatory variability: changes in tongue-to-palate contact using electropalatography (EPG, Experiment 1), changes in midsagittal spline of the tongue using ultrasound (Experiment 2), and acoustic changes manifested as voice-onset time (VOT). These three sources provide converging evidence that articulatory variability increases when competing onsets differ by one phonological feature, but the increase is attenuated when onsets differ by two features. This finding provides clear evidence, based solely on production, that the articulation of phonemes is influenced by cascading activation from the speech plan. PMID- 20947070 TI - Transcutaneous immunization with hydrophilic recombinant gp100 protein induces antigen-specific cellular immune response. AB - The objective of this study was to evaluate the potential of transcutaneous immunization with tumor antigen to induce cell-mediated immunity. For this purpose, hydrophilic recombinant gp100 protein (HR-gp100) was topically applied on human intact skin in vitro, and used as a vaccine in a mouse model. We demonstrate that HR-gp100 permeates into human skin, and is processed and presented by human dendritic cells. In a mouse model, an HR-gp100-based vaccine triggered antigen-specific T cell responses, as shown by proliferation assays, ELISA and intracellular staining for IFN-gamma. Transcutaneous antigen delivery may provide a safe, simple and effective method to elicit cell-mediated immunity. PMID- 20947072 TI - A comparison of endometrial and subendometrial vascularity assessed by three dimensional ultrasonography and power Doppler angiography between healthy fertile women and women with unexplained primary recurrent miscarriage. AB - We compared the characteristics of endometrial-subendometrial vascularity 7 days after ovulation of a natural cycle by transvaginal three-dimensional ultrasonography and power Doppler angiography between 88 patients with unexplained recurrent miscarriage and 46 healthy fertile women. Endometrial vascularization index, flow index, and vascularization flow index, as well as subendometrial vascularization index and vascularization flow index, were reduced significantly in the group with unexplained recurrent miscarriage. PMID- 20947073 TI - Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome. AB - OBJECTIVE: To improve the interpretation of future studies in women who are initially diagnosed with a pregnancy of unknown location (PUL), we propose a consensus statement with definitions of population, target disease, and final outcome. DESIGN: A review of literature and a series of collaborative international meetings were used to develop a consensus for definitions and final outcomes of women initially diagnosed with a PUL. RESULT(S): Global differences were noted in populations studied and in the definitions of outcomes. We propose to define initial ultrasound classification of findings into five categories: definite ectopic pregnancy (EP), probable EP, PUL, probable intrauterine pregnancy (IUP), and definite IUP. Patients with a PUL should be followed and final outcomes should be categorized as visualized EP, visualized IUP, spontaneously resolved PUL, and persisting PUL. Those with the transient condition of a persisting PUL should ultimately be classified as nonvisualized EP, treated persistent PUL, resolved persistent PUL, or histologic IUP. These specific categories can be used to characterize the natural history or location (intrauterine vs. extrauterine) of any early gestation where the initial location is unknown. CONCLUSION(S): Careful definition of populations and classification of outcomes should optimize objective interpretation of research, allow objective assessment of future reproductive prognosis, and hopefully lead to improved clinical care of women initially identified to have a PUL. PMID- 20947074 TI - Ovarian leiomyoma as a potential cause of compromised fertility. AB - OBJECTIVE: To analyze cases of ovarian leiomyomas and to discuss the proper surgical management. DESIGN: A case series and discussion. SETTING: General university hospital and healthcare center. PATIENT(S): Nine patients who were diagnosed with ovarian leiomyomas after surgery between 1993 and 2009. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): A preoperative diagnosis that was matched to the postoperative diagnosis and the type of surgery. RESULT(S): In all cases, ovarian leiomyoma was misdiagnosed preoperatively as pedunculated uterine myoma, ovarian fibroma, or even ovarian endometrioma. Seven (77.8%) of the nine patients underwent a salpingo-oophorectomy or an oophorectomy with or without hysterectomy, and only two (22.2%) patients were submitted to an ovary-preserving surgery (i.e., a cystectomy or ovarian wedge resection). CONCLUSION(S): Because of their extreme rarity, ovarian leiomyomas are seldom suspected intraoperatively or preoperatively. However, most of these tumors appear at reproductive age and have a benign nature, similar to uterine myomas. Therefore, surgeons should perform ovary-preserving management, especially in young patients. PMID- 20947075 TI - The risk of cytogenetic abnormalities in the late first trimester of pregnancies conceived through assisted reproduction. AB - OBJECTIVE: To determine if pregnancies conceived through infertility treatment are at increased risk of cytogenetic abnormalities in the late first trimester compared with spontaneously conceived pregnancies, or if there is increased risk when comparing less invasive infertility treatment (in vivo group) to in vitro fertilization (in vitro group). DESIGN: Retrospective case-controlled study. SETTING: University hospital. PATIENT(S): A total of 1,606 women who spontaneously conceived and 559 women who conceived through infertility treatment undergoing chorionic villus sampling (CVS). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cytogenetic abnormalities diagnosed by CVS. RESULT(S): No difference in cytogenetic abnormalities was found when comparing spontaneously conceived pregnancies to those conceived through infertility treatment (7.0% versus 5.4%). We also found no difference in the prevalence of cytogenetic abnormalities when comparing in vivo and in vitro fertilization subgroups (4.7% versus 5.8%). Finally, no difference was found when comparing the prevalence of different types of cytogenetic abnormalities between groups. CONCLUSION(S): Infertility treatment does not increase the risk of carrying a cytogenetically abnormal fetus in the late first trimester, nor does it increase the preponderance for any specific type of abnormality. PMID- 20947076 TI - Novel homozygous p.R454C mutation in the CYP11B1 gene leads to 11beta-hydroxylase deficiency in a Chinese patient. AB - OBJECTIVE: To show mutational analysis for 11beta-hydroxylase deficiency (11beta OHD). DESIGN: Case report. SETTING: A laboratory of endocrinology at a university hospital. PATIENT(S): One Chinese woman with 11beta-OHD referred to our clinic was observed in our study. INTERVENTION(S): Genomic DNA was extracted from peripheral blood leukocytes, and coding sequence abnormalities of the CYP11B1 gene were assessed by polymerase chain reaction and then direct sequencing analysis. MAIN OUTCOME MEASURE(S): Molecular characterization of the CYP11B1 gene. RESULT(S): A novel missense mutation (p.R454C) in the CYP11B1 gene was identified in our patient. CONCLUSION(S): Our study identified one novel mutation in the CYP11B1 gene. The expanded mutation database should benefit patients in the diagnosis and treatment of 11beta-OHD. PMID- 20947077 TI - Protocol of surgical treatment of long bone pathological fractures. AB - Long bone pathological fractures in patients with primary and metastatic bone tumours are difficult to treat and their management may alter the prognosis of the disease and jeopardize survival. The aim of this article was to review the relevant studies reporting on the management of tumour patients with pathological fractures of the long bones, to discuss the most suitable approach in these patients, to highlight specific treatment recommendations, and finally based on this analysis and our clinical practice, to propose a treatment algorithm for decision making and treatment. PMID- 20947078 TI - Treatment of femoral diaphyseal non-unions: our experience. AB - Despite the continuous advances of surgical solutions, still 1-7% of fractures develop non-unions. The delays in fracture healing increase the period of incapacity of the patient with major consequences, on the psychological and functional recovery, but also on the direct and indirect health-related costs. In particular, femoral diaphyseal non-unions are often characterised by a challenging and long-lasting period of healing. The clinician treating these complex cases has to consider amongst other parameters, the condition of the soft tissue envelope, the adequacy of any pre-existing fixation, the alignment and length of the affected limb, the potential presence of an infection, as well as the general condition of the patient. Open reduction and plate fixation of femoral diaphyseal non-unions offers a valid alternative of stabilisation and if applied to carefully selected cases, can give optimal results. PMID- 20947079 TI - Decreasing strain on the surgeon in gynecologic minimally invasive surgery by using semi-active robotics. AB - OBJECTIVE: To assess the advantages of a surgeon-controlled robotic endoscope holder in gynecologic minimally invasive solo-surgery as compared with conventional assistance with a second surgeon. METHODS: One hundred gynecologic laparoscopies were consecutively allocated to surgery with either a robot as the surgical assistant or a conventional assistant surgeon. Total operation time, image stability, and frequency of corrective maneuvers of the camera, in addition to the surgeon's satisfaction regarding the ergonomics of the intervention, were recorded. All interventions were performed by the same surgeon. All laparoscopic surgery was classified as either easy or advanced surgery. RESULTS: The image stability score was significantly higher (10 vs 7; P<0.001) and fewer corrective maneuvers of the robotic endoscope were necessary (1 vs 5; P<0.001) with the robotic laparoscope holder; in addition, the surgeon recorded a significantly higher satisfaction score for the ergonomics of the semi-active robot (10 vs 7; P<0.001). CONCLUSION: The robot does not prolong total operation time and increases the surgeon's comfort by improving image stability and laparoscope handling. It could provide major benefit, especially in complex gynecologic laparoscopic surgery. PMID- 20947080 TI - Efficacy of intermittent preventive treatment with sulfadoxine-pyrimethamine on placental parasitemia in pregnant women in midwestern Nigeria. AB - OBJECTIVE: To assess the effect of intermittent preventive treatment with sulfadoxine and pyrimethamine (IPT-SP) on placental parasitemia and maternal and perinatal outcome. METHODS: We compared placental malaria parasitemia during pregnancy and pregnancy outcome in 2 groups of women receiving antenatal care at University of Benin Teaching Hospital. One group was prophylactically treated with IPT-SP and the other was not treated. RESULTS: The parasitemia rates for peripheral, placental, and cord blood were 11.9%, 11.4%, and 2.7% in the IPT-SP group (n=370) and 19.1%, 22.6%, and 6.2% in the control group (n=371) (P=0.006, P=0.002, and P=0.02, respectively). The treatment reduced the odds of placental parasitemia by 37% (OR 0.63; 95% CI, 0.48-0.81). Peripheral (P=0.002) and placental (P=0.001) parasitemia were significantly reduced in the subgroup of women who took 2 or 3 doses of SP. Fewer women (16.2%) in the IPT-SP group than the control group (23.7%) had symptomatic malaria. Anemia at delivery was significantly lower in the IPT-SP group (10.8 vs 1.6%). The risks of abortion, preterm delivery, and low birth weight were also significantly lower in the IPT SP group. CONCLUSION: IPT-SP is effective in preventing placental parasitemia, and reduces rates of malaria, maternal anemia, abortion, preterm delivery and low birth weight among pregnant women. PMID- 20947081 TI - Uterine artery sparing robotic radical trachelectomy (AS-RRT) for early cancer of the cervix. AB - OBJECTIVE: To describe the surgical technique of uterine artery sparing robotic assisted radical trachelectomy (AS-RRT) for early stage cervical cancer. METHODS: We used our experience with AS-RRT performed at the University of Wisconsin Carbone Comprehensive Cancer Center, USA, to present a detailed description of the surgical technique. RESULTS: The report details, step-by-step, our innovative surgical technique, supported by photos and illustrations. We also discuss potential difficulties with the surgical technique and offer solutions. CONCLUSION: Technically, the surgery is feasible and could be performed by any gynecologic oncologist who is skilled in radical pelvic surgery and the robotic system. The long-term obstetric and oncologic outcome of this technique would be expected to match the outcome of the other radical trachelectomy techniques in the published literature, but is yet to be fully elucidated. PMID- 20947082 TI - The clinical learning environment and supervision instrument (CLES): validity and reliability of the Dutch version (CLES+NL). AB - BACKGROUND: The clinical learning environment and supervision scale (CLES) is a valid and reliable tool that was developed to assess the quality of nursing students' clinical placements. OBJECTIVES: To obtain a reliable and valid Dutch version of the CLES that is in line with the Flemish culture and educational context. DESIGN: Scale validation study on data provided by a cross-sectional survey. SETTINGS: 190 wards in 31 institutions for healthcare in Flanders, Belgium. PARTICIPANTS: 768 student nurses enrolled in the 3 year bachelor programme at University College Ghent, Faculty of Healthcare Vesalius. METHODS: Face and content validation was followed by data collection. Factor analysis was performed using varimax rotation. Subsequently, internal consistency reliability was tested on the total scale and its subdimensions using Cronbach's alpha. RESULTS: We gathered 768 questionnaires. Factor analysis revealed 5 subdimensions with an eigenvalue greater than 1, explaining 71.281% of the variance. The overall internal consistency and the consistency of the five subdimensions is high. Our data supports face, content and construct validity of the CLES+NL. CONCLUSIONS: The CLES+NL is a valid and reliable instrument that can be used to evaluate the quality of nursing wards as learning environments in Flanders. PMID- 20947083 TI - Loneliness and social support among nursing home residents without cognitive impairment: a questionnaire survey. AB - BACKGROUND AND OBJECTIVES: Few studies have examined the association between social support and loneliness among nursing home residents without cognitive impairment. The main aims of this study were to examine the frequency of contact and loneliness and the association between loneliness and the social support dimensions: attachment, social integration, reassurance of worth and opportunities for nurturance. DESIGN: A cross-sectional, descriptive, correlational design. SETTINGS: All 30 nursing homes in the city of Bergen in western Norway. PARTICIPANTS: A total of 227 long-term nursing home residents 65 years and older without cognitive impairment. METHODS: Data were obtained through face-to-face interviews using the global question "Do you sometimes feel lonely?", the Social Provisions Scale and one multiple-item question of the Family and Friendship Contacts Scale. Possible relationships between the Family and Friendship Contacts Scale, Social Provisions Scale and loneliness were analyzed using logistic regression while controlling for sex, age group, marital status, education, having a primary nurse, telephone contact and having hobby and interests. RESULTS: In total, 56% experienced loneliness. No social support variable was significantly correlated with loneliness before adjusting for sociodemographic variables. Attachment was nearly statistically significant (P=0.07). When the sociodemographic variables (sex, children, age group, marital status, education, primary nurse, telephone contact, hobbies and Functional Comorbidity Index) were adjusted for, attachment was significant (P=0.03). The social support variables social integration, nurturance and reassurance of worth were not associated with loneliness. Among the sociodemographic variables, sex and marital status were significantly associated with loneliness (P<0.05). CONCLUSIONS: Emotional closeness to significant others from which one derives a sense of security appears to be important for loneliness, and the frequency of contact with family and friends did not explain the experience of loneliness. Clinical nurses should recognize that social support is associated with loneliness and pay attention to the importance of social support for the residents in daily practice. PMID- 20947084 TI - Reward frustration at work and intention to leave the nursing profession- prospective results from the European longitudinal NEXT study. AB - BACKGROUND: Many countries are facing a serious situation of nursing shortage, and retention of nurses is a challenge. OBJECTIVES: To examine whether reward frustration at work, as measured by the effort-reward imbalance model, predicts intention to leave the nursing profession, using data from the European longitudinal nurses' early exit study. DESIGN: A prospective study with one-year follow-up. METHODS: 6469 registered female nurses working in hospitals in seven European countries who did not have intention to leave the nursing profession at baseline were included in our analyses by multivariate Poisson regression. RESULTS: 8.24% nurses newly developed intention to leave during follow-up. High effort-reward imbalance at baseline predicted an elevated risk of intention to leave the profession (relative risk 1.33, 95% confidence interval 1.22-1.45), and reward frustration (poor salary and promotion prospects, lack of esteem) showed the strongest explanatory power. Findings were similar in a majority of the countries. CONCLUSIONS: Results suggest that improving the psychosocial work environment, and specifically occupational rewards, may be helpful in retaining nurses and consequently reducing nursing shortage in Europe. PMID- 20947085 TI - Work motivation of nurses: a literature review. AB - OBJECTIVES: The aim of this review is to describe nurses' work motivation from the perspective of staff nurses. This information would be useful for the development of motivation strategies and further research into nurses' work motivation. DESIGN: A thorough review of the research literature. DATA SOURCES: The literature search was performed using four databases: CINAHL, PubMed, PsychINFO, and SocINDEX. Only studies that met the following criteria were selected for review: (1) were published between 1990 and 2009, (2) were written in English, (3) dealt with work motivation, (4) concerned working staff nurses, (5) involved empirical research, (6) clearly and explicitly provided the research results about the factors affecting nurses' work motivation. Altogether 24 studies met these criteria and were included in this review. REVIEW METHODS: Inductive content analysis was carried out to analyse and categorise the data. RESULTS: Nursing research has neither clear understanding nor consensus about the concept of work motivation; nor has a universal definition been adopted. Despite limited empirical evidence it may be concluded that staff nurses appear to be motivated. Five categories of factors affecting their work motivation were identified: (1) work-place characteristics, (2) working conditions, (3) personal characteristics, (4) individual priorities, and (5) internal psychological states. CONCLUSIONS: Further research is needed to gain a more comprehensive insight into nurses' work motivation and the factors affecting it. This can be achieved by defining the concept of work motivation as precisely as possible, working out a pertinent research methodology, and subsequently developing and testing a theoretical model of nurses' work motivation. PMID- 20947086 TI - The free oxygen radicals test (FORT) to assess circulating oxidative stress in patients with acute myocardial infarction. AB - BACKGROUND AND AIM: Reactive oxygen species (ROS) play an important role in the pathogenesis of many diseases including cardiovascular diseases. Several methods have been developed for the direct or indirect measurement of oxygen free radical and its by-products. The current study was designed to validate the new free oxygen radicals test (FORT) and to investigate the potential relationships between ROS and clinical or biological factors in male patients with acute myocardial infarction (AMI). METHODS: We analysed FORT values in samples from 66 patients with AMI. RESULTS: FORT values ranged from 324 to 1198 FORT units, with a median value of 581 (494-754) FORT units. In univariate analysis, FORT values were positively related only to LVEF <40% (p=0.005), levels of CRP (r=0.438, p<0.001) and peak CK (r=0.274, p=0.028). Multiple linear regression analysis showed that CRP (p=0.023), LVEF <40% (p<0.001) and the presence of diabetes (p=0.039) were independent predictors of serum FORT values. This statistical model can explain 45% of the variance in FORT values (R(2)=0.45). CONCLUSIONS: The FORT is a simple tool to assess circulating ROS in routine clinical practice. Oxidative conditions such as inflammation and diabetes are the major determinants of FORT values in patients with AMI. PMID- 20947087 TI - Physicians' perception, knowledge and awareness of cardiovascular risk factors and adherence to prevention guidelines: the PERCRO-DOC survey. AB - BACKGROUND: Cardiovascular diseases (CVD) are the major cause of premature death in the world. This study was designed to examine the physicians' knowledge and perception of CVD risk factors and perceived implementation of CVD prevention guidelines as well as barriers to their implementation. METHODS: A questionnaire survey by face-to-face interviews was performed among 1382 randomly selected physicians (general practitioners/family medicine specialists, internists and cardiologists) from different regions of Croatia. RESULTS: Most physicians believe that guidelines are useful but only 56.9% are really using some guidelines. 40.2% favour Joint European guidelines. More primary care physicians use their own personal experience in prevention while internists and cardiologists tend more to use the guidelines. 80.6% believe that they treat their patients with dyslipidemia well but only 53.3% knew the LDL-cholesterol goal value for high-risk patients and only 56.2% knew which HDL-cholesterol level is the marker of increased risk. Hypertension was perceived as the most important risk factor, particularly by primary care physicians, while cardiologists tend to favour diabetes. Although most physicians considered the lack of financial resources as the main barrier in CVD prevention, at the same time most of them believe that it could primarily be improved by better patient education. CONCLUSIONS: Although most physicians support the guidelines use, only half of them use them and in average their knowledge of guidelines is not satisfactory. This is, together with the lack of time and finances and perceived lack of patients' awareness, probably one of the main causes why they do not manage risk factors better. PMID- 20947088 TI - Visceral adiposity and the severity of coronary artery disease in middle-aged subjects with normal waist circumference and its relation with lipocalin-2 and MCP-1. AB - OBJECTIVE: Visceral adipose tissue has emerged as a key organ contributing to the development of coronary artery disease (CAD). However, defining central obesity by waist circumference (WC) may underestimate visceral adiposity in lean patients. The aim of this study was to investigate the relationship between visceral adiposity and severity of CAD in subjects with normal WC. METHODS: Among 365 patients with documented CAD, 90 male subjects with normal WC (<90 cm) were selected and their visceral fat areas (VFA) were examined using computed tomography. Lipid profiles and levels of adipokines including lipocalin-2, high molecular weight adiponectin, and monocyte chemoattractant protein (MCP)-1 were measured. Patients were divided into tertiles based on VFA at the L4 vertebra level. RESULTS: Patients with single-vessel disease had significantly lower VFA than those with multi-vessel disease (P<0.05; 86.0 vs. 97.5 vs. 99.6 cm(2) for single- , double- , and triple-vessel diseases, respectively). Positive association between the extent of CAD and VFA was clearly demonstrated and logistic regression analysis showed that subjects in the upper tertile for VFA had a 4.5-fold higher risk of having multi-vessel disease compared with those in the lowest tertile (P<0.05; odds ratio=4.51; 95% confidence interval=1.10-18.45). Circulating levels of lipocalin-2 and MCP-1 were significantly higher in the upper tertiles of VFA. CONCLUSION: Increased visceral adiposity is significantly associated with the severity of CAD, even in subjects without central obesity as determined by WC measurements. Abnormalities in adipokine regulation may provide a novel mechanistic connection between visceral adiposity and associated cardiovascular complications. PMID- 20947089 TI - Separation and quantitation of milk whey proteins of close isoelectric points by on-line capillary isoelectric focusing--electrospray ionization mass spectrometry in glycerol-water media. AB - On-line coupling between CIEF and ESI/MS based on the use of bare fused-silica capillaries and glycerol-water media, recently developed in our laboratory, has been investigated for the separation of milk whey proteins that present close pI values. First, a new rinsing procedure, compatible with MS detection, has been developed to desorb these rather hydrophobic proteins (alpha-casein (alpha-CN), bovine serum albumin (BSA), lactoferrin (LF)) from the inner capillary wall and to avoid capillary blockages. Common hydrochloric acid washing solution was replaced by a multi-step sequence based on the use of TFA, ammonia and ethanol. To achieve the separation of major whey proteins (beta-lactoglobulin A (beta-LG A), beta-lactoglobulin B (beta-LG B), alpha-lactalbumin (alpha-LA) and BSA, which possess close pI values (4.5-5.35), CIEF parameters i.e. carrier ampholyte nature, capillary partial filling length with ampholyte/protein mixture and focusing time, have been optimized with respect to total analysis time, sensitivity and precision on pI determination. After optimization of sheath liquid composition (80:20 (v/v) methanol-water+1% HCOOH), quantitation of beta-LG A, beta-LG B, alpha-LA and BSA was performed. The limits of detection obtained from extracted ion current (EIC) and single ion monitoring (SIM) modes were in the 57-136 nM and 11-68 nM range, respectively. Finally, first results obtained from biological samples demonstrated the suitability of CIEF-MS as a potential alternative methodology to 2D-PAGE to diagnose milk protein allergies. PMID- 20947090 TI - Separation of triphenyl atropisomers of a pharmaceutical compound on a novel mixed mode stationary phase: a case study involving dynamic chromatography, dynamic NMR and molecular modeling. AB - Analysis of atropisomers is of considerable interest in the pharmaceutical industry. For complex chiral molecules with several chiral centers hindered axial rotation can lead to formation of interconverting diastereomers that should be separable on achiral stationary phases. However, achieving the actual separation may be difficult as the on-column separation speed must match or be faster then the rate of isomer interconversion. Often, this requirement can be satisfied by using low-temperature conditions and by improving selectivity via use of chiral stationary phases. In the current study, we present an alternative approach utilizing an Obelisc R column, a novel mixed mode stationary phase that provided acceptable separation of triphenyl atropisomers inside a conventional HPLC temperature range. The separation was investigated under various chromatographic conditions. The interconversion chromatograms exhibited classic peak-plateau-peak behavior indicating the simultaneous atropisomer separation and interconversion. The elution profiles were integrated in order to deconvolute the peak areas of the "pure" (non-exchanged) and interconverted species; these data were used to obtain kinetic information. Analysis of retention data rendered thermodynamic information on the mechanism of retention and selectivity. Chromatographic kinetic data were complemented with variable-temperature NMR and molecular modeling studies, which provided additional support and insights into the energetics of the interconversion process. PMID- 20947091 TI - Ordered dispersion of ZnO quantum dots in SiO2 matrix and its strong emission properties. AB - ZnO nanoparticles in the form of quantum dots (QDs) have been dispersed in SiO(2) matrix using StOber method to form ZnO QDs-SiO(2) nanocomposites. Addition of tetraethyl orthosilicate (TEOS) to an ethanolic solution of ZnO nanoparticles produces random dispersion. On the other hand, addition of ZnO nanoparticles to an already hydrolyzed ethanolic TEOS solution results in a chain-like ordered dispersion. The photoluminescence spectra of the as-grown nanocomposites show strong emission in the ultraviolet region. When annealed at higher temperature, depending on the sample type, these show strong red or white emission. Interestingly, when the excitation is removed, the orderly dispersed ZnO QDs SiO(2) composite shows a very bright blue fluorescence visible by naked eyes for few seconds indicating their promise for display applications. The emission property has been explained in the light of structure-property relationship. PMID- 20947092 TI - Nanoparticle carriers based on copolymers of poly(epsilon-caprolactone) and hyperbranched polymers for drug delivery. AB - Novel amphiphilic copolymers based on poly(epsilon-caprolactone) (PCL) and hyperbranched poly (amine-ester) (HPAE) with various compositions were synthesized. The amphiphilic copolymers can self-assemble into nanoscopic micelles and their hydrophobic cores can encapsulate doxorubicin (DOX) in aqueous solutions. The DOX-loaded HPAE-co-PCL nanoparticles diameter increased from 121 to 184 nm with the increasing PCL segment in the copolymer composition. An in vitro study at 37 degrees C demonstrated that DOX-release from nanoparticles at pH 5.0 was much faster than that at pH 7.4. The cytotoxicity for HeLa cells study demonstrated that DOX-loaded HPAE-co-PCL nanoparticles exhibited the anti-tumor effect was enhanced significantly, suggesting that the DOX-loaded HPAE-co-PCL nanoparticles have great potential as a tumor drug carrier. PMID- 20947093 TI - Investigation of sub-monolayer, monolayer, and multilayer self-assembled semifluorinated alkylsilane films. AB - Semifluorinated self-assembled (FAS SA) films fabricated from trifunctional precursors are frequently used in myriad applications, yet an understanding of the effects of fabrication conditions, including deposition time, on adsorption mechanisms and molecular architectures is still being developed. In this work we prepared SA films based on the F(CF(2))(8)(CH(2))(2)SiCl(3) (FAS-17) precursor and characterized these films using a suite of surface analytical techniques. Contact angle, sum frequency generation (SFG) spectroscopy, X-ray photoelectron spectroscopy (XPS), and ellipsometry results are consistent with the formation of disordered sub-monolayer structures at short deposition times, well-ordered monolayers at intermediate deposition times, and inhomogeneous multilayers at long deposition times. Correlation of SFG and XPS results demonstrates a change in FAS-17 chain orientation as the deposition time increases from 2 s to 5 min. Group theory-based calculations, SFG studies, and Fourier-transform infrared (FTIR) results also afford additional evidence in support of the assignment of the SFG signals at ~1345 and ~1370 cm(-1) to the asymmetric stretching mode of the semifluorinated silane chain's terminal CF(3) group rather than to its axial CF(2) stretches. To our knowledge, this is the first report of SFG studies on semifluoroalkyl silane self-assembled films in the C-F stretching frequency region. PMID- 20947094 TI - Listener perceptions of stuttering, prolonged speech, and verbal avoidance behaviors. AB - This study examined listener perceptions of different ways of speaking often produced by people who stutter. Each of 115 independent listeners made quantitative and qualitative judgments upon watching one of four randomly assigned speech samples. Each of the four video clips showed the same everyday conversation between three young men, but differed in how the target person spoke. The four ways of speaking comprised: (1) stuttered speech, i.e., a speech containing repetitions, prolongations, and blocks, (2) hesitant speech, i.e., a speech containing verbal avoidance behaviors like interjections and revisions, (3) a mix of both, and (4) prolonged speech learned in fluency-shaping therapy. Quantitative data revealed that listeners perceived a speaker producing hesitant speech as less pleasant, self-confident, and communicatively competent than a speaker producing stuttered speech or prolonged speech. There were no differences between stuttered speech and prolonged speech. Ratings were partly dependent on the listeners' implicit theory of speaking difficulties, that is, whether they assumed a chronic speech defect or a temporary problem. Implications of these findings are discussed. LEARNING OUTCOMES: The reader will: (1) be able to summarize how different ways of speaking produced by people who stutter are connected with different listener perceptions; (2) be able to explain how the listener's implicit theory of speaking problems influences these perceptions; (3) learn about the clinical implications of the data from this study. PMID- 20947095 TI - Speaking rate characteristics of elementary-school-aged children who do and do not stutter. AB - PURPOSE: To compare articulation and speech rates of school-aged children who do and do not stutter across sentence priming, structured conversation, and narration tasks and to determine factors that predict children's speech and articulation rates. METHOD: 34 children who stutter (CWS) and 34 age- and gender matched children who do not stutter (CWNS) were divided into younger (M age=6;10) and older (M age=9;6) subgroups. Speech samples were elicited using the Modeled Sentences, Structured Conversation, and Narration tasks from an experimental version of the Test of Childhood Stuttering (Gillam, Logan, & Pearson, 2009). Speech rates (based on both fluent and disfluent utterances), articulation rates (based on only fluent utterances), disfluency frequency, and utterance length were compared across groups and tasks. RESULTS: CWNS had faster speech rates than CWS. Older children had faster speech rates than younger children during Modeled Sentences, and their Modeled Sentences speech rates were faster than their Structured Conversation and Narration speech rates. Disfluency frequency predicted speech rate better than age or utterance length for CWS and CWNS. Speech rate was negatively correlated with stuttering severity for CWS. Articulation rates for CWNS and CWS were not significantly different; however, older children had faster articulation rates than younger children, and articulation rates for both age groups were fastest during Modeled Sentences. CONCLUSIONS: Results provide age-based reference data for the speech and articulation rates of school-aged CWS and CWNS on three TOCS tasks and offer insight into the relative contributions of age, disfluency frequency, and utterance length to children's rate performance. LEARNING OUTCOMES: After reading this paper readers should be able to: (1) summarize the main findings from past studies of children's speech rate and articulation rate; (2) describe how school aged children who stutter compare to age-matched children who do not stutter with regard to speech rate and articulation rate; (3) explain the extent to which age, speaking task, disfluency frequency, and utterance length affect children's rate performance; (4) discuss the advantages and disadvantages of various approaches to rate measurement. PMID- 20947096 TI - The BigCAT: a normative and comparative investigation of the communication attitude of nonstuttering and stuttering adults. AB - The purpose of this investigation was to provide normative and comparative data for the BigCAT, the adult form of the Communication Attitude Test, a sub-test of the Behavior Assessment Battery. The BigCAT, a 35-item self-report test of speech associated attitude was administered to 96 adults who stutter (PWS) and 216 adults who do not (PWNS). The difference in the extent to which the two groups of participants reported a negative attitude toward their speech and speech ability, as measured by the BigCAT, was statistically significant. Moreover, the overlap in the scores of the PWS and PWNS was minimal, and the effect size attributable to group membership was very large. The BigCAT's high Cronbach Alpha coefficients, together with the fact that each of its items significantly differentiated PWS from PWNS, indicate that the BigCAT is an internally consistent measure of the attitude that they have about their speech. Gender did not have a significant influence on the attitude toward speech or speech ability of either the PWS or PWNS. Overall, the present data suggest that the BigCAT holds promise as an aid to clinical decision making that relates to the assessment and treatment of those who stutter. LEARNING OUTCOMES: (1) The reader will learn about the BigCAT, a self-report measure of speech-associated attitude. (2) The reader will be given normative and comparative data that relate to the speech-associated attitude of PWS and PWNS as measured by the BigCAT. This will enable the clinician to use the BigCAT data as a useful source of information in clinical decision making that relates to assessment and treatment. (3) The reader will be informed about the internal reliability and content validity of the BigCAT, a gender-free measure of the speech-associated attitude of PWS and PWNS. PMID- 20947098 TI - Clinical study on CXCL13, CCL17, CCL20 and IL-17 as immune cell migration navigators in relapsing-remitting multiple sclerosis patients. AB - BACKGROUND: There has been a growing evidence for the role of chemokines in the pathology of multiple sclerosis. Recently, there has been great emphasis placed on humoral immunity and the T(H)-17 response, which has not yet been thoroughly described in MS. The aim of this study was to investigate the role of specific chemokines involved in B-cell migration (CXCL13) and in the T(H)-17 immune response (IL-17, CCL17, CCL20). METHODS: Using ELISA, the chosen chemokine concentrations were measured in the serum and cerebrospinal fluid of relapsing remitting MS patients with both active and stable disease, and the relapse prediction rate was calculated. RESULTS: We found that the CSF concentrations of CXCL13 in patients with RRMS both, during relapse and remission, were significantly higher than in controls. CCL17 and CCL20 were not detected in CSF in either of the groups, whereas serum CCL20 level was significantly higher in remission than during relapse. Intravenous methylprednisolone treatment of patients with relapse did not influence serum CXCL13 and CCL20 levels. However, it did lower CCL17 and IL-17 concentrations. CONCLUSIONS: CXCL13 is an important mediator in MS that is strongly linked to the neuroinflammatory activity of the disease. However, more studies are needed for elucidating the roles of CCL17, CCL20 and IL-17 in MS pathology. PMID- 20947097 TI - Randomized controlled trial of lung lavage with dilute surfactant for meconium aspiration syndrome. AB - OBJECTIVE: To evaluate whether lung lavage with surfactant changes the duration of mechanical respiratory support or other outcomes in meconium aspiration syndrome (MAS). STUDY DESIGN: We conducted a randomized controlled trial that enrolled ventilated infants with MAS. Infants randomized to lavage received two 15-mL/kg aliquots of dilute bovine surfactant instilled into, and recovered from, the lung. Control subjects received standard care, which in both groups included high frequency ventilation, nitric oxide, and, where available, extracorporeal membrane oxygenation (ECMO). RESULTS: Sixty-six infants were randomized, with one ineligible infant excluded from analysis. Median duration of respiratory support was similar in infants who underwent lavage and control subjects (5.5 versus 6.0 days, P = .77). Requirement for high frequency ventilation and nitric oxide did not differ between the groups. Fewer infants who underwent lavage died or required ECMO: 10% (3/30) compared with 31% (11/35) in the control group (odds ratio, 0.24; 95% confidence interval, 0.060-0.97). Lavage transiently reduced oxygen saturation without substantial heart rate or blood pressure alterations. Mean airway pressure was more rapidly weaned in the lavage group after randomization. CONCLUSION: Lung lavage with dilute surfactant does not alter duration of respiratory support, but may reduce mortality, especially in units not offering ECMO. PMID- 20947099 TI - Small-bore wire-guided chest drains: safety, tolerability, and effectiveness in pneumothorax, malignant effusions, and pleural empyema. AB - BACKGROUND: The use of small-bore wire-guided chest drains for pleural effusions and pneumothorax has become popular; however, limited data are available on its efficacy and morbidity. The aim of this retrospective study is to measure, via the analysis of the so far largest reported cohort, the efficacy, safety, and tolerability of this approach in different clinical conditions. METHODS: In the period from January 2002 to December 2008, 1092 patients have undergone the positioning of a small-bore wire-guided chest drain (12F) for the evidence of pneumothorax or pleural effusion and have been monitored over time for morbidity, pain at the time of insertion (measured via the visual analogue scale), and drain failure for misplacement or blockage. Patients with trauma were excluded from this study. RESULTS: Male/female ratio and mean age were respectively 418:674 and 55.85 +/- 18.6. Three-hundred ninety-nine (36.5%) drains were inserted for pneumothorax, 324 (29.7%) for malignant effusion, 97 (8.9%) for empyema, and 272 (24.9%) for nonmalignant effusion. The pain experience was on average "very mild" (mean visual analogue scale = 4.6 mm). The overall drain failure rate was 12.9%. The percentage of successful cases was 93.8% in malignant effusion, 93% in pneumothorax, and 92.3% in nonmalignant effusion; in the cases of pathologically diagnosed empyema, drains were more likely to get blocked (74.2%). We recorded 1 serious complication within the malignant effusion group. CONCLUSIONS: Wire guided 12F Seldinger-type drains are a well-tolerated and effective method of treating pneumothorax and uncomplicated pleural effusions (malignant and nonmalignant) with acceptable morbidity. The use of 12F small-bore chest drain is not indicated for the treatment of empyema. PMID- 20947100 TI - Automatic aortic anastomosis with an innovative computer-controlled circular stapler for surgical treatment of aortic aneurysm. AB - OBJECTIVE: This study applied a computer-controlled mechanical stapler to vascular end-to-end anastomosis to achieve an automatic aortic anastomosis between the aorta and an artificial graft. In this experimental study, we created a mechanical end-to-end anastomotic model and assessed the strength of the anastomotic site under high pressure. METHODS: We used a computer-controlled circular stapler named iDrive (Power Medical Interventions, Covidien plc, Dublin, Ireland) for the anastomosis between the porcine aorta and an artificial graft. Then the mechanically stapled group (group A) and the manually sutured group (group B) were compared 10 times, and we assessed the differences at several levels of pressure. RESULTS: To use a mechanical stapler in vascular anastomosis, some special preparations of both the aorta and the artificial graft are necessary to narrow the open end before the procedures. To solve this problem, we established a specially designed purse-string suture for both and finally established end-to-end vascular anastomosis. The anastomosis speed of group A was statistically significantly faster than that of group B (P < .01). The group A anastomotic sites also showed significantly more tolerance to high pressure than those of group B. CONCLUSIONS: The computer-controlled stapling device enabled reliable anastomosis of the aorta and the artificial graft. This study showed that mechanical vascular anastomosis with the iDrive was sufficiently strong and safe relative to manual suturing. PMID- 20947101 TI - Regime shifts in the marine environment: the scientific basis and political context. AB - Regime shifts in the marine environment have recently received much attention. To date, however, few large-scale meta-analyses have been carried out due to insufficient data coverage and integration between sustained observational datasets because of diverse methodologies used in data collection, recording and archival. Here we review the available data on regime shifts globally, followed by a review of current and planned policies with relevance to regime shifts. We then focus on the North and Baltic Seas, providing examples of existing efforts for data integration in the MarBEF Network of Excellence. Existing gaps in data coverage are identified, and the added value from meta-analyses of multiple datasets demonstrated using examples from the MarBEF integrated data project LargeNet. We discuss whether these efforts are addressing current policy needs and close with recommendations for future integrated data networks to increase our ability to understand, identify and predict recent and future regime shifts. PMID- 20947102 TI - Incidence and characteristics of Staphylococcus aureus and Listeria monocytogenes from the Japan and South China seas. AB - The distribution of Staphylococcus aureus and Listeria monocytogenes in the sea water and marine organisms of Peter the Great and Nha Trang bays, the phenotypic properties and antibiotic sensitivity of the isolates were studied. S. aureus was recorded from 9.3% samples in the Sea of Japan and from 20.4% samples in the South China Sea, L. monocytogenes respectively from 5.9 % and 5.8 % samples. S. aureus and L. monocytogenes found in the tropics differed in their phenotypic properties from those found in the temperate zone. Antibiotic resistance was detected in 81.8% and 71.8% of S. aureus strains and in 19% and 71.4% of L. monocytogenes strains respectively from Peter the Great Bay and from Vietnam. The results show that multiresistant strains of S. aureus and L. monocytogenes are widespread throughout Peter the Great and Nha Trang bays and present a hazard to the health of humans and marine animals. PMID- 20947103 TI - Longitudinal assessment of metabolic abnormalities in adolescents and young adults with HIV-infection acquired perinatally or in early childhood. AB - Metabolic complications of HIV pose challenges for health maintenance among young adults who acquired HIV in early childhood. Between July 2004 and July 2009, we evaluated 47 HIV-infected subjects who acquired HIV in early life. Participants completed glucose tolerance testing; insulin, lipid, urine albumin, and creatinine determinations; and dual-energy x-ray absorptiometry scans. Longitudinal data were available for 39 subjects; duration of follow-up was 26.4 +/- 16.8 months. At baseline, participants were 17.1 +/- 3.9 years old; and duration of antiretroviral therapy was 12.7 +/- 3.4 years. CD4 count was 658 +/- 374 cells per cubic millimeter, and 55% had undetectable viral load. Impaired glucose tolerance was present in 15%; 33% had insulin resistance (homeostasis model assessment of insulin resistance >4.0). Furthermore, 52% had triglycerides of at least 150 mg/dL, 36% had high-density lipoprotein cholesterol less than 40 mg/dL, 18% had low-density lipoprotein cholesterol of at least 130 mg/dL, and 25% had total cholesterol of at least 200 mg/dL. Microalbuminuria was present in 15% of participants and was inversely correlated with CD4% (P = .001). During follow up, more than one third remained insulin resistant; lipid parameters tended to improve. There were significant increases in body mass index (P = .0002), percentage leg fat (P = .008), and percentage trunk fat (P = .002). Impaired glucose tolerance, insulin resistance, dyslipidemia, and microalbuminuria are common among young adults with HIV. Long-term exposure to therapy may translate into substantial persistent metabolic risk. PMID- 20947104 TI - Postprandial effects of almond consumption on human osteoclast precursors--an ex vivo study. AB - Consumption of almonds has been associated with increased bone mineral density, but the direct effects of almonds on bone cells are not known. We determined whether serum obtained following the consumption of a meal containing 60 g of almonds affects human osteoclast formation, function, and gene expression in vitro. Human osteoclast precursors were cultured in medium containing 10% serum obtained from 14 healthy subjects at baseline and 4 hours following the consumption of 3 test meals containing almonds, potatoes, and rice and balanced for macronutrient composition. Osteoclast formation was determined by the number of tartrate-resistant acid phosphatase (TRAP)(+) multinucleated cells, and osteoclast function was assessed by measuring TRAP activity in the culture medium and calcium released from OsteoAssay (Lonza Walkersville, Walkersville, MD, USA) plates. The expression of cathepsin K, receptor activator of nuclear factor kB, and matrix metalloproteinase-9 genes was measured by real-time reverse transcriptase-polymerase chain reaction. Compared with serum obtained at baseline, serum obtained 4 hours following the consumption of the almond meal reduced osteoclast formation by approximately 20%, TRAP activity by approximately 15%, calcium release by approximately 65%, and the expression of cathepsin K, receptor activator of nuclear factor kB, and matrix metalloproteinase-9 by 13% to 23%. No effects were observed with serum obtained from the other test meals. Serum obtained 4 hours following the consumption of an almond meal inhibits osteoclast formation, function, and gene expression in cultured human osteoclast precursors, and provides evidence for a positive effect of almonds on bone health. PMID- 20947105 TI - CD36 deficiency predisposing young children to fasting hypoglycemia. AB - Fatty acid (FA) beta-oxidation defects cause hypoglycemia. Our aim was to determine if CD36--a membrane transporter for long-chain FAs--deficiency predisposes children to hypoglycemia. After overnight fasting, we measured parameters for carbohydrate and FA metabolisms at 12-, 14-, and 16-hour fasting points in 51 preschool children with histories of episodic hypoglycemia and 49 age-matched healthy controls. Simultaneously, the expressions of CD36 on platelets and monocytes were examined to determine the phenotypes. Six of the 51 hypoglycemic children and none of the 49 control children were diagnosed as having type I CD36 deficiency. Four and 3 children were diagnosed as having type II CD36 deficiency, respectively. Hypoglycemia was often recurrent in the type I CD36 group. At any fasting point, the type I CD36 group showed significantly lower blood glucose and insulin concentrations than the other groups: glucose, P < .001 vs control group and P < .01 or P < .001 vs type II/wild-type CD36 hypoglycemic groups; insulin, P < .001 vs control group and P < .01 vs type II/wild-type CD36 hypoglycemic groups. Free FA concentration in the type I group was always 1.5- to 2.0-fold higher than that in the other groups, whereas the total ketone body concentration was consistently about two thirds of that in the other groups. Among the type II, wild-type, and control groups, there were no significant differences in the parameters except that the wild-type group showed significantly lower FFA concentration (P < .05). These results suggested that type I CD36 deficiency but not type II CD36 deficiency predisposes preschool children to hypoglycemia. PMID- 20947106 TI - Chemical structure and selected biological properties of a glucomannan from the lichenized fungus Heterodermia obscurata. AB - Successive aqueous and alkaline extraction of the thallus of the lichenized fungus Heterodermia obscurata provided a highly branched glucomannan fraction (GM), whose chemical structure was determined. This was based on monosaccharide composition, methylation, partial acid hydrolysis, and NMR spectroscopic analysis. It consisted of a main chain of (1->6)-linked alpha-D-mannopyranosyl units, almost all being substituted at O-2 with alpha-D-glucopyranosyl, alpha-D mannopyranosyl, and 4-O-substituted alpha-D-mannopyranosyl groups. Intra peritoneal administration of this GM induced a marked and dose-dependent inhibition of acetic acid-induced visceral pain with an ID(50) of 0.6 (0.2-2.0) mg/kg and inhibition of 88+/-4%. It also reduced leukocyte migration by 58+/-4%, but did not alter plasmatic extravasation to the peritoneal cavity. The results suggest that the glucomannan from the H. obscurata might have potential for antinociceptive and anti-inflammatory utilization. PMID- 20947107 TI - [Pediatric imaging case presented at the General Case Reading Session of the XXX National Congress of the SERAM, A Coruna. May 2010]. PMID- 20947108 TI - [Thoracic imaging case presented at the General Case Reading Session of the XXX National Congress of the SERAM, A Coruna. May 2010]. PMID- 20947109 TI - [My experience as a member of the SERAM's Steering Committee?]. PMID- 20947110 TI - Immunogenicity of a DNA vaccine of Avian Reovirus orally delivered by attenuated Salmonella typhimurium. AB - This study aimed to assess the ability of a Salmonella typhimurium-mediated Avain Reovirus DNA vaccine in eliciting antibody production. Six-day-old SPF chickens were orally immunized with SL7207 (pVAX-sigmaC) twice at 2-week interval, detectable antibody was generated 2 weeks after immunization and was significantly higher than the control groups (P<0.01) and ten chickens (66.7%) were considered safe in the subsequent challenge. These results show that SL7207 (pVAX-sigmaC) can induce protective antibody in chickens and the newly constructed vaccine is also effective in protection chickens against ARV infection. PMID- 20947111 TI - Recombinant pseudorabies virus expressing P12A and 3C of FMDV can partially protect piglets against FMDV challenge. AB - One of the crucial factors for evaluation of an effective genetically engineered vaccine is whether susceptible animals are protected from virus challenge after vaccination. In this study, a recombinant pseudorabies virus (PRV-P12A3C) that expressed capsid precursor polypeptide P12A and nonstructural protein 3C of foot and-mouth disease virus (FMDV) was used as a vaccine. The expression of P12A3C and its immunogenicity and protective efficacy against FMDV challenge were measured. Humoral and cellular immune responses were evaluated after each immunization. Subsequently, each piglet was challenged with 1000 ID(50) (50% infection dose) FMDV serotype O, named OR/80, which is used to produce vaccine in China. PRV-P12A3C induced a high level of neutralizing antibody and FMDV-specific lymphocytes. Inactivated vaccine provided 100% protection, and the vector strain (TK(-)/gE(-)/gI(-)) showed no protection. PRV-P12A3C induced 60% protection, compared with piglets that were vaccinated with TK(-)/gE(-)/gI(-). The severity of clinical signs for the remaining two piglets was lighter and the appearance of vesicles was delayed. PMID- 20947112 TI - [Behavioral and psychological symptoms of dementia in a pilot psychogeriatric unit: management and outcomes]. AB - BACKGROUND: Behavioral and psychological symptoms in dementia (BPSD) are a major concern. The French government gave a consensual definition of reinforced intermediate-term care units for BPSD within the project "Plan Alzheimer 2008/2012". OBJECTIVE: Our aim was to report one of the first experiences of this unit in France. RESULTS: Fifty-two patients (38 females, 14 males) were included, mean age 82.07+/-7.84 (73-97). About 80% of patients were improved and there was a high discharge rate to home of about 30%. Night-time behaviors, aberrant motor behaviors and agitation were the most frequent symptoms. CONCLUSION: Our study confirms that demented elderly patients greatly benefit from a specific BPSD care unit in agreement with the objective of Plan Alzheimer 2008/2012. PMID- 20947113 TI - Robot assisted transaxillary surgery (RATS) for the removal of thyroid and parathyroid glands. AB - BACKGROUND: Robotic assisted transaxillary surgery (RATS) is a minimally invasive approach for the removal of the thyroid and/or parathyroid glands through the axilla. This anatomically directed technique, popularized by Chung, eliminates a visible scar and affords excellent high definition optics of the cervical anatomy. We report an initial series of single access RATS in the U.S. METHODS: The prospective endocrine surgery database at a tertiary care center was used to capture all patients who underwent RATS between October 2009 and March 2010. All procedures were performed using a single transaxillary incision. RESULTS: Fourteen operations were performed on 13 patients. Indications for RATS were indeterminate thyroid nodules in 11 patients, the need for completion thyroidectomy in 1 patient, and primary hyperparathyroidism in 2 patients. For patients who underwent robotic assisted thyroid lobectomy, the median thyroid nodule size was 2.1 cm (range, 0.8-2.8 cm), and the median body mass index was 25.33 (range, 21.3-34.4). Mean and median total operative times for robotic assisted thyroid lobectomies were 142 minutes and 137 minutes respectively (range, 113-192 minutes). Operative time for the 2 patients who underwent robotic assisted parathyroidectomy was 115 and 102 minutes. Minor complications occurred in 4 patients (28.5%), with no significant perioperative morbidity or mortality. CONCLUSION: RATS is feasible. We believe that further study of the RATS technique for removing thyroid lobes and parathyroid glands is warranted. This initial series suggests that careful, continued investigation is necessary prior to routine implementation into clinical practice across the U.S. PMID- 20947114 TI - The inability of vaccinia virus A33R protein to form intermolecular disulfide bonded homodimers does not affect the production of infectious extracellular virus. AB - The orthopoxvirus protein A33 forms a disulfide-bonded high molecular weight species that could be either a homodimer or a heteromultimer. The protein is a major target for neutralizing antibodies and the majority of antibodies raised against A33 only recognize the disulfide-bonded form. Here, we report that A33 is present as a disulfide-bonded homodimer during infection. Additionally, we examined the function of intermolecular disulfide bonding in A33 homodimerization during infection. We show that the cysteine at amino acid 62 is required for intermolecular disulfide bonding, but not dimerization as this mutant was still able to form homodimers. To investigate the role of disulfide-bonded homodimers during viral morphogenesis, recombinant viruses that express an A33R with cysteine 62 mutated to serine were generated. The recombinant viruses had growth characteristics similar to their parental viruses, indicating that intermolecular disulfide-bonded homodimerization of A33 is not required for its function. PMID- 20947115 TI - Molecular adaptation of an H7N3 wild duck influenza virus following experimental multiple passages in quail and turkey. AB - To investigate the molecular adaptation of influenza viruses during natural interspecies transmission, we performed a phenotypic and genotypic analysis of a low-pathogenic duck H7N3 influenza virus after experimental passages in turkey and quail. Results obtained showed differences in the HA receptor-binding and in NA enzyme activities in viruses recovered after passages in quail, compared to those obtained from passages in turkey. Sequencing of the HA, NA and genes of internal proteins of the viruses obtained from quail and turkey, identified several amino acid substitutions in comparison with the progenitor virus. Of note, in the quail-adapted viruses the emergence of a 23-amino acid deletion in the stalk of the NA and the introduction of a glycosylation site in the HA were a reminiscence of changes typically observed in nature confirming a potential role of the quail in the adaptation of wild birds viruses to domestic poultry. PMID- 20947116 TI - Coreceptor usage by HIV-1 and HIV-2 primary isolates: the relevance of CCR8 chemokine receptor as an alternative coreceptor. AB - The human immunodeficiency virus replication cycle begins by sequential interactions between viral envelope glycoproteins with CD4 molecule and a member of the seven-transmembrane, G-protein-coupled, receptors' family (coreceptor). In this report we focused on the contribution of CCR8 as alternative coreceptor for HIV-1 and HIV-2 isolates. We found that this coreceptor was efficiently used not only by HIV-2 but particularly by HIV-1 isolates. We demonstrate that CXCR4 usage, either alone or together with CCR5 and/or CCR8, was more frequently observed in HIV-1 than in HIV-2 isolates. Directly related to this is the finding that the non-usage of CXCR4 is significantly more common in HIV-2 isolates; both features could be associated with the slower disease progression generally observed in HIV-2 infected patients. The ability of some viral isolates to use alternative coreceptors besides CCR5 and CXCR4 could further impact on the efficacy of entry inhibitor therapy and possibly also in HIV pathogenesis. PMID- 20947117 TI - 1st International Workshop on Papillomavirus E5 Oncogene-a report. AB - The 1st International Workshop on Papillomavirus E5 Oncogene was held in Capri, Italy, 27-28 May 2010. Here we present a brief report of the various lectures which addressed the multiple facets of the E5 protein. PMID- 20947118 TI - Release of organic P forms from lake sediments. AB - The effects of different physical and chemical conditions on the decomposition and release of organic and inorganic P compound groups from the sediment of Lake Erken were investigated in a series of laboratory experiments. Conditions investigated were temperature, oxygen level, and the effects of additions of carbon substrate (glucose) and poison (formalin). The effects on the P compound groups were determined by measurements with (31)P NMR before and after the experiments, as well as analysis of P in effluent water throughout the experiment. Phosphate analysis of the effluent water showed that oxygen level was the most influential in terms of release rates, with the sediments under anoxic conditions generally releasing more phosphate than the other treatments. (31)P NMR showed that the various treatments did influence the P compound group composition of the sediment. In particular, the addition of glucose led to a decrease in orthophosphate and polyphosphate while the addition of formalin led to a decrease in phosphorus lipids, DNA-phosphate and polyphosphate. Oxic conditions resulted in an increase in polyphosphates, and anoxic conditions in a decrease in these. Temperature did not seem to affect the composition significantly. PMID- 20947119 TI - As(V) removal using carbonized yeast cells containing silver nanoparticles. AB - The present study involves the development of adsorbent containing silver nanoparticles for arsenate removal using silver reducing property of a novel yeast strain Saccharomyces cerevisiae BU-MBT-CY1 isolated from coconut cell sap. Biological reduction of silver by the isolate was deduced at various time intervals. The yeast cells after biological silver reduction were harvested and subjected to carbonization at 400 degrees C for 1 h and its properties were analyzed using Fourier Transform Infra-Red spectroscopy, X-ray diffraction, scanning electron microscope attached with energy dispersive spectroscopy and transmission electron microscope. The average size of the silver nanoparticles present on the surface of the carbonized silver containing yeast cells (CSY) was 19 +/- 9 nm. The carbonized control yeast cells (CCY) did not contain any particles on its surface. As(V) adsorption efficiency of CCY and CSY was deduced in batch mode by varying parameters like contact time, initial concentration, and pH. Desorption studies were also carried out by varying the pH. The experimental data were fitted onto Langmuir and D-R Isotherms and Lagergren and pseudo second order kinetic models. The CSY was more efficient in arsenate removal when compared to CCY. PMID- 20947120 TI - Aggregation and transport of nano-TiO2 in saturated porous media: effects of pH, surfactants and flow velocity. AB - Transport of manufactured nano-TiO(2) in saturated porous media was investigated as a function of morphology characteristics, pH of solutions, flow velocity, and the presence of anionic and non-ionic surfactants in different concentrations. Surfactants enhanced the transport of nano-TiO(2) in saturated porous media while a pH approaching the point of zero charge of nano-TiO(2) limited their transport. The deposition process, a retention mechanism of nano-TiO(2) in saturated porous media was impacted by surfactant and pH. In Dispersion 1 systems (pH 7), the size of the nano-TiO(2) aggregates was directly related to the presence of surfactants. The presence of non-ionic surfactant (Triton X-100) induced a size reduction of nano-TiO(2) aggregates that was dependent on the critical micelle concentration. In Dispersion 2 systems (pH 9), the stability provided by the pH had a significant effect on the size of nano-TiO(2) aggregates; the addition of surfactants did impact the size of the nano-TiO(2) aggregates but in less significance as compared to Dispersion 1 systems. The electrostatic and steric repulsion forces in connection with the size of nano-TiO(2) aggregates and flow velocity impacted the single-collector efficiency and attachment efficiency which dictated the maximum transport distance of nano-TiO(2) for the Dispersion 1 and Dispersion 2 systems. By doubling the flow velocity at pH 9, the No Surfactant, 50% CMC Triton X-100, 100% CMC Triton X-100 and 100% CMC SDBS dispersion systems allowed nano-TiO(2) to attain maximum transport distances of 0.898, 2.17, 2.29 and 1.12 m, respectively. Secondary energy minima played a critical role in the deposition mechanisms of nano-TiO(2). Nano-TiO(2) deposited in the secondary energy wells may be released because of changes in solution chemistry. The deposition of nano-TiO(2) in primary and secondary energy minima, the reversibility of their deposition should be characterized to analyze the transport of nanoparticles in porous media. This is necessary to assess the risk of nanoparticles to the environment and public health. PMID- 20947121 TI - Critical flux and chemical cleaning-in-place during the long-term operation of a pilot-scale submerged membrane bioreactor for municipal wastewater treatment. AB - The critical flux and chemical cleaning-in-place (CIP) in a long-term operation of a pilot-scale submerged membrane bioreactor for municipal wastewater treatment were investigated. Steady filtration under high flux (30 L/(m(2) h)) was successfully achieved due to effective membrane fouling control by sub-critical flux operation and chemical CIP with sodium hypochlorite (NaClO) in both trans membrane pressure (TMP) controlling mode (cleaning with high concentration NaClO of 2000-3000 mg/L in terms of effective chorine was performed when TMP rose to 15 kPa) and time controlling mode (cleanings were performed weekly and monthly respectively with low concentration NaClO (500-1000 mg/L) and high concentration NaClO (3000 mg/L)). Microscopic analysis on membrane fibers before and after high concentration NaClO was also conducted. Images of scanning electron microscopy (SEM) and atomic force microscopy (AFM) showed that NaClO CIP could effectively remove gel layer, the dominant fouling under sub-critical flux operation. Porosity measurements indicated that NaClO CIP could partially remove pore blockage fouling. The analyses from fourier transform infrared spectrometry (FTIR) with attenuated total reflectance accessory (ATR) and energy dispersive spectrometer (EDS) demonstrated that protein-like macromolecular organics and inorganics were the important components of the fouling layer. The analysis of effluent quality before and after NaClO CIP showed no obvious effect on effluent quality. PMID- 20947122 TI - 1,2,4-Triazoloazine derivatives as a new type of herpes simplex virus inhibitors. AB - A new class of inhibitors of herpes simplex virus replication was found. The compounds under study are derived from condensed 1,2,4-triazolo[5,1 c][1,2,4]triazines and 1,2,4-triazolo[1,5-a]pyrimidines, structural analogues of natural nucleic bases. Antiherpetic activity and cytotoxicity of the compounds were studied. The corresponding triphosphates of several active compounds were prepared and tested as inhibitors of DNA synthesis catalyzed by herpes simplex virus polymerase. The potential mechanism of their action is blocking of DNA dependent DNA polymerase, a key enzyme of viral replication. PMID- 20947123 TI - Applicability of microwave-assisted extraction combined with LC-MS/MS in the evaluation of booster biocide levels in harbour sediments. AB - A new sample treatment method for the determination of four common booster biocides (Diuron, TCMTB, Irgarol 1051 and Dichlofluanid) in harbour sediment samples has been developed that uses liquid chromatography-tandem mass spectrometry (LC-MS/MS) after microwave-assisted extraction, followed by clean-up and a solid phase extraction preconcentration step (MAE-SPE). The effects of different variables on MAE-SPE were studied. The recoveries obtained were greater than 75%, and the relative standard deviation was less than 7%. The detection limits ranged between 0.1 and 0.3 ng g-1. The developed methodology was successfully applied to the evaluation of the presence of booster biocides in sediment samples from different harbours and marinas of Gran Canaria Island (Canary Islands, Spain). PMID- 20947124 TI - Fate and transport of carbamazepine in soil aquifer treatment (SAT) infiltration basin soils. AB - The transport and fate of the pharmaceutical carbamazepine (CBZ) were investigated in the Dan Region Reclamation Project (SHAFDAN), Tel-Aviv, Israel. Soil samples were taken from seven subsections of soil profiles (150 cm) in infiltration basins of a soil aquifer treatment (SAT) system. The transport characteristics were studied from the release dynamics of soil-resident CBZ and, subsequently, from applying a pulse input of wastewater containing CBZ. In addition, a monitoring study was performed to evaluate the fate of CBZ after the SAT. Results of this study indicate adsorption, and consequently retardation, in CBZ transport through the top soil layer (0-5 cm) and to a lesser extent in the second layer (5-25 cm), but not in deeper soil layers (25-150 cm). The soluble and adsorbed fractions of CBZ obtained from the two upper soil layers comprised 45% of the total CBZ content in the entire soil profile. This behavior correlated to the higher organic matter content observed in the upper soil layers (0-25 cm). It is therefore deduced that when accounting for the full flow path of CBZ through the vadose zone to the groundwater region, the overall transport of CBZ in the SAT system is essentially conservative. The monitoring study revealed that the average concentration of CBZ decreased from 1094 +/- 166 ng L-1 in the recharged wastewater to 560 +/- 175 ng L-1 after the SAT. This reduction is explained by dilution of the recharged wastewater with resident groundwater, which may occur as it flows to active reclamation wells. PMID- 20947125 TI - Evaluation of an approach for the characterization of reactive and available pools of 20 potentially toxic elements in soils: part II--solid-solution partition relationships and ion activity in soil solutions. AB - To assess environmental risks related to contaminants in soil it is essential to predict the available pool of inorganic contaminants at regional scales, accounting for differences between soils from variable geologic and climatic origins. An approach composed of a well-accepted soil extraction procedure (0.01 M CaCl(2)) and empirical Freundlich-type models in combination with mechanistically based models which to date have been used only in temperate regions was applied to 136 soils from a South European area and evaluated for its possible general use in risk assessment. Empirical models based on reactive element pools and soil properties (pH, organic carbon, clay, total Al, Fe and Mn) provided good estimations of available concentrations for a broad range of contaminants including As, Ba, Cd, Co, Cu, Hg, Mo, Ni, Pb, Sb, Se and Zn (r(2): 0.46-0.89). The variation of the pools of total Al in soils expressed the sorptive capacity of aluminosilicates and Al oxides at the surfaces and edges of clay minerals better than the actual variability of clay contents. The approach has led to recommendations for further research with particular emphasis on the impact of clay on the solubility of As and Sb, on the mechanisms controlling Cr and U availability and on differences in binding properties of soil organic matter from different climatic regions. This study showed that such approach may be included with a good degree of certainty for first step risk assessment procedures to identify potential risk areas for leaching and uptake of inorganic contaminants in different environmental settings. PMID- 20947126 TI - Diamondback terrapins as indicator species of persistent organic pollutants: Using Barnegat Bay, New Jersey as a case study. AB - The diamondback terrapin's (Malaclemys terrapin) wide geographic distribution, long life span, occurrence in a variety of habitats within the saltmarsh ecosystem, predatory foraging behavior, and high site fidelity make it a useful indicator species for contaminant monitoring in estuarine ecosystems. In this study fat biopsies and plasma samples were collected from males and females from two sites within Barnegat Bay, New Jersey, as well as tissues from a gravid female and blue mussels (Mytilus edulis), which are terrapin prey. Samples were analyzed for persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), chlorinated pesticides, and methyl-triclosan. Terrapins from the northern site, Spizzle Creek, closest to influences from industrial areas, had higher POP concentrations for both tissues than terrapins from the less impacted Forsythe National Wildlife Refuge. Sex differences were observed with males having higher contaminant concentrations in fat and females in plasma. PCB patterns in terrapin fat and plasma were comparable to other wildlife. An atypical PBDE pattern was observed, dominated by PBDEs 153 and 100 instead of PBDEs 47 and 99, which has been documented in only a few other turtle species. The typical PBDE patterns measured in mussels, terrapin prey, suggests that the terrapin may efficiently biotransform or eliminate PBDE 47 and possibly PBDE 99. Plasma contaminant concentrations significantly and positively correlated with those in fat. This study addresses several aspects of using the terrapin as an indicator species for POP monitoring: site and sex differences, tissue sampling choices, maternal transfer, and biomagnification. PMID- 20947127 TI - Organochlorine pesticide residues in sediments from the Uganda side of Lake Victoria. AB - Organochlorine (OC) residues were analysed in 117 sediment samples collected from four bays of the Uganda side of Lake Victoria. The sediments were collected with a corer at a depth of 0-20 cm, and extracted for OC residues using a solid dispersion method. The extracts were cleaned using gel permeation chromatography and analysed for pesticide residues using a gas chromatograph (GC) equipped with an electron capture detector. The results were confirmed using a GC equipped with a mass spectrometer (MS). A total of 16 OC residues, most of them persistent organic pollutants (POPs) were identified and quantified. The OC residue levels were expressed on an oven dry weight (d.w.) basis. Endosulphan sulphate, in the range of 0.82-5.62 MUg kg-1 d.w., was the most frequently detected residue. Aldrin and dieldrin were in the ranges of 0.22-15.96 and 0.94-7.18 MUg kg-1 d.w., respectively. DDT and its metabolites lay between 0.11-3.59 for p,p'-DDE, 0.38 4.02 for p,p'-DDD, 0.04-1.46 for p,p'-DDT, 0.07-2.72 for o,p'-DDE and 0.01-1.63 MUg kg-1 d.w. for o,p'-DDT. The levels of gamma-HCH varied from 0.05 to 5.48 MUg kg-1 d.w. Heptachlor was detected only once at a level of 0.81 MUg kg-1 d.w., while its photo-oxidation product, heptachlor epoxide, ranged between non detectable (ND) to 3.19 MUg kg-1 d.w. Chlordane ranged from ND to 0.76 MUg kg-1 d.w. Based on the threshold effect concentration (TEC) for fresh water ecosystems, aldrin and dieldrin were the only OCs that seemed to be a threat to the lake environment. PMID- 20947128 TI - Optimum conditions for microbial carbonate precipitation. AB - The type of bacteria, bacterial cell concentration, initial urea concentration, reaction temperature, the initial Ca(2+) concentration, ionic strength, and the pH of the media are some factors that control the activity of the urease enzyme, and may have a significant impact on microbial carbonate precipitation (MCP). Factorial experiments were designed based on these factors to determine the optimum conditions that take into consideration economic advantage while at the same time giving quality results. Sporosarcina pasteurii strain ATCC 11859 was used at constant temperature (25 degrees C) and ionic strength with varying amounts of urea, Ca(2+), and bacterial cell concentration. The results indicate that the rate of ureolysis (k(urea)) increases with bacterial cell concentration, and the bacterial cell concentration had a greater influence on k(urea) than initial urea concentration. At 25 mM Ca(2+) concentration, increasing bacterial cell concentration from 10(6) to 10(8)cells mL-1 increased the CaCO(3) precipitated and CO(2) sequestrated by over 30%. However, when the Ca(2+) concentration was increased 10-fold to 250 mM Ca(2+), the amount of CaCO(3) precipitated and CO(2) sequestrated increased by over 100% irrespective of initial urea concentration. Consequently, the optimum conditions for MCP under our experimental conditions were 666 mM urea and 250 mM Ca(2+) at 2.3*108 cells mL-1 bacterial cell concentration. However, a greater CaCO(3) deposition is achievable with higher concentrations of urea, Ca(2+), and bacterial cells so long as the respective quantities are within their economic advantage. X-ray Diffraction, Scanning Electron Microscopy and Energy Dispersive X-ray analyzes confirmed that the precipitate formed was CaCO(3) and composed of predominantly calcite crystals with little vaterite crystals. PMID- 20947129 TI - Polycyclic aromatic hydrocarbons in cigarette sidestream smoke particulates from a Taiwanese brand and their carcinogenic relevance. AB - Polycyclic aromatic hydrocarbons (PAHs) adsorbed on cigarette sidestream smoke particulates (CSSPs) have been regarded as important contributors to lung carcinogenesis in never smokers. However, limited information is available on PAH levels in cigarette sidestream smoke. Here we determine the concentrations of 22 PAHs, including 16 US EPA priority PAHs, in CSSPs generated from a high market share domestic brand in Taiwan. Five of the 22 PAHs are undetectable. The remaining 17 PAHs constitute about 0.022% of the total mass of CSSPs. Near one fifth of the PAH mass come from IARC group 1 and group 2 carcinogens. Carcinogenic potency is equivalent to 144 ng benzo[a]pyrene per cigarette converted according to potency equivalency factors (PEFs). The CSSP condensate could activate AhR activity and induce AhR target gene expression. High concentrations of CSSPs also exhibited AhR-independent cytotoxicity. However, mixing the 17 PAHs as the composition in the CSSP condensate could not reconstitute either capacity. Since AhR activation and cytotoxicity are important mechanisms underlying carcinogenic potency, the results suggest that other component compounds play a more active role in carcinogenesis. The approach of individual PAH profiling plus PEF conversion commonly used in risk assessment is likely to underestimate the risk caused by environmental cigarette smoke exposure. PMID- 20947130 TI - Chemical composition of burnt smell caused by accidental fires: environmental contaminants. AB - The chemical composition of the odors typical of fires has recently been deciphered. Basically the constituents are mixtures of acetophenone, benzyl alcohol, hydroxylated derivatives of benzaldehyde, methoxylated and/or alkylated phenols and naphthalene. This finding makes it possible to develop objective, practical analytic measurement methods for the burnt smell as a contribution to improving fire damage assessment and remediation monitoring. With the aid of an artificially produced burnt smell and a panel of testers the odor detection threshold of a test mixture was determined olfactometrically to 2 MUg m-3. Using a defined burnt-smell atmosphere in a test chamber, analytical methods with active sampling, the adsorbents XAD 7 and TENAX TA, and GC/MS measurement were then optimized and tested with a view to being able to carry out sensitive quantitative measurement of burnt smells. A further practical method with particular application to the qualitative characterization of this odor is based on the use of a new SPME (solid-phase microextraction) field sampler with DVB/CAR/PDMS (divinylbenzene/CarboxenTM/polydimethylsiloxane) fibers. PMID- 20947131 TI - Assessment of five bioaccessibility assays for predicting the efficacy of petroleum hydrocarbon biodegradation in aged contaminated soils. AB - In this study, the bioaccessibility of petroleum hydrocarbons in aged contaminated soils (1.6-67gkg(-1)) was assessed using four non-exhaustive extraction techniques (100% 1-butanol, 100% 1-propanol, 50% 1-propanol in water and hydroxypropyl-beta-cyclodextrin) and the persulfate oxidation method. Using linear regression analysis, residual hydrocarbon concentrations following bioaccessibility assessment were compared to residual hydrocarbon concentrations following biodegradation in laboratory-scale microcosms in order to determine whether bioaccessibility assays can predict the endpoint of hydrocarbon biodegradation. The relationship between residual hydrocarbon concentrations following microcosm biodegradation and bioaccessibility assessment was linear (r(2)=0.71-0.97) indicating that bioaccessibility assays have the potential to predict the extent of hydrocarbon biodegradation. However, the slope of best fit varied depending on the hydrocarbon fractional range assessed. For the C(10) C(14) hydrocarbon fraction, the slope of best fit ranged from 0.12 to 0.27 indicating that the non-exhaustive or persulfate oxidation methods removed 3.5-8 times more hydrocarbons than biodegradation. Conversely, for the higher molecular weight hydrocarbon fractions (C(29)-C(36) and C(37)-C(40)), biodegradation removed up to 3.3 times more hydrocarbons compared to bioaccessibility assays with the resulting slope of best fit ranging from 1.0-1.9 to 2.0-3.3 respectively. For mid-range hydrocarbons (C(15)-C(28)), a slope of approximately one was obtained indicating that C(15)-C(28) hydrocarbon removal by these bioaccessibility assays may approximate the extent of biodegradation. While this study demonstrates the potential of predicting biodegradation endpoints using bioaccessibility assays, limitations of the study include a small data set and that all soils were collected from a single site, presumably resulting from a single contamination source. Further evaluation and validation is required using soils from a range of hydrocarbon contamination sources in order to develop robust assays for predicting bioremediation endpoints in the field. PMID- 20947132 TI - Landscapes of human evolution: models and methods of tectonic geomorphology and the reconstruction of hominin landscapes. AB - This paper examines the relationship between complex and tectonically active landscapes and patterns of human evolution. We show how active tectonics can produce dynamic landscapes with geomorphological and topographic features that may be critical to long-term patterns of hominin land use, but which are not typically addressed in landscape reconstructions based on existing geological and paleoenvironmental principles. We describe methods of representing topography at a range of scales using measures of roughness based on digital elevation data, and combine the resulting maps with satellite imagery and ground observations to reconstruct features of the wider landscape as they existed at the time of hominin occupation and activity. We apply these methods to sites in South Africa, where relatively stable topography facilitates reconstruction. We demonstrate the presence of previously unrecognized tectonic effects and their implications for the interpretation of hominin habitats and land use. In parts of the East African Rift, reconstruction is more difficult because of dramatic changes since the time of hominin occupation, while fossils are often found in places where activity has now almost ceased. However, we show that original, dynamic landscape features can be assessed by analogy with parts of the Rift that are currently active and indicate how this approach can complement other sources of information to add new insights and pose new questions for future investigation of hominin land use and habitats. PMID- 20947133 TI - Testing the validity of a Cd soil quality standard in representative Mediterranean agricultural soils under an accumulator crop. AB - The validity of a quality standard for cadmium (Cd) in representative agricultural Mediterranean soils under an accumulator crop (Lactuca sativa L.) is evaluated in this work considering both its effect on the crop growth (biomass production) and the metal accumulation in the edible part of the plant. Four soils with different properties relevant to regulate the behaviour of heavy metals were selected from the Valencian Region, a representative area of the European Mediterranean Region. For all soils, the effective concentration of added Cd causing 50% inhibition (EC(50)) on the biomass production was much higher than the minimum legal concentration used to declare soils as contaminated by cadmium, i.e. 100 times the baseline value for Cd, in Spain (Spanish Royal Decree 9/2005). As expected, Cd toxicity in the crop was higher in the soils having less carbonate content. On the other hand, for all soils, from the second dose on, which represents 10-times the baseline value for Cd, the metal content in crops exceeded the maximum level established for leaf crops by the European legislation (Regulation EC no. 466/2001). Soil salinity and coarse textures make the accumulation of Cd in the edible part of the plant easier. Therefore, the legal baseline soil cadmium content established by the Spanish legislation seems not valid neither from the point of view of the effect on the crop growth nor from the point of view of the metal accumulation in the edible part of the plant. In order to realistically declare contaminated soils by heavy metals, soil quality standards should be proposed taking into account the soil properties. Further research in other agricultural areas of the region would improve the basis for proposing adequate soil quality standards for heavy metals as highlighted by the European Thematic Strategy for Soil Protection. PMID- 20947134 TI - Dust particulate absorption by ivy (Hedera helix L) on historic walls in urban environments. AB - The potential bio-protective role of urban greenery and how it interacts with airborne dust and pollutants has been the subject of much recent research. As particulate pollution has been implicated in both the deterioration of building materials and in damaging human health, understanding how it interacts with urban greenery is of great applied interest. Common or English Ivy (Hedera helix L) grows widely on urban walls in many parts of the world, and thus any bio protective role it might play is of broad relevance. Using Scanning Electron Microscopy ivy leaves collected on roadways were examined to determine if ivy can absorb dust and pollutants that can instigate decay processes on stone walls and impact human health in urban environments. Results showed that ivy acts as a 'particle sink', absorbing particulate matter, particularly in high-traffic areas. It was effective in adhering fine (<2.5MUm) and ultra-fine (<1MUm) particles at densities of up to 2.9*10(10) per m(2). Our findings suggest that through absorbing pollutant particles ivy can retard bio-deteriorative processes on historic walls and reduce human exposure to respiratory problems caused by vehicle pollutants. PMID- 20947135 TI - Effects of complex hydrodynamic processes on the horizontal and vertical distribution of Tc-99 in the Irish Sea. AB - The increased discharge of Tc-99 from the Sellafield plant following the commissioning of the Enhance Actinide Removal Plant in 1994 was reflected in higher Tc-99 activity concentrations over much of the Irish Sea. The presence of this radionuclide in the marine environment is of concern not only because of its long half life but also high bio-concentration factor in commercially valuable species, such Norway lobster (Nephrops norvegicus) and common lobster (Homarus gammarus). Accurate predictions of the transport, and spatial and temporal distributions of Tc-99 in the Irish Sea have important environmental and commercial implications. In this study, transport of the Tc-99 material was simulated in order to develop an increased understanding of long-term horizontal and vertical distributions. In particular, impact of seasonal hydrodynamic features such as the summer stratification on the surface-to-bottom Tc-99 ratio was of interest. Also, material retention mechanisms within the western Irish Sea were explored and flushing rates under various release conditions and meteorological forcing were estimated. The results show that highest vertical gradients are observed between June and July in the deepest regions of the North Channel and the western Irish Sea where radionuclide-rich saline-poor water overlays radionuclide-poor saline-rich Atlantic water masses. Strong correlation between top-to-bottom ratio of Tc-99 and strength of stratification was found. Flushing studies demonstrate that as the stratification intensifies, residence times within the western Irish Sea increase. In stratified waters of the gyre Tc 99 material is flushed out from the upper layer much quicker than from the bottom zone. The research also shows that in the gyre the biologically active upper layers above the thermocline are likely to contain higher concentrations than the near-bed region. Long-term horizontal and vertical distributions as determined in this study provide a basis for assessment of a potential biota exposure to Tc-99. PMID- 20947136 TI - Modeling the impact of climate variability on diarrhea-associated diseases in Taiwan (1996-2007). AB - Diarrhea is an important public health problem in Taiwan. Climatic changes and an increase in extreme weather events (extreme heat, drought or rainfalls) have been strongly linked to the incidence of diarrhea-associated disease. This study investigated and quantified the relationship between climate variations and diarrhea-associated morbidity in subtropical Taiwan. Specifically, this study analyzed the local climatic variables and the number of diarrhea-associated infection cases from 1996 to 2007. This study applied a climate variation-guided Poisson regression model to predict the dynamics of diarrhea-associated morbidity. The proposed model allows for climate factors (relative humidity, maximum temperature and the numbers of extreme rainfall), autoregression, long term trends and seasonality, and a lag-time effect. Results indicated that the maximum temperature and extreme rainfall days were strongly related to diarrhea associated morbidity. The impact of maximum temperature on diarrhea-associated morbidity appeared primarily among children (0-14years) and older adults (40 64years), and had less of an effect on adults (15-39years). Otherwise, relative humidity and extreme rainfall days significantly contributed to the diarrhea associated morbidity in adult. This suggested that children and older adults were the most susceptible to diarrhea-associated morbidity caused by climatic variation. Because climatic variation contributed to diarrhea morbidity in Taiwan, it is necessary to develop an early warning system based on the climatic variation information for disease control management. PMID- 20947138 TI - Comparison of the fibrinogen Clauss assay and the fibrinogen PT derived method in patients with dysfibrinogenemia. AB - Fibrinogen assays are an important screening tool for blood coagulation disorders. Although different methods are available, no consensus has been reached as to which method is preferable. In 27 patients with dysfibrinogenemia, plasma fibrinogen concentration was measured by Clauss and PT-derived methods on two fully automated coagulation analyzers utilizing different reagents. In addition, immunological and heat fibrinogen concentrations as well as global coagulation tests were measured. RESULTS: The median fibrinogen determined by the Clauss assay was 0.40 g/l, with a range of 0.30-2.07 g/l (normal range: 2.67-4.37 g/l) and 0.60 g/l, with a range of 0.60-2.20 g/l (normal range: 1.5-4.5 g/l) using two different reagents. The median fibrinogen determined by the PT-derived method was 2.41 g/l, with a range of 0.97-4.87 g/l (normal range: 1.84-4.8 g/l) and 2.64 g/l, ranging from 1.38 to 4.39 g/l (normal range: 2.0-4.0 g/l) by the use of two different reagents. No correlation was found when comparing both methods using two reagents from different manufacturers. The PT-derived method "overestimated" the fibrinogen by approximately five times the value measured by the Clauss assay. While fibrinogen measured by the PT-derived method correlated with fibrinogen antigen concentrations measured by the immunological fibrinogen (p<0.002) or heat fibrinogen method (p<0.002), fibrinogen measured by the Clauss method correlated with functional coagulation parameters, such as Reptilase Time (p<0.002), Thrombin Time (p<0.002) or Prothrombin Time (p<0.02). CONCLUSION: Although many patients with dysfibinogenemia are asymptomatic, in case of bleeding, immediately diagnosis and treatment is warranted. The Clauss assay is the diagnostic tool of choice when diagnosing or treating patients with low fibrinogen levels. The use of the PT-derived method may potentially pose a greater risk to patients, as the plasma concentration may be erroneously reported as normal. PMID- 20947137 TI - The roles of anatomic factors, thrombophilia, and antithrombotic therapies in childhood-onset arterial ischemic stroke. AB - Childhood-onset arterial ischemic stroke (AIS) is a rare disorder with high risks of both recurrent stroke and life-long neurological morbidity. Anatomic risk factors for primary and/or recurrent AIS include a venous thrombotic source for paradoxical embolism via a patent foramen ovale, primary cardioembolism, extracranial dissection, and intracranial arteriopathies, among others. Genetic and acquired thrombophilias are common, some of which have been shown to have prognostic influence on risk of recurrent AIS. While knowledge of childhood AIS risk factors has grown considerably in recent years, an evidence-based understanding of optimal antithrombotic therapy strategies has not yet been attained. Consensus-based guidelines have been developed, but future research must emphasize identification of additional prognostic factors and the initiation of cooperative randomized controlled clinical trials. PMID- 20947139 TI - Calretinin immunoreactivity in normal and carbon tetrachloride-induced nephrotoxic rats. AB - Carbon tetrachloride (CCl(4)) is a potent hepatotoxic and nephrotoxic chemical. Little, however, is known about the association of CCl(4)-induced nephrotoxicity and calretinin. We hypothesized that calretinin might be localized in the proximal tubule cells and play a role against CCl(4)-induced nephrotoxicity, since the target of CCl(4) is the brush border-bearing tubule cells. CCl(4) (1 ml/kg) was administrated by oral gavage to 8-week old male Sprague-Dawley rats once a week for 4 weeks. A significant increase in serum blood urea nitrogen and creatinine was confirmed by serum analysis. Calretinin immunolocalization was compared with the calbindin D-28k immunoreactivity in normal and CCl(4)-treated kidneys. Calretinin was clearly immunolocalized in the apical surface of proximal convoluted tubule in the deeper cortex of normal kidney and blurred after CCl(4) administration, with only minor changes of calbindin D-28k immunoreactivity in the distal convoluted tubules and collecting ducts, irrelevant to the CCl(4) treatment. These findings might have significance since decreased immunolocalization of calretinin with CCl(4)-induced nephrotoxicity may contribute to the toxicity-related decrease in calcium transport or calcium buffering activity in the kidney. PMID- 20947140 TI - Importance of erythrocyte band III anion transporter (SLC4A1) on oxalate clearance of calcium oxalate monohydrate stone-formering patients vs. normal controls. AB - OBJECTIVES: To examine erythrocyte band III transport protein (SLC4A1), erythrocyte oxalate flux, and plasmatic, cellular, and urine oxalate concentrations and blood gas analyses in calcium oxalate monohydrate stone forming patients (COM) in comparison with normal controls (NC). METHODS: Isolated red cells from 51 NC and 25 COM cases were divided for cellular oxalate measurement and for measurement of transcellular erythrocyte oxalate flux (pH 7.48-8.24). SLC4A1 protein levels were determined by Western blot analyses. Plasmatic and urinary oxalate levels and the venous blood gas analysis were measured simultaneously. RESULTS: SLC4A1 protein levels were significantly higher in COM (8.76 +/- 2.12) than in NC (4.17 +/- 0.61; P < .02). Cellular oxalate and venous HCO(3)(-) were significantly lower in COM (2.35 +/- 0.26 MUmol/L) and (24.06 +/- 0.24 mmo/l) than in NC (4.03 +/- 0.49 MUmol/L; P < .05) and (24.93 +/- 0.17 mmol/L; P < .01). Urinary oxalate was significantly higher in COM (0.31 +/- 0.02 mmol/L) than in NC (0.25 +/- 0.01 mmol/L; P < .04). The erythrocyte transmembrane oxalate flux correlated with the pH value and with the urinary oxalate in both groups (r = .25-.55; P = .01). With increased pH values, the oxalate flux showed inverse effects in both groups. CONCLUSIONS: SLC4A1 associated changes of HCO(3)(-) and pH levels influenced the cellular oxalate levels and urinary oxalate clearance. Under normal conditions (pH 7.55) the oxalate efflux in COM was comparable with the acid stimulated oxalate efflux in NC. The addition of HCO(3)(-) compensated the flux of COM stone formers to the levels of normal controls. PMID- 20947141 TI - Long-term follow-up of infantile Wilms tumor treated according to International Society of Pediatric Oncology protocol: seven years' follow-up. AB - OBJECTIVES: To report the long-term follow-up of patients with infantile Wilms tumor treated according to the International Society of Pediatric Oncology study 9 protocol. METHODS: We retrospectively reviewed our medical reports for diagnosed WT in patients aged 6-12 months from January 2001 to January 2009. The clinical presentation, stage, operative details, pathologic findings, and outcomes for these infants were analyzed. We reviewed the charts of these patients throughout the whole disease course through long-term follow-up, paying particular attention to the details of the clinical presentation, stage at presentation versus postoperative stage, intraoperative findings, pathologic findings, and outcomes. RESULTS: The records revealed 16 patients with a median age of 7.5 months. All patients had presented with an abdominal mass, and 25% had presented with abdominal pain and hematuria. Associated congenital anomalies were observed in 16.7% of the patients. A favorable histologic type was found in 91.7% of the patients and 8.3% had an unfavorable histologic type. The median follow-up period was 57 months. Postoperative complete remission was achieved in all patients who underwent surgery. Relapse developed in 1 patient. The 7-year disease-free survival rate was 93.8%, and the 7-year overall survival rate was 75%. CONCLUSIONS: The long-term follow-up data using the International Society of Pediatric Oncology study 9 protocol revealed good outcomes. The protocol was a safe and an effective line of therapy, associated with decreased morbidity and improved survival. Also, the reduction in tumor volume resulted in easier surgical procedures, with no intraoperative complications. PMID- 20947142 TI - Renal pelvic diameters in human fetuses: anatomical reference for diagnosis of fetal hydronephrosis. AB - OBJECTIVE: To evaluate renal pelvis diameters in human fetuses, to establish normative patterns of their growth and size during the second gestational trimester. METHODS: We studied 140 kidneys (70 fetuses; 38 male, 32 female) ranging in age from 12-25 weeks' postconception. The renal pelvis was dissected and the transverse and longitudinal diameters were measured. The renal length, width, and thickness were assessed. To compare the quantitative data in both sexes, Student's t-test was used (P <.05). RESULTS: The mean transverse diameter in male fetuses was 3.61 mm in the right side and 3.58 mm in the left. In female fetuses, it was 3.51 mm in the right side and 3.43 mm in the left. There was no statistical significant difference between the sides either in males (P <.81) or in females (P <.33). There was no significant difference in the mean transverse diameter between male and female fetuses (P <.9). The mean longitudinal diameter in male fetuses was 4.28 mm in the right side and 4.31 mm in the left. In female fetuses, it was 4.17 mm in the right side and 4.33 mm in the left. There was no significant statistical difference between the sides in either males (P <.82) or females (P <.33). There was no significant difference in the mean longitudinal diameter between male and female fetuses (P <.9). CONCLUSIONS: Transverse and longitudinal diameters are useful as parameters for assessment of the renal pelvis in human fetuses. PMID- 20947143 TI - The efficacy of enuresis alarm treatment in pharmacotherapy-resistant nocturnal enuresis. AB - OBJECTIVES: To assess the efficacy of enuresis alarm (EA) treatment in pharmacotherapy-resistant nocturnal enuresis (PRNE). MATERIAL AND METHODS: A retrospective study was performed in children who received EA treatment as a form of combination treatment for PRNE from June 1999 to December 2007. The children included 54 monosymptomatic nocturnal enuresis (MNE) children who had partial response or nonresponse to desmopressin (group 1), 25 nonmonosymptomatic nocturnal enuresis (NMNE) children who had partial response or nonresponse to extended release oxybutynin plus desmopressin (group 2), and 21 MNE or NMNE children who relapsed after responding fully to first-line pharmacotherapy (group 3). EA treatment outcomes were determined as outlined by the International Children's Continence Society Standardisation Committee. RESULTS: Overall, 50% and 53.7%, 40%, and 52.4% of children in groups 1, 2, and 3, respectively, responded fully to EA treatment (no significant differences). In groups 1 and 2, 54.4% (31/57) of the partial responders and 36.4% (8/22) of the nonresponders showed full response (FR) after EA treatment was initiated. Of the children with small bladder capacities, 56.7% showed FR. Of the full responders in each group, 60.7%, 88.9%, and 54.5% of groups 1, 2, and 3, respectively, did not have relapse 6 months after cessation of treatment. CONCLUSIONS: Overall, half of the total population achieved FR, and continued success was observed in more than half of full responders irrespective of the groups. Thus, adding EA treatment to pharmacotherapy is an effective second-line therapeutic strategy for children with PRNE. PMID- 20947144 TI - Urological diseases of the Byzantine emperors (330-1453). AB - OBJECTIVES: To offer historical evidence of Byzantine urology and the variety of operations or other healing techniques as applied on the selected group of the Emperors who presented with diseases of the kidney and the urinary tract. METHODS: The health problems of all 87 Byzantine Emperors have been reviewed and focus has been made on the urological diseases, followed by an analysis of the diagnostic and therapeutic processes. RESULTS: Byzantine medicine is the heir of the Ancient Greek and Roman scientific knowledge, enriched by the personal experience of the physicians of the era and the evolution in anatomic researches. In the field of urology, various operative techniques were applied and the surgeons attempted to cure problems of the bladder, urethra, and external genitalia, aiming to restore the health of the State leader. The healing methods applied to the urological problems of the Emperors represent the highest level of this branch of Byzantine surgery, because the best quality of surgeons performed their profession in the capital of the Empire, Constantinople, and were also responsible for the health of the Royal Family. The descriptions of all of these well-known diseases of the urological system and their therapies are contained in the extended compilations of the medical authors of the era, and historical and other nonmedical sources complete the panoramic view of Byzantine urology. CONCLUSIONS: The diagnosis and the healing methods for the urological diseases of the Emperors represent the general level of Byzantine Surgery and especially of urology, as well as the anatomic knowledge of the genital and the urological systems. PMID- 20947145 TI - Distal ureteral calcification secondary to deflux injection: a reality or myth? AB - Dextranomer/hyaluronic acid (Dx/HA) copolymer (Deflux) subureteral injection has become a widely accepted form of treatment for vesicoureteral reflux. Long-term histologic studies, both experimental and clinical, have supported and proven the occurrence of calcification at the site of previous injection. These calcifications in clinical settings may be perceived as ureteral stones. We report a case of an adolescent female with unresolved right-sided abdominal pain with a past surgical history of Deflux injection, who presented with a distal ureteral calcification. Upon further investigation the calcification was found to be confined to the submural portion rather than the intraluminal ureter. PMID- 20947146 TI - XRCC3 T241M polymorphism and bladder cancer risk: a meta-analysis. AB - OBJECTIVES: To evaluate the role of the X-ray repair cross complementing group 3 (XRCC3) T241M polymorphism in bladder cancer susceptibility. Studies of the polymorphism of XRCC3 have shown inconclusive trends in the risk of bladder cancer. METHODS: We performed a meta-analysis of all available studies, which included 5298 cases and 6614 controls. RESULTS: Overall, a significant risk effect of the T241M polymorphism was found under homologous contrast (MM vs TT; P = .02, odds ratio [OR] 1.16, 95% confidence interval [CI] 1.02-1.33). Subtle, but insignificantly increased, risks were observed under recessive model contrast [MM vs (MT+TT); P = .05, OR 1.13, 95% CI 1.00-1.27] in all subjects, with homologous contrast (P = .05, OR 1.16, 95% CI 1.00-1.34) and recessive model contrast (P = .06, OR 1.13, 95% CI 0.99-1.29) observed in the European subgroup. CONCLUSIONS: Taken together, our meta-analysis had suggested an increased risk role of XRCC3 241MM genotype in bladder cancer among all subjects, and the effect of T241M polymorphism on bladder susceptibility should be studied with a larger, stratified population. PMID- 20947147 TI - Leiomyoma of the urinary bladder: a series of nine cases and review of the literature. AB - OBJECTIVES: To present our experience with 9 cases of bladder leiomyomas and a review of the relevant published data. METHODS: During a 13-year period, 9 patients were treated for bladder leiomyoma. Their medical records were retrospectively reviewed, and data, including age, sex, symptoms, tumor size and location, cystoscopy results, radiologic examination findings, method of extirpation, pathology slides, and follow-up results, were analyzed. RESULTS: All 9 patients were women, with a mean age of 43.6 years (range 24-65). Of the 9 patients, 5 reported urinary symptoms, 1 presented with gross hematuria, and 3 were asymptomatic. The mean tumor size was 4.2 cm (range 2.4-7). The tumor size was larger in symptomatic patients than in the asymptomatic patients. All tumors were endovesical lesions; 1 patient had a concomitant extravesical tumor. Transurethral resection was performed in 6 patients, partial cystectomy in 2, and enucleation in 1. Microscopically, the tumors were composed of bland, spindle shaped cells. Recurrence developed in 2 patients. Both patients underwent repeat resection, and no additional recurrence developed. CONCLUSIONS: Leiomyoma of the bladder is rare and occurs predominantly in women. The size, rather than the location, of the tumor appeared to be more closely related to the occurrence of symptoms. Surgical excision is the standard approach to diagnosis and treatment. PMID- 20947148 TI - Magnetic anchoring and guidance system instrumentation for laparo-endoscopic single-site surgery/natural orifice transluminal endoscopic surgery: lack of histologic damage after prolonged magnetic coupling across the abdominal wall. AB - OBJECTIVES: To study the potential pathologic effect of prolonged compression of abdominal wall between the components. Magnetic Anchoring and Guidance System (MAGS) instruments ameliorate some of the challenges in triangulation created by laparo-endoscopic single-site and natural orifice translumenal endoscopic surgery. They consist of an intracorporeal magnetic device coupled to an external hand-held magnet used to anchor and "steer" it around the peritoneal cavity. METHODS: Three pigs (45.5-48.6 kg) underwent laparoscopic placement of magnetic devices in 4 quadrants, with the devices left in place for 2 or 4 hours. Full thickness abdominal wall sections (mean 2.1 cm thick) where each MAGS platform was placed plus a control were harvested at 0, 2, or 14 days after surgery. Histologic assessment was then performed. RESULTS: Beyond mild blanching of the peritoneal surface with a few petechiae immediately after internal component removal, no gross tissue damage was seen. These changes were undetectable by 48 hours and no intra-abdominal adhesions were identified at necropsy. NADH stain for tissue viability in the 4 nonsurvival specimens showed no tissue damage. Hematoxylin and eosin stain showed no necrosis of either superficial or deep muscle, skin, or subcutaneous fat tissue in all 12 specimens when compared with the control. CONCLUSIONS: MAGS instruments do not appear to cause tissue damage or adverse clinical outcomes when coupled across thin porcine abdominal walls for up to 4 hours. Because the distance across the abdominal wall is generally greater in adult human beings, these findings support the further clinical development of magnetic instruments to be used in human patients. PMID- 20947149 TI - Flexible ureteroscopy is effective for proximal ureteral stones in both obese and nonobese patients: a two-year, single-surgeon experience. AB - OBJECTIVE: To report a retrospective series of proximal ureteral stone ureteroscopies (URS) by a single surgeon, using results presented in a recommended format from the American Urological Association Ureteral Stone Guideline panel, with an emphasis on outcomes related to obesity. METHODS: A retrospective chart review of a single surgeon's 2-year URS experience was performed. Of the 55 ureteroscopies for proximal ureteral calculi, 49 cases involving 43 patients had evaluable postoperative imaging. RESULTS: Mean patient age was 56 years and average body mass index was 32.5 kg/m(2). Average ureteral stone size was 9.1 mm; 51% had been preoperatively stented and 93% were stented postoperatively. The overall ureteral stone-free rate was 86%. Overall, 5/43 patients (11%), none of whom were obese, required a second procedure. Obese patients had a 91% stone-free rate, statistically equivalent to the 81% rate in the nonobese. Three patients (7%) developed postoperative urinary tract infections. One patient came to the emergency department for stent-related discomfort. One patient treated in a staged setting for bilateral ureteral calculi developed urinary tract infection and systemic inflammatory response system complicated by alcohol withdrawal requiring a 3-day non-intensive care unit admission. CONCLUSIONS: Proximal ureteral calculi can be successfully treated with URS most of the time, but the risk for persistent renal calculi and fragments exists. The complication rate is low and operative times are short. Obese patients can also be successfully treated ureteroscopically. PMID- 20947150 TI - MicroRNA miR-886-5p inhibits apoptosis by down-regulating Bax expression in human cervical carcinoma cells. AB - OBJECTIVE: MicroRNA (miRNA) plays an essential role in the progression of a variety of cancers, but its role in cervical cancer progression is not well defined. We aimed to test whether special miRNAs and their target mRNAs contribute to cervical cancer progression. METHODS: The expression profiles of 1145 microRNAs in cervical squamous cell carcinomas (CSCC) and adjacent non-tumor tissues were investigated using an Illumina microRNA microarray platform. Differentially expressed miRNAs were validated by RT-PCR. Downstream target validation was performed for miR-886-5p. RESULTS: We found that the expression levels of seven miRNAs differed significantly between CSCC tissues and adjacent non-tumor tissues. Forced expression of one miRNA, miR-886-5p, over-expressed in CSCC tissues lowered expression of the pro-apoptotic protein Bax, reduced apoptosis and promoted cell proliferation in H8, an HPV16-immortalized human cervical squamous epithelial cell line. Knockdown of miR-886-5p increased Bax protein and apoptotic cell death in cells of the cervical squamous carcinoma cell line, SiHa. CONCLUSION: MicroRNA miR-886-5p inhibits apoptosis of cervical cancer cells by down-regulating the production of Bax. PMID- 20947151 TI - Ventral hernia following primary laparotomy for ovarian, fallopian tube, and primary peritoneal cancers. AB - OBJECTIVES: To evaluate the incidence and risk factors for ventral hernia development following primary laparotomy for ovarian, fallopian tube, and peritoneal cancers. METHODS: All patients who underwent primary laparotomy for ovarian, tubal, or peritoneal cancer from 3/05 to 12/07 were identified. Hernias were identified radiographically or during physical exam. One-year and 2-year hernia rates were calculated. Clinicopathologic factors were evaluated for an association with the development of hernia using univariate and multivariate analysis. RESULTS: We identified 239 cases with 12 months of follow-up. Median age was 60 years (17-89 years), and median body mass index (BMI) was 25.0 kg/m(2) (16.9-58.5 kg/m(2)). Advanced stage disease (FIGO stage III/IV) was diagnosed in 182/239 (76%). The 1-year hernia rate was 8.8% (21/239): 13/21 (61.9%) were symptomatic, and 8/21 (38.1%) underwent hernia repair operations. On multivariate analysis, only BMI (p=0.004) and intraperitoneal (IP) chemotherapy (p=0.016) retained their independent association with hernia development by 12 months. Of the 239 patients, 167 had 24 months of follow-up. The 2-year hernia rate was 23.4% (39/167): 25/39 (64.1%) were symptomatic, and 17/39 (43.6%) underwent hernia repair operations. Multivariate analysis in this group demonstrated that advanced stage (p=0.033), wound complications (p=0.029), and BMI (p=0.012) were independently associated with hernia development by 24 months. CONCLUSIONS: The development of ventral hernia is a significant postoperative morbidity in patients undergoing primary surgery for ovarian, tubal, or peritoneal cancer. Independent associations with hernia development include: BMI and IP chemotherapy by Year 1, and BMI, wound complications and advanced stage by Year 2. PMID- 20947152 TI - CA 125 normalization with chemotherapy is independently predictive of survival in advanced endometrial cancer. AB - OBJECTIVE: Changes in CA 125 with chemotherapy predict outcome for epithelial ovarian cancer. There is no such data for advanced endometrial cancer. METHOD: Retrospective review of all women receiving carboplatin and paclitaxel for advanced endometrial cancer at any of the institutions of the British Columbia Cancer Agency between September 1995 and September 2006. RESULTS: 185 newly diagnosed women were treated. Univariable analysis for progression-free survival identified as adverse predictors: grade 3, positive residual, age > 60, deep myometrial invasion, increasing stage/substage, papillary serous subtype, presence of cervical involvement, ECOG 1 or greater, CA 125 above 35 either preoperatively or at start of cycle 1 and CA 125 greater than 24 at the start of cycle 3. Upon multivariate analysis, CA 125 above 24 at cycle 3, grade 3 and positive residual remained as independent predictors. The single most important factor identified by decision tree analysis was CA 125 level at cycle 3. CONCLUSION: As with epithelial ovarian cancer, changes in CA 125 are highly predictive of outcome for advanced, chemotherapy treated endometrial cancer. PMID- 20947153 TI - Association between prostaglandin E receptor 3 polymorphisms and Stevens-Johnson syndrome identified by means of a genome-wide association study. AB - BACKGROUND: Stevens-Johnson syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucosa. They often affect the ocular surface and can result in permanent visual dysfunction. OBJECTIVES: We sought to discover genetic markers for SJS/TEN susceptibility. METHODS: We performed a genome-wide association study with 60 patients and 300 control subjects. We applied stringent filter and visual assessments for selecting single nucleotide polymorphisms (SNPs) and a high false discovery rate threshold. We fine-mapped the region where a candidate SNP was found and confirmed the results by means of sequencing. We evaluated the function of agonist-activated prostaglandin E receptor 3 (EP3), the gene for which contained several SNPs, in regulating cytokine production in human conjunctival epithelial (CE) cells. The expression levels of EP3 in the CE cells from patients and control subjects were also compared. RESULTS: We identified 3 SNPs that passed the false discovery rate threshold. One (rs17131450) was close to the EP3 gene. Therefore we analyzed the EP3 region in detail and identified 5 other SNPs. We confirmed the association between SJS/TEN and all 6 SNPs. Activated EP3 was expressed in control CE cells, and it suppressed polyI:C-stimulated cytokine production, suggesting that EP3 might help prevent ocular surface inflammation. Concordantly, the EP3 levels were much lower in the CE cells of the patients than in those of the control subjects. CONCLUSION: We demonstrated, using both genetic and functional analyses, that EP3 could be a key player in the pathogenesis of SJS/TEN accompanied by ocular complications. PMID- 20947154 TI - Hemispheric asymmetries in processing L1 and L2 idioms: effects of salience and context. AB - This study investigates the contribution of the left and right hemispheres to the comprehension of bilingual figurative language and the joint effects of salience and context on the differential cerebral involvement in idiom processing. The divided visual field and the lexical decision priming paradigms were employed to examine the activation of salient and nonsalient ambiguous idiom interpretations (i.e., literal vs. non-literal) in the two hemispheres. Literally plausible ambiguous idioms, L1 (Polish) and L2 (English), were embedded in unconstraining ambiguous (e.g., I knew he kept an ace up his sleeve) or constraining unambiguous context clearly favoring their conventional idiomatic interpretation (e.g., The debating president kept an ace up his sleeve). Idioms were presented centrally, followed by laterally presented targets related to the figurative (e.g., GAIN) or literal (e.g., SHIRT) meaning of the idiom and displayed at Interstimulus Intervals (ISIs) of 0 ms (Experiment 1), 300 ms (Experiment 2), and 800 ms (Experiment 3). Results indicate that context and salience effects are significantly modulated by the language (native vs. nonnative) of the stimulus materials being presented to each hemisphere. Literal facilitation was found for L2 idioms in all three ISI conditions, which supports the notion of the special status that literal meanings of L2 idioms enjoy in the course of their processing by nonnative language users. No significant differences were found between the right and left hemispheres in regards to their sensitivity to contextual constraints. Results are discussed in terms of the Graded Salience Hypothesis and the Fine/Coarse Coding Theory. PMID- 20947155 TI - Eight-year clinical evaluation of a 2-step self-etch adhesive with and without selective enamel etching. AB - OBJECTIVES: The objective of this randomized controlled clinical trial was to evaluate the 8-year clinical performance of a mild 2-step self-etch adhesive in non-carious Class-V lesions with and without prior selective phosphoric acid etching of the enamel cavity margins. METHODS: A total of 100 non-carious Class-V lesions in 29 patients were restored with Clearfil AP-X (Kuraray). The composite restorations were bonded following two different approaches: (1) application of Clearfil SE (Kuraray) following a self-etch approach (control group; C-SE non etch), (2) selective phosphoric acid-etching of the enamel cavity margins before application of Clearfil SE (experimental group; C-SE etch). The restorations were evaluated after 6 months, 1, 2, 3, 5 and 8 years of clinical service regarding their retention, marginal integrity and discoloration, caries occurrence, preservation of tooth vitality and post-operative sensitivity. RESULTS: The recall rate at 8 years was 76%. Only two restorations, one of the C-SE non-etch group and one of the C-SE etch group, were clinically unacceptable due to loss of retention leading to a retention rate and a clinical success rate of 97% in both groups. Aging of the restorations was characterized by an increase in the percentage of restorations with a small but clinically acceptable marginal defect (C-SE non-etch: 92%; C-SE etch: 84%) and/or a superficial marginal discoloration (C-SE non-etch: 44%; C-SE etch: 28%). At the enamel side, the presence of small marginal defects (C-SE non-etch: 86%; C-SE etch: 65%) and superficial marginal discoloration (C-SE non-etch: 11%; C-SE etch%) was more frequently noticed in the control group than in the experimental group. The difference, however, was only statistically significant for the presence of superficial marginal discoloration (McNemar, p=0.01). SIGNIFICANCE: After 8 years of clinical functioning, the clinical effectiveness of Clearfil SE remained excellent, with selective acid etching of the enamel cavity margins only having some minor positive effect on marginal integrity and absence of marginal discoloration at enamel. PMID- 20947156 TI - Correlation between microtensile bond strength data and clinical outcome of Class V restorations. AB - OBJECTIVE: To determine if the results of resin-dentin microtensile bond strength (MUTBS) is correlated with the outcome parameters of clinical studies on non retentive Class V restorations. METHODS: Resin-dentin MUTBS data were obtained from one test center; the in vitro tests were all performed by the same operator. The MUTBS testing was performed 8 h after bonding and after 6 months of storing the specimens in water. Pre-test failures (PTFs) of specimens were included in the analysis, attributing them a value of 1MPa. Prospective clinical studies on cervical restorations (Class V) with an observation period of at least 18 months were searched in the literature. The clinical outcome variables were retention loss, marginal discoloration and marginal integrity. Furthermore, an index was formulated to be better able to compare the laboratory and clinical results. Estimates of adhesive effects in a linear mixed model were used to summarize the clinical performance of each adhesive between 12 and 36 months. Spearman correlations between these clinical performances and the MUTBS values were calculated subsequently. RESULTS: Thirty-six clinical studies with 15 adhesive/restorative systems for which MUTBS data were also available were included in the statistical analysis. In general 3-step and 2-step etch-and-rinse systems showed higher bond strength values than the 2-step/3-step self-etching systems, which, however, produced higher values than the 1-step self-etching and the resin modified glass ionomer systems. Prolonged water storage of specimens resulted in a significant decrease of the mean bond strength values in 5 adhesive systems (Wilcoxon, p<0.05). There was a significant correlation between MUTBS values both after 8 h and 6 months of storage and marginal discoloration (r=0.54 and r=0.67, respectively). However, the same correlation was not found between MUTBS values and the retention rate, clinical index or marginal integrity. SIGNIFICANCE: As MUTBS data of adhesive systems, especially after water storage for 6 months, showed a good correlation with marginal discoloration in short-term clinical Class V restorations, longitudinal clinical trials should explore whether early marginal staining is predictive for future retention loss in non carious cervical restorations. PMID- 20947158 TI - A gene transfection for rat mesenchymal stromal cells in biodegradable gelatin scaffolds containing cationized polysaccharides. AB - The objective of this study was to design three-dimensional scaffolds of bone marrow-derived stem cells capable of their gene transfection and evaluate the transfection extent. Three-dimensional scaffolds of gelatin and beta-tricalcium phosphate (beta-TCP) were prepared. Spermine-introduced pullulan (spermine pullulan) was prepared as the non-viral carrier of gene transfection. The spermine-pullulan was mixed with a luciferase plasmid DNA to prepare their polyion complex. The scaffolds were treated with succinylated gelatin (suc-gel) at different concentrations, treated in different methods of freeze-drying and dehydrothermal treatment, and placed in the aqueous of complexes to prepare various scaffolds containing the complex. When the stem cells were seeded into the scaffolds to evaluate the gene transfection of cells, the level of plasmid DNA transfection depended on the method of complex containing scaffolds preparation. The complexes were released with time from the scaffolds although the release profile depended on the type of scaffolds. The order of gene transfection for the stem cells in the scaffolds was in good accordance with that of plasmid DNA released. It is possible that cells were transfected with the complexes released from the scaffolds. PMID- 20947159 TI - Synthesis and biological activities of a library of glycosaminoglycans mimetic oligosaccharides. AB - Biologically active oligosaccharides related to glycosaminoglycans are accumulating increased attention because of their therapeutic potential and for their value in mechanistic studies. Heparan mimetics (HMs) are a family of dextran based polymer known to mimic the properties of glycosaminoglycans, and particularly those of heparan sulfates, as to interact with heparin binding proteins. HMs have shown to stimulate tissue repair in various animal models. Here, we use different methods to depolymerize HMs in order to produce a library of related oligosaccharides and study their biological activities. Since HMs were resistant to endoglycanases activities, depolymerization was achieved by chemical approaches. In vitro biological studies showed that HM oligosaccharides can differentially potentiate FGF-2 mitogenic and antithrombotic activities. In vivo, a selected oligosaccharide (H-dp12) showed to be able to regenerate tissue almost as well as the related polymeric product. The very low anticoagulant activity and high biological activity of low mass oligosaccharides give to these products a new therapeutic potential. PMID- 20947157 TI - Delivery of rosiglitazone from an injectable triple interpenetrating network hydrogel composed of naturally derived materials. AB - An in situ gelable and biodegradable triple-interpenetrating network (3XN) hydrogel, completely devoid of potentially cytotoxic extraneous small molecule crosslinkers, is formulated from partially oxidized dextran (Odex), teleostean and N-carboxyethyl chitosan (CEC). Both the rheological profile and mechanical strength of the 3XN hydrogel approximate the combined characteristics of the three individual hydrogels composed of the binary partial formulations (i.e., Odex/CEC, Odex/teleostean, and CEC/teleostean). The 3XN hydrogel is considerably more resistant to fibroblast-mediated degradation compared to each partial formulation in cell culture models; this is attributable to the interpenetrating triple-network structure. The presence of teleostean in the 3XN hydrogel imparts cell affinity, constituting an environment amenable to fibroblast growth. in vivo subdermal injection into mouse model shows that the 3XN hydrogel does not induce extensive inflammatory response nor is there any evidence of tissue necrosis, further confirming the non-cytotoxicity of the hydrogel and its degradation byproducts. Importantly, the capability of the 3XN hydrogel to serve as a sustained drug delivery vehicle is confirmed using rosiglitazone as a model drug. The presence of rosiglitazone profoundly changes the cell/tissue interactions with the subdermally injected 3XN hydrogel. Rosiglitazone suppresses both the inflammatory response and tissue repair in a dose-dependent manner and considerably moderated the hydrogel degradation. PMID- 20947160 TI - Electroporation-mediated transfer of Runx2 and Osterix genes to enhance osteogenesis of adipose stem cells. AB - In the present study, we tested the hypothesis that electroporation-mediated transfer of Runx2, Osterix, or both genes enhances the in vitro and in vivo osteogenesis from adipose stem cells (ASCs). ASCs were transfected with Runx2, Osterix, or both genes using electroporation, and further cultured in monolayer or in PLGA scaffold under osteogenic medium for 14 days, then analyzed for in vitro osteogenic differentiation. Transfected ASC-PLGA scaffold hybrids were also implanted on nude mice to test for in vivo ectopic bone formation. Runx2 and Osterix genes were strongly expressed in ASCs transfected with each gene on day 7, decreasing rapidly on day 14. Runx2 protein was strongly expressed in ASCs transfected with the Runx2 gene, while Osterix protein was strongly expressed in ASCs transfected with either or both Runx2 and Osterix genes. Overexpression of Runx2 and Osterix significantly increased the gene expression of osteogenic differentiation markers (alkaline phosphatase [ALP], osteocalcin [OCN], type I collagen [COL1A1], and bone sialoprotein [BSP]) in ASCs. Transfection of Runx2 and Osterix genes enhanced the protein expression of OCN, type I collagen, and BSP, as demonstrated by Western blot analysis, and ALP activity as well as enhancing mineralization in the monolayer culture and ASC-PLGA scaffold hybrids. Runx2- or Osterix-transfected ASC-PLGA scaffold hybrids promoted bone formation in nude mice after 6 weeks of in vivo implantation. PMID- 20947161 TI - Evaluating DNA methylation and gene expression variability in the human term placenta. AB - Obtaining representative samples from a term placenta for gene-expression studies is confounded by both within placental heterogeneity and sampling effects such as sample location and processing time. Epigenetic processes involved in the regulation of gene expression, such as DNA methylation, may show similar variability, but are less well studied. Therefore, we investigated the nature of within and between- placenta variation in gene expression and DNA methylation of genes that were chosen for being differentially expressed or methylated by cell type within the placenta. METHODS: In total, two or more samples from each of 38 normal term placentae were utilized. The expression levels of CDH1, CDH11, ID2, PLAC1 and KISS1 were evaluated by real-time PCR. DNA methylation levels of LINE1 elements and CpGs within the promoter regions of KISS1, PTPN6, CASP8, and APC were similarly quantified by pyrosequencing. RESULTS: Despite considerable sample to-sample variability within each placenta, the within-placenta correlation for both gene expression and methylation was significant for each studied gene. Most of this variability was not due to sample location. However, between placental differences in gene expression were inflated by the dramatic effect of processing time (0-24 h) on mRNA levels, particularly for PLAC1 and KISS1 (both expressed in the apical syncytiotrophoblast). In contrast, DNA methylation levels remained relatively constant over this same time period. CONCLUSION: Due to extensive site to-site variability, multiple sampled sites are needed to accurately represent a placenta for molecular studies. Furthermore, mRNA quantitation of some genes may be hampered by its rapid degradation post-delivery (and possibly perinatally) and thus processing time should be considered in such analyses. Within-placenta correlations in expression and methylation from unrelated genes raise the possibility that methylation and expression variation may potentially reflect cell composition differences between samples rather than true differences occurring at the cellular level. PMID- 20947162 TI - Thomas George Lee - Implantation and early development of North American rodents. AB - A century ago Thomas G. Lee amassed an unparalleled collection of developmental series of North American rodents such as the thirteen-lined ground squirrel, the Plains pocket gopher and Merriam's kangaroo rat. He was the first to describe the initial attachment of the squirrel blastocyst to the antimesometrial side of the uterus. The full potential of Lee's material was not realized until after his death, when it came into the possession of Mossman. The latter relied heavily on Lee's collection when writing his seminal monograph on the comparative morphogenesis of fetal membranes and much of Lee's material was subsequently described in detail by Mossman and others. It now forms part of the Harland W. Mossman Collection at the University of Wisconsin. PMID- 20947163 TI - Pathological characteristics of a series of rare chronic histiocytic intervillositis of the placenta. AB - Chronic histiocytic intervillositis of the placenta (CHI) is a rare and poorly understood pathology which may occur in all trimesters. The most conspicuous feature is a histiocytic infiltration of the intervillous space without involvement of the villous parenchyma. In this report on CHI, we re-evaluate a series of four cases and focus on histological, immunohistological and fluorescence in situ hybridisation-derived findings, fetal status and clinical data for previously unrecognised CHI-associated features. Our approach revealed that assisted reproduction-induced pregnancy had been performed in 2 of 4 CHI cases, but other factors and comorbidities are likely to contribute to CHI. PMID- 20947164 TI - Pericyte coverage of fetoplacental vessels in pregnancies complicated by Type 1 diabetes mellitus. AB - Placentas from pregnancies complicated by Type 1 diabetes mellitus (DM 1) display altered vascular morphology and function. Here we studied the extent of pericyte coverage in microvessels of normal pregnancies and pregnancies complicated by DM 1. We used smooth muscle actin (SMA) as a marker for quantitation of pericyte coverage in placental capillaries. The extent of pericyte coverage around the vessel circumference was 38 +/- 11% in normal vs. 33 +/- 10% in DM 1 pregnancies. We found that there is no statistically significant difference in the extent of pericyte coverage around the capillary circumference between DM 1 and normal pregnancies. PMID- 20947165 TI - On the assessment of dasatinib-induced autophagy in CLL. PMID- 20947166 TI - "Too stubborn to ever be governed by enforced insanity": Some therapeutic jurisprudence dilemmas in the representation of criminal defendants in incompetency and insanity cases. AB - Little attention has been paid to the importance of the relationship between therapeutic jurisprudence (TJ) and the role of criminal defense lawyers in insanity and incompetency-to-stand-trial (IST) cases. That inattention is especially noteworthy in light of the dismal track record of counsel providing services to defendants who are part of this cohort of incompetency-status-raisers and insanity-defense-pleaders. On one hand, this lack of attention is a surprise as TJ scholars have, in recent years, turned their attention to virtually every other aspect of the legal system. On the other hand, it is not a surprise, given the omnipresence of sanism, an irrational prejudice of the same quality and character of other irrational prejudices that cause (and are reflected in) prevailing social attitudes of racism, sexism, homophobia, and ethnic bigotry, that infects both our jurisprudence and our lawyering practices. Sanism is largely invisible and largely socially acceptable, and is based predominantly upon stereotype, myth, superstition, and deindividualization. It is sustained and perpetuated by our use of alleged "ordinary common sense" (OCS) and heuristic reasoning in an unconscious response to events both in everyday life and in the legal process. This paper examines the literature that seeks to apply TJ principles to the criminal law process in general, drawing mostly on the work of Professor David Wexler. It considers why the lack of attention that I have referred to already is surprising (given TJ's mandate and the fact that many TJ issues are inevitably raised in any insanity or IST case). The paper then considers why this lack of attention is not surprising, given the omnipresence of sanism. It will consider some of the actual counseling issues that might arise in these contexts, and offer some suggestions to lawyers representing clients in cases in which mental status issues may be raised. The paper concludes that we must rigorously apply therapeutic jurisprudence principles to these issues, so as to strip away sanist behavior, pretextual reasoning and teleological decision making from the criminal competency and responsibility processes, so as to enable us to confront the pretextual use of social science data in an open and meaningful way. This gambit would also allow us to address-in a more successful way than has ever yet been done-the problems raised by the omnipresence of ineffective counsel in cases involving defendants with mental disabilities. PMID- 20947167 TI - Heredity, reproduction, and perfectibility in revolutionary and Napoleonic France, 1789-1815. AB - During the French Revolution, there appeared a striking and far-ranging medical literature on heredity, reproduction and biological 'perfectibility'. In some ways anticipating ideas associated with modern eugenics, these writings emerged from radical revolutionary projects for 'physical and moral regeneration' and incarnated deep-seated desires to transform French society and make a 'new man' in mind and body. But by breaking down boundaries between public and private life, doctors did more than just try to regulate intimate sexual behaviour. Instead, they proffered a more intimate vision of civic volunteerism, in which sexual hygiene and domestic practices allowed their patients to imagine new forms of society and gave them ways to attain these socio-political dreams. Moreover, they were responding to powerful new worries about heredity and sought to counsel their patients in the ways of family panning. By the end of revolutionary period, then, medical and lay thinkers had transformed the marriage bed and household into a specially controlled environment - a kind of affective laboratory - in which conscientious parents could make healthy children and raise them in the context of specific political and social values. PMID- 20947168 TI - Assessing the role of Asp 194 in the transmembrane domains of the alpha-chain of the high-affinity receptor complex for immunoglobulin E in signal transduction. AB - The high-affinity receptor complex for IgE plays a pivotal role in allergic responses since cross-linking of the high-affinity IgE receptor (FcERI) on target cells initiates a signaling cascade facilitating release of inflammatory mediators causing allergic responses. The transmembrane regions of the ligand binding domains of the high-affinity IgE and low-affinity IgG receptors share an invariant motif (LFAVDTGL) containing a polar aspartate within a predominantly non-polar setting. The functional importance of this aspartate residue (D194) in FcERI-mediated receptor signaling was assessed by site-directed mutagenesis. Rat basophilic leukemia cells (RBL-2H3) transfected with the human IgE binding subunit (FcERIalpha) incorporating polar substitutions like asparagine (D194N) or threonine (D194T) resulted in the formation of a functional rat/human chimeric receptor complex. When activated via huIgE and antigen, cells transfected with these variant receptor subunits supported mediator release, intracellular calcium mobilisation and tyrosine phosphorylation of gamma-chain and Syk kinase while a non-polar substitution (D194L) gave rise to cell surface expression of the mutated receptor subunit but failed to initiate downstream signaling. No cell surface expression of huFcERIalpha gene constructs was observed when D194 was replaced with the non-polar Ile (D194I) residue of similar size, the larger positively charged Arg (D194R) or lysine (D194K) residues, or the negatively charged glutamate (D194E) and smaller polar Ser (D194S) non-polar Ala (D194A) and V (D194V). These observations highlight importance of the size and charge of amino acid residue at position 194 in determining IgE receptor subunit interactions, cell surface localization, and initiation of downstream signaling events. PMID- 20947169 TI - Ligation of the BT3 molecules, members of the B7 family, enhance the proinflammatory responses of human monocytes and monocyte-derived dendritic cells. AB - BT3 is a new family of immunoreceptors belonging to the extended B7 family. BT3 molecules are expressed on the surface of resting and activated monocytes and monocyte-derived dendritic cells (iDC). We show that BT3 cross-linking, in the absence of other survival factors, provides a survival signal for monocytes and iDC and induces up-regulation of costimulatory molecules, such as CD80 and CD86, and HLA-DR. We further analyzed the effects of BT3 cross-linking on various proinflammatory responses on monocytes and iDC. The results obtained showed that BT3 engagement is able to modulate the production of IL8/CXCL8, IL-1beta and IL 12/p70. Moreover, we demonstrated a synergistic effect between BT3 and Toll-like receptors ligands on both monocytes and iDC in up-regulating the production of proinflammatory cytokines. Thus, BT3 could be involved in the regulation of the balance between immune activation and suppression. A better understanding of its physiological role of these families of receptors awaits the precise identification of the nature, origin, expression, and distribution of their ligands. PMID- 20947170 TI - Viral induction of Zac1b through TLR3- and IRF3-dependent pathways. AB - Zinc finger protein regulator of apoptosis and cell cycle arrest (Zac1) is a transcription factor able to induce apoptosis or cell cycle arrest through independent pathways. In spite of the important potential functions attributed to Zac1, little is known of its physiological regulation and biological function. We discovered that variant Zac1b was expressed in murine embryonic fibroblasts (MEFs) treated with polyriboinosinic polyribocytidylic acid [poly(I:C)], a synthetic double-stranded RNA. This regulation occurred mainly through Toll-Like Receptor 3 (TLR3)- and Interferon Regulatory Factor 3 (IRF3)-dependent pathways. As TLR3 and IRF3 are central activators of antiviral immunity, we hypothesized that Zac1 may be implicated in antiviral responses. In line with this notion, we observed that Zac1b was expressed in MEFs infected with Encephalomyocarditis virus (EMCV). We also observed that Zac1-deficient MEFs were less sensitive to EMCV-induced cell death than wild-type MEFs. However, Zac1 gene inactivation had no effect on the survival of mice infected with EMCV. In conclusion, this study describes for the first time a transcriptional regulation of Zac1b, induced by synthetic dsRNA and RNA viruses, the functional significance of which remains to be further investigated. PMID- 20947171 TI - Visual acuity testing using autorefraction or pinhole occluder compared with a manual protocol refraction in individuals with diabetes. AB - PURPOSE: To compare visual acuity (VA) scores obtained after autorefraction or using a pinhole occluder to scores obtained after refraction according to a standard clinical research protocol. DESIGN: Prospective, comparative case series. PARTICIPANTS: One hundred ten study participants (209 eyes) with diabetes mellitus and a broad range of diabetic retinopathy severity and VA. METHODS: We measured VA after autorefraction by a Topcon KR-8000 autorefractor as well as after a Diabetic Retinopathy Clinical Research Network (DRCR.net) protocol manual refraction. The order of testing was randomized and examiners were masked to the source of each refraction. A second VA measurement, utilizing an identical DRCR.net manual refraction, was made in a subset of eyes (n = 144; 69%) to establish test-retest variability for comparison purposes. All eyes underwent VA testing using a pinhole occluder. MAIN OUTCOME MEASURES: Best corrected VA as measured by the Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Test (E-ETDRS). RESULTS: In all eyes, the median E-ETDRS VA letter score (EVA) obtained after manual refraction (MR-EVA) was 69 (Snellen equivalent 20/40), ranging from 4 to 93 (20/800 to 20/16). The median MR-EVA was slightly better than the median EVA obtained after autorefraction (AR-EVA), with a median difference (AR-EVA - MR-EVA) of -1 letter (25th, 75th percentiles, -4, 2 letters). The absolute difference between AR-EVA and MR-EVA was similar to the test-retest variability of MR-EVA alone. In contrast, MR-EVA was better than EVA obtained using a pinhole occluder (PH-EVA; median PH-EVA - MR-EVA, -4 letters [ 9, 0]), and had significantly less test-retest variability (P<0.001). Generally, the spherical equivalent of autorefraction was slightly more hyperopic (or less myopic) than the spherical equivalent of manual refraction (median difference, +0.25 diopters [0, +0.63]). CONCLUSIONS: Given the substantial time and effort required for training and certification of study protocol refractionists, and the similarity between AR-EVA and MR-EVA, further evaluation of autorefraction, but not pinhole occluder testing, as an alternative to the current clinical research gold standard of ETDRS protocol manual refraction in study participants with diabetic retinopathy is warranted. PMID- 20947172 TI - Ocular medulloepithelioma chemosensitivity. PMID- 20947173 TI - Maternal stress and perceptions of self-efficacy in socioeconomically disadvantaged mothers: an explicative model. AB - Studies have demonstrated that maternal stress and perceptions of self-efficacy influence a mother's performance, affecting her ability to interact with her child and to understand and answer his needs. The purpose of this study was to evaluate maternal stress and the perception of self-efficacy in the mothers of infants who are cared for in child-care centers and belong to the poorest segment of the Chilean population. To this end, these aspects were studied in 121 low income, high-social-risk mothers with children between the ages of 4 and 9 months. The final goal was to generate an explicative model of self-efficacy and maternal stress that considered characteristics of the family and the child. The results revealed that family characteristics - especially household size, per capita incomes and mother age - are more relevant for explaining maternal self efficacy and stress. The findings and implications for practice are discussed. PMID- 20947174 TI - Paliperidone extended-release as adjunctive therapy to lithium or valproate in the treatment of acute mania: a randomized, placebo-controlled study. AB - BACKGROUND: Combination treatment with atypical antipsychotics and a mood stabilizer is often recommended for treatment of manic or mixed episodes associated with bipolar I disorder. METHODS: Eligible patients (n=300) with a Young Mania Rating Scale (YMRS) total score >=20 were randomly allocated (1:1) to continue mood stabilizer monotherapy or receive flexibly-dosed paliperidone ER (3 12 mg/day) in addition (combination treatment) for 6 weeks. The primary efficacy variable was the change from baseline to endpoint in the YMRS total score. RESULTS: The mean (SD) YMRS total score at baseline was 26.7 (5.26); 33% of patients presented with a mixed (as distinct from a manic) episode and 62% were on valproate and 38% on lithium. The mean (SD) change from baseline to endpoint in the YMRS total score was not significantly different for combination treatment (-14.3 [10.0]) compared with mood stabilizer monotherapy (-13.2 [10.9]; p=0.16). Combination treatment also failed to separate from mood stabilizer monotherapy for the secondary efficacy measures. The incidence of treatment-emergent adverse events was higher with combination treatment (70%) than with mood stabilizer monotherapy (54%); insomnia was the most common adverse event in both treatment groups (11%). LIMITATIONS: The relatively low doses of paliperidone ER used in this study and the conduct across different countries may have contributed to its failure to differentiate combination treatment from mood stabilizer monotherapy for the primary and secondary efficacy measures. CONCLUSIONS: In this study, flexibly-dosed paliperidone ER used as adjunctive therapy to mood stabilizers did not demonstrate efficacy over mood stabilizer monotherapy. No new safety signals were observed with combination treatment in this population. PMID- 20947175 TI - Different aspects of theory of mind in paranoid schizophrenia: evidence from a video-based assessment. AB - In schizophrenia, impairments of theory of mind (ToM) may be due to excessive ('overmentalizing') or defective ('undermentalizing') attribution of mental states. However, most ToM tests differentiate neither between 'overmentalizing' and 'undermentalizing' nor between cognitive and affective ToM in schizophrenia. This study aimed at differentiating these aspects of ToM in 80 patients diagnosed with paranoid schizophrenia and 80 matched healthy controls using the 'Movie for the Assessment of Social Cognition' (MASC). Outcome parameters comprised 1) error counts representing 'undermentalizing' or 'overmentalizing', 2) decoding of cognitive or emotional mental states and 3) non-social inferencing. Multivariate analysis of covariance (MANCOVA) showed significantly abnormal scores for two dimensions of 'undermentalizing' as well as for cognitive and emotional ToM that were not explained by global cognitive deficits. Scores for 'overmentalizing' did not differ between groups, when age, gender, non-social reasoning and memory were controlled. In schizophrenic patients, negative symptoms were associated with a lack of a mental state concept, while positive symptoms like delusions were associated with 'overmentalizing', supporting respective etiological concepts of delusions. PMID- 20947176 TI - Emerging disease-modifying oral therapies for multiple sclerosis. AB - Although therapy for multiple sclerosis (MS) has changed substantially over the past few decades, introducing immunomodulatory drugs into everyday clinical practice, it is still not satisfactory enough in halting the disease progression and increasing disability. Moreover, its injection-based administration leads to suboptimal adherence, even further reducing the potential treatment benefits. Emerging disease-modifying oral agents for MS are therefore warranted. In this paper advances in the novel oral therapeutic approaches to MS treatment are reviewed. PMID- 20947177 TI - Guillain-Barre syndrome: clinical variants and their pathogenesis. AB - Numerous clinical subtypes of Guillain-Barre syndrome have been described over the century since the original description of the syndrome. These variants of Guillain-Barre syndrome are discussed and their immunological pathogenesis reviewed. PMID- 20947178 TI - CASP8 in MS. PMID- 20947180 TI - Characterization of the multixenobiotic resistance (MXR) mechanism in embryos and larvae of the zebra mussel (Dreissena polymorpha) and studies on its role in tolerance to single and mixture combinations of toxicants. AB - The study of the cellular mechanisms of tolerance of organisms to pollution is a key issue in aquatic environmental risk assessment. Recent evidence indicates that multixenobiotic resistance (MXR) mechanisms represent a general biological defense of many marine and freshwater organisms against environmental toxicants. In this work, toxicologically relevant xenobiotic efflux transporters were studied in early life stages of zebra mussels (Dreissena polymorpha). Expression of a P-gp1 (ABCB1) transporter gene and its associated efflux activities during development were studied, using qRT-PCR and the fluorescent transporter substrates rhodamine B and calcein-AM combined with specific transporter inhibitors (chemosensitizers). Toxicity bioassays with the model P-gp1 chemotherapeutic drug vinblastine applied singly and in combination with different chemosensitizers were performed to elucidate the tolerance role of the P-gp1 efflux transporter. Results evidenced that the gene expression and associated efflux activities of ABC transporters were low or absent in eggs and increased significantly in 1-3d old trochophora and veliger larvae. Specific inhibitors of Pgp1 and/or MRP transport activities including cyclosporine A, MK571, verapamil and reversin 205 and the musk celestolide resulted in a concentration dependent inhibition of related transport activities in zebra mussel veliger larvae, with IC50 values in the lower micromolar range and similar to those reported for mammals, fish and mussels. Binary mixtures of the tested transporter inhibitors except celestolide with the anticancer drug and P-gp1 substrate vinblastine increased the toxicity of the former compound more than additively. These results indicate that MXR transporter activity is high in early life-stages of the zebra mussel and that may play an important role in the tolerance to environmental contaminants. PMID- 20947181 TI - Microsomal biotransformation of chlorpyrifos, parathion and fenthion in rainbow trout (Oncorhynchus mykiss) and coho salmon (Oncorhynchus kisutch): mechanistic insights into interspecific differences in toxicity. AB - Rainbow trout often serve as a surrogate species evaluating xenobiotic toxicity in cold-water species including other salmonids of the same genus, which are listed as threatened or endangered. Biotransformation tends to show species specific patterns that influence susceptibility to xenobiotic toxicity, particularly organophosphate insecticides (OPs). To evaluate the contribution of biotransformation in the mechanism of toxicity of three organophosphate (phosphorothionate) insecticides, (chlorpyrifos, parathion and fenthion), microsomal bioactivation and detoxification pathways were measured in gills, liver and olfactory tissues in juvenile rainbow trout (Oncorhynchus mykiss) and compared to juvenile coho salmon (Oncorhynchus kisutch). Consistent with species differences in acute toxicity, significantly higher chlorpyrifos bioactivation was found in liver microsomes of rainbow trout (up to 2-fold) when compared with coho salmon. Although bioactivation to the oxon was observed, the catalytic efficiency towards chlorpyrifos dearylation (detoxification) was significantly higher in liver for both species (1.82 and 0.79 for trout and salmon, respectively) when compared to desulfuration (bioactivation). Bioactivation of parathion to paraoxon was significantly higher (up to 2.2-fold) than detoxification to p-nitrophenol in all tissues of both species with rates of conversion in rainbow trout, again significantly higher than coho salmon. Production of fenoxon and fenthion sulfoxides from fenthion was detected only in liver and gills of both species with activities in rainbow trout significantly higher than coho salmon. NADPH-dependent cleavage of fenthion was observed in all tissues, and was the only activity detected in olfactory tissues. These results indicate rainbow trout are more sensitive than coho salmon to the acute toxicity of OP pesticides because trout have higher catalytic rates of oxon formation. Thus, rainbow trout may serve as a conservative surrogate species for the evaluation of OP pesticides in coho salmon. PMID- 20947179 TI - Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications. AB - Autophagy is a highly conserved intracellular pathway involved in the elimination of proteins and organelles by lysosomes. Known originally as an adaptive response to nutrient deprivation in mitotic cells, autophagy is now recognized as an arbiter of neuronal survival and death decisions in neurodegenerative diseases. Studies using postmortem human tissue, genetic and toxin-induced animal and cellular models indicate that many of the etiological factors associated with neurodegenerative disorders can perturb the autophagy process. Emerging data support the view that dysregulation of autophagy might play a critical role in the pathogenesis of neurodegenerative disorders. In this review, we highlight the pathophysiological roles of autophagy and its potential therapeutic implications in debilitating neurodegenerative disorders, including amyotrophic lateral sclerosis and Alzheimer's, Parkinson's and Huntington's diseases. PMID- 20947182 TI - Low dose TBT exposure decreases amphipod immunocompetence and reproductive fitness. AB - The antifouling agent tributyltin (TBT) is a highly toxic pollutant present in many aquatic ecosystems. Despite of regulations on the usage of TBT, it remains in high concentrations in sediments both in harbors and in off-shore sites. The toxicity of TBT in mollusks is well documented. However, adverse effects in other aquatic organisms, such as crustaceans, are less well known. This study is an effort to assess the effects of environmentally realistic concentrations of TBT on an ecologically important species in Swedish fresh and brackish water ecosystems, the benthic amphipod Monoporeia affinis. Field collected animals were exposed during gonad maturation to TBT (70 and 170 ng/g sediment d wt) for five weeks in static microcosms with natural sediment. Exposure concentrations were chosen to reflect effects at concentrations found in Swedish coastal sediment, but below expected effects on survival. TBT exposure resulted in a statistically significant adverse effect on oocyte viability and a doubling of the prevalence of microsporidian parasites in females, from 17% in the control to 34% in the 170 ng TBT/g sediment d wt exposure. No effects on survival were observed. Borderline significant effects were observed on male sexual maturation in the 70 ng TBT/g d wt exposure and on ecdysteroid levels in the 170 ng/g sediment d wt exposure. Both reproduction and parasite infection effects are of ecological importance since they have the potential to affect population viability in the field. This study gives further evidence to the connection between low dose contaminant exposure and increases in microsporidian parasite infection. PMID- 20947183 TI - Selenium in water enhances antioxidant defenses and protects against copper induced DNA damage in the blue mussel Mytilus edulis. AB - Selenium and copper are naturally occurring elements in the environment that have important roles in cellular function. Selenium is known for its role in antioxidant defense, whereas copper is a redox-active metal capable of acting as a pro-oxidant. We investigated the effects of short term selenium (Na(2)SeO(3)) supplementation (4 MUg/L for 3 days) on antioxidant parameters of the blue mussel, Mytilus edulis, and its possible protective effects against a subsequent copper (CuSO(4)) exposure (56 MUg/L for 3 days). Selenium supplementation caused a 4-fold increase in glutathione levels in gills. The activity of selenium dependent glutathione peroxidase was modulated by selenium in gills (2-fold increase) and also in cell-free haemolymph (40% increase). Copper exposure produced decreases in protein thiol levels (35%) and in thioredoxin reductase activity (60%) in gills and induced an increase in DNA damage in haemocytes (70% increase in % tail DNA observed using the comet assay). The decrease in thioredoxin reductase activity may constitute a mechanism of copper toxicity in bivalves, warranting further investigation. Pre-treatment with selenium largely prevented these deleterious effects of copper on protein thiols, thioredoxin reductase activity and DNA damage. The results suggest that induction of key antioxidant defenses such as glutathione and selenium-dependent glutathione peroxidase, as a result of selenium supplementation, may play an important role in protection of aquatic organisms against oxidative stress. PMID- 20947184 TI - Gender differences in the association between socioeconomic status (SES) and depressive symptoms in older adults. AB - With rapid population aging, increasing attention is given to the mental health of older people. This study examined the association between SES and depressive symptoms in older adults. The study population consisted of a representative community sample of 4165 persons aged 65 and older from Wave 1 of the Korean Longitudinal Study of Aging. The Center for Epidemiologic Studies Depression scale was used to measure the extent of depressive symptoms. Socioeconomic indicators included education, household income, and net worth. Analyses were conducted by gender, using multiple linear regression analysis, to identify independent effects of socioeconomic variables on depressive symptoms, controlling for demographics and health-related variables. There was an inverse association between higher levels of socioeconomic factors and depressive symptoms in the study population. A clear difference in the association between depressive symptoms and socioeconomic factors by gender was observed. In the multivariate analysis, wealth was significantly associated with depressive symptoms in men, whereas education and income was so in women. Gender disparities in depressive symptoms across social gradients suggest the need for gender sensitive investments in health and social services for the disadvantaged segments of the older population. PMID- 20947185 TI - Improving outpatient services for elderly patients in Taiwan: a qualitative study. AB - The rapid pace of population aging poses significant importance of establishing an age-friendly health care system, including outpatient, inpatient, intermediate, and long-term care. The main purpose of this study is to evaluate the quality of outpatient services for elderly patients in Taiwan. Quality function deployment (QFD) is a tool effectively shortening the research-and development period, reducing costs, and fulfilling customer needs (CNs). This study applied Kano's model and the analytic network process (ANP) to improve the basic framework of QFD. Kano's model enables a thorough understanding of elderly patients' needs and problems with regard to medical care services, so that appropriate outpatient services can be offered to them from the outset. In addition, adapting the supermatrix of ANP to the calculation of the house of quality (HoQ) will reduce subjective judgments. Using Kano's model and an integrated ANP-QFD approach, we extracted five needs of elderly patients and calculated their priorities: 'Professional medical care services convincing patients' (27%), 'With sufficient knowledge to answer patients' questions' (23.5%), 'Providing fast services to solve patients' problems' (19.3%), 'Voluntarily serving patients' (19.1%), and 'Providing proper medical equipment to patients' (11.1%). We then identified six outpatient service attributes deserving of improvement and their priorities: 'Physician with a high level of professionalism and giving clear interpretation of patient's condition' (25%), 'Staff with good communication skills and assistance to patients' (22%), 'High standardization of operating procedures' (18%), 'Staff getting on-the-job training periodically' (15%), 'Facilities sufficient and fitting for elderly patients' (10%), and 'Applying IT (internet) to help patients to receive medical care' (10%). In conclusion, we reconstructed an integrated QFD model which will not only reduce costs but also reveal the crucial outpatient service items that will improve the quality of medical care for elderly people. PMID- 20947186 TI - Screening cognitive impairment among institutionalized older Chinese men in Taiwan: a new minimum data set-based dementia screening tool is needed. AB - Dementia screening is of great importance in various health settings for older people, long-term care facilities are no exception. The need for an effective dementia screening tool being culture sensitive is important. Minimum data set (MDS) is a population instrument for health care management in the world, which also covers dementia screening. The main purpose of this study was to evaluate the effectiveness of the MDS-based dementia screening tools among older Chinese men in the Veteran Home in Taiwan. Overall, 576 participants (mean age: 80.9+/ 5.3 years, all males, 92.7% physically independent), 18.6% had cognitive impairment according to the mini-mental state examination (MMSE) (mean score: 26.7+/-3.9). However, the prevalence of cognitive impairment was 5.5% by MDS cognitive performance scale (CPS) and 18.9% by MDS cognition scale (MDS-COGS). The screening results of CPS and MDS-COGS were highly interrelated (gamma=0.93, p<0.001), and MMSE scores were also significantly associated with CPS and MDS COGS status (gamma=-0.50, p<0.001 and gamma=-0.52, p<0.001, respectively). Although the prevalence of cognitive impairment by MMSE and MDS-COGS are similar, the results are significantly inconsistent (p<0.001). In conclusion, both MDS COGS and CPS were significantly correlated with MMSE scores, but significant inconsistence was noted between screening results of MMSE, CPS and MDS-COGS. Further study is needed to develop MDS-based dementia screening tools for older Chinese men in Taiwan. PMID- 20947187 TI - Spontaneous hemothorax following rupture of a major aorto-pulmonary collateral artery. PMID- 20947189 TI - Coronary syndrome Y: should we focus more on extra-cardiac conditions including renal disease and its management? PMID- 20947188 TI - Outcomes in younger and older adults with chronic advanced systolic heart failure: a propensity-matched study. AB - BACKGROUND: Older age is an independent predictor of all-cause mortality in patients with mild to moderate heart failure (HF). Whether older age is also an independent predictor of mortality in patients with more advanced HF is unknown. METHODS: Of the 2707 Beta-Blocker Evaluation of Survival Trial (BEST) participants with ambulatory chronic HF (New York Heart Association class III/IV and left ventricular ejection fraction <35%), 1091 were elderly (>= 65 years). Propensity scores for older age, estimated for each of the 2707 patients, were used to assemble a cohort of 603 pairs of younger and older patients, balanced on 66 baseline characteristics. RESULTS: All-cause mortality occurred in 33% and 36% of younger and older matched patients respectively during 4 years of follow-up (hazard ratio {HR} associated with age >= 65 years, 1.05; 95% confidence interval {CI}, 0.87-1.27; P=0.614). HF hospitalization occurred in 38% and 40% of younger and older matched patients respectively (HR, 1.01; 95% CI, 0.84-1.21; P=0.951). Among 603 pairs of unmatched and unbalanced patients, all-cause mortality occurred in 28% and 36% of younger and older patients respectively (HR, 1.34; 95% CI, 1.10-1.64; P=0.004) and HF hospitalization occurred in 34% and 40% of younger and older unmatched patients respectively (HR, 1.24; 95% CI, 1.03-1.50; P=0.024). CONCLUSION: Significant bivariate associations suggest that older age is a useful marker of poor outcomes in patients with advanced chronic systolic HF. However, lack of significant independent associations suggests that older age per se has no intrinsic effect on outcomes in these patients. PMID- 20947190 TI - Association of right coronary artery (RCA) motion at 75% phase with heart rate during multi-row detector cardiac tomography angiography. PMID- 20947192 TI - QTc prolongation due to dextromethorphan. PMID- 20947191 TI - Pre-procedural use of statins for all patients undergoing percutaneous coronary intervention. PMID- 20947193 TI - Clinical impact of screening for sleep related breathing disorders in atrial fibrillation. AB - OBJECTIVE: The aim of this study was to quantify daytime symptoms in atrial fibrillation (AF) patients with and without sleep related breathing disorders (SRBD). BACKGROUND: SRBD are common in patients with AF but little is known about daytime symptoms among those with SRBD. METHODS: Patients with AF admitted to clinics of two tertiary referral hospitals for a variety of different cardiovascular diseases were screened with a trans-nasal airflow measurement device allowing measurement of the apnea-hypopnea-index. Data on cardiac risk factors, left ventricular ejection fraction (LVEF) and cardiac medication were collected. Presence of SRBD was defined as an AHI >= 15/h. The Epworth sleepiness scale (ESS) was used to quantify daytime symptoms. RESULTS: Of 102 screened patients 8 were excluded due to device malfunction (n=1), dislocation of nasal cannula (n=6), or hyperthyroidism (n=1). Among the remaining 94 patients, 40 (43%) were diagnosed with SRBD. Patients with and without SRBD had similar age, body mass index, LVEF and cardiac medication. The prevalence of coronary artery disease was higher in patients with SRBD than in those without (50 vs. 17%; p=0.0007). ESS score was low and similar in both groups (no SRBD: median 4, interquartile range (IQR) 2-4 vs. SRBD: 5, IQR 3-8; p=0.14). Only 6/40 (5%) of the patients underwent overnight polysomnography and 2 (5%) started CPAP ventilation during follow-up. CONCLUSIONS: Even though SRBD are common in patients with AF, the prevalence of daytime symptoms is rare. Consequently, most patients will not initiate CPAP ventilation after positive SRBD screening. PMID- 20947194 TI - Spatial and genotypic clustering of Salmonella over time in a swine production unit. AB - Transmission patterns of Salmonella in a swine production unit were investigated by statistical analysis of the spatial distribution of isolates and the clustering of genotypes over a 12-week period. The study unit was a breeding gestation building in a single-site farrow-to-finish swine production system. During the summer of 2003, 1746 pen floor samples were collected during 6 visits conducted at 2-week intervals. Genotyping was performed on the 107 Salmonella isolates obtained using repetitive sequence PCR (3 primers: REP, BOX, ERIC). Genetic similarity was evaluated by DNA fragment matching and hierarchical cluster analysis based on genetic similarities. For each visit, the distance at which spatial clustering of Salmonella isolates occurred was estimated using second order analyses. Significant spatial clustering of Salmonella up to a distance of 15.2m was identified for 4 of the 6 farm visits, those for which the prevalence of Salmonella was the highest. Cluster analysis of genetic similarities identified 4 groups of Salmonella isolates at the level of at least 85% similarity in rep-PCR fragment matching patterns. Genetic clusters were relatively homogeneous for time of visit, with each genetic cluster consisting of isolates from the same or temporally adjacent visits. The correlation between genetic similarity and spatial proximity between pairs of Salmonella isolates, and the correlation between these measures and differences in time of sampling, were evaluated using Mantel's r. There was a strong positive correlation (r=0.62, p<0.0001) between genetic distance and time of sampling, indicating evolution of the Salmonella population over time. For 4 of the 6 visits, a pattern of decreasing genetic similarity between isolates with increasing distance between sampling locations was apparent. However, when viewed over all 6 visits, Salmonella was concentrated in one area of the building and did not move in any specific direction. These results suggest that a particular genotype of Salmonella, if introduced in the breeding-gestation unit of a swine farm would evolve slowly over short time intervals; its spatial distribution would be limited primarily to adjacent or nearby pens. In this study spatial analysis (e.g., Ripley's K-function) and matrix correlation methods (e.g., Mantel's r) expanded upon cluster analysis of genotypic similarities to provide additional interpretable information regarding the spatial distances to which Salmonella is transmitted over time in swine production facilities. PMID- 20947196 TI - Temporal distributions of respiratory disease events within cohorts of feedlot cattle and associations with cattle health and performance indices. AB - Bovine respiratory disease complex (BRDC), the most common cause of post-weaning disease in North American beef cattle, is a multifaceted process involving pathogen, host, environment, and management factors. Although the importance of describing and evaluating the timing of BRDC cases has been recognized, a formal analysis of the temporal patterns of BRDC has not been described in the literature. Our objectives were to classify within-cohort temporal patterns of BRDC cases during the first 100 days at risk, using operational data from commercial feedlots, and then to evaluate associations among temporal patterns and common cohort-level measures of feedlot performance and health, while controlling for common potential confounders. We used retrospective cohort-level and individual animal health data (2000-2008) from 10 U.S. feedlots. We defined cumulative distributions representing the timing of cases within cohorts using the daily percentage of cases relative to the total number of cases within a cohort. Ward's hierarchical clustering method was used to group cohorts exhibiting similar cumulative distributions of BRDC cases. Linear mixed models and generalized estimating equations then were used to determine associations between temporal patterns and economically important measures of cattle performance (mean daily weight gain, total days on feed, and carcass measures) and health (mortality risk and retreatment risk) outcomes, while accounting for possible confounding variables (gender, arrival month, arrival year, arrival weight, arrival risk classification, cumulative morbidity, and the feedlot itself). Cluster analysis identified seven different cohort-level temporal patterns of BRDC cases. Our independent variable of interest (temporal pattern) was associated with mean daily weight gain, total days on feed, and carcass weight, and the estimated effects were modified by arrival weight category and risk classification. Temporal patterns also were associated with USDA measures of carcass yield and quality that largely affect carcass price. We also found associations among temporal patterns and health outcomes (cumulative mortality and retreatment risk), and these effects were significantly modified by arrival weight and cumulative morbidity. Our results are the first to demonstrate that there are several temporal patterns of BRDC repeatedly observed among cohorts of feedlot cattle, and that these BRDC patterns may differentially affect cattle health and performance. PMID- 20947197 TI - Inhibitory effects of lactic acid and lauricidin on spoilage organisms of chicken breast during storage at chilled temperature. AB - Different concentrations of lauricidin (LU, containing 1% lactic acid) and lactic acid alone (LA) were evaluated for their effectiveness in reducing naturally occurring microflora of raw chicken breasts. Chicken breasts were dipped in 0 (control), 0.5, 1.0, 1.5, and 2.0% solutions of LU (w/v) or LA (v/v) for 10, 20, and 30 min and stored at 4 degrees C for 14 d. Total Plate Counts (TPC) and populations of Pseudomonas spp. and Enterobacteriaceae were determined before and after dipping and after storing for 1, 3, 7, 10, and 14 d. Additionally, Hunter L, a, and b values and pH of the chicken breast were also determined. From the obtained results, TPC on chicken breast treated with LU was found to be decreased by 0.92 to 1.2 log CFU/g from a mean initial log 5.69 CFU/g, while those dipped in LA decreased by 0.53 to 2.36 log CFU/g. Pseudomonas population on chicken breast dipped in LU decreased by 0.79 to 1.77 log CFU/g from an initial 3.90 log CFU/g, while in LA treated it decreased by 0.39 to 1.82 log CFU/g. Enterobacteriaceae counts were also found to be reduced by 0.14 to 1.14 log CFU/g on chicken breast dipped in LU, while the reduction was from 0.59 to 2.18 log CFU/g in chicken breast dipped in LA. The major bacterial types isolated from LU treated chicken breast belonged to the Enterobacteriaceae group, which included: Enterobacter, E. coli and Citrobacter. Whereas, in the LA treated breast it belonged to: Pseudomonas, E. coli, and Kocuria rhizophila (formerly Micrococcus luteus). Dipping chicken breast in LU and LA caused a significant decrease (p <= 0.05) in their pH values. Also, treatment with LU and LA caused a slight darkening in color (decreased Hunter L value), increase in redness (increased Hunter a value), and increase in yellowness (increased Hunter b value). Based on the results obtained in the present study, Lactic acid and Lauricidin showed high potential to be used as a sanitizer in reducing the population of spoilage microorganisms naturally occurring on raw chicken, and can be explored commercially for extension of their shelf life. PMID- 20947198 TI - Cholesterol synthesis is increased and absorption decreased in non-alcoholic fatty liver disease independent of obesity. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with impaired glucose and lipoprotein metabolism. However, the metabolism of cholesterol in NAFLD remains unexplored. We investigated how fatty liver influences cholesterol metabolism in 242 non-diabetic subjects. METHODS: Liver fat content was measured with proton magnetic resonance spectroscopy. Cholesterol metabolism was assayed with serum non-cholesterol sterols, surrogate markers of cholesterol synthesis and absorption. The analyses were performed with gas-liquid chromatography. RESULTS: A total of 114 subjects had NAFLD and 128 subjects had normal liver fat content. Non-cholesterol sterols reflecting cholesterol synthesis (cholestenol, desmosterol, and lathosterol) were higher, and those reflecting cholesterol absorption (cholestanol and plant sterols) were lower in subjects with NAFLD than in controls, independent of body mass index. Liver fat content was positively associated with markers of cholesterol synthesis (r = from 0.262 to 0.344, p < 0.001 for all) and inversely associated with markers of cholesterol absorption (r = from -0.299 to -0.336, p < 0.001 for all). In the entire study group, synthesis and absorption markers were interrelated, indicating that the homeostasis of cholesterol metabolism was maintained. LDL cholesterol was similar in the two groups. CONCLUSIONS: We demonstrated that although LDL cholesterol concentrations are unchanged, cholesterol metabolism in NAFLD is characterized by increased synthesis and diminished absorption of cholesterol. These changes are associated with liver fat content independent of body weight. PMID- 20947199 TI - Gene networks controlling the initiation of flower development. AB - The onset of flower formation is a key regulatory event during the life cycle of angiosperm plants, which marks the beginning of the reproductive phase of development. It has been shown that floral initiation is under tight genetic control, and deciphering the underlying molecular mechanisms has been a main area of interest in plant biology for the past two decades. Here, we provide an overview of the developmental and genetic processes that occur during floral initiation. We further review recent studies that have led to the genome-wide identification of target genes of key floral regulators and discuss how they have contributed to an in-depth understanding of the gene regulatory networks controlling early flower development. We focus especially on a master regulator of floral initiation in Arabidopsis thaliana APETALA1 (AP1), but also outline what is known about the AP1 network in other plant species and the evolutionary implications. PMID- 20947200 TI - Illness perceptions and quality of life in Japanese and Dutch patients with non small-cell lung cancer. AB - This study examined quality of life (QOL) and illness perceptions in Dutch and Japanese patients with non-small-cell lung cancer, thereby extending the body of knowledge on cultural differences and psychosocial aspects of this illness. 24 Dutch and 22 Japanese patients with non-small-cell lung cancer filled out questionnaires on three occasions: immediately before chemotherapy, 1 week later, and 8 weeks after the initial chemotherapy. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed QOL, and the Brief Illness Perception Questionnaire (B-IPQ) illness perceptions. Scores on several QOL measures indicated (a) major impact of first chemotherapy sessions, and (b) some tendency to returning to baseline measures at 8 weeks. Differences between Japanese and Dutch samples were found on five EORTC QLQ-C30 dimensions: global health status, emotional functioning, social functioning, constipation, and financial difficulties, with the Dutch patients reporting more favorable scores. Regarding illness perceptions, Japanese patients had higher means on perceived treatment control and personal control, expressing a higher sense of belief in the success of medical treatment than Dutch patients. In both Japanese and Dutch patients, impact of chemotherapy on QOL was evident. Some differences in illness perceptions and QOL between the two samples were observed, with implications for integral medical management. Both samples reported illness perceptions that reflect the major consequences of non-small cell lung cancer. Incorporating symptom reports, illness perceptions, and QOL into medical management may have positive consequences for patients with non small-cell lung cancer. PMID- 20947201 TI - Modelling of an enhanced PAH attenuation experiment and associated biogeochemical changes at a former gasworks site in southern Germany. AB - Former manufactured gas plant sites often form a widespread contaminant source in the subsurface, leading to large plumes that contain a wide variety of tar-oil related compounds. Although most of these compounds eventually degrade naturally, the relevant processes tend to be slow and inefficient, often leaving active remediation as the only viable option to eliminate the risks of toxic substances to reach potential receptors such as surface waters or drinking water wells. In this study we use a reactive transport model to analyse the fate of a contaminant plume containing acenaphthene, methylbenzofurans and dimethylbenzofurans (i) prior to the installation of an active remediation scheme and (ii) for an enhanced remediation experiment during which O(2) and H(2)O(2) were added to the contaminated groundwater through a recirculation well. The numerical model developed for this study considers the primary contaminant degradation reactions (i.e., microbially mediated redox reactions) as well as secondary and competing mineral precipitation/dissolution reactions that affect the site's hydrochemistry and/or contaminant fate. The model was calibrated using a variety of constraints to test the uncertainty on model predictions resulting from the undocumented presence of reductants such as pyrite. The results highlight the important role of reactive transport modelling for the development of a comprehensive process understanding. PMID- 20947202 TI - D-chiro-inositol affects accumulation of raffinose family oligosaccharides in developing embryos of Pisum sativum. AB - Developing garden pea embryos are able to take up exogenously applied cyclitols: myo-inositol, which naturally occurs in pea, and two cyclitols absent in pea plants: d-chiro-inositol and d-pinitol. The competition in the uptake of cyclitols by pea embryo, insensitivity to glucose and sucrose, and susceptibility to inhibitor(s) of H(+)-symporters (e.g. CCCP and antimycin A) suggest that a common cyclitol transporter is involved. Both d-chiro-inositol and d-pinitol can be translocated through the pea plant to developing embryos. During seed maturation drying, they are used for synthesis of mainly mono-galactosides, such as fagopyritol B1 and galactosyl pinitol A. Accumulation of d-chiro-inositol (and formation of fagopyritols), but not d-pinitol, strongly reduces accumulation of verbascose, the main raffinose oligosaccharide in pea seeds. The reasons for the observed changes are discussed. PMID- 20947203 TI - Iron deficiency in female pattern hair loss, chronic telogen effluvium, and control groups. AB - BACKGROUND: The literature suggests that iron deficiency (ID) may play a role in female pattern hair loss (FPHL) or in chronic telogen effluvium (CTE). OBJECTIVE: We sought to determine if ID is more common in women with FPHL and/or CTE than in control subjects without hair loss. METHODS: This was a controlled study of 381 Caucasian women aged 18 years or older with FPHL or CTE seen in the Duke University Hair Disorders Clinic, Durham, NC, and 76 Caucasian women aged 18 years or older from the university environs who had no history or physical findings of hair loss (control subjects). All participants had to have at least a serum ferritin and hemoglobin reading and history of menopausal status. RESULTS: When ferritin less than or equal to 15 MUg/L was used as the definition, ID occurred in 12.4%, 12.1%, and 29.8% of premenopausal women with FPHL (n = 170), CTE (n = 58), and control subjects (n = 47), respectively, and in 1.7%, 10.5%, and 6.9% of postmenopausal women with FPHL (n = 115), CTE (n = 38), and control subjects (n = 29), respectively. When ferritin less than or equal to 40 MUg/L was used as the definition, ID occurred in 58.8%, 63.8%, and 72.3% of premenopausal women with FPHL, CTE, and control subjects, respectively, and in 26.1%, 36.8%, and 20.7% of postmenopausal women with FPHL, CTE, and control subjects, respectively. There was no statistically significant increase in the incidence of ID in premenopausal or postmenopausal women with FPHL or CTE versus control subjects. LIMITATIONS: The effect of correction of ID on hair loss is unknown. CONCLUSION: ID is common in women but not increased in patients with FPHL or CTE compared with control subjects. PMID- 20947204 TI - Implementation of a journal peer reviewer stratification system based on quality and reliability. AB - STUDY OBJECTIVE: Before starting this study, Annals of Emergency Medicine had a large and unwieldy reviewer pool that demonstrated substantial variability in quality and reliability. We hypothesize that a tiered reviewer stratification system might enable our journal editors to target the bulk of their review invitations to our better reviewers and thus improve our efficiency. METHODS: In 2003, we instituted a 3-tiered hierarchic classification for our reviewers and stratified them within these categories according to predefined criteria for reviewer quality and reliability. Our approximately 50 editors then targeted the bulk of their review invitations to the top performance tier. RESULTS: Comparing 2009 data with 2002 (the year before the system), we found fewer late reviews (13% versus 32%) and fewer reviewers not used in a given year (28% versus 59%). More top-tier reviewer invitations led to an on-time review (48% versus 37%) in 2009 compared with 2002. Editors have found the system to be simple and easy to use. No serious problems have been identified. CONCLUSION: Implementation of a tiered system stratifying journal peer reviewers by quality and reliability was readily accomplished by Annals and has appeared to improve the efficiency of our peer review. PMID- 20947205 TI - Evidence-based emergency medicine. The clinical diagnosis of arrhythmias in patients presenting with palpitations. PMID- 20947206 TI - Alfentanil for procedural sedation in the emergency department. AB - STUDY OBJECTIVE: We administer alfentanil sedation for minor procedures in the emergency department (ED), and our primary objective is to assess the incidence of airway and respiratory adverse events leading to an intervention. Our secondary goals are to assess for other adverse events, the depth and duration of sedation, the incidence of subclinical respiratory depression, and patient perceptions of the quality of the sedation. METHODS: In this observational study of adults receiving alfentanil for ED procedures, we recorded the incidence of airway or respiratory adverse events leading to an intervention (increase/addition of supplemental oxygen, bag-valve-mask ventilation, airway repositioning, or stimulation to induce breathing). Secondary goals were assessed with monitoring (including capnography), the Observer's Assessment of Alertness/Sedation (OAA/S) scale, and postprocedure patient visual analog scale ratings of pain, recall, and satisfaction. RESULTS: Airway or respiratory events leading to intervention were observed in 39% of the 148 subjects (supplemental oxygen 18%, bag-valve mask 3%, airway repositioning 2%, stimulation 18%); none were clinically significant. The median OAA/S nadir was 4 (interquartile range 3 to 5). Median patient ratings were positive (pain 26 mm, recall 98, satisfaction 100 mm). CONCLUSION: Alfentanil appears effective for ED procedural sedation but displays a rate of airway or respiratory events leading to an intervention similar to that of previous reports of deeper sedation with propofol. PMID- 20947207 TI - A rapid medical screening process improves emergency department patient flow during surge associated with novel H1N1 influenza virus. AB - STUDY OBJECTIVE: We compare emergency department (ED) patient flow during the fall 2009 novel H1N1-associated surge in patient volumes at an urban, tertiary care, pediatric medical center to that in the previous winter virus season. METHODS: A rapid medical screening process was instituted to manage the surge in patient census. The process included the use of a new, separate clinical area converted from office space adjacent to the ED, the introduction of a new preprinted checklist for rapid documentation of medical history and physical examination of patients with influenza-like illness, the use of classroom-style parent discharge education, and the use of preprinted discharge prescription and instructions. We compared patient flow parameters, including waiting time, length of stay, and elopement rates, and returns within 48 hours and 7 days for a comparable period in winter 2008 to 2009. RESULTS: During the first 30 days of the novel H1N1-associated surge in patient volumes (October 12 to November 10, 2009), overall ED daily volumes increased by a mean of 113 (51.8%) compared with baseline (daily increase range 49 to 118 patients). Of the 10,013 patients treated during this period, 4,287 (42.8%) had complaints consistent with influenza-like illness and 1,767 (17.6%) were treated with the rapid screening process. The mean wait time decreased from 92.9 to 81.2 minutes (difference 11.7 minutes; 95% confidence interval [CI] 10.2 to 13.2 minutes). Overall mean ED length of stay decreased from 241 to 212.3 minutes (difference 28.7 minutes; 95% CI 25.8 to 31.6 minutes). Rates of elopement were unchanged, and elopement rates as a function of daily patient volumes showed improved responsiveness to high volumes. Rates of return were unchanged within 48 hours (3.0% in 2009 versus 2.9% in 2008; odds ratio 1.03 [0.91 to 1.18]) and within 7 days (6.2% in 2009 versus 5.7% in 2008; odds ratio 1.09 [0.99 to 1.20]). The use of the rapid screening process required a mean of 23.5 (95% CI 16.4 to 30.6) additional hours per day of physician staffing and a mean of 26.3 (95% CI 18.5 to 34.1) additional hours of nursing staffing. CONCLUSION: The implementation of a rapid screening process during the fall 2009 H1N1-associated surge in patient volumes was associated with improved patient flow without affecting rates of return to the ED within 48 hours or 7 days. This was accomplished with only a modest increase in staffing. PMID- 20947208 TI - Comparison of the use of conventional and prewired electrodes for electrocardiography in an emergency setting: the spaghetti study. AB - STUDY OBJECTIVE: We compare the quality of ECG recordings obtained with conventional and prewired electrodes in an emergency setting. METHODS: This was a prospective, randomized, open comparison study in an emergency medical services setting. Participants were patients undergoing ECG between April and May 2007 (n=105). Two 12-lead ECG recordings were made in random order with conventional and prewired electrodes. Artifacts, ie, signal noise (>0.4 seconds of recording affected) and baseline instability (>1-mV variation), were analyzed and scored by 3 blinded reviewers. Results were expressed as number of affected leads, score/lead (0 to 3 scale for signal noise; 0 to 4 scale for baseline instability), and number of leads that were totally artifact free. Time to make recordings was measured. RESULTS: Recordings were nearly as easy and took 20% less time with prewired than with conventional electrodes (118 [interquartile ratio (IQR) 90 to 150] versus 144 [IQR 120 to 182]). With prewired electrodes, fewer leads were affected by noise (1 [IQR 0 to 3] versus 3 [IQR 0 to 6]) and baseline instability (0 [IQR 0 to 2] versus 2 [IQR 0 to 4]). The mean score/lead was lower for both noise (1 [IQR 0 to 3] versus 3 [IQR 0 to 8]) and instability (0 [IQR 0 to 2] versus 2 [IQR 0 to 5]); the number of artifact-free leads was greater (38 [36%] versus 19 [18%]). There was no significant difference between electrode types in the prevalence of P-wave and QRS complex abnormalities. CONCLUSION: Recordings with prewired electrodes took significantly less time. Signal noise and baseline instability were significantly reduced. The time saved was not at the expense of the quality of the recording. PMID- 20947209 TI - Systemic fibrinolysis through intraosseous vascular access in ST-segment elevation myocardial infarction. AB - In emergency situations, intraosseous cannulation represents an alternative route of vascular access when peripheral vein insertion is difficult. We present the first documented case of intraosseous systemic fibrinolysis in a patient with ST segment elevation myocardial infarction. In this case, repetitive episodes of ventricular fibrillation occurred soon after first contact with emergency care providers. Given that the patient had difficult peripheral venous access, an intraosseous catheter was inserted. Fibrinolytics and antiarrhythmic drugs were administered though this line, resulting in resolution of coronary ischemia and electrical instability, without complications. Intraosseous cannulation represents a novel route for administration of systemic fibrinolysis in cases of difficult peripheral venous access in the out-of-hospital setting. PMID- 20947210 TI - A blinded, randomized controlled trial to evaluate ketamine/propofol versus ketamine alone for procedural sedation in children. AB - STUDY OBJECTIVE: The primary objective is to compare total sedation time when ketamine/propofol is used compared with ketamine alone for pediatric procedural sedation and analgesia. Secondary objectives include time to recovery, adverse events, efficacy, and satisfaction scores. METHODS: Children (aged 2 to 17 years) requiring procedural sedation and analgesia for management of an isolated orthopedic extremity injury were randomized to receive either ketamine/propofol or ketamine. Physicians, nurses, research assistants, and patients were blinded. Ketamine/propofol patients received an initial intravenous bolus dose of ketamine 0.5 mg/kg and propofol 0.5 mg/kg, followed by propofol 0.5 mg/kg and saline solution placebo every 2 minutes, titrated to deep sedation. Ketamine patients received an initial intravenous bolus dose of ketamine 1.0 mg/kg and Intralipid placebo, followed by ketamine 0.25 mg/kg and Intralipid placebo every 2 minutes, as required. RESULTS: One hundred thirty-six patients (67 ketamine/propofol, 69 ketamine) completed the trial. Median total sedation time was shorter (P=0.04) with ketamine/propofol (13 minutes) than with ketamine (16 minutes) alone (Delta 3 minutes; 95% confidence interval [CI] -5 to -2 minutes). Median recovery time was faster with ketamine/propofol (10 minutes) than with ketamine (12 minutes) alone (Delta -2 minutes; 95% CI -4 to -1 minute). There was less vomiting in the ketamine/propofol (2%) group compared with the ketamine (12%) group (Delta -10%; 95% CI -18% to -2%). All satisfaction scores were higher (P<0.05) with ketamine/propofol. CONCLUSION: When compared with ketamine alone for pediatric orthopedic reductions, the combination of ketamine and propofol produced slightly faster recoveries while also demonstrating less vomiting, higher satisfaction scores, and similar efficacy and airway complications. PMID- 20947211 TI - Herbal treatment of allergic rhinitis: the use of Nigella sativa. AB - BACKGROUND AND AIMS: Allergic rhinitis is the most common chronic and allergic disease, especially in children. This study aimed to investigate the anti inflammatory effects of Nigella sativa and its effects on inflammatory factors in patients with allergic rhinitis symptoms and the process their clinical study charges. SETTING: The present study is a clinical trial that conducted as prospective and double blind with descriptive analytic. MATERIALS AND METHODS: The sample included 66 patients (case and placebo) with allergic rhinitis exposed to N. sativa oil. Individual characteristics, including age and sex, and characteristics of the disease, including nasal congestion, runny nose, itchy nose, and sneezing attacks, were evaluated. From the start of the study, that is, day 0, up to the end of the study, that is, day 30, an observer completed the symptoms severity questionnaire. STATISTICAL ANALYSIS: Data were presented as means +/- SEM. Comparisons between groups were performed by using paired Student t test. Differences were considered significant if P values are less than .05 and .01. RESULTS: In the present study, 66 patients with allergic rhinitis, including 22 males (33.3%) and 44 females (66.7%) with a mean age of 47.19 years, were included. Immunoglobulin E total of more than 100 was reported in 38 patients before treatment. Immunoglobulin E in nasal wash from 7 patients was observed and was not measurable in 59 cases. Only 6.1% of the study population had nasal mucosal eosinophil. CONCLUSION: The results show that N. sativa could reduce the presence of the nasal mucosal congestion, nasal itching, runny nose, sneezing attacks, turbinate hypertrophy, and mucosal pallor during the first 2 weeks (day 15). The present findings are consistent with evidence that the antiallergic effects of N. sativa components could be attributed to allergic rhinitis. Moreover, N. sativa should be considered for treating allergic rhinitis when the effects of other antiallergic drugs need to be avoided. PMID- 20947212 TI - Founder effect and estimation of the age of the Progranulin Thr272fs mutation in 14 Italian pedigrees with frontotemporal lobar degeneration. AB - Progranulin (PGRN) mutations have been recognized to be monogenic causes of frontotemporal lobar degeneration (FTLD). PGRN Thr272fs mutation in the Italian population has been previously identified. In the present study, we evaluated the occurrence of a founder effect studying 8 polymorphic microsatellite markers flanking the PGRN gene in 14 apparently unrelated families. We identified a common haplotype associated with PGRN Thr272fs carriers, assuming common ancestry. The inferred age analysis (range between 260 [95% credible set: 227 374] and 295 [95% credible set: 205-397] generations) places the introduction of the mutation back to the Neolithic era when the Celts, the population of that period, settled in Northern Italy. PGRN Thr272fs mutation appears to be as either behavioral frontotemporal dementia (80%) or primary progressive aphasia (20%), it was equally distributed between male and female, and the mean age at onset was 59.6 +/- 5.9 (range 53-68). In 14 families, autosomal dominant pattern of inheritance was present in 64.2% of cases. No clinical predictors of disease onset were demonstrated. The identification of a large cohort of frontotemporal lobar degeneration (FTLD) patients with homogeneous genetic background well may be used in the search of disease modulators to elucidate genotype-phenotype correlations of progranulopathies. PMID- 20947213 TI - Diagnosis of progressive supranuclear palsy: can measurement of tau forms help? AB - Recently, a new assay for the differential diagnosis of progressive supranuclear palsy (PSP) was proposed. It was shown that the ratio of 33/55 kDa tau forms in cerebrospinal fluid (CSF) was specifically reduced in PSP CSF. We aimed to reproduce these results, but were not able to detect the tau forms in CSF. We demonstrate that i) CSF total tau levels are too low to be detected by the published protocol, and ii) the described 33 and 55 kDa bands are likely the heavy and light chains of IgG used in the assay. We conclude that more sensitive techniques are needed to measure tau forms in CSF. PMID- 20947215 TI - Paraoxonase-1 polymorphisms in Alzheimer's disease, Parkinson's disease, and AD PD spectrum diseases. AB - Paraoxonase-1 (PON1) is a serum arylsulfatase that metabolizes organophosphate pesticides and protects low-density lipoprotein from oxidation. Case-control studies of PON1 genetic variants in Alzheimer's disease (AD) and Parkinson's disease (PD) have revealed some positive albeit inconsistent associations with 2 PON1 coding polymorphisms: Q192R (rs662) and L55M (rs854560). Because AD and PD exist along a spectrum of disorders with shared epidemiologic, clinical, and pathologic features, here we evaluated PON1 variants in a cohort of 746 AD, 566 PD, 132 AD-PD, and 719 cognitively normal age-matched controls. In the combined AD and Caucasian PD cohorts we had 80% power to detect a relative risk of at least 1.25 and 1.35, respectively, for each polymorphism. We found no association between 2 PON1 coding polymorphisms and AD in African Americans or Caucasians, and no association with PD or AD-PD in Caucasians. There was also no evidence of an interaction between PON1 and apolipoprotein E for any of these diseases. Our results suggest that either these functional PON1 polymorphisms are not associated with AD and PD spectrum disorders, or that the relative risk conferred is small. PMID- 20947214 TI - The effect of aging on the density of the sensory nerve fiber innervation of bone and acute skeletal pain. AB - As humans age there is a decline in most sensory systems including vision, hearing, taste, smell, and tactile acuity. In contrast, the frequency and severity of musculoskeletal pain generally increases with age. To determine whether the density of sensory nerve fibers that transduce skeletal pain changes with age, calcitonin gene related peptide (CGRP) and neurofilament 200 kDa (NF200) sensory nerve fibers that innervate the femur were examined in the femurs of young (4-month-old), middle-aged (13-month-old) and old (36-month-old) male F344/BNF1 rats. Whereas the bone quality showed a significant age-related decline, the density of CGRP(+) and NF200(+) nerve fibers that innervate the bone remained remarkably unchanged as did the severity of acute skeletal fracture pain. Thus, while bone mass, quality, and strength undergo a significant decline with age, the density of sensory nerve fibers that transduce noxious stimuli remain largely intact. These data may in part explain why musculoskeletal pain increases with age. PMID- 20947217 TI - [Complete recovery of renal function and acute functional dependency due to severe rhabdomyolisis in an elderly patient]. PMID- 20947216 TI - Molecular changes in brain aging and Alzheimer's disease are mirrored in experimentally silenced cortical neuron networks. AB - Activity-dependent modulation of neuronal gene expression promotes neuronal survival and plasticity, and neuronal network activity is perturbed in aging and Alzheimer's disease (AD). Here we show that cerebral cortical neurons respond to chronic suppression of excitability by downregulating the expression of genes and their encoded proteins involved in inhibitory transmission (GABAergic and somatostatin) and Ca(2+) signaling; alterations in pathways involved in lipid metabolism and energy management are also features of silenced neuronal networks. A molecular fingerprint strikingly similar to that of diminished network activity occurs in the human brain during aging and in AD, and opposite changes occur in response to activation of N-methyl-D-aspartate (NMDA) and brain-derived neurotrophic factor (BDNF) receptors in cultured cortical neurons and in mice in response to an enriched environment or electroconvulsive shock. Our findings suggest that reduced inhibitory neurotransmission during aging and in AD may be the result of compensatory responses that, paradoxically, render the neurons vulnerable to Ca(2+)-mediated degeneration. PMID- 20947218 TI - [Laparoscopic repair of Bochdalek hernia in an 80-years-old woman with recurrent obstructive episodes]. PMID- 20947220 TI - The synthesis of phenylalanine-derived C5-substituted rhodanines and their activity against selected methicillin-resistant Staphylococcus aureus (MRSA) strains. AB - A series of rhodanine compounds containing various substituents at the N3- and C5 positions were synthesized and their in vitro activity against a panel of clinically relevant MRSA strains was determined. The anti-MRSA activity of compounds 21 (MIC=3.9 MUg/mL, MBC=7.8 MUg/mL) and 22 (MIC=1.95 MUg/mL, MBC=7.8 MUg/mL) was significantly greater than that of the lead compounds, 1-3 and reference antibiotics penicillin G (MIC=31.25 MUg/mL) and ciprofloxacin (MIC=7.8 MUg/mL) and comparable to that of vancomycin (MIC=0.97 MUg/mL). Compounds 21 and 22 were found to be bactericidal at only 2-4-fold higher than their MIC concentrations. In addition, their MIC values remained unchanged in the presence or absence of 10% serum. Overall, the results suggest that compounds 21 and 22 may be of potential use in the treatment of MRSA infections. PMID- 20947221 TI - Synthesis, crystal structure and biological evaluation of novel 2-(5 (hydroxymethyl)-3-phenyl-1H-pyrazol-1-yl)-1-phenylethanol derivatives. AB - A series of novel 2-(5-(hydroxymethyl)-3-phenyl-1H-pyrazol-1-yl)-1-phenylethanol derivatives (4) was synthesized from ethyl 1-(2-oxo-2-phenylethyl)-3-phenyl-1H pyrazole-5-carboxylate derivatives (3) and characterized by means of IR, 1H NMR, HRMS and X-ray crystal diffraction. Structures of 4a, 4d, 4e and 4f were also determined by 13C NMR. Isomeric intermediates, 3a and 5a, were unambiguously confirmed by X-ray crystal structure analysis and successfully differentiated with 1H NMR chemical shifts of methylene bonded to pyrazole ring. Preliminary biological evaluation showed that compounds 4d and 4e could suppress A549 lung cancer cell growth through cell cycle arrest and autophagy. PMID- 20947222 TI - Synthesis and anticonvulsant activity of N-3-arylamide substituted 5,5 cyclopropanespirohydantoin derivatives. AB - In the present study on the development of new anticonvulsants, twenty new N-3 arylamide substituted 5,5-cyclopropanespirohydantoin derivatives were synthesized and tested for anticonvulsant activity using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. Three compounds 5d, 5j and 5t showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 5j showed the MES-induced seizures with ED50 value of 9.2 mg/kg and TD50 value of 421.6 mg/kg after intraperitoneally injection to mice, which provided compound 5j with a protective index (TD50/ED50) of 45.8 in the MES test. PMID- 20947223 TI - Regiospecific synthesis and biological evaluation of spirooxindolopyrrolizidines via [3+2] cycloaddition of azomethine ylide. AB - Reaction of (E)-3-aryl-1-(thiophen-2-yl)prop-2-en-1-ones with azomethine ylide (generated in situ via decarboxylative condensation of isatin with l-proline) in refluxing methanol afforded 1'-(aryl)-2'-(2-thienylcarbonyl)-spiro[3H-indole-3,3' [3H]pyrrolizin]-2-ones as the sole product in a regiospecific manner. The synthesized compounds have been characterized by their elemental, analytical and spectral studies. The synthesized compounds were screened for their antibacterial and antifungal activities against a spectrum of microbial organisms. These studies proved that compounds 1'-(p-chlorophenyl)-2'-(2-thienylcarbonyl)-spiro[3H indole-3,3'-[3H]pyrrolizin]-2-one (4b), 1'-(p-fluorophenyl)-2'-(2 thienylcarbonyl)-spiro[3H-indole-3,3'-[3H]pyrrolizin]-2-one (4d) and 1'-(p methoxyphenyl)-2'-(2-thienylcarbonyl)-spiro[3H-indole-3,3'-[3H]pyrrolizin]-2-one (4h) against Staphylococcus aureus, 1'-(p-chlorophenyl)-2'-(2-thienylcarbonyl) spiro[3H-indole-3,3'-[3H]pyrrolizin]-2-one (4b), 1'-(p-methylphenyl)-2'-(2 thienylcarbonyl)-spiro[3H-indole-3,3'-[3H]pyrrolizin]-2-one (4c) and 1'-(p fluorophenyl)-2'-(2-thienylcarbonyl)-spiro[3H-indole-3,3'-[3H]pyrrolizin]-2-one (4d) against Salmonella typhi show maximum inhibition potency at low concentration (6.25 MUg/mL) whereas 4d against Candida albicans and 4b and 4d against Rhizopus sp. showed beneficial antifungal activity at minimum concentration. PMID- 20947224 TI - Should nursing-related work experience be a prerequisite for acceptance into a nursing programme? A study of students' reasons for withdrawing from undergraduate nursing at an Australian university. AB - AIM: This paper reports on two studies that examined why students withdrew from a Bachelor of Nursing degree. BACKGROUND: With the aim of recruiting undergraduate candidates who are the most likely to complete the degree and pursue a nursing career, the University of Adelaide requires high matriculation scores and satisfactory performance in a structured oral assessment as part of the process of selection. METHOD: In the first study, two questionnaires were used to collect data from all applicants before and after an oral assessment. The degree of personal desire and motivation to become a Registered Nurse, including knowledge about nursing and the profession were among qualities rated. For the second study, semi-structured telephone interviews were conducted with students who had withdrawn. RESULTS: Statistical comparison showed there were significant differences between continuing and withdrawing applicants in whether or not they had previous nursing-related experience and in knowing someone who was a nurse. The qualitative data reinforced the importance of these factors for attrition. Participants identified emotional issues surrounding an aversion to illness, sickness, pain, suffering and blood. CONCLUSION: The results of both studies suggest that a primary factor in attrition is a lack of realistic expectation regarding nursing as a profession. PMID- 20947225 TI - 210Pb-dating of a lake sediment core from Lough Carra (Co. Mayo, western Ireland): use of paleolimnological data for chronology validation below the 210Pb dating horizon. AB - The chronologies and sediment accumulation rates for a lake sediment sequence from Lough Carra (Co. Mayo, western Ireland) were established by applying the constant initial concentration (CIC) and constant rate of supply (CRS) hypotheses to the measured (210)Pb(excess) profile. The resulting chronologies were validated using the artificial fallout radionuclides (137)Cs and (241)Am, which provide independent chronostratigraphic markers for the second half of the 20th century. The validity of extrapolating the derived CIC and CRS dates below the (210)Pb dating horizon using average sedimentation rates was investigated using supplementary paleolimnological information and historical data. Our data confirm that such an extrapolation is well justified at sites characterised by relatively stable sedimentation conditions. PMID- 20947226 TI - Characteristics of iatrogenic mandibular fractures associated with tooth removal: review and analysis of 189 cases. AB - Fracture of the mandible during exodontia is fortunately rare, but is under reported. A review identified 189 documented cases of iatrogenic fractures of the mandible (IFM) associated with the removal of teeth. The reasons for its occurrence are thought to be multifactorial and include age, sex, degree of tooth impaction, relative volume of the tooth in the jaw, pre-existing infection or bony lesions, failure to maintain a soft diet in the early postoperative period, and the surgical technique. The clinical experience of the surgeon does not seem to have an important role. We review the aetiology of iatrogenic mandibular fracture and summarise the ways of minimising this complication. PMID- 20947227 TI - Use of stereolithographic cutting guides in corrective (wedge) Lefort I osteotomy. PMID- 20947228 TI - Way to increase mechanical strength during distraction osteogenesis of the mandibular symphysis: technical note. PMID- 20947229 TI - Primary non-Hodgkin B-cell lymphoma of the tongue. AB - A 96-year-old woman was admitted with a mass in the tongue. Examination and imaging (computed tomography and magnetic resonance imaging) showed a mass (2cm*2cm*1.5cm) in the dorsal aspect of the tongue, which was biopsied. Histologically there was diffuse proliferation of large malignant lymphoid cells. Mitotic figures and apoptotic cells were scattered. Immunohistochemically, the atypical lymphoid cells stained for CD45, CD20, p53 protein, and KI-67 antigen (labelling=100%). In contrast, they did not stain for various cytokeratins, epithelial membrane antigen, CD3, CD30, CD45RO, or TdT. The pathological diagnosis was diffuse large B-cell carcinoma of the tongue. Systemic imaging studies showed no other tumours. There was no lymphadenopathy. The patient was given R-CHOP chemotherapy and radiation and the tumour disappeared. She is still free of symptoms 5 years after her initial presentation. PMID- 20947230 TI - Routinisation and constraints on informed choice in a one-stop clinic offering first trimester chromosomal antenatal screening for Down's syndrome. AB - OBJECTIVE: to explore routinisation and constraints on informed choice in a one stop clinic offering first trimester antenatal chromosomal screening for Down's syndrome. DESIGN: recordings of booking appointments and pre-screening consultations in both a community and a hospital clinic setting. SETTING: one antenatal clinic site in the UK offering first trimester nuchal translucency screening in combination with maternal serum screening. PARTICIPANTS: 57 taped clinical consultations involving pregnant women and midwives and health-care assistants (HCAs). FINDINGS: midwives and HCAs expected women to make informed decisions about screening for Down's syndrome. However, midwives' attempts to maintain the normality of pregnancy and avoid discussions about potential scenarios, as well as their emphasis on the high accuracy rate of first trimester screening have routinised first trimester antenatal screening for Down's syndrome. Also, a general expectation in the clinic to take up screening and the constrained service context in which midwives and HCAs work had implications for women's informed choices. KEY CONCLUSIONS: directive information combined with lack of purposeful dialogue with pregnant women have constrained the process of information-giving about antenatal screening for Down's syndrome. IMPLICATIONS: the provision of information about antenatal screening for Down's syndrome is a challenging role for midwives. Changes in midwifery practice resulting from continuing education as well as less constraining service contexts could improve the quality of information about antenatal screening for Down's syndrome. PMID- 20947231 TI - Correlations between strength and quantitative computed tomography measurement of callus mineralization in experimental tibial fractures. AB - BACKGROUND: the evaluation of fracture healing in the clinic has not changed significantly during the past few decades, despite the development of modern tissue-imaging tools. Recent publications have reported significant and interesting associations between biomechanical properties and quantitative computed tomography data of fractures and grafts. We therefore studied the correlations between the strength and segmented quantitative computed tomography data of tibial diaphyseal fractures. METHODS: forty male rats received a tibial shaft osteotomy that was initially stabilized with either intramedullary nailing or external fixation. Evaluation at 30 and 60 days post-osteotomy included X-ray, quantitative computed tomography and bending testing. Quantitative computed tomography data were segmented by voxel density into soft callus (171-539 mg/cm(3)), hard callus (540-1199 mg/cm(3)) and cortical bone (>= 1200mg/cm(3)), and volumetric bone mineral density was calculated. FINDINGS: all fractures demonstrated pronounced formation of soft and hard callus tissues at 30 days post osteotomy, and at 60 days the cortical bone volume was significantly increased with callus resorption. Bending strength correlated significantly and positively with fracture-site cortical bone volume and volumetric bone mineral density in the intramedullary nailed group in the early phase of healing. INTERPRETATION: quantitative computed tomography was used to quantify characteristic secondary healing. The observed correlations indicate that biomechanically important mineralization can be measured by quantitative computed tomography in the early phase of healing in flexibly fixed fractures. PMID- 20947232 TI - Integrated care in the emergency department: a complex adaptive systems perspective. AB - Emergency clinicians undertake boundary-work as they facilitate patient trajectories through the Emergency Department (ED). Emergency clinicians must manage the constantly-changing dynamics at the boundaries of the ED and other hospital departments and organizations whose services emergency clinicians seek to integrate. Integrating the care that differing clinical groups provide, the services EDs offer, and patients' needs across this journey is challenging. The journey is usually accounted for in a linear way - as a "continuity of care" problem. In this paper, we instead conceptualize integrated care in the ED using a complex adaptive systems (CAS) perspective. A CAS perspective accounts for the degree to which other departments and units outside of the ED are integrated, and appropriately described, using CAS concepts and language. One year of ethnographic research was conducted, combining observation and semi-structured interviews, in the EDs of two tertiary referral hospitals in Sydney, Australia. We found the CAS approach to be salient to analyzing integrated care in the ED because the processes of categorization, diagnosis and discharge are primarily about the linkages between services, and the communication and negotiation required to enact those linkages, however imperfectly they occur in practice. Emergency clinicians rapidly process large numbers of high-need patients, in a relatively efficient system of care inadequately explained by linear models. A CAS perspective exposes integrated care as management of the patient trajectory within porous, shifting and negotiable boundaries. PMID- 20947233 TI - 'Vulnerability is universal': considering the place of 'security' and 'vulnerability' within contemporary global health discourse. AB - The question of global health has, at least since 9/11, (re)emerged as one of the world's key geopolitical issues and, as many scholars have noted, this increased attention to the state of world health is especially focused on questions of national security and vulnerability. Despite its prominence in political, health policy and scholarly circles, health geographers have tended to overlook this particular aspect of global health discourse. This paper seeks to redress this lacuna. It does so for three reasons. The first lies in the idea that this discourse is inherently geographical; after all, it is in essence concerned with the flows of human and non-human agents within and, more importantly here, across, national borders. It is also of interest because a focus on vulnerability allows for an analysis that goes beyond the current fixation with emerging and re emerging infectious diseases. Although it is certainly true that the concern with such diseases dominates, and the recent focus upon H1N1 swine flu is testament to that, there is also a suggestion that the processes associated with the enhanced threat posed by these diseases are similar to those that have caused non communicable diseases to become a global health problem too. A third reason for focussing on this aspect of the global health discourse is that the subsequent search for 'security' is highly problematic; especially if we consider the question of "who is to be protected, and from what". The aim of the paper is, then, to offer a critical review of the international discourse on global health and to highlight its relevance to scholars that self-identify as health and medical geographers. PMID- 20947234 TI - Metropolitan isolation segregation and Black-White disparities in very preterm birth: a test of mediating pathways and variance explained. AB - Residential isolation segregation (a measure of residential inter-racial exposure) has been associated with rates of preterm birth (<37 weeks gestation) experienced by Black women. Epidemiologic differences between very preterm (<32 weeks gestation) and moderately preterm births (32-36 weeks) raise questions about whether this association is similar across gestational ages, and through what pathways it might be mediated. Hierarchical Bayesian models were fit to answer three questions: is the isolation-prematurity association similar for very and moderately preterm birth; is this association mediated by maternal chronic disease, socioeconomic status, or metropolitan area crime and poverty rates; and how much of the geographic variation in Black-White very preterm birth disparities is explained by isolation segregation? Singleton births to Black and White women in 231 U.S. metropolitan statistical areas in 2000-2002 were analyzed and isolation segregation was calculated for each. We found that among Black women, isolation is associated with very preterm birth and moderately preterm birth. The association may be partially mediated by individual level socioeconomic characteristics and metropolitan level violent crime rates. There is no association between segregation and prematurity among White women. Isolation segregation explains 28% of the geographic variation in Black-White very preterm birth disparities. Our findings highlight the importance of isolation segregation for the high-burden outcome of very preterm birth, but unexplained excess risk for prematurity among Black women is substantial. PMID- 20947235 TI - Reducing child malnutrition in Nigeria: combined effects of income growth and provision of information about mothers' access to health care services. AB - Using a sample of 1359 Nigerian households from the 2003 Demographic and Health Surveys, this article investigates the contribution of improved maternal information about access to community health services toward the reduction of child stunting and undernourishment. The analysis shows that family wealth and region-specific knowledge about community health care access positively affects child nutrition status measured by height-for-age and weight-for-age. However, these nutrition gains can be reinforced or tempered by differences in mother's education and/or her access to community health services. These findings suggest that interventions which enhance public knowledge about availability and access to health care could strengthen more general development-oriented child nutrition enhancing interventions, such as poverty reduction or growth in health services infrastructure. PMID- 20947236 TI - [Presentation of a flap web space laterodigital in cleft foot]. AB - Cleft foot deformity is characterized by the absence of one or more median rays of the foot. This rare polymorphous congenital anomaly occurs more frequently in males, with a frequent autosomal dominant type of transmission. The purpose of surgical treatment is to narrow the width of the foot, but also to improve its global aesthetic look. Toe reparation, and more specifically web space reconstruction, provide the main technical challenges. We present an adaptation to the foot of a laterodigital cutaneous flap published by Barsky in 1964 for commissural reconstruction in cleft hand syndroms. The anatomical structure of fingers and toes commisures being different, this flap seems more adapted to the surgery of the foot. We gathered seven patients' files treated for ectrodactyly of the foot with this technique by the same surgeon from 2005 to 2008. No particular postoperative complications were noted, and the patients all expressed their satisfaction regarding the improvement of the appearance of their foot. We recommend to add the use of this flap in the "tool box" of the surgeon in charge of the management of foot deformities. PMID- 20947237 TI - The effect of induced hypothermia on respiratory parameters in mechanically ventilated patients. AB - AIM: Mild hypothermia is increasingly applied in the intensive care unit. Knowledge on the effects of hypothermia on respiratory parameters during mechanical ventilation is limited. In this retrospective study, we describe the effect of hypothermia on gas exchange in patients cooled for 24 h after a cardiac arrest. METHODS: Respiratory parameters were derived from electronic patient files from 65 patients at the start and end of the hypothermic phase and at every centigrade increase in body temperature until normo-temperature, including tidal volume, positive end expiratory pressure (PEEP), plateau pressure, respiratory rate, exhaled CO(2) concentrations (etCO(2)) and FIO(2). Static compliance was calculated as V(T)/P(plateau)-PEEP. Dead space ventilation was calculated as (PaCO(2)-etCO(2))/PaCO(2). RESULTS: During hypothermia, PaCO(2) decreased, at unchanged PaCO(2)-etCO(2) gap and minute ventilation. During rewarming, PaCO(2) did not change, while etCO(2) increased at unchanged minute ventilation. Dead space ventilation did not change during hypothermia, but lowered during rewarming. During hypothermia, PaO(2)/FIO(2) ratio increased at unchanged PEEP levels. Respiratory static compliance did not change during hypothermia, nor during rewarming. CONCLUSION: Hypothermia possibly improves oxygenation and ventilation in mechanically ventilated patients. Results may accord with the hypothesis that reducing metabolism with applied hypothermia may be beneficial in patients with acute lung injury, in whom low minute ventilation results in severe hypercapnia. PMID- 20947238 TI - Efficacy and safety of the EZ-IOTM intraosseous device: Out-of-hospital implementation of a management algorithm for difficult vascular access. AB - OBJECTIVE: Intraosseous access is a rapid and safe alternative when peripheral vascular access is difficult. Our aim was to assess the safety and efficacy of a semi-automatic intraosseous infusion device (EZ-IO) when using a management algorithm for difficult vascular access in an out-of-hospital setting. METHODS: This was a one-year prospective, observational study by mobile intensive care units. After staff training in the use of the EZ-IO device and provision of a management algorithm for difficult vascular access, all vehicles were equipped with the device. We determined device success rate and ease of use, resuscitation fluid volume and drugs administered by the intraosseous route, and complications at insertion site. RESULTS: A total of 4666 patients required vascular access. The EZ-IO device was used in 30 cardiac arrest patients (25 adults; 5 children) and 9 adults with spontaneous cardiac activity. The success rate for first insertion was 84%. Overall success rate (max. 2 attempts) was 97%. The device was used for fluid resuscitation in 16 patients (mean volume: 680ml), adrenaline administration in 24 patients, and rapid sequence induction in 2 patients. There was only one local complication (transient local inflammation). CONCLUSIONS: On implementation of an algorithm for the management of difficult vascular access, the EZ-IO device proved safe and highly effective in both adult and paediatric patients in an out-of-hospital emergency setting. It is a suitable device for consideration as a first-line option for difficult vascular access in this setting. PMID- 20947239 TI - Resuscitation quality assurance for out-of-hospital cardiac arrest--setting-up an ambulance defibrillator telemetry network. AB - BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a leading cause of pre hospital mortality. Chest compressions performed during cardiopulmonary resuscitation aim to provide adequate perfusion to the vital organs during cardiac arrest. Poor resuscitation technique and the quality of pre-hospital CPR influences outcome from OHCA. Transthoracic impedance (TTI) measurement is a useful tool in the assessment of the quality of pre-hospital resuscitation by ambulance crews but TTI telemetry has not yet been performed in the United Kingdom. We describe a pilot study to implement a data network to collect defibrillator TTI data via telemetry from ambulances. METHODS: Prospective, observational pilot study over a 5-month period. Modems were fitted to 40 defibrillators on ambulances based in Edinburgh. TTI data was sent to a receiving computer after resuscitation attempts for OHCA. RESULTS: 58 TTI traces were transmitted during the pilot period. Compliance with the telemetry system was high. The mean ratio of chest compressions was 73% (95% CI 69-77%), the mean chest compression rate was 128 (95% CI 122-134). The mean time interval from chest compression interruption to shock delivery was 27 s (95% CI 22-32 s). CONCLUSION: Trans-thoracic impedance analysis is an effective means of recording important measures of resuscitation quality including the hands-on-the-chest time, compression rate and defibrillation interval time. TTI data transmission via telemetry is straightforward, efficient and allows resuscitation data to be captured and analysed from a large geographical area. Further research is warranted on the impact of post-resuscitation reporting on the quality of resuscitation delivered by ambulance crews. PMID- 20947240 TI - New conventional long-term survival normovolemic cardiac arrest pig model. AB - AIM OF THE STUDY: A reproducible long-term intensive care and outcome cardiac arrest model for exploring new cerebral preservation strategies is needed. We tried to determine effects and limitations of current therapies after different 'no-flow' times. METHODS: Thirty-five female Large White Breed pigs (26-37kg) were included in the study. Three pigs served as sham animals without cardiac arrest (CA). Ventricular fibrillation (VF) CA was induced in 32 animals for 0, 7, 10 and 13min (each group consisting of 8 animals), followed by 8min of chest compressions, mechanical ventilation and vasopressors. Thereafter, up to 3 defibrillations were delivered. After restoration of spontaneous circulation (ROSC), the animals underwent intensive care for 20h. Neurologic examination was performed at designated time points using a neurologic deficit (ND) and an overall performance category (OPC) score. RESULTS: Restoration of spontaneous circulation was achieved in 8 of 8 animals in the 0min-group, 6 of 8 in the 7min group, 7 of 8 in the 10min-group and 0 of 8 in the 13min-group. All animals of the sham-group and 0min-group were neurologically intact survivors; the 7 and 10min-groups showed a median ND of 55%(26;94) and 73%(58;78), respectively. There were no significant differences between the 7 and 10min-groups regarding OPC and NDS. Coronary perfusion pressure during CPR decreased concordantly with 'no-flow' times with a tendency towards significance. CONCLUSION: This study established a reproducible cardiac arrest and resuscitation model in pigs which will be used to test novel resuscitation strategies to improve neurologic outcome after cardiac arrest. PMID- 20947241 TI - Performer fatigue and CPR quality comparing 30:2 to 15:2 compression to ventilation ratios in older bystanders: A randomized crossover trial. AB - OBJECTIVES: We sought to compare bystander fatigue and CPR quality after 5min of CPR using the 30:2 vs. the 15:2 chest compression:ventilation ratios in a population of older participants. METHODS: This randomized cross-over study included independent-living participants aged >=55. Participants completed two 5 min CPR sessions (using 30:2 and 15:2 ratios) on a recording manikin, separated by a 5-min rest. We measured changes in heart rate (HR), mean arterial pressure (MAP), venous lactate (VL; in selected participants), and perceived level of exhaustion (Borg Scale and subjective). CPR quality measures included total number of chest compressions and number of adequate compressions. RESULTS: The 42 enrolled participants were: mean age 66.0 (range 55-84), female 69.0%, and previously CPR trained 66.7%. Measures of bystander fatigue were similar for each CPR ratio: mean difference in increased HR 1.5 (95%CI -1.5 to 4.5), MAP 1.5 (-1.8 to 4.8), VL 0.2 (-1.1 to 1.4), Borg 0.2 (-0.2 to 0.8), but subjectively reported fatigue level was higher after the 30:2 session. Participants attempted more chest compressions per session using the 30:2 vs. the 15:2 ratio: mean diff. 78.6 (69.5-87.7), but did not complete more adequate compressions: mean diff. 1.9 ( 18.9 to 22.9). The decline in number of adequate compressions/min over time was significant but similar in each group. CONCLUSIONS: In this study of older volunteers, the 30:2 CPR ratio resulted in similar objective measures of fatigue, but higher perceived fatigue than the 15:2 ratio. The 30:2 ratio resulted in proportionally more inadequate compressions. PMID- 20947242 TI - Devils lake emergency outlet diversion conflict. AB - The Devils Lake Emergency Outlet Diversion conflict is systematically studied from a strategic viewpoint using the Graph Model for Conflict Resolution in order to obtain insights about the resolution of this nagging international dispute. By modelling the conflict for the situation existing as of July 2005, just before the project began operation, the dispute is put into proper perspective and, subsequently, a stability analysis is carried out to obtain potential resolutions or equilibria. The results of a sensitivity analysis accurately predict the deal which actually took place when Canada and the American state of North Dakota reached a negotiated settlement. Finally, suggestions are put forward for improving the Boundary Waters Treaty of 1909 between Canada and the United States. PMID- 20947243 TI - New methods for the analysis of invasion processes: multi-criteria evaluation of the invasion of Hydrilla verticillata in Guatemala. AB - The study described in this article incorporates stakeholders' views on aquatic invasion processes and combines expert analysis with information from field work into an evaluation exercise. Management scenarios are designed based on available technical data and stakeholders' perceptions. These scenarios are evaluated using the Social Multi-Criteria Evaluation framework employing the NAIADE model. Two evaluations are carried out, technical and social. Social acceptance of different management scenarios, distribution of costs and benefits, and attribution of responsibility are discussed. The case study was carried out on Lake Izabal, a body of water connected to the Caribbean Sea in Northeastern Guatemala. In 2000, local fishermen reported the presence of an alien species in the lake, the macrophyte Hydrilla verticillata. Two years later, this alien species was established around the entire lakeshore, damaging the ecosystem, endangering native species and the subsistence of local inhabitants through impacts on transportation, fishing practices, and tourism. PMID- 20947244 TI - Prostate cancer detection in the "grey area" of prostate-specific antigen below 10 ng/ml: head-to-head comparison of the updated PCPT calculator and Chun's nomogram, two risk estimators incorporating prostate cancer antigen 3. AB - BACKGROUND: Prostate cancer antigen 3 (PCA3) holds promise in diagnosing prostate cancer (PCa), but no consensus has been reached on its clinical use. Multivariable predictive models have shown increased accuracy over individual risk factors. OBJECTIVE: To compare the performance of the two available risk estimators incorporating PCA3 in the detection of PCa in the "grey area" of prostate-specific antigen (PSA) <10 ng/ml: the updated Prostate Cancer Prevention Trial (PCPT) calculator and Chun's nomogram. DESIGN, SETTING, AND PARTICIPANTS: Two hundred eighteen patients presenting with an abnormal PSA (excluding those with PSA >10 ng/ml) and/or abnormal digital rectal examination were prospectively enrolled in a multicentre Italian study between October 2008 and October 2009. All patients underwent >=12-core prostate biopsy. MEASUREMENTS: PCA3 scores were assessed using the Progensa assay (Gen-Probe, San Diego, CA, USA). Comparisons between the two models were performed using tests of accuracy (area under the receiver operating characteristic curve [AUC-ROC]), calibration plots, and decision curve analysis. Biopsy predictors were identified by univariable and multivariable logistic regression. In addition, performance of PCA3 was analysed through AUC-ROC and predictive values. RESULTS AND LIMITATIONS: PCa was detected in 73 patients (33.5%). Among predictors included in the models, only PCA3, PSA, and prostate volume retained significant predictive value. AUC-ROC was higher for the updated PCPT calculator compared to Chun's nomogram (79.6% vs 71.5%; p=0.043); however, Chun's nomogram displayed better overall calibration and a higher net benefit on decision curve analysis. Using a probability threshold of 25%, no high-grade cancers would be missed; the PCPT calculator would save 11% of biopsies, missing no cancer, whereas Chun's nomogram would save 22% of avoidable biopsies, although missing 4.1% non-high-grade cancers. The small number of patients may account for the lack of statistical significance in the predictive value of individual variables or model comparison. CONCLUSIONS: Both Chun's nomogram and the PCPT calculator, by incorporating PCA3, can assist in the decision to biopsy by assignment of an individual risk of PCa, specifically in the PSA levels <10 ng/ml. PMID- 20947245 TI - A primary study of diffusion tensor imaging-based histogram analysis in vascular cognitive impairment with no dementia. AB - PURPOSE: This study performed diffusion tensor imaging (DTI) histogram analysis and voxel-based analysis (VBA) to detect white matter (WM) damage in patients with vascular cognitive impairment with no dementia (VCIND) and to determine correlations between DTI histogram-derived measures and cognitive dysfunction in these patients. MATERIALS AND METHODS: Among patients with subcortical ischemic vascular disease, 18 patients with VCIND were selected along with 18 age- and sex matched cognitive-normal subjects. Both groups underwent magnetic resonance and DTI scans, and fractional anisotropy (FA) changes in VBA between the two groups were assessed. Further, mean diffusivity (MD) and FA histograms of WM and normal appearing WM (NAWM) in each subject were evaluated. RESULTS: Compared to control, the VCIND group showed lower FA values throughout the brain. FA and MD histogram patterns of WM and NAWM were significantly different between the groups. Significant differences were found in all DTI histogram-derived measures, except in the mean FA peak height of WM and mean MD peak location of NAWM. Neuropsychological results (z-scores) were found to be significantly correlated with mean FA peak location, average MD, mean MD peak location of WM, and mean FA peak height, average MD, mean MD peak location of NAWM. CONCLUSIONS: Results of VBA and diffusion tensor imaging-based histogram analysis suggest that VCIND patients have more severe damage in WM and NAWM than the control. Thus, the severity of damage in WM and NAWM may be related with cognitive dysfunction in VCIND patients, and DTI histogram analysis can help in further understanding VCIND. PMID- 20947246 TI - Postoperative treatment and prognosis of patients with resected single brain metastasis: how useful are established prognostic scores? AB - OBJECTIVE: To evaluate postoperative prognosis and the performance of known prognostic scores in patients treated with surgical resection for single brain metastasis. METHODS: We evaluated prognostic factors and five previously published prognostic scores in a group of 74 patients with single brain metastasis treated with surgery with or without immediate whole-brain radiotherapy (WBRT). RESULTS: In multivariate analysis, good performance status, absence of extracranial metastases and primary tumor control were significantly associated with improved overall survival. Survival (median 10.8 months) was not significantly prolonged by immediate WBRT. Salvage treatment was necessary in 87% of patients without immediate WBRT. All five scores identified groups of patients with superior prognosis. The recursive partitioning analysis (RPA) classes, the graded prognostic assessment (GPA) score and the score developed by Rades et al. identified a poor prognosis group, but the numbers of poor prognosis patients were very small. CONCLUSIONS: RPA and GPA appear to have the most utility in delineating exceptionally good or poor prognosis patients after resection of single brain metastasis, but this finding remains to be validated in a larger study population. Identification and validation of suitable prognostic scores hopefully will guide decision making regarding local treatment of solitary brain metastasis. PMID- 20947247 TI - Microsurgical management of tuberculum sellae meningiomas by the frontolateral approach: surgical technique and visual outcome. AB - OBJECTIVES: The aim of this study was to evaluate visual outcome in patients with tuberculum sellae meningioma (TSM) treated microsurgically using the frontolateral or fronto-orbital approach and optic canal unroofing to resect tumor involvement of the optic canal. METHODS: Data from 67 patients with TSMs who underwent microsurgical treatment by a frontolateral approach (n=44) or fronto-orbital approach (n=23) between January 2002 and December 2008 were retrospectively collected and analyzed. Change in visual function was evaluated as the main outcome. RESULTS: Total tumor resection was achieved in 62 of 67 cases (92.4%). Postoperative, visual acuity was improved in 87 eyes (64.9%) and unchanged in 39 eyes (29.1%), and the optic nerve was therefore preserved in 126 of 134 eyes (94.0%). Visual field deficits were improved or stable in 65 eyes, no patient experienced worsening of vision in both eyes. There was no mortality in our series. CONCLUSIONS: The frontolateral approach with microsurgical dissection of the Sylvian fissure provides quick access to TSMs, which can be resected safely and totally. Visual function is improved and neurological and ophthalmological morbidity is minimal. Optic nerve decompression by intradural clinoidectomy and optic canal unroofing is likely to increase the rate of reducing or eliminating preoperative visual symptoms. PMID- 20947249 TI - Partner responses to patient pain and well behaviors and their relationship to patient pain behavior, functioning, and depression. AB - The goals of the current study were to examine the associations between patient reported spouse responses to pain and well behaviors as assessed by the Spouse Response Inventory (SRI) [22] and (1) patient-reported pain behavior, (2) depression, and (3) physical dysfunction, independent of patient demographics and pain severity. Moreover, we sought to examine the potential moderating influence of marital satisfaction on these relationships. We also evaluated the construct and concurrent validity and internal reliability of the SRI. The findings indicate that encouragement of well behaviors is related to lower levels of patient-reported pain behaviors, while negative responses to well behavior is related to greater patient physical dysfunction. Likewise, higher levels of negative responses to pain behaviors, as well as higher levels of solicitous responses to pain behaviors are generally related to poorer patient functioning. Furthermore, marital satisfaction did not moderate the relationship between any SRI subscales and patient-reported pain behaviors. In summary, our results support the internal reliability and validity of the SRI scales as measures of spousal responses to both pain and well behaviors. The current study also supports the importance of examining the potential impact of responses to both well and pain behaviors. Further research is needed to examine the potential impact of other contextual variables and marital satisfaction on the relationship of spouse responses to both well and pain behaviors. PMID- 20947250 TI - Is duloxetine useful for central neuropathic pain? PMID- 20947248 TI - Targeting SRC in glioblastoma tumors and brain metastases: rationale and preclinical studies. AB - Glioblastoma (GBM) is an extremely aggressive, infiltrative tumor with a poor prognosis. The regulatory approval of bevacizumab for recurrent GBM has confirmed that molecularly targeted agents have potential for GBM treatment. Preclinical data showing that SRC and SRC-family kinases (SFKs) mediate intracellular signaling pathways controlling key biologic/oncogenic processes provide a strong rationale for investigating SRC/SFK inhibitors, e.g., dasatinib, in GBM and clinical studies are underway. The activity of these agents against solid tumors suggests that they may also be useful in treating brain metastases. This article reviews the potential for using SRC/SFK inhibitors to treat GBM and brain metastases. PMID- 20947251 TI - TNF-alpha in CRPS and 'normal' trauma--significant differences between tissue and serum. AB - Posttraumatic TNF-alpha signaling may be one of the factors responsible for pain and hyperalgesia in complex regional pain syndromes (CRPS). In order to further specify the role of TNF-alpha we investigated tissue (skin) and serum concentrations in three different patient groups: patients with osteoarthritis and planned surgery, with acute traumatic upper limb bone fracture waiting for surgery, and with CRPS I. Thirty patients (10 in each group) were recruited. Mean CRPS duration was 36.1 +/- 8.1 weeks (range 8- 90 weeks). Skin punch biopsies were taken at the beginning of the surgery in osteoarthritis and fracture patients and from the affected side in CRPS patients. Blood samples were taken before the respective procedures. Skin and serum TNF-alpha levels were quantified by ELISA. Compared to patients with osteoarthritis, skin TNF-alpha was significantly elevated in CRPS (p<0.001) and fracture patients (p<0.04). Skin TNF alpha in CRPS patients was higher than in patients with acute bone fracture (p<0.02). In contrast, serum TNF-alpha values were the same in osteoarthritis and CRPS, and lower in fracture patients (p<0.03). Our results indicate a local but not systemic increase of TNF-alpha in CRPS patients. This increase persists for months after limb trauma and may offer the opportunity for targeted treatment. PMID- 20947252 TI - Sheep scab control using trans-cinnamic acid. AB - A series of in vitro and in vivo assays were conducted to examine the effects of trans-cinnamic acid ethyl ester on Psoroptes mange mites. In vitro, 24h after exposure to the test material at concentrations of 10, 1 or 0.1% (v/v), 100, 74 and 20% of mites had died, respectively, compared to 8% following exposure to the control (0.05% SDS only). The different life-cycle stages were affected similarly by the test compound. The concentration required to produce 95% mortality 24h after exposure to the test compound was 6.29% (95% confidence interval 4.98 8.88). Tarsal contact of the mites with the test compound was also sufficient to achieve high levels of mortality; 100% death was observed when the mites were placed in contact with either sheep skin circles treated to give 0.01 ml/cm(2) or polyester cloth circles treated with 0.03 ml/cm(2). However, the residual activity of both skin and cloth treated with 0.03 ml/cm(2) was completely lost after 7 days. In vivo, trans-cinnamic acid ethyl ester suspended in 2% (w/v) lecithin was applied as a spray formulation to eight sheep with active artificial infestations of sheep scab. Seven of the 8 treated sheep were cured and remained completely clear of scab mites for 56 days. However, 33 days after treatment 2 adult female mites were observed on one of the eight treated sheep and the mite population on this sheep subsequently recovered. In contrast, in a control group of two infested sheep, treated with a 2% (w/v) lecithin only, mite populations increased as expected in a typical scab infestation, but eventually self-cured in one animal. The data suggest that, with appropriate development of suitable application technology, trans-cinnamic acid ethyl ester could have a role as a potential therapeutic treatment for active sheep scab, however the short residual period of activity is likely to limit its use in commercial sheep flocks. PMID- 20947253 TI - In vitro acaricidal effect of tannin-rich plants against the cattle tick Rhipicephalus (Boophilus) microplus (Acari: Ixodidae). AB - The objectives of this study were to evaluate the in vitro acaricidal effects of lyophilized extracts of four tannin rich plants (Acacia pennatula, Piscidia piscipula, Leucaena leucocephala and Lysiloma latisiliquum) against diverse stages of Rhipicephalus (Boophilus) microplus, and to asses whether tannins were involved in the acaricidal effect using polyethylene glycol (PEG) to block tannins. Larval immersion (LIT) and adult immersion (AIT) tests were used to evaluate the acaricidal effect of each of the lyophilized extracts against larval and adult stages of R. microplus respectively. Larvae and adult ticks were exposed to increasing concentrations of each plant extract (0, 1200, 2400, 4800, 9600 and 19,200 MUg ml(-1)) for 10 min. Larval mortality was recorded at 48 h post-incubation. Adult mortality was recorded daily over 14 days, at which point their reproductive efficiency was evaluated. PEG was added to the extracts to verify whether tannins were involved in the acaricidal effect. The effect on egg laying inhibition and larval mortality was analyzed using the GLM procedure in SAS. A Kruskal-Wallis test was used to assess the effect of PEG on LIT results. Calculation of the lethal concentration 50 (LC50) was performed using a probit analysis. All extracts reduced the viability of R. microplus larval stages (P<0.001), and viability was restored with the addition of PEG suggesting an important role of tannins in the acaricidal effect (P<0.001). The LC50 values of L. latisiliquum and P. piscipula plant extracts were 6.402 and 2.466 MUg ml(-1). None of the tannin-rich plant extracts affected adult mortality (P>0.05). Lysiloma latisiliquum extract inhibited egg hatching of R. microplus (P<0.01). Tannin-rich plant extracts from A. pennatula, P. piscipula, L. leucocephala and L. latisiliquum showed potential acaricidal activity. Further in vivo studies are needed to confirm this finding. PMID- 20947254 TI - New insights into the morphology, molecular characterization and identification of Baylisascaris transfuga (Ascaridida, Ascarididae). AB - Species ranked within the genus Baylisascaris (Ascaridida, Ascarididae) have been implicated in clinical and subclinical intestinal diseases in their natural hosts (e.g., raccoons and bears) as well as in life-threatening larva migrans syndromes in a number of incidental hosts, including humans. Following the diagnosis of Baylisascaris transfuga infestation in two captive polar bears, living in the zoo park of Pistoia (Tuscany, Italy), nematodes (n=300; both sexes) have been characterized by morphological and molecular methods by sequencing and analysing ribosomal (large ribosomal DNA (28S) and internal transcribed spacer region 1 and 2 (ITSs)) and mitochondrial (cytochrome c oxidase subunit 1 (cox1) and cytochrome c oxidase subunit 2 (cox2)) target regions. In addition, seven faecal samples were collected from the animal enclosure and submitted to copromicroscopic and molecular examination. All nematodes were morphologically identified as B. transfuga and their main distinctive features are here presented. No variation in size and nucleotide polymorphisms was detected within each target sequence among all samples analysed. These data contribute to facilitate an accurate diagnosis of this little known nematode infestation in order to apply appropriate anthelmintic strategies. PMID- 20947255 TI - Autochtonous infection of dogs and slugs with Angiostrongylus vasorum in Hungary. AB - On the course of a helminthological survey of the dogs of Baranya County, Hungary Angiostrongylus vasorum infection was detected in two asymptomatic dogs. Identification of the parasite was based on morphology of the first-stage larvae (L1) isolated from droppings, and successful experimental infection with first stage larvae to laboratory reared Discus rotundatus and Lissachatina fulica snails, in order to exclude species of the family Filaroididae that have similar larvae to A. vasorum. While angiostrongylosis is widespread among foxes, this is the first report of A. vasorum infection in housedog in Hungary. In gardens, where infected dogs were being kept 91 specimens of 6 species of limacid and arionid slugs were collected of which 5 specimens of Arion lusitanicus were found to carry larvae of A. vasorum. Dogs usually do not ingest such large slugs willingly. Frogs are known to act as paratenic hosts in the life cycle of A. vasorum. Since one of the infected dogs harboured also infection with the intestinal trematode Alaria alata, of which frogs certainly play the role of the second intermediate host, therefore it is assumed that in this case the dog became infected with A. vasorum by eating frogs. PMID- 20947256 TI - The nutritional background of the host alters the disease course in a fish myxosporean system. AB - The aim of the present work was to determine if a practical plant protein-based diet containing vegetable oils (VO) as the major lipid source could alter the disease course when challenged with the myxosporean Enteromyxum leei, a wide spread parasite in the Mediterranean basin causing heavy economic losses. Gilthead sea bream (Sparus aurata) fed for 9 months either a fish oil (FO) diet or a blend of VOs at 66% of replacement (66VO diet) were challenged by exposure to parasite-contaminated water effluent. All fish were periodically and non lethally sampled to obtain biometrical data and to know their infection status. After 102 days of exposure, fish were euthanized and haematological, biometrical, histological, immunological, glutathione and anti-oxidant data were obtained from tissue, blood and serum samples. Anorexia appeared in both exposed groups, but feed intake reduction was higher in 66VO fish. The signs of disease (lower growth, condition factor, specific growth rate, haematocrit) as well as the disease course were worse in fish from 66VO group, with a higher prevalence and intensity of infection, a higher percentage of fish harbouring the parasite in the entire intestinal tract, and a faster establishment of the parasite. Parasite intensity of infection was negatively correlated with growth parameters and haematocrit in both groups, and with complement, lysozyme and hepatic total glutathione in 66VO fish. PMID- 20947258 TI - Antibiotics in childhood burns. PMID- 20947259 TI - Prevention of burns: 13 years' experience in Northeastern India. AB - Burns are noteworthy causes of morbidity and mortality in India. Community-based interventions in the forms of multi-strategic and multi-focussed preventive programs are, however, lacking. This study, undertaken in the remote corner of Northeastern India, aims at reducing the incidence of burns through focussed attention towards sensitising the community with well-structured preventive programmes. Participatory community seminars, shop floor visit to industrial locations, use of print and electronic media and lectures and demonstrations in schools were the tools used in the preventive programmes. Analysis of inpatient and outpatient records of burn-injured patients treated in the Burn Unit and a scoring system in the school education programme helped in the assessment of the impact of Burn Preventive Programs (BPPs). For convenience of assessment, a comparative analysis of the results in early (block I) and later part (block II) of the study period was made. Results showed reduction of admission and also reduction in percent total body surface area (%TBSA) burn in the majority of the patients in block II in comparison to block I. Water was used to extinguish fire in 36.1% patients in block I and 73.4% patients in block II. Water was also used to cool burn wounds by 31% patients in Block I, and by 72% patients in block II. While 80% of the patients made inappropriate topical applications on the wounds in block I, only 34.4% did so in block II. Increased awareness amongst the general population was reflected by reduction of average reporting time in hospital after injury and significant reduction of firecracker burns from 21.5% (block I) to 14.6% (block II). Similarly, improved awareness amongst the students was evident from the improved scoring by the majority of the students and reduction in burns amongst them in the later part of block II. The results indicate that BPP has made a positive impact in society. PMID- 20947260 TI - The long-term effects of childhood maltreatment experiences on subsequent illicit drug use and drug-related problems in young adulthood. AB - OBJECTIVES: The objective of this study was to examine the associations between (a) childhood maltreatment (i.e., physical abuse, sexual abuse, and neglect) and subsequent illicit drug use and (b) childhood maltreatment and drug-related problems in young adulthood. METHODS: Wave 1 and Wave 3 public-use data from the National Longitudinal Study of Adolescent Health were used. Logistic regressions, controlling for adolescent drug use and other important family and peer contextual processes, were estimated to determine the associations between (a) childhood maltreatment experiences and subsequent illicit drug use and (b) childhood maltreatment and drug-related problems in young adulthood. RESULTS: Among the participants, 31.9% reported some form of childhood maltreatment. Childhood physical abuse was associated with a 37% (OR=1.37; 95% CI=1.04, 1.80) increase in illicit drug use during the 30 days prior to the Wave 3 survey, a 48% (OR=1.48; 95% CI=1.16, 1.89) increase in illicit drug use during the year prior to the Wave 3 survey, and a 96% (OR=1.96; 95% CI=1.40, 2.76) increase in drug related problems in young adulthood. The latter two associations persisted even after controlling for illicit drug use in adolescence. Neglect among females was associated with a higher likelihood of past year illicit drug use in young adulthood (OR=1.31; 95% CI=1.002, 1.71). However, this association was not significant once the effect of illicit drug use in adolescence was statistically controlled for. CONCLUSIONS: The present findings suggest that childhood maltreatment is related to subsequent illicit drug use and drug-related problems in young adulthood and that some of these associations differ by gender. Implications for preventive intervention are discussed. PMID- 20947261 TI - Combination therapy targeting cancer metabolism. AB - Cancer cells undergo significant metabolic adaptation. Cellular transformation enhances both glycolysis and mitochondrial respiration efficiency through the induction of HIF-1alpha and HIF-2alpha. In this process, energy production and synthesis of macromolecules are maximized with minimal ROS accumulation. Furthermore, a series of antioxidant enzymes are induced to mitigate the damaging effects of ROS. Examination of these metabolic changes provides rationale for a synergistic approach to combination anti-cancer therapy; targeted inhibition of HIF and inhibition of cellular defenses against oxidative stress. PMID- 20947262 TI - The expression of MUC mucin in cholangiocarcinoma. AB - Cholangiocarcinoma (CC) is a highly malignant epithelial cancer of the biliary tract, the cellular and molecular pathogenesis of which remains unclear. Malignant transformation of glandular epithelial cells is associated with the altered expression of mucin. We investigated the type of mucins expressed in CC. Twenty-six patients with histologically confirmed CC were included in this study. The expression of mucin was studied by immunohistochemistry using antibodies to MUC1, MUC1 core, MUC2, MUC3, MUC4, MUC5AC, and MUC6. There was extensive (>50%) expression of mucin, mainly MUC1 in 11/25 and MUC5AC in 12/26 cases. In the case of MUC3, 6/26 cases expressed mucin extensively, whilst only 1/26 had MUC2, MUC4, and MUC6 expression. Well-differentiated tumors significantly expressed MUC3 extensively compared to poor or moderately differentiated tumors (p=0.003). Fifteen of 25 cases had metastatic disease. MUC1 was extensively expressed in 9/15 cases with metastatic disease. In contrast, MUC1 expression was present in 2/10 cases where metastases were absent. Hilar lesions were less likely to express MUC1, but this was not statistically significant. Fifteen of 25 cases had metastatic disease. Extensive MUC3 expression was significantly associated with well-differentiated tumors, whilst there was an approaching significance between the extensive expression of MUC1 and metastasis in cholangiocarcinoma. PMID- 20947263 TI - Interfraction liver shape variability and impact on GTV position during liver stereotactic radiotherapy using abdominal compression. AB - PURPOSE: For patients receiving liver stereotactic body radiotherapy (SBRT), abdominal compression can reduce organ motion, and daily image guidance can reduce setup error. The reproducibility of liver shape under compression may impact treatment delivery accuracy. The purpose of this study was to measure the interfractional variability in liver shape under compression, after best-fit rigid liver-to-liver registration from kilovoltage (kV) cone beam computed tomography (CBCT) scans to planning computed tomography (CT) scans and its impact on gross tumor volume (GTV) position. METHODS AND MATERIALS: Evaluable patients were treated in a Research Ethics Board-approved SBRT six-fraction study with abdominal compression. Kilovoltage CBCT scans were acquired before treatment and reconstructed as respiratory sorted CBCT scans offline. Manual rigid liver-to liver registrations were performed from exhale-phase CBCT scans to exhale planning CT scans. Each CBCT liver was contoured, exported, and compared with the planning CT scan for spatial differences, by use of in house-developed finite element model-based deformable registration (MORFEUS). RESULTS: We evaluated 83 CBCT scans from 16 patients with 30 GTVs. The mean volume of liver that deformed by greater than 3 mm was 21.7%. Excluding 1 outlier, the maximum volume that deformed by greater than 3 mm was 36.3% in a single patient. Over all patients, the absolute maximum deformations in the left-right (LR), anterior-posterior (AP), and superior-inferior directions were 10.5 mm (SD, 2.2), 12.9 mm (SD, 3.6), and 5.6 mm (SD, 2.7), respectively. The absolute mean predicted impact of liver volume displacements on GTV by use of center of mass displacements was 0.09 mm (SD, 0.13), 0.13 mm (SD, 0.18), and 0.08 mm (SD, 0.07) in the left-right, anterior-posterior, and superior-inferior directions, respectively. CONCLUSIONS: Interfraction liver deformations in patients undergoing SBRT under abdominal compression after rigid liver-to-liver registrations on respiratory sorted CBCT scans were small in most patients (<5 mm). PMID- 20947264 TI - The impact of individual in vivo repair of DNA double-strand breaks on oral mucositis in adjuvant radiotherapy of head-and-neck cancer. AB - PURPOSE: To evaluate the impact of individual in vivo DNA double-strand break (DSB) repair capacity on the incidence of severe oral mucositis in patients with head-and-neck cancer undergoing adjuvant radiotherapy (RT) or radiochemotherapy (RCT). PATIENTS AND METHODS: Thirty-one patients with resected head-and-neck cancer undergoing adjuvant RT or RCT were examined. Patients underwent RT of the primary tumor site and locoregional lymph nodes with a total dose of 60-66 Gy (single dose 2 Gy, five fractions per week). Chemotherapy consisted of two cycles of cisplatin and 5-fluorouracil. To assess DSB repair, gamma-H2AX foci in blood lymphocytes were quantified before and 0.5 h, 2.5 h, 5 h, and 24 h after in vivo radiation exposure (the first fraction of RT). World Health Organization scores for oral mucositis were documented weekly and correlated with DSB repair. RESULTS: Sixteen patients received RT alone; 15 patients received RCT. In patients who developed Grade>=3 mucositis (n=18) the amount of unrepaired DSBs 24 h after radiation exposure and DSB repair half-times did not differ significantly from patients with Grade<=2 mucositis (n=13). Patients with a proportion of unrepaired DSBs after 24 h higher than the mean value + one standard deviation had an increased incidence of severe oral mucositis. CONCLUSIONS: Evaluation of in vivo DSB repair by determination of gamma-H2AX foci loss is feasible in clinical practice and allows identification of patients with impaired DSB repair. The incidence of oral mucositis is not closely correlated with DSB repair under the evaluated conditions. PMID- 20947265 TI - Long-term outcomes of patients with spinal cord gliomas treated by modern conformal radiation techniques. AB - PURPOSE: This study retrospectively examines the long-term therapeutic outcomes of 32 patients with primary spinal cord gliomas at Massachusetts General Hospital between 1991 and 2005 treated by either photon intensity-modulated radiotherapy or conformal proton radiotherapy. METHODS AND MATERIALS: Individual patient tumor types included 14 ependymomas, 17 astrocytomas, and one oligodendroglioma. Twenty two patients were treated with photon beam radiation therapy, and 10 patients were treated with proton beam therapy. The overall survival and time to progression were analyzed. Average radiation dose for patients was 51 Gy in 1.8 median daily fractions over 29 treatments. RESULTS: For all 32 patients, the overall 5-year survival was 65% and the progression-free survival was 61%, respectively. Overall survival was significantly worse for patients more than 55 years of age (p=0.02). Ependymoma patients had significantly longer survival times than astrocytoma patients (p=0.05). Patients who had undergone a biopsy developed worse outcomes then those with a resection (p=0.05). With the caveat of a limited number of patients, the multivariate model seems to suggest improved overall survival for younger patients (<54 years of age), ependymoma histology, and photon vs. proton treatment. CONCLUSION: For patients with spinal cord gliomas, significant factors associated with patient outcome include tumor pathology, age, extent of surgery, and treatment. PMID- 20947266 TI - Interfractional variations in the setup of pelvic bony anatomy and soft tissue, and their implications on the delivery of proton therapy for localized prostate cancer. AB - PURPOSE: To quantify daily variations in the anatomy of patients undergoing radiation therapy for prostate carcinoma, to estimate their effect on dose distribution, and to evaluate the effectiveness of current standard planning and setup approaches employed in proton therapy. METHODS: We used series of computed tomography data, which included the pretreatment scan, and between 21 and 43 in room scans acquired on different treatment days, from 10 patients treated with intensity-modulated radiation therapy at Morristown Memorial Hospital. Variations in femur rotation angles, thickness of subcutaneous adipose tissue, and physical depth to the distal surface of the prostate for lateral beam arrangement were recorded. Proton dose distributions were planned with the standard approach. Daily variations in the location of the prescription isodose were evaluated. RESULTS: In all 10 datasets, substantial variation was observed in the lateral tissue thickness (standard deviation of 1.7-3.6 mm for individual patients, variations of >5 mm from the planning computed tomography observed in all series), and femur rotation angle (standard deviation between 1.3 degrees and 4.8 degrees , with the maximum excursion exceeding 10 degrees in 6 of 10 datasets). Shifts in the position of treated volume (98% isodose) were correlated with the variations in the lateral tissue thickness. CONCLUSIONS: Analysis suggests that, combined with image-guided setup verification, the range compensator expansion technique prevents loss of dose to target from femur rotation and soft-tissue deformation, in the majority of cases. Anatomic changes coupled with the uncertainties of particle penetration in tissue restrict possibilities for margin reduction in proton therapy of prostate cancer. PMID- 20947267 TI - Neoadjuvant bevacizumab, oxaliplatin, 5-fluorouracil, and radiation for rectal cancer. AB - PURPOSE: To evaluate the feasibility and pathologic complete response rate of induction bevacizumab + modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen followed by concurrent bevacizumab, oxaliplatin, continuous infusion 5-fluorouracil (5-FU), and radiation for patients with rectal cancer. METHODS AND MATERIALS: Eligible patients received 1 month of induction bevacizumab and mFOLFOX6. Patients then received 50.4 Gy of radiation and concurrent bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/m(2)/week for 6 weeks), and continuous infusion 5-FU (200 mg/m(2)/day). Because of gastrointestinal toxicity, the oxaliplatin dose was reduced to 40 mg/m(2)/week. Resection was performed 4-8 weeks after the completion of chemoradiation. RESULTS: The trial was terminated early because of toxicity after 26 eligible patients were treated. Only 1 patient had significant toxicity (arrhythmia) during induction treatment and was removed from the study. During chemoradiation, Grade 3/4 toxicity was experienced by 19 of 25 patients (76%). The most common Grade 3/4 toxicities were diarrhea, neutropenia, and pain. Five of 25 patients (20%) had a complete pathologic response. Nine of 25 patients (36%) developed postoperative complications including infection (n = 4), delayed healing (n = 3), leak/abscess (n = 2), sterile fluid collection (n = 2), ischemic colonic reservoir (n = 1), and fistula (n = 1). CONCLUSIONS: Concurrent oxaliplatin, bevacizumab, continuous infusion 5-FU, and radiation causes significant gastrointestinal toxicity. The pathologic complete response rate of this regimen was similar to other fluorouracil chemoradiation regimens. The high incidence of postoperative wound complications is concerning and consistent with other reports utilizing bevacizumab with chemoradiation before major surgical resections. PMID- 20947268 TI - SmartArc-based volumetric modulated arc therapy for oropharyngeal cancer: a dosimetric comparison with both intensity-modulated radiation therapy and helical tomotherapy. AB - PURPOSE: To investigate the roles of volumetric modulated arc therapy with SmartArc (VMAT-S), intensity-modulated radiation therapy (IMRT), and helical tomotherapy (HT) for oropharyngeal cancer using a simultaneous integrated boost (SIB) approach. METHODS AND MATERIALS: Eight patients treated with IMRT were selected at random. Plans were computed for both IMRT and VMAT-S (using Pinnacle TPS for an Elekta Infinity linac) along with HT. A three-dose level prescription was used to deliver 70 Gy, 63 Gy, and 58.1 Gy to regions of macroscopic, microscopic high-risk, and microscopic low-risk disease, respectively. All doses were given in 35 fractions. Comparisons were performed on dose-volume histogram data, monitor units per fraction (MU/fx), and delivery time. RESULTS: VMAT-S target coverage was close to that achieved by IMRT, but inferior to HT. The conformity and homogeneity within the PTV were improved for HT over all strategies. Sparing of the organs at risk (OAR) was achieved with all modalities. VMAT-S (along with HT) shortened delivery time (mean, -38%) and reduced MU/fx (mean, -28%) compared with IMRT. CONCLUSION: VMAT-S represents an attractive solution because of the shorter delivery time and the lower number of MU/fx compared with IMRT. However, in this complex clinical setting, current VMAT-S does not appear to provide any distinct advantage compared with helical tomotherapy. PMID- 20947269 TI - Concurrent cisplatin and radiation versus cetuximab and radiation for locally advanced head-and-neck cancer. AB - PURPOSE: To compare concurrent cisplatin (CDDP) and radiation (RT) with cetuximab (C225) and RT for locally advanced head-and-neck cancer (LAHNC). METHODS AND MATERIALS: This study retrospectively compared 174 consecutive, newly diagnosed LAHNC patients definitively treated from March 1, 2006, to April 1, 2008, with single-agent CDDP/RT (n = 125) or C225/RT (n = 49). We excluded patients who received additional concurrent, induction, or adjuvant systemic therapy; weekly cisplatin; prior head-and-neck radiotherapy; or primary surgical resection. Outcomes were analyzed by the Kaplan-Meier method, Cox model, and competing-risks analysis tools. RESULTS: The C225/RT patients were older and had decreased creatinine clearance. At a median follow-up of 22.5 months for living patients, the 2-year locoregional failure rate was 5.7% for CDDP/RT and 39.9% for C225/RT (p < 0.0001). The 2-year failure-free survival (FFS) and overall survival (OS) rates were 87.4% vs. 44.5% (p < 0.0001) and 92.8% vs. 66.6% (p = 0.0003), respectively, in favor of CDDP/RT. When the Cox proportional hazards model was used for multivariate analysis, treatment with CDDP/RT predicted for improved locoregional control (p < 0.0001), FFS (p < 0.0001), and OS (p = 0.01). Late Grade 3 or 4 toxicity or feeding tube dependence 9 months after completion of RT was observed in 21% of patients in the CDDP/RT cohort and 24% in the C225/RT cohort (p = 0.66). CONCLUSIONS: In this study of LAHNC patients, CDDP/RT achieved better locoregional control, FFS, and OS than C225/RT. Although the results were upheld on multivariate analysis, they must be interpreted cautiously because of the retrospective nature of the study and significant differences in patient selection. There was no statistically significant difference in late Grade 3 or 4 effects or feeding tube dependence. PMID- 20947270 TI - KRAS and BRAF mutations and PTEN expression do not predict efficacy of cetuximab based chemoradiotherapy in locally advanced rectal cancer. AB - PURPOSE: Mutations in KRAS and BRAF genes as well as the loss of expression of phosphatase and tensin homolog (PTEN) (deleted on chromosome 10) are associated with impaired activity of antibodies directed against epidermal growth factor receptor in patients with metastatic colorectal cancer. The predictive and prognostic value of the KRAS and BRAF point mutations as well as PTEN expression in patients with locally advanced rectal cancer (LARC) treated with cetuximab based neoadjuvant chemoradiotherapy is unknown. METHODS AND MATERIALS: We have conducted phase I and II trials of the combination of weekly administration of cetuximab and irinotecan and daily doses of capecitabine in conjunction with radiotherapy (45 Gy plus 5.4 Gy) in patients with LARC (stage uT3/4 or uN+). The status of KRAS and BRAF mutations was determined with direct sequencing, and PTEN expression status was determined with immunohistochemistry testing of diagnostic tumor biopsies. Tumor regression was evaluated by using standardized regression grading, and disease-free survival (DFS) was calculated according to the Kaplan Meier method. RESULTS: A total of 57 patients were available for analyses. A total of 31.6% of patients carried mutations in the KRAS genes. No BRAF mutations were found, while the loss of PTEN expression was observed in 9.6% of patients. Six patients achieved complete remission, and the 3-year DFS rate was 73%. No correlation was seen between tumor regression or DFS rate and a single marker or a combination of all markers. CONCLUSIONS: In the present series, no BRAF mutation was detected. The presence of KRAS mutations and loss of PTEN expression were not associated with impaired response to cetuximab-based chemoradiotherapy and 3-year DFS. PMID- 20947271 TI - Oral infection with a Shiga toxin-negative Escherichia coli O157:H7 strain elicits humoral and cellular responses but does not protect sheep from colonisation with the homologous strain. AB - We have previously shown that rectally inoculated sheep excrete Escherichia coli O157:H7 during weeks to months without developing a clear antibody response. However, antibodies against this bacterium were observed in naturally infected sheep, which most likely became orally infected. To understand this difference, sheep were orally inoculated with the same Shiga toxin-negative E. coli O157:H7 strain that was used for the rectal inoculation. A primary oral inoculation resulted in shedding of E. coli O157:H7 in the faeces and detection of antibody responses against intimin, EspA and EspB. The antibody titres waned as shedding decreased. A secondary inoculation resulted in longer shedding, even though a booster antibody response occurred. Cellular responses followed a similar pattern as the antibody levels, albeit with a lower secondary response. The presence of antigen-specific antibody-secreting cells indicates involvement of both a systemic response in the spleen and a local immune response in the terminal rectum. These results suggest that E. coli O157:H7 has to pass the small intestine to evoke antibody responses. PMID- 20947272 TI - The quality of fetal arm movements as indicators of fetal stress. AB - BACKGROUND: Although a number of studies have found that maternal stress affects the fetus, it is unclear whether jerky fetal movements observed on ultrasound scans are indicative of fetal stress, or whether they are part of normal development. AIMS: The present study was designed to examine the relationship between jerky fetal arm movements in relation to fetal age and stress. METHODS: Video recordings were made of routine ultrasound scans of 57 fetuses (age range 8 to 33 weeks) classified into three age groups: 1st trimester (8-12 weeks, N=9), 2nd trimester (13-24 weeks, N=38), and 3rd trimester (26-33 weeks, N=10). Following previous research on stress behaviour in neonates, a fetal index of stress was derived from frequency of hiccup, back arch and rhythmical mouthing. RESULTS: Results indicated that while stress level was unrelated to fetal age, jerkiness of arm movements was significantly associated with the fetal stress index but not age. CONCLUSIONS: Our findings suggest that jerky arm movements in fetuses are suggestive of fetal stress. PMID- 20947273 TI - Antioxidant supplements for long-term health and to prevent disease. PMID- 20947274 TI - Consistency and reproducibility in fingermark deposition. AB - A review of the available literature and previous research has suggested that there are several factors associated with the deposition of friction ridge skin marks that can affect the quality of the resultant marks, including the quantity of force applied, the angle of friction ridge and surface contact and the duration of friction ridge and surface contact. A device referred to as a fingerprint sampler was designed and constructed to facilitate the deposition of fingermarks for research projects. Fingermarks were deposited with and without the fingerprint sampler and examined for evidence of distortion. The quality of the marks was also assessed. The results of this study suggested that the fingerprint sampler deposited fingermarks without distortion caused by some physical factors associated with deposition and that the marks were of a statistically significantly higher quality than marks deposited without its use. PMID- 20947275 TI - [Mucocutaneous leishmaniasis in Morocco, evidence of the parasite's ecological evolution?]. PMID- 20947276 TI - Development and application of a validated HPLC method for the analysis of dissolution samples of levothyroxine sodium drug products. AB - A rapid, selective, and sensitive gradient HPLC method was developed for the analysis of dissolution samples of levothyroxine sodium tablets. Current USP methodology for levothyroxine (L-T(4)) was not adequate to resolve co-elutants from a variety of levothyroxine drug product formulations. The USP method for analyzing dissolution samples of the drug product has shown significant intra- and inter-day variability. The sources of method variability include chromatographic interferences introduced by the dissolution media and the formulation excipients. In the present work, chromatographic separation of levothyroxine was achieved on an Agilent 1100 Series HPLC with a Waters Nova-pak column (250 mm * 3.9 mm) using a 0.01 M phosphate buffer (pH 3.0)-methanol (55:45, v/v) in a gradient elution mobile phase at a flow rate of 1.0 mL/min and detection UV wavelength of 225 nm. The injection volume was 800 MUL and the column temperature was maintained at 28 degrees C. The method was validated according to USP Category I requirements. The validation characteristics included accuracy, precision, specificity, linearity, and analytical range. The standard curve was found to have a linear relationship (r(2)>0.99) over the analytical range of 0.08-0.8 MUg/mL. Accuracy ranged from 90 to 110% for low quality control (QC) standards and 95 to 105% for medium and high QC standards. Precision was <2% at all QC levels. The method was found to be accurate, precise, selective, and linear for L-T(4) over the analytical range. The HPLC method was successfully applied to the analysis of dissolution samples of marketed levothyroxine sodium tablets. PMID- 20947277 TI - Characterisation of transmission Raman spectroscopy for rapid quantitative analysis of intact multi-component pharmaceutical capsules. AB - A detailed characterisation of the performance of transmission Raman spectroscopy was performed from the standpoint of rapid quantitative analysis of pharmaceutical capsules using production relevant formulations comprising of active pharmaceutical ingredient (API) and 3 common pharmaceutical excipients. This research builds on our earlier studies that identified the unique benefits of transmission Raman spectroscopy compared to conventional Raman spectroscopy. These include the ability to provide bulk information of the content of capsules, thus avoiding the sub-sampling problem, and the suppression of interference from the capsule shell. This study demonstrates, for the first time, the technique's insensitivity to the amount of material held within the capsules. Different capsules sizes with different overall fill weights (100-400 mg) and capsule shell colours were assayed with a single calibration model developed using only one weight and size sample set (100 mg) to a relative error of typically <3%. The relative root mean square error of prediction of the concentration of API for the main sample set (nominal content 75%, w/w) was 1.5% with a 5s acquisition time. Models built using the same calibration set also predicted the 3 low level excipients with relative errors of 5-15%. The quantity of API was also predicted (with a relative error within ~3%) using the same model for capsules prepared with different generations of API (i.e. API manufactured via different processes). The study provides further foundation blocks for the establishment of this emerging technique as a routine pharmaceutical analysis tool, capitalising on the inherently high chemical specificity of Raman spectroscopy and the non invasive nature of the measurement. Ultimately, this technique has significant promise as a Process Analytical Technology (PAT) tool for online production application. PMID- 20947278 TI - Procedural sedation and analgesia in a Canadian ED: a time-in-motion study. AB - INTRODUCTION: Some patients presenting to emergency departments (EDs) suffer from conditions requiring potentially painful treatment; procedural sedation and analgesia (PSA) are important components of their management. The purpose of this study was to determine the resources used during the administration of PSA. METHODS: This prospective observational study was conducted in a Canadian urban teaching center. Detailed data concerning the dosage of PSA medications, adverse events, and ED times for patients requiring PSA for treatment of fractures, reductions of joint dislocations, and cardioversion for atrial fibrillation were collected. Descriptive analyses included proportions, means with standard deviations, and medians with interquartile ranges. RESULTS: Of the 177 PSA cases considered for analysis, 69.5% were orthopedic manipulations and 30.5% were cardioversions. Propofol alone or combined with fentanyl was the commonest medication, and 27 minor adverse events were documented. The median number of staff used in each PSA was 4 (4, 4). The median time from triage to the start of the procedure was 175 minutes (98, 259). The median time from the end of monitoring to discharge was 186 minutes (104, 316). The median time from the start of PSA administration to the end of patient monitoring was 12 minutes for fractures/dislocations and 7 minutes for cardioversion. The total ED length of stay was 6.6 hours. CONCLUSION: Procedural sedation and analgesia are potentially time-consuming interventions requiring the coordination of ED staff; delays in procedures represent opportunities to reduce ED overcrowding. Procedural sedation and analgesia guidelines may assist with standardization. PMID- 20947279 TI - Ultrasound determination of chest wall thickness: implications for needle thoracostomy. AB - OBJECTIVE: Computed tomography measurements of chest wall thickness (CWT) suggest that standard-length angiocatheters (4.5 cm) may fail to decompress tension pneumothoraces. We used an alternative modality, ultrasound, to measure CWT. We correlated CWT with body mass index (BMI) and used national data to estimate the percentage of patients with CWT greater than 4.5 cm. METHODS: This was an observational, cross-sectional study of a convenience sample. We recorded standing height, weight, and sex. We measured CWT with ultrasound at the second intercostal space, midclavicular line and at the fourth intercostal space, midaxillary line on supine subjects. We correlated BMI (weight [in kilograms]/height(2) [in square meters]) with CWT using linear regression. 95% Confidence intervals (CIs) assessed statistical significance. National Health and Nutrition Examination Survey results for 2007-2008 were combined to estimate national BMI adult measurements. RESULTS: Of 51 subjects, 33 (65%) were male and 18 (35%) were female. Mean anterior CWT (male, 2.1 cm; CI, 1.9-2.3; female, 2.3 cm; CI, 1.7-2.7), lateral CWT (male, 2.4 cm; CI, 2.1-2.6; female, 2.5 cm; CI 2.0 2.9), and BMI (male, 27.7; CI, 26.1-29.3; female, 30.0; CI, 25.8-34.2) did not differ by sex. Lateral CWT was greater than anterior CWT (0.2 cm; CI, 0.1-0.4; P < .01). Only one subject with a BMI of 48.2 had a CWT that exceeded 4.5 cm. Using national BMI estimates, less than 1% of the US population would be expected to have CWT greater than 4.5 cm. CONCLUSIONS: Ultrasound measurements suggest that most patients will have CWT less than 4.5 cm and that CWT may not be the source of the high failure rate of needle decompression in tension pneumothorax. PMID- 20947280 TI - Fever and rash in a young man. PMID- 20947281 TI - Hemichorea: a rare neurological deficit in the emergency department. PMID- 20947282 TI - Thoracic trauma in polo: two cases and a review of the literature. AB - BACKGROUND: The traditional sport of polo has been played for centuries and has been deemed one of the most dangerous sports due to its high speed and the uncertainty of what might happen as directions change and contact occurs between horses and riders as well as with balls and mallets. Despite its longevity, there is very little in the medical literature about the sport of polo. OBJECTIVES: Two cases of thoracic trauma after falls from horses while playing polo are presented. Both falls resulted in similar injury patterns to the riders. A discussion follows that reviews the medical literature on equestrian injuries in general and polo injuries in particular. DISCUSSION: Both cases show a similar injury pattern of clavicle fracture, multiple rib fractures, and lung injury (pulmonary contusion and pneumothorax). Literature review reveals severe injury including head and spinal trauma to be disproportionately represented in the equestrian sports. CONCLUSION: Emergency physicians should look for significant injuries when evaluating victims of polo accidents, as the forces generated can be quite high. Protective equipment, although potentially helpful, has not been studied and may not prevent these high-velocity injuries. PMID- 20947283 TI - Limping in toddlers: pelvic abscess presenting with transient synovitis picture. AB - BACKGROUND: Limping is a common presenting pediatric complaint, caused by conditions originating in the lower extremities as well as in anatomical areas surrounding the hip joint. Pathologic processes presenting with limping include trauma, inflammation, infection, and malignancy. OBJECTIVES: In this report, we present a case of pelvic abscess presenting with limping in a toddler. We review common conditions presenting with limping in this age group, and discuss laboratory and radiographic evaluation of limping in toddlers. CASE REPORT: A 20 month-old previously healthy boy presented for evaluation of limping and history of fever. The physical examination was suggestive of transient synovitis. Radiological evaluation revealed normal hip X-ray study, a normal complete blood count, and a moderately increased erythrocyte sedimentation rate. Due to the persistence of limping, tenderness over the inguinal area and subsequent development of edema over the inguinal area, magnetic resonance images of the hip and pelvis were obtained, which revealed a pelvic abscess. The patient improved after ultrasound-guided drainage of the abscess and a course of intravenous antibiotics. CONCLUSION: Although transient synovitis is the most common pathology that causes limping in toddlers, limping can also be a presentation of pelvic pathology. Thus, in this age group, a detailed physical examination of the patient with special emphasis on structures adjacent to the hip joint is extremely important. Laboratory evaluation and additional imaging help confirm the suspected diagnosis. PMID- 20947284 TI - Patient-provider communication and reproductive health among HIV-positive women in Rio de Janeiro, Brazil. AB - OBJECTIVE: To qualitatively assess the influence of patient-provider communication on contraceptive choice among HIV-positive women in the context of universal antiretroviral therapy (ART) access. METHODS: Focus group discussions (FGD; n=3), in-depth (IDI; n=15) and freelist interviews (FLI; n=36) were conducted with HIV-positive women aged 18-40 years recruited from public health units in Rio de Janeiro/Brazil. RESULTS: Of 70 participants, 49 used ART and the median time since HIV diagnosis was 6 years (range: 1-18). The majority of participants (71.4%) reported some degree of dissatisfaction with their health providers (usually lack of open dialogue) and a few reported experiences of stigma/prejudice during appointments. Intra, interpersonal and social factors modulated behaviors and reproductive health decisions, and those issues were rarely addressed by providers during HIV clinical care. CONCLUSION: Despite dramatic increases in survival and life quality after universal ART implementation in Brazil, reproductive health issues are neglected by multiple cadres of HIV health providers. Communication on reproductive health issues remains fragmented and potentially contradictory, compromising care in these settings. PRACTICE IMPLICATIONS: Adequate provider training to address reproductive health-related issues in a comprehensive, culturally sensitive manner and improved integration of HIV and reproductive health care are urgently needed in this setting. PMID- 20947285 TI - Occupational turnover intentions among substance abuse counselors. AB - This study examined predictor, moderator, and mediator variables of occupational turnover intention (OcTI) among substance abuse counselors. Data were obtained via questionnaires from 929 counselors working in 225 private substance abuse treatment (SAT) programs across the United States. Hierarchical multiple regression models were conducted to assess predictor, moderator, and mediator variables of OcTI. OcTI scores were relatively low on a 7-point scale, indicating that very few counselors definitely intended to leave the SAT field. Age, certification, positive perceptions of procedural and distributive justice, and hospital-based status negatively predicted OcTI. Counselors' substance use disorder-impacted history moderated the association between organizational commitment and OcTI. Organizational turnover intention partially mediated the link between organizational commitment and OcTI. Workforce stability might be achieved by promoting perceptions of advantages to working in a particular treatment program, having organizational commitment, showing appreciation for counselors' work, and valuing employees from diverse backgrounds. PMID- 20947287 TI - Physical activity and breast cancer outcome: a brief review of evidence, current practice and future direction. AB - There have been several publications of large scale studies with long-term follow up addressing the role of physical activity in the management of breast cancer. Of the twelve studies specifically addressing the effect of physical activity on breast cancer survival, eight showed a statistically significant 50% risk reduction in breast cancer mortality in women who engaged in moderate intensity physical activity before and after their diagnosis of breast cancer. Four smaller studies demonstrated no benefit. Almost all of these observational studies predominantly involved white, professional women from North America and Europe. The positive effects of physical activity were seen for all stages of cancer, with the greatest benefit in steroid receptor positive breast tumours. These studies relied on self-reported questionnaires for recording the levels of physical activity. Despite including thousands of patients, published studies offer no data related to the optimum type, duration and timing of physical activity. Only a few studies provided objective data on physical activity, cardio respiratory and general fitness. Thus, potential role of physical activity in the management of breast cancer remains far from established. If the beneficial effect of physical activity as demonstrated in the observational studies can be replicated in robust, well designed and well-executed prospective randomised controlled trials, this would provide a tremendous opportunity to enhance adjuvant treatment of breast cancer. By adding physical activity to the spectrum of adjuvant therapies offered to women survival from breast cancer may be enhanced. PMID- 20947286 TI - Varenicline for tobacco dependence treatment in recovering alcohol-dependent smokers: an open-label pilot study. AB - The purpose of this study was to obtain preliminary evidence of the efficacy of a 12-week course of varenicline for 7-day point prevalence smoking abstinence among recovering alcohol-dependent smokers. We enrolled 32 smokers with 6 months or more of recovery from alcohol dependence in an open-label clinical trial. Participants received varenicline 1 mg twice daily and 12 weeks of behavioral counseling. Participants were 69% men, 94% Caucasian, and smoking an average of 20.3 +/- 5.0 cigarettes per day. After 12 weeks of treatment, 31% were biochemically confirmed 7-day point prevalence abstinent from smoking and 28% had prolonged smoking abstinence (2 weeks after target quit date onward). The most common adverse effects were mild to moderate nausea (28%) and sleep disturbance (19%). No serious adverse events were reported. Varenicline may be a useful aid for treating tobacco dependence among smokers who are in stable recovery from alcohol dependence. Further study of this treatment is warranted. PMID- 20947288 TI - Use of an automated circuit for isolated limb infusion for malignancy. AB - BACKGROUND: Isolated limb infusion (ILI) for recurrent or in-transit melanoma is an accepted technique that allows high-dose chemotherapy to be delivered to an extremity with minimal systemic toxicity. Current infusion systems have relied on manual delivery of drugs and circulation of blood during the treatment. Herein, we document our initial results with an automated circuit for ILI as an alternative to the manual technique. METHODS: Patients undergoing ILI with an automated circuit for recurrent or advanced malignancy were identified. ILI was performed utilizing a Sarns 8000 roller pump attached to a Cobe 4:1 cardioplegia set with heat exchanger with a total priming volume of 80 ml. Melphalan (7.5 mg/L) and Dactinomycin (75 MUg/L) doses which were corrected for ideal body weight were delivered via the infusion circuit after limb temperature reached 38 degrees C. RESULTS: Fourteen lower extremity infusion procedures were performed in 10 patients. Successful infusion procedures were completed in all patients using the automated circuit. Constant flow rates of 50-70 cc/minute were achievable with the automated circuit. Acute toxicity and clinical results were similar to that reported with manual delivery systems. CONCLUSION: ILI for advanced malignancy utilizing an automated circuit is feasible and safe. This automated system offers a safe and reliable alternative to the manual infusion technique. PMID- 20947289 TI - Comparison of arthroscopic and open assessment of size and grade of cartilage defects of the knee. AB - PURPOSE: The purpose of our study was to compare arthroscopic versus open measurement of cartilage defects and determination of defect grade according to the International Cartilage Repair Society (ICRS) classification. METHODS: Arthroscopic determination of defect size and grade according to the ICRS classification of 450 focal cartilage defects in 407 patients who underwent autologous chondrocyte implantation was compared with definite findings at the time of open knee surgery. Results were analyzed based on defect location, defect size, and experience of the treating surgeon. RESULTS: Open evaluation of all cartilage defects showed a mean size of 4.54 +/- 2.11 cm2, whereas arthroscopic determination resulted in a significantly larger mean defect size of 5.69 +/- 1.81 cm2 (P < .001, r = 0.757). This observation was found in all subgroups concerning defect location and experience of the treating surgeon (P < .001). Overestimation was pronounced among inexperienced surgeons (all P < .01) and in smaller defects (P < .01). Concerning grading of the defect according to the ICRS classification, there was a consensus in 80.9% of the cases when arthroscopic grading was compared with open grading. No differences were found based on defect location or experience of the treating surgeon (P > .05). CONCLUSIONS: Although a high correlation was found between arthroscopic and open evaluation of the cartilage defect size, there is a significant overestimation of the cartilage defect size during arthroscopy. This observation is independent of defect location. Smaller defects and inexperienced surgeons are factors that make an overestimation of defect size more likely. Arthroscopic detection and estimation of the full-thickness cartilage defects according to the ICRS classification seem reliable. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 20947290 TI - Blocking of PI3K/AKT induces apoptosis by its effect on NF-kappaB activity in gastric carcinoma cell line SGC7901. AB - NF-kappaB plays an important role in many aspects of tumorigenesis and tumor progression by its antiapoptosis effect. Hence, NF-kappaB has been regarded as a therapeutic target in cancer, because inhibition of NF-kappaB not only induces enhancing apoptosis but also causes increasing sensitivity to radiation or chemotherapy in several tumor cells. The activation of NF-kappaB is presumed to be associated with PI3K/Akt signal pathway in gastric carcinoma, but the underlying molecular mechanism remains unclear. Our work demonstrates that blocking PI3K/Akt by LY294002 inhibits the NF-kappaB activity with significantly increased apoptosis in gastric cancer cell. Furthermore, when the cells were pretreated with IKK siRNA and/or IkappaB siRNA then exposed to LY294002, the results suggest that the regulatory significantly increased apoptosis in gastric cancer cell. Furthermore, when the cells were pretreated, effect of PI3K/AKT on NF-kappaB activity is associated with the influence of PI3K/AKT on IKK/IkappaB. The apoptosis induced by blocking PI3K/AKT might be ascribed to inhibition of NF kappaB activity through IKK/IkappaB at least in part. PMID- 20947291 TI - Missed and/or misinterpreted lesions in breast ultrasound: reasons and solutions. PMID- 20947292 TI - Magnetic resonance arthrography of glenohumeral lesions: anatomy and arthroscopically confirmed pathology. AB - Interpretation of magnetic resonance (MR) arthrography images of the glenohumeral ligaments is made difficult by anatomical variations and by the lack of descriptions of signs of pathology of the ligaments. In this review, we describe the normal and pathologic appearance of the glenohumeral ligaments of the shoulder. These ligaments play an important role in stabilization of the shoulder. Both 1.5 and 3 T MR units were used to acquire the MR images. The principal investigator reviewed the imaging reports and arthroscopic reports. All cases were correlated with arthroscopy. Lesions of the superior glenohumeral, middle glenohumeral, and inferior glenohumeral, including humeral avulsion of the glenoid ligament are discussed. Diagnosis of lesions of the glenohumeral ligaments remains a challenge. PMID- 20947293 TI - Renal embolization and nephrectomy in a single surgical act in high-risk renal tumor pathology. AB - BACKGROUND: Renal artery embolization is a procedure that has been shown to be useful as a concomitant treatment for the resection of large renal tumors. Over the years, preoperative renal artery embolization concomitant with nephrectomy as a treatment option has proved to be useful in reducing morbi-mortality rates; however this procedure is not exempt from significant iatrogenia. Performing this technique in conjunction with nephrectomy in a single surgical act helps to maintain the advantages of this treatment, which in turn considerably reduces the associated morbi-mortality rates. METHODS: This study presents seven patients selected by the Urology Service in a nonconsecutive manner who underwent renal artery embolization concomitant with nephrectomy in a single surgical procedure for large renal tumors, thus presenting a variation to the usual techniques to improve and simplify the procedure. RESULTS: General data were obtained from all patients including age, gender, characteristics of the tumor, and symptomatology at the time of diagnosis. For all the cases, use of resources was analyzed in terms of duration of surgery, the amount of iodinated contrast medium used during the embolization procedure, and the mean duration of hospital and intensive care unit stay. Complications were evaluated with respect to general morbi-mortality associated with the complete procedure, hematic losses during the procedure, transfusion requirements, and renal function (calculated by measuring preoperative and 48-hour postoperative serum creatinine levels). All patients reported having symptoms at the time of diagnosis, all of them had tumors measuring >13 cm in diameter (major). In all the cases, 100% technical success was obtained with the embolization and nephrectomy. The mean duration of surgery in the case of embolization with coils was 45 minutes, and 25 minutes in the case of embolization with Amplatzer. A mean volume of 115 mL of contrast medium was used in the case of embolization with coils, whereas for the other cases, a mean volume of 71 mL of iodinated contrast was used. Among all the patients, only two of them required to be cared at the intensive care unit during 24 hours. On an average, reported blood loss was 380 mL. During the procedure, two patients (28.6%) required a transfusion of two units of red cells. No cases of perioperative or postoperative mortality were reported. With respect to morbidity, only one patient (14.3%) experienced a complication in the form of a superficial infection of the surgical wound, which was later resolved by antibiotic therapy. One patient (14.3%) presented a slightly higher preintervention level of creatinine (1.42). Two patients (28.6%), both of whom underwent embolization by using coils, experienced deterioration of postoperative renal function. CONCLUSION: Preoperative embolization of the renal artery as a coadjuvant treatment option in high-risk renal neoplasia has clear technical benefits for the subsequent nephrectomy and also medical benefits for the patients. Performing both the procedures concomitantly as a single surgical act seems to retain the advantages of the embolization procedure, by reducing mortality rates and producing little associated morbidity. Technically, embolization with Amplatzer plugs seems to be faster and easier as compared with embolization with coils. PMID- 20947294 TI - Considerable variation in NNT - a study based on Monte Carlo simulations. AB - OBJECTIVE: The aim of this analysis was to explore the variation in measures of effect, such as the number-needed-to-treat (NNT) and the relative risk (RR). STUDY DESIGN AND SETTING: We performed Monte Carlo simulations of therapies using binominal distributions based on different true absolute risk reductions (ARR), number of patients (n), and the baseline risk of adverse events (p(0)) as parameters and presented results in histograms with NNT and RR. We also estimated the probability of observing no or a negative treatment effect, given that the true effect is positive. RESULTS: When RR is used to express treatment effectiveness, it has a regular distribution around the expected value for various values of true ARR, n, and p(0). The equivalent distribution of NNT is by definition nonconnected at zero and is also irregular. The probability that the observed treatment effectiveness is zero or negative when the true value is positive depends on n, p(0), and the true ARR. In some cases, this probability is even higher than 50%. CONCLUSION: For realistic values of true ARR, n, and p(0), the observed NNT varies much more than the observed ARR and RR. Clinicians should use NNT cautiously when expressing treatment benefits. PMID- 20947295 TI - Level of evidence and conflict of interest disclosure associated with higher citation rates in orthopedics. AB - OBJECTIVE: To identify the scientific and nonscientific factors associated with rates of citation in the orthopedic literature. STUDY DESIGN AND SETTING: All original clinical articles published in three general orthopedics journals between July 2002 and December 2003 were reviewed. Information was collected on variables plausibly related to rates of citation, including scientific and nonscientific factors. The number of citations at 5 years was ascertained and linear regression was used to identify factors associated with rates of citation. RESULTS: In the multivariate analysis, factors associated with increased rates of citation at 5 years were high level of evidence (22.2 citations for level I or II vs. 10.8 citations for level III or IV; P=0.0001), large sample size (18.8 citations for sample size of 100 or more vs. 7.9 citations for sample size of 25 or fewer; P<0.0001), multiple institutions (15.2 citations for two or more centers vs. 11.1 citations for single center; P=0.023), self-reported conflict of interest disclosure involving a nonprofit organization (17.4 citations for nonprofit disclosure vs. 10.6 citations for no disclosure; P=0.027), and self reported conflict of interest disclosure involving a for-profit company (26.1 citations for for-profit disclosure vs. 10.6 citations for no disclosure; P=0.011). CONCLUSION: High level of evidence, large sample size, representation from multiple institutions, and conflict of interest disclosure are associated with higher rates of citation in orthopedics. PMID- 20947296 TI - Cardiovascular disease and musculoskeletal disorder labels in family practice acted as markers of physical health severity. AB - OBJECTIVE: Family practitioner diagnostic labels applied in consultation provide a signpost for treatment and management. Yet, it is unknown whether each label reflects the health of the respective patient group. STUDY DESIGN AND SETTING: Consultation records of 7,799 patients aged 50 years and older from six family practices were linked to a cross-sectional baseline health survey. Associations between six mutually exclusive cardiovascular disease and nine mutually exclusive musculoskeletal disorder categories, and physical health severity as measured by the Short Form-12 questionnaire were examined. RESULTS: There were 2,447 (31.4%) cardiovascular disease and 3,321 (42.6%) musculoskeletal disorder consulters. The mean physical health scores ranged from 38.38 (95% confidence interval [CI]: 37.8 39.0) for hypertension to the poorest score of health 28.98 (95% CI: 27.5-30.5) for consulters with heart failure, whereas in the musculoskeletal disorder group, scores ranged from 44.85 (95% CI: 42.2-47.5) for soft tissue disorder to 28.79 (95% CI: 26.8-30.8) for consulters with inflammatory polyarthropathy (trend P<0.001). This trend in the association between diagnostic categories and physical health severity within both spectrums remained after adjustment for confounders. CONCLUSION: Specific diagnostic labels for selected chronic illness indicate the severity of physical health for the corresponding consulting population. PMID- 20947297 TI - Inconsistent results in meta-analyses for the prevention of falls are found between study-level data and patient-level data. AB - OBJECTIVE: This study seeks to examine whether existing study-level data meta analysis approaches can be used to produce unbiased and precise effect estimates relative to meta-analyses conducted using patient-level data, where a recurrent event is the outcome of interest. STUDY DESIGN AND SETTING: Data from two studies focusing on the prevention of falls in the hospital setting (N=1,838 total) was divided into the three hospital sites from which data were collected. Outcome data were considered as recurrent event survival data, single event survival data, count data, rate data, and binary data. A range of analysis approaches were considered. RESULTS: Andersen-Gill, negative binomial, bootstrap resampling, and modified relative risk analysis approaches produced congruous point estimates of effect, whereas modified relative risk analysis produced considerably smaller standard errors. Pooled effect point estimates derived from these approaches were not consistent when using study-level data as opposed to patient-level data, and 95% confidence intervals were excessively wide when between-study heterogeneity was present. CONCLUSION: Conducting meta-analysis using patient-level data (if possible) or presenting results from individual trials without pooling of effect estimates may be preferable to presenting pooled effect estimates from meta analysis of study-level data, where the outcome is a recurrent event. PMID- 20947299 TI - Cranial nerve injury after Le Fort I osteotomy. AB - A Le Fort I osteotomy is widely used to correct dentofacial deformity because it is a safe and reliable surgical method. Although rare, various complications have been reported in relation to pterygomaxillary separation. Cranial nerve damage is one of the serious complications that can occur after Le Fort I osteotomy. In this report, a 19-year-old man with unilateral cleft lip and palate underwent surgery to correct maxillary hypoplasia, asymmetry and mandibular prognathism. After the Le Fort I maxillary osteotomy, the patient showed multiple cranial nerve damage; an impairment of outward movement of the eye (abducens nerve), decreased vision (optic nerve), and paraesthesia of the frontal and upper cheek area (ophthalmic and maxillary nerve). The damage to the cranial nerve was related to an unexpected sphenoid bone fracture and subsequent trauma in the cavernous sinus during the pterygomaxillary osteotomy. PMID- 20947298 TI - Diverse roles of leptin in the gastrointestinal tract: modulation of motility, absorption, growth, and inflammation. AB - OBJECTIVE: Leptin was discovered in 1994 as a hormone produced by adipose tissue with a modulatory effect on feeding behavior and weight control. Recently, the stomach has been identified as an important source of leptin and growing evidence has shown diverse functions for leptin in the gastrointestinal tract. METHODS: Using leptin as a keyword in PubMed, more than 17 000 articles were identified, of which more than 500 articles were related to the role of leptin in the gastrointestinal tract. Available abstracts were reviewed and more than 200 original articles were reviewed in detail. RESULTS: The available literature demonstrated that leptin can modulate several important functions of the gastrointestinal tract. Leptin interacts with the vagus nerve and cholecystokinin to delay gastric emptying and has a complex effect on motility of the small bowel. Leptin modulates absorption of macronutrients in the gastrointestinal tract differentially in physiologic and pathologic states. In physiologic states, exogenous leptin has been shown to decrease carbohydrate absorption and to increase the absorption of small peptides by the PepT1 di-/tripeptide transporter. In certain pathologic states, leptin has been shown to increase absorption of carbohydrates, proteins, and fat. Leptin has been shown to be upregulated in the colonic mucosa in patients with inflammatory bowel disease. Leptin stimulates gut mucosal cell proliferation and inhibits apoptosis. These functions have led to speculation about the role of leptin in tumorigenesis in the gastrointestinal tract, which is complicated by the multiple immunoregulatory effects of leptin. CONCLUSION: Leptin is an important modulator of major aspects of gastrointestinal tract functions, independent of its more well-described roles in appetite regulation and obesity. PMID- 20947300 TI - Prognostic factors, morbidity and mortality in tonic-clonic status epilepticus: a review. AB - OBJECTIVES: to determine how the duration of SE, the EEG findings during/after SE, the depth of coma at presentation and age impact on the prognosis of convulsive status epilepticus indepedent of aetiology and to analyse the outcome of status epilepticus with respect to mortality and morbidity (the latter measured in terms of functional decline, cognitive/intellectual decline and the prospective risk of epilepsy). DESIGN: a systematic review of all studies of status epilepticus (SE) with greater then 30 patients published from the 01/01/1990 up until 31/12/2009. RESULTS: oveall the longer the duration of SE the worse the prognosis particularly after 1-2h of continuous seizures although this affect may be lost after 10h. The depth of coma correlates well with outcome. Only periodic epileptiform discharges (PEDs) have been shown to be associated with a poorer outcome in most (but not all) studies although this is probably related to the underlying aetiology. Age is an important prognostic factor with children having a better prognosis then adults. CONCLUSIONS: age and depth of coma at presentation appear to be the strongest predictors of outcome of SE independent of aetiology with the duration of SE and the EEG findings less important. PMID- 20947302 TI - Knowledge, attitude and practice with respect to epilepsy among school teachers in Assiut city, Egypt. AB - OBJECTIVE: This study was designed to assess knowledge, attitude and practice with respect to epilepsy among secondary school teachers in Assiut city, Egypt. METHODS: A cross sectional study was applied among secondary schools in Assiut city, Egypt. A 12-item questionnaire was self administered to 189 teachers, who selected randomly. RESULTS: All teachers had heard about epilepsy. 54% of teachers deal with students with epilepsy as normal students. About one quarter (23.8%) of teachers accepted to give student with fit in the class first aid measures and 12.7% accepted to give the student, who was having a seizure in the class any form of prescribed treatment. Positive attitudes were common among females and single teachers. CONCLUSION: The current study suggests that, a well directed health educational program about causes and management of epileptic seizures may improve the perception of epilepsy by teachers in Egypt. Teacher targeted interventions aimed at reducing epilepsy-associated stigma and its sequel in Egyptian students. PMID- 20947301 TI - EEG dipole source localization of interictal spikes in non-lesional TLE with and without hippocampal sclerosis. AB - PURPOSE: A subgroup of patients with non-lesional temporal lobe epilepsy (NLTLE) have no evidence of hippocampal sclerosis (HS) on MRI or on histopathology. It is controversial whether this represents a different clinicopathological syndrome from NLTLE with HS, or whether both subgroups represent different ends of the spectrum of mesial TLE. Here the EEG source localization dipoles were compared between NLTLE patients with HS (HS+) and without HS (HS-), and the relationship with post-surgical outcome was investigated. METHODS: EEG dipole source localization of interictal epileptiform spikes recorded during prolonged video EEG monitoring was performed from 22 consecutive HS+ and 12 HS- NLTLE patients. EEG was acquired using 29 scalp electrodes, including an inferior temporal row. Up to 13 spikes per patient were averaged and sources localized using a boundary element model based on the patients volumetric MRI. RESULTS: 21/34 patients (62%) had dipoles for the interictal spikes localized to the epileptogenic temporal lobe. The site of the intratemporal localization did not differ significantly between the HS+ and HS- patients, with the dipoles localizing to the mesial temporal region in 27% of HS+ and 25% of HS- patients. There was no significant relationship between the localization and orientation of the dipoles and the surgical outcome. CONCLUSION: The dipoles for interictal spikes do not differ between HS+ and HS- patients, suggesting that these subgroups of NLTLE patients do not have distinct cerebral generators. PMID- 20947303 TI - Zonisamide suppresses the tonic phase but not the clonic phase of generalized seizures in developing rats. AB - Zonisamide is increasingly used in pediatric neurology but there are no experimental data for immature animals. Zonisamide (12.5-100 mg/kg i.p.) was tested against pentetrazol-induced seizures in 7-, 12-, 18-, 25- and 90-day-old rats. Minimal clonic seizures were not suppressed by zonisamide. Selective suppression of tonic phase of generalized tonic-clonic seizures was demonstrated in all age groups. This effect indicates possible action of zonisamide against generalized tonic-clonic seizures during brain maturation. PMID- 20947305 TI - Amphetamine-related improvement in executive function in patients with chronic schizophrenia is modulated by practice effects. AB - BACKGROUND: Amelioration of cognitive impairment is an important treatment goal for a broad range of neuropsychiatric disorders, including schizophrenia. One critical issue in clinical trial design is the extent to which repeated exposure to cognitive tests (i.e., practice effects) may lead to improvement in performance on the cognitive tests in the absence of any true treatment effect. The current study examined the extent to which practice effects on a measure of executive function may influence the sensitivity of that task to detecting the cognitive-enhancing effects of a single acute dose of d-amphetamine in individuals with chronic schizophrenia. METHODS: Twenty-four men with chronic schizophrenia were randomized to receive a constant or random/matched alternate form version of a hidden maze learning measure of executive function (Groton Maze Learning Test; GMLT) on four separate occasions in one month. They also completed a measure of psychomotor speed. Using a double-blind, placebo-controlled, parallel groups design, cognitive function following administration of a single dose of d-amphetamine (20mg p.o) or placebo was then assessed. RESULTS: The group who received the constant-pathway version of the GMLT showed a large practice effect (d = 2.05) over four practice sessions. Consequently, they did not evidence any improvement on the GMLT following d-amphetamine administration. In contrast, the group who received the random/matched alternate version of the GMLT showed a statistically significant and large effect size (d = .84) improvement on this measure. Both groups showed d-amphetamine-related improvement on a measure of psychomotor speed. CONCLUSIONS: Results of this study suggest that practice effects associated with repeated exposure to a cognitive test could obscure the sensitivity of the test to detecting true treatment-related cognitive improvement. PMID- 20947306 TI - Phenotypic characteristics in metabolically obese but normal weight non-diabetic patients with schizophrenia. AB - BACKGROUND: A unique group of individuals termed metabolically obese but normal weight (MONW) has been identified in the general population. The present study examined phenotypic characteristics of MONW individuals in a sample of normal weight, non-diabetic patients with schizophrenia. METHODS: Outpatients 19 to 75 years old diagnosed with schizophrenia or schizoaffective disorder participated in a multi-center, cross-sectional study. Those with normal weight (body-mass index (BMI)<25 kg/m(2)) were included in the present analysis. Patients were further defined as MONW or metabolically nonobese based on a cut-off value of the homeostasis model assessment of insulin resistance (HOMA-IR = 1.86). Fasting blood samples were collected to determine levels of various metabolic parameters. In addition, lipoprotein subclass concentrations and sizes were analyzed using nuclear magnetic resonance (NMR) spectroscopy. RESULTS: Seventeen MONW individuals and 17 metabolically nonobese individuals matched by BMI and gender were identified from a study sample of 206 patients with schizophrenia. There were no significant differences between the two groups on anthropometric measures (waist circumference and waist/hip ratio, ps>0.3). However, the MONW group had significantly higher levels of intermediate VLDL particle and Apolipoprotein B, and significantly lower levels of large HDL particle compared with the metabolically nonobese group (p = 0.012, p = 0.036 and p = 0.041 respectively). CONCLUSION: The MONW individuals in non-diabetic schizophrenia patients seem to have an unfavorable metabolic profile and significant atherogenecity. Clinicians should be vigilant about the risk of cardiometabolic comorbidity even when the patient' body weight is normal. PMID- 20947307 TI - Mapping of a novel locus for keratosis follicularis squamosa on chromosome 7p14.3 7p12.1. PMID- 20947304 TI - Peripheral oxytocin is associated with reduced symptom severity in schizophrenia. AB - BACKGROUND: Emerging evidence from clinical trials suggests that oral estrogen and intranasal oxytocin might reduce symptom severity in schizophrenia. Whether increases in endogenous hormones are similarly associated with improved symptoms is unknown. We investigated the effects of menstrual cycle phase and related fluctuations in peripheral hormone levels on clinical symptoms in women with chronic schizophrenia. METHOD: Twenty-three women with schizophrenia were administered the Positive and Negative Syndrome Scale (PANSS), a measure of clinical symptom severity, at two menstrual cycle phases: 1) early follicular (Days 2-4; low estrogen/progesterone) and 2) midluteal (Days 20-22; high estrogen/progesterone). Twenty-seven males with schizophrenia and 58 controls (31 female) completed testing at comparable intervals. Men were included to examine whether the relationships between clinical symptoms and hormone levels in women generalize to men. Plasma hormone assays of estrogen, oxytocin, progesterone, and testosterone were obtained. RESULTS: Female patients showed less severe symptoms during the midluteal versus early follicular phase (p's<0.01). Oxytocin did not fluctuate across phases, but in female patients (p's<0.01) higher oxytocin levels were associated with less severe positive symptoms and overall psychopathology. In both sexes, higher oxytocin levels were associated with more prosocial behaviors (p<0.05). CONCLUSION: Consistent with previous findings in acutely ill patients, our results suggest that clinical symptoms vary across the menstrual cycle in patients with chronic schizophrenia. Similar to recent findings regarding benefits of intranasal oxytocin, these new findings indicate that high levels of endogenous oxytocin might improve positive symptom severity and general psychopathology in women and social behaviors in both sexes. PMID- 20947308 TI - The establishment and characterization of immortalized human dermal papilla cells and their hair growth promoting effects. PMID- 20947309 TI - Disulphide bonds of the peptide protegrin-1 are not essential for antimicrobial activity and haemolytic activity. PMID- 20947310 TI - Treatment of murine Fusarium verticillioides infection with liposomal amphotericin B plus terbinafine. AB - Using a murine model of disseminated infection by Fusarium verticillioides, the efficacy of liposomal amphotericin (L-AmB) B at 10mg/kg body weight once daily and terbinafine (TRB) at 150 mg/kg body weight twice daily, alone and in combination, was evaluated. The combination of L-AmB with TRB was the only treatment able to prolong survival and to reduce fungal loads in the spleen and kidneys of mice infected with either strain of F. verticillioides used. The results suggest that this combination may have a role in the treatment of F. verticillioides infection. PMID- 20947311 TI - Antiviral activity of 5'-O-carbonate-2',3'-dideoxy-3'-thiacytidine prodrugs against hepatitis B virus in HepG2 2.2.15 cells. AB - The antiviral activities of lamivudine (3TC; 2',3'-dideoxy-3'-thiacytidine) and six 5'-O-carbonates of 3TC were determined by inhibition of hepatitis B virus (HBV) replication in HepG2 2.2.15 cells. HBV DNA in cell supernatants was quantified by real-time polymerase chain reaction (PCR). The results showed that 3TC-Etha was six times more active than 3TC and that 3TC-Buta, 3TC-Hexa and 3TC Octa were approximately three times more active than 3TC. In contrast, 3TC-Penta and 3TC-Metha showed anti-HBV activity similar to that of the parent compound 3TC. In conclusion, 5'-O-carbonates of 3TC appear to be promising candidates as anti-HBV compounds. This modification could optimise the use of 3TC, a well tolerated, effective and inexpensive drug, in monotherapy or combined therapy for chronic HBV infections as well as human immunodeficiency virus (HIV)/HBV co infections. PMID- 20947312 TI - The Nationwide Austrian Aspergillus Registry: a prospective data collection on epidemiology, therapy and outcome of invasive mould infections in immunocompromised and/or immunosuppressed patients. AB - A prospective, observational, multicentre study was performed to assess the incidence, diagnosis, epidemiology and outcome of invasive mould infections (IMIs) reported to the Nationwide Austrian Aspergillus Registry. In total, 186 cases were recorded, corresponding to an annual incidence of 42 cases/1000 patients at risk or 2.36 cases/100000 inhabitants. Patients with acute myelogenous leukaemia (34%) and lung transplant recipients (17%) are currently at highest risk for IMI, followed by a mixed population with impaired immunity (14%). In total, 34%, 30% and 36% were proven, probable and possible cases of IMI. Predominant pathogens were Aspergillus spp. (67%), followed by the zygomycetes (28%). Voriconazole was the most frequently administered agent (38%), followed by caspofungin (20%) and posaconazole (19%). Eighty patients (43%) received antifungal prophylaxis for >=7 days, 30% of whom (24 patients) suffered from a breakthrough infection. The overall crude 12-week mortality was 34%. Multivariate analysis showed that outcome and survival did not correlate with the status of fungal disease, breakthrough infection, fungal species or age (P>0.05). Aspergillosis remains the most commonly identified IMI amongst immunocompromised and/or immunosuppressed patients, but other moulds constitute a significant problem. Survival from IMIs appears to have improved and the main challenge is to overcome breakthrough fungal infections. PMID- 20947313 TI - Antimicrobial activities of trimethoprim/sulfamethoxazole, 5-iodo-2'-deoxyuridine and rifampicin against Staphylococcus aureus. AB - Trimethoprim/sulfamethoxazole (SXT), alone and in combination with rifampicin (RIF), is a therapeutic option against Staphylococcus aureus, including strains expressing meticillin resistance. However, the antimicrobial activity of SXT is antagonised by thymidine, which can be present in infected and/or inflamed tissues such as the airways of cystic fibrosis (CF) patients. In this study, thymidine concentrations in CF sputa were determined and the antimicrobial activities of SXT, 5-iodo-2'-deoxyuridine (IdUrd) and RIF alone and in combination against S. aureus were analysed. Thymidine concentrations in the sputa of ten different CF patients varied from <100 MUg/L to 38845 MUg/L. The abolished antimicrobial activity of SXT against 22 S. aureus strains in the presence of thymidine was restored by combination with IdUrd. In contrast, SXT combined with RIF in the presence of thymidine did not show a synergistic effect and, furthermore, allowed the emergence of RIF-resistant bacteria. Adding RIF to the combination of SXT and IdUrd did not improve antimicrobial activity against S. aureus. In conclusion, the combination of SXT and RIF as a therapeutic option against S. aureus infections in chronic inflamed tissues should be judged critically. PMID- 20947315 TI - ? PMID- 20947314 TI - A novel family (QnrAS) of plasmid-mediated quinolone resistance determinant. PMID- 20947316 TI - ISCTM: Implementing phase 2 dose finding adaptive clinical trials. AB - Adaptive clinical trial designs offer significant opportunities to optimize the conduct of clinical trials for the benefit of the subjects in the trial, the subjects that may be treated after the trial and the trial sponsor. However currently, the use of adaptive designs is limited, due to statistical, regulatory and logistical concerns. In this article we share our experience of overcoming the last of these over a range of phase 2, response adaptive, dose finding studies. Based on our experience we feel quite strongly that the logistics of executing adaptive trials should not be a barrier to their use. PMID- 20947317 TI - Effects of behavioral therapy or pharmacotherapy on brain glucose metabolism in subjects with obsessive-compulsive disorder as assessed by brain FDG PET. AB - This prospective study investigated the effect of pharmacotherapy (PT) and cognitive behavioral therapy (CBT) on cerebral glucose metabolism in adults with obsessive-compulsive disorder (OCD). Dynamic positron emission tomography (PET) of the brain with F-18-fluorodeoxyglucose (FDG) was performed before and after treatment in 16 subjects diagnosed for OCD for at least 2 years (PT: n=7). Pre-to post-treatment change of scaled local metabolic rate of glucose (SLMRGlc) was assessed separately in therapy responders and non-responders. Correlation was tested between SLMRGlc change and change of OCD, depression, or anxiety symptoms. SLMRGlc increased in the right caudate after successful therapy. The increase tended to correlate with the improvement of OCD symptom severity. The finding of increased local caudate activity after successful therapy is in contrast to most previous studies. Possible explanations include effects of therapy on concomitant depression symptoms and/or the large proportion of early-onset OCD in the present sample. PMID- 20947318 TI - A multi-module case-based biofeedback system for stress treatment. AB - OBJECTIVE: Biofeedback is today a recognized treatment method for a number of physical and psychological problems. Experienced clinicians often achieve good results in these areas and their success largely builds on many years of experience and often thousands of treated patients. Unfortunately many of the areas where biofeedback is used are very complex, e.g. diagnosis and treatment of stress. Less experienced clinicians may even have difficulties to initially classify the patient correctly. Often there are only a few experts available to assist less experienced clinicians. To reduce this problem we propose a computer assisted biofeedback system helping in classification, parameter setting and biofeedback training. METHODS: The decision support system (DSS) analysis finger temperature in time series signal where the derivative of temperature in time is calculated to extract the features. The case-based reasoning (CBR) is used in three modules to classify a patient, estimate parameters and biofeedback. In each and every module the CBR approach retrieves most similar cases by comparing a new finger temperature measurement with previously solved measurements. Three different methods are used to calculate similarity between features, they are: modified distance function, similarity matrix and fuzzy similarity. RESULTS AND CONCLUSION: We explore how such a DSS can be designed and validated the approach in the area of stress where the system assists in the classification, parameter setting and finally in the training. In this case study we show that the case based biofeedback system outperforms trainee clinicians based on a case library of cases authorized by an expert. PMID- 20947319 TI - Should vitamin D status be assessed in patients with congestive heart failure? AB - For decades the vitamin D biological system has been considered almost exclusively as the master integrator of calcium-phosphate homeostasis and bone metabolism. More recently, the discovery that many human tissues and cells, which do not directly participate in mineral ion homeostasis, express the vitamin D receptor (VDR) and are able to convert the circulating pro-hormone 25 hydroxyvitamin D in its active form, 1,25-dihydroxyvitamin D, has provided new insights into the biological function of this peculiar endocrine system. Several reports have highlighted a variety of human diseases possibly related to vitamin D insufficiency or deficiency (respectively defined as 25-hydroxyvitamin D serum levels lower than 30 or lower than 20 ng/ml). In particular, experimental and observational studies, including those published in this journal issue, support the concept that vitamin D deficiency is involved in the pathogenesis of congestive heart failure, a disabling condition affecting over 15 million of patients worldwide. Considering that circulating levels of 25-hydroxyvitamin D represent the accepted clinical indicator of individual vitamin D status, the measurement of this pro-hormone can be regarded as an appropriate and cost effective screening tool in patients with chronic heart failure. PMID- 20947320 TI - Surgical prosection in a traditional anatomical curriculum-Tubingens' Sectio chirurgica. AB - Despite the rapid rise of integrated curricula, the teaching of gross anatomy by traditional dissection remains a central element in most medical programs worldwide. However, modern didactic concepts demand the integration of clinical content in preclinical settings. The implementation of interdisciplinary tools often leads to a reduction in teaching of comprehensive anatomy. 'Tubingen's Sectio chirurgica' (TSC) introduces a concept of a teaching activity in which surgical prosection is performed in addition to the traditional dissection course. TSC is designed to integrate clinical and preclinical content in a traditional medical curriculum without affecting the systematic presentation of anatomical content. In the past 2 years, about 10,000 medical students have participated in the use of telemedical transmissions of 'live surgery' in a total of 25 sessions of TSC. Here we describe the organisational plan of TSC and the results of an evaluation which was performed to monitor the influence of TSC on student motivation for surgical disciplines as well as for the learning of anatomical factual content. We demonstrate that additional surgical prosection is a valuable tool in increasing the coherence between preclinical and clinical parts of medical education programs. PMID- 20947321 TI - The nuts and bolts of germ-cell migration. AB - In many species, primordial germ cells (PGCs) migrate from the position where they are specified to the site where the gonad develops, where they differentiate into sperm and egg. Germ cells thus serve as an excellent model for studying cell migration in the context of the live organism. In recent years, a number of cues directing the migration of the cells towards their target were identified and some of the relevant molecules and biochemical pathways were revealed. In this review we present those results, focusing on 'cell mechanics' of the process including cell adhesion, traction generation and cell polarization. PMID- 20947322 TI - Disaster waste management research needs. PMID- 20947323 TI - A voltammetric immunosensor based on nanobiocomposite materials for the determination of alpha-fetoprotein in serum. AB - The development of a voltammetric immunosensor for determination of alpha fetoprotein (AFP) in serum is presented. ELISA assays with voltammetric reading were carried out exploiting the peculiar properties of nanobiocomposite materials based on gold nanoparticles for the immobilization of Antibody (Ab)/Antigen/Antibody-HRP (Horseradish Peroxidase) sandwich on the glassy carbon (GC) electrode surface. The electrochemical transduction was mediated by thionin, which was used in its monomeric form dissolved in the reading solution, so avoiding critical immobilization procedures. The study was aimed at the development and validation of an immunosensor able to provide results in short time, simple to use, rugged and cost-effective for AFP monitoring purposes. A crucial aspect of the study was the development of an experimental protocol leading to highly standardized and consequently reproducible sensors. Two-way analysis of variance (ANOVA) was applied to study the effect of the concentration of the solutions used for the incubation of the antibodies. The sensor was validated in serum assessing stability of the immunocomplex, linearity of response, limit of detection (3.7 ng/ml) and limit of quantitation (11 ng/ml), precision (intra- and inter-sensor repeatability) and recovery rate (103%). The stability of the GC/Ab functionalized substrate was demonstrated over one month, showing variation coefficients below 5%. Experiments carried out with real samples of clinical interest evidenced that the developed immunosensor can be considered as powerful tool in cancer screening programmes. PMID- 20947324 TI - Enhanced direct electrochemistry of glucose oxidase and biosensing for glucose via synergy effect of graphene and CdS nanocrystals. AB - Integrating graphene-based composites with enzyme provides a potent strategy to enhance biosensor performance due to their unique physicochemical properties. Herein we report on the utilization of graphene-CdS (G-CdS) nanocomposite as a novel immobilization matrix for the enzymes, which glucose oxidase (GOD) was chosen as model enzyme. In comparison with the graphene sheet and CdS nanocrystal, G-CdS nanocomposite exhibited excellent electron transfer properties for GOD with the rate constant (k(s)) of 5.9 s(-1) due to the synergy effect of graphene sheet and CdS nanocrystals. Further, based on the decrease of the electrocatalytic response of the reduced form of GOD to dissolved oxygen, the obtained glucose biosensor displays satisfactory analytical performance over an acceptable linear range from 2.0 to 16 mM with a detection limit of 0.7 mM, and also prevents the effects of interfering species, which is suitable for glucose determination by real samples. These results mean that this immobilization matrix not only can be used for immobilizing GOD, but also can be extended to other enzymes and bioactive molecules, thus providing a promising platform for the development of biosensors. PMID- 20947325 TI - A micro potentiometric immunosensor for hemoglobin-A1c level detection based on mixed SAMs wrapped nano-spheres array. AB - A micro potentiometric immunosensor based on mixed SAMs wrapped nano-spheres array for the detection of hemoglobin-A1c level is presented in this paper. Nano spheres array is prepared by wrapping nano-gold particle with mixed SAMs on the surface of micro immunosensor. Mixed SAMs make the nano-gold particles distribute uniformly without aggregation and render the signal less susceptible to noise. Based on this nano-spheres array, antibody is covalently immobilized on the immunosensor surface. The micro immunosensor, consisting of ISFET integrated chip and MEMS electrodes array is applied to measure hemoglobin-A1c level by detecting the concentration of hemoglobin-A1c and hemoglobin simultaneously. The responses of the immunosensor are linear over the concentration range of 166.7-570 ng/ml hemoglobin and 50-170.5 ng/ml HbA1c. Whole blood sample obtained from hospital was also examined using this immunosensor. The low relative deviation shows that this micro immunosensor may provide an alternative tool for the determination of HbA1c level. PMID- 20947326 TI - A highly sensitive nanostructure-based electrochemical sensor for electrocatalytic determination of norepinephrine in the presence of acetaminophen and tryptophan. AB - A new electrochemical sensor for the determination of norepinephrine (NE), acetaminophen (AC) and tryptophan (Trp) is described. The sensor is based on carbon paste electrode (CPE) modified with 3,4-dihydroxybenzaldehyde-2,4 dinitrophenylhydrazone (DDP) and takes the advantages of carbon nanotubes (CNTs), which makes the modified electrode highly sensitive for the electrochemical detection of these compounds. Cyclic voltammetry (CV) at various scan rates was used to investigate the redox properties of the modified electrode. The apparent charge transfer rate constant, k(s), and transfer coefficient, alpha, for electron transfer between DDP and CNT paste electrode were calculated. The mediated oxidation of NE at the modified electrode was investigated by CV and the values of k, alpha and diffusion coefficient (D) were calculated. Under the optimum pH of 7.0, the oxidation of NE occurs at a potential about 215 mV less positive than that of the unmodified CPE. Differential pulse voltammetry (DPV) of NE at the modified electrode exhibited two linear dynamic ranges with a detection limit (3sigma) of 77+/-2 nM. DPV was used for simultaneous determination of NE, AC and Trp at the modified electrode, and quantitation of NE in some real samples by the standard addition method. PMID- 20947327 TI - Simultaneous detection of multiple chemical residues in milk using broad specificity antibodies in a hybrid immunosorbent assay. AB - In this study, a novel immunoassay using 2 types of sensors (QDs and an enzyme) were simultaneously used for detecting multiple structurally different molecules in milk. The method integrates the fluorescence-linked immunosorbent assay (FLISA) using QD605 and QD655 as probes and an enzyme-linked immunosorbent assay (ELISA) using horseradish peroxidase (HRP) labeled secondary antibody. The FLISA was produced by anti-sulfonamide and anti-quinolone broad-specificity monoclonal antibodies (MAbs) for simultaneously detecting 6 sulfonamides and 11 quinolones. Combined with the FLISA, an ELISA was utilized for detecting melamine from the same milk samples. The cross-reactivity of the MAbs was retained while binding the QDs by using avidin and a secondary antibody as bridges. Milk samples were detected using this hybrid immunoassay, with limits of detection (LOD) of the quinolones (0.18 ng mL(-1)), sulfonamides (0.17 ng mL(-1)) and melamine (7.5 ng mL(-1)), respectively. The results demonstrated that the detection limits of the integrated methods were better than required and simplified the sample pretreatment process. The developed immunoassay is suitable for high-throughput screening of low-molecular weight contaminants. PMID- 20947328 TI - Fabrication and characterization of a radiation sensor based on bacteriorhodopsin. AB - Available techniques of X-ray detection have been under development due to specific shortcomings such as finite lifetime, low sensitivity, and post processing requirements. Here we report on the fabrication of an X-ray sensor based on bacteriorhodopsin (BR) with a radius of r=3mm as the sensing area on a flexible substrate. The flexible X-ray detector can be placed on the targeted area for real-time monitoring of radiation dosage. We show that BR sensor is a potential candidate for such a powerful sensing device. For this purpose, we measure the electrical current generated by the BR sensor under different radiation dosages, energies and dose rates. This averaged current is in the range of nanoampere and is proportional to the dose rate of the received X-ray. The current also increases with the increase of radiation energy. BR radiation sensor can be readily miniaturized and is relatively easy to fabricate. The capability for real-time data collection and reusability are other advantages of this radiation sensor. PMID- 20947329 TI - Fabrication of stainless steel mesh gas diffusion electrode for power generation in microbial fuel cell. AB - This study reports the fabrication of a new membrane electrode assembly by using stainless steel mesh (SSM) as raw material and its effectiveness as gas diffusion electrode (GDE) for electrochemical oxygen reduction in microbial fuel cell (MFC). Based on feeding glucose (0.5 g L(-1)) substrate to a single-chambered MFC, power generation using SSM-based GDE was increased with the decrease of polytetrafluoroethylene (PTFE) content applied during fabrication, reaching the optimum power density of 951.6 mW m(-2) at 20% PTFE. Repeatable cell voltage of 0.51 V (external resistance of 400 Omega) and maximum power density of 951.6 mW m(-2) produced for the MFC with SSM-based GDE are comparable to that of 0.52 V and 972.6 mW m(-2), respectively obtained for the MFC containing typical carbon cloth (CC)-made GDE. Besides, Coulombic efficiency (CE) is found higher for GDE (SSM or CC) with membrane assembly than without, which results preliminarily from the mitigation of Coulombic loss being associated with oxygen diffusion and substrate crossover. This study demonstrates that with its good electrical conductivity and much lower cost, the SSM-made GDE suggests a promising alternative as efficient and more economically viable material to conventional typical carbon for power production from biomass in MFC. PMID- 20947330 TI - An amperometric biosensor based on rat cytochrome p450 1A1 for benzo[a]pyrene determination. AB - Using the plasmid pCW, high-level expression of rat cytochrome p4501A1 (CYP1A1) has been achieved by making NH(2)-terminal translational fusions to bacterial leader sequences ompA (ompA-1A1/pCW). The construct ompA-1A1 was compared with an expression construct in which the Ala codon GCT was placed in the second position and 5'-terminal codons were maximized for A T content (1A1/pCW). Both constructs produced spectrally active, functional protein. However, the ompA-1A1 fusion gave higher levels of expression, and a marked improvement in the recovery of active P450 in bacterial membrane fractions, when compared with the construct 1A1/pCW. The expressed 1A1 from the construct ompA-1A1/pCW in bacterial membrane fractions were collected and immobilized in nano-Na-montmorillonite (nano-SWy-2) and dihexadecylphosphate (DHP) composite film. The direct electrochemistry of CYP1A1 in a nano-SWy-2-DHP film on an edge-plane pyrolytic graphite electrode (EPG) has been obtained and the catalytic activity of the enzyme to benzo[a]pyrene has been investigated by the cyclic voltammetry. The immobilized CYP1A1 displayed a pair of redox peaks with a formal potential of -0.36 mV in pH 7.0 O(2)-free phosphate buffers at scan rate of 1 V s(-1). The CYP1A1 in the nano-SWy-2-DHP film retained its bioactivity and could catalyze the reduction of dissolved oxygen. Upon the addition of its substrate benzo[a]pyrene (B[a]P) to the air-saturated solution, the reduction peak current of dissolved oxygen increased, which indicates the catalytic behavior of CYP1A1 to B[a]P. By amperometry a calibration linear range for B[a]P was obtained to be 3.31-16.56 MUM with a sensitivity of 58.57 MUA mM( 1). And the apparent Michaelis-Menten constant for the electrocatalytic activity of CYP1A1 was estimated to be 46.27 MUM for B[a]P. PMID- 20947331 TI - Highly effective protein detection for avidin-biotin system based on colloidal photonic crystals enhanced fluoroimmunoassay. AB - There has been immense interest in both instruments and methods to enhance fluorescence signal and achieve highly sensitive fluoroimmunoassay (FIA). In this paper, we present a facile, low-cost and general method of biotinylated colloidal photonic crystal (PC) to improve the FIA of avidin (avidin FIA). The fluorescence signal intensity of the avidin FIA on the colloidal PC can be enhanced over two orders of magnitude relative to the control sample, attributed to the large surface area, resonance field and coherent scattering effect of the colloidal PC. The detection limit is shrunk to 1/69 of that of the control sample. Furthermore, the signal to interference ratio (S/I ratio) is increased because the band-edge induced fluorescence enhancement is wavelength-selective. The interference fluorescence does not go up proportionally while the signal is significantly enhanced by the colloidal PCs. It is believed that the colloidal PC modified with biotin can act as an effective material for a general and sensitive fluoroimmunoassay. PMID- 20947332 TI - RGB colour coding of Y-shaped DNA for simultaneous tri-analyte solid phase hybridization detection. AB - We present a new concept for tri-analyte DNA detection based on the idea of a Y shaped capture probe which, after tri-target and fluorescently labeled reporter probe binding, becomes colour-coded to generate images in an RGB colour scheme. Hence, the RGB value of the resulting secondary pseudo-colour presented by the hybridized Y-DNA can be related to the ratio of the primary pseudo-colours present in its make-up, and thus to the ratio of the three target concentrations. As a proof of concept we detect sequences from the genes of the pathogenic bacterial strains Escherichia coli O157:H7, Vibrio cholera and Salmonella enteric in a semi-quantitative manner across the range 20-167 nM. The assay was relatively quick, with a time from hybridization to completed data interpretation of approximately 4 h. PMID- 20947333 TI - Enzymatically amplified electrochemical detection for lipopolysaccharide using ferrocene-attached polymyxin B and its analogue. AB - Ferrocene-attached polymyxin B (PMB-Fc) was prepared by the reaction of polymyxin B with ferrocenoyl chloride in a toluene/pyridine mixture. An electrochemical detection of lipopolysaccharide (LPS) was carried out using a combination of PMB Fc and an enzyme-modified electrode constructed from a glassy carbon electrode modified with a bovine serum albumin membrane containing glucose oxidase. The ferrocene units of the PMB-Fc molecules were oxidized on the electrode, and then reduced to the original neutral form by a glucose oxidase-catalyzed reaction in the presence of D-glucose. The consumption/regeneration cycle for PMB-Fc resulted in a chemically amplified current response. The current response for PMB-Fc decreased in association with its complexation with LPS, and the magnitude of this current decrease caused by LPS was also amplified by the recycling process. The enzyme-modified electrode exhibited a rapid response of 5 min for LPS with the detection limit as low as 50 ng ml(-1). Further, the addition of D-solbitol or poly(vinyl alcohol) of high concentration over 1 mg ml(-1) substantially induced no response, and three kinds of LPS from different strains exhibited similar magnitudes of current response for the same concentrations; these results suggest the advantages of this detection system for practical applications. Ferrocene-attached colistin, an analogue of PMB-Fc, was also effective for the LPS detection using the glucose oxidase-modified electrode. PMID- 20947334 TI - Electrogenerated chemiluminescence detection of adenosine based on triplex DNA biosensor. AB - A novel electrogenerated chemiluminescence (ECL) biosensor based on the construction of triplex DNA for the detection of adenosine was designed. The ECL biosensor employs an aptamer as a molecular recognition element, and quenches ECL of tris(2,2'-bipyridine) ruthenium (Ru(bpy)(3)(2+)) by ferrocenemonocarboxylic acid (FcA). Through self-assembly technology, the ECL probe of thiolated hairpin adenosine aptamer tagged was self-assembled onto the surface of a gold electrode with an ECL signal producer Ru(bpy)(3)(2+) derivative (Ru-DNA-1). The adenosine aptamer, including a section of triplex characteristic chain, formatted triplex DNA with two other DNAs (DNA-2, Fc-DNA-3) in the presence of triplex DNA binder coralyne chloride (CORA). Fc-DNA-3 was tagged with an ECL quencher ferrocenemonocarboxylic acid (FcA), a quenching probe. In the presence of adenosine, the aptamer sequence (Ru-DNA-1) prefers to form the aptamer-adenosine complex with hairpin configuration and the switch of the DNA-1 occurs in conjunction with the generation of a strong ECL signal owing to the dissociation of a quenching probe. Meanwhile, a control experiment was performed; the ECL duplex biosensor was designed to detect adenosine. The detection limits were 2.7*10(-10) mol L(-1) and 2.3*10(-9) mol L(-1) for the ECL-triplex DNA biosensor and ECL-duplex DNA biosensor, respectively, which demonstrated that the ECL triplex DNA biosensor improved the sensitivity and specificity greatly. PMID- 20947335 TI - Imaging local estrogen production in single living cells with recombinant fluorescent indicators. AB - Estrogens are steroid hormones with many systemic effects in addition to development and maintenance of the female reproductive system, and ligands of estrogen receptors are of clinical importance because of their use as oral contraceptive, hormone replacement and antitumoral therapy. In addition, tumoral tissues have been found to express aromatase and other steroidogenic enzymes synthesizing estradiol. To aid in the understanding of these processes, we have developed assays to image the local production of estrogens in isolated living mammalian cells. We constructed biosensors based on estrogen receptor alpha ligand binding domain and fluorescent proteins by following two approaches. First, the ligand binding domain and a short fragment of steroid receptor coactivator-1 were appended to a circularly permuted yellow fluorescent protein to construct an excitation ratio estrogen indicator. In the second strategy, we constructed emission ratio sensors based on fluorescence resonance energy transfer, containing the ligand binding domain flanked by donor and acceptor fluorescent proteins. Estrogens altered the fluorescence signal of cells transfected with the indicators in a dose-dependent manner. We imaged local estrogen production in adrenocortical H295 cells expressing aromatase and transfected with the fluorescent sensors. In addition, paracrine detection was observed in HeLa cells harboring the indicators and co-cultured with H295 cells. This imaging approach may allow detection of physiological levels of these hormones in suitable animal models. PMID- 20947336 TI - Coupling cellular oscillators--circadian and cell division cycles in cyanobacteria. AB - Understanding how different cellular subsystems are coupled to each other is a fundamental question in the quest for reliably predicting the dynamic state of a cell. Coupling of oscillatory subsystems is especially interesting as dynamic interactions play an important role in cell physiology. Here we review recent efforts that investigate and quantify the coupling between the circadian and cell cycle clocks in cyanobacteria as a model system. We discuss studies that quantify the coupling from a systems point of view in which the oscillators are described in abstract terms. We also emphasize recent developments aimed at uncovering the molecular details underlying the coupling between these systems. Finally we review recent studies that describe a potentially more overarching regulation scheme through global circadian regulation of DNA packing and gene expression. PMID- 20947337 TI - Consumption of animal products, olive oil and dietary fat and results from the Belgian case-control study on bladder cancer risk. AB - AIM: The Western diet typically consists of high levels of saturated fat from animal products and has been associated with an increased risk of bladder cancer. Whilst olive oil, the predominant fat in the Mediterranean diet, has been associated with many health benefits its role in bladder cancer aetiology is still unknown. Therefore, we investigated the effect of intake of animal products, olive oil and other major dietary fats on bladder cancer risk. METHODS: Dietary data were collected from 200 cases and 386 controls participating in a Belgian case-control study on bladder cancer. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) by comparing the highest with the lowest tertiles of intake between cases and controls using unconditional logistic regression. Adjustment was made for age, sex, smoking characteristics, occupational exposures and calorie intake. RESULTS: There was a statistically significant inverse association between olive oil intake and bladder cancer consistent with a linear dose-response relationship: middle versus the lowest tertile (OR: 0.62; 95% CI: 0.39-0.99) and the highest versus the lowest tertile (OR: 0.47; 95% CI: 0.28 0.78; p-trend = 0.002). We also observed borderline statistically significant increased odds of bladder cancer for the highest versus the lowest intake of cheese (OR: 1.53; 95% CI: 0.95-2.46; p-trend = 0.08). No potential associations were detected for any other source or type of dietary fat. CONCLUSION: We observed evidence for a protective effect by olive oil and a possible increased risk of bladder cancer associated with a high intake of cheese. Our results require further investigation and confirmation by other studies. PMID- 20947338 TI - Reliability and construct validity of the oral mucositis daily questionnaire in children with cancer. AB - BACKGROUND: The objective of this study was to examine the test-retest reliability and construct validity of parent-reported Oral Mucositis Daily Questionnaire (OMDQ) in children receiving intensive chemotherapy. METHODS: Parents of children with cancer receiving intensive chemotherapy for leukaemia/lymphoma or undergoing stem cell transplantation (SCT) were asked to complete OMDQ daily for 21 d after chemotherapy. Other measures of mucositis obtained concurrently with OMDQ included the World Health Organization (WHO) Mucositis Scale, pain Visual Analogue Scale (VAS) and the Functional Assessment of Cancer Therapy Esophageal Cancer Sub-scale (FACT-ECS). RESULTS: Parents of 59 children (median age = 5.62) provided complete OMDQ data for inclusion in analysis. The majority of children (73%) received SCT. Test-retest reliability of OMDQ exceeded the expected moderate reliability threshold established a priori and in particular, was good to excellent when mucositis was expected. In general, items of OMDQ that relate to pain, swallowing, drinking, eating and talking demonstrated moderate correlations with WHO, VAS and FACT-ECS indices with correlation coefficients >= 0.5. CONCLUSIONS: Parent-report of a modified version of OMDQ is reliable and the questions relating to mouth and throat pain, as well as effect on function display construct validity for this population of children receiving intensive chemotherapy. PMID- 20947339 TI - A UV-induced mutant of Pichia stipitis with increased ethanol production from xylose and selection of a spontaneous mutant with increased ethanol tolerance. AB - In the fermentation process of lignocellulosic biomass (such as wood and rice straw), efficient conversion of pentose (mainly xylose) into ethanol is important. Mutants of Pichia stipitis NBRC1687 were obtained after UV mutagenesis and selection of large colonies on ethanol-containing medium. One mutant, PXF58, produced 4.3% ethanol from 11.4% xylose while the parent strain only produced 3.1%. The ethanol productivities of PXF58 from glucose and fructose were about were about 1.4-fold higher than those of the parent strain. After continuous cultivation of PXF58 in YNB (yeast nitrogen base) medium containing 2% xylose and 5-7% ethanol, an ethanol-tolerant mutant, PET41, was obtained. Strain PET41 was able to produce 4.4% ethanol when first supplied with xylose then with glucose. This isolate might be thus useful for two-phase fermentation in which xylan is saccharified by xylanase to produce xylose, and glucan is saccharified later by cellulase and beta-glucosidase to produce glucose. PMID- 20947340 TI - Effect of membrane bioreactor configurations on sludge structure and microbial activity. AB - The aim of this paper was to determine the effect of two different membrane bioreactor (MBR) configurations (external/immersed) on sludge structure and microbial activity. Sludge structure was deduced from rheological measurements. The high shear stress induced by the recirculation pump in the external MBR was shown to result in decreasing viscosity due to activated sludge (AS) deflocculation. Besides, soluble microbial products (SMP) release was higher in the external MBR (5 mgCOD gMLVSS(-1)) than in the immersed configuration (2 mgCOD gMLVSS(-1)). Microbial activity was followed from respirometry tests by focusing on the distinction between heterotrophs and autotrophs. An easier autotrophic microbe development was then observed in the immersed MBR compared to the external one. However, the external MBR was shown to allow better heterotrophic microbe development. PMID- 20947341 TI - Effect of nutrients on growth and lipid accumulation in the green algae Dunaliella tertiolecta. AB - Production of biofuel from algae is dependent on the microalgal biomass production rate and lipid content. Both biomass production and lipid accumulation are limited by several factors, of which nutrients play a key role. In this research, the marine microalgae Dunaliella tertiolecta was used as a model organism and a profile of its nutritional requirements was determined. Inorganic phosphate PO4(3-) and trace elements: cobalt (Co2+), iron (Fe3+), molybdenum (Mo2+) and manganese (Mn2+) were identified as required for algae optimum growth. Inorganic nitrogen in the form of nitrate NO3- instead of ammonium (NH4+) was required for maximal biomass production. Lipids accumulated under nitrogen starvation growth condition and this was time-dependent. Results of this research can be applied to maximize production of microalgal lipids in optimally designed photobioreactors. PMID- 20947342 TI - Simultaneous production of 1,3-dihydroxyacetone and xylitol from glycerol and xylose using a nanoparticle-supported multi-enzyme system with in situ cofactor regeneration. AB - Cofactor-dependent biotransformations often require consumption of a secondary substrate for cofactor regeneration. Alternatively, two synthetic reactions may be coupled together through cofactor regeneration cycles. Simultaneous production of value-added products from glycerol and xylose was realized in this work through an enzymatic NAD(H) regeneration cycle involving two enzymes. Glycerol dehydrogenase (GDH) catalyzed the production of 1,3-dihydroxyacetone (DHA) from glycerol, while xylose reductase (XR) enabled the reduction of xylose to xylitol using the protons released from glycerol. Both enzymes were immobilized with P(MMA-EDMA-MAA) nanoparticles. Interestingly, the immobilized multi-enzyme system showed much improved productivity and stability as compared to native enzymes, such that the total turnover number (TTN) reached 82 for cofactor regeneration while the yield reached 160g/g-immobilized GDH for DHA production. PMID- 20947343 TI - Enhanced protease production in a polymethylmethacrylate conico-cylindrical flask by two biofilm-forming bacteria. AB - A polymethylmethacrylate (PMMA) conico-cylindrical flask (CCF) with an inner arrangement consisting of eight equidistantly spaced rectangular strips mounted radially on a circular disk to provide additional surface area for microbial attachment was employed for protease production by two biofilm-forming bacteria, an intertidal gamma-Proteobacterium (DGII) and a chicken meat isolate, Virgibacillus pantothenticus. The flask design allowed comparison of protease production during cultivation with a hydrophilic (glass) or hydrophobic (PMMA) surface. Compared to the Erlenmeyer flask, the CCF allowed protease production that was 30% and 35% higher and growth that was 20% and 345% higher for DGII and V. pantothenticus, respectively. Protease production increased by 202% and 22% and growth by 19,275% and 940% for DGII and V. pantothenticus, respectively, in the presence of a hydrophobic as compared to a hydrophilic surface. This investigation pioneers the application of a vessel beyond the traditional shake flask for enhancing protease production by biofilm-formers. PMID- 20947344 TI - Response surface optimization of oxalic acid pretreatment of yellow poplar (Liriodendron tulipifera) for production of glucose and xylose monosaccarides. AB - The primary goal of this study was to determine the optimal condition to obtain fermentable monosaccharides (xylose and glucose) from hydrolysates of yellow poplar (Liriodendron tulipifera) by oxalic acid pretreatment as a potential bio ethanol source. Based on 2(3) factorial design, fifteen operations were performed by varying on acid loading, reaction time and temperature, and the components of the solid and liquid fractions were analyzed. The sugar concentration (g/L) in hydrolysates and xylose solubilization (%) were applied to response surface methodology. The optimal condition for producing sugars was 151 degrees C, 0.042 g/g (weight of oxalic acid/dry matter), 13 min with predicted yield of 37.4 g/L, and for the xylose solubilization was 158 degrees C, 0.037 g/g, 13 min yielding 72.0% of the predicted value. Severe conditions generated inhibitors. By measuring the concentrations, the possibility utilizing hydrolysates for fermentation were estimated. PMID- 20947345 TI - Chemo-microbial conversion of cellulose into polyhydroxybutyrate through ruthenium-catalyzed hydrolysis of cellulose into glucose. AB - Cellulose-derived glucose generated using the supported ruthenium catalyst was applied to poly(3-hydroxybutyrate) [P(3HB)] production in recombinant Escherichia coli. By the reaction with the catalyst at 220 degrees C, 15-20 carbon mol% of cellulose was converted into glucose. The hydrolysate also contained byproducts such as fructose, mannose, levoglucosan, oligomeric cellulose, 5 hydroxymethylfurfural (5-HMF), and furfural together with unidentified compounds. Setting the reaction temperature lower (215 degrees C) improved the ratio of glucose to 5-HMF, which was a main inhibiting factor for the cell growth. Indeed, the recombinant E. coli exhibited better performance on the hydrolysate generated at 215 degrees C and accumulated P(3HB) up to 42 wt%, which was the same as the case of the same concentration of analytical grade glucose. The result indicated that the ruthenium-mediated cellulose hydrolysis has a potency as a useful biorefinery process for production of bio-based plastic from cellulosic biomass. PMID- 20947346 TI - Low temperature catalytic gasification of pig compost to produce H2 rich gas. AB - The low temperature catalytic gasification of pig compost before and after acid washing was carried out to produce H2 rich gas using a two-stage fixed-bed reactor. Little effect of the minerals on the manure pyrolysis is determined. Under the presence of Ni/Al2O3 catalyst nearly all the tarry matters were cracked into H2, CO, CO2 and residual carbon. High H2 and CO yields were obtained by low temperature catalytic steam gasification. Acid washing results in the decrease in the content of the ease-hydrolyzed organic components, which volatilize at low temperature. The change in the gas yields from the manure during catalytic decomposition is in accordance with its pyrolysis behavior. PMID- 20947347 TI - Labeling study of avidin by modular method for affinity labeling (MoAL). AB - We studied the specific labeling of avidin with biotinylated modular ligand catalysts via MoAL, which we recently established. The labeling yield was found to depend on the linker length connecting the catalytic site to biotin in the modular ligand catalyst 1, and the maximum yield was obtained with 1d possessing octamethylene linker. The labeling reaction reached a maximum rate with only 4 equiv of the ligand catalyst. Presumably, all the subunits of avidin with homotetrameric structure formed a stable complex with 4 equiv of the catalyst because of the extremely high affinity. The ligand catalyst bound to avidin first catalyzed N-triazinylation of the epsilon-amino group of Lys111, and the resulting regenerated catalyst then catalyzed the reaction of Asp108 and CDMT. PMID- 20947348 TI - Synthesis and in vitro antifungal activities of new 3-substituted benzopyrone derivatives. AB - A series of new benzopyrone compounds were designed and synthesized and their antifungal activities in vitro were evaluated. The results showed that the benzopyrone derivatives with short terminal alkyl chain exhibited potent antifungal activity, which represent a novel class of promising leads for the development of novel non-azole antifungal agents. Compound 5j is the most potent one with MIC(80) value 1.5 MUg/mL against Trichophyton rubrum. Flexible molecular docking was used to analyze the structure-activity relationships (SARs) of the compounds. The designed compounds interact with CA-CYP51 through hydrophobic and van der Waals interactions. PMID- 20947349 TI - A targeted low molecular weight near-infrared fluorescent probe for prostate cancer. AB - Prostate-specific membrane antigen (PSMA) remains an active target for imaging and therapeutic applications for prostate cancer. Although radionuclide-based imaging is generally more sensitive and also has been deeply explored, near infrared fluorescence imaging agents are simple to prepare and compatible with long-term storage conditions. In the present study, a near-infrared fluorescent imaging probe (Cy5.5-CTT-54.2) has been developed by chemical conjugation of Cy5.5N-hydroxysuccinimide ester (Cy5.5-NHS) with a potent PSMA inhibitor CTT-54.2 (IC(50)=144 nM). The probe displays a highly potency (IC(50)=0.55 nM) against PSMA and has demonstrated successful application for specifically labeling PSMA positive prostate cancer cells in both two and three-dimensional cell culture conditions. These results suggest that the potent, near-infrared Cy5.5-PSMA inhibitor conjugate may be useful for the detection of prostate tumor cells by optical in vivo imaging. PMID- 20947350 TI - Synthesis, antioxidant and toxicological study of novel pyrimido quinoline derivatives from 4-hydroxy-3-acyl quinolin-2-one. AB - A series of novel pyrimido and other fused quinoline derivatives like 4-methyl pyrimido [5,4-c]quinoline-2,5(1H,6H)-dione (4a), 4-methyl-2-thioxo-1,2 dihydropyrimido [5,4-c]quinoline-5(6H)-one (4b), 2-amino-4-methyl-1,2 dihydropyrimido [5,4-c]quinolin-5(6H)-one (4c), 3-methylisoxazolo [4,5-c]quinolin 4(5H)-one (4d), 3-methyl-1H-pyrazolo [4,3-c]quinoline-4(5H)-one (5e), 5-methyl-1H [1,2,4] triazepino [6,5-c]quinoline-2,6(3H,7H)-dione (5f), 5-methyl-2-thioxo-2,3 dihydro-1H-[1,2,4]triazepino [6,5-c]quinolin-6(7H)-one (5 g) were synthesized regioselectively from 4-hydroxy-3-acyl quinolin-2-one 3. They were screened for their in vitro antioxidant activities against radical scavenging capacity using DPPH(), Trolox equivalent antioxidant capacity (TEAC), total antioxidant activity by FRAP, superoxide radical (O(2)( degrees -)) scavenging activity, metal chelating activity and nitric oxide scavenging activity. Among the compounds screened, 4c and 5 g exhibited significant antioxidant activities. PMID- 20947351 TI - Inhibitors selective for HDAC6 in enzymes and cells. AB - Histone deacetylase inhibitors with anticancer or anti-inflammatory activity bind to Class I or Class I and II HDAC enzymes. Here we compare selectivity of inhibitors of a Class II HDAC enzyme (HDAC6) and find one that retains high selectivity in macrophages. PMID- 20947352 TI - Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepines as novel TRPV1 antagonists. AB - Utilization of a tetrahydro-pyrimdoazepine core as a bioisosteric replacement for a piperazine-urea resulted in the discovery a novel series of potent antagonists of TRPV1. The tetrahydro-pyrimdoazepines have been identified as having good in vitro and in vivo potency and acceptable physical properties. PMID- 20947353 TI - The test-retest reliability of centre of pressure measures in bipedal static task conditions--a systematic review of the literature. AB - SUMMARY OF BACKGROUND DATA: The analysis of centre of pressure (COP) excursions is used as an index of postural stability in standing. Conflicting data have been reported over the past 20 years regarding the reliability of COP measures and no standard procedure for COP measure use in study design has been established. SEARCH METHODS: Six online databases (January 1980 to February 2009) were systematically searched followed by a manual search of retrieved papers. RESULTS: Thirty-two papers met the inclusion criteria. The majority of the papers (26/32, 81.3%) demonstrated acceptable reliability. While COP mean velocity (mVel) demonstrated variable but generally good reliability throughout the different studies (r=0.32-0.94), no single measurement of COP appeared significantly more reliable than the others. Regarding data acquisition duration, a minimum of 90 s is required to reach acceptable reliability for most COP parameters. This review further suggests that while eyes closed readings may show slightly higher reliability coefficients, both eyes open and closed setups allow acceptable readings under the described conditions (r >= 0.75). Also averaging the results of three to five repetitions on firm surface is necessary to obtain acceptable reliability. A sampling frequency of 100 Hz with a cut-off frequency of 10 Hz is also recommended. No final conclusion regarding the feet position could be reached. CONCLUSIONS: The studies reviewed show that bipedal static COP measures may be used as a reliable tool for investigating general postural stability and balance performance under specific conditions. Recommendations for maximizing the reliability of COP data are provided. PMID- 20947354 TI - Altered inter-joint coordination during walking in patients with total hip arthroplasty. AB - The purpose of this study was to investigate the pattern and variability of inter joint coordination for both surgical and non-surgical limbs during walking in patients before and after total hip arthroplasty (THA). Gait analysis of THA patients (n=20) and age-matched controls (n=10) was performed. THA patients were tested at pre-surgery, 6-week and 16-week post surgery. Continuous relative phase (CRP) was used to assess the inter-joint coordination pattern and variability. Variability of coordination for each subject was calculated over a gait cycle with the deviation phase (DP). Between-subject group differences in CRP patterns were examined with cross-correlation measures and root-mean-square (RMS) differences. The surgical limb demonstrated significantly higher DP values comparing to the controls at pre-surgery. Compared to pre-surgery, significant time effects on THA patients were detected in hip-knee DP values at 16-week post surgery for both limbs, and in knee-ankle DP values at 16-week post surgery for the surgical limb. RMS differences for hip-knee and knee-ankle CRP decreased gradually after surgery for both limbs. Cross-correlation measures were overall strong for CRP patterns of both limbs, with r(2) values greater than 0.94. Our results suggested that both hip-knee and knee-ankle coordination, especially the surgical limb, were altered with a higher variability to compromise the deteriorated hip joint. Asymmetric changes in accommodations and variability of bilateral lower extremities may contribute to the residual gait problems observed in THA patients. Therefore, clinical efforts may exert to improve the inter-joint coordination in this population. PMID- 20947355 TI - Changes of locomotion in old age depend on task setting. AB - BACKGROUND: Laboratory settings may differ from everyday life with respect to factors such as attention, motivation, intention, and self-efficacy. Since those factors are likely to influence subjects' performance on locomotor tasks, we evaluated whether the age-related changes of locomotion previously observed under laboratory conditions are equally present in a real life-like scenario. METHODS: 15 young and 15 older subjects walked along a marked path of 25 m length and 0.3m width in a laboratory environment. 14 young and 13 older subjects walked in a community park along a 3 km path, with a straight and level registration section located after 1.5 km. RESULTS: Step duration was longer, angular limb excursion was smaller, and the spatio-temporal gait variability was higher in the laboratory than in the park. Analysis of co-variance revealed that these changes cannot be traced back to a single cause. The variability of step duration and of limb excursion increased in old age under laboratory conditions, but only the latter parameter increased under real life-like conditions. DISCUSSION: Our laboratory setting destabilized the gait pattern more than our real life-like setting, thus accentuating age-related changes. PMID- 20947356 TI - Occipital interhemispheric transtentorial approach to the superior cerebellum. AB - The occipital interhemispheric transtentorial approach is commonly used for pineal region tumors. However, there are few reports of this approach for lesions in the superior cerebellum. We present a 47-year-old male patient with an incidental cystic lesion in the superior cerebellum, detected on MRI consistent with cerebellar hemangioblastoma. The patient initially underwent stereotactic radiosurgery. After 5 months he presented with dizziness. A repeat MRI scan revealed an interval increase in lesion size. We performed surgery using the occipital interhemispheric transtentorial approach to remove the lesion. There were no intraoperative complications and the patient tolerated the procedure well. We describe our approach, supplemented by a short video, and review operative approaches to the superior cerebellum. PMID- 20947358 TI - An intraoperatively moulded PMMA prostheses like spacer for two-stage revision of infected total knee arthroplasty. AB - We report a series of 16 consecutive total knee arthroplasty (TKA) revision procedures for deep infection, treated with a newly developed intraoperatively moulded PMMA cement-prostheses-like spacer (CPLS). The standard treatment consisted of a two-stage protocol with initial explantation of the infected components combined with radical debridement, followed by implantation of a temporary cement spacer and final reimplantation of a new TKA. A sterilizeable Teflon tapered aluminium mould was developed for production of a custom made CPLS during the intervention. Stable implantation of the CPLS was achieved with a second cementation, allowing for correct alignment and ligament balancing. The spacer remained 3.5 months on average until reimplantation of a TKA occurred. At time of reimplantation, patients had an average KSS score of 84.44 points with an average flexion capacity of 102 degrees . There was no recurrent infection during the study period of minimum 2 years. With this new technique, a low friction articulation with good stability, high comfort and a better range of motion compared to handcrafted spacers was achieved. The use of this spacer is a time sparing, cheap and convenient option in 2-stage TKA revision. PMID- 20947357 TI - ATR: a master conductor of cellular responses to DNA replication stress. AB - The integrity of the genome is constantly challenged by intrinsic and extrinsic genotoxic stresses that damage DNA. The cellular responses to DNA damage are orchestrated by DNA damage signaling pathways, also known as DNA damage checkpoints. These signaling pathways play crucial roles in detecting DNA damage, regulating DNA repair and coordinating DNA repair with other cellular processes. In vertebrates, the ATM- and Rad3-related (ATR) kinase plays a key role in the response to a broad spectrum of DNA damage and DNA replication stress. Here, we will discuss the recent findings on how ATR is activated by DNA damage and how it protects the genome against interference with DNA replication. PMID- 20947359 TI - Synthesis and evaluation of pyrazolone compounds as SARS-coronavirus 3C-like protease inhibitors. AB - A series of pyrazolone compounds as possible SARS-CoV 3CL protease inhibitors were designed, synthesized, and evaluated by in vitro protease assay using fluorogenic substrate peptide in which several showed potent inhibition against the 3CL protease. Interestingly, one of the inhibitors was also active against 3C protease from coxsackievirus B3. These inhibitors could be potentially developed into anti-coronaviral and anti-picornaviral agents. PMID- 20947360 TI - Structural insights into the hot spot amino acid residues of mushroom tyrosinase for the bindings of thujaplicins. AB - Tyrosinase inhibitors are important agents for cosmetic products. We examined here the inhibitory effects of three isomers of thujaplicins (alpha, beta and gamma) on mushroom tyrosinase and analyzed their binding modes using a homology model from the crystal structure of Streptomyces castaneoglobisporus tyrosinase (PDB ID: 1wx2). All the thujaplicins were found to be competitive inhibitors and gamma-thujaplicin has the most potent inhibitory activity (IC(50)=0.07MUM). It is noted that there are good correlations between their observed IC(50) values and their binding free energies calculated by MM-GB/SA. The binding modes of thujaplicins were predicted to be similar to that of Tyr98 of caddie protein (ORF378), which was co-crystallized with S. castaneoglobisporus tyrosinase. Furthermore, free energy decomposition analysis indicated that the potent inhibitory activity of gamma-thujaplicin is due to the interactions with His242, Val243 and Pro257 (hot spot amino acid residues) at the active site of tyrosinase. These results provide a novel structural insight into the hot spot of mushroom tyrosinase for the specific binding of gamma-thujaplicin. PMID- 20947361 TI - The binding of beta-d-glucopyranosyl-thiosemicarbazone derivatives to glycogen phosphorylase: A new class of inhibitors. AB - Glycogen phosphorylase (GP) is a promising target for the treatment of type 2 diabetes. In the process of structure based drug design for GP, a group of 15 aromatic aldehyde 4-(beta-d-glucopyranosyl)thiosemicarbazones have been synthesized and evaluated as inhibitors of rabbit muscle glycogen phosphorylase b (GPb) by kinetic studies. These compounds are competitive inhibitors of GPb with respect to alpha-d-glucose-1-phosphate with IC(50) values ranging from 5.7 to 524.3MUM. In order to elucidate the structural basis of their inhibition, the crystal structures of these compounds in complex with GPb at 1.95-2.23A resolution were determined. The complex structures reveal that the inhibitors are accommodated at the catalytic site with the glucopyranosyl moiety at approximately the same position as alpha-d-glucose and stabilize the T conformation of the 280s loop. The thiosemicarbazone part of the studied glucosyl thiosemicarbazones possess a moiety derived from substituted benzaldehydes with NO(2), F, Cl, Br, OH, OMe, CF(3), or Me at the ortho-, meta- or para-position of the aromatic ring as well as a moiety derived from 4-pyridinecarboxaldehyde. These fit tightly into the beta-pocket, a side channel from the catalytic site with no access to the bulk solvent. The differences in their inhibitory potency can be interpreted in terms of variations in the interactions of the aldehyde derived moiety with protein residues in the beta-pocket. In addition, 14 out of the 15 studied inhibitors were found bound at the new allosteric site of the enzyme. PMID- 20947362 TI - Synthesis, biological evaluation, and molecular docking studies of 2 chloropyridine derivatives possessing 1,3,4-oxadiazole moiety as potential antitumor agents. AB - A series of new 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moiety were synthesized. Antiproliferative assay results indicated that compounds 6o and 6u exhibited the most potent activity against gastric cancer cell SGC-7901, which was more potent than the positive control. Especially, compound 6o exhibited significant telomerase inhibitory activity (IC(50)=2.3+/-0.07MUM), which was comparable to the positive control ethidium bromide. Docking simulation was performed to position compound 6o into the active site of telomerase (3DU6) to determine the probable binding model. PMID- 20947363 TI - Pharmacology of ionotropic glutamate receptors: A structural perspective. AB - The impact of structural biology on the design of ligands (agonists, antagonists and modulators) for ionotropic glutamate receptors is reviewed. PMID- 20947364 TI - Rapid sequential determination of Pu, 90Sr and 241Am nuclides in environmental samples using an anion exchange and Sr-Spec resins. AB - This paper presents a quantitative and rapid method of sequential separation of Pu, (90)Sr and (241)Am nuclides in environmental soil samples with an anion exchange resin and Sr Spec resin. After the sample solution was passed through an anion exchange column connected to a Sr Spec column, Pu isotopes were purified from the anion exchange column. Strontium-90 was separated from other interfering elements by the Sr Spec column. Americium-241 was purified from lanthanides by the anion exchange resin after oxalate co-precipitation. Measurement of Pu and Am isotopes was carried out using an alpha-spectrometer. Strontium-90 was measured by a low-level liquid scintillation counter. The radiochemical procedure of Pu, (90)Sr and (241)Am nuclides investigated in this study validated by application to IAEA reference materials and environmental soil samples. PMID- 20947365 TI - Assessment of mitochondria as a compartment for phosphatidylinositol synthesis in Solanum tuberosum. AB - The outer mitochondrial membrane is particularly rich in phosphatidylinositol (PtdIns), a phospholipid found in different amounts in all eukaryotic membranes, but not synthesized in situ by all. PtdIns is therefore subjected to traffic from the synthesizing membranes to the non-synthesizing ones. The contribution of mitochondria to the cell PtdIns pool has never been the focus of a specific study in plants, whereas in yeast, the presence of the enzyme responsible for synthesis, PtdIns synthase (PIS, cytidine 5'-diphospho-1,2-diacyl-sn-glycerol:myo inositol 3-phosphatidyltransferase, EC 2.7.8.11), has clearly been demonstrated in mitochondria. As these organelles have now been shown to be responsible for the synthesis of several lipids, the present work aimed at evaluating mitochondria as a compartment for the synthesis of PtdIns in plants. The sub cellular localization of PIS was studied in Solanum tuberosum L. by membrane fractionation, enzymatic analysis and by confocal microscopy in living cells. In potato, beside the endoplasmic reticulum, the activity of PIS was found to be tightly associated to mitochondria. Using a fluorescent reporter fusion, the enzyme was also found to be associated to these organelles. The enzyme was not present at the plasma membrane. A comparison of the localization in other cell systems suggests that the mitochondrial localization could be regulated. PMID- 20947366 TI - Cell-scaffold transplant of hydrogel seeded with rat bone marrow progenitors for bone regeneration. AB - Bone is the second most frequently transplanted tissue in humans and efforts are focused on developing cell-scaffold constructs which can be employed for autologous implantation in place of allogenic transplants. The objective of the present study was to examine the efficacy of a gelatin-based hydrogel scaffold to support osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells (MSCs) and its application in a cranial defect model. MSCs which were cultured on hydrogel under osteogenic conditions demonstrated typical osteogenic differentiation which included cluster formation with positive Alizarin Red S staining, sedimentation of calcium phosphate as defined by SEM and EDS spectroscopy and expression of mRNA osteogenic markers. Empty scaffolds or those containing either differentiated cells or naive cells were implanted into cranial defects of athymic nude mice and the healing process was followed by MUCT. Substantial bone formation (65%) was observed with osteogenic cell-scaffold constructs when compared to the naive cell construct (25%) and the cell free scaffold (10%). Results demonstrated the potential of hydrogel scaffolds to serve as a supportive carrier for bone marrow-derived MSCs. PMID- 20947367 TI - UV index forecasts and measurements of health-effective radiation. AB - While erythemal irradiance as a potentially damaging effect to the skin has been extensively studied and short-term forecasts have been issued to the public to reduce detrimental immediate and long-term effects such as sunburn and skin cancer by overexposure, beneficial effects to human health such as vitamin D(3) production by UV radiation and melatonin suppression by blue visible light have attained more and more attention, though both of them have not become part of forecasting yet. Using 4years of solar radiation data measured at the mid latitude site Lindenberg (52 degrees N), and forecast daily maximum UV index values, an overall good correspondence has been found. The data base of solar UV radiation and illuminance has also been used to analyze effects of clouds and aerosols on the effective irradiance. Optically thick clouds can strongly modify the ratios between erythemal and vitamin D(3) effective irradiance such that direct radiative transfer modeling of the latter in future UV forecasts should be preferably used. If parameterizations of vitamin D(3) effective irradiance from erythemal irradiance are used instead, the optical cloud depth would have to be taken into account to avoid an overestimation of vitamin D(3) with parameterizations neglecting cloud optical depth. Particular emphasis for the beneficial effects has been laid in our study on low exposure. Daily doses of solar irradiation for both vitamin D(3) and melatonin suppression do not reach minimum threshold doses even with clear sky and unobstructed horizon during the winter months. PMID- 20947368 TI - Akt isoforms and glucose homeostasis - the leptin connection. AB - The serine/threonine kinase Akt, also known as protein kinase B, has been the focus of substantial attention, largely because it is frequently activated in human cancers. However, relatively little is known about the roles of Akt, particularly the individual isoforms of Akt, in glucose homeostasis in vivo. This review summarizes data on the role of Akt isoforms in glucose homeostasis and diabetes. Emphasis is given to the observation that certain combinations of whole body Akt1 and Akt2 deficiencies reduce circulating levels of leptin and that restoration of leptin levels restores normal glucose homeostasis in diabetic Akt deficient mice. The significance of these findings, together with recent observations suggesting that leptin emulates insulin action, is also discussed. PMID- 20947369 TI - Imaging of human lens lipids by desorption electrospray ionization mass spectrometry. AB - The lipid composition of the human lens is distinct from most other tissues in that it is high in dihydrosphingomyelin and the most abundant glycerophospholipids in the lens are unusual 1-O-alkyl-ether linked phosphatidylethanolamines and phosphatidylserines. In this study, desorption electrospray ionization (DESI) mass spectrometry-imaging was used to determine the distribution of these lipids in the human lens along with other lipids including, ceramides, ceramide-1-phosphates, and lyso 1-O-alkyl ethers. To achieve this, 25 MUm lens slices were mounted onto glass slides and analyzed using a linear ion-trap mass spectrometer equipped with a custom-built, 2-D automated DESI source. In contrast to other tissues that have been previously analyzed by DESI, the presence of a strong acid in the spray solvent was required to desorb lipids directly from lens tissue. Distinctive distributions were observed for [M + H](+) ions arising from each lipid class. Of particular interest were ionized 1-O-alkyl phosphatidylethanolamines and phosphatidylserines, PE (18:1e/18:1), and PS (18:1e/18:1), which were found in a thin ring in the outermost region of the lens. This distribution was confirmed by quantitative analysis of lenses that were sectioned into four distinct regions (outer, barrier, inner, and core), extracted and analyzed by electrospray ionization tandem mass spectrometry. DESI-imaging also revealed a complementary distribution for the structurally-related lyso 1-O-alkyl phosphatidylethanolamine, LPE (18:1e), which was localized closer to the centre of the lens. The data obtained in this study indicate that DESI-imaging is a powerful tool for determining the spatial distribution of human lens lipids. PMID- 20947371 TI - Absolute assignment of constitutional isomers via structurally diagnostic fragment ions: the challenging case of alpha- and beta-acyl naphthalenes. AB - A general mass spectrometric method is described for the absolute assignment of alpha- or beta-acyl naphthalenes, via which the gaseous alpha- and beta-naphthoyl cations of m/z 155 are used as structurally diagnostic fragment ions (SDFI). These stable acylium ions are common and normally abundant fragment ions of acylnaphthalenes in general. Using a pentaquadrupole mass spectrometer, CID experiments with argon and ion/molecule reactions with 2-methyl-1,3-dioxolane, isoprene, acetonitrile and propionitrile were performed but failed to distinguish the two SDFI. Reactions with ethyl vinyl ether and several homologues as well as ethyl vinyl thioether were, however, successful. In reactions with ethyl vinyl ether, the alpha-SDFI form a pair of diagnostic product ions of m/z 165 and m/z 181, which are absent in the corresponding spectrum of the beta-SDFI. Methyl 4-(1 naphthyl)-2,4-dioxobutanoate was used as a test molecule for this class of constitutional isomers and absolute structural assignment as an alpha-acyl naphthalene was correctly performed via the characterization of its alpha-SDFI. PMID- 20947370 TI - The extent and effects of peptide sequence scrambling via formation of macrocyclic B ions in model proteins. AB - The extent and effects of sequence scrambling in peptide ions during tandem mass spectrometry (MS/MS) have been examined using tryptic peptides from model proteins. Sequence-scrambled b ions appeared in about 35% of 43 tryptic peptides examined under MS/MS conditions. In general, these ions had relatively low abundances with averages of 8% and 16%, depending on the instrumentation used. A few tryptic peptides gave abundant scrambled b ions in MS/MS. However, peptide and protein identifications under proteomic conditions with Mascot were not affected, even for these peptides wherein scrambling was prominent. From the 43 tryptic peptides that have been investigated, the conclusion is that sequence scrambling is unlikely to impact negatively on the accuracy of automated peptide and protein identifications in proteomics. PMID- 20947372 TI - Cigarette smoking women of reproductive age who use oral contraceptives: results from the 2002 and 2004 behavioral risk factor surveillance systems. AB - BACKGROUND: Despite health warnings about the increased risk of cerebrovascular disease among women who smoke while using oral contraceptives (OCs), prior research suggests that OC use is still prevalent among women who smoke cigarettes. Our objective was to investigate the prevalence of OC use among cigarette smoking women of reproductive age in the United States. STUDY DESIGN: We extracted data from the 2002 and 2004 Behavioral Risk Factor Surveillance System surveys of 76,544 women between 18 and 44 years of age who reported using some form of contraception. OC use, or self-reported use of "the pill," was examined among those who currently smoke, either everyday or some days. Multivariable logistic regression models were used to compare OC use between smoking and nonsmoking women. RESULTS: One fourth (26.9%) of U.S. women who smoke compared with 34.6% of nonsmoking women reported currently using OCs. After adjusting for age, race/ethnicity, marital status, education level, binge drinking, and health care coverage, women who smoke were 0.6 (95% confidence interval [CI], 0.6-0.7) times as likely to use OCs as nonsmoking women. Among women aged 35 to 44 years, the odds of OC use among smokers was even further reduced (odds ratio [OR], 0.3; 95% CI, 0.3-0.4) compared with nonsmokers. CONCLUSION: Among U.S. women of reproductive age who use contraception, particularly among women aged 35 to 44 years, those who smoke cigarettes are significantly less likely to use OCs than those who do not. PMID- 20947373 TI - Quadriceps activation normative values and the affect of subcutaneous tissue thickness. AB - Calculation of the central activation ratio (CAR) using the superimposed burst technique (SIB) is widely used. 0.95 is considered a normal value of the CAR in healthy subjects, but it has not been objectively examined. Since an electrical stimulation penetrates the subcutaneous tissue, the intensity of electrical stimulation may vary depending on the subcutaneous tissue thickness. Subjects performed a maximal voluntary isometric contraction (MVIC) of the quadriceps with the knee at 90 degrees . Once the MVIC reached a plateau, an electrical stimulation was manually delivered to the quadriceps. Quadriceps CAR was quantified using the equation: CAR=MVIC/MVIC+SIB torque. Quadriceps subcutaneous thickness was measured using ultrasound imaging and skinfolder pinch calipers. CAR values were estimated at 0.95 +/- 0.04 for dominant and 0.93 +/- 0.05 for non dominant limbs. Pearson's correlation coefficient revealed that there were negative correlations for quadriceps torque output (Nm/kg) and subcutaneous tissue thickness measured by ultrasound imaging (dominant: r=-0.54, p<0.001; non dominant: r=-0.53, p<0.001). We found no relationship between CAR and subcutaneous tissue thickness. A CAR of 0.95 may be considered full activation in healthy young adults, and CAR in healthy adults generated by the SIB technique may not be dependent on subcutaneous thickness. PMID- 20947374 TI - Safety of the novel protease-activated receptor-1 antagonist vorapaxar in Japanese patients with a history of ischemic stroke. AB - BACKGROUND: Vorapaxar, formerly SCH 530348, is a novel, orally active, potent thrombin receptor inhibitor selective for the protease-activated receptor-1 (PAR 1). Previous phase II studies of patients undergoing urgent or scheduled percutaneous coronary intervention treated with vorapaxar plus aspirin and clopidogrel or ticlopidine showed a trend toward reducing major adverse cardiac events, particularly myocardial infarction, without increasing bleeding risk. The present study evaluated the safety of vorapaxar in Japanese patients with a history of ischemic stroke receiving aspirin. METHODS: Ninety patients with previous ischemic stroke (>=14 days to <1 year before randomization) were randomized to receive vorapaxar (1 or 2.5 mg) or placebo once daily for 60 days. All patients received aspirin (75-150 mg/day). The primary endpoint was overall incidence of adverse events during the protocol-defined treatment phase (60 days). RESULTS: Addition of vorapaxar to aspirin did not significantly increase the overall incidence of adverse events, including serious adverse events. None of the patients treated with vorapaxar plus aspirin experienced thrombolysis in myocardial infarction major or minor bleeding versus 1 patient treated with placebo. Nonfatal stroke occurred in 1 patient allocated to placebo and 1 patient allocated to vorapaxar. CONCLUSIONS: Vorapaxar used in combination with standard doses of aspirin was safe and well tolerated in Japanese subjects with a history of ischemic stroke. PMID- 20947375 TI - Clinical features and neurologic severity in stroke patients with mild to moderate renal dysfunction. AB - BACKGROUND: To evaluate the independent effect of moderate renal dysfunction on stroke severity and to disclose the clinical features of stroke patients with moderate renal dysfunction. METHODS: We studied consecutive stroke patients presenting within 48 hours of onset. The National Institutes of Health Stroke Scale (NIHSS) score at the time of presentation was used as an index of stroke severity. Patients were categorized into 2 groups based on their estimated glomerular filtration rates (eGFRs). RESULTS: Of the 475 patients with an eGFR >15 mL per minute per 1.73 m(2), 158 patients (33.3%) had an eGFR <60 mL per minute per 1.73 m(2). These patients were older and included significantly more cases with hypertension and atrial fibrillation. The NIHSS score at the time of admission was higher among the patients with renal dysfunction. In a multivariable model with adjustments for other clinical background factors, moderate renal dysfunction was an independent predictor of the neurologic severity of stroke at the time of admission (odds ratio, 1.261; 95% confidence interval, 1.032-1.545; P = .0244). CONCLUSIONS: Stroke patients with moderate renal dysfunction had a higher prevalence of hypertension and atrial fibrillation. Moderate renal dysfunction was associated with a higher severity of stroke on admission. PMID- 20947376 TI - Surgical treatment of a sylvian-middle fossa dural arteriovenous fistula draining into the basal vein of rosenthal with frontotemporal craniotomy. AB - A 61-year-old man presented with left lower quadrianopsia caused by cerebral infarction in the right occpital lobe. Cerebral angiography revealed occlusion of right transverse sinus and Sylvian-middle fossa dural arteriovenous fistula (d AVF) draining into the Sylvian vein and dilation of basal vein of Rosenthal. Surgical operation with right frontotemporal craniotomy was carried out to obliterate the fistula point and resection of the dura mater containing vasculature networks. Histologically, the thickening of walls of dural arteries and veins lacking internal elastica lamina were observed. Interestingly, the dura mater involving d-AVF was hyalinized and lacked collagen fibers, resembling local hypoxia and suggesting the possible role of dural hypoxia with pathogenesis of d AVF. The present case indicates that open surgery can be effective for Sylvian middle fossa d-AVF for the purpose of obliteration of fistula point and resection of the dura for histopathologic analyses. PMID- 20947377 TI - Elevated anti-heat shock protein 60 antibody titer is related to white matter hyperintensities. AB - BACKGROUND: There are many reports that the antibody against heat shock protein 60 (Hsp60) is present in most patients with coronary artery disease and atherosclerosis, and that its titer correlates with disease severity. However, few reports have described the association between anti-Hsp60 antibody and cerebrovascular disease. METHODS: We determined the anti-Hsp60 antibody titer in patients with neurologic diseases and healthy subjects using enzyme-linked immunosorbent assay (ELISA) and evaluated their findings of brain magnetic resonance imaging (MRI) of the white matter. White matter hyperintensities (WMHs) on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images were classified into 2 categories: periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH). The lesions in each category were then divided into 4 grades (grades 0-3) according to the Fazekas rating scale. RESULTS: There were no significant differences in the titer between patients with neurologic diseases and healthy subjects. The mean grade of DWMHs (mean +/- SD, 1.56 +/- 0.70) was significantly higher in 18 subjects in the high-titer group (>=39.8 ng/mL; mean titer + 2 SD in sera from 23 healthy subjects) than in 86 subjects (mean +/- SD, 0.09 +/- 0.76) in the normal-titer group (<39.8 ng/mL; P < .003). The mean grade of PVHs (mean +/- SD, 1.50 +/- 0.71) was also significantly higher in the high titer group than in the normal-titer group (mean +/- SD, 1.17 +/- 0.62; P < .02). CONCLUSIONS: A significant correlation was noted between anti-Hsp60 antibody titer and the severity of WMHs on brain MR images. We suggest that an elevated titer of the anti-Hsp60 antibody could be a risk factor for cerebral small-vessel disease. PMID- 20947378 TI - Delayed catastrophic intracerebral hemorrhage preceded by progressive recovery after carotid stenting for acute ischemic stroke. AB - BACKGROUND: Hemorrhagic transformation (HT) is a feared complication of reperfusion therapy for treatment of acute ischemic stroke. Generally, HT occurs within 24-36 hours after thrombolysis. SUMMARY OF CASE: We present a case of a fatal symptomatic HT of an infarction that occurred 7 days after acute ischemic stroke which was preceded by a remarkable recovery following a combination of acute revascularization therapies. CONCLUSION: Fatal symptomatic HT is a rare potential complication that can occur after several days of treatment of acute ischemic stroke. PMID- 20947379 TI - Contemporary fluid management in cardiac anesthesia. PMID- 20947380 TI - Propofol inhibits desflurane-induced preconditioning in rabbits. AB - OBJECTIVES: The authors tested the hypothesis that ischemic and desflurane induced preconditioning are blocked by propofol. DESIGN: A prospective, randomized, vehicle-controlled study. SETTING: A university research laboratory. SUBJECTS: New Zealand white rabbits (n = 52). METHODS: Pentobarbital-anesthetized rabbits were subjected to 30 minutes of coronary artery occlusion followed by 3 hours of reperfusion. Rabbits received 0.0 (control) or 1.0 minimum alveolar concentration of desflurane (30 minutes' duration and a 30-minute memory period) or ischemic preconditioning (5 minutes of ischemia and a 30-minute memory period) in the absence or presence of propofol (10 mg/kg/h intravenously) or its vehicle (10% Intralipid emulsion; B Braun, Melsungen, Germany). The myocardial infarct size was measured with triphenyltetrazolium staining. Statistical analysis was performed with 1-way and 2-way analysis of variance when appropriate, followed by a post hoc Duncan test. Data are mean +/- standard deviation. RESULTS: Myocardial infarct size was 56% +/- 8% in control animals (n = 7). Desflurane significantly (p < 0.05) reduced the infarct size to 37% +/- 6% (n = 7). Desflurane-induced preconditioning was blocked by propofol (65% +/- 10%, n = 7) but not by its vehicle (45% +/- 11%, n = 5). Propofol and its vehicle alone had no effect on the infarct size (62% +/- 8% [n = 6] and 58% +/- 3% [n=5], respectively). Ischemic preconditioning reduced infarct size in the absence or presence of propofol to 24% +/- 7% (n = 7) and 29% +/- 12% (n = 6). CONCLUSION: Desflurane-induced preconditioning markedly reduced infarct size and was blocked by propofol, whereas ischemic preconditioning was not blocked by propofol. The results suggest an important interference between propofol and anesthetic-induced preconditioning and might explain some contradictory findings in studies in humans. PMID- 20947381 TI - Simultaneous delivery of inhaled prostacyclin and milrinone through a double nebulizer system. PMID- 20947382 TI - Thoracic epidural analgesia with levobupivacaine for 6 postoperative days attenuates sympathetic activation after thoracic surgery. AB - OBJECTIVE: To investigate the impact of 2 postoperative analgesic regimens on heart rate variability in patients who underwent thoracotomy. DESIGN: A prospective, randomized trial. SETTING: A single-institutional study in a university hospital. PARTICIPANTS: Fifty patients who underwent thoracotomy under combined general anesthesia and thoracic epidural analgesia divided by a number generator into 2 equal groups (A and B). INTERVENTIONS: In group A, postoperative analgesia consisted of thoracic epidural analgesia with levobupivacaine for 6 postoperative days. In group B, on the 3rd postoperative day this regimen was changed to patient-controlled intravenous morphine. Heart rate variability recordings were performed on the day before surgery, after the epidural, after operation, and on every postoperative day. Statistical analysis used chi-square and Student t tests (Bonferroni correction). MEASUREMENTS AND MAIN RESULTS: In both groups, the low-frequency component of the analyzed recordings declined after epidural and after surgery. In group A, the low-frequency component was significantly lower compared with baseline from the 2nd postoperative day onward, whereas in group B it was significantly higher compared with A on the 4th and 6th postoperative days. In both groups, the changes in high frequency were statistically insignificant. Intergroup comparisons of the low-/high-frequency ratio showed statistical difference on the last day of observation. There was no difference between the groups in hemodynamic variables and visual analog scale/10 scores. CONCLUSIONS: Postoperatively decreased cardiac sympathetic outflow continues with epidural analgesia, whereas it is abolished by the change to intravenous patient-controlled morphine. PMID- 20947383 TI - Pharmacokinetics and pharmacodynamics of rivaroxaban and its effect on biomarkers of hypercoagulability in patients with chronic heart failure. AB - BACKGROUND: Heart failure (HF) is associated with a hypercoagulable state that predisposes to thromboembolism and anti-coagulation may improve clinical outcomes. The oral, direct Factor Xa inhibitor, rivaroxaban, has not been studied in patients with HF. We hypothesized that rivaroxaban would also reduce biomarkers of hypercoagulability in patients with HF. METHODS: This study consisted of two cohorts: Cohort 1, open-label, actively controlled with enoxaparin 40 mg once daily, included 8 patients with acute decompensated HF; Cohort 2, double-blind and placebo-controlled, included 18 patients with stable, severe New York Heart Association Class III/IV HF. RESULTS: The pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban were similar across both cohorts. Biomarker assessments were performed in Cohort 2; prothrombin fragment 1.2 (F1.2) mean concentration decreased by 2.7 ng/ml over 7 days with rivaroxaban, and increased by 11.6 ng/ml with placebo, an absolute difference of 14.3 ng/ml (p = 0.0009). A non-significant reduction in rate of increase of D-dimer (DD) and thrombin-anti-thrombin complex (TAT) levels with rivaroxaban was observed over 7 days (p = 0.31 and p = 0.77, respectively). CONCLUSION: Rivaroxaban has similar PK/PD in patients with either acute or chronic HF. In vivo, hypercoagulability biomarkers appear to increase over time. Rivaroxaban reversed this trend for F1.2, and may reduce the rate of increase of DD and TAT in patients with stable, severe HF. PMID- 20947384 TI - Increased risk of venous thromboembolism with a sirolimus-based immunosuppression regimen in lung transplantation. AB - BACKGROUND: Sirolimus (rapamycin) is a potent anti-proliferative agent with immunosuppressive properties that is increasingly being used in solid-organ and hematopoietic stem cell transplantation. In addition, this drug is being investigated for treatment of a broad range of disorders, including cardiovascular disease, malignancies, tuberous sclerosis, and lymphangeioleiomyomatosis. In this study, we found an increased risk of venous thromboembolism (VTE) in lung transplant recipients treated with a sirolimus (SIR)-based immunosuppressive regimen. METHODS: One hundred eighty-one lung transplant recipients were enrolled in a prospective, multicenter, randomized, open-label trial comparing a tacrolimus (TAC)/SIR/prednisone immunosuppression regimen with a TAC/azathioprine (AZA)/prednisone immunosuppressive regimen. The differences in rates of VTE were examined. RESULTS: There was a significantly higher occurrence of VTE in the SIR cohort [15 of 87 (17.2%)] compared with the AZA cohort [3 of 94 (3.2%)] (stratified log-rank statistic = 7.44, p < 0.01). When adjusted for pre-transplant diagnosis and stratified by transplant center, this difference remained essentially unchanged (hazard ratio for SIR vs AZA = 5.2, 95% confidence interval 1.4 to 19.5, p = 0.01). CONCLUSION: Clinicians prescribing SIR should maintain a high level of vigilance for VTE, particularly among patients with other risk factors for this complication. PMID- 20947385 TI - PRP-paradigm provides evidence for a perceptual origin of the negative compatibility effect. AB - Visual stimuli (primes) that are made invisible by masking can affect motor responses to a subsequent target stimulus. When a prime is followed by a mask which is followed by a target stimulus, an inverse priming effect (or negative compatibility effect) has been found: Responses are slow and frequently incorrect when prime and target stimuli are congruent, but fast and accurate when prime and target stimuli are incongruent. To functionally localize the origins of inverse priming effects, we applied the psychological refractory period (PRP-) paradigm which distinguishes a perceptual level, a central bottleneck, and a level of motor execution. Two dual-task experiments were run with the PRP-paradigm to localize the inverse priming effect relative to the central bottleneck. Together, results of the Effect-Absorption and the Effect-Propagation Procedure suggest that inverse priming effects are generated by perceptual mechanisms. We suggest two perceptual mechanisms as the source of inverse priming effects. PMID- 20947386 TI - Measuring small airways in transverse CT images correction for partial volume averaging and airway tilt. AB - RATIONALE AND OBJECTIVES: Airway wall dimensions can be determined in vivo using transverse computed tomographic (CT) images, but the measurement of airway phantoms shows that the wall thickness is consistently overestimated for small airways. This phantom study was performed to derive and test corrections to the measurements on the basis of consideration of partial volume averaging and tilt effects. MATERIALS AND METHODS: A lung phantom with six polycarbonate tubes embedded in foam was scanned, and the cross-sectional dimensions of the tubes were determined using the full width at half maximum, zero crossing, and phase congruency edge detection methods. Equations were derived using the reported wall intensity to correct for partial volume averaging. Corrections for the overestimation of the wall thickness due to the tilt of the tube with respect to the CT z-axis were also derived. RESULTS: All three methods (full width at half maximum, zero crossing, and phase congruency) overestimated the wall thickness of the small polycarbonate tubes. It was verified that two sources of error were partial volume averaging and tilt that was introduced when the phantom was positioned with tube axes at an angle to the CT z-axis. The corrections were applied to the measured tube wall dimensions and substantially reduced the deviation of the CT measurements from the true values. CONCLUSIONS: Correcting for partial volume effects and airway tilt greatly increases the accuracy of simulated airway wall measurements in transverse CT images. PMID- 20947387 TI - Effects of contrast agent on water suppression and shimming of kidney single volume proton MR spectroscopy at 3.0T. AB - RATIONALE AND OBJECTIVES: The aim of this study was to determine whether the administration of gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA) significantly affects shimming and water suppression on kidney magnetic resonance spectroscopic prescanning and whether the impact of shimming and water suppression is changed with time after intravenous administration on a 3.0-T system. METHODS: Forty patients (two patients were excluded from analysis because of motion) were examined before and after the administration of Gd-DTPA (the interval between the right and left kidneys was approximately 40 seconds). Regions of interest were carefully positioned in the region of the corresponding location of both kidneys separately. Line widths (full width at half maximum) and water suppression were obtained. A paired t test for comparison of means was used. In addition, repeat measurements with a shorter time interval (obtained 120 130 seconds after the injection) and a longer time interval (obtained 150-160 seconds after the injection) were performed in five patients in the same regions of interest of the right kidney. Sequential 1H magnetic resonance spectroscopic prescanning in the same region of interest was performed in one patient. RESULTS: The left kidney had slightly better shimming and water suppression effects than the right kidney after contrast agent administration (all P values < .01). The limiting resolution of both shimming and water suppression effects was decreased on enhanced images in both kidneys (all P values < .01). The longer time interval group had better shimming and water suppression effects than the shorter time interval group (all P values < .01). After the administration of Gd-DTPA in one patient, sequential values of shimming and water suppression in the right and left kidneys, respectively, were 13 Hz and 97% and 12 Hz and 97% prior to the examination, 34 Hz and 86% and 30 Hz and 88% at 5 minutes, 32 Hz and 89% and 27 Hz and 90% at 10 minutes, 28 Hz and 91% and 24 Hz and 91% at 15 minutes, and 24 Hz and 92% and 20 Hz and 92% at 25 minutes. CONCLUSIONS: Gd-DTPA exerts adverse effects on water suppression and shimming, both of which show a trend of becoming well gradually with time extension after the injection of Gd-DTPA. This phenomenon limits the diagnostic use of kidney magnetic resonance spectroscopy performed immediately after contrast-enhanced magnetic resonance imaging. PMID- 20947388 TI - Peripheral MRA with k-space segmentation and blood-pool contrast agent. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to perform high resolution contrast-enhanced peripheral multistation magnetic resonance angiography using a new blood-pool contrast agent (gadofosveset trisodium; Vasovist) while suppressing venous signal by using an acquisition scheme with k space segmentation. MATERIALS AND METHODS: Multistation peripheral magnetic resonance angiography with Vasovist was performed in 20 patients with known peripheral arterial occlusive disease. The k-space of the three-dimensional data sets was segmented such that the central parts were acquired during the first pass of the blood-pool agent, while the peripheral parts were acquired in the steady state. A third magnetic resonance angiographic data set acquired using the conventional technique served as comparison for venous overlay. Two radiologists blindly compared vessel sharpness, conspicuity, and venous contamination. Furthermore, a semiautomatic program to compare edge sharpness was used. Results were compared by means of Wilcoxon's signed rank sum test. RESULTS: Comparison of vessel sharpness revealed statistically significant differences in favor of the fused data sets in all three stations. Arteries were depicted more sharply in the fused images and over longer parts, while veins were almost completely suppressed. CONCLUSIONS: Peripheral contrast-enhanced magnetic resonance angiography with first-pass and steady-state k-space segmentation using a blood pool contrast agent proved feasible and provided high-resolution data with sharp delineation of the arteries while reducing venous contamination. PMID- 20947389 TI - The relationship between small pulmonary vascular alteration and aortic atherosclerosis in chronic obstructive pulmonary disease: quantitative CT analysis. AB - RATIONALE AND OBJECTIVES: The relationship between chronic obstructive pulmonary disease (COPD) and atherosclerosis has been suggested; this association may relate to systemic inflammation and endothelial dysfunction, which can lead to alteration of small pulmonary vessels. The relationship between atherosclerosis and small pulmonary vessel alteration, however, has not been assessed in COPD patients. We tested the hypothesis that the severity of thoracic aortic calcification measured by computed tomography (CT) would be associated with the total cross-sectional area of small pulmonary vessels (CSA) on CT images. MATERIALS AND METHODS: The study was approved by the institutional review board and was Health Insurance Portability and Accountability Act-compliant. Informed consent was waived. For 51 COPD patients enrolled in the National Heart, Lung, and Blood Institute Lung Tissue Research Consortium, we calculated the percentage of total CSAs of less than 5 mm2 for the total lung area (%CSA<5). Thoracic aortic calcification, quantified by modified Agatston score, was measured. The correlations between thoracic aortic calcification score and %CSA<5, pulmonary function, and extent of emphysema were evaluated. Multiple linear regression analysis using aortic calcification score as the dependent outcome was also performed. RESULTS: The %CSA<5 had a significant negative correlation with the thoracic aortic calcification score (r = -0.566, P < .0001). Multiple linear regression analysis showed significant correlation between the aortic calcification score and %CSA<5 (P < .0001) independent of age, pack-years, extent of emphysema, and FEV1%. CONCLUSIONS: Atherosclerosis, assessed by aortic calcification, is associated with the small pulmonary vascular alteration in COPD. Systemic inflammation and endothelial dysfunction may cause the close relationship between atherosclerosis and small pulmonary vessel alteration. PMID- 20947391 TI - Estimation of the ischemic penumbra based on CT perfusion a pilot study. AB - RATIONALE AND OBJECTIVES: Ischemic penumbra (IP), the target of thrombolytic therapies, could be estimated by the mismatch region between magnetic resonance imaging (MRI) diffusion- and perfusion-defined abnormalities; however, the accuracy of this method has been challenged recently. In this study, we try to establish a method for calculating IP size based on computed tomography perfusion (CTP) and to observe the early evolution of IP in detail. MATERIALS AND METHODS: The middle cerebral artery occlusion (MCAO) model in monkey was used to compare the accuracy in estimating the IP between CTP and MRI methods. A receiver operating characteristic (ROC) curve was performed to calculate the IP threshold of the different CTP parameters, and then the best parameter was obtained. The dynamic evolutions of estimated size of IP by these two methods were compared. RESULTS: Among the three CTP parameters, relative cerebral blood flow (rCBF) had the highest sensitivity (83.3%) and specificity (98.5%) in estimating the IP. The optimal cutoff threshold of rCBF was 0.203. During the first 15 hours of the MCAO model, the estimated size of IP by the rCBF was larger than that of the MRI method; however, this relationship was reversed 15 hours later. CONCLUSION: This study suggests that the rCBF method is more accurate in estimating the IP since previous studies have reported that the MRI method underestimated the exact IP in the early stage of ischemia and overestimated the exact IP in the later stages. Further experimental and clinical studies are needed to validate the conclusion. PMID- 20947390 TI - Increased epicardial, pericardial, and subcutaneous adipose tissue is associated with the presence and severity of coronary artery calcium. AB - RATIONALE AND OBJECTIVES: Epicardial adipose tissue (EAT), pericardial adipose tissue (PAT), and subcutaneous adipose tissue (SAT) are mediators of metabolic risk and may be involved in the pathogenesis of coronary artery disease. The aim of this study was to investigate the association of visceral and subcutaneous fat depots with the presence and severity of coronary artery calcium (CAC) in asymptomatic individuals. MATERIALS AND METHODS: One hundred eleven consecutive subjects underwent CAC assessment, and their Framingham risk scores were measured. EAT, total thoracic adipose tissue, and SAT volumes were measured from slice level 15 mm above to 30 mm below the ostium of the left main coronary artery. PAT was calculated as thoracic adipose tissue - EAT. SAT was defined as the volume of fat depot anterior to the sternum and posterior to the vertebra. CAC was defined as 0, 1 to 100, 101 to 400, or >= 400. Relative risk regression analysis was used to assess the association between fat depots and CAC. RESULTS: There were modest correlations between EAT (r = 0.58), PAT (r = 0.47), SAT (r = 0.34), and CAC (P < .01). EAT, PAT, and SAT increased proportionally with the severity of CAC in both genders (P < .05). After adjustment for cardiovascular risk factors and body mass index, the relative risks for each standard deviation increase in EAT, PAT, and SAT were 3.3 (95% confidence interval, 1.9-5.6), 2.7 (95% confidence interval, 1.6-3.9), and 2.6 (95% confidence interval, 1.5-4.4) for CAC >= 100 compared to CAC 0, respectively (P < .05). The area under the receiver-operating characteristic curve to predict CAC >= 100 was higher in each fat depot compared to Framingham risk score, and addition of fat depots to Framingham risk score provided maximum prognostication value to detect CAC >= 100. CONCLUSIONS: Increased EAT, PAT, and SAT are associated with the severity of CAC independent of risk factors. PMID- 20947392 TI - Good long term patency rates associated with an alternative technique in vascular access surgery--the adductor loop arteriovenous graft. AB - INTRODUCTION: We have modified the arteriovenous groin loop procedure and present a technique associated with good patency rates and low infection rates. METHODS: We describe an alternative femoro-femoral arteriovenous loop technique which utilises the mid-thigh sub-sartorial Superficial Femoral Artery and Femoral Vein. We then performed a retrospective analysis of all such cases performed in our unit to date and analysed the patency and infection rates associated with the technique. RESULTS: 16 cases have been performed to date with a median follow-up of 18 months. The primary and secondary patency rates at one year were 70% and 90% respectively. The overall infection rate was only 12.5%. CONCLUSIONS: Our technique is associated with good patency rates and low infection rates. In addition it preserves modesty whilst on dialysis and the groin vessels for further vascular access surgery if needed. PMID- 20947393 TI - Expression of HER-2 and nuclear localization of HER-3 protein in canine mammary tumors: histopathological and immunohistochemical study. AB - HER-2 and HER-3 are transmembrane receptor proteins that are considered to be important but poorly understood biomarkers in canine tumors. In this study, the expression and the localization of HER-2 and HER-3 were evaluated immunohistochemically in canine mammary tumors (n=64; 12 benign, 52 malignant). HER-2 overexpression was identified in 2/12 (16.7%) benign and in 18/51 (35.3%) malignant cases. HER-3 was expressed in a non-nuclear localization in 11/12 (91.7%) benign and 18/52 (34.6%) malignant tumors. In contrast, HER-3 was expressed in the nucleus of neoplastic cells in 0/12 (0%) benign and 22/52 (42.3%) malignant tumors. Nuclear HER-3 expression was higher in neoplastic epithelial cells compared to myoepithelial cells, and positively correlated with high histological grade and lymphatic vessel invasion. These results suggest that nuclear HER-3 expression is significantly associated with tumor progression and metastasis and may serve as a useful prognostic biomarker in canine malignant mammary tumors. PMID- 20947394 TI - Early detection of bovine respiratory disease in young bulls using reticulo-rumen temperature boluses. AB - The use of reticulo-rumen temperature boluses to detect bovine respiratory disease (BRD) was investigated in young bulls following their entry into a fattening unit. Twenty-four bulls received a bolus at entry and were observed for 40 days. As soon as a reticulo-rumen hyperthermia (RH) episode was detected using the bolus, clinical examination was performed by a veterinarian and then repeated every 12-24h until the end of RH episode. Fifty-two RH episodes were detected in 22 animals. High rectal temperatures (40.1+/-0.6 degrees C) were observed during these episodes. BRD was diagnosed on the basis of clinical examination during 38/52 RH episodes in 21 animals (positive predictive value 73%). The onset of BRD signs always occurred after the onset of RH episodes, with a time-lag from 12 to 136 h, depending on BRD signs. Monitoring reticulo-rumen temperature permits early detection of BRD; however, clinical examination is required to confirm BRD. PMID- 20947395 TI - The effect of contrast-enhanced ultrasound on the kidneys in eight cats. AB - Contrast-enhanced ultrasound (CEUS) of the left kidney was performed on eight non anesthetized, young, purpose bred, domestic shorthaired cats. Each cat underwent a physical examination before and 4h and 48h after CEUS. Complete blood count (CBC), serum biochemical analysis, urinalysis, including evaluation of the enzymatic activities of urinary N-acetyl-beta-d-glucosaminidase (NAG) and gamma glutamyl transferase (GGT), were also performed. No changes were observed in CBC or serum biochemical analyses, with the exception of a decrease in blood urea concentration at 48h post-contrast ultrasound. A small elevation in NAG (U/g creatinine) was observed with a mean (SD) increase from 0.53 (0.35) to 1.43 (0.59) U/g creatinine. The magnitude of the rise was less than the circadian variation reported earlier for healthy cats. These results suggest that CEUS can be safely used to assess kidney perfusion in cats. The changes observed in laboratory values after CEUS did not appear to be related to detrimental effects on the kidneys. PMID- 20947396 TI - Intra-articular drug delivery: the challenge to extend drug residence time within the joint. AB - The rationale behind developing sustained release microsphere formulations of non steroidal anti-inflammatory drugs (NSAIDs) administered via the intra-articular (IA) route is to minimise the systemic bioavailability and attendant side-effects associated with oral drug administration. Overall dose is reduced whilst therapeutic benefit within the joint is maintained. The potential benefits of IA therapy for osteoarthritis (OA) are not achieved using currently available medications and delivery vehicles due to the rapid clearance of therapeutic substances from the synovial space. There is a need for sustained release delivery systems if the potential of IA drug administration is to be realised. Rationally designed microspheres taken up by synovial macrophages offer a strategy to sustain drug delivery within the joint, and to deliver NSAIDs directly to pivotal inflammatory cells. The efficacy of microsphere candidates may be evaluated in large animal models of OA. The principles of IA microsphere drug delivery may also be applicable to other classes of drugs. PMID- 20947397 TI - MRI of the central nervous system in MS patients with and without pain. AB - BACKGROUND: Central pain (CP) is a common symptom in MS. Multiple theories are present about the mechanism of CP. Previous studies suggested that lesion of the spinothalamic tract is a necessary condition for development of CP. No previous study has in detail evaluated the association between the specific site of demyelinations and the presence of CP in MS. OBJECTIVE: The study aimed to evaluate the location of plaques in MS patients with CP including a group of MS patients without pain as a reference group. METHODS: All patients underwent a bedside sensory examination and MRI of the brain and spinal cord. MR imaging was acquired on an 1.5 Tesla MR equipment. A trained neuroradiologist, blinded to pain status, evaluated the MRI. RESULTS: Thirteen MS patients with CP and 10 MS patients without pain were included. Allodynia and/or dysesthesia were more frequent in pain patients (11/13 vs. 1/10, P<0.01). No difference was found in the number of patients with plaques in spinothalamic tract, dorsal column-medial lemniscus, dorsolateral funiculus, grey substance, thalamus or capsula interna. A non-significantly lower number of pain patients had lesions in thalamo-cortical pathways (8/13 vs. 10/10, P=0.027). CONCLUSIONS: No association between CP and site of demyelinations was found, although a trend toward a higher prevalence of intact thalamo-cortical pathways was seen in pain patients. CP was associated with allodynia, suggesting central hyperexcitability. PMID- 20947398 TI - Altered nociceptive C fibre input to primary somatosensory cortex in an animal model of hyperalgesia. AB - Evaluating potentially analgesic effects of drugs and various treatments is critically dependent on valid animal models of pain. Since primary somatosensory (SI) cortex is likely to play an important role in processing sensory aspects of pain, we here assess whether monitoring SI cortex nociceptive C fibre evoked potentials can provide useful information about central changes related to hyperalgesia in rats. Recordings of tactile and CO(2)-laser C fibre evoked potentials (LCEPs) in forelimb and hind limb SI cortex were made 20-24h after UV B irradiation of the heel at a dose that produced behavioural signs of hyperalgesia. LCEPs from irradiated skin increased significantly in duration but showed no significant change in magnitude, measured as area under curve (AUC). By contrast, LCEPs in hind limb SI cortex from skin sites nearby the irradiated skin showed no increase in duration or onset latency but increased significantly in magnitude after UV-B irradiation. The LCEPs in forelimb or hind limb SI cortex elicited from forelimb skin did not change in magnitude, but were significantly delayed in hind limb SI cortex. Tramadol, a centrally acting analgesic known to reduce hyperalgesia, induced changes that counteracted the changes produced by UV B irradiation on transmission to SI cortex from the hind paw, but had no significant effect on time course of LCEPs from forelimb skin. Tactile evoked potentials were not affected by UV-B irradiation or tramadol. We conclude that altered sensory processing related to hyperalgesia is reflected in altered LCEPs in SI cortex. PMID- 20947399 TI - Driving functions in a video simulator in chronic non-malignant pain patients using and not using codeine. AB - BACKGROUND AND AIMS: A considerable number of Europeans suffer from chronic pain and are using opioids, particularly of the weak type. It is a clinical impression that many of these are driving or wish to drive a car. The aims of this study were to investigate if codeine influences driving ability in a simulator, and to examine if chronic pain per se might impair such functions. METHODS: Twenty patients with chronic pain on long-term codeine therapy were compared to 20 chronic pain patients not using codeine in a video driving simulator test. The chronic pain patients were then compared to 20 healthy controls. The primary outcome measures were reaction time and number of missed reactions. RESULTS: The patients using codeine 120-270 mg (mean 180 mg) daily showed the same driving skills as patients not using codeine, and the codeine level did not affect the results. This was the case both 1h after intake of a single dose of 60 mg codeine and five or more hours after the last codeine intake. The reaction times were significantly slower for the chronic pain patients, in both rural and urban driving conditions, compared to the healthy controls (difference 0.11s. and 0.12s., respectively). The chronic pain patients missed almost twice as many reactions to traffic signs. There were no difference between the groups in steering precision. CONCLUSION: The main finding in this simulator study was that codeine does not impair driving-related abilities over and above what is associated with chronic pain per se. PMID- 20947400 TI - Hemoglobin precipitation greatly improves 4-methylumbelliferone-based diagnostic assays for lysosomal storage diseases in dried blood spots. AB - Derivatives of 4-methylumbelliferone (4MU) are favorite substrates for the measurement of lysosomal enzyme activities in a wide variety of cell and tissue specimens. Hydrolysis of these artificial substrates at acidic pH leads to the formation of 4-methylumbelliferone, which is highly fluorescent at a pH above 10. When used for the assay of enzyme activities in dried blood spots the light emission signal can be very low due to the small sample size so that the patient and control ranges are not widely separated. We have investigated the hypothesis that quenching of the fluorescence by hemoglobin leads to appreciable loss of signal and we show that the precipitation of hemoglobin with trichloroacetic acid prior to the measurement of 4-methylumbelliferone increases the height of the output signal up to eight fold. The modified method provides a clear separation of patients' and controls' ranges for ten different lysosomal enzyme assays in dried blood spots, and approaches the conventional leukocyte assays in outcome quality. PMID- 20947401 TI - Androgen receptor htSNPs in relation to androgen levels and OC use in young women from high-risk breast cancer families. AB - High testosterone levels have been associated with breast cancer. BRCA1 may function as an androgen receptor (AR) co-regulator. We aimed to examine AR haplotype-tagging single-nucleotide polymorphisms (AR htSNPs) and diplotypes in relation to in vivo androgen levels, combined OC use, CAG and GGC genotypes, and BRCA1/2/X family status in 269 young healthy women from breast cancer high-risk families and 56 additional BRCA1/2 mutation carriers. Testosterone, androstenedione, dehydroepiandrosterone sulfate, and body constitution were measured on cycle days 18-23. Six AR htSNPs and CAG and GGC repeat lengths were genotyped. Most OC users had lower androgen levels than non-users (all Ps<0.0001). Rare variant diplotypes were associated with higher testosterone levels in OC users than in non-users (P(interaction)=0.011). The interaction remained after adjustment for family clustering. Neither individual AR htSNPs nor other diplotypes were significantly associated with androgen levels and did not tag for CAG or GGC genotypes. In the first included woman from each family, the odds of having the most common diplotype was lower in BRCA1 families compared to other families OR 0.41 (95% CI 0.22-0.78). In conclusion, we found few associations between AR htSNPs or diplotypes and androgen levels in women. Diplotypes cannot replace genotyping of microsatellites CAG or GGC. Since testosterone levels are not affected the same way by combined OC use among all women, young women who have higher testosterone levels during combined OC use may belong to the subgroup of women who will not be helped by combined OCs for treatment of androgen-dependent conditions and may be at higher risk for early onset breast cancer. Whether these women can be identified with AR genotyping needs to be confirmed in an independent cohort. PMID- 20947402 TI - Clinical trial for toxoplasmic lymphadenitis. PMID- 20947403 TI - Utility of human embryonic kidney cell line HEK-293 for rapid isolation of fixed and street rabies viruses: comparison with Neuro-2a and BHK-21 cell lines. AB - BACKGROUND: A confirmatory rabies diagnosis can be achieved by rapid virus isolation in cell culture using brain tissue from the suspect animal. Several cell lines have been used for this purpose and the murine neuroblastoma cell line Neuro-2a has been found to be the most sensitive. The human embryonic kidney cell line HEK-293 is known to express several neuronal proteins and is believed to be of neuronal origin. We hypothesized that this cell line could be susceptible to rabies virus, which is highly neurotropic. METHODS: First we tested the sensitivity of HEK-293 cells to the laboratory strain, challenge virus standard (CVS). We then tested 120 brain samples from different animals and humans suspected to have died of rabies by fluorescent antibody test (FAT). Both FAT positive and FAT-negative brains were tested for virus isolation using Neuro-2a, BHK-21, and HEK-293 cell lines and also by mouse inoculation. RESULTS: There was 100% correlation between FAT, virus isolation in Neuro-2a and HEK-293 cells, and mouse inoculation. However, the rate of virus isolation in the BHK-21 cell line was only 28% when compared to the other cell lines. The sensitivity of HEK-293 to CVS strain of virus was similar to that of Neuro-2a. CONCLUSIONS: We conclude that the HEK-293 cell line is as sensitive as the Neuro-2a cell line for the rapid isolation of rabies virus and may serve as an alternative cell line for rabies diagnosis and future research. PMID- 20947404 TI - Hypersensitivity pneumonitis due to high-dose colistin aerosol therapy. AB - We report a case of hypersensitivity pneumonitis, possibly due to aerosolized colistin therapy for severe multi-resistant Gram-negative pneumonia. Microbiological eradication was achieved with colistin therapy, which was stopped after 12 days in view of rising eosinophilia and possible lung fibrosis. The eosinophil count started to normalize 3 days after stopping colistin therapy and the patient was eventually weaned to minimal ventilatory support. PMID- 20947405 TI - How patients' attitudes and opinions influence self-care behaviours in type 2 diabetes. Insights from the French DIABASIS Survey. AB - AIM: This study evaluated the profiles of patients with type 2 diabetes (T2DM) to identify sets of opinions and attitudes towards the disease that might influence self-care behaviours. METHODS: Altogether, 1,092 patients with T2DM, aged 45 or older from a large representative French cohort, completed a self-questionnaire exploring their knowledge and perceptions of diabetes, its impact on various aspects of daily life and self-management practices. Canonical and cluster analyses were used to identify sets of homogeneous 'profiles' of patients linking attitudes and opinions to specific disease-related behaviours (such as changes in lifestyle, drug compliance, treatment satisfaction, impact on everyday life and weight gain). RESULTS: Demographics of the T2DM study population were previously reported along with the main results (60% male; mean age: 66 years; mean age at diagnosis: 55 years; mean BMI: 29kg/m(2)). Five distinct patient types emerged from the typological approach: 'committed' (25%); 'carefree' (23%); 'bitter' (19%); 'disheartened' (19%); and 'overwhelmed' (15%). Each patient type defined a set of attitudes and beliefs towards T2DM that influenced disease-related behaviours, leading to different degrees of diabetes self-management. CONCLUSION: The DIABASIS survey provides important information for diabetes care by identifying distinct patients' profiles that express different degrees of difficulty in implementing self-management. For this reason, patients in each category require different kinds of customized support from their physician to induce behavioural changes that may be key in improving their metabolic control. PMID- 20947406 TI - Spontaneous migration of a polymethylmethacrylate mass after vertebroplasty in osteoporotic lumbar compression fracture with avascular osteonecrosis: a case report. PMID- 20947407 TI - FATCO syndrome--fibular aplasia, tibial campomelia and oligosyndactyly. PMID- 20947408 TI - Bilateral pigmented villonodular synovitis of the knee. PMID- 20947409 TI - The effect of vessel material properties and pulsatile wall motion on the fixation of a proximal stent of an endovascular graft. AB - Migration is a serious failure mechanism associated with endovascular abdominal aortic aneurysm (AAA) repair (EVAR). The effect of vessel material properties and pulsatile wall motion on stent fixation has not been previously investigated. A proximal stent from a commercially available stent graft was implanted into the proximal neck of silicone rubber abdominal aortic aneurysm models of varying proximal neck stiffness (beta=25.39 and 20.44). The stent was then dislodged by placing distal force on the stent struts. The peak force to completely dislodge the stent was measured using a loadcell. Dislodgment was performed at ambient pressure with no flow (NF) and during pulsatile flow (PF) at pressures of 120/80 mmHg and 140/100 mmHg to determine if pulsatile wall motions affected the dislodgement force. An imaging analysis was performed at ambient pressure and at pressures of 120 mmHg and 140 mmHg to investigate diameter changes on the model due to the radial force of the stent and internal pressurisation. Stent displacement forces were ~50% higher in the stiffer model (7.16-8.4 N) than in the more compliant model (3.67-4.21 N). The mean displacement force was significantly reduced by 10.95-12.83% from the case of NF to the case of PF at 120/80 mmHg. A further increase in pressure to 140/120 mmHg had no significant effect on the displacement force. The imaging analysis showed that the diameter in the region of the stent was 0.37 mm greater in the less stiff model at all the pressures which could reduce the fixation of the stent. The results suggest that the fixation of passively fixated aortic stents could be comprised in more compliant walls and that pulsatile motions of the wall can reduce the maximum stent fixation. PMID- 20947411 TI - Apoptosis assays for quantifying the bioactivity of anticancer drug products. AB - The goal of cancer therapy is to kill cancer cells. Many anticancer drugs are designed to kill cells by inducing apoptosis. However, the potency assays used for measuring the bioactivity of these products are generally cell viability assays which do not distinguish between cell death and growth inhibition. There are a number of commercial assays available to measure apoptosis; however, many of these assays are not appropriate for use in high-throughput screening formats preferred by industry to measure drug activity, also known as potency, due to their inherent low robustness and/or high variability. This review outlines the strengths and weaknesses of current apoptosis assays and highlights new promising assay developments for evaluation of anticancer therapeutics, such as the design of fluorescent and luminescent constructs to be applied as caspase substrates. PMID- 20947410 TI - Interleukin-26: an IL-10-related cytokine produced by Th17 cells. AB - IL-26 is classified as a member of the IL-10 cytokine family because it has limited sequence homology to IL-10 and the IL-10-related cytokines. The human IL 26 gene, IL26, is located on chromosome 12q15 between the genes for two other important class-2 cytokines, IFNG (IFN-gamma) and IL22 (IL-22). IL-26 is often co expressed with IL-22 by activated T cells, especially Th17 cells. It signals through a heterodimeric receptor complex composed of the IL-20R1 and IL-10R2 chains. IL-26 receptors are primarily expressed on non-hematopoietic cell types, particularly epithelial cells. Signaling through IL-26 receptor complexes results in the activation of STAT1 and STAT3 with subsequent induction of IL-26 responsive genes. The biological functions of IL-26 have only begun to be defined. PMID- 20947412 TI - Re: use of Lugol's iodine in oral cancer diagnosis: an overview. PMID- 20947413 TI - Management of adult soft tissue sarcomas of the head and neck. AB - Adult soft tissue sarcoma of the head and neck are rare and represent a heterogeneous group of tumours of different histological variants. Management of these neoplasms presents a great challenge. Malignant fibrous histiocytoma, fibrosarcoma, angiosarcoma and malignant peripheral nerve sheath tumour are the most frequently found sarcoma types in the head and neck. Although traditional morphological assessment is the foundation of clinical decision making, the role of immunohistochemistry and molecular biology are useful for diagnosis, prognosis and identification of possible targets for molecular therapy. The most frequently involved tumour sites are scalp/face, sinonasal tract/anterior skull base and parotid/neck. The management of soft tissue sarcomas in the head and neck is primarily surgical. Since it is difficult to obtain wide margins during surgical treatment in head and neck sarcomas, because of anatomic constraints, most patients undergo post-operative irradiation. Survival varies from 50 to 80%. Prognostic factors are tumour grade, margin status and tumour size. With further insight into the biology of soft tissue sarcoma, modern imaging techniques and new treatment options, we will most certainly be able to improve clinical outcome in patients with soft tissue sarcoma in the upcoming years. PMID- 20947414 TI - Photophysical insights into supramolecular interaction of a designed bisporphyrin with fullerenes C60 and C70. AB - The present paper reports the photophysical investigations of a designed bisporphyrin (1), and its supramolecular complexes with C60 and C70 in toluene medium. UV-vis studies reveal appreciable ground state interaction between fullerenes and 1. The stoichiometry of the fullerene complexes of 1 is found to be 1:1. Steady state fluorescence studies elicit quenching of fluorescence of 1 in the presence of fullerenes. The binding constants of the C60/1 and C70/1 complexes are estimated to be 3760 and 31,222.5 dm3 mol(-1), respectively. Time resolved emission studies establish relatively long-lived charge separated state for the C70/1 complex. Molecular mechanics calculations in vacuo evoke the stereoscopic structures of the fullerene/1 complexes and interpret the stability difference between C60 and C70 complexes of 1 in terms of heat of formation values. PMID- 20947415 TI - The impact of electronic medical record systems on outpatient workflows: a longitudinal evaluation of its workflow effects. AB - CONTEXT: The promise of the electronic medical record (EMR) lies in its ability to reduce the costs of health care delivery and improve the overall quality of care--a promise that is realized through major changes in workflows within the health care organization. Yet little systematic information exists about the workflow effects of EMRs. Moreover, some of the research to-date points to reduced satisfaction among physicians after implementation of the EMR and increased time, i.e., negative workflow effects. A better understanding of the impact of the EMR on workflows is, hence, vital to understanding what the technology really does offer that is new and unique. OBJECTIVE: (i) To empirically develop a physician centric conceptual model of the workflow effects of EMRs; (ii) To use the model to understand the antecedents to the physicians' workflow expectation from the new EMR; (iii) To track physicians' satisfaction overtime, 3 months and 20 months after implementation of the EMR; (iv) To explore the impact of technology learning curves on physicians' reported satisfaction levels. DESIGN: The current research uses the mixed-method technique of concept mapping to empirically develop the conceptual model of an EMR's workflow effects. The model is then used within a controlled study to track physician expectations from a new EMR system as well as their assessments of the EMR's performance 3 months and 20 months after implementation. SETTING: The research tracks the actual implementation of a new EMR within the outpatient clinics of a large northeastern research hospital. PARTICIPANTS: The pre-implementation survey netted 20 physician responses; post-implementation Time 1 survey netted 22 responses, and Time 2 survey netted 26 physician responses. INTERVENTION: The implementation of the actual EMR served as the intervention. Since the study was conducted within the same setting and tracked a homogenous group of respondents, the overall study design ensured against extraneous influences on the results. MAIN OUTCOME MEASURES: Outcome measures were derived empirically from the conceptual model. They included 85 items that measured physician perceptions of the EMR's workflow effect on the following eight issues: (1) administration, (2) efficiency in patient processing, (3) basic clinical processes, (4) documentation of patient encounter, (5) economic challenges and reimbursement, (6) technical issues, (7) patient safety and care, and (8) communication and confidentiality. The items were used to track expectations prior to implementation and they served as retrospective measures of satisfaction with the EMR in post-implementation Time 1 and Time 2. RESULTS: The findings suggest that physicians conceptualize EMRs as an incremental extension of older computerized provider order entries (CPOEs) rather than as a new innovation. The EMRs major functional advantages are seen to be very similar to, if not the same as, those of CPOEs. Technology learning curves play a statistically significant though minor role in shaping physician perceptions. CONCLUSIONS: The physicians' expectations from the EMR are based on their prior beliefs rather than on a rational evaluation of the EMR's fit, functionality, or performance. Their decision regarding the usefulness of the EMR is made very early, within the first few months of use of the EMR. These early perceptions then remain stable and become the lens through which subsequent experience with the EMR is interpreted. The findings suggest a need for communication based interventions aimed at explaining the value, fit, and usefulness of EMRs to physicians early in the pre- and immediate post-EMR implementation stages. PMID- 20947416 TI - Long-term evaluation of patients with sustained virologic remission by highly sensitive HCV RNA assays: no evidence for viral persistence. PMID- 20947417 TI - A rapid and simple isothermal nucleic acid amplification test for detection of herpes simplex virus types 1 and 2. AB - BACKGROUND: A simple and rapid IsoAmp HSV assay has been developed for qualitative detection of herpes simplex virus (HSV) types 1 and 2 from genital lesions. Sample preparation involved a simple dilution step and the diluted specimens were directly added to the device and amplified by isothermal helicase dependent amplification (HDA). Amplification products were then detected by a DNA strip embedded in a disposable cassette without any instrument. The total test turn-around time is less than 1.5h from specimen processing to result reporting. OBJECTIVES: To evaluate the analytical and clinical performance of the IsoAmp HSV assay as well as the robustness and reproducibility of the assay. STUDY DESIGN: The analytical sensitivity of the IsoAmp HSV assay was determined using both HSV 1 and HSV-2. Clinical performance was evaluated using 135 frozen specimens collected from patients with suspected HSV infection in genital area. RESULTS: The analytical sensitivity of the assays was 5.5 and 34.1 copies/reaction for HSV 1 and HSV-2 respectively with a 95% confidence interval. When the herpes viral culture was used as the reference standard, the clinical sensitivity and specificity of the IsoAmp HSV assay were 100.0% and 96.3% respectively. The inter laboratory reproducibility achieved an overall 97.5% agreement by testing a total of 80 blinded HSV-1 samples among five laboratories. CONCLUSION: Adequate analytical and clinical performance of the IsoAmp HSV assay was demonstrated. This assay is simple to perform and has acceptable inter-laboratory reproducibility. PMID- 20947418 TI - Endogenous adenosine A1 receptor activation underlies the transient post-ischemic rhythmic delta EEG activity. AB - OBJECTIVE: Emergence of slow EEG rhythms within the delta frequency band following an ischemic insult of the brain has long been considered a marker of irreversible anatomical damage. Here we investigated whether ischemic adenosine release and subsequent functional inhibition via the adenosine A(1) receptor (A(1)R) contributes to post-ischemic delta activity. METHODS: Rats were subjected to episodes of non-injuring transient global cerebral ischemia (GCI) under chloral hydrate anesthesia. RESULTS: We found that a GCI lasting only 10s was enough to induce a brief discharge of rhythmic delta activity (RDA) with a peak frequency just below 1 Hz quantified as an increase by twofold of the 0.5-1.5 Hz spectral power. This post-ischemic RDA did not occur following administration of the A(1)R antagonist 8-cyclopentyl-1,3-dipropylxanthine. Nevertheless, a similar RDA could be induced in rats not subjected to GCI, by systemic administration of the A(1)R agonist N(6)-cyclopentyladenosine. CONCLUSIONS: Our data suggest that A(1)R activation at levels that occur following cerebral ischemia underlies the transient post-ischemic RDA. SIGNIFICANCE: It is likely that the functional, thus potentially reversible, synaptic disconnection by A(1)R activation promotes slow oscillations in the cortical networks. This should be accounted for in the interpretation of early post-ischemic EEG delta activity. PMID- 20947419 TI - Mu rhythm in a 13-month old toddler. PMID- 20947420 TI - Ce3+-induced exopolysaccharide production by Bradyrhizobium sp. MAFF211645. AB - Ce3+, a rare earth element (REE), has been widely used in high-technology industries. Despite the importance of Ce3+ in the fields of chemistry and physics, the role of Ce3+ in biology has been ignored. To investigate physiological effects of Ce3+ on microorganisms, we screened microorganisms that showed peculiar growth in the presence of Ce3+. We isolated a free-living soil bacterium that produced exopolysaccharide (EPS) around its colonies on 1/100 nutrient agar with 30 MUM CeCl3 or 1.0% D-mannitol. The bacterium was identified as Bradyrhizobium sp. by morphological, biochemical, and physiological tests as well as 16S rDNA sequence analysis. La3+, Pr3+, and Nd3+ also induced EPS production in large quantities, while Sm3+ did in small amounts. However, other heavier REEs from Eu3+ to Lu3+, and metals such as Na+, Al3+, K+, Ca2+, V3+, Cr3+, Co2+, Ni2+, Sr2+, Ba2+, and Pb2+ did not induce EPS production. The mean molecular weight of EPS was estimated to be approximately 1 x 106 by Sepharose CL 4B column chromatography. TLC revealed that EPS was composed of L-rhamnose. Quantitative analysis of alditol acetate derivatives of acid hydrolyzate of EPS by GLC revealed that EPS was composed of more than 95% L-rhamnose, indicating that this EPS was a rhamnan. The spectrum of FT-IR of the rhamnan demonstrated that L-rhamnose residues in the rhamnan were alpha-linked. GC/MS analysis of methylated alditol acetate derivatives of the rhamnan demonstrated that it was composed of main chain alpha-(1->4)-linked L-rhamnopyranosyl residues. From spectral analyses of 1H-NMR and FT-IR, EPS produced in the presence of 1.0% D mannitol was found to be structurally similar to rhamnans. PMID- 20947421 TI - Thermodynamic analysis of alcohol effect on thermal stability of proteins. AB - Thermal unfolding of ribonuclease A and alpha-chymotrypsinogen A was analyzed in various alcohol solutions of methanol, ethanol, 1-propanol, 2-propanol, 1 butanol, 2-butanol, tert-butanol, trifluoroethanol, and glycerol. The change in thermal unfolding ratio with temperature was described well by the van't Hoff equation and the melting temperature and the enthalpy of protein unfolding were obtained. The reciprocal form of the Wyman-Tanford equation, which describes the unfolded-to-folded protein ratio as a function of water activity, was applied to obtain a linear plot. From the slope of this plot and water activity, the stabilization free energy (DeltaDeltaG) in a solution was calculated. This shows an important role of water activity in protein stability. DeltaDeltaG was linearly dependent on alcohol concentration and m-values of alcohols for protein unfolding were obtained. This provides a theoretical basis for the linear extrapolation model (LEM). The m-values for alcohols were negative except for glycerol. The negative higher m-value for longer and linear chain alcohols suggested the important role of the disturbance of hydrophobic interactions as well as the hydrogen-bonding in the mechanism of protein destabilization by alcohols. The number of change in bound-alcohol molecules upon protein unfolding was also obtained. PMID- 20947422 TI - Material-binding peptide application--ZnO crystal structure control by means of a ZnO-binding peptide. AB - Recently, a zinc oxide (ZnO)-binding peptide (ZnOBP) has been identified and has been used to assist the synthesis of unique crystalline ZnO particles. We analyzed the influence of ZnOBP on the crystal growth of ZnO structures formed from zinc hydroxide. The addition of ZnOBP in the hydrothermal synthesis of ZnO suppressed [0001] crystal growth in the ZnO particles, indicating that the specificity of the material-binding peptide for specific inorganic crystal faces controlled the crystal growth. Furthermore, the dipeptides with a partial sequence of ZnO-binding "hot spot" in ZnOBP were used to synthesize ZnO particles, and we found that the presence of these dipeptides more strictly suppressed (0001) growth in ZnO crystals than did the complete ZnOBP sequence. These results demonstrate the applicability of dipeptides selected from material binding peptides to control inorganic crystal growth. PMID- 20947423 TI - Improvement of galactose induction system in Saccharomyces cerevisiae. AB - Here we report a significant enhancement of galactose response without altering the characteristics of glucose repression. To improve the galactose response, we fabricated transgenic yeasts harboring HIS3pro-GAL1, HIS3pro-GAL2 and GAL10pro GAL4, and evaluated the synergistic effects of these three genes by immunoblot and flow cytometry analyses. PMID- 20947424 TI - Restless legs syndrome during pregnancy in Brazilian women. AB - OBJECTIVE: The objective of this study was to identify the prevalence of restless legs syndrome (RLS) among pregnant Brazilian women, with individual diagnostic clinical interviews during the trimesters of pregnancy, and to determine the severity. METHODS: It was a cross-sectional study. We interviewed 524 pregnant women (18-45 years old) who came to the prenatal outpatient clinic to consult an obstetrician. We used a RLS clinical-diagnostic interview and the International RLS Study Group rating scale (IRLS). RESULTS: The prevalence of RLS during pregnancy was 13.5% in our sample, among which 90.1% of the cases started with their symptoms during pregnancy. More than half of the patients (53.5%) presented severe or very severe symptoms and the largest proportion of them (15.2%) were in their third trimester. We did not observe any demographic differences among the trimesters for RLS prevalence and RLS severity. CONCLUSION: RLS during pregnancy is more frequent than in the general population, such that more than half of the pregnant women with RLS present it severely or very severely. It occurs especially in the third trimester. PMID- 20947425 TI - Multicellular signalling and growth of Pseudomonas aeruginosa. AB - The main reason for Pseudomonas aeruginosa persistence within the lungs of chronically infected cystic fibrosis patients seems to be that the bacteria reside within biofilm structures which protect them from diverse adverse environmental conditions, antibiotic treatment, and from the host immune response. Thereby, it may be of great significance that the human defence systems do not face single bacteria but multicellular communities in which the high level of diversity of both phenotypes and genotypes provides insurance for bacterial survival. Indeed, in the last decade, the orthodox view of bacterial populations as being a homogeneous collection of sibling cells has been abandoned, and there is accumulating evidence of bacterial interactiveness within biofilm structures, which is supported by the identification of signalling molecules that mediate cooperative traits and a coordinated behaviour. A detailed understanding of the molecular mechanisms that contribute to multicellular development in bacterial biofilms will be pivotal for the identification of novel targets as the basis for the development of new alternative treatment strategies directed against chronic persistent biofilm infections. PMID- 20947426 TI - Protein secretion systems in Pseudomonas aeruginosa: A wealth of pathogenic weapons. AB - Pathogenic microorganisms have to face hostile environments while colonizing and infecting their hosts. Unfortunately, they can cope with it and have evolved a number of complex secretion systems, which direct virulence factors either at the bacterial cell surface into the environmental extracellular milieu or into the host cell cytosol. Six different classes of secretion systems have been described so far, currently identified as type I secretion system (T1SS) up to type VI secretion system (T6SS). The Gram-negative opportunistic human pathogen Pseudomonas aeruginosa possesses a broad panel of secretion systems. Five of the six secretion machines characterized in Gram-negative bacteria are at P. aeruginosa disposal, sometimes in several copies. All these machines are dedicated to the specific secretion of exoproteins, which display various activities useful for bacterial adaptation to the environment or for bacterial pathogenicity. This review will summarize the functional organization of these different secretion systems, which could constitute potential targets for therapeutic treatment of patients infected by one of the most potent nosocomial pathogens identified nowadays. PMID- 20947427 TI - What do our elite athletes really deserve? PMID- 20947428 TI - Apropos "Establishment of innovative specialist cardiac indigenous outreach service in rural and remote Queensland". PMID- 20947429 TI - Prospective Coronary CT Angiography 128-MDCT Versus Retrospective 64-MDCT: Improved Image Quality and Reduced Radiation Dose. AB - OBJECTIVE: new technologies for computed tomography coronary arteries imaging aim to reduce the radiation dose whilst maintaining image quality. The purpose of our study was to compare radiation dose and image quality parameters of Coronary Computed Tomography Angiography (CCTA) performed with retrospective 64-MDCT and prospective 128-MDCT. PATIENTS AND METHODS: a series of 77 consecutive patients were first randomised to either retrospective 64-MDCT (n=37) or prospective 128 MDCT (n=40) for CCTA. All patients in the retrospective 64-MDCT group were scanned with tube current modulation as strategy for reduction dose. Data regarding acquisition time and radiation dose were recorded. Two blinded radiologists independently assessed image quality of all coronary segments by using a four-point scale (1, excellent; 4, poor). Discrepancies were settled by consensus. RESULTS: No significant differences were found regarding sex, age, body weight and heart rate. CTTA effective radiation dose was 2.1 +/- 0.9 vs. 8.2 +/- 4mSv in prospective and retrospective ECG-gating MDCT groups, respectively. Mean image quality score was 2.2 +/- 0.9 for prospective 128-MDCT group and 1.4 +/- 0.7 points for retrospective 64-MDCT representing a mean difference of 0.8 points (CI: 0.9 to 0.7). CONCLUSION: in selected patients, CCTA using a 128-MDCT with prospective ECG-gating provides higher image quality with significant lower radiation dose when compared to 64-MDCT using retrospective ECG-gating. PMID- 20947431 TI - A genetic perspective on coeliac disease. AB - Coeliac disease is an inflammatory disorder of the small intestine with an autoimmune component and strong heritability. Genetic studies have confirmed strong association to HLA and identified 39 nonHLA risk genes, mostly immune related. Over 50% of the disease-associated single nucleotide polymorphisms are correlated with gene expression. Most of the coeliac disease-associated regions are shared with other immune-related diseases, as well as with metabolic, haematological or neurological traits, or cancer. We review recent progress in the genetics of coeliac disease and describe the pathways these genes are in, the functional consequences of the associated markers on gene expression and the genes shared between coeliac disease and other traits. PMID- 20947430 TI - Glucocorticoid use in acute lymphoblastic leukaemia. AB - Glucocorticoids (prednisone and dexamethasone) play an essential part in the treatment of acute lymphoblastic leukaemia (ALL), but their optimum doses and bioequivalence have not been established. Results of preclinical studies have shown that dexamethasone has a longer half-life and better CNS penetration than does prednisone. In prospective randomised trials, dexamethasone improved control of CNS leukaemia. At a prednisone-to-dexamethasone dose ratio of less than seven, dexamethasone (6-18 mg/m(2) per day) resulted in a better event-free survival than did prednisone (40-120 mg/m(2) per day), and high-dose dexamethasone (10-18 mg/m(2) per day) improved the outcome of T-cell ALL and high-risk ALL. However, dexamethasone caused more adverse effects, including infection, bone fracture, osteonecrosis, mood and behaviour problems, and myopathy. At a dose ratio greater than seven, the two drugs showed no difference in efficacy. Therefore, the efficacy of prednisone and dexamethasone is dose dependent and needs to be carefully assessed against the toxic effects. Moreover, although dexamethasone generally showed increased activity in ALL cells in vitro, the dose ratio of the two drugs that exerted equivalent cytotoxic effects differed substantially in samples from individuals. The selection of the type and dose of glucocorticoid should be based on the risk of relapse, treatment phase, and the chemotherapeutic drugs used concomitantly. PMID- 20947432 TI - Structure and function of the tuberculous lung: considerations for inhaled therapies. AB - Inhaled therapies for pulmonary tuberculosis are in development and appear promising at first look. A fundamental premise of such therapy is efficient delivery of drug at high concentrations to the active disease site, while minimizing systemic delivery. This assumes that inhaled drug will actually reach the diseased lung, which while intuitive for healthy lungs, may be untrue for diseased lungs with abnormal structure or function. This review discusses the structural and functional aspects of respiratory physiology that are likely to impact local drug delivery and presents the available evidence on how this pertains to tuberculous lungs. PMID- 20947433 TI - Toll-like receptor 2 induces mucosal homing receptor expression and IgA production by human B cells. AB - There is a need for developing vaccines that elicit mucosal immunity. Although oral or nasal vaccination methods would be ideal, current strategies have yielded mixed success. Toll-like receptor 2 (TLR2) ligands are effective adjuvants and are currently used in the Haemophilus influenzae type B vaccine. Induction of humoral immunity in the mucosa is critical for effective vaccination; thus, we sought to determine the effects of TLR2 ligands on human mucosal B cell differentiation. We demonstrate that TLR2 ligands induce CCR9 and CCR10 expression by circulating B cells and increased chemotaxis to cognate chemokines CCL25 and CCL28 suggesting that TLR2 induces B cell homing to the gastrointestinal tract. TLR2 stimulation of B cells also induced J chain and IgA production demonstrating the induction of mucosal-like antibody secreting cells. These observations suggest that vaccines containing TLR2-ligands as adjuvants could induce mucosal B cell immunity even when delivered in a non-mucosal manner. PMID- 20947434 TI - Multiple myeloma patients at peripheral blood stem cell harvest: restricted usage of TCR beta variable families. AB - The immune systems of multiple myeloma patients are suppressed by the disease itself, and this immunosuppression is further enhanced by standard therapies. The aim of our study was to evaluate the effects of initial chemotherapy and a peripheral blood mobilisation regimen on T-cell population diversity. Reverse transcription-polymerase chain reaction (RT-PCR) with a new set of primers, in combination with capillary electrophoresis, was established. The methodology was used to analyse the relative expression of 27 T-cell receptor beta variable gene families (BV families) in multiple myeloma patients undergoing peripheral blood stem cell harvest. We found that the overall BV family usage in these patients was restricted; the relative expression of 10 BV families was significantly depressed in patients compared to healthy donors. These findings demonstrate that the preparative regimen for autologous stem cell transplantation affects the T cell population in terms of the restriction of its T-cell receptor diversity. PMID- 20947435 TI - Differential contributions of objective memory and mood to subjective memory complaints in refractory focal epilepsy. AB - People with epilepsy frequently present with bitter memory complaints. Previous research variously attributes this to symptoms of mood disturbance or objective memory deficits. To investigate the influence of the epileptogenic region on this variability, we examined interrelationships between mood, objective memory, and memory complaints in a sample of patients with refractory focal epilepsy and controls (N = 96). Patients had either mesial temporal (MT, n = 39) or non mesial temporal (NMT, n = 21) foci. In contrast to controls (n = 36), both patient groups were highly concerned about their memory (P<0.001) and were more likely to have a history of depression (P = 0.005). Multiple regression showed that objective memory dysfunction and current depressive symptoms predicted the memory complaints of patients with MT epilepsy (P = 0.005), whereas a history of depression predicted the complaints of patients with NMT epilepsy (P = 0.008). These findings suggest that patients have concerns about their memory underpinned by distinct psychological and neurobiological factors depending on the location of their epileptogenic focus. PMID- 20947436 TI - Unusual cortical stimulation findings: connectivity between primary motor and supplementary motor areas. AB - We describe a 42-year old patient with right hand sensorimotor seizures who underwent extraoperative cortical stimulation mapping (CSM) of the left primary motor cortex (M1). Cortical stimulation of the region where primary motor cortex was expected evoked exclusively complex motor responses with proximal right arm and proximal left leg asymmetric tonic movements that are usually observed on stimulation of the supplementary motor area (SMA). Right hand function could not be isolated during either extraoperative or intraoperative cortical stimulation of the anatomical M1 representation. Ictal and interictal activity was contained within the region with the abnormal motor response, and MEG of interictal activity showed spike propagation from the left mesial to lateral frontal cortex. This propagation pathway may have facilitated M1-to-SMA connectivity and therefore explain the unusual motor response after stimulation of M1. This case highlights the potential impact of interictal activity on plasticity of the motor cortex. PMID- 20947437 TI - Introduction to genetic epidemiology. AB - Genetic epidemiology is of topical and increasingly practical relevance. The subject attempts to answer 2 questions: (1) is there a genetic component to a disease, and (2) what genes are involved? This article summarizes genetic epidemiologic methods, describing family- and population-based methods used to locate and identify genes and the advantages and disadvantages of each approach. Health care professionals are faced with more and more genetic information, both from interested patients and from the media, and understanding the principles underlying genetic studies allows such information to be placed in context. PMID- 20947438 TI - Iatrogenically induced Stevens-Johnson syndrome after a car accident. AB - BACKGROUND: Stevens-Johnson syndrome (SJS) is a hypersensitivity reaction that targets the skin and mucosal membranes. Ophthalmic manifestations may include conjunctival and corneal keratinization, shortening of the fornices, symblepharon, entropion, trichiasis, and adnexal cutaneous blisters. The syndrome is often misdiagnosed, and patients are treated incompletely with topical agents only leading to a worsening of the condition and graduated symptoms. CASE: A 61 year-old black man was admitted to the hospital for management and rehabilitation of multiple lower limb fractures after an automobile accident. The ophthalmic service was consulted regarding a persistent bilateral conjunctivitis that was worsening and recalcitrant to standard topical antimicrobial therapies. Best corrected visual acuities were 20/70 in the right eye (O.D.) and the left eye (O.S.) secondary to grade III punctate corneal epitheliopathy resulting from evolving cicatricial ectropion. Anterior segment examination uncovered maderosis, blepharoconjunctivitis and dense corneal subepithelial infiltration from 3 to 5 o'clock. Externally there was bilateral juxtaorbital and transfacial skin blistering. After a review of history, the diagnosis of SJS was made, presumably secondary to recent oral antibiotic administration. Topical and oral steroids were initiated while concurrently seeking a dermatologic consult. The dermatologist agreed with our findings and management. The disease responded to the oral and topical regimen with significant reduction of signs and symptoms. An immediate physical improvement was evident within 10 days. CONCLUSIONS: Stevens Johnson syndrome is a multifactorial hypersensitivity reaction requiring prompt systemic and local anti-inflammatory therapy. PMID- 20947439 TI - Posterior iliac crest pain after posterolateral fusion with or without iliac crest graft harvest. AB - BACKGROUND CONTEXT: Considerable debate exists regarding the incidence of persistent pain from the iliac crest bone graft (ICBG) harvest site. Different study designs have led to a variety of reported rates. PURPOSE: The purpose of this study was to determine the incidence and severity of bone graft site pain after iliac crest harvest. STUDY DESIGN: Cross-sectional. PATIENT SAMPLE: One hundred and twelve patients, who had a posterior lumbar fusion, seen at a tertiary spine center for a routine postoperative visit. OUTCOME MEASURES: Numeric rating scales (0-10) for pain over lower back, right, and left posterior iliac crests. METHODS: An independent investigator, not directly involved in the care of the patient and unaware of the type of bone graft used in the fusion, examined the patient for tenderness over the surgical site as well as the left and right posterior iliac crest. After the examination, data on the source of grafting material, complications during harvest, and backfilling of the graft site defect were collected from the medical records. The patients were then classified as to whether ICBG was harvested or not. Chi-square test was used to determine any difference in the proportion of iliac crest pain between the bone graft group and no bone graft group. Correlations between body mass index (BMI), time since surgery, and the incidence and severity of bone graft site pain were also determined. RESULTS: There were 72 women and 40 men with a mean age of 56.6 years (range, 16-84). Mean follow-up was 41 months (range, 6-211 months) with a median of 25 months. Iliac crest bone graft was harvested in 53 (47.3%) patients through the midline incision used for lumbar fusion. In 59 patients (52.7%), recombinant human bone morphogenetic protein-2 was used with no graft harvest. There was no statistically significant difference in the proportion of patients complaining of tenderness over both or either iliac crest between the two groups. Only 10 patients had pain over the same crest from which the graft was harvested. No correlations between number of levels fused, levels fused, BMI, length of follow-up, and the incidence and severity of bone graft site pain were seen. CONCLUSIONS: The results of this study highlight the difficulty in differentiating pain originating from the graft site versus residual low back pain. The incidence of pain over the iliac crest was similar in patients in which iliac crest was harvested and those in which no graft was harvested. PMID- 20947440 TI - Incidence of low vitamin A levels and ocular symptoms after Roux-en-Y gastric bypass. AB - BACKGROUND: Previous reports have demonstrated a significant incidence of fat soluble vitamin deficiency after bariatric surgery. The purpose of the present study was to determine the incidence of vitamin A deficiency after Roux-en-Y gastric bypass and to correlate the laboratory findings with ocular symptoms potentially related to vitamin A deficiency. METHODS: All patients who had undergone Roux-en-Y gastric bypass were invited to participate in a nutritional screening. The patients completed a detailed survey concerning ocular symptoms and had their vitamin A level evaluated. RESULTS: A low vitamin A level was identified in 7 (11%) of 64 RYBG patients. Ocular xerosis was present in 18 patients (27%), with night vision changes reported in 45 (68%). Visual disturbances were present in 7 patients (11%) found to have low vitamin A levels, with hypovitaminosis A present in 22% of patients with xerosis (P <.05). CONCLUSION: Low vitamin A levels and frequent ocular complaints that might be associated with decreased vitamin A are common findings in the post-RYBG patient population. Additional study is needed to assess the role of routine vitamin A screening and replacement in the postbariatric surgery patient. PMID- 20947441 TI - Clinical case report: psychosocial issues in adolescent bariatric surgery. PMID- 20947442 TI - Acute diaphragmatic herniation as cause of small bowel obstruction after gastric bypass. PMID- 20947443 TI - Gastric necrosis due to type II paraesophageal hernia in obese patient with gastric band: rescue sleeve gastrectomy. PMID- 20947444 TI - New adjustable gastric bands available in the United States: a comparative study. AB - BACKGROUND: New gastric bands have been available for the past 3 years in the United States: Lap-Band AP (LBAP), Realize Band (RB), and Realize Band C (RBC). No RBC data have been previously published. The objective of the present study was to report our experience with 3 newer gastric bands in an experienced, private, U.S. bariatric surgery center. METHODS: Data were prospectively collected and retrospectively reviewed. The characteristics evaluated include age, body mass index (BMI), gender, percentage of excess weight loss, band fill volumes, and complications. RESULTS: From April 2007 through February 2010, 633 patients (mean age 42.3 +/- 10.3 years) underwent laparoscopic band placement. The LBAP was placed in 384 patients (78% women, BMI 45.4 +/- 6.9 kg/m(2)), the RB in 167 patients (84% women, BMI 46.4 +/- 7.9), and the RBC in 82 patients (76% women, BMI 46.1 +/- 8.2). The corresponding mean 1-year percentage of excess weight loss was 44.4% +/- 19%, 38.9% +/- 16.2%, and 32.1% +/- 16.1% (LBAP versus RB and RBC, P <.05), with a 91%, 90%, and 83% follow-up rate. The 2-year percentage of excess weight loss for the LBAP and RB patients was 52.5 +/- 21.2 and 43.3 +/- 21.3 (P <.05), respectively, with a 76% and 67% follow-up rate. The corresponding mean band volumes at 1 year were 4.6, 7.6, and 10.2 mL, with 2%, 12%, and 38% of the bands filled more than the manufacturer's maximal volume capacity recommendation. The postoperative complications included slippages and erosions in .5% and .5% of the LBAP, .6% and 1.8% of the RB, and 1.2% and 0% of the RBC patients, respectively. CONCLUSION: Of the new bands available in the United States, the LBAP provided significantly better weight loss in our private practice setting. The RBC patients had the least weight loss, with a high band fill volume needed to achieve effective restriction. PMID- 20947445 TI - Bleeding from sclerotherapy-induced anastomotic ulcers. PMID- 20947446 TI - Changes in quality of life and body image after gastric bypass surgery. AB - BACKGROUND: Improvements in psychosocial status are an important aspect of successful outcomes after bariatric surgery. Relatively few studies have investigated the changes in psychosocial functioning at a number of points in the first few postoperative years. The present study was undertaken to assess the changes in quality of life and body image after gastric bypass surgery. The present study was performed at an academic medical center. METHODS: A total of 200 men and women were enrolled in the study and completed psychometric measures of quality of life and body image before surgery and again 20, 40, and 92 weeks postoperatively. RESULTS: The participants reported significant improvements in several domains of health- and weight-related quality of life, as well as changes in body image, after surgery. These changes were correlated with the percentage of weight loss. CONCLUSION: Those who undergo gastric bypass surgery experienced significant improvements in quality of life and body image within the first few months after surgery. These changes were, with few exceptions, maintained into the second postoperative year. PMID- 20947447 TI - Sleeve gastrectomy and type 2 diabetes mellitus: a systematic review. AB - BACKGROUND: Existing evidence has suggested that bariatric surgery produces sustainable weight loss and remission or cure of type 2 diabetes mellitus (DM). Laparoscopic sleeve gastrectomy (LSG) has garnered considerable interest as a low morbidity bariatric surgical procedure that leads to effective weight loss and control of co-morbid disease. The objective of the present study was to systematically review the effect of LSG on type 2 DM. METHODS: An electronic data search of MEDLINE, PubMed, Embase, Scopus, Dare, Clinical Evidence, TRIP, Health Technology Database, Conference abstracts, clinical trials, and the Cochrane Library database was completed. The search terms used included LSG, vertical gastrectomy, bariatric surgery, metabolic surgery, and diabetes (DM), type 2 DM, or co-morbidities. All human studies, not limited to those in the English language, that had been reported from 2000 to April 2010 were included. RESULTS: After an initial screen of 3621 titles, 289 abstracts were reviewed, and 28 studies met the inclusion criteria and the full report was assessed. One study was excluded after a careful assessment because the investigators had combined LSG with ileal interposition. A total of 27 studies and 673 patients were analyzed. The baseline mean body mass index for the 673 patients was 47.4 kg/m(2) (range 31.0-53.5). The mean percentage of excess weight loss was 47.3% (range 6.3 74.6%), with a mean follow-up of 13.1 months (range 3-36). DM had resolved in 66.2% of the patients, improved in 26.9%, and remained stable in 13.1%. The mean decrease in blood glucose and hemoglobin A1c after sleeve gastrectomy was -88.2 mg/dL and -1.7%, respectively. CONCLUSION: Most patients with type 2 DM experienced resolution or improvement in DM markers after LSG. LSG might play an important role as a metabolic therapy for patients with type 2 DM. PMID- 20947448 TI - Laparoscopic reversal of gastric bypass with sleeve gastrectomy for treatment of recurrent retrograde intussusception and Roux stasis syndrome. AB - BACKGROUND: We reported on our experience of 23 patients with retrograde intussusception (RINT) in 2007. That series has increased to 54 patients. Surgical resection of the jejunojejunostomy appears to be the most effective treatment. We treated 8 patients with documented or suspected recurrent RINT despite resection, by reversing their gastric bypass with sleeve gastrectomy to avoid weight regain. METHODS: The medical records of 8 patients who had undergone treatment of suspected recurrent RINT with reversal of their gastric bypass followed by sleeve gastrectomy were reviewed to evaluate the outcomes, complications, weight loss, and relief of symptoms. RESULTS: All 8 patients were women, aged 29-56 years. The mean body mass index at reversal was 22.3-36.5 kg/m(2) (mean 30). The follow-up period was 1-28 months (mean 20.8). The body mass index at the last visit was 21.3-33 kg/m(2) (mean 26). Complications occurred in 5 patients. Patient 1 developed delayed splenic bleeding that required splenectomy on the second postoperative day. Patient 2 developed a gastric fistula 6 weeks after surgery after dilation. Patient 4 developed a superior mesenteric vein thrombosis at 2 weeks postoperatively. Patient 7 developed a proximal small bowel obstruction. Also, 4 patients required dilation of the gastrogastrostomy. At the last follow-up visit, the patients did not have symptoms of recurrent RINT and had not regained their weight. CONCLUSION: Laparoscopic reversal of gastric bypass with sleeve gastrectomy for recurrent RINT or RINT-like symptoms (Roux stasis symptoms) resulted in a significant risk of complications in this small group of patients but appears to be effective for relieving the symptoms of RINT with minimal risk of weight regain, at least in the medium term. PMID- 20947449 TI - Positive relationship between support group attendance and one-year postoperative weight loss in gastric banding patients. AB - BACKGROUND: Few empirical reports of studies examining the association between bariatric after care support group attendance and weight loss outcomes have been published. The present study investigated the association between the number of support group meetings attended and percentage of excess weight loss at 12 months after gastric banding surgery. The setting was a private practice at which no cost, professionally led support group meetings were held weekly. METHODS: The medical records and support group attendance logs were examined for the dates of attendance, frequency of attendance (or no attendance) in relation to the percentage of excess weight loss (n = 102; 88.2% women; mean age 45.6 +/- 11.3 years; mean baseline body mass index 46.4 +/- 8.8 kg/m(2)). Linear regression models were used to assess the relationship between the number of group meetings attended and the percentage of excess weight of loss with age and baseline body mass index used as optional independent variables. RESULTS: A significant linear relationship was found between support group meeting attendance and the percentage of excess weight loss with simple regression analysis (adjusted R(2) = .061, P = .007), with age (adjusted R(2) = .100, P = .002) and the baseline body mass index added to the model (adjusted R(2) = .072, P = .011). CONCLUSION: The results of the present study add to the growing evidence of the positive relationship between the frequency of support group attendance and the percentage of excess weight loss. Future studies should examine patient motivational characteristics in relation to support group participation and other aspects of compliance with aftercare recommendations to investigate unique effects of each part of the treatment program on weight loss outcomes. PMID- 20947450 TI - Chylous ascites mimicking peritonitis after laparoscopic Roux-en-Y gastric bypass for morbid obesity. PMID- 20947451 TI - Transoral gastric volume reduction for weight management: technique and feasibility in 18 patients. AB - BACKGROUND: Endoluminal suturing to reduce the gastric volume might provide an additional option for the treatment of obesity. Potential advantages of a nonoperative endoluminal intervention include less pain, the ability to perform it as an outpatient procedure, and a high level of patient acceptance. The purpose of the present pilot study was to demonstrate the feasibility and procedural safety of transoral gastric volume reduction (TRIM procedure) using the Restore Suturing System in patients with a body mass index of 30-45 kg/m(2). Successful completion of the procedure and adverse events were evaluated at academic/university hospitals. METHODS: This was a nonrandomized feasibility study performed at 2 institutions. After institutional review board approval, the patients underwent the TRIM endoluminal gastric plication procedure with the Restore Suturing System (Restore device). Gastric plications were completed to approximate the anterior and posterior gastric walls to achieve restriction of the upper stomach. The number and location of successful plications were recorded, and patients were monitored for complications. The present report described the short-term procedural results (<= 24 hours after the procedure) of the studied cohort. RESULTS: A total of 18 patients were enrolled in the present study. The TRIM procedure was successfully completed in all patients, with placement of 4-8 plications (average 6 per patient). The average procedure time was 125 +/- 23 minutes, and no serious or significant procedure-related complications occurred. After the procedure, common patient complaints were nausea, vomiting, and abdominal discomfort. The first 10 patients enrolled were kept overnight according to the study protocol, and the remaining 8 patients were discharged on the day of the procedure. CONCLUSION: Endoluminal suturing using the TRIM procedure and the Restore device was technically feasible, and no serious or significant procedure-related complications were reported. Weight loss, co-morbidity improvement, and durability are under assessment. PMID- 20947452 TI - Lack of DNA polymerase MU affects the kinetics of DNA double-strand break repair and impacts on cellular senescence. AB - The specialised DNA polymerase MU (pol MU) affects a sub-class of immunoglobulin genes rearrangements and haematopoietic development in vivo. These effects appear linked to double-strand breaks (DSBs) repair, but it is still unclear how and to what extent pol MU intervenes in this process. Using high-resolution quantitative imaging of DNA damage in irradiated wild-type and pol MU-(/)- mouse embryonic fibroblasts (MEFs) we show that lack of pol MU results in delayed DSB repair kinetics and in persistent DNA damage. DNA damage triggers cellular senescence, and this response is thought to suppress cancer. Independent investigations either report or not a proliferative decline for MEFs lacking pol MU. Here we show pronounced senescence in pol MU-(/)- MEFs, associated with high levels of the tumor-suppressor p16(INK4A) and the DNA damage response kinase CHK2. Importantly, cellular senescence is induced by culture stress and exacerbated by low doses of irradiation in pol MU-(/)- MEFs. We also found that low doses of irradiation provoke delayed immortalisation in MEFs lacking pol MU. Pol MU-(/)- MEFs thus exhibit a robust anti-proliferative defence in response to irreparable DNA damage. These findings indicate that sub-optimal DSB repair, due to the absence of an auxiliary DNA damage repair factor, can impact on cell fitness and thereby on cell fate. PMID- 20947454 TI - A novel defect in mitochondrial p53 accumulation following DNA damage confers apoptosis resistance in Ataxia Telangiectasia and Nijmegen Breakage Syndrome T cells. AB - We have previously shown that whereas T-cells from normal individuals undergo accumulation of p53 and apoptosis when treated with the genotoxic agent Actinomycin D (ActD), those from Ataxia Telangiectasia (AT) and Nijmegen Breakage Syndrome (NBS) patients resist ActD-induced apoptosis [1]. We have now found similar resistance by the p53-null Jurkat T-cell line and by siRNA p53-knockdown normal T-cells. This evidence that ActD initiates a p53-dependent apoptotic responce prompted us to look for defective p53 accumulation by AT and NBS T cells. Surprisingly the total p53 level was only slightly reduced compared to normal T cells but its intracellular localization was highly defective: p53 was poorly accumulated in the cytosol and nearly undetectable in mitochondria. In accordance with the dependence of ActD-induced apoptosis on a mitochondrial p53 function, in control T-cells specific inhibition of mitochondrial p53 translocation with MU pifithrin reduced apoptosis by 86%, whereas treatment with alpha pifithrin, which blocks p53-mediated transcription, had no effect. We also showed that nuclear export is not required for mitochondrial p53 translocation. Observation of an altered p53 ubiquitination pattern and Mdm2 accumulation in ActD-treated AT and NBS T-cells provided a mechanistic link to their defective extranuclear p53 localization. Our results disclose an undescribed defect in mitochondrial p53 accumulation in AT and NBS T-cells that makes them resistant to apoptosis following unrepairable DNA damage. PMID- 20947455 TI - Lactate in cystic fibrosis sputum. AB - BACKGROUND: Antibiotic therapy is thought to improve lung function in patients with cystic fibrosis (CF) by decreasing neutrophil-derived inflammation. We investigated the origin and clinical significance of lactate in the chronically inflamed CF lung. METHODS: Lactate was measured in sputa of 18 exacerbated and 25 stable CF patients via spectrophotometry and gaschromatography. Lung function was assessed via spirometry. Seven patients with chronic obstructive pulmonary disease (COPD) and three patients with acute lung inflammation served as control groups. Neutrophil and bacterial lactate production was assessed under aerobic and anaerobic conditions. RESULTS: In sputum specimens of patients with respiratory exacerbations lactate concentrations decreased significantly (p<0.005) from 3.4+/-2.3mmol/L to 1.4+/-1.4mmol/L after 2-3 weeks of intravenous antibiotics. Successful treatment was reflected in 16 patients (88.9%) by FVC increase associated with lactate decrease (p<0.05). In every single sputum lactate was detectable (3.0+/-3.1mmol/L, range 0.2-14.1mmol/L). Lactate was lower (1.6+/-0.8mmol/L) in sputa from seven COPD patients, and it was below the detection limit in three patients with acute lung inflammation. Neutrophil lactate production accumulated up to 10.5mmol/L after 4 days, whereas bacterial lactate production did not appear to contribute substantially to sputum lactate concentrations. CONCLUSIONS: Successful antibiotic therapy is reflected by a decrease in lactate concentrations. Neutrophils are the most likely source for lactate in sputum of CF patients. Therefore lactate may be used to monitor responses to antibiotic therapy as an adjunct to lung function measurements. PMID- 20947453 TI - UV-induced histone H2AX phosphorylation and DNA damage related proteins accumulate and persist in nucleotide excision repair-deficient XP-B cells. AB - DNA double strand breaks (DSB) may be caused by ionizing radiation. In contrast, UV exposure forms dipyrimidine photoproducts and is not considered an inducer of DSB. We found that uniform or localized UV treatment induced phosphorylation of the DNA damage related (DDR) proteins H2AX, ATM and NBS1 and co-localization of gamma-H2AX with the DDR proteins p-ATM, p-NBS1, Rad51 and FANCD2 that persisted for about 6h in normal human fibroblasts. This post-UV phosphorylation was observed in the absence of nucleotide excision repair (NER), since NER deficient XP-B cells (lacking functional XPB DNA repair helicase) and global genome repair deficient rodent cells also showed phosphorylation and localization of these DDR proteins. Resolution of the DDR proteins was dependent on NER, since they persisted for 24h in the XP-B cells. In the normal and XP-B cells p53 and p21 was detected at 6h and 24h but Mdm2 was not induced in the XP-B cells. Post-UV induction of Wip1 phosphatase was detected in the normal cells but not in the XP B cells. DNA DSB were detected with a neutral comet assay at 6h and 24h post-UV in the normal and XP-B cells. These results indicate that UV damage can activate the DDR pathway in the absence of NER. However, a later step in DNA damage processing involving induction of Wip1 and resolution of DDR proteins was not observed in the absence of NER. PMID- 20947456 TI - Methodological contributions towards LC-MS/MS quantification of free VX in plasma: An innovative approach. AB - A novel analytical method has been developed to detect and quantify VX (O-ethyl S (2(diisopropylamino) ethyl) (methylphosphonothioate)) in plasma using an LC-MS/MS technique. VX detection and quantification in plasma following percutaneous exposure represent a formidable challenge and it is an important part of the ongoing struggle against chemical warfare agents. Liquid-liquid extraction of VX from plasma was performed and it generated a recovery rate of approximately 65% followed by an LC-MS/MS analysis in a 100% organic phase. An Allure biphenyl column (Restek) was tested with detection limit at 0.5 pg/mL (5 MUL injected). Initial application was focused on human skin grafted on nude mice as an experimental model with proper adjustments done for very small quantities of plasma. PMID- 20947457 TI - Large balloon dilatation following endoscopic sphincterotomy using a balloon enteroscope for the bile duct stone extractions in patients with Roux-en-Y anastomosis. AB - BACKGROUND: Extraction of bile duct stones in patients who have undergone Roux-en Y anastomosis can be challenging. Recently, large balloon dilation following endoscopic sphincterotomy has been shown to be useful for the removal of bile duct stones. AIM: We retrospectively evaluated the feasibility and safety of endoscopic sphincterotomy large balloon dilation for the removal of bile duct stones in patients with Roux-en-Y anastomosis. METHODS: Large balloon papillary dilation following EST for the removal of bile duct stones was performed on the intact papilla in 15 patients with Roux-en-Y anastomosis at our institution. When we could not use the long-type accessories, a conventional forward-viewing upper endoscope passed through the over tube of the single-balloon or double-balloon enteroscope for the use of short-type accessories. Following endoscopic sphincterotomy, a large balloon catheter was positioned across the main duodenal papilla. The size of large balloon used ranged from 15mm to 20mm. RESULTS: Complete clearance of bile duct stones was achieved in all cases in the initial session without any adverse events. A mechanical lithotriptor for crushing stones was used in one patient (6.7%). CONCLUSION: Large balloon papillary dilation following EST appears to be an effective and safe treatment for difficult-to remove bile duct stones in patients with Roux-en-Y anastomosis . PMID- 20947458 TI - Ethanol sclerotherapy with 'injection and aspiration technique' for giant lymphatic malformation in adult cases. AB - Ethanol is a commonly used sclerosant for lymphatic malformation (LM), and recent evidence has shown that macrocystic LMs respond very well to percutaneous sclerotherapy. However, the volume of absolute ethanol that can be injected safely is small (0.5-1 ml/kg), and that is the reason it is often ineffective in extensive LM. We report two cases of giant LM with occasional high fever and pain or abnormal gait. To overcome dose limitation and to prevent systematic toxicities, we performed both injection of absolute ethanol and aspiration of it after 5 min exposure to LM. The injected maximum ethanol dose per one session is 70-260 ml and no systemic complication occurred. The 1-3 sessions of those procedures reduced the frequency of high fever and improved the swelling of those lesions. The injection and aspiration technique maximises the efficacy of sclerotherapy for extensive macrocystic LM in adults. PMID- 20947459 TI - Investigation into accuracy and reproducibility of a 3D breast imaging system using multiple stereo cameras. AB - BACKGROUND: The aim of this study was to evaluate the validity of a three dimensional (3D) multiple stereo camera system for objective breast assessment. METHODS: A multiple stereo camera system, which consisted of four pods and eight cameras, two cameras on each pod, developed by Glasgow University, was used. Nine specially shaped plaster breast models were captured once, 3Dmodels were constructed and the volume of each plaster model was measured 10 times by the breast analysis tool (BAT) software. A comparison was conducted with water displacement method, and measurements were repeated 10 times. The breast of six live volunteers was captured six times; from each breast capture, a 3D model was constructed and the volume was measured with BAT software. Breast volume assessment by the water displacement method was repeated six times. RESULTS: In all plaster casts, the discrepancies in volume measurements between 3D imaging and water displacement methods did not exceed 40 cc. The overall mean relative difference was 5%. The differences of the two methods were not significant at p = 0.189, overall mean difference: 11.1 cc and 95% confidence interval (CI) was ( 6.732, 28.976). In the live models, the differences in breast volume measurements between the 3D imaging and water displacement methods were significant at p <= 0.017, overall mean difference: 207.05 cc and 95% CI (56.12, 357.98). Measurements by 3D imaging were consistently smaller. In the live models, 3D imaging overall was a more reproducible method for measuring breast volume than the water displacement method with a standard deviation of 36 units cc(-1) and 62.6 units cc(-1), respectively. CONCLUSIONS: The 3D breast imaging system using multiple stereo cameras was accurate for measuring the volumes of breast-shaped plaster models, and it was more reproducible than the water displacement method in live models. 3D imaging is a reliable method for the comparative assessment of breast volume. PMID- 20947460 TI - The effect of group clinics in the control of diabetes. AB - OBJECTIVES: Novel interventions are needed for long-term maintenance of diabetes control. We studied the effects of a group diabetes clinic (GDC) on diabetes control when compared to usual care with primary care providers (PCP). RESEARCH DESIGN/METHODS: Data from the electronic medical records of 56 patients were collected. Twenty-nine patients were in the group diabetes clinic (GDC) while 27 patients followed with their PCP. Outcome variables, A1c, LDL, and blood pressure (BP) were measured at baseline and every 6 months for a 2 year period. RESULTS: A1c, LDL and BP were no different at the end of 2 years in the GDC cohort and the PCP cohort. Slight upward trend in time was detected for A1c in both groups, but more so in the PCP group. CONCLUSION: GDC can lead to maintenance of diabetes control in a population with difficult to manage diabetes as effectively as and more efficiently than usual care. PMID- 20947461 TI - Developmental validation of the IrisPlex system: determination of blue and brown iris colour for forensic intelligence. AB - The IrisPlex system consists of a highly sensitive multiplex genotyping assay together with a statistical prediction model, providing users with the ability to predict blue and brown human eye colour from DNA samples with over 90% precision. This 'DNA intelligence' system is expected to aid police investigations by providing phenotypic information on unknown individuals when conventional DNA profiling is not informative. Falling within the new area of forensic DNA phenotyping, this paper describes the developmental validation of the IrisPlex assay following the Scientific Working Group on DNA Analysis Methods (SWGDAM) guidelines for the application of DNA-based eye colour prediction to forensic casework. The IrisPlex assay produces complete SNP genotypes with only 31pg of DNA, approximately six human diploid cell equivalents, and is therefore more sensitive than commercial STR kits currently used in forensics. Species testing revealed human and primate specificity for a complete SNP profile. The assay is capable of producing accurate results from simulated casework samples such as blood, semen, saliva, hair, and trace DNA samples, including extremely low quantity samples. Due to its design, it can also produce full profiles with highly degraded samples often found in forensic casework. Concordance testing between three independent laboratories displayed reproducible results of consistent levels on varying types of simulated casework samples. With such high levels of sensitivity, specificity, consistency and reliability, this genotyping assay, as a core part of the IrisPlex system, operates in accordance with SWGDAM guidelines. Furthermore, as we demonstrated previously, the IrisPlex eye colour prediction system provides reliable results without the need for knowledge on the bio-geographic ancestry of the sample donor. Hence, the IrisPlex system, with its model-based prediction probability estimation of blue and brown human eye colour, represents a useful tool for immediate application in accredited forensic laboratories, to be used for forensic intelligence in tracing unknown individuals from crime scene samples. PMID- 20947462 TI - Practical determination of the low template DNA threshold. AB - The low template stochastic DNA threshold is used to infer the genotype of a single STR allelic peak. For example, within the context of the UK National DNA Database, the stochastic threshold is used to decide whether a DNA profile, consisting of a peak in position of allele a, is uploaded as aF or as an aa homozygote. The F designation acts as a 'fail-safe' wild card that is designed to capture the possibility of allele drop-out and to do this it will match any allele. If a profile is wrongly designated as an aa homozygote, the database search will be unnecessarily restricted and may fail to match a perpetrator reference sample on the database. If the stochastic threshold is too high, then this increases the number of adventitious matches, which in turn compromises the utility of the national DNA database. There are many different methods used to process DNA profiles. Often, the same stochastic threshold is used for each process (typically 150rfu). But this means that more sensitive methods will have a threshold that is too low (and vice versa) and the risks of a wrongful designation are correspondingly greater. Recently, it was suggested that logistic regression could be used to relate the stochastic threshold to a defined probability of drop-out in order to properly evaluate the risks associated with a given stochastic threshold. In this article we introduce a new methodology to calculate the stochastic threshold that a practitioner could easily implement. The threshold depends on the sensitivity of the method employed, and is adjusted to be equivalent across all methods used to analyse DNA profiles. This ensures that risks associated with misdesignation are equivalent across all methods. In effect a uniformity of methods, underpinned by an analysis of risks associated with misdesignation can be achieved. PMID- 20947463 TI - Inequalities in adoption of cancer screening from a diffusion of innovation perspective: identification of late adopters. AB - BACKGROUND: Although national-level organized cancer screening programs have reduced barriers to screening for people of low socioeconomic status, barriers to early screening remain. Our aim was to determine the diffusion pattern and identify the factors associated with early participation in stomach and breast cancer screening programs. METHODS: The study population was derived from the Korean National Cancer Screening Survey, conducted in 2007. A stratified random sample of people aged 40 years and older from a nationwide population-based database was gathered in Korea (n=1,517) in 2007. Time of participation in early screening was defined as the number of years that had elapsed between the participant's 30th birthday and the age at first screening. RESULTS: Significant differences were observed in the probability of adopting stomach and breast cancer screening in relation to education, household income, and job level. Results from Cox's proportional hazard model indicated that higher household income was significantly associated with an increased probability of adopting stomach cancer screening earlier (p<0.05), and people with high household incomes were more likely to adopt breast cancer screening earlier than were those with incomes under US$1,500 per month (p<0.01). When considered at a significance level of 0.1, we found that the most highly educated women were more likely than the least educated to be screened early. CONCLUSIONS: Despite organized governmental screening programs, there are still inequalities in the early adoption of cancer screening. The results of this study also suggest that inequalities in early adoption may affect participation in regular screening. PMID- 20947464 TI - Colorectal cancer after breast cancer: a case-control study. AB - INTRODUCTION: The risk of colorectal cancer (CRC) after BC and the additional risk factor of tamoxifen exposure were investigated by several studies with conflicting results. We performed a case-control study aimed at investigating if a past history of breast cancer is a risk factor of developing adenomas or CRC and establishing whether tamoxifen exposure is an additional risk factor. MATERIALS AND METHODS: We enrolled 175 asymptomatic women with a past history of BC and invited them to undergo a screening colonoscopy. In the same period, we enrolled 201 healthy asymptomatic women (HG) with no family history of CRC which were referred to our Unit for a colonoscopy. RESULTS: Mean age at colonoscopy was 56.9 years for BC patients vs. 56.3 years for HG (p=0.58). In 32/175 (18.3%) BC patients, 38 lesions and in 17/201 (8.4%) controls, 20 lesions (p=0.029) were diagnosed. BC patients had 5/32 CRC vs. no CRC in the HG. Multivariate analysis of age, family history of CRC, timing from BC diagnosis and first colonoscopy, tamoxifen treatment revealed that none of the variables were predictive of the presence or absence of adenomas or CRC in the BC group. DISCUSSION: In the present study BC group had a significant higher prevalence of adenoma or CRC than controls. Tamoxifen exposure did not increase the risk of adenoma or CRC. Our data support the hypothesis that BC is a risk condition for adenomas or CRC. The risk is small but present and a screening colonoscopy should be offered to these patients. PMID- 20947465 TI - Factors associated with use of ultrasonography screening for hepatocellular carcinoma among hepatitis B or C carriers. AB - OBJECTIVES: Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are important risk factors for hepatocellular carcinoma (HCC). Yet, there have been few studies on adherence to screening recommendations for groups at high risk for HCC. We assessed whether demographic factors or medical conditions affected screening participation among HBV/HCV carriers. METHODS: The study population consisted of 15565 men and women who visited the National Cancer Center, Korea between August 2002 and July 2009. A self-administered questionnaire was used to collect information on demographic characteristics, medical history, including chronic HBV and HCV infection, and health check-up history. HBV surface antigen and HCV antibody levels were measured in serum. RESULTS: Among 781 HBV carriers, 596 (76.3%) were aware of their infection and 451 (57.8%) had ever been tested by ultrasonography. Among HCV carriers, 49 of 127 (36.6%) were aware of their infection and 61 (48.0%) had ever been tested by ultrasonography. Among HBV carriers, male sex (OR, 1.68; 95% CI, 1.22-2.31), family history of liver disease (OR, 2.04; 95% CI, 1.43-2.90), medical history of hyperlipidemia (OR, 2.70; 95% CI, 1.36-5.33), and awareness of infection status (OR, 4.30; 95% CI, 2.99-6.17) were associated with being tested. Among HCV carriers, awareness of infection (OR, 3.77; 95% CI, 1.72-8.26) was significantly associated with being tested by ultrasonography. CONCLUSION: Male sex, family history of liver disease, medical history of hyperlipidemia, and awareness of high risk status were associated with being tested by ultrasonography. PMID- 20947466 TI - Examination of lower facial skin movements during left- and right-side chewing. AB - PURPOSE: The purpose of this study was to temporally and spatially analyze movements of lower facial skin during left- and right-side chewing in order to examine, from the viewpoint of kinematics, whether functional differences existed between these movements on the two sides. METHODS: Ten healthy young subjects (aged 24-32 years, mean age 26.7 years) were included in this study. The test bolus used in this study was sufficiently softened chewing gum. The cycle time, mean square error value and mean difference vector value of chewing paths were used as parameters. RESULTS: Cycle times of movements of lower facial skin during gum chewing were invariant and stable on each chewing side, and showed no significant differences between the sides. The similarities of chewing paths and directions of movements of lower facial skin during gum chewing showed mirror image relationships between the sides. Furthermore, these relationships during gum chewing were stable on both sides. CONCLUSIONS: Based on these findings, it was found that movements of lower facial skin during left- and right-side chewing in healthy subjects were temporally and spatially invariant, stable and similar on both sides. Moreover, the present results suggest, from the viewpoint of kinematics, that a functional difference may not exist between these movements on the two sides. PMID- 20947468 TI - Global climate change and children's health: threats and strategies for prevention. AB - BACKGROUND: Global climate change will have multiple effects on human health. Vulnerable populations-children, the elderly, and the poor-will be disproportionately affected. OBJECTIVE: We reviewed projected impacts of climate change on children's health, the pathways involved in these effects, and prevention strategies. DATA SOURCES: We assessed primary studies, review articles, and organizational reports. DATA SYNTHESIS: Climate change is increasing the global burden of disease and in the year 2000 was responsible for > 150,000 deaths worldwide. Of this disease burden, 88% fell upon children. Documented health effects include changing ranges of vector-borne diseases such as malaria and dengue; increased diarrheal and respiratory disease; increased morbidity and mortality from extreme weather; changed exposures to toxic chemicals; worsened poverty; food and physical insecurity; and threats to human habitation. Heat-related health effects for which research is emerging include diminished school performance, increased rates of pregnancy complications, and renal effects. Stark variation in these outcomes is evident by geographic region and socioeconomic status, and these impacts will exacerbate health disparities. Prevention strategies to reduce health impacts of climate change include reduction of greenhouse gas emissions and adaptation through multiple public health interventions. CONCLUSIONS: Further quantification of the effects of climate change on children's health is needed globally and also at regional and local levels through enhanced monitoring of children's environmental health and by tracking selected indicators. Climate change preparedness strategies need to be incorporated into public health programs. PMID- 20947470 TI - In vitro chemosensitivity of head and neck cancer cell lines. AB - BACKGROUND: Systemic treatment of head and neck squamous cell carcinoma (HNSCC) includes a variety of antineoplastic drugs. However, drug-resistance interferes with the effectiveness of chemotherapy. Preclinical testing models are needed in order to develop approaches to overcome chemoresistance. - METHODS: Ten human cell lines were obtained from HNSCC, including one with experimentally-induced cisplatin resistance. Inhibition of cell growth by seven chemotherapeutic agents (cisplatin, carboplatin, 5- fluorouracil, methotrexate, bleomycin, vincristin, and paclitaxel) was measured using metabolic MTT-uptake assay and correlated to clinically-achievable plasma concentrations. - RESULTS: All drugs inhibited cell growth in a concentration-dependent manner with an IC50 comparable to that achievable in vivo. However, response curves for methotrexate were unsatisfactory and for paclitaxel, the solubilizer cremophor EL was toxic. Cross-resistance was observed between cisplatin and carboplatin. - CONCLUSION: Chemosensitivity of HNSCC cell lines can be determined using the MTT-uptake assay. For DNA interfering cytostatics and vinca alkaloids this is a simple and reproducible procedure. Determined in vitro chemosensitivity serves as a baseline for further experimental approaches aiming to modulate chemoresistance in HNSCC with potential clinical significance. PMID- 20947467 TI - Proton magnetic resonance spectroscopy in adults with childhood lead exposure. AB - BACKGROUND: Childhood lead exposure adversely affects neurodevelopment. However, few studies have examined changes in human brain metabolism that may underlie known adverse cognitive and behavioral outcomes. OBJECTIVE: We examined the association between mean childhood blood lead levels and in vivo brain metabolite concentrations as adults, determined by proton magnetic resonance spectroscopy (MRS) in a birth cohort with documented low-to-moderate lead exposure. METHODS: Adult participants from the Cincinnati Lead Study [n = 159; mean age (+/- SD), 20.8 +/- 0.9 years] completed a quantitative, short-echo proton MRS protocol evaluating seven regions to determine brain concentrations of N-acetyl aspartate (NAA), creatine and phosphocreatine (Cr), cholines (Cho), myo-inositol, and a composite of glutamate and glutamine (GLX). Correlation and multiple linear regression analyses were conducted. RESULTS: Mean childhood blood lead levels were associated with regionally specific brain metabolite concentrations adjusted for age at imaging and Full-Scale intelligence quotient. Adjusted analyses estimated for a unit (micrograms per deciliter) increase in mean childhood blood lead concentrations, a decrease of NAA and Cr concentration levels in the basal ganglia, a decrease of NAA and a decrease of Cho concentration levels in the cerebellar hemisphere, a decrease of GLX concentration levels in vermis, a decrease of Cho and a decrease of GLX concentration levels in parietal white matter, and a decrease of Cho concentration levels in frontal white matter. CONCLUSIONS: Gray-matter NAA reductions associated with increasing childhood blood lead levels suggest that sustained childhood lead exposure produces an irreversible pattern of neuronal dysfunction, whereas associated white-matter choline declines indicate a permanent alteration to myelin architecture. PMID- 20947471 TI - Liver volume measurement: reason of the difference between in vivo CT-volumetry and intraoperative ex vivo determination and how to cope it. AB - PURPOSE: Volumetric assessment of the liver regularly yields discrepant results between pre- and intraoperatively determined volumes. Nevertheless, the main factor responsible for this discrepancy remains still unclear. The aim of this study was to systematically determine the difference between in vivo CT-volumetry and ex vivo volumetry in a pig animal model. MATERIAL AND METHODS: Eleven pigs were studied. Liver density assessment, CT-volumetry and water displacement volumetry was performed after surgical removal of the complete liver. Known possible errors of volume determination like resection or segmentation borders were eliminated in this model. Regression analysis was performed and differences between CT-volumetry and water displacement determined. RESULTS: Median liver density was 1.07g/ml. Regression analysis showed a high correlation of r(2) = 0.985 between CT-volumetry and water displacement. CT-volumetry was found to be 13% higher than water displacement volumetry (p<0.0001). CONCLUSION: In this study the only relevant factor leading to the difference between in vivo CT volumetry and ex vivo water displacement volumetry seems to be blood perfusion of the liver. The systematic difference of 13 percent has to be taken in account when dealing with those measures. PMID- 20947472 TI - Different surgical strategies for chronic pancreatitis significantly improve long term outcome: a comparative single center study. AB - OBJECTIVE: In general, chronic pancreatitis (CP) primarily requires conservative treatment. The chronic pain syndrome and complications make patients seek surgical advice, frequently after years of progression. In the past, surgical procedures involving drainage as well as resection have been employed successfully. The present study compared the different surgical strategies. - PATIENTS AND METHODS: From March 2000 until April 2005, a total of 51 patients underwent surgical treatment for CP at the Department of surgery, University of Schleswig-Holstein, Campus Lubeck. Out of those 51 patients, 39 (76.5%) were operated according to the Frey procedure, and in 12 cases (23.5%) the Whipple procedure was performed. Patient data were documented prospectively throughout the duration of the hospital stay. The evaluation of the postoperative pain score was carried out retrospectively with a validated questionnaire. RESULTS: Average operating time was 240 minutes for the Frey group and 411 minutes for the Whipple group. The medium number of blood transfusions was 1 in the Frey group and 4.5 in the Whipple group. Overall morbidity was 21% in the Frey group and 42% in the Whipple group. 30-day mortality was zero for all patients. During the median follow-up period of 50 months, an improvement in pain score was observed in 93% of the patients of the Frey group and 67% of the patients treated according to the Whipple procedure. CONCLUSION: The results show that both the Frey procedure as well as partial pancreaticoduodenectomy are capable of improving chronic pain symptoms in CP. As far as later endocrine and exocrine pancreatic insufficiency is concerned, however, the extended drainage operation according to Frey proves to be advantageous compared to the traditional resection procedure by Whipple. Accordingly, the Frey procedure provides us with an organ-preserving surgical procedure which treats the complications of CP sufficiently, thus being an alternative to partial pancreaticoduodenectomy if there is no suspicion of malignancy. PMID- 20947473 TI - Tumor markers as a diagnostic key for hilar cholangiocarcinoma. AB - OBJECTIVE: Hilar cholangiocarcinoma is the fourth most common gastrointestinal malignancy. CA19-9 and CEA are helpful devices in the management of gastrointestinal malignancies and belong to clinical routine in surgical oncology. But the validity of these parameters in terms of tumor extension and prognosis of bile duct malignancies still remains unclear. METHODS: From 1998 to 2008, we obtained preoperative CA19-9 and CEA serum levels in 136 patients with hilar cholangiocarcinoma. We correlated tumor stage, resectability rate and survival with preoperative CA 19-9 and CEA serum levels. RESULTS: CA19-9 (UICC I: 253 +/- 561U/ml; UICC II: 742 +/- 1572 U/ml; UICC III: 906 +/- 1708 U/ml; UICC IV: 1707 +/- 3053U/ml) and CEA levels (UICC I: 2.9 +/- 3.8U/ml; UICC II: 4.6 +/- 6.5 U/ml; UICC III: 18.1 +/- 29.6 U/ml; UICC IV: 22.7 +/- 53.9 U/ml) increase significantly with rising tumor stage. Patients with pre?operative serum levels of CA19-9 (>1000U/ml) and CEA (>14.4ng/ml) showed a significant poorer resectability rate and survival than patients with lower CA19-9 and CEA serum levels respectively. CONCLUSION: CA19-9 and CEA serum levels are associated with the tumor stage. If preoperatively obtained CA19-9 and CEA serum levels are highly elevated patients have an even worse survival and the frequency of irresectability is significantly higher. PMID- 20947474 TI - What harm does a second delivery to the pelvic floor? AB - OBJECTIVE: To compare the pelvic floor function of primiparous women to women after a second delivery regarding symptoms of urinary and anal incontinence, anal sphincter ruptures and bladder-neck mobility. METHODS: A questionnaire evaluating symptoms of urinary and anal incontinence was used in nulliparous women before and 27 months after childbirth. Furthermore these symptoms were correlated with functional changes of the pelvic floor based on a careful gynecologic examination as well as perineal and endoanal ultrasound. RESULTS: 112 nulliparous women were included, 49 women returned for follow-up on average 27 months (SD 4.4 months) after the first delivery. 39 women (group A) had just one delivery, 10 women (group B ? 10/49) had had a second delivery. Apart from levator ani muscle strength, no significant difference between pelvic floor function of group A vs group B was demonstrable. Furthermore, we could show no significant difference for symptoms of urinary (11 (28.2%) vs. 5 (50.0%)) and anal incontinence (14 (35.9%) vs. 4 (40.0%)) between both groups. However, we found a lasting increase of stress urinary and anal incontinence as well as overactive bladder symptoms after one or more deliveries. The position of the bladder neck at rest was lower in both groups compared to the position before the first delivery and bladder neck mobility increased after one or more deliveries. DISCUSSION: Our study shows several statistically significant changes of the pelvic floor function even on average 27 months after delivery, but a subsequent delivery did not compromise the pelvic floor any further. PMID- 20947475 TI - Extranodal diffuse non hodgkin lymphoma in the thigh. AB - Diffuse large B-cell lymphoma usually starts as a rapidly growing mass in an internal lymph node and can grow in other areas such as the bone or intestines. About 1/3 of these lymphomas are confined to one part of the body when they are localized. In the case of a 78-year-old man, an extensive tumour was located on the right thigh. Biopsies of the tumour revealed diffuse proliferation of large lymphoid cells which have totally affected the normal architecture of striated muscle. The patient received multimodality treatment including chemotherapy of the CHOP regimen and adjuvant radiotherapy. Despite this being a fast growing lymphoma, about 3 out of 4 people will have no signs of disease after initial treatment, and about half of all people with this lymphoma are cured with therapy. PMID- 20947476 TI - [Communication around the cancer diagnosis: patient satisfaction and process quality in French Comprehensive Cancer Centers]. AB - BACKGROUND: Our survey was designed to evaluate the satisfaction of patients treated in French Comprehensive Cancer Centers (CCC) with the communication of their cancer diagnosis and treatments, and to use the data obtained to optimize current practices. METHODS: One thousand six hundred (and) six CCC patients participated in a telephone survey. Eligible patients were attending a visit to a CCC for initial care of their disease (i.e. not a relapse). The questionnaire assessed patient satisfaction with the communication of diagnosis and treatment options, globally and with respect to potential individual determinants of satisfaction. FINDINGS: Complete satisfaction was recorded by 77% of patients with their overall care at the CCC and by 63% of patients with the initial consultation when diagnosis was communicated and/or treatment discussed. Overall, 90% of patients were satisfied with the level of their implication in discussions about their care. A model established by Partial Least Squares (PLS) regression analysis, identified four major areas and their relative contributions to patient satisfaction: patient's relationship with their physician (64%); nature of the information provided (14%; influenced strongly by information on type, duration and practical organization of planned treatment); agenda/diary issues (14%; influenced strongly by waiting room delay); accompaniment (8%; influenced equally by support from close family and patient association/self-help groups). INTERPRETATION: Overall satisfaction was high in cancer patients attending visits for initial care in French CCC. The model we devised to understand components of satisfaction could serve as a benchmark for evolution of outcomes in this field. PMID- 20947477 TI - The Nobel Prize in physiology or medicine 2009 "for telomere biology" and its relevance to cancer and related diseases. PMID- 20947478 TI - Telemedicine: shortening distances. PMID- 20947479 TI - Myelodysplastic syndromes: an update on molecular pathology. AB - The myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid disorders characterised by impaired peripheral blood cell production due to bone marrow dysplasia affecting one or more of the major myeloid cell lines. MDS are one of five major categories of myeloid neoplasms according to the World Health Organization (WHO) classification system for haematological cancers. Given their cytological and cytogenetic heterogeneity, these diseases probably constitute a group of molecularly distinct entities with variable degrees of ineffective haematopoiesis and susceptibility to leukaemic transformation. Recent studies provide some insights into the physiopathology of MDS. In the early stages, one mechanism contributing to hypercellular marrow and peripheral blood cytopenia is a significant increase in programmed cell death (apoptosis) in haematopoietic cells. Furthermore, altered responses in relation to cytokines, the immune system and bone marrow stroma also contribute to the disease phenotype. Deletions of chromosome 5q31-q32 are the most common recurring cytogenetic abnormalities detected in MDS. The 5q- syndrome is a new entity recognised in the WHO classification since 2001 and is associated with a good prognosis. Haploinsufficiency of multiple genes mapping to the common deleted region at 5q31 32 may contribute to the pathogenesis of 5q- syndrome and other MDS with 5q- deletion. Many studies have demonstrated that altered DNA methylation and histone acetylation can alter gene transcription. Abnormal methylation of transcription promoter sites is universal in patients with MDS, and the number of involved loci is increased in high-risk disease and secondary leukaemias. A better understanding of the pathogenesis of MDS can contribute to the development of new treatments such as hypomethylating drugs, immunomodulatory agents such as lenalidomide, and immunosuppressive drugs aimed at reversing the specific alteration that results in improvement in patients with MDS. PMID- 20947481 TI - Clinical implications of KIT and PDGFRA genotyping in GIST. AB - Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs are characterised by the expression of KIT, a type III tyrosine kinase receptor, and the presence of mutations in KIT or PDGFRA in about 80-85% of cases. The primary treatment for GIST is surgery, which cures most patients with low- or intermediate-risk tumours. The introduction of the kinase inhibitor imatinib mesylate, and sunitinib in second line, against KIT and PDGFRA has provided the first evidence of directed therapy in GIST. The aim of this review is to highlight the growing evidence that KIT and PDGFRA genotyping provides valuable information for the clinical management of GIST patients. We show that KIT and PDGFRA genotyping has emerged as one of the principal factors in the evaluation of GISTs, particularly in those tumours that are clearly malignant or have a high risk of recurrence. In addition to helping establish the diagnosis of GIST in unusual cases, genotyping can be very useful to physicians and patients in deciding on imatinib dose, in estimating the likelihood and duration of benefit, and potentially in selecting second-line therapies. PMID- 20947480 TI - Targeting cytoskeleton reorganisation as antimetastatic treatment. AB - Metastatic relapse is responsible for 90% of cancer-related deaths. The process of distant spreading is a cascade of events that is regulated in a highly complex manner; one cellular phenomenon underlying all the events is cytoskeletal reorganisation. Despite the fact that the ability to leave the primary site and establish a viable mass in a distant site is a hallmark of cancer, targeting cytoskeletal reorganisation is an emerging field. In this review we describe the key signalling pathways controlling cytoskeletal reorganisation and the current targeted therapies against the "druggable" nodes. Finally, we discuss potential implications of trial design that can play a role in detecting the specific activity of this drug class. PMID- 20947482 TI - Updating controversies on the multidisciplinary management of gastric cancer. AB - The rates of relapse and death remain high in gastric cancer patients, especially in advanced stages. Local relapses in the tumour bed and regional lymph nodes, peritoneal spread as abdominal carcinomatosis, and distant metastasis are common mechanisms of failure after a R0 resection. To overcome this, a multidisciplinary approach has been prompted. In recent years, multidisciplinary treatment has been strengthened by some randomised controlled trials and it is now considered the standard by most groups, although the improvement in long-term survival rates achieved is still limited. This new therapeutic approach in gastric cancer is rapidly evolving and has led to a series of controversies on the best strategy to follow. Some of these controversies are discussed in this paper. PMID- 20947483 TI - Smoking habits in elderly lung cancer patients: still no changes in epidemiology? A single-center experience. AB - PURPOSE: Our goal was to describe the clinical, histological, and epidemiological characteristics of lung cancer diagnoses in people >=70 years of age. MATERIALS AND METHODS: Information on patients diagnosed with lung cancer from January 2006 to February 2008 was prospectively collected from the outpatient oncology department at a regional hospital. A total of 83 patients (97.6% men; mean age 77 years) were studied. There was a higher ratio of men to women than that reported in younger populations. Mean age was higher than that reported for randomized studies: 65.1% were >=75 years old. Patients >80 years constituted 28.9% of the study population. Most patients (96.4%) had a history of smoking; they were predominantly former smokers (72.5% vs. 27.5%). RESULTS: The most common histological types were squamous cell (61.3%) and small cell (14.5%) carcinoma. Metastasis was present in 36.1% of patients. Stage was significantly associated with survival (logrank p < 0.001). There was no association between age and survival. Squamous cell lung cancer was associated with a better survival (p = 0.003). CONCLUSIONS: Elderly lung cancer patients who attended clinical practice were older than those included in prospective studies. The predominance of men and squamous cell carcinoma is associated with a smoking history. The epidemiological and histological patterns of younger patients have changed, possibly in relation to changes in smoking habits. The translation of these changes to elderly patients will be evidenced in the future. Only prospective epidemiologic studies will determine whether smoking habits are changing epidemiology in elderly lung cancer patients. PMID- 20947484 TI - Cost-effectiveness analyses of docetaxel versus paclitaxel once weekly in patients with metastatic breast cancer in progression following anthracycline chemotherapy, in Spain. AB - OBJECTIVES: Our aim was to evaluate the cost-effectiveness of docetaxel versus weekly paclitaxel regimen in patients with metastatic breast cancer previously treated with anthracycline from the Spanish National Health Service (NHS) perspective. METHODS: A Markov model with a 21-day cycle duration was developed to estimate total treatment-related costs and clinical benefits over 5 years of docetaxel (100 mg/m2) and weekly paclitaxel (80 mg/m2). Patient data were obtained from the Randomized Phase III Study of Docetaxel Compared with Paclitaxel in Metastatic Breast Cancer (TAX- 311) and Anglo-Celtic IV trials. Utilities were obtained from literature, and unitary costs (?2009) from a Spanish health-cost database and the Catalogue of Medicines. Cost and benefits [life years gained (LYG) and quality-adjusted life years (QALY)] were discounted at 3%. Sensitivity analyses were performed. RESULTS: Docetaxel yields higher health benefits (1.83 LYG; 1.08 QALY) than paclitaxel (1.46 LYG; 0.84 QALY). Global costs (treatment, concomitant medication, adverse events management, progression, best supportive care, and end of life phase) per patient were ?20,052 and ?9,982 with docetaxel and paclitaxel, respectively. Incremental cost-effectiveness ratio (ICER) of docetaxel versus paclitaxel was ?190/LYG and ?295/QALY. Based on a ?30,000/QALY threshold, docetaxel has 99% probability of being cost-effective. ICER was mostly sensitive to hazard ratio (HR) (when varied from 1.46 to 1.09; ?3,517/ QALY), discount over the ex-lab price of Taxol(r) (75%; ?6,396/QALY) and granulocyte colony-stimulating factor (G-CSF) prophylactic treatment (when administered in 60% of cycles instead of 100%; cost saving). Variations in other inputs, such as time horizon (3-10 years), discount rate (0-5%), or adverse event cost (+/- 25%) were shown not to have relevant influence on the results. CONCLUSION: Compared to weekly paclitaxel, docetaxel therapy is cost effective for treating metastatic breast cancer patients. PMID- 20947485 TI - Ocular relapse of primary brain lymphoma in immunocompetent patient, treated with intrathecal rituximab. AB - Primary brain lymphoma is a rare variant of extranodal non-Hodgkin's B-cell lymphoma. In >90% of cases, this is diffuse large B-cell lymphoma with CD20 expression and is confined to the brain, meninges, spinal cord, and eyes. It accounts for fewer than 7% of primary brain tumors. Its incidence has been rising in recent years in immunocompetent patients in their fifth and sixth decades. The rate of relapse after initial therapy based on high-dose methotrexate and/or total brain irradiation is high. There is no consensus for treating relapse, which ranges from retreatment with high doses of methotrexate, polychemotherapy, high doses of chemotherapy backed up by autologous stem-cell transplant to intrathecal chemotherapy, with widely differing results. Given the lack of consensus and poor results, new therapy options have appeared, including immunotherapy with rituximab. At a systemic level, alongside chemotherapy, its results are very modest and limited due to the low concentration it reaches in cerebrospinal fluid (CSF). However, its intrathecal and intraventricular use, though only isolated cases have been reported, has provided promising results. PMID- 20947486 TI - Cystosarcoma phyllodes of the breast: a case report in a 12-year-old girl. AB - Breast tumors in adolescents are very rare and mostly benign. Fibroadenomas are the most frequent, but within the extensive differential diagnosis, the phyllodes tumor must be mentioned, which accounts for about 1% of breast tumors and the diagnosis of which is very rare in patients younger than 20 years. There are no specific symptoms or radiological images to distinguish phyllodes tumor from fibroadenoma; therefore, histological examination is mandatory for diagnosis. Histology also allows the classification of phyllodes tumor into benign, borderline, or malignant types for appropriate surgical treatment: freemargin excision in benign tumors and mastectomy in the other two types. Fortunately, the majority of these tumors are benign, and treatment maximizes breast conservation with free infiltration margins surgery, given that this fact is the most important factor to prevent local recurrence. In this article, we describe a rare case of borderline cystosarcoma phyllodes in a 12-year-old girl. PMID- 20947487 TI - A comprehensive survey of clonal diversity measures in Barrett's esophagus as biomarkers of progression to esophageal adenocarcinoma. AB - Neoplastic progression is an evolutionary process driven by the generation of clonal diversity and natural selection on that diversity within a neoplasm. We hypothesized that clonal diversity is associated with risk of progression to cancer. We obtained molecular data from a cohort of 239 participants with Barrett's esophagus, including microsatellite shifts and loss of heterozygosity, DNA content tetraploidy and aneuploidy, methylation, and sequence mutations. Using these data, we tested all major diversity measurement methods, including genetic divergence and entropy-based measures, to determine which measures are correlated with risk of progression to esophageal adenocarcinoma. We also tested whether the use of different sets of loci and alterations to define clones (e.g., selectively advantageous versus evolutionarily neutral) improved the predictive value of the diversity indices. All diversity measures were strong and highly significant predictors of progression (Cox proportional hazards model, P < 0.001). The type of alterations evaluated had little effect on the predictive value of most of the diversity measures. In summary, diversity measures are robust predictors of progression to cancer in this cohort. PMID- 20947488 TI - Metformin and cancer risk in diabetic patients: a systematic review and meta analysis. AB - Metformin, an insulin-lowering agent, has been associated with decreased cancer risk in epidemiologic studies in diabetic patients. We performed a comprehensive literature search and meta-analysis of epidemiologic studies to assess the effect of metformin on cancer incidence and mortality in diabetic patients, using Pubmed, ISI Web of Science, Embase, and the Cochrane library until May 2009, with no language or time restrictions. Independent reports with sufficient information to allow risk estimation of cancer risk/mortality and a measure of uncertainty were reviewed and cross-checked independently by three investigators. Eleven studies were selected for relevance in terms of intervention, population studied, independence, and reporting of cancer incidence or mortality data, reporting 4,042 cancer events and 529 cancer deaths. A 31% reduction in overall summary relative risk (0.69; 95% confidence interval, 0.61-0.79) was found in subjects taking metformin compared with other antidiabetic drugs. The inverse association was significant for pancreatic and hepatocellular cancer, and nonsignificant for colon, breast, and prostate cancer. A trend to a dose-response relationship was noted. Metformin is associated with a decreased risk of cancer incidence compared with other treatments among diabetic patients. Given the retrospective nature of most studies and the possibility that the control treatments increase risk, phase II trials are needed before large cancer prevention trials are launched. PMID- 20947489 TI - A mouse model for human anal cancer. AB - Human anal cancers are associated with high-risk human papillomaviruses (HPV) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncogenic properties including, but not limited to, their capacity to inactivate the cellular tumor suppressors p53 and pRb, respectively. Both E6 and E7 were found to be functionally expressed in the anal epithelia of K14E6/K14E7 transgenic mice. To assess the susceptibility of these mice to anal cancer, mice were treated topically with dimethylbenz[a]anthracene (DMBA), a chemical carcinogen that is known to induce squamous cell carcinomas in other sites. Nearly 50% of DMBA-treated HPV16 E6/E7 transgenic mice showed overt signs of tumors, whereas none of the like-treated nontransgenic mice showed tumors. Histopathologic analyses confirmed that the HPV16 transgenic mice were increased in their susceptibility to anal cancers and precancerous lesions. Biomarker analyses demonstrated that these mouse anal cancers exhibit properties that are similar to those observed in HPV-positive precursors to human anal cancer. This is the first mouse model for investigating the contributions of viral and cellular factors in anal carcinogenesis, and should provide a platform for assessing new therapeutic modalities for treating and/or preventing this type of cancer. PMID- 20947490 TI - Proanthocyanidins inhibit photocarcinogenesis through enhancement of DNA repair and xeroderma pigmentosum group A-dependent mechanism. AB - Dietary grape seed proanthocyanidins (GSP) inhibit photocarcinogenesis in mice; however, the molecular mechanisms underlying this effect have not been fully elucidated. As ultraviolet B (UVB)-induced DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) has been implicated in skin cancer risk, we studied whether dietary GSPs enhance repair of UVB-induced DNA damage and, if so, what is the potential mechanism? Supplementation of GSPs (0.5%, w/w) with AIN76A control diet significantly reduced the levels of CPD(+) cells in UVB-exposed mouse skin; however, GSPs did not significantly reduce UVB-induced CPD(+) cells in the skin of interleukin-12p40 (IL-12) knockout (KO) mice, suggesting that IL-12 is required for the repair of CPDs by GSPs. Using IL-12 KO mice and their wild-type counterparts and standard photocarcinogenesis protocol, we found that supplementation of control diet with GSPs (0.5%, w/w) significantly reduced UVB induced skin tumor development in wild-type mice, which was associated with the elevated mRNA levels of nucleotide excision repair genes, such as XPA, XPC, DDB2, and RPA1; however, this effect of GSPs was less pronounced in IL-12 KO mice. Cytostaining analysis revealed that GSPs repaired UV-induced CPD(+) cells in xeroderma pigmentosum complementation group A (XPA)-proficient fibroblasts from a healthy individual but did not repair in XPA-deficient fibroblasts from XPA patients. Furthermore, GSPs enhance nuclear translocation of XPA and enhanced its interactions with other DNA repair protein ERCC1. Together, our findings reveal that prevention of photocarcinogenesis by GSPs is mediated through enhanced DNA repair in epidermal cells by IL-12- and XPA-dependent mechanisms. PMID- 20947491 TI - Oscillatory MEG motor activity reflects therapy-related plasticity in stroke patients. AB - BACKGROUND: A goal of stroke rehabilitation is to harness the capacity of the brain to reorganize following neurological damage and enable restoration of function. OBJECTIVE: To understand how neural oscillatory motor responses change following a therapeutic intervention and to illuminate whether these neurophysiological alterations correlate with improvements on behavioral measurements. METHODS: Magnetoencephalography (MEG) was used to evaluate plasticity in motor networks following 2 weeks of intensive task-oriented therapy, which was paired with sham or peripheral nerve stimulation (PNS). Patients completed unilateral finger tapping before and 3 weeks after therapy as whole-head MEG data were acquired. MEG data were imaged using beamforming, and the resulting event-related synchronizations and desynchronizations (ERSs/ERDs) were subjected to region-of-interest (ROI) analyses. For each ROI, the authors compared the baseline and postintervention MEG response amplitude, volume, and peak location for premovement beta ERD, movement-onset gamma ERS, and postmovement beta ERS. RESULTS: Following therapy, all patients showed reduced postmovement beta ERS response amplitudes in bilateral precentral gyri and reduced gamma ERS amplitudes in the precentral gyrus of the affected hemisphere. This latter response also distinguished treatment groups, as the posttherapy gamma reduction was greater in patients who received PNS. Finally, both beta and gamma response amplitudes were significantly correlated with improvement on several behavioral indices of motor function. DISCUSSION: These case-series data indicate that oscillatory MEG responses may be useful in gauging plasticity in motor cortices following therapy in stroke patients. PMID- 20947492 TI - Mesencephalic corticospinal atrophy predicts baseline deficit but not response to unilateral or bilateral arm training in chronic stroke. AB - OBJECTIVE: Stroke survivors with motor deficits often have pyramidal tract atrophy caused by degeneration of corticospinal fibers. The authors hypothesized that the degree of atrophy correlates with severity of motor impairment in patients with chronic stroke and predicts the response to rehabilitation training. METHODS: They performed a post hoc analysis of 42 hemiparetic patients (>6 months) who had been randomized to either 6 weeks of bilateral arm training with rhythmic auditory cueing (BATRAC) or dose-matched therapeutic exercise (DMTE). Arm function was measured using the Fugl-Meyer (FM) and modified Wolf Motor Function Test (WMFT). Structural MRI and diffusion tensor imaging (DTI) on the pontine level measured corticospinal tract (CST) atrophy by planimetric measurement of the mesencephalon (mesencephalic atrophy ratio) and fractional anisotropy (FA), respectively. Voxel-based lesion symptom mapping (VLSM) was used to determine the lesions associated with highest degrees of atrophy. The predictive value of CST atrophy for impairment and training response was analyzed. RESULTS: CST atrophy predicted baseline motor arm function measured by the FM and WMFT. The authors found only a trend for the correlation with FA. No measure of atrophy predicted response to either BATRAC or DMTE. CST atrophy was higher with larger lesions and those that affected the CST. VLSM identified internal capsule lesions as being associated with highest CST atrophy. CONCLUSION: Larger lesions, internal capsule lesions, and those overlapping the pyramidal tract are associated with greater CST atrophy. CST atrophy explains in part the variability of baseline deficits but does not seem to predict the response to BATRAC or unilateral arm training on upper-extremity function. PMID- 20947493 TI - Randomized trial of distributed constraint-induced therapy versus bilateral arm training for the rehabilitation of upper-limb motor control and function after stroke. AB - BACKGROUND AND OBJECTIVE: This study compared the efficacy of distributed constraint-induced therapy (dCIT), bilateral arm training (BAT), and control treatment (CT) on motor control and functional performance of the upper limb in stroke patients. METHODS: A total of 66 patients with mean stroke onset of 16.20 months and mild to moderate motor impairment were randomized to dCIT, BAT, or CT groups. Each group received treatment for 2 h/d and 5 d/wk for 3 weeks. Pretreatment and posttreatment measures included reaching kinematic variables in unilateral and bilateral tasks, the Wolf Motor Function Test (WMFT), and the Motor Activity Log (MAL). RESULTS: The dCIT and BAT groups had smoother reaching trajectories in the unilateral and bilateral tasks than the CT group. The BAT group, but not the dCIT group, generated greater force at movement initiation than the CT group during the unilateral and bilateral tasks. The dCIT patients had decreased WMFT time and higher functional ability scores than the CT patients. MAL results pointed to better performance in the amount and quality of use of the affected arm than BAT and CT patients. CONCLUSIONS: BAT and dCIT exhibited similar beneficial effects on movement smoothness but differential effects on force at movement initiation and functional performance. Therefore, BAT is a better option if improvement of force generation is the treatment goal, and dCIT is more appropriate for improving functional ability and use of the affected arm in daily life. These findings may assist in the planning of individually tailored rehabilitation therapies. PMID- 20947494 TI - Assessing the streamlined Wolf motor function test as an outcome measure for stroke rehabilitation. AB - OBJECTIVE: This study investigates the clinimetric properties of the streamlined Wolf Motor Function Test (WMFT), a 6-item version of the performance time scale of the WMFT. METHODS: The streamlined WMFT, along with 2 criterion measures, the Fugl-Meyer Assessment (FMA) and the Stroke Impact Scale (SIS), were administered to 64 stroke patients before and after a 3-week intervention. Responsiveness was examined using the Wilcoxon signed rank test and standardized response mean (SRM). Criterion-related validity was investigated using the Spearman correlation coefficient (rho). RESULTS: The mean score on the baseline FMA upper extremity of the patients was 44.84 (standard deviation = 12.77). The streamlined WMFT and the original performance time scale showed comparable responsiveness (SRM = 0.29 and 0.37, respectively). The concurrent validity of the streamlined WMFT was good (rho = 0.57-0.69). For predictive validity, the streamlined WMFT showed slightly better association with the criterion measures (rho = 0.60-0.68) than did the original scale (rho = 0.56-0.64). CONCLUSIONS: Compared with the original scale, the streamlined WMFT showed improved clinical utility. PMID- 20947495 TI - Neuronal inactivation of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) protects mice from diet-induced obesity and leads to degenerative lesions. AB - Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is a transcriptional coactivator that regulates diverse aspects of energy metabolism in peripheral tissues. Mice deficient in PGC-1alpha have elevated metabolic rate and are resistant to diet-induced obesity. However, it remains unknown whether this alteration in energy balance is due to the action of PGC 1alpha in peripheral tissues or the central nervous system. In this study, we generated neuronal PGC-1alpha knock-out mice (BalphaKO) using calcium/calmodulin dependent protein kinase IIalpha (CaMKIIalpha)-Cre to address its role in the regulation of energy balance and neuronal function. Unlike whole body PGC-1alpha null mice, BalphaKO mice have normal adaptive metabolic response to starvation and cold exposure in peripheral tissues. In contrast, BalphaKO mice are hypermetabolic, and similar to whole body PGC-1alpha null mice, are also resistant to diet-induced obesity, resulting in significantly improved metabolic profiles. Neuronal inactivation of PGC-1alpha leads to striatal lesions that are reminiscent of neurodegeneration in whole body PGC-1alpha null brain and impairs nutritional regulation of hypothalamic expression of genes that regulate systemic energy balance. Together, these studies have demonstrated a physiological role for neuronal PGC-1alpha in the control of energy balance. Our results also implicate CaMKIIalpha-positive neurons as an important part of the neural circuitry that governs energy expenditure in vivo. PMID- 20947496 TI - GPRC6A mediates the non-genomic effects of steroids. AB - The identity of the putative G-protein coupled receptor (GPCR) that mediates the non-genomic effects of androgens is unknown. We present in vitro and in vivo evidence that the orphan GPRC6A receptor, a widely expressed calcium and amino acid sensing GPCR, transduces the non-genomic effects of testosterone and other steroids. Overexpression of GPRC6A imparts the ability of extracellular testosterone to illicit a rapid, non-genomic signaling response in HEK-293 cells lacking the androgen receptor. Conversely, testosterone-stimulated rapid signaling and phosphorylation of ERK is attenuated in bone marrow stromal cells derived from GPRC6A(-/-) mice and in 22Rv1 prostate cancer cells after siRNA mediated knockdown of GPRC6A. Compared with wild-type controls, GPRC6A(-/-) null mice exhibit significantly less ERK activation and Egr-1 expression in both bone marrow and testis in response to pharmacological doses of testosterone in vivo. In addition, testosterone administration results in suppression of luteinizing hormone in wild-type male mice, but paradoxically stimulates serum luteinizing hormone levels in GPRC6A(-/-) null mice. These results suggest that GPRC6A is functionally important in regulating non-genomic effects of androgens in multiple tissues. PMID- 20947497 TI - Extended binding site on fibronectin for the functional upstream domain of protein F1 of Streptococcus pyogenes. AB - The 49-residue functional upstream domain (FUD) of Streptococcus pyogenes F1 adhesin interacts with fibronectin (FN) in a heretofore unknown manner that prevents assembly of a FN matrix. Biotinylated FUD (b-FUD) bound to adsorbed FN or its recombinant N-terminal 70-kDa fibrin- and gelatin-binding fragment (70K). Binding was blocked by FN or 70K, but not by fibrin- or gelatin-binding subfragments of 70K. Isothermal titration calorimetry showed that FUD binds with K(d) values of 5.2 and 59 nM to soluble 70K and FN, respectively. We tested sets of FUD mutants and epitope-mapped monoclonal antibodies (mAbs) for ability to compete with b-FUD for binding to FN or to block FN assembly by cultured fibroblasts. Deletions or alanine substitutions throughout FUD caused loss of both activities. mAb 4D1 to the (2)FNI module had little effect, whereas mAb 7D5 to the (4)FNI module in the fibrin-binding region, 5C3 to the (9)FNI module in the gelatin-binding region, or L8 to the G-strand of (1)FNIII module adjacent to (9)FNI caused loss of binding of b-FUD to FN and decreased FN assembly. Conversely, FUD blocked binding of 7D5, 5C3, or L8, but not of 4D1, to FN. Circular dichroism indicated that FUD binds to 70K by beta-strand addition, a possibility supported by modeling based on crystal structures of peptides bound to (2)FNI-(5)FNI of the fibrin-binding domain and (8)FNI-(9)FNI of the gelatin binding domain. Thus, the interaction likely involves an extensive anti-parallel beta-zipper in which FUD interacts with the E-strands of (2)FNI-(5)FNI and (8)FNI (9)FNI. PMID- 20947498 TI - Annexin 2 regulates endothelial morphogenesis by controlling AKT activation and junctional integrity. AB - Sprouting angiogenesis is a multistep process that involves endothelial cell activation, basement membrane degradation, proliferation, lumen formation, and stabilization. In this study, we identified annexin 2 as a regulator of endothelial morphogenesis using a three-dimensional in vitro model where sprouting angiogenesis was driven by sphingosine 1-phosphate and angiogenic growth factors. We observed that sphingosine 1-phosphate triggered annexin 2 translocation from the cytosol to the plasma membrane and its association with vascular endothelial (VE)-cadherin. In addition, annexin 2 depletion attenuated Akt activation, which was associated with increased phosphorylation of VE cadherin and endothelial barrier leakage. Disrupting homotypic VE-cadherin interactions with EGTA, antibodies to the extracellular domain of VE-cadherin, or gene silencing all resulted in decreased Akt (but not Erk1/2) activation. Furthermore, expression of constitutively active Akt restored reduced endothelial sprouting responses observed with annexin 2 and VE-cadherin knockdown. Collectively, we report that annexin 2 regulates endothelial morphogenesis through an adherens junction-mediated pathway upstream of Akt. PMID- 20947499 TI - Proline periodicity modulates the self-assembly properties of elastin-like polypeptides. AB - Elastin is a self-assembling protein of the extracellular matrix that provides tissues with elastic extensibility and recoil. The monomeric precursor, tropoelastin, is highly hydrophobic yet remains substantially disordered and flexible in solution, due in large part to a high combined threshold of proline and glycine residues within hydrophobic sequences. In fact, proline-poor elastin like sequences are known to form amyloid-like fibrils, rich in beta-structure, from solution. On this basis, it is clear that hydrophobic elastin sequences are in general optimized to avoid an amyloid fate. However, a small number of hydrophobic domains near the C terminus of tropoelastin are substantially depleted of proline residues. Here we investigated the specific contribution of proline number and spacing to the structure and self-assembly propensities of elastin-like polypeptides. Increasing the spacing between proline residues significantly decreased the ability of polypeptides to reversibly self-associate. Real-time imaging of the assembly process revealed the presence of smaller colloidal droplets that displayed enhanced propensity to cluster into dense networks. Structural characterization showed that these aggregates were enriched in beta-structure but unable to bind thioflavin-T. These data strongly support a model where proline-poor regions of the elastin monomer provide a unique contribution to assembly and suggest a role for localized beta-sheet in mediating self-assembly interactions. PMID- 20947500 TI - The hyperthermia-enhanced association between tropoelastin and its 67-kDa chaperone results in better deposition of elastic fibers. AB - The results of our in vitro experiments indicate that exposing cultured human aortic smooth muscle cells and dermal fibroblasts to 39 to 41 degrees C induces a significant up-regulation in the net deposition of elastic fibers, but not of collagen I or fibronectin, and also decreases the deposition of chondroitin sulfate-containing moieties. We further demonstrate that mild hyperthermia also rectifies the insufficient elastogenesis notable in cultures of fibroblasts derived from the stretch-marked skin of adult patients and in cultures of dermal fibroblasts from children with Costello syndrome, which is characterized by the accumulation of chondroitin 6-sulfate glycosaminoglycans that induce shedding and inactivation of the 67-kDa elastin-binding protein. We have previously established that this protein serves as a reusable chaperone for tropoelastin and that its recycling is essential for the normal deposition of elastic fibers. We now report that hyperthermia not only inhibits deposition of chondroitin 6 sulfate moieties and the consequent preservation of elastin-binding protein molecules but also induces their faster recycling. This, in turn, triggers a more efficient preservation of tropoelastin, enhancement of its secretion and extracellular assembly into elastic fibers. The presented results encourage using mild hyperthermia to restore elastic fiber production in damaged adult skin and to enhance elastogenesis in children with genetic elastinopathies. PMID- 20947501 TI - Histone deacetylase 9 (HDAC9) regulates the functions of the ATDC (TRIM29) protein. AB - Histone deacetylase 9 (HDAC9), like most Class II HDACs, catalyzes the removal of acetyl moieties from the epsilon-amino groups of conserved lysine residues in the N-terminal tail of histones. Biologically, HDAC9 regulates a wide variety of normal and abnormal physiological functions, including cardiac growth, T regulatory cell function, neuronal disorders, muscle differentiation, development, and cancer. In a biochemical approach to identify non-histone substrates of HDAC9, we found that HDAC9 co-purifies specifically with the ataxia telangiectasia group D-complementing (ATDC; also called TRIM29) protein. HDAC9 deacetylates ATDC, alters the ability of ATDC to associate with p53, and consequently inhibits the cell proliferation-promoting activity of ATDC. These results implicate the importance of non-histone deacetylation by HDAC9 and confirm and further extend the multifunctions of this Class II deacetylase. PMID- 20947502 TI - Galantamine-induced amyloid-{beta} clearance mediated via stimulation of microglial nicotinic acetylcholine receptors. AB - Reduction of brain amyloid-beta (Abeta) has been proposed as a therapeutic target for Alzheimer disease (AD), and microglial Abeta phagocytosis is noted as an Abeta clearance system in brains. Galantamine is an acetylcholinesterase inhibitor approved for symptomatic treatment of AD. Galantamine also acts as an allosterically potentiating ligand (APL) for nicotinic acetylcholine receptors (nAChRs). APL-binding site is located close to but distinct from that for acetylcholine on nAChRs, and FK1 antibody specifically binds to the APL-binding site without interfering with the acetylcholine-binding site. We found that in human AD brain, microglia accumulated on Abeta deposits and expressed alpha7 nAChRs including the APL-binding site recognized with FK1 antibody. Treatment of rat microglia with galantamine significantly enhanced microglial Abeta phagocytosis, and acetylcholine competitive antagonists as well as FK1 antibody inhibited the enhancement. Thus, the galantamine-enhanced microglial Abeta phagocytosis required the combined actions of an acetylcholine competitive agonist and the APL for nAChRs. Indeed, depletion of choline, an acetylcholine competitive alpha7 nAChR agonist, from the culture medium impeded the enhancement. Similarly, Ca(2+) depletion or inhibition of the calmodulin dependent pathways for the actin reorganization abolished the enhancement. These results suggest that galantamine sensitizes microglial alpha7 nAChRs to choline and induces Ca(2+) influx into microglia. The Ca(2+)-induced intracellular signaling cascades may then stimulate Abeta phagocytosis through the actin reorganization. We further demonstrated that galantamine treatment facilitated Abeta clearance in brains of rodent AD models. In conclusion, we propose a further advantage of galantamine in clinical AD treatment and microglial nAChRs as a new therapeutic target. PMID- 20947503 TI - Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) potentiates cardiac contractility via activation of the ryanodine receptor. AB - Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) is the most recently identified phosphoinositide, and its functions have yet to be fully elucidated. Recently, members of our muscle group have shown that PI(3,5)P2 plays an important role in skeletal muscle function by altering Ca(2+) homeostasis. Therefore, we hypothesized that PI(3,5)P2 may also modulate cardiac muscle contractility by altering intracellular Ca(2+) ([Ca(2+)](i)) in cardiac myocytes. We first confirmed that PI(3,5)P2 was present and increased by insulin treatment of cardiomyocytes via immunohistochemistry. To examine the acute effects of PI(3,5)P2 treatment, electrically paced left ventricular muscle strips were incubated with PI(3,5)P2. Treatment with PI(3,5)P2 increased the magnitude of isometric force, the rate of force development, and the area associated with the contractile waveforms. These enhanced contractile responses were also observed in MIP/Mtmr14(-/-) mouse hearts, which we found to have elevated levels of PI(3,5)P2. In cardiac myocytes loaded with fura-2, PI(3,5)P2 produced a robust elevation in [Ca(2+)](i). The PI(3,5)P2-induced elevation of [Ca(2+)](i) was not present in conditions free of extracellular Ca(2+) and was completely blocked by ryanodine. We investigated whether the phosphoinositide acted directly with the Ca(2+) release channels of the sarcoplasmic reticulum (ryanodine receptors; RyR2). PI(3,5)P2 increased [(3)H]ryanodine binding and increased the open probability (P(o)) of single RyR2 channels reconstituted in lipid bilayers. This strongly suggests that the phosphoinositide binds directly to the RyR2 channel. Thus, we provide inaugural evidence that PI(3,5)P2 is a powerful activator of sarcoplasmic reticulum Ca(2+) release and thereby modulates cardiac contractility. PMID- 20947505 TI - Heteromeric interactions required for abundance and subcellular localization of human CDC50 proteins and class 1 P4-ATPases. AB - Members of the P(4) family of P-type ATPases (P(4)-ATPases) are believed to function as phospholipid flippases in complex with CDC50 proteins. Mutations in the human class 1 P(4)-ATPase gene ATP8B1 cause a severe syndrome characterized by impaired bile flow (intrahepatic cholestasis), often leading to end-stage liver failure in childhood. In this study, we determined the specificity of human class 1 P(4)-ATPase interactions with CDC50 proteins and the functional consequences of these interactions on protein abundance and localization of both protein classes. ATP8B1 and ATP8B2 co-immunoprecipitated with CDC50A and CDC50B, whereas ATP8B4, ATP8A1, and ATP8A2 associated only with CDC50A. ATP8B1 shifted from the endoplasmic reticulum (ER) to the plasma membrane upon coexpression of CDC50A or CDC50B. ATP8A1 and ATP8A2 translocated from the ER to the Golgi complex and plasma membrane upon coexpression of CDC50A, but not CDC50B. ATP8B2 and ATP8B4 already displayed partial plasma membrane localization in the absence of CDC50 coexpression but displayed a large increase in plasma membrane abundance upon coexpression of CDC50A. ATP8B3 did not bind CDC50A and CDC50B and was invariably present in the ER. Our data show that interactions between CDC50 proteins and class 1 P(4)-ATPases are essential for ER exit and stability of both subunits. Furthermore, the subcellular localization of the complex is determined by the P(4)-ATPase, not the CDC50 protein. The interactions of CDC50A and CDC50B with multiple members of the human P(4)-ATPase family suggest that these proteins perform broader functions in human physiology than thus far assumed. PMID- 20947504 TI - Docking-dependent ubiquitination of the interferon regulatory factor-1 tumor suppressor protein by the ubiquitin ligase CHIP. AB - Characteristically for a regulatory protein, the IRF-1 tumor suppressor turns over rapidly with a half-life of between 20-40 min. This allows IRF-1 to reach new steady state protein levels swiftly in response to changing environmental conditions. Whereas CHIP (C terminus of Hsc70-interacting protein), appears to chaperone IRF-1 in unstressed cells, formation of a stable IRF-1.CHIP complex is seen under specific stress conditions. Complex formation, in heat- or heavy metal treated cells, is accompanied by a decrease in IRF-1 steady state levels and an increase in IRF-1 ubiquitination. CHIP binds directly to an intrinsically disordered domain in the central region of IRF-1 (residues 106-140), and this site is sufficient to form a stable complex with CHIP in cells and to compete in trans with full-length IRF-1, leading to a reduction in its ubiquitination. The study reveals a complex relationship between CHIP and IRF-1 and highlights the role that direct binding or "docking" of CHIP to its substrate(s) can play in its mechanism of action as an E3 ligase. PMID- 20947506 TI - Cytochrome P450 2B1 mediates complement-dependent sublytic injury in a model of membranous nephropathy. AB - Membranous nephropathy is a disease that affects the filtering units of the kidney, the glomeruli, and results in proteinuria accompanied by loss of kidney function. Passive Heymann nephritis is an experimental model that mimics membranous nephropathy in humans, wherein the glomerular epithelial cell (GEC) injury induced by complement C5b-9 leads to proteinuria. We examined the role of cytochrome P450 2B1 (CYP2B1) in this complement-mediated sublytic injury. Overexpression of CYP2B1 in GECs significantly increased the formation of reactive oxygen species, cytotoxicity, and collapse of the actin cytoskeleton following treatment with anti-tubular brush-border antiserum (anti-Fx1A). In contrast, silencing of CYP2B1 markedly attenuated anti-Fx1A-induced reactive oxygen species generation and cytotoxicity with preservation of the actin cytoskeleton. Gelsolin, which maintains an organized actin cytoskeleton, was significantly decreased by complement C5b-9-mediated injury but was preserved in CYP2B1-silenced cells. In rats injected with anti-Fx1A, the cytochrome P450 inhibitor cimetidine blocked an increase in catalytic iron and ROS generation, reduced the formation of malondialdehyde adducts, maintained a normal distribution of nephrin in the glomeruli, and provided significant protection at the onset of proteinuria. Thus, GEC CYP2B1 contributes to complement C5b-9 mediated injury and plays an important role in the pathogenesis of passive Heymann nephritis. PMID- 20947507 TI - NF-kappaB down-regulates expression of the B-lymphoma marker CD10 through a miR 155/PU.1 pathway. AB - Cell-surface protein CD10 is a prognostic marker for diffuse large B-cell lymphoma (DLBCL), where high expression of CD10 is found in the germinal center B cell (GCB) subtype and CD10 expression is low or absent in the activated B-cell (ABC) subtype. As compared with the GCB subtype, patients with ABC DLBCL have a poorer prognosis after standard treatment, and ABC tumor cells have higher NF kappaB activity. Herein, we show that increased expression of the NF-kappaB target micro-RNA miR-155 is correlated with reduced expression of transcription factor PU.1 and CD10 in several B-lymphoma cell lines. Moreover, electromobility shift assays and luciferase reporter assays indicate that PU.1 can directly activate expression from the CD10 promoter. Expression of a DLBCL-derived mutant of the adaptor CARD11 (a constitutive activator of NF-kappaB) in the GCB-like human BJAB cell line or v-Rel in the chicken DT40 B-lymphoma cell line causes reduced expression of PU.1. The CARD11 mutant also causes a decrease in CD10 levels in BJAB cells. Similarly, overexpression of miR-155, which is known to down-regulate PU.1, leads to reduced expression of CD10 in BJAB cells. Finally, we show that CD10 expression is reduced in BJAB cells after treatment with the NF kappaB inducer lipopolysaccharide (LPS). Additionally, miR-155 is induced by LPS treatment or expression of the CARD11 mutant in BJAB cells. These results point to an NF-kappaB-dependent mechanism for down-regulation of CD10 in B-cell lymphoma: namely, that increased NF-kappaB activity leads to increased miR-155, which results in decreased PU.1, and consequently reduced CD10 mRNA and protein. PMID- 20947508 TI - Glucocorticoid-induced Leucine zipper 1 stimulates the epithelial sodium channel by regulating serum- and glucocorticoid-induced kinase 1 stability and subcellular localization. AB - Serum- and glucocorticoid-induced kinase 1 (SGK1) is a multifunctional protein kinase that markedly influences various cellular processes such as proliferation, apoptosis, glucose metabolism, and sodium (Na(+)) transport via the epithelial Na(+) channel, ENaC. SGK1 is a short-lived protein, which is predominantly targeted to the endoplasmic reticulum (ER) to undergo rapid proteasome-mediated degradation through the ER-associated degradation (ERAD) system. We show here that the aldosterone-induced chaperone, GILZ1 (glucocorticoid-induced leucine zipper protein-1) selectively decreases SGK1 localization to ER as well as its interaction with ER-associated E3 ubiquitin ligases, HRD1 and CHIP. GILZ1 inhibits SGK1 ubiquitinylation and subsequent proteasome-mediated degradation, thereby prolonging its half-life and increasing its steady-state expression. Furthermore, comparison of the effect of GILZ1 with that of proteasome inhibition (by MG-132) supports the idea that these effects of GILZ1 are secondary to physical interaction of GILZ1 with SGK1 and enhanced recruitment of SGK1 to targets within an "ENaC regulatory complex," thus making less SGK1 available to the ERAD machinery. Finally, effects of GILZ1 knockdown and overexpression strongly support the idea that these effects of GILZ1 are functionally important for ENaC regulation. These data provide new insight into how the manifold activities of SGK1 are selectively deployed and strengthened through modulation of its molecular interactions, subcellular localization, and stability. PMID- 20947509 TI - Genetic analysis of type-1 insulin-like growth factor receptor signaling through insulin receptor substrate-1 and -2 in pancreatic beta cells. AB - Signaling by receptor tyrosine kinases regulates pancreatic beta cell function. Inactivation of insulin receptor (InsR), IGF1 receptor (Igf1r), or Irs1 in beta cells impairs insulin secretion. Conversely, Irs2 ablation impairs beta cell replication. In this study, we examined aspects of the Igf1r regulatory signaling cascade in beta cells. To examine genetically the involvement of Irs1 and Irs2 in Igf1r signaling, we generated double mutant mice lacking Igf1r specifically in pancreatic beta cells in an Irs1- or Irs2-null background. We show that Igf1r/Irs1 double mutants do not differ phenotypically from Irs1 single mutants and exhibit hyperinsulinemia, while maintaining normal beta cell mass and glucose tolerance. In contrast, lack of Igf1r function in beta cells aggravates the consequences of Irs2 ablation in double mutants and results in lethal diabetes by 6 weeks of age. This additivity of phenotypic manifestations indicates that Irs2 serves a pathway that is largely independent of Igf1r signaling. Consistent with the view that the latter is the InsR pathway, we show that combined beta cell specific knock-out of both Insr and Igf1r results in a phenocopy of double mutants lacking Igf1r and Irs2. We conclude that Igf1r signals primarily through Irs1 and affects insulin secretion, whereas beta cell proliferation is mainly regulated by InsR using Irs2 as a downstream signaling effector. The insulin and IGF pathways appear to control beta cell functions independently and selectively. PMID- 20947510 TI - Perturbed heme binding is responsible for the blistering phenotype associated with mutations in the Caenorhabditis elegans dual oxidase 1 (DUOX1) peroxidase domain. AB - Dual oxidase (DUOX) enzymes support a wide variety of essential reactions, from cellular signaling to thyroid hormone biosynthesis. In Caenorhabditis elegans, the DUOX system (CeDUOX1/2) plays a crucial role in innate immunity and in stabilizing the cuticle by forming tyrosine cross-links. The current model suggests that superoxide generated by CeDUOX1 at the C-terminal NADPH oxidase domain is rapidly converted to H(2)O(2). The H(2)O(2) is then utilized by the N terminal peroxidase-like domain to cross-link tyrosines. We have now created a series of mutations in the isolated peroxidase domain, CeDUOX1(1-589). One set of mutations investigate the roles of a putative distal tyrosine (Tyr(105)) and Glu(238), a proposed covalent heme-binding residue. The results confirm that Glu(238) covalently binds to the heme group. A second set of mutations (G246D and D392N) responsible for a C. elegans blistering cuticle phenotype was also investigated. Surprisingly, although not among the catalytic residues, both mutations affected heme co-factor binding. The G246D mutant bound less total heme than the wild type, but a higher fraction of it was covalently bound. In contrast, the D392N mutant appears to fold normally but does not bind heme. Molecular dynamics simulations of a CeDUOX1(1-589) homology model implicate displacements of the proximal histidine residue as the likely cause. Both enzymes are structurally stable and through altered heme interactions exhibit partial or complete loss of tyrosine cross-linking activity, explaining the blistering phenotype. This result argues that the CeDUOX peroxidase domain is primarily responsible for tyrosine cross-linking. PMID- 20947511 TI - Novel channel enzyme fusion proteins confer arsenate resistance. AB - Steady exposure to environmental arsenic has led to the evolution of vital cellular detoxification mechanisms. Under aerobic conditions, a two-step process appears most common among microorganisms involving reduction of predominant, oxidized arsenate (H(2)As(V)O(4)(-)/HAs(V)O(4)(2-)) to arsenite (As(III)(OH)(3)) by a cytosolic enzyme (ArsC; Escherichia coli type arsenate reductase) and subsequent extrusion via ArsB (E. coli type arsenite transporter)/ACR3 (yeast type arsenite transporter). Here, we describe novel fusion proteins consisting of an aquaglyceroporin-derived arsenite channel with a C-terminal arsenate reductase domain of phosphotyrosine-phosphatase origin, providing transposable, single gene encoded arsenate resistance. The fusion occurred in actinobacteria from soil, Frankia alni, and marine environments, Salinispora tropica; Mycobacterium tuberculosis encodes an analogous ACR3-ArsC fusion. Mutations rendered the aquaglyceroporin channel more polar resulting in lower glycerol permeability and enhanced arsenite selectivity. The arsenate reductase domain couples to thioredoxin and can complement arsenate-sensitive yeast strains. A second isoform with a nonfunctional channel may use the mycothiol/mycoredoxin cofactor pool. These channel enzymes constitute prototypes of a novel concept in metabolism in which a substrate is generated and compartmentalized by the same molecule. Immediate diffusion maintains the dynamic equilibrium and prevents toxic accumulation of metabolites in an energy-saving fashion. PMID- 20947513 TI - Blau syndrome. PMID- 20947512 TI - Identification of microRNAs regulating reprogramming factor LIN28 in embryonic stem cells and cancer cells. AB - LIN28 (a homologue of the Caenorhabditis elegans lin-28 gene) is an evolutionarily conserved RNA-binding protein and a master regulator controlling the pluripotency of embryonic stem cells. Together with OCT4, SOX2, and NANOG, LIN28 can reprogram somatic cells, producing induced pluripotent stem cells. Expression of LIN28 is highly restricted to embryonic stem cells and developing tissues. In human tumors, LIN28 is up-regulated and functions as an oncogene promoting malignant transformation and tumor progression. However, the mechanisms of transcriptional and post-transcriptional regulation of LIN28 are still largely unknown. To examine microRNAs (miRNAs) that repress LIN28 expression, a combined in silico prediction and miRNA library screening approach was used in the present study. Four miRNAs directly regulating LIN28 (let-7, mir-125, mir-9, and mir-30) were initially identified by this approach and further validated by quantitative RT-PCR, Western blot analysis, and a LIN28 3'-UTR reporter assay. We found that expression levels of these four miRNAs were clustered together and inversely correlated with LIN28 expression during embryonic stem cell differentiation. In addition, the expression of these miRNAs was remarkably lower in LIN28-positive tumor cells compared with LIN28-negative tumor cells. Importantly, we demonstrated that these miRNAs were able to regulate the expression and activity of let-7, mediated by LIN28. Taken together, our studies demonstrate that miRNAs let-7, mir-125, mir-9, and mir-30 directly repress LIN28 expression in embryonic stem and cancer cells. Global down-regulation of these miRNAs may be one of the mechanisms of LIN28 reactivation in human cancers. PMID- 20947514 TI - Expression of snail in upper urinary tract urothelial carcinoma: prognostic significance and implications for tumor invasion. AB - PURPOSE: There are few molecular markers known to predict upper urinary tract urothelial carcinomas (UTUC) prognosis. Snail, which contributes to epithelial mesenchymal transition (EMT), has been documented in cancer progression, but not clear yet in UTUC. We therefore addressed the expression and biological significance of Snail in UTUC. EXPERIMENTAL DESIGN: To elucidate the biological significance of Snail in UTUC, we examined the immunohistochemical expression of snail in UTUC and analyzed its clinical significance in 150 patients with UTUC. Biological effects of Snail in EMT and invasion were evaluated by using small interfering RNA (siRNA) specific for Snail in urothelial carcinoma cell lines and the Matrigel invasion assay. RESULTS: Nuclear Snail staining was very weak in superficial UTUC. In contrast, strong Snail staining was observed in many of the nucleus of invasive UTUC. Snail expression was significantly higher in the high tumor stage, high grade, and in tumors showing lymphovascular invasion (LVI). Multivariate Cox regression analysis revealed that elevated Snail expression was a significant and an independent prognostic predictor of recurrence-free survival and cancer-specific survival. Patients with positive LVI and high Snail expression showed the worse outcome. Targeting of Snail mRNA expression in UMUC-3 cells with Snail-specific siRNA downregulated the mRNA expression of Snail, Vimentin, MMP2, and MMP9. Furthermore, the cells with siRNA for Snail showed decreased invasion activity in comparison with the cells transfected with a nontargeting siRNA. CONCLUSION: Snail-induced EMT represents a clinically relevant mechanism of UTUC progression and an attractive target for the treatment of patients with UTUC. PMID- 20947515 TI - A first-in-human study of conatumumab in adult patients with advanced solid tumors. AB - PURPOSE: To determine the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of conatumumab, an investigational, fully human monoclonal agonist antibody against human death receptor 5, in patients with advanced solid tumors. EXPERIMENTAL DESIGN: In the dose-escalation phase, patients received escalating intravenous doses of conatumumab (0.3, 1, 3, 10, or 20 mg/kg, 3-9 per cohort) every 2 weeks. In the dose-expansion phase, 10 patients with colorectal cancer (CRC) and 7 with non-small cell lung cancer (NSCLC) received 20 mg/kg of conatumumab every 2 weeks. RESULTS: Thirty-seven patients received 1 or more doses of conatumumab. Conatumumab seemed to be well tolerated; there were no dose limiting toxicities. Of adverse events possibly related to treatment, only 3 patients (8%) had a grade 3 event (fatigue and/or elevated lipase), and no anticonatumumab antibodies were detected. An MTD was not reached. Conatumumab exhibited dose linear kinetics from 3 to 20 mg/kg, with a mean terminal half-life of 13 to 19 days. One patient with NSCLC (0.3 mg/kg) had a confirmed partial response (PR) at week 32 (38% reduction in tumor size), with further reduction (48%) by week 96; this patient remains on conatumumab after 4.2 years with a sustained PR. Fourteen patients had a best response of stable disease, 2 for 32 weeks or more. One patient with CRC (0.3 mg/kg) and stable disease for 24 weeks had a 24% reduction in tumor size by RECIST (Response Evaluation Criteria in Solid Tumors) and a 35% reduction in the sum of standardized uptake values of all lesions measured by [18F]fluorodeoxyglucose positron emission tomographic scan. Changes in tumor levels of activated caspase-3 did not appear to be associated with tumor response. CONCLUSIONS: Conatumumab can be administered safely up to the target dose of 20 mg/kg every 2 weeks. PMID- 20947517 TI - Integrative genomics analyses reveal molecularly distinct subgroups of B-cell chronic lymphocytic leukemia patients with 13q14 deletion. AB - PURPOSE: Chromosome 13q14 deletion occurs in a substantial number of chronic lymphocytic leukemia (CLL) patients and it is believed to play a pathogenetic role. The exact mechanisms involved in this lesion have not yet been fully elucidated because of its heterogeneity and the imprecise knowledge of the implicated genes. This study was addressed to further contribute to the molecular definition of this lesion in CLL. EXPERIMENTAL DESIGN: We applied single nucleotide polymorphism (SNP)-array technology and gene expression profiling data to investigate the 13q14 deletion occurring in a panel of 100 untreated, early stage (Binet A) patients representative of the major genetics, molecular, and biological features of the disease. RESULTS: Concordantly with FISH analysis, SNP arrays identified 44 patients with del(13)(q14) including 11 cases with a biallelic deletion. The shorter monoallelic deletion was 635-kb long. The loss of the miR-15a/16-1 cluster occurred in all del(13)(q14) cases except in 2 patients with a monoallelic deletion, who retained both copies. MiR-15a/16 expression was significantly downregulated only in patients with the biallelic loss of the miRNA cluster compared to 13q normal cases. Finally, the natural grouping of SNP profiles by nonnegative matrix factorization algorithm showed that patients could be classified into 2 separate clusters, mainly characterized by short/biallelic versus wide/monoallelic 13q14 deletions. Supervised analyses of expression data showed that specific transcriptional profiles are correlated with these 2 genomic subgroups. CONCLUSIONS: Overall, our data highlight the presence of 2 distinct molecular types of 13q14 deletions, which may be of clinical relevance in CLL. PMID- 20947516 TI - Inflammatory and microRNA gene expression as prognostic classifier of Barrett's associated esophageal adenocarcinoma. AB - PURPOSE: Esophageal cancer is one of the most aggressive and deadly forms of cancer; highlighting the need to identify biomarkers for early detection and prognostic classification. Our recent studies have identified inflammatory gene and microRNA signatures derived from tumor and nontumor tissues as prognostic biomarkers of hepatocellular, lung, and colorectal adenocarcinoma. Here, we examine the relationship between expression of these inflammatory genes and micro RNA (miRNA) expression in esophageal adenocarcinoma and patient survival. EXPERIMENTAL DESIGN: We measured the expression of 23 inflammation-associated genes in tumors and adjacent normal tissues from 93 patients (58 Barrett's and 35 Sporadic adenocarcinomas) by quantitative reverse transcription-polymerase chain reaction. These data were used to build an inflammatory risk model, based on multivariate Cox regression, to predict survival in a training cohort (n = 47). We then determined whether this model could predict survival in a cohort of 46 patients. Expression data for miRNA-375 were available for these patients and was combined with inflammatory gene expression. RESULTS: IFN-gamma, IL-1alpha, IL-8, IL-21, IL-23, and proteoglycan expression in tumor and nontumor samples were each associated with poor prognosis based on Cox regression [(Z-score)>1.5] and therefore were used to generate an inflammatory risk score (IRS). Patients with a high IRS had poor prognosis compared with those with a low IRS in the training (P = 0.002) and test (P = 0.012) cohorts. This association was stronger in the group with Barrett's history. When combining with miRNA-375, the combined IRS/miR signature was an improved prognostic classifier than either one alone. CONCLUSION: Transcriptional profiling of inflammation-associated genes and miRNA expression in resected esophageal Barrett's-associated adenocarcinoma tissues may have clinical utility as predictors of prognosis. PMID- 20947519 TI - Androgen-induced TMPRSS2:ERG fusion in nonmalignant prostate epithelial cells. AB - Fusion genes play important roles in tumorigenesis. The identification of the high-frequency TMPRSS2 fusion with ERG and other ETS family genes in prostate cancer highlights the importance of fusion genes in solid tumor development and progression. However, the mechanisms leading to these fusions are unclear. We investigated whether androgen, through stimulating its receptor, could promote spatial genome reorganization and contribute to the generation of the TMPRSS2:ERG fusion. We show that treatment with androgen can induce the TMPRSS2:ERG fusion in both malignant and nonmalignant prostate epithelial cells. Although the fusion could be detected in malignant cells following 24-hour treatment, prolonged exposure to androgen was required to detect the fusion transcript in nonmalignant cells. We associated the fusion incidence with genetic factors, including androgen-induced gene proximity, androgen receptor exon1 CAG repeat length and expression of the PIWIL1 gene. This study demonstrates that fusions can be induced prior to malignant transformation and generation of the fusion is associated with both gene proximity and loss of the ability to prevent double strand breaks. PMID- 20947520 TI - IL-2 costimulation enables statin-mediated activation of human NK cells, preferentially through a mechanism involving CD56+ dendritic cells. AB - Statins are inhibitors of cholesterol biosynthesis and protein prenylation that also have been studied in cancer therapy and chemoprevention. With regard to natural killer (NK) cells, only inhibitory effects of statins such as suppression of granule exocytosis have been reported so far. In this study, we show that statins can cooperate with IL-2 to potently induce the activation of CD56(dim) NK cells in a synergistic, time- and dose-dependent fashion. Supplementation experiments revealed that the statin effect was specific to inhibition of their target hydroxymethylglutaryl coenzyme A reductase and that downstream depletion of geranylgeranyl pyrophosphate was responsible for cooperating with IL-2 in NK cell activation. Mechanistic studies revealed that CD56(+)HLA-DR(+)CD14(+) dendritic cell (DC)-like accessory cells mediated the ability of statin to activate NK cells. In contrast, BDCA-1(+) (CD1c(+)) myeloid DCs, which partially expressed CD56, were somewhat less potent. Conventional blood monocytes, which lack CD56, exhibited the lowest accessory cell capacity. NK cell IFN-gamma production was IL-12 independent but required endogenous IL-18, IL-1beta, and caspase-1 activity. Statins directly induced apoptosis in human cancer cell lines and cooperated with NK cell-derived IFN-gamma to generate potent cytotoxic antitumor effects in vitro even in the presence of statin-mediated inhibitory effects on granule exocytosis. Our work reveals novel and unexpected immunomodulatory properties of statins, which might be harnessed for the treatment of cancer. PMID- 20947523 TI - The SMARTCyp cytochrome P450 metabolism prediction server. AB - SUMMARY: The SMARTCyp server is the first web application for site of metabolism prediction of cytochrome P450-mediated drug metabolism. AVAILABILITY: The SMARTCyp server is freely available for use on the web at www.farma.ku.dk/smartcyp where the SMARTCyp Java program and source code is also available for download. CONTACT: smartcyp@farma.ku.dk; lo@farma.ku.dk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 20947521 TI - Hippo pathway effector Yap is an ovarian cancer oncogene. AB - The Hippo pathway regulates organ size and tumorigenesis in Drosophila and mammals and is altered in a variety of human cancers, yet it remains unclear if the Hippo pathway is of prognostic significance to cancer patients. Here we show that the key targets of Hippo signaling, transcriptional coactivators Yki and Yap, play a conserved role in promoting ovarian cancer in flies and humans, respectively. Whereas studies linking Yap to cancer in other tissues have focused on overall Yap levels, we show for the first time that subcellular levels of Yap show an exceptionally strong association with poor patient survival. Specifically, high levels of nuclear Yap (nYap), or low levels of cytoplasmic phosphorylated Yap (cpYap), associated with poor survival from ovarian cancer. Patients with both high nYap and low cpYap had ~50% lower 5-year survival, and this combination is an independent prognostic marker for survival, with an exceptionally high hazard ratio of 7.8. We find that Yap2 is the predominantly expressed Yap isoform in both the ovarian surface epithelium (OSE) and epithelial ovarian cancers. Overexpression of Yap2 and phosphorylation-defective Yap2-5SA in immortalized OSE cells resulted in increased cell proliferation, resistance to cisplatin-induced apoptosis, faster cell migration, and anchorage-independent growth, whereas Yap knockdown resulted in increased sensitivity to cisplatin induced apoptosis. Findings argue that the Hippo signaling pathway defines an important pathway in progression of ovarian cancer. PMID- 20947524 TI - OmicsAnalyzer: a Cytoscape plug-in suite for modeling omics data. AB - SUMMARY: OmicsAnalyzer is a Cytoscape plug-in for visual omics-based network analysis that (i) integrates hetero-omics data for one or more species; (ii) performs statistical tests on the integrated datasets; and (iii) visualizes results in a network context. AVAILABILITY: Implemented in Java, OmicsAnalyzer runs with Cytoscape 2.6 and 2.7. Binaries, documentation and video walkthroughs are freely available at http://vrac.iastate.edu/~jlv/omicsanalyzer/ CONTACT: julied@iastate.edu; netscape@iastate.edu PMID- 20947525 TI - Model quality assessment for membrane proteins. AB - MOTIVATION: Learning-based model quality assessment programs have been quite successful at discriminating between high- and low-quality protein structures. Here, we show that it is possible to improve this performance significantly by restricting the learning space to a specific context, in this case membrane proteins. Since these are among the most important structures from a pharmaceutical point-of-view, it is particularly interesting to resolve local model quality for regions corresponding, e.g. to binding sites. RESULTS: Our new ProQM method uses a support vector machine with a combination of general and membrane protein-specific features. For the transmembrane region, ProQM clearly outperforms all methods developed for generic proteins, and it does so while maintaining performance for extra-membrane domains; in this region it is only matched by ProQres. The predictor is shown to accurately predict quality both on the global and local level when applied to GPCR models, and clearly outperforms consensus-based scoring. Finally, the combination of ProQM and the Rosetta low resolution energy function achieve a 7-fold enrichment in selection of near native structural models, at very limited computational cost. AVAILABILITY: ProQM is available as a server at +proqm.cbr.su.se+. PMID- 20947526 TI - CellPublisher: a web platform for the intuitive visualization and sharing of metabolic, signalling and regulatory pathways. AB - SUMMARY: Systems biology relies increasingly on collaborations between several groups with different expertise. Therefore, the systems biology community is adopting standards that allow effective communication of concepts, as well as transmission and processing of pathway information. The Systems Biology Graphical Notation (SBGN) is a graphical language for biological pathways that has both a biological as well as a computational meaning. The program CellDesigner allows the codification of biological phenomena in an SBGN compliant form. CellPublisher is a web server that allows the conversion of CellDesigner files to web-based navigatable diagrams based on the user interface of Google maps. Thus, CellPublisher complements CellDesigner by facilitating the understanding of complex diagrams and by providing the possibility to share any CellDesigner diagram online with collaborators and get their feedback. Due to the intuitive interface of the online diagrams, CellPublisher serves as a basis for discovery of novel properties of the modelled networks. AVAILABILITY: The freely available web server and the documentation can be accessed at: http://cellpublisher.gobics.de/. The source code and the offline version for Microsoft Windows are freely available at http://sourceforge.net/projects/cellpublisher/. CONTACT: jstuelk@gwdg.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 20947527 TI - Investigating the correlations among the chemical structures, bioactivity profiles and molecular targets of small molecules. AB - MOTIVATION: Most of the previous data mining studies based on the NCI-60 dataset, due to its intrinsic cell-based nature, can hardly provide insights into the molecular targets for screened compounds. On the other hand, the abundant information of the compound-target associations in PubChem can offer extensive experimental evidence of molecular targets for tested compounds. Therefore, by taking advantages of the data from both public repositories, one may investigate the correlations between the bioactivity profiles of small molecules from the NCI 60 dataset (cellular level) and their patterns of interactions with relevant protein targets from PubChem (molecular level) simultaneously. RESULTS: We investigated a set of 37 small molecules by providing links among their bioactivity profiles, protein targets and chemical structures. Hierarchical clustering of compounds was carried out based on their bioactivity profiles. We found that compounds were clustered into groups with similar mode of actions, which strongly correlated with chemical structures. Furthermore, we observed that compounds similar in bioactivity profiles also shared similar patterns of interactions with relevant protein targets, especially when chemical structures were related. The current work presents a new strategy for combining and data mining the NCI-60 dataset and PubChem. This analysis shows that bioactivity profile comparison can provide insights into the mode of actions at the molecular level, thus will facilitate the knowledge-based discovery of novel compounds with desired pharmacological properties. AVAILABILITY: The bioactivity profiling data and the target annotation information are publicly available in the PubChem BioAssay database (ftp://ftp.ncbi.nlm.nih.gov/pubchem/Bioassay/). PMID- 20947528 TI - Implantable devices currently used in cardiology therapy. PMID- 20947529 TI - Rheumatology and work. PMID- 20947530 TI - Beyond the reach of traditional analyses: using Rasch to evaluate the DASH in people with multiple sclerosis. AB - BACKGROUND: Few upper limb functioning patient rating scales have been used in multiple sclerosis (MS) research and none developed specifically for people with MS. OBJECTIVES: In this study, we examined the Disabilities of the Arm, Shoulder and Hand (DASH) to determine its utility as a useful, scientifically robust and clinically meaningful tool in MS. METHODS: DASH data from 300 people with MS underwent two independent phases of psychometric analyses: (1) a traditional psychometric analysis (including data quality, scaling assumptions, reliability and validity); and (2) a Rasch analysis (including response option thresholds ordering, tests of fit, spread of item locations, residual correlations, and person separation index). RESULTS: Overall, the traditional psychometric analysis supported the DASH as a reliable and valid measure of upper limb function in people with MS. However, several issues were raised by the Rasch analysis that questioned the validity of the DASH, including misfit in 13/30 items, disordered item response option thresholds for 9/30 items, and six pairs of items with high residual correlations (> 0.60). CONCLUSION: Rasch analysis highlights areas for potential improvement for the use of the DASH. Our findings further support our previous arguments that traditional psychometric methods provide weak scale evaluations and can mislead clinicians as to the reliability and validity of outcome measures. PMID- 20947531 TI - Elevated phenylalanine on newborn screening: follow-up testing may reveal undiagnosed galactosaemia. AB - Introduction Newborn screening for phenylketonuria (PKU) can reveal other conditions which lead to an increased blood spot phenylalanine (Phe) concentration. We have investigated the proportion of blood spot samples that gave a positive screen due to clinically significant conditions other than PKU, compared the positive predictive value (PPV) of our referral Phe cut-off with that recommended by the UK Newborn Screening Programme Centre (UKNSPC) (>210 and >240 MUmol/L, respectively) and evaluated the effectiveness of reflex testing for galactosaemia using a lower blood spot Phe cut-off concentration of 130 MUmol/L. METHODS: All blood spot samples that screened positive, for an increased Phe concentration, between April 2001 and March 2008, were identified from the records of the Sheffield Newborn Screening Laboratory and the diagnoses noted. In addition, all cases of galactosaemia detected in or notified to our screening laboratory within this time were also examined and the screened Phe concentrations compared. RESULTS: Out of 438,674 babies who were screened, 67 had Phe concentration >210 MUmol/L (15 per 100,000). Of these, 40 had PKU or persistent hyperphenylalaninaemia with a Phe concentration identified by screening between 270 and 2350 MUmol/L. A further 11 were diagnosed with another clinically significant disorder: galactosaemia (n = 8), biopterin defects (n = 2), tyrosinaemia Type 1 (n = 1). In addition, 16 had transient elevations in Phe. In total, nine cases of galactosaemia were identified, of whom, three had Phe concentrations <240 MUmol/L with one asymptomatic individual having a concentration <210 MUmol/L. CONCLUSIONS: Adoption of the UKNSPC recommended cut off (>240 MUmol/L) will not affect the detection rate of classical PKU, but will improve the PPV from 76% to 80%. The use of a lower cut-off (130 MUmol/L) for reflex galactosaemia testing enables the timely identification of asymptomatic cases that benefit particularly from early treatment, without prompting any unnecessary clinical referrals or delaying any referrals. This intervention may reduce mortality in this vulnerable group. PMID- 20947532 TI - Decay of vertebrate characters in hagfish and lamprey (Cyclostomata) and the implications for the vertebrate fossil record. AB - The timing and sequence of events underlying the origin and early evolution of vertebrates remains poorly understood. The palaeontological evidence should shed light on these issues, but difficulties in interpretation of the non biomineralized fossil record make this problematic. Here we present an experimental analysis of decay of vertebrate characters based on the extant jawless vertebrates (Lampetra and Myxine). This provides a framework for the interpretation of the anatomy of soft-bodied fossil vertebrates and putative cyclostomes, and a context for reading the fossil record of non-biomineralized vertebrate characters. Decay results in transformation and non-random loss of characters. In both lamprey and hagfish, different types of cartilage decay at different rates, resulting in taphonomic bias towards loss of 'soft' cartilages containing vertebrate-specific Col2alpha1 extracellular matrix proteins; phylogenetically informative soft-tissue characters decay before more plesiomorphic characters. As such, synapomorphic decay bias, previously recognized in early chordates, is more pervasive, and needs to be taken into account when interpreting the anatomy of any non-biomineralized fossil vertebrate, such as Haikouichthys, Mayomyzon and Hardistiella. PMID- 20947533 TI - A composite score of protein-energy nutritional status predicts mortality in haemodialysis patients no better than its individual components. AB - BACKGROUND: Protein-energy wasting is tightly associated with mortality in haemodialysis patients. An expert panel of the International Society of Renal Nutrition and Metabolism (ISRNM) has published a consensus on the parameters that define protein-energy nutritional status and posed the question, 'which scoring system most effectively predicts outcome?' The aim of our study was therefore to develop a composite score of protein-energy nutritional status (cPENS) and to assess its prediction of all-cause mortality. METHODS: We used the data of 560 haemodialysis patients participating in the CONvective TRAnsport STudy (CONTRAST). All participants were followed for occurrence of death. Internationally recommended nutritional targets were used as components of the cPENS, including the subjective global assessment (target score >= 6), albumin (>= 4.0 g/dL), normalized protein nitrogen appearance (>= 0.8 g/kg/day), cholesterol (>= 100 mg/dL), creatinine (>= 10 mg/dL) and BMI (> 23 kg/m(2)). A Cox regression model was used to analyse the relation between different cPENS variants and mortality. RESULTS: The median follow-up time was 1.4 years (max 4.2). One hundred and five patients (19%) died. A cPENS variant based on albumin, BMI, creatinine and the nPNA yielded the strongest relation with mortality (hazard ratio 0.63, 95% confidence interval 0.54-0.74, P < 0.001), after adjustments for confounders. Some of the individual parameters of the cPENS, notably albumin and creatinine, were related to mortality with similar strength and magnitude. CONCLUSIONS: In conclusion, albumin reflects mortality risk similarly to multiple nutritional parameters combined. This questions the clinical value of the proposed diagnostic criteria for protein-energy wasting. PMID- 20947534 TI - Effectiveness of cinacalcet in patients with recurrent/persistent secondary hyperparathyroidism following parathyroidectomy: results of the ECHO study. AB - BACKGROUND: Progressive secondary hyperparathyroidism (sHPT) is characterized by parathyroid gland hyperplasia which may ultimately require parathyroidectomy (PTX). Although PTX is generally a successful treatment for those patients subjected to surgery, a significant proportion develops recurrent sHPT following PTX. ECHO was a pan-European observational study which evaluated the achievement of KDOQI(TM) treatment targets with cinacalcet use in patients on dialysis. Previously published results showed that cinacalcet plus flexible vitamin D therapy lowered serum PTH, phosphorus and calcium in the clinical practice with similar efficacy as seen in phase III trials. METHODS: This subgroup analysis of ECHO describes the real-world cinacalcet treatment effect in patients with recurrent or persistent sHPT after PTX (n = 153) compared to sHPT patients without prior history of PTX (n = 1696). RESULTS: Both groups of patients had substantially elevated serum PTH with comparable sHPT severity at baseline. After 12 months of cinacalcet treatment, 20.3% (26/128) of patients with prior PTX and 18.2% (253/1388) of patients without prior PTX achieved serum PTH and Ca * P values within the recommended KDOQI(TM) target ranges. CONCLUSIONS: Our data support the successful use of cinacalcet in patients with recurrent/persistent sHPT after PTX. PMID- 20947535 TI - ADAMTS-13 deficiency: can it cause chronic renal failure? AB - We describe a case of a 45-year-old woman with progressive chronic kidney disease (CKD), macrocytic anaemia without fragments or thrombocytopaenia, and thrombotic microangiopathy on renal biopsy. 'A disintegrin and metalloprotease, with thrombospondin-1-like domains' (ADAMTS-13) deficiency was detected, and genotyping revealed single-nucleotide polymorphisms known to be associated with reduced ADAMTS-13 secretion and activity. Congenital thrombotic thrombocytopaenic purpura was diagnosed with unusual features of late presentation and absent neurological involvement. ADAMTS-13 deficiency should be considered a cause of CKD when features of thrombotic microangiopathy are present on renal biopsy. PMID- 20947536 TI - Arterial functions: how to interpret the complex physiology. AB - Arterial pressure is a cyclic phenomenon characterized by a pressure wave oscillating around the mean blood pressure, from diastolic to systolic blood pressure, defining the pulse pressure. Aortic input impedance is a measure of the opposition of the circulation to an oscillatory flow input (stroke volume generated by heart work). Aortic input impedance integrates factors opposing LV ejection, such as peripheral resistance, viscoelastic properties and dimensions of the large central arteries, and the intensity and timing of the pressure wave reflections, associated with the opposition to LV ejection influenced by inertial forces. The two most frequently used methods of arterial stiffness are measurement of PWV and central (aortic or common carotid artery) pulse wave analysis, recorded directly at the carotid artery or indirectly in the ascending aorta from radial artery pressure curve. The arterial system is heterogenous and characterized by the existence of a stiffness gradient with progressive stiffness increase (PWV) from ascending aorta and large elastic proximal arteries to the peripheral muscular conduit arteries. Analysis of aortic or carotid pressure waveform and amplitude concerns the effect of reflected waves on pressure shape and amplitude, estimated in absolute terms, augmented pressure in millimetre of mercury, or, in relative terms, 'augmentation index' (Aix in percentage of pulse pressure). Finally, if the aortic PWV has the highest predictive value for prognosis, the aortic or central artery pressure waveform should be recorded and analysed in parallel with the measure of PWV to allow a deeper analysis of arterial haemodynamics. PMID- 20947537 TI - Early and delayed effects of AST-120 on chronic cyclosporine nephropathy. AB - BACKGROUND: Removal of uraemic toxins by AST-120 (Kremezin((r))) decreases the progression of chronic kidney disease by reducing oxidative stress. We performed this study to evaluate whether AST-120 has a similar effect on progression of cyclosporine (CsA)-induced renal injury. METHODS: Two separate studies were performed in adult Sprague-Dawley rats. First, AST-120 was administered with CsA (15 mg/kg) for 4 weeks (early treatment). Second, AST-120 was administered to the rats for 3 weeks after treatment with CsA for 3 weeks (delayed treatment). Uraemic toxin and oxidative stress were evaluated with plasma indoxyl sulphate (IS) levels and urinary 8-OHdG excretion. The effects of AST-120 on CsA-induced renal injury were evaluated in terms of renal function, interstitial fibrosis, inflammation, and apoptotic cell death. RESULTS: CsA treatment for 4 weeks showed 2-fold increase in plasma IS and urinary 8-OHdG levels compared with the VH group. Early treatment with AST-120 significantly decreased both parameters, and this was accompanied by improved renal function and decreased interstitial inflammation, fibrosis, and apoptotic cell death compared with those of rats that received CsA alone. Delayed treatment with AST-120 also decreased the plasma IS and urinary 8-OHdG levels, and reduced the progression of chronic CsA nephropathy. Furthermore, delayed AST-120 treatment decreased the epithelial mesenchymal transition in chronic CsA nephropathy. CONCLUSIONS: Removal of uraemic toxins with AST-120 treatment is effective in decreasing the progression of CsA-induced renal injury by reducing oxidative stress. PMID- 20947538 TI - Vitamin D status and clinical outcomes in incident dialysis patients: results from the NECOSAD study. AB - BACKGROUND: The majority of dialysis patients suffer from vitamin D deficiency, which might contribute to an adverse health outcome. We aimed to elucidate whether European dialysis patients with low 25-hydroxyvitamin D (25(OH)D) levels are at increased risk of mortality and specific fatal events. METHODS: This was a prospective cohort study of incident dialysis patients in the Netherlands (the NECOSAD). We selected all patients with measured 25(OH)D at 12 months after the start of dialysis, the baseline for our study. By Cox regression analyses, we assessed the impact of 25(OH)D levels on short-term (6 months of follow-up) as well as longer-term mortality (3 years of follow-up). Associations of 25(OH)D levels with cardiovascular and non-cardiovascular mortality were also determined. RESULTS: The data from 762 patients (39% females, age 59 +/- 15 years, 25(OH)D = 18 +/- 11 ng/mL) were available. Fifty-one and 213 patients died during a follow up of 6 months and 3 years, respectively. After adjustments for possible confounders, the hazard ratio (HR) (with 95% CI) for mortality was 2.0 (1.0-3.8) for short-term and 1.5 (1.0-2.1) for longer-term mortality when comparing patients with 25(OH)D levels <= 10 ng/mL with those presenting with 25(OH)D levels > 10 ng/mL. Adjusted HRs for cardiovascular mortality were 2.7 (1.1-6.5) and 1.7 (1.1-2.7) for short- and longer-term mortality, respectively. For non cardiovascular mortality, we observed no relevant association overall. The impact of 25(OH)D levels on clinical events was modified by parathyroid hormone (PTH) status, with low 25(OH)D levels meaningfully affecting outcomes only in patients with PTH levels above the median of 123 pmol/L. CONCLUSIONS: Vitamin D deficiency in dialysis patients is associated with an adverse health outcome, in particular with short-term cardiovascular mortality. Intervention studies are urgently needed to evaluate whether vitamin D supplementation improves health outcomes of dialysis patients. PMID- 20947539 TI - Renoprotective effects of green tea extract on renin-angiotensin-aldosterone system in chronic cyclosporine-treated rats. AB - BACKGROUND: Renin-angiotensin-aldosterone system (RAAS) activation plays an important role in cyclosporine (CsA)-induced nephropathy. The main aim of this study was to test whether the administration of green tea extract (GTE) prevents the development of CsA-induced nephrotoxicity. METHODS: The rats were treated for 21 days and divided into four groups (n = 6/group): control group (0.9% saline injection), CsA group (30 mg/kg/day by intraperitoneal injection), CsA-GTE group (CsA plus GTE 100 mg/kg/day subcutaneous injection) and GTE group (GTE alone). RESULTS: There were significant increased levels of serum blood urea nitrogen and creatinine in the CsA group compared with that of the control group and significantly improved in the CsA-GTE group. Biochemical analysis showed that the plasma renin activity (PRA) and serum concentration of aldosterone were significantly increased in the CsA group compared with the control group and significantly decreased in the CsA-GTE group compared with the CsA group. The total level of renin protein expression was significantly higher in the CsA group than in the control group, and it was lower in the CsA-GTE group than in the CsA group. CONCLUSIONS: CsA treatment increases the PRA and intrarenal renin levels and induces nephrotoxicity. The protective effects of GTE on CsA-induced structural and functional alternations of the kidney may be the blockage of RAAS. PMID- 20947540 TI - Enhanced sensitivity to rapamycin following long-term oestrogen deprivation in MCF-7, T-47-D and ZR-75-1 human breast cancer cells. AB - Human breast cancer cells (MCF-7, T-47-D and ZR-75-1) can adapt to circumvent any reduced growth rate during long-term oestrogen deprivation, and this provides three model systems to investigate mechanisms of endocrine resistance in breast cancer. In this paper we report consistent differences in the effects of three growth inhibitors following long-term oestrogen deprivation in all three cell models. Long-term oestrogen deprivation of MCF-7, T-47-D and ZR-75-1 cells resulted in reduced growth inhibition by PD98059 (2-10 MUg/ml), implying a loss of dependence on mitogen-activated protein kinase pathways for growth. The growth inhibitor LY294002 (2-10 MUM) inhibited growth of both oestrogen-maintained and oestrogen-deprived cells with similar dose-responses, implying continued similar dependence on phosphoinositide 3-kinase (PI3K) pathways with no alteration after adaptation to oestrogen independent growth. However, by contrast, long-term oestrogen deprivation resulted in an increased sensitivity to growth inhibition by rapamycin, which was not reduced by readdition of oestradiol. The enhanced inhibition of long-term oestrogen-deprived MCF-7-ED, T-47-D-ED and ZR-75-1-ED cell growth by combining rapamycin with LY294002 at concentrations where each alone had little effect, offers preclinical support to the development of therapeutic combinations of rapamycin analogues with other PI3K inhibitors in endocrine-resistant breast cancer. PMID- 20947541 TI - Pregnancy outcome in 396 pregnancies in patients with SLE in Saudi Arabia. AB - The aim of this study was to examine the pregnancy outcomes in patients with systemic lupus erythematosus (SLE) and the effect of SLE flare and treatment on pregnancy outcomes. We performed a retrospective evaluation of all pregnancies occurring in patients with SLE during the 27-year period from 1980 to 2006. Of the 319 women with SLE planning pregnancy after SLE onset, 176 (55.2%) conceived resulting in 396 pregnancies. Live births were significantly lower in proportion (70.2% vs. 85.7%) and more likely to end in fetal deaths (29.7% vs. 14.2%) and preterm births (26.7% vs. 5.8 %) in pregnancies occurring after SLE onset than in pregnancies occurring before SLE onset (p < 0.0001). With respect to different disease manifestations, we found that fetal loss was significantly higher in patients with antiphospholipid (aPL) antibodies than without (p < 0.001). Preterm deliveries were significantly more frequent in patients with lupus nephritis, anti-Ro/SSA antibodies, hypertension, history of intravenous cyclophosphamide treatment and aPL than those without these features (p < 0.05). Neonates with intrauterine growth retardation (IUGR) neonates were more common in hypertensive and Raynaud's-positive pregnancies (p < 0.05). SLE flares occurred in 30.8% pregnancies. There was increased risk of fetal loss, preterm births and IUGR in pregnancies with SLE exacerbations than without (p < 0.05). Prednisolone was found to improve the rate of live births, although it was also a predictor of prematurity. The predictors of pregnancy loss were lupus nephritis (odds ratio (OR) 7.3), aPL (OR 3.9), and SLE flares in pregnancy (OR 1.9). There was higher risk of preterm deliveries in patients with lupus nephritis (OR 18.9), anti-Ro antibodies (OR 13.9), hypertension (OR 15.7) and SLE flares (OR 2.5). IUGR was found to be associated with hypertension (OR 37.7), Raynaud's (OR 12.3), and SLE flares (OR 4.2). In conclusion, pregnancies in SLE patients with active lupus nephritis, anti-Ro/SSA antibodies, aPL, hypertension, Raynaud's phenomenon, active disease at conception and SLE exacerbations are at a higher risk of adverse pregnancy outcomes. It is important to carefully plan pregnancy, and experienced rheumatologists and obstetricians should monitor SLE patients in pregnancy and postpartum. PMID- 20947542 TI - Why another issue on lupus in Asia? Foreword. PMID- 20947543 TI - Two perspectives on lupus: patient and doctor. PMID- 20947544 TI - Epidemiology of systemic lupus erythematosus in Asia. AB - In this paper we aim to review the prevalence, incidence and disease presentation of lupus patients in Asian populations. The database of the National Library of Medicine (MEDLINE) through PUBMED up to September 2009 was searched for relevant articles using the search terms 'systemic lupus erythematosus', 'epidemiology', and 'Asia'. Articles on lupus prevalence, incidence, and clinical manifestations were retrieved and their bibliographies further screened for relevant articles. Proceedings of national, regional, and international rheumatology and SLE conferences were likewise searched for relevant abstracts. Retrieval rate of relevant articles was approximately 80%. Prevalence and incidence figures are expressed per 100,000 populations. Among the articles reviewed, epidemiologic information was usually obtained through population surveys or hospital cohorts. Prevalence data are available from 24 countries, and generally fall within 30 50/100,000 population. However, one survey showed a higher prevalence of 70 (Shanghai), while three others showed a lower prevalence of 3.2-19.3 (India, Japan, Saudi Arabia). Only three countries have recorded incidence rates and these varied from 0.9 to 3.1 per annum. Thirty articles from 21 countries describe lupus disease presentation. Common manifestations include mucocutaneous lesions (seen in 52-98% of patients) and arthritis/musculoskeletal complaints (36 95%). Antinuclear antibodies were generally positive in 89-100% of patients, except for two studies. Renal involvement ranged from 18% to 100% with most articles reporting this in >50% of their patients. Discoid lesions, serositis, and neurologic involvement were the least frequently seen symptoms. There is varying epidemiologic information regarding systemic lupus erythematosus among countries in Asia. Prevalence rates usually fall within 30-50/100,000 population. Incidence rates, as reported from three countries, varied from 0.9/100,000 to 3.1% per annum. It is difficult to make generalizations about how the epidemiologic character of the disease varies from country to country. However, similarities in disease manifestations can be observed. . PMID- 20947545 TI - Current advances in lupus genetic and genomic studies in Asia. AB - The genetic components in systemic lupus erythematosus (SLE) have long been established, however, it has been unclear for many years whether the same genetic risk factors for SLE are shared across different ethnic groups. Over the past few years, a number of genetic and genomic studies have been conducted in Asian populations to address this question. These studies have demonstrated that genetic heterogeneity does exist in SLE across different ethnic groups. With these studies, it has been established that a number of genes associated with SLE in Caucasians are also risk factors in Asians: HLA class II genes, STAT4, BANK1, BLK, IRF5, TNFSF4, ITGAM, etc., while there are also novel genetic risk factors identified by these studies in Asians, for instance, the ETS1 and WDFY4 in Chinese. For the genomic studies, the interferon signature has been confirmed as a major lupus molecular phenotype in Asians the same as in Caucasians; microRNA expression profiling and its novel role in regulating the interferon pathway has been first revealed in Asians. Further understanding of the function of lupus disease genes and delineating the key molecular pathway(s) will enhance the development of novel therapeutic targets and biomarkers for individualized clinical management for lupus patients. PMID- 20947546 TI - Do Asian patients have worse lupus? AB - The predisposition to and clinical phenotype of systemic lupus erythematosus, an autoimmune disease that is associated with significant morbidity and mortality, are affected by genetic and environmental factors. This article aims to examine whether Asians have worse lupus by reviewing the literature on genetic predisposition and clinical outcomes, including major organ involvement, damage score and mortality in Asian populations compared with other ethnicities. A number of lupus nephritis susceptibility genes have been identified in Asians and White patients, with further variations among different Asian populations. Meta analysis studies on various Fcgamma receptor subtypes revealed that FcgammaRIIIA F158 allele, which is associated with low binding affinity to IgG1 and IgG3, predisposed to lupus nephritis in Asian patients. Asian patients were reported to have higher rates of lupus nephritis-associated autoantibodies, lupus nephritis and more active glomerulonephritis compared with White patients. Renal outcome and the level of immunosuppressant use in Asians were comparable to Afro-American Blacks in some studies. Asians were also found to have higher overall damage scores compared with Whites. The difference in mortality between Asian patients and other ethnicities in different geographical regions was found to vary depending on socioeconomic factors such as access to health care. Poverty, education level, cultural and behavioural factors are confounders to ethnicity in determining clinical outcome of systemic lupus erythematosus. PMID- 20947547 TI - Major lupus organ involvement: severe lupus nephritis. AB - Lupus nephritis is a common and severe complication of systemic lupus erythematosus. A number of patients have nephritis as a presenting feature that, in its severe form, can shortly lead to end-stage renal disease and/or death. Renal flare usually occurs a few years after the first episode and is remarkably predominant in the Asian population. Frequent monitoring for renal flare enhances early recognition and timely treatment. The mainstay therapy continues to be the prolonged use of cytotoxic/immunosuppressive drugs that have a number of undesirable effects, particularly ovarian failure and development of opportunistic infections. This review will focus on the pathogenesis and the unique genetic factors found in Asian patients with lupus nephritis. Here, we propose an appropriate management scheme for the treatment of lupus nephritis in Asian patients. PMID- 20947548 TI - Neuropsychiatric lupus: clinical challenges, brain-reactive autoantibodies and treatment strategies. AB - Neurological manifestations in lupus can be due to active lupus disease affecting the brain or to other reasons. Reversible posterior leucoencephalopathy syndrome, primary lymphoma of the central nervous system, cerebral infections by bacteria (e.g. mycobacteria), viruses (e.g. JC virus), fungi (e.g. Cryptococcus) and parasites (e.g. Acanthamoeba), steroid-induced psychosis and reactive depression need to be excluded. Brain-reactive autoantibodies have been described as associating with neuropsychiatric lupus. The strongest associations described to date are with antiribosomal P protein and antiphospholipid antibodies. However these autoantibodies have not been shown to play significant roles in the pathogenesis. Treatment strategy for severe neuropsychiatric lupus include establishing definitive diagnosis, early identification and treatment of aggravating factors, appropriate symptomatic treatment, adequate immunosuppression, selective B-cell depletion and autologous haematopoietic stem cell transplant. Systematic reviews have shown that cyclophosphamide administration is superior to pulse methylprednisolone as a maintenance therapy. Mycophenolate mofetil has been shown to have modest effect and should only be considered if cyclophosphamide cannot be administered. PMID- 20947549 TI - Major gastrointestinal manifestations in lupus patients in Asia: lupus enteritis, intestinal pseudo-obstruction, and protein-losing gastroenteropathy. AB - Gastrointestinal (GI) symptoms are common in patients with systemic lupus erythematosus (SLE) and may be due to the disease itself, side-effects of medications, or non-SLE causes. However, GI manifestations of lupus attract far less attention than the other major organ involvements, are infrequently reviewed and rarely documented in published lupus databases or cohort studies including those from countries in Asia. According to three reports from two countries in Asia, the cumulative prevalence of SLE GI manifestations range from 3.8% to 18%. In this review, we focus on three major GI manifestations in patients from Asian countries: lupus enteritis, intestinal pseudo-obstruction, and protein-losing gastroenteropathy, for which early recognition improves outcome and reduces morbidity and mortality. PMID- 20947550 TI - Pediatric lupus in Asia. AB - Of all patients with systemic lupus erythematosus (SLE), 15-20% are diagnosed during childhood, with disease onset prior to the age of 16 years. Because disease expression in SLE is influenced by environment factors and differs between racial and ethnic groups. The aims of this review were to describe prevalence, clinical manifestations, common infectious complications, and outcome of pediatric-onset SLE in Asia. The prevalence of pediatric-onset SLE was 6.3 19.3 per 100,000 in Asia. The ratio of female to male was 4.7-6.2. The mean age at diagnosis of pediatric-onset SLE was 8.6-13.5 years. The most common clinical features of pediatric-onset SLE in Asia were cutaneous rashes, arthritis, hematological involvement and nephritis. The occurrence of nephritis varies from 29% to 81%. The most common histopathology of lupus nephritis was diffuse proliferative glomerulonephritis (WHO Class-IV) which occurred in 39.4-54% of case of lupus nephritis. Pediatric-onset SLE patients with infections have poor outcomes than uninfected patients. Gram-negative bacilli are the most common microorganisms responsible for bacteremia in Asian patients with SLE. Recurrent major infections predict poorer disease outcome and associated organ damage in pediatric-onset SLE. Improving the survival of SLE patients was reported in Asia in recent decades. The survival was 92% at the age of 5 years, 86% at 10 years and 79% at 15 years in children with SLE in Taiwan in 2008. PMID- 20947551 TI - Infections in systemic lupus erythematosus. AB - Infections are an important cause of morbidity and mortality in systemic lupus erythematosus (SLE). Survival rates for SLE patients in developing countries are comparatively lower than those reported in industrialized countries, with early death from infection and active disease. In addition to the role of immunosuppressive agents in enhancing susceptibility to infection, infectious agents are also known to trigger lupus disease expression and activity. The endemicity of certain infections like tuberculosis further poses a special health issue in developing countries. PMID- 20947552 TI - Alternative therapies: what role do they have in the management of lupus? AB - Systemic lupus erythematosus (SLE) is an autoimmune disease with higher morbidity and mortality among ethnic Chinese patients than Whites. Corticosteroid and other immunosuppressive drugs, including cyclophosphamide, azathioprine, and hydroxychloroquine are traditional therapies for this disease. Since the year 2000, mycophenolate mofetil and rituximab have been widely used in refractory SLE or severe lupus nephritis. Because the high disease activity remains, even after active therapy, and serious side effects from Western medicines may develop, more than 40% of SLE patients in Western countries are pursuing complementary and alternative therapies (CATs). CAT remedies are multiplex, and include herbal medicines, diets and vitamins, acupuncture, chiropractice, folk medicine, massage, spiritual healing, etc. Many herbal formulas have been used but in general their efficacy in treating lupus is doubted because of the lack of strong evidence. Tripterygium (T2) has demonstrated good efficacy in rheumatoid arthritis (RA) and SLE, but widespread use is limited due to the side effects. Through randomized clinical trials, we hope in the future that some Chinese medicines may be found helpful as CATs for SLE. PMID- 20947553 TI - Health-related quality of life of patients with systemic lupus erythematosus in Asia: how can this be improved? AB - The multicultural and multilinguistic landscape in Asia poses interesting challenges in the assessment and improvement of Health-Related Quality of Life (HRQoL) in Asian patients with systemic lupus erythematosus (SLE). This article highlights some of these challenges and addresses the issue of how to improve HRQoL of these patients by: (1) framing important concepts in HRQoL in relation to the chronic relapsing nature and multisystem involvement in this condition; (2) discussing ways to improve measurement of HRQoL of SLE patients in Asia by reviewing existing HRQoL instruments (both generic (i.e. the SF-36) and disease specific (i.e. the L-QoL, LupusQoL, SLEQoL and SLE Symptom Checklist)) and item banking; and (3) discussing approaches to improving HRQoL in SLE. PMID- 20947554 TI - Lupus organ damage: what is damaged in Asian patients? AB - Assessment of organ damage has become the standard outcome measure for morbidity and mortality in patients with lupus. Ethnicity is thought to be a marker for genetic, environmental, behavioral, and other variables that may affect disease outcomes. Previous studies suggest that Asians residing in western countries had significantly higher prevalence of damage compared with Whites. In contrast, studies performed in Chinese, Korean and Arab patients showed that the overall prevalence of damage and the most commonly involved organs (neuropsychiatric and musculoskeletal) were similar to Whites. Compared with their Asian counterparts, Pakistani and Jewish patients appeared to have a higher prevalence of damage, most likely secondary to longer disease duration. Chinese patients had an increased prevalence of premature gonadal failure, whereas patients residing in western and southern Asia had more skin damage. When compared with Whites, Asian patients had more renal damage but less ocular and cardiovascular damage. Risk factors associated with organ damage in Asian lupus patients included older age, higher disease activity, and the use of cyclophosphamide and steroids. Further investigations into other determinants such as genetic predisposition, socioeconomic factors, prevalence and severity of disease manifestations, and treatment, is needed in order to understand the variation in damage accrual in lupus patients from different ethnicities. PMID- 20947555 TI - The economic burden of systemic lupus erythematosus in Asia: the current state. AB - Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory disorder which imposes considerable negative impact on patients' function and quality of life, and it appears to entail substantial loss of work productivity and healthcare cost. Although much has been studied regarding the epidemiology, pathogenesis, disease activity, disease damage and pharmacological treatment of SLE, publications on the economic burden of lupus are scarce. As the majority of lupus patients are residing in the Asia Pacific region where many are financially and socially deprived, and, from what we know from the current literature, work disability of lupus patients in Asia is substantial, cost-of-illness studies on SLE are thus particularly relevant in countries around the region. Reliable data from properly conducted prospective SLE cost studies are imperative for policymakers to efficiently distribute healthcare resources, especially in Asia where limited resources are unable to cope with the huge population. In this paper, we review the current state of cost-of-illness research on lupus in Asia and analyze the reasons why such studies are urgently required in the Asia Pacific region. PMID- 20947556 TI - Cardiovascular co-morbidity in Asians with lupus: theoretical concern or clinical reality? AB - Immuno-inflammatory diseases like lupus are associated with premature atherosclerosis. With improved survival, atherosclerotic cardiovascular disease has emerged as an important late complication of systemic lupus erythematosus. The burden of this co-morbidity in Asian patients is not fully known but is likely to be high. We review the literature available and draw attention to this oft overlooked problem. PMID- 20947557 TI - What can we learn from genetic studies of systemic lupus erythematosus? Implications of genetic heterogeneity among populations in SLE. AB - Recent progress in genetics has expanded the number of the genes associated with SLE to more than 20 in the past 2 years. One might assign these candidate genetic factors into several pre-existing biological pathways: (i) innate immune response including TLR/interferon signaling pathways (IRF5, STAT4, TNFAIP3, and TREX1); (ii) adaptive immune response (HLA-DR, PTPN22, PDCD1, STAT4, LYN, BLK, and BANK1) including B, T cells, and antigen-presenting cells; and (iii) immune complex clearance mechanism (FCGRs, CRP, and ITGAM). In addition, there are also several genes and loci that could not be assigned into previous known pathways (KIAA1542, PXK, XKR6, ATG5, etc), providing possible novel mechanisms in SLE. It has also been evident that there are similarities and differences in SLE susceptibility loci across ethnic groups. Here we categorize the susceptible genes into four groups. The first group is the consistently associated genes with similar risk allele frequency between multiple ethnic populations such as STAT4, TNFAIP3, BANK1, and IRAK1/MECP2. The second group is the genes that are consistently associated but show marked difference in risk allele frequency (BLK, IRF5). The third group is the genes in which different risk variants exist within a gene or genetic loci (allelic heterogeneity) such as HLA-DR, FCGRs, and IRF5. The fourth group is the genes that show consistently discrepancy between populations such as PTPN22 and possibly ITGAM, PXK, and LYN (genetic heterogeneity). The possible explanations for differences of susceptible genetic factors between populations could be different genetic backgrounds, contribution of gene-gene or gene environment interaction, and the relation between marker and causal variants. Therefore, efforts to identify ethnic-specific genetic factors or disease causing variants should be necessary for individualized therapy for SLE in future. PMID- 20947558 TI - Anticytokine therapy in systemic lupus erythematosus. AB - Systemic lupus erythematosus is a prototype of heterogeneous autoimmune disease. There have been few newly approved therapeutic agents in lupus treatment for many reasons. Several animal studies and human data have shown that many potential cytokines are related to the pathogenesis and disease activity of systemic lupus erythematosus. Cytokines are produced by many immune cell types and have variable functions in the immune system. Following the success of biological agents in the treatment of inflammatory arthritis, inflammatory bowel disease, and psoriasis, biological targeting to specific cytokines or receptor molecules is now promising in the treatment of systemic lupus erythematosus. In addition to B-cell deleting modalities, clinical trials targeting potential cytokines associated with disease pathogenesis are underway at various clinical stages. Among potential cytokines, targeting agents against B-cell activating factor and interferon-alpha are in the most advanced stage, and belimumab (anti-B-cell activating factor antibody) could be the first biological agent approved in the treatment of systemic lupus erythematosus. Anti-tumor necrosis factor was tried with some success, but with a potential risk of infection in a small number of patients. In this review, we discuss the rationale for anticytokine therapies and review agents currently in clinical trials, and those that could be developed in the near future for systemic lupus erythematosus. We present the results mostly from published trials and data from http://clinicaltrials.gov/ct2/ PMID- 20947559 TI - Stem cell transplantation: progress in Asia. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multiorgan involvement and high mortality, which was reduced because of the most widely and classically used immunosuppressive therapies. However, some patients continue to have significant mortality. So a shift in the approach to the treatment of SLE is needed. In the past decade, most transplants have been performed in the treatment of SLE with allogeneic or autologous hematopoietic stem cells and currently emerging mesenchymal stem cells. There are some important differences between the two procedures. PMID- 20947560 TI - The future of lupus therapy modulating autoantigen recognition. AB - The mainstay of the current treatment for systemic lupus erythematosus consists of steroids and immunosuppressants. However, these non-specific immunosuppressive therapies can cause infection and other serious adverse events. The regulation of the autoantigen-specific immune response is a promising therapeutic approach with maximal efficacy and minimal adverse effects. T cells are essential components of antigen-specificity in the immune system. At present, we do not have a sufficient strategy for manipulating the responses of antigen-specific T cells. In this review, we describe the efficacy of two therapeutic approaches involving the modulation of autoantigen recognition by T cells in lupus model mice: (1) therapy involving engineered autoantigen-specific regulatory T cells generated by the gene transfer of autoantigen-specific TCR genes and appropriate regulatory genes into self lymphocytes; (2) therapy involving selective depletion of autoantigen presenting phagocytes. These selective immunosuppressive approaches could be useful strategies for the treatment of systemic lupus erythematosus. PMID- 20947562 TI - HitPredict: a database of quality assessed protein-protein interactions in nine species. AB - Despite the availability of a large number of protein-protein interactions (PPIs) in several species, researchers are often limited to using very small subsets in a few organisms due to the high prevalence of spurious interactions. In spite of the importance of quality assessment of experimentally determined PPIs, a surprisingly small number of databases provide interactions with scores and confidence levels. We introduce HitPredict (http://hintdb.hgc.jp/htp/), a database with quality assessed PPIs in nine species. HitPredict assigns a confidence level to interactions based on a reliability score that is computed using evidence from sequence, structure and functional annotations of the interacting proteins. HitPredict was first released in 2005 and is updated annually. The current release contains 36,930 proteins with 176,983 non redundant, physical interactions, of which 116,198 (66%) are predicted to be of high confidence. PMID- 20947561 TI - Mental health in youth infected with and affected by HIV: the role of caregiver HIV. AB - OBJECTIVE: To examine the association of youth and caregiver HIV status, and other contextual and social regulation factors with youth mental health. METHOD: Data were from two longitudinal studies of urban youth perinatally infected, affected, and unaffected by HIV (N = 545; 36% PHIV+ youth; 45.7% HIV+ caregivers). Youth mental health was measured using the Child Behavior Checklist, the Child Depression Inventory, and the State-Trait Anxiety Inventory for Children. RESULTS: HIV+ youth reported elevated scores on the CDI compared with HIV- youth. HIV+ caregivers reported fewer symptoms and were less likely to report scores in the clinical range for their children on the CBCL compared with HIV- caregivers. Caregiver mental health and parent-child communication and involvement were also associated with youth mental health. CONCLUSIONS: Youth who resided with HIV+ caregivers had better mental health. Future research needs to further explore the role of caregiver HIV infection in youth mental health. Understanding and building upon strengths of HIV-affected families may be an effective focus of interventions for this population. PMID- 20947563 TI - Fluorescent xDNA nucleotides as efficient substrates for a template-independent polymerase. AB - Template independent polymerases, and terminal deoxynucleotidyl transferase (TdT) in particular, have been widely used in enzymatic labeling of DNA 3'-ends, yielding fluorescently-labeled polymers. The majority of fluorescent nucleotides used as TdT substrates contain tethered fluorophores attached to a natural nucleotide, and can be hindered by undesired fluorescence characteristics such as self-quenching. We previously documented the inherent fluorescence of a set of four benzo-expanded deoxynucleoside analogs (xDNA) that maintain Watson-Crick base pairing and base stacking ability; however, their substrate abilities for standard template-dependent polymerases were hampered by their large size. However, it seemed possible that a template-independent enzyme, due to lowered geometric constraints, might be less restrictive of nucleobase size. Here, we report the synthesis and study of xDNA nucleoside triphosphates, and studies of their substrate abilities with TdT. We find that this polymerase can incorporate each of the four xDNA monomers with kinetic efficiencies that are nearly the same as those of natural nucleotides, as measured by steady-state methods. As many as 30 consecutive monomers could be incorporated. Fluorescence changes over time could be observed in solution during the enzymatic incorporation of expanded adenine (dxATP) and cytosine (dxCTP) analogs, and after incorporation, when attached to a glass solid support. For (dxA)(n) polymers, monomer emission quenching and long-wavelength excimer emission was observed. For (dxC)(n), fluorescence enhancement was observed in the polymer. TdT-mediated synthesis may be a useful approach for creating xDNA labels or tags on DNA, making use of the fluorescence and strong hybridization properties of the xDNA. PMID- 20947564 TI - ViralZone: a knowledge resource to understand virus diversity. AB - The molecular diversity of viruses complicates the interpretation of viral genomic and proteomic data. To make sense of viral gene functions, investigators must be familiar with the virus host range, replication cycle and virion structure. Our aim is to provide a comprehensive resource bridging together textbook knowledge with genomic and proteomic sequences. ViralZone web resource (www.expasy.org/viralzone/) provides fact sheets on all known virus families/genera with easy access to sequence data. A selection of reference strains (RefStrain) provides annotated standards to circumvent the exponential increase of virus sequences. Moreover ViralZone offers a complete set of detailed and accurate virion pictures. PMID- 20947565 TI - Rapamycin increases rDNA stability by enhancing association of Sir2 with rDNA in Saccharomyces cerevisiae. AB - The target of rapamycin (TOR) kinase is an evolutionarily conserved key regulator of eukaryotic cell growth and proliferation. Recently, it has been reported that inhibition of TOR signaling pathway can delay aging and extend lifespan in several eukaryotic organisms, but how lifespan extension is mediated by inhibition of TOR signaling is poorly understood. Here we report that rapamycin treatment and nitrogen starvation, both of which cause inactivation of TOR complex 1 (TORC1), lead to enhanced association of Sir2 with ribosomal DNA (rDNA) in Saccharomyces cerevisiae. TORC1 inhibition increases transcriptional silencing of RNA polymerase II-transcribed gene integrated at the rDNA locus and reduces homologous recombination between rDNA repeats that causes formation of toxic extrachromosomal rDNA circles. In addition, TORC1 inhibition induces deacetylation of histones at rDNA. We also found that Pnc1 and Net1 are required for enhancement of association of Sir2 with rDNA under TORC1 inhibition. Taken together, our findings suggest that inhibition of TORC1 signaling stabilizes the rDNA locus by enhancing association of Sir2 with rDNA, thereby leading to extension of replicative lifespan in S. cerevisiae. PMID- 20947566 TI - The expression of myogenic microRNAs indirectly requires protein arginine methyltransferase (Prmt)5 but directly requires Prmt4. AB - Myogenic microRNAs are important regulators of muscle development and differentiation. To better understand the roles of chromatin-modifying and remodeling enzymes in the activation of myogenic microRNA expression, we have functionally analyzed two different protein arginine methyltransferases, Prmt5 and Prmt4, both of which have previously been implicated in the regulation of myogenic mRNA expression. Both Prmts are required for myogenic microRNA induction during differentiation. Prmt5 is indirectly required due to the necessity of Prmt5 for expression of the transcriptional regulator, myogenin, as ectopic expression of myogenin eliminates Prmt5 dependency. By contrast, Prmt4 binds to the upstream regulatory regions of myogenic microRNAs and is required for dimethylation of the Prmt4 substrate, H3R17, at microRNA regulatory sequences. Deletion of Prmt4 does not alter MyoD binding at myogenic microRNA regulatory sequences but prevents the binding of both myogenin and the Brg1 ATPase that catalyzes SWI/SNF-dependent chromatin remodeling, resulting in an inhibition of microRNA expression. PMID- 20947567 TI - Visualization of the protein-coding regions with a self adaptive spectral rotation approach. AB - Identifying protein-coding regions in DNA sequences is an active issue in computational biology. In this study, we present a self adaptive spectral rotation (SASR) approach, which visualizes coding regions in DNA sequences, based on investigation of the Triplet Periodicity property, without any preceding training process. It is proposed to help with the rough coding regions prediction when there is no extra information for the training required by other outstanding methods. In this approach, at each position in the DNA sequence, a Fourier spectrum is calculated from the posterior subsequence. Following the spectrums, a random walk in complex plane is generated as the SASR's graphic output. Applications of the SASR on real DNA data show that patterns in the graphic output reveal locations of the coding regions and the frame shifts between them: arcs indicate coding regions, stable points indicate non-coding regions and corners' shapes reveal frame shifts. Tests on genomic data set from Saccharomyces Cerevisiae reveal that the graphic patterns for coding and non-coding regions differ to a great extent, so that the coding regions can be visually distinguished. Meanwhile, a time cost test shows that the SASR can be easily implemented with the computational complexity of O(N). PMID- 20947568 TI - Implantable cardioverter defibrillator in paediatric patients. PMID- 20947569 TI - Recurrence of B-cell lymphoma within an implantable cardioverter defibrillator wound scar. AB - A 79-year-old man presented with relapse of non-Hodgkin's B-cell lymphoma within the scar from his implantable cardioverter defibrillator (ICD) implantation. The ICD was re-sited before he proceeded to chest wall radiotherapy, which resulted in complete remission of the lymphoma. This is the first reported case of lymphoma recurrence within an ICD wound scar. PMID- 20947570 TI - Catheter ablation of electrical storm in patients with structural heart disease. AB - AIMS: Electrical storm (ES) adversely affects prognosis of patients and may become a life-threatening event. Catheter ablation (CA) has been proposed for the treatment of ES. Our goal was to evaluate the efficacy of CA ablation both in acute and long-term suppression of ES. METHODS AND RESULTS: Fifty consecutive patients with coronary artery disease (38), idiopathic dilated cardiomyopathy (5), arrhythmogenic right ventricular cardiomyopathy (6), and/or with combined aetiology (1) underwent CA for ES. Mean left ventricular ejection fraction (LVEF) was 29 +/- 11%. All patients underwent electroanatomical mapping, and CA was performed to abolish all inducible ventricular arrhythmias. The ES was suppressed by CA in 84% of patients. During the follow-up of 18 +/- 16 months, 24 patients had no recurrences of any ventricular tachycardia (VT; 48%). Repeated procedure was necessary to suppress the recurrent ES in 13 cases (26%). Statistical analysis revealed that low LVEF (22 +/- 3 vs. 31 +/- 12%; P < 0.001), increased LVend-diastolic diameter (72 +/- 9.1 vs. 64 +/- 8.9 mm; P = 0.0135), and renal insufficiency (P < 0.001) were the univariate predictors of early mortality or necessity for heart transplantation. Recurrence of ES despite previous CA procedure was associated with a higher risk of death or heart transplant during follow-up (P < 0.05). CONCLUSION: Catheter ablation is effective in acute suppression of ES and often represents a life-saving therapy. In the long term, it prevents recurrences of any VT in about half of the treated patients. PMID- 20947571 TI - Assessment of a novel device-based diagnostic algorithm to monitor patient status in moderate-to-severe heart failure: rationale and design of the CLEPSYDRA study. AB - AIMS: Monitoring systems integrated into electronic implantable devices for heart failure (HF) have significantly expanded the possibility of obtaining diagnostic information and can be used to enhance patient follow-up. The ability to obtain advance warning of worsening HF is currently being explored using a variety of diagnostic parameters. A novel device-based algorithm, physiological diagnostic (PhD), combines data from minute ventilation and accelerometer sensors to provide an indicator of the overall status of HF patients and detect clinically relevant acute HF events. The objective of this study was to evaluate the effectiveness of the PhD algorithm for detecting HF events in patients with HF. METHODS: CLEPSYDRA is a multicentre, prospective, non-randomized, single-arm double-blinded study in 62 centres in Europe, the USA, and Canada. Patients with moderate-to-severe HF, on stable optimal pharmacological therapy, QRS>=120 ms, and ejection fraction<=0.35% will be included. Patients will be followed at 3-month intervals until study end, or for a minimum of 13 months. The primary endpoint is the sensitivity of the PhD (proportion of HF-related clinical events occurring within a 4-week period after a PhD HF indication). Secondary endpoints include the sensitivity of PhD with regard to HF events related to oral treatment modification, and adverse events. The first patient was included in October 2009. At the time of manuscript submission (Week 26, 2010), 214 patients had been enrolled. Study results are expected in 2012. PERSPECTIVE: CLEPSYDRA will provide essential data on the utility of the PhD algorithm in a HF population with blinded investigators and patients. A successful outcome will demonstrate the potential for the algorithm to be implemented in clinical practice. This would improve clinical management and further the ability to generate dynamic and reliable risk profiles for patients with HF. PMID- 20947572 TI - Non-selective vs. selective beta-blocker treatment and the risk of thrombo embolic events in patients with heart failure. AB - AIMS: Heart failure (HF) is associated with a prothrombotic state, resulting in an increased risk for thrombo-embolic events. Studies suggest a reduced prothrombotic state when non-selective beta-blockers relative to selective beta blockers are given. We studied the influence of non-selective beta-blockers compared with selective beta-blockers on the occurrence of arterial and venous thrombo-embolic events in patients with HF. METHODS AND RESULTS: Data were obtained from the PHARMO Record Linkage System, a population-based registry of pharmacy records linked with hospital discharge records in The Netherlands. In the period of 1998-2007, 20 870 patients were hospitalized for HF. We used Cox regression analysis with time-varying beta-blocker covariate to assess the difference in the incidence of thrombo-embolic events [acute coronary syndrome (ACS), stroke, or pulmonary embolism] among patients. Median follow-up was 2.0 years (inter-quartile range: 0.7-4.1). Directly after discharge, 6558 patients were prescribed a selective beta-blocker and 2202 patients a non-selective beta blocker. The hazard ratio (HR) for any thrombo-embolic event for non-selective beta-blockers compared with selective beta-blockers was 0.76 [95% confidence interval (CI): 0.64-0.89]. After adjustment, the difference remained (HR 0.84, 95% CI: 0.72-0.99). The effect was most prominent for ACS (HR 0.78, 95% CI: 0.65 0.93), and not clear for stroke (HR 1.00, 95% CI: 0.67-1.50) or pulmonary embolism (HR 1.33, 95% CI: 0.66-2.71). CONCLUSION: In patients with HF, the use of non-selective beta-blockers was associated with a lower risk of thrombo embolic events than selective beta-blockers. Whether this beneficial effect is caused by the additional beta2-receptor blockade remains to be elucidated. These findings need to be validated in a well-designed randomized study. PMID- 20947573 TI - Innovative strategy for implementing chronic heart failure guidelines among family physicians in different healthcare settings in Berlin. AB - AIMS: The aim of this study was to improve drug therapy for chronic heart failure (CHF) patients. METHODS AND RESULTS: This prospective interventional pilot study was performed with cross-sectional comparative analysis before and after the intervention. Usual pharmacotherapy was observed for 8 months in two different outpatient healthcare settings in Berlin [11 family physicians from individual GP (IGP) practices and 12 working in a medical care centre (MCC)]. Medical care centres provide a novel structure for outpatient care and have recently been introduced in Germany. The subsequent intervention entailed implementation of heart failure guidelines via a computer-based reminder system, followed by renewed cross-sectional observation of prescription behaviour for 1 year. Family physicians recruited patients, assessed CHF severity according to the NYHA class, and referred patients for echocardiography. The study included 190 patients in the baseline phase and 209 in the intervention phase. Longitudinal follow-up was performed in 172 cases. Echocardiography was ordered by 94.6% of MCC-physicians and 79.9% of IGP's. Undermedication was observed in both settings. Guideline based beta-blocker therapy was prescribed for 46.3% of patients (44.8% of IGPs and 48.5% of MCC-GPs). Prescription improved by 12.3% after the intervention. There were marked deficiencies in the prescription of aldosterone antagonists (35%) for severe heart failure, which improved to 44.2% after the intervention. CONCLUSION: The problem of inadequate implementation of evidence-based therapy for CHF was partially overcome by using the reminder system, which provided participating physicians with short guideline recommendations during the intervention phase. PMID- 20947574 TI - The rhizosphere-competent entomopathogen Metarhizium anisopliae expresses a specific subset of genes in plant root exudate. AB - Metarhizium anisopliae and Beauveria bassiana are ubiquitous insect pathogens and possible plant symbionts, as some strains are endophytic or colonize the rhizosphere. We evaluated 11 strains of M. anisopliae and B. bassiana, and two soil saprophytes (the non-rhizospheric Aspergillus niger and the rhizosphere competent Trichoderma harzianum) for their ability to germinate in bean root exudates (REs). Our results showed that some generalist strains of M. anisopliae were as good at germinating in RE as T. harzianum, although germination rates of the specialized acridid pathogen Metarhizium acridum and the B. bassiana strains were significantly lower. At RE concentrations of <1 mg ml(-1), M. anisopliae strain ARSEF 2575 showed higher germination rates than T. harzianum. Microarrays showed that strain 2575 upregulated 29 genes over a 12 h period in RE. A similar number of genes (21) were downregulated. Upregulated genes were involved in carbohydrate metabolism, lipid metabolism, cofactors and vitamins, energy metabolism, proteolysis, extracellular matrix/cell wall proteins, transport proteins, DNA synthesis, the sexual cycle and stress response. However, 41.3% of the upregulated genes were hypothetical or orphan sequences, indicating that many previously uncharacterized genes have functions related to saprophytic survival. Genes upregulated in response to RE included the subtilisin Pr1A, which is also involved in pathogenicity to insects. However, the upregulated Mad2 adhesin specifically mediates adhesion to plant surfaces, demonstrating that M. anisopliae has genes for rhizosphere competence that are induced by RE. PMID- 20947575 TI - ArgR is an essential local transcriptional regulator of the arcABC operon in Streptococcus suis and is crucial for biological fitness in an acidic environment. AB - Streptococcus suis is one of the most important pathogens in pigs and can also cause severe infections in humans. Despite its clinical relevance, very little is known about the factors that contribute to its virulence. Recently, we identified a new putative virulence factor in S. suis, the arginine deiminase system (ADS), an arginine catabolic enzyme system encoded by the arcABC operon, which enables S. suis to survive in an acidic environment. In this study, we focused on ArgR, an ADS-associated regulator belonging to the ArgR/AhrC arginine repressor family. Using an argR knockout strain we were able to show that ArgR is essential for arcABC operon expression and necessary for the biological fitness of S. suis. By cDNA expression microarray analyses and quantitative real-time RT-PCR we found that the arcABC operon is the only gene cluster regulated by ArgR, which is in contrast to the situation in many other bacteria. Reporter gene analysis with gfp under the control of the arcABC promoter demonstrated that ArgR is able to activate the arcABC promoter. Electrophoretic mobility shift assays with fragments of the arcABC promoter and recombinant ArgR, and chromatin immunoprecipitation with antibodies directed against ArgR, revealed that ArgR interacts with the arcABC promoter in vitro and in vivo by binding to a region from -147 to -72 bp upstream of the transcriptional start point. Overall, our results show that in S. suis, ArgR is an essential, system-specific transcriptional regulator of the ADS that interacts directly with the arcABC promoter in vivo. PMID- 20947576 TI - Do patients want a choice and does it work? PMID- 20947577 TI - Implementing shared decision making in the NHS. PMID- 20947579 TI - An open letter to the health secretary: how to really save money on the NHS. PMID- 20947582 TI - New York City push against sugary drinks sparks controversy. PMID- 20947585 TI - Food and drink sponsorship of children's sport in Australia: who pays? AB - The creation of health promoting sports clubs may support the promotion and adoption of healthy behaviours by children. Sponsorship is one aspect of clubs, with potential influence on clubs and their participants. In particular, sponsorship influences brand awareness and attitudes, so that the sponsorship of children's sport by unhealthy food companies may contribute to food preferences and poor eating habits. This study aimed to determine the nature and extent of food and beverage sponsorship of children's sport. Sports clubs (n = 108) for the nine most popular sports for children aged 5-14 were randomly sampled from three large geographical areas in Australia. A purpose-designed telephone questionnaire was developed to determine the extent of sponsorship. Experts from different fields were approached (n = 10) to generate a consensus on the elements of sponsors that are more/less health promoting. The survey response rate was 99%. Of the 347 sponsors identified, 17% were food or beverage companies. Fifty percent of food company sponsorship arrangements did not meet criteria for healthy sponsors. For most clubs, less than a quarter of their income came from sponsorship. A considerable proportion of clubs with food company sponsors had the company's signage on players' uniforms (53%), distributed rewards using the company's name (24%) or gave vouchers to players for the company's products (29%). Any restriction of unhealthy food and beverage company sponsorship of children's sport may not result in major funding difficulties for clubs, as this funding represents a relatively small proportion of their income base, even though it provides major promotional opportunities to sponsors. PMID- 20947586 TI - Evaluating the maximum patient radiation dose in cardiac interventional procedures. AB - Many of the X-ray systems that are used for cardiac interventional radiology provide no way to evaluate the patient maximum skin dose (MSD). The authors report a new method for evaluating the MSD by using the cumulative patient entrance skin dose (ESD), which includes a back-scatter factor and the number of cineangiography frames during percutaneous coronary intervention (PCI). Four hundred consecutive PCI patients (315 men and 85 women) were studied. The correlation between the cumulative ESD and number of cineangiography frames was investigated. The irradiation and overlapping fields were verified using dose mapping software. A good correlation was found between the cumulative ESD and the number of cineangiography frames. The MSD could be estimated using the proportion of cineangiography frames used for the main angle of view relative to the total number of cineangiography frames and multiplying this by the cumulative ESD. The average MSD (3.0 +/- 1.9 Gy) was lower than the average cumulative ESD (4.6 +/- 2.6 Gy). This method is an easy way to estimate the MSD during PCI. PMID- 20947587 TI - Is alpha spectrometry reliable for 210Po urine bioassay? AB - Typically the bioassay method for (210)Po in urine by alpha spectrometry (AS) involves wet decomposition of the sample, which may cause a loss of (210)Po if volatile species are present. To test this hypothesis, urine samples collected from two rats that were i.v. administered with polonium citrate were measured by both AS and liquid scintillation counting, where urine samples were mixed with a scintillation cocktail without any treatment. A split-plot design method was used to compare results from the two measurement methods, showing no evidence of a difference between the two methods. This suggests that the AS method is reliable for (210)Po urine bioassay. PMID- 20947588 TI - Estimation of dose rates to humans exposed to elevated natural radioactivity through different pathways in the island of Ikaria, Greece. AB - A radiological survey has been carried out in the island of Ikaria based on the natural radionuclide inventory in abiotic environment and the consequent dose rate assessment for the critical groups of population. The island of Ikaria Aegean Sea, Greece is characterised by the presence of mineral and thermo-mineral springs, which have an apparent influence on natural background radiation of the island. The levels of natural radionuclides in spring water (either for spa treatment and household use), potable water (local domestic network), and rock and soil samples were measured in this island. The concentrations of (222)Rn and natural gamma emitters were found to be significantly elevated in spring water and some rock and soil samples. In terms of NORM and TENORM, the external and internal dose rates (mSv y(-1)) were estimated in three groups of population selected on the basis of water use as: habitants of the island, working personnel and bathers in spa installations. According to the derived results, the working personnel in the thermal spa installations are exposed to significant radiological risk due to waterborne (222)Rn with a maximum dose rate up to 35 mSv y(-1), which led to overexposure in terms of the 20 mSv y(-1) professional limits. Therefore, this group can be considered as the critical one for the radiological impact assessment in the island. PMID- 20947589 TI - Contribution of activation products to occupational exposure following treatment using high-energy photons in radiotherapy. AB - When high-energy photon beams are used for irradiation in radiotherapy, neutrons that are the result of photonuclear reactions create activation products that affect the occupational dose of radiotherapy staff. For the assessment of activation products in situ gamma spectroscopy was performed parallel to dose rate measurements following irradiation, by using a high-energy photon beam from a linear accelerator Elekta Precise (Elekta, Stockholm, Sweden) used in radiotherapy. The major identified activation products were the following radioisotopes: (28)Al, (24)Na, (56)Mn, (54)Mn, (187)W, (64)Cu and (62)Cu. Based on the typical workload and dose-rate measurement, the assessed additional annual occupational dose ranged from 1.7 to 0.25 mSv. As the measured dose rate arising from the activation products rapidly decreases as a function of time, the assessed additional dose is negligible after 10 min following irradiation. To keep the occupational dose as low as reasonably achievable, it is recommended to delay entrance to the therapy room at least 2-4 min, when high-energy photons are used. This would reduce the effective dose by 30%. PMID- 20947590 TI - Independent evaluation of optically stimulated luminescence (OSL) 'dot' dosemeters for environmental monitoring. AB - Optically stimulated luminescence (OSL) 'dot' dosemeters (manufactured by Landauer(r)) are reported to have a high degree of environmental stability, high level of sensitivity and provide wide range of dose measuring capabilities from 0.05 mGy to 100 Gy. The optical read out method is fast and relatively simple and permits repeated read out, but few studies have been performed about its application in monitoring radiation in the environment. This study was initiated to independently test the performance of OSL dot dosemeters for the application of measuring doses of radiation in the outdoor environment. Testing was performed in the laboratory to evaluate reproducibility and stability and in the field to evaluate accuracy relative to calibrated high-pressure ionisation chambers. The results showed that OSL dot dosemeters had good reproducibility and stability in both laboratory and field tests and met the performance requirements of standards of the American National Standards Institute. PMID- 20947591 TI - Spinal anaesthesia for ambulatory arthroscopic surgery of the knee: a comparison of low-dose prilocaine and fentanyl with bupivacaine and fentanyl. AB - BACKGROUND: Prospective data on the use of prilocaine for ambulatory spinal anaesthesia remain limited. We compared the behaviour and characteristics of subarachnoid block using prilocaine and fentanyl with that of bupivacaine and fentanyl. METHODS: In a prospective, double-blind, randomized controlled trial, 50 patients undergoing elective ambulatory arthroscopic knee surgery received subarachnoid anaesthesia, with either prilocaine 20 mg and fentanyl 20 ug (Group P) or plain bupivacaine 7.5 mg and fentanyl 20 ug (Group B). Primary endpoints included times for onset of maximum sensory block level and regression of sensory block to L4, and also motor block at 1 and 2 h, and levels of haemodynamic stability. Comparisons between the groups were made by chi2 test for proportions and the Mann-Whitney test for ordinal data. Time-to-event data were analysed by the Mann-Whitney test for uncensored data or the logrank test for censored data. RESULTS: At 2 h, motor block in Group P had fully resolved in 86% of patients, compared with 27% in Group B (P<0.001). Median time to regression of sensory block to L4 was significantly shorter in Group P (97 min) than in Group B (280 min) (P<0.001). A clinically significant decrease in arterial pressure was more common in Group B (73%) than in Group P (32%) (P=0.004). Two patients in Group P required conversion to general anaesthesia, but for reasons unrelated to prilocaine itself. CONCLUSIONS: The combination of prilocaine and fentanyl is a better alternative to that of low-dose bupivacaine and fentanyl, for spinal anaesthesia in ambulatory arthroscopic knee surgery. PMID- 20947592 TI - Efficacy and safety of paravertebral blocks in breast surgery: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Thoracic paravertebral blocks (PVBs) are successfully performed for pain management after breast surgery. The aim of the present quantitative systematic review was to assess the efficacy and adverse events of PVB in women undergoing breast surgery. METHODS: The systematic search, data extraction, critical appraisal, and pooled analysis were performed according to the PRISMA statement. The relative risk (RR), mean difference (MD), and their corresponding 95% confidence intervals (CIs) were calculated using the RevMan statistical software for dichotomous and continuous outcomes, respectively. Pain scores were converted to a scale ranging from 0 (no pain) to 10 (worst pain). RESULTS: Fifteen randomized controlled trials (published between 1999 and 2009) including 877 patients met the inclusion criteria. There was a significant difference in worst postoperative pain scores between PVB and general anaesthesia (GA) at <2 h (MD: -2.68; 95% CI: -3.33 to -2.02; P<0.00001), 2-24 h (MD: -2.34; 95% CI: -2.42 to -1.12; P<0.00001), and 24-48 h (MD: -1.75; 95% CI: -3.19 to 0.31; P=0.02). Accordingly, lower pain scores were observed for combined PVB with GA compared with GA alone for <2 h (MD: -1.87; 95% CI: -2.53 to -1.21; P<0.00001), 2-24 h (MD: -2.21; 95% CI: -3.07 to -1.35; P<0.00001), and 24-48 h (MD: -1.80; 95% CI: 2.92 to 0.68; P=0.002). The RR for the reported adverse events (e.g. pneumothorax) was low. CONCLUSIONS: There is considerable evidence that PVB in addition to GA or alone provide a better postoperative pain control with little adverse effects compared with other analgesic treatment strategies. PMID- 20947593 TI - Dose-related attenuation of cardiovascular responses to tracheal intubation by intravenous remifentanil bolus in severe pre-eclamptic patients undergoing Caesarean delivery. AB - BACKGROUND: The optimal dose of remifentanil to attenuate the cardiovascular responses to tracheal intubation in pre-eclamptic patients undergoing Caesarean delivery under general anaesthesia has not been established. We compared the effects of two low doses of remifentanil on the cardiovascular responses to tracheal intubation and neonatal outcomes. METHODS: Forty-eight women with severe pre-eclampsia were randomly assigned to receive either remifentanil 0.5 ug kg-1 (R0.5 group, n=24) or 1 ug kg-1 (R1.0 group, n=24) over 30 s before induction of anaesthesia using thiopental 5 mg kg-1 and succinylcholine 1.5 mg kg-1. Systolic arterial pressure (SAP), heart rate (HR), and plasma catecholamine concentrations were measured. Neonatal effects were assessed using Apgar scores and umbilical cord blood gas analysis. RESULTS: SAP was decreased by induction of anaesthesia and increased by tracheal intubation in both groups. The peak SAP after intubation was greater in the R0.5 group than in the R1.0 group, whereas it did not exceed baseline values in either group. HR increased significantly above baseline in both groups with no significant differences between the groups. Three subjects in the R1.0 group received ephedrine due to hypotension (SAP < 90 mm Hg). Norepinephrine concentrations remained unaltered after intubation and increased significantly at delivery with no significant differences between the groups. Neonatal Apgar scores and umbilical arterial and venous pH and blood gas values were comparable between the groups. CONCLUSIONS: Both doses of remifentanil effectively attenuated haemodynamic responses to tracheal intubation with transient neonatal respiratory depression in pre-eclamptic patients undergoing Caesarean delivery under general anaesthesia. The 1.0 ug kg-1 dose was associated with hypotension in three of 24 subjects. PMID- 20947594 TI - Carbon monoxide re-breathing during low-flow anaesthesia in infants and children. AB - BACKGROUND: Carbon monoxide (CO) has been detected within anaesthesia breathing systems. One potential source in this setting is exhaled endogenous CO. We hypothesized that CO is re-breathed during low-flow anaesthesia (LFA) in infants and children. METHODS: Twenty children (age 2 months-7 yr) undergoing general anaesthesia were evaluated in a prospective observation study. LFA was established for 60 min followed by high-flow anaesthesia (HFA) for the next 60 min. Exhaled and inspired CO were measured every 5 min within the breathing circuit. Carboxyhaemoglobin (COHb%) was measured at baseline, at 60 min, after LFA, and at 120 min, after HFA. RESULTS: CO concentrations increased during LFA. Inspired CO peaked at 14 ppm. During HFA, exhaled CO levels remained constant whereas inspired CO decreased markedly. Exhaled and inspired CO during HFA differed significantly from LFA. The trajectory of change in exhaled and inspired CO was most closely associated with the fresh-gas flow (FGF):minute ventilation ratio. COHb% significantly increased in children <2 yr of age at 60 min after LFA and remained increased. CONCLUSIONS: LFA increased exhaled and inspired CO and increased COHb% in children <2 yr of age. Thus, LFA resulted in re-breathing of exhaled CO and exposure, especially in the youngest children. Re-breathing exhaled gas during LFA could pose a risk for an acute CO exposure in patients who have elevated COHb and high baseline levels of exhaled CO. If practitioners match or exceed minute ventilation with FGF to avoid LFA, CO re-breathing can be limited. PMID- 20947595 TI - Bypass grafts and cell transplant in heart failure with low ejection fraction. AB - From June 2004 to October 2007, 34 patients with chronic heart failure and low ejection fraction underwent surgical revascularization; 23 received bypass grafting plus transplantation of bone marrow-derived stem cells (study group) and 11 had revascularization only (control group). The stem cells were implanted into nonviable myocardial areas, bypass grafting was performed in viable myocardial areas. In the study group, the ejection fraction increased from the baseline 26.4% +/- 4% to 37.3% +/- 11.5% after 26 months. In the control group, ejection fraction increased from 29% +/- 2% to 31.5% +/- 4.3% after 27 months. The improvement in the study group was significantly greater than that in the control group. Functional class improved significantly from 3.2 to 1.2 in the study group vs. 3.0 to 2.3 in the control group. Stem cell transplantation associated with bypass grafting is feasible and safe in patients with chronic heart failure with low ejection fractions, and it improves ventricular systolic function and functional class. PMID- 20947596 TI - Prosthetic valve endocarditis in a multicenter registry of Chinese patients. AB - We evaluated the clinical outcomes of prosthetic valve endocarditis in 2 major tertiary referral centers in Hong Kong. The study population comprised 80 consecutive Chinese patients who fulfilled the modified Duke criteria for prosthetic valve endocarditis from March 2000 to June 2007. The major clinical endpoints analyzed were hospital mortality, need for valve surgery, and relapse of prosthetic endocarditis. The mean age at presentation was 56 +/- 13 years, with a slight male preponderance. There were 76 (95%) patients with involvement of a mechanical prosthesis; the majority (69%) had late prosthetic endocarditis. Major hospital complications occurred in 49 (61%) patients. The overall hospital mortality was 28% (22 patients). Thirty-four (42%) patients required valve surgery during index hospitalization, of whom 5 (15%) died due to uncontrolled sepsis. Factors associated with hospital mortality were older age at presentation, Staphylococcus aureus infection, embolic events, severe heart failure, valve surgery, and any major complication. On multivariate analysis, severe heart failure was the only independent predictor of hospital death. Among the 58 hospital survivors followed up for a mean of 48 +/- 31 months, 6 (10%) developed late complications related to prosthetic valve endocarditis, with 5 documented cases of relapse. PMID- 20947597 TI - A proposal for management after lung resection, using a flexible silastic drain. AB - We advocate a technique using a small silastic flexible drain for air leaks after pulmonary resection. Patients undergoing lung resection by video-assisted thoracic surgery were enrolled in this study. The 331 patients consisted of 227 men and 104 women, with a median age of 58 years. The surgical procedures were lobectomy in 145, wedge resection in 177, and segmentectomy in 9. At the end of the operation, a 19F silastic drain under a pressure of -7 cm H(2)O was inserted. When no air leak was observed, we removed the drain on postoperative day 1. When an air leak was observed, the suction mode was changed to a water seal. The mean duration of chest tube drainage was 1.9 days. The chest tube was removed on postoperative day 1 in 243 (73.4%) patients. Postoperative complications, other than prolonged air leak, occurred in 5 (1.5%) patients. The drain was not effective in 4 (1.2%) patients, and it was replaced with a conventional rigid drain. Management of air leaks using silastic flexible drains is safe and effective after wedge resection. Care should be taken in cases of lobectomy and segmentectomy when a large air leak is anticipated. PMID- 20947598 TI - Bronchial stump coverage and postpneumonectomy bronchopleural fistula. AB - To prevent postpneumonectomy bronchopleural fistula, coverage of the bronchial stump is recommended, especially for patients treated with neoadjuvant and adjuvant chemotherapy or radiochemotherapy. We compared outcomes after proximal pericardial fat pad coverage and coverage with pleura and surrounding tissues, by retrospective analysis of the records of 243 patients. Postpneumonectomy bronchopleural fistula occurred in 7/143 (4.9%) patients who had pericardial fat pad coverage, and in 6/100 (6.0%) treated by pleural covering. Bronchopleural fistula occurred in 11 patients within 21 days, in one after 2 months, and one after 6 months. Univariate analysis of comorbidities and risk factors did not show any significant differences between the groups. Advanced T stage and carcinomatous lymphangiosis at the resection margin were associated with a higher risk of bronchopleural fistula development, independent of the technique. Reinforcement of the bronchial stump by proximal pericardial fat pad coverage appears to be safe and feasible. It is comparable to coverage with pleura and surrounding tissues. PMID- 20947599 TI - Hemodynamics and outcomes of aortic valve replacement with a 17- or 19-mm valve. AB - When aortic valve replacement is performed in patients with a small aortic annulus, prosthesis-patient mismatch is of concern because it may affect postoperative clinical status. We conducted a retrospective study of outcomes in 65 patients with aortic stenosis requiring valve replacement. Fifty were given a 17-mm or 19-mm St. Jude Regent mechanical valve, and 15 were given a 19-mm Medtronic Mosaic bioprosthesis. Echocardiography was carried out preoperatively, at discharge, and at follow-up. There was 1 (2%) operative death in the Regent group and none in the Mosaic group. There was no valve-related event. Follow-up echocardiography in both groups revealed a significant increase in the mean effective orifice area index, a decrease in the mean left ventricular-aortic pressure gradient, and a decrease in the mean left ventricular mass index. Prosthesis-patient mismatch (effective orifice area index <0.85 cm(2) . m(-2)) existed in 13 (26%) patients in the Regent group and 11 (73%) in the Mosaic group at discharge. All patients improved to New York Heart Association functional class II or better. A small-sized prosthesis may provide satisfactory clinical and hemodynamic results in patients with a small aortic annulus. PMID- 20947600 TI - Computed tomography of aortic intramural hematoma and thrombosed dissection. AB - A retrospective study was undertaken to evaluate the appearance of the aortic wall on computed tomography for the purpose of developing criteria for differentiating acute aortic intramural hematoma from thrombosed false lumen seen in aortic dissection. Computed tomography angiography findings of the thoracoabdominal aorta in 23 patients with suspected intramural hematoma and 25 with thrombosed false lumen were reviewed. The more common features of an intramural hematoma were hyperattenuation of the aortic wall, wall thickness less than a quarter of the aortic diameter, intrinsic wall calcification, a lesion extending around the entire aortic circumference, and ulcer-like projections that may be precursors of intramural hematoma. Wall thickness less than a quarter of the aortic diameter, lesion extending around the entire aortic circumference, and ulcer-like projections were the most useful indicators for distinguishing intramural hematoma from the thrombosed false lumen in aortic dissection. PMID- 20947601 TI - Is epidural analgesia necessary after video-assisted thoracoscopic lobectomy? AB - Most studies have shown that thoracic epidural analgesia reduces postoperative pain, but it carries potential risks. Recently, video-assisted thoracoscopic surgery has become an established technique that causes minimal postoperative pain. This report shows that thoracic epidural analgesia is not always necessary after video-assisted thoracoscopic lobectomy. From January to December 2007, 30 consecutive patients who underwent video-assisted thoracoscopic lobectomy were examined retrospectively. We analyzed the necessity for routine thoracic epidural analgesia. The continuous subcutaneous analgesia catheter for morphine (2 mg in 48 h) was removed from 15 patients on postoperative day 1, and from the other 15 on day 2. We administered loxoprofen sodium hydrate, diclofenac sodium suppository, pentazocine hydrochloride, and mexiletine hydrochloride for postoperative analgesia, as needed. The mean pain score was no more than 1.0. The maximum score was 3.0 on day 0, and 2.0 on day 14; subsequently, no pain score exceeded 2.0. The postoperative hospital stay was 8.7 +/- 0.8 days. All patients made uneventful postoperative recoveries. There is no need for thoracic epidural analgesia after every video-assisted thoracoscopic lobectomy because our patients recovered with no serious complication. Less invasive surgical approaches should require simpler postoperative pain management. PMID- 20947602 TI - Predictors of quality of life in Chinese patients with acute coronary syndrome. AB - Predictors of quality of life in Chinese patients with acute coronary syndrome remain unknown. Between January 2006 and March 2009, a prospective cohort study of 782 patients with acute coronary syndrome was carried out, with follow-up 7 months later. Depression and anxiety symptoms were measured using the Hospital Anxiety and Depression Scale. Quality of life was assessed using the 36-Item Short-Form Health Survey. To identify predictors of decreased quality of life, both the physical and mental component summary scores were analyzed using multiple and ordinal logistic regression. In our quality-of-life model, diabetes mellitus was an independent risk factor for a low mental component summary score. Anxiety symptoms and the baseline mental component summary score were significant independent predictors of a low mental component summary score. Acute myocardial infarction was found to be a risk factor for a low physical component summary score. Anxiety symptoms, baseline physical component summary score, and systolic blood pressure on admission were significant independent predictive factors. Among patients with acute coronary syndrome, those with acute myocardial infarction, diabetes, or a low baseline quality of life need more care and effective intervention to improve their quality of life. PMID- 20947603 TI - An adult case of giant bronchogenic cyst mimicking tension pneumothorax. AB - Bronchogenic cysts are usually discovered only incidentally in the adult. A giant bronchogenic cyst in a 19-year-old woman presenting with pain and shortness of breath was mistaken for tension pneumothorax and initially treated with tube thoracostomy. Giant bullae were diagnosed by computed tomography. Bullae resection was undertaken, but the remaining lung tissue required pneumonectomy. Pathologic examination of the specimen confirmed bronchogenic cyst. PMID- 20947604 TI - Pleuroperitoneal shunting for intractable cardiogenic pleural effusions. AB - A 72-year-old man underwent post-infarction ventricular septal defect repair. Postoperatively, he required prolonged ventilation and could not be weaned from positive-pressure-assisted ventilation because of intractable bilateral pleural effusions. Conservative therapy was ineffective. After instituting pleuroperitoneal shunting, the patient could be weaned easily from a respirator. PMID- 20947605 TI - Bicuspid aortic valve replacement with stentless autologous pericardial valve. AB - Bicuspid aortic valve is a common congenital cardiac anomaly that poses a surgical challenge in young patients. We describe replacement of a bicuspid aortic valve with a stentless glutaraldehyde-treated autologous pericardial prosthesis in a 16-year-old girl. PMID- 20947606 TI - Application of lobe-selective bronchial blockade against airway bleeding. AB - A 48-year-old man underwent resection of a right upper lobe necrotic tumor and part of his chest wall. Lobe-selective bronchial blockade of bleeding from the right upper lobe was achieved by combining a left-side double-lumen endotracheal tube with a bronchial blocker placed at the right intermediate bronchus. The bleeding right upper lobe was isolated, and the other lobes were protected from blood contamination during the lobectomy procedure. PMID- 20947607 TI - Ectopic congenital thymic cyst in the right pleural cavity. AB - A 37-year-old man with a huge pleural cyst, presented with symptoms of right heart compression. The mass on the right side of the chest seemed initially to be in connection with the mediastinum. Computed tomography failed to define its relationship with the pericardium, and echocardiography excluded any involvement of the mediastinal structures. The final diagnosis was a congenital thymic cyst exclusively located in the pleural cavity. PMID- 20947608 TI - Beating-heart tricuspid annuloplasty using the Tailor Flexible Ring. AB - We describe a standard procedure of tricuspid annuloplasty using the St. Jude Medical Tailor Flexible Ring with a beating-heart technique. This flexible ring is supposed to be more physiological than a rigid ring for reducing mechanical stress on the annulus. To avoid zigzag the flexible ring when tying the sutures, they must be placed at exactly the same distance apart on both the tricuspid annulus and the ring. PMID- 20947609 TI - Subtotal aortic and bilateral renal artery stenoses in a 9-year-old patient. PMID- 20947610 TI - A case of lung hypoplasia in adulthood. PMID- 20947611 TI - Aortic arch surgery: moderate or mild hypothermic circulatory arrest? PMID- 20947612 TI - En-bloc free gastroepiploic artery graft with gastroepiploic vein. PMID- 20947613 TI - Nitinol stents: safe or not? PMID- 20947614 TI - Autophagy gets in on the regulatory act. AB - Autophagy down-regulates the Wnt signal transduction pathway via targeted degradation of a key signaling protein. This may provide an explanation for autophagy's role in tumor suppression. PMID- 20947615 TI - Evaluating correlates of adolescent physical activity duration towards National Health Objectives: analysis of the Colorado Youth Risk Behavioral Survey, 2005. AB - BACKGROUND: While numerous studies have examined the relationships among correlates of physical activity (PA), less attention has been given to identifying the correlates of low PA duration. The main objective of the current study was to examine correlates of low PA duration, team sports participation and smoking behaviors among adolescents. METHODS: Data from the 2005 Colorado Youth Behavioral Risk Survey were analyzed using Cox proportional hazard models. We evaluated associations between two measures of low PA duration, assessed as per Healthy People 2010 (HP2010) objectives and 2008 Physical Activity Guidelines (PAG) for Americans, and smoking behaviors, participation in the physical education (PE) and team sports, controlling for age, gender and other behavioral characteristics. RESULTS: Forty percent and 70%, respectively, of adolescents did not meet the 2008 PAG and HP2010 objectives. After adjustment, smoking remained associated with failure to meet the 2008 PAG. However, no significant relationship was found with low PA duration as per the HP2010 objectives. The risk of low PA was higher among girls for both outcome measures. Likewise, adolescents who reported no participation in team sports presented a 7-fold higher risk of low PA as per the 2008 PAG and 51% higher risk of low PA as per the HP2010 objectives compared with the group with team sports participation. CONCLUSIONS: Regular participation in school PE and team sports may represent an important avenue for increasing PA duration and reducing smoking behaviors among adolescents. PMID- 20947616 TI - A Baeyer-Villiger oxidation specifically catalyzed by human flavin-containing monooxygenase 5. AB - 10-((4-Hydroxypiperidin-1-yl)methyl)chromeno[4,3,2-de]phthalazin-3(2H)-one (E7016), an inhibitor of poly(ADP-ribose) polymerase, is being developed for anticancer therapy. One of the major metabolites identified in preclinical animal studies was the product of an apparent oxidation and ring opening of the 4 hydroxypiperidine. In vitro, this oxidized metabolite could not be generated by incubating E7016 with animal or human liver microsomes. Further studies revealed the formation of this unique metabolite in hepatocytes. In a NAD(P)(+)-dependent manner, this metabolite was also generated by liver S9 fractions and recombinant human flavin-containing monooxygenase (FMO) 5 that was fortified with liver cytosol fractions. In animal and human liver S9, this metabolic pathway could be inhibited by 4-methylpyrazole, bis-p-nitrophenylphosphate (BNPP), or a brief heat treatment at 50 degrees C. Based on these results, the overall metabolic pathway was believed to involve a two-step oxidation process: dehydrogenation of the secondary alcohol in liver cytosol followed by an FMO5-mediated Baeyer-Villiger oxidation in liver microsomes. The two oxidation steps were coupled via regeneration of NAD(P)(+) and NAD(P)H. To further confirm this mechanism, the proposed ketone intermediate was independently synthesized. In an NAD(P)H dependent manner, the synthetic ketone intermediate was metabolized to the same ring-opened metabolite in animal and human liver microsomes. This metabolic reaction was also inhibited by BNPP or a brief heat treatment at 50 degrees C. Methimazole, the substrate/inhibitor of FMO1 and FMO3, did not inhibit this reaction. The specificity of FMO5 toward catalyzing this Baeyer-Villiger oxidation was further demonstrated by incubating the synthetic ketone intermediate in recombinant enzymes. PMID- 20947617 TI - Whole-body physiologically based pharmacokinetic model for nutlin-3a in mice after intravenous and oral administration. AB - Nutlin-3a is an MDM2 inhibitor that is under investigation in preclinical models for a variety of pediatric malignancies, including retinoblastoma, rhabdomyosarcoma, neuroblastoma, and leukemia. We used physiologically based pharmacokinetic (PBPK) modeling to characterize the disposition of nutlin-3a in the mouse. Plasma protein binding and blood partitioning were assessed by in vitro studies. After intravenous (10 and 20 mg/kg) and oral (50, 100, and 200 mg/kg) dosing, tissue concentrations of nutlin-3a were determined in plasma, liver, spleen, intestine, muscle, lung, adipose, bone marrow, adrenal gland, brain, retina, and vitreous fluid. The PBPK model was simultaneously fit to all pharmacokinetic data using NONMEM. Nutlin-3a exhibited nonlinear binding to murine plasma proteins, with the unbound fraction ranging from 0.7 to 11.8%. Nutlin-3a disposition was characterized by rapid absorption with peak plasma concentrations at approximately 2 h and biphasic elimination consistent with a saturable clearance process. The final PBPK model successfully described the plasma and tissue disposition of nutlin-3a. Simulations suggested high bioavailability, rapid attainment of steady state, and little accumulation when administered once or twice daily at dosages up to 400 mg/kg. The final model was used to perform simulations of unbound tissue concentrations to determine which dosing regimens are appropriate for preclinical models of several pediatric malignancies. PMID- 20947618 TI - Activation of the acute inflammatory response alters cytochrome P450 expression and eicosanoid metabolism. AB - Cytochrome P450 (P450)-mediated metabolism of arachidonic acid regulates inflammation in hepatic and extrahepatic tissue. CYP2C/CYP2J-derived epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EET+DHET) elicit anti inflammatory effects, whereas CYP4A/CYP4F-derived 20-hydroxyeicosatetraenoic acid (20-HETE) is proinflammatory. Because the impact of inflammation on P450-mediated formation of endogenous eicosanoids is unclear, we evaluated P450 mRNA levels and P450 epoxygenase (EET+DHET) and omega-hydroxylase (20-HETE) metabolic activity in liver, kidney, lung, and heart in mice 3, 6, 24, and 48 h after intraperitoneal lipopolysaccharide (LPS) (1 mg/kg) or saline administration. Hepatic Cyp2c29, Cyp2c44, and Cyp2j5 mRNA levels and EET+DHET formation were significantly lower 24 and 48 h after LPS administration. Hepatic Cyp4a12a, Cyp4a12b, and Cyp4f13 mRNA levels and 20-HETE formation were also significantly lower at 24 h, but recovered to baseline at 48 h, resulting in a significantly higher 20 HETE/EET+DHET formation rate ratio compared with that for saline-treated mice. Renal P450 mRNA levels and P450-mediated eicosanoid metabolism were similarly suppressed 24 h after LPS treatment. Pulmonary EET+DHET formation was lower at all time points after LPS administration, whereas 20-HETE formation was suppressed in a time-dependent manner, with the lowest formation rate observed at 24 h. No differences in EET+DHET or 20-HETE formation were observed in heart. Collectively, these data demonstrate that acute activation of the innate immune response alters P450 expression and eicosanoid metabolism in mice in an isoform-, tissue-, and time-dependent manner. Further study is necessary to determine whether therapeutic restoration of the functional balance between the P450 epoxygenase and omega-hydroxylase pathways is an effective anti-inflammatory strategy. PMID- 20947619 TI - The genetic environment of armA on pHNE, an IncN plasmid, in one Escherichia coli isolate from a chicken. PMID- 20947620 TI - Importance of appropriate empirical antibiotic therapy for methicillin-resistant Staphylococcus aureus bacteraemia. AB - OBJECTIVES: To document the effects of appropriate and inappropriate empirical antibiotic therapy on mortality in a cohort of patients with bacteraemia due to methicillin-resistant Staphylococcus aureus (MRSA) and to summarize effects with previous studies. METHODS: In the retrospective cohort study, episodes of clinically significant MRSA bacteraemia during a 15 year period were included. Polymicrobial episodes were excluded unless MRSA was isolated in more than one bottle and co-pathogens were given appropriate empirical antibiotic treatment. Appropriate empirical treatment was defined as matching in vitro susceptibility and started within 48 h of blood-culture taking, except for single aminoglycosides or rifampicin. We assessed univariate and multivariate associations between appropriate empirical therapy and 30 day all-cause mortality. Multivariable analysis was conducted using backward stepwise logistic regression. We reviewed all studies assessing the effects of appropriate empirical antibiotic treatment on mortality for MRSA infections and compiled adjusted odds ratios (ORs) using a random effects meta-analysis. RESULTS: Five hundred and ten episodes of MRSA bacteraemia were included. There were no cases of community-acquired infection. The 30 day mortality was 43.9% (224/510) and was stable throughout the study period. Mortality was significantly higher among patients receiving inappropriate (168/342, 49.1%) compared with those receiving appropriate (56/168, 33.3%) empirical antibiotic treatment, P = 0.001. In the adjusted analysis the OR was 2.15 [95% confidence interval (CI) 1.34-3.46]. Pooling of six studies using adequate methodology for the adjusted analysis resulted in an OR of 1.98 (95% CI 1.62-2.44). CONCLUSIONS: Appropriate empirical antibiotic treatment has a significant survival benefit in MRSA bacteraemia. Treatment guidelines should consider this benefit. PMID- 20947621 TI - Time-kill kinetics of anti-tuberculosis drugs, and emergence of resistance, in relation to metabolic activity of Mycobacterium tuberculosis. AB - OBJECTIVES: The pharmacodynamics of tuberculosis (TB) treatment should be further explored, to prevent emergence of resistance, treatment failure and relapse of infection. The diagnostic drug susceptibility tests guiding TB therapy investigate metabolically active Mycobacterium tuberculosis (Mtb) isolates under static conditions and as such are not informative with respect to the time-kill kinetics of anti-TB drugs and the emergence of resistance in metabolically lowly active or even dormant mycobacterial cells. METHODS: In vitro, the killing capacity of rifampicin, isoniazid, ethambutol and amikacin regarding the degree of killing, killing rate and selection of resistant mutants was investigated in metabolically highly active versus metabolically lowly active Mtb cells. RESULTS: Isoniazid showed rapid and high killing capacity towards highly active mycobacteria, but due to the emergence of resistance could not eliminate the Mtb. Efflux pump-mediated isoniazid resistance was predominant. Rifampicin revealed a relatively slow and time-dependent killing capacity, but achieved elimination of all mycobacteria. Ethambutol was not bactericidal. Amikacin showed a high and extremely rapid killing activity that was not time dependent and could eliminate all mycobacteria. Exposure of lowly active Mtb populations to isoniazid, rifampicin or amikacin led to the emergence of resistant mutants. Compared with the highly active mycobacteria, elimination of the susceptible lowly active mycobacteria required a 64-fold increased isoniazid concentration and a 4-fold increased rifampicin concentration, whereas amikacin was equally effective irrespective of the metabolic state of the mycobacteria. CONCLUSIONS: The anti-TB drugs differ significantly regarding their time-kill kinetics. In addition, the metabolic state of Mtb significantly affects its susceptibility to antimicrobials, with the exception of amikacin. Optimization of dosage of anti-TB drugs is required to achieve maximum drug concentrations at the site of infection in order to maximize reduction in Mtb load and to minimize the emergence and selection of resistance. PMID- 20947622 TI - A sensitive phenotypic assay for the determination of human immunodeficiency virus type 1 tropism. AB - OBJECTIVES: To develop a sensitive phenotypic assay based on recombinant viruses (RVs) for characterizing HIV-1 tropism. METHODS: Viral tropism was assessed in 159 plasma samples. The env gene was amplified and ligated into pNL-lacZ/env-Ren, which carries a luciferase reporter gene. Resulting constructs were transfected into HEK293T cells to generate RVs. To assess co-receptor tropism, U87.CD4.CXCR4/CCR5 cells were infected and luciferase activity was measured. RESULTS: RVs containing env from different HIV-1 subtypes were replication competent. Minor variants were detectable in 1% of the viral population. Tropism was determined in 65% of samples with a viral load of <1000 copies/mL. The phenotypic assay described here was validated with the TrofileTM and TrofileTMES assays. Considering the TrofileTM assay as a reference, the sensitivity for R5 and R5X4/X4 detection was 90% and 77%, and the specificity was 77% and 90%, respectively. Our assay was 86% concordant with TrofileTM (90% for R5 and 77% for R5X4/X4). When our system was compared with TrofileTMES, the concordance was 89% (86% for R5 and 92% for R5X4/X4), the sensitivity for R5 was 86% and for R5X4/X4 was 92%, and the specificity for R5 was 92% and for R5X4/X4 was 86%. The phenotypic results were compared with those obtained using the following V3 genotypic prediction tools: position-specific scoring matrix; geno2pheno[coreceptor]; C4.5; C4.5 using positions 8 and 12; PART; support vector machines; and the charge rule. CONCLUSIONS: We describe a system to assess co receptor tropism based on the generation of chimeric replication-competent viruses with high sensitivity in the detection of minor populations. A good correlation of our results with TrofileTM assays was found. PMID- 20947623 TI - Prognostic factors in young Japanese women with breast cancer: prognostic value of age at diagnosis. AB - OBJECTIVE: The primary objective of this study was to verify whether breast cancer patients aged <35 at diagnosis have poorer prognoses than those aged 35 39, in other words, to identify the prognostic value of age in younger premenopausal patients under 40 years old. The secondary objective was to assess prognostic factors specific for younger premenopausal patients. METHODS: We identified 242 consecutive patients who were diagnosed with stage I-III breast cancer before the age of 40 and underwent surgery between 1990 and 2004. We compared disease-free survival and overall survival in patients aged <35 years and those aged 35-39 years, and evaluated clinicopathological factors associated with disease-free survival or overall survival in each age group and in all patients under the age of 40. RESULTS: Ninety-nine (41%) patients were younger than 35 years and 143 (59%) were between 35 and 39 years. No significant difference in disease-free survival or overall survival was found between the two groups. In our cohort of patients under the age of 40, the independent factors associated with poor disease-free survival and overall survival included positive axillary lymph nodes and triple-negative status, but not age at diagnosis. Adverse prognostic factors also did not differ considerably between the two age groups. CONCLUSIONS: Age at diagnosis was not an independent prognostic factor in our study. Our findings suggest that other clinicopathological features rather than age should be used to determine individualized treatment courses for breast cancer patients younger than 40 years. PMID- 20947624 TI - Serum testosterone level to predict the efficacy of sequential use of antiandrogens as second-line treatment following androgen deprivation monotherapy in patients with castration-resistant prostate cancer. AB - OBJECTIVE: We investigated whether serum testosterone after the failure of androgen deprivation monotherapy predicted the efficacy of antiandrogens added to androgen deprivation monotherapy as second-line treatments for patients with castration-resistant prostate cancer. METHODS: We reviewed 30 patients with castration-resistant prostate cancer who received maximal androgen blockade with addition of an antiandrogen (delayed maximal androgen blockade) (bicalutamide 80 mg daily for 21 patients and flutamide 375 mg daily for 9 patients) as the second line treatment. The patients were divided into two groups by serum testosterone before delayed maximal androgen blockade: 22 in the testosterone >= 5 ng/dl group and 8 in the testosterone <5 ng/dl group. A prostate-specific antigen response was defined as a prostate-specific antigen decline of >= 50% from the pre treatment level. RESULTS: The response rate was significantly higher in the testosterone >= 5 ng/dl group than in the testosterone <5 ng/dl group (77.3 vs. 37.5%, P =0.04). During the median follow-up period of 52.5 months, 24 patients (80.0%) developed prostate-specific antigen progression. A serum testosterone level of <5 ng/dl was an independent factor to predict prostate-specific antigen progression in a reduced and full model setting on multivariate analysis (hazard ratio 6.03, P =0.003 and 5.99, P =0.003, respectively). The 1-year prostate specific antigen progression-free survival rate was significantly higher in the testosterone >= 5 ng/dl group than in the testosterone <5 ng/dl group (52.9 vs. 0%, P =0.002), as was cause-specific survival (5 years: 66.0 vs. 33.3%, P =0.007). CONCLUSIONS: Serum testosterone could play an important role when delayed maximal androgen blockade is indicated as the second-line treatment in patients with castration-resistant prostate cancer. Delayed maximal androgen blockade might be more beneficial in patients with a serum testosterone level of >= 5ng/dl. PMID- 20947625 TI - Chronic uremia stimulates LDL carbamylation and atherosclerosis. AB - Carbamylated LDL (cLDL) is a potential atherogenic factor in chronic kidney disease (CKD). However, whether elevated plasma cLDL associates with atherosclerosis in vivo is unknown. Here, we induced CKD surgically in apolipoprotein E-deficient (ApoE(-/-)) mice fed a high-fat diet to promote the development of atherosclerosis. These mice had two- to threefold higher plasma levels of both oxidized LDL (oxLDL) and cLDL compared with control mice. Oral administration of urea increased cLDL approximately eightfold in ApoE(-/-) mice subjected to unilateral nephrectomy and a high-fat diet, but oxLDL did not rise. Regardless of the model, the uremic mice with high plasma cLDL had more severe atherosclerosis as measured by intravital ultrasound echography and en face aortic staining of lipid deposits. Furthermore, cLDL accumulated in the aortic wall and colocalized with ICAM-1 and macrophage infiltration. In summary, these data demonstrate that elevated plasma cLDL may represent an independent risk factor for uremia-induced atherosclerosis. PMID- 20947627 TI - Tubular reabsorption of albumin: it's all about cubilin. PMID- 20947626 TI - Fetuin-mineral complex reflects extraosseous calcification stress in CKD. AB - Fetuin-A is an important inhibitor of extraosseous calcification, but some of the studies that used ELISAs did not identify a significant relationship between serum fetuin-A levels and vascular calcification in patients with chronic kidney disease (CKD). Here, we used centrifugation to separate a fetuin-mineral complex (FMC) composed of fetuin-A, fibrinogen, fibronectin-1, and calcium from the serum of hemodialysis patients. In addition, we analyzed serum fetuin-A levels of 73 patients with diabetes and CKD (predialysis) after centrifugation. Fetuin-A concentrations were significantly lower in supernatants than in serum from patients at any stage of CKD, indicating systemic circulation of FMC in these patients. With greater severity of CKD, the contribution of FMC to total fetuin-A increased. Despite the absence of a correlation between serum fetuin-A and coronary artery calcification scores (CACS), supernatant fetuin-A negatively correlated with CACS and the extent to which centrifugation reduced fetuin-A (reduction ratio [RR]) positively correlated with CACS. In a longitudinal study of 12 hemodialysis patients with secondary hyperparathyroidism, parathyroidectomy and cinacalcet therapy each significantly reduced the RR without changing supernatant fetuin-A levels after 1 month, suggesting a reduction in FMC. Moreover, the magnitude of cinacalcet-induced reduction in parathyroid hormone correlated with the decrease in RR but not with changes in serum or supernatant fetuin-A. These data suggest that a quantitative measure of FMC, not supernatant or serum fetuin-A as measured in previous studies, reflects extraosseous calcification stress. PMID- 20947628 TI - RGS2 proteins regulate blood pressure. PMID- 20947629 TI - Blood pressure and mortality among ESRD patients: all patients are not created equal. PMID- 20947630 TI - Rate of kidney function decline associates with increased risk of death. PMID- 20947631 TI - Electrical forces determine glomerular permeability. AB - There is ongoing controversy about the mechanisms that determine the characteristics of the glomerular filter. Here, we tested whether flow across the glomerular filter generates extracellular electrical potential differences, which could be an important determinant of glomerular filtration. In micropuncture experiments in Necturus maculosus, we measured a potential difference across the glomerular filtration barrier that was proportional to filtration pressure ( 0.045 mV/10 cm H2O). The filtration-dependent potential was generated without temporal delay and was negative within Bowman's space. Perfusion with the cationic polymer protamine abolished the potential difference. We propose a mathematical model that considers the relative contributions of diffusion, convection, and electrophoretic effects on the total flux of albumin across the filter. According to this model, potential differences of -0.02 to -0.05 mV can induce electrophoretic effects that significantly influence the glomerular sieving coefficient of albumin. This model of glomerular filtration has the potential to provide a mechanistic theory, based on experimental data, about the filtration characteristics of the glomerular filtration barrier. It provides a unique approach to the microanatomy of the glomerulus, renal autoregulation, and the pathogenesis of proteinuria. PMID- 20947632 TI - Age, race, diabetes, blood pressure, and mortality among hemodialysis patients. AB - Observational studies involving hemodialysis patients suggest a U-shaped relationship between BP and mortality, but the majority of these studies followed large, heterogeneous cohorts. To examine whether age, race, and diabetes status affect the association between systolic BP (SBP; predialysis) and mortality, we studied a cohort of 16,283 incident hemodialysis patients. We constructed a series of multivariate proportional hazards models, adding age and BP to the analyses as cubic polynomial splines to model potential nonlinear relationships with mortality. Overall, low SBP associated with increased mortality, and the association was more pronounced among older patients and those with diabetes. Higher SBP associated with increased mortality among younger patients, regardless of race or diabetes status. We observed a survival advantage for black patients primarily among older patients. Diabetes associated with increased mortality mainly among older patients with low BP. In conclusion, the design of randomized clinical trials to identify optimal BP targets for patients with ESRD should take age and diabetes status into consideration. PMID- 20947633 TI - Sodium and potassium balance depends on alphaENaC expression in connecting tubule. AB - Mutations in alpha, beta, or gamma subunits of the epithelial sodium channel (ENaC) can downregulate ENaC activity and cause a severe salt-losing syndrome with hyperkalemia and metabolic acidosis, designated pseudohypoaldosteronism type 1 in humans. In contrast, mice with selective inactivation of alphaENaC in the collecting duct (CD) maintain sodium and potassium balance, suggesting that the late distal convoluted tubule (DCT2) and/or the connecting tubule (CNT) participates in sodium homeostasis. To investigate the relative importance of ENaC-mediated sodium absorption in the CNT, we used Cre-lox technology to generate mice lacking alphaENaC in the aquaporin 2-expressing CNT and CD. Western blot analysis of microdissected cortical CD (CCD) and CNT revealed absence of alphaENaC in the CCD and weak alphaENaC expression in the CNT. These mice exhibited a significantly higher urinary sodium excretion, a lower urine osmolality, and an increased urine volume compared with control mice. Furthermore, serum sodium was lower and potassium levels were higher in the genetically modified mice. With dietary sodium restriction, these mice experienced significant weight loss, increased urinary sodium excretion, and hyperkalemia. Plasma aldosterone levels were significantly elevated under both standard and sodium-restricted diets. In summary, alphaENaC expression within the CNT/CD is crucial for sodium and potassium homeostasis and causes signs and symptoms of pseudohypoaldosteronism type 1 if missing. PMID- 20947634 TI - Rate of kidney function decline associates with mortality. AB - The effect of rate of decline of kidney function on risk for death is not well understood. Using the Department of Veterans Affairs national databases, we retrospectively studied a cohort of 4171 patients who had rheumatoid arthritis and early stage 3 chronic kidney disease (CKD; estimated GFR 45 to 60 ml/min) and followed them longitudinally to characterize predictors of disease progression and the effect of rate of kidney function decline on mortality. After a median of 2.6 years, 1604 (38%) maintained stable kidney function; 426 (10%), 1147 (28%), and 994 (24%) experienced mild, moderate, and severe progression of CKD, respectively (defined as estimated GFR decline of 0 to 1, 1 to 4, and >4 ml/min per yr). Peripheral artery disease predicted moderate progression of CKD progression. Black race, hypertension, diabetes, cardiovascular disease, and peripheral artery disease predicted severe progression of CKD. After a median of 5.7 years, patients with severe progression had a significantly increased risk for mortality (hazard ratio 1.54; 95% confidence interval 1.30 to 1.82) compared with those with mild progression; patients with moderate progression exhibited a similar trend (hazard ratio 1.10; 95% confidence interval 0.98 to 1.30). Our results demonstrate an independent and graded association between the rate of kidney function decline and mortality. Incorporating the rate of decline into the definition of CKD may transform a static definition into a dynamic one that more accurately describes the potential consequences of the disease for an individual. PMID- 20947635 TI - In vivo chronic intermittent ethanol exposure reverses the polarity of synaptic plasticity in the nucleus accumbens shell. AB - Glutamatergic synaptic plasticity in the nucleus accumbens (NAc) is implicated in response to sensitization to psychomotor-stimulating agents, yet ethanol effects here are undefined. We studied the acute in vitro and in vivo effects of ethanol in medium spiny neurons from the shell NAc subregion of slices of C57BL/6 mice by using whole-cell voltage-clamp recordings of alpha-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid (AMPA) excitatory postsynaptic current (EPSCs). Synaptic conditioning (low-frequency stimulation with concurrent postsynaptic depolarization) reliably depressed AMPA EPSCs by nearly 30%; this accumbal long term depression (LTD) was blocked by a nonselective N-methyl-D-aspartate (NMDA) receptor antagonist (DL-2-amino-5-phosphonovaleric acid) and a selective NMDA receptor 2B antagonist [R-(R*,S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4 (phenylmethyl)-1-piperidine propanol]. Acute ethanol exposure inhibited the depression of AMPA EPSCs differentially with increasing concentrations, but this inhibitory action of ethanol was occluded by a D1-selective dopamine receptor agonist. Ethanol dependence was elicited in C57BL/6 mice by two separate 4-day bouts of chronic intermittent ethanol (CIE) vapor exposure. When assessed 24 h after a single bout of in vivo CIE vapor exposure, NAc LTD was absent, and instead NMDA receptor-dependent synaptic potentiation [long-term potentiation (LTP)] was reliably observed. It is noteworthy that both LTP and LTD were completely absent after an extended withdrawal (72 h) after a single 3-day CIE vapor bout. These observations demonstrate that 1) accumbal synaptic depression is mediated by NR2B receptors, 2) accumbal synaptic depression is highly sensitive to both acute and chronic ethanol exposure, and 3) alterations in this synaptic process may constitute a neural adaptation that contributes to the induction and/or expression of ethanol dependence. PMID- 20947637 TI - Interaction of the diguanylate cyclase YdeH of Escherichia coli with 2',(3') substituted purine and pyrimidine nucleotides. AB - Diguanylate cyclases (DGCs) synthesize the bacterial second messenger cyclic 3',5'-diguanosine monophosphate (c-di-GMP), which is degraded by specific phosphodiesterases. c-di-GMP levels control the transition of bacteria from a motile to a biofilm-forming lifestyle. These bacterial communities are highly resistant to antibiotic treatment and represent the predominant lifestyle in most chronic infections. Hence, DGCs serve as starting point for the development of novel therapeutics interfering with the second messenger-signaling network in bacteria. In previous studies, we showed that 2'(3')-O-(N-methylanthraniloyl) (MANT)- and 2',3'-O-(2,4,6-trinitrophenyl) (TNP)-substituted nucleotides are potent adenylyl and guanylyl cyclase inhibitors. The catalytic domain of DGCs is homologous to the mammalian adenylyl cyclase catalytic domain. Therefore, we investigated the interaction of various MANT purine and pyrimidine nucleotides with the model DGC YdeH from Escherichia coli. We observed strong fluorescence resonance energy transfer between tryptophan and tyrosine residues of YdeH and the MANT group of MANT-NTPs (MANT-ATP, -CTP, -GTP, -ITP, -UTP, and -XTP) and an enhanced direct MANT fluorescence upon interaction with YdeH. We assessed the affinity of MANT-NTPs to YdeH by performing competition assays with NTPs. We conducted an amino acid alignment of YdeH with the earlier crystallized Caulobacter crescentus DGC PleD and found high similarities in the nucleotide binding site of PleD. In vitro mass-spectrometric activity assays with YdeH resulted in the identification of new MANT/TNP nucleotide-based inhibitors of DGC activity. Together, the analysis of interactions between MANT/TNP nucleotides and YdeH provides a new basis for the identification and development of DGC inhibitors and allows insights into nucleotide-protein interactions. PMID- 20947636 TI - Iron-induced cardiac damage: role of apoptosis and deferasirox intervention. AB - Excess cardiac iron levels are associated with cardiac damage and can result in increased morbidity and mortality. Here, we hypothesize that elevations in tissue iron can activate caspase-dependent signaling, which leads to increased cardiac apoptosis and fibrosis, and that these alterations can be attenuated by iron chelation. Using an iron-overloaded gerbil model, we show that increased cardiac iron is associated with reduced activation of Akt (Ser473 and Thr308), diminished phosphorylation of the proapoptotic regulator Bad (Ser136), and an increased Bax/Bcl-2 ratio. These iron-overload-induced alterations in Akt/Bad phosphorylation and Bax/Bcl-2 ratio were coupled with increased activation of the downstream caspase-9 (40/38- and 17-kDa fragments) and apoptosis executioner caspase-3 (19- and 17-kDa fragments), which were accompanied by evidence of elevated cytoskeletal alpha-fodrin cleavage (150- and 120-kDa fragments), discontinuity of myocardial membrane dystrophin immunoreactivity, increases in the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells (nucleic DNA fragmentation), and cardiac fibrosis. We demonstrate that the administration of deferasirox, a tridentate iron chelator, is associated with diminished tissue iron deposition, attenuated activation of caspases, reduced alpha-fodrin cleavage, improved membrane integrity, decreased TUNEL reactivity, and attenuated cardiac fibrosis. These results suggest that the activation of caspase-dependent signaling may play a role in the development of iron-induced cardiac apoptosis and fibrosis, and deferasirox, via a reduction in cardiac tissue iron levels, may be useful for decreasing the extent of iron induced cardiac damage. PMID- 20947638 TI - N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1 methyl-1H-imidazole-4-carboxamide (THIIC), a novel metabotropic glutamate 2 potentiator with potential anxiolytic/antidepressant properties: in vivo profiling suggests a link between behavioral and central nervous system neurochemical changes. AB - The normalization of excessive glutamatergic neurotransmission through the activation of metabotropic glutamate 2 (mGlu2) receptors may have therapeutic potential in a variety of psychiatric disorders, including anxiety/depression and schizophrenia. Here, we characterize the pharmacological properties of N-(4-((2 (trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H imidazole-4-carboxamide (THIIC), a structurally novel, potent, and selective allosteric potentiator of human and rat mGlu2 receptors (EC(50) = 23 and 13 nM, respectively). THIIC produced anxiolytic-like efficacy in the rat stress-induced hyperthermia assay and the mouse stress-induced elevation of cerebellar cGMP and marble-burying assays. THIIC also produced robust activity in three assays that detect antidepressant-like activity, including the mouse forced-swim test, the rat differential reinforcement of low rate 72-s assay, and the rat dominant submissive test, with a maximal response similar to that of imipramine. Effects of THIIC in the forced-swim test and marble burying were deleted in mGlu2 receptor null mice. Analysis of sleep electroencephalogram (EEG) showed that THIIC had a sleep-promoting profile with increased non-rapid eye movement (REM) and decreased REM sleep. THIIC also decreased the dark phase increase in extracellular histamine in the medial prefrontal cortex and decreased levels of the histamine metabolite tele-methylhistamine (t-MeHA) in rat cerebrospinal fluid. Collectively, these results indicate that the novel mGlu2-positive allosteric modulator THIIC has robust activity in models used to predict anxiolytic/antidepressant efficacy, substantiating, at least with this molecule, differentiation in the biological impact of mGlu2 potentiation versus mGlu2/3 orthosteric agonism. In addition, we provide evidence that sleep EEG and CSF t MeHA might function as viable biomarker approaches to facilitate the translational development of THIIC and other mGlu2 potentiators. PMID- 20947640 TI - Diffusion MR imaging features of skull base osteomyelitis compared with skull base malignancy. AB - BACKGROUND AND PURPOSE: SBO is a life-threatening infection that may have radiologic features similar to those of the neoplastic processes. The purpose of this study was to evaluate the DWI findings in SBO to facilitate the differential diagnosis. MATERIALS AND METHODS: The MR imaging findings of 9 patients with SBO were retrospectively evaluated and compared with MR imaging studies from 9 patients with NPC, 9 with lymphoma, and 9 with metastatic disease of the skull base. ADC measurements were performed from the ADC(ST) and the ADC(NST) in all 4 groups. RESULTS: The mean ADC(ST) values were 1.26 +/- 0.19 * 10(-3) mm(2)/s for SBO, 0.74 +/- 0.18 * 10(-3) mm(2)/s for NPC, 0.59 +/- 0.11 * 10(-3) mm(2)/s for lymphoma, and 0.99 +/- 0.34 * 10(-3) mm(2)/s for metastatic disease, respectively. The mean ADC value of SBO was significantly higher than those of NPC and lymphoma (P < .0001). There was no significant difference for the comparison of SBO and metastatic lesions. When an ADC value equal to or higher than 1.08 * 10(-3) mm(2)/s was used to rule out lymphoma and NPC, the accuracy was 96%. CONCLUSIONS: Although SBO is a relatively rare condition, its differential diagnosis from neoplastic processes of the skull base is essential to start appropriate treatment promptly. ADC values may help to distinguish patients with SBO from those with malignant lesions. PMID- 20947639 TI - Sustained ligand-activated preconditioning via delta-opioid receptors. AB - We have previously described novel cardioprotection in response to sustained morphine exposure, efficacious in young to aged myocardium and mechanistically distinct from conventional opioid or preconditioning (PC) responses. We further investigate opioid-dependent sustained ligand-activated preconditioning (SLP), assessing duration of protection, opioid receptor involvement, additivity with conventional responses, and signaling underlying preischemic induction of the phenotype. Male C57BL/6 mice were treated with morphine (75-mg subcutaneous pellet) for 5 days followed by morphine-free periods (0, 3, 5, or 7 days) before ex vivo assessment of myocardial tolerance to 25-min ischemia/45-min reperfusion. SLP substantially reduced infarction (by ~50%) and postischemic contractile dysfunction (eliminating contracture, doubling force development). Cardioprotection persisted for 5 to 7 days after treatment. SLP was induced specifically by delta-receptor and not kappa- or MU-opioid receptor agonism, was eliminated by delta-receptor and nonselective antagonism, and was additive with adenosinergic but not acute morphine- or PC-triggered protection. Cotreatment during preischemic morphine exposure with the phosphoinositide-3 kinase (PI3K) inhibitor wortmannin, but not the protein kinase A (PKA) inhibitor myristoylated PKI-(14-22)-amide, prevented induction of SLP. This was consistent with shifts in total and phospho-Akt during the induction period. In summary, data reveal that SLP triggers sustained protection from ischemia for up to 7 days after stimulus, is delta-opioid receptor mediated, is induced in a PI3K-dependent/PKA-independent manner, and augments adenosinergic protection. Mechanisms underlying SLP may be useful targets for manipulation of ischemic tolerance in young or aged myocardium. PMID- 20947641 TI - Copper deficiency myelopathy can also involve the brain stem. PMID- 20947642 TI - Velocity measurements in the middle cerebral arteries of healthy volunteers using 3D radial phase-contrast HYPRFlow: comparison with transcranial Doppler sonography and 2D phase-contrast MR imaging. AB - BACKGROUND AND PURPOSE: We have developed PC HYPRFlow, a comprehensive MRA technique that includes a whole-brain CE dynamic series followed by PC velocity encoding, yielding a time series of high-resolution morphologic angiograms with associated velocity information. In this study, we present velocity data acquired by using the PC component of PC HYPRFlow (PC-VIPR). MATERIALS AND METHODS: Ten healthy volunteers (6 women, 4 men) were scanned by using PC HYPRFlow and 2D-PC imaging, immediately followed by velocity measurements by using TCD. Velocity measurements were made in the M1 segments of the MCAs from the PC-VIPR, 2D-PC, and TCD examinations. RESULTS: PC-VIPR showed approximately 30% lower mean velocity compared with TCD, consistent with other comparisons of TCD with PC-MRA. The correlation with TCD was r = 0.793, and the correlation of PC-VIPR with 2D-PC was r = 0.723. CONCLUSIONS: PC-VIPR is a technique capable of acquiring high resolution MRA of diagnostic quality with velocity data comparable with TCD and 2D-PC. The combination of velocity information and fast high-resolution whole brain morphologic angiograms makes PC HYPRFlow an attractive alternative to current MRA methods. PMID- 20947643 TI - Blood-brain barrier permeability assessed by perfusion CT predicts symptomatic hemorrhagic transformation and malignant edema in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: SHT and ME are feared complications in patients with acute ischemic stroke. They occur >10 times more frequently in tPA-treated versus placebo-treated patients. Our goal was to evaluate the sensitivity and specificity of admission BBBP measurements derived from PCT in predicting the development of SHT and ME in patients with acute ischemic stroke. MATERIALS AND METHODS: We retrospectively analyzed a dataset consisting of 32 consecutive patients with acute ischemic stroke with appropriate admission and follow-up imaging. We calculated admission BBBP by using delayed-acquisition PCT data and the Patlak model. Collateral flow was assessed on the admission CTA, while recanalization and reperfusion were assessed on the follow-up CTA and PCT, respectively. SHT and ME were defined according to ECASS III criteria. Clinical data were obtained from chart review. In our univariate and forward selection based multivariate analysis for predictors of SHT and ME, we incorporated both clinical and imaging variables, including age, admission NIHSS score, admission blood glucose level, admission blood pressure, time from symptom onset to scanning, treatment type, admission PCT-defined infarct volume, admission BBBP, collateral flow, recanalization, and reperfusion. Optimal sensitivity and specificity for SHT and ME prediction were calculated by using ROC analysis. RESULTS: In our sample of 32 patients, 3 developed SHT and 3 developed ME. Of the 3 patients with SHT, 2 received IV tPA, while 1 received IA tPA and treatment with the Merci device; of the 3 patients with ME, 2 received IV tPA, while 1 received IA tPA and treatment with the Merci device. Admission BBBP measurements above the threshold were 100% sensitive and 79% specific in predicting SHT and ME. Furthermore, all patients with SHT and ME--and only those with SHT and ME- had admission BBBP measurements above the threshold, were older than 65 years of age, and received tPA. Admission BBBP, age, and tPA were the independent predictors of SHT and ME in our forward selection-based multivariate analysis. Of these 3 variables, only BBBP measurements and age were known before making the decision of administering tPA and thus are clinically meaningful. CONCLUSIONS: Admission BBBP, a pretreatment measurement, was 100% sensitive and 79% specific in predicting SHT and ME. PMID- 20947644 TI - Measuring myelin repair and axonal loss with diffusion tensor imaging. AB - BACKGROUND AND PURPOSE: DTI is an MR imaging measure of brain tissue integrity and provides an attractive metric for use in neuroprotection clinical trials. The purpose of our study was to use DTI to evaluate the longitudinal changes in brain tissue integrity in a group of patients with MS. MATERIALS AND METHODS: Twenty one patients with MS starting natalizumab were imaged serially for 12 months. Gadolinium-enhancing lesions and 20 regions of interest from normal-appearing white and gray matter brain tissue were followed longitudinally. Average values within each region of interest were derived for FA, lambda(?), lambda(?), and MD. New T1 black holes were identified at 12 months. Analysis was performed by using mixed-model regression analysis with slope (ie, DTI change per month) as the dependent variable. RESULTS: During 1 year, FA increased in gadolinium-enhancing lesions but decreased in NABT (P < .0001 for both). Changes in FA within gadolinium-enhancing lesions were driven by decreased lambda(?) (P < .001), and within NABT, by decreased lambda(?) (P < .0001). A higher lambda(?) within gadolinium-enhancing lesions at baseline predicted conversion to T1 black holes at 12 months. MD was unchanged in both gadolinium-enhancing lesions and NABT. CONCLUSIONS: We observed changes in DTI measures during 1 year in both gadolinium enhancing lesions and NABT. The DTI results may represent possible remyelination within acute lesions and chronic axonal degeneration in NAWM. These results support the use of DTI as a measure of tissue integrity for studies of neuroprotective therapies. PMID- 20947645 TI - Diffusion tensor MR imaging of cerebral gliomas: evaluating fractional anisotropy characteristics. AB - BACKGROUND AND PURPOSE: FA correlation to glioma tumor grade has been mixed if not disappointing. There are several potential underlying fundamental issues that have contributed to these results. In an attempt to overcome these past shortfalls, we evaluated characteristics of FA of the solid tissue components of gliomas, including whether high-grade gliomas have a greater variation of FA than low-grade gliomas. MATERIALS AND METHODS: Thirty-four patients with gliomas (9 grade II, 8 grade III, and 17 grade IV) underwent diffusion tensor imaging at 3T. Mean FA, maximum FA, and minimum FA values were measured within the solid tissue components of the tumors. The variations of FA were evaluated by determining the range of FA values and the maximum SDs of FA. The variations of FA values among different tumor grades were compared statistically. We also correlated FA variations with minimum FA and maximum FA. RESULTS: The maximum FA, FA range, and maximum SD for grade II tumors were significantly lower than those for grade III and IV tumors (P < .0001 ~ P = .0164). A very good correlation of maximum FA to FA range (r = 0.931) and maximum SD (r = 0.889) was observed. CONCLUSIONS: The FA range and maximum SD appear useful for differentiating low- and high-grade gliomas. This analysis added value to the findings on conventional MR imaging. In addition, focal maximum FA is a key factor contributing to the larger FA variation within high-grade gliomas. PMID- 20947646 TI - A transverse and longitudinal MR imaging voxel-based morphometry study in patients with primary cervical dystonia. AB - BACKGROUND AND PURPOSE: Findings of standard MR imaging examinations are usually normal in primary CD. These findings are now increasingly challenged by studies using advanced neuroimaging techniques detecting abnormalities in brain areas that may be functionally involved in the pathophysiology of CD. Our purpose was to evaluate GM volumes in patients with CD at baseline and 5 years later. MATERIALS AND METHODS: We enrolled 19 patients (F/M = 15:4, mean age = 53.2 + 11.2 years), 12 of whom were studied at baseline and again approximately 5 years later. Twenty-eight healthy volunteers acted as controls (F/M = 17:11, mean age = 47.5 + 15.6 years). The subjects were imaged with a 1.5T scanner by using a 3D T1 weighted sequence on 150 contiguous axial 1-mm-thick sections to apply VBM. RESULTS: At entry, VBM analysis disclosed significantly lower GM volumes in the left caudate head and putamen and in the premotor and primary sensorimotor cortices bilaterally in patients than in controls. No correlation was found between decreased GM volumes and patient age, severity of dystonia, or disease duration. At the 5-year follow-up, GM volumes in the left primary sensorimotor cortex in patients had decreased significantly from baseline. CONCLUSIONS: The findings obtained at entry and after a 5-year follow-up consistently showed decreased caudate, putamen, and sensorimotor cortex GM volumes in patients with CD, and they probably play a pathophysiologic role in CD. PMID- 20947647 TI - Prenatal MR imaging detection of deep medullary vein involvement in fetal brain damage. AB - Looking for anomalies distributed in DMV territory, we reviewed 78 fetal MR imaging examinations performed at our institution reporting unequivocal cerebral clastic lesions. We selected 3 cases, all of which had severe cardiocirculatory failure and parenchymal frontoparietal WM hemorrhagic lesions with characteristic fan-shaped distribution. Brain edema and other signs of venous hypertension were also evident. Our data suggest that in utero transient venous hypertension may be responsible for the onset of atypical frontal-located PVL. PMID- 20947648 TI - The effect of supplemental oxygen on hypercapnia in subjects with obesity associated hypoventilation: a randomized, crossover, clinical study. AB - BACKGROUND: It is unknown whether oxygen therapy causes worsening hypercapnia in patients with obesity-associated hypoventilation (OAH), similar to the response observed in COPD. The objectives of this study were to investigate whether breathing 100% oxygen results in an increase in hypercapnia in patients with OAH and the mechanisms of any effect. METHODS: In this double-blind, randomized, controlled, crossover trial, 24 outpatients with newly diagnosed OAH inhaled 100% oxygen or room air for 20 min on 2 separate days. Transcutaneous CO(2) tension (Ptco(2)), minute ventilation, and volume of dead space to tidal volume ratio were measured at baseline and at 20 min. A mixed linear model was used to determine differences between the two treatments. RESULTS: The study was terminated in three subjects breathing 100% oxygen due to a Ptco(2) increase >= 10 mm Hg, which occurred after 10:35, 13:20, and 15:51 min. Ptco(2) increased by 5.0 mm Hg (95% CI, 3.1-6.8; P < .001) with oxygen compared with room air. Minute ventilation decreased by 1.4 L/min (95% CI, 0.11-2.6 L/min; P = .03), and volume of dead space to tidal volume ratio increased by 0.067 (95% CI, 0.035-0.10; P < .001) with oxygen compared with room air. CONCLUSIONS: Breathing 100% oxygen causes worsening hypercapnia in stable patients with OAH. TRIAL REGISTRY: Australia New Zealand Clinical Trials Registry; No.: ACTRN 12608000592347; URL: www.anzctr.org.au. PMID- 20947649 TI - Can chest ultrasonography replace standard chest radiography for evaluation of acute dyspnea in the ED? AB - BACKGROUND: We examined the concordance between chest ultrasonography and chest radiography in patients with dyspnea, using chest CT scanning as the gold standard in case of mismatch between the two modalities. METHODS: A prospective, blinded, observational study was conducted in the ED of a university-affiliated teaching hospital. All consecutive patients presenting for dyspnea during a single emergency physician shift were enrolled independently from the underlying disease. Only patients with trauma were excluded. RESULTS: Both ultrasonography and radiography were performed in 404 patients; CT scanning was performed in 118 patients. Ultrasound interpretation was completed during the scan, whereas the average time between radiograph request and its final interpretation was 1 h and 35 min. Ultrasonography and radiography exhibited high concordance in most pulmonary diseases, especially in pulmonary edema (kappa = 95%). For lung abnormalities such as free pleural effusion, loculated pleural effusion, pneumothorax, and lung consolidation, the concordance was similar for both left- and right-side lungs (all P not significant). When ultrasound scans and radiographs gave discordant results, CT scans confirmed the ultrasound findings in 63% of patients (P < .0001). Particularly, ultrasonography exhibited greater sensitivity than radiography in patients with free pleural effusion (P < .0001). CONCLUSIONS: When performed by one highly trained physician, our study demonstrated high concordance between ultrasonography and radiography. When ultrasound scans and radiographs disagreed, ultrasonography proved to be more accurate in distinguishing free pleural effusion. Thus, considering the short time needed to have a final ultrasound report, this technique could become the routine imaging modality for patients with dyspnea presenting to the ED. PMID- 20947650 TI - Minimally important change in a Parent-Proxy Quality-of-Life questionnaire for pediatric chronic cough. AB - BACKGROUND: The Parent Cough-Specific Quality-of-Life questionnaire (PC-QOL) has relevance and clinical utility as a cough-specific QOL measure for pediatric use. Its validity has been demonstrated. This study sought to determine the minimally important difference (MID) for the PC-QOL completed by parents of young children with chronic cough. METHOD: Thirty-four children (22 boys, 12 girls; median age, 26.5 months; interquartile range, 17.3-38.8 months) and their mothers participated. Mothers completed a cough-related measure (verbal category descriptive score) and the PC-QOL on two occasions separated by 2 to 3 weeks. Two approaches were used to calculate MID. RESULTS: Distribution-based approaches to estimating MID resulted in ranges of 0.50 to 0.78 (effect size method), 0.30 to 0.48 (SE of measurement method), and 0.60 to 0.69 (one-half SD method) for PC-QOL overall and domain scales. Based on verbal category descriptive score change, an anchor-based approach resulted in an MID estimate of 0.9 for overall PC-QOL change and ranged from 0.71 to 0.95 for individual domain PC-QOL change. CONCLUSION: An MID for the PC-QOL of 0.9 is recommended in interpreting health status change in children with chronic cough and will aid clinicians and researchers in interpreting health-related QOL changes following treatments and clinical trials. PMID- 20947651 TI - 131I-labeled lipiodol-induced interstitial pneumonia: a series of 15 cases. AB - BACKGROUND: The drug (131)I-labeled lipiodol is used as internal radiotherapy for unresectable hepatocellular carcinoma. Although the drug was considered safe during preapproval studies, we observed several cases of interstitial pneumonia following its administration. METHODS: Cases were retrospectively identified through the drug safety unit database of Rennes University Hospital. RESULTS: From 1994 to 2009, interstitial pneumonia developed in 15 patients following (131)I-labeled lipiodol administration, with an estimated prevalence of 15.5 cases (95% CI, 7.7-23.2) per 1,000 treated patients. Mean age of the patients was 60 +/- 8 years, and the male to female ratio was 6.5:1. All patients had cirrhosis, mainly related to long-term alcohol intoxication (n = 12). Most (n = 10) cases occurred after the second (131)I-labeled lipiodol injection. The median delay between last (131)I-labeled lipiodol administration and first respiratory symptoms was 30 days (interquartile range, 16.5-45 days). All patients presented with shortness of breath. Physical examination mostly revealed fever (n = 11) and bilateral crackles (n = 12). Chest CT scan showed bilateral ground-glass opacities (n = 8) with septal thickening, retraction, or both (n = 8). BAL (n = 7) was remarkable for increased neutrophils (n = 4) or CD8(+) T cell count (n = 3). Despite corticosteroids, 12 (80%) patients died, mostly of untractable respiratory failure (n = 9). Median delay between last (131)I-labeled lipiodol injection and death was 63 days (interquartile range, 34-129 days). CONCLUSIONS: Interstitial pneumonia may be a serious and not uncommon complication of (131)I labeled lipiodol administration. PMID- 20947652 TI - Osteopontin in patients with idiopathic pulmonary hypertension. AB - BACKGROUND: Osteopontin (OPN) is a pleiotropic cytokine that has been postulated to play a role in the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). OPN plasma levels may be related to disease severity and mortality in patients with PAH. METHODS: OPN plasma levels obtained during right-sided heart catheterization were assessed by a commercially available enzyme-linked immunosorbent assay and related to hemodynamics, exercise capacity, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level, uric acid level, C-reactive protein level, and survival in two cohorts of patients with IPAH: a 4-year retrospective cohort (n = 70) and a prospective cohort (n = 25) followed for 3 months after initiation of therapy. Forty apparently healthy individuals served as control subjects. RESULTS: Baseline OPN levels were elevated in patients with IPAH compared with healthy control subjects (50.2 +/- 35.9 vs 23.7 +/- 2.8 ng/mL, P < .0001). In the retrospective as well as in the prospective cohort, OPN levels correlated with mean right atrial pressure and NT-BNP. In the retrospective cohort, OPN levels also correlated with age (r = 0.3, P = .02), 6-min walking distance (r=-0.4, P = .05), and New York Heart Association class (r = 0.4, P = .001). Multivariate Cox analysis demonstrated that baseline OPN levels were independent predictors of mortality (P = .02). When patients were divided according to their baseline OPN values, being normal or elevated at baseline (below or above 34.5 ng/mL), proportional survival rates were 100% vs 80% after 1 year and 77% vs 51% after 3 years, respectively. CONCLUSION: Circulating OPN predicts survival in patients with IPAH and is associated with a higher New York Heart Association class. OPN, thus, may be useful as a biomarker in IPAH. PMID- 20947653 TI - Toxic effect of PBDE-47 on thyroid development, learning, and memory, and the interaction between PBDE-47 and PCB153 that enhances toxicity in rats. AB - Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are widespread environmental contaminants. There are potential interactive effects between PBDEs and PCBs, as these compounds share similar structures. The developmental neurotoxicity of 2, 2', 4, 4'-tetrabromodiphenyl ether (PBDE-47) and the interaction of PBDE-47 with 2, 2', 4, 4', 5, 5'-hexachlorobipheny (PCB153) were investigated herein, as the dominant congener forms of PBDEs and PCBs, respectively. SD rats were exposed to a single oral dose of PBDE-47 (1, 5, and 10 MUg/g) and/or PCB153 (5 MUg/g) on post-natal day (PND) 10. Concentrations of PBDE-47, triiodothyronine (T(3)), thyroxine (T(4)), and thyroid-stimulating hormone (TSH) in serum; organ-to-body weight ratios; as well as long-term learning and memory were measured in 2-month-old rats. The present study found that some doses of PBDE-47 decreased the organ-to-body weight ratios of the thyroid and uterus, decreased the concentration of T(4) in serum, and increased the organ-to-body weight ratio of the ovaries (p < 0.05). PCB153 could increase the action of PBDE-47 during combined exposure, but this interaction was not found between PBDE-47 and PCB153. In a Morris water maze experiment, the latency periods were significantly prolonged and time ratios were obviously depressed in all PBDE-47-treated groups compared to the control (p < 0.05); furthermore, significant interactions between PBDE-47 and PCB153 were observed (p < 0.05). In conclusion, PBDE-47 may depress thyroid development as well as the long-term learning and memory capabilities in adult rats exposed to PBDE-47 on PND 10. PCB153 can interact with PBDE-47, resulting in an increase in developmental neurotoxicity. PMID- 20947654 TI - Comparison of combinatory effects of PCBs (118, 138, 153 and 180) with 17 beta estradiol on proliferation and apoptosis in MCF-7 breast cancer cells. AB - We analyzed whether polychlorinated biphenyls (PCBs) interfere with the activity of 17 beta-estradiol in the proliferation and apoptosis of the MCF-7 cell line. MCF-7 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) without phenol red supplemented with 5% charcoal-treated fetal bovine serum (CD-FBS) for 3 days with 10 nM 17 beta-estradiol or 0.1 uM, 0.5 uM and 1 uM of the tested PCB congeners (118, 138, 153 and 180), or both. Cell proliferation was determined by measuring 5-bromo-2'-deoxyuridine (BrdU) incorporation, and cell apoptosis was measured by caspase-9 activity. From the PCB congeners tested, PCB138 and 153 had the highest stimulatory effects on basal cell proliferation as well as the highest inhibitory actions on basal caspase-9 activity. The proliferative and anti-apoptotic actions of PCB138 and 153 were still observed in the presence of 17 beta-estradiol, while the actions of PCB118 and 180 were reversed. In conclusion, the results of this study suggest the possibility that PCB138 and 153 contribute to the action of endogenous 17 beta-estradiol on cell proliferation and apoptosis in the breast cancer cell line MCF-7. PMID- 20947655 TI - Corrections to: ''Age distribution of cancer in mice''. AB - We found a crucial error in an earlier paper on cancer in elderly mice, Age distribution of cancer in mice: the incidence turnover at old age (Pompei et al., 2001). That paper's principal data set, the ED01 records, was scrambled when read and analyzed with a statistical software package. Having done our best to correct the error, and having subjected the data to a more exact extension of originally published methods, we arrive at conclusions significantly different from those proposed in the original article. What appeared to be a dramatic fall off of the cancer mortality rate in mice over 2 years of age is now found to be a continuation or flattening of approximately exponential growth. This new finding is entirely at odds with the old, and does not support our later work on humans. Two of this paper's authors, F Pompei and R Wilson, contributed to the original article. We are informing authors who have cited our paper in the past and apologize deeply for any wasted time or lost work. We should have subjected the ED01 records to more error checks. We thank Jennifer Blank for helping us discover and correct this error. The ED01 records and our earlier research are available http://physics.harvard.edu/~wilson/cancer&chemicals/ED01. PMID- 20947656 TI - Neurotoxic and immunotoxic effects of fenthion and omethoate on frogs at acute exposure. AB - The study was carried out to investigate the neurotoxic and immunotoxic effects of fenthion- and omethoate-used agricultural areas on frogs (Rana ridibunda) at acute exposure. The neurotoxic effects of the chemicals were evaluated by measuring the activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Biomarkers selected for immunotoxic monitoring were the activities of adenosine deaminase (ADA) and myeloperoxidase (MPO) in various tissues of frogs exposed to 10 or 20 parts per million (ppm) dosages of fenthion and omethoate for 24, 48, 72 and 96 hours. Results showed that the administrations of chemicals fluctuated AChE and BChE activities in some tissues of frogs treated with both dosages at all the periods. With regard to the immunotoxic effects, MPO activity was increased in almost all the tissues of frogs after 10 and 20 ppm dosages and for 24, 48, 72 and 96 hours exposure of fenthion and omethoate as compared to those of control whereas ADA activity did not change in all the tissues. This may reflect the potential role of these parameters as useful biomarkers for toxicity of fenthion and omethoate. PMID- 20947657 TI - Protective effect of hawthorn extract against genotoxicity induced by methyl methanesulfonate in human lymphocytes. AB - The preventive effect of hawthorn (Crataegus microphylla) fruit extract against genotoxicity induced by methyl methanesulfonate (MMS) has been investigated in human cultured blood lymphocytes. Peripheral blood samples were collected from human volunteers at 0 (10 minutes before), and at 1 and 2 hours after a single oral ingestion of 1 g hawthorn powder extract. At each time point, the whole blood was treated in vitro with MMS (200 umol) at 24 hours after cell culture, and then the lymphocytes were cultured with mitogenic stimulation to determine the micronuclei in cytokinesis-blocked binucleated cells. The lymphocytes treated with hawthorn and MMS to exhibit a significant decreasing in the incidence of micronucleated binucleated cells, as compared with similarly MMS-treated lymphocytes from blood samples collected at 0 hour. The maximum protection and decreasing in frequency of micronuclei (36%) was observed at 1 hour after ingestion of hawthorn extract. The high performance liquid chromatography (HPLC) analysis showed that hawthorn contained chlorogenic acid, epicatechin and hyperoside. It is obvious that hawthorn, particularly flavonoids constituents with antioxidative activity, reduced the oxidative stress and genotoxicity induced by toxic compounds. This set of data may have an important application for the protection of human lymphocyte from the genetic damage and side effects induced by chemicals hazardous in people. PMID- 20947658 TI - Ambient particulate matter on DNA damage in HepG2 cells. AB - Ambient particulate matter (PM) has been reported to be associated with increased respiratory, cardiovascular, and malignant lung diseases. The aim of the present study was to investigate the variability of the DNA-damage induced by thoracic particles (PM( 10)) sampled in different locations and seasons (2006) in Dalian, China, in human hepatoma G2 (HepG2) cells. Significant differences in percentage of tail DNA induced by the extractable organic matter of PM(10) were revealed between summer and winter seasons and among monitoring sites in single cell gel electrophoresis (SCGE) assay. The percentage of tail DNA in HepG2 cells significantly increased in a dose-dependent manner after exposure to 7.5 and 30 MUg/mL extractable organic matter of PM(10) for 1 hour. In order to clarify the underlying mechanisms, we evaluated the level of reactive oxygen species (ROS) production with the 2, 7-dichloro-fluorescein diacetate (DCFH-DA) assay. Significantly increased level of ROS was observed in HepG2 cells at higher concentrations (15 and 30 MUg/mL). Significantly increased levels of 8 hydroxydeoxyguanosine (8-OHdG) were also shown in HepG2 cells. In this study, the accumulation of nuclear factor kappa B (NF-kappaB) p65 protein induced by the extractable organic matter of PM(10) was detected by western blotting in HepG2 cells, and the protein expression of NF-kappaB p65 significantly increased after the treatment with 30 MUg/mL extractable organic matter of PM(10) for 24 hours. These results indicate that the extractable organic matter of PM(10) causes DNA strand breaks in HepG2 cells, and significant differences in percentage of tail DNA in dependence on locality and season are revealed. The extractable organic matter of PM(10) exerts DNA damage effects in HepG2 cells, probably through oxidative DNA damage induced by intracellular ROS, increase of 8-OHdG formation, and protein expression of NF-kappaB p65. PMID- 20947659 TI - Large-scale screening of the Gaucher's disease-related glucocerebrosidase gene in Europeans with Parkinson's disease. AB - Pathogenic variants in the glucocerebrosidase gene (GBA) encoding the enzyme deficient in Gaucher's disease (GD) are associated with Parkinson's disease (PD). To investigate the sequence variants, their association with PD and the related phenotypes in a large cohort of European, mostly French, patients and controls, we sequenced all exons of GBA in 786 PD patients from 525 unrelated multiplex families, 605 patients with apparently sporadic PD and 391 ethnically matched controls. GBA mutations were significantly more frequent (odds ratio=6.98, 95% confidence interval 2.54-19.21; P=0.00002) in the PD patients (76/1130=6.7%) than in controls (4/391=1.0%) and in patients with family histories of PD (8.4%) than in isolated cases (5.3%). Twenty-eight different mutations were identified in patient and control groups, including seven novel variants. N370S and L444P accounted for 70% of all mutant alleles in the patient group. PD patients with GBA mutations more frequently had bradykinesia as the presenting symptom and levodopa-induced dyskinesias. The phenotype was similar in patients with one, two or complex GBA mutations, although the two patients with c.1263del+RecTL and N370S/RecDelta55 mutations had signs of GD. Segregation analyses in 21 multiplex families showed that 17% of the affected relatives did not carry GBA mutations found in the given family, indicating heterogeneity of the aetiology, but 46% of the unaffected relatives were GBA mutation carriers. These genotype and clinical analyses on the largest homogeneous sample of European patients studied to date confirmed that GBA mutations are the most common genetic risk factor for PD, particularly in familial forms. PMID- 20947660 TI - Dystrophin conferral using human endothelium expressing HLA-E in the non immunosuppressive murine model of Duchenne muscular dystrophy. AB - Human leukocyte antigen (HLA)-E is a non-classical major histocompatibility complex class I (Ib) molecule, which plays an important role in immunosuppression. In this study, we investigated the immunomodulating effect of HLA-E in a xenogeneic system, using human placental artery-derived endothelial (hPAE) cells expressing HLA-E in a mouse model. In vitro cell lysis analysis by primed lymphocytes in combination with siRNA transfection showed that HLA-E is necessary for inhibition of the immune response. Similarly, in vivo cell implantation analysis with siRNA-mediated down-regulation of HLA-E demonstrates that HLA-E is involved in immunosuppression. As hPAE cells efficiently transdifferentiate into myoblasts/myocytes in vitro, we transplanted the cells into mdx mice, a model of Duchenne muscular dystrophy. hPAE cells conferred dystrophin to myocytes of the 'immunocompetent' mdx mice with extremely high efficiency. These findings suggest that HLA-E-expressing cells with a myogenic potential represent a promising source for cell-based therapy of patients with muscular dystrophy. PMID- 20947662 TI - The human Cas1 protein: a sialic acid-specific O-acetyltransferase? AB - Sialic acids are important sugars at the reducing end of glycoproteins and glycolipids. They are among many other functions involved in cell-cell interactions, host-pathogen recognition and the regulation of serum half-life of glycoproteins. An important modification of sialic acids is O-acetylation, which can alter or mask the biological properties of the parent sialic acid molecule. The nature of mammalian sialate-O-acetyltransferases (EC 2.3.1.45) involved in their biosynthesis is still unknown. We have identified the human CasD1 (capsule structure1 domain containing 1) gene as a candidate to encode the elusive enzyme. The human CasD1 gene encodes a protein with a serine-glycine-asparagine-histidine hydrolase domain and a hydrophobic transmembrane domain. Expression of the Cas1 protein tagged with enhanced green fluorescent protein in mammalian and insect cells directed the protein to the medial and trans-cisternae of the Golgi. Overexpression of the Cas1 protein in combination with alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 (GD3 synthase) resulted in an up to 40% increased biosynthesis of 7-O-acetylated ganglioside GD3. By quantitative real-time polymerase chain reaction, we found up to 5-fold increase in CasD1 mRNA in tumor cells overexpressing O-Ac-GD3. CasD1-specific small interfering RNA reduced O acetylation in tumor cells. These results suggest that the human Cas1 protein is directly involved in O-acetylation of alpha2-8-linked sialic acids. PMID- 20947661 TI - Age-related differences in human skin proteoglycans. AB - Previous work has shown that versican, decorin and a catabolic fragment of decorin, termed decorunt, are the most abundant proteoglycans in human skin. Further analysis of versican indicates that four major core protein species are present in human skin at all ages examined from fetal to adult. Two of these are identified as the V0 and V1 isoforms, with the latter predominating. The other two species are catabolic fragments of V0 and V1, which have the amino acid sequence DPEAAE as their carboxyl terminus. Although the core proteins of human skin versican show no major age-related differences, the glycosaminoglycans (GAGs) of adult skin versican are smaller in size and show differences in their sulfation pattern relative to those in fetal skin versican. In contrast to human skin versican, human skin decorin shows minimal age-related differences in its sulfation pattern, although, like versican, the GAGs of adult skin decorin are smaller than those of fetal skin decorin. Analysis of the catabolic fragments of decorin from adult skin reveals the presence of other fragments in addition to decorunt, although the core proteins of these additional decorin catabolic fragments have not been identified. Thus, versican and decorin of human skin show age-related differences, versican primarily in the size and the sulfation pattern of its GAGs and decorin in the size of its GAGs. The catabolic fragments of versican are detected at all ages examined, but appear to be in lower abundance in adult skin compared with fetal skin. In contrast, the catabolic fragments of decorin are present in adult skin, but are virtually absent from fetal skin. Taken together, these data suggest that there are age-related differences in the catabolism of proteoglycans in human skin. These age-related differences in proteoglycan patterns and catabolism may play a role in the age-related changes in the physical properties and injury response of human skin. PMID- 20947663 TI - Molecular analysis of faecal and duodenal samples reveals significantly higher prevalence and numbers of Pseudomonas aeruginosa in irritable bowel syndrome. AB - Intestinal microbiota may play a role in the pathophysiology of irritable bowel syndrome (IBS). In this case-control study, mucosa-associated small intestinal and faecal microbiota of IBS patients and healthy subjects were analysed using molecular-based methods. Duodenal mucosal brush and faecal samples were collected from 37 IBS patients and 20 healthy subjects. The bacterial 16S rRNA gene was amplified and analysed using PCR denaturing gradient gel electrophoresis (DGGE). Pooled average DGGE profiles of all IBS patients and all healthy subjects from both sampling sites were generated and fingerprints of both groups were compared. The DGGE band fragments which were confined to one group were further characterized by sequence analysis. Quantitative real-time PCR (q-PCR) was used to quantify the disease-associated microbiota. Averaged DGGE profiles of both groups were identical for 78.2 % in the small intestinal samples and for 86.25 % in the faecal samples. Cloning and sequencing of the specific bands isolated from small intestinal and faecal DGGE patterns of IBS patients showed that 45.8 % of the clones belonged to the genus Pseudomonas, of which Pseudomonas aeruginosa was the predominant species. q-PCR analysis revealed higher levels (P<0.001) of P. aeruginosa in the small intestine of IBS patients (8.3 %+/-0.950) than in the small intestine of healthy subjects (0.1 %+/-0.069). P. aeruginosa was also significantly (P<0.001) more abundant (2.34 %+/-0.31) in faeces of IBS patients than in faeces of healthy subjects (0.003 %+/-0.0027). This study shows that P. aeruginosa is detected more frequently and at higher levels in IBS patients than in healthy subjects, suggesting its potential role in the pathophysiology of IBS. PMID- 20947664 TI - Refractory Bartonella quintana bacillary angiomatosis following chemotherapy for chronic lymphocytic leukaemia. AB - Bacillary angiomatosis is a well-recognized infection with cutaneous and systemic manifestations caused by Bartonella henselae or Bartonella quintana and occurs in immunocompromised patients. We report a case of B. quintana bacillary angiomatosis following fludarabine-based chemotherapy for chronic lymphocytic leukaemia that was refractory to standard treatment and was complicated by lymphadenopathy and osteomyelitis. PMID- 20947665 TI - Caspofungin primes the immune response of the larvae of Galleria mellonella and induces a non-specific antimicrobial response. AB - The echinocandins (e.g. caspofungin) function by inhibiting the synthesis of 1,3 beta-glucan in the fungal cell wall. While the potent antifungal activity of caspofungin has been well characterized in mammals, this study investigated the in vivo antifungal effect of caspofungin using larvae of the insect Galleria mellonella. Caspofungin was successful in increasing the survival of larvae that were inoculated with Candida albicans 1 h before the drug was administered, particularly when a concentration of 0.19 MUg ml(-1) was used. Pre-injecting larvae with caspofungin also increased their survival when they were inoculated with either Staphylococcus aureus or C. albicans. Caspofungin administration resulted in an increase in the number of circulating immune cells (haemocytes), an increase in the expression of the genes encoding IMPI and transferrin, and an increase in the expression of a number of proteins (identified by liquid chromatography-mass spectrometry) some of which have immune functions. This work indicates that administration of caspofungin can increase the survival of infected G. mellonella larvae, and this is due to the antifungal properties of caspofungin and also to the ability of caspofungin to prime the insect's immune response. PMID- 20947666 TI - Integron types, gene cassettes, antimicrobial resistance genes and plasmids of Shigella sonnei isolates from outbreaks and sporadic cases in Taiwan. AB - This study analysed the presence, location and transferability of integrons and antibiotic resistance genes in 103 Shigella sonnei outbreak isolates and in 32 sporadic isolates from Taiwan. Multiple antimicrobial resistance was common in both outbreak (95 %) and sporadic (97 %) isolates. Class 1 integrons were present in 34 outbreak isolates (33 %) and in six sporadic isolates (19 %). This study is the first, to our knowledge, to identify an atypical sul3-associated class 1 integron carrying the estX-psp-aadA2-cmlA-aadA1-qacH cassette array in Shigella. Class 2 integrons carrying the dfr1-sat2-aadA1 cassette array were predominant in outbreak isolates (90 %) but were not present in sporadic isolates. Other antimicrobial resistance genes not associated with integrons were found to encode resistance to ampicillin (bla(TEM)), chloramphenicol (cat1), sulfonamide (sul2) and tetracycline (tetA and tetB). The most common plasmid size was 130 kb (observed in 43 and 97 % of 1998 outbreak and sporadic isolates, respectively). In conclusion, the plasmid location of resistance genes and horizontal plasmid transfer promote the spread of multiple resistance genes in outbreak and sporadic isolates of S. sonnei. PMID- 20947667 TI - Increased human pathogenic potential of Escherichia coli from polymicrobial urinary tract infections in comparison to isolates from monomicrobial culture samples. AB - The current diagnostic standard procedure outlined by the Health Protection Agency for urinary tract infections (UTIs) in clinical laboratories does not report bacteria isolated from samples containing three or more different bacterial species. As a result many UTIs go unreported and untreated, particularly in elderly patients, where polymicrobial UTI samples are especially prevalent. This study reports the presence of the major uropathogenic species in mixed culture urine samples from elderly patients, and of resistance to front line antibiotics, with potentially increased levels of resistance to ciprofloxacin and trimethoprim. Most importantly, the study highlights that Escherichia coli present in polymicrobial UTI samples are statistically more invasive (P<0.001) in in vitro epithelial cell infection assays than those isolated from monomicrobial culture samples. In summary, the results of this study suggest that the current diagnostic standard procedure for polymicrobial UTI samples needs to be reassessed, and that E. coli present in polymicrobial UTI samples may pose an increased risk to human health. PMID- 20947668 TI - Application of quantitative PCR to the diagnosis and monitoring of Pseudomonas aeruginosa colonization in 5-18-year-old cystic fibrosis patients. AB - Early detection of Pseudomonas aeruginosa and early aggressive treatment are recommended to delay chronic infection in cystic fibrosis (CF) patients. The aim of this study was to assess a quantitative PCR (q-PCR) assay for the diagnosis of early P. aeruginosa colonization in 23 young CF patients (group A, age range 7-18 years) and to survey the eradication of P. aeruginosa in 10 young CF patients (group B, age range 5-18 years) after an initial antibiotic treatment. q-PCR results for consecutive sputum samples from each patient during a period of 18 months were compared with bacterial cultures during the same period plus an additional period of 12 months, and with concomitant clinical signs of pulmonary exacerbation. The q-PCR and bacterial cultures were negative for 17 of the 23 patients in group A and six of the 10 patients in group B during the study period. However, consecutive positive q-PCR results were observed for one patient in group A and three patients in group B, while the bacterial cultures for the same sputum sample remained negative. They preceded positive P. aeruginosa bacterial cultures at 7 and 8 months for two patients in group B. These positive results were associated with a worsening of the clinical status of patients, but pulmonary exacerbation appeared non-specific for the diagnosis of early P. aeruginosa colonization since pulmonary exacerbations were observed in patients in whom q-PCR or bacterial culture remained negative. In conclusion, q-PCR may be a useful additional tool to provide information on the P. aeruginosa status of CF patients. PMID- 20947669 TI - Nitrogen stress response of a hybrid species: a gene expression study. AB - BACKGROUND AND AIMS: Low soil fertility limits growth and productivity in many natural and agricultural systems, where the ability to sense and respond to nutrient limitation is important for success. Helianthus anomalus is an annual sunflower of hybrid origin that is adapted to desert sand-dune substrates with lower fertility than its parental species, H. annuus and H. petiolaris. Previous studies have shown that H. anomalus has traits generally associated with adaptation to low-fertility habitats, including a lower inherent relative growth rate and longer leaf lifetime. METHODS: Here, a cDNA microarray is used to identify gene expression differences that potentially contribute to increased tolerance of low fertility of the hybrid species by comparing the nitrogen stress response of all three species with high- and low-nutrient treatments. KEY RESULTS: Relative to the set of genes on the microarray, the genes showing differential expression in the hybrid species compared with its parents are enriched in stress-response genes, developmental genes, and genes involved in responses to biotic or abiotic stimuli. After a correction for multiple comparisons, five unique genes show a significantly different response to nitrogen limitation in H. anomalus compared with H. petiolaris and H. annuus. The Arabidopsis thaliana homologue of one of the five genes, catalase 1, has been shown to affect the timing of leaf senescence, and thus leaf lifespan. CONCLUSIONS: The five genes identified in this analysis will be examined further as candidate genes for the adaptive stress response in H. anomalus. Genes that improve growth and productivity under nutrient stress could be used to improve crops for lower soil fertility which is common in marginal agricultural settings. PMID- 20947670 TI - Conservative management of cardiac haemangioma. AB - Cardiac haemangiomas are rare forms of cardiac tumours which can present at any age and in any cardiac location. The clinical presentations of patients vary and preoperative diagnosis of cardiac haemangiomas is usually made using echocardiography and magnetic resonance imaging (MRI). Surgical resection is the treatment of choice and follow-up is recommended to avoid any recurrence. We report a particular case of cardiac haemangiomas which was referred to us and eventually managed conservatively. The medical history, physical examination and surgical/non-surgical management are discussed. PMID- 20947672 TI - Minimal detectable change of the timed "up & go" test and the dynamic gait index in people with Parkinson disease. AB - BACKGROUND: The minimal detectable change (MDC) is the smallest amount of difference in individual scores that represents true change (beyond random measurement error). The MDCs of the Timed "Up & Go" Test (TUG) and the Dynamic Gait Index (DGI) in people with Parkinson disease (PD) are largely unknown, limiting the interpretability of the change scores of both measures. OBJECTIVE: The purpose of this study was to estimate the MDCs of the TUG and the DGI in people with PD. DESIGN: This investigation was a prospective cohort study. METHODS: Seventy-two participants were recruited from special clinics for movement disorders at a university hospital. Their mean age was 67.5 years, and 61% were men. All participants completed the TUG and the DGI assessments twice, about 14 days apart. The MDC was calculated from the standard error of measurement. The percentage MDC (MDC%) was calculated as the MDC divided by the mean of all scores for the sample. Furthermore, the intraclass correlation coefficient was used to examine the reproducibility between testing sessions (test-retest reliability). RESULTS: The respective MDC and MDC% of the TUG were 3.5 seconds and 29.8, and those of the DGI were 2.9 points and 13.3. The test retest reliability values for the TUG and the DGI were high; the intraclass correlation coefficients were .80 and .84, respectively. LIMITATIONS: The study sample was a convenience sample, and the participants had mild to moderately severe PD. CONCLUSIONS: The results showed that the TUG and the DGI have generally acceptable random measurement error and test-retest reliability. These findings should help clinicians and researchers determine whether a change in an individual patient with PD is a true change. PMID- 20947671 TI - Microarray analysis of the abscission-related transcriptome in the tomato flower abscission zone in response to auxin depletion. AB - The abscission process is initiated by changes in the auxin gradient across the abscission zone (AZ) and is triggered by ethylene. Although changes in gene expression have been correlated with the ethylene-mediated execution of abscission, there is almost no information on the molecular and biochemical basis of the increased AZ sensitivity to ethylene. We examined transcriptome changes in the tomato (Solanum lycopersicum 'Shiran 1335') flower AZ during the rapid acquisition of ethylene sensitivity following flower removal, which depletes the AZ from auxin, with or without preexposure to 1-methylcyclopropene or application of indole-3-acetic acid after flower removal. Microarray analysis using the Affymetrix Tomato GeneChip revealed changes in expression, occurring prior to and during pedicel abscission, of many genes with possible regulatory functions. They included a range of auxin- and ethylene-related transcription factors, other transcription factors and regulatory genes that are transiently induced early, 2 h after flower removal, and a set of novel AZ-specific genes. All gene expressions initiated by flower removal and leading to pedicel abscission were inhibited by indole-3-acetic acid application, while 1-methylcyclopropene pretreatment inhibited only the ethylene-induced expressions, including those induced by wound-associated ethylene signals. These results confirm our hypothesis that acquisition of ethylene sensitivity in the AZ is associated with altered expression of auxin-regulated genes resulting from auxin depletion. Our results shed light on the regulatory control of abscission at the molecular level and further expand our knowledge of auxin-ethylene cross talk during the initial controlling stages of the process. PMID- 20947673 TI - Cross-cultural differences in knee functional status outcomes in a polyglot society represented true disparities not biased by differential item functioning. AB - BACKGROUND: Comparative effectiveness research across cultures requires unbiased measures that accurately detect clinical differences between patient groups. OBJECTIVE: The purpose of this study was to assess the presence and impact of differential item functioning (DIF) in knee functional status (FS) items administered using computerized adaptive testing (CAT) as a possible cause for observed differences in outcomes between 2 cultural patient groups in a polyglot society. DESIGN: This study was a secondary analysis of prospectively collected data. METHODS: We evaluated data from 9,134 patients with knee impairments from outpatient physical therapy clinics in Israel. Items were analyzed for DIF related to sex, age, symptom acuity, surgical history, exercise history, and language used to complete the functional survey (Hebrew versus Russian). RESULTS: Several items exhibited DIF, but unadjusted FS estimates and FS estimates that accounted for DIF were essentially equal (intraclass correlation coefficient [2,1]>.999). No individual patient had a difference between unadjusted and adjusted FS estimates as large as the median standard error of the unadjusted estimates. Differences between groups defined by any of the covariates considered were essentially unchanged when using adjusted instead of unadjusted FS estimates. The greatest group-level impact was <0.3% of 1 standard deviation of the unadjusted FS estimates. LIMITATIONS: Complete data where patients answered all items in the scale would have been preferred for DIF analysis, but only CAT data were available. CONCLUSIONS: Differences in FS outcomes between groups of patients with knee impairments who answered the knee CAT in Hebrew or Russian in Israel most likely reflected true differences that may reflect societal disparities in this health outcome. PMID- 20947674 TI - Thermostabilization of an esterase by alignment-guided focussed directed evolution. AB - Site-saturation libraries of the Pseudomonas fluorescens esterase were created targeting three surface positions to increase its thermostability on the basis of the B-factor iterative test principle. All three positions were saturated simultaneously using our recently developed protocol for the design of 'small, but smart' mutant libraries bearing only consensus-like mutations. Hence, the library size could be significantly reduced while ensuring a high hit rate. Variants could be identified that showed significantly improved stability (8 degrees C higher compared with the wild type) without compromising specific activity. Subsequent iterative saturation mutagenesis gave an esterase mutant with a 9 degrees C increased melting point, but unchanged catalytic properties. PMID- 20947675 TI - Strong, non-local interactions: the Hong Kong bond. PMID- 20947676 TI - The effect of ambient air pollution on exhaled nitric oxide in the Children's Health Study. AB - We assessed the effect of daily variations in ambient air pollutants on exhaled nitric oxide fraction (F(eNO)) using data from a cohort of school children with large differences in air pollutant exposures from the Children's Health Study. Based on a cohort of 2,240 school children from 13 Southern Californian communities, cumulative lagged average regression models were fitted to determine the association between F(eNO) and ambient air pollution levels from central site monitors with lags of up to 30 days prior to F(eNO) testing. Daily 24-h cumulative lagged averages of particles with a 50% cut-off aerodynamic diameter of 2.5 um (PM2.5; over 1-8 days) and particles with a 50% cut-off aerodynamic diameter of 10 um (PM10; over 1-7 days), as well as 10:00-18:00 h cumulative lagged average of O3 (over 1-23 days) were significantly associated with 17.42% (p<0.01), 9.25% (p<0.05) and 14.25% (p<0.01) higher F(eNO) levels over the interquartile range of 7.5 MUg.m-3, 12.97 MUg.m-3 and 15.42 ppb, respectively. The effects of PM2.5, PM10 and O3 were higher in the warm season. The particulate matter effects were robust to adjustments for effects of O3 and temperature and did not vary by asthma or allergy status. In summary, short-term increases in PM2.5, PM10 and O3 were associated with airway inflammation independent of asthma and allergy status, with PM10 effects significantly higher in the warm season. PMID- 20947677 TI - Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats. AB - Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by vasoconstriction and remodelling of the pulmonary vasculature. The serotonin (5-hydroxytryptamine (5-HT)) pathway has been shown to play a major role in the pathogenesis of PAH, but pharmacological modulation of this pathway for treatment of PAH is, to date, at a pre-clinical level. Terguride is a 5-HT receptor (5-HTR) antagonist that is well tolerated and clinically approved for ovulation disorders. Immunohistochemistry against 5-HTR(2A/B) on human lungs revealed their localisation to the vascular smooth muscle layer and quantitative RT-PCR showed 5 HTR(2B) upregulation in pulmonary artery smooth muscle cells (PASMC) isolated from PAH patients. Proliferation and migration of cultured primary human PASMC were dose-dependently blocked by terguride. Therapeutic 5-HT signalling inhibition was 1) demonstrated in isolated, ventilated and perfused rat lungs and 2) by chronic terguride treatment of rats with monocrotaline (MCT)-induced pulmonary hypertension in a preventive or curative approach. Terguride inhibited proliferation of PASMCs and abolished 5-HT-induced pulmonary vasoconstriction. Chronic terguride treatment prevented dose-dependently the development and progression of MCT-induced PAH in rats. Thus, terguride represents a valuable novel therapeutic approach in PAH. PMID- 20947678 TI - Clinical management of tuberculosis and HIV-1 co-infection. AB - In many parts of the world the commonest serious opportunistic infection that occurs in HIV-1 infected persons is tuberculosis (TB). HIV-1 co-infection modifies the natural history and clinical presentation, and adversely affects the outcome of TB. Severe disseminated disease is well-recognised but it is increasingly appreciated that early disease characterised by very few or no symptoms is also common. Immunodiagnostic methods to ascertain latent TB in HIV-1 infected persons are compromised in sensitivity. Chemoprevention of HIV-1 associated TB is effective, its benefits are restricted to those which have evidence of immune sensitisation and appear short-lived in areas of high TB burden. Although promising advances in the microbiological diagnosis of TB have recently occurred, the diagnosis of HIV-1-associated TB remains difficult because of more frequent presentation as sputum negative or extrapulmonary disease. Management of co-infected patients can be complex because of overlapping drug toxicities and interactions. Nevertheless consensus is developing that antiretroviral therapy should be provided as soon as practicable after starting TB treatment in HIV-1 co-infected persons. This has the consequence of increasing the frequency of immune reconstitution inflammatory syndrome, the pathogenesis and management of which is poorly defined. PMID- 20947679 TI - Tuberculosis and noncommunicable diseases: neglected links and missed opportunities. AB - Globally, the incidence of tuberculosis (TB) is declining very slowly, and the noncommunicable disease (NCD) burden for many countries is steadily increasing. Several NCDs, such as diabetes mellitus, alcohol use disorders and smoking related conditions, are responsible for a significant proportion of TB cases globally, and in the European region, represent a larger attributable fraction for TB disease than HIV. Concrete steps are needed to address NCDs and their risk factors. We reviewed published studies involving TB and NCDs, and present a review and discussion of how they are linked, the implications for case detection and management, and how prevention efforts may be strengthened by integration of services. These NCDs put patients at increased risk for developing TB and at risk for poor treatment outcomes. However, they also present an opportunity to provide better care through increased case-detection activities, improved clinical management and better access to care for both TB and NCDs. Hastening the global decline in TB incidence may be assisted by strengthening these types of activities. PMID- 20947680 TI - Effects of intermittent hypoxia on erythropoietin, soluble erythropoietin receptor and ventilation in humans. AB - Erythropoietin (EPO) and soluble EPO receptors (sEPOR) have been proposed to play a central role in the ventilatory acclimatisation to continuous hypoxia in mice. In this study, we demonstrated for the first time in humans (n = 9) that sEPOR is downregulated upon daytime exposure to 4 days of intermittent hypoxia (IH; 6 h.day-1, cycles of 2 min of hypoxia followed by 2 min of reoxygenation; peak end tidal oxygen tension (P(ET,O2)) 88 Torr, nadir P(ET,O2)) 45 Torr), thereby allowing EPO concentration to rise. We also determined the strength of the association between these haematological adaptations and alterations in the acute hypoxic ventilatory response (AHVR). We observed a nadir in sEPOR on day 2 ( 70%), concomitant with the peak in EPO concentration (+50%). Following exposure to IH, tidal volume (V(T)) increased, respiratory frequency remained unchanged, and minute ventilation (V'(E)) was increased. There was a negative correlation between EPO and sEPOR (r = -0.261; p = 0.05), and between sEPOR and V(T) (r = 0.331; p = 0.02). EPO was positively correlated with V'(E) (r = 0.458; p = 0.001). In conclusion, the downregulation of sEPOR by IH modulates the subsequent EPO response. Furthermore, the alterations in AHVR and breathing pattern following IH appear to be mediated, at least in part, by the increase in EPO. PMID- 20947681 TI - Spontaneous pneumothorax and tuberculosis: long-term follow-up. AB - Though spontaneous pneumothorax (SP) is a well-known complication of pulmonary tuberculosis (TB), there are very few reports addressing this topic. For this reason, we retrospectively analysed the experience of SP in patients diagnosed with TB in our hospital between 1989 and 2010. Out of 872 patients treated for SP during this period, 47 (5.4%) had TB antecedents, 21 with active TB (0.95% of the 2,089 TB cases diagnosed during this period) and 26 with residual inactive TB. 46 cases were treated with pleural drainage (PD): 40 (85%) with only one PD, two with two, and four with three. The mean +/- SD length of PD treatment was 12.9 +/ 11.3 days. In 11 (23%) cases, a relapse of SP occurred, with no statistical relationship between the different studied variables. In 13 (28%) cases, it became necessary to carry out a resection (atypical segmentectomy in all cases) for persistent air leaks with PD. Survival statistics were unfavourable only in elderly patients and those infected with HIV. We conclude that the treatment of SP secondary to TB with PD is usually a sound response, with a good general prognosis and a low percentage of cases that require another PD and surgical treatment. PMID- 20947682 TI - Nature and severity of lung function abnormalities in extremely pre-term children at 11 years of age. AB - Advances in neonatal care have resulted in increased survival of children born extremely pre-term (EP). Nevertheless the incidence of bronchopulmonary dysplasia and long-term respiratory morbidity remains high. We investigated the nature of pathophysiological changes at 11 yrs of age to ascertain whether respiratory morbidity in EP children primarily reflects alterations in the lung periphery or more centralised airway function in this population. Spirometry, plethysmography, diffusing capacity, exhaled nitric oxide, multiple-breath washout, skin tests and methacholine challenge were used during laboratory-based assessments in a subgroup of the 1995 EPICure cohort and in controls. Results were obtained in 49 EP and 52 control children. Lung function abnormalities were found in 78% of EP children, with evidence of airway obstruction, ventilation inhomogeneity, gas trapping and airway hyperresponsiveness. Levels of atopy and exhaled nitric oxide were similar between the groups. Prior wheeze was associated with significant reductions in forced flows and volumes. By contrast, abnormalities of the lung periphery appear to be mediated primarily through EP birth per se. The prevalence of lung function abnormalities, which is largely obstructive in nature and likely to have long-term implications, remains high among 11-yr-old children born EP. Spirometry proved an effective means of detecting these persistent abnormalities. PMID- 20947683 TI - Atelectasis and survival after bronchoscopic lung volume reduction for COPD. AB - Bronchoscopic therapies to reduce lung volumes in chronic obstructive pulmonary disease are intended to avoid the risks associated with lung volume reduction surgery (LVRS) or to be used in patient groups in whom LVRS is not appropriate. Bronchoscopic lung volume reduction (BLVR) using endobronchial valves to target unilateral lobar occlusion can improve lung function and exercise capacity in patients with emphysema. The benefit is most pronounced in, though not confined to, patients where lobar atelectasis has occurred. Few data exist on their long term outcome. 19 patients (16 males; mean+/-sd forced expiratory volume in 1 s 28.4+/-11.9% predicted) underwent BLVR between July 2002 and February 2004. Radiological atelectasis was observed in five patients. Survival data was available for all patients up to February 2010. None of the patients in whom atelectasis occurred died during follow-up, whereas eight out of 14 in the nonatelectasis group died (Chi-squared p=0.026). There was no significant difference between the groups at baseline in lung function, quality of life, exacerbation rate, exercise capacity (shuttle walk test or cycle ergometry) or computed tomography appearances, although body mass index was significantly higher in the atelectasis group (21.6+/-2.9 versus 28.4+/-2.9 kg.m(-2); p<0.001). The data in the present study suggest that atelectasis following BLVR is associated with a survival benefit that is not explained by baseline differences. PMID- 20947684 TI - Cellular context-dependent effects of H2ax and p53 deletion on the development of thymic lymphoma. AB - H2AX and Artemis each cooperate with p53 to suppress lymphoma. Germline H2ax(-/ )p53(-/-) mice die of T-cell receptor-beta(-) (TCR-beta(-)) thymic lymphomas with translocations and other lesions characteristic of human T-cell acute lymphoblastic leukemia. Here, we demonstrate that mice with inactivation of H2ax and p53 in thymocytes die at later ages to TCR-beta(-) or TCR-beta(+) thymic lymphomas containing a similar pattern of translocations as H2ax(-/-)p53(-/-) tumors. Germline Artemis(-/-) p53(-/-) mice die of lymphomas with antigen receptor locus translocations, whereas Artemis(-/-)H2ax(-/-)p53(-/-) mice die at earlier ages from multiple malignancies. We show here that Artemis(-/-) mice with p53 deletion in thymocytes die of TCR-beta(-) tumors containing Tcralpha/delta translocations, other clonal translocations, or aneuploidy, as well as Notch1 mutations. Strikingly, Artemis(-/-) mice with H2ax and p53 deletion in thymocytes exhibited a lower rate of mortality from TCR-beta(-) tumors, which harbored significantly elevated levels of genomic instability. Our data reveal that the cellular origin of H2ax and p53 loss impacts the rate of mortality from and developmental stage of thymic lymphomas, and suggest that conditional deletion of tumor suppressor genes may provide more physiologic models for human lymphoid malignancies than germline inactivation. PMID- 20947685 TI - Impaired angiogenesis and altered Notch signaling in mice overexpressing endothelial Egfl7. AB - Epidermal growth factor-like domain 7 (Egfl7) is important for regulating tubulogenesis in zebrafish, but its role in mammals remains unresolved. We show here that endothelial overexpression of Egfl7 in transgenic mice leads to partial lethality, hemorrhaging, and altered cardiac morphogenesis. These defects are accompanied by abnormal vascular patterning and remodeling in both the embryonic and postnatal vasculature. Egfl7 overexpression in the neonatal retina results in a hyperangiogenic response, and EGFL7 knockdown in human primary endothelial cells suppresses endothelial cell proliferation, sprouting, and migration. These phenotypes are reminiscent of Notch inhibition. In addition, our results show that EGFL7 and endothelial-specific NOTCH physically interact in vivo and strongly suggest that Egfl7 antagonizes Notch in both the postnatal retina and in primary endothelial cells. Specifically, Egfl7 inhibits Notch reporter activity and down-regulates the level of Notch target genes when overexpressed. In conclusion, we have uncovered a critical role for Egfl7 in vascular development and have shown that some of these functions are mediated through modulation of Notch signaling. PMID- 20947686 TI - A WHIM-sical zebrafish. AB - In this issue of Blood, Walters and colleagues describe an elegant model of WHIM syndrome in the zebrafish embryo. By allowing the movement of WHIM neutrophils to be observed in live animals, this model dramatically illustrates the dynamics of the interaction between the neutrophil chemokine receptor CXCR4 and its receptor ligand (stromal-derived factor-1 [SDF-1], also known as CXCL12) in th hallmark of WHIM-excessive neutrophil adhesion to the marrow stroma. PMID- 20947687 TI - Personalized medicine for AML? AB - Almost a decade ago, Gillil and proposed a model of leukemogenesis for acute myeloid leukemia (AML). In this model, AML results from activating mutations in genes that confer increased proliferation and survival capabilities (class I mutations) acting in concert with chromosomal abnormalities or gene mutations that block differentiation and subsequent apoptosis (class II mutations). In this issue of Blood, Bach as and colleagues present data that clearly demonstrate mutational shifts in class I/II genes that occur between diagnosis and relapse in children with AML. The authors suggest that these findings may allow for personalized treatment. PMID- 20947688 TI - Finding a diamond in the (mouse is) rough. AB - In this issue of Blood, Devlin and colleagues use a new strategy to create a mouse model for the inherited bone marrow failure syndrome, DBA.The result, while recapitulating certain aspects of the disease and representing a positive step forward, also demonstrates that significant hurdles remain in faithfully creating a mammalian model for DBA. PMID- 20947689 TI - Shear stress: devil's in the details. AB - In this issue of Blood, Ni et al use an in vivo mouse model of disturbed flow that results in accelerated atherosclerosis to identify novel mechanosensitive genes. PMID- 20947690 TI - Dynamic International Prognostic Scoring System (DIPSS) predicts progression to acute myeloid leukemia in primary myelofibrosis. PMID- 20947691 TI - Toxic effects of sorafenib when given early after allogeneic hematopoietic stem cell transplantation. PMID- 20947692 TI - Connecting the dots: monocyte/DC and NK subsets in human peripheral blood. PMID- 20947693 TI - Why do women have similar erythropoietin levels to men but lower hemoglobin levels? PMID- 20947694 TI - Potential Pain Management Programmes in primary care. A UK-wide questionnaire and Delphi survey of experts. AB - BACKGROUND: Most chronic pain patients are treated in primary care and their management is often challenging. Secondary care- or private sector-based Pain Management Programmes (PMPs) offering intensive multidisciplinary approaches have been found to improve participants' physical performance and psychological well being. OBJECTIVES: We aimed to identify the components and perceived outcomes of multidisciplinary PMPs in the UK and to explore expert health care providers' opinions about important characteristics of an ideal yet practical PMP for delivery in primary care. METHODS: All PMPs in the UK (n = 77), identified through the British Pain Society, were invited to participate. Each PMP was sent a postal questionnaire. We then conducted a modified Delphi survey with 18 pain management experts from a range of professional backgrounds. RESULTS: A representative from 54 (response rate 70.1%) PMPs completed a questionnaire. Most PMPs were delivered in National Health Service outpatient secondary care by physiotherapists (98%), psychologists (94%), pain specialists (61%), nurses (54%) and occupational therapists (52%). There was evidence of reasonably prolonged follow-up of participants and use of a range of clinical outcome measures. Consensus was reached on most components and outcomes of a potential primary care based PMP. 'Necessary' components included training in, and information about, self-management, general fitness, posture and mobility. Input from a physiotherapist and clinical or health psychologist was identified as key to the PMP. Preferred patient outcome measures were related to emotional well-being, self-efficacy and coping and quality of life. CONCLUSION: Future research should look to design, deliver and evaluate a primary care-based intervention based on these findings. PMID- 20947695 TI - Assignment of 3 genetic linkage groups to 3 chromosomes of narrow-leafed lupin. AB - The legume genus, Lupinus, has many notable properties that make it interesting from a scientific perspective, including its basal position in the evolution of Papilionoid legumes. As the most economically important legume species, L. angustifolius L. (narrow-leafed lupin) has been subjected to much genetic analysis including linkage mapping and genomic library development. Cytogenetic analysis has been hindered by the large number of small morphologically uniform chromosomes (2n = 40). Here, we present a significant advance: the development of chromosome-specific cytogenetic markers and assignment of the first genetic linkage groups (LGs) to chromosomal maps of L. angustifolius using the bacterial artificial chromosome (BAC)-fluorescence in situ hybridization approach. Twelve clones produced single-locus signals that "landed" on 7 different chromosomes. Based on BAC-end sequences of those clones, genetic markers were generated. Eight clones localized on 3 chromosomes, allowed these chromosomes to be assigned to 3 LGs. An additional single-locus clone may be useful to combine an unassigned group (Cluster-2) with main LGs. This work provides a strong foundation for future identification of all chromosomes with specific markers and for complete integration of narrow-leafed lupin LGs. This resource will greatly facilitate the chromosome assignment and ordering of sequence contigs in sequencing the L. angustifolius genome. PMID- 20947696 TI - Automated extraction of DNA and RNA from a single formalin-fixed paraffin embedded tissue section for analysis of both single-nucleotide polymorphisms and mRNA expression. AB - BACKGROUND: There is an increasing need for the identification of both DNA and RNA biomarkers from pathodiagnostic formalin-fixed paraffin-embedded (FFPE) tissue samples for the exploration of individualized therapy strategies in cancer. We investigated a fully automated, xylene-free nucleic acid extraction method for the simultaneous analysis of RNA and DNA biomarkers related to breast cancer. METHODS: We copurified both RNA and DNA from a single 10-MUm section of 210 paired samples of FFPE tumor and adjacent normal tissues (1-25 years of archival time) using a fully automated extraction method. Half of the eluate was DNase I digested for mRNA expression analysis performed by using reverse transcription quantitative PCR for the genes estrogen receptor 1 (ESR1), progesterone receptor (PGR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) (ERBB2), epoxide hydrolase 1 (EPHX1), baculoviral IAP repeat-containing 5 (BIRC5), matrix metallopeptidase 7 (MMP7), vascular endothelial growth factor A (VEGFA), and topoisomerase (DNA) II alpha 170kDa (TOP2A). The remaining undigested aliquot was used for the analysis of 7 single-nucleotide polymorphisms (SNPs) by MALDI-TOF mass spectrometry. RESULTS: In 208 of 210 samples (99.0%) the protocol yielded robust quantification-cycle values for both RNA and DNA normalization. Expression of the 8 breast cancer genes was detected in 81%-100% of tumor tissues and 21% 100% of normal tissues. The 7 SNPs were successfully genotyped in 91%-97% of tumor and 94%-97% of normal tissues. Allele concordance between tumor and normal tissue was 98.9%-99.5%. CONCLUSIONS: This fully automated process allowed an efficient simultaneous extraction of both RNA and DNA from a single FFPE section and subsequent dual analysis of selected genes. High gene expression and genotyping detection rates demonstrate the feasibility of molecular profiling from limited archival patient samples. PMID- 20947697 TI - Agreement between fasting and postprandial LDL cholesterol measured with 3 methods in patients with type 2 diabetes mellitus. AB - BACKGROUND: LDL cholesterol (LDL-C) is a modifiable cardiovascular disease risk factor. We used 3 LDL-C methods to study the agreement between fasting and postprandial LDL-C in type 2 diabetes (T2DM) patients. METHODS: We served 74 T2DM patients a standardized meal and sampled blood at fasting and 1.5, 3.0, 4.5, and 6.0 h postprandially. We measured LDL-C by use of modified beta quantification (MBQ), the Friedewald equation (FE), and a direct homogeneous assay (DA). We evaluated agreement using 95% limits of agreement (LOA) within +/-0.20 mmol/L (+/ 7.7 mg/dL). RESULTS: LDL-C concentrations at all postprandial times disagreed with those at fasting for all methods. In 66 patients who had complete measurements with all LDL-C methods, maximum mean differences (95% LOA) in postprandial vs fasting LDL-C were -0.16 mmol/L (-0.51; 0.19) [-6.2 mg/dL (-19.7; 7.3)] with MBQ at 3 h; -0.36 mmol/L (-0.89; 0.17) [-13.9 mg/dL (-34; 6.6)] with FE at 4.5 h; and -0.24 mmol/L (-0.62; 0.05) [-9.3 mg/dL (-24; 1.9)] with DA at 6.0 h. In postprandial samples, FE misclassified 38% of patients (two-thirds of statin users) into lower Adult Treatment Panel III (ATP III) risk categories. Greater disagreement between fasting and postprandial LDL-C was observed in individuals with postprandial triglyceride concentrations >2.08 mmol/L (>184 mg/dL) and in women (interactions: P <= 0.038). CONCLUSIONS: Differences up to 0.89 mmol/L (34 mg/dL) between fasting and postprandial LDL-C concentrations, with postprandial LDL-C concentrations usually being lower, were found in T2DM by 3 different LDL-C methods. Such differences are potentially relevant clinically and suggest that, irrespective of measurement method, postprandial LDL-C concentrations should not be used to assess cardiovascular disease risk. PMID- 20947698 TI - Therapist awareness and responsibility in working with sexual offenders. AB - The article aims to address the ethical implications of therapist reactions to sexual offender treatment and, in doing so, increase awareness and understanding of the interaction between the clinician and the challenges of working with sexual offenders. The effects of providing psychological services in general, and to sexual offenders specifically, are reviewed, including the impact on services provided. Practice implications are also discussed as the authors consider the negative effects (e.g., burnout) that therapists experience due to treatment quality and the ethical issues and responsibilities surrounding clinical reactions. Finally, the authors summarize research on self-care and practice recommendations for effectively and ethically working with sexual offenders. PMID- 20947699 TI - An exploratory study of Internet-initiated sexual offenses and the chat room sex offender: has the Internet enabled a new typology of sex offender? AB - This exploratory study examined 51 participants convicted of an Internet initiated sex offense in which they attempted to entice an adolescent into a sexual relationship using an Internet chat room. All participants were convicted of a sex offense and subject to an evaluation as a part of sentencing requirements in Colorado. Clinical and behavioral data were obtained from each subject's offense-specific evaluation and chat room transcripts. The results of the study found that 90% of the participants were apprehended as a result of an Internet sex sting. The authors conclude that Internet chat room sex offenders constitute a separate group characterized by less severe criminogenic factors than other sex offenders (rapists, child molesters). It can be hypothesized that chat room sex offenders avoid relationships and spend a significant amount of time in online chat rooms as a primary social and sexual outlet, and engage in other sexually compulsive behaviors. Within this offender group, it was discovered that two subgroups exist: a contact-driven group motivated to engage in offline sexual behavior with an adolescent and a fantasy-driven group motivated to engage an adolescent in online cybersex without an express intent to meet offline. The chat room sex offender presents a significant clinical issue to treatment providers as a live victim does not exist. Thus, it is unclear if Internet sex stings prevent incidents of child sexual exploitation and may result in convictions of individuals who may never have abused a child. The data suggest a tentative sex offender typology, including subtypes, which need to be replicated in future studies. PMID- 20947700 TI - Evolutionary bangs and whimpers: methodological advances and conceptual frameworks for studying exceptional diversification. PMID- 20947701 TI - A novel protein kinase D inhibitor attenuates early events of experimental pancreatitis in isolated rat acini. AB - Novel protein kinase C isoforms (PKC delta and epsilon) mediate early events in acute pancreatitis. Protein kinase D (PKD/PKD1) is a convergent point of PKC delta and epsilon in the signaling pathways triggered through CCK or cholinergic receptors and has been shown to activate the transcription factor NF-kappaB in acute pancreatitis. For the present study we hypothesized that a newly developed PKD/PKD1 inhibitor, CRT0066101, would prevent the initial events leading to pancreatitis. We pretreated isolated rat pancreatic acinar cells with CRT0066101 and a commercially available inhibitor Go6976 (10 MUM). This was followed by stimulation for 60 min with high concentrations of cholecystokinin (CCK, 0.1 MUM), carbachol (CCh, 1 mM), or bombesin (10 MUM) to induce initial events of pancreatitis. PKD/PKD1 phosphorylation and activity were measured as well as zymogen activation, amylase secretion, cell injury and NF-kappaB activation. CRT0066101 dose dependently inhibited secretagogue-induced PKD/PKD1 activation and autophosphorylation at Ser-916 with an IC(50) ~3.75-5 MUM but had no effect on PKC-dependent phosphorylation of the PKD/PKD1 activation loop (Ser-744/748). Furthermore, CRT0066101 reduced secretagogue-induced zymogen activation and amylase secretion. Go6976 reduced zymogen activation but not amylase secretion. Neither inhibitor affected basal zymogen activation or secretion. CRT0066101 did not affect secretagogue-induced cell injury or changes in cell morphology, but it reduced NF-kappaB activation by 75% of maximal for CCK- and CCh-stimulated acinar cells. In conclusion, CRT0066101 is a potent and specific PKD family inhibitor. Furthermore, PKD/PKD1 is a potential mediator of zymogen activation, amylase secretion, and NF-kappaB activation induced by a range of secretagogues in pancreatic acinar cells. PMID- 20947702 TI - Differential organization of excitatory and inhibitory synapses within the rat dorsal vagal complex. AB - The dorsal motor nucleus of the vagus (DMV) is pivotal in the regulation of upper gastrointestinal functions, including motility and both gastric and pancreatic secretion. DMV neurons receive robust GABA- and glutamatergic inputs. Microinjection of the GABA(A) antagonist bicuculline (BIC) into the DMV increases pancreatic secretion and gastric motility, whereas the glutamatergic antagonist kynurenic acid (KYN) is ineffective unless preceded by microinjection of BIC. We used whole cell patch-clamp recordings with the aim of unveiling the brain stem neurocircuitry that uses tonic GABA- and glutamatergic synapses to control the activity of DMV neurons in a brain stem slice preparation. Perfusion with BIC altered the firing frequency of 71% of DMV neurons, increasing firing frequency in 80% of the responsive neurons and decreasing firing frequency in 20%. Addition of KYN to the perfusate either decreased (52%) or increased (25%) the firing frequency of BIC-sensitive neurons. When KYN was applied first, the firing rate was decreased in 43% and increased in 21% of the neurons; further perfusion with BIC had no additional effect in the majority of neurons. Our results indicate that there are several permutations in the arrangements of GABA- and glutamatergic inputs controlling the activity of DMV neurons. Our data support the concept of brain stem neuronal circuitry that may be wired in a finely tuned organ- or function-specific manner that permits precise and discrete modulation of the vagal motor output to the gastrointestinal tract. PMID- 20947703 TI - Random mutagenesis of the mouse genome: a strategy for discovering gene function and the molecular basis of disease. AB - Mutagenesis of mice with N-ethyl-N-nitrosourea (ENU) is a phenotype-driven approach to unravel gene function and discover new biological pathways. Phenotype driven approaches have the advantage of making no assumptions about the function of genes and their products and have been successfully applied to the discovery of novel gene-phenotype relationships in many physiological systems. ENU mutagenesis of mice is used in many large-scale and more focused projects to generate and identify novel mouse models for the study of gene functions and human disease. This review examines the strategies and tools used in ENU mutagenesis screens to efficiently generate and identify functional mutations. PMID- 20947705 TI - Advanced clinical interpretation of the WAIS-IV and WMS-IV: prevalence of low scores varies by level of intelligence and years of education. AB - Clinicians can use the base rates of low scores in healthy people to reduce the likelihood of misdiagnosing cognitive impairment. In the present study, base rates were developed for the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) and Wechsler Memory Scale-Fourth Edition (WMS-IV) using 900 healthy adults and validated on 28 patients with moderate or severe traumatic brain injuries (TBIs). Results indicated that healthy people obtain some low scores on the WAIS-IV/WMS-IV, with prevalence rates increasing with fewer years of education and lower predicted intelligence. When applying the base rates information to the clinical sample, the TBI patients were 13 times more likely to be identified as having a low cognitive profile compared with the controls. Using the base rates information is a psychometrically advanced method for establishing criteria to determine low cognitive abilities on the WAIS-IV/WMS-IV. PMID- 20947704 TI - Differential immune and genetic responses in rat models of Crohn's colitis and ulcerative colitis. AB - Crohn's disease and ulcerative colitis are clinically, immunologically, and morphologically distinct forms of inflammatory bowel disease (IBD). However, smooth muscle function is impaired similarly in both diseases, resulting in diarrhea. We tested the hypothesis that differential cellular, genetic, and immunological mechanisms mediate smooth muscle dysfunction in two animal models believed to represent the two diseases. We used the rat models of trinitrobenzene sulfonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced colonic inflammations, which closely mimic the clinical and morphological features of Crohn's disease and ulcerative colitis, respectively. DSS inflammation induced oxidative stress initially in mucosa/submucosa, which then propagated to the muscularis externa to impair smooth muscle function. The muscularis externa showed no increase of cytokines/chemokines. On the other hand, TNBS inflammation almost simultaneously induced oxidative stress, recruited or activated immune cells, and generated cytokines/chemokines in both mucosa/submucosa and muscularis externa. The generation of cytokines/chemokines did not correlate with the recruitment and activation of immune cells. Consequently, the impairment of smooth muscle function in DSS inflammation was primarily due to oxidative stress, whereas that in TNBS inflammation was due to both oxidative stress and proinflammatory cytokines. The impairment of smooth muscle function in DSS inflammation was due to suppression of Galpha(q) protein of the excitation contraction coupling. In TNBS inflammation, it was due to suppression of the alpha(1C)1b subunit of Ca(v)1.2b channels, CPI-17 and Galpha(q). TNBS inflammation increased IGF-1 and TGF-beta time dependently in the muscularis externa. IGF-1 induced smooth muscle hyperplasia; both IGF-1 and TGF-beta induced hypertrophy. In conclusion, both TNBS and DSS induce transmural inflammation, albeit with different types of inflammatory mediators. The recruitment or activation of immune cells does not correlate directly with the intensity of generation of inflammatory mediators. The inflammatory mediators in TNBS and DSS inflammations target different genes to impair smooth muscle function. PMID- 20947706 TI - Dimensionality of the hospital anxiety and depression scale (HADS) in cardiac patients: comparison of Mokken scale analysis and factor analysis. AB - The hospital anxiety and depression scale (HADS) measures anxiety and depressive symptoms and is widely used in clinical and nonclinical populations. However, there is some debate about the number of dimensions represented by the HADS. In a sample of 534 Dutch cardiac patients, this study examined (a) the dimensionality of the HADS using Mokken scale analysis and factor analysis and (b) the scale properties of the HADS. Mokken scale analysis and factor analysis suggested that three dimensions adequately capture the structure of the HADS. Of the three corresponding scales, two scales of five items each were found to be structurally sound and reliable. These scales covered the two key attributes of anxiety and (anhedonic) depression. The findings suggest that the HADS may be reduced to a 10 item questionnaire comprising two 5-item scales measuring anxiety and depressive symptoms. PMID- 20947707 TI - Update and new trends in antiemetic therapy: the continuing need for novel therapies. AB - Chemotherapy-induced nausea and vomiting (CINV) continues to be one of the most feared side effects of chemotherapy. Inadequately controlled CINV can have a significant negative impact on quality of life and can in some cases compromise adherence to treatment. However, the repercussions of CINV for patients are often underestimated. Advances in our understanding of the physiology of CINV and the identification of risk factors have greatly contributed towards improvements in the control of CINV. A number of antiemetic agents are currently available for the prophylaxis and treatment of CINV, including 5-hydroxytryptamine 3 receptor antagonists corticosteroids, neurokinin 1 receptor antagonists, dopamine receptor antagonists, benzodiazepines, neuroleptics and cannabinoids. With the correct use of these agents, CINV can be prevented to a great extent; however, adherence to guidelines is disappointingly low. Furthermore, a significant number of patients still experience nausea and vomiting despite optimal treatment. More effective therapies are, therefore, greatly needed, with the ultimate goal of attaining complete control of CINV. This review focuses on the current understanding of CINV, problems associated with its management and the status of promising antiemetic therapies. PMID- 20947708 TI - Splenic volume can be a novel predictive parameter for the prognosis of chronic lymphocytic leukemia? PMID- 20947709 TI - Production of VEGF receptor 1 and 2 mRNA and protein during endochondral bone repair is differential and healing phase specific. AB - Physiological disturbances, including temporary hypoxia, are expected to drive angiogenesis during bone repair. Evidence suggests that the angiogenic ligand vascular endothelial growth factor (VEGF)-A plays an important role in this process. We characterized the expression of two receptors that are essential for mediating VEGF signaling, VEGFR1/Flt-1 and VEGFR2/Flk-1/KDR, in a mouse rib fracture model. Their mRNA and protein levels were assessed in four healing phases, which were characterized histologically as hemorrhage formation on postfracture day (PFD) 1, inflammatory response on PFD 3, initiation of callus development on PFD 7, and the presence of a mature callus on PFD 14. Transcript was detected for VEGFR1 and VEGFR2, as well as VEGF. While mRNA expression of VEGFR1 was monophasic throughout all healing phases, VEGFR2 showed a biphasic profile with significantly increased mRNA expression during callus formation and maturation. Expression of VEGF mRNA was characterized by a more gradual increase during callus formation. The protein level for VEGFR1 was below detection sensitivity during the initial healing phase. It was then restored to a stable level, detectable through the subsequent healing phases. Hence, the VEGFR1 protein levels partially mirrored the transcript expression profile. In comparison, the protein level of VEGFR2 increased gradually during the healing phases and peaked at callus maturation. This correlated well with the transcriptional expression of VEGFR2. Intact bone from age-matched male mice had considerable protein levels of VEGFR1 and VEGF, but no detectable VEGFR2. Together, these findings uncovered expression signatures of the VEGF-VEGFR axis in endochondral bone repair. PMID- 20947710 TI - Muscle use during double poling evaluated by positron emission tomography. AB - Due to the complexity of movement in cross-country skiing (XCS), the muscle activation patterns are not well elucidated. Previous studies have applied surface electromyography (SEMG); however, recent gains in three-dimensional (3D) imaging techniques such as positron emission tomography (PET) have rendered an alternative approach to investigate muscle activation. The purpose of the present study was to examine muscle use during double poling (DP) at two work intensities by use of PET. Eight male subjects performed two 20-min DP bouts on separate days. Work intensity was ~ 53 and 74% of peak oxygen uptake (Vo(2peak)), respectively. During exercise 188 +/- 8 MBq of [(18)F]fluorodeoxyglucose ([(18)F]FDG) was injected, and subsequent to exercise a full-body PET scan was conducted. Regions of interest (ROI) were defined within 15 relevant muscles, and a glucose uptake index (GUI) was determined for all ROIs. The muscles that span the shoulder and elbow joints, the abdominal muscles, and hip flexors displayed the greatest GUI during DP. Glucose uptake did not increase significantly from low to high intensity in most upper body muscles; however, an increased GUI (P < 0.05) was seen for the knee flexor (27%) and extensor muscles (16%), and for abdominal muscles (21%). The present data confirm previous findings that muscles of the upper limb are the primary working muscles in DP. The present data further suggest that when exercise intensity increases, the muscles that span the lumbar spine, hip, and knee joints contribute increasingly. Finally, PET provides a promising alternative or supplement to existing methods to assess muscle activation in complex human movements. PMID- 20947712 TI - CCL2 and CCR2 variants are associated with skeletal muscle strength and change in strength with resistance training. AB - Baseline muscle size and muscle adaptation to exercise are traits with high variability across individuals. Recent research has implicated several chemokines and their receptors in the pathogenesis of many conditions that are influenced by inflammatory processes, including muscle damage and repair. One specific chemokine, chemokine (C-C motif) ligand 2 (CCL2), is expressed by macrophages and muscle satellite cells, increases expression dramatically following muscle damage, and increases expression further with repeated bouts of exercise, suggesting that CCL2 plays a key role in muscle adaptation. The present study hypothesizes that genetic variations in CCL2 and its receptor (CCR2) may help explain muscle trait variability. College-aged subjects [n = 874, Functional Single-Nucleotide Polymorphisms Associated With Muscle Size and Strength (FAMUSS) cohort] underwent a 12-wk supervised strength-training program for the upper arm muscles. Muscle size (via MR imaging) and elbow flexion strength (1 repetition maximum and isometric) measurements were taken before and after training. The study participants were then genotyped for 11 genetic variants in CCL2 and five variants in CCR2. Variants in the CCL2 and CCR2 genes show strong associations with several pretraining muscle strength traits, indicating that inflammatory genes in skeletal muscle contribute to the polygenic system that determines muscle phenotypes. These associations extend across both sexes, and several of these genetic variants have been shown to influence gene regulation. PMID- 20947711 TI - Temporal response of canine flexor tendon to limb suspension. AB - Tendon disuse, or stress deprivation, frequently accompanies clinical disorders and treatments, yet the metabolism of tendons subject to stress deprivation has rarely been investigated systematically. The effects of stress deprivation on canine flexor tendon were investigated in this study. One adult canine forepaw was suspended for 21 or 42 days. Control forepaws were collected from dogs that had no intervention on their limbs and paws. The expression of collagen I and III was not significantly altered in the tendons disused for 21 days but was significantly decreased at 42 days (P < 0.03). The expression of collagen II, aggrecan, decorin, and fibronectin was significantly decreased in the tendons in the suspended limbs at 21 days (P < 0.002) and further reduced at 42 days. With stress deprivation, the expression of matrix metalloproteinase 2 (MMP2) was significantly increased (P < 0.004) at 21 and 42 days. The expression of MMP3 was significantly decreased at 21 and 42 days (P < 0.03). The expression of MMP13 was not altered with stress deprivation at 21 and 42 days. The expression of MMP14 was significantly increased at 21 days (P = 0.0015) and returned to the control level at 42 days. Tissue inhibitor of metalloproteinase 1 (TIMP1) expression was decreased after the limbs were suspended for 42 days (P = 0.0043), but not 21 days. However, TIMP2 expression was not significantly different from control at 21 or 42 days. Furthermore, the cross-sectional area of the stress-deprived tendons at 42 days was decreased compared with the control group (P < 0.01). The intervention method in this study did not result in any alteration of stiffness of the tendon. Our study demonstrated that stress deprivation decreases the anabolic process and increases the catabolic process of extracellular matrix in flexor tendon. PMID- 20947713 TI - Recruitment and rate-coding strategies of the human genioglossus muscle. AB - Single motor unit (SMU) analysis provides a means to examine the motor control of a muscle. SMUs in the genioglossus show considerable complexity, with several different firing patterns. Two of the primary stimuli that contribute to genioglossal activation are carbon dioxide (CO(2)) and negative pressure, which act through chemoreceptor and mechanoreceptor activation, respectively. We sought to determine how these stimuli affect the behavior of genioglossus SMUs. We quantified genioglossus SMU discharge activity during periods of quiet breathing, elevated CO(2) (facilitation), and continuous positive airway pressure (CPAP) administration (inhibition). CPAP was applied in 2-cmH(2)O increments until 10 cmH(2)O during hypercapnia. Five hundred ninety-one periods (each ~ 3 breaths) of genioglossus SMU data were recorded using wire electrodes(n = 96 units) from 15 awake, supine subjects. Overall hypercapnic stimulation increased the discharge rate of genioglossus units (20.9 +/- 1.0 vs. 22.7 +/- 0.9 Hz). Inspiratory units were activated ~ 13% earlier in the inspiratory cycle, and the units fired for a longer duration (80.6 +/- 5.1 vs. 105.3 +/- 4.2% inspiratory time; P < 0.05). Compared with baseline, an additional 32% of distinguishable SMUs within the selective electrode recording area were recruited with hypercapnia. CPAP led to progressive SMU inhibition; at ~ 6 cmH(2)O, there were similar numbers of SMUs active compared with baseline, with peak frequencies of inspiratory units close to baseline, despite elevated CO(2) levels. At 10 cmH(2)O, the number of units was 36% less than baseline. Genioglossus inspiratory phasic SMUs respond to hypercapnic stimulation with changes in recruitment and rate coding. The SMUs respond to CPAP with derecruitment as a homogeneous population, and inspiratory phasic units show slower discharge rates. Understanding upper airway muscle recruitment/derecruitment may yield therapeutic targets for maintenance of pharyngeal patency. PMID- 20947714 TI - Epicardial fat gene expression after aerobic exercise training in pigs with coronary atherosclerosis: relationship to visceral and subcutaneous fat. AB - Epicardial adipose tissue (EAT) is contiguous with coronary arteries and myocardium and potentially may play a role in coronary atherosclerosis (CAD). Exercise is known to improve cardiovascular disease risk factors. The purpose of this study was to investigate the effect of aerobic exercise training on the expression of 18 genes, measured by RT-PCR and selected for their role in chronic inflammation, oxidative stress, and adipocyte metabolism, in peri-coronary epicardial (cEAT), peri-myocardial epicardial (mEAT), visceral abdominal (VAT), and subcutaneous (SAT) adipose tissues from a castrate male pig model of familial hypercholesterolemia with CAD. We tested the hypothesis that aerobic exercise training for 16 wk would reduce the inflammatory profile of mRNAs in both components of EAT and VAT but would have little effect on SAT. Exercise increased mEAT and total heart weights. EAT and heart weights were directly correlated. Compared with sedentary pigs matched for body weight to exercised animals, aerobic exercise training reduced the inflammatory response in mEAT but not cEAT, had no effect on inflammatory genes but preferentially decreased expression of adiponectin and other adipocyte-specific genes in VAT, and had no effect in SAT except that IL-6 mRNA went down and VEGFa mRNA went up. We conclude that 1) EAT is not homogeneous in its inflammatory response to aerobic exercise training, 2) cEAT around CAD remains proinflammatory after chronic exercise, 3) cEAT and VAT share similar inflammatory expression profiles but different metabolic mRNA responses to exercise, and 4) gene expression in SAT cannot be extrapolated to VAT and heart adipose tissues in exercise intervention studies. PMID- 20947715 TI - Physiological complexity and system adaptability: evidence from postural control dynamics of older adults. AB - The degree of multiscale complexity in human behavioral regulation, such as that required for postural control, appears to decrease with advanced aging or disease. To help delineate causes and functional consequences of complexity loss, we examined the effects of visual and somatosensory impairment on the complexity of postural sway during quiet standing and its relationship to postural adaptation to cognitive dual tasking. Participants of the MOBILIZE Boston Study were classified into mutually exclusive groups: controls [intact vision and foot somatosensation, n = 299, 76 +/- 5 (SD) yr old], visual impairment only (<20/40 vision, n = 81, 77 +/- 4 yr old), somatosensory impairment only (inability to perceive 5.07 monofilament on plantar halluxes, n = 48, 80 +/- 5 yr old), and combined impairments (n = 25, 80 +/- 4 yr old). Postural sway (i.e., center-of pressure) dynamics were assessed during quiet standing and cognitive dual tasking, and a complexity index was quantified using multiscale entropy analysis. Postural sway speed and area, which did not correlate with complexity, were also computed. During quiet standing, the complexity index (mean +/- SD) was highest in controls (9.5 +/- 1.2) and successively lower in the visual (9.1 +/- 1.1), somatosensory (8.6 +/- 1.6), and combined (7.8 +/- 1.3) impairment groups (P = 0.001). Dual tasking resulted in increased sway speed and area but reduced complexity (P < 0.01). Lower complexity during quiet standing correlated with greater absolute (R = -0.34, P = 0.002) and percent (R = -0.45, P < 0.001) increases in postural sway speed from quiet standing to dual-tasking conditions. Sensory impairments contributed to decreased postural sway complexity, which reflected reduced adaptive capacity of the postural control system. Relatively low baseline complexity may, therefore, indicate control systems that are more vulnerable to cognitive and other stressors. PMID- 20947716 TI - The Na+/Ca2+ exchanger-1 mediates left ventricular dysfunction in mice with chronic intermittent hypoxia. AB - Chronic intermittent hypoxia (CIH) and cardiovascular dysfunction occur in patients with obstructive sleep apnea. We hypothesized that the Na(+)/Ca(2+) exchanger-1 (NCX1) mediates, at least partially, left ventricular (LV) dysfunction in CIH. Four groups of mice (N = 15-17 per group), either cardiac specific NCX1 knockouts (KO) or wild types (WT), were exposed to either CIH or normoxia [i.e., handled controls (HC)] 10 h/day for 8 wk. As expected, myocardial expression of NCX1 was greater in WT than in KO animals, both in HC and CIH exposed groups. In both CIH groups (WT or KO), but not the HC groups, blood pressure increased by 10% at week 1 over their baseline and remained elevated for all 8 wk, with no differences between WT and KO. LV dilation (increased diastolic and systolic dimension) and hypertrophy (increased left heart weight), along with LV dysfunction (greater end-diastolic pressure and lower ejection fraction), were observed in the WT animals compared with the KO following CIH exposure. Compared with HC, CIH exposure was associated with apoptosis (terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling and caspase-3) in WT, but not KO, mice. We conclude that myocardial NCX1 does not mediate changes in blood pressure, but is one of the mediators for LV global dysfunction and cardiomyocyte injury in CIH. PMID- 20947717 TI - Application of the U.S. EPA mode of action Framework for purposes of guiding future research: a case study involving the oral carcinogenicity of hexavalent chromium. AB - Mode of action (MOA) analysis provides a systematic description of key events leading to adverse health effects in animal bioassays for the purpose of informing human health risk assessment. Uncertainties and data gaps identified in the MOA analysis may also be used to guide future research to improve understanding of the MOAs underlying a specific toxic response and foster development of toxicokinetic and toxicodynamic models. An MOA analysis, consistent with approaches outlined in the MOA Framework as described in the Guidelines for Carcinogen Risk Assessment, was conducted to evaluate small intestinal tumors observed in mice chronically exposed to relatively high concentrations of hexavalent chromium (Cr(VI)) in drinking water. Based on review of the literature, key events in the MOA are hypothesized to include saturation of the reductive capacity of the upper gastrointestinal tract, absorption of Cr(VI) into the intestinal epithelium, oxidative stress and inflammation, cell proliferation, direct and/or indirect DNA modification, and mutagenesis. Although available data generally support the plausibility of these key events, several unresolved questions and data gaps were identified, highlighting the need for obtaining critical toxicokinetic and toxicodynamic data in the target tissue and in the low-dose range. Experimental assays that can address these data gaps are discussed along with strategies for comparisons between responsive and nonresponsive tissues and species. This analysis provides a practical application of MOA Framework guidance and is instructive for the design of studies to improve upon the information available for quantitative risk assessment. PMID- 20947718 TI - Predicting skin permeability from complex chemical mixtures: dependency of quantitative structure permeation relationships on biology of skin model used. AB - Dermal absorption of topically applied chemicals usually occurs from complex chemical mixtures; yet, most attempts to quantitate dermal permeability use data collected from single chemical exposure in aqueous solutions. The focus of this research was to develop quantitative structure permeation relationships (QSPR) for predicting chemical absorption from mixtures through skin using two levels of in vitro porcine skin biological systems. A total of 16 diverse chemicals were applied in 384 treatment mixture combinations in flow-through diffusion cells and 20 chemicals in 119 treatment combinations in isolated perfused porcine skin. Penetrating chemical flux into perfusate from diffusion cells was analyzed to estimate a normalized dermal absorptive flux, operationally an apparent permeability coefficient, and total perfusate area under the curve from perfused skin studies. These data were then fit to a modified dermal QSPR model of Abraham and Martin including a sixth term to account for mixture interactions based on physical chemical properties of the mixture components. Goodness of fit was assessed using correlation coefficients (r2), internal and external validation metrics (q2L00, q2L25%, q2EXT), and applicable chemical domain determinations. The best QSPR equations selected for each experimental biological system had r2 values of 0.69-0.73, improving fits over the base equation without the mixture effects. Different mixture factors were needed for each model system. Significantly, the model of Abraham and Martin could also be reduced to four terms in each system; however, different terms could be deleted for each of the two biological systems. These findings suggest that a QSPR model for estimating percutaneous absorption as a function of chemical mixture composition is possible and that the nature of the QSPR model selected is dependent upon the biological level of the in vitro test system used, both findings having significant implications when dermal absorption data are used for in vivo risk assessments. PMID- 20947719 TI - Addressing oncology pharmacy & policy. PMID- 20947720 TI - Exploring pharmacy and drug policy concerns. PMID- 20947721 TI - Managed care & medical oncology: the focus is on value. AB - A previous NCCN Oncology Insights Reportdescribed the factors making cancer care a priority for managed care organizations (MCOs) and emerging trends in managing costs of cancer care. To better understand the concerns of MCOs and how they are addressing cancer costs and quality, NCCN interviewed senior physician executives from the 3 largest payors in the United States. The interviews provided insights into how these companies managed oncology care, with an emphasis on drugs and biologics. As a follow-up to the previous report, NCCN conducted additional interviews with medical executives from 10 MCOs between February and April 2010. The organizations represented in these interviews were Aetna, BlueCross BlueShield of Minnesota, BlueShield of Michigan, CareFirst BlueCross BlueShield, Empire BlueCross BlueShield, HealthNow, Humana, Independence BlueCross, Priority Health, and UnitedHealthcare. Although this group is diverse, it does not constitute a representative cross-section of MCOs across the United States. NCCN interviewed these executives about the priority of cancer care management for their organizations and the strategies being used to address cost and quality of cancer care. The information garnered from these interviews was qualitative in nature. A separate quantitative analysis of trends in oncology managed care has already been published, and throughout this report, data from the 2009-2010 Genentech Oncology Trend Report are referenced to supplement findings from the NCCN interviews. PMID- 20947723 TI - Changes to medicare part D: who benefits? PMID- 20947722 TI - Insights and perspectives in the clinical and operational management of cancer related anemia. AB - Management of anemia in patients with cancer presents challenges from clinical, operational, and economic perspectives. Clinically, anemia in these patients may result from treatment (chemotherapy, radiation therapy, or surgical interventions) or from the malignancy itself. Anemia not only contributes to cancer-related fatigue and other quality of life issues, but also affects prognosis. From the operational perspective, a patient with cancer who is also anemic may consume more laboratory, pharmacy, and clinical resources than other patients with cancer. PMID- 20947724 TI - NCCN Oncology Risk Evaluation and Mitigation Strategies White Paper: Recommendations for Stakeholders. AB - REMS are a particularly important issue for oncology and the National Comprehensive Cancer Network (NCCN). A disproportionate number of drugs with complex REMS are used in patients with cancer or hematologic disorders. REMS policies and processes within oncology may act as a model for other clinical areas. A breadth of experience and access to a wide knowledge base exists within oncology that will ensure appropriate development and consideration of the practical implications of REMS. NCCN is uniquely positioned to assume a leadership role in this process given its status as the arbiter of high-quality cancer care based on its world-leading institutions and clinicians. Notwithstanding the potential benefits, the successful design, implementation, and analysis of the FDA's recent requirement for REMS for some high-risk drugs and biologics will present significant challenges for stakeholders, including patients, providers, cancer centers, manufacturers, payors, health information technology vendors, and regulatory agencies. To provide guidance to these stakeholders regarding REMS challenges, the NCCN assembled a work group comprised of thought leaders from NCCN Member Institutions and other outside experts. The Work Group identified challenges across the REMS spectrum, including the areas of standardization, development and assessment of REMS programs, medication guides, provider knowledge and impact on prescribing, provider burden and compensation, and incorporation of REMS into clinical practice. PMID- 20947725 TI - PiggyBac transposon mutagenesis: a tool for cancer gene discovery in mice. AB - Transposons are mobile DNA segments that can disrupt gene function by inserting in or near genes. Here, we show that insertional mutagenesis by the PiggyBac transposon can be used for cancer gene discovery in mice. PiggyBac transposition in genetically engineered transposon-transposase mice induced cancers whose type (hematopoietic versus solid) and latency were dependent on the regulatory elements introduced into transposons. Analysis of 63 hematopoietic tumors revealed that PiggyBac is capable of genome-wide mutagenesis. The PiggyBac screen uncovered many cancer genes not identified in previous retroviral or Sleeping Beauty transposon screens, including Spic, which encodes a PU.1-related transcription factor, and Hdac7, a histone deacetylase gene. PiggyBac and Sleeping Beauty have different integration preferences. To maximize the utility of the tool, we engineered 21 mouse lines to be compatible with both transposon systems in constitutive, tissue- or temporal-specific mutagenesis. Mice with different transposon types, copy numbers, and chromosomal locations support wide applicability. PMID- 20947726 TI - Broken-symmetry states in doubly gated suspended bilayer graphene. AB - The single-particle energy spectra of graphene and its bilayer counterpart exhibit multiple degeneracies that arise through inherent symmetries. Interactions among charge carriers should spontaneously break these symmetries and lead to ordered states that exhibit energy gaps. In the quantum Hall regime, these states are predicted to be ferromagnetic in nature, whereby the system becomes spin polarized, layer polarized, or both. The parabolic dispersion of bilayer graphene makes it susceptible to interaction-induced symmetry breaking even at zero magnetic field. We investigated the underlying order of the various broken-symmetry states in bilayer graphene suspended between top and bottom gate electrodes. We deduced the order parameter of the various quantum Hall ferromagnetic states by controllably breaking the spin and sublattice symmetries. At small carrier density, we identified three distinct broken-symmetry states, one of which is consistent with either spontaneously broken time-reversal symmetry or spontaneously broken rotational symmetry. PMID- 20947727 TI - A low-magnetic-field soft gamma repeater. AB - Soft gamma repeaters (SGRs) and anomalous x-ray pulsars form a rapidly increasing group of x-ray sources exhibiting sporadic emission of short bursts. They are believed to be magnetars, that is, neutron stars powered by extreme magnetic fields, B ~ 10(14) to 10(15) gauss. We report on a soft gamma repeater with low magnetic field, SGR 0418+5729, recently detected after it emitted bursts similar to those of magnetars. X-ray observations show that its dipolar magnetic field cannot be greater than 7.5 * 10(12) gauss, well in the range of ordinary radio pulsars, implying that a high surface dipolar magnetic field is not necessarily required for magnetar-like activity. The magnetar population may thus include objects with a wider range of B-field strengths, ages, and evolutionary stages than observed so far. PMID- 20947728 TI - Spin-light coherence for single-spin measurement and control in diamond. AB - The exceptional spin coherence of nitrogen-vacancy centers in diamond motivates their function in emerging quantum technologies. Traditionally, the spin state of individual centers is measured optically and destructively. We demonstrate dispersive, single-spin coupling to light for both nondestructive spin measurement, through the Faraday effect, and coherent spin manipulation, through the optical Stark effect. These interactions can enable the coherent exchange of quantum information between single nitrogen-vacancy spins and light, facilitating coherent measurement, control, and entanglement that is scalable over large distances. PMID- 20947729 TI - The role of discharge variation in scaling of drainage area and food chain length in rivers. AB - Food chain length (FCL) is a fundamental component of food web structure. Studies in a variety of ecosystems suggest that FCL is determined by energy supply, environmental stability, and/or ecosystem size, but the nature of the relationship between environmental stability and FCL, and the mechanism linking ecosystem size to FCL, remain unclear. Here we show that FCL increases with drainage area and decreases with hydrologic variability and intermittency across 36 North American rivers. Our analysis further suggests that hydrologic variability is the mechanism underlying the correlation between ecosystem size and FCL in rivers. Ecosystem size lengthens river food chains by integrating and attenuating discharge variation through stream networks, thereby enhancing environmental stability in larger river systems. PMID- 20947730 TI - Germany's energy research plan. PMID- 20947732 TI - Economics Nobel. Three laureates explained why unemployment is inevitable. PMID- 20947731 TI - Gulf oil spill. Government chided for poor planning and communication. PMID- 20947733 TI - Immunology. Painful failure of promising genital herpes vaccine. PMID- 20947734 TI - Climate change. Climate talks still at impasse, China buffs its green reputation. PMID- 20947735 TI - Undergraduate science. Better intro courses seen as key to reducing attrition of STEM majors. PMID- 20947737 TI - Chemistry. Carbon-linking catalysts get Nobel nod. PMID- 20947738 TI - Computational biology. Custom-built supercomputer brings protein folding into view. PMID- 20947739 TI - Can the census go digital? PMID- 20947740 TI - Soap or census? PMID- 20947741 TI - Zoonoses. In China's backcountry, tracking lethal bird flu. PMID- 20947742 TI - Nanotechnology. Nanoparticle Trojan horses gallop from the lab into the clinic. PMID- 20947743 TI - Machine science: what's missing. PMID- 20947744 TI - Machine science: truly machine-aided science. PMID- 20947745 TI - Machine science: the human side. PMID- 20947746 TI - Comment on "Narrow primary feather rachises in Confuciusornis and Archaeopteryx suggest poor flight ability". AB - Nudds and Dyke (Reports, 14 May 2010, p. 887) compared the rachis diameters of the primary feathers of Archaeopteryx and Confuciusornis to those of modern birds and found that the primary feathers of these two basal birds were too weak to support sustained flight. Our measurements of Confuciusornis specimens suggest that their conclusions need to be further evaluated. PMID- 20947747 TI - Comment on "Narrow primary feather rachises in Confuciusornis and Archaeopteryx suggest poor flight ability". AB - Nudds and Dyke (Reports, 14 May 2010, p. 887) reported that the primary features of the early birds Archaeopteryx and Confuciusornis were too weak to power flight. This conclusion is not supported because the authors overestimated the mass of the subjects and understated the strength of the primary shafts in at least one example. The total biology of the birds indicates that they could achieve flapping flight. PMID- 20947748 TI - Conservation. Ecosystem services for 2020. PMID- 20947749 TI - Medicine. Stopping the stones. PMID- 20947750 TI - Evolution. Variation catches a ride. PMID- 20947751 TI - Applied physics. Filling the light pipe. PMID- 20947752 TI - Circadian rhythms. Temperatures to communicate by. PMID- 20947753 TI - Evolution. RNA GPS. PMID- 20947754 TI - Social science. The benefits of multilingualism. PMID- 20947755 TI - Materials science. Recasting metal alloy phases with block copolymers. PMID- 20947756 TI - Why testing improves memory: mediator effectiveness hypothesis. AB - A wealth of research has established that practice tests improve memory for the tested material. Although the benefits of practice tests are well documented, the mechanisms underlying testing effects are not well understood. We propose the mediator effectiveness hypothesis, which states that more-effective mediators (that is, information linking cues to targets) are generated during practice involving tests with restudy versus during restudy only. Effective mediators must be retrievable at time of test and must elicit the target response. We evaluated these two components of mediator effectiveness for learning foreign language translations during practice involving either test-restudy or restudy only. Supporting the mediator effectiveness hypothesis, test-restudy practice resulted in mediators that were more likely to be retrieved and more likely to elicit targets on a final test. PMID- 20947757 TI - Crystal growth inhibitors for the prevention of L-cystine kidney stones through molecular design. AB - Crystallization of L-cystine is a critical step in the pathogenesis of cystine kidney stones. Treatments for this disease are somewhat effective but often lead to adverse side effects. Real-time in situ atomic force microscopy (AFM) reveals that L-cystine dimethylester (L-CDME) and L-cystine methylester (L-CME) dramatically reduce the growth velocity of the six symmetry-equivalent {100} steps because of specific binding at the crystal surface, which frustrates the attachment of L-cystine molecules. L-CDME and L-CME produce l-cystine crystals with different habits that reveal distinct binding modes at the crystal surfaces. The AFM observations are mirrored by reduced crystal yield and crystal size in the presence of L-CDME and L-CME, collectively suggesting a new pathway to the prevention of L-cystine stones by rational design of crystal growth inhibitors. PMID- 20947758 TI - Atomic-level characterization of the structural dynamics of proteins. AB - Molecular dynamics (MD) simulations are widely used to study protein motions at an atomic level of detail, but they have been limited to time scales shorter than those of many biologically critical conformational changes. We examined two fundamental processes in protein dynamics--protein folding and conformational change within the folded state--by means of extremely long all-atom MD simulations conducted on a special-purpose machine. Equilibrium simulations of a WW protein domain captured multiple folding and unfolding events that consistently follow a well-defined folding pathway; separate simulations of the protein's constituent substructures shed light on possible determinants of this pathway. A 1-millisecond simulation of the folded protein BPTI reveals a small number of structurally distinct conformational states whose reversible interconversion is slower than local relaxations within those states by a factor of more than 1000. PMID- 20947759 TI - Discovery of a Frank-Kasper sigma phase in sphere-forming block copolymer melts. AB - Sphere-forming block copolymers are known to self-assemble into body-centered cubic crystals near the order-disorder transition temperature. Small-angle x-ray scattering and transmission electron microscopy experiments on diblock and tetrablock copolymer melts have revealed an equilibrium phase characterized by a large tetragonal unit cell containing 30 microphase-separated spheres. This structure, referred to as the sigma (sigma) phase by Frank and Kasper more than 50 years ago, nucleates and grows from the body-centered cubic phase similar to its occurrence in metal alloys and is a crystal approximant to dodecagonal quasicrystals. Formation of the sigma phase in undiluted linear block copolymers (and certain branched dendrimers) appears to be mediated by macromolecular packing frustration, an entropic contribution to the interparticle interactions that control the sphere-packing geometry. PMID- 20947760 TI - Room-temperature detection of a single molecule's absorption by photothermal contrast. AB - So far, single-molecule imaging has predominantly relied on fluorescence detection. We imaged single nonfluorescent azo dye molecules in room-temperature glycerol by the refractive effect of the heat that they release in their environment upon intense illumination. This photothermal technique provides contrast for the absorbing objects only, irrespective of scattering by defects or roughness, with a signal-to-noise ratio of ~10 for a single molecule in an integration time of 300 milliseconds. In the absence of oxygen, virtually no bleaching event was observed, even after more than 10 minutes of illumination. In a solution saturated with oxygen, the average bleaching time was of the order of 1 minute. No blinking was observed in the absorption signal. On the basis of bleaching steps, we obtained an average absorption cross section of 4 angstroms(2) for a single chromophore. PMID- 20947761 TI - Atmospheric CO2: principal control knob governing Earth's temperature. AB - Ample physical evidence shows that carbon dioxide (CO(2)) is the single most important climate-relevant greenhouse gas in Earth's atmosphere. This is because CO(2), like ozone, N(2)O, CH(4), and chlorofluorocarbons, does not condense and precipitate from the atmosphere at current climate temperatures, whereas water vapor can and does. Noncondensing greenhouse gases, which account for 25% of the total terrestrial greenhouse effect, thus serve to provide the stable temperature structure that sustains the current levels of atmospheric water vapor and clouds via feedback processes that account for the remaining 75% of the greenhouse effect. Without the radiative forcing supplied by CO(2) and the other noncondensing greenhouse gases, the terrestrial greenhouse would collapse, plunging the global climate into an icebound Earth state. PMID- 20947762 TI - The structure of iron in Earth's inner core. AB - Earth's solid inner core is mainly composed of iron (Fe). Because the relevant ultrahigh pressure and temperature conditions are difficult to produce experimentally, the preferred crystal structure of Fe at the inner core remains uncertain. Static compression experiments showed that the hexagonal close-packed (hcp) structure of Fe is stable up to 377 gigapascals and 5700 kelvin, corresponding to inner core conditions. The observed weak temperature dependence of the c/a axial ratio suggests that hcp Fe is elastically anisotropic at core temperatures. Preferred orientation of the hcp phase may explain previously observed inner core seismic anisotropy. PMID- 20947763 TI - Intravascular danger signals guide neutrophils to sites of sterile inflammation. AB - Neutrophils are recruited from the blood to sites of sterile inflammation, where they contribute to wound healing but may also cause tissue damage. By using spinning disk confocal intravital microscopy, we examined the kinetics and molecular mechanisms of neutrophil recruitment to sites of focal hepatic necrosis in vivo. Adenosine triphosphate released from necrotic cells activated the Nlrp3 inflammasome to generate an inflammatory microenvironment that alerted circulating neutrophils to adhere within liver sinusoids. Subsequently, generation of an intravascular chemokine gradient directed neutrophil migration through healthy tissue toward foci of damage. Lastly, formyl-peptide signals released from necrotic cells guided neutrophils through nonperfused sinusoids into the injury. Thus, dynamic in vivo imaging revealed a multistep hierarchy of directional cues that guide neutrophil localization to sites of sterile inflammation. PMID- 20947764 TI - Granulosa cell ligand NPPC and its receptor NPR2 maintain meiotic arrest in mouse oocytes. AB - Granulosa cells of mammalian Graafian follicles maintain oocytes in meiotic arrest, which prevents their precocious maturation. We show that mouse mural granulosa cells, which line the follicle wall, express natriuretic peptide precursor type C (Nppc) messenger RNA (mRNA), whereas cumulus cells surrounding oocytes express mRNA of the NPPC receptor NPR2, a guanylyl cyclase. NPPC increased cGMP levels in cumulus cells and oocytes and inhibited meiotic resumption in vitro. Meiotic arrest was not sustained in most Graafian follicles of Nppc or Npr2 mutant mice, and meiosis resumed precociously. Oocyte-derived paracrine factors promoted cumulus cell expression of Npr2 mRNA. Therefore, the granulosa cell ligand NPPC and its receptor NPR2 in cumulus cells prevent precocious meiotic maturation, which is critical for maturation and ovulation synchrony and for normal female fertility. PMID- 20947765 TI - Dom34:Hbs1 promotes subunit dissociation and peptidyl-tRNA drop-off to initiate no-go decay. AB - No-go decay (NGD) is one of several messenger RNA (mRNA) surveillance systems dedicated to the removal of defective mRNAs from the available pool. Two interacting factors, Dom34 and Hbs1, are genetically implicated in NGD in yeast. Using a reconstituted yeast translation system, we show that Dom34:Hbs1 interacts with the ribosome to promote subunit dissociation and peptidyl-tRNA drop-off. Our data further indicate that these recycling activities are shared by the homologous translation termination factor complex eRF1:eRF3, suggesting a common ancestral function. Because Dom34:Hbs1 activity exhibits no dependence on either peptide length or A-site codon identity, we propose that this quality-control system functions broadly to recycle ribosomes throughout the translation cycle whenever stalls occur. PMID- 20947766 TI - Selection at linked sites shapes heritable phenotypic variation in C. elegans. AB - Mutation generates the heritable variation that genetic drift and natural selection shape. In classical quantitative genetic models, drift is a function of the effective population size and acts uniformly across traits, whereas mutation and selection act trait-specifically. We identified thousands of quantitative trait loci (QTLs) influencing transcript abundance traits in a cross of two Caenorhabditis elegans strains; although trait-specific mutation and selection explained some of the observed pattern of QTL distribution, the pattern was better explained by trait-independent variation in the intensity of selection on linked sites. Our results suggest that traits in C. elegans exhibit different levels of variation less because of their own attributes than because of differences in the effective population sizes of the genomic regions harboring their underlying loci. PMID- 20947767 TI - Rapid construction of empirical RNA fitness landscapes. AB - Evolution is an adaptive walk through a hypothetical fitness landscape, which depicts the relationship between genotypes and the fitness of each corresponding phenotype. We constructed an empirical fitness landscape for a catalytic RNA by combining next-generation sequencing, computational analysis, and "serial depletion," an in vitro selection protocol. By determining the reaction rate constant for every point mutant of a catalytic RNA, we demonstrated that abundance in serially depleted pools correlates with biochemical activity (correlation coefficient r = 0.67, standard score Z = 7.4). Therefore, enumeration of each genotype by deep sequencing yielded a fitness landscape containing ~10(7) unique sequences, without requiring measurement of the phenotypic fitness for each sequence. High-throughput mapping between genotype and phenotype may apply to artificial selections, host-pathogen interactions, and other biomedically relevant evolutionary phenomena. PMID- 20947768 TI - Temperature as a universal resetting cue for mammalian circadian oscillators. AB - Environmental temperature cycles are a universal entraining cue for all circadian systems at the organismal level with the exception of homeothermic vertebrates. We report here that resistance to temperature entrainment is a property of the suprachiasmatic nucleus (SCN) network and is not a cell-autonomous property of mammalian clocks. This differential sensitivity to temperature allows the SCN to drive circadian rhythms in body temperature, which can then act as a universal cue for the entrainment of cell-autonomous oscillators throughout the body. Pharmacological experiments show that network interactions in the SCN are required for temperature resistance and that the heat shock pathway is integral to temperature resetting and temperature compensation in mammalian cells. These results suggest that the evolutionarily ancient temperature resetting response can be used in homeothermic animals to enhance internal circadian synchronization. PMID- 20947769 TI - Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward. AB - The nucleus accumbens is a key mediator of cocaine reward, but the distinct roles of the two subpopulations of nucleus accumbens projection neurons, those expressing dopamine D1 versus D2 receptors, are poorly understood. We show that deletion of TrkB, the brain-derived neurotrophic factor (BDNF) receptor, selectively from D1+ or D2+ neurons oppositely affects cocaine reward. Because loss of TrkB in D2+ neurons increases their neuronal excitability, we next used optogenetic tools to control selectively the firing rate of D1+ and D2+ nucleus accumbens neurons and studied consequent effects on cocaine reward. Activation of D2+ neurons, mimicking the loss of TrkB, suppresses cocaine reward, with opposite effects induced by activation of D1+ neurons. These results provide insight into the molecular control of D1+ and D2+ neuronal activity as well as the circuit level contribution of these cell types to cocaine reward. PMID- 20947770 TI - Salmonella pathogenesis and processing of secreted effectors by caspase-3. AB - The enteric pathogen Salmonella enterica serovar Typhimurium causes food poisoning resulting in gastroenteritis. The S. Typhimurium effector Salmonella invasion protein A (SipA) promotes gastroenteritis by functional motifs that trigger either mechanisms of inflammation or bacterial entry. During infection of intestinal epithelial cells, SipA was found to be responsible for the early activation of caspase-3, an enzyme that is required for SipA cleavage at a specific recognition motif that divided the protein into its two functional domains and activated SipA in a manner necessary for pathogenicity. Other caspase 3 cleavage sites identified in S. Typhimurium appeared to be restricted to secreted effector proteins, which indicates that this may be a general strategy used by this pathogen for processing of its secreted effectors. PMID- 20947771 TI - Are two narcissists better than one? The link between narcissism, perceived creativity, and creative performance. AB - The current research examines the link between narcissism and creativity at the individual, relational, and group levels of analysis. It finds that narcissists are not necessarily more creative than others, but they think they are, and they are adept at persuading others to agree with them. In the first study, narcissism was positively associated with self-rated creativity, despite the fact that blind coders saw no difference between the creative products offered by those low and high on narcissism. In a second study, more narcissistic individuals asked to pitch creative ideas to a target person were judged by the targets as being more creative than were less narcissistic individuals, in part because narcissists were more enthusiastic. Finally, a study of group creativity finds evidence of a curvilinear effect: Having more narcissists is better for generating creative outcomes (but having too many provides diminishing returns). PMID- 20947772 TI - Truth from language and truth from fit: the impact of linguistic concreteness and level of construal on subjective truth. AB - In four experiments, the impact of concreteness of language on judgments of truth was examined. In Experiments 1 and 2, it was found that statements of the very same content were judged as more probably true when they were written in concrete language than when they were written in abstract language. Findings of Experiment 2 also showed that this linguistic concreteness effect on judgments of truth could most likely be attributed to greater perceived vividness of concrete compared to abstract statements. Two further experiments demonstrated an additional fit effect: The truth advantage of concrete statements occurred especially when participants were primed with a concrete (vs. abstract) mind-set (Experiment 3) or when the statements were presented in a spatially proximal (vs. distant) location (Experiment 4). Implications for communication strategies are discussed. PMID- 20947773 TI - Moral credentialing by association: the importance of choice and relationship closeness. AB - People express more prejudice if they have established their "moral credentials." Five studies explored the acquisition of moral credentials through associations with racial minorities, particularly close relationships that are personally chosen. Participants choosing to write about a positive experience with a Black person (Study 1) or Hispanic person (Study 2) subsequently expressed more preference for Whites and tolerance of prejudice than did other participants. In Study 3, the credentialing effect of choice was diminished when participants were given an incentive for that choice. Participants in Study 4 who wrote about a Black friend were more credentialed than those who wrote about a Black acquaintance, regardless of whether the experience was positive or negative. Study 5 suggested that participants strategically referred to close associations with minorities when warned of a future situation in which they might appear prejudiced. PMID- 20947774 TI - The cultural dynamics of rewarding honesty and punishing deception. AB - Recent research suggests that individuals reward honesty more than they punish deception. Five experiments showed that different patterns of rewards and punishments emerge for North American and East Asian cultures. Experiment 1 demonstrated that Americans rewarded more than they punished, whereas East Asians rewarded and punished in equivalent amounts. Experiments 2 and 3 revealed that these divergent patterns by culture could be explained by greater social mobility experienced by Americans. Experiments 4 and 5 examined how certain consequences of social mobility, approach-avoidance behavioral motivations and trust and felt obligation, can lead to disparate reward and punishment decisions within the two cultures. Moreover, Experiment 4 revealed that Americans exhibited stronger evaluative reactions toward deception but stronger behavioral intentions toward honesty; East Asians did not exhibit this evaluative-behavioral asymmetry. The cross-cultural implications for understanding rewards and punishments in an increasingly globalized world are discussed. PMID- 20947775 TI - When you accept me for me: the relational benefits of intrinsic affirmations from one's relationship partner. AB - Research suggests that not all affirmations of self-worth are created equal affirming intrinsic aspects of the self (i.e., a person's stable, intrinsic qualities) leads to better outcomes for the individual compared to affirming extrinsic aspects (i.e., a person's deeds and accomplishments). Extending this research to the domain of romantic relationships, the current research compared the relational benefits of recalling intrinsic versus extrinsic affirmations from a romantic partner among people high versus low in baseline relationship satisfaction. Across three experiments, as predicted, people low but not high in baseline satisfaction reported higher relationship quality and more pro relationship responses after recalling a time of intrinsic compared to extrinsic affirmation from a romantic partner. Together, these experiments suggest that affirmations from relationship partners may be important for enhancing relationships, but only if they emphasize intrinsic qualities of the self. PMID- 20947776 TI - Empowering or oppressing? Development and exploration of the Enjoyment of Sexualization Scale. AB - Sexualization of girls and women in America is rampant and has many negative consequences. Women, however, often report enjoying being sexually admired by men. Given this paradox, it is unclear whether such enjoyment represents an authentic empowerment of women's sexuality or is related to traditional feminine norms and sexist beliefs. In Studies 1 and 2, the authors developed and tested the eight-item Enjoyment of Sexualization Scale (ESS). It had good reliability and was differentiated from related constructs including body surveillance, body shame, self-sexualizing behaviors, and appearance-contingent self-esteem. In Study 3, endorsement of traditional gender norms, endorsement of benevolent sexism, and endorsement of hostile sexism were all positively related to the ESS. Moreover, women who both enjoyed sexualization and engaged in self objectification reported more negative eating attitudes. Overall, there was little support for positive effects of enjoying sexualization. The extent to which enjoying sexualization actually empowers women or contributes to their oppression is discussed. PMID- 20947777 TI - Depression predicts elevated endothelin-1 in patients with coronary artery disease. AB - OBJECTIVE: To examine the relationship of depression severity to circulating endothelin-1 (ET-1), which has previously been linked to plaque rupture and postacute coronary syndrome (ACS) survival. Depression carries an independent two to four-fold increased risk of early morbidity and mortality after ACS. The pathway(s) linking depression to event-free survival remains to be determined. METHODS: Patients with documented history of coronary artery disease (n = 101) provided a resting morning blood sample that was assayed for ET-1, and they completed the Beck Depression Inventory (BDI). ET-1 was treated as a log transformed continuous variable (logET-1), and as a dichotomous variable using a post-ACS risk threshold previously reported (>=1.16 fmol/mL). RESULTS: BDI score was related to logET-1 in both unadjusted and adjusted models. In addition, unadjusted and adjusted logistic regression models with dichotomous ET-1 revealed that, for each point increase in BDI score, there was approximately a 14% increased likelihood of being at or above ET-1 risk threshold. Secondary logistic regression models demonstrated a >3.5-fold likelihood of being at or above this risk threshold in association with a BDI score of >=10. CONCLUSIONS: Depression symptom severity predicts ET-1 elevation that has previously been linked to post ACS survival, with the greatest risk of elevation among those patients with worse depression symptoms. This link may identify a vulnerability to triggered ACS and poorer survival associated with depression. Future research should establish whether the observed relationship of depressive symptoms to ET-1 level mediates the link between depression and survival. PMID- 20947778 TI - Methylation at 5HTT mediates the impact of child sex abuse on women's antisocial behavior: an examination of the Iowa adoptee sample. AB - OBJECTIVE: To examine epigenetic processes linking childhood sex abuse to symptoms of antisocial personality disorder (ASPD) in adulthood and to investigate the possibility that the link between childhood sex abuse and deoxyribonucleic acid methylation at the 5HTT promoter might represent a pathway of long-term impact on symptoms of ASPD. METHOD: Deoxyribonucleic acid was prepared from lymphoblast cell lines derived from 155 female participants in the latest wave of the Iowa Adoptee Study. Methylation at 71 CpG residues was determined by quantitative mass spectroscopy, and the resulting values were averaged to produce an average CpG ratio for each participant. Simple associations and path analyses within an Mplus framework were examined to characterize the relationships among childhood sex abuse, overall level of methylation among women, and subsequent antisocial behavior in adulthood. Direct effects of biological parent psychopathology and 5HTT genotype were controlled. RESULTS: Replicating prior work, we found that a significant effect of childhood sex abuse on methylation of the 5HTT promoter region emerged for women. In addition, a significant effect of methylation at 5HTT on symptoms of ASPD emerged. CONCLUSIONS: Child sex abuse may create long-lasting changes in methylation of the promoter region of 5HTT in women. Furthermore, hypermethylation may be one mechanism linking childhood sex abuse to changes in risk for adult antisocial behavior in women. Better understanding of the methylome may prove critical in understanding the role of childhood environments on long-term psychiatric sequelae. PMID- 20947779 TI - Nine-year stability of type D personality: contributions of genes and environment. AB - OBJECTIVE: To assess longitudinal changes in genetic and environmental influences on Type D personality and its subcomponents negative affectivity (NA) and social inhibition (SI) over a 9-year period. Most personality constructs have good retest reliability over long periods, with stability attributed to genes, and changes to environmental factors. Type D personality is stable across an 18-month period and is influenced by genetic factors. However, there is no knowledge on long-term stability, and the contributions of genes and environment to that stability. METHODS: Type D personality was determined from survey data collected in 1991 (n = 3235; mean age = 17.3 years), 1997 (n = 3133; mean age = 25.3 years), and 2000 (n = 4456; mean age = 29.6 years) in a population sample of healthy twins. Multivariate structural equation modeling was employed. RESULTS: Type D heritability ranged from 50% in 1997 to 34% in 2000, with the same genetic factor affecting Type D at all time points. Heritability of SI ranged from 49% (1991) to 42% (2000), with the same genetic factor influencing SI at all times. Heritability estimates for NA ranged from 45% (1991) to 40% (2000), with one genetic factor influencing NA at all times, and one genetic factor influencing NA at the second and third occasions. Different environmental factors acted on Type D, NA, and SI at each of the three measurement occasions. CONCLUSION: Type D personality and both subcomponents are stable over time, which is largely due to genetic factors. Different unique environmental factors influence the Type D components at different occasions. PMID- 20947780 TI - Ethnic and gender differences in the relationship between hostility and metabolic and autonomic risk factors for coronary heart disease. AB - OBJECTIVE: To examine the relationship between hostility and biological risk factors for coronary heart disease (CHD) in a population of white European and South Asian men and women living in the United Kingdom. METHODS: This cross sectional study involved a community-based sample of 1,757 healthy white and South Asian men and women aged between 35 years and 75 years from West London. Participants completed the Cook-Medley Hostility Scale, together with measures of standard biological risk factors and heart rate variability. Associations between hostility and CHD risk factors were evaluated, controlling for age, education, smoking, physical activity, body mass index, and waist/hip ratio, using regression models. RESULTS: In white men, hostility was associated positively with fasting glucose, glycosylated hemoglobin, and negatively with high-density lipoprotein cholesterol. High levels of hostility were also related to increased prevalence of diabetes and the metabolic syndrome in white men. Hostility in South Asian men was associated with impaired autonomic function. Hostility was not related to any biological CHD risk factors in South Asian or white women. CONCLUSIONS: Our results showed that hostility was independently associated with glucose metabolism and dyslipidemia in white men, and with autonomic dysfunction in South Asian men. Hostility was found not to be relevant for measured CHD risk factors in females. Longitudinal data are required to establish whether the impact of hostility on CHD risk in men is mediated through metabolic and autonomic processes. PMID- 20947781 TI - Associations between job strain and the cortisol/DHEA-S ratio among management and nonmanagement personnel. AB - OBJECTIVE: To assess associations between the main, nonlinear, and interactive effects of the demand-control-support (DCS) model and the cortisol/dehydroepiandrosterone sulfate (DHEA-S) ratio, a biomarker of psychophysical well-being. METHODS: Subjects were 596 employees from all occupational levels of a German airplane manufacturing plant. Multiple regression models controlling for age and gender were computed separately for employees with (n = 103) and without (n = 493) management responsibilities. RESULTS: Among employees without management responsibilities, the dimensions of the DCS model did not predict the cortisol/DHEA-S ratio. In contrast, among employees with management responsibilities, both linear and nonlinear job demand effects explained a substantial fraction of the cortisol/DHEA-S variance. Increasing levels of job demands were associated with decreasing cortisol/DHEA-S ratios (linear effect) with the quartile of moderately high levels of job demands representing an optimal level. Furthermore, we observed a significant nonlinear effect with job control and a significant interaction between job demands and job control among employees with management responsibilities. These results suggest a beneficial effect associated with moderate levels of job control. This may be due to a buffering effect against adverse levels of job demands (interactive effect) and the independent association with decreased cortisol/DHEA-S ratios (nonlinear effect). CONCLUSION: This is the first study that provides evidence that the DCS model is associated with the cortisol/DHEA-S ratio. Among employees with management responsibilities, moderate levels of job control may help managers to cope effectively with job demands and may induce a favorable cortisol/DHEA-S ratio. PMID- 20947782 TI - Sex differences in heart rate responses to script-driven imagery soon after trauma and risk of posttraumatic stress disorder. AB - OBJECTIVE: To investigate in trauma survivors the predictive validity of heightened physiological responsivity to script-driven imagery for the development of posttraumatic stress disorder (PTSD) and to evaluate the interactive effect of survivors' sex. Physiological responses to idiosyncratic trauma reminders may be predictive of later PTSD. The majority of previous studies have been cross sectional and have produced mixed findings. Sex differences may contribute to this heterogeneity. METHODS: Heart rate (HR) and respiratory sinus arrhythmia were measured at 2 weeks post trauma in 158 assault survivors during baseline and as they listened to an idiosyncratic trauma script. At 6 months, 15.2% of male and 28.1% of female participants met the diagnostic criteria for PTSD. RESULTS: Generalized linear model and logistic regression analyses showed that HR response to script-driven imagery and sex interacted in predicting PTSD symptom severity at 6 months. Women had greater PTSD symptom severities overall. Female HR responders to script-driven imagery showed the highest PTSD symptom severities and were almost three times more likely to develop PTSD at 6 months compared with men and female nonresponders (odds ratio, 2.72; 95% confidence interval, 1.13-6.57). Respiratory sinus arrhythmia responder type did not predict PTSD (odds ratio, 0.64; 95% confidence interval, 0.30-1.33). CONCLUSION: Female trauma survivors who respond to trauma reminders with increased HR may be at particular risk of developing PTSD. Physiological reactivity to trauma cues may be a useful index for screening and prevention of PTSD. PMID- 20947784 TI - Association of body composition with survival among patients on hemodialysis. PMID- 20947783 TI - Selective serotonin reuptake inhibitor suppression of HIV infectivity and replication. AB - OBJECTIVE: To test the hypothesis that the selective serotonin reuptake inhibitor (SSRI) citalopram would down-regulate human immunodeficiency virus (HIV) infectivity and that the greatest effects would be seen in people with depression. Depression is a risk factor for morbidity and mortality in HIV/acquired immune deficiency syndrome. Serotonin (5-HT) neurotransmission has been implicated in the pathobiology of depression, and pharmacologic therapies for depression target this system. The 5-HT transporter and 5-HT receptors are widely distributed throughout the central nervous and immune systems. Depression has been associated with suppression of natural killer cells and CD8(+) lymphocytes, key regulators of HIV infection. METHODS: Ex vivo models for acute and chronic HIV infection were used to study the effects of citalopram on HIV viral infection and replication in 48 depressed and nondepressed women. For both the acute and chronic infection models, HIV reverse transcriptase activity was measured in the citalopram treatment condition and the control condition. RESULTS: The SSRI significantly down-regulated the reverse transcriptase response in both the acute and chronic infection models. Specifically, citalopram significantly decreased the acute HIV infectivity of macrophages. Citalopram also significantly decreased HIV viral replication in the latently infected T-cell line and in the latently infected macrophage cell line. There was no difference in down-regulation by depression status. CONCLUSIONS: These studies suggest that an SSRI enhances natural killer/CD8 noncytolytic HIV suppression in HIV/acquired immune deficiency syndrome and decreases HIV viral infectivity of macrophages, ex vivo, suggesting the need for in vivo studies to determine a potential role for agents targeting serotonin in the host defense against HIV. PMID- 20947786 TI - Nasal carriage of methicillin-resistant Staphylococcus aureus is associated with higher all-cause mortality in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) nasal carriage is a recognized risk factor for subsequent endogenous infections. However, the association between MRSA carriage and patient survival in hemodialysis patients has not been established. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In March 2007, this prospective cohort study enrolled 306 outpatients under maintenance hemodialysis from a hospital-based dialysis center in Taiwan. They received two consecutive weekly nasal swab cultures at the beginning of the study. Patients having at least one positive culture of MRSA were defined as MRSA carriers. Subjects were followed up until December 31, 2008. The primary outcome was all-cause mortality. Main secondary outcomes were infection-related mortality and morbidity. RESULTS: We identified 29 MRSA carriers (9.48%) at study entry. After a median of 613 days of follow-up, Kaplan Meier analysis showed significant survival differences between MRSA carriers and noncarriers (log-rank P = 0.02). Compared with noncarriers, MRSA carriers had a 2.46-fold increased risk of dying from any cause, after adjusting for covariates at the start of follow-up. The adjusted hazard ratios of infection-related mortality and occurrence of subsequent S. aureus infection in carriers were 4.99 and 4.31, respectively. CONCLUSIONS: A major limitation is the relatively small sample size of MRSA carriers. Nevertheless, we demonstrated that there may be an association between MRSA nasal carriage and poor clinical outcomes in an outpatient hemodialysis population. This underscores the need for routine surveillance of MRSA nasal carriage and should alert the physicians of a group at high risk of morbidity and mortality. PMID- 20947785 TI - Clinical value of NPHS2 analysis in early- and adult-onset steroid-resistant nephrotic syndrome. AB - BACKGROUND AND OBJECTIVES: To date, very few cases with adult-onset focal segmental glomerulosclerosis (FSGS) carrying NPHS2 variants have been described, all of them being compound heterozygous for the p.R229Q variant and one pathogenic mutation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Mutation analysis was performed in 148 unrelated Spanish patients, of whom 50 presented with FSGS after 18 years of age. Pathogenicity of amino acid substitutions was evaluated through an in silico scoring system. Haplotype analysis was carried out using NPHS2 single nucleotide polymorphism and microsatellite markers. RESULTS: Compound heterozygous or homozygous NPHS2 pathogenic mutations were identified in seven childhood-onset steroid-resistant nephrotic syndrome (SRNS) cases. Six additional cases with late childhood- and adult-onset SRNS were compound heterozygotes for p.R229Q and one pathogenic mutation, mostly p.A284V. p.R229Q was more frequent among SRNS cases relative to controls (odds ratio=2.65; P=0.02). Significantly higher age at onset of the disease and slower progression to ESRD were found in patients with one pathogenic mutation plus the p.R229Q variant in respect to patients with two NPHS2 pathogenic mutations. CONCLUSIONS: NPHS2 analysis has a clinical value in both childhood- and adult-onset SRNS patients. For adult-onset patients, the first step should be screening for p.R229Q and, if positive, for p.A284V. These alleles are present in conserved haplotypes, suggesting a common origin for these substitutions. Patients carrying this specific NPHS2 allele combination did not respond to corticoids or immunosuppressors and showed FSGS, average 8-year progression to ESRD, and low risk for recurrence of FSGS after kidney transplant. PMID- 20947787 TI - Processes of care and reduced mortality among hemodialysis patients in the United States. PMID- 20947788 TI - Abandoning peracetic acid-based dialyzer reuse is associated with improved survival. AB - BACKGROUND AND OBJECTIVES: Higher mortality risk reported with reuse versus single use of dialyzers is potentially related to reuse reagents that modify membrane surface characteristics and the blood-membrane interface. A key mechanism may involve stimulation of an inflammatory response. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a prospective crossover design, laboratory markers and mortality from 23 hemodialysis facilities abandoning reuse with peracetic acid mixture were tracked. C-reactive protein (CRP), white blood cell (WBC) count, albumin, and prealbumin were measured for 2 consecutive months before abandoning reuse and subsequently within 3 and 6 months on single use. Survival models were utilized to compare the 6-month period before abandoning reuse (baseline) and the 6-month period on single use of dialyzers after a 3 month "washout period." RESULTS: Patients from baseline and single-use periods had a mean age of approximately 63 years; 44% were female, 54% were diabetic, 60% were white, and the mean vintage was approximately 3.2 years. The unadjusted hazard ratio for death was 0.70 and after case-mix adjustment was 0.74 for single use compared with reuse. Patients with CRP>=5 mg/L during reuse (mean CRP=26.6 mg/ml in April) declined on single use to 20.2 mg/L by August and 20.4 mg/L by November. WBC count declined slightly during single use, but nutritional markers were unchanged. CONCLUSIONS: Abandonment of peracetic-acid-based reuse was associated with improved survival and lower levels of inflammatory but not nutritional markers. Further study is needed to evaluate a potential link between dialyzer reuse, inflammation, and mortality. PMID- 20947789 TI - Mid-arm muscle circumference and quality of life and survival in maintenance hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Maintenance hemodialysis (MHD) patients with larger body or fat mass have greater survival than normal to low mass. We hypothesized that mid-arm muscle circumference (MAMC), a conveniently measured surrogate of lean body mass (LBM), has stronger association with clinical outcomes than triceps skinfold (TSF), a surrogate of fat mass. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: The associations of TSF, MAMC, and serum creatinine, another LBM surrogate, with baseline short form 36 quality-of-life scores and 5-year survival were examined in 792 MHD patients. In a randomly selected subsample of 118 subjects, LBM was measured by dual-energy x-ray absorptiometry. RESULTS: Dual energy x-ray absorptiometry-assessed LBM correlated most strongly with MAMC and serum creatinine. Higher MAMC was associated with better short form 36 mental health scale and lower death hazard ratios (HRs) after adjustment for case-mix, malnutrition-inflammation-cachexia syndrome, and inflammatory markers. Adjusted death HRs were 1.00, 0.86, 0.69, and 0.63 for the first to fourth MAMC quartiles, respectively. Higher serum creatinine and TSF were also associated with lower death HRs, but these associations were mitigated after multivariate adjustments. Using median values of TSF and MAMC to dichotomize, combined high MAMC with either high or low TSF (compared with low MAMC/TSF) exhibited the greatest survival, i.e., death HRs of 0.52 and 0.59, respectively. CONCLUSIONS: Higher MAMC is a surrogate of larger LBM and an independent predictor of better mental health and greater survival in MHD patients. Sarcopenia-correcting interventions to improve clinical outcomes in this patient population warrant controlled trials. PMID- 20947790 TI - Comparative effectiveness of calcium-containing phosphate binders in incident U.S. dialysis patients. AB - BACKGROUND AND OBJECTIVES: Few studies have assessed the association between phosphate binder use and hard outcomes in dialysis patients. Furthermore, the comparative effectiveness of calcium carbonate and acetate is untested. We studied the association between use versus nonuse of calcium-containing phosphate binders (CCPBs) and mortality from any cause. We also tested whether mortality differed among users of individual CCPBs. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A nationally representative prospective cohort of incident U.S. dialysis patients (1996 to 1997), assembled before the availability of sevelamer and lanthanum, was used. Use of each CCPB was ascertained from chart abstraction records. A large number of sociodemographic, clinical, and laboratory characteristics were available for confounding control in multivariate and propensity score-matched Cox regression models. RESULTS: Among 3603 incident dialysis patients, 77.5% used a CCPB, whereas 22.5% did not. Baseline use of CCPB was associated with an adjusted 19% lower mortality rate among CCPB users compared with nonusers. With successful matching of 800 exposed and nonexposed individuals on their exposure propensity score, however, CCPB users and nonusers had similar mortality. No mortality differences were observed between calcium acetate and calcium carbonate users in crude, adjusted, or propensity-matched analyses. CONCLUSIONS: No association was found between CCPB use and 1-year mortality in incident dialysis patients; choice of calcium carbonate versus acetate was also not associated with this outcome. Randomized trials are necessary to understand whether the prevailing practice of phosphate-binding therapy actually reduces adverse clinical outcomes. PMID- 20947792 TI - Lessons from Haiti on disaster relief. PMID- 20947791 TI - Systemic diseases: from amyloidosis to cryoglobulinemia. PMID- 20947793 TI - What do adolescents think about teen parenting? AB - Unexpected increases in the teen birth rates have stimulated a renewed focus on the prevention of teen pregnancy. Although many adults believe there are certain costs associated with teen parenting, the attitudes of teens toward the parenting experience are not known. The purpose of this descriptive study was to determine teens' thoughts on how their lives would change if they experienced a teen birth in the areas of relationships, vocation, and life impacts. The Thoughts on Teen Parenting Survey (TTPS), designed to measure demographic variables and perspectives on the costs and rewards of teen parenting, was administered to 695 high school students. The survey yielded a composite score, subscale scores, and aggregate data measuring teen thoughts on the consequences of the teen parenting experience. Findings may be used to identify teens at risk for pregnancy, develop interventions, and evaluate prevention strategies based on the insights of teens. PMID- 20947794 TI - Intravascular thrombophlebitis related to the peripheral infusion of amiodarone and vancomycin. AB - Patients on a telemetry unit experienced an increase in thrombophlebitis in 2004. The purpose of this research was to determine if peripheral IV amiodarone and vancomycin influenced the incidence of thrombophlebitis in an adult cardiothoracic population. Amiodarone phlebitis rates range up to 27%. In December 2004, Pharmacy diluted the amiodarone concentration to 600 mg/500 ml. By 2005, data demonstrated a consistent decrease in the incidence of thrombophlebitis. However, related to institutional policies and patient safety concerns, the amiodarone infusion concentration was reversed back to 900 mg/500 ml in October 2005. Thrombophlebitis increased after the return to a more concentrated amiodarone IV solution. Vancomycin infusion administration did not change during this time period. A retrospective chart review and observational, before and after study, demonstrated a correlation between amiodarone concentration and the incidence of thrombophlebitis. Vancomycin infusions appeared to prevent peripheral thrombophlebitis in the study population. Data was compelling and resulted in the institution standardizing the more dilute amiodarone IV concentration. PMID- 20947795 TI - Predictors of psychosocial adjustment during the postradiation treatment transition. AB - The aim of this study was to examine the role of cognitive appraisal in predicting psychosocial adjustment during the postradiation treatment transition. A predictive correlational design was used in a convenience sample of 80 patients with breast, lung, and prostate cancer who were receiving radiation therapy. Two weeks prior to completion of treatment, participants completed instruments to measure symptom distress, uncertainty, cognitive appraisal, social support, and self-efficacy for coping. The Psychosocial Adjustment to Illness Scale was administered 1 month after therapy. Adjustment was significantly correlated with all independent variables, age, and comorbidity. Young age and high amounts of threat appraisal, harm/loss appraisal, uncertainty, and symptom distress were significantly associated with poor adjustment. The model predicted 52% of the variability in adjustment. Cognitive appraisal was not a significant explanatory variable for adjustment when controlling for uncertainty, cancer stage, age, and symptom distress. Symptom distress was the only significant predictor of adjustment. PMID- 20947796 TI - Regional differences in physical appearance identity among young adult women in Thailand. AB - Physical appearance concerns lead to serious health compromising behaviors among women in Thailand. The purpose of this study was to examine differences in physical appearance identity among young women in four regions of Thailand based on 30 physical appearance characteristics generated and validated in two previous samples of young Thai women. Using Q methodology, 200 Thai young women sorted the physical appearance characteristics in terms of importance. Across-region differences exist for the most important physical appearance characteristics. Regional differences in physical appearance identity may explain the variety of behaviors used by Thai women to enhance their physical appearance. Further research should focus on regional factors that contribute to these aspects of physical appearance becoming a dominant source of self-definition so that effective prevention strategies can be developed and targeted to women at high risk. PMID- 20947797 TI - Licensed nurses disciplined in Oregon between September 1996 and June 2008. AB - This study is undertaken to better identify the types of errors being made by nurses in Oregon, to have a more thorough understanding of who is making the errors, and to examine how the Board is sanctioning nurses through Board (Board of Nursing) discipline. Results show that older nurses, and a disproportionately high number of male nurses, are being disciplined. RNs tend to be disciplined more for substance abuse and LPNs for substandard or inadequate care or for unprofessional conduct. RNs tend to be reprimanded more often than other licensure types, and LPNs receive more licensure suspensions. It may be helpful for administrators and nurse managers to use the information for staff education and development decisions. It may also inform Oregon nursing regulators, charged with protecting the public, when developing strategies aimed at ensuring equity and consistency in Board actions. PMID- 20947800 TI - Photooxidation of cytochrome P450-BM3. AB - High-valent iron-oxo species are thought to be intermediates in the catalytic cycles of oxygenases and peroxidases. An attractive route to these iron-oxo intermediates involves laser flash-quench oxidation of ferric hemes, as demonstrated by our work on the ferryl (compound II) and ferryl porphyrin radical cation (compound I) intermediates of horseradish peroxidase. Extension of this work to include cytochrome P450-BM3 (CYP102A1) has required covalent attachment of a Ru(II) photosensitizer to a nonnative cysteine near the heme (RuIIK97C FeIIIP450), in order to promote electron transfer from the Fe(III) porphyrin to photogenerated Ru(III). The conjugate was structurally characterized by X-ray crystallography (2.4 A resolution; Ru-Fe distance, 24 A). Flash-quench oxidation of the ferric-aquo heme produces an Fe(IV)-hydroxide species (compound II) within 2 ms. Difference spectra for three singly oxidized P450-BM3 intermediates were obtained from kinetics modeling of the transient absorption data in combination with generalized singular value decomposition analysis and multiexponential fitting. PMID- 20947802 TI - Planar oxide supported rhodium nanoparticles as model catalysts. AB - C(2)H(4)/CO/H(2) reaction is investigated on Rh/SiO(2) model catalyst surfaces. Kinetic reactivity and infrared spectroscopic measurements are investigated as a function of Rh particle size under near atmospheric reaction conditions. Results show that propionaldehyde turnover frequency (TOF) (CO insertion pathway) exhibits a maximum activity near = 2.5 nm. Polarization modulation infrared reflection absorption spectroscopy under CO and reaction (C(2)H(4)/CO/H(2)) conditions indicate the presence of Rh carbonyl species (Rh(CO)(2), Rh(CO)H) on small Rh particles, whereas larger particles appear resistant to dispersion and carbonyl formation. Combined these observations suggest the observed particle size dependence for propionaldehyde production via CO insertion is driven by two factors: (i) an increase in propionaldehyde formation on undercoordinated Rh sites and (ii) creation of carbonyl hydride species (Rh(CO)H)) on smaller Rh particles, whose presence correlates with the lower activity for propionaldehyde formation for < 2.5 nm. PMID- 20947803 TI - Patient and physician predictors of peritoneal dialysis technique failure: a population based, retrospective cohort study. AB - BACKGROUND: The use of peritoneal dialysis (PD) has been declining over the past decade in Canada, and high technique failure rates have been implicated. Studies have examined clinical risk factors for PD technique failure, but few studies have addressed sociodemographic factors driving technique failure. There are no studies examining the effect of physician factors on technique failure. METHODS: We conducted a retrospective cohort study using Ontario healthcare databases from 1 April 1995 to 31 March 2005 to examine the effects of patient sociodemographic and physician characteristics on PD technique failure. The primary outcome was time to technique failure. Secondary outcomes included the proportion of patients experiencing technique failure during the first year and the proportion of patients experiencing death during the study period. A competing risks analysis was applied to the Cox proportional hazards model to determine the predictors of technique failure, death, and kidney transplantation. RESULTS: In 5162 incident PD patients, the probability of technique success and patient survival at 5 years was 58.2% and 46.9% respectively. Of patients failing PD, 43.5% failed during the first year of treatment. Statistically significant predictors of technique failure included increasing age [hazard ratio (HR) 1.02], diabetes mellitus (HR 1.32), lower neighborhood education level (HR 2.93), and receiving transient (<= 3 months) hemodialysis before starting PD (HR 1.24). Predictors of patient death included increasing age (HR 1.05), diabetes mellitus (HR 1.44), coronary artery disease (HR 1.26), congestive heart failure (HR 1.58), and late referral to the nephrologist (HR 1.27). Distance from treating dialysis center and residing in a rural area did not impact the risk of technique failure or death. Male physician gender increased the risk of technique failure (HR 1.31). Increased PD patient volume decreased the risk of technique failure (HR 0.98). None of the physician factors were predictors of patient death. CONCLUSION: These findings support the need for implementing strategies to reduce technique failure, which could include increasing educational resources for patients initiating PD, aggressive risk factor modification in patients with multiple comorbidities, and increasing physician awareness regarding the detrimental outcomes associated with late referral and late PD start. PMID- 20947801 TI - Identification of a helical intermediate in trifluoroethanol-induced alpha synuclein aggregation. AB - Because oligomers and aggregates of the protein alpha-synuclein (alphaS) are implicated in the initiation and progression of Parkinson's disease, investigation of various alphaS aggregation pathways and intermediates aims to clarify the etiology of this common neurodegenerative disorder. Here, we report the formation of short, flexible, beta-sheet-rich fibrillar species by incubation of alphaS in the presence of intermediate (10-20% v/v) concentrations of 2,2,2 trifluoroethanol (TFE). We find that efficient production of these TFE fibrils is strongly correlated with the TFE-induced formation of a monomeric, partly helical intermediate conformation of alphaS, which exists in equilibrium with the natively disordered state at low [TFE] and with a highly alpha-helical conformation at high [TFE]. This partially helical intermediate is on-pathway to the TFE-induced formation of both the highly helical monomeric conformation and the fibrillar species. TFE-induced conformational changes in the monomer protein are similar for wild-type alphaS and the C-terminal truncation mutant alphaS1 102, indicating that TFE-induced structural transitions involve the N terminus of the protein. Moreover, the secondary structural transitions of three Parkinson's disease-associated mutants, A30P, A53T, and E46K, are nearly identical to wild type alphaS, but oligomerization rates differ substantially among the mutants. Our results add to a growing body of evidence indicating the involvement of helical intermediates in protein aggregation processes. Given that alphaS is known to populate both highly and partially helical states upon association with membranes, these TFE-induced conformations imply relevant pathways for membrane induced alphaS aggregation both in vitro and in vivo. PMID- 20947804 TI - Clinicopathological characteristics of triple-negative invasive mammary carcinomas in African-American versus Caucasian women. AB - African-American (AA) women are more likely to have late stage, aggressive, rapidly growing, and less hormone-responsive breast tumors. An aggressive subtype of cancer, known as "Triple-Negative" (TN), that is negative for Her-2 and for estrogen and progesterone receptors (ER and PR), is reported to be more common in AA women. We examined the clinical, histopathologic, and prognostic features of TN tumors in AA and Caucasian women. Tumor size, grade, histologic type, lymphovascular invasion (LVI), lymph node status, patient survival, ploidy status, and expression of ER, PR, p53, epidermal growth factor receptor (EGFR), MIB-1, Bcl-2, Her-2, p27, and p21 were evaluated. The TN tumors (75%) were high grade, large, aneuploid tumors that occurred in younger women and were more likely to have a high rate of LVI, elevated MIB-1 score, and nodal metastases. Patients with TN tumors showed poorer overall survival. There was no difference in overall or disease-free survival (p = 0.46) in the AA versus Caucasian women. LVI was a significant predictor of overall survival in AA but not in Caucasian women. There were minor differences in histopathologic features, biomarker expressions, and survival in AA and Caucasian women with TN tumors. The absence of LVI in AA patients predicted an excellent probability of survival. PMID- 20947805 TI - Adjuvant role of p53 immunostaining in detecting BK viral infection in renal allograft biopsies. AB - BK virus infection is a significant threat to renal transplant outcome. Detecting viral infection in renal transplant biopsies using SV40 staining is less than ideal. SV40 antibody reacts with the large T-antigen of BK virus only at the early phases of infection and can miss cells in later stages of infection. As p53 is upregulated during both early and late phases of infection, this study set out to determine whether p53 staining could improve detection of BK virus infection in renal transplant patients. The control group consisted of 16 renal allograft biopsies without histologic evidence of BK virus infection, while the BK group consisted of 15 renal allograft biopsies with histologic evidence of BK virus infection. The biopsies from both groups were immunohistochemically stained with both SV40 and p53 antibodies. Dual staining with both markers was also performed to identify their nuclear co-localization. In the BK group, the percent of p53 staining (16.6 +/- 4.8 %) was significantly higher than the percent of SV40 staining (5.4 +/- 2.7%). BK virus infected cells revealed a unique p53 immunostaining pattern (strong nuclear staining with a central halo). Co localization of SV40 and p53 was identified in cells that had characteristic nuclear features of BK virus infection by histology. The sensitivity and specificity for using p53 staining to identify BK infected cells was 92% and 86 %, respectively. In conclusion, p53 staining detects a higher percentage of BK virus infected cells than SV40 staining alone. Thus, for diagnosis of BK virus infection in renal allograft biopsies, p53 staining is a sensitive and specific method when used along with SV40 staining. PMID- 20947806 TI - Donor-specific HLA class I and CREG antibodies in complement-dependent cytotoxicity-negative renal transplants. AB - Development of a solid-phase, single antigen panel reactive antibody test (SA PRA) permits the analysis of antibody specificities. This study determined the impact of donor-specific antibodies (DSA) against class I HLA private antigens (DS-HLA) or HLA-A and -B cross-reactive group (DS-CREG) in kidney transplantation. Pre- and post-transplant sera of 133 renal allograft patients who had negative pretransplant complement-dependent cytotoxicity were tested for HLA class I antibody specificities by SA-PRA. Clinical relevance of the flow cytometric crossmatch test (FCXM) for the detection of class I DS-HLA or DS-CREG was analyzed. The sensitivity of FCXM to detect SA-PRA-defined class I DSA was 50% (5/10) and the specificity was 98.4% (121/123). Of 133 renal allograft recipients, including 26 patients with biopsy-proven acute antibody-mediated rejection (AMR), pretransplant DS-HLA or DS-CREG were detected in 10 patients. Pretransplant DSA were associated with AMR (p = 0.012) and a low calculated glomerular filtration rate (p = 0.036). In the analysis of post-transplant sera, the presence of either type of HLA antibodies and the de novo development of DSA were correlated with AMR (p <0.001). This study demonstrates that detection of DSA, including DS-HLA and DS-CREG, using the SA-PRA assay is useful to identify the renal allograft recipients with poor transplant outcome. PMID- 20947807 TI - Plasma biomarkers in the diagnosis of acute ischemic stroke. AB - Rapid diagnosis and timely treatment improves the outcome in patients with ischemic stroke, but a rapid and sensitive blood test for ischemic stroke does not exist. This study tested whether a panel of biomarkers might be useful in the diagnosis of acute ischemic stroke. Consecutive patients with suspected stroke presenting to the emergency department of a university hospital in Korea were enrolled. Plasma specimens were assayed for brain natriuretic peptide, D-dimer, matrix metalloproteinase-9, S100beta, and a proprietary composite multimarker index (MMX). There were 139 patients in this study, 89 of whom were diagnosed with acute ischemic stroke, 11 with acute cerebral hemorrhage, and 39 with other brain disorders. The MMX value was significantly higher in the patients with acute ischemic stroke in comparison to 57 healthy controls (p <0.001), but there was no significant difference between the MMX value in patients with acute ischemic stroke vs those with acute cerebral hemorrhage (p = 0.884). The discriminatory capacity of MMX was modest, with an area under the receiver operating-characteristic curve of 0.714 for acute stroke. Ischemic stroke was not diagnosed by any of the biochemical markers individually. Although the data suggest that MMX may be helpful to diagnose an acute stroke, it does not discriminate between acute ischemic stroke and acute hemorrhagic stroke. PMID- 20947808 TI - Thrombin-antithrombin III complex, proinflammatory cytokines, and fibrinolytic indices for assessing the severity of inflammation in pleural effusions. AB - This study investigated coagulation-related variables, proinflammatory cytokines, and fibrinolytic indices to assess the severity of inflammation in patients with pleural effusions. Tuberculous pleural fluids revealed significantly higher concentrations of tumor necrosis factor-alpha (TNF-alpha) and plasminogen activator inhibitor type I (PAI-1) than did malignant and pneumonic pleural fluids. Among the coagulation-related variables, thrombin-antithrombin III complex (TAT) exhibited the largest difference in mean values between pleural fluids and blood samples (125.4 +/- 45.1 vs 14.3 +/- 20.3 ng/ml, p <0.05). Inflammatory parameters were more closely associated with TAT than tissue type plasminogen activator (tPA), PAI-1, and D-dimers. TAT levels in the severe inflammation group (153.8 +/- 45.6 ng/ml) were significantly above those in the mild inflammation group (105.6 +/- 38.5 ng/ml, p <0.05); however, no significant differences were observed in PAI-1 and D-dimers levels between the two groups. In conclusion, TNF-alpha and PAI-1 are important indicators in patients with tuberculous pleural effusions, and measurement of TAT is useful for assessing the severity of inflammation in pleural fluids. PMID- 20947809 TI - Polyclonal free light chain of Ig may interfere with interpretation of monoclonal free light chain kappa/lambda ratio. AB - There is controversy about whether a sensitive assay for the serum Ig free light chain (FLC) kappa/lambda ratio can replace urine immunofixation electrophoresis (UIFE). This report describes two untreated patients in whom monoclonal FLCs were identified in urine despite normal serum FLC kappa/lambda ratios. Unlike the classical serum electrophoretic patterns in multiple myeloma, both serum samples showed adequate amounts of polyclonal Ig. The most likely explanation is a masking effect by polyclonal FLC on the serum kappa/lambda ratio when sufficient concentrations of polyclonal FLC exist. These cases illustrate this likely effect and attest to the continued importance of UIFE for initial screening of patients for Bence-Jones protein. PMID- 20947810 TI - Sulforaphane attenuates matrix metalloproteinase-9 expression following spinal cord injury in mice. AB - Inflammation plays an important role in the pathogenesis of secondary damage after spinal cord injury (SCI). The present study explored the effect of sulforaphane (SFN), a potent anti-inflammatory extract of cruciferous vegetables, on the expression of two inflammatory mediators, metalloproteinase (MMP)-9 and TNF-alpha, in a murine model of SCI. Murine spinal cord injury was induced by the application of vascular clips (force of 10 g) to the dura after a three-level T8 T10 laminectomy. The wet/dry weight ratio was used to reflect the percentage of water content of impaired spinal cord tissue at 48 hr after SCI. The mRNA levels of MMP-9 were determined using the reverse-transcriptase polymerase chain reaction (RT-PCR), and protein levels of TNF-alpha and MMP-9 were detected by enzyme-linked immunosorbent assays (ELISA) at 24 hr after SCI. Gelatin zymography was used to determine MMP-9 activity of spinal cord tissue at 24 hr after SCI. Mice treated with SFN at 1 hr after SCI had lower expression and activity of MMP 9 compared to mice with SCI. The decrease of MMP-9 in mice treated with SFN was associated with decreased levels of spinal cord water content and TNF-alpha. In summary, suforaphane decreases MMP-9 and TNF-alpha expression and vascular permeability changes following spinal cord injury in mice. PMID- 20947811 TI - Phylogenetic groups and virulence factors in pathogenic and commensal strains of Escherichia coli and their association with blaCTX-M. AB - We compared the distribution of phylogenetic groups and nine virulence factors among the pathogenic (isolated from blood and urine) and commensal (isolated from feces of healthy individuals) strains of Escherichia coli, and also compared the occurrence of virulence factors according to the production of (bla)(CTX-M) among the pathogenic strains. A total of 550 non-duplicate E. coli isolates (145 from blood, 200 from urine, 205 from feces) were collected. Phylogenetic grouping and virulence genotyping were done by PCR for all isolates. For pathogenic strains, antimicrobial susceptibility tests and PCR for (bla)(CTX-M) were performed. The distribution of phylogenetic groups was similar between isolates from blood and urine: B2 (44.8%; 58.5%, respectively) > D (29.0%; 23.0%, respectively) > A (18.6%; 9.5%, respectively) > B1 (7.6% and 9.0%, respectively). Phylogenetic groups B2 and D were also frequent (22.9% and 21.0%, respectively) among isolates from feces. The prevalence of all virulence factors except S fimbrial adhesion was significantly higher in pathogenic strains than in commensal strains and they were most frequent in phylogenetic group B2. alpha-Haemolysin, yersiniabactin receptor, serum resistance-associated outer membrane protein (traT), and aerobactin receptor (iutA) were found to be independent predictors for pathogenicity, and of them, iutA and traT were significantly more common in (bla)(CTX-M-1 group) and (bla)(CTX-M-9 group,) respectively. Considering the possibility that these virulence genes, together with antimicrobial resistance genes, can spread to other strains, further study and ongoing surveillance seem to be required. PMID- 20947812 TI - Association between survivor motor neuron 2 (SMN2) gene homozygous deletion and sporadic lower motor neuron disease in a Korean population. AB - The association between survivor motor neuron (SMN) gene deletions and motor neuron diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) suggest that sporadic lower motor neuron disease (LMND) may be related to SMN gene deletion. We examined the association between copy numbers of SMN and the risk of LMND among Koreans. We genotyped the copy number of SMN1 and SMN2 in 18 patients diagnosed with sporadic LMND and 100 neurologically healthy subjects using the multiplex ligation-dependent probe amplification (MLPA) method. A total of eight SMN1:SMN2 genotypes (1:1, 1:3, 2:0, 2:1, 2:2, 2:3, 3:2, and 2:2/3:1 of exon7/exon8) were found. We found that homozygous deletion of SMN2 was significantly related to LMND (OR 20.7; 95% CI 2.8-150.5; p = 0.003). There was no significant difference in the distribution of the SMN1 copy number between the LMND patients and controls. In contrast to ALS, the risk of which is influenced by various factors other than SMN copy number itself, the association studies in LMND show a consistent finding that homozygous deletion of SMN2 may be specifically related to LMND, despite the small number of subjects. PMID- 20947813 TI - Clinical and genetic analysis of a Korean family with hereditary spastic paraplegia type 3. AB - Hereditary spastic paraplegia (HSP) is a neurodegenerative disease characterized by progressive spasticity in the lower extremities. Mutations in the atlastin GTPase 1 (ATL1) gene cause approximately 10% of autosomal dominantly inherited HSP. For many subjects with an ATL1 mutation, spastic gait begins in early childhood and does not significantly worsen, even over many years; such cases resemble spastic diplegic cerebral palsy. Herein we report a heterozygous R239C mutation in the ATL1 gene in a Korean family. The family members exhibited early onset pure spastic paraplegia and had been previously diagnosed with the diplegic form of cerebral palsy. We suggest that spastic paraplegia type 3 (SPG3A) be included in the differential diagnosis of early onset spastic paraplegia. To the best of our knowledge, this is the first report of a genetically confirmed family affected with SPG3A in Korea. PMID- 20947814 TI - Two novel missense mutations in the TECTA gene in Korean families with autosomal dominant nonsyndromic hearing loss. AB - The TECTA gene, which encodes alpha-tectorin, is known as a causative gene for DFNA8/DFNA12, and DFNB21 hearing loss in humans. In the present study, mutation analysis of the TECTA gene was performed in 62 Korean patients with hereditary hearing loss. Two novel nucleotide substitutions, p.V317E and p.T1866M, were identified for the first time in the Korean population. These mutations result in the substitution of amino acids in the zonadhesin (ZA) and the zona pellucida (ZP) domains, and show a genotype-phenotype correlation, which is a characteristic of TECTA-related mutations in autosomal dominant nonsyndromic hearing loss. Both mutations are located in highly conserved regions of alpha tectorin and were not found in 120 unrelated control subjects with normal hearing. Based on this evidence, it is likely that both mutations are the pathogenic ones causing the hearing loss. This study provides useful information for the functional study of hereditary hearing loss caused by tectorial membrane defects. PMID- 20947815 TI - Diagnosis and treatment of tumors by physicians in antiquity. PMID- 20947817 TI - Increased serum N-terminal pro-B-type natriuretic peptide levels in patients with medial arterial calcification and poorly compressible leg arteries. AB - OBJECTIVE: To determine whether serum levels of N-terminal (NT) pro-B-type natriuretic peptide (pro-BNP) are higher in patients with poorly compressible arteries (PCA) than in patients with peripheral artery disease (PAD) and control subjects without PCA or PAD. METHODS AND RESULTS: Medial arterial calcification in the lower extremities results in PCA and may be associated with increased arterial stiffness and hemodynamic/myocardial stress. PCA was defined as having an ankle-brachial index >1.4 or an ankle blood pressure >255 mm Hg, whereas PAD was defined as having an ankle-brachial index <=0.9. Study participants with PCA (n=100; aged 71+/-10 years; 70% men) and age- and sex-matched patients with PAD (n=300) were recruited from the noninvasive vascular laboratory. Age- and sex matched controls (n=300) were identified from a community-based cohort and had no history of PAD. NT pro-BNP levels were approximately 2.5-fold higher in patients with PCA than in patients with PAD and approximately 4-fold higher than in age- and sex-matched controls. In multivariable regression analyses that adjusted for age, sex, smoking, hypertension, history of coronary heart disease/stroke, systolic blood pressure, and serum creatinine, NT pro-BNP levels remained significantly higher in patients with PCA than in patients with PAD and controls (P<0.001). CONCLUSIONS: Patients with medial arterial calcification and PCA have higher serum levels of NT pro-BNP than patients with PAD and controls, which is suggestive of an adverse hemodynamic milieu and increased risk for adverse cardiovascular outcomes. PMID- 20947818 TI - Annexin A5 therapy attenuates vascular inflammation and remodeling and improves endothelial function in mice. AB - OBJECTIVE: Annexin A5 (AnxA5) has antithrombotic, antiapoptotic, and antiinflammatory properties; we investigated its effectiveness against vascular inflammation, remodeling, and dysfunction in accelerated atherosclerosis. METHODS AND RESULTS: AnxA5 (1 mg/kg per day or vehicle) was investigated in vascular injury models in hypercholesterolemic apolipoprotein E (ApoE)3*Leiden mice. AnxA5 treatment reduced adhesion and infiltration of leukocytes by 71% to 69% (P=0.015, P=0.031) and macrophages by 51% to 87% (P=0.014, P=0.018), as well as monocyte chemotactic protein-1 and tumor necrosis factor-alpha expression in a femoral artery inflammation model (perivascular cuff for 3 days), indicating reduced vascular inflammation. In a vein graft model, 28 days of AnxA5 treatment reduced vein graft thickening (48%; P=0.006) and leukocyte infiltration (46%; P=0.003). In these mice, reduced plasma concentrations of IFN-gamma (-72%; P=0.040), granulocyte colony-stimulating factor (-41%; P=0.010), and macrophage inflammatory protein-1beta (MIP-1beta) (-66%; P=0.020) were measured, indicating reduced systemic inflammation. An in vitro endothelial cell model shows the importance of AnxA5's anticoagulant properties in reducing vascular inflammation. Endothelium-mediated dilatation in hypercholesterolemic ApoE((-/-)) mice was improved by 3 days of AnxA5 treatment, shown by improved systolic and diastolic blood pressure reductions in response to metacholine, which could be abolished by l-Nitro-Arginine-Methyl Ester (l-NAME), indicating nitric oxide involvement. CONCLUSIONS: AnxA5 reduced local vascular and systemic inflammation and vascular remodeling and improved vascular function, indicating that it has a therapeutic potential against atherosclerotic cardiovascular diseases. PMID- 20947819 TI - Differential effects of rosiglitazone and metformin on postprandial lipemia in patients with HIV-lipodystrophy. AB - OBJECTIVE: To compare the effects of rosiglitazone (8 mg/d, n=19) and metformin (2 g/d, n=18) on postprandial lipemia in patients with HIV-lipodystrophy. METHODS AND RESULTS: Lipodystrophy in HIV is associated with insulin resistance and disturbed postprandial triglyceride and free fatty acid (FFA) metabolism. We conducted an open randomized 6-month study with standardized 10-h oral fat loading tests at baseline and after treatment. Rosiglitazone (-34%) and metformin (-37%) reduced homeostasis model assessment similarly (P<0.05). Rosiglitazone did not change the area under the curve for FFA and triglyceride; however, it did reduce the area under the curve for hydroxybutyric acid (a marker of hepatic FFA oxidation) by 25% (P<0.05). Rosiglitazone increased the area under the curve for remnantlike particle cholesterol by 40% (P<0.01) compared with baseline. Metformin did not change any of the postprandial measurements. CONCLUSIONS: Rosiglitazone improved insulin sensitivity and decreased postprandial hydroxybutyric acid levels in patients with HIV-lipodystrophy, suggesting improved FFA handling. Despite metabolic improvements, rosiglitazone caused a marked increase in postprandial remnantlike particle cholesterol, which may adversely affect cardiovascular risk. Metformin did not affect postprandial lipemia and could be used to treat insulin resistance in this population. PMID- 20947820 TI - Matrix metalloproteinase activation predicts amelioration of remodeling after dietary modification in injured arteries. AB - OBJECTIVE: To establish and validate early noninvasive imaging of matrix metalloproteinase (MMP) activation for monitoring the progression of vascular remodeling and response to dietary modification. METHODS AND RESULTS: Apolipoprotein E(-/-) mice that were fed a high-fat diet underwent left common carotid artery wire injury. One week after surgery, a group of animals were withdrawn from the high-fat diet. The other group of animals continued that diet throughout the study. Micro single-photon emission computed tomographic (microSPECT)/CT imaging with RP805 (a (99m)Tc-labeled tracer targeting activated MMPs) was repeatedly performed at 2 and 4 weeks after surgery. Histological analysis at 4 weeks showed significant left carotid neointima formation, monocyte/macrophage infiltration, and upregulation of several MMPs, which were ameliorated by withdrawal from the high-fat diet. In vivo microSPECT/CT images visualized significant RP805 uptake, reflecting MMP activation, in the injured carotid arteries. MMP activation was reduced as early as 1 week after withdrawal from the high-fat diet and significantly correlated with neointimal area at 4 weeks after surgery. CONCLUSIONS: MMP activation predicts the progression of vascular remodeling and can track the effect of dietary modification after vascular injury. PMID- 20947821 TI - Differential endothelial transcriptomics identifies semaphorin 3G as a vascular class 3 semaphorin. AB - OBJECTIVE: To characterize the role of a vascular-expressed class 3 semaphorin (semaphorin 3G [Sema3G]). METHODS AND RESULTS: Semaphorins have been identified as axon guidance molecules. Yet, they have more recently also been characterized as attractive and repulsive regulators of angiogenesis. Through a transcriptomic screen, we identified Sema3G as a molecule of angiogenic endothelial cells. Sema3G-deficient mice are viable and exhibit no overt vascular phenotype. Yet, LacZ expression in the Sema3G locus revealed intense arterial vascular staining in the angiogenic vasculature, starting at E9.5, which was detectable throughout adolescence and downregulated in adult vasculature. Sema3G is expressed as a full length 100-kDa secreted molecule that is processed by furin proteases to yield 95 and a 65-kDa Sema domain-containing subunits. Full-length Sema3G binds to NP2, whereas processed Sema3G binds to NP1 and NP2. Expression profiling and cellular experiments identified autocrine effects of Sema3G on endothelial cells and paracrine effects on smooth muscle cells. CONCLUSIONS: Although the mouse knockout phenotype suggests compensatory mechanisms, the experiments identify Sema3G as a primarily endothelial cell-expressed class 3 semaphorin that controls endothelial and smooth muscle cell functions in autocrine and paracrine manners, respectively. PMID- 20947822 TI - p53 impairs endothelial function by transcriptionally repressing Kruppel-Like Factor 2. AB - OBJECTIVE: To evaluate if p53 decreases Kruppel-Like Factor 2 (KLF2) expression and determine whether p53-mediated suppression of KLF2 plays a role in p53 induced endothelial dysfunction. METHODS AND RESULTS: Endothelial KLF2 mediates endothelium-dependent vascular homeostasis by differentially regulating endothelial genes, leading to an anti-inflammatory and antithrombotic endothelial surface with normal vasodilatory function. In contrast, the tumor suppressor p53 leads to inflammatory gene expression and impairs endothelium-dependent vasodilatation, thus promoting endothelial dysfunction. The effect of p53 on KLF2 expression was determined. p53 inhibited KLF2 transcription in a histone deacetylase-dependent and a histone acetyltransferase-independent fashion. KLF2 expression was suppressed by p53 via a conserved p53-binding repressor sequence in its promoter. p53 bound to, and stimulated, deacetylation of Histone H3 at the KLF2 promoter. The effect of p53 on endothelial KLF2 target genes was examined. Downregulation of p53 increased expression of endothelial NO synthase and thrombomodulin and inhibited expression of plasminogen activator inhibitor 1. Conversely, overexpression of p53 suppressed endothelial NO synthase and thrombomodulin expression and stimulated plasminogen activator inhibitor 1 and endothelin-1 expression. Knockdown of KLF2 abolished the p53-induced decrease in thrombomodulin and increase in endothelin-1. Both, overexpression of p53 and knockdown of KLF2 in endothelial cells increased blood coagulation on an endothelial cell monolayer. The p53-induced increase in coagulation was rescued by forced expression of KLF2. p53 also impaired endothelium-dependent vasodilatation and decreased bioavailable vascular NO, both of which were rescued by forced KLF2 expression. CONCLUSIONS: These findings illustrate a novel p53 dependent mechanism for the regulation of endothelial KLF2 expression. In addition, they show that downregulation of KLF2, in part, mediates a p53 stimulated dysfunctional endothelium. PMID- 20947823 TI - Increase in GLUT1 in smooth muscle alters vascular contractility and increases inflammation in response to vascular injury. AB - OBJECTIVE: The goal of this study was to test the contributing role of increasing glucose uptake in vascular smooth muscle cells (VSMCs) in vascular complications and disease. METHODS AND RESULTS: A murine genetic model was established in which glucose trasporter 1 (GLUT1), the non-insulin-dependent glucose transporter protein, was overexpressed in smooth muscle using the sm22alpha promoter. Overexpression of GLUT1 in smooth muscle led to significant increases in glucose uptake (n=3, P<0.0001) as measured using radiolabeled 2-deoxyglucose. Fasting blood glucose, insulin, and nonesterified fatty acids were unchanged. Contractility in aortic ring segments was decreased in sm22alpha-GLUT1 mice (n=10, P<0.04). In response to vascular injury, sm22alpha-GLUT1 mice exhibited a proinflammatory phenotype, including a significant increase in the percentage of neutrophils in the lesion (n=4, P<0.04) and an increase in monocyte chemoattractant protein-1 (MCP-1) immunofluorescence. Circulating haptoglobin and glutathione/total glutathione were significantly higher in the sm22alpha-GLUT1 mice postinjury compared with controls (n=4, P<0.05), suggesting increased flux through the pentose phosphate pathway. sm22alpha-GLUT1 mice exhibited significant medial hypertrophy following injury that was associated with a significant increase in the percentage of VSMCs in the media staining positive for nuclear phosphoSMAD2/3 (n=4, P<0.003). CONCLUSIONS: In summary, these findings suggest that increased glucose uptake in VSMCs impairs vascular contractility and accelerates a proinflammatory, neutrophil-rich lesion in response to injury, as well as medial hypertrophy, which is associated with enhanced transforming growth factor-beta activity. PMID- 20947824 TI - Sphingosine-1-phosphate receptor-2 function in myeloid cells regulates vascular inflammation and atherosclerosis. AB - OBJECTIVE: Sphingomyelin deposition and metabolism occurs in the atherosclerotic plaque, leading to the formation of sphingosine-1-phosphate (S1P), which activates G protein-coupled receptors to regulate vascular and immune cells. The role of S1P receptors in atherosclerosis has not been examined. METHODS AND RESULTS: We tested the hypothesis that S1P receptor-2 (S1PR2) regulates atherosclerosis. Apoe(-/-) S1pr2(-/-) mice showed greatly attenuated atherosclerosis compared with the Apoe(-/-) mice. Bone marrow transplant experiments indicate that S1PR2 function in the hematopoietic compartment is critical. S1PR2 is expressed in bone marrow-derived macrophages and in macrophage like foam cells in atherosclerotic plaques. Reduced macrophage-like foam cells were found in the atherosclerotic plaques of Apoe(-/-)S1pr2(-/-) mice, suggesting that S1PR2 retains macrophages in atherosclerotic plaques. Lipoprotein profiles, plasma lipids, and oxidized low-density lipoprotein uptake by bone marrow-derived macrophages were not altered by the S1pr2 genotype. In contrast, endotoxin induced inflammatory cytokine (interleukin [IL]-1beta, IL-18) levels in the serum of S1PR2 knockout mice were significantly reduced. Furthermore, treatment of wild type mice with S1PR2 antagonist JTE-013 suppressed IL-1beta and IL-18 levels in plasma. CONCLUSIONS: These data suggest that S1PR2 signaling in the plaque macrophage regulates macrophage retention and inflammatory cytokine secretion, thereby promoting atherosclerosis. PMID- 20947825 TI - Increased 12/15-lipoxygenase enhances cell growth, fibronectin deposition, and neointimal formation in response to carotid injury. AB - OBJECTIVE: To determine whether increased 12/15-lipoxygenase (12/15LO) expression in vivo enhances neointimal formation in response to injury. METHODS AND RESULTS: 12/15LO expression in the vessel wall is increased in animal models of metabolic syndrome and diabetes mellitus. Increased expression of 12/15LO enhances cultured vascular smooth muscle cell (VSMC) proliferation, an effect mediated by the helix loop-helix factor inhibitor of differentiation 3 (Id3). Carotid endothelial denudation was performed on apolipoprotein (Apo) E(-/-), ApoE(-/-)/12/15LO(-/-), C57BL/6, and 12/15LO-overexpressing transgenic mice. ApoE(-/-)/12/15LO(-/-) mice had attenuated and 12/15LO-overexpressing transgenic mice had enhanced neointimal formation compared with control mice. 12/15LO-overexpressing transgenic mice had greater postinjury carotid Id3 and Ki-67 expression, cell number, and fibronectin deposition compared with C57BL/6 mice. Loss of 12/15LO attenuated proliferation of cultured ApoE(-/-) VSMCs, whereas 12/15LO overexpression induced VSMC proliferation. Loss of Id3 enhanced immunoglobulin trascription factor (ITF)-2b binding to and activation of the p21(cip1) promoter and abrogated 12/15LO-induced VSMC proliferation. CONCLUSIONS: To our knowledge, these data are the first demonstration that increased expression of 12/15LO in the vessel wall enhances Id3-dependent cell proliferation, fibronectin deposition, and neointimal formation in response to injury. Results identify p21(cip1) as a potential target of the 12/15LO-Id3 pathway and suggest that modulation of this pathway may have therapeutic implications for targeting the increased risk of restenosis in patients with diabetes. PMID- 20947826 TI - NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection. AB - OBJECTIVE: To test the hypothesis that NF-E2-related factor 2 (Nrf2) expression plays an antiatherogenic role by its vascular antioxidant and anti-inflammatory properties. METHODS AND RESULTS: Nrf2 is an important transcription factor that regulates the expression of phase 2 detoxifying enzymes and antioxidant genes. Its expression in vascular cells appears to be an important factor in the protection against vascular oxidative stress and inflammation. We developed Nrf2 heterozygous (HET) and homozygous knockout (KO) mice on an apolipoprotein (apo) E null background by sequential breeding, resulting in Nrf2(-/-), apoE(-/-) (KO), Nrf2(-/+), apoE(-/-) (HET) and Nrf2(+/+), and apoE(-/-) wild-type littermates. KO mice exhibited decreased levels of antioxidant genes with evidence of increased reactive oxygen species generation compared with wild-type controls. Surprisingly, KO males exhibited 47% and 53% reductions in the degree of aortic atherosclerosis compared with HET or wild-type littermates, respectively. Decreased atherosclerosis in KO mice correlated with lower plasma total cholesterol in a sex-dependent manner. KO mice also had a decreased hepatic cholesterol content and a lower expression of lipogenic genes, suggesting that hepatic lipogenesis could be reduced. In addition, KO mice exhibited atherosclerotic plaques characterized by a lesser macrophage component and decreased foam cell formation in an in vitro lipid-loading assay. This was associated with a lower rate of cholesterol influx, mediated in part by decreased expression of the scavenger receptor CD36. CONCLUSIONS: Nrf2 expression unexpectedly promotes atherosclerotic lesion formation in a sex-dependent manner, most likely by a combination of systemic metabolic and local vascular effects. PMID- 20947827 TI - Activation of NAD(P)H oxidases by thromboxane A2 receptor uncouples endothelial nitric oxide synthase. AB - OBJECTIVE: The thromboxane receptor (TPr) and multiple TPr ligands, including thromboxane A(2) (TxA(2)) and prostaglandin H(2), are elevated during vascular and atherothrombotic diseases. How TPr stimulation causes vascular injury remains poorly defined. This study was conducted to investigate the mechanism by which TPr stimulation leads to vascular injury. METHODS AND RESULTS: Exposure of bovine aortic endothelial cells to either [1S-(1alpha,2beta(5Z),3alpha(1E,3R),4alpha]-7 [3-(3-hydroxy-4-(d'-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1] heptan-2-yl]-5' heptenoic acid (IBOP) or U46619, 2 structurally related TxA(2) mimetics, for 24 hours markedly increased the release of superoxide anions (O(2)(.-)) and peroxynitrite (ONOO(-)) but reduced cyclic GMP, an index of nitric oxide bioactivity. IBOP also significantly suppressed activity of endothelial nitric oxide synthase (eNOS), increased enzyme-inactive eNOS monomers, and reduced levels of tetrahydrobiopterin, an essential eNOS cofactor. IBOP- and U46619 induced increases in O(2)(.-) were accompanied by the membrane translocation of the p67(phox) subunit of NAD(P)H oxidase. Pharmacological or genetic inhibition of either NAD(P)H oxidase or TPr abolished IBOP-induced O(2)(.-) formation. Furthermore, TPr activation significantly increased protein kinase C-zeta (PKC zeta) in membrane fractions and PKC-zeta phosphorylation at Thr410. Consistently, PKC-zeta inhibition abolished TPr activation-induced membrane translocation of p67(phox) and O(2)(.-) production. Finally, exposure of isolated mouse aortae to IBOP markedly increased O(2)(.-) in wild-type but not in those from gp91(phox) knockout mice. CONCLUSIONS: We conclude that TPr activation via PKC-zeta-mediated NAD(P)H oxidase activation increases both O(2)(.-) and ONOO(-), resulting in eNOS uncoupling in endothelial cells. PMID- 20947828 TI - A major role for HERG in determining frequency of reentry in neonatal rat ventricular myocyte monolayer. AB - RATIONALE: the rapid delayed rectifier potassium current, I(Kr), which flows through the human ether-a-go-go-related (hERG) channel, is a major determinant of the shape and duration of the human cardiac action potential (APD). However, it is unknown whether the time dependency of I(Kr) enables it to control APD, conduction velocity (CV), and wavelength (WL) at the exceedingly high activation frequencies that are relevant to cardiac reentry and fibrillation. OBJECTIVE: to test the hypothesis that upregulation of hERG increases functional reentry frequency and contributes to its stability. METHODS AND RESULTS: using optical mapping, we investigated the effects of I(Kr) upregulation on reentry frequency, APD, CV, and WL in neonatal rat ventricular myocyte (NRVM) monolayers infected with GFP (control), hERG (I(Kr)), or dominant negative mutant hERG G628S. Reentry frequency was higher in the I(Kr)-infected monolayers (21.12 +/- 0.8 Hz; n=43 versus 9.21 +/- 0.58 Hz; n=16; P<0.001) but slightly reduced in G628S-infected monolayers. APD(80) in the I(Kr)-infected monolayers was shorter (>50%) than control during pacing at 1 to 5 Hz. CV was similar in both groups at low frequency pacing. In contrast, during high-frequency reentry, the CV measured at varying distances from the center of rotation was significantly faster in I(Kr) infected monolayers than controls. Simulations using a modified NRVM model predicted that rotor acceleration was attributable, in part, to a transient hyperpolarization immediately following the AP. The transient hyperpolarization was confirmed experimentally. CONCLUSIONS: hERG overexpression dramatically accelerates reentry frequency in NRVM monolayers. Both APD and WL shortening, together with transient hyperpolarization, underlies the increased rotor frequency and stability. PMID- 20947829 TI - MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling. AB - RATIONALE: Establishment of a functional vasculature requires the interconnection and remodeling of nascent blood vessels. Precise regulation of factors that influence endothelial cell migration and function is essential for these stereotypical vascular patterning events. The secreted Slit ligands and their Robo receptors constitute a critical signaling pathway controlling the directed migration of both neurons and vascular endothelial cells during embryonic development, but the mechanisms of their regulation are incompletely understood. OBJECTIVE: To identify microRNAs regulating aspects of the Slit-Robo pathway and vascular patterning. METHODS AND RESULTS: Here, we provide evidence that microRNA (miR)-218, which is encoded by an intron of the Slit genes, inhibits the expression of Robo1 and Robo2 and multiple components of the heparan sulfate biosynthetic pathway. Using in vitro and in vivo approaches, we demonstrate that miR-218 directly represses the expression of Robo1, Robo2, and glucuronyl C5 epimerase (GLCE), and that an intact miR-218-Slit-Robo regulatory network is essential for normal vascularization of the retina. Knockdown of miR-218 results in aberrant regulation of this signaling axis, abnormal endothelial cell migration, and reduced complexity of the retinal vasculature. CONCLUSIONS: Our findings link Slit gene expression to the posttranscriptional regulation of Robo receptors and heparan sulfate biosynthetic enzymes, allowing for precise control over vascular guidance cues influencing the organization of blood vessels during development. PMID- 20947831 TI - The critical role of neutral cholesterol ester hydrolase 1 in cholesterol removal from human macrophages. AB - RATIONALE: Hydrolysis of intracellular cholesterol ester (CE) is the key step in the reverse cholesterol transport in macrophage foam cells. We have recently shown that neutral cholesterol ester hydrolase (Nceh)1 and hormone-sensitive lipase (Lipe) are key regulators of this process in mouse macrophages. However, it remains unknown which enzyme is critical in human macrophages and atherosclerosis. OBJECTIVE: We aimed to identify the enzyme responsible for the CE hydrolysis in human macrophages and to determine its expression in human atherosclerosis. METHODS AND RESULTS: We compared the expression of NCEH1, LIPE, and cholesterol ester hydrolase (CES1) in human monocyte-derived macrophages (HMMs) and examined the effects of inhibition or overexpression of each enzyme in the cholesterol trafficking. The pattern of expression of NCEH1 was similar to that of neutral CE hydrolase activity during the differentiation of HMMs. Overexpression of human NCEH1 increased the hydrolysis of CE, thereby stimulating cholesterol mobilization from THP-1 macrophages. Knockdown of NCEH1 specifically reduced the neutral CE hydrolase activity. Pharmacological inhibition of NCEH1 also increased the cellular CE in HMMs. In contrast, LIPE was barely detectable in HMMs, and its inhibition did not decrease neutral CE hydrolase activity. Neither overexpression nor knockdown of CES1 affected the neutral CE hydrolase activity. NCEH1 was expressed in CD68-positive macrophage foam cells of human atherosclerotic lesions. CONCLUSIONS: NCEH1 is expressed in human atheromatous lesions, where it plays a critical role in the hydrolysis of CE in human macrophage foam cells, thereby contributing to the initial part of reverse cholesterol transport in human atherosclerosis. PMID- 20947830 TI - Deacetylation of FoxO by Sirt1 Plays an Essential Role in Mediating Starvation Induced Autophagy in Cardiac Myocytes. AB - RATIONALE: autophagy, a bulk degradation process of cytosolic proteins and organelles, is protective during nutrient starvation in cardiomyocytes (CMs). However, the underlying signaling mechanism mediating autophagy is not well understood. OBJECTIVE: we investigated the role of FoxOs and its posttranslational modification in mediating starvation-induced autophagy. METHODS AND RESULTS: glucose deprivation (GD) increased autophagic flux in cultured CMs, as evidenced by increased mRFP-GFP-LC3 puncta and decreases in p62, which was accompanied by upregulation of Sirt1 and FoxO1. Overexpression of either Sirt1 or FoxO1 was sufficient for inducing autophagic flux, whereas both Sirt1 and FoxO1 were required for GD-induced autophagy. GD increased deacetylation of FoxO1, and Sirt1 was required for GD-induced deacetylation of FoxO1. Overexpression of FoxO1(3A/LXXAA), which cannot interact with Sirt1, or p300, a histone acetylase, increased acetylation of FoxO1 and inhibited GD-induced autophagy. FoxO1 increased expression of Rab7, a small GTP-binding protein that mediates late autophagosome-lysosome fusion, which was both necessary and sufficient for mediating FoxO1-induced increases in autophagic flux. Although cardiac function was maintained in control mice after 48 hours of food starvation, it was significantly deteriorated in mice with cardiac-specific overexpression of FoxO1(3A/LXXAA), those with cardiac-specific homozygous deletion of FoxO1 (c FoxO1(-/-)), and beclin1(+/-) mice, in which autophagy is significantly inhibited. CONCLUSIONS: these results suggest that Sirt1-mediated deacetylation of FoxO1 and upregulation of Rab7 play an important role in mediating starvation induced increases in autophagic flux, which in turn plays an essential role in maintaining left ventricular function during starvation. PMID- 20947833 TI - Every day is a world stroke day: act now, be a stroke champion and a torchbearer! PMID- 20947832 TI - Clonal analysis reveals a common progenitor for endothelial, myeloid, and lymphoid precursors in umbilical cord blood. AB - RATIONALE: several studies demonstrate that hematopoietic tissues are a source of endothelial progenitor cells, which contribute to newly formed blood vessels during tissue repair in adults. However, it is not clear which cell type in these hematopoietic tissues gives rise to endothelial progenitor cells. OBJECTIVE: to identity the origin of endothelial progenitors within the hematopoietic hierarchy and to assess their in vivo revascularization potential. METHODS AND RESULTS: using a single-cell sorting approach and in vitro multilineage differentiation assays, here we show that individual CD34(+)CD45(+)CD133(+)CD38(+) cells from cord blood uniquely have the ability to differentiate into T- and B-lymphoid, myeloid, and endothelial cells. The latter were characterized by the expression of VE-cadherin, KDR, von Willebrand factor, endothelial nitric oxide synthase, the lack of CD45, CD133, and c-fms (colony stimulating factor-1 receptor). Unexpectedly when transplanted into hindlimb ischemic NOD-scid IL2Rgamma(null) mice, freshly isolated CD34(+)CD45(+)CD133(+)CD38(+) cells maintained their hematopoietic identity and were rarely found to integrate into host blood vessels. Nevertheless, they significantly improved perfusion, most likely through a paracrine mechanism. On the other hand, CD34(+)CD45(+)CD133(+)CD38(+) cells differentiated in vitro into endothelial cells were able to form vessels in vivo in both Matrigel plug and hindlimb ischemia transplantation assays. CONCLUSIONS: these findings indicate that the CD34(+)CD45(+)CD133(+)CD38(+) cell fraction contains a common progenitor for the hematopoietic and vascular lineages and may represent a valuable cell source for therapeutic applications. PMID- 20947834 TI - How does self-reported history of stroke compare to hospitalization data in a population-based survey in New Zealand? AB - BACKGROUND AND PURPOSE: There is mixed evidence concerning the validity of self reported history of stroke in population-based studies. We aimed to examine the validity of self-reported stroke using hospitalization with a primary diagnosis of stroke as the reference group. METHODS: Self-reported history of stroke was taken from the Survey of Families, Income, and Employment (N=18 950; 2004-2005) and defined as a respondent answering yes to the question, "Have you ever been told by a doctor that you have had a stroke?". Survey of Families, Income, and Employment respondents consented to link their data to the New Zealand Health Information Service records of publically funded hospitalizations between 1990 and 2006. We calculated positive predictive value, sensitivity, and specificity of self-reported stroke against hospitalization for stroke. RESULTS: Approximately 2% of the adult Survey of Families, Income, and Employment population reported they had been told by a doctor that they had a stroke. Only 1% had evidence of hospitalization for stroke since 1990. The sensitivity of self reported stroke was 73% and specificity was 98%. However, the positive predictive value, people who reported having a stroke with confirmation of hospitalization for stroke, was low at 29%. CONCLUSIONS: The use of self-reported stroke will most likely overestimate the prevalence of stroke. A combination of methods is required to determine prevalence in population-based studies. PMID- 20947835 TI - Utility of dysphagia screening results in predicting poststroke pneumonia. AB - BACKGROUND AND PURPOSE: Dysphagia screening before oral intake (DS) is a stroke care quality indicator. The value of DS is unproven. Quality adherence and outcome data from the Paul Coverdell National Acute Stroke Registry were examined to establish value of DS. METHODS: Adherence to the DS quality indicator was examined in patients with stroke discharged from Paul Coverdell National Acute Stroke Registry hospitals between March 1 and December 31, 2009. Patients were classified as unscreened (US), screened and passed (S/P), and screened and failed. Associations between screening status and pneumonia rate were assessed by logistic regression models after adjustment for selected variables. RESULTS: A total of 18 017 patients with stroke discharged from 222 hospitals in 6 states were included. A total of 4509 (25%) were US; 8406 (47%) were S/P, and 5099 (28%) were screened and failed. Compared with US patients, screened patients were significantly more impaired. Pneumonia rates were: US 4.2%, S/P 2.0%, and screened and failed 6.8%. After adjustment for demographic and clinical features, US patients were at a higher risk of pneumonia (OR, 2.2; 95% CI, 1.7 to 2.7) compared with S/P patients. CONCLUSIONS: Data suggest that patients are selectively screened based on stroke severity. Pneumonia rate was higher in US patients compared with S/P patients. Clinical judgment regarding who should be screened is imperfect. S/P patients have a lower pneumonia rate indicating that DS adds accuracy in predicting pneumonia risk. The Joint Commission recently retired DS as a performance indicator for Primary Stroke Center certification. These results suggest the need to implement a DS performance measure for patients with acute stroke. PMID- 20947836 TI - Reflux esophagitis and stroke: which is the cause? PMID- 20947837 TI - Triggers of ischemic stroke: a systematic review. AB - BACKGROUND AND PURPOSE: Several studies have suggested that exposure to "triggers," could precipitate the onset of ischemic stroke (IS). We performed a systematic review of the potential triggers of IS. METHODS: Two independent reviewers identified studies published between January 1980 and June 2010 from MEDLINE and Embase. Where appropriate, odds ratios (ORs) were combined. RESULTS: A total of 26 studies identified 12 potential triggers. Twenty-two studies used a case-control design, and hazard period durations ranged from 2 hours to 3 months. The majority of studies were dedicated to alcohol abuse (n = 10) and clinical infection (n = 12). There was a significant association between IS and alcohol abuse of > 40 to 60 g within the preceding 24 hours (OR = 2.66; 95% CI, 1.54 to 4.61) or > 150 g within the previous week (OR = 2.47; 95% CI, 1.52 to 4.02) and infection within the previous week (OR = 2.91; 95% CI, 1.41 to 6.00) or within the previous month (OR = 2.41; 95% CI, 1.78 to 3.27). Other triggers have been far less investigated. There was a significant association between IS and anger, heavy eating, negative or positive emotions, sudden posture change in response to a startling event, birthday, and psychological distress and no significant association with drug abuse or heavy physical exertion. Regarding methodological issues, patients were rarely blinded to study objectives, and interviewers were rarely blinded to patient status. CONCLUSIONS: Research on triggers of IS has been mainly focused on acute alcohol abuse and clinical infection. More research is needed on factors such as physical exertion or acute stress. Future studies should use more appropriate designs and examine different hazard periods. PMID- 20947838 TI - Incidence and case-fatality of stroke on the East border of the European union: The Grodno Stroke Study. AB - BACKGROUND AND PURPOSE: The epidemiology of stroke in Belarus is unclear. Therefore, a population-based register of stroke was set up in western Belarus to determine incidence and case-fatality in a defined urban population. METHODS: The Grodno Stroke Study is a prospective community-based research among 311 134 residents of the city of Grodno, Belarus. Standard definitions and multiple overlapping sources of ascertainment were used to identify all cases of first ever-in-a-lifetime strokes in all age groups occurring between January 1, 2001, and December 31, 2003. RESULTS: During 3 years, 2069 cases of first-ever-in-a lifetime strokes were registered. Mean age at stroke onset was 65.8 +/- 11.6 years; rate of hospitalization was 89.7%. The crude annual incidence rate of first-ever-in-a-lifetime strokes for the study period was 222 per 100,000 (95% CI, 212 to 233). Incidence adjusted to the European standard population and to the World Health Organization world standard population was 287 per 100,000 (95% CI, 274 to 301) and 220 per 100,000 (95% CI, 210 to 231), respectively. The 28 day case-fatality rate was 26.1%. The prevalence of hypertension among all first ever-in-a-lifetime stroke patients was 87.5%; 529 (25.6%) were current smokers. A total 23.1% of patients had atrial fibrillation, 19.1% had past myocardial infarction, 14.7% had diabetes mellitus, and 22.1% had hypercholesterolemia. CONCLUSIONS: High incidence and case-fatality rates determine the considerable burden of stroke in Belarus and might at least partly be related to the high prevalence of risk factors among the population. PMID- 20947839 TI - Drinking water and risk of stroke: the hidden element. PMID- 20947840 TI - Early protective effect of bone marrow mononuclear cells against ischemic white matter damage through augmentation of cerebral blood flow. AB - BACKGROUND AND PURPOSE: To investigate the efficacy of bone marrow mononuclear cell (BMMNC) treatment against ischemic white matter (WM) damage in a hypoperfused brain. METHODS: Mice were administered intravenous treatment of vehicle, spleen-derived marrow mononuclear cells (MNCs), or BMMNCs (5 * 106 cells) obtained from enhanced green fluorescent protein transgenic mice 24 hours after bilateral common carotid artery stenosis (BCAS), and then euthanized at either 1 day or 30 days after treatment. RESULTS: Laser speckle perfusion imaging analyses revealed marked recovery of cerebral blood flow (CBF) in the early phase after BMMNC treatment (6 hours after administration), before histological evidence of angiogenesis was assessed by fluorescein-isothiocyanate-dextran perfusion assay. BMMNC treatment induced an increase in vascular endothelial growth factor and Ser1177 phosphorylated endothelial nitric oxide synthase levels in the BCAS-induced mouse brains at 1 day after the treatment. BCAS-induced ischemic WM lesions were significantly improved 30 days after BMMNC treatment despite any evidence of direct structural incorporation of donor BMMNCs into endothelial cells and oligodendrocytes. Instead, enhanced green fluorescent protein-positive donor cells with morphological features of pericytes were observed in the vessel walls. Post-BMMNC administration of an NOS inhibitor abolished early CBF recovery and produced protective effects against ischemic WM damage. CONCLUSIONS: BMMNC treatment provides marked protection against ischemic WM damage, enhancing CBF in the early phase and in subsequent angiogenesis, both of which involve nitric oxide synthase activation. These findings suggest promise for the application of BMMNCs for subcortical ischemic vascular dementia. PMID- 20947841 TI - Exertion fatigue and chronic fatigue are two distinct constructs in people post stroke. AB - BACKGROUND AND PURPOSE: Post-stroke fatigue is a common and neglected issue despite the fact that it impacts daily functions, quality of life, and has been linked with a higher mortality rate because of its association with a sedentary lifestyle. The purpose of this study was to identify the contributing factors of exertion fatigue and chronic fatigue in people post-stroke. METHODS: Twenty-one post-stroke people (12 males, 9 females; 59.5 +/- 10.3 years of age; time after stroke 4.1 +/- 3.5 years) participated in the study. The response variables included exertion fatigue and chronic fatigue. Participants underwent a standardized fatigue-inducing exercise on a recumbent stepper. Exertion fatigue level was assessed at rest and immediately after exercise using the Visual Analog Fatigue Scale. Chronic fatigue was measured by the Fatigue Severity Scale. The explanatory variables included aerobic fitness, motor control, and depressive symptoms measured by peak oxygen uptake, Fugl-Meyer motor score, and the Geriatric Depression Scale, respectively. RESULTS: Using forward stepwise regression, we found that peak oxygen uptake was an independent predictor of exertion fatigue (P = 0.006), whereas depression was an independent predictor of chronic fatigue (P = 0.002). CONCLUSIONS: Exertion fatigue and chronic fatigue are 2 distinct fatigue constructs, as identified by 2 different contributing factors. PMID- 20947842 TI - The significance of blood pressure variability for the development of hemorrhagic transformation in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Elevated blood pressure (BP) is commonly observed in acute ischemic stroke and is known to be associated with hemorrhagic transformation (HT). However, the effect of BP variability on the development of HT is not known well. METHODS: A consecutive series of patients with acute ischemic stroke, who were hospitalized within 24 hours of onset and showed no HT on initial gradient echo MRI, were enrolled in this study. BP measurements during the first 72 hours were obtained, and BP variability of each patient was described using various summary parameters: SD, maximum (max), minimum (min), difference between max and min (max-min), average squared difference between successive measurements (sv), and maximum sv (svmax). RESULTS: Of 792 patients meeting the eligibility criteria, 70 (8.8%) developed HT. Among BP variability parameters categorized into quartiles, SBP(max), SBP(min), SBP(max-min), SBP(svmax), DBP(SD), DBP(max), DBP(min), DBP(max-min), and DBP(svmax) were significantly associated with HT independent of mean SBP, age, interval from onset to arrival, initial stroke severity, diabetes mellitus, stroke subtype, thrombolysis, initial glucose, and total cholesterol (P<0.05 on likelihood ratio test of trend). The analyses about the interaction between thrombolysis and variability parameters showed that the effects of BP variability on the development of HT did not differ by whether patients received thrombolysis or not. CONCLUSIONS: Our study suggests that we may consider not only the absolute level of BP but also its variability to prevent hemorrhagic transformation. PMID- 20947844 TI - Testing for inherited thrombophilias in arterial stroke: can it cause more harm than good? AB - BACKGROUND AND PURPOSE: Despite a paucity of evidence supporting a true association of ischemic stroke and the inherited thrombophilias, it is common practice for many neurologists to order these tests as part of the work-up of ischemic stroke, especially in young patients. Treatment with oral anticoagulation is often used in patients with positive results for the inherited thrombophilias. METHODS: We reviewed the literature focusing on case-control studies of the 5 most commonly inherited disorders of coagulation: protein C deficiency, protein S deficiency, antithrombin deficiency, and the factor V Leiden and prothrombin gene mutations in patients with stroke. We also analyzed the available data on stroke patients with inherited thrombophilia and patent foramen ovale. RESULTS: Multiple case-control studies have not convincingly shown an association of the inherited thrombophilias with ischemic stroke, even in young patients and patients with patent foramen ovale. CONCLUSIONS: If there is an association between the inherited thrombophilias and arterial stroke, then it is a weak one, likely enhanced by other prothrombotic risk factors. The consequences of ordering these tests and attributing causality to an arterial event can result in significant costs to the health care system and pose a potential risk to patients, because this may lead to inappropriate use of long term oral anticoagulants, exposing patients to harm without a clearly defined benefit. PMID- 20947843 TI - White matter hyperintensity burden and susceptibility to cerebral ischemia. AB - BACKGROUND AND PURPOSE: White matter hyperintensity (WMH) burden increases risk of ischemic stroke; furthermore, it predicts infarct growth in acute cerebral ischemia. We hypothesized that WMH would be less severe in patients with TIA as compared to those with acute ischemic stroke and completed infarct. METHODS: Cases (TIA, n = 30) and controls (acute ischemic stroke, n = 120) were selected from an ongoing longitudinal cohort study of patients with stroke and matched for age, gender, and race/ethnicity. All subjects had brain MRI within 48 hours of presentation to evaluate for evidence of acute cerebral ischemia. WMH burden on MRI was quantified using a validated computer-assisted program with high inter rater reliability. RESULTS: Median WMH volume in individuals with TIA was 3.7 cm3 (interquartile range, 1.5 - 8.33 cm3) compared to 6.9 cm3 (interquartile range, 3.1-11.9 cm3) in acute ischemic stroke (P < 0.04). In multivariable analysis, the odds of completed infarct were higher (OR, 2.19; 95% CI, 1.27-3.77; P < 0.005) in subjects with larger volumes of WMH. CONCLUSIONS: WMH burden was significantly less in subjects with TIA as opposed to those with ischemic stroke. These data provide further evidence to support a detrimental role of WMH burden on the capacity of cerebral tissue to survive acute ischemia. PMID- 20947845 TI - Acute basilar artery occlusion in the Basilar Artery International Cooperation Study: does gender matter? AB - BACKGROUND AND PURPOSE: Randomized trials suggested a different benefit of intravenous thrombolysis (IVT) and intra-arterial thrombolysis (IAT) between men and women with anterior circulation stroke because of a worse outcome of women in the control group. METHODS: We compared outcome and recanalization in men and women with basilar artery occlusion treated with antithrombotic treatment alone, IVT or combined IVT-IAT, or IAT in the Basilar Artery International Cooperation Study. RESULTS: Overall, 389 male and 226 female patients were analyzed. In the antithrombotic treatment group, 68 of 111 (61%) men and 47 of 70 (67%) women had a poor outcome defined as a modified Rankin Scale score of 4 to 6 (adjusted risk ratio [aRR], 0.96; 95% CI, 0.75 to 1.24), in the IVT/combined IVT-IAT group, 47 of 77 (61%) men and 24 of 43 (56%) women (aRR, 1.19; 95% CI, 0.89 to 1.60), and in the IAT group, 142 of 185 (77%) men and 71 of 102 (70%) women (aRR, 1.01; 95% CI, 0.88 to 1.17). Mortality was not different between men and women in the antithrombotic treatment group (aRR, 0.80; 95% CI, 0.55 to 1.16), the IVT/combined IVT-IAT group (aRR, 1.11; 95% CI, 0.72 to 1.73), or in the IAT group (aRR, 1.01; 95% CI, 0.75 to 1.36). Insufficient recanalization after combined IVT IAT or IAT was similar in men and women (23% versus 22%; aRR, 0.92; 95% CI, 0.58 to 1.46). CONCLUSIONS: In patients with acute basilar artery occlusion, no significant gender differences for outcome and recanalization were observed, regardless of treatment modality. PMID- 20947846 TI - Anamnestic recall of stroke-related deficits: an animal model. AB - BACKGROUND AND PURPOSE: Anamnestic recall of stroke-related deficits is a common clinical observation, especially during periods of systemic infection. The pathophysiology of this transient re-emergence of neurological dysfunction is unknown. METHODS: Male Lewis rats underwent 3 hours middle cerebral artery occlusion and were treated with lipopolysaccharide or saline at the time of reperfusion. The delayed-type hypersensitivity (DTH) response to myelin basic protein was examined 28 days after middle cerebral artery occlusion. Changes in behavioral outcomes were assessed after DTH testing and repeat administration of lipopolysaccharide or saline at 34 days. At the time of euthanasia (36 days), the immunologic response of splenocytes to myelin basic protein, neuron-specific enolase, and proteolipid protein was determined by enzyme-linked immunospot assay and the number of lymphocytes in the brain determined by immunocytochemistry. RESULTS: Animals treated with lipopolysaccharide at middle cerebral artery occlusion had a greater DTH response to myelin basic protein than animals treated with saline. Among those animals that had fully recovered on a given behavioral test before DTH testing, those treated with lipopolysaccharide at middle cerebral artery occlusion displayed more neurological deterioration after DTH testing and had more CD8(+) lymphocytes within the ischemic core of the brain. Furthermore, the Th1 immune response to brain antigens in the spleen was more robust among those animals that deteriorated after DTH testing and there were more CD4(+) lymphocytes in the penumbral region of animals with a Th1 response to myelin basic protein. CONCLUSIONS: Our data suggest that an immune response to the brain contributes to the phenomenon of anamnestic recall of stroke-related deficits after an infection. The contribution of the immune response to this phenomenon deserves further investigation. PMID- 20947847 TI - Autoantibodies against oxidized low-density lipoprotein in cerebral small vessel disease. AB - BACKGROUND AND PURPOSE: Oxidized low-density lipoprotein (oxLDL) induces endothelial dysfunction and antibody formation. Because endothelial dysfunction is involved in cerebral small vessel disease (CSVD) (dilated Virchow Robin spaces, lacunar infarcts, and white matter lesions), oxLDL antibodies could play a role in CSVD pathogenesis. Therefore, we studied oxLDL antibodies in patients with high prevalence of CSVD: lacunar stroke patients and essential hypertensive patients. METHODS: A total of 158 lacunar stroke patients, 158 hypertensive patients, and 43 healthy controls were included. We determined levels of IgG and IgM against hypochlorite (HOCl) and malondialdehyde (MDA) oxLDL using ELISA (values in optical density). RESULTS: Patients with CSVD had higher levels of IgG HOCl-oxLDL (0.77 versus 0.70; P<0.01), as well as lower levels of IgM-MDA-oxLDL (0.55 versus 0.65; P<0.05) than patients without such lesions. Higher IgG-HOCl oxLDL levels were only independently associated with higher numbers of Virchow Robin spaces at the level of the basal ganglia (beta=0.218; P<0.001). CONCLUSIONS: An autoinflammatory process with lower levels of IgM antibodies and higher levels of IgG antibodies against oxLDL may be involved in CSVD. PMID- 20947848 TI - Stent-assisted mechanical recanalization for treatment of acute intracerebral artery occlusions. AB - BACKGROUND AND PURPOSE: The purpose of this study was to demonstrate a new approach to the use of a self-expanding stent in the treatment of acute ischemic stroke. METHODS: Twenty-two consecutive patients with acute intracerebral artery occlusions were treated with a self-expandable intracranial stent, which was withdrawn in its unfolded state. For this technique, we used the Solitaire AB/FR, which is the only intracranial stent that is fully recoverable. Eight patients had an occlusion of the basilar artery, 12 had a middle cerebral artery occlusion, and 2 had terminal carotid artery occlusions; 6 of these had to be treated first for an acute occlusion originating in the internal carotid artery. Recanalization results were assessed by follow-up angiography immediately after the procedure. Neurologic status was evaluated before and after treatment (90-day follow-up) according to the National Institutes of Health Stroke Scale and modified Rankin scale. RESULTS: Successful revascularization was achieved in 20 of 22 (90.9%) patients (thrombolysis in cerebral infarction [TICI] 2a/b and 3), a TICI 3 state was accomplished in 12 patients, and partial recanalization or slow distal branch filling with filling of more than two-thirds of the vessel territory was achieved in 8 patients (TICI 2b). There was immediate flow restoration in 21 of 22 (95.4%) cases after deployment of the device. The stent was removed in its unfolded state in all patients. The mean time from stroke symptom onset to recanalization was 277 minutes, with a standard deviation of 118 minutes. Mean National Institutes of Health Stroke Scale score on admission was 19.4, with a standard deviation of 5.7. Almost two-thirds of the patients (63.6%) improved by > 10 points on the National Institutes of Health Stroke Scale at discharge, and 50% showed a modified Rankin scale score of <= 2 at 90 days (59% with a modified Rankin scale <= 3). Mortality was 18.1%. In 1 case, an asymptomatic intracranial hemorrhage was detected on control computed tomography, and 2 patients had a symptomatic intracranial hemorrhage. CONCLUSIONS: Withdrawal of an unfolded, fully recoverable, intracranial stent yielded very promising angiographic and clinical results. It combines the advantages of prompt flow restoration and mechanical thrombectomy. PMID- 20947849 TI - MRI profile of the perihematomal region in acute intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: The pathophysiology of the presumed perihematomal edema immediately surrounding an acute intracerebral hemorrhage is poorly understood, and its composition may influence clinical outcome. Method-Twenty-three patients from the Diagnostic Accuracy of MRI in Spontaneous intracerebral Hemorrhage (DASH) study were prospectively enrolled and studied with MRI. Perfusion-weighted imaging, diffusion-weighted imaging, and fluid-attenuated inversion recovery sequences were coregistered. TMax (the time when the residue function reaches its maximum) and apparent diffusion coefficient values in the presumed perihematomal edema regions of interest were compared with contralateral mirror and remote ipsilateral hemispheric regions of interest. RESULTS: Compared with mirror and ipsilateral hemispheric regions of interest, TMax (the time when the residue function reaches its maximum) and apparent diffusion coefficient were consistently increased in the presumed perihematomal edema. Two thirds of the patients also exhibited patchy regions of restricted diffusion in the presumed perihematomal edema. CONCLUSIONS: The MRI profile of the presumed perihematomal edema in acute intracerebral hemorrhage exhibits delayed perfusion and increased diffusivity mixed with areas of reduced diffusion. PMID- 20947850 TI - Leonurine protects middle cerebral artery occluded rats through antioxidant effect and regulation of mitochondrial function. AB - BACKGROUND AND PURPOSE: Oxidative stress is known to be involved in ischemic stroke. Intense interest is drawn to the therapeutic potential of Chinese herbs on ischemic stroke because many of them contain antioxidant properties. Leonurine, 1 of the active compounds from purified Herba Leonuri, was studied to evaluate its possible therapeutic effects on ischemic stroke. Method-Middle cerebral artery occlusion was selected as our model of study. The animals were pretreated with Leonurine orally for 7 days and the surgery was done. One day after surgery, 2,3,5-triphenyltetrazolium chloride staining and neurological deficit score were carried out to evaluate the functional outcome of animals, whereas levels of superoxide dismutase, glutathione peroxidase, and malondialdehyde were analyzed for oxidative stress analysis. For mitochondrial studies, 3 hours after surgery, mitochondria were isolated for analysis of reactive oxygen species production, adenosine triphosphate biosynthesis, oxygen consumption, and respiratory control ratio value. Result-In in vivo experiments, Leonurine pretreatment reduced infarct volume, improved neurological deficit in stroke groups, increased activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase, and decreased levels from the lipid peroxidation marker malondialdehyde. In terms of mitochondrial modulation, Leonurine inhibited mitochondrial reactive oxygen species production and adenosine triphosphate biosynthesis. Animal studies also demonstrated that the mitochondrial function and redox state were restored by Leonurine treatment. CONCLUSIONS: Leonurine has neuroprotective effects and carries a therapeutic potential of stroke prevention. PMID- 20947851 TI - Burden among stroke caregivers: results of a community-based study from Kolkata, India. AB - BACKGROUND AND PURPOSE: Stroke causes significant caregiver (CG) stress, which is under-reported in India. This study assesses the financial, physical, psychological, and family burden on CG of stroke patients in an urban community. METHODS: Cross-sectional survey of stroke patients and CG were selected from a community-based registry using validated scales through face-to-face interviews. RESULTS: Data were available from 199 stroke survivors and a similar number of CG. Increased workload, related anxiety and depression, and sleep disturbance were reported by 70%, 76%, and 43% of CG, respectively, whereas >80% reported financial worry, which was greater among slum dwellers and less educated families. CG of patients with dementia and depression experienced greater stress. Female CG received more appreciation and family bonding was well-maintained. CONCLUSIONS: Financial stress was prominent and common among the socioeconomically weaker section. Psychological stress is similar to that of other studies. Women CG received greater appreciation. Family bonding was well preserved in contrast to that of a western report. PMID- 20947852 TI - Thrombolysis is associated with consistent functional improvement across baseline stroke severity: a comparison of outcomes in patients from the Virtual International Stroke Trials Archive (VISTA). AB - BACKGROUND AND PURPOSE: Baseline stroke severity predicts outcomes among thrombolysed patients. The baseline National Institutes of Health Stroke Scale (NIHSS) thresholds are sometimes used to select patients for thrombolysis, clinical trial enrollment, or both. Using data lodged with Virtual International Stroke Trials Archive, we compared adjusted outcomes between thrombolysed and nonthrombolysed patients enrolled in neuroprotection trials (1998-2007) to assess the influence of various levels of baseline NIHSS. Method-We assessed the association of treatment with outcome, measured across the modified Rankin scale score distribution, in patients categorized by baseline NIHSS in increments of 4. We used an age and baseline NIHSS adjusted Cochran-Mantel-Haenszel test followed by proportional odds logistic regression analysis. We report the Cochran-Mantel Haenszel P values and estimated odds ratios (OR) for improved modified Rankin scale score distribution with treatment for patients within each baseline NIHSS category. RESULTS: Data were available for 5817 patients (1585 thrombolysed and 4232 nonthrombolysed). Baseline severity was greater among thrombolysed than nonthrombolysed (median baseline NIHSS, 14 vs 13; P < 0.05). An association of treatment with outcome was seen independently and was of similar magnitude within each of the baseline NIHSS categories 5 to 8 (P=0.04; OR, 1.25; 95% confidence interval [CI], 1.0-1.6; N = 278/934 thrombolysed/nonthrombolysed), 9 to 12 (P = 0.01; OR, 1.3; 95% CI, 1.1-1.6; N = 404/942), 13 to 16 (P < 0.05; OR, 1.6; 95% CI, 1.3-2.1; N = 342/814), 17 to 20 (P < 0.05; OR, 1.7; 95% CI, 1.3-2.1; N = 311/736), and 21 to 24 (P < 0.05; OR, 1.6; 95% CI, 1.1-2.1; N = 178/466). No association was observed within baseline NIHSS categories 1 to 4 (P = 0.8; OR, 1.1; 95% CI, 0.3-4.4; N = 8/161) or >= 25 (P = 0.08; OR, 1.1; 95% CI, 0.7-1.9; N = 64/179). CONCLUSIONS: In this nonrandomized comparison, outcomes after thrombolysis were significantly better than in untreated comparators across baseline NIHSS 5 to 24. The significant association was lost only at extremes of baseline NIHSS when sample sizes were small and confidence limits were wide. PMID- 20947853 TI - Early intracerebral hematoma expansion after aneurysmal rupture. AB - BACKGROUND AND PURPOSE: Intracerebral hematomas (ICHs) often increase in size in the initial hours. It is unknown whether expansion of ICHs after aneurysmal rupture in the acute phase is always a sign of rerupture of the original aneurysm. METHODS: We included patients with an ICH from a ruptured aneurysm who underwent computed tomography imaging within 24 hours of symptom onset and a repeat computed tomography within 48 hours. Hematoma growth was considered present when there was a 33% increase in hematoma volume, as assessed by the ABC/2 method. Clinical and radiologic characteristics were compared between patients with ICH growth, with and without clinical signs of rerupture. Rerupture was defined as a sudden deterioration in the level of consciousness in the absence of ventricular enlargement or a systemic cause. RESULTS: Hematoma expansion within 48 hours after onset occurred in 12 of the 49 included patients and was preceded by clinical evidence of rerupture in 6 of these 12 patients. Of the 6 patients without an evident rerupture, 3 had no clinical deterioration, 1 had respiratory failure due to pneumonia, another had temporal brain herniation, and the last had acute hydrocephalus. CONCLUSIONS: Only half of the patients with early ICH expansion after aneurysmal rupture had clinical signs of rerupture of the aneurysm. Early ICH expansion after aneurysmal rupture can be caused by other mechanisms, which are possibly comparable to those responsible for hematoma expansion in spontaneous ICH. PMID- 20947854 TI - Prescribing antiplatelet medicine and subsequent events after intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Antiplatelet medicines are commonly perceived as contraindicated after intracerebral hemorrhage (ICH). Many ICH patients have or will have indications for antiplatelet therapy. This observational study describes the level of antiplatelet prescribing and rate of subsequent events after ICH in Tayside, Scotland. METHODS: This study used record-linkage of an existing stroke cohort with antiplatelet prescribing data from 1994 to 2005. Patients were followed-up from discharge after index event. The primary outcome was recurrent ICH. Other outcomes were subsequent ischemic stroke and a composite of ischemic stroke or myocardial infarction. Event rates were calculated as the number of events divided by patient-years of exposure. Univariate hazard ratios associated with antiplatelet exposure were derived from a Cox model using a time dependent covariate. RESULTS: There were 417 ICH patients who survived to discharge. Of these, 120 patients were prescribed subsequent antiplatelet medicines (28.8%). The median time from discharge to antiplatelet use was 14.8 months (range, 2 days-7.5 years). Among all survivors, there were 14 recurrent ICH (rate, 9.7 per 1000 patient-years; 95% confidence interval [CI], 5.3-16.4), 29 subsequent ischemic strokes (rate, 20.6; 95% CI, 13.8-29.6), and 40 subsequent ischemic strokes or myocardial infarctions (rate, 28.7; 95% CI, 20.5-39.0). Hazard ratios associated with antiplatelet exposure were 1.07 (95% CI, 0.24-4.84) for recurrent ICH, 0.23 (95% CI, 0.03-1.68) for ischemic stroke, and 0.72 (95% CI, 0.25-2.02) for ischemic strokes or myocardial infarction. CONCLUSIONS: Antiplatelet prescribing was common after ICH. Subsequent ischemic strokes or myocardial infarctions were more common than recurrent ICH. Antiplatelet prescribing did not appear to have a clinically significant impact on outcomes measured. Despite being contraindicated, antiplatelet use was not a major hazard for recurrent ICH. PMID- 20947855 TI - Early mobilization after stroke: an example of an individual patient data meta analysis of a complex intervention. AB - BACKGROUND AND PURPOSE: Very early mobilization (VEM) is a distinctive characteristic of care in some stroke units; however, evidence of the effectiveness of this approach is limited. To date, only 2 phase II trials have compared VEM with standard care: A Very Early Rehabilitation Trial (AVERT) in Australia and the recently completed Very Early Rehabilitation or Intensive Telemetry after Stroke trial in the United Kingdom. The Very Early Rehabilitation or Intensive Telemetry after Stroke protocol was designed to complement that of AVERT in a number of key areas. The aim of this analysis was to investigate the impact of VEM on independence by pooling data from these 2 comparable trials. METHODS: Individual data from the 2 trials were pooled. Overall, patients were between 27 and 97 years old, had first or recurring stroke, and were treated within 36 hours after stroke onset. The primary outcome was independence, defined as modified Rankin scale score of 0 to 2 at 3 months. The secondary outcomes included complications of immobility and activities of daily living. Logistic regression was used to assess the effect of VEM on outcome, adjusting for known confounders including age, baseline stroke severity, and premorbid modified Rankin scale score. Findings-All patients in AVERT and Very Early Rehabilitation or Intensive Telemetry after Stroke were included, resulting in 54 patients in the VEM group and 49 patients in the standard care group. The baseline characteristics of VEM patients were largely comparable with standard care patients. Time to first mobilization from symptom onset was significantly shorter among VEM patients (median, 21 hours; interquartile range, 15.8-27.8 hours) compared with standard care patients (median, 31 hours; interquartile range, 23.0 41.2 hours). VEM patients had significantly greater odds of independence compared with standard care patients (adjusted odds ratio, 3.11; 95% confidence interval, 1.03-9.33). CONCLUSIONS: Planned collaborations between stroke researchers to conduct trials with common protocols and outcome measures can help advance rehabilitation science. VEM was associated with improved independence at 3 months compared with standard care. However, both trials are limited by small sample sizes. Larger trials (such as AVERT phase III) are still needed in this field. PMID- 20947856 TI - Stratified, urgent care for transient ischemic attack results in low stroke rates. AB - BACKGROUND AND PURPOSE: Transient ischemic attack (TIA) is a marker for early risk of stroke. No previous studies have assessed the use of urgent stroke prevention clinics for emergency department (ED) patients with TIA. We hypothesized that an ABCD2-based ED triaging tool for TIA with outpatient management would be associated with lower 90-day stroke rate than that predicted by ABCD2. METHODS: A cohort of prospectively identified patients presenting with symptoms suggestive of TIA seen in 2 tertiary-care EDs. These patients were divided into 3 strata based on their ACBD2 score, and triage targets were set for each stratum. All patients received the same standard of care in the Stroke Clinic regardless of their risk score. Primary outcome was stroke by 90 days of index TIA. Secondary outcomes were subsequent TIA, myocardial infarction, or death. RESULTS: One-thousand ninety-three patients met the inclusion criteria; 982 patients completed 90-day follow-up and comprised the final cohort. After stratification, 32%, 49%, and 19% of patients were categorized as low-, moderate , or high-risk, respectively. The overall 90-day risk of stroke in all patients was 3.2%, compared with the ABCD2-predicted risk of 9.2%. Only 1.6% of patients with TIA/minor stroke were admitted from the ED. The risk of subsequent TIA, myocardial infarction, or death by 90 days was 5.5%, 0.1%, and 1.7%, respectively. CONCLUSIONS: Outpatient care in a rapid-access stroke prevention clinic using the ABCD2 score for triage resulted in a low 90-day stroke rate for patients in the ED with TIA. Benefit occurred without requiring admission for most patients. PMID- 20947857 TI - Safety of intravenous fibrinolysis in imaging-confirmed single penetrator artery infarcts. AB - BACKGROUND AND PURPOSE: Hemorrhagic transformation (HT) after fibrinolytic therapy may be less common in patients with acute cerebral ischemia confined to single penetrator artery (SPA) territories than in patients with large artery ischemia. Previous investigations of HT diagnosed small vessel ischemia based on lacunar clinical syndromes, an approach known to yield misdiagnosis in one-third to one-half of cases. METHODS: Consecutive intravenous tissue plasminogen activator-treated patients in a prospectively maintained hospital registry were analyzed. Patients were classified as having SPA ischemia if they had imaging evidence of: (1) deep location; (2) diameter <= 1.5 cm; and (3) distribution in a single penetrator territory, regardless of presenting clinical syndrome. Lacunar clinical syndrome was defined according to the Oxfordshire Community Stroke Project classification. RESULTS: Among 93 intravenous tissue plasminogen activator-treated patients, mean age was 71.5, 62.4% were female, and median pretreatment National Institutes of Health Stroke Scale score was 14. Single penetrator artery ischemia was imaged in 13 (14.0%) and large artery ischemia was imaged in 75 (80.6%), with no visualized ischemic injury in 5 (5.4%). Lacunar clinical syndromes were present in 23 (24.7%), including 10 with SPA ischemia and 9 with large artery ischemia. No patient with imaging-confirmed SPA infarcts experienced any hemorrhagic transformation, whereas any radiological HT occurred in 29.3% of large artery infarcts (P=0.03). Symptomatic intracerebral hemorrhage occurred in 0% of SPA infarcts vs 4.0% of large artery infarcts. CONCLUSIONS: HT after lytic therapy in imaging-confirmed SPA infarcts is uncommon. Imaging demonstration of ischemia confined to SPA territory better-identifies this population at low risk for hemorrhagic complications than clinical lacunar syndromes. PMID- 20947858 TI - Arsenic in drinking water and stroke hospitalizations in Michigan. AB - BACKGROUND AND PURPOSE: Mechanistic and human studies suggest a role for arsenic in ischemic stroke; however, risks from chronic, low-level exposures are uncertain and US studies are lacking. The objective was to investigate the association between low-level arsenic exposure in drinking water and ischemic stroke hospital admissions in Michigan. METHODS: Ischemic stroke hospital admissions among those aged >= 45 years were identified (1994 to 2006). Population-weighted average arsenic concentrations were estimated for each Michigan county (n = 83) and for zip codes in Genesee County (n=27) where there is greater variation in arsenic concentrations. US Census data provided age- and sex-specific population counts and other county- and zip code-level variables (race, income), which were adjusted for in multilevel negative binomial regression models of arsenic and stroke admissions. Hospital admissions for duodenal ulcer and hernia, not hypothesized to be associated with arsenic, were also evaluated. RESULTS: Adjusted county-level analyses suggested a relationship between arsenic and ischemic stroke hospital admissions, although similar associations were observed for duodenal ulcer and hernia. In zip code-level analysis, arsenic was associated with an increased risk of stroke admission (relative risk, 1.03; 95% CI, 1.01 to 1.05 per MUg/L increase in arsenic) after adjustment for confounders, and null or negative associations were found between arsenic and nonvascular outcomes. CONCLUSIONS: Findings from this study suggest that exposure to even low levels of arsenic in drinking water may be associated with a higher risk of incident stroke. Given the ecological nature of the analysis, further epidemiological study with individual-level data on arsenic exposure and incident stroke is warranted. PMID- 20947859 TI - AXIS: a trial of intravenous granulocyte colony-stimulating factor in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Granulocyte colony-stimulating factor (G-CSF) is a promising stroke drug candidate. The present phase IIa study assessed safety and tolerability over a broad dose range of G-CSF doses in acute ischemic stroke patients and explored outcome data. METHODS: Four intravenous dose regimens (total cumulative doses of 30-180 MUg/kg over the course of 3 days) of G-CSF were tested in 44 patients in a national, multicenter, randomized, placebo-controlled dose escalation study (NCT00132470; www.clinicaltrial.gov). Main inclusion criteria were a 12-hour time window after stroke onset, infarct localization to the middle cerebral artery territory, a baseline National Institutes of Health Stroke Scale range of 4 to 22, and presence of diffusion-weighted imaging/perfusion-weighted imaging mismatch. RESULTS: Concerning the primary safety end points, we observed no increase of thromboembolic events in the active treatment groups, and no increase in related serious adverse events. G-CSF led to expected increases in neutrophils and monocytes that resolved rapidly after end of treatment. We observed a clinically insignificant drug-related decrease of platelets. As expected from the low number of patients, we did not observe significant differences in clinical outcome in treatment vs. placebo. In exploratory analyses, we observed an interesting dose-dependent beneficial effect of treatment in patients with DWI lesions > 14-17 cm3. CONCLUSIONS: We conclude that G-CSF was well-tolerated even at high dosages in patients with acute ischemic stroke, and that a substantial increase in leukocytes appears not problematic in stroke patients. In addition, exploratory analyses suggest treatment effects in patients with larger baseline diffusion-weighted imaging lesions. The obtained data provide the basis for a second trial aimed to demonstrate safety and efficacy of G-CSF on clinical end points. PMID- 20947860 TI - Prevalence and predictors of paroxysmal atrial fibrillation on Holter monitor in patients with stroke or transient ischemic attack. AB - BACKGROUND AND PURPOSE: Our aims were to quantify the yield of Holter monitor for detection of paroxysmal atrial fibrillation (PAF) in patients with stroke and TIA, and to determine potential predictors of PAF to allow more focused testing. METHODS: We reviewed records of 1128 consecutive patients attending a university stroke clinic from September 2005 to September 2006 and identified 426 patients with definite TIA or stroke. We abstracted clinical, cardiac imaging, and neuroimaging data. Logistic regression analysis was performed to determine independent predictors of PAF on Holter monitor. RESULTS: Overall, 413 of 426 patients (65 +/- 15 years; male, 49.8%) with a definite TIA (53%) or stroke (47%) underwent Holter monitoring for a mean of 22.6 hours. PAF occurred in 39 patients (9.2%) all older than age 55 years. PAF lasting > 30 seconds was evident in 11 patients (2.5%). The other 28 patients had PAF < 30 seconds (6.5%). In multivariate analyses, number of acute (odds ratio [OR], 1.7 for each 1 lesion increase; 95% confidence interval [CI], 1.2-2.6; P = 0.0047) and chronic (OR, 1.6 for each 1 lesion increase; 95% CI, 1.2-2.3; P = 0.0001) infarcts on brain CT, number of chronic infarcts on MRI (OR, 3.0 for each 1 lesion increase; 95% CI, 1.7-5.1; P < 0.0001), and any acute cortical infarct on imaging (OR, 5.8; 95% CI, 1.9-17.8; P = 0.0023) were associated with PAF. CONCLUSIONS: PAF is present in 9.2% of patients with definite stroke or TIA. Age older than 55 years and presence of acute or chronic brain infarcts on neuroimaging are strongly associated with PAF. PMID- 20947862 TI - Does oxidative DNA damage cause atherosclerosis and metabolic syndrome?: new insights into which came first: the chicken or the egg. PMID- 20947863 TI - The role of wnt signaling in physiological and pathological angiogenesis. AB - Early stages of vascular development include endothelial cell differentiation in a network of arteries, veins, and lymphatics. Subsequently, to respond to the specific needs of the organs, endothelial cells acquire specialized properties such as permeability control, expression of specific transcellular transport systems, membrane adhesive molecules, and others. Endothelial cell differentiation depends on communication between the surrounding tissues, which is mediated by growth and differentiation factors able to activate specific gene expression programs. Recent reports underline the important role of the Wnt system in vascular morphogenesis in the embryo and in organ-specific endothelial differentiation. Wnt signaling regulates fundamental aspects of development, including cell fate specification, proliferation, and survival, and may use different receptors and signaling pathways. Both loss- and gain-of-function experiments of members of the Wnt signaling pathway were found to cause marked alterations of vascular development and endothelial cell specification. Furthermore, altered Wnt signaling in the endothelium may contribute to pathological conditions such as retinopathies, pulmonary arterial hypertension, stroke, and others. Continued progress in this field holds the potential to identify novel therapeutics for the treatment of these diseases. PMID- 20947864 TI - Role of the dihydrofolate reductase DfrA (Rv2763c) in trimethoprim sulfamethoxazole (co-trimoxazole) resistance in Mycobacterium tuberculosis. PMID- 20947865 TI - Elevated oxidative stress markers and its relationship with endothelial dysfunction in Behcet disease. AB - Behcet's disease (BD) is a multisystemic disorder characterized by endothelial dysfunction. However, the relationship between oxidative stress and endothelial function has not been clearly shown. We investigated the relationship between oxidative stress markers and endothelial function in patients with BD. Patients with BD (n = 40) having active disease and sex- and age-matched 40 controls were included. Endothelial function was assessed by flow-mediated dilatation (FMD) technique. Serum gamma-glutamyltransferase (GGT) and high-sensitive C-reactive protein levels (hsCRP) were measured in all participants. Brachial artery FMD was significantly lower in patients with BD than in controls. Gamma glutamyltransferase and hsCRP levels were higher in patients with BD than in controls. Also, GGT and hsCRP levels were inversely correlated with endothelial function. Oxidative stress markers are elevated in patients with BD having active disease. This may be one of the reasons behind the vasculitis in active BD. PMID- 20947866 TI - Impact of contrast-induced nephropathy and cardiovascular events by serum cystatin C in renal insufficiency patients undergoing cardiac catheterization. AB - We assessed the usefulness of serum cystatin C for predicting contrast-induced nephropathy (CIN) in patients (n = 100) undergoing coronary catheterization. After a 12-month follow-up, the incidence of CIN was 8.3% (n = 5) in patients with mild renal insufficiency (estimated glomerular filtration rate [eGFR] 60-89 mL/min per 1.73 m2), 34.4% (n = 10) in those with moderate renal insufficiency (eGFR 30-59 mL/min per 1.73 m2), and 100% (n = 3) in those with severe renal insufficiency (eGFR 15-29 mL/min per 1.73 m2). The sensitivity was 81.8% and specificity was 90.9% at the cutoff level of serum cystatin C >1.18 mg/L. Serum cystatin C levels were significantly (P < .001) higher in the patients with moderate renal insufficiency in the CIN group than those in the non-CIN group. Multivariate logistic regression analysis demonstrated that baseline serum cystatin C independently predicted short-term mortality (odds ratio [OR], 0.311; 95% confidence interval [CI] 0.058-0.538; P = .026). Baseline serum cystatin C significantly predicted the occurrence of CIN in the patients with moderate renal insufficiency. PMID- 20947867 TI - Stroke risk estimation across nine European countries in the MORGAM project. AB - BACKGROUND: Previous tools for stroke risk assessment have either been developed for specific populations or lack data on non-fatal events or uniform data collection. The purpose of this study was to develop a stepwise model for the estimation of 10 year risk of stroke in nine different countries across Europe. METHODS: Using data from the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) Project, sex-specific models estimating 10 year risk of stroke were developed using a Cox regression model stratified by country and including modelling of competing risks. Models were developed in a stepwise manner first using only data from questionnaires, and then adding data from physical examinations and finally data from blood samples. RESULTS: During 1,176,296 years of observation, 2928 incident fatal and non-fatal events of stroke were registered. The developed model showed good calibration and accuracy of prediction. The discrimination of the model varied between sex and country but increased with increasing number of variables used (area under the receiver operating characteristic curve between 0.77 and 0.79 in men and between 0.75 and 0.80 in women). CONCLUSION: The present study shows that using a large multicountry cohort from nine European countries it is possible to develop a stepwise risk estimation model for 10 year risk of stroke tailored to different availability of risk factors and still obtain valid measures of risk even in the simplest form of the model, with increasing performance of the model following increasing complexity. The methods chosen which separate this model from previous models (competing risk and stepwise approach) should be considered for future risk estimation models. PMID- 20947868 TI - Limited lymph-node recovery based on lymph-node localisation is sufficient for accurate staging. AB - AIMS: To assess the reliability of nodal staging in colorectal carcinomas (CRCs) when only lymph nodes close to the tumour are recovered and examined histologically. METHODS: Lymph nodes from CRC resection specimens were recovered into two fractions: one from around the tumour and the 3 cm sidelong bowel segment associated with it in the proximal and distal directions, and another from the remaining part of the resection specimen. RESULTS: Of the 762 CRCs (239 right colon, 251 left colon, 257 rectum, 15 unspecified localisation) there were 393 node-negative and 369 node-positive cases. The median number of LNs examined was 18. The assessment of the LNs located in the close fraction (median 13) yielded an adequate qualitative nodal status in 756 patients (99.2%). In four cases (two rectal and two right colic), no LN metastases could be identified in the close-fraction lymph nodes, but nodes from the distant fraction contained metastases. Of the node-positive carcinomas which had at least one positive lymph node in the close fraction, 203 belonged to the pN1 category and 162 to the pN2 category of the Tumour Node Metastasis staging system. Only 14 cases (10 rectal, two right and two left colic tumours) were misclassified as pN1 (on the basis of lymph nodes recovered from the close fraction) although they were of the pN2 category. CONCLUSIONS: In general, nodal status of CRCs may be adequately assessed by examining the lymph nodes from the close fraction around the tumour and the 3 cm sidelong bowel segment in both directions. PMID- 20947869 TI - Serum ferritin values in primary care: are high values overlooked? AB - OBJECTIVE: To examine serum ferritin values in iron-replete patients in primary care and determine the action taken on those patients with very high values (>1000 MUg/l). METHODS: Serum ferritin values from 4170 consecutive patients in primary care were examined. All measurements had been made at the request of the general practitioner. RESULTS: Ferritin values in males reached a steady state by 30 years and did not increase thereafter. Values above 300 MUg/l were found in 17% of all males. Female values rose progressively with age. Less than 10% of women <50 years had values >100 MUg/l. By the age of 70 years, 8% had values >300 MUg/l. Ferritin values >1000 MUg/l were found in 59 patients. This rise was neither explained nor investigated in 32 cases. CONCLUSION: Raised ferritin values are frequently found in samples submitted from primary care and most so in adult males. The authors also conclude that general practitioners require more guidance from haematologists in the management of patients with very high values. PMID- 20947870 TI - Lymphatic vessel density and its prognostic value in stage I colorectal carcinoma. AB - AIMS: The assessment of lymphatic vessel density (LVD) has been suggested as a tool to determine the metastatic risk of neoplasias. On this premise, the authors aimed to verify whether progression risk of stage I colorectal cancer may be related to LVD. The authors also evaluated and correlated vascular endothelial growth factor (VEGF)-A expression with LVD revealed in the same cases in order to investigate its potential lymphangiogenic role in the early stage colorectal cancer. METHODS: LVD and VEGF immunoexpression were analysed and compared in series of 29 stage I surgically resected colorectal carcinomas obtained from patients showing disease progression and in a cohort of 23 stage I colorectal cancers from patients with no evidence of disease progression. The prognostic value of LVD and of VEGF expression on the progression-free survival to colorectal cancer was investigated. RESULTS: A high density of peritumoural lymphatics (P-LVD) was significantly associated with high VEGF expression and disease progression. Moreover, high P-LVD and high VEGF expression were significant negative prognostic parameters associated with a shorter disease-free interval in stage I colorectal cancer. CONCLUSIONS: If our findings are further confirmed in other studies, the assessment of P-LVD on surgical specimens might be used as a tool to identify patients with stage I colorectal cancer at higher risk of progression in order to submit them to adjuvant therapies. Since P-LVD seems to show a VEGF-A mediated regulation in stage I colorectal cancer, therapies targeting this factor might be exploited to reduce lymphangiogenesis and the progression risk of this neoplasia. PMID- 20947871 TI - Alcohol outlet density, levels of drinking and alcohol-related harm in New Zealand: a national study. AB - BACKGROUND: Previous research shows associations of geographical density of alcohol outlets with a range of alcohol-related harms. Socioeconomic conditions that are associated with both outlet density and alcohol-related outcomes may confound many studies. We examined the association of outlet density with both consumption and harm throughout New Zealand while controlling for indicators of area deprivation and individual socioeconomic status (SES). METHODS: Individual alcohol consumption and drinking consequences were measured in a 2007 national survey of 18-70 year olds (n=1925). All alcohol outlets in New Zealand were geocoded. Outlet density was the number of outlets of each type (off-licences (stores that sell alcoholic beverages for consumption elsewhere), bars, clubs, restaurants) within 1 km of a person's home. We modelled the association of outlet density with total consumption, binge drinking, risky drinking (above New Zealand guidelines) and two measures of effects ('harms' and 'troubles' due to drinking) in the previous year. Logistic regression and zero-inflated Poisson models were used, adjusting for sex, educational level, a deprivation index (NZDep06) and a rurality index. RESULTS: No statistically significant association was seen between outlet density and either average alcohol consumption or risky drinking. Density of off-licences was positively associated with binge drinking, and density of all types of outlet was associated with alcohol-related harm scores, before and after adjustment for SES. Associations of off-licences and clubs with trouble scores were no longer statistically significant in the adjusted analysis. CONCLUSIONS: The positive associations seen between alcohol outlet density and both individual level binge drinking and alcohol-related problems appear to be independent of individual and neighbourhood SES. Reducing density of alcohol outlets may reduce alcohol-related harm among those who live nearby. PMID- 20947872 TI - The GRADE approach and Bradford Hill's criteria for causation. AB - This article describes how the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to grading the quality of evidence and strength of recommendations considers the Bradford Hill criteria for causation and how GRADE may relate to questions in public health. A primary concern in public health is that evidence from non-randomised studies may provide a more adequate or best available measure of a public health strategy's impact, but that such evidence might be graded as lower quality in the GRADE framework. GRADE, however, presents a framework that describes both criteria for assessing the quality of research evidence and the strength of recommendations that includes considerations arising from the Bradford Hill criteria. GRADE places emphasis on recommendations and in assessing quality of evidence; GRADE notes that randomisation is only one of many relevant factors. This article describes how causation may relate to developing recommendations and how the Bradford Hill criteria are considered in GRADE, using examples from the public health literature with a focus on immunisation. PMID- 20947873 TI - Risk for attempted suicide in children and youths after contact with somatic hospitals: a Danish register based nested case-control study. AB - BACKGROUND: A range of studies have found an association between some somatic diseases and increased risk of suicide and attempted suicide. These studies are mostly analyses of adult populations and illnesses related to adulthood. OBJECTIVES: To study the risk of attempted suicide in children and youths with a somatic diagnosis, and to assess a possible association from a somatic perspective. METHODS: From a cohort of 403 431 individuals (born 1983-89), 3465 children and youths who had attempted suicide were identified. Each case was matched with 20 population controls. 72 765 children and youths constituted the case-control population. All data were obtained from national population registers and analysed in a nested case-control design. RESULTS: Contact of children and youths with a somatic hospital is correlated with increased risk of attempted suicide; the risk peaks in the time immediately after contact. Risk factors were treatment for injury caused by violence, epilepsy, asthma and malformation for males; and spontaneous and medical abortions, treatment for injury caused by violence, epilepsy, asthma, insulin dependent diabetes mellitus and malformation for females. Not all the mentioned diagnoses were significant in the adjusted model. CONCLUSIONS: Based on the results of the study a strategy to minimise the risk of attempted suicide among children and youths must be implemented. The strategy should mainly focus on children at high risk-that is, children from families with low socioeconomic status, and children with a psychiatric history, a history of previous suicide attempts and with an unstable somatic disease subsequently causing many admissions. PMID- 20947874 TI - Sense of community-belonging and health-behaviour change in Canada. AB - BACKGROUND: Research indicates that primary prevention targeting individual behaviours should incorporate contextual factors. The objectives of this study are to examine the role of community-belonging and contextual factors on health behaviour change in Canada, and whether the influence of community-belonging on behaviour change varies by specific types of behaviours and contextual factors. METHODS: Data on individual-level community-belonging, socio-demographics and self-rated health were obtained for 119 693 respondents from the 2007/2008 Canadian Community Health Survey located within 100 health regions across Canada. Contextual factors were based on health-region groupings of socio-economic determinants of health. Multilevel models were used to estimate the influence of community-belonging and health-region contextual factors on general, and specific, health-behaviour changes in the past year. RESULTS: After controlling for individual and contextual factors, community-belonging showed a positive dose response relationship with health-behaviour change. Health-region contextual factors were only slightly associated with behaviour change; however, the influence of community-belonging on behaviour change showed significant variability based on health-region contextual factors. The influence of community belonging also varied by specific health-behaviour changes, but for most prominent health behaviours (exercise, weight loss and improved diet) the effect was consistent. CONCLUSIONS: Community-belonging was strongly related to health behaviour change in Canada and may be an important component of population health prevention strategies. Efforts to increase community-belonging, however, need to be considered along with contextual factors. PMID- 20947875 TI - Older adults' preferences for independent or delegated end-of-life medical decision making. AB - OBJECTIVE: This study assesses the proportions of participants who prefer independent or delegated medical decision making at the end of life and examines the relationships of personal beliefs, affiliative beliefs, and end-of-life planning behaviors to decision-making preference. METHOD: Data are drawn from the Wisconsin Longitudinal Study, a sample of nearly 4,500 healthy White Midwestern high school graduates in their mid-60s. RESULTS: Four fifths of participants wanted to make decisions independently. Valuing independence, being less avoidant of thoughts of death, and valuing quality of life over length of life had strong associations with a preference for independent decision making. Those concerned about burdening a caregiver wanted to make independent decisions. Persons who both executed a living will and appointed a durable power of attorney for health care preferred independent decision making. DISCUSSION: Older adults cite personal and affiliative beliefs, not lack of autonomy, as reasons for their choice to decide independently or delegate. PMID- 20947876 TI - Psychotropic drugs and falls in the elderly people: updated literature review and meta-analysis. AB - OBJECTIVE: To carry out meta-analyses on psychotropic drugs and to provide an update of the risk of falling in the elderly people related to psychotropic drugs. DESIGN: Meta-analyses of studies on psychotropic drugs. RESULTS: 177 studies are included, of which 71 have data on risk factors associated with psychotropic drugs. The odds ratio and 95% Cl for associations between use of psychotropic drugs and fall are 1.78 and 1.57-2.01, respectively. This result is statistically heterogeneous. This heterogeneity disappears in the group of very old participants for each class. CONCLUSION: Our study confirms the association between falls in the elderly people and psychotropic drugs. These results are similar to those of former meta-analyses but with different methods. It shows that these meta-analyses on psychotropic drugs have a small impact on prescribing habits. They only give evidence to support the association between psychotropic drugs and falls even if there is no proven link. PMID- 20947877 TI - Colorectal cancer screening: will global warming affect the accuracy of FIT testing? PMID- 20947878 TI - Field defects in DNA repair: is loss of MGMT an initial event in colorectal carcinogenesis? PMID- 20947879 TI - Optimal treatment of metastatic pancreatic cancer. PMID- 20947880 TI - Acute-on-chronic liver failure: an early biopsy is essential? PMID- 20947881 TI - Empirical levofloxacin-containing versus clarithromycin-containing sequential therapy for Helicobacter pylori eradication: a randomised trial. AB - BACKGROUND AND AIMS: Antimicrobial drug resistance is a major cause of the failure of Helicobacter pylori eradication and is largely responsible for the decline in eradication rate. Quadruple therapy has been suggested as a first-line regimen in areas with clarithromycin resistance rate >15%. This randomised trial aimed at evaluating the efficacy of a levofloxacin-containing sequential regimen in the eradication of H pylori-infected patients in a geographical area with >15% prevalence of clarithromycin resistance versus a clarithromycin containing sequential therapy. METHODS: 375 patients who were infected with H pylori and naive to treatment were randomly assigned to one of the following treatments: (1) 5 days omeprazole 20 mg twice daily + amoxicillin 1 g twice daily followed by 5 days omeprazole 20 mg twice daily +clarithromycin 500 mg twice daily + tinidazole 500 mg twice daily; or (2) omeprazole 20 mg twice daily +amoxicillin 1 g twice daily followed by omeprazole 20 mg twice daily + levofloxacin 250 mg twice daily +tinidazole 500 mg twice daily; or (3) omeprazole 20 mg twice daily + amoxicillin 1 g twice daily followed by omeprazole 20 mg twice daily + levofloxacin 500 mg twice daily + tinidazole 500 mg twice daily. Antimicrobial resistance was assessed by the E-test. Efficacy, adverse events and costs were determined for each group. RESULTS: Eradication rates in the intention-to-treat analyses were 80.8% (95% CI, 72.8% to 87.3%) with clarithromycin sequential therapy, 96.0% (95% CI, 90.9%to 98.7%) with levofloxacin-250 sequential therapy, and 96.8% (95% CI, 92.0% to 99.1%) with levofloxacin-500 sequential therapy. No differences in prevalence of antimicrobial resistance or incidence of adverse events were observed between groups. Levofloxacin-250 therapy was cost-saving compared with clarithromycin sequential therapy. CONCLUSION: In an area with >15% prevalence of clarithromycin resistant H pylori strains, a levofloxacin containing sequential therapy is more effective, equally safe and cost-saving compared to a clarithromycin containing sequential therapy. PMID- 20947882 TI - A nationwide population-based study to determine whether coeliac disease is associated with infertility. AB - BACKGROUND AND OBJECTIVE: Previous studies suggest that women with coeliac disease (CD) have reproductive difficulties but the data are often inconclusive and contradictory. Fertility in women with biopsy-verified CD was examined. METHODS: Swedish population-based cohort study. Duodenal/jejunal biopsy data on CD (Marsh III; villous atrophy (VA); n=18,005 unique women) were collected from all (n=28) pathology departments in Sweden. From this dataset, 11,495 women with CD, aged 18-45 years, were identified at some point before the end of follow-up. Multinomial logistic regression and Cox regression were used to estimate fertility in these women compared with that in 51,109 age-matched reference women. Fertility was defined as the number of children according to the Swedish Multi-Generation Register. Results During follow-up, 16,309 births occurred in women with CD and 69,245 in the reference women. The cumulative number of children slightly increased in women with CD compared with the reference group. Adjusting for age, calendar period and parity and stratifying by education, the overall fertility hazard ratio (HR) in CD was 1.03 (95% CI 1.01 to 1.05). Specifically, the fertility HR was 1.05 (95% CI 0.96 to 1.14) for CD diagnosed in women before 18 years, 1.04 (95% CI 1.01 to 1.07) for CD diagnosed in women between 18 and 45 years and 1.02 (95% CI 0.99 to 1.04) for CD diagnosed in women > 45 years of age. Taking date of CD diagnosis into account, fertility was decreased 0-2 years before time of diagnosis (HR=0.63; 95% CI 0.57 to 0.70), was identical to that of controls 0-5 years subsequent to diagnosis and increased to 1.12 (95% CI 1.03 to 1.21) thereafter. Conclusion Overall, women with CD had a normal fertility, but their fertility was decreased in the last 2 years preceding CD diagnosis. PMID- 20947883 TI - Intestinal alkaline phosphatase preserves the normal homeostasis of gut microbiota. AB - BACKGROUND AND AIMS: The intestinal microbiota plays a critical role in maintaining human health; however, the mechanisms governing the normal homeostatic number and composition of these microbes are largely unknown. Previously it was shown that intestinal alkaline phosphatase (IAP), a small intestinal brush border enzyme, functions as a gut mucosal defence factor limiting the translocation of gut bacteria to mesenteric lymph nodes. In this study the role of IAP in the preservation of the normal homeostasis of the gut microbiota was investigated. METHODS: Bacterial culture was performed in aerobic and anaerobic conditions to quantify the number of bacteria in the stools of wild type (WT) and IAP knockout (IAP-KO) C57BL/6 mice. Terminal restriction fragment length polymorphism, phylogenetic analyses and quantitative real-time PCR of subphylum-specific bacterial 16S rRNA genes were used to determine the compositional profiles of microbiotas. Oral supplementation of calf IAP (cIAP) was used to determine its effects on the recovery of commensal gut microbiota after antibiotic treatment and also on the colonisation of pathogenic bacteria. RESULTS: IAP-KO mice had dramatically fewer and also different types of aerobic and anaerobic microbes in their stools compared with WT mice. Oral supplementation of IAP favoured the growth of commensal bacteria, enhanced restoration of gut microbiota lost due to antibiotic treatment and inhibited the growth of a pathogenic bacterium (Salmonella typhimurium). CONCLUSIONS: IAP is involved in the maintenance of normal gut microbial homeostasis and may have therapeutic potential against dysbiosis and pathogenic infections. PMID- 20947884 TI - Anti-CD3 antibody visilizumab is not effective in patients with intravenous corticosteroid-refractory ulcerative colitis. AB - BACKGROUND AND AIMS: Pilot studies with visilizumab, a humanised monoclonal antibody to CD3, suggest efficacy for corticosteroid-refractory ulcerative colitis (UC). A placebo-controlled trial was warranted. METHODS: A randomised, double-blind, placebo-controlled study evaluated the efficacy of visilizumab induction treatment in 127 patients with severely active UC despite treatment with >=5 days of intravenous corticosteroids. Patients received placebo or visilizumab 5MUg/kg intravenously on days 1 and 2. Corticosteroids were tapered according to disease activity. Patients were followed up for 90 days. The primary end point was induction of response at day 45. Secondary end points included remission and mucosal healing at day 45, symptomatic response at day 15 and colectomy. RESULTS: Response at day 45 occurred in 55% of patients receiving visilizumab compared with 47% of those who received placebo (p=0.475). Remission at day 45 occurred in 8% of patients receiving visilizumab compared with 9% of those who received placebo (p=0.704). Mucosal healing at day 45 occurred in 29% of patients receiving visilizumab compared with 26% of those who received placebo (p=0.799). Symptomatic response at day 15 occurred in 82% of patients receiving visilizumab compared with 74% of those who received placebo (p=0.244). Colectomy was performed in 18% of patients receiving visilizumab compared with 7% of those who received placebo (p=0.130). Cardiac disorders and vascular disorders occurred more frequently in the patients who received visilizumab. CONCLUSION: Visilizumab at a dose of 5MUg/kg for two consecutive days was not effective for severe, corticosteroid-refractory UC and was associated with increased cardiac and vascular adverse events. (Registered at http://www.clinicaltrials.govNCT00279422/). PMID- 20947885 TI - Low molecular weight heat shock protein HSP27 is a prognostic indicator in rectal cancer but not colon cancer. AB - OBJECTIVE: There are currently no biomarkers in routine clinical use for determining prognosis in rectal cancer. In a preliminary proteomic study, variation in the levels of heat shock protein 27 (HSP27) in colorectal cancer samples was observed. The expression of HSP27 in a cohort of 404 patients with colorectal cancer with a predominantly poor prognosis was characterised and an investigation was undertaken of whether the differences were related to clinical outcome. HSP27 levels in diagnostic rectal biopsies were compared with matched surgical samples to determine whether changes in expression occurred in the time between biopsy and surgery and to investigate whether preoperative radiotherapy affected expression. Finally, the relationship between HSP27 expression and outcome was examined in an independent cohort of 315 patients with a predominantly good prognosis. METHODS: HSP27 levels were determined using combined two-dimensional gel electrophoresis and tandem mass spectrometry (12 cases) and by immunohistochemistry using tissue microarrays of colorectal cancers sampled at surgery and 80 diagnostic rectal biopsies. RESULTS: HSP27 overexpression was strongly associated with poor cancer-specific survival in rectal cancer (n=205, p=0.0063) but not colon cancer (n=199, p=0.7385) in the cohort with a poor prognosis. Multivariate Cox regression confirmed nodal metastases (p=0.0001) and HSP27 expression (p=0.0233) as independent markers of survival in rectal cancer. HSP27 levels remained unchanged in the majority of cases (65/80, 81%) between diagnostic biopsies and matched surgical samples, regardless of whether patients had undergone preoperative radiotherapy. In the cohort with a good prognosis the association between HSP27 and survival was not observed in patients with either rectal (n=115; p=0.308) or colon cancer (n=200; p=0.713). CONCLUSION: In a large cohort of patients with a poor prognosis, HSP27 is an independent marker of poor outcome in rectal cancer; its expression is not altered by neoadjuvant radiotherapy. This finding requires validation in an independent similar cohort of patients with rectal cancer. HSP27 levels merit evaluation as a stratification factor for treatment of rectal cancer. PMID- 20947886 TI - Methylation tolerance due to an O6-methylguanine DNA methyltransferase (MGMT) field defect in the colonic mucosa: an initiating step in the development of mismatch repair-deficient colorectal cancers. AB - BACKGROUND AND AIMS: O(6)-Methylguanine-DNA methyltransferase (MGMT) removes methyl adducts from O(6)-guanine. Known as methylation tolerance, selection for mismatch repair (MMR)-deficient cells that are unable to initiate lethal processing of O(6)-methylguanine-induced mismatches in DNA is observed in vitro as a consequence of MGMT deficiency. It was therefore hypothesised that an MGMT field defect may constitute a preneoplastic event for the development of MMR deficient tumours displaying microsatellite instability (MSI). METHODS: MGMT expression was investigated by immunohistochemistry and the methylation status of the gene promoter by PCR in neoplastic, adjacent and distant mucosal tissues of patients with MSI or non-MSI (MSS) colorectal cancer (CRC). The cancers were familial (42 MSI, 13 MSS) or sporadic (40 MSI, 49 MSS) in origin, or arose in the context of inflammatory bowel disease (IBD; 13 MSI, 36 MSS). Colonic mucosa from patients with diverticulitis (n=20) or IBD (n=39 in 27 patients) without cancer served as controls. RESULTS: Loss of MGMT expression was more frequent in MSI than MSS CRC (p=0.047). In comparison with MSS tumours, MSI CRC occurred more frequently adjacent to patches of mucosa that lacked MGMT expression (p=0.002). Overall, loss of MGMT expression was associated with MGMT gene promoter methylation (p=0.03). CONCLUSION: MGMT field defects are more frequently associated with MSI than MSS CRC. These findings indicate that methylation tolerance may be a crucial initiating step prior to MMR deficiency in the development of MSI CRC in familial, sporadic and IBD settings. PMID- 20947887 TI - Combination 5-fluorouracil, folinic acid and cisplatin (LV5FU2-CDDP) followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: final results of a randomised strategic phase III trial (FFCD 0301). AB - PURPOSE: Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma. Although the 5-fluorouracil (5FU), folinic acid and cisplatin combination (LV5FU2-CDDP) is an option, the optimal order of the regimens must be determined. The first strategic phase III trial comparing LV5FU2 CDDP followed by gemcitabine versus gemcitabine followed by LV5FU2-CDDP was conducted. METHODS: Patients with metastatic pancreatic adenocarcinoma, performance status (PS) 0-2, without prior chemotherapy were randomly assigned (1:1) to receive either LV5FU2-CDDP followed by gemcitabine at disease progression or toxicity (Arm A), or the opposite sequence (Arm B). 202 patients had to be included and 170 deaths had to be observed to detect an expected improvement in median overall survival (OS) from 6.5 to 10 months in Arm A (two sided alpha = 5% and beta = 20%). RESULTS: 202 patients were included (Arm A, 102; Arm B, 100). Median age, male/female ratio, PS 0-1 and previous surgery were similar in the two arms. After a median follow-up of 44 months, median OS in Arm A was 6.6 months versus 8.0 months in Arm B (p = 0.85). Median progression-free survival was similar between Arms A and B. More grade 3/4 toxicities were observed when LV5FU2-CDDP was administered as a first-line treatment compared with gemcitabine: 79% versus 64% (p = 0.018). CONCLUSION: This trial did not show any strategic advantage to using LV5FU2-CDDP as a first-line treatment and suggests that gemcitabine remains the standard first-line treatment. Sixty-one per cent of patients were able to receive a second line of chemotherapy. PMID- 20947889 TI - HCV iatrogenic and intrafamilial transmission in Greater Cairo, Egypt. AB - OBJECTIVES: To document hepatitis C virus (HCV) intrafamilial transmission and assess its relative importance in comparison to other current modes of transmission in the country with the largest HCV epidemic in the world. HCV intrafamilial transmission was defined as HCV transmission among relatives living in the same household. DESIGN: Case-control study. Cases were adult patients with acute hepatitis C diagnosed in two 'fever hospitals' of Cairo. Controls were adult patients with acute hepatitis A diagnosed in the same two hospitals, and family members of cases. All consenting household members of cases provided blood for HCV serological and RNA testing. Homology of viral sequences (NS5b region) within households was used to ascertain HCV intrafamilial transmission. Exposures at risk for HCV during the 1-6 months previous to onset of symptoms were assessed in all cases and controls. RESULTS: From April 2002 to June 2007, 100 cases with acute hepatitis C, and 678 controls (416 household members and 262 patients with acute hepatitis A) were recruited in the study. Factors independently associated with HCV infection and their attributable fractions (AFs) were the following: having had a catheter (OR=5.0, 95% CI=1.4 to 17.8; AF=6.7%), an intravenous perfusion (OR=5.8, 95% CI=2.5 to 13.3; AF=20.1%), stitches (OR=2.0, 95% CI=1.3 to 6.6; AF=10.7%), gum treatment (OR=3.7, 95% CI=1.1 to 11.9; AF=3.8%) and being illiterate (OR=2.4, 95% CI=1.4 to 4.4). Of the 100 cases, 18 had viraemic HCV infected household members. Three long-married (>15 years) couples were infected with virtually identical sequences and none of the three index patients reported any exposure at risk, suggesting HCV intra-familial transmission. CONCLUSION: While three new HCV infections out of 100 could be linked to intra familial transmission, parenteral iatrogenic transmission (dental care included) was accountable for 34.6% of these new infections. Thus, the relative contribution of intrafamilial transmission to HCV spread seems to be limited. PMID- 20947888 TI - PRSS3 promotes tumour growth and metastasis of human pancreatic cancer. AB - BACKGROUND AND AIMS: Metastasis accounts for the poor outcome of patients with pancreatic cancer. We recently discovered PRSS3 to be over-expressed in metastatic human pancreatic cancer cells. This study aimed to elucidate the role of PRSS3 in the growth and metastasis of human pancreatic cancer. METHODS: PRSS3 expression in human pancreatic cancer cell lines was detected by qPCR and immunoblotting. The effect of PRSS3 on cancer cell proliferation, migration and invasion in vitro, tumour growth and metastasis in vivo were investigated by manipulation of PRSS3 expression in human pancreatic cancer cell lines. VEGF expression was detected by ELISA, and the pathway through which PRSS3 regulates VEGF expression was investigated. The therapeutic effect of targeting this pathway on metastasis was assessed in vivo. Immunohistochemistry was employed to detect PRSS3 expression in human pancreatic cancer tissues. RESULTS: PRSS3 was over-expressed in the metastatic PaTu8988s cell line, but not in the non metastatic PaTu8988t cell line. Over-expression of PRSS3 promoted pancreatic cancer cell proliferation as well as invasion in vitro, and tumour progression and metastasis in vivo. Stepwise investigations demonstrated that PRSS3 upregulates VEGF expression via the PAR1-mediated ERK pathway. ERK inhibitor significantly delayed the progression of metastases of pancreatic cancer and prolonged the survival of animals bearing metastatic pancreatic cancer (p<0.05). 40.54% of human pancreatic cancers (n=74) were positive for PRSS3 protein. A significant correlation was observed between PRSS3 expression and metastasis (p<0.01). Multivariate Cox regression analysis indicated that patients with PRSS3 expression in their tumours had a shorter survival time compared to those without PRSS3 expression (p<0.05). CONCLUSION: PRSS3 plays an important role in the progression, metastasis and prognosis of human pancreatic cancer. Targeting the PRSS3 signalling pathway may be an effective and feasible approach for treatment of this lethal cancer. PMID- 20947890 TI - Right vocal cord paralysis and mediastinal lymphadenopathy. PMID- 20947891 TI - Ventilator modes and settings during non-invasive ventilation: effects on respiratory events and implications for their identification. AB - Compared with invasive ventilation, non-invasive ventilation (NIV) has two unique characteristics: the non-hermetic nature of the system and the fact that the ventilator-lung assembly cannot be considered as a single-compartment model because of the presence of variable resistance represented by the upper airway. When NIV is initiated, the ventilator settings are determined empirically based on a clinical evaluation and diurnal blood gas variations. However, NIV is predominantly applied during sleep. Consequently, to assess overnight patient machine 'agreement' and efficacy of ventilation, more specific and sophisticated monitoring is needed. The effectiveness of NIV might therefore be more correctly assessed by sleep studies than by daytime assessment. The most available and simple monitoring can be done from flow and pressure curves from the mask or the ventilator circuit. Examination of these tracings can give useful information to evaluate if the settings chosen by the operator were the right ones for that patient. However, as NIV allows a large range of ventilatory parameters and settings, it is mandatory to have information about this to better understand patient-ventilator interaction. Ventilatory modality, mode of triggering, pressurisation slope, use or not of positive end expiratory pressure and type of exhalation as well as ventilator performances may all have physiological consequences. Leaks and upper airway resistance variations may, in turn, modify these patterns. This article discusses the equipment available for NIV, analyses the effect of different ventilator modes and settings and of exhalation and connecting circuits on ventilatory traces and gives the background necessary to understand their impact on nocturnal monitoring of NIV. PMID- 20947892 TI - Can financial incentives for improvements in healthcare quality enhance identification of COPD in primary care? PMID- 20947893 TI - Predicting CAP-related mortality with CRB-65. PMID- 20947897 TI - Implementing the change in National Institute for Health and Clinical Excellence guidance on airflow obstruction grading in chronic obstructive pulmonary disease. PMID- 20947898 TI - A comparison between interferon gamma release assays and the tuberculin skin test in the contact tracing of patients with chronic kidney disease. PMID- 20947904 TI - A letter from New Orleans five years later. PMID- 20947905 TI - Should cigarette smoke exposure be a criterion to treat latent tuberculous infection? PMID- 20947906 TI - Diagnostic evaluation of respiratory failure in patients with cancer: narrowing the evidence gap. PMID- 20947907 TI - Prevention of ventilator-associated pneumonia: bugs or drugs? PMID- 20947908 TI - Utility of a provocation test for diagnosis of chronic pigeon breeder's disease. PMID- 20947909 TI - Occupational exposure to gases, fumes, or chemicals and risk of community acquired pneumonia. PMID- 20947910 TI - BODE plus DOSE plus PaO2 equals DO RE MI BOX? PMID- 20947911 TI - Steroid-sensitive post-viral inflammatory pneumonitis (PVIP). PMID- 20947912 TI - Acute abdomen with coffee bean sign. PMID- 20947914 TI - Lay basic life support: the current situation in a medium-sized German town. AB - OBJECTIVE: Basic life support (BLS) by laypersons is essential for surviving sudden cardiac death in the community. The present study investigates BLS skill knowledge of German laypersons in a public community place and examines the effect of the interval between the last BLS course and present skills in cardiopulmonary resuscitation (CPR). METHODS: Participants were randomly recruited at a public place in a medium-sized German town. Volunteers were confronted with a fictitious cardiac arrest situation using a BLS training manikin and were asked to help. Using a standardised evaluation sheet, measures were documented. Participants' demographic data were evaluated after completion of the scenario. RESULTS: None of the participants (n=89; male=42, female=47) followed the current BLS algorithm correctly; independent from the last CPR course was attended. Most steps were performed in random order. 43% (n=38) of participants checked for responsiveness, 65% (n=58) performed chest compressions, and 63% (n=56) delivered rescue breathing. 10% (n=9) of participants were unable to name a national emergency telephone number. Laypersons who attended a BLS course more than 10 years ago showed a significant lack of BLS knowledge and failed more often to deliver chest compressions and rescue breathing. CONCLUSIONS: The present study demonstrates that current CPR guidelines for BLS are not followed by laypersons in a medium-sized town in Germany. These data suggest that CPR refresher courses as well as implication of BLS guidelines in daily life are warranted. PMID- 20947915 TI - Acute respiratory failure in a neurologically impaired woman. PMID- 20947916 TI - Cardioversion of acute atrial fibrillation in the short observation unit: comparison of a protocol focused on electrical cardioversion with simple antiarrhythmic treatment. AB - BACKGROUND: Direct current cardioversion (DCC) has been shown to be effective for the management of atrial fibrillation (AF) in the emergency department (ED). Pharmacological cardioversion was compared with a strategy including DCC on patients with uncomplicated, recent-onset (<48 h) AF managed in a short observation unit (SOU). METHODS: A prospective observational study was undertaken over a period of 13 months in two institutions. A DCC-centred protocol was applied to 171 AF cases in a hospital (DCC-cohort) and pharmacological cardioversion to 151 AF cases in another hospital (P-cohort). Patients remaining in AF after 24 h were admitted. The outcomes were rate of discharge in sinus rhythm, length of stay in the ED-SOU, rate of hospitalisation and complications of treatment. Data collected were analysed according to Student t test and chi(2) statistics. RESULTS: Discharge in sinus rhythm was achieved in 159/171 cases in the DCC-cohort and 77/151 cases in the P-cohort (93% vs 51%; number needed to treat (NNT) 2.4; 95% CI 2.0 to 3.1, p<0.001), whereas mean length of stay was 7+7 h in the DCC-cohort and 9+6 h in the P-cohort (p=0.43). Eleven cases from the DCC cohort and 67 from the P-cohort were admitted (admission rate 6% vs 44%; NNT 2.6; 95% CI 2.2 to 3.5, p<0.001). Three short-term complications occurred in the DCC cohort and five in the P-cohort (2% vs 3%, p=0.59). Two strokes were registered in the DCC-cohort during 6-month follow-up (p undefined). CONCLUSIONS: Electrical cardioversion of recent-onset AF in the SOU is safe, effective and reduces hospitalisations. Further studies are needed to identify the most cost-effective strategy for the management of AF patients in emergency settings. PMID- 20947917 TI - Comparison of the over-the-head, lateral and alternating positions during cardiopulmonary resuscitation performed by a single rescuer with a bag--valve- mask device. AB - BACKGROUND: The 2005 guidelines for cardiopulmonary resuscitation (CPR) do not include a statement on performance of basic life support by a single healthcare professional using a bag-valve-mask device. Three positions are possible: chest compressions and ventilations from over the head of the casualty (over-the-head CPR), from the side of the casualty (lateral CPR), and chest compressions from the side and ventilations from over the head of the casualty (alternating CPR). The aim of this study was to compare CPR quality of these three positions. METHODS: 102 healthcare professionals were randomised to a crossover design and performed a 2-min CPR test on a manikin for each position. RESULTS: The hands-off time over a 2-min interval was not significantly different between over-the-head (median 31 s) and lateral (31 s) CPR, but these compared favourably with alternating CPR (36 s). Over-the-head CPR resulted in significantly more chest compressions (155) compared with lateral (152) and alternating CPR (149); the number of correct chest compressions did not differ significantly (119 vs 122 vs 109). Alternating CPR resulted in significantly less inflations (eight) compared with over-the-head (ten) and lateral CPR (ten). Lateral CPR led to significantly less correct inflations (three) compared with over-the-head (five) and alternating CPR (four). CONCLUSIONS: In the case of a single healthcare professional using a bag-valve-mask device, the quality of over-the-head CPR is at least equivalent to lateral, and superior to alternating CPR. Because of the potential difficulties in bag-valve-mask ventilation in the lateral position, the authors recommend over-the-head CPR. PMID- 20947918 TI - Knowledge of autonomic dysreflexia in the emergency department. AB - OBJECTIVES: To determine the level of knowledge that medical staff in the emergency department and spinal unit have of autonomic dysreflexia, its causes, symptoms, treatment and complications; and to educate the participating staff about autonomic dysreflexia. METHOD: The study design was a prospective questionnaire, which was completed by 91 staff in the spinal unit and emergency department in Christchurch, who then undertook a teaching session on autonomic dysreflexia. RESULTS: 29 of 70 staff in emergency department could not answer any questions. The average mark out of 29 was 2 for the emergency department and 12 for the spinal unit. Only 16 staff in the emergency department had had teaching on autonomic dysreflexia previously. CONCLUSION: Due to the potentially serious complications of autonomic dysreflexia, staff require teaching on autonomic dysreflexia accompanied by permanent reminders in the form of posters. PMID- 20947919 TI - An unusual case of bowel obstruction: phytobezoar mimicking narcotic drug packs. PMID- 20947920 TI - How does extracerebral trauma affect the clinical value of S100B measurements? AB - BACKGROUND: Protein S100B has proven to be a useful biomarker for cerebral damage. The predictive ability of S100B may, however, be affected by extracerebral injuries. The aim of this study was to investigate serum levels of S100B in patients with either isolated head injury (IHI), multi trauma with head injury (MTHI), or no head injury (NHI). The primary aim was to assess if a significant difference in serum levels of S100B could be found between IHI and MTHI patients. METHODS: Patients (233) were primarily admitted to the trauma centre. Serum samples were drawn on admission and 6 h after trauma and then stored at -80 degrees C until analysed. Variables included Abbreviated Injury Scale (AIS) for head trauma, Injury Severity Score (ISS) and 30-day survival. RESULTS: Two patients could not be classified. IHI occurred in 28, MTHI in 102 and NHI was found in 101. The median S100B concentrations on arrival were 0.47, 1.68 and 0.49 MUg/l, respectively (p<0.0001). The corresponding values at 6 h were 0.14, 0.31 and 0.15 MUg/l, respectively (p<0.0001). S100B was significantly higher in patients with MTHI than in patients with IHI at both time points (p values 0.0005 and 0.01). There was no significant difference in S100B between patients having IHI and patients with NHI (p=0.81 and p=0.67). CONCLUSIONS: High serum levels of S100B were found early after trauma. The highest concentrations of S100B were found in patients with multi trauma. This suggests that S100B serum concentrations are significantly affected by extracerebral injuries. PMID- 20947921 TI - Systematic review of alcohol screening tools for use in the emergency department. AB - To ascertain which alcohol screening tool is most accurate in identifying alcohol misuse in patients in the emergency department a systematic review of diagnostic cohort studies of appropriate alcohol screening tools was performed. A thorough search of medical databases and relevant peer journals was conducted. Citation and author tracking was also utilised due to an initial paucity of relevant literature. Seven relevant papers were identified from this search, which allowed a review of the quality of the following alcohol screening tools: the fast alcohol screening tool (FAST), the Paddington alcohol test (PAT), the rapid alcohol problem screen (RAPS-4) and the TWEAK (where TWEAK is an acronym of the first letter of the key words in the questions of this screening tool: tolerance, worried, eye-opener, amnesia, K (cut-down)). The most sensitive screening tool within this review appears to be the FAST (93-94%), which has a specificity of 86 88% with a positive predicted value of 86-87%. Although the FAST appears to be the best for accurately identifying alcohol misuse within emergency department patients, it was assessed as a universal screening tool, and it may not be feasible (time or cost) to screen all who present to this service. In contrast, the PAT has been developed to be used on a select population within the emergency department and has already been shown to be cost-effective. PMID- 20947922 TI - A novel ED-based sexual assault centre in western Kenya: description of patients and analysis of treatment patterns. AB - BACKGROUND: The aim of this study was to establish the feasibility of a Kenyan emergency department (ED)-based sexual assault centre; and to improve knowledge of the characteristics of sexual assault in the region. METHODS: The Center for Assault Recovery-Eldoret (CAR-E) was established to provide timely, culturally sensitive treatment of Kenyan sexual assault survivors using a standardised evaluation/treatment protocol. A retrospective review of charts of all sexual assault survivors attending CAR-E from May 2007-May 2008 was performed. Simple descriptive statistics, t tests, and OR were calculated. RESULTS: CAR-E treated 321 survivors over 13 months. Patients' mean age was 15.9 years; 50% were younger than 14years old. Survivors were predominately female and single. Most knew their assailant. Younger age was associated with increased likelihood of genital trauma. Only 43% of assaults were reported to the police. Sexually transmitted infection prophylaxis was given per protocol to 84% eligible; emergency contraception to 64%; and HIV prophylaxis to 63%. Only 44% received counselling. Survivors were more likely to get sexually transmitted infection and HIV prophylaxis, and emergency contraception if they had genital injury. CONCLUSIONS: Development of an ED-based sexual assault centre at a referral hospital in Kenya using a standardised history, physical, and treatment protocol was feasible, and high rates of prophylaxis were provided. Based on characteristics of people who have been assaulted, community prevention efforts should concentrate on decreasing the societal acceptability of rape. In conjunction with improvement of protocols at the centre under consideration, development of similar centres in sub-Saharan African ED should be encouraged. PMID- 20947926 TI - A randomized phase II trial to test the efficacy of intra-peritoneal paclitaxel for gastric cancer with high risk for the peritoneal metastasis (INPACT trial). AB - Owing to its peculiar pharmacological characteristics, paclitaxel attains substantial intra-peritoneal concentration for a prolonged period when delivered intra-peritoneally, and is active against peritoneal metastasis of ovarian cancer. It is also considered promising against disseminated gastric cancer. However, the fact that the intra-peritoneal paclitaxel has not been approved in Japan has rendered its evaluation by a formal clinical trial impossible. The authors designed a randomized phase II trial using the Kodo Iryo Hyoka system, a new system to legally test an yet unapproved mode of treatment. It is hoped that this trial will result in a breakthrough in the treatment of peritoneal carcinomatosis from gastric cancer. PMID- 20947927 TI - Low-dose acyclovir is effective for prevention of herpes zoster in myeloma patients treated with bortezomib: a report from the Korean Multiple Myeloma Working Party (KMMWP) Retrospective Study. AB - OBJECTIVE: Acyclovir prophylaxis has been considered as mandatory for patients receiving bortezomib because herpes zoster is a common adverse event associated with the use of bortezomib. Although the minimal effective dose of acyclovir for prophylaxis has not yet established, the efficacy of low-dose acyclovir prophylaxis, 400 mg once daily, has been suggested. METHODS: We retrospectively reviewed the patients receiving the low-dose acyclovir which was defined as the once daily administration of acyclovir 400 or 200 mg. All patients received bortezomib-containing chemotherapy in the setting of relapsed or refractory myeloma. RESULTS: Eighty patients received bortezomib-containing treatment as a salvage therapy. All patients received at least one or more treatments prior to bortezomib treatment, including autologous stem cell transplantation. Sixty-one patients received 400 mg of acyclovir once daily while 19 patients received 200 mg. Although seven cases of herpes zoster were observed from 80 patients (7/80, 8.75%), two cases of herpes zoster received 400 mg during the limited period from the first to the fourth cycle, and the other five received 200 mg. Therefore, there was no herpes zoster in patients who received 400 mg of acyclovir till the last cycle of bortezomib treatment. There were no adverse events associated with the use of acyclovir prophylaxis. CONCLUSIONS: The administration of acyclovir 400 mg once daily during the bortezomib treatment is an effective prophylaxis for herpes zoster in patients receiving bortezomib irrespective of disease state and the type of chemotherapy regimen. PMID- 20947928 TI - Large cell neuroendocrine carcinoma of the ampulla of vater with adenocarcinoma and squamous cell carcinoma components. AB - A 73-year-old woman visited our hospital complaining of general fatigue and jaundice. Laboratory tests revealed an elevated total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and gamma glutamyltransferase. Computed tomography and magnetic resonance imaging demonstrated a mass lesion at the ampulla of Vater with dilatation of the common bile duct and main pancreatic duct. Percutaneous transhepatic cholangiography revealed dilatation of the bile duct and a negative filling defect due to the tumor. Pancreatoduodenectomy was performed. The specimen included an ulcerated firm tumor of the papilla Vater. The surface of the ampulla consisted of well differentiated papillary adenocarcinoma, whereas the deep layer, such as submucosal or muscular layer, contained large cell neuroendocrine carcinoma and squamous cell carcinoma. Immunohistochemistry revealed that the large cell neuroendocrine carcinoma component was positive for chromogranin A, synaptophysin and CD56. The patient died from multiple liver and bone metastases 13 months after surgery. This is a very rare case of a large cell neuroendocrine carcinoma accompanied by adenocarcinoma and squamous cell carcinoma components. PMID- 20947929 TI - Aspiration thrombectomy with primary PCI for STEMI: review of the data and current guidelines. AB - The presence of visible thrombus at the time of primary PCI for STEMI is associated with poor procedural and clinical outcomes. Aspiration thrombectomy has been used with primary PCI in an attempt to improve these outcomes. The TAPAS (Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction) Trial found that aspiration improved myocardial blush scores and ST-segment resolution (STR), and also was associated with lower mortality at 1 year. Four meta-analyses have shown improved measures of myocardial reperfusion (TIMI flow, myocardial blush, and STR) and improved procedural outcomes (reduced no-reflow and distal embolization), and three of four trials have shown reduced mortality. Aspiration thrombectomy has received a Class IIa indication with primary PCI in the recent ACC/AHA and ESC Guidelines. Unanswered questions include whether there is truly a mortality benefit with aspiration, which subgroups may and may not benefit from aspiration, and whether patients with large thrombus burden are better treated with mechanical thrombectomy. PMID- 20947930 TI - Angiographic thrombus burden classification in patients with ST-segment elevation myocardial infarction treated with percutaneous coronary intervention. AB - The presence of thrombus is associated with adverse clinical outcomes. Our aim was to develop a classification of thrombus burden (TB) in patients with ST segment elevation myocardial infarction (STEMI). METHODS: We retrospectively analyzed 900 consecutive patients treated with percutaneous coronary intervention for STEMI. Drug-eluting stents were used in 90.1%. TB was graded (G) as G0 = no thrombus, G1 = possible thrombus, G2 = small [greatest dimension <= 1/2 vessel diameter (VD)], G3 = moderate (> 1/2 but < 2VD), G4 = large (>= 2VD), G5 = unable to assess TB due to vessel occlusion. Patients with G5 were reclassified to a thrombus category after flow achievement either with a guidewire or a small (1.5 mm) balloon. The incidence of major adverse cardiac events (MACE) - defined as death, myocardial infarction and infarct-related artery revascularization - was computed using the Kaplan-Meier method. RESULTS: Median duration of follow-up was 18.5 months. G5 patients constituted 57.7% of all patients and reclassification was achieved in 97.9%. TB after reclassification was G0, 8.1%; G1, 19%; G2, 24.5%, G3,16.6%, G4, 30%, G5, 1.9%. The 2-year cumulative MACE-free survival was comparable in G1, G2, G3 (84.5%, 85.9% and 87% respectively, p = 0.83), while G0 (75.8%) and G4 (75%) did significantly worse (p = 0.001). After stratification in two groups of small (G0-3) and large (G4) TB, the latter was found to be an independent predictor for 2-year mortality (HR: 1.66, 95% CI: 1.04-2.68, p = 0.035) and MACE rate (HR: 2.04, 95% CI: 1.44-2.88, p < 0.001). CONCLUSIONS: In patients with STEMI, TB can be reliably estimated in occluded infarct-related arteries. Large thrombus (>= 2 VD) is a significant independent predictor for mortality and MACE. PMID- 20947931 TI - Role of AngioJet rheolytic thrombectomy catheter: Mount Sinai Hospital experience. PMID- 20947932 TI - The current role of AngioJet rheolytic thrombectomy in acute myocardial infarction. PMID- 20947933 TI - JETSTENT trial results: impact on ST-segment elevation myocardial infarction interventions. AB - The results of meta-analyses of studies on manual thrombus aspiration and mechanical thrombectomy support the use of manual aspiration catheters and contraindicate the use of mechanical thrombectomy devices. However, the two largest studies dominate the meta-analysis results, the Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction Study (TAPAS) for the manual aspiration study group, and the Angiojet rheolytic thrombectomy In patients undergoing primary angioplasty for acute Myocardial Infarction (AIMI) trial for the mechanical thrombectomy group. The first demonstrated a clinical benefit of thrombus removal using the manual aspiration catheter. The AIMI trial, which included 480 patients, showed a negative and harmful impact on survival of rheolytic thrombectomy. The results of the recently concluded AngioJET Rheolytic Thrombectomy Before Direct Infarct Artery STENTing with Direct Stenting Alone in Patients with Acute Myocardial Infarction (JETSTENT) trial, which included 501 patients and showed a strong clinical benefit of rheolytic thrombectomy in the setting of primary PCI for acute myocardial infarction (AMI), adds new arguments in support of rheolytic thrombectomy in AMI. PMID- 20947934 TI - Panel summary and recommendations on the role of thrombectomy with primary PCI for STEMI. PMID- 20947935 TI - Unconventional gap state of trapped exciton in lead sulfide quantum dots. AB - Exciton states in lead selenide (PbSe) and lead sulfide (PbS) quantum dots have been studied extensively. However, relatively less attention has been paid to the states within the quantum dot bandgap. Our experimental results have revealed a single in-gap state which bears confinement dependence yet cannot be explained by dark exciton theory, nor is it a trap state related to quantum dot surface defects as previously observed. A detailed analysis of the temperature dependence of photoluminescence, Stokes shift, absorption and photoinduced absorption indicates the unconventional GS is a new state of a trapped exciton in a QD film. With appropriate design engineering, these trapped excitons might be harvested in solar cells and other optoelectronic devices. PMID- 20947936 TI - Energy dissipation measurements in frequency-modulated scanning probe microscopy. AB - Local dissipation measurements by scanning probe microscopy have attracted increasing interest as a method for probing energy losses and hysteretic phenomena due to magnetic, electrical, and structural transformations at the tip surface junction. One challenge of this technique is the lack of a standard for ensuring quantification of the dissipation signal. In the following, we explored magnetic dissipation imaging of an yttrium-iron garnet (YIG) sample, using a number of similar but not identical cantilever probes. Typical frequency dependent dispersion of the actuator-probe assembly commonly approached +/- 1 part in 10(3) Hz(-1), much larger than the minimum detectable level of +/- 1 part in 10(5) Hz(-1). This cantilever-dependent behavior results in a strong crosstalk between the conservative (frequency) and dissipative channels. This crosstalk was very apparent in the YIG dissipation images and in fact should be an inherent feature of single-frequency heterodyne detection schemes. It may also be a common effect in other dissipation imaging, even down to the atomic level, and in particular may be a significant issue when there are correlations between the conservative and dissipative components. On the other hand, we present a simple method for correcting for this effect. This correction technique resulted in self consistent results for the YIG dissipation measurements and would presumably be effective for other systems as well. PMID- 20947937 TI - Poly(acrylic acid)-stabilized colloidal gold nanoparticles: synthesis and properties. AB - Combining the intriguing optical properties of gold nanoparticles with the inherent physical and dynamic properties of polymers can give rise to interesting hybrid nanomaterials. In this study, we report the synthesis of poly(acrylic acid) (PAA)-capped gold nanoparticles. The polyelectrolyte-wrapped gold nanoparticles were fully characterized and studied via a combination of techniques, i.e. UV-vis and infrared spectroscopy, dark field optical microscopy, SEM imaging, dynamic light scattering and zeta potential measurements. Although PAA-capped nanoparticles have been previously reported, this study revealed some interesting aspects of the colloidal stability and morphological change of the polymer coating on the nanoparticle surface in an electrolytic environment, at various pH values and at different temperatures. PMID- 20947938 TI - Fade and quench-resistant emission in calcium phosphate nanoreactors. AB - The fluorescence emission and photodegradation properties of fluorescein dye inside fluid-filled spherical nanoreactors ~ 150 nm in diameter and surrounded by a few nanometres thick layer of calcium phosphate are considered in detail. Steady state, stopped flow, and laser pulsed fluorescence spectroscopies, absorption spectroscopy, dynamic light scattering and electron microscopy were used to characterize the materials as a function of encapsulated dye concentration, particle concentration, illumination time, and pH. Fluorescein tends to form stable J-aggregates inside the nanoreactors. The molecular collision rate constants between the dye aggregates and between the dyes and soluble quenchers are greatly reduced inside the nanoreactors and are responsible for the observed resistance to photodegradation and reduced emission quenching. A model for dye behaviour in nanoreactors is suggested. Nanoreactors can be concentrated to a high suspension concentration, yielding exceptionally strong luminescence affected only by inner filter effects absent particle-particle crosstalk. These and similar nanoreactors can be utilized as building blocks for three-dimensional photo-optical devices, and as versatile and resilient supramolecular chromophores or tracers in complex fluids, cells and microfluidic systems where high resolution visualization is needed. PMID- 20947939 TI - An efficient and biocompatible fluorescence resonance energy transfer system based on lanthanide-doped nanoparticles. AB - This work demonstrates an efficient and bio-friendly fluorescence resonance energy transfer (FRET) system based on lanthanide-doped inorganic nanoparticles. A facile aqueous route was used to synthesize the CePO(4):Tb nanorods with homogeneous colloidal dispersion, which emits a bright green light with a high quantum yield (~0.36) and a long fluorescence lifetime (~3.50 ms) upon UV excitation. Upon treatment of CePO(4):Tb with aqueous Rhodamine B (RhB), an efficient FRET occurs from the Tb(3+) to the RhB molecules, giving rise to well resolved and ratiometric emissions of donors and acceptors, respectively, with an energy transfer efficiency of up to 0.85. When incubated with HeLa cells at 37 degrees C, the CePO(4):Tb treated with RhB shows bright intracellular luminescence, indicating that it can be successfully internalized inside the cells and the FRET remains in the living cells. Moreover, the cytotoxic measurements demonstrate good biocompatibility and low cytotoxicity of our present FRET system. The advantages presented above including high quantum yield of donors, high energy transfer efficiency, ratiometric fluorescent emission and good biocompatibility, indicate the high potential of the CePO(4):Tb/RhB FRET system for monitoring biological events. PMID- 20947940 TI - One-dimensional germanium nanostructures--formation and their electron field emission properties. AB - Ge nanostructures were synthesized by reduction of GeO(2) in H(2) atmosphere at various temperatures. Entangled and straight Ge nanowires with oxide shells were grown at high temperatures. Ge nanowires with various numbers of nodules were obtained at low temperatures. Ge nanowires without nodules exhibited remarkable field emission properties with a turn-on field of 4.6 V um(-1) and field enhancement factor of 1242. PMID- 20947941 TI - Low- and high-temperature controls in carbon nanofiber growth in reactive plasmas. AB - A numerical growth model is used to describe the catalyzed growth of carbon nanofibers in the sheath of a low-temperature plasma. Using the model, the effects of variation in the plasma sheath parameters and substrate potential on the carbon nanofiber growth characteristics, such as the growth rate, the effective carbon flux to the catalyst surface, and surface coverages, have been investigated. It is shown that variations in the parameters, which change the sheath width, mainly affect the growth parameters at the low catalyst temperatures, whereas the other parameters such as the gas pressure, ion temperature, and percentages of the hydrocarbon and etching gases, strongly affect the carbon nanofiber growth at higher temperatures. The conditions under which the carbon nanofiber growth can still proceed under low nanodevice-friendly process temperatures have been formulated and summarized. These results are consistent with the available experimental results and can also be used for catalyzed growth of other high-aspect-ratio nanostructures in low-temperature plasmas. PMID- 20947942 TI - Flip-chip fabrication of nanoscale co-planar embedded electrodes with controlled exposed areas. AB - We discuss the fabrication of closely spaced nanoscale embedded co-planar electrodes with concealed contact wires, using a GaAs-based flip-chip technology. The co-planarity of the electrodes with the substrate and the low roughness of the exposed surface are achieved by templating the deposition of both the dielectric and electrode metal onto a smooth GaAs substrate. The resulting electrodes, with sizes of around 300 nm and separations as low as 25 nm, have RMS roughnesses of less than 0.2 nm and a co-planarity of around 1 nm. PMID- 20947943 TI - The interaction of an atomic force microscope tip with a nano-object: a model for determining the lateral force. AB - A calculation of the lateral force interaction between an atomic force microscope (AFM) tip and a nano-object on a substrate is presented. In particular, the case where the AFM tip is used to manipulate the nano-object is considered; i.e., the tip is displaced across the nano-object with the feedback off. The Hamaker equations are used to calculate the force when the tip and sample are not in contact and the Johnson, Kendall and Roberts (JKR) or Derjaguin, Muller and Toporov (DMT) formalisms are used for the contact force. The effect of the material parameters, the choice of contact theory and the shape of the nano object on the resulting lateral forces are explored. The calculation is applied to an experimental system consisting of a cadmium selenide nanorod on graphite. PMID- 20947944 TI - Gain without inversion in hybrid quantum dot-metallic nanoparticle systems. AB - We study the generation of tunable gain without inversion in semiconductor quantum dots using plasmonic effects. For this we investigate the impact of localized surface plasmons on coherent nonlinear exciton effects in a quantum dot when it is located in the vicinity of a metallic nanoparticle. It is shown that when such a system is exposed to a laser field and the distance between the quantum dot and the metallic nanoparticle is reduced the initial impact of plasmons is enhancement of the ac-Stark shift in the quantum dot. When this distance is reduced beyond a critical value, the results show abrupt formation of a significant of amount of gain without inversion in the quantum dot. We show that such a 'molecular' gain is associated with the plasmonic metaresonance (PMR) formed via combined effects of laser-induced coherence in the quantum dot and plasmons. PMID- 20947945 TI - Growth of Ga-doped ZnS nanowires constructed by self-assembled hexagonal platelets with excellent photocatalytic properties. AB - A new process for making single crystalline undoped and Ga-doped ZnS nanowires with simple evaporation and condensation procedures on Si and GaN is introduced. The process does not need additional catalysts or precursors. The growth mechanism is studied using transmission electron microscopy (TEM), x-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. TEM images show that the undoped ZnS nanowires exhibit an ordinary straight morphology, whereas the Ga doped nanowires are composed of aligned hexagonal platelets, connected in the center into nanowires to maximize surface area. The Ga 2p3 and S 2p peaks in the XPS results confirm the presence of Ga doping in the form of Ga-S bonding. Raman spectra show that the ZnS LO peak is red-shifted from 349 to 347 cm(-1), indicative of a tensile stress caused by the Ga dopants. The growth mechanism and photocatalytic activity of the Ga-doped ZnS nanowires are discussed. We also demonstrate the excellent photocatalytic activity of Ga-doped ZnS nanowires as compared to those of undoped ZnS nanowires and Ga-doped ZnS nanosheets. PMID- 20947946 TI - Ultrabroadband photodetection based on graphene ink. AB - We report photodetection in a very large spectral bandwidth, which encompasses ultraviolet, visible and near infrared, using graphene inks or graphene inks functionalized with either gold or silver nanoparticles, or gold nanoparticles further encapsulated with bovine serum albumin deposited on interdigitated electrodes fabricated on a silicon dioxide/silicon substrate. In contrast to gold functionalized graphene inks, which have responsivities better than 1 mA W(-1) at a 0.1 V bias over the huge bandwidth extending from 215 to 2500 nm, Ag functionalized inks show at least a four-fold increased responsivity, with a record value of 13.7 mA W(-1) in near infrared. PMID- 20947947 TI - Three-dimensional mesoporous gold film to enhance the sensitivity of electrochemical detection. AB - Cell-cell and cell-extracellular matrix (ECM) adhesion are fundamental and important in the development of a cell-based chip. In this study, a novel, simple, rapid, and one-step technique was developed for the fabrication of a uniform three-dimensional mesoporous gold thin film (MPGF) onto a gold (Au) coated glass plate based on an electrochemical deposition method. Scanning electron microscopy images demonstrated that the resulting MPGF electrode had uniformly distributed pores with diameters of about 20 nm. The cyclic voltammetric behavior of [Fe(CN)(6)](4-/3-) coupled onto MPGF and Au electrodes demonstrated that the MPGF electrode had a higher electrocatalytic sensitivity and reversibility than the bare Au electrode. The Arg-Gly-Asp (RGD) sequence containing the peptide was immobilized on the MPGF and bare Au substrates. HeLa cancer cells were then cultured on the RGD peptide layer. The successful immobilization of the peptide and cells was confirmed by atomic force microscopy. The cell proliferation and viability were evaluated by cyclic voltammetry and Trypan blue dyeing assay. These results indicated that the RGD/MPGF modified electrodes showed an electrochemical sensitivity in the detection of cancer cells which is approximately three times higher, especially at low cell density, than RGD/Au electrodes. This much improved sensitivity of the MPGF modified electrode demonstrates the potential for the fabrication of a highly sensitive and low-cost cell-based chip for rapid cancer detection. PMID- 20947948 TI - Gallium-assisted growth of silicon nanowires by electron cyclotron resonance plasmas. AB - The use of gallium droplets for growing Si nanowires (SiNWs) by electron cyclotron resonance plasmas is investigated. First, the relationship between evaporation time and resultant size of the gallium droplets is studied. Through the use of spectroscopic ellipsometry, the dependence of the surface plasmon resonance (SPR) energy on the droplet size is determined. From these gallium droplets, SiNWs were grown at 300 and 550 degrees C in electron cyclotron resonance plasmas containing SiH(4), Ar, and H(2). Scanning electron microscopy results show that tapered NWs are obtained for a wide range of growth conditions. Besides, it is found that H(2) plays an important role in the parasitic axial growth of the SiNWs. Namely, H(2) inhibits the radial growth and contributes dramatically to increasing the SiNW defects. PMID- 20947949 TI - Aptamer conjugated magnetic nanoparticles as nanosurgeons. AB - Magnetic nanoparticles have shown promise in the fields of targeted drug delivery, hyperthermia and magnetic resonance imaging (MRI) in cancer therapy. The ability of magnetic nanoparticles to undergo surface modification and the effect of external magnetic field in the dynamics of their movement make them an excellent nanoplatform for cancer destruction. Surgical removal of cancerous or unwanted cells selectively from the interior of an organ or tissue without any collateral damage is a serious problem due to the highly infiltrative nature of cancer. To address this problem in surgery, we have developed a nanosurgeon for the selective removal of target cells using aptamer conjugated magnetic nanoparticles controlled by an externally applied three-dimensional rotational magnetic field. With the help of the nanosurgeon, we were able to perform surgical actions on target cells in in vitro studies. LDH and intracellular calcium release assay confirmed the death of cancer cells due to the action of the nanosurgeon which in turn nullifies the possibility of proliferation by the removed cells. The nanosurgeon will be a useful tool in the medical field for selective surgery and cell manipulation studies. Additionally, this system could be upgraded for the selective removal of complex cancers from diverse tissues by incorporating various target specific ligands on magnetic nanoparticles. PMID- 20947950 TI - Atomic scale interface engineering for strain compensated epitaxially grown InAs/AlSb superlattices. AB - This paper presents a systematic investigation of strain compensation schemes for InAs/AlSb superlattices (SLs) on GaSb substrates. Short growth interruptions (soak times) under varying arsenic and/or antimony beam equivalent pressures in InAs/AlSb SLs with exemplary dimensions of about ((2.4/2.4) +/- 0.2) nm were investigated to achieve strain compensation. When using uncracked As(4), strain compensation was found to be unaccomplishable unless sub-monolayer AlAs spikes were inserted at the InAs -> AlSb interface. In contrast, the supply of cracked As(2) dimers leads directly to the formation of strain compensating AlAs-like interfaces. This mechanism allows various growth sequences for strain compensated superlattices, including soak-time-free and Sb-soak-only SL growth. Each of the two latter approaches yields layers with excellent crystal quality and minimal intermixing at the heterointerfaces as verified by high resolution x-ray diffraction analysis and transmission electron microscopy. PMID- 20947951 TI - Nanopillar growth by focused helium ion-beam-induced deposition. AB - A 25 keV focused helium ion beam has been used to grow PtC nanopillars on a silicon substrate by beam-induced decomposition of a (CH(3))(3)Pt(C(P)CH(3)) precursor gas. The ion beam diameter was about 1 nm. The observed relatively high growth rates suggest that electronic excitation is the dominant mechanism in helium ion-beam-induced deposition. Pillars grown at low beam currents are narrow and have sharp tips. For a constant dose, the pillar height decreases with increasing current, pointing to depletion of precursor molecules at the beam impact site. Furthermore, the diameter increases rapidly and the total pillar volume decreases slowly with increasing current. Monte Carlo simulations have been performed with realistic values for the fundamental deposition processes. The simulation results are in good agreement with experimental observations. In particular, they reproduce the current dependences of the vertical and lateral growth rates and of the volumetric deposition efficiency. Furthermore, the simulations reveal that the vertical pillar growth is due to type-1 secondary electrons and primary ions, while the lateral outgrowth is due to type-2 secondary electrons and scattered ions. PMID- 20947952 TI - Electroluminescence from silicon nanoparticles fabricated from the gas phase. AB - Electroluminescence from as-prepared silicon nanoparticles, fabricated by gas phase synthesis, is demonstrated. The particles are embedded between an n-doped GaAs substrate and a semitransparent indium tin oxide top electrode. The total electroluminescence intensity of the Si nanoparticles is more than a factor of three higher than the corresponding signal from the epitaxial III-V semiconductor. This, together with the low threshold voltage for electroluminescence, shows the good optical properties of these untreated particles and the efficient electrical injection into the device. Impact ionization by electrons emitted from the top electrode is identified as the origin of the electrically driven light emission. PMID- 20947953 TI - Simultaneous quantification of multiple magnetic nanoparticles. AB - Distinct magnetic nanoparticle designs can have unique spectral responses to an AC magnetic field in a technique called the magnetic spectroscopy of Brownian motion (MSB). The spectra of the particles have been measured using desktop spectrometers and in vivo measurements. If multiple particle types are present in a region of interest, the unique spectral signatures allow for the simultaneous quantification of the various particles. We demonstrate such a potential experimentally with up to three particle types. This ability to concurrently detect multiple particles will enable new biomedical applications. PMID- 20947954 TI - Presidential address. PMID- 20947955 TI - Std trends in chengalpattu hospital. AB - A retrospective data analysis was carried out to find the trends in frequency and distribution of different STDs at Chengalpattu during 1988-1994. Of the 4549 patients who attended the clinic 3621 (79.6%) were males and 928 (20.4%) were females. The commonest STD was Chancroid (24.4%) in men and Syphillis (29%) in women. Balanoposthitis (11.4%) ranked third among STDs in males. Though the STD attendance showed a declining trend, most diseases showed a constant distribution. The percentage composition of secondary and latent syphillis, Genital Warts, Genital Herpes and the Non-Venereal group showed an increased composition in recent years. Primary syphillis in females showed a definite declining trend. The HIV sero-positive detection rate was 2.06%. Of the 1116 patients screened for HIV antibody, 23 patients were detected sero-positive. Time Series Regression Analysis was used to predict the number of patients who would attend the STD clinic with various STDs in 1995 and 1996 to help in the understanding of the disease load and pattern in future, in resources management and in developing and evaluating preventive measures. PMID- 20947956 TI - Is keratosis punctata of the palmar creases rare? AB - We determined the prevalence of keratosis punctata of the palmar creases (KPPC) in 5000 individuals. The group screened included patients, visitors and children. Fifteen (0.3%) cases were discovered to have characteristic KPPC lesions. The patients were mainly young with a male predominance (14M : 1F). The lesions in almost all cases were asymptomatic. No predisposing factors could be ascertained by history. Histopathologically, the lesions consisted of focal hyperkeratosis, and an epidermal depression corresponding to the pits. Special stains did not reveal any dermal components in the keratin masses. On comparing our findings with those reported earlier it appears that KPPC is not so rare as believed. PMID- 20947957 TI - Rifampicin and dapsone in superficial pustular folliculitis. AB - Fifty male patients diagnosed to have superficial pustular folliculitis (SPF) were included in an open trial to study the effects of rifampicin vs dapsone. Rifampicin, in a dose of 10mg/kg body weight for a period of 8 weeks was given for 25 patients in phase I and the drug cleared the lesions in 72%. Dapsone in a dose of 100 mg/day produced moderate response in 20% only. 17 patients who did not clear with dapsone were started on rifampicin (phase II) and 7/17 showed marked improvement. Remissions with rifampicin ranged from 3-9 months or longer. In patients who relapsed, a second course of the drug was effective. PMID- 20947958 TI - New focus of cutaneous leishmaniasis in India : Preliminary report. AB - An epidemiological investigation was carried out in hilly areas of western ghats of Kerala state, India during 1993, to verify a focus of cutaneous leishmaniasis. Out of 406 surveyed population, 11 cases were detected, among which two were positive for LD bodies in slit skin scraping examination. The disease was indigenously transmitted. Further investigation is advocated to identify leishmania species, vector and the reservoir. PMID- 20947959 TI - Oral psoralens vs injection placental extract plus oral psoralens in vitiligo. AB - One hundred patients with vitiligo were enrolled from out patient department from the year 1990-91 for screening the therapeutic effect of injection placental extract (Placentrex). Patients were divided into two groups of 50 each, age and sex matched and were given two different regimens of treatment. In Regimen- I, patients were given oral psoralens followed by sun exposure after 2 hours and then application of topical betamethasone-17 valerate. In Regimen-ll patients were given treatment as in regimen-l along with injection of placental extract. It was found that initial response rate of Regimen-ll therapy was 36% higher than Regimen-l whereas total efficacy of R-ll was 20% higher than R-l. PMID- 20947960 TI - Disability in leprosy patients after MDT. AB - Disabilities continue to develop and increase in severity with dapsone monotherapy. This study shows the impact of MDT on disabilities. We interviewed the patients of Chiraigaon block (population,185,521) who had completed MDT under NLEP. There had been significant increase in number of patients with grade-ll and III disability during the course of MDT. This could have been reduced if regular disability examination was done. Long lag period between the onset of disease and start of MDT was an important reason for high disability rate. PMID- 20947961 TI - Dowling-degos disease. AB - Four cases of Dowling-Degos disease with classical reticulate,flexural pigmentation are described.One of the four patients had milia,while all of them had perioral pitted scars. PMID- 20947962 TI - Azathioprine as a corticosteroid-sparing agent in air-borne contact dermatitis. AB - Two patients having air-borne contact dermatitis (ABCD) caused by Parthenium hysterophorus.for 10 and 15 years respectively and without having had complete remissions in spite of oral betamethasone in a dose of 2-3 mg per day, experienced complete relief while taking 50-100 mg azathioprine for 5 and 12 weeks without having to take systemic corticosteroids. There were no side effects of azathioprine. With further experience and standardization of the treatment schedule, it may be possible to use azathioprine as a corticosteroid-sparing agent to reduce the side effects of corticosteroids in patients having ABCD. PMID- 20947963 TI - Fixed duration MDT in leprosy and clinical cure. AB - Fixed duration multi drug therapy has been found to be very effective in elimination of leprosy from public health point of view. This study was conducted to see its effectiveness so far as 'clinical cure' is concerned. One hundred consecutive patients attending a consultant's clinic were followed till a period of 6 months and 2 years in PB and MB cases of leprosy respectively. Sixty four percent of the total patients had 'clinical cure' at the end of prescribed treatment. PMID- 20947964 TI - Darier's disease with warty dyskeratoma and basal cell epithelioma. AB - A 48-year old man with warty dirty papules over the seborrhoeic areas, also had a nodule with a central keratotic crater over the right cheek. Biopsy of this nodule revealed features of Darier's disease, warty dyskeratoma and basal cell epithelioma. Even though Darier's disease and warty dyskeratoma are considered as a distinct entities, the presence in the same lesion emphasizes the need for further studies on this association. PMID- 20947966 TI - Cutaneous leishmaniasis in Assam. AB - A case of cutaneous leishmaniasis is being reported from Assam, a North Eastern state of India. Clinical feature and direct smear examination of the case confirmed the diagnosis. Dramatic resolution of the lesions with sodium antimony gluconate during 10 days of therapy was achieved. PMID- 20947965 TI - Acrokeratosis paraneoplastica. AB - A 60-year old man with squamous cell carcinoma of hypopharynx and acrokeratosis paraneoplastica (Bazex syndrome) is reported. PMID- 20947967 TI - Tinea faciei and tinea capitis in a 15-day-old infant. AB - A case of tinea faciei and tinea capitis in a 15-day-old male infant caused by Trichophyton tonsurans is being reported because of its rarity. This may be the youngest infant from India where source of infection was his elder brother who had black dot type of tinea capitis and incubation period in the present case was 7 days. PMID- 20947968 TI - Condylomata acuminata in a child. AB - Perianal condylomata acuminata in a 21/2-year-old female child was seen. Younger age and site of lesion is interesting feature of this case. PMID- 20947969 TI - Relapse, reinfection or inadequate MDT ? AB - Relapse by all standard definitions is reported in a middle aged woman after PB MDT. Since she belonged to a family of treated leprosy sufferers (husband and his elder brother) and her daughter has now developed infectious type of leprosy, the possibility of reinfection can also not be ruled out. PMID- 20947970 TI - Follicular infundibulum tumour presenting as cutaneous horn. AB - Tumour of follicular infundibulum is an organoid tumour with a plate like growth attached to the epidermis with connection from the follicular epithelium. We are reporting such a case unusually presenting as cutaneous horn. PMID- 20947971 TI - Wrinkles due to idiopathic dermal elastolysis. AB - This report deals with the skin changes in a 9-year-old male patient, appearing clinically as a localized area of wrinkling of skin accompanied by follicular prominences over the involved skin, and characterized histopathologically by dermal loss of elastic tissue. PMID- 20947972 TI - Angiokeratoma of scrotum (fordyce). AB - Four cases of angiokeratoma of scrotum (Fordyce) in persons aged 30, 55, 50 and 58 years of 2, 5, 8 and 3 years duration respectively are reported. Three patients had fungal infection along with dermatitis while the other had piles and fissure. No abnormality was detected in systemic examination. Routine laboratory tests were normal. Histology confirmed the diagnosis. Each individual lesion was electrodessicated with no recurrence in 2 years of follow-up. PMID- 20947973 TI - Severe bullous fixed drug eruption due to metronidazole mimicking a localized form of toxic epidermal necrolysis. AB - A 55-year-old diabetic male who had severe bullous fixed drug eruption mimicking a localized form of toxic epidermal necrolysis 8 hours after taking metronidazole is presented. PMID- 20947974 TI - Hyalinosis cutis et mucosae with rare ocular involvement. PMID- 20947975 TI - Acute reversible hepatic toxicity by trimethoxy psoralen. PMID- 20947976 TI - Incontinentia pigmenti. PMID- 20947977 TI - 21 Hydroxylase deficiency manifesting with acne. PMID- 20947978 TI - Primary localised cutaneous amyloidosis. PMID- 20947980 TI - Contact leucoderma caused by lemon. PMID- 20947979 TI - Ulcerative lichen planus of the foot. PMID- 20947981 TI - Epidermodysplasia verruciformis. PMID- 20947982 TI - Hypervitaminosis - a. PMID- 20947983 TI - Plasma cell cheilitis. PMID- 20947984 TI - Preherpetic neuralgia masquerading as angina. PMID- 20947985 TI - Immunocytochemistry in dermatopathology : methodology. AB - Immunohistochemical staining methods are so widely used today that they can be truly referred to as just another special stain. These techniques are used to recognize, classify and understand the pathogenesis of a variety of skin processes, ranging from the identification of poorly differentiated tumours to the classification of autoimmune diseases. It is the purpose of this review article to provide an understanding of these immunoenzyme techniques. PMID- 20947986 TI - Chronic folliculitis in Sri Lanka. AB - Chronic folliculitis (CF) is a chronic infection of hair follicles leading to atrophy and loss of the affected hairs. This study was done on 51 patients with CF presenting at the Dermatology Clinic at General Hospital Matara, Sri Lanka, to identify specific clinical features and aetiological factors, and to study histopathology. Pus cultures were done on 25 cases. Biopsies were done on 6 patients. CF was commoner in males (59%); 76% were under 34 years, and 39% had occupational exposure to possible irritants. Thirty five precent admitted of scrubbing legs with rough objects. Ichthyosis vulgaris was evident in 47%. All pus cultures revealed Staphylococcus aureus. Clinical features and histopathological features were similar to those described by Harman (1968). Rough scrubbing, ichthyosis and occupational exposure to irritants may be aetiologically relevant. PMID- 20947987 TI - Normal variants of skin in neonates. AB - 2221 consecutive live births taking place between March 1994 and February 1995 were evaluated for a minimum period of 5 days to note for the occurrence of various normal anatomical variants specially those of skin. Birth weight, gestational age, maternal age, socio-economic status and consanguinity were carefully recorded in all the cases. Mongolian spots (72%), Epstein pearls (43.8%), Milia (26.2%) and Erythema toxicum (25.2%), were the common dermatological variants noted. Maturity of the babies and possibly genetic factors (consanguinity) are important factors in their causation as ordered in our study. PMID- 20947988 TI - Sulfasalazine in treatment of psoriasis. AB - A 5-lipoxygenase inhibitor-sulfasalazine was compared to a known effective drug methotrexate in psoriasis. Fifteen patients each were put on sulfasalazine (1500 mg/day) and methotrexate (7.5 mg/week). Assessment was made on the basis of EST (Erythema, Scaling and Thickness) scale, initially and then weekly upto 4 weeks followed by 4 weekly upto 12 weeks. Efficacy was comparable for the 2 drugs: decrease in mean EST in patients on methotrexate and sulfasalazine therapy was 86.55% and 83.64% at 4 weeks; and 92.86% and 92.13% at 12 weeks respectively. Nine patients on sulfasalazine therapy and 10 patients on methotrexate therapy had complete clearance at the end of 12 weeks. PMID- 20947989 TI - HBsAg and sexually transmitted diseases. AB - HBsAg was studied in 50 patients of STD's and promiscuous persons. In 10.52% cases it was positive. Vaccination against Hepatitis-B was recommended in promiscuous individuals. PMID- 20947990 TI - A combination of amoxicillin and clavulanic acid in the treatment of pyoderma in children. AB - The efficacy and safety of amoxicillin plus clavulanic acid was compared with that of amoxicillin, erythromycin and co-trimoxazole in an open label, randomized trial in 50 children in each group (total 200) with mild to severe pyodermas. Majority (47%) had impetigo. Fifty (25%) children had mild pyoderma, 56 (28%) had moderate and 94 (47%) children had severe pyoderma. Pure growth of S aureus was isolated in 130 (65%) children, S pyogenes in 42 (21%) and both organisms in 28 (14%) children. In mild to moderate pyoderma either of the drug tried was equally effective. In severe pyoderma, 24 of twenty five (96%) children receiving amoxicillin plus clavulanic acid, 18 of twenty (90%) children in amoxicillin group, 20 of twenty four (83.3%) children in erythromycin group and 13 of twenty five (52%) children in co-trimoxazole group showed clinical cure of therapy. Amoxicillin combined with clavulanic acid was well tolerated in children and there was no significant side effect except mild diarrhoea in two cases (4%) which was well controlled by taking the drug with meals. PMID- 20947991 TI - Chlamydia trachomatis antigen in female genital tract infection. AB - Thirty cases of female genital tract infection were investigated for the presence of Chlamydia trachomatis antigen. Endocervical swabs obtained were subjected to antigen detection by enzyme immunoassay. Rabbit antiserum to chlamydial lipopolysaccharide was used in a card test. Anti rabbit immunoglobulin G conjugated to alkaline phosphatase with a chromogenic substrate 5 bromo-4 chloro 3-indolyl phosphate and nitro blue tetrazolium were used for the enzymatic reaction. Chlamydial antigen could be detected in four out of thirty samples (13.3%). In contrast direct immunofluorescence detected 5 cases (16.6%). Although less sensitive, enzyme immunoassay can be used as a rapid diagnostic tool in detecting Chlamydia trachomatis antigen in genital infections. PMID- 20947992 TI - Atypical manifestations of tinea faciei. AB - A study of 58 paitents of tinea faciei was conducted. Twenty five (43.1%) patients had history of photosensitivity. Twenty eight (48.2%) patients were applying topical steroids, 2 (3.4%) patients were on 10 mg of prednisolone daily. Associated tinea of other sites were observed in 14 (24.13%). 23 (39.6%) patients had typical circinate, arcuate, annular plaques with raised margin showing vesiculo-pustules. Atypical manifestations were in the form of arcuate plaques on the pinna in 4 patients, erythematous plaques full of vesiculo-pustules without central clearing in 3. Thirty two (55.17%) patients had plaques with broad edges and indistinct central clearing. In 2 patients lesions resembled discoid lupus erythematosus. Skin scrapings for fungus was positive in 36 (62.06%) cases. All patients responded to systemic griseofulvin 10mg/kg with 1% clotrimazole topicaly in 4-8 weeks. PMID- 20947993 TI - Bullous pemphigoid in childhood. AB - A young child with clinical presentation and histology like chronic bullous dermatosis of childhood and immunopathology of bullous pemphigoid is being reported to make the readers aware of its existence in Indian population and to stress the importance of immunopathology in bullous disorders of childhood. PMID- 20947994 TI - Psoriasiform sarcoidosis associated with depigmentation. AB - A 65-year-old female had psoriasiform, depigmented, angiolupoid, lupus pernio, papular and verrucous plague type of cutaneous sarcoidosis. Systemic involvement (hepatomegaly, bilateral persistent swelling of the parotid glands, pain in the hands, weakness and atrophic rhinitis of the left nasal cavity) was also present. The histopathological features of a non-caseating epithelioid cell granuloma with giant cells confirmed the diagnosis. The patient is responding favourably to prednisolone 10 mg daily. PMID- 20947995 TI - Alopecia totalis treated with oral mini-pulse (OMP) therapy with betamethasone. AB - An 8-year-old girl having alopecia areata which progressed to alopecia totalis in 11/2 years showed an incomplete regrowth of the hair when treated with our standard regime of 1 mg betamethasone per day orally in spite of the treatment having been continued for 8 months. She had also increased her body weight by 4 kg during this period. On instituting the OMP regime consisting of 5 mg betamethasone as a single oral dose with breakfast on two consecutive days per week, she showed complete regrowth of the hair over the entire scalp during the next 3 months, and there were no side effects. We recommend OMP as another choice for patients having alopecia areata especially in recalcitrant cases where the treatment has to be given for prolonged periods. PMID- 20947996 TI - Lichen planus and lupus erythematosus overlap syndrome. AB - A 45-year-old woman with livid plaques showing central atrophy and erythematous vesicular borders over both dorsa of feet and buttocks, and follicular and papular lesions over buttocks and lumbar area, was difficult to diagnose as either lichen planus (LP) or lupus erythematosus (LE). The histological studies from two places showed features of both LE and LP. Laboratory findings were within normal limits first, but follow up studies for two years showed persistent albuminurea, leucopenia, arthritis and erythema over the exposed areas with same histology suggesting that eruption may be an unusual variant of LE. PMID- 20947997 TI - Disseminate and persistent infundibulo-folliculitis. AB - An 18-year-old girl presented with a persistent skin eruption of 6 years duration. She had skin-coloured follicular papules involving the trunk, proximal extremities, neck and face. Histopathology revealed spongiosis of the follicular infundibulum and infiltration with lymphocytes and neutrophils. Treatment with oral vitamin A and topical retinoic acid was ineffective. PMID- 20947998 TI - Continual skin peeling syndrome. AB - Two cases of continual skin peeling syndrome (CSPS) are presented. PMID- 20947999 TI - Trichotillomania in a 2-year-old child. AB - A case report of a 2-year-old child with trichotillomania is described. PMID- 20948000 TI - Granular cell tumour. AB - A 51/2-years-old boy presented with multiple skin coloured subcutaneous nodules on scrotum and penoscrotal regions. Oldest lesion started 8 months back and new lesion was one month old. Biopsy report revealed the tumour to be granular cell tumour. PMID- 20948001 TI - Localised cutaneous blastomycosis : Response to fluconazole. AB - A case of atypical cutaneous blastomycosis is reported. Patient responded to oral fluconazole 200 mg per day given for 9 months. PMID- 20948002 TI - Tuberous sclerosis with interesting features. AB - A case of tuberous sclerosis with intracranial calcification, retinal phakoma and premature canities is reported for its interesting features. PMID- 20948003 TI - Calcinosis universalis in childhood. PMID- 20948004 TI - Extensive tinea corporis caused by T verrucosum in a patient of HIV infection. PMID- 20948005 TI - Oral lichen planus caused by dental amalgam. PMID- 20948006 TI - Benign familial chronic pemphigus in a diabetic. PMID- 20948007 TI - Tropical triamcinolone acetonide in an indigenous orabase in oral lichen planus. PMID- 20948008 TI - Aids related kaposi's sarcoma - Like lesion. PMID- 20948009 TI - Alopecia areata and xerosis in down's syndrome. PMID- 20948010 TI - Why lesions of morphoea are often hyperpigmented ? PMID- 20948011 TI - Clearance of plaque psoriasis following irritation due to calcipotriol. PMID- 20948012 TI - Evidence for cytomegalovirus infection as the cause of vitiligo. PMID- 20948014 TI - Sneddon-wilkinson disease. PMID- 20948013 TI - Sporotrichoid mycobacteriosis. PMID- 20948015 TI - Pentoxiphylline in contact hypersensitivity reactions. PMID- 20948016 TI - Therapeutic spot and regional dermabrasion in stable vitiligo. AB - Therapeutic spot or regional dermabrasion was carried out at 64 sites located over cosmetically unimportant hairy areas (52) and non-hairy areas (12) in 15 cases of stable vitiligo. Lesions were individually dermabraded first with either electric or manual dermabraders till pinpoint bleeding occurred. They were further deep demabraded to an appropriate depth manually. On healing, all the 64 sites were further treated with PUVA or PUVASOL. Out of 52 hairy sites 46 sites (88.5%) showed total pigmentation, 2 showed partial pigmentation and in 4 sites there was no pigmentation. Out of 12 non-hairy sites, 10 sites (88.3%) showed only perilesional hyperpigmentation along the borders with no change in the remaining 2 sites. Side effects were superficial scarring (5) and hypopigmentation (4) which improved over next 6 months. Complications were deep scarring (3) and secondary infection (1). Therapeutic spot or regional dermabrasion is useful alone or in combination with PUVA/PUVASOL for treating stable vitiligo (hairy areas). PMID- 20948017 TI - Chrysotherapy in psoriasis. AB - Efficacy of oral gold was assessed in 23 patients with psoriasis of various types with excellent or good response in 14 patients (60%) whereas patients belonging to the age group of 11-20 years showed beneficial response in 10 out of 12 patients (83%). None of the patients experienced any side effect. It was concluded that oral gold (6mg/ day) for 3 to 6 months can be used as an alternative therapy in psoriasis especially in younger age group. PMID- 20948018 TI - Cutaneous leishmaniasis in Jodhpur district. AB - Cutaneous leishmaniasis is a disease with a wide geographical distribution in a range of climate and with different epidemiological patterns. In Rajasthan a new endemic zone of the disease has been found at Jodhpur district. The clincial features of 21 smear positive cases of oriental sore from Jodhpur district studied during a period of 1 year have been described. Also the importance of intralesional berberine sulphate in the treatment of oriental sore has been highlighted. PMID- 20948019 TI - Histopathological study of 60 cases of cutaneous vasculitis. AB - Sixty cases of cutaneous vasculitis were selected from department of Skin and STD, Government Medical College/Rajendra Hospital, Patiala. Detailed history, general physical examination, systemic examination and dermatological examination were conducted in each and every case. Routine investigations were done. Clinical diagnosis was confirmed by biopsy. Histopathologic study was conducted by using H & E stain under 100X and 400X by light microscopy. PMID- 20948020 TI - Dermatological manifestations of chronic renal failure. AB - Dermatological manifestations of chronic renal failure were studied in 35 cases. Xerosis was seen in 16 cases. Pruritus was observed in 12 cases and hyperpigmentation on exposed areas was seen in 8 patients. Acquired perforating disorder and half and half nail were seen in 6 cases each. Skin Biopsies performed in 6 cases of APD showed typical changes only in 3 cases. PMID- 20948021 TI - Botryomycosis. AB - Three cases (two male, one female) of botryomycosis are reported. All were adults and had no predisposing factors or immunosuppression. Staphylococcus, Pesudomonas and E coli were grown on bacterial culture. Patients were treated with antibiotics based on the sensitivity pattern with fairly good response. No systemic involvement was present in any case. PMID- 20948022 TI - Topical tretinoin in acanthosis nigricans. AB - Efficacy of topical tretinoin was assessed in 30 cases of idiopathic acanthosis nigricans which were recalcitrant to conventional modalities of treatment. Topical tretinoin once at night application was found to be very effective both clinically and histologically. PMID- 20948023 TI - Accessory tragi in three successive generations. AB - A 40-year-old man presented with clinical and histopathological features of accessory tragi. His father and 3 sons and 1 daughter had similar lesions. In view of this vertical transmission through 3 successive generations involving both the sexes, an autosomal dominant mode of inheritance is suggested. PMID- 20948024 TI - Pentoxifylline in reactions in leprosy. AB - A study was conducted to assess the response of reactions in leprosy to pentoxifylline therapy. Ten cases were studied; 8 cases had type 2 reaction and 2 cases had type 1 reaction. Pentoxifylline was given orally 400 mg three times daily. In patients with type 2 reaction, good response was observed within one week. There was near complete regression of ENL lesions within one month. Cases with type 1 reaction did not respond to pentoxifylline. PMID- 20948025 TI - Chloroquine-induced photosensitive dermatoses. AB - Two female patients suffering from rheumatoid arthritis were put on chloroquine 250 mg bid. After a period of 4 weeks, both of them developed photosensitive dermatitis. Following withdrawal of chloroqunie, both of them showed improvement in dermatitis gradually over a period of 3-4 months. PMID- 20948026 TI - Chloroquine-induced toxic epidermal necrolysis. AB - Two female patients aged 25 and 12 years suffering from malaria presented with picture of Stevens Johnson syndrome. Each of them had received daily doses of chloroquine phosphate by intramuscular injection for 3 days. They progressed to toxic epidermal necrolysis and could not be saved despite best of efforts. PMID- 20948027 TI - Congenital leukaemia presenting with skin nodules. AB - A 2-month-old infant presented with the skin nodules of 11/2 months duration. Routine investigation and bone marrow examination showed the presence of myeloblastic Ieukaemia-M4 type, FAB classification. PMID- 20948028 TI - Cutaneous sarcoidosis. AB - Cutaneous sarcoidosis in a middle aged lady is reported. Though sarcoidosis is rare in our country, an awarenesss about this condition is required to prevent misdiagnosis. PMID- 20948029 TI - Numerous giant mollusca contagiosa and kaposi's sarcomas with HIV disease. AB - A 50-year old man with a history of multiple contacts with commercial sex workers and two episodes of blood transfusions in Bombay, presented with giant mollusca contagiosa, Kaposi's sarcomas and refractory pulmonary tuberculosis. Patient was confirmed to be infected with HIV by ELISA and Western blot method. PMID- 20948030 TI - Congenital multiple cutaneous mastocytoma. AB - A rare case of multiple cutaneous mastocytoma presenting at birth with multiple skin coloured to hyperpigmented papulonodules and plaques all over the body is being reported. PMID- 20948031 TI - Osteoma cutis. AB - A very rare case of osteoma cutis is being presented here. Cutaneous involvement was very extensive in this case. PMID- 20948032 TI - Disseminated superficial actinic porokeratosis. AB - Disseminated superficial actinic porokeratosis in a 40-year-old man is described. The diagnosis was confirmed by histopathology in which the classical cornoid lamella was seen. PMID- 20948033 TI - Nodular colloid degeneration over herpes zoster scars. AB - A rare case of nodular colloid degeneration is reported which presented clinically as plaques studded with soft yellow papules simulating adult colloid milia superimposed only on herpes zoster scars of right side of the face. PMID- 20948034 TI - Multiple painful neurilemmomas. AB - A 40-year-old male with painful neurilemmoma is reported. Clinically the patient had multiple painful nodular lesions over the right lower limb. Histopathology confirmed the diagnosis of neurilemmoma. The probable mechanism for painful nodular presentation is highlighted. PMID- 20948035 TI - Zosteriform network of spiradenoma. AB - Spiradenoma is a solitary, deep seated nodule occurring on the ventral surface of the body, especially over the upper half. We are describing a case of spiradenoma with zosteriform arrangement. PMID- 20948036 TI - Mutilating acral keratoderma. AB - A 15-year-old male, born of non-consanguineous marriage started developing thickening of skin of sole of the both feet at the age of 7 which progressed to involve whole of both feet by 11th year. Patient later developed painful autoamputation of little toes of both feet due to pseudoainhum. Involvement of the palms was limited to a localised area over palmar aspect of right middle finger and was non-progressive. No other family member was affected. This may represent a variant of Vohwinkel's syndrome or the rarer form of acral keratoderma. PMID- 20948037 TI - Hereditary motor and sensory neuropathy mimicking hansen's disease. AB - A rare case of hereditary motor and sensory neuropathy in a 45 year old man with glove and stocking hypoaesthesia, bilateral clawing, foot drop and thickening of the peripheral nerves mimicking Hansen's disease is reported. PMID- 20948038 TI - Cutaneous complications of parenteral pentazocine abuse. AB - A 26-year-old man, a parenteral pentazocine abuser for past 10 years, presented with woody induration on the areas of injections and multiple, punched-out, deep, painless ulcers surrounded by hyperpigmented halo. This appears to be the first report from India on skin manifestations of pentazocine abuse. PMID- 20948039 TI - Corticosteroids : Use in herpes zoster. PMID- 20948041 TI - Infectivity of varicella and herpes zoster. PMID- 20948042 TI - Malignant acanthosis nigricans. PMID- 20948040 TI - Keratoacanthoma masquerading as squamous cell carcinoma. PMID- 20948043 TI - Benign mucous membrane pemphigoid simulating genitoulcerative disease. PMID- 20948044 TI - Seborrhoeic keratosis of the external genitalia. PMID- 20948045 TI - Alopecia areata in identical twins. PMID- 20948046 TI - Levamisole in vitiligo of eyelids. PMID- 20948047 TI - Genesis of cutaneous depigmentation. PMID- 20948048 TI - Hypohidrotic ectodermal dysplasia in two siblings. PMID- 20948050 TI - Ecthyma gangrenosum without bacteremia. PMID- 20948049 TI - Clinical profile of psoriasis in Western Rajasthan: Study of 300 cases. PMID- 20948051 TI - Silent renal carcinoma presenting as cutaneous metastasis. PMID- 20948052 TI - Paucity of immune complexes in skin lesions of lichen planus. PMID- 20948053 TI - Erythromelalgia responding to aspirin. PMID- 20948054 TI - Diagnostic value of hypomelanotic macules of tuberous sclerosis. PMID- 20948055 TI - Clinicomycological study of tinea capitis. AB - Clinicomycological spectrum of 72 patients of tinea capitis attending dermatological out patient departments of Kalawati Saran Children and Sucheta Kriplani Hospitals, New Delhi from May 1992 to April 1994 is studied. Majority of the patients were children (94%). Males and females were equally involved. Most of them belonged to low socioeconomic group; lived in the crowded environment; had regular bathing habit; used mustard oil and shared combs. Family history of tinea capitis was available in 29% of the cases. Duration of disease varied from 20 days to 10 years. Large number (60%) of patients had multiple lesions. Commonest site involved was occiput. Non inflammatory type of lesions were observed in 68% of the cases. KOH examnination revealed endothrix and ectothrix spores in 56 and 7 patients respectively. Positivity of culture was observed in 47% of the cases and Trichophyton violaceum was the commonest species isolated. PMID- 20948056 TI - Clinicomicrobiological aspects of tinea cruris in madras. AB - A total of 242 patients with clinically diagnosed tinea cruris were screened and 181 (74.7 %) were found to be positive in culture for dermatophytes. 93.9% of infections were caused by Trichophyton spp., of which 58.4% were Trichophyton rubrum, 5.5% were Epidermophyton floccosum, 3.8% were Trichophyton tonsurans and we had a single isolate of Microsporum gypseum complex. Incidence of tinea cruris was higher in males (95.6%) than in females (4.4%). 45% of the cases were recurrent and 38% of cases were chronic tinea cruris. Three patients had granulomatous lesion. Zoophilic T mentagrophytes was the major aetiologic agent isolated from all the 3 cases of granulomatous tinea cruris. PMID- 20948057 TI - Lichen dyschromicum perstans. AB - A disorder of hyperpigmentation is described which is seen commonly in middle aged individuals. Face and neck including upper part of the trunk are mostly affected. The lesions are usually bilaterally symmetrical and occur in a localized or generalized distribution. Oral mucosa is infrequently involved. The colour of pigmentation varies from grey, blue and brown to black and it persists for years. None of the patients had any features of lichen planus. Histopathology reveals varying rates of lichenoid tissue reactions. We have tentatively designated this disorder as lichen dyschromicum perstans. Its relationship with other similar disorders is discussed. PMID- 20948058 TI - Contactants in 'Kum-Kum' dermatitis. AB - Twenty patients having contact dermatitis on the forehead due to Kum-Kum were patch tested with the commercially available Kum-Kum used by the patient as such, and also the extended European standard series of allergens, as well as brilliant lake red R, sudan I, aminoazobenzene and canaga oil since analysis of the Kum-Kum by thin-layer chromatography showed presence of these constituents. Patch tests were positive in all the patients with the commercial Kum-Kum and brilliant lake red R, sudan I, aminoazobenzene and canaga oil, but not with the extended European standard series of allergens. PMID- 20948059 TI - Kyrle's disease : a cutaneous marker of renal disorder. AB - Twenty one cases of Kyrle's disease were subjected to a thorough clinical examination and various investigations in order to find out the association of Kyrle's disease with other systemic disorders and to elucidate the association between specific biochemical abnormalities and Kyrle's disease. It was found that all the cases of Kyrle's disease were associated with systemic disorders and that the major systemic disorder was nephropathy. The significant biochemical abnormality detected was a raised phosphorus level. So it is probable that the elevated phosphorus may be triggering the occurrence of Kyrle's disease. PMID- 20948060 TI - Acrochordon, diabetes and associations. AB - A study of clinical profile of acrochordons was carried out in 100 patients. Their association with diabetes mellitus and other disorders was studied. Acrochordons were found to be closely associated with pseudo-acanthosis nigricans, seborrhoeic keratosis, obesity and non-insulin dependent diabetes mellitus. PMID- 20948061 TI - Laser therapy in post herpetic neuralgia. AB - Combi laser therapy was evaluated in 50 cases of established post herpetic neuralgia (PHN). Established PHN term was used when neuralgia persisted after 3 months of disappearance of herpes zoster (HZ) vesicles. Twenty exposures were given and affected areas were irradiated from a distance of 2 cm at a frequency of 5000 Hz each area being exposed for a period of 1.23 minutes ie, 8J/cm2 of beam was given. Therapeutic evaluation was done on 4th, 8th, 12th, 16th, and 20th day. All 17 cases of established PHN of duration upto 3 months healed after 16 exposures and in the end 44/50 had cure, 5/50 had partial relief and one patient left trial after 2nd exposure. PMID- 20948062 TI - Mesalazine in treatment of psoriasis. AB - Mesalazine- a 5 lipoxygenase inhibitor was tried in this open trial on 20 psoriatics. Whereas 50% patients (10) had complete clearance in 4 weeks, by 12 weeks 85% (17) patients had good response and 15% (3) patients had no relief at all. No side effects were observed. Further longitudinal double-blind trials of this drug, which has an advantage of not causing bone marrow depression and oligospermia over sulfasalazine, another 5 lipoxygenase inhibitor, are advocated. PMID- 20948063 TI - A piebald family. AB - Piebaldism is an uncommon congenital hypomelanotic disorder characterized by a white forelock and vitiligo like amelanotic macules. We report a family with piebaldism affecting four successive generations. The disease was present in 16 members of the family. PMID- 20948064 TI - Genodermatoses in paediatric age group. AB - Pattern of genodermatoses in paediatric age group was studied. The relative incidence of genodermatoses in paediatric dermatology out patient department was 0.62%. The commonest genodermatoses observed was ichthyosis. PMID- 20948065 TI - Treatment of reiter's disease. AB - Two classical cases of Reiter's disease, one successfully treated with methotrexate and the other with sulphasalazine are reported. PMID- 20948066 TI - Tuberous sclerosis. AB - Although tuberous sclerosis has been described with a diagnostic triad, it is not present consistently in all cases. Variety of skin manifestations were reported in tuberous sclerosis. This studay was undertaken to assess the frequency of various skin changes in tuberous sclerosis. Ten consecutive cases of tuberous sclerosis were studied. Angiofibroma was the commonest cutaneous manifestation. Atypical fibroxanthoma, dermatofibroma and neurofibroma were also noticed as interesting associations. PMID- 20948067 TI - Topical fluocinolone acetonide acetate ointment in autosomal dominant congenital hypotrichosis. AB - Hypotrichosis present at birth occurring as an isolated defect in three members of an Afghan family and transmitted as an autosomal dominant trait, responded to topical applications of fluocinolone acetonide acetate ointment. The patients were a 9-year-old boy, his 7-year-old sister and their 30-year-old mother who since birth, had sparse, light-coloured and thin hairs on their scalp which would not grow longer than 1 cm in length. Microscopic examination revealed the hairs to be thin and fragile, but of a uniform thickness. Some of the hairs showed secondary trichorrhexis. Following topical applications of 0.1% fluocinolone ointment, the hairs became coarser and increased in length from an ayerage of 0.7 cm before treatment to 6.2 and 7.1 cm in the two children after 10 months. The mother who started the treatment later also showed improvement. PMID- 20948068 TI - Glucagonoma syndrome. AB - A case of glucagonoma is being presented. The patient presented with erosions, crusts, bullous dermatitis, glucose intolerance and weight loss. PMID- 20948069 TI - Naevus comedonicus associated with epidermoid cyst. AB - Naevus comedonicus associated with epidermoid cyst is a rare association. Two such case reports are presented. PMID- 20948070 TI - Lichen planus in monozygotic twins. AB - A pair of identical twins presented with lichen planus involving skin and nails. PMID- 20948071 TI - Mutilating keratoderma with deaf-mutism. AB - A 30 year old woman presented with typical lesions of mutilating keratoderma. The patient was deaf and dumb. Hyperkeratosis of palms and soles was present since infancy. Constriction of digits started by the age of 5 years. The clinical diagnosis was supported by histopathological examination. PMID- 20948072 TI - Reversible onychomadesis induced by carbamazepine. AB - An epileptic teenager put on carbamazepine therapy presented with onychomadesis 6 months later. Carbamazepine was substituted with phenytoin. Affected nails were shed and healthy nails regrew in 5 months. PMID- 20948073 TI - Livedo reticularis with acute rheumatic fever. AB - A 10-year-old boy, a diagnosed case of acute rheumatic fever, presented with livedo reticularis involving whole of body except face. Livedo reticularis has been very rarely reported in rheumatic fever. PMID- 20948074 TI - Cutaneous focal mucinosis. AB - A 26-year-old male presented with asymptomatic, flesh coloured nodules on right elbow, forehead and right retroauricular region. A skin biopsy form the nodule stained with hematoxylin and eosin and special stain (mucicarmine) showed focal deposition of mucin in the dermis. PMID- 20948076 TI - Onychomadesis in stevens johnson syndrome. PMID- 20948075 TI - Progressive reticulate zosteriform hyperpigmentation. AB - A 24-year-old healthy Bengali woman presented with progressive, macular tanned lesions in a zosteriform pattern located upon her right upper limb, breast and chest. The biopsy from the tanned lesion showed mild increase in the pigment in the basal layer. PMID- 20948077 TI - Atypical subcorneal pustular dermatosis. PMID- 20948078 TI - High incidence of polymorphic light eruption in Kota. PMID- 20948080 TI - Blister beetle dermatitis. PMID- 20948079 TI - Bart syndrome. PMID- 20948081 TI - Body hair distribution of women attending endocrine OPD. PMID- 20948082 TI - Topical vitamin A in exfoliative cheilitis. PMID- 20948083 TI - Cutis verticis gyrata with epilepsy. PMID- 20948084 TI - Balanoposthitis in children with scabies. PMID- 20948085 TI - Systemic corticosteroids in toxic epidermal necrolysis. PMID- 20948086 TI - Cowpox. PMID- 20948087 TI - Becker's naevus on lower limb. PMID- 20948088 TI - Cutaneous sarcoidosis without systemic involvement : response to intralesional corticosteroid. PMID- 20948089 TI - Epidermolysis bullosa: diagnosis and prenatal diagnosis. AB - Recent advances in the diagnosis and prenatal diagnosis of severe forms of epidermolysis bullosa (EB) have been reviewed. Using electron microscopy and immunohistochemistry of specific monoclonal antibody, foetal skin biopsy during the second trimester of pregnancy has been utilized successfully for the prenatal diagnosis of EB. Recently, elucidation of the specific gene mutation in affected individuals allowed us to perform DNA-based prenatal diagnosis during the first trimester of pregnancy. Our own experience with prenatal diagnosis of EB at the Special Clinic for Inherited Skin Disorders at Keio University Hospital for the last six years is summarized. PMID- 20948090 TI - Mucocutaneous disorders in Hiv positive patients. AB - Twenty eight HIV positive patients were included in this study. They were evaluated for their mucocutaneous disorders, sexually transmitted diseases and other systemic disorders between 1994-95 in the department of Dermatology and STD Dr R M L Hospital of New Delhi. The heterosexual contact with commercial sex workers (CSWs) was the most common route of HIV transmission. Chancroid, syphilis and genital warts were common STDs found in HIV positive patients. Oral thrush (67.9%) was the commonest mucocutaneous disorder found in these patients followed by herpes zoster (25%) and seborrhoeic dermatitis (21.4%). There was no unusual clinical presentation seen in mucocutaneous disorders and STDs. PMID- 20948091 TI - Dressing wounds with potato peel. AB - The use of boiled potato peel (PP) in dressing of various skin conditions was studied. A total of 11 patients were selected, which included resistant wounds of pemphigus, bullous pemphigoid and leg ulcers. An autoclaved PP dressing with a thin layer of antiseptic cream was applied at 25 sites. It was covered with multilayered gauze and the dressing was secured firmly with either a roller bandage or with an adhesive tape. Complete epithelization was seen at 20 sites (80%), near complete epithelization at one site. There was no satisfactory response at three sites and at one site the result could not be evaluated. The mean duration of healing was one week for superficial wounds and three weeks for deep wounds. The PP dressing facilitates the wound and three weeks for deep wounds. The PP dressing facilitates the wound healing process by providing and maintaining a moist environment. The PP dressing is easy to prepare, apply as well as remove. It is a comfortable dressing and is also cost effective. PMID- 20948093 TI - Study of blood groups in HIV seropositive patients. AB - Blood groups in 104 cases of HIV infection and 300 normal persons were determined. A relatively increased incidence of HIV infection was observed in persons with blood group O and relativey lower incidence in blood group B. Incidence of HIV infection was also low in Rh negative subjects. These results suggest a possible relationship between the incidence of blood group and the natural defence mechanism against HIV infection. PMID- 20948092 TI - Fluticasone propionate (0.05%) cream compared to betamethasone valerate (0.12%) cream in the treatment of steroid-responsive dermatoses: a multicentric study. AB - Fluticasone propionate is a new topical steroid developed as a result of modification of the 19-carbon androstane structure. In the present study, efficacy of this steroid was compared with betamethasone valerate cream in patients with psoriasis and eczema. Though fluticasone propionate was marginally more effective than betamethasone valerate, this difference was not statistically significant. PMID- 20948094 TI - A double-blind comparison of 2% ketoconazole and 1% clotrimazole in the treatment of pityriasis versicolor. AB - Forty adult patients of pityriasis versicolor were treated with either topical 2% ketoconazole cream (20 patients) or topical 1% clotrimazole cream (20 patients). In global assessment of treatment after 2 weeks, 18 (90%) out of 20 patients treated with ketoconazole cream were cured while 2 cases had considerable residual lesions. In clotrimazole treated group, 17 (85%) out of 20 patients were cured and 3 still had considerable lesions. No significant difference was observed in response rates in the two groups. No side effects were reported in either groups. PMID- 20948095 TI - Follow up of patients of acne vulgaris treated with tetracyclines. AB - Tetracyclines have been used extensively for the management of moderately severe to severe acne. In this study we studied the effect of withdrawal of tetracycline and minocycline on the course of acne. Ninety seven clinically controlled patients of acne vulgaris who had earlier taken tetracycline (1G daily) or minocycline (100 mg daily) were followed up at 4 weekly intervals for a period of 12 weeks after stopping all anti-acne therapy. At each visit the acne lesion score (ALS) was calculated. It was found that in the group of 48 patients who had previously received tetracyclines, 25% continued to improve at 12 weeks while 16.7% had relapsed. In the group of 49 patients who had earlier taken minocycline, 69.4% continued to improve and none had relapsed at 12 weeks. Similarly, when the mean acne lesion score of the 2 groups was compared at 12 weeks, it was found that response persisted in the group of acne patients who had been treated previously with minocycline and not in the group treated with tetracyclines. PMID- 20948096 TI - Comparison of topical tretinoin and betamethasone in oral lichen planus. AB - Thirty-one patients of oral lichen planus were enrolled in this study and two groups were made. Group 1 consisting of 16 patients who applied topical tretinoin 0.05% and Group 2 comprising of 15 patients who were given topical betamethasone dipropionate 0.05%. The patients applying tretinoin showed statistically significant improvement as compared to patients applying betamethasone. PMID- 20948097 TI - Gammabenzene hexachloride-induced convulsions in an HIV positive individual. AB - A case report of chancroid with scabies with HIV positivity is being presented. The individual was treated with 1% gamma benzene hexachloride for scabies and developed convulsions. PMID- 20948098 TI - Psoriasis in identical twins: simultaneous occurrence on same sites. AB - A pair of 12-year-old identical male twins presented to us with dull erythematous plaques with coarse scaling and deep fissuring over soles of both feet starting simultaneously 18 months ago. The diagnosis of psoriasis was confirmed by histopathological examination of the biopsy specimen. PMID- 20948099 TI - Eccrine poroma. AB - Eccrine poroma is a benign tumour, usually found over palms and soles. A 35-year old lady presented with a raised nodule of 0.75 cm over the right palm. On excision biopsy it showed tumour masses consisting anastomosing bands with ductal lumina lined by an eosinophilic cuticle. A diagnosis of eccrine poroma was made. Due to paucity of reports in Indian literature we are reporting this case. PMID- 20948100 TI - Pustular psoriasis: treatment with antibiotics. AB - A 17 years old boy presented clinically with typical lesions of pustular posriasis. Although his pus culture from the pocket of pus did not reveal any organism, his blood culture reports showed growth of Diplococci pneumoniae, which was sensitive to gentamycin. The patient was completely cured of the lesion after gentamycin therapy. PMID- 20948101 TI - Congenital cutis laxa. AB - A 16 days old male baby had congenital cutis laxa without family history. He had redundant and lax skin all over the body with slanting of the palpebral fissures medially and broad nasal root. PMID- 20948102 TI - Atypical fibroxanthoma in tuberous sclerosis. AB - Atypical fibroxanthoma is not an uncommon condition occurring in elderly on the sun exposed areas. We report a case of atypical fibroxanthoma in a patient with tuberous sclerosis. The lesion was excised surgically. There was no evidence of any metastasis. PMID- 20948103 TI - Pilomatrixoma. AB - Clinical and histopathological features of two cases of pilomatrixoma are reported. The tumour in each case was slow-growing, asymptomatic and at the same site. Histopathology showed classical eosinophilic ghost cell, surrounded by basophilic cells, along with areas of calcification and keratinization. PMID- 20948104 TI - Unilateral atrophoderma vermiculatum. AB - Atrophoderma vermiculatum is an autosomal dominant disorder with small pitted scars over cheek and forehead. A 25-year-old male had multiple 1-2 mm sized pitted scars with ridges producing a reticulated honeycomb appearance on the left cheek since childhood. The lesions were unilateral and there was no other family member with similar lesions. PMID- 20948105 TI - Cowden's disease. AB - A 24-year old male patient developed multiple lesions of keratoacanthoma in the epidermal verrucous naevus. He also had multiple papillomatous lesions on the lips, buccal mucosa, gingiva and tongue, with positive family history of similar lesions. He also had multiple skin tags and patchy palmoplantar keratoderma and minimal kyphoscoliosis. PMID- 20948106 TI - Subcutaneous sarcoidosis. PMID- 20948107 TI - Aggressive infantile fibromatosis. AB - An 8-month-old infant presented with 2 ulcerated indurated plaques in the right lower limb. The lesions grew rapidly initially but for the last 2 months, they have been stationary. Biopsy showed proliferation of fusiform fibroblasts some of which were arranged in whorls. The clinical picture and the histopathology suggested the diagnosis of an aggressive infantile fibromatosis. This is one of the types of juvenile fibromatoses, a group of tumours characterised by fibrous tissue proliferation present at birth or acquired early in childhood. PMID- 20948108 TI - Speckled lentiginous naevus. AB - A case of speckled lentiginous naevus over face is reported in a 13-year-old girl due to its extreme rarity. The clinical diagnosis was confirmed histopathologically. PMID- 20948109 TI - Disseminated and atypical molluscum contagiosum in an AIDS patient. AB - A case of disseminated molluscum contagiosum (MC) has been reported in a patient suffering from AIDS. Most of the lesions were erythematous papules and nodules with central unbilication. A few giant lesions and lesions over genitalia were also observed. PMID- 20948110 TI - Arthritis mutilans. PMID- 20948111 TI - Minocycline in chronic folliculitis of legs. PMID- 20948112 TI - Griseofulvin - induced acute glomerulonephritis. PMID- 20948113 TI - Mixed connective tissue disorder. PMID- 20948114 TI - Mycological aspects of dermatomycosis. PMID- 20948115 TI - Cutaneous drug reactions. PMID- 20948117 TI - Zosteriform lichen planus. PMID- 20948116 TI - Recalcitrant psoriasis treated with tretinoin 0.05% cream. PMID- 20948118 TI - Adenosine deaminase activity in serum and lymphocytes of multibacillary leprosy patients. AB - Adenosine deaminase (ADA) activity was measured in serum and lymphocytes of 25 untreated patients with multibacillary leprosy. Both serum and lymphocyte ADA levels were significantly high in multibacillary leprosy patients compared to healthy controls. The results obtained did not establish any significant relationship between ADA activity and the type of leprosy. PMID- 20948119 TI - In vitro drug sensitivity of trichophyton rubrum against griseofulvin, ketoconazole and fluconazole. AB - The invitro activity of griseofulvin, ketoconazole and fiuconazole was investigated against 50 isolates of Trichophyton rubrum. Ketoconazole was more active, inhibiting all the 50 isolates at a concentration of 5 MUgm/ml (MIC range 0.5-5 MUgm/ml). Griseofulvin (MIC range 2.5-20 MUgm/ml) required 20 MUgm/ml of the drug for inhibition of all the isolates. Fluconazole was least active as it inhibited only 2 isolates at a concentration of 20 MUgm/ml, which was the upper limit of the test system. PMID- 20948120 TI - Comparative efficacy of topical anthralin and intralesional triamcinolone in the treatment of alopecia areata. AB - Efficacy of intralesional triamcinolone acetonide (10mg/ml) and topical anthralin 1.15% cream was compared in the treatment of alopecia areata. Study groups consisted of 37 patients for injection and 32 patients for cream. All of them belonged to Type I of Ikeda's classification. The study showed that triamcinolone induces more adequate response in terms of regrowth of hairs than anthralin. However, the relapse rate was higher with triamcinolone. No difference was noted in terms of complete regrowth of hairs on the lesional skin and side effects of drugs. PMID- 20948121 TI - Clinicopathological correlation in 50 cases of erythroderma. AB - Fifty cases of erythroderma were studied clinically and histopathologically. Clinically 11 were of eczemas, 12 of psoriasis, 14 were drug-induced, 11 of idiopathic group and 1 each of pemphigus foliaceus (PF) and cogenital bullous ichthyosiform erythroderma (CBIE). Histopathologically 10 cases of psoriasis, 1 of PF and 1 of CBIE showed specific histopathology and therefore clinical histopathological correlation was possible only in 12 (24%) cases. Exact differentiation in erythroderma due to eczemas, drugs or idiopathic was not possible histopathologically. PMID- 20948123 TI - Secondary cutaneous carcinomatosis. AB - Secondary cutaneous carcinomatosis may be the primary menifestation of malignancies. Due to the help of modern investigative techniques primary malignant sites can be detected. But in many circumstances the primary site can not be detected in spite of available investigation. The cases presented here clearly show that the secondary cutaneous menifestation may be the first clue for detecting a hidden primary maligmancy. PMID- 20948122 TI - Status of dermatology in the coal Belts of eastern India. AB - Health survey of 2 major coal mines in Eastern India reveals that skin lesions are very common. Out of usual skin lesions occupational dermatitis tops the list. Health statistics show that dermatological problems are the third major health hazard in mines. PMID- 20948124 TI - Serum immunoglobulin estimation in 30 cases of cutaneous vasculitis. AB - Clinically diagnosed and histopathologically proved 30 cases of cutaneous vasculitis (CV) were collected from Dermatovenereology department. Serum immunoglobulins (Igs) estimation was done in all cases. Nineteen cases showed increased levels of Igs, 4 had decreased levels, while in 7 cases Igs levels remained normal. Seventeen had increase in IgG, 17 cases had in IgA and 10 in IgM and decrease in levels of IgM was seen in 3, and IgA in 2 cases. But the fluctuation in levels of Igs was statistically insignificant. PMID- 20948125 TI - Patch testing in contact dermatitis of hands and feet. AB - Eighty clinically diagnosed cases of allergic contact dermatitis of hands and feet when subjected to patch testing, Seventy four (92.5%) cases showed positive patch test reactions to different suspected antigens. Maximum number of cases belonged to housewives and tea garden workers which showed positive patch test reaction to vegetables and soaps and detergents and pesticides, respectively. PMID- 20948126 TI - Primary cutaneous phaeohyphomycosis. AB - A rare case of phaeohyphomycosis presenting with a solitary nodule on right lower leg of 2 years duration is being reported. The disease showed marked response to oral fluconazole. PMID- 20948127 TI - Capillary haemangioma. AB - A 16-year-old boy presented with a hyperpigmented, velvety, not compressible, plaque on the medial side of right leg just below the knee for the last 10 years. Biopsy report revealed the lesion was nothing but capillary haemangioma. The case is presented here due to unusual presentation with a tendency to persist. PMID- 20948128 TI - Congenital bilateral sensory neural deafness, postaxial polydactyly, scrotal tongue and recurrent pyogenic infections. AB - A case report of a 40-year-old male with congenital bilateral sensory neural deafness, postaxial polydactyly involving hands and feet, scrotal tongue and recurrent pyogenic infections is described. PMID- 20948129 TI - Steatocystoma multiplex. AB - A case of steatocystoma multiplex in a 45-year-old male is reported. The diagnosis was based on clinical as well as histopathological findings. PMID- 20948130 TI - Lupus miliaris disseminatus faciei. AB - Lupus miliaris disseminatus faciei also known as acne agminata is a rare disease affecting face in adults. Previously, it was thought to be a tuberculid; and its relation with rosacea is undefined. We report a case who had multiple yellowish brown to erythematous small papular lesions and many pitted atrophic scars on the face of 8 months duration. Investigations for tuberculosis were negative. Histopathology revealed tuberculoid granuloma. PMID- 20948131 TI - Indeterminate hansen's disease in a patient with hereditary sensory and autonomic neuropathy. AB - Hereditary sensory and autonomic neuropathy (HSAN) is a group of rare hereditary diseases. A young female with Type I HSAN with indeterminate Hansen's disease (HD) is reported which is a rare association. PMID- 20948132 TI - Lipoid proteinosis. AB - A 20-year old male presented with hoarseness of voice since birth, beaded papular lesions on both eyelids, multiple hypopigmented atrophic scars on trunk and extremities and yellowish infiltrated plaques on tongue, palate and buccal mucosae. Patient was diagnosed clinically as a case of lipoid proteinosis. It was confirmed by mucosal biopsy. PMID- 20948133 TI - Erythema annulare centrifugum. AB - A 45-year old female presented with recurrent eruption of polycyclic erythematous lesion for nearly 2 years. During this period of observation no cause could be determined. Biopsy report was consistent with diagnosis of erythema annulare centrifugum. PMID- 20948134 TI - Ichthyosis linearis circumflexa. AB - A case of ichthyosis linearis circumflexa in a 9-year old boy is reported here for its rarity. PMID- 20948135 TI - Verrucous haemangioma. AB - A case of verrucous haemangioma in a 25-year-old male is reported for its rarity and not to be confused with any other verrucous naevi or infective conditions. PMID- 20948136 TI - Necrobiotic xanthogranuloma with paraproteinaemia. AB - Necrobiotic xanthogranuloma is a subset of inflammatory form of normolipaemic xanthomas. Because of its characteristic clinical and histopathological findings necrobiotic xanthogranuloma may be regarded as a specific marker of paraproteinaemia. PMID- 20948137 TI - Treament of bechcet's disease. AB - A case of Behcet's disease treated initially wiht corticosteroids to which dapsone was added subsequently and being kept in remission with dapsone alone is presented. High maintenance dose of corticosteroids necessitated the substitution with dapsone. PMID- 20948138 TI - Monilethrix in pedigree. AB - A 30-year-old female patient presented with tiny papular scalp lesions with sparse, very short, curly hair of only 8 to 12 mm. Microscopic examination of hair revealed typical beaded or moniliform appearance. She also had typical lesions of psoriasis for past 2 months. Her father, 2 sisters and her 6-year-old daughter had similar types of beaded scalp hair. PMID- 20948139 TI - Unilateral darier's disease. AB - Various variations of Darier's disease have been mentioned in the literature. Here we describe a young male with unilateral involvement with clinical and histopathological features typical of Darier's disease. PMID- 20948140 TI - Self-healing juvenile cutaneous mucinosis. AB - The clinical evolution and histological features of skin lesions in a 14-year-old boy were characteristic of self-healing juvenile cutaneous mucinosis. They were (a) early age of onset with fever, (b) plaque lesion over the nape of the neck and thigh, (c) nodular lesions over the scalp, face and periarticular regions and (d) spontaneous resolution. PMID- 20948141 TI - Gottron's papules with raised CPK level without other manifestations of dermatomyositis. AB - Dermatomyositis without myositis has been reported rarely and has been given several names such as dermatomyositis sine myositis and amyopathic dermatomyositis. We report a 19-year-old male patient with Gottron's papules and raised CPK level. The patient has been followed for 10 months and has not developed other features of myositis. PMID- 20948142 TI - Non-healing diabetic ulcer treated by biobeam 660. AB - A case of 75-year-old male patient with a non-healing ulcer over left sole is reported. Patient was a known diabetic with CCF. The ulcer was not healing for one month with routine treatment. The patient was given BIOBEAM 660 therapy every alternate days for a month which led to complete healing of the ulcer without complications. PMID- 20948143 TI - Recurrent post-herpetic erythema multiforme, herpes labialis and secondary vitiligo in siblings. AB - Presence of recurrent herpes labialis with resultant secondary vitiligo associated with recurrent erythema multiforme further leading to depigmentation of skin in relation to target shaped maculopapular lesions in two real sisters was observed as a unique phenomenon which probably has not been reported earlier. PMID- 20948144 TI - Penile haemangioma. PMID- 20948145 TI - Topical ketoconazole therapy in a recalcitrant case of seborrhoeic dermatitis. AB - Ketoconazole 2% cream and 2% shampoo were found to be effective in controlling seborrhoeic dermatitis in a recalcitrant case. This topical ketoconazole therapy seems to be better than other conventional topical preparations prescribed in seborrhoeic dermatitis. PMID- 20948146 TI - Vulval lichen planus leading to urethral stenosis. AB - An 8-year-old female child presented with difficulty in micturition preceded by some vulval lesions. She had itching around vulva associated with burning sensation and gradually developed a whitish patch. Histology was compatible with lichen planus. PMID- 20948147 TI - Pedunculated digitate papillomatosis around rectum. AB - This is a report on unusual case of proliferation of dermal and epidermal components having finger-like projection around rectum with extension towards natal cleft in a patient suffering from Hansen's infection. PMID- 20948148 TI - Pigmentary stage of incontinentia pigmenti : is it a distinct entity? PMID- 20948149 TI - Terfenadine precipitating erythroderma in psoriasis. PMID- 20948150 TI - Hypertrophic lichen planus simulating seborrhoeic keratosis. PMID- 20948151 TI - PKDL mimicking post-inflammatory changes of pityriasis rosea. PMID- 20948152 TI - Fixed duration MDT in leprosy. PMID- 20948153 TI - [Research and development of hormone-related anti-prostate cancer drugs-17, 20 lyase inhibitors for prostate cancer]. PMID- 20948154 TI - [Survivin supressant: a promising target for cancer therapy and pharmacological profiles of YM155]. PMID- 20948155 TI - [Current status of VEGF-targeted therapy and multiple-targeted receptor tyrosine kinase inhibitors targeting VEGF and FGF-receptors]. PMID- 20948156 TI - [Current status and prospects of antibody drugs-trastuzumab]. PMID- 20948157 TI - [G protein-coupled receptor kinase (GRK)]. PMID- 20948158 TI - [Influences of febrile seizures on developing neuronal circuits: cellular and molecular approaches using animal models]. PMID- 20948159 TI - [Evaluation of insulin-induced GLUT4 vesicle transport and insulin resistance]. PMID- 20948160 TI - [Translational PK/PD study of the anticoagulant warfarin]. PMID- 20948161 TI - [Pharmacological and clinical profiles of a human GLP-1 analogue, liraglutide (Victoza((r)))]. PMID- 20948162 TI - Serum high-molecular-weight adiponectin as a marker for the evaluation and care of subjects with metabolic syndrome and related disorders. AB - In 1996, adiponectin was reported to be the most abundant transcript in adipose tissue. Animal studies revealed that administering adiponectin improves insulin resistance and blood glucose levels and inhibits atherosclerosis. In the present article, we review the significance of measuring serum high-molecular-weight (HMW) adiponectin levels in human subjects. Our cross-sectional studies revealed that the serum HMW adiponectin concentration was 1.9 times higher in healthy Japanese females than males and had a strong positive correlation with HDL cholesterol but a negative correlation with BMI and the homeostasis model assessment insulin resistance index (HOMA-IR). They also indicated that the serum HMW adiponectin concentration had a stronger association with HOMA-IR and metabolic syndrome than the total adiponectin concentration. Our longitudinal study, a 6-year follow-up of Japanese men, suggested that a decreased level of HMW adiponectin is a predictor of progression to metabolic syndrome. In another intervention study, lifestyle modification for 3 months induced a decrease in BMI and waist circumference and an increase in serum HMW adiponectin but not the total adiponectin level in 16 Japanese males with metabolic syndrome. Administering thiazolidinediones to diabetic patients increased the serum HMW adiponectin concentration 3 fold and improved glucose and lipid profiles and blood pressure. Some people may inherit a lower serum concentration of adiponectin, and have a higher risk of developing cardiovascular diseases.It is suggested that HMW adiponectin is a useful marker for the evaluation and care of subjects with metabolic syndrome and related disorders. PMID- 20948163 TI - Derived (mutated)-types of TRPV6 channels elicit greater Ca2+ influx into the cells than ancestral-types of TRPV6: evidence from Xenopus oocytes and mammalian cell expression system. AB - The frequency of the allele containing three derived nonsynonymous SNPs (157C, 378M, 681M) of the gene encoding calcium permeable TRPV6 channels expressed in the intestine has been increased by positive selection in non-African populations. To understand the nature of these SNPs, we compared the properties of Ca2+ influx of ancestral (in African populations) and derived-TRPV6 (in non African populations) channels with electrophysiological, Ca2+-imaging, and morphological methods using both the Xenopus oocyte and mammalian cell expression systems. Functional electrophysiological and Ca2+-imaging analyses indicated that the derived-TRPV6 elicited more Ca2+ influx than the ancestral one in TRPV6 expressing cells where both channels were equally expressed in the cells. Ca2+ inactivation properties in the ancestral- and derived-TRPV6 were almost the same. Furthermore, fluorescence resonance energy transfer (FRET) analysis showed that both channels have similar multimeric formation properties, suggesting that derived-TRPV6 itself could cause higher Ca2+ influx. These findings suggest that populations having derived-TRPV6 in non-African areas may absorb higher Ca2+ from the intestine than ancestral-TRPV6 in the African area. PMID- 20948164 TI - RhoA, a possible target for treatment of airway hyperresponsiveness in bronchial asthma. AB - Airway hyperresponsiveness to nonspecific stimuli is one of the characteristic features of allergic bronchial asthma. An elevated contractility of bronchial smooth muscle has been considered as one of the causes of the airway hyperresponsiveness. The contraction of smooth muscles including airway smooth muscles is mediated by both Ca2+-dependent and Ca2+-independent pathways. The latter Ca2+-independent pathway, termed Ca2+ sensitization, is mainly regulated by a monomeric GTP-binding protein, RhoA, and its downstream target Rho-kinase. In animal models of allergic bronchial asthma, an augmented agonist-induced, RhoA mediated contraction of bronchial smooth muscle has been suggested. The RhoA/Rho kinase signaling is now proposed as a novel target for the treatment of airway hyperresponsiveness in asthma. Herein, we will discuss the mechanism of development of bronchial smooth muscle hyperresponsiveness, one of the causes of the airway hyperresponsiveness, based on the recent studies using animal models of allergic bronchial asthma and/or cultured airway smooth muscle cells. The possibility of RhoA as a therapeutic target in asthma, especially airway hyperresponsiveness, will also be described. PMID- 20948165 TI - SKI-II, an inhibitor of sphingosine kinase, ameliorates antigen-induced bronchial smooth muscle hyperresponsiveness, but not airway inflammation, in mice. AB - To determine if endogenously generated sphingosine-1-phosphate (S1P) is involved in the development of allergic bronchial asthma, the effects of systemic treatments with SKI-II, a specific inhibitor of sphingosine kinase, on antigen induced bronchial smooth muscle (BSM) hyperresponsiveness and airway inflammation were examined in mice. Male BALB/c mice were actively sensitized with ovalbumin (OA) antigen and were repeatedly challenged with aerosolized antigen. Animals also received intraperitoneal injections with SKI-II (50 mg/kg) 1 h prior to each antigen challenge. The acetylcholine (ACh)-induced contraction of BSM isolated from the repeatedly antigen-challenged mice was significantly augmented, that is, BSM hyperresponsiveness, as compared with that from the control animals (P < 0.05). The BSM hyperresponsiveness induced by antigen exposure was ameliorated by the systemic treatment with SKI-II, whereas the treatments had no effect on BSM responsiveness to ACh in control animals. On the other hand, the systemic treatments with SKI-II had no effect on antigen-induced inflammatory signs, such as increase in cell counts in bronchoalveolar lavage fluids (BALFs) and change in airway histology; upregulation of BALF cytokines, such as interleukin-4 (IL-4) and IL-13; and elevation of total and OA-specific immunoglobulin E (IgE) in sera. These findings suggest that sphingosine kinase inhibitors such as SKI-II have an ability to prevent the development of BSM hyperresponsiveness, but not of allergic airway inflammation. The endogenously generated S1P might be one of the exacerbating factors for the airway hyperresponsiveness, one of the characteristic features of allergic bronchial asthma. PMID- 20948166 TI - Inhibitory effects of the methanol extract of Ganoderma lucidum on mosquito allergy-induced itch-associated responses in mice. AB - Recently, we showed that a methanol extract of Ganoderma lucidum inhibits scratching, an itch-related response, induced by intradermal injections of some pruritogens in mice. The present study investigated whether G. lucidum extract would inhibit allergic itch. In mice sensitized with an extract of salivary gland of mosquito (ESGM), an intradermal injection of ESGM elicited scratching, which was suppressed by oral administration of G. lucidum extract (100 and 300 mg/kg). The scratching was inhibited by the H1 histamine-receptor antagonist azelastine, but not by the peripherally acting H1-antagonist terfenadine, at the oral dose of 30 mg/kg. In sensitized mice, ESGM increased the activity of cutaneous nerve, which was suppressed by G. lucidum extract (300 mg/kg). Although terfenadine (30 mg/kg) inhibited plasma extravasation induced by ESGM in the sensitized mice, G. lucidum extract (300 mg/kg) was without effect. These results suggest that G. lucidum extract relieves allergic itch through a peripheral action. The results support the idea that mast cells and H1 histamine receptors are not the primary sites of the antipruritic action of G. lucidum extract. PMID- 20948167 TI - Zonisamide attenuates MPTP neurotoxicity in marmosets. AB - MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces parkinsonism in humans and animals. The effects of zonisamide on dopamine neurons were studied in MPTP-treated common marmosets (Callithrix jacchus). Groups of animals (n = 3) were treated with MPTP (2.5 mg/kg, every 24 h x 3); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (a known MAO B inhibitor) (2 mg/kg administered 1 h before each MPTP dose); and saline controls. An immunohistochemical study of the substantia nigra was performed 14 days after MPTP treatment in each group. MPTP reduced the mean number of tyrosine hydroxylase (TH)-positive neurons to 10% of the normal control group and mean cell size was significantly (P < 0.001) reduced from 424 to 159 um2. In the group pre-treated with zonisamide, the mean number of TH-positive neurons was reduced to 26% of that in the normal control group and the mean neuron size was significantly (P < 0.05) increased from 159 to 273 um2 compared with the group treated with MPTP alone. Moreover, in the group pre-treated with selegiline, the mean number of TH-positive neurons was 47% of that in the normal control group and the mean neuron size was increased significantly (P < 0.01) from 159 to 319 um2 compared to the group treated with MPTP alone. This observation suggests that zonisamide reduces MPTP toxicity. PMID- 20948168 TI - Surveillance of avian influenza virus in migratory water birds in eastern Hokkaido, Japan. AB - The epidemiological information has obtained on avian influenza virus (AIV) in eastern Hokkaido, Japan, where AIV surveillance has not been performed. Cloacal or fecal samples obtained from migratory water birds were screened for AIV both by real-time reverse transcriptase polymerase chain reaction to detect the influenza A virus matrix (M) gene and by egg inoculation. Between 2007 and 2009, a total of 2,488 samples were collected from various avian species in Abashiri, Kushiro, Nemuro and Tokachi districts of eastern Hokkaido. AIVs were isolated from 18 of those samples (0.7%). No AIV was isolated from the 1,449 samples collected in Abashiri, Kushiro and Nemuro districts, although 6 were positive for the M gene by RRT-PCR. In contrast, 52 (5.0%) of the 1,039 samples collected from ducks in Tokachi district were M gene positive; AIVs were isolated from 18 of those samples (1.7%). The isolates included H3N5 (1 isolate), H3N6 (1), H3N8 (9), H4N2 (1), H4N6 (2), H6N5 (1), H6N8 (1), and H11N3 (2) subtypes. H3N5 and H11N3 subtypes have not been frequently isolated, and our study is the first to report H3N5 and the second to report H11N3 in Japan. Phylogenetic analysis revealed that the M genes of all isolates belonged to the Eurasian lineage. PMID- 20948169 TI - Serotypes, antimicrobial susceptibility, and minimal inhibitory concentrations of Actionbacillus pleuropneumoniae isolated from slaughter pigs in Taiwan (2002 2007). AB - In total, 211 isolates of A. pleuropneumoniae were collected from pigs with hemorrhagic pneumonia at slaughterhouses during 2002-2007. Serotypes, antimicrobial susceptibility and minimum inhibitory concentration (MIC) values were determined for each isolate of A. pleuropneumoniae to 10 antimicrobial agents. Serovar 1 of A. pleuropneumoniae was predominant in Taiwan in 138 of the 211 isolates, followed by serovars 2 and 5. More than 90% of collected isolates were sensitive to ceftiofur, cephalothin, and chloramphenical. However, lincospectin and gentamicin were relatively less susceptible with sensitivities of only 2.4 and 5.7%, respectively. Additionally, ceftiofur had the highest in vitro activity with an MIC(50) of 2.2 ug/ml, followed by cephalothin (2.7 ug/ml) and chloramphenicol (7.9 ug/ml). Lincospectin had the least activity with MIC(50) and MIC(90) values of 73.9 and 114.5 ug/ml, respectively. The data indicate that ceftiofur and cephalothin were extremely active against A. pleuropneumoniae and with minimum MIC values. These drugs are suitable for controlling and treating hemorrhagic pleuropneumonia outbreaks in swine. PMID- 20948170 TI - Surgical intrauterine insemination with cat semen cryopreserved with Orvus ES paste or sodium lauryl sulfate. AB - The mean post-thaw sperm motilities of feline frozen semen prepared with 1% OEP or 3 g/ml SLS as a cryoprotective agent, in addition to 7% glycerin, were 35.0 +/ 2.4 and 37.0 +/- 2.5%, respectively, showing no significant difference. On unilateral intrauterine insemination (UIUI) using these semen samples at a sperm number of 40 * 10(6), the conception rate was 70.0% (7/10) in the OEP group and 30% (3/10) in the SLS group, showing that the rate was higher in the OEP group, but the difference was not significant. It was suggested that sperm in frozen semen showing the above qualities were transferred to the contralateral uterine horn on UIUI. PMID- 20948171 TI - Bacillary hemoglobinuria in Japanese black cattle in Hiroshima, Japan: a case study. AB - Three Japanese Black cows housed with 6 other cows exhibited main clinical symptoms of severe hemoglobinuria. Hematological analyses conducted after antibiotic therapy demonstrated severe anemia, and biochemical analyses indicated both severe hemolysis and disruption of hepatic function. One of the three cows died. Based on the above analyses and observation of typical clinical symptoms, a speculative diagnosis of bacillary hemoglobinuria was made, and immediate high dose antibiotic treatment improved the general conditions of the surviving animals. Blood samples from the other 2 cows were collected sequentially after antibacterial therapy. Clostridium haemolyticum was detected by a nested polymerase chain reaction analysis of the blood samples. The cows were diagnosed with the second recorded occurrence of bacillary hemoglobinuria in Japan. PMID- 20948172 TI - Detection of Chlamydophila psittaci by using SYBR green real-time PCR. AB - Chlamydophila psittaci is the causative agent of human psittacosis and avian chlamydiosis. This zoonotic pathogen is frequently transmitted from infected birds to humans. Therefore proper and rapid detection of C. psittaci in birds is important to control this disease. We developed a method for detecting C. psittaci by using SYBR Green Real-time PCR based on targeting the cysteine-rich protein gene (envB) of C. psittaci. This one step procedure was highly sensitive and rapid for detection and quantification of C. psittaci from fecal samples. This assay was also able to detect other zoonotic Chlamydophila species such as C. abortus and C. felis. The assay is well suited for use as a routine detection method in veterinary medicine. PMID- 20948173 TI - Gravity at sea--A memoir of a marine geophysicist. AB - A history of studies on the gravity measurements at sea in Japan is reviewed with an emphasis on the contribution of the author. The first successful measurements at sea were made in 1923 by Vening Meinesz in the Netherlands using the pendulum apparatus installed in a submarine. However, the gravity measurements using a submarine are not convenient because the access to a submarine is limited. Professor Chuji Tsuboi made a number of unsuccessful attempts at developing a gravity meter that can be operated on a normal surface ship by reducing the noise by minimizing the motion of the gravity meter through a mechanical design. I have chosen a new approach toward the measurements of gravity on a surface ship by simplifying the mechanical part using a string gravity meter that was installed directly on a vertical gyroscope in combination with the numerical and/or electronic reduction of noises. With this gravity meter TSSG (Tokyo Surface Ship Gravity Meter), we firstly succeeded in measuring gravity at sea onboard a surface ship in July 1961 and the measurements have been extended to the northwestern Pacific and beyond. The results reveal the fine structures of gravity field in and around trenches that provide important clues as to a number of geodynamic issues including the nature of the trench-trench interaction and the interaction of trenches with seamounts. PMID- 20948174 TI - The selective elimination of messenger RNA underlies the mitosis-meiosis switch in fission yeast. AB - The cellular programs for meiosis and mitosis must be strictly distinguished but the mechanisms controlling the entry to meiosis remain largely elusive in higher organisms. In contrast, recent analyses in yeast have shed new light on the mechanisms underlying the mitosis-meiosis switch. In this review, the current understanding of these mechanisms in the fission yeast Schizosaccharomyces pombe is discussed. Meiosis-inducing signals in this microbe emanating from environmental conditions including the nutrient status converge on the activity of an RRM-type RNA-binding protein, Mei2. This protein plays pivotal roles in both the induction and progression of meiosis and has now been found to govern the meiotic program in a quite unexpected manner. Fission yeast contains an RNA degradation system that selectively eliminates meiosis-specific mRNAs during the mitotic cell cycle. Mmi1, a novel RNA-binding protein of the YTH-family, is essential for this process. Mei2 tethers Mmi1 and thereby stabilizes the transcripts necessary for the progression of meiosis. PMID- 20948175 TI - Our trails and trials in the subsarcolemmal cytoskeleton network and muscular dystrophy researches in the dystrophin era. AB - In 1987, about 150 years after the discovery of Duchenne muscular dystrophy (DMD), its responsible gene, the dystrophin gene, was cloned by Kunkel. This was a new substance. During these 20 odd years after the cloning, our understanding on dystrophin as a component of the subsarcolemmal cytoskeleton networks and on the pathomechanisms of and experimental therapeutics for DMD has been greatly enhanced. During this paradigm change, I was fortunately able to work as an active researcher on its frontiers for 12 years. After we discovered that dystrophin is located on the cell membrane in 1988, we studied the architecture of dystrophin and dystrophin-associated proteins (DAPs) complex in order to investigate the function of dystrophin and pathomechanism of DMD. During the conduct of these studies, we came to consider that the dystrophin-DAP complex serves to transmembranously connect the subsarcolemmal cytoskeleton networks and basal lamina to protect the lipid bilayer. It then became our working hypothesis that injury of the lipid bilayer upon muscle contraction is the cause of DMD. During this process, we predicted that subunits of the sarcoglycan (SG) complex are responsible for respective types of DMD-like muscular dystrophy with autosomal recessive inheritance. Our prediction was confirmed to be true by many researchers including ourselves. In this review, I will try to explain what we observed and how we considered concerning the architecture and function of the dystrophin-DAP complex, and the pathomechanisms of DMD and related muscular dystrophies. PMID- 20948176 TI - Reflections on my career in analytical chemistry and biochemistry. AB - My career has been focused in two major areas, analytical chemistry and biochemistry of complex lipids and glycoconjugates. Included here are the pioneering work on the gas chromatography of long-chain sphingolipid bases, carbohydrates, steroids and urinary organic acids. Mass spectrometry was utilized extensively in structural studies of sphingolipids, fatty acids, carbohydrates, steroids, urinary organic acids, polyisoprenoid alcohols, and juvenile hormone. Computer systems were developed for the acquisition and analysis of mass spectra, and were used for development of automated metabolic profiling of complex mixtures of metabolites. Fabry's disease was discovered to be a glycosphingolipidosis. Enzymes of lysosomal metabolism of glycosphingolipids were purified, characterized, and used in one of the first demonstrations of the feasibility of enzyme replacement therapy in a lysosomal storage disorder (Fabry's disease). Extracellular sialidases were studied to evaluate the hypothesis that they might be involved in the regulation of membrane growth factor receptors. The enzyme for hematoside synthesis was purified and characterized. PMID- 20948177 TI - Development of fluorescent probes for bioimaging applications. AB - Fluorescent probes, which allow visualization of cations such as Ca(2+), Zn(2+) etc., small biomolecules such as nitric oxide (NO) or enzyme activities in living cells by means of fluorescence microscopy, have become indispensable tools for clarifying functions in biological systems. This review deals with the general principles for the design of bioimaging fluorescent probes by modulating the fluorescence properties of fluorophores, employing mechanisms such as acceptor excited Photoinduced electron Transfer (a-PeT), donor-excited Photoinduced electron Transfer (d-PeT), and spirocyclization, which have been established by our group. The a-PeT and d-PeT mechanisms are widely applicable for the design of bioimaging probes based on many fluorophores and the spirocyclization process is also expected to be useful as a fluorescence off/on switching mechanism. Fluorescence modulation mechanisms are essential for the rational design of novel fluorescence probes for target molecules. Based on these mechanisms, we have developed more than fifty bioimaging probes, of which fourteen are commercially available. The review also describes some applications of the probes developed by our group to in vitro and in vivo systems. PMID- 20948179 TI - Vagal nerve regulation is essential for the increase in gastric motility in response to mild exercise. AB - It has been shown that mild to moderate exercise can accelerate gastric emptying in humans. However, understanding of the underlying mechanism is hampered by the lack of appropriate animal models. To investigate the effects of mild exercise on gastric motility, we developed an animal model, in which strain gauge transducers were surgically planted on the antral surfaces of female Sprague-Dawley rats. We continuously recorded the contractions of gastric circular muscle in unrestrained conscious rats, divided into four groups: sham-operated exercise, sham-operated sedentary, vagotomized exercise, and vagotomized sedentary. The rats were trained for 3 weeks, and gastric motility was monitored before and after exercise. Although exercise accelerates gastric antral contraction in sham-operated rats, this effect was absent in the vagotomized exercise group, indicating the involvement of the vagal nerve in the exercise-mediated increase in gastric motility. Among the four groups, daily food intake was highest in the sham operated exercise group. In contrast, the vagotomized exercise group exhibited the smallest body weight gain. Severe gastric retention was observed in vagotomized rats, suggesting a role of the vagal nerve in facilitating food movement and digestion in the stomach. Moreover, at the end of the 3-week exercise, there were no differences in plasma levels of growth hormone, peptid YY, and ghrelin among the four groups. These results indicate that in response to a mild physical exercise challenge, the vagal nerve stimulates gastric motility and enhances the ability of the stomach to process food. Our findings highlight the significance of neuronal control of stomach function. PMID- 20948178 TI - Molecular biology of histidine decarboxylase and prostaglandin receptors. AB - Histamine and prostaglandins (PGs) play a variety of physiological roles as autacoids, which function in the vicinity of their sources and maintain local homeostasis in the body. They stimulate target cells by acting on their specific receptors, which are coupled to trimeric G proteins. For the precise understanding of the physiological roles of histamine and PGs, it is necessary to clarify the molecular mechanisms involved in their synthesis as well as their receptor-mediated responses. We cloned the cDNAs for mouse L-histidine decarboxylase (HDC) and 6 mouse prostanoid receptors (4 PGE(2) receptors, PGF receptor, and PGI receptor). We then characterized the expression patterns and functions of these genes. Furthermore, we established gene-targeted mouse strains for HDC and PG receptors to explore the novel pathophysiological roles of histamine and PGs. We have here summarized our research, which should contribute to progress in the molecular biology of HDC and PG receptors. PMID- 20948181 TI - Longitudinal changes in the corpus callosum following pediatric traumatic brain injury. AB - BACKGROUND: Atrophy of the corpus callosum (CC) is a documented consequence of moderate-to-severe traumatic brain injury (TBI), which has been expressed as volume loss using quantitative magnetic resonance imaging (MRI). Other advanced imaging modalities such as diffusion tensor imaging (DTI) have also detected white matter microstructural alteration following TBI in the CC. The manner and degree to which macrostructural changes such as volume and microstructural changes develop over time following pediatric TBI, and their relation to a measure of processing speed is the focus of this longitudinal investigation. As such, DTI and volumetric changes in the CC in participants with TBI and a comparison group at approximately 3 and 18 months after injury as well as their relation to processing speed were determined. METHODS: Forty-eight children and adolescents aged 7-17 years who sustained either complicated mild or moderate-to severe TBI (n = 23) or orthopedic injury (OI; n = 25) were studied. The participants underwent brain MRI and were administered the Eriksen flanker task at both time points. RESULTS: At 3 months after injury, there were significant group differences in DTI metrics in the total CC and its subregions (genu/anterior, body/central and splenium/posterior), with the TBI group demonstrating significantly lower fractional anisotropy (FA) and a higher apparent diffusion coefficient (ADC) in comparison to the OI group. These group differences were also present at 18 months after injury in all CC subregions, with lower FA and a higher ADC in the TBI group. In terms of longitudinal changes in DTI, despite the group difference in mean FA, both groups generally demonstrated a modest increase in FA over time though this increase was only significant in the splenium/posterior subregion. Interestingly, the TBI group also generally demonstrated ADC increases from 3 to 18 months though the OI group demonstrated ADC decreases over time. Volumetrically, the group differences at 3 months were marginal for the midanterior and body/central subregions and total CC. However, by 18 months, the TBI group demonstrated a significantly decreased volume in all subregions except the splenium/posterior area relative to the OI group. Unlike the OI group, which showed a significant volume increase in subregions of the CC over time, the TBI group demonstrated a significant and consistent volume decrease. Performance on a measure of processing speed did not differentiate the groups at either visit, and only the OI group showed significantly improved performance over time. Processing speed was related to FA in the splenium/posterior and total CC only in the TBI group on both occasions, with a stronger relation at 18 months. CONCLUSION: In response to TBI, macrostructural volume loss in the CC occurred over time; yet, at the microstructural level, DTI demonstrated both indicators of continued maturation and development even in the damaged CC, as well as evidence of potential degenerative change. Unlike volumetrics, which likely reflects the degree of overall neuronal loss and axonal damage, DTI may reflect some aspects of postinjury maturation and adaptation in white matter following TBI. Multimodality imaging studies may be important to further understand the long-term consequences of pediatric TBI. PMID- 20948182 TI - Prenatal infection decreases calbindin, decreases Purkinje cell volume and density and produces long-term motor deficits in Sprague-Dawley rats. AB - The cerebellum is involved in the control of motor functions with Purkinje cells serving as the only output from the cerebellum. Purkinje cells are important targets for toxic substances and are vulnerable to prenatal insults. Intrauterine infection (IUI) has been shown to selectively target the developing cerebral white matter through lesioning, necrosis and inflammatory cytokine activation. Developmental and cognitive delays have been associated with animal models of IUI. The aim of this study was to determine if IUI leads to damage to Purkinje cells in the developing cerebellum and if any damage is associated with decreases in calbindin and motor behaviors in surviving pups. Pregnant rats were injected with Escherichia coli (1 * 105 colony-forming units) or sterile saline at gestational day 17. Beginning at postnatal day (PND) 2, the pups were subjected to a series of developmental tests to examine developmental milestones. At PND 16, some pups were sacrificed and their brains extracted and processed for histology or protein studies. Hematoxylin and eosin (HE) staining was done to examine the general morphology of the Purkinje cells and to examine Purkinje cell density, area and volume. Calbindin expression was examined in the cerebellum via immunohistochemistry and Western blot techniques. The remaining rat pups were used to examine motor coordination and balance on a rotating rotarod at the prepubertal and adult ages. Prenatal E. coli injection did not significantly change birth weight or delivery time, but did delay surface righting and negative geotaxis in pups. Pups in the E. coli group also had a decrease in the number of Purkinje cells, as well as a decrease in Purkinje cell density and volume. HE staining demonstrated a change in Purkinje cell morphology. Calbindin expression was decreased in rats from the E. coli group as well. Locomotor tests indicated that while there were no significant changes in gross motor activity, motor coordination and balance was impaired in both prepubertal and adult rats from the E. coli group. In this model of IUI, we observed changes in Purkinje cell development which were associated with alterations in cerebellum-dependent motor behaviors. The decreases in calbindin and Purkinje cells were associated with developmental delays. These data further support the importance of IUI in brain development. PMID- 20948183 TI - Dyspnea during speech in chronic obstructive pulmonary disease patients: effects of pulmonary rehabilitation. AB - BACKGROUND: For patients with limited physical activities who use oral communication for most social activities, the assessment of dyspnea during speech activities (DS) may provide relevant measurement criteria. Although speech production is altered by lung disease it has not been included in current dyspnea assessment tools. OBJECTIVES: We evaluated DS in patients with chronic obstructive pulmonary disease (COPD) with the aim of assessing: (i) the responsiveness to treatment of this newly developed evaluative dyspnea tool and (ii) whether DS is an independent measurement of other traditional outcomes. METHODS: We assessed lung function, the 6-min walking test (6'WT), chronic exertional dyspnea (MRC and BDI/TDI), and DS using the speech section of the University of Cincinnati Dyspnea Questionnaire (UCDQ) before and after a pulmonary rehabilitation program in 31 patients with COPD. RESULTS: The following items of the speech section of the UCDQ caused dyspnea: conversation, raising the voice, phoning, speaking to a group, talking in a noisy place, and singing. The mean overall DS score was 60 +/- 23% of a maximal potential DS score. Pulmonary rehabilitation reduced each item of DS independently of change in lung function, chronic exertional dyspnea, and 6'WT. CONCLUSIONS: We concluded that DS is responsive to a respiratory rehabilitation program in patients with COPD. Evidence of independent objective measures supports the validity of a routine multivariable assessment including DS. We recommend assessment of DS particularly for patients who rely extensively on speech for communication. PMID- 20948184 TI - Supramaximal flows: comparison between asthmatics and patients with chronic obstructive pulmonary disease. AB - BACKGROUND: The major motive that prompted this study was to investigate whether or not the differences in supramaximal flow (SF) behavior between patients suffering from asthma and patients suffering from chronic obstructive pulmonary disease (COPD) might aid in clarifying the differences in the physiopathology of the two diseases. OBJECTIVES: The aim of the present study was therefore to compare SFs in asthma and COPD patients with similar degrees of air-flow limitation. METHODS: Twelve asthmatic patients were individually matched with 12 COPD patients by forced expiratory volume during the first second (FEV(1)) as a percent (+/-5%) of the reference value (DeltaFEV(1)) and by age (+/-4 years). The subjects performed baseline maximal expiratory flow-volume curves (MEFV) and then repeated the same maneuvers through a valve that occluded the air flow 6 times per second with an open/closed time ratio of 4/1. We then plotted an envelope of the expiration-interrupted curve passing through the SF peaks, measured the increase in flow at 50% of the forced vital capacity between the baseline curve and the envelope curves (DeltaVmax(50)), and compared the FEV(1) of the interrupted curve to the FEV(1) obtained from control MEFV curves (DeltaFEV(1)). RESULTS: We found significantly higher values for DeltaVmax(50) (p < 0.03) and DeltaFEV(1) (p < 0.01) in the asthmatics compared to the COPD patients. CONCLUSIONS: The differences reported here are best explained by a greater preservation of elastic recoil pressure at a similar degree of air-flow limitation in the asthmatics than in the COPD patients. PMID- 20948185 TI - A 19-year-old man with dyspnea and stridor after surgery. PMID- 20948186 TI - Investigative clinical study on prostate cancer part III: exploring total PSA and free testosterone distributions and linear correlations in groups and subgroups of operated prostate cancer patients according to the total PSA/FT ratio. AB - OBJECTIVES: Prostate cancer is an interesting tumor for endocrine investigation. The prostate-specific antigen/free testosterone (PSA/FT) ratio has been shown to be effective in clustering patients in prognostic groups as follows: low risk (PSA/FT <=0.20), intermediate risk (PSA/FT >0.20 and <=0.40) and high risk (PSA/FT >0.40 and <=1.5). In the present study we explored the total PSA and FT distributions, and linear regression of FT predicting PSA in the different groups (PSA/FT, pT and pG) and subgroups (pT and pG) of patients according to the prognostic PSA/FT ratio. PATIENTS AND METHODS: The study included 128 operated prostate cancer patients. Pretreatment simultaneous serum samples were obtained for measuring free testosterone (FT) and total PSA levels. Patients were grouped according to the total PSA/FT ratio prognostic clusters (<=0.20, >0.20 and <=0.40, >0.40), pT (2, 3a and 3b+4) and pathological Gleason score (pG) (<=6, = 7 >3 + 4, >=7 >4 + 3). The pT and pG sets were subgrouped according to the prognostic PSA/FT ratio. Linear regression analysis of FT predicting total PSA was computed according to the different PSA/FT prognostic clusters for the: (1) total sample population, (2) pT and pG groups, (3) intraprostatic (pT2) and extraprostatic disease (pT3a/3b/4), and (4) low-intermediate grade (pG <=6) and high-grade (pG >=7) prostate cancer. RESULTS: Analysis of variance always showed highly significant different PSA distributions for (1) the different PSA/FT, pT and pG groups; and (2) the pT and pG prognostic subgroups. Significant FT distributions were detected for the (1) PSA/FT and pT groups; and (2) the pT2, pT3a and pG <=6 prognostic PSA/FT subgroups. Correlation, variance and linear regression analysis of FT predicting total PSA was significant for (1) the PSA/FT prognostic clusters, (2) all the pT2 and pT3a subgroups, and (3) the pT3b/4 subgroup with PSA/FT >0.20 and <=0.40, and (4) all the pG subsets. Linear regression analysis showed that the slopes of the predicting variable (FT) were always highly significant for patients with (1) intraprostate and extraprostate disease, and (2) low-grade and high-grade prostate cancer. CONCLUSIONS: According to the prognostic PSA/FT ratio, significantly lower levels of FT are detected in prostate cancer patients with extensive and high-grade disease. Also, significant linear correlations of FT predicting PSA are assessed in the different groups and subgroups of patients clustered according to the prognostic PSA/FT ratio. Confirmatory studies are needed. PMID- 20948187 TI - Pathophysiological response to experimental diffuse brain trauma differs as a function of developmental age. AB - The purpose of experimental models of traumatic brain injury (TBI) is to reproduce selected aspects of human head injury such as brain edema, contusion or concussion, and functional deficits, among others. As the immature brain may be particularly vulnerable to injury during critical periods of development, and pediatric TBI may cause neurobehavioral deficits, our aim was to develop and characterize as a function of developmental age a model of diffuse TBI (DTBI) with quantifiable functional deficits. We modified a DTBI rat model initially developed by us in adult animals to study the graded response to injury as a function of developmental age - 7-, 14- and 21-day-old rats compared to young adult (3-month-old) animals. Our model caused motor deficits that persisted even after the pups reached adulthood, as well as reduced cognitive performance 2 weeks after injury. Moreover, our model induced prominent edema often seen in pediatric TBI, particularly evident in 7- and 14-day-old animals, as measured by both the wet weight/dry weight method and diffusion-weighted MRI. Blood-brain barrier permeability, as measured by the Evans blue dye technique, peaked at 20 min after trauma in all age groups, with a second peak found only in adult animals at 24 h after injury. Phosphorus MR spectroscopy showed no significant changes in the brain energy metabolism of immature rats with moderate DTBI, in contrast to significant decreases previously identified in adult animals. PMID- 20948188 TI - Hippocampal neurogenesis and cortical cellular plasticity in Wahlberg's epauletted fruit bat: a qualitative and quantitative study. AB - Species-specific characteristics of neuronal plasticity emerging from comparative studies can address the functional relevance of hippocampal or cortical plasticity in the light of ecological adaptation and evolutionary history of a given species. Here, we present a quantitative and qualitative analysis of neurogenesis in young and adult free-living Wahlberg's epauletted fruit bats. Using the markers for proliferating cell nuclear antigen (PCNA), bromodeoxyuridine (BrdU), doublecortin (DCX) and polysialic acid neural cell adhesion molecule (PSA-NCAM), our findings in the hippocampus, olfactory bulb and cortical regions are described and compared to reports in other mammals. Expressed as a percentage of the total number of granule cells, PCNA- and BrdU positive cells accounted for 0.04 in young to 0.01% in adult animals; DCX positive cells for 0.05 (young) to 0.01% (adult); PSA-NCAM-positive cells for 0.1 (young) to 0.02% (adult), and pyknotic cells for 0.007 (young) to 0.005% (adult). The numbers were comparable to other long-lived, late-maturing mammals such as primates. A significant increase in the total granule cell number from young to adult animals demonstrated the successful formation and integration of new cells. In adulthood, granule cell number appeared stable and was surprisingly low in comparison to other species. Observations in the olfactory bulb and rostral migratory stream were qualitatively similar to descriptions in other species. In the ventral horn of the lateral ventricle, we noted prominent expression of DCX and PSA-NCAM forming a temporal migratory stream targeting the piriform cortex, possibly reflecting the importance of olfaction to these species. Low, but persistent hippocampal neurogenesis in non-echolocating fruit bats contrasted the findings in echolocating microbats, in which hippocampal neurogenesis was largely absent. Together with the observed intense cortical plasticity in the olfactory system of fruit bats we suggest a differential influence of sensory modalities on hippocampal and cortical plasticity in this mammalian order. PMID- 20948189 TI - Clotting factors and eicosanoids protect against nematode infections. AB - We show that hemolymph clotting protects Drosophila melanogaster against infections with an entomopathogenic nematode and its symbiotic bacterium. We also provide biochemical and genetic evidence for an involvement of eicosanoids in the same infection model. Taken together, our results confirm the conserved nature of the immune function of clot formation. PMID- 20948190 TI - An unusual case of ankylosing spondylitis presenting with severe anemia. PMID- 20948191 TI - IFN-gamma and TNF-alpha synergistically induce microRNA-155 which regulates TAB2/IP-10 expression in human mesangial cells. AB - BACKGROUND/AIMS: MicroRNAs are noncoding small RNA molecules that posttranscriptionally regulate gene expression. microRNA-155 (miR-155), one of the microRNAs, is involved in the control of various genes. However, the role of miR-155 in inflammatory responses in mesangial cells is not known. In the present study, we examined the expression of miR-155 in mesangial cells. METHODS: The expression of miR-155 in cultured normal human mesangial cells treated with interferon-gamma (IFN-gamma) and/or tumor-necrosis factor-alpha (TNF-alpha) was examined. The cells were transfected with miR-155 mimic, siRNA against transforming growth factor-beta-activated kinase-1 (TAK1)-binding protein 2 (TAB2) or siRNA against nuclear factor-kappaB (NF-kappaB). RESULTS: IFN-gamma and TNF-alpha synergistically induced the expression of miR-155. Transfection of cells with miR-155 mimic inhibited the expression of TAB2 and IFN-gamma-inducible protein of 10 kDa (IP-10). The expression of IP-10 was suppressed by knockdown of TAB2. Induction of miR-155 was inhibited by RNA interference against TAB2 or NF kappaB. CONCLUSION: Combined stimulation with IFN-gamma and TNF-alpha induces miR 155 via TAB2 and NF-kappaB. miR-155 negatively regulates TAB2, as a negative feedback system, to lower IP-10 expression. miR-155 may play a role in the regulation of inflammatory and immune reactions in the kidney. PMID- 20948192 TI - The G allele of transcobalamin 2 c.776C->G is associated with an unfavorable lipoprotein profile. AB - BACKGROUND/AIM: Recent studies have suggested a relation of homocysteine with lipid metabolism. The aim of this study was to analyze a possible genetic basis for such a relation in 504 individuals including 135 consecutive Caucasian patients diagnosed with cerebrovascular disease as well as the patients' healthy spouses (n = 100) and offspring (n = 269). METHODS: We analyzed the association of plasma levels of lipoprotein(a), total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides with plasma homocysteine levels and with the following 7 variants of homocysteine metabolism: dihydrofolate reductase c.594 + 59del19bp, cystathionine beta-synthase c.844_855ins68, methionine synthase c.2756A->G, methylenetetrahydrofolate reductase c.677C->T and c.1298A->C, reduced folate carrier 1 c.80G->A, and transcobalamin 2 (Tc2) c.776C->G. RESULTS: Linear regression analysis showed an association of Tc2 c.776C->G with LDL (p = 0.010), HDL (p = 0.009), and TG (p = 0.007), with the G allele of Tc2 c.776C->G associated with an unfavorable blood lipid profile. Moreover, the G allele of Tc2 c.776C->G was associated with higher homocysteine plasma levels in the subgroup of patients (p = 0.013, 1-way ANOVA). CONCLUSION: These data support the hypothesis that alterations in homocysteine metabolism and an unfavorable blood lipoprotein profile may have a common genetic basis. Such conditions may be relevant for studies investigating independent risk factors for vascular disease. PMID- 20948193 TI - The effect of sugar-sweetened beverage intake on energy intake in an ad libitum 6 month low-fat high-carbohydrate diet. AB - BACKGROUND/AIMS: The increased incidence of obesity coincides with an increased consumption of sugar-sweetened beverages (SSBs). This study investigated the effect of SSB intake on energy intake in an ad libitum 6-month low-fat high carbohydrate diet in a reanalysis of the CARMEN data. METHODS: Forty-seven overweight-to-obese men and women participated in the Maastricht centre of the randomized controlled CARMEN study. They were allocated to a control (habitual) diet group (CD), a low-fat (-10 energy percent, En%) high simple carbohydrate (SCHO) or low-fat high complex carbohydrate group (CCHO) (SCHO vs. CCHO: 1.5 vs. 0.5) using a controlled laboratory shop system. Reanalyses were made for the energy, amount and density of all drinks and in particular of sweetened beverages (SBs). The SCHO and CD group could select non-diet SBs, including soft drinks and fruit juices, while the CCHO group received SB alternatives. RESULTS: Energy intake decreased in the CCHO and SCHO groups versus the CD group (-2.7 +/- 0.4 MJ/day CCHO group vs. -0.2 +/- 0.5 MJ/day CD group, p < 0.01; -1.4 +/- 0.4 MJ/day SCHO group, not significant). Simple carbohydrate intake increased significantly in the SCHO group versus the CCHO and CD groups (+10.8 +/- 1.6 vs. -2.0 +/- 0.9 and -0.5 +/- 1.1 En%; p < 0.001). In the SCHO and CD groups, energy intake from SBs increased significantly (+187 +/- 114 and +101 +/- 83 kJ/day, respectively; 432 +/- 72 kJ/day in the CCHO group; p < 0.001). CONCLUSION: Simple carbohydrate intake increased through enhanced intake of non-diet SBs in the SCHO group. Fat reduction combined with only diet SBs in an ad libitum situation has a greater impact on energy intake than fat reduction combined with non-diet SBs. PMID- 20948194 TI - The rs1466113 polymorphism in the somatostatin receptor 2 gene is associated with obesity and food intake in a Mediterranean population. AB - BACKGROUND: A genome-wide association study identified rs1466113 (G>C) in the somatostatin receptor 2 (SSTR2) gene as one of the polymorphisms most significantly associated with body mass index (BMI). As replication is required, we examined the association between this polymorphism and anthropometric variables and food intake in a Mediterranean population. METHODS: We studied 945 high cardiovascular-risk subjects (340 men and 605 women) aged 67 +/- 6 years, participating in the PREDIMED-Valencia Study. Demographic, clinical, biochemical, dietary, genetic and anthropometric data were obtained. RESULTS: We found recessive effects for the association between this polymorphism and anthropometric variables. Homozygous subjects for the C allele had significantly lower BMI than G-allele carriers (29.9 +/- 4.5 in CC vs. 31.0 +/- 4.9 in GG + GC; p = 0.035). Likewise, odds ratio for obesity was lower in CC subjects in comparison with G-allele carriers, even after adjustment for potential confounders (odds ratio: 0.60, 95% confidence interval: 0.38-0.94; p = 0.028). We also found significant differences in food (meats, dairy products and legumes) and nutrient (protein) intakes between CC- and G-allele carriers. CONCLUSION: The rs1466113 polymorphism in the SSTR2 gene is associated with anthropometric variables in the Mediterranean population replicating previous results in the Framingham study. We also observed differences in food intake between genotypes. PMID- 20948195 TI - Intratympanic methylprednisolone improves hearing function in refractory sudden sensorineural hearing loss: a control study. AB - OBJECTIVE: The aim of this study was to describe our experience with intratympanic (IT) steroid treatment of sudden sensorineural hearing loss (SSNHL) after the failure of intravenous (IV) steroid treatment and to examine the efficacy of this treatment. METHODS: We recruited 65 patients with SSNHL who did not respond to IV treatment with prednisolone. These patients were randomized into 3 groups: treatment with IT steroid, treatment with steroid in ear drops, and blank control. The 24 patients in the IT group received an IT injection of methylprednisolone and the 21 patients in the ear drop group received methylprednisolone that was directly dropped onto the tympanic membrane through the ear canal. The 20 patients in the blank control group did not receive any treatment after the completion of the IV prednisolone injection. Audiograms were performed at the beginning of the study and 2 months after the end of the study. RESULTS: In the IT treatment group, audiogram results showed that the average of the pure tone speech frequencies (500-4000 Hz) was 64.8 (range 40-101 dB) at baseline, 60.7 (range 35-92 dB) at the end of systemic treatment, and 52.9 (range 35-73 dB) at the end of IT treatment. The improvement in the IT group was significantly better than that in the other two groups, with 37% of the IT patients having significant improvement in their hearing (baseline to after systemic treatment). During IT treatment, only 1 patient developed a persistent tympanic membrane perforation, and no serious complications such as chronic otitis media, disequilibrium, and dysgeusia developed. CONCLUSIONS: IT steroid therapy can improve hearing function in patients with SSNHL after the failure of systemic steroid treatment. PMID- 20948196 TI - International survey on the management of acute kidney injury in critically ill patients: year 2007. AB - INTRODUCTION: Several aspects of acute kidney injury (AKI) management, including medical approaches to AKI patients and the optimal form of renal replacement therapy (RRT), remain a matter of debate. SUBJECTS AND METHODS: The responses of 440 participants to a questionnaire on several points of AKI management, submitted during the 4th International Course on Critical Care Nephrology in June 2007, were analyzed. RESULTS: The most common answer to the definition of AKI was the use of the RIFLE criteria (55%), followed by the presence of oligoanuria (24%). Responders seemed to preferentially start dialysis within a creatinine range from 2.3-3.4 mg/dl (28%) to 3.4-4.5 mg/dl (26%) and with a urine output level of 150-200 ml/12 h (43%). About 30% of responders showed that they would prescribe dialysis only in case of severe fluid overload (requiring mechanical ventilation and/or causing impaired skin integrity). Continuous RRT is used by most specialists (86%), followed by intermittent hemodialysis (65%), sustained low-efficiency dialysis (28%) and peritoneal dialysis (30%). The preferred RRT dosage was '35 ml/kg/h' (46%) but 37% of responders did not explicitly answer this critical question. Bleeding, hypotension, filter clotting, vascular access and sepsis treatment were the most frequent complications and concerns of RRT. CONCLUSIONS: New classifications such as the RIFLE criteria did improve the well known uncertainty about the definition of AKI. Awareness of the prescription and standardization of an adequate treatment dose seemed to have increased in recent years, even if there is still a significant level of uncertainty on this specific issue. Several concerns and RRT complications, such as bleeding and anticoagulation strategies, still need further exploration and development. PMID- 20948197 TI - High-grade internal carotid artery stenosis and chronic brain damage: a volumetric magnetic resonance imaging study. AB - BACKGROUND: Experimental data suggest that high-grade vascular stenosis may induce chronic cerebral tissue damage. METHODS: We tested this hypothesis in 97 patients with a >=70% unilateral internal carotid artery (ICA) stenosis (mean age: 69.1 +/- 10.2 years), comparing intraindividual side-to-side differences in hemispheric brain and white matter hyperintensity (WMH) volumes. Patients with a supratentorial infarct exceeding 1.5 cm in diameter were excluded. RESULTS: Overall, the median WMH volume was greater in the hemisphere ipsilateral to the stenotic ICA (1.13 +/- 2.65 vs. 0.77 +/- 2.26 cm3; p = 0.005), but there were no differences in hemispheric brain volumes between the stenotic and nonstenotic sides. In the subgroup of patients with moderate and severe WMH (n = 41), the hemispheric volume ipsilateral to the stenotic ICA was significantly smaller (543.46 +/- 22.17 vs. 548.66 +/- 26.7 cm3; p = 0.03). Multivariate linear regression analysis revealed an independent effect of WMH grade on interhemispheric volume differences relative to the side of stenosis. CONCLUSIONS: Chronic tissue damage may occur in a subset of individuals with >=70% ICA stenosis, globally exhibiting more extensive WMH. PMID- 20948198 TI - CT perfusion with angiography as a substitute for both conventional digital subtraction angiography and acetazolamide-challenged SPECT in the follow-up of postbypass patients. AB - BACKGROUND: We evaluated the clinical usefulness of CT perfusion (CTP) with angiography (CTA) as an alternative to digital subtraction angiography (DSA) and acetazolamide (ACZ)-challenged single-photon emission computed tomography (SPECT) in the follow-up evaluation of hemodynamic changes and bypass patency after bypass surgery in chronic cerebral ischemic diseases. METHODS: Thirty-five patients who underwent superficial temporal artery/middle cerebral artery bypass surgery for chronic cerebral ischemic diseases were retrospectively enrolled. We assessed the relationship between CTP parameters [cerebral blood volume, cerebral blood flow (CBF), mean transit time (MTT), affected-to-unaffected hemisphere (ATU) ratio of perfusion parameters and MTT differences between hemispheres] and SPECT parameters (regional CBF and cerebrovascular reserve) and compared the preoperative CTP parameters with the postoperative ones. For the bypass patency, we compared CTA with DSA. RESULTS: MTT showed the best correlation with CVR of SPECT (r = -0.343; p < 0.001). ATU ratio (r = -0.547; p < 0.001) and ATU differences (r = -0.592; p < 0.001) of MTT correlated well with the ATU ratio of rCBF on ACZ-challenged SPECT. Significant improvement of perfusion parameters could be demonstrated in the affected vascular territory with postoperative CTP. The CTA findings were consistent with those of DSA in 96% of the cases. The examination-related complication rate was 0, 2.8 and 8.6% for CT studies, DSA and SPECT, respectively. CONCLUSIONS: CTP performed simultaneously with CTA seems to be a safe and efficient substitute for DSA and ACZ-challenged SPECT in the follow up evaluation after bypass surgery in patients with chronic cerebral ischemic diseases. PMID- 20948199 TI - Medical prophylaxis following hospitalization for ischemic stroke: age- and sex related differences and relation to mortality. AB - BACKGROUND: The extent and implications of age- and sex-related differences in prophylaxis following ischemic stroke are unknown. We examined differences in the use of medical prophylaxis across age and sex groups in stroke patients after hospital discharge in Denmark and estimated the possible impact on age- and sex related differences in mortality. METHODS: A nationwide population-based follow up study was conducted involving 28,634 patients hospitalized for ischemic stroke in 2003-2006 who survived 30 days after discharge. The proportion of patients who filled prescriptions for cardiovascular drugs within 0-6 and 12-18 months after discharge was determined. Mortality rates were compared across age and sex groups with and without controlling for use of medical prophylaxis. RESULTS: Increasing age was associated with lower prophylaxis. Adjusted odds ratios for the use of a combination of a platelet inhibitor, an antihypertensive and a statin were 0.45 [95% confidence interval (CI): 0.38-0.54] and 0.52 (95% CI: 0.43-0.62) for men and women >80 years, respectively, compared with men <=65 years. No systematic sex-related differences were identified. Continued drug use ranged from 66.1 to 91.9% for different drugs 12-18 months after discharge, with the lowest rate of continued use found among patients >80 years. Controlling for use of medical prophylaxis was associated with lower mortality rate ratios for elderly compared with younger patients. CONCLUSIONS: Continuous efforts are warranted to ensure implementation of evidence-based secondary prophylaxis among elderly patients with ischemic stroke. PMID- 20948200 TI - Neural correlates of hemispatial neglect: a voxel-based SPECT study. AB - BACKGROUND: Despite many studies that investigated the neural correlates of hemispatial neglect (HN) with structural imaging, studies using voxel-wise analyses of functional imaging are not available. Furthermore, previous studies neither considered the neglect severity nor investigated whether there are differences in these neural correlates according to each neglect subtest. This study aimed to investigate the neural correlates of HN by correlating the total and the individual neglect score with hypoperfusion value on single photon emission computed tomography (SPECT) using voxel-wise analyses. METHODS: Forty two patients with acute right hemisphere strokes underwent a neglect test battery consisting of 3 bisection tasks, 2 cancellation tasks and 2 copying tasks. The SPECT images were acquired in these patients and 10 age- and education-matched normal controls. RESULTS: Patients with HN, compared to those without HN, had hypoperfusion in the right middle temporal-occipital junction, inferior frontal gyrus and retrosplenial area. The total neglect score correlated with the hypoperfusion in the right middle temporal-occipital junction, fusiform gyrus, parahippocampal gyrus, inferior temporal gyrus, anterior part of the superior and middle temporal gyri, cuneus, lingual gyrus, angular gyrus, and the cerebellum. Across the neglect subtests similar correlation patterns were observed with minor variations. CONCLUSIONS: Unlike the results of previous studies showing that the critical neural correlates for HN are inferior parietal lobule or superior temporal gyrus, our study showed that the lesions that critically contribute to the neglect severity were located in the posterior parts of the middle temporal gyrus (temporal-occipital junction). PMID- 20948201 TI - Predictors of acute poststroke seizures. AB - BACKGROUND: In this study, we tried to identify predictors of acute poststroke seizures (aPSS) in stroke patients. METHODS: We analyzed a large prospective hospital-based stroke registry in Germany. 58,874 patients with the diagnosis of transient ischemic attack (TIA), ischemic stroke (IS) or intracerebral hemorrhage (ICH) were admitted within 24 h after symptom onset. Predictors for aPSS were identified using multivariate regression analysis adjusted for age, gender, stroke severity, vascular risk factors, acute nonneurologic infection, history of TIA and length of hospital stay. RESULTS: aPSS occurred in 0.7% of patients with TIA (mean duration of hospitalization 8 days), in 2.2% of patients with IS (12 days) and in 5.1% of patients with ICH (13 days). A lower age, a higher stroke severity, acute nonneurologic infection, a history of diabetes mellitus and a history of preceding TIA were identified to be independent predictors of aPSS in IS, whereas younger age, acute infection and a history of TIA were found predictive for aPSS in ICH. CONCLUSIONS: This study characterized so far unknown predictors of aPSS and may help to improve the identification of patients with a high risk of aPSS. PMID- 20948202 TI - Bilirubin and UGT1A1*28 are not associated with lower risk for ischemic stroke in a prospective nested case-referent setting. AB - BACKGROUND: Bilirubin, an antioxidant, has been associated with reduced cardiovascular disease risk. A major cause of elevated plasma bilirubin is the common UGT1A1*28 promoter polymorphism in the gene of the bilirubin-conjugating enzyme UDP-glucuronosyltransferase 1A1, which reduces transcription by 70%. Earlier studies reporting a protective effect of bilirubin on stroke have not included analysis of UGT1A1*28. The purpose of this study is to investigate if bilirubin and UGT1A1*28 are protective against ischemic stroke in a prospective case-referent setting. METHODS: Cases with first-ever ischemic stroke (n = 231; median lag time 4.9 years) and 462 matched referents from the Northern Sweden Health and Disease Study Cohort were included. Plasma bilirubin was measured and UGT1A1*28 was analyzed by fragment analysis. RESULTS: Plasma bilirubin was lower in cases than in referents, but the difference reached significance only for women. The UGT1A1*28 polymorphism (allele frequency 30%) showed a strong gene dose relationship with bilirubin levels both among cases and referents, but was not associated with risk for stroke. Among multiple other variables analyzed, the strongest correlation with bilirubin was found for plasma iron. CONCLUSIONS: There was no evidence for a protective effect of the UGT1A1*28 polymorphism against stroke and consequently neither for bilirubin. The findings suggest that other factors influencing the risk for stroke might also affect bilirubin levels. PMID- 20948203 TI - Transient ischaemic attack mimics revealing focal subarachnoid haemorrhage. AB - We describe here 7 elderly patients with a transient neurological deficit due to a focal subarachnoid haemorrhage, identified from the Dijon Stroke Registry over 4 years. These 7 patients presented a clinical pattern marked by focal paraesthesia, with several stereotyped focal episodes (5 of the 7 cases), lasting less than 30 min (6 of the 7 cases), and associated with a cognitive decline (4 of the 7 cases). Headache was present in only 1 case. Neuroimaging revealed focal haemorrhage present in a cortical sulcus contralateral to the symptoms. No vascular lesions nor epileptic mechanisms nor ischemic lesions were observed. This syndrome could be explained by a spreading depression, and the focal subarachnoid haemorrhage could reflect possible cerebral amyloid angiopathy, suggested by the cognitive decline present in more than 50% of our series. Our observations suggest that focal subarachnoid haemorrhage may be diagnosed by MRI in the absence of acute headache and it may be revealed by transient focal and repetitive sensory perturbations. In medical practice, it is important to evoke this diagnosis in the elderly to avoid inappropriate treatment. PMID- 20948204 TI - The possible risk for strokes complicating cardiac surgery in patients with intraoperative hypothermia. AB - BACKGROUND: The effect of hypothermia as a possible neuroprotective tool on the outcome of cardiac surgery is still controversial. METHODS: We retrospectively assessed all patients who underwent cardiac surgery within a 14-year period and compared patients with and without postoperative stroke. RESULTS: Stroke occurred more frequently in patients who underwent valve repair/replacement combined with coronary artery bypass grafting (CABG) than in patients who had CABG alone (p = 0.0002). All strokes (1.4%) were ischemic and mostly of large-vessel etiology. All patients with stroke had intraoperative minimal temperature <34 degrees C. More patients in this group than in the group without stroke had an intraoperative minimal temperature <30 degrees C (p = 0.01). Stepwise multivariate analysis of all pre- and intraoperative parameters identified significant risk factors for stroke: hypertension, diabetes mellitus and previous stroke as preoperative risk factors, but only lower minimal temperature as a significant intraoperative risk factor (p = 0.03; odds ratio 1.080/1 degrees C, 95% confidence interval 1.004-1.152). The mean intraoperative temperature was 28 +/- 4 degrees C in patients who developed stroke and 30 +/- 3 degrees C in patients without stroke. CONCLUSIONS: Intraoperative hypothermia around 28 degrees C might be harmful and associated with increased risk for postsurgical stroke. PMID- 20948205 TI - Morphological classification of mobile plaques and their association with early recurrence of stroke. AB - BACKGROUND: The present study investigated the frequency and morphological characteristics of carotid mobile plaques and examined the relationship between carotid mobile plaques and recurrent strokes. METHODS: The study included 94 consecutive acute stroke patients with large-artery atherosclerosis associated with extracranial carotid stenosis. We investigated the presence of mobile plaques by carotid ultrasonography and classified patients into two groups (mobile group and non-mobile group). We compared backgrounds, MRI and ultrasonographic findings, neurological severity on admission and at discharge, and the rate of early recurrent stroke between both groups. RESULTS: Mobile plaques were detected in 12 patients (12.8%). There were four types of mobile plaques: (1) the jellyfish-type plaque, in which the fibrous cap fluctuated like a jellyfish; (2) the streaming-band-type plaque, in which the string attached to the plaque was swaying; (3) the mobile-thrombus-type plaque, in which a mobile mass was attached to the plaque surface, and (4) the fluctuating-ulcer-type plaque, which contained a mobile substance in the plaque ulcer. Although National Institutes of Health Stroke Scale (NIHSS) scores on admission were less severe in the mobile group than in the non-mobile group (median 1 vs. 4, respectively; p = 0.004), the rate of early recurrent stroke was significantly higher in the mobile group than in the non-mobile group (33.3 vs. 7.3%, respectively; p = 0.022). There were no significant differences in NIHSS scores at discharge between groups. CONCLUSIONS: Morphologically, several types of mobile plaques were detected in consecutive patients with acute stroke associated with carotid stenosis. Mobile plaques are strongly associated with an early recurrence of stroke. PMID- 20948206 TI - Does external counterpulsation augment mean cerebral blood flow in the healthy brain? Effects of external counterpulsation on middle cerebral artery flow velocity and cerebrovascular regulatory response in healthy subjects. AB - BACKGROUND AND PURPOSE: External counterpulsation (ECP) noninvasively improves myocardial and organ perfusion via diastolic augmentation. The effects on cerebral blood flow velocities (CBFV) and hemodynamics are controversial. In this study, the effect of active ECP treatment on CBF in healthy subjects was continuously measured. METHODS: In 9 healthy volunteers (mean age 34.1 +/- 11.1 years, 4 females), 20-min active ECP treatment was performed. CBFV in the middle cerebral artery were detected via transcranial Doppler. CBFV were registered continuously before, during and after ECP. The protocol was repeated twice. RESULTS: At onset of ECP, immediate changes in CBFV were observed: peak diastolic blood flow velocities increased from baseline to treatment (63 vs. 76 cm/s; p < 0.001) and diastolic blood flow augmentation was maintained throughout ECP. Peak systolic (87 vs. 78 cm/s; p < 0.001) and end-diastolic velocities (40 vs. 28 cm/s; p < 0.001) decreased significantly, while mean CBFV maintained constant (59 vs. 58 cm/s; not significant). The pulsatility index and resistance index as indirect parameters for peripheral vascular resistance increased during ECP (pulsatility index 0.79 vs. 0.89, p < 0.001; resistance index 0.54 vs. 0.64; p < 0.001). CONCLUSIONS: ECP did not increase mean CBFV in healthy subjects even though peak diastolic CBFV were significantly augmented. Changes in CBFV and transcranial Doppler waveform characteristics suggest that the mean flow of the middle cerebral artery is maintained stable via cerebrovascular autoregulatory mechanisms. PMID- 20948207 TI - Association of a functional polymorphism in the MMP-3 gene with Moyamoya Disease in the Chinese Han population. AB - BACKGROUND: Moyamoya disease (MMD) is an uncommon cerebrovascular disease characterized by progressive stenosis of the intracranial internal carotid arteries and their proximal branches. The important role of genetic factors in the etiology and pathogenesis of MMD is being increasingly recognized. The study was designed to examine the association of single nucleotide polymorphisms in matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP) genes with MMD occurrence. METHODS: A case-control study was performed. Five functional promoter polymorphisms in the MMP-2, MMP-3, MMP-9 and MMP-13 genes and a potentially functional promoter polymorphism in the TIMP-2 gene were determined by polymerase chain reaction-restriction fragment length polymorphism. Their associations with MMD were analyzed by multivariate logistic regression. RESULTS: In total, 208 definite patients with MMD (including 31 familial MMD, FMMD, patients) and 224 healthy subjects were recruited. The frequency of the MMP-3 5A/6A and 5A/5A genotypes was significantly lower in MMD patients (OR = 0.57, 95% CI 0.38-0.86, p(corr) = 0.042) compared with healthy controls in a dominant genetic model. Significant differences of the MMP-3 5A/6A polymorphism were also detected between FMMD patients and controls both in the dominant genetic model (OR = 0.23, 95% CI 0.08-0.68, p(corr) = 0.048) and the additive genetic model (OR = 0.24, 95% CI 0.08-0.69, p(corr) = 0.048). CONCLUSION: The functional polymorphism in the MMP-3 promoter might be associated with susceptibility to both MMD and FMMD in the Chinese Han population. The findings need to be validated in further studies including more subjects from different populations. PMID- 20948208 TI - Acute vertigo with double vision - brainstem stroke or stroke mimic? PMID- 20948209 TI - Chemoprophylactic activity of flubendazole in cystic echinococcosis. AB - BACKGROUND: Cystic echinococcosis (CE) is an important public health problem worldwide. Flubendazole, administered in tablets, has shown poor in vivo efficacy against CE in humans. However, flubendazole prepared as a solution caused a marked reduction in hydatid cysts developed in mice. The goal of the current work was to compare the chemoprophylactic effect of flubendazole formulated either as a hydroxypropyl-beta-cyclodextrin solution or as a carboxymethylcellulose suspension in secondary CE in mice. METHODS: Balb/C mice were infected with Echinococcus granulosus protoscoleces. One day after infection, the animals were allocated into 3 different experimental groups: unmedicated control and treated at the time point of infection with flubendazole either prepared as a solution or suspension given twice a day during 15 days. Six months after infection, the animals were sacrificed to collect and weight parasitic cysts. Cyst samples recovered from infected mice of each experimental group were prepared for both scanning and transmission electron microscopy. RESULTS: Both flubendazole formulations induced a significant reduction in cyst weight compared to the cysts recovered from the unmedicated control animals. Both formulations showed similar flubendazole-induced ultrastructural morphological changes. CONCLUSION: Flubendazole offers a great potential to become a drug of choice in the preventive treatment of cystic echinococcosis. PMID- 20948210 TI - Antitumor effects of ginkgolic acid in human cancer cell occur via cell cycle arrest and decrease the Bcl-2/Bax ratio to induce apoptosis. AB - BACKGROUND: Ginkgolic acids (GAs), extracted from the seed coat of Ginkgo biloba L. Our previous study has shown that GA monomer could inhibit the growth of Hep-2 significantly and induce the fragmentation of the chromosomal DNA. To further assess the antitumor potential and turn it into a candidate new antitumor drug, the antitumor mechanism of GA was investigated. METHOD: The cytotoxicity and antitumor effect of GA monomer were assayed by MTT colorimetric assay with nontumorogenic MC-3T3-E1 as well as tumorogenic Hep-2 and Tac8113 cell lines. The effect of GA monomer on the proliferation of tumor cell lines was analyzed with MTT colorimetric and CFSE labeled assay. Cell cycle distribution and measurement of the percentage of apoptotic cells were performed by flow cytometry following stained with propidium iodide, annexin V-FITC. The expression of apoptotic proteins Bcl-2, Bax and caspase-3 was analyzed with Western blot. RESULT: GA only inhibited the growth of tumorogenic cell lines in a both dose- and time-dependent manner. Tumor cells were treated with GA for 72 h, 70.53 +/- 4.54% Hep-2 and 63.5 +/- 7.2% Tca8113 cells were retarded at GO/G1 phase, and the percentage of apoptosis was 40.4 +/- 1.58 and 38.4 +/- 1.7%, respectively. GA-treated activated caspase-3 downregulated the expression of anti-apoptotic Bcl-2 protein and upregulated the expression of pro-apoptotic Bax protein, eventually leading to a decrease in the Bcl-2/Bax ratio in tumor cells. CONCLUSIONS: The antitumor action of GA was due to inhibiting the proliferation in a manner of inhibiting division, retarding the progress of cell cycle and inducing apoptosis, making GA a candidate as new antitumor drug. PMID- 20948211 TI - Comparison of accumulation, subcellular location, and sonodynamic cytotoxicity between hematoporphyrin and protoporphyrin IX in L1210 cells. AB - BACKGROUND: Sonodynamic therapy (SDT) is a promising modality for cancer treatment which requires the synergistic effect of ultrasound and tumor-localized sonosensitizers. Sonodynamic efficacy can be improved through a better understanding of the accumulation and subcellular location of sonosensitizers. Here, a comparison of the accumulation, sublocation, and sonodynamic effect of hematoporphyrin (Hp) and protoporphyrin IX (PpIX) was studied in L1210 cells. METHODS: The kinetics of intracellular Hp and PpIX accumulation were detected using a fluorescence spectrophotometer. The subcellular distributions of Hp and PpIX were monitored by laser scanning confocal microscopy. The cytotoxic effects of Hp-mediated SDT (Hp-SDT) and PpIX-mediated SDT (PpIX-SDT) were evaluated by MTT assay. RESULTS: The accumulation of Hp and PpIX presented different kinetic changes depending on the time, and was also concentration- and temperature dependent. The intracellular PpIX content was much higher than that of Hp under the same conditions; however, there were no obvious differences in terms of their subcellular locations, and both of them mainly accumulated on the mitochondria and the plasma membrane in L1210 cells. PpIX exhibited more potential cytotoxicity than did Hp when they were irradiated with ultrasound under the same experimental conditions. CONCLUSION: Our results indicate that there were significant differences regarding the intracellular accumulation features between Hp and PpIX. PpIX-SDT produced a more serious cytotoxic effect than did Hp-SDT, which may be due to the higher PpIX uptake in L1210 cells compared to that of Hp at the same concentrations. Additionally, the absorption of Hp and PpIX in L1210 cells might be energy dependent. PMID- 20948212 TI - Comparative activity of telavancin and other antimicrobial agents against methicillin-resistant Staphylococcus aureus isolates collected from 1991 to 2006. AB - BACKGROUND: Increasingly frequent reports of vancomycin treatment failures for serious methicillin-resistant Staphylococcus aureus (MRSA) infections provide impetus for comparative in vitro studies to assess the activity of newer antimicrobial agents against a range of MRSA isolates. METHODS: A sample of 168 MRSA derived from a long-term MRSA collection was subjected to susceptibility testing to telavancin, daptomycin, linezolid, tigecycline and vancomycin by broth micro-dilution. Data were reviewed for sporadic occurrence of isolates with reduced susceptibility. Analyses were performed to test for temporal trends toward decreasing susceptibility and to compare susceptibility of isolates from different infection sites. RESULTS: No MRSA isolate from any time period was resistant to test antibiotics. For daptomycin, linezolid and tigecycline, there were no susceptibility differences between the pre- and postclinical availability periods. All newer agents were active against MRSA isolates with minimum inhibitory concentrations (MICs) of vancomycin >1 mg/l, but there were significant correlations in susceptibility among several pairs of antibiotics. CONCLUSIONS: Telavancin and other newer antistaphylococcal agents were fully active against MRSA from various infection sites including isolates with vancomycin MIC >1 mg/l. PMID- 20948213 TI - Lack of accuracy for the proposed 'Dubois criteria' in Alzheimer's disease: a validation study from the Swedish brain power initiative. AB - BACKGROUND/AIMS: Our purpose was to investigate whether the new research criteria for Alzheimer's disease proposed in 2007 by Dubois et al. are valid in a naturalistic memory clinic sample. METHOD: Retrospective diagnostic analyses were carried out to compare the traditional diagnostic criteria for dementia with the new criteria suggested by Dubois et al. No patient had gone through all procedures postulated as additional features in the proposed new Dubois criteria. MATERIAL: Two independent experienced geriatricians re-examined 150 complete patients' records. The study physicians were blinded to any of the results of the core and additional features suggested by Dubois et al. to avoid circular diagnostic bias. RESULTS: Among our 96 patients with a clinical diagnosis of subjective cognitive impairment and/or mild cognitive impairment, 2 of the patients with subjective cognitive impairment and 5 patients with mild cognitive impairment would classify as pre-dementia Alzheimer's disease according to the Dubois criteria. In our 23 Alzheimer patients diagnosed clinically, only 12 of the cases fulfilled the criteria for Alzheimer's disease suggested by Dubois et al. INTERPRETATION: The proposed new criteria for Alzheimer's disease are valid in 55% of our patients clinically diagnosed as having full-blown Alzheimer dementia. Additionally, 7.3% 'true' Alzheimer cases will be identified in a group of 96 clinically non-demented patients. Our results show that there is a large heterogeneity in a clinical naturalistic sample of patients with an Alzheimer phenotype. CONCLUSION: There is a need to further validate the currently existing biomarkers in large unselected samples and avoid the pitfall of workup bias and circular diagnostic processes. Additionally, valid age-specific cut-off values for the diagnostic markers in question have to be defined. PMID- 20948214 TI - Incidence, pattern and management of bile duct injuries during cholecystectomy: experience from a single center. AB - BACKGROUND: The incidence and pattern of bile duct injury (BDI) may be underreported because of the heterogeneous referral from multiple institutions. METHODS: Retrospective analysis of data from 5,782 cholecystectomies performed between 1989 and 2007 was done. BDI were categorized into Strasberg types. RESULTS: Fifty-seven (1%) patients sustained BDI. Ten of 57 (18%) patients had minor BDI (type A-10), 25/57 (44%) had major BDI (type C-3, type D-14, type E-8) and BDI could not be classified in the remaining 22/57 (39%) patients. Twenty-one of 25 (84%) major BDI were detected at operation - 21/57 (37%) injuries were detected and repaired intra-operatively. The other 36/57 (63%) injuries were detected after operation - 11 were managed expectantly, 5 had endoscopic stenting, 3 underwent percutaneous drainage of bilioma, 1 had a laparoscopic clipping of the subvesical duct, 4 underwent laparotomy and 12 required a combination of interventions. Five of the 57 (9%) patients died. At follow-up, 1 patient developed bile duct stricture which was managed endoscopically. All other patients were doing well at the last follow-up. CONCLUSIONS: In experienced centers, most of the major BDI can be detected and managed during cholecystectomy. Good results can be achieved by judicious selection of a combination of interventions in the majority of patients. PMID- 20948215 TI - Gastric cancer in Poland - clinical characteristics and results of surgery. AB - AIMS: The aim of the study was to assess the long-term outcomes of the surgical only management of gastric cancer (GC) patients treated in a single centre over 10-year span preceding introduction of multimodal therapy to the clinical practice. METHODS: Two hundred and one patients with pathologic confirmation of GC treated for resectable tumor mostly with curative intent were enrolled in the study. The analysis comprised a review of the medical histories, descriptions of the operations, results of histopathological studies and long-time survival. RESULTS: Median survival time and 5-year survival rate for patients with R0 vs. R1 and R2 resection were 3.85 years and 43.5% versus 0.86 years and 7.8%, respectively. Univariate analyses showed that 5-year survival rates were correlated with histopathological type according to Lauren, type of lymphadenectomy performed, spleen preservation, stage of disease and the degree of radical resection. Independent prognostic factors in multivariate analysis were: no residual tumor after resection, type of lymphadenectomy, depth of tumor invasion in the gastric wall and lymph nodes status. CONCLUSIONS: Retrospective analysis of the long-term results of the surgical-only management of GC patients may be useful in assessment of the quality of medical services, especially prior to introduction of multimodal therapy. PMID- 20948216 TI - Percutaneous cholecystostomy in critically ill patients with a cholecystitis: a safe option. AB - BACKGROUND: Cholecystectomy is the standard procedure in patients with acute cholecystitis. However, some patients might not be able to undergo immediate surgery because of severe sepsis or underlying comorbid conditions. Percutaneous cholecystostomy is a minimally invasive radiological procedure under local anesthesia which seems to be an effective alternative to conservative treatment or immediate laparoscopic/open cholecystectomy. METHODS: We retrospectively analyzed 35 patients who underwent percutaneous cholecystostomy between 2003 and 2009. RESULTS: Percutaneous cholecystostomy was technically successful in all patients. Symptoms resolved within 3 days in 33/35 patients. Two patients needed an emergency laparotomy. The catheter dislodged in 5 patients and was replaced in 2/5. The 30-day mortality rate was 3/35 (8.7%) due to gallbladder necrosis, myocardial infarction and multiorgan failure. Median length of hospital stay was 17 days and median drainage time was 28 days. 23 patients (66%) underwent open or laparoscopic cholecystectomy after a median interval of 44 days. CONCLUSION: Percutaneous cholecystostomy is an effective procedure and a good alternative for patients unfit to undergo immediate surgery because of severe sepsis or underlying comorbid conditions, preferably followed by interval cholecystectomy to prevent recurrent cholecystitis. PMID- 20948217 TI - How useful are bowel sounds in assessing the abdomen? AB - BACKGROUND: The purpose of our study is to determine the accuracy of bowel sounds in the diagnosis of ileus and bowel obstruction. METHODS: Healthy volunteers (n = 10) and patients with radiologically or laparotomy confirmed small bowel obstruction (n = 9) and ileus (n = 7) were enrolled. Two 30-second recordings from each subject were obtained using an electronic stethoscope. Study physicians (n = 20) were then presented with 43 recordings in blinded fashion and were asked whether each was from a normal subject or from a subject with bowel obstruction or ileus. RESULTS: Physicians arrived at the correct diagnosis a median of 30 times out of 43 (69.8%). Intra-observer variation (kappa = 0.72, agreement 81.3%) and intra-subject variation (kappa = 0.63, agreement 78.7%) were very good. Bowel sounds from subjects with ileus and normal bowel sounds were correctly identified most of the time (84.5 and 78.1%, respectively). Bowel sounds from patients with obstruction were correctly identified only 42.1% of the time, but if a physician believed he or she was hearing a bowel obstruction, this had a strong positive predictive value (PPV, 72.7%). CONCLUSION: Our results suggest that the auscultation of bowel sounds is useful, especially in detecting ileus. The diagnosis of obstruction had a high PPV. PMID- 20948218 TI - Intravenous tissue plasminogen activator thrombolysis in patients without major arterial occlusion seems to be safe and effective. AB - BACKGROUND: It is not clear whether tissue plasminogen activator (t-PA) thrombolysis in patients without major arterial occlusion is effective or safe. METHODS: Consecutive anterior circulation stroke patients treated with t-PA within 3 h of onset were studied. The patients were divided into three groups according to magnetic resonance angiography findings before t-PA infusion: ICA group, ICA occlusion; MCA group, M1 and M2 occlusion, and no occlusion group. Clinical characteristics, the presence of hemorrhagic transformation on T2* at 24 h after t-PA thrombolysis, and outcome at 3 months were compared among the three groups. RESULTS: 112 patients were enrolled. The no occlusion group had 21 (18.8%) patients, the ICA group had 29 (25.9%), and the MCA group had 62 (55.4%). The frequency of hemorrhagic transformation was only 4.8% in the no occlusion group (31.0% for the ICA group, and 48.4% for the MCA group, p = 0.0012). At 3 months after t-PA therapy, 61.5% of the no occlusion group had a favorable outcome (modified Rankin score 0-1), which was the highest among the three groups (15.0% for the ICA group, and 41.5% for the MCA group, p = 0.0203). CONCLUSION: Intravenous t-PA therapy in acute stroke patients without major artery occlusion seems to be safe and effective. PMID- 20948219 TI - Increasing genotype-phenotype model determinism: application to bivariate reading/language traits and epistatic interactions in language-impaired families. AB - While advances in network and pathway analysis have flourished in the era of genome-wide association analysis, understanding the genetic mechanism of individual loci on phenotypes is still readily accomplished using genetic modeling approaches. Here, we demonstrate two novel genotype-phenotype models implemented in a flexible genetic modeling platform. The examples come from analysis of families with specific language impairment (SLI), a failure to develop normal language without explanatory factors such as low IQ or inadequate environment. In previous genome-wide studies, we observed strong evidence for linkage to 13q21 with a reading phenotype in language-impaired families. First, we elucidate the genetic architecture of reading impairment and quantitative language variation in our samples using a bivariate analysis of reading impairment in affected individuals jointly with language quantitative phenotypes in unaffected individuals. This analysis largely recapitulates the baseline analysis using the categorical trait data (posterior probability of linkage (PPL) = 80%), indicating that our reading impairment phenotype captured poor readers who also have low language ability. Second, we performed epistasis analysis using a functional coding variant in the brain-derived neurotrophic factor (BDNF) gene previously associated with reduced performance on working memory tasks. Modeling epistasis doubled the evidence on 13q21 and raised the PPL to 99.9%, indicating that BDNF and 13q21 susceptibility alleles are jointly part of the genetic architecture of SLI. These analyses provide possible mechanistic insights for further cognitive neuroscience studies based on the models developed herein. PMID- 20948220 TI - Long-range comparison between genes and languages based on syntactic distances. AB - OBJECTIVE: To propose a new approach for comparing genetic and linguistic diversity in populations belonging to distantly related groups. BACKGROUND: Comparisons of linguistic and genetic differences have proved powerful tools to reconstruct human demographic history. Current models assume on both sides that similarities reflect either descent from common ancestry or the balance between isolation and contact. Most linguistic phylogenies are ultimately based on lexical evidence (roughly, words and morphemes with their sounds and meanings). However, measures of lexical divergence are reliable only for closely related languages, thus large-scale comparisons of genetic and linguistic diversity have appeared problematic so far. METHODS: Syntax (abstract rules to combine words into sentences) appears more measurable, universally comparable, and stable than the lexicon, and hence certain syntactic similarities might reflect deeper linguistic relationships, such as those between distant language families. In this study, we for the first time compared genetic data to a matrix of syntactic differences among selected populations of three continents. RESULTS: Comparing two databases of microsatellite (Short Tandem Repeat) markers and Single Nucleotides Polymorphisms (SNPs), with a linguistic matrix based on the values of 62 grammatical parameters, we show that there is indeed a correlation of syntactic and genetic distances. We also identified a few outliers and suggest a possible interpretation of the overall pattern. CONCLUSIONS: These results strongly support the possibility of better investigating population history by combining genetic data with linguistic information of a new type, provided by a theoretically more sophisticated method to assess the relationships between distantly related languages and language families. PMID- 20948221 TI - Characterization of a late gene, ORF134, from Bombyx mori nucleopolyhedrovirus. AB - OBJECTIVE: ORF134 of Bombyx mori nucleopolyhedrovirus (BmNPV) is a homolog of Autographa californica multiple NPV ORF5, but its function is unknown so far. The aim of this study is to characterize BmNPV ORF134 (Bm134). METHODS: Transcription, protein expression and subcellular localization of Bm134 in BmN cells and silkworm midguts were analyzed using real-time polymerase chain reaction (RT-PCR), Western blot and immunofluorescence, respectively. RESULTS: Both the transcription and protein expression of Bm134 were not detected until 24 h post-infection (p.i.) by RT-PCR and Western blot, indicating that Bm134 is a late gene. Western blot revealed that Bm134 encodes an expected 12.4-kDa structural protein that is associated with occlusion-derived virus (ODV), not with budded virus. Immunofluorescence analysis showed that the Bm134 was first detected in the cytoplasm 24 h p.i. and then transported to the nucleus during later infection. Transcripts of Bm134 and the corresponding protein were only detected 48-72 h p.i. in BmNPV-infected larvae of 306, a highly BmNPV-susceptible silkworm strain, but not in the NB strain that is resistant to BmNPV infection. CONCLUSION: Taken together, our data suggest that Bm134 is a late gene of BmNPV and may function as an ODV structural protein. PMID- 20948222 TI - High conservation of hepatitis B virus surface genes during maternal vertical transmission despite active and passive vaccination. AB - OBJECTIVE: Our purpose was to explore the relationship between hepatitis B virus (HBV) gene heterogeneity and maternal vertical transmission. METHODS: HBsAg positive mothers and their neonates were selected and classified into a vertical infection neonate group (group N), a vertical infection mother group (group M) and a control group (group C). Serum HBsAg and HBeAg were examined. HBV gene fragments, including the pre-S1, and pre-S2 and S coding regions, were amplified and sequenced, and the genotype and serotype of the sequences were identified. Mutation sites and frequency of mutations were then compared between group N and group C. RESULTS: A total of 104 HBV clone sequences were obtained. All obtained sequences belonged to genotype C and serotype adr. Upon comparing sequences between group N and group C, 4 nonsynonymous mutations were found with significant difference in mutation frequency (p < 0.05). When the mothers were both HBsAg and HBeAg positive, 10 nonsynonymous mutations were found. The frequencies of these mutations were significantly lower in group N than in group C (p < 0.05). CONCLUSION: The 10 HBV mutations were negatively associated with vertical transmission when maternal HBeAg was positive. Furthermore, the species that were vertically transmitted to the fetus were mainly wild-type. PMID- 20948223 TI - Genotypic analysis of Epstein-Barr virus isolates associated with nasopharyngeal carcinoma in Northern China. AB - OBJECTIVES: To characterize the specific Epstein-Barr virus (EBV) polymorphisms from nasopharyngeal carcinoma (NPC) patients and healthy donors in Northern China, and to explore the relationship between the EBV genotypes and NPC. METHODS: The genotypes of EBV strains were analyzed by the polymerase chain reaction and restriction fragment length polymorphism. RESULTS: The predominant EBV type was A, C or F in both NPC and healthy individuals. The distributions of the EBV subtypes between NPC and healthy donors were not significantly different (p > 0.05). The frequency of type f strains in NPC was significantly lower in Northern China than in Southern China. CONCLUSIONS: No evidence of special EBV genotypes associated with NPC was found, suggesting that EBV strains derived from the NPC patients may reflect geographic distribution rather than being NPC restricted. PMID- 20948224 TI - The first Crimean-Congo hemorrhagic fever case in the winter season from Turkey. AB - Turkey is one of the countries in which Crimean-Congo hemorrhagic fever is frequently seen and most of the cases are reported between April and August. We describe the first case of Crimean-Congo hemorrhagic fever in the winter season, when Hyalomma tick activity is absent, from Turkey. PMID- 20948225 TI - HPV-58 molecular variants exhibit different transcriptional activity. AB - Early promoter activity of HPV-58 molecular variants isolated from high-grade cervical lesions in Brazil was compared. Luciferase reporter assays were conducted in C33 cells transfected with the complete long control region of 3 molecular variants of HPV-58 as well as HPV-58, -18 or -16 prototypes. The HPV-58 prototype and Bsb-329 and Bsb-367 variants showed a promoter activity similar to that of HPV-16, but lower than that of Bsb-295 and HPV-18. The introduction of the Bsb-295 7788 mutation into the HPV-58 prototype resulted in the enhancement of transcription closer to Bsb-295 and HPV-18. These results could impact the expression of E6 and E7 viral oncogenes. PMID- 20948226 TI - Gene expression of FTO in human subcutaneous adipose tissue, peripheral blood mononuclear cells and adipocyte cell line. AB - BACKGROUND/AIMS: The common polymorphism rs9939609 of the fat mass and obesity associated gene (FTO) is strongly associated with obesity, but the biological function is still unknown. We compared the FTO gene expression in subcutaneous adipose tissue and peripheral blood mononuclear cells (PBMCs) between overweight and normal weight individuals. We also investigated if mRNA levels of FTO in adipose tissue correlated with the adiposity or inflammatory markers and mRNA levels of genes involved in the response to hypoxia (HIF-1a) and cell death(HMGB1). RESULTS: The mRNA expression of FTO in adipose tissue was greater in obese than normal weight individuals (p < 0.001), but there was no difference in FTO expression in PBMCs. FTO mRNA levels did not correlate with adiposity or inflammatory markers and FTO expression was not influenced by the FTO rs9939609 genotype. FTO mRNA level correlated positively with gene expression levels of HIF 1a and HMGB1 in subcutaneous adipose tissue (r = 0.59, p < 0.001; r = 0.69, p < 0.001, respectively; adjusted for BMI and adipocyte cell size). CONCLUSIONS: Altogether, FTO expression appeared not to have a well-defined impact on clinical or biochemical parameters comprising the metabolic syndrome. The correlations with the genes related to hypoxia and cell death suggest novel biological activities for FTO. PMID- 20948227 TI - Gender differences in chronic kidney disease: underpinnings and therapeutic implications. AB - In nephrology, gender differences exist with regard to the epidemiology, evolution and prognosis of chronic kidney disease (CKD). In some cases, these differences run contrary to the general population trends. This review discusses such gender and sex disparities, including differing impact of traditional and novel risk factors, prescription patterns, differences in the responses to therapies, as well as hormonal factors, all of them potentially influencing propensity, progression and biochemical and psychological aspects of CKD. Through the integration of gender aspects in CKD research and management, we may be able not only to identify novel therapeutic targets but also improve existing treatment options. PMID- 20948228 TI - Uromodulin and chronic kidney disease. AB - Uromodulin (Tamm-Horsfall protein) is produced in the kidney by cells of the thick ascending limb and distal tubule. Recent genetic studies suggest a role of uromodulin in chronic kidney disease. Mutations in the UMOD gene cause uromodulin storage disease. They code for amino acid substitutions that lead to misfolding of the molecule and its retention in the endoplasmic reticulum. Single nucleotide polymorphisms in the region of the UMOD gene have been shown to be associated with chronic kidney disease and reduced glomerular filtration rate. These polymorphisms affect uromodulin concentration in the urine, and lower genetically determined urinary uromodulin concentrations seem to protect against renal disease. Chronic kidney disease is associated with higher serum levels of uromodulin. From animal experiments and human studies it is hypothesized that uromodulin entering the renal interstitium either by basolateral secretion or urinary back-leakage in damaged tubuli interacts with and stimulates cells of the immune system and thereby causes inflammation and progression of chronic kidney disease. PMID- 20948229 TI - Hemolytic uremic syndrome: epidemiological and clinical features of a pediatric population in Tuscany. AB - We retrospectively analyzed etiological, pathological and clinical features of the patients with hemolytic uremic syndrome (HUS) observed in the Pediatric Nephrology Unit at AOU Meyer of Florence. From January 1997 to December 2008, 22 cases were identified, with an annual incidence of 0.05 cases per 100,000 inhabitants, and 0.34 cases per 100,000 children <15 years old. 60% of the patients were D+ and 40% were D-, with an age distribution from 12 days to 13 years. Twenty patients (90%) had oligoanuria, lasting 6.4 +/- 4 days for D+ patients versus 11.8 +/- 4 days for D- patients. The development of chronic kidney disease positively correlates with the initial blood pressure value, the length of oligoanuria, and hospitalization. Microbiological investigations showed an association of D+HUS with different strains of Shiga toxin-producing Escherichia coli in 54% of the cases. D-HUS was associated with complement factor H deficiency in one patient. In the other cases, the triggering factors were pertussis, urinary tract infections and upper airway infections. While clinical and prognostic features correspond with literature data, in Tuscany the annual incidence is lower, and the percentage of D-HUS patients is higher than that observed in other studies. PMID- 20948230 TI - Africa and nephrology: the forgotten continent. AB - Chronic kidney disease (CKD) is not a priority on the health agenda in Africa and it remains a 'forgotten condition'. Most people in Africa do not have access to dialysis or transplantation, if they develop end-stage renal disease. Cardiovascular disease (CVD) and HIV/AIDS enjoy a more prominent profile as a serious cause of morbidity and mortality, but despite the clear links of CVD and HIV with CKD, there has been a failure to highlight the link between chronic illnesses like diabetes, hypertension and HIV/AIDS and both CKD and CVD. Management of chronic illnesses requires a functioning public health system and good links between primary and specialist care. Despite calls to establish CKD prevention programs, there are very few in Africa and they have not been integrated into existing primary healthcare systems. This is aggravated by shortages of both financial and human resources and failure to strengthen health systems managing chronic diseases. The result is that very few people in Africa with CKD are managed early or receive dialysis or transplantation. This article investigates some of the issues impacting on the recognition of CKD as a public health issue, and will also consider some factors which could make CKD a more prominent chronic disease in Africa. PMID- 20948231 TI - The best way to detect elevated albuminuria. AB - BACKGROUND: It has been reported that first morning specimens are more reliable than random spot specimens to assess 24-hour urinary albumin excretion rate (UAER), especially if albuminuria is expressed as albuminuria to creatininuria ratio. We aimed to investigate the influence of (a) posture and activity and (b) the units to best estimate 24-hour albuminuria. METHODS: In this retrospective study, 24-hour UAER was compared to 60 min 'supine' and 90 min 'activity' albuminuria in 124 patients tested for resistant hypertension. The ability to adjust urinary albumin concentration (UAC) to creatininuria (ACR) or to collection duration (tAER) values in order to increase the reliability of albuminuria values was also analyzed. RESULTS: Compared to 24-hour UAER, UAC (mg/l), tAER (MUg/min) and ACR (mg/mmol) during the supine period had a similar concordance rate in normo-, micro- and macroalbuminuric patients. The UAC in the supine period was well related to 24-hour UAER. However, UAC almost doubled during activity. Adjustment to creatininuria improved the correlation between albuminuria during both periods and 24-hour UAER, but mainly during the activity period. CONCLUSIONS: Our results confirm that UAC is dependent on physical activity. Correction of UAC by creatininuria (ACR) provides a satisfactory estimation of 24-hour UAER. Thus, for practical reasons, it is advisable to use ACR, where no differences appear to exist, whether a supine urine sample or an activity urine sample is obtained. PMID- 20948232 TI - Predictive factors associated with the period of time before initiation of hemodialysis in CKD stages 4 and 5. AB - BACKGROUND: A majority of patients with chronic kidney disease (CKD) have cardiovascular disease at the initiation of dialysis therapy, suggesting that periodic echocardiographic examinations are important in such patients. The purpose of the present study was to evaluate the correlation between echocardiographic parameters and period of time before initiation of hemodialysis (iHD) in patients with CKD. METHODS: 140 patients with CKD stages 4 and 5 were enrolled. They were divided into diabetes and nondiabetes groups. Cardiac predictive parameters for the period of time before iHD were investigated in the patients using univariate and multivariate regression analyses. RESULTS: In the nondiabetes group, systolic blood pressure (SBP) and left atrial volume index (LAVi) were identified as independent risk factors for the period of time before iHD by multivariate regression analysis. Serum albumin level was identified as an independent risk factor in the diabetes group. SBP, LAVi and serum albumin level were identified as independent risk factors in the combined diabetes and nondiabetes groups. CONCLUSION: LAVi measurements during echocardiography, together with SBP and serum albumin levels, may be useful predictive factors for the period of time before iHD in patients with CKD stages 4 and 5. PMID- 20948233 TI - Single estimated glomerular filtration rate and albuminuria measurement substantially overestimates prevalence of chronic kidney disease. AB - BACKGROUND/AIMS: Guidelines require repeatedly diminished estimated glomerular filtration rate (eGFR) and/or albuminuria to diagnose chronic kidney disease (CKD), and advise screening only in select populations. Many estimates of CKD prevalence have used single measurements. This longitudinal study assessed eGFR and albuminuria reproducibility, and impact on estimate of CKD prevalence, in factory workers. METHODS: A total of 512 white workers in a Belarusian industrial factory were initially tested, identifying 206 with abnormal (eGFR <59 ml/min/1.73 m(2) or albuminuria) or near-abnormal (eGFR up to 1 SD above abnormal) renal function. At 3 months, 142 of the abnormal/near-abnormal cohort were re-tested. RESULTS: Analysis of repeat samples revealed no significant change in eGFR in this population, however 21% individually changed CKD stage. Initial proteinuria was reproducible in only 48% at 3 months. This had a major impact on estimated CKD prevalence: a point prevalence of 8.2% halved with repeat testing. The predictive value of initially abnormal eGFR or albuminuria for repeat abnormality at 3 months was 0.5. CONCLUSION: Non-targeted screening for CKD is inaccurate and can overestimate prevalence. This study emphasises the importance of confirming abnormal eGFR and proteinuria on at least one further sample 3 months apart before categorising the individual as having CKD. This has wide implications for screening in European general populations. PMID- 20948234 TI - Is Carotid atherosclerosis epidemiology changed among Egyptians? PMID- 20948235 TI - Low ultraviolet B and increased risk of brain cancer: an ecological study of 175 countries. AB - BACKGROUND: The purpose of this study was to determine whether an inverse association exists between latitude, solar ultraviolet B (UVB) irradiance, modeled 25-hydroxyvitamin D [25(OH)D] levels and incidence rates of cancer of the brain. METHODS: Associations of latitude and UVB irradiance with age-standardized incidence rates of cancer of the brain were analyzed for 175 countries while controlling for proportion of population overweight, energy from animal sources, fish consumption, cigarette and alcohol consumption and per capita health expenditures, using multiple regression. Serum 25(OH)D levels were modeled for each country, and their association with brain cancer also was determined. RESULTS: The incidence rates of brain cancer were higher at higher latitudes (R(2) for males = 0.45, p <= 0.0001; R(2) for females = 0.35, p < 0.0001). After adjustment for potential confounders, UVB irradiance (p <= 0.0001) and modeled serum 25(OH)D were inversely associated with incidence rates. CONCLUSIONS: Countries with low solar UVB irradiance and estimated mean serum 25(OH)D levels generally had higher age-standardized incidence rates of brain cancer. Since this was an ecological study, further research would be worthwhile on the association of prediagnostic serum 25(OH)D with incidence rate in studies of cohorts of individuals. PMID- 20948236 TI - Epidemiology of major neurological disorders project in Al Kharga district, New Valley, Egypt. AB - BACKGROUND/METHODS: A door-to-door ('every door') study was carried out to assess the incidence and prevalence rates of epilepsy, stroke, Bell's palsy and cerebral palsy, as well as the prevalence of dementia, extrapyramidal syndromes, muscle and neuromuscular disorders, cerebellar ataxia and primary nocturnal enuresis among the urban and rural populations of Al Kharga district, New Valley, Egypt. The study was carried out in 3 stages from June 1, 2005 to May 31, 2009. A door to-door screening including every door was carried out using a standardized questionnaire, which was administered by 3 neurologists to all inhabitants (62,583) of Al Kharga district. The study was designed to assess the prevalence, incidence and risk factors of major neurological disorders in Al Kharga district and aimed to reduce the burden of these neurological disorders in the entire region. RESULTS/CONCLUSIONS: This study clarified that dementia, primary nocturnal enuresis, epilepsy, stroke and cerebral palsy are the most common neurological disorders. On the other hand, Bell's palsy, extrapyramidal syndromes, cerebellar ataxia, muscle dystrophies and myasthenia gravis are less common neurological disorders in Al Kharga district. PMID- 20948237 TI - Effect of combination therapy with angiotensin receptor blocker and 1,25 dihydroxyvitamin D(3) in type 2 diabetic nephropathy in KK-A(y)/Ta mice. AB - BACKGROUND: Although angiotensin II type 1 receptor blockers (ARB) have beneficial effects in patients with diabetic nephropathy, they may induce a compensatory increase in renin. Renin exhibits profibrotic actions independent of angiotensin II, which is regulated by extracellular signal-regulated kinase 1 and 2 (ERK1/2). Calcitriol (1,25(OH)(2)D(3)) is a negative inhibitor of the renin angiotensin system and the present study examined the effects of combination therapy with an ARB and 1,25(OH)(2)D(3) on diabetic nephropathy in KK-A(y)/Ta mice. METHODS: KK-A(y)/Ta mice were divided into four groups: ARB group, 1,25(OH)(2)D(3) group, combination group, and control group. The urinary albumin/creatinine ratio (ACR) was measured and the renal expression of renin, p ERK1/2 and TGF-beta1 protein determined. RESULTS: The levels of urinary ACR in the combination group were significantly lower than those in the ARB or control group. Renal expression of renin in the ARB group was significantly increased compared with the control group but was significantly decreased in both the 1,25(OH)(2)D(3) and combination group. Renal expression of p-ERK1/2 in the combination group was significantly decreased compared with the control or ARB group. Expression of TGF-beta1 protein in the ARB and combination groups, especially the combination group, was significantly decreased compared with those in the control group. CONCLUSIONS: These data suggest that the addition of 1,25(OH)(2)D(3) to therapy with ARB further reduced proteinuria by suppressing the compensatory increase in renin expression in type 2 diabetic nephropathy. These effects might relate to suppression of renin, ERK1/2 and TGF-beta1 expression which may or may not depend on angiotensin II. PMID- 20948238 TI - Effect of nilvadipine on central visual field in retinitis pigmentosa: a 30-month clinical trial. AB - PURPOSE: To assess the effects of nilvadipine on the progression of central visual field defect in retinitis pigmentosa (RP). DESIGN: Prospective, randomized, nonmasked, single-center trial. METHODS: Patients with RP were randomly divided into a treated group receiving oral nilvadipine at 4 mg/day for >=30 months and a control group receiving tocopherol nicotinate at 300 mg/day, helenien at 15 mg/day or no medication for the same periods. Progression of RP was evaluated using the 10-2 SITA Fast Program of the Humphrey Visual Field Analyzer, and regression coefficients calculated from the time courses of mean deviation (MD slope) were compared between groups. RESULTS: Nineteen patients in the treated group and 14 patients in the control group completed the follow-up for >=30 months. The mean (+/-standard deviation) duration of observation was 48.8 +/- 11.8 months (median 48 months, range 30-66 months) for the treated group and 49.2 +/- 18.1 months (median 48 months, range 30-90 months) for the control group (p = 0.94). Mean (+/-standard error of the mean, SEM) regression coefficients of the averaged MD values for the initial 30 months were -0.35 +/- 0.17 dB/year in the treated group and -0.75 +/- 0.06 dB/year in the control group (p < 0.01). Mean (+/-SEM) MD slopes for total observational periods were -0.49 +/ 0.17 dB/year in the treated group and -0.89 +/- 0.16 dB/year in the control group (mean +/- SEM, p = 0.042). CONCLUSION: Nilvadipine at 4 mg/day significantly retarded progression of central visual field defects in RP in this small patient series. PMID- 20948239 TI - Axial length of myopia: a review of current research. AB - Myopia, or nearsightedness, is a worldwide common type of refractive error. It is a non-life-threatening disorder with huge social and economic consequences due to its increasing prevalence. Axial length (AL) is the primary determinant of non syndromic myopia. It is a parameter representing the combination of anterior chamber depth, lens thickness and vitreous chamber depth of the eye. AL can also be treated as an endophenotype of myopia and may provide extra advantages in the investigation of its genetic basis. The study of AL will not only identify the determinants of eye elongation, but also provide aetiological evidence for myopia. The purpose of this review is to outline the current state of AL research. Epidemiological evidence, genetic determinants, the relationship with other eye components and relative animal models of AL are summarised. PMID- 20948240 TI - A new noncontact tonometer using corneal photoelasticity: porcine eye study. AB - PURPOSE: To propose a new noncontact tonometer based on corneal photoelasticity. METHOD: In this study, we experimented with 18 enucleated porcine eyes. The anterior chamber was infused with a physiological solution. A circular polarizing filter was attached to an ophthalmic surgical microscope. Color fringe changes at the peripheral cornea related to its photoelasticity were recorded using an ophthalmic surgical microscope equipped with a charge-coupled device camera while intraocular pressure (IOP) changes were determined by the height of the physiological solution bottle. A peak intensity of the color fringes was determined by Image J software. RESULTS: Circular, rainbow-like color fringes, a phenomenon that is the basis of photoelasticity, were detected in the peripheral cornea. When IOP increased from 7 to 29 mm Hg, the color fringes moved more peripherally becoming narrower with their peak intensity increasing. At an IOP of 7, 15, 22 and 29 mm Hg, the mean peak intensity of the color fringes had a gray value of 113.6, 114.2, 114.7 and 115.5, respectively. Correlation analysis between IOP and peak intensity of the color fringes in these porcine eyes showed a significant positive correlation with a Pearson correlation coefficient of 0.993 (p < 0.01). CONCLUSIONS: The proposed noncontact tonometer based on photoelasticity of the cornea could become a true noncontact device that could be used for the screening of glaucoma or as an IOP follow-up for glaucoma patients. PMID- 20948241 TI - It is tough to make predictions, especially about the future. PMID- 20948242 TI - Commissural myelotomy in the treatment of intractable visceral pain: technique and outcomes. AB - BACKGROUND: Commissural myelotomy can be valuable for patients with intractable pain associated with malignancy in the abdominal or pelvic region. METHODS: Between December 1992 and June 2009, 11 patients underwent commissural myelotomy at the University of Texas MD Anderson Cancer Center for the treatment of intractable lower extremity, thoracic, pelvic or sacral pain associated with unresectable tumors. The various surgical approaches to myelotomy are discussed. RESULTS: Eight patients had excellent or good outcomes with regard to pain relief, defined as no further pain (excellent) or a significant reduction in pain and not requiring opioids stronger than codeine (good). Complications included new leg weakness (n = 3) and bladder dysfunction (n = 1). CONCLUSION: We found that for the properly selected patient, open midline commissural myelotomy can provide effective pain relief with acceptable postoperative morbidity. PMID- 20948243 TI - Surgical outcome and improvement in quality of life after microvascular decompression for hemifacial spasms: a case series assessment using a validated disease-specific scale. AB - BACKGROUND: Hemifacial spasm (HFS) is a movement disorder characterized by intermittent, involuntary clonic or tonic-clonic contractions of muscles innervated by the ipsilateral facial nerve. Recent studies have documented change in quality of life after HFS management with botulinum toxin injection. However, we failed to locate any study that documented change in quality of life after surgical management with retrosigmoid microvascular decompression (MVD). METHODS: Our study objectives were 3-fold. Firstly, to use a disease-specific, validated quality of life assessment scale to document any change in quality of life after MVD for HFS. Secondly, to determine the time period in which the majority of patients undergoing MVD could be expected to benefit from surgery. Finally, to determine factors affecting the postoperative quality of life following MVD. A retrospective analysis of HFS patients treated with MVD at a single institution by a single surgeon (K.J.B.) between January 2000 and December 2007 was undertaken. A modification of a previously developed validated disease-specific quality of life assessment scale that included the addition of a parameter for difficulty in sleep was used to assess quality of life before and after surgery. RESULTS: A total of 21 patients (14 female and 7 male) underwent treatment as specified. Eighty-five percent (17/20) of the patients reported prolonged remission of symptoms (mean follow-up period = 4.15 years). Five percent (1/20) reported occasional recurrence of twitches. The overall mean quality of life score improved from 11.1 preoperatively to 2.2 postoperatively. CONCLUSIONS: MVD offers significant and prolonged improvement in quality of life for the HFS patients we studied, as measured using a disease-specific, validated quality of life assessment scale. Postoperative quality of life, however, was strongly influenced by both the success of surgery in resolving the symptoms and the absence of any permanent complications of surgery. PMID- 20948244 TI - [Microdose clinical trial--impact of PET molecular imaging]. AB - Microdose (MD) clinical trial and exploratory IND study including sub-therapeutic dose and therapeutic dose which are higher than microdoses are expected to bring about innovations in drug development. The outlines of guidances for microdose clinical trial and ICH-M3 (R2) issued by the MHLW in June, 2008, and February, 2010, are first explained, respectively, and some examples of their application to clinical developments of therapeutic drugs in the infection and cancer fields are introduced. Especially, thanks to the progress of molecular imaging research, a new field of drug development is explored by using imaging biomarkers for efficacy or safety evaluation which visualize biomarkers by PET imaging agents. Finally, the roadmap for drug development in infection and cancer fields utilizing PET molecular imaging is discussed. PMID- 20948245 TI - [Introduction to palliative care for the oncologist-history and basic principles of palliative care]. AB - The basic principle of palliative care has evolved over time and is the historical origin of the modern hospice. WHO proposed the first definition of palliative care in 1989, and the definition was revised in 2002. These definitions have something in common. Both relieve the pain and suffering to improve QOL. Palliative care is also good for any kind of life-threatening disease, regardless of whether it requires short or long term recuperation. That also need to be able to accept equally all the people of the community. The provision of general palliative care is the responsibility of all medical, nursing, and health professionals for the welfare of all patients with life threatening disease. Specialist palliative care is based on the basic principles of palliative care, intensive clinical training, and systematic acquisition of knowledge and skills training to support palliative care education, clinical research and training provided by the profession. It has been established by nursing and medical experts in palliative care that palliative care can provide expertise in interdisciplinary teams in different settings. It is necessary that the medical system. PMID- 20948246 TI - [Pain management in cancer patients]. AB - Cancer pain management is expected to become more important because of the growing number of cancer patients in the years to come. To improve cancer pain relief requires understanding and adequate application of the WHO three-step analgesic ladder. Selective cox-2 inhibitors have efficacy in decreasing side effects. Tramadol and a new type of transdermal fentanyl patch that provides 24 hour sustained release of fentanyl is commercially available to alleviate pain. New anti-seizure drugs such as Gabapentin and Pregabalin can be used for neuropathic pain and cancer pain as analgesic adjuvant drugs. They allow simple use than with palliative drugs so far. Palliation of cancer pain requires a multi discipline approach for intensive management of symptoms. PMID- 20948247 TI - [Psycho-oncology]. AB - Total palliative care from the early phase of cancer treatment is recommended to relieve both physical and psychological distress. To accomplish total palliative care, psycho-oncology plays an important role in psychological care. Psycho oncology investigates the relationship between cancer and psychological issues, and has two aspects. The first and main aspect is to investigate the influence of cancer on the psychological status of patients with cancer. The other aspect is to investigate the influence of psychological issues on survival of patients with cancer or its prevention. In fact, psychological symptoms are frequent in patients with cancer, and depression is one of the most important because it could cause suicides. However, previous studies have shown that depression is often missed and untreated. Therefore, depression should be detected and treated early. PMID- 20948248 TI - [Palliative home care]. AB - Palliative home care supports the quality of life (QOL) of a patient and family as a whole. Team care is an effective method corresponding to the various needs of the patient and family. Cooperation of various types of professions can meet the need for high-quality outpatient medical care. Social work serves as a coordinator of the care team. One of its important tasks in palliative home care is support of the patient discharge procedure from the hospital. Discharge from the hospital must be carried out before the patient's condition worsens. Prompt support of the discharge is indispensable so that the patient may spend substantial time with high QOL at home. Palliative home care means care for the dying. Therefore, spirituality issues are important. Palliative home care must respect and understand the spirituality of the patient and family. The patient can be discharged from the hospital in peace when there is general support for the physical, psycho-social and spiritual needs of both patient and family. PMID- 20948249 TI - [Pain control for bone metastasis using radioactive strontium]. AB - Palliative therapy using radioactive strontium (89Sr) was performed on 60 patients suffering from cancer. Seventy-one percent of the patients had stopped or reduced their opiates and/or analgesics. Pain relief continued for up to three months. Patients with breast and prostatic cancer showed the best pain reduction. However, pain reduction was limited for lung cancer patients. Repeated usage of 89Sr with/without opiate and analgesics served to maintain the reduced level of pain. Side effects of repeated usage of 89Sr were decrease of hemoglobin, WBC, and platelets. The decreased level was limited within Level 1. The indication of 89Sr therapy is important. DIC cases and renal failure cases will have increased side effect risk. Image diagnosis is also important. A bone scan is a minimum requirement. Poor accumulation of 99mTc-MDP cases are not indication. Rapidly progressive disease cases, radiculopathy cases, and soft tissue invasion cases should not be given 89Sr therapy. At present, the uses of 89Sr are limited to end stage patients. The use of 89Sr should change from end stage to early stage in combination with chemotherapy. PMID- 20948250 TI - [Adjuvant trastuzumab can be infused safely over 30 minutes]. AB - It has been thought that there is a possibility that infusion speed generally affects the manifested frequency of infusion reaction and its strength. The infusion prescription time of trastuzumab should be over 90 minutes according to the package insert. In the infusion US, is possible over 30 minutes after the second time. We sought to evaluate the safety and tolerability of trastuzumab administered as a 30-minute infusion. PATIENTS: Eighteen patients of HER2 positive breast cancer were treated, and their age ranged from 37 to 65 years old(median, 54 years old). METHOD: PATIENTS were infused with 8 mg/kg of trastuzumab over 90 minutes and, if tolerated, all subsequent maintenance doses of 6 mg/kg are over 30 minutes. RESULT: The infusion times for 30 minutes were twice to 17 times(16 times the median). Mild infusion reactions were seen in 2 cases at the time of the initial prescription, but the infusion reaction was not judged from the prescription for 30 minutes. Mild eczema was admitted by 3 cases after prescription. No decline in cardiac function was seen. CONCLUSION: Our data strongly suggest that trastuzumab can be safely infused over 30 minutes for 6 mg/kg maintenance doses. However, it is thought that the number of cases will increase in future, and confirmation is necessary. PMID- 20948251 TI - [Medical economics evaluation of 5-HT3 receptor antagonist drugs]. AB - At Komaki City Hospital, the drug cost in connection with cancer chemotherapy was re-examined as part of improved management along with the introduction of DPC in July 2008. With due attention to the 5-HT3 receptor antagonists, both the change from injections to oral drugs and the change from brand-name drugs to generic drugs were tried between July 2008 and June 2009. After that, in order to examine the economic impact of these changes, we investigated and analyzed the number of medications, the cost of medicine purchased, and the average drug cost per medication of the 5-HT3 receptor antagonists between April 2008 and September 2009. As a result, the cost of 5-HT3 receptor antagonists purchased decreased greatly, and the impact of the improvement was mainly due to the change to oral drugs, and partially to the change to generic drugs. Therefore, from the viewpoint of hospital economic improvement in DPC, it was thought that the change to oral drugs(5-HT3 receptor antagonists)is given top priority. PMID- 20948252 TI - [Comparison between single-agent and platinum-doublet chemotherapy in elderly patients with non-small cell lung cancer]. AB - BACKGROUND: The standard therapy for young patients with advanced non-small cell lung cancer (NSCLC) is platinum doublet therapy, whereas that for elderly patients with NSCLC is single-agent therapy. However, there is limited information about the platinum-based treatment for elderly patients. PURPOSE: The aim of this study is to examine the efficacy and safety of platinum-doublet therapy for elderly patients, retrospectively. METHODS: There were 76 patients 75 years old or more with advanced NSCLC for whom chemotherapy was performed between June, 2008 and January, 2005. Among them, 65 patients except for 11 who underwent first-line gefitinib therapy were retrospectively reviewed. RESULTS: Median age: 77 years old (range 75-83 years old), gender: male/female; 51/14, stage: III B/ IV ; 15/50, pathology: adeno/squamous/other; 41/13/11, PS: 0/1/2; 14/44/7 patients. Fifty-three patients received single-agent (S), whereas 12 patients received platinum-doublet (D). Even in the analysis of patients with PS 0-1, similar results were obtained. Progression-free survival (PFS)was 107 versus 85 days, and overall survival(OS)was 270 versus 262 days between S and D, in patients with PS 0-1. In addition, we did not recognize a large difference in toxicity between S and D. CONCLUSION: In this examination, we could not show a large difference in efficacy and toxicity between platinum-doublet therapy and single-agent therapy. Further study would be needed to confirm our results. PMID- 20948253 TI - [Efficacy of concomitant therapy with S-1, CDGP, and radiation for laryngeal cancer]. AB - OBJECTIVE: Several clinical trials examining treatment strategies for advanced laryngeal cancer have demonstrated that concurrent chemoradiotherapy is the most effective treatment for improving the patient response to radiotherapy and laryngeal preservation. We evaluated a new regimen of S-1/CDGP(Nedaplatin) with radiotherapy (RT), and established that it represented an effective new treatment option that allowed for the preservation of the larynx. METHODS: A total of 16 patients with stage II to IV laryngeal cancer(excluding T4 stage)who had been treated at our institution from 2001 to 2007 were recruited for the present study. All patients had histologically-confirmed squamous cell carcinomas. RESULTS: The administration of S-1/CDGP/RT led to a complete response (CCR) in all patients with stage II or IV disease, with preservation of the larynx in all of these cases. For patients with stage III disease, 6 (85%) experienced CR, and 1 patient (15%) had a partial response. The laryngeal preservation rate for these patients was 85%. Severe toxicities, i. e., neutropenia, thrombocytopenia, and dermatitis of grade 3, were observed. The overall five-year survival rate was 72%, and the disease specific survival rate was 92%. PMID- 20948254 TI - [Re-treatment with epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI)for lung adenocarcinoma]. AB - BACKGROUND: EGFR-TKI yields a long survival period in cases of non-small cell lung cancer (NSCLC), especially those with EGFR gene mutations, but the effect is limited. The later treatment strategy is still a large problem. Efficacy by re treatment with EGFR-TKI is sometimes reported, but its clinical significance is not clear. METHODS: We reviewed retrospectively 22 cases (gefitinib 11 cases and erlotinib 11 cases) of NSCLC re-treated with EGFR-TKI in our hospital from August 2004 to August 2009. RESULTS: After re-treatment with gefitinib, four cases showed disease control. Efficacy of erlotinib was recognized in the cases in which disease control was obtained by initial treatment with gefitinib. The disease control rate was 36% (4/11) in the gefitinib group and 45% (5/11) in the erlotinib group. Median survival time was 212 days and 292 days from re-treatment with EGFR-TKI, respectively. CONCLUSION: Re-administration of EGFR-TKI was effective, and therefore is considered one of the treatment options for patients who once respond to gefitinib, until new anti-cancer drugs are available. PMID- 20948255 TI - [Feasibility of adjuvant docetaxel plus cyclophosphamide therapy for breast cancer]. AB - PURPOSE: To evaluate the feasibility of adjuvant docetaxel plus cyclophosphamide(TC)therapy for breast cancer. PATIENTS AND METHODS: A total of 16 patients with intermediate risk-breast cancer were enrolled. TC therapy consisted of four courses of docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2 intravenous administration over three weeks. Every infusion was premedicated with intravenous administration of granisetron 3 mg plus dexamethasone 16 mg, followed by dexamethasone 8 mg p. o. on days 2 and 3. RESULTS: Due to the allergic reaction, one patient discontinued TC therapy. Fifteen (94%) of the 16 patients completed the scheduled TC therapy. Feasibility was 93.7%. Grade 3/4 toxicity was limited to leucopenia, neutropenia, and febrile neutropenia. No non-hematological serious adverse events were observed. CONCLUSION: Adjuvant TC therapy is a feasible option for breast cancer. PMID- 20948256 TI - [The role of adjuvant chemotherapy with S-1 for gastric cancer patients]. AB - A randomized controlled trial of adjuvant chemotherapy with S-1 for gastric cancer (ACTS-GC) demonstrated that the chemotherapy with S-1 improved the relapse free survival and overall survival rates of patients with locally advanced gastric cancer. We examined retrospectively 47 patients with locally advanced gastric cancer, who received adjuvant chemotherapy with S-1 after curative gastrectomy. Patients who received more than 50% of the total scheduled dose of S 1 during the first 1 year after starting the chemotherapy showed a tendency to favorable outcome in terms of relapse-free survival compared with patients who received less than 50% of the dose, although no statistical significance was detected. Age did not show a significant correlation with tolerability. The number of elderly people with gastric cancer will increase in the next decade. They should be candidates for adjuvant chemotherapy on the basis of a geriatric assessment. PMID- 20948257 TI - [Chemo-endocrine therapy with low-dose cisplatin, UFT, and dexamethasone for hormone-refractory prostate cancer patients]. AB - Since September 2005, twenty-two patients with hormone-refractory prostate cancer (aged 55-81 years) were treated with LH-RH agonist and low-dose cisplatin, UFT, and dexamethasone after proving resistant to estramustine phosphate therapy. The regimen of this therapy consists of 5 mg/body of cisplatin intravenously once a week, 300 mg/day of UFT and 1 mg/day of dexamethasone orally, every day. All patients suffered from clinical progression such as local recurrence in 11 patients who had already received radiation therapy, lymph node metastasis in 7 patients, and bone metastasis in 15 patients. Initial PSA value ranged from 1.7 ng/mL to 215.1 ng/mL. The PSA response rate, which decreased more than 50% in PSA values was 72. 7% (16/22). The follow-up term ranged from 2 to 43 months, and nine patients died of cancer progression. The median time to progression was 11 months, and median overall survival was 19 months. There were no severe adverse effects, and stoppages of the therapy for 13 patients were all due to disease progression. Following this therapy, 9 patients received best supportive care and 4 patients received docetaxel chemotherapy. We considered this therapy to be effective for patients with hormone-refractory prostate cancer because it maintained their good QOL. PMID- 20948258 TI - [Safety issues of chemo drug administration handling by nurses from an occupational exposure viewpoint-through visualization with contrast media for ophthalmic vasculature]. AB - A number of studies on health effects of exposure to antineoplastic agents by health professionals have been reported recently. The health effects suggested are mutagenic, teratogenic and/or carcinogenic effects. In the United States or in EU countries cancer chemotherapy nursing guidelines have been already established, whereas in Japan the management of chemotherapy agents is left to each facility and the drug is administered based on the standard of each facility. We used a chemical in this study during preparation and administrations of antineoplastic agents to visualize spills that could be generated during the procedures so that we can sort out safety issues of chemo drug handling by nurses from an occupational exposure point of view. The result showed spills all over in the procedures by nurses in the study: specifically splash to environment around the drug preparation area, contamination of needles which were used for drug preparations, contamination of environment as the result of priming with chemo agents and spills at the exchange of IV bottle or at removal of the IV line from the patient without rinsing with normal saline. For future protective measures from exposure to antineoplastic agents, it is considered that the current administration method must be reviewed, and new methods to avoid the current safe handling issues must be developed and evaluated. Furthermore, strict conformity to chemo drug administration procedures based on the authorized guideline is very important in addition to the standard of the administration procedures in each facility. Hence, the work to prepare for the upcoming Japanese guideline is expected beyond the work to translate the US chemotherapy administration guideline by the Oncology Nursing Society (ONS) into the Japanese language. PMID- 20948259 TI - [A case of submandibular gland cancer in elderly patients showed significant effect by S-1 and intravenous docetaxel chemotherapy concurrent with radiotherapy]. AB - An elderly case of with advanced head and neck cancer treated by intravenous infusion chemotherapy with weekly docetaxel( DOC)and concurrent radiotherapy was reported. The patient was a 77-year-old man. Clinical diagnosis was submandibular gland carcinoma. He was treated by intravenous infusion chemotherapy with weekly DOC and concurrent radiotherapy (total dose 66 Gy). Two months after irradiation, PET-CT showed a partial response (PR). Therefore, chemotherapy of S-1 (80 mg/day) for 2 weeks every 3 weeks was performed. Two months after the end of chemotherapy, PET-CT showed a complete response(CR). This therapy is effective for the treatment of advanced head and neck cancers for elderly inoperable patients. PMID- 20948260 TI - [A case of esophageal small cell carcinoma with syndrome of inappropriate antidiuretic hormone secretion]. AB - A 66-year-old man was referred to our hospital with esophageal tumor. He was diagnosed with esophageal small cell carcinoma by endoscopic biopsy. He had a low serum sodium level at admission and was diagnosed syndrome of inappropriate secretion of antidiuretic hormone (SIADH). His CT scan revealed esophageal wall thickness and swelling of thoracic and abdominal lymph nodes. He was classified as Stage IV a (cT3cN4cM0). He received systemic chemotherapy with CDDP and CPT 11. After three courses of chemotherapy, his tumor disappeared on CT scan and endoscopy. He was diagnosed as in complete remission and his SIADH recovered. The patient was then discharged and visited our outpatient clinic. Seven months after diagnosis, a tumor recurrence was indicated by CT scan and endoscopy. He received radiation therapy, and chemotherapy of paclitaxel, followed by CBDCA+VP-16. He is presently alive sixteen months after diagnosis. PMID- 20948261 TI - [Syndrome of inappropriate antidiuretic hormone secretion following adjuvant CDDP and 5-FU administration in a patient with esophageal carcinoma]. AB - A case of hyponatremia following the first course of systemic adjuvant chemotherapy with cisplatin (CDDP) and 5-FU in a previously treated patient with esophageal cancer is reported. A 61-year-old man was admitted to our hospital for adjuvant chemotherapy after transthoracic esophagectomy and 3-field lymphadenectomy for esophageal cancer. Six days following chemotherapy, his serum sodium concentration was found to be 118 mEq/L, without edema or dehydration. This hyponatremic state was diagnosed as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) induced by CDDP, based on the hypo-osmolality of his serum and urine, and an inappropriate level of plasma vasopressin. PMID- 20948262 TI - [A successful resected case of far-advanced cancer at the esophagogastric junction by chemoradiotherapy with docetaxel, nedaplatin and 5-fluorouracil]. AB - The patient, a 73-year-old male, was admitted to our hospital because of dysphagia. A far-advanced cancer was diagnosed at the esophagogastric junction by upper gastrointestinal endoscopic examination. Pathological biopsy examinations revealed poorly-differentiated adenocarcinoma. Computed tomography (CT) of the chest and abdomen showed invasion to the diaphragm. Clinical Stage was IV in an unresectable far-advanced tumor. He received radiation therapy (40 Gy/total, 2 Gy/day*20 times) in combination with chemotherapy using docetaxel (40 mg/m2, day 1), nedaplatin (10mg/body, days 1-5) and 5-fluorouracil (500 mg/body, days 1-5). After this combination chemoradiation therapy (CRT), macroscopic examinations showed significant reductions in the size of tumor, leading a partial response according to the RECIST guidelines. He underwent total gastrectomy, partial resection of the lower esophagus via left thoracotomy, and Roux-en Y reconstruction with jejunostomy. Pathological examination of the resected specimens revealed Stage IV (T3N2P1CY0). The postoperative course was uneventful. He was treated on an outpatient basis without adjuvant therapy, and died 6 months after the operation by liver, spleen and lymph node metastases. PMID- 20948263 TI - [A case of gastric small cell carcinoma with metastatic liver tumors responding to adjuvant chemotherapy]. AB - A 71-year-old man, whose chief complaint was a faecal occult blood, had gastrointestinal endoscopy and gastric cancer was diagnosed. CT scan and intraoperative findings revealed metastatic liver tumors. We performed total gastrectomy with D2 lymph dissection, partial hepatic resections and microwave coagulation therapy. Small cell carcinoma of the stomach was diagnosed by histopathological findings. We used combination chemotherapy consisting of carboplatin, epirubicin, etoposide and 5-FU was performed. After one course, he suffered from leucopenia and agranulocytosis of grade 3, thrombocytopenia of grade 4, so we reduced the dose and performed 6 courses in total. The patient remains alive without recurrence 48 months after operation. We conclude that adjuvant chemotherapy was effective for small cell carcinoma of the stomach, which was to be considered to have a poor prognosis. PMID- 20948264 TI - [A case of mucosa-associated lymphoid tissue lymphoma with penicillin allergy successfully treated with levofloxacin, minomycin and rabeprazole]. AB - A 52-year-old Japanese woman was referred to our Institute because of Helicobacter pylori(H. pylori)-positive gastric mucosa-associated lymphoid tissue(MALT)lymphoma. Since she had a penicillin allergy, we could not eradicate H. pylori using the standard triple therapy including amoxicillin. Additionally, H. pylori was resistant to both clarithromycin and metronidazole. So she was treated with minomycin (MINO), levofloxacin (LVFX), and rabeprazole (RPZ) based on a drug sensitivity test. MINO+LVFX+RPZ appear to be a promising, appropriate, and well-tolerated eradication regimen for H. pylori demonstrating resistance to both clarithromycin and metronidazole, and for patients who are allergic to penicillin. PMID- 20948265 TI - [A case of locally advanced gastric cancer responding to pathological CR treated with S-1/CDDP neoadjuvant chemotherapy]. AB - A 75-year-old woman was referred to our hospital because of locally advanced gastric cancer. Gastrointestinal fiberscopy revealed type 3 advanced gastric cancer in the posterior wall of the gastric cardia extending to the middle body. Abdominal CT scan revealed direct invasion of pancreas and regional lymph node metastases, indicating clinical stage IV (cT4N2H0P0M0). After two courses of S 1/CDDP, neoadjuvant chemotherapy was administered, and total gastrectomy with D2 lymphadectomy was performed. Histological examination revealed no residual cancer cells in the surgically obtained stomach and lymph nodes, suggesting a complete pathological response (Grade 3). She was treated with S-1 for one year after operation and presently, 16 months after operation, she is in good health without recurrence. PMID- 20948266 TI - [A case of malignant peritoneal mesothelioma treated effectively with cisplatin and gemcitabine]. AB - Peritoneal mesothelioma presents difficulty in early diagnosis and establishment of standard treatment. We report a case of malignant peritoneal mesothelioma treated effectively with cisplatin and gemcitabine. A 53-year-old man, presenting with abdominal fullness and massive ascites was first admitted to our hospital in April, 2006. Although we conducted upper gastrointestinal endoscopy, total colonoscopy, chest-abdominal computed tomography, and FDG-PET, suspected with disseminated metastasis of cancer, we could not detect the original cancer lesion. Then, a diagnostic laparoscopy revealed many gray-colored nodules diffusely in the peritoneum. The peritoneal biopsy demonstrated that tumor cells grow papillarly and show a strongly positive image for calretinin, but a negative image for Ber-EP4. Therefore, we have diagnosed this case as a malignant peritoneal mesothelioma. Treatment with cisplatin 60 mg/m2 and intraperitoneal instillation of mitomycin C 10 mg/m2 were not so effective. Then, cisplatin 60 mg/m2 and gemcitabine 1,000 mg/m2 were administered biweekly. The tumor marker decreased remarkably and the massive ascites disappeared. Therefore, the chemotherapy could be done on an outpatient basis. PMID- 20948267 TI - [A case of diffuse peritoneal malignant mesothelioma--intraabdominal administration of cisplatin is useful for diminishing ascites]. AB - A 59-year-old man with a history of exposure to asbestos suffered from abdominal distension and visited our hospital. Abdominal CT revealed vast ascites but there was no obvious primary lesion. Serum tumor markers and hyaluronate were within the normal range. Abdominal puncture was carried out, and cytology of ascites was negative. We suspected diffuse malignant peritoneal mesothelioma because hyaluronate in ascites rose to 10*104 ng/mL. Ga-scintigraphy and FDG-PET were negative. We performed laparoscopic observation for definite diagnosis and found fine white particles at the peritoneum. The result of biopsy was malignant mesothelioma. The patient underwent intraperitoneal administration of cisplatin and his ascites was diminished. He lived for a year with no recurrence but died 23 months after diagnosis because of progression of pleural mesothelioma and liver metastases. Relapse of ascites was not found in the entire clinical course. Cisplatin administration in the peritoneal cavity is thus very effective in preventing progression of ascites. PMID- 20948268 TI - [A long-term survivor treated with S-1 and gemcitabine for recurrence following an operation for advanced gall bladder cancer]. AB - The patient was a 75-year-old woman who had undergone an operation for T4, N0: stage IV a gall bladder cancer in May of 2003. UFT was given as adjuvant chemotherapy. Then S-1 and gemcitabine (GEM) were given because of the recurrence of peritoneal dissemination in June 2006. Though a partial response was maintained, it was judged as progressive disease in July 2007. The peritoneal tumor was solitary, and an operation was performed. S-1 and GEM were given again in January 2008 because of multiple lung metastases. Long-term survival was confirmed until she died of peritonitis carcinomatosa in August 2009. To our knowledge, no case of a long survivor with S-1 and GEM for recurrence after a gall bladder cancer operation has been reported in the literature. Thus, future clinical trials and the accumulation of further cases are warranted. PMID- 20948269 TI - [A case of curatively resected locally advanced pancreatic cancer after chemoradiation therapy]. AB - A 68-year-old man admitted for pancreatic tumor detected by US was found by computed tomography(CT)to have locally advanced pancreatic cancer invading the portal vein and neural plexus of the superior mesenteric artery without distant metastasis. We conducted preoperative chemoradiation therapy containing S-1 and hyperfractionated accelerated radiation therapy (50 Gy). Reevaluation of CT after chemoradiation therapy showed that the primary tumor reduced 52% without distant metastasis. Based on these findings, we conducted subtotal stomach-preserving pancreaticoduodenectomy with portal vein resection. Pathological examination revealed moderately-differentiated adenocarcinoma. Extensive fibrosis with a small amount of cancer cells was observed in the marginal area of the tumor. The portal vein was surrounded with extensive fibrosis and free from cancer cells. Extrapancreatic nerve plexus invasion and lymph node metastasis were not observed. There were no residual cancer cells (R0). The postoperative course was uneventful, and adjuvant chemotherapy (S-1) was started. The patient remains well without recurrence 12 months after surgery. PMID- 20948270 TI - [A case of liver metastasis of pancreatic acinar cell carcinoma treated with S-1 and intra-arterial CDDP combination therapy]. AB - A 55-year-old man underwent a pylorus-preserving pancreatoduodenectomy in August 2006 because of acinar cell carcinoma of the head of the pancreas. Since abdominal CT revealed multiple liver metastases, we started systemic chemotherapy with gemcitabine (1,400 mg/body, day 1, 8, 15/q4w) in October 2006. At the beginning of this treatment, it seemed to be a stable disease, but CT revealed tumor progression in January 2007. Despite the change to oral chemotherapy with S 1 (100 mg/body, day 1-14/q3w), tumors were markedly enlarged in March 2007. Therefore, we selected combination chemotherapy with oral S-1 and hepatic arterial infusion of CDDP (50 mg/body) as third-line. After 6 months of treatment, abdominal CT revealed marked shrinkage of tumors, accompanied by a decrease in AFP level. Though the patient died of hepatic failure in July 2009 (33 months after recurrence), he spent most of his time at home and worked as usual. We suggest that combination chemotherapy with oral S-1 and intra-arterial CDDP can be effective treatments for pancreatic acinar cell carcinoma. PMID- 20948271 TI - [Effective made of octreotide intravenous administration for malignant gastrointestinal obstruction in terminal cancer patients]. AB - Continuous subcutaneous administration of octreotide acetate (SMS201-995: SMS) has not been done in Meiwa Hospital for malignant gastrointestinal obstruction in terminal patients for the following reasons: First, patients and families refuse an indwelling needle on the abdominal wall; second, an additional route limits daily activity; third, the needle site becomes inflamed or sclerosed; and fourth, an infusion pump is required. Hence, the effectiveness of three types of intravenous administration was investigated retrospectively in 15 patients in our hospital: 7 cases received intermittent IV drip infusion; 4 continuous IV drip infusion; and 4 bolus IV injection. As a result, 6 cases (86%), 2 cases (50%), and 1 case (25%), respectively, were successfully treated. These results suggested that intermittent IV administration of SMS is efficient, safe, and very convenient, while continuous IV administration is also efficient as long as the SMS potency is not reduced by mixed drugs. PMID- 20948272 TI - [A case of high CEA colon cancer responding to neoadjuvant chemotherapy with FOLFIRI]. AB - We report a case of high CEA advanced colon cancer, which we were able to down stage after treatment with FOLFIRI-1. The patient was a 56-year-old woman who had advanced sigmoid colon cancer with high CEA. It was suspected that the tumor had directly invaded the ovary by CT scan. For curative operation, hysterectomy was considered necessary. Neoadjuvant therapy was performed to avoid an extensive operation. After the fourth course, according to colonoscopy and CT findings, a significant tumor reduction was obtained. Sigmoid colorectomy with D3 nodal dissection was then performed. The histological diagnosis was pT1, pN0, PStage I. The histological effect was observed in lymph node metastasis. The patient was recurrence free at her 3-year follow-up examination. PMID- 20948273 TI - [A case report of anorectal malignant melanoma showing a complete response after DTIC/ACNU/VCR therapy]. AB - We report herein the case of a 64-year-old male who presented with hematochezia. The patient was diagnosed with malignant melanoma of the anorectum using colonoscopy. Preoperative studies revealed no distant metastases, and he underwent Miles operation. Pathological exams revealed that the tumor had invaded the submucosa with lymphatic and venous invasion. Cancer cells were found in regional lymph nodes. Post-operative CT scan demonstrated multiple metastases in the liver, and he received two courses of combined chemotherapy, DAV regimen (dacarbazine: DTIC 100 mg iv days 1-5, nimustine hydrochloride: ACNU 100 mg iv day 1, vincristine sulfate: VCR 1 mg iv day 1), leading to a complete response. However, malignant melanoma cells were found in hernia contents at the operation for left inguinal hernia, which led to a diagnosis of recurrent malignant melanoma. The patient has subsequently been well without any sign of recurrence including liver metastases. To our knowledge, this is the first report of a complete response in a patient with multiple liver metastases of anorectal malignant melanoma after DAV regimen. PMID- 20948274 TI - [A case of recurrent high-grade endometrial stromal sarcoma controlled by a combination of Ifosfamide, adriamycin, and cisplatin]. AB - A 52-year-old woman with recurrent high-grade endometrial stromal sarcoma presented with left hypochondralgia. She had undergone total hysterectomy and bilateral salpingo-oophorectomy for the disease over the past six months, and preferred not to receive additional treatment. The following regimen of chemotherapy was given: each course consisted of ifosfamide (1,000 mg/m2) on days 1-5, adriamycin (60 mg/m2) on day 1, and cisplatin (15 mg/m2) on days 1-5. After 4 courses of the chemotherapy, the intraabdominal mass and multiple pulmonary nodules were reduced 45. 1% from the beginning. This case suggests that IAP might be effective chemotherapy for patients with high-grade endometrial stromal sarcoma. PMID- 20948275 TI - [Tegafur-uracil markedly reduced pulmonary metastasis from renal cell carcinoma refractory to sorafenib, interferon and interleukin 2]. AB - In September 2003, a 68-year-old man was with renal cell carcinoma(RCC)underwent left radical nephrectomy. The pathological diagnosis was renal cell carcinoma, clear cell type, grade 1, pT3bNxMx stage III. Seventeen months later, lung metastasis was detected by CT and treated with recombinant interferon(IFN) alpha2b (Intron A(r)) 600*104 units until the regrowth lung metastasis in May, 2008. Sorafenib, an antiangiogenic molecular-targeted agent, at a dose of 800 mg per day, was administered as the second time treatment. Nevertheless, it was discontinued in 2 months because of an increase in tumor size, severe hand-foot syndrome and thrombocytopenia. Therefore, the treatment was switched to natural human IFNa with tegafur-uracil at 300 mg per day since February 2009. After that, a nearly complete disappearance of the lung lesion was obtained 7 months later and maintained for 9 months. PMID- 20948276 TI - [Therapeutic results in patients with biphenotypic acute leukemia at Sapporo Medical University Hospital]. AB - We reviewed the results of 6 patients with biphenotypic acute leukemia (BAL) which the diagnostic standard of the European Group for the Immunological Characterization of Leukemia (EGIL) at Sapporo Medical University Hospital between 2006 and 2008. There were 5 males and 1 females with an average age of 35 years. Among them, 4 were B lymphoid and myeloid, 2 were T lymphoid and myeloid, and one was T/B lymphoid. Two of 4 patients did not attain complete remission, and two relapsed after first treatment with acute myeloblastic leukemia (AML) protocol. On the other hand, two showed complete remission after the acute lymphoblastic leukemia (ALL) protocol. One of 4 patients survived who had been treated with hematopoietic stem cell transplantation as a post-remission therapy. The ALL protocol was good for the induction therapy. However, overall treatment related deaths were 4 patients and considerable caution was necessary. PMID- 20948277 TI - [Analysis of the risk factors for vascular pain induced by the administration of pirarubicin]. PMID- 20948278 TI - [Introductory remarks of the 9th International Conference of the Asian Clinical Oncology Society (ACOS) Congress--Talk to the World Wide from Asia]. AB - ACOS 2010 was held last August 25 through 27, with the president of doctor Shigetoyo Saji (Professor emeritus of Gifu University) at a beautiful Nagara River side of Gifu city, Japan. This ACOS was first proposed and organized by doctor Tetsuo Taguchi, Professor Emeritus of Surgical Department of the Medical School, Osaka University. Professor Yan Sun, a well known medical oncologist of The Peoples, Republic of China has had a major rule to develop this academic meeting in various sites of Asia in last 20 years with Dr. Taguchi. According to Dr. Saji, more than 500 papers were presented and more than 1, 000 participants from many Asiatic countries attended at this Congress. Since there were many presentations(symposium, workshop, special presentations, oral and paper presentations and others)it was impossible to cover all of the contents, so that in this paper, outline of this congress 2010 was introduced only. However, it is recommended to refer to a booklet, Recent Advances of Cancer in Asian Countries published by Gan to Kagakuryoho-sha (Cancer and Chemotherapy Publishers Company, Tokyo). PMID- 20948279 TI - Nuclear factor of activated T cells negatively regulates expression of the tumor necrosis factor receptor-related 2 gene in T cells. AB - Tumor necrosis factor receptor-related 2 (TR2, HVEM or TNFRSF-14) plays an important role in immune responses, however, the mechanisms regulating its expression are unclear. To understand the control of TR2 gene expression, we studied the upstream region of the gene. Gel supershift assays revealed inducible binding of nuclear factor of activated T cells (NFAT) to a putative NFAT site within the TR2 promoter. Furthermore, cotransfection of a dominant negative NFAT construct, or siRNA for NFAT, resulted in increased expression of a TR2 reporter gene. Our findings demonstrate that NFAT negatively regulates TR2 expression in activated T cells. PMID- 20948280 TI - Building a great wall around mitosis: evolutionary conserved roles for the Greatwall/MASTL kinases in securing chromosome stability. PMID- 20948281 TI - Controlled chaos: new insights into genetically programmed cell cycle asynchrony. PMID- 20948282 TI - A swim in the same cytoplasm is no cure for nonconformity. PMID- 20948283 TI - ING2 in cell cycle regulation. PMID- 20948284 TI - Deciphering the DNA damage histone code. PMID- 20948285 TI - A dynamic methylome; implications of non-CG methylation/demethylation. PMID- 20948286 TI - Feature series: Bioscience around the globe: in focus: Georgia. PMID- 20948287 TI - Promoter context determines the role of proteasome in ligand-dependent occupancy of retinoic acid responsive elements. AB - Retinoid acid receptors are DNA-binding proteins mediating the biological effects of ligands through transcriptional activation. It is known that the activity of the 26S proteasome is important for nuclear receptor-activated gene transcription. However, the molecular mechanism by which the 26S proteasome participates in this process is not well understood. Here we report that the proteasome activity is essential for ligand-dependent interaction of RAR with its co-regulators such as SRC, p300 and RXR. We also determined that the proteasome activity is required for the association of liganded RAR to the genomic DNA and, consequently, for the recruitment of the coactivator complex to the retinoic acid responsive elements. Moreover, the requirement of proteasome activity for the activator activity of RAR is determined by the promoter context. Our study suggests that the 26S proteasome regulates directly the activity of RAR as an activator. PMID- 20948289 TI - Managing the patent thicket and maximizing patent lifetime in vaccine technology. AB - Patents are exclusive rights for a limited period of time that are granted to provide an incentive for innovation and in exchange for the public disclosure of an invention. Patenting in the medical field, especially in the field of human vaccine technologies, is full of pitfalls, because the products that finally access the market are often covered by a multitude of exclusive IP rights. This commentary gives an overview on obstacles in vaccine patenting and how to overcome them, and intends to provide a patenting guideline for researchers. PMID- 20948288 TI - APC/C(Cdc20) targets E2F1 for degradation in prometaphase. AB - The mechanisms that control E2F-1 activity are complex. We previously showed that Chk1 and Chk2 are required for E2F1 stabilization and p73 target gene induction following DNA damage. To gain further insight into the processes regulating E2F1 protein stability, we focused our investigation on the mechanisms responsible for regulating E2F1 turnover. Here we show that E2F1 is a substrate of the anaphase promoting complex or cyclosome (APC/C), a ubiquitin ligase that plays an important role in cell cycle progression. Ectopic expression of the APC/C activators Cdh1 and Cdc20 reduced the levels of co-expressed E2F-1 protein. Co expression of DP1 with E2F1 blocked APC/C-induced E2F1 degradation, suggesting that the E2F1/DP1 heterodimer is protected from APC/C regulation. Following Cdc20 knockdown, E2F1 levels increased and remained stable in extracts over a time course, indicating that APC/C(Cdc20) is a primary regulator of E2F1 stability in vivo. Moreover, cell synchronization experiments showed that siRNA directed against Cdc20 induced an accumulation of E2F1 protein in prometaphase cells. These data suggest that APC/C(Cdc20) specifically targets E2F1 for degradation in early mitosis and reveal a novel mechanism for limiting free E2F1 levels in cells, failure of which may compromise cell survival and/or homeostasis. PMID- 20948290 TI - Glutaminolysis: supplying carbon or nitrogen or both for cancer cells? AB - A cancer cell comprising largely of carbon, hydrogen, oxygen, phosphorus, nitrogen and sulfur requires not only glucose, which is avidly transported and converted to lactate by aerobic glycolysis or the Warburg effect, but also glutamine as a major substrate. Glutamine and essential amino acids, such as methionine, provide energy through the TCA cycle as well as nitrogen, sulfur and carbon skeletons for growing and proliferating cancer cells. The interplay between utilization of glutamine and glucose is likely to depend on the genetic make-up of a cancer cell. While the MYC oncogene induces both aerobic glycolysis and glutaminolysis, activated beta-catenin induces glutamine synthesis in hepatocellular carcinoma. Cancer cells that have elevated glutamine synthetase can use glutamate and ammonia to synthesize glutamine and are hence not addicted to glutamine. As such, cancer cells have many degrees of freedom for re programming cell metabolism, which with better understanding will result in novel therapeutic approaches. PMID- 20948291 TI - Antibody immunosuppressive therapy in solid organ transplant: Part II. AB - The use of antibodies in transplantation dates to 1986 when muromonab CD3, a monoclonal antibody (mAb) targeting CD3, was first approved for prevention and treatment of renal allograft rejection. These agents have largely been used in a brief adjunctive manner to provide immunosuppression during the initial period after solid organ transplantation or during an episode of acute rejection. Recent advances in our understanding of transplant immunology have allowed emergence of numerous new mAbs, targeting co-stimulatory signals, cell surface receptors and novel protein constructs. During the next decade, transplant professionals will increasingly require knowledge of the mechanisms and pharmacologic characteristics of these novel therapeutic agents. PMID- 20948292 TI - Prion transmission: prion excretion and occurrence in the environment. AB - Prion diseases range from being highly infectious, for example scrapie and CWD, which show facile transmission between susceptible individuals, to showing negligible horizontal transmission, such as BSE and CJD, which are spread via food or iatrogenically, respectively. Scrapie and CWD display considerable in vivo dissemination, with PrP(Sc) and infectivity being found in a range of peripheral tissues. This in vivo dissemination appears to facilitate the recently reported excretion of prion through multiple routes such as from skin, feces, urine, milk, nasal secretions, saliva and placenta. Furthermore, excreted scrapie and CWD agent is detected within environmental samples such as water and on the surfaces of inanimate objects. The cycle of "uptake of prion from the environment -widespread in vivo prion dissemination--prion excretion--prion persistence in the environment" is likely to explain the facile transmission and maintenance of these diseases within wild and farmed populations over many years. PMID- 20948293 TI - Heat shock-triggered Ca2+ mobilization accompanied by pectin methylesterase activity and cytosolic Ca2+ oscillation are crucial for plant thermotolerance. AB - Apoplastic Ca(2+) concentration controls membrane permeability, cell wall stabilization, and cell integrity; however, little is known about its role in thermotolerance in plants. Here, we report that the acquired thermotolerance of etiolated rice seedlings (Oryza sativa) was abolished by an exogenously supplied Ca(2+) chelator, EGTA, related to increased cellular content leakage during heat shock (HS) treatment. Thermotolerance was restored by the addition of Ca(2+) during EGTA incubation. Pectin methylesterase (EC 3.1.1.11), a cell-wall remodeling enzyme, was activated in response to HS, and its elevated activity was related to the recovery of the HS-released Ca(2+) concentration. EGTA interfered with the capability of HS to increase oscillation of [Ca(2+)]cyt content. We assume that heat-activated PME activity is involved in cell-wall-localized Ca(2+). The removal of apoplastic Ca(2+) might participate in HS signaling to induce HS protein expression and cell-wall remodeling to retain plasma membrane integrity, prevent cellular content leakage and confer thermoprotection. PMID- 20948295 TI - Differential basal levels of MDM-2 transcription induced by p53-P72 and p53-R72. PMID- 20948296 TI - p53: guardian of reprogramming. AB - The reprogramming of somatic cells to induced pluripotent stem (iPS) cells is one of the major discoveries of recent years. The development and application of patient specific iPS lines could potentially revolutionise cell-based therapy, facilitating the treatment of a wide range of diseases. Despite the numerous technological advancements in the field, an in-depth mechanistical understanding of the pathways involved in reprogramming is still lacking. Several groups have recently provided a mechanistical insight into the role of the p53 tumour suppressor pathway in reprogramming. The repercussions of these findings are profound and reveal an unexpected role of p53 as a "guardian of reprogramming", ensuring genomic integrity during reprogramming at the cost of a reduced efficiency of the process. Here we analyse the latest findings in the field and discuss their relevance for future applications of iPS cell technology. PMID- 20948294 TI - MIRA-SNuPE, a quantitative, multiplex method for measuring allele-specific DNA methylation. AB - 5-methyl-C (5mC) and 5-hydroxymethyl-C (5hmC) are epigenetic marks with well known and putative roles in gene regulation, respectively. These two DNA covalent modifications cannot be distinguished by bisulfite sequencing or restriction digestion, the standard methods of 5mC detection. The methylated CpG island recovery assay (MIRA), however, specifically detects 5mC but not 5hmC. We further developed MIRA for the analysis of allele-specific CpG methylation at differentially methylated regions (DMRs) of imprinted genes. MIRA specifically distinguished between the parental alleles by capturing the paternally methylated H19/Igf2 DMR and maternally methylated KvDMR1 in mouse embryo fibroblasts (MEFs) carrying paternal and maternal duplication of mouse distal Chr7, respectively. MIRA in combination with multiplex single nucleotide primer extension (SNuPE) assays specifically captured the methylated parental allele from normal cells at a set of maternally and paternally methylated DMRs. The assay correctly recognized aberrant biallelic methylation in a case of loss-of imprinting. The MIRA-SNuPE assays revealed that placenta exhibited less DNA methylation bias at DMRs compared to yolk sac, amnion, brain, heart, kidney, liver and muscle. This method should be useful for the analysis of allele-specific methylation events related to genomic imprinting, X chromosome inactivation and for verifying and screening haplotype-associated methylation differences in the human population. PMID- 20948297 TI - G proteins as regulators in ethylene-mediated hypoxia signaling. AB - Waterlogging or flooding are frequently or constitutively encountered by many plant species. The resulting reduction in endogenous O2 concentration poses a severe threat. Numerous adaptations at the anatomical, morphological and metabolic level help plants to either escape low oxygen conditions or to endure them. Formation of aerenchyma or rapid shoot elongation are escape responses, as is the formation of adventitious roots. The metabolic shift from aerobic respiration to anaerobic fermentation contributes to a basal energy supply at low oxygen conditions. Ethylene plays a central role in hypoxic stress signaling, and G proteins have been recognized as crucial signal transducers in various hypoxic signaling pathways. The programmed death of parenchyma cells that results in hypoxia-induced aerenchyma formation is an ethylene response. In maize, aerenchyma are induced in the absence of ethylene when G proteins are constitutively activated. Similarly, ethylene induced death of epidermal cells that cover adventitious roots at the stem node of rice is strictly dependent on heterotrimeric G protein activity. Knock down of the unique Galpha gene RGA1 in rice prevents epidermal cell death. Finally, in Arabidopsis, induction of alcohol dehydrogenase with resulting increased plant survival relies on the balanced activities of a small Rop G protein and its deactivating protein RopGAP4. Identifying the general mechanisms of G protein signaling in hypoxia adaptation of plants is one of the tasks ahead. PMID- 20948299 TI - Setting the F-BAR: functions and regulation of the F-BAR protein family. AB - F-BAR domain proteins serve as transient linkers between the cell cortex and the cytoskeleton in multiple biological contexts. Recent studies have detailed roles for this protein family in endocytosis, cytokinesis, neurotransmission, motility and cellular morphogenesis. Here, we review emerging functional information regarding the recently recognized F-BAR domain family and the regulatory mechanisms whereby F-BAR proteins are deployed in diverse processes. PMID- 20948300 TI - Nitric oxide modulates specific steps of auxin-induced adventitious rooting in sunflower. AB - Present work on indole-3-acetic acid (IAA)-induced adventitious rooting in sunflower hypocotyl highlights a clear demarcation of nitric oxide (NO)-dependent and NO-independent roles of auxin in this developmental process. Of the three phases of adventitious rooting, induction is strictly auxin-dependent though initiation and extension are regulated by an interaction of IAA with NO. A vital role of auxin-efflux transporters (PIN) is also evident from 1-napthylphthalamic acid (NPA)-triggered suppression of adventitious roots (AR). Use of actin depolymerizing agent, Latrunculin B (Lat B), has demonstrated the necessity of functional actin filaments in auxin-induced AR response, possibly through its effect on actin-mediated recycling of auxin transporter proteins. Thus, evidence for a linkage between IAA, NO and actin during AR formation has been established. PMID- 20948301 TI - Integration of biological knowledge and gene expression data for biomarker selection: FN1 as a potential predictor of radiation resistance in head and neck cancer. PMID- 20948303 TI - Initiating bacterial mitosis: understanding the mechanism of ParA-mediated chromosome segregation. PMID- 20948302 TI - Nucleic acid-free mutation of prion strains. AB - While prions share the ability to propagate strain information with nucleic acid based pathogens, it is unclear how they mutate and acquire fitness in the absence of this informational component. Because prion diseases occur as epidemics, understanding this mechanism is of paramount importance for implementing control strategies to limit their spread and for evaluating their zoonotic potential. Here we review emerging evidence indicating how prion protein primary structures, in concert with PrP(Sc) conformational compatibility, determine prion strain mutation. PMID- 20948304 TI - Cell adhesion molecules in context: CAM function depends on the neighborhood. AB - Cell adhesion molecules (CAMs) are now known to mediate much more than adhesion between cells and between cells and the extracellular matrix. Work by many researchers has illuminated their roles in modulating activation of molecules such as receptor tyrosine kinases, with subsequent effects on cell survival, migration, and process extension. CAMs also are known to serve as substrates for proteases which can create diffusible fragments capable of signaling independently from the CAM. The diversity of interactions is further modulated by membrane rafts, which can co-localize or separate potential signaling partners to affect the likelihood of a given signaling pathway being activated. Given the ever-growing number of known CAMs and the fact that their heterophilic binding in cis or in trans can affect their interactions with other molecules, including membrane-bound receptors, one would predict a wide range of effects attributable to a particular CAM in a particular cell at a particular stage of development. The function(s) of a given CAM must therefore be considered in the context of the history of the cell expressing it and the repertoire of molecules expressed both by that cell and its neighbors. PMID- 20948305 TI - A model for phospho-caveolin-1-driven turnover of focal adhesions. AB - The regulation of Focal Adhesion (FA) dynamics is a key aspect of cellular motility. FAs concentrate integrins and associated cytoskeletal elements as well as a large number of regulatory proteins, including adapters, kinases and small GTPases of the Rho Family. We have recently shown that activated Rac1 can localize to FAs and can initiate the accumulation of the adapter protein Caveolin1 (Cav1) at FAs. As reported by several groups including ours, this translocation requires Cav1 phosphorylation at Tyr14, presumably by Src. Here we provide additional data regarding this process and briefly review recent literature. Finally, we incorporated the different pieces of available information into a mechanistic model. This model proposes that local Rac1 activation initiates a series of events that involve endosomal traffic of Cav1 and Src, targeting these proteins to or near FAs. Next, within specific membrane domains, Src can mediate the phosphorylation of Cav1 at Tyr 14, which is important for the stable FA localization of Cav1. Finally, dephosphorylation of Cav1 may represent a key step required for internalization, FA turnover and cell motility. PMID- 20948306 TI - Reactivation of MASPIN in non-small cell lung carcinoma (NSCLC) cells by artificial transcription factors (ATFs). AB - Tumor suppressor genes have antiproliferative and antimetastatic functions, and thus, they negatively affect tumor progression. Reactivating specific tumor suppressor genes would offer an important therapeutic strategy to block tumor progression. Mammary Serine Protease Inhibitor (MASPIN) is a tumor suppressor gene that is not mutated or rearranged in tumor cells, but is silenced during metastatic progression by transcriptional and epigenetic mechanisms. In this work, we have investigated the ability of Artificial Transcription Factors (ATFs) to reactivate MASPIN expression and to reduce tumor growth and metastatic dissemination in Non-Small Cell Lung Carcinoma (NSCLC) cell lines carrying a hypermethylated MASPIN promoter. We found that the ATFs linked to transactivator domains were able to demethylate the MASPIN promoter. Consistently, we observed that co-treatment of ATF-transduced cells with methyltransferase inhibitors enhanced MASPIN expression as well as induction of tumor cell apoptosis. In addition to tumor suppressive functions, restoration of endogenous MASPIN expression was accompanied by inhibition of metastatic dissemination in nude mice. ATF-mediated reactivation of MASPIN lead to changes in cell motility and to induction of E-CADHERIN. These data suggest that ATFs are able to reprogram aggressive lung tumor cells towards a more epithelial, differentiated phenotype, and thus, represent novel therapeutic agents for metastatic lung cancers. PMID- 20948307 TI - Epithelial-to-mesenchymal transition in pancreatic islet beta cells. AB - In vitro generation of insulin-producing cells from stem/progenitor cells presents a promising approach to overcome the scarcity of donor pancreas for cell replacement therapy in diabetes. In this regard, pancreatic islet-derived progenitors are proposed to be a better alternative as they are obtained from cells that can efficiently produce insulin under physiological conditions and are supposed to retain the epigenetic memory for producing 'insulin' even after transition to a mesenchymal-like cell type. However, in last few years there has been significant debate in understanding the origin of such islet-derived mesenchymal-like progenitor cells in vitro. The initial idea proposed that human insulin-producing beta-cells contribute to generation of a population of islet derived endocrine progenitor cells by a process of epithelial-to-mesenchymal transition (EMT) in vitro. This idea was challenged by a series of lineage tracing studies in mice demonstrating the non-beta origin of mesenchymal cells in culture. However, recent observations made by two independent groups confirm that human islet insulin-producing cells can proliferate and contribute to mesenchymal like cell populations in vitro. Here, we provide a fact sheet about the observations that are till now reported by several groups regarding origin of mesenchymal-like cells in the cultures of pancreatic islets. PMID- 20948308 TI - Life or death: p53-induced apoptosis requires DNA binding cooperativity. AB - The tumor suppressor p53 provides exquisite protection from cancer by balancing cell survival and death in response to stress. Sustained stress or irreparable damage trigger p53's killer functions to permanently eliminate genetically altered cells as a potential source of cancer. To prevent the unnecessary loss of cells that could cause premature aging as a result of stem cell attrition, the killer functions of p53 are tightly regulated and balanced against protector functions that promote damage repair and support survival in response to low stress or mild damage. In molecular terms these p53-based cell fate decisions involve protein interactions with cofactors and modifying enzymes, which modulate the activation of distinct sets of p53 target genes. In addition, we demonstrate that part of this regulation occurs at the level of DNA binding. We show that the killer function of p53 requires the four DNA binding domains within the p53 tetramer to interact with one another. These intermolecular interactions enable cooperative binding of p53 to less perfect response elements in the genome, which are present in many target genes essential for apoptosis. Modulating p53 interactions within the tetramer could therefore present a novel promising strategy to fine-tune p53-based cell fate decisions. PMID- 20948309 TI - AMPK as a therapeutic target in renal cell carcinoma. AB - AMPK is a cellular energy sensor that negatively regulates the mTOR signaling pathway. As mTOR plays critical roles in cell growth and tumorigenesis of renal cell carcinoma (RCC), we examined whether exogenous induction of AMPK activity exhibits inhibitory effects on growth and survival of renal cell carcinoma cells. Activation of AMPK by AICAR resulted in potent suppressive effects on RCC growth, while combinations of AICAR with statins were potent inducers of apoptosis in such cells. The effects of AICAR resulted from inhibition of mTOR and its effectors, resulting from induction of AMPK activity. Similar results on RCC cell growth were obtained when combinations of metformin with statins were examined. Importantly, studies to examine the effects of AICAR or metformin, alone or in combinations with statins, on anchorage-independent growth demonstrated potent suppressive effects on RCC tumorigenicity in vitro. Altogether, our studies demonstrate that AMPK plays critical regulatory roles in the regulation of growth of RCC cells and raise the prospect of future use of AMPK activators in the treatment of renal cell carcinoma in humans. PMID- 20948310 TI - eIF4B controls survival and proliferation and is regulated by proto-oncogenic signaling pathways. AB - Messenger RNA translation or protein synthesis, is a fundamental biological process affecting cell growth, survival and proliferation. Initiation is the rate limiting and hence the most regulated step of translation. In eukaryotes, translation initiation is facilitated by multiple protein factors collectively called eIFs (for eukaryotic translation initiation factors). The complex consisting of the eIF4 group factors including the mRNA cap-binding eIF4E protein, large scaffolding protein eIF4G and RNA helicase eIF4A is assisted by the eIF4B co-factor to unwind local secondary structures and create a ribosome landing pad on mRNA. Recruitment of the ribosome and augmentation in the mRNA scanning process culminates in the positioning of the ribosome over the start codon. Deregulated translational control is believed to play an important role in oncogenic transformation. Indeed, many eIFs are bona fide proto-oncogenes. In many types of human cancers, eIFs are either overexpressed or ectopically activated by Ras-MAPK and PI3K-mTOR signaling cascades, resulting in increased survival and accelerated proliferation. In this review we will analyze the bulk of data describing eIF4B and its role in cell survival and proliferation. Recent studies have shown that eIF4B is phosphorylated and activated by Ras-MAPK and PI3K-mTOR signaling cascades. In addition, eIF4B regulates translation of proliferative and pro-survival mRNAs. Moreover, eIF4B depletion in cancer cells attenuates proliferation, sensitizes them to genotoxic stress-driven apoptosis. Taken together, these findings identify eIF4B as a potential target for development of anti-cancer therapies. PMID- 20948311 TI - Taking apart Rap1: an adaptor protein with telomeric and non-telomeric functions. AB - Mammalian Rap1, a TRF2-interacting protein in the telomeric shelterin complex, was recently shown to repress homology-directed repair at chromosome ends. In addition, Rap1 plays a role in transcriptional regulation and NFkappaB signaling. Rap1 is unique among the components of shelterin in that it is conserved in budding yeast and has non-telomeric functions. Comparison of mammalian Rap1 to the Rap1 proteins of several budding yeasts and fission yeast reveal both striking similarities and notable differences. The protean nature of Rap1 is best understood by viewing it as an adaptor that can mediate a variety of protein protein and protein-DNA interactions depending on the organism and the complex in which it is functioning. PMID- 20948312 TI - Striatal pathology underlies prion infection-mediated hyperactivity in mice. AB - Although prion diseases are most commonly modeled using the laboratory mouse, the diversity of prion strains, behavioral testing and neuropathological assessments hamper our collective understanding of mouse models of prion disease. Here we compared several commonly used murine strains of prions in C57BL/6J female mice in a detailed home cage behavior detection system and a systematic study of pathological markers and neurotransmitter systems. We observed that mice inoculated with RML or 139A prions develop a severe hyperactivity phenotype in the home cage. A detailed assessment of pathology markers, such as microglial marker IBA1, astroglial marker GFAP and degeneration staining indicate early striatal pathology in mice inoculated with RML or 139A but not in those inoculated with 22L prions. An assessment of neuromodulatory systems including serotonin, dopamine, noradrenalin and acetylcholine showed surprisingly little decline in neuronal cell bodies or their innervations of regions controlling locomotor behavior, except for a small decrease in dopaminergic innervations of the dorsal striatum. These results implicate the dorsal striatum in mediating the major behavioral phenotype of 139A and RML prions. Further, they suggest that measurements of activity may be a sensitive manner in which to diagnose murine prion disease. With respect to neuropathology, our results indicate that pathological stains as opposed to neurotransmitter markers are much more informative and sensitive as markers of prion disease in mouse models. PMID- 20948313 TI - Role of Puralpha in the cellular response to ultraviolet-C radiation. AB - Puralpha is a nucleic acid-binding protein with DNA-unwinding activity, which has recently been shown to have a role in the cellular response to DNA damage. We have investigated the function of Puralpha in Ultraviolet-C (UVC) radiation induced DNA damage and nucleotide excision repair (NER). Mouse embryo fibroblasts from PURA(-/-) knockout mice, which lack Puralpha, showed enhanced sensitivity to UVC irradiation as assessed by assays for cell viability and clonogenicity compared to Puralpha positive control cultures. In reporter plasmid reactivation assays to measure the removal of DNA adducts induced in vitro by UVC, the Puralpha-negative cells were less efficient in DNA damage repair. Puralpha negative cells were also more sensitive to UVC-induced DNA damage measured by Comet assay and showed a decreased ability to remove UVC-induced cyclobutane pyrimidine dimers. In wild-type mouse fibroblasts, expression of Puralpha is induced following S-phase checkpoint activation by UVC in a similar manner to the NER factor TFIIH. Moreover, co-immunoprecipitation experiments showed that Puralpha physically associates with TFIIH. Thus, Puralpha has a role in NER and the repair of UVC-induced DNA damage. PMID- 20948314 TI - Excess histone levels mediate cytotoxicity via multiple mechanisms. AB - The accumulation of excess histone proteins in cells has deleterious consequences such as genomic instability in the form of excessive chromosome loss, enhanced sensitivity to DNA damaging agents and cytotoxicity. Hence, the synthesis of histone proteins is tightly regulated at multiple steps and transcriptional as well as posttranscriptional regulation of histone proteins is well established. Additionally, we have recently demonstrated that histone protein levels are regulated posttranslationally by the DNA damage checkpoint kinase Rad53 and ubiquitin-proteasome dependent proteolysis in the budding yeast. However, the underlying mechanism/s via which excess histones exert their deleterious effects in vivo are not clear. Here we have investigated the mechanistic basis for the deleterious effects of excess histones in budding yeast. We find that the presence of excess histones saturates certain histone modifying enzymes, potentially interfering with their activities. Additionally, excess histones appear to bind non-specifically to DNA as well as RNA, which can adversely affect their metabolism. Microarray analysis revealed that upon overexpression of histone gene pairs, about 240 genes were either up or downregulated by 2-fold or more. Overall, we present evidence that excess histones are likely to mediate their cytotoxic effects via multiple mechanisms that are primarily dependent on inappropriate electrostatic interactions between the positively charged histones and diverse negatively charged molecules in the cell. Our findings help explain the basis for the existence of multiple distinct mechanisms that contribute to the tight control of histone protein levels in cells and highlight their importance in maintaining genomic stability and cell viability. PMID- 20948315 TI - RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. AB - In breast cancer, inactivation of the RB tumor suppressor gene is believed to occur via multiple mechanisms to facilitate tumorigenesis. However, the prognostic and predictive value of RB status in disease-specific clinical outcomes has remained uncertain. We investigated RB pathway deregulation in the context of both ER-positive and ER-negative disease using combined microarray datasets encompassing over 900 breast cancer patient samples. Disease-specific characteristics of RB pathway deregulation were investigated in this dataset by evaluating correlation among pathway genes as well as differential expression across patient tumor populations defined by ER status. Survival analysis among these breast cancer samples demonstrates that the RB-loss signature is associated with poor disease outcome within several independent cohorts. Within the ER negative subpopulation, the RB-loss signature is associated with improved response to chemotherapy and longer relapse-free survival. Additionally, while individual genes in the RB target signature closely reproduce its prognostic value, they also serve to predict and monitor response to therapeutic compounds, such as the cytostatic agent PD-0332991. These results indicate that the RB-loss signature expression is associated with poor outcome in breast cancer, but predicts improved response to chemotherapy based on data in ER-negative populations. While the RB-loss signature, as a whole, demonstrates prognostic and predictive utility, a small subset of markers could be sufficient to stratify patients based on RB function and inform the selection of appropriate therapeutic regimens. PMID- 20948316 TI - Expression of the kinetochore protein Hec1 during the cell cycle in normal and cancer cells and its regulation by the pRb pathway. AB - Highly Expressed in Cancer protein 1 (Hec1) is a subunit of the Ndc80 complex, a constituent of the mitotic kinetochore. HEC1 has been shown to be overexpressed in many cancers, suggesting that HEC1 upregulation is involved in the generation and/or maintenance of the tumour phenotype. However, the regulation of Hec1 expression in normal and tumour cells and the molecular alterations promoting accumulation of this protein in cancer cells are still unknown. Here we show that elevated Hec1 protein levels are characteristic of transformed cell lines of different origins and that kinetochore recruitment of this protein is also increased in cancer cell lines in comparison with normal human cells. Using different cell synchronization strategies, Hec1 expression was found to be tightly regulated during the cell cycle in both normal and cancer cells. A limited proteasome-dependent degradation of Hec1 cellular content was observed at mitotic exit, with no evident differences between normal and cancer cells. Interestingly, increased expression of HEC1 mRNA and Hec1 protein was observed after transient silencing of the retinoblastoma gene by siRNA or following microRNA-mediated permanent depletion of the retinoblastoma protein in HCT116 cells. Our data provide evidence for a functional link between Hec1 expression and the pRb pathway. These observations suggest that disruption of pRb function may lead to chromosome segregation errors and mitotic defects through Hec1 overexpression. This may importantly contribute to aneuploidy and chromosomal instability in RB-defective cancer cells. PMID- 20948317 TI - CD44+ CD133+ population exhibits cancer stem cell-like characteristics in human gallbladder carcinoma. AB - Cancer stem cells (CSCs)/tumor-initiating cells have been defined as a subset of tumor cells responsible for initiating and sustaining tumor development. Emerging evidence strongly supports the existence of CSCs in various solid tumors, but they have not yet been identified in human gallbladder carcinomas (GBC). In this study, we identified CSCs in primary GBC and in the cell line GBC-SD using the cell surface markers CD44 and CD133. The percentages of CD44+CD133+ cells were 1.76-3.05% in primary tumors and 40.29% in GBC-SD cells. These cells showed stem cell properties, including self-renewal, differentiation potential, and high tumorigenicity. In vitro culture experiments revealed that CD44+CD133+ GBC cells possessed a higher spheroid-colony forming ability in serum-free media than other subpopulations. When injected into nonobese diabetic/severe combined immunodeficient mice, these cells formed new tumors and generated CD44+CD133+, CD44-, and CD133- progeny. CD44+CD133+ cells also showed a high degree of chemoresistance, possibly due to upregulation of the breast cancer resistance protein (ABCG2) and the transcription factor Gli1 in these highly tumorigenic cells. These results suggest that the CD44+CD133+ population exhibited CSC-like characteristics and may thus provide a novel approach to the diagnosis and treatment of GBC. PMID- 20948320 TI - Clinical and biological impact of EphA2 overexpression and angiogenesis in endometrial cancer. AB - OBJECTIVE: EphA2 overexpression predicts poor prognosis in endometrial cancer. To explore mechanisms for this association and assess its potential as therapeutic target, the relationship of EphA2 expression to markers of angiogenesis was examined using patient samples and an orthotopic mouse model of uterine cancer. EXPERIMENTAL DESIGN: Expression of EphA2, estrogen receptor (ER), progesterone receptor (PR), Ki-67, vascular endothelial growth factor (VEGF) and microvessel density (MVD) was evaluated using immunohistochemistry in 85 endometrioid endometrial adenocarcinomas (EEC) by two independent investigators. Results were correlated with clinicopathological characteristics. The effect of EphA2- agonist monoclonal antibody EA5, alone or in combination with docetaxel was studied in vitro and in vivo. Samples were analyzed for markers of angiogenesis, proliferation and apoptosis. RESULTS: Of 85 EEC samples, EphA2 was overexpressed in 47% of tumors and was significantly associated with high VEGF expression (p=0.001) and high MVD counts (p=0.02). High EphA2 expression, high VEGF expression and high MVD counts were significantly associated with shorter disease specific survival. EA5 led to decrease in EphA2 expression and phosphorylation in vitro. In the murine model, while EA5 (33-88%) and docetaxel (23-55%) individually led to tumor inhibition over controls, combination therapy had the greatest efficacy (78-92%, p. PMID- 20948371 TI - Gastroduodenal mucosal defense. AB - PURPOSE OF REVIEW: We have summarized recent findings related to gastroduodenal mucosal defense as well as factors contributing to defensive failure, highlighting findings that illuminate new pathophysiological mechanisms. RECENT FINDINGS: Gastroduodenal bicarbonate secretion is mediated by prostaglandin E receptors and stimulated by the prostone lubiprostone. Toll-like receptor (TLR)4 signaling is protective against gastric injury. Intestinal alkaline phosphatase (IAP) is a chemosensor that regulates the duodenal mucosal surface pH. Lipopolysaccharide (LPS) increases gastric permeability; IAP secreted during fat digestion may detoxify colonic LPS. NADPH oxidase activity mediates ischemia/reperfusion-related gastric mucosal damage. Heat shock protein 70 (HSP70) protects the gastric mucosa through inhibition of apoptosis, proinflammatory cytokines, and cell adhesion molecules (CAMs). HSP90 may be a contributing factor in impaired adaptive cytoprotection. Proteinase-activated receptor-1 (PAR-1) is protective against Helicobacter-induced gastritis, mediated by the suppression of proinflammatory pathways. IKK beta/NF-kappaB signaling decreases chronic Helicobacter-induced inflammation by inhibiting cellular apoptosis and necrosis. Activation of A2A adenosine receptors decreases inflammation and gastritis but leads to persistent Helicobacter pylori infection. SUMMARY: Enhanced understanding of the mechanisms of gastroduodenal defense and injury provides new insight into potential therapeutic targets, contributing towards the development of better tolerated and more effective therapies. PMID- 20948318 TI - Enhancing mda-7/IL-24 therapy in renal carcinoma cells by inhibiting multiple protective signaling pathways using sorafenib and by Ad.5/3 gene delivery. AB - We have determined whether an adenovirus that comprises the tail and shaft domains of a serotype 5 virus and the knob domain of a serotype 3 virus expressing MDA-7/IL-24, Ad.5/3-mda-7, more effectively infects and kills renal carcinoma cells (RCCs) compared to a serotype 5 virus, Ad.5-mda-7. RCCs are a tumor cell type that generally does not express the receptor for the type 5 adenovirus; the coxsackie and adenovirus receptor (CAR). Ad.5/3-mda-7 infected RCCs to a much greater degree than Ad.5-mda-7. MDA-7/IL-24 protein secreted from Ad.5/3-mda-7-infected RCCs induced MDA-7/IL-24 expression and promoted apoptosis in uninfected "bystander" RCCs. MDA-7/IL-24 killed both infected and bystander RCCs via CD95 activation. Knockdown of intracellular MDA-7/IL-24 in uninfected RCCs blocked the lethal effects of conditioned media. Infection of RCC tumors in one flank, with Ad.5/3-mda-7, suppressed growth of infected tumors and reduced the growth rate of uninfected tumors implanted on the opposite flank. The toxicity of the serotype 5/3 recombinant adenovirus to express MDA-7/IL-24 was enhanced by combined molecular or small molecule inhibition of MEK1/2 and PI3K; inhibition of mTOR, PI3K and MEK1/2; or use of the multi-kinase inhibitor sorafenib. In RCCs, combined inhibition of cytoprotective cell signaling pathways enhanced the MDA-7/IL-24-induction of CD95 activation, with greater mitochondrial dysfunction due to loss of MCL-1 and BCL-XL expression, and tumor cell death. Treatment of RCC tumors in vivo with sorafenib also enhanced Ad.5/3-mda-7 toxicity and prolonged animal survival. Future combinations of these approaches hold promise for developing a more effective therapy for kidney cancer. PMID- 20948319 TI - p38alpha MAPK is a MTOC-associated protein regulating spindle assembly, spindle length and accurate chromosome segregation during mouse oocyte meiotic maturation. AB - P38alphaMAPK (p38alpha) is usually activated in response to various stresses and plays a role in the inhibition of cell proliferation and tumor progression, but little is known about its roles in meiotic spindle assembly. In this study, we characterized the dynamic localization of p38alpha and explored its function in mouse oocyte meiotic maturation. P38alpha specifically colocalized with gamma tubulin and Plk1 at the center of MTOCs and spindle poles. Depletion of p38alpha by specific morpholino injection resulted in severely defective spindles and misaligned chromosomes probably via MK2 dephosphorylation. Notably, depletion of p38alpha led to significant spindle pole defects, spindle elongation, non tethered kinetochore microtubules and increased microtubule tension. The disruption of spindle stability was coupled with decreased gamma-tubulin and Plk1 at MTOCs. Overexpression of Eg5, a conserved motor protein, also caused spindle elongation and its morpholino injection almost completely rescued spindle elongation caused by p38alpha depletion. In addition, p38alpha-depletion decreased BubR1 and interfered with spindle assembly checkpoint (SAC), which resulted in aneuploid oocytes. Together, these data indicate that p38alpha is an important component of MTOCs, which regulates spindle assembly and spindle length, as well as stabilizes the spindle and spindle poles. Perturbed SAC and abnormal microtubule tension may be responsible for the misaligned chromosomes and high aneuploidy in p38alpha-depleted mouse oocytes. PMID- 20948372 TI - NSAID-induced gastrointestinal and cardiovascular injury. AB - PURPOSE OF REVIEW: To review recent publications related to NSAID-induced adverse effects on the gastrointestinal and cardiovascular systems. RECENT FINDINGS: This paper explores novel mechanisms of NSAID-induced gastrointestinal injury, highlights new composite endpoints evaluating adverse events of NSAIDs in the entire gastrointestinal tract, and combines published data to establish evidence based guidance on the best use of NSAIDs to achieve optimal clinical outcomes whilst minimizing cardiovascular and gastrointestinal injuries. SUMMARY: NSAIDs can induce peptic ulcers via epithelial cell membrane disruption and the renin angiotensin system, independent of the cyclooxygenase (COX) pathways, whereas mast cells and bile acid sensors may have a protective effect on NSAID-induced gastrointestinal damage. Patients with arthritis treated with a COX-2 inhibitor are less likely to develop upper and lower gastrointestinal complications than those who are treated with diclofenac plus a proton pump inhibitor (PPI). PPI therapy is recommended in patients receiving dual antiplatelet treatment but observational studies show that clopidogrel users taking PPIs have an increased risk of cardiovascular events. Until further reliable controlled data are available, this potential, but currently unproven, clinical interaction can be minimized by widely separating the dosing of clopidogrel and PPI. Histamine-2 antagonists may be an alternative to PPI for the prevention of peptic ulcers in patients taking low-dose aspirin. PMID- 20948373 TI - Bibliography. Immunology. Current world literature. PMID- 20948375 TI - Bibliography. Hemopoietic stem cell transplantation. Current world literature. PMID- 20948378 TI - Screening and management of pretransplant cardiovascular disease. AB - PURPOSE OF REVIEW: Cardiovascular disease is the leading cause of death in kidney transplant recipients. Hence, accurate cardiac risk assessment in potential candidates is an important issue. The purpose of this review is to examine the existing research on the screening and management of pretransplant cardiovascular disease, with an emphasis on defining the optimal approach for asymptomatic high risk candidates. RECENT FINDINGS: Randomized controlled trials (RCTs) in the general population demonstrate that prophylactic revascularization in stable patients prior to major noncardiac surgery does not reduce cardiac events or improve survival postoperatively. The benefit of noninvasive stress testing in this population is doubtful based on smaller RCTs and observational studies. Perioperative beta-blockade in intermediate-risk or high-risk candidates appears to be beneficial but acute administration is harmful. SUMMARY: Investigation for coronary artery disease is warranted for kidney transplant candidates with symptoms of myocardial ischemia. However, there is insufficient evidence to support routine cardiovascular screening in asymptomatic candidates regardless of their cardiac risk factor status. RCTs specifically looking at this issue in renal transplant candidates are a research priority. PMID- 20948381 TI - Current world literature. PMID- 20948377 TI - Periodontal disease as a risk marker in coronary heart disease and chronic kidney disease. AB - PURPOSE OF REVIEW: More than half a million Americans die each year from coronary heart disease (CHD), 26 million suffer from chronic kidney disease (CKD), and a large proportion have periodontal disease, a chronic infection of the tissues surrounding teeth. Chronic inflammation contributes to CHD and CKD occurrence and progression, and periodontal disease contributes to the cumulated chronic systemic inflammatory burden. This review examines recent evidence regarding the role of periodontal disease in CHD and CKD. RECENT FINDINGS: Periodontal pathogens cause both local infection and bacteremia, eliciting local and systemic inflammatory responses. Periodontal disease is associated with the systemic inflammatory reactant C-reactive protein (CRP), a major risk factor for both CHD and CKD. Nonsurgical periodontal disease treatment is shown to improve periodontal health, endothelial function, levels of CRP, and other inflammatory markers. Evidence for the association of periodontal disease with CKD consists of a small body of literature represented mainly by cross-sectional studies. No definitive randomized controlled trials exist with either CHD or CKD as primary endpoints. SUMMARY: Recent evidence links periodontal disease with CHD and CKD. Adding oral health self-care and referral for professional periodontal assessment and therapy to the repertoire of medical care recommendations is prudent to improve patients' oral health and possibly reduce CHD and CKD risk. PMID- 20948382 TI - Lung perfusion scan is not superior to contrast-enhanced echocardiography for the diagnosis of the hepatopulmonary syndrome in chronic liver disease. PMID- 20948383 TI - Acoustic radiation force impulse liver stiffness measurement: interlobe differences demand standardized examination procedures. PMID- 20948385 TI - The influence of splenectomy on the infectious complications and outcomes of people with HIV: marked, sustained elevation in risk of severe infection with bacteria including Streptococcus pneumoniae. PMID- 20948386 TI - Asymmetry of the regimen is correlated to self-reported suboptimal adherence: results from AdUCSC, a cohort study on adherence in Italy. PMID- 20948387 TI - World digestive health day: a year in review and looking ahead. PMID- 20948389 TI - Stevens-Johnson syndrome and acetazolamide. PMID- 20948390 TI - Assessment of exercise blood pressure and heart rate in patients with coronary artery disease: is it worth it? PMID- 20948391 TI - Obesity and left ventricular hypertrophy: does my heart look big on this? PMID- 20948392 TI - Treatment of resistant hypertension. PMID- 20948393 TI - Contrast medium-induced seizures and prolonged motor weakness after cerebral angiography: case report. AB - BACKGROUND AND IMPORTANCE: Neurological complications of cerebral angiography are usually embolic events resulting in stroke or seizure of vascular origin. Contrast media rarely induce neurological complications. CLINICAL PRESENTATION: Repeated seizures and prolonged motor weakness developed in a 26-year-old woman after cerebral angiography. Neurological deficits remained the next day with slow recovery. Repeat magnetic resonance imaging did not demonstrate any cerebral ischemia even on diffusion-weighted images. The contrast medium was the most likely cause of the neurological deficits. She recovered completely after infusion of the osmotic diuretic. CONCLUSION: Although rare, we should take into consideration that contrast media may induce neurological complications after cerebral angiography. PMID- 20948394 TI - Spinal intradural extramedullary hydatidosis: report of 3 cases. PMID- 20948397 TI - The registrar. PMID- 20948398 TI - A mechanism for the rapid development of intracranial aneurysms: a case study. AB - BACKGROUND: Despite technical and diagnostic progress there are still open questions in the understanding of the pathophysiology of intracranial aneurysms. OBJECTIVE: Within 44 days we observed the de novo genesis and rupture of an aneurysm of the basilar artery in a patient. We performed computational fluid dynamics on 3-dimensional (3D) models of the inconspicuous vessel and the same vessel with aneurysm. Based on the simulations we propose a mechanism of genesis of fast-growing aneurysms. METHODS: Three-dimensional mesh models were built using computed tomography-angiography slices. Flow was modeled as a non-Newtonian blood model with shear-dependent dynamic viscosity. We investigated flow velocity, wall pressure, impingement point, wall shear stress (WSS), and asymmetric flows in 3D models of the vessel tree of the basilar artery. RESULTS: Impingement point and wall pressure had no clear relation to the origin of the aneurysm. The impingement point faded away during aneurysm growth. Instead we found an area of permanently low WSS in the original basilar artery. This location corresponded to the origin of the later developing aneurysm. Aneurysm growth was facilitated by an increasing overall expansion of the basilar tip and a constant decrease of WSS. CONCLUSION: Assuming a preexisting reduced resistibility of the vessel wall to pressure changes and an area of permanently low WSS, an increase in pressure induces geometrical changes. These cause changes of intravascular flow distribution, lowering the already low WSS in specific locations. This leads to endothelial damage in this area and to a decreasing stability of the vessel wall, causing aneurysm development, growth, and rupture. PMID- 20948399 TI - Spontaneous intracerebral hemorrhage with ventricular extension and the grading of obstructive hydrocephalus: the prediction of outcome of a special life threatening entity. AB - BACKGROUND: Primary spontaneous intracerebral hemorrhage (SICH) with secondary intraventricular hemorrhage (IVH) accounts for the highest in-hospital mortality after stroke. OBJECTIVE: To analyze predictors and the role of acute hydrocephalus in outcome, especially 30-day mortality or an unfavorable outcome at 6 months. In addition, a new risk stratification tool for SICH- IVH was developed. METHODS: Hospital charts of 104 of 110 SICH-IVH patients were retrospectively analyzed. All patients underwent at least 1 external ventricular drainage. Multivariate logistic regression analysis was used to identify independent prognostic predictors for 30-day mortality and outcome. Outcome was determined by the modified Rankin Scale. On the basis of the independent predictors, we developed an IVH scoring system. The IVH score was tested with prospective data from 51 patients and was compared with established intracerebral hemorrhage scoring systems. RESULTS: An initial SICH volume of 60 cm3 or greater, severe hydrocephalus, Glasgow Coma Scale score of 8 or less, and age 70 years and older were independent outcome predictors. Different cutoff values for the prediction of 30-day mortality and functional outcome were defined. The IVH score was best for the prediction of 30-day mortality. CONCLUSION: Severe hydrocephalus is an independent predictor of 30-day mortality in SICH with ventricular extension. The IVH score is a simple and reliable tool for predicting 30-day mortality. PMID- 20948400 TI - Treatment of giant cerebral arteriovenous malformation: hypofractionated stereotactic radiation as the first stage. AB - BACKGROUND: Treatment of giant cerebral arteriovenous malformations (AVMs) remains a challenge. OBJECTIVE: To propose hypofractionated stereotactic radiotherapy (HSRT) as a part of staged treatment, and evaluate its effect by analyzing AVM volume changes. METHODS: From 2001 to 2007, 20 AVMs larger than 5 cm were treated by HSRT and followed up using magnetic resonance imaging. Patients' median age was 34 years (8-61 years). Eleven patients presented with hemorrhage and 9 with seizure. Ten patients had previous embolization and radiosurgery had failed in 4. Thirteen AVMs (65%) were classified as Spetzler Martin grade V and 7 as grade IV. Median pretreatment volume was 46.84 cm3 (12.51 155.38 cm3). Dose was 25 to 30 Gy in 5 to 6 daily fractions. Median follow-up was 32 months. RESULTS: Median AVM volume decreased to 13.51 cm3 (range, 0.55-147.14 cm3). Residual volume varied from 1.5% to 98%. Volume decreased 44% every year on average. We noted that 6-Gy fractions were more effective (P = .040); embolized AVM tended to respond less (P = .085). After HSRT, we reirradiated 4 AVMs, with 3 amenable to single dose and one with fractions. After HSRT, one patient had an ischemic stroke and one had increased seizure frequency. One AVM bled during follow-up (2.06%/year). No complete obliteration was confirmed. CONCLUSION: HSRT can turn some giant AVMs manageable for single-dose radiosurgery. Six-Gray fractions were better than 5-Gy and routine embolization seemed unhelpful. There was no increase in bleeding risk with this approach. Future studies with longer follow-up are necessary to confirm our observation. PMID- 20948401 TI - Role of shear stress in the blister formation of cerebral aneurysms. AB - BACKGROUND: The development of cerebral aneurysms is related to hemodynamic stress. OBJECTIVE: To elucidate the role of shear stress in the blister formation of cerebral aneurysms. METHODS: Among 82 aneurysms detected during catheter-based 3D rotational angiography (3DRA), 4 aneurysms enlarged with blister formation during a mean follow-up period of 10.1 month. Three of these 4 aneurysms were analyzed in this study. The regions of blister formation were characterized by comparing 3DRA before and after blister formation, and computational fluid dynamic simulations were performed based on the aneurysm geometry before blister formation. RESULTS: The spatially averaged shear magnitude was lower in the aneurysm region (0.97 +/- 0.39 Pa) than in the parent artery (2.75 +/- 0.92 Pa). The spatially averaged shear magnitude of the blister-forming area was extremely low (0.48 +/- 0.12 Pa), and the shear magnitude dropped precipitately to subphysiological levels, resulting in a high shear gradient near the border of the blister-forming area. CONCLUSION: These data suggest that low shear magnitude may trigger the progression of cerebral aneurysms and that blister formation is associated with high shear gradient in the large region of low shear magnitude on the aneurysm wall. PMID- 20948402 TI - Surgical treatment of giant intracranial arteriovenous malformations. AB - BACKGROUND: The treatment of giant arteriovenous malformations (AVMs) remains a challenge in the neurosurgical field. Microsurgery is one of the most effective ways for eliminating giant cerebral AVMs. OBJECTIVE: To review surgical outcomes in treating the disease, and form conclusions regarding the indications for and outcomes of surgical treatment in giant intracranial AVMs. METHODS: We studied 40 consecutive cases of giant AVMs treated in Beijing Tiantan Hospital between 2000 and 2008. The radiologic and clinical features were analyzed. The Spetzler-Martin grading system was used to classify the patients. All patients were surgically treated, and the final outcomes of the patients were gathered for analysis. RESULTS: The major presenting symptoms were seizures, headaches, hemorrhage, and neurological deficits. The mean AVM diameter was 6.3 cm. According to the Spetzler-Martin grading system, 5 patients had grade III lesions, 21 had grade IV lesions, and 14 had grade V lesions. Out of the total 40 patients, 31 (77.5%) demonstrated excellent or good outcome. Complications included hemiparalysis, aphasia, hemianopia, cranial nerve dysfunction, and seizures. After follow-up, 27 of 30 (90%) surviving patients presented normal function or minimal symptoms. CONCLUSION: Presurgical evaluation of every candidate and treatment choice is the determining factor in therapy for giant AVMs. For giant cerebral AVMs located superficially or not involving critical components, a good outcome can be expected through surgical resection. The obliteration and recurrence rates were satisfying, and the complication rate was acceptable. PMID- 20948403 TI - Carotid artery sacrifice for unclippable and uncoilable aneurysms: endovascular occlusion vs common carotid artery ligation. AB - BACKGROUND: Optimal treatment of intracranial aneurysms involves complete occlusion of the aneurysm with preservation of the parent artery and all of its branches. Attempts to occlude the aneurysm and preserve the parent artery may be associated with a higher level of risk than parent vessel occlusion or trapping. OBJECTIVE: To evaluate our series of patients with large and giant aneurysms who underwent treatment via endovascular coiling with parent artery sacrifice or surgical ligation of the common carotid artery (CCA) and gain insight into the advantages and risks of each of these alternatives. METHODS: We retrospectively reviewed all patients with aneurysms who underwent carotid sacrifice via endovascular occlusion or surgical CCA ligation during an 8-year period at our institution. RESULTS: Twenty-seven patients with large and giant aneurysms of the internal carotid artery underwent carotid artery sacrifice via endovascular occlusion (n = 15) or CCA ligation (n = 12). Of the patients who underwent endovascular occlusion, 3 developed groin complications, 1 developed a new sixth nerve palsy, 1 died from vasospasm related to subarachnoid hemorrhage, and 1 died secondary to rupture of an associated 3-mm anterior communicating artery aneurysm 5 days postoperatively. Of the patients undergoing CCA ligation, 1 patient developed a partial hypoglossal palsy. Clinical improvement of presenting symptoms was observed in all surviving patients regardless of the method of treatment. Complete aneurysm obliteration was documented in all patients during the initial hospital stay. The mean radiographic long-term follow-up was 14.2 months, which was available in 20 of the 25 surviving patients (80%). Complete obliteration was confirmed at follow-up in all but 2 patients with large cavernous aneurysms; 1 was initially treated with endovascular occlusion and the other with carotid ligation. CONCLUSION: Parent artery sacrifice is still a viable treatment for some complex aneurysms of the internal carotid artery. CCA ligation is a reasonable alternative to endovascular arterial sacrifice. PMID- 20948404 TI - Mortality resulting from head injury in professional boxing. AB - BACKGROUND: The majority of boxing-related fatalities result from traumatic brain injury. Biomechanical forces in boxing result in rotational acceleration with resultant subdural hematoma and diffuse axonal injury. OBJECTIVE: Given the inherent risk and the ongoing criticism boxing has received, we evaluated mortalities associated with professional boxing. METHODS: We used the Velaquez Fatality Collection of boxing injuries and supplementary sources to analyze mortality from 1950 to 2007. Variables evaluated included age at time of death, association with knockout or other outcome of match, rounds fought, weight class, location of fight, and location of pretermial event. RESULTS: There were 339 mortalities between 1950 and 2007 (mean age, 24 +/- 3.8 years); 64% were associated with knockout and 15% with technical knockout. A higher percentage occurred in the lower weight classes. The preterminal event occurred in the ring (61%), in the locker room (17%), and outside the arena (22%), We evaluated for significant changes after 1983 when championship bouts were reduced from 15 to 12 rounds. CONCLUSION: There was a significant decline in mortality after 1983. We found no significant variables to support that this decline is related to a reduction in rounds. Rather, we hypothesize the decline to be the result of a reduction in exposure to repetitive head trauma (shorter careers and fewer fights), along with increased medical oversight and stricter safety regulations. Increased efforts should be made to improve medical supervisions of boxers. Mandatory central nervous system imaging after a knockout could lead to a significant reduction in associated mortality. PMID- 20948407 TI - Rice bodies, millet seeds, and melon seeds in tuberculous tenosynovitis of the hand and wrist. AB - Tuberculosis (TB) is still endemic in many developed countries. Involvement of the hand and wrist at presentation is extremely rare, and the diagnosis is often missed. Operative findings of "rice bodies, millet seeds, or melon seeds" are highly suggestive of tuberculous tenosynovitis. Six patients with TB of the hand and wrist at various stages of disease with characteristic operative findings are reviewed. Four patients had underlying immunosuppression. One patient had previous pulmonary TB, whereas 3 patients had radiographic evidence of previously undiagnosed pulmonary TB. The interval to presentation ranged from 1 week to 2 years. Two patients had median nerve irritation, 3 patients had osteomyelitis, and 1 patient had flexor tendon rupture. Mycobacterial cultures were positive in 4 patients; acid-fast bacilli stain, and polymerase chain reaction were positive in remaining 1 patient; and both stain and culture were negative in the last patient who had history of pulmonary TB. All 6 patients were managed with combination therapy comprising antituberculous chemotherapy and at least 1 debulking tenosynovectomy. Two patients had 2 debridements. Of these 2 patients, 1 underwent wrist arthrodesis during the second procedure. Mean follow-up was 4 years. There were no recurrences after the most recent debridement. The diagnosis of TB of the hand and wrist is often missed. The surgeon has to be aware of the significance of loose bodies when performing routine excision of innocuous looking wrist ganglia. Combination therapy comprising thorough excisional debridement and antituberculous chemotherapy will minimize recurrence of this difficult-to-treat disease. PMID- 20948408 TI - Diagnostic value and cost-effectiveness of good quality digital images accompanying electronic referrals for suspected skin malignancies. AB - OBJECTIVES: The aim of this study was to investigate the outcome and cost effectiveness of good and poor quality photographs accompanying the electronic referrals for suspected skin malignancies. MATERIALS AND METHODS: A retrospective study of 100 patients, divided into 2 groups, 50 with good quality photographs and 50 with poor quality photographs. Patients with no digital images, or who failed to attend, or patients with incomplete notes were excluded from the study. The treatment pathway, waiting times, and estimated cost between the 2 groups were compared. RESULTS: Good photographs were more likely to be treated at the 1 Stop Clinic (P = 0.05). Good images had a better positive predictive value than poor quality images (62.55% vs. 42.86%). CONCLUSION: Good quality images are more accurate than poor quality images in triaging of patients, and thus more effective in facilitating the treatment of malignant lesions timely. Good quality photographs allow a delayed appropriate treatment of benign lesions. This increases the safety for patients in a queue in a rationed health care system, and improves patient flow. PMID- 20948409 TI - A successful neurotization of two different muscles using a single intact motor nerve: experimental study on rats. AB - The development of microsurgical techniques and better understanding of nerve biology has resulted in significant improvement in the results of nerve repair. Some problems are still present. What would be the method of choice if 2 transected nerves were to be coapted and only one neighboring intact nerve was available? We performed neurotization of 2 different muscles by a single intact nerve, using only one nerve graft by reverse end-to-side coaptation that has already been introduced into the literature. We assessed the results histomorphologically and functionally. Twenty-four adult rats were used in the present study and equally divided into 4 groups. Group 1 (n = 6): Control group; Group 2 (n = 6): Unrepaired nerve damage group; Group 3 (n = 6): End-to-end repair group. The peroneal branch of the sciatic nerve was excised to obtain an approximate size of 2 cm-graft, which was subsequently divided into 2 equal pieces to obtain 2 pieces of grafts each 1 cm long. Then, the tibial branch of the sciatic nerve was also cut to produce a nerve defect. End-to-end coaptation was obtained. A "V" shape was obtained. Group 4 (n = 6): Reverse end-to-side repair group. The peroneal branch of the sciatic nerve was excised as a graft approximately 2-cm in length. Subsequently a defect was produced by cutting the tibial branch of the sciatic nerve. Coaptation was performed by suturing the dissected proximal end of the tibial nerve by reverse end-to-side coaptation. A "U" shape resembling a horse shoe was obtained. The success of Group 4 was demonstrated when both peek-to-peek and latency timing of extensor digitorum and gastrocnemius muscles, determined as the target organ, were evaluated. Besides, an equal distribution was observed in Group 4 when number of myelinated (P = 0.596) and unmyelinated (P = 0.936) axons in both legs of grafts were compared with each other. However, myelinated axons were not equally distributed between the legs of the nerve graft in Group 3 (P = 0.027). In conclusion, reverse end-to side coaptation is a useful technique for 2 different muscle neurotization via a single nerve graft and a single nerve coaptation with a donor nerve. PMID- 20948410 TI - An alternative frontalis suspension technique: triband suspension--a modified Garcia's procedure. AB - Blepharoptosis surgery is one of the most common oculoplastic procedures, and the aim is to clear the visual axis. Many surgical techniques for the correction of ptosis have been described and performed, but the operative approach is based on the extent of eyelid excursion, the amount of levator function, and the degree of ptosis.In this study, the frontalis sling procedure with triband suspension was performed on 32 eyelids of 23 patients. All the patients had visual loss because of blepharoptosis with only 0 to 3 mm of measurable levator function. Postoperatively, the palpebral fissure was increased in all the patients. The purpose of this study was to report the use of a modified frontalis sling procedure for congenital ptosis patients with minimal to no levator function. In conclusion, this modified frontalis sling technique if used maximizes the frontalis muscle, creating sufficient eyelid elevation, with stable effect over time. PMID- 20948411 TI - Effects of human cord blood mesenchymal stem cells on cutaneous wound healing in leprdb mice. AB - PURPOSE: In the present study, we used the diabetic mouse as a model of delayed wound healing to investigate the effects of human cord blood mesenchymal stem cells (CB-MSC) on wound healing. METHODS: A delayed wound healing model was used by db/db mice. Study models were divided by an injection of human CB-MSC with phosphate buffered solution (PBS) by a different method. One was a locally topical injection, the other was a systemic injection via the end tail vein. Both models were treated with 2.0 * 10(6) CB-MSC after an 8-mm full thickness defect was made by a skin punch biopsy on the back. We evaluated the wound size, transforming growth factor (TGF)-beta, and vascular endothelial growth factor histologic evaluation, and vessel counts. Engraft of CB-MSC was detected by an antihuman antibody. RESULT: Wound healing was accelerated in the experimental group in the topical injection model with statistical significance on the 6th, 9th, and 12th day (P < 0.05). In the systemic injection model, wound healing was completed from the 9th day, but there was no statistical significance. TGF-beta increased in the first week and decreased in the third week in the experimental groups of both models. But there were opposite results in the control groups of both models. The statistical differences were found in first and third week in topical injection and in the third week in systemic injection (P < 0.05). Vascular endothelial growth factor increased in all groups and in all models as the wound healing. But statistical significance did not show between all experimental and control groups. Anti-human antibody immunochemical staining was positive in the wound. CONCLUSION: We concluded that CB-MSC had a positive effect on wound healing. Statistically significant results were noted in the topical injection model. We also reported good effects on the systemic injection model, although we did not find any statistical significance. CB-MSC may influence wound healing by TGF-beta. PMID- 20948412 TI - The variable position of the ear in lambdoid synostosis. AB - Isolated unilateral lambdoid craniosynostosis is often confused with posterior positional plagiocephaly because of a general overlap in their clinical presentations; however, distinction between these 2 entities is important because of the differences in appropriate management. Historical literature teaches that ear position is posterior in lambdoid synostosis, whereas it is anterior in positional plagiocephaly. Recently, several cases of anterior ear position in isolated unilateral lambdoid synostosis presented to the Texas Children's Hospital. A review of the cases and literature revealed that there are now 37 cases of unilateral lambdoid synostosis in the literature in which ipsilateral ear position is reported. Twelve cases (32%) had anteriorly displaced ears, 6 cases (16%) were nondisplaced, 7 cases (19%) were displaced posteriorly, 4 cases (11%) anteroinferiorly, 1 case (3%) inferiorly, and 7 cases (19%) posteroinferiorly. Based on this review, it seems that the diagnostic significance of the external ear position is unclear at this point. PMID- 20948413 TI - Phosphorylcholine-coated silicone implants: effect on inflammatory response and fibrous capsule formation. AB - INTRODUCTION: The formation of capsular fibrosis around silicone breast implants is a common complication in reconstructive and plastic surgery. Foreign body reaction-induced infections are quite common because of the hydrophobic surface properties of silicone and are, in addition, considered to be a causative factor of capsular fibrosis. METHODS: In this experimental pilot study, 2 groups of 7 Sprague-Dawley rats were established to evaluate the periprosthetic collagen synthesis after implantation of coated silicone implants. In the first group, the textured minisilicone implants were implanted submuscularly. The second group received the biotechnologically, surface-modified phosphorylcholine (PC)-coated implants. After a 3-month period, all the rats were killed, and the capsules were examined in a histologic (hematoxylin-eosin and Masson-trichrom) and immunohistologic way (CD4, CD8, CD68, TGF-beta, fibroblasts, collagen type I, and collagen type III). RESULTS: Significant differences were found to occur between the PC-coated and standard, textured implants with respect to the inflammatory reaction and collagen synthesis. CONCLUSIONS: The production of hydrophilic surfaces in silicone implants by way of PC-coating causes a decrease in the inflammatory reaction, and thus, a reduction of periprosthetic fibrosis. This could form the basis of a cost-effective, preventive, and therapeutic strategy with respect to the decrease in capsular fibrosis occurrence. PMID- 20948414 TI - Iatrogenic fluoroscopy injury to the skin. AB - Iatrogenic radiation injuries are an accepted complication of therapeutic radiation therapy, however, they can also occur during fluoroscopic procedures. These are challenging wounds and are often misdiagnosed, leading to frustration for the patient and treating physicians. We reviewed 3 cases of severe fluoroscopic burns with ulceration, non healing wounds, and preoperative debilitating pain. The average number of fluoroscopy procedures was 2.7, with an average total fluoroscopy procedure time of 10 hours. The skin changes presented at 2.3 weeks with the time to surgical intervention being on average 19 months. All patients had immediate resolution of their preoperative pain and a stable healed wound at follow-up. Fluoroscopic radiation burns can be adequately treated with wide excision of all affected tissue and vascularized flap coverage. PMID- 20948415 TI - A donor-site preference utility study for three flaps used in lower extremity microvascular reconstruction. AB - Fasciocutaneous free flaps are commonly used in reconstruction of the lower extremity. The purpose of this study was to compare preferences in donor-site scar location among 3 flaps capable of covering a wound that is 4 to 6 cm wide with primary closure of the donor-site. The locations chosen were the lateral arm, the anterolateral thigh, and the proximal lateral calf. Survey participants were presented a hypothetical scenario of a trauma patient with an open anterior tibial wound, requiring free flap reconstruction. In an internet-based survey, respondents were asked to take on the role of the patient and to rate the 3 donor site scar locations with a visual analog scale and rank them in order of preference. One hundred ninety-eight respondents (mean age 24.7 +/- 2.9 years, 49.1% men) responded to the survey, and 171 were included. The anterolateral thigh was the most preferred donor site (88.9% ranked first, rated 8.24 +/- 1.86), followed by the proximal lateral calf (8.7% ranked first, rated 5.03 +/- 1.96), and the lateral arm was last (2.3% ranked first, rated 2.18 +/- 1.62). Survey participants clearly preferred the anterolateral thigh as a donor site. This preference may be related to the ability to conceal the scar under clothing, whereas the proximal lateral calf could keep scars in a smaller topographical area of the body. When other aspects of the reconstruction are equal, it may be important for the surgeon and patient to discuss the goals of concealing the donor-site scar versus keeping the wound and reconstruction-related scars in a smaller topographical area of the body. PMID- 20948416 TI - A new experimental reversed-flow flap model: tail artery based skin flap on the dorsum of the rat. AB - Reversed-flow flaps are widely preferred particularly in reconstruction of the defects of distal part of the extremities. To overcome the drawbacks faced during clinical practice of this flap type, experimental models in economical species are required. This study provides a new reversed-flow flap model on the dorsum of the rat which is supplied by the ipsilateral lateral caudal artery. It is designed as a triangle with a 4-cm long base and 5 cm long height and it is well protected from autocannibalization and environmental conditions because of its dorsal location. When compared with the present models, we believe that this simple, reproducible, and practical flap model can be considered as advantageous, and will be preferred by the researchers for future experimental studies in hemodynamics and physiology of reversed-flow flaps. PMID- 20948417 TI - Intraoperative measurements of harvestable septal cartilage in rhinoplasty. AB - The aim of this study was to assess the dimensions of the septal cartilage available for grafting in patients undergoing open rhinoplasty and analyze whether the size of the external nose might be a useful indicator of the size and amount of harvestable septal cartilage. A prospective study was conducted on 55 Korean rhinoplasties. Intraoperative measurement of the harvested septal cartilage with preservation of 10 mm width l-strut was performed. The correlation between the quantity and size of the septal cartilage in situ with anthropometric measurements were evaluated. The mean caudal length of the harvested septal cartilage was 15.1 mm, the mean dorsal length was 18.2 mm, and the mean area was 520.9 mm2. Only 5 patients (9.1%) had cartilage sufficient for full-length dorsal onlay grafts, whereas 10 patients (18.2%) had septal cartilages of length >25 mm that could be used as spreader grafts. Dimensions of the septal cartilage in situ did not correlate with preoperative external nose measurements. The amount of harvested septal cartilage is usually insufficient for simultaneous use for multiple grafts in Korean. External nose size may not be a useful indicator of the availability of adequate septal cartilage for rhinoplasty. The need to harvest additional graft material should be kept in mind during preoperative planning for rhinoplasty procedures. PMID- 20948418 TI - A qualitative study of recovery from type III-B and III-C tibial fractures. AB - The literature has shown that long-term outcomes for both below-knee amputation and reconstruction after type III-B and III-C tibial fracture are poor. Yet, patients often report satisfaction with their treatment and outcomes. The aim of this study was to explore the relationship between patient outcomes and satisfaction after open tibial fractures via qualitative methodology. Twenty patients who were treated for open tibial fractures at one institution were selected using purposeful sampling and interviewed in-person in a semi-structured manner. Data were analyzed using grounded theory methodology. Despite reporting marked physical and psychosocial deficits, participants relayed high satisfaction. We hypothesize that the use of adaptive coping techniques successfully reduces stress, which leads to an increase in coping self-efficacy that results in the further use of adaptive coping strategies, culminating in personal growth. This stress reduction and personal growth leads to satisfaction despite poor functional and emotional outcomes. PMID- 20948419 TI - Lateral arm free flap for oral tongue reconstruction: an analysis of surgical details, morbidity, and functional and aesthetic outcome. AB - The purpose of this study was to report the effectiveness of the lateral arm free flap (LAFF) in the reconstruction of oral tongue defects, the subsite in which it may have advantage over the other donor sites. This is a retrospective analysis of 48 consecutive cases of LAFF used for the reconstruction of partial glossectomy defects for squamous cell carcinoma of the oral tongue. Primary defect and donor-site morbidity and the functional and aesthetic outcomes were assessed in 37 evaluable patients, with a minimum of 6 months follow-up. Patient reported Visual Analog Scale score from 0 (minimum satisfaction) to 10 (maximum satisfaction) was used to evaluate the aesthetic outcome. The follow-up was for 6 to 52 months (mean, 24 months). The flap was successful in 45 (93.8%) patients. The commonest observed donor-site morbidity was a broad scar, but it did not cause much patient dissatisfaction because it could be covered with appropriate dressing. Speech was normal or near-normal in all patients. Poor functional outcome was associated with adjuvant postoperative radiotherapy. The visual analog scale score for the aesthetic satisfaction (mean [standard deviation]) was 6.58 (1.82) for primary site and 7.13 (1.99) for the donor site. LAFF is an excellent option for the reconstruction of partial glossectomy defects of oral tongue without significant involvement of the floor of mouth and base of tongue. PMID- 20948420 TI - Zone of injury: a critical review of the literature. AB - The response of tissue to trauma is difficult to define. The zone of injury is an area surrounding a wound that, though traumatized, may not appear nonviable at initial debridement. Because of this, a policy of repeated debridements has been followed to monitor tissues for viability before final tissue coverage. Appreciation of the zone of injury has led to a controversy in the literature about how to define and approach the management of traumatic injuries requiring free-tissue coverage. This review examines the current literature with regard to the definition of the zone of injury, and seeks to establish a consensus statement about the application of free flaps to traumatized wounds. We have investigated the literature supporting the use of free flaps relying on proximally or distally based recipient vessels. Critical appraisal of this literature includes study design, determination of the power of the study, subject classification, inclusion and exclusion criteria, follow-up, and outcomes (free flap success). There has been little attempt in the literature to fully and objectively define the zone of injury. All studies to date have been observational alone. Although it would be impossible to rid a definition of the zone of injury of subjectivity entirely, a more objective, reproducible definition is vitally needed. Without a clear definition of what the zone of injury is, there can only be anecdotal, technique reports of the placement of free flap anastomoses. In this time of rising costs and lower reimbursements, this is one area that could provide vital information to improve care for patients, lessen costs, and further medical knowledge. PMID- 20948421 TI - Applying amphibian limb regeneration to human wound healing: a review. AB - In contrast to the limited regenerative ability found in human wound healing, which often results in unsatisfying and deficient scar formation, urodele amphibians, with the Mexican axolotl as a prime example, expose an extraordinary regenerative capacity. This regeneration leads to a perfect restoration of tissue architecture, function, and aesthetics with the axolotl being actually able to reclaim complete limbs. Evolutionary considerations suggest that regeneration might be a biologic principle which also underlies human wound healing. Experimental findings, such as comparative studies on transforming growth factor beta and fibroblast growth factor accentuate this assumption. Regeneration, as recent data indicate, might be a question of adaptive immunity. The loss of regenerative potency correlates with the decrease of regeneration in most species, whereas the Mexican axolotl lacks adaptive immunity throughout its life. The characterization of molecular pathways as a prerequisite for any control of regenerative processes sets an increasing indication toward the transfer into human beings. Some regenerative techniques, eg, recombinant transforming growth factor-beta have already emerged. Molecular findings suggest that there is an intrinsic regenerative capacity in humans which might be initiated under appropriate circumstances. The Mexican axolotl is liable to diverse surgical and molecular approaches. Though well-known among developmental biologists, its exploitation for experimental Plastic Surgery still has to be established. We therefore intend to give an introduction to amphibian regeneration and the common evolutionary roots of regeneration and human wound healing, as we believe that Plastic Surgery takes a unique advantage of performing basic research on amphibian regeneration. PMID- 20948422 TI - Chest wall reconstruction in thoracoabdominal ectopia cordis: using the pedicled osteomuscular latissimus dorsi composite flap. AB - Ectopia cordis is a rare congenital defect characterized by complete or partial displacement of the heart outside the thoracic cavity. Repair of ectopia cordis can present a reconstructive challenge often requiring a staged approach. Ideally, structural integrity and protection of the heart are restored using autologous tissues capable of growth. In addition, reconstruction of the thorax must proceed without compromise to pulmonary or cardiovascular stability. The following article describes repair of thoracoabdominal ectopia cordis in a patient with pentalogy of Cantrell. Reconstruction of the chest wall was accomplished using a musculoosseus composite flap involving segments of the 9th and 10th ribs and overlying pedicled latissimus dorsi muscle. This is the first report known to the authors of such a repair. PMID- 20948423 TI - Study of the dimension change after grafting of bone from the outer mandibular table to different maxillofacial recipient sites. AB - BACKGROUND: The object of this study was to investigate the dimension change after bone of the outer mandibular table had been grafted to different facial recipient sites. METHODS: Six cases of hemifacial skeleton dysplasia had accepted therapeutics of onlay bone grafting at both mandibular angle and infraorbital regions of the affected side. Grafted bones had been harvested from the outer mandibular table of the uninjured side. For each patient, computed tomography scans were taken of immediate postoperative and 6 months postoperative results. By a technique based on 3-dimensional spiral computed tomography separated reconstruction and registration, grafted bones both at mandibular angle and infraorbital regions were independent. Volume of the grafted bone was measured, and 3-dimensional analysis was done. RESULTS: At 6 months after the operation, the volume of the bone that had been grafted to the infraorbital region had a reduction rate of 11.2% +/- 2.3%, and for the bone that had been grafted to the mandibular angle region, the volumetric reduction rate was 20.8% +/- 7.2%. The difference of grafted bone resorption rate between the 2 recipient areas has statistical significance (<0.05). Three-dimensional analysis of grafted bones shows that the resorption took place mainly at the length-breadth direction and decreased thickness was less. Of the bone that had been grafted to the mandibular angle area, resorption mainly occurred at the inferior and posterior border of mandible. CONCLUSIONS: As an autogenous bone graft resource for reparation and reconstruction of maxillofacial bone deformity, the outer mandibular table has a different rate of resorption after it had been onlay grafted to various maxillofacial recipient sites, and the difference of the local mechanical environment maybe an influencing factor. Quantization of bone resorption rate could better guide the clinical use of outer mandibular table as an onlay bone graft resource. PMID- 20948424 TI - Synmastia: prevention and correction. AB - Synmastia is a condition of aberrant communication of the breasts. Apart from the rare congenital cases, this is usually a result of technical complications during breast augmentation surgery caused by an overdissection at the medial side of the pocket, over the sternum, in the subglandular plane; or overdivision of the major pectoralis muscle insertion along the sternum, in the submuscular plane. A multidatabase search about synmastia has been performed. Between November 2004 and April 2009, the senior author (G.S.) has performed 924 breast augmentations and his experience in preventing synmastia is discussed and compared with the literature. Accurate surgical plan, correct choice of implants' size, and correct surgical technique are the most important rules to prevent synmastia. It is difficult to correct synmastia: additional reoperations expose patient to risks, cost, and dissatisfaction. On the basis of the recent literature and personal experience, we propose some classifications and guidelines to prevent synmastia. PMID- 20948425 TI - Functional outcomes of nonunion scaphoid fracture treated by pronator quadratus pedicled bone graft. AB - Between 1998 and 2007, a pronator quadratus pedicled bone graft was performed for 45 patients of ununited scaphoid fracture. One of them had bilateral ununited scaphoid fracture. There were 29 men and 16 women with a median age at operation of 24 (16-32) years. The affected side was the right side (dominant hand) in 32 patients whereas 13 patients had fracture of the nondominant left side. There had been 32 proximal pseudoarthrosis (through or proximal to the junction of the proximal and middle thirds of the bone) and 14 of the middle third of the scaphoid. The original fractures were caused by motor cycle accidents in 23 patients, falling on outstretched hand in 15 patients, and sport injuries in the remaining 7 patients. Surgery was indicated from 5 months to 6 years after injury (average 43 months) because of complaints of pain on heavy work. The fracture has been missed at the initial examination in 23 patients whereas cast immobilization was done for 6 weeks and 3 months in 15 and 7 cases, respectively, that had failed to result in union. There were no preoperative osteoarthritic changes, but in 25 cases, there were avascular necrosis of the proximal fragment of the scaphoid. Forty-three patients showed radiographic union after an average of 14 weeks (12-16 weeks). One patient had dislodgement of the graft and refused to do it again. The average range of movement of wrist improved after operation. Taken as a percentage of the normal range, dorsiflexion increased from 69% to 80%, palmar flexion from 66% to 76%, radial deviation from 45% to 70%, and ulnar deviation from 67% to 84%. Grip strength improved from 82% to 92% of normal. All the patients have been able to return to their former activities with no pain. PMID- 20948426 TI - Z-shaped asymmetric hump resection and unilateral osteotomy for treatment of deviated noses. AB - Numerous techniques have been described to correct deviated nose deformities. This article discussed the Z-shaped asymmetric hump resection combined with unilateral osteotomy. Fifty-eight cases that we operated between 2003 and 2009 for deviated nose deformity were included in the study. In this study, septoplasty was performed in all patients, and hump was resected Z-shaped whereas osteotomy was carried out in a unilateral low to low fashion. Edema and periorbital ecchymosis were minimal on the nonosteotomy side in early postoperative period in all cases, and deviation was noted to be satisfactorily corrected in the late postoperative period. Three cases were reoperated in late stage for mucosal synechiae and 1 case for a new postoperative trauma (6.8% revision). Z-shaped asymmetric hump resection combined with unilateral osteotomy is one of the minimally traumatic methods that can safely be used to correct deviated nose. PMID- 20948427 TI - Hand surgery volume and the US economy: is there a statistical correlation? AB - BACKGROUND: To the best of our knowledge, there have been no previous studies evaluating the correlation of the US economy and hand surgery volume. Therefore, in light of the current recession, our objective was to study our institution's hand surgery volume over the last 17 years in relation to the nation's economy. METHODS: A retrospective analysis of our institution's hand surgery volume, as represented by our most common procedure (ie, carpal tunnel release), was performed between January 1992 and October 2008. Liposuction and breast augmentation volumes were chosen to serve as cosmetic plastic surgery comparison groups. Pearson correlation statistics were used to estimate the relationship between the surgical volume and the US economy, as represented by the 3 market indices (Dow Jones, NASDAQ, and S&P500). RESULTS: A combined total of 7884 hand surgery carpal tunnel release (open or endoscopic) patients were identified. There were 1927 (24%) and 5957 (76%) patients within the departments of plastic and orthopedic surgery, respectively. In the plastic surgery department, there was a strong negative (ie, inverse relationship) correlation between hand surgery volume and the economy (P < 0.001). In converse, the orthopedic department's hand surgery volume demonstrated a positive (ie, parallel) correlation (P < 0.001). The volumes of liposuction and breast augmentation also showed a positive correlation (P < 0.001). CONCLUSION: To our knowledge, we have demonstrated for the first time an inverse (ie, negative) correlation between hand surgery volumes performed by plastic surgeons in relation to the US economy, as represented by the 3 major market indices. In contrast, orthopedic hand surgery volume and cosmetic surgery show a parallel (ie, positive) correlation. This data suggests that plastic surgeons are increasing their cosmetic surgery-to reconstructive/hand surgery ratio during strong economic times and vice versa during times of economic slowdown. PMID- 20948428 TI - Ursolic acid induces HL60 monocytic differentiation and upregulates C/EBPbeta expression by ERK pathway activation. AB - Ursolic acid (UA), a pentacyclic triterpenoid compound, is widely distributed in the plant kingdom and has a broad range of biological effects. This study was carried out for the first time to investigate the potential role of UA in the differentiation of human leukemia HL60 cells and the underlying mechanisms in it. UA could induce differentiation of HL60 cells into the monocytic lineage, as assessed by the morphological change, nitroblue tetrazolium reduction assay, and expression of CD14 and CD11b surface antigens. Moreover, UA activated the extracellular signal-regulated kinase (ERK) pathway in both dose-dependent and time-dependent manners. Inhibiting ERK pathway activation with PD98059 could significantly block the differentiation induced by UA. Consistent with the induced differentiation, the upregulation of CCAAT/enhancer-binding protein beta by UA was also eliminated by PD98059. Taken together, the results reported here show that UA can promote the monocytic differentiation of HL60 cells and increase the expression of CCAAT/enhancer-binding protein beta by activating the ERK pathway, suggesting that UA could be a potential candidate as a differentiation inducing agent for the therapeutic treatment of leukemia. PMID- 20948429 TI - Vinflunine as second-line treatment in platin-resistant metastatic urothelial carcinoma: a review. AB - The novel third-generation bifluorinated semisynthetic vinca alkaloid, vinflunine, is a microtubule inhibitor that shows superior antitumor activity and a favorable safety profile compared with other vinca alkaloids. The main antineoplastic effects of vinflunine arise from its interaction with tubulin, the major component of microtubules in mitotic spindles. Vinflunine is known to have low affinity for tubulin, high intracellular accumulation, and important effects on microtubule dynamics. It has been shown to have activity against transitional cell carcinoma of the urothelial tract. Vinflunine was investigated in a randomized phase III clinical trial comparing vinflunine and best supportive care versus best supportive care alone in patients with advanced transitional cell carcinoma of the urothelial tract, who were progressive after first-line platinum containing therapy. At an acceptable safety profile without cumulative toxicity, second-line treatment with vinflunine has shown a survival advantage and has therefore been approved in 2009 for this indication. This review gives a brief outline on vinflunine as a second-line treatment for platin-resistant advanced urothelial carcinoma; it describes pharmacology, efficacy studies, tolerance, and side effects and briefly discusses future clinical perspectives. PMID- 20948430 TI - NCPMF-60 induces G2/M cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. AB - We recently established that NCPMF-60, a newly synthesized flavonoid, is an active cytotoxic component. The molecular mechanisms by which NCPMF-60 exerts its cytotoxic activity are currently unknown. In this study, we show that NCPMF-60 induces G2/M phase arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. After treatment of HepG2 cells with NCPMF-60, cell cycle-related proteins, such as cyclin B1, cyclin H, CDK7, and p-CDK1 (Thr161), were downregulated, whereas p21 and p-CDK1 (Thr14/Tyr15) were upregulated. The activity of CDK1/cyclinB complex was also inhibited by NCPMF-60. In addition, we observed poly(ADP-ribose) polymerase cleavage and activation of caspase 3 and caspase 9. The expression ratio of Bax/Bcl-2 was increased in the treated cells, in which Bax was also upregulated. We also found that the expression of p53 and its phosphorylation at Ser15 accumulated after the treatment of NCPMF-60. Moreover, upregulation of p21, p53-upregulated modifier of apoptosis, and Bax, three p53 target gene products, and the downregulation of Bcl-2 and MDM2, were observed in NCPMF-60-treated cells. However, p53 is not the only regulator in the stimulation of NCPMF-60 on p21 transcriptional level and posttranscriptional level. These results suggested that NCPMF-60 indeed activated the p53 pathway, which may contribute to its induction of cell cycle arrest and apoptosis in HepG2 cells. Collectively, our findings show that cell cycle arrest and apoptosis induced by NCPMF-60 was associated with the activation of p53 pathway and the inhibition of CDK-activating kinase activity in HepG2 cells. PMID- 20948431 TI - Potent antitumor actions of the new antibiotic boningmycin through induction of apoptosis and cellular senescence. AB - Boningmycin, a new antibiotic of the bleomycin family, is isolated from the fermentation broth of Streptomyces verticillus var. pingyangensis n.sp. This study aimed to evaluate its antitumor actions and mechanism. The results showed that boningmycin exhibited potent inhibitory effects on several human solid tumor cells and that it was stronger than bleomycin. The administration of boningmycin inhibited the growth of human hepatoma HepG2 xenografts in nude mice, with more efficacy than that of bleomycin. Boningmycin led to an increase of the reactive oxygen species involving iron and caused G2/M phase accumulation in the HepG2 and human breast cancer MCF-7 cells. Two types of cell death, apoptosis and senescence, were detected after exposure to boningmycin. The accumulation of sub G1 phase cells, an index of apoptosis, and the activation of caspase apoptotic pathways were detected after treatment with higher concentrations of boningmycin. Low concentrations of boningmycin led to a senescent phenotype with an increase in senescence-associated beta-galactosidase activity and the time-dependent increase of p21, p27, and p53 expressions from 48 to120 h. Taken together, the results showed that boningmycin exhibits potent antitumor actions through the induction of apoptosis and cellular senescence. PMID- 20948432 TI - Dose correspondence between olanzapine long-acting injection and oral olanzapine: recommendations for switching. AB - Oral-to-depot dose correspondence was explored in a 24-week study of olanzapine long-acting injection (LAI). Patients with schizophrenia stabilized on oral olanzapine of 10, 15, or 20 mg/day (n=1065) were randomized to continue their oral treatment or switch directly to a fixed dose of olanzapine LAI [(mg/weeks) 45/4, 150/2, 405/4, or 300/2] without oral supplementation. Six-month relapse rates for each LAI-dose group stratified by earlier oral dose were analyzed using a Cox proportional hazard model assessing risk of relapse relative to each oral dose. Relapse rates for the therapeutic LAI doses (>= 150 mg) varied depending on earlier oral dose, ranging from 1.5% (patients switched from 10 mg/day to 300 mg/2 weeks) to 18.8% (patients switched from 20 mg/day to 150 mg/2 weeks). Switching from 10 mg/day to 405 mg/4 weeks produced a comparable risk of relapse as remaining on that oral dose [Hazard ratio (HR)=1.03]. Switching from 15 or 20 mg/day to 300 mg/2 weeks produced comparable risk of relapse as remaining on those oral doses (HR=0.68 and 1.13, respectively). Pharmacokinetic modeling was conducted to evaluate the resulting dosing recommendations. Findings suggest that patients can be switched directly from oral to olanzapine LAI without the need for oral supplementation and with a low risk of relapse when initiated on an appropriate LAI dose. PMID- 20948433 TI - 14G2a anti-GD2 crossreactivity with the CD166 antigen. PMID- 20948434 TI - Novel management of pruritus in patients treated with IL-2 for metastatic renal cell carcinoma and malignant melanoma. AB - Pruritus has been a side effect, associated with several biologic response modifiers, most commonly interferons and interleukins. Reports of pruritus are anecdotal and have not been a focus of attention. Itch fibers are essentially pain fibers, and gabapentin is used for neuropathic pain. This has led to our formal investigation of gabapentin for interleukin-2 (IL-2)-related pruritus. Clinical records of 54 patients treated with high-dose IL-2 from January 2005 to December 2006 were reviewed. Among 30 patients, who complained of pruritus, 17 patients were given gabapentin. These 17 patients were interviewed using a specific IRB approved questionnaire, which quantified pruritus according to CTCAE v3.0 criteria. According to CTCAE scale, the mean pruritus before gabapentin was 2.41, which decreased to 0.65 after gabapentin treatment and was statistically significant (P<0.0005). IL-2 therapy is frequently associated with varying degrees of peripheral eosinophilia. Relationship between pruritus and the degree of eosinophilia was also analyzed. Patients grouped into mild eosinophilia (eosinophil count<1500/mL) and moderate to severe eosinophilia (eosinophil count>1500/mL) during HDIL-2 therapy was evaluated for pruritus. chi2 test for independence of variable between degree of eosinophilia and pruritus was 0.714 with no statistically significant correlation. To summarize, gabapentin is used in our facility with excellent response against pruritus. Hypothesizing the likely mechanism of pruritus in patients treated with IL-2, we suggest that gabapentin should be considered an effective and safe treatment in IL-2-related pruritus, and this concept could be applied to pruritus encountered in similar clinical settings. PMID- 20948435 TI - Phase II study of interleukin-4 in indolent B-cell non-Hodgkin lymphoma and B cell chronic lymphocytic leukemia: a study of the Eastern Cooperative Oncology Group (E5Y92). AB - Recombinant interleukin (IL)-4, 5 MUg/kg thrice weekly for 3 weeks followed by a 2-week rest period (1 cycle) was administered to 32 eligible previously treated B cell chronic lymphocytic leukemia (7 patients) or low-grade B-cell lymphoma patients (25 patients). Two cycles were given before response was evaluated. IL-6 serum levels were evaluated before therapy in all patients and at 12 weeks on study in 7 patients. None of the chronic lymphocytic leukemia patients responded. A partial response was observed in 3 lymphoma patients of 1.2, 3.0, and 3.5 months' duration and stable disease (median 1.5 mo) was observed in another 7 lymphoma patients. The median survival from registration on study was 29.7 months with 7 patients alive at the time of analysis for a median follow-up of 72.8 months. Toxicity was generally mild with no grade 4 nonhematologic toxicity observed. Recombinant IL-4 treatment was well tolerated in this study but had minimal antitumor activity. PMID- 20948436 TI - Cross-trial analysis of immunologic and clinical data resulting from phase I and II trials of MVA-5T4 (TroVax) in colorectal, renal, and prostate cancer patients. AB - The attenuated vaccinia virus MVA has been engineered to deliver the tumor antigen 5T4 (MVA-5T4; TroVax), a surface glycoprotein expressed by most solid tumors. MVA-5T4 has been tested in 2 phase I/II and 7 phase II clinical trials in colorectal (4 trials), renal (4 trials), and prostate (1 trial) advanced cancer patients. Data have been collated from all 9 studies and used to investigate the magnitude and kinetics of 5T4-specific antibody responses after vaccination and to identify potential associations between the immune response and patient survival. Antibody responses specific for the 5T4 tumor antigen and the MVA viral vector were quantified in plasma samples taken from cancer patients before and after the treatment with MVA-5T4. Immunologic and survival data were analyzed using proportional hazards regression adjusting for age and gender. Both survival and immunologic response data were available for 189 patients with colorectal (n=73), renal (n=89), and prostate (n=27) cancer. Before the treatment with MVA 5T4, 5T4-specific antibody levels were significantly elevated in cancer patients compared with healthy donors. After MVA-5T4 administration, 5T4-specific antibody responses increased significantly and peaked after 3 to 4 vaccinations. Exploratory analyses showed significant associations between 5T4 antibody responses and overall survival across all 9 trials and in patients with colorectal cancer. The 5T4-specific antibodies were present at higher levels in cancer patients compared with healthy donors and increased significantly after treatment with MVA-5T4. Although the studies were uncontrolled, there were encouraging signs of activity which is associated with the magnitude of 5T4 specific antibody responses. PMID- 20948437 TI - A decrease of regulatory T cells correlates with overall survival after sunitinib based antiangiogenic therapy in metastatic renal cancer patients. AB - Sunitinib, an antiangiogenic molecule, is one of the first-line standard of care in the treatment of patients with metastatic renal cell carcinoma. However, it only benefits to a subgroup of patients and no predictive markers of sunitinib efficacy have been identified. Twenty-eight metastatic renal cell carcinomas were treated with sunitinib-based therapy and another subgroup of 7 primary renal cell cancer patients were also treated by sunitinib in a neoadjuvant trial. Measurements of CD3+CD4+CD25(hi) Foxp3+ regulatory T cells, an immunosuppressive cell population, were performed before and after each cycle of treatment in blood and tumor in a prospective study. We observed a decrease in the number of peripheral blood Foxp3+ regulatory T cells after each cycle of sunitinib-based therapy. The overall survival was significantly longer in patients showing a decrease in the number of Foxp3+ regulatory T cells after 2 or 3 cycles of treatment (P<0.05). The decrease in the number of regulatory T cells positively correlated with their number at baseline (P<0.01), but not with modification of tumor volume defined by Response Evaluation Criteria in Solid Tumors criteria. The clinical relevance of these results was also supported by an intratumoral decrease of regulatory T cells in 5 out of 7 patients treated by sunitinib in a neoadjuvant trial. Our study represents the first work reporting that the measurement of regulatory T cells may have a predictive value on antiangiogenic response. Antiangiogenic therapy also reversed immunosuppression in the tumor microenvironment which provides novel argument in human to favor its combination with immunotherapy. PMID- 20948438 TI - Adoptive transfer of EBV-specific T cells results in sustained clinical responses in patients with locoregional nasopharyngeal carcinoma. AB - Patients with recurrent or refractory Epstein Barr Virus (EBV)-positive nasopharyngeal carcinoma (NPC) continue to have poor outcomes. Our earlier Phase I dose escalation clinical study of 10 NPC patients showed that infusion of EBV specific cytotoxic T cells (EBV-CTLs) was safe and had antitumor activity. To better define the overall response rate and discover whether disease status, EBV antigen specificity, and/or in vivo expansion of infused EBV-CTLs predicted outcome, we treated 13 additional NPC patients with EBV-CTLs in a fixed-dose, Phase II component of the study. We assessed toxicity, efficacy, specificity, and expansion of infused CTLs for all 23 recurrent/refractory NPC patients treated on this Phase I/II clinical study. At the time of CTL infusion, 8 relapsed NPC patients were in remission and 15 had active disease. No significant toxicity was observed. Of the relapsed patients treated in their second or subsequent remission, 62% (5/8) remain disease free (at 17 to 75 mo), whereas 48.7% (7/15) of those with active disease had a CR/CRu (33.3%) or PR (15.4%). In contrast to locoregional disease, metastatic disease was associated with an increased risk of disease progression (HR: 3.91, P=0.015) and decreased overall survival (HR: 5.55, P=0.022). Neither the specificity of the infused CTLs for particular EBV antigens nor their measurable in vivo expansion discernibly influenced outcome. In conclusion, treatment of patients with relapsed/refractory EBV-positive NPC with EBV-CTLs is safe and can be associated with significant, long-term clinical benefit, particularly for patients with locoregional disease. PMID- 20948439 TI - Lovastatin inhibits T-cell proliferation while preserving the cytolytic function of EBV, CMV, and MART-1-specific CTLs. AB - Statin treatment has been shown to reduce graft-versus-host disease while preserving graft-versus-tumor effect in allogeneic stem cell transplantation. Herein, we investigated whether lovastatin treatment affects the function of human cytolytic T lymphocytes (CTLs). Upon T-cell receptor stimulation, lovastatin significantly inhibited the proliferation of both CD4+ and CD8+ T cells from healthy donors whereas their intracellular cytokine production including interferon-gamma and tumor necrosis factor-alpha remained the same with a slight decrease of interleukin-2. Moreover, the specific lysis of target cells by CTL lines derived from patients and normal donors specific for Epstein-Barr virus-encoded antigen latent membrane protein-2 or cytomegalovirus-encoded antigen pp65 was uncompromised in the presence of lovastatin. In addition, we evaluated the effect of lovastatin on the proliferation and effector function of the CD8+ tumor-infiltrating lymphocytes (TILs) derived from melanoma patients specific for MART-1 antigen. Lovastatin significantly reduced the expansion of antigen-specific TILs upon MART-1 stimulation. However, the effector function of TILs, including the specific lysis of target cells and secretion of cytokine interferon-gamma, remained intact with lovastatin treatment. Taken together, these data demonstrated that lovastatin inhibits the proliferation of Epstein Barr virus, cytomegalovirus, and MART-1-specific CTLs without affecting cytolytic capacity. The differential effect of lovastatin on the proliferation versus cytotoxicity of CTLs might shed some light on elucidating the possible mechanisms of graft-versus-host disease and graft-versus-tumor effect elicited by alloimmune responses. PMID- 20948440 TI - Interferons induce CXCR3-cognate chemokine production by human metastatic melanoma. AB - Immune-mediated cancer regression requires tumor infiltration by antigen-specific effector T cells, but lymphocytes are commonly sparse in melanoma metastases. Activated T cells express CXCR3, whose cognate chemokines are CXCL9/MIG, CXCL10/IP-10, and CXCL11/I-TAC. Little is known about expression of these chemokines in lymph node (LN) metastases of melanoma. We evaluated whether metastatic melanoma induces these CXCR3-cognate chemokines in human LN-derived tissues. In addition, as these chemokines can be induced by interferon (IFN), we evaluated whether type I or II IFNs (IFN-alpha or IFN-gamma, respectively) can modulate chemokine expression in an in vitro model of the human tumor microenvironment. Production of CXCL9-11 by melanoma-infiltrated nodes (MIN) was no different than tumor-free nodes; both produced less chemokine than activated LN (sentinel immunized nodes, SIN). These data suggest that melanoma infiltration into LN neither induces nor reduces CXCL9-11. Stimulation with IFN-alpha or IFN gamma increased production of CXCL10-11 from MIN, but not tumor-free node or SIN. IFN-gamma also increased production of CXCL9 in MIN. In IFN-treated SIN, CD14+ cells were the primary source of CXCL9-11, whereas melanoma cells were the source of chemokine in MIN. Melanoma cells in MIN express IFN receptors. Consistent with these observations, multiple human melanoma lines expressed IFN receptors and produced CXCL9-11 in response to IFN treatment. Thus, melanoma infiltration of LN is insufficient to induce the production of CXCL9-11, but melanoma may be a significant source of IFN-induced chemokines. Collectively, these data suggest that IFN-alpha or IFN-gamma may act in the tumor microenvironment to increase the chemotactic gradient for CXCR3+ T cells. PMID- 20948441 TI - Selection of CD8+PD-1+ lymphocytes in fresh human melanomas enriches for tumor reactive T cells. AB - CD8+ tumor-infiltrating lymphocytes (TILs) in human melanomas express high levels of PD-1 and are functionally impaired. However, adoptive cell therapy using in vitro-expanded TIL can be a highly effective therapy for patients with advanced melanoma. This discrepancy led us to further analyze the CD8+PD-1+ TILs. We found that the percentage of PD-1-expressing CD8+ T cells was higher in the tumor digests that generate tumor-reactive TILs after in vitro culture in interleukin-2 (P=0.0007). Also sorted and expanded CD8+PD-1+ T cells in tumor digests showed much higher tumor-specific interferon-gamma production compared with CD8+PD-1- T cells. These results suggested that tumor-specific CD8+ T cells in melanoma tumor digests are largely PD-1, and this population can recover function after culturing in interleukin-2. PD-1 has been reported as an inhibitory receptor on T cells. We found that the in vitro functional suppression of cultured-TILs from native levels of PD-L1 expression on melanomas was minimal, and moreover expression level of PD-1 on CD8+ tumor-specific TILs decreased during the culture. As a consequence, the PD-1 receptor can be a useful biomarker for enriching tumor-specific T cells from fresh melanomas. PMID- 20948442 TI - Gene expression analysis of ex vivo expanded and freshly isolated NK cells from cancer patients. AB - The infusion of natural killer (NK) cells is a promising therapy for patients with advanced malignancies. Clinical expanded NK-cell products were compared with freshly isolated NK cells. Autologous peripheral blood mononuclear cells were collected by apheresis from 8 patients. NK cells were isolated by anti-CD3 negative selection followed by anti-CD56-positive selection. They were then expanded by co-culture with interleukin-2 and an irradiated Epstein-Barr virus (EBV)-transformed lymphoblastoid cell line (EBV-TM-LCL) to produce 14 NK-cell products. Molecular changes in the 14 NK-cell products were characterized using gene and microRNA expression microarrays. EBV-TM-LCL feeder cells from 3 lots were also analyzed as they were expanded for over 90 days and each lot was used for multiple NK-cell expansions. The gene expression profiles among the 3 EBV-TM LCL lots used showed no differences and were not affected by their time in culture. Freshly isolated and expanded NK cells had distinct gene and microRNA expression profiles. Compared with fresh NK cells, expanded NK cells overexpressed 1098 genes and 28 human microRNAs. Genes in the crosstalk between dendritic and NK cells and metabolic pathways were up-regulated in expanded NK cells, whereas genes in a number of immune function pathways were down-regulated. Among all the most up-regulated genes were the NK cell-activating receptor natural cytotoxicity triggering receptor 3, myxovirus restistance 1, lymphotoxin beta, and BCL2-associated X protein. Although some expanded NK-cell product variability was observed, perhaps related to patient factors, further studies on larger numbers of products will be needed to determine the impact of these differences on clinical outcomes. PMID- 20948443 TI - Delivery of immunostimulatory RNA oligonucleotides by gelatin nanoparticles triggers an efficient antitumoral response. AB - RNA oligonucleotides have emerged as a new class of biologicals that can silence gene expression but also stimulate immune responses through specific pattern recognition receptors. The development of effective delivery systems remains a major challenge for the therapeutic application of the RNA oligonucleotides. In this study, we have established a novel biodegradable carrier system that is highly effective for the delivery of immunostimulatory RNA oligonucleotides. Formulation of RNA oligonucleotides with cationized gelatin nanoparticles potentiates immune activation through the Toll-like receptor 7 (TLR7) in both myeloid and plasmacytoid dendritic cells. Further, nanoparticle-delivered RNA oligonucleotides trigger production of the antitumoral cytokines IL-12 and IFN alpha. Binding to gelatin nanoparticles protects RNA oligonucleotides from degradation by nucleases, facilitates their uptake by dendritic cells, and targets these nucleic acids to the endosomal compartment in which they are recognized by TLR7. In these effects, the nanoparticles are superior to the conventional transfection reagents lipofectamine, polyethylenimine, and DOTAP. In vivo, the delivery of TLR7-activating RNA oligonucleotides by gelatin nanoparticles triggers antigen-specific CD8+ T-cell and antibody responses. Indeed, immunization with RNA-loaded nanoparticles leads to an efficient antitumoral immune response in two different mouse tumor models. Thus, gelatin based nanoparticles represent a novel delivery system for immunostimulatory RNA oligonucleotides that is both effective and nontoxic. PMID- 20948444 TI - Tumor-specific crosslinking of GITR as costimulation for immunotherapy. AB - Activation of murine glucocorticoid-induced tumor necrosis factor-related receptor (mGITR) by its natural ligand (GITRL) or antiGITR agonist mAb enhances T cell responses, inhibits regulatory T-cell (Treg)-mediated suppression and induces tumor immunity in a variety of murine tumor models. However, systemic administration of these costimulatory agents can lead to global T-cell activation and autoimmunity. To specifically manipulate the T-cell compartment in the tumor microenvironment we propose to target the tumor infiltrating T cells with a bispecific mGITRL fusion protein. For that purpose, mGITRL is linked to a single chain antibody targeting fibroblast activation protein (FAP) as FAP expression is restricted to cancer-associated fibroblasts (CAFs) found in the stroma of epithelial cancers. AntiFAP-mGITRL fusion protein forms dimers and binds to murine GITR with 1.2 MUM affinity and to murine FAP with 4.5 nM. The construct is able to costimulate CD8+ and CD4+ effector T cells resulting in increased proliferation, IFN-gamma and IL-2 production. This costimulatory effect is enhanced when the fusion protein is bound to a FAP-positive cell line mimicking FAP CAFs. In suppression assays, membrane-bound antiFAP-mGITRL is 100-fold more effective in overcoming Treg-mediated suppression than unbound fusion protein. These studies suggest that targeted tumor therapy with antiFAP-mGITRL fusion protein could induce tumor rejection while minimizing autoimmune side effects. PMID- 20948445 TI - Health status of patients with Alagille syndrome. AB - OBJECTIVES: The aim of the study was to assess health-related quality of life (HRQOL) in children with Alagille syndrome (AGS) in comparison with a normative population and other chronic diseases, and also to examine the effect of AGS specific morbidities on HRQOL. PATIENTS AND METHODS: A cross-sectional study was performed using the Child Health Questionnaire Parent Form 50 (CHQ-PF50) to measure HRQOL in patients with AGS. AGS HRQOL was compared with that of a normative population and those previously studied by the CHQ, including juvenile rheumatoid arthritis, attention-deficit/hyperactivity disorder, and liver transplantation. AGS-specific questions were used in multiple regression analysis to determine correlation of features and symptoms of AGS with HRQOL. RESULTS: Seventy-one patients with AGS, ages 5 to 18 years, were studied. Those families completing surveys demonstrated that children with AGS had significantly lower HRQOL (P < 0.05) compared with the normative sample. In comparison with children with juvenile rheumatoid arthritis, children with AGS had lower psychosocial function scores (P < 0.0005). In comparison with children with attention deficit/hyperactivity disorder, children with AGS had lower physical function scores (P < 0.0005) but higher psychosocial function scores (P < 0.0005). Children with AGS had lower physical function scores than a liver transplant population (P < 0.05). Regression analysis indicated that cardiac catheterization or surgery, mental health diagnoses, and poor sleep were associated with lower CHQ scores in children with AGS. CONCLUSIONS: In the first descriptive report of HRQOL in a large cohort of patients with AGS, HRQOL was impaired, indicating a significant burden of chronic disease in both physical and psychosocial health. Additional prospective evaluation is needed in multicenter collaboration. PMID- 20948446 TI - Lymphoma with central nervous system involvement in a young patient with Crohn disease treated with azathioprine. PMID- 20948447 TI - Use of oral naltrexone for severe pruritus due to cholestatic liver disease in children. PMID- 20948448 TI - Carcinoid tumors of the appendix in children: experience from a tertiary center in northern Greece. AB - BACKGROUND AND OBJECTIVE: Carcinoid tumors of the appendix are rare in childhood and usually have a benign clinical course. Their incidence in appendectomy specimens ranges from 0.1% to 0.9%. The aim of the study was to report the frequency, clinical presentation, tumor characteristics, and outcome of children with appendiceal carcinoid treated in a pediatric oncology department. PATIENTS AND METHODS: All of the cases referred during a 19-year period (1990-2008) were studied retrospectively. Demographics, clinical presentation, tumor characteristics, and follow-up results were recorded. RESULTS: Among 839 admissions, 19 patients (9 boys) with appendiceal carcinoid were identified during the study period. Their median age was 10.5 years (range 4.5-13.2 years). In all of the cases, diagnosis was established after appendectomy. The mean tumor diameter was 4.55 (+/- 3.45) mm (range 1-15 mm). Concomitant appendicitis was diagnosed in 12 patients. In 18 children tumor size was <= 10 mm and did not infiltrate surrounding tissues. In 1 patient the size was 15 mm and a microscopic rupture of the appendix with infiltration of the surrounding fat was present. All of the tumors were located at the tip of the appendix and were of the classic histological type. Staging and follow-up consisted of abdominal ultrasound, chest and abdominal computed tomography scans, Tc bone scan, urine 5 hydroxylindoloacetic acid levels, and 111In octreotide scan. No patient had metastases requiring further therapeutic interventions. No relapses or other neoplasms occurred during a median follow-up period of 45 months (range 6-118 months). CONCLUSIONS: Carcinoid tumors of the appendix in children are rare. Long term follow-up revealed that a good prognosis is possible provided they are diagnosed and surgically removed at an early stage. PMID- 20948449 TI - The role of arthrography in selecting an osteotomy for the correction of genu varum in pediatric patients with achondroplasia. AB - Genu varum is a common manifestation of achondroplasia. In the pediatric population, determination of the appropriate corrective osteotomy can be challenging because of a large cartilage envelope. To determine whether osteotomy based on radiographs alone corresponded to osteotomy based on arthrography and radiography, we retrospectively studied 41 patients (75 limbs) and identified the appropriate osteotomy based on (i) radiographs alone and (ii) radiographs and arthrography. We found that the osteotomy choice changed in 45 limbs (60.8%) overall and in 34 limbs (94.44%) of patients aged below 8 years. PMID- 20948450 TI - Spontaneous regression of transplacental metastases from maternal melanoma in a newborn: case report and review of the literature. AB - We describe a rare case of transplacental-transmitted maternal melanoma to the placenta and foetus during the second pregnancy of a 28-year-old woman. She was aware of a greyish-brown nodular lesion on the right gluteus during her first pregnancy. On histological examination, this lesion resulted to be an amelanocitic melanoma. Breast metastases occurred during her second pregnancy, 18 months after the surgical excision; an emergency Caesarean section performed for the recrudement of her clinical conditions confirmed widespread metastases to the liver, spleen and peritoneum. The patient died 2 weeks after delivery. The newborn, at 3 months of age, presented metastases secondary to maternal melanoma, which were resistant to chemotherapy. The disease regressed spontaneously and the child is now 24 months, alive in complete remission. PMID- 20948451 TI - No link of serotonin 2C receptor editing to serotonin transporter genotype. AB - RNA editing is a post-transcriptional process, which has the potential to alter the function of encoded proteins. In particular, serotonin 2C receptor (5-HT2cR) mRNA editing can produce 24 protein isoforms of varying functionality. Rodent studies have shown that 5-HT2cR editing is dynamically modulated in response to environmental challenges. Basal extracellular serotonin, which is strongly influenced by serotonin transporter (SERT), was proposed as a potential trigger for this modulation; however, the data remain inconclusive. Here, 5-HT2cR editing is evaluated in SERT mutant versus wild-type rats, and in humans with different SERT genotypes. Our findings argue against the hypothesis that 5-HT2cR editing efficiency is regulated by extracellular serotonin levels. PMID- 20948452 TI - Biodistribution and radiation dosimetry of the hypoxia marker 18F-HX4 in monkeys and humans determined by using whole-body PET/CT. AB - OBJECTIVES: F-HX4 is a novel positron emission tomography (PET) tracer for imaging hypoxia. The purpose of this study was to determine the biodistribution and estimate the radiation dose of F-HX4 using whole-body PET/computed tomography (CT) scans in monkeys and humans. METHODS: Successive whole-body PET/CT scans were done after the injection of F-HX4 in four healthy humans (422+/-142 MBq) and in three rhesus monkeys (189+/-3 MBq). Biodistribution was determined from PET images and organ doses were estimated using OLINDA/EXM software. RESULTS: The bladder, liver, and kidneys showed the highest percentage of the injected radioactivity for humans and monkeys. For humans, approximately 45% of the activity is eliminated by bladder voiding in 3.6 h, and for monkeys 60% is in the bladder content after 3 h. The critical organ is the urinary bladder wall with the highest absorbed radiation dose of 415+/-18 (monkeys) and 299+/-38 MUGy/MBq (humans), in the 4.8-h bladder voiding interval model. The average value of effective dose for the adult male was estimated at 42+/-4.2 MUSv/MBq from monkey data and 27+/-2 MUSv/MBq from human data. CONCLUSION: Bladder, kidneys, and liver have the highest uptake of injected F-HX4 activity for both monkeys and humans. The urinary bladder wall receives the highest dose of F-HX4 and is the critical organ. Thus, patients should be encouraged to maintain adequate hydration and void frequently. The effective dose of F-HX4 is comparable with that of other F based imaging agents. PMID- 20948453 TI - Immunogenicity and safety of an investigational combined haemophilus influenzae type B-Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine. AB - BACKGROUND: Neisseria meningitidis serogroups B, C, and Y cause most meningococcal disease in industrialized countries. A Haemophilus influenzae type b-meningococcal serogroups C and Y-tetanus toxoid conjugate vaccine (HibMenCY-TT) was evaluated. METHODS: A total of 1104 infants (randomized 3:1:1) were vaccinated at 2, 4, and 6 months with HibMenCY-TT, MenC-CRM197 + Hib-TT, or Hib TT. At 12 to 15 months, HibMenCY-TT and MenC-CRM-primed children received HibMenCY-TT; Hib-TT-primed received N. meningitidis serogroup B Hib-outer membrane protein complex. Antibody concentrations and rabbit/human complement serum bactericidal antibody titers (rSBA/hSBA) were determined. Safety was monitored after each dose (diary cards for first 31 days) until 6 months postdose 4. RESULTS: Postdose 3, rates of antipolyribosylribitol phosphate >= 1 MUg/mL and rSBA-MenC >=1:128 in HibMenCY-TT recipients were noninferior to licensed controls. Percentages reaching 0.15 MUg/mL (1.0 MUg/mL postdose 3) and antipolyribosylribitol phosphate GMC were significantly higher after HibMenCY-TT than Hib-TT postdose 2 and postdose 3. The GMC remained significantly higher before and after dose 4. Proportions of HibMenCY-TT recipients with rSBA >= 1:8 were 95.6% (MenC), 98.6% (MenY) postdose-2, >= 99% for MenC/Y postdose 3 and 4; hSBA >= 1:4 were 95.5% (MenC), 89.8% (MenY) postdose 2, >97% for MenC/Y postdose 3 and 4. HibMenCY-TT had a similar safety profile to control vaccines. CONCLUSIONS: HibMenCY-TT induced noninferior Hib and MenC responses compared with monovalent Hib and MenC conjugates with a comparable safety profile. Bactericidal antibodies against MenC/Y were induced after 2 doses of HibMenCY-TT. PMID- 20948454 TI - Human parechovirus 3 causing sepsis-like illness in children from midwestern United States. AB - BACKGROUND: : Human parechovirus (HPeV) infections of the central nervous system (CNS) in children can be associated with severe outcomes such as neonatal sepsis like illness, meningitis, or paralysis. We sought to determine the prevalence of HPeV CNS infections and clinical presentation in children from the United States. METHODS: : Frozen nucleic acid extracts from enterovirus-negative cerebrospinal fluid (CSF) obtained at the Children's Mercy Hospitals and Clinics, in Kansas City from 2006 (n = 242), 2007 (n = 324), and 2008 (n = 218) were tested by 2 step HPeV real-time reverse transcription polymerase chain reaction. HPeV genotype was determined by sequencing the VP3/VP1 junction. Demographic and clinical data were abstracted from medical records. RESULTS: : Overall HPeV was detected in 58/780 (7%) of tested CSF samples; 4/218 (2%) in 2006, 54/320 (17%) in 2007, and 0/242 (0%) in 2008. HPeV (17%) and enterovirus (20%) detection were comparable in 2007. HPeV-3 genotype was detected in 52/53 specimens successfully sequenced. Detection was seasonal (June-October). HPeV-3-CNS-infection occurred at a mean age of 6.6 +/- 4.4 weeks and predominantly in males (71%). The most common clinical presentation was sepsis-like syndrome (66%). The most common symptoms were irritability (98%), fever (95%), and nonspecific rash (58.6%), while neurologic manifestations were rare (5%). CONCLUSIONS: : To our knowledge, this is the first multiyear prevalence report of HPeV CNS infection in the United States. HPeV CNS infection was detected mostly in male infants with sepsis-like illness during the late summer/autumn season. Routine seasonal CSF testing in infants for HPeV plus enterovirus may improve etiologic detection and clinical management of infantile sepsis-like presentations. PMID- 20948455 TI - Nasal Staphylococcus aureus colonization among mothers of term and late preterm previously healthy neonates with community-acquired Staphylococcus aureus infections. AB - We enrolled 35 case neonates with community-acquired Staphylococcus aureus infection and their mothers and 19 control mother-neonate pairs. We obtained neonatal and maternal anterior nasal cultures, and clinical isolates. S. aureus nasal colonization was greater in case than control pairs. Neonates were more often infected with their nasal strain than their mother's nasal strain. PMID- 20948456 TI - Acute rheumatic fever associated with household crowding in a developed country. AB - BACKGROUND: Acute rheumatic fever (ARF) and its sequelae, chronic rheumatic heart disease, remain important causes of morbidity and mortality worldwide, but there is little recent information about risk factors. The aim of this study was to examine the association between ARF and household crowding in New Zealand between 1996 and 2005. METHODS: This ecologic study used hospitalization data and census data to calculate incidence rates by census area unit (CAU). Rates of ARF were examined in relation to individual factors (age, ethnicity) and area factors based on the CAU of home address (household crowding, New Zealand deprivation index, household income, and proportion of children aged 5-14 years). The multivariate relationship between ARF incidence and CAU-based variables was assessed using a zero-inflated negative binomial model. RESULTS: This study included 1249 new cases of ARF between 1996 and 2005. At the univariate level, ARF rates were associated with household crowding across all age groups and ethnicities. ARF rates were significantly and positively related to household crowding after controlling for age, ethnicity, household income, and the density of children in the neighborhood. The incidence rate ratio was 1.065 (95% confidence interval, 1.052-1.079) for the total population. CONCLUSIONS: In New Zealand, ARF rates are associated with household crowding at the CAU level. This finding supports action to reduce household crowding to improve health and reduce health inequalities. Our conclusion could be further investigated using a case control study. PMID- 20948457 TI - Primary care pediatricians' perceptions of vaccine refusal in europe. AB - An electronic survey assessing primary care pediatricians' estimations and practices regarding parents' vaccination refusal was sent to 395 members of the European Academy of Pediatrics Research in Ambulatory Setting network, with a response rate of 87%. Of respondents who vaccinate in the clinic, 93% estimated the total vaccine refusal rate as <1%. Of all respondents, 69% prefer a shared decision-making approach to handle refusing parents. PMID- 20948458 TI - Photodynamic therapy, ranibizumab, and ranibizumab with photodynamic therapy for the treatment of polypoidal choroidal vasculopathy. AB - PURPOSE: The purpose of this study was to compare photodynamic therapy (PDT), ranibizumab, and ranibizumab with PDT in polypoidal choroidal vasculopathy. METHODS: In this retrospective comparative study, 30 eyes of 30 patients with polypoidal choroidal vasculopathy were assigned to 1 of the 3 groups. The patients in Group 1 (n = 11) received 1 session of PDT. The patients in Group 2 (n = 10) received 3 monthly intravitreal injections of 0.5 mg ranibizumab, and the patients in Group 3 (n = 9) received 1 session of PDT and 3 injections of 0.5 mg ranibizumab. Retreatment, with the same therapeutic scheme in each group, was considered in case of leaking polyps on the indocyanine green angiography in Groups 1 and 3 and persistence or recurrence of subretinal fluid, intraretinal fluid, and/or hemorrhages in Group 2. RESULTS: All the patients completed 12 months of follow-up. The visual acuity in the patients of Group 1 improved by 0.25 logarithm of the minimum angle of resolution units (P < 0.001), whereas the differences in the visual acuity in the other 2 groups were not statistically significant (0.04 logarithm of the minimum angle of resolution, P = 0.8118 in Group 2 and 0.18 logarithm of the minimum angle of resolution, P > 0.05 in Group 3). Of the patients in Group 1, 45.45% gained more than 3 lines (P = 0.0056), whereas no patient in Groups 2 and 3 experienced such a difference. No patient in Group 1 and 11.1% (n = 1) in Group 3 had angiographically evident polyps at 12 months, whereas 90% (n = 9) of the patients in Group 2 had persistent leakage. No extensive submacular hemorrhage or other complications were noted during the follow-up period. CONCLUSION: Photodynamic therapy resulted in a significantly better outcome at the end of the follow-up, whereas the patients who received ranibizumab or PDT and ranibizumab experienced a stabilization of the disease. PMID- 20948459 TI - Ocular side effects associated with peribulbar injections of triamcinolone acetonide for diabetic macular edema. AB - PURPOSE: To evaluate long-term effects of anterior and posterior peribulbar injections of triamcinolone acetonide on intraocular pressure (IOP) elevation and cataract development. METHODS: This study reports on IOP and cataract progression through 2 years in 96 eyes with diabetic macular edema randomized to focal/grid photocoagulation, 20 mg triamcinolone acetonide anterior injection, anterior injection followed by laser, 40 mg triamcinolone acetonide posterior injection, or posterior injection followed by laser. RESULTS: Intraocular pressure increased from baseline by >= 10 mmHg at >= 1 visit through 2 years in 2 eyes (8%) in the laser group, 11 eyes (31%) in the anterior groups, and 6 eyes (17%) in the posterior groups. Among phakic eyes at baseline, 0, 5 (17%), and 1 (3%) in the 3 groups, respectively, underwent cataract surgery before the 2-year visit. CONCLUSION: Based on this small randomized trial, it appears that over 2 years, anterior peribulbar triamcinolone acetonide injections are associated with an increased incidence of IOP elevation and an increased risk of cataract development compared with laser or posterior peribulbar injections. The association of posterior injections with IOP elevation is less certain. Although the study involved eyes with diabetic macular edema, the results should be relevant to other conditions treated with peribulbar corticosteroids. PMID- 20948460 TI - Subfoveal choroidal thickness after treatment of Vogt-Koyanagi-Harada disease. AB - PURPOSE: To evaluate the subfoveal choroidal thickness in Vogt-Koyanagi-Harada (VKH) disease using enhanced depth imaging optical coherence tomography. METHODS: Retrospective observational study. Subfoveal choroidal thickness was measured using enhanced depth imaging optical coherence tomography, in which the optical coherence tomography instrument was placed close enough to the eye to obtain an inverted image, which was averaged for 100 scans. All patients were diagnosed as having the ocular findings of VKH disease with or without extraocular disorders. The patients were followed during their initial treatment with corticosteroids. RESULTS: All 8 patients (16 eyes) with acute phase VKH disease presented with thickening of the choroid. The serous retinal detachment disappeared in 1 month after corticosteroid treatment. The mean choroidal thickness in 16 eyes decreased from 805 +/- 173 MUm at the first visit to 524 +/- 151 MUm at 3 days (P < 0.001) and 341 +/- 70 MUm by 2 weeks (P < 0.001). CONCLUSION: Patients with active VKH disease have markedly thickened choroids, possibly related not only to inflammatory infiltration but also to increased exudation. Both the choroidal thickness and the exudative retinal detachment decreased quickly with corticosteroid treatment. Enhanced depth imaging optical coherence tomography can be used to evaluate the choroidal involvement in VKH disease in the acute stages and may prove useful in the diagnosis and management of this disease noninvasively. PMID- 20948461 TI - Posterior multilevel vertebral osteotomy for severe and rigid idiopathic and nonidiopathic kyphoscoliosis: a further experience with minimum two-year follow up. AB - STUDY DESIGN: Prospective randomized study. OBJECTIVE: To evaluate the clinica! and radiologic outcome of posterior multilevel vertebral osteotomy (PMVO) in patients with severe kyphoscoliosis. SUMMARY OF BACKGROUND DATA: Authors have developed and reported results of PMVO for correction of neuromuscular scoliosis. PMVO has advantages such as, posterior-only procedure which avoids risk to pulmonary complications and gives satisfactory correction. However, its effect in correcting severe scoliosis in presence of rigid kyphosis has not been reported. METHODS: Thirteen patients (7 idiopathic, 4 cerebral palsy, and 2 congenital scoliosis) with severe and rigid kyphoscoliosis were operated by posterior-only correction with pedicle screw fixation using PMVO. As per pathology, and associated severity of kyphosis little modification in the original technique was applied while correction and osteotomy. Neuromonitoring was applied in all patients during operation. The radiologic and clinical results were evaluated with an average follow-up of 42.9+/-11 months. All postoperative complications were also noted during the follow-up period. RESULTS: Average number of osteotomy was 4.2+/-0.8 (range, 3-5). Average preoperative Cobb angle, pelvic obliquity, thoracic kyphosis, and lumbar lordosis were 99.2 degrees +/-29.6 degrees , 8.6 degrees +/-9 degrees , 73.6 degrees +/-56.9 degrees , and -47.2 degrees +/-63.2 degrees , respectively, which improved after surgery to 44.7 degrees +/-12.3 degrees , 2.8 degrees +/-2.9 degrees , 45.3 degrees +/-15.9 degrees , and -47.7 degrees +/-12.2 degrees . All corrections were maintained at final follow-up. A 54.3% correction was achieved in coronal plane; and, full correction was achieved in sagital plane as thoracic kyphosis was restored within normal range. Average blood loss and operative time was 3015+/-1213 mL and 6.01+/-1.09 hours, respectively. Three patients had postoperative respiratory complications; 2 had hemothorax and 1 had atelectasis; none had follow-up consequences. All pulmonary complications were due to associated thoracoplasty during which pleura was ruptured intraoperatively. Two patients had complication related with the implants; 1 screw breakage and other screw prominence. There was no neurologic injury intraoperatively on motor-evoked po- tentials (MEP) or clinically after surgery. CONCLUSION: PMVO exhibited satisfactory clinical and radiologic results in patients with severe and rigid scoliosis associated with hyperkyphosis at minimum 2-year follow-up. It can be safely applied with modifications in original technique for complex congenital scoliosis with multilevel hemi or block vertebrae and idiopathic/nonidiopathic spinal deformities. PMID- 20948463 TI - Robot-assisted anterior lumbar interbody fusion in a Swine model in vivo test of the da vinci surgical-assisted spinal surgery system. AB - STUDY DESIGN: the use of the da Vinci Surgical System to perform an anterior lumbar interbody fusion in a swine model to identify the technical properties, processes, merits, demerits, and limitations of a video-assisted robotic surgical system. OBJECTIVE: this study was designed to demonstrate the feasibility of using a robotic surgical system to perform spinal surgery. SUMMARY OF BACKGROUND DATA: video-assisted laparoscopic anterior fusion was first reported in 1995 and afterward was spotlighted for several years. However, this technique has not become popular because of technical difficulties and complications associated with video-assisted procedures on the spine. As such, there is a demand for investigations to improve this technology. The da Vinci Surgical System provides 3-dimensional visualization as well as uniquely dexterous instruments that are remarkably similar to human hands. Video-assisted surgery with the da Vinci Surgical System robot has already provided great value to the fields of urology, cardiology, gynecology, and general surgery over the last decade. Preclinical studies for application of this system in spinal surgery have recently been conducted. METHODS: a pig underwent anterior lumbar interbody fusion using da Vinci Surgical System assistance, with Tyche expandable cages used for preparation of endplates and cage placement. The setup time, operation time, amount of bleeding, and the number of complications associated with robotic manipulation were recorded. Before euthanasia, the animal underwent radiologic examination to confirm proper placement of cages. RESULTS: the total duration of the procedure took 6 hours, with some complications related to frozen armsand robotic arm collision. Even so, there was neither any significant nerve or vessel injury nor peritoneal organ damage. Furthermore, radiologic assessment confirmed proper position of the cage in the center of the disc space. CONCLUSION: use of the da Vinci Surgical System to perform an anterior spinal procedure was shown to be safe and effective in a swine animal model. The utilization of this advanced technology shows promise to reduce the incidence of complications compared with other approaches. It requires further testing in animal models and cadavers, along with serial comparisons to current procedures. PMID- 20948464 TI - The effect of irradiation and methylprednisolone in spinal cord injured rats. AB - STUDY DESIGN: This study investigated the outcome of combined therapy with irradiation and methylprednisolone (MP) after a traumatic spinal cord injury (SCI). OBJECTIVE: To evaluate the neurologic outcomes as well as the antiapoptotic and anti-inflammatory effects on traumatic SCI in rats after combined therapy. SUMMARY OF BACKGROUND DATA: Although irradiation carries the risk of secondary SCI, it has been effective for the regeneration of the axons of nerve cells by reducing gliosis. Thus, to minimize apoptosis and irradiation risks after SCI, this study investigated the effects of steroid injections before irradiation. METHODS: Thirty-two rats were used for the experimental procedure. After a traumatic SCI, they were divided into 4 groups of 8 rats each: (1) a control group that only had rats with a SCI (Group 1); (2) a group that received MP at 30 minutes, 6 hours and 24 hours, and then received irradiation 2 days after the SCI (Group 2); (3) a group that received MP at 30 minutes, and irradiation 2 days after the SCI (Group 3); and (4) a group that received irradiation 2 days after the traumatic SCI (Group 4). RESULTS: The degree of recovery using the inclined plane climbing test was greatest in Group 2, followed by Group 3, Group 4, and Group 1. The cavitation lesions, Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling -positive apoptosis, glial fibrillary acidic protein-positive astrocyte count, and CC-1-positive oligodendrocyte count significantly decreased in the irradiated groups (Groups 2, 3, 4) compared to the control group (Group 1). In particular, they decreased considerably more in the group that received MP 3 times (Group 2) compared to the group that received MP only once (Group 3). CONCLUSION: These results suggest that the combined therapy was effective and might provide synergistic effects for neurologic recovery after a traumatic SCI. PMID- 20948465 TI - Prolonged upright posture induces degenerative changes in intervertebral discs of rat cervical spine. AB - STUDY DESIGN: An in vivo study of the cervical intervertebral discs (IVDs) response to upright posture was performed using an amputated bipedal rat model. OBJECTIVE: To investigate the effects of upright posture on IVDs of rat cervical spine. SUMMARY OF BACKGROUND DATA: The distinct arrangement of human neck muscle from that of cat and rhesus indicated that in the evolution process, upright posture might have affected cervical spine of human ancestors. However, the effects of upright posture on cervical spine have not been assessed. METHODS: Forty-one-month-old rats were randomly divided into 5-month-control, 5-month surgery, 7-month-control, and 7-month surgery group (n = 10 per group). Both forelimbs of 2 surgery group rats were amputated, and those rats were then induced to be upright in the custom-made cages. Two control group rats were kept in regular cages. These rats were respectively killed at the fifth and seventh month after surgery and the IVD samples of lumbar spine were harvested for histologic and immunohistochemical studies. Total RNA isolated from these samples were used for real-time polymerase chain reaction of type II collagen (Col2a1), type X collagen, matrix metalloproteinase 13 (MMP-13), MMP-3, aggre-can, and aggrecanase-2 (ADAMTS-5). RESULTS: Upright posture affects histologic changes of the cervical IVDs such as fissures of anulus fibrosus and decreased height of disc, decreased protein level of Col2a1 at nucleus pulposus and anulus fibrosus, up-regulated MMP-13, MMP-3, ADAMTS-5, and type X collagen mRNA expression, and downregulated mRNA expression of Col2a1 and aggrecan. CONCLUSION: Upright stance accelerates cervical disc degeneration in rats. PMID- 20948466 TI - A game of cat and mouse. PMID- 20948467 TI - Brief interventions: a useful tool for stroke nurses. PMID- 20948468 TI - Home enteral tube feeding in older people: consideration of the issues. AB - The demand for acute medical services for older people has risen in recent years and increasing numbers of older people are having enteral feeding tubes placed to ensure they receive appropriate levels of nutrition and fluid safely once oral diet becomes unsafe or insufficient. However, their care may be complicated by cognitive or functional deterioration as a result of comorbidities and polypharmacy. Consequently, providing enteral tube feeding in the community, once the patient is discharged from hospital, may not be straightforward. There are a number of benefits to providing enteral feeding at home; however, problems will arise if appropriate training and aftercare are not provided. This article will address some of the issues that arise when patients who require home enteral feeding are discharged from hospital into their own homes, or into a care home, and examines the knowledge that is required to enable the patient and/or carer to safely manage the feeding tube and feeding regimen, and addresses some of the more common problems that may arise. PMID- 20948469 TI - An examination of the relationship between breakfast, weight and shape. AB - In recent years, the number of people described as being either overweight and obese has increased dramatically, and especially among children. Breakfast has long been recommended as part of a healthy diet and, for some time, evidence has been accumulating that people who eat breakfast regularly are slimmer than those who skip breakfast. This article examines the supporting evidence for this claim, in both adults and children, and discusses the importance of a healthy diet and plenty of exercise, as well as methods the nurse can use to help patients remain aware of their shape and weight. PMID- 20948470 TI - Vitamin D: the sunshine vitamin. AB - Vitamin D has recently attracted a considerable amount of media attention. This article investigates whether the notion of a widespread vitamin D deficiency is justified in the UK, and what effect it might have on the general populace. Also considered are which physiological systems vitamin D affects in addition to bone remodelling, as well as the latest findings as to how this vitamin can benefit the body. Reasers are also given information as to which medications might adversely affect vitamin absorption, which patient groups are most at risk of deficiency, and the most practical and cost-effective means to treat patients suffering from a lack of vitamin D. PMID- 20948472 TI - Recognizing the evidence and changing practice on injection sites. AB - Evidence-based practice requires the integration of the best available evidence in conjunction with clinical expertise to make decisions about patient care. At times new research and evidence will contradict established or traditional methods and clinical textbooks: this is in the nature of progress, and the challenge lies in disseminating this new evidence throughout the profession as quickly and widely as possible. The nursing literature cites a number of barriers to evidence-based nursing, and notes that the research evidence for clinical practice utilization does not always percolate down to the clinical setting. This article considers the attitudes of nurses to evidence that challenges traditional practice, focusing in particular on conventional and contemporary best practice regarding injection sites. Nurses in clinical practice continue to use and instruct student nurses in the use of the dorsogluteal (the large gluteal muscle in the buttocks) injection site as the site of choice for intramuscular injections, despite abundant evidence regarding the complications associated with using this site. Advancing the use of the ventrogluteal (located in the hip) injection site is a challenge, primarily owing to nurses' lack of familiarity with its anatomical landmarks and the published evidence on its benefits. The authors of this article present the current evidence on the dorsogluteal and ventrogluteal intramuscular injection sites in an attempt to assist nurse decision-making and guarantee the integration of evidence-based knowledge in order to improve patient care. PMID- 20948471 TI - Respiratory practitioners' experience of end-of-life discussions in COPD. AB - The importance of palliative care and implementing end-of-life tools nationally is well recognized, yet inequalities in care between patients with malignant and non-malignant disease are well documented. There is little evidence that open discussions regarding end-of-life decision-making are taking place routinely with patients who have non-malignant disease, so it seemed appropriate to investigate health professionals' perspectives. AIM: This study aimed to explore and provide insight into respiratory health professionals' experiences of their discussions with patients with life-limiting chronic obstructive pulmonary disease (COPD). METHOD: A qualitative phenomenology approach was used. In-depth, face-to-face interviews were conducted with a purposive sample of three respiratory nurses, two lung cancer nurse specialists, and two respiratory physicians. FINDINGS: The seven in-depth interviews were thematically analysed so that the data could be categorized. The themes that emerged were: choosing the right time; the skill of picking up and receiving cues; deciding when, what and how to tell; boundaries to discussion; and working with emotions. CONCLUSIONS: The main findings highlighted the difference in approach in discussions between patients with cancer and those with non-malignant disease. The emotional phenomena that emerged could have significant implications for clinical practice. The findings suggest that the emotional dimension plays a crucial part in engaging with patients and involving them in end-of-life care planning. PMID- 20948473 TI - Thromboprophylaxis awareness among hospital staff. AB - AIM: Following the introduction of thromboprophylaxis risk assessment tools at Southampton University Hospitals Trust in April 2008, this audit aimed to assess the level of understanding for correct thromboprophylaxis use for patients among hospital staff within the trust. METHODOLOGY: 50 members of staff, including doctors, nurses and pharmacists, chosen at random, were surveyed using a questionnaire. They were asked whether they thought venous thromboembolism was a problem among hospital patients; their awareness of the current prevention tools in the trust; whether they complete the assessment labels in patients' admission notes; and whether they have seen incorrect use of thromboprophylaxis and had they taken appropriate action to correct the errors. OUTCOMES/RESULTS: The authors found that while the general level of awareness for thromboprophylaxis is good within the organization, compliance with the Trust guidelines was inadequate at 32%, resulting in high levels of inappropriate thromboprophylaxis use which is poorly recognized by staff. In particular, there is a lack of participation from nursing staff owing to a lack of motivation and confidence. Only half of the doctors surveyed completed thromboprophylaxis assessment labels on patients' admission notes; all were junior doctors. Pharmacists were generally better at recognizing and correcting errors in thromboprophylaxis prescription compared with doctors. CONCLUSIONS: It is clear from this audit that staff knowledge and attitudes to thromboprophylaxis must be improved further by reinforcing educational programmes for both medical and non-medical health professionals. A thromboprophylaxis lead should be appointed for each professional group to ensure efficient monitoring. Teaching should be extended to patients to ensure individualized care for all. PMID- 20948474 TI - Early warning scoring systems: observation of care in practice. AB - This article describes the outcomes of an observation of care in an acute setting undertaken as part of the Royal College of Nursing Clinical Leadership Programme. Positive responses of staff and managers to the findings and a subsequent education programme have ensured that the use of early warning scores, and indeed early interventions, have been implemented with consequent improvements in patient care. PMID- 20948475 TI - Using vignettes to explore work-based learning: part 2. AB - This is the second of two articles exploring the use of vignettes as an alternative method of presenting the data arising from interviews. The interviews were carried out as part of research into work-based learning: both articles are based on findings from a hermeneutic phenomenological study into the lived experience of foundation degree mentors and their students-healthcare assistants undertaking a foundation degree in health and social care in order to become assistant practitioners. Part 2 presents a vignette of a notional assistant practitioner, Michelle, that describes her lived experience as a foundation degree student. Michelle's perspective is a distillation of data arising from interviews with 11 former foundation degree students. The vignette attempts to demonstrate the features of 'knowing' and 'becoming' in the practice of foundation degree students, and the impact that being a work-based learner has on students' perceptions of lifelong learning. PMID- 20948477 TI - A perspective on changing dynamics in nursing over the past 20 years. AB - The quest to provide individuals with good quality health care has been a long term goal in which the contribution of health professionals, specifically nurses, has been vital. However, over the years ever-increasing demands from both the government and the general public for higher levels of performance, combined with problems associated with the long-standing issue of staff shortages, and the constant drive for cost-effectiveness, has meant achieving this objective has become more difficult. PMID- 20948478 TI - The bonfire of the regulators: a phoenix from the ashes? AB - Jean McHale considers the implications of the Government's recent report, Liberating the NHS: Report of the arm's-length bodies review. The report proposes to abolish a number of regulatory and other arm's-length bodies: does this restructuring offer an opportunity to rationalize the regulation of medical research in the UK? PMID- 20948479 TI - The Government's eight-point plan for improving end-of-life care. AB - Professor Alan Glasper appraises the Government's end-of-life care strategy, and highlights the key part nurses will play in improving care for the growing number of people approaching end of life in the UK. PMID- 20948480 TI - 'Reality shock' and burnout among nurses. PMID- 20948481 TI - Cuts and consequences. PMID- 20948482 TI - The importance of effective catheter securement. AB - This article examines the importance of securing/fixing indwelling urinary catheters. The Oxford English dictionary interlinks the two words-'secure' and 'fix'-as having the same meaning. To secure the catheter should not be confused with 'support', whereby the weight of the urine drainage bag is supported with the use of velcro straps or a sleeve. The author introduces the need for the concept of this practice to be at the forefront of nurses' minds in all settings, and this is demonstrated through the use of case studies. Current guidance in this area is reviewed, as well as the problems that can arise when catheters are not secured properly and the available products for health professionals to use. PMID- 20948483 TI - Continence myths: the need for evidence-based practice. PMID- 20948484 TI - The management of stress urinary incontinence. AB - This article examines the issues of stress urinary incontinence (SUI) in women and a new treatment option now available; FemSoft, an intraurethral insert. SUI is the most common type of urinary incontinence in women. There are many causes, risks and predisposing factors that nurses need to be aware of, both in treating the complaint and preventing future episodes. As incontinence causes a high level of embarrassment, patients are reluctant to seek help, so when the patient presents, nurses need to be able to provide accurate information on all treatments available. A brief description will be given of other management options, but the main focus will be on FemSoft, describing its features, benefits and research evidence so far. PMID- 20948485 TI - Documented adherence to standards and guidelines: an audit. AB - The authors conducted a cross-sectional audit within Newcastle-upon-Tyne Hospitals NHS Foundation Trust to determine the prevalence of urethral catheterisation and documented adherence to relevant NHS standards. An on-line audit questionnaire was completed for all 80 inpatient wards within the Trust on a single day during the third week in June 2009. The tool collected data on prevalence and care requirements detailed in the Department of Health's (DH) Saving Lives High Impact Intervention 6 (2007). Data were analysed using Snap survey software. Overall, 172 of 1187 (14.5%) inpatients were catheterized and all were using a closed drainage system or catheter valve. Evidence of correct continuing catheter care was documented for 168 (98%) patients, while details of catheter insertion were identified in 153 (89%) patient records. Eight (4.5%) patients were being treated for a urinary tract infection. The authors found satisfactory adherence to basic documentation standards with regard to catheter care. This was associated with a low prevalence rate of catheterization and catheter-associated urinary infection within the Trust relative to previously published figures. Details of catheter insertion were missing from 10% of patient records, requiring further development of accessible and transferable documentation tools. Provision of relevant information to patients is also a target for development. PMID- 20948486 TI - Effective evidence-based intermittent self-catheterization: an update. PMID- 20948488 TI - Let's listen and learn from our patients. PMID- 20948487 TI - RCT of urethral versus suprapubic catheterization. AB - OBJECTIVE: To compare the use of intermittent urethral catheterization with indwelling suprapubic catheterization in women undergoing surgery for urodynamic stress incontinence or uterovaginal prolapse. DESIGN: Randomized controlled trial. SETTING: Tertiary referral urogynaecology unit. POPULATION: Women undergoing surgery for pelvic organ prolapse and/or stress urinary incontinence. METHODS: Women were randomized into one of two groups. Group 1 had bladder drainage using a suprapubic catheter inserted in theatre. The catheter was left on free drainage for 48 hours post-operatively before clamping. Group 2 was catheterized intermittently post-operatively. MAIN OUTCOME MEASURES: Length of post-operative hospital stay: time to resume normal voiding (defined as voided volumes greater than 200 mls and residual urine volumes less than 100 mls on three occasions); number of urinary tract infections (UTIs); catheterization costs; patient experience (determined from questionnaire); and a pain score. RESULTS: 75 women were randomized; 38 to suprapubic catheterization; 37 to intermittent catheterization. Three were withdrawn from study, leaving 36 women in each group. Groups were closely matched for age and type of surgery undertaken. Length of hospital stay and total duration of catheterization were both significantly shorter for the intermittent catheterization group; although there was no difference in the rate of UTI between the two groups. There was no clear patient preference for a specific catheterization method. CONCLUSIONS: The use of intermittent catheterization following urogynaecological surgery is associated with a more rapid return to normal micturition and a shorter hospital stay, although the clinical significance of the difference is perhaps limited. PMID- 20948489 TI - Effect of elasticity on subbandage pressure of three layer tubular compression bandages in healthy volunteers: a RCT. AB - OBJECTIVE: To estimate the difference between mean interface sub-bandage pressures of two multilayer compression bandage systems in healthy volunteers when supine, standing, exercising and during recovery. METHOD: Inelastic and elastic compression bandages were randomised to opposite limbs of each participant. Sub-bandage interface pressures for both bandages were compared within person. Participants and study staff were aware of the treatment. A pressure transducer measured sub-bandage pressures on the medial aspect of the lower leg, at the transition of the gastrocnemius muscle into the Achilles tendon (B1). The difference in interface pressure for the two different compression bandages was measured at level B1 during supine resting, standing, exercise and recovery. We defined the pressure difference between active standing and lying as a measure of stiffness, and amplitude as the range of pressures during plantar flexion while standing. The two bandage systems (inelastic and elastic) were applied from the base of the toes to just below knee and remained in place for the duration of the experiment. Elastic bandage consisted of three layers of graduated tubular bandage (83% cotton, 9% Lycra, 8% polyamide). Inelastic or short-stretch bandage consisted of 100% cotton crepe bandage. RESULTS: Interface sub-bandage pressures varied during different activities, but the mean difference in interface pressures between inelastic and elastic bandages was consistently at least 13 mm Hg. Stiffness was 7.3 mm Hg higher in the inelastic group (95% CI 5.1 9.5). The estimated difference in amplitude of sub-bandage pressure between the bandages during exercise was 15.5 mm Hg (95% CI 12.2-18.9). CONCLUSION: We found in vivo interface sub-bandage pressures varied with the type of bandage and activity phase. Inelastic bandages resulted in an increased mean interface sub bandage pressure when resting and recovering, which was further increased when standing or exercising. Bandage stiffness and amplitude were also greater for inelastic compared with elastic bandages. CONFLICT OF INTEREST: None. PMID- 20948490 TI - A discussion of the potential mechanisms for wound dressings' apparent analgesic effects. AB - Evidence has been developing about the potential analgesic effects of wound dressings. Several theories have been formulated as to how a dressing placed over a wound might contribute to pain relief. This paper reviews these potential mechanisms. In all, 10 are discussed here, most of which will probably overlap, leading to a high degree of complexity and interdependence. The psychological components inherent in the biopsychosocial model of pain make a key contribution to any analgesic effects that occur following dressing application. The 10 mechanisms identified in this paper will need significant and rigorous testing to determine which, if any, can be confirmed as analgesic. PMID- 20948491 TI - Superficial swab cultures in open fracture management: insights from a resource poor setting. AB - OBJECTIVE: To identify bacterial isolates from superficial swabs of open fracture wounds at presentation and after infection has been established, and to determine if there are correlations between them. METHOD: Patients who presented with open fractures at the Wesley Guild Hospital, Ilesa, Nigeria between December 2004 and May 2006 were recruited into this prospective study. Superficial wound swabs were taken at presentation and if patient showed evidence of wound infection. RESULTS: Sixty patients had open fractures. The initial bacteria culture of wound swabs taken on the day of presentation was positive in 41 (68.3%) patients. Of these, 19 (46.3%) yielded one bacteria isolate, 17 (41.5%) yielded two and 5 (12.2%) yielded three, making a total of 68 organisms. The most common organism was Staphylococcus aureus. However, as a group, more aerobic Gram-negative rods were isolated than any other bacteria groups. Eleven (18.3%) patients developed wound infections, all of which were polymicrobial. In 10 (90.9%) of these, the microbial isolate of the final wound swab included at least one organism that was present in the initial wound culture. No patient with an initial negative culture went on to develop a wound infection. The mean presentation interval of patients with wounds that became infected was 15.2 +/- 7.9 hours (95% CI 9.8-20.5 hours) compared with 2.9 +/- 3.1 hours (95% CI 2.0-3.8 hours) for those who did not develop a wound infection (p>0.01). CONCLUSION: In a resource-poor setting, where pre-hospital care is unavailable and patients present late, superficial wound swabs are effective in predicting subsequent organisms that may cause wound infections. CONFLICT OF INTEREST: None. PMID- 20948492 TI - Honey promotes angiogeneic activity in the rat aortic ring assay. AB - OBJECTIVE: To investigate possible effects of honey on angiogenesis, using in vitro analogues of angiogenesis and an endothelial proliferation assay. METHOD: Using an in vitro rat aortic ring assay we compared pseudotubule formation by medicinal honey (Activon), supermarket honey (Rowse) and a honey-based ointment (Mesitran), with that of artificial honey (70% w/w sugar glucose/fructose). Pseudotubules were analysed using TCS Cellworks AngioSys software. The Angiokit sytem was used to validate the results. Using the MTT [3-(4,5-Dimethylthiazol-2 yl)-2,5-Diphenyltetrazolium. Bromide] assay, toxicity was also assessed on human umbilical vein endothelial cells (HUVEC) directly adherent to plastic. RESULTS: All honey preparations stimulated pseudotubule formation, maximal at around 0.2% honey. Medicinal honeys were more active than Rowse. The effect was not attributable to the sugar content. Among the honeys tested, the Manuka-based Activon preparation reduced residual viable biomass compared with a sugar control at > 0.32% v/v concentration. Rowse had a similar effect only at 2.5%, the highest dose tested. CONCLUSION: The influence of honey constituents on angiogenesis in a wound dressing context is likely to be positive, but would depend on the effective dilution of the honey and the penetration of the active constituents against an osmotic gradient. The extent to which this occurs has yet to be established. CONFLICT OF INTEREST: This work was conceived, designed and executed by the authors. Medical honey preparations were supplied unconditionally but free of charge by the distributors. PMID- 20948493 TI - Treatment of symptomatic abnormal skin scars with electrical stimulation. AB - OBJECTIVE: To evaluate the effect of non-invasive biofeedback electrical stimulation on symptomatic abnormal skin scars. METHOD: Thirty patients with over 140 scars with long-term pain and itch were recruited into the study. Patients monitored the intensity of symptoms (pain and itching) on a numerical rating scale. In addition, a modified Manchester scar scale was used to objectively assess digital photographs of each scar in terms of colour, contour, distortion and texture, while a non-invasive spectrophotometric intracutaneous analysis was used to monitor the scars' physical characteristics. RESULTS: The electrical stimulation device resulted in a clinically and statistically significant (p < 0.05) reduction of symptoms and scar scores. Pain and itch scores were both reduced to a median score of 0 by 2 months, from a baseline of 7 and 6 respectively. Scar scores were reduced from a baseline of 14 to a median score of 11 by 2 months. CONCLUSION: These results give a preliminary indication of the potential role of non-invasive biofeedback electrical stimulation in the management of chronic scar pain and itch. However, further large scale controlled studies are warranted to elucidate its overall efficacy and mechanistic action. CONFLICT OF INTEREST: Funding was provided from Fenzian Ltd for this study. PMID- 20948494 TI - Necrotising fasciitis of the cervicofacial region: a bizarre presentation. AB - The following paper presents the case of a middle-aged woman, who presented with a necrotising soft tissue infection of the cervicofacial region with maggots in situ. She was managed with aggressive surgical debridement, but eventually succumbed to the disease because of erosion of the great vessels of the neck by the maggots. The purpose of this case report is to emphasise the severity of this disease and also to present an unusual case, which had a fatal outcome. PMID- 20948495 TI - Negative pressure dressings for severe hidradenitis suppurativa (acne inversa): a case report. AB - Hidradenitis suppurativa (HS) is a frustrating disease to treat for both the patient and the practitioner. In severe cases, aggressive management will often have a more tolerable outcome. We present the case of a 46-year-old gentleman with a long-standing history of severe HS, who was treated successfully with wide surgical excision, followed by a full-thickness skin graft and negative pressure wound therapy (both pre- and post-operatively). A review of the literature revealed few reports of HS treatment using these sequential steps. PMID- 20948496 TI - Two new alkaloids from Narcissus serotinus L. AB - The Amaryllidaceae family is well known for the presence of an exclusive group of alkaloids with a wide range of biological activities. Narcissus serotinus L. is a plant belonging to this family and its geographical distribution is mainly located along the Mediterranean coast. In the present work, specimens collected near Casablanca (Morocco) were used to study the alkaloid content of this species. Starting with 350 g of the whole plant we used standard extraction and purification procedures to obtain fractions and compounds for GC-MS and NMR analysis. As well as five known alkaloids, we isolated two new compounds: 1-O-(3' acetoxybutanoyl)lycorine and narseronine. The latter has been previously published, but with an erroneous structure. PMID- 20948497 TI - Bignoniaceae metabolites as semiochemicals. AB - Members of the family Bignoniaceae are mostly found in tropical and neo-tropical regions in America, Asia and Africa, although some of them are cultivated in other regions as ornamentals. Species belonging to this family have been extensively studied in regard to their pharmacological properties (as extracts and isolated compounds). The aim of this review is to summarize the reported scientific evidence about the chemical properties as well as that of the extracts and isolated compounds from species of this family, focusing mainly in insect plant interactions. As it is known, this family is recognized for the presence of iridoids which are markers of oviposition and feeding preference to species which have became specialist feeders. Some herbivore species have also evolved to the point of been able to sequester iridoids and use them as defenses against their predators. However, iridoids also exhibit anti-insect properties, and therefore they may be good lead molecules to develop botanical pesticides. Other secondary metabolites, such as quinones, and whole extracts have also shown potential as anti-insect agents. PMID- 20948498 TI - A new xanthone from the bark extract of Rheedia acuminata and antiplasmodial activity of its major compounds. AB - Bioassay-guided fractionation of the ethyl acetate bark extract of Rheedia acuminata led to the isolation of the new compound 1,5,6-trihydroxy-3-methoxy-7 geranyl-xanthone, together with four known compounds. These compounds were tested in vitro for their antiplasmodial activity on a chloroquine-resistant strain of Plasmodium falciparum (FcB1) and for their cytotoxicity against the human diploid embryonic lung cell line MRC-5. PMID- 20948499 TI - Inhibitory effects of resveratrol on the Epstein-Barr virus lytic cycle. AB - Reactivation of Epstein-Barr virus (EBV) from latency to the lytic cycle is required for the production of viral particles. Here, we examine the capacity of resveratrol to inhibit the EBV lytic cycle. Our results show that resveratrol inhibits the transcription of EBV immediate early genes, the expression of EBV lytic proteins, including Rta, Zta, and EA-D and reduces viron production, suggesting that this compound may be useful for preventing the proliferation of the virus. PMID- 20948500 TI - Effects of low-dose of niacin associated to simvastatin in the treatment of mixed dyslipidemia Salgad. AB - AIM: The aim of this study was to evaluate the effects of low-dose niacin extended-release (niacin-ER) combined with simvastatin (SV) in the treatment of patients with mixed dyslipidemia who have not normalized their lipid profile with statin therapy alone. METHODS: A prospective, clinical trial of 35 patients with mixed dyslipidemia who were treated with niacin-ER and SV. The dosage administrated were 250 mg niacin-ER plus 10 mg SV in the first two weeks, 500 mg/20 mg in the next two weeks, and 750 mg/20 mg in the final four weeks. Patients received 200 mg of acetylsalicylic acid 30 minutes before each drug administration. RESULTS: There were significant increases of apolipoprotein A-I and HDL; and decrease of apolipoprotein B, LDL, triglycerides, and total cholesterol. There was low frequency of flushing (10%) and no worsening in the control of fasting and postprandial glycemia and glycated hemoglobin. CONCLUSION: Low-dose niacin-ER associated to simvastatin may be useful for achieving improvement in lipid profile or even to achieve the targets recommended for prevention of cardiovascular disease. Other advantages are the low frequency of flushing, which improved adherence to treatment, and no worsening of insulin resistance in patients with or without diabetes mellitus. PMID- 20948501 TI - Positive exercise tolerance test (ETT) on asymptomatic Iranian cases aged over 60 years. AB - AIM: The purpose of this study was to determine the prognostic importance of positive exercise treadmill test (ETT) in predicting coronary artery disease (CAD) among asymptomatic population based on coronary angiographic findings. METHODS: The comparative study was conducted on a sample of over 60-year-old asymptomatic and symptomatic patients referred to our clinics for screening and clinical reasons between September 2006 and September 2007. All subjects with a positive ETT provided information about their cardiovascular risk factors through a validated questionnaire. The relationship between ETT performance and the CAD risk factors with coronary angiography were studied and compared between the two groups. RESULTS: Seven hundred thirty one symptomatic and 160 asymptomatic individuals were enrolled in the study. In the symptomatic group, gender, blood pressure and diabetes were significantly related with the angiographic findings, while blood pressure failed to show such a relation in the asymptomatic group. CONCLUSION: There is an association between positive ETT and the presence of CAD among asymptomatic elderly men but also women with diabetes or high blood pressure. PMID- 20948502 TI - Rehabilitative treatment in peripheral artery disease: protocol application and follow-up. AB - AIM: Peripheral arterial disease (PAD) is a chronic figure suitable to be treated at the II stage to prevent the extreme developments both of the critical limb ischemia and the amputation, as well. The aim of this study was to establish a rehabilitation program (pharmacological and physical) focused not only on the improvement of the flow but also on the metabolic rebalancing in the claudicant limb. METHODS: The study enrolled 222 patients, (125 non-diabetics and 97 diabetics): 54 II A and 168 II B stage; 172 patients (131 II B and 41 II A; 104 non-diabetics and 68 diabetics) were submitted to iv. L-propionil carnytine (Lpc) and physical training on treadmill or exercise bike and 50 patients to iv. therapy alone. Instrumental (Rheoscreen, Oximetry, ABI, walking distance measurement) and clinical checks (questionnaire - Appendix 1) were performed at days: T0, T45,T 90,T180, T230 and during the follow up stated at T 90,T180,T360 from T 230 (end of DH). RESULTS: A significant increasing of the walking distance has been reached in the group undergoing the rehabilitation program. Treadmill: non-diabetics +261.48% at 0% and +122.53% at slope 10% (T230) further increasing to +502.31% at 0% and +289.42% at slope 10% (T360); diabetics: + 158.49% at T0 and + 98.26% at slope 10% (T230) further increased to +287.74% at 0% and +197.39% at 10% (T360) in comparison with the group which had only iv. Lpc : non-diabetics +141.63% at 0% and +104.08% at slope 10% (T230) further increased to +202.064% at 0% and +155.10% at slope 10% (T360); diabetics: +109.124% at T0 and +100% at slop 10% (T230) further increased to +171.08% at 0% and +140% at 10% (T360) . Exercise bike: non-diabetics: +170.27% at T230 in comparison T0 increased to +305.4% at T360; diabetics: +166.66 at T230 reaching +288.88% at T 360. CONCLUSION: Our rehabilitative program gives not only good results at the end of the treatment but mainly stable, with the chance to reach further improving of both walking distance and quality of life, particularly in those patients which observe constantly the physical training. PMID- 20948503 TI - Paclitaxel-coated balloons - Survey of preclinical data. AB - Restenosis following interventions in the coronary or peripheral arteries develops over weeks to months. In coronary arteries the restenosis rate has been markedly reduced since the advent of drug-eluting stents. Non-stent-based methods for local drug delivery enable restenosis inhibition without the need for stent implantation, does not permanently change the structure of the vessel, are repeatable, and seems to be applicable where drug-eluting stents provide insufficient protection. Preclinical data indicate that short exposure of the vessel wall to a lipophilic inhibitor of cell proliferation is sufficient for preventing restenosis. Initial evidence to this effect emerged from an investigation of paclitaxel embedded in a matrix that enhances the solubility and release of the agent from the balloon coating as well as its transfer to the vessel wall. Further corroborating data from preclinical and clinical studies demonstrating a reduction in late lumen loss and lower restenosis rates led to the market introduction of a variety of paclitaxel-coated angioplasty balloons. The effectiveness of restenosis inhibition is not determined by the active agent alone. Other factors that are crucial for the effectiveness and safety of drug coated angioplasty balloons are the formulation containing the agent and the coating technique. In this review we first outline the development of paclitaxel coated balloons to then provide an overview of the preclinical results obtained with different paclitaxel-coated balloons and finally compare these with the outcome in patients. The article concludes with a short outlook on initial results with a zotarolimus-coated angioplasty balloon. PMID- 20948504 TI - Treatment of coronary in-stent restenosis with a novel paclitaxel urea coated balloon. AB - Randomized clinical trials investigating the treatment of coronary in-stent restenosis with paclitaxel iopromide coated balloon catheters have shown favorable results. The aim of the present clinical investigation was to assess the efficacy of a novel paclitaxel urea coated angioplasty balloon in the treatment of coronary in-stent restenosis. A total of 26 restenotic bare metal stents in 23 patients with a lesion length of 22.8 +/- 11.1 mm and a reference vessel diameter of 2.64 +/- 0.31 mm were treated. Up to six months and including the six-month angiographic control, only one target lesion revascularization was necessary; in total, the rate of major adverse cardiovascular events until six month follow-up was 4.3 %. In-stent late lumen loss was 0.07 +/- 0.37 mm, in segment late lumen loss 0.02 +/- 0.50 mm. Binary restenosis was present in one patient (4.3%). The results of this first-in-human series with a paclitaxel urea coated balloon are comparable to paclitaxel iopromide coated balloon catheters. Randomized, controlled clinical trials are warranted to further evaluate this promising approach. PMID- 20948505 TI - Reduction of mitral valve regurgitation with Mitraclip(r) percutaneous system. AB - Mitral regurgitation (MR) is the second most common heart valve disease worldwide and the current gold-standard treatment is surgical repair or replacement. Nevertheless, many patients do not undergo surgical intervention due to several comorbidities. Percutaneous "edge-to-edge" mitral valve repair using the MitraClip System is an emerging and effective option to this subset of patients. This device has been used to treat both functional and degenerative mitral valve regurgitation and has been compared to surgery in the Endovascular Valve Edge-to Edge Repair Study II (EVEREST II) randomized trial. Although the field of percutaneous management of MR is at an early stage, it has been demonstrated that percutaneous approaches can reduce MR, suggesting there is a great deal of potential for clinical benefit to patients with MR. PMID- 20948506 TI - NoboriTM drug eluting stent system: clinical evidence update. AB - Drug eluting stents (DES) have changed the landscape of interventional cardiology with their high efficacy in preventing restenosis. Several DES are available for clinical use with different drugs, polymers and platforms. The NoboriTM is a novel generation drug eluting stent. The drug, Biolimus A9TM, a sirolimus analogue, is immersed in a biodegradable polymer which is applied solely to the abluminal surface of a flexible stainless steel stent platform. The drug-polymer matrix is designed to release the drug simultaneously with the polymer degradation in a process lasting between 6-9 months. The coating design along with the lipophilicity of the drug is expected to optimize drug distribution and to reduce its release into the peripheral circulation. The drug free luminal surface might reduce negative impact on endothelization observed with DES with circumferential coating and durable polymers. NoboriTM stent is extensively studied in the comprehensive NOBORI clinical program. This stent showed superiority versus Taxus Liberte stent for in-stent late loss at 9 months in NOBORI 1 study, similarity to Cypher stent in NOBORI CORE study and superior performance versus both Taxus and Cypher stent in the study indirectly assessing endothelial function at 6-9 months after stent implantation. The landmark of NOBORI trials is very low rate of late and very late stent thrombosis along with exceptionally low target lesion revascularization rate. PMID- 20948507 TI - Estimated lifetime risk for diagnosis of HIV infection among Hispanics/Latinos -- 37 states and Puerto Rico, 2007. AB - In 2008, the annual rate of diagnosis with human immunodeficiency virus (HIV) infection in the United States for Hispanics/Latinos (25.0 per 100,000 population) was approximately three times that for whites (8.2). To calculate the estimated lifetime risk (ELR) and age-conditional risk for diagnosis of HIV infection among Hispanics/Latinos in 37 states and Puerto Rico, CDC analyzed HIV surveillance data, vital statistics data on general and HIV-specific mortality, and U.S. census data from 2007. The results of those analyses indicated that an estimated 1.92% (one in 52) of Hispanics/Latinos would receive HIV diagnoses during their lifetimes, compared with an ELR for HIV diagnosis of 0.59% (one in 170) for whites and 4.65% (one in 22) for blacks/African Americans. Among Hispanics/Latinos, those aged 35 years had the greatest risk for HIV diagnosis (males: 0.77% and females: 0.24%) during the next 10 years. Reducing HIV risk behaviors and increasing access to testing and care are important to decrease the number of diagnoses of HIV infection among disproportionately affected population groups. PMID- 20948508 TI - Tetanus and pertussis vaccination coverage among adults aged >= 18 years --- United States, 1999 and 2008. AB - In 2005, the Advisory Committee on Immunization Practices (ACIP) recommended that the newly licensed tetanus, diphtheria, and acellular pertussis (Tdap) vaccine replace a single decennial dose of tetanus diphtheria (Td) vaccine for persons aged 10-64 years. According to these recommendations, Tdap may be used to protect against pertussis even when <10 years have passed since the most recent tetanus vaccination. For adults with infant contact and health-care personnel (HCP) with direct patient contact (two groups at increased risk for transmitting pertussis to those who are most susceptible), the single recommended Tdap dose is suggested to be administered as soon as 2 years after the last tetanus vaccination. To assess changes in tetanus vaccination coverage and the use of Tdap among U.S. adults, CDC analyzed data from the National Health Interview Survey (NHIS) for 1999 and 2008. This report summarizes the results of that analysis, which indicated that self-reported tetanus vaccination coverage (vaccination within the preceding 10 years) was 60.4% in 1999 and 61.6% in 2008. Among adults aged 18-64 years, Tdap coverage was estimated to be 5.9% in 2008. Of those who reported receiving a tetanus vaccination during 2005-2008, 52.0% reported receiving Tdap. Tdap vaccination coverage among adults with infant contact was 5.0% and among HCP was 15.9%. Of those adults with infant contact and HCP who had received a tetanus vaccination during 2005-2008, 60.0% and 60.3% reported receiving Tdap, respectively. Health-care providers should recommend Tdap vaccination to adults aged 18-64 years whose most recent tetanus vaccination was >=10 years prior; the interval for HCP and persons with infant contact can be as short as 2 years. PMID- 20948509 TI - Progress toward control of rubella and prevention of congenital rubella syndrome -- worldwide, 2009. AB - Rubella usually is a mild, febrile rash illness in children and adults; however, infection early in a woman's pregnancy, particularly during the first 16 weeks, can result in miscarriage, fetal death, or an infant born with birth defects (i.e., congenital rubella syndrome [CRS]). In 2000, the World Health Organization (WHO) published the first rubella vaccine position paper to guide introduction of rubella-containing vaccine (RCV) in national childhood immunization schedules. As of December 2009, a total of 130 WHO member states have introduced RCV, a 57% increase from 83 member states in 1996. In addition, goals to eliminate rubella and CRS have been established in the WHO Region of the Americas (by 2010) and the WHO European Region (by 2015), and the WHO Western Pacific Region has established targets for accelerated rubella control and CRS prevention by 2015. During 2009, a total of 121,344 rubella cases were reported from 167 member states to WHO, an 82% decrease from 670,894 cases reported in 2000 from 102 member states. This report summarizes reported rubella and CRS cases globally and progress toward global introduction and use of RCV. PMID- 20948510 TI - The serotonin 5-HT2C receptor in medial prefrontal cortex exerts rheostatic control over the motivational salience of cocaine-associated cues: new observations from preclinical animal research. PMID- 20948511 TI - Preclinical data elucidate molecular and neural mechanisms of perinatal nicotine effects on neurodevelopment and behavior: translational opportunities and implications. PMID- 20948512 TI - Weight reduction in obese adolescents with and without binge eating. AB - Little is known about binge eating (BE) in adolescents. The primary aim of the present study was to examine the relationship between BE and weight loss in adolescents (BMI >=95th percentile) enrolled in a randomized controlled trial of behavioral and pharmacologic treatment of obesity. Participants were 82 treatment seeking adolescents (BMI = 37.9 +/- 3.8 kg/m(2); age = 14.1 +/- 1.2 years; 67% females; 42% African American, 55% white). Participants completed the Children's Depression Inventory (CDI), the Piers Harris Self-Esteem Questionnaire, and the Eating Inventory (including cognitive restraint, disinhibition, and hunger scales). BE was assessed by a questionnaire and a confirmatory interview. At baseline, 24% of participants met criteria for BE (N = 13 met full BE disorder (BED) criteria; N = 7 met subthreshold BE). There were no significant differences in percentage reduction in initial BMI between participants with or without BE at month 6 (-7.0 +/- 1.6 vs. -6.9 +/- 0.9%) or month 12 (-8.8 +/- 2.4 vs. -8.3 +/- 1.3%) (omnibus main effect BE P = 0.89, interaction BE * time P = 0.84, interaction BE * drug P = 0.61). The rate of BE declined significantly over time from 24% (n = 20) at baseline to 8% (n = 6) at month 6 and 3% (n = 2) at month 12 (P = 0.003). There were significant decreases in hunger and disinhibition as well as an increase in cognitive restraint over time (all P <= 0.0001). Findings suggest a combination of behavioral and pharmacologic therapy may produce both weight loss and improvement in BE. PMID- 20948513 TI - Morphological and receptorial changes in the epididymal adipose tissue of rats subjected to a stressful stimulus. AB - Obesity is nowadays related to other pathological conditions such as inflammation, insulin resistance, and diabetes, but little is known about the relationship between psychological stress and adipocytes. We decided to study the expression of the translocator protein (TSPO) 18-kDa, peroxisome proliferator activated receptor-gamma (PPAR-gamma), mitochondrial uncoupling protein-1 (UCP 1), and adipocyte morphology in the adipose tissue of rats subjected to stress conditions. In our model of stress, rats fasted for 24 h were placed in a restraint cage and then immersed vertically to the level of the xiphoid process in a water bath at 23 degrees C for 7 h. After that period, we removed the epididymal adipose tissues for the subsequent analysis. The optical and electron microscopy revealed that adipocytes of control rats formed a continuous epithelial-like cell layer; on the contrary in the adipocytes of stressed rats some cells have merged together and the number of vessels formed seems to increase. Stressed adipocytes presented unilocular cells with numerous mitochondria with a morphology ranging between that of brown adipose tissue (BAT) and white adipose tissue (WAT). Interestingly, when we investigated the subcellular distribution of UCP-1 by immunogold electron microscopy, the adipose tissue of stressed rats was positive for UCP-1. From the immunoblot analysis with anti-PPAR-gamma antibody, we observed an increased expression of PPAR-gamma in the adipocytes of stressed group compared with control group (P < 0.05). Stress induced the expression of TSPO 18-kDa receptor (B(max) = 106.45 +/- 5.87 fmol/mg proteins), which is undetectable by saturation-binding assay with [(3)H]PK 11195 in the control group. PMID- 20948514 TI - The relationship of waist circumference and BMI to visceral, subcutaneous, and total body fat: sex and race differences. AB - The purpose of this study was to examine sex and race differences in the relationship between anthropometric measurements and adiposity in white and African-American (AA) adults. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured with computed tomography (CT). Fat mass (FM) was measured with dual-energy-X-ray absorptiometry (DXA). Correlation coefficients were used to assess the relationship of waist circumference (WC) and BMI to VAT, SAT, and FM within sex-by-race groups. General linear models were used to compare relationships between WC or BMI, and adiposity across sex and race, within age groups (18-39 and 40-64 years). The sample included 1,667 adults (men: 489 white; 120 AA; women: 666 white, 392 AA). WC and BMI correlations were highest for FM and SAT compared to VAT. Women had higher FM levels than men regardless of WC, but the sex difference in FM was attenuated in younger AA adults with a high BMI. For a given level of WC or BMI, women had higher levels of SAT than men; however, significant interactions indicated that the relationship was not consistent across all levels of BMI and WC. Sex and race differences in VAT varied significantly with WC and BMI. In general, white adults had higher levels of VAT than AA adults at higher levels of BMI and WC. Sex differences, and in some instances race differences, in the relationships between anthropometry and fat-specific depots demonstrate that these characteristics need to be considered when predicting adiposity from WC or BMI. PMID- 20948515 TI - Internalized societal attitudes moderate the impact of weight stigma on avoidance of exercise. AB - Experiences with weight stigma negatively impact both psychological outcomes (e.g., body dissatisfaction, depression) and behavioral outcomes (e.g., dieting, exercise). However, not everyone is equally affected by experiences with weight stigma. This study examined whether internalized societal attitudes about weight moderated the impact of weight stigma. Adult participants (n = 111) completed measures of experiences with weight stigma, as well as two indexes of internalized societal attitudes (the moderators): Internalized anti-fat attitudes and internalization of societal standards of attractiveness. Psychological outcomes included self-esteem, body dissatisfaction, drive for thinness, and bulimic symptoms; behavioral outcomes included avoidance of exercise and self reported exercise behavior. Weight stigma was positively correlated with body dissatisfaction, drive for thinness, and bulimic symptoms, and was negatively correlated with state and trait self-esteem. Both indexes of internalized attitudes moderated the association between weight stigma and avoidance of exercise: Individuals high in anti-fat attitudes and high in internalization of societal standards of attractiveness were more motivated to avoid exercise if they also experienced a high degree of weight stigma; individuals low in anti-fat attitudes and low in internalization were relatively unaffected. Avoidance of exercise was negatively correlated with self-reported strenuous exercise. These findings suggest that weight stigma can negatively influence motivation to exercise, particularly among individuals who have internalized societal attitudes about weight. Reducing internalization might be a means of minimizing the negative impact of weight stigma and of facilitating healthy weight management efforts. PMID- 20948517 TI - Factors associated with tracking of BMI: a meta-regression analysis on BMI tracking. AB - Stable tracking of body composition is a prerequisite for the long-term effect of preventive measures against obesity and its harmful effects. As BMI tracking estimates reported by individual studies vary considerably, we performed a meta regression analysis to provide a summary estimate and to assess determinants of BMI tracking. Using the Medline and EMBASE databases, a systematic review was conducted to identify publications reporting correlation coefficients as tracking estimates between BMI at baseline and follow-up measurements and the time interval between these measurements. Additional information recorded included age at baseline measurement, gender, and origin of the studied population. Based on the extracted data, a meta-regression analysis was performed using mixed effects models to account for multiple measurements of the same cohorts. Data on 55,072 individuals (797,094 person-years) extracted from 48 publications with follow-up times between 0.5 and 44 years entered the analysis. The overall estimates for the 1-year tracking correlation coefficient were strong (r = 0.78-0.86 depending on age at baseline measurement) and gradually decreasing over time (0.67-0.78 after 10 years, and 0.27-0.47 after 30 years). Study origin classified by continent was another significant predictor of BMI tracking whereas gender was not. In conclusion, this meta-regression analysis showed a high degree of BMI tracking across all age groups investigated and independent of BMI. Successful prevention in weight control is likely to have long term effects at any age, thereby being beneficial with respect to the associated risks of over- and underweight. PMID- 20948516 TI - F2-isoprostanes and adiposity in older adults. AB - We examined whether a systemic marker of oxidative stress, F(2)-isoprostanes (F(2)-IPs), was associated with total and regional adiposity, adipocytokines, and change in adiposity. Using data from 726 participants enrolled in the Health, Aging, and Body Composition (Health ABC) study, F(2)-IPs and adipocytokines were measured from baseline plasma samples. Total adiposity was measured by whole-body dual-energy X-ray absorptiometry and regional adiposity by abdominal and thigh computed tomography scans at baseline and 5-year follow-up. ANOVA models were estimated to examine associations between F(2)-IP tertiles and baseline adiposity and changes in body composition. Median F(2)-IPs was 54.3 pg/ml; women had significantly higher levels than men (61.5 vs. 48.9 pg/ml, P < 0.001). F(2)-IPs were associated with higher levels of adiponectin, leptin, and tumor necrosis factor-alpha (TNF-alpha). Positive associations were found between F(2)-IPs and all measures of total and regional adiposity among women. In linear regression models, adipocytokines mediated associations among women. Over 5 years of follow up, women in the highest vs. lowest F(2)-IP tertile exhibited significant loss of weight (lowest tertile: -1.1 kg, highest tertile: -2.7 kg, P < 0.05). In conclusion, F(2)-IPs were associated with measures of total and regional adiposity in women alone and these associations were partially explained by adipocytokines. F(2)-IPs predicted loss of total adiposity over time among women. PMID- 20948518 TI - Duodenum electrical stimulation delays gastric emptying, reduces food intake and accelerates small bowel transit in pigs. AB - Duodenum electrical stimulation (DES) has been shown to delay gastric emptying and reduce food intake in dogs. The aim of this study was to investigate the effects of DES on gastric emptying, small bowel transit and food intake in pigs, a large animal model of obesity. The study consisted of three experiments (gastric emptying, small bowel transit, and food intake) in pigs implanted with internal duodenal electrodes for DES and one or two duodenal cannulas for gastric emptying and small bowel transit. We found that (i) gastric emptying was dose dependently delayed by DES of different stimulation parameters; (ii) small bowel transit was significantly accelerated with continuous DES in proximal intestine but not with intermittent DES; (iii) DES significantly reduced body weight gain with 100% duty cycle (DC), but not with DES with 40% DC. A marginal difference was noted in food intake among 100% DC session, 40% DC session, and control session. DES with long pulses energy-dependently inhibits gastric emptying in pigs. DES with appropriate parameters accelerates proximal small bowel transit in pigs. DES reduces body weight gain in obese pigs, and this therapeutic effect on obesity is mediated by inhibiting gastric emptying and food intake, and may also possibly by accelerating intestinal transit. DES may have a potential application to treat patients with obesity. PMID- 20948519 TI - Stress and adiposity: a meta-analysis of longitudinal studies. AB - Psychosocial stress has been strongly implicated in the biology of adiposity but epidemiological studies have produced inconsistent results. The aim of this analysis was to bring together results from published, longitudinal, prospective studies examining associations between psychosocial stress and objectively measured adiposity in a meta-analysis. Searches were conducted on Medline, PsycINFO, Web of Science, and PubMed (to January 2009) and reference lists from relevant articles were examined. Prospective studies relating psychosocial stress (general life stress (including caregiver stress), work stress) to BMI, body fat, body weight, waist circumference, or waist-to-hip ratio were included. Analyses from 14 cohorts were collated and evaluated. There was no significant heterogeneity, no evidence of publication bias, and no association between study quality and outcomes. The majority of analyses found no significant relationship between stress and adiposity (69%), but among those with significant effects, more found positive than negative associations (25 vs. 6%). Combining results in a meta-analysis showed that stress was associated with increasing adiposity (r = 0.014; confidence interval (CI) = 0.002-0.025, P < 0.05). Effects were stronger for men than women, in analyses with longer rather than shorter follow-ups, and in better quality studies. We conclude that psychosocial stress is a risk factor for weight gain but effects are very small. Variability across studies indicates there are moderating variables to be elucidated. PMID- 20948520 TI - Mechanisms behind the portion size effect: visibility and bite size. AB - Increases in portion size lead to increases in energy intake, yet the mechanisms behind this "portion size effect" are unclear. This study tested possible mechanisms of the portion size effect, i.e., bite size and visual cues. A 2 * 2 repeated measures, within-subject design was used to test the effects of portion size (410 g vs. 820 g of a pasta dish) and visual cues (blindfolded vs. visible) on energy intake in 30 individuals (15 men, 15 women). At each meal participants were exposed to one of four experimental conditions (small portion/visible; small portion/blindfold; large portion/visible; large portion/blindfold). Participant characteristics, food intake, number of bites, meal duration, palatability measures and hunger and fullness were assessed. In response to a doubling of the portion presented, entree energy intake increased 26% (220 kcal; P < 0.001) and mean bite size increased 2.4 g/bite (P < 0.05). Overweight (OW) individuals consumed 40% (334 kcal) more of the entree in response to the large portion condition (P < 0.05), while lean individuals' intakes did not differ (P < 0.56). A 12% (122 kcal) decrease in entree intake was observed in the blindfolded condition (P < 0.01), but no portion by visual cue interaction was found; indicating that blindfolding did not significantly attenuate the portion size effect. These data suggest that the portion size effect is not impacted by removing the visual cue of food and that this effect occurs via changes in bite size in adults. PMID- 20948521 TI - Comprehensive human adipose tissue mRNA and microRNA endogenous control selection for quantitative real-time-PCR normalization. AB - The accurate quantification of cellular and tissue mRNA and microRNA content is reliant upon the selection of stable endogenous control transcripts for normalizing quantitative real-time-PCR (qRT-PCR) data. Using the combination of unbiased and informed approaches and a wide range of human adipose tissues and cells, we sought to identify invariant control transcripts for mRNA and microRNA. A total of 26 mRNA transcript candidates were selected from the literature. MicroRNA candidates were selected from a microRNA-microarray (Agilent, n = 22 tissues), and together with candidates from the literature resulted in 14 different microRNAs. The variability of these mRNA and microRNA transcripts were then tested in a large (n = 180) collection of a variety of human adipose tissues and cell samples. Phosphoglycerate kinase-1 (PGK1) and peptidylprolyl isomerase A (PPIA) were identified as the most stable mRNAs across all tissues and panels. MiR-103 was overall the most stable microRNA transcript across all biological backgrounds. Several proposed and commonly used normalization transcripts were found to be highly variable. We then tested the effect on expression of two established adipocyte-related transcripts (fatty acid binding protein 4 (FABP4) and microRNA-145 (miR-145)), either normalized to the optimal or a commonly used controls transcript. This test clearly indicated that spurious results could arise from using less stable control transcripts for mRNA and microRNA qRT-PCR. PMID- 20948522 TI - The relationship between sleep and weight in a sample of adolescents. AB - Research to date in young children and adults shows a strong, inverse relationship between sleep duration and risk for overweight and obesity. Fewer studies examining this relationship have been conducted in adolescents. The purpose of the article is to describe the relationship between sleep and weight in a population of adolescents, controlling for demographics, energy intake, energy expenditure, and depression. This is a cross-sectional study of 723 adolescents participating in population-based studies of the etiologic factors related to obesity. We examined the relationship between three weight-related dependent variables obtained through a clinical assessment and three sleep variables obtained through self-report. Average caloric intake from dietary recalls, average activity counts based on accelerometers, and depression were included as covariates and the analysis was stratified by gender and grade level. Our results show that the relationship between sleep duration and BMI is evident in middle-school boys (beta = -0.32, s.e. = 0.06: P < 0.001) and girls (beta = 0.18, s.e. = 0.08: P = 0.02) but largely absent in high-school students. Differences in sleep patterns have little association with weight in males, but in high-school girls, waking up late on weekends as compared to weekdays is associated with lower body fat (beta = -0.80, s.e. = 0.40: P = 0.05) and a healthy weight status (beta = -0.28, s.e. = 0.14: P = 0.05). This study adds to the evidence that, particularly for middle-school boys and girls, inadequate sleep is a risk factor for early adolescent obesity. Future research needs to examine the relationship longitudinally and to study potential mediators of the relationship. PMID- 20948523 TI - Sex hormones in postmenopausal women receiving low-dose hormone therapy: the effect of BMI. AB - The aim of our study was to evaluate the effect of BMI on the change in circulating sex hormone in postmenopausal women during 6 months of oral continuous combined low-dose hormone therapy (HT). Fifty postmenopausal women were allocated to receive daily one tablet containing combination of 17beta estradiol (1 mg)/norethindrone acetate (0.5 mg) for 6 months. Serum levels of follicle-stimulating hormone (FSH), estradiol, total testosterone, sex hormone binding globulin (SHBG), free androgen index (FAI), free estrogen index (FEI), Delta4-androstendione (Delta4A), and dehydroepiandrosterone sulfate were assessed at baseline and at the end of 6 months. Mean absolute values and percent changes from baseline were compared between lean and overweight women. Mean FSH decreased and mean 17beta-estradiol increased significantly in both groups (FSH lean: 82.3 +/- 26.7 decreased to 45.0 +/- 17.0 mIU/ml, P = 0.0001; FSH overweight: 85.5 +/- 22.1 decreased to 52.3 +/- 23.8 mIU/ml, P = 0.003; P between groups = 0.661; E2 lean: 23.24 +/- 12.55 increased to 53.62 +/- 28.29 pg/ml, P = 0.006; E2 overweight: 24.17 +/- 10.88 increased to 68.36 +/- 53.99 pg/ml, P = 0.0001; P between groups = 0.619). Lean individuals had statistically significant higher increments of FAI and specifically FEI compared to overweight (FEI lean; 0.14 +/- 0.09 increased to 0.29 +/- 0.14, P = 0.009; overweight 0.23 +/- 0.18 increased to 0.52 +/- 0.40, P = 0.126; P between groups = 0.034). Although BMI does not affect total 17beta-estradiol changes, free sex steroid concentrations increase more steeply in lean compared to overweight women receiving oral low-dose HT. PMID- 20948524 TI - Pericardial fat amount is an independent risk factor of coronary artery stenosis assessed by multidetector-row computed tomography: the Korean Atherosclerosis Study 2. AB - Pericardial fat surrounding the heart and coronary arteries might aggravate vessel wall inflammation and stimulate the progression of coronary atherosclerosis. However, there has been little comprehensive evaluation of the effects of pericardial fat on coronary artery disease (CAD). We investigated the relationship between pericardial fat volume and the severity of coronary artery stenosis assessed by computed tomography and angiography among patients with suspected CAD. Participants from the cohort of the Korean Atherosclerosis Study 2 (n = 402, mean age of 54 years, 57.0% men) underwent 64-slice multidetector-row computed tomography (MDCT) to assess pericardial fat amount, coronary artery calcium score (CACS), severity of coronary artery stenosis, and plaque characteristics. Patients with atherosclerotic lesion had significantly larger volume of pericardial fat than patients without atherosclerosis (308 +/- 96 cm(3) vs. 251 +/- 93 cm(3); P < 0.01). In a multivariate regression analysis adjusting for age, gender and BMI, subjects with more pericardial fat had a higher risk for significant (>50%) stenosed coronary vessels (odds ratio (OR) = 1.012; 95% confidence interval (CI) 1.001-1.030; P = 0.017). This association remained after adjusting for hypertension, diabetes, smoking status, and lipid profiles (OR = 1.007; 95% CI 1.001-1.014; P = 0.042). In conclusion, an increased pericardial fat volume was an independent risk factor for stenotic CAD and could be helpful in assessing subclinical CADs. PMID- 20948525 TI - Sugar content of popular sweetened beverages based on objective laboratory analysis: focus on fructose content. AB - The consumption of fructose, largely in the form of high fructose corn syrup (HFCS), has risen over the past several decades and is thought to contribute negatively to metabolic health. However, the fructose content of foods and beverages produced with HFCS is not disclosed and estimates of fructose content are based on the common assumption that the HFCS used contains 55% fructose. The objective of this study was to conduct an objective laboratory analysis of the sugar content and composition in popular sugar-sweetened beverages with a particular focus on fructose content. Twenty-three sugar-sweetened beverages along with four standard solutions were analyzed for sugar profiles using high performance liquid chromatography (HPLC) in an independent, certified laboratory. Total sugar content was calculated as well as percent fructose in the beverages that use HFCS as the sole source of fructose. Results showed that the total sugar content of the beverages ranged from 85 to 128% of what was listed on the food label. The mean fructose content in the HFCS used was 59% (range 47-65%) and several major brands appear to be produced with HFCS that is 65% fructose. Finally, the sugar profile analyses detected forms of sugar that were inconsistent with what was listed on the food labels. This analysis revealed significant deviations in sugar amount and composition relative to disclosures from producers. In addition, the tendency for use of HFCS that is higher in fructose could be contributing to higher fructose consumption than would otherwise be assumed. PMID- 20948526 TI - Respective contributions of maternal insulin resistance and diet to metabolic and hypothalamic phenotypes of progeny. AB - Maternal obesity can influence susceptibility to obesity and type 2 diabetes in progeny. We examined the relationship of maternal insulin resistance (IR), a metabolically important consequence of increased adiposity, to adverse consequences of obesity for fetal development. We used mice heterozygous for a null allele of the insulin receptor (Insr) to study the contributions of maternal IR to offspring phenotype without the potential confound of obesity per se, and how maternal consumption of high-fat diet (HFD) may, independently and interactively, affect progeny. In progeny fed a 60% HFD, body weight and adiposity were transiently (5-7 weeks) increased in wild-type (+/+) offspring of Insr(+/-) HFD-fed dams compared to offspring of wild-type HFD-fed dams. Offspring of HFD-fed wild-type dams had increased body weight, blood glucose, and plasma insulin concentrations compared to offspring of chow-fed wild-type dams. Quantification of proopiomelanocortin (POMC) and neuropeptide-Y (NPY) populations in the arcuate nucleus of the hypothalamus (ARH) of offspring of wild-type vs. Insr(+/-) dams was performed to determine whether maternal IR affects the formation of central feeding circuits. We found a 20% increase in the number of Pomc-expressing cells at postnatal day 9 in offspring of Insr(+/-) dams. In conclusion, maternal HFD consumption-distinct from overt obesity per se-was a major contributor to increased body weight, adiposity, IR, and liver triglyceride (TG) phenotypes in progeny. Maternal IR played a minor role in predisposing progeny to obesity and IR, though it acted synergistically with maternal HFD to exacerbate early obesity in progeny. PMID- 20948528 TI - Uric acid as a marker of oxidative stress in dilatation of the ascending aorta. AB - BACKGROUND: Increased serum uric acid (UA) has been shown to directly promote oxidative stress. Recent studies point toward a role for oxidative stress in the pathogenesis of ascending aortic aneurysms (AscAAs). This study was designed to examine the relationship between serum UA concentrations, total antioxidant reductive capacity, and AscAAs. METHODS: The serum UA concentrations, total antioxidant reductive capacity were compared in 60 patients with ascending aortic dilatation (ectasia group (3.8-4.3 cm), 34 patients; aneurysmal group (>=4.4 cm), 26 patients) vs. 30 control subjects. The patients were evaluated by a complete transthoracic echocardiographic examination including measurement of the aortic dimensions. RESULTS: The serum UA concentration and total antioxidant reductive capacity were significantly higher in patients with AscAAs. In multiple linear regression analysis, hypertension and serum UA concentration were significantly associated with aortic dilatation (beta = 0.3, P = 0.03; beta = 0.15, P < 0.001, respectively). CONCLUSIONS: In conclusion, we found that serum UA concentration and total antioxidant capacity (TAC) were significantly associated with aortic dilatation. The higher serum UA concentration may be responsible for the elevated serum antioxidant capacity that was observed among individuals with AscAA. Large scale epidemiological studies conducted over several years are required to correlate the cross-sectional findings from this study with clinical outcome. PMID- 20948527 TI - Contribution of adipose tissue to plasma 25-hydroxyvitamin D concentrations during weight loss following gastric bypass surgery. AB - Roux-en-y gastric bypass (RYGB) surgery is associated with dramatic improvements in obesity-related comorbidity, but also with nutritional deficiencies. Vitamin D concentrations are depressed in the severely obese, but the impact of weight loss via RYGB is unknown. We determined associations between adiposity and systemic 25 hydroxyvitamin D (25(OH)D) during weight loss and the immediate and longer-term effects of RYGB. Plasma 25(OH)D concentrations and fat mass (FAT) were determined by immunoassay and air displacement plethysmography, respectively, at 0 (before RYGB surgery), and at 1, 6, and 24 months in severely obese white and African American (AA) women (n = 20). Decreases in adiposity were observed at 1, 6, and 24 months following RYGB (P < 0.05). Plasma 25(OH)D concentrations increased at 1 month (P = 0.004); a decreasing trend occurred over the remainder months after surgery (P = 0.02). Despite temporary improvement in vitamin D status, a high prevalence of vitamin D insufficiency was observed (76, 71, 67, and 82%, at baseline, 1, 6, and 24 months, respectively), and plasma 25(OH)D concentrations were lower in AA compared to white patients (P < 0.05). Strong positive baseline and 1 month cross-sectional correlations between FAT and plasma 25(OH)D were observed, which remained after adjustment for age and race subgroup (beta = 0.76 and 0.61, respectively, P = 0.02). In conclusion, 25(OH)D concentrations increased temporarily and then decreased during the 24 months following RYGB. The acute increase and the positive associations observed between adipose tissue mass and systemic 25(OH)D concentrations suggest storage in adipose tissue and release during weight loss. PMID- 20948529 TI - Recent findings in the genetics of blood pressure and hypertension traits. AB - We provide an overview of ongoing discovery efforts in the genetics of blood pressure (BP) and hypertension (HTN) traits. Two large genome-wide association meta-analyses of individuals of European descent were recently published, revealing ~13 new loci for BP traits. Only two of these loci harbor genes in a pathway known to affect BP (CYP17A1 and NPPA/NPPB). Functional variants in these loci are still unknown. Few genome-wide association studies (GWAS) of complex diseases have been published from non-European populations. The study of populations with different evolutionary history and linkage disequilibrium (LD) structure, such as individuals of African ancestry, may provide an opportunity to further narrow these regions to identify the causal gene(s). Several collaborative efforts toward discovery of low-frequency variants and copy number variation for BP traits are currently underway. As evidence for new loci for complex diseases accumulates the assessment of the epidemiologic architecture of these variants in populations assumes higher priority. The impact of public health-relevant contexts such as diet, physical activity, psychosocial factors, and aging has not been examined for most common variants associated with BP. PMID- 20948531 TI - Central mechanisms of pathological pain. AB - Chronic pain is a major challenge to clinical practice and basic science. The peripheral and central neural networks that mediate nociception show extensive plasticity in pathological disease states. Disease-induced plasticity can occur at both structural and functional levels and is manifest as changes in individual molecules, synapses, cellular function and network activity. Recent work has yielded a better understanding of communication within the neural matrix of physiological pain and has also brought important advances in concepts of injury induced hyperalgesia and tactile allodynia and how these might contribute to the complex, multidimensional state of chronic pain. This review focuses on the molecular determinants of network plasticity in the central nervous system (CNS) and discusses their relevance to the development of new therapeutic approaches. PMID- 20948530 TI - Nociceptor sensitization in pain pathogenesis. AB - The incidence of chronic pain is estimated to be 20-25% worldwide. Few patients with chronic pain obtain complete relief from the drugs that are currently available, and more than half report inadequate relief. Underlying the challenge of developing better drugs to manage chronic pain is incomplete understanding of the heterogeneity of mechanisms that contribute to the transition from acute tissue insult to chronic pain and to pain conditions for which the underlying pathology is not apparent. An intact central nervous system (CNS) is required for the conscious perception of pain, and changes in the CNS are clearly evident in chronic pain states. However, the blockage of nociceptive input into the CNS can effectively relieve or markedly attenuate discomfort and pain, revealing the importance of ongoing peripheral input to the maintenance of chronic pain. Accordingly, we focus here on nociceptors: their excitability, their heterogeneity and their role in initiating and maintaining pain. PMID- 20948532 TI - Advances in clinical research methodology for pain clinical trials. AB - Pain is a ubiquitous phenomenon, but the experience of pain varies considerably from person to person. Advances in understanding of the growing number of pathophysiologic mechanisms that underlie the generation of pain and the influence of the brain on the experience of pain led to the investigation of numerous compounds for treating pain. Improved knowledge of the subjective nature of pain, the variations in the measurement of pain, the mind-body placebo effect and the impact of differences in the conduct of a clinical trial on the outcome have changed approaches to design and implement studies. Careful consideration of how these concepts affect the choice of study population, the randomization and blinding process, the measurement and collection of data, and the analysis and interpretation of results should improve the quality of clinical trials for potential pain therapies. PMID- 20948533 TI - Getting the pain you expect: mechanisms of placebo, nocebo and reappraisal effects in humans. AB - The perception of pain is subject to powerful influences. Understanding how these are mediated at a neuroanatomical and neurobiological level provides us with valuable information that has a direct impact on our ability to harness positive and minimize negative effects therapeutically, as well as optimize clinical trial designs when developing new analgesics. This is particularly relevant for placebo and nocebo effects. New research findings have directly contributed to an increased understanding of how placebo and nocebo effects are produced and what biological and psychological factors influence variances in the magnitude of the effect. The findings have relevance for chronic pain states and other disorders, where abnormal functioning of crucial brain regions might affect analgesic outcome even in the normal therapeutic setting. PMID- 20948534 TI - Overcoming obstacles to developing new analgesics. AB - Despite substantial investment by the pharmaceutical industry over several decades, there has been little progress in developing new, efficacious and safe analgesics. As a result, many large pharmaceutical companies are leaving the area of pain medication. Nevertheless, the chances of success could increase if analgesic drug development strategy changed. To achieve such a paradigm shift we must understand why development of drugs for pain relief is so challenging. PMID- 20948537 TI - Professor Karl Julius Ullrich--in memoriam. PMID- 20948539 TI - What's a CLIC doing in the podocyte? AB - Chloride intracellular channel (CLIC) proteins are proposed to have numerous functions, including chloride channel activity, regulation of gene expression, and serving as a component of the cytoskeleton. Pierchala et al. have identified CLIC5A in podocytes, where it is complexed with ezrin, podocalyxin, and the actin cytoskeleton. Absence of CLIC5A results in altered podocyte morphology and proteinuria. Exactly how CLIC5A supports podocyte function is unclear. Potential mechanisms in which cytoskeletal interactions could regulate other functions of CLIC5A are discussed. PMID- 20948535 TI - Interactions between the immune and nervous systems in pain. AB - Immune cells and glia interact with neurons to alter pain sensitivity and to mediate the transition from acute to chronic pain. In response to injury, resident immune cells are activated and blood-borne immune cells are recruited to the site of injury. Immune cells not only contribute to immune protection but also initiate the sensitization of peripheral nociceptors. Through the synthesis and release of inflammatory mediators and interactions with neurotransmitters and their receptors, the immune cells, glia and neurons form an integrated network that coordinates immune responses and modulates the excitability of pain pathways. The immune system also reduces sensitization by producing immune derived analgesic and anti-inflammatory or proresolution agents. A greater understanding of the role of the immune system in pain processing and modulation reveals potential targets for analgesic drug development and new therapeutic opportunities for managing chronic pain. PMID- 20948540 TI - Automated monitoring of hemodialysis adequacy by dialysis machines: potential benefits to patients and cost savings. AB - Hemodialysis adequacy can be quantified using ultraviolet absorbance of the spent dialysate, or by analysis of dialysate conductivity at the dialyzer inlet and outlet in response to changes in dialysate electrolyte concentration. These measurements can be made at every dialysis, including initial and acute treatments and can help detect access recirculation. No disposables or reagents are required. Cost may be reduced by reducing the need for blood sampling and laboratory analysis. PMID- 20948542 TI - Fibrin plug. PMID- 20948541 TI - FIH1 (factor inhibiting HIF-1) in the kidney: more than an oxygen sensor? AB - Factor inhibiting HIF-1 (FIH1) inhibits the activity of hypoxia-inducible factor 1 (HIF-1) by preventing HIF-1alpha from binding to p300/CBP. Schodel et al. demonstrate that, in the kidney, FIH1 is expressed selectively in the distal tubules and podocytes. Although FIH1 functions as a transcriptional repressor of HIF target genes in tubular cells, it does not do so in podocytes. This study suggests that FIH1 may have diverse implications for distal tubular function and podocyte biology. PMID- 20948543 TI - Crystal structure of zinc-finger domain of Nanos and its functional implications. AB - Nanos is an RNA-binding protein that is involved in the development and maintenance of germ cells. In combination with Pumilio, Nanos binds to the 3' untranslated region of a messenger RNA and represses its translation. Nanos has two conserved Cys-Cys-His-Cys zinc-finger motifs that are indispensable for its function. In this study, we have determined the crystal structure of the zinc finger domain of zebrafish Nanos, for the first time revealing that Nanos adopts a novel zinc-finger structure. In addition, Nanos has a conserved basic surface that is directly involved in RNA binding. Our results provide the structural basis for further studies to clarify Nanos function. PMID- 20948544 TI - Traf7, a MyoD1 transcriptional target, regulates nuclear factor-kappaB activity during myogenesis. AB - We have identified the E3 ligase Traf7 as a direct MyoD1 target and show that cell cycle exit-an early event in muscle differentiation-is linked to decreased Traf7 expression. Depletion of Traf7 accelerates myogenesis, in part through downregulation of nuclear factor-kappaB (NF-kappaB) activity. We used a proteomic screen to identify NEMO, the NF-kappaB essential modulator, as a Traf7 interacting protein. Finally, we show that ubiquitylation of NF-kappaB essential modulator is regulated exclusively by Traf7 activity in myoblasts. Our results suggest a new mechanism by which MyoD1 function is coupled to NF-kappaB activity through Traf7, regulating the balance between cell cycle progression and differentiation during myogenesis. PMID- 20948545 TI - One man's meat is another man's poison. Science & Society series on food and science. PMID- 20948546 TI - Protein phosphatase 1gamma is responsible for dephosphorylation of histone H3 at Thr 11 after DNA damage. AB - The DNA-damage-induced transcriptional suppression of cell cycle regulatory genes correlates with a reduction in histone H3-Thr 11 phosphorylation (H3-pThr 11) on their promoters that is partly mediated by the dissociation of Chk1 from chromatin. In this study, we identify protein phosphatase 1gamma (PP1gamma) as a phosphatase responsible for DNA-damage-induced H3-pThr 11 dephosphorylation. PP1gamma is activated after DNA damage, which is mainly mediated by a reduction in Cdk-dependent phosphorylation of PP1gamma at Thr 311. The depletion of PP1gamma sensitizes HCT116 cells to DNA damage. Our results suggest that the ataxia telangiectasia, mutated and Rad3-related-Chk1 axis regulates H3-pThr 11 dephosphorylation on DNA damage, at least in part by the activation of PP1gamma through Chk1-dependent inhibition of Cdks. PMID- 20948547 TI - Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. AB - Researchers working on the development of vaccines face an inherent dilemma: to maximize immunogenicity without compromising safety and tolerability. Early vaccines often induced long-lived protective immune responses, but tolerability was a major problem. Newer vaccines have very few side effects but can be of limited immunogenicity. One way to tackle this problem is to design vaccines that have all the properties of pathogens with the exception of causing disease. Key features of pathogens that can be mimicked by vaccine delivery systems are their size, shape and surface molecule organization. In addition, pathogen-associated molecular patterns can be used to induce innate immune responses that promote adaptive immunity. In this Review, we discuss the approaches currently being used to optimize the delivery of antigens and enhance vaccine efficacy. PMID- 20948548 TI - The importance of natural IgM: scavenger, protector and regulator. AB - The existence of IgM has been known for more than a century, but its importance in immunity and autoimmunity continues to emerge. Studies of mice deficient in secreted IgM have provided unexpected insights into its role in several diverse processes, from B cell survival to atherosclerosis, as well as in autoimmunity and protection against infection. Among the various distinct properties that underlie the functions of IgM, two stand out: its polyreactivity and its ability to facilitate the removal of apoptotic cells. In addition, new B cell-targeted therapies for the treatment of autoimmunity have been shown to cause a reduction in serum IgM, potentially disrupting the functions of this immunoregulatory molecule and increasing susceptibility to infection. PMID- 20948549 TI - Genome annotation: man versus machine. PMID- 20948550 TI - Protein glycosylation in bacteria: sweeter than ever. AB - Investigations into bacterial protein glycosylation continue to progress rapidly. It is now established that bacteria possess both N-linked and O-linked glycosylation pathways that display many commonalities with their eukaryotic and archaeal counterparts as well as some unexpected variations. In bacteria, protein glycosylation is not restricted to pathogens but also exists in commensal organisms such as certain Bacteroides species, and both the N-linked and O-linked glycosylation pathways can modify multiple proteins. Improving our understanding of the intricacies of bacterial protein glycosylation systems should lead to new opportunities to manipulate these pathways in order to engineer glycoproteins with potential value as novel vaccines. PMID- 20948551 TI - Microorganisms and climate change: terrestrial feedbacks and mitigation options. AB - Microbial processes have a central role in the global fluxes of the key biogenic greenhouse gases (carbon dioxide, methane and nitrous oxide) and are likely to respond rapidly to climate change. Whether changes in microbial processes lead to a net positive or negative feedback for greenhouse gas emissions is unclear. To improve the prediction of climate models, it is important to understand the mechanisms by which microorganisms regulate terrestrial greenhouse gas flux. This involves consideration of the complex interactions that occur between microorganisms and other biotic and abiotic factors. The potential to mitigate climate change by reducing greenhouse gas emissions through managing terrestrial microbial processes is a tantalizing prospect for the future. PMID- 20948552 TI - Organotypic 3D cell culture models: using the rotating wall vessel to study host pathogen interactions. AB - Appropriately simulating the three-dimensional (3D) environment in which tissues normally develop and function is crucial for engineering in vitro models that can be used for the meaningful dissection of host-pathogen interactions. This Review highlights how the rotating wall vessel bioreactor has been used to establish 3D hierarchical models that range in complexity from a single cell type to multicellular co-culture models that recapitulate the 3D architecture of tissues observed in vivo. The application of these models to the study of infectious diseases is discussed. PMID- 20948554 TI - Further advantage of SBCS. PMID- 20948555 TI - Long-term follow-up with optical coherence tomography and microperimetry in eyes with metamorphopsia after macula-off retinal detachment repair. AB - PURPOSE: to report the long-term sequential morphological and functional results in eyes with metamorphopsia after retinal detachment (RD) repair. PATIENTS AND METHODS: in six eyes of six patients aged 58.7 +/- 11.0 years with metamorphopsia after successful buckling surgery for macula-off RD, best-corrected visual acuity (BCVA), fundus biomicroscopy, Amsler grid test, time-domain optical coherence tomography (TD-OCT) and central 12 degrees microperimetry (MP-1) were performed at months 1, 3, 6, 12, and 18. At 5 to 6 years after surgery all patients underwent also spectral domain (SD)-OCT. RESULTS: three eyes slowly recovered pre RD BCVA. In the remaining three eyes-with good final BCVA-the interrupted junction line between photoreceptor cell inner and outer segments (IS/OS) was progressively less evident after RD surgery; and the external limiting membrane was preserved on SD-OCT examination. In all eyes post-operative metamorphopsia faded with time, but fully disappeared in 6 years only in two eyes without photoreceptor abnormalities. One of the two eyes with subretinal fluid up to 6 months and IS/OS disruption had central dense scotoma with relatively unstable fixation on MP-1 and persistent metamorphopsia. Macular sensitivity (MS) increased from 9.7 +/- 7.1 at month 1 to 13.5 +/- 5.6 dB at the final check, and was weakly (r=0.33) correlated with post-operative BCVA and OCT abnormalities. CONCLUSION: long-standing metamorphopsia can occur after successful macula-off RD repair even without detectable photoreceptor disruption on OCT. Post-operative BCVA recovery weakly correlates with increasing MS, and late restoration of the photoreceptor layer may be observed. PMID- 20948553 TI - Developing vaccines to combat hookworm infection and intestinal schistosomiasis. AB - Hookworm infection and schistosomiasis rank among the most important health problems in developing countries. Both cause anaemia and malnutrition, and schistosomiasis also results in substantial intestinal, liver and genitourinary pathology. In sub-Saharan Africa and Brazil, co-infections with the hookworm, Necator americanus, and the intestinal schistosome, Schistosoma mansoni, are common. The development of vaccines for these infections could substantially reduce the global disability associated with these helminthiases. New genomic, proteomic, immunological and X-ray crystallographic data have led to the discovery of several promising candidate vaccine antigens. Here, we describe recent progress in this field and the rationale for vaccine development. PMID- 20948556 TI - Visual outcomes following Artisan aphakia iris claw lens implantation. AB - OBJECTIVE: To assess the visual outcome of eyes undergoing Artisan lens implantation for aphakia, to identify reasons for poor outcomes, and to report incidences of post-operative uveitis, glaucoma, or hyphaema. METHODS: A retrospective analysis of 32 eyes rendered aphakic through various causes, which subsequently underwent Artisan lens implantation. RESULTS: A total of 32 eyes from 31 patients were reviewed. Follow-up ranged from 6 to 42 months, mean 17.3 months. The commonest cause of aphakia was following complicated phacoemulsification in 17 of the 32 eyes (53.1%). At final follow-up, 21 of the 32 eyes (65.6%) achieved best-corrected visual acuity (BCVA) better than that measured pre-operatively and 10 of the 32 eyes (31.3%) matched their pre operative BCVA. Of 33 eyes, only 1 (0.03%) attained a final BCVA worse than pre operatively, owing to non-arteritic anterior ischaemic optic neuropathy. A total of 4 of the 33 eyes (12.5%) had pre-existing glaucoma or ocular hypertension; no additional intraocular pressure problems were identified during the follow-up period. CONCLUSION: This study suggests that Artisan iris claw lens insertion is beneficial in acquired aphakia, matching or exceeding pre-operative BCVA in the overwhelming majority of the cases. In addition, this series did not identify any post-operative problems with uveitis, glaucoma, or hyphaema. PMID- 20948557 TI - Impact of maternal diet during pregnancy and breastfeeding on infant metabolic programming: a prospective randomized controlled study. AB - OBJECTIVES: To evaluate the impact of maternal diet and intensive dietary counselling during pregnancy and breastfeeding on the infant's metabolic status. SUBJECTS/METHODS: At the first trimester of pregnancy, 256 women were randomized into a control/placebo group and two dietary counselling groups (diet/probiotics and diet/placebo). The counselling, with double-blind randomization to probiotics (Lactobacillus rhamnosus GG and Bifidobacterium lactis) or placebo, targeted excessive saturated fat and low fibre consumption. Maternal diet was evaluated repeatedly during pregnancy and postpartum by means of 3 days' food diaries. Metabolic markers, serum 32-33 split and intact proinsulin, leptin/adiponectin ratio, skinfold thickness and waist circumference were measured of 194 healthy infants at the age of 6 months, and the high levels were taken to mirror adverse metabolic status. RESULTS: The proportion of infants with a high 32-33 split proinsulin was significantly lower in dietary counselling with probiotics (n = 6/62, 9.7%) or placebo (n = 7/69, 10.1%) compared with the control/placebo group (n = 17/63, 27.0%). The high split proinsulin was associated with larger skinfold thickness, waist circumference and higher leptin/adiponectin ratio in the infants (P < 0.05). With respect to maternal diet during pregnancy, the highest and lowest tertiles of fat intake increased the infant's risk of high split proinsulin, whereas those of butter associated correspondingly with the infant's waist circumference. Further, breastfed infants showed a reduced risk of high split proinsulin and leptin/adiponectin ratio compared with formula-fed infants. CONCLUSIONS: Modification of maternal diet during pregnancy and breastfeeding may benefit infant metabolic health. High split proinsulin reflects adverse metabolic status in infancy, which can be improved by early dietary counselling. PMID- 20948558 TI - Diet and hip fractures among elderly Europeans in the EPIC cohort. AB - BACKGROUND/OBJECTIVES: Evidence on the role of diet during adulthood and beyond on fracture occurrence is limited. We investigated diet and hip fracture incidence in a population of elderly Europeans, participants in the European Prospective Investigation into Cancer and nutrition study. SUBJECTS/METHODS: 29, 122 volunteers (10,538 men, 18,584 women) aged 60 years and above (mean age: 64.3) from five countries were followed up for a median of 8 years and 275 incident hip fractures (222 women and 53 men) were recorded. Diet was assessed at baseline through validated dietary questionnaires. Data were analyzed through Cox proportional-hazards regression with adjustment for potential confounders. RESULTS: No food group or nutrient was significantly associated with hip fracture occurrence. There were suggestive inverse associations, however, with vegetable consumption (hazard ratio (HR) per increasing sex-specific quintile: 0.93, 95% confidence interval (CI): 0.85-1.01), fish consumption (HR per increasing sex specific quintile: 0.93, 95% CI: 0.85-1.02) and polyunsaturated lipid intake (HR per increasing sex-specific quintile: 0.92, 95% CI: 0.82-1.02), whereas saturated lipid intake was positively associated with hip fracture risk (HR per increasing sex-specific quintile: 1.13, 95% CI: 0.99-1.29). Consumption of dairy products did not appear to influence the risk (HR per increasing sex-specific quintile: 1.02, 95% CI: 0.93-1.12). CONCLUSIONS: In a prospective study of the elderly, diet, including consumption of dairy products, alcohol and vitamin D, did not appear to play a major role in hip fracture incidence. There is however, weak and statistically non-significant evidence that vegetable and fish consumption and intake of polyunsaturated lipids may have a beneficial, whereas saturated lipid intake a detrimental effect. PMID- 20948559 TI - Polymorphisms in alpha- and beta-Adrenergic Receptor Genes, Hypertension, and Obstructive Sleep Apnea: The Skaraborg Sleep Study. AB - The sympathetic nervous system and the adrenergic receptors play an important role in regulation of blood pressure. This study explored the associations between functional polymorphisms of the alpha(2B)-, beta(1)-, and beta(2) adrenergic receptor genes and obstructive sleep apnea (OSA) in hypertensive patients and hypertension in patients with OSA in a populationbased sample of 157 hypertensive patients and 181 healthy control subjects. Only the Arg389Gly polymorphism of the beta(1)-adrenergic receptor gene was associated with increased risk for mild OSA in hypertensive patients (Arg/Arg versus Gly/Arg/Gly/Gly, 2.1, 95% CI, 1.02-4.7). Hypertensive men carrying the Arg389Arg genotype had higher crude and age-adjusted AHI than carriers of the Arg389Gly/Gly389Gly genotypes. When adjusted also for BMI this difference became borderline significant. This difference was not observed in women. The risk of hypertension in mild OSA was associated with increasing number of Arg-alleles (Arg/Arg OR 5.4, 95% CI 1.4-21.2). PMID- 20948560 TI - Sociodemographic risk factors of diabetes and hypertension prevalence in republic of Korea. AB - This study examined the relationships between SES and diabetes and hypertension for Korean adults using the Korean National Health and Nutritional Examination Survey. To handle the four dummy dependent variables: Diabetes and Hypertension, Diabetes alone, Hypertension alone, and Diabetes or Hypertension, four different logistic models were conducted. The descriptive statistics showed a considerable amount of comorbidity between the combined dependent variable of diabetes and hypertension. To gauge more realistic measures of SES, education and income were combined together as four dummy categories. The SES factor indeed had significant impacts on diabetes and hypertension. Socioeconomically disadvantaged groups demonstrated to have increased likelihood of having these diseases. However, we could not find the strong compensating effect between education and income; the higher level of education but lower income variable was only significant in having both diseases, and the higher income but lower level of education variable was only significant in having hypertension alone and either one of the diseases. Only the highest SES one, the one with a higher level of education and a higher income, was significantly lowering the likelihood of having these diseases in all models. Therefore, public policy and intervention programs should focus on individuals matching these socioeconomic characteristics. PMID- 20948561 TI - Genetic determinants of osteoporosis: common bases to cardiovascular diseases? AB - Osteoporosis is the most common and serious age-related skeletal disorder, characterized by a low bone mass and bone microarchitectural deterioration, with a consequent increase in bone fragility and susceptibility to spontaneous fractures, and it represents a major worldwide health care problem with important implications for health care costs, morbidity and mortality. Today is well accepted that osteoporosis is a multifactorial disorder caused by the interaction between environment and genes that singularly exert modest effects on bone mass and other aspects of bone strength and fracture risk. The individuation of genetic factors responsible for osteoporosis predisposition and development is fundamental for the disease prevention and for the setting of novel therapies, before fracture occurrence. In the last decades the interest of the Scientific Community has been concentrated in the understanding the genetic bases of this disease but with controversial and/or inconclusive results. This review tries to summarize data on the most representative osteoporosis candidate genes. Moreover, since recently osteoporosis and cardiovascular diseases have shown to share common physiopathological mechanisms, this review also provides information on the current understanding of osteoporosis and cardiovascular diseases common genetic bases. PMID- 20948562 TI - Methods for imaging Renin-synthesizing, -storing, and -secreting cells. AB - Renin-producing cells have been the object of intense research efforts for the past fifty years within the field of hypertension. Two decades ago, research focused on the concept and characterization of the intrarenal renin-angiotensin system. Early morphological studies led to the concept of the juxtaglomerular apparatus, a minute organ that links tubulovascular structures and function at the single nephron level. The kidney, thus, appears as a highly "topological organ" in which anatomy and function are intimately linked. This point is reflected by a concurrent and constant development of functional and structural approaches. After summarizing our current knowledge about renin cells and their distribution along the renal vascular tree, particularly along glomerular afferent arterioles, we reviewed a variety of imaging techniques that permit a fine characterization of renin synthesis, storage, and release at the single arteriolar, -cell, or -granule level. Powerful tools such as multiphoton microscopy and transgenesis bear the promises of future developments of the field. PMID- 20948563 TI - Cardiovascular Disease, Single Nucleotide Polymorphisms; and the Renin Angiotensin System: Is There a MicroRNA Connection? AB - Essential hypertension is a complex disorder, caused by the interplay between many genetic variants, gene-gene interactions, and environmental factors. Given that the renin-angiotensin system (RAS) plays an important role in blood pressure (BP) control, cardiovascular regulation, and cardiovascular remodeling, special attention has been devoted to the investigation of single-nucleotide polymorphisms (SNP) harbored in RAS genes that may be associated with hypertension and cardiovascular disease. MicroRNAs (miRNAs) are a family of small, ~21-nucleotide long, and nonprotein-coding RNAs that recognize target mRNAs through partial complementary elements in the 3'-untranslated region (3' UTR) of mRNAs and inhibit gene expression by targeting mRNAs for translational repression or destabilization. Since miRNA SNPs (miRSNPs) can create, destroy, or modify miRNA binding sites, this review focuses on the hypothesis that transcribed target SNPs harbored in RAS mRNAs, that alter miRNA gene regulation and consequently protein expression, may contribute to cardiovascular disease susceptibility. PMID- 20948564 TI - Data integration in genetics and genomics: methods and challenges. AB - Due to rapid technological advances, various types of genomic and proteomic data with different sizes, formats, and structures have become available. Among them are gene expression, single nucleotide polymorphism, copy number variation, and protein-protein/gene-gene interactions. Each of these distinct data types provides a different, partly independent and complementary, view of the whole genome. However, understanding functions of genes, proteins, and other aspects of the genome requires more information than provided by each of the datasets. Integrating data from different sources is, therefore, an important part of current research in genomics and proteomics. Data integration also plays important roles in combining clinical, environmental, and demographic data with high-throughput genomic data. Nevertheless, the concept of data integration is not well defined in the literature and it may mean different things to different researchers. In this paper, we first propose a conceptual framework for integrating genetic, genomic, and proteomic data. The framework captures fundamental aspects of data integration and is developed taking the key steps in genetic, genomic, and proteomic data fusion. Secondly, we provide a review of some of the most commonly used current methods and approaches for combining genomic data with focus on the statistical aspects. PMID- 20948565 TI - A new scientific journal linked to a genetic database: towards a novel publication modality. PMID- 20948566 TI - Prediction of disease severity in patients with early rheumatoid arthritis by gene expression profiling. AB - In order to test the ability of peripheral blood gene expression profiles to predict future disease severity in patients with early rheumatoid arthritis (RA), a group of 17 patients (1 +/- 0.2 years disease duration) was evaluated at baseline for gene expression profiles. Disease status was evaluated after a mean of 5 years using an index combining pain, global and recoded MHAQ scores. Unsupervised and supervised algorithms identified "predictor genes" whose combined expression levels correlated with follow-up disease severity scores. Unsupervised clustering algorithms separated patients into two branches. The only significant difference between these two groups was the disease severity score; demographic variables and medication usage were not different. Supervised T-Test analysis identified 19 "predictor genes" of future disease severity. Results were validated in an independent cohort of subjects of established RA with using Support Vector Machines and K-Nearest-Neighbor Classification. Our study demonstrates that peripheral blood gene expression profiles may be a useful tool to predict future disease severity in patients with early and established RA. PMID- 20948567 TI - Development of Potential Pharmacodynamic and Diagnostic Markers for Anti-IFN alpha Monoclonal Antibody Trials in Systemic Lupus Erythematosus. AB - To identify potential pharmacodynamic biomarkers to guide dose selection in clinical trials using anti-interferon-alpha (IFN-alpha) monoclonal antibody (mAb) therapy for systemic lupus erythematosus (SLE), we used an Affymetrix human genome array platform and identified 110 IFN-alpha/beta-inducible transcripts significantly upregulated in whole blood (WB) of 41 SLE patients. The overexpression of these genes was confirmed prospectively in 54 additional SLE patients and allowed for the categorization of the SLE patients into groups of high, moderate, and weak overexpressers of IFN-alpha/beta-inducible genes. This approach could potentially allow for an accurate assessment of drug target neutralization in early trials of anti-IFN-alpha mAb therapy for SLE. Furthermore, ex vivo stimulation of healthy donor peripheral blood mononuclear cells with SLE patient serum and subsequent neutralization with anti-IFN-alpha mAb or anti-IFN-alpha receptor mAb showed that anti-IFN-alpha mAb has comparable effects of neutralizing the overexpression of type I IFN-inducible genes as that of anti-IFNAR mAb. These results suggest that IFN-alpha, and not other members of type I IFN family in SLE patients, is mainly responsible for the induction of type I IFN-inducible genes in WB of SLE patients. Taken together, these data strengthen the view of IFN-alpha as a therapeutic target for SLE. PMID- 20948570 TI - Review of maxillary expansion appliance activation methods: engineering and clinical perspectives. AB - Objective. Review the reported activation methods of maxillary expansion devices for midpalatal suture separation from an engineering perspective and suggest areas of improvement. Materials and Methods. A literature search of Scopus and PubMed was used to determine current expansion methods. A U.S. and Canadian patent database search was also conducted using patent classification and keywords. Any paper presenting a new method of expansion was included. Results. Expansion methods in use, or patented, can be classified as either a screw- or spring-type, magnetic, or shape memory alloy expansion appliance. Conclusions. Each activation method presented unique advantages and disadvantages from both clinical and engineering perspectives. Areas for improvement still remain and are identified in the paper. PMID- 20948569 TI - Mechanical strength and viscoelastic response of the periodontal ligament in relation to structure. AB - The mechanical strength of the periodontal ligament (PDL) was first measured as force required to extract a tooth from its socket using human specimens. Thereafter, tooth-PDL-bone preparations have extensively been used for measurement of the mechanical response of the PDL. In vitro treatments of such specimens with specific enzymes allowed one to investigate into the roles of the structural components in the mechanical support of the PDL. The viscoelastic responses of the PDL may be examined by analysis of the stress-relaxation. Video polarised microscopy suggested that the collagen molecules and fibrils in the stretched fibre bundles progressively align along the deformation direction during the relaxation. The stress-relaxation process of the PDL can be well expressed by a function with three exponential decay terms. Analysis after in vitro digestion of the collagen fibres by collagenase revealed that the collagen fibre components may play an important role in the long-term relaxation component of the stress-relaxation process of the PDL. The dynamic measurements of the viscoelastic properties of the PDL have recently suggested that the PDL can absorb more energy in compression than in shear and tension. These viscoelastic mechanisms of the PDL tissue could reduce the risk of injury to the PDL. PMID- 20948568 TI - Proteomics: challenges, techniques and possibilities to overcome biological sample complexity. AB - Proteomics is the large-scale study of the structure and function of proteins in complex biological sample. Such an approach has the potential value to understand the complex nature of the organism. Current proteomic tools allow large-scale, high-throughput analyses for the detection, identification, and functional investigation of proteome. Advances in protein fractionation and labeling techniques have improved protein identification to include the least abundant proteins. In addition, proteomics has been complemented by the analysis of posttranslational modifications and techniques for the quantitative comparison of different proteomes. However, the major limitation of proteomic investigations remains the complexity of biological structures and physiological processes, rendering the path of exploration paved with various difficulties and pitfalls. The quantity of data that is acquired with new techniques places new challenges on data processing and analysis. This article provides a brief overview of currently available proteomic techniques and their applications, followed by detailed description of advantages and technical challenges. Some solutions to circumvent technical difficulties are proposed. PMID- 20948571 TI - Measurement of orthodontic bracket tie wing elastic and plastic deformation by arch wire torque expression utilizing an optical image correlation technique. AB - Orthodontic lingual root movement (torque) is an important aspect of treatment biomechanics and is typically achieved by torsion of a rectangular wire within the orthodontic bracket slot which introduces a force couple. The magnitude of the force moment achieved by wire torsion may be influenced by deformation of the orthodontic bracket. A device utilizing an optical image correlation technique has been developed to accurately quantify bracket slot dimensional changes during application of wire torsion. Simultaneous torque moment magnitude, degrees of wire twist, and bracket slot dimension data can be gathered. Bracket tie wing elastic deformation when loaded was demonstrated and plastic deformation was also observed with a single rotation of the wire. PMID- 20948572 TI - Coupled Nanomechanical and Raman Microspectroscopic Investigation of Human Third Molar DEJ. AB - The dentino-enamel junction (DEJ) connects enamel, that covers the outer surface of a tooth, to a thicker underlying dentin. The DEJ is a critical interface that permits joining these materials that have widely dissimilar mechanical properties. AFM-based nanoindentation and Raman microspectroscopy were used to define the width and composition of human molar DEJ. Indentation elastic modulus and hardness of enamel, dentin, and DEJ were determined along lines of indents made at 2 MUm intervals across the DEJ. Indents made at maximum loads at each end of the indent lines were used to make visible markers allowing Raman microspectroscopy at 1 MUm intervals across the DEJ, while using the nanoindent markers for orientation and location. Functional DEJ width estimates were made based on results from nanoindentation and Raman microspectroscopy. DEJ width estimates ranged from 4.7 (+/-1.2) MUm to 6.1 (+/-1.9) MUm based on hardness and 4.9 (+/-1.1) MUm to 6.9 (+/-1.9) MUm based on modulus. DEJ width based on Raman peak intensity variations were 8.0 (+/-3.2) MUm to 8.5 (+/-3.1) MUm based on the phosphate peak, and 7.6 (+/-3.2) MUm to 8.0 (+/-2.6) MUm for C-H stretching mode. These estimates are in the range of DEJ width estimates reported using nanoindentation. PMID- 20948573 TI - Shrinkage Stresses Generated during Resin-Composite Applications: A Review. AB - Many developments have been made in the field of resin composites for dental applications. However, the manifestation of shrinkage due to the polymerization process continues to be a major problem. The material's shrinkage, associated with dynamic development of elastic modulus, creates stresses within the material and its interface with the tooth structure. As a consequence, marginal failure and subsequent secondary caries, marginal staining, restoration displacement, tooth fracture, and/or post-operative sensitivity are clinical drawbacks of resin composite applications. The aim of the current paper is to present an overview about the shrinkage stresses created during resin-composite applications, consequences, and advances. The paper is based on results of many researches that are available in the literature. PMID- 20948574 TI - Bone density and cortical thickness in normal, osteopenic, and osteoporotic sacra. AB - It is unclear if a decrease in cancellous bone density or cortical bone thickness is related to sacral insufficiency fractures. We hypothesized that reduction in overall bone density leads to local reductions in bone density and cortical thickness in cadaveric sacra that match clinically observed fracture patterns in patients with sacral insufficiency fractures. We used quantitative computed tomography to measure cancellous density and cortical thickness in multiple areas of normal, osteopenic, and osteoporotic sacra. Cancellous bone density was significantly lower in osteoporotic specimens in the central and anterior regions of the sacral ala compared with other regions of these specimens. Cortical thickness decreased uniformly in all regions of osteopenic and osteoporotic specimens. These results support our hypothesis that areas of the sacrum where sacral insufficiency fractures often occur have significantly larger decreases in cancellous bone density; however, they do not support the hypothesis that these areas have local reduction of cortical bone thickness. PMID- 20948575 TI - SOST and DKK: Antagonists of LRP Family Signaling as Targets for Treating Bone Disease. AB - The study of rare human genetic disorders has often led to some of the most significant advances in biomedical research. One such example was the body of work that resulted in the identification of the Low Density Lipoprotein-Related Protein (LRP5) as a key regulator of bone mass. Point mutations were identified that encoded forms of LRP5 associated with very high bone mass (HBM). HBM patients live to a normal age and do not appear to have increased susceptibility to carcinogenesis or other disease. Thus, devising methods to mimic the molecular consequences of this mutation to treat bone diseases associated with low bone mass is a promising avenue to pursue. Two groups of agents related to putative LRP5/6 functions are under development. One group, the focus of this paper, is based on antagonizing the functions of putative inhibitors of Wnt signaling, Dickkopf-1 (DKK1), and Sclerostin (SOST). Another group of reagents under development is based on the observation that LRP5 may function to control bone mass by regulating the secretion of serotonin from the enterrochromaffin cells of the duodenum. PMID- 20948576 TI - Odanacatib, a new drug for the treatment of osteoporosis: review of the results in postmenopausal women. AB - Osteoclasts are specialized cells that initiate the process of bone resorption, which has two phases, dissolution of the mineral component and degradation of the organic matrix, in which cathepsin K plays a key role. Cathepsin K inhibitors, which block the activity of cathepsin on bone resorption lacunae, may be a new therapeutic option in osteoporosis. Odanacatib is a nonpeptidic biaryl inhibitor of cathepsin K. Two studies have evaluated the efficacy and safety of odanacatib, a phase I study to determine the dose and a phase II study of safety and efficacy. Due to the long half-life of odanacatib and the similar effects of different doses on bone remodeling markers, a weekly dosage was chosen for the phase II trail, with the best results being obtained with a dose of 50 mg. At 36 months, increases in bone mineral density similar to those produced by other powerful antiresorptive drugs (zoledronate and denosumab) were observed but there were differences in the behaviour of bone remodeling markers. Data on fractures from the phase III trial currently in development are required to confirm these possible advantages. PMID- 20948577 TI - Retaining Residual Ovarian Tissue following Ovarian Failure Has Limited Influence on Bone Loss in Aged Mice. AB - Previous work showed that retaining residual ovarian tissue protects young mice from accelerated bone loss following ovarian failure. The present study was designed to determine whether this protection is also present in aged animals. Aged (9-12 months) C57BL/6Hsd female mice were divided into: CON (vehicle), VCD (160 mg/kg; 15d), or OVX (ovariectomized). Lumbar BMD was monitored by DXA and MUCT used to assess vertebral microarchitecture. BMD was not different between VCD and CON at any time point but was lower (P < .05) than baseline, starting 1 month after ovarian failure in VCD and OVX mice. Following MUCT analysis there were no differences between CON and VCD, but OVX mice had lower bone volume fraction, trabecular thickness, and a trend for decreased connectivity density. These findings provide evidence that retention of residual ovarian tissue may protect aged follicle-depleted mice from accelerated bone loss to a lesser extent than that observed in young mice. PMID- 20948578 TI - A longitudinal study of the effect of genistein on bone in two different murine models of diminished estrogen-producing capacity. AB - This experiment was designed to assess the capacity of dietary genistein (GEN), to attenuate bone loss in ovariectomized (OVX) and ovary-intact VCD-treated mice. Pretreatment of mice with 4-vinylcyclohexene diepoxide (VCD) gradually and selectively destroys ovarian follicles whilst leaving ovarian androgen-producing cells largely intact. VCD induces a perimenopause-like condition prior to the onset of reproductive acyclicity. Sixteen-week-old C57BL/6J mice were randomized to five treatment groups: sham(SHM), OVX, SHM + VCD, OVX + GEN, and SHM + VCD + GEN. In vivo, blood samples were drawn for hormone and isoflavone analyses, estrous cycles were monitored, and X-ray imaging was performed to assess changes in bone parameters. Following sacrifice, ovaries were assessed histologically, bone microarchitecture was evaluated via microcomputed tomography, and bone mechanical properties were measured. Some effects of GEN were observed in OVX mice, but GEN effects were not able to be evaluated in VCD-treated mice due to the subtle diminution of bone during the 4 months of this experiment. PMID- 20948580 TI - Stress and the neuroendocrine system: the role of exercise as a stressor and modifier of stress. AB - In this article, the physiological impact of one form of stress - physical exercise - on the neuroendocrine system will be discussed. The specific intent of the review is to present an overview of stress endocrinology, the conceptual models associated with this area of study, and a discourse on the dual role of exercise as both a stressor and a modifier of stress within the neuroendocrine system. These points are addressed with respect to the current research literature dealing with exercise endocrinology in an adult population. PMID- 20948581 TI - Stereoselective synthesis of the C(1)-C(12) segment of iriomoteolide 1a: a very potent macrolide antitumor agent. AB - A stereoselective synthesis of the C(1)-C(12) segment of the potent cytotoxic macrolide, iriomoteolide 1a, has been accomplished. The key steps involve an enzymatic kinetic resolution of a beta-hydroxy amide, a Pd-catalyzed cross coupling to a substituted allylsilane, a highly regio- and stereoselective conjugate addition of lithium dimethylcopper to an alpha, beta-acetylenic esters and an elaboration of the C(6)-C(7) trans-olefin geometry by a Julia-Kocienski olefination. PMID- 20948582 TI - Connectivity Analysis is Essential to Understand Neurological Disorders. AB - Neurological and neuropsychiatric disorders are major causes of morbidity worldwide. A systems level analysis including functional and structural neuroimaging is particularly useful when the pathology leads to disorders of higher order cognitive functions in human patients. However, an analysis that is restricted to regional effects is impoverished and insensitive, compared to the analysis of distributed brain networks. We discuss the issues to consider when choosing an appropriate connectivity method, and compare the results from several different methods that are relevant to fMRI and PET data. These include psychophysiological interactions in general linear models, structural equation modeling, dynamic causal modeling, and independent components analysis. The advantages of connectivity analysis are illustrated with a range of structural and neurodegenerative brain disorders. We illustrate the sensitivity of these methods to the presence or severity of disease and/or treatment, even where analyses of voxel-wise activations are insensitive. However, functional and structural connectivity methods should be seen as complementary to, not a substitute for, other imaging and behavioral approaches. The functional relevance of changes in connectivity, to motor or cognitive performance, are considered alongside the complex relationship between structural and functional changes and neuropathology. Finally some of the problems associated with connectivity analysis are discussed. We suggest that the analysis of brain connectivity is an essential complement to the analysis of regionally specific dysfunction, in order to understand neurological and neuropsychiatric disease, and to evaluate the mechanisms of effective therapies. PMID- 20948583 TI - Pulvinar and Affective Significance: Responses Track Moment-to-Moment Stimulus Visibility. AB - Research on emotion has considered the pulvinar to be an important component of a subcortical pathway conveying visual information to the amygdala in a largely "automatic" fashion. An older literature has focused on understanding the role of the pulvinar in visual attention. To address the inconsistency between these independent literatures, in the present study, we investigated how pulvinar responses are involved in the processing of affectively significant stimuli and how they are influenced by stimulus visibility during attentionally demanding conditions. Subjects performed an attentional blink task during fMRI scanning involving affectively significant (CS+) and neutral stimuli (CS-). Pulvinar responses were not influenced by affective significance (CS+ vs. CS-) per se. Instead, evoked responses were only modulated by affective significance during hit trials, but not during miss trials. Importantly, moment-to-moment fluctuations in response magnitude closely tracked trial-by-trial detection performance, and thereby visibility. This relationship was only reliably detected during the affective condition. Our results do not support a passive role of the pulvinar in affective processing, as invoked in the context of the subcortical pathway hypothesis. Instead, the pulvinar appears to be involved in mechanisms that are closely linked to attention and awareness. As part of thalamocortical loops with diverse cortical territories, we argue that the medial pulvinar is well positioned to influence information processing in the brain according to a stimulus's biological significance. In particular, when weak and/or brief visual stimuli have affective significance, cortico-pulvino-cortical circuits may act to coordinate and amplify signals in a manner that enhances their behavioral impact. PMID- 20948585 TI - Assessing periodicity of periodic leg movements during sleep. AB - BACKGROUND: Periodic leg movements (PLM) during sleep consist of involuntary periodic movements of the lower extremities. The debated functional relevance of PLM during sleep is based on correlation of clinical parameters with the PLM index (PLMI). However, periodicity in movements may not be reflected best by the PLMI. Here, an approach novel to the field of sleep research is used to reveal intrinsic periodicity in inter movement intervals (IMI) in patients with PLM. METHODS: Three patient groups of 10 patients showing PLM with OSA (group 1), PLM without OSA or RLS (group 2) and PLM with RLS (group 3) are considered. Applying the "unfolding" procedure, a method developed in statistical physics, enhances or even reveals intrinsic periodicity of PLM. The degree of periodicity of PLM is assessed by fitting one-parameter distributions to the unfolded IMI distributions. Finally, it is investigated whether the shape of the IMI distributions allows to separate patients into different groups. RESULTS: Despite applying the unfolding procedure, periodicity is neither homogeneous within nor considerably different between the three clinically defined groups. Data-driven clustering reveals more homogeneous and better separated clusters. However, they consist of patients with heterogeneous demographic data and comorbidities, including RLS and OSA. CONCLUSIONS: The unfolding procedure may be necessary to enhance or reveal periodicity. Thus this method is proposed as a pre-processing step before analyzing PLM statistically. Data-driven clustering yields much more reasonable results when applied to the unfolded IMI distributions than to the original data. Despite this effort no correlation between the degree of periodicity and demographic data or comorbidities is found. However, there are indications that the nature of the periodicity might be determined by long-range interactions between LM of patients with PLM and OSA. PMID- 20948586 TI - Automated algorithm for atlas-based segmentation of the heart and pericardium from non-contrast CT. AB - Automated segmentation of the 3D heart region from non-contrast CT is a pre requisite for automated quantification of coronary calcium and pericardial fat. We aimed to develop and validate an automated, efficient atlas-based algorithm for segmentation of the heart and pericardium from non-contrast CT.A co registered non-contrast CT atlas is first created from multiple manually segmented non-contrast CT data. Non-contrast CT data included in the atlas are co registered to each other using iterative affine registration, followed by a deformable transformation using the iterative demons algorithm; the final transformation is also applied to the segmented masks. New CT datasets are segmented by first co-registering to an atlas image, and by voxel classification using a weighted decision function applied to all co-registered/pre-segmented atlas images. This automated segmentation method was applied to 12 CT datasets, with a co-registered atlas created from 8 datasets. Algorithm performance was compared to expert manual quantification.Cardiac region volume quantified by the algorithm (609.0 +/- 39.8 cc) and the expert (624.4 +/- 38.4 cc) were not significantly different (p=0.1, mean percent difference 3.8 +/- 3.0%) and showed excellent correlation (r=0.98, p<0.0001). The algorithm achieved a mean voxel overlap of 0.89 (range 0.86-0.91). The total time was <45 sec on a standard windows computer (100 iterations). Fast robust automated atlas-based segmentation of the heart and pericardium from non-contrast CT is feasible. PMID- 20948587 TI - Proteomics of saliva: personal experience. AB - The salivary proteome is a complex protein mixture resulting from the activity of salivary glands with the contribution of other components that form the oral environment such as oral tissues and micro-organisms. For diagnosis purposes, saliva collection has the great advantage of being an easy and non-invasive technique. Human saliva proteomics have proven to be a novel approach in the search for protein biomarkers for detection of different local and systemic diseases. Currently, more than 1400 salivary proteins have been identified. In the last few years, our research group has extensively studied the salivary proteomics in order to analyse the salivary composition, investigating the major families of proteins present in human and mammalian saliva, the post translational modifications, the different contributions of glands, the physiological and pathological modifications of saliva. The aim of this report is to present our personal experience in salivary proteomics. In conclusion, salivary proteome analysis represents an important field both for diagnosis and monitoring of various diseases and could be considered a novel approach to prevention of various pathological conditions. PMID- 20948584 TI - Mechanisms of induction and maintenance of spike-timing dependent plasticity in biophysical synapse models. AB - We review biophysical models of synaptic plasticity, with a focus on spike-timing dependent plasticity (STDP). The common property of the discussed models is that synaptic changes depend on the dynamics of the intracellular calcium concentration, which itself depends on pre- and postsynaptic activity. We start by discussing simple models in which plasticity changes are based directly on calcium amplitude and dynamics. We then consider models in which dynamic intracellular signaling cascades form the link between the calcium dynamics and the plasticity changes. Both mechanisms of induction of STDP (through the ability of pre/postsynaptic spikes to evoke changes in the state of the synapse) and of maintenance of the evoked changes (through bistability) are discussed. PMID- 20948588 TI - Safety, tolerability and efficacy of sublingual allergoid immunotherapy with three different shortened up-dosing administration schedules. AB - Sublingual immunotherapy with monomeric allergoid, given according to the standard schedule, was reported to be effective and safe in many clinical trials. However, a long period of time may elapse before achievement of a clinical benefit. This study was thus performed using two different shortened (4-day) induction (= up-dosing) schedules, which allowed a rapid achievement of the maintenance dosage. Overall, 86 patients suffering from rhinitis and oculorhinitis have been recruited, none of whom had received immunotherapy before. The study design was prospective, randomized, with three parallel groups receiving, according to a randomization list, one of the three induction (two up dosing one no-up-dosing) phase schedules under study. A fourth group of patients served as controls, and did not receive any sublingual immunotherapy but only rescue medications if and when necessary. All patients were evaluated to assess their baseline conditions, and thereafter at 3 and 6 months. The evaluation parameters were: Visual Analogue Scale, symptom-medication scores, nasal provocation test. All three induction schedules under study were well accepted by the patients, with very few adverse reactions. The clinical efficacy, evaluated with Visual Analogue Scale (p < 0.001), symptom-medication scores (p < 0.02) and nasal provocation tests (p < 0.01), was found to be significant in all three sublingual immunotherapy-treated groups of 64 (n86) patients, but was not significant in controls 22 (n86). According to the Authors, with this simplified schedule process, sublingual immunotherapy is a therapeutic option that is becoming increasingly well-accepted not only by allergy specialists but also by patients. PMID- 20948589 TI - Microdebrider-assisted versus radiofrequency-assisted inferior turbinoplasty: a prospective study with objective and subjective outcome measures. AB - In order to relieve the symptoms of nasal obstruction in patients with inferior turbinate hypertrophy, various surgical methods have been used. Aim of this study was to compare post-operative outcome between radiofrequency and microdebrider assisted partial turbinoplasty. A prospective study was performed in 268 patients with nasal obstruction and hypertrophied turbinate mucosa refractory to medical treatment, from December 2000 to December 2005. Overall, 124 patients were treated with microdebrider (Group 1) and 144 patients with radiofrequency (Group 2). Post-operative changes in the degree of nasal obstruction, nasal discharge, hyposmia and headache were evaluated prospectively on the 7(th) day, 1(st), and 3(rd) months after the procedure. Rhinomanometric evaluation was also performed for objective comparison. Both procedures were perfectly tolerated by the patients. The nasal obstruction scale improved significantly in Group 1 on day 7, and within the periods of 1(st) and 3(rd) months after surgery, while the significant improvement took place in Group 2 only in the 1(st) and 3(rd) months after surgery. The comparison between the two groups showed that symptom improvement was statistically significant in Group 1 on the 7(th) day, 1(st) and 3(rd) months after surgery. Severity of nasal discharge, headache and hyposmia grades improved significantly in the first week after the operation both in the microdebrider and radiofrequency group and persisted during the 1(st) and 3(rd) months after the operation. Since microdebrider can effectively widen the nasal airway, the rhinomanometric measurements of these patients were found to be lower than in the radiofrequency group. Moreover, patient satisfaction in the microdebrider group was higher than that in the radiofrequency group. In conclusion, this study suggests that microdebrider-assisted partial turbinoplasty is more effective and satisfactory in relieving nasal obstruction. PMID- 20948590 TI - Tongue Base Reduction with Thyro-Hyoido-Pexy (TBRTHP) vs. Tongue Base Reduction with Hyo-Epiglottoplasty (TBRHE) in mild-severe OSAHS adult treatment. Preliminary findings from a prospective randomised trial. AB - In a preliminary prospective randomised study, a series of 5 patients submitted to classic Tongue Base Reduction with Hyo-Epiglottoplasty (TBRHE according to Chabolle et al., 1998) is compared to a series of 7 patients submitted to a modified version of Chabolle's procedure. The changes introduced in the new surgical technique can be summarised as follows: a) lower neck skin incision; b) different neurovascular bundle identification; c) submucosal tongue base muscle resection; d) variation of the caudal hyoid stabilisation, already described by the Authors in 2008 (Tongue Base Reduction with Thyro-Hyoido-Pexy). The objective has been primarily to compare the feasibility, functional effectiveness and overall tolerability of the modified procedure. In this preliminary study Tongue Base Reduction with Thyro-Hyoido-Pexy has proven to be an easy and rapid procedure, with shorter post-operative functional recovery and comparable polysomnographic and neuro-psychological short time results. PMID- 20948591 TI - Percutaneous sclerotherapy for arteriovenous malformations of the face in the outpatient clinic. AB - Sclerotherapy for arteriovenous malformations has to be performed under general anaesthesia because of the pain during injection and the need of careful monitoring. Two cases with arteriovenous malformations of the face regions are presented in whom percutaneous sclerotherapy was performed under local anaesthesia in the outpatient clinic. The sessions were uneventful and there was a visible decrease in the overall size and an improvement in skin colour of the lesion could be seen. Sclerotherapy can be used in the outpatient clinic to treat arteriovenous malformations that have a slow flow or a venous outflow that can be compressed to artificially slow the flow during injection. PMID- 20948592 TI - Otosclerosis associated with type B-1 inner ear malformation. AB - Malformations of bony inner ear are rare anomalies occurring in approximately 20% of patients with congenital sensorineural hearing loss. Conductive hearing loss is usually associated with abnormalities of the external and middle ear. Recent reports of patients with lateral semicircular canal malformations indicate inner ear malformations to be associated with sensorineural or conductive hearing loss. Differential diagnosis of conductive hearing loss should include otosclerosis, isolated ossicular deformities, inner ear anomalies or a combination of these. In this report, a case is described with right vestibule-lateral semicircular canal dysplasia presenting at our centre with bilateral otosclerosis. PMID- 20948593 TI - A case of an uncommon anatomic variation of the middle turbinate associated with headache. AB - Headache due to the pressure of nasal mucosa in the absence of inflammation of the nose and paranasal sinuses is a clinical entity that has gained wide acceptance. Concha bullosa is the most commonly observed anatomical variation of the lateral nasal wall. The case is presented of a 31-year-old female with a history of intermittent frontal headache and bilateral nasal obstruction in whom we found the concha bullosa containing another, smaller concha bullosa inside. This is the first report of a case in which both outer and inner concha bullosa were septated (with two air cells inside). After resecting the lateral portion of outer concha bullosa and removing the inner concha bullosa, the patient reported no further headaches. The differential diagnosis of the variations of the middle turbinate and the relationships between the anatomic variations and pathophysiology of contact point headaches are discussed herewith. PMID- 20948594 TI - Late diagnosis of a solitary fibrous tumour of the parapharyngeal space in a continuous positive airway pressure-treated patient. AB - Solitary fibrous tumours of the parapharyngeal space are a very rare finding and have been described less than 10 times in the English literature. The Authors discuss a clinical case of a solitary fibrous tumour in the parapharyngeal space in a 77-year-old male, who had begun treatment for a newly discovered obstructive sleep apnoea syndrome with a continuous positive airway pressure - device one year prior to diagnosis. This rare location of an uncommon lesion often gives rise to difficulty in diagnosis or to misdiagnosis and the Authors, therefore, made a review of the scientific literature and analysed the diagnostic and therapeutic procedures used. The importance of this report lies mainly in two aspects: on the one hand, the discussion concerning the diagnostic and therapeutic procedures and on the other, the need of a thorough evaluation in obstructive sleep apnoea syndrome patients before treating them with a chronic device like the continuous positive airway pressure device. PMID- 20948595 TI - Natural killer T cell recognition of lipid antigens. AB - Natural killer T cells recognize lipid antigens in the context of CD1 molecules. Recent publications show that this mode of recognition differs substantially from that of classic T-cell receptor peptide-major histocompatibility complex interaction. PMID- 20948596 TI - Putative functions of caspase-2. AB - Caspase-2 is the most evolutionarily conserved of caspase family members, yet its physiological function has remained unclear and is a matter of considerable debate. Newly published data now suggest that caspase-2 is required for cell cycle regulation, repair of damaged DNA, and in suppressing Myc-induced lymphomagenesis. Additionally, loss of Casp2 in mice leads to features of premature ageing. These findings suggest that caspase-2 has non-apoptotic functions in addition to its context-dependent roles in cell death. PMID- 20948597 TI - Current themes and recent advances in modelling species occurrences. AB - Recent years have seen a huge expansion in the range of methods and approaches that are being used to predict species occurrences. This expansion has been accompanied by many improvements in statistical methods, including more accurate ways of comparing models, better null models, methods to cope with autocorrelation, and greater awareness of the importance of scale and prevalence. However, the field still suffers from problems with incorporating temporal variation, overfitted models and poor out-of-sample prediction, confusion between explanation and prediction, simplistic assumptions, and a focus on pattern over process. The greatest advances in recent years have come from integrative studies that have linked species occurrence models with other themes and topics in ecology, such as island biogeography, climate change, disease geography, and invasive species. PMID- 20948598 TI - Aberrant mRNA transcripts and nonsense-mediated decay. AB - Nobody's perfect, and even the cell turns out a certain fraction of erroneous mRNA transcripts. One of the key quality control mechanisms put in place to recognize and eliminate these transcripts before they can be translated into faulty proteins is nonsense-mediated decay. Proteins involved in nonsense mediated decay are highly conserved across species from plants to humans, and recent studies in Arabidopsis thaliana reveal both intriguing similarities and differences in the mechanisms employed to carry it out. PMID- 20948599 TI - Insulators: linking genome architecture to gene regulation. AB - Insulator elements have long been associated with a proposed domain boundary function, ensuring appropriate associations between regulatory elements and transcription units through the physical organisation of the genome into looped domains. Recent experiments in Drosophila have, however, highlighted a more direct involvement of insulators in transcriptional regulation. PMID- 20948600 TI - Prediction of function in protein superfamilies. AB - Assignment of function for enzymes encoded in sequenced genomes is a challenging task. Predictions of enzyme function can be made using clues from superfamily assignment, structure, genome context, phylogenetic conservation, and virtual screening to identify potential ligands. Ultimately, confident assignment of function requires experimental verification as well as an understanding of the physiological role of an enzyme in the context of the metabolic network. PMID- 20948601 TI - Gut commensal flora: tolerance and homeostasis. AB - Commensal microorganisms are not ignored by the intestinal immune system. Recent evidence shows that commensals actively participate in maintaining intestinal immune homeostasis by interacting with intestinal epithelial cells and delivering tolerogenic signals that are transmitted to the underlying cells of the immune system. PMID- 20948602 TI - Unnatural amino acids: better than the real things? AB - Considerable effort has been dedicated to the development of technology for the site-specific incorporation of unnatural amino acids into proteins, with nonsense codon suppression and expressed protein ligation emerging as two of the most promising methods. Recent research advances in which these methods have been applied to study protein function and mechanism are briefly highlighted, and the potential of the methods for efficient, widespread future use in vitro and in vivo is critically evaluated. PMID- 20948604 TI - A direct measurement of crossing over in human prophase oocytes. AB - The nature of the relationship between crossing over and failed segregation in human oocytes is of obvious interest. A recent paper by Cheng and colleagues provides important insights into the distribution of crossover events (as marked by MLH1 foci) in human oocytes and raises complex questions regarding discrepancies between direct cytological assessment of exchange and measurement of crossing over by linkage analysis. PMID- 20948603 TI - Biased agonism. AB - Seven-transmembrane receptors are commonly coupled to multiple signaling pathways in cells. The simple model describing agonists for these receptors as producing a common active state to induce uniform activation of the pathways linked to the receptor has been shown to be untenable in light of a large body of data that suggest that some agonists produce activation of some but not all available pathways. These agonists are referred to as 'biased' in that they select which signaling pathways become activated upon binding to the receptor. The data to support this mechanism as well as ideas on the possible therapeutic application of this effect will be discussed. PMID- 20948606 TI - Evaluation of global change impacts on diffuse pollution. AB - In a global change context, several recent advances in the field of hydrology and biogeochemistry suggest that a move from a riparian to a river drainage basin perspective is necessary to reframe research and thus provide a more integrated scientific understanding to inform water- and land-use management and policy. We explore this assertion using the control of diffuse pollution as an exemplar. PMID- 20948605 TI - Induced pluripotent stem (iPS) cells: an up-to-the-minute review. AB - Recent advances in nuclear reprogramming technology allow the transformation of terminally differentiated, adult cells into induced pluripotent stem cells whose phenotype is indistinguishable from that of embryonic stem cells. This leap forward enables the creation of patient-specific pluripotent cell lines that carry disease genotypes. These cell lines could be used both as in vitro models for the study of disease and as potential sources of material for cell replacement therapy. Ultimately, a greater understanding of the process by which cellular identity is shaped and altered may allow the generation of particular cell types for the treatment of degenerative disease. PMID- 20948607 TI - Genetic reprogramming of host cells by bacterial pathogens. AB - During the course of infection, pathogens often induce changes in gene expression in host cells and these changes can be long lasting and global or transient and of limited amplitude. Defining how, when, and why bacterial pathogens reprogram host cells represents an exciting challenge that opens up the opportunity to grasp the essence of pathogenesis and its molecular details. PMID- 20948608 TI - Regulation of the mTOR signaling pathway: from laboratory bench to bedside and back again. AB - Recent publications have moved us significantly closer to a complete understanding of the mammalian target of rapamycin (mTOR) signaling pathway, which plays a central role in the control of growth and metabolism and is dysregulated in a broad spectrum of human diseases, including cancer, tuberous sclerosis, diabetes, and cardiovascular and neurodegenerative diseases. Rapamycin related mTOR inhibitors have shown clinical efficacy in several of these diseases, and novel inhibitors currently in development will be valuable tools for further dissections of the mTOR signaling network in human health and disease. PMID- 20948609 TI - Inhibitor of Apoptosis (IAP) proteins as drug targets for the treatment of cancer. AB - Three companies, Genentech, Aegera Therapeutics/Human Genome Sciences, and Novartis, have commenced phase 1 clinical trials of inhibitor of apoptosis (IAP) antagonist 'Smac mimetic' compounds for the treatment of cancer. These trials represent the culmination of a line of research that commenced with analysis of how insect viruses stop host cells from killing themselves and led to the discovery of a family of proteins that regulate development in insects and signalling by tumour necrosis factor superfamily members in mammals, which prompted development of drugs that mimic natural IAP-binding proteins to promote cell death. PMID- 20948611 TI - Bitopic ligands: all-in-one orthosteric and allosteric. AB - Natural ligands of G-protein-coupled receptors interact with the orthosteric ligand binding site, as do most of the classical synthetic ligands. The discovery of ligands targeting different, allosteric binding sites considerably expanded the repertoire of G-protein-coupled receptor ligands. More recently, bitopic ligands have been described that target both orthosteric and allosteric sites at the same time. PMID- 20948610 TI - Music drives brain plasticity. AB - Music is becoming more and more of an issue in the cognitive neurosciences. A major finding in this research area is that musical practice is associated with structural and functional plasticity of the brain. In this brief review, I will give an overview of the most recent findings of this research area. PMID- 20948612 TI - When transcription meets recombination: a lesson from the human RECQ protein complexes. AB - Since the cloning of the first human RECQ gene, RECQ1, more than 15 years ago, RECQ helicases have been a major focus in cancer research. Recent studies of human RECQ protein complexes are providing insight into their roles in various DNA metabolic pathways that protect the integrity of our genome. PMID- 20948613 TI - 'Functional' body composition: differentiating between benign and non-benign obesity. AB - Recent body composition analyses, together with assessments of insulin resistance, aerobic fitness, and intima-media thickness of the common carotid artery, have shown that metabolically-benign obese subjects have a similar BMI, waist circumference, and subcutaneous abdominal fat compared with non metabolically-benign obese subjects. Research has suggested that 25-30% of the obese population do not need either treatment or prevention of secondary disorders. Therefore, assessment of functional body composition should replace nutritional status-based risk assessments (such as the body mass index) in both metabolic research and clinical decision making. The concept of 'functional' body composition gives us a more sophisticated view on nutritional status, metabolism, endocrinology, and diseases. Knowledge of detailed body composition enables characterization of biomedical traits which will give functional evidence relating genetic variants. PMID- 20948614 TI - The posterior parietal cortex and non-spatial cognition. AB - The primate posterior parietal cortex (PPC) processes information related to environmental physical space. The human PPC has apparently expanded not only in size but also in its functional range to encompass certain abstract and higher order conceptual spaces. In this report, we review various forms of non-spatial representation in the PPC. These forms are presented roughly in order of the level of abstraction of the 'objects' and pseudo-spatial relations represented. Also, we consider mechanisms that could have enabled the hominid PPC to establish such representations. Lastly, we offer a general principle to unify the newer forms of representation with the original functions of the PPC. PMID- 20948615 TI - Customized care 2020: how medical sequencing and network biology will enable personalized medicine. AB - Applications of next-generation nucleic acid sequencing technologies will lead to the development of precision diagnostics that will, in turn, be a major technology enabler of precision medicine. Terabyte-scale, multidimensional data sets derived using these technologies will be used to reverse engineer the specific disease networks that underlie individual patients' conditions. Modeling and simulation of these networks in the presence of virtual drugs, and combinations of drugs, will identify the most efficacious therapy for precision medicine and customized care. In coming years the practice of medicine will routinely employ network biology analytics supported by high-performance supercomputing. PMID- 20948616 TI - HIV-1 host interactions: integration of large-scale datasets. AB - HIV-1 replication and viral pathogenesis are dependent on numerous host factors. A series of recent papers apply genome-wide and large-scale approaches to map host-virus interactions and to identify host proteins capable of restricting (that is, controlling) the virus. Strategies include genome-wide association studies, small interfering RNA screens, genome-wide transcriptome profiling, proteome studies, and the assessment of the role of host-encoded microRNAs in infection. The various layers of large-scale data are brought together through meta-analytical procedures. PMID- 20948617 TI - Targeting cytokines in inflammatory diseases: focus on interleukin-1-mediated autoinflammation. AB - In this commentary, we summarize the most recent advances in the cytokine targeting therapies. We focus on new aspects of interleukin-1 (IL-1)-mediated autoinflammation and novel strategies to target IL-1. PMID- 20948618 TI - Implications of the RecA structure. AB - The RecA protein has been the most intensively studied protein involved in homologous genetic recombination, but until recently very little has been known about the molecular details of how RecA can bring two DNA molecules into juxtaposition and switch strands between them. A recent RecA-DNA crystal structure provides some striking new insights. PMID- 20948619 TI - The roles, mechanisms, and controversies of autophagy in mammalian biology. AB - Autophagy is a universally conserved metabolic program of catabolism that plays important roles in energy homeostasis and impacts both normal physiology and multiple disease processes, including cancer. Autophagy has been documented as a pro-survival mechanism used to maintain viability under starvation conditions; however, conflicting findings have also implicated autophagy in the control of cell death. Adding to the controversy, central mediators of autophagy have been implicated in both pro-survival and pro-death processes. This report highlights recent insights into our understanding of how autophagy is regulated and newly discovered physiological roles for autophagy in normal biology and disease. PMID- 20948620 TI - Integrin-independent movement of immune cells. AB - Cell motility requires the temporal and spatial coordination of the actin cytoskeleton with cell-matrix adhesions. Since their discovery more than 20 years ago, integrins have been at the center of cell-matrix adhesion research. Integrin mediated adhesions link the actin network to the extracellular matrix and are commonly observed as cells migrate across rigid two-dimensional substrates. However, as more cell motility studies are being conducted in three-dimensional (3D) culture systems and in vivo, the role of integrins has become less clear. Recent work has shown that leukocyte migration in 3D contexts can be integrin independent and that alternative mechanisms of cell adhesion are employed. PMID- 20948621 TI - Depression and metabolism: linking changes in leptin and ghrelin to mood. AB - Major depressive disorder is associated with an elevated risk of numerous metabolic disturbances, including obesity, metabolic syndrome, insulin-dependent diabetes mellitus type II, and death after myocardial infarction. Several recent papers also indicate that disturbances of mood may alter peripheral signaling pathways that regulate metabolic processes, including those involving leptin and ghrelin. PMID- 20948622 TI - Autoimmune channelopathies: new antibody-mediated disorders of the central nervous system. AB - Contrary to established wisdom, there now appear to be antibody-mediated central nervous system (CNS) disorders. Over the last few years, a number of patients have been defined with antibodies to voltage-gated (VGKC) or ligand-gated (NMDAR, GlyR) ion channels or ungated water (AQP4) channels. Some of the disorders improve spontaneously over time, others may be more chronic and relapsing remitting, but immunotherapies reduce antibody levels and improve clinical outcomes. These are exciting developments that herald a new era of immunotherapy responsive CNS diseases, and they raise interesting questions regarding the aetiological and pathogenic mechanisms mediating these conditions. PMID- 20948623 TI - Thymic egress: S1P of 1000. AB - Recent studies have begun to illuminate the mechanism of T-cell export from the thymus, with the identification of a required lysophospholipid receptor, two upstream transcription factors, and several downstream regulators of cytoskeleton dynamics. This work has generated immediate translational impact, aiding the design of immunosuppressant drugs and the identification of a novel form of human immunodeficiency. PMID- 20948624 TI - The unforeseeable hammerhead ribozyme. AB - Despite its small size, the complex behavior of the hammerhead ribozyme keeps surprising us, even more than 20 years after its discovery. Here, we summarize recent developments in the field, in particular the discovery of the first split hammerhead ribozyme. PMID- 20948626 TI - Cell biology of mechanotransduction in inner-ear hair cells. AB - The cloning of deafness genes, especially those for Usher syndrome, has helped to identify a variety of structural proteins involved in the development and function of hair-cell stereocilia. These include novel cadherins, a handful of myosin motors, and scaffolding proteins. Yet a new understanding of these proteins has upended the orthodox view of mechanosensation by hair cells. PMID- 20948625 TI - Intracellular trafficking and signaling in development. AB - Tissue patterning during development relies on cell communication by secreted proteins and receptors that engage in complex signaling crosstalk to induce distinct cell behaviors in a context-dependent fashion. Here I summarize recent insights into basic mechanisms that control the distribution and activities of transforming growth factor beta, Wnt, Hedgehog, and Notch proteins, by regulating trafficking decisions during secretion and endocytosis. PMID- 20948627 TI - The dark side of clock-controlled flowering. AB - Perception of seasonal changes in day length allows plants to properly maintain daily biological rhythms and determine the most favorable time for flowering. Important knowledge has been gained recently on the molecular basis of this process, which depends not only on light perception at certain times of day but also on its dark phase. PMID- 20948628 TI - Development of object recognition in humans. AB - Although the ability to perceive simple shapes emerges in infancy, the ability to recognize individual objects as well as adults do continues to develop through childhood into adolescence. Despite this slow development, recent neuroimaging studies have revealed that an area of the ventral visual cortex that responds selectively to the category of common objects is adult-like by 5-8 years of age. The challenge for future research will be to identify the specific visual skills involved in object recognition that continue to develop through childhood and adolescence, and the neural mechanisms underlying this protracted development. PMID- 20948630 TI - A current view of Alzheimer's disease. AB - Several genes that influence susceptibility to Alzheimer's disease (AD) have been known for over two decades. Recent advances have elucidated novel candidate genes and the pathogenetic mechanisms underlying neurodegeneration in AD. Here, we summarize what we have learned from studies of the known AD genes with regard to the causes of AD and emerging therapies. We also review key recent discoveries that have enhanced our understanding of the etiology and pathogenesis of this devastating disease, based on new investigations into the genes and molecular mechanisms underlying AD. PMID- 20948629 TI - Two mechanisms that account for major histocompatibility complex restriction of T cells. AB - In recent studies, two distinct mechanisms have been proposed to account for major histocompatibility complex (MHC) restriction of T-cell activity: (a) evolution-driven interactions between T-cell receptor (TCR) variable regions and MHC, and (b) a requirement for CD4 or CD8 binding to MHC to initiate signalling through the TCR complex. Both mechanisms are likely to be essential, but for different reasons. PMID- 20948631 TI - Using the ribosome to synthesize peptidomimetics. AB - Peptidomimetic research is an approach to identify peptide-based drugs designed to mimic structural, conformational, and biological properties of peptides while overcoming their limitations, such as protease instability and poor cell penetration. With recent advances in ribosomal synthesis of peptides containing unnatural amino acids, this technology appears suitable for preparing large structurally diverse libraries of peptidomimetics for drug discovery screening. PMID- 20948632 TI - Microtubule motors: moving forward on many fronts. AB - Microtubule motors drive the movement of many different cargoes in eukaryotic cells. A combination of in vitro and in vivo approaches has led to a better understanding of their mechanism of action and function and are also revealing that the microtubule track itself may have an important role to play in directing cargo movement within the cell. PMID- 20948633 TI - Molecular dynamics-based approaches for enhanced sampling of long-time, large scale conformational changes in biomolecules. AB - The rugged energy landscape of biomolecules together with shortcomings of traditional molecular dynamics (MD) simulations require specialized methods for capturing large-scale, long-time configurational changes along with chemical dynamics behavior. In this report, MD-based methods for biomolecules are surveyed, involving modification of the potential, simulation protocol, or algorithm as well as global reformulations. While many of these methods are successful at probing the thermally accessible configuration space at the expense of altered kinetics, more sophisticated approaches like transition path sampling or Markov chain models are required to obtain mechanistic information, reaction pathways, and/or reaction rates. Divide-and-conquer methods for sampling and for piecing together reaction rate information are especially suitable for readily available computer cluster networks. Successful applications to biomolecules remain a challenge. PMID- 20948634 TI - Lessons from the failure of the adenovector HIV vaccine. AB - The much-publicised halting of the joint Merck/HIV Vaccine Trials Network phase IIB candidate HIV-1 vaccine trial in 2007 has led to an unprecedented degree of discussion and introspection amongst the HIV research community. In this commentary, we will summarise the lessons learned from the trial and examine the current state of HIV vaccine research. PMID- 20948635 TI - Duality in the Th17-Treg developmental decision. AB - Each of the effector CD4 T-cell lineages - Th1, Th2, and the more recently identified Th17 - arises from pluripotent naive precursors whose developmental fate is largely controlled by cytokines that act in concert with antigenic signals. Remarkably, development of the Th17 lineage has been linked to that of regulatory T cells, which obviate or downregulate Th17 responses to preserve immune homeostasis, through a shared requirement for the cytokine transforming growth factor-beta. Several new studies offer insights into the mechanism whereby the precursors of these subsets are directed into distinct lineages. PMID- 20948636 TI - Clearance of germ granules in the soma. AB - Germ granules are ribonucleoprotein complexes specifically segregated into germ cell lineages in diverse organisms. Recent studies indicate that multiple mechanisms are involved in the clearance of germ granules and their components in somatic cells in Caenorhabditis elegans embryos. PMID- 20948637 TI - Monte Carlo, harmonic approximation, and coarse-graining approaches for enhanced sampling of biomolecular structure. AB - The rugged energy landscape of biomolecules and associated large-scale conformational changes have triggered the development of many innovative enhanced sampling methods, either based or not based on molecular dynamics (MD) simulations. Surveyed here are methods in the latter class - including Monte Carlo methods, harmonic approximations, and coarse graining - many of which yield valuable conformational insights into biomolecular structure and flexibility, despite altered kinetics. MD-based methods are surveyed in an upcoming issue of F1000 Biology Reports. PMID- 20948638 TI - The role of malate in plant homeostasis. AB - Malate is a central metabolite of the plant cell with important roles in plant physiology and metabolism. Here, we summarize the most recent advances in our understanding of malate homeostasis in central metabolism, guard cell functioning, and root exudation. PMID- 20948639 TI - Purinergic cotransmission. AB - ATP is a cotransmitter with classical transmitters in most nerves in the peripheral nervous system and central nervous system, although the proportions vary between species and tissues and in different developmental, physiological and pathophysiological conditions. ATP is released together with noradrenaline and neuropeptide Y from sympathetic nerves. It is released as a cotransmitter with acetylcholine from parasympathetic nerves supplying the bladder, developing skeletal neuromuscular junctions and some neurons in the brain. It is also released with nitric oxide and vasoactive intestinal polypeptide from non adrenergic inhibitory enteric nerves, with glutamate from primary afferent sensory nerves and in the hypothalamus, and with dopamine and 5-hydroxytryptamine from some neurons in the central nervous system. Cotransmission offers subtle, local variations in neurotransmission and neuromodulation mechanisms. PMID- 20948640 TI - Shaping the meristem by mechanical forces. AB - A recent report shows that cells in the Arabidopsis apical meristem orientate their cortical microtubules along mechanical stress patterns generated during tissue morphogenesis. This in turn is expected to influence the mechanical properties of the cell via the modification of the cortical microtubule network and the cell wall. This feedback loop controlling the shape of the meristem may act in parallel with auxin signalling, which determines the site of organ primordium formation. PMID- 20948641 TI - Extinction risks from climate change: macroecological and historical insights. AB - Human-induced climate change may threaten a large proportion of Earth's biota, but the uncertainties involved in projecting the future geographical distributions of species make quantitative predictions of extinction risk difficult to make. I discuss how insight from recent advances in macroecology and knowledge about species responses to past climate change can help predict extinction risks more accurately. PMID- 20948642 TI - Evolutionary impacts of fishing: overfishing's 'Darwinian debt'. AB - Human harvesting of fish results in far greater mortality than natural causes, with enormous potential to affect the phenotypic traits of fish populations, even after exploitation stops. Central to understanding these effects is the untangling of the genetic versus environmental components of phenotypic response. Evolutionary consequences of harvesting must be incorporated into conservation and management strategies. PMID- 20948643 TI - Role of neuropeptides, hormones, and growth factors in regulating thymopoiesis in middle to old age. AB - The deterioration in adaptive immunity and T-lymphocyte output and the narrowing of the T cell receptor repertoire with age are largely attributable to thymic involution. The loss of thymic function with age may be due to diminished numbers of early thymic progenitors and epithelial cells, and the loss of critical tropic factors within the thymic microenvironment. Here we review some of the recent literature demonstrating a role for neuropeptides, hormones, and growth factors that can influence thymopoiesis associated with stress and aging. PMID- 20948644 TI - New antibiotics for antibiotic-resistant bacteria. AB - The need for new antibiotics to effectively treat antibiotic-resistant infections remains unfulfilled. Despite the well-publicised concern over this issue, only two novel antibiotic classes have been introduced in the past 20 years alongside several new agents of existing classes. Accordingly, the current antibiotic armoury remains inadequate to meet the challenges posed by resistance today. More worryingly, there are very few new agents being developed that can be expected to replace existing antibiotics that succumb to the rising tide of resistance. PMID- 20948645 TI - Roles of the small GTPases RhoA and Rac1 in cell behavior. AB - The Rho-family GTPases are proving to have a variety of biological functions apart from their well known effects on the cytoskeleton. Recent work indicates their involvement in signaling between the adhesion receptors integrin and syndecan, effects on the recruitment of beta-catenin to the nucleus, and potential roles in the nucleus as well as the cytoplasm. PMID- 20948646 TI - B cell-targeted therapies in autoimmunity: rationale and progress. AB - B cells are recognized as main actors in the autoimmune process. Autoreactive B cells can arise in the bone marrow or in the periphery and, if not properly inhibited or eliminated, can lead to autoimmune diseases through several mechanisms: autoantibody production and immune complex formation, cytokine and chemokine synthesis, antigen presentation, T cell activation, and ectopic lymphogenesis. The availability of agents capable of depleting B cells (that is, anti-CD20 and anti-CD22 monoclonal antibodies) or targeting B cell survival factors (atacicept and belimumab) opens new perspectives in the treatment of diseases such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. PMID- 20948647 TI - Describing protein conformational ensembles: beyond static snapshots. AB - Protein molecules are not static but are in varying degrees of motion. Of course, the breadth of structural arrangements in an ensemble will vary tremendously. Some proteins are like 'rocks' and are very tightly constrained in terms of deviations of their coordinates from their averages. Others are 'writhing snakes', with little recognized persistent structure, and then there is everything in between. Through the work of many, there is an increasing awareness of the role of dynamics in the biological function of proteins, and new computational and experimental methods are allowing us to make these connections. A personal perspective on the state of affairs is offered with examples primarily from the author's own work. PMID- 20948648 TI - Detailed mechanism for transposition by TnpA transposase involves DNA shape rather than direct protein-DNA recognition to generate an active nucleoprotein complex. AB - A series of single-crystal structures determined by Barabas and colleagues provides a detailed mechanism for how the TnpA transposase from Helicobacter pylori recognizes, cleaves, and integrates the IS200/IS605 class of transposable elements. An interesting aspect of the mechanism is that the transposase recognizes the transposon through the unique fold-back structure adopted by the sequences of the DNA components, rather than through direct protein-DNA interactions. This is an example of indirect readout that is reminiscent of how four-stranded junctions are recognized by recombination proteins, but is also analogous to ribonucleoproteins, in that the DNA facilitates formation of an active nucleic acid-protein complex. PMID- 20948649 TI - The consequences of human-driven ocean acidification for marine life. AB - Rising atmospheric carbon dioxide is causing a wholesale shift in surface seawater chemistry, potentially threatening many marine organisms that form shells and skeletons from calcium carbonate. Recent papers suggest that the biological consequences of ocean acidification already may be underway and may be more complex, nuanced and widespread than previously thought. PMID- 20948650 TI - Emerging technologies for the genomic analysis of cancer. AB - Cancer-cell survival, growth and metastatic potential are directed by dominant molecular signalling patterns, the components of which have been shown to be qualitatively different from their normal tissue counterparts. These signalling patterns can now be further distinguished by quantitative assessment, either at a single point in time or at intervals. This commentary will focus on the emergence of proteomic analysis which, in conjunction with the genomic expression data, is an evolving technology that one day will enable personalized therapeutic strategies that are differentially targeted against cancer. PMID- 20948651 TI - Electron transport chains of lactic acid bacteria - walking on crutches is part of their lifestyle. AB - A variety of lactic acid bacteria contain rudimentary electron transport chains that can be reconstituted by the addition of heme and menaquinone to the growth medium. These activated electron transport chains lead to higher biomass production and increased robustness, which is beneficial for industrial applications, but a major concern when dealing with pathogenic lactic acid bacteria. PMID- 20948652 TI - Ubiquitous antisense transcription in eukaryotes: novel regulatory mechanism or byproduct of opportunistic RNA polymerase? AB - One of the more notable observations made in the last few years in gene regulation is that eukaryotic genomes appear to be pervasively transcribed. Recent transcriptome mapping studies have shown that much of the genome is transcribed, and in some instances transcripts from both strands of specific genomic loci are detectable. While some of these transcripts map to known RNA polymerase II transcription units [that is, protein encoding open reading frames (ORFs)], many are derived from regions of DNA thought to be non-genic. Parallel chromatin immunoprecipitation studies of template-bound RNA polymerase II have shown that it is indeed resident on those regions found to be transcribed, both ORF and non-ORF. However, the strandedness of these pervasive transcripts has never been measured on a genome-wide basis. Four recent reports have addressed this question and, in the process, have made the startling discovery that many loci of mRNA sense gene transcription are associated with very active antisense or divergent transcription that begins at mapped transcription start sites and proceeds in an upstream direction. PMID- 20948653 TI - Applications of high-throughput sequencing to chromatin structure and function in mammals. AB - High-throughput DNA sequencing approaches have enabled direct interrogation of chromatin samples from mammalian cells. We are beginning to develop a genome-wide description of nuclear function during development, but further data collection, refinement, and integration are needed. PMID- 20948654 TI - Long-distance transport of macromolecules through the phloem. AB - Long-distance phloem transport of small metabolites has long been the subject of many different studies concentrating on resource allocation and signalling between plant organs. Also, phloem movement of viruses has long been examined as the route for systemic infection of the plant. Only recently, the transport of macromolecules, such as proteins and nucleic acids, has received increasing attention because they are regarded as being a new class of potential information transmitter. A set of recent publications allows the first insights into the important roles that phloem-mobile macromolecules might play in the regulation of development and the responses to stress. Furthermore, they start to shed light on the mechanisms involved in systemic macromolecule transport. PMID- 20948655 TI - The role of microbial polysaccharides in host-pathogen interaction. AB - Bacteria are capable of expressing a diverse range of cell surface polysaccharides from capsules and lipopolysaccharides through teichoic acid molecules to lipoarabinomannans. This review will focus on the expression of capsular polysaccharides and their interaction with the host. In particular, it will focus on the role of capsular polysaccharides as immunomodulatory molecules. PMID- 20948656 TI - Sources of the spatial code within the hippocampus. AB - Neurons in the hippocampus are thought to provide information on an animal's location within its environment. Input to the hippocampus comes via afferents from the entorhinal cortex, which are separated into several major pathways serving different hippocampal regions. Recent studies show the significance of individual afferent pathways in location perception, enhancing our understanding of hippocampal function. PMID- 20948657 TI - Single-molecule dynamics of nuclear mRNA. AB - In eukaryotes, mRNA molecules are transcribed from nuclear DNA and commute through a labyrinth of nucleoplasmic passageways to the nuclear envelope where they are exported to the cytoplasm. New findings provide tools and insights into the biophysical properties that govern mRNA translocations en route to the cytoplasm and suggest that mRNA molecules move in a discontinuous manner due to transient interactions with the nuclear environment. PMID- 20948658 TI - A novel mucosal RORgammatNKp46 cell subset is a source of interleukin-22. AB - Lymphoid tissue-inducer cells are hematopoietic cells essential for the organogenesis of several lymphoid structures during both fetal and adult life, whereas natural killer cells are key effector lymphocytes of the innate immune system. A series of recent reports has identified RORgammat(+)NKp46(+) interleukin-22-producing cells in gut and tonsils that share features with both lymphoid tissue-inducer cells and natural killer cells and that may be involved in mucosal immunity and homeostasis. PMID- 20948659 TI - The growth cone: an integrator of unique cues into refined axon guidance. AB - One of the challenges to understanding nervous system development is to establish how a fairly limited number of axon guidance cues can set up the patterning of very complex nervous systems. Most of the recent insights relevant to guidance mechanisms have come from cell biologists focusing on processes and molecular machinery controlling the guidance responses in the growth cone. PMID- 20948660 TI - Toward understanding the effect of top predators on ecosystems. AB - To what extent top predators - carnivores at the top of food chains - drive or just respond to ecosystem dynamics is a central, but partially unresolved, question in ecology. In this report, we highlight how different research approaches employed in aquatic and terrestrial ecology may have a bearing on how the role of top predators in ecosystems is perceived. PMID- 20948661 TI - Bioinformatic detection of horizontally transferred DNA in bacterial genomes. AB - We highlight a selection of recent research on computational methods and associated challenges surrounding the prediction of bacterial horizontal gene transfer. This research area continues to face controversy, but is becoming more critical as the importance of horizontal gene transfer in medically and ecologically important prokaryotic evolution is further appreciated. PMID- 20948662 TI - Nuclear magnetic resonance captures the elusive. AB - Innovative nuclear magnetic resonance approaches have emerged as outstanding means of tracking down functionally important properties of biomolecular assemblies that evade detection. These enigmatic attributes include dynamic equilibria with very lightly populated excited states and structures of complexes obscured by slow tumbling in solution. PMID- 20948663 TI - The ABCB1 transporter gene and antidepressant response. AB - P-glycoprotein, encoded by the ABCB1 gene, may modulate the brain concentration of several antidepressants. Functional genetic variation is thought to exist in this gene, and here we review several studies that have attempted to associate this variation with clinical response to antidepressant treatment. PMID- 20948664 TI - 'A mover and a shaker': 53BP1 allows DNA doublestrand breaks a chance to dance and unite. AB - The DNA damage response mediator protein, p53-binding protein 1 (53BP1), is dispensable for the repair of most DNA doublestrand breaks (DSBs) induced by ionising radiation. However, two recent studies have shown that 53BP1 is required for rejoining of distant DSB ends and that it promotes the movement of uncapped telomeres. These results are discussed in the light of recent findings, and a model for the role of 53BP1 in DSB rejoining is presented. PMID- 20948665 TI - Breaking the A chain: regulating mRNAs in development through CCR4 deadenylase. AB - Post-transcriptional mechanisms of gene regulation have long been implicated in specifying embryonic pattern in many organisms. Experiments in Caenorhabditis elegans, Drosophila, and Xenopus have recently converged, pointing to the CCR4 deadenylase complex as a key effector that modulates the expression of proteins from specific germline mRNAs. PMID- 20948666 TI - Alternative macrophage activation and the regulation of metabolism. AB - Macrophages are white blood cells that have important roles in phagocytosis and immune responses. A series of recent papers reveals that nuclear receptors influence the precise pathway of macrophage phenotype polarization and that these effects protect against insulin resistance and metabolic syndrome, the most important group of diseases facing the industrialized world. PMID- 20948667 TI - All change: protein conformation and the ubiquitination reaction cascade. AB - The structures of enzymes that collectively modify proteins by covalent addition of ubiquitin-like protein moieties have provided significant insights into the regulatory pathways they compose and have highlighted the importance of protein flexibility for the mechanism and regulation of the ubiquitination reaction. PMID- 20948668 TI - Malarial parasite pathogenesis and drug targets. AB - This report highlights recent insights into malarial parasite pathogenesis that are relevant for new antimalarial drug discovery. PMID- 20948669 TI - Mitochondria and apoptosis: a quick take on a long view. AB - Fifteen years of apoptosis research have led to the widely accepted idea that the major form of programmed cell death in mammals proceeds via the mitochondria, and that mitochondrial control of apoptosis is regulated by a specialized family of proteins known as the Bcl-2 family. Here we will consider some very recent data that has shed new insight into the regulation of these proteins and the impact of mitochondrial dynamics on mitochondrial outer membrane permeabilization (MOMP) and apoptosis. PMID- 20948670 TI - Climate change and biodiversity conservation: impacts, adaptation strategies and future research directions. AB - The impacts of climate change pose fundamental challenges for current approaches to biodiversity conservation. Changing temperature and precipitation regimes will interact with existing drivers such as habitat loss to influence species distributions despite their protection within reserve boundaries. In this report we summarize a suite of current adaptation proposals for conservation, and highlight some key issues to be resolved. PMID- 20948671 TI - The inflammasome and alum-mediated adjuvanticity. AB - Recent reports have implicated the NLRP3-associated inflammasome in the adjuvanticity of alum. Here, we summarize the major findings and ask what this may mean for improving human vaccination. PMID- 20948672 TI - Trace elements: too little or too much and how plants cope. AB - Plants acquire essential trace elements from the rhizosphere and must adapt to conditions that can range from deficiency to excess. Knowledge of how trace elements move from root to shoot to seed is critical for agriculture and human nutrition. PMID- 20948673 TI - Regulatory roles of the cadherin superfamily. AB - Charged with the task of providing a molecular link between adjacent cells, the cadherin superfamily consists of over 100 members and populates the genomes of organisms ranging from vertebrates to cniderians. This breadth hints at what decades of research has confirmed: that cadherin-based adhesion and signaling events regulate diverse cellular processes including cell-sorting, differentiation, cell survival, proliferation, cell polarity, and cytoskeletal organization. PMID- 20948674 TI - Recent strategies to identify broadly neutralizing antibodies against influenza A virus. AB - Recent technologies have made it possible to efficiently identify several broadly cross-neutralizing antibodies against the hemagglutinin of influenza A virus. With these advances comes a potential new age in influenza virus vaccine development and the possibility of effective, therapeutic immunotherapy. PMID- 20948675 TI - G-protein-coupled receptor structure: what can we learn? AB - The first, long-awaited, structures of non-visual G-protein-coupled receptors have provided important insights into the process of ligand binding and receptor activation. Here I explore the technological advances that enabled the resolution of the crystal structures of the beta(1)- and beta(2)-adrenergic receptors, and review what we have learnt and what is still to be discovered. PMID- 20948676 TI - Central control of feeding. AB - The rising rate of obesity in Western countries has led to intensified efforts to understand the molecular mechanisms underlying the central control of appetite and feeding behavior. This report highlights studies published from 2006 to 2008 revealing novel centrally acting anorexigenic hormones, the continued unraveling of complex hypothalamic intracellular signaling pathways that regulate feeding, and insights into leptin resistance. PMID- 20948678 TI - Management of pulmonary nontuberculous mycobacterial disease. AB - Nontuberculous mycobacteria are increasingly recognized as causes of chronic pulmonary disease. Treatment decisions are guided by the clinical presentation, microbial isolate, and condition of the patient. Management may include antibiotic therapy, surgical resection, or observation. Definitive trials are lacking, and optimum management remains uncertain. PMID- 20948677 TI - Recent advances in neural development. AB - A surprisingly small number of signalling pathways are used reiteratively during neural development, eliciting very different responses depending on the cellular context. Thus, the way a neural cell responds to a given signal is as important as the signal itself and this responsiveness, also called competence, changes with time. Here we describe recent advances in elucidating the signalling pathways that operate in brain development. PMID- 20948679 TI - Prognostic value of echocardiography with particular reference to patients with valvular heart disease. AB - Echocardiography is comparatively inexpensive relative to other modern cardiovascular imaging tools. It is widely available, even in poor countries, and provides a comprehensive evaluation of cardiac structure and function. It is an ideal tool for the evaluation of patients with valvular heart disease and provides important prognostic information. This review of recent literature highlights reports on outcomes data and provides a clinically valuable summary in table format. PMID- 20948680 TI - Recent advances in mast cell clonality and anaphylaxis. AB - Clonal expansion of mast cells carrying the D816V c-kit mutation results in mastocytosis. Recent studies identified the presence of clonal mast cells carrying this mutation in patients with anaphylaxis without classic diagnostic findings of systemic mastocytosis. PMID- 20948681 TI - Recent advances in managing osteoporosis. AB - Osteoporosis is a common disease associated with increased morbidity and mortality. However, osteoporosis continues to be under-recognized, and the majority of men and women with fractures go untreated. FRAX((r)) is a tool that has been developed by the World Health Organization to better identify people at high absolute risk of fracture. Modalities to assess bone quality, an important component of bone strength, have also emerged. Combined with new therapeutic options that promise increased compliance with therapy, the burden of this ever growing and costly disease may be reduced. PMID- 20948682 TI - The scientific basis for novel treatments of systemic sclerosis. AB - In recent years, many potential antifibrotic treatment strategies have emerged from molecular studies of systemic sclerosis. Few biologicals have already entered clinical trials and these may hopefully prove to be effective in this progressive, profibrotic disease. PMID- 20948683 TI - New therapies for recurrent glioblastomas. AB - Glioblastomas are the most common and deadliest form of malignant primary brain tumor. Until recently, therapies for tumors that recur after standard treatment have been largely ineffective. Recent phase II studies with the humanized monoclonal antibody against vascular endothelial growth factor bevacizumab suggest that this agent is active in recurrent glioblastomas, producing response rates of 26-40% and prolonging 6-month progression-free survival to 36-50%. As a result of these studies, the US Food and Drug Administration recently granted accelerated approval for bevacizumab as a treatment for recurrent glioblastomas. PMID- 20948685 TI - Advances in the management of male infertility. AB - Male infertility can be treated by surgical procedures (e.g., varicocelectomy) or by administration of drugs if causal factors (e.g., seminal tract infections) are detected. In more severe cases, methods of assisted fertilization often have to be applied, but even these have only a limited success rate. Recent studies have demonstrated that disturbances of sperm DNA integrity (determined by the acridine orange test) can explain certain cases of fertilization failure and failure to achieve pregnancy following in vitro fertilisation with intracytoplasmic sperm injection. The evaluation of DNA integrity should be considered when diagnosing male infertility as it has been shown to be an independent factor and can be used as a supplement to standard semen analysis. Analysis of DNA integrity may, therefore, provide further information about altered male fertility and lead to administration of more appropriate therapy. PMID- 20948684 TI - Therapeutic options for lymphangioleiomyomatosis (LAM): where we are and where we are going. AB - Lymphangioleiomyomatosis (LAM), a multisystem disease affecting predominantly premenopausal and middle-aged women, causes progressive respiratory failure due to cystic lung destruction and is associated with lymphatic and kidney tumors. In the past, the treatment of LAM comprised exclusively anti-estrogen and related hormonal therapies. These treatments, however, have not been proven effective. In this article, we discuss new findings regarding the molecular mechanisms involved in the regulation of LAM cell growth, which may offer opportunities to develop effective and targeted therapeutic agents. PMID- 20948686 TI - Rescue strategies for refractory hypoxemia: a critical appraisal. AB - Mechanical ventilation is the most important aspect of supportive care of patients with severe acute respiratory failure. Most research directed to improving the prognosis of these patients has focused on improving support of the injured lung. In this report, current knowledge on innovative ways to manage refractory hypoxemia and ventilation without further damaging the injured lung is briefly discussed. PMID- 20948687 TI - Recent advances in management of renal cancer. AB - Therapeutic options for patients with metastatic renal cell carcinoma have significantly improved over the past few years, resulting in prolonged progression-free and overall survival. PMID- 20948688 TI - Prevention of awareness during general anesthesia. AB - Awareness during general anesthesia with subsequent explicit recall is a serious and frequently preventable problem that is gaining attention from clinicians and patients alike. Cost-effective interventions that increase vigilance should be implemented to decrease the likelihood of this complication. PMID- 20948690 TI - Cartilage repair in osteoarthritic patients: utopia or real opportunity? AB - As medical advances lengthen average life expectancy, osteoarthritis (OA) will become a larger public health problem - not only because it is a manifestation of aging but also because it usually takes many years to reach clinical relevance. OA is already one of the ten most disabling diseases in industrialized countries. The huge financial burden emphasizes the acute need for new and more effective treatments for articular cartilage defects, especially since there are few disease modifying drugs or treatments for OA. There is no cure for OA and the management of OA is largely palliative, focusing on the alleviation of symptoms. Recent longitudinal non-controlled trials suggest that autologous chondrocyte transplantation techniques, which are indicated for young people with traumatic cartilage defects, could also be used in degenerative defects of elderly people with OA. This report discusses this therapeutic opportunity in view of some recently published data. PMID- 20948689 TI - Coma due to cardiac arrest: prognosis and contemporary treatment. AB - Approximately 80% of patients who are successfully resuscitated from cardiac arrest do not regain consciousness immediately after return of spontaneous circulation, and may remain in a coma for hours or weeks, or even be in a persistent vegetative state. Recent investigations have focused on the identification of early clinical characteristics and biomarkers that can reliably predict emergence from coma in those who survive, and on therapies that might improve neurologic outcome from the ischemic brain injury that can be caused by cardiac arrest. PMID- 20948691 TI - Advances in managing pelvic floor disorders. AB - The last 10-12 years have seen an avalanche of changes in both the management of incontinence and genital prolapse. So many new procedures continue to appear that often the clinician is confused as to which approach to adopt. Complications are now being reported, creating a need to reappraise the situation. PMID- 20948692 TI - Abdominal compartment syndrome. AB - The abdominal compartment syndrome (ACS) was first described in surgical patients with abdominal aortic aneurysm repair, trauma, bleeding, or infection, but in recent years it has also been described in patients with other pathologies such as burn injury and sepsis and in medical patients. This F1000 Medicine Report is intended to provide critical care physicians a clear insight into the current state of knowledge regarding intra-abdominal hypertension (IAH) and ACS, and will focus primarily on the recent literature as well as on the definitions and recommendations published by the World Society of the Abdominal Compartment Syndrome. The definitions regarding increased intra-abdominal pressure (IAP) will be listed, followed by a brief but comprehensive overview of the different mechanisms of organ dysfunction associated with IAH. The gold standard measurement technique for IAP as well as recommendations for organ function support in patients with IAH and options for medical and surgical treatment of IAH and ACS will be discussed. PMID- 20948693 TI - Baseline serum 25-hydroxy vitamin D in predicting glycemic status and insulin levels. AB - Vitamin D may have a protective role in insulin secretion and an effect on insulin resistance. Low levels of vitamin D are indicated as a risk factor for both type 1 and type 2 diabetes, however, clinical evidence that increased vitamin D levels benefit diabetic patients has not yet been established. PMID- 20948694 TI - Recent changes in the epidemiology and management of extended-spectrum beta lactamase-producing Enterobacteriaceae. AB - Since 2000, Escherichia coli producing CTX-M enzymes (especially CTX-M-15) have emerged worldwide as important causes of community-onset urinary tract and blood stream infections due to extended-spectrum beta-lactamase (ESBL) producing bacteria. Studies suggest that the sudden worldwide increase of CTX-M-15 producing E. coli is mostly due to a single clone named ST131 and that foreign travel to high-risk areas, such as the Indian subcontinent, play in part a role in the spread of this clone across different continents. Empiric antibiotic coverage for these resistant organisms should be considered in community patients presenting with sepsis involving the urinary tract, especially if a patient recently traveled to a high-risk area. If this emerging public health threat is ignored, it is possible that the medical community may be forced in the near future to use carbapenems as the first choice for the empirical treatment of serious infections associated with urinary tract infections originating in the community. PMID- 20948695 TI - The importance of the descending monoamine system for the pain experience and its treatment. AB - Brainstem and midbrain areas engage descending facilitatory and inhibitory neurones to potentiate or suppress the passage of sensory inputs from spinal loci to the brain. The balance between descending controls, both excitatory and inhibitory, can be altered in various pain states and can critically determine the efficacy of certain analgesic drugs. There is good evidence for a prominent alpha(2) adrenoceptor-mediated inhibitory system and for 5-HT(3) receptor mediated excitatory control of spinal cord activity that originates in supraspinal areas. Given the multiple roles of these transmitters in pain and functions such as sleep, depression, and anxiety, the link between spinal and supraspinal processing of noxious inputs (via the monoamine transmitters) could be pivotal for linking the sensory and affective components of pain and their common co-morbidities, and also may potentially explain differences in pain scores and treatment outcomes in the patient population. PMID- 20948696 TI - Recent imaging advances in the diagnosis and management of Parkinson's disease. AB - In this review we report novel sensitive imaging biomarkers for Parkinson's disease (PD) and its atypical variants. Diffusion tensor imaging and transcranial brain sonography are potentially promising techniques that can differentiate typical PD from atypical variants (multiple system atrophy and progressive supranuclear palsy) and from benign tremor disorders. Non-motor symptoms, such as dementia, depression, and sleep disruption, are often more distressing to PD patients than their slowness and stiffness. Dopamine replacement treatment can also lead to complications such as dyskinesias, impulse control disorders, and psychosis. Recent positron emission tomography studies have helped to clarify the physiopathological mechanisms underlying dementia and compulsive gambling in PD and provide a rationale for therapeutic strategies. PMID- 20948697 TI - Advances in the management of asymptomatic hyperparathyroidism. AB - Asymptomatic primary hyperparathyroidism (PHPT), a condition defined as hyperparathyroidism that lacks specific symptoms or signs and with calcium levels of less than 1 mg/dL above the upper limit of normal, is a common clinical problem. Two previous conferences on the management of asymptomatic PHPT (a Consensus Development Conference and a National Institutes of Health workshop) indicated that medical monitoring rather than surgery is appropriate in certain patients with this condition. The Third International Workshop on the management of PHPT reviewed evidence that has become available since the last workshop in 2002. The purpose of this report is to describe recent advances reviewed during the third workshop on asymptomatic PHPT held in 2008. PMID- 20948698 TI - Natural orifice transluminal endoscopic surgery (NOTES): implications for anesthesia. AB - Natural orifice transluminal endoscopic surgery (NOTES) has recently evolved as a novel approach for abdominal surgery with great potential to further improve the advantages of laparoscopy over laparotomy. The first patients undergoing NOTES cholecystectomy or appendectomy reported no or only minimal pain, required no narcotic analgesics, and were discharged early from the hospital and immediately resumed daily activities. If this is confirmed by randomized controlled clinical trials, what are the potential implications for anesthesia? PMID- 20948699 TI - Intensity of antiplatelet therapy and percutaneous coronary intervention. AB - Thienopyridine derivatives such as clopidogrel have been shown to reduce the incidence of death in patients undergoing percutaneous coronary intervention when used in conjunction with aspirin. Recently, a new thienopyridine, prasugrel, significantly reduced the primary endpoint of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke to 9.9% compared to 12.1% for clopidogrel. Prasugrel has been shown to be more efficacious than clopidigrel in reducing ischemic events and stent thrombosis, but does cause more life threatening bleeding in patients undergoing percutaneous coronary intervention. PMID- 20948700 TI - Management of infections due to KPC-producing Klebsiella pneumoniae. AB - The emergence of the Klebsiella pneumoniae carbapenemases in K. pneumoniae and other Gram-negative bacteria, usually on a background of multidrug resistance, has led to difficult therapeutic choices. Among available antibiotics, tigecycline and the polymyxins are the most frequently active against these organisms in vitro. Optimal therapy of infections due to these bacteria may involve maximization of antibiotic dose as well as their use in combination. PMID- 20948702 TI - Perioperative use of beta-blockers. AB - Perioperative beta-blocker therapy has been considered a mainstay of perioperative cardioprotection in patients with or at risk of coronary artery diseases. However, current recommendations for perioperative beta blockade are based mainly on the findings of trials with inadequate methodology and data analysis. The recently published results of the first adequately powered large controlled randomized trial on the efficacy and safety of perioperative beta blocker therapy confirmed the benefit of such therapy on the perioperative incidence of non-fatal myocardial infarctions. However, such a benefit occurred at the expense of increased total mortality and increased incidence of stroke, negating any beneficial effect. A subsequently published meta-analysis confirmed, in large part, these findings. Given these recent publications, most of the current recommendations for perioperative beta-blocker therapy are no longer supported by evidence, therefore respective revision is needed. PMID- 20948701 TI - Cardiorenal syndrome. AB - Kidney dysfunction in patients with heart failure and cardiovascular disorders in patients with chronic kidney disease are common. A recently proposed consensus definition of cardiorenal syndrome stresses the bidirectional nature of these heart-kidney interactions. The treatment of cardiorenal syndrome is challenging, however, promising new therapeutic options are currently being investigated in recent and ongoing clinical trials. PMID- 20948703 TI - Diagnosis and assessment of neuropathic pain. AB - Neuropathic pain and pain that has a predominant neuropathic component can be difficult to diagnose in primary care. Several screening questionnaires that incorporate patient symptoms and signs have been developed, and some are supplemented with simple bedside clinical tests for nerve dysfunction. These tools should enable a more rapid and confident diagnosis by the nonspecialist and the earlier start of appropriate treatment. PMID- 20948704 TI - Recent advances in managing triple-negative breast cancers. AB - Triple-negative breast cancer (TNBC) has been recently recognized as an important subgroup of breast cancer with a distinct outcome and therapeutic approach compared with other breast cancer subgroups. Because TNBC is defined by the absence of a target (either hormone receptors or HER-2), conventional cytotoxic therapy is still the mainstay of treatment. This report focuses on the current state and recent advances in managing TNBC. PMID- 20948705 TI - Advances in the management of uterine fibroids. AB - Uterine fibroids are extremely common, with major surgery the current main management option; uterine artery embolisation is an alternative, but risks to fertility are unclear. Minimally invasive procedures are becoming more commonly performed via both the hysteroscope and laparoscope, minimising recovery time for patients. Recently, small doses of progesterone receptor modulators (mifepristone and asoprisnil) have been shown to be effective in reducing menstrual blood loss and fibroid size. Progress from here should include the development of a well tolerated oral preparation that will maintain fertility. PMID- 20948706 TI - Assessing the prognosis of dengue-infected patients. AB - Dengue infections pose a huge burden to health care providers in most tropical countries. Careful clinical examination and history-taking supplemented by newer rapid diagnostic tests may lead to early etiological diagnosis. For severe dengue, early recognition of vascular permeability followed by rapid physiological replacement of fluids is life-saving. Prognosis of patients depends upon optimum management, an outcome that requires preparation via organization, training, and use of evidence-based practice guidelines. PMID- 20948707 TI - Recent advances in airway management in children. AB - Recent anatomic findings, technological progress, and both in vitro and in vivo studies of the pressure generated in the cuff of endotracheal tubes and supraglottic airways should lead to modification of the way we control the pediatric upper airway. PMID- 20948708 TI - Treatment of ventricular tachycardia: consider ablation sooner. AB - Ventricular tachycardia (VT) is a leading cause of morbidity and mortality for many patients, with a significant emotional and economic burden caused by implantable cardioverter-defibrillator (ICD) shocks and the requirement of medication with significant side effects. Additionally, 10% of VT occurs in patients with no structural heart disease. Until quite recently, ablation for VT has been reserved as the procedure of last hope for those who have ongoing recurrences despite maximal medical therapy and who are traumatized by multiple ICD shocks [1]. However, recent advances in imaging technology and three dimensional intracardiac mapping systems have significantly improved the safety and efficacy of VT ablation procedures. Thus, ablation for VT should no longer be reserved as a last-resort bailout procedure and should move into the realm of routine electrophysiology treatment. PMID- 20948709 TI - Radioiodine treatment for non-toxic goitre. AB - There is no ideal treatment for benign multinodular goitre. Besides surgery, which is recommended for large goitres or when malignancy cannot be excluded, the non-surgical treatment options are levothyroxine therapy and radioiodine ((131)I) therapy. Conventional (131)I therapy [without recombinant human thyroid stimulating hormone (rhTSH)] has been used for more than a decade in symptomatic non-toxic multinodular goitre, and although it does lead to significant thyroid volume reduction, relatively high activities of radioiodine are needed because of a frequent finding of a low thyroid radioiodine uptake. rhTSH, even when used in very small doses in combination with (131)I therapy, enhances the thyroid volume reduction at lower (131)I activities by doubling the thyroid radioiodine uptake. However, before rhTSH stimulation can be routinely used by clinicians to optimise the (131)I therapy in multinodular goitre, aspects of this association, such as the cost-benefit and optimum rhTSH dose and safety, will have to be sufficiently clarified. PMID- 20948710 TI - Management of Barrett's oesophagus. AB - Barrett's oesophagus, which is thought to be a consequence of gastro-oesophageal reflux disease (GORD), is a well-recognized precursor of oesophageal adenocarcinoma. Medical therapies and anti-reflux surgeries for GORD have shown conflicting results regarding the progression of Barrett's metaplasia to neoplasia. After high-grade dysplasia or intramucosal cancer is identified, it has been standard practice to conduct an oesophagectomy, despite this having an associated risk of morbidity and mortality. In recent years however, endoscopic therapy has become a viable alternative to oesophagectomy in treating early neoplasia. PMID- 20948711 TI - Has anesthesia care become safer and is anesthesia-related mortality decreasing? AB - In well-resourced areas of the world anesthesia has become safer over the past decades, and anesthesia mortality does seem to be reducing. However, there is a lack of international agreement over definitions of anesthetic mortality and, therefore, difficulty in knowing exactly what the rate of anesthetic mortality is. Avoidable harm from error is still a problem, and sophisticated analysis suggests that more deaths than generally appreciated may be attributable to factors under the control of anesthetists. Mortality rates in low income areas of the world are unacceptably high. There is more to be done if anesthesia is to become truly safe for all patients. PMID- 20948712 TI - Clinically relevant advances in rheumatoid arthritis therapy. AB - Owing to the success of biologics in the treatment of rheumatoid arthritis (RA), several novel drugs have been introduced in the therapeutic armamentarium, although not all of them have been approved in all countries worldwide. Among the drugs are tumour necrosis factor (TNF) inhibitors such as certolizumab pegol and golimumab (the latter of which was the first TNF blocker shown to be effective in patients who had been unsuccessfully treated with other TNF blockers and which can be applied only once a month), and the interleukin-6 receptor antagonist tocilizumab, which not only opens up a completely new field of anti-inflammatory modulation of RA pathophysiology, but also highlights the challenge of novel potential side effects. Moreover, aside from clinical studies showing efficacy in the inhibition of osteoclast activation by the anti-RANKL (receptor activator of nuclear factor-kappa B ligand) antibody denosumab, an improved form of steroid application known as slow-release 'tempus tablet' for treatment of RA and several developments in the small-molecule area have been addressed by clinical trials. PMID- 20948713 TI - Non-cystic fibrosis bronchiectasis: review and recent advances. AB - Bronchiectasis is an abnormal dilatation of bronchi and bronchioles associated with repeated cycles of airway infection and inflammation. This review will focus on non-cystic fibrosis bronchiectasis in children, with regard to etiology, diagnosis, treatment options, and recent advances. PMID- 20948714 TI - Recent advances in pulse oximetry. AB - Conventional pulse oximetry uses two wavelengths of light (red and infrared) transmitted through a finger and a photodetector to analyze arterial hemoglobin oxygen saturation and pulse rate. Recent advances in pulse oximetry include: extended analysis of the photo plethysmographic waveform; use of multiple wavelengths of light to quantify methemoglobin, carboxyhemoglobin and total hemoglobin content in blood; and use of electronic processes to improve pulse oximeter signal processing during conditions of low signal-to-noise ratio. These advances have opened new clinical applications for pulse oximeters that will have an impact on patient monitoring and management. PMID- 20948715 TI - Ultrasound-guided central venous access. AB - Central venous catheterization is a critical component of management for the critically ill patient in the operating room and intensive care unit. When using ultrasound techniques for central venous access, access is achieved with fewer attempts, a reduced incidence of carotid artery punctures or 'hits', an increased success rate, and a decreased duration of procedure compared to the traditional landmark approach. PMID- 20948716 TI - New treatment guidelines on Cushing's disease. AB - It is important to treat patients with Cushing's disease as rapidly as possible to limit its long-term mortality and morbidity. Selective transphenoidal pituitary adenomectomy remains the treatment of choice but, unfortunately, the rate of cure at long-term follow-up is suboptimal and recurrences are high, even in the hands of expert neurosurgeons. Treatment options for persistent or relapsed disease include repeat trasphenoidal pituitary surgery, radiotherapy or bilateral adrenalectomy. Medical treatment, a second-line treatment option, may have either a primary or adjunctive role if the patient cannot safely undergo surgery, if surgery fails, or if the tumor recurs. Cabergoline and pasireotide (SOM230), two pituitary tumor-directed drugs, are the most exciting news in the human pharmacological approach. However, the use of these drugs in clinical practice and their real impact in the management of patients is yet to be determined. The treatment of patients with Cushing's disease is complex and requires a multidisciplinary and individualized approach to patient management using cost-benefit analyses. PMID- 20948717 TI - Hypopituitarism and brain injury: recent advances in screening and management. AB - This review gives an overview of the research on hypothalamopituitary dysfunction as a potential consequence of traumatic brain injury, including the natural history of this complication and its clinical and public health implications. PMID- 20948718 TI - Anti-insulin growth factor receptor therapy in Ewing sarcoma. AB - The insulin-like growth factor (IGF) signal transduction pathway appears to play a key role in the development and proliferation of the Ewing sarcoma family of tumors. Integration of anti-IGF-1 receptor therapy into the standard treatment for these patients is a novel approach that will likely be incorporated into future treatment to determine whether such agents will improve the outcome for patients with this malignancy. PMID- 20948720 TI - Is spinal surgery effective for back pain? AB - There have only been a few randomized controlled trials of surgical treatment of chronic low back pain caused by degenerative disc disease. Fusion surgery has been compared primarily with nonoperative treatment, whereas disc arthroplasty has been compared with fusion surgery. The results for either of the two surgical procedures are modest in terms of pain relief and improved function. PMID- 20948719 TI - Advances in the genetics of schizophrenia: will high-risk copy number variants be useful in clinical genetics or diagnostics? AB - Schizophrenia is a highly heritable, common mental illness, affecting 1% of the population worldwide. It is currently diagnosed using exclusive clinical criteria, and at present there are no genetic tests to facilitate this process. There are also no reliable means to predict who will develop the disease in later life. Genetic counselling uses crude estimates of risk based on family history, as the strongest predictive factor is having an affected first-degree relative. It has recently become apparent that large de novo deletions in the genome (copy number variants, or CNVs) can increase risk of the disease by tenfold or more. The purpose of this report is to assess whether these 'high risk' pathogenic CNVs might be useful in a clinical genetic or diagnostic setting. Routine use of laboratory techniques such as comparative genome hybridisation will reveal these de novo CNVs in standard investigative procedures for referrals to clinical genetics. The lack of disease specificity of CNVs presents problems for their use in diagnosis at present. Currently, there is also insufficient evidence in relation to schizophrenia to suggest that clear clinical benefit would be gained from learning one's genetic status pre-symptomatically. However, this is likely to change rapidly in the near future as knowledge of the genetic and environmental basis of schizophrenia accrues and increasingly effective measures for early intervention and risk reduction are developed. PMID- 20948721 TI - Prognostic value of coronary computed tomography (CT) angiography. AB - Coronary computed tomography angiography (CTA) allows increasingly reliable visualization of the coronary arteries. Over the past two years, several relevant scientific studies on the clinical utility and prognostic value of CT angiography have been published, and this review will provide a summary of the currently available data. PMID- 20948722 TI - Transcranial direct current stimulation - what is the evidence for its efficacy and safety? AB - Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, has emerged in the past decade as a useful investigative and therapeutic technique. A number of recent studies suggest that tDCS is safe and may be efficacious in the treatment of a variety of psychiatric and neurological disorders, including major depressive disorder, chronic neuropathic pain, and stroke. More evidence is necessary, however, before it can be recommended for general clinical application. PMID- 20948723 TI - How should we treat vascular and fibrotic lung disease in scleroderma? AB - Recent randomized trials suggest that evidence-based algorithms for systemic sclerosis can be developed to identify patients at risk for lung disease, follow lung disease progression, and modify disease with therapies of proven benefit. Recognition of disease subsets allows physicians to integrate physiology, overlapping disease manifestations, and predictable drug effects into a comprehensive disease management program. PMID- 20948724 TI - Blood transfusion in critical care. AB - Blood transfusion is frequent in critical care. Transfusion raises the mass of transfused blood components and is lifesaving in acute hemorrhage. In massive transfusion (>10 units of red blood cells), early attempts to restore coagulation function appear helpful. Transfusion in non-bleeding patients is largely prophylactic, is seldom evidence-based, and may be deleterious. In hemodynamically stable critical care patients, level I evidence suggests that a hemoglobin of >7 g/dL and platelet counts of >10,000/MUL are well tolerated. PMID- 20948725 TI - Factors affecting prognosis in myelofibrosis. AB - Studies investigating factors affecting prognosis in primary myelofibrosis have been numerous over the years because of the high heterogeneity with regard to its natural clinical course. Recently, the increasing application of reduced intensity conditioning with allogeneic hematopoietic stem cell transplantation as well as the ongoing rapid development of new experimental agents, such as JAK2 inhibitors, have made the requirement for simple and accurate scoring systems to select individual patients for the most appropriate treatment strategy even more critical. This short report summarizes the state of the art and the most recent advances in this area. PMID- 20948726 TI - Treatment advances in Alzheimer's disease based on the oxidative stress model. AB - Effective therapy for Alzheimer's disease (AD), up to this point, has been hampered by our inability to diagnose the disease in its early stages, before the occurrence of significant neurodegeneration and clinical symptoms. Because AD historically has been defined by neuropathologic criteria, treatment strategies have been aimed at diminishing the pathologic end result of the disease process, namely neurodegenerative changes associated with extracellular amyloid-beta containing plaques, as well as intracellular neurofibrillary tangles of the hyper phosphorylated microtubule protein, tau. While these avenues continue to be pursued, results thus far have been disappointing. It is now understood that oxidative stress plays a key role in the shared pathophysiology of neurodegenerative diseases and aging. For experimental treatment of AD, the focus of research and development efforts is increasingly shifting to target mechanisms of oxidative stress. Most recently, dimebon, whose mechanism of action relates to improved mitochondrial function, has emerged as a promising candidate for experimental treatment of AD. PMID- 20948727 TI - Recent advances in management of ureteral calculi. AB - The management of patients with urinary tract stone disease has changed dramatically over recent years, with current treatment modalities focused on their minimal invasiveness. In this article we will discuss the recent advances in the field of urolithiasis management, with a focus on medical expulsive therapy, extra-corporeal shockwave lithotripsy and ureteroscopy. PMID- 20948728 TI - Genetic testing in specific cardiomyopathies. AB - An increasing number of genetic tests for cardiomyopathies are becoming available for clinical use. This commentary will give a short overview of indications and challenges concerning genetic testing for these conditions. PMID- 20948729 TI - Recent advances in psychosocial treatments for borderline personality disorder. AB - In the past three years, several psychosocial treatments for borderline personality disorder have received empirical support. This review highlights findings from recent treatment studies and discusses how these findings have dramatically altered clinical practice for this disorder. PMID- 20948730 TI - Is there an effective therapy available for non-alcoholic fatty liver disease? AB - Non-alcoholic fatty liver disease (NAFLD) is defined as fat accumulation in the liver, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Although it used to be considered a benign condition, nowadays it is known to be associated with liver injury and the development of end-stage liver disease. NAFLD is the hepatic manifestation of metabolic syndrome (MS) with an incidence rising in accordance with the increased prevalence of MS, the latter being considered the most common cause of liver enzyme elevation in Western countries. To date, no medications or surgical procedures have been approved for effective treatment of NAFLD, and all of the therapies tested so far must still be regarded as experimental. It is expected that, based on the large amount of data produced in the last few years and the ongoing large multicenter clinical trials, the effective treatment(s) for NASH will soon be defined. Meanwhile, lifestyle interventions and behavior therapy, the only treatments shown to be effective, must be introduced in daily clinical practice and, if possible, supported by public health programs. PMID- 20948731 TI - Pain management during labor. AB - Recent studies investigating the management of analgesia in childbirth have demonstrated that pain relief can be started early in labor with no negative consequences. Also of particular importance are studies showing that automated delivery of large boluses of diluted local anesthetic with opioids might be more effective than continuous background infusion of these drugs in patient controlled epidural analgesia. PMID- 20948732 TI - Recent advances in management of cerebrovascular diseases. AB - A comprehensive approach to managing the vascular risk factors in both primary and secondary stroke prevention settings can lower the risk of first and recurrent stroke. Recent studies highlight the benefits of blood pressure treatment in the elderly, use of statins in healthy subjects with normal low density lipoprotein levels, and comparison of various anti-platelet agents. For acute stroke the efficacy of thrombolysis beyond 3 hours has recently been shown. PMID- 20948733 TI - Advances in the management of adult obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is associated with cognitive impairment, daytime sleepiness, and cardiovascular and cerebrovascular morbidity and mortality. Continuous positive airway pressure (CPAP) remains the primary treatment for this disorder, and recent data provide novel insight regarding optimal CPAP application and compliance. Promising alternate forms of OSA treatment have also been addressed with recent clinical research. PMID- 20948734 TI - Combination therapy of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chronic kidney disease. AB - Dual blockade of the renin-angiotensin system (RAS) with a combination of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for the treatment of hypertension and proteinuria has been tested in several randomized trials among patients with chronic kidney disease (CKD). Although combination therapy reduces proteinuria and blood pressure, adequately powered studies evaluating time to end-stage renal disease, death, or cardiovascular outcomes in patients with CKD have not been done. Dual blockade of RAS can cause hyperkalemia, renal failure, and orthostatic hypotension and potentially worsen outcomes; therefore, the risk-benefit ratio in patients with CKD remains unclear. A recent randomized trial in patients with cardiovascular disease or high-risk diabetes raises concerns about the safety of this combination therapy. PMID- 20948735 TI - Diagnosis and treatment of eosinophilic esophagitis. AB - Eosinophilic esophagitis is a newer disease entity that has been diagnosed with increasing frequency over the past 10 years. Patients present with a variety of symptoms including vomiting, failure to thrive, abdominal pain, dysphagia, and/or food impaction depending on the age of the patient. The diagnosis is confirmed by endoscopy with eosinophilic inflammation localized to the oesophagus, an area typically void of eosinophils. PMID- 20948736 TI - Recent advances in therapy for sexual offenders. AB - This report focuses on recent policy, and academic and clinical developments in the therapeutic management of sex offenders, including the need for more robust assessment and risk management protocols. Information is provided on current thinking about psychological and pharmacological interventions. Meta-analytic studies clearly indicate that cognitive behavioural and relapse prevention programmes are the most effective intervention, but there is a small amount of literature suggesting that pharmacological treatments may have some utility. With advances in our understanding of the neural substrates of deviant sexual arousal we may be able to develop and trial novel neuropharmacological agents that target dysfunctional neurochemical circuits in this field. PMID- 20948737 TI - Recent advances in peptic ulcer bleeding. AB - Peptic ulcer bleeding remains a common cause of hospital admission, morbidity and mortality. Data published since 2006 illustrate that assessment, endoscopic and pharmacological management, and follow-up strategies can be refined to improve the overall prognosis of peptic ulcer bleeding. PMID- 20948738 TI - Cardiovascular, renal and liver events associated with human immunodeficiency virus type 1 infection and antiretroviral therapy. AB - The first 15 years of the human immunodeficiency virus type 1 epidemic was characterized by patients progressing to clinical acquired immunodeficiency syndrome and death. The availability of potent antiretrovirals led to the recognition of unique adverse events associated with select drugs. More recent data suggest that end-organ damage may be associated with ongoing viremia. Further understanding of the potential role different drugs and the virus itself has on various organs can enhance the clinician's ability to manage patients in the clinic. PMID- 20948739 TI - Optimum serum glucose levels for patients with severe traumatic brain injury. AB - Tight glucose control during the acute care of patients with severe traumatic brain injury has recently been advocated based on experimental concerns about deleterious effects of presenting the injured brain with a high glucose load, however, there is little or no clinical evidence that hyperglycemia worsens neurologic injury. The majority of the clinical studies of tight glucose control find that it is associated with an increased risk of hypoglycemic episodes and cellular injury, when compared to conventional glucose control protocols. PMID- 20948740 TI - Antiproliferative effects of somatostatin analogs in endocrine tumours. AB - Somatostatin has been discovered as a somatotroph release inhibitory factor (SRIF), and it has been demonstrated that SRIF and its analogs can inhibit hormone secretion and control the neoplastic bulk of several endocrine tumours. In vitro studies have contributed to the current knowledge of the mechanisms by which SRIF and its analogs may influence endocrine tumour proliferation, opening the way to new possible therapeutic strategies. Here, we focus on the studies concerning the antiproliferative effects of SRIF and its analogs that provide the basis for future investigations, both at basic and clinical levels, into the application of SRIF analogs in the endocrine field. PMID- 20948741 TI - Advances in the management of atrial fibrillation in congestive heart failure. AB - Atrial fibrillation, a common problem in patients with heart failure, is associated with increased mortality and morbidity. Pharmacological as well as invasive management and the endpoints of such management are complex. Recent randomized trials indicate that a rate-control strategy, along with anticoagulation treatment with warfarin, when appropriate, has a similar outcome in terms of mortality and morbidity as rhythm control, and could, therefore, be considered as the primary management strategy for atrial fibrillation in patients with heart failure. PMID- 20948742 TI - Recent advances in the pharmacological management of migraine. AB - Pharmacological treatment of migraine includes acute and, in some patients, preventive medications. Here, the most relevant recent advances in migraine management are reviewed. Regarding acute treatment, new data indicate that early treatment of migraine attacks should be recommended to those patients who do not show a clear response when pain is already moderate or severe. It has also been shown that, in terms of efficacy, the combination of a nonsteroidal anti inflammatory drug plus a triptan is superior to monotherapy. In the immediate future it seems that a new class, the antagonists of calcitonin gene-related peptide, will offer at least the same efficacy as that of potent triptans, but a much better tolerability and no vascular contraindications. Concerning migraine prevention, news has been concentrated on the management of chronic migraine, with the appearance of guidelines for clinical trials in chronic migraine and the demonstration that it is a treatable entity, even in the presence of overuse criteria. PMID- 20948744 TI - Penile traction therapy in Peyronie's disease. AB - Penile traction therapy has traditionally been implemented to increase penile length but has recently been investigated for reducing the curvature associated with Peyronie's disease. The results of a few initial investigations have been conflicting, and further research is needed to confirm the true benefit of such therapy and its potential role in treating Peyronie's disease as both a monotherapy and in combination with other therapeutic options. PMID- 20948743 TI - Recent advances in therapies for the eating disorders. AB - In the first part of this decade, many reviews of the impact of treatments for the eating disorders were conducted, with broadly similar conclusions. This review provides an update on progress (or otherwise) in the field over the past three years. PMID- 20948745 TI - The clinical value of new diagnostic tools for tuberculosis. AB - Barriers to global tuberculosis (TB) control include multidrug resistance, HIV infection, and weak health systems. Case detection is critical to TB control and is affected by all three of these. Currently, most low- and middle-income countries (LMICs) rely on direct sputum smear microscopy for diagnosis. Modern culture methods and molecular tests, previously considered too complex or too expensive for implementation in LMICs, are now being introduced there in parallel with a global effort to strengthen laboratories. It remains to be seen whether services based on these tools can be made widely accessible to patients. New point-of-care tests for TB are urgently needed but cannot be expected in the near future. In the meantime, diagnostic tools based on optimized smear microscopy, although less sensitive than reference laboratory tests, may be more accessible and have more impact on case finding. It is a matter of urgency that these improved microscopy services be integrated with services based on rapid methods that can identify multidrug-resistant cases. PMID- 20948746 TI - New oral disease-modifying therapies for multiple sclerosis. AB - Several promising, oral disease-modifying therapies for multiple sclerosis are currently being evaluated in clinical trials. The arrival of effective oral agents for multiple sclerosis will be a major advance in the global effort to alter the natural history of this chronic disease. PMID- 20948747 TI - Diagnosis and management of vasospasm. AB - An overview of the main features of cerebral vasospasm is provided in this report, highlighting the possible future direction of development in the diagnosis and management of this severe complication of aneurysmal subarachnoid hemorrhage. PMID- 20948748 TI - Diagnosis and treatment of coeliac disease. AB - It is now clearly established that coeliac disease is much more common than originally considered. While in the past it was taught that coeliac disease was mainly a disease of children, it is clear now that it may be diagnosed at any age. The clinical presentation of adolescents and adults is, however, less typical. Recent evidence suggests that coeliac disease is a multi-organ disease. The diagnostic techniques involving histology and serologic testing have been improved and the involvement of environmental and genetic factors in the pathogenesis of this immune disorder has been clarified, although the pathogenesis is not yet completely understood. Complications are now better identified, and new treatment strategies are under consideration. PMID- 20948749 TI - Update on the utility of prognostic biomarkers in ovarian cancer. AB - There is considerable interest in the gynecologic cancer community for the development of biomarkers that will be of utility in routine management of women with advanced ovarian cancer. However, at the present time, there remains limited evidence for the usefulness of any such test other than the serum cancer antigen (CA)-125 level, employed to monitor the course of disease in response to treatment or during periods of observation. PMID- 20948750 TI - The role of TNF inhibitors in psoriasis therapy: new implications for associated comorbidities. AB - Over the past several years, tumor necrosis factor (TNF) antagonists have become first-line agents in the treatment of moderate-to-severe psoriasis. These medications are highly effective in treating both psoriasis and psoriatic arthritis and may also reduce the risk of cardiovascular events in patients with chronic inflammatory disorders. In this article we review the use of anti-TNF therapy in psoriasis and its implications in regards to the co-morbid conditions associated with psoriasis. PMID- 20948751 TI - Septic shock: the changing Zeitgeist of management. AB - Most interventions in critically unwell patients with septic shock are poorly supported by evidence, in part reflecting the difficulty of conducting trials in this heterogeneous group. Four important clinical trials in 2001-2 appeared to demonstrate mortality benefits associated with early goal-directed resuscitation, intensive glycaemic control, physiological-dose steroid replacement and activated protein C. However, recent evidence has not confirmed the beneficial effect of these interventions. PMID- 20948752 TI - Impulse control disorders in Parkinson's disease. AB - Since the original descriptions of hedonistic homeostatic dysregulation syndrome and pathological gambling in Parkinson's disease, impulse control disorders, such as compulsive spending, punding, or binge eating, are increasingly recognized. Although the term hedonistic homeostatic dysregulation syndrome has been supplanted by the concept of the dopamine dysregulation syndrome, the features of severe dyskinesias, cyclical mood disorder with hypomania or manic psychosis, and impairment of social and occupational functioning in the setting of increased intake of antiparkinson therapy remain. At this time, impulse control disorder is defined as maladaptive behaviors that emerge with disease progression and increasing antiparkinson medications. These behaviors may be disruptive, such as punding, or destructive, such as compulsive spending, gambling, binge eating, or hypersexuality. PMID- 20948753 TI - Two negative randomized controlled trials in lupus: now what? AB - Recently, two large randomized controlled trials of distinct biologic therapies in systemic lupus erythematosus, B-cell depletion with rituximab and co stimulatory blockade with CTLA4Ig (abatacept), failed to meet primary endpoints. Given the great need for new treatments in lupus, these results were met with disappointment and have left the rheumatology and immunology community searching for an explanation. Are these experimental agents ineffective in lupus or are there trial design issues or other considerations? In this commentary, we discuss our perspective on these results within the context of current understanding of the pathophysiology of lupus and the mechanism of action of biologic therapies. PMID- 20948754 TI - Remote monitoring of patients with cardiac failure. AB - The area of remote monitoring in cardiac failure is developing rapidly. However, the term is used widely and inconsistently, resulting in difficulty interpreting the literature. Here we assess the recent research into this area and the potential implications for clinical practice. PMID- 20948755 TI - Recent advances in medical treatment and percutaneous, transapical and surgical interventions in aortic-valve stenosis. AB - This review focuses on recent advances in the treatment of aortic-valve stenosis with special emphasis on medical treatment for preventing disease progression, and on novel surgical and percutaneous approaches. PMID- 20948756 TI - Clostridium difficile and inflammatory bowel disease: implications for current clinical practice. AB - Clostridium difficile infection should always be included in the differential diagnosis of patients with refractory inflammatory bowel disease (IBD) symptoms, as it is well known to induce or mimic a flare of IBD. There is currently an alarming increase in the incidence of C. difficile infection in Europe and North America. Current epidemiologic data suggest that more virulent strains, such as C. difficile 027/NAP1/BI, are emerging. Testing for both C. difficile toxins A and B should be done, and often serial stool samples may be required, especially if the index of suspicion is high. Patients with IBD do not necessarily require a history of antibiotic use or hospitalization to acquire the infection and most do not have pseudomembranes on sigmoidoscopy. C. difficile infection is associated with longer hospital stays, increased mortality, and higher complication rates, including colectomy. Treatment with oral vancomycin is probably the drug of choice as one study suggests that patients had lower colectomy rates on this drug. Further work is required to clarify the best management strategies for C. difficile in IBD patients, and more effort is needed to halt the rising incidence of this infection, perhaps with adherence to safer antibiotic prescribing guidelines, hand washing, and cleaner hospital environments, which should reduce the risk of acquiring and spreading this preventable infection. PMID- 20948757 TI - Individualization of treatment in non-small cell lung cancer. AB - Two recently reported randomized studies discussed below are paving the way for personalized treatment approaches for patients with non-small cell lung cancer (NSCLC). Both studies show that accurate subclassification of NSCLC will become necessary to prescribe chemotherapy doublets and epidermal growth factor receptor tyrosine kinase inhibitors. It is expected that the practice of the last 30 years of lumping all NSCLC subtypes together will soon come to an end. PMID- 20948758 TI - Recent advances in rehabilitation of stroke survivors. AB - This report discusses the newest approaches to rehabilitation of post-stroke patients. Recent studies have clinical implications for the treatment of stroke at all stages, and chronic aphasia. PMID- 20948759 TI - The role of antibiotics in the prevention of preterm birth. AB - THERE ARE MULTIPLE USES FOR ANTIBIOTICS DURING PREGNANCY: treatment of intercurrent bacterial infections such as urinary or respiratory tract infections, maternal treatment to prevent fetal or neonatal disease, prophylactic treatment for surgical procedures, and treatment of puerperal infections. This report will summarize the current recommendations for the use of antibiotics specifically to reduce the risk of preterm birth. PMID- 20948761 TI - HER2 status and breast cancer therapy: recent advances. AB - The phenotype imparted by expression of the HER2 gene in breast cancer and progress made in modifying the disease's natural history through pharmacologically modulating its function has served as a paradigm for rationally targeted therapy and personalized medicine. About 20-25% of breast cancer cases are associated with HER2 gene amplification and overexpression, creating a distinct subtype of breast cancer that is associated with more aggressive behaviour, higher likelihood of overall and brain metastases, and differential responsiveness to certain hormonal and chemotherapeutic agents. Anti-HER2 monoclonal antibodies have led to significant improvements in survival for both advanced and early stage HER2+ breast cancer, while newer agents, including other antibodies and HER2 receptor tyrosine kinase inhibitors and signal transduction modulators, are also demonstrating clinical activity and represent further opportunities to improve curability and quality of life. PMID- 20948760 TI - Biomarkers in predicting mortality and treatment in hemodialysis patients. AB - Circulating natriuretic peptides are useful biomarkers of left ventricular dysfunction and heart failure in the general population. Cardiac troponin T (cTnT) is also considered a sensitive marker of myocardial injury. However, the fact that levels of circulating natriuretic peptides and cTnT are almost invariably increased in end-stage renal disease patients has been considered a major limitation for their use as diagnostic or prognostic tools in this population. We provide an updated review on the role of natriuretic peptides and cTnT as biomarkers in predicting outcome and treatment in the hemodialysis population. PMID- 20948762 TI - Androgen deprivation therapy for prostate cancer: indications, contraindications and possible consequences. AB - Androgen deprivation therapy (ADT) has been the mainstay of palliative treatment in advanced and metastatic prostate cancer for many years. It is also increasingly being used in patients with localized disease. Here we review some recent trials that are providing information on its benefits and disadvantages in different circumstances. PMID- 20948763 TI - Diagnosis of medullary thyroid cancer. AB - Medullary thyroid cancer (MTC) accounts for 5-10% of all thyroid cancers. The majority of medullary thyroid cancers are sporadic, but 25% of cases are inherited as a result of germline mutations in the RET proto-oncogene. In sporadic cases MTC presents as a thyroid nodule discovered at palpation or at thyroid ultrasonography, and is indistinguishable from thyroid nodules of different histology. Since effective treatment of MTC is only possible when the tumour is limited to the thyroid gland, early discovery has a decisive impact on how radical initial surgical treatment needs to be. Recent data suggest that in sporadic cases, early discovery of thyroid nodular disease is possible when screening serum calcitonin measurement, while screening for germline RET proto oncogene mutations is fundamental in first degree relatives of patients with hereditary MTC. PMID- 20948764 TI - Current concepts in the management of carotid stenosis. AB - Several large randomized clinical trials in North America and Europe concluded over a decade ago that carotid endarterectomy plus medical management was significantly better than medical management alone for stroke prevention in either symptomatic or asymptomatic patients with severe carotid stenosis. Percutaneous carotid angioplasty now represents another treatment option that currently seems most appropriate either in the context of prospectively randomized trials or for patients who are at a higher than average risk for conventional surgical treatment. PMID- 20948765 TI - Updates in colorectal cancer screening. AB - Recent advances in the field of colorectal cancer screening have led to updated guidelines from several national societies. Although various strategies have been illustrated to reduce mortality from colorectal cancer, screening tests differ in their ability to detect neoplasia. While this is an issue for all lesions, it is a particular problem for non-polypoid or 'flat' colonic neoplasia, which has been recognized to be prevalent in Western countries. Guidelines also recommend the age at which screening is initiated and discontinued; however, emerging data suggest these thresholds may lead to missed lesions. Finally, evidence points to disparities in the availability and utilization of colorectal cancer screening tests, which may be successfully addressed through interventions that educate both patients and their providers. The focus of future efforts includes increasing adherence to recommended screening strategies. PMID- 20948766 TI - Non-pharmacological approaches for treating children with ADHD inattentive type. AB - The behavioral difficulties of children with attention-deficit/hyperactivity disorder (ADHD) inattentive type differ from those of children with ADHD combined or hyperactive/impulsive type. Existing evidence-based interventions primarily target the disruptive and impulsive behaviors exhibited by children with ADHD combined and hyperactive/impulsive type. A number of recent advances have been made in the non-pharmacological treatment of behavioral difficulties associated with ADHD inattentive type. Additional research using randomized controlled research designs and long-term follow-up evaluation is necessary before these interventions may be considered established evidence-based interventions for patients with ADHD inattentive type. PMID- 20948767 TI - Diagnosis and clinical severity markers of bullous pemphigoid. AB - The use of a broad spectrum of novel detection systems for autoantibodies to the basement membrane proteins BP180 and BP230 has greatly facilitated the diagnosis of bullous pemphigoid, which most likely explains its increasing incidence in central Europe. Because the pathogenic relevance of antibodies to human BP180 has been convincingly shown both in vitro and in vivo, repeated testing for these antibodies appears to be helpful in guiding treatment decisions during the course of the disease. PMID- 20948768 TI - Postoperative cognitive dysfunction. AB - Postoperative cognitive dysfunction (POCD) refers to a deterioration in cognition noted to occur after surgery and anesthesia. Recent studies have demonstrated a number of correlates and risk factors for this condition, although much remains to be elucidated in terms of the true incidence, etiology, prevention, and treatment. PMID- 20948769 TI - Recent advances in the treatment of B-cell lymphoma. AB - There have been unprecedented advances in the management of B-cell lymphoma in the last decade. These include staging, treatment, and bench observations. PMID- 20948770 TI - Recent updates in mechanical ventilation. AB - Recently, several studies have been performed to better outline the pathophysiology of acute respiratory failure and evaluate the therapeutic profile of different modes of ventilation and ventilator settings. Here we briefly report those we consider most relevant for daily intensive care unit clinical practice. PMID- 20948771 TI - Hematopoietic stem cell transplantation in patients with myelodysplastic syndrome. AB - Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for patients with myelodysplastic syndrome (MDS). However, the morbidity and mortality associated with conventional HSCT have traditionally prevented many patients from undergoing such treatment. Recent advances, including better prognostic algorithms, the introduction of reduced intensity conditioning regimens, and experience with alternative donors, have made HSCT a realistic option for an increasing number of patients with MDS. PMID- 20948772 TI - Does infliximab increase complications after surgery for inflammatory bowel disease? AB - Conflicting data exist regarding the association between pre-operative monoclonal anti-tumor necrosis factor-alpha antibody therapy with infliximab for Crohn disease and chronic ulcerative colitis, and the occurrence of post-operative complications. This report reviews the current literature that supports and refutes this association. PMID- 20948773 TI - Radiation exposure in cardiac multislice spiral computed tomography (MSCT). AB - Computed tomographic (CT) imaging involves exposure to ionizing radiation, with a consequent potential risk to the patient. Here we review the technical factors that affect the radiation dose in cardiac CT diagnostic procedures, the parameters that are used to measure and compare radiation doses, the magnitude of radiation exposure, and how to efficiently reduce it. PMID- 20948774 TI - The quality of pain management in German hospitals. AB - BACKGROUND: The Pain-Free Hospital Project was initiated in 2003 with the aim of improving pain management throughout Germany. We assessed the current state of pain management in German hospitals. METHODS: From 2004 to 2006, data were obtained anonymously from 2252 patients who had undergone surgery, and 999 who had been treated non-surgically, in a total of 25 hospitals. They were interviewed about the intensity of pain they had experienced and about the effectiveness of its treatment. RESULTS: No pain at all was reported by 12.4% of patients who had undergone surgery and by 16.7% of the non-surgically treated patients. Moderate to severe pain at rest was reported by 29.5% of the surgical group and 36.8% of the non-surgical group. More than 50% of the overall group reported pain on movement. 55% of the surgical group, and 57% of the non-surgical group, were dissatisfied with their pain management. Peak pain tended to occur outside normal working hours. No analgesic treatment at all was given to 39% of patients in the non-surgical group, even though they were in pain; the corresponding figure for the surgical group was 15% (a significant difference, p<0.001). Inadequately effective pain management was reported by 45.6% of patients in the non-surgical group and 29.6% in the operative group (again, a significant difference. Cancer patients were treated more often with potent opioids. CONCLUSION: Severe postoperative pain is still too common among hospitalized patients, particularly pain that is induced by movement. Patients being treated on non-surgical wards also often suffer severe pain needlessly. Pain management seems to be worse for non-surgical patients (cancer patients excepted) than for surgical patients: waiting times for medication are longer, and ineffective medications are given more often. On the other hand, a number of hospitals provide positive examples of the potential effectiveness of pain management for both surgical and non-surgical patients. PMID- 20948775 TI - The changing prevalence of attention-deficit/hyperactivity disorder and methylphenidate prescriptions: a study of data from a random sample of insurees of the AOK Health Insurance Company in the German State of Hesse, 2000-2007. AB - BACKGROUND: The goal of this study is to assess changes in the prevalence of attention-deficit/hyperactivity disorder (ADHD) and methylphenidate prescriptions over the period 2000 to 2007 on the basis of data from a German statutory health insurance carrier. METHODS: In a cross-sectional study, we analyzed data from a random sample of insurees of the AOK health insurance company in the German state of Hesse for the years 2000 to 2007. Per calender year, 50,000 to 63,000 children and adolescents were retrospectively observed with respect to the documentation of ADHD diagnosis (ICD-10 diagnosis F90) and the prescribing of methylphenidate (ATC: N06BA04). RESULTS: In 2007, the overall prevalence of ADHD in all age groups (0-18 years) was 2.21% (95% CI: 2.09-2.34). This figure was 45% greater than the corresponding figure for the year 2000. The prevalence increased by a larger amount among girls aged 6 to 18 years than among boys in the same age group (+69% vs. +53%). In 2007, 1.06% (95% CI: 0.98-1.16) of the children/adolescents received at least one prescription for methylphenidate; this was a 96% increase over the prescription rate for 2000. A comparison of the two years 2000 and 2007 reveals a clear prevalence shift towards the older age groups, as well as an 82% increase in the average number of daily doses per recipient. Outpatient departments of child and adolescent psychiatry initiated more treatments in 2007 than in 2000. CONCLUSION: The 1% prevalence of methylphenidate use among children and adolescents that was found in this study is the same as that reported in other European countries, such as Switzerland, the Netherlands, and Norway. A drawback of our study is its limitation to a single insurance carrier in a single region. Nonetheless, data of this type are useful for monitoring. The findings suggest further issues worth studying, e.g., off-label use or the indications for treatment in older age groups. PMID- 20948776 TI - Recurrent tonsillitis in adults: quality of life after tonsillectomy. AB - BACKGROUND: The aim of this study was to assess the effect of tonsillectomy in adults with recurrent tonsillitis on their quality of life and on their use of medical resources. METHOD: 114 patients who had had at least three episodes of acute tonsillitis in the 12 months preceding tonsillectomy were evaluated pre- and postoperatively with a questionnaire developed by the authors, and with the Glasgow Benefit Inventory. RESULTS: 97 patients (85%) filled out the questionnaires completely. The Glasgow Benefit Inventory revealed an improvement in the overall score (+19) and in the partial scores for general well-being (+18) and physical health (+39). The degree of support from friends and family was unchanged (+/-0). Significant decreases were observed in visits to a physician, analgesic and antibiotic consumption, days off from work, and episodes of sore throat. The number of visits to a physician because of sore throat decreased from an average of five preoperatively to one postoperatively; the number of episodes of sore throat, from seven to two; and the number of days taken off from work, from twelve to one per year. 65% of the patients surveyed took analgesics for sore throat preoperatively, 7% postoperatively. 95% took antibiotics for sore throat preoperatively, 22% postoperatively. CONCLUSION: Although this study had a number of limitations (small size, retrospective design, short follow-up), it was able to show that tonsillectomy for adults with recurrent tonsillitis improves health and quality of life and reduces the need to consume medical resources. PMID- 20948777 TI - Correspondence (letter to the editor): Radical surgery. PMID- 20948780 TI - Correspondence (letter to the editor): Important study should have been considered. PMID- 20948781 TI - Recent advances in regulation of flowering. AB - The control of flowering time in plants is critical for plant fitness and for agriculture. The genetic pathways governing this developmental transition are reasonably well understood in Arabidopsis, although substantial new gains are still being made in this system. Much new work is focusing on how the genetic networks governing flowering function in other species. PMID- 20948782 TI - Recent advances in plant metabolomics and greener pastures. AB - Metabolomics is an extension of the omics concept and experimental approaches. However, is metabolomics just another trendy omics fashion perturbation or is metabolomics actually delivering novel content and value? This article highlights some recent advances that definitely support the role of plant metabolomics in the movement toward greener pastures. PMID- 20948783 TI - Hidden ribozymes in eukaryotic genome sequence. AB - The small self-cleaving ribozymes fold into complex tertiary structures to promote autocatalytic cleavage or ligation at a precise position within their sequence. Until recently, relatively few examples had been identified. Two papers now reveal that self-cleaving ribozymes are prevalent in eukaryotic genomes and, in some cases, might play a role in regulating gene expression. PMID- 20948784 TI - Neuronal calcium sensor proteins: emerging roles in membrane traffic and synaptic plasticity. AB - Ca(2+) plays a crucial role in the regulation of neuronal function. Recent work has revealed important functions for two families of neuronally expressed Ca(2+) sensor proteins. These include roles in membrane traffic and in alterations in synaptic plasticity underlying changes in behaviour. PMID- 20948785 TI - Recent advances in computational modeling as a conduit to understand the plant circadian clock. AB - The circadian clock is necessary for plants to anticipate environmental changes. This leads to a coordination of plant development and growth and thus to increased fitness. Many clock components were identified by genetic and biochemical approaches, and studies on these components revealed a core oscillator with multiple feedback loops. A suite of computation analyses is uncovering the outputs of this oscillating network. Mathematical analysis is contributing to our understanding of the network under clock control, moving toward an explanation of how the clock integrates and coordinates various developmental programs with daily environmental cues. From there, these systems approaches will look to establish further nodes within the clock network. PMID- 20948786 TI - Role of caspases and non-caspase proteases in cell death. AB - Undoubtedly, caspases are the major driving force for apoptosis execution and mechanisms of their activation and inhibition have been largely unveiled. Recent progress has been made with regard to the exact intracellular ordering of caspases, monitoring their activities in vivo and unveiling their substrate degradomes. Moreover, non-caspase proteases seem to assist caspases in the completion of the death execution program. Here we will consider some very recent data dealing with these aspects. We will also provide novel insights into the mechanisms that dictate apoptotic variability within a cell population. PMID- 20948787 TI - De novo prions. AB - Prions are responsible for a heterogeneous group of fatal neurodegenerative diseases. They occur in three forms - sporadic, genetic, or acquired - and involve non-covalent post-translational modifications of the cellular prion protein (PrP(C)). Prions (PrP(Sc)) are characterized by their infectious properties and intrinsic ability to act as a template, converting the normal, physiological PrP(C) into the pathological form, PrP(Sc). The 'protein-only' hypothesis, postulated by Stanley B Prusiner, implies that the generation of de novo prions is possible. Exciting recent work, in vivo and in vitro, has further strengthened this postulate. PMID- 20948788 TI - Autophagy of intracellular microbes and mitochondria: two sides of the same coin? AB - Autophagy has become a biological paradigm of how eukaryotic cells, especially those that are long lived, maintain their vitality, control the quality of cytoplasmic organelles, and stay alive or die when growth factors are withdrawn and there is an energy or nutrient crisis. The role of autophagy has been extended to innate and adaptive immunity functions, which surpassed all initial expectations in terms of how immunity and autophagy are interconnected. Of particular interest at the moment is the growing appreciation of the similarity between how mitochondria and intracellular pathogens are handled by autophagy in its function of sanitizing the cytoplasm. An emerging framework from this may link the roots of cell defense against infection with cell longevity and programmed cell death. PMID- 20948789 TI - Retrotransposons and germ cells: reproduction, death, and diversity. AB - The evolutionary success of retrotransposable elements is reflected by their abundance in mammalian genomes. To restrict their further advance, a number of defence mechanisms have been put in place by the host. These seem to be particularly effective in the germ line while somatic lineages might be more permissive to new insertions, as recent work by Kano and colleagues suggests. PMID- 20948790 TI - An uncorrelated state for the cortex? AB - The spike trains of nearby neurons in the sensory cortex are typically thought to be correlated due to mutual connections and common input. Multiple studies have measured these correlations and found them to be substantial (in the range of 10 40%). Two recent papers, however, reported that average correlations can be an order of magnitude smaller. Such low correlations could indicate an 'uncorrelated state' for the cortex, where cortical neurons act independently even in the face of strong common input. PMID- 20948791 TI - Do apicomplexan parasites hijack the host cell microRNA pathway for their intracellular development? AB - RNA silencing plays an important role in development through the action of microRNAs, which fine tune the expression of a large portion of the genome. It is also very important in innate immune responses, especially in antiviral and antibacterial defenses in plants, insects, and animals. Two recent papers now indicate that apicomplexan parasites display the ability to interfere with host microRNA populations. PMID- 20948792 TI - Advances in the genetics of primary torsion dystonia. AB - Knowledge about the genetics of primary torsion dystonia (PTD) has been progressing at a very slow pace compared with other movement disorders. For many years, only one causative gene was known, DYT1/TOR1A, yet the recent identification of a second PTD causative gene (DYT6/THAP1), the detection of subclinical alterations caused by mutations in PTD genes in some healthy non penetrant individuals, and functional studies on TOR1A and THAP1 protein products have significantly improved mutation detection, genotype-phenotype correlates, and our understanding of the cellular mechanisms underlying the development of dystonia. PMID- 20948793 TI - The role of IL-23 in the immunopathogenesis of psoriasis. AB - In just 10 years from its discovery in 2000, interleukin-23 has quickly moved from being recognized as a pro-inflammatory cytokine to a key player and potential therapeutic target in psoriasis. PMID- 20948795 TI - Structure of spliceosomal ribonucleoproteins. AB - Splicing of the precursors of eukaryotic mRNA and some non-coding RNAs is catalyzed by the 'spliceosome', which comprises five RNA-protein complexes (small nuclear ribonucleoproteins, or snRNPs) that assemble in an ordered manner onto precursor-mRNAs. Much progress has been made in determining the gross morphology of spliceosomal assembly intermediates. Recently, the first crystal structure of a spliceosomal snRNP has provided significant insight into assembly and architecture of spliceosomal snRNPs in general and the structure-function relationship of human U1 snRNP in particular. PMID- 20948794 TI - Dysfunction of the Ca(V)2.1 calcium channel in cerebellar ataxias. AB - Mutations in the CACNA1A gene are associated with episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). CACNA1A encodes the alpha-subunit of the P/Q-type calcium channel or Ca(V)2.1, which is highly enriched in the cerebellum. It is one of the main channels linked to synaptic transmission throughout the human central nervous system. Here, we compare recent advances in the understanding of the genetic changes that underlie EA2 and SCA6 and what these new findings suggest about the mechanism of the disease. PMID- 20948796 TI - Destroy to create: E3 ubiquitin ligases in neurogenesis. AB - The ubiquitin proteasome system (UPS) has drawn tremendous attention in the field of neuroscience. In recent years, we have gained insights into UPS-dependent mechanisms in brain development and disease. Several interesting studies over the past two years have highlighted the role of distinct E3 ubiquitin ligases in neurogenesis. Here, we will review the major findings in these studies and discuss their implications. PMID- 20948797 TI - PRDM9 sticks its zinc fingers into recombination hotspots and between species. AB - Meiotic recombination events typically cluster within narrow regions of the genome termed hotspots. A series of recent papers reveals that PRDM9, a C2H2-type zinc-finger protein with histone H3 lysine 4 methyltransferase activity, plays a major role in the specification of hotspots. The zinc fingers that contact DNA in a sequence-dependent manner evolve rapidly and are under positive selection, leading to differences in the location of recombination hotspots as well as hybrid sterility. PMID- 20948798 TI - Bacterial surface proteins and vaccines. AB - Surface-associated proteins play a key role in bacterial physiology and pathogenesis and are the major targets for vaccine development. Recent advances in defining the proteins associated with, and protruding out of, bacterial cells to a high level of accuracy are substantially contributing to accelerating the process of vaccine target identification and development. PMID- 20948799 TI - Membrane deformation and separation. AB - Biological membranes are highly dynamic (e.g., during cell division, organelle biosynthesis, vesicular transport, and neurotransmitter release). They can be shaped into protein-coated transport vesicles or tubules and undergo regulated fusion. The life of transport vesicles depends on highly specific and tightly regulated protein machineries, which not only shape the donor membrane into nascent budding structures but also help to overcome the energy barrier to break the bilayers apart in order to pinch off nascent vesicles. Ultimately, vesicular membranes have to fuse with a target lipid bilayer, a process that again requires remodeling. Here, we highlight recent insights into mechanisms that lead to membrane deformation in the process of vesicular budding. PMID- 20948800 TI - Seeing with the mind's eye: top-down, bottom-up, and conscious awareness. AB - With the advent of functional brain imaging techniques and recent developments in the analysis of cortical connectivity, the focus of mental imagery studies has shifted from a semi-modular approach to an integrated cortical network perspective. Functional magnetic resonance imaging studies of visual imagery of faces and objects show that activation of content-specific representations stored in the ventral visual stream is top-down-modulated by parietal and frontal regions. Recent findings in patients with conscious awareness disorders reveal that mental imagery can be used to map patterns of residual cognitive function in their brain and to provide diagnostic and prognostic indicators. PMID- 20948801 TI - A virtual cycle: theory and experiment converge on the exit from mitosis. AB - The cell division cycle can be modelled as a series of quantitative thresholds of cyclin-dependent kinase (CDK) activity. DNA synthesis has a lower threshold requirement for CDK than does entry into mitosis, and mitotic exit and re-setting of replication origins occur upon collapse of CDK activity below both thresholds, so that the simple rise and fall of CDK with each cell cycle might suffice to ensure repeated alternation of chromosome duplication and segregation. Recent experimental dissections of mitotic exit, which have both guided and been informed by computational modelling, suggest a more complicated mechanism, in which unidirectional progression is ensured by systems-level control of CDK function and the balance between mitotic CDK and phosphatase activities. PMID- 20948802 TI - Doing cell biology in embryos: regulated membrane traffic and its implications for cadherin biology. AB - Regulated trafficking of cadherin adhesion molecules is often invoked as a mechanism to generate dynamic adhesive cell-cell contacts for tissue modeling and morphogenesis. The past 2-3 years have seen several important papers that tackle the cell biology of cadherin trafficking in organismal systems to provide new insights into both mechanism and morphogenetic impact. PMID- 20948803 TI - Ocular immune privilege. AB - The eye attempts to limit local immune and inflammatory responses to preserve vision. This phenomenon, known as ocular immune privilege, is mediated by a combination of local and systemic mechanisms. While immune privilege is believed to protect the eye from day-to-day inflammatory insults, it is not absolute and its mechanisms are still incompletely understood. PMID- 20948804 TI - Why is Pseudomonas aeruginosa a pathogen? AB - Despite the expression of a myriad of virulence factors, healthy individuals are generally able to resist infections with Pseudomonas aeruginosa. Polymorphonuclear leukocyte-dependent killing is the major mechanism responsible for resistance; dysregulation of host defense mechanisms in addition to expression of specific bacterial factors can result in life-threatening infections with this bacterium. PMID- 20948805 TI - LOV conquers (sm)All GTPases. AB - Knowledge of spatial patterning of GTPases is critical to understanding protein function since subcellular localization is essential for normal protein function. In this paper, we discuss how Hahn's group has created a new type of genetically encoded, light-activated enzyme that allows precise temporal and spatial control of the small GTPase, Rac1. This reagent enables this group to analyze the roles of effector proteins in Rac1 function and may be applicable to other signaling proteins. PMID- 20948806 TI - Advances in understanding the interaction between the gut microbiota and adaptive mucosal immune responses. AB - Commensal gut bacteria are necessary for the complete development of mucosal innate and adaptive immunity and thus may influence intestinal and systemic immune disorders. Recent work has advanced our understanding of this association by identification of a single taxon of the murine microbiota which can stimulate T-cell development and differentiation. It is hoped that further characterization of the mechanisms involved will enable targeted manipulation of the microbiota immune system relationship. PMID- 20948807 TI - The garden of antimicrobial delights. AB - Major advances in genomics, cloning and chemistry will re-stock the dwindling supply of effective antimicrobials and meet the threat of antibiotic resistance development. PMID- 20948808 TI - Plant asymmetric cell division regulators: pinch-hitting for PARs? AB - Like animals, plants use asymmetric cell divisions to create pattern and diversity. Due to a rigid cell wall and lack of cell migrations, these asymmetric divisions incur the additional constraints of being locked into their initial orientations. How do plants specify and carry out asymmetric divisions? Intercellular communication has been suspected for some time and recent developments identify these signals as well as point to segregated determinants and proteins with PAR-like functions as parts of the answer. PMID- 20948809 TI - Recent insights into fatty acid acquisition and metabolism in malarial parasites. AB - The malarial parasite has a tremendous requirement for fatty acids during the replicative stages that take place in the mammalian host. A series of recent papers, discussed below, have revealed some of the mechanisms employed by the parasite to meet these demands. PMID- 20948810 TI - Epigenetic regulation of antigen receptor gene rearrangement. AB - V(D)J recombination assembles antigen-specific immunoglobulin and T-cell receptor variable region genes from germline V, D, and J segments during lymphocyte development. Regulation of this site-specific DNA rearrangement process occurs with respect to the cell type and stage of differentiation, order of locus recombination, and allele usage. Many of these controls are mediated via the modulation of gene accessibility to the V(D)J recombinase. Here, we summarise recent advances regarding the impact of nuclear organisation and epigenetic-based mechanisms on the regulation of V(D)J recombination. PMID- 20948811 TI - Genetics of pulmonary arterial hypertension: do the molecular findings have translational value? AB - Pulmonary arterial hypertension (PAH) is usually a devastating condition with a poor prognosis. Nearly 10 years ago, the underlying molecular basis of heritable PAH was elucidated with the identification of mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR-II). This discovery is now beginning to suggest novel approaches to therapy in heritable PAH. Moreover, recent studies provide evidence that dysfunction of the BMPR-II pathway is a feature of non-familial forms of PAH, broadening the scope for intervention in this pathway. PMID- 20948812 TI - An update on pathobiologic roles of anti-glycan antibodies in Guillain-Barre syndrome. AB - Anti-glycan antibodies directed against gangliosides are now considered the major immune effectors that induce damage to intact nerve fibers in some variants of the monophasic neuropathic disorders that comprise Guillain-Barre syndrome. Recent experimental studies elucidating the complexity of anti-glycan antibody mediated pathobiologic effects on intact and injured nerves undergoing repair are discussed. PMID- 20948813 TI - Multiple functions of dopamine neurons. AB - Dopamine neurons carry phasic signals for a limited number of behavioural events. The events include, in descending order, reward, physically intense stimuli, risk and punishment. Recent neurophysiological studies have provided interesting details on these functions. PMID- 20948814 TI - Control of Schwann cell myelination. AB - Schwann cells ensheath all axons of peripheral nerves. Only around large-diameter axons do they elaborate myelin, forming insulating sheaths that are vital for fast conduction of axon potentials. A series of recent papers has illuminated some of the ways in which the process of myelination is controlled, both by signals from axons and by positive and negative transcriptional mechanisms within the Schwann cells themselves. PMID- 20948815 TI - Mapping chromatin conformation. AB - Chromatin conformation capture (3C) and related techniques have become well established methods to examine which distal DNA sequences are spatially located close to a locus of interest. Hi-C is a new addition to the growing set of 3C based techniques that has extended the approach to a genome-wide analysis of nuclear chromatin using high-throughput DNA sequencing to generate global interaction maps for the entire genome. PMID- 20948816 TI - The pathophysiology of diastolic heart failure. AB - Whilst resting disturbances of both diastolic and long-axis systolic function are observed in patients with heart failure who have normal left ventricular ejection fraction, recent evidence suggests that dynamic disturbances in cardiac function occur during exercise. A paradoxical slowing of left ventricular active relaxation during exercise limits cardiac filling and therefore stroke volume and appears to be due to the combination of cardiac energetic impairment and disturbed ventricular-vascular coupling. PMID- 20948817 TI - Abscisic acid (ABA) receptors: light at the end of the tunnel. AB - The plant hormone abscisic acid (ABA) plays a role in several aspects of plant growth and development. Understanding how this hormonal stimulus is sensed and transduced turned out to be one of the major tasks in the field of plant signaling. A series of recent papers proposed several different proteins that could receive the ABA signal and initiate the signaling cascade. The winner appears to be PYR/PYL/RCAR (PYrabactin Resistance/PYrabactin Resistance Like/Regulatory Component of Abscisic acid Receptor) proteins, as crystal structures were recently published. The crystal structures support the idea that upon ABA binding to a PYR/PYL/RCAR protein, the activity of a phosphatase 2C, with known repressive activity on ABA signaling, is inhibited. PMID- 20948818 TI - Regulation of the IgE response. AB - IgE was the last of the five immunoglobulin classes to be discovered and is the antibody that is responsible for much of human type I allergic disease. This review summarizes recent developments with respect to control of IgE synthesis with an emphasis on Th2 (T helper 2) control and regulation using IgE Fc receptors. PMID- 20948819 TI - Stress and eating behavior. AB - How stress, the stress response, and the adaptation of the stress response influence our eating behavior is a central question in brain research and medicine. In this report, we highlight recent advances showing the close links between eating behavior, the stress system, and neurometabolism. PMID- 20948820 TI - TRPV4 as a target for bladder overactivity. AB - Several papers published in the last 2-3 years suggest that transient receptor potential vanilloid 4 (TRPV4) channels are candidates as mechanosensors in the urinary bladder (including human) and indicate that modulation (inhibition) of these channels could represent a novel therapy for overactive bladder and storage dysfunction. The effects of only agonists on the bladder have been described up to now, although some compounds endowed with antagonistic activity were reported in the last year. Therefore, it is to be hoped that the effects of these compounds in different models of bladder overactivity will be evaluated. PMID- 20948821 TI - Distinct disorders affecting the brain share common genetic origins. AB - Over the last few years, large cohorts of patients with distinct brain disorders of neuropsychiatric and neurological origin have been analyzed for copy number variation. Surprisingly, the same genetic abnormalities were found in cohorts of patients affected with mental retardation, autism, or schizophrenia. PMID- 20948822 TI - PARP inhibitors in BRCA1/BRCA2 germline mutation carriers with ovarian and breast cancer. AB - BRCA and poly-ADP ribose polymerase (PARP) regulate pathways of DNA repair. Due to the accumulation of mutations introduced by error-prone DNA repair, breast and ovarian cancers develop in the setting of BRCA deficiency. A series of recent clinical trials has tested the use of PARP inhibition as a therapeutic strategy to target BRCA-deficient tumors. PMID- 20948824 TI - Recent advances in management of bladder overactivity. AB - Pharmacologic therapies, primarily antimuscarinic agents, have been the mainstay of treatment for overactive bladder. These drugs produce variable efficacy, a moderate rate of side effects, and rare occurrences of cure. The search for newer and better formulations and derivatives of this class of medication as well as novel therapies is ongoing and primarily fueled by the high prevalence of overactive bladder and the tremendous number of health care dollars spent on current therapy. Surgical options for overactive bladder have evolved slowly and are currently reserved for medical treatment failures and drug intolerance. This article will highlight the new drugs and therapies brought into clinical use for the treatment of overactive bladder over the last few years as well as a promising new agent in the advanced stages of development. PMID- 20948823 TI - Eco-evolutionary dynamics: intertwining ecological and evolutionary processes in contemporary time. AB - Evolution occurring over contemporary time scales can have important effects on populations, communities, and ecosystems. Recent studies show that the magnitude of these effects can be large and can generate feedbacks that further shape evolution. PMID- 20948825 TI - Recent advances in closure of atrial septal defects and patent foramen ovale. AB - Transcatheter closure of secundum atrial septal defect (ASD) and patent foramen ovale (PFO) is now widely accepted as an alternative to surgical closure. With currently available devices and techniques, approximately 80-90% of secundum ASDs and all PFOs can be closed percutaneously. While many devices are available, the use of any particular device is dictated largely by individual defect anatomy, device availability, long-term considerations, approval status (US Food and Drug Administration approval versus CE mark), and physician preference. PMID- 20948826 TI - Pulmonary remodeling in asthma. AB - The inflammatory and immunologic processes responsible for asthma can produce permanently fixed obstructive lung disease unresponsive to medical therapy. This can be manifested clinically by the failure of a childhood asthmatic to reach full expected lung capacity at adulthood and by an accelerated decline in pulmonary capacity in adults. Recent studies have furthered our insight into the pathologic processes underlying these changes and the potential effects of therapy to prevent them. PMID- 20948827 TI - Recent advances in diagnosis and treatment of atypical haemolytic uraemic syndrome. AB - New understanding of the underlying pathology of the thrombotic microangiopathies has resulted in guidelines for the investigation and management of atypical haemolytic uraemic syndrome in children and adults and the prospect of new therapies, which are in clinical trial. Patients should be investigated for defects in complement pathways and a trial of plasma exchange is indicated. PMID- 20948828 TI - Update on the management of chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease is a highly prevalent, underdiagnosed, and undertreated chronic lung disease. Early and appropriate treatment may help modify the course of the disease with respect to exacerbation timing and frequency, quality of life, and mortality. Steady progress continues to be made in understanding the disease pathogenesis and treatment modalities, and there is some evidence that outcomes are improving. PMID- 20948829 TI - Recanalization and reperfusion in acute ischemic stroke. AB - Revascularization remains the most intuitive strategy to reverse ischemic injury associated with arterial occlusion in acute stroke. Revascularization may lead to opening of an occluded artery, or recanalization, yet restoration of downstream flow, or reperfusion, may not ensue. Revascularization strategies and novel devices continue to broaden options for the treatment of acute stroke, but it is increasingly apparent that selection criteria to identify ideal cases are needed to refine triage and minimize adverse events. The results of recent work on reperfusion may rapidly alter routine clinical practice for evolving ischemia in the brain. PMID- 20948830 TI - Predictors of continuous positive airway pressure adherence. AB - Continuous positive airway pressure (CPAP) is the leading treatment for obstructive sleep apnoea (OSA), a prevalent disorder of breathing in sleep strongly associated with obesity. OSA has serious adverse health, social and community effects arising from disturbed breathing, loud snoring, poor quality sleep and cardiovascular sequelae. When used appropriately, CPAP treatment is highly effective in normalising breathing and sleep, improving symptoms and lowering adverse event risk. However, patients do not necessarily accept, tolerate or comply with treatment, with many factors influencing CPAP uptake and longer term use. Although knowledge to address challenges affecting CPAP adherence and CPAP mask and machine technologies continue to improve incrementally, optimising CPAP treatment adherence is an ongoing challenge in sleep medicine. PMID- 20948831 TI - Diagnosing malabsorption in the intensive care unit. AB - Malabsorption as a result of decreased intestinal function is a frequently occurring problem in intensive care units. Small bowel dysfunction may lead to malnutrition and may predispose patients to infectious complications (sepsis) and may be linked to increased hospitalization duration, morbidity and mortality. There are several small bowel function tests, such as faecal fat excretion and sugar absorption tests, but data specifically applicable to the intensive care setting are limited. Moreover, there are multiple confounders such as altered intestinal permeability, changed transit time and renal dysfunction. A more specific test, fasting plasma citrulline concentration, has poor test characteristics for detection of decreased intestinal function in patients with dysfunctional enterocytes. Therefore, a citrulline generation test was recently developed in order to measure the conversion of glutamine (administered either enterally or intravenously) into citrulline. This conversion takes place exclusively in a properly functioning enterocyte; therefore, citrulline generation upon glutamine stimulation may be a promising biomarker for assessment of the small bowel function. PMID- 20948832 TI - Placenta: chronicle of intrauterine growth restriction. AB - The foundation for adult health is laid in utero and requires a healthy placenta. A common manifestation of abnormal placental development is impaired fetal growth. While placental pathology is the final common denominator in many cases of fetal growth restriction, a variety of discreet lesions have been described involving both the maternal and fetal circulations at their confluence in the placenta. Detailed examination of the placenta provides a means of elucidating the pathophysiology of poor fetal growth. This is an essential step in developing effective strategies for the prediction, prevention, and possible treatment of the growth restricted fetus. PMID- 20948833 TI - Intravesical botulinum toxin for lower urinary tract dysfunction. AB - Botulinum neurotoxin has achieved substantial clinical benefits in neurogenic detrusor overactivity. More contentious has been its extension to management of refractory idiopathic detrusor overactivity, in which risk of impaired voiding function and consequent need for intermittent catheterisation may counteract the quality-of-life benefits of improved storage function. Several issues remain uncertain for this unlicensed treatment, and clear insights into long-term consequences are needed before it can be regarded as an established mainstream treatment. PMID- 20948834 TI - Approaching patients with irritable bowel syndrome. AB - Treatment of functional gastrointestinal disorders remains difficult with many very different approaches showing similar response rates, regardless of whether they target luminal contents (e.g., presumed bacterial overgrowth), signaling within the gut wall (e.g., serotonin agonists or antagonists) or processing in the brain (e.g., cognitive behavioral therapy). Discrepancies between recent clinical trials and a meta-analysis have forced us to re-examine the use of antidepressants. Other studies have looked beyond the traditional drug therapies and have suggested other options such as dietary interventions and communication strategies that address relevant disease mechanisms and enable us to understand patient concerns, with the ultimate goal being to individualize and thus improve treatment outcomes. PMID- 20948835 TI - Computer-delivered cognitive behavioural therapy: effective and getting ready for dissemination. AB - Computer-delivered cognitive behavioural therapy (CCBT) is emerging as a promising strategy for improving access to mental health services. Randomized controlled trials have confirmed the efficacy of guided CCBT in treating depression, generalized anxiety disorder, panic disorder, social phobia, and other common mental disorders. With proper guidance, effect sizes are comparable to those obtained in face-to-face cognitive behavioural therapy, treatment is cost-effective, and preliminary data indicate that CCBT is acceptable to patients. Trials are beginning to evaluate optimal strategies for integrating CCBT within existing systems of mental health care. PMID- 20948836 TI - Optimal timing of chemotherapy and cystectomy. AB - Radical cystectomy with pelvic lymphadenectomy is the standard treatment for muscle-invasive bladder cancer. However, the high recurrence rates and high death rate from metastases after radical cystectomy for locally advanced bladder cancer emphasize the high risk of occult distant disease. To improve patient survival, multimodal therapy whereby chemotherapy and surgery are used in concert with each other is necessary. The preponderance of data suggests that neoadjuvant chemotherapy offers patients a clear - albeit small - survival advantage, whereas the data for adjuvant chemotherapy are less convincing. Currently, trials to improve the results of such neoadjuvant therapy using biologic targets in conjunction with cytotoxic regimens are under way. PMID- 20948837 TI - Pharmaceutical treatment of acute bipolar depression. AB - The treatment of bipolar depression is one of the most challenging fields in contemporary psychiatry. The best data concern the antipsychotics quetiapine and the olanzapine-fluoxetine combination. However, the usefulness of antidepressants in bipolar depression remains controversial; positive data are available for fluoxetine but negative results have been published for paroxetine. Accumulated knowledge so far suggests that bipolar patients need continuous administration of an antimanic agent even during the acute depressive phase. Although our knowledge is indeed limited, the development of guidelines for polypharmacy is necessary and should be done as soon as possible. PMID- 20948839 TI - Human gammadelta T lymphocytes for immunotherapeutic strategies against cancer. AB - gammadelta T lymphocytes are a numerically small subset of T cells with potent cytotoxic activity against a variety of tumor cells. Human gammadelta T cells expressing the Vgamma9Vdelta2 T cell antigen receptor recognize endogenous pyrophosphate molecules that are overproduced in transformed cells. Moreover, the intracellular accumulation of such pyrophosphates is strongly enhanced by aminobisphosphonates used in the treatment of osteoporosis and bone metastasis in certain cancer patients. A new concept of cancer immunotherapy is based on the endogenous activation of gammadelta T cells with aminobisphosphonates plus low dose interleukin-2. PMID- 20948838 TI - Recent advances in diagnosing cutaneous melanomas. AB - Early detection of lesions while minimising the unnecessary removal of benign lesions is the clinical aim in melanoma diagnosis. In this context, several non invasive diagnostic modalities, such as dermoscopy, total body photography, and reflectance confocal microscopy have emerged in recent years aiming at increasing diagnostic accuracy. The main developments in this field are the integration of dermoscopy and digital photography into clinical practice. PMID- 20948840 TI - Reconstructing blood from induced pluripotent stem cells. AB - The direct reprogramming of human somatic cells to induced pluripotent stem cells (iPSCs) offers exciting prospects for disease modelling and regenerative medicine. Several recent reports support the feasibility of generating various blood cell types from iPSCs through in vitro-directed differentiation. However, the derivation of hematopoietic stem cells (HSCs) capable of long-term reconstitution of all hematopoietic lineages appears to be more challenging. These hurdles notwithstanding, cell engineering strategies aiming to correct genetic defects at the stem cell level are already emerging. Robust methodologies for the generation of definitive human HSCs conferring high-level, multilineage, long-term, hematopoietic reconstitution thus are direly needed before the therapeutic potential and safety of iPSC-derived cell products can be thoroughly investigated. PMID- 20948841 TI - Glucokinase activators (GKAs) promise a new pharmacotherapy for diabetics. AB - The glucose-phosphorylating enzyme glucokinase, a promising target for developing new antidiabetic agents, was identified through the combined efforts of basic research and human biochemical genetics. Allosteric glucokinase activators (GKAs) were discovered by high-throughput screening of a large compound library and first reported in 2003. GKAs stimulate insulin release and glucose metabolism in the liver thereby lowering blood sugar, and promising trials in humans demonstrate that they are highly effective in patients with type 2 diabetes mellitus. Many companies are now attempting to develop effective and safe GKAs for treating diabetics. PMID- 20948842 TI - Efforts to expand the donor pool for liver transplantation. AB - Liver transplantation has become a victim of its own success in that there are no longer enough suitable livers for transplantation while at the same time the indications for transplantation increase. Efforts to expand the number of recipients who benefit from this life-saving procedure are being made, in particular through the use of split grafts and live donors. However, such grafts are associated with increased morbidity and mortality related to their reduced size. PMID- 20948843 TI - Can we reduce the spread of HIV infection by suppressing herpes simplex virus type 2 infection? AB - Overwhelming evidence from observational epidemiological studies indicates that herpes simplex virus type 2 (HSV-2) infection enhances the risk of acquiring HIV infection. Studies of genital shedding of HIV have suggested that HSV-2 infection also increases the onward transmission of HIV-1 by HIV/HSV-2 co-infected patients. Several randomized controlled trials were initiated to assess the impact of HSV-2 suppressive therapy on the acquisition of HIV infection by HSV-2 infected men and women, and on the onward transmission of HIV by HSV-2/HIV co infected men and women. In the past 2 years the results of these trials have been published. HSV-2 suppressive therapy was not found to have any effect on HIV acquisition nor on onward transmission of HIV. However, suppressive therapy with acyclovir was found to slow down disease progression in HIV/HSV-2 co-infected patients. The effect was rather modest and cost-effectiveness studies are needed to assess whether HSV-2 suppressive therapy has a place in the management of HIV 1 infected patients, especially in low and middle income countries. PMID- 20948844 TI - Managing septic shock. AB - Although several successful clinical trials in the last 2-3 years have been greeted with enthusiasm by intensivists, severe sepsis and septic shock still have increasing incidence and more or less unchanged mortality. Within the last few years, the progress in sepsis research covering definitions, epidemiology, pathophysiology, diagnosis, and standard and adjunctive therapy as well as general measures such as treatment bundles is encouraging. In this report, a small selection of recent publications, focusing on the current discussion of activated protein C as well as the relevance of the Surviving Sepsis Campaign bundle therapy, is presented and the possible impact on clinical routine is discussed. PMID- 20948845 TI - Diabetes, insulin treatment, and cancer risk: what is the evidence? AB - Diabetes, in particular type 2, is associated with an increased incidence of cancer. Although the mortality attributable to cancer in type 2 diabetes is overshadowed by that due to cardiovascular disease, emerging data from epidemiologic studies suggest that insulin therapy may confer added risk for cancer, perhaps mediated by signaling through the IGF-1 (insulin-like growth factor-1) receptor. Co-administered metformin seems to mitigate the risk associated with insulin. A recent series of publications in Diabetologia addresses the possibility that glargine, the most widely used long-acting insulin analogue, may confer a greater risk than other insulin preparations, particularly for breast cancer. This has led to a heated controversy. Despite this, there is a consensus that the currently available data are not conclusive and should not be the basis for any change in practice. Further studies and more thorough surveillance of cancer in diabetes are needed to address this important issue. PMID- 20948846 TI - Recent advances in pruritus - what we have learned and where are we headed. AB - Chronic pruritus is an emerging health problem with a significant impact on quality of life. Recent advances in our understanding of newly discovered pathways and receptors for itch have been made. It is hoped that recent advancements will also drive the development of novel therapies for this often neglected and bothersome symptom. PMID- 20948847 TI - The potential for using risk models in future lung cancer screening trials. AB - Computed tomography screening for early diagnosis of lung cancer is one of the more potentially useful strategies, aside from smoking cessation programmes, for reducing mortality and improving the current poor survival from this disease. The long-term success of lung cancer screening will be dependent upon identifying populations at sufficient risk in order to maximise the benefit-to-harm ratio of the intervention. Risk prediction models could potentially play a major role in the selection of high-risk individuals who would benefit most from screening intervention programmes for the early detection of lung cancer. Improvements of developed lung cancer risk prediction models (through incorporation of objective clinical factors and genetic and molecular biomarkers for precise and accurate estimation of risks), demonstration of their clinical usefulness in decision making, and their use in future screening programmes are the focus of current research. PMID- 20948848 TI - Post-operative thromboprophylaxis: new oral thrombin and factor X inhibitors and their place in clinical practice. AB - Thromboprophylaxis can reduce the incidence of postoperative thromboembolic events by two-thirds. Traditionally, unfractionated heparin, low-molecular-weight heparins, vitamin K antagonists, and mechanical methods have been used. Recently, thrombin and factor Xa (FXa) antagonists have been introduced in clinical practice. Advantages are oral administration, potentially higher efficacy in reducing thromboembolic events without increasing major bleeding, and no need for monitoring of the anticoagulatory effect. So far these drugs have mainly been tested after total hip and knee arthroplasties. However, data after most other orthopedic and surgical procedures are sparse. In special populations - for example, patients with renal failure - these drugs have not been sufficiently tested yet. Accordingly, the clinical use of these promising new drugs should be restricted to situations where efficacy has been proven with clear evidence from controlled clinical trials. PMID- 20948850 TI - Perioperative protective effects of statins. AB - Although statins decrease cholesterol synthesis, they also possess 'pleiotropic' effects, such as enhancing the function of vascular endothelium and the stability of atherosclerotic plaques. Furthermore, they attenuate oxidative stress, inflammation, and the prothrombotic response. These diverse biological actions may explain their perioperative protective effects, especially in patients undergoing cardiac and major vascular procedures. Beyond reductions in perioperative mortality and cardiorenal complications, recent evidence also suggests outcome benefits from statin exposure in sepsis, airway hyperreactivity, and venous thromboembolism. It is likely that these agents will be increasingly prescribed perioperatively as high-quality evidence from well-designed randomized trials becomes available in the near future. PMID- 20948849 TI - Recent advances in the management of gastrointestinal stromal tumors. AB - This report focuses mainly on the major reduction of the risk of relapse of gastrointestinal stromal tumor (GIST) treated with imatinib, as identified in the American College of Surgeons Oncology Group (ACOSOG) Z9001 trial. It also focuses on the many unknowns associated with adjuvant imatinib therapy despite approvals by the US Food and Drug Administration and the European Medicines Agency, and on a new marker for the diagnosis of GIST. PMID- 20948851 TI - New insights into thyroid hormone replacement therapy. AB - It is widely accepted that thyroid hormone replacement for patients with hypothyroidism can be fully accomplished with levothyroxine monotherapy, as assessed by serum thyroid function tests. However, approximately 10% of hypothyroid patients are dissatisfied with the outcome of levothyroxine monotherapy, and physicians continue to report benefits from combined levothyroxine-triidothyronine therapy for some hypothyroid patients. Recently, a large prospective study reported that the benefit of the combined levothyroxine triidothyronine therapy is associated with the Thr92Ala polymorphism in the type 2 deiodinase gene, which is present in about 15% of the general population. If confirmed, these findings indicate that personalized medicine is rapidly catching up with modern thyroidology. PMID- 20948852 TI - Adequacy of haemodialysis and or haemofiltration treatments for patients with acute kidney injury. AB - Traditionally, the dose of haemodialysis or haemofiltration delivered to patients with kidney failure is assessed by urea clearance. For patients with chronic kidney disease below a critical urea clearance threshold, patient wellbeing is compromised. It was suggested, therefore, that the dose of dialysis or haemofiltration delivered could also affect outcomes for patients with acute kidney injury. Two major prospective multicentre clinical trials have recently reported that a higher intensity of renal support, by either intermittent haemodialysis or continuous renal replacement therapy, did not improve patient survival or recovery from dialysis. It must be recognised, however, that urea clearance is only one component of renal supportive therapy, and other aspects, including volume control, electrolyte homeostasis and acid-base balance, may be equally important targets for patients with acute kidney injury. PMID- 20948853 TI - Diagnosis and treatment of constrictive bronchiolitis. AB - Constrictive bronchiolitis is a bronchiolar airway disease that surrounds the lumen with fibrotic concentric narrowing and obliteration. The mosaic pattern seen on the expiratory high-resolution chest CT scan is diagnostic in an individual with shortness of breath, early inspiratory crackles, and irreversible airflow obstruction. Swyer-James-MacLeod syndrome is no longer considered a congenital disorder but as constrictive bronchiolitis detected in young adults who had infectious pneumonia during infancy. For lung transplant recipients, tacrolimus continues to be an important immune suppression medication, extracorporeal photopheresis may improve the decline of pulmonary function, and azithromycin may be effective in some lung transplant recipients for treatment of bronchiolitis obliterans syndrome for prevention of constrictive bronchiolitis. PMID- 20948854 TI - Advances in systolic heart failure. AB - Heart failure due to systolic dysfunction has enormous global impact. Medical management based on an understanding of the pathophysiology of the disease as well as its neurohormonal mechanisms has greatly advanced over the past 25 years. Below is a review of recent and emerging data on epidemiology and diagnosis of heart failure due to systolic dysfunction and the current and future management techniques to ameliorate this disease. At the end, we will highlight three significant trials in the field in 2009 that will impact heart failure care: STICH, MADIT-CRT, and HeartMate II. PMID- 20948855 TI - New insights in the pathogenesis and genetics of leprosy. AB - In the last 30 years the leprosy burden has been dramatically reduced but over the last 5 years still more than 200,000 new cases were detected each year. Advances in immunology, pathogenesis, and genetics of leprosy have been reported. A deeper understanding of the mechanisms of infection will ultimately improve our ability to fight against this potentially devastating infectious disease. PMID- 20948856 TI - Periodic fever syndrome and autoinflammatory diseases. AB - The concept of autoinflammatory disease as a new disease classification has resulted in a paradigm shift in our understanding of the the broad spectrum of immunological diseases. The effectiveness of interleukin-1 blockade in a variety of disorders has resulted in a marked reduction in suffering for many of these patients. PMID- 20948857 TI - Recent studies that influence the chemotherapeutic paradigm in the management of advanced ovarian cancer. AB - Several recently reported evidence-based phase 3 trials that focus on the role of cytotoxic chemotherapy have the potential to strongly influence the care of women with advanced epithelial ovarian cancer. Particular areas of interest include: (a) neoadjuvant chemotherapy; (b) chemotherapy of recurrent platinum-sensitive ovarian cancer; and (c) the relevance of paclitaxel scheduling in the primary chemotherapeutic management of the malignancy. This report will briefly discuss the results of these studies and the potential implications of the findings for routine care of patients in these clinical settings. PMID- 20948858 TI - Cardiovascular risk management in patients with inflammatory arthritis: what is good for the joint is good for the heart and vice versa! AB - Owing to the prominent long-term systemic inflammatory reaction in patients with arthritides and a growing body of data illustrating that this inflammatory reaction imposes a considerable risk for the development or aggravation of cardiovascular (CV) disease or overall CV risk, numerous researchers and clinicians have put enormous effort into the analysis of the effects of risk factors on the course of CV disease in these patients and the therapeutic options to antagonize progressive atherosclerosis. To achieve this challenging goal, investigators have shown that all treatment strategies must include the 'non rheumatic' approaches, such as lowering blood pressure, stopping smoking, and improving metabolic status, in tight association with lowering the overall disease activity of the underlying rheumatic entity using antiphlogistic drugs and conventional as well as biologic disease-modifying drugs. PMID- 20948859 TI - Primary and secondary prophylaxis of gastric variceal bleeding. AB - Gastric variceal bleeding is a common problem in patients with cirrhosis and is associated with increased morbidity and mortality. Management is complex and includes pharmacotherapy, endoscopic therapy, and shunt placement. Recent studies indicate that endoscopic therapy with tissue adhesives has similar hemostasis rates and outcomes in terms of mortality as shunt placement but has a lower complication rate and therefore could be considered the first line therapy for acute bleeding and secondary prophylaxis of gastric varices. PMID- 20948860 TI - Update on the management of adolescent varicocele. AB - The management of adolescent varicocele has evolved over the last 30 years. This article briefly reviews some of the current issues regarding the adolescent varicocele, including (a) the progressive nature of the adolescent varicocele, (b) the degree of asymmetry that necessitates surgery, (c) the wide variability in percentage of repairs performed bilaterally in published adolescent series, and (d) the choice of surgical procedure to be performed. PMID- 20948861 TI - Stroke prevention: carotid stenting versus carotid endarterectomy. AB - Revascularization of the extracranial carotid arteries is a commonly performed surgical procedure to prevent stroke. Open surgery (i.e., carotid endarterectomy [CEA]) is a well-established stroke prevention procedure but is being 'challenged' by a less invasive percutaneous procedure (i.e., carotid artery stent [CAS] placement). Clinical trials comparing CAS and CEA for average surgical-risk patients have demonstrated mixed results, whereas the data for CAS compared with CEA in high-surgical-risk patients have demonstrated non inferiority. The impending Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) results will have a major impact on the utility of CAS relative to CEA in average-surgical-risk patients. PMID- 20948862 TI - Non-surgical management of stage I lung cancer. AB - Stage I lung cancer has a high cure rate with surgery, although many patients are not surgical candidates due to comorbid conditions. Historically, non-operative treatment has been disappointing. New and promising ablative therapies offer a curative option. PMID- 20948863 TI - Allogeneic stem cell transplantation for rheumatic autoimmune diseases. AB - Haematopoietic stem cell transplantation (HSCT) has evolved from an experimental concept to an effective treatment option for severe autoimmune diseases and has a unique ability to restore immune regulation. It is a complex multistep procedure involving the administration of high doses of immunosuppressive medication and transplantation of stem cells. Most HSCT procedures in autoimmune disease have involved autologous stem cells. In the case of allogeneic transplantation, stem cells are derived from peripheral blood or bone marrow of a healthy HLA-matched donor. Allogeneic HSCT has curative potential based on studies in experimental models of autoimmune disease, case reports, and a registry analysis but carries significant risks of rejection and graft-versus-host disease. Unless these risks become manageable, allogeneic HSCT should be offered only if all alternative treatment options have failed, if a patient has a suitable donor, and if a patient still has a chance to benefit significantly from the procedure. PMID- 20948864 TI - Percutaneous mitral valve repair: the beginning of the end or the end of the beginning? AB - The new percutaneous mitral valve repair techniques are at an early stage. Preliminary series show that they are feasible; however, they need to be further evaluated in comparison with contemporary treatment to accurately assess their efficiency. Potential applications may benefit high-risk patients after thorough evaluation. PMID- 20948865 TI - Management of Helicobacter pylori. AB - Meta-analysis has shown that successful Helicobacter pylori eradication therapy improved atrophic gastritis and intestinal metaplasia. Moreover, successful eradication therapy against atrophic gastritis has led to the suppression of the incidence of metachronous gastric cancer. Thus, the Japanese Society for Helicobacter Research concluded that all 'H. pylori-infected persons' should be considered for eradication therapy, irrespective of any background diseases. Successful eradication can prevent transmission of this bacterium, and recent publications show that curing H. pylori infection seems to reduce the risk of gastric cancer. PMID- 20948866 TI - The diagnosis of coccidioidomycosis. AB - Until recently, culture, microscopy, and serology have been the available methods for the diagnosis of coccidioidomycosis. While Coccidioides is frequently isolated by culture, special precautions must be taken because of the risk of laboratory infection and because Coccidioides is on the Select Agent list. Serology is useful but the sensitivity remains lower than desired. A commercially available test for coccidioidal galactomannan antigenuria now exists and appears useful for immunocompromised hosts with severe disease. Polymerase chain reaction assays targeting specific coccidioidal genes have demonstrated utility but are not commercially available. Moreover, their sensitivity and the best sample type remain unestablished. PMID- 20948867 TI - Recent advances in the management of hypertension. AB - Recently, there have been several reports related to the adequacy of blood pressure (BP) control in high-risk hypertensive patients. These aspects have been reviewed in the recently published reappraisal of the European Society of Hypertension guidelines, and this short review comments on and briefly extends the discussion of this situation. In summary, a low BP goal when cardiorenal disease is advanced can be risky. However, attaining normal BP levels at earlier stages in the cardiorenal continuum is probably totally adequate. PMID- 20948868 TI - Renin angiotensin aldosterone system (RAAS) inhibitors in the prevention of early renal disease in diabetes. AB - Diabetic nephropathy (diabetic kidney disease) is defined as a rise in urinary albumin excretion rate, often associated with an increase in blood pressure, and typically with concomitant retinopathy but without evidence of other causes of renal disease. It is characterized first by albuminuria and then by a progressive decline in glomerular filtration rate, eventually resulting in end-stage renal disease (ESRD). Diabetic nephropathy occurs in approximately 30-35% of type 1 and type 2 patients and tends to cluster in families. Diabetic kidney disease is associated with a very marked increase in cardiovascular disease and, even from the earliest stages, with microalbuminuria. A diabetic milieu is required for the diabetic glomerular lesion to develop, and the renin angiotensin aldosterone system (RAAS) has been implicated in the development and progression of diabetic nephropathy. Most patients with diabetes and renal impairment die from a cardiovascular disease event before they progress to ESRD. From the studies described in this review, we think that clear evidence of RAAS inhibition in the prevention of diabetic nephropathy is lacking and more studies are warranted. Nevertheless, tight blood pressure control with inhibitor of RAAS and multifactorial intervention (glycaemic, lipid control and so on) are warranted for secondary prevention and treatment of chronic kidney disease in diabetes. PMID- 20948869 TI - Recent advances in managing human papillomavirus-positive oropharyngeal tumors. AB - Human papillomavirus (HPV) is detected in a subset of patients with head and neck squamous cell carcinoma, most frequently in tumors in the Waldeyer's ring (palatine tonsil and base of tongue). Several studies suggest that patients with HPV-positive tumors have better survival with either concurrent chemoradiation therapy or surgery followed by radiation compared with HPV-negative patients. However, some possible confounding clinicopathologic variables may challenge the validity of this statement, for example, some authors used the TNM (tumor, node, metastasis) grouping stage while others used the primary tumor (T stage), and other studies have demonstrated that tumors with advanced T stage were less likely to be infected with HPV. A large clinical trial with stratification of patients according to all known tumor prognostic factors is crucial to solve the question. PMID- 20948870 TI - Recent advances in diagnosis and treatment of chronic myeloproliferative neoplasms. AB - The Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) have recently been the focus of tremendous advances in basic knowledge of disease pathophysiology following the recognition of mutations in JAK2 and MPL. These discoveries also led to refinement of the criteria employed for diagnosis. The prognostic roles of the JAK2 V617F mutation and of leukocytosis as independent risk factors for thrombosis, which represents the leading cause of death in patients with polycythemia vera and essential thrombocythemia, are supported by retrospective studies. A new risk stratification approach to the patient with primary myelofibrosis allows clinicians to distinguish categories of patients with significantly different expected survival. Finally, new drugs are currently being tested for MPNs, and molecular discoveries could ultimately lead to the development of a specific targeted therapy. Overall, significant advances in diagnosis, prognostication, and treatment have taken place in the last couple of years in the field of MPNs. PMID- 20948871 TI - Prevention of ventilator-associated pneumonia in adults. AB - Ventilator-associated pneumonia, broadly defined as pneumonia that develops after 48 hours of intubation, is a common mechanical ventilation complication that causes significant morbidity and mortality in critically ill patients. Prevention strategies are continually evolving to decrease the impact of this serious and costly disease. PMID- 20948872 TI - Genetic screening for multiple endocrine neoplasia syndrome type 1 (MEN-1): when and how. AB - Multiple endocrine neoplasia syndrome type 1 (MEN1) syndrome has benefited from the identification of the gene whose mutations account for the genetic susceptibility to develop endocrine tumors. Asymptomatic MEN1 mutant carriers need to be clearly recognized because the gene-related mutations confer a high risk of multiple primary cancers, occur at younger ages, and affect multiple family members who inherit the cancer-predisposing genetic mutation. PMID- 20948873 TI - Update on bioagent therapy in sarcoidosis. AB - Corticosteroids are still the cornerstone of treatment for patients with sarcoidosis requiring systemic therapy. However, alternative agents and especially methotrexate may be considered for patients with refractory disease or requiring prolonged treatment with intolerable side effects. Although bioagent therapies have hitherto not clearly demonstrated superior efficacy and safety over corticosteroids in pulmonary sarcoidosis, infliximab may modestly improve lung function in patients with active disease resistant to steroids. Further studies will be needed to assess both safety and efficacy of infliximab in pulmonary sarcoidosis. Infliximab may be considered in a limited number of patients with severe extrapulmonary systemic manifestations of sarcoidosis, with careful individual evaluation of the risk-benefit ratio. PMID- 20948874 TI - Advances in cord blood transplants in adults. AB - Umbilical cord blood is an acceptable source of hematopoietic stem cells for patients with malignant diseases but has limitations in its use. In this review, we will discuss these limitations and the recent advances in cord blood transplants that may enable cord blood to become more widely available as an alternative stem cell source for adults for the treatment of malignant diseases and for use in regenerative medicine. PMID- 20948875 TI - Recent advances in managing hepatitis B. AB - In the past two years, several national and international bodies have made recommendations and published updated practice guidelines for hepatitis B. In addition, new drugs have become available for treatment of hepatitis B. This article will review the new recommendations for screening for hepatitis B and for first-line antiviral medications to use for treatment. In addition, I will discuss the recent recommendations on treating hepatitis B and human immunodeficiency virus co-infection and the screening of people receiving immunosuppressive therapy. PMID- 20948876 TI - Pulmonary hypertension in hemolytic anemias. AB - Pulmonary hypertension (PH) has been reported with nearly all forms of the inherited as well as the acquired hemolytic anemias. Recent research investigating the pathophysiology of PH in sickle cell disease and thalassemia has helped elucidate the central role of hemolysis-mediated endothelial dysfunction in the development of PH in these populations. Although the most appropriate treatment of PH in patients with hemolytic anemia is not clearly defined, the associated significant increased risk of death underscores the need for randomized clinical trials in this area. PMID- 20948877 TI - Recent advances in focal therapy of prostate and kidney cancer. AB - The concept of focal therapy in oncologic surgery refers to maximizing healthy tissue preservation while maintaining excellent cancer control outcomes. Herein, we address the recent advantages in the field of focal therapy for both kidney and prostate cancer, focusing on technological achievements and future perspectives. PMID- 20948878 TI - FeNO as a Marker of Airways Inflammation: The Possible Implications in Childhood Asthma Management. AB - The aim of this study was to verify FeNO usefulness, as a marker of bronchial inflammation, in the assessment of therapeutic management of childhood asthma. We performed a prospective 1-year randomized clinical trial evaluating two groups of 32 children with allergic asthma: "GINA group", in which therapy was assessed only by GINA guidelines and "FeNO group", who followed a therapeutic program assessed also on FeNO measurements. Asthma Severity score (ASs), Asthma Exacerbation Frequency (AEf), and Asthma Therapy score (ATs) were evaluated at the start of the study (T1), 6 months (T2), and 1 year after (T3). ASs and AEf significantly decreased only in the FeNO group at times T2 and T3 (p[T1-T2] = 0.0001, and p[T1-T3] = 0.01; p[T1-T2] = 0.0001; and p[T1-T3] < 0.0001, resp.). After six months of follow-up, we found a significant increase of patients under inhaled corticosteroid and/or antileukotrienes in the GINA group compared to the FeNO group (P = .02). Our data show that FeNO measurements, might be a very useful additional parameter for management of asthma, which is able to avoid unnecessary inhaled corticosteroid and antileukotrienes therapies, however, mantaining a treatment sufficient to obtain a meaningful improvement of asthma. PMID- 20948879 TI - Evaluation of a Novel Rapid Test System for the Detection of Allergic Sensitization to Timothy Grass Pollen against Established Laboratory Methods and Skin Prick Test. AB - Type I hypersensitivity is driven by allergen specific immunoglobulin E (sIgE) and thus sIgE represents a marker for modern allergy diagnosis. Recently, a rapid assay for the detection of sIgE, termed as (Allergy Lateral Flow Assay) ALFA, has been developed. The objective of our study is the evaluation of a scanner-based system for the semiquantitative interpretation of ALFA results. Agreement to Skin Prick Test (SPT, Allergopharma), ALLERG-O-LIQ System (Dr. Fooke), and ImmunoCAP (Phadia) was investigated using 50 sera tested for specific IgE to timothy grass pollen (g6). 35/50 sera were positive by SPT, ALLERG-O-LIQ, and ImmunoCAP. Excellent agreement was observed between ALFA results and SPT, ImmunoCAP, and ALLERG-O-LIQ. Area under the curve (AUC) values were found at 1.0, and 100% sensitivity and specificity was found versus all other methods. Visual- and scanner-based interpretation of the ALFA results revealed excellent agreement. PMID- 20948880 TI - The Relationship between Mold Exposure and Allergic Response in Post-Katrina New Orleans. AB - Objectives. The study's objective was to examine the relation between mold/dampness exposure and mold sensitization among residents of Greater New Orleans following Hurricane Katrina. Methods. Patients were recruited from the Allergy Clinic of a major medical facility. Any patient receiving a skin prick test for one of 24 molds between December 1, 2005 and December 31, 2008 was eligible for the study. Exposure was assessed using standardized questionnaires. Positive mold reactivity was defined as a wheal diameter >3 mm to any mold genera. Results. Approximately 57% of participants tested positive to any indoor allergen, 10% to any mold. Over half of respondents had significant home damage, 34% reported dampness/mold in their home, half engaged in renovation, and one third lived in a home undergoing renovation. Despite extensive exposure, and multiple measures of exposure, we found no relationship between mold/dampness exposure and sensitivity to mold allergens. Conclusions. These results along with results of earlier research indicate no excess risk of adverse respiratory effects for residents living in New Orleans after the devastation of Hurricane Katrina. PMID- 20948881 TI - In vitro determination of the allergenic potential of egg white in processed meat. AB - Hen's egg white has been reported as a causative agent of allergic reactions, with ovalbumin, conalbumin, ovomucoid, and lysozyme being the major allergens. However, little is known about the effects of processing with heat and high pressure on the allergenicity of egg white proteins as ingredients in meat. For this purpose, the allergenic characteristics of such treated preparations were studied. The IgE-binding capacity was analyzed by EAST inhibition in raw and processed meat preparations using sera from patients with hen's egg specific IgE. Increasing heat treatment as well as the application of high pressure decreased IgE binding, which is a measure of allergenic potential. The combined application of heat (70 degrees C) and high pressure had synergistic effects in reducing the allergenic potential nearly twice as the sum of the single treatments conducted separately. PMID- 20948882 TI - Residential Proximity to Freeways is Associated with Uncontrolled Asthma in Inner City Hispanic Children and Adolescents. AB - Background. Proximity to heavy traffic has been linked to increased asthma severity. However, it is unknown whether exposure to heavy traffic is associated with the ability to maintain asthma control. Objectives. This study examines whether exposure to heavy traffic is associated with the ability to maintain asthma control in inner-city children. Methods. 756 inner-city asthmatic Hispanic children were followed for one year in a pediatric asthma management program (Breathmobile). At each scheduled visit, asthma specialist tracked patients' asthma severity and managed their asthma based on the NAEPP guidelines. The patients' residential distance from the nearest freeway was calculated based on residential address at study entry. Distance to nearest freeway was used as a surrogate marker for high exposure from traffic-related air pollutants. Results. Patients who lived near a freeway were significantly more likely to have asthma that was not well controlled (P = .03). Patients with intermittent and mild baseline severity have a two-fold increased risk of having asthma that is uncontrolled if they lived <2 miles from a freeway (OR = 2.2, P = .04). Conclusion. In children with asthma, residential proximity to freeways is associated with uncontrolled asthma. PMID- 20948883 TI - Cultured human airway epithelial cells (calu-3): a model of human respiratory function, structure, and inflammatory responses. AB - This article reviews the application of the human airway Calu-3 cell line as a respiratory model for studying the effects of gas concentrations, exposure time, biophysical stress, and biological agents on human airway epithelial cells. Calu 3 cells are grown to confluence at an air-liquid interface on permeable supports. To model human respiratory conditions and treatment modalities, monolayers are placed in an environmental chamber, and exposed to specific levels of oxygen or other therapeutic modalities such as positive pressure and medications to assess the effect of interventions on inflammatory mediators, immunologic proteins, and antibacterial outcomes. Monolayer integrity and permeability and cell histology and viability also measure cellular response to therapeutic interventions. Calu-3 cells exposed to graded oxygen concentrations demonstrate cell dysfunction and inflammation in a dose-dependent manner. Modeling positive airway pressure reveals that pressure may exert a greater injurious effect and cytokine response than oxygen. In experiments with pharmacological agents, Lucinactant is protective of Calu-3 cells compared with Beractant and control, and perfluorocarbons also protect against hyperoxia-induced airway epithelial cell injury. The Calu-3 cell preparation is a sensitive and efficient preclinical model to study human respiratory processes and diseases related to oxygen- and ventilator-induced lung injury. PMID- 20948884 TI - Gasping in response to basic resuscitation efforts: observation in a Swine model of cardiac arrest. AB - Objective. To analyze the effect of basic resuscitation efforts on gasping and of gasping on survival. Methods. This is secondary analysis of a previously reported study comparing continuous chest compressions (CCC CPR) versus chest compressions plus ventilation (30:2 CPR) on survival. 64 swine were randomized to 1 of these 2 basic CPR approaches after either short (3 or 4 minutes) or long (5 or 6 minutes) durations of untreated VF. At 12 minutes of VF, all received the same Guidelines 2005 Advanced Cardiac Life Support. Neurologically status was evaluated at 24 hours. A score of 1 is normal, 2 is abnormal, such as not eating or drinking normally, unsteady gait, or slight resistance to restraint, 3 severely abnormal, where the animal is recumbent and unable to stand, 4 is comatose, and 5 is dead. For this analysis a neurological outcome score of 1 or 2 was classified as "good", and a score of 3, 4, or 5 was classified as "poor." Results. Gasping was more likely to continue or if absent, to resume in the animals with short durations of untreated VF before basic resuscitation efforts. With long durations of untreated VF, the frequency of gasping and survival was better in swine receiving CCC CPR. In the absence of frequent gasping, intact survival was rare in the long duration of untreated VF group. Conclusions. Gasping is an important phenomenon during basic resuscitation efforts for VF arrest and in this model was more frequent with CCC-CPR. PMID- 20948885 TI - Prophylactic administration of surfactant in extremely premature infants. AB - Objective. To investigate whether prophylactic surfactant administration is superior over selective treatment in preterm infants with respiratory distress syndrome (RDS). Methods. In our retrospective analysis, we compared premature infants (23 + 0 to 26 + 6 weeks) receiving 200 mg/kg surfactant (curosurf((r))) within five minutes after birth (prophylactic group, N = 31) with those infants who received surfactant therapy for established RDS (selective group, N = 34). Results. Prophylactic therapy significantly decreased the need for mechanical ventilation (74 hours per patient versus 171 hours per patient, resp.). We observed a reduced incidence of interstitial emphysema (0% versus 9%, resp.), pneumothoraces (3% versus 9%, resp.), chronic lung disease (26% versus 38%, resp.), and surfactant doses per patient (1.3 versus 1.8, resp.), although those variables did not reach significance. Conclusion. We conclude that infants under 27 weeks' gestation profit from prophylactic surfactant administration by reducing the time of mechanical ventilation. This in turn could contribute to reduce the risk for mechanical ventilation associated complications, without any detrimental short-term side effects. PMID- 20948886 TI - Safety and efficacy of erythropoietin in traumatic brain injury patients: a pilot randomized trial. AB - Background. Erythropoietin (EPO) is a neuroprotective agent utilized in stroke patients. This pilot study represents the first randomized trial of EPO in traumatic brain injury (TBI) patients. Methods. Adult, blunt trauma patients with evidence of TBI were randomized to EPO or placebo within 6 hours of injury. Baseline and daily serum S-100B and Neuron Specific Enolase (NSE) levels were measured. Results. TBI was worse in the EPO (n = 11) group compared to placebo patients (n = 5). The use of EPO did not impact NSE (P = .89) or S100 B (P = .53) levels compared to placebo. Conclusions. At the dose used, EPO did not reduce neuronal cell death compared to placebo; however, TBI severity was worse in the EPO group while levels of NSE and S100-B were similar to the less injured placebo group making it difficult to rule out a treatment effect. A larger, balanced study is necessary to confirm a potential treatment effect. PMID- 20948887 TI - Decompressive abdominal laparotomy for abdominal compartment syndrome in an unengrafted bone marrow recipient with septic shock. AB - Objective. To describe a profoundly immunocompromised (panleukopenia) child with septic shock who developed abdominal compartment syndrome (ACS) and was successfully treated with surgical decompression. Design. Individual case report. Setting. Pediatric intensive care unit of a tertiary children's hospital. Patient. A 32-month-old male with Fanconi anemia who underwent bone marrow transplantation (BMT) 5 days prior to developing septic shock secondary to Streptococcus viridans and Escherichia coli ACS developed after massive fluid resuscitation, leading to cardiopulmonary instability. Interventions. Emergent surgical bedside laparotomy and silo placement. Measurements and Main Results. The patient's cardiopulmonary status stabilized after decompressive laparotomy. The abdomen was closed and the patient survived to hospital discharge without cardiac, respiratory, or renal dysfunction. Conclusions. The use of laparotomy and silo placement in an unengrafted BMT patient with ACS and septic shock did not result in additional complications. Surgical intervention for ACS is a reasonable option for high risk, profoundly immunocompromised patients. PMID- 20948888 TI - Camptocormia in Parkinson's disease. AB - Objectives. Abnormalities of posture represent one of the main features of Parkinson's disease (PD). Among them, camptocormia has been considered as rare in PD. We investigated frequency and clinical features of camptocormia in PD patients. Methods. 153 PD patients (mean 68.5 +/- 10.7 years old, duration 5.9 +/ 2.4 years) outpatiently recruited. After neurologic examination, patients were rated on the Unified PD Rating Scale motor scale (UPDRS Part III), minimental state examination (MMSE). Also we evaluated patients with camptocormia by MRI. Of the 153 PD patients, 27 had camptocormia (mean age, 67.9 +/- 7.9 years old; disease duration, 6.1 +/- 3.9 years). For further evaluation, we recruited age- and sex-matched 27 PD patients without camptocormia (11 men and 16 women; mean age +/- SD, 69.2 +/- 10.1 years, duration 6.0 +/- 2.7 years) These selected 54 patients completed several self-assessments. Lumbar and thoracic paraspinal muscles were studied by EMG. Results. There were no significant differences in age, duration, severity, and drug dose between patients with and without camptocormia. Analysis of NMSS subitems indicated that PD patients tended to show lower scores for sleep/fatigue, attention/memory, and miscellaneous items. Conclusions. We found significant differences concerning nonmotor signs and symptoms evaluated by FAB, PDQ-8, FSQ, VAS-F, and NMSS between patients with and without camptocormia. Our findings indicate that camptocormia is a relatively common sign in PD and that patients with camptocormia scores on the PDQ-8 compared with PD patients without camptocormia. This suggests that improvements in camptocormia of PD patients may improve their QOL. PMID- 20948889 TI - The Impact of Clinical and Cognitive Variables on Social Functioning in Parkinson's Disease: Patient versus Examiner Estimates. AB - Purpose. To assess the impact of clinical variables on social skills and behaviors in Parkinson's disease (PD) patients and patient versus examiner estimates of social functioning. Methods. Twenty-eight patients with PD and 32 controls with chronic disease were assessed with a battery of neuropsychologic, personality, mood, and social function tests. Results. Patients' estimates of their own social functioning were not significantly different from examiners' estimates. The impact of clinical variables on social functioning in PD revealed depression to be the strongest association of social functioning in PD on both the patient and the examiner version of the Social Adaptation Self-Evaluation Scale. Conclusions. PD patients appear to be well aware of their social strengths and weaknesses. Depression and motor symptom severity are significant predictors of both self- and examiner reported social functioning in patients with PD. Assessment and treatment of depression in patients with PD may improve social functioning and overall quality of life. PMID- 20948890 TI - Parkinsonian Symptomatology May Correlate with CT Findings before and after Shunting in Idiopathic Normal Pressure Hydrocephalus. AB - We aimed to investigate the characteristics of Parkinsonian features assessed by the unified Parkinson's disease rating scale (UPDRS) and determine their correlations with the computed tomography (CT) findings in patients with idiopathic normal pressure hydrocephalus (iNPH). The total score and the scores for arising from chair, gait, postural stability, and body hypokinesia in the motor examination section of UPDRS were significantly improved after shunt operations. Stepwise multiple regression analysis revealed that postural stability was the determinant of the gait domain score of the iNPH grading scale. The canonical correlation analysis between the CT findings and the shunt responsive Parkinsonian features indicated that Evans index rather than midbrain diameters had a large influence on the postural stability. Thus, the pathophysiology of postural instability as a cardinal feature of gait disturbance may be associated with impaired frontal projections close to the frontal horns of the lateral ventricles in the iNPH patients. PMID- 20948892 TI - Placement of the Internal Pulse Generator for Deep Brain Stimulation in the Upper Back to Prevent Fracture of the Extension Wire due to Generator Rotation: Case Report. AB - Deep brain stimulation (DBS) is a common surgical procedure used for the treatment of Parkinson's disease (PD) and essential tremor. A potential complication of this procedure is hardware failure. The authors report a case of DBS hardware failure in which repeated fractures of the extension wire were caused by abnormal rotational movements of the IPG placed in the loose subclavicular tissue of an overweight female. Implantation of the IPG in the suprascapular area prevented further extension wire fractures. This strategy may be especially relevant in overweight females with loose subclavicular tissue. PMID- 20948891 TI - Neuroprotection and Functional Recovery Associated with Decreased Microglial Activation Following Selective Activation of mGluR2/3 Receptors in a Rodent Model of Parkinson's Disease. AB - Clinical trials have demonstrated positive proof of efficacy of dual metabotropic glutamate receptor 2/3 (mGluR2/3) agonists in both anxiety and schizophrenia. Importantly, evidence suggests that these drugs may also be neuroprotective against glutamate excitotoxicity, implicated in the pathogenesis of Parkinson's disease (PD). However, whether this neuroprotection also translates into functional recovery is unclear. In the current study, we examined the neuroprotective efficacy of the dual mGluR2/3 agonist, 2R,4R-4-aminopyrrolidine 2,4-dicarboxylate (2R,4R-APDC), and whether this is accompanied by behavioral recovery in a rodent 6-hydroxydopamine (6-OHDA) model of PD. We now report that delayed post lesion treatment with 2R,4R-APDC (10 nmol), results in robust neuroprotection of the nigrostriatal system, which translated into functional recovery as measured by improved forelimb use asymmetry and reduced (+) amphetamine-induced rotation compared to vehicle treated animals. Interestingly, these beneficial effects were associated with a decrease in microglial markers in the SNc, which may suggest an antiinflammatory action of this drug. PMID- 20948893 TI - Energy medicine. PMID- 20948894 TI - Meditation on OM: Relevance from ancient texts and contemporary science. AB - BACKGROUND: In Indian scriptures the sacred syllable Om is the primordial sound from which all other sounds and creation emerge which signifies the Supreme Power. AIMS: To explore the significance of the syllable OM from ancient texts and effects of OM meditation in contemporary science. DESCRIPTIONS FROM ANCIENT TEXTS: The descriptions of Om have been taken from four Upanisads (Mundaka, Mandukya, Svetasvatara, and Katha), the Bhagvad Gita, and Patanjali's Yoga Sutras. SCIENTIFIC STUDIES ON OM: Autonomic and respiratory studies suggest that there is a combination of mental alertness with physiological rest during the practice of Om meditation. Evoked potentials studies suggest a decrease in sensory transmission time at the level of the auditory association cortices, along with recruitment of more neurons at mesencephalic-diencephalic levels. CONCLUSIONS: It is considered that a person who realizes Om, merges with the Absolute. Scientific studies on Om suggest that the mental repetition of Om results in physiological alertness, and increased sensitivity to sensory transmission. PMID- 20948895 TI - Measures of heart rate variability in women following a meditation technique. AB - Certain time domain, frequency domain and a nonlinear measure of heart rate variability are studied in women following a meditative practice called cyclic meditation. The nonlinear measure studied is the sampling entropy. We show that there is an increase in the sampling entropy in the meditative group as compared to the control group. The time domain measure called pNNx is shown to be useful in distinguishing between the meditative state and a normal resting state. PMID- 20948896 TI - Effect of yoga on quality of life of CLBP patients: A randomized control study. AB - CONTEXT: In two of the earlier Randomized Control Trials on yoga for chronic lower back pain (CLBP), 12 to 16 weeks of intervention were found effective in reducing pain and disability. AIM: To study the efficacy of a residential short term intensive yoga program on quality of life in CLBP. MATERIALS AND METHODS: About 80 patients with CLBP (females 37) registered for a week long treatment at SVYASA Holistic Health Centre in Bengaluru, India. They were randomized into two groups (40 each). The yoga group practiced a specific module for CLBP comprising of asanas (physical postures), pranayama (breathing practices), meditation and lectures on yoga philosophy. The control group practiced physical therapy exercises for back pain. Perceived stress scale (PSS) was used to measure baseline stress levels. Outcome measures were WHOQOL Bref for quality of life and straight leg raising test (SLR) using a Goniometer. RESULTS: There were significant negative correlations (Pearson's, P<0.005, r>0.30) between baseline PSS with all four domains and the total score of WHOQOLBref. All the four domains' WHOQOLBref improved in the yoga group (repeated measures ANOVA P=0.001) with significant group*time interaction (P<0.05) and differences between groups (P<0.01). SLR increased in both groups (P=0.001) with higher increase in yoga (31.1 % right, 28.4 % left) than control (18.7% right, 21.5 % left) group with significant group*time interaction (SLR right leg P=0.044). CONCLUSION: In CLBP, a negative correlation exists between stress and quality of life. Yoga increases quality of life and spinal flexibility better than physical therapy exercises. PMID- 20948897 TI - Complimentary effect of yogic sound resonance relaxation technique in patients with common neck pain. AB - BACKGROUND: Studies have shown that conventional treatment methods with drugs, physiotherapy and exercises for common neck pain (CNP) may be inadequate. Yoga techniques have been found to be effective complimentary therapies in chronic low back pain and also for stress reduction in other diseases. OBJECTIVE: The aim of the study was to examine the complimentary role of a yogic relaxation called mind sound resonance technique (MSRT) in non-surgical management of CNP. MATERIALS AND METHODS: In this randomized controlled study, 60 patients with CNP were assigned to two groups (yoga, n=30) and (control, n=30). The yoga group received yogic MSRT for 20 minutes in supine position after the conventional physiotherapy program for 30 minutes using pre-recorded audio CD and the control group had non guided supine rest for 20 minutes (after physiotherapy), for 10 days. MSRT provides deep relaxation for both mind and body by introspective experience of the sound resonance in the whole body while repeating the syllables A, U, M and Om and a long chant (Mahamrityunjaya mantra) several times in a meaningful sequence. Both the groups had pre and post assessments using visual pain analog scale, tenderness scoring key, neck disability score (NDS) questionnaire, goniometric measurement of cervical spinal flexibility, and state and trait anxiety inventory-Y1 (STAI-Y1). RESULTS: Mann-Whitney U test showed significant difference between groups in pain (P<0.01), tenderness (P<0.01), neck movements (P<0.01). NDS (P<0.01) and state anxiety (STAI-Y1) showed higher reduction in yoga (P<0.01) than that in the control group. Wilcoxon's test showed a significant improvement in both groups on all variables (P<0.01). CONCLUSIONS: Yoga relaxation through MSRT adds significant complimentary benefits to conventional physiotherapy for CNP by reducing pain, tenderness, disability and state anxiety and providing improved flexibility. PMID- 20948898 TI - Application of integrated yoga therapy to increase imitation skills in children with autism spectrum disorder. AB - BACKGROUND/AIM: Children with autism exhibit significant deficits in imitation skills, which impede the acquisition of more complex behavior and socialization. Imitation is often targeted early in intervention plans and continues to be addressed throughout the child's treatment. The use of integrated approach to yoga therapy (IAYT) as a complementary therapy for children diagnosed with autism spectrum disorder (ASD) is rarely reported and little is known on the effectiveness of such therapies. This study investigated IAYT as a treatment method with children with ASD to increase imitative skills. MATERIALS AND METHODS: Parents and six children with ASD participated in a 10-month program of 5-weekly sessions and regular practice at home. Pre, mid and post treatment assessments included observers and parent ratings of children's imitation skills in tasks related to imitation skills such as gross motor actions, vocalization, complex imitation, oral facial movements and imitating breathing exercises. RESULTS: Improvement in children's imitation skills especially pointing to body, postural and oral facial movements. Parents reported change in the play pattern of these children with toys, peers and objects at home. CONCLUSIONS: This study indicates that IAYT may offer benefits as an effective tool to increase imitation, cognitive skills and social-communicative behaviors in children with ASD. In addition, children exhibited increased skills in eye contact, sitting tolerance, non-verbal communication and receptive skills to verbal commands related to spatial relationship. PMID- 20948899 TI - Marine polysaccharides in pharmaceutical applications: an overview. AB - The enormous variety of polysaccharides that can be extracted from marine plants and animal organisms or produced by marine bacteria means that the field of marine polysaccharides is constantly evolving. Recent advances in biological techniques allow high levels of polysaccharides of interest to be produced in vitro. Biotechnology is a powerful tool to obtain polysaccharides from a variety of micro-organisms, by controlling the growth conditions in a bioreactor while tailoring the production of biologically active compounds. Following an overview of the current knowledge on marine polysaccharides, with special attention to potential pharmaceutical applications and to more recent progress on the discovering of new polysaccharides with biological appealing characteristics, this review will focus on possible strategies for chemical or physical modification aimed to tailor the final properties of interest. PMID- 20948900 TI - Marine myxobacteria as a source of antibiotics--comparison of physiology, polyketide-type genes and antibiotic production of three new isolates of Enhygromyxa salina. AB - Three myxobacterial strains, designated SWB004, SWB005 and SWB006, were obtained from beach sand samples from the Pacific Ocean and the North Sea. The strains were cultivated in salt water containing media and subjected to studies to determine their taxonomic status, the presence of genes for the biosynthesis of polyketides and antibiotic production. 16S rDNA sequence analysis revealed the type strain Enhygromyxa salina SHK-1(T) as their closest homolog, displaying between 98% (SWB005) and 99% (SWB004 and SWB006) sequence similarity. All isolates were rod-shaped cells showing gliding motility and fruiting body formation as is known for myxobacteria. They required NaCl for growth, with an optimum concentration of around 2% [w/v]. The G + C-content of genomic DNA ranged from 63.0 to 67.3 mol%. Further, the strains were analyzed for their potential to produce polyketide-type structures. PCR amplified ketosynthase-like gene fragments from all three isolates enhances the assumption that these bacteria produce polyketides. SWB005 was shown to produce metabolites with prominent antibacterial activity, including activity towards methicillin resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE). PMID- 20948901 TI - Nature and lability of northern Adriatic macroaggregates. AB - The key organic constituents of marine macroaggregates (macrogels) of prevalently phytoplankton origin, periodically occurring in the northern Adriatic Sea, are proteins, lipids and especially polysaccharides. In this article, the reactivity of various macroaggregate fractions in relation to their composition in order to decode the potentially "bioavailable" fractions is summarized and discussed. The enzymatic hydrolysis of the macroaggregate matrix, using alpha-amylase, beta glucosidase, protease, proteinase and lipase, revealed the simultaneous degradation of polysaccharides and proteins, while lipids seem largely preserved. In the fresh surface macroaggregate samples, a pronounced degradation of the alpha-glycosidic bond compared to beta-linkages. Degradation of the colloidal fraction proceeded faster in the higher molecular weight (MW) fractions. N containing polysaccharides can be important constituents of the higher MW fraction while the lower MW constituents can mostly be composed of poly- and oligosaccharides. Since the polysaccharide component in the higher MW fraction is more degradable compared to N-containing polysaccharides, the higher MW fraction represents a possible path of organic nitrogen preservation. Enzymatic hydrolysis, using alpha-amylase and beta-glucosidase, revealed the presence of alpha- and beta-glycosidic linkages in all fractions with similar decomposition kinetics. Our results indicate that different fractions of macroaggregates are subjected to compositional selective reactivity with important implications for macroaggregate persistence in the seawater column and deposition. PMID- 20948903 TI - Assessing pearl quality using reflectance UV-Vis spectroscopy: does the same donor produce consistent pearl quality? AB - Two groups of commercial quality ("acceptable") pearls produced using two donors, and a group of "acceptable" pearls from other donors were analyzed using reflectance UV-Vis spectrophotometry. Three pearls with different colors produced by the same donor showed different absorption spectra. Cream and gold colored pearls showed a wide absorption from 320 to about 460 nm, while there was just slight reflectance around 400 nm by the white pearl with a pink overtone. Cream and gold pearls reached a reflectance peak at 560 to 590 nm, while the white pearl with pink overtone showed slightly wider absorption in this region. Both cream and gold pearls showed an absorption peak after the reflectance peak, at about 700 nm for the cream pearl and 750 nm for the gold pearl. Two other pearls produced by the same donor (white with cream overtone and cream with various overtones) showed similar spectra, which differed in their intensity. One of these pearls had very high lustre and its spectrum showed a much higher percentage reflectance than the second pearl with inferior lustre. This result may indicate that reflectance is a useful quantitative indicator of pearl lustre. The spectra of two white pearls resulting from different donors with the same color nacre (silver) showed a reflectance at 260 nm, followed by absorption at 280 nm and another reflectance peak at 340 nm. After this peak the spectra for these pearls remained flat until a slight absorption peak around 700 nm. Throughout the visible region, all white pearls used in this study showed similar reflectance spectra although there were differences in reflectance intensity. Unlike the spectral results from white pearls, the results from yellow and gold pearls varied according to color saturation of the pearl. The results of this study show that similarities between absorption and reflectance spectra of cultured pearls resulting from the same saibo donor are negligible and could not be detected with UV-Vis spectrophotometry. Nevertheless, this technique could have a role to play in developing less subjective methods of assessing pearl quality and in further studies of the relationships between pearl quality and that of the donor and recipient oysters. PMID- 20948902 TI - N-acetylglucosamine: production and applications. AB - N-Acetylglucosamine (GlcNAc) is a monosaccharide that usually polymerizes linearly through (1,4)-beta-linkages. GlcNAc is the monomeric unit of the polymer chitin, the second most abundant carbohydrate after cellulose. In addition to serving as a component of this homogeneous polysaccharide, GlcNAc is also a basic component of hyaluronic acid and keratin sulfate on the cell surface. In this review, we discuss the industrial production of GlcNAc, using chitin as a substrate, by chemical, enzymatic and biotransformation methods. Also, newly developed methods to obtain GlcNAc using glucose as a substrate in genetically modified microorganisms are introduced. Moreover, GlcNAc has generated interest not only as an underutilized resource but also as a new functional material with high potential in various fields. Here we also take a closer look at the current applications of GlcNAc, and several new and cutting edge approaches in this fascinating area are thoroughly discussed. PMID- 20948904 TI - TFA and EPA productivities of Nannochloropsis salina influenced by temperature and nitrate stimuli in turbidostatic controlled experiments. AB - The influence of different nitrate concentrations in combination with three cultivation temperatures on the total fatty acids (TFA) and eicosapentaenoic acid (EPA) content of Nannochloropsis salina was investigated. This was done by virtue of turbidostatic controlled cultures. This control mode enables the cultivation of microalgae under defined conditions and, therefore, the influence of single parameters on the fatty acid synthesis of Nannochloropsis salina can be investigated. Generally, growth rates decreased under low nitrate concentrations. This effect was reinforced when cells were exposed to lower temperatures (from 26 degrees C down to 17 degrees C). Considering the cellular TFA concentration, nitrate provoked an increase of TFA under nitrate limitation up to 70% of the biological dry mass (BDM). In contrast to this finding, the EPA content decreased under low nitrate concentrations. Nevertheless, both TFA and EPA contents increased under a low culture temperature (17 degrees C) compared to moderate temperatures of 21 degrees C and 26 degrees C. In terms of biotechnological production, the growth rate has to be taken into account. Therefore, for both TFA and EPA production, a temperature of 17 degrees C and a nitrate concentration of 1800 MUmol L-1 afforded the highest productivities. Temperatures of 21 degrees C and 26 degrees C in combination with 1800 MUmol L-1 nitrate showed slightly lower TFA and EPA productivities. PMID- 20948905 TI - In-depth analysis of exoproteomes from marine bacteria by shotgun liquid chromatography-tandem mass spectrometry: the Ruegeria pomeroyi DSS-3 case-study. AB - Microorganisms secrete into their extracellular environment numerous compounds that are required for their survival. Many of these compounds could be of great interest for biotechnology applications and their genes used in synthetic biology design. The secreted proteins and the components of the translocation systems themselves can be scrutinized in-depth by the most recent proteomic tools. While the secretomes of pathogens are well-documented, those of non-pathogens remain largely to be established. Here, we present the analysis of the exoproteome from the marine bacterium Ruegeria pomeroyi DSS-3 grown in standard laboratory conditions. We used a shotgun approach consisting of trypsin digestion of the exoproteome, and identification of the resulting peptides by liquid chromatography coupled to tandem mass spectrometry. Three different proteins that have domains homologous to those observed in RTX toxins were uncovered and were semi-quantified as the most abundantly secreted proteins. One of these proteins clearly stands out from the catalogue, representing over half of the total exoproteome. We also listed many soluble proteins related to ABC and TRAP transporters implied in the uptake of nutrients. The Ruegeria pomeroyi DSS-3 case study illustrates the power of the shotgun nano-LC-MS/MS strategy to decipher the exoproteome from marine bacteria and to contribute to environmental proteomics. PMID- 20948906 TI - Characterization of the exopolysaccharide produced by Salipiger mucosus A3, a halophilic species belonging to the Alphaproteobacteria, isolated on the Spanish Mediterranean seaboard. AB - We have studied the exopolysaccharide produced by the type strain of Salipiger mucosus, a species of halophilic, EPS-producing (exopolysaccharide-producing) bacterium belonging to the Alphaproteobacteria. The strain, isolated on the Mediterranean seaboard, produced a polysaccharide, mainly during its exponential growth phase but also to a lesser extent during the stationary phase. Culture parameters influenced bacterial growth and EPS production. Yield was always directly related to the quantity of biomass in the culture. The polymer is a heteropolysaccharide with a molecular mass of 250 kDa and its components are glucose (19.7%, w/w), mannose (34%, w/w), galactose (32.9%, w/w) and fucose (13.4%, w/w). Fucose and fucose-rich oligosaccharides have applications in the fields of medicine and cosmetics. The chemical or enzymatic hydrolysis of fucose rich polysaccharides offers a new efficient way to process fucose. The exopolysaccharide in question produces a solution of very low viscosity that shows pseudoplastic behavior and emulsifying activity on several hydrophobic substrates. It also has a high capacity for binding cations and incorporating considerable quantities of sulfates, this latter feature being very unusual in bacterial polysaccharides. PMID- 20948907 TI - Chitosan composites for bone tissue engineering--an overview. AB - Bone contains considerable amounts of minerals and proteins. Hydroxyapatite [Ca10(PO4)6(OH)2] is one of the most stable forms of calcium phosphate and it occurs in bones as major component (60 to 65%), along with other materials including collagen, chondroitin sulfate, keratin sulfate and lipids. In recent years, significant progress has been made in organ transplantation, surgical reconstruction and the use of artificial prostheses to treat the loss or failure of an organ or bone tissue. Chitosan has played a major role in bone tissue engineering over the last two decades, being a natural polymer obtained from chitin, which forms a major component of crustacean exoskeleton. In recent years, considerable attention has been given to chitosan composite materials and their applications in the field of bone tissue engineering due to its minimal foreign body reactions, an intrinsic antibacterial nature, biocompatibility, biodegradability, and the ability to be molded into various geometries and forms such as porous structures, suitable for cell ingrowth and osteoconduction. The composite of chitosan including hydroxyapatite is very popular because of the biodegradability and biocompatibility in nature. Recently, grafted chitosan natural polymer with carbon nanotubes has been incorporated to increase the mechanical strength of these composites. Chitosan composites are thus emerging as potential materials for artificial bone and bone regeneration in tissue engineering. Herein, the preparation, mechanical properties, chemical interactions and in vitro activity of chitosan composites for bone tissue engineering will be discussed. PMID- 20948908 TI - An update on the therapeutic role of alkylglycerols. AB - Scandinavian folk medicine used shark liver oil for the treatment of cancers and other ailments based on the rarity of tumors in sharks and their ability to resist infections. Shark liver oil is a source of alkylglycerols which have been studied as anti-cancer agents in several clinical trials. Moreover, alkylglycerols have been investigated for the treatment of radiation induced side effects and for their ability to boost the immune system. Several experimental studies have shown the ability of alkylglycerols to open the blood brain barrier to facilitate the access of therapeutic drugs to the central nervous system. This review covers the most important studies of alkylglycerols in both animals and humans. PMID- 20948909 TI - Halogenated compounds from marine algae. AB - Marine algae produce a cocktail of halogenated metabolites with potential commercial value. Structures exhibited by these compounds go from acyclic entities with a linear chain to complex polycyclic molecules. Their medical and pharmaceutical application has been investigated for a few decades, however other properties, such as antifouling, are not to be discarded. Many compounds were discovered in the last years, although the need for new drugs keeps this field open as many algal species are poorly screened. The ecological role of marine algal halogenated metabolites has somehow been overlooked. This new research field will provide valuable and novel insight into the marine ecosystem dynamics as well as a new approach to comprehending biodiversity. Furthermore, understanding interactions between halogenated compound production by algae and the environment, including anthropogenic or global climate changes, is a challenging target for the coming years. Research of halogenated metabolites has been more focused on macroalgae than on phytoplankton. However, phytoplankton could be a very promising material since it is the base of the marine food chain with quick adaptation to environmental changes, which undoubtedly has consequences on secondary metabolism. This paper reviews recent progress on this field and presents trends on the role of marine algae as producers of halogenated compounds. PMID- 20948910 TI - Impact of ocean acidification on energy metabolism of oyster, Crassostrea gigas- changes in metabolic pathways and thermal response. AB - Climate change with increasing temperature and ocean acidification (OA) poses risks for marine ecosystems. According to Portner and Farrell, synergistic effects of elevated temperature and CO2-induced OA on energy metabolism will narrow the thermal tolerance window of marine ectothermal animals. To test this hypothesis, we investigated the effect of an acute temperature rise on energy metabolism of the oyster, Crassostrea gigas chronically exposed to elevated CO2 levels (partial pressure of CO2 in the seawater ~0.15 kPa, seawater pH ~ 7.7). Within one month of incubation at elevated PCo2 and 15 degrees C hemolymph pH fell (pH(e) = 7.1 +/- 0.2 (CO2-group) vs. 7.6 +/- 0.1 (control)) and P(e)CO2 values in hemolymph increased (0.5 +/- 0.2 kPa (CO2-group) vs. 0.2 +/- 0.04 kPa (control)). Slightly but significantly elevated bicarbonate concentrations in the hemolymph of CO2-incubated oysters ([HCO3-](e) = 1.8 +/- 0.3 mM (CO2-group) vs. 1.3 +/- 0.1 mM (control)) indicate only minimal regulation of extracellular acid base status. At the acclimation temperature of 15 degrees C the OA-induced decrease in pH(e) did not lead to metabolic depression in oysters as standard metabolism rates (SMR) of CO2-exposed oysters were similar to controls. Upon acute warming SMR rose in both groups, but displayed a stronger increase in the CO2-incubated group. Investigation in isolated gill cells revealed a similar temperature dependence of respiration between groups. Furthermore, the fraction of cellular energy demand for ion regulation via Na+/K+-ATPase was not affected by chronic hypercapnia or temperature. Metabolic profiling using 1H-NMR spectroscopy revealed substantial changes in some tissues following OA exposure at 15 degrees C. In mantle tissue alanine and ATP levels decreased significantly whereas an increase in succinate levels was observed in gill tissue. These findings suggest shifts in metabolic pathways following OA-exposure. Our study confirms that OA affects energy metabolism in oysters and suggests that climate change may affect populations of sessile coastal invertebrates such as mollusks. PMID- 20948912 TI - Applications of chemical shift imaging to marine sciences. AB - The successful applications of magnetic resonance imaging (MRI) in medicine are mostly due to the non-invasive and non-destructive nature of MRI techniques. Longitudinal studies of humans and animals are easily accomplished, taking advantage of the fact that MRI does not use harmful radiation that would be needed for plain film radiographic, computerized tomography (CT) or positron emission (PET) scans. Routine anatomic and functional studies using the strong signal from the most abundant magnetic nucleus, the proton, can also provide metabolic information when combined with in vivo magnetic resonance spectroscopy (MRS). MRS can be performed using either protons or hetero-nuclei (meaning any magnetic nuclei other than protons or 1H) including carbon (13C) or phosphorus (31P). In vivo MR spectra can be obtained from single region of interest (ROI or voxel) or multiple ROIs simultaneously using the technique typically called chemical shift imaging (CSI). Here we report applications of CSI to marine samples and describe a technique to study in vivo glycine metabolism in oysters using 13C MRS 12 h after immersion in a sea water chamber dosed with [2-13C] glycine. This is the first report of 13C CSI in a marine organism. PMID- 20948911 TI - Terpenes from marine-derived fungi. AB - Terpenes from marine-derived fungi show a pronounced degree of structural diversity, and due to their interesting biological and pharmacological properties many of them have aroused interest from synthetic chemists and the pharmaceutical industry alike. The aim of this paper is to give an overview of the structural diversity of terpenes from marine-derived fungi, highlighting individual examples of chemical structures and placing them in a context of other terpenes of fungal origin. Wherever possible, information regarding the biological activity is presented. PMID- 20948913 TI - Total synthesis and antimicrobial activity of a natural cycloheptapeptide of marine origin. AB - The present study deals with the first total synthesis of the proline-rich cyclopolypeptide stylisin 2 via a solution phase technique by coupling of the Boc L-Pro-L-Ile-L-Pro-OH tripeptide unit with the L-Phe-L-Pro-L-Pro-L-Tyr-OMe tetrapeptide unit, followed by cyclization of the resulting linear heptapeptide fragment. The chemical structure of the finally synthesized peptide was elucidated by FTIR, 1H/13C-NMR and FAB MS spectral data, as well as elemental analyses. The newly synthesized peptide was subjected to antimicrobial screening against eight pathogenic microbes and found to exhibit potent antimicrobial activity against Pseudomonas aeruginosa, Klebsiella pneumoniae and Candida albicans, in addition to moderate antidermatophyte activity against pathogenic Trichophyton mentagrophytes and Microsporum audouinii when compared to standard drugs--gatifloxacin and griseofulvin. PMID- 20948914 TI - New one-pot methodologies for the modification or synthesis of alkaloid scaffolds. AB - There are several avenues by which promising bioactive natural products can be produced in sufficient quantities to enable lead optimization and medicinal chemistry studies. The total synthesis of natural products is an important, but sometimes difficult, approach and requires the development of innovative synthetic methodologies to simplify the synthesis of complex molecules. Various classes of natural product alkaloids are both common and widely distributed in plants, bacteria, fungi, insects and marine organisms. This mini-review will discuss the scope, mechanistic insights and enantioselectivity aspects of selected examples of recently developed one-pot methods that have been published in 2009 for the synthesis of substituted piperidines, quinolizidines, pyrrolidines, hexahydropyrrolizines, octahydroindolizines and gamma-lactams. In addition, progress on the synthesis of beta-carboline (manzamine) alkaloids will also be discussed. PMID- 20948916 TI - RNA regulation in neurologic disease and cancer. AB - The paraneoplastic neurologic diseases (PNDs) are brain degenerations that develop in the setting of clinically inapparent cancers. PNDs arise when common cancers express brain proteins, triggering an anti-tumor immune response and tumor immunity. Research on these brain-cancer proteins has revealed a new world of neuron-specific RNA binding proteins whose functions may be aberrantly used by tumor cells. Efforts to gain insight into their function has led to the development of new methods and strategies to understand RNA protein regulation in living tissues. PMID- 20948915 TI - Pharmacological analyses of protein kinases regulating egg maturation in marine nemertean worms: a review and comparison with Mammalian eggs. AB - For development to proceed normally, animal eggs must undergo a maturation process that ultimately depends on phosphorylations of key regulatory proteins. To analyze the kinases that mediate these phosphorylations, eggs of marine nemertean worms have been treated with pharmacological modulators of intracellular signaling pathways and subsequently probed with immunoblots employing phospho-specific antibodies. This article both reviews such analyses and compares them with those conducted on mammals, while focusing on how egg maturation in nemerteans is affected by signaling pathways involving cAMP, mitogen-activated protein kinases, Src-family kinases, protein kinase C isotypes, AMP-activated kinase, and the Cdc2 kinase of maturation-promoting factor. PMID- 20948917 TI - Quality of life of long-term survivors after a distal subtotal gastrectomy. AB - PURPOSE: The aim of this study was to investigate the impact of a distal subtotal gastrectomy on the quality of life (QoL). MATERIALS AND METHODS: The QoL data of 126 patients were obtained on their 5th annual follow-up visit after a curative distal subtotal gastrectomy for gastric cancer (Group A). The QoL data of 130 age and gender-adjusted healthy population were obtained from the individuals who visited the health screening center for a medical check-up (Group B). There were 42 women and 84 men in the study group and their mean age was 56.0+/-11.1 years. QoL was assessed using the Korean versions of the European Organization for Research and Treatment of Cancer (EORTC) QoL Questionnaire Core 30 (QLQ-C30) and QLQ-STO22. RESULTS: The EORTC QLQ-C30 global health status and QoL scores of Group A and Group B were 63.9+/-22.7 and 61.3+/-22.1, respectively (p=0.361). Group A revealed a better score for emotional functioning (84.1+/-16.1 and 75.2+/ 21.4, respectively; p<0.001), cognitive functioning (82.0+/-16.4 and 75.0+/-21.4, respectively; p=0.004) and fatigue (27.7+/-20.8 and 33.8+/-23.2, respectively; p=0.028). However, Group A revealed a worse score for nausea and vomiting (14.8+/ 20.0 and 10.2+/-16.0, respectively; p=0.042), financial difficulties (14.8+/-22.9 and 7.1+/-16.1, respectively; p=0.002), reflux (16.7+/-17.7 and 10.1+/-17.0, respectively; p=0.003), eating restrictions (13.6+/-15.2 and 6.6+/-10.2, respectively; p<0.001) and body image (23.3+/-25.4 and 16.2+/-24.6, respectively; p=0.023). CONCLUSION: The QoL of long-term survivors after a distal subtotal gastrectomy is still influenced by the surgery itself even though they are considered to be free of disease. PMID- 20948918 TI - Clinicopathological and immunohistochemical features of gastointestinal stromal tumors. AB - PURPOSE: The purpose of this study was to evaluate the clinicopathological features and immunohistochemical features of gastrointestinal stromal tumor (GIST), and specifically the expressions of platelet derived growth factor receptor A (PDGFRA), protein kinase C theta (PKC theta), discovered on GIST-1 (DOG-1), p16 and p27. MATERIALS AND METHODS: Total 118 patients who underwent surgical resection for GIST at our institution between Jan 1997 and Dec 2007 were retrospectively studied. Immunohistochemical staining for c-kit, PDGFRA, PKC theta, DOG-1, p16 and p27 was performed on a tissue microarray of the 118 GIST. The clinicopathologic parameters, the disease-free survival (DFS) and the overall survival rate were analyzed along with immunohistochemistry. RESULTS: The immunohistochemical stains for c-kit, CD34, PKC-theta, PDGFRA, DOG-1, p16 and p27 were positive in 89.8%, 72.0%, 56.8%, 94.9%, 90.7%, 69.5% and 44.1% of the tumor samples, respectively. The immunohistochemical expression of c-kit was strongly correlated with PKC-theta (p=0.000), DOG-1 (p=0.000) and CD34 (p=0.002). The DFS rate was significantly decreased for the patients with peritoneal GIST, high risk GIST, >=10 cm-sized GIST, >=10 mitoses/50 high power fields (HPFs) and p16 positivity (p=0.001, p=0.004, p=0.001, p=0.003 and p=0.028). GISTs >=10 cm, epithelioid tumor cell type, and c-kit, and DOG-1 negativity were significantly associated with shorter period of overall survival (p=0.048, p=0.006, p=0.000 and p=0.000). CONCLUSION: The expression of p16 and no expression of c-kit and DOG-1 in GISTs, as well as peritoneal tumor site, high risk group, large tumor size, epithelioid tumor cell type and numerous mitoses, may be potentially prognostic factors for predicting worse outcome for patients who suffer from GIST. PMID- 20948919 TI - Prognostic role of Rb, p16, Cyclin D1 proteins in soft tissue sarcomas. AB - PURPOSE: The aim of this study was to determine the expressions of Rb, p16, and cyclin D1 in soft tissue sarcomas, and we also wanted to identify the prognostic factors according to the clinicalpathologic features. MATERIALS AND METHODS: We reviewed the charts and radiographic films of 66 sarcoma patients. Tissue samples were collected from these patients. Immunochemistry was performed using formalin fixed, paraffin-embedded tissue samples to examine the expressions of p16, Rb, and cyclin D1 proteins. RESULTS: The median duration of overall survival was 47.8 months (range, 20.0 to 70.7 months) and the 5 years survival rate was 39%. As for the correlation between the degree of immunohistochemical staining for Rb protein and the histological tumor grades, there was a significant difference with a p value of 0.019. However, no significant correlation was shown for p16 and cyclin D1. The overall survival duration of the Rb negative group (staining cell <20%) and the heterogeneous group (cell staining 20 to 80%) was 53.5+/-6.6 months and the overall survival duration of the Rb homogeneous group was 18.3+/-6.4 months, and there was a significant difference with a p-value of 0.016. However, no significant difference was shown between the survival rate according to the p16 and cyclin D1 expressions. On the multivariate analysis that was done with Rb, p16, the tumor size, grade and site, and patient age, the Rb gene expression was the most significant independent prognostic factor with a risk ratio of 3.01 (p=0.04). CONCLUSION: The expression of Rb protein was correlated with the histologic grade and overall survival of patients with soft tissue sarcomas. PMID- 20948920 TI - Up-regulation of RhoGDI2 in human breast cancer and its prognostic implications. AB - PURPOSE: Recent research has identified many genes and proteins that play specific roles in the process of systemic metastasis in various types of cancer. Rho GDP dissociation inhibitor 2 (RhoGDI2) has been shown to inhibit metastasis in human bladder cancer, but its role in breast cancer is controversial. MATERIALS AND METHODS: We examined the regulation and clinical significance of RhoGDI2 in Korean breast cancer patients by using proteomic approaches. RESULTS: By using a proteomic approach, we observed an increased expression of RhoGDI2 in human breast cancer tissues when compared to that of the normal breast tissues, and we validated its up-regulation in an independent cohort of 8 breast cancer patients. The clinical implication of a RhoGDI2 expression was investigated in 57 breast cancer patients by performing immunohistochemistry. RhoGDI2 did not show a significant association with the tumor size, lymph node metastasis, the histologic grade or the hormone receptor status. However, the patients with RhoGDI2-expressing tumors had significantly shorter disease-free survival (p=0.043; hazard ratio, 3.87) and distant metastasis-free survival (p=0.039; hazard ratio, 5.15). CONCLUSION: Our results demonstrated a potential role of RhoGDI2 as a poor prognostic marker as well as a potential therapeutic target. The pro-metastatic nature of RhoGDI2 shown in our study may indicate its organ specific role in cancer metastasis. PMID- 20948921 TI - Bcl-2 as a predictive factor for biochemical recurrence after radical prostatectomy: an interim analysis. AB - PURPOSE: The objective of this study was to determine Bcl-2 expression in localized prostate cancer and its potential role as a predictive factor for biochemical recurrence (BCR). MATERIALS AND METHODS: This study included 171 Korean patients with newly diagnosed adenocarcinoma of the prostate who underwent radical prostatectomy (RP) without neoadjuvant therapy at a single center between February 2005 and May 2009. RP specimens obtained from these patients were analyzed for the expression of Bcl-2 using tissue microarray. The values of Bcl-2 and other clinicopathologic factors were evaluated. Statistical analysis was performed with contingency table analysis, chi-square tests, and a Cox proportional hazard model. RESULTS: Bcl-2 expression was immunohistologically confirmed in 42 patients (24.6%). Bcl-2 expression was not associated with conventional clinicopathologic factors. Bcl-2 negative patients had a significantly longer mean BCR-free survival than Bcl-2-positive patients (p=0.036). Among several variables, a high Gleason score in the RP specimen (>=8), extraprostatic extension, seminal vesicle invasion (SVI), lymphovascular invasion (LVI), and Bcl-2 expression were significant predictors of BCR based on univariate analysis. Multivariate Cox proportional hazards analysis revealed that BCR was significantly associated with a high prostate specific antigen level (p=0.047), SVI (p<0.001), a positive surgical margin (p=0.004) and Bcl-2 expression (p=0.012). CONCLUSION: Bcl-2 expression in RP specimens is associated with a significantly worse outcome, suggesting a potential clinical role for Bcl 2. Post-operative Bcl-2 could be a significant predictor of outcome after RP. PMID- 20948922 TI - Influence of reduced folate carrier and dihydrofolate reductase genes on methotrexate-induced cytotoxicity. AB - PURPOSE: The aim of this study is to investigate the effect of genetic variations and the expression of the reduced folate carrier (RFC) and dihydrofolate reductase (DHFR) on the drug sensitivity to methotrexate (MTX) in different cancer cell lines. MATERIALS AND METHODS: We examined the six human cancer cell lines (MCF-7, AGS, A549, NCI-H23, HCT-116 and Saos-2). The cytotoxicity of MTX was measured by sulforhodamine B (SRB) assay. The expressions of the DHFR and RFC were evaluated by real-time PCR and western blotting. Four single nucleotide polymorphisms (SNPs) of the DHFR and two SNPs of the RFC were genotyped. RESULTS: The IC50s of MTX was in an extensively broad range from 6.05+/-0.81 nM to>1,000 nM in the cell lines. The Saos-2 (>1,000 nM) and MCF-7 (114.31+/-5.34 nM) cells were most resistant to MTX; in contrast, the AGS and HCT-116 cells were highly sensitive to MTX with an IC(50) of 6.05+/-0.81 nM and 13.56+/-3.76 nM, respectively. A reciprocal change of the RFC and DHFR mRNA expression was found between the MTX-sensitive AGS and MTX-resistant Saos-2 cells. There was no significant difference in the expression levels of RFC protein in both the AGS and Saos-2 cells, whereas DHFR protein was more increased in the MTX-resistant Saos-2 cells treated with MTX. The genotype of the MTX-sensitive AGS cells were mutant variants of the DHFR; in contrast, the Saos-2 cells had the wild-type of the DHFR. CONCLUSION: In conclusion, this study showed that inverse change of the RFC and DHFR mRNA and protein expression was associated with RFC and DHFR polymorphisms and it is postulated that this phenomenon might play an important role in sensitivity of certain cancers to MTX. PMID- 20948923 TI - A case of metachronous metastasis to the breast from non-small cell lung carcinoma. AB - Breast metastases from an extramammary primary tumor are very rare and the prognosis for such patients is generally poor. We report here on a case of a 42 year-old female with metastasis of non-small cell lung cancer to the breast, and she is now being followed up on an outpatient basis. In 2004, she presented with a solitary pulmonary nodule in the left lung, and this lesion had been noted to have gradually increased in size over time. The final pathological diagnosis was adenocarcinoma, and the diagnosis was made by performing percutaneous needle aspiration and lobectomy of the left upper lobe. Adjuvant chemotherapy and radiotherapy were given. Unfortunately, a nodule in the left breast was noted three years later, and metastatic non-small-cell lung cancer to the breast was diagnosed by excisional biopsy. Making the correct diagnosis to distinguish a primary breast carcinoma from a metastatic one is important, because the therapeutic plan and outcome for these two types of cancer are quite different. PMID- 20948924 TI - Recurrent and metastatic trichilemmal carcinoma of the skin over the thigh: a case report. AB - Trichilemmal carcinoma (TC) is an uncommon cutaneous neoplasm that develops from the external root sheath of the hair follicle. It is considered to be a low-grade carcinoma with low metastatic potential. Local recurrence and metastasis are rare after surgical excision. We report here on a case of metastatic TC in the skin over the thigh, and this tumor was treated with cisplatin and cyclophosphamide combination chemotherapy. PMID- 20948925 TI - Novel sunitinib strategy in metastatic renal cell carcinoma on hemodialysis: intermittent dose of sunitinib after hemodialysis. AB - The proper dose and schedule of sunitinib have yet to be established for patients with metastatic renal cell carcinoma (RCC) on hemodialysis. We reviewed two patients with metastatic RCC on hemodialysis who had been treated with sunitinib in Yonsei Cancer Center, Yonsei University College of Medicine. Fifty milligrams of sunitinib was administered intermittently after each hemodialysis session (3 or 4 times a week). Overall responses were partial response in both cases. Progression-free survivals were 16 and 6 months, respectively, at the time of reporting (April 2010). Both subjects tolerated the treatment. PMID- 20948926 TI - Characterization and cytotoxic assessment of ballistic aerosol particulates for tungsten alloy penetrators into steel target plates. AB - The nature and constituents of ballistic aerosol created by kinetic energy penetrator rods of tungsten heavy alloys (W-Fe-Ni and W-Fe-Co) perforating steel target plates was characterized by scanning and transmission electron microscopy. These aerosol regimes, which can occur in closed, armored military vehicle penetration, are of concern for potential health effects, especially as a consequence of being inhaled. In a controlled volume containing 10 equispaced steel target plates, particulates were systematically collected onto special filters. Filter collections were examined by scanning and transmission electron microscopy (SEM and TEM) which included energy-dispersive (X-ray) spectrometry (EDS). Dark-field TEM identified a significant nanoparticle concentration while EDS in the SEM identified the propensity of mass fraction particulates to consist of Fe and FeO, representing target erosion and formation of an accumulating debris field. Direct exposure of human epithelial cells (A549), a model for lung tissue, to particulates (especially nanoparticulates) collected on individual filters demonstrated induction of rapid and global cell death to the extent that production of inflammatory cytokines was entirely inhibited. These observations along with comparisons of a wide range of other nanoparticulate species exhibiting cell death in A549 culture may suggest severe human toxicity potential for inhaled ballistic aerosol, but the complexity of the aerosol (particulate) mix has not yet allowed any particular chemical composition to be identified. PMID- 20948928 TI - Modified perfluorocarbon tracer method for measuring effective multizone air exchange rates. AB - A modified procedure was developed for the measurement of the effective air exchange rate, which represents the relationship between the pollutants emitted from indoor sources and the residents' level of exposure, by placing the dosers of tracer gas at locations that resemble indoor emission sources. To measure the 24-h-average effective air exchange rates in future surveys based on this procedure, a low-cost, easy-to-use perfluorocarbon tracer (PFT) doser with a stable dosing rate was developed by using double glass vials, a needle, a polyethylene-sintered filter, and a diffusion tube. Carbon molecular sieve cartridges and carbon disulfide (CS2) were used for passive sampling and extraction of the tracer gas, respectively. Recovery efficiencies, sampling rates, and lower detection limits for 24-h sampling of hexafluorobenzene, octafluorotoluene, and perfluoroallylbenzene were 40% +/- 3%, 72% +/- 5%, and 84% +/- 6%; 10.5 +/- 1.1, 14.4 +/- 1.4, and 12.2 +/- 0.49 mL min-1; and 0.20, 0.17, and 0.26 MUg m-3, respectively. PMID- 20948927 TI - An examination of the association of selected toxic metals with total and central obesity indices: NHANES 99-02. AB - It is conceivable that toxic metals contribute to obesity by influencing various aspects of metabolism, such as by substituting for essential micronutrients and vital metals, or by inducing oxidative stress. Deficiency of the essential metal zinc decreases adiposity in humans and rodent models, whereas deficiencies of chromium, copper, iron, and magnesium increases adiposity. This study utilized the NHANES 99-02 data to explore the association between waist circumference and body mass index with the body burdens of selected toxic metals (barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, and tungsten). Some of the associations were significant direct relationships (barium and thallium), and some of the associations were significant inverse relationships (cadmium, cobalt, cesium, and lead). Molybdenum, antimony, and tungsten had mostly insignificant associations with waist circumference and body mass index. This is novel result for most of the toxic metals studied, and a surprising result for lead because high stored lead levels have been shown to correlate with higher rates of diabetes, and obesity may be a key risk factor for developing diabetes. These associations suggest the possibility that environmental exposure to metals may contribute to variations in human weight gain/loss. Future research, such as prospective studies rather than the cross-sectional studies presented here, is warranted to confirm these findings. PMID- 20948929 TI - Attractive "quiet" courtyards: a potential modifier of urban residents' responses to road traffic noise? AB - The present paper explores the influence of the physical environmental qualities of "quiet". courtyards (degree of naturalness and utilization) on residents' noise responses. A questionnaire study was conducted in urban residential areas with road-traffic noise exposure between L(Aeq,24h) 58 to 68 dB at the most exposed facade. The dwellings had "quiet" indoor section/s and faced a "quiet" outdoor courtyard (L(Aeq,24h) < 48 dB facade reflex included). Data were collected from 385 residents and four groups were formed based on sound-level categories (58-62 and 63-68 dB) and classification of the "quiet" courtyards into groups with low and high physical environmental quality. At both sound-level categories, the results indicate that access to high-quality "quiet" courtyards is associated with less noise annoyance and noise-disturbed outdoor activities among the residents. Compared to low-quality "quiet" courtyards, high-quality courtyards can function as an attractive restorative environment providing residents with a positive soundscape, opportunities for rest, relaxation and play as well as social relations that potentially reduce the adverse effects of noise. However, access to quietness and a high-quality courtyard can only compensate partly for high sound levels at facades facing the streets, thus, 16% and 29% were still noise annoyed at 58-62 and 63-68 dB, respectively. Implications of the "quiet"-side concept are discussed. PMID- 20948930 TI - Different length (DL) qPCR for quantification of cell killing by UV-induced DNA damage. AB - We describe the different length (DL) qPCR method for quantification of UV induced DNA damage in cell killing. The principle of DL qPCR is that DNA damage inhibits PCR. Applications with different lengths can therefore be used to detect different levels of UV-induced DNA damage. The assay was evaluated on three strains of Escherichia coli exposed to varying levels of ultraviolet (UV) radiation. We show that DL qPCR sensitivity and reproducibility are within the range of practical application to detect the effect of UV cell killing. PMID- 20948931 TI - Aircraft noise and quality of life around Frankfurt Airport. AB - In a survey of 2,312 residents living near Frankfurt Airport aircraft noise annoyance and disturbances as well as environmental (EQoL) and health-related quality of life (HQoL) were assessed and compared with data on exposure due to aircraft, road traffic, and railway noise. Results indicate higher noise annoyance than predicted from general exposure-response curves. Beside aircraft sound levels source-related attitudes were associated with reactions to aircraft noise. Furthermore, aircraft noise affected EQoL in general, although to a much smaller extent. HQoL was associated with aircraft noise annoyance, noise sensitivity and partly with aircraft noise exposure, in particular in the subgroup of multimorbid residents. The results suggest a recursive relationship between noise and health, yet this cannot be tested in cross-sectional studies. Longitudinal studies would be recommendable to get more insight in the causal paths underlying the noise-health relationship. PMID- 20948932 TI - Human blood concentrations of cotinine, a biomonitoring marker for tobacco smoke, extrapolated from nicotine metabolism in rats and humans and physiologically based pharmacokinetic modeling. AB - The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for nicotine and its primary metabolite cotinine in humans, based on metabolic parameters determined in vitro using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and an established rat PBPK model. The model consists of an absorption compartment, a metabolizing compartment, and a central compartment for nicotine and three equivalent compartments for cotinine. Evaluation of a rat model was performed by making comparisons with predicted concentrations in blood and in vivo experimental pharmacokinetic values obtained from rats after oral treatment with nicotine (1.0 mg/kg, a no-observed-adverseeffect level) for 14 days. Elimination rates of nicotine in vitro were established from data from rat liver microsomes and from human pooled liver microsomes. Human biomonitoring data (17 ng nicotine and 150 ng cotinine per mL plasma 1 h after smoking) from pooled five male Japanese smokers (daily intake of 43 mg nicotine by smoking) revealed that these blood concentrations could be calculated using a human PBPK model. These results indicate that a simplified PBPK model for nicotine/cotinine is useful for a forward dosimetry approach in humans and for estimating blood concentrations of other related compounds resulting from exposure to low chemical doses. PMID- 20948933 TI - Evaluation of the removal of indicator bacteria from domestic sludge processed by Autothermal Thermophilic Aerobic Digestion (ATAD). AB - The degradation of sludge solids in an insulated reactor during Autothermal Thermophilic Aerobic Digestion (ATAD) processing results in auto-heating, thermal treatment and total solids reduction, however, the ability to eliminate pathogenic organisms has not been analysed under large scale process conditions. We evaluated the ATAD process over a period of one year in a two stage, full scale Irish ATAD plant established in Killarney and treating mixed primary and secondary sludge, by examining the sludge microbiologically at various stages during and following ATAD processing to determine its ability to eliminate indicator organisms. Salmonella spp. (pathogen) and fecal-coliform (indicator) densities were well below the limits used to validate class A biosolids in the final product. Enteric pathogens present at inlet were deactivated during the ATAD process and were not detected in the final product using both traditional microbial culture and molecular phylogenetic techniques. A high DNase activity was detected in the bulk sludge during the thermophilic digestion stage which may be responsible for the rapid turn over of DNA from lysed cells and the removal of mobile DNA. These results offer assurance for the safe use of ATAD sludge as a soil supplement following processing. PMID- 20948934 TI - Mineral composition of organically grown wheat genotypes: contribution to daily minerals intake. AB - In this study, 321 winter and spring wheat genotypes were analysed for twelve nutritionally important minerals (B, Cu, Fe, Se, Mg, Zn, Ca, Mn, Mo, P, S and K). Some of the genotypes used were from multiple locations and years, resulting in a total number of 493 samples. Investigated genotypes were divided into six genotype groups i.e., selections, old landraces, primitive wheat, spelt, old cultivars and cultivars. For some of the investigated minerals higher concentrations were observed in selections, primitive wheat, and old cultivars as compared to more modern wheat material, e.g., cultivars and spelt wheat. Location was found to have a significant effect on mineral concentration for all genotype groups, although for primitive wheat, genotype had a higher impact than location. Spring wheat was observed to have significantly higher values for B, Cu, Fe, Zn, Ca, S and K as compared to winter wheat. Higher levels of several minerals were observed in the present study, as compared to previous studies carried out in inorganic systems, indicating that organic conditions with suitable genotypes may enhance mineral concentration in wheat grain. This study also showed that a very high mineral concentration, close to daily requirements, can be produced by growing specific primitive wheat genotypes in an organic farming system. Thus, by selecting genotypes for further breeding, nutritional value of the wheat flour for human consumption can be improved. PMID- 20948935 TI - Associations between chronic community noise exposure and blood pressure at rest and during acute noise and non-noise stressors among urban school children in India. AB - The present study builds on prior research that has examined the association between children's chronic exposure to community noise and resting blood pressure and blood pressure dysregulation during exposure to acute stressors. A novel contribution of the study is that it examines how chronic noise exposure relates to blood pressure responses during exposure to both noise and non-noise acute stressors. The acute noise stressor was recorded street noise and the non-noise stressor was mental arithmetic. The sample consisted of 189 3rd and 6th grade children (51.9% percent boys; 52.9% 3rd graders) from a noisy (n = 95) or relatively quiet (n = 94) public school in the city of Pune, India. There were no statistically significant differences between chronic noise levels and resting blood pressure levels. However, relative to quiet-school children, noisy-school children had significantly lower increases in blood pressure when exposed to either an acute noise or non-noise stressor. This finding suggests that chronic noise exposure may result in hypo-reactivity to a variety of stressors and not just habituation to noise stressors. PMID- 20948937 TI - Levels of reconstruction as complementarity in mixed methods research: a social theory-based conceptual framework for integrating qualitative and quantitative research. AB - Like other areas of health research, there has been increasing use of qualitative methods to study public health problems such as injuries and injury prevention. Likewise, the integration of qualitative and quantitative research (mixed methods) is beginning to assume a more prominent role in public health studies. Likewise, using mixed-methods has great potential for gaining a broad and comprehensive understanding of injuries and their prevention. However, qualitative and quantitative research methods are based on two inherently different paradigms, and their integration requires a conceptual framework that permits the unity of these two methods. We present a theory-driven framework for viewing qualitative and quantitative research, which enables us to integrate them in a conceptually sound and useful manner. This framework has its foundation within the philosophical concept of complementarity, as espoused in the physical and social sciences, and draws on Bergson's metaphysical work on the 'ways of knowing'. Through understanding how data are constructed and reconstructed, and the different levels of meaning that can be ascribed to qualitative and quantitative findings, we can use a mixed-methods approach to gain a conceptually sound, holistic knowledge about injury phenomena that will enhance our development of relevant and successful interventions. PMID- 20948936 TI - Research into mercury exposure and health education in subsistence fish-eating communities of the Amazon basin: potential effects on public health policy. AB - The neurotoxic effects of fish-methylmercury (meHg) consumed regularly are considered hazardous to fetuses and newborn infants; as a result fish consumption advisories are an important asset to control meHg exposure in affluent societies. These concerns are now part of health promotion programs for Amazon subsistence villagers. While urban dwellers in affluent societies can choose an alternative nutritious diet, traditional and subsistence communities are caught up in controversial issues and lifestyle changes with unintended health consequences. Traditional fish-eating populations of industrialized and non-industrialized regions may be exposed to different neurotoxic substances: man-made pollutants and environmentally occurring meHg. Additionally, in non-industrialized countries, pregnant women and infants are still being immunized with thimerosal containing vaccines (TCVs) which degrade to ethylmercury (etHg). Therefore, the complexity involving fish-meHg associated with wild-fish choices and Hg exposure derived from TCVs is difficult to disentangle and evaluate: are villagers able to distinguish exposure to differently hazardous chemical forms of Hg (inorganic, fish-meHg, and injected etHg)? Is it possible that instead of helping to prevent a plausible (unperceived) fish-meHg associated neurocognitive delay we may inadvertently arouse panic surrounding Hg exposure and disrupt subsistence fish eating habits (necessary for survival) and life-saving vaccination programs (required by public health authorities)? These questions characterize the incompleteness of information related on the various chemical forms of Hg exposure and the need to convey messages that do not disrupt nutritional balance and disease prevention policies directed at Amazonian subsistence communities. PMID- 20948938 TI - Acetaldehyde removal from indoor air through chemical absorption using L cysteine. AB - The irreversible removal of acetaldehyde from indoor air via a chemical reaction with amino acids was investigated. To compare effectiveness, five types of amino acid (glycine, l-lysine, l-methionine, l-cysteine, and l-cystine) were used as the reactants. First, acetaldehyde-laden air was introduced into aqueous solutions of each amino acid and the removal abilities were compared. Among the five amino acids, l-cysteine solution showed much higher removal efficiency, while the other amino acids solutions didn't show any significant differences from the removal efficiency of water used as a control. Next, as a test of the removal abilities of acetaldehyde by semi-solid l-cysteine, a gel containing l cysteine solution was put in a fluororesin bag filled with acetaldehyde gas, and the change of acetaldehyde concentration was measured. The l-cysteine-containing gel removed 80% of the acetaldehyde in the air within 24 hours. The removal ability likely depended on the unique reaction whereby acetaldehyde and l cysteine rapidly produce 2-methylthiazolidine-4-carboxylic acid. These results suggested that the reaction between acetaldehyde and l-cysteine has possibilities for irreversibly removing toxic acetaldehyde from indoor air. PMID- 20948940 TI - Comparison of laboratory and field remote sensing methods to measure forage quality. AB - Recent research in range ecology has emphasized the importance of forage quality as a key indicator of rangeland condition. However, we lack tools to evaluate forage quality at scales appropriate for management. Using canopy reflectance data to measure forage quality has been conducted at both laboratory and field levels separately, but little work has been conducted to evaluate these methods simultaneously. The objective of this study is to find a reliable way of assessing grassland quality through measuring forage chemistry with reflectance. We studied a mixed grass ecosystem in Grasslands National Park of Canada and surrounding pastures, located in southern Saskatchewan. Spectral reflectance was collected at both in-situ field level and in the laboratory. Vegetation samples were collected at each site, sorted into the green grass portion, and then sent to a chemical company for measuring forage quality variables, including protein, lignin, ash, moisture at 135 degrees C, Neutral Detergent Fiber (NDF), Acid Detergent Fiber (ADF), Total Digestible, Digestible Energy, Net Energy for Lactation, Net Energy for Maintenance, and Net Energy for Gain. Reflectance data were processed with the first derivative transformation and continuum removal method. Correlation analysis was conducted on spectral and forage quality variables. A regression model was further built to investigate the possibility of using canopy spectral measurements to predict the grassland quality. Results indicated that field level prediction of protein of mixed grass species was possible (r2 = 0.63). However, the relationship between canopy reflectance and the other forage quality variables was not strong. PMID- 20948939 TI - Aging images as a motivational trigger for smoking cessation in young women. AB - Recruiting adolescents into smoking cessation programs has been challenging, and there is a lack of effective smoking cessation interventions for this age group. We aimed to assess whether the approach of using aging images can be used to recruit young, female smokers for a smoking cessation course. In this study, 853 14- to 18-year-old subjects were photographed (2006-2007). After software-aided aging, the images evoked strong emotions, especially in subjects with an advanced motivational stage to quit. Twenty-four percent of current smokers reported that the aging images increased their motivation to quit smoking (pre-contemplation: 8%; contemplation: 32%; and preparation: 71%). In multivariate analyses, the aged images had a high motivational impact to quit smoking that was associated with an increased readiness to stop smoking and the individual's assessment of the aging images as shocking, but not with the number of previous attempts to quit and the assessment of the pictures as realistic. However, it was not possible to recruit the study population for a smoking cessation course. We concluded that aging images are a promising intervention for reaching young women and increasing their motivation to stop smoking. However, smoking cessation courses may not be appropriate for this age group: none of the recruits agreed to take a cessation course. PMID- 20948941 TI - Is malnutrition associated with crowding in permanent dentition? AB - Evidence suggests that energy-protein malnutrition is associated with impaired growth and development of facial bones. The objective of this study was to investigate the association between nutritional status and reduced space for dental eruption (crowding) in permanent dentition. A cross-sectional study with probabilistic sampling design was used. We evaluated 2,060 students aged 12 to 15 years enrolled in schools in the northeast of Brazil. Crowding was defined according to World Health Organization (WHO) as misalignment of teeth due to lack of space for them to erupt in the correct position. Nutritional status was evaluated by means of body mass index and height-for-age, using the WHO's reference curves. Parents and adolescents responded to a questionnaire about demographic, socioeconomic, biological and behavioral characteristics. The associations were estimated by odds ratio (OR) in multivariate logistic regression analysis (alpha = 0.05). Confounding and effect-modification were taken into account. An association between low height-for-age (z-score < -1SD) and crowding was only observed in adolescents with a prolonged history of mouth breathing (OR = 3.1). No association was observed between underweight and crowding. Malnutrition is related to crowding in permanent dentition among mouth breathing adolescents. Policy actions aimed at reducing low height-for-age and unhealthy oral habits are strongly recommended. However, further studies are needed to increase the consistency of these findings and improve understanding of the subject. PMID- 20948942 TI - Time-series MODIS image-based retrieval and distribution analysis of total suspended matter concentrations in Lake Taihu (China). AB - Although there has been considerable effort to use remotely sensed images to provide synoptic maps of total suspended matter (TSM), there are limited studies on universal TSM retrieval models. In this paper, we have developed a TSM retrieval model for Lake Taihu using TSM concentrations measured in situ and a time series of quasi-synchronous MODIS 250 m images from 2005. After simple geometric and atmospheric correction, we found a significant relationship (R = 0.8736, N = 166) between in situ measured TSM concentrations and MODIS band normalization difference of band 3 and band 1. From this, we retrieved TSM concentrations in eight regions of Lake Taihu in 2007 and analyzed the characteristic distribution and variation of TSM. Synoptic maps of model estimated TSM of 2007 showed clear geographical and seasonal variations. TSM in Central Lake and Southern Lakeshore were consistently higher than in other regions, while TSM in East Taihu was generally the lowest among the regions throughout the year. Furthermore, a wide range of TSM concentrations appeared from winter to summer. TSM in winter could be several times that in summer. PMID- 20948943 TI - Adaptation to impacts of climate change on aeroallergens and allergic respiratory diseases. AB - Climate change has the potential to have many significant impacts on aeroallergens such as pollen and mould spores, and therefore related diseases such as asthma and allergic rhinitis. This paper critically reviews this topic, with a focus on the potential adaptation measures that have been identified to date. These are aeroallergen monitoring; aeroallergen forecasting; allergenic plant management; planting practices and policies; urban/settlement planning; building design and heating, ventilating, and air-conditioning (HVAC); access to health care and medications; education; and research. PMID- 20948944 TI - Micro data analysis of medical and long-term care utilization among the elderly in Japan. AB - Japan is currently experiencing the most rapid population aging among all OECD countries. Increasing expenditures on medical care in Japan have been attributed to the aging of the population. Authors in the recent debate on end-of-life care and long-term care (LTC) cost in the United States and Europe have attributed time to death and non-medical care cost for the aged as a source of rising expenditures. In this study, we analyzed a large sample of local public insurance claim data to investigate medical and LTC expenditures in Japan. We examined the impact of aging, time to death, survivorship, and use of LTC on medical care expenditure for people aged 65 and above. On the basis of these findings, we conclude that age is a contributing factor to the rising expenditures on LTC, and that the contribution of aging to rising medical care expenditures should be distinguished according to survivorship. PMID- 20948945 TI - Can intensive use of alcohol-based hand rubs lead to passive alcoholization? AB - Hand disinfection with alcohols-based hand rubs (ABHRs) are known to be the most effective measure to prevent nosocomial infections in healthcare. ABHRs contain on average 70% by weight of one or more alcohols. During the hand rubbing procedure, users are exposed to these alcohols not only through dermal contact, but also via inhalation, due to the physical and chemical properties of alcohols volatilizing from alcoholic solutions or gels into the air. Ethanol ingestion is well known to increase risks of several diseases (affecting the pancreas, liver, cardiovascular system...), but there is a lack of knowledge about the effects of exposure to other alcohols (including n- or isopropanol) via inhalation and dermal contact, despite the worldwide use of ABHRs. This work aims at discussing possible health effects related to unintentional alcoholization (via inhalation and dermal contact) from professional ABHR usage to suggest the need for more research in this area (but not to question the value of ABHRs). Based upon an average of 30 hand rubbings per healthcare professional per day, it can be assumed that a healthcare worker may be exposed to a maximum 5,500 mg/m(3) per work shift, five times above the recommended occupational time weighted average limit. Thus, in order to answer the question posed in the title, studies on spatial and temporal variability of alcohol emission from ABHRs in real world situations and studies on certain high risk individuals are needed. PMID- 20948946 TI - Evaporative gasoline emissions and asthma symptoms. AB - Attached garages are known to be associated with indoor air volatile organic compounds (VOCs). This study looked at indoor exposure to VOCs presumably from evaporative emissions of gasoline. Alaskan gasoline contains 5% benzene making benzene a marker for gasoline exposure. A survey of randomly chosen houses with attached garages was done in Anchorage Alaska to determine the exposure and assess respiratory health. Householders were asked to complete a health survey for each person and a household survey. They monitored indoor air in their primary living space for benzene, toluene, ethylbenzene and xylenes for one week using passive organic vapor monitoring badges. Benzene levels in homes ranged from undetectable to 58 parts per billion. The median benzene level in 509 homes tested was 2.96 ppb. Elevated benzene levels in the home were strongly associated with small engines and gasoline stored in the garage. High concentrations of benzene in gasoline increase indoor air levels of benzene in residences with attached garages exposing people to benzene at levels above ATSDR's minimal risk level. Residents reported more severe symptoms of asthma in the homes with high gasoline exposure (16%) where benzene levels exceeded the 9 ppb. PMID- 20948947 TI - Promotion of physical activity using point-of-decision prompts in Berlin underground stations. AB - To evaluate point-of-decision prompts in the promotion of stair use in Germany, motivational posters were placed at three underground stations in Berlin. The proportion of passengers using stairs or stairways was counted before, during installation, and two weeks after removal of posters. In total, 5,467 passersby were counted. Stair use increased significantly in women, but not in men. The present pilot study thereby shows that the use of point-of-decision prompts is also feasible in Germany and it provides some evidence of effectiveness. Methodologically rigorous studies are warranted to confirm these findings. PMID- 20948948 TI - The more the worse: the grade of noise-induced hearing loss associates with the severity of tinnitus. AB - Tinnitus disturbs lives and negatively affects the quality of life of about 2% of the adult world population. Research has shown that the main cause of tinnitus is hearing loss. To analyze a possible association of the degree of hearing loss with the severity of tinnitus, we have performed a retrospective study using admission data on 531 patients suffering from chronic tinnitus. We have found that 83% of our tinnitus patients had a high frequency hearing loss corresponding to a noise-induced hearing loss (NIHL). There was a significant correlation between the mean hearing loss and the tinnitus loudness (p < 0.0001). Interestingly, patients suffering from decompensated chronic tinnitus had a greater degree of hearing loss than the patients with compensated form of tinnitus. In addition, we demonstrate that the degree of hearing loss positively correlates with the two subscales ("intrusiveness" and "auditory perceptional difficulties") of the Tinnitus Questionnaire. Our retrospective study provides indirect evidence supporting the hypothesis that the degree of noise-induced hearing loss influences the severity of tinnitus. PMID- 20948949 TI - Predictors of indoor air concentrations in smoking and non-smoking residences. AB - Indoor concentrations of air pollutants (benzene, toluene, formaldehyde, acetaldehyde, acrolein, nitrogen dioxide, particulate matter, elemental carbon and ozone) were measured in residences in Regina, Saskatchewan, Canada. Data were collected in 106 homes in winter and 111 homes in summer of 2007, with 71 homes participating in both seasons. In addition, data for relative humidity, temperature, air exchange rates, housing characteristics and occupants' activities during sampling were collected. Multiple linear regression analysis was used to construct season-specific models for the air pollutants. Where smoking was a major contributor to indoor concentrations, separate models were constructed for all homes and for those homes with no cigarette smoke exposure. The housing characteristics and occupants' activities investigated in this study explained between 11% and 53% of the variability in indoor air pollutant concentrations, with ventilation, age of home and attached garage being important predictors for many pollutants. PMID- 20948950 TI - Comparative assessment of soil contamination by lead and heavy metals in riparian and agricultural areas (southern Quebec, Canada). AB - Soils contaminated with hydrocarbons (C(10)-C(50)), PAHS, lead and other heavy metals were recently found in the banks of two major rivers in southern Quebec. Alluvial soils are contaminated over a distance of 100 kilometers. Eight sampling sites, including some located in agriculture areas (farm woodlots) have been selected to compare air pollution (aerosol fallout and rainout) and river pollution values. The concentrations detected in soil profiles for As, Cd and Pb vary between 3.01 to 37.88 mg kg(-1) (As), 0.11 to 0.81 mg kg(-1) (Cd) 12.32 to 149.13 mg kg(-1) (Pb). These metallic elements are considered highly toxic and can harm wildlife and human health at high levels. The maximum concentration of Pb (149.13 mg kg(-1)) in soils of the riparian zone is twelve times higher than the average Pb concentration found in a natural state evaluated at 15.3 mg kg(-1) (SD 17.5). Pb concentrations in soils of agricultural areas (woodland control sites) range between 12 and 22 mg kg(-1), and given that these values are recorded in surrounding cultivated land, the issue of the quality of agricultural products (crops and forage) to feed livestock or destined for human consumption must be further addressed in detail. PMID- 20948951 TI - Factors associated to endemic dental fluorosis in Brazilian rural communities. AB - The present paper examines the relationship between hydrochemical characteristics and endemic dental fluorosis, controlling for variables with information on an individual level. An epidemiological survey was carried out in seven rural communities in two municipalities in the state of Minas Gerais, Brazil. The Thystrup & Fejerskov index was employed by a single examiner for the diagnosis of dental fluorosis. A sampling campaign of deep groundwater in the rural communities of interest was carried out concomitantly to the epidemiological survey for the determination of physiochemical parameters. Multilevel modeling of 276 individuals from seven rural communities was achieved using the non-linear logit link function. Parameters were estimated using the restricted maximum likelihood method. Analysis was carried out considering two response variables: presence (TF 1 to 9) or absence (TF = 0) of any degree of dental fluorosis; and presence (TF >= 5-with loss of enamel structure) or absence of severe dental fluorosis (TF <= 4-with no loss of enamel structure). Hydrogeological analyses revealed that dental fluorosis is influenced by the concentration of fluoride (OR = 2.59 CI95% 1.07-6.27; p = 0.073) and bicarbonate (OR = 1.02 CI95% 1.01-1.03; p = 0.060) in the water of deep wells. No other variable was associated with this prevalence (p > 0.05). More severe dental fluorosis (TF >= 5) was only associated with age group (p < 0.05). No other variable was associated to the severe dental fluorosis (p > 0.05). Dental fluorosis was found to be highly prevalent and severe. A chemical element besides fluoride was found to be associated (p > 0.05) to the prevalence of dental fluorosis, although this last finding should be interpreted with caution due to its p value. PMID- 20948952 TI - Lime-based sorbents for high-temperature CO2 capture--a review of sorbent modification methods. AB - This paper presents a review of the research on CO(2) capture by lime-based looping cycles undertaken at CanmetENERGY's (Ottawa, Canada) research laboratories. This is a new and very promising technology that may help in mitigation of global warming and climate change caused primarily by the use of fossil fuels. The intensity of the anticipated changes urgently requires solutions such as more cost-effective technologies for CO(2) capture. This new technology is based on the use of lime-based sorbents in a dual fluidized bed combustion (FBC) reactor which contains a carbonator-a unit for CO(2) capture, and a calciner-a unit for CaO regeneration. However, even though natural materials are cheap and abundant and very good candidates as solid CO(2) carriers, their performance in a practical system still shows significant limitations. These limitations include rapid loss of activity during the capture cycles, which is a result of sintering, attrition, and consequent elutriation from FBC reactors. Therefore, research on sorbent performance is critical and this paper reviews some of the promising ways to overcome these shortcomings. It is shown that reactivation by steam/water, thermal pre-treatment, and doping simultaneously with sorbent reforming and pelletization are promising potential solutions to reduce the loss of activity of these sorbents over multiple cycles of use. PMID- 20948953 TI - The global challenge of antimicrobial resistance: insights from economic analysis. AB - The prevalence of antimicrobial resistance (AR) limits the therapeutic options for treatment of infections, and increases the social benefit from disease prevention. Like an environmental resource, antimicrobials require stewardship. The effectiveness of an antimicrobial agent is a global public good. We argue for greater use of economic analysis as an input to policy discussion about AR, including for understanding the incentives underlying health behaviors that spawn AR, and to supplement other methods of tracing the evolution of AR internationally. We also discuss integrating antimicrobial stewardship into global health governance. PMID- 20948954 TI - Economic evaluation of lifestyle interventions for preventing diabetes and cardiovascular diseases. AB - Lifestyle interventions (i.e., diet and/or physical activity) are effective in delaying or preventing the onset of diabetes and cardiovascular disease. However, policymakers must know the cost-effectiveness of such interventions before implementing them at the large-scale population level. This review discusses various issues (e.g., characteristics, modeling, and long-term effectiveness) in the economic evaluation of lifestyle interventions for the primary and secondary prevention of diabetes and cardiovascular disease. The diverse nature of lifestyle interventions, i.e., type of intervention, means of provision, target groups, setting, and methodology, are the main obstacles to comparing evaluation results. However, most lifestyle interventions are among the intervention options usually regarded as cost-effective. Diabetes prevention programs, such as interventions starting with targeted or universal screening, childhood obesity prevention, and community-based interventions, have reported favorable cost effectiveness ratios. PMID- 20948957 TI - Microfungi in drinking water: the role of the frog Litoria caerulea. AB - Microfungi were recovered from all parts of a municipal water distribution system in sub-tropical Australia even though virtually no colony-forming units were recovered from the treated water as it left the treatment plant. A study was then undertaken to determine the potential sources of the microfungal population in the distribution system. Observation of frogs (Litoria caerulea) using the internal infrastructure of a reservoir as diurnal sleeping places, together with observation of visible microfungal growth on their faecal pellets, led to an investigation of the possible involvement of this animal. Old faecal pellets were collected and sporulating fungal colonies growing on their surfaces were identified. Fresh faecal pellets were collected and analysed for microfungal content, and skin swabs were analysed for yeasts. It was found that the faeces and skin of L. caerulea carried large numbers of yeasts as well as spores of various filamentous fungal genera. While there are many possible sources of microfungal contamination of municipal drinking water supplies, this study has revealed that the Australian green tree frog L. caerulea is one of the important sources of filamentous microfungi and yeasts in water storage reservoirs in sub tropical Australia where the animal is endemic. PMID- 20948955 TI - Relation between temperature and mortality in thirteen Spanish cities. AB - In this study we examined the shape of the association between temperature and mortality in 13 Spanish cities representing a wide range of climatic and socio demographic conditions. The temperature value linked with minimum mortality (MMT) and the slopes before and after the turning point (MMT) were calculated. Most cities showed a V-shaped temperature-mortality relationship. MMTs were generally higher in cities with warmer climates. Cold and heat effects also depended on climate: effects were greater in hotter cities but lesser in cities with higher variability. The effect of heat was greater than the effect of cold. The effect of cold and MMT was, in general, greater for cardio-respiratory mortality than for total mortality, while the effect of heat was, in general, greater among the elderly. PMID- 20948956 TI - Exploring variation and predictors of residential fine particulate matter infiltration. AB - Although individuals spend the majority of their time indoors, most epidemiological studies estimate personal air pollution exposures based on outdoor levels. This almost certainly results in exposure misclassification as pollutant infiltration varies between homes. However, it is often not possible to collect detailed measures of infiltration for individual homes in large-scale epidemiological studies and thus there is currently a need to develop models that can be used to predict these values. To address this need, we examined infiltration of fine particulate matter (PM(2.5)) and identified determinants of infiltration for 46 residential homes in Toronto, Canada. Infiltration was estimated using the indoor/outdoor sulphur ratio and information on hypothesized predictors of infiltration were collected using questionnaires and publicly available databases. Multiple linear regression was used to develop the models. Mean infiltration was 0.52 +/- 0.21 with no significant difference across heating and non-heating seasons. Predictors of infiltration were air exchange, presence of central air conditioning, and forced air heating. These variables accounted for 38% of the variability in infiltration. Without air exchange, the model accounted for 26% of the variability. Effective modelling of infiltration in individual homes remains difficult, although key variables such as use of central air conditioning show potential as an easily attainable indicator of infiltration. PMID- 20948958 TI - Aging risk and health care expenditure in Korea. AB - This paper analyzes the impact of population aging on health care expenditures in Korea. Examination of the age-expenditure profile reveals that health care resources are allocated more for the older cohort of population over time, suggesting significant growth of health care expenditures due to population aging. We contend, however, that population aging is considered as a parameter rather than an independent variable to explain rising health care expenditures. This paper shows that population aging is not found to be a significant determinant of health care expenditures according to the econometric analysis using OECD health data and time-series data for Korea. Using the components decomposition method, which measures the contribution of each component of health care expenditure, we estimate that population aging contributes only less than 10 percent. PMID- 20948959 TI - Noise in schools: a holistic approach to the issue. AB - Much of the research evidence relating to the physical learning environment of schools is inconclusive, contradictory or incomplete. Nevertheless, within this confusing area, research from a number of disciplines, using a range of methodologies, points to the negative impact of noise on students' learning. In this paper, drawing on our systematic review of learning environments we review the weight of evidence in relation to noise, considering what implications the results of these studies have for the design and use of learning spaces in schools. We make four key points. Firstly that noise over a given level does appear to have a negative impact on learning. Secondly that beneath these levels noise may or may not be problematic, depending on the social, cultural and pedagogical expectations of the students and teachers. Thirdly we argue that when noise is deemed to be a difficulty, this finding cannot simply be translated into design prescriptions. The reasons for this indeterminacy include differing understandings of the routes through which noise produces learning deficits, as well as relationships between noise and other elements of the environment, particularly the impacts of physical solutions to noise problems. Finally, we suggest that solutions to noise problems will not be produced by viewing noise in isolation, or even as part of the physical environment, but through participatory approaches to understanding and adapting the structure, organisation and use of learning spaces in schools. PMID- 20948960 TI - Do questions reflecting indoor air pollutant exposure from a questionnaire predict direct measure of exposure in owner-occupied houses? AB - Home characteristic questions are used in epidemiological studies and clinical settings to assess potentially harmful exposures in the home. The objective of this study was to determine whether questionnaire-reported home characteristics can predict directly measured pollutants. Sixty home inspections were conducted on a subsample of the 2006 population-based Toronto Child Health Evaluation Questionnaire. Indoor/outdoor air and settled dust samples were analyzed. Mean Fel d 1 was higher (p < 0.0001) in homes with a cat (450.58 MUg/g) versus without (22.28 MUg/g). Mean indoor NO(2) was higher (p = 0.003) in homes with gas stoves (14.98 ppb) versus without (8.31 ppb). Self-reported musty odours predicted higher glucan levels (10554.37 MUg/g versus 6308.58 MUg/g, p = 0.0077). Der f 1 was predicted by the home's age, but not by reports of carpets, and was higher in homes with mean relative humidity > 50% (61.30 MUg/g, versus 6.24 MUg/g, p = 0.002). Self-reported presence of a cat, a gas stove, musty odours, mice, and the home's age and indoor relative humidity over 50% predicted measured indoor levels of cat allergens, NO(2), fungal glucan, mouse allergens and dust mite allergens, respectively. These results are helpful for understanding the significance of indoor exposures ascertained by self-reporting in large epidemiological studies and also in the clinical setting. PMID- 20948961 TI - Toxicity of the herbicide atrazine: effects on lipid peroxidation and activities of antioxidant enzymes in the freshwater fish Channa punctatus (Bloch). AB - The present study was undertaken to evaluate the toxicity and effects of a commercial formulation of the herbicide atrazine (Rasayanzine) on lipid peroxidation and antioxidant enzyme system in the freshwater air breathing fish Channa punctatus. The 12, 24, 48, 72 and 96 h LC(50) of atrazine, calculated by probit analysis, were determined to be 77.091, 64.053, 49.100, 44.412 and 42.381 mg.L(-1), respectively, in a semi static system with significant difference (p < 0.05) in LC(10-90) values obtained for different times of exposure. In addition to concentration and time dependent decrease in mortality rate, stress signs in the form of behavioral changes were also observed in response to the test chemical. In fish exposed for 15 days to different sublethal concentrations of the herbicide (1/4 LC(50) = ~10.600 mg.L(-1), 1/8 LC(50) = ~5.300 mg.L(-1) and 1/10 LC(50) = ~4.238 mg.L(-1)) induction of oxidative stress in the liver was evidence by increased lipid peroxidation levels. The antioxidants superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GR) responded positively in a concentration dependent pattern, thus, suggesting the use of these antioxidants as potential biomarkers of toxicity associated with contaminations exposure in freshwater fishes. PMID- 20948962 TI - Illusory sensation of movement induced by repetitive transcranial magnetic stimulation. AB - Human movement sense relies on both somatosensory feedback and on knowledge of the motor commands used to produce the movement. We have induced a movement illusion using repetitive transcranial magnetic stimulation over primary motor cortex and dorsal premotor cortex in the absence of limb movement and its associated somatosensory feedback. Afferent and efferent neural signalling was abolished in the arm with ischemic nerve block, and in the leg with spinal nerve block. Movement sensation was assessed following trains of high-frequency repetitive transcranial magnetic stimulation applied over primary motor cortex, dorsal premotor cortex, and a control area (posterior parietal cortex). Magnetic stimulation over primary motor cortex and dorsal premotor cortex produced a movement sensation that was significantly greater than stimulation over the control region. Movement sensation after dorsal premotor cortex stimulation was less affected by sensory and motor deprivation than was primary motor cortex stimulation. We propose that repetitive transcranial magnetic stimulation over dorsal premotor cortex produces a corollary discharge that is perceived as movement. PMID- 20948963 TI - Knowledge, health seeking behavior and perceived stigma towards tuberculosis among tuberculosis suspects in a rural community in southwest Ethiopia. AB - BACKGROUND: Perceived stigma and lack of awareness could contribute to the late presentation and low detection rate of tuberculosis (TB). We conducted a study in rural southwest Ethiopia among TB suspects to assess knowledge about and stigma towards TB and their health seeking behavior. METHODS: A community based cross sectional survey was conducted from February to March 2009 in the Gilgel Gibe field research area. Any person 15 years and above with cough for at least 2 weeks was considered a TB suspect and included in the study. Data were collected by trained personnel using a pretested structured questionnaire. Logistic regression analysis was done using SPSS 15.0 statistical software. RESULTS: Of the 476 pulmonary TB suspects, 395 (83.0%) had ever heard of TB; "evil eye" (50.4%) was the commonly mentioned cause of TB. Individuals who could read and write were more likely to be aware about TB [(crude OR = 2.98, (95%CI: 1.25, 7.08)] and more likely to know that TB is caused by a microorganism [(adjusted OR = 3.16, (95%CI: 1.77, 5.65)] than non-educated individuals. Males were more likely to know the cause of TB [(adjusted OR = 1.92, (95%CI: 1.22, 3.03)] than females. 51.3% of TB suspects perceived that other people would consider them inferior if they had TB. High stigma towards TB was reported by 199(51.2%). 220 (46.2%) did not seek help for their illness. Individuals who had previous anti-TB treatment were more likely to have appropriate health seeking behavior [(adjusted OR = 3.65, (95%CI: 1.89, 7.06)] than those who had not. CONCLUSION: There was little knowledge about TB in the Gilgel Gibe field research area. We observed inappropriate health seeking behavior and stigma towards TB. TB control programs in Ethiopia should educate rural communities, particularly females and non educated individuals, about the cause and the importance of early diagnosis and treatment of TB. PMID- 20948964 TI - Near-membrane dynamics and capture of TRPM8 channels within transient confinement domains. AB - BACKGROUND: The cold and menthol receptor, TRPM8, is a non-selective cation channel expressed in a subset of peripheral neurons that is responsible for neuronal detection of environmental cold stimuli. It was previously shown that members of the transient receptor potential (TRP) family of ion channels are translocated toward the plasma membrane (PM) in response to agonist stimulation. Because the spatial and temporal dynamics of cold receptor cell-surface residence may determine neuronal activity, we hypothesized that the movement of TRPM8 to and from the PM might be a regulated process. Single particle tracking (SPT) is a useful tool for probing the organization and dynamics of protein constituents in the plasma membrane. METHODOLOGY/PRINCIPAL FINDINGS: We used SPT to study the receptor dynamics and describe membrane/near-membrane behavior of particles containing TRPM8-EGFP in transfected HEK-293T and F-11 cells. Cells were imaged using total internal reflection fluorescence (TIRF) microscopy and the 2D and 3D trajectories of TRPM8 molecules were calculated by analyzing mean-square particle displacement against time. Four characteristic types of motion were observed: stationary mode, simple Brownian diffusion, directed motion, and confined diffusion. In the absence of cold or menthol to activate the channel, most TRPM8 particles move in network covering the PM, periodically lingering for 2-8 s in confined microdomains of about 800 nm radius. Removing cholesterol with methyl beta-cyclodextrin (MbetaCD) stabilizes TRPM8 motion in the PM and is correlated with larger TRPM8 current amplitude that results from an increase in the number of available channels without a change in open probability. CONCLUSIONS/SIGNIFICANCE: These results reveal a novel mechanism for regulating TRPM8 channel activity, and suggest that PM dynamics may play an important role in controlling electrical activity in cold-sensitive neurons. PMID- 20948965 TI - Deciphering heterogeneity in pig genome assembly Sscrofa9 by isochore and isochore-like region analyses. AB - BACKGROUND: The isochore, a large DNA sequence with relatively small GC variance, is one of the most important structures in eukaryotic genomes. Although the isochore has been widely studied in humans and other species, little is known about its distribution in pigs. PRINCIPAL FINDINGS: In this paper, we construct a map of long homogeneous genome regions (LHGRs), i.e., isochores and isochore-like regions, in pigs to provide an intuitive version of GC heterogeneity in each chromosome. The LHGR pattern study not only quantifies heterogeneities, but also reveals some primary characteristics of the chromatin organization, including the followings: (1) the majority of LHGRs belong to GC-poor families and are in long length; (2) a high gene density tends to occur with the appearance of GC-rich LHGRs; and (3) the density of LINE repeats decreases with an increase in the GC content of LHGRs. Furthermore, a portion of LHGRs with particular GC ranges (50% 51% and 54%-55%) tend to have abnormally high gene densities, suggesting that biased gene conversion (BGC), as well as time- and energy-saving principles, could be of importance to the formation of genome organization. CONCLUSION: This study significantly improves our knowledge of chromatin organization in the pig genome. Correlations between the different biological features (e.g., gene density and repeat density) and GC content of LHGRs provide a unique glimpse of in silico gene and repeats prediction. PMID- 20948966 TI - Genome-wide data-mining of candidate human splice translational efficiency polymorphisms (STEPs) and an online database. AB - BACKGROUND: Variation in pre-mRNA splicing is common and in some cases caused by genetic variants in intronic splicing motifs. Recent studies into the insulin gene (INS) discovered a polymorphism in a 5' non-coding intron that influences the likelihood of intron retention in the final mRNA, extending the 5' untranslated region and maintaining protein quality. Retention was also associated with increased insulin levels, suggesting that such variants--splice translational efficiency polymorphisms (STEPs)--may relate to disease phenotypes through differential protein expression. We set out to explore the prevalence of STEPs in the human genome and validate this new category of protein quantitative trait loci (pQTL) using publicly available data. METHODOLOGY/PRINCIPAL FINDINGS: Gene transcript and variant data were collected and mined for candidate STEPs in motif regions. Sequences from transcripts containing potential STEPs were analysed for evidence of splice site recognition and an effect in expressed sequence tags (ESTs). 16 publicly released genome-wide association data sets of common diseases were searched for association to candidate polymorphisms with HapMap frequency data. Our study found 3324 candidate STEPs lying in motif sequences of 5' non-coding introns and further mining revealed 170 with transcript evidence of intron retention. 21 potential STEPs had EST evidence of intron retention or exon extension, as well as population frequency data for comparison. CONCLUSIONS/SIGNIFICANCE: Results suggest that the insulin STEP was not a unique example and that many STEPs may occur genome-wide with potentially causal effects in complex disease. An online database of STEPs is freely accessible at http://dbstep.genes.org.uk/. PMID- 20948967 TI - Mutant INS-gene induced diabetes of youth: proinsulin cysteine residues impose dominant-negative inhibition on wild-type proinsulin transport. AB - Recently, a syndrome of Mutant INS-gene-induced Diabetes of Youth (MIDY, derived from one of 26 distinct mutations) has been identified as a cause of insulin deficient diabetes, resulting from expression of a misfolded mutant proinsulin protein in the endoplasmic reticulum (ER) of insulin-producing pancreatic beta cells. Genetic deletion of one, two, or even three alleles encoding insulin in mice does not necessarily lead to diabetes. Yet MIDY patients are INS-gene heterozygotes; inheritance of even one MIDY allele, causes diabetes. Although a favored explanation for the onset of diabetes is that insurmountable ER stress and ER stress response from the mutant proinsulin causes a net loss of beta cells, in this report we present three surprising and interlinked discoveries. First, in the presence of MIDY mutants, an increased fraction of wild-type proinsulin becomes recruited into nonnative disulfide-linked protein complexes. Second, regardless of whether MIDY mutations result in the loss, or creation, of an extra unpaired cysteine within proinsulin, Cys residues in the mutant protein are nevertheless essential in causing intracellular entrapment of co-expressed wild-type proinsulin, blocking insulin production. Third, while each of the MIDY mutants induces ER stress and ER stress response; ER stress and ER stress response alone appear insufficient to account for blockade of wild-type proinsulin. While there is general agreement that ultimately, as diabetes progresses, a significant loss of beta cell mass occurs, the early events described herein precede cell death and loss of beta cell mass. We conclude that the molecular pathogenesis of MIDY is initiated by perturbation of the disulfide coupled folding pathway of wild-type proinsulin. PMID- 20948968 TI - Inhibition of the nuclear factor-kappaB pathway prevents beta cell failure and diet induced diabetes in Psammomys obesus. AB - BACKGROUND: High doses of anti-inflammatory drugs, such as aspirin and salicylates, improve glucose metabolism in insulin resistant and type 2 diabetic patients. It has also been shown that the glucose lowering effect is related to the unspecific ability of these drugs to inhibit inhibitor kinasebeta (IKKbeta). In this study we have investigated the effect of a selective IKKbeta-inhibitor on beta cell survival and the prevention of diet induced type 2 diabetes in the gerbil Psammomys obesus (P. obesus). METHODOLOGY/PRINCIPAL FINDINGS: P. obesus were fed a diabetes inducing high energy diet for one month in the absence or presence of the IKKbeta-inhibitor. Body mass, blood glucose, HbA(1C), insulin production and pancreatic insulin stores were measured. The effects on beta cell survival were also studied in INS-1 cells and primary islets. The cells were exposed to IL-1beta and subsequently reactive oxygen species, insulin release and cell death were measured in the absence or presence of the IKKbeta-inhibitor. In primary islets and beta cells, IL-1beta induced the production of reactive oxygen species, reduced insulin production and increased beta cell death, which were all reversed by pre-treatment with the IKKbeta-inhibitor. In P. obesus the IKKbeta inhibitor prevented the development of hyperglycaemia and hyperinsulinaemia, and maintained pancreatic insulin stores with no effect on body weight. CONCLUSIONS/SIGNIFICANCE: Inhibition of IKKbeta activity prevents diet-induced diabetes in P. obesus and inhibits IL-1beta induced reactive oxygen species, loss of insulin production and beta cell death in vitro. PMID- 20948969 TI - Functional analysis of phosphorylation on Saccharomyces cerevisiae syntaxin 1 homologues Sso1p and Sso2p. AB - BACKGROUND: The Saccharomyces cerevisiae syntaxin1 homologues Sso1p and Sso2p perform an essential function in membrane fusion in exocytosis. While deletion of either SSO1 or SSO2 causes no obvious phenotype in vegetatively grown cells, deletion of both genes is lethal. In sporulating diploid S. cerevisiae cells only Sso1p, but not Sso2p, is needed for membrane fusion during prospore membrane formation. Mass spectrometry and in vivo labeling data suggest that serines 23, 24, and 79 in Sso1p and serines 31 and 34 in Sso2p can be phosphorylated in vivo. Here we set out to assess the contribution of phosphorylation on Sso protein in vivo function. PRINCIPAL FINDINGS: Different mutant versions of SSO1 and SSO2 were generated to target the phosphorylation sites in Sso1p and Sso2p. Basal or overexpression of phospho-mimicking or putative non-phosphorylated Sso1p or Sso2p mutants resulted in no obvious growth phenotype. However, S79A and S79E mutations caused a mild defect in the ability of Sso1p to complement the temperature sensitive growth phenotype of sso2-1 sso1Delta cells. Combination of all mutations did not additionally compromise Sso1p in vivo function. When compared to the wild type SSO1 and SSO2, the phosphoamino acid mutants displayed similar genetic interactions with late acting sec mutants. Furthermore, diploid cells expressing only the mutant versions of Sso1p had no detectable sporulation defects. In addition to sporulation, also pseudohyphal and invasive growth modes are regulated by the availability of nutrients. In contrast to sporulating diploid cells, deletion of SSO1 or SSO2, or expression of the phospho-mutant versions of SSO1 or SSO2 as the sole copies of SSO genes caused no defects in haploid or diploid pseudohyphal and invasive growth. CONCLUSIONS: The identified phosphorylation sites do not significantly contribute to the in vivo functionality of Sso1p and Sso2p in S. cerevisiae. PMID- 20948970 TI - Less is More: How manipulative features affect children's learning from picture books. AB - Picture books are ubiquitous in young children's lives and are assumed to support children's acquisition of information about the world. Given their importance, relatively little research has directly examined children's learning from picture books. We report two studies examining children's acquisition of labels and facts from picture books that vary on two dimensions: iconicity of the pictures and presence of manipulative features (or "pop-ups"). In Study 1, 20-month-old children generalized novel labels less well when taught from a book with manipulative features than from standard picture books without such elements. In Study 2, 30- and 36-month-old children learned fewer facts when taught from a manipulative picture book with drawings than from a standard picture book with realistic images and no manipulative features. The results of the two studies indicate that children's learning from picture books is facilitated by realistic illustrations, but impeded by manipulative features. PMID- 20948971 TI - Social Capital, Savings, and Educational Performance of Orphaned Adolescents in Sub-Saharan Africa. AB - We examine the impact of social capital on savings and educational performance of orphaned adolescents participating in a family-level economic strengthening program in Uganda. Findings indicate that if given the opportunity, poor families in Uganda will use financial institutions to save for the education of their adolescent youth. Moreover, although the results are mixed, overall, adolescents with higher levels of social capital and social support, including participation in youth groups, are likely to report better saving performance compared to their counterparts with lower levels of social capital and social support. The results point to: (1) the role for family-economic strengthening programs specifically focused on improving the educational outcomes of orphaned adolescents in sub Saharan Africa, and (2) the need for adolescents to be encouraged to participate in youth groups since these groups seem to offer the much needed supportive informal institutional structure for positive adolescent outcomes. PMID- 20948972 TI - The Effects of Survey Administration on Disclosure Rates to Sensitive Items Among Men: A Comparison of an Internet Panel Sample with a RDD Telephone Sample. AB - Research using Internet surveys is an emerging field, yet research on the legitimacy of using Internet studies, particularly those targeting sensitive topics, remains under-investigated. The current study builds on the existing literature by exploring the demographic differences between Internet panel and RDD telephone survey samples, as well as differences in responses with regard to experiences of intimate partner violence perpetration and victimization, alcohol and substance use/abuse, PTSD symptomatology, and social support. Analyses indicated that after controlling for demographic differences, there were few differences between the samples in their disclosure of sensitive information, and that the online sample was more socially isolated than the phone sample. Results are discussed in terms of their implications for using Internet samples in research on sensitive topics. PMID- 20948974 TI - Generalized Additive Models and Inflated Type I Error Rates of Smoother Significance Tests. AB - Generalized additive models (GAMs) have distinct advantages over generalized linear models as they allow investigators to make inferences about associations between outcomes and predictors without placing parametric restrictions on the associations. The variable of interest is often smoothed using a locally weighted regression (LOESS) and the optimal span (degree of smoothing) can be determined by minimizing the Akaike Information Criterion (AIC). A natural hypothesis when using GAMs is to test whether the smoothing term is necessary or if a simpler model would suffice. The statistic of interest is the difference in deviances between models including and excluding the smoothed term. As approximate chi square tests of this hypothesis are known to be biased, permutation tests are a reasonable alternative. We compare the type I error rates of the chi-square test and of three permutation test methods using synthetic data generated under the null hypothesis. In each permutation method a distribution of differences in deviances is obtained from 999 permuted datasets and the null hypothesis is rejected if the observed statistic falls in the upper 5% of the distribution. One test is a conditional permutation test using the optimal span size for the observed data; this span size is held constant for all permutations. This test is shown to have an inflated type I error rate. Alternatively, the span size can be fixed a priori such that the span selection technique is not reliant on the observed data. This test is shown to be unbiased; however, the choice of span size is not clear. A third method is an unconditional permutation test where the optimal span size is selected for observed and permuted datasets. This test is unbiased though computationally intensive. PMID- 20948973 TI - Temperament as a moderator of the relation between neighborhood and children's adjustment. AB - Although proposed by bioecological models, there has been minimal empirical examination of whether children's individual differences moderate neighborhood effects on development. We used an urban community sample (8-12 years, N = 316) to examine interactions among neighborhood characteristics (problems and social organization) and children's temperament (fear, irritability and impulsivity) in predicting psychosocial adjustment. The main effects of neighborhood and temperament on outcomes were consistent with previous research. Findings show that development is challenging in disadvantaged neighborhoods whatever one's temperament, however, some effects of neighborhood were conditioned by temperament, particularly children's fear and irritability. Neighborhood problems were more strongly related to lower social competence for fearful and for less irritable children. Neighborhood problems were more strongly related to higher internalizing problems for low-fear children. Neighborhood social organization was more strongly related to greater social competence for low-fear children. Findings are discussed in relation to "diathesis-stress" and "differential responsiveness" models of temperament. PMID- 20948975 TI - Interferometric Synthetic Aperture Microscopy: Computed Imaging for Scanned Coherent Microscopy. AB - Three-dimensional image formation in microscopy is greatly enhanced by the use of computed imaging techniques. In particular, Interferometric Synthetic Aperture Microscopy (ISAM) allows the removal of out-of-focus blur in broadband, coherent microscopy. Earlier methods, such as optical coherence tomography (OCT), utilize interferometric ranging, but do not apply computed imaging methods and therefore must scan the focal depth to acquire extended volumetric images. ISAM removes the need to scan the focus by allowing volumetric image reconstruction from data collected at a single focal depth. ISAM signal processing techniques are similar to the Fourier migration methods of seismology and the Fourier reconstruction methods of Synthetic Aperture Radar (SAR). In this article ISAM is described and the close ties between ISAM and SAR are explored. ISAM and a simple strip-map SAR system are placed in a common mathematical framework and compared to OCT and radar respectively. This article is intended to serve as a review of ISAM, and will be especially useful to readers with a background in SAR. PMID- 20948976 TI - Association of nuclear localization of a long interspersed nuclear element-1 protein in breast tumors with poor prognostic outcomes. AB - Within healthy human somatic cells, retrotransposition by long interspersed nuclear element-1 (also known as LINE-1 or L1) is thought to be held in check by a variety of mechanisms, including DNA methylation and RNAi. The expression of L1 ORF1 protein, which is rarely found in normal tissue, was assayed using antibodies with a variety of clinical cancer specimens and cancer cell lines. L1 ORF1p expression was detected in nearly all breast tumors that the authors examined, and the protein was also present in a high percentage of ileal carcinoids, bladder, and pancreatic neuroendocrine tumors, as well as in a smaller percentage of prostate and colorectal tumors. Tumors generally demonstrated cytoplasmic L1-ORF1p; however, in several breast cancers, L1-ORF1p was nuclear. Patients with breast tumors displaying nuclear L1-ORF1p had a greater incidence of both local recurrence and distal metastases and also showed poorer overall survival when compared with patients with tumors displaying cytoplasmic L1-ORF1p. These data suggest that expression of L1-ORF1p is widespread in many cancers and that redistribution from cytoplasm to nucleus could be a poor prognostic indicator during breast cancer. High expression and nuclear localization of L1-ORF1p may result in a higher rate of L1 retrotransposition, which could increase genomic instability. PMID- 20948977 TI - Adaptive CT for High-Resolution, Controlled-Dose, Region-of-Interest Imaging. AB - We have developed a flexible x-ray micro-CT system, named FaCT, capable of changing its geometric configuration and acquisition protocol in order to best suit an object being imaged for a particular diagnostic task. High-performance computing technologies have been a major enabling factor for this adaptive CT system in terms of system control, fast reconstruction, and data analysis. In this work, we demonstrate an adaptive procedure in which a quick, sparse projection pre-scan is performed, the data are reconstructed, and a region of interest is identified. Next, a diagnostic-quality scan is performed where, given the region of interest, the control computer calculates an illumination window for on-line control of an x-ray source masking aperture to transmit radiation only through the region of interest throughout the scan trajectory. Finally, the diagnostic scan data are reconstructed, with the region of interest being clearly resolved. We use a combination of a multi-core CPU and a pair of NVIDIA Tesla GPUs to perform these tasks. PMID- 20948978 TI - The Relationship between Behavior Ratings and Concurrent and Subsequent Mental and Motor Performance in Toddlers Born at Extremely Low Birth Weight. AB - When predicting child developmental outcomes, reliance on children's scores on measures of developmental functioning alone might mask more subtle behavioral difficulties especially in children with developmental risk factors. The current study examined predictors and stability of examiner behavior ratings and their association with concurrent and subsequent mental and motor performance in toddlers born at extremely low birth weight. Toddlers were evaluated using the Behavior Rating scale (BRS) and the mental and psychomotor indexes of the Bayley II at 18 and 30 months corrected age. BRS total and factor scores showed moderate stability between 18 and 30 months. These scores also predicted 30-month Mental Scale and Psychomotor Scale scores above and beyond prior mental and motor performance. Our findings suggest that early behavior ratings are associated with child mental and motor performance; therefore, behavior ratings might be useful in identifying toddlers at developmental risk and who might benefit from early intervention. PMID- 20948979 TI - Pragmatic Assessment in Autism Spectrum Disorders: A Comparison of a Standard Measure With Parent Report. AB - The purpose of this study was to investigate the concurrent validity of subtests on the Comprehensive Assessment of Spoken Language (CASL) by comparing them with the assessment of communication and social skills on the Vineland Adaptive Behavior Scales (Vineland). The participants were 35 children and adolescents with higher functioning autism spectrum disorders (ASD) who had received both the CASL and the Vineland. Results of the study suggest that the Pragmatic Judgment and Inferences subtests of the CASL appeared to document the difficulties that individuals with ASD had in adaptive use of language for communication. PMID- 20948981 TI - Therapy Operating Characteristic (TOC) Curves and their Application to the Evaluation of Segmentation Algorithms. AB - This paper presents a general framework for assessing imaging systems and image analysis methods on the basis of therapeutic rather than diagnostic efficacy. By analogy to receiver operating characteristic (ROC) curves, it utilizes the Therapy Operating Characteristic or TOC curve, which is a plot of the probability of tumor control vs. the probability of normal-tissue complications as the overall level of a radiotherapy treatment beam is varied. The proposed figure of merit is the area under the TOC, denoted AUTOC. If the treatment planning algorithm is held constant, AUTOC is a metric for the imaging and image-analysis components, and in particular for segmentation algorithms that are used to delineate tumors and normal tissues. On the other hand, for a given set of segmented images, AUTOC can also be used as a metric for the treatment plan itself. A general mathematical theory of TOC and AUTOC is presented and then specialized to segmentation problems. Practical approaches to implementation of the theory in both simulation and clinical studies are presented. The method is illustrated with a a brief study of segmentation methods for prostate cancer. PMID- 20948980 TI - Maintenance of a functional higher order chromatin structure: The role of the nuclear matrix in normal and disease states. AB - The ordered packaging of DNA within the nucleus of somatic cells reflects a dynamic supportive structure that facilitates stable transcription interrupted by intermittent cycles of extreme condensation. This dynamic mode of packing and unpacking chromatin is intimately linked to the ability of the genome to specifically complex with both histones and non-histone proteins. Understanding the underlying mechanism that governs the formation of higher order chromatin structures is a key to understanding how local architecture modulates transcription. In part, the formation of these structures appears to be regulated through genomic looping that is dynamically mediated by attachment to the nuclear scaffold/matrix at S/MARs, i.e., Scaffold/Matrix Attachment Regions. Although the mechanism guiding the formation and use of these higher-ordered structures remains unknown, S/MARs continue to reveal a multitude of roles in development and the pathogenesis of disease. PMID- 20948982 TI - Family and Community Influences on Educational Outcomes Among Appalachian Youth. PMID- 20948983 TI - Routine Discovery of Complex Genetic Models using Genetic Algorithms. AB - Simulation studies are useful in various disciplines for a number of reasons including the development and evaluation of new computational and statistical methods. This is particularly true in human genetics and genetic epidemiology where new analytical methods are needed for the detection and characterization of disease susceptibility genes whose effects are complex, nonlinear, and partially or solely dependent on the effects of other genes (i.e. epistasis or gene-gene interaction). Despite this need, the development of complex genetic models that can be used to simulate data is not always intuitive. In fact, only a few such models have been published. We have previously developed a genetic algorithm approach to discovering complex genetic models in which two single nucleotide polymorphisms (SNPs) influence disease risk solely through nonlinear interactions. In this paper, we extend this approach for the discovery of high order epistasis models involving three to five SNPs. We demonstrate that the genetic algorithm is capable of routinely discovering interesting high-order epistasis models in which each SNP influences risk of disease only through interactions with the other SNPs in the model. This study opens the door for routine simulation of complex gene-gene interactions among SNPs for the development and evaluation of new statistical and computational approaches for identifying common, complex multifactorial disease susceptibility genes. PMID- 20948984 TI - Statistical Characterization of Radiological Images: Basic Principles and Recent Progress. AB - This paper surveys our current understanding of the statistical properties of radiological images and their effect on image quality. Attention is given to statistical descriptions needed to compute the performance of ideal or ideal linear observers on detection and estimation tasks. The effects of measurement noise, random objects and random imaging system are analyzed by nested conditional averaging, leading to a three-term expansion of the data covariance matrix. Characteristic functionals are introduced to account for the object statistics, and it is shown how they can be used to compute the image statistics. PMID- 20948985 TI - The Relationship Between Lower Extremity Alignment Characteristics and Anterior Knee Joint Laxity. AB - BACKGROUND: Lower extremity alignment may influence the load distribution at the knee, potentially predisposing the anterior cruciate ligament to greater stress. We examined whether lower extremity alignment predicted the magnitude of anterior knee laxity in men and women. HYPOTHESIS: Greater anterior pelvic angle, hip anteversion, tibiofemoral angle, genu recurvatum, and navicular drop will predict greater anterior knee laxity. STUDY DESIGN: Descriptive laboratory study. METHODS: Women (n = 122) and men (n = 97) were measured for anterior knee laxity and 7 lower extremity alignment variables on their dominant stance leg. Linear regression determined the extent to which the alignment variables predicted anterior knee laxity for each sex. RESULTS: Lower anterior pelvic tilt and tibiofemoral angle, and greater genu recurvatum and navicular drop were related to greater anterior knee laxity in women, explaining 28.1% of the variance (P < .001). Lower anterior pelvic tilt and greater hip anteversion, genu recurvatum and navicular drop were predictors of greater anterior knee laxity in men, explaining 26.5% of the variance (P < .001). CONCLUSION: Lower anterior pelvic tilt, greater knee hyperextension, and foot pronation predicted greater anterior knee laxity in both men and women, with genu recurvatum and navicular drop having the greatest impact on anterior knee laxity. Greater hip anteversion was also a strong predictor in men, while a lower tibiofemoral angle was a significant predictor in women. CLINICAL RELEVANCE: The associations between lower extremity alignment and anterior knee laxity suggest that alignment of the hip, knee, and ankle may be linked to or contribute to abnormal loading patterns at the knee, potentially stressing the capsuloligamentous structures and promoting greater joint laxity. PMID- 20948986 TI - Age Differences in the Demand-Control Model of Work Stress: An Examination of Data From 15 European Countries. AB - There have been many tests of Karasek's demand-control model of work stress. However, no studies have examined how the model may differentially apply to older versus younger workers. Due to age changes in cognitive processing, the psychological demands of jobs may interact differently with controls for younger versus older workers. Therefore, the study uses data from the Eurobarometer to examine how the demand-control model of work stress may function differently for older versus younger workers. The results indicate that different controls may in fact buffer different types of job demands for younger versus older workers. The findings reveal that only the interaction between problem solving and time to complete tasks was significant for younger workers. For older workers, however, the interactions between time deadlines and having sufficient time to complete tasks, autonomy, and the interaction between problem solving and schedule flexibility are significant predictors of self-reported stress. PMID- 20948987 TI - Gene expression profiling reveals distinct cocaine-responsive genes in human fetal CNS cell types. AB - OBJECTIVES: Prenatal exposure to cocaine causes cytoarchitectural alterations in the developing neocortex. Previously, we reported that cocaine inhibits neural progenitor cell proliferation through oxidative endoplasmic reticulum stress and consequent down-regulation of cyclin A, whereas cyclin A expression was increased in astrocytes. In the present study, cell type-specific responses to cocaine were further explored. METHODS: Gene expression profiles were examined in five types of cells obtained from the human fetal cerebral cortex at 20 weeks gestation. Cells were treated with 100 uM cocaine in vitro for 24 hr, followed by gene expression analysis using a human neural/stem cell/drug abuse-focused cDNA array, with verification by quantitative real-time RT-PCR. RESULTS: Cocaine influenced transcription of distinct categories of genes in a cell type-specific manner. Cocaine down-regulated cytoskeleton-related genes including ezrin, gamma2 actin, alpha3d tubulin and alpha8 tubulin in neural and/or A2B5+ progenitor cells. In contrast, cocaine modulated immune and cell death-related genes in microglia and astrocytes. In microglia, cocaine up-regulated the immunoregulatory and pro apoptotic genes IL-1beta and BAX. In astrocytes, cocaine down-regulated the immune response gene glucocorticoid receptor and up-regulated the anti-apoptotic genes 14-3-3 epsilon and HVEM. Therefore, cell types comprising the developing neocortex show differential responses to cocaine. CONCLUSIONS: These data suggest that cocaine causes cytoskeletal abnormalities leading to disturbances in neural differentiation and migration in progenitor cells, while altering immune and apoptotic responses in glia. Understanding the mechanisms of cocaine's effects on human CNS cells may help in the development of therapeutic strategies to prevent or ameliorate cocaine-induced impairments in fetal brain development. PMID- 20948988 TI - Genetic Programming Neural Networks: A Powerful Bioinformatics Tool for Human Genetics. AB - The identification of genes that influence the risk of common, complex disease primarily through interactions with other genes and environmental factors remains a statistical and computational challenge in genetic epidemiology. This challenge is partly due to the limitations of parametric statistical methods for detecting genetic effects that are dependent solely or partially on interactions. We have previously introduced a genetic programming neural network (GPNN) as a method for optimizing the architecture of a neural network to improve the identification of genetic and gene-environment combinations associated with disease risk. Previous empirical studies suggest GPNN has excellent power for identifying gene-gene and gene-environment interactions. The goal of this study was to compare the power of GPNN to stepwise logistic regression (SLR) and classification and regression trees (CART) for identifying gene-gene and gene-environment interactions. SLR and CART are standard methods of analysis for genetic association studies. Using simulated data, we show that GPNN has higher power to identify gene-gene and gene environment interactions than SLR and CART. These results indicate that GPNN may be a useful pattern recognition approach for detecting gene-gene and gene environment interactions in studies of human disease. PMID- 20948989 TI - miR-449a causes Rb-dependent cell cycle arrest and senescence in prostate cancer cells. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) that regulate gene expression by repressing translation or triggering the degradation of complementary mRNA sequences. Certain miRNAs have been shown to function as integral components of the p53 and/or retinoblastoma (Rb) regulatory networks. As such, miRNA dysregulation can have a profound effect on cancer development. Previous studies have shown that miR-449a is down-regulated in human prostate cancer tissue and possesses potential tumor suppressor function. In the present study, we identify miR-449a-mediated growth arrest in prostate cancer cells is dependent on the Rb protein. We show that mutant Rb prostate cancer cells (DU- 145) are resistant to cell cycle arrest and cellular senescence induced by miR- 449a, while overexpression of wild-type Rb in DU-145 sublines (DU-1.1 and B5) restores miR-449a function. In silico analysis of 3'UTR regions reveal a putative miR-449a target site in the transcript of Cyclin D1 (CCND1); an oncogene involved in directly regulating Rb activity and cell cycle progression. Luciferase 3'UTR reporter constructs and inhibitory oligonucleotides confirm that Cyclin D1 is a direct downstream target of miR-449a. We also reveal that miR-449a suppresses Rb phosphorylation through the knockdown of Cyclin D1 and previously validated target HDAC1. By targeting genes involved in controlling Rb activity, miR- 449a regulates growth and senescence in an Rb-dependent manner. These data indicate that miR-449a is a miRNA component of the Rb pathway and its tumor suppressor like effects, in part, depends on Rb status in prostate cancer cells. PMID- 20948990 TI - Exhaled breath analysis: The new interface between medicine and engineering. AB - Exhaled breath testing is becoming an increasingly important non-invasive diagnostic method that can be used in the evaluation of health and disease states in the lung and beyond. Potential advantages of breath tests over other conventional medical tests include their non-invasive nature, low cost, and safety. To advance in this area further, however, there has to be a close collaboration between technical experts and engineers who have devices looking for clinical application(s), the medical experts who have the clinical problems looking for a test/biomarker that can be helpful in diagnosis or monitoring, and industry/commercial experts who can build and commercialize the final product. PMID- 20948991 TI - Modeling and optimization of printed spiral coils in air, saline, and muscle tissue environments. AB - Printed spiral coils (PSCs) are viable candidates for near-field wireless power transmission to the next generation of high-performance neuroprosthetic devices with extreme size constraints, which will target intraocular and intracranial spaces. Optimizing the PSC geometries to maximize the power transfer efficiency of the wireless link is imperative to reduce the size of the external energy source, heating of the tissue, and interference with other devices. Implantable devices need to be hermetically sealed in biocompatible materials and placed in a conductive environment with high permittivity (tissue), which can affect the PSC characteristics. We have constructed a detailed model that includes the effects of the surrounding environment on the PSC parasitic components and eventually on the power transfer efficiency. We have combined this model with an iterative design method that starts with a set of realistic design constraints and ends with the optimal PSC geometries. We applied our design methodology to optimize the wireless link of a 1-cm (2) implantable device example, operating at 13.56 MHz. Measurement results showed that optimized PSC pairs, coated with 0.3 mm of silicone, achieved 72.2%, 51.8%, and 30.8% efficiencies at a face-to-face relative distance of 10 mm in air, saline, and muscle, respectively. The PSC, which was optimized for air, could only bear 40.8% and 21.8% efficiencies in saline and muscle, respectively, showing that by including the PSC tissue environment in the design process the result can be more than a 9% improvement in the power transfer efficiency. PMID- 20948995 TI - The potential of medical abortion to reduce maternal mortality in Africa: what benefits for Tanzania and Ethiopia? AB - BACKGROUND: Unsafe abortion is estimated to account for 13% of maternal mortality globally. Medical abortion is a safe alternative. METHODS: By estimating mortality risks for unsafe and medical abortion and childbirth for Tanzania and Ethiopia, we modelled changes in maternal mortality that are achievable if unsafe abortion were replaced by medical abortion. We selected Ethiopia and Tanzania because of their high maternal mortality ratios (MMRatios) and contrasting situations regarding health care provision and abortion legislation. We focused on misoprostol-only regimens due to the drug's low cost and accessibility. We included the impact of medical abortion on women who would otherwise choose unsafe abortion and on women with unwanted/mistimed pregnancies who would otherwise carry to term. RESULTS: Thousands of lives could be saved each year in each country by implementing medical abortion using misoprostol (2122 in Tanzania and 2551 in Ethiopia assuming coverage equals family planning services levels: 56% for Tanzania, 31% for Ethiopia). Changes in MMRatios would be less pronounced because the intervention would also affect national birth rates. CONCLUSIONS: This is the first analysis of impact of medical abortion provision which takes into account additional potential users other than those currently using unsafe abortion. Thousands of women's lives could be saved, but this may not be reflected in as substantial changes in MMRatios because of medical abortion's demographic impact. Therefore policy makers must be aware of the inability of some traditional measures of maternal mortality to detect the real benefits offered by such an intervention. PMID- 20948996 TI - Soluble fms-Like tyrosine kinase 1 (sFlt1), endoglin and placental growth factor (PlGF) in preeclampsia among high risk pregnancies. AB - BACKGROUND: Differences in circulating concentrations of antiangiogenic factors sFlt1 and soluble endoglin (sEng) and the pro-angiogenic growth factor PlGF are reported to precede the onset of preeclampsia weeks to months in low-risk pregnant women. The objective of this study was to investigate whether similar changes can be detected in pregnant women at high-risk to develop the syndrome. METHODS: This study is a secondary analysis of the NICHD MFMU trial of aspirin to prevent preeclampsia in high-risk pregnancies. Serum samples were available from 194 women with pre-existing diabetes, 313 with chronic hypertension, 234 with multifetal gestation, and 252 with a history of preeclampsia in a previous pregnancy. Samples collected across pregnancy were analyzed in a blinded fashion for sFlt1, sEng and PlGF. RESULTS: The odds of developing preeclampsia were significantly increased among women with multiple fetuses for each 2-fold elevation in sFlt1, sEng and the ratio of angiogenic factors (e.g. OR 2.18, 95% CI 1.46-3.32), and significantly decreased for each 2-fold elevation in circulating PlGF (OR 0.50, 95% CI 0.30-0.82) between 7 and 26 weeks' gestation. Cross-sectional analysis of the angiogenic factors across gestation showed significant differences during the third trimester in women who develop preeclampsia compared with appropriate controls in all high-risk groups. However, when data were examined in relation to the gestational week when preeclampsia was diagnosed only sFlt1 was significantly higher 2 to 5 weeks before the clinical onset of preeclampsia and only in women with previous preeclampsia. CONCLUSIONS: The pattern of elevated concentrations of sFlt1 and sEng, and low PlGF in high risk pregnant subjects who develop preeclampsia is similar to that reported in low-risk pregnant women. However, differences in these factors among high-risk women who do and do not develop preeclampsia are modest, and do not appear to be clinically useful predictors in these high-risk pregnant women. PMID- 20948997 TI - Discovery of a novel and rich source of gluten-degrading microbial enzymes in the oral cavity. AB - BACKGROUND: Celiac disease is a T cell mediated-inflammatory enteropathy caused by the ingestion of gluten in genetically predisposed individuals carrying HLA DQ2 or HLA-DQ8. The immunogenic gliadin epitopes, containing multiple glutamine and proline residues, are largely resistant to degradation by gastric and intestinal proteases. Salivary microorganisms however exhibit glutamine endoprotease activity, discovered towards glutamine- and proline-rich salivary proteins. The aim was to explore if gliadins can serve as substrates for oral microbial enzymes. METHODOLOGY/PRINCIPAL FINDINGS: Proteolytic activity in suspended dental plaque was studied towards a) gliadin-derived paranitroanilide(pNA)-linked synthetic enzyme substrates b) a mixture of natural gliadins and c) synthetic highly immunogenic gliadin peptides (33-mer of alpha2 gliadin and 26-mer of gamma-gliadin). In addition, gliadin zymography was conducted to obtain the approximate molecular weights and pH activity profiles of the gliadin-degrading oral enzymes and liquid iso-electric focusing was performed to establish overall enzyme iso-electric points. Plaque bacteria efficiently hydrolyzed Z-YPQ-pNA, Z-QQP-pNA, Z-PPF-pNA and Z-PFP-pNA, with Z-YPQ-pNA being most rapidly cleaved. Gliadin immunogenic domains were extensively degraded in the presence of oral bacteria. Gliadin zymography revealed that prominent enzymes exhibit molecular weights >70 kD and are active over a broad pH range from 3 to 10. Liquid iso-electric focusing indicated that most gliadin-degrading enzymes are acidic in nature with iso-electric points between 2.5 and 4.0. CONCLUSIONS/SIGNIFICANCE: This is the first reported evidence for gluten degrading microorganisms associated with the upper gastro-intestinal tract. Such microorganisms may play a hitherto unappreciated role in the digestion of dietary gluten and thus protection from celiac disease in subjects at risk. PMID- 20948998 TI - Variants of the FADS1 FADS2 gene cluster, blood levels of polyunsaturated fatty acids and eczema in children within the first 2 years of life. AB - BACKGROUND: Association of genetic-variants in the FADS1-FADS2-gene-cluster with fatty-acid-composition in blood of adult-populations is well established. We analyze this genetic-association in two children-cohort-studies. In addition, the association between variants in the FADS-gene-cluster and blood-fatty-acid composition with eczema was studied. METHODS AND PRINCIPAL FINDINGS: Data of two population-based-birth-cohorts in The Netherlands and Germany (KOALA, LISA) were pooled (n = 879) and analyzed by (logistic) regression regarding the mutual influence of single-nucleotide-polymorphisms (SNPs) in the FADS-gene-cluster (rs174545, rs174546, rs174556, rs174561, rs3834458), on polyunsaturated fatty acids (PUFA) in blood and parent-reported eczema until the age of 2 years. All SNPs were highly significantly associated with all PUFAs except for alpha linolenic-acid and eicosapentaenoic-acid, also after correction for multiple testing. All tested SNPs showed associations with eczema in the LISA-study, but not in the KOALA-study. None of the PUFAs was significantly associated with eczema neither in the pooled nor in the analyses stratified by study-cohort. CONCLUSIONS AND SIGNIFICANCE: PUFA-composition in young children's blood is under strong control of the FADS-gene-cluster. Inconsistent results were found for a link between these genetic-variants with eczema. PUFA in blood was not associated with eczema. Thus the hypothesis of an inflammatory-link between PUFA and eczema by the metabolic-pathway of LC-PUFAs as precursors for inflammatory prostaglandins and leukotrienes could not be confirmed by these data. PMID- 20948999 TI - Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. AB - Tar DNA Binding Protein-43 (TDP-43) is a principle component of inclusions in many cases of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). TDP-43 resides predominantly in the nucleus, but in affected areas of ALS and FTLD-U central nervous system, TDP-43 is aberrantly processed and forms cytoplasmic inclusions. The mechanisms governing TDP-43 inclusion formation are poorly understood. Increasing evidence indicates that TDP-43 regulates mRNA metabolism by interacting with mRNA binding proteins that are known to associate with RNA granules. Here we show that TDP-43 can be induced to form inclusions in cell culture and that most TDP-43 inclusions co-localize with SGs. SGs are cytoplasmic RNA granules that consist of mixed protein-RNA complexes. Under stressful conditions SGs are generated by the reversible aggregation of prion-like proteins, such as TIA-1, to regulate mRNA metabolism and protein translation. We also show that disease-linked mutations in TDP-43 increased TDP-43 inclusion formation in response to stressful stimuli. Biochemical studies demonstrated that the increased TDP-43 inclusion formation is associated with accumulation of TDP-43 detergent insoluble complexes. TDP-43 associates with SG by interacting with SG proteins, such as TIA-1, via direct protein-protein interactions, as well as RNA-dependent interactions. The signaling pathway that regulates SGs formation also modulates TDP-43 inclusion formation. We observed that inclusion formation mediated by WT or mutant TDP-43 can be suppressed by treatment with translational inhibitors that suppress or reverse SG formation. Finally, using Sudan black to quench endogenous autofluorescence, we also demonstrate that TDP-43 positive-inclusions in pathological CNS tissue co-localize with multiple protein markers of stress granules, including TIA-1 and eIF3. These data provide support for accumulating evidence that TDP-43 participates in the SG pathway. PMID- 20949000 TI - Identification of the essential Brucella melitensis porin Omp2b as a suppressor of Bax-induced cell death in yeast in a genome-wide screening. AB - BACKGROUND: Inhibition of apoptosis is one of the mechanisms selected by numerous intracellular pathogenic bacteria to control their host cell. Brucellae, which are the causative agent of a worldwide zoonosis, prevent apoptosis of infected cells, probably to support survival of their replication niche. METHODOLOGY/PRINCIPAL FINDINGS: In order to identify Brucella melitensis anti apoptotic effector candidates, we performed a genome-wide functional screening in yeast. The B. melitensis ORFeome was screened to identify inhibitors of Bax induced cell death in S. cerevisiae. B. melitensis porin Omp2b, here shown to be essential, prevents Bax lethal effect in yeast, unlike its close paralog Omp2a. Our results based on Omp2b size variants characterization suggest that signal peptide processing is required for Omp2b effect in yeast. CONCLUSION/SIGNIFICANCE: We report here the first application to a bacterial genome-wide library of coding sequences of this "yeast-rescue" screening strategy, previously used to highlight several new apoptosis regulators. Our work provides B. melitensis proteins that are candidates for an anti-apoptotic function, and can be tested in mammalian cells in the future. Hypotheses on possible molecular mechanisms of Bax inhibition by the B. melitensis porin Omp2b are discussed. PMID- 20949001 TI - Identification of Mendel's white flower character. AB - BACKGROUND: The genetic regulation of flower color has been widely studied, notably as a character used by Mendel and his predecessors in the study of inheritance in pea. METHODOLOGY/PRINCIPAL FINDINGS: We used the genome sequence of model legumes, together with their known synteny to the pea genome to identify candidate genes for the A and A2 loci in pea. We then used a combination of genetic mapping, fast neutron mutant analysis, allelic diversity, transcript quantification and transient expression complementation studies to confirm the identity of the candidates. CONCLUSIONS/SIGNIFICANCE: We have identified the pea genes A and A2. A is the factor determining anthocyanin pigmentation in pea that was used by Gregor Mendel 150 years ago in his study of inheritance. The A gene encodes a bHLH transcription factor. The white flowered mutant allele most likely used by Mendel is a simple G to A transition in a splice donor site that leads to a mis-spliced mRNA with a premature stop codon, and we have identified a second rare mutant allele. The A2 gene encodes a WD40 protein that is part of an evolutionarily conserved regulatory complex. PMID- 20949002 TI - Differential genetic regulation of canine hip dysplasia and osteoarthritis. AB - BACKGROUND: Canine hip dysplasia (HD) is a common polygenic trait characterized by hip malformation that results in osteoarthritis (OA). The condition in dogs is very similar to developmental dysplasia of the human hip which also leads to OA. METHODOLOGY/PRINCIPAL FINDINGS: A total of 721 dogs, including both an association and linkage population, were genotyped. The association population included 8 pure breeds (Labrador retriever, Greyhounds, German Shepherd, Newfoundland, Golden retriever, Rottweiler, Border Collie and Bernese Mountain Dog). The linkage population included Labrador retrievers, Greyhounds, and their crosses. Of these, 366 dogs were genotyped at ~22,000 single nucleotide polymorphism (SNP) loci and a targeted screen across 8 chromosomes with ~3,300 SNPs was performed on 551 dogs (196 dogs were common to both sets). A mixed linear model approach was used to perform an association study on this combined association and linkage population. The study identified 4 susceptibility SNPs associated with HD and 2 SNPs associated with hip OA. CONCLUSION/SIGNIFICANCE: The identified SNPs included those near known genes (PTPRD, PARD3B, and COL15A1) reported to be associated with, or expressed in, OA in humans. This suggested that the canine model could provide a unique opportunity to identify genes underlying natural HD and hip OA, which are common and debilitating conditions in both dogs and humans. PMID- 20949003 TI - Inhibition of toxic shock by human monoclonal antibodies against staphylococcal enterotoxin B. AB - BACKGROUND: Staphylococcus aureus is implicated in many opportunistic bacterial infections around the world. Rising antibiotic resistance and few alternative methods of treatment are just two looming problems associated with clinical management of S. aureus. Among numerous virulence factors produced by S. aureus, staphylococcal enterotoxin (SE) B is a secreted protein that binds T-cell receptor and major histocompatibility complex class II, potentially causing toxic shock mediated by pathological activation of T cells. Recombinant monoclonal antibodies that target SEB and block receptor interactions can be of therapeutic value. METHODOLOGY/PRINCIPAL FINDINGS: The inhibitory and biophysical properties of ten human monoclonal antibodies, isolated from a recombinant library by panning against SEB vaccine (STEBVax), were examined as bivalent Fabs and native full-length IgG (Mab). The best performing Fabs had binding affinities equal to polyclonal IgG, low nanomolar IC(50)s against SEB in cell culture assays, and protected mice from SEB-induced toxic shock. The orthologous staphylococcal proteins, SEC1 and SEC2, as well as streptococcal pyrogenic exotoxin C were recognized by several Fabs. Four Fabs against SEB, with the lowest IC(50)s, were converted into native full-length Mabs. Although SEB-binding kinetics were identical between each Fab and respective Mab, a 250-fold greater inhibition of SEB-induced T-cell activation was observed with two Mabs. CONCLUSIONS/SIGNIFICANCE: Results suggest that these human monoclonal antibodies possess high affinity, target specificity, and toxin neutralization qualities essential for any therapeutic agent. PMID- 20949004 TI - Evaluation of the influenza A replicon for transient expression of recombinant proteins in mammalian cells. AB - Recombinant protein expression in mammalian cells has become a very important technique over the last twenty years. It is mainly used for production of complex proteins for biopharmaceutical applications. Transient recombinant protein expression is a possible strategy to produce high quality material for preclinical trials within days. Viral replicon based expression systems have been established over the years and are ideal for transient protein expression. In this study we describe the evaluation of an influenza A replicon for the expression of recombinant proteins. We investigated transfection and expression levels in HEK-293 cells with EGFP and firefly luciferase as reporter proteins. Furthermore, we studied the influence of different influenza non-coding regions and temperature optima for protein expression as well. Additionally, we exploited the viral replication machinery for the expression of an antiviral protein, the human monoclonal anti-HIV-gp41 antibody 3D6. Finally we could demonstrate that the expression of a single secreted protein, an antibody light chain, by the influenza replicon, resulted in fivefold higher expression levels compared to the usually used CMV promoter based expression. We emphasize that the influenza A replicon system is feasible for high level expression of complex proteins in mammalian cells. PMID- 20949005 TI - From knockouts to networks: establishing direct cause-effect relationships through graph analysis. AB - BACKGROUND: Reverse-engineering gene networks from expression profiles is a difficult problem for which a multitude of techniques have been developed over the last decade. The yearly organized DREAM challenges allow for a fair evaluation and unbiased comparison of these methods. RESULTS: We propose an inference algorithm that combines confidence matrices, computed as the standard scores from single-gene knockout data, with the down-ranking of feed-forward edges. Substantial improvements on the predictions can be obtained after the execution of this second step. CONCLUSIONS: Our algorithm was awarded the best overall performance at the DREAM4 In Silico 100-gene network sub-challenge, proving to be effective in inferring medium-size gene regulatory networks. This success demonstrates once again the decisive importance of gene expression data obtained after systematic gene perturbations and highlights the usefulness of graph analysis to increase the reliability of inference. PMID- 20949006 TI - Pregnancy does not affect HIV incidence test results obtained using the BED capture enzyme immunoassay or an antibody avidity assay. AB - BACKGROUND: Accurate incidence estimates are needed for surveillance of the HIV epidemic. HIV surveillance occurs at maternal-child health clinics, but it is not known if pregnancy affects HIV incidence testing. METHODS: We used the BED capture immunoassay (BED) and an antibody avidity assay to test longitudinal samples from 51 HIV-infected Ugandan women infected with subtype A, C, D and intersubtype recombinant HIV who were enrolled in the HIVNET 012 trial (37 baseline samples collected near the time of delivery and 135 follow-up samples collected 3, 4 or 5 years later). Nineteen of 51 women were also pregnant at the time of one or more of the follow-up visits. The BED assay was performed according to the manufacturer's instructions. The avidity assay was performed using a Genetic Systems HIV-1/HIV-2 + O EIA using 0.1M diethylamine as the chaotropic agent. RESULTS: During the HIVNET 012 follow-up study, there was no difference in normalized optical density values (OD-n) obtained with the BED assay or in the avidity test results (%) when women were pregnant (n = 20 results) compared to those obtained when women were not pregnant (n = 115; for BED: p = 0.9, generalized estimating equations model; for avidity: p = 0.7, Wilcoxon rank sum). In addition, BED and avidity results were almost exactly the same in longitudinal samples from the 18 women who were pregnant at only one study visit during the follow-up study (p = 0.6, paired t-test). CONCLUSIONS: These results from 51 Ugandan women suggest that any changes in the antibody response to HIV infection that occur during pregnancy are not sufficient to alter results obtained with the BED and avidity assays. Confirmation with larger studies and with other HIV subtypes is needed. PMID- 20949007 TI - The whale pump: marine mammals enhance primary productivity in a coastal basin. AB - It is well known that microbes, zooplankton, and fish are important sources of recycled nitrogen in coastal waters, yet marine mammals have largely been ignored or dismissed in this cycle. Using field measurements and population data, we find that marine mammals can enhance primary productivity in their feeding areas by concentrating nitrogen near the surface through the release of flocculent fecal plumes. Whales and seals may be responsible for replenishing 2.3*10(4) metric tons of N per year in the Gulf of Maine's euphotic zone, more than the input of all rivers combined. This upward "whale pump" played a much larger role before commercial harvest, when marine mammal recycling of nitrogen was likely more than three times atmospheric N input. Even with reduced populations, marine mammals provide an important ecosystem service by sustaining productivity in regions where they occur in high densities. PMID- 20949008 TI - In vivo mapping of vascular inflammation using multimodal imaging. AB - BACKGROUND: Plaque vulnerability to rupture has emerged as a critical correlate to risk of adverse coronary events but there is as yet no clinical method to assess plaque stability in vivo. In the search to identify biomarkers of vulnerable plaques an association has been found between macrophages and plaque stability--the density and pattern of macrophage localization in lesions is indicative of probability to rupture. In very unstable plaques, macrophages are found in high densities and concentrated in the plaque shoulders. Therefore, the ability to map macrophages in plaques could allow noninvasive assessment of plaque stability. We use a multimodality imaging approach to noninvasively map the distribution of macrophages in vivo. The use of multiple modalities allows us to combine the complementary strengths of each modality to better visualize features of interest. Our combined use of Positron Emission Tomography and Magnetic Resonance Imaging (PET/MRI) allows high sensitivity PET screening to identify putative lesions in a whole body view, and high resolution MRI for detailed mapping of biomarker expression in the lesions. METHODOLOGY/PRINCIPAL FINDINGS: Macromolecular and nanoparticle contrast agents targeted to macrophages were developed and tested in three different mouse and rat models of atherosclerosis in which inflamed vascular plaques form spontaneously and/or are induced by injury. For multimodal detection, the probes were designed to contain gadolinium (T1 MRI) or iron oxide (T2 MRI), and Cu-64 (PET). PET imaging was utilized to identify regions of macrophage accumulation; these regions were further probed by MRI to visualize macrophage distribution at high resolution. In both PET and MR images the probes enhanced contrast at sites of vascular inflammation, but not in normal vessel walls. MRI was able to identify discrete sites of inflammation that were blurred together at the low resolution of PET. Macrophage content in the lesions was confirmed by histology. CONCLUSIONS/SIGNIFICANCE: The multimodal imaging approach allowed high sensitivity and high-resolution mapping of biomarker distribution and may lead to a clinical method to predict plaque probability to rupture. PMID- 20949010 TI - Patients present earlier and survival has improved, but pre-ART attrition is high in a six-year HIV cohort data from Ethiopia. AB - BACKGROUND: Previous studies showed higher early mortality rates among patients treated with antiretroviral drugs in settings with limited resources. One of the reasons was late presentation of patients to care. With improved access to HIV services, we expect improvements in disease stage at presentation. Our objective was to assess the effect of improved availability of HIV services on patient presentation to care and subsequent pre-ART and on-ART outcomes. METHODOLOGY AND PRINCIPAL FINDINGS: At Arba Minch Hospital in Ethiopia, we reviewed baseline characteristics and outcomes of 2191 adult HIV patients. Nearly a half were in WHO stage III at presentation. About two-thirds of the patients (1428) started ART. Patients enrolled in the early phase (OR = 4.03, 95% CI 3.07-5.27), men (OR = 1.78, 95%CI 1.47-2.16), and those aged 45 years and above (OR = 2.04, 95%CI 1.48-2.82) were at higher risk of being in advanced clinical stage at presentation. The pre-treatment mortality rate was 13.1 per 100 PYO, ranging from 1.4 in the rapid scale-up phase to 25.9 per 100 PYO in the early phase. A quarter of the patients were lost to follow-up before starting treatment. Being in less advanced stage (HR = 1.9, 95% CI = 1.6, 2.2), being in the recent cohort (HR = 2.0, 95% CI = 1.6, 2.6), and rural residence (HR = 1.8, 95% CI = 1.5, 2.2) were independent predictors of pre-ART loss to follow-up. Of those who started ART, 13.4% were lost to follow-up and 15.4% died. The survival improved during the study. Patients with advanced disease, men and older people had higher death rates. CONCLUSIONS AND SIGNIFICANCE: Patients started to present at earlier stages of their illness and death has decreased among adult HIV patients visiting Arba Minch Hospital. However, many patients were lost from pre-treatment follow up. Early treatment start contributed to improved survival. Both pre-ART and on ART patient retention mechanisms should be strengthened. PMID- 20949009 TI - Insights on glucocorticoid receptor activity modulation through the binding of rigid steroids. AB - BACKGROUND: The glucocorticoid receptor (GR) is a transcription factor that regulates gene expression in a ligand-dependent fashion. This modular protein is one of the major pharmacological targets due to its involvement in both cause and treatment of many human diseases. Intense efforts have been made to get information about the molecular basis of GR activity. METHODOLOGY/PRINCIPAL FINDINGS: Here, the behavior of four GR-ligand complexes with different glucocorticoid and antiglucocorticoid properties were evaluated. The ability of GR-ligand complexes to oligomerize in vivo was analyzed by performing the novel Number and Brightness assay. Results showed that most of GR molecules form homodimers inside the nucleus upon ligand binding. Additionally, in vitro GR-DNA binding analyses suggest that ligand structure modulates GR-DNA interaction dynamics rather than the receptor's ability to bind DNA. On the other hand, by coimmunoprecipitation studies we evaluated the in vivo interaction between the transcriptional intermediary factor 2 (TIF2) coactivator and different GR-ligand complexes. No correlation was found between GR intranuclear distribution, cofactor recruitment and the homodimerization process. Finally, Molecular determinants that support the observed experimental GR LBD-ligand/TIF2 interaction were found by Molecular Dynamics simulation. CONCLUSIONS/SIGNIFICANCE: The data presented here sustain the idea that in vivo GR homodimerization inside the nucleus can be achieved in a DNA-independent fashion, without ruling out a dependent pathway as well. Moreover, since at least one GR-ligand complex is able to induce homodimer formation while preventing TIF2 coactivator interaction, results suggest that these two events might be independent from each other. Finally, 21-hydroxy-6,19-epoxyprogesterone arises as a selective glucocorticoid with potential pharmacological interest. Taking into account that GR homodimerization and cofactor recruitment are considered essential steps in the receptor activation pathway, results presented here contribute to understand how specific ligands influence GR behavior. PMID- 20949012 TI - A genetic screen for attenuated growth identifies genes crucial for intraerythrocytic development of Plasmodium falciparum. AB - A majority of the Plasmodium falciparum genome codes for genes with unknown functions, which presents a major challenge to understanding the parasite's biology. Large-scale functional analysis of the parasite genome is essential to pave the way for novel therapeutic intervention strategies against the disease and yet difficulties in genetic manipulation of this deadly human malaria parasite have been a major hindrance for functional analysis of its genome. Here, we used a forward functional genomic approach to study P. falciparum and identify genes important for optimal parasite development in the disease-causing, intraerythrocytic stages. We analyzed 123 piggyBac insertion mutants of P. falciparum for proliferation efficiency in the intraerythrocytic stages, in vitro. Almost 50% of the analyzed mutants showed significant reduction in proliferation efficiency, with 20% displaying severe defects. Functional categorization of genes in the severely attenuated mutants revealed significant enrichment for RNA binding proteins, suggesting the significance of post transcriptional gene regulation in parasite development and emphasizing its importance as an antimalarial target. This study demonstrates the feasibility of much needed forward genetics approaches for P. falciparum to better characterize its genome and accelerate drug and vaccine development. PMID- 20949011 TI - Gene expression profiling of U12-type spliceosome mutant Drosophila reveals widespread changes in metabolic pathways. AB - BACKGROUND: The U12-type spliceosome is responsible for the removal of a subset of introns from eukaryotic mRNAs. U12-type introns are spliced less efficiently than normal U2-type introns, which suggests a rate-limiting role in gene expression. The Drosophila genome contains about 20 U12-type introns, many of them in essential genes, and the U12-type spliceosome has previously been shown to be essential in the fly. METHODOLOGY/PRINCIPAL FINDINGS: We have used a Drosophila line with a P-element insertion in U6atac snRNA, an essential component of the U12-type spliceosome, to investigate the impact of U12-type introns on gene expression at the organismal level during fly development. This line exhibits progressive accumulation of unspliced U12-type introns during larval development and the death of larvae at the third instar stage. Surprisingly, microarray and RT-PCR analyses revealed that most genes containing U12-type introns showed only mild perturbations in the splicing of U12-type introns. In contrast, we detected widespread downstream effects on genes that do not contain U12-type introns, with genes related to various metabolic pathways constituting the largest group. CONCLUSIONS/SIGNIFICANCE: U12-type intron containing genes exhibited variable gene-specific responses to the splicing defect, with some genes showing up- or downregulation, while most did not change significantly. The observed residual U12-type splicing activity could be explained with the mutant U6atac allele having a low level of catalytic activity. Detailed analysis of all genes suggested that a defect in the splicing of the U12 type intron of the mitochondrial prohibitin gene may be the primary cause of the various downstream effects detected in the microarray analysis. PMID- 20949013 TI - Retinoic acid increases proliferation of human osteoclast progenitors and inhibits RANKL-stimulated osteoclast differentiation by suppressing RANK. AB - It has been shown that high vitamin A intake is associated with bone fragility and fractures in both animals and humans. However, the mechanism by which vitamin A affects bones is unclear. In the present study, the direct effects of retinoic acid (RA) on human and murine osteoclastogenesis were evaluated using cultured peripheral blood CD14(+) monocytes and RAW264.7 cells. Both the activity of the osteoclast marker tartrate resistant acid phosphatase (TRAP) in culture supernatant and the expression of the genes involved in osteoclast differentiation together with bone resorption were measured. To our knowledge, this is the first time that the effects of RA on human osteoclast progenitors and mature osteoclasts have been studied in vitro. RA stimulated proliferation of osteoclast progenitors both from humans and mice. In contrast, RA inhibited differentiation of the receptor activator of nuclear factor kappaB ligand (RANKL) induced osteoclastogenesis of human and murine osteoclast progenitors via retinoic acid receptors (RARs). We also show that the mRNA levels of receptor activator of nuclear factor kappaB (RANK), the key initiating factor and osteoclast associated receptor for RANKL, were potently suppressed by RA in osteoclast progenitors. More importantly, RA abolished the RANK protein in osteoclast progenitors. This inhibition could be partially reversed by a RAR pan antagonist. Furthermore, RA treatment suppressed the expression of the transcription factor nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and increased the expression of interferon regulatory factor-8 (IRF-8) in osteoclast progenitors via RARs. Also, RA demonstrated differential effects depending on the material supporting the cell culture. RA did not affect TRAP activity in the culture supernatant in the bone slice culture system, but inhibited the release of TRAP activity if cells were cultured on plastic. In conclusion, our results suggest that retinoic acid increases proliferation of human osteoclast progenitors and that it inhibits RANK-stimulated osteoclast differentiation by suppressing RANK. PMID- 20949014 TI - Sex-specific differences in shoaling affect parasite transmission in guppies. AB - BACKGROUND: Individuals have to trade-off the costs and benefits of group membership during shoaling behaviour. Shoaling can increase the risk of parasite transmission, but this cost has rarely been quantified experimentally. Guppies (Poecilia reticulata) are a model system for behavioural studies, and they are commonly infected by gyrodactylid parasites, notorious fish pathogens that are directly transmitted between guppy hosts. METHODOLOGY/PRINCIPAL FINDINGS: Parasite transmission in single sex shoals of male and female guppies were observed using an experimental infection of Gyrodactylus turnbulli. Parasite transmission was affected by sex-specific differences in host behaviour, and significantly more parasites were transmitted when fish had more frequent and more prolonged contact with each other. Females shoaled significantly more than males and had a four times higher risk to contract an infection. CONCLUSIONS/SIGNIFICANCE: Intersexual differences in host behaviours such as shoaling are driven by differences in natural and sexual selection experienced by both sexes. Here we show that the potential benefits of an increased shoaling tendency are traded off against increased risks of contracting an infectious parasite in a group-living species. PMID- 20949015 TI - The Dictyostelium discoideum acaA gene is transcribed from alternative promoters during aggregation and multicellular development. AB - BACKGROUND: Extracellular cAMP is a key extracellular signaling molecule that regulates aggregation, cell differentiation and morphogenesis during multi cellular development of the social amoeba Dictyostelium discoideum. This molecule is produced by three different adenylyl cyclases, encoded by the genes acaA, acrA and acgA, expressed at different stages of development and in different structures. METHODOLOGY/PRINCIPAL FINDINGS: This article describes the characterization of the promoter region of the acaA gene, showing that it is transcribed from three different alternative promoters. The distal promoter, promoter 1, is active during the aggregation process while the more proximal promoters are active in tip-organiser and posterior regions of the structures. A DNA fragment containing the three promoters drove expression to these same regions and similar results were obtained by in situ hybridization. Analyses of mRNA expression by quantitative RT-PCR with specific primers for each of the three transcripts also demonstrated their different temporal patterns of expression. CONCLUSIONS/SIGNIFICANCE: The existence of an aggregation-specific promoter can be associated with the use of cAMP as chemo-attractant molecule, which is specific for some Dictyostelium species. Expression at late developmental stages indicates that adenylyl cyclase A might play a more important role in post-aggregative development than previously considered. PMID- 20949017 TI - Characterizing DNA condensation and conformational changes in organic solvents. AB - Organic solvents offer a new approach to formulate DNA into novel structures suitable for gene delivery. In this study, we examined the in situ behavior of DNA in N, N-dimethylformamide (DMF) at low concentration via laser light scattering (LLS), TEM, UV absorbance and Zeta potential analysis. Results revealed that, in DMF, a 21bp oligonucleotide remained intact, while calf thymus DNA and supercoiled plasmid DNA were condensed and denatured. During condensation and denaturation, the size was decreased by a factor of 8-10, with calf thymus DNA forming spherical globules while plasmid DNA exhibited a toroid-like conformation. In the condensed state, DNA molecules were still able to release the counterions to be negatively charged, indicating that the condensation was mainly driven by the excluded volume interactions. The condensation induced by DMF was reversible for plasmid DNA but not for calf thymus DNA. When plasmid DNA was removed from DMF and resuspended in an aqueous solution, the DNA was quickly regained a double stranded configuration. These findings provide further insight into the behavior and condensation mechanism of DNA in an organic solvent and may aid in developing more efficient non-viral gene delivery systems. PMID- 20949016 TI - Promoting functional health in midlife and old age: long-term protective effects of control beliefs, social support, and physical exercise. AB - BACKGROUND: Previous studies have examined physical risk factors in relation to functional health, but less work has focused on the protective role of psychological and social factors. We examined the individual and joint protective contribution of control beliefs, social support and physical exercise to changes in functional health, beyond the influence of health status and physical risk factors in middle-aged and older adults. Given that functional health typically declines throughout adulthood, it is important to identify modifiable factors that can be implemented to maintain functioning, improve quality of life, and reduce disability. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a national longitudinal study, Midlife in the United States (MIDUS), with assessments in 1995-1996 and 2004-2006, and 3,626 community-residing adults, aged 32 to 84, were included in the analyses. Functional health (Physical Functioning subscale of the SF-36) and protective factors were measured at both occasions. While controlling for socio-demographic, health status, and physical risk factors (large waist circumference, smoking, and alcohol or drug problems), a composite of the three protective variables (control beliefs, social support, and physical exercise) at Time 1 was significantly related to functional health change. The more of these factors at Time 1, the better the health maintenance over 10 years. Among middle aged and older adults, declines in health were significantly reduced with an increased number of protective factors. CONCLUSION/SIGNIFICANCE: Age-related declines in health were reduced among those with more protective factors up to a decade earlier in life. Modifiable psychological, social, and physical protective factors, individually and in the aggregate, are associated with maintenance of functional health, beyond the damaging effects of physical risk factors. The results are encouraging for the prospect of developing interventions to promote functional health and for reducing public health expenditures for physical disability in later life. PMID- 20949018 TI - 26S proteasome activity is down-regulated in lung cancer stem-like cells propagated in vitro. AB - Cancer stem cells (CSCs) are a small subset of cancer cells capable of self renewal and tumor maintenance. Eradicating cancer stem cells, the root of tumor origin and recurrence, has emerged as one promising approach to improve lung cancer survival. Cancer stem cells are reported to reside in the side population (SP) of cultured lung cancer cells. We report here the coexistence of a distinct population of non-SP (NSP) cells that have equivalent self-renewal capacity compared to SP cells in a lung tumor sphere assay. Compared with the corresponding cells in monolayer cultures, lung tumor spheres, formed from human non-small cell lung carcinoma cell lines A549 or H1299, showed marked morphologic differences and increased expression of the stem cell markers CD133 and OCT3/4. Lung tumor spheres also exhibited increased tumorigenic potential as only 10,000 lung tumor sphere cells were required to produce xenografts tumors in nude mice, whereas the same number of monolayer cells failed to induce tumors. We also demonstrate that lung tumor spheres showed decreased 26S proteasome activity compared to monolayer. By using the ZsGreen-cODC (C-terminal sequence that directs degradation of Ornithine Decarboxylase) reporter assay in NSCLC cell lines, only less than 1% monolayer cultures were ZsGreen positive indicating low 26S proteasome, whereas lung tumor sphere showed increased numbers of ZsGreen positive cells, suggesting the enrichment of CSCs in sphere cultures. PMID- 20949019 TI - Quantifiable biomarkers of normal aging in the Japanese medaka fish (Oryzias latipes). AB - BACKGROUND: Small laboratory fish share many anatomical and histological characteristics with other vertebrates, yet can be maintained in large numbers at low cost for lifetime studies. Here we characterize biomarkers associated with normal aging in the Japanese medaka (Oryzias latipes), a species that has been widely used in toxicology studies and has potential utility as a model organism for experimental aging research. PRINCIPAL FINDINGS: The median lifespan of medaka was approximately 22 months under laboratory conditions. We performed quantitative histological analysis of tissues from age-grouped individuals representing young adults (6 months old), mature adults (16 months old), and adults that had survived beyond the median lifespan (24 months). Livers of 24 month old individuals showed extensive morphologic changes, including spongiosis hepatis, steatosis, ballooning degeneration, inflammation, and nuclear pyknosis. There were also phagolysosomes, vacuoles, and residual bodies in parenchymal cells and congestion of sinusoidal vessels. Livers of aged individuals were characterized by increases in lipofuscin deposits and in the number of TUNEL positive apoptotic cells. Some of these degenerative characteristics were seen, to a lesser extent, in the livers of 16-month old individuals, but not in 6-month old individuals. The basal layer of the dermis showed an age-dependent decline in the number of dividing cells and an increase in senescence-associated beta galactosidase. The hearts of aged individuals were characterized by fibrosis and lipofuscin deposition. There was also a loss of pigmented cells from the retinal epithelium. By contrast, age-associated changes were not apparent in skeletal muscle, the ocular lens, or the brain. SIGNIFICANCE: The results provide a set of markers that can be used to trace the process of normal tissue aging in medaka and to evaluate the effect of environmental stressors. PMID- 20949020 TI - Counter-gradient variation in respiratory performance of coral reef fishes at elevated temperatures. AB - The response of species to global warming depends on how different populations are affected by increasing temperature throughout the species' geographic range. Local adaptation to thermal gradients could cause populations in different parts of the range to respond differently. In aquatic systems, keeping pace with increased oxygen demand is the key parameter affecting species' response to higher temperatures. Therefore, respiratory performance is expected to vary between populations at different latitudes because they experience different thermal environments. We tested for geographical variation in respiratory performance of tropical marine fishes by comparing thermal effects on resting and maximum rates of oxygen uptake for six species of coral reef fish at two locations on the Great Barrier Reef (GBR), Australia. The two locations, Heron Island and Lizard Island, are separated by approximately 1200 km along a latitudinal gradient. We found strong counter-gradient variation in aerobic scope between locations in four species from two families (Pomacentridae and Apogonidae). High-latitude populations (Heron Island, southern GBR) performed significantly better than low-latitude populations (Lizard Island, northern GBR) at temperatures up to 5 degrees C above average summer surface-water temperature. The other two species showed no difference in aerobic scope between locations. Latitudinal variation in aerobic scope was primarily driven by up to 80% higher maximum rates of oxygen uptake in the higher latitude populations. Our findings suggest that compensatory mechanisms in high-latitude populations enhance their performance at extreme temperatures, and consequently, that high-latitude populations of reef fishes will be less impacted by ocean warming than will low latitude populations. PMID- 20949021 TI - Cerenkov radiation energy transfer (CRET) imaging: a novel method for optical imaging of PET isotopes in biological systems. AB - BACKGROUND: Positron emission tomography (PET) allows sensitive, non-invasive analysis of the distribution of radiopharmaceutical tracers labeled with positron (beta(+))-emitting radionuclides in small animals and humans. Upon beta(+) decay, the initial velocity of high-energy beta(+) particles can momentarily exceed the speed of light in tissue, producing Cerenkov radiation that is detectable by optical imaging, but is highly absorbed in living organisms. PRINCIPAL FINDINGS: To improve optical imaging of Cerenkov radiation in biological systems, we demonstrate that Cerenkov radiation from decay of the PET isotopes (64)Cu and (18)F can be spectrally coupled by energy transfer to high Stokes-shift quantum nanoparticles (Qtracker705) to produce highly red-shifted photonic emissions. Efficient energy transfer was not detected with (99m)Tc, a predominantly gamma emitting isotope. Similar to bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET), herein we define the Cerenkov radiation energy transfer (CRET) ratio as the normalized quotient of light detected within a spectral window centered on the fluorophore emission divided by light detected within a spectral window of the Cerenkov radiation emission to quantify imaging signals. Optical images of solutions containing Qtracker705 nanoparticles and [(18)F]FDG showed CRET ratios in vitro as high as 8.8+/-1.1, while images of mice with subcutaneous pseudotumors impregnated with Qtracker705 following intravenous injection of [(18)F]FDG showed CRET ratios in vivo as high as 3.5+/-0.3. CONCLUSIONS: Quantitative CRET imaging may afford a variety of novel optical imaging applications and activation strategies for PET radiopharmaceuticals and other isotopes in biomaterials, tissues and live animals. PMID- 20949022 TI - Viral replication rate regulates clinical outcome and CD8 T cell responses during highly pathogenic H5N1 influenza virus infection in mice. AB - Since the first recorded infection of humans with H5N1 viruses of avian origin in 1997, sporadic human infections continue to occur with a staggering mortality rate of >60%. Although sustained human-to-human transmission has not occurred yet, there is a growing concern that these H5N1 viruses might acquire this trait and raise the specter of a pandemic. Despite progress in deciphering viral determinants of pathogenicity, we still lack crucial information on virus/immune system interactions pertaining to severe disease and high mortality associated with human H5N1 influenza virus infections. Using two human isolates of H5N1 viruses that differ in their pathogenicity in mice, we have defined mechanistic links among the rate of viral replication, mortality, CD8 T cell responses, and immunopathology. The extreme pathogenicity of H5N1 viruses was directly linked to the ability of the virus to replicate rapidly, and swiftly attain high steady state titers in the lungs within 48 hours after infection. The remarkably high replication rate of the highly pathogenic H5N1 virus did not prevent the induction of IFN-beta or activation of CD8 T cells, but the CD8 T cell response was ineffective in controlling viral replication in the lungs and CD8 T cell deficiency did not affect viral titers or mortality. Additionally, BIM deficiency ameliorated lung pathology and inhibited T cell apoptosis without affecting survival of mice. Therefore, rapidly replicating, highly lethal H5N1 viruses could simply outpace and overwhelm the adaptive immune responses, and kill the host by direct cytopathic effects. However, therapeutic suppression of early viral replication and the associated enhancement of CD8 T cell responses improved the survival of mice following a lethal H5N1 infection. These findings suggest that suppression of early H5N1 virus replication is key to the programming of an effective host response, which has implications in treatment of this infection in humans. PMID- 20949025 TI - Using effective subnetworks to predict selected properties of gene networks. AB - BACKGROUND: Difficulties associated with implementing gene therapy are caused by the complexity of the underlying regulatory networks. The forms of interactions between the hundreds of genes, proteins, and metabolites in these networks are not known very accurately. An alternative approach is to limit consideration to genes on the network. Steady state measurements of these influence networks can be obtained from DNA microarray experiments. However, since they contain a large number of nodes, the computation of influence networks requires a prohibitively large set of microarray experiments. Furthermore, error estimates of the network make verifiable predictions impossible. METHODOLOGY/PRINCIPAL FINDINGS: Here, we propose an alternative approach. Rather than attempting to derive an accurate model of the network, we ask what questions can be addressed using lower dimensional, highly simplified models. More importantly, is it possible to use such robust features in applications? We first identify a small group of genes that can be used to affect changes in other nodes of the network. The reduced effective empirical subnetwork (EES) can be computed using steady state measurements on a small number of genetically perturbed systems. We show that the EES can be used to make predictions on expression profiles of other mutants, and to compute how to implement pre-specified changes in the steady state of the underlying biological process. These assertions are verified in a synthetic influence network. We also use previously published experimental data to compute the EES associated with an oxygen deprivation network of E.coli, and use it to predict gene expression levels on a double mutant. The predictions are significantly different from the experimental results for less than of genes. CONCLUSIONS/SIGNIFICANCE: The constraints imposed by gene expression levels of mutants can be used to address a selected set of questions about a gene network. PMID- 20949024 TI - alphaB crystallin is apically secreted within exosomes by polarized human retinal pigment epithelium and provides neuroprotection to adjacent cells. AB - alphaB crystallin is a chaperone protein with anti-apoptotic and anti inflammatory functions and has been identified as a biomarker in age-related macular degeneration. The purpose of this study was to determine whether alphaB crystallin is secreted from retinal pigment epithelial (RPE) cells, the mechanism of this secretory pathway and to determine whether extracellular alphaB crystallin can be taken up by adjacent retinal cells and provide protection from oxidant stress. We used human RPE cells to establish that alphaB crystallin is secreted by a non-classical pathway that involves exosomes. Evidence for the release of exosomes by RPE and localization of alphaB crystallin within the exosomes was achieved by immunoblot, immunofluorescence, and electron microscopic analyses. Inhibition of lipid rafts or exosomes significantly reduced alphaB crystallin secretion, while inhibitors of classic secretory pathways had no effect. In highly polarized RPE monolayers, alphaB crystallin was selectively secreted towards the apical, photoreceptor-facing side. In support, confocal microscopy established that alphaB crystallin was localized predominantly in the apical compartment of RPE monolayers, where it co-localized in part with exosomal marker CD63. Severe oxidative stress resulted in barrier breakdown and release of alphaB crystallin to the basolateral side. In normal mouse retinal sections, alphaB crystallin was identified in the interphotoreceptor matrix. An increased uptake of exogenous alphaB crystallin and protection from apoptosis by inhibition of caspase 3 and PARP activation were observed in stressed RPE cultures. alphaB Crystallin was taken up by photoreceptors in mouse retinal explants exposed to oxidative stress. These results demonstrate an important role for alphaB crystallin in maintaining and facilitating a neuroprotective outer retinal environment and may also explain the accumulation of alphaB crystallin in extracellular sub-RPE deposits in the stressed microenvironment in age-related macular degeneration. Thus evidence from our studies supports a neuroprotective role for alphaB crystallin in ocular diseases. PMID- 20949026 TI - The bile acid sensor FXR protects against dyslipidemia and aortic plaques development induced by the HIV protease inhibitor ritonavir in mice. AB - BACKGROUND: Although human immunodeficiency virus (HIV)-related morbidity and mortality rates in patients treated with a combination of high active antiretroviral therapy (HAART) have declined, significant metabolic/vascular adverse effects associated with the long term use of HIV protease inhibitors (PIs) have emerged as a significant side effect. Here we illustrate that targeting the bile acid sensor farnesoid X receptor (FXR) protects against dyslipidemia and vascular injury induced HIV-PIs in rodents. METHODOLOGY/PRINCIPAL FINDINGS: Administration of the HIV PI ritonavir to wild type mice increased plasma triacylglycerols and cholesterol levels and this effect was exacerbated by dosing ritonavir to mice harbouring a disrupted FXR. Dyslipidemia induced by ritonavir associated with a shift in the liver expression of signature genes, Sterol Regulatory Element-Binding Protein (SREBP)-1 and fatty acid synthase. Treating wild type mice with the FXR agonist (chenodeoxycholic acid, CDCA) protected against development of dyslipidemia induced by ritonavir. Administration of ritonavir to ApoE(-/-) mice, a strain that develop spontaneously atherosclerosis, increased the extent of aortic plaques without worsening the dyslipidemia. Treating these mice with CDCA reduced the extent of aortic plaques by 70% without changing plasma lipoproteins or the liver expression of signature genes. A beneficial effect on aortic plaques was also obtained by treating ApoE(-/-) mice with gemfibrozil, a PPARalpha agonist. FXR activation counter-regulated induction of expression/activity of CD36 caused by HIV-PIs in circulating monocytes and aortic plaques. In macrophages cell lines, CDCA attenuated CD36 induction and uptake of acetylated LDL caused by ritonavir. Natural and synthetic FXR ligands reduced the nuclear translocation of SREBP1c caused by ritonavir. CONCLUSIONS/SIGNIFICANCE: Activation of the bile acid sensor FXR protects against dyslipidemia and atherosclerotic caused by ritonavir, a widely used HIV PI. From a mechanistic stand point it appears that besides reducing the liver expression of genes involved in fatty acid synthesis, FXR activation counter-regulates the expression/activity of CD36 on monocytes. FXR ligands might hold promise in the treatment dyslipidemia induced by ritonavir. PMID- 20949027 TI - Selection of potent non-toxic inhibitory sequences from a randomized HIV-1 specific lentiviral short hairpin RNA library. AB - RNA interference (RNAi) has been considered as an efficient therapeutic approach against the human immunodeficiency virus type 1 (HIV-1). However, to establish a durable inhibition of HIV-1, multiple effective short hairpin RNAs (shRNAs) need to be stably expressed to prevent the emergence of viral escape variants. In this study, we engineered a randomized lentiviral H1-promoter driven shRNA-library against the viral genome. Potent HIV-1 specific shRNAs were selected by ganciclovir treatment of cell lines stably expressing the cDNA of Herpes Simplex Virus thymidine kinase (HSV-TK) fused to HIV-1 nucleotide sequences. More than 50% of 200 selected shRNAs inhibited an HIV-1 based luciferase reporter assay by more than 70%. Stable expression of some of those shRNAs in an HIV-1 permissive HeLa cell line inhibited infection of wild-type HIV-1 by more than 90%. The combination of a randomized shRNA-library directed against HIV-1 with a live cell selection procedure yielded non-toxic and highly efficient HIV-1 specific inhibitory sequences that could serve as valuable candidates for gene therapy studies. PMID- 20949028 TI - Ultra-deep sequencing reveals the microRNA expression pattern of the human stomach. AB - BACKGROUND: While microRNAs (miRNAs) play important roles in tissue differentiation and in maintaining basal physiology, little is known about the miRNA expression levels in stomach tissue. Alterations in the miRNA profile can lead to cell deregulation, which can induce neoplasia. METHODOLOGY/PRINCIPAL FINDINGS: A small RNA library of stomach tissue was sequenced using high throughput SOLiD sequencing technology. We obtained 261,274 quality reads with perfect matches to the human miRnome, and 42% of known miRNAs were identified. Digital Gene Expression profiling (DGE) was performed based on read abundance and showed that fifteen miRNAs were highly expressed in gastric tissue. Subsequently, the expression of these miRNAs was validated in 10 healthy individuals by RT-PCR showed a significant correlation of 83.97% (P<0.05). Six miRNAs showed a low variable pattern of expression (miR-29b, miR-29c, miR-19b, miR-31, miR-148a, miR 451) and could be considered part of the expression pattern of the healthy gastric tissue. CONCLUSIONS/SIGNIFICANCE: This study aimed to validate normal miRNA profiles of human gastric tissue to establish a reference profile for healthy individuals. Determining the regulatory processes acting in the stomach will be important in the fight against gastric cancer, which is the second leading cause of cancer mortality worldwide. PMID- 20949029 TI - Comparison of computational models for assessing conservation of gene expression across species. AB - Assessing conservation/divergence of gene expression across species is important for the understanding of gene regulation evolution. Although advances in microarray technology have provided massive high-dimensional gene expression data, the analysis of such data is still challenging. To date, assessing cross species conservation of gene expression using microarray data has been mainly based on comparison of expression patterns across corresponding tissues, or comparison of co-expression of a gene with a reference set of genes. Because direct and reliable high-throughput experimental data on conservation of gene expression are often unavailable, the assessment of these two computational models is very challenging and has not been reported yet. In this study, we compared one corresponding tissue based method and three co-expression based methods for assessing conservation of gene expression, in terms of their pair wise agreements, using a frequently used human-mouse tissue expression dataset. We find that 1) the co-expression based methods are only moderately correlated with the corresponding tissue based methods, 2) the reliability of co-expression based methods is affected by the size of the reference ortholog set, and 3) the corresponding tissue based methods may lose some information for assessing conservation of gene expression. We suggest that the use of either of these two computational models to study the evolution of a gene's expression may be subject to great uncertainty, and the investigation of changes in both gene expression patterns over corresponding tissues and co-expression of the gene with other genes is necessary. PMID- 20949030 TI - Current patterns of macroalgal diversity and biomass in northern hemisphere rocky shores. AB - Latitudinal gradients in species abundance and diversity have been postulated for nearshore taxa but few analyses have been done over sufficiently broad geographic scales incorporating various nearshore depth strata to empirically test these gradients. Typically, gradients are based on literature reviews and species lists and have focused on alpha diversity across the entire nearshore zone. No studies have used a standardized protocol in the field to examine species density among sites across a large spatial scale while also focusing on particular depth strata. The present research used field collected samples in the northern hemisphere to explore the relationships between macroalgal species density and biomass along intertidal heights and subtidal depths and latitude. Results indicated no overall correlations between either estimates of species density or biomass with latitude, although the highest numbers of both were found at mid latitudes. However, when strata were examined separately, significant positive correlations were found for both species numbers and biomass at particular strata, namely the intertidal ones. While the data presented in this paper have some limitations, we show that latitudinal macroalgal trends in species density and biomass do exist for some strata in the northern hemisphere with more taxa and biomass at higher latitudes. PMID- 20949031 TI - Non-invasive prenatal detection of trisomy 21 using tandem single nucleotide polymorphisms. AB - BACKGROUND: Screening tests for Trisomy 21 (T21), also known as Down syndrome, are routinely performed for the majority of pregnant women. However, current tests rely on either evaluating non-specific markers, which lead to false negative and false positive results, or on invasive tests, which while highly accurate, are expensive and carry a risk of fetal loss. We outline a novel, rapid, highly sensitive, and targeted approach to non-invasively detect fetal T21 using maternal plasma DNA. METHODS AND FINDINGS: Highly heterozygous tandem Single Nucleotide Polymorphism (SNP) sequences on chromosome 21 were analyzed using High-Fidelity PCR and Cycling Temperature Capillary Electrophoresis (CTCE). This approach was used to blindly analyze plasma DNA obtained from peripheral blood from 40 high risk pregnant women, in adherence to a Medical College of Wisconsin Institutional Review Board approved protocol. Tandem SNP sequences were informative when the mother was heterozygous and a third paternal haplotype was present, permitting a quantitative comparison between the maternally inherited haplotype and the paternally inherited haplotype to infer fetal chromosomal dosage by calculating a Haplotype Ratio (HR). 27 subjects were assessable; 13 subjects were not informative due to either low DNA yield or were not informative at the tandem SNP sequences examined. All results were confirmed by a procedure (amniocentesis/CVS) or at postnatal follow-up. Twenty subjects were identified as carrying a disomy 21 fetus (with two copies of chromosome 21) and seven subjects were identified as carrying a T21 fetus. The sensitivity and the specificity of the assay was 100% when HR values lying between 3/5 and 5/3 were used as a threshold for normal subjects. CONCLUSIONS: In summary, a targeted approach, based on calculation of Haplotype Ratios from tandem SNP sequences combined with a sensitive and quantitative DNA measurement technology can be used to accurately detect fetal T21 in maternal plasma when sufficient fetal DNA is present in maternal plasma. PMID- 20949032 TI - Chronic myeloid leukemia patients sensitive and resistant to imatinib treatment show different metabolic responses. AB - The BCR-ABL tyrosine kinase inhibitor imatinib is highly effective for chronic myeloid leukemia (CML). However, some patients gradually develop resistance to imatinib, resulting in therapeutic failure. Metabonomic and genomic profiling of patients' responses to drug interventions can provide novel information about the in vivo metabolism of low-molecular-weight compounds and extend our insight into the mechanism of drug resistance. Based on a multi-platform of high-throughput metabonomics, SNP array analysis, karyotype and mutation, the metabolic phenotypes and genomic polymorphisms of CML patients and their diverse responses to imatinib were characterized. The untreated CML patients (UCML) showed different metabolic patterns from those of healthy controls, and the discriminatory metabolites suggested the perturbed metabolism of the urea cycle, tricarboxylic acid cycle, lipid metabolism, and amino acid turnover in UCML. After imatinib treatment, patients sensitive to imatinib (SCML) and patients resistant to imatinib (RCML) had similar metabolic phenotypes to those of healthy controls and UCML, respectively. SCML showed a significant metabolic response to imatinib, with marked restoration of the perturbed metabolism. Most of the metabolites characterizing CML were adjusted to normal levels, including the intermediates of the urea cycle and tricarboxylic acid cycle (TCA). In contrast, neither cytogenetic nor metabonomic analysis indicated any positive response to imatinib in RCML. We report for the first time the associated genetic and metabonomic responses of CML patients to imatinib and show that the perturbed in vivo metabolism of UCML is independent of imatinib treatment in resistant patients. Thus, metabonomics can potentially characterize patients' sensitivity or resistance to drug intervention. PMID- 20949033 TI - Drosophila Porin/VDAC affects mitochondrial morphology. AB - Voltage-dependent anion channel (VDAC) has been suggested to be a mediator of mitochondrial-dependent cell death induced by Ca(2+) overload, oxidative stress and Bax-Bid activation. To confirm this hypothesis in vivo, we generated and characterized Drosophila VDAC (porin) mutants and found that Porin is not required for mitochondrial apoptosis, which is consistent with the previous mouse studies. We also reported a novel physiological role of Porin. Loss of porin resulted in locomotive defects and male sterility. Intriguingly, porin mutants exhibited elongated mitochondria in indirect flight muscle, whereas Porin overexpression produced fragmented mitochondria. Through genetic analysis with the components of mitochondrial fission and fusion, we found that the elongated mitochondria phenotype in porin mutants were suppressed by increased mitochondrial fission, but enhanced by increased mitochondrial fusion. Furthermore, increased mitochondrial fission by Drp1 expression suppressed the flight defects in the porin mutants. Collectively, our study showed that loss of Drosophila Porin results in mitochondrial morphological defects and suggested that the defective mitochondrial function by Porin deficiency affects the mitochondrial remodeling process. PMID- 20949034 TI - Deciphering the structure, growth and assembly of amyloid-like fibrils using high speed atomic force microscopy. AB - Formation of fibrillar structures of proteins that deposit into aggregates has been suggested to play a key role in various neurodegenerative diseases. However mechanisms and dynamics of fibrillization remains to be elucidated. We have previously established that lithostathine, a protein overexpressed in the pre clinical stages of Alzheimer's disease and present in the pathognomonic lesions associated with this disease, form fibrillar aggregates after its N-terminal truncation. In this paper we visualized, using high-speed atomic force microscopy (HS-AFM), growth and assembly of lithostathine protofibrils under physiological conditions with a time resolution of one image/s. Real-time imaging highlighted a very high velocity of elongation. Formation of fibrils via protofibril lateral association and stacking was also monitored revealing a zipper-like mechanism of association. We also demonstrate that, like other amyloid beta peptides, two lithostathine protofibrils can associate to form helical fibrils. Another striking finding is the propensity of the end of a growing protofibril or fibril to associate with the edge of a second fibril, forming false branching point. Taken together this study provides new clues about fibrillization mechanism of amyloid proteins. PMID- 20949035 TI - Staphylococcal peptidoglycan co-localizes with Nod2 and TLR2 and activates innate immune response via both receptors in primary murine keratinocytes. AB - In mammalian host cells staphylococcal peptidoglycan (PGN) is recognized by Nod2. Whether PGN is also recognized by TLR2 is disputed. Here we carried out PGN co localization and stimulation studies with TLR2 and Nod2 in wild type and mutant host cells. To exclude contamination with lipoproteins, polymeric staphylococcal PGN (PGN(pol)) was isolated from Staphylococcus aureus Deltalgt (lacking lipidated prelipoproteins). PGN(pol) was biotinylated (PGN-Bio) for fluorescence monitoring with specific antibodies. Keratinocytes from murine oral epithelium (MK) readily internalized PGN-Bio in an endocytosis-like process. In wt MK, PGN(pol) induced intracellular accumulation of Nod2 and TLR2 and co-localized with Nod2 and TLR2, but not with TLR4. In TLR2-deficient MK Nod2 and in Nod2 deficient MK TLR2 was induced, indicating that PGN(pol) recognition by Nod2 is independent of TLR2 and vice versa. In both mutants IL-6 and IL-1B release was decreased by approximately 50% compared to wt MK, suggesting that the immune responses induced by Nod2 and TLR2 are comparable and that the two receptors act additively in MK. In TLR2-transfected HEK293 cells PGN(pol) induced NFkB-promoter fused luciferase expression. To support the data, co-localization and signaling studies were carried out with SHL-PGN, a lipase protein covalently tethered to PGN-fragments of varying sizes at its C-terminus. SHL-PGN also co-localized with Nod2 or TLR2 and induced their accumulation, while SHL without PGN did not. The results show that staphylococcal PGN not only co-localizes with Nod2 but also with TLR2. PGN is able to stimulate the immune system via both receptors. PMID- 20949037 TI - Dinoflagellate phylogeny as inferred from heat shock protein 90 and ribosomal gene sequences. AB - BACKGROUND: Interrelationships among dinoflagellates in molecular phylogenies are largely unresolved, especially in the deepest branches. Ribosomal DNA (rDNA) sequences provide phylogenetic signals only at the tips of the dinoflagellate tree. Two reasons for the poor resolution of deep dinoflagellate relationships using rDNA sequences are (1) most sites are relatively conserved and (2) there are different evolutionary rates among sites in different lineages. Therefore, alternative molecular markers are required to address the deeper phylogenetic relationships among dinoflagellates. Preliminary evidence indicates that the heat shock protein 90 gene (Hsp90) will provide an informative marker, mainly because this gene is relatively long and appears to have relatively uniform rates of evolution in different lineages. METHODOLOGY/PRINCIPAL FINDINGS: We more than doubled the previous dataset of Hsp90 sequences from dinoflagellates by generating additional sequences from 17 different species, representing seven different orders. In order to concatenate the Hsp90 data with rDNA sequences, we supplemented the Hsp90 sequences with three new SSU rDNA sequences and five new LSU rDNA sequences. The new Hsp90 sequences were generated, in part, from four additional heterotrophic dinoflagellates and the type species for six different genera. Molecular phylogenetic analyses resulted in a paraphyletic assemblage near the base of the dinoflagellate tree consisting of only athecate species. However, Noctiluca was never part of this assemblage and branched in a position that was nested within other lineages of dinokaryotes. The phylogenetic trees inferred from Hsp90 sequences were consistent with trees inferred from rDNA sequences in that the backbone of the dinoflagellate clade was largely unresolved. CONCLUSIONS/SIGNIFICANCE: The sequence conservation in both Hsp90 and rDNA sequences and the poor resolution of the deepest nodes suggests that dinoflagellates reflect an explosive radiation in morphological diversity in their recent evolutionary past. Nonetheless, the more comprehensive analysis of Hsp90 sequences enabled us to infer phylogenetic interrelationships of dinoflagellates more rigorously. For instance, the phylogenetic position of Noctiluca, which possesses several unusual features, was incongruent with previous phylogenetic studies. Therefore, the generation of additional dinoflagellate Hsp90 sequences is expected to refine the stem group of athecate species observed here and contribute to future multi-gene analyses of dinoflagellate interrelationships. PMID- 20949036 TI - Comparative genomic evidence for a complete nuclear pore complex in the last eukaryotic common ancestor. AB - BACKGROUND: The Nuclear Pore Complex (NPC) facilitates molecular trafficking between nucleus and cytoplasm and is an integral feature of the eukaryote cell. It exhibits eight-fold rotational symmetry and is comprised of approximately 30 nucleoporins (Nups) in different stoichiometries. Nups are broadly conserved between yeast, vertebrates and plants, but few have been identified among other major eukaryotic groups. METHODOLOGY/PRINCIPAL FINDINGS: We screened for Nups across 60 eukaryote genomes and report that 19 Nups (spanning all major protein subcomplexes) are found in all eukaryote supergroups represented in our study (Opisthokonts, Amoebozoa, Viridiplantae, Chromalveolates and Excavates). Based on parsimony, between 23 and 26 of 31 Nups can be placed in LECA. Notably, they include central components of the anchoring system (Ndc1 and Gp210) indicating that the anchoring system did not evolve by convergence, as has previously been suggested. These results significantly extend earlier results and, importantly, unambiguously place a fully-fledged NPC in LECA. We also test the proposal that transmembrane Pom proteins in vertebrates and yeasts may account for their variant forms of mitosis (open mitoses in vertebrates, closed among yeasts). The distribution of homologues of vertebrate Pom121 and yeast Pom152 is not consistent with this suggestion, but the distribution of fungal Pom34 fits a scenario wherein it was integral to the evolution of closed mitosis in ascomycetes. We also report an updated screen for vesicle coating complexes, which share a common evolutionary origin with Nups, and can be traced back to LECA. Surprisingly, we find only three supergroup-level differences (one gain and two losses) between the constituents of COPI, COPII and Clathrin complexes. CONCLUSIONS/SIGNIFICANCE: Our results indicate that all major protein subcomplexes in the Nuclear Pore Complex are traceable to the Last Eukaryotic Common Ancestor (LECA). In contrast to previous screens, we demonstrate that our conclusions hold regardless of the position of the root of the eukaryote tree. PMID- 20949038 TI - Rational design of a plasmid origin that replicates efficiently in both gram positive and gram-negative bacteria. AB - BACKGROUND: Most plasmids replicate only within a particular genus or family. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe an engineered high copy number expression vector, pBAV1K-T5, that produces varying quantities of active reporter proteins in Escherichia coli, Acinetobacter baylyi ADP1, Agrobacterium tumefaciens, (all gram-negative), Streptococcus pneumoniae, Leifsonia shinshuensis, Peanibacillus sp. S18-36 and Bacillus subtilis (gram-positive). CONCLUSIONS/SIGNIFICANCE: Our results demonstrate the efficiency of pBAV1K-T5 replication in different bacterial species, thereby facilitating the study of proteins that don't fold well in E. coli and pathogens not amenable to existing genetic tools. PMID- 20949039 TI - Characterization of membrane potential dependency of mitochondrial Ca2+ uptake by an improved biophysical model of mitochondrial Ca2+ uniporter. AB - Mitochondrial Ca(2+) uniporter is the primary influx pathway for Ca(2+) into respiring mitochondria, and hence plays a key role in mitochondrial Ca(2+) homeostasis. Though the mechanism of extra-matrix Ca(2+) dependency of mitochondrial Ca(2+) uptake has been well characterized both experimentally and mathematically, the mechanism of membrane potential (DeltaPsi) dependency of mitochondrial Ca(2+) uptake has not been completely characterized. In this paper, we perform a quantitative reevaluation of a previous biophysical model of mitochondrial Ca(2+) uniporter that characterized the possible mechanism of DeltaPsi dependency of mitochondrial Ca(2+) uptake. Based on a model simulation analysis, we show that model predictions with a variant assumption (Case 2: external and internal Ca(2+) binding constants for the uniporter are distinct), that provides the best possible description of the DeltaPsi dependency, are highly sensitive to variation in matrix [Ca(2+)], indicating limitations in the variant assumption (Case 2) in providing physiologically plausible description of the observed DeltaPsi dependency. This sensitivity is attributed to negative estimate of a biophysical parameter that characterizes binding of internal Ca(2+) to the uniporter. Reparameterization of the model with additional nonnengativity constraints on the biophysical parameters showed that the two variant assumptions (Case 1 and Case 2) are indistinguishable, indicating that the external and internal Ca(2+) binding constants for the uniporter may be equal (Case 1). The model predictions in this case are insensitive to variation in matrix [Ca(2+)] but do not match the DeltaPsi dependent data in the domain DeltaPsi<=120 mV. To effectively characterize this DeltaPsi dependency, we reformulate the DeltaPsi dependencies of the rate constants of Ca(2+) translocation via the uniporter by exclusively redefining the biophysical parameters associated with the free-energy barrier of Ca(2+) translocation based on a generalized, non-linear Goldman Hodgkin-Katz formulation. This alternate uniporter model has all the characteristics of the previous uniporter model and is also able to characterize the possible mechanisms of both the extra-matrix Ca(2+) and DeltaPsi dependencies of mitochondrial Ca(2+) uptake. In addition, the model is insensitive to variation in matrix [Ca(2+)], predicting relatively stable physiological operation. The model is critical in developing mechanistic, integrated models of mitochondrial bioenergetics and Ca(2+) handling. PMID- 20949040 TI - Inside the outbreak of the 2009 influenza A (H1N1)v virus in Mexico. AB - BACKGROUND: Influenza viruses pose a threat to human health because of their potential to cause global disease. Between mid March and mid April a pandemic influenza A virus emerged in Mexico. This report details 202 cases of infection of humans with the 2009 influenza A virus (H1N1)v which occurred in Mexico City as well as the spread of the virus throughout the entire country. METHODOLOGY AND FINDINGS: From May 1st to May 5th nasopharyngeal swabs, derived from 751 patients, were collected at 220 outpatient clinics and 28 hospitals distributed throughout Mexico City. Analysis of samples using real time RT-PCR revealed that 202 patients out of the 751 subjects (26.9%) were confirmed to be infected with the new virus. All confirmed cases of human infection with the strain influenza (H1N1)v suffered respiratory symptoms. The greatest number of confirmed cases during the outbreak of the 2009 influenza A (H1N1)v were seen in neighbourhoods on the northeast side of Mexico City including Iztapalapa, Gustavo A. Madero, Iztacalco, and Tlahuac which are the most populated areas in Mexico City. Using these data, together with data reported by the Mexican Secretariat of Health (MSH) to date, we plot the course of influenza (H1N1)v activity throughout Mexico. CONCLUSIONS: Our data, which is backed up by MSH data, show that the greatest numbers of the 2009 influenza A (H1N1) cases were seen in the most populated areas. We speculate on conditions in Mexico which may have sparked this flu pandemic, the first in 41 years. We accept the hypothesis that high population density and a mass gathering which took in Iztapalapa contributed to the rapid spread of the disease which developed in three peaks of activity throughout the Country. PMID- 20949041 TI - 1H-NMR-based metabolomic profiling of CSF in early amyotrophic lateral sclerosis. AB - BACKGROUND: Pathophysiological mechanisms involved in amyotrophic lateral sclerosis (ALS) are complex and none has identified reliable markers useful in routine patient evaluation. The aim of this study was to analyze the CSF of patients with ALS by (1)H NMR (Nuclear Magnetic Resonance) spectroscopy in order to identify biomarkers in the early stages of the disease, and to evaluate the biochemical factors involved in ALS. METHODOLOGY: CSF samples were collected from patients with ALS at the time of diagnosis and from patients without neurodegenerative diseases. One and two-dimensional (1)H NMR analyses were performed and metabolites were quantified by the ERETIC method. We compared the concentrations of CSF metabolites between both groups. Finally, we performed principal component (PCA) and discriminant analyses. PRINCIPAL FINDINGS: Fifty CSF samples from ALS patients and 44 from controls were analyzed. We quantified 17 metabolites including amino-acids, organic acids, and ketone bodies. Quantitative analysis revealed significantly lower acetate concentrations (p = 0.0002) in ALS patients compared to controls. Concentration of acetone trended higher (p = 0.015), and those of pyruvate (p = 0.002) and ascorbate (p = 0.003) were higher in the ALS group. PCA demonstrated that the pattern of analyzed metabolites discriminated between groups. Discriminant analysis using an algorithm of 17 metabolites revealed that patients were accurately classified 81.6% of the time. CONCLUSION/SIGNIFICANCE: CSF screening by NMR spectroscopy could be a useful, simple and low cost tool to improve the early diagnosis of ALS. The results indicate a perturbation of glucose metabolism, and the need to further explore cerebral energetic metabolism. PMID- 20949042 TI - Signal transduction protein array analysis links LRRK2 to Ste20 kinases and PKC zeta that modulate neuronal plasticity. AB - BACKGROUND: Dominant mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, however, the underlying pathogenic mechanisms are poorly understood. Several in vitro studies have shown that the most frequent mutation, LRRK2(G2019S), increases kinase activity and impairs neuronal survival. LRRK2 has been linked to the mitogen-activated protein kinase kinase kinase family and the receptor-interacting protein kinases based on sequence similarity within the kinase domain and in vitro substrate phosphorylation. METHODOLOGY/PRINCIPAL FINDINGS: We used an unbiased proteomic approach to identify the kinase signaling pathways wherein LRRK2 may be active. By incubation of protein microarrays containing 260 signal transduction proteins we detected four arrayed Ste20 serine/threonine kinase family members (TAOK3, STK3, STK24, STK25) as novel LRRK2 substrates and LRRK2 interacting proteins, respectively. Moreover, we found that protein kinase C (PKC) zeta binds and phosphorylates LRRK2 both in vitro and in vivo. CONCLUSIONS/SIGNIFICANCE: Ste20 kinases and PKC zeta contribute to neuronal Tau phosphorylation, neurite outgrowth and synaptic plasticity under physiological conditions. Our data suggest that these kinases may also be involved in synaptic dysfunction and neurite fragmentation in transgenic mice and in human PD patients carrying toxic gain-of-function LRRK2 mutations. PMID- 20949043 TI - EhMAPK, the mitogen-activated protein kinase from Entamoeba histolytica is associated with cell survival. AB - Mitogen Activated Protein Kinases (MAPKs) are a class of serine/threonine kinases that regulate a number of different cellular activities including cell proliferation, differentiation, survival and even death. The pathogen Entamoeba histolytica possess a single homologue of a typical MAPK gene (EhMAPK) whose identification was previously reported by us but its functional implications remained unexplored. EhMAPK, the only mitogen-activated protein kinase from the parasitic protist Entamoeba histolytica with Threonine-X-Tyrosine (TXY) phosphorylation motif was cloned, expressed in E. coli and functionally characterized under different stress conditions. The expression profile of EhMAPK at the protein and mRNA level remained similar among untreated, heat shocked and hydrogen peroxide-treated samples in all cases of dose and time. But a significant difference was obtained in the phosphorylation status of the protein in response to different stresses. Heat shock at 43 degrees C or 0.5 mM H(2)O(2) treatment enhanced the phosphorylation status of EhMAPK and augmented the kinase activity of the protein whereas 2.0 mM H(2)O(2) treatment induced dephosphorylation of EhMAPK and loss of kinase activity. 2.0 mM H(2)O(2) treatment reduced parasite viability significantly but heat shock and 0.5 mM H(2)O(2) treatment failed to adversely affect E. histolytica viability. Therefore, a distinct possibility that activation of EhMAPK is associated with stress survival in E. histolytica is seen. Our study also gives a glimpse of the regulatory mechanism of the protein under in vivo conditions. Since the parasite genome lacks any typical homologue of mammalian MEK, the dual specificity kinases which are the upstream activators of MAPK, indications of the existence of some alternate regulatory mechanisms of the EhMAPK activity is perceived. These may include the autophosphorylation activity of the protein itself in combination with some upstream phosphatases which are not yet identified. PMID- 20949044 TI - Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. AB - BACKGROUND: Exosomes play a major role in cell-to-cell communication, targeting cells to transfer exosomal molecules including proteins, mRNAs, and microRNAs (miRNAs) by an endocytosis-like pathway. miRNAs are small noncoding RNA molecules on average 22 nucleotides in length that regulate numerous biological processes including cancer pathogenesis and mediate gene down-regulation by targeting mRNAs to induce RNA degradation and/or interfering with translation. Recent reports imply that miRNAs can be stably detected in circulating plasma and serum since miRNAs are packaged by exosomes to be protected from RNA degradation. Thus, profiling exosomal miRNAs are in need to clarify intercellular signaling and discover a novel disease marker as well. METHODOLOGY/PRINCIPAL FINDINGS: Exosomes were isolated from cultured cancer cell lines and their quality was validated by analyses of transmission electron microscopy and western blotting. One of the cell lines tested, a metastatic gastric cancer cell line, AZ-P7a, showed the highest RNA yield in the released exosomes and distinctive shape in morphology. In addition, RNAs were isolated from cells and culture media, and profiles of these three miRNA fractions were obtained using microarray analysis. By comparing signal intensities of microarray data and the following validation using RT-PCR analysis, we found that let-7 miRNA family was abundant in both the intracellular and extracellular fractions from AZ-P7a cells, while low metastatic AZ-521, the parental cell line of AZ-P7a, as well as other cancer cell lines showed no such propensity. CONCLUSIONS/SIGNIFICANCE: The enrichment of let-7 miRNA family in the extracellular fractions, particularly, in the exosomes from AZ-P7a cells may reflect their oncogenic characteristics including tumorigenesis and metastasis. Since let-7 miRNAs generally play a tumor-suppressive role as targeting oncogenes such as RAS and HMGA2, our results suggest that AZ-P7a cells release let-7 miRNAs via exosomes into the extracellular environment to maintain their oncogenesis. PMID- 20949046 TI - Neurocognitive systems related to real-world prospective memory. AB - BACKGROUND: Prospective memory (PM) denotes the ability to remember to perform actions in the future. It has been argued that standard laboratory paradigms fail to capture core aspects of PM. METHODOLOGY/PRINCIPAL FINDINGS: We combined functional MRI, virtual reality, eye-tracking and verbal reports to explore the dynamic allocation of neurocognitive processes during a naturalistic PM task where individuals performed errands in a realistic model of their residential town. Based on eye movement data and verbal reports, we modeled PM as an iterative loop of five sustained and transient phases: intention maintenance before target detection (TD), TD, intention maintenance after TD, action, and switching, the latter representing the activation of a new intention in mind. The fMRI analyses revealed continuous engagement of a top-down fronto-parietal network throughout the entire task, likely subserving goal maintenance in mind. In addition, a shift was observed from a perceptual (occipital) system while searching for places to go, to a mnemonic (temporo-parietal, fronto-hippocampal) system for remembering what actions to perform after TD. Updating of the top-down fronto-parietal network occurred at both TD and switching, the latter likely also being characterized by frontopolar activity. CONCLUSION/SIGNIFICANCE: Taken together, these findings show how brain systems complementary interact during real-world PM, and support a more complete model of PM that can be applied to naturalistic PM tasks and that we named PROspective MEmory DYnamic (PROMEDY) model because of its dynamics on both multi-phase iteration and the interactions of distinct neurocognitive networks. PMID- 20949047 TI - Absence of cue-recruitment for extrinsic signals: sounds, spots, and swirling dots fail to influence perceived 3D rotation direction after training. AB - The visual system can learn to use information in new ways to construct appearance. Thus, signals such as the location or translation direction of an ambiguously rotating wire frame cube, which are normally uninformative, can be learned as cues to determine the rotation direction. This perceptual learning occurs when the formerly uninformative signal is statistically associated with long-trusted visual cues (such as binocular disparity) that disambiguate appearance during training. In previous demonstrations, the newly learned cue was intrinsic to the perceived object, in that the signal was conveyed by the same image elements as the object itself. Here we used extrinsic new signals and observed no learning. We correlated three new signals with long-trusted cues in the rotating cube paradigm: one crossmodal (an auditory signal) and two within modality (visual). Cue recruitment did not occur in any of these conditions, either in single sessions or in ten sessions across as many days. These results suggest that the intrinsic/extrinsic distinction is important for the perceptual system in determining whether it can learn and use new information from the environment to construct appearance. Extrinsic cues do have perceptual effects (e.g. the "bounce-pass" illusion and McGurk effect), so we speculate that extrinsic signals must be recruited for perception, but only if certain conditions are met. These conditions might specify the age of the observer, the strength of the long-trusted cues, or the amount of exposure to the correlation. PMID- 20949048 TI - Allelopathic effects of water hyacinth [Eichhornia crassipes]. AB - Eichhornia crassipes (Mart) Solms is an invasive weed known to out-compete native plants and negatively affect microbes including phytoplankton. The spread and population density of E. crassipes will be favored by global warming. The aim here was to identify compounds that underlie the effects on microbes. The entire plant of E. crassipes was collected from El Zomor canal, River Nile (Egypt), washed clean, then air dried. Plant tissue was extracted three times with methanol and fractionated by thin layer chromatography (TLC). The crude methanolic extract and five fractions from TLC (A-E) were tested for antimicrobial (bacteria and fungal) and anti-algal activities (green microalgae and cyanobacteria) using paper disc diffusion bioassay. The crude extract as well as all five TLC fractions exhibited antibacterial activities against both the gram positive bacteria; Bacillus subtilis and Streptococcus faecalis; and the gram negative bacteria; Escherichia coli and Staphylococcus aureus. Growth of Aspergillus flavus and Aspergillus niger were not inhibited by either E. crassipes crude extract nor its five fractions. In contrast, Candida albicans (yeast) was inhibited by all. Some antialgal activity of the crude extract and its fractions was manifest against the green microalgae; Chlorella vulgaris and Dictyochloropsis splendida as well as the cyanobacteria; Spirulina platensis and Nostoc piscinale. High antialgal activity was only recorded against Chlorella vulgaris. Identifications of the active antimicrobial and antialgal compounds of the crude extract as well as the five TLC fractions were carried out using gas chromatography combined with mass spectroscopy. The analyses showed the presence of an alkaloid (fraction A) and four phthalate derivatives (Fractions B-E) that exhibited the antimicrobial and antialgal activities. PMID- 20949049 TI - Developing a simplified consent form for biobanking. AB - BACKGROUND: Consent forms have lengthened over time and become harder for participants to understand. We sought to demonstrate the feasibility of creating a simplified consent form for biobanking that comprises the minimum information necessary to meet ethical and regulatory requirements. We then gathered preliminary data concerning its content from hypothetical biobank participants. METHODOLOGY/PRINCIPAL FINDINGS: We followed basic principles of plain-language writing and incorporated into a 2-page form (not including the signature page) those elements of information required by federal regulations and recommended by best practice guidelines for biobanking. We then recruited diabetes patients from community-based practices and randomized half (n = 56) to read the 2-page form, first on paper and then a second time on a tablet computer. Participants were encouraged to use "More information" buttons on the electronic version whenever they had questions or desired further information. These buttons led to a series of "Frequently Asked Questions" (FAQs) that contained additional detailed information. Participants were asked to identify specific sentences in the FAQs they thought would be important if they were considering taking part in a biorepository. On average, participants identified 7 FAQ sentences as important (mean 6.6, SD 14.7, range: 0-71). No one sentence was highlighted by a majority of participants; further, 34 (60.7%) participants did not highlight any FAQ sentences. CONCLUSIONS: Our preliminary findings suggest that our 2-page form contains the information that most prospective participants identify as important. Combining simplified forms with supplemental material for those participants who desire more information could help minimize consent form length and complexity, allowing the most substantively material information to be better highlighted and enabling potential participants to read the form and ask questions more effectively. PMID- 20949045 TI - Severe imported falciparum malaria: a cohort study in 400 critically ill adults. AB - BACKGROUND: Large studies on severe imported malaria in non-endemic industrialized countries are lacking. We sought to describe the clinical spectrum of severe imported malaria in French adults and to identify risk factors for mortality at admission to the intensive care unit. METHODOLOGY AND PRINCIPAL FINDINGS: Retrospective review of severe Plasmodium falciparum malaria episodes according to the 2000 World Health Organization definition and requiring admission to the intensive care unit. Data were collected from medical charts using standardised case-report forms, in 45 French intensive care units in 2000 2006. Risk factors for in-hospital mortality were identified by univariate and multivariate analyses. Data from 400 adults admitted to the intensive care unit were analysed, representing the largest series of severe imported malaria to date. Median age was 45 years; 60% of patients were white, 96% acquired the disease in sub-Saharan Africa, and 65% had not taken antimalarial chemoprophylaxis. Curative quinine treatment was used in 97% of patients. Intensive care unit mortality was 10.5% (42 deaths). By multivariate analysis, three variables at intensive care unit admission were independently associated with hospital death: older age (per 10-year increment, odds ratio [OR], 1.72; 95% confidence interval [95%CI], 1.28-2.32; P = 0.0004), Glasgow Coma Scale score (per 1-point decrease, OR, 1.32; 95%CI, 1.20-1.45; P<0.0001), and higher parasitemia (per 5% increment, OR, 1.41; 95%CI, 1.22-1.62; P<0.0001). CONCLUSIONS AND SIGNIFICANCE: In a large population of adults treated in a non-endemic industrialized country, severe malaria still carried a high mortality rate. Our data, including predictors of death, can probably be generalized to other non endemic countries where high-quality healthcare is available. PMID- 20949050 TI - Resistance to bleomycin-induced lung fibrosis in MMP-8 deficient mice is mediated by interleukin-10. AB - BACKGROUND: Matrix metalloproteinases (MMPs) may have pro and antifibrotic roles within the lungs, due to its ability to modulate collagen turnover and immune mediators. MMP-8 is a collagenase that also cleaves a number of cytokines and chemokines. METHODOLOGY AND PRINCIPAL FINDINGS: To evaluate its relevance in lung fibrosis, wildtype and Mmp8(-/-) mice were treated with either intratracheal bleomycin or saline, and lungs were harvested at different time points. Fibrosis, collagen, collagenases, gelatinases, TGFbeta and IL-10 were measured in lung tissue. Mmp8(-/-) mice developed less fibrosis than their wildtype counterparts. This was related to an increase in lung inflammatory cells, MMP-9 and IL-10 levels in these mutant animals. In vitro experiments showed that MMP-8 cleaves murine and human IL-10, and tissue from knockout animals showed decreased IL-10 processing. Additionally, lung fibroblasts from these mice were cultured in the presence of bleomycin and collagen, IL-10 and STAT3 activation (downstream signal in response to IL-10) measured by western blotting. In cell cultures, bleomycin increased collagen synthesis only in wildtype mice. Fibroblasts from knockout mice did not show increased collagen synthesis, but increased levels of unprocessed IL-10 and STAT3 phosphorylation. Blockade of IL-10 reverted this phenotype, increasing collagen in cultures. CONCLUSIONS: According to these results, we conclude that the absence of MMP-8 has an antifibrotic effect by increasing IL-10 and propose that this metalloprotease could be a relevant modulator of IL-10 metabolism in vivo. PMID- 20949052 TI - Stranger to familiar: wild strepsirhines manage xenophobia by playing. AB - The power of play in limiting xenophobia is a well-known phenomenon in humans. Yet, the evidence in social animals remains meager. Here, we aim to determine whether play promotes social tolerance toward strangers in one of the most basal group of primates, the strepsirhines. We observed two groups of wild lemurs (Propithecus verreauxi, Verreaux's sifaka) during the mating season. Data were also collected on nine visiting, outgroup males. We compared the distribution of play, grooming, and aggressive interactions across three conditions: OUT (resident/outgroup interactions), IN (resident/resident interactions in presence of outgroups) and BL-IN (baseline of resident/resident interactions in absence of outgroups). Play frequency between males was higher in OUT than in IN and BL-IN conditions; whereas, grooming was more frequent in IN than in OUT and BL-IN conditions. Aggression rates between resident and outgroup males were significantly higher than those between residents. However, aggressions between resident and outgroup males significantly decreased after the first play session and became comparable with resident-resident aggression levels. The presence of strangers in a well-established group implies the onset of novel social circumstances, which sifaka males cope with by two different tactics: grooming with ingroup males and playing with outgroup ones. The grooming peak, concurrently with the visit of outgroups, probably represents a social shield adopted by resident males to make their pre-existing affiliation more evident to the stranger "audience". Being mostly restricted to unfamiliar males, adult play in sifaka appears to have a role in managing new social situations more than in maintaining old relationships. In particular, our results indicate not only that play is the interface between strangers but also that it has a specific function in reducing xenophobia. In conclusion, play appears to be an ice-breaker mechanism in the critical process that "upgrades" an individual from stranger to familiar. PMID- 20949054 TI - Private sector participation and health system performance in sub-saharan Africa. AB - BACKGROUND: The role of the private health sector in developing countries remains a much-debated and contentious issue. Critics argue that the high prices charged in the private sector limits the use of health care among the poorest, consequently reducing access and equity in the use of health care. Supporters argue that increased private sector participation might improve access and equity by bringing in much needed resources for health care and by allowing governments to increase focus on underserved populations. However, little empirical exists for or against either side of this debate. METHODOLOGY/PRINCIPAL FINDINGS: We examine the association between private sector participation and self-reported measures of utilization and equity in deliveries and treatment of childhood respiratory disease using regression analysis, across a sample of nationally representative Demographic and Health Surveys from 34 SSA economies. We also examine the correlation between private sector participation and key background factors (socioeconomic development, business environment and governance) and use multivariate regression to control for potential confounders. Private sector participation is positively associated with greater overall access and reduced disparities between rich and poor as well as urban and rural populations. The positive association between private sector participation and improved health system performance is robust to controlling for confounders including per capita income and maternal education. Private sector participation is positively correlated with measures of socio-economic development and favorable business environment. CONCLUSIONS/SIGNIFICANCE: Greater participation is associated with favorable intermediate outcomes in terms of access and equity. While these results do not establish a causal link between private sector participation and health system performance, they suggest that there is no deleterious link between private sector participation and health system performance in SSA. PMID- 20949053 TI - Real time imaging of human progenitor neurogenesis. AB - Human neural progenitors are increasingly being employed in drug screens and emerging cell therapies targeted towards neurological disorders where neurogenesis is thought to play a key role including developmental disorders, Alzheimer's disease, and depression. Key to the success of these applications is understanding the mechanisms by which neurons arise. Our understanding of development can provide some guidance but since little is known about the specifics of human neural development and the requirement that cultures be expanded in vitro prior to use, it is unclear whether neural progenitors obey the same developmental mechanisms that exist in vivo. In previous studies we have shown that progenitors derived from fetal cortex can be cultured for many weeks in vitro as undifferentiated neurospheres and then induced to undergo neurogenesis by removing mitogens and exposing them to supportive substrates. Here we use live time lapse imaging and immunocytochemical analysis to show that neural progenitors use developmental mechanisms to generate neurons. Cells with morphologies and marker profiles consistent with radial glia and recently described outer radial glia divide asymmetrically and symmetrically to generate multipolar intermediate progenitors, a portion of which express ASCL1. These multipolar intermediate progenitors subsequently divide symmetrically to produce CTIP2(+) neurons. This 3-cell neurogenic scheme echoes observations in rodents in vivo and in human fetal slice cultures in vitro, providing evidence that hNPCs represent a renewable and robust in vitro assay system to explore mechanisms of human neurogenesis without the continual need for fresh primary human fetal tissue. Knowledge provided by this and future explorations of human neural progenitor neurogenesis will help maximize the safety and efficacy of new stem cell therapies by providing an understanding of how to generate physiologically relevant cell types that maintain their identities when placed in diagnostic or transplantation environments. PMID- 20949055 TI - Loss of LMO4 in the retina leads to reduction of GABAergic amacrine cells and functional deficits. AB - BACKGROUND: LMO4 is a transcription cofactor expressed during retinal development and in amacrine neurons at birth. A previous study in zebrafish reported that morpholino RNA ablation of one of two related genes, LMO4b, increases the size of eyes in embryos. However, the significance of LMO4 in mammalian eye development and function remained unknown since LMO4 null mice die prior to birth. METHODOLOGY/PRINCIPAL FINDINGS: We observed the presence of a smaller eye and/or coloboma in ~40% LMO4 null mouse embryos. To investigate the postnatal role of LMO4 in retinal development and function, LMO4 was conditionally ablated in retinal progenitor cells using the Pax6 alpha-enhancer Cre/LMO4flox mice. We found that these mice have fewer Bhlhb5-positive GABAergic amacrine and OFF-cone bipolar cells. The deficit appears to affect the postnatal wave of Bhlhb5+ neurons, suggesting a temporal requirement for LMO4 in retinal neuron development. In contrast, cholinergic and dopaminergic amacrine, rod bipolar and photoreceptor cell numbers were not affected. The selective reduction in these interneurons was accompanied by a functional deficit revealed by electroretinography, with reduced amplitude of b-waves, indicating deficits in the inner nuclear layer of the retina. CONCLUSIONS/SIGNIFICANCE: Inhibitory GABAergic interneurons play a critical function in controlling retinal image processing, and are important for neural networks in the central nervous system. Our finding of an essential postnatal function of LMO4 in the differentiation of Bhlhb5-expressing inhibitory interneurons in the retina may be a general mechanism whereby LMO4 controls the production of inhibitory interneurons in the nervous system. PMID- 20949056 TI - Inhibition of Plasmodium falciparum field isolates-mediated endothelial cell apoptosis by Fasudil: therapeutic implications for severe malaria. AB - Plasmodium falciparum infection can abruptly progress to severe malaria, a life threatening complication resulting from sequestration of parasitized red blood cells (PRBC) in the microvasculature of various organs such as the brain and lungs. PRBC adhesion can induce endothelial cell (EC) activation and apoptosis, thereby disrupting the blood-brain barrier. Moreover, hemozoin, the malarial pigment, induces the erythroid precursor apoptosis. Despite the current efficiency of antimalarial drugs in killing parasites, severe malaria still causes up to one million deaths every year. A new strategy targeting both parasite elimination and EC protection is urgently needed in the field. Recently, a rho-kinase inhibitor Fasudil, a drug already in clinical use in humans for cardio- and neuro-vascular diseases, was successfully tested on laboratory strains of P. falciparum to protect and to reverse damages of the endothelium. We therefore assessed herein whether Fasudil would have a similar efficiency on P. falciparum taken directly from malaria patients using contact and non-contact experiments. Seven (23.3%) of 30 PRBC preparations from different patients were apoptogenic, four (13.3%) acting by cytoadherence and three (10%) via soluble factors. None of the apoptogenic PRBC preparations used both mechanisms indicating a possible mutual exclusion of signal transduction ligand. Three PRBC preparations (42.9%) induced EC apoptosis by cytoadherence after 4 h of coculture ("rapid transducers"), and four (57.1%) after a minimum of 24 h ("slow transducers"). The intensity of apoptosis increased with time. Interestingly, Fasudil inhibited EC apoptosis mediated both by cell-cell contact and by soluble factors but did not affect PRBC cytoadherence. Fasudil was found to be able to prevent endothelium apoptosis from all the P. falciparum isolates tested. Our data provide evidence of the strong anti-apoptogenic effect of Fasudil and show that endothelial cell-P. falciparum interactions are more complicated than previously thought. These findings may warrant clinical trials of Fasudil in severe malaria management. PMID- 20949057 TI - Identification of genetic and epigenetic marks involved in population structure. AB - Population structure is well known as a prevalent and important factor in genetic studies, but its relevance in epigenetics is unclear. Very little is known about the affected epigenetic markers and their connections with genetics. In this study we assessed the impact of population diversity on genome wide single nucleotide polymorphisms (SNPs) and DNA methylation levels in 196 participants from five ethnic groups, using principle and independent component analyses. Three population stratification factors (PSFs) were identified in the genomic SNP dataset, accounting for a relatively large portion of total variance (6%). In contrast, only one PSF was identified in genomic methylation dataset accounting for 0.2% of total variance. This methylation PSF, however, was significantly correlated with the largest SNP PSF (r = 0.72, p<1E-23). We then investigated the top contributing markers in these two linked PSFs. The SNP PSF predominantly consists of 8 SNPs from three genes, SLC45A2, HERC2 and CTNNA2, known to encode skin/hair/eye color. The methylation PSF includes 48 methylated sites in 44 genes coding for basic molecular functions, including transcription regulation, DNA binding, cytokine, and transferase activity. Among them, 8 sites are either hypo- or hyper-methylated correlating to minor alleles of SNPs in the SNP PSF. We found that the genes in SNP and methylation PSFs share common biological processes including sexual/multicellular organism reproduction, cell-cell signaling and cytoskeleton organization. We further investigated the transcription regulatory network operating at these genes and identified that most of genes closely interact with ID2, which encodes for a helix-loop-helix inhibitor of DNA binding. Overall, our results show a significant correlation between genetic and epigenetic population stratification, and suggest that the interrelationship between genetic and epigenetic population structure is mediated via complex multiple gene interactions in shared biological processes, through possibly, SNP dependent modulation and ID2 repressor function. PMID- 20949058 TI - Wired to be social: the ontogeny of human interaction. AB - BACKGROUND: Newborns come into the world wired to socially interact. Is a propensity to socially oriented action already present before birth? Twin pregnancies provide a unique opportunity to investigate the social pre-wiring hypothesis. Although various types of inter-twins contact have been demonstrated starting from the 11(th) week of gestation, no study has so far investigated the critical question whether intra-pair contact is the result of motor planning rather then the accidental outcome of spatial proximity. METHODOLOGY/PRINCIPAL FINDINGS: Kinematic profiles of movements in five pairs of twin foetuses were studied by using four-dimensional ultrasonography during two separate recording sessions carried out at the 14(th) and 18(th) week of gestation. We demonstrate that by the 14th week of gestation twin foetuses do not only display movements directed towards the uterine wall and self-directed movements, but also movements specifically aimed at the co-twin, the proportion of which increases between the 14(th) and 18(th) gestational week. Kinematic analysis revealed that movement duration was longer and deceleration time was prolonged for other-directed movements compared to movements directed towards the uterine wall. Similar kinematic profiles were observed for movements directed towards the co-twin and self-directed movements aimed at the eye-region, i.e. the most delicate region of the body. CONCLUSIONS/SIGNIFICANCE: We conclude that performance of movements towards the co-twin is not accidental: already starting from the 14th week of gestation twin foetuses execute movements specifically aimed at the co-twin. PMID- 20949059 TI - Evaluation of a cervical cancer screening program based on HPV testing and LLETZ excision in a low resource setting. AB - We conducted studies in Vanuatu to evaluate potential screening and treatment strategies to assist with control of cervical cancer. In a pilot study of 496 women, visual inspection and cytology were evaluated as screening tests for detection of CIN 2 or worse (CIN2+), observed in 21 of 206 subjects biopsied on the basis of abnormal visual inspection or cytology. Sensitivity of visual inspection with Lugol's Iodine for detection of CIN2+ on biopsy was 0.63, specificity was 0.32, and the positive predictive value was 0.09. For HSIL cytology, sensitivity was 0.99, specificity was 0.77, and the positive predictive value was 0.88. HSIL cytology was significantly more sensitive and had a significantly higher PPV for CIN 2+ than visual inspection (p<0.01). In a further study of 514 women, we compared testing for HR HPV and cytology as predictors of biopsy proven CIN 2+. Sensitivity of HSIL cytology for CIN2+ as established by loop excision of the cervix was 0.81, specificity was 0.94, and positive predictive value was 0.48. Sensitivity of a positive test for HR HPV for detection of CIN2+ was non-significantly different from cytology at 0.81, specificity was 0.94, and positive predictive value was 0.42. Combining the two tests gave a significantly lower sensitivity of 0.63, a specificity of 0.98, and a positive predictive value of 0.68. For women over 30 in a low resource setting without access to cytology, a single locally conducted test for high risk HPV with effective intervention could reduce cervical cancer risk as effectively as intervention based on cytology conducted in an accredited laboratory. PMID- 20949060 TI - The multifunctional host defense peptide SPLUNC1 is critical for homeostasis of the mammalian upper airway. AB - Otitis media (OM) is a highly prevalent pediatric disease caused by normal flora of the nasopharynx that ascend the Eustachian tube and enter the middle ear. As OM is a disease of opportunity, it is critical to gain an increased understanding of immune system components that are operational in the upper airway and aid in prevention of this disease. SPLUNC1 is an antimicrobial host defense peptide that is hypothesized to contribute to the health of the airway both through bactericidal and non-bactericidal mechanisms. We used small interfering RNA (siRNA) technology to knock down expression of the chinchilla ortholog of human SPLUNC1 (cSPLUNC1) to begin to determine the role that this protein played in prevention of OM. We showed that knock down of cSPLUNC1 expression did not impact survival of nontypeable Haemophilus influenzae, a predominant causative agent of OM, in the chinchilla middle ear under the conditions tested. In contrast, expression of cSPLUNC1 was essential for maintenance of middle ear pressure and efficient mucociliary clearance, key defense mechanisms of the tubotympanum. Collectively, our data have provided the first in vivo evidence that cSPLUNC1 functions to maintain homeostasis of the upper airway and, thereby, is critical for protection of the middle ear. PMID- 20949061 TI - Differentiation of the endometrial macrophage during pregnancy in the cow. AB - BACKGROUND: The presence of conceptus alloantigens necessitates changes in maternal immune function. One player in this process may be the macrophage. In the cow, there is large-scale recruitment of macrophages expressing CD68 and CD14 to the uterine endometrium during pregnancy. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, the function of endometrial macrophages during pregnancy was inferred by comparison of the transcriptome of endometrial CD14(+) cells isolated from pregnant cows as compared to that of blood CD14(+) cells. The pattern of gene expression was largely similar for CD14(+) cells from both sources, suggesting that cells from both tissues are from the monocyte/macrophage lineage. A total of 1,364 unique genes were differentially expressed, with 680 genes upregulated in endometrial CD14(+) cells as compared to blood CD14(+) cells and with 674 genes downregulated in endometrial CD14(+) cells as compared to blood CD14(+) cells. Twelve genes characteristic of M2 activated macrophages (SLCO2B1, GATM, MRC1, ALDH1A1, PTGS1, RNASE6, CLEC7A, DPEP2, CD163, CCL22, CCL24, and CDH1) were upregulated in endometrial CD14(+) cells. M2 macrophages play roles in immune regulation, tissue remodeling, angiogenesis and apoptosis. Consistent with a role in tissue remodeling, there was over-representation of differentially expressed genes in endometrium for three ontologies related to proteolysis. A role in apoptosis is suggested by the observation that the most overrepresented gene in endometrial CD14(+) cells was GZMA. CONCLUSIONS: Results indicate that at least a subpopulation of endometrial macrophages cells differentiates along an M2 activation pathway during pregnancy and that the cells are likely to play roles in immune regulation, tissue remodeling, angiogenesis, and apoptosis. PMID- 20949062 TI - Surface covering of downed logs: drivers of a neglected process in dead wood ecology. AB - Many species use coarse woody debris (CWD) and are disadvantaged by the forestry induced loss of this resource. A neglected process affecting CWD is the covering of the surfaces of downed logs caused by sinking into the ground (increasing soil contact, mostly covering the underside of the log), and dense overgrowth by ground vegetation. Such cover is likely to profoundly influence the quality and accessibility of CWD for wood-inhabiting organisms, but the factors affecting covering are largely unknown. In a five-year experiment we determined predictors of covering rate of fresh logs in boreal forests and clear-cuts. Logs with branches were little covered because they had low longitudinal ground contact. For branchless logs, longitudinal ground contact was most strongly related to estimated peat depth (positive relation). The strongest predictor for total cover of branchless logs was longitudinal ground contact. To evaluate the effect on cover of factors other than longitudinal ground contact, we separately analyzed data from only those log sections that were in contact with the ground. Four factors were prominent predictors of percentage cover of such log sections: estimated peat depth, canopy shade (both increasing cover), potential solar radiation calculated from slope and slope aspect, and diameter of the log (both reducing cover). Peat increased cover directly through its low resistance, which allowed logs to sink and soil contact to increase. High moisture and low temperatures in pole-ward facing slopes and under a canopy favor peat formation through lowered decomposition and enhanced growth of peat-forming mosses, which also proved to rapidly overgrow logs. We found that in some boreal forests, peat and fast-growing mosses can rapidly cover logs lying on the ground. When actively introducing CWD for conservation purposes, we recommend that such rapid covering is avoided, thereby most likely improving the CWD's longevity as habitat for many species. PMID- 20949063 TI - Structural transformation of the tandem ubiquitin-interacting motifs in ataxin-3 and their cooperative interactions with ubiquitin chains. AB - The ubiquitin-interacting motif (UIM) is a short peptide with dual function of binding ubiquitin (Ub) and promoting ubiquitination. We elucidated the structures and dynamics of the tandem UIMs of ataxin-3 (AT3-UIM12) both in free and Ub-bound forms. The solution structure of free AT3-UIM12 consists of two alpha-helices and a flexible linker, whereas that of the Ub-bound form is much more compact with hydrophobic contacts between the two helices. NMR dynamics indicates that the flexible linker becomes rigid when AT3-UIM12 binds with Ub. Isothermal titration calorimetry and NMR titration demonstrate that AT3-UIM12 binds diUb with two distinct affinities, and the linker plays a critical role in association of the two helices in diUb binding. These results provide an implication that the tandem UIM12 interacts with Ub or diUb in a cooperative manner through an allosteric effect and dynamics change of the linker region, which might be related to its recognitions with various Ub chains and ubiquitinated substrates. PMID- 20949064 TI - Environmental symbiont acquisition may not be the solution to warming seas for reef-building corals. AB - BACKGROUND: Coral reefs worldwide are in decline. Much of the mortality can be attributed to coral bleaching (loss of the coral's intracellular photosynthetic algal symbiont) associated with global warming. How corals will respond to increasing oceanic temperatures has been an area of extensive study and debate. Recovery after a bleaching event is dependent on regaining symbionts, but the source of repopulating symbionts is poorly understood. Possibilities include recovery from the proliferation of endogenous symbionts or recovery by uptake of exogenous stress-tolerant symbionts. METHODOLOGY/PRINCIPAL FINDINGS: To test one of these possibilities, the ability of corals to acquire exogenous symbionts, bleached colonies of Porites divaricata were exposed to symbiont types not normally found within this coral and symbiont acquisition was monitored. After three weeks exposure to exogenous symbionts, these novel symbionts were detected in some of the recovering corals, providing the first experimental evidence that scleractinian corals are capable of temporarily acquiring symbionts from the water column after bleaching. However, the acquisition was transient, indicating that the new symbioses were unstable. Only those symbiont types present before bleaching were stable upon recovery, demonstrating that recovery was from the resident in situ symbiont populations. CONCLUSIONS/SIGNIFICANCE: These findings suggest that some corals do not have the ability to adjust to climate warming by acquiring and maintaining exogenous, more stress-tolerant symbionts. This has serious ramifications for the success of coral reefs and surrounding ecosystems and suggests that unless actions are taken to reverse it, climate change will lead to decreases in biodiversity and a loss of coral reefs. PMID- 20949065 TI - Crystal structure of Legionella DotD: insights into the relationship between type IVB and type II/III secretion systems. AB - The Dot/Icm type IVB secretion system (T4BSS) is a pivotal determinant of Legionella pneumophila pathogenesis. L. pneumophila translocate more than 100 effector proteins into host cytoplasm using Dot/Icm T4BSS, modulating host cellular functions to establish a replicative niche within host cells. The T4BSS core complex spanning the inner and outer membranes is thought to be made up of at least five proteins: DotC, DotD, DotF, DotG and DotH. DotH is the outer membrane protein; its targeting depends on lipoproteins DotC and DotD. However, the core complex structure and assembly mechanism are still unknown. Here, we report the crystal structure of DotD at 2.0 A resolution. The structure of DotD is distinct from that of VirB7, the outer membrane lipoprotein of the type IVA secretion system. In contrast, the C-terminal domain of DotD is remarkably similar to the N-terminal subdomain of secretins, the integral outer membrane proteins that form substrate conduits for the type II and the type III secretion systems (T2SS and T3SS). A short beta-segment in the otherwise disordered N terminal region, located on the hydrophobic cleft of the C-terminal domain, is essential for outer membrane targeting of DotH and Dot/Icm T4BSS core complex formation. These findings uncover an intriguing link between T4BSS and T2SS/T3SS. PMID- 20949066 TI - The SR-BI partner PDZK1 facilitates hepatitis C virus entry. AB - Entry of hepatitis C virus (HCV) into hepatocytes is a multi-step process that involves a number of different host cell factors. Following initial engagement with glycosaminoglycans and the low-density lipoprotein receptor, it is thought that HCV entry proceeds via interactions with the tetraspanin CD81, scavenger receptor class B type I (SR-BI), and the tight-junction proteins claudin-1 (CLDN1) and occludin (OCLN), culminating in clathrin-dependent endocytosis of HCV particles and their pH-dependent fusion with endosomal membranes. Physiologically, SR-BI is the major receptor for high-density lipoproteins (HDL) in the liver, where its expression is primarily controlled at the post transcriptional level by its interaction with the scaffold protein PDZK1. However, the importance of interaction with PDZK1 to the involvement of SR-BI in HCV entry is unclear. Here we demonstrate that stable shRNA-knockdown of PDZK1 expression in human hepatoma cells significantly reduces their susceptibility to HCV infection, and that this effect can be reversed by overexpression of full length PDZK1 but not the first PDZ domain of PDZK1 alone. Furthermore, we found that overexpression of a green fluorescent protein chimera of the cytoplasmic carboxy-terminus of SR-BI (amino acids 479-509) in Huh-7 cells resulted in its interaction with PDZK1 and a reduced susceptibility to HCV infection. In contrast a similar chimera lacking the final amino acid of SR-BI (amino acids 479-508) failed to interact with PDZK1 and did not inhibit HCV infection. Taken together these results indicate an indirect involvement of PDZK1 in HCV entry via its ability to interact with SR-BI and enhance its activity as an HCV entry factor. PMID- 20949067 TI - Dengue virus ensures its fusion in late endosomes using compartment-specific lipids. AB - Many enveloped viruses invade cells via endocytosis and use different environmental factors as triggers for virus-endosome fusion that delivers viral genome into cytosol. Intriguingly, dengue virus (DEN), the most prevalent mosquito-borne virus that infects up to 100 million people each year, fuses only in late endosomes, while activation of DEN protein fusogen glycoprotein E is triggered already at pH characteristic for early endosomes. Are there any cofactors that time DEN fusion to virion entry into late endosomes? Here we show that DEN utilizes bis(monoacylglycero)phosphate, a lipid specific to late endosomes, as a co-factor for its endosomal acidification-dependent fusion machinery. Effective virus fusion to plasma- and intracellular- membranes, as well as to protein-free liposomes, requires the target membrane to contain anionic lipids such as bis(monoacylglycero)phosphate and phosphatidylserine. Anionic lipids act downstream of low-pH-dependent fusion stages and promote the advance from the earliest hemifusion intermediates to the fusion pore opening. To reach anionic lipid-enriched late endosomes, DEN travels through acidified early endosomes, but we found that low pH-dependent loss of fusogenic properties of DEN is relatively slow in the presence of anionic lipid-free target membranes. We propose that anionic lipid-dependence of DEN fusion machinery protects it against premature irreversible restructuring and inactivation and ensures viral fusion in late endosomes, where the virus encounters anionic lipids for the first time during entry. Currently there are neither vaccines nor effective therapies for DEN, and the essential role of the newly identified DEN bis(monoacylglycero)phosphate interactions in viral genome escape from the endosome suggests a novel target for drug design. PMID- 20949068 TI - Concerted action of two formins in gliding motility and host cell invasion by Toxoplasma gondii. AB - The invasive forms of apicomplexan parasites share a conserved form of gliding motility that powers parasite migration across biological barriers, host cell invasion and egress from infected cells. Previous studies have established that the duration and direction of gliding motility are determined by actin polymerization; however, regulators of actin dynamics in apicomplexans remain poorly characterized. In the absence of a complete ARP2/3 complex, the formin homology 2 domain containing proteins and the accessory protein profilin are presumed to orchestrate actin polymerization during host cell invasion. Here, we have undertaken the biochemical and functional characterization of two Toxoplasma gondii formins and established that they act in concert as actin nucleators during invasion. The importance of TgFRM1 for parasite motility has been assessed by conditional gene disruption. The contribution of each formin individually and jointly was revealed by an approach based upon the expression of dominant mutants with modified FH2 domains impaired in actin binding but still able to dimerize with their respective endogenous formin. These mutated FH2 domains were fused to the ligand-controlled destabilization domain (DD-FKBP) to achieve conditional expression. This strategy proved unique in identifying the non-redundant and critical roles of both formins in invasion. These findings provide new insights into how controlled actin polymerization drives the directional movement required for productive penetration of parasites into host cells. PMID- 20949070 TI - H3K27me3 profiling of the endosperm implies exclusion of polycomb group protein targeting by DNA methylation. AB - Polycomb group (PcG) proteins act as evolutionary conserved epigenetic mediators of cell identity because they repress transcriptional programs that are not required at particular developmental stages. Each tissue is likely to have a specific epigenetic profile, which acts as a blueprint for its developmental fate. A hallmark for Polycomb Repressive Complex 2 (PRC2) activity is trimethylated lysine 27 on histone H3 (H3K27me3). In plants, there are distinct PRC2 complexes for vegetative and reproductive development, and it was unknown so far whether these complexes have target gene specificity. The Fertilization Independent Seed (FIS) PRC2 complex is specifically expressed in the endosperm and is required for its development; loss of FIS function causes endosperm hyperproliferation and seed abortion. The endosperm nourishes the embryo, similar to the physiological function of the placenta in mammals. We established the endosperm H3K27me3 profile and identified specific target genes of the FIS complex with functional roles in endosperm cellularization and chromatin architecture, implicating that distinct PRC2 complexes have a subset of specific target genes. Importantly, our study revealed that selected transposable elements and protein coding genes are specifically targeted by the FIS PcG complex in the endosperm, whereas these elements and genes are densely marked by DNA methylation in vegetative tissues, suggesting that DNA methylation prevents targeting by PcG proteins in vegetative tissues. PMID- 20949069 TI - Staphylococcus epidermidis strategies to avoid killing by human neutrophils. AB - Staphylococcus epidermidis is a leading nosocomial pathogen. In contrast to its more aggressive relative S. aureus, it causes chronic rather than acute infections. In highly virulent S. aureus, phenol-soluble modulins (PSMs) contribute significantly to immune evasion and aggressive virulence by their strong ability to lyse human neutrophils. Members of the PSM family are also produced by S. epidermidis, but their role in immune evasion is not known. Notably, strong cytolytic capacity of S. epidermidis PSMs would be at odds with the notion that S. epidermidis is a less aggressive pathogen than S. aureus, prompting us to examine the biological activities of S. epidermidis PSMs. Surprisingly, we found that S. epidermidis has the capacity to produce PSMdelta, a potent leukocyte toxin, representing the first potent cytolysin to be identified in that pathogen. However, production of strongly cytolytic PSMs was low in S. epidermidis, explaining its low cytolytic potency. Interestingly, the different approaches of S. epidermidis and S. aureus to causing human disease are thus reflected by the adaptation of biological activities within one family of virulence determinants, the PSMs. Nevertheless, S. epidermidis has the capacity to evade neutrophil killing, a phenomenon we found is partly mediated by resistance mechanisms to antimicrobial peptides (AMPs), including the protease SepA, which degrades AMPs, and the AMP sensor/resistance regulator, Aps (GraRS). These findings establish a significant function of SepA and Aps in S. epidermidis immune evasion and explain in part why S. epidermidis may evade elimination by innate host defense despite the lack of cytolytic toxin expression. Our study shows that the strategy of S. epidermidis to evade elimination by human neutrophils is characterized by a passive defense approach and provides molecular evidence to support the notion that S. epidermidis is a less aggressive pathogen than S. aureus. PMID- 20949071 TI - Release of intracellular calcium stores facilitates coxsackievirus entry into polarized endothelial cells. AB - Group B coxsackieviruses (CVB) are associated with viral-induced heart disease and are among the leading causes of aseptic meningitis worldwide. Here we show that CVB entry into polarized brain microvasculature and aortic endothelial cells triggers a depletion of intracellular calcium stores initiated through viral attachment to the apical attachment factor decay-accelerating factor. Calcium release was dependent upon a signaling cascade that required the activity of the Src family of tyrosine kinases, phospholipase C, and the inositol 1,4,5 trisphosphate receptor isoform 3. CVB-mediated calcium release was required for the activation of calpain-2, a calcium-dependent cysteine protease, which controlled the vesicular trafficking of internalized CVB particles. These data point to a specific role for calcium signaling in CVB entry into polarized endothelial monolayers and highlight the unique signaling mechanisms used by these viruses to cross endothelial barriers. PMID- 20949072 TI - Distinct clones of Yersinia pestis caused the black death. AB - From AD 1347 to AD 1353, the Black Death killed tens of millions of people in Europe, leaving misery and devastation in its wake, with successive epidemics ravaging the continent until the 18(th) century. The etiology of this disease has remained highly controversial, ranging from claims based on genetics and the historical descriptions of symptoms that it was caused by Yersinia pestis to conclusions that it must have been caused by other pathogens. It has also been disputed whether plague had the same etiology in northern and southern Europe. Here we identified DNA and protein signatures specific for Y. pestis in human skeletons from mass graves in northern, central and southern Europe that were associated archaeologically with the Black Death and subsequent resurgences. We confirm that Y. pestis caused the Black Death and later epidemics on the entire European continent over the course of four centuries. Furthermore, on the basis of 17 single nucleotide polymorphisms plus the absence of a deletion in glpD gene, our aDNA results identified two previously unknown but related clades of Y. pestis associated with distinct medieval mass graves. These findings suggest that plague was imported to Europe on two or more occasions, each following a distinct route. These two clades are ancestral to modern isolates of Y. pestis biovars Orientalis and Medievalis. Our results clarify the etiology of the Black Death and provide a paradigm for a detailed historical reconstruction of the infection routes followed by this disease. PMID- 20949073 TI - Alternative splicing at a NAGNAG acceptor site as a novel phenotype modifier. AB - Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to result in insertion or deletion (indel) of three nucleotides. We identified such a mechanism as the origin of the mild to asymptomatic phenotype observed in cystic fibrosis patients homozygous for the E831X mutation (2623G>T) in the CFTR gene. Analyses performed on nasal epithelial cell mRNA detected three distinct isoforms, a considerably more complex situation than expected for a single nucleotide substitution. Structure-function studies and in silico analyses provided the first experimental evidence of an indel of a stop codon by alternative splicing at a NAGNAG acceptor site. In addition to contributing to proteome plasticity, alternative splicing at a NAGNAG tandem site can thus remove a disease-causing UAG stop codon. This molecular study reveals a naturally occurring mechanism where the effect of either modifier genes or epigenetic factors could be suspected. This finding is of importance for genetic counseling as well as for deciding appropriate therapeutic strategies. PMID- 20949074 TI - Transforming growth factor-beta: activation by neuraminidase and role in highly pathogenic H5N1 influenza pathogenesis. AB - Transforming growth factor-beta (TGF-beta), a multifunctional cytokine regulating several immunologic processes, is expressed by virtually all cells as a biologically inactive molecule termed latent TGF-beta (LTGF-beta). We have previously shown that TGF-beta activity increases during influenza virus infection in mice and suggested that the neuraminidase (NA) protein mediates this activation. In the current study, we determined the mechanism of activation of LTGF-beta by NA from the influenza virus A/Gray Teal/Australia/2/1979 by mobility shift and enzyme inhibition assays. We also investigated whether exogenous TGF beta administered via a replication-deficient adenovirus vector provides protection from H5N1 influenza pathogenesis and whether depletion of TGF-beta during virus infection increases morbidity in mice. We found that both the influenza and bacterial NA activate LTGF-beta by removing sialic acid motifs from LTGF-beta, each NA being specific for the sialic acid linkages cleaved. Further, NA likely activates LTGF-beta primarily via its enzymatic activity, but proteases might also play a role in this process. Several influenza A virus subtypes (H1N1, H1N2, H3N2, H5N9, H6N1, and H7N3) except the highly pathogenic H5N1 strains activated LTGF-beta in vitro and in vivo. Addition of exogenous TGF-beta to H5N1 influenza virus-infected mice delayed mortality and reduced viral titers whereas neutralization of TGF-beta during H5N1 and pandemic 2009 H1N1 infection increased morbidity. Together, these data show that microbe-associated NAs can directly activate LTGF-beta and that TGF-beta plays a pivotal role protecting the host from influenza pathogenesis. PMID- 20949075 TI - Retroviral RNA dimerization and packaging: the what, how, when, where, and why. PMID- 20949076 TI - Gene annotation and drug target discovery in Candida albicans with a tagged transposon mutant collection. AB - Candida albicans is the most common human fungal pathogen, causing infections that can be lethal in immunocompromised patients. Although Saccharomyces cerevisiae has been used as a model for C. albicans, it lacks C. albicans' diverse morphogenic forms and is primarily non-pathogenic. Comprehensive genetic analyses that have been instrumental for determining gene function in S. cerevisiae are hampered in C. albicans, due in part to limited resources to systematically assay phenotypes of loss-of-function alleles. Here, we constructed and screened a library of 3633 tagged heterozygous transposon disruption mutants, using them in a competitive growth assay to examine nutrient- and drug-dependent haploinsufficiency. We identified 269 genes that were haploinsufficient in four growth conditions, the majority of which were condition-specific. These screens identified two new genes necessary for filamentous growth as well as ten genes that function in essential processes. We also screened 57 chemically diverse compounds that more potently inhibited growth of C. albicans versus S. cerevisiae. For four of these compounds, we examined the genetic basis of this differential inhibition. Notably, Sec7p was identified as the target of brefeldin A in C. albicans screens, while S. cerevisiae screens with this compound failed to identify this target. We also uncovered a new C. albicans-specific target, Tfp1p, for the synthetic compound 0136-0228. These results highlight the value of haploinsufficiency screens directly in this pathogen for gene annotation and drug target identification. PMID- 20949077 TI - Parvovirus minute virus of mice induces a DNA damage response that facilitates viral replication. AB - Infection by DNA viruses can elicit DNA damage responses (DDRs) in host cells. In some cases the DDR presents a block to viral replication that must be overcome, and in other cases the infecting agent exploits the DDR to facilitate replication. We find that low multiplicity infection with the autonomous parvovirus minute virus of mice (MVM) results in the activation of a DDR, characterized by the phosphorylation of H2AX, Nbs1, RPA32, Chk2 and p53. These proteins are recruited to MVM replication centers, where they co-localize with the main viral replication protein, NS1. The response is seen in both human and murine cell lines following infection with either the MVMp or MVMi strains. Replication of the virus is required for DNA damage signaling. Damage response proteins, including the ATM kinase, accumulate in viral-induced replication centers. Using mutant cell lines and specific kinase inhibitors, we show that ATM is the main transducer of the signaling events in the normal murine host. ATM inhibitors restrict MVM replication and ameliorate virus-induced cell cycle arrest, suggesting that DNA damage signaling facilitates virus replication, perhaps in part by promoting cell cycle arrest. Thus it appears that MVM exploits the cellular DNA damage response machinery early in infection to enhance its replication in host cells. PMID- 20949078 TI - Requirements for receptor engagement during infection by adenovirus complexed with blood coagulation factor X. AB - Human adenoviruses from multiple species bind to coagulation factor X (FX), yet the importance of this interaction in adenovirus dissemination is unknown. Upon contact with blood, vectors based on adenovirus serotype 5 (Ad5) binds to FX via the hexon protein with nanomolar affinity, leading to selective uptake of the complex into the liver and spleen. The Ad5:FX complex putatively targets heparan sulfate proteoglycans (HSPGs). The aim of this study was to elucidate the specific requirements for Ad5:FX-mediated cellular uptake in this high-affinity pathway, specifically the HSPG receptor requirements as well as the role of penton base-mediated integrin engagement in subsequent internalisation. Removal of HS sidechains by enzymatic digestion or competition with highly-sulfated heparins/heparan sulfates significantly decreased FX-mediated Ad5 cell binding in vitro and ex vivo. Removal of N-linked and, in particular, O-linked sulfate groups significantly attenuated the inhibitory capabilities of heparin, while the chemical inhibition of endogenous HSPG sulfation dose-dependently reduced FX mediated Ad5 cellular uptake. Unlike native heparin, modified heparins lacking O- or N-linked sulfate groups were unable to inhibit Ad5 accumulation in the liver 1h after intravascular administration of adenovirus. Similar results were observed in vitro using Ad5 vectors possessing mutations ablating CAR- and/or alpha(v) integrin binding, demonstrating that attachment of the Ad5:FX complex to the cell surface involves HSPG sulfation. Interestingly, Ad5 vectors ablated for alpha(v) integrin binding showed markedly delayed cell entry, highlighting the need for an efficient post-attachment internalisation signal for optimal Ad5 uptake and transport following surface binding mediated through FX. This study therefore integrates the established model of alpha(v) integrin-dependent adenoviral infection with the high-affinity FX-mediated pathway. This has important implications for mechanisms that define organ targeting following contact of human adenoviruses with blood. PMID- 20949079 TI - Wolbachia stimulates immune gene expression and inhibits plasmodium development in Anopheles gambiae. AB - The over-replicating wMelPop strain of the endosymbiont Wolbachia pipientis has recently been shown to be capable of inducing immune upregulation and inhibition of pathogen transmission in Aedes aegypti mosquitoes. In order to examine whether comparable effects would be seen in the malaria vector Anopheles gambiae, transient somatic infections of wMelPop were created by intrathoracic inoculation. Upregulation of six selected immune genes was observed compared to controls, at least two of which (LRIM1 and TEP1) influence the development of malaria parasites. A stably infected An. gambiae cell line also showed increased expression of malaria-related immune genes. Highly significant reductions in Plasmodium infection intensity were observed in the wMelPop-infected cohort, and using gene knockdown, evidence for the role of TEP1 in this phenotype was obtained. Comparing the levels of upregulation in somatic and stably inherited wMelPop infections in Ae. aegypti revealed that levels of upregulation were lower in the somatic infections than in the stably transinfected line; inhibition of development of Brugia filarial nematodes was nevertheless observed in the somatic wMelPop infected females. Thus we consider that the effects observed in An. gambiae are also likely to be more pronounced if stably inherited wMelPop transinfections can be created, and that somatic infections of Wolbachia provide a useful model for examining effects on pathogen development or dissemination. The data are discussed with respect to the comparative effects on malaria vectorial capacity of life shortening and direct inhibition of Plasmodium development that can be produced by Wolbachia. PMID- 20949080 TI - Autoimmunity in Arabidopsis acd11 is mediated by epigenetic regulation of an immune receptor. AB - Certain pathogens deliver effectors into plant cells to modify host protein targets and thereby suppress immunity. These target modifications can be detected by intracellular immune receptors, or Resistance (R) proteins, that trigger strong immune responses including localized host cell death. The accelerated cell death 11 (acd11) "lesion mimic" mutant of Arabidopsis thaliana exhibits autoimmune phenotypes such as constitutive defense responses and cell death without pathogen perception. ACD11 encodes a putative sphingosine transfer protein, but its precise role during these processes is unknown. In a screen for lazarus (laz) mutants that suppress acd11 death we identified two genes, LAZ2 and LAZ5. LAZ2 encodes the histone lysine methyltransferase SDG8, previously shown to epigenetically regulate flowering time via modification of histone 3 (H3). LAZ5 encodes an RPS4-like R-protein, defined by several dominant negative alleles. Microarray and chromatin immunoprecipitation analyses showed that LAZ2/SDG8 is required for LAZ5 expression and H3 lysine 36 trimethylation at LAZ5 chromatin to maintain a transcriptionally active state. We hypothesize that LAZ5 triggers cell death in the absence of ACD11, and that cell death in other lesion mimic mutants may also be caused by inappropriate activation of R genes. Moreover, SDG8 is required for basal and R protein-mediated pathogen resistance in Arabidopsis, revealing the importance of chromatin remodeling as a key process in plant innate immunity. PMID- 20949081 TI - Calcineurin inhibition at the clinical phase of prion disease reduces neurodegeneration, improves behavioral alterations and increases animal survival. AB - Prion diseases are fatal neurodegenerative disorders characterized by a long pre symptomatic phase followed by rapid and progressive clinical phase. Although rare in humans, the unconventional infectious nature of the disease raises the potential for an epidemic. Unfortunately, no treatment is currently available. The hallmark event in prion diseases is the accumulation of a misfolded and infectious form of the prion protein (PrP(Sc)). Previous reports have shown that PrP(Sc) induces endoplasmic reticulum stress and changes in calcium homeostasis in the brain of affected individuals. In this study we show that the calcium dependent phosphatase Calcineurin (CaN) is hyperactivated both in vitro and in vivo as a result of PrP(Sc) formation. CaN activation mediates prion-induced neurodegeneration, suggesting that inhibition of this phosphatase could be a target for therapy. To test this hypothesis, prion infected wild type mice were treated intra-peritoneally with the CaN inhibitor FK506 at the clinical phase of the disease. Treated animals exhibited reduced severity of the clinical abnormalities and increased survival time compared to vehicle treated controls. Treatment also led to a significant increase in the brain levels of the CaN downstream targets pCREB and pBAD, which paralleled the decrease of CaN activity. Importantly, we observed a lower degree of neurodegeneration in animals treated with the drug as revealed by a higher number of neurons and a lower quantity of degenerating nerve cells. These changes were not dependent on PrP(Sc) formation, since the protein accumulated in the brain to the same levels as in the untreated mice. Our findings contribute to an understanding of the mechanism of neurodegeneration in prion diseases and more importantly may provide a novel strategy for therapy that is beneficial at the clinical phase of the disease. PMID- 20949082 TI - Characterization of the functional domain of beta2-microglobulin from the Asian seabass, Lates calcarifer. AB - BACKGROUND: beta2-Microglobulin (beta(2)M) is the light chain of major histocompatibility class I (MHC I) that binds non-covalently with the alpha heavy chain. Both proteins attach to the antigen peptide, presenting a complex to the T cell to be destroyed via the immune mechanism. METHODOLOGY/PRINCIPAL FINDINGS: In this study, a cDNA sequence encoding beta(2)M in the Asian seabass (Lates calcarifer) was identified and analyzed using in silico approaches to predict and characterize its functional domain. The beta(2)M cDNA contains an open reading frame (ORF) of 351 bases with a coding capacity of 116 amino acids. A large portion of the protein consists of the IG constant domain (IGc1), similar to beta(2)M sequences from other species studied thus far. Alignment of the IGc1 domains of beta(2)M from L. calcarifer and other species shows a high degree of overall conservation. Seven amino acids were found to be conserved across taxa whereas conservation between L. calcarifer and other fish species was restricted to 14 amino acids at identical conserved positions. CONCLUSION/SIGNIFICANCE: As the L. calcarifer beta(2)M protein analyzed in this study contains a functional domain similar to that of beta(2)M proteins in other species, it can be postulated that the beta(2)M proteins from L. calcarifer and other organisms are derived from a common ancestor and thus have a similar immune function. Interestingly, fish beta(2)M genes could also be classified according to the ecological habitat of the species, i.e. whether it is from a freshwater, marine or euryhaline environment. PMID- 20949083 TI - Patches of bare ground as a staple commodity for declining ground-foraging insectivorous farmland birds. AB - Conceived to combat widescale biodiversity erosion in farmland, agri-environment schemes have largely failed to deliver their promises despite massive financial support. While several common species have shown to react positively to existing measures, rare species have continued to decline in most European countries. Of particular concern is the status of insectivorous farmland birds that forage on the ground. We modelled the foraging habitat preferences of four declining insectivorous bird species (hoopoe, wryneck, woodlark, common redstart) inhabiting fruit tree plantations, orchards and vineyards. All species preferred foraging in habitat mosaics consisting of patches of grass and bare ground, with an optimal, species-specific bare ground coverage of 30-70% at the foraging patch scale. In the study areas, birds thrived in intensively cultivated farmland where such ground vegetation mosaics existed. Not promoted by conventional agri environment schemes until now, patches of bare ground should be implemented throughout grassland in order to prevent further decline of insectivorous farmland birds. PMID- 20949084 TI - R-SNARE homolog MoSec22 is required for conidiogenesis, cell wall integrity, and pathogenesis of Magnaporthe oryzae. AB - Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins mediate intracellular vesicle fusion, which is an essential cellular process of the eukaryotic cells. To investigate the role of SNARE proteins in the rice blast fungus Magnaporthe oryzae, MoSec22, an ortholog of Saccharomyces cerevisiae SNARE protein Sec22, was identified and the MoSEC22 gene disrupted. MoSec22 restored a S. cerevisiae sec22 mutant in resistance to cell wall perturbing agents, and the DeltaMosec22 mutant also exhibited defects in mycelial growth, conidial production, and infection of the host plant. Treatment with oxidative stress inducers indicated a breach in cell wall integrity, and staining and quantification assays suggested abnormal chitin deposition on the lateral walls of hyphae of the DeltaMosec22 mutant. Furthermore, hypersensitivity to the oxidative stress correlates with the reduced expression of the extracellular enzymes peroxidases and laccases. Our study thus provides new evidence on the conserved function of Sec22 among fungal organisms and indicates that MoSec22 has a role in maintaining cell wall integrity affecting the growth, morphogenesis, and virulence of M. oryzae. PMID- 20949085 TI - Body composition in severe refractory asthma: comparison with COPD patients and healthy smokers. AB - BACKGROUND: Body composition is an important parameter for patients with chronic obstructive pulmonary disease (COPD) whereas the association between asthma and obesity is not fully understood. The impact of severe refractory asthma (SRA) on fat free mass (FFM) has not been investigated. METHODOLOGY AND PRINCIPAL FINDINGS: 213 subjects (70 healthy smokers, 71 COPD patients and 72 asthma patients) without significant comorbidities were included in the study. In all patients, body composition assessment (using bioelectrical impendance analysis, skinfold and anthropometric measurements) and spirometry were performed. Differences in fat free mass index (FFMI) between groups were assessed and determinants of FFMI in asthma were evaluated. Patients with SRA had lower values of FFMI compared to patients with mild-to-moderate asthma [18.0(17.3-18.3) 19.5(18.4-21.5), p<0.001], despite the fact that they were more obese. The levels of FFMI in SRA were lower than those of GOLD stage I-III COPD and comparable to those of stage IV COPD patients [18.0(17.3-18.3)-18.8(17.8-20.1), p = ns]. These differences were present even after proper adjustments for sex, age, smoking status, daily dose of inhaled corticosteroids (ICS) and daily use of oral corticosteroids (OCS). In multivariate analysis, independent predictors of FFMI in asthmatic patients were age, use of OCS and the presence of SRA, but not smoking, sex or cumulative dose of ICS used. CONCLUSIONS AND SIGNIFICANCE: SRA is related to the presence of low FFMI that is comparable to that of GOLD stage IV COPD. The impact of this observation on asthma mechanisms and outcomes should be further investigated in large prospective studies. PMID- 20949086 TI - A gene in the process of endosymbiotic transfer. AB - BACKGROUND: The endosymbiotic birth of organelles is accompanied by massive transfer of endosymbiont genes to the eukaryotic host nucleus. In the centric diatom Thalassiosira pseudonana the Psb28 protein is encoded in the plastid genome while a second version is nuclear-encoded and possesses a bipartite N terminal presequence necessary to target the protein into the diatom complex plastid. Thus it can represent a gene captured during endosymbiotic gene transfer. METHODOLOGY/PRINCIPAL FINDINGS: To specify the origin of nuclear- and plastid-encoded Psb28 in T. pseudonana we have performed extensive phylogenetic analyses of both mentioned genes. We have also experimentally tested the intracellular location of the nuclear-encoded Psb28 protein (nuPsb28) through transformation of the diatom Phaeodactylum tricornutum with the gene in question fused to EYFP. CONCLUSIONS/SIGNIFICANCE: We show here that both versions of the psb28 gene in T. pseudonana are transcribed. We also provide experimental evidence for successful targeting of the nuPsb28 fused with EYFP to the diatom complex plastid. Extensive phylogenetic analyses demonstrate that nucleotide composition of the analyzed genes deeply influences the tree topology and that appropriate methods designed to deal with a compositional bias of the sequences and the long branch attraction artefact (LBA) need to be used to overcome this obstacle. We propose that nuclear psb28 in T. pseudonana is a duplicate of a plastid localized version, and that it has been transferred from its endosymbiont. PMID- 20949087 TI - Strand transfer and elongation of HIV-1 reverse transcription is facilitated by cell factors in vitro. AB - Recent work suggests a role for multiple host factors in facilitating HIV-1 reverse transcription. Previously, we identified a cellular activity which increases the efficiency of HIV-1 reverse transcription in vitro. Here, we describe aspects of the activity which shed light on its function. The cellular factor did not affect synthesis of strong-stop DNA but did improve downstream DNA synthesis. The stimulatory activity was isolated by gel filtration in a single fraction of the exclusion volume. Velocity-gradient purified HIV-1, which was free of detectable RNase activity, showed poor reverse transcription efficiency but was strongly stimulated by partially purified cell proteins. Hence, the cell factor(s) did not inactivate an RNase activity that might degrade the viral genomic RNA and block completion of reverse transcription. Instead, the cell factor(s) enhanced first strand transfer and synthesis of late reverse transcription suggesting it stabilized the reverse transcription complex. The factor did not affect lysis of HIV-1 by Triton X-100 in the endogenous reverse transcription (ERT) system, and ERT reactions with HIV-1 containing capsid mutations, which varied the biochemical stability of viral core structures and impeded reverse transcription in cells, showed no difference in the ability to be stimulated by the cell factor(s) suggesting a lack of involvement of the capsid in the in vitro assay. In addition, reverse transcription products were found to be resistant to exogenous DNase I activity when the active fraction was present in the ERT assay. These results indicate that the cell factor(s) may improve reverse transcription by facilitating DNA strand transfer and DNA synthesis. It also had a protective function for the reverse transcription products, but it is unclear if this is related to improved DNA synthesis. PMID- 20949088 TI - Correlation analysis for protein evolutionary family based on amino acid position mutations and application in PDZ domain. AB - BACKGROUND: It has been widely recognized that the mutations at specific directions are caused by the functional constraints in protein family and the directional mutations at certain positions control the evolutionary direction of the protein family. The mutations at different positions, even distantly separated, are mutually coupled and form an evolutionary network. Finding the controlling mutative positions and the mutative network among residues are firstly important for protein rational design and enzyme engineering. METHODOLOGY: A computational approach, namely amino acid position conservation mutation correlation analysis (CMCA), is developed to predict mutually mutative positions and find the evolutionary network in protein family. The amino acid position mutative function, which is the foundational equation of CMCA measuring the mutation of a residue at a position, is derived from the MSA (multiple structure alignment) database of protein evolutionary family. Then the position conservation correlation matrix and position mutation correlation matrix is constructed from the amino acid position mutative equation. Unlike traditional SCA (statistical coupling analysis) approach, which is based on the statistical analysis of position conservations, the CMCA focuses on the correlation analysis of position mutations. CONCLUSIONS: As an example the CMCA approach is used to study the PDZ domain of protein family, and the results well illustrate the distantly allosteric mechanism in PDZ protein family, and find the functional mutative network among residues. We expect that the CMCA approach may find applications in protein engineering study, and suggest new strategy to improve bioactivities and physicochemical properties of enzymes. PMID- 20949089 TI - The effects of sleep hypoxia on coagulant factors and hepatic inflammation in emphysematous rats. AB - OBJECTIVES: To develop a sleep hypoxia (SH) in emphysema (SHE) rat model and to explore whether SHE results in more severe hepatic inflammation than emphysema alone and whether the inflammation changes levels of coagulant/anticoagulant factors synthesized in the liver. METHODS: Seventy-five rats were put into 5 groups: SH control (SHCtrl), treated with sham smoke exposure (16 weeks) and SH exposure (12.5% O(2), 3 h/d, latter 8 weeks); emphysema control (ECtrl), smoke exposure and sham SH exposure (21% O(2)); short SHE (SHEShort), smoke exposure and short SH exposure (1.5 h/d); mild SHE (SHEMild), smoke exposure and mild SH exposure (15% O(2)); standard SHE (SHEStand), smoke exposure and SH exposure. Therefore, ECtrl, SHEShort, SHEMild and SHEStand group were among emphysematous groups. Arterial blood gas (ABG) data was obtained during preliminary tests. After exposure, hepatic inflammation (interleukin -6 [IL-6] mRNA and protein, tumor necrosis factor alpha [TNFalpha] mRNA and protein) and liver coagulant/anticoagulant factors (antithrombin [AT], fibrinogen [FIB] and Factor VIII [F VIII]) were evaluated. SPSS 11.5 software was used for statistical analysis. RESULTS: Characteristics of emphysema were obvious in emphysematous groups and ABGs reached SH criteria on hypoxia exposure. Hepatic inflammation parameters and coagulant factors are the lowest in SHCtrl and the highest in SHEStand while AT is the highest in SHCtrl and the lowest in SHEStand. Inflammatory cytokines of liver correlate well with coagulant factors positively and with AT negatively. CONCLUSIONS: When SH is combined with emphysema, hepatic inflammation and coagulability enhance each other synergistically and produce a more significant liver-derivative inflammatory and prothrombotic status. PMID- 20949090 TI - In vivo islet protection by a nuclear import inhibitor in a mouse model of type 1 diabetes. AB - BACKGROUND: Insulin-dependent Type 1 diabetes (T1D) is a devastating autoimmune disease that destroys beta cells within the pancreatic islets and afflicts over 10 million people worldwide. These patients face life-long risks for blindness, cardiovascular and renal diseases, and complications of insulin treatment. New therapies that protect islets from autoimmune destruction and allow continuing insulin production are needed. Increasing evidence regarding the pathomechanism of T1D indicates that islets are destroyed by the relentless attack by autoreactive immune cells evolving from an aberrant action of the innate, in addition to adaptive, immune system that produces islet-toxic cytokines, chemokines, and other effectors of islet inflammation. We tested the hypothesis that targeting nuclear import of stress-responsive transcription factors evoked by agonist-stimulated innate and adaptive immunity receptors would protect islets from autoimmune destruction. PRINCIPAL FINDINGS: Here we show that a first-in class inhibitor of nuclear import, cSN50 peptide, affords in vivo islet protection following a 2-day course of intense treatment in NOD mice, which resulted in a diabetes-free state for one year without apparent toxicity. This nuclear import inhibitor precipitously reduces the accumulation of islet destructive autoreactive lymphocytes while enhancing activation-induced cell death of T and B lymphocytes derived from autoimmune diabetes-prone, non-obese diabetic (NOD) mice that develop T1D. Moreover, in this widely used model of human T1D we noted attenuation of pro-inflammatory cytokine and chemokine production in immune cells. CONCLUSIONS: These results indicate that a novel form of immunotherapy that targets nuclear import can arrest inflammation-driven destruction of insulin-producing beta cells at the site of autoimmune attack within pancreatic islets during the progression of T1D. PMID- 20949091 TI - Social capital and mental health in Japan: a multilevel analysis. AB - BACKGROUND: A national cross-sectional survey was conducted in Japan. This is because the growing recognition of the social determinants of health has stimulated research on social capital and mental health. In recent years, systematic reviews have found that social capital may be a useful factor in the prevention of mental illness. Despite these studies, evidence on the association between social capital and mental health is limited as there have been few empirical discussions that adopt a multilevel framework to assess whether social capital at the ecological level is associated with individual mental health. The aim of this study was to use the multilevel approach to investigate the association between neighborhood social capital and mental health after taking into account potential individual confounders. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a multilevel analysis on 5,956 individuals nested within 199 neighborhoods. The outcome variable of self-reported mental health was measured by the one dimension of SF-36 and was summed to calculate a score ranging from 0 to 100. This study showed that high levels of cognitive social capital, measured by trust (regression coefficient = 9.56), and high levels of structural social capital, measured by membership in sports, recreation, hobby, or cultural groups (regression coefficient = 8.72), were associated with better mental health after adjusting for age, sex, household income, and educational attainment. Furthermore, after adjusting for social capital perceptions at the individual level, we found that the association between social capital and mental health also remained. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that both cognitive and structural social capital at the ecological level may influence mental health, even after adjusting for individual potential confounders including social capital perceptions. Promoting social capital may contribute to enhancing the mental health of the Japanese. PMID- 20949092 TI - Suboptimal porcine endogenous retrovirus infection in non-human primate cells: implication for preclinical xenotransplantation. AB - BACKGROUND: Porcine endogenous retrovirus (PERV) poses a potential risk of zoonotic infection in xenotransplantation. Preclinical transplantation trials using non-human primates (NHP) as recipients of porcine xenografts present the opportunity to assess the zoonosis risk in vivo. However, PERV poorly infects NHP cells for unclear reasons and therefore NHP may represent a suboptimal animal model to assess the risk of PERV zoonoses. We investigated the mechanism responsible for the low efficiency of PERV-A infection in NHP cells. PRINCIPAL FINDINGS: Two steps, cell entry and exit, were inefficient for the replication of high-titer, human-tropic A/C recombinant PERV. A restriction factor, tetherin, is likely to be responsible for the block to matured virion release, supported by the correlation between the levels of inhibition and tetherin expression. In rhesus macaque, cynomolgus macaque and baboon the main receptor for PERV entry, PERV-A receptor 1 (PAR-1), was found to be genetically deficient: PAR-1 genes in these species encode serine at amino acid 109 in place of the leucine in human PAR-1. This genetic defect inevitably impacts in vivo sensitivity to PERV infection of these species. In contrast, African green monkey (AGM) PAR-1 is functional, but PERV infection is still poor. Although the mechanism is unclear, tunicamycin treatment, which removes N-glycosylated sugar chains, increases PERV infection, suggesting a possible role for the glycosylation of the receptors. CONCLUSIONS: Since cynomolgus macaque and baboon, species often used in pig-to NHP xenotransplantation experiments, have a defective PAR-1, they hardly represent an ideal animal model to assess the risk of PERV transmission in xenotransplantation. Alternatively, NHP species, like AGM, whose both PARs are functional may represent a better model than baboon and cynomolgus macaque for PERV zoonosis in vivo studies. PMID- 20949093 TI - Facilitating memory for novel characters by reducing neural repetition suppression in the left fusiform cortex. AB - BACKGROUND: The left midfusiform and adjacent regions have been implicated in processing and memorizing familiar words, yet its role in memorizing novel characters has not been well understood. METHODOLOGY/PRINCIPAL FINDINGS: Using functional MRI, the present study examined the hypothesis that the left midfusiform is also involved in memorizing novel characters and spaced learning could enhance the memory by enhancing the left midfusiform activity during learning. Nineteen native Chinese readers were scanned while memorizing the visual form of 120 Korean characters that were novel to the subjects. Each character was repeated four times during learning. Repetition suppression was manipulated by using two different repetition schedules: massed learning and spaced learning, pseudo-randomly mixed within the same scanning session. Under the massed learning condition, the four repetitions were consecutive (with a jittered inter-repetition interval to improve the design efficiency). Under the spaced learning condition, the four repetitions were interleaved with a minimal inter-repetition lag of 6 stimuli. Spaced learning significantly improved participants' performance during the recognition memory test administered one hour after the scan. Stronger left midfusiform and inferior temporal gyrus activities during learning (summed across four repetitions) were associated with better memory of the characters, based on both within- and cross-subjects analyses. Compared to massed learning, spaced learning significantly reduced neural repetition suppression and increased the overall activities in these regions, which were associated with better memory for novel characters. CONCLUSIONS/SIGNIFICANCE: These results demonstrated a strong link between cortical activity in the left midfusiform and memory for novel characters, and thus challenge the visual word form area (VWFA) hypothesis. Our results also shed light on the neural mechanisms of the spacing effect in memorizing novel characters. PMID- 20949095 TI - Potential tumor suppressor role for the c-Myb oncogene in luminal breast cancer. AB - BACKGROUND: The transcription factor c-Myb has been well characterized as an oncogene in several human tumor types, and its expression in the hematopoietic stem/progenitor cell population is essential for proper hematopoiesis. However, the role of c-Myb in mammopoeisis and breast tumorigenesis is poorly understood, despite its high expression in the majority of breast cancer cases (60-80%). METHODOLOGY/PRINCIPAL FINDINGS: We find that c-Myb high expression in human breast tumors correlates with the luminal/ER+ phenotype and a good prognosis. Stable RNAi knock-down of endogenous c-Myb in the MCF7 luminal breast tumor cell line increased tumorigenesis both in vitro and in vivo, suggesting a possible tumor suppressor role in luminal breast cancer. We created a mammary-derived c Myb expression signature, comprised of both direct and indirect c-Myb target genes, and found it to be highly correlated with a published mature luminal mammary cell signature and least correlated with a mammary stem/progenitor lineage gene signature. CONCLUSIONS/SIGNIFICANCE: These data describe, for the first time, a possible tumor suppressor role for the c-Myb proto-oncogene in breast cancer that has implications for the understanding of luminal tumorigenesis and for guiding treatment. PMID- 20949097 TI - A computational framework for influenza antigenic cartography. AB - Influenza viruses have been responsible for large losses of lives around the world and continue to present a great public health challenge. Antigenic characterization based on hemagglutination inhibition (HI) assay is one of the routine procedures for influenza vaccine strain selection. However, HI assay is only a crude experiment reflecting the antigenic correlations among testing antigens (viruses) and reference antisera (antibodies). Moreover, antigenic characterization is usually based on more than one HI dataset. The combination of multiple datasets results in an incomplete HI matrix with many unobserved entries. This paper proposes a new computational framework for constructing an influenza antigenic cartography from this incomplete matrix, which we refer to as Matrix Completion-Multidimensional Scaling (MC-MDS). In this approach, we first reconstruct the HI matrices with viruses and antibodies using low-rank matrix completion, and then generate the two-dimensional antigenic cartography using multidimensional scaling. Moreover, for influenza HI tables with herd immunity effect (such as those from Human influenza viruses), we propose a temporal model to reduce the inherent temporal bias of HI tables caused by herd immunity. By applying our method in HI datasets containing H3N2 influenza A viruses isolated from 1968 to 2003, we identified eleven clusters of antigenic variants, representing all major antigenic drift events in these 36 years. Our results showed that both the completed HI matrix and the antigenic cartography obtained via MC-MDS are useful in identifying influenza antigenic variants and thus can be used to facilitate influenza vaccine strain selection. The webserver is available at http://sysbio.cvm.msstate.edu/AntigenMap. PMID- 20949096 TI - Evaluation of a quantitative real-time PCR assay to measure HIV-specific mucosal CD8+ T cell responses in the cervix. AB - Several candidate HIV vaccines aim to induce virus-specific cellular immunity particularly in the genital tract, typically the initial site of HIV acquisition. However, standardized and sensitive methods for evaluating HIV-specific immune responses at the genital level are lacking. Therefore we evaluated real-time quantitative PCR (qPCR) as a potential platform to measure these responses. beta Actin and GAPDH were identified as the most stable housekeeping reference genes in peripheral blood mononuclear cells (PBMCs) and cervical mononuclear cells (CMCs) respectively and were used for normalizing transcript mRNA expression. HIV specific cellular T cell immune responses to a pool of optimized CD8+ HIV epitopes (HIV epitope pool) and Staphylococcal enterotoxin B (SEB) superantigen control were assayed in HIV infected PBMC by qPCR, with parallel assessment of cytokine protein production. Peak HIV-specific mRNA expression of IFNgamma, IL-2 and TNFalpha occurred after 3, 5 and 12 hours respectively. PBMCs were titrated to cervical appropriate cell numbers to determine minimum required assay input cell numbers; qPCR retained sensitivity with input of at least 2.5*10(4) PBMCs. This optimized qPCR assay was then used to assess HIV-specific cellular T cell responses in cytobrush-derived cervical T cells from HIV positive individuals. SEB induced IFNgamma mRNA transcription was detected in CMCs and correlated positively with IFNgamma protein production. However, qPCR was unable to detect HIV-induced cytokine mRNA production in the cervix of HIV-infected women despite robust detection of gene induction in PBMCs. In conclusion, although qPCR can be used to measure ex vivo cellular immune responses to HIV in blood, HIV-specific responses in the cervix may fall below the threshold of qPCR detection. Nonetheless, this platform may have a potential role in measuring mitogen-induced immune responses in the genital tract. PMID- 20949098 TI - Selection upon genome architecture: conservation of functional neighborhoods with changing genes. AB - An increasing number of evidences show that genes are not distributed randomly across eukaryotic chromosomes, but rather in functional neighborhoods. Nevertheless, the driving force that originated and maintains such neighborhoods is still a matter of controversy. We present the first detailed multispecies cartography of genome regions enriched in genes with related functions and study the evolutionary implications of such clustering. Our results indicate that the chromosomes of higher eukaryotic genomes contain up to 12% of genes arranged in functional neighborhoods, with a high level of gene co-expression, which are consistently distributed in phylogenies. Unexpectedly, neighborhoods with homologous functions are formed by different (non-orthologous) genes in different species. Actually, instead of being conserved, functional neighborhoods present a higher degree of synteny breaks than the genome average. This scenario is compatible with the existence of selective pressures optimizing the coordinated transcription of blocks of functionally related genes. If these neighborhoods were broken by chromosomal rearrangements, selection would favor further rearrangements reconstructing other neighborhoods of similar function. The picture arising from this study is a dynamic genomic landscape with a high level of functional organization. PMID- 20949099 TI - Transcript profiling of Elf5+/- mammary glands during pregnancy identifies novel targets of Elf5. AB - BACKGROUND: Elf5, an epithelial specific Ets transcription factor, plays a crucial role in the pregnancy-associated development of the mouse mammary gland. Elf5(-/-) embryos do not survive, however the Elf5(+/-) mammary gland displays a severe pregnancy-associated developmental defect. While it is known that Elf5 is crucial for correct mammary development and lactation, the molecular mechanisms employed by Elf5 to exert its effects on the mammary gland are largely unknown. PRINCIPAL FINDINGS: Transcript profiling was used to investigate the transcriptional changes that occur as a result of Elf5 haploinsufficiency in the Elf5(+/-) mouse model. We show that the development of the mouse Elf5(+/-) mammary gland is delayed at a transcriptional and morphological level, due to the delayed increase in Elf5 protein in these glands. We also identify a number of potential Elf5 target genes, including Mucin 4, whose expression, is directly regulated by the binding of Elf5 to an Ets binding site within its promoter. CONCLUSION: We identify novel transcriptional targets of Elf5 and show that Muc4 is a direct target of Elf5, further elucidating the mechanisms through which Elf5 regulates proliferation and differentiation in the mammary gland. PMID- 20949100 TI - Expression of rod-derived cone viability factor: dual role of CRX in regulating promoter activity and cell-type specificity. AB - BACKGROUND: RdCVF and RdCVF2, encoded by the nucleoredoxin-like genes NXNL1 and NXNL2, are trophic factors with therapeutic potential that are involved in cone photoreceptor survival. Studying how their expression is regulated in the retina has implications for understanding both their activity and the mechanisms determining cell-type specificity within the retina. METHODOLOGY/PRINCIPAL FINDINGS: In order to define and characterize their promoters, a series of luciferase/GFP reporter constructs that contain various fragments of the 5' upstream region of each gene, both murine and human, were tested in photoreceptor like and non-photoreceptor cell lines and also in a biologically more relevant mouse retinal explant system. For NXNL1, 5'-deletion analysis identified the human -205/+57 bp and murine -351/+51 bp regions as having promoter activity. Moreover, in the retinal explants these constructs drove expression specifically to photoreceptor cells. For NXNL2, the human -393/+27 bp and murine -195/+70 bp regions were found to be sufficient for promoter activity. However, despite the fact that endogenous NXNL2 expression is photoreceptor-specific within the retina, neither of these DNA sequences nor larger upstream regions demonstrated photoreceptor-specific expression. Further analysis showed that a 79 bp NXNL2 positive regulatory sequence (-393 to 315 bp) combined with a 134 bp inactive minimal NXNL1 promoter fragment (-77 to +57 bp) was able to drive photoreceptor specific expression, suggesting that the minimal NXNL1 fragment contains latent elements that encode cell-type specificity. Finally, based on bioinformatic analysis that suggested the importance of a CRX binding site within the minimal NXNL1 fragment, we found by mutation analysis that, depending on the context, the CRX site can play a dual role. CONCLUSIONS/SIGNIFICANCE: The regulation of the Nucleoredoxin-like genes involves a CRX responsive element that can act as both as a positive regulator of promoter activity and as a modulator of cell-type specificity. PMID- 20949101 TI - Critical dynamics in the evolution of stochastic strategies for the iterated prisoner's dilemma. AB - The observed cooperation on the level of genes, cells, tissues, and individuals has been the object of intense study by evolutionary biologists, mainly because cooperation often flourishes in biological systems in apparent contradiction to the selfish goal of survival inherent in Darwinian evolution. In order to resolve this paradox, evolutionary game theory has focused on the Prisoner's Dilemma (PD), which incorporates the essence of this conflict. Here, we encode strategies for the iterated Prisoner's Dilemma (IPD) in terms of conditional probabilities that represent the response of decision pathways given previous plays. We find that if these stochastic strategies are encoded as genes that undergo Darwinian evolution, the environmental conditions that the strategies are adapting to determine the fixed point of the evolutionary trajectory, which could be either cooperation or defection. A transition between cooperative and defective attractors occurs as a function of different parameters such as mutation rate, replacement rate, and memory, all of which affect a player's ability to predict an opponent's behavior. These results imply that in populations of players that can use previous decisions to plan future ones, cooperation depends critically on whether the players can rely on facing the same strategies that they have adapted to. Defection, on the other hand, is the optimal adaptive response in environments that change so quickly that the information gathered from previous plays cannot usefully be integrated for a response. PMID- 20949102 TI - Automatic figure ranking and user interfacing for intelligent figure search. AB - BACKGROUND: Figures are important experimental results that are typically reported in full-text bioscience articles. Bioscience researchers need to access figures to validate research facts and to formulate or to test novel research hypotheses. On the other hand, the sheer volume of bioscience literature has made it difficult to access figures. Therefore, we are developing an intelligent figure search engine (http://figuresearch.askhermes.org). Existing research in figure search treats each figure equally, but we introduce a novel concept of "figure ranking": figures appearing in a full-text biomedical article can be ranked by their contribution to the knowledge discovery. METHODOLOGY/FINDINGS: We empirically validated the hypothesis of figure ranking with over 100 bioscience researchers, and then developed unsupervised natural language processing (NLP) approaches to automatically rank figures. Evaluating on a collection of 202 full text articles in which authors have ranked the figures based on importance, our best system achieved a weighted error rate of 0.2, which is significantly better than several other baseline systems we explored. We further explored a user interfacing application in which we built novel user interfaces (UIs) incorporating figure ranking, allowing bioscience researchers to efficiently access important figures. Our evaluation results show that 92% of the bioscience researchers prefer as the top two choices the user interfaces in which the most important figures are enlarged. With our automatic figure ranking NLP system, bioscience researchers preferred the UIs in which the most important figures were predicted by our NLP system than the UIs in which the most important figures were randomly assigned. In addition, our results show that there was no statistical difference in bioscience researchers' preference in the UIs generated by automatic figure ranking and UIs by human ranking annotation. CONCLUSION/SIGNIFICANCE: The evaluation results conclude that automatic figure ranking and user interfacing as we reported in this study can be fully implemented in online publishing. The novel user interface integrated with the automatic figure ranking system provides a more efficient and robust way to access scientific information in the biomedical domain, which will further enhance our existing figure search engine to better facilitate accessing figures of interest for bioscientists. PMID- 20949103 TI - Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies. AB - A steady increase in knowledge of the molecular and antigenic structure of the gp120 and gp41 HIV-1 envelope glycoproteins (Env) is yielding important new insights for vaccine design, but it has been difficult to translate this information to an immunogen that elicits broadly neutralizing antibodies. To help bridge this gap, we used phylogenetically corrected statistical methods to identify amino acid signature patterns in Envs derived from people who have made potently neutralizing antibodies, with the hypothesis that these Envs may share common features that would be useful for incorporation in a vaccine immunogen. Before attempting this, essentially as a control, we explored the utility of our computational methods for defining signatures of complex neutralization phenotypes by analyzing Env sequences from 251 clonal viruses that were differentially sensitive to neutralization by the well-characterized gp120 specific monoclonal antibody, b12. We identified ten b12-neutralization signatures, including seven either in the b12-binding surface of gp120 or in the V2 region of gp120 that have been previously shown to impact b12 sensitivity. A simple algorithm based on the b12 signature pattern was predictive of b12 sensitivity/resistance in an additional blinded panel of 57 viruses. Upon obtaining these reassuring outcomes, we went on to apply these same computational methods to define signature patterns in Env from HIV-1 infected individuals who had potent, broadly neutralizing responses. We analyzed a checkerboard-style neutralization dataset with sera from 69 HIV-1-infected individuals tested against a panel of 25 different Envs. Distinct clusters of sera with high and low neutralization potencies were identified. Six signature positions in Env sequences obtained from the 69 samples were found to be strongly associated with either the high or low potency responses. Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an important role for this region in the elicitation of broadly neutralizing antibody responses against HIV-1. PMID- 20949104 TI - Prevalence of transmitted drug resistance and impact of transmitted resistance on treatment success in the German HIV-1 Seroconverter Cohort. AB - BACKGROUND: The aim of this study is to analyse the prevalence of transmitted drug resistance, TDR, and the impact of TDR on treatment success in the German HIV-1 Seroconverter Cohort. METHODS: Genotypic resistance analysis was performed in treatment-naive study patients whose sample was available 1,312/1,564 (83.9% October 2008). A genotypic resistance result was obtained for 1,276/1,312 (97.3%). The resistance associated mutations were identified according to the surveillance drug resistance mutations list recommended for drug-naive patients. Treatment success was determined as viral suppression below 500 copies/ml. RESULTS: Prevalence of TDR was stable at a high level between 1996 and 2007 in the German HIV-1 Seroconverter Cohort (N = 158/1,276; 12.4%; CI(wilson) 10.7 14.3; p(for trend) = 0.25). NRTI resistance was predominant (7.5%) but decreased significantly over time (CI(Wilson): 6.2-9.1, p(for trend) = 0.02). NNRTI resistance tended to increase over time (NNRTI: 3.5%; CI(Wilson): 2.6-4.6; p(for trend)= 0.07), whereas PI resistance remained stable (PI: 3.0%; CI(Wilson): 2.1 4.0; p(for trend) = 0.24). Resistance to all drug classes was frequently caused by singleton resistance mutations (NRTI 55.6%, PI 68.4%, NNRTI 99.1%). The majority of NRTI-resistant strains (79.8%) carried resistance-associated mutations selected by the thymidine analogues zidovudine and stavudine. Preferably 2NRTI/1PIr combinations were prescribed as first line regimen in patients with resistant HIV as well as in patients with susceptible strains (susceptible 45.3%; 173/382 vs. resistant 65.5%; 40/61). The majority of patients in both groups were treated successfully within the first year after ART initiation (susceptible: 89.9%; 62/69; resistant: 7/9; 77.8%). CONCLUSION: Overall prevalence of TDR remained stable at a high level but trends of resistance against drug classes differed over time. The significant decrease of NRTI-resistance in patients newly infected with HIV might be related to the introduction of novel antiretroviral drugs and a wider use of genotypic resistance analysis prior to treatment initiation. PMID- 20949105 TI - The zwitterionic cell wall teichoic acid of Staphylococcus aureus provokes skin abscesses in mice by a novel CD4+ T-cell-dependent mechanism. AB - Zwitterionic polysaccharide (ZPS) components of the bacterial cell envelope have been shown to exert a major histocompatibility complex (MHC) II-dependent activation of CD4+ T cells, which in turn can modulate the outcome and progression of infections in animal models. We investigated the impact of zwitterionic cell wall teichoic acid (WTA) produced by Staphylococcus aureus on the development of skin abscesses in a mouse model. We also compared the relative biological activities of WTA and capsular polysaccharide (CP), important S. aureus pathogenicity factors, in abscess formation. Expression of both WTA and CP markedly affected the ability of S. aureus to induce skin abscess formation in mice. Purified wild-type zwitterionic WTA was more active in inducing abscess formation than negatively charged mutant WTA or purified CP8. To assess the ability of purified native WTA to stimulate T cell proliferation in vitro, we co cultivated WTA with human T-cells and antigen presenting cells in the presence and absence of various inhibitors of MHC-II presentation. Wild-type WTA induced T cell proliferation to a significantly greater extent than negatively charged WTA. T cell activation was dependent on the presentation of WTA on MHC II, since inhibitors of MHC II-dependent presentation and antibodies to MHC II significantly reduced T cell proliferation. T cells activated in vitro with wild type WTA, but not negatively charged WTA, induced abscess formation when injected subcutaneously into wild-type mice. CD4-/- mice similarly injected with WTA failed to develop abscesses. Our results demonstrate that the zwitterionic WTA of S. aureus induces CD4+ T-cell proliferation in an MHCII-dependent manner, which in turn modulates abscess formation in a mouse skin infection model. An understanding of this novel T cell-dependent host response to staphylococcal abscess formation may lead to the development of new strategies to combat S. aureus skin and soft tissue infections. PMID- 20949106 TI - Tight regulation of the intS gene of the KplE1 prophage: a new paradigm for integrase gene regulation. AB - Temperate phages have the ability to maintain their genome in their host, a process called lysogeny. For most, passive replication of the phage genome relies on integration into the host's chromosome and becoming a prophage. Prophages remain silent in the absence of stress and replicate passively within their host genome. However, when stressful conditions occur, a prophage excises itself and resumes the viral cycle. Integration and excision of phage genomes are mediated by regulated site-specific recombination catalyzed by tyrosine and serine recombinases. In the KplE1 prophage, site-specific recombination is mediated by the IntS integrase and the TorI recombination directionality factor (RDF). We previously described a sub-family of temperate phages that is characterized by an unusual organization of the recombination module. Consequently, the attL recombination region overlaps with the integrase promoter, and the integrase and RDF genes do not share a common activated promoter upon lytic induction as in the lambda prophage. In this study, we show that the intS gene is tightly regulated by its own product as well as by the TorI RDF protein. In silico analysis revealed that overlap of the attL region with the integrase promoter is widely encountered in prophages present in prokaryotic genomes, suggesting a general occurrence of negatively autoregulated integrase genes. The prediction that these integrase genes are negatively autoregulated was biologically assessed by studying the regulation of several integrase genes from two different Escherichia coli strains. Our results suggest that the majority of tRNA-associated integrase genes in prokaryotic genomes could be autoregulated and that this might be correlated with the recombination efficiency as in KplE1. The consequences of this unprecedented regulation for excessive recombination are discussed. PMID- 20949107 TI - Solution structure and dynamics of the I214V mutant of the rabbit prion protein. AB - BACKGROUND: The conformational conversion of the host-derived cellular prion protein (PrP(C)) into the disease-associated scrapie isoform (PrP(Sc)) is responsible for the pathogenesis of transmissible spongiform encephalopathies (TSEs). Various single-point mutations in PrP(C)s could cause structural changes and thereby distinctly influence the conformational conversion. Elucidation of the differences between the wild-type rabbit PrP(C) (RaPrP(C)) and various mutants would be of great help to understand the ability of RaPrP(C) to be resistant to TSE agents. METHODOLOGY/PRINCIPAL FINDINGS: We determined the solution structure of the I214V mutant of RaPrP(C)(91-228) and detected the backbone dynamics of its structured C-terminal domain (121-228). The I214V mutant displays a visible shift of surface charge distribution that may have a potential effect on the binding specificity and affinity with other chaperones. The number of hydrogen bonds declines dramatically. Urea-induced transition experiments reveal an obvious decrease in the conformational stability. Furthermore, the NMR dynamics analysis discloses a significant increase in the backbone flexibility on the pico- to nanosecond time scale, indicative of lower energy barrier for structural rearrangement. CONCLUSIONS/SIGNIFICANCE: Our results suggest that both the surface charge distribution and the intrinsic backbone flexibility greatly contribute to species barriers for the transmission of TSEs, and thereby provide valuable hints for understanding the inability of the conformational conversion for RaPrP(C). PMID- 20949108 TI - Characterization of LINE-1 ribonucleoprotein particles. AB - The average human genome contains a small cohort of active L1 retrotransposons that encode two proteins (ORF1p and ORF2p) required for their mobility (i.e., retrotransposition). Prior studies demonstrated that human ORF1p, L1 RNA, and an ORF2p-encoded reverse transcriptase activity are present in ribonucleoprotein (RNP) complexes. However, the inability to physically detect ORF2p from engineered human L1 constructs has remained a technical challenge in the field. Here, we have employed an epitope/RNA tagging strategy with engineered human L1 retrotransposons to identify ORF1p, ORF2p, and L1 RNA in a RNP complex. We next used this system to assess how mutations in ORF1p and/or ORF2p impact RNP formation. Importantly, we demonstrate that mutations in the coiled-coil domain and RNA recognition motif of ORF1p, as well as the cysteine-rich domain of ORF2p, reduce the levels of ORF1p and/or ORF2p in L1 RNPs. Finally, we used this tagging strategy to localize the L1-encoded proteins and L1 RNA to cytoplasmic foci that often were associated with stress granules. Thus, we conclude that a precise interplay among ORF1p, ORF2p, and L1 RNA is critical for L1 RNP assembly, function, and L1 retrotransposition. PMID- 20949109 TI - CpG-ODN and MPLA prevent mortality in a murine model of post-hemorrhage Staphyloccocus aureus pneumonia. AB - Infections are the most frequent cause of complications in trauma patients. Post traumatic immune suppression (IS) exposes patients to pneumonia (PN). The main pathogen involved in PN is Methicillin Susceptible Staphylococcus aureus (MSSA). Dendritic cells () may be centrally involved in the IS. We assessed the consequences of hemorrhage on pneumonia outcomes and investigated its consequences on DCs functions. A murine model of hemorrhagic shock with a subsequent MSSA pneumonia was used. Hemorrhage decreased the survival rate of infected mice, increased systemic dissemination of sepsis and worsened inflammatory lung lesions. The mRNA expression of Tumor Necrosis Factor-alpha (TNF-alpha), Interferon-beta (IFN-beta) and Interleukin (IL)-12p40 were mitigated for hemorrhaged-mice. The effects of hemorrhage on subsequent PN were apparent on the pDCs phenotype (reduced MHC class II, CD80, and CD86 molecule membrane expression). In addition, hemorrhage dramatically decreased CD8(+) cDCs- and CD8( ) cDCs-induced allogeneic T-cell proliferation during PN compared with mice that did not undergo hemorrhage. In conclusion, hemorrhage increased morbidity and mortality associated with PN; induced severe phenotypic disturbances of the pDCs subset and functional alterations of the cDCs subset. After hemorrhage, a preventive treatment with CpG-ODN or Monophosphoryl Lipid A increased transcriptional activity in DCs (TNF-alpha, IFN-beta and IL-12p40) and decreased mortality of post-hemorrhage MSSA pneumonia. PMID- 20949110 TI - European bone mineral density loci are also associated with BMD in East-Asian populations. AB - Most genome-wide association (GWA) studies have focused on populations of European ancestry with limited assessment of the influence of the sequence variants on populations of other ethnicities. To determine whether markers that we have recently shown to associate with Bone Mineral Density (BMD) in Europeans also associate with BMD in East-Asians we analysed 50 markers from 23 genomic loci in samples from Korea (n = 1,397) and two Chinese Hong Kong sample sets (n = 3,869 and n = 785). Through this effort we identified fourteen loci that associated with BMD in East-Asian samples using a false discovery rate (FDR) of 0.05; 1p36 (ZBTB40, P = 4.3*10(-9)), 1p31 (GPR177, P = 0.00012), 3p22 (CTNNB1, P = 0.00013), 4q22 (MEPE, P = 0.0026), 5q14 (MEF2C, P = 1.3*10(-5)), 6q25 (ESR1, P = 0.0011), 7p14 (STARD3NL, P = 0.00025), 7q21 (FLJ42280, P = 0.00017), 8q24 (TNFRSF11B, P = 3.4*10(-5)), 11p15 (SOX6, P = 0.00033), 11q13 (LRP5, P = 0.0033), 13q14 (TNFSF11, P = 7.5*10(-5)), 16q24 (FOXL1, P = 0.0010) and 17q21 (SOST, P = 0.015). Our study marks an early effort towards the challenge of cataloguing bone density variants shared by many ethnicities by testing BMD variants that have been established in Europeans, in East-Asians. PMID- 20949112 TI - Deconstructing doctoral dissertations: how many papers does it take to make a PhD? AB - A collection of coauthored papers is the new norm for doctoral dissertations in the natural and biomedical sciences, yet there is no consensus on how to partition authorship credit between PhD candidates and their coauthors. Guidelines for PhD programs vary but tend to specify only a suggested range for the number of papers to be submitted for evaluation, sometimes supplemented with a requirement for the PhD candidate to be the principal author on the majority of submitted papers. Here I use harmonic counting to quantify the actual amount of authorship credit attributable to individual PhD graduates from two Scandinavian universities in 2008. Harmonic counting corrects for the inherent inflationary and equalizing biases of routine counting methods, thereby allowing the bibliometrically identifiable amount of authorship credit in approved dissertations to be analyzed with unprecedented accuracy. Unbiased partitioning of authorship credit between graduates and their coauthors provides a post hoc bibliometric measure of current PhD requirements, and sets a de facto baseline for the requisite scientific productivity of these contemporary PhD's at a median value of approximately 1.6 undivided papers per dissertation. Comparison with previous census data suggests that the baseline has shifted over the past two decades as a result of a decrease in the number of submitted papers per candidate and an increase in the number of coauthors per paper. A simple solution to this shifting baseline syndrome would be to benchmark the amount of unbiased authorship credit deemed necessary for successful completion of a specific PhD program, and then monitor for departures from this level over time. Harmonic partitioning of authorship credit also facilitates cross-disciplinary and inter institutional analysis of the scientific output from different PhD programs. Juxtaposing bibliometric benchmarks with current baselines may thus assist the development of harmonized guidelines and transparent transnational quality assurance procedures for doctoral programs by providing a robust and meaningful standard for further exploration of the causes of intra- and inter-institutional variation in the amount of unbiased authorship credit per dissertation. PMID- 20949111 TI - Simultaneous disruption of two DNA polymerases, Poleta and Polzeta, in Avian DT40 cells unmasks the role of Poleta in cellular response to various DNA lesions. AB - Replicative DNA polymerases are frequently stalled by DNA lesions. The resulting replication blockage is released by homologous recombination (HR) and translesion DNA synthesis (TLS). TLS employs specialized TLS polymerases to bypass DNA lesions. We provide striking in vivo evidence of the cooperation between DNA polymerase eta, which is mutated in the variant form of the cancer predisposition disorder xeroderma pigmentosum (XP-V), and DNA polymerase zeta by generating POLeta(-/-)/POLzeta(-/-) cells from the chicken DT40 cell line. POLzeta(-/-) cells are hypersensitive to a very wide range of DNA damaging agents, whereas XP V cells exhibit moderate sensitivity to ultraviolet light (UV) only in the presence of caffeine treatment and exhibit no significant sensitivity to any other damaging agents. It is therefore widely believed that Poleta plays a very specific role in cellular tolerance to UV-induced DNA damage. The evidence we present challenges this assumption. The phenotypic analysis of POLeta(-/ )/POLzeta(-/-) cells shows that, unexpectedly, the loss of Poleta significantly rescued all mutant phenotypes of POLzeta(-/-) cells and results in the restoration of the DNA damage tolerance by a backup pathway including HR. Taken together, Poleta contributes to a much wide range of TLS events than had been predicted by the phenotype of XP-V cells. PMID- 20949113 TI - Hepatitis B Therapy in Pregnancy. AB - All decisions about initiating, continuing, or stopping therapy of the hepatitis B virus (HBV) during pregnancy must include an analysis of the risks and benefits for mother and fetus. The trimester of the pregnancy and the stage of the mother's liver disease are important factors. Treatment in the third trimester may be initiated to aid in preventing perinatal transmission, which appears to be most pronounced in mothers with high viral loads. Consideration of initiating treatment in the third trimester should occur after a high viral load is documented in the latter part of the second trimester, to allow adequate time for initiation of antiviral therapy with significant viral suppression before delivery. This discussion should include the topic of breastfeeding, because it is generally not recommended while receiving antiviral therapy. Currently, lamivudine and tenofovir appear to be the therapeutic options with the most reasonable safety data in pregnancy. PMID- 20949114 TI - The Role of Interferon in Hepatitis B Therapy. AB - Despite the introduction of new nucleos(t)ide analogues in recent years, peginterferon is still recommended as a potential first-line treatment option by current practice guidelines for the management of chronic hepatitis B. Peginterferon offers the advantage of higher sustained off-treatment response rates compared to nucleos(t)ide analogues because of its immunomodulatory effects. Sustained transition to the inactive hepatitis B surface antigen (HBsAg) carrier state can be achieved in about 30% of hepatitis B e antigen (HBeAg) positive patients and 20% of HBeAg-negative patients. Recent studies have focused on identification of pretreatment and on-treatment factors that allow the selection of patients who are likely to achieve a sustained response to peginterferon therapy in order to avoid the side-effects and costs associated with unnecessary treatment. Future studies need to address whether specific virologic benchmarks can guide individualized decisions concerning therapy continuation and whether peginterferon combined with new potent nucleos(t)ide analogues improves treatment outcomes. PMID- 20949116 TI - Effects of Habitat Structure and Fragmentation on Diversity and Abundance of Primates in Tropical Deciduous Forests in Bolivia. AB - Habitat structure and anthropogenic disturbance are known to affect primate diversity and abundance. However, researchers have focused on lowland rain forests, whereas endangered deciduous forests have been neglected. We aimed to investigate the relationships between primate diversity and abundance and habitat parameters in 10 deciduous forest fragments southeast of Santa Cruz, Bolivia. We obtained primate data via line-transect surveys and visual and acoustic observations. In addition, we assessed the vegetation structure (canopy height, understory density), size, isolation time, and surrounding forest area of the fragments. We interpreted our results in the context of the historical distribution data for primates in the area before fragmentation and interviews with local people. We detected 5 of the 8 historically observed primate species: Alouatta caraya, Aotus azarae boliviensis, Callithrix melanura, Callicebus donacophilus, and Cebus libidinosus juruanus. Total species number and detection rates decreased with understory density. Detection rates also negatively correlated with forest areas in the surroundings of a fragment, which may be due to variables not assessed, i.e., fragment shape, distance to nearest town. Observations for Alouatta and Aotus were too few to conduct further statistics. Cebus and Callicebus were present in 90% and 70% of the sites, respectively, and their density did not correlate with any of the habitat variables assessed, signaling high ecological plasticity and adaptability to anthropogenic impact in these species. Detections of Callithrix were higher in areas with low forest strata. Our study provides baseline data for future fragmentation studies in Neotropical dry deciduous forests and sets a base for specific conservation measures. PMID- 20949115 TI - Functions of Intermittent Locomotion in Mustached Tamarins (Saguinus mystax). AB - Many animals interrupt their moving with brief pauses, which appear to serve several different functions. We examined the function of such intermittent locomotion in wild living mustached tamarins (Saguinus mystax), small arboreal New World primates that form mixed-species groups with saddleback tamarins (Saguinus fuscicollis). We investigated how different environmental and social factors affect pausing during locomotion and used these data to infer the function of this behavior. As measures of intermittent locomotion, we used percentage of time spent pausing and pause rate. We considered 3 possible functions that are not mutually exclusive: increased endurance, route planning, and antipredator vigilance. Mustached tamarins spent on average (mean +/- SE) 55.1 +/- 1.0% of time pausing, which makes effective resource exploitation more time consuming and needs to be outweighed by correspondingly large benefits. Percentage of time spent pausing decreased in larger mixed-species groups vs. smaller mixed-species groups and decreased with height and in monkeys carrying infants. It was not affected by sex, age, spatial arrangement, or single-species group size. Pause rate increased in individuals traveling independently compared to those traveling in file, but was not affected by other factors. The group size effect in mixed-species groups lends support to the notion that pausing during locomotion is an antipredator tactic that can be reduced in the increased safety of larger groups, but other results suggest that additional functions, particularly route planning, are also of great importance. Benefits in terms of predator confusion and group movement coordination are also likely to play a role and remain a topic for further research. PMID- 20949117 TI - Peruvian Red Uakaris (Cacajao calvus ucayalii) Are Not Flooded-Forest Specialists. AB - In the literature, particularly in primatological books, the Peruvian red uakari (Cacajao calvus ucayalii) is generally considered as a species that is specialized on living in flooded forest, despite existing evidence to the contrary. Here we review all available information on habitats where Cacajao calvus ucayalii have been observed. Most sightings are from terra firme, including palm swamps, or from mixed habitats, including terra firme and flooded forest. Therefore, we conclude that the species is not a flooded-forest specialist, but is flexible in its habitat requirements and generally uses terra firme forests or a mixture of habitats. Proper recognition of habitat requirements is important for understanding the ecoethological adaptations of a species and for appropriate conservation measures. PMID- 20949118 TI - Polymeric Functionalized Stationary Phase for Separation of Ionic Compounds by IC. AB - Synthesis and properties are described of multilayered stationary phases containing quaternary amine functional groups used for the analysis of inorganic anions by ion chromatography. The bonded phases were characterized by elemental analysis, solid state (13)C NMR spectroscopy and chromatographic methods. The surface of polyhydroxyethyl methacrylate (solid support) was coated with polymeric layers formed by condensation polymerization of primary amine with diepoxide. Each layer of the anion exchange stationary phase consisted of methylamine and 1,4-butanedioldiglycidyl ether copolymer. A series of stationary phases with different number of polymerized layers were tested. Separation of inorganic anions, such as F(-), Cl(-), NO(2) (-), Br(-), NO(3) (-), were performed. Aqueous hydroxide, carbonate and bicarbonate solutions were used as mobile phases. PMID- 20949119 TI - Effect of photon flux densities on regulation of carotenogenesis and cell viability of Haematococcus pluvialis (Chlorophyceae). AB - The green alga Haematococcus pluvialis produces large amounts of the pink carotenoid astaxanthin under high photon flux density (PFD) and other oxidative stress conditions. However, the regulation and physiological role of carotenogenesis leading to astaxanthin formation is not well understood. Comparative transcriptional expression of five carotenoid genes along with growth and pigment composition as a function of PFD was studied using a wild-type and an astaxanthin-overproduction mutant of H. pluvialis NIES144. The results indicate that astaxanthin biosynthesis was mainly under transcriptional control of the gene encoding carotenoid hydroxylase, and to a lesser extent, the genes encoding isopentenyl isomerase and phytoene desaturase, and to the least extent, the genes encoding phytoene synthase and carotenoid oxygenase. The expression of a plastid terminal oxidase (PTOX) gene ptox2 underwent transient up-regulation under elevated PFDs, suggesting that PTOX may be functionally coupled with phytoene desaturase through the plastoquinone pool and may play a role in reducing redox potential-dependent and oxygen-concentration-dependent formation of reactive oxygen species in the chloroplast. Over-expression of both the carotenogenic and PTOX genes confers to the astaxanthin-overproduction mutant more effective photoprotective capability than that of the wild type under photooxidative stress. PMID- 20949120 TI - The Effects of Rumination and Depressive Symptoms on the Prediction of Negative Attributional Style Among College Students. AB - Research on cognitive vulnerability to depression has identified negative cognitive style and rumination as distinct risk factors for depression but how rumination would influence negative cognitive style remains unclear. The present study investigated the relationship between rumination and negative attributional style and specifically tested the potential moderating effect of depressive symptoms and processing mode during rumination on activating negative attributional style. After completing the baseline measures of depressive symptoms, dysphoric affect, and negative attributional style, participants were randomly assigned to three experimental conditions: analytical self-focus, experiential self-focus, and distraction, in which the degree of self-focus and mode of processing were manipulated. A second set of mood and cognitive measures was administered afterwards. Results showed that a stronger positive relationship between negative attributional style and level of depressive symptoms was found in the analytical self-focus condition, relative to the experiential and distraction conditions. This finding suggested that processing mode in rumination interacted with depressive symptoms to predict negative attributional style. PMID- 20949121 TI - Recording 2-D Nutation NQR Spectra by Random Sampling Method. AB - The method of random sampling was introduced for the first time in the nutation nuclear quadrupole resonance (NQR) spectroscopy where the nutation spectra show characteristic singularities in the form of shoulders. The analytic formulae for complex two-dimensional (2-D) nutation NQR spectra (I = 3/2) were obtained and the condition for resolving the spectral singularities for small values of an asymmetry parameter eta was determined. Our results show that the method of random sampling of a nutation interferogram allows significant reduction of time required to perform a 2-D nutation experiment and does not worsen the spectral resolution. PMID- 20949124 TI - Influence of the time scale on the construction of financial networks. AB - BACKGROUND: In this paper we investigate the definition and formation of financial networks. Specifically, we study the influence of the time scale on their construction. METHODOLOGY/PRINCIPAL FINDINGS: For our analysis we use correlation-based networks obtained from the daily closing prices of stock market data. More precisely, we use the stocks that currently comprise the Dow Jones Industrial Average (DJIA) and estimate financial networks where nodes correspond to stocks and edges correspond to none vanishing correlation coefficients. That means only if a correlation coefficient is statistically significant different from zero, we include an edge in the network. This construction procedure results in unweighted, undirected networks. By separating the time series of stock prices in non-overlapping intervals, we obtain one network per interval. The length of these intervals corresponds to the time scale of the data, whose influence on the construction of the networks will be studied in this paper. CONCLUSIONS/SIGNIFICANCE: Numerical analysis of four different measures in dependence on the time scale for the construction of networks allows us to gain insights about the intrinsic time scale of the stock market with respect to a meaningful graph-theoretical analysis. PMID- 20949122 TI - APBSmem: a graphical interface for electrostatic calculations at the membrane. AB - Electrostatic forces are one of the primary determinants of molecular interactions. They help guide the folding of proteins, increase the binding of one protein to another and facilitate protein-DNA and protein-ligand binding. A popular method for computing the electrostatic properties of biological systems is to numerically solve the Poisson-Boltzmann (PB) equation, and there are several easy-to-use software packages available that solve the PB equation for soluble proteins. Here we present a freely available program, called APBSmem, for carrying out these calculations in the presence of a membrane. The Adaptive Poisson-Boltzmann Solver (APBS) is used as a back-end for solving the PB equation, and a Java-based graphical user interface (GUI) coordinates a set of routines that introduce the influence of the membrane, determine its placement relative to the protein, and set the membrane potential. The software Jmol is embedded in the GUI to visualize the protein inserted in the membrane before the calculation and the electrostatic potential after completing the computation. We expect that the ease with which the GUI allows one to carry out these calculations will make this software a useful resource for experimenters and computational researchers alike. Three examples of membrane protein electrostatic calculations are carried out to illustrate how to use APBSmem and to highlight the different quantities of interest that can be calculated. PMID- 20949125 TI - SH2 modified STAT1 induces HLA-I expression and improves IFN-gamma signaling in IFN-alpha resistant HCV replicon cells. AB - BACKGROUND: We have developed multiple stable cell lines containing subgenomic HCV RNA that are resistant to treatment with interferon alpha (IFN-alpha. Characterization of these IFN-alpha resistant replicon cells showed defects in the phosphorylation and nuclear translocation of STAT1 and STAT2 proteins due to a defective Jak-STAT pathway. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have developed an alternative strategy to overcome interferon resistance in a cell culture model by improving intracellular STAT1 signaling. An engineered STAT1-CC molecule with double cysteine substitutions in the Src-homology 2 (SH2) domains of STAT1 (at Ala-656 and Asn-658) efficiently phosphorylates and translocates to the nucleus of IFN-resistant cells in an IFN-gamma dependent manner. Transfection of a plasmid clone containing STAT1-CC significantly activated the GAS promoter compared to wild type STAT1 and STAT3. The activity of the engineered STAT1-CC is dependent upon the phosphorylation of tyrosine residue 701, since the construct with a substituted phenylalanine residue at position 701 (STAT1-CC-Y701F) failed to activate GAS promoter in the replicon cells. Intracellular expression of STAT1-CC protein showed phosphorylation and nuclear translocation in the resistant cell line after IFN-gamma treatment. Transient transfection of STAT1-CC plasmid clone into an interferon resistant cell line resulted in inhibition of viral replication and viral clearance in an IFN-gamma dependent manner. Furthermore, the resistant replicon cells transfected with STAT1-CC constructs significantly up regulated surface HLA-1 expression when compared to the wild type and Y to F mutant controls. CONCLUSIONS: These results suggest that modification of the SH2 domain of the STAT1 molecule allows for improved IFN-gamma signaling through increased STAT1 phosphorylation, nuclear translocation, HLA-1 surface expression, and prolonged interferon antiviral gene activation. PMID- 20949126 TI - Type I error rates, coverage of confidence intervals, and variance estimation in propensity-score matched analyses. AB - Propensity-score matching is frequently used in the medical literature to reduce or eliminate the effect of treatment selection bias when estimating the effect of treatments or exposures on outcomes using observational data. In propensity-score matching, pairs of treated and untreated subjects with similar propensity scores are formed. Recent systematic reviews of the use of propensity-score matching found that the large majority of researchers ignore the matched nature of the propensity-score matched sample when estimating the statistical significance of the treatment effect. We conducted a series of Monte Carlo simulations to examine the impact of ignoring the matched nature of the propensity-score matched sample on Type I error rates, coverage of confidence intervals, and variance estimation of the treatment effect. We examined estimating differences in means, relative risks, odds ratios, rate ratios from Poisson models, and hazard ratios from Cox regression models. We demonstrated that accounting for the matched nature of the propensity-score matched sample tended to result in type I error rates that were closer to the advertised level compared to when matching was not incorporated into the analyses. Similarly, accounting for the matched nature of the sample tended to result in confidence intervals with coverage rates that were closer to the nominal level, compared to when matching was not taken into account. Finally, accounting for the matched nature of the sample resulted in estimates of standard error that more closely reflected the sampling variability of the treatment effect compared to when matching was not taken into account. PMID- 20949127 TI - A comparison of the statistical power of different methods for the analysis of repeated cross-sectional cluster randomization trials with binary outcomes. AB - Repeated cross-sectional cluster randomization trials are cluster randomization trials in which the response variable is measured on a sample of subjects from each cluster at baseline and on a different sample of subjects from each cluster at follow-up. One can estimate the effect of the intervention on the follow-up response alone, on the follow-up responses after adjusting for baseline responses, or on the change in the follow-up response from the baseline response. We used Monte Carlo simulations to determine the relative statistical power of different methods of analysis. We examined methods of analysis based on generalized estimating equations (GEE) and a random effects model to account for within-cluster homogeneity. We also examined cluster-level analyses that treated the cluster as the unit of analysis. We found that the use of random effects models to estimate the effect of the intervention on the change in the follow-up response from the baseline response had lower statistical power compared to the other competing methods across a wide range of scenarios. The other methods tended to have similar statistical power in many settings. However, in some scenarios, those analyses that adjusted for the baseline response tended to have marginally greater power than did methods that did not account for the baseline response. PMID- 20949128 TI - Estimating multilevel logistic regression models when the number of clusters is low: a comparison of different statistical software procedures. AB - Multilevel logistic regression models are increasingly being used to analyze clustered data in medical, public health, epidemiological, and educational research. Procedures for estimating the parameters of such models are available in many statistical software packages. There is currently little evidence on the minimum number of clusters necessary to reliably fit multilevel regression models. We conducted a Monte Carlo study to compare the performance of different statistical software procedures for estimating multilevel logistic regression models when the number of clusters was low. We examined procedures available in BUGS, HLM, R, SAS, and Stata. We found that there were qualitative differences in the performance of different software procedures for estimating multilevel logistic models when the number of clusters was low. Among the likelihood-based procedures, estimation methods based on adaptive Gauss-Hermite approximations to the likelihood (glmer in R and xtlogit in Stata) or adaptive Gaussian quadrature (Proc NLMIXED in SAS) tended to have superior performance for estimating variance components when the number of clusters was small, compared to software procedures based on penalized quasi-likelihood. However, only Bayesian estimation with BUGS allowed for accurate estimation of variance components when there were fewer than 10 clusters. For all statistical software procedures, estimation of variance components tended to be poor when there were only five subjects per cluster, regardless of the number of clusters. PMID- 20949129 TI - Cohort differences in 3-year adaptation to health problems among Dutch middle aged, 1992-1995 and 2002-2005. AB - Midlife is a period during which ageing-related health problems first emerge. In view of increasing life expectancy, it is of great importance that people in midlife adapt to possible health problems, to be able to lead productive and engaged lives as long as possible. It may be expected that given the better circumstances in which more recent cohorts grew up, they are better equipped to adapt to health problems than earlier cohorts. This study addresses the question if the way people in midlife adapt to health problems is or is not improving in the Netherlands. The study is based on the nationally representative 1992-1993 and 2002-2003 cohorts of the Longitudinal Aging Study Amsterdam (ages 55-64 years), with follow-up cycles in 1995-1996 (n = 811) and 2005-2006 (n = 829), respectively. Mastery is considered as a measure of adaptation, and 3-year change in mastery is compared in subjects without and with health problems at baseline. A rise was observed in the prevalence of diabetes, chronic lung disease, arthritis, subthreshold depression, and disability. Subjects without health problems in the recent cohort had better mastery than their counterparts in the early cohort. Regardless of cohort membership, mastery declined over 3 years for those with subthreshold depression, mild disability, chronic lung disease, and stroke. In the recent cohort only, mastery declined for those with cognitive impairment, but improved for those with heart disease. These findings do not support the expectation that recent cohorts are better equipped to deal with health problems for conditions other than heart disease. PMID- 20949130 TI - Bending it like Beckham: how to visually fool the goalkeeper. AB - BACKGROUND: As bending free-kicks becomes the norm in modern day soccer, implications for goalkeepers have largely been ignored. Although it has been reported that poor sensitivity to visual acceleration makes it harder for expert goalkeepers to perceptually judge where the curved free-kicks will cross the goal line, it is unknown how this affects the goalkeeper's actual movements. METHODOLOGY/PRINCIPAL FINDINGS: Here, an in-depth analysis of goalkeepers' hand movements in immersive, interactive virtual reality shows that they do not fully account for spin-induced lateral ball acceleration. Hand movements were found to be biased in the direction of initial ball heading, and for curved free-kicks this resulted in biases in a direction opposite to those necessary to save the free-kick. These movement errors result in less time to cover a now greater distance to stop the ball entering the goal. These and other details of the interceptive behaviour are explained using a simple mathematical model which shows how the goalkeeper controls his movements online with respect to the ball's current heading direction. Furthermore our results and model suggest how visual landmarks, such as the goalposts in this instance, may constrain the extent of the movement biases. CONCLUSIONS: While it has previously been shown that humans can internalize the effects of gravitational acceleration, these results show that it is much more difficult for goalkeepers to account for spin-induced visual acceleration, which varies from situation to situation. The limited sensitivity of the human visual system for detecting acceleration, suggests that curved free kicks are an important goal-scoring opportunity in the game of soccer. PMID- 20949131 TI - Profiling of substrate specificity of SARS-CoV 3CL. AB - BACKGROUND: The 3C-like protease (3CL(pro)) of severe acute respiratory syndrome coronavirus is required for autoprocessing of the polyprotein, and is a potential target for treating coronaviral infection. METHODOLOGY/PRINCIPAL FINDINGS: To obtain a thorough understanding of substrate specificity of the protease, a substrate library of 198 variants was created by performing saturation mutagenesis on the autocleavage sequence at P5 to P3' positions. The substrate sequences were inserted between cyan and yellow fluorescent proteins so that the cleavage rates were monitored by in vitro fluorescence resonance energy transfer. The relative cleavage rate for different substrate sequences was correlated with various structural properties. P5 and P3 positions prefer residues with high beta sheet propensity; P4 prefers small hydrophobic residues; P2 prefers hydrophobic residues without beta-branch. Gln is the best residue at P1 position, but observable cleavage can be detected with His and Met substitutions. P1' position prefers small residues, while P2' and P3' positions have no strong preference on residue substitutions. Noteworthy, solvent exposed sites such as P5, P3 and P3' positions favour positively charged residues over negatively charged one, suggesting that electrostatic interactions may play a role in catalysis. A super active substrate, which combined the preferred residues at P5 to P1 positions, was found to have 2.8 fold higher activity than the wild-type sequence. CONCLUSIONS/SIGNIFICANCE: Our results demonstrated a strong structure-activity relationship between the 3CL(pro) and its substrate. The substrate specificity profiled in this study may provide insights into a rational design of peptidomimetic inhibitors. PMID- 20949132 TI - Modelling the role of UCH-L1 on protein aggregation in age-related neurodegeneration. AB - Overexpression of the de-ubiquitinating enzyme UCH-L1 leads to inclusion formation in response to proteasome impairment. These inclusions contain components of the ubiquitin-proteasome system and alpha-synuclein confirming that the ubiquitin-proteasome system plays an important role in protein aggregation. The processes involved are very complex and so we have chosen to take a systems biology approach to examine the system whereby we combine mathematical modelling with experiments in an iterative process. The experiments show that cells are very heterogeneous with respect to inclusion formation and so we use stochastic simulation. The model shows that the variability is partly due to stochastic effects but also depends on protein expression levels of UCH-L1 within cells. The model also indicates that the aggregation process can start even before any proteasome inhibition is present, but that proteasome inhibition greatly accelerates aggregation progression. This leads to less efficient protein degradation and hence more aggregation suggesting that there is a vicious cycle. However, proteasome inhibition may not necessarily be the initiating event. Our combined modelling and experimental approach show that stochastic effects play an important role in the aggregation process and could explain the variability in the age of disease onset. Furthermore, our model provides a valuable tool, as it can be easily modified and extended to incorporate new experimental data, test hypotheses and make testable predictions. PMID- 20949133 TI - Effects of maraviroc and efavirenz on markers of immune activation and inflammation and associations with CD4+ cell rises in HIV-infected patients. AB - BACKGROUND: Maraviroc treatment for HIV-1 infected patients results in larger CD4(+) T cell rises than are attributable to its antiviral activity alone. We investigated whether this is due to modulation of T cell activation and inflammation. METHODS AND FINDINGS: Thirty maraviroc-treated patients from the Maraviroc versus Efavirenz Regimens as Initial Therapy (MERIT) study were randomly selected from among those who had CCR5-tropic (R5) HIV on screening and achieved undetectable HIV RNA (<50 copies/mL) by Week 48. Efavirenz-treated controls were matched for baseline characteristics to the maraviroc-treated patients selected for this substudy. Changes in immune activation and inflammation markers were examined for associations with CD4(+) T cell changes. Maraviroc treatment tended to result in more rapid decreases in CD38 expression on CD4(+) T cells and in plasma D-dimer concentrations than did treatment with efavirenz. The proportion of patients with high-sensitivity C-reactive protein >2 ug/mL increased from 45% to 66% in the efavirenz arm, but remained constant in the maraviroc arm (P = 0.033). Decreases in CD38 expression on CD8(+) T cells were correlated with CD4(+) T cell rises for maraviroc treatment (r = -0.4, P = 0.048), but not for treatment with efavirenz. CONCLUSIONS: Maraviroc-treated patients had earlier, modest decreases in certain markers of immune activation and inflammation, although in this small study, many of the differences were not statistically significant. Levels of high-sensitivity C-reactive protein remained constant in the maraviroc arm and increased in the efavirenz arm. Decreases in immune activation correlated with increased CD4(+) T cell gains. TRIAL REGISTRATION: ClinicalTrials.gov NCT00098293. PMID- 20949134 TI - Dissociable processes of cognitive control during error and non-error conflicts: a study of the stop signal task. AB - BACKGROUND: Conflict detection and subsequent behavioral adjustment are critical to daily life, and how this process is controlled has been increasingly of interest. A medial cortical region which includes the anterior cingulate cortex (ACC) has been theorized to act as a conflict detector that can direct prefrontal activity for behavioral adjustments. This conflict monitoring hypothesis was supported by many imaging studies of the Stroop task, with a focus on non-error processes. Here we sought to examine whether this circuit could be generalized to the stop signal task (SST), another behavioral paradigm widely used to study cognitive control. In particular, with a procedure to elicit errors in the SST, we examined whether error and non-error control were mediated by the same pathways. METHODOLOGY/PRINCIPAL FINDINGS: In functional magnetic resonance imaging of 60 healthy adults, we demonstrated that the medial cortical activity during stop success (SS) as compared to go success (G) trials is correlated with increased prefrontal activity in post-stop SS as compared to post-go SS trials, though this correlation was not specific to the medial cortical region. Furthermore, thalamic and insular rather than medial cortical activation during stop error (SE) as compared to G trials correlated with increased prefrontal activity in post-stop SS as compared to post-go SS trials. CONCLUSIONS/SIGNIFICANCE: Taken together, these new findings challenge a specific role of the ACC and support distinct pathways for error and non-error conflict processing in cognitive control. PMID- 20949135 TI - A compartmental model analysis of integrative and self-regulatory ion dynamics in pollen tube growth. AB - Sexual reproduction in higher plants relies upon the polarised growth of pollen tubes. The growth-site at the pollen tube tip responds to signalling processes to successfully steer the tube to an ovule. Essential features of pollen tube growth are polarisation of ion fluxes, intracellular ion gradients, and oscillating dynamics. However, little is known about how these features are generated and how they are causally related. We propose that ion dynamics in biological systems should be studied in an integrative and self-regulatory way. Here we have developed a two-compartment model by integrating major ion transporters at both the tip and shank of pollen tubes. We demonstrate that the physiological features of polarised growth in the pollen tube can be explained by the localised distribution of transporters at the tip and shank. Model analysis reveals that the tip and shank compartments integrate into a self-regulatory dynamic system, however the oscillatory dynamics at the tip do not play an important role in maintaining ion gradients. Furthermore, an electric current travelling along the pollen tube contributes to the regulation of ion dynamics. Two candidate mechanisms for growth-induced oscillations are proposed: the transition of tip membrane into shank membrane, and growth-induced changes in kinetic parameters of ion transporters. The methodology and principles developed here are applicable to the study of ion dynamics and their interactions with other functional modules in any plant cellular system. PMID- 20949136 TI - Domain-based identification and analysis of glutamate receptor ion channels and their relatives in prokaryotes. AB - Voltage-gated and ligand-gated ion channels are used in eukaryotic organisms for the purpose of electrochemical signaling. There are prokaryotic homologues to major eukaryotic channels of these sorts, including voltage-gated sodium, potassium, and calcium channels, Ach-receptor and glutamate-receptor channels. The prokaryotic homologues have been less well characterized functionally than their eukaryotic counterparts. In this study we identify likely prokaryotic functional counterparts of eukaryotic glutamate receptor channels by comprehensive analysis of the prokaryotic sequences in the context of known functional domains present in the eukaryotic members of this family. In particular, we searched the nonredundant protein database for all proteins containing the following motif: the two sections of the extracellular glutamate binding domain flanking two transmembrane helices. We discovered 100 prokaryotic sequences containing this motif, with a wide variety of functional annotations. Two groups within this family have the same topology as eukaryotic glutamate receptor channels. Group 1 has a potassium-like selectivity filter. Group 2 is most closely related to eukaryotic glutamate receptor channels. We present analysis of the functional domain architecture for the group of 100, a putative phylogenetic tree, comparison of the protein phylogeny with the corresponding species phylogeny, consideration of the distribution of these proteins among classes of prokaryotes, and orthologous relationships between prokaryotic and human glutamate receptor channels. We introduce a construct called the Evolutionary Domain Network, which represents a putative pathway of domain rearrangements underlying the domain composition of present channels. We believe that scientists interested in ion channels in general, and ligand-gated ion channels in particular, will be interested in this work. The work should also be of interest to bioinformatics researchers who are interested in the use of functional domain-based analysis in evolutionary and functional discovery. PMID- 20949137 TI - Investigation of K14/K5 as a stem cell marker in the limbal region of the bovine cornea. AB - BACKGROUND: Identification of stem cells from a corneal epithelial cell population by specific molecular markers has been investigated previously. Expressions of P63, ABCG2 and K14/K5 have all been linked to mammalian corneal epithelial stem cells. Here we report on the limitations of K14/K5 as a limbal stem cell marker. METHODOLOGY/PRINCIPAL FINDINGS: K14/K5 expression was measured by immunohistochemistry, Western blotting and Real time PCR and compared between bovine epithelial cells in the limbus and central cornea. A functional study was also included to investigate changes in K5/14 expression within cultured limbal epithelial cells undergoing forced differentiation. K14 expression (or its partner K5) was detected in quiescent epithelial cells from both the limbal area and central cornea. K14 was localized predominantly to basal epithelial cells in the limbus and suprabasal epithelial cells in the central cornea. Western blotting revealed K14 expression in both limbus and central cornea (higher levels in the limbus). Similarly, quantitative real time PCR found K5, partner to K14, to be expressed in both the central cornea and limbus. Following forced differentiation in culture the limbal epithelial cells revealed an increase in K5/14 gene/protein expression levels in concert with a predictable rise in a known differentiation marker. CONCLUSIONS/SIGNIFICANCE: K14 and its partner K5 are limited not only to the limbus but also to the central bovine cornea epithelial cells suggesting K14/K5 is not limbal specific in situ. Furthermore K14/K5 expression levels were not lowered (in fact they increased) within a limbal epithelial cell culture undergoing forced differentiation suggesting K14/K5 is an unreliable maker for undifferentiated cells ex vivo. PMID- 20949138 TI - Iridovirus and microsporidian linked to honey bee colony decline. AB - BACKGROUND: In 2010 Colony Collapse Disorder (CCD), again devastated honey bee colonies in the USA, indicating that the problem is neither diminishing nor has it been resolved. Many CCD investigations, using sensitive genome-based methods, have found small RNA bee viruses and the microsporidia, Nosema apis and N. ceranae in healthy and collapsing colonies alike with no single pathogen firmly linked to honey bee losses. METHODOLOGY/PRINCIPAL FINDINGS: We used Mass spectrometry-based proteomics (MSP) to identify and quantify thousands of proteins from healthy and collapsing bee colonies. MSP revealed two unreported RNA viruses in North American honey bees, Varroa destructor-1 virus and Kakugo virus, and identified an invertebrate iridescent virus (IIV) (Iridoviridae) associated with CCD colonies. Prevalence of IIV significantly discriminated among strong, failing, and collapsed colonies. In addition, bees in failing colonies contained not only IIV, but also Nosema. Co-occurrence of these microbes consistently marked CCD in (1) bees from commercial apiaries sampled across the U.S. in 2006-2007, (2) bees sequentially sampled as the disorder progressed in an observation hive colony in 2008, and (3) bees from a recurrence of CCD in Florida in 2009. The pathogen pairing was not observed in samples from colonies with no history of CCD, namely bees from Australia and a large, non-migratory beekeeping business in Montana. Laboratory cage trials with a strain of IIV type 6 and Nosema ceranae confirmed that co-infection with these two pathogens was more lethal to bees than either pathogen alone. CONCLUSIONS/SIGNIFICANCE: These findings implicate co-infection by IIV and Nosema with honey bee colony decline, giving credence to older research pointing to IIV, interacting with Nosema and mites, as probable cause of bee losses in the USA, Europe, and Asia. We next need to characterize the IIV and Nosema that we detected and develop management practices to reduce honey bee losses. PMID- 20949139 TI - Homogeneous assays using aptamers. AB - Aptamers are DNA or RNA oligonucleotides that can bind with high affinity and specificity to a wide range of targets such as proteins, metal ions or pathogenic microorganisms. Soluble aptamers and aptazymes have been used as sensing elements for developing homogeneous assays in a solution phase, the whole sensing process being carried out in a homogeneous solution. Contrary to most conventional heterogeneous assays that are time-consuming and labor-intensive, aptamer-based homogeneous assays are simple, easy-to-perform, rapid and do not require immobilization nor washing steps. To our knowledge, this review is the first entirely dedicated to aptamer-based homogeneous assays. Optical detection appears as the most developed technique. Colorimetry represents the simplest sensing mode that occupies a very important position among aptamer-based assays, involving gold nanoparticle aggregation (with unmodified or aptamer-modified gold NPs), the formation of HRP-mimicking DNAzyme with hemin, dye displacement or interactions with a cationic polymer. Fluorescence that is highly sensitive offers the most developed detection mode. Aptamers can be labeled or not, to give rise to turn-on or usually less sensitive turn-off fluorescent assays. Newly reported and thus less developed non-conventional magnetic resonance imaging (MRI) and electrochemistry also recently appeared in the literature, thrombin still remains the main detected target. Homogeneous assays based on aptazyme, an aptamer sequence connected to a known ribozyme motif, are also described in this review, involving optical detection, by colorimetry or fluorescence. PMID- 20949140 TI - Rational strategy of magnetic relaxation switches for glycoprotein sensing. AB - A rational strategy of magnetic relaxation switches was proposed here to detect a(1)-acid glycoprotein (AGP), an acute phase a-globulin plasma glycoprotein. The assay was based on the relaxation time change between the aggregation of magnetic nanoparticles with concanavalin A and the redispersion with AGP, which can avoid the prozone effect and improve the detection accuracy. The assay was an easy and efficient method with two mixing steps and one measurement step, showing a detection limit of 0.66 nM in 0~0.3 MUg mL(-1) AGP, which was far lower than its normal level in human plasma. PMID- 20949141 TI - The influence of micelle formation on the stability of colloid surfactant mixtures. AB - The stability of colloidal dispersions can be severely affected by the presence of surfactants. Because surfactants can adsorb at colloidal surfaces as well as form micelles, one can expect an interplay between both phenomena. Using grand canonical coarse-grained Monte Carlo simulations on surfactant solutions confined between two surfaces, we investigate how adsorption and micelle formation affects the effective interaction between two colloidal particles, and hence, the stability of the colloidal dispersion. For solvophilic colloidal surfaces, we observe a short-ranged oscillatory solvation pressure that is hardly affected by the presence of surfactants in the system. The effective surface-surface interaction, however, reveals a decrease in solvophilic stabilization as a function of surfactant chemical potential. For solvophobic surfaces, we find that the capillary evaporation observed in a confined pure solvent, is counteracted by the addition of surfactants. Around the critical micelle concentration (CMC), the surface-surface interaction even becomes repulsive, enhancing stabilization of the colloidal dispersion. In contrast, the formation of micelles at concentrations above the CMC causes an additional depletion effect, resulting in an effective attraction, which in turn can destabilize a colloidal dispersion. PMID- 20949142 TI - Symmetry forbidden vibronic spectra and internal conversion in benzene. AB - The spectra of symmetry-forbidden transitions and internal conversion were investigated in the present work. Temperature dependence was taken into account for the spectra simulation. The vibronic coupling, essential in the two processes, was calculated based on the Herzberg-Teller theory within the Born Oppenheimer approximation. The approach was employed for the symmetry-forbidden absorption/fluorescence, and internal conversion between 1(1)A(1g) and 1(1)B(2u) states in benzene. Vibrational frequencies, normal coordinates, electronic transition dipole moments, and non-adiabatic coupling matrix elements were obtained by ab initio quantum chemical methods. The main peaks, along with the weak peaks, were in good agreement with the observed ones. The rate constant of the 1(1)A(1g)<- 1(1)B(2u) internal conversion was estimated within the order of 10(3) s(-1). This could be regarded as the lower limit (about 4.8 * 10(3) s(-1)) of the internal conversion. It is stressed that the distortion effect was taken into account both in the symmetry-forbidden absorption/fluorescence, and the rate constants of internal conversion in the present work. The distortion effects complicate the spectra and increase the rate constants of internal conversion. PMID- 20949143 TI - A density functional theory approach to noncovalent interactions via interacting monomer densities. AB - A recently proposed "DFT + dispersion" treatment (Rajchel et al., Phys. Rev. Lett., 2010, 104, 163001) is described in detail and illustrated by more examples. The formalism derives the dispersion-free density functional theory (DFT) interaction energy and combines it with the dispersion energy from separate DFT calculations. It consists of the self-consistent polarization of DFT monomers restrained by the exclusion principle via the Pauli blockade technique. Within the monomers a complete exchange-correlation potential should be used, but between them only the exact exchange operates. The application to a wide range of molecular complexes from rare-gas dimers to hydrogen-bonds to pi-electron interactions shows good agreement with benchmark values. PMID- 20949144 TI - Solid-state transformation of [Co(NCS)2(pyridine)4] into [Co(NCS)2(pyridine)2]n: from Curie-Weiss paramagnetism to single chain magnetic behaviour. AB - Reaction of Co(NCS)(2) with pyridine (pyr) in aqueous solution at room temperature leads to the formation of the pyridine-rich 1:4 compound of composition [Co(NCS)(2)(pyridine)(4)] (1) reported recently. On heating, the pyridine-rich 1:4 compound transforms into its corresponding pyridine-deficient 1:2 compound of composition [Co(NCS)(2)(pyridine)(2)](n) (2), which decomposes on further heating. In the crystal structure of compound 2 the metal cations are coordinated by four N-atoms of two pyridine ligands and two N-bonded thiocyanato anions, each in mutually trans orientation, and by two S-atoms of two adjacent thiocyanato anions in a slightly distorted octahedral geometry. The thiocyanato anions bridge the metal cations forming one-dimensional polymeric chains. IR spectroscopic investigations on the pyridine-deficient 1:2 compound prepared in thermal decomposition are in accordance with bridging thiocyanato anions. Magnetic measurements of the pyridine-rich 1:4 compound and pyridine-deficient 1:2 compound reveal different behaviour with Curie-Weiss paramagnetism for compound 1 and single chain magnetic behaviour for compound 2, with a Mydosh parameter phi = 0.12 and an effective energy barrier (-U(eff)/k(B)) of 62.5 K for the spin relaxation. PMID- 20949145 TI - Self-selective recovery of photoluminescence in amphiphilic polymer encapsulated PbS quantum dots. AB - Self-selected recovery of the photoluminescence (PL) of amphiphilic polymer encapsulated PbS quantum dots (QDs) was observed in water for the first time and possible mechanisms were proposed based on investigations by means of transmission electron microscopy, X-ray photoelectron spectroscopy (XPS), X-ray diffraction and fluorescence spectroscopy. Water-soluble PbS QDs were synthesized by transferring monodispersed QDs capped with hydrophobic ligands of oleylamine from an organic solvent into water via amphiphilic polymers poly(maleic anhydride alt-1-octadecene-co-poly(ethylene glycol)). The water transfer process leads to a double size distribution (5.6 +/- 0.9 nm and 2.7 +/- 0.4 nm), attributed to ligand etching together with Ostwald ripening, as well as the fast decay of PL. The automatic recovery of the PL in PbS QDs stored in water in the dark for 3 months was only observed for the subset of smaller QDs and is largely due to the removal of surface defects with aging, as evidenced by the decreased percentage of unpassivated surface atoms from XPS studies. In contrast, the PL of the subset of larger QDs in the same sample does not self-recover in water and can only be slightly recovered by transferring them into environments with less external quenches. The results strongly suggest that it is the surface defect in the larger QDs themselves, introduced during Ostwald ripening, that is primarily responsible for their non-emitting status or rather low PL intensity under different conditions. The increase of unpassivated Pb atoms in larger PbS QDs after the 3 month aging has been confirmed by XPS, which explains their non recovery behavior in water. The PL-recovered QD sample in water is very stable and shows comparable photostability to the initial QDs dispersed in an organic phase. PMID- 20949146 TI - One pot-synthesis of chiral Ni6 clusters involving Ni3 subunits: a combined structural, magnetic and DFT study. AB - Ni(6) clusters of the general formula [{Ni(3)L(n)(OAc)(OH)}(2)(X)(OAc)(H(2)O)(2)] (n = 1, 2; X = Cl(-) or N(3)(-), (L(n))(3-) = hexadentate tritopic ligands) can be isolated by spontaneous self-assembly, from mixtures of Ni(OAc)(2), H(3)L(n), NMe(4)OH.5H(2)O and NaX in adequate molar ratios. Thus, four new hexanuclear complexes [{Ni(3)L(1)(OAc)(OH)}(2)Cl(OAc)(H(2)O)(2)].7.5H(2)O (1.7.5H(2)O), [{Ni(3)L(2)(OAc)(OH)}(2)Cl(OAc)(H(2)O)(2)].2H(2)O.7.5MeOH (2.2H(2)O.7.5MeOH), [{Ni(3)L(1)(OAc)(OH)}(2)(N(3))(OAc)(H(2)O)(2)].6H(2)O (3.6H(2)O) and [{Ni(3)L(2)(OAc)(OH)}(2)(N(3))(OAc)(H(2)O)(2)].4H(2)O (4.4H(2)O) were obtained and fully characterised. 1.7.5H(2)O and 2.2H(2)O.7.5MeOH were isolated in the form of single crystals, the latter losing solvate on drying, to yield 2.2H(2)O. Recrystallisation of 3.6H(2)O in MeCN/MeOH also generates single crystals of 3.H(2)O.2MeOH.2MeCN. Their X-ray characterisation shows that these Ni(6) clusters can be considered to be built from two triangular trinuclear [Ni(3)L(n)(OAc)(OH)](+) subunits with different connectors. In addition, these studies demonstrate that the (L(n))(3-) ligands behave as trinucleating, adopting such a conformation that induces chirality in the isolated compounds. In this way, 3.H(2)O.2MeOH.2MeCN appears particularly interesting, since it emerges as homochiral after undergoing spontaneous resolution upon crystallisation. The magnetic characterisation of 1.7.5H(2)O to 3.6H(2)O reveals that the three compounds present an overall antiferromagnetic coupling. The intricate magnetic behaviour of these clusters, mediated by a total of 14 bridges of different kinds, was analysed and satisfactorily interpreted in light of DFT calculations. PMID- 20949147 TI - Structure elucidation of the unprecedented asymmetric bis-chelate complex [Pd(1,3 bis(di(o-methoxy-m-methylphenyl)phosphino)propane)2]2+ in the solid state and in solution. AB - Complexes of the type [Pd(ligand)(2)](anion)(2) were prepared with a series of bidentate di(o-methoxyphenyl)phosphine ligands with increasing steric bulk on the meta position of the phenyl groups: m-H (L1); m-MeO (L2); and m-Me (L3). The solid-state structure of [Pd(L2)(2)](OTs)(2) revealed that the two ligands are symmetrically coordinated to Pd(2+). In the solid state structure of [Pd(L3)(2)](OTs)(2) however, the two ligands are unsymmetrically coordinated to Pd(2+), yielding an unprecedented conformation of this bis-chelate P(4)Pd(2+) complex. (1)H-(1)H-COSY and NOESY analysis and a (31)P-NMR simulation showed that the asymmetric structure of [Pd(L3)(2)](OTs)(2) is retained in solution. PMID- 20949148 TI - Crystallization and formation mechanisms of nanostructures. PMID- 20949188 TI - Methods for in situ spectroscopic probing of the synthesis of a zeolite. AB - Unraveling the crystallization mechanism of zeolites remains an increasingly important challenge in chemistry. During the last decade, in situ spectroscopic methods have provided an unprecedented level of detail of the underlying molecular mechanisms and their kinetics. Magnetic resonance, vibrational and X ray absorption techniques have emerged as principal tools for the in situ observation of crystallization. In this tutorial review, we discuss how these in situ methods have contributed to our understanding of the complex and diverse molecular processes that govern zeolite crystallization. PMID- 20949189 TI - Effect of solvent and additives on the open-circuit voltage of ZnO-based dye sensitized solar cells: a combined theoretical and experimental study. AB - We have investigated the role of electrolyte composition, in terms of solvent and additive, on the open-circuit voltage (V(oc)) of ZnO-based dye-sensitized solar cells (DSSCs) using a combined experimental and theoretical approach. Calculations based on density functional theory (DFT) have been performed in order to describe the geometries and adsorption energies of various adsorbed solvents (nitromethane, acetonitrile and dimethylformamide) and p-tert butylpyridine (TBP) (modeled by methylpyridine) on the ZnO (100) surface using a periodic approach. The densities of states (DOS) have been calculated and the energy position of the conduction band edge (CBE) has been evaluated for the different molecules adsorbed. The effect of the electrolyte composition on the standard redox potential of the iodide/triiodide redox couple has been experimentally determined. These two data values (CBE and standard redox potential) allowed us to determine the dependence of V(oc) on the electrolyte composition. The variations determined using this method were in good agreement with the measured V(oc) for cells made of electrodeposited ZnO films sensitized using D149 (indoline) dye. As in the case of TiO(2)-based cells, a correlation of V(oc) with the donor number of the adsorbed species was found. The present study clearly points out that both the CBE energy and the redox potential variation are important for explaining the experimentally observed changes in the V(oc) of DSSCs. PMID- 20949190 TI - A novel bio-electrochemical ascorbic acid sensor modified with Cu4(OH)6SO4 nanorods. AB - Cu(4)(OH)(6)SO(4) (brochantite) is an undesirable oxidation product of copper bearing sulfides, and it is seldom considered to be biologically and electrochemically active. In this paper, we report that Cu(4)(OH)(6)SO(4) nanoparticles in fact possess an intrinsic electrocatalytic activity, which is explored as a biosensing material to oxidize L-ascorbic acid (AA). The Cu(4)(OH)(6)SO(4) nanorod modified biosensor exhibits excellent performance for the determination of l-ascorbic acid with a response time of less than 8 s, a linear range between 0.017 and 6 mM, and a sensitivity of 17.53 MUA mM(-1). A high selectivity towards the oxidation of AA in the presence of dopamine (DA) and acetyl aminophenol (AP) is also observed at their maximum physiological concentrations. The good analytical performance and long-term stability, low cost and straightforward fabrication method made the Cu(4)(OH)(6)SO(4) nanomaterials promising for the development of effective electrochemical sensors for a wide range of potential applications in medicine, biotechnology and environmental chemistry. PMID- 20949191 TI - An alternative route to detect parity violating energy differences through Bose Einstein condensation of chiral molecules. AB - Interactions which do not conserve parity might influence chiral compounds giving rise to a parity violating energy difference (PVED) that might have affected the evolution towards homochirality. However, this tiny effect predicted by electroweak-quantum chemistry calculations is easily masked by thermal effects, making it desirable to reach cold regimes in the laboratory. As an alternative route to the detection of the PVED, we study a simplified model of Bose-Einstein condensation of a sample of non-interacting chiral molecules, showing that it leads to a nonzero optical activity of the condensate and also to a subcritical temperature in the heat capacity, due to the internal structure of the molecule characterized by tunneling and parity violation. This predicted singular behavior found for the specific heat, below the condensation temperature, might shed some light on the existence of the thus far elusive PVED between enantiomers. PMID- 20949192 TI - Theoretical investigations into the enantiomeric and racemic forms of alpha (trifluoromethyl)lactic acid. AB - There are many different hypotheses on the origin of biomolecular homochirality. One possible scenario concerns the enantiomeric enrichment of a nearly racemic solid via self-disproportionation of enantiomers. In particular, in a recent paper Soloshonok and co-workers showed a first example of optical self purification of alpha-(trifluoromethyl)lactic acid by sublimation [V. A. Soloshonok et al., J. Am. Chem. Soc. 2007, 129, 12112]. Here we present detailed theoretical studies of alpha-(trifluoromethyl)lactic acid in the solid state as well as in the gas-phase dimeric form. The calculations of energy differences between dimers show that in the solid state the enantiomeric pure compound is energetically preferred, while in the gas phase the equilibrium shifts towards the racemic mixture although thermodynamic corrections cannot be neglected, thus providing a detailed microscopic explanation for the enantio-purification process for the first time. PMID- 20949193 TI - Light at the interface: the potential of attenuated total reflection infrared spectroscopy for understanding heterogeneous catalysis in water. AB - IR spectroscopy has been an important tool for studying detailed interactions of reactants and reaction-intermediates with catalyst surfaces. Studying reactions in water is, however, far from trivial, due to the excessive absorption of infrared light by water. One way to deal with this is the use of Attenuated Total Reflection spectroscopy (ATR-IR) minimizing the path length of infrared light through the water. Moreover, ATR-IR allows for a direct comparison of reactions in gas and water on the same sample, which bridges the gap between separate catalyst investigations in gas and liquid phase. This tutorial review describes recent progress in using ATR-IR for studying heterogeneous catalysts in water. An overview is given of the important aspects to be taken into account when using ATR-IR to study heterogeneous catalysts in liquid phase, like the procedure to prepare stable catalyst layers on the internal reflection element. As a case study, CO adsorption and oxidation on noble metal catalysts is investigated with ATR-IR in gas and water. The results show a large effect of water and pH on the adsorption and oxidation of CO on Pt/Al(2)O(3) and Pd/Al(2)O(3). From the results it is concluded that water affects the metal particle potential as well as the adsorbed CO molecule directly, resulting in higher oxidation rates in water compared to gas phase. Moreover, also pH influences the metal particle potential with a clear effect on the observed oxidation rates. Finally, the future outlook illustrates that ATR-IR spectroscopy holds great promise in the field of liquid phase heterogeneous catalysis. PMID- 20949194 TI - Impact of microcystin containing diets on physiological performance of Nile tilapia (Oreochromis niloticus) concerning detoxification. AB - Nile tilapia (Oreochromis niloticus) were fed by diets supplemented with cyanobacteria containing in part the cyanotoxin microcystin-LR (MC-LR) to determine the potential impacts on detoxification. Four different diets were prepared based on a commercial diet: (1) control, (2) MC-5% (containing 5% dried Microcystis sp. biomass with 4.92 MUg MC-LR g(-1) diet), (3) MC-20% (containing 20% dried Microcystis sp. biomass with 19.54 MUg MC-LR g(-1) diet), and (4) Arthr 20% (containing 20% dried Arthrospira sp. biomass without MC-LR). Blood and liver samples were taken after one, 7, and 28 days and protein has been determined in plasma and liver. In the liver, impacts on detoxification were measured by glutathione-S-transferase (GST) activities and gene expression of multi drug resistance protein (MDRP). Plasma protein did not change between all four diets at any sampling time whereas liver protein was significantly elevated already after one day in Arthr-20% and after 28 days in both, MC-20% and Arthr-20%. Biochemical measurements of GST activities revealed no significant impact at any sampling time. In order to characterize the potential effect of MC-LR on MDRP, RT qPCR method was established. However, as for GST activities no significant changes in MDRP gene expression have been observed. Thus, in summary, oral exposure of MC-LR containing cyanobacteria to Nile tilapia via feed ingestion did not impact significantly detoxification in liver concerning GST activities and MDRP expression despite biochemical composition concerning liver protein was significantly elevated by the diets containing 20% cyanobacteria biomass, regardless whether they contained MC-LR or not. PMID- 20949195 TI - Exposure to airborne organophosphates originating from hydraulic and turbine oils among aviation technicians and loaders. AB - This study describes the potential for occupational exposure to organophosphates (OPs) originating from turbine and hydraulic oils, among ground personnel within the aviation industry. The OPs tri-n-butyl phosphate (TnBP), dibutyl phenyl phosphate (DBPP), triphenyl phosphate (TPP) and tricresyl phosphate (TCP) have been emphasized due to their use in such oils. Oil aerosol/vapor and total volatile organic compounds (tVOCs) in air were also determined. In total, 228 and 182 OPs and oil aerosol/vapor samples from technician and loader work tasks during work on 42 and 21 aircrafts, respectively, were collected in pairs. In general, the measured exposure levels were below the limit of quantification (LOQ) for 84%/98% (oil aerosol) and 82%/90% (TCP) of the samples collected during technician/loader work tasks. The air concentration ranges for all samples related to technician work were 1 MHz) due to generation of reactive species at lower frequencies. Combined voltage and frequency sweeps enable the generation of complex maps of physiological state. PMID- 20949198 TI - Self-assembled magnetic filter for highly efficient immunomagnetic separation. AB - We have developed a compact and inexpensive microfluidic chip, the self-assembled magnetic filter, to efficiently remove magnetically tagged cells from suspension. The self-assembled magnetic filter consists of a microfluidic channel built directly above a self-assembled NdFeB magnet. Micrometre-sized grains of NdFeB assemble to form alternating magnetic dipoles, creating a magnetic field with a very strong magnitude B (from the material) and field gradient ?B (from the configuration) in the microfluidic channel. The magnetic force imparted on magnetic beads is measured to be comparable to state-of-the-art microfabricated magnets, allowing for efficient separations to be performed in a compact, simple device. The efficiency of the magnetic filter is characterized by sorting non magnetic (polystyrene) beads from magnetic beads (iron oxide). The filter enriches the population of non-magnetic beads to magnetic beads by a factor of >10(5) with a recovery rate of 90% at 1 mL h(-1). The utility of the magnetic filter is demonstrated with a microfluidic device that sorts tumor cells from leukocytes using negative immunomagnetic selection, and concentrates the tumor cells on an integrated membrane filter for optical detection. PMID- 20949200 TI - Synthesis and characterization of one-dimensional flat ZnO nanotower arrays as high-efficiency adsorbents for the photocatalytic remediation of water pollutants. AB - We report on facile fabrication of 1-D flat ZnO nanotower arrays on various substrates, including a metal, a semiconductor and an insulator. The nanotowers have a unique flat basal section near the substrate and taper in stages to wire like at the tip. Electron microscopy and X-ray photoelectron spectroscopy are used to characterize these new nanostructures, revealing that their morphologies are significantly influenced by reaction temperature. A qualitative formation mechanism is proposed based on the experimental observations. A proof-of-concept demonstration shows that the ZnO nanotower arrays are highly effective at adsorbing and subsequently photo-remediating a model pollutant (Eosin B) from water. These observations could promote new applications of photocatalytic adsorbents for wastewater treatment utilizing oxide semiconductor nanostructures. PMID- 20949199 TI - Predicting conserved essential genes in bacteria: in silico identification of putative drug targets. AB - Many genes have been listed as putatively essential for bacterial viability in the Database of Essential Genomes (DEG), although few have been experimentally validated. By prioritising targets according to the criteria suggested by the Research and Training in Tropical Diseases (TDR) Targets database, we have developed a modified down-selection tool to identify essential genes conserved across diverse genera. Using this approach we identified 52 proteins conserved to 7 or more of the 14 genomes in DEG. We confirmed the validity of the down selection by attempting to make mutants of 8 of these targets in a model organism, Yersinia pseudotuberculosis, which is not closely related to any of the bacteria in DEG. Mutants were recovered for only one of the 8 targets, suggesting that the other 7 were essential in Y. pseudotuberculosis, an impressive success rate compared to other approaches of identification for such targets. Identification of essential proteins common in diverse bacterial genera can then be used to facilitate the selection of effective targets for novel broad-spectrum antibiotics. PMID- 20949201 TI - Vibrational frequencies in Car-Parrinello molecular dynamics. AB - Car-Parrinello molecular dynamics (CPMD) are widely used to investigate the dynamical properties of molecular systems. An important issue in such applications is the dependence of dynamical quantities such as molecular vibrational frequencies upon the fictitious orbital mass MU. Although it is known that the correct Born-Oppenheimer dynamics are recovered at zero MU, it is not clear how these dynamical quantities are to be rigorously extracted from CPMD calculations. Our work addresses this issue for vibrational frequencies. We show that when the system is sufficiently close to the ground state the calculated ionic vibrational frequencies are omega(M) = omega(0M)[1 -C(MU/M)] for small MU/M, where omega(0M) is the Born-Oppenheimer ionic frequency, M the ionic mass, and C a constant that depends upon the ion-orbital coupling force constants. Our analysis also provides a quantitative understanding of the orbital oscillation amplitudes, leading to a relationship between the adiabaticity of a system and the ion-orbital coupling constants. In particular, we show that there is a significant systematic dependence of calculated vibrational frequencies upon how close the CPMD trajectory is to the Born-Oppenheimer surface. We verify our analytical results with numerical simulations for N(2), Sn(2), and H/Si(100) (2*1). PMID- 20949202 TI - Synthesis and characterization of nanostructured bismuth selenide thin films. AB - Nanostructured bismuth selenide thin films have been successfully fabricated on a silicon substrate at low temperature by rational design of the precursor solution. Bi(2)Se(3) thin films were constructed of coalesced lamella in the thickness of 50-80 nm. The nucleation and growth process of Bi(2)Se(3) thin films, as well as the influence of solution chemistry on the film structure were investigated in detail. As one of the most promising thermoelectric materials, the thermoelectric properties of the prepared Bi(2)Se(3) thin films were also investigated. The power factor increased with increasing carrier mobility, coming from the enlarged crystallites and enhanced coalesced structure, and reached 1 MUW cm(-1) K(-1). PMID- 20949203 TI - Discrimination of zone-specific spectral signatures in normal human prostate using Raman spectroscopy. AB - The prostate gland is the most common site of pathology in human males. Using the urethra as an anatomical reference point, it can be divided into three distinct zones known as the transition zone (TZ), peripheral zone (PZ) and central zone (CZ). The pathological conditions of benign prostatic hypertrophy and/or prostate adenocarcinoma are highly prevalent in this gland. This preliminary study set out to determine whether biochemical intra-individual differences between normal prostate zones could be identified using Raman spectroscopy with subsequent exploratory analyses. A normal (benign) prostate transverse tissue section perpendicular to the rectal surface and above the verumontanum was obtained in a paraffin-embedded block. A 10-um-thick slice was floated onto a gold substrate, de-waxed and analysed using Raman spectroscopy (200 epithelial-cell and 140 stromal spectra/zone). Raman spectra were subsequently processed in the 1800-367 cm(-1) spectral region employing principal component analysis (PCA) to determine whether wavenumber-intensity relationships expressed as single points in hyperspace might reveal biochemical differences associated with inter-zone pathological susceptibility. Visualisation of PCA scores plots and their corresponding loadings plots highlighted 781 cm(-1) (cytosine/uracil) and 787 cm( 1) (DNA) as the key discriminating factors segregating PZ from less susceptible TZ and CZ epithelia (P < 0.001). Conversely, 1459 cm(-1) (lipids and proteins) and 1003 cm(-1) (phenylalanine) were identified as the key biochemical factor distinguishing TZ from CZ epithelia (P < 0.05). All stromal zones were discriminated by the protein/lipid region (1459 cm(-1) and 1100 cm(-1)) with DNA/RNA region (781 cm(-1) and 787 cm(-1)) only highlighted between PZ and CZ (P < 0.05). This novel approach identifies biochemical markers that may have aetiological functional roles towards susceptibility of human prostate zones to specific pathological conditions. PMID- 20949204 TI - Effects of unsteadiness of the rates of flow on the dynamics of formation of droplets in microfluidic systems. AB - Oscillations of the input rates of flow have a significant impact on the dynamics of formation of droplets in microfluidic systems and on the quality of generated emulsions. PMID- 20949209 TI - Evaluation of Raman probe for oesophageal cancer diagnostics. AB - Early detection of (pre-)cancerous changes improves prognosis, therefore in the UK patients at high risk of developing gastrointestinal cancers are enrolled on endoscopic surveillance programmes or the Bowel Cancer Screening Programme. The current gold standard technique for the detection of pre-cancerous changes in the gastrointestinal tract is histopathological analysis of biopsy tissue collected at endoscopy. This relies upon subjective assessment of morphological changes within the excised tissue samples and poor targeting of pre-malignant lesions. Raman spectroscopy offers a number of potential advantages for in vivo assessment of tissue at endoscopy. The performance of a custom built Raman probe as a biopsy targeting tool has been evaluated using excised biopsy material. Multivariate classification models have been used to demonstrate the likely ability of a miniature, confocal, fibre optic Raman probe to be used as an optical biopsy tool at endoscopy to provide spectral information in clinically practicable timescales. This technique could facilitate improved targeting of excisional biopsy with associated clinical benefits. PMID- 20949210 TI - Engineering 3D ordered molecular thin films by nanoscale control. AB - This perspective aims to report on experimental preparation and investigation tools for engineering molecular thin films with a three-dimensional (3D) nanoscale control that is of relevant interest for different emerging applications as well as for the development of calibration standards. Such thin films may be obtained by man-made methods, self-assembly or spatio-temporal self organization and/or by the combination of these last approaches with external tools. Understanding the main features and the physical-chemistry underlying the related ordering phenomena is in due course and a theoretical framework is under development. In this respect it is of fundamental importance to achieve the ability to get 3D structural images with a nanoscale detail. This issue is at the early stage and novel techniques like electron tomography and scanning transmission X-ray microscopy are very promising. PMID- 20949211 TI - Functionalized gold nanoparticles: a detailed in vivo multimodal microscopic brain distribution study. AB - In the present study, the in vivo distribution of polyelectrolyte multilayer coated gold nanoparticles is shown, starting from the living animal down to cellular level. The coating was designed with functional moieties to serve as a potential nano drug for prion disease. With near infrared time-domain imaging we followed the biodistribution in mice up to 7 days after intravenous injection of the nanoparticles. The peak concentration in the head of mice was detected between 19 and 24 h. The precise particle distribution in the brain was studied ex vivo by X-ray microtomography, confocal laser and fluorescence microscopy. We found that the particles mainly accumulate in the hippocampus, thalamus, hypothalamus, and the cerebral cortex. PMID- 20949212 TI - Simulation of the resonance Raman intensities of a ruthenium-palladium photocatalyst by time dependent density functional theory. AB - The absorption and resonance Raman (RR) properties of the [(tbbpy)(2)Ru(tpphz)PdCl(2)](2+) photocatalyst have been investigated by means of time-dependent density functional theory calculations. With the intention of evaluating the accuracy of the computations, three different exchange-correlation (XC) functionals, namely B3LYP, B3LYP-35 and CAM-B3LYP, have been considered and the effects of the solvent have been described within the polarizable continuum model. It is demonstrated that the inclusion of the solvent effects within the simulations is mandatory to obtain a correct description of the excited states contributing to the first absorption band. The RR spectra of the complex have been simulated for several excitation wavelengths and have allowed an assignment of all the intense experimental bands. The calculations succeed in reproducing several aspects of the experimental absorption and RR spectra, but it is also seen that the choice of the XC functional can lead to significant differences in the simulated spectra and that none of the considered functionals succeed in reproducing all the experimental features. PMID- 20949213 TI - Identification of single nanoparticles. AB - The physicochemical properties of nanomaterials significantly depend on their three-dimensional (3D) morphologies (sizes, shapes and surface topography), the surrounding media, and their spatial arrangement. Systematically and precisely correlating these parameters with the related physicochemical properties of specific single nanoparticles (NPs) is a fundamental requirement for the discovery of their novel properties and applications, as well as for advancing the fundamental and practical knowledge required for the design and fabrication of new materials. In this article, the progress in the identification of the specific individual NP is summarized, including the in situ methods and the spatial-localization methods based on plasmonic NPs as model. Identification of single NPs based on local surface plasmon resonance observed by fluorescent inverted optical microscopy, dark-field microscopy, scanning near-field optical microscopy, atomic force microscopy, and transmission electron microscope are reviewed. Recent progress in the investigation of 3D morphology-dependent optical properties by these methods is described. Experimental and theoretical developments in single-NP identification for the purpose of understanding the physicochemical properties are discussed. PMID- 20949214 TI - Synthesis and assignment of stereochemistry of the antibacterial cyclic peptide xenematide. AB - The synthesis of the antimicrobial cyclic peptide xenematide was accomplished by Fmoc solid phase peptide synthesis and the key esterification reaction was achieved using a modified Yamaguchi esterification. Comparison of the optical rotation and NMR data of the synthesized diastereomers to that of the natural product confirmed the structure of xenematide to be PA-L-[Thr-L-Trp-D-Trp-beta Ala]. (PA = phenylacetyl). PMID- 20949216 TI - SN2 fluorination reactions in ionic liquids: a mechanistic study towards solvent engineering. AB - In the catalysis of S(N)2 fluorination reactions, the ionic liquid anion plays a key role as a Lewis base by binding to the counterion Cs(+) and thereby reducing the retarding Coulombic influence of Cs(+) on the nucleophile F(-). The reaction rates also depend critically on the structures of ionic liquid cation, for example, n-butyl imidazolium gives no S(N)2 products, whereas n-butylmethyl imidazolium works well. The origin of the observed phenomenal synergetic effects by the ionic liquid [mim-(t)OH][OMs], in which t-butanol is bonded covalently to the cation [mim], is that the t-butanol moiety binds to the leaving group of the substrate, moderating the retarding interactions between the acidic hydrogen and F(-). This work is a significant step toward designing and engineering solvents for promoting specific chemical reactions. PMID- 20949215 TI - Chemical genetics approach to identify new small molecule modulators of cell growth by phenotypic screening of Saccharomyces cerevisiae strains with a library of morpholine-derived compounds. AB - A chemical genetics approach has been applied in the screening of yeast deletants strains with a pool of morpholine-derived compounds in order to identify candidate small molecules able to produce phenotypic effects on yeast cells. The analysis of the effects of structurally diverse molecules towards cell growth rate in both exponential and stationary phases provides a tool to select candidate compounds for subsequent assays to identify new chemical entities as chemical probes for drug discovery. PMID- 20949217 TI - Construction of photoresponsive RNA for photoswitching RNA hybridization. AB - By introducing azobenzenes into RNA using d-threoninol as a scaffold, a photoresponsive RNA was constructed for efficiently photoswitching the formation and dissociation of RNA/RNA duplexes. The difference in melting temperature (T(m)) between the trans and cis forms was so large that efficient photoregulation of RNA hybridization became possible, irrespective of the sequence adjacent to the introduced azobenzene. Compared to the corresponding photoresponsive DNA, the photoregulatory efficiency of azobenzene-modified RNA was even higher due to the drastic destabilization by cis-azobenzene. Structural analysis by NMR and molecular modeling indicated that the planar trans-azobenzene could not stabilize the RNA/RNA duplex with a rigid A-form structure by base pair stacking. However, the large steric hindrance caused by nonplanar cis-azobenzene was quite effective at distorting and destabilizing the duplex structure. We also discuss the effect of methylation of azobenzene at the ortho positions on photoregulation of RNA/RNA duplex formation. This newly constructed photoresponsive RNA has promising applications such as photoswitching of RNA functions. PMID- 20949218 TI - Millimeter-scale contact printing of aqueous solutions using a stamp made out of paper and tape. AB - This communication describes a simple method for printing aqueous solutions with millimeter-scale patterns on a variety of substrates using an easily fabricated, paper-based microfluidic device (a paper-based "stamp") as a contact printing device. The device is made from inexpensive materials, and it is easily assembled by hand; this method is thus accessible to a wide range of laboratories and budgets. A single device was used to print over 2500 spots in less than three minutes at a density of 16 spots per square centimetre. This method provides a new tool to pattern biochemicals-reagents, antigens, proteins, and DNA-on planar substrates. The accuracy of the volume of fluid delivered in simple paper-to paper printing is low, and although the pattern transfer is rapid, it is better suited for qualitative than accurate, quantitative work. By patterning the paper to which the transfer occurs using wax printing or an equivalent technique, accuracy increases substantially. PMID- 20949219 TI - First observation in the gas phase of the ultrafast electronic relaxation pathways of the S(2) states of heme and hemin. AB - The time evolution of electronically excited heme (iron II protoporphyrin IX, [Fe(II) PP]) and its associated salt hemin (iron III protoporphyrin IX chloride, [Fe(III) PP-Cl]), has been investigated for the first time in the gas phase by femtosecond pump-probe spectroscopy. The porphyrins were excited at 400 nm in the S(2) state (Soret band) and their relaxation dynamics was probed by multiphoton ionization at 800 nm. This time evolution was compared with that of the excited state of zinc protoporphyrin IX [Zn PP] whose S(2) excited state likely decays to the long lived S(1) state through a conical intersection, in less than 100 fs. Instead, for [Fe(II) PP] and [Fe(III) PP-Cl], the key relaxation step from S(2) is interpreted as an ultrafast charge transfer from the porphyrin excited orbital pi* to a vacant d orbital on the iron atom (ligand to metal charge transfer, LMCT). This intermediate LMCT state then relaxes to the ground state within 250 fs. Through this work a new, serendipitous, preparation step was found for Fe(II) porphyrins, in the gas phase. PMID- 20949220 TI - Molecular structures of dicarboxylated viologens on a Cu(100) surface during an ongoing charge transfer reaction. AB - Molecular structures of dicarboxylated viologens (1,1'-bis (7-carboxyheptyl)-4,4' bipyridinium dibromide molecules, V-(C(7)-COOH)(2)) on a Cu(100) surface are studied by means of in situ scanning tunneling microscopy (STM) in combination with cyclic voltammetry (CV). Self-assembled monolayers of adsorbed dicarboxylated viologens form during an ongoing charge transfer reaction. Mainly six structures of the organic molecules are observed, including a dot array, metastable phases, stripe patterns, a closed stacking stripe pattern, chloride desorption, and a dimer phase. The molecular structural models for all the structures have been successfully established. The carboxylated viologen molecules in the dicationic state prefer the face-on configuration on the surface and form the dot array phase. The other phases are shown by the radical state of the viologens. The metastable phases show two forms: cluster-like and stripe pattern-like structures. Main features of the metastable phases are face-to-face configurations of the radical viologens in pi-stacking form between neighboring parallel bipyridiniums. Hydrogen bonding is considered to be the major factor in constructing the network of the stripe pattern. At a more negative potential, the bilayers of the stripe pattern transform to be a monolayer of the closed stacking stripe pattern because of the enhanced electrostatic force. The closed stacking stripe pattern is stable on the surface until chloride desorption. As the chloride anions desorb from the Cu(100) surface, the disordered dimers transform to an ordered dimer phase on a Cu(100)-1*1 surface due to the hydrogen bonding between neighboring dimer rows. PMID- 20949222 TI - Paramagnetic nanofibrous composite films enhance the osteogenic responses of pre osteoblast cells. AB - In this work, a paramagnetic nanofibrous composite film was fabricated with poly lactide, hydroxyapatite and gamma-Fe(2)0(3) nanoparticles using the electrospinning technique. The composite film significantly enhanced the proliferation, differentiation and ECM secretion of the osteoblast cells under a static magnetic field, which offers promising application potentials in bone tissue engineering and bone regeneration therapy. PMID- 20949221 TI - Open access microfluidic device for the study of cell migration during chemotaxis. AB - Cells sense and interpret chemical gradients, and respond by localized responses that lead to directed migration. An open microfluidic device (OMD) was developed to provide quantitative information on both the gradient and morphological changes that occurred as cells crawled through various microfabricated channels. This device overcame problems that many current devices have been plagued with, such as complicated cell loading, media evaporation and channel blockage by air bubbles. We used a micropipette to set up stable gradients formed by passive diffusion and thus avoided confounding cellular responses produced by shear forces. Two versions of the OMD are reported here: one device that has channels with widths of 6, 8, 10 and 12 MUm, while the other has two large 100 MUm channels to minimize cellular interaction with lateral walls. These experiments compared the migration rates and qualitative behavior of Dictyostelium discoideum cells responding to measurable cAMP and folic acid gradients in small and large channels. We report on the influence that polarity has on a cell's ability to migrate when confined in a channel. Polarized cells that migrated to cAMP were significantly faster than the unpolarized cells that crawled toward folic acid. Unpolarized cells in wide channels often strayed off course, yet migrated faster than unpolarized cells in confined channels. Cells in channels farthest from the micropipette migrated through the channels at rates similar to cells in channels with higher concentrations, suggesting that cell speed was independent of mean concentration. Lastly, it was found that the polarized cells could easily change migration direction even when only the leading edge of the cell was exposed to a lateral gradient. PMID- 20949223 TI - Understanding the DNA binding of novel non-symmetrical guanidinium/2 aminoimidazolinium derivatives. AB - Biophysical studies have been carried out on a family of asymmetric guanidinium based diaromatic derivatives to assess their potential as DNA minor groove binding agents. To experimentally assess the binding of these compounds to DNA, solution phase biophysical studies have been performed. Thus, surface plasmon resonance, UV-visible spectroscopy and circular and linear dichroism have been utilized to evaluate binding constants, stoichiometry and mode of binding. In addition, the thermodynamics of the binding process have been determined by using isothermal titration calorimetry. These results show significant DNA binding affinity that correlates with the expected 1 : 1 binding ratio usually observed for minor groove binders. Moreover, a simple computational approach has been devised to assess the potential as DNA binders of this family of compounds. PMID- 20949224 TI - Biological activity and coordination modes of copper(II) complexes of Schiff base derived coumarin ligands. AB - The coordination modes of copper(II) complexes of Schiff base-derived coumarin ligands, which had previously shown good anti-Candida activity, were investigated by pH-potentiometric and UV-Vis spectroscopic methods. These studies confirmed the coordination mode of the ligands to be through the N of the imine and deprotonated phenol of the coumarin-derived ligand in solution. In addition, the more active complexes and their corresponding ligands were investigated in the presence of copper(II) in liquid and frozen solution by ESR spectroscopic methods. A series of secondary amine derivatives of the Schiff base ligands, were isolated with good solubility characteristics but showed little anti-Candida activity. However, cytotoxicity studies of the secondary amines, together with the copper complexes and their corresponding ligands, against human colon cancer and human breast cancer cells identified the chemotherapeutic potential of these new ligands. PMID- 20949225 TI - Myocardial perfusion alterations observed months after radiotherapy are related to the cellular damage. AB - AIM: Myocardial perfusion scintigraphy (MPS) is one of the widely used tools to follow developing radiation-induced heart disease (RIHD). But the clinical significance of MPS defects has not been fully understood. We have investigated the biodistribution alterations related to perfusion defects following radiotherapy (RT) and showed coexisting morphologic changes. ANIMALS, METHODS: A total of 18 Wistar rats were divided into three groups (1 control and 2 irradiated groups). A single cardiac 20 Gy radiation dose was used to induce long term cardiac defects. Biodistribution studies with technetium (99mTc) sestamibi and histological evaluations were performed 4 and 6 months after irradiation. The percent radioactivity (%ID/g) was calculated for each heart. For determination of the myocardial damage, positive apoptotic cardiomyocytes, myocardial cell degeneration, myocardial fibrosis, vascular damage and ultrastructural structures were evaluated. RESULTS: Six months after treatment, a significant drop of myocardial uptake was observed (p < 0.05). Irradiation-induced apoptosis rose within the first 4 months after radiation treatment and were stayed elevated until the end of the observation period (p < 0.05). Also, the irradiation has induced myocardial degeneration, perivascular and interstitial fibrosis in the heart at the end of six and four months (p < 0.01). The severity and extent of myocardial injury has became more evident at the end of six month (p < 0.05). At ultrastructural level, prominent changes have been observed in the capillary endothelial and myocardial cells. CONCLUSION: Our findings suggest that the reduced rest myocardial perfusion, occurring months after the radiation, indicates a serious myocard tissue damage which is characterized by myocardial degeneration and fibrosis. PMID- 20949226 TI - Epidemiological, clinical e therapeutic profile of heart failure in a tertiary hospital. AB - BACKGROUND: Heart failure is a complex syndrome with multiple risk factors involved in its genesis, making its prevention and management difficult to achieve. OBJECTIVE: To identify the main etiologies and risk factors in heart failure; to compare clinical and demographic characteristics of patients according to the etiology; analyze whether the treatment is according to that recommended by the Brazilian guidelines. METHODS: Retrospective, descriptive and observational study, carried out at Hospital das Clinicas of Universidade Federal de Goias. The patients were divided in four groups, according to the etiology, for comparison: chagasic cardiomyopathy, hypertensive cardiomyopathy, dilated cardiomyopathy and others, ischemic cardiomyopathy. The Chi-square and Fisher's Exact tests, ANOVA and Kruskal-Wallis tests were used in the analysis of the groups and types of treatment. RESULTS: A total of 144 patients' files were analyzed; the patients' mean age was 61 +/- 15 years and 54.2% of them were males. Chagasic cardiomyopathy was the main etiology (41%). Arterial hypertension (48.6%), anemia (22.9%), coronary disease (19.4%), dyslipidemia (17.3%) and diabetes (16.6%) were the main risk factors. There was a higher prevalence of female individuals among the hypertensive patients (p=0.044) as well as a higher frequency of pulmonary rales (p < 0.01). Heart rate was lower among chagasic patients (p < 0.001). The most often prescribed medications were diuretics (81.2%), angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (77.7%), beta-blockers (45.8%), spironolactone (35.4%), digitalis (30.5%) and vasodilators (8.3%). CONCLUSION: Chagasic cardiomyopathy was the main cause of heart failure. No significant clinical differences were observed among patients from the four etiologic groups. PMID- 20949227 TI - The effects of knee extensor eccentric training on functional tests in healthy subjects. AB - BACKGROUND: It is well known that eccentric training increases muscle strength and promotes greater neural activation, and therefore has been used in the recovery of knee extensors. The hypothesis of this study was that there would be a strong correlation between knee extensor torque and functional tests. OBJECTIVES: To investigate the relationship between knee extensor peak torque and functional tests of agility (runs) and propulsion (hop for distance) after short term isokinetic eccentric training. METHODS: Twenty healthy and active male undergraduate students (age 22.5 +/- 2.1 years; height 1.72 +/- 0.10 m; weight 67.8 +/- 9.5 kg; body mass index: 22.5 +/- 2.0 kg/m2), with no abnormalities or history of injury of the limbs, performed an isokinetic assessment of the knee extensors and flexors and also functional tests before and after isokinetic training, which consisted of 3 sets of 10 MVECs at 30o/s, with 3 minutes of rest between sets, twice a week for 6 weeks. RESULTS: The eccentric training increased the extensor peak torque (16, 27 and 17%; P<0.01) and decreased the H/Q ratio (10, 20 and 13%; P<0.01) for the isometric and eccentric modes at 30 degrees /s and 120 degrees /s, respectively. It also decreased the time in two of the five agility tests (carioca and pivot diagonal; P<0.01), and increased the distance in the hop tests, for both dominant and non-dominant limbs (P<0.01). CONCLUSIONS: Although the eccentric training led to an increase in extensor peak torques as well as an improvement in most of the functional tests, the hypothesis that a strong correlation would be observed between peak torques and functional tests was not confirmed. Article registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) under the number 12607000590460. PMID- 20949228 TI - Quality of life and discriminating power of two questionnaires in fibromyalgia patients: Fibromyalgia Impact Questionnaire and Medical Outcomes Study 36-Item Short-Form Health Survey. AB - BACKGROUND: Fibromyalgia is a painful syndrome characterized by widespread chronic pain and associated symptoms with a negative impact on quality of life. OBJECTIVES: Considering the subjectivity of quality of life measurements, the aim of this study was to verify the discriminating power of two quality of life questionnaires in patients with fibromyalgia: the generic Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the specific Fibromyalgia Impact Questionnaire (FIQ). METHODS: A cross-sectional study was conducted on 150 participants divided into Fibromyalgia Group (FG) and Control Group (CG) (n=75 in each group). The participants were evaluated using the SF-36 and the FIQ. The data were analyzed by the Student t-test (alpha=0.05) and inferential analysis using the Receiver Operating Characteristics (ROC) Curve--sensitivity, specificity and area under the curve (AUC). The significance level was 0.05. RESULTS: The sample was similar for age (CG: 47.8 +/- 8.1; FG: 47.0 +/- 7.7 years). A significant difference was observed in quality of life assessment in all aspects of both questionnaires (p<0.05). Higher sensibility, specificity and AUC were obtained by the FIQ (96%, 96%, 0.985, respectively), followed by the SF 36 (88%, 89% and 0.948 AUC). CONCLUSION: The FIQ presented the highest sensibility, specificity and AUC showing the most discriminating power. However the SF-36 is also a good instrument to assess quality of life in fibromyalgia patients, and we suggest that both should be used in parallel because they evaluate relevant and complementary aspects of quality of life. PMID- 20949229 TI - Noninvasive ventilation in the immediate postoperative of gastrojejunal derivation with Roux-en-Y gastric bypass. AB - BACKGROUND: Morbidly obese patients develop more atelectasis during general anesthesia than non-obese ones, and these atelectasis persist for 24 hours after the end of the surgical procedure. OBJECTIVES: This study evaluated the effect of noninvasive ventilation with two pressure levels (BiPAP) in the pulmonary function, incidence of immediate postoperative pulmonary complications and the development of anastomotic dehiscence in morbid obese patients submitted to gastrojejunal derivation in Roux-en-Y (RYGB). METHODS: It was an analytical and clinical study involving patients who were submitted to RYGB, had a body mass index (BMI) of at least 35 kg/cm2, and were randomly chosen to receive BiPAP (experimental group) or standard oxygen therapy (control group), in the first four hours of the post-operation period. Patients with chronic or acute pulmonary disease were not included, and neither were the ones who needed invasive mechanical ventilation by the end of the surgery. Vital capacity, maximal inspiratory and expiratory pressure, and arterial blood gases were measured in the preoperative and in the first postoperative. Chest X-ray was performed in the third postoperative. RESULTS: Eighteen patients were chosen for the study: ten received BiPAP and eight received standard oxygen therapy. The study group had better partial oxygen pressure and lower maximal expiratory pressure levels in the postoperative state than the control group. Anastomotic dehiscence was not observed in any group. There was no significant difference between the control group and the study group relating to the loss of vital capacity, maximal inspiratory pressure in the postoperative period or the incidence of atelectasis. CONCLUSION: The BiPAP in the postoperative period of gastroplasty was useful to improve oxygenation and did not increase the incidence of anastomotic dehiscence. PMID- 20949230 TI - Relationship between quadriceps angle (Q) and plantar pressure distribution in football players. AB - OBJECTIVES: To determine whether there is an association between the Q-angle (Q) and the distribution of plantar pressure in football players, and to compare the characteristics of these athletes with non-practitioners of this sport. METHODS: 121 male participants were selected: 50 football practitioners (FP) and 71 non practitioners (NP). We concurrently evaluated the Q-angle and the plantar pressure through the software of postural assessment (SPA) and the F-Mat System, respectively. To verify the correlation between the Q-angle and peak pressure values in four segments of the foot (medial and lateral forefoot, medium-foot and hind-foot), the Pearson coefficient (r) for parametric analysis was used. The independent t-test was used to compare these variables between the groups. Data normality was verified by the skewness values, adopting a significance level of 5%. RESULTS: A negative and weak correlation was found (r=-0.32) between the Q angle and the plantar pressure in the right medium-foot. The groups differed with regards to the right Q-angle (11.36o in FP versus 13.80o in NP) and the left Q angle (11.03o in FP versus 13.96o in NP). Plantar pressure was also different between the groups, with FP showing higher mean values for the right side and for the left side of the forefoot (0.77 kg/cm2 in FP versus 0.63 kg/cm2 in NP, and 0.65 kg/cm2 in FP versus 0.54 kg/cm2 in NP, respectively). However, mean peak pressure values for the left medium-foot were higher among NP (0.37 kg/cm2 in FP versus 0.46 kg/cm2 in NP). CONCLUSIONS: There was no evidence of an association between the Q-angle and the distribution of plantar pressure in FP. The athletes showed reduced Q-angle values and higher mean peak pressure values for the right and left aspects of the forefoot, suggesting a varus malalignment and a supine distribution of plantar bases. PMID- 20949231 TI - Calibration of low-level laser therapy equipment. AB - BACKGROUND: Despite the increase in the use of low-level laser therapy (LLLT), there is still a lack of consensus in the literature regarding how often the equipment must be calibrated. OBJECTIVE: To evaluate the real average power of LLLT devices in the Greater Sao Paulo area. METHODS: For the evaluation, a LaserCheck power meter designed to calibrate continuous equipment was used. The power meter was programmed with data related to the laser's wavelength to gauge the real average power being emitted. The LLLT devices were evaluated in two ways: first with the device cooled down and then with the device warmed up for 10 minutes. For each condition, three tests were performed. The laser probe was aligned with the power meter, which provided the real average power being emitted by the LLLT device. All of the data and information related to the laser application were collected with the use of a questionnaire filled in by the supervising therapists. RESULTS: The 60 devices evaluated showed deficit in real average power in the cooled-down and warmed-up condition. The statistical analysis (ANOVA) showed a significant decrease (p<0.05) in the real average power measured in relation to the manufacturer's average power. On average, the most common dose in the clinics was 4 J/cm2, and the most desired effects were healing and anti-inflammatory effects. According to the World Association for Laser Therapy (WALT), 1 to 4 J of final energy are necessary to achieve these effects, however only one device was able to reach the recommended therapeutic window. CONCLUSION: The LLLT devices showed a deficit in real average power that emphasized a lack of order in the application of this tool. The present study also showed the need for periodical calibration of LLLT equipment and a better technical knowledge of the therapists involved. PMID- 20949232 TI - Determinant factors of functional status among the oldest old. AB - BACKGROUND: The fastest-growing age group in Brazil and around the world is the oldest-old group (aged 80 and over). Among these individuals, the prevalence of disability and morbidity is higher than in other groups. OBJECTIVES: To investigate the influence of socioeconomic, demographic, biological, health, nutritional, and social factors, as well as perceived health, on the functional status of the oldest old. METHODS: This was a cross-sectional population-based study in which the data were collected by means of questionnaires and anthropometric measurements. The functional status was evaluated according to the model developed by Andreotti and Okuma (1999). Univariate and multivariate analyses were used. RESULTS: The independent factors associated with worse functional status were: age 85 years and over (OR=2.91), female gender (OR=0.69), continuous use of five or more medications (OR=2.67), no visits to friends and/or relatives at least once a week (OR=11.91), and worse perceived health relative to peers (OR=4.40). CONCLUSIONS: The results suggest that functional status is associated with a complex web of multidimensional factors. Thus, it is important to develop programs related to the factors that are susceptible to intervention in order to provide a better quality of life to the oldest old. PMID- 20949233 TI - Head and shoulder alignment among patients with unilateral vestibular hypofunction. AB - OBJECTIVES: To investigate head and shoulder alignment among patients with unilateral vestibular hypofunction (UVH), using computerized biophotogrammetry (CB) and to correlate these measurements with gender, age, duration of clinical evolution, self-perception of intensity of dizziness and occurrences of falls. METHODS: This was a cross-sectional study. Thirty individuals with UVH and 30 with normal vestibular function and without complaints of dizziness underwent CB in the anterior, right and left and posterior views, in an upright standing position. AlcimageTM 2.0 was used to evaluate three angles in order to verify the anterior deviation and inclination of the head, and the alignment of the shoulders. The groups were paired according to age, gender and height. The statistical analysis consisted of the Mann-Whitney test, Kruskal-Wallis test followed by the Dunn test, and the Spearman Correlation Coefficient. RESULTS: The patients with UVH had greater forward (55.44 +/- 16.33) and lateral (2.03 +/- 1.37) head deviation angles than did the normal individuals (34.34 +/- 4.60 and 1.34 +/- 1.05 respectively), with a statistically significant difference (p<0.001). The increment of forward and lateral deviation in the UVH group was 38.05% and 33.78% respectively. Forward head was associated with the duration of clinical symptoms of the vestibular disease (p=0.003), age (p=0.006), intensity of dizziness (p<0.001) and occurrence of falls (p=0.002). CONCLUSIONS: Patients with UVH had greater forward and lateral head deviations. Forward head deviation increased with age, duration of clinical symptoms and greater self-perception of the intensity of dizziness. Forward head deviation was also greater among patients who reported having had falls. PMID- 20949234 TI - Ventilatory and muscular assessment in healthy subjects during an activity of daily living with unsupported arm elevation. AB - INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) report dyspnea when performing activities of daily living (ADLs) with elevated upper limbs. To elucidate the determinants of dyspnea, it is important to study the changes in the respiratory pattern of these patients and the electromyographic activity of their accessory muscles of respiration during ADLs. In the literature, there are no reports of a normative parameter, therefore it is necessary to study how these variables behave in healthy subjects. OBJECTIVES: To verify, in healthy subjects, the existence of changes in the respiratory pattern and activation of the sternocleidomastoid (SCM) muscle during an ADL with unsupported arm elevation. METHODS: Thirteen male subjects, 60.57 (+/- 6.42) years old, with normal spirometry values for age and sex, were evaluated using surface electromyography (EMG) and respiratory inductive plethysmography (RIP) collected at rest and during the activity of combing their hair with elevated and unsupported upper limbs. The data distribution was assessed using Shapiro-Wilk's test. ANOVA was used to compare the phases, and when the difference was significant (p<0.05), Tukey's test was applied. RESULTS: The RIP during the ADL showed a significant increase in tidal volume, minute ventilation, respiratory frequency and mean inspiratory flow. Thoracoabdominal asynchrony was identified in percentage of asynchrony in inspiration, expiration, and Phase Angle (p<0.05). The EMG showed an increase in SMC muscle recruitment (p<0.05). CONCLUSIONS: Healthy subjects increased their SCM muscle activation and changed their breathing pattern when performing the ADL with unsupported arm elevation, resulting in thoracoabdominal asynchrony. PMID- 20949235 TI - Effects of treadmill-walking training with additional body load on quality of life in subjects with Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) causes motor and non-motor impairments that affect the subject's quality of life. OBJECTIVE: To assess the effects of treadmill-walking training with additional body load on the quality of life and motor function of subjects with PD. METHODS: Nine subjects with PD, Hoehn and Yahr stages 2-3, not demented and with capability to ambulate independently took part in this study. The training program was divided into three phases (A1-B-A2): treadmill training with additional body load (A1), control condition (conventional physical therapy group; B) and a second period of treadmill training with load (A2). Each phase lasted six weeks. Quality of life and motor function were assessed by the PDQ-39 and the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS), respectively. The evaluations and the training were performed during the on-phase of the medication cycle. RESULTS: There was improvement in the total PDQ-39 score across the training period. The subscores mobility, activities of daily living and cognition subscores significantly improved after the training period. The improvement in the total score was associated with motor and non-motor factors in all of the training phases. The UPDRS motor score also improved, however it did not present any association with the improvement in quality of life. CONCLUSIONS: The results showed that the treadmill-walking training with additional body load allowed an improvement in motor and non-motor aspects related to quality of life and motor function in subjects with PD. PMID- 20949236 TI - Electromyographic activity during active prone hip extension did not discriminate individuals with and without low back pain. AB - BACKGROUND: Changes in activation of the trunk and hip extensor muscles can result in excessive stress on the lumbar spinal structures, predisposing them to lesions and pain. OBJECTIVES: To compare electromyographic activity of the gluteus maximus, semitendinosus and the erector spinae muscles between asymptomatic and individuals with low back pain during active prone hip extension exercises. METHODS: Fifty individuals were recruited and divided into two groups: 30 asymptomatic (24.5 +/- 3.47 years) and 20 with mechanical low back pain (28.75 +/- 5.52 years). They performed active prone hip extension exercises, while the activation parameters (latency, duration and quantity of activation) of the investigated muscles were recorded by electromyography. The beginnings of the movements were detected by a motion capture system. Differences between the groups were investigated employing Student t-tests or Mann-Whitney-U tests, according to the data distribution. RESULTS: No significant differences were found between the groups for any of the investigated muscles. Muscular activation patterns were similar for both groups, starting with the semitendinosus, followed by the erector spinae, and then, by the gluteus maximus. For both groups, significant delays in the onset of the gluteus maximus were observed. CONCLUSIONS: The assessment of the electromyographic activity was not capable of discriminating individuals with and without low back pain, suggesting an overlap in the studied populations. PMID- 20949237 TI - Education does not equally influence all the Mini Mental State Examination subscales and items: inferences from a Brazilian community sample. AB - OBJECTIVE: Mini-Mental State Examination cutoffs have been presented for schooling levels to screen cognitive impairment. However, items may behave differently with regards to education. The objective of this study was to examine the impact of education on MMSE subscales and items. METHOD: Community-dwelling participants aged 65 years or more (n = 990, females = 637, age = 74.1 years, range 65-108) were stratified as illiterate (n = 373), 1-8 (n = 540), 9-12 (n = 63), and more than 12 years of schooling (n = 14) and were screened with MMSE and Pfeffer Functional Activities Questionnaire. To make the Mini-Mental State Examination items comparable, each item was transformed into z scores. Multiple linear regression was used to estimate the effect of schooling on MMSE subs and items controlling for age, sex, and activities of daily life. RESULTS: Temporal and space orientation, attention/calculation, repetition, reading, writing, and drawing scores improved as education increased, but not memory registration, three step command, and naming. Reading and writing displayed the largest coefficients, whereas education exerted no influence on naming and three step command tasks. CONCLUSION: Education does not exert an important effect on naming, three step command, memory registration, and delayed recall. As memory is a key factor for diagnosing dementia, these items could be considered despite education. PMID- 20949238 TI - [Identification and description of a new epistemological category of inferential reasoning related to meta-naturalistic science]. AB - Modern science underwent a substantial shift of methodology passing from naturalistic science to meta-naturalistic science, the latter addressed to introduce "Technologically Modified Beings or Objects" (TMB - TMO) in nature, with the intention to utilize them for some endpoints. Classically, naturalistic science draws epistemological inferences using the traditional criteria of induction, deduction or abduction. The question arises: "What is the epistemological criterion of inference used by meta-naturalistic science?". Meditating on this question, I have identified the new epistemological category of reasoning that characterizes the meta-naturalistic science, calling it: "Adduction". Adduction can be defined as "A new epistemological category of inferential reasoning, beside induction, deduction, abduction, currently used in meta-naturalistic science, that consists in deriving inferences to what it has not been yet scientifically experimented, demonstrated and validated, simply by adducing, as a support to the inference, the motivation itself for which the scientists were exerted to produce their meta-naturalistic artifacts. In so doing, the inference is no other than an aprioristic, adubitative assertion of a thesis that gives an authorization to the scope and a certainty to the results, without knowing whether or not the promised endpoints will be fulfilled. In conclusion, adduction is a convolute (sometime, tautological and para-sylogistic) process of reasoning that makes "prospective prophecies" because of its inference to the predicted premises rather than to the demonstrated conclusions". PMID- 20949239 TI - Open comparison study of oxidative stress markers between patients with chronic renal failure in conservative therapy and patients in haemodialysis. AB - AIMS: Oxidative stress is defined as tissue damage caused by an imbalance between the excessive production of the oxidant components and an insufficient defence mechanism. It has been observed, as in patients with chronic kidney failure, that there exists a pro-oxidant state characterised by a higher level of reactive oxygen species (ROS), and that oxidative stress in dialysis patients can be aggravated by the activation of neutrophils associated with the production of free radicals. In patients undergoing dialysis even the molecules other than those of cytokines can accumulate and provoke an inflammatory response. This study proposes an analysis based on the total antioxidant capacity (TAC), thiol concentration (TC) and pro-oxidant capacity (POC) in the serum of various groups of patients: one group of dialysis subjects who had been undergoing substitutive treatment for more than ten years at the time of the study; one group of subjects with chronic renal insufficiency in its pre-terminal stage and subjected to conservative therapy; and the control group consisting of healthy volunteers. MATERIALS AND METHODS: Three types of tests were employed to assess the level of oxidative stress: oxy-adsorbent test, d-ROMS test, and SHp- test. Thirty-three subjects were selected: 11 undergoing haemodialysis for over then years; 14 patients with chronic kidney failure in its pre-terminal stage, and 8 normal subjects. In patients undergoing renal substitutive treatment, the serum levels (mean+/-sd) of TAC were 272.98+/-20.54; TC, 249.19+/-92.48, and POC, 95.06+/ 15.70. In patients with chronic renal insufficiency in its pre-terminal stage and undergoing conservative treatment, the value of TAC was 226.5+/-27.89; TC, 336.42+/-102.08; and POC, 80.78+/-15.69. The levels of TAC in the serum of the controls were 335.62+/-46.35; TC, 434.09+/-22.23; and POC, 56.31+/-7.41. CONCLUSION: The analysed data suggest that in dialysis the patients with chronic kidney failure, whether undergoing conservative therapy during its pre-terminal stage or in substitution treatment during its terminal stage, there is a reduction in the antioxidant defence (in terms of TAC and thiolic barrier) and an increase in POC compared to the healthy subjects in the control group. Uraemia and haemodialysis increase the inflammatory response: an initial signal provokes the inflammatory state with the production of cytokines and free radicals or reactive oxygen, so that the lack of an antioxidant defence mechanism can bring about a vicious circle with the continual production of other free radicals. PMID- 20949240 TI - Assessment of the oxidative stress markers in patients with chronic renal insufficiency undergoing dialysis treatment. AB - AIMS: Uraemia is a disease characterised by a significant oxidative stress, and it is a wide agreement that oxidative stress which accompanies uraemia, increases the inflammatory state and promotes the alterations of tiny molecules such as amino acids, proteins, lipids, and carbohydrates. There are numerous records of how ROS are connected to the pathology of end stage renal disease (ESRD). The aim of this study is to assess the Total Antioxidant Capacity (TAC), the Thiolic Capacity (TC) and the Pro-Oxidant Capacity (POC) in the serum of patients undergoing dialysis treatment. MATERIALS AND METHODS: Forthy-six patients have been recruited (32 men, 14 women; mean age 68.5+/-15.8) who received hemodialytic treatment triweekly. Three methods have been used: oxy adsorbent test (mmol/l) to determine TAC values; d-ROM test (mg/100 mg/H2O2) to determine POC; SHp-test (mmol/l) to determine TC. RESULTS: In patients who underwent hemodialysis, TAC levels were: pre-dialysis, 265.9+/-30.5; post-dialysis, 300.0+/-40.6; TC levels: pre-dialysis, 267.4+/-59.1; post-dialysis, 303.2+/-116.7; POC levels: predialysis, 86.2+/-16.9; post-dialysis, 98.6+/-17.0; NS: TAC, 335.6+/-46.3; TC, 434.0+/-22.2; POC, 56.3+/-7.4. TAC in both pre- and post-dialysis is reduced compared to the NS (p < 0.05); moreover TAC increases after dialysis (p < 0.05). Pre- and post-dialysis TC is reduced compared to NS (p < 0.05); available TC increases after dialysis, although not statistically significant. Pre- and post dialysis POC in patients undergoing dialysis is increased compared to the NS (p < 0.05); moreover, POC tends to increase after dialysis ( p < 0.05). The data obtained from our study also show that the TAC is reduced in the patients subjected to hemodialysis compared to the NS, both before and after dialysis treatment; TAC increased after dialysis, even though it did not reach the level of the control group. CONCLUSION: Our study has demonstrated that exists a profound imbalance between antioxidants and the production of ROS in ESRD patients, which determines oxidative stress and eventually leads to atherosclerosis and cardiovascular complications. This, in turn, represents the major cause of morbidity and mortality in these patients. PMID- 20949241 TI - Non-secretory multiple myeloma with diagnostic challenges. AB - Non-secretory multiple myeloma (NSMM) is a rare variant of the classic form of multiple myeloma (MM). In NSMM, no monoclonal gammopathy can be detected in serum or urine by conventional techniques, making the diagnosis more difficult. We describe a 71-year-old man who had been diagnosed and treated for granulocytic sarcoma one year prior to his recent problems of progressive low-back pain of two months duration. Skeletal X-rays showed diffuse osteolytic lesions with multiple pathological fractures but there was no monoclonal gammopathy in the serum or urine. The biopsy of the lytic lesion on the upper part of the femur showed infiltration by abnormal plasma cells. A diagnosis of NSMM was made and he was treated with chemotherapy. The early diagnostic difficulty and the challenges faced regarding the case are discussed. PMID- 20949242 TI - Incidental finding of double nodular microscopic hyperplasia versus adenoma of the retinal pigment epithelium in an eye eviscerated for phthisis bulbi. AB - Neoplasms of the retinal pigment epithelium (RPE) are very rare and can clinically simulate choroidal melanoma. The clinical, histopathological and immunohistochemical features of incidental double pseudo-neoplastic proliferation of the RPE in an eviscerated eye for phthisis bulbi are reported. The differential diagnosis of RPE neoplasms and the utility of histopatological examination of eviscerated/enucleated eyes are discussed. PMID- 20949243 TI - Successful free omental flap and skin graft reconstruction of scalp avulsion injury. AB - For the management of a full-thickness scalp avulsion injury, thorough wound debridement and immediate primary revascularization or a split-thickness skin graft may be necessary. Graft failure may be common situation thereby predisposing the individuals to unnecessary multiple operations. In the recent times, the use of omental graft has gained much popularity. In the present study, we describe an interesting case of chronic non healing scalp ulcer in a young woman who eventually underwent a free omental flap reconstruction with split thickness skin graft and had satisfactory outcome. PMID- 20949244 TI - Familial primary hyperhidrosis: a disabling social disease. AB - The incidence of primary hyperhidrosis ranges between 2-5%. This condition is more common than previously thought of and has been linked to a familial predisposition. It is socially disabling to the affected individuals. In the current era of minimally invasive surgery, the video assisted thoracoscopic sympathectomy has become the definitive treatment with minimal complications. We report on a case of two siblings with primary hyperhidrosis that was treated successfully at our institution with the aim to share our experience and attract awareness among medical practitioners of the availability of a cure for this condition. PMID- 20949245 TI - [The HPA axis in the pathogenesis of chronic fatigue syndrome]. AB - Chronic fatigue syndrome (CFS) is a clinical syndrome characterized by profound disabling chronic fatigue associated with a wide array of other physical symptoms. Its etiology is currently unknown. Among the various hypotheses, considerable interest has been placed in the hypothalamus-pituitary-adrenal axis as a possible target of the pathogenesis of CFS. This article reviews the available scientific evidence about a role of hypothalamic-pituitary-adrenal axis in the pathogenesis of chronic fatigue syndrome. PMID- 20949246 TI - [Influence between sleep and epilepsy: synopsis and prospectus]. AB - The authors studied the possible theories on the function of the sleep and provided specific information on its representation. They believe useful the hypnogram in monitoring on the pathophysiology of the processes characterized by clinical and subclinical sleep involvement. The continuous and simultaneous registration of the sleep activities by polysomnography have been developed for the evaluation of neurologic diseases with various technique applications: electroencephalography (EEG), electromyography (EMG), and electroculography (EOG). Cyiclic Alternative Pattern (CAP) represents two alternate phases of partial awakening followed from deepened sleeping. Besides CAP rate measures percentage of CAP relative to the quiet sleep or non-Rapid Eyes Movement (non REM) sleep. There is an intimate relationship between sleep and epilepsy. Sleep is an important activator of interictal epileptiform discharges. The localization of the primary epileptogenic area is more reliable in REM sleep than in wakefulness, and in wakefulness more than in slow-wave sleep. The authors also discuss the role of sleep and sleep deprivation in the EEG evaluation of epilepsy. PMID- 20949247 TI - Ethical approaches to triage in public health emergencies. AB - General concepts and about medical disasters, public health and triage are outlined. Ethical values at stake are summarized. A special attention is given to conflicts between protection of individual interests (typical of clinical ethics) and collective interests (typical of public health and triage). Hippocratic ethics is compared to utilitarian ethics and to perspectives that emphasize the principle of justice. Three attitudes are suggested: protection of human dignity, precaution, solidarity. A personalistic perspective is suggested to deepen solidarity as a pillar both of clinical and public health ethics. PMID- 20949248 TI - New perspectives: role of sunitinib in breast cancer. AB - Sunitinib malate (SU11248) is a multitarget oral tyrosine kinase receptor (RTKs) inhibitor which was approved by FDA in renal cells carcinoma (RCC) and imatinib resistant or imatinib-intollerant gastrointestinal stromal tumour (GIST). Sunitinib is able to inhibit RTKs such as receptors for platelet-derived growth factor (PDGF-R alpha and beta) and for vascular endothelial growth factor (VEGFRs). It is able to inhibit KIT receptor, colony stimulating factor type 1 receptor (CSF- 1R), glial cell line neutrophic factor receptor (RET), fms-like tyrosine kinase receptor-3 (FLT-3 or CD135), signal transducer and activator of transcription 3 (STAT3) and AKT (protein kinase B) in tumour cells. Many sunitinib targets play important roles in growth and survival of human breast cancer (BC). The "rationale" of sunitinib in BC (with or without others antiagiogenetic therapy) is its ability to block simultaneously intracellular portion of RTKs inhibiting many downstream signals. We overviewed the most relevant studies concerning sunitinib in metastatic BC. PMID- 20949249 TI - Quantitative analysis of human behavior. AB - Many aspects of individual as well as social behaviours of human beings can be analyzed in a quantitative way using typical scientific methods, based on empirical measurements and mathematical inference. Measurements are made possible today by the large variety of sensing devices, while formal models are synthesized using modern system and information theories. PMID- 20949250 TI - Role for the families in child involving research. AB - In a clinical research which involves disabled children, family plays a fundamental role for the stipulation of consent - according to international ethical guidelines - as well as it has to be considered one of the main caregivers in this context. Therefore this fundamental role has to be recognized when considering the development of pediatric research programs, in which the family should be involved. In fact, therapeutic alliance between families and researchers should be considered, not only as a fundamental basis for children health and well-being, but also as an important resource for better outcomes in terms of research, health care and efficacy. PMID- 20949251 TI - Stereotypical movements. AB - A 'stereotypical movement' denotes a movement reproduced in a standardised form. The term is used in two fields, in movement science and in medical assessments of pathology. The former recognises the occurrence of regular patterns of movement across individuals expressed at regular points in development, such as the pre reach in early infancy. The latter specifies a pathological form of repetitive movement by one individual symptomatic of, for example, autism. This entry explores the interindividual use of the term in movement science and touches on ongoing work to better classify and quantify stereotypical movements for better psychophysiological understanding of action development, and possible sensitive measures of them. PMID- 20949252 TI - [Diagnosis and treatment of varicose veins. Part 1: definition, epidemiology, etiology, classification, clinical aspects, diagnostic and indications]. AB - This is the first of two articles on the diagnosis and treatment of varicose veins. Primary varicosis is a congenital degenerative disease of the peripheral venous system of the lower extremities. The realisation factors are age, female sex and pregnancy. Degeneration of the peripheral veins leads to dilatation of the lumen and insufficient closure of the valves resulting in a backflow of blood from deep to the superficial venous system. This leads to ambulatory hypertension in the superficial venous system and recirculation of noteworthy amounts of venous drainage blood in the affected leg. Without treatment this results in the long term in variable degrees of decompensation of the recirculation pathways and an increasing (volume-induced) secondary insufficiency of the deep venous system. The result corresponds to the clinical symptoms of chronic venous insufficiency (CVI). When treatment is started early enough the pathological course can be reduced or avoided. The various therapeutic measures will be described in the second article of this series. PMID- 20949253 TI - [Automated breast volume scanner (ABVS) : a new approach for breast imaging]. AB - The automated breast ultrasound technique has been known for a long time but did not play an important role in diagnostics due to its inferior sensitivity for small solid lesions with low frequency transducers and its uncomfortable examination technique with the patients in a supine position and the breast immersed in water. The automated breast volume scanner (AVBS) is a high-end ultrasound scanner which employs frequencies of 5-14 MHz and consists of a flexible arm with the transducer at the end, a touchscreen and a 3D workstation. The scan is performed with the patient in the prone position. Depending on the breast size, various presettings are available from which the examiner may select the most appropriate. AVBS has various major advantages, such as being independent from the experience of the operator as well as supplying consistent and reproducible results. Additionally, for the first time it became possible to obtain coronal images of the complete breast, which greatly assists the planning of surgical interventions. In this article the ABVS technique will be described and results will be illustrated by means of clinical examples. PMID- 20949254 TI - [Paleopathology and the history of medicine: the example of influenza pandemics]. AB - The paper examines the history of former influenza pandemics from the perspective of changing nosographic categories. Special emphasis is put on the so-called Spanish flu of 1918. Due to its high mortality rates this pandemic is often highlighted as a warning sign for what may happen during a future pandemic. After a short introduction into the problematic status of the validity of retrospective diagnoses the history of influenza pandemics is discussed. The pandemic of 1918 is analysed from the perspective of the public health system being connected to and relying on medical and scientific debates. The reasons for this pandemic's rank as the long forgotten pandemic are discussed. PMID- 20949255 TI - [Cyst, endometriosis, borderline tumor, CUP : diagnostic stations of a supposedly simple renal cyst]. AB - Symptomatic renal cysts are not uncommon and can be treated by puncture, sclerotherapy, or laparoscopic fenestration. We report the case of a female patient in whom the diagnosis of a supposedly simple symptomatic renal cyst changed over endometriosis and borderline malignancy to a CUP. This case shows that in spite of all diagnostic measures and care the final diagnosis can be a surprise. PMID- 20949256 TI - [Birt-Hogg-Dube syndrome : bilateral oncocytic kidney tumors in a patient]. AB - We report on a rare case of bilateral oncocytic kidney tumors in a patient with Birt-Hogg-Dube syndrome (BHD). BHD is an autosomal inherited cancer syndrome associated with multiple kidney tumors, benign cutaneous tumors, and pulmonary cysts with spontaneous pneumothorax. To date about 50 BHD families have been described. Patients are best treated with nephron-sparing surgery. Close follow up is mandatory because recurrence in previously operated kidneys and metastatic tumor progression can occur. Family members at risk should also early be screened for BHD. PMID- 20949257 TI - Metacarpal thickness, width, length and medullary diameter in children--reference curves from the First Zurich Longitudinal Study. AB - SUMMARY: Metacarpal thickness (T), width (W), length (L) and medullary diameter (M) were measured in 3,121 X-rays from 231 healthy Caucasian children aged 3 to 19 years and analysed for bone age, age, height, weight and gender-related characteristics, showing highly differentiated growth patterns with prepubertal dips. Reference data for the four metacarpal measures are presented. INTRODUCTION: The aim of the study was to create and explore a reference database for metacarpal T, W, L and M in children. METHODS: Three thousand one hundred twenty-one left-hand X-rays (1,661 from boys) from 231 healthy Caucasian subjects (119 boys) aged 3 to 19 years were analysed by BoneXpert, a programme for automatic analysis of hand X-rays and bone age (BA; in years). RESULTS: In boys, growth of T, W and L shows a prepubertal decrease from BA 7 to 13 and then accelerates again. In girls, the same is seen only for T starting from BA 8 to 11, whereas W and L grow at a declining rate. M shows steady growth until BA 10.5 in girls and BA 13.5 in boys and then grows smaller in both. W is greater in boys from BA 6 onwards, while L is greater in girls from BA 9 to 13 and T from BA 11 to 14. BA is reflected best by L until start of puberty and by T and L thereafter. CONCLUSION: T, W, L and M show highly differentiated growth patterns. These reference data provide a basis for further research into skeletal development and the management of hormone therapies in children. PMID- 20949258 TI - Antiarrhythmic and antioxidant activity of novel pyrrolidin-2-one derivatives with adrenolytic properties. AB - A series of novel pyrrolidin-2-one derivatives (17 compounds) with adrenolytic properties was evaluated for antiarrhythmic, electrocardiographic and antioxidant activity. Some of them displayed antiarrhythmic activity in barium chloride induced arrhythmia and in the rat coronary artery ligation-reperfusion model, and slightly decreased the heart rate, prolonged P-Q, Q-T intervals and QRS complex. Among them, compound EP-40 (1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1 yl]propyl]pyrrolidin-2-one showed excellent antiarrhythmic activity. This compound had significantly antioxidant effect, too. The present results suggest that the antiarrhythmic effect of compound EP-40 is related to their adrenolytic and antioxidant properties. A biological activity prediction using the PASS software shows that compound EP-35 and EP-40 can be characterized by antiischemic activity; whereas, compound EP-68, EP-70, EP-71 could be good tachycardia agents. PMID- 20949259 TI - Development of an analytical procedure for evaluation of the protective behaviour of innovative fungal patinas on archaeological and artistic metal artefacts. AB - In the literature, the ability to transform metal compounds into metal oxalates has been reported for different species of fungi. This could be an innovative conservation method for archaeological and artistic metal artefacts. In fact, with a high degree of insolubility and chemical stability even in acid atmospheres (pH 3), metal oxalates provide the surface with good protection. Within the framework of the EU-ARTECH project, different fungal strains have been used to transform existing corrosion patinas on outdoor bronze monuments into copper oxalates, while preserving the physical appearance of these artefacts. Given the promising results obtained with this first attempt, the same approach is now applied within the BAHAMAS (Marie Curie Intra European Fellowship action) project, but extended to other metal substrates, for example iron and silver, which are frequently found in cultural heritage artworks and also encounter several problems of active corrosion. The research is investigating the formation mechanisms and adhesion properties of the newly formed metal oxalates by means of complementary analytical techniques (X-ray diffraction (XRD), FTIR microscopy, Raman microscopy, scanning electron microscopy (SEM-EDS), electrochemical impedance spectroscopy (EIS), colorimetry). For each metal substrate, the most appropriate fungal strain is going to be identified and applied to corroded sheets and the novel fungal treatment compared with those used so far. Treated metal sheets will be monitored during 1-year exposure to different cycles of artificial ageing, to evaluate the corrosion resistance of the fungal patinas obtained. The objective of this contribution is to present the first results achieved so far on naturally corroded bronze sheets during the EU-ARTECH project and the analytical procedure used for the testing of the proposed treatment performances during the BAHAMAS project. PMID- 20949260 TI - Upgrading bioluminescent bacterial bioreporter performance by splitting the lux operon. AB - Bioluminescent bacterial bioreporters harbor a fusion of bacterial bioluminescence genes (luxCDABE), acting as the reporting element, to a stress response promoter, serving as the sensing element. Upon exposure to conditions that activate the promoter, such as an environmental stress or the presence of an inducing chemical, the promoter::reporter fusion generates a dose-dependent bioluminescent signal. In order to improve bioluminescent bioreporter performance we have split the luxCDABE genes of Photorhabdus luminescens into two smaller functional units: luxAB, that encode for the luciferase enzyme, which catalyzes the luminescence reaction, and luxCDE that encode for the enzymatic complex responsible for synthesis of the reaction's substrate, a long-chain aldehyde. The expression of each subunit was put under the control of either an inducible stress-responsive promoter or a synthetic constitutive promoter, and different combinations of the two units were tested for their response to selected chemicals in Escherichia coli. In all cases tested, the split combinations proved to be superior to the native luxCDABE configuration, suggesting an improved efficiency in the transcription and/or translation of two small gene units instead of a larger one with the same genes. The best combination was that of an inducible luxAB and a constitutive luxCDE, indicating that aldehyde availability is limited when the five genes are expressed together in E. coli, and demonstrating that improved biosensor performance may be achieved by rearrangement of the lux operon genes. PMID- 20949261 TI - NMR of heparin API: investigation of unidentified signals in the USP-specified range of 2.12-3.00 ppm. AB - This article addresses the identification and quantification of the chemical species resulting in resonances at 2.17 and 2.25 ppm in the (1)H nuclear magnetic resonance (NMR) spectrum of pharmaceutical-grade heparin sodium. The NMR signals in question were first confirmed to arise from chemical moieties covalently attached to the heparin molecule through NMR diffusion experiments as well as chemical treatment of heparin active pharmaceutical ingredient (API) containing the resonances. The material responsible for the extra NMR signals was then demonstrated by NMR spiking studies to be something other than oversulfated chondroitin sulfate and was finally identified as an O-acetylation product of heparin through (13)C labeling experiments with subsequent NMR analysis. The extent of O-acetylation was quantified using three orthogonal techniques: (1)H NMR, ion chromatography, and headspace gas chromatography/mass spectrometry. The results of this work showed good agreement between the three quantitative methods developed to analyze the signals in the United States Pharmacopeia-specified region of 2.12-3.00 ppm for heparin API. PMID- 20949262 TI - Optimality vs. variability: an example of multi-finger redundant tasks. AB - Two approaches to motor redundancy, optimization and the principle of abundance, seem incompatible. The former predicts a single, optimal solution for each task, while the latter assumes that families of equivalent solutions are used. We explored the two approaches using a four-finger pressing task with the requirement to produce certain combination of total normal force and a linear combination of normal forces that approximated the total moment of force in static conditions. In the first set of trials, many force-moment combinations were used. Principal component (PC) analysis showed that over 90% of finger force variance was accounted for by the first two PCs. The analytical inverse optimization (ANIO) approach was applied to these data resulting in quadratic cost functions with linear terms. Optimal solutions formed a hyperplane ("optimal plane") in the four-dimensional finger force space. In the second set of trials, only four force-moment combinations were used with multiple repetitions. Finger force variance within each force-moment combination in the second set was analyzed within the uncontrolled manifold (UCM) hypothesis. Most finger force variance was confined to a hyperplane (the UCM) compatible with the required force-moment values. We conclude that there is no absolute optimal behavior, and the ANIO yields the best fit to a family of optimal solutions that differ across trials. The difference in the force-producing capabilities of the fingers and in their moment arms may lead to deviations of the "optimal plane" from the subspace orthogonal to the UCM. We suggest that the ANIO and UCM approaches may be complementary in the analysis of motor variability in redundant systems. PMID- 20949263 TI - Comparative oral bioavailability of non-fixed and fixed combinations of artesunate and amodiaquine in healthy Indian male volunteers. AB - OBJECTIVE: The aim of the present study was to compare the pharmacokinetic properties, bioavailability and tolerability of artesunate (AS) and amodiaquine (AQ) administered as a fixed-dose combination (Amonate FDC tablets; Dafra Pharma, Turnhout, Belgium) or as a non-fixed dose combination of separate AS tablets (Arsuamoon; Guilin Pharmaceutical Co, Shanghai, China) and AQ tablets (Flavoquine; Sanofi-Aventis, Paris, France). METHODS: This was a randomized, open label, two-period, two-treatment, two-sequence, cross-over study in which 60 healthy male Indian volunteers were given a single total oral dose of 100 mg AS and 400 mg AQ hydrochloride either as two tablets of Amonate FDC (AS 50 mg and AQ hydrochloride 200 mg) or as two AS tablets of the co-blister Arsuamoon (50 mg AS) together with two Flavoquine tablets (200 mg AQ hydrochloride). Plasma AS and blood AQ concentrations, as well as those of their respective active metabolites dihydroartemisinin (DHA) and desethylamodiaquine (DEAQ), were measured by high performance liquid chromatography-tandem spectrometry. The pharmacokinetic parameters of AS, DHA, AQ and DEAQ were determined by non-compartmental analysis. Bioequivalence assessment was performed by analysis of variance (ANOVA), and calculation of the 90% confidence intervals of the geometric mean ratio test (fixed)/reference (non-fixed) for AUC(0-t) and C(max) for AS, AQ, DHA and DEAQ. RESULTS: Interim analysis showed that both treatments were not bioequivalent; therefore, statistical analysis was carried out on the results of all subjects for whom blood/plasma concentrations were available for all four analytes (n=26). The C(max) (maximum plasma/blood concentration) of AS was 67.0 +/- 37.1 and 154.8 +/- 116.2 ng/mL for the fixed-dose and non-fixed dose administration, respectively. The AUC(0-t) (area under the plasma concentration-time curve from time zero to the last measurable concentration) of AS was 60.1 +/- 27.5 and 81.8 +/- 44.3 ng h/mL for the fixed-dose and non-fixed dose administration, respectively. The 90% confidence intervals for C(max) and AUC(0-t) of AS were outside the 80-125% acceptance range: 37.02-61.62% and 70.10-83.47%, respectively. The C(max) of AQ was 33.8 +/- 13.6 and 31.4 +/- 14.1 ng/mL for the fixed-dose and non-fixed dose administration, respectively. The AUC(0-t) of AQ was 332.3 +/- 116.6 and 329.8 +/- 99.5 ng h/mL for the fixed and non-fixed dose administration, respectively. For AQ, the 90% CIs for C(max) and AUC(0-t) were within the 80-125% acceptance range: 99.17-121.71 and 89.53-107.35%, respectively. Bioequivalence assessment based on the active metabolite data supported the bioequivalence conclusions based on the parent compound data. Both the fixed-dose and non-fixed dose administration of 100 mg AS and 400 mg AQ were well tolerated. CONCLUSION: Bioequivalence of the fixed-dose AS/AQ formulation with the non-fixed dose combination of the same drugs was not demonstrated for AS, but it was shown for AQ for both C(max) and AUC(0-t). The results obtained on the active metabolites support this conclusion. Overall, the fixed-dose 50 mg AS/200 mg AQ tablets were not technically bioequivalent with 50 mg AS tablets and 200 mg AQ tablets administered separately. The difference cannot be explained by the pharmaceutical properties of the tablets and seems to be biologically related. PMID- 20949264 TI - Focal nodular hyperplasia in children, adolescents, and young adults. AB - BACKGROUND: Focal nodular hyperplasia (FNH) is a benign hepatic tumor that is rare in children. In order to understand whether there are differences in the etiology or appearance of FNH in children, we analyzed the clinical information and imaging of pathologically proven cases. MATERIALS AND METHODS: A pathology database was used to identify all cases of FNH diagnosed at our institution. Each patient's imaging was evaluated for the characteristics of FNH lesions. Clinical information was obtained on each patient. RESULTS: Thirteen patients with FNH were identified (7 male/6 female, mean age 14.3 years, range 1-27 years). Seven patients (5 male/2 female) had a remote history of childhood malignancy. The time interval between the diagnoses of malignancy and FNH ranged from 9 to 27 years (mean 14.4 years). On imaging, all seven cancer survivors had multiple liver lesions. In the remaining six patients (2 male/4 female), there was no history of malignancy and all but one of these patients had a solitary FNH. CONCLUSION: Half of the patients with FNH in this study were long-term cancer survivors and each of these patients had multiple masses. Recognizing the features of FNH will aid in diagnosis and appropriate management. PMID- 20949265 TI - Multidetector CT venography and contrast-enhanced MR venography of the inferior mesenteric vein in paediatric extrahepatic portal vein obstruction. AB - BACKGROUND: Extrahepatic portal vein obstruction (EHPVO) is a common cause of paediatric portal hypertension and the only permanent treatment is shunt surgery. The inferior mesenteric vein (IMV) is a portal venous channel that can be used for the shunt when the splenic vein/superior mesenteric vein is thrombosed or when a lienorenal shunt is not possible. OBJECTIVE: To compare MDCT venography (MDCTV) and contrast-enhanced MR venography (CEMRV) for visualisation of the IMV in children with EHPVO. MATERIALS AND METHODS: This was a prospective study of 26 children (4-12 years, median 10 years) who underwent MDCTV and CEMRV. The IMV visualisation was graded using 4- and 2-point scales and the difference in visualisation was assessed by calculating the exact significance probability (P). RESULTS: The IMV was visualised in all children on MDCTV and 25/26 children on CEMRV (96%). The images were diagnostic in 23/26 children (88%) on MDCTV and in 18/26 (69%) children on CEMRV (P=0.063). CONCLUSION: MDCTV and CEMRV are comparable for IMV visualisation with a tendency toward MDCTV being superior. PMID- 20949266 TI - Localized IR spectroscopy of hemoglobin. AB - IR absorption spectroscopy of hemoglobin was performed using an infrared (IR) optical parametric oscillator laser and a commercial atomic force microscope (AFM) in a novel experimental arrangement based on the use of a bottom-up excitation alignment. This experimental approach enables detection of protein samples with resolution much higher than that of standard IR spectroscopy. Presented here are AFM-based IR absorption spectra of micron-sized hemoglobin features. PMID- 20949267 TI - Pressure and temperature stability of the main apple allergen Mal d1. AB - High-pressure Fourier-transform infrared (FTIR) spectroscopy was used to determine the pressure and temperature stability of Mal d1. This study was triggered by contradictory results in the literature regarding the success of pressure treatment in the destruction of the allergen. The protein unfolded at 55 degrees C when heated at normal atmospheric pressure. We also studied the effect exerted on pressure stability by environmental factors, which can be important for the stability of the protein in the apple. The pressure unfolding was measured under different pD conditions, and the effect of sugar mixture similar to that of the apple and the effect of ionic strength were also studied. In all cases the allergen unfolded with a transition midpoint in the range of 150-250 MPa. Unfolding was irreversible and was followed by aggregation of the unfolded protein. Lowering the pD destabilized the protein, while addition of sugar mixture and of KCl had stabilizing effect. PMID- 20949268 TI - Elaboration of antibiofilm materials by chemical grafting of an antimicrobial peptide. AB - A peptide antibiotic, gramicidin A, was covalently bound to cystamine self assembled monolayers on gold surfaces. Each step of the surface functionalization was characterized by polarization modulation infrared reflection absorption spectroscopy and X-ray photoelectron spectroscopy. The antimicrobial activity of the anchored gramicidin was tested against three Gram-positive bacteria (Listeria ivanovii, Enterococcus faecalis, and Staphylococcus aureus), the Gram-negative bacterium Escherichia coli and the yeast Candida albicans. The results revealed that the adsorbed gramicidin reduced, from 60% for E. coli to 90% for C. albicans, the number of culturable microorganisms attached to the surface. The activity was proven to be persistent overtime, up to 6 months after the first use. The bacteria attached to the functionalized surfaces were permeabilized as shown by confocal microscopy. Taken together, these results indicate a bacteriostatic mode of action of the immobilized peptide. Finally, using green fluorescent protein-expressing bacteria, it was shown that the development of a bacterial biofilm was delayed on peptide-grafted surfaces for at least 24 h. PMID- 20949269 TI - Diversity and abundance of anammox bacterial community in the deep-ocean surface sediment from equatorial Pacific. AB - The community structure and diversity of anaerobic ammonium oxidation (anammox) bacteria in the surface sediments of equatorial Pacific were investigated by phylogenic analysis of 16S rRNA and hydrazine oxidoreductase (hzo) genes and PCoA (principal coordinates analysis) statistical analysis. Results indicated that 16S rRNA and hzo sequences in the P2 (off the center of western Pacific warm pool) and P3 (in the eastern equatorial Pacific) sites all belong to the Candidatus "Scalindua", the dominate anammox bacteria in the low-temperature marine environment proved by previous studies. However, in the P1 site (in center of warm pool of western Pacific), large part of 16S rRNA gene sequences formed a separated cluster. Meanwhile, hzo gene sequences from P1 sediment also grouped into a single cluster. PCoA analysis demonstrated that the anammox community structure in the P1 has significant geographical distributional difference from that of P2, P3, and other marine environments based on 16S rRNA and hzo genes. The abundances of anammox bacteria in surface sediments of equatorial Pacific were quantified by q-PCR analysis of hzo genes, which ranged from 3.98 * 10(3) to 1.17 * 10(4) copies g(-1) dry sediments. These results suggested that a special anammox bacteria phylotypes exist in the surface sediment of the western Pacific warm pool, which adapted to the specific habitat and maybe involved in the nitrogen loss process from the fixed inventory in the habitat. PMID- 20949270 TI - Uniform stable-isotope labeling in mammalian cells: formulation of a cost effective culture medium. AB - Uniform stable-isotope labeling of mammalian cells is achieved via a novel formulation of a serum-free cell culture medium that is based on stable-isotope labeled autolysates and lipid extracts of various microbiological origin. Yeast autolysates allow complete replacement of individual amino acids and organic acids in a chemically defined medium (DMEM/F12), enabling a cost-effective formulation of a stable-isotope-labeled culture medium for mammalian cells. In addition, biomass-derived hydrolysates, autolysates, and lipid extracts of various classes of algae were explored as cell culture components, both separately and in combination with yeast autolysates. Optimal autolysate concentrations were established. Such novel medium formulations were tested on mammalian cell lines, often used for recombinant protein production, i.e., Chinese hamster ovary (CHO) and human embryonic kidney (HEK 293). Special attention was paid to the adaptation of these mammalian cell lines to serum-free media. Formulation of the novel proprietary cell culture medium PLIm, based on yeastolates instead of individual amino acids and organic acids, allows a four- to eightfold cost reduction for (15)N and (13)C,(15)N stable-isotope-labeling, respectively, in CHO cells and a three- to sixfold cost reduction in HEK 293 cells. A high level of stable-isotope enrichment of mammalian cells (>90%) was achieved within four passages by complete replacement of carbon and nitrogen sources in the medium with their stable-isotope-labeled analogs. These conditions can be used to more cost-effectively produce labeled recombinant proteins in mammalian cells. PMID- 20949271 TI - Endoscopic transsphenoidal optic nerve decompression: an anatomical study. AB - PURPOSE: The endoscopic transnasal, transsphenoidal approach is considered by many a valid option to reach the sellar region and, in selected cases, to decompress the optic nerve. However, few data are available in literature about the real effectiveness of the procedure and the extent of nerve decompression needed to obtain a clinical result. The aim of this anatomical study was to describe the most important landmarks of the endoscopic transsphenoidal approach to the optic nerve. METHODS: Six silicone-injected cadaver heads were dissected via the endoscopic transnasal approach, performing a bilateral optic nerve decompression. The lateral optocarotid recess (OCR) and optic canal were identified in each case. Moreover, the relationship between the ophthalmic artery at its origin and the optic nerve was examined. RESULTS: Twelve decompressions of the optic nerve were performed, obtaining the following measurements: intercarotid distance 12 mm +/- 1.5, median length of OCR 5 mm +/- 1 and average length of optic nerve decompression 15 mm +/- 2. The ophthalmic artery was observed emerging from the internal carotid artery (ICA) medially in six cases, ventrally in four cases and laterally in two cases. CONCLUSION: A wide optic nerve decompression may be obtained with transsphenoidal approach. However, the risk of ophthalmic artery injury seems to be more relevant than with supratentorial approaches, due to the intimate relationship between artery and nerve on its inferior surface. Knowledge of anatomical landmarks, such as lateral OCR and the position of the ophthalmic artery, is useful to prevent this injury. PMID- 20949272 TI - MLL-aberrant leukemia: complete cytogenetic remission following treatment with a histone deacetylase inhibitor (HDACi). PMID- 20949273 TI - Rapid spontaneous regression of multicentric infantile myofibromatosis in the posterior fossa and lumbar vertebra. PMID- 20949274 TI - Generalized peritonitis due to perforated diverticulitis: Hartmann's procedure or primary anastomosis? AB - PURPOSE: Hartmann's procedure (HP) still remains the most frequently performed procedure for diffuse peritonitis due to perforated diverticulitis. The aims of this study were to assess the feasibility and safety of resection with primary anastomosis (RPA) in patients with purulent or fecal diverticular peritonitis and review morbidity and mortality after single stage procedure and Hartmann in our experience. METHODS: From January 1995 through December 2008, patients operated for generalized diverticular peritonitis were studied. Patients were classified into two main groups: RPA and HP. RESULTS: A total of 87 patients underwent emergency surgery for diverticulitis complicated with purulent or diffuse fecal peritonitis. Sixty (69%) had undergone HP while RPA was performed in 27 patients (31%). At the multivariate analysis, RPA was associated with less post-operative complications (P < 0.05). Three out of the 27 patients with RPA (11.1%) developed a clinical anastomotic leakage and needed re-operation. CONCLUSIONS: RPA can be safely performed without adding morbidity and mortality in cases of diffuse diverticular peritonitis. HP should be reserved only for hemodynamically unstable or high-risk patients. Specialization in colorectal surgery improves mortality and raises the percentage of one-stage procedures. PMID- 20949275 TI - Totally double laparoscopic colon resection with intracorporeal anastomosis and transvaginal specimens extraction. PMID- 20949276 TI - Accuracy of predicting 18 years of age from mandibular third molar development in an Indian sample using Demirjian's ten-stage criteria. AB - Predicting 18 years of age can be crucial in forensic contexts. The third molar is the only tooth developing during this chronological period and has been used to estimate minority/majority status (=18 years). Conventionally, Demirjian's grading has been used to assess third molar development although the method was not originally intended for evaluating this tooth. Demirjian incorporated third molar assessment in a recent modification and replaced the alphabetical grading (A to H) with a numerical scale (0 to 9). The new grading system is untested on third molars and this study assessed the tooth's development on orthopantomograms of 221 Indian subjects (68 males, 153 females; age range 15-21 years). The tendency to correctly determine majority/minority status was assessed using three different statistical approaches, viz. traditional regression analysis, logistic regression analysis and Bayesian prediction. The sample was divided in to a reference sample of 180 cases and a test group of 41 subjects. All three statistical methods correctly predicted an individual as being =18 years in 73.2% of test subjects. Their ability to correctly identify a minor/juvenile was higher (85.7%) than their capacity to properly identify a major/adult (60%). Using the revised grading system, and irrespective of the statistical method applied, over one quarter of Indian subjects requiring identification as a major/minor were categorised in to the wrong age group. This level of accuracy may be inadequate for courts of law to rule with sufficient levels of certainty about the juvenile/adult status of an individual using third molar development. PMID- 20949277 TI - Correlation between nerve fibre layer thickness measured with spectral domain OCT and visual field in patients with different stages of glaucoma. AB - BACKGROUND: To measure retinal nerve fibre layer (RNFL) thickness with spectral domain OCT (SD-OCT) in patients with glaucoma, and to evaluate the correlation between visual field parameters and RNFL thickness. METHODS: Two hundred twelve subjects-55 normal, 37 with preperimetric glaucoma (PPG) and 119 with different stages of primary open angle glaucoma (POAG) were enrolled in this study. Standard automated perimetry was performed in all eyes. RNFL thickness was measured for 6 segments of the 3.4 mm diameter circle and for 8 areas corresponding to the Early Treatment Diabetic Retinopathy Study (ETDRS) grid, both centred on the optic disc. RNFL thickness values were calculated for the inner ring surrounding the optic disc border and the outer ring of the ETDRS grid. The association between visual field parameters and RNFL thickness was evaluated with regression analysis and Pearson correlation coefficients. RESULTS: In the normal group, mean RNFL thickness was 93 +/- 9 MUm for circle and 91 +/- 14 MUm for inner ring, for the POAG group the values were 58 +/- 21 MUm for circle and 40 +/- 21 MUm for inner ring, and for the PPG group the values were 77 +/- 15 MUm and 59 +/- 15 MUm, respectively. The differences in RNFL thickness between normal and glaucoma eyes were significant (p < 0.001) for all measurements. Mean RNFL thickness between normal and PPG eyes was significantly different for all regions except for the superior-temporal and temporal sector of the circle and for area 7 of the ETDRS grid. In POAG eyes only, RNFL thickness and both mean sensitivity (r = 0.558) and mean defect (r = -0.549) correlated significantly. The best parameters for differentiating normal from PPG eyes were inner ring surrounding the optic disc border (area under receiver operator characteristic curves (AUROC) = 0.940) and area 4 values (AUROC = 0.903) of the ETDRS grid. CONCLUSIONS: SD-OCT showed significantly decreased mean RNFL thickness of the inner ring surrounding the optic disc border of the ETDRS grid by 35% in PPG eyes and by 46% in eyes with early glaucoma compared to the control group. These results support the usefulness of this technology. PMID- 20949278 TI - OCT for optic disc evaluation in idiopathic intracranial hypertension. AB - BACKGROUND: Optical coherence tomography (OCT) enables quantification of retinal layer thicknesses. Studies evaluating the ability of OCT to identify and quantify papilledema are few. Therefore, the aim was to evaluate the applicability of peripapillary OCT evaluation in an unselected, consecutive series of patients with confirmed idiopathic intracranial hypertension (IIH). METHODS: A case control study of 20 patients with newly diagnosed IIH and 20 healthy subjects. Subjects were evaluated by means of direct ophthalmoscopy, masked evaluations of fundus photography, peripapillary retinal nerve fiber layer thickness (RNFLT), and peripapillary average retinal thickness (PART) measurements (Stratus OCT-3, fast RNFL 3.4 protocol). RESULTS: OCT evaluation of PART revealed the highest number of patients (n = 20) with optic disc abnormalities in either eye (90%), compared with 85%, 80% and 70% for RNFLT measurements, direct ophthalmoscopy, and fundus photography respectively. There was a linear association between means and differences of OCT data (RNFLT, PART) with a slope of 0.54 (SE 0.025), p < 0.001. CONCLUSION: Peripapillary OCT is a promising objective examination modality for optic disc evaluation in IIH, and may improve the identification of subtle disc swellings. Underestimation of RNFLT for increasing severities of papilledemas is suspected, making PART a more reliable parameter compared to RNFLT. Future larger validation studies are needed. PMID- 20949279 TI - Race and gender of faces can be ignored. AB - Past research indicates that faces can be more difficult to ignore than other types of stimuli. Given the important social and biological relevance of race and gender, the present study examined whether the processing of these facial characteristics is mandatory. Both unfamiliar and famous faces were assessed. Participants made speeded judgments about either the race (Experiment 1) or gender (Experiments 2-4) of a target name under varying levels of perceptual load, while ignoring a flanking distractor face that was either congruent or incongruent with the race/gender of the target name. In general, distractor target congruency effects emerged when the perceptual load of the relevant task was low but not when the load was high, regardless of whether the distractor face was unfamiliar or famous. These findings suggest that face processing is not necessarily mandatory, and some aspects of faces can be ignored. PMID- 20949280 TI - Characterization of the subcellular localization of herpes simplex virus type 1 proteins in living cells. AB - In this study, we presented the construction of a library of expression clones for the herpes simplex virus type 1 (HSV-1) proteome and subcellular localization map of HSV-1 proteins in living cells using yellow fluorescent protein (YFP) fusion proteins. As a result, 21 proteins showed cytoplasmic or subcytoplasmic localization, 16 proteins showed nuclear or subnuclear localization, and others were present both in the nucleus and cytoplasm. Interestingly, most capsid proteins showed enriched or exclusive localization in the nucleus, and most of the envelope proteins showed cytoplasmic localization, suggesting that subcellular localization of the proteins correlated with their functions during virus replication. These results present a subcellular localization map of HSV-1 proteins in living cells, which provide useful information to further characterize the functions of these proteins. PMID- 20949281 TI - Molecular genetic evidence for polyandry in Ascaris suum. AB - The aim of this study was to determine whether single Ascaris suum female could mate with multiple males. Seven sex-linked microsatellite markers were employed and paternal genetic analyses were conducted. Totally, 62 offspring individuals from three single females were screened, and the numbers of fathers in each family were determined using allele counting methods and the program GERUD, version 2.0. The seven sex-linked microsatellite loci showed high polymorphism and revealed that one out of three families (allele counts) and two out of three families (GERUD) of the sampled families had at least two sires (2-6), indicating that females of A. suum can mate with multiple males. These findings provide the first molecular genetic evidence for polyandry of female A. suum and lay a foundation for further studies on the impacts of polyandry on population genetic parameters, the parasite population's genetic diversity, the potential for infection of different host species, and for the rate of spread of drug resistance. PMID- 20949282 TI - Morphology of the infective larval stage of the equid parasite Habronema muscae (Spirurida: Habronematidae), from houseflies (Musca domestica). AB - The infective larva of the spirurid nematode Habronema muscae, a parasite of houseflies, was measured and specimens fixed in Karnovsky's fluid were examined by scanning electron microscopy. The oral opening contains six teeth and is surrounded by large bilobed dorsal and ventral lips and smaller lateral lips. A pair of amphids lie behind the lateral lips. There are two rows of four cephalic papillae. The body is deeply ridged, both transversely and longitudinally. The caudal end of the worm is studded by small papillae. The position of the anal opening is somewhat ambiguous. These larval morphological features are discussed, as well as the changes which must have occurred in the metamorphosis of the infective larva to the adult in the stomach of horses. PMID- 20949283 TI - Isoprostane levels in urine of preterm newborns treated with ibuprofen for patent ductus arteriosus closure. AB - Patent ductus arteriosus (PDA) is the most common cardiovascular abnormality of the preterm infant usually treated with ibuprofen (IBU). PDA is strictly related to oxidative stress (OS) in neonates. This study tests the hypothesis that OS occurs in neonates with PDA and that IBU treatment reduces OS. Forty-three preterm babies with gestational age (GA) <33 weeks were studied prospectively. Three urine samples were collected: at time 0 (before starting treatment), time 1 (after pharmacological PDA closure), and time 2 (7 days after the end of treatment) in all patients. OS was studied by measuring urinary isoprostane (IPs) levels. The results showed significant changes in urinary IP levels from time 0 to time 2 (Kruskal-Wallis, p=0.047). Time trend showed a significant decrease in IPs from time 0 to time 1 after IBU therapy (p=0.0067). This decrease was followed by an increase in IPs levels 7 days after treatment. IBU therapy for PDA closure reduced the risk of OS related to free-radical (FR) generation. This antioxidant effect of IBU may be beneficial in preterm babies with PDA who are at high risk for OS. PMID- 20949284 TI - Advances in our understanding of the pathogenesis of glomerular thrombotic microangiopathy. AB - Glomerular thrombotic microangiopathy is a hallmark feature of haemolytic uraemic syndrome, the leading cause of acute renal failure in childhood. This paper is a review of the different mechanistic pathways that lead to this histological picture in the kidney. It will focus on atypical HUS and complement dysregulation, but will also highlight some other recent advances in our understanding of this condition, including the potential role of the molecule vascular endothelial growth factor-A (VEGF-A). PMID- 20949286 TI - Estimation of the tourism climate in the Hunter Region, Australia, in the early twenty-first century. AB - Existing tourism-related climate information and evaluation are typically based on mean monthly conditions of air temperature and precipitation and do not include thermal perception and other climate parameters relevant for tourists. Here, we quantify climate based on the climate facets relevant to tourism (thermal, physical, aesthetical), and apply the results to the Climate-Tourism Information-Scheme (CTIS). This paper presents bioclimatic and tourism climatological conditions in the Hunter Region-one of Australia's most popular tourist destinations. In the Hunter Region, generally, temperatures below 15 degrees C occur from April through October, temperatures less than 25 degrees C are expected throughout the whole year, while humidity sits around 50%. As expected, large differences between air temperature and physiologically equivalent temperature (PET) were clearly identified. The widest differences were seen in summer time rather than in the winter period. In addition, cold stress was observed less than 10% of the time in winter while around 40-60% of heat stress was observed in summer time. This correlates with the highest numbers of international visitors, who usually seek a warmer weather, at the beginning of summer time (November and December) and also to the number of domestic visitors, who tend to seek cooler places for recreation and leisure, in late summer (January-March). It was concluded that thermal bioclimate assessment such as PET and CTIS can be applied in the Hunter region, and that local governments and the tourism industry should take an integrated approach to providing more relevant weather and climate information for both domestic and international tourists in the near future. PMID- 20949285 TI - Comparison of heat dissipation response between Malaysian and Japanese males during exercise in humid heat stress. AB - This study investigated the differences in heat dissipation response to intense heat stress during exercise in hot and humid environments between tropical and temperate indigenes with matched physical characteristics. Ten Japanese (JP) and ten Malaysian (MY) males participated in this study. Subjects performed exercise for 60 min at 55% peak oxygen uptake in 32 degrees C air with 70% relative humidity, followed by 30 min recovery. The increase in rectal temperature (T(re)) was smaller in MY during exercise compared to JP. The local sweat rate and total body mass loss were similar in both groups. Both skin blood flow and mean skin temperature was lower in MY compared to JP. A significantly greater increase in hand skin temperature was observed in MY during exercise, which is attributable to heat loss due to the greater surface area to mass ratio and large number of arteriovenous anastomoses. Also, the smaller increase in T(re) in MY may be explained by the presence of a significantly greater core-skin temperature gradient in MY than JP. The thermal gradient is also a major factor in increasing the convective heat transfer from core to skin as well as skin blood flow. It is concluded that the greater core-skin temperature gradient observed in MY is responsible for the smaller increase in T(re). PMID- 20949287 TI - Evaluation of performance of two high-frequency oscillatory ventilators using a model lung with a position sensor. AB - PURPOSE: High-frequency oscillatory ventilation (HFOV) is thought to protect the lungs of acute respiratory distress syndrome (ARDS) patients. The performance and mechanical characteristics of high-frequency oscillatory ventilators, especially with regard to delivering appropriate tidal volume (V(T)) to compromised lungs, might affect the outcome of patients. We evaluated the performance of two such ventilators using a model lung with a position sensor. METHODS: We tested the Metran R100 and SensorMedics 3100B. V(T) was measured using the model lung with the compliance set at 20 or 50 ml/cmH2O and the resistance at 0 or 20 cmH2O/l/s. Oscillator frequency was set at 5, 7, and 9 Hz, and amplitude was set at 25%, 50%, 75%, and 100% (100% being maximum amplitude available at each setting configuration). RESULTS: At each model lung setting, R100 delivered greater V(T) at 5 Hz. V(T) differences between the ventilators decreased as frequency increased and were negligible at 9 Hz. At each model lung setting and frequency, as amplitude increased from 25% to 100%, V(T) increased proportionally more with R100. With an I:E ratio of 1:1, 3100B delivered greater V(T) than with 1:2. CONCLUSION: Because it is able to deliver comparably greater V(T), R100 may be a better choice for HFOV in critical ARDS patients. Better proportionality may be a result of more effective amplitude titration for adjusting PaCO2 during oscillation. PMID- 20949288 TI - Severe burn injury associated with misuse of forced-air warming device. PMID- 20949291 TI - Hyperostosing meningiomas of the cranial vault with and without tumor mass. AB - OBJECTIVE: This study represents the first clinical series in the reported literature exclusively concentrating on the clinicoradiological features of non sphenoidal hyperostosing meningiomas. It attempts to identify the factors that may have an impact on the surgical strategy and results of this unique subgroup of meningiomas. METHODS: In the vault, we distinguished between meningiomas with and without tumor mass according to their thickness (<1.5 vs >= 1.5 cm) and between convexity (lateral) and calvarial (midline) meningiomas according to their location. The clinical, radiological, surgical and prognostic characteristics of the tumors were examined. RESULTS: Over a 10-year period, we observed 24 cases, 18 of which in the convexity (nine without and nine with tumor mass) and six calvarial (one without and five with tumor mass). Six patients presented with neurological signs, while the majority showed bony hyperostosis (n = 19). Brain edema (n = 7) was found only in cases with tumor mass, in all neurologically impaired patients, and only in one intact patient. Total removal was obtained in 92% patients. Small residual tumors attached to the superior sagittal sinus and perisinusal dura were coagulated in situ and not excised. Morbidity occurred in three symptomatic patients with tumor mass and brain edema (mental confusion in one case and hemiparesis in two cases). Mortality was nil. After a mean follow-up of 4.8 years, three cases relapsed, all of which had initially presented with atypical meningiomas. CONCLUSIONS: The rare hyperostosing cranial vault meningiomas may be classified as being with and without tumor mass. A number of categorical differences exist in their distribution, pattern of hyperostosis, surrounding arachnoidal plane, and their prognosis. Careful preoperative planning aimed at tailoring the extent of tumor removal and reconstruction in the neighboring infiltrated structures enables a good outcome to be achieved. PMID- 20949289 TI - Surgery versus conservative management of sciatica due to a lumbar herniated disc: a systematic review. AB - The effectiveness of surgery in patients with sciatica due to lumbar disc herniations is not without dispute. The goal of this study was to assess the effects of surgery versus conservative therapy (including epidural injections) for patients with sciatica due to lumbar disc herniation. A comprehensive search was conducted in MEDLINE, EMBASE, CINAHL, CENTRAL, and PEDro up to October 2009. Randomised controlled trials of adults with lumbar radicular pain, which evaluated at least one clinically relevant outcome measure (pain, functional status, perceived recovery, lost days of work) were included. Two authors assessed risk of bias according to Cochrane criteria and extracted the data. In total, five studies were identified, two of which with a low risk of bias. One study compared early surgery with prolonged conservative care followed by surgery if needed; three studies compared surgery with usual conservative care, and one study compared surgery with epidural injections. Data were not pooled because of clinical heterogeneity and poor reporting of data. One large low-risk-of-bias trial demonstrated that early surgery in patients with 6-12 weeks of radicular pain leads to faster pain relief when compared with prolonged conservative treatment, but there were no differences after 1 and 2 years. Another large low risk-of-bias trial between surgery and usual conservative care found no statistically significant differences on any of the primary outcome measures after 1 and 2 years. Future studies should evaluate who benefits more from surgery and who from conservative care. PMID- 20949292 TI - Long-term experience with intraoperative microrecording during DBS neurosurgery in STN and GPi. AB - BACKGROUND: Intraoperative microelectrode recording (MER) for targeting during deep brain stimulation (DBS) procedures has been evaluated over a period of 4 years, in 57 consecutive patients with Parkinson's disease, who received DBS in the subthalamic nucleus (STN-DBS), and 28 consecutive patients with either dystonia (23) or Parkinson's disease (five), in whom the internal segment of the globus pallidus (GPi-DBS) was targeted. METHODS: The procedure for DBS was a one stage bilateral stereotactic approach using a combined electrode for both MER and macrostimulation. Up to five micro/macro-electrodes were used in an array with a central, lateral, medial, anterior, and posterior position. Final target location was based on intraoperative test stimulation. FINDINGS: For the STN, the central trajectory was chosen for implantation in 50% of the cases and for the globus pallidus internus (GPi) in 57% of the cases. Furthermore, in 64% of the cases, the channel selected for the permanent electrode corresponded with the trajectory having the longest segment of STN MER activity. For the GPi, this was the case in 61%. The mean and standard deviation of the deepest contact point with respect to the magnetic resonance imaging (MRI)-based target for the STN was 2.1 +/- 1.5 mm and for the GPi was -0.5 +/- 1.2 mm. CONCLUSIONS: MER facilitates the selection of the final electrode location in STN-DBS and GPi-DBS, and based on the observed MER activity, a pre-selection could be made as to which channel would be the best candidate for macro-test stimulation and at which depth should be stimulated. The choice of the final location is based on intraoperative test stimulation, and it is demonstrated that regularly it is not the central channel that is chosen for implantation. On average, the target as defined by MER activity intensity was in accordance with the MRI-based targets both for the STN and GPi. However, the position of the best MER activity did not necessarily correlate with the locus that produced the most beneficial clinical response on macroelectrode testing intraoperatively. PMID- 20949293 TI - An analysis of failed microvascular decompression in patients with hemifacial spasm: focused on the early reoperative findings. AB - BACKGROUND: Although the microvascular decompression (MVD) has become a definitive treatment for the primary hemifacial spasm (HFS), there still are some failed cases. To obtain a satisfactory postoperative outcome, those failure cases of MVD need to be analyzed. METHOD: Between January and October 2009, 393 patients with primary HFS underwent MVD. Postoperatively, 375 presented complete spasm-free, 7 improved apparently, and 11 without any improvement at all. A reoperation was performed in 9 of the 11 patients who had poor outcome within 5 days. Those redo MVD cases were reviewed. FINDINGS: After the reoperation, the symptom of those patients all disappeared immediately. Therefore, the final outcomes were excellent in 97.7%, good in 1.8%, and poor in 0.5%. Up to the 1 year follow-up period, neither recurrence nor change was found. For the two patients without reoperation, their symptoms remained. The previous surgery was a failure due to insufficient decompression in two and conflict missed in seven. CONCLUSIONS: A successful MVD operation is attributable to a thorough exploration of the entire nerve course. An early relief should become the ambition of the operator while performing MVD. PMID- 20949294 TI - The DSM IV diagnoses of melancholic and atypical depression in pregnancy. AB - Atypical and melancholic subtypes of depression based on the Diagnostic and Statistical Manual (DSM) IV are important concepts, especially for biological psychiatry. The aim of this study was to determine whether the symptoms used for the diagnoses of atypical and melancholic depression can distinguish these subtypes during pregnancy. A modified version of the Structured Clinical Interview for DSM IV (SCID interview) was used that allowed assessment of all DSM IV symptoms of melancholic and atypical depression with depressed and non depressed women in pregnancy. A Swiss cohort of 449 women was interviewed. Four diagnostic groups were compared: women with melancholic, atypical or non specified depression, and those without depression. Seventeen per cent of the cohort met SCID criteria for a depressive episode of depression at least once in pregnancy, with melancholic depression 2.4%, atypical depression 4.4% and non specified depression 10.2%. Many of the symptoms used to distinguish atypical and melancholic depression did not discriminate between these groups during pregnancy. However some, such as mood reactivity, distinct quality of mood and sleep pattern, did discriminate. Differential diagnosis between melancholic and atypical depression in pregnancy needs to be based on pregnancy specific definitions. The possible therapeutic consequences and the neurobiological basis for these findings warrant further research. PMID- 20949295 TI - Counting touching cell nuclei using fast ellipse detection to assess in vitro cell characteristics: a feasibility study. AB - In this article, we describe a new image analysis software that allows rapid segmentation and separation of fluorescently stained cell nuclei using a fast ellipse detection algorithm. Detection time ranged between 1.84 and 3.14 s. Segmentation results were compared with manual evaluation. The achieved over segmentation rate was 0.11 (0.1 double counts and 0.01 false positive detections), and the under-segmentation rate was of 0.03 over all images. We demonstrate the applicability of the proposed algorithm to automated counting of fluorescent-labeled cell nuclei and to tissue characterization. Moreover, the performance of the proposed algorithm is compared with preexisting automated image analysis techniques described by others. PMID- 20949296 TI - Erdheim-Chester disease. AB - Erdheim-Chester disease is characterized by long bone pain and symmetric sclerosis of the diametaphyseal portions of the long bones. It is an important differential diagnosis of sclerotic disease of the bones. PMID- 20949297 TI - Cutaneous manifestations of Churg-Strauss syndrome: report of two cases and review of the literature. AB - Churg-Strauss syndrome (CSS) is a small-vessel vasculitis characterized by severe asthma, lung/tissues infiltrates, extravascular necrotizing granulomas, and eosinophilia. Cutaneous involvement is common but may not be highly suggestive. Two typical cases of CSS with cutaneous involvement are herein reported, both females, 37 and 54 years old, presenting with lower limbs palpable purpura and urticarial lesions of the neck, respectively. A comprehensive review of the literature showed that cutaneous manifestations occurred in 40-81% of CSS patients and were the presenting sign in 14% of the patients. Moreover, a total of 68 cases of CSS with a detailed description of the cutaneous lesions have been published. In the majority of these patients, skin lesions allowed for the histopathological diagnosis of CSS. The most common clinical features were papulo nodules with the histological picture of extravascular Churg-Strauss granuloma followed by purpuric and/or necrotic lesions in the lower limbs corresponding to small-vessel vasculitis with eosinophils. Less common lesions included urticarial lesions and livedo reticularis. Therefore, a high index of suspicion on skin lesions and the proper lesion selection for histological examination may be very important for early diagnosis of CSS. Clinical-pathological correlation is essential, as both clinical and histological features are not pathognomonic. PMID- 20949298 TI - Osteomalacia revisited : a report on 28 cases. AB - The aim of this study was to analyse the clinical manifestations and the most frequent causes of osteomalacia (OM) in a group of 28 patients diagnosed with this disorder during a 20-year period. OM was diagnosed by bone biopsy and/or by Bingham and Fitzpatrick criteria (two of the following: low calcium, low phosphate, elevated total alkaline phosphatase [total AP] or suggestive radiographs). Of these patients, 13 had vitamin D deficiency OM (VD-OM), 14 hypophosphatemic OM (HypoP-OM) and one had OM-associated hypophosphatasia. Deficient sun exposure and celiac disease were the most frequent etiologies of VD OM, whereas most HypoP-OM were hereditary forms. The main clinical symptoms were polyarthralgias (89%), frequently associated with fractures (75%). Fifty seven percent had densitometric criteria of osteoporosis. Patients with VD-OM showed significantly higher total AP and PTH serum values, but lower vitamin D, serum calcium, calciuria and bone mass than patients with HypoP-OM. Conversely, HypoP OM patients had significantly lower serum phosphate and higher phosphaturia than patients with VD-OM. Briefly, high total AP, low serum calcium and low serum phosphate were observed in 85%, 65% and 15%, respectively, of patients with VD OM, being observed in 64%, 14% and 100%, respectively, of HypoP-OM patients. Nearly 50% of these latter showed increased FGF23 levels. In conclusion, in this study, the frequencies of HypoP-OM and VD-OM were similar. The most frequent laboratory abnormalities were increased total AP and decreased serum phosphate. A urinary calcium loss of less than 50 mg/dl was highly discriminatory for VD-OM and a serum phosphate less than 2.3 mg/dl was also high discriminatory for HypoP OM. Low densitometric values and fractures were frequent among these patients. PMID- 20949299 TI - Clinical and microbiological characteristics of urine culture-confirmed genitourinary tuberculosis at medical centers in Taiwan from 1995 to 2007. AB - All patients with urine culture-confirmed genitourinary tuberculosis (GUTB) diagnosed between 1995 and 2007 at two medical centers in northern Taiwan were included in this retrospective study. Genotypes of 48 preserved Mycobacterium tuberculosis (MTB) isolates from these patients were determined by spoligotyping and double repetitive element PCR (DRE-PCR) analysis. Among the 64 patients, 38 (59.4%) were male with a mean +/-SD age of 60.3 +/- 16.1 years old. The overall mortality rate was 26.2%. Poor prognostic factors included age over 65 years (HR = 4.03; 95%; CI: 1.27-12.76), cardiovascular disease (HR = 5.96; 95% CI: 1.98 17.92), receiving steroids (HR = 10.16; 95% CI: 2.27-45.47), not being treated (HR 4.81; 95% CI 1.12-20.67). Spoligotyping and DRE-PCR of the 48 MTB isolates revealed that 20 (41.7%) belonged to the Beijing family and 40 (83.3%) had a clustering pattern. Identification of a Beijing family isolate was not correlated with drug resistance or mortality. Clustering strains were likely to be resistant to isoniazid (OR = 4.71; 95% CI: 1.10 to 23.53). In this study of patients with urine culture-confirmed GUTB, age and coexisting diseases were independently associated with an unfavorable outcome. The Beijing family was the dominant genotype of GUTB isolates, but did not correlate with drug resistance or outcome. PMID- 20949300 TI - Peripheral ophthalmic artery aneurysm. AB - Generally speaking, the term "ophthalmic aneurysms" refers to carotid-ophthalmic aneurysms, which arise from the internal carotid artery (ICA) wall at or around the origin of the ophthalmic artery (OA). In contrast, aneurysms arising from the OA stem or its branches, separate from the ICA are called peripheral OA aneurysms (POAAs). POAAs are a rare entity, which clinical features and natural course are not fully understood. A comprehensive literature review of reported aneurysms involving each segment of the OA was undertaken. The demographics, aetiology, clinical manifestations and treatment of reported POAAs are discussed. Of 35 retrieved cases, ten involved the intracranial segment, two were fusiform aneurysms in the optic canal, 17 arose from the intraorbital segment, and 6 involved either the lacrimal or the anterior ethmoidal branches. In 34 cases, clinical details were available; 18 patients experienced moderate to severe visual impairment including blindness, while seven patients had improvement in visual acuity as a result of surgical treatment. The present clinical review reveals that aneurysms of the OA stem and lacrimal branch are potentially threatening to visual acuity, while intracranial segment and anterior ethmoidal aneurysms can rupture and cause subarachnoid or intraparenchymal haemorrhage. Surgical intervention is mandatory in symptomatic cases to prevent visual deterioration or treat aneurismal rupture; alternatively, for small incidental POAAs "watchful waiting" may be indicated. PMID- 20949301 TI - The distribution of the anal glands and the variable regional occurrence of fistula-in-ano: is there a relationship? AB - BACKGROUND: Fistula in ano is a rather common condition, but the disease process is not yet fully understood. The aim of our study was to determine how the distribution of anal glands contributes to the variable occurrence of fistula-in ano in the perineum. METHODS: we conducted a blinded two-phase prospective study. In the first phase, the perineum of the patients with primary fistulae was anatomically divided into right upper and lower and left upper and lower quadrants in the lithotomy position. The fistulae were classified according to what quadrant the external and internal openings and the tract pathway were in. In the second phase, using 10 human cadaver specimens, full thickness tissue samples were taken from each quadrant of the anus. Samples were histologically evaluated for the volume fractions of the anal glands in each quadrant. RESULTS: The new classification system we propose revealed that the largest number of fistulae 43% (17/39) were in the right lower quadrant, and 22% (9/39), 12% (5/39) and 8% (3/39) were in the left lower, right upper and left upper quadrants, respectively. It was also observed that 14% (5/39) of fistulae were in more than one quadrant. The volume fractions of each quadrant showed that the largest volume fraction of the anal glands was in the right lower quadrant (right lower quadrant: 0.64, left lower quadrant: 0.35, right upper quadrant: 0.26 and left upper quadrant: 0.22, P = 0.001). CONCLUSIONS: To the best of our knowledge, this is the first study that has objectively shown that the distribution of the anal glands is variable, and the highest density of anal glands is in the right lower quadrant of the anus. This variable distribution may be associated with the variable occurrence in fistula in ano. PMID- 20949302 TI - Wegener's granulomatosis complicated by pulmonary embolism: a case report and review of the literature. AB - We describe the case of a 79-year-old lady who developed pulmonary emboli on a background of active Wegener's granulomatosis (WG). The literature reports an increased association of venous thromboembolic disease and the small vessel vasculitides, including WG. This case report explores the issues surrounding systemic anticoagulation in the context of a systemic vasculitis that predisposes to severe bleeding, in particular from the respiratory tract. PMID- 20949303 TI - On the welfare theoretic foundation of CEA: comment. AB - This is a comment on a recent paper by Bengt Liljas (Eur J Health Econ 11:5-13, 2010) in this Journal. The author's analysis is flawed because he fails to take the envelope theorem into account. As a bottom line, we conclude that from a welfare theoretic point of view, future consumption and future labor hours should not be considered in a valid CEA. PMID- 20949304 TI - Antagonistic activity of Bacillus sp. obtained from an Algerian oilfield and chemical biocide THPS against sulfate-reducing bacteria consortium inducing corrosion in the oil industry. AB - The present study enlightens the role of the antagonistic potential of nonpathogenic strain B21 against sulfate-reducing bacteria (SRB) consortium. The inhibitor effects of strain B21 were compared with those of the chemical biocide tetrakishydroxymethylphosphonium sulfate (THPS), generally used in the petroleum industry. The biological inhibitor exhibited much better and effective performance. Growth of SRB in coculture with bacteria strain B21 antagonist exhibited decline in SRB growth, reduction in production of sulfides, with consumption of sulfate. The observed effect seems more important in comparison with the effect caused by the tested biocide (THPS). Strain B21, a dominant facultative aerobic species, has salt growth requirement always above 5% (w/v) salts with optimal concentration of 10-15%. Phylogenetic analysis based on partial 16S rRNA gene sequences showed that strain B21 is a member of the genus Bacillus, being most closely related to Bacillus qingdaonensis DQ115802 (94.0% sequence similarity), Bacillus aidingensis DQ504377 (94.0%), and Bacillus salarius AY667494 (92.2%). Comparative analysis of partial 16S rRNA gene sequence data plus physiological, biochemical, and phenotypic features of the novel isolate and related species of Bacillus indicated that strain B21 may represent a novel species within the genus Bacillus, named Bacillus sp. (EMBL, FR671419). The results of this study indicate the application potential of Bacillus strain B21 as a biocontrol agent to fight corrosion in the oil industry. PMID- 20949305 TI - Prediction of malignancy grading using computed tomography perfusion imaging in nonenhancing supratentorial gliomas. AB - Tumor grade differentiation is often difficult using routine neuroimaging alone. Computed tomography perfusion imaging (CTP) provides quantitative information on tumor vasculature that closely parallels the degree of tumor malignancy. This study examined whether CTP is useful for preoperatively predicting the grade of malignancy in glioma showing no enhancement on contrast-enhanced magnetic resonance imaging (MRI). Subjects comprised 17 patients with supratentorial glioma without enhancement on MRI. CTP was performed preoperatively, and absolute values and normalized ratios of parameters were calculated. Postoperatively, subjects were classified into two groups according to histological diagnosis of grade 3 (G3) glioma or grade 2 (G2) glioma. Absolute values and normalized ratios for each parameter were compared between G3 and G2. Accuracies of normalized ratios for cerebral blood flow (nCBF) and cerebral blood volume (nCBV) in predicting a diagnosis of G3 were assessed. In addition, nCBV was compared between diffuse astrocytoma, G2 oligodendroglial tumor (OT), and G3 OT. Values for nCBF and nCBV differed significantly between G3 and G2. Using nCBV of 1.6 as a cutoff, specificity and sensitivity for distinguishing G3 were 83.3% and 90.9%, respectively. No significant difference in nCBV was seen between diffuse astrocytoma and G2 OT, whereas differences were noted between G2 and G3 OTs, and between diffuse astrocytoma and G3 OT. CTP offers a useful method for differentiating between G3 and G2 in nonenhancing gliomas. PMID- 20949306 TI - Spontaneous regression of germinoma in the pineal region before endoscopic surgery: a pitfall of modern strategy for pineal germ cell tumors. AB - Since its introduction in the neurosurgical field, neuroendoscopy has played an important role in the treatment of pineal germ cell tumors. The authors report a case of pineal germinoma revealing spontaneous regression before neuroendoscopic surgery. A 15-year-old boy presented with chronic headache, deterioration of his visual acuity, and diplopia. Head magnetic resonance imaging (MRI) revealed a large tumor in the pineal region and triventricular hydrocephalus due to occlusion of the aqueduct. As levels of tumor markers in serum and cerebrospinal fluid, including those of alpha-fetoprotein, carcinoembryonic antigen, human chorionic gonadotropin (hCG), and the beta-subunit of hCG, were all within the normal ranges, endoscopic surgery for biopsy and third ventriculocisternostomy was performed. Under endoscopic view, the tumor was revealed to be smaller than expected from preoperative images. MRI obtained 14 days after admission disclosed marked shrinkage of the tumor. The histopathological diagnosis was pure germinoma, and the patient underwent chemotherapy combined with fractionated radiotherapy. The tumor disappeared, and the patient did not show any signs of relapse. Spontaneous regression is a very rare phenomenon in malignant brain tumors, and in the literature it has been uncommonly described in pineal germ cell tumors. Our case disclosed a pitfall of modern strategy for this pathology with neuroendoscopy. Dilated ventricles and a certain amount of lesion are factors for safe endoscopic biopsy of pineal tumors. Radiographic images shortly before surgery are warranted, especially in patients whose symptoms of intracranial hypertension have already improved before surgery. PMID- 20949307 TI - A simple strategy for 13C, 1H labeling at the Ile-gamma2 methyl position in highly deuterated proteins. AB - A straightforward approach for the production of highly deuterated proteins labeled with 13C and 1H at Ile-gamma2 methyl positions is described. The utility of the methodology is illustrated with an application involving the half proteasome (360 kDa). High quality 2D Ile 13C(gamma)2,1H(gamma)2 HMQC data sets, exploiting the methyl-TROSY principle, are recorded with excellent sensitivity and resolution, that compare favorably with Ile 13C(delta)1,1H(delta)1 spectra. This labeling scheme adds to a growing list of different approaches that are significantly impacting the utility of solution NMR spectroscopy in studies of supra-molecular systems. PMID- 20949308 TI - Molecular characterization, expression pattern, and functional analysis of the OsIRL gene family encoding intracellular Ras-group-related LRR proteins in rice. AB - Leucine-rich repeat proteins constitute a large gene family and play important roles in plant growth and development. Among them, Arabidopsis PIRL is a plant specific class of intracellular Ras-group-related leucine-rich repeat proteins. In this study, we identified eight homologues of PIRLs in rice and designated them as OsIRL proteins. We described the gene structures, chromosome localizations, protein motifs, and phylogenetic relationships of the OsIRL gene family. The expression profiles of OsIRL genes were analyzed throughout the entire rice life cycle, along with light and three hormone stress conditions, using quantitative RT-PCR and microarray data. All OsIRL genes were expressed in at least one experimental stage and exhibited divergent expression patterns, with several genes showing preferential expression at specific stages. OsIRL4 and OsIRL5 showed higher expression levels under light compared to dark. OsIRL4 and OsIRL7 exhibited significant differential expression in response to hormone treatments. Six T-DNA or Tos17 insertion lines for five individual OsIRL genes were identified and examined morphologically. The comprehensive expression profile elucidated in this investigation together with the characterized insertion lines will provide a solid foundation for in-depth dissection of OsIRL functions. PMID- 20949309 TI - Identifying disease polymorphisms from case-control genetic association data. AB - In case-control association studies, it is typical to observe several associated polymorphisms in a gene region. Often the most significantly associated polymorphism is considered to be the disease polymorphism; however, it is not clear whether it is the disease polymorphism or there is more than one disease polymorphism in the gene region. Currently, there is no method that can handle these problems based on the linkage disequilibrium (LD) relationship between polymorphisms. To distinguish real disease polymorphisms from markers in LD, a method that can detect disease polymorphisms in a gene region has been developed. Relying on the LD between polymorphisms in controls, the proposed method utilizes model-based likelihood ratio tests to find disease polymorphisms. This method shows reliable Type I and Type II error rates when sample sizes are large enough, and works better with re-sequenced data. Applying this method to fine mapping using re-sequencing or dense genotyping data would provide important information regarding the genetic architecture of complex traits. PMID- 20949310 TI - A semi-mechanistic gastric emptying model for the population pharmacokinetic analysis of orally administered acetaminophen in critically ill patients. AB - PURPOSE: To develop a semi-mechanistic population pharmacokinetic model based on gastric emptying function for acetaminophen plasma concentration in critically ill patients tolerant and intolerant to enteral nutrition before and after prokinetic therapy. METHODS: Acetaminophen plasma concentrations were available from a study with 10 tolerant and 20 intolerant patients before and after prokinetic therapy with either erythromycin or metoclopramide. Population pharmacokinetic modelling was carried out in a nonlinear mixed effects analysis software, NONMEM. RESULTS: A four-compartment semi-mechanistic model for stomach, intestine, central and peripheral compartments was described. The rate of emptying of the stomach was described by a first-order rate parameter. The final model has two gastric emptying rate constant parameters: kg1 (1.30 h(-1), RSE=53.84%, T1/2=0.53 h) for the intolerant group before prokinetic therapy and kg2 (27.8 h(-1), RSE=59.35%, T1/2=0.025 h) for both the intolerant group after prokinetic therapy and the tolerant group. Other parameters and estimates (RSE) in the model were ka=5.12 h(-1) (28.13%), CL=13.0 L/h (19.62%), CLD=22.6 L/h (19.78%), V1=63.8 L (12.79%) and V2=69 L (38.70%). CONCLUSIONS: The four compartment semi-mechanistic population pharmacokinetic model adequately described the data. The gastric emptying half-time is improved by a factor of about 20 in the patients that are intolerant to enteral nutrition after treatment with prokinetic agents. PMID- 20949312 TI - An approach to model Right Iliac Fossa pain using pain-only-parameters for screening acute appendicitis. AB - Acute appendicitis (AA) is one of the commonest of multiple possible pathologies at the backdrop of Right Iliac Fossa (RIF) pain. RIF is the most common acute surgical condition of the abdomen. Even though AA is a recognized disease entity since decades, its diagnosis still lacks clinical confidence and mandates laboratory tests. Given the issue, this paper proposes a mathematical model using Pain-Only-Parameters (POP) obtained from available literature to screen AA. Weights have been assigned for each POP to create a training data matrix (N = 51) and used to calculate the cumulative effect or weighted sum, which is termed as the Pain Confidence Score (PCS). Based on PCS, a group of real-world patients (N = 40; AA and NA = 20 each) are classified as cases of AA or non-appendicitis (NA) with satisfactory results (sensitivity 85%, specificity 75%, precision 77%, and accuracy 80%). Most rural health centers (RHC) in developing nations lack specialist services and related infrastructure. Hence, such a tool could be useful in RHC to assist general physicians in screening AA and their timely referral to higher centers. PMID- 20949311 TI - Biomagnetic methods: technologies applied to pharmaceutical research. AB - Biomagnetic methods have been designed for a wide range of applications. Recently, such methods have been proposed as alternatives to scintigraphy for evaluating of a number of pharmaceutical processes in vitro as well as under the influence of gastrointestinal physiological parameters. In this review, physical characterization as well as the most recent applications of Superconducting Quantum Interference Device (SQUID), Anisotropic Magnetoresistive (AMR) and AC Biosusceptometry (ACB) in the pharmaceutical research will be explored. Moreover, their current status and how these technologies can be employed to improve the knowledge about the impact of gastrointestinal physiology on drug delivery in association with pharmacokinetic outcomes, termed pharmacomagnetography, will be presented. PMID- 20949313 TI - Daily assessment of alcohol consumption and condom use with known and casual partners among young female bar drinkers. AB - The relationship between alcohol and condom use has been studied extensively over the past several decades. Reviews of event-level studies suggest that alcohol's effect on risky sexual behavior are not due to simple main effects, but appear to be dependent upon individual characteristics, and situational or contextual factors. In the current study, we assessed the temporal relationship between daily alcohol consumption and unprotected sexual behavior, taking into account sexual partner type (casual or known) as well as individual and situational characteristics among a group of young female bar drinkers. Greater alcohol consumption was not associated with unprotected sex. However, greater alcohol consumption was associated with an increase in sex (protected and unprotected) with casual partners. Having less HIV knowledge was associated with increased unprotected sex, while greater frequency of drinking in bars was associated with increased protected sex with casual partners. These findings are discussed in terms of possible prevention programs that increase HIV knowledge and decrease alcohol consumption to reduce young women's risky sexual behavior. PMID- 20949314 TI - Abortive meiosis in the oogenesis of parthenogenetic Daphnia pulex. AB - Most daphnid species adopt parthenogenesis and sexual reproduction differentially in response to varied environmental cues, resulting in the production of diploid progenies in both cases. Previous studies have reportedly suggested that daphnids produce their parthenogenetic eggs via apomixis; the nuclear division of mature oocytes should be an equational division similar to somatic mitosis. However, it seems premature to conclude that this has been unequivocally established in any daphnids. Therefore, the objective of our research was to precisely reveal the process and mechanism of parthenogenetic oogenesis and maintenance of diploidy in Daphnia pulex through histology, karyology, and immunohistochemistry. We found that, when a parthenogenetic egg entered the first meiosis, division was arrested in the early first anaphase. Then, two half-bivalents, which were dismembered from each bivalent, moved back to the equatorial plate and assembled to form a diploid equatorial plate. Finally, the sister chromatids were separated and moved to opposite poles in the same manner as the second meiotic division followed by the extrusion of one extremely small daughter cell (resembling a polar body). These results suggest that parthenogenetic D. pulex do not adopt typical apomixis. We hypothesize that D. pulex switches reproductive mode depending on whether the egg is fertilized or not. PMID- 20949315 TI - Spatio-temporal pattern and rationality of land reclamation and cropland abandonment in mid-eastern Inner Mongolia of China in 1990-2005. AB - The Mid-eastern Inner Mongolia of China, a typical agro-pastoral transitional zone, has undergone rapid agricultural land use changes including land reclamation and cropland abandonment in past decades due to growing population and food demand, climatic variability, and land use policy such as the "Grain for Green" Project (GFG Project). It is significant to the regional ecology and sustainability to examine the pattern and its rationality of land use change. The processes of land reclamation and cropland abandonment were accessed by using land use change dataset for four periods of 1990, 1995, 2000, and 2005, derived from the interpretation of Landsat TM images. And then the rationality of land reclamation and cropland abandonment was analyzed based on the habitat suitability for cultivation. The results indicated that: (1) land reclamation was the dominant form of agricultural land use change from 1990 to 2005, the total cropland area increased from 64,954.64 km(2) in 1990 to 76,258.51 km(2) in 2005; However, the speed of land reclamation decreased while cropland abandonment increased around 2000. The Land Reclamation Degree decreased from 1995-2000 to 2000-2005, meanwhile, Cropland Abandonment Degree increased. (2) As for the habitat suitability levels, moderately and marginally suitable levels had largest areas where cropland was widespread. Pattern of agricultural land use trended to become more rational due to the decrease of land reclamation area in low suitable levels and the increase of cropland abandonment in unsuitable area after 2000. (3) The habitat suitability-based rationality analysis of agricultural land use implicated that the GFG Project should take cultivation habitat suitability assessment into account. PMID- 20949316 TI - Incidence of organochlorine pesticides and the health condition of nestling ospreys (Pandion haliaetus) at Laguna San Ignacio, a pristine area of Baja California Sur, Mexico. AB - We identified and quantified organochlorine (OC) pesticide residues in the plasma of 28 osprey (Pandion haliaetus) nestlings from a dense population in Laguna San Ignacio, a pristine area of Baja California Sur, Mexico, during the 2001 breeding season. Sixteen OC pesticides were identified and quantified. alpha-, beta-, delta- and gamma-hexachlorocyclohexane, heptaclor, heptachlor epoxide, endosulfan I and II, endosulfan-sulfate, p,p'-DDE, p,p'-DDD, aldrin, dieldrin, endrin, endrin aldehyde, and endrin ketone were the OCs found in the plasma of nestlings, ranging from 0.002 to 6.856 pg/MUl (parts per billion). No differences were found in the concentration of pesticides between genders (P > 0.05). In our work, the concentrations detected in the plasma were lower than those reported to be a threat for the species and that affect the survival and reproduction of birds. The presence of OC pesticides in the remote Laguna San Ignacio osprey population is an indication of the ubiquitous nature of these contaminants. OCs are apparently able to travel long distances from their source to the study area. A significant relationship between hemoglobin and mean corpuscular hemoglobin concentrations and OC concentrations were found suggesting that a potential effect on the health of chicks may exist in this osprey population caused by the OC, e.g. anemia. The total proteins were positively correlated with alpha-BHC, endosulfan I, and p,p'-DDD. It has been suggested that OC also affects competitive interactions and population status over the long term in vertebrate species, and our results could be used as reference information for comparison with other more exposed osprey populations. PMID- 20949317 TI - Enhanced yield performance of Bt rice under target-insect attacks: implications for field insect management. AB - The rapid development of transgenic biotechnology has greatly promoted the breeding of genetically engineered (GE) rice in China, and many GE rice lines are in the pipeline for commercialization. To understand field performances of GE rice, key agronomic traits of two insect-resistant Bt rice lines that have been granted biosafety certificates for commercial production in China were evaluated together with their nontransgenic counterparts under environmental conditions with significant differences in insect pressure. Results from the experiments showed enhanced field performances of the Bt GE rice lines compared with the non GE counterparts for yield-related traits such as number of panicles and filled seeds per plant, under environmental conditions with no insecticide application. No detectable underlying cost of the Bt transgene was observed in the two insect resistant GE rice lines, particularly in the GE hybrid rice line. Results further indicated significantly greater yield performances of the two insect-resistant GE rice lines under environmental conditions with non-target insect control compared with no insect control. It is concluded from this study that insect-resistant Bt GE rice, particularly the hybrid line, has great potential to maintain its high yield when ambient insect pressure is high. In addition, proper application of insecticides to control non-target insects will guarantee optimal performance of insect-resistant Bt GE rice. PMID- 20949319 TI - Analysis of morphology of platelet aggregates formed on collagen under laminar blood flow. AB - In a focal injury model, platelets adhere and activate under flow on a collagen coated surface, creating a field of individual platelet aggregates. These aggregates exhibit distinct structural characteristics that are linked to the local flow conditions. By combining image analysis techniques and epifluorescence microscopy, we developed a robust strategy for quantifying the characteristic instantaneous width and length of a growing platelet deposit. We have confirmed the technique using model images consisting of ellipsoid objects and quantified the shear rate-dependent nature of aggregate morphology. Venous wall shear rate conditions (100 s(-1)) generated small, circular platelet deposits, whereas elevated arterial shear rates (500 and 1000 s(-1)) generated platelet masses elongated twofold in the direction of flow. At 2000 s(-1), an important regime for von Willebrand Factor (vWF)-mediated recruitment, we observed sporadic platelet capture events on collagen that led to rapidly growing deposits. Furthermore, inter-donor differences were investigated with respect to aggregate growth rate. After perfusion at elevated shear rates (1000 s(-1)) for 5 min, we identified a twofold increase in aggregate size (81.5 +/- 24.6 MUm; p < 0.1) and a threefold increase in growth rate parallel to the flow (0.40 +/- 0.09 MUm/s; p < 0.01) for an individual donor. Suspecting a role for vWF, we found that this donor had a twofold increase in soluble vWF relative to the other donors and pooled plasma. Microfluidic devices in combination with automated morphology analysis offer new tools for characterizing clot development under flow. PMID- 20949318 TI - Depressive symptoms and chronic kidney disease: results from the National Health and Nutrition Examination Survey (NHANES) 2005-2006. AB - BACKGROUND AND OBJECTIVE: Depression is common in individuals with end-stage renal disease. However, its relationship with earlier stages of chronic kidney disease (CKD) is less well known. In this study, we examined the association between depressive symptoms and CKD. METHODS: Cross-sectional analysis of the prevalence and correlates of depressive symptoms were measured by the Patient Health Questionnaire (PHQ-9) among adult participants with CKD in the National Health and Nutrition Examination Survey 2005-2006. CKD was defined according to estimated glomerular filtration rate by Modification of Diet in Renal Disease Study equation of <60 ml/min/1.73 m(2) or the presence of microalbuminuria (>= 30 mg/g creatinine), using the Kidney Disease Outcomes Quality Initiative classification. A PHQ-9 score >= 10 was considered to be indicative of depressive symptoms. RESULTS: Among 3653 subjects in our study sample, 683 (15.2%) met laboratory criteria for CKD. The prevalence of depressive symptoms was 7% (95% confidence interval [CI] 3.2-10.8%) in subjects with CKD and 6% (95% CI 4.6-7.4%) in subjects without CKD (P = 0.6). In regression analysis, the presence of CKD was not significantly associated with depressive symptoms (adjusted odds ratio = 0.96 [95% CI 0.51, 1.78], P = 0.9). CONCLUSIONS: We found no difference in the prevalence of depressive symptoms among individuals with or without CKD. PMID- 20949320 TI - Morphological evaluation of cell differentiation after the isolation of single cells by a femtosecond laser-induced impulsive force. AB - When nerve growth factor (NGF) is interacted with PC12 cells derived from rat pheochromocytoma, they are partially differentiated into neuron-like cells with neurites. In this work, PC12 cells differentiated by NGF were selectively isolated using a localized impulsive force in a MUm-scale area, which was generated by focusing an infrared femtosecond laser into a cell culture medium. In order to evaluate the ability of the isolation method, differentiated and undifferentiated cells were isolated and their morphological changes after the isolation were compared. In both cases, their neurites were once contracted and some of them gradually regenerated day by day. When differentiated cells were isolated, the percentage of differentiated cells with regenerated neurites, 6 h after the isolation, was about 3.3 times higher than that when undifferentiated ones were isolated. This result was compared with a control trypsin experiment. In the comparison, it was indicated that the same degree of cell function was maintained when the present isolation method was used. PMID- 20949321 TI - Bioethical concepts in theory and practice: an exploratory study of prenatal screening in Iceland. AB - A hallmark of good antenatal care is to respect prospective parent's choices and provide information in a way that encourages their autonomy and informed decision making. In this paper, we analyse the meaning of autonomous and informed decision making from the theoretical perspective and attempt to show how those concepts are described among prospective parents in early pregnancy and in the public media in a society where NT screening is almost a norm. We use interviews with Icelandic prospective parents in early pregnancy (N = 40) and material covering the discourse around prenatal screening in the media over 5 years period. Our analysis indicates that both prospective parents and the public media include ethical terms in their rhetoric around prenatal screening although those concepts differ in their expression. We conclude that the context in which these decisions are taken does not encourage moral reflection. Prospective parents describe that there is a lack of dialogue with professionals when decisions are made about screening. With routine offer of screening the conceptualization of bioethical concepts finds its own way through a mainstream discourse which has limited connections to the theoretical notions. This has been neglected in the implementation of screening, as limited effort has been subject to audit with reference to explore how the offer of screening and informed choice is experienced among prospective parents. PMID- 20949322 TI - Does lack of multinutrient supplementation during early pregnancy increase vulnerability to alcohol-related preterm or small-for-gestational-age births? AB - The objective of this study was to assess whether women who do not take multinutrient supplements during early pregnancy are more susceptible to the effects of low-to-moderate alcohol consumption on preterm birth and small-for gestational-age birth (SGA) compared to women who do take multinutrients. This analysis included 800 singleton live births to mothers from a cohort of pregnant women recruited for a population-based cohort study conducted in the Kaiser Permanente Medical Care Program in Northern California. Participants were recruited in their first trimester of pregnancy and information about their alcohol use and supplement intake during pregnancy was collected. Preterm birth (n=53, 7%) was defined as a delivery prior to 37 completed weeks of gestation and SGA birth (n=124, 16%) was defined as birth weight less than the 10th percentile for the infant's gestational age and sex compared to US singleton live births. A twofold increase in the odds of SGA birth attributed to low-to-moderate alcohol intake was found among multinutrient supplement non-users (95% CI: 1.1, 5.3). Yet, among multinutrient supplement users, there was no increased risk of an SGA birth for women who drank low-to-moderately compared to women who abstained (aOR: 0.97, 95% CI: 0.6, 1.6). Similar results emerged for preterm birth. Our findings provide marginal evidence that multinutrient supplementation during early pregnancy may modify the risk of SGA births and preterm birth associated with alcohol consumption during pregnancy and may have important implications for pregnant women and women of child-bearing age. However, future research needs to be conducted. PMID- 20949323 TI - Resveratrol enhances anti-proliferative effect of VACM-1/cul5 in T47D cancer cells. AB - Vasopressin-activated calcium-mobilizing (VACM-1) protein is a cul-5 gene product that forms complexes with a subclass of ubiquitin E3 ligases involved in proteasomal protein degradation. The expression of VACM-1 cDNA in the T47D breast cancer cell line inhibits growth and decreases phosphorylation of mitogen activated protein kinase. Factors that regulate expression or stability of VACM-1 protein have not been identified, however. In our search to identify drugs/substances that may control VACM-1 protein expression, we examined the effects of resveratrol (trans-3,5,4'-trihydroxystilbene), a natural component in the human diet which inhibits tumor initiation and promotion. CMV vector and VACM 1 cDNA stably transfected T47D breast cancer-derived cells were treated with resveratrol and cell growth and VACM-1 protein concentrations were measured. Since the cellular mechanism of resveratrol-dependent inhibition of cell growth also involves the regulation of estrogen receptors, the effect of 17-beta estradiol and resveratrol on ERalpha levels and on cell growth was examined in control and in VACM-1 cDNA transfected cells. Our results demonstrate that antiproliferative effect of resveratrol observed in the control T47D cancer cells was significantly enhanced in VACM-1 cDNA transfected T47D cells. Western blot results indicated that resveratrol increased VACM-1 protein concentration. Finally, treatment with resveratrol for 24 and 48 h attenuated 17-beta-estradiol induced increase in cell growth both in control and in VACM-1 cDNA transfected cells. The effect was significantly higher in the VACM-1 cDNA transfected cells when compared to controls. These results indicate that the antiproliferative effect of resveratrol may involve induction of VACM-1/cul5. PMID- 20949324 TI - Changing intraoperative parathyroid hormone collection sites from peripheral to central does not affect predictive accuracy during minimally invasive parathyroidectomy. AB - BACKGROUND: Intraoperative parathyroid hormone (ioPTH) monitoring (IPM) is vital to minimally invasive parathyroidectomy. Techniques vary in assay sampling, potentially affecting predictive accuracy of operative success. Initial guidelines were established using peripheral sites, but central sites may be preferred or necessary when peripheral access is not feasible. We hypothesize that changing collection sites from preexcision peripheral sites to postexcision central sites would not affect IPM accuracy. METHODS: Analysis of 64 consecutive patients who underwent parathyroidectomy for primary hyperparathyroidism was undertaken. PTH assays were collected simultaneously from a peripheral vein (PV) and central vein (CV) preexcision and at a 10-min interval after initial parathyroid excision. IPM success was defined as PTH decrease >=50% 10 min after initial excision. Predictive accuracy was determined by the need to resect another abnormal gland and biochemical normalization in the postoperative clinic. Receiver operating characteristic (ROC) method with area under the curve (AUC) compared diagnostic accuracy of different assay approaches. RESULTS: Centrally, a statistically higher mean pre- and postexcision ioPTH of 391 pg/ml and 58 pg/ml was found compared with peripheral means of 156 pg/ml and 49 pg/ml, respectively (p < 0.001). The AUC when changing from a PV preexcision to a CV postexcision ioPTH was 0.89, comparable to AUC for peripheral or central assay collections alone (AUC = 0.83 and 0.85, respectively). CONCLUSIONS: This study suggests that altering collection sites does not alter assay validity. In cases where peripheral sampling is compromised, changing from a peripheral to central sites will not likely alter the predictive accuracy of IPM significantly. PMID- 20949325 TI - The relationship between extravascular lung water and oxygenation in three patients with influenza A (H1N1)-induced respiratory failure. AB - This case series reports the correlation between extravascular lung water (EVLW) and the partial arterial oxygen pressure/fractional inspiratory oxygen (PaO(2)/FiO(2)) ratio in three patients with severe influenza A (H1N1)-induced respiratory failure. All patients suffered from grave hypoxia (PaO(2), 26-42 mmHg) and were mechanically ventilated using biphasic airway pressure (PEEP, 12 15 mmHg; FiO(2), 0.8-1) in combination with prone positioning at 12 hourly intervals. All patients were monitored using the PICCO system for 8-11 days. During mechanical ventilation, a total of 62 simultaneous determinations of the PaO(2)/FiO(2) ratio and EVLW were performed. A significant correlation between EVLW and the PaO(2)/FiO(2) ratio (Spearman-rho correlation coefficient, -0.852; p < 0.001) was observed. In all patients, a decrease in EVLW was accompanied by an improvement in oxygenation. Serum lactate dehydrogenase levels were elevated in all patients and significantly correlated with EVLW during the intensive care unit stay (Spearman-rho correlation coefficient, 0.786; p < 0.001). In conclusion, EVLW seems increased in patients with severe H1N1-induced respiratory failure and appears to be closely correlated with impairments of oxygenatory function. PMID- 20949326 TI - Rotator cable at MR imaging: considerations on morphological aspects and biomechanical role. AB - PURPOSE: The rotator cable (RC) is a thickening of the coracohumeral ligament. It extends from the coracohumeral ligament to the inferior border of the infraspinatus tendon, with fibres running perpendicularly to the rotator cuff fibres. According to some authors, the RC tends to thicken with age, thus allowing some individuals with a cuff lesion to preserve normal shoulder function. We evaluated the RC with magnetic resonance (MR) imaging and investigated its possible role in the biomechanics of the shoulder affected by cuff lesions. MATERIALS AND METHODS: Between November 2007 and May 2008, we performed shoulder MR examinations for shoulder pain or disability on 94 patients (46 males, 48 females; age range 16-79 years; mean age 54.09 +/- 15.09 years) for a total of 104 shoulders (62 right, 42 left). RESULTS: RC was more easily detectable in oblique coronal scans where it appeared as a crescent-shaped, regularly marginated structure adjacent to the articular surface of the supraspinatus tendon and medial to the insertion point of this tendon on the greater tuberosity. Its thickness was 2.8 +/- 0.3 mm. The structure was identified in 62% of cases (mean patient age 55.3 +/- 14.9 years). No statistically significant difference in age was found between patients with and without evidence of RC (Student's t test=0.05; p=0.82). Among patients with partial- or full-thickness supraspinatus tendon lesions at MR imaging, no statistically significant difference was found between the presence or absence of RC and disability on Jobe's test (chi(2)=1.17; p>0.05). CONCLUSIONS: RC can be observed at MR imaging in >60% cases. In our sample it did not seem to influence shoulder function in patients with cuff lesions. PMID- 20949327 TI - July spike in fatal medication errors. PMID- 20949329 TI - Jejunojejunal intussusception after Roux-en-Y gastric bypass: a review. AB - Small bowel intussusception is a rare long-term complication after Roux-en-Y gastric bypass, the etiology of which remains unclear. Except for one series reporting on 23 patients, case reports represent the vast majority of all cases reported so far. With this complete review of the world literature, based on a total of 63 patients including 2 of our own cases, we provide an extensive overview of the subject. The origin of intussusception after gastric bypass is different from that of intussusception of other causes, in that there is usually no lead point. It is likely related to motility disorders in the divided small bowel, especially in the Roux limb. This rare condition may cause obstruction and lead to bowel necrosis if not recognized and treated promptly. Clinical presentation is not specific. Computerized tomography scan represents the diagnostic test of choice, but surgery is sometimes the only way to establish the diagnosis. Treatment may be limited to reduction if the small bowel is viable, but resection of the affected segment is recommended on the basis of this review, since it seems to result in fewer recurrences. Knowledge of this entity and a high index of suspicion are required to make the correct diagnosis and offer appropriate treatment in a timely fashion. PMID- 20949330 TI - Vectors for glucose-dependent protein expression in Saccharomyces cerevisiae. AB - Based on the p426 series of expression vectors developed by Mumberg et al. (Gene 156, 119-122, 1995), we have generated a set of plasmids that allow the glucose dependent expression of target genes in the yeast, Saccharomyces cerevisiae. The ADH1 promoter in plasmid p426-ADH1 was replaced by the 1-kb 5'-region from either of the following genes: HXK1, YGR243, HXT4 and HXT7. Expression mediated by the respective 5'-regions was monitored with EGFP, yEGFP3-CLN2pest and TurboGFP as marker genes. Fluorescence is induced 2.7-fold using the HXK1, 2.3-fold using the YGR243-, 5-fold using the HXT7- and 12.6-fold using the HXT4 5'-regions upon depletion of glucose to a concentration of <0.5 g/l. PMID- 20949328 TI - Are physicians' recommendations for colorectal cancer screening guideline consistent? AB - BACKGROUND: Many older adults in the U.S. do not receive appropriate colorectal cancer (CRC) screening. Although primary care physicians' recommendations to their patients are central to the screening process, little information is available about their recommendations in relation to guidelines for the menu of CRC screening modalities, including fecal occult blood testing (FOBT), flexible sigmoidoscopy (FS), colonoscopy, and double contrast barium enema (DCBE). The objective of this study was to explore potentially modifiable physician and practice factors associated with guideline-consistent recommendations for the menu of CRC screening modalities. METHODS: We examined data from a nationally representative sample of 1266 physicians in the U.S. surveyed in 2007. The survey included questions about physician and practice characteristics, perceptions about screening, and recommendations for age of initiation and screening interval for FOBT, FS, colonoscopy and DCBE in average risk adults. Physicians' screening recommendations were classified as guideline consistent for all, some, or none of the CRC screening modalities recommended. Analyses used descriptive statistics and polytomous logit regression models. RESULTS: Few (19.1%; 95% CI:16.9%, 21.5%) physicians made guideline-consistent recommendations across all CRC screening modalities that they recommended. In multivariate analysis, younger physician age, board certification, north central geographic region, single specialty or multi-specialty practice type, fewer patients per week, higher number of recommended modalities, use of electronic medical records, greater influence of patient preferences for screening, and published clinical evidence were associated with guideline-consistent screening recommendations (p < 0.05). CONCLUSIONS: Physicians' CRC screening recommendations reflect both overuse and underuse, and few made guideline-consistent CRC screening recommendations across all modalities they recommended. Interventions that focus on potentially modifiable physician and practice factors that influence overuse and underuse and address the menu of recommended screening modalities will be important for improving screening practice. PMID- 20949331 TI - Transdermal nicotine replacement therapy in cigarette smokers with acute subarachnoid hemorrhage. AB - BACKGROUND: We evaluated the safety of nicotine replacement therapy (NRT) in active smokers with acute (aneurysmal) subarachnoid hemorrhage (SAH). METHODS: A retrospective observational cohort study was conducted in a prospectively collected database including all SAH patients admitted to an 18-bed neuro-ICU between January 1, 2001 and October 1, 2007. Univariate and multivariable models were constructed, employing stepwise logistic regression. The primary endpoint was 3-month mortality. Delayed cerebral ischemia (DCI) due to vasospasm, angiographic and TCD evidence of vasospasm, and delirium were secondary endpoints. RESULTS: Active cigarette smokers admitted with SAH included 128 that received NRT and 106 that did not. Patients were well-matched for age, admission Hunt-Hess Grade, radiographic findings, and APACHE II scores, but those who received NRT were more likely to be heavy smokers (>10 cigarettes daily), diabetic, heavy alcohol users, and to have cerebral edema on admission. NRT was associated in multivariate analysis with a lower risk of death at 3 months (OR 0.12, 95% CI 0.04-0.37, P < 0.001). There were no differences in the frequency of DCI and most other medical complications, but delirium (19 vs. 9%, P = 0.006) and seizures (9 vs. 2%, P = 0.024) were more common in patients who received NRT. CONCLUSIONS: Despite vasoactive properties, administration of NRT among active smokers with acute SAH appeared to be safe, with similar rates of vasospasm and DCI, and a slightly higher rate of seizures. The association of NRT with lower mortality could be due to chance, to uncontrolled factors, or to a neuroprotective effect of nicotine in active smokers hospitalized with SAH, and should be tested prospectively. PMID- 20949332 TI - Beyond gastritis and before cancer: the strange case of Menetrier's disease. PMID- 20949333 TI - Time intervals and myocardial performance index by tissue Doppler imaging. AB - The application of tissue Doppler imaging (TDI) has shown remarkable growth in clinical practice during the past few years, especially, in risk stratification of patients with coronary heart disease or heart failure (systolic and diastolic). Myocardial performance index (MPI) is a Doppler echocardiographic parameter defined as the sum of the isovolemic contraction and relaxation times divided by the ejection time. It is considered as a reliable parameter to assess global left ventricular function. Cardiac time intervals and MPI have also been found as new applications in diagnosing cardiotoxicity from chemotherapy, COPD, valvular heart disease, pulmonary hypertension and endocrinopathies. PMID- 20949334 TI - T(1;21;8)(p34;q22;q22): a novel variant of t(8;21) in acute myeloblastic leukemia with maturation. AB - The complex variants of t(8;21) involving chromosomes 8 and 21 as well as another chromosome account for approximately 3% of acute myeloid leukemia patients. We report here a 30-year-old male patient with AML-M2. Fluorescence in situ hybridization analysis using dual-color fluorescence ETO and AML1 probes located at 8q22 and 21q22 respectively showed an AML1/ETO fusion signal on the derivative chromosome 8. Whole chromosome painting probes were used for chromosome 1, 8 and 21 and revealed a three-way translocation (1;21;8)(p34 ~ p35;q22;q22). Involvement of chromosome region 1p34 has never been reported earlier, although region 1p35 as a variant in AML with t(8;21) has been reported with an AML1/ETO fusion signal on the 1p35 rather than der(8). In conclusion, combining conventional karyotype, FISH or RT-PCR analyses are a rational strategy for the identification of the complex variants of t(8;21) translocation which could be critical events responsible for leukemogenesis. PMID- 20949335 TI - Nitazoxanide use in rota viral diarrhea. Cure or controversy? PMID- 20949336 TI - Surgical treatment of Kawasaki disease with intestinal pseudo-obstruction. AB - A 5-year-old boy suffering from abdominal pain accompanied by a fever of up to 39.5 degrees C for 2 days was admitted to the hospital. Although Flomoxef was administered following admission, the boy's fever persisted and abdominal distension gradually worsened. On the 4th day, dry lips, red eyes and a strawberry tongue were noted. An echocardiogram revealed pericoronary enhancement with mild mitral valve regurgitation and a small degree of pericardial effusion, characteristics compatible with Kawasaki disease. Although intravenous immunoglobulin was administered, the fever and abdominal distension persisted. On the 8th day, a pediatric surgeon was consulted and an exploratory laparotomy was arranged. During the operation, intestinal pseudo-obstruction and fibrin coatings around the intestine near the splenic flexure were found. A colostomy was performed for decompression of the dilated bowel and a biopsy of the lymph node surrounding the splenic flexure was taken. The fever subsided dramatically after decompression of the bowel and the recovery course was uneventful. The pathologic report revealed necrotic lymphadenitis. We report this rare case and review the literature. PMID- 20949337 TI - Prophylactic citalopram treatment in hepatitis C patients on antiviral therapy: Will it limit drug-induced depression and enhance adherence? PMID- 20949338 TI - The role of percutaneous renal biopsy in the management of small renal masses. AB - The use of percutaneous renal mass biopsy (RMB) has increased in recent years, likely in parallel with the growing incidence of renal cell carcinoma and small renal masses in particular. Biopsy and imaging techniques are improving, and diagnostic sufficiency and accuracy of RMB now are much higher in large-volume, experienced centers. Overall morbidity is low. This has led to a significant expansion of the indications for biopsy beyond documenting renal involvement for patients with metastatic disease or other systemic illnesses. While there still are limitations to its use and clinical judgment is paramount, RMB is proving to be a valuable tool in the clinical diagnosis and management of small renal masses. PMID- 20949339 TI - Contemporary imaging of the renal mass. AB - Renal masses increasingly are detected incidentally in asymptomatic individuals. Accurate characterization of these lesions is important for clinical management, planning intervention, and avoiding unnecessary procedures. Ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) are the mainstays of renal mass detection and characterization. Ultrasonography is useful for distinguishing cystic from solid lesions and can detect lesion vascularity, especially with use of ultrasound contrast agents, but is less sensitive, less specific, and less reproducible than CT and MRI. CT, with and without intravenous contrast, is the primary imaging test for characterization and staging of renal lesions, and is utilized more often than MRI. Current multidetector CT technology provides near isotropic acquisition, with three-dimensional reformatting capabilities. Due to lack of exposure to iodinated contrast and ionizing radiation and superior soft tissue contrast, MRI is being increasingly utilized as a problem-solving tool for diagnosis, staging, and preoperative planning for renal malignancies. Future directions for imaging of primary renal neoplasm include accurate characterization of renal cell cancer subtype, assistance with treatment planning, and evaluation of treatment response. PMID- 20949340 TI - Real-life dosage and clinical efficacy of biphasic insulin preparations in patients with type 2 diabetes. AB - INTRODUCTION: This retrospective study used data from a primary care database to compare two insulin products in routine clinical practice for the treatment of type 2 diabetes in the UK. PATIENTS AND METHODS: Records were analyzed for patients with type 2 diabetes who had been initiated on biphasic insulin aspart 30 (BIAsp30) (n=632) or biphasic isophane human insulin 30 (BHI30) (n=762) and who had a glycated hemoglobin (HbA1(c)) measurement at baseline (up to 6 months before the index date) and end of study (6-12 months after index date). Regression analyses were used to test for a statistically significant interaction between reduction in HbA1(c) from baseline to end of study and the log transformed average daily dose (logADD) of insulin. RESULTS: With BIAsp30 a significantly lower dose of insulin (47.74 insulin units [IU]/day vs. 66.63 IU/day, P<0.0001) was required to obtain a similar HbA1(c) reduction (1.71%-point vs. 1.55%-point, P=0.24). To achieve an additional reduction of 0.1 percentage points in HbA1(c) (eg, reduction from 9% to 7.9% HbA1(c) instead of from 9% to 8%), the dose of BIAsp30 would need to be increased by a factor of 1.15. For BHI30, a greater increase in dose would be needed to achieve the same additional HbA1(c) reduction (dose increase by a factor of 1.74). CONCLUSION: Clinically meaningful reductions in HbA1(c) can be achieved at lower insulin doses with BIAsp30 treatment than with BHI30. Lower insulin doses may have important implications for medication costs. PMID- 20949341 TI - Food effects on the pharmacokinetics of morphine sulfate and naltrexone hydrochloride extended release capsules. AB - INTRODUCTION: Morphine sulfate and naltrexone hydrochloride extended release capsules, indicated for chronic moderate-to-severe pain, contain extended-release morphine pellets with a sequestered naltrexone core. If pellets are tampered by crushing, naltrexone is released to reduce morphine-induced effects that appeal to opioid abusers. The primary objective of this study was to assess single-dose relative bioavailability of morphine when morphine sulfate and naltrexone hydrochloride extended release capsules were taken under fed and fasting conditions and when pellets were sprinkled on apple sauce. METHODS: This was a single-center, randomized, open-label study in 36 healthy adult volunteers. Subjects took a 100-mg morphine sulfate and naltrexone hydrochloride extended release capsule intact with 240 mL water, under fed and fasted conditions, and when the capsule was opened and pellets were sprinkled over apple sauce and consumed without chewing; each treatment was separated by a 14-day washout. Plasma samples were collected just before dosing through 72 hours postdose for pharmacokinetic analyses of morphine, and through 168 hours postdose for naltrexone and its major metabolite 6-beta-naltrexol. RESULTS: Morphine bioavailability was similar for all treatments. There was a lack of sprinkle effect (sprinkle vs. whole, fasted); 90% confidence intervals (CIs) of ratios of log-transformed least squares means for area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) fell within 80%-125% boundaries. For the food effect, 90% CIs were within the boundaries for AUC, but C(max) was reduced and time to C(max) was delayed by 2.5 hours under fed conditions. Naltrexone remained sequestered under all treatment conditions with only trace systemic exposure. CONCLUSION: Results indicated that morphine sulfate and naltrexone hydrochloride extended release capsules can be administered without regard to meals, and contents can be sprinkled over apple sauce and consumed without chewing by patients with difficulty swallowing. PMID- 20949343 TI - [Upper airway management in a patient with an asymptomatic laryngeal cyst]. PMID- 20949342 TI - The influence of social-cognitive factors on personal hygiene practices to protect against influenzas: using modelling to compare avian A/H5N1 and 2009 pandemic A/H1N1 influenzas in Hong Kong. AB - BACKGROUND: Understanding population responses to influenza helps optimize public health interventions. Relevant theoretical frameworks remain nascent. PURPOSE: To model associations between trust in information, perceived hygiene effectiveness, knowledge about the causes of influenza, perceived susceptibility and worry, and personal hygiene practices (PHPs) associated with influenza. METHODS: Cross sectional household telephone surveys on avian influenza A/H5N1 (2006) and pandemic influenza A/H1N1 (2009) gathered comparable data on trust in formal and informal sources of influenza information, influenza-related knowledge, perceived hygiene effectiveness, worry, perceived susceptibility, and PHPs. Exploratory factor analysis confirmed domain content while confirmatory factor analysis was used to evaluate the extracted factors. The hypothesized model, compiled from different theoretical frameworks, was optimized with structural equation modelling using the A/H5N1 data. The optimized model was then tested against the A/H1N1 dataset. RESULTS: The model was robust across datasets though corresponding path weights differed. Trust in formal information was positively associated with perceived hygiene effectiveness which was positively associated with PHPs in both datasets. Trust in formal information was positively associated with influenza worry in A/H5N1 data, and with knowledge of influenza cause in A/H1N1 data, both variables being positively associated with PHPs. Trust in informal information was positively associated with influenza worry in both datasets. Independent of information trust, perceived influenza susceptibility associated with influenza worry. Worry associated with PHPs in A/H5N1 data only. CONCLUSIONS: Knowledge of influenza cause and perceived PHP effectiveness were associated with PHPs. Improving trust in formal information should increase PHPs. Worry was significantly associated with PHPs in A/H5N1. PMID- 20949344 TI - [Probable basidiobolomycosis in a Togolese rural young successfully treated with ketoconazole]. AB - Basidiobolomycosis is a deep mycosis which preferentially affects rural young people in tropical countries. We report a case of basidiobolomycosis successfully treated with ketoconazole. It was a 9-year-old boy of rural origin in whom the diagnosis of basidiobolomycosis was suspected due to a deep skin infiltration involving the chest and neck. Histology revealed hypodermic granulomatous inflammation with predominantly macrophage and eosinophils. The child was treated successfully with ketoconazole in eight weeks. Treatment of basidiobolomycosis is based on azole derivatives which are particularly effective. Histopathology is very important in the diagnosis of this affection, especially in tropical countries where it may simulate Mycobacterium ulcerans infection. PMID- 20949346 TI - [Radiation hygiene in medical X-ray imaging: part 2: Assessment of radiation exposure and radiation protection measures]. AB - In order to secure and continually improve radiation protection standards in the field of medical X-ray imaging, the German X-Ray Ordinance requires that each individual examination be properly justified and that any procedure undertaken be optimized. Diagnostic reference levels have been introduced in Germany as a measure of optimization for common and/or high-dose X-ray procedures, and are regularly checked for compliance by the competent Medical Experts Office. A prerequisite for the implementation of these regulatory requirements is the determination of readily measurable dose quantities. They also form the basis for the estimation of organ doses and of the effective dose for exposure and risk assessment. The aim of this paper is to describe the essential dosimetric concepts and methods used for the assessment of radiographic, fluoroscopic, and CT procedures. In addition, practical measures for reducing the radiation exposure of patients and personnel will be discussed. PMID- 20949348 TI - The dicarboxylate carrier plays a role in mitochondrial malate transport and in the regulation of glucose-stimulated insulin secretion from rat pancreatic beta cells. AB - AIMS/HYPOTHESIS: We have previously described a strong correlation between pyruvate cycling and insulin secretion. We have also demonstrated a particularly important role for a pyruvate-isocitrate cycling pathway involving the mitochondrial citrate/isocitrate carrier (CIC) and cytosolic NADP-dependent isocitrate dehydrogenase. CIC requires cytosolic malate as a counter-substrate during citrate and isocitrate export. Thus, considering that the mitochondrial dicarboxylate carrier (DIC) provides an important source of cytosolic malate, we investigated the potential role of DIC in control of glucose-stimulated insulin secretion (GSIS). METHODS: We used pharmacological and small interfering RNA (siRNA) tools to assess the role of DIC in insulin release in clonal insulin secreting 832/13 cells and isolated rat islets. RESULTS: Butylmalonate, an inhibitor of malate transport, reduced cytosolic malate and citrate levels, and inhibited GSIS in a dose-dependent manner in 832/13 cells. Suppression of DIC expression resulted in inhibition of GSIS by 5% to 69%, the extent of inhibition of insulin secretion being proportional to the level of Dic (also known as Slc25a10) gene knockdown. The most effective siRNA duplex against Dic did not affect glucose utilisation, glucose oxidation or ATP/ADP ratio, but did suppress glucose-induced increments of the NADPH/NADP(+) ratio. Confirmation of our results in primary cultures of isolated rat islets showed that butylmalonate and an adenovirus expressing an siRNA against Dic-inhibited GSIS. CONCLUSIONS/INTERPRETATION: Malate transport by DIC may play an important role in GSIS, possibly by providing cytosolic malate as a counter-substrate for citrate and/or isocitrate export by CIC. These studies also suggest that malate transport by DIC is (1) a critical component of NADPH production mediated by pyruvate cycling and (2) regulates GSIS. PMID- 20949349 TI - Effects of norepinephrine on renal perfusion, filtration and oxygenation in vasodilatory shock and acute kidney injury. AB - PURPOSE: The use of norepinephrine (NE) in patients with volume-resuscitated vasodilatory shock and acute kidney injury (AKI) remains the subject of much debate and controversy. The effects of NE-induced variations in mean arterial blood pressure (MAP) on renal blood flow (RBF), oxygen delivery (RDO(2)), glomerular filtration rate (GFR) and the renal oxygen supply/demand relationship (renal oxygenation) in vasodilatory shock with AKI have not been previously studied. METHODS: Twelve post-cardiac surgery patients with NE-dependent vasodilatory shock and AKI were studied 2-6 days after surgery. NE infusion rate was randomly and sequentially titrated to target MAPs of 60, 75 and 90 mmHg. At each target MAP, data on systemic haemodynamics, RBF, GFR and renal oxygen extraction were obtained by pulmonary artery catheter, by the renal vein thermodilution technique and by renal extraction of (51)Cr-ethylenediamine tetraacetic acid ((51)Cr-EDTA), respectively. RESULTS: At target MAP of 75 mmHg, RDO(2) (13%), GFR (27%) and urine flow were higher and renal oxygen extraction was lower (-7.4%) compared with at target MAP of 60 mmHg. However, the renal variables did not differ when compared at target MAPs of 75 and 90 mmHg. Cardiac index increased dose-dependently with NE. CONCLUSIONS: Restoration of MAP from 60 to 75 mmHg improves renal oxygen delivery, GFR and the renal oxygen supply/demand relationship in post-cardiac surgery patients with vasodilatory shock and AKI. This pressure-dependent renal perfusion, filtration and oxygenation at levels of MAP below 75 mmHg reflect a more or less exhausted renal autoregulatory reserve. PMID- 20949350 TI - Sildenafil adjunctive therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled trial. AB - RATIONAL: It has been suggested that phosphodiesterase 5 inhibitors such as sildenafil may be effective in the treatment of negative symptoms of schizophrenia. OBJECTIVE: This study was designed to investigate the effect of sildenafil added to risperidone as augmentation therapy in patients with chronic schizophrenia and prominent negative symptoms in a double-blind and randomized clinical trial. METHODS: Eligible participants in the study were 40 patients with chronic schizophrenia with ages ranging from 18 to 45 years. All patients were inpatients and were in the active phase of the illness and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion: 20 to risperidone (6 mg/day) plus sildenafil (75 mg/day) and 20 to risperidone (6 mg/day) plus placebo. The principal measure of outcome was Positive and Negative Syndrome Scale (PANSS). RESULTS: Although both protocols significantly decreased the score of the positive, negative, and general psychopathological symptoms over the trial period, the combination of risperidone and sildenafil showed a significant superiority over risperidone alone in decreasing negative symptoms and PANSS total scores over the 8-week trial (between-subjects factor; F = 4.77, df = 1; P = 0.03; F = 5.91, df = 1, P = 0.02 respectively). CONCLUSION: Therapy with 75 mg/day of sildenafil was well tolerated, and no clinically important side effects were observed. The present study indicates sildenafil as a potential adjunctive treatment strategy for treatment of negative symptoms of schizophrenia. This trial is registered with the Iranian Clinical Trials Registry (IRCT1138901151556N11). PMID- 20949352 TI - The extent of arsenic and of metal uptake by aboveground tissues of Pteris vittata and Cyperus involucratus growing in copper- and cobalt-rich tailings of the Zambian copperbelt. AB - The extent of arsenic (As) and metal accumulation in fronds of the As hyperaccumulator Pteris vittata (Chinese brake fern) and in leaves of Cyperus involucratus, which grow on the surface of an old flotation tailings pond in the Zambian Copperbelt province, was studied. The tailings consist of two types of material with distinct chemical composition: (1) reddish-brown tailings rich in As, iron (Fe), and other metals, and (2) grey-green tailings with a lower content of As, Fe, and other metals, apart from manganese (Mn). P. vittata accumulates from 2350 to 5018 MUg g(-1) As (total dry weight [dw]) in its fronds regardless of different total and plant-available As concentrations in both types of tailings. Concentrations of As in C. involucratus leaves are much lower (0.24 30.3 MUg g(-1) dw). Contents of copper (Cu) and cobalt (Co) in fronds of P. vittata (151-237 and 18-38 MUg g(-1) dw, respectively) and in leaves of C. involucratus (96-151 and 9-14 MUg g(-1) dw, respectively) are high, whereas concentrations of other metals (Fe, Mn, and zinc [Zn]) are low and comparable with contents of the given metals in common plants. Despite great differences in metal concentrations in the two types of deposited materials, concentrations of most metals in plant tissues are very similar. This indicates an exclusion or avoidance mechanism operating when concentrations of the metals in substrate are particularly high. The results of the investigation show that Chinese brake fern is not only a hyperaccumulator of As but has adapted itself to high concentrations of Cu and Co in flotation tailings of the Zambian Copperbelt. PMID- 20949351 TI - Prenatal stress: role in psychotic and depressive diseases. AB - RATIONALE: The birth of neurons, their migration to appropriate positions in the brain, and their establishment of the proper synaptic contacts happen predominately during the prenatal period. Environmental stressors during gestation can exert a major impact on brain development and thereby contribute to the pathogenesis of neuropsychiatric illnesses, such as depression and psychotic disorders including schizophrenia. OBJECTIVE: The objectives here are to present recent preclinical studies of the impact of prenatal exposure to gestational stressors on the developing fetal brain and discuss their relevance to the neurobiological basis of mental illness. The focus is on maternal immune activation, psychological stresses, and malnutrition, due to the abundant clinical literature supporting their role in the etiology of neuropsychiatric illnesses. RESULTS: Prenatal maternal immune activation, viral infection, unpredictable psychological stress, and malnutrition all appear to foster the development of behavioral abnormalities in exposed offspring that may be relevant to the symptom domains of schizophrenia and psychosis, including sensorimotor gating, information processing, cognition, social function, and subcortical hyperdopaminergia. Depression-related phenotypes, such as learned helplessness or anxiety, are also observed in some model systems. These changes appear to be mediated by the presence of proinflammatory cytokines and/or corticosteroids in the fetal compartment that alter the development the neuroanatomical substrates involved in these behaviors. CONCLUSION: Prenatal exposure to environmental stressors alters the trajectory of brain development and can be used to generate animal preparations that may be informative in understanding the pathophysiological processes involved in several human neuropsychiatric disorders. PMID- 20949353 TI - Genomic plasticity of the MHC class I A region in rhesus macaques: extensive haplotype diversity at the population level as revealed by microsatellites. AB - The Mamu-A genes of the rhesus macaque show different degrees of polymorphism, transcription level variation, and differential haplotype distribution. Per haplotype, usually one "major" transcribed gene is present, A1 (A7), in various combinations with "minor" genes, A2 to A6. In silico analysis of the physical map of a heterozygous animal revealed the presence of similar Mamu-A regions consisting of four duplication units, but with dissimilar positions of the A1 genes on both haplotypes, and in combination with different minor genes. Two microsatellites, D6S2854 and D6S2859, have been selected as potential tools to characterize this complex region. Subsequent analysis of a large breeding colony resulted in the description of highly discriminative patterns, displaying copy number variation in concert with microsatellite repeat length differences. Sequencing and segregation analyses revealed that these patterns are unique for each Mamu-A haplotype. In animals of Indian, Burmese, and Chinese origin, 19, 15, or 9 haplotypes, respectively, could be defined, illustrating the occurrence of differential block duplications and subsequent rearrangements by recombination. The haplotypes can be assigned to 12 unique combinations of genes (region configurations). Although most configurations harbor two transcribed A genes, one or three genes per haplotype are also present. Additionally, haplotypes lacking an A1 gene or with an A1 duplication appear to exist. The presence of different transcribed A genes/alleles in monkeys from various origins may have an impact on differential disease susceptibilities. The high-throughput microsatellite technique will be a valuable tool in animal selection for diverse biomedical research projects. PMID- 20949354 TI - Heart surgery in patients on chronic dialysis: is there still room for improvement in early and long-term outcome? AB - The purpose of this study was to review the outcome of dialysis-dependent patients undergoing cardiac surgery. We retrospectively reviewed 81 dialysis dependent patients with a mean age of 62.5 +/- 9.4 years who underwent cardiac operations. Mean EuroScore was 7.1 +/- 3.9 (>9 in 18 patients). Surgery included coronary artery bypass grafting (CABG) in 43 patients (53.1%), valve surgery in 16 (19.7%), combined CABG plus valve surgery in 19 (23.5%) and major aortic surgery in three patients. In-hospital mortality rate was 13.6%. Most of the deaths occurred in patients who underwent valve procedures or combined surgery. Preoperative New York Heart Association class IV, previous acute myocardial infarction, combined surgical procedures, major aortic surgery, age >70 years, history of heart failure, female gender, the duration of dialysis >= 5 years and urgent/emergent surgery were associated with high relative risk for perioperative death. The actuarial survival was 72.2% at 5 years. Predictors of increased late mortality were heart failure, urgent/emergent surgery, the complexity of the surgical procedures (valve surgery, combined CABG + valve and major aortic surgery) and postoperative low cardiac output syndrome. In dialysis-dependent patients, CABG has an acceptable risk. Results in patients affected by valve lesions associated or not with coronary artery disease are improved by an early referral to surgery, before the onset of symptoms of heart failure. PMID- 20949355 TI - Endothelial dysfunction in young patients with acute ST-elevation myocardial infarction. AB - Endothelial dysfunction may be particularly important in the pathogenesis of young patients with acute myocardial infarction (AMI), because they have different clinical characteristics compared with older patients. We investigated endothelial function in relation to AMI in this young age group. From January 2005 to March 2008, 29 of 31 consecutive patients with acute ST-elevation myocardial infarction (STEMI) who were <40 years old and received direct percutaneous coronary intervention (PCI) were enrolled in the study. We compared the coronary risk factors and flow-mediated vasodilation (FMD) in the brachial artery between the acute STEMI patients and 29 age- and gender-matched controls that did not have AMI. Baseline brachial artery diameter and responses to glyceryl trinitrate were similar between the two groups. In contrast, FMD was significantly lower in the young acute STEMI group than in the control (3.47 +/- 4.08 vs. 7.45 +/- 4.67%, p = 0.001) and correlated with the Thrombolysis in Myocardial Infarction (TIMI) risk score. The impaired FMD in the acute STEMI group was independent of smoking, hyperlipidemia, hypertension, nitrate use, or body mass index. In multiple logistic regression analysis, only FMD and age, not traditional cardiovascular risk factors, were found to be significantly associated with acute STEMI (odds ratio = 0.75, 95% CI 0.63-0.90, p < 0.01). In conclusion, independent of conventional risk factors, severe endothelial dysfunction occurs in young acute STEMI patients and correlates with TIMI score. In addition to age, impaired FMD is the only significant factor associated with acute STEMI in this young population. PMID- 20949356 TI - The effect of cold stress on polycystic ovary syndrome in rat: before and during modeling. AB - PURPOSE: The aim of this study was the evaluation effects of a chronic intermittent cold stress regimen before and during PCO modeling in rat. METHODS: Forty-eight rats were treated with estradiol valerate for 60 days in order to induction of follicular cysts (PCO modeling). Rats were divided into two groups: (1) before (cold stress 3 weeks then PCO modeling) and (2) during modeling (cold stress and PCO simultaneous). RESULTS: The biochemical and histological findings show that in simultaneous cold stress and estradiol injection group PCOS modeling has been done successfully and in the other group cold stress prevents induction of PCO in rats. CONCLUSION: The present study is the first survey that reports 3 week chronic stress before estradiol injection prevents the induction of PCO in rats. PMID- 20949357 TI - Extraovarian conditions mimicking ovarian cancer: a single center experience of 15 years. AB - OBJECTIVE: This study aims to review cases of extra-ovarian conditions that resembled ovarian malignancy and thus, to evaluate the distribution of primary pathology mimicking ovarian malignancy. METHODS: A retrospective review of women, with final pathology of extra-ovarian diseases mimicking ovarian malignancy, which were managed at Zekai Tahir Burak Women's Health Education and Research Hospital, from January 1995 to April 2010 was undertaken. RESULTS: Among the 2,210 women treated during the study period, extra-ovarian diseases accounted for 5.11% (113/2,210) of all the cases. Of the 113 extra-ovarian diseases, 42 (37.17%) were peritoneal tuberculosis, 25 (22.13%) were gastrointestinal malignancies, 20 (17.70%) were pelvic abscess, 8 (7.08%) were pelvic echinococcosis, 8 (7.08) were schwannoma and other retroperitoneal tumors, 4 (3.53%) were malignant lymphoma, 2 (1.77%) were chronic ectopic pregnancy, gossypiboma, and mesenteric cyst, respectively. CONCLUSION: Medical awareness of infectious diseases such as peritoneal tuberculosis, pelvic abscess, and pelvic echinococcosis in the differential diagnosis of ovarian malignancy is still lacking, especially in developing countries. In addition, in case of a pelvic mass, gastrointestinal and retroperitoneal tumors and malignant lymphoma should always be considered to avoid pitfalls in diagnosis and therapy. PMID- 20949358 TI - Does primary breast cancer in older women (>=80 years) have unfavorable histological characteristics? AB - INTRODUCTION: Although the majority of breast cancer patients are older than 65 years, limited data exist regarding the pathological features in very elderly patients. The aim of this study was to evaluate the histological characteristics of breast cancer in women aged over 80 years. METHODS: The histological data were reviewed for 137 women aged 80 years and older who were diagnosed with primary breast carcinoma at a university clinic during the period 1990-2005. RESULTS: Although it is believed that older women have more advanced tumor, the majority of the tumors were assessed as stage I (35%) and II (32.9%). Mucinous, papillary, medullary, tubular, and cribriform histological subtypes have been demonstrated often in this age group (16.8%). In 49.7 and 70.6% of cases, respectively, there were no regional lymph node metastases and no distant metastases. The frequency of ER-positive (72%) and PR-positive (56%) tumors in these patients is high. CONCLUSIONS: An accurate prognostic evaluation at the time of initial diagnosis is of high importance for older patients, since this could avoid unnecessary and risky therapies. As an increasing number of women >=80 years old may be diagnosed with breast cancer in the coming years, treatment in this specific age group should be individualized to the patient and tumor factors. PMID- 20949359 TI - Intervention in at-risk states for developing psychosis. AB - Indicated prevention is currently one of the most promising approaches to fight the individual and societal burden associated with psychosis and particularly schizophrenia. The number of studies is still limited, yet encouraging results have been reported from pharmacological and psychotherapeutic trials. Furthermore, it has become clear that persons characterized by the at-risk criteria are already ill and do not only need preventive intervention but also treatment. As is indicated by a recent study successfully using omega-3 fatty acids for both purposes, it may be promising to develop and investigate interventions especially for the at-risk state, independent of their effectiveness in manifest disease states. An overview on the current findings and ongoing research in this area is provided. PMID- 20949360 TI - Evaluation of the thermal insulation of clothing of infants sleeping outdoors in Northern winter. AB - It is a common practice in Northern countries that children aged about 2 weeks to 2 years take their daytime sleep outdoors in prams in winter. The aim was to evaluate the thermal insulation of clothing of infants sleeping outdoors in winter. Clothing data of infants aged 3.5 months was collected, and sleep duration, skin and microclimate temperatures, humidity inside middle wear, air temperature and velocity of the outdoor environment were recorded during sleep taken outdoors (n = 34) and indoors (n = 33) in families' homes. The insulation of clothing ensembles was measured by using a baby-size thermal manikin, and the values were used for defining clothing insulation of the observed infants. Required clothing insulation for each condition was estimated according to ISO 11079. Clothing insulation did not correlate with ambient air temperature. The observed and required insulation of the study group was equal at about -5 degrees C, but overdressing existed in warmer and deficiency in thermal insulation in colder temperatures (r (s) 0.739, p < 0.001). However, even at -5 degrees C a slow cooling (ca. 0.012 degrees C/min) of mean skin temperature (T (sk)) was observed. When the difference between observed and required insulation increased, the cooling rate of T (sk) increased linearly (r (s) 0.605, p < 0.001) and the infants slept for a shorter period (r (s) 0.524, p = 0.001). The results of this study show the difficulty of adjusting systematically the optimal thermal insulation for outdoor sleeping infants during northern winter. Therefore, the necessity for guidelines is obvious. The study provides information for adequate cold protection of infants sleeping in cold conditions. PMID- 20949362 TI - Symptoms, psychological distress, and supportive care needs in lung cancer patients. AB - PURPOSE: The purpose of this study was to examine the level of symptoms, psychological distress, and supportive care needs and factors related to five unmet need domains in lung cancer patients. METHODS: A cross-sectional study of 152 lung cancer patients at a medical center in Taiwan assessed their symptoms, psychological distress, and unmet supportive needs in five major care domains. Logistic regression was applied to examine the related factors of unmet supportive care needs. RESULTS: In general, patients had mild-to-moderate levels of symptoms and high prevalence of psychological distress. Regardless of their treatment status, they reported high levels of supportive care needs. The top three need domains were: (1) health system and information, (2) psychological, and (3) patient care and support. Levels of symptoms, anxiety, and depression were the most significant factors in unmet supportive care needs. CONCLUSION: The effect of symptoms and psychological distress on unmet supportive care needs is substantial. Therefore, a systematic assessment of patients' distress and care needs is important for clinical lung cancer care. Further intervention consisting of symptom management, continuing counseling, and preparation for transition from active treatment to the follow-up stages are essential in improving quality of care. PMID- 20949361 TI - Changes in gene expression of DOR and other thyroid hormone receptors in rat liver during acute-phase response. AB - Non-thyroidal illness is characterized by low tri-iodothyronine (T3) serum level under acute-phase conditions. We studied hepatic gene expression of the newly identified thyroid hormone receptor (TR) cofactor DOR/TP53INP2 together with TRs in a rat model of aseptic abscesses induced by injecting intramuscular turpentine oil into each hind limb. A fast (4-6 h) decrease in the serum level of free thyroxine and free T3 was observed. By immunohistology, abundant DOR protein expression was detected in the nuclei of hepatocytes and ED-1(+) (mononuclear phagocytes), CK-19(+) (biliary cells), and SMA(+) (mesenchymal cells of the portal tract) cells. DOR signal was reduced with a minimum at 6-12 h after the acute-phase reaction (APR). Immunohistology also showed a similar pattern of protein expression in TRalpha1 but without a significant change during APR. Transcripts specific for DOR, nuclear receptor co-repressor 1 (NCoR-1), and TRbeta1 were down-regulated with a minimum at 6-12 h, whereas expression for TRalpha1 and TRalpha2 was slightly and significantly up-regulated, respectively, with a maximum at 24 h after APR was initiated. In cultured hepatocytes, acute phase cytokines interleukin-1beta (IL-1beta) and IL-6 down-regulated DOR and TRbeta1 at the mRNA level. Moreover, gene expression of DOR and TRs (TRalpha1, TRalpha2, and TRbeta1) was up-regulated in hepatocytes by adding T3 to the culture medium; this up-regulation was almost completely blocked by treating the cells with IL-6. Thus, TRbeta1, NCoR-1, and the recently identified DOR/TP53INP2 are abundantly expressed and down-regulated in liver cells during APR. Their down regulation is attributable to the decreased serum level of thyroid hormones and most probably also to the direct action of the main acute-phase cytokines. PMID- 20949363 TI - Advanced glycation endproducts and their pathogenic roles in neurological disorders. AB - Glycation is implicated in neurological disorders. In some cases it plays a key role in the pathogenesis, in others it plays a co-adjuvant role or it appears as a consequence of degenerative changes and protein accumulation stemming from other pathways. In this work, we attempt to provide a concise, updated review of the major recent findings concerning glycation in neurological diseases. After a short introduction covering advanced glycation endproducts (AGEs) and the receptor for AGEs (RAGE), we will discuss the impact of glycation in central nervous system disorders including Alzheimer's, Parkinson's and Creutzfeldt-Jakob disease, as well as peripheral diabetic polyneuropathies. Therapies directed at lowering the concentrations of RAGE ligands including AGEs, blocking RAGE signaling, preventing oxidative stress or lowering methylglyoxal (MGO) levels may significantly decrease the development of AGE-related pathologies in patients with neurological disorders. Many drugs are on the pipeline and the future clinical trials will reveal if the promising results translate into clinical application. PMID- 20949364 TI - Health effects of dietary Maillard reaction products: the results of ICARE and other studies. AB - In food science the Maillard reaction is well known to cause degradation of amino acids and an overall decrease in the nutritional value of foods that have been subjected to heat in processing. There has been evidence more recently of the endogenous formation of some Maillard reaction products (MRPs) in biological systems and their association with pathophysiological conditions including diabetes, renal disease and cardiovascular disease. Several studies have suggested that dietary MRPs increase the in vivo pool of MRPs after intestinal absorption and contribute to the development of diabetes and related complications. This review focuses on the animal and human studies which have assessed the eventual implications of dietary MRPs on human health, highlighting the different diets tested, the experimental designs and the biomarkers selected to estimate the health effects. The results of these studies are compared to those of the recently published ICARE study. In this latter study an accurate determination of the MRP content of the diets was achieved, allowing the calculation of the contribution of individual food groups to daily MRP intakes in a regular western diet. PMID- 20949365 TI - Physiological relevance of dietary melanoidins. AB - Melanoidins are the final products of the Maillard reaction. The main dietary sources of melanoidins are coffee, bread crust, bakery products, black beer and cocoa. Although the chemical structures of melanoidins are widely unknown, data from gravimetric techniques allow to roughly estimate a daily intake in the order of 10 g with a Western diet. Melanoidins contribute to the sensorial properties, modulating texture and flavour of foods. Growing evidence also suggests that melanoidins have health beneficial properties, such as chemopreventive, antioxidant and antimicrobial activities, and the ability to chelate different minerals. In the gastrointestinal tract, melanoidins behave not only as antioxidants, but also as dietary fibre by promoting the growth of bifidobacteria. This array of biological activities suggests the need for analytical techniques to identify the melanoidin structures and to control their formation during thermal food processing. PMID- 20949366 TI - Mental health problems in youths committed to juvenile institutions: prevalences and treatment needs. AB - Many international studies show that adolescents in coercive institutional care display high prevalences of mental disorders, especially in the form of disruptive behavior disorders [including attention-deficit/hyperactivity disorder (AD/HD), oppositional defiant disorder, and conduct disorder], anxiety disorders, and mood disorders. High degrees of overlap across mental disorders have also been reported. In addition, institutionalized adolescents are often traumatized. Despite this well-documented psychiatric morbidity, the mental health care needs of detained adolescents are often overlooked. The main objective of this study is to assess prevalences of psychiatric disorders, results of intelligence tests, and previous contacts with child and adolescent psychiatric services among adolescents in institutional care. DSM-IV diagnoses, mental health contacts, substance abuse, neurocognitive abilities, and school performance were registered in 100 adolescents (92 boys, 8 girls) aged 12-19 years (mean age 16.0; SD +/- 1.5) consecutively committed to Swedish juvenile institutions between 2004 and 2007. At least one psychiatric disorder was diagnosed in 73% of the subjects: 48% met DSM-IV diagnostic criteria for AD/HD, 17% for an autism spectrum disorder, and 10% for a mental retardation. The collapsed prevalence for psychiatric disorders requiring specialist attention was 63%. Our data indicate that systematic diagnostic procedures are crucial in the treatment planning for institutionalized adolescents. Adequate treatment strategies need to be designed and implemented to meet the extensive mental health care needs of this vulnerable population. PMID- 20949367 TI - Systemic chemotherapy for peritoneal disseminated gastric cancer with inadequate oral intake: a retrospective study. AB - BACKGROUND: Oral fluoropyrimidines are widely used as standard treatment for gastric cancer, but peritoneal disseminated gastric cancer patients are often ineligible for chemotherapy using oral anticancer agents because of inadequate oral intake. The purpose of this study was to evaluate the treatment outcome and identify the prognostic factors in gastric cancer patients with inadequate oral intake resulting from peritoneal dissemination. METHODS: Seventy-nine patients with peritoneal disseminated gastric cancer receiving systemic chemotherapy as the first-line treatment option at our hospital between April 1999 and December 2006, and who were administered intravenous drip infusion because of inadequate oral intake, were retrospectively analyzed. RESULTS: All patients received 5 fluorouracil (5-FU)-based chemotherapy. Of the 79 treated patients, 71 had ascites as peritoneal dissemination and the remaining 8 had only gastrointestinal stenosis without ascites. Eleven (15%) patients showed an improvement in ascites. Proportion of oral intake improvement was 33%. Median time to progression and overall survival time was 1.7 months [95% confidence interval (CI), 0.9-2.4 months] and 3.3 months (95% CI, 2.1-4.5 months), respectively. Four independent poor prognostic factors were identified in multivariate analysis: serum albumin < 3.0 g/dl [hazard ratio (HR) 1.69, P = 0.03], performance status >= 3 (HR 1.78, P = 0.05), massive ascites (HR 1.79, P = 0.04), and serum C-reactive protein >= 2.0 mg/dl (HR 2.03, P < 0.01). CONCLUSION: The efficacy of 5-FU-based chemotherapy for peritoneal disseminated gastric cancer patients with inadequate oral intake was unsatisfactory. PMID- 20949369 TI - 1-naphthol 2-hydroxylase from Pseudomonas sp. strain C6: purification, characterization and chemical modification studies. AB - 1-Naphthol 2-hydroxylase (1-NH) which catalyzes the conversion of 1-naphthol to 1,2-dihydroxynaphthalene was purified to homogeneity from carbaryl-degrading Pseudomonas sp. strain C6. The enzyme was found to be a homodimer with subunit molecular weight of 66 kDa. UV, visible and fluorescence spectral properties, identification of flavin moiety by HPLC as FAD, and reconstitution of apoenzyme by FAD suggest that enzyme is FAD-dependent. 1-NH accepts electron from NADH as well as NADPH. Besides 1-naphthol (K(m), 9.1 MUM), the enzyme also accepts 5 amino 1-naphthol (K(m), 6.4 MUM) and 4-chloro 1-naphthol (K(m), 2.3 MUM) as substrates. Enzyme showed substrate inhibition phenomenon at high concentration of 1-naphthol (K(i), 283 MUM). Stoichiometric consumption of oxygen and NADH, and biochemical properties suggest that 1-NH belongs to FAD containing external flavomonooxygenase group of oxido-reductase class of enzymes. Based on biochemical and kinetic properties, 1-NH from Pseudomonas sp. strain C6 appears to be different than that reported earlier from Pseudomonas sp. strain C4. Chemical modification and protection by 1-naphthol and NADH suggest that His, Arg, Cys, Tyr and Trp are at or near the active site of 1-NH. PMID- 20949368 TI - Apoptotic cell-derived factors induce arginase II expression in murine macrophages by activating ERK5/CREB. AB - Apoptotic cell (AC)-derived factors alter the physiology of macrophages (MPhis) towards a regulatory phenotype, characterized by reduced nitric oxide (NO) production. Impaired NO formation in response to AC-conditioned medium (CM) was facilitated by arginase II (ARG II) expression, which competes with inducible NO synthase for L-arginine. Here we explored signaling pathways allowing CM to upregulate ARG II in RAW264.7 MPhis. Sphingosine-1-phosphate (S1P) was required and acted synergistically with a so far unidentified factor to elicit high ARG II expression. S1P activated S1P(2), since S1P(2) knockdown prevented ARG II upregulation. Furthermore, ERK5 knockdown attenuated CM-mediated ARG II protein induction. CREB was implicated as shown by EMSA analysis and decoy oligonucleotides scavenging CREB in RAW264.7 MPhis, which blocked ARG II expression. We conclude that AC-derived S1P binds to S1P(2) and acts synergistically with other factors to activate ERK5 and concomitantly CREB. This signaling cascade shapes an anti-inflammatory MPhi phenotype by ARG II induction. PMID- 20949370 TI - Genetic variance in a component of the language acquisition device: ROBO1 polymorphisms associated with phonological buffer deficits. AB - The region containing ROBO1 (Chromosome 3p12.3) has been implicated as a susceptibility gene for reading disorder and language deficit by translocation and linkage data. No association studies have yet been reported supporting any candidate gene. Here we report the first association of this gene with language deficits, specifically with phonological buffer deficits (a phenotype implicated in language acquisition, Specific Language Impairment and Speech Sound Disorder) and dyslexia (reading and spelling ability traits) in an unselected sample of adolescent twins and their siblings. Family-based analyses were performed on 144 tag SNPs in ROBO1, typed in 538 families with up to five offspring and tested for association with a developmental marker of language impairment (phonological buffer capacity, assessed using non word repetition). A reading and spelling ability measure--based on validated measures of lexical processing (irregular word) and grapheme-phoneme decoding (pseudo word)--and measures of short-term and working memory were also analysed. Significant association for phonological buffer capacity was observed for 21 of 144 SNPs tested, peaking at 8.70 * 10(-05) and 9.30 * 10(-05) for SNPs rs6803202 and rs4535189 respectively for nonword repetition, values that survive correction for multiple testing. Twenty-two SNPs showed significant associations for verbal storage (forward digit span)--a trait linked to phonological span. By contrast, just 5 SNPs reached nominal significance for working-memory, not surviving correction, and, importantly, only one SNP in the 144 tested reached nominal significance (0.04) for association with reading and spelling ability. These results provide strong support for ROBO1 as a gene involved in a core trait underpinning language acquisition, with a specific function in supporting a short-term buffer for arbitrary phonological strings. These effects of ROBO1 appear to be unrelated to brain mechanisms underpinning reading ability, at least by adolescence. While replication will be critical, the present results strongly support ROBO1 as the first gene discovered to be associated with language deficits affecting normal variation in language ability. Its functional role in neuronal migration underlying bilateral symmetry and lateralization of neuronal function further suggests a role in the evolution of human language ability. PMID- 20949371 TI - Need for clarification of results in the recent meta-analysis about SULT1A1 codon 213 polymorphism and breast cancer risk. PMID- 20949372 TI - Analysis and effect of water sources used as diluents on Newcastle disease vaccine efficacy in chickens in the Sudan. AB - Samples of artesian well, shallow well, surface water, tap water, and bottled water were collected from different areas in Khartoum; these were chemically analyzed and used as diluents to vaccinate chicks against Newcastle disease. Immune response in vaccinated chicks, as measured by the hemagglutination inhibition test, was significantly better in birds which received the vaccine diluted in bottled water followed by those vaccinated using tap water. It appears that water with low turbidity and total dissolved solids were the best water for vaccine dilution. The order of preference of water source, according to this study was bottled water, tap water, shallow well water, artesian well water, and finally surface water. PMID- 20949373 TI - SSIEM reflections 2004-2010: the growing stature of our society. PMID- 20949374 TI - Factors affecting perceived quality of life of older persons with self-reported visual disability. AB - PURPOSE: The purpose of this paper was to determine the extent to which factors thought to be related to quality of life (QoL) among older persons with a visual disability impact on their perceived QoL (PQol). METHOD: Analysis was conducted on responses from the second wave of a large population-based longitudinal study of those aged 57-72 years (i.e., HWR Study). The sample was split between those who identified as having difficulty seeing newsprint (n = 265) and those who did not (n = 1987). The groups were compared on 11 variables thought to affect QoL plus their response to a single-item measure of PQoL. Variables found to differ across the groups were entered into a standard multiple regression to determine the extent to which they predicted PQoL among those who had difficulty seeing. RESULTS AND CONCLUSIONS: Significant differences were found between the groups on PQoL and seven of the other variables assessed. Of those, three were found to make a significant and unique contribution to the prediction of PQoL. These were satisfaction with life, ability to get around, and number of diagnosed health conditions reported in that order. Together, they accounted for 64% of the observed variance in PQoL. PMID- 20949375 TI - Tufted hair folliculitis in a woman treated with trastuzumab. AB - Chemotherapeutic agents targeting the human epidermal receptor (HER) family are being used with increasing frequency for a variety of solid tumors. Cutaneous side effects are commonly reported with HER inhibitors, especially those agents that inhibit epidermal growth factor receptor (EGFR) or HER1. However, inhibitors of HER2 are not associated with specific skin toxicity. We present a case of tufted hair folliculitis, an inflammatory scalp condition causing scaling and pruritus, in a woman being treated with trastuzumab, a selective HER2 inhibitor. This finding has not previously been reported as a side effect of trastuzumab therapy. PMID- 20949376 TI - Prevention of selenite-induced cataractogenesis by an ethanolic extract of Cineraria maritima: an experimental evaluation of the traditional eye medication. AB - In the present study, the antioxidant potential of an ethanolic extract of Cineraria maritima and its efficacy in preventing selenite-induced cataractogenesis were assessed in vitro and in vivo. In the in vitro phase of the study, lenses dissected out from the eyes of Wistar rats were incubated for 24 h at 37 degrees C in Dulbecco's modified Eagle medium (DMEM) alone (group I), in DMEM containing 100 MUM of selenite only (group II), or in DMEM containing 100 MUM of selenite and 300 MUg/ml C. maritima extract added at the same time (group III). Gross morphological examination of the lenses revealed dense opacification in group II, minimal opacification in group III, and no opacification in group I lenses. The mean activities of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase were significantly lower in group II than in group I or group III lenses, while malondialdehyde concentration was significantly higher in group II lenses than in group I and group III lenses. In the in vivo phase of the study, dense opacification of lenses was noted in all rat pups (100%) that had received a single subcutaneous injection of sodium selenite alone (19 MUM/kg body weight) on postpartum day 10, whereas cataract formation occurred in only 33.3% of rat pups that had received selenite as well as an intraperitoneal injection of the extract of C. maritima (350 mg/kg body weight) for five consecutive days. These observations suggest that the ethanolic extract of C. maritima may prevent experimental selenite-induced cataractogenesis. PMID- 20949377 TI - Successful diagnosis of gallbladder carcinoma coexisting with adenomyomatosis by 18F-FDG-PET--report of a case. PMID- 20949378 TI - Real anal leiomyoma: a case report. AB - Leiomyoma of the rectum and anal canal is an unusual benign mesenchymal neoplasm that originates from smooth muscle cells. We describe the clinical presentation, MRI findings, and surgical treatment of a rare case of perianal leiomyoma confirmed by immunohistochemistry. We also report a review of the world's literature on the subject. PMID- 20949379 TI - FDG PET imaging and cardiovascular inflammation. AB - The underlying pathologic mechanism of most acute coronary syndromes is atherosclerotic plaque rupture. One cause of rupture is plaque inflammation, leading to fibrous cap destabilization. Several imaging techniques, including x ray coronary angiography and multislice CT, can be used for the detection of coronary atherosclerosis. However, these anatomical methods cannot measure arterial inflammation. Positron emission tomography imaging of atherosclerosis using the metabolic marker fluorodeoxyglucose allows quantification of arterial inflammation across multiple vessels. This review discusses the rationale, utility, potential future applications, and limitations of this emerging biomarker of cardiovascular risk. PMID- 20949382 TI - Genetic research and biobanks. AB - Human biobanks, and genetic research databases, as referred to by the Organisation for Economic Co-operation and Development (OECD), are essential tools for modern biomedical research. Biobanks may consist in collections created in clinical diagnosis (such as pathology tissue samples in hospitals) or collections created for large-scale longitudinal research (such as the UK Biobank). Human tissue collections are regulated by a patchwork of national laws. However, there is an increasing international uniformity in national privacy laws based on 1980s OECD standards. There are similar uniform standards developing in national research ethics guidelines. As biobanks develop collaborations and linkages, international harmonisation of legislation and human research regulation will be required across jurisdictions. It is essential that international public trust is maintained in biobanking research. PMID- 20949380 TI - Posterior kyphectomy for myelomeningocele with anterior placement of fixation: a retrospective review. AB - BACKGROUND: Kyphosis in myelomeningocele is a rare and difficult problem. Many strategies have been used with no single procedure universally agreed on. Techniques involving anterior and posterior fixation may provide better fusion. QUESTIONS/PURPOSES: We describe a novel procedure for anteroposterior kyphectomy in patients with myelomeningocele. Apical posterior kyphectomy is followed by the insertion of two rods distally into the vertebral bodies and sacrum. Sublaminar wires are placed superiorly and the kyphosis is reduced by sequential tightening. We determined kyphosis correction and intraoperative blood loss for this new procedure. METHODS: We retrospectively reviewed 22 patients (average age, 7.6 years [range, 2-17 years]) who underwent apical kyphectomy from 1982 to 2008. Charts were examined and radiographs measured preoperatively, immediately postoperatively, and at final followup. Followup averaged 6.4 years (range, 0-14 years) with 19 patients having at least 2 years of followup. RESULTS: Kyphosis decreased from a mean of 123 degrees (range, 79 degrees -163 degrees ) preoperatively to 40 degrees (range, 13 degrees -92 degrees ) immediately postoperatively and was a mean of 60 degrees (range, 14 degrees -126 degrees ) at final followup. Operating time was 248 minutes (range, 180-345 minutes), estimated blood loss was 765 mL (range, 140-2100 mL), and length of stay was 14 days (range, 1-57 days). Ten of the 22 patients had complications with eight requiring reoperation. CONCLUSIONS: This anteroposterior kyphectomy provided a high level of kyphosis correction, which was largely maintained over the study period. Blood loss, surgical time, and complication rates were acceptable as compared with other techniques reported in the literature. PMID- 20949381 TI - Lung cancer patients' decisions about clinical trials and the theory of planned behavior. AB - The theory of planned behavior explores the relationship between behavior, beliefs, attitudes, and intentions presupposing that behavioral intention is influenced by a person's attitude about the behavior and beliefs about whether individuals, who are important to them, approve or disapprove of the behavior (subjective norm). An added dimension to the theory is the idea of perceived behavioral control, or the belief that one has control over performing the behavior. The theory of planned behavior suggests that people may make greater efforts to perform a behavior if they feel they have a high level of control over it. In this examination of data, we explored the application of the theory of planned behavior to patient's decisions about participating in a clinic trial. Twelve respondents in this study had previously participated in a clinical trial for lung cancer and nine respondents had declined a clinical trial for lung cancer. The data were analyzed with regard to the four constructs associated with the theory of planned behavior: behavioral intention, attitude, subjective norm, and perceived behavioral control. Results indicate that the theory of planned behavior may be a useful tool to examine psychosocial needs in relation to behavioral intention of clinical trial participation. PMID- 20949383 TI - The need to downregulate: a minimal ethical framework for biobank research. AB - There are currently multiple international bodies suggesting legal and ethical frameworks for regulating international biobank research. One will for obvious reasons find inconsistencies in terminology and differences in procedures suggested for biobank research among all those guidelines, emanating from many different moral and legal traditions. A central question is whether this constitutes a threat to making progress in international biobank research, as some have argued. In this book, Chapter 1 suggests that there are sufficient and well-established instruments and ethical principles available to guide research in this area. Basically I argue that there is no need for a top-down superstructure of detailed rules and guidelines to be imposed on biobank researchers. With the existing ethical review boards (ERBs) playing a central role guided by well-established ethical guidelines (e.g., the Helsinki Declaration) and solutions to specific ethical problems suggested in the literature, self-regulation by researchers providing arguments for balancing of interests in association with different research initiatives and protocols will be sufficient. Traditional information and consent procedures suffice and data protection implies a sovereign right of the individual citizen to grant the use of biobank material and personal data that is needed for biobank research. Clearly, there may still be inconsistencies in terminology when researchers of different nationalities meet in common enterprises, but both they and the ERBs are well equipped to sort out what is actually meant and propose different instruments for, for example, coding following recently established nomenclatures. The existing ERBs should play the key role, guided by the sound argumentation of the researchers in their applications to the board. PMID- 20949384 TI - Nordic biological specimen bank cohorts as basis for studies of cancer causes and control: quality control tools for study cohorts with more than two million sample donors and 130,000 prospective cancers. AB - The Nordic countries have a long tradition of large-scale biobanking and comprehensive, population-based health data registries linkable on unique personal identifiers, enabling follow-up studies spanning many decades. Joint Nordic biobank-based studies provide unique opportunities for longitudinal molecular epidemiological research. The Nordic Biological Specimen Banks working group on Cancer Causes and Control (NBSBCCC) has worked out very precise quality assurance principles for handling of the samples, based on the tradition in biobank culture. The aim of this paper is to demonstrate how high standards of quality assurance can also be developed for the data related to the subjects and samples in the biobanks. Some of the practices adopted from the strong Nordic cohort study experience evidently improve quality of nested case-control studies nested in biobank cohorts. The data quality requirements for the standardised incidence ratio calculation offer a good way to check and improve accuracy of person identifiers and completeness of follow-up for vital status, which are crucial in case-control studies for picking up right controls for the cases. The nested case-control design applying incidence-density sampling is recommended as an optimal design for most biobank-based studies. It is demonstrated how some types of biobanks have a period immediately after sampling, when the cancer risk is not comparable with the cancer risk in the base population, and how many of the biobanks never represent the normal average population of the region. The estimates on the population-representativeness of the biobanks assist in interpretation of generalisability of results of the studies based on these samples, and the systematic tabulations of numbers of cancer cases will serve in study power estimations. The well over 130,000 prospective cancer cases registered among subjects in the NBSBCCC biobank cohorts have already offered unique possibilities for tens of strong studies, but for rare exposure-outcome combinations predictions on future numbers of cases improve the chance to select the right moment when the study will have accurate statistical power. PMID- 20949385 TI - Biobanks collected for routine healthcare purposes: build-up and use for epidemiologic research. AB - The routine health services collect large amount of samples for biobanking, particularly in clinical laboratory medicine, mainly for clinical diagnostic purposes. These samples provide a large-scale and clinically relevant biobanking infrastructure that can be used for research if these conditions apply. There must be a system for database management that can obtain data on clinical endpoints, vital status, and additional required information via registry linkages. There must be an appropriate ethical system for handling consent for research use. There should be an active effort to optimize the usefulness of clinical biobanks also for research use. Major steps in this direction include measures to stop the ongoing discarding of old samples, reformatting to minimize pick-up times, external quality assurance and formal accreditation of biobanks, building of a dedicated high-quality database that is regularly used for registry linkages, and considerations on whether usefulness and accessibility for research can be optimized by extended saving or pre-treatment of samples. Systematic clinical biobanking could become a major asset for clinical research and public health if biobanking is considered as a routine part of everyday clinical practice, and the science of biobanking is considered an essential part of the science of laboratory medicine. PMID- 20949386 TI - Biobanks and registers in epidemiologic research on cancer. AB - The Nordic countries have a long tradition of register-based epidemiologic studies. Numerous population-based specialized registers offer high-quality data from individuals, and the extensive use of register data further improves the quality of the registers. Unique personal identity codes given to every resident and used in all registers guarantee easy and accurate record linkage. A legislation that makes the use of the existing data possible for purposes that benefit both registered individuals and the society - instead of forcing researchers to use their energy in repeated questionnaire studies, disturbing individuals' privacy and leading to response and recall biases - is a prerequisite for effective epidemiologic research. Biobanks can be considered an additional type of registers. They may offer data from individuals that cannot be reliably collected via questionnaire surveys. In turn, other types of registers are crucial in biobank-based studies (1) in defining for how long the persons in biobank cohorts are at risk of getting the diseases, (2) to get information on cofactors that may modify the relative risk measured by the biomarkers, and (3) to get information on the long-term outcome events. This chapter describes the possibilities of register use mainly in Finland - a typical representative of the Nordic "paradise of register-based epidemiological research" - in research of cancer etiology. The ongoing Nordic research project Changing work life and cancer risk in the Nordic countries (NOCCA) will be described as an example of a massive register use, including both direct linkages on an individual level and indirect group level linkages. PMID- 20949387 TI - Study designs for biobank-based epidemiologic research on chronic diseases. AB - A review is given on design options to be considered in epidemiologic studies on cancers or other chronic diseases in relation to risk factors, the measurement of which is based on stored specimens in large biobanks. The two major choices for valid and cost-efficient sampling of risk factor data from large biobank cohorts are provided by the nested case-control design, and the case-cohort design. The main features of both designs are outlined and their relative merits are compared. Special issues such as matching, stratification, and statistical analysis are also briefly discussed. It is concluded that the nested case-control design is -better suited for studies involving biomarkers that can be influenced by analytic batch, long-term storage, and freeze-thaw cycles. The case-cohort design is useful, especially when several outcomes are of interest, given that the measurements on stored materials remain sufficiently stable during the study. PMID- 20949388 TI - The European Prospective Investigation into Cancer and Nutrition biobank. AB - The European Prospective Investigation into Cancer and Nutrition (EPIC) is a multi-center prospective cohort study designed to investigate the relationship between nutrition and cancer, with the potential for studying many etiologic or genetic factors as well as other disease end-points. The study includes 521,448 participants (367,993 women and 153,455 men, mostly aged 35-70 years) recruited in 23 centers located in ten European countries, who are followed up for cancer incidence and cause-specific mortality for several decades. At enrolment, which took place between 1992 and 2000 at each of the centers, information was collected through a non-dietary questionnaire on lifestyle variables and through a dietary questionnaire addressing usual diet. Anthropometric measurements were performed and blood samples taken, from which plasma, serum, red cells, and buffy coat fractions were separated and aliquoted. A central biobanking facility, located at the International Agency for Research on Cancer, Lyon, was developed for the long-term storage of the specimens in liquid nitrogen. The biobank operates as a service provider and sample distribution center for scientific consortia engaged in studies involving biomarker analyses. To date, EPIC represents the largest single resource worldwide for prospective investigations on the etiology of cancers that can integrate questionnaire data on lifestyle and diet, and can also provide access to measurements of biomarkers of diet and of endogenous metabolism (e.g., hormones and growth factors) and genetic polymorphisms. This chapter describes the building up of the EPIC central biobank and the mechanisms that have been developed to manage the access to specimens by a large number of different users. PMID- 20949389 TI - The AIDS and Cancer Specimen Resource. AB - The AIDS and Cancer Specimen Resource (ACSR) is a cooperative agreement among the United States National Cancer Institute (NCI) (Office of the Director, Office of HIV and AIDS Malignancy (OHAM)) and regional US consortia, University of California, San Francisco (West Coast), George Washington University (East Coast), and The Ohio State University (Mid-Region). The ACSR's main objective is to collect, preserve, and disperse HIV-related tissues and biologic fluids along with clinical data to qualified investigators with a focus on HIV/AIDS-related malignancies. The ACSR biorepository has more than 265,000 human HIV-positive and control samples available from 39 processing types, 16 specimen types, and 52 anatomical site types. These HIV-infected biological fluids and tissues are made available to funded approved investigators at no fee. Technical support such as HIV DNA identification in tissues and tissue microarray (TMA) blocks are available to assist approved investigators. Research needs may be filled through ACSR cooperative arrangements when not met by currently banked material. Those participating with the ACSR are expected to share their research findings with the scientific community. Some 117 abstract/poster and podium reports at national and international scientific meetings and 94 publications have been contributed to the scientific literature (as of 2010). Investigators can browse the ACSR Internet site at http://acsr.ucsf.edu for biospecimens to support their scientific initiatives, including basic, translational, biomarker discovery, and molecular epidemiology studies. PMID- 20949390 TI - Specific advantages of twin registries and biobanks. AB - This chapter briefly reviews the role of twin studies and study designs based on using twins in different settings. In the Nordic countries, twin registers and cohorts have existed already for many decades. These are a unique resource for scientific studies; a major strength being their unselected and representative nature. In the past years, biological samples are also being collected within the studies conducted on the Nordic twins. PMID- 20949391 TI - The Swedish Multi-generation Register. AB - The Swedish Multi-generation Register consists of data of more than nine million individuals, with information available on mothers in 97% and on fathers in 95% of index persons. Index persons are confined to those born from 1932 onwards and those alive on January 1, 1961. This register is a unique resource but is still underutilized. PMID- 20949392 TI - Multigenerational information: the example of the Icelandic Genealogy Database. AB - The first part of the chapter describes the Icelandic Genealogical Database, how it was created, what it contains, and how it operates. In the second part, an overview of research accomplished with material from the database is given. PMID- 20949393 TI - Creation of a new prospective research biobank: the example of HUNT3. AB - When establishing a biobank, there are a number of issues to consider with significant impact on the outcome of your efforts and the quality of your work. Some of the most relevant are: (1) study design, (2) the size and composition of your cohort, (3) the nature and desired quality of the biological material, and (4) how to handle, store, and retrieve your samples to maintain the best quality for future analyses. In this chapter, we in particular describe the organisation of biobanks derived from population-based prospective health surveys illustrated by the Norwegian HUNT study as a basis for more general considerations. PMID- 20949394 TI - Best practices for establishing a biobank. AB - A biobank may be defined as the long-term storage of biological samples for research or clinical purposes. In addition to storage facilities, a biobank may comprise a complete organization with biological samples, data, personnel, policies, and procedures for handling specimens and performing other services, such as the management of the database and the planning of scientific studies. This combination of facilities, policies, and processes may also be called a biological resource center (BRC) ( www.iarc.fr ). Research using specimens from biobanks is regulated by European Union (EU) recommendations (Recommendations on Research on Human Biological Materials. The draft recommendation on research on human biological materials was approved by CDBI at its plenary meeting on 20 October 2005) and by voluntary best practices from the U.S. National Cancer Institute (NCI) ( http://biospecimens.cancer.gov ) and other organizations. Best practices for the management of research biobanks vary according to the institution and differing international regulations and standards. However, there are many areas of agreement that have resulted in best practices that should be followed in order to establish a biobank for the custodianship of high-quality specimens and data. PMID- 20949395 TI - Extraction, quantitation, and evaluation of function DNA from various sample types. AB - Two vital pre-requisites for genetic epidemiology have been fullfiled during the past decade and have led to a virtual explosion of knowledge concerning disease risks. Reliable databases over genetic variation derived from, e.g. the HUGO and HapMap projects, coupled with technological advances make large-scale genetic analyses and downstream bioinformatics suddenly affordable. Although recent prospective population-based biobanks have included DNA collection and purification in their planning, it is the older projects that currently are of greatest value due to the numbers of accumulated disease endpoints. In this chapter, methods to purify and use DNA derived from a variety of archival materials, including whole blood, formalin-fixed paraffin-embedded (FFPE) tissues, sera, dried blood spots (DBS), cervical cell suspensions, and mouthwash are presented and evaluated in a context of quality control guidelines to provide objective measure of the usefulness of various sample types for genetic epidemiology. PMID- 20949396 TI - Cervical cytology biobanks as a resource for molecular epidemiology. AB - A cervical cytology biobank (CCB) is an extension of current cytopathology laboratory practice consisting in the systematic storage of Pap smears or liquid based cytology samples from women participating in cervical cancer screening with the explicit purpose of facilitating future scientific research and quality audit of preventive services. A CCB should use an internationally agreed uniform cytology terminology, be integrated in a national or regional screening registry, and linked to other registries (histology, cancer, and vaccination). Legal and ethical principles concerning personal integrity and data safety must be respected strictly. Biobank-based studies require approval from ethical review boards. A CCB constitutes a nearly inexhaustible resource to perform fundamental and applied biologic research. In particular, it can contribute in answering questions on the natural history of HPV infection and HPV-induced lesions and cancers, screening effectiveness, exploration of new biomarkers, and surveillance of short- and long-term effects of the introduction of HPV vaccination. To understand the limitations of CCB, more studies are needed on quality of samples in relation to sample type, storage procedures, and duration of storage. PMID- 20949397 TI - Biobanking of fresh frozen tissue from clinical surgical specimens: transport logistics, sample selection, and histologic characterization. AB - Access to high-quality fresh frozen tissue is critical for translational cancer research and molecular -diagnostics. Here we describe a workflow for the collection of frozen solid tissue samples derived from fresh human patient specimens after surgery. The routines have been in operation at Uppsala University Hospital since 2001. We have integrated cryosection and histopathologic examination of each biobank sample into the biobank manual. In this way, even small, macroscopically ill-defined lesions can be -procured without a diagnostic hazard due to the removal of uncharacterized tissue from a clinical -specimen. Also, knowledge of the histomorphology of the frozen tissue sample - tumor cell content, stromal components, and presence of necrosis - is pivotal before entering a biobank case into costly molecular profiling studies. PMID- 20949398 TI - Protein extraction from solid tissue. AB - Maximal extraction and solubilization of protein from diseased or healthy tissue is important to make the whole protein complement available for proteomic analysis. It also helps to maximize reproducibility and to minimize waste. Minimal degradation of the protein amino acid backbone or dephosphorylation is essential to preserve the analytical utility of the extract. Containment of the sample is important to minimize the risk of contamination to and from the sample. The proposed standard protocol for protein extraction and solubilization can result in 98% solubilization of brain tissue, corresponding to about 100 MUg protein per mg tissue wet weight, by a frozen disintegration/SDS-based solubilization method: Tissue is crushed in the frozen state in a cryotube by shaking with a sterile steel ball. The crushing is followed by the extraction and solubilization in 2% SDS for 10 min, at 70 degrees C, in a volume corresponding to ten times the tissue wet weight, with shaking. The containment in a cryotube helps to prevent contamination. The treatment with SDS sample buffer can inhibit protease and phosphatase activity. The resulting protein extracts can be used for SDS PAGE, 2-D PAGE, Western blotting, ESI-MS, and ELISA. The proposed standard protocol has the potential to find wide application where protein extraction, solubilization, identification, and quantitation from cryopreserved clinical samples are desirable. PMID- 20949399 TI - Collection and preservation of frozen microorganisms. AB - The storage of the different microorganisms over long periods is necessary to ensure reproducible results and continuity in research and in biomedical processes and also for commercial purposes. Effective storage means that a microorganism is maintained in a viable state free of contamination or genetic drift and must be easily restored without genotypic or phenotypic alterations to its original characteristics and properties. To this end, different techniques have been described and advances in cryopreservation technology have led to methods that allow low-temperature maintenance of a variety of cell types, minimizing the risks of genetic change and are now recommended for long-term storage of most microorganisms.This chapter summarizes the most important steps and components in the process of low- and -ultra-low temperatures freezing of bacteria, parasites, yeasts and fungi, viruses, and recombinant microorganisms. PMID- 20949400 TI - Handling of solid brain tumor tissue for protein analysis. AB - Optimal protein analysis requires unfixed tissue samples. We suggest handling the brain tumor tissue sterilely and coldly (on ice) for as short time as possible prior to processing, but for no more than 8 h. This simple protocol results in apparently intact morphology, immunoreactivity, protein integrity, and protein phosphorylation with the criteria we apply. Sample handling for Pathological Anatomical Diagnosis (PAD) and for protein analysis can be one and the same. PMID- 20949401 TI - Blood plasma handling for protein analysis. AB - Blood handling routines have been worked out that result in consistent protein analytic results in clinical practice. It would seem reasonable to build on this experience when devising handling routines for new protein biomarker discovery. Consequently, normal blood sample handling precautions apply to blood sample handling for new biomarker discovery. The blood sample handling protocol mentioned below describes room temperature, or 4 degrees C, platelet poor EDTA plasma collected within 90 min of venipuncture, handled, and screened to eliminate hemolysis. DNA can be isolated from the "buffy coat" that results as blood cells are sedimented to isolate the plasma. PMID- 20949402 TI - Biobank informatics: connecting genotypes and phenotypes. AB - The sequencing of the human genome, completed at the dawn of the twenty-first century, allows researchers to integrate new data on genetic risk factors with demographic and lifestyle data collected via modern communication technologies. The technical prerequisites now exist for merging these cascades of molecular genetic information, not only to national health registers, but also to epidemiology and clinical data. Long-term storage of biological materials and data is a critical component of any epidemiological or clinical study. In designing Biobanks, informatics plays a vital role for the handling of samples and data in a timely fashion. Biobank Informatics contains important elements concerning definition, structure, and standardization of information that has been gathered from a multitude of sources from population-based registries, biobanks, patient records, and from large-scale molecular measurements. PMID- 20949403 TI - A practical guide to constructing and using tissue microarrays. AB - Tissue microarray (TMA) technology is a robust "high throughput" method of tissue analysis, whereby a large number of patient samples can be examined in a short time using a minimum number of slides. In a TMA, cylinders of tissue are cored out of formalin-fixed, paraffin-embedded tissue blocks and slotted in a regular grid pattern into a blank recipient paraffin wax block. The TMA block is then cut using a standard laboratory microtome. Sections generated are suitable for all in situ techniques, such as immunohistochemistry (IHC) and in situ hybridisation, using essentially the same protocols as are used in conventional sections. The principle advantages of TMAs are that they save valuable biological material and ensure more reproducible reaction conditions while at the same time reducing re agent costs and laboratory processing. Immunohistochemical studies designed to examine the prognostic utility of TMAs compared with large sections have generally found that they are comparable. PMID- 20949404 TI - Breast cancer genomics based on biobanks. AB - Attempts to find genes contribution to complex diseases, such as cancer, require new study designs which incorporate an efficient use of population resources and modern genotyping technologies. We describe here two approaches, used by us for the study of breast cancer, both of which take the use of biobanks. One uses a cancer registry as a source of case information, which is then linked to a biobank on blood DNA. The biobank provides also samples from matched controls. After genotyping, clinical data are retrieved from hospital records, and the results can be presented for genotype-specific cancer risks, or similarly for genotype-specific clinical and survival parameters. The second approach uses registered data on cancer in families or among twins. On defined groups of patients, paraffin tissue is collected by contacting the pathology departments of the hospitals where the patients were diagnosed. Tumor and healthy tissue is prepared and used for mutation, the loss of heterozygosity, or copy number analysis. We believe that in the era of whole-genome genotyping technologies, the importance of well-characterized sample sets cannot be overemphasized. Samples rather than technologies limit the rate of gene discovery in complex diseases. PMID- 20949405 TI - Monitoring, alarm, and data visualization service on sample preparing and sample storing devices in biobanks. AB - An important feature in "Good Biobanking Practices" is to monitor and log conditions of sample storing devices. The Institute of Laboratory Medicine at Landspitali University Hospital in Reykjavik, Iceland, has installed a temperature monitoring and alarm system for freezers, incubators, and refrigerators as a part of its quality program. This paper describes the key features of the system, how it works, and what has been learned. PMID- 20949406 TI - Fresh frozen tissue: RNA extraction and quality control. AB - Since RNA is believed to be the most vulnerable molecular component of unfixed tissue, preserved RNA integrity can be used as a general quality indicator in fresh frozen tissue biobanks. As the size of samples and biopsies often is small, in the range of millimeters or milligrams, it is important to implement quality control procedures adapted to minute the amounts of tissue. To this end, we here describe RNA extraction from one or a few frozen tissue sections and subsequent analysis of structural RNA integrity by microcapillary gel electrophoresis. PMID- 20949407 TI - Can complementary medicine be based on evidence? PMID- 20949408 TI - [Food allergies: significance, interfaces, and prospects in otorhinolaryngology]. AB - Perceived and objective food hypersensitivity reactions are increasing steadily in the western countries. Therefore, otorhinolaryngologists are facing more frequently the challenge to evaluate individual food hypersensitivity reactions, to set these reactions into context with otorhinolaryngologic symptoms and to start systemic and appropriate diagnostic procedures and possibly therapy. Although a good portion of the perceived food hypersensitivity reactions can neither be objectivated nor causaly linked to the occurring symptoms, the recent literature provides documentation, suggestions and prospects for the link between food hypersensitivity reactions and distinct ENT-diseases. Based on that, this review intends to provide an overview of the current knowledge about the impact of food hypersensitivity reactions on otorhinolaryngologic diseases. The aim of the article is to give support in assessing this intricate issue in the daily otorhinolaryngological practice. PMID- 20949410 TI - [Time course of microbial colonization of different voice prostheses]. AB - OBJECTIVE: For the vocal rehabilitation of laryngectomized patients, voice prostheses are actually one of the best known methods. Caused by the surface colonisation with bacteria and fungi the life time of the prostheses is limited to 3-4 months. MATERIAL AND METHODS: In a time period of 127 months we analysed the surface colonisation of 118 voice prostheses. RESULTS: The mean life time of the prostheses was 156 days. In reference to the prosthesis model we also recorded different times of usage (ESKA-Herrmann 141, Provox 2 184 and Provox 1 204 days (p>0.05)). In the microbiological examination the dominating bacteria were S. aureus, Klebsiella sp. and Proteus sp. It was possible to cultivate all these bacteria on every type of prosthesis used in the study. In addition C. albicans, C. glabrata, C. krusei and C. tropicalis were the main fungi on the silicone surface. Thereby a more frequent colonisation with C. krusei on ESKA Herrmann prostheses was measured, caused by the bigger contact area with saliva on this model (p=0.034). CONCLUSIONS: Because of the similar position and way of function, all types of voice prostheses are colonized by almost the same species of bacteria and fungi. But in dependency of the type an affinity of individual species to special prostheses exist. The knowledge of these individual affinities is necessary for the further development of voice prostheses. Furthermore the diversity of bacteria and fungi species showed a level of saturation on the surface. This is caused by the limited space on the silicone prostheses. PMID- 20949411 TI - [No legal consequences for the anesthetist in purely surgical complications. Decision of the Paderborn federal court May 19 2005 - 2 O 467/96]. PMID- 20949412 TI - [Treatment of infants with Pierre Robin sequence]. AB - The Pierre Robin sequence (PRS) characterized by mandibular micro- or retrognathia and glossoptosis with or without cleft palate, presents clinically with intermittent upper airway obstruction (UAO). It is associated with other malformations in about half the cases. The incidence is about 1:8,500. Isolated PRS without other malformations does not, by itself, appear to affect neurodevelopment. Active intervention may therefore be required to reduce the risk for neurocognitive impairment resulting from UAO. Current treatment options for UAO range from prone positioning, use of a nasopharyngeal tube, glossopexy via tongue lip adhesion, mandibular distraction to tracheostomy. An effective, non-invasive treatment protocol which includes implementation of an intraoral orthodontic appliance with velar extension (the pre-epiglottic baton plate; PEBP) is presented in this article. PMID- 20949413 TI - Per oral dual-scope rendezvous technique for endoscopic bridging of complete pancreatic duct disruption. PMID- 20949415 TI - [Leukodystrophies--loss of myelin leads to severe disabilities]. PMID- 20949416 TI - The emerging role of Wolbachia species in heartworm disease. AB - Heartworm disease was first recognized in dogs more than 100 years ago and is still prevalent among dogs and found in cats worldwide. The complications of heartworm disease can be devastating, and treatment carries risks. Wolbachia spp are gram-negative bacteria that infect filarial nematodes, including Dirofilaria immitis, and elicit an inflammatory response in cats and dogs. Antimicrobial therapy directed against these bacteria has resulted in decreased microfilarial loads, inhibition of the development of larval worms, female worm infertility, and reduced numbers of Wolbachia organisms. Antimicrobial therapy against Wolbachia spp may be useful in treating heartworm disease in cats and dogs, but further research is needed. PMID- 20949417 TI - Radiation therapy in horses. AB - Although the diagnosis of cancer is relatively uncommon in horses, tumors do occur in this species. Surgery, radiation, and chemotherapy are traditional cancer treatments in all species. In equine patients, surgery has often been the only treatment offered; however, not all tumors can be controlled with surgery alone. In small animal oncology, newer and better therapies are in demand and available. Radiation therapy is often used to control or palliate tumors locally, especially to satisfy clients who demand sophisticated treatments. The large size of equine patients can make radiation therapy difficult, but it is a valuable tool for treating cancer and should not be overlooked when treating horses. PMID- 20949418 TI - Canine bronchoesophageal fistulas: case report and literature review. AB - A bronchoesophageal fistula (BEF) is defined as a communication between the esophagus and one or more bronchi. BEFs are commonly associated with esophageal diverticula, which are circumscribed outpouchings of the esophageal wall. This article presents the report of a case seen at Louisiana State University Veterinary Teaching Hospital and Clinics in 2006 and reviews the pathogenesis, diagnosis, and treatment of esophageal diverticula and BEFs. The BEF in the case presented was of a very rare form, involving only the accessory lung lobe bronchus. PMID- 20949419 TI - Guidelines for reducing pathogens in veterinary hospitals: hospital design and special considerations. AB - Prevention of nosocomial infection begins with the hospital layout and identification of special considerations for particular patients. The construction of a new hospital or renovation of an existing hospital requires careful planning and consideration of the needs of the expected patient population and hospital staff. This article discusses considerations for preventing cross-contamination of pathogens through hospital design, as well as special considerations for particular patients, specifically those in isolation areas and surgical suites. PMID- 20949420 TI - Guidelines for reducing pathogens in veterinary hospitals: disinfectant selection, cleaning protocols, and hand hygiene. AB - Antibiotic resistance is a growing problem in the hospital setting. Organisms that cause hospital-acquired infections are generally highly resistant, requiring expensive antibiotics and further hospitalization. As a result, many owners of infected pets choose euthanasia. Appropriate hospital disinfection and staff hygiene practices can prevent such infections by reducing the pathogen load in a facility in accordance with the "nosocomial prevention triad"-appropriate antibiotic usage, staff and patient hygiene, and hospital maintenance and disinfection. This review outlines the development and implementation of hospital disinfection protocols and hand hygiene practices in small animal veterinary hospitals. PMID- 20949421 TI - Crusty cats: feline pemphigus foliaceus. AB - Pemphigus foliaceus (PF) is an immune-mediated disease that causes pustules and crusted lesions, most commonly on the pinnae, nasal planum, periocular area, chin, and feet of affected cats. Acantholytic cells caused by degradation of intercellular adhesions are often seen on cytology but are not pathognomonic for PF. A definitive diagnosis is made based on histopathology showing subcorneal pustules with nondegenerate neutrophils and acantholytic cells. PF is treated with immunosuppressive doses of corticosteroids alone or in combination with other immunosuppressive medications, such as chlorambucil or cyclosporine. Most patients require lifelong treatment with these medications to keep the disease in remission. PMID- 20949422 TI - Feeding large-breed puppies. AB - Growth is a physiologically demanding process that requires adequate amounts of energy as well as optimal intake of essential nutrients. Key nutritional factors, including energy and calcium, have been identified as important during growth. Large-breed puppies have a genetic tendency toward fast growth rates that can stress developing skeletal structures and result in malformations if left unchecked. Overnutrition in large-breed puppies leads to not only heavier body weight but also faster bone growth with abnormal bone remodeling. The end result is a larger but less dense skeletal structure supporting a load that is heavier than ideal. Controlling the growth rate and providing nutrients in amounts adjusted for energy intake can help decrease the risks of skeletal abnormalities caused by rapid growth in large-breed puppies. PMID- 20949423 TI - Methods of urolith removal. AB - Multiple techniques exist to remove uroliths from each section of the urinary tract. Minimally invasive methods for removing lower urinary tract stones include voiding urohydropropulsion, retrograde urohydropropulsion followed by dissolution or removal, catheter retrieval, cystoscopic removal, and cystoscopy-assisted laser lithotripsy and surgery. Laparoscopic cystotomy is less invasive than surgical cystotomy. Extracorporeal shock wave lithotripsy can be used for nephroliths and ureteroliths. Nephrotomy, pyelotomy, or urethrotomy may be recommended in certain situations. This article discusses each technique and gives guidance for selecting the most appropriate technique for an individual patient. PMID- 20949424 TI - Canine influenza. AB - Canine influenza virus (CIV) is a newly identified, highly contagious respiratory pathogen of dogs. The clinical disease has high morbidity and low mortality. Diagnosis of canine influenza is based on acute and convalescent serum samples, history, and clinical signs. Phylogenetic analysis has shown that the etiologic agent is an influenza A virus that is closely related to the equine influenza A (H3N8) virus. Data collected thus far support transmission from horses to dogs with horizontal spread in the canine population. This interspecies jump and the close companionship of dogs and people warrant close monitoring of CIV for potential transmission to humans. PMID- 20949425 TI - Suspensory ligament rupture technique during ovariohysterectomy in small animals. AB - During ovariohysterectomy, suspensory ligament (SL) rupture permits retraction of the ovary and distal ovarian pedicle through a limited ventral midline incision. This allows the surgeon to confirm that the pedicle is securely double ligated and includes no ovarian remnant. For less experienced surgeons, SL rupture is often difficult and daunting because the ligament is buried within the abdominal viscera and must be identified blindly by palpation. Furthermore, in dogs, the ligament must be digitally disrupted, which may cause hemorrhage and serious injury to surrounding structures such as the ovarian pedicle. This article describes step-by-step techniques to disrupt the SL in dogs and cats. We have found that these techniques can be taught easily and successfully to novice surgeons. PMID- 20949426 TI - Vector-borne diseases in pets: the stealth health threat. PMID- 20949427 TI - Hemodynamic effects of an intravenous infusion of medetomidine at six different dose regimens in isoflurane-anesthetized dogs. AB - This study investigated the dose dependency of the hemodynamic effects of IV medetomidine (MED) constant-rate infusion (CRI) during isoflurane anesthesia. Twenty-four healthy beagles randomly received one of six MED CRI regimens. A loading dose of MED was administered IV at 0.2, 0.5, 1.0, 1.7, 4.0, or 12.0 ug/kg 1 for 10 minutes, followed by a maintenance CRI providing identical dose amounts over 60 minutes. Heart rate and mean arterial blood pressure were recorded, blood gases were analyzed, and cardiac index (CI) was determined. Statistical analysis involved a repeated measures linear model. Baseline CI demonstrated a dose dependent decrease as the MED dose increased, with decreases of 14.9% (SD, 12.7%), 21.7% (17.9%), 27.1% (13.2%), 44.2% (9.7%), 47.9% (8.1%), and 61.2% (14.1%) at doses of 0.2, 0.5, 1.0, 1.7, 4.0, and 12.0 ug/kg-1, respectively. The four lowest doses induced limited and transient changes in heart rate, mean arterial pressure, and CI. Further investigation into potential perioperative uses of MED CRI is warranted. PMID- 20949428 TI - Pilot immunization of mice infected with an equine strain of Corynebacterium pseudotuberculosis. AB - This pilot study evaluated protection of an equine autogenous bacterin-toxoid vaccine against Corynebacterium pseudotuberculosis infection. Twenty-four BALB/c mice were inoculated with two doses of bacterin-toxoid vaccine or two injections of a placebo. Clinical, microbiologic, and pathologic outcomes were assessed after intradermal infection with one of two equine-origin C. pseudotuberculosis strains. Mice receiving bacterin-toxoid from fast-growing C. pseudotuberculosis showed significant protection from challenge infection, as evidenced by a higher survival rate, fewer gross and histopathologic lesions, and lower bacterial levels on culture. Successful protection via a vaccine against equine internal abscesses might provide supplementary management options against an important, potentially fatal disease. PMID- 20949429 TI - Single-dose oral pharmacokinetics of pergolide mesylate in healthy adult mares. AB - Pituitary pars intermedia dysfunction (PPID) is probably the most common disease of geriatric horses. Affected horses show a variety of clinical signs, including hirsutism, polyuria/polydipsia, immunosuppression, muscle wasting, and laminitis. The most common treatment for PPID is pergolide, a dopamine agonist; however, there are no pharmacokinetic data about the use of this drug in horses. This article describes a study designed to address this complete lack of pharmacokinetic information. The pharmacokinetics of pergolide are described in a small group of relatively young, healthy mares (n = 6), with the objective of generating data on which to base larger studies in the future. To make definitive dosing recommendations to clinicians, more studies will be needed to investigate the relationship between plasma pergolide concentrations and clinical outcomes, as well as the effect of gender, age, and concomitant disease on the absorption and disposition of this drug. PMID- 20949430 TI - A surgical robot with vision field control for single port endoscopic surgery. AB - BACKGROUND: Robotic end-effectors for single port endoscopic surgery (SPS) require a manual change of vision field that slows surgery and increases the degrees of freedom (DOFs) of the manipulator. METHODS: A new surgical prototype robot has dynamic vision field control and a master controller to manipulate the endoscopic view. It uses positioning (4 DOF) and sheath (2 DOF) manipulators for vision field control, and dual tool tissue manipulators (gripping, 5 DOF; cautery, 3 DOF). RESULTS: The robot is feasible in vitro. 'Cut and vision field control' (using tool manipulators) was suitable for precise cutting tasks in risky areas; 'cut by vision field control' (using the vision field control manipulator) was effective for rapid macro cutting of tissues. A resection was performed using a combination of both methods. CONCLUSIONS: The novel robotic system is feasible, but further studies are needed to address its performance in vivo. PMID- 20949431 TI - Purification of arsenic (+3 oxidation state) methyltransferase from rat liver cytosol. AB - Demonstrating the enzymatic basis of arsenic methylation is critical to further studies of the pathway for the conversion of inorganic arsenic into a variety of methylated metabolites. This protocol describes a procedure for the purification of an arsenic methyltransferase from rat liver cytosol. Purification of this enzyme and subsequent cloning of its gene has permitted studies of enzyme structure and function, and has lead to the identification of orthologous genes in genomes of organisms ranging in complexity from sea urchins to humans. These proteins are referred to as arsenic (+3 oxidation state) methyltransferases. PMID- 20949432 TI - Manipulation of expression of arsenic (+3 oxidation state) methyltransferase in cultured cells. AB - Methylation of inorganic arsenic to produce mono-, di-, or trimethylated products is the central process in the cellular metabolism of arsenic. Identification of arsenic (+3 oxidation state) methyltransferase (As3mt) as the enzyme that could catalyze all the steps in the pathway for arsenic methylation suggests that expression of this enzyme could be a useful target for manipulation. Here, methods are described for heterologous expression of the rat As3mt gene in a human urothelial cell line that normally does not express this enzyme and for silencing of the AS3MT gene by RNA interference in a human hepatoma cell line. These tools can be applied to elucidating the role of methylation in the toxic and carcinogenic effects of arsenicals. PMID- 20949434 TI - Measurement of bioavailability: measurement of absorption through skin in vitro. AB - New therapeutic compounds intended for use on the skin or for delivery through application to the skin and agrochemicals, whose use may result in skin exposure, must be tested for bioavailability as the result of absorption. This unit contains a protocol for measuring skin absorption in vitro using the diffusion cell skin absorption method (SAM), which can be used to measure percutaneous absorption after topical application. Usually a radiolabeled compound is used, but if a suitable specific assay is available, nonradioactive compounds may be tested. The procedure is applicable to skin from a variety of species. PMID- 20949433 TI - Measurement of cysteine S-conjugate beta-lyase activity. AB - Cysteine S-conjugate beta-lyases are pyridoxal 5'-phosphate (PLP)-containing enzymes that catalyze the conversion of cysteine S-conjugates [RSCH(2)CH(NH(3) (+))CO(2) (-)] and selenium Se-conjugates [RSeCH(2)CH(NH(3) (+))CO(2) (-)] that contain a leaving group in the beta position to pyruvate, ammonium and a sulfur containing fragment (RSH) or selenium-containing fragment (RSeH), respectively. In mammals, at least ten PLP enzymes catalyze beta-elimination reactions with such cysteine S-conjugates. All are enzymes involved in amino acid metabolism that do not normally catalyze a beta-lyase reaction, but catalyze a non physiological beta-lyase side-reaction that depends on the electron-withdrawing properties of the -SR or -SeR moiety. In the case of cysteine S-conjugates, if the eliminated RSH is stable, the compound may be S-thiomethylated and excreted (thiomethyl shunt) or S-glucuronidated and harmlessly excreted. However, if RSH is chemically reactive, the cysteine S-conjugate may be toxic as a result of the beta-lyase reaction. The cysteine S-conjugate beta-lyase pathway is of particular interest to toxicologists because it is involved in the bioactivation (toxification) of halogenated alkenes and certain drugs. This unit provides protocols for the analysis of cysteine S-conjugate beta-lyase activity. PMID- 20949435 TI - Measurement of bioavailability: measuring absorption through skin in vivo in rats and humans. AB - Absorption through the skin is a route of exposure to a wide variety of therapeutic and/or environmental compounds. In vivo assays are advantageous in that they retain intact epidermal and dermal structures and thus reflect a more normal situation. The test compound is applied to the skin in a protected area for a specified period of time. At the end of the incubation, skin, tissues, and excreta are assessed for the presence of the test compound. The assay can also be performed with volatile compounds. When performed using laboratory animals, it is possible to assess the distribution of the compound throughout the body. If human volunteers are studied such analysis is limited to the skin, blood, and excreta. PMID- 20949436 TI - Measurement of disposition half-life, clearance, and residence times. AB - This unit provides an overview of the principles underlying the elimination process. Experimental design issues, methods of data analysis, and complications that may be encountered are discussed. A complete worked example is provided to exemplify the methods of analysis that are available. PMID- 20949437 TI - Isolated perfused porcine skin flap. AB - The isolated porcine skin flap is used to determine the rate and extent of absorption of chemicals through skin. This ex vivo model system allows cutaneous toxicology and pharmacology studies to be conducted in viable skin that has a normal structure and intact microvasculature. Porcine skin is also anatomically and physiologically similar to human skin, therefore data from studies using this ex vivo system can in some cases to predict dermatopharmacokinetics and dermotoxicity to test compounds in humans. PMID- 20949438 TI - Porcine skin flow-through diffusion cell system. AB - Porcine Skin Flow-Through Diffusion Cell System (Ronald E. Baynes, North Carolina State University, Raleigh, North Carolina). Porcine skin can be used in a diffusion cell apparatus to study the rate and extent of absorption of topically applied chemicals through the skin. Although the skin of a number of animals can be used in this system, that of the pig most closely approximates human skin anatomically and physiologically. PMID- 20949439 TI - Toxicant transport by P-glycoprotein. PMID- 20949440 TI - Collection of bile and urine samples for determining the urinary and hepatobiliary disposition of xenobiotics in mice. AB - One of the most simple and informative method commonly used by researchers in the field of xenobiotics metabolism and disposition to investigate the fate of chemicals in living organisms involves identification and/or quantitation of metabolites in excreta such as urine and bile. This method can be performed on dogs and larger rodents such as rats and hamsters rather easily. However, many investigators find it difficult to collect bile samples from mice. This unit describes, in detail, how to collect urine and bile samples from a mouse for further metabolite analysis. PMID- 20949441 TI - Pain management in children and adolescents with sickle cell disease. AB - In a cohort of 2,194 children with sickle cell disease (SCD) treated in community based services, we explored the types of medications used to treat vaso-occlusive (VOC) pain episodes, and the relative effectiveness of nonsteroidal anti inflammatory drugs (NSAIDs), opioids, and adjunctive antidepressants or anticonvulsant medications on reducing acute VOC pain visits over time. Pharmacologic treatments for VOC pain consisted mainly of NSAIDs and weak opioids. Significantly more patients with more than 3 inpatient or ER VOC pain visits during their first year of SCD treatment were prescribed stronger opioids, SSRIs, SNRI/heterocyclics, and anticonvulsants. Prescription of both stronger opioids and SSRI antidepressants or anticonvulsants was significantly associated with lower cumulative rates of acute VOC pain visits over time. Using an observational study design and existing clinical data, these findings are intended to illustrate the potential clinical advantages of combining adjunctive antidepressants or anticonvulsants with primary pain medications for relief of acute VOC pain over time. PMID- 20949442 TI - Differences in patellofemoral kinematics between weight-bearing and non-weight bearing conditions in patients with patellofemoral pain. AB - Patellar maltracking is thought to be one source of patellofemoral pain. Measurements of patellar tracking are frequently obtained during non-weight bearing knee extension; however, pain typically arises during highly loaded activities, such as squatting, stair climbing, and running. It is unclear whether patellofemoral joint kinematics during lightly loaded tasks replicate patellofemoral joint motion during weight-bearing activities. The purpose of this study was to: evaluate differences between upright, weight-bearing and supine, non-weight-bearing joint kinematics in patients with patellofemoral pain; and evaluate whether the kinematics in subjects with maltracking respond differently to weight-bearing than those in nonmaltrackers. We used real-time magnetic resonance imaging to visualize the patellofemoral joint during dynamic knee extension from 30 degrees to 0 degrees of knee flexion during two conditions: upright, weight-bearing and supine, non-weight-bearing. We compared patellofemoral kinematics measured from the images. The patella translated more laterally during the supine task compared to the weight-bearing task for knee flexion angles between 0 degrees and 5 degrees (p = 0.001). The kinematics of the maltrackers responded differently to joint loading than those of the non maltrackers. In subjects with excessive lateral patellar translation, the patella translated more laterally during upright, weight-bearing knee extension for knee flexion angles between 25 degrees and 30 degrees (p = 0.001). However, in subjects with normal patellar translation, the patella translated more laterally during supine, non-weight-bearing knee extension near full extension (p = 0.001). These results suggest that patellofemoral kinematics measured during supine, unloaded tasks do not accurately represent the joint motion during weight-bearing activities. PMID- 20949443 TI - A rat model of massive rotator cuff tears. AB - Rotator cuff tears (RCTs) are the most common tendon injury seen in orthopedic patients. Massive RCT does not heal spontaneously and results in poor clinical outcomes. Muscle atrophy and fatty infiltration in rotator cuff muscles are major complications of chronic massive RCT and are thought to be the key factors responsible for the failure of attempted massive RCT repair. However, the pathophysiology of rotator cuff muscle atrophy and fat infiltration remains largely unknown, and no small animal model has been shown to reproduce the histologic and molecular changes seen in massive RCT. In this article, we report a novel rat massive RCT model, in which significant and consistent muscle atrophy and fat infiltration were observed in the rotator cuff muscles after rotator cuff tendon transection and denervation. The supraspinatus and infraspinatus muscle lost 25.4% and 28.9% of their wet weight 2 weeks after complete tendon transection, respectively. Six weeks after surgery, the average wet weight of supraspinatus and infraspinatus muscles decreased 13.2% and 28.3%, respectively. Significant fat infiltration was only observed in infraspinatus 6 weeks after tendon transection. PMID- 20949444 TI - Improved recombinant protein yield using a codon deoptimized DHFR selectable marker in a CHEF1 expression plasmid. AB - The CHEF1 expression plasmid utilizes regulatory domains of the Chinese Hamster Elongation Factor 1 (CHEF1) housekeeping gene to drive stable recombinant protein expression in Chinese Hamster Ovary (CHO) cells. Rapid development of stable CHEF1 cell lines is possible, in part, because high titer pools are produced in the absence of methotrexate-induced DHFR amplification. Inhibiting DHFR activity with methotrexate increases the selection pressure on transfected cells and can result in a compensatory event to ensure cell survival, such as dhfr gene amplification or integration into a transcriptionally active genomic site. Methotrexate amplification often results in improved cell line productivity but it is a time-consuming process. Herein, we describe a novel mechanism to increase selection stringency via codon deoptimization of the mouse dhfr selectable marker utilizing hamster codon preference that results in improved expression of a linked recombinant protein compared to wild-type DHFR selection. We show that deoptimizing the translatability of the dhfr gene reduces the expression level of the DHFR protein in CHO transfection pools and derived clones. Lower DHFR expression increases the transfection selection stringency, shown as lower transfection efficiency in pools, and correlates with increased recombinant protein expression in both pools and clones. These results demonstrate a new mechanism for increasing selection stringency and improving recombinant protein production during cell line development without time-consuming gene amplification steps. PMID- 20949445 TI - Enzymatic fragmentation of cation exchange membrane bound immunoglobulin G. AB - Immunoglobulin G (IgG) was immobilized on a stack of microporous cation-exchange membranes and pulsed with pepsin solution. Fc fragment and its sub-fragments thus produced were removed along with the reaction flow-through, whereas F(ab')(2) which remained membrane bound could subsequently be eluted in a pure form using salt. The extent of IgG fragmentation and the apparent reaction rate constant were both significantly higher than in equivalent liquid phase reaction, presumably due to a combination of mass transport, steric, and substrate concentration effects. This approach of using a membrane surface as molecule cutting board could be attractive in niche applications such as integrated enzymatic reaction and purification processes involving macromolecular substrates. PMID- 20949446 TI - Gene expression profiling in head and neck squamous cell carcinoma: Clinical perspectives. AB - BACKGROUND: To date, more than 60 gene expression profiling (GEP) studies have been published in the field of head and neck squamous cell carcinoma (HNSCC) with variable objectives, methods, and results. METHODS: The purpose of this study was to present a state-of-the-art review of GEP in HNSCC focusing on the current advances and perspectives for clinical applications. RESULTS: Gene expression signatures have been developed to identify screening and diagnostic molecular markers, to improve tumor staging (cervical lymph node and distant metastasis prediction), to differentiate lung metastasis of HNSCC from primary lung squamous cell carcinoma, to predict tumor response to chemoradiotherapy, and to provide outcome predictors. CONCLUSION: Some transcriptional signatures that could improve HNSCC management have been identified, but further analyses are required to properly validate and to precisely evaluate their clinical relevance. After an exploratory phase, the completion of large scale projects with stringent methodology is now necessary to transfer GEP from bench to bedside. PMID- 20949447 TI - Association between a functional polymorphism (-1195T>C) in the IGFBP5 promoter and head and neck cancer risk. AB - BACKGROUND: To the best of our knowledge, no studies to date have evaluated roles of insulin-like growth factor binding protein 5 (IGFBP5) polymorphisms in risk of squamous cell carcinoma of the head and neck (SCCHN). METHODS: A hospital-based study of 1082 patients with SCCHN and 1120 cancer-free controls was performed to investigate associations between 2 functional polymorphisms, -1195T>C and 709G>C, in the IGFBP5 promoter region and SCCHN risk. RESULTS: We demonstrated that the transcription factor, activator protein 1 (AP-1), differentially bound to T or C variants at -1195 in the promoter to regulate the IGFBP5 promoter activity and that the C variant genotypes were associated with deferential risk of late-stage SCCHN, compared to the TT genotype, particularly for human papillomavirus (HPV)-unrelated sites (adjusted odds ratio [OR], 2.21; 95% confidence interval [CI], 1.19-4.11 for CC vs TT). CONCLUSION: The IGFBP5 1195T>C polymorphism is functional and may potentially be a biomarker for susceptibility to late-stage SCCHN. PMID- 20949449 TI - Transcriptional overexpression of CYP6B8/CYP6B28 and CYP6B9 is a mechanism associated with cypermethrin survivorship in field-collected Helicoverpa zea (Lepidoptera: Noctuidae) moths. AB - BACKGROUND: There are multiple reports of resistance to pyrethroid insecticides in Helicoverpa zea (Boddie); however, metabolic mechanisms responsible for insect survivorship have yet to be elucidated at the molecular level. Here, the transcriptional expression of two cytochrome P450 genes involved in pyrethroid metabolism, CYP6B8/CYP6B28 and CYP6B9, in H. zea male moths surviving discriminating dosages of cypermethrin in the adult vial test were investigated using quantitative PCR. RESULTS: Insects classified as cypermethrin resistant in the adult vial assay contained significantly higher levels of both transcripts compared with the susceptible (ranging from a factor of 3.7 to 34.9 for CYP6B8/CYP6B28 and from 5.6 to 39.6 for CYP6B9), and in individual insects both transcripts were present at similar levels. Analysis of individual males collected across ecological regions and years in Texas showed overexpression of these genes. CONCLUSIONS: This paper is the first to identify transcriptional overexpression of CYP genes associated with pyrethroid survivorship in field collected H. zea. This discovery will allow for greater focus on increased metabolism studies at the population level. Understanding mechanisms responsible for resistance will greatly improve the ability to monitor resistance and make better control recommendations, as metabolic resistance may threaten the success not only of pyrethroids but also of other synthetic pesticides. PMID- 20949448 TI - High rates of regional failure in squamous cell carcinoma of the hard palate and maxillary alveolus. AB - BACKGROUND: The purpose of this study was to determine the incidence of neck metastasis in hard palate and maxillary alveolus squamous cell carcinoma (SCC) and to identify factors predictive of regional failure. METHODS: In 139 patients treated for SCC of the hard palate and maxillary alveolus (from 1985-2006), the incidence rates of regional metastasis at presentation and at recurrence were calculated. Factors predictive of regional recurrence-free survival were identified on Cox multivariable regression analysis. RESULTS: Regional failure occurred in 28.4% of patients and was significantly associated with pathologic T classification, ranging from 18.7% (pT1) to 37.3% (pT4). T classification was an independent predictor of regional recurrence-free survival (RRFS) on multivariable analysis. Most patients (65.6%) with regional recurrence were not able to be salvaged. CONCLUSION: Patients with T2 to T4 primary tumors of the hard palate and maxillary alveolus exhibited high rates of regional failure. In most cases, successful salvage was not achieved. Elective treatment of the neck with surgery or radiation is therefore recommended. PMID- 20949450 TI - Cytologic differentiation of squamous elements in the pancreas. PMID- 20949451 TI - Rapid prescreening is as effective at reducing screening error as postscreening with the FocalPoint automated screening device. AB - Both manual (rapid prescreening) and automated methods have been devised to reduce screening error compared with routine review of 10% of negative gynecologic cases. To date these two methods have not been compared. A total of 5,139 liquid-based (SurePath Pap Test, BD Diagnostics) cases were subjected to 100% rapid prescreening and routine manual screening. All cases diagnosed as negative on routine screening were placed on the FocalPoint (BD Diagnostics, Franklin Lakes, NJ) automated screening device. All cases that were negative on routine screening and abnormal on rapid prescreening or in the top 15% of cases by FocalPoint were rescreened and a final diagnosis obtained. Cases were blinded during rapid prescreening and routine manual screening. Abnormal was defined as any diagnosis of atypical squamous cells (ASC) or worse. A total of 427 (8%) of cases were abnormal on routine screening. The sensitivity of rapid prescreening was 44.6%. Rapid prescreening identified an additional 14 abnormal cases (13 ASC and 1 LSIL) and FocalPoint identified nine cases (eight ASC, one LSIL) that were not detected by routine screening. Three of these cases were detected by both methods. The sensitivity of routine screening was 93.1%. Rapid prescreening increased the overall sensitivity significantly (96.0%, P = 0.04); FocalPoint increased the sensitivity but this change was not significant (95.0%, P = 0.21). Estimated screening time was 30 seconds for rapid prescreening and 6 minutes for routine screening with the result that rapid prescreening required 2,570 minutes while review of the FocalPoint Slides required 2,694 minutes. The sensitivity of routine screening in the second half of the study (95.3%) was higher than that in the first half of the study (91.6%) but the difference was not significant (P = 0.11). Rapid prescreening is as effective as directed review using FocalPoint at reducing screening errors and requires no additional screening time. Continued use of these methods may improve the sensitivity of routine screening PMID- 20949452 TI - Rare endocervical tumour may be a diagnostic dilemma on Papanicolaou smear. PMID- 20949453 TI - Vaginal lubricant gel as an artefact on a Pap smear. PMID- 20949454 TI - Papillary tissue fragments in cervicovaginal (Pap) smears: cytomorphologic characteristics and clinicopathologic significance. AB - Papillary epithelial fragments (PEFs) are a rarely described architectural feature in cervicovaginal (Pap) smears. Morphologically, PEFs often consist of small, finely branching glandular tissue fragments with varying cytomorphology. This study identified 21 Pap smears (1978-2009) containing PEFs to determine the clinicopathologic significance of such findings. Patients ranged in age from 36 to 81 years (mean, 54 years). The Pap smear diagnoses consisted of 48% overt malignant neoplasms, 24% atypical fragments, and 28% benign entities. The papillary fragments featured a range of cytomorphologies consisting of benign features, mild to marked atypia, and overt malignancy. PEFs were more commonly found (57%) in specimens from patients with significant pathologic outcomes. Hence, the presence of PEFs in a Pap smear should raise concern for a neoplastic process. In smears displaying atypical to malignant cytomorphologic features recommendations for further clinical work-up and/or tissue studies should be made. PMID- 20949455 TI - Diagnostic utility of PAX8 and PAX2 immunohistochemistry in the identification of metastatic Mullerian carcinoma in effusions. AB - Morphologic distinction of Mullerian carcinomas from non-Mullerian carcinomas in effusion specimens by cytomorphology alone can be diagnostically challenging. Therefore, immunohistochemical adjuncts can be useful in differentiating Mullerian from non-Mullerian metastases. In this study, we evaluated the expression of PAX8 and PAX2 in malignant effusions collected from patients with known Mullerian and non-Mullerian carcinomas. Sections from cell blocks prepared from 152 effusion specimens (54 and 98 cases representing metastases from Mullerian and non-Mullerian primaries, respectively) were immunostained with rabbit polyclonal antibodies against PAX8 and PAX2. Immunopositivity was defined as the presence of strong nuclear staining in at least 25% of the tumor cells. Fifty-two (96%) and 13 (24%) of the 54 Mullerian carcinomas were positive for PAX8 and PAX2, respectively. PAX8 positivity was seen in only four (4%) of 98 non Mullerian carcinomas; these represented metastasis from a large cell neuroendocrine lung carcinoma, papillary thyroid carcinoma, renal cell carcinoma, and acinic cell carcinoma of the parotid gland. PAX2 positivity was not seen in any of the non-Mullerian carcinomas. The results demonstrate that both PAX8 and PAX2 are highly specific markers for metastatic Mullerian carcinomas in cell block preparations from effusion specimens (96% and 100%, respectively). PAX8, however, is more sensitive than PAX2 in identifying Mullerian carcinomas in fluids (96% versus 24%). Overall, immunohistochemistry for PAX8 and PAX2 represent diagnostically useful adjuncts in identifying a Mullerian carcinoma as a source of a malignant effusion. PMID- 20949456 TI - Cytologic diagnosis of recurrent medullary thyroid carcinoma with oncocytic change twenty-one years post-thyroidectomy: case report and review of the literature. AB - A 66-year-old woman presented 21 years prior with diarrhea and elevated serum calcitonin levels. The left lobe of the thyroid was aspirated but specimen was unsatisfactory. Nevertheless, based on the radiological and clinical impressions, the patient underwent total thyroidectomy and the histologic examination established the diagnosis of medullary thyroid carcinoma (MTC). Approximately 5 years later, the patient had a recurrence of the disease and underwent a neck lymph node dissection, which showed metastatic MTC in a lymph node. Sixteen years later, the patient presented with left neck mass detected by ultrasound in the area of thyroid bed. Fine needle aspiration (FNA) of this area was performed and the FNA diagnosis was consistent with oncocytic variant of MTC. This case illustrates a first report of this uncommon variant of MTC diagnosed by FNA cytology of the thyroid bed. PMID- 20949457 TI - Core needle biopsy versus fine needle aspiration biopsy in breast--a historical perspective and opportunities in the modern era. AB - Breast fine-needle aspiration biopsy (FNAB) by palpation is on the decline, due to its limitations in diagnostic accuracy, decreased sensitivity, and its replacement with core needle biopsy (CNB). Despite its decreasing utility, superficial fine-needle aspiration (FNA) in breast is still the main modality for evaluating metastatic lesions, recurrence, and axillary lymph node metastasis. New modalities including proteomic pattern expression and methylation profiling of breast lesions are other promising techniques that can be used as ancillary tests for refining the diagnosis of breast lesions using FNAB. Image-guided breast FNA proves to be a successful alternative with high sensitivity and specificity. In this review, the advantages, disadvantages, and inherent limitations of breast FNA and CNB, and new advanced techniques are discussed. PMID- 20949458 TI - Neutrophil phagocytosis by tumor cells--a cytological study. AB - Cell cannibalism is defined as the ability of a cell to phagocytose another cell. Malignant tumor cells may develop phagocytic property and demonstrate phagocytosis of own cells or cells of other series like neutrophils and lymphocytes. We report 11 cases in which the tumor cells showed evidence of neutrophil phagocytosis/emperipolesis on FNAC smears. Cases of malignancies diagnosed on FNA over a period of 1 year were retrieved, and smears were examined for neutrophil phagocytosis by tumor cells. These cases were classified according to type and differentiation of malignancy. The cytomorphological features and background inflammation were also studied at both primary and metastatic site. Of 362 malignant cases diagnosed on FNA smears, in 11 cases (3.09%), tumor cells showed neutrophil phagocytosis. The background showed increase in polymorphs in all cases. All the cases were associated with metastasis at presentation and were high-grade tumors cytologically. There were three cases of anaplastic carcinoma, two cases of adenocarcinoma, two cases of carcinoma breast, two cases of anaplastic non-Hodgkins lymphoma, one case each of squamous cell carcinoma and small cell carcinoma from larynx and lung, respectively. Phagocytic activity by tumor cells is uncommon and usually seen in high-grade/poorly differentiated malignancies. It is frequently associated with metastatic disease. On cytology smears, true phagocytosis of neutrophils by tumor cells has to be distinguished from superimposed inflammatory cells from the background. The tumor cells also need to be distinguished from histiocytes displaying phagocytosis. PMID- 20949459 TI - Cytology of a giant adult-type rhabdomyoma of the tongue. AB - Adult rhabdomyoma is a rare primary benign tumour of striated muscle origin that almost exclusively presents in the head and neck region with predilection for male. We herein report a case of an adult rhabdomyoma in a 67-year-old male with cytologic features. The lesions was located in the tongue extended to the left parapharyngeal region. We discuss the cytological findings with a brief review of the literature on this entity. PMID- 20949460 TI - Cytomorphology of kidney "thyroidization". PMID- 20949461 TI - Primary CNS plasmablastic lymphoma: report of a case with CSF cytology, flow cytometry, radiology, histological correlation, and review of the literature. AB - Plasmablastic lymphoma (PBL) is a rare subtype of diffuse large B cell lymphoma and commonly presents as an oral mass in HIV patients. Extraoral PBL has been reported, including one case of primary central nervous system PBL (PCNSPBL). The cytological features of PBL have been described, including cerebrospinal fluid (CSF) cytology findings for secondary CNS involvement by PBL. The etiology of PCNSPBL is still unknown. We report here the CSF cytology of a PCNSPBL, which shows a hypercellular specimen composed of markedly atypical, singly dispersed plasmacytoid cells with frequent abnormal mitoses and binucleation. The neoplastic cells are positive for CD138. Flow cytometry of the CSF specimen demonstrates a monoclonal neoplastic cell population, which is CD138 positive, kappa light chain positive, lambda light chain negative, and CD19 negative. Molecular analysis and immunohistochemical stains on a tissue biopsy confirmed the diagnosis and reveal concurrent infections with Epstein-Barr virus and human polyomavirus JC virus. Clinical and radiological correlations are reported, and the literature is reviewed. To the best of our knowledge, this is the first case report for CSF cytology of a PCNSPBL, demonstrating the utility of the cytological examination in the triage and diagnosis of this disease. Because of its dismal prognosis, it is critical for cytopathologists to be aware of the entity and recognize the neoplastic cells in CSF specimen. This report also emphasizes the importance of clinical and radiological correlation in the diagnosis of this lethal disease. PMID- 20949462 TI - Clinicopathological study of Papanicolaou (Pap) smears for diagnosing of cervical infections. AB - Cervical infections are not uncommon in our population especially in young and sexually active women. One thousand samples of married women, aged between 20 and 70 years, were studied by conventional Papanicolaou smears. These samples were examined in the Department of Pathology, King Edward Medical University, Lahore from January 2007 to June 2009. Only cases without (pre)neoplastic cytology were included. Six types of infections were diagnosed cytologically. The overall frequency of normal, inadequate, neoplastic, and infective smears was 50%, 1.8%, 10.2%, and 38.3%, respectively. Most of the patients (67%) were in the reproductive age group with mean age 34.7 +/- 2.6 years. The commonest clinical sign seen in 354/383 (92%) cases and symptom in (349/383; 91%) cases were vaginal discharge and pruritis vulvae. Among the infective smears, 290 cases (75.7%), the cytologic diagnosis was nonspecific inflammation. Most of these 290 smears contained clue cells (indicating Gardnerella infection) and a lack of lactobacilli. Such smears are predominant in patients suffering from bacterial vaginosis (BV). Twenty-eight smears (7.3%) were positive for Trichomonas vaginalis, 27 cases (7%) were smears with koilocytic change pathognomonic of human papilloma virus infection. Twenty-five smears (6.5%) were positive for fungal infection. Seven cases (1.8%) were diagnosed as herpes simplex virus infection. Finally, there were six cases (1.5%) with atrophic vaginitis. We conclude that the cervical smear is well suited for diagnosing cervical infections. It is clear that Gardnerella, known to be associated with bacterial vaginosis, is a major problem in our Pakistani population. PMID- 20949463 TI - Pneumocystis jirovecii in a bronchoalveolar lavage specimen on ThinPrep(r) cytology. PMID- 20949464 TI - Rhinosporidium seeberi in nasal smears. PMID- 20949465 TI - The prevalence and importance of karyorrhexis in lymphocytic effusions. PMID- 20949466 TI - Disseminated blastomycosis diagnosed by fine-needle aspiration of the thyroid. AB - Blastomycosis is an uncommon disease caused by the dimorphic fungus Blastomyces dermatitidis. It can manifest as chronic pulmonary symptoms or disseminated disease. Only three previous cases of blastomycosis involving the thyroid have been reported, of which two were diagnosed by fine-needle aspiration. We present a case of disseminated blastomycosis initially diagnosed by thyroid fine-needle aspiration. Our case was a 47-year-old man with past medical history significant for diabetes, hyperlipidemia, and chronic pancreatitis who presented with a 2 week history of fever, chills, rigors, constipation, and 10 pound weight loss. Abdominal CT revealed chronic pancreatitis and a calcified mass in the pancreas. Chest CT revealed a single 1.5-2 cm thyroid mass and innumerably small 2-3 mm pulmonary nodule bilaterally. Fine-needle aspiration of the thyroid demonstrated 10-20 MUm broad-based budding yeasts with thick-walled, refractile capsules amidst a background of granulomatous inflammation, and was diagnosed as a fungal infection consistent with blastomycosis. The patient was started on treatment with itraconazole based upon the FNA diagnosis. Concurrent lung biopsy demonstrated rare possible yeast forms on histology. A specimen from the lung was sent for culture, and was positive for B. dermatitidis, confirming the diagnosis. Disseminated blastomycosis rarely involves the thyroid. However, the thyroid is amenable to fine-needle aspiration. Fungal and mycobacterial cultures and special stains for fungal organisms should be requested on all thyroid fine-needle aspiration biopsies with granulomatous inflammation. PMID- 20949467 TI - Cytological study of exfoliative buccal mucosal cells of Qat chewers in Yemen. AB - Prevalence of oral cancer is relatively increasing in Yemen in recent years, which is ascribed to Qat with other carcinogens. Since the establishment of a simple and reliable method for the detection of oral cancerous and precancerous lesions is essential, exfoliative cytology (EC) was applied to a case-control study to appraise the presence and severity of oral epithelial atypia in 300 subjects (150 were Qat chewers and 150 were non-Qat users) without prior knowledge of the subjects' Qat exposure. Ten patients with oral squamous-cell carcinoma (OSCC) were included as internal controls. Cytological atypia and hyperkeratosis were demonstrated in six and 24 subjects, respectively, and could not be ascertained in the remaining 294 and 276 correspondingly. All of the 30 (six atypia and 24 hyperkeratosis) were among the 150 Qat chewers. Cytological atypia was found in all the 10 control cases with OSCCs (eight with severe degree and two with mild atypia). For the Qat among those with atypia and hyperkeratosis, the adjusted OR and the 95% confidence level were found to be 1.6 (0.8-7.2) and 3 (10.1-21.9), respectively. In view of these findings, we suggest the use of EC for detection and assessment of oral cytological atypia. Qat use contributes to the occurrence of cytological atypia that might develop to oral precancerous or cancerous lesions. PMID- 20949468 TI - Loss of Reprimo and S100A2 expression in human gastric adenocarcinoma. AB - Reprimo and S100A2 are two newly identified candidate tumor-suppressor genes, which play an important role in the regulation of p53-dependent cell cycle. In this study, we examined the expressions of Reprimo and S100A2 in surgical specimens of gastric adenocarcinoma and correlated these results with pathological and clinical parameters. Tissues were obtained from 100 gastric adenocarcinoma patients that underwent curative gastrectomy. Reprimo and S100A2 expressions were evaluated by immunohistochemical analysis. Loss of Reprimo and S100A2 expressions occurred in 65 and 52% of the patients, respectively. Loss of Reprimo expression was significantly correlated with the depth of tumor invasion (P = 0.000), lymphatic vessel invasion (P = 0.006), and lymph node metastasis (P = 0.000). Loss of S100A2 expression was significantly associated with histological type (P = 0.009), depth of invasion (P = 0.033), lymphatic vessel invasion (P = 0.01), and lymph node metastasis (P = 0.001). In addition, there was a significant positive association between the expressions of Reprimo and S100A2 (P < 0.01). The results suggest that loss of Reprimo and S100A2 expressions occurs frequently in gastric adenocarcinomas. The expressions of Reprimo and S100A2 may be potential biomarkers for gastric adenocarcinomas detection. PMID- 20949469 TI - CellientTM automated cell block versus traditional cell block preparation: a comparison of morphologic features and immunohistochemical staining. AB - Traditional cell block (TCB) sections serve as an important diagnostic adjunct to cytologic smears but are also used today as a reliable preparation for immunohistochemical (IHC) studies. There are many ways to prepare a cell block and the methods continue to be revised. In this study, we compare the TCB with the CellientTM automated cell block system. Thirty-five cell blocks were obtained from 16 benign and 19 malignant nongynecologic cytology specimens at a large university teaching hospital and prepared according to TCB and Cellient protocols. Cell block sections from both methods were compared for possible differences in various morphologic features and immunohistochemical staining patterns. In the 16 benign cases, no significant morphologic differences were found between the TCB and Cellient cell block sections. For the 19 malignant cases, some noticeable differences in the nuclear chromatin and cellularity were identified, although statistical significance was not attained. Immunohistochemical or special stains were performed on 89% of the malignant cases (17/19). Inadequate cellularity precluded full evaluation in 23% of Cellient cell block IHC preparations (4/17). Of the malignant cases with adequate cellularity (13/17), the immunohistochemical staining patterns from the different methods were identical in 53% of cases. The traditional and Cellient cell block sections showed similar morphologic and immunohistochemical staining patterns. The only significant difference between the two methods concerned the lower overall cell block cellularity identified during immunohistochemical staining in the Cellient cell block sections. PMID- 20949470 TI - A comparative study of 200 head and neck FNAs performed by a cytopathologist with versus without ultrasound guidance: evidence for improved diagnostic value with ultrasound guidance. AB - Our previous study showed that the sensitivity of head and neck fine-needle aspiration (FNA) procedures was significantly better in the cytopathologist performed group than in the noncytopathologist-performed group (96 versus 67%). Recently, cytopathologists have learned to use ultrasound machines to assist them in performing FNA procedures. This study was designed to assess whether cytopathologist-performed FNAs with ultrasound guidance can improve diagnostic value in comparison to those done without ultrasound guidance. Two hundred consecutive head and neck FNA cases performed by the same cytopathologist with and without ultrasound guidance were reviewed. Cases consisted of 100 ultrasound guided FNAs (USGFNAs) performed between July 2008 and March 2009 and 100 palpation-guided FNAs (PGFNAs) performed before July 2008. These cases were correlated with follow-up surgical diagnosis. The diagnostic, suspicious/atypical/suggestive, and nondiagnostic rates (%) for the head and neck FNAs were 83 versus 86, 10 versus 13, and 7 versus 1 in PGFNA group versus USGFNA group, respectively. Surgical follow-up specimens were found in 50 PGFNAs versus 35 USGFNAs. The true-positive, true-negative, false-positive, and false-negative rates (%) were 92, 2, 2, and 4 versus 80, 17, 3, and 0 in PGFNAs versus USGFNAs, respectively. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 96, 50, 98, 33, and 94% in PGFNAs versus 100, 86, 97, 100, and 97% in the USGFNA group, respectively. This study also shows increased FNAs of thyroid and salivary glands and other smaller nonpalpable lesions with ultrasound guidance. USGFNAs performed by a cytopathologist could significantly improve the specificity and NPV (P = 0.04) while preserving virtually the same excellent sensitivity and PPV as those of PGFNAs. With ultrasound guidance, a cytopathologist will be able to perform FNAs in smaller, nonpalpable lesions and target complex lesions with confidence and accuracy, thus achieving a better outcome. PMID- 20949471 TI - Minimizing the diagnosis of "follicular lesion of undetermined significance" and identifying predictive features for neoplasia. AB - We used proposed standard morphologic criteria as a guideline to conduct a 10 year retrospective review of thyroid fine-needle aspiration specimens that were originally interpreted as "follicular lesion of undetermined significance" and followed by surgical intervention. We sought to investigate whether the indeterminate diagnosis could be minimized by assessing various cytomorphologic features and identifying the features predictive of neoplasia. Using the standard morphologic criteria, we semi-quantitatively assessed a total of 24 cytomorphologic features in 123 aspirates and recorded an overall interpretation on completion of the review. Cyto-histologic correlation was evaluated and logistic regression model was performed to identify cytomorphologic features predictive of neoplasia. Although 32 of 123 aspirates remained in the indeterminate category, the retrospective review reclassified 64 aspirates as non neoplasia and 27 aspirates as neoplasia. Histologic confirmation was achieved in 47 (73.4%) non-neoplastic and 15 (55.6%) neoplastic aspirates with a diagnostic accuracy of 68.1%. Furthermore, our analysis demonstrated that neoplasia is positively associated with the presence of syncytial tissue fragments, isolated microfollicles, follicles with scalloped borders, scant cytoplasm, irregular nuclear membranes, nuclear overlapping, coarse chromatin, and increased cellularity. On the contrary, the presence of honeycombing tissue fragments, background colloid, and histiocytes inversely correlated with neoplasia. Overall, using proposed standard morphological criteria can minimize the diagnosis of "follicular lesion of undetermined significance," and allow for more accurate cyto-histologic correlation, and thereby playing a substantial role in reducing unnecessary surgical intervention. PMID- 20949472 TI - Unusual clinical presentation of cutaneous malignant melanoma metastatic to the parotid gland; initially discovered by fine needle aspiration: case report and review of literature. AB - We report a case of malignant melanoma (MM) metastatic to the parotid gland, initially discovered on fine needle aspiration (FNA). The patient presented with a mass in the parotid gland area with previous history only significant for prostatic carcinoma. The initial FNA impression was melanoma. The smears were hypercellular with bloody necrotic background. The cells were epithelioid with mild nuclear atypia. Discrete cytoplasmic pigmentation was seen. No lymphoglandular bodies were noticed. Fragments of benign salivary gland were also identified. The cytological diagnosis of MM triggered onsite thorough physical examination for potential primary, where a scalp pigmented lesion was discovered hidden by overlying covering hair. Our differential diagnosis included melanoma, metastatic carcinoma, and lymphoma. Further work up for melanoma with S100, HMB45, and Mart 1 confirmed our top differential diagnosis. We emphasize thorough physical examination in such circumstances, and the importance of onsite evaluation guiding clinicians looking for primary. PMID- 20949473 TI - Adrenal histoplasmosis: a diagnosis on fine needle aspiration cytology. AB - Histoplasmosis is a fungal disease endemic in central and eastern states of United States, South America, Africa, and Asia. It may present as chronic pulmonary infection or in disseminated form of infection. The disseminated form of histoplasmosis frequently affects the adrenal gland and is more likely to affect immunocompromised patients as compared to immunocompetent individuals. There are very few cases of adrenal histoplasmosis diagnosed on fine needle aspiration cytology. In the present era when fine needle aspiration has become popular modality for diagnosis, adrenal fine needle aspiration is still a less commonly practiced technique. We report eight cases of adrenal histoplasmosis diagnosed on fine needle aspiration cytology in patients with bilateral adrenal masses. The present case series supports the role of fine needle aspiration cytology of adrenal gland infections where surgery can be prevented and a definitive diagnosis can be made on which treatment can be offered. PMID- 20949474 TI - Extramedullary hematopoiesis presented as solitary renal mass: a case report with review of literature. AB - In this article, we described a case of extramedullary hematopoiesis (EMH) in a 12-year-old boy with the clinical and hematological features of hemolytic anemia of unknown cause. The patient presented with a solitary well circumscribed mass in right kidney. Ultrasound guided fine-needle aspiration cytology showed myelocytes, metamyelocytes, megakaryocytes, and immature erythroid cells. A cytological diagnosis of EMH was made. PMID- 20949475 TI - Signet ring cell carcinoma of the cervix on cervical smear. PMID- 20949476 TI - Cytomorphological spectrum of amoebic liver abscess in an uncommon case, clinically masquerading as malignancy. PMID- 20949477 TI - Cytological diagnosis of sarcoidosis revisited: a state of the art review. AB - Diagnosis of sarcoidosis has never been an easy task. This is primarily because there is no single diagnostic test that can clinch the diagnosis. Demonstration of granulomas remains an essential criteria, but as granulomatous inflammation can be seen in host of conditions, it is necessary to exclude all possible causes, as well as to correlate with other findings, before arriving at the diagnosis of sarcoidosis. Cytology has been used effectively since the last few decades in demonstration of granulomas in various organs. Recent developments in various fields of cytodiagnosis of sarcoidosis including transesophageal ultrasound-guided fine-needle aspiration and endobronchial ultrasonograpy-guided transbronchial needle aspiration have revolutionized this field. These techniques are safe, minimally invasive, and give real-time information during aspiration. In comparision to the conventional methods, these allow easier sampling and have better sensitivity. In addition to these methods, a variety of ancillary techniques are also utilized and are reviewed here. PMID- 20949478 TI - Chondrogenesis in perfusion bioreactors using porous silk scaffolds and hESC derived MSCs. AB - Tissue engineered cartilage can be grown in vitro with the use of cell-scaffold constructs and bioreactors. The present study was designed to investigate the effects of perfusion bioreactors on the chondrogenic potential of engineered constructs prepared from porous silk fibroin scaffolds seeded with human embryonic stem cell (hESC)-derived mesencyhmal stem cells (MSCs). After four weeks of incubation, constructs cultured in perfusion bioreactors showed significantly higher amounts of glycosaminoglycans (GAGs) (p < 0.001), DNA (p < 0.001), total collagen (p < 0.01), and collagen II (p < 0.01) in comparison to static culture. Mechanical stiffness of constructs increased 3.7-fold under dynamic culture conditions and RT-PCR results concluded that cells cultured in perfusion bioreactors highly expressed (p < 0.001) cartilage-related genes when compared with static culture. Distinct differences were noted in tissue morphology, including polygonal extracellular matrix structure of engineered constructs in thin superficial zones and an inner zone under static and dynamic conditions, respectively. The results suggest that the utility of perfusion bioreactors to modulate the growth of tissue-engineered cartilage and enhance tissue growth in vitro. PMID- 20949479 TI - Added value, decreased cost: the evolving role of the cytotechnologist for preliminary screening and triage of thyroid aspirates. AB - Immediate adequacy assessment for thyroid fine-needle aspirations (FNAs) is standard practice in many cytopathology laboratories. A pathologist is usually present for these time consuming assessments. The purpose of this 5 month study (January 2008-May 2008) was to show that cytotechnologists can accurately provide the majority of immediate adequacy assessments for thyroid FNAs, saving both time and money for pathologists, clinicians, and patients. The study consisted of 167 thyroid nodule FNAs performed in twice weekly thyroid FNA clinics. A comparison was made of the immediate assessments by five participating cytotechnologists and the preliminary and final diagnoses by three pathologists. The cytotechnologist prepared the slides, assessed the air-dried Hema-DiffTM stained slides for adequacy, and the pathologist viewed the slides remotely via real-time video streaming. Results were recorded in an Excel spreadsheet. There was a discordance rate of 1.2% when comparing the cytotechnologist's adequacy interpretation and the pathologist's preliminary diagnosis; both clinically insignificant. By cytotechnologist assessment, 79.0% of the cases were benign and 6.6% were nondiagnostic. 14.4% of the cases were assessed as cellular nodule or neoplastic lesion; all requiring pathologist's preliminary diagnosis. Utilizing a cytotechnologist to provide adequacy, instead of a pathologist, saved $464.10/case (2.38 passes/case) based on current gross technical and professional charges. On the basis of our findings, cytotechnologists can accurately provide immediate onsite adequacy assessments for thyroid nodule FNAs. Affording cytotechnologists the opportunity to preliminarily assess FNAs for adequacy also creates a new role in the laboratory. Furthermore, cost-savings are realized for patients and the health care system. PMID- 20949480 TI - Transthyretin, identified by proteomics, is overabundant in pancreatic juice from pancreatic carcinoma and originates from pancreatic islets. AB - Analyses of pancreatic juice by proteomics have identified many proteins that are overabundant in pancreatic cancer (PC) juice. The mechanism by which secretion of these proteins occur remains unclear. Pancreatic juice was collected from patients with three pancreatic diseases: PC, chronic pancreatitis (CP), and simple choledocholithiasis (CDS), and analyzed by 2-DE, MALDI-TOF/MS, and Western blot. Five PC cell lines, 30 PC tissues and their corresponding adjacent pancreatic tissues were used to validate the expression of genes which code for overabundant proteins in PC juice. The mRNA and protein levels were measured by RT-PCR and immunohistochemistry, respectively. Using proteomics, it was demonstrated that the protein transthyretin (TTR) was upregulated more than 2 fold in PC juice compared with CP and CDS, while apolipoprotein A-I, lithostathine, and regenerating islet-derived 1 beta precursor were downregulated more than 2-fold. Western blots confirmed that TTR was overabundant in the PC juice. However, TTR mRNA was not detected in any of the five PC cell lines, and was only detected in islet cells. By microscopy, it was shown that islet architecture was almost completely destroyed, and the islet's maximum diameter appeared larger in PC tissues than in normal. Some overabundant proteins in PC juice, such as TTR expressed only in islets, leak into the pancreatic ductal system due to hyperplasia and architectural damage in PC tissues. The destruction of organ and tissue architecture by tumor growth may result in novel tumor markers even if the markers are not secreted directly by tumor cells. PMID- 20949481 TI - Peripheral nerve regeneration using composite poly(lactic acid caprolactone)/nerve growth factor conduits prepared by coaxial electrospinning. AB - Many neurotrophic factors have been shown to promote neurite outgrowth by improving the microenvironment that is required for nerve regeneration. However, the delivery of these bioactive agents to the nerve injury site, as well as effective and local release, remains a challenging problem. We have developed a novel composite nerve conduit comprised of poly(lactic acid-caprolactone) (P(LLA CL)) and nerve growth factor (NGF). This was developed from core-shell structured biodegradable nanofibers, which were fabricated by coaxial electrospinning of P(LLA-CL) for the shell and bovine serum albumin (BSA) or BSA/NGF for the core. In rats, gaps of 10-mm long sciatic nerves were bridged using an autograft, an empty P(LLA-CL) conduit, a NGF injection P(LLA-CL) conduit, a P(LLA-CL)/NGF composite conduit, respectively. Regenerated nerve fibers were harvested and morphological and functional evaluation of nerve regeneration was performed at 12 weeks postsurgery. Although partial biodegradation and small cracks in the conduits were observed, the conduit outlines remained intact for 12 weeks after surgery. Based on functional and histological observations, the number and arrangement of regenerated nerve fibers, myelination, and nerve function reconstruction was similar in the P(LLA-CL)/NGF conduit group to that of the nerve autograft group (p > 0.05), but was significantly greater to the empty P(LLA-CL) and injection NGF P(LLA-CL) conduit groups (both p < 0.05). Therefore, the composite P(LLA-CL)/NGF conduit, which exhibited favorable mechanical properties and biocompatibility, could effectively promote sciatic nerve regeneration in rats. PMID- 20949482 TI - Early tissue response to citric acid-based micro- and nanocomposites. AB - Composites based on calcium phosphates and biodegradable polymers are desirable for orthopedic applications because of their potential to mimic bone. Herein, we describe the fabrication, characterization, and in vivo response of novel citric acid-based microcomposites and nanocomposites. Poly(1,8-octanediol-co-citrate) (POC) was mixed with increasing amounts of hydroxyapatite (HA) nanoparticles or microparticles (up to 60 wt %), and the morphology and mechanical properties of the resulting composites were assessed. To investigate tissue response, nanocomposites, microcomposites, POC, and poly(L-lactide) were implanted in osteochondral defects in rabbits and harvested at 6 weeks for histological evaluation. Scanning electron microscopy confirmed increased surface roughness of microcomposites relative to nanocomposites. The mechanical properties of both types of composites increased with increasing amounts of HA (8-328 MPa), although nanocomposites with 60 wt % HA displayed the highest strength and stiffness. Based on tissue-implant interfacial assessments, all implants integrated well with the surrounding bone and cartilage with no evidence of inflammation. Both nanocomposites and microcomposites supported bone remodeling; however, nanocomposites induced more trabecular bone formation at the tissue-implant interface. The mechanical properties of citric acid-based composites are within the range of human trabecular bone (1-1524 MPa, 211 +/- 78 MPa mean modulus), and tissue response was dependent on the size and content of HA, providing new perspectives of design and fabrication criteria for orthopedic devices such as interference screws and fixation pins. PMID- 20949483 TI - Improving the blood compatibility of material surfaces via biomolecule immobilized mussel-inspired coatings. AB - In this article, we presented a general protocol to prepare biomolecule immobilized mussel-inspired polydopamine (PDA) coatings to improve the blood compatibility of broad ranges of material surfaces. It needs only a simple immersion of substrates in dopamine solution at alkaline pH to form mussel inspired PDA coating, and then immersing the PDA coated substrates into biomolecule solution to conjugate biomolecules. XPS, water contact angle analysis, and protein assay confirmed that biomolecules could be successfully coated on several material surfaces, including nylon, cellulose, and polyethersulfone membrane surfaces. For the protein fouling resistance, the bovine serum albumin (BSA) modified surfaces were more effective than the amino acid modified surfaces. And the platelet adhesion on the BSA-modified material surfaces was obviously depressed. These results indicated that the blood compatibility of the surfaces was improved by the biomacromolecule-immobilized mussel-inspired coating which might be considered as a universal coating to modify a wide variety of materials. PMID- 20949484 TI - A problem in diagnostic imaging. AB - Many pathological processes can present as a swelling in the groin. We present a case of complex, ruptured pyonephrosis causing a psoas collection, which in turn presented clinically as an apparent right "incarcerated inguinal hernia." The patient was successfully treated with antibiotics and ultrasound-guided drainage of the abscess. The anatomical basis of the inguinal presentation of this complex pyonephrosis can be understood in the arrangement of the renal (Gerota's) fascia. PMID- 20949485 TI - The relationships between learning outcomes and methods of teaching anatomy as perceived by medical students. AB - The best method to teach anatomy continues to be widely debated. Many UK medical schools have recently changed their course structure with the use of cadaveric dissection declining. A recent study by Patel and Moxham ([ 2008] Clin. Anat. 21:182-189) found that professional anatomists viewed dissection to be the most suitable method to fulfil anatomical learning outcomes. The opinion of 580 second year medical students across two UK medical schools was surveyed. A methodology similar to that employed by Patel and Moxham ([ 2008] Clin. Anat. 21:182-189) aimed to explore which teaching methods students considered best to fulfil a prescribed set of anatomical learning outcomes. A total of 302 responses were returned (52%). Difference in students' opinion with regard to the teaching methods was statistically significant (P < 0.0001). A statistically significant agreement was found between the opinions of students from Imperial and Nottingham, and between the anatomists and the students, regarding the effectiveness of all teaching methods at meeting learning outcomes. Dissection was overall most "fit for purpose" in meeting learning outcomes, but no single teaching modality met all aspects of the curriculum. Dissection should remain a leading teaching modality in modern medical school anatomy courses. In addition to its role in the teaching of anatomy, it enables learning in a social context and holds broader learning opportunities to help future doctors best fulfill Good Medical Practice guidelines (General Medical Council, 2006). This, however, should be in the context of a multi-modal approach to the teaching of anatomy. PMID- 20949486 TI - Ectopic pancreas, intussusception, and a ruptured mesenteric band: an unusual association. AB - Although ectopic pancreas and intussusception are not unusual conditions, intussusception caused by ectopic pancreas is extremely rare. Its presence along with a ruptured congenital mesenteric vascular band raises the possibility of an anomaly of the vitelline vascular system. We report the case of a 26-year-old man presenting with acute abdominal pain, vomiting, and diarrhea. CT scan showed a large amount of free fluid in his abdomen and an ileo-ileal intussusception. At laparotomy he was found to have hemoperitoneum with a ruptured, actively bleeding congenital band attached to the ileal mesentery, which was ligated, with ileo ileal intussusception that was resected. Histopathology showed ectopic pancreatic tissue as the lead point for the intussusception. It was likely to be a ruptured mesodiverticular band and along with other findings suggested a constellation of anomalies of the vitello-intestinal tract. PMID- 20949487 TI - Spina bifida: a diagnostic dilemma in paleopathology. AB - This article provides information regarding the etiology, pathogenesis, and skeletal manifestation of spina bifida or spinal dysraphisms. On the basis of a review of the medical literature, it addresses discrepancies in documentation and interpretation of spina bifida in paleopathology. Furthermore, it offers suggestions for use of universal terminology and highlights the difficulties in the specific diagnosis of dysraphisms in skeletal remains. In addition, the necessity of examining the entire skeleton for abnormalities to distinguish simple delay/failure of fusion of the posterior neural arches from other occult spinal dysraphisms is emphasized, as it is the need for stratification of the sample by age and sex when reporting frequencies of sacral spina bifida occulta. PMID- 20949488 TI - Structure and functional significance of the transverse vesical fold. AB - The plica vesicalis transversa or transverse vesical fold (TVF) is a peritoneal fold extending from the lateral side of the bladder to the side of the lesser pelvis near the deep inguinal ring. It is an important landmark in laparoscopic surgery of the pelvis but is variably observed in the embalmed cadaver. We investigated the gross anatomy of this structure in the cadaver and confirmed that its medial portion corresponds to the location of the superior vesical artery(ies), thus supporting the idea that the TVF is "mesovesical." However, no large vessels were observed grossly in the lateral portion of the TVF. The hypothesis that the lateral TVF has a suspensory function was tested histologically by comparison with the suspensory ligament of the duodenum and the phrenicocolic ligament, both of which have smooth muscle contributing to their inferred suspensory function. Microscopic examination of prepared samples from 20 cadavers shows that the TVF evinces no smooth muscle in either its lateral or medial segments. The TVF is demonstrated to be a mesentery-like reflection of peritoneum raised by branches of the superior vesical artery which provides no demonstrable structural support for the bladder. Implications of these findings include avoidance of sectioning of medial TVF during laparoscopic surgery because of its vascular nature, and inadvisability of utilizing any portion of theTVF for an anchor in reconstruction of the anterior pelvic floor within the paravesical fossae. PMID- 20949489 TI - Anatomical variations of the human sural nerve and its role in clinical and surgical procedures. AB - The sural nerve is the most commonly nerve used in nerve transplantation, and so the aim of this study was to determine the variations of the sural nerve in the back of the leg, its relations to the calcaneal tendon and lateral malleolus, and determine the patterns of its distribution on the dorsum of the foot. Twenty-four Egyptian legs and feet were dissected. The results showed that the sural communicating nerve connected with the sural nerve in 87.5%. The predominant site of union between these two nerves was in the lower one-third of the leg and ankle region (62%). There was only one right leg that the sural nerve passed through the gastrocnemius. The small saphenous vein passed along the medial side of the sural nerve in 100%. The sural nerve crossed the lateral border of the calcaneal tendon in 50%. The distance between the sural nerve and insertion of calcaneal tendon was 16 + 7 mm in 91.7%. There were four types of pattern of innervation of the toes by the sural nerve. The predominant pattern was type I (45.8%), where the lateral side of the little toe was supplied by the sural nerve alone. The second pattern was type IV (29.2%), where the lateral 2 1/2 toes were supplied by the sural nerve alone. These findings are important for sural nerve biopsy and grafts, surgical repair of the calcaneal tendon, and regional anesthesia of the foot. PMID- 20949490 TI - What impact does anatomy education have on clinical practice? AB - There is continuing debate regarding doctors' knowledge of anatomy as an appropriate preparation for professional practice. This exploratory case study examined alumni's experiences of learning anatomy. The aim was to inform curriculum development and to gain a better understanding of how anatomy knowledge is applied in practice. A total of 140 medical student alumni from the University of Southampton participated in this study (49% males, 51% females). Participants completed a Likert scale questionnaire with free comment sections. Descriptive results found that: using cadaveric material was an effective way of learning anatomy; assessment was a major motivator; and around half of students forgot a lot of anatomy but that knowledge came back easily. Statistical analysis revealed associations between certain positive and negative factors in learning. Links were also seen with current job role, revealing that those who responded to positive factors were involved in careers which involved a great deal of anatomy and vice versa. To facilitate learning, anatomy should be taught throughout the curriculum and use human cadavers. Relating knowledge to practice requires transformation of knowledge and is best facilitated by the learning being situated in clinical contexts. PMID- 20949492 TI - Three-dimensional morphometrical analysis of the M1 segment of the middle cerebral artery: potential clinical and neurosurgical implications. AB - With an increase in the understanding of the formation and treatment of cerebral aneurysms and an improvement in imaging technology, actual standardized measurement values for the cerebral arteries are necessary. Therefore, the aim of this study was to provide a detailed assessment of the three-dimension (3D) morphology (vessel's curvature and trajectory) and 3D-morphometry of the M1 segment of the middle cerebral artery using computer tomography angiography (CTA) images. The DICOM files from CTA of 40 male and 75 female individuals with a mean age of 50.1 years were analyzed using an interactive postprocessing 3D volume rendering algorithm. Specifically, the M1 segment was evaluated. Calculations included the length, internal diameter, volume, deviation (DI) and tortuosity indices (TI). The M1 segment had a mean internal diameter of 2.23 mm and was greater in men. M1 asymmetry was identified in 23.4% of the individuals and was more common in women. The mean length was 15.62 mm and the left M1 segments were a little longer. The mean volume of the M1 segments was 63.92 mm(3) , and this was typically greater in men and on the left sides. The mean TI and DI for the M1 segment were 0.91 and 2.17 mm, respectively. Therefore, the M1 segments are only slightly curved or straight in their course. In addition, the longest vascular M1 segments are more deviated (curved) and more tortuous. Such standardized data as presented herein may be useful in the preprocedural evaluation of patients with intracranial vascular pathology of the M1 segment. PMID- 20949493 TI - An oblique rotator belly of the abductor digiti minimi manus. PMID- 20949494 TI - Anatomical relationships within the human pterygomandibular space: Relevance to local anesthesia. AB - A thorough understanding of the anatomy of the pterygomandibular space is fundamental to the successful administration of inferior alveolar nerve (IAN) blocks, which are frequently used in dentistry for mandibular anesthesia. However, the nature and extent of anatomical variations and relationships within this space are not well documented, and descriptions vary within the literature. This study analyzed the anatomical patterns and relationships of structures in the pterygomandibular space of 56 human cadaver hemi-heads, with both left and right sides from 10 individuals being available, and described the range of variability. In most cases, the IAN was anterior to the inferior alveolar vasculature with the inferior alveolar vein(s) being closest to the bone. On average, there were two veins per specimen. The position of the inferior alveolar neurovascular bundle expressed as the ratio of its distance from the anterior border of the ramus to the total anteroposterior length of the ramus was 0.60 (standard deviation [SD] = 0.07). The distance of anterior and medial displacement of the lingual nerve to the IAN was 7.3 mm (SD = 2.4 mm) and 3.9 mm (SD = 1.6 mm), respectively. The direct distance between the IAN and lingual nerve was 8.5 mm (SD = 2.4 mm). The sphenomandibular ligament always appeared dense and fibrous, medial to the neurovascular bundle. This anatomical study highlights the extent of variations in the positioning of anatomical structures directly relevant to IAN blocks, and reassesses the rationale for the direct approach, which is currently taught and practiced throughout many countries. PMID- 20949495 TI - The prevalence of absence of the palmaris longus muscle in the Bahraini population. AB - Absence of the palmaris longus muscle has been well documented in several populations at a prevalence rate ranging between 2.2 and 63.9% which varies according to race, sex, and side of the body. There is little documentation of the prevalence of absence of this muscle from populations in the Arabian Gulf region. We examined 1,043 subjects, 3-85 years old, from the Kingdom of Bahrain for the presence or absence of the palmaris longus muscle using the conventional test for the presence of this muscle. Statistical analyses investigated the association of muscle absence with sex, hand dominance, and laterality. The palmaris longus muscle was absent in 36.8% of subjects. Bilateral absence (19%) was more common than unilateral absence (17.9%) with preponderance in female subjects. The muscle was absent more often on the left side than the right (P = 0.003). In the right upper limbs the muscle was absent in female subjects more than male subjects (P = 0.031). This study reaffirms that there is population variation in the frequency of absence of the palmaris longus muscle. The tendon of the palmaris longus bifurcated at the wrist in 7.1% of subjects, with male subjects showing this feature more frequently than female subjects in the right hand (P = 0.037) and the left hand (P = 0.030). This has not been reported before. The clinical significance of our findings is discussed. PMID- 20949496 TI - The normal and pathologic MRI appearance of the tibialis anterior proximal motor branch. AB - Foot drop, the clinical manifestation of tibialis anterior (TA) muscle dysfunction, may be caused by pathologies involving selectively the TA motor nerve branches. Recently, in patients with fibular intraneural ganglion cysts, cystic involvement of the TA motor branch from the articular branch was demonstrated. However, no imaging characteristics of this functionally important TA proximal motor branch have been reported. We hypothesized that this particular TA proximal motor branch could be visualized and characterized on high-resolution clinical magnetic resonance imaging (MRI) in both normal and pathologic cases. Twenty-six consecutive high-resolution knee MRI examinations performed for routine indications such as exclusion of intra-articular pathology and four illustrative cases imaged to evaluate pathology of the common fibular nerve and its branches (specifically the TA proximal motor branch) were retrospectively reviewed. In cases without fibular nerve pathology, the TA proximal motor branch was visualized in 21 of the 26 patients. In the cases in which the nerve was not visualized, the imaging techniques could explain the nonvisualization of the branch. The involvement of the proximal branch to the TA was evident in the four patients with pathology, which included a perineurioma, a fibular intraneural ganglion cyst, a plexiform neurofibroma, and an inflammation of the nerve. In both normal and pathologic cases, the functionally important TA proximal motor branch originating from the articular branch can be consistently visualized on high-resolution MRI. This branch can be selectively affected by a variety of pathologies and its identification on imaging may help elucidate the predominant TA muscle involvement in these patients. PMID- 20949497 TI - Surgical approach for a new knee prosthesis concept (TSTP) retaining both cruciate ligaments. AB - The transversal support tibial plateau (TSTP) concept was developed to retain both cruciate ligaments during total knee arthroplasty. TSTP design consists of two individual joint surfaces, reinforced beneath the joint line by two joint surface supports and buttressed by a single transversal support (TS). This configuration is devised to provide good bony anchoring especially for the TS, and to ensure long-term alignment of the individual joint surfaces. TS insertion requires a small extra incision. This study assessed techniques to implant the TS into the tibia. Using a specially designed aiming device, TS insertion from each side was evaluated in 13 human cadaveric knees (10 formalin-fixed, two Thiel embalmed, one fresh) at defined intervals of 15, 25, and 35 mm beneath the joint line. Particular attention was paid to potentially endangered structures, e.g., the medial collateral ligament (MCL), pes anserinus, and common peroneal nerve, as well as impediments to insertion, e.g., the fibula. TS implantation was successfully performed using both medial and lateral approaches. From medial, the TS was inserted safely at the 15 mm interval with the knee in maximum flexion and external rotation. With increasing intervals, however, the MCL and pes anserinus became progressively more susceptible to injury. In contrast, with the lateral approach, the operative field was quite close to the fibular head for the 25 mm interval. However, with the knee in extension, no other important structures were at risk. PMID- 20949498 TI - Mid-twentieth-century anatomical transparencies and the depiction of three dimensional form. AB - Before the advent of digital visualization, the "anatomical transparency"- layered images of organ systems, printed on a transparent medium--flourished in the mid-twentieth century as an interactive means to represent complex anatomical relationships to medical professionals and lay audiences. This article introduces the transparency work of medical illustrators Gladys McHugh and Ernest W. Beck, situating it in the historical context of strategies to represent three dimensional anatomical relationships using print media. PMID- 20949499 TI - The developmental anatomy of the human superior hypogastric plexus: A morphometrical investigation with clinical and surgical correlations. AB - The superior hypogastric plexus (SHP) is the part of the autonomic nervous system, which is responsible for the sympathetic innervation of pelvic organs and extrapelvic genitals in humans of both sexes. The SHP also functions as the anatomic pathway for the major part of visceral sensitive fibers originating from pelvic viscera. In this study, the morphology of the SHP was analyzed through anatomical dissections performed both in human adult and fetal cadavers. A computerized morphometrical investigation of the SHP was also performed and the resulting quantitative data statistically assessed. The comparison between fetal and adult SHP revealed that in the male group there was a developmental increase of six times (in height) and of about five times (in width); while in the female group, there was a developmental increase of 3.5 times both in height and width values. In addition, the distance from the superior border of the SHP to the bifurcation of the common iliac arteries presented a developmental increase of about six times in the male group, and about four times in the female group. We propose an original morphological classification with six types, based upon the anatomical arrangement of the nervous fibers in this autonomic plexus. PMID- 20949500 TI - A simple and rapid dispersive liquid-liquid microextraction method followed by GC FID for determination of N-methylpyrrolidine in cefepime. AB - A simple, rapid and efficient sample preparation technique, dispersive liquid liquid microextraction, coupled with gas chromatography-flame ionization detection has been developed to determine N-methylpyrrolidine in cefepime. The effect of various experimental factors on the preparation procedure, such as the nature and volume of extraction and disperser solvents, extraction time, the nature of buffer and its pH, and salt effect, was investigated, optimized and the following results were obtained: extraction solvent, chloroform; dispersive solvent and solvent for dissolving cefepime, a mixture of methanol/water (88:12, v/v); salting out agent, NaCl; and buffer, carbonate/bicarbonate (C=0.5 M, pH=12). The optimized conditions were applied to the real sample (cefepime) for the extraction and determination of N-methylpyrrolidine. The calibration graph is linear from 0.02 to 850 mg/L with the square of correlation coefficient 0.999. LOD and LOQ are 6.4 and 21.2 MUg/L in solution, respectively, and 0.2 (2*10(-5) ) and 0.6 (6*10(-5) ) MUg/g (%, w/w) in cefepime powder, respectively, using sample size 50 mg. Repeatability of the method is good and RSD% for six repeated experiments (C=170 mg/L) is 6.35%. PMID- 20949501 TI - Resolution of multicomponent mixture of amino acids using environmentally benign eluents: A green chromatographic approach. AB - A new green TLC has been used for identifying and monitoring the migration behavior of amino acids through silica and kieselguhr static flat bed in contact of n-butyl alcohol, ethyl acetate or ethylene glycol and their mixtures. From the point of view of chromatographic performance, a mixture of n-butyl alcohol-70% aqueous ethylene glycol-ethyl acetate ratio 5:3:2 by volume proves to be more efficient than the individual components for separation of amino acids from their binary, ternary and quaternary mixtures and the chromatographic parameters like DeltaR(F) , separation factor (alpha) and resolution (R(S) ) for the separation were calculated. Effect of the presence of foreign substances such as metal cations, anions, vitamins and pesticides as impurities in the sample on the separation was also examined. Effect of substitution of butanol by various alcohols has been examined to assess the impact of hydrophobicity of alcohols on the separation of amino acids. The limits of detection for tyrosine, tryptophan, alanine, isoleucine, methionine and serine were found to be 0.10 MUg/spot, whereas for lysine it is 0.05 MUg/spot. Application of the selected TLC system for the identification and separation of amino acids present in drugs/pharmaceuticals has been performed. PMID- 20949502 TI - Characterization of synthetic copolymers by interaction polymer chromatography: Separation by microstructure. AB - Gradient elution of synthetic polymers has been studied both theoretically and experimentally using normal and reversed-phase HPLC systems. An accurate equation describing the gradient elution of polymer-homologous series in the context of continuous random-flight model of a flexible polymer chain interacting with attractive surface of the porous material has been derived and experimentally verified against a series of narrow polystyrene standards. Both the theory and the experiment predict the existence of molar mass-independent gradient elution at critical point of adsorption (CPA). The extension of the theory to synthetic copolymers predicts the existence of the CPA for statistical copolymers and describes its dependence on chemical composition and microstructure (blockiness) of the polymer chains. One of the important theoretical conclusions is that blockiness always increases the retention, so that blockier polymer chains elute later than their more random counterparts with the same chemical composition. This prediction has been confirmed experimentally using block and statistical styrene-methylmethacrylate copolymers. Block copolymers do not have CPA and always elute between critical points of the corresponding homopolymers. The retention depends on the polymer molar mass and increases with the length of the blocks from a stronger absorbing monomer. These findings provide theoretical and experimental bases for separation of statistical and block copolymers by chemical composition and microstructure of polymer chains. PMID- 20949503 TI - Unbalanced 3;22 translocation with 22q11 and 3p deletion syndrome. AB - This report describes a 25-day-old Turkish boy with unbalanced 3;22 translocation that includes the 22q11.2 deletion and 3p25 deletion syndrome. The karyotype was 45, XY,der(3)t(3;22)(p25;q11),-22. Although no immunological dysfunction could be demonstrated, the boy presented some manifestations of DiGeorge anomaly (DGA), which has been associated with monosomy for the same region of chromosome 22, velocardiofacial syndrome (VCFS), and the 3p deletion syndrome. Clinical features include short stature, hypertelorism, low set ears, cleft lip with cleft palate, short neck, truncus arteriosus, micropenis, clubfoot, over riding toes on right foot, four digits on left foot and growth delay. In addition he had feeding difficulties, respiratory infections, and developmental delay. Fluorescence in situ hybridization (FISH) studies confirmed loss of the proximal DiGeorge chromosomal region (DGCR). Array CGH analysis showed the deletion sites on chromosomes 3 and 22. This report documents a rare chromosomal aberration that causes the 22q11 and 3p deletion syndrome simultaneously. PMID- 20949504 TI - Clues to an early diagnosis of Kallmann syndrome. AB - Kallmann syndrome (KS) is defined by the association of idiopathic hypogonadotropic hypogonadism and anosmia/hyposmia. Diagnosis is frequently delayed, however, because hypogonadotropic hypogonadism is usually not apparent until puberty and individuals with anosmia/hyposmia are often unaware of this sensory deficit. Mutations in at least six genes have been associated with KS; however, the sensitivity of molecular testing is only about 30% and, therefore, the diagnosis is largely based on clinical findings. We describe the findings in six individuals with KS, which demonstrate the utility of associated anomalies in making this diagnosis. Analysis of our case series and literature review suggests the consideration of KS for males with microphallus and/or cryptorchidism and for any patient with hearing loss, renal agenesis, and/or synkinesis. Conversely, patients with features of KS should have an audiology evaluation and a renal ultrasound. PMID- 20949505 TI - Giant axonal neuropathy caused by compound heterozygosity for a maternally inherited microdeletion and a paternal mutation within the GAN gene. AB - Different missense, nonsense and frameshift mutations in the GAN gene encoding gigaxonin have been described to cause giant axonal neuropathy, a severe early onset progressive neurological disease with autosomal recessive inheritance. By oligonucleotide array CGH analysis, we identified a 57-131 kb microdeletion affecting this gene in a patient with developmental delay, ataxia, areflexia, macrocephaly, and strikingly frizzy hair. The microdeletion was inherited from the mother and mutation analysis revealed a paternally inherited missense mutation c.1456G>A in exon 9 on the other allele. Our findings illustrate the power of higher resolution array CGH studies and highlight the importance of considering copy number variations in autosomal recessive diseases. PMID- 20949506 TI - Revisiting the recurrence risk of nonsyndromic cleft lip with or without cleft palate. AB - Sub-epithelial defects (i.e., discontinuities) of the superior orbicularis oris (OO) muscle appear to be a part of the phenotypic spectrum of cleft lip with or without cleft palate (CL +/- P). Analysis of the OO phenotype as a clinical tool is hypothesized to improve familial recurrence risk estimates of CL +/- P. Study subjects (n = 3,912) were drawn from 835 families. Occurrences of CL +/- P were compared in families with and without members with an OO defect. Empiric recurrence risks were calculated for CL +/- P and OO defects among first-degree relatives (FDRs). Risks were compared to published data and/or to other outcomes of this study using chi-square or Fisher's exact tests. In our cohort, the occurrence of CL +/- P was significantly increased in families with OO defects versus those without (P < 0.01, OR = 1.74). The total FDR recurrence of isolated OO defects in this cohort is 16.4%; the sibling recurrence is 17.2%. The chance for one or more FDRs of a CL +/- P proband to have an OO defect is 11.4%; or 14.7% for a sibling. Conversely, the chance for any FDR of an individual with an OO defect to have CL +/- P is 7.3%; or for a sibling, 3.3%; similar to published recurrence risk estimates of nonsyndromic (NS) CL +/- P. This study supports sub epithelial OO muscle defects as being part of the CL +/- P spectrum and suggests a modification to recurrence risk estimates of CL +/- P by utilizing OO defect information. PMID- 20949507 TI - Fetal alcohol spectrum disorders: Extending the range of structural defects. AB - Although the structural phenotype of fetal alcohol syndrome (FAS) is established, prenatal exposure to alcohol may produce a broader spectrum of defects, fetal alcohol spectrum disorder (FASD). Documenting the full spectrum of defects associated with FASD is critical to determining the true incidence of this disorder. We examined 831 children from the Collaborative Initiative on Fetal Alcohol Spectrum Disorders using a structured protocol for diagnosis of FAS using the cardinal facial and growth features, and assessment of additional structural defects thought to occur more often in children with prenatal alcohol exposure. Subjects were classified as FAS, Deferred (some characteristic features of FAS), or No FAS, Groups were compared on prevalence of additional features and number of additional features observed, stratified by diagnostic category, sex, race, and age. Prevalence of most additional features was greatest among subjects with FAS and least among No FAS. A higher frequency of additional features was observed among FAS and Deferred subjects >=12 years of age than among those under 12. FAS and Deferred Whites had greater frequency of additional features than Cape Colored. Prenatal alcohol exposure may produce a broad spectrum of structural defects that goes beyond FAS with implications regarding the impact of alcohol on the developing fetus, a prerequisite for ultimate prevention of FASD. PMID- 20949508 TI - Phenotype and natural history in Marshall-Smith syndrome. AB - Marshall-Smith syndrome (MSS) is a distinctive entity of unknown etiology with fewer than 50 patients described in the medical literature to date. Through an International collaboration and use of an online wiki to facilitate data collection and sharing, we further delineate the phenotype and natural history of this syndrome. We present 15 new patients, the oldest being 30 years, provide an update on four previously published cases, and compare all patients with other patients reported in literature. Main clinical features are moderate to severe developmental delay with absent or limited speech, unusual behavior, dysharmonic bone maturation, respiratory compromise secondary to upper airway obstruction, short stature, and kyphoscoliosis. Facial features are characteristic with high forehead, underdeveloped midface, proptosis, anteverted nares, and everted lips. Minor abnormalities of brain morphology such as hypoplasia of the corpus callosum are common. Mortality from respiratory complications is high, but airway support increasingly allows survival into adulthood. Array-CGH was performed on 12 of the cohort and no copy number variants of clear clinical relevance were identified. The present study is the first reported use of an online wiki to aid delineation of a genetic syndrome, and illustrates its value in collecting detailed data in rare conditions. PMID- 20949509 TI - Co-occurrence of early-onset Parkinson disease and 22q11.2 deletion syndrome: Potential role for dopamine transporter imaging. PMID- 20949510 TI - The temperature intervals with global exchange of replicas empirical accelerated sampling method: parameter sensitivity and extension to a complex molecular system. AB - The recently developed "temperature intervals with global exchange of replicas" (TIGER2) algorithm is an efficient replica-exchange sampling algorithm that provides the freedom to specify the number of replicas and temperature levels independently of the size of the system and temperature range to be spanned, thus making it particularly well suited for sampling molecular systems that are considered to be too large to be sampled using conventional replica exchange methods. Although the TIGER2 method is empirical in nature, when appropriately applied it is able to provide sampling that satisfies the balance condition and closely approximates a Boltzmann-weighted ensemble of states. In this work, we evaluated the influence of factors such as temperature range, temperature spacing, replica number, and sampling cycle design on the accuracy of a TIGER2 simulation based on molecular dynamics simulations of alanine dipeptide in implicit solvent. The influence of these factors is further examined by calculating the properties of a complex system composed of the B1 immunoglobulin binding domain of streptococcal protein G (protein G) in aqueous solution. The accuracy of a TIGER2 simulation is particularly sensitive to the maximum temperature level selected for the simulation. A method to determine the appropriate maximum temperature level to be used in a TIGER2 simulation is presented. PMID- 20949511 TI - Theoretical study on the kinetics of OH radical reactions with CH3OOH and CH3CH2OOH. AB - The mechanisms and kinetics studies of the OH radical with alkyl hydroperoxides CH(3)OOH and CH(3)CH(2)OOH reactions have been carried out theoretically. The geometries and frequencies of all the stationary points are calculated at the UBHandHLYP/6-311G(d,p) level, and the energy profiles are further refined by interpolated single-point energies method at the MC-QCISD level of theory. For two reactions, five H-abstraction channels are found and five products (CH(3)OO, CH(2)OOH, CH(3)CH(2)OO, CH(2)CH(2)OOH, and CH(3)CHOOH) are produced during the above processes. The rate constants for the CH(3)OOH/CH(3)CH(2)OOH + OH reactions are corrected by canonical variational transition state theory within 250-1500 K, and the small-curvature tunneling is included. The total rate constants are evaluated from the sum of the individual rate constants and the branching ratios are in good agreement with the experimental data. The Arrhenius expressions for the reactions are obtained. PMID- 20949512 TI - Crystal molecular dynamics simulations to speed up MM/PB(GB)SA evaluation of binding free energies of di-mannose deoxy analogs with P51G-m4-Cyanovirin-N. AB - Complexes of two Cyanovirin-N (CVN) mutants, m4-CVN and P51G-m4-CVN, with deoxy di-mannose analogs were employed as models to generate conformational ensembles using explicit water Molecular Dynamics (MD) simulations in solution and in crystal environment. The results were utilized for evaluation of binding free energies with the molecular mechanics Poisson-Boltzmann (or Generalized Born) surface area, MM/PB(GB)SA, methods. The calculations provided the ranking of deoxy di-mannose ligands affinity in agreement with available qualitative experimental evidences. This confirms the importance of the hydrogen-bond network between di-mannose 3'- and 4'-hydroxyl groups and the protein binding site B(M) as a basis of the CVN activity as an effective HIV fusion inhibitor. Comparison of binding free energies averaged over snapshots from the solution and crystal simulations showed high promises in the use of the crystal matrix for acceleration of the conformational ensemble generation, the most time consuming step in MM/PB(GB)SA approach. Correlation between energy values based on solution versus crystal ensembles is 0.95 for both MM/PBSA and MM/GBSA methods. PMID- 20949513 TI - Structure and dynamics of methanol in water: a quantum mechanical charge field molecular dynamics study. AB - An ab initio quantum mechanical charge field molecular dynamics simulation was carried out for one methanol molecule in water to analyze the structure and dynamics of hydrophobic and hydrophilic groups. It is found that water molecules around the methyl group form a cage-like structure whereas the hydroxyl group acts as both hydrogen bond donor and acceptor, thus forming several hydrogen bonds with water molecules. The dynamic analyses correlate well with the structural data, evaluated by means of radial distribution functions, angular distribution functions, and coordination number distributions. The overall ligand mean residence time, tau identifies the methanol molecule as structure maker. The relative dynamics data of hydrogen bonds between hydroxyl of methanol and water molecules prove the existence of both strong and weak hydrogen bonds. The results obtained from the simulation are in excellent agreement with the experimental results for dilute solution of CH(3)OH in water. The overall hydration shell of methanol consists in average of 18 water molecules out of which three are hydrogen bonded. PMID- 20949514 TI - Rapid evaluation of the binding energies in hydrogen-bonded amide-thymine and amide-uracil dimers in gas phase. AB - The binding energies and the equilibrium hydrogen bond distances as well as the potential energy curves of 48 hydrogen-bonded amide-thymine and amide-uracil dimers are evaluated from the analytic potential energy function established in our lab recently. The calculation results show that the potential energy curves obtained from the analytic potential energy function are in good agreement with those obtained from MP2/6-311+G** calculations by including the BSSE correction. For all the 48 dimers, the analytic potential energy function yields the binding energies of the MP2/6-311+G** with BSSE correction within the error limits of 0.50 kcal/mol for 46 dimers, only two differences are larger than 0.50 kcal/mol and the largest one is only 0.60 kcal/mol. The analytic potential energy function produces the equilibrium hydrogen bond distances of the MP2/6-311+G** with BSSE correction within the error limits of 0.050 A for all the 48 dimers. The analytic potential energy function is further applied to four more complicated hydrogen bonded amide-base systems involving amino acid side chain and beta-sheet. The values of the binding energies and equilibrium hydrogen bond distances obtained from the analytic potential energy function are also in good agreement with those obtained from MP2 calculations with the BSSE correction. These results demonstrate that the analytic potential energy function can be used to evaluate the binding energies in hydrogen-bonded amide-base dimers quickly and accurately. PMID- 20949515 TI - A minimal implementation of the AMBER-GAUSSIAN interface for ab initio QM/MM-MD simulation. AB - For applying to a number of theoretical methodologies based on an ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics method connecting AMBER9 with GAUSSIAN03, we have developed an AMBER-GAUSSIAN interface (AG-IF), which can be one of the simplest architectures. In the AG-IF, only a few subroutines addition is necessary to retrieve the QM/MM energy and forces, obtained by GAUSSIAN, for solving a set of Newtonian equations of motion in AMBER. It is, therefore, easy to be modified for individual applications since AG IF utilizes most of those functions originally equipped not only in AMBER but also in GAUSSIAN. In the present minimal implementation, only AMBER is modified, whereas GAUSSIAN is left unchanged. Moreover, a different method of calculating electrostatic forces of MM atoms interacting with QM region is proposed. Using the AG-IF, we also demonstrate three examples of application: (i) the QM versus MM comparison in the radial distribution function, (ii) the free energy gradient method, and (iii) the charge from interaction energy and forces. PMID- 20949516 TI - Electronic and vibrational linear and nonlinear polarizabilities of Li@C60 and [Li@C60]+. AB - Electronic and vibrational nuclear relaxation (NR) contributions to the dipole (hyper)polarizabilities of the endohedral fullerene Li@C(60) and its monovalent cation [Li@C(60)](+) are calculated at the (U)B3LYP level. Many results are new, while others differ significantly from those reported previously using more approximate methods. The properties are compared with those of the corresponding hypothetical noninteracting systems with a valence electron transferred from Li to the cage. Whereas the NR contribution to the static linear polarizabilities is small in comparison with the corresponding electronic property, the opposite is true for the static hyperpolarizabilities. A relatively small, but non negligible, NR contribution to the dc-Pockels effect is obtained in the infinite frequency approximation. PMID- 20949517 TI - Assessing the performance of the molecular mechanics/Poisson Boltzmann surface area and molecular mechanics/generalized Born surface area methods. II. The accuracy of ranking poses generated from docking. AB - In molecular docking, it is challenging to develop a scoring function that is accurate to conduct high-throughput screenings. Most scoring functions implemented in popular docking software packages were developed with many approximations for computational efficiency, which sacrifices the accuracy of prediction. With advanced technology and powerful computational hardware nowadays, it is feasible to use rigorous scoring functions, such as molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) and molecular mechanics/generalized Born surface area (MM/GBSA) in molecular docking studies. Here, we systematically investigated the performance of MM/PBSA and MM/GBSA to identify the correct binding conformations and predict the binding free energies for 98 protein-ligand complexes. Comparison studies showed that MM/GBSA (69.4%) outperformed MM/PBSA (45.5%) and many popular scoring functions to identify the correct binding conformations. Moreover, we found that molecular dynamics simulations are necessary for some systems to identify the correct binding conformations. Based on our results, we proposed the guideline for MM/GBSA to predict the binding conformations. We then tested the performance of MM/GBSA and MM/PBSA to reproduce the binding free energies of the 98 protein-ligand complexes. The best prediction of MM/GBSA model with internal dielectric constant 2.0, produced a Spearman's correlation coefficient of 0.66, which is better than MM/PBSA (0.49) and almost all scoring functions used in molecular docking. In summary, MM/GBSA performs well for both binding pose predictions and binding free energy estimations and is efficient to re-score the top-hit poses produced by other less-accurate scoring functions. PMID- 20949518 TI - A novel predictive model for formation enthalpies of Si and Ge hydrides with propane- and butane-like structures. AB - Butane- and propane-like silicon-germanium hydrides and chlorinated derivatives represent a new class of precursors for the fabrication of novel metastable materials at low-temperature regimes compatible with selective growth and commensurate with the emerging demand for the reduced thermal budgets of complementary metal oxide semiconductor integration. However, predictive simulation studies of the growth process and reaction mechanisms of these new compounds, needed to accelerate their deployment and fine-tune the unprecedented low-temperature and low-pressure synthesis protocols, require experimental thermodynamic data, which are currently unavailable. Furthermore, traditional quantum chemistry approaches lack the accuracy needed to treat large molecules containing third-row elements such as Ge. Accordingly, here we develop a method to accurately predict the formation enthalpy of these compounds using atom-wise corrections for Si, Ge, Cl, and H. For a test set of 15 well-known hydrides of Si and Ge and their chlorides, such as Si(3)H(8), Ge(2)H(6), SiGeH(6), SiHCl(3), and GeCl(4), our approach reduces the deviations between the experimental and predicted formation enthalpies obtained from complete basis set (CBS-QB3), G2, and B3LPY thermochemistry to levels of 1-3 kcal/mol, or a factor of ~5 over the corresponding uncorrected values. We show that our approach yields results comparable or better than those obtained using homodesmic reactions while circumventing the need for thermochemical data of the associated reaction species. Optimized atom-wise corrections are then used to generate accurate enthalpies of formation for 39 pure Si-Ge hydrides and a selected group of 20 chlorinated analogs, of which some have recently been synthesized for the first time. Our corrected enthalpies perfectly reproduce the experimental stability trends of heavy butane-like compounds containing Ge. This is in contrast to the direct application of the CBS-QB3 method, which yields erratic predictions. Our approach also provides quantitative bond-additivity rules for the chlorination of these heavier species. Finally, we discuss structure and bonding trends across the entire sequence of butane-, propane-, and ethane-like molecules with a special focus on the isomeric variations. PMID- 20949519 TI - A theoretical survey on the structures, energetics, and isomerization pathways of the B(5)O radical. AB - Boron-centered radicals have received growing interest. Recently, two groups reported density functional theory investigations (GGA-PW91 and B3LYP) on a hexa atomic boron-oxide radical, B(5)O, which has led to great discrepancies on the type of low-lying structures. In this article, we not only explore the energetics of doublet and quartet B(5)O isomers at high electron-correlated levels (CCSD(T)/6-311+G(2df), CCSD(T)/aug-cc-pVTZ, and G3B3) but also investigate the isomerization and fragmentation stability of the low-lying B(5)O isomers. All the high-level studies consistently show that the B(5)O radical possesses a belt-like ground structure (2)01 in doublet electronic state followed by isomer (2)02 with an exocyclic - BO moiety at around 3.0 kcal/mol. Kinetically, (2)01 and (2)02 are separated by a considerable barrier of about 20 kcal/mol. Thus, the two isomeric forms of B(5)O radical should be very promising for isolation in laboratory. However, the other four isomers reported recently are all kinetically unstable toward conversion to (2)01 and (2)02. The high thermodynamic and kinetic stability of (2)01 and (2)02 might make them as important building cores in the growth of boron-oxide clusters. This results would also help deeply understand the oxidation and doping mechanism of pure boron clusters. PMID- 20949520 TI - The importance of mentors in a 20-year gestation. PMID- 20949521 TI - Tibial developmental field defect in valproic acid embryopathy: Report on three cases. AB - Prenatal exposure to valproic acid (VA) is associated with an increased risk of congenital malformations, especially limb defects like radial ray defects. Tibial developmental field defect in VA embryopathy remains exceptional. We report on three patients presenting with tibial hypo/aplasia associated with either femoral bifurcation or radial ray defect following prenatal exposure to VA. Femoral bifurcation and tibial agenesis has been described in the Gollop-Wolfgang complex and in the tibial agenesis-ectrodactyly syndrome. Tibial agenesis has also been reported in VACTERL association. The relation between prenatal exposure to VA and tibial agenesis is discussed. PMID- 20949522 TI - Discordance for Schimmelpenning-Feuerstein-Mims syndrome in monochorionic twins supports the concept of a postzygotic mutation. AB - The Schimmelpenning-Feuerstein-Mims (SFM) syndrome comprises a craniofacial nevus sebaceus, seizures, developmental delay, ocular and skeletal abnormalities. It is a sporadic condition and hypothesized to result from mosaicism involving a lethal autosomal dominant gene. We report a second occurrence of discordant monozygotic (MZ) twins with severe SFM, supporting the concept of a postzygotic mutation. PMID- 20949523 TI - Use of irinotecan for treatment of small cell carcinoma of the prostate. AB - BACKGROUND: Prostatic small cell carcinoma (SCC) is a rare variant of prostate cancer. It is extremely aggressive and resistant to available therapies with a median survival range of 5-17 months. No standard chemotherapeutic regimen has been established for its treatment. In search of a new therapeutic approach, we examined the response of patient-derived prostatic SCC tissue xenografts to irinotecan, a topoisomerase I inhibitor. METHODS: A tumor tissue line was established from a patient's prostatic SCC by subrenal capsule grafting using NOD SCID mice. Mice carrying subcutaneous transplants of the tumor line were then treated for 2 weeks with irinotecan alone and in combination with cisplatin. The effect on tumor volume, histopathology, and apoptosis were determined. RESULTS: The prostatic SCC tissue line resembled the donor tissue in morphologic and immunohistochemical features. Irinotecan (20 mg/kg/day; days 1-3, 8-10) completely arrested xenograft growth with a small reduction in tumor volume and only minor weight loss of the hosts (7%); irinotecan (12 mg/kg; same schedule) + cisplatin (2.5 mg/kg/day; days 1 and 8) had a similar effect, but with lower weight loss. While the growth inhibition involved apoptosis, it was also associated with a marked increase in autophagy. CONCLUSIONS: Tumor tissue lines established via subrenal capsule xenografting provide models with clinical relevance and the present study suggests that irinotecan could be useful for therapy of refractory prostatic SCC, in particular in combination with cisplatin. PMID- 20949524 TI - Natural history of Christianson syndrome. AB - Christianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types. Gilfillan et al.2008] reported mutations in SLC9A6, the gene encoding the sodium/hydrogen exchanger NHE6, in the family first reported and in three others. They also noted the clinical similarities to Angelman syndrome and found cerebellar atrophy on MRI and elevated glutamate/glutamine in the basal ganglia on MRS. Here we report on nonsense mutations in two additional families. The natural history is detailed in childhood and adult life, the similarities to Angelman syndrome confirmed, and the MRI/MRS findings documented in three affected boys. PMID- 20949525 TI - Expression and activation of ephexin is altered after spinal cord injury. AB - Failure of axon regeneration after traumatic spinal cord injury (SCI) is attributable in part to the presence of inhibitory molecular interactions. Recent evidence demonstrates that activation of Eph signaling pathways leads to modulation of growth cone dynamics and repulsion through the activation of ephexin, a novel guanine nucleotide exchange factor (GEF). However, little is known about the expression and modulation of Eph molecular targets in the injured spinal cord. In this study, we determined the expression profile of ephexin after a moderate spinal cord contusion at thoracic level (T10) in young adult rats. Western-blot studies showed increased protein expression in injured rats at 4 and 7 days postinjury (DPI) when compared with control animals. The protein levels returned to normal at 14 DPI and remained steady until 28 DPI. However, immunoprecipitation studies of the phosphorylated ephexin demonstrated that this protein is activated by day 2 until 14 DPI. Expression of ephexin was noticeable in neurons, axons, microglia/macrophages, and reactive astrocytes, and co localized with EphA3, A4, and A7. These results demonstrate the presence of ephexin in the adult spinal cord and its activation after SCI. Therefore, we show, for the first time, the spatiotemporal pattern of ephexin expression and activation after contusive SCI. Collectively, our data support our previous findings on the putative nonpermissive roles of Eph receptors after SCI and the possible involvement of ephexin in the intracellular cascade of events. PMID- 20949526 TI - The effect of environmental harshness on neurogenesis: a large-scale comparison. AB - Harsh environmental conditions may produce strong selection pressure on traits, such as memory, that may enhance fitness. Enhanced memory may be crucial for survival in animals that use memory to find food and, thus, particularly important in environments where food sources may be unpredictable. For example, animals that cache and later retrieve their food may exhibit enhanced spatial memory in harsh environments compared with those in mild environments. One way that selection may enhance memory is via the hippocampus, a brain region involved in spatial memory. In a previous study, we established a positive relationship between environmental severity and hippocampal morphology in food-caching black capped chickadees (Poecile atricapillus). Here, we expanded upon this previous work to investigate the relationship between environmental harshness and neurogenesis, a process that may support hippocampal cytoarchitecture. We report a significant and positive relationship between the degree of environmental harshness across several populations over a large geographic area and (1) the total number of immature hippocampal neurons, (2) the number of immature neurons relative to the hippocampal volume, and (3) the number of immature neurons relative to the total number of hippocampal neurons. Our results suggest that hippocampal neurogenesis may play an important role in environments where increased reliance on memory for cache recovery is critical. PMID- 20949527 TI - Elsahy-Waters syndrome: Evidence for autosomal recessive inheritance. AB - Elsahy-Waters or branchioskeletogenital syndrome is a rare MCA/MR syndrome characterized by moderate mental retardation, hypospadias and characteristic craniofacial morphology, which includes brachycephaly, facial asymmetry, exotropia, hypertelorism/telechantus, broad nose, concave nasal ridge, underdeveloped midface, prognathism, and radicular dentin dysplasia. Here we report on a 44-year-old woman and her 45-year-old brother, born to consanguineous parents, who show a striking resemblance to the earlier described patients. The hitherto reported patients were male and in one pedigree parents were consanguineous. The present report of an affected woman and her brother, born to consanguineous parents, supports autosomal recessive inheritance of this condition. We provide a short review of all previously reported patients with Elsahy-Waters syndrome and related entities. PMID- 20949528 TI - Germline mosaicism for the c.2021G > A (p.Arg674Gln) mutation in siblings with trismus pseudocamptodactyly. PMID- 20949529 TI - Elbow deformities in a patient with mandibuloacral dysplasia type A. PMID- 20949530 TI - The progeny of homozygous identical reciprocal translocation carrier mother. PMID- 20949531 TI - A novel homozygous Arg222Trp missense mutation in WNT7A in two sisters with severe Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. AB - Al-Awadi/Raas-Rothschild/Schinzel phocomelia (AARRS) syndrome, a rare autosomal recessive disorder, comprises malformations of upper and lower limbs with severely hypoplastic pelvis and abnormal genitalia. Mutations in WNT7A have been reported as cause of the syndrome. We report on two sisters in a Thai family with short and malformed long bones, absent fibulae, flexion contracture of digits, and a/hypoplastic nails. Fusion between severely malformed femora and slender tibiae has never been reported in patients with WNT7A mutations. Lower limbs were more severely malformed than the upper ones and the pelvis was also severely affected. Multiple fusions of long bones and of the femoral heads to the acetabula were evident. A novel homozygous missense mutation in coding exon 4 of the WNT7A was detected in both affected daughters (c.664C > T) leading to an amino acid exchange from arginine to tryptophan (p.Arg222Trp; R222W). The phenotype is likely to result from an abnormality of all three signaling centers in the developing limb resulting in ventralization with a loss of dorsal structures (aplasia/hypoplasia of nails) a loss of anterior-posterior identity (single distal bones in lower limb without polarity) and an outgrowth defect resulting in distal truncations. PMID- 20949532 TI - Typical cMRI pattern as diagnostic clue for D-bifunctional protein deficiency without apparent biochemical abnormalities in plasma. AB - D-bifunctional protein deficiency (DBPD) is an autosomal recessive disease caused by a defect in peroxisomal beta-oxidation. The majority of patients suffer from a severe neurological disease with neonatal hypotonia and seizures and die within the first 2 years of life. Few patients show milder clinical phenotypes with prolonged survival. The diagnosis relies on the clinical presentation, measurement of peroxisomal markers, including very long chain fatty acids (VLCFA) in plasma, followed by enzymatic studies in fibroblasts and genetic testing. Diagnosis can be difficult to establish in milder cases, especially if VLCFA concentration in plasma is not or only mildly elevated. We report on siblings in which initial measurement of plasma VLCFA did not indicate a peroxisomal disease. Nevertheless, cMRI showed a pattern typical for an inborn peroxisomal disease with cerebral and cerebellar leukencephalopathy, perisylvic polymicrogyria, and frontoparietal pachygyria. Repeated measurements of peroxisomal metabolites in plasma prompted by the cMRI findings showed values in the upper normal or mildly elevated range and led to further diagnostic steps. The diagnosis of a type III DBPD with a missense mutation (T15A) in the HSD17B4 gene, coding for D bifunctional protein (DBP), could be established. We conclude that a typical "peroxisomal pattern" in cMRI including cerebral and cerebellar leukencephalopathy, perisylvic polymicrogyria and pachygyria is a valuable clue to the diagnosis of DBPD, especially in cases with no or only very mild abnormalities in plasma. PMID- 20949533 TI - A novel X-linked multiple congenital anomaly syndrome associated with an EBP mutation. AB - Mutations of the gene coding for emopamil binding protein (EBP) can lead to deficient activity of 3-beta-hydroxysteroid Delta(8), Delta(7) isomerase and are most commonly identified in. association with the X-linked dominant (male lethal) chondrodysplasia punctata (CDPX2), also known as Conradi-Hunermann syndrome. Our group has identified a hemizygous EBP mutation in males with a phenotype remarkable for Dandy-Walker malformation, cataracts, collodion skin and cryptorchidism. Additional findings of hydrocephalus, dysplasia of the corpus callosum, cardiovascular, craniofacial and skeletal anomalies were regularly seen in affected males and the family histories were supportive of an X-linked recessive condition. The regularly reproducible constellation of cardinal features aligns very nicely with other disorders of sterol biosynthesis and is further distinguished by an absence of arty clinical manifestations in obligate carrier females. Biochemical analysis of blood from cases demonstrated markedly increased levels of 8(9)-cholestenol, and 8-dehydroeholesterol and a mildly increased level of 7-dehydrocholesterol; a similar pattern to what is seen in CDPX2. Sequence analysis of EJJP revealed a novel hemizygous missense mutation at position 141, predictive of a tryptophan to cysteine substitution (c.141G>T, p.W47C). The unaffected mothers were heterozygous for the c.141G>T mutation arid showed random X-inactivation pattern upon. PMID- 20949534 TI - Abstracts of the 4th Cornelia de Lange Syndrome Scientific Symposium. June 24, 2010. Dallas, Texas, USA. PMID- 20949535 TI - Role of serum carbohydrate antigen 19-9 and carcinoembryonic antigen in distinguishing between benign and invasive intraductal papillary mucinous neoplasm of the pancreas. AB - BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has malignant potential. Although serum levels of carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) are known to be raised in pancreatic ductal adenocarcinoma, little has been reported about their significance in IPMN. METHODS: Preoperative CA19-9 and CEA levels were measured in consecutive patients undergoing surgical resection for IPMN. Results were correlated with histopathological and clinical features. RESULTS: In 142 patients, raised CEA and CA19-9 serum levels were significantly associated with invasiveness in both branch-duct and main-duct/mixed-type IPMN. Some 74 per cent of patients with an invasive IPMN had raised levels of CA19-9, compared with only 14 per cent who had non-invasive tumours. With a cut-off level of 37 units/ml, CA19-9 had a specificity of 85.9 per cent, a negative predictive value of 85.9 per cent, a positive predictive value of 74.0 per cent and accuracy of 81.7 per cent. Overall, 80 per cent of patients with an invasive IPMN had raised serum levels of CA19-9 and/or CEA compared with only 18 per cent of those with a non-invasive tumour (P < 0.001). CONCLUSION: Serum CA19-9 is a useful non-invasive preoperative tool for differentiating between invasive and benign IPMN, and should be taken into account in the decision to offer surgery. Patients with an IPMN and positive tumour markers have a high risk of malignant disease. PMID- 20949536 TI - Clinical characterization of a girl with trisomy 20q13.2qter and monosomy 13q33.1qter: Delineating phenotype-genotype correlations. PMID- 20949537 TI - Candidate gene sequencing of LHX2, HESX1, and SOX2 in a large schizencephaly cohort. AB - Schizencephaly is a malformation of cortical development characterized by gray matter-lined clefts in the cerebral cortex and a range of neurological presentations. In some cases, there are features of septo-optic dysplasia concurrently with schizencephaly. The etiologies of both schizencephaly and septo optic dysplasia are thought to be heterogeneous, but there is evidence that at least some cases have genetic origin. We hypothesized that these disorders may be caused by mutations in three candidate genes: LHX2, a gene with an important cortical patterning role, and HESX1 and SOX2, genes that have been associated with septo-optic dysplasia. We sequenced a large cohort of patients with schizencephaly, some with features of septo-optic dysplasia, for mutations in these genes. No pathogenic mutations were observed, suggesting that other genes or non-genetic factors influencing genes critical to brain development must be responsible for schizencephaly. PMID- 20949538 TI - Nickel nanocone-array supported silicon anode for high-performance lithium-ion batteries. PMID- 20949539 TI - X-ray detected magnetic hysteresis of thermally evaporated terbium double-decker oriented films. PMID- 20949540 TI - A graphene nanoribbon memory cell. PMID- 20949541 TI - Poly-beta-hydroxybutyrate accumulation in cyanobacteria under photoautotrophy. AB - Poly-beta-hydroxybutyrate (PHB) is a biodegradable and biocompatible polymer that has immense potential in the field of environmental, agricultural and biomedical sciences. An alternative host system has been explored in this study for low-cost production. Examination of 25 cyanobacterial species from 19 different genera for photoautrophic production of polyhydroxyalkanoates (PHAs) under batch culture demonstrated that 20 species were poly-beta-hydroxybutyrate (PHB) accumulators, while others were found to be negative. Presence of PHB was confirmed by UV spectroscopy, (1)H-NMR spectroscopy and GC-MS analysis. Accumulation of PHB in cyanobacteria was found to be species specific. The PHB extracted from Nostoc muscorum exhibited comparable material properties with the commercial PHB, thus advocating its potential applications in various fields. PMID- 20949542 TI - Glycosylation influences on the aggregation propensity of therapeutic monoclonal antibodies. AB - Monoclonal antibodies are the fastest growing class of biologics in the pharmaceutical industry. The correlation between mAb glycosylation and aggregation has not been elucidated in detail, yet understanding the structure stability relationship involving glycosylation is critical for developing successful drug formulations. We conducted studies of temperature-induced aggregation and compared the stability of both glycosylated and aglycosylated forms of a human IgG1. In parallel, we also performed molecular dynamics simulations of the glycosylated full antibody to gain an understanding of the polysaccharide surroundings at the molecular level. Aglycosylated mAbs are somewhat less stable and therefore aggregate more easily than the glycosylated form at the temperatures studied. Glycosylation seems to enhance solubility and stability of these therapeutics and thus might be important for long-term storage. PMID- 20949543 TI - A MEMS-based spiral channel dielectrophoretic chromatography system for cytometry applications. AB - In this paper design, fabrication, and evaluation of an easy-to-use and low cost dielectrophoretic quantizer are introduced. The device works with standard tools in a biomedical laboratory: a stereo microscope with CCD camera and a voltage supply. A novel spiral microchannel geometry together with the coaxial electrode configuration is established. The device works with a droplet of sample, eliminating microfluidic connections, and external syringes. The proposed geometry decreases the footprint, therefore reduces the device cost, without compromizing the separation and quantization performances. Coaxial electrode geometry enables continuous electric-field application with simple voltage supplies. The devices are fabricated using a simple 3-mask process, and experiments are realized with 1 and 10 MUm polystyrene beads. The results show that 1 MUm particles have an average speed of 4.57 MUm/s with 1.06 MUm/s SD, and 10 MUm particles have an average speed of 544 MUm/s with 105 MUm/s SD. The speed variation coefficient for 1 and 10 MUm beads can be calculated as 23 and 19%, respectively. The size accuracy of the device is +/- 10%, while the resolution is 20%, i.e., particles with radii different from each other by 20% can be separated. Hence, moderate separation performance with minimized cost and standard laboratory equipment is enabled. PMID- 20949544 TI - Absence of microcephalin gene mutations in a large cohort of non-consanguineous patients with autosomal recessive primary microcephaly. PMID- 20949545 TI - Statement on national worklife priorities. AB - The National Institute for Occupational Safety and Health (NIOSH) WorkLife Initiative (WLI) [http://www.cdc.gov/niosh/worklife] seeks to promote workplace programs, policies, and practices that result in healthier, more productive employees through a focus simultaneously on disease prevention, health promotion, and accommodations to age, family, and life stage. The Initiative incorporates the Institute's foundational commitment to workplaces free of recognized hazards into broader consideration of the factors that affect worker health and wellbeing. Workplace hazards, such as physical demands, chemical exposures, and work organization, often interact with non-work factors such as family demands and health behaviors to increase health and safety risks. New workplace interventions being tested by the first three NIOSH WLI Centers of WorkLife Excellence are exploring innovative models for employee health programs to reduce the human, social, and economic costs of compromised health and quality of life. Many parties in industry, labor, and government share the goals of improving employee health while controlling health care costs. NIOSH convened a workshop in 2008 with representatives of the three Centers of Excellence to develop a comprehensive, long-range strategy for advancing the WorkLife Initiative. The recommendations below fall into three areas: practice, research, and policy. Responding to these recommendations would permit the WorkLife Center system to establish a new infrastructure for workplace prevention programs by compiling and disseminating the innovative practices being developed and tested at the Centers, and elsewhere. The WLI would also extend the customary scope of NIOSH by engaging with multiple NIH Institutes that are already generating research-to-practice programs involving the working-age population, in areas such as chronic disease prevention and management. Research to Practice (r2p) is a concept focused on the translation of research findings, technologies, and information into evidence based prevention practices and products that are adopted in the workplace or other "real-world" settings. NIOSH's goal is to overcome the translational issues that now prevent state-of-the-art occupational health, health promotion, and chronic disease research findings from benefiting working age populations immediately, regardless of workplace size, work sector, or region of the country. PMID- 20949546 TI - A role for class 3 semaphorins in prostate cancer. AB - BACKGROUND: Class 3 semaphorins are secreted proteins that act as guidance cues for migrating cells via their transmembrane receptors plexins and neuropilins. Semaphorins have a role in cancer affecting tumor progression both directly, and indirectly by affecting angiogenesis. METHODS: The expression of semaphorins and their receptors in prostate cancer cell lines and tissue was determined by RT PCR, Western blotting and immunohistochemistry. The effect of Sema3E on prostate cancer cell lines was determined by adhesion assays and transwell migration assays. RESULTS: Semaphorins and their receptors, plexins and neuropilins, are widely co-expressed in prostate cancer cell lines and tissue with a significant overexpression of Sema3E in tumor tissue. Sema3E affected integrin-mediated adhesion to fibronectin of prostate cancer cells, and inhibited their motility. Expression of Sema3C was upregulated and Sema3A and Sema3E were down regulated in prostate cells by hypoxia, consistent with an additional role for Sema3A and 3E as anti-angiogenic factors in prostate cancer. CONCLUSIONS: Semaphorin 3E is aberrantly expressed in prostate cancer and affects adhesion and motility of prostate cancer cells, indicating a role for the Sema3E/PlexinD1 signaling pathway in prostate cancer and identifying a new possible target for therapy. PMID- 20949547 TI - Attraction of Chrysoperla carnea complex and Chrysopa spp. lacewings (Neuroptera: Chrysopidae) to aphid sex pheromone components and a synthetic blend of floral compounds in Hungary. AB - BACKGROUND: The deployment of synthetic attractants for the manipulation of lacewing populations as aphid predators is currently used in integrated pest management. This study investigates a synthetic bait comprising floral compounds previously found to attract the Chrysoperla carnea complex, and, for the first time, the aphid sex pheromone components (1R,4aS,7S,7aR)-nepetalactol and (4aS,7S,7aR)-nepetalactone, in field experiments in Hungary, for their ability to manipulate lacewing populations. RESULTS: The synthetic floral bait attracted both sexes of the Chrysoperla carnea complex, and Chrysopa formosa Brauer showed minimal attraction. The aphid sex pheromone compounds alone attracted males of C. formosa and C. pallens (Rambur). When the two baits were combined, Chrysopa catches were similar to those with aphid sex pheromone baits alone, but carnea complex catches decreased significantly (by 85-88%). CONCLUSION: As the floral bait alone attracted both sexes of the carnea complex, it showed potential to manipulate the location of larval density via altering the site of oviposition. Aphid sex pheromone compounds alone attracted predatory males of Chrysopa spp. and can potentially be used to enhance biological control of aphids. For the carnea complex, however, a combination of both baits is not advantageous because of the decrease in adults attracted. Assumptions of intraguild avoidance underlying this phenomenon are discussed. PMID- 20949548 TI - Efficacy of fungicides with various modes of action in controlling the early stages of an Erysiphe necator-induced epidemic. AB - BACKGROUND: Limiting the use of fungicides is due to become an important issue in managing Erysiphe necator (Schwein) Burrill infections in vineyards. The authors determined how three fungicides currently used by vine growers could be managed to control the early stages of an E. necator-induced epidemic. RESULTS: Leaf-disc bioassays and field experiments suggested that the protectant quinoxyfen induced minor disruption in E. necator development, but compounds with protectant and curative properties (tebuconazole and trifloxystrobin) caused significant, although different, disruption during E. necator-induced epidemics. Bioassays showed that each of the antifungals were most effective at different stages of fungal development, tebuconazole before sporulation and trifloxystrobin after sporulation of the colonies. Results from the bioassay also highlighted likely occurrences in the field, where several stages of fungal development are encountered simultaneously. CONCLUSION: The present findings were complementary: leaf-disc tests showed when the fungicides were most effective at inhibiting E. necator infection cycles; the field trial provided results in terms of incidence and severity of disease on bunches without reference to the pathogenic cycle development. A protection strategy combining the different types of fungicide under study is suggested. PMID- 20949549 TI - Evaluation of alternative rice planthopper control by the combined action of oil formulated Metarhizium anisopliae and low-rate buprofezin. AB - BACKGROUND: High resistance of brown planthopper (BPH) Nilaparvata lugens Stal to common insecticides is a challenge for control of the pest. An alternative control strategy based on the combined application of fungal and chemical agents has been evaluated. RESULTS: Three gradient spore concentrations of oil formulated Metarhizium anisopliae (Metschnikoff) Sorokin (Ma456) were sprayed onto third-instar nymphs in five bioassays comprising the low buprofezin rates of 0, 10, 20, 30 and 40 ug mL(-1) respectively. Fungal LC(50) after 1 week at 25 degrees C and 14:10 h light:dark photoperiod decreased from 386 conidia mm(-2) in the buprofezin-free bioassay to 40 at the highest chemical rate. Buprofezin (LC(50): 1647, 486 and 233 ug mL(-1) on days 2 to 4) had no significant effect on the fungal outgrowths of mycosis-killed cadavers at the low application rates. The fungal infection was found to cause 81% reduction in reproductive potential of BPH adults. In two 40 day field trials, significant planthopper (mainly BPH) control (54-60%) was achieved by biweekly sprays of two fungal candidates (Ma456 and Ma576) at 1.5 * 10(13) conidia ha(-1) and elevated to 80-83% by incorporating 30.8 g buprofezin ha(-1) into the fungal sprays. CONCLUSION: The combined application of the fungal and chemical agents is a promising alternative strategy for BPH control. PMID- 20949550 TI - Fascin stain as a potential marker of invasiveness in carcinomas of the urinary bladder: a retrospective study with biopsy and cytology correlation. AB - The evaluation of invasion in urothelial carcinomas of the urinary bladder cannot be determined on cytology and can be particularly challenging in biopsy cases with limited sampling. Recent studies of bladder resection specimens suggest that fascin overexpression may be a marker of aggressive urothelial carcinomas and can help facilitate the assessment of invasion. In this study, we evaluated urine cytology and corresponding biopsy specimens with proven invasive urothelial carcinoma for fascin expression by immunohistochemistry. Thirty-five patients diagnosed with positive urine cytology and biopsy-proven invasive urothelial carcinoma between January 2003 and February 2009 were identified. We found increased fascin expression in 100% (35/35) of SurePathTM urine cytology preparations as well as 100% (35/35) of corresponding biopsy cases with invasive urothelial carcinoma. On urine cytology, cytoplasmic fascin staining was moderate to intense in malignant tumor cell clusters and single cells and not observed in benign urothelial cells. Staining in biopsy cases was generally intense and cytoplasmic and present in both the invasive (100%) and noninvasive (31%) components of the lesion. These findings uphold the association of increased fascin expression in invasive urothelial carcinomas of the urinary bladder. We furthermore demonstrate that fascin staining can be performed successfully on SurePathTM urine cytology preparations in which increased fascin expression correlates with invasion on biopsy. While not a definitive marker of invasion, as it is observed in in situ carcinoma, we conclude that the utilization of fascin immunohistochemistry on urine cytology might serve as a useful adjunct in predicting invasiveness in subsequent biopsies. PMID- 20949551 TI - Characterization of antioxidant olive oil biophenols by spectroscopic methods. AB - BACKGROUND: Olive oil contains numerous phenolic components with well-recognized health-beneficial activity. The major phenolic compounds present in olives and virgin olive oil-hydroxytyrosol, oleuropein and the oleuropein aglycones 3,4 DHPEA-EA and 3,4-DHPEA-EDA-as well as some of their metabolites were studied in the present work, regarding their main structural preferences. Vibrational spectroscopy (Raman) coupled to theoretical methods were used, aiming at fully characterizing the systems and therefore enabling their quick and reliable identification in food samples. RESULTS: The raman data, assisted by the theoretical simulations, allowed us to obtain the main geometrical and spectroscopic features of the olive oil constituents under study, which determine their known antioxidant and chemoprotective properties. In fact, it was verified that the spectra comprise distinctive bands for each compound, allowing their ready detection and differentiation. CONCLUSION: This is the first reported study on the structural behaviour of olive oil phenolic compounds, and it established Raman spectroscopy as a rapid, non-destructive and reliable analytical technique for identifying these bioactive components in dietary extracts. It can surpass other analytical methods currently used, once it allows the concomitant identification of several olive oil components in a particular sample. PMID- 20949554 TI - Meta-analysis of observational studies on the safety and effectiveness of robotic gynaecological surgery. AB - BACKGROUND: The safety and effectiveness of robotic, open and conventional laparoscopic surgery in gynaecological surgery was assessed in a systematic review of the literature. This will enable the general surgical community to understand where robotic surgery stands in gynaecology. METHODS: A search was made for previous systematic reviews in the Abstracts of Reviews of Effects, Health Technology Assessment, Cochrane Collaboration and Hayes Inc. databases. In addition, the MEDLINE, Embase and CINAHL databases were searched for primary studies. The quality of studies was assessed and meta-analyses were performed. RESULTS: Twenty-two studies were included in the review. All were controlled but none was randomized. The majority were retrospective with historical controls. The settings in which robotic surgery was used included hysterectomy for malignant and benign disease, myomectomy, sacrocolpopexy, fallopian tube reanastomosis and adnexectomy. Robotic surgery achieved a shorter hospital stay and less blood loss than open surgery. Compared with conventional laparoscopic surgery, robotic surgery achieved reduced blood loss and fewer conversions during the staging of endometrial cancer. No clinically significant differences were recorded for the other indications tested. CONCLUSION: The available evidence shows that robotic surgery offers limited advantages with respect to short-term outcomes. However, the clinical outcomes should be interpreted with caution owing to the methodological quality of the studies. PMID- 20949553 TI - Organic anion-transporting polypeptide 1b2 (Oatp1b2) is important for the hepatic uptake of unconjugated bile acids: Studies in Oatp1b2-null mice. AB - The organic anion-transporting polypeptide 1b family (Oatp1b2 in rodents and OATP1B1/1B3 in humans) is liver-specific and transports various chemicals into the liver. However, the role of the Oatp1b family in the hepatic uptake of bile acids (BAs) into the liver is unknown. Therefore, in Oatp1b2-null mice, the concentrations of BAs in plasma, liver, and bile were compared with wild-type (WT) mice. It was first determined that livers of the Oatp1b2-null mice were not compensated by altered expression of other hepatic transporters. However, the messenger RNA of Cyp7a1 was 70% lower in the Oatp1b2-null mice. Increased expression of fibroblast growth factor 15 in intestines of Oatp1b2-null mice might be responsible for decreased hepatic expression of Cyp7a1 in Oatp1b2-null mice. The hepatic concentration and biliary excretion of conjugated and unconjugated BAs were essentially the same in Oatp1b2-null and WT mice. The serum concentration of taurine-conjugated BAs was essentially the same in the two genotypes. In contrast, the serum concentrations of unconjugated BAs were 3-45 times higher in Oatp1b2-null than WT mice. After intravenous administration of cholate to Oatp1b2-null mice, its clearance was 50% lower than in WT mice, but the clearance of taurocholate was similar in the two genotypes. CONCLUSION: This study indicates that Oatp1b2 has a major role in the hepatic uptake of unconjugated BAs. PMID- 20949555 TI - The rectal 'no man's land' and sphincter preservation during rectal excision. PMID- 20949552 TI - Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. AB - Acute liver failure (ALF) due to drug-induced liver injury (DILI), though uncommon, is a concern for both clinicians and patients. The Acute Liver Failure Study Group has prospectively collected cases of all forms of acute liver failure since 1998. We describe here cases of idiosyncratic DILI ALF enrolled during a 10.5-year period. Data were collected prospectively, using detailed case report forms, from 1198 subjects enrolled at 23 sites in the United States, all of which had transplant services. A total of 133 (11.1%) ALF subjects were deemed by expert opinion to have DILI; 81.1% were considered highly likely, 15.0% probable, and 3.8% possible. Subjects were mostly women (70.7%) and there was overrepresentation of minorities for unclear reasons. Over 60 individual agents were implicated, the most common were antimicrobials (46%). Transplant-free (3 week) survival was poor (27.1%), but with highly successful transplantation in 42.1%, overall survival was 66.2%. Transplant-free survival in DILI ALF is determined by the degree of liver dysfunction, specifically baseline levels of bilirubin, prothrombin time/international normalized ratio, and Model for End Stage Liver Disease scores. CONCLUSION: DILI is an uncommon cause of ALF that evolves slowly, affects a disproportionate number of women and minorities, and shows infrequent spontaneous recovery, but transplantation affords excellent survival. PMID- 20949556 TI - Reference ranges for Doppler assessment of uterine artery resistance and pulsatility indices in dichorionic twin pregnancies. AB - OBJECTIVES: To construct reference ranges of uterine artery Doppler parameters against gestation in twin pregnancies and to present charts of the pulsatility index (PI) and resistance index (RI) for clinical use. METHODS: This was an observational study of the uterine circulation in 557 women with dichorionic twin pregnancies at 17-38 weeks' gestation. Uterine artery measurements were performed by color and pulsed Doppler imaging. The uterine artery PI and RI were calculated as a mean of both sides. Reference ranges were constructed by regression of each index on gestational age. For this purpose, a regression model with fractional polynomials was fitted to the data. Furthermore, the presence of uterine artery notching was recorded. RESULTS: New reference curves and tables of percentiles of the uterine artery PI and RI are presented. The calculated indices both showed a significant decrease with gestational age. Compared with singleton values, mean twin PI values were lower during the whole course of pregnancy. The prevalence of bilateral notching was 4.6% at 17-19 weeks' gestation and 3.1% at 20-24 weeks. CONCLUSIONS: Uterine artery Doppler indices in twin pregnancies are lower than in singleton pregnancies. Therefore, the use of uterine artery reference ranges adapted to twin gestations seems more appropriate for identifying low- and high risk groups. PMID- 20949558 TI - Association of Merkel cell polyomavirus infection with tumor p53, KIT, stem cell factor, PDGFR-alpha and survival in Merkel cell carcinoma. AB - Most Merkel cell carcinomas (MCCs) contain Merkel cell polyomavirus (MCPyV) DNA, and the virus likely has a pivotal role in tumor pathogenesis. p53 and the KIT receptor tyrosine kinase have also been implicated in MCC pathogenesis, but little is known about their association with MCPyV infection. We identified 207 patients diagnosed with MCC in Finland in 1979-2004 and reviewed the histological diagnoses. Adequate clinical information, tumor tissue and DNA were available from 87 confirmed MCC cases. Presence of MCPyV DNA was assessed using quantitative PCR; p53, KIT, phospho-KIT, stem cell factor (SCF) and PDGFRalpha expression using immunohistochemistry and presence of mutations in KIT exons 9, 11, 13 and 17 and PDGFRA exons 10, 12, 14 and 18 using DNA sequencing. Most (77.0%) of the 87 tumors contained MCPyV DNA and 37 (42.5%) expressed KIT, whereas PDGFRalpha, p53, SCF and pKIT expression was less common (31.9, 22.8, 8.6 and 4.8%, respectively). No KIT or PFGFRA mutations were detected, but 10 (12.5%) of the 80 tumors studied harbored common PDGFRA exon 10 S478P substitution. Tumor p53 and KIT expression were associated with absence of MCPyV DNA (p = 0.01 and 0.009, respectively). Tumor p53 expression was associated with unfavorable MCC specific survival (p = 0.021) and overall survival (p = 0.046), but tumor KIT expression only when stratified by presence of MCPyV DNA. The results suggest that p53 and KIT expression are associated with absence of MCPyV DNA in MCC, and that the molecular pathogenesis of MCC is multifactorial. PMID- 20949557 TI - Genetic variation in C-reactive protein in relation to colon and rectal cancer risk and survival. AB - C-reactive protein (CRP), a biomarker of inflammation, has been shown to be influenced by genetic variation in the CRP gene. In this study, we test the hypothesis that genetic variation in CRP influences both the risk of developing colon and rectal cancer and survival. Two population-based studies of colon cancer (n = 1,574 cases, 1,970 controls) and rectal (n = 791 cases, 999 controls) were conducted. We evaluated four CRP tagSNPs: rs1205 (G > A, 3' UTR); rs1417938 (T > A, intron); rs1800947 (G > C, L184L); and rs3093075 (C > A, 3' flanking). The CRP rs1205 AA genotype was associated with an increased risk of colon cancer (OR 1.3, 95%CI 1.1-1.7), whereas the rs3093075 A allele was associated with a reduced risk of rectal cancer (OR 0.7, 95%CI 0.5-0.9). The strongest association for the rs1205 polymorphism and colon cancer was observed among those with KRAS2 mutations (OR 1.5, 95%CI 1.1-2.0). The CRP rs1205 AA genotype also was associated with an increased risk of CIMP+ rectal tumors (OR 2.5, 95%CI 1.2-5.3); conversely, the rs1417938 A allele was associated with a reduced risk of CIMP+ rectal tumors (OR 0.5, 95%CI 0.3-0.9). We observed interactions between CRP rs1800947 and BMI and family history of CRC in modifying risk of both colon and rectal cancer. These data suggest that genetic variation in the CRP gene influences risk of both colon and rectal cancer development. PMID- 20949559 TI - Herpesvirus saimiri-based endothelin-converting enzyme-1 shRNA expression decreases prostate cancer cell invasion and migration. AB - The zinc metalloprotease, endothelin-converting enzyme-1 (ECE-1), which converts the mitogenic peptide endothelin-1 (ET-1) from its biologically inactive precursor big-ET-1, is commonly upregulated in prostate cancer (PC) cells. Consequently, we have sought to suppress ECE-1 expression by using RNAi as a potentially novel therapeutic approach. Therefore, a synthetic 64-nt short hairpin RNA (shRNA), designed to target the ECE-1 gene, was expressed in an Herpesvirus saimiri (HVS)-based delivery vector. ECE-1 expression in cells transduced with the vector was examined by real-time PCR and Western blotting. The effects of ECE-1 knockdown on PC cell migration and invasion were studied using a scratch assay and Matrigel invasion. These studies, in vitro and ex vivo, demonstrated that the HVS-shRNA viruses could infect and silence ECE-1 expression effectively in human PC cells. Furthermore, it was observed that ECE-1 knockdown in either stromal cells or epithelial cells could significantly reduce invasion of PC-3 cells in coculture by 33 and 31%, respectively. In addition, suppressed migration was also observed in HVS-ECE-1 shRNA-infected PC-3 cells compared to uninfected and HVS-GFP-infected control cell cultures. These findings highlight the potential tumor-suppressing effect of ECE-1 knockdown in cancer cells and novel strategies for future therapeutic developments in advanced PC. PMID- 20949560 TI - Endometriosis as a prognostic factor for cancer survival. AB - Studies have shown an increased risk of malignancies in women with endometriosis. Little is known about the impact of endometriosis on cancer survival. We investigated whether the survival after a diagnosis of a malignancy differs in women with a previously diagnosed endometriosis compared to other women. Women with a first time diagnosis of a malignancy in 1969-2005, were identified using the National Swedish Cancer Register (NSCR). By use of the National Swedish Patient Register (NSPR) we identified all women with a diagnosis of endometriosis during the same period and linked these patients with the data from the NSCR. The cohort comprised 4,278 women with endometriosis and a malignancy, and 41,831 randomly selected matched women without endometriosis. Cox regression was used for all calculations to obtain crude and adjusted cause specific mortality rates, measured as hazard ratios (HR) with 95% confidence intervals (CI). A total of 46,109 women entered the study. There was a statistically significant better survival for women with endometriosis for all malignancies combined (HR=0.92) and for breast cancer (HR=0.86) and ovarian cancer (HR=0.81) specifically. For breast cancer the survival enhancing effect in women with endometriosis decreased with increasing parity. There was poorer survival in malignant melanoma for women with endometriosis (HR=1.52). The survival in a malignancy is better in women with a previously diagnosed endometriosis compared to women without endometriosis especially for breast and ovarian cancers. The prognosis of malignant melanoma is poorer in women with endometriosis. PMID- 20949561 TI - Risk factors for non-Hodgkin lymphoma subtypes defined by histology and t(14;18) in a population-based case-control study. AB - The t(14;18) chromosomal translocation is the most common cytogenetic abnormality in non-Hodgkin lymphoma (NHL), occurring in 70-90% of follicular lymphomas (FL) and 30-50% of diffuse large B-cell lymphomas (DLBCL). Previous t(14;18)-NHL studies have not evaluated risk factors for NHL defined by both t(14;18) status and histology. In this population-based case-control study, t(14;18) status was determined in DLBCL cases using fluorescence in situ hybridization on paraffin embedded tumor sections. Polytomous logistic regression was used to evaluate the association between a wide variety of exposures and t(14;18)-positive (N=109) and -negative DLBCL (N=125) and FL (N=318), adjusting for sex, age, race, and study center. Taller height, more lifetime surgeries, and PCB180 exposure were associated with t(14;18)-positivity. Taller individuals (third tertile vs. first tertile) had elevated risks of t(14;18)-positive DLBCL (odds ratio [OR] = 1.8, 95% confidence interval [CI] 1.1-3.0) and FL (OR=1.4, 95%CI 1.0-1.9) but not t(14;18)-negative DLBCL. Similar patterns were seen for individuals with more lifetime surgeries (13+ vs. 0-12 surgeries; t(14;18)-positive DLBCL OR=1.4, 95%CI 0.7-2.7; FL OR=1.6, 95%CI 1.1-2.5) and individuals exposed to PCB180 greater than 20.8 ng/g (t(14;18)-positive DLBCL OR=1.3, 95%CI 0.6-2.9; FL OR=1.7, 95%CI 1.0 2.8). In contrast, termite treatment and high alpha-chlordane levels were associated with t(14;18)-negative DLBCL only, suggesting that these exposures do not act through t(14;18). Our findings suggest that putative associations between NHL and height, surgeries, and PCB180 may be t(14;18)-mediated and provide support for case-subtyping based on molecular and histologic subtypes. Future efforts should focus on pooling data to confirm and extend previous research on risk factors for t(14;18)-NHL subtypes. PMID- 20949562 TI - Overexpression of SOCS3 exhibits preclinical antitumor activity against malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis for which an effective therapy remains to be established. Our study investigated the therapeutic potential of the suppressor of cytokine signaling 3 (SOCS3), an endogenous inhibitor of intracellular signaling pathways, for treatment of MPM. We infected MPM cells (H226, EHMES-1, MESO-1 and MESO-4) with an adenovirus expressing SOCS3 (AdSOCS3) to examine the effect of SOCS3 overexpression on MPM cells. SOCS3 overexpression reduced MPM proliferation and induced apoptosis and partial G0/G1 arrest. SOCS3 also inhibited the proliferation of MPM cells via multiple signaling pathways including Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK) and p53 pathways. Notably, AdSOCS3 treatment inhibited tumor growth in an MPM pleural xenograft model. These findings demonstrate that overexpression of SOCS3 has a potent antitumor effect against MPM both in vitro and in vivo and indicate the potential for clinical use of SOCS3 for MPM treatment. PMID- 20949563 TI - A strategy for distinguishing optimal cancer subtypes. AB - Much attention is directed currently to identifying subtypes of cancers that are genetically and clinically distinct. The expectation is that subtyping on the basis of somatic genomic characteristics will supplant traditional pathological subtypes with respect to relevance for targeted therapies and clinical course. Less attention has been paid to the goal of validating subtypes on the basis of the distinctiveness of their etiologies. In this article it is shown that studies of individuals with double primary malignancies provide uniquely valuable information for establishing the etiologic distinctiveness of candidate tumor subtypes. Studies of double primaries have the potential to definitively rank candidate taxonomic systems with respect to their etiological relevance by determining which subtypes are most highly correlated in the double primaries. The concept is illustrated with data from studies of the concordance of estrogen and progestin status in bilateral breast cancers, where it is shown that double primaries are much more likely to be concordant with respect to estrogen receptor (ER) status than for PR status. The high concordance of ER status is consistent with a growing literature demonstrating the etiologic distinctiveness of ER+ and ER- tumors. PMID- 20949565 TI - Functional materials: from hard to soft porous frameworks. AB - This Review aims to give an overview of recent research in the area of porous, organic-inorganic and purely organic, functional materials. Possibilities for introducing organic groups that exhibit chemical and/or physical functions into porous materials will be described, with a focus on the incorporation of such functional groups as a supporting part of the pore walls. The number of organic groups in the network can be increased such that porous, purely organic materials are obtained. PMID- 20949564 TI - Micro-RNA profiles in osteosarcoma as a predictive tool for ifosfamide response. AB - Micro-RNAs (miRNA) are currently used as cancer biomarkers for hematological cancers and solid tumors. Osteosarcoma is the first primary malignant bone tumor, characterized by a complex genetic and resistance to conventional treatments. For this latter property, the median survival has not been improved since 1990 despite preoperative administration of chemotherapeutic agents. The prediction of tumor response before chemotherapy treatment would constitute a major progress for this pathology. We assessed in this study if miRNA profiling could surpass the current limitations for osteosarcoma diagnosis. We measured the miRNA expression in different osteosarcoma samples: (i) 27 osteosarcoma paraffin embedded tumors from patients, (ii) human osteosarcoma cell lines, and (iii) tumors from a syngeneic rat osteosarcoma model, recapitulating human osteosarcoma. miRNA profiles were determined using microfluidic cards performing high-throughput TaqMan((r)) -based PCR assays, called TaqMan((r)) Low Density Arrays. Osteosarcoma of rat and human origins showed a miRNA signature, which could discriminate good from bad responders. In particular, we identified five discriminating miRNAs (miR-92a, miR-99b, miR-132, miR-193a-5p and miR-422a) in patient tumors, which could be easily transferable to diagnosis. These discriminating miRNAs, as well as those identified in rat, targeted the TGFbeta, the Wnt and the MAP kinase pathways. These results indicate that our platform constitutes a potent diagnostic tool to predict tumor sensitivity to a drug in attempt to better adapt treatment to tumor biological specificities and also to identify new potential therapeutic strategies. PMID- 20949566 TI - Optimizing thiopurine therapy in inflammatory bowel disease. AB - Despite recent advances, the therapeutic armamentarium for inflammatory bowel disease (IBD) is still limited. In addition, a step-up approach is recommended for most IBD patients. Thus, optimizing each medical therapy before switching to another drug class is the rule in clinical practice. Conventional therapies for IBD have not received the same amount of attention as biologic therapies over the last decade. However, due to their efficacy, safety, and low cost the thiopurine drugs azathioprine and 6-mercaptopurine remain the backbone of therapy for IBD. Pharmacogenomic advances and increased knowledge of their metabolism are allowing dosage optimization. Herein, after describing the pharmacogenetics and pharmacokinetics of thiopurines, we will discuss how to optimize thiopurine therapy. We will then underscore the need to take into account safety issues when optimizing thiopurine treatment. PMID- 20949567 TI - Mechanism of thermal reversal of the (fulvalene)tetracarbonyldiruthenium photoisomerization: toward molecular solar-thermal energy storage. PMID- 20949569 TI - Myoepithelioma of the hand and carpal tunnel: An unusual cause of median nerve compression. AB - Myoepitheliomas are rare tumors increasingly recognized to occur in the soft tissues. Although the hand and carpal tunnel are exceptional locations, the presence of these lesions in such sites constitutes a potential cause of debilitating symptoms. We report the case of a patient with severe pain secondary to median nerve compression and displacement of flexor tendons caused by a rapidly growing myoepithelioma. This is the first sonographic description of this tumor producing carpal tunnel syndrome and disabling pain. High-resolution sonography allowed evaluation of gross tumor morphology and real-time assessment of its interactions with surrounding structures. PMID- 20949568 TI - Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions. AB - Angiosarcoma (AS) is a distinct group of sarcomas characterized by upregulation of vascular-specific receptor tyrosine kinases, including TIE1, KDR, TEK, and FLT1. In keeping with the clinical heterogeneity, gene-expression profiling distinguishes two AS genomic clusters, which correlate with anatomical location and prior exposure to radiation. Furthermore, a high percentage of secondary AS, but not primary AS, shows distinct 8q24 chromosomal gains, due to MYC amplification. In this study, we mined the transcriptional output of 10 secondary and 11 primary AS to better define the dichotomy in the pathogenesis of these two clinical subsets. The oncogenic role of MYC was investigated further in secondary AS as well as in radiation-induced atypical vascular lesions (AVL) and other radiation-associated sarcomas. High-level MYC amplification was found in 100% of secondary AS, but in none of the AVL or other radiation-associated sarcomas. Coamplification of FLT4 (encoding VEGFR3) was identified in 25% of secondary AS, but not in other types. Our findings reinforce the distinct pathogenesis of AS subtypes, with MYC amplification being an early, but necessary event in secondary AS. Secondary genetic hits, such as FLT4 gene coamplification or KDR mutations, may play a role in tumor progression as well as potential therapeutic targeting. PMID- 20949570 TI - Role of intraoperative microvascular Doppler in the microsurgical management of intracranial aneurysms. AB - BACKGROUND: The outcome of surgical treatment of intracranial aneurysms may be influenced by incomplete exclusion of the aneurysm or stenosis of the parent vessels. The goal of this study was to evaluate the usefulness and reliability of intraoperative microvascular Doppler (IMD) in guiding optimal clip placement in aneurysm surgery. METHODS: We conducted a retrospective analysis of 79 patients, with a total of 85 intracranial aneurysms, operated between January 2004 and April 2009, who were evaluated with IMD using a 20-MHz probe before and after clip application. IMD was used to examine the aneurysmal sac and adjacent vessels. RESULTS: The findings of IMD helped in adjusting the clip placement. In 9 (10.6%) of the 85 aneurysms, IMD revealed a persistent blood flow through the aneurysmal sac after clip application and the clip was repositioned. IMD showed relevant stenosis of adjacent vessels induced by the clip positioning in 10 of 79 (12.7%) cases. In six cases (7.6%), a blood flow reduction in the artery feeding the aneurysm was evident after clipping; in the other four cases (5.1%), the clip produced a severe blood flow reduction in other adjacent vessels. In addition, in two of these cases, an initial stenosis induced by clip positioning that had escaped detection by visual inspection through the operating microscope was identified by IMD. There were no complications related to the use of IMD. CONCLUSIONS: IMD is a safe, feasible, and very reliable technique and should be used routinely in intracranial aneurysm surgery. PMID- 20949571 TI - Sonographic appearance of a cholesterol granuloma within a renal epithelioid angiomyolipoma. AB - We present the sonographic characteristics of a rare case of cholesterol granuloma within a renal epithelioid angiomyolipoma (AML) in a 57-year-old woman. Sonography showed acoustic shadowing distal to the central region of the AML behind a hyperechoic cholesterol, which was hypoattenuating on CT with no contrast enhancement. Microscopic examination confirmed that this central area was a cholesterol granuloma. The patient was treated successfully with radical nephrectomy. PMID- 20949572 TI - Soft tissue volume of upper arm in predicting small-for-gestational-age fetuses using three-dimensional ultrasound. AB - PURPOSE: To assess the value of fetal soft tissue volume (STV) of the upper arm in predicting small-for-gestational-age (SGA) fetuses using three-dimensional (3D) ultrasound (US). METHODS: We used 3D US to test the accuracy of fetal STV of the upper arm measurement in predicting SGA in a prospective cross-sectional study. RESULTS: Fetal STV of the upper arm assessed by 3D US can differentiate SGA fetuses from appropriate-for-gestational-age (AGA) fetuses. Using the 5th percentile as the cutoff, the sensitivity of fetal upper arm STV in predicting SGA fetuses was 84.1%, specificity, 93.4%, positive predictive value, 71.1%, negative predictive value, 96.8%, and overall accuracy, 91.9%. In addition, the diagnostic accuracy of fetal arm STV was better than that of the biparietal diameter, abdominal circumference, and femur length. CONCLUSION: Fetal STV of upper arm assessment by 3D US is a novel method to predict SGA fetuses. PMID- 20949573 TI - Single-walled carbon nanotubes alter Schwann cell behavior differentially within 2D and 3D environments. AB - Both spinal cord injury (SCI) and large-gap peripheral nerve defects can be debilitating affecting a patient's long-term quality of life and presently, there is no suitable treatment for functional regeneration of these injured tissues. A number of works have suggested the benefits of electrical stimulation to promote both glial migration and neuronal extension. In this work, an electrically conductive hydrogel containing single-walled carbon nanotubes (SWCNT) for neural engineering applications is presented and the Schwann cell (SC) response to SWCNT is examined in both 2D and 3D microenvironments. Results from clonogenic and alamarBlue(r) assays in 2D indicate that SWCNT (10-50 MUg mL(-1)) inhibit SC proliferation but do not affect cell viability. Following SWCNT exposure in 2D, changes in SC morphology can be observed with the nanomaterial attached to the cell membrane at concentrations as low as 10 MUg mL(-1). In contrast to the results gathered in 2D, SC embedded within the 3D hydrogel loaded with 10-50 MUg mL(-1) of SWCNT exhibited little or no measurable change in cell proliferation, viability, or morphology as assessed using a digestion assay, alamarBlue, and confocal microscopy. Collectively, this highlights that an electrically conductive SWCNT collagen I-MatrigelTM biomaterial may be suitable for neural tissue engineering and is able to sustain populations of SC. Findings suggest that 2D nanoparticle toxicity assays may not be accurate predictors of the 3D response, further motivating the examination of these materials in a more physiologically relevant environment. PMID- 20949574 TI - The diagnosis of anomalous origin of the left coronary artery from the pulmonary artery by echocardiography: Case report. AB - The anomalous origin of the left coronary artery from the pulmonary artery is a rare congenital heart disease that affects 1 of 300,000 live births. We present the case of an 18-year-old female presenting with chest pain and dyspnea after vigorous exercise, and whose two-dimensional echocardiogram initially displayed a "normal connection" between the left coronary artery with the aortic sinus of Valsalva. Using a systematic diagnostic echocardiography approach, we rightfully diagnosed it as anomalous origin of the left coronary artery from the pulmonary artery. PMID- 20949575 TI - Teaching technological innovation and entrepreneurship in polymeric biomaterials. AB - A model for incorporating an entrepreneurship module has been developed in an upper-division and graduate-level engineering elective on Polymeric Biomaterials (27-311/42-311/27-711/42-711) at Carnegie Mellon University. A combination of lectures, assignments, and a team-based project were used to provide students with a framework for applying their technical skills in the development of new technologies and a basic understanding of the issues related to translational research and technology commercialization. The specific approach to the project established in the course, which represented 20% of the students' grades, and the grading rubric for each of the milestones are described along with suggestions for generalizing this approach to different applications of biomaterials or other engineering electives. Incorporating this model of entrepreneurship into electives teaches students course content within the framework of technological innovation and many of the concepts and tools need to practice it. For students with situational or individual interest in the project, it would also serve to deepen their understanding of the traditional course components as well as provide a foundation for integrating technological innovation and lifelong learning. PMID- 20949576 TI - Proto-calcite and proto-vaterite in amorphous calcium carbonates. PMID- 20949577 TI - Photothermal multispectral image cytometry for quantitative histology of nanoparticles and micrometastasis in intact, stained and selectively burned tissues. AB - There is a rapidly growing interest in the advanced analysis of histological data and the development of appropriate detection technologies in particular for mapping of nanoparticle distributions in tissue in nanomedicine applications. We evaluated photothermal (PT) scanning cytometry for color-coded imaging, spectral identification, and quantitative detection of individual nanoparticles and abnormal cells in histological samples with and without staining. Using this tool, individual carbon nanotubes, gold nanorods, and melanoma cells with intrinsic melanin markers were identified in unstained (e.g. sentinel lymph nodes) and conventionally-stained tissues. In addition, we introduced a spectral burning technique for histology through selective laser bleaching areas with nondesired absorption background and nanobubble-based PT signal amplification. The obtained data demonstrated the promise of PT cytometry in the analysis of low absorption samples and mapping of various individual nanoparticles' distribution that would be impossible with existing assays. Comparison of PT cytometry and photoacoustic (PA) cytometry previously developed by us, revealed that these methods supplement each other with a sensitivity advantage (up to 10-fold) of contactless PT technique in assessment of thin (<=100 MUm) histological samples, while PA imaging provides characterization of thicker samples which, however, requires an acoustic contact with transducers. A potential of high-speed integrated PT-PA cytometry for express histology and immunohistochemistry of both intact and stained heterogeneous tissues with high sensitivity at the zepromolar concentration level is further highlighted. PMID- 20949578 TI - Three-component coupling reactions of silyl glyoxylates, vinyl Grignard reagent, and nitroalkenes: an efficient, highly diastereoselective approach to nitrocyclopentanols. PMID- 20949579 TI - Reliability of sentinel node technique in the treatment of N0 supraglottic laryngeal cancer. AB - OBJECTIVE: To study the reliability of the sentinel node technique (SNT) in the management of the N0 neck in patients with supraglottic laryngeal cancer. METHODS: Patients presenting to our department, between 2001 and 2004, with T1-T3 supraglottic cancer and N0 neck, clinically and radiologically, were included in the study. All patients underwent sentinel lymph node detection, using the hand held gamma probe followed by bilateral modified radical neck dissection (MRND) and resection of the primary tumor. We compared the results of the SNT with those of the gold standard MRND for the staging of the neck. The histologic examination was performed after fixation for both the products of SNT and MRND. RESULTS: Twenty-nine patients were included in the study. Twenty-one had T2, 2 had T1, and 6 had T3 tumors. Patients had transoral CO(2) laser-assisted resection of the primary tumor. All the patients underwent bilateral neck dissection immediately after the sentinel node biopsy. Of the 95 sentinel lymph nodes harvested, 22 were positive for lymph node metastasis. The mean number of sentinel node per patient was 3. Of the 58 modified neck dissections (2 neck sides/patient), there was 1 additional positive lymph node, in the prelaryngeal area, and the patient had already positive sentinel lymph nodes. The SNT allowed the identification of node metastasis in 100% of the cases with a sensitivity of 100 (48-100), specificity of 78 (64-88), negative predictive value of 100 (91-100). CONCLUSIONS: SNT is reliable in the staging of the clinically N0 neck in patients with supraglottic cancer. PMID- 20949580 TI - Efficient hydrosilylation of carbonyl compounds with the simple amide catalyst [Fe{N(SiMe3)2}2]. PMID- 20949581 TI - Computed tomographic analysis of frontal recess anatomy and its effect on the development of frontal sinusitis. AB - OBJECTIVES/HYPOTHESIS: To use computed tomography to determine the association of frontal recess cells with the development of frontal sinusitis. STUDY DESIGN: Retrospective analysis. METHODS: We retrospectively analyzed various frontal recess cells on spiral computed tomographic images of sinuses between November 2007 and May 2009. Exclusion criteria included previous sinus surgery, sinonasal polyposis, age younger than 18 years, maxillofacial fracture, incomplete sections of computed tomography, and sinonasal malignancy. We used logistic regression analysis to compare the distribution of various frontal recess cells in patients with frontal sinusitis and those without frontal sinusitis. RESULTS: A total of 192 patients met the criteria, and only 363 sides were distinguishable. The presence of suprabullar cells, supraorbital ethmoid cells, frontal bullar cells, and recessus terminalis was significantly associated with the development of frontal sinusitis by multiple logistic regression models. CONCLUSIONS: The frequency of frontal recess cells analyzed in Taiwanese adult patients was similar to that analyzed in other Asian adult populations (Chinese and Korean). The frontoethmoid cells posterior and posterolateral to the frontal recess (suprabullar cells, frontal bullar cells, and supraorbital ethmoid cells) might reveal a more significant association with the development of frontal sinusitis than those anterior to the frontal recess (agger nasi cells, frontal cell types 1 3). The presence of supraorbital ethmoid cells on computed tomographic images might indicate the highest odds of frontal sinusitis, followed by the presence of suprabullar cells, frontal bullar cells, and recessus terminalis. PMID- 20949582 TI - Product study of the OH radical and Cl atom initiated oxidation of 1,3-dioxane. AB - The products of the hydroxyl (OH) radical and chlorine (Cl) atom initiated oxidation of 1,3-dioxane are determined under various reaction conditions in a 50 L teflon reaction chamber using FTIR spectroscopy for analysis. The major products detected in all experiments are (2-oxoethoxy)methyl formate, formic acid and methylene glycol diformate with average molar yields of 0.50+/-0.05, 0.41+/ 0.02 and 0.03+/-0.01 respectively for the OH initiated oxidation in the presence of NO(x). The yields of these products do not vary significantly with O(2) partial pressure or oxidising agent (OH or Cl). However, the yield of formic acid decreased by at least a factor of two in the absence of NO(x). The results of these experiments are used to elucidate a simplified gas-phase atmospheric degradation scheme for 1,3-dioxane and also provide valuable information on the atmospheric fate of the cyclic and linear alkoxy radicals produced in these and similar reactions. The available experimental data suggests that the relative importance of the competing pathways (reaction with O(2) and ring opening by C-C or C-O bond fission) is a strong function of the ring strain in the cycloalkoxy radicals. PMID- 20949583 TI - The ratio of contrast volume to glomerular filtration rate predicts outcomes after percutaneous coronary intervention for ST-segment elevation acute myocardial infarction. AB - OBJECTIVE: To assess the value of the ratio between contrast medium volume and glomerular filtration rate (CMGFRr) for prediction of development of contrast induced nephropathy (CIN) and mortality in patients with ST-segment elevation acute myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). BACKGROUND: Renal function is a strong predictor of outcome in patients with STEMI. CIN may complicate the course of primary PCI in these patients. METHODS: The study population included all 871 consecutive patients with STEMI without cardiogenic shock who underwent primary PCI at our center from January 1, 2001, to October 30, 2006. CIN was defined as an absolute increase in serum creatinine > 0.5 mg/dL or a relative increase >25% within 48 hr after PCI. RESULTS: In-hospital CIN developed in 72 (8.3%) patients. On linear regression analysis, the following variables were independently associated with CIN: male sex (odds ratio [OR] = 0.42, 95% confidence interval [CI], 0.18-0.97, P = 0.04), GFR < 60 (OR = 3.6, 95% CI, 2.79-4.78, P < 0.0001), multivessel coronary artery disease (OR = 1.67, 95% CI, 1.08-2.58, P = 0.02), CMGFRr (OR = 1.53, 95% CI, 1.01 2.31, P = 0.04, for upper tertile vs. lower two tertiles), and Killip class > 1 (OR = 1.35, 95% CI, 1.03-1.76, P = 0.03). CMGFRr > 3.7 was a strong independent predictor of CIN (OR = 3.87, 95% CI, 1.72-8.68, P = 0.001). Twenty-six (2.9%) patients died at 1 month after PCI. The following variables were independently predictive of 1-month mortality: CMGFRr > 3.7 (OR = 3.3, 95% CI, 1.22-9.04, P = 0.018) and multivessel coronary artery disease (OR = 2.3, 95% CI, 1.28-4.07, P = 0.005). CONCLUSION: The contrast medium-to-GFR ratio is a strong predictor of CIN and of 1-month mortality in patients undergoing primary PCI for STEMI. PMID- 20949584 TI - Synthesis, cytotoxicity, and COMPARE analysis of ferrocene and [3]ferrocenophane tetrasubstituted olefin derivatives against human cancer cells. AB - Herein we report the antiproliferative effects of a series of 28 compounds against the MDA-MB-231 breast cancer cell line, including the synthesis of seven new [3]ferrocenophanyl and four new ferrocenyl compounds. For each p-R-phenyl substitution pattern investigated, the [3]ferrocenophanyl derivatives were more cytotoxic than the corresponding ferrocenyl derivative, with the highest activity found for compounds with protic substituents. Theoretical calculations of the HOMO-LUMO gap for the molecules in the Fe3(+) oxidation state suggest a higher reactivity for the [3]ferrocenophanyl derivatives. A lead compound from each series, a [3]ferrocenophanyl and a ferrocenyl compound, possessing two phenol groups, were screened against the NCI/DTP 60-cell-line panel. The mean activity over all cell lines was better than cisplatin for both compounds, and both compounds showed subpanel selectivity for leukemia, CNS cancer, and renal cancer. Low systemic toxicity and lack of interaction with DNA (when in the reduced form), suggest that the compounds may act as prodrugs. PMID- 20949585 TI - Assessment of fungicide resistance and pathogen diversity in Erysiphe necator using quantitative real-time PCR assays. AB - BACKGROUND: Management of grapevine powdery mildew Erysiphe necator Schw. requires fungicide treatments such as sterol demethylation inhibitors (DMIs) or mitochondrial inhibitors (QoIs). Recently, reduction in the efficacy of DMIs or QoIs was reported in Europe and the United States. The aim of the present study was to develop real-time qPCR tools to detect and quantify several CYP51 gene variants of E. necator: (i) A versus B groups (G37A) and (ii) sensitive versus resistant to sterol demethylase inhibitor fungicides (Y136F). RESULTS: The efficacy of the qPCR tools developed was better than the CAPS method, with a limit of 2 pg for E necator DNA, 0.06 ng for genetic group A and 1.4 ng for the DMI-resistant allele. The detection limits of qPCR protocols (LOD) ranged from 0.72 to 0.85%, and the quantification limits (LOQ) ranged from 2.4 to 2.85% for the two alleles G47A and Y136F respectively. The application of qPCR to field isolates from French vineyards showed the presence of DMI-resistant and/or QoI resistant alleles in French pathogen populations, linked to genetic group B. CONCLUSION: The real-time PCR assay developed in this study provides a potentially useful tool for efficient quantification of different alleles of interest for fungicide monitoring and for population structure of E. necator. PMID- 20949586 TI - Multiple mechanisms account for resistance to sterol 14alpha-demethylation inhibitors in field isolates of Mycosphaerella graminicola. AB - BACKGROUND: Sterol 14alpha-demethylation inhibitors (DMIs) have been widely used in many European countries to control septoria leaf blotch, which is caused by Mycosphaerella graminicola (Fuckel) J Schrot (anamorph Septoria tritici Berk & MA Curtis). However, treatment efficacy has declined, and significant shifts in population susceptibility have occurred in recent years, with the isolation of particularly highly resistant strains from French, English and Irish populations. The present aim was to determine the phenotypic characteristics of these field isolates and to identify the possible resistance mechanisms. RESULTS: Target alteration, linked to 11 possible changes in the gene encoding 14alpha demethylase (Cyp51), was the basic resistance mechanism in weakly, moderately and highly resistant strains. Changes in Cyp51 combined with the overexpression of drug efflux transporters probably result in multidrug resistance in some of the most resistant phenotypes. Finally, some moderately or highly resistant isolates were found to harbour an insertion in the Cyp51 promoter and/or new combinations of known mutations in the target gene. CONCLUSION: An updated overview of M. graminicola field strains displaying low to high resistance to DMIs is provided here. The management of field resistance and efficacy should be adapted to take these findings into account. PMID- 20949587 TI - A radiotherapy planning study of RapidArc, intensity modulated radiotherapy, three-dimensional conformal radiotherapy, and parallel opposed beams in the treatment of pediatric retroperitoneal tumors. AB - BACKGROUND: This planning study compared RapidArc, fixed-field IMRT (cIMRT), 3D conformal radiotherapy (3D-CRT), and a parallel-opposed pair (POP) for children with retroperitoneal tumors. PROCEDURE: Plans were generated in eight patients to treat the PTV (dose range 19.8-45 Gy) while limiting kidney and liver doses. In selected patients, vertebral body (VB) dose heterogeneity was minimized. Cumulative DVH parameters, monitor units (MU), and treatment times were compared for the four techniques using the Wilcoxon matched pairs test. RESULTS: RapidArc and cIMRT covered target volumes more conformally than 3D-CRT and POP (P = 0.012). There was no difference in the ability to meet kidney dose constraints. A significantly lower volume of the liver received 12 Gy with cIMRT or RapidArc compared with 3D-CRT (P = 0.028). Where VB was included in PTV, VB dose homogeneity was generally within 94-104% of the prescription dose. Time to deliver a single fraction with RapidArc, POP, 3D-CRT, and cIMRT was 1.25 +/- 0.01, 1.38 +/- 0.10, 2.6 +/- 0.45, and 4.02 +/- 1.12 min, respectively (P = 0.012). Monitor units for a single fraction with POP, 3D-CRT, RapidArc, and cIMRT were 203 +/- 26, 235 +/- 32, 325 +/- 71, and 665 +/- 215, respectively (P < 0.05). CONCLUSIONS: POP resulted in favorable MU, treatment time and dosimetry but had poor conformality. 3D-CRT was more conformal but had higher MU and treatment time. RapidArc and cIMRT were generally no better dosimetrically than conformal techniques. RapidArc was dosimetrically very similar to cIMRT, but resulted in a major reduction in time and MU used to deliver the radiation. PMID- 20949588 TI - Focal nodular hyperplasia in pediatric patients with and without oncologic history. AB - The diagnosis of FNH is warranted by the possibility of avoiding unnecessary hepatic resections. The 18 patients of our series, 6 of whom were long-term survivors of malignant, non-hepatic tumors, underwent either a biopsy or a complete excision to obtain the diagnosis. The imaging characteristics could not be considered pathognomonic. The lesion remained stable after the biopsy in 8 patients; no complications were observed in other 10 patients who underwent resection of the mass. The outcome of all our patients with or without previous oncological disease was benign. PMID- 20949589 TI - B1 and B0 inhomogeneity mitigation in the human brain at 7 T with selective pulses by using average Hamiltonian theory. AB - A novel method based on average Hamiltonian theory to design selective pulses is reported. With this tool, it is first shown how to shape the radiofrequency and gradient pulses to generate a desired rotation matrix, which is independent of the position through the slice of interest. After theoretical examination of the concept, it is applied to the strongly modulating pulses' recipe developed by the same authors and initially designed to be nonselective, to mitigate the amplitude of (excitation) radiofrequency field and amplitude of static (polarizing) field inhomogeneity problems at high field. Two in vivo human brain imaging experiments at 7 T are reported to prove the validity of the technique. PMID- 20949590 TI - Cooperating G6PD mutations associated with severe neonatal hyperbilirubinemia and cholestasis. AB - We report a novel glucose-6-phosphate dehydrogenase (G6PD) mutation, which we propose to name G6PD Cincinnati (c.1037A > T, p.N346I), found in combination with G6PD Gastonia (c.637G > T, p.V213L) in an infant who presented with neonatal cholestasis. The G6PD Cincinnati mutation results in a non-conservative amino acid substitution at the tetramer interface disturbing its formation, as seen by native gel electrophoresis and immunoblotting. G6PD Gastonia disrupts dimerization of the enzyme and by itself causes chronic non-spherocytic hemolytic anemia. The G6PD Cincinnati mutation may have aggravated the clinical picture of G6PD Gastonia with the result of severe perinatal hemolysis causing cholestasis and associated liver injury. PMID- 20949591 TI - Ambulatory high-dose methotrexate administration among pediatric osteosarcoma patients in an urban, underserved setting is feasible, safe, and cost-effective. AB - BACKGROUND: We describe the safety, feasibility, and provide a cost-estimate of outpatient high-dose methotrexate administration (HDMTX) among an urban, underserved population. PROCEDURE: A retrospective analysis of ambulatory HDMTX administration among osteosarcoma patients, at Montefiore Medical Center's Children's Hospital (Bronx, NY) was performed. HDMTX (12 g/m(2)) was given intravenously (IV) over 4 hr after urine alkalinization. Patients were discharged home to continue IV hydration and alkalinization delivered via a home infusion pump. Families were instructed to monitor urine pH overnight and management was adjusted according to our institution's treatment algorithm until MTX level <= 0.1 umol/L. A cost estimate was performed to assess the difference in costs for outpatient versus hypothetical inpatient administrations. RESULTS: Of the 97 ambulatory HDMTX administrations, 99% were successfully completed. One patient failed outpatient administration secondary to home infusion pump malfunction. This patient successfully completed subsequent courses as an outpatient. Most patients (72%) had a MTX level of < 10 umol/L at 24 hr post-HDMTX. No patients were found to have a MTX level of > 50 umol/L at 24 hr. About 26% of courses were associated with grade III or IV neutropenia, 4% were associated with grade III or IV thrombocytopenia and 1% were associated with grade III/IV leukopenia. Compared to a hypothetical hospital inpatient stay, the hospital costs for ambulatory HDMTX were an average of $1400 less per cycle. CONCLUSION: Ambulatory HDMTX administration among an underserved, urban population is safe, feasible, and cost effective. PMID- 20949592 TI - Recurrent pure CNS germinoma with markedly elevated serum and cerebrospinal fluid human chorionic gonadotropin-beta (HCGbeta). AB - Controversy continues regarding what level of serum and/or cerebrospinal fluid (CSF) human chorionic gonadotrophin-beta (HCGbeta) is consistent with pure germinoma of the central nervous system (CNS). We report a 10-year female with biopsy-proven pure germinoma and normal serum and CSF HCGbeta who experienced subsequent biopsy-proven recurrences of germinoma. At recurrence, serum and CSF HCGbeta levels were 560 and 3,202 mIU/ml, respectively, although final autopsy demonstrated pure germinoma. This case illustrates the need to re-evaluate the assumption that pathologically pure germinomas may be associated with high levels of HCGbeta which are unrelated to nongerminomatous germ cell tumor (NGGCT)/choriocarcinomatous elements. PMID- 20949593 TI - High reticulocyte count is an independent risk factor for cerebrovascular disease in children with sickle cell anemia. AB - BACKGROUND: Transcranial Doppler ultrasonography (TCD) is an important way of detecting risk of ischemic stroke in children with sickle cell anemia. PROCEDURE: A random sample of 262 FS-hemoglobin children from a newborn screening inception cohort in Brazil (1998-2005) was followed up to May 2009. Pulsed TCD followed STOP protocol. Children with mean blood flow velocity < 170 cm/sec in cerebral arteries were classified as low risk; between 170 and 184, low conditional risk; between 185 and 199, high conditional risk; and >= 200, high risk. RESULTS: Median age, 6.2 years (2-11.2 years); 147 female; 13 children (5%) had ischemic stroke prior to TCD; 186/249 (74.7%) were classified as low risk; 19 (7.6%) as low conditional; 7 (2.8%) as high conditional; and 8 (3.2%) as high risk; inadequate tests, 11.6%. The probability of ischemic stroke at 10 years was 8.3% (SEM 2.3%); of stroke or high-risk TCD 15.6% (3.5%). Children with stroke or altered TCD (conditional and high risk) were compared to children with normal examinations. They were younger (P = 0.03), with lower hemoglobin (P = 0.003), higher leukocytosis (P = 0.015), and higher reticulocytosis (P < 0.001). Episodes per year of acute chest syndrome were also higher in that group, but not significantly (P = 0.09). Reticulocytosis remained the only significant variable upon multivariate analysis (P = 0.004). Basilar and middle cerebral artery velocities were significantly correlated (R = 0.55; P < 0.001). CONCLUSIONS: Probability of stroke was similar to international reports; of belonging to high risk group, lower. High-reticulocyte count was the most important factor associated with cerebrovascular disease. Basilar artery velocity > 130 cm/sec seems to be an indirect sign of an underlying cerebrovascular disease. PMID- 20949594 TI - Metabolomic pattern of childhood neuroblastoma obtained by 1H-high-resolution magic angle spinning (HRMAS) NMR spectroscopy. AB - BACKGROUND: The aim of this preliminary study is to characterize by 1H high resolution magic angle spinning NMR spectroscopy (HRMAS) the metabolic content of intact biopsy samples obtained from 12 patients suffering from neuroblastoma (NB). PROCEDURE: The biochemical NB profile was first compared to normal adrenal medulla. In a second step, the relationship between the tumor metabolic profile and the patients' clinical data was investigated. RESULTS: A higher level of creatine, glutamine/glutamate, acetate and glycine characterized NB biopsies while healthy adrenal medulla tissue contained adrenaline and a larger amount of ascorbic acid. Adrenaline, which was undetectable in NB spectra, represented the metabolic signature of normal adrenal medulla. NB from patients younger than 12 months contained a higher level of acetate and lysine. Conversely, higher amounts of glutathione, glutamate, myo-inositol, glycine, serine and ascorbic acid were detected in NB samples belonging to younger children. Glutamine/glutamate, aspartate, creatine, glycine were characteristic of stage I-II NB. Acetate and creatine were characteristic of stage IV NB. Finally, a relatively higher amount of aspartate, succinate, and glutathione was detected in patients alive without active disease after a mean follow-up of 7 years whereas a higher concentration of acetate and taurine was characteristic of patients with worse prognosis. CONCLUSIONS: Our preliminary results suggest the existence of a complex metabolic reality in NB, probably representative of tumor behavior. However, the real impact of these promising results should be assessed by long-term prospective studies on a larger cohort of patients. PMID- 20949595 TI - Finite RF pulse correction on DESPOT2. AB - Magnetization transfer and finite radiofrequency (RF) pulses affect the steady state of balanced steady state free precession. As quantification of transverse relaxation (T2) with driven equilibrium single pulse observation of T2 is based on two balanced steady state free precession acquisitions, both effects can influence the outcome of this method: a short RF pulse per repetition time (TRF/TR?1) leads to considerable magnetization transfer effects, whereas prolonged RF pulses (TRF/TR>0.2) minimize magnetization transfer effects, but lead to increased finite pulse effects. A correction for finite pulse effects is thus implemented in the driven equilibrium single pulse observation of T2 theory to compensate for reduced transverse relaxation effects during excitation. It is shown that the correction successfully removes the driven equilibrium single pulse observation of T2 dependency on the RF pulse duration. A reduction of the variation in obtained T2 from over 50% to less than 10% is achieved. We hereby provide a means of acquiring magnetization transfer-free balanced steady state free precession images to yield accurate T2 values using elongated RF pulses. PMID- 20949596 TI - Cancer at ages 15-29 years: the contrasting incidence in India and England. AB - BACKGROUND: There has been a steady increase in published research from Europe and North America on the epidemiology of cancers in young people. There are limited data from the developing world. We contrast the incidence of cancer at ages 15-29 years in India and England. PROCEDURE: Malignant neoplasms in those aged 15-29 years registered during 2001-2003 in five urban population-based cancer registries (PBCRs) of India and in eight PBCRs in England were included. Site-based classification was used. Age-standardized incidence rates were expressed per 100,000 person years. RESULTS: In India, 4,864 (5.8%) of 84,450 cases and in England, 8,137 (1.2%) of 65,6752 cancer cases occurred in those aged 15-29 years. For this age group, the incidence rate for males and females in India were 12.91 and 14.19, and in England were 27.75 and 28.88, respectively. In males aged 15-29 years, the three most common cancers in India were leukemia, lymphoma, and central nervous system tumors and in England were cancers of male genital organs, lymphoma, and leukemia. Cancers of female genital organs, breast, and leukemia were most common in females in India and cancers of female genital organs, lymphoma, and melanoma in England. For cancers of mouth, stomach, and gall bladder, the incidence was higher in India. CONCLUSION: Incidence of cancer at ages 15-29 years in England is higher at most sites than in India. Variation in environmental exposures between the two countries might be an explanation. Under-ascertainment of cases and gender bias in seeking healthcare may also influence reported incidence rates in India. PMID- 20949597 TI - Pyuria is absent during urinary tract infections in neutropenic patients. AB - To investigate the diagnostic significance of a normal urine sediment in the work up for fever of unknown origin in neutropenia. Urinary tract infection was defined as >=10(5) urinary pathogens in the absence of another focus. Pyuria was found in only 1/23 neutropenic episodes compared to 21/31 in controls (P < 0.0001). PMID- 20949598 TI - Sonographic transvaginal bladder wall thickness: does the measurement discriminate between urodynamic diagnoses? AB - INTRODUCTION: Measurement of bladder wall thickness (BWT) using transvaginal ultrasound has previously been shown to discriminate between women with confirmed detrusor overactivity and those with urodynamic stress incontinence. Aim of the current study was to determine if vaginally measured BWT correlates with urodynamic diagnoses in a female population. PATIENTS AND METHODS: Between December 2008 and February 2010, adult female consecutive patients undergoing urogynaecologic investigation for lower urinary symptoms were approached to participate in this study. Ethical consent for the current study was obtained. Patients underwent multichannel urodynamics and transvaginal ultrasound measuring the bladder in three location with an emptied bladder. RESULTS: 123 patients were included in the study with a median age of 69 years (range 40-93), median parity of 2 (range 0-3) and a median body mass index of 29.5 kg/m(2) (range 23-38). Urodynamic stress incontinence was diagnosed in 59 patients, DO in 40 and obstruction in 24 cases. Bladder wall thickness was significantly higher in DO patients and in obstruction than in urodynamic stress incontinence. Detrusor pressure at maximum flow rate (pdet/Q(max) ) correlated significantly with BWT. CONCLUSION: Bladder wall thickness shows a significantly positive correlation to pdet/Q(max) and to urodynamic diagnoses of stress incontinence, DO and obstruction. PMID- 20949599 TI - Single-wall carbon nanotubes assisted photothermal cancer therapy: animal study with a murine model of squamous cell carcinoma. AB - BACKGROUND AND OBJECTIVES: There has been a dramatic increase in photothermal therapy as a minimally invasive treatment modality for cancer treatment due to the development of novel nanomaterials as the light absorption agents. Single wall carbon nanotubes (SWNTs) with strong optical absorption in the broad visible and near IR offer unique advantages for photothermal cancer therapy. A broad range of wavelengths can be used for the treatment with SWNTs, whereas conventional photothermal therapeutic agent is designed to absorb light only near one selected wavelength. The objective of this study is to validate the hypothesis that intratumoral injected SWNTs can absorb 785 nm near IR laser light and generate significant local hyperthermia to destroy tumors. STUDY DESIGN/MATERIALS AND METHODS: SCCVII tumor in C3H/HeN mice was exposed to 785-nm laser after intratumoral injection of SWNTs with different light and SWNTs dose combinations. The temperatures of the tumor with laser irradiation were monitored. In vivo and ex vivo Raman spectra in different organs were obtained with a rapid Raman system. Tumor responses (tumor volume and mouse survival) were documented daily after treatment up to day 45 to assess the effectiveness of the treatment. RESULTS: The temperature within the tumors increased in a light- and SWNTs-dose dependent manner. Squamous cell carcinomas can be eradicated at a moderate light irradiance and fluence (200 mW/cm2 and 120 J/cm2). This light dose is also comparable to those used with photodynamic therapy. Tissue Raman spectroscopy measurements revealed that SWNTs remained localized in the tumor even 3 months after injection but was not found in other organs. CONCLUSIONS: This animal study represents a significant step forward towards the goal of advancing SWNTs based photothermal cancer therapy into clinical applications. PMID- 20949600 TI - Sweep MRI with algebraic reconstruction. AB - In the recently proposed technique Sweep Imaging with Fourier Transform (SWIFT), frequency-modulated radiofrequency pulses are used in concert with simultaneous acquisition to facilitate MRI of samples with very short transverse relaxation time. In the present work, sweep MRI is reviewed from a reconstruction perspective and several extensions and modifications of the current methodology are proposed. An algorithm for algebraic image reconstruction is derived from a comprehensive description of signal formation, including interleaved radiofrequency transmission and acquisition of arbitrary timing as well as the relevant filtering and decimation steps along the receiver chain. The new reconstruction approach readily permits several measures of optimising the signal sampling strategy as demonstrated in simulations and imaging experiments. Employing a variety of radiofrequency pulse envelopes, water and rubber phantoms as well as bone samples with transverse relaxation time in the order of 500 MUsec were imaged at signal bandwidths of up to 96 kHz. PMID- 20949601 TI - Association of microtia with maternal obesity and periconceptional folic acid use. AB - The study objective was to examine the association of microtia with maternal intake of folic-acid-containing supplements and obesity. The study data included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Non-syndromic cases of microtia were compared to non-malformed, population-based liveborn control infants, by estimating adjusted odds ratios (AORs) and 95% confidence intervals (CIs) from logistic regression models that included maternal race/ethnicity, education, and study site. Maternal obesity was only weakly associated with microtia. Maternal periconceptional intake of folic-acid containing vitamin supplements reduced the risk for microtia, but only among non obese women (OR: 0.63; 95% CI: 0.44-0.91). The reduced risk was stronger when analyses were restricted to isolated cases (OR: 0.51; 95% CI: 0.34-0.77), and it was independent of the level of maternal dietary folate intake. Adjusting for maternal race/ethnicity did not reveal alternative interpretations of this association. This analysis suggests that maternal periconceptional intake of folic-acid-containing supplements may provide protection from microtia for non obese women. PMID- 20949602 TI - Development of a process to manufacture PEGylated orally bioavailable insulin. AB - To make insulin orally bioavailable, insulin was modified by covalent attachment (conjugation) of a short-chain methoxy polyethylene glycol (mPEG) derivative to the epsilon-amino group of a specific amino acid residue (LysB(29)). During the conjugation process, activated PEG can react with any of the free amino groups, the N-terminal of the B chain (PheB(1)), the N-terminal of the A chain (GlyA(1)), and the epsilon-amino group of amino acid (LysB(29)), resulting in a heterogeneous mixture of conjugated products. The abundance of the desired product (Methoxy-PEG(3)-propionyl--insulin at LysB(29):IN-105) in the conjugation reaction can be controlled by changing the conjugation reaction conditions. Reaction conditions were optimized for maximal yield by varying the proportions of protein to mPEG molecule at various values of pH and different salt and solvent concentrations. The desired conjugated molecule (IN-105) was purified to homogeneity using RP-HPLC. The purified product, IN-105, was crystallized and lyophilized into powder form. The purified product was characterized using multiple analytical methods including ESI-TOF and peptide mapping to verify its chemical structure. In this work, we report the process development of new modified insulin prepared by covalent conjugation of short chain mPEG to the insulin molecule. The attachment of PEG to insulin resulted in a conjugated insulin derivative that was biologically active, orally bioavailable and that showed a dose-dependent glucose lowering effect in Type 2 diabetes patients. PMID- 20949603 TI - X-linked hereditary hemihypotrophy hemiparesis hemiathetosis. AB - Hereditary hemihypotrophy hemiparesis hemiathetosis syndrome (HHHH; OMIM 306960) was first reported in a family with congenital left hemiplegia in two males and moderately affected females. We describe a family with three males demonstrating congenital right hemiplegia with porencephalic lesions of the left internal capsule and putamen, or the periventricular white matter just above the internal capsule. Clinical findings within each family are limited to the same side, though sidedness differed between families. Both pedigrees were most consistent with X-linked inheritance. Genome-wide linkage analysis in our family further supports a locus for HHHH on chromosome X. PMID- 20949604 TI - Milk intake and risk of hip fracture in men and women: a meta-analysis of prospective cohort studies. AB - Milk contains calcium, phosphorus, and protein and is fortified with vitamin D in the United States. All these ingredients may improve bone health. However, the potential benefit of milk on hip fracture prevention is not well established. The objective of this study was to assess the association of milk intake with risk of hip fracture based on a meta-analysis of cohort studies in middle-aged or older men and women. Data sources for this study were English and non-English publications via Medline (Ovid, PubMed) and EMBASE search up to June 2010, experts in the field, and reference lists. The idea was to compare prospective cohort studies on the same scale so that we could calculate the relative risk (RR) of hip fracture per glass of milk intake daily (approximately 300 mg calcium per glass of milk). Pooled analyses were based on random effects models. The data were extracted by two independent observers. The results show that in women (6 studies, 195,102 women, 3574 hip fractures), there was no overall association between total milk intake and hip fracture risk (pooled RR per glass of milk per day = 0.99; 95% confidence interval [CI] 0.96-1.02; Q-test p = .37). In men (3 studies, 75,149 men, 195 hip fractures), the pooled RR per daily glass of milk was 0.91 (95% CI 0.81-1.01). Our conclusion is that in our meta-analysis of cohort studies, there was no overall association between milk intake and hip fracture risk in women but that more data are needed in men. PMID- 20949606 TI - Amstracts of the American Society of Cytopathology 57th Annual Scientific Meeting Platform and Poster Presentations: supplement to Cancer Cytopathology. November 12-16, 2010, Boston. PMID- 20949605 TI - A novel mutation c.4003 G>C in the CREBBP gene in an adult female with Rubinstein Taybi syndrome presenting with subtle dysmorphic features. PMID- 20949607 TI - The Chehr Abad "Salt men" and the isotopic ecology of humans in ancient Iran. AB - We have carried out isotopic analysis (delta(13)C and delta(15)N) on five salt preserved bodies from the salt mine at Chehr Abad, Iran, dating from the 4th C. BC through to the 4th C. AD. In an attempt to identify the geographical origins of these people, we have analyzed over a hundred archeological bone samples from various archeological sites in Iran. From the faunal remains, we observe that the entire ecosystem appears to be enriched in (15)N, which we suggest is due to the semi-arid nature of the region. We have also observed a number of cattle remains from one site (Nargas Tepe) which have a significant C(4) component to their diet from the 4th millennium BC. By combining our data with those published by [Bocherens et al.: Environ Archaeol 5 (2000) 1-19; Bocherens et al.: J Arch Sci 33 (2006) 253-264], we suggest that two of the "mummies" may have come from the Tehran/Qazvin Plain region (i.e., relatively local to the salt mine), and a further two appear on isotopic grounds to have come from the northeast of Iran or the Turkmenistan steppes. The fifth (no. 4), the best preserved, appears to have come from further afield. Collectively, these mummies and their contexts augment our knowledge of social mobility and technical innovation in Iran during the Achaemenid period. PMID- 20949608 TI - Comparison between morphological and genetic data to estimate biological relationship: the case of the Egyin Gol necropolis (Mongolia). AB - Osseous and dental nonmetric (discrete) traits have long been used to assess population variability and affinity in anthropological and archaeological contexts. However, the full extent to which nonmetric traits can reliably be used as a proxy for genetic data when assessing close or familial relationships is currently poorly understood. This study represents the unique opportunity to directly compare genetic and nonmetric data for the same individuals excavated from the Egyin Gol necropolis, Mongolia. These data were analyzed to consider the general efficacy of nonmetric traits for detecting familial groupings in the absence of available genetic data. The results showed that the Egyin Gol population is quite homogenous both metrically and genetically confirming a previous suggestion that the same people occupied the necropolis throughout the five centuries of its existence. Kinship analysis detected the presence of potential family burials in the necropolis. Moreover, individuals buried in one sector of the necropolis were differentiated from other sectors on the basis of nonmetric data. This separation is likely due to an outside Turkish influence in the paternal line, as indicated by the results of Y-chromosome analysis. Affinity matrices based on nonmetric and genetic data were correlated demonstrating the potential of nonmetric traits for detecting relationships in the absence of genetic data. However, the strengths of the correlations were relatively low, cautioning against the use of nonmetric traits when the resolution of the familial relationships is low. PMID- 20949609 TI - Earliest colobine skeletons from Nakali, Kenya. AB - Old World monkeys represent one of the most successful adaptive radiations of modern primates, but a sparse fossil record has limited our knowledge about the early evolution of this clade. We report the discovery of two partial skeletons of an early colobine monkey (Microcolobus) from the Nakali Formation (9.8-9.9 Ma) in Kenya that share postcranial synapomorphies with extant colobines in relation to arboreality such as mediolaterally wide distal humeral joint, globular humeral capitulum, distinctly angled zona conoidea, reduced medial trochlear keel, long medial epicondyle with weak retroflexion, narrow and tall olecranon, posteriorly dislocated fovea on the radial head, low projection of the femoral greater trochanter, wide talar head with a greater rotation, and proximodistally short cuboid and ectocuneiform. Microcolobus in Nakali clearly differs from the stem cercopithecoid Victoriapithecus regarding these features, as Victoriapithecus is postcranially similar to extant small-sized terrestrial cercopithecines. However, degeneration of the thumb, a hallmark of modern colobines, is not observed, suggesting that this was a late event in colobine evolution. This discovery contradicts the prevailing hypothesis that the forest invasion by cercopithecids first occurred in the Plio-Pleistocene, and shows that this event occurred by the late Miocene at a time when ape diversity declined. PMID- 20949610 TI - Astragalar morphology of Afradapis, a large adapiform primate from the earliest late Eocene of Egypt. AB - The ~37 million-year-old Birket Qarun Locality 2 (BQ-2), in the Birket Qarun Formation of Egypt's Fayum Depression, yields evidence for a diverse primate fauna, including the earliest known lorisiforms, parapithecoid anthropoids, and Afradapis longicristatus, a large folivorous adapiform. Phylogenetic analysis has placed Afradapis as a stem strepsirrhine within a clade of caenopithecine adapiforms, contradicting the recently popularized alternative hypothesis aligning adapiforms with haplorhines or anthropoids. We describe an astragalus from BQ-2 (DPC 21445C), attributable to Afradapis on the basis of size and relative abundance. The astragalus is remarkably similar to those of extant lorises, having a low body, no posterior shelf, a broad head and neck. It is like extant strepsirrhines more generally, in having a fibular facet that slopes gently away from the lateral tibial facet, and in having a groove for the tendon of flexor fibularis that is lateral to the tibial facet. Comparisons to a sample of euarchontan astragali show the new fossil to be most similar to those of adapines and lorisids. The astragali of other adapiforms are most similar to those of lemurs, but distinctly different from those of all anthropoids. Our measurements show that in extant strepsirrhines and adapiforms the fibular facet slopes away from the lateral tibial facet at a gradual angle (112-126 degrees ), in contrast to the anthropoid fibular facet, which forms a sharper angle (87-101 degrees ). Phylogenetic analyses incorporating new information from the astragalus continue to support strepsirrhine affinities for adapiforms under varying models of character evolution. PMID- 20949611 TI - The biomechanics of leaping in gibbons. AB - Gibbons are skilled brachiators but they are also highly capable leapers, crossing distances in excess of 10 m in the wild. Despite this impressive performance capability, no detailed biomechanical studies of leaping in gibbons have been undertaken to date. We measured ground reaction forces and derived kinematic parameters from high-speed videos during gibbon leaps in a captive zoo environment. We identified four distinct leap types defined by the number of feet used during take-off and the orientation of the trunk, orthograde single-footed, orthograde two-footed, orthograde squat, and pronograde single-footed leaps. The center of mass trajectories of three of the four leap types were broadly similar, with the pronograde single-footed leaps exhibiting less vertical displacement of the center of mass than the other three types. Mechanical energy at take-off was similar in all four leap types. The ratio of kinetic energy to mechanical energy was highest in pronograde single-footed leaps and similar in the other three leap types. The highest mechanical work and power were generated during orthograde squat leaps. Take-off angle decreased with take-off velocity and the hind limbs showed a proximal to distal extension sequence during take-off. In the forelimbs, the shoulder joints were always flexed at take-off, while the kinematics of the distal joints (elbow and wrist joints) were variable between leaps. It is possible that gibbons may utilize more metabolically expensive orthograde squat leaps when a safe landing is uncertain, while more rapid (less expensive) pronograde single-footed leaps might be used during bouts of rapid locomotion when a safe landing is more certain. PMID- 20949612 TI - Sexual dimorphism in chin shape: implications for adaptive hypotheses. AB - The chin, or mentum osseum, is one of the most distinctive anatomical traits of modern humans. A variety of hypotheses for the adaptive value of the chin have been proposed, ranging from mechanical stress resistance to sexual selection via mate choice. While the sexual selection hypothesis predicts dimorphism in chin shape, most biomechanical hypotheses preclude it. Therefore determining the presence or absence of significant sexual dimorphism in chin shape provides a useful method for differentiating between various adaptive hypotheses; however, this has yet to be done due to a lack of quantitative data on chin shape. The goals of this study are therefore: (1) to introduce a new method for quantifying chin shape and (2) to determine the presence or absence of sexual dimorphism in chin shape in a diverse sample of modern humans. Samples were drawn from recent human skeletal collections representing nine geographic regions. Outlines of mentum osseum contours were quantified using elliptical Fourier function analysis (EFFA). Fourier coefficients were analyzed using principal components analysis (PCA). Sexual dimorphism in chin shape was assessed using PC loadings in the pooled geographic sample, and statistically significant differences were found. These findings provide the first quantitative, morphologically based evidence in support of adaptive hypotheses that predict dimorphism in chin shape, including the sexual selection hypothesis. PMID- 20949613 TI - A preliminary 3D computed tomography study of the human maxillary sinus and nasal cavity. AB - Despite centuries of investigation, the function of the maxillary sinus (MS) and underlying patterns governing its form remain elusive. In this study, we articulate a methodology for collecting volumetric data for the MS and nasal cavity (NC) from computed tomography (CT) scans and report details for a small sample of 39 dried human crania of known ecogeographic provenience useful for assessing variation in MS size and shape. We use scaling analyses to preliminarily test the hypothesis that volumes of the nasal cavity (NCV) and maxillary sinus (MSV) are inversely correlated such that the NC covaries with size of the face, whereas the MS "fills in" the leftover space [proposed by Shea: Am J Phys Anthropol 47 (1977):289-300]. Against expectation, MSV is not significantly correlated with NCV or any cranial size variable. NCV, on the other hand, scales isometrically with facial size. The results of this pilot study suggest that NCV covaries with facial size, but that the MS does not simply fill in the leftover space in the face. The role, if any, of the MSs in midfacial function and architecture remains unclear. Larger sample sizes, additional environmental variables, and assessment of MS and NC shape are necessary to resolve this issue. PMID- 20949614 TI - Regional shape change in adult facial bone curvature with age. AB - Life expectancies have increased dramatically over the last 100 years, affording greater opportunities to study the impact of age on adult craniofacial morphology. This article employs a novel application of established geometric morphometric methods to examine shape differences in adult regional facial bone curvature with age. Three-dimensional semilandmarks representing the curvature of the orbits, zygomatic arches, nasal aperture, and maxillary alveolar process were collected from a cross-sectional cranial sample of mixed sex and ancestry (male and female; African- and European-American), partitioned into three age groups (young adult = 18-39; middle-aged = 40-59 years; and elderly = 60+ years). Each facial region's semilandmarks were aligned into a common coordinate system via generalized Procrustes superimposition. Regional variation in shape was then explored via a battery of multivariate statistical techniques. Age-related shape differences were detected in the orbits, zygomatic arches, and maxillary alveolar process. Interactions between age, sex, and ancestry were also identified. Vector plots revealed patterns of superoinferior compression, lateral expansion, and posterior recession depending on the population/subpopulation, location, and age groups examined. These findings indicate that adult craniofacial curvature shape is not static throughout human life. Instead, age-related spatial modifications occur in various regions of the craniofacial skeleton. Moreover, these regional alterations vary not only through time, but across human populations and the sexes. PMID- 20949615 TI - Applying tribology to teeth of hoofed mammals. AB - Mammals inhabit all types of environments and have evolved chewing systems capable of processing a huge variety of structurally diverse food components. Surface textures of cheek teeth should thus reflect the mechanisms of wear as well as the functional traits involved. We employed surface textures parameters from ISO/DIS 25178 and scale-sensitive fractal analysis (SSFA) to quantify dental wear in herbivorous mammals at the level of an individual wear enamel facet. We evaluated cheek dentitions of two grazing ungulates: the Blue Wildebeest (Connochaetes taurinus) and the Grevy's Zebra (Equus grevyi). Both inhabit the east African grassland savanna habitat, but they belong to fundamentally different taxonomic units. We tested the hypothesis that the foregut fermenting wildebeest and the hindgut fermenting zebra show functional traits in their dentitions that relate to their specific mode of food-composition processing and digestion. In general, surface texture parameters from SSFA as well as ISO/DIS 25178 indicated that individual enamel ridges acting as crushing blades and individual wear facets of upper cheek teeth are significantly different in surface textures in the zebra when compared with the wildebeest. We interpreted the complexity and anisotropy signals to be clearly related to the brittle, dry grass component in the diet of the zebra, unlike the wildebeest, which ingests a more heterogeneous diet including fresh grass and herbs. Thus, SSFA and ISO parameters allow distinctions within the subtle dietary strategies that evolved in herbivorous ungulates with fundamentally different systematic affinities but which exploit a similar dietary niche. PMID- 20949616 TI - Considerations for the incorporation of measured surfaces in finite element models. AB - This work discusses some of the benefits, techniques, challenges, and considerations associated with the incorporation of measured surfaces in finite element (FE) models including how much surface data to measure and import into the model, the shape of the surface geometry to create, the presence and effect of surface layers and impurities, the required mesh density for rough surfaces, the nature of the element formulations and material properties at small length scales, the differences between measurement and FE coordinate systems, the limitations and idealizations of the FE method, issues associated with boundary conditions and their ability to impose or prevent conformal contact, and issues associated with the size of the pinball region and the contact stiffness relative to the nature of the surface. It also describes some current and future research directions that can be used to validate and expand existing techniques and to improve our understanding of surface phenomena. PMID- 20949617 TI - The use of frequency and wavelet analysis for monitoring surface quality of wood machining applications. AB - The research described in this study is part of a project to provide the technology and theory to quantify surface quality for a variety of wood and wood based products. The ultimate goal is to provide a means of monitoring trends in surface quality, which can be used to discriminate between "good" products and "bad" products (the methods described in this research are not intended to provide "grading" of individual workpieces) as well as to provide information to the machine operator as to the source of poor-quality machined surfaces. This research investigates the use of both frequency domain analysis as well as the more advanced joint time frequency analysis (JTFA). The disadvantages of traditional frequency analysis as well as the potential of the JTFA are illustrated. Sample surface profiles from actual machining defects were analyzed using traditional frequency analysis. A surface with multiple machining defects was analyzed with both traditional frequency analysis and JTFA (harmonic wavelet). Although the analysis was empirical in nature, the results show that the harmonic wavelet transform is able to detect both stationary and non stationary surface irregularities as well as pulses (localized defects). PMID- 20949618 TI - Investigation of surface topography differences in native and exotic invertebrates in the St. Lawrence River. AB - The texture, or topography, interior of shells from native and exotic mollusks are measured and compared to determine if they can be discriminated. Area-scale fractal analysis is used to calculate relative areas as a function of scale, and the relative areas are used to evaluate the measurements. Measurements from a scanning laser profiler and from confocal and interferometric microscopes are compared, as are measurements of an original and a replica. The relative areas indicate clear differences between the measurement instruments. The largest relative areas are calculated from the confocal measurements. The trueness of the measurements has not been determined. However, the relative areas calculated from the confocal measurements are capable of discriminating the native clam from the exotic mussels with a confidence of greater than 99% at scales below 10 um2. PMID- 20949619 TI - MET mutations in cancers of unknown primary origin (CUPs). AB - Cancer of unknown primary origin (CUP) defines metastatic disease of unknown origin, accounting for 3-5% of all cancers. Growing evidence demonstrates that inappropriate execution of a genetic program named "invasive growth," driven by the MET oncogene, is implicated in the metastatic process. MET activation in cancers is mainly consequent to overexpression, whereas mutations are rarely found. We reasoned that the occurrence of MET somatic mutations might sustain premature occult dissemination of cancer cells, such as that observed in CUPs. We sequenced MET in genomic DNA obtained from 47 early metastatic cancers. By extensive immunohistochemical analysis a primary site was afterward postulated in 24 patients, whereas 23 cases remained of unknown primary (CUPs). MET somatic mutations were found in seven cases, all belonging to the CUP cohort. Mutational incidence (30%) was thus significantly higher than the expected one (4%), in the absence of high mutational background. Several nucleotide changes were novel and clustered either in the kinase domain or in the extracellular semaphorin domain. Mutated receptors were functional and sustained the transformed phenotype, suggesting that MET activating mutations are genetic markers associated with the CUP syndrome. PMID- 20949620 TI - D-glyceric aciduria is caused by genetic deficiency of D-glycerate kinase (GLYCTK). AB - D-glyceric aciduria is a rare inborn error of serine and fructose metabolism that was first described in 1974. Most affected individuals have presented with neurological symptoms. The molecular basis of D-glyceric aciduria is largely unknown; possible causes that have been discussed are deficiencies of D-glycerate dehydrogenase, triokinase, and D-glycerate kinase. In 1989, van Schaftingen has reported decreased D-glycerate kinase activity in the liver of a single patient with D-glyceric aciduria. However, this analysis has not been performed in other affected individuals, and the underlying defect has remained unknown on the gene level until now. We report three patients with deficiency of D-glycerate kinase. They are of Serbian, Mexican, and Turkish origin and include the patient initially reported in 1974. All had homozygous mutations in exon 5 of the GLYCTK gene encoding D-glycerate kinase: c.1448delT (p.Phe483SerfsX2), c.1478T>G (p.Phe493Cys), or c.1558delC (p.Leu520CysfsX108). Transient overexpression of the variant GLYCTK genes in HEK293 cells clearly showed loss of enzyme activity and immunoreactivity when compared to the reference enzyme. Our work has revealed mutations in the GLYCTK gene as the cause of D-glycerate kinase deficiency and D glyceric aciduria and provides a noninvasive approach for further diagnostic workup and research. PMID- 20949622 TI - Unique variants of human papillomavirus genotypes 52 and 58 and risk of cervical neoplasia. AB - Human papillomavirus (HPV) 52 and 58 are oncogenic HPV types prevalent in Asia. Our study aims to explore intratypic variants of HPV 52 and 58 in Taiwan. A total of 11,923 women were enrolled from seven townships in 1991-1992. HPV DNA in their cervical cells was detected and typed by EasyChip(r) HPV blot. Among 424 participants infected with HPV 52 and/or 58, nucleotide variations were determined in cervical cell samples of 406 participants by the polymerase chain reaction sequencing of the long control region, E6 and E7 genes. Nonprototype like variants including lineages B and C were detected in 278 (99.3%) of 280 HPV 52 samples. The prototype and prototype-like group (lineage A) of HPV58 was found in 132 (98.5%) of 134 HPV 58 samples, with sublineage A1, A2 and A3 variant in 14.2, 27.6 and 56.7%, respectively. Among women infected with single HPV 52 type, the C variant (vs. B variant) was associated with an increased prevalence of cytologically diagnosed high-grade squamous intraepithelial lesion or worse lesions showing an age-adjusted odds ratio (95% confidence interval, CI) of 5.2 (1.0-27.6) and an increased prevalence of histologically confirmed high-grade cervical intraepithelial neoplasia or more severe lesions with an age-adjusted odds ratio (95% CI) of 7.6 (1.3-43.8). It was concluded that frequency distributions of HPV 52 and 58 variants in Taiwan were different from those in European and American populations. The association between C variant of HPV 52 and prevalence of cervical neoplasia needs further validation. PMID- 20949623 TI - Adenocarcinoma in situ and associated human papillomavirus type distribution observed in two clinical trials of a quadrivalent human papillomavirus vaccine. AB - The primary objective of this report is to describe the detection of adenocarcinoma in situ (AIS) and associated human papillomavirus (HPV) type distribution that was observed in the context of two phase 3 clinical trials of a quadrivalent HPV6/11/16/18 vaccine. In this intention-to-treat analysis, we include all women who had at least one follow-up visit postenrollment. Healthy women (17,622) aged 15-26 with no history of HPV disease and a lifetime number of less than five sex partners (average follow-up of 3.6 years) were randomized (1:1) to receive vaccine or placebo at day 1, months 2, and 6. Women underwent colposcopy and biopsy according to a Papanicolaou triage algorithm. All tissue specimens were tested for 14 HPV types and were adjudicated by a pathology panel. During the trials, 22 women were diagnosed with AIS (six vaccine and 16 placebo). There were 25 AIS lesions in total, with HPV16/18 present in 96% (24 of 25 with 15 of 25 as single infections). Only two of 22 women had concomitant cytology results suggesting glandular abnormality. Colposcopic impressions (25 total) were either negative or indicated squamous lesions only. Of women with AIS, all six in the vaccine cohort and seven of 16 in the placebo cohort were infected at baseline with the same HPV type that was detected in the AIS lesion. Concurrent squamous lesions were detected in 20 of these 22 women. In summary, our findings show that AIS evades colposcopic and cervical cytologic detection. As most AIS lesions were HPV16/18-related, prophylactic HPV vaccination should reduce the incidence of invasive adenocarcinoma. PMID- 20949621 TI - Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders. AB - The KRAS gene is the most common locus for somatic gain-of-function mutations in human cancer. Germline KRAS mutations were shown recently to be associated with developmental disorders, including Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFCS), and Costello syndrome (CS). The molecular basis of this broad phenotypic variability has in part remained elusive so far. Here, we comprehensively analyzed the biochemical and structural features of ten germline KRAS mutations using physical and cellular biochemistry. According to their distinct biochemical and structural alterations, the mutants can be grouped into five distinct classes, four of which markedly differ from RAS oncoproteins. Investigated functional alterations comprise the enhancement of intrinsic and guanine nucleotide exchange factor (GEF) catalyzed nucleotide exchange, which is alternatively accompanied by an impaired GTPase-activating protein (GAP) stimulated GTP hydrolysis, an overall loss of functional properties, and a deficiency in effector interaction. In conclusion, our data underscore the important role of RAS in the pathogenesis of the group of related disorders including NS, CFCS, and CS, and provide clues to the high phenotypic variability of patients with germline KRAS mutations. PMID- 20949624 TI - Higher bone mineral density is associated with a decreased risk of colorectal adenomas. AB - Bone mineral density (BMD) is a biomarker for cumulative exposure to multiple factors including estrogen, calcium, vitamin D and physical activity, which have all been independently associated with colorectal cancer. Furthermore, higher levels of BMD have been inversely associated with colorectal cancer risk, particularly in postmenopausal women. However, no prior studies have examined the potential association between BMD and colorectal adenomas, which are precursor lesions to most colorectal cancers. Therefore, we evaluated the association between BMD, which was measured using a whole body, dual-energy X-ray absorptiometry scan and colorectal adenomas in 167 patients who underwent colonoscopy screening. We found that patients in the highest tertile of total body BMD (>1.294 g/cm(2)) and in the middle tertile (>=1.167 to <=1.294 g/cm(2)) compared to those with a total body BMD in the lowest tertile (<1.167 g/cm(2)) had a lower risk of colorectal adenomas (highest vs. lowest tertile: OR = 0.29 (0.10-0.84); middle vs. lowest tertile: OR=0.26 (0.08-0.80); p-trend=0.02). Stratification by gender revealed that this association was more pronounced in women (highest (>1.280 g/cm(2)) vs. lowest (<1.130 g/cm(2)) tertile: OR=0.08 (0.01-0.70); middle (>=1.130 to <=1.280 g/cm(2)) vs. lowest tertile: OR=0.15 (0.04-0.94); p-trend=0.02) even after excluding hormone replacement therapy users (highest (>1.295 g/cm(2)) and middle (>=1.132 to <=1.295 g/cm(2)) vs. lowest (<1.132 g/cm(2)) tertile: OR=0.17 (0.03-0.97); p-trend=0.04). Our results show, for the first time, that BMD is inversely associated with colorectal adenomas, particularly in women. Although additional larger, prospective studies are needed, our results suggest that BMD may be a biomarker for colorectal cancer precursor lesions. PMID- 20949626 TI - Haploinsufficiency of the LIM domain containing preferred translocation partner in lipoma (LPP) gene in patients with tetralogy of Fallot and VACTERL association. PMID- 20949627 TI - Unilateral agenesis of the abdominal wall musculature: An early muscle deficiency. AB - Prune-belly sequence (PBS) usually results from early urethral obstruction. In rare cases, PBS seems to be due to a faulty primary development of the parietal mesenchyme leading to underdevelopment of the abdominal wall musculature, and disorganization of the smooth muscles in the urinary tract. We report on two patients with segmental, unilateral wall musculature deficiency associated with homolateral agenesis of ribs. One patient also had hemivertebrae and the other one ipsilateral diaphragmatic eventration and aplasia cutis. This combination of anomalies may represent a localized deficiency in the development of somitic mesoderm mesenchyme during early embryogenesis. PMID- 20949625 TI - The sensors and regulators of cell-matrix surveillance in anoikis resistance of tumors. AB - Normal cells continuously monitor the nature of their respective cellular microenvironment. They are equipped with an inherent molecular defense to detect changes that can precipitate and trigger an oncogenic cascade in the internal and external environment of cells. The process called anoikis unleashes many a characteristic molecular change in the cells which eventually program to cell death in response to cell detachment and inappropriate cellular attachment, both of which can otherwise potentiate the ability of cells to preferentially pursue a malignant course due to the release of molecular discipline which conforms them to a benign structural and functional spectrum. The initiation and propagation of signaling that serves as a switch to cell survival or cell death mediated by surveillance of cell microenvironment is comprised of many heterogeneous sets of molecules interacting mainly at the interface of cell-extracellular matrix. Transforming cells continuously reprogram their signaling characteristics in sensing and modulating the stimuli from cell surface molecules like integrins, cadherins and immunoglobulin family of cell adhesion molecules at adhesion complexes, which enables them to resist anoikis and metastasize to different organs. Actin cytoskeleton binds BIM and Bcl2 modifying factor (BMF), which are regulated by the adhesion status and consequent conformation of cytoskeleton in the cells. This review aims at an integrated synopsis of fundamental mechanisms of the critical interactions of cell surface molecules to facilitate a focused analysis of the differential regulation of signaling processes at cell-ECM junctions that collectively rein the anoikis resistance, which in turn impacts metastatic aggressiveness and drug resistance of tumors originating from respective organs. PMID- 20949628 TI - Evaluation of germline BMP4 mutation as a cause of colorectal cancer. AB - Transforming growth factor-beta (TGF-beta) signalling plays a key role in colorectal cancer (CRC). Bone morphogenetic protein-4 (BMP4) is a member of the TGF-beta family of signal transduction molecules. To examine if germline mutation in BMP4 causes CRC we analysed 504 genetically enriched CRC cases (by virtue of early-onset disease, family history of CRC) for mutations in the coding sequence of BMP4. We identified three pathogenic mutations, p.R286X (g.8330C>T), p.W325C (g.8449G>T) and p.C373S (g.8592G>C), amongst the CRC cases which were not observed in 524 healthy controls. p.R286X localizes to the N-terminal of the TGF beta1 prodomain truncating the protein prior to the active domain. p.W325C and p.C373S mutations are predicted from protein homology modelling with BMP2 to impact deleteriously on BMP4 function. Segregation of p.C373S with adenoma and hyperplastic polyp in first-degree relatives of the case suggests germline mutations may confer a juvenile polyposis-type phenotype. These findings suggest mutation of BMP4is a cause of CRC and the value of protein-based modelling in the elucidation of rare disease-causing variants. PMID- 20949629 TI - The impact of medical insurance for the poor in Georgia: a regression discontinuity approach. AB - Improving access to health care and financial protection of the poor is a key concern for policymakers in low- and middle-income countries, but there have been few rigorous program evaluations. The Medical Insurance Program for the Poor in the republic of Georgia provides a free and extensive benefit package and operates through a publicly funded voucher program, enabling beneficiaries to choose their own private insurance company. Eligibility is determined by a proxy means test administered to applicant households. The objective of this study is to evaluate the program's impact on key outcomes including utilization, financial risk protection, and health behavior and management. A dedicated survey of approximately 3500 households around the thresholds was designed to minimize unobserved heterogeneity by sampling clusters with both beneficiary and non beneficiary households. The research design exploits the sharp discontinuities at two regional eligibility thresholds to estimate local average treatment effects. Results suggest that the program did not affect utilization of health services but decreased mean out-of-pocket expenditures for some groups and reduced the risk of high inpatient expenditures. There are no systematic impacts on health behavior, management of chronic illnesses, and patient satisfaction. PMID- 20949631 TI - MRI studies of the hydrodynamics in a USP 4 dissolution testing cell. AB - We present a detailed study of hydrodynamics inside the flow-through dissolution apparatus when operated according to USP recommendations. The pulsatile flow inside the flow-through cell was measured quantitatively using magnetic resonance imaging (MRI) at a spatial resolution of 234 * 234 MUm(2) and slice thickness of 1 mm. We report the experimental protocols developed for in situ MRI studies and the effect that the operating conditions and tablet orientation have on the hydrodynamics inside commercial flow cells. It was found that the flow field inside the dissolution cells was, at most operating conditions, heterogeneous, rather than fully developed laminar flow, and characterised by re-circulation and backward flow. A model tablet was shown to be contacted by a wide distribution of local velocities as a function of position and orientation in the flow cell. The use of 1 mm beads acted as a distributor of the flow but did not suffice to ensure a fully developed laminar flow profile. These results emphasise the necessity to understand the influence of test conditions on dissolution behaviour in defining robust flow-through dissolution methods. PMID- 20949630 TI - Frameshift mutations in dentin phosphoprotein and dependence of dentin disease phenotype on mutation location. AB - We describe results from a mutational analysis of the region of the dentin sialophosphoprotein (DSPP) gene encoding dentin phosphoprotein (DPP) in 12 families with dominantly inherited dentin diseases. In eight families (five mutations in the N-terminal third of DPP), the clinical and radiologic features were uniform and compatible with dentin dysplasia type II (DD-II) with major clinical signs in the deciduous dentition. In the other families (four mutations in the more C-terminal part), the permanent teeth also were affected, and the diseases could be classified as variants of dentinogenesis imperfecta. Attrition was not prominent, but periapical infections were common. Discoloring with varying intensity was evident, and pulps and root canals were obliterated in the permanent dentition. All mutations caused a frameshift that replaced the Ser-Ser Asx repeat by a code for a hydrophobic downstream sequence of approximately original length. We conclude that frameshift mutations in DSPP explain a significant part of dentin diseases. Furthermore, we propose that the location of the mutation is reflected in the phenotypic features as a gradient from DD-II to more severe disease that does not conform to the classic definitions of DI-II. PMID- 20949632 TI - Smoothing molecular interactions: the "kinetic buffer" effect of intrinsically disordered proteins. AB - Intrinsically disordered proteins (IDPs) widely participate in molecular recognition and signaling processes in cells by interacting with other molecules. Compared with ordered proteins, IDPs usually possess stronger intermolecular interactions in binding. As a result, the interface structure of IDPs in complexes is distinct from that of ordered-protein complexes, and this difference may have essential effect on the response to various perturbations in a cell. In this study, we examined the perturbations of intermolecular interactions and temperature on the coupled folding and binding processes of pKID to KIX domains by performing molecular dynamics simulations. By comparing a series of virtual pKID systems with various degree of disorder, we found that the complex stability and the binding kinetics of the disordered systems were less sensitive to the perturbations than the ordered systems. The origin of the lower response sensitivity of IDPs was attributed to their higher flexibility in the complex interface, which was further supported by an analysis on protein complex structures. On the basis of our simulations and results from the literature, we speculate IDPs may not only interact with their biological partners with high specificity and low affinity but also may be resistant to the perturbations in the environment and transmit signals fast and smooth. We proposed to name it the "kinetic buffer" effect. PMID- 20949633 TI - Analysis of chemoresistance in lung cancer with a simple microfluidic device. AB - Microchip-based systems have been developed rapidly due to their desirable advantages over conventional platforms. Higher level system integration and complex microdevices are emerging to satisfy the demand for high-throughput and large-scale applications. However, most of the devices need to be fabricated with complicated microvalves and micropumps, which, to some extent, limit the use of the novel technique. In this study, a simple microdevice was developed to perform chemotherapy resistance analysis in lung cancer cell line SPCA1. This device includes a PDMS chip for which a simple external small clip served as a microvalve to control the fluid flow so that the parallel control experiment could be carried out simultaneously, and a syringe pump, which supplied the cells with fresh medium mimicking the microenvironment in vivo. Cell culture, detection of drug resistance related protein P-glycoprotein (P-gp) and glutathione S transferase-pi (GST-pi) and cell viability after VP-16 treatment on experimental (pretreated with corresponding inhibitors) and control groups were achieved. The results demonstrated that the cells could grow and spread well for at least 3 days. The expression of P-gp and GST-pi was obviously downregulated by corresponding inhibitors. The percentage of apoptotic cells for P-gp inhibition group increased 2.9-fold compared with that of control group (23.7 +/- 2.6 versus 8.1 +/- 3.0%, p<0.05), while for GST-pi inhibition, there was no obvious distinction between the experimental and control group. The simple microdevice is capable of integrating parallel operations involving cell culture and functional analysis, offering an easy and flexible platform for a stable long-term cell culture and comparison research. PMID- 20949634 TI - Iopamidol as a responsive MRI-chemical exchange saturation transfer contrast agent for pH mapping of kidneys: In vivo studies in mice at 7 T. AB - Iopamidol (Isovue(r)-Bracco Diagnostic Inc.) is a clinically approved X-Ray contrast agent used in the last 30 years for a wide variety of diagnostic applications with a very good clinical acceptance. Iopamidol contains two types of amide functionalities that can be exploited for the generation of chemical exchange saturation transfer effect. The exchange rate of the two amide proton pools is markedly pH-dependent. Thus, a ratiometric method for pH assessment has been set-up based on the comparison of the saturation transfer effects induced by selective irradiation of the two resonances. This ratiometric approach allows to rule out the concentration effect of the contrast agent and provides accurate pH measurements in the 5.5-7.4 range. Upon injection of Iopamidol into healthy mice, it has been possible to acquire pH maps of kidney regions. Furthermore, it has been also shown that the proposed method is able to report about pH-changes induced in control mice fed with acidified or basified water for a period of a week before image acquisition. PMID- 20949635 TI - A review of clinical diagnostic applications of liquid chromatography-tandem mass spectrometry. AB - Liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) technology is emerging as a complementary method to traditional methodology used for clinical applications. Enhanced specificity and high-throughput capabilities are providing significant benefits to clinical diagnostic laboratories conducting routine analyses. This technology is expected to expand rapidly as scientists focus on more complicated challenges that can be solved efficiently by adding LC/MS/MS to their arsenal of techniques. PMID- 20949636 TI - Testing non-inferiority and superiority for two endpoints for several treatments with a control. AB - Some multiple comparison procedures are described for multiple armed studies. The procedures are appropriate for testing all hypotheses for comparing two endpoints and multiple test arms to a single control group, for example three different fixed doses compared to a placebo. The procedure assumes that among the two endpoints, one is designated as a primary endpoint such that for a given treatment arm, no hypothesis for the secondary endpoint can be rejected unless the hypothesis for the primary endpoint was rejected. The procedures described control the family-wise error rate in the strong sense at a specified level alpha. PMID- 20949638 TI - Evoked local field potentials can explain temporal variation in blood oxygenation level-dependent responses in rat somatosensory cortex. AB - The aim of this study was to explain the temporal variations between subjects in the blood oxygenation level-dependent (BOLD) response. Somatosensory responses were elicited with the electrical forepaw stimulus at a frequency of 10 Hz in urethane-anesthetized rats, and functional magnetic resonance imaging (fMRI) with BOLD contrast and local field potential (LFP) measurements were performed simultaneously. BOLD fMRI activation was evaluated by two different models, one based on the stimulus paradigm (the block model) and the other on the simultaneously measured evoked LFP responses. In the initial analysis, the LFP model captured the BOLD activation in the primary somatosensory cortex in all cases, and the block model in 10 of 12 rats. A statistical comparison of the two models revealed that the LFP-derived model was able to explain additional BOLD variation over the block model in the somatosensory cortex in nine of 12 rats. These results suggest that there is more information regarding neuronal activity in the BOLD signal than can be exploited using the block model alone. Furthermore, the hemodynamic coupling remains unchanged in the case of temporally variable BOLD signals. PMID- 20949637 TI - Quantitative T2* imaging of metastatic human breast cancer to brain in the nude rat at 3 T. AB - This study uses quantitative T(2)* imaging to track ferumoxides--protamine sulfate (FEPro)-labeled MDA-MB-231BR-Luc (231BRL) human breast cancer cells that metastasize to the nude rat brain. Four cohorts of nude rats were injected intracardially with FEPro-labeled, unlabeled or tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)-treated (to induce apoptosis) 231BRL cells, or saline, in order to develop metastatic breast cancer in the brain. The heads of the rats were imaged serially over 3-4 weeks using gradient multi-echo and turbo spin-echo pulse sequences at 3 T with a solenoid receive-only 4-cm-diameter coil. Quantitative T(2)* maps of the whole brain were obtained by the application of single-exponential fitting to the signal intensity of T(2)* images, and the distribution of T(2)* values in brain voxels was calculated. MRI findings were correlated with Prussian blue staining and immunohistochemical staining for iron in breast cancer and macrophages. Quantitative analysis of T(2)* from brain voxels demonstrated a significant shift to lower values following the intracardiac injection of FEPro-labeled 231BRL cells, relative to animals receiving unlabeled cells, apoptotic cells or saline. Quartile analysis based on the T(2)* distribution obtained from brain voxels demonstrated significant differences (p < 0.0083) in the number of voxels with T(2)* values in the ranges 10-35 ms (Q1), 36-60 ms (Q2) and 61-86 ms (Q3) from 1 day to 3 weeks post infusion of labeled 231BRL cells, compared with baseline scans. There were no significant differences in the distribution of T(2)* obtained from serial MRI in rats receiving unlabeled or TRAIL-treated cells or saline. Histologic analysis demonstrated isolated Prussian blue-positive breast cancer cells scattered in the brains of rats receiving labeled cells, relative to animals receiving unlabeled or apoptotic cells. Quantitative T(2)* analysis of FEPro-labeled metastasized cancer cells was possible even after the hypointense voxels were no longer visible on T(2)*-weighted images. PMID- 20949639 TI - Mechanisms of genetic variation in polioviruses. AB - Polioviruses, as with all RNA viruses, are in a constant process of evolution driven by different mechanisms. With multiple mechanisms for genetic variability, they are successful conformists, adapting to changes in their habitat. The evolution of polioviruses may occur with generation of point mutations followed by genetic drift and selection. The mutation rate of polioviruses based on several studies is approximately 3 * 10(-2) mutations/synonymous site/year in the gene encoding viral protein 1. Genetic variation in polioviruses may also be increased by sharing of genetic data of two different poliovirus lineages by means of homologous recombination. According to the current view, recombination is considered usually to occur by strand-switching, but a non-replicative model has also been described. In recombination, polioviruses may either gain a set of advantageous mutations selected and fixed in previous generations of the parental viruses or get rid of deleterious ones. The prerequisites and constraints of the evolution mechanisms will be discussed. Furthermore, consequences of poliovirus evolution will be reviewed in the light of observations made on currently circulating polioviruses. We will also describe how polioviruses strike back: as wild type polioviruses approach eradication, vaccine derived strains increase their occurrence and genetic variability. PMID- 20949640 TI - A subset of human pancreatic beta cells express functional CD14 receptors: a signaling pathway for beta cell-related glycolipids, sulfatide and beta galactosylceramide. AB - BACKGROUND: T1DM is a T-cell-mediated autoimmune disease targeting insulin producing beta-cells. Multiple factors may contribute to the development of T1DM. Among these, the metabolic state of beta-cells and pro-inflammatory cytokines, produced by infiltrating immune cells, have been implicated in the precipitation of T1DM. METHODS AND RESULTS: In this study, confocal immunofluorescence microscopy of human pancreata revealed a distinct subset of beta-cells expressing the innate LPS co-receptor CD14. Human islets expressed fully functional CD14 as LPS stimulation led to a dose-dependent secretion of tumour necrosis factor (TNFalpha), interleukin (IL)-1beta and IL-8, which were substantially inhibited by a blocking anti-CD14 mAb. In addition, LPS stimulation impaired the glucose mediated insulin secretion in rat islets. beta-GalCer and sulfatide, glycolipids that are related to insulin processing and secretion, are possibly interacting with the CD14 receptor complex. beta-GalCer had an LPS-like, serum- and CD14 dependent effect on the induction of pro-inflammatory cytokines in a human monocyte cell line. In contrast, the LPS-mediated cytokine production was inhibited by sulfatide. Human islets also responded to beta-GalCer (10 ug/mL) by secreting TNFalpha, IL-1beta and IL-8, whereas sulfatide partly inhibited the effect of LPS. CONCLUSIONS: A subset of human beta-cells expresses functional CD14 receptor and thus is able to recognize both exogenous bacterial (LPS) as well as endogenous ligands (e.g. glycolipids of beta-cell origin). The CD14 expression on a subset of human beta-cells may play a role in the innate surveillance of the endocrine environment but may also contribute to innate immune mechanisms in the early stages of beta-cell aggression. PMID- 20949641 TI - A comparison of single-voxel clinical in vivo hepatic 31P MR spectra acquired at 1.5 and 3.0 Tesla in health and diseased states. AB - With the increasing availability of human MR scanners at various field strengths, the optimal field strength for in vivo clinical MR studies of the liver has become a focus of attention. Comparison between results at 3.0 and 1.5 T is of particular clinical interest, especially for multicentre studies. For MRS studies, higher field strengths should be advantageous, because improved sensitivity and chemical shift dispersion are expected. We report a comparison between single-voxel hepatic proton-decoupled (31)P MRS performed at 1.5 and 3.0 T in the same subjects using similar methodologies. Twelve healthy volunteers and 15 patients with chronic liver disease were studied. Improved spectral resolution was achieved using proton decoupling, and there was an improvement (21%) in the signal-to-noise ratio (SNR) of the phosphomonoester (PME) resonance at 3.0 T relative to 1.5 T. There was no significant change in nuclear Overhauser effects for PME or phosphodiesters (PDEs) between the two field strengths. The T(1) value of PDE was significantly longer at 3 T, although there was no significant change in the T(1) value of PME. There was no significant difference in the mean PME/PDE ratios for either the control or patient groups at both 1.5 and 3.0 T, but there was a small positive mean difference in PME/PDE at 3.0 T on pairwise testing between field strengths (+ 0.05, p < 0.01). There were significant correlations between PME/PDE values at the two magnetic field strengths (r = 0.806, p < 0.001). The underlying broad resonance was reduced at 3.0 T relative to 1.5 T, related to line broadening of the phospholipid bilayer signal. In conclusion, there was an improvement in hepatic (31)P MR signal quality at 3.0 T relative to 1.5 T. Broadly similar hepatic (31)P MR parameters were obtained at 1.5 and 3.0 T. The modest difference noted in the PME/PDE ratio between field strengths for patients with chronic liver disease should inform multicentre study design involving these field strengths. PMID- 20949642 TI - Analysis of secondary ultrasound markers in the first trimester before chorionic villus sampling. AB - OBJECTIVE: To evaluate detection and false-positive rates of the ultrasound markers-nasal bone (NB), ductus venosus (DV) flow and tricuspid regurgitation (TR)-during the first trimester in a population at high genetic risk, and to study the influence of a two-stage screening policy alter previous combined screening on the rate of invasive procedures. METHODS: A total of 333 chorionic villus samples were obtained in singleton pregnancies. Before biopsy, the ultrasound markers-NB, DV, and TR-were assessed, although the findings were not used to recalculate the previously determined risk for Down syndrome. RESULTS: Detection and false-positive rates for Down syndrome were 63.2% and 3.4% for NB, 65% and 3.1% for DV, and 50% and 2.1% for TR. All three markers were normal in 30% [84/277, 95% confidence interval (CI) 25%-36%] of chorionic villus sampling (CVS) cases performed for abnormal findings at the first trimester genetic screen, with 0% (0/20, 95% CI 0%-17%) false-negative rate for Down syndrome. CONCLUSION: Assessment of secondary ultrasound markers is feasible in clinical practice and their use could reduce the number of unnecessary invasive procedures by 30%. PMID- 20949643 TI - First-trimester molecular prenatal diagnosis of a thanatophoric dysplasia. PMID- 20949644 TI - Molecular diagnosis of Down syndrome using quantitative APEX-2 microarrays. AB - OBJECTIVE: To develop a new rapid and high-throughput microarray-based prenatal diagnostic test for the detection of trisomy 21 (T21). METHODS: The T21 arrayed primer extension-2 (APEX-2) assay discriminates between trisomy and euploid DNA samples by comparing the signal intensities of allelic fractions of heterozygous single nucleotide polymorphisms (SNPs) after APEX reaction. After preliminary validation using DNA samples from Down syndrome patients, we analyzed DNA samples from cultured and uncultured amniocytes and chorionic villus for 90 SNPs with high heterozygosity from the 21(q21.1q22.2) region. Differences in allelic ratios of heterozygous SNPs in normal and T21 individuals were verified by t-test. RESULTS: Analysis of the T21 APEX-2 assay results revealed that 90 SNPs were sufficient for reliable discrimination between T21 and euploid DNA samples (P<=0.05 for one or both strands). Using 134 clinical samples from cultured or uncultured fetal cells, both the sensitivity and the specificity of the assay were 100%. CONCLUSION: Our study provides a proof of principle demonstration of the use of the modified APEX-2 assay as a new, fast and reliable method for prenatal diagnosis of fetal T21. PMID- 20949645 TI - What determines influenza vaccination take-up of elderly Europeans? AB - We analyse the determinants of influenza vaccination take-up of Europeans above the age of 50 years using the first two waves of the Survey of Health, Ageing, and Retirement (SHARE). Using quality-of-care indicators, special emphasis is put on the measurement and the impact of physician quality. We find that age, health status, lifestyle, labour-force status, and the family structure are important determinants of the decision to get a flu shot. Physician quality, as measured by four indicators, also positively affects the probability of getting a flu shot. PMID- 20949647 TI - Prostate cancer: Acupuncture can alleviate hot flashes in prostate cancer patients. PMID- 20949646 TI - Prostate cancer: Postoperative PSA surveillance in patients treated with radical prostatectomy: might less be more? PMID- 20949648 TI - Prostate cancer: High-intensity focused ultrasound therapy: effects on urinary and erectile function and quality of life. PMID- 20949649 TI - Prostate cancer: Commonly used medications cause clinically relevant decreases in serum PSA levels. PMID- 20949650 TI - Androgens and vitamin D levels. PMID- 20949651 TI - Surgery: Is lymphadenectomy necessary for high-risk penile cancer? PMID- 20949652 TI - Prostate cancer: Effects of 10-plus-core biopsy on erectile and voiding function. PMID- 20949653 TI - Urothelial carcinoma: A novel nomogram for post-nephroureterectomy prognosis. PMID- 20949654 TI - Quality of life: Questionnaire developed specifically for older people with cancer. PMID- 20949655 TI - Abstracts of the XXI Annual Meeting of the Sociedad Latino-Americana de Endocrinologia Pediatrica (SLEP). Costa do Sauipe, Bahia, Brazil. October 27-30, 2010. PMID- 20949656 TI - Robotic resection of pheochromocytoma in the second trimester of pregnancy. AB - Pheochromocytoma is a rare neuroendocrine tumor diagnosed in 1:50,000 pregnancies. Normal physiologic changes associated with pregnancy often make early recognition difficult and diagnosis delayed. Treatment consists of medical followed by surgical intervention. This case of a 34-year African-American female diagnosed with an adrenal pheochromocytoma during her second trimester of pregnancy is the first reported case of successful robotic resection. The robot provided advantages, such as enhanced visualisation and freedom of dissection, within this confined space. These added benefits over traditional laparoscopy provide a means for performing difficult procedures within decreased space possibly allowing for interventions in later or larger pregnancies. PMID- 20949657 TI - Abstracts of the 28th World Congress of Endourology& SWL. August 31-September 4, 2010. Chicago, Illinois, USA. PMID- 20949659 TI - Multiple sclerosis: OAS1 genotype linked to multiple sclerosis severity. PMID- 20949660 TI - Stroke: S-roscovitine--a potential neuroprotectant for stroke. PMID- 20949661 TI - Brain injury: severely disabled patients can communicate and control their environment using a sniffing mechanism. PMID- 20949662 TI - Know your A1c number or your A1c range? The need to implement glycemic numeracy into policy and practice. PMID- 20949663 TI - Abstracts of ACG 2010, American College of Gastroenterology Annual Scientific Meeting. October 15-20, 2010. San Antonio, Texas, USA. PMID- 20949664 TI - Abstracts of the 20th World Congress on Ultrasound in Obstetrics and Gynecology. October 10-14, 2010. Prague, Czech Republic. PMID- 20949665 TI - Retracted manuscript: Overexpression of transketolase protein TKTL1 is associated with occurrence and progression in nasopharyngeal carcinoma. PMID- 20949666 TI - Recurrence risks for Bardet-Biedl syndrome: Implications of locus heterogeneity. AB - PURPOSE: Bardet-Biedl syndrome is a pleiotropic multiple anomaly syndrome inherited in an autosomal recessive pattern. It is now known that this disorder has locus heterogeneity, with causative mutations identified in as many as 14 genes. The aim of this study was to derive locus-specific recurrence risk estimates for family members of a proband affected with Bardet-Biedl syndrome. METHODS: Mutation data from 187 probands affected with Bardet-Biedl syndrome were used. The authors counted the relative proportion of families with mutations at each of 10 loci and estimated locus-specific carrier rates for mutations using Hardy-Weinberg principles and an aggregate population frequency of 1/100,000 for the phenotype. Locus-specific recurrence risks were calculated for relatives of an affected proband. RESULTS: Locus-specific carrier frequencies range from 1/250 to 1/2200, and the risks for an offspring of the sibling of an affected individual range from 1/1,500 to 1/13,000. The estimate of this risk derived under a locus homogeneity model is 1/960. CONCLUSION: Variation of recurrence risks of this magnitude may have implications for genetic counseling of families with affected individuals, in particular about prenatal testing and other reproductive options. Similar analyses to determine locus-specific carrier frequencies for other phenotypes with significant locus heterogeneity may yield similarly relevant results. PMID- 20949667 TI - Abstracts of the American College of Veterinary Pathologists Annual Meeting: Combined 61st and 45th Annual Meetings of the American College of Veterinary Pathologists and the American Society for Veterinary Clinical Pathology. Baltimore, Maryland, USA. October 30-November 3, 2010. PMID- 20949668 TI - Human papillomavirus and oropharyngeal cancer survival. PMID- 20949669 TI - An entirely subcutaneous implantable cardioverter-defibrillator. PMID- 20949670 TI - Interstitial lung disease and gefitinib. PMID- 20949671 TI - Dietary therapy in hypertension. PMID- 20949672 TI - Dietary therapy in hypertension. PMID- 20949673 TI - Dietary therapy in hypertension. PMID- 20949674 TI - Dietary therapy in hypertension. PMID- 20949675 TI - Pseudopapilloedema and optic disc haemorrhages in a child misdiagnosed as optic disc swelling. PMID- 20949677 TI - Offending is a public health issue, argues Sean Duggan from the Centre for Mental Health. PMID- 20949678 TI - Bedlam. Interview by Carole Woddis. PMID- 20949679 TI - A personal service. PMID- 20949680 TI - All change? PMID- 20949681 TI - Government benefit cuts will set neighbour against neighbour. PMID- 20949682 TI - Links between creativity and mental illness. PMID- 20949683 TI - Getting patient and service user views is key to effective monitoring. PMID- 20949684 TI - Young people and mental health. Your guide to today's mental health issues. PMID- 20949685 TI - Reform of NHS commissioning. PMID- 20949686 TI - The Mental Capacity Act isn't working. PMID- 20949687 TI - Network becomes fully independent. PMID- 20949688 TI - A practical guide to personalisation in mental health. PMID- 20949689 TI - What's next? PMID- 20949690 TI - Carers included. PMID- 20949691 TI - Looking at ordinary people's tales of living with their mental illness. Interview by Alita Howe. PMID- 20949692 TI - Re: Who's your nanny. PMID- 20949693 TI - Re: Response to primary care: building the health care institutions of the future. PMID- 20949694 TI - Comments on 'The worst doctor in the worst clinic'. PMID- 20949695 TI - Abstracts of the American Association for the Study of Liver Diseases 61st Annual Meeting and Postgraduate Course. October 29-November 2, 2010. Boston, Massachusetts, USA. PMID- 20949696 TI - Massive splenomegaly and extramedullary hematopoiesis in chronic idiopathic myelofibrosis. PMID- 20949697 TI - Performance psychology: theory and application in industry, sports, human services, and behavioral healthcare. Introduction to the special issue. PMID- 20949698 TI - Liraglutide: can it make a difference in the treatment of type 2 diabetes? AB - Despite advances in the management of type 2 diabetes, glycaemic control remains suboptimal for many patients because of the complexities of disease progression and the need to balance improved glycaemic control against adverse treatment effects, particularly weight gain and hypoglycaemia. Thus, the development of new antidiabetes therapies continues in earnest. Incretin hormones have been the recent focus of research, as they account for up to 70% of the insulin response following a meal. There is also a high concordance between the physiological actions of one hormone, glucagon-like peptide-1 (GLP-1), and the therapeutic needs of patients. As native human GLP-1 has a half life of only approximately 2 min, researchers have developed molecules that act as GLP-1 receptor agonists or inhibit the enzyme responsible for GLP-1 degradation (dipeptidyl peptidase-4). Liraglutide, a human GLP-1 analogue sharing 97% of its amino acid sequence identity with native GLP-1, has been approved for use as monotherapy (not in Europe) and in combination with selected oral agents. In this supplement, we summarise key liraglutide data, offer practical insight into what we might expect of liraglutide in clinical use and examine selected case studies. For reasons of the safety and efficacy of GLP-1 receptor agonists, many thought leaders believe that these will become background therapy for majority of patients in the coming years. This supplement will serve as a resource from which readers can extract information concerning the potential benefits for patients who are overweight, losing pancreatic beta-cell function and drifting towards the ravaging effects of chronic hyperglycaemia. PMID- 20949700 TI - Controlling rubella and preventing congenital rubella syndrome - global progress, 2009. PMID- 20949699 TI - Liraglutide in clinical practice: dosing, safety and efficacy. AB - AIMS: This article reviews practical issues that healthcare providers need to consider when implementing therapy with the once-daily glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. KEY POINTS: Liraglutide is administered once daily by subcutaneous injection, independent of meals and at any time of day. To improve gastro-intestinal tolerability, the starting dose is 0.6 mg liraglutide daily. After at least 1 week, the dose should be increased to 1.2 mg. Some patients may benefit from an additional increment to the maximum recommended daily dose of 1.8 mg. Daily blood glucose monitoring is not required, although may be necessary if liraglutide is used with a sulphonylurea (SU). Treatment is contraindicated in patients with known hypersensitivity to liraglutide or an excipient. Liraglutide slows gastric emptying, but does not interact with acetaminophen, oral contraceptives, atorvastatin, griseofulvin, lisinopril or digoxin in a way that necessitates dose adjustments of these agents. The efficacy and safety of liraglutide are not influenced by differences in gender, age or ethnicity and race. Overall, liraglutide is generally well tolerated. Patients can experience gastrointestinal side effects, such as nausea, which diminish over time. As liraglutide increases insulin production in a glucose-dependent manner, the incidence of hypoglycaemia largely depends on the hypoglycaemic risk profile of the selected oral antidiabetic with which it is used. The use of an SU may increase the risk of hypoglycaemia; this risk can be lowered by reducing the SU dose. CONCLUSIONS: Liraglutide is a once-daily treatment option that can be used in adults with type 2 diabetes regardless of gender, age (although therapeutic experience in patients over 75 years of age is limited) and ethnicity or race. PMID- 20949701 TI - Antigenic and genetic characteristics of influenza A(H5N1)and influenza A(H9N2) viruses and candidate vaccine viruses developed for potential use in human vaccines. PMID- 20949702 TI - Leiomyomas of spermatic cord and testis presenting as hernia--chromosomal analysis. AB - We report a rare case of three leiomyomas of the permatic cord and testis in a 73 year-old man. Indirect, large, painful, non-reducible inguinal hernia was diagnosed at admission. During surgery, the hernia was revealed. Furthermore, two tumors were found, both attached on the spermatic cord, and a third tumor close to the testis. All the tumors were carefully removed and no orchidectomy was performed. Hernia repair was performed and the removed tumors were sent to the Pathology Department. All tumors were benign. At the first follow up, chromosomal analysis was also performed. Chromosomal lymphocyte analysis revealed increased fragility at site 4q31. Two years after surgery, the patient was admitted again with a new similar tumor, and underwent a new surgical treatment. In the case of large non-reducible inguinal hernias, surgeons have to consider tumors in the inguinal area in their differential diagnosis. PMID- 20949703 TI - What are the possible reasons for urethral PSA varieties after radical prostatectomy? AB - OBJECTIVE: To examine the possible reasons for great varieties in urethral prostate specific antigen (urPSA) levels, in patients after radical prostatectomy (RP). MATERIALS AND METHODS: In 46 patients with pros-tate cancer, PSA, urPSA, total testosterone, body-mass index (BMI) and the stage of androgenic alopecia (AGA) were determined. Forty-five patients underwent retropubic RP, while one underwent cystoprostatectomy with orthotopic bladder construction, due to bladder cancer. RESULTS: Average patients age prior to surgery plus or minus standard deviation was 65.2 +/- 5.8 years. Average urPSA was 20.9 +/- 47.5 ng/ml (0.05 to 212 ng/ml, median 2.24 ng/ml). With urethral PSA cut-off of 2.0 ng/ml, two groups were formed: A (urPSA < 2.0 ng/ml) and B (urPSA = 2.0 ng/ml). Patients in the group A had significantly lower average AGA score, than the patients from the group B (2.4 +/- 1.3 vs. 4.4 +/- 2.2, p = 0.0003). In addition, patients from the group A had significantly lower pos-toperative PSA (0.07+0.08 ng/ml vs. 0.14 +/- 0.06 ng/ml, p = 0.0014). CONCLUSIONS: The patients with higher urPSA have higher AGA scores and higher postoperative PSA. This phenomenon is probably the consequence of higher local dihydrotestosterone activity in the scalp and PSA secreting urethral glands. PMID- 20949704 TI - Correlation between pathological distal esophageal acid exposure and ineffective esophageal motility. AB - AIM: To assess the correlation between esophageal dysmotility, characterized as inefficient esophageal motility (IEM), and the presence of pathological acid reflux due to a structurally defective lower esophageal sphincter (LES), hiatus hernia. (HH), or esophagitis in patients with suspected gastroesophageal reflux disease (GERD). METHODS: 311 patients referred for GERD diagnostic procedures in a gastroesopahgeal motility laboratory were included in the study. Patients underwent an interview regarding their clinical symptoms, upper endoscopy (UE), stationary esophageal manometry, and 24-h esophageal pH-metry. The following risk factors of patients in the negative pH-metry group were compared to those in the positive pH-metry group: IEM, defective LES, HH, and esophagitis. The association between IEM and positive pH-metry results was first assessed by means of univariate analysis and later determined with multivariate logistic regression analysis. RESULTS: Out of the total of 311 studied patients, 208 met the inclusion criteria; 88 had normal and 120 had positive pH-metry results. Univariate analysis revealed that the occurrence of IEM, defective LES, and HH was significantly greater in the positive pH-metry group. Following logistic regression analysis, the occurrence of IEM remained significantly greater in the positive pH-metry group. CONCLUSIONS: IEM is associated with the presence of abnormal acid reflux, as assessed by 24-h esophageal pH-metry, regardless of the presence of defective LES, HH, or esophagitis. PMID- 20949705 TI - Prolene hernia system, ultrapro hernia system and 3D patch devices in the treatment of inguinal, femoral, umbilical and small incisional hernias in outpatient surgery. AB - INTRODUCTION: The employment of a diversity of prosthetic materials and several types of mesh different in construction is opening a new chapter in hernia surgery and tension-free techniques are becoming a "golden standard" for repairing abdominal wall defects, whereas the conventional methods, i.e., the tension techniques are performed on young patients having small direct, indirect, or femoral hernias. AIM: The aim of this retrospective study is to present the results of using Prolene Hernia System (PHS), Ultrapro Hernia System (UHS) and 3D Patch (3DP) devices in the treatment of inguinal, femoral, umbilical and small incisional hernias in outpatient surgery. MATERIAL AND METHODS: From January 2006 to January 2009, 70 patients were operated on for abdominal wall hernias (54 inguinal, 4 femoral, 8 umbilical and 4 small incisional hernias) using PHS, UHS and 3DP devices. All the patients underwent surgery under local infiltrative anaesthesia. All the surgical operations were performed by a single surgeon, 19 of them in the General Hospital and 51 in a private polyclinic. RESULTS: The mean size of the hernia defect in the inguinal, femoral and umbilical hernias was 2.5 cm (1-4 cm), while in the incisional hernias it was 4.5 cm (3-6 cm). The mean operating time was 2.4 hrs (2-6 hrs). There were no requirement for urinary drains. The mean follow-up was 18 months (0-36 months). The incidence of infection, chronic pain and recurrence was 0%. Three of the patients had complications: seroma in one patient with an incisional hernia and hematoma in two patients after inguinal hernia repair. CONCLUSION: The employment of PHS, UHS and 3DP devices, which have not yet been widely accepted in our hospitals, has had outstanding results in outpatient surgery. In addition, the type of anaesthesia and the 3D mesh construction prepare the way for a short hospital stay, smooth recovery and a swift return to normal activity. PMID- 20949706 TI - The presentation and management of presacral tumors. AB - OBJECTIVES: Retrorectal masses are uncommon lesions. They remain a difficult diagnostic and therapeutic challenge despite the use of newer imaging modalities and improvement in preoperative care. Although useful for planning a resection, neither CT nor MRI can provide a definitive diagnosis. The objective was to remove the entire lesion as revealed by the radiological study to avoid any recurrence of disease and malignant degeneration, but with the least amount of consequential impairment. METHODS: We present our experience with 9 (nine) presacral tumors during 10 year period 1998-2007. The files and charts of adults' patients who underwent treatment for presacral tumors were collected and retrospectively reviewed. RESULTS: From January 1998 to December 2007, a total of 9 adult patients were evaluated for primary tumors originating in retrorectal space in Surgical Clinic of Oncology near University Hospital Center "Mother Teresa". Four patients were males and five were females. The diagnosis of these retrorectal tumors were, developmental tail gut cyst, teratoma, chordoma and chondrosarcoma. In six patients were achieved good results during surgical treatment. Coccygeal resection in one case. In three cases we couldn't perform sarectomy. CONCLUSION: In conclusion, presacral tumors are uncommon. They can be congenital or acquired, benign or malignant, which forms the basis for a simple classification. Their treatment is always surgical. The good results were obtained in the benign lesions. PMID- 20949707 TI - Bilateral ureteral obstruction due to primary myelofibrosis caused hyperuricaemia. AB - In healthy population, uric acid comprises the major component of 10-20% of renal stones. Extreme hiperuricaemia is seen in cancer patients with tumour lysis syndrome (TLS) which is classically associated with haematological malignancies with rapid tumour growth rates such as acute lymphoid leukaemia and high grade lymphomas. Primary melofibrosis (Agnogenic myeloid metaplasia-AMM) is a chronic myeloproliferative disease characterized by splenomegaly, a leukoerythroblastic blood picture, teardrop poikilocytosis and varying degrees of marrow fibrosis. Due to the increased extramedullary haematopoiesis, hiperuricemia may occur. However, TLS in patients with AMM is, according to the available literature, described just in one patient. In this paper we present a case of a 47-year-old male patient who was admitted to the hospital with symptoms of fatigue and small amount of urine, and clinical signs of plethora and enlarged spleen. The laboratory findings showed leuko-and erythrocytosis, increased levels of urea-BUN (32 mmol/l) and creatinine (766 mmol/l) as well as uric acid (920 mmol/l). The immediate abdominal ultrasound confirmed extreme splenomegaly, but also showed bilateral hydronephrosis of grade II-III with two stones in proximal part of right ureter and one in proximal part of left ureter as well as empty bladder. Stones were not seen on plain film. Since the patient was in complete anuria, with further rapid elevation of BUN and creatinine levels, bilateral ureteral stents were applicated together with extensive hydration, urine alkalization and administration of allopurinol which resulted in the complete recovery of kidney function. The bone marrow biopsy was also performed and histopathological diagnosis was: Hypercellulary phase of AMM. PMID- 20949708 TI - Incidental gallbladder carcinoma in regional clinical centre. AB - BACKGROUND AND OBJECTIVES: The aim of the study is to assess the characteristics, TNM stage and survival rate of incidental gallbladder carcinoma in patients who underwent open cholecystectomy in regional clinical centre. PATIENTS AND METHODS: We retrospectively analyzed all consecutive cholecystectomies during four years period in surgery department and determined incidence, pathological stage and survival rate of incidental gallbladder cancer. Demographics data, surgical management, adjuvant therapy, death or last follow-up. We compared common characteristics and survival between pTis,1a-b and pT2-3 groups of patients who underwent cholecytectomy alone. RESULTS: Gallbladder carcinoma was diagnosed in 21 patients of 3007 cholecystectomies (0.69%). The most of patients had abdominal pain, cholelithiasis and fever. Postoperative pathology showed 20 adenocarcinomas and 1 squamous carcinoma. Seven cases were stage I, 7 stage II, 5 stage III. There was no patient in pT4 stage. The mean age was 60.6 years range (43-75). The 4 patients with pTis and 3 patients with pT1 had a 5-year survival rate of 100%. Patients with pT2-3 GBC had 5-year survival rate 8.34%. We noticed significant difference between those two cancer groups p < 0.001. CONCLUSIONS: The incidence of incidental gallbladder cancer in this study was 0.69%. The pT-stage is very important factor in overall survival those patients. All cases of pT2-3 incidental GBC should be considered for extended radical resection after cholecystectomy alone. PMID- 20949709 TI - Thalassemia major. A report of two cases with severe skeletal involvement. AB - Beta thalassemia major is rare in Serbia. Previously incurable, affected patients now live to adulthood with regular blood transfusions. The improvement in supportive treatment over recent decades has given rise to many more patients suffering from the associated metabolic complications of anaemia and iron overload, such as osteopenia and other skeletal changes. We present two patients with severe beta thalassemia major from early childhood, who encountered pathological long-bone fractures during the clinical course of their disease. One suffered a distal femoral diaphyseal fracture, and the second a distal tibia fracture. Both fractures occurred in osteopenic bone and were managed non operatively due to the patients' general medical condition. Despite intense medical intervention, both patients died from disease progression within one year of their fractures, aged 23 and 24 years. As life expectancy rises it is anticipated that an increased number of beta thalassemia major patients will suffer pathological long-bone and other osteoporotic fractures. These fractures appear to both herald and contribute to a general clinical deterioration of this disease. Advances in stem-cell technology may hold the key for a definitive cure. PMID- 20949710 TI - The case of cavernous testicular hemangioma. AB - OBJECTIVE: To present the rare case of testicular hemangioma. CASE REPORT: A 45 year-old clerk presented with painless swelling in the left testicle, which he noticed one month ago. Inguinal orchidectomy on the left side was performed and pathological report proved cavernous hemangioma. CONCLUSION: Hemangioma of the testis is very rare clinical condition. Clinical appearance and diagnostic exams are usually not sufficient for the diagnosis. Sometimes, hyperechoic lesion with increased vascularity can be seen on Doppler ultrasonography. PMID- 20949711 TI - Challenges in the treatment of breast cancer in developing countries. PMID- 20949712 TI - Obamacare: next steps in US healthcare reform. PMID- 20949713 TI - Validation of self-reported smoking status by measuring serum cotinine levels: an Indian perspective. AB - BACKGROUND: Serum cotinine levels are a reliable marker of tobacco use. Few studies have validated questionnaires assessing smoking and exposure to environmental tobacco smoke (ETS) against serum levels. We undertook such a study in industrial workers in India. METHODS: We chose 426 individuals by stratified random sampling from a database of 3397 individuals surveyed at New Delhi for the cardiovascular disease surveillance programme in a large industrial setting. Questionnaires assessing details of smoking practices and duration of exposure to ETS (if any) were administered. Cotinine levels were measured in the blood samples of these individuals. RESULTS: The study population comprised 142 nonsmokers not exposed to ETS, 142 non-smokers exposed to ETS and 142 active smokers. Cotinine levels among nonsmokers not exposed to ETS were non-detectable; and for non-smokers exposed to ETS and active smokers, the median (interquartile range) levels were non-detectable (non-detectable to 46.1 ng/ml) and 336 ng/ml (204-500 ng/ml), respectively. The best combined sensitivity (91%) and specificity (87.2%) yielded a cotinine cut-off level of 40.35 ng/ml to differentiate active smokers from non-smokers not exposed to ETS and those exposed to ETS (area under the curve 0.902). The cut-off cotinine level was estimated at 10.95 ng/ml using a similar analysis (sensitivity 43%, specificity 82%; area under the curve 0.64) to distinguish non-smokers not exposed to ETS from those exposed to ETS. The misclassification rate was estimated at 19% and 57.1% among self-reported non-smokers not exposed to ETS and those exposed to ETS, respectively. CONCLUSIONS: Obtaining a history of tobacco use is an accurate method of detecting smokers in epidemiological studies whereas serum cotinine levels accurately differentiate smokers from non-smokers. However, a brief questionnaire assessing passive exposure to smoke has poor sensitivity in distinguishing non-smokers exposed to ETS from those not exposed to ETS. PMID- 20949714 TI - Strategies to improve the performance of female health workers in West Bengal: a cross-sectional survey. AB - BACKGROUND: Female health workers in India face an increasing workload that affects their performance. We did a study in 2 districts of West Bengal, India, to quantify their workload and identify determinants of good performance. METHODS: We randomly sampled female health workers from the health department's list. First, we quantified the time allocated to tasks through observations of work sessions. Second, we estimated the prevalence ratio (PR) of above-average performance for three indicators (DPT-booster coverage, antenatal check-up coverage and family planning performance) according to selected potential determinants. RESULTS: Female health workers spent 26% of their time in documentation. We recruited 42 female health workers (average population covered: 6495). Larger floor space (PR 2.5; 95% CI 1.2-5.3), use of simplified documentation procedures (PR 2.5; 95% CI 1.2-5.2) and monthly supervision (PR 3.0; 95% CI 1.1-8.5) were associated with above-average DPT-booster coverage. Availability of a private space was associated with above-average coverage in antenatal check-up (PR 1.9; 95% CI 1.0-3.5) and family planning (PR 2.5; 95% CI 1.2-5.2). Workers who used existing resources to cope with multi-tasking performed better. CONCLUSION: Female health workers spent excessive time in documentation which left less time for service delivery. Infrastructure, planning and supervision affected performance and these areas must be strengthened to improve primary healthcare services. PMID- 20949715 TI - Absenteeism among nurses in a tertiary care hospital in India. AB - BACKGROUND: Absence due to sickness among nurses has not been studied in-depth in the Indian setting. METHODS: We studied the sickness pattern among 385 nurses during one calendar year and retrospectively compared the absenteeism among nurses in different work areas of a tertiary care hospital. RESULTS: Sickness leave was availed by 68.9% of nurses at least once during the year. Nurses in the ward area were significantly older (43 [5.4] years of age) than those in operation theatres (38 [6.2] years of age) and intensive care units (39 [5.9] years of age). The average annual duration of absenteeism per nurse (index of severity) was 27.7 days/ person. The average sickness leave days/spell (index of duration) was 8.82 days/person. The annual inception rate of non-sickness leave (index of frequency) was 1.57 spells/person and for sickness leave was 1.27 spells/person. While nurses working in the ward area took the highest number of unplanned sickness leave (7.36 days/spell), the planned sickness leaves were highest (64.8 days/spell) among those in operation theatres. About half the episodes of sickness were related to diseases of the respiratory tract, digestive system, Infections and Injury. Planned sickness leave mainly constituted maternity leave related to childbearing and was highest among younger nurses in operation theatres and intensive care units. CONCLUSION: Unplanned leave demands greater administrative adjustments and substitution. Inappropriate substitution may compromise patient care and sharing of work by the staff present; it may increase the workload and absenteeism. Occupational welfare services at tertiary care hospitals should work towards decreasing absence due to sickness among nurses. PMID- 20949716 TI - Patterns of infections among blood donors in a tertiary care centre: a retrospective study. AB - BACKGROUND: Transfusion-transmitted infections continue to be a threat to safe transfusion practices. We analysed the prevalence and patterns of co-infections among voluntary and replacement donors. METHODS: Blood donations collected over a 5-year period were studied for the type of donation (voluntary or replacement), number of seroreactive cases and the number, type and distribution of co infections. RESULTS: Of the 42 439 units of blood collected over a 5-year period, 19 118 (45%) were from voluntary and 23 321 (55%) from replacement donors. There were 1603 seroreactive cases (3.8%). These included 250 with HIV (0.6%), 734 with hepatitis B surface antigen (HBsAg; 1.7%), 337 with hepatitis C virus (HCV; 0.8%) and 282 (0.7%) with VDRL (Venereal Diseases Research Laboratory) reactivity. Twenty-three (0.05%) of these had > or = 2 seroreactive infections; 20 of these were in replacement donors and only 3 in voluntary donors and the difference was statistically significant (p < 0.005). Among HIV seropositive donors, there were 4 seroreactive for syphilis and 5 for HBsAg. Among HIV seronegative donors, 5 were seroreactive for HBsAg and VDRL, 4 for HCV and VDRL, and 2 for HBsAg and HCV. One person was seroreactive for HIV, HBsAg and VDRL. The multiple infection rate showed a decreasing trend over the years. CONCLUSION: Multiple infections pose a small but definite risk to the recipients of blood products. Voluntary donations are safer as compared with replacement ones and need to be encouraged. PMID- 20949717 TI - Methyl ethyl ketone peroxide ingestion: a rare cause of corrosive chemical poisoning. AB - Methyl ethyl ketone peroxide, commonly used in the lamination industry, is a highly inflammable substance. Ingestion of methyl ethyl ketone peroxide is associated with a high morbidity and mortality. It can cause injury to the gastrointestinal tract on ingestion, leading to gangrene or perforation. Gastric lavage is contraindicated as it is a highly corrosive substance. We report a patient with poisoning due to methyl ethyl ketone peroxide who presented with upper gastrointestinal bleeding, and developed gangrene of the bowel and died of septicaemia and multiorgan failure. PMID- 20949718 TI - Mammographic screening for breast cancer: when and how frequent? PMID- 20949719 TI - Progress in the treatment of ovarian cancer? PMID- 20949720 TI - Medical education in India: is it still possible to reverse the downhill trend? PMID- 20949721 TI - Structured internship orientation programme for undergraduate students: easy transition to clinical work. AB - BACKGROUND: Internship is a phase of training when a new graduate is expected to acquire skills under supervision, so that he/she may become capable of functioning independently. Often, new graduates go through this period without a clear aim. We conducted an orientation programme before fresh graduates started their 1-year internship to familiarize them with their clinical tasks and their role in the community. METHODS: Interns were invited to participate in a one-and a-half day programme conducted by faculty members and administrators that included interactive lectures, structured panel discussions, group discussions and role plays. The participants provided feedback using a structured questionnaire and during informal group discussions. They were also evaluated by a pre-test and post-test questionnaire. RESULTS: Of the 41 interns who attended the programme on day 1 and the 28 who completed it on day 2, 19 completed the post-test questionnaire. The post-test score (median 14.5; range 10-18) represented a significant improvement over the pre-test score (median 13, range 3 16). All participants felt that the workshop was successful in achieving its objectives. CONCLUSION: A brief and structured orientation programme before internship offers a practical means of making the transition of new graduates from students to practising doctors smoother. PMID- 20949722 TI - User charges as a feature of health policy in India: a perspective. PMID- 20949723 TI - Sri Venkateswara Medical College and Sri Venkateswara Ramnarain Ruia (SVRR) Government General Hospital, Tirupati. PMID- 20949724 TI - Deemed universities. PMID- 20949725 TI - Road traffic injuries. PMID- 20949726 TI - Psycho-socio-economic stress as a risk factor for preterm labour: a community based, case-control study from rural South India. PMID- 20949728 TI - Organ donation for transplantation: hurdles imposed by thoughtless officials. PMID- 20949729 TI - Death penalty to Kasab: time to revisit the role of health professionals in capital punishment in India. PMID- 20949727 TI - Cobblestone streets of Paris: remembering Professor H. D. Tandon. PMID- 20949730 TI - Weaning from mechanical ventilator. PMID- 20949731 TI - Domestic cooking fuel exposure and tuberculosis in Indian women. AB - BACKGROUND; A case-controlled study was undertaken to find out the possible relationship of biomass fuel and pulmonary tuberculosis. METHODS: Ninety-five non smoking females with sputum positive tuberculosis (TB) and 109 healthy controls were interviewed using a questionnaire to obtain detailed information on type of fuel used in homes, duration of cooking, passive smoking, location of kitchen, socio-economic status, adequacy of ventilation, number of people per room and respiratory symptoms occurring during cooking. Odds ratio (OR) was ascertained by logistic regression analysis. RESULTS: The cases were from a low socio-economic status and the kitchens used by them were inadequately ventilated. Controls had less smoke accumulation in the rooms while cooking and cases had associated respiratory symptoms more often. Logistic regression analysis revealed that TB was significantly influenced by the location of the kitchen (OR 0.201, 95% confidence interval [CI] 0.08-0.51) and the presence of respiratory symptoms while cooking (OR 10.70, 95% CI 2.90-39.56). The odds of having TB did not differ significantly among various fuel types either on univariate (OR 0.99, 95% CI 0.45 2.22) or multivariate analysis (OR 0.60, 95% CI 0.22-1.63). CONCLUSIONS: No association was found between type of fuel used and TB. However, low socio economic status, smoky rooms, location of the kitchen, ventilation and associated respiratory symptoms during cooking are likely to be important contributors. PMID- 20949732 TI - Prevalence of bronchial asthma in school children of 6-13 years of age in Shimla city. AB - BACKGROUND: Asthma is a major public health problem worldwide. However, there is limited data on asthma prevalence among school children in Shimla. The present study was undertaken to determine the prevalence of asthma in Shimla city and also to examine the different factors influencing its occurrence. METHODS: This was a questionnaire-based study (International Study of Asthma and Allergies in Childhood [ISAAC] protocol) carried out in four randomly selected schools in the city of Shimla. The questionnaire was pre-tested in 50 school children. The age group included in the study was 6-13 years. The questionnaire was distributed to all the children (n = 1136). A response rate of 89.5% was achieved. The socio economic status was determined on the basis of monthly income (cumulative square root value method). The ISAAC questionnaire was given standard scores. Various factors influencing the prevalence of asthma, such as socio-economic status, history of asthma and other allergic disorders in the family, type of cooking fuel used, history of active and passive smoking were elucidated from the history. RESULTS: Overall prevalence of asthma in our study was found to be 2.3 percent. Boys had a higher prevalence (3.1%) than girls (1.4%). We found a significant association between asthma prevalence and family history of asthma and other atopic manifestations. There was no significant association of socio economic factors and exposure to smoking with prevalence of asthma. CONCLUSION: In the present study, the prevalence of bronchial asthma in school children in the age group of 6-13 years is 2.3 percent. PMID- 20949734 TI - Role of corticosteroids in the treatment of tuberculosis: an evidence-based update. AB - Corticosteroids are often used as an adjunct in the treatment of various forms of tuberculosis (TB) and for the prevention of complications, such as constrictive pericarditis, hydrocephalus, focal neurological deficits, pleural adhesions, and intestinal strictures. Notwithstanding, they have been proven in clinical trials to improve the following outcomes only--death or disability in human immunodeficiency virus (HIV)-seronegative patients with tubercular meningitis and tubercular pericarditis. Despite a lack of specific evidence for efficacy in HIV co-infected patients with tubercular meningitis or pericarditis, corticosteroids are generally recommended in them as well. Corticosteroids significantly decrease the risk of pleural thickening in patients with tubercular pleural effusion; the clinical significance of this finding, however, is unclear. Recently, it has been demonstrated that use of corticosteroids improve the morbidity in HIV co-infected patients with paradoxical TB immune reconstitution inflammatory syndrome (IRIS). However, evidence favouring the use of corticosteroids in other clinical situations is sparse or lacking. Likewise, the biological mechanisms underlying their beneficial effect in TB meningitis and pericarditis remain poorly understood. PMID- 20949733 TI - Acute accidental exposure to chlorine gas: clinical presentation, pulmonary functions and outcomes. AB - BACKGROUND: To study the clinical presentation, pulmonary functions and outcomes in subjects who were accidentally exposed to chlorine gas. METHODS: Prospective observational study of 64 patients who sustained acute accidental exposure to chlorine gas during a leak in the chlorination system of the public bathing pool of a temple. RESULTS: The major presenting symptoms and signs included acute dyspnoea (100%), chest discomfort (100%), cough (97%), eye irritation (88%), giddiness (72%), vomiting (46%), and heaviness in the head (44%); tachycardia (100%), tachypnoea (96%) and polyphonic wheezing (28%). All patients were managed in the emergency room with humidified oxygen inhalation and beta-2 agonist nebulisation and 52 were discharged within six hours. Twelve patients were severely affected and required hospitalisation; three of them were admitted into the intensive care unit. Three patients developed pulmonary oedema six to eight hours following admission. Pulmonary function testing (n = 12) at presentation revealed obstructive defect in eight and mixed obstructive-cum-restrictive defect in four patients. The mean duration of hospital stay was 5.1 +/- 2.1 days. None of the patients died. Reactive airway dysfunction syndrome (RADS) was observed in three of the 12 hospitalised patients, who complained of manifested persistent cough that lasted for three months period following discharge. Serial pulmonary functions recovered to normal range by the end of the six months in all patients and remained so at one-year follow-up. CONCLUSION: Acute exposure to chlorine gas is an uncommon, but important public health hazard and can cause RADS, acute lung injury and pulmonary function abnormalities, which are reversible on prompt and appropriate management. PMID- 20949735 TI - Autobullectomy in idiopathic giant bullous lung disease. PMID- 20949736 TI - Bronchoscopic management of bronchopleural fistula. AB - In recent years successful bronchoscopic management of bronchopleural fistulas (BPFs) by locating its site and then blocking the leaking segment with any of the several agents available has gained recognition. It is now considered as an alternate mode of management of BPF. Here we present a case of non-resolving pneumothorax that was managed successfully using bronchoscopic glue (cyanoacrylate glue) instillation. PMID- 20949737 TI - Re-expansion pulmonary oedema in chronic pneumothorax. AB - A case of unilateral re-expansion pulmonary oedema in a chronic pneumothorax is presented. The patient had a longstanding left-sided pneumothorax. Intercostal drainage tube was inserted following which the patient developed severe hypotension and respiratory failure. Chest radiograph (postero-anterior view) showed partial lung expansion with unilateral pulmonary oedema. The patient responded to the standard management of pulmonary oedema and the lung was fully re-expanded. PMID- 20949738 TI - Primary pleuro-pulmonary synovial sarcoma. AB - Primary pleuro-pulmonary synovial sarcoma (PPSS) is a rare tumour and poses adiagnostic challenge particularly when unusual histological features are present. We report a case of a 30-year-old immunocompromised human immunodeficiency virus (HIV) sero-positive male who was referred to us with complaints of cough, breathlessness and left-sided chestpain for the past two months. The PPSS can be confirmed on tru-cut biopsy. PMID- 20949739 TI - Improvised chest tube valve for intra-hospital patient transportation. PMID- 20949740 TI - Atonic pupils after uncomplicated phacoemulsification and intraocular lens implantation. AB - OBJECTIVES: An atonic pupil, defined as a dilated pupil of unknown origin, is a rare postoperative complication of ophthalmic surgery. We studied the incidence of atonic pupils after uncomplicated phacoemulsification and intraocular lens implantation (PEA+IOL) and analyzed the clinical profiles of four cases of atonic pupil. METHODS: We surveyed 54 ophthalmologists in 28 hospitals to determine their clinical experience with atonic pupils after uncomplicated PEA+IOL procedures and the total number of PEA+IOL procedures performed. The medical charts of four cases of atonic pupils were reviewed retrospectively. RESULTS: The response rate was 77.8% (42/54). Surgeon experience with PEA+IOL ranged from 1 to 15 years. Three of 42 ophthalmologists (7.1%) had had at least one case of an atonic pupil after uncomplicated PEA+IOL. Four of 58,887 cases (incidence, 0.0067%) developed an atonic pupil after uncomplicated PEA+IOL. All four cases had glare and three cases were treated with an iris contact lens, an iris diaphragm ring, and photochromic lenses. There were no specific common characteristics among the cases beyond ocular pain and headache perioperatively. CONCLUSIONS: The incidence of atonic pupil was very low. Most patients with an atonic pupil have some symptoms that require treatment. PMID- 20949741 TI - The challenge of measuring lung structure. On the "Standards for the Quantitative Assessment of Lung Structure". AB - The purpose of this review is to call attention of respiratory scientists to an Official Policy Statement jointly issued by the American Thoracic Society and the European Respiratory Society on "Standards for the Quantitative Assessment of Lung Structure", based on an extended report of a joint task force of 20 experts, and recently published in the Am. J. Respir. Crit. Care Med. This document provides investigators of normal and diseased lung structure with a review of the stereological methods that allow measurements to be done on sections. It critically discusses the preparation procedures, the conditions for unbiased sampling of the lung for microscopic study, and the potential applications of such methods. Here we present some case studies that underpin the importance of using accurate methods of structure quantification and outline paths into the future for structure-function studies on lung diseases. PMID- 20949742 TI - Regulator presses for change to EU rules on language testing. PMID- 20949743 TI - The human touch. AB - 'Look, Listen, Feel' encourages nurses to improve the patient experience by using all their senses rather than being over-reliant on technology when assessing patients. PMID- 20949744 TI - A year to remember. Interview by Lynne Pearce. AB - Since being named Nursing Standard's 2009 nurse of the year, Lin Graham-Ray has worked hard to raise the profile of looked-after children. PMID- 20949745 TI - Forgotten generation. AB - Older people have been left out of campaigns about sexually transmitted diseases, something the Family Planning Association hopes to address. PMID- 20949746 TI - The first to feel it. PMID- 20949747 TI - Medicines management. PMID- 20949748 TI - Introduction to the pain series. PMID- 20949749 TI - Basic principles of pain management: assessment and intervention. AB - This article, the first in a series written by pain nurse specialists, provides an overview of the nature, causes and structured management of acute, chronic and neuropathic pain. The differences between nociceptive and neuropathic pain, and treatment options are identified. The pain management service's roles are described in the context that a person's experience of pain is the result of biological, psychological and social factors. Future articles will explore the physiology and pharmacology of pain, how patients express pain and interventions for acute and chronic pain. They will also provide guidance on managing pain in challenging circumstances. PMID- 20949750 TI - Supporting and mentoring nursing students in practice. AB - Decision making is a fundamental skill required by the Nursing and Midwifery Council (NMC) for entry to the nurse register. It is required for the completion of the essential skills clusters - skills identified by the NMC that must be achieved in pre-registration nursing programmes. Often students do not recognise that many of the tasks they perform on clinical placement involve decision-making skills and therefore find it difficult to show their attainment in their record of achievement. This article explores how students can demonstrate their decision making and suggests techniques for mentors to support students. PMID- 20949751 TI - Importance of nutrition in palliative care of patients with chronic disease. AB - Good nutrition is important in caring for patients with life-limiting illness, not only for meeting the body's physical requirements but also because of its associated social, cultural and psychological benefits. A decision to provide nutritional care and support requires an understanding of and respect for patients' wishes, as well as an appreciation of their expectations and the benefits and burdens of such support. The patient, his or her family and healthcare professionals should openly discuss and agree the goals of nutritional care and support at an early stage, rather than waiting until patients are unable to discuss their preferences with family and carers. PMID- 20949752 TI - Travel immunisation. PMID- 20949754 TI - Fair chance of success. PMID- 20949753 TI - Home sweet home. PMID- 20949755 TI - Delivering for midwives. Interview by Christian Duffin. PMID- 20949756 TI - Advantages and disadvantages of the use of bisphosphonates in oral and maxillofacial surgery. AB - Bisphosphonates are a class of drugs of proven efficacy in the prevention and treatment of various bone diseases, affecting bone turnover by decreasing bone resorption by different mechanisms. In recent years, this class of drugs has become the target of numerous studies in relation to oral and maxillofacial surgery. The aim of this paper is to review the literature on the effects of bisphosphonates in this context, especially in the development of osteonecrosis and as adjuvant in implant placement, osteogenic distraction and bone grafting surgery. PMID- 20949757 TI - Artificial intelligence: contemporary applications and future compass. AB - The clinical use of information technology in the dental profession has increased substantially in the past 10 to 20 years. In most developing countries an insufficiency of medical and dental specialists has increased the mortality of patients suffering from various diseases. Employing technology, especially artificial intelligence technology, in medical and dental application could reduce cost, time, human expertise and medical error. This approach has the potential to revolutionise the dental public health scenario in developing countries. Clinical decision support systems (CDSS) are computer programs that are designed to provide expert support for health professionals. The applications in dental sciences vary from dental emergencies to differential diagnosis of orofacial pain, radiographic interpretations, analysis of facial growth in orthodontia to prosthetic dentistry. However, despite the recognised need for CDSS, the implementation of these systems has been limited and slow. This can be attributed to lack of formal evaluation of the systems, challenges in developing standard representations, cost and practitioner scepticism about the value and feasibility of CDSS. Increasing public awareness of safety and quality has accelerated the adoption of generic knowledge based CDSS. Information technology applications for dental practice continue to develop rapidly and will hopefully contribute to reduce the morbidity and mortality of oral and maxillofacial diseases and in turn impact patient care. PMID- 20949758 TI - Dental caries in adolescents from public schools in Maputo, Mozambique. AB - AIM: To assess dental caries prevalence in adolescents at urban and sub-urban areas of Maputo-City, Mozambique and to identify its relationship with dental fluorosis, dental plaque, nutritional status, frequency of sugar consumption and the concentration of fluoride in public water supply. METHODS: Subjects (n=601) were randomly selected from five urban schools and five sub-urban schools. Clinical examinations were performed under standardised conditions by a trained examiner using DMFT index, SiC index, fluorosis index, PHP, BMI, a sugar consumption questionnaire and water supply analysis. The bivariate analysis and Pearson correlation was used (p < 0.05). RESULTS: The mean (DMFT) was 0.9 (+/- 1.65 SD). Children in urban schools showed less dental caries (0.8 +/- 1.49 SD) than children in sub-urban schools (1.1 +/- 1.80 SD, p = 0.03). Only 8.15% had very mild to moderate fluorosis but most presented poor oral hygiene. Cases of malnutrition were found in more sub-urban schools (n=109; 36.22%) than in urban schools (n=66; 22.00%) (p = 0.03). The frequency of sugar consumption was higher among urban children compared to suburban schools (p < 0.00). The level of fluoride in water consumption in urban schools was 0.4 ppmF, above the level of fluoride in sub-urban schools, 0.2 ppmF. CONCLUSION: Dental caries should not be considered a major oral health problem in Maputo at the moment. However the data suggest the implementation of a population strategy to reduce dental caries rates, in children of both urban and sub-urban areas, in Maputo. PMID- 20949759 TI - An evaluation of the Cariogram as a predictor model. AB - As dentistry moves towards earlier detection of lesions and a more preventive rather than restorative approach, it is essential to improve the predictive values of new screening and diagnostic methods. This study was conducted to evaluate the accuracy of the Cariogram in predicting the occurrence of caries in first permanent molars. Thirty children aged 8 years were included who were divided in two groups depending on presence of carious or non carious first permanent molars. Their Cariograms were plotted and the likelihood of caries as indicated by the Cariogram was compared to the actual occurrence of caries in first permanent molars. Results revealed that the Cariogram had a diagnostic accuracy of 63.33% thus emphasising the need for better prediction models. PMID- 20949760 TI - How well prepared are Australian dentists for retirement? A survey of practitioners aged 50 and above. AB - AIMS: To determine how financially prepared Australian dentists are for retirement. METHODS: Information was collected in the Dentist Retirement Intentions Study from members of the New South Wales branch of the Australian Dental Association, all of whom were aged over 50 years. One way ANOVAs were used to test for differences between groups of variables. A forward stepwise multivariate regression identified predictors of the expected value of savings at retirement. RESULTS: It was found that while there was variation in preferred retirement income, there was general agreement that this preferred retirement income would be achieved. Current assets mostly totalled between dollars 250,000 and dollars 2 million (Australian dollars), with 35% of assets held in the family home. However, 7% of dentists had no net savings or were in net debt. Half the surveyed dentists predicted their savings at retirement to be more than $2 million. Superannuation was the most commonly cited predicted source of retirement funding. CONCLUSIONS: Most, but not all, dentists are generally well prepared for retirement. They have a significant amount of wealth, which is above that generally recommended for a comfortable living standard in retirement in Australia, they have this wealth stored in easily accessed, high return assets, and they also intend to spend this wealth on financing their retirement rather than running down their capital. PMID- 20949761 TI - Periodontal diseases in Greek adults between 1985 and 2005--risk indicators. AB - AIM: This study provides data on the periodontal status of Greek adults aged 35 44-years-old in relation to socio-demographic and behavioural parameters and compares these data with those of 1985. MATERIAL AND METHODS: A stratified cluster sample was selected according to WHO guidelines for national pathfinder surveys. Periodontal and oral hygiene status were assessed using the CPI index and the OHI-S index respectively. Socio-demographic and behavioural data were collected through face-to-face interviews. RESULTS: In 2005, 9.5% of the participants had healthy periodontium, 16.2% bleeding on probing, 46.8% calculus, 24.2% shallow pockets and 3.3% deep pockets. Half of the individuals (52.1%) had good oral hygiene status, 39.8% fair and 8.1% poor. Most of them (79%) brushed their teeth at least once a day, but only 25.4% used dental floss. Higher CPI scores were associated with living in rural areas, having a lower educational attainment and brushing and flossing teeth less frequently. Better oral hygiene status was associated with having a higher educational attainment and income, as well as brushing and flossing teeth more frequently. Comparisons with the 1985 findings indicate that severe periodontal diseases may be declining in Greece, whereas gingivitis may be increasing. CONCLUSIONS: The prevalence of severe periodontal diseases in Greek adults is not high and their periodontal health has improved since 1985. As long as their oral hygiene status and preventive dental behaviour cannot be considered as satisfactory, there is room for further improvement. PMID- 20949762 TI - Dermatoglyphics--a marker for malocclusion? AB - INTRODUCTION: Dermatoglyphics is the study of dermal ridge configurations on palmar and plantar surfaces of hands and feet. Dermal ridges and craniofacial structures are both formed during 6-7th week of intra-uterine life. It is believed that hereditary and environmental factors leading to malocclusion may also cause peculiarities in fingerprint patterns. OBJECTIVE: To study and assess the relationship between fingerprints and malocclusion among a group of high school children aged 12-16 years in Dharwad, Karnataka, India. DESIGN: A total of 696 high school children aged 12-16 years were randomly selected. Their fingerprints were recorded using duplicating ink and malocclusion status was clinically assessed using Angle's classification. RESULTS: Chi-square analysis revealed statistical association between whorl patterns and classes 1 and 2 malocclusion (p < 0.05). However, no overall statistical association was observed between fingerprint patterns and malocclusion (p > 0.05). CONCLUSION: Dermatoglyphics might be an appropriate marker for malocclusion and further studies are required to elucidate an association between fingerprint patterns and malocclusion. PMID- 20949763 TI - Do preoperative cutaneous bleeding time tests predict the outcome of intraoral surgical bleeding? AB - PURPOSE: To determine whether cutaneous bleeding time (BT) is related to perioperative bleeding outcome measures after tooth extraction. To determine whether this investigation is reliable to predict bleeding outcome after an intraoral surgical procedure. METHODS: A prospective clinical pilot study of 30 subjects. Cutaneous BT was evaluated before tooth extraction. After extraction, an oral BT was determined. Subjects were contacted 2-5 hours after extraction to assess further post operative bleeding. RESULTS: The mean cutaneous BT was 2.3 minutes (range 1.5-3.5). The mean oral BT was 9.1 (range 7-12). Cutaneous BT did not correlate with oral BT or any other measures of prospective bleeding. However, the time necessary for extraction correlated with extraction site bleeding 2-5 hours after surgery. CONCLUSION: There was no relationship between cutaneous and oral post extraction BT. The use of BT test as a screening procedure is unnecessary for prediction of prolonged bleeding after tooth extraction or minor surgical procedures in the present situation. PMID- 20949764 TI - Changes in dentist and dental hygienist numbers in the European Union and economic area. AB - AIM: To investigate the extent to which changes in the numbers of dental hygienists and dentists have occurred in the Member States of the European Union and Economic Area (EU/EEA) during the last ten years and discuss the changes in relation to the possibilities of sharing tasks between the two groups. METHODS: Numbers for active dentists, registered hygienists and EU/EEA member state populations in 2007 were taken from the website of the Council of European Chief Dental Officers (CECDO) (www.cecdo.org) and from CECDO records for the EU/EEA member states in 1998 and for the new EU member states (who joined in 2004 and 2007) in 2000. From these data, population: active dentists, population: registered dental hygienist and active dentists: registered dental hygienist ratios were calculated together with percentage changes in the number of dentists and dental hygienists by member state, between 1998 and 2007 for the old and between 2000 and 2007 for the new EU member states. RESULTS: In 2007, there were a total of 343,922 active dentists and 30,963 registered dental hygienists in the 30 EU/EEA member states plus Switzerland. The mean population to dentist ratio was about 1500:1 and the mean population to dental hygienist ratio (in the 25 states where dental hygienists were registered) was 13,454:1. During the study period, the population of the EU/EEA plus Switzerland increased by less that 3%, the number of dentists increased by 13% and the number dental hygienists by 42%. The overall ratio of active dentists: dental hygienists changed from 18:1 to 11:1. In six of the 30 member states plus Switzerland the population to dental hygienist ratio was between 2000:1 and 6000:1 and the dentist: dental hygienist ratio less than 1:3. CONCLUSIONS: Although, most member states educate dental hygienists and their numbers in the EU/EEA during the last 10 years have risen more than the dentist numbers, there are still only a handful countries where the hygienist numbers are great enough to make a significant difference to the delivery of oral health care. PMID- 20949765 TI - Can medical assistants give shots? A question finally answered. PMID- 20949767 TI - Mismanaged medication, the doctor's fault? PMID- 20949766 TI - Children and secondhand smoke exposure. PMID- 20949768 TI - Physicians' alter egos. Hobbies relieve stress and allow self expression. PMID- 20949769 TI - Venous thromboembolism: appropriate risk assessment and treatment can save lives. PMID- 20949770 TI - Prevalence of visual impairment and eye diseases in Arkansas. AB - Visual impairment and eye diseases are major public health concerns of the 21st century, particularly as our population ages. The prevalence of these conditions has not been described in Arkansas. We analyzed the vision module of the Arkansas behavioral risk factor surveillance system to estimate the burden due to these disabling conditions. The prevalence of glaucoma, age-related macular degeneration, and cataract among Arkansans > 40 years was found to be 5.5% (95% CI, 4.7 - 6.3), 5.3% (95% CI, 4.5 - 6.0), and 13.7% (95% CI, 12.6 - 14.8), respectively. Vision related quality of life was also studied. Public health strategies to reduce the burden due to visual impairment and eye diseases are the need of the hour. PMID- 20949771 TI - Obstructive sleep-disordered breathing in children: assessment and treatment at Arkansas Children's Hospital. AB - Obstructive sleep-disordered breathing is associated with upper airway obstruction during sleep, which negatively affects sleep quality, ventilation, and/or oxygenation. The condition affects 2-11% of children. In this paper we discuss the epidemiology, pathophysiology, clinical features, diagnosis, and management of obstructive sleep-disordered breathing in children and provide a brief overview of the Arkansas Children's Hospital Sleep Disorder Center. PMID- 20949772 TI - Learning impact of education during pulmonary rehabilitation program. An observational short-term cohort study. AB - BACKGROUND: Among the several components constituting a pulmonary rehabilitation (PR) course, education may contribute to an individual's recognition of symptoms and worsening of the disease. However, the specific benefits of education is far greater than can be clearly documented to the health care providers. The aim of our preliminary study was to assess the learning impact of educational sessions (ES) in Chronic Obstructive Pulmonary Disease (COPD) patients referred to standard PR. METHODS: Six ES on 3 areas (Symptoms-Therapies, Aids, Mood) were applied during PR at our clinic. The learning effect was prospectively evaluated by a specific questionnaire (ESQ) in 285 COPD patients (age 69 +/- 8 years, FEV1 53 +/- 14 % pred), then grouped into those who have completed ES (Completers group, n = 226) or who did not (mean 2 +/- 1 ES) (Control group, n = 59). Total and partial ESQ scores, and PR outcomes (6-minute walking test-6MWD, effort dyspnoea at Medical Research Council scale-MRC, and health-related quality of life scale-SGRQ) were assessed in a pre (T0) to post (Tend) design. RESULTS: Similar improvement in PR outcomes was recorded in both groups at Tend, whereas ESQ total and partial scores significantly increased in 'Completers' only (p < 0.001). ESQ-Aids score improved to a greater extent in Completers than in Control (+0.60 +/- 1.03 vs +0.27 +/- 1.27 point respectively, p = 0.036). A higher proportion of Completers improved above the median change of both ESQ total and aids scores (p < 0.05). CONCLUSION: Attending educational sessions produces a specific short-term learning effect during rehabilitation of COPD patients. PMID- 20949773 TI - Low-technology exercise test in the preoperative evaluation of lung resection candidates. AB - Exercise tests are increasingly used in the preoperative functional evaluation of lung resection candidates. Low-technology exercise tests include six minute walking, shuttle walking and stair climbing. Conflicting evidence has been reported regarding 6 minute walking test. This test should not be used to select patients for lung resection. An incremental shuttle walk test is easier to replicate than 6 minute walking test. Most patients achieving 25 shuttles or 400 m have a maximum oxygen consumption measured at cardiopulmonary exercise test greater than 15 l/Kg/min. Although this test tends to underestimate performance at the lower range compared to peak oxygen consumption it can be used a screening test before lung resection. Excluding patients from operation based on this test alone is however not recommended and a formal cardiopulmonary exercise test should be always used in those walking less than 400 m. Stair climbing has been extensively studied in thoracic surgery. Several studies have found that poor performance in this test is indicative of cardiopulmonary complications and mortality after lung resection. In particular, climbing less than 12 m represents very high risk, whereas climbing more than 22 m is associated with a favourable outcome. Recent guidelines recommend referring all patients climbing lower than 22 m to cardiopulmonary exercise test. Stair climbing can be used as a screening test in cases cardiopulmonary exercise test is not readily available. In general, patients climbing more than 22 m can proceed to surgery without further evaluation. PMID- 20949774 TI - Treatment of malignant pleural mesothelioma: current status and future directions. AB - Previously considered to be rare, malignant pleural mesothelioma (MPM) is a highly aggressive tumour that has become a very important issue over recent years due to its poor prognosis and its increasing incidence mostly linked to previous asbestos exposure. An optimal treatment for MPM is not established yet; new therapies and predictive tools are still needed in the management of this cancer. Thus the aim of this review is to provide clinicians clear and up-to-dated data on the latest therapeutic strategies for MPM patients in 2010. The guidelines recently proposed by the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS) taskforce are summarized here. The authors also briefly reviewed the future directions in MPM treatment including targeted therapies, gene or cell therapies. PMID- 20949775 TI - Association of severity of COPD with IgE and interleukin-1 beta. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a pulmonary inflammatory disease characterised by airflow limitation. The role of various inflammatory mediators such as interleukin-1beta (IL-beta) and Immunoglobulin E (IgE) have been implicated in COPD. In present study we aimed to establish if there is an association between the serum levels of IL-1beta and IgE and the severity of airway obstruction. MATERIALS AND METHODS: The study group comprised of 30 non atopic smokers, suffering from COPD and 30 non smoker, healthy controls. Serum levels of IgE and IL-1beta were assayed by ELISA in all subjects along with their pulmonary function tests. RESULTS: Serum IgE and IL-1beta levels were significantly raised in COPD patients as compared to healthy controls. IL 1beta was negatively correlated with FEV1 (r = -0.624, p = 0.003) and IgE showed a negative correlation with FVC (r = -0.477, p = 0.034). CONCLUSION: Our study suggests that in COPD IL-1beta and IgE serum levels correlate with clinical aspects of disease severity. We suggest that the production of IgE and IL-1beta in the airways of patients with COPD may be related to smoking which affects airway obstruction. PMID- 20949776 TI - Successful treatment of persistent postoperative air leaks following the placement of an endobronchial one-way valve. AB - Treatment of persistent air leaks due to pulmonary resection in pathological conditions of the lung involve a very large spectrum of available methods, from chest drainage and placement of Heimlich valves to surgical repair or pleural decortication. However, in some of these patients surgery may be contraindicated. This report describes an endobronchial approach to the control of marked and prolonged air leaks in four patients using a newly designed one-way airway valve (Pulmonx Corporation; Redwood City, Ca.USA) placed into the segmental bronchus that is the source of air leakage. As the device is a one-way inspiratory airway blocker, it can be used to control persistent air leaks while maintaining the drainage of mucus. This approach potentially provides an effective nonsurgical and minimally invasive alternative addition to the armamentarium of treatments for patients who suffer with persistent post-operative air leaks where other methods have failed or in frail patients who are categorised as a high surgical risk. PMID- 20949778 TI - From Russia with love. PMID- 20949777 TI - Influenza A H1N1 pneumonia in a patient with hairy-cell leukemia. AB - Severe pandemic influenza A virus (H1N1) infection is associated with risk factors such as pregnancy, obesity and immunosuppression. Immunocompromised patients are at increased risk of more severe or prolonged infection. We report a case of a hairy cell leukemia patient with H1N1 pneumonia which caused severe and prolonged illness. H1N1 virus pneumonia with meticillin-resistant Staphilococcus Aerues (MRSA) coinfection causing Acute Lung Injury (ALI) was treated with a double-dose of osentamyvir, a high dose of teicoplanin and a low dose of corticosteroids. Haematological findings included leucopenia, neutropenia, lymphopenia, reduction of gamma-globulins and natural killer (NK) cells. Reduction of NK and gamma-globulins may explain the development of severe illness and the prolonged illness Neutropenia may explain the MRSA co-infection. Lymphopenia is directly associated with virus action and is considered to be a marker of the swine influenza in adults. PMID- 20949779 TI - Marion's message. Study shows mothers' lives saved. PMID- 20949780 TI - The amniotomy question: examining the pros and cons of rupturing membranes. AB - The culture of birth establishes practices and embraces rituals. Currently there is a movement toward midwifery and away from hospital births as women and professions question the values of some practices and interventions common in hospital births. Amniotomy is a well-established practice that is accepted as an intervention to help women in their birth process, with the hope that it will shorten labor. There is little research regarding the psychological implication of amniotomy on the infant. This paper explores the pros and cons of amniotomy, its role as a ritual for birth attendants and the possible psychological effects on the infant. PMID- 20949781 TI - Ordinary miracle: the homebirth of Ava Christine. PMID- 20949782 TI - Like cures like: homeopathy for labor and birth. PMID- 20949783 TI - Deceleration phase. PMID- 20949784 TI - Birthing to redeem. PMID- 20949785 TI - The gift of intuition. PMID- 20949786 TI - The epidural trip: why are so many women taking dangerous drugs during labor? AB - Two million American women will take an epidural trip this year during childbirth. In most cases, they'll be ill-informed as to possible side effects or alternate methods of pain relief. In many ways, epidurals are the drug trip of the current generation. Similar to street drug pushers, most anesthesiologists in the delivery rooms maintain a low profile, avoid making eye contact and threaten to walk out if they don't get total cooperation. Women get epidurals for one of the main reasons so many women smoked pot in the 1970s-their friends are doing it. This article examines why so many women in the Western world are compelled to take powerful drugs during their labor and exposes the risks epidurals pose to both mother and baby. PMID- 20949787 TI - Who counts where I come from? PMID- 20949788 TI - Santa Fe homebirth. PMID- 20949789 TI - Beyond fear, tension and panic: helping men enjoy the birth experience. PMID- 20949790 TI - A story of homebirth after cesarean. PMID- 20949791 TI - Gestational diabetes: an update for midwives. PMID- 20949792 TI - Before the first wave: midwife Carol Gautschi shares her views on first stage. Interview by Kelly Moyer. PMID- 20949793 TI - First stage: preparing the fetus ejection reflex. PMID- 20949794 TI - A family-centered cesarean birth. PMID- 20949795 TI - Turn, baby turn: new maneuvers for turning a malpositioned baby. PMID- 20949796 TI - The choices we make: building trust between midwife and client. PMID- 20949797 TI - Kangaroo care in Mexico. PMID- 20949798 TI - Midwifery in Austrailia. PMID- 20949799 TI - We'll grow back when the rain comes: an update from Haiti. PMID- 20949800 TI - Born in Borneo. PMID- 20949801 TI - Fight for your right: successful VBAC in an Australian hospital. PMID- 20949802 TI - One midwife's journey; stories from Papua New Guinea and beyond. PMID- 20949803 TI - The value of continuing nursing education. PMID- 20949804 TI - When worlds collide: advocacy. PMID- 20949805 TI - Applicability of the FISH test for bladder cancer. AB - Fluorescence in situ hybridization (FISH) analysis is an FDA-approved, urine based marker that assists in diagnosis and surveillance of invasive urothelial cancer. This article provides an overview and case study demonstrating the clinical use of this analysis. As a systematic review of non-randomized and randomized clinical trials, this article provides Level I evidence. PMID- 20949806 TI - Using an acuity-adaptable unit for urological services. AB - The University of Pittsburgh Medical Center--Shadyside Campus uses an acuity adaptable unit model that has streamlined patient care. Pre-operative preparation and post-operative recovery nursing care on one designated nursing unit provide a less stressful experience for the surgical patient. PMID- 20949807 TI - Botulinum toxin type A for the treatment of urinary tract dysfunction in neurological disorders. AB - Botulinum toxin type A injections represent an important therapeutic option for patients with neurogenic urinary dysfunction in whom conservative treatment has not been effective. The nurse's role in ensuring that these patients receive appropriate assessment and treatment is discussed. PMID- 20949808 TI - Incidence, prevalence, and under-recognition of delirium in urology patients. AB - Unrecognized delirium may lead to negative outcomes, such as increased morbidity, longer hospital stays, and increased health care costs. A prospective cohort design study was used to determine the incidence and prevalence of delirium and percentage of patients with unrecognized delirium in a hospital inpatient unit. The sample consisted of 141 patients admitted to a urology/nephrology unit over a six-week period. Data were collected using the Confusion Assessment Method (CAM) and the Charlson Comorbidity Index (CCI). Results showed the incidence of delirium was 6%, and the prevalence was 12% in this sample. Out of 17 patients with delirium, 6 patient records (35%) had no documentation of delirium by physicians. In the nursing assessment, 1 of 17 (6%) had no documentation of any signs/symptoms of delirium. This study provided baseline data for the development, implementation, and evaluation of a delirium recognition program using the CAM. The CAM may represent an easy-to-use, valid, and reliable instrument to detect delirium as part of a routine nursing assessment. PMID- 20949809 TI - Obesity--America's health crisis. AB - Obesity has been associated with a 36% increase in health care spending, and treating the obese patient can be medically challenging. This article provides a brief overview of treating patients who are obese or overweight, and how urologic nurses can educate their patients and others on treatment options. The impact of healthy diet and exercise, as well as considering overweight individuals without bias or prejudice, are discussed. PMID- 20949810 TI - Getting ready for certification: bladder cancer. PMID- 20949811 TI - Treatment options for female sexual arousal disorder: part II. AB - Female sexual arousal disorder (FSAD) occurs when a woman experiences distress due to the inability to attain or maintain adequate vaginal lubrication. Many treatments are still under investigation, and at this time, there are no FDA approved medications available for the treatment of FSAD. Treatment options include "off-label" medications, vaginal estrogen, compounded preparations, and over-the-counter products. PMID- 20949813 TI - Insurance industry listens to physicians. PMID- 20949812 TI - Gelnique (oxybutynin chloride) 10% gel for overactive bladder. AB - This article provides an overview of oxybutynin transdermal gel (Gelnique), its uses, and product information. PMID- 20949814 TI - Using scientific evidence to shape research, intervention programs, and policy in a statewide effort to reduce infant mortality, 2004-2009. AB - Based on steadily increasing rates from the mid-1990s through 2005 (e.g., rates reached a high of 9.3 deaths per 1,000 live births in the 2000-2004 time frame), the Delaware infant mortality initiative began in 2004. The initiative consisted of a synthesis of quantitative analyses and state-led programs at all public health agencies as directed from the Governor's Office. Throughout the first four years of implementation, Division of Public Health (DPH) staff utilized vital statistics data to produce a statewide research agenda that included reviewing vital record reporting procedures, highlighting infant mortality disparities by birthweight and race, studying the effect of plural births and other demographic factors on infant deaths, and using data to justify proposed research projects. Results indicated that black infants were dying at twice the rate of white infants (Disparity Ratio: 2.2), and extremely low birth weight infants were the biggest contributing population to infant mortality, specifically births of infants less than 500 grams. Further results indicated that intervention efforts should focus on preconception care for women of reproductive age and prevention of prematurity. These findings led to the implementation of research-based statewide surveillance programs and registries to identify women who experienced poor birth outcomes. Additionally, analyses provided the basis for implementing two major intervention programs, statewide education campaigns, and proposed revision of state standards. This paper illustrates the translation of research findings into practically applicable recommendations for statewide surveillance, programs, and policy development. PMID- 20949815 TI - Do you work with hospitalists? PMID- 20949816 TI - 'Our campaign will expose where the real waste is in the NHS'. Interview by Petra Kendall-Raynor. PMID- 20949817 TI - Making sense of autism. AB - Children with autism are more prone to certain mental health disorders than their counterparts, but services to meet their special needs are lacking. PMID- 20949818 TI - Making the link. Interview by Mary-Claire Mason. AB - An interactive website will bring together nurses in an NHS trust and the independent sector to share best practice. PMID- 20949819 TI - War on attrition. Interview by Adele Waters. AB - The University of Glamorgan prides itself on the support it gives to nursing students, both practically and emotionally. PMID- 20949820 TI - Striking a positive note. Interview by Sue Learner. AB - A wide range of arts and music therapies help the residents of Adamwood Nursing Home realise their full potential. PMID- 20949821 TI - Research does count, but experience should as well. PMID- 20949822 TI - Assessment and expression of pain. AB - This article, the second in a series of articles on pain, describes the importance of pain assessment. It explores the individuality of patients' pain expression and the effect of healthcare professionals' reactions to people experiencing pain. The role of the nurse is analysed, focusing on multidimensional pain assessment and the use of pain assessment scales. PMID- 20949823 TI - Tuberculosis: infection control in hospital and at home. AB - This article examines infection control issues relating to tuberculosis (TB) in acute and community settings. Background information on TB is discussed briefly along with key challenges to global and national control. A programme to prevent infection composed of specific hierarchical levels is outlined, using national and international guidance, and suggestions are made for infection control in the community. The article will be useful for nurses involved in the care of patients with confirmed or suspected TB. PMID- 20949824 TI - Auditing hand hygiene practice. AB - Hand hygiene is regarded as the most effective way of preventing healthcare associated infections. Thus hand hygiene audits are frequently undertaken by infection prevention and control teams. Although apparently straightforward, hand hygiene audit requires careful planning and conduct. Healthcare professionals need to understand the principles that underpin effective hand hygiene audit to improve their own practice and help patients, carers and the public to interpret the findings. PMID- 20949825 TI - Adherence to medication. PMID- 20949826 TI - The value of reflection. PMID- 20949827 TI - Back behind the counter. Interview by Lynne Wallis. PMID- 20949829 TI - Is there a universal definition of nursing? PMID- 20949828 TI - A grounding for good practice. PMID- 20949830 TI - Nursing theory as the foundation for interdisciplinary success. PMID- 20949831 TI - Evidence-based staffing: a different perspective. PMID- 20949832 TI - Describing the problem for an evidence-based practice improvement project: a missing ingredient. PMID- 20949833 TI - Nurse dose: validation and refinement of a concept. AB - In this article, we report the results of two studies aimed at validating the concept of nurse dose. The first study examined the relevance of the critical attributes and empirical indicators in accurately reflecting the concept of nurse dose. Ten experts in staffing research rated the relevance of the attributes and indicators. The second study explored the factorial structure of the nurse dose concept. Data on the nurse dose indicators were obtained from 26 inpatient units. The operationalization of nurse dose was refined based on the two studies' results. Nurse dose is posited as a structural variable capturing nurses' capacity to deliver high quality care in acute care hospitals. It is defined as the level (i.e., number and type) of nursing staff required to provide care that produces intended patient outcomes. Nurse dose is reflected in two attributes: (1) active ingredients representing the essential elements that distinguish nurses from other health care professionals and operationalized in nurses' theoretical and practical knowledge, and skill mix; and (2) intensity representing the potential for nurse-patient interactions and operationalized in terms of amount (indicated by full-time equivalent) and frequency (indicated by nurse-patient ratio and hours per patient day). The concept of nurse dose has the potential for guiding future staffing research. PMID- 20949834 TI - Theory of planned behavior, self-care motivation, and blood pressure self-care. AB - The theory of planned behavior (TPB) was integrated within the theory of self care (SCT) to explore the predictive value of extending TPB to measure attitudes and beliefs regarding a behavioral goal, and determine the ability of goal beliefs to predict engagement in the combined, multiple behaviors necessary to control BP. The hypothesized model was evaluated in a sample of 306 community dwelling African Americans between 21 and 65 years of age. Scales developed for the study achieved acceptable reliability (alpha = .68-.95). Structural equation modeling analysis resulted in a second-order factor structure with attitude, subjective norm, perceived behavioral control, and intention modeled as indicators of a construct representing goal beliefs related to keeping BP within normal limits. This latent construct was conceptualized within the theory of self care as "self-care motivation," and predicted 18% of the variance in self-care behaviors necessary for BP control. The model achieved acceptable fit (CMIN/df = 2.32; CFI = .95; RMSEA = .066). Final assessment of fit was done using multi group SEM and bootstrapping techniques. In this extension of the TPB attitudes and beliefs regarding the goal of keeping BP within normal limits were found to determine one's motivation to engage in the multiple behaviors necessary for BP control. PMID- 20949835 TI - Predictors of condom use among Mexican adolescents. AB - Mexican adolescents continue to be at increased risk for HIV infection due to inconsistent condom use. The purpose of this study was to identify predictors of condom use intentions and condom use among Mexican adolescents who participated in a randomized control trial designed to test a sexual-risk reduction intervention. Data from sexually active adolescents 17 to 21 years (n = 157) of age who were assigned to the control group were analyzed 48 months post intervention. Regression analysis showed that positive attitudes toward condoms, subjective norms, and control beliefs significantly explained intention to use condoms (R2 = .75, p < .001). Attitudes toward condoms (beta = .67, p <.001), technical skills (beta = .13, p = .01), and condom use self-efficacy (beta = .24, p < .001) were significant predictors of condom use intention. Compared to those who inconsistently used condoms, adolescents who used condoms consistently had greater intention to use condoms and greater impulse control. Findings suggest that attitudes and control beliefs should be further explored with Mexican adolescents in order to support consistent condom use. PMID- 20949836 TI - Factors related to health practices: cervical cancer screening among Filipino women. AB - This correlational study developed and tested theory to better understand health practices, including cervical cancer screening, among young Filipino women. It tested theoretical relationships postulated among (a) positive health practices, (b) cervical cancer screening, (c) social support, (d) acculturation, and (e) optimism. A convenience sample of 89 young Filipino women in an urban setting was obtained. Participants completed a demographic sheet and five instruments. Significant positive correlations were found between PHP and social support (r = .169, p <.05) and previous cervical cancer screening behavior (r = .285, p <.01) and cervical cancer screening frequency (r = .33, p <.01). Social support was not significantly related to cervical cancer screening. Previous cervical cancer screening behavior was significantly related to optimism (r = .285, p <.01) and screening frequency (r = .924, p <.01). Optimism was significantly related to positive health practices (r = .209, p <.05) and cervical cancer screening knowledge (r = .224, p <.05) but not significantly related to previous cervical cancer screening behavior or screening frequency. Findings contribute to a more comprehensive knowledge base regarding positive health practices, including cervical cancer screenings, among young Filipino women. PMID- 20949837 TI - Getting past the accident: explosive devices, limb loss, and refashioning a life in a military medical center. AB - I describe the refashioning of a sense of self and identity of a junior officer in the U.S. Army who was injured in Iraq. Ethnographic data for this article were collected between July 2006 and January 2008. The setting for this article is the U.S. Armed Forces Amputee Patient Care Program at Walter Reed Army Medical Center. Two models of rehabilitation are contrasted in the rehabilitation program. The first focuses on the refashioning of identity through a sports model of rehabilitation emphasizing physical functioning. The second approaches rehabilitation by emphasizing individual interests and the concern of a person who has a future life to develop. I conclude by arguing that understanding the process of rehabilitation from traumatic injury would benefit from a perspective that melds multiple dimensions, taking into account both the physical body and the social world that patients have inhabited and will inhabit. PMID- 20949838 TI - The language of "Circule": discursive construction of false referral in Iranian teaching hospitals. AB - This article explores the practice of false patient out-referral by medical students in Iranian teaching hospital emergency departments. Drawing on participant-observations and interviews during eight months in six hospitals in Tehran, we investigate how discourse is appropriated to construct and legitimate out-referrals through four general strategies of sympathy, mystification, intimidation, and procrastination. Based on a critical approach to false out referral discourse, we revisit the medical and educational functioning of teaching hospitals in Iran: Focusing on medical students involved in false out referrals, their discursive reproduction of deception is examined along with their legitimate challenges to institutional structures. Moreover, focusing on the institution of hospital, institutional corruption is discussed along with the problematic of covert cultural defiance faced by a modernist organizational construct in a nonmainstream cultural context. Finally, we argue that the discourse of false out-referral calls for more profound public awareness in dealing with health institutions. PMID- 20949839 TI - "A disease of frozen feelings": ethically working on emotional worlds in a Russian Orthodox Church drug rehabilitation program. AB - In a Russian Orthodox Church drug rehabilitation program in St. Petersburg, drug addiction was often described as a disease of frozen feelings. This image suggests that rehabilitation is a process of thawing emotional worlds and, thus, allows the emotions to flow once again. In this article I argue that "frozen feelings" is better understood as the unsocial emotional worlds many drug users experience, and that rehabilitation in this church-run program particularly focuses on the cultivation of an emotional world that supports sociality. This is done, I argue, by means of ethically training rehabilitants to learn how to control and manage their emotional worlds, and in so doing, rehabilitants become new moral persons better able to live in the social world. PMID- 20949840 TI - Female sex workers and the social context of workplace violence in Tijuana, Mexico. AB - Gender-based violence in the workplace impacts the physical and emotional wellbeing of sex workers and may lead to other health problems, such as PTSD and depression, drug abuse, and a greater likelihood of sexually transmitted infections. This study examines the social context of workplace violence and risk avoidance in the context of legal regulations meant to reduce harms associated with the industry. Ethnographic research, including 18 months of extended field observations and interviews with 190 female sex workers, is used to illustrate how sex workers in Tijuana, Mexico, experience and manage workplace violence. Multiple subthemes emerge from this analysis, including deciding where to work, working with a third party, avoiding theft, and dealing with police. These findings support the idea that the risk of violence is part of a larger "hierarchy of risk" that can result in a "tradeoff" of harms. PMID- 20949841 TI - "All I eat is ARVs": the paradox of AIDS treatment interventions in central Mozambique. AB - The number of people on antiretroviral treatment in Mozambique has increased by over 1,500 percent since it first became free and publicly available in 2004. The rising count of "lives saved" seems to portray a success story of high-tech treatment being provided in one of the poorest contexts in the world, as people with AIDS experience dramatic recoveries and live longer. The "scale-up" has had significant social effects, however, as it unfolds in a region with a complicated history and persistent problems related to poverty. Hunger is the principal complaint of people on antiretroviral treatment. The inability of current interventions to adequately address this issue leads to intense competition among people living with HIV/AIDS for the scarce resources available, undermining social solidarity and the potential for further community action around HIV/AIDS issues. Discourses of hunger serve as a critique of these shortcomings, and of the wider political economy underlying the HIV/AIDS epidemic. PMID- 20949842 TI - Perils to pregnancies: on social sorrows and strategies surrounding pregnancy loss in Cameroon. AB - This article explores the local perceptions and practices surrounding pregnancy loss in Cameroon--a topic that has long been neglected in international reproductive health debates. Based on extended periods of anthropological fieldwork in an urban and a rural setting in the East province of the country, it shows the inherent ambiguities that underlie pregnancies and their perceived dangers. By situating meanings of pregnancy loss within the complex dynamics of marriage and kinship, pregnant bodies are argued to be social bodies--the actions and interpretations of which shift along with social situations. This approach not only forms an alternative to the current focus on the body politic in global discourses on fertility risks but also shows how conventional assumptions such as the rigid distinction between voluntary and involuntary pregnancy loss distort ambiguous daily life realities for Cameroonian women whose pregnancies are not being carried to term. PMID- 20949843 TI - Malaria, danger, and risk perceptions among the Yao in rural Malawi. AB - Findings from a study designed to discover how local understanding of malaria among Yao in Malawi relate to pregnancy risk definitions reveal that malaria in pregnancy is not perceived as a major risk. Using extended ethnographic field research and multiple methods, we argue a shift from narrow single-disease approaches to malaria during pregnancy is required and document women's concerns about exposure to multiple vulnerabilities during pregnancy, including witchcraft, extramarital affairs, and multiple dangerous illnesses. Four dimensions are implicated in Yao perceptions of risk: perceived adverse consequences in pregnancy; ease of treatment and cure; transmission and agency to control; and type of risk (social-medical). We discuss implications and consider malaria program features needed to address the complexity of perceived vulnerabilities and living conditions in resource-poor settings. PMID- 20949844 TI - Effects of balance training on postural sway, leg extensor strength, and jumping height in adolescents. AB - Deficits in strength of the lower extremities and postural control have been associated with a high risk of sustaining sport-related injuries. Such injuries often occur during physical education (PE) classes and mostly affect the lower extremities. Thus, the objectives of this study were to investigate the effects of balance training on postural sway, leg extensor strength, and jumping height in adolescents. Twenty high school students participated in this study and were assigned to either an intervention (n = 10) or control group (n = 10). The intervention group participated in a 4-week balance-training program integrated in their physical education lessons. Pre- and posttests included the measurements of postural sway on a balance platform, jumping height on a force platform, and maximal isometric leg extension force on a leg-press. Balance training resulted in significantly improved postural control, increased jumping height, and enhanced rate of force development of the leg extensors. Physiological adaptations rather than learning effects seem to be responsible for the observed findings. These results could have an impact on improving the performance level in various sports and on reducing the injury prevalence of the lower extremities. PMID- 20949845 TI - Effect of a storyboarding technique on selected measures of fitness among university employees. AB - The purpose of this study was to determine the effectiveness of storyboarding (i.e., participants' written narrative) on improving fitness among university employees over 10 weeks. Groups consisted of storytelling during the program orientation, storytelling plus two coaching sessions, or the normal program only (control). Using difference (pretest from posttest) scores, a one-way multivariate analysis of variance indicated significant differences between groups (p < .01). For percent body fat, only the coached group was statistically superior to the control group (p < .03), while the two experimental groups were statistically similar. For submax VO2, both storyboarding groups were superior to the control group (p < .04). It was concluded that storyboarding may be an effective means for changing selected health behaviors. PMID- 20949846 TI - Dog ownership, dog walking, and children's and parents' physical activity. AB - This study aimed to determine cross-sectional associations of dog ownership, dog walking, and physical activity (PA) among children and their parents. Objective measures of PA were obtained for children ages 5-6 and 10-12 years from 19 primary schools across Melbourne, Australia. Parents self-reported their PA, dog ownership, and frequency of dog walking: 53% of families owned a dog, 41% of children who owned a dog did not walk their dog at all, and 32% reported never or rarely walking their dog as a family. Dog ownership was associated with an additional 29 min/day in PA among younger girls, and 70 and 59 min/week more in PA among mothers of younger boys and older girls, respectively. Among mothers of older girls, dog owners were 1.6 times as likely to meet PA guidelines. Mothers with older boys and girls, and fathers with younger boys, who reported walking the dog regularly as a family, spent more time in PA (105, 90, and 158 more min/week, respectively). Promoting dog ownership and dog walking among children and as a family are potential strategies for increasing PA participation in some families. PMID- 20949848 TI - Physical activity motivation in late adolescence: refinement of a recent multidimensional model. AB - Recent research (Martin et al., 2006) presented a new, multidimensional approach to physical activity motivation (using the Physical Activity Motivation Scale [PAMS]) operationalized through four factors: adaptive cognition, adaptive behavior; impeding/maladaptive cognition, and maladaptive behavior. The present study extends this early research by recruiting a larger sample of 705 young people, in late adolescence, using a shortened form of PAMS (PAMS-Revised), and including physical and nonphysical correlates as a means of better understanding its validity. Findings confirmed a sound four-factor framework comprising reliable factors. Findings also demonstrated hypothesized relations between physical activity motivation and physical correlates and, to a lesser extent, between physical activity motivation and more general life correlates. PMID- 20949847 TI - The relationship between selected body composition variables and muscular endurance in women. AB - The primary purpose of this study was to determine if muscular endurance is affected by referenced waist circumference groupings, independent of body mass and subcutaneous abdominal fat, in women. This study also explored whether selected body composition measures were associated with muscular endurance. Eighty-four women were measured for height, weight, body mass index (BMI), waist circumference (WC), and abdominal skinfold thickness (SFAB) and performed 60-s sit-ups (SU) and maximal push-ups (PU) tests. Mean differences in SU and PU scores were tested across three groups based on WC as follows: WCG1 < 70 cm; WCG2 between 70 and 89 cm; WCG3 > or = 90 cm. There were no significant differences in SU and PU scores between WCG1 and WCG2. WCG3 had significantly lower SU and PU scores compared to the other groups. After adjusting for the influence of SFAB, BMI, and weight, the differences disappeared. The regression analysis revealed a two-variable (BMI and SFAB) model that accounted for the variation in SU performance. For PU, only BMI loaded into the regression model. The results of this study suggest that women with a WC > or = 90 cm have decreased muscular endurance compared to their lower WC counterparts. This difference is related to higher body masses. PMID- 20949849 TI - The relationship among motor proficiency, physical fitness, and body composition in children with and without visual impairments. AB - This study compares the motor skills and physical fitness of school-age children (6-12 years) with visual impairments (VI; n = 60) and sighted children (n = 60). The relationships between the performance parameters and the children's body composition are investigated as well as the role of the severity of the impairment. The degree of VI did not differentially affect the outcomes. Compared to their sighted peers, the children with VI scored lower on the locomotor and object control skills as assessed with the Test of Gross Motor Development-2, and the physical fitness (Eurofit) parameters of plate tapping, the standing broad jump, the modified 5 x 10-m shuttle run, and 20-m multistage shuttle run (20 MST). Their body mass and body fat indexes were inversely correlated with the standing broad jump and the 20-MST but positively correlated with handgrip strength. Moreover significant inverse correlations were found between their locomotor and object control skills on the one hand and plate tapping and the 5 x 10-m shuttle run on the other hand. Given the relatively high proportion (25%) of overweight/obese children within the VI sample, educators are recommended to promote health-related activities and help enhance motor skills in this population. PMID- 20949850 TI - Detecting and correcting errors in rapid aiming movements: effects of movement time, distance, and velocity. AB - According to closed-loop accounts of motor control, movement errors are detected by comparing sensory feedback to an acquired reference state. Differences between the reference state and the movement-produced feedback results in an error signal that serves as a basis for a correction. The main question addressed in the current study was how distance, movement time, and velocity influence both spatial or temporal error detection. Forty college-aged participants (30 women and 10 men) performed rapid aiming movements over 30 degrees or 50 degrees in either 210 ms or 350 ms without vision. The participants verbally estimated the distance moved and the movement time during acquisition before knowledge of results was given and during an immediate retention test without knowledge of results. Spatial and temporal objective-subjective correlations were greater in the 210-ms condition compared to the 350-ms condition, but were not related to movement velocity. PMID- 20949851 TI - Motivational responses to fitness testing by award status and gender. AB - Fitness testing is a prominent element in many physical education programs, but there has been limited investigation concerning motivation constructs associated with the testing. This study investigated the relationships among physical education students' award status and gender to achievement goals, intrinsic motivation, and intentions. After they had completed a battery of fitness tests, 123 fifth-grade physical education students were classified into two groups: those who received awards and those who did not. They completed a series of questionnaires assessing motivational constructs. Analyses of variance revealed that students who received a fitness award reported higher levels of task involvement, perceived competence, effort, enjoyment, and future intention than those who did not. Boys reported higher levels of ego-involvement than girls, but no other gender differences were evident. The findings from this study can be used to inform practitioners, test designers, and researchers about the ways fitness testing programs can be structured so that all students receive the potential benefits from participating in such assessments. PMID- 20949852 TI - ATriple Iron triathlon leads to a decrease in total body mass but not to dehydration. AB - A loss in total body mass during an ultraendurance performance is usually attributed to dehydration. We identified the changes in total body mass, fat mass, skeletal muscle mass, and selected markers of hydration status in 31 male nonprofessional ultratriathletes participating in a Triple Iron triathlon involving 11.4 km swimming, 540 km cycling and 126.6 km running. Measurements were taken prior to starting the race and after arrival at the finish line. Total body mass decreased by 1.66 kg (SD = 1.92; -5.3 kg to +1.2 kg; p < .001), skeletal muscle mass by 1.00 kg (SD = 0.90; -2.54 kg to +2.07 kg; p < .001), and fat mass by 0.58 kg (SD = 0.78; -1.74 kg to +0.87 kg; p < .001). The decrease in total body mass was associated with the decrease in skeletal muscle mass (r = .44; p < .05) and fat mass (r = .51; p < .05). Total body water and urinary specific gravity did not significantly change. Plasma urea increased significantly (p < .001); the decrease in skeletal muscle mass and the increase in plasma urea were associated (r = .39; p < .05). We conclude that completing a Triple Iron triathlon leads to decreased total body mass due to reduced fat mass and skeletal muscle mass but not to dehydration. The association of decrease in skeletal muscle mass and increased plasma urea suggests a loss in skeletal muscle mass. PMID- 20949854 TI - Aggressor-victim dissent in perceived legitimacy of aggression in soccer: the moderating role of situational background. AB - The purpose of this study was to investigate the aggressor-victim difference in perceived legitimacy of aggression in soccer as a function of score information (tied, favorable, unfavorable), sporting penalization (no risk, yellow card, red card), and type of aggression (instrumental, hostile). French male soccer players (N = 133) read written scenarios and rated the legitimacy of the described aggressive act depending on a specific perspective (aggressor or victim) and situational information. A significant aggressor-victim difference in perception of instrumental aggression was found in situations where the score was tied or where there was no risk to be caught. In addition, aggressors were affected by such information, whereas victims were not. The discussion focuses on explanations and implications of such divergences in aggressive sport situations. PMID- 20949853 TI - Potential mediating pathways through which sports participation relates to reduced risk of suicidal ideation. AB - Suicide ranks as the third leading cause of death for American youth. Researchers examining sport participation and suicidal behavior have regularly found inverse relationships. This study represents the first effort to test a model depicting potential mechanisms through which sport participation relates to reduced risk of suicidal ideation. The participants were 450 undergraduate students. Measures assessed participants' involvement in university-run sports and other activities; frequency of physical activity; and perceived social support, self-esteem, depression, hopelessness, loneliness, and suicidal ideation. Regression analyses confirmed a path model and tested for mediation effects. Vigorous activity mediated relationships between sport participation and self-esteem and depression; and self-esteem and depression mediated the relationship between vigorous activity and suicidal ideation. Social support mediated relationships between sport participation and depression, hopelessness, and loneliness; and each of these risk factors partially mediated the relationship between social support and suicidal ideation. However no variable fully mediated the relationship between sport participation and suicidal ideation. This study provides a foundation for research designed to examine pathways through which sport participation relates to reduced risk of suicidal behavior. PMID- 20949855 TI - The influence of exercise intensity on frontal electroencephalographic asymmetry and self-reported affect. AB - The "feel better" effect of exercise has been well established, but the optimal intensity needed to elicit a positive affective response is controversial. In addition, the mechanisms underlying such a response are unclear To clarify these issues, female undergraduate students were monitored for electroencephalographic (EEG) and self-reported affective responses during the recovery period following rest, low, moderate, and high intensities of treadmill running, each lasting 30 min. Frontal EEG asymmetry and self-reported vigor scores following exercise at all three intensities were significantly elevated compared to those observed following rest. The results suggest that steady-state aerobic exercise bouts executed at varying intensities induce a similar affective response during the recovery period when assessed at both the behavioral and psychophysiological levels. PMID- 20949856 TI - Bargaining with patriarchy: former female coaches' experiences and their decision to leave collegiate coaching. AB - The purpose of this study was to better understand the experiences of former female coaches and their decision to terminate their careers. A feminist perspective and mixed-methods (surveys and interviews) were used to allow for a richer understanding of their experiences. The survey findings, which included 121 former female coaches, suggest that time and family commitments were the main reasons they left coaching. Also, a small number (18%) left coaching for reasons such as opportunity for promotion. Six women from the survey sample were individually interviewed. Through a descriptive analytic strategy and indexing process (Creswell, 1998), three general themes emerged: (a) gender disparities in women's work, (b) technical demands of coaching, and (c) college coaching and normalized sexualities. Overall, the interview findings confirmed the open-ended responses on the survey and described gender discrimination, the centrality of male coaches, and rampant homophobia in U.S. collegiate coaching. In addition, some female coaches discussed perceptions of conflict between working as a coach and motherhood, or women with children as being "distracted" by motherhood. Collectively, the survey and interview results revealed that women have multiple, complex, and overlapping reasons for leaving collegiate coaching. PMID- 20949857 TI - Expert baseball batters have greater sensitivity in making swing decisions. PMID- 20949858 TI - Short-term effects of midseason coach turnover on team performance in soccer. PMID- 20949859 TI - Sustaining excellence. PMID- 20949860 TI - What is the essence of Christian nursing? PMID- 20949861 TI - What ever happened to missionary nursing? PMID- 20949862 TI - How can I give spiritual care to those with special needs? PMID- 20949863 TI - Working with the poor: doing good or do-gooder? PMID- 20949864 TI - Searching for greatness? PMID- 20949865 TI - Universal principles for culturally sensitive diabetic education. AB - Most nurses will not go to another county and provide healthcare education, but will care for patients from other countries and faiths who practice traditions that impact how they manage their illness. This author shares his experience in Mauritania, which provides an excellent example for understanding issues in cross cultural diabetic education. Universal principles for cross-cultural health education are offered. PMID- 20949866 TI - Domestic violence and the role of the parish nurse. AB - Domestic violence is physical, sexual, or psychological violence within intimate relationships. The identification of victims--adults, children, elders, males, or females-is problematic. Parish nurses are in an ideal position to identify and help those experiencing domestic violence. The Initial Domestic Violence Assessment Guideline (2010 J. Routson) provides parameters for the parish nurse to gather data and design helpful interventions. PMID- 20949867 TI - Exploring the compassionate care connection. AB - Although the word "compassion" is an integral component of nursing care, a clear conceptualization of the term is lacking. This article examines compassion from historical, biblical, and global perspectives; spiritual connections; and calls for research to help build our understanding of what compassion means and how to enter into other's suffering. PMID- 20949868 TI - Unexpected grace: a case study in prayer. AB - A nurse uses prayer as part of the therapeutic nursing intervention with a young mother in acute crisis and the patient outcome is unexpectedly changed. PMID- 20949869 TI - Christian nursing in a non-Christian country. AB - Reflecting on Christian nursing in a non-Christian country, a Chinese nurse shares about encouraging a mother of a sick child using the Bible. Christianity offers distinct contributions in nursing that non-Christian religions in China do not offer: an internalized and externalized God, opportunity for prayer, and Bible verses for any patient need. Insights are offered on how to use Scripture in nursing practice. PMID- 20949870 TI - The healing power of tears. PMID- 20949871 TI - TV nurses: promoting a positive image of nursing? AB - It's understood that medical dramas are meant to entertain, not serve as documentaries. Nevertheless, media-driven messages are powerful, influencing the culture and collective mindset. This article evaluates current images of nurses in the media and challenges nurses to engage in professional and public service designed to promote a positive media and public image of nursing. PMID- 20949872 TI - Master mentor and connoisseur coach: learn from the best! AB - Peer support can have a significant impact on nurse wellbeing and patient outcomes. Mentoring and coaching, elements of support, positively impact novice nurse development, staff satisfaction, and patient care. In this article, mentoring and coaching are explored and best practices identified from the ministries of Jesus and the Apostle Paul. PMID- 20949873 TI - Nurses go to war: a grandmother's tour of duty. PMID- 20949874 TI - Two-dimensional devotion. PMID- 20949875 TI - Significance of vascular endothelial growth factor expression in skin melanoma. AB - BACKGROUND/AIM: Melanoma is a heterogeneous disease of skin and mucous membranes which shows significant increase in incidence worldwide in the past decades. In the process of forming new blood vessels stimulators of angiogenesis participate. There is an increase production of vascular endothelial growth factor (VEGF-C and VEGF-D), which expression cause change of endothelial cells, and higher degree of tumor's aggressiveness. The aim of this research was to determine the level of VEGF expression in skin melanoma in different body regions and in different primary stages of the disease. METHODS: The research was conducted on bioptic materials of skin in 39 patients. On excision-made materials a routine histological preparation was done and following parameters were determined: histological type, alteration thickness (according to Breslow), Clark level, TNM (Tumor Nodus Metastasis) stage (pT), alteration width, thickness of lymphocytic infiltration in the tumor, mitotic index, phase of the tumor growth, presence of ulcerations, cellular type of the tumor, localization and level of VEGF expression. RESULTS: Analysis confirmed that 61.54% of skin melanoma showed a high VEGF expression. Nodular and acral lentiginous melanomas showed more frequently a high level of VEGF expression, while superficial spreading melanoma showed a lower level of VEGF expression (p = 0.032, p < 0.05). A higher level of expression was present in thicker melanomas (higher in the Breslow stage; p = 0.011, p < 0.05). The width of the lesion did not have an influence on the level of VEGF expression in melanoma (U =142.000, p = 0.273). CONCLUSION: Melanomas show a higher level of VEGF expression. Nodular and acral lentiginous types of melanoma show a high level of VEGF expression, while superficial spreading melanoma shows a lower level of VEGF expression. Melanomas in higher-stage disease (Breslow, Clark, pTNM) show a higher level of VEGF expression. PMID- 20949876 TI - Comparison between auditory steady-state responses and pure-tone audiometry. AB - BACKGROUND/AIM: A more recent method, the auditory steady-state response (ASSR), has become more and more important test method due to difference that was found in previous investigations between hearing thresholds determined by the ASSR and the pure-tone audiometry (PTA). The aim of this study was to evaluate the reliability of the ASSR in determining the frequency specific hearing thresholds by establishing a correlation between the thresholds determined by PTA, as well as to evaluate the reliability of ASSR in determining the hearing threshold with respect to the level of hearing loss and the configuration of the PTA findings. METHODS: The prospective study included 46 subjects (92 ears) which were assigned to groups based on their level of hearing loss and audiometric configuration. All the subjects underwent determination of hearing thresholds by PTA and ASSR without insight into their previously obtained PTA results. RESULTS: The overall sample differences between the ASSR and PTA thresholds were 4.1, 2.5, 4.4, and 4.2 dB at 0.5, 1, 2, and 4 kHz, respectively. A high level of correlation was achieved in groups with different configurations of PTA findings. The correlation coefficients between the hearing thresholds determined by ASSR and PTA were significant in subjects with all levels of hearing loss. The differences between hearing thresholds determined by ASSR and PTA were less than 10 dB in 85% of subjects (ranging from 4 dB for moderately severe hearing loss to 7.2 dB for normal hearing). CONCLUSION: The ASSR is an excellent complementary method for the determination of hearing thresholds at the 4 carrier frequencies, as well as determination of the level of hearing loss and the audiometric configuration. PMID- 20949877 TI - Ethics and deontology in forensic medicine. PMID- 20949879 TI - Acupuncture for chronic back pain: what level of evidence? PMID- 20949880 TI - HIV testing: removing barriers can lead to earlier detection and reduced transmission. PMID- 20949882 TI - Translating a guideline into practice: The USPSTF recommendations on screening for depression in adults. PMID- 20949884 TI - Anterior cruciate ligament injury: diagnosis, management, and prevention. AB - There are an estimated 80,000 to 100,000 anterior cruciate ligament (ACL) repairs in the United States each year. Most ACL tears occur from noncontact injuries. Women experience ACL tears up to nine times more often than men. Evaluation of the ACL should be performed immediately after an injury if possible, but is often limited by swelling and pain. When performed properly, a complete knee examination is more than 80 percent sensitive for an ACL injury. The Lachman test is the most accurate test for detecting an ACL tear. Magnetic resonance imaging is the primary study used to diagnose ACL injury in the United States. It can also identify concomitant meniscal injury, collateral ligament tear, and bone contusions. Treatment consists of conservative management or surgical intervention, with the latter being the better option for patients who want to return to a high level of activity. Patients who undergo surgery must commit to appropriate rehabilitation for the best outcome. Long-term sequelae of ACL injury include knee osteoarthritis in up to 90 percent of patients. Primary prevention of ACL injury includes specific proprioceptive and neuromuscular training exercises to improve knee stability. PMID- 20949885 TI - ACL Injuries. PMID- 20949886 TI - Postpartum major depression. AB - Postpartum major depression is a disorder that is often unrecognized and must be distinguished from "baby blues." Antenatal depressive symptoms, a history of major depressive disorder, or previous postpartum major depression significantly increase the risk of postpartum major depression. Screening with the Edinburgh Postnatal Depression Scale may be appropriate. Some women with postpartum major depression may experience suicidal ideation or obsessive thoughts of harming their infants, but they are reluctant to volunteer this information unless asked directly. Psychotherapy or selective serotonin reuptake inhibitors may be used to treat the condition. In patients with moderate to severe postpartum major depression, psychotherapy may be used as an adjunct to medication. No evidence suggests that one antidepressant is superior to others. Antidepressants vary in the amount secreted into breast milk. If left untreated, postpartum major depression can lead to poor mother-infant bonding, delays in infant growth and development, and an increased risk of anxiety or depressive symptoms in the infant later in life. PMID- 20949887 TI - Postpartum depression. PMID- 20949888 TI - Common types of supraventricular tachycardia: diagnosis and management. AB - The most common types of supraventricular tachycardia are caused by a reentry phenomenon producing accelerated heart rates. Symptoms may include palpitations (pulsation in the neck), chest pain, lightheadedness or dizziness, and dyspnea. It is unusual for supraventricular tachycardia to be caused by structurally abnormal hearts. Diagnosis is often delayed because of the misdiagnosis of anxiety or panic disorder. Patient history is important in uncovering the diagnosis, whereas the physical examination may or may not be helpful, and usually necessitates use of a Holter monitor or an event recorder to capture the arrhythmia and confirm a diagnosis. Treatment consists of short-term or as needed pharmacotherapy using calcium channel or beta blockers when vagal maneuvers fail to halt or slow the rhythm. In those who require long-term pharmacotherapy, atrioventricular nodal blocking agents or class IC or III antiarrhythmics can be used; however, these agents should generally be managed by a cardiologist. Catheter ablation is an option in patients with persistent or recurrent supraventricular tachycardia who are unable to tolerate long-term pharmacologic management. If Wolff-Parkinson-White syndrome is present, expedient referral to a cardiologist is warranted because ablation is a potentially curative option. PMID- 20949889 TI - Supraventricular tachycardia. PMID- 20949890 TI - Radiologic evaluation of chronic neck pain. AB - For many years, there were no guidelines for evaluating patients with chronic neck pain. However, in the past 15 years, considerable research has led to recommendations regarding whiplash-associated disorders. This article summarizes the American College of Radiology Appropriateness Criteria for chronic neck pain. Imaging plays an important role in evaluating patients with chronic neck pain. Five radiographic views (anteroposterior, lateral, open-mouth, and both oblique views) are recommended for all patients with chronic neck pain with or without a history of trauma. Magnetic resonance imaging should be performed in patients with chronic neurologic signs or symptoms, regardless of radiographic findings. The role of magnetic resonance imaging in evaluating ligamentous and membranous abnormalities in persons with whiplash-associated disorders is controversial. If there is a contraindication to magnetic resonance imaging, computed tomography myelography is recommended. Patients with normal radiographic findings and no neurologic signs or symptoms, or patients with radiographic evidence of spondylosis and no neurologic findings, need no further imaging studies. PMID- 20949891 TI - Right-sided cardiophrenic mass in an older woman. PMID- 20949894 TI - Screening for depression in adults. PMID- 20949895 TI - Sunscreen use for skin cancer prevention. PMID- 20949898 TI - A sol-gel-derived acetylcholinesterase microarray for nanovolume small-molecule screening. AB - A fluorimetric acetylcholinesterase (AChE) assay was developed and characterized both in solution and with the enzyme entrapped in sol-gel-derived silica. The assay is based on a disulfide-thiol interchange reaction between the intramolecularly quenched dimeric dye BODIPY FL l-cystine and thiocholine generated by the AChE-catalyzed hydrolysis of acetylthiocholine (ATCh), which results in a brightly fluorescent monomeric product owing to the cleavage of the disulfide-coupled form of the dye. The new assay was validated by comparison with the Ellman assay performed under parallel conditions and was used in both kinetic and end point assays. The assay was extended to the fabrication of functional AChE microarrays using contact pin-printing of sol-gel-derived silica. A total of 392 sol-gel formulations were screened for gelation times and 192 of these were further evaluated for array fabrication on four different surfaces using a factor analysis approach. Of these, 66 sol-gel/surface combinations produced robust microarrays, while 26 sol-gel/surface combinations were identified that could produce highly active AChE microarrays. The Z' factor for the on-array assay using an optimal sol-gel/surface combination, which considers both signal variability and difference in signals between positive and negative controls, was determined to be 0.60, which is above the minimum level required for applicability to screening. By overprinting nanoliter volumes of solutions containing the dye, ATCh, and potential inhibitors, these microarrays could be used to screen two libraries of small molecules, one composed of newly synthesized alkaloids and another consisting of ~1000 known bioactive compounds, both as discrete compounds and mixtures thereof, for activity against AChE. IC(50) values were obtained on microarrays for compounds showing significant inhibitory activity, demonstrating the utility of arrays for quantitative inhibition assays. PMID- 20949899 TI - Parallel electrophoretic analysis of segmented samples on chip for high throughput determination of enzyme activities. AB - Capillary electrophoresis (CE) on microfabricated structures has achieved impressive sample throughput by combining fast separation speed and parallel operations. One obstacle to further increasing throughput has been lack of methods for loading and injecting individual samples at a rate that matches analysis speed. To address this issue, we have developed a microfluidic device in which samples stored as nanoliter volume plugs segmented by a fluorocarbon oil are introduced sequentially to an array of three electrophoresis channels. A microfluidic interface consisting of patterned surface chemistry and geometric restriction was used to extract samples from each segmented flow channel and transfer to the respective electrophoresis channel for separation. Fluorescence detection was achieved by imaging the chip using a fluorescence microscope equipped with a charge-coupled device. Characterization of the system shows that injection volume is controlled by sample plug volume, flow rate during introduction, and voltage applied to the electrophoresis channel. The system was tested for a GTPase assay. Peak area ratios of enzyme product and internal standard had 6% relative standard deviations. Cross-contamination between peaks was 7%. Throughput of 120 samples in 10 min was achieved. Further development of the system may allow application to high-throughput applications such as drug screening. PMID- 20949900 TI - Relationships between water wettability and ice adhesion. AB - Ice formation and accretion may hinder the operation of many systems critical to national infrastructure, including airplanes, power lines, windmills, ships, and telecommunications equipment. Yet despite the pervasiveness of the icing problem, the fundamentals of ice adhesion have received relatively little attention in the scientific literature and it is not widely understood which attributes must be tuned to systematically design "icephobic" surfaces that are resistant to icing. Here we probe the relationships between advancing/receding water contact angles and the strength of ice adhesion to bare steel and twenty-one different test coatings (~200-300 nm thick) applied to the nominally smooth steel discs. Contact angles are measured using a commercially available goniometer, whereas the average strengths of ice adhesion are evaluated with a custom-built laboratory scale adhesion apparatus. The coatings investigated comprise commercially available polymers and fluorinated polyhedral oligomeric silsesquioxane (fluorodecyl POSS), a low-surface-energy additive known to enhance liquid repellency. Ice adhesion strength correlates strongly with the practical work of adhesion required to remove a liquid water drop from each test surface (i.e., with the quantity [1 + cos theta(rec)]), and the average strength of ice adhesion was reduced by as much as a factor of 4.2 when bare steel discs were coated with fluorodecyl POSS-containing materials. We argue that any further appreciable reduction in ice adhesion strength will require textured surfaces, as no known materials exhibit receding water contact angles on smooth/flat surfaces that are significantly above those reported here (i.e., the values of [1 + cos theta(rec)] reported here have essentially reached a minimum for known materials). PMID- 20949901 TI - Preparation of covalently functionalized graphene using residual oxygen containing functional groups. AB - When fabricated by thermal exfoliation, graphene can be covalently functionalized more easily by applying a direct ring-opening reaction between the residual epoxide functional groups on the graphene and the amine-bearing molecules. Investigation by X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and transmission electron microscopy (TEM) all confirm that these molecules were covalently grafted to the surface of graphene. The resulting dispersion in an organic solvent demonstrated a long-term homogeneous stability of the products. Furthermore, comparison with traditional free radical functionalization shows the extent of the defects characterized by TEM and Raman spectroscopy and reveals that direct functionalization enables graphene to be covalently functionalized on the surface without causing any further damage to the surface structure. Thermogravmetric analysis (TGA) shows that the nondestroyed graphene structure provides greater thermal stability not only for the grafted molecules but also, more importantly, for the graphene itself, compared to the free-radical grafting method. PMID- 20949902 TI - Flash-quench technique employed to study the one-electron reduction of triiodide in acetonitrile: evidence for a diiodide reaction product. AB - The one-electron reduction of triiodide (I(3)(-)) by a reduced ruthenium polypyridyl compound was studied in an acetonitrile solution with the flash quench technique. Reductive quenching of the metal-to-ligand charge-transfer excited state of [Ru(II)(deeb)(3)](2+) by iodide generated the reduced ruthenium compound [Ru(II)(deeb(-))(deeb)(2)](+) and diiodide (I(2)(*-)). The subsequent reaction of [Ru(II)(deeb(-))(deeb)(2)](+) with I(3)(-) indicated that I(2)(*-) was a product that appeared with a second-order rate constant of (5.1 +/- 0.2) * 10(9) M(-1) s(-1). After correction for diffusion and some assumptions, Marcus theory predicted a formal potential of -0.58 V (vs SCE) for the one-electron reduction of I(3)(-). The relevance of this reaction to solar energy conversion is discussed. PMID- 20949903 TI - Preparation and bifunctional gas sensing properties of porous In2O3-CeO2 binary oxide nanotubes. AB - The porous binary In(2)O(3)-CeO(2) oxides nanotubes (NTs) in cubic phase were first fabricated by electrospinning (ESP) method and characterized by SEM, TEM, XRD, XPS and UV-vis absorption techniques. By adjusting the In(2)O(3) and CeO(2) molar ratio, the out diameters and wall thicknesses of the final composites were tuned ranging of 90-180 nm and 15-9 nm, respectively. The band gap of the binary oxides gradually decreases, and the ratio of Ce(3+) to Ce(4+) increases with the increase of CeO(2), implying that surface oxygen vacancies gradually increase. The gas sensing test reveals that when the content of CeO(2) is appropriate, the as fabricated In(2)O(3)-CeO(2) NTs could be bifunctional gas sensors to detect H(2)S at low temperature(25-110 degrees C) while acetone at relative high temperature (300 degrees C). The In(75)Ce(25) NTs sensor is an optimum one, which exhibits the highest response of 498 to H(2)S at 80 degrees C and the highest response of 30 to acetone at 300 degrees C. In contrast to the pure In(2)O(3) sensor, the response and recovery times, as well as the sensing reaction barrier height, for In(75)Ce(25) both degrade considerably. The above temperature-dependent sensing properties were attributed to two different gas sensing mechanisms, sulfuration at low temperature and adsorption at high temperature. PMID- 20949904 TI - Formation of diaryl telluroxides and tellurones by photosensitized oxygenation of diaryl tellurides. AB - Aerobic oxygenation of diaryl tellurides under photosensitized conditions is investigated. Unlike Ph(2)S and Ph(2)Se, reaction of diaryl tellurides with singlet oxygen proceeds smoothly to yield diaryl telluroxides and the corresponding tellurones. The product distribution is largely affected by the substrate and the reaction conditions. In particular, the photooxygenation of bulky diaryl tellurides principally produces tellurones. The results of a series of trapping experiments suggest that the diaryl telluroxides can capture transient intermediates such as Me(2)S(+)OO(-) and Ar(2)Te(+)OO(-), generated in the singlet oxygen oxidation of chalcogenides, to yield diaryl tellurones, and therefore it may be the most potent precursors of the tellurones. PMID- 20949906 TI - Pyrene excimer-based calix[4]arene FRET chemosensor for mercury(II). AB - A novel calix[4]arene derivative locked in the 1,3-alternate conformation (2) bearing two pyrene and rhodamine fluorophores was synthesized as a selective sensor for the Hg(2+) ion. The sensoring is based on FRET from pyrene excimer emissions to ring-opened rhodamine absorption upon complexation of the Hg(2+) ion. Addition of Hg(2+) to a mixed solution of 2 gave significantly enhanced fluorescence at ~576 nm via FRET with excitation at 343 nm. We also found that the pyrene excimer emissions formed by the intramolecular pi-pi interactions are more effective in obtaining strong FRET bands than those by intermolecular pi-pi interactions. PMID- 20949905 TI - Coordination-driven self-assembly of truncated tetrahedra capable of encapsulating 1,3,5-triphenylbenzene. AB - The design and synthesis of coordinative truncated tetrahedra is described. The coordination-driven self-assembly of a truncated tetrahedron was achieved using 90 degrees organoplatinum acceptors and a hexapyridyl ligand with six-fold symmetry under mild conditions. This tetrahedron can act as a host toward 1,3,5 triphenylbenzene. The truncated tetrahedral structures and the host-guest complex were identified using multinuclear ((31)P and (1)H) NMR spectroscopy, electrospray ionization mass spectrometry, X-ray crystallography, and pulsed field-gradient spin-echo NMR, along with computational simulations. PMID- 20949907 TI - First-principles prediction of the pK(a)s of anti-inflammatory oxicams. AB - The gas- and aqueous-phase acidities of a series of oxicams have been computed by combining M05-2X/6-311+G(3df,2p) gas-phase free energies with solvation free energies from the CPCM-UAKS, COSMO-RS, and SMD solvent models. To facilitate accurate gas-phase calculations, a benchmarking study was further carried out to assess the performance of various density functional theory methods against the high-level composite method G3MP2(+). Oxicams are typically diprotic acids, and several tautomers are possible in each protonation state. The direct thermodynamic cycle and the proton exchange scheme have been employed to compute the microscopic pK(a)s on both solution- and gas-phase equilibrium conformers, and these were combined to yield the macroscopic pK(a) values. Using the direct cycle of pK(a) calculation, the CPCM-UAKS model delivered reasonably accurate results with MAD ~ 1, whereas the SMD and COSMO-RS models' performance was less satisfactory with MAD ~ 3. Comparison with experiment also indicates that direct cycle calculations based on solution conformers generally deliver better accuracy. The proton exchange cycle affords further improvement for all solvent models through systematic error cancellation and therefore provides better reliability for the pK(a) prediction of compounds of these types. The latter approach has been applied to predict the pK(a)s of several recently synthesized oxicam derivatives. PMID- 20949908 TI - Characterization and comparison of two binding sites on obscurin for small ankyrin 1. AB - Obscurin A, an ~720 kDa modular protein of striated muscles, binds to small ankyrin 1 (sAnk1, Ank 1.5), an integral protein of the sarcoplasmic reticulum, through two distinct carboxy-terminal sequences, Obsc(6316-6436) and Obsc(6236 6260). We hypothesized that these sequences differ in affinity but that they compete for the same binding site on sAnk1. We show that the sequence within Obsc(6316-6436) that binds to sAnk1 is limited to residues 6316-6345. Comparison of Obsc(6231-6260) to Obsc(6316-6345) reveals that Obsc(6316-6345) binds sAnk1 with an affinity (133 +/- 43 nM) comparable to that of the Obsc(6316-6436) fusion protein, whereas Obsc(6231-6260) binds with lower affinity (384 +/- 53 nM). Oligopeptides of each sequence compete for binding with both sites at half maximal inhibitory concentrations consistent with the affinities measured directly. Five of six site-directed mutants of sAnk1 showed similar reductions in binding to each binding site on obscurin, suggesting that they dock to many of the same residues of sAnk1. Circular dichroism (CD) analysis of the synthetic oligopeptides revealed a 2-fold greater alpha-helical content in Obsc(6316-6346), ~35%, than Obsc(6231-6260,) ~17%. Using these data, structural prediction algorithms, and homology modeling, we predict that Obsc(6316-6345) contains a bent alpha-helix of 12 amino acids, flanked by short disordered regions, and that Obsc(6231-6260) has a short, N-terminal alpha-helix of 4-5 residues followed by a long disordered region. Our results are consistent with a model in which both sequences of obscurin differ significantly in structure but bind to the ankyrin like repeat motifs of sAnk1 in a similar though not identical manner. PMID- 20949910 TI - Conjugates of a novel 7-substituted camptothecin with RGD-peptides as alpha(v)beta3 integrin ligands: An approach to tumor-targeted therapy. AB - Eight conjugates of a novel camptothecin derivative (Namitecan, NMT) with RGD peptides have been synthesized and biologically evaluated. This study focused on factors that optimize the drug linkage to the transport vector. The different linkages investigated consist of heterofunctional glycol fragments and a lysosomally cleavable peptide. The linkage length and conformation were systematically modified with the purpose to understand their effect on receptor affinity, systemic stability, cytotoxicity, and solubility of the corresponding conjugates. Among the new conjugates prepared, C6 and C7 showed high receptor affinity and tumor cell adhesion, acceptable stability in murine blood, and high cytotoxic activity (IC50 = 8 nM). The rationale, synthetic strategy, and preliminary biological results will be presented. PMID- 20949909 TI - Self-protecting bactericidal titanium alloy surface formed by covalent bonding of daptomycin bisphosphonates. AB - Infections are a devastating complication of titanium alloy orthopedic implants. Current therapy includes antibiotic-impregnated bone cement and antibiotic containing coatings. We hypothesized that daptomycin, a Gram-positive peptide antibiotic, could prevent bacterial colonization on titanium alloy surfaces if covalently bonded via a flexible, hydrophilic spacer. We designed and synthesized a series of daptomycin conjugates for bonding to the surface of 1.0 cm2 Ti6Al4V foils through bisphosphonate groups, reaching a maximum yield of 180 pmol/cm2. Daptomycin-bonded foils killed 53 +/- 5% of a high challenge dose of 3 * 105 cfu Staphylococcus aureus ATCC 29213. PMID- 20949911 TI - Alternative routes for dissemination of Legionella pneumophila causing three outbreaks in Norway. AB - Three outbreaks of Legionnaires' disease were reported in the Fredrikstad/Sarpsborg community, Norway, in 2005 and 2008 caused by the L. pneumophila ST15 and ST462 strains determined by sequence based typing. In this retrospective study, we suggest that the aeration ponds, a part of the biological treatment plant at Borregaard Ind. Ltd., are the main amplifiers and primary disseminators of the outbreak L. pneumophila strains. This result is supported by the finding that the ST15 and ST462 strains were not able to survive in air scrubber liquid media more than two days of incubation at the scrubber's operating conditions during the 2005 and 2008 outbreaks. In 2008, >1010 CFU/L of L. pneumophila ST462 were detected in the aeration ponds. ST15 and ST462 were also detected in the river Glomma in 2005 and 2008, respectively, downstream of the wastewater outlet from the treatment plant (105CFU/L). These findings strongly suggest that the presence of L. pneumophila in the river is due to the release of wastewater from the industrial aeration ponds, demonstrating that the river Glomma may be an additional disseminator of L. pneumophila during the outbreaks. This work emphasizes the need for preventive actions against the release of wastewater containing human pathogens to the environment. PMID- 20949912 TI - Beach boundary layer: a framework for addressing recreational water quality impairment at enclosed beaches. AB - Nearshore waters in bays, harbors, and estuaries are frequently contaminated with human pathogens and fecal indicator bacteria. Tracking down and mitigating this contamination is complicated by the many point and nonpoint sources of fecal pollution that can degrade water quality along the shore. From a survey of the published literature, we propose a conceptual and mathematical framework, the "beach boundary layer model", for understanding and quantifying the relative impact of beach-side and bay-side sources of fecal pollution on nearshore water quality. In the model, bacterial concentration in ankle depth water C(ankle) [bacteria L(-3)] depends on the flux m'' [bacteria L(-2) T(-1)] of fecal bacteria from beach-side sources (bather shedding, bird and dog feces, tidal washing of sediments, decaying vegetation, runoff from small drains, and shallow groundwater discharge), a cross-shore mass transfer velocity k [L T(-1)] that accounts for the physics of nearshore transport and mixing, and a background concentration C(bay) [bacteria L(-3)] attributable to bay-side sources of pollution that impact water quality over large regions (sewage outfalls, creeks and rivers): C(ankle) = m''/k + C(bay). We demonstrate the utility of the model for identifying risk factors and pollution sources likely to impact shoreline water quality, and evaluate the model's underlying assumptions using computational fluid dynamic simulations of flow, turbulence, and mass transport in a trapezoidal channel. PMID- 20949914 TI - Development of a colloidal lithography method for patterning nonplanar surfaces. AB - A colloidal lithography method has been developed for patterning nonplanar surfaces. Hexagonal noncontiguously packed (HNCP) colloidal particles 127 nm-2.7 MUm in diameter were first formed at the air-water interface and then adsorbed onto a substrate coated with a layer of polymer adhesive ~17 nm thick. The adhesive layer plays the critical role of securing the order of the particles against the destructive lateral capillary force generated by a thin film of water after the initial transfer of the particles from the air-water interface. The soft lithography method is robust and very simple to carry out. It is applicable to a variety of surface curvatures and for both inorganic and organic colloidal particles. PMID- 20949913 TI - Covalent immobilization of protein onto a functionalized hydrogenated diamond like carbon substrate. AB - Hydrogenated diamond-like carbon (HDLC) has an atomically smooth surface that can be deposited on high-surface area substrata and functionalized with reactive chemical groups, providing an ideal substrate for protein immobilization. A synthetic sequence is described involving deposition and hydrogenation of DLC followed by chemical functionalization. These functional groups are reacted with amines on proteins causing covalent immobilization on contact. Raman measurements confirm the presence of these surface functional groups, and Fourier transform infrared spectroscopy (FTIR) confirms covalent protein immobilization. Atomic force microscopy (AFM) of immobilized proteins is reproducible because proteins do not move as a result of interactions with the AFM probe-tip, thus providing an advantage over mica substrata typically used in AFM studies of protein. HDLC offers many of the same technical advantages as oxidized graphene but also allows for coating large surface areas of biomaterials relevant to the fabrication of medical/biosensor devices. PMID- 20949915 TI - Penasins A-E, long-chain cytotoxic sphingoid bases, from a marine sponge Penares sp. AB - Five sphingoid bases, penasin A (1), penasin B (2), and a mixture of penasins C-E (3-5), were identified from a marine sponge Penares sp. as cytotoxic constituents. The structure of the common polar head part was assigned by analysis of the NMR data, whereas the structures of the long aliphatic chains including the locations of double bond(s) and a branched methyl group were determined by analysis of tandem FABMS and (13)C NMR data together with the GC-MS analysis of ozonolysis products. The absolute configuration of the headgroup was defined for the mixture of 3-5 by the modified Mosher method. Penasins exhibit moderate cytotoxicity against HeLa and P388 cells. PMID- 20949916 TI - Structure and cytotoxicity of diterpenoids from Isodon eriocalyx. AB - A new ent-atisanoid, eriocatisin A (1), six new ent-abietanoids, eriocasins B-E (2-4, 7), 3-acetyleriocasin C (5), and 3beta-acetoxyeriocasin D (6), and seven new ent-kauranoids, maoesins A-F (8, 10-14) and 3alpha-acetoxy-maoesin A (9), together with 21 known compounds, were isolated from the aerial parts of Isodon eriocalyx. The structures of 1-14 were determined by spectroscopic data interpretation. All compounds isolated were evaluated for their in vitro growth inhibitory activity against the HT-29, BEL-7402, and SK-OV-3 human cancer cell lines. Compounds 17, 18, and 20 showed inhibitory effects for all three tumor cell lines used, with IC(50) values in the range 2.1-7.3 MUM. PMID- 20949917 TI - pH-dependent toxicity of high aspect ratio ZnO nanowires in macrophages due to intracellular dissolution. AB - High-aspect ratio ZnO nanowires have become one of the most promising products in the nanosciences within the past few years with a multitude of applications at the interface of optics and electronics. The interaction of zinc with cells and organisms is complex, with both deficiency and excess causing severe effects. The emerging significance of zinc for many cellular processes makes it imperative to investigate the biological safety of ZnO nanowires in order to guarantee their safe economic exploitation. In this study, ZnO nanowires were found to be toxic to human monocyte macrophages (HMMs) at similar concentrations as ZnCl(2). Confocal microscopy on live cells confirmed a rise in intracellular Zn(2+) concentrations prior to cell death. In vitro, ZnO nanowires dissolved very rapidly in a simulated body fluid of lysosomal pH, whereas they were comparatively stable at extracellular pH. Bright-field transmission electron microscopy (TEM) showed a rapid macrophage uptake of ZnO nanowire aggregates by phagocytosis. Nanowire dissolution occurred within membrane-bound compartments, triggered by the acidic pH of the lysosomes. ZnO nanowire dissolution was confirmed by scanning electron microscopy/energy-dispersive X-ray spectrometry. Deposition of electron-dense material throughout the ZnO nanowire structures observed by TEM could indicate adsorption of cellular components onto the wires or localized zinc-induced protein precipitation. Our study demonstrates that ZnO nanowire toxicity in HMMs is due to pH-triggered, intracellular release of ionic Zn(2+) rather than the high-aspect nature of the wires. Cell death had features of necrosis as well as apoptosis, with mitochondria displaying severe structural changes. The implications of these findings for the application of ZnO nanowires are discussed. PMID- 20949919 TI - Cluster analysis and artificial neural networks multivariate classification of onion varieties. AB - Eight cultivars of different colored onions (white, golden, and red) were evaluated for fresh bulbs cultivated and grown under the same environmental and agronomical conditions. Cluster analysis and principal component analysis, based on different flavonoids, total phenols, and pungency, data showed that the onions were not clustered according to variety (genetic similarity degree), whereas the color was the variable with the highest influence, ranging between 50 and 70%. Artificial neural networks were applied to study the possibility of discriminating among onion varieties. Characterization of the onion according to variety and procedence of the seeds was around 95-100%. Samples belonging to the Carrizal Alto procedence had an incorrect classification for 25% of the data. PMID- 20949918 TI - Process for coproduction of crude immunoglobulin y and high-density lipoproteins from hen egg yolk. AB - High value-added products from hen egg are receiving increasing attention from both egg academic and industrial circles due to their potential applications in research and medicine as well as the benefits they bring to egg-breaking industries. This paper reports a simple method for the preparation of immunoglobulin Y (IgY) and high-density lipoproteins (HDL) from hen egg yolk. A water dilution method coupled with (NH4)2SO4 precipitation was employed to prepare the two target proteins. SDS-PAGE under reducing or nonreducing conditions and liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) were used to characterize the two products. Western blotting and histobiochemical staining were utilized to qualitatively analyze IgY and HDL, respectively. The purities of prepared IgY and HDL were detected by ELISA and a direct high-density lipoprotein-cholesterol assay, respectively. Results show that dilution times 15 makes IgY and HDL separate well from each other. Western blotting proves IgY has an immunocompetence similar to that of human IgG. Histobiochemical staining shows HDL is composed of sugar, lipid, and protein. The quantitative evaluation of the products indicates that approximately 3 kg of IgY and 2 kg of HDL with purities of 72.7 and 71.9%, respectively, are available from 1 ton of shell eggs via this process. PMID- 20949920 TI - Palladium-catalyzed reductive ortho-arylation: evidence for the decomposition of 1,2-dimethoxyethane and subsequent arylpalladium(II) reduction. AB - A palladium-catalyzed crossed biaryl coupling/reduction sequence enables the formation of meta-substituted biaryls via solvent-mediated arylpalladium(II) reduction. Isotope labeling studies determined that the decomposition of 1,2 dimethoxyethane (DME) is indeed involved in the reductive process. PMID- 20949921 TI - Analysis of phthalate migration from plastic containers to packaged cooking oil and mineral water. AB - The migration of phthalates (PAEs), a class of typical environmental estrogen contaminants in food, from food packaging to packaged food attracts more and more attention worldwide. Many factors will affect the migration processes. The purpose of this study was to evaluate PAE migration from plastic containers to cooking oil and mineral water packed in authentic commercial packaging and stored under various conditions (different storage temperatures, contact times, and storage states (static or dynamic state)) and to identify a potential relationship between the amount and type of PAEs migrated and the lipophilic character of the food matrix. The samples were analyzed by a novel method of liquid chromatography combined with solid-phase extraction by an electrospun nylon 6 nanofibers mat, with PAE detection limits of 0.001 MUg/L in mineral water and 0.020 MUg/L in cooking oil, respectively. The results demonstrated that the cooking oil was a more suitable medium for the migration of PAEs from packages into foodstuffs than mineral water. Scilicet, the migration potential of the PAEs into foodstuffs, depends on the lipophilic characteristics of the food matrix. The results also demonstrated that migrations were more significant at higher temperature, longer contact time, and higher dynamic frequency; thus, the migration tests should be evaluated with consideration of different storage temperatures and contact times. Mathematical models with good logarithmic relationships were established to demonstrate the relationship between the PAE migration and food/packaging contact time for different storage temperatures. These established mathematical models would be expected to become a set of practical tools for the prediction of PAE migration. PMID- 20949923 TI - Template-assisted fabrication of magnetically responsive hollow titania capsules. AB - This study reports on the fabrication of magnetically responsive hollow titania capsules by confining the superparamagnetic Fe(3)O(4) nanoparticles within a hollow and porous titania (TiO(2)) shell. The employed protocol involves precipitation of titania shell on the magnetite (Fe(3)O(4)) encapsulated polystyrene beads followed by the calcination of resulting composite particles at elevated temperature. Scanning electron microscopy and transmission electron microscopy reveal the presence of a thick, complete but irregular titania shell on the magnetic polystyrene beads after the templating process. Electron energy loss mapping image analysis has been employed to investigate the spatial distribution of titania and magnetite phases of magnetic hollow titania capsules (MHTCs). Magnetic characterization indicates that both titania-coated magnetic polystyrene beads (TMPBs) and MHTCs are superparamagnetic in nature with the saturated magnetizations of 5.6 and 8.1 emu/g, respectively. X-ray diffraction (XRD) analysis reveals that titania shell of these capsules is composed of photoactive anatase phase. Nitrogen adsorption-desorption analysis has been employed to estimate the specific surface area and the average pore diameter of the fabricated hollow structures. Photocatalytic activity of the fabricated MHTCs for the photodegradation of rhodamine 6G dye has been demonstrated and compared with that of bulk titania nanoparticles. PMID- 20949922 TI - Global proteome quantification for discovering imatinib-induced perturbation of multiple biological pathways in K562 human chronic myeloid leukemia cells. AB - Imatinib mesylate, currently marketed by Novartis as Gleevec in the U.S., has emerged as the leading compound to treat the chronic phase of chronic myeloid leukemia (CML), through its inhibition of Bcr-Abl tyrosine kinases, and other cancers. However, resistance to imatinib develops frequently, particularly in late-stage disease. To identify new cellular pathways affected by imatinib treatment, we applied mass spectrometry together with stable isotope labeling by amino acids in cell culture (SILAC) for the comparative study of protein expression in K562 cells that were untreated or treated with a clinically relevant concentration of imatinib. Our results revealed that, among the 1344 quantified proteins, 73 had significantly altered levels of expression induced by imatinib and could be quantified in both forward and reverse SILAC labeling experiments. These included the down-regulation of thymidylate synthase, S adenosylmethionine synthetase, and glycerol-3-phosphate dehydrogenase as well as the up-regulation of poly(ADP-ribose) polymerase 1, hemoglobins, and enzymes involved in heme biosynthesis. We also found, by assessing alteration in the acetylation level in histone H4 upon imatinib treatment, that the imatinib induced hemoglobinization and erythroid differentiation in K562 cells are associated with global histone H4 hyperacetylation. Overall, these results provided potential biomarkers for monitoring the therapeutic intervention of CML using imatinib and offered important new knowledge for gaining insight into the molecular mechanisms of action of imatinib. PMID- 20949924 TI - Desorption corona beam ionization coupled with a poly(dimethylsiloxane) substrate: broadening the application of ambient ionization for water samples. AB - Current direct analysis methods in mass spectrometry (MS) are predominantly focused on desorbing and ionizing samples in the solid phase. Some sampling difficulties are associated with liquid (solution) or gas samples. The present study has expanded direct MS analysis to solution samples by using the desorption corona beam ionization (DCBI) technique in combination with poly(dimethylsiloxane) (PDMS) substrate sampling. Typically, the PDMS substrate is dipped in water for microextraction of pesticide compounds and then is transferred to an MS ion source for desorption and ionization. This approach improves the detection limit for DCBI and allows more organic compounds in complex mixtures to be identified within seconds. The practical application of this device is demonstrated by identifying five pesticides (acephate, isoprocarb, dimethoate, dichlorvos, and dicofol) in water. The obtained detection limits of pesticides are 1 MUg/L, the measured dynamic ranges are 3 orders of magnitude, the calculated correlation coefficients are between 0.939 and 0.979 at concentration levels of 5-5000 MUg/L, and the repeatabilities defined as a relative standard deviation of five successive injections are in the range of 13 17%. The results indicate that the DCBI technique coupled with PDMS sampling is an excellent method for the analysis of organic pesticides in solution, and it also opens up a new avenue for direct MS studies of solution samples with general importance. PMID- 20949925 TI - Localized high resolution electrochemistry and multifunctional imaging: scanning electrochemical cell microscopy. AB - We describe highly localized electrochemical measurements and imaging using a simple, mobile theta pipet cell. Each channel (diameter <500 nm) of a tapered theta pipet is filled with electrolyte solution and a Ag/AgCl electrode, between which a bias is applied, resulting in a conductance current across a thin meniscus of solution at the end of the pipet, which is typically deployed in air or a controlled gaseous environment. When the position of the pipet normal to a surface of interest is oscillated, an oscillating component in the conductance current is generated when the meniscus at the end of the probe comes into contact with the surface and undergoes periodic (reversible) deformation, so as to modulate the solution resistance. This oscillating current component can be used to maintain gentle contact of the solution from the pipet cell with the surface and as a set point for high resolution topographical imaging with the pipet. Simultaneously, the mean conductance current that flows between the pipet channels can be measured and is sensitive to the local nature of the interface, informing one, for example, on wettability and ion flow into or out of the surface investigated. Furthermore, conductor or semiconductor surfaces can be connected as a working electrode, with one of the electrodes in the pipet serving as a quasi-reference electrode. This pipet cell then constitutes part of a dynamic electrochemical cell, with which direct voltammetric-amperometric imaging can be carried out simultaneously with conductance and topographical imaging. This provides multifunctional electrochemical maps of surfaces and interfaces at high spatial resolution. The prospects for the use of this new methodology widely are highlighted through exemplar studies and a brief discussion of future applications. PMID- 20949926 TI - A new high-pressure polar phase of crystalline bromoform: a first-principles study. AB - The high-pressure phases of bromoform at zero temperature have been investigated by first-principles pseudopotential plane-wave calculations based on the density functional theory. A new high-pressure polar phase, epsilon, with space group CC has been found after a series of simulated annealing and geometry optimizations. Our calculated enthalpies showed that the transition from beta phase to gamma phase occurs at 1 GPa, then the gamma phase transforms to the epsilon phase at 90 GPa. In addition, the Br...Br and C-H...Br interactions are the key factors for the polar aggregation in the epsilon phase. Further calculations show that the insulate-metal transition in epsilon phase due to band overlap happens at ~130 GPa. PMID- 20949927 TI - Metallopolymer capacitor in "one pot" by self-directed UV-assisted process. AB - Silver metalized methacrylate films are prepared by single-step UV curing process with good conductivity on both sides. The major component of the composite is Bisphenol A ethoxylate dimethacrylate, which can be photopolymerized by a photoreactive initiator under UV light. Under the same conditions of UV irradiation, silver ions are deposited as metal nanoparticles while the pyrrole is oxidized to polypyrrole. The migration of silver ions and pyrrole toward both surfaces during polymerization leads to the formation of a metallo-polymer capacitor. The composite films are characterized by SEM-EDX and electrical measurements for possible applications as capacitors in flexible and/or nonplanar electronics. PMID- 20949928 TI - Structural study of the Li(0.5)Na(0.5)MnFe2(PO4)3 and Li(0.75)Na(0.25)MnFe2(PO4)3 alluaudite phases and their electrochemical properties as positive electrodes in lithium batteries. AB - The alluaudite lithiated phases Li(0.5)Na(0.5)MnFe(2)(PO(4))(3) and Li(0.75)Na(0.25)MnFe(2)(PO(4))(3) were prepared via a sol-gel synthesis, leading to powders with spongy characteristics. The Rietveld refinement of the X-ray and neutron diffraction data coupled with ab initio calculations allowed us for the first time to accurately localize the lithium ions in the alluaudite structure. Actually, the lithium ions are localized in the A(1) and A(1)' sites of the tunnel. Mossbauer measurements showed the presence of some Fe(2+) that decreased with increasing Li content. Neutron diffraction revealed the presence of a partial Mn/Fe exchange between the two transition metal sites that shows clearly that the oxidation state of the element is fixed by the type of occupied site. The electrochemical properties of the two phases were studied as positive electrodes in lithium batteries in the 4.5-1.5 V potential window, but they exhibit smaller electrochemical reversible capacity compared with the non lithiated NaMnFe(2)(PO(4))(3). The possibility of Na(+)/Li(+) ion deintercalation from (Na,Li)MnFe(2)(PO(4))(3) was also investigated by DFT+U calculations. PMID- 20949930 TI - Trapping unstable terminal M-O multiple bonds of monocyclopentadienyl niobium and tantalum complexes with Lewis acids. AB - Hydrolysis of [NbCp'Cl(4)] (Cp' = eta(5)-C(5)H(4)SiMe(3)) with the water adduct H(2)O.B(C(6)F(5))(3) afforded the oxo-borane compound [NbCp'Cl(2){O.B(C(6)F(5))(3)}] (2a). This compound reacted with [MgBz(2)(THF)(2)] giving [NbCp'Bz(2){O.B(C(6)F(5))(3)}] (2b), whereas [NbCp'Me(2){O.B(C(6)F(5))(3)}] (2c) was obtained from the reaction of [NbCp'Me(4)] with H(2)O.B(C(6)F(5))(3). Addition of Al(C(6)F(5))(3) to solutions containing the oxo-borane compounds [MCp(R)X(2){O.B(C(6)F(5))(3)}] (M = Ta, Cp(R) = eta(5)-C(5)Me(5) (Cp*), X = Cl 1a, Bz 1b, Me 1c; M = Nb, Cp(R) = Cp', X = Cl 2a) afforded the oxo-alane complexes [MCp(R)X(2){O.Al(C(6)F(5))(3)}] (M = Ta, Cp(R) = Cp*, X = Cl 3a, Bz 3b, Me 3c; M = Nb, Cp(R) = Cp', X = Cl 4a), releasing B(C(6)F(5))(3). Compound 3a was also obtained by addition of Al(C(6)F(5))(3) to the dinuclear MU-oxo compound [TaCp*Cl(2)(MU-O)](2), meanwhile addition of the water adduct H(2)O.Al(C(6)F(5))(3) to [TaCp*Me(4)] gave complex 3c. The structure of 2a and 3a was obtained by X-ray diffraction studies. Density functional theory (DFT) calculations were carried out to further understand these types of oxo compounds. PMID- 20949929 TI - Conformationally restricted homotryptamines. Part 7: 3-cis-(3 aminocyclopentyl)indoles as potent selective serotonin reuptake inhibitors. AB - A series of conformationally restricted homotryptamines has been synthesized and shown to be potent inhibitors of hSERT. Conformational restriction of the homotryptamine side chain was attained by the insertion of a cyclopentyl ring, with the indole ring and the terminal dialkylamino group occupying the 1- and 3 positions, respectively. Nitrile and fluoro substitutions at the indole 5 position gave highest hSERT potency. Preferred cyclopentane ring stereochemistry in both series was cis (1S,3R for 5-CN compound 8a, 1R,3S for 5-F compound 9a). High hSERT binding affinity was observed for 8a and 9a (0.22 and 0.63 nM, respectively). The corresponding trans isomers were 4-9 times less potent. 8a, dosed at 1 and 3 mg/kg po, produced a robust, dose-dependent increase in extracellular serotonin in the frontal cortex of rats, similar to that induced by paroxetine at 5 mg/kg, po. By contrast, 9a did not produce a significant increase in extracellular serotonin in rat frontal cortex at 3 mg/kg po due to relatively low brain and plasma levels. PMID- 20949931 TI - Cooperative binding isotherms for nearest neighbor interacting ligands on platonic solids: a simple model for viral capture nanotherapy. AB - The binding polynomial formalism is used to calculate binding isotherms for nearest neighbor interacting ligands on the platonic solids, i.e., tetrahedron, cube, octahedron, dodecahedron, and icosahedron. The activity of ligand (concentration multiplied by intrinsic binding constant of ligand to single sites) at half occupancy is precisely determined by the product of the coordination number or valence of the vertices and the free energy of interaction, regardless of other geometrical and topological features. More importantly, the sharpness of binding curves increases with interaction strength, with Hill exponents approaching the number of binding sites per solid particle, i.e., the number of vertices or the number of faces. Potential applications of the model to viral capture nanotherapy are suggested. PMID- 20949932 TI - Electron transfer between physically bound electron donors and acceptors: a fluorescence blob model approach. AB - The present study reports on the applicability of the fluorescence blob model (FBM) to analyze the complex fluorescence decays obtained with DNA-intercalated ethidium bromide (EB) as it transfers an electron to copper cations bound to the DNA helix. Traditionally, the information retrieved about the electron transfer process taking place between an electron donor intercalated in DNA and an electron acceptor physically and randomly bound to DNA has been limited due to the distribution of distances that quenching can occur over, which leads to a distribution of rate constants resulting in complex fluorescence decays. These complications can be overcome by analyzing the fluorescence data with a fluorescence blob model (FBM) that allows for the study of fluorescence quenching between fluorophores and quenchers randomly spaced along a polymeric backbone. The fluorescence decays obtained for EB intercalated between two DNA base pairs (bp) as it transfers an electron to copper randomly bound to the DNA were well fit with the FBM. In the FBM analysis, electron transfer is characterized by the size of a blob in term of base pairs, N(blob), over which electron transfer occurs, as well as the rate constant of electron transfer inside a blob, k(blob). The present work demonstrates that electron transfer between intercalated EB and randomly bound copper occurs over an average distance that increases with increasing duplex length up to a duplex length of 12 bp, beyond which the distance over which electron transfer occurs remains constant with duplex length and equals 10.8 +/- 0.4 bp. PMID- 20949933 TI - A colorimetric sensor array for detection of triacetone triperoxide vapor. AB - Triacetone triperoxide (TATP), one of the most dangerous primary explosives, has emerged as an explosive of choice for terrorists in recent years. Owing to the lack of UV absorbance, fluorescence, or facile ionization, TATP is extremely difficult to detect directly. Techniques that are able to detect generally require expensive instrumentation, need extensive sample preparation, or cannot detect TATP in the gas phase. Here we report a simple and highly sensitive colorimetric sensor for the detection of TATP vapor with semiquantitative analysis from 50 ppb to 10 ppm. By using a solid acid catalyst to pretreat a gas stream, we have discovered that a colorimetric sensor array of redox sensitive dyes can detect even very low levels of TATP vapor from its acid decomposition products (e.g., H(2)O(2)) with limits of detection (LOD) below 2 ppb (i.e., <0.02% of its saturation vapor pressure). Common potential interferences (e.g., humidity, personal hygiene products, perfume, laundry supplies, volatile organic compounds, etc.) do not generate an array response, and the array can also differentiate TATP from other chemical oxidants (e.g., hydrogen peroxide, bleach, tert-butylhydroperoxide, peracetic acid). PMID- 20949934 TI - Packing of soft asymmetric dumbbells. AB - We use numerical simulations to study the phase behavior of a system of purely repulsive soft dumbbells as a function of size ratio of the two components and their relative degree of deformability. We find a plethora of different phases, which includes most of the mesophases observed in self-assembly of block copolymers but also crystalline structures formed by asymmetric, hard binary mixtures. Our results detail the phenomenological behavior of these systems when softness is introduced in terms of two different classes of interparticle interactions: (a) the elastic Hertz potential, which has a finite energy cost for complete overlap of any two components, and (b) a generic power-law repulsion with tunable exponent. We discuss how simple geometric arguments can be used to account for the large structural variety observed in these systems and detail the similarities and differences in the phase behavior for the two classes of potentials under consideration. PMID- 20949935 TI - "Click" synthesis and properties of carborane-appended large dendrimers. AB - Large dendrimers, noted G(n)-3(n+2)cage, containing 3(n+2) o-carborane cluster cages MeC(2)B(10)H(10) at their peripheries (n = number of generation noted G(n)) have been synthesized by Huisgen-type azide alkyne Cu(I)-catalyzed dipolar "click" cycloaddition reactions (CuAAC) between an o-carborane monomeric cluster containing an ethynyl group and arene-centered azido-terminated dendrimers G(n) 3(n+2)N(3) of generations 0, 1, and 2. Attempts to synthesize higher-generation dendrimers of this family yielded insoluble materials. The carborane dendrimers G(0)-9cage, G(1)-27cage, and G(2)-81cage have been characterized by (1)H, (13)C, (11)B NMR, elemental analysis, matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectroscopy, and size exclusion chromatography (SEC) showing low polydispersities, dynamic light scattering (DLS) showing hydrodynamic diameters of 5.7 nm for the G(1)-27cage and the 12.9 nm for the G(2)-81cage. These dendrimers are extremely robust thermally, with 10% mass loss temperatures of 411 degrees C for the G(0)-9cage, 371 degrees C for the G(1)-27cage, and 392 degrees C for the G(2)-81cage. They all showed a strong absorption in the UV region peaking at 258 nm, whereas emission spectra of low intensities were observed between 280 and 480 nm. PMID- 20949936 TI - Graphene nanoribbon thin films using layer-by-layer assembly. AB - Described here is a room temperature procedure to fabricate graphene nanoribbon (GNR) thin films. The GNRs, synthesized by unzipping carbon nanotubes, were reduced and functionalized. The functionalized GNRs are negatively or positively charged, which are suitable to assemble thin films by electrostatic layer-by layer absorption. The homogenous full GNR films were fabricated on various substrates with controllable thicknesses. By assembling the GNRs films on silicon oxide/silicon surfaces, bottom-gated GNR thin-film transistors were fabricated in a solution processed technique. PMID- 20949937 TI - Addition of chitosan to silicate cross-linked PEO for tuning osteoblast cell adhesion and mineralization. AB - The addition of chitosan to silicate (Laponite) cross-linked poly(ethylene oxide) (PEO) is used for tuning nanocomposite material properties and tailoring cellular adhesion and bioactivity. By combining the characteristics of chitosan (which promotes cell adhesion and growth, antimicrobial) with properties of PEO (prevents protein and cell adhesion) and those of Laponite (bioactive), the resulting material properties can be used to tune cellular adhesion and control biomineralization. Here, we present the hydration, dissolution, degradation, and mechanical properties of multiphase bio-nanocomposites and relate these to the cell growth of MC3T3-E1 mouse preosteoblast cells. We find that the structural integrity of these bio-nanocomposites is improved by the addition of chitosan, but the release of entrapped proteins is suppressed. Overall, this study shows how chitosan can be used to tune properties in Laponite cross-linked PEO for creating bioactive scaffolds to be considered for bone repair. PMID- 20949938 TI - Monodisperse, micrometer-scale, highly crystalline, nanotextured Ag dendrites: rapid, large-scale, wet-chemical synthesis and their application as SERS substrates. AB - In this letter, we report on our interesting finding that the direct mixing of aqueous AgNO(3) and NH(2)OH solutions at room temperature leads to rapid, high yield production of monodisperse, micrometer-scale, highly crystalline, nanotextured Ag dendrites. The surface-enhanced Raman scattering (SERS) effect of these Ag dendrites was evaluated by using 4-aminothiophenol (p-ATP) as the Raman probe and the results demonstrate that they exhibit strong SERS effects. PMID- 20949939 TI - Ion mobility mass spectrometry of two tetrameric membrane protein complexes reveals compact structures and differences in stability and packing. AB - Here we examined the gas-phase structures of two tetrameric membrane protein complexes by ion mobility mass spectrometry. The collision cross sections measured for the ion channel are in accord with a compact configuration of subunits, suggesting that the native-like structure can be preserved under the harsh activation conditions required to release it from the detergent micelle into the gas phase. We also found that the quaternary structure of the transporter, which has fewer transmembrane subunits than the ion channel, is less stable once stripped of detergents and bulk water. These results highlight the potential of ion mobility mass spectrometry for characterizing the overall topologies of membrane protein complexes and the structural changes associated with nucleotide, lipid, and drug binding. PMID- 20949940 TI - 3-D carbon nanotube structures used as high performance catalyst for oxygen reduction reaction. AB - We report a high performance oxygen reduction reaction (ORR) catalyst based on vertically aligned, nitrogen-doped carbon nanotube (VA-NCNT) arrays. Characterization in conditions analogous to the operation of a polymer electrolyte membrane fuel cell show ORR taking place on the catalyst at a favorable reduction potential with a superior current density and greater rate constant. PMID- 20949941 TI - Beryllosilicate frameworks and zeolites. AB - Using inspiration derived from studying naturally occurring minerals, a series of framework beryllosilicates have been synthesized under hydrothermal conditions. These include two new zeolite topologies, a unique layered beryllosilicate, and beryllosilicate analogues of numerous aluminosilicate zeolites. Materials with the structure of the rare zeolite mineral nabesite have been synthesized for the first time, including both sodium and potassium derivatives. The structural chemistry of these beryllosilicates frameworks is discussed with reference to the networks of linked tetrahedra, which include the first instance of pentagonal, two-dimensional Cairo-tiling of silicate tetrahedra in one of the new zeolite topologies, their porosity, and their thermal stability. PMID- 20949942 TI - Influence of concentration and temperature on the dynamics of water in the hydrophobic hydration shell of tetramethylurea. AB - We study the influence of the amphipilic compound tetramethylurea (TMU) on the dynamical properties of water, using dielectric relaxation spectroscopy in the regime between 0.2 GHz and 2 THz. This technique is capable of resolving different water species, their relative fractions, and their corresponding reorientation dynamics. We find that the reorientation dynamics of water molecules in the hydration shell of the hydrophobic groups of TMU is between 3 (at low concentrations) and 10 (at higher concentrations) times slower than the dynamics of bulk water. The data indicate that the effect of hydrophobic groups on water is strong but relatively short-ranged. With increasing temperature, the fraction of water contained in the hydrophobic hydration shell decreases, which implies that the overall effect of hydrophobic groups on water becomes smaller. PMID- 20949943 TI - Interaction-dependent PCR: identification of ligand-target pairs from libraries of ligands and libraries of targets in a single solution-phase experiment. AB - Interaction-dependent PCR (IDPCR) is a solution-phase method to identify binding partners from combined libraries of small-molecule ligands and targets in a single experiment. Binding between DNA-linked targets and DNA-linked ligands induces formation of an extendable duplex. Extension links codes that identify the ligand and target into one selectively amplifiable DNA molecule. In a model selection, IDPCR resulted in the enrichment of DNA encoding all five known protein-ligand pairs out of 67 599 possible sequences. PMID- 20949944 TI - Deactivation of soybean agglutinin by enzymatic and other physical treatments. AB - The main objective of this study was to eliminate the hemagglutination activity of an antinutritional factor in soybeans, soybean agglutinin (SBA). A series of experiments was designed to enzymatically modify SBA structure and to use other physical treatments to reduce activity. SBA extract was prepared from soy flour and used as the substrate for all treatments. Deglycosylation by enzyme decreased activity of SBA by 21%, but not to the level of denaturation by heat or by denaturing reagents (47-77% residual activity). Single enzymes, such as trypsin, chymotrypsin, thermolysin, and endoproteinase Glu-C, did not hydrolyze native SBA, but they hydrolyzed heat- or organic solute-denatured SBA. Even after hydrolysis, SBA still had 44-62% residual activity. Combinations of enzymes with thermolysin fully deactivated heat- or guanidine hydrochloride- and urea-treated SBA. Pepsin and pancreatin hydrolysis fully deactivated not only heated but also native SBA. Tea polyphenols, metal ions, and chelating agents were also tested, and they showed no significant effect on SBA activity. N-Acetylgalactosamine agarose beads specifically but not fully removed SBA from the soy protein mixture. In general, SBA needs to be denatured first for an effective enzymatic hydrolysis, and multiple enzymes are needed to fully deactivate SBA. Pepsin and pancreatin treatment showed great promise in fully reducing SBA activity, and it would be further tested using soy flour as a model system. PMID- 20949945 TI - Characterization, quantification, and yearly variation of the naturally occurring polyphenols in a common red variety of curly kale ( Brassica oleracea L. convar. acephala var. sabellica cv. 'Redbor'). AB - This study focuses on the characterization and quantification of polyphenols in the edible leaves of red curly kale ( Brassica oleracea L. convar. acephala (DC.) Alef. var. sabellica L.), variety 'Redbor F1 hybrid'. The kale was grown at an experimental field (59 degrees 40' N) in the years 2007-2009. The analysis of kale extract by HPLC-DAD-ESI-MS has allowed the determination of 47 different acylated and nonacylated flavonoid glycosides and complex hydroxycinnamic acids. Those compounds included mono- to tetraglycosides of quercetin, kaempferol, and cyanidin and derivatives of p-coumaric, ferulic, sinapic, and caffeic acid. Among the compounds characterized, four flavonols, three anthocyanins, and three phenolic acids were identified in the Brassica family for the first time. Aglycones and conjugated polyphenols were quantified by HPLC-DAD using commercially available standards. The main flavonol, anthocyanin, and phenolic acid were kaempferol-3-sinapoyl-diglucoside-7-diglucoside, cyanidin-3-sinapoyl feruloyl-diglucoside-5-glucoside, and disinapoyl-diglucoside, respectively, each representing 9.8, 10.3, and 4.9% of the total amount of 872 mg polyphenol equivalents per 100 g of fresh kale. Variations between individual plants and growing seasons were of the same order of magnitude for total phenolics and total monomeric anthocyanins. PMID- 20949946 TI - Dietary phenolic acids and derivatives. Evaluation of the antioxidant activity of sinapic acid and its alkyl esters. AB - The action of sinapic acid and its alkyl esters as potential antioxidants has been investigated. For this purpose, a series of sinapic acid ester derivatives was synthesized and their antioxidant activities were evaluated using distinctive analytical methods, namely, 2,2-diphenyl-1-picrylhydrazyl (DPPH) and FRAP UV-vis methods and differential scanning calorimetry. The electron-donating activity and lipophilicity of these phenolic compounds were also evaluated. From the overall results it was concluded that alkyl ester sinapates (linear alkyl esters) present almost the same antioxidant activity, albeit slightly lower, exhibited by the parent compound (sinapic acid). Furthermore, the addition of an alkyl ester side chain has a positive effect on the partition coefficient of sinapic acid, improving its utility as an antioxidant in a more lipophilic medium. The data on the antioxidant activity obtained by different analytical methods correlated well with each other and have revealed interesting antioxidant data of alkyl esters of sinapic acid. PMID- 20949947 TI - Artificial metalloenzymes based on the biotin-avidin technology: enantioselective catalysis and beyond. AB - Artificial metalloenzymes are created by incorporating an organometallic catalyst within a host protein. The resulting hybrid can thus provide access to the best features of two distinct, and often complementary, systems: homogeneous and enzymatic catalysts. The coenzyme may be positioned with covalent, dative, or supramolecular anchoring strategies. Although initial reports date to the late 1970s, artificial metalloenzymes for enantioselective catalysis have gained significant momentum only in the past decade, with the aim of complementing homogeneous, enzymatic, heterogeneous, and organic catalysts. Inspired by a visionary report by Wilson and Whitesides in 1978, we have exploited the potential of biotin-avidin technology in creating artificial metalloenzymes. Owing to the remarkable affinity of biotin for either avidin or streptavidin, covalent linking of a biotin anchor to a catalyst precursor ensures that, upon stoichiometric addition of (strept)avidin, the metal moiety is quantitatively incorporated within the host protein. In this Account, we review our progress in preparing and optimizing these artificial metalloenzymes, beginning with catalytic hydrogenation as a model and expanding from there. These artificial metalloenzymes can be optimized by both chemical (variation of the biotin-spacer ligand moiety) and genetic (mutation of avidin or streptavidin) means. Such chemogenetic optimization schemes were applied to various enantioselective transformations. The reactions implemented thus far include the following: (i) The rhodium-diphosphine catalyzed hydrogenation of N-protected dehydroaminoacids (ee up to 95%); (ii) the palladium-diphosphine catalyzed allylic alkylation of 1,3-diphenylallylacetate (ee up to 95%); (iii) the ruthenium pianostool-catalyzed transfer hydrogenation of prochiral ketones (ee up to 97% for aryl-alkyl ketones and ee up to 90% for dialkyl ketones); (iv) the vanadyl-catalyzed oxidation of prochiral sulfides (ee up to 93%). A number of noteworthy features are reminiscent of homogeneous catalysis, including straightforward access to both enantiomers of the product, the broad substrate scope, organic solvent tolerance, and an accessible range of reactions that are typical of homogeneous catalysts. Enzyme-like features include access to genetic optimization, an aqueous medium as the preferred solvent, Michaelis-Menten behavior, and single-substrate derivatization. The X-ray characterization of artificial metalloenzymes provides fascinating insight into possible enantioselection mechanisms involving a well defined second coordination sphere environment. Thus, such artificial metalloenzymes combine attractive features of both homogeneous and enzymatic kingdoms. In the spirit of surface borrowing, that is, modulating ligand affinity by harnessing existing protein surfaces, this strategy can be extended to selectively binding streptavidin-incorporated biotinylated ruthenium pianostool complexes to telomeric DNA. This application paves the way for chemical biology applications of artificial metalloenzymes. PMID- 20949948 TI - Land use greenhouse gas emissions from conventional oil production and oil sands. AB - Debates surrounding the greenhouse gas (GHG) emissions from land use of biofuels production have created a need to quantify the relative land use GHG intensity of fossil fuels. When contrasting land use GHG intensity of fossil fuel and biofuel production, it is the energy yield that greatly distinguishes the two. Although emissions released from land disturbed by fossil fuels can be comparable or higher than biofuels, the energy yield of oil production is typically 2-3 orders of magnitude higher, (0.33-2.6, 0.61-1.2, and 2.2 5.1 PJ/ha) for conventional oil production, oil sands surface mining, and in situ production, respectively). We found that land use contributes small portions of GHGs to life cycle emissions of California crude and in situ oil sands production ( <0.4% or < 0.4 gCO2e/MJ crude refinery feedstock) and small to modest portions for Alberta conventional oil (0.1-4% or 0.1-3.4 gCO2e/MJ) and surface mining of oil sands (0.9-11% or 0.8-10.2 gCO2e/MJ).Our estimates are based on assumptions aggregated over large spatial and temporal scales and assuming 100% reclamation. Values on finer spatial and temporal scales that are relevant to policy targets need to account for site specific information, the baseline natural and anthropogenic disturbance. PMID- 20949949 TI - Application of Raman microscopy for simultaneous and quantitative evaluation of multiple intracellular polymers dynamics functionally relevant to enhanced biological phosphorus removal processes. AB - Polyphosphate (poly-P), polyhydroxyalkanoates (PHAs), and glycogen are the key functionally relevant intracellular polymers involved in the enhanced biological phosphorus removal (EBPR) process. Further understanding of the mechanisms of EBPR has been hampered by the lack of cellular level quantification tools to accurately measure the dynamics of these polymers during the EBPR process. In this study, we developed a novel Raman microscopy method for simultaneous identification and quantification of poly-P, PHB, and glycogen abundance in each individual cell and their distribution among the populations in EBPR. Validation of the method was demonstrated via a batch phosphorus uptake and release test, in which the total intracellular polymers abundance determined via Raman approach correlated well with those measured via conventional bulk chemical analysis (correlation coefficient r = 0.8 for poly-P, r = 0.94 for PHB, and r = 0.7 for glycogen). Raman results, for the first time, clearly showed the distributions of microbial cells containing different abundance levels of the three intracellular polymers under the same environmental conditions (at a given time point), indicating population heterogeneity exists. The results revealed the intracellular distribution and dynamics of the functionally relevant polymers in different metabolic stages of the EBPR process and elucidated the association of cellular metabolic state with the fate of these polymers during various substrates availability conditions. PMID- 20949950 TI - Extracellular polymeric substances (EPS) in a hybrid growth membrane bioreactor (HG-MBR): viscoelastic and adherence characteristics. AB - Extracellular polymeric substances (EPS) comprising the microbial biofilms in membrane bioreactor (MBR) systems are considered the most significant factor affecting sludge viscoelastic properties as well as membrane fouling. Understanding the water chemistry effects on EPS viscoelastic, conformational, and adherence properties are critical for defining the microbial biofilm's propensity of fouling the membrane surface. In this study, EPS extracted from a hybrid growth membrane bioreactor (HG-MBR) were analyzed for their adherence, viscoelastic properties and size distribution using quartz crystal microbalance with dissipation monitoring (QCM-D) and dynamic light scattering (DLS), respectively. Also, adsorption characteristics of EPS extracted from different locations in the HG-MBR (bioreactor liquor, fluidized carriers, and membrane surface) were defined and linked to the extent of the total polysaccharide content in the EPS. In accordance with the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory, more EPS were adsorbed at higher ionic strength, lower pH and in the presence of calcium cations. Based on the QCM-D results, the calculated thickness of the EPS adsorbed layer was increased at lower ionic strength, higher pH, and only had a minor increase in the presence of calcium cations. The calculated shear modules and shear viscosity suggest that at lower pH and in the presence of calcium, EPS becomes more viscous and elastic, respectively. DLS analysis correlated to the QCM-D results: A decrease in the hydrodynamic radius of the EPS colloids was observed at lower pH, and in the presence of calcium, most likely attributed to intermolecular attraction forces. Based on this study, low pH and presence of calcium may induce flocs' stability that resist erosion in the MBRs, while on the other hand, these conditions may induce the formation of an elastic and viscous EPS layer fouling the ultrafiltration (UF) membrane. PMID- 20949951 TI - Concentrations, distribution, and persistence of perfluoroalkylates in sludge applied soils near Decatur, Alabama, USA. AB - Sludges generated at a wastewater treatment plant (WWTP) in Decatur, Alabama have been applied to agricultural fields for more than a decade. Waste-stream sources to this WWTP during this period included industries that work with fluorotelomer compounds, and sludges from this facility have been found to be elevated in perfluoroalkylates (PFAs). With this knowledge, the U.S. Environmental Protection Agency collected soil samples from sludge-applied fields as well as nearby "background" fields for PFA analysis. Samples from the sludge-applied fields had PFAs at much higher concentrations than in the background fields; generally the highest concentrations were perfluorodecanoic acid (<= 990 ng/g), perfluorododecanoic acid (<= 530 ng/g), perfluorooctanoic acid (<= 320 ng/g), and perfluorooctane sulfonate (<= 410 ng/g). Contrasts in PFA concentration between surface and deeper soil samples tended to be more pronounced in long-chain congeners than shorter chains, perhaps reflecting relatively lower environmental mobilities for longer chains. Several PFAs were correlated with secondary fluorotelomer alcohols (sec-FTOHs) suggesting that PFAs are being formed by degradation of sec-FTOHs. Calculated PFA disappearance half-lives for C6 through C11 alkylates ranged from about 1 to 3 years and increase with increasing chain length, again perhaps reflecting lower mobility of the longer-chained compounds. PMID- 20949952 TI - Concentrations, distribution, and persistence of fluorotelomer alcohols in sludge applied soils near Decatur, Alabama, USA. AB - Soil samples were collected for fluorotelomer alcohol (FTOH) analyses from six fields to which sludge had been applied and one "background" field that had not received sludge. Ten analytes in soil extracts were quantified using GC/MS. Sludge-applied fields had surface soil FTOH concentrations exceeding levels found in the background field. For 8:2nFTOH, which can degrade to perfluorooctanoic acid, impacted surface-soils ranged from 5 to 73 ng/g dry weight, clearly exceeding the background field in which 8:2nFTOH was not detected. The highest [FTOH] generally was 10:2nFTOH, which had concentrations of <5.6 to 166 ng/g. For the first time, we document the persistence of straight-chained primary FTOHs (n FTOHs) and branch-chained secondary FTOHs (sec-FTOHs), which are transformation products of n-FTOHs, in field soils for at least five years after sludge application. Ratios of sec-FTOHs to n-FTOHs were highest for 7:2sFTOH/8:2nFTOH (~50%) and decreased with increasing chain length to a minimum for the longest chained analytes, 13:2sFTOH/14:2nFTOH (~10%). Disappearance half-lives for FTOHs, calculated with these data, ranged from 0.85 to 1.8 years. These analytical results show that the practice of sludge application to land is a pathway for the introduction of FTOHs and, accordingly, their transformation products, perfluorocarboxylic acids, into the environment. PMID- 20949953 TI - Solvothermal synthesis of two polymorphs of an indium germanate incorporating an organic amine ligand: beta- and gamma-In2Ge6O15(NH2CH2CH2NH2)2. AB - Two new polymorphs, beta- and gamma-In(2)Ge(6)O(15)(NH(2)CH(2)CH(2)NH(2))(2), have been synthesized under solvothermal conditions using 2 methylpentamethylenediamine as a solvent and structurally characterized by single crystal X-ray diffraction. Both structures contain single layers with the composition [Ge(6)O(15)] that are connected by In(2)O(6)N(4) octahedral dimers to form 3D frameworks. The germanate layers contain four-, six-, and eight-membered rings and six-membered rings in the beta and gamma polymorphs, respectively. Compounds with related structures are discussed for comparison. PMID- 20949954 TI - First-principles study of the separation of Am(III)/Cm(III) from Eu(III) with Cyanex301. AB - The experimentally observed extraction complexes of trivalent lanthanide Eu(III) and actinide Am(III)/Cm(III) cations with purified Cyanex301 [bis(2,4,4 trimethylpentyl)dithiophosphinic acid, HBTMPDTP denoted as HL], i.e., ML(3) (M = Eu, Am, Cm) as well as the postulated complexes HAmL(4) and HEuL(4)(H(2)O) have been studied by using energy-consistent 4f- and 5f-in-core pseudopotentials for trivalent f elements, combined with density functional theory and second-order Moller-Plesset perturbation theory. Special attention was paid to explaining the high selectivity of Cyanex301 for Am(III)/Cm(III) over Eu(III). It is shown that the neutral complexes ML(3), where L acts as a bidentate ligand and the metal cation is coordinated by six S atoms, are most likely the most stable extraction complexes. The calculated metal-sulfur bond distances for ML(3) do reflect the cation employed; i.e., the larger the cation, the longer the metal-sulfur bond distances. The calculated M-S and M-P bond lengths agree very well with the available experimental data. The obtained changes of the Gibbs free energies in the extraction reactions M(3+) + 3HL -> ML(3) + 3H(+) agree with the thermodynamical priority for Am(3+) and Cm(3+). Moreover, the ionic metal-ligand dissociation energies of the extraction complexes ML(3) show that, although EuL(3) is the most stable complex in the gas phase, it is the least stable in aqueous solution. PMID- 20949955 TI - Energetics and molecular structure of 2,5-dimethyl-1-phenylpyrrole and 2,5 dimethyl-1-(4-nitrophenyl)pyrrole. AB - Thermochemical and thermodynamic properties of 2,5-dimethyl-1-phenylpyrrole and 2,5-dimethyl-1-(4-nitrophenyl)pyrrole have been determined by using a combination of calorimetric and effusion techniques as well as high-level ab initio molecular orbital calculations. The standard (p degrees = 0.1 MPa) molar enthalpies of formation, in the crystalline state, Delta(f)H(m) degrees (cr), at T = 298.15 K, were derived from the standard molar enthalpies of combustion, Delta(c)H(m) degrees , which were obtained from static bomb combustion calorimetry. The Knudsen mass-loss effusion technique was used to determine the standard molar enthalpies of sublimation, Delta(cr)(g)H(m) degrees , at T = 298.15 K. From the experimental results, the standard molar enthalpies of formation, in the gaseous phase, at T = 298.15 K, were derived. The results were analyzed and interpreted in terms of enthalpic increments and molecular structure. For comparison purposes, standard ab initio molecular calculations at the G3(MP2)//B3LYP level were performed, using a set of working reactions and the gas-phase enthalpies of formation of both compounds were estimated; the results are in excellent agreement with experimental data. The computational study was also extended to the determination of proton and electron affinities, basicities and adiabatic ionization enthalpies. PMID- 20949956 TI - Statistical rate theory insight into evaporation and condensation in multicomponent systems. AB - Current approaches to mathematically modeling liquid-vapor mass transport (e.g., film theory, penetration theory, boundary layer theory) treat bulk phase transport accurately with diffusion models, but leave the transport across the interface to be described by empirically determined mass transfer coefficients. In multicomponent systems, this requires empirical mixing rules for the single component mass transfer coefficients. Such approaches can only give estimates of net rates at the interface but cannot examine the movement of individual components. Here we use statistical rate theory to provide new physical insight into evaporation and condensation at interfaces in systems containing multiple volatile components. In contrast to the traditional multicomponent mass transfer approach, we show ranges where one component evaporates while the other condenses even when the net transport is unidirectional. PMID- 20949958 TI - Biological identification of peptides that specifically bind to poly(phenylene vinylene) surfaces: recognition of the branched or linear structure of the conjugated polymer. AB - Peptides that bind to poly(phenylene vinylene) (PPV) were identified by the phage display method. Aromatic amino acids were enriched in these peptide sequences, suggesting that a pi-pi interaction is the key interaction between the peptides and PPV. The surface plasmon resonance (SPR) experiments using chemically synthesized peptides demonstrated that the Hyp01 peptide, with the sequence His Thr-Asp-Trp-Arg-Leu-Gly-Thr-Trp-His-His-Ser, showed an affinity constant (7.7 * 10(5) M(-1)) for the target, hyperbranched PPV (hypPPV) film. This value is 15 fold greater than its affinity for linear PPV (linPPV). In contrast, the peptide screened for linPPV (Lin01) showed the reverse specificity for linPPV. These results suggested that the Hyp01 and Lin01 peptides selectively recognized the linear or branched structure of PPVs. The Ala-scanning experiment, circular dichroism (CD) spectrometry, and molecular modeling of the Hyp01 peptide indicated that adequate location of two Trp residues by forming the polyproline type II (P(II)) helical conformation allowed the peptide to specifically interact with hypPPV. PMID- 20949959 TI - On the self-assembly of a highly selective benzothiazole-based TIM inhibitor in aqueous solution. AB - Benzothiazole is a common scaffold on which many bioactive structures, including protein inhibitors and biosensors, are based. The potential self-aggregation of such molecules to form nanoparticles is relevant for a number of practical applications. 3-(2-Benzothiazolylthio)-propanesulfonic acid (BTS) has been reported as a powerful and selective inhibitor of triosephosphate isomerase from Trypanosoma cruzi, the parasite that causes the Chagas' disease. Electrical conductivity, sound velocity, density, and nuclear magnetic resonance experiments as a function of temperature and of NaCl concentration have been performed in the present work to provide a comprehensive physicochemical description of this compound in aqueous solution. Molecular dynamics simulations of the same system were also performed to characterize the structure and dynamic behavior of the corresponding aggregates at several concentrations of BTS. PMID- 20949957 TI - New two-photon-absorbing probe with efficient superfluorescent properties. AB - The synthesis, linear photophysical, and photochemical parameters, two-photon absorption (2PA), and superfluorescence properties of 2,2'-(5,5'-(9,9-didecyl-9H fluorene-2,7-diyl)bis(ethyne-2,1-diyl)bis(thiophene-5,2-diyl))dibenzo[d]thiazole (1) were investigated, suggesting its potential as an efficient fluorescent probe for bioimaging applications. The steady-state absorption, fluorescence, and excitation anisotropy spectra of 1 were measured in several organic solvents and aqueous media. Probe 1 exhibited high fluorescence quantum yield (~0.7-0.8) and photochemical stability (photobleaching quantum yield ~(3-7) * 10(-6)). The 2PA spectra were determined over a broad spectral range (640-920 nm) using a standard two-photon induced fluorescence method under femtosecond excitation. A well defined two-photon allowed absorption band at 680-720 nm with corresponding 2PA cross sections delta(2PA) ~ 800-900 GM was observed. The use of probe 1 in bioimaging was shown via one- and two-photon fluorescence imaging of HCT-116 cells. An amplification of the stimulated emission of 1 was demonstrated in organic solvents and thin polystyrene films, which potentially can be used for the development of new fluorescent labels with increased spectral brightness. PMID- 20949960 TI - Dynamic response of AFM cantilevers to dissimilar functionalized silica surfaces in aqueous electrolyte solutions. AB - The dynamic response of an oscillating microcantilever with a gold-coated tip interacting with dissimilar functionalized silica surfaces was studied in electrolyte solutions with pH ranging from 4 to 9. Silica surfaces were chemically modified, yielding dissimilar surfaces with -Br, -NH(2), and -CH(3) functional group terminations. The relative hydrophobicity of the surfaces was characterized by contact angle measurements. The surface charge of the functionalized surfaces was first probed with commonly used static AFM measurements and serves as a reference to the dynamic response data. The amplitude and phase of the cantilever oscillation were monitored and used to calculate the effective interaction stiffness and damping coefficient, which relate to the electrical double layer interactions and also to distance-dependent hydrodynamic damping at the solid/water interface. The data for the dynamic response of the AFM over silica surfaces as a function of chemical functionalization and electrolyte pH show that the effective stiffness has a distinctive dependence on the surface charge of functionalized silica surfaces. The hydrodynamic damping also correlates strongly with the relative hydrophobicity of the surface. The data reported here indicate that interfacial properties can be strongly affected by changing the chemical composition of surfaces. PMID- 20949961 TI - In situ scanning tunneling microscopy investigation of sulfur oxidative underpotential deposition on Ag(100) and Ag(110). AB - Underpotential (UPD) deposition of sulfur from Na(2)S solution in 0.1 M NaOH was studied on Ag(100) and Ag(110) using in situ scanning tunneling microscopy (STM). The cyclic voltammogram on Ag(100) presents two broad peaks, whereas three partial overlapping peaks and a sharper one are observed on Ag(110). STM measurements carried out during the whole UPD process show that progressively more compact structures are formed as the applied potential is scanned toward more positive potentials. More precisely, p(2*2), c(2*6), and c(2*2) were found on Ag(100) at E = -1.25, -1.0, and -0.9 V, respectively. Less definite conclusions can be drawn for the structures of S overlayers on Ag(110). However, the experimental findings are consistent with an incomplete p(2*1) at potentials preceding the sharp peak, and with a c(2*2) structure at E = -0.9 V vs Ag/AgCl, KCl(sat). The coverage values calculated on the basis of the hypothesized structures have been compared with the values obtained from chronocoulometric measurements at the most positive potentials investigated. Thus, the experimental coverage theta = 0.5 coincides with the coverage calculated for the c(2*2) structure found on Ag(110) at E = -0.9 V by STM, whereas the experimental coverage theta = 0.42 suggests that a mixture of structures c(2*6) and c(2*2) is formed on Ag(100). PMID- 20949962 TI - Thiol with an unusual adsorption-desorption behavior: 6-mercaptopurine on Au(111). AB - A multitechnique study of 6-mercaptopurine (6MP) adsorption on Au(111) is presented. The molecule adsorbs on Au(111), originating short-range ordered domains and irregular nanosized aggregates with a total surface coverage by chemisorbed species smaller than those found for alkanethiol SAMs, as derived from scanning tunneling microscopy (STM) and electrochemical results. X-ray photoelectron spectroscopy (XPS) results show the presence of a thiolate bond, whereas density functional theory (DFT) data indicate strong chemisorption via a S-Au bond and additional binding to the surface via a N-Au bond. From DFT data, the positive charge on the Au topmost surface atoms is markedly smaller than that found for Au atoms in alkanethiolate SAMs. The adsorption of 6MP originates Au atom removal from step edges but no vacancy island formation at (111) terraces. The small coverage of Au islands after 6MP desorption strongly suggests the presence of only a small population of Au adatom-thiolate complexes. We propose that the absence of the Au-S interface reconstruction results from the lack of significant repulsive forces acting at the Au surface atoms. PMID- 20949963 TI - Controlling the formation of capillary bridges in binary liquid mixtures. AB - We study the formation of capillary bridges between micrometer-sized glass spheres immersed in a binary liquid mixture using bright field and confocal microscopy. The bridges form upon heating due to the preferential wetting of the hydrophilic glass surface by the water-rich phase. If the system is cooled below the demixing temperature, the bridges disappear within a few seconds by intermolecular diffusion. Thus, this system offers the opportunity to switch the bridges on and off and to tune precisely the bridge volume by altering the temperature in a convenient range. We measure the bridge geometry as a function of the temperature from bright field images and calculate the cohesive force. We discuss the influence of the solvent composition on the bridge formation temperature, the strength of the capillary force, and the bridge volume growth rate. Furthermore, we find that the onset of bridge formation coincides with the water-lutidine bulk coexistence curve. PMID- 20949964 TI - Conformational preferences of X-Pro sequences: Ala-Pro and Aib-Pro motifs. AB - Conformational preferences and prolyl cis-trans isomerizations of the X-Pro motifs (Ac-X-Pro-NHMe, X = Ala and Aib) are explored using the meta-hybrid functional M06-2X and the double-hybrid functional B2PLYP-D with empirical dispersion corrections in the gas phase and in water, where solvation free energies were calculated using the implicit SMD model. Ac-Ala-Pro-NHMe favors the type VI beta-turns in the gas phase and the open conformations in water. The populations of type VI beta-turns decrease from 71% in the gas phase to 21% in water, which is reasonably consistent with IR and NMR experimental results on tBoc-Ala-Pro-NHMe. However, Ac-Aib-Pro-NHMe prefers the type I beta-turns with alpha-helical structures for both residues in the gas phase and in water, whose populations are estimated to be 66% in both phases. These calculated results may rationalize why most of the peptaibiotics containing the Aib-Pro sequence have a regular alpha-helical conformation at the N- or C-terminus but a kinked alpha helical structure in the middle of the helix. The cis-trans isomerizations of the Ala-Pro and Aib-Pro peptide bonds proceed via the clockwise rotation with the different backbone conformations. The rotational barriers to cis-to-trans isomerization are estimated to be 19.73 kcal/mol for the Ala-Pro tripeptide and 16.64 kcal/mol for the Aib-Pro tripeptide in water, which indicates that the rotational barrier becomes lower by ~3 kcal/mol for the Aib-Pro peptide bond. The calculated rotational barrier for Ac-Ala-Pro-NHMe is consistent with the observed value of 19.3 kcal/mol for Suc-Ala-Ala-Pro-Phe-pNA from NMR experiments in a buffered solution. PMID- 20949965 TI - Chitosan-g-MPEG-modified alginate/chitosan hydrogel microcapsules: a quantitative study of the effect of polymer architecture on the resistance to protein adsorption. AB - The chemical modification of the alginate/chitosan/alginate (ACA) hydrogel microcapsule with methoxy poly(ethylene glycol) (MPEG) was investigated to reduce nonspecific protein adsorption and improve biocompatibility in vivo. The graft copolymer chitosan-g-MPEG (CS-g-MPEG) was synthesized, and then alginate/chitosan/alginate/CS-g-MPEG (ACAC(PEG)) multilayer hydrogel microcapsules were fabricated by the layer-by-layer (LBL) polyelectrolyte self assembly method. A quantitative study of the modification was carried out by the gel permeation chromatography (GPC) technique, and protein adsorption on the modified microcapsules was also investigated. The results showed that the apparent graft density of the MPEG side chain on the microcapsules decreased with increases in the degree of substitution (DS) and the MPEG chain length. During the binding process, the apparent graft density of CS-g-MPEG showed rapid growth plateau-rapid growth behavior. CS-g-MPEG was not only bound to the surface but also penetrated a certain depth into the microcapsule membranes. The copolymers that penetrated the microcapsules made a smaller contribution to protein repulsion than did the copolymers on the surfaces of the microcapsules. The protein repulsion ability decreased with the increase in DS from 7 to 29% with the same chain length of MPEG 2K. CS-g-MPEG with MPEG 2K was more effective at protein repulsion than CS-g-MPEG with MPEG 550, having a similar DS below 20%. In this study, the microcapsules modified with CS-g-MPEG2K-DS7% had the lowest IgG adsorption of 3.0 +/- 0.6 MUg/cm(2), a reduction of 61% compared to that on the chitosan surface. PMID- 20949966 TI - Microviscosity inside a nanocavity: a femtosecond fluorescence up-conversion study of malachite green. AB - Femtosecond fluorescence up-conversion measurements of malachite green (MG) have been carried out to confirm the relaxation pathway and subsequently to probe the microviscosity of water trapped in a nanoconfined environment using an AOT (sodium dioctylsulfosuccinate, aerosol-OT) reverse micelle as a model system. The experimental results reveal a strong dependence of S(1) state relaxation dynamics of MG on solvent viscosity while a very weak dependence has been observed for the S(2) state relaxation. The time-dependent density functional theory (TD-DFT) calculations have been used to construct potential energy surfaces of MG by pursuing an intramolecular rotation along the torsional coordinate of the phenyl rings. On synchronization with the experimental observations, the computational results comprehend the existence of a conical intersection along the S(1) and S(0) potential energy surfaces, which leads to mixed vibrational levels of S(1) and S(0) characteristics. The results suggest that the conical intersection is along the torsional coordinate of N,N-dimethyl substituted phenyl ring. Correlating the observed dynamics of MG in a confined system with the relaxation time of MG in different glycerol-water mixtures, we assert the determination of the microviscosity of water inside the AOT reverse micelle. The data confer that the microviscosity of water in an AOT water pool of w(0) = 2 (9 cP) is almost 9 times higher than the bulk water. As we increase the w(0) from 2 to 40, the microviscosity decreases monotonically to 5.68 cP, and the decrease is observed to be exponential in nature. PMID- 20949967 TI - A mint purified extract protects human keratinocytes from short-term, chemically induced oxidative stress. AB - Oxidative stress is strictly correlated to the pathogenesis of many diseases, and a diet rich in fruits and vegetables, or adequately integrated, is currently considered to be a protective and preventive factor. This study aimed to analyze the efficacy of a 1 h preincubation with the highest nontoxic dose of a characterized Mentha longifolia extract (80 MUg/mL) in protecting human keratinocytes (NCTC2544) from chemically induced oxidative stress (500 MUM H2O2 for 2, 16, and 24 h). As reference synthetic pure compounds rosmarinic acid (360.31 MUg/mL), a major mint phenolic constituent, and resveratrol (31.95 mg/mL), a well-known antioxidant, were used. Cellular viability was significantly protected by mint, which limited protein and DNA damage, decreased lipid peroxidation, and preserved glutathione and superoxide dismutase activity in the shorter phases of oxidative stress induction, in extents comparable to or better than those of pure compounds. These data suggest that mint use as only a flavoring has to be revised, taking into consideration its enrichment in foodstuff and cosmetics. PMID- 20949968 TI - Shape-dependent catalytic properties of Pt nanoparticles. AB - Tailoring the chemical reactivity of nanomaterials at the atomic level is one of the most important challenges in catalysis research. In order to achieve this elusive goal, fundamental understanding of the geometric and electronic structure of these complex systems at the atomic level must be obtained. This article reports the influence of the nanoparticle shape on the reactivity of Pt nanocatalysts supported on gamma-Al(2)O(3). Nanoparticles with analogous average size distributions (~0.8-1 nm), but with different shapes, synthesized by inverse micelle encapsulation, were found to display distinct reactivities for the oxidation of 2-propanol. A correlation between the number of undercoordinated atoms at the nanoparticle surface and the onset temperature for 2-propanol oxidation was observed, demonstrating that catalytic properties can be controlled through shape-selective synthesis. PMID- 20949969 TI - Two-way photoswitching using one type of near-infrared light, upconverting nanoparticles, and changing only the light intensity. AB - Only one type of lanthanide-doped upconverting nanoparticle (UCNP) is needed to reversibly toggle photoresponsive organic compounds between their two unique optical, electronic, and structural states by modulating merely the intensity of the 980 nm excitation light. This reversible "remote-control" photoswitching employs an excitation wavelength not directly absorbed by the organic chromophores and takes advantage of the fact that designer core-shell-shell NaYF(4) nanoparticles containing Er(3+)/Yb(3+) and Tm(3+)/Yb(3+) ions doped into separate layers change the type of light they emit when the power density of the near-infrared light is increased or decreased. At high power densities, the dominant emissions are ultraviolet and are appropriate to drive the ring-closing, forward reactions of dithienylethene (DTE) photoswitches. The visible light generated from the same core-shell-shell UCNPs at low power densities triggers the reverse, ring-opening reactions and regenerates the original photoisomers. The "remote-control" photoswitching using NIR light is as equally effective as the direct switching with UV and visible light, albeit the reaction rates are slower. This technology offers a highly convenient and versatile method to spatially and temporally regulate photochemical reactions using a single light source and changing either its power or its focal point. PMID- 20949970 TI - Solution synthesis of large-scale, high-sensitivity ZnO/Si hierarchical nanoheterostructure photodetectors. AB - This Communication reports a low-cost solution fabrication of wafer-scale ZnO/Si branched nanowire heterostructures and their high photodetection sensitivity, with an ON/OFF ratio larger than 250 and a peak photoresponsivity of 12.8 mA/W at 900 nm. This reported unique 3D branched nanowire structure offers a generic approach for the integration of new functional materials for photodetection and photovoltaic applications. PMID- 20949971 TI - Heronapyrroles A-C: farnesylated 2-nitropyrroles from an Australian marine derived Streptomyces sp. AB - Chemical analysis of a marine-derived Streptomyces sp. (CMB-M0423) isolated from beach sand off Heron Island, Australia, yielded three new members of the rare pyrroloterpene biosynthetic structure class. Identified by detailed spectroscopic analysis as the first reported examples of naturally occurring 2-nitropyrroles, heronapyrroles A-C (1-3) displayed promising biological activity-with low to submicromolar IC(50) activity against Gram-positive bacteria but no cytotoxicity toward mammalian cell lines. PMID- 20949972 TI - Palladium-catalyzed dynamic kinetic asymmetric transformations of vinyl aziridines with nitrogen heterocycles: rapid access to biologically active pyrroles and indoles. AB - We report that nitrogen heterocycles can serve as competent nucleophiles in the palladium-catalyzed dynamic kinetic asymmetric alkylation of vinyl aziridines. The resulting alkylated products were obtained with high regio-, chemo-, and enantioselectivity. Both substituted 1H-pyrroles and 1H-indoles were successfully employed to give exclusively the branched N-alkylated products. The synthetic utility of this process was demonstrated by applying this method to the preparation of several medicinal chemistry lead compounds and bromopyrrole alkaloids including longamide B, longamide B methyl ester, hanishin, agesamides A and B, and cyclooroidin. PMID- 20949973 TI - Immunoproteomics profiling of blood stage Plasmodium vivax infection by high throughput screening assays. AB - Completed genome sequences and stage-specific transcriptomes of the intraerythrocytic developmental cycle of Plasmodium vivax offers the opportunity to profile immune responses against P. vivax infection using innovative screening approaches. To detect the immune responses to blood stage-specific proteins, we applied a protein array technology to screen the sera of vivax malaria patients. Herein, a set of genes from the P. vivax blood stage was cloned using the In Fusion cloning method and expressed by a wheat germ cell-free system. A total of 94 open reading frames (ORFs) were cloned and 89 (95%, 89/94) proteins were expressed, which were screened with sera from P. vivax-infected patients and healthy individuals using protein arrays. A total of 18 (19.1%, 18/94) highly immunoreactive proteins were identified, including 7 well-characterized vivax vaccine candidates. The remaining 11 ORFs have not been previously described as immunologically reactive. These novel immunoproteomes of the vivax malaria blood stage will be further studied as potential vaccine candidates. In this first report, high-throughput screening assays have been applied to investigate blood stage-specific immunoproteomes from vivax malaria. These methods may be used to determine immunodominant candidate antigens from the P. vivax genome. PMID- 20949974 TI - Chips from chips: application to the study of antibody responses to methylated proteins. AB - Peptide microarrays are useful tools for the characterization of humoral responses against peptide antigens. The study of post-translational modifications requires the printing of appropriately modified peptides, whose synthesis can be time-consuming and expensive. We describe here a method named "chips from chips", which allows probing the presence of antibodies directed toward modified peptide antigens starting from unmodified peptide microarrays. The chip from chip concept is based on the modification of peptide microspots by simple chemical reactions. The starting peptide chip (parent chip) is covered by the reagent solution, thereby allowing the modification of specific residues to occur, resulting in the production of a modified peptide chip (daughter chip). Both parent and daughter chips can then be used for interaction studies. The method is illustrated using reductive methylation for converting lysines into dimethyllysines. The rate of methylation was studied using specific antibodies and fluorescence detection, or surface-assisted laser desorption ionization mass spectrometry. This later technique showed unambiguously the efficient methylation of the peptide probes. The method was then used to study the humoral response against the Mycobacterium tuberculosis heparin-binding hemagglutinin, a methylated surface-associated virulence factor and powerful diagnostic and protective antigen. PMID- 20949976 TI - Folding proteome of Yarrowia lipolytica targeting with uracil permease mutants. AB - The acquisition of the correct folding of membrane proteins is a crucial process that involves several steps from the recognition of nascent protein, its targeting to the endoplasmic reticulum membrane, its insertion, and its sorting to its final destination. Yarrowia lipolytica is a hemiascomycetous dimorphic yeast and an alternative eukaryotic yeast model with an efficient secretion pathway. To better understand the quality control of membrane proteins, we constructed a model system based on the uracil permease. Mutated forms of the permease were stabilized and retained in the cell and made the strains resistant to the 5-fluorouracil drug. To identify proteins involved in the quality control, we separated proteins extracted in nondenaturing conditions on blue native gels to keep proteins associated in complexes. Some gel fragments where the model protein was immunodetected were subjected to mass spectrometry analysis. The proteins identified gave a picture of the folding proteome, from the translocation across the endoplasmic reticulum membrane, the folding of the proteins, to the vesicle transport to Golgi or the degradation via the proteasome. For example, EMC complex, Gsf2p or Yet3p, chaperone membrane proteins of the endoplasmic reticulum were identified in the Y. lipolytica native proteome. PMID- 20949977 TI - Ferrocene-terminated monolayers covalently bound to hydrogen-terminated silicon surfaces. Toward the development of charge storage and communication devices. AB - The combination of monocrystalline silicon's well-defined structure and the ability to prepare hydrogen-terminated surfaces (Si-H) easily and reproducibly has made this material a very attractive substrate for immobilizing functional molecules. The functionalization of Si-H using the covalent attachment of organic monolayers has received intense attention due to the numerous potential applications of controlled and robust organic/Si interfaces. Researchers have investigated these materials in diverse fields such as molecular electronics, chemistry, and bioanalytical chemistry. Applications include the preparation of surface insulators, the incorporation of chemical or biochemical functionality at interfaces for use in photovoltaic conversion, and the development of new chemical and biological sensing devices. Unlike those of gold, silicon's electronic properties are tunable, and researchers can directly integrate silicon based devices within electronic circuitry. Moreover, the technological processes used for the micro- and nanopatterning of silicon are numerous and mature enough for producing highly miniaturized functional electronic components. In this Account, we describe a powerful approach that integrates redox-active molecules, such as ferrocene, onto silicon toward electrically addressable systems devoted to information storage or transfer. Ferrocene exhibits attractive electrochemical characteristics: fast electron-transfer rate, low oxidation potential, and two stable redox states (neutral ferrocene and oxidized ferrocenium). Accordingly, ferrocene-modified silicon surfaces could be used as charge storage components with the bound ferrocene center as the memory element. Upon application of a positive potential to silicon, ferrocene is oxidized to its corresponding ferrocenium form. This redox change is equivalent to the change of a bit of information from the "0" to "1" state. To erase the stored charge and return the device to its initial state, a low potential must be applied to reduce the whole generated ferrocenium. In this type of application, the electron is transferred from the ferrocene headgroups to the underlying conducting silicon surface by a tunneling process across the monolayer. To produce a stable and reproducible electrical response, this process must be efficient, fast, and reversible. The stability, charge density, and capacitance performances of high-quality ferrocene terminated monolayers could compete with those of the existing semiconductor based memory devices, such as dynamic random access memories, DRAMs. Moreover, we provide experimental evidence that a series of immobilized ferrocene centers can efficiently communicate via a lateral electron hopping process. Using these modified interfaces, we demonstrate that the thin redox-active monolayer can behave as a purely conducting material, highlighting an unprecedented very fast electron communication between immobilized redox groups. Perhaps more importantly, the surface coverage of ferrocene allows us to precisely control the rate of this process. Such characteristics are relevant not only for electrocatalytic reactions but also for widening the potential applications of these assemblies to novel molecular electronic devices (e.g. chemiresistors, chemically sensitive field-effect transistors (CHEMFETs)) and redox chemistry on insulating surfaces. PMID- 20949975 TI - Diverse effects on the native beta-sheet of the human prion protein due to disease-associated mutations. AB - Prion diseases are fatal neurodegenerative disorders that involve the conversion of the normal cellular form of the prion protein (PrP(C)) to a misfolded pathogenic form (PrP(Sc)). There are many genetic mutations of PrP associated with human prion diseases. Three of these point mutations are located at the first strand of the native beta-sheet in human PrP: G131V, S132I, and A133V. To understand the underlying structural and dynamic effects of these disease-causing mutations on the human PrP, we performed molecular dynamics of wild-type and mutated human PrP. The results indicate that the mutations induced different effects but they were all related to misfolding of the native beta-sheet: G131V caused the elongation of the native beta-sheet, A133V disrupted the native beta sheet, and S132I converted the native beta-sheet to an alpha-sheet. The observed changes were due to the reorientation of side chain-side chain interactions upon introducing the mutations. In addition, all mutations impaired a structurally conserved water site at the native beta-sheet. Our work suggests various misfolding pathways for human PrP in response to mutation. PMID- 20949978 TI - Communication: Thermodynamics of water modeled using ab initio simulations. AB - We regularize the potential distribution framework to calculate the excess free energy of liquid water simulated with the BLYP-D density functional. Assuming classical statistical mechanical simulations at 350 K model the liquid at 298 K, the calculated free energy is found in fair agreement with experiments, but the excess internal energy and hence also the excess entropy are not. The utility of thermodynamic characterization in understanding the role of high temperatures to mimic nuclear quantum effects and in evaluating ab initio simulations is noted. PMID- 20949979 TI - Communication: ROHF theory made simple. AB - Restricted open-shell Hartree-Fock (ROHF) theory is formulated as a projected self-consistent unrestricted HF (UHF) model by mathematically constraining spin density eigenvalues. This constrained UHF (CUHF) wave function is identical to that obtained from Roothaan's effective Fock operator. The alpha and beta CUHF Fock operators are parameter-free and have eigenvalues (orbital energies) that are physically meaningful as in UHF, except for eliminating spin contamination. This new way of solving ROHF leads to orbitals that turn out to be identical to semicanonical orbitals. The present approach removes ambiguities in ROHF orbital energies. PMID- 20949980 TI - Communication: Second-order multireference perturbation theory with explicit correlation: CASPT2-F12. AB - An explicitly correlated complete active space second-order perturbation (CASPT2 F12) method is presented which strongly accelerates the convergence of CASPT2 energies and properties with respect to the basis set size. A Slater-type geminal function is employed as a correlation factor to represent the electron-electron cusp of the wave function. The explicitly correlated terms in the wave function are internally contracted. The required density matrix elements and coupling coefficients are the same as in conventional CASPT2, and the additional computational effort for the F12 correction is small. The CASPT2-F12 method is applied to the singlet-triplet splitting of methylene, the dissociation energy of ozone, and low-lying excited states of pyrrole. PMID- 20949981 TI - Effective numbers of modes applied to analysis of internal dynamics of weakly bound clusters. AB - The dependence of the volume of the chaotic component in the internal dynamics of triatomic van der Waals clusters on the angular momentum is calculated using the Monte Carlo and molecular dynamics methods. It has been found that this dependence is nonmonotonic and that its functional form varies for different values of the total energy. The effective number of rotational modes was used to clarify why a change in the volume of chaotic component of the phase space happens for certain values of the angular momentum. We conclude that a large fraction of regular trajectories in relation to all trajectories appears only when there is a possibility for the regular motion to perform a rotation different from that for a chaotic motion. When such difference is small, the regular motion disappears. The effective number of rotational modes can be used to estimate the difference in the type of rotation and is a convenient parameter which controls changes in the dynamics of the system. PMID- 20949982 TI - Performance of W4 theory for spectroscopic constants and electrical properties of small molecules. AB - Accurate spectroscopic constants and electrical properties of small molecules are determined by means of W4 and post-W4 theories. For a set of 28 first- and second row diatomic molecules for which very accurate experimental spectroscopic constants are available, W4 theory affords near-spectroscopic or better predictions. Specifically, the root-mean-square deviations (RMSDs) from experiment are 0.04 pm for the equilibrium bond distances (r(e)), 1.03 cm(-1) for the harmonic frequencies (omega(e)), 0.20 cm(-1) for the first anharmonicity constants (omega(e)x(e)), 0.10 cm(-1) for the second anharmonicity constants (omega(e)y(e)), and 0.001 cm(-1) for the vibration-rotation coupling constants (alpha(e)). These RMSDs imply 95% confidence intervals of about 0.1 pm for r(e), 2.0 cm(-1) for omega(e), 0.4 cm(-1) for omega(e)x(e), and 0.2 cm(-1) for omega(e)y(e). We find that post-CCSD(T) contributions are essential to achieve such narrow confidence intervals for r(e) and omega(e), but have little effect on omega(e)x(e) and alpha(e), and virtually none on omega(e)y(e). Higher-order connected triples T(3)-(T) improve the agreement with experiment for the hydride systems, but their inclusion (in the absence of T(4)) tends to worsen the agreement with experiment for the nonhydride systems. Connected quadruple excitations T(4) have significant and systematic effects on r(e), omega(e), and omega(e)x(e), in particular they universally increase r(e) (by up to 0.5 pm), universally reduce omega(e) (by up to 32 cm(-1)), and universally increase omega(e)x(e) (by up to 1 cm(-1)). Connected quintuple excitations T(5) are spectroscopically significant for omega(e) of the nonhydride systems, affecting omega(e) by up to 4 cm(-1). Diagonal Born-Oppenheimer corrections have systematic and spectroscopically significant effects on r(e) and omega(e) of the hydride systems, universally increasing r(e) by 0.01-0.06 pm and decreasing omega(e) by 0.3-2.1 cm(-1). Obtaining r(e) and omega(e) of the pathologically multireference BN and BeO systems with near-spectroscopic accuracy requires large basis sets in the core-valence CCSD(T) step and augmented basis sets in the valence post CCSD(T) steps in W4 theory. The triatomic molecules H(2)O, CO(2), and O(3) are also considered. The equilibrium geometries and harmonic frequencies (with the exception of the asymmetric stretch of O(3)) are obtained with near-spectroscopic accuracy at the W4 level. The asymmetric stretch of ozone represents a severe challenge to W4 theory, in particular the connected quadruple contribution converges very slowly with the basis set size. Finally, the importance of post CCSD(T) correlation effects for electrical properties, namely, dipole moments (MU), polarizabilities (alpha), and first hyperpolarizabilities (beta), is evaluated. PMID- 20949983 TI - A theoretical investigation of electric properties of L-arginine phosphate monohydrate including environment polarization effects. AB - The dipole moment (MU), linear polarizability (alpha), and first hyperpolarizability (beta(tot)) of the asymmetric unit of L-arginine phosphate (LAP) monohydrate crystal are investigated using the supermolecule approach in combination with an iterative electrostatic polarization scheme. Environment polarization effects are attained by assuring the convergence of the dipole moment of LAP embedded in the polarization field of the surrounding molecules whose atomic sites are treated as point charges. The results obtained show that in the presence of the embedding charges, the value of MU is increased by 9% but the static values of alpha and beta(tot) are decreased, respectively, by 3% and 13%, as compared with the isolated situation. The MP2/6-311+G(d) model predicts for the in-crystal dipole moment the converged value of 33 D, in good concordance with the available experimental result of 32 D. Our estimates for the converged results of alpha and beta(tot) are, respectively, 22.51*10(-24) and 5.01*10(-30) esu. Dispersion effects are found to have a small impact on the nonlinear optical responses of LAP in the visible region. In addition, MP2/6-311G results obtained for beta(tot) by using isolated and embedded LAP dimers show that crystal packing effects have a significant contribution of the electrostatic interactions. Our results suggest that the role of the crystal environment is to minimize the effects of the intermolecular interactions in the electric properties. That is, MU and beta(tot) gain a more additive character in the presence of the field of the embedding charges. This is specially marked for beta(tot). PMID- 20949984 TI - On the measure of electron correlation and entanglement in quantum chemistry based on the cumulant of the second-order reduced density matrix. AB - In this paper we propose a functional of the many-body cumulant of the second order reduced density matrix within the spin-free formalism of quantum chemistry which quantifies the idea of electron correlation and allows one to detect spin entanglement. Its properties are rigorously stated and discussed for spin-adapted pure states. Numerical determinations are performed for both equilibrium conformations and dissociation processes in molecular systems. PMID- 20949985 TI - Energy surface, chemical potentials, Kohn-Sham energies in spin-polarized density functional theory. AB - On the basis of the zero-temperature grand canonical ensemble generalization of the energy E[N,N(s),v,B] for fractional particle N and spin N(s) numbers, the energy surface over the (N,N(s)) plane is displayed and analyzed in the case of homogeneous external magnetic fields B(r). The (negative of the) left-/right-side derivatives of the energy with respect to N, N(?), and N(?) give the fixed-N(s), spin-up, and spin-down ionization potentials/electron affinities, respectively, while the derivative of E[N,N(s),v,B] with respect to N(s) gives the (signed) half excitation energy to the lowest-lying state with N(s) increased (or decreased) by 2. The highest occupied and lowest unoccupied Kohn-Sham spin orbital energies are identified as the corresponding spin-up and spin-down ionization potentials and electron affinities. The excitation energies to the lowest-lying states with N(s)+/-2 can be obtained as the differences between the lowest unoccupied and the opposite-spin highest occupied spin-orbital energies, if the (N,N(s)) representation of the Kohn-Sham spin-potentials is used. The cases where the convexity condition on the energy does not hold are also discussed. Finally, the discontinuities of the energy derivatives and the Kohn Sham potential are analyzed and related. PMID- 20949986 TI - Benchmarking NMR indirect nuclear spin-spin coupling constants: SOPPA, SOPPA(CC2), and SOPPA(CCSD) versus CCSD. AB - Accurate calculations of NMR indirect nuclear spin-spin coupling constants require especially optimized basis sets and correlated wave function methods such as CCSD or SOPPA(CCSD). Both methods scale as N(6), where N is the number of orbitals, which prevents routine applications to molecules with more than 10-15 nonhydrogen atoms. We have therefore developed a modification of the SOPPA(CCSD) method in which the CCSD singles and doubles amplitudes are replaced by CC2 singles and doubles amplitudes. This new method, called SOPPA(CC2), scales only as N(5), like the original SOPPA-method. The performance of the SOPPA(CC2) method for the calculation of indirect nuclear spin-spin coupling constants is compared to SOPPA and SOPPA(CCSD) employing a set of benchmark molecules. We also investigate the basis set dependence by employing three different basis sets optimized for spin-spin coupling constants, namely the HuzIV-su4, ccJ-pVTZ, and ccJ-pVQZ basis sets. The results of the corresponding CCSD calculations are used as a theoretical reference. PMID- 20949987 TI - Unified treatment of coherent and incoherent electronic energy transfer dynamics using classical electrodynamics. AB - Recent experiments on resonance energy transfer (RET) in photosynthetic systems have found evidence of quantum coherence between the donor and the acceptor. Under these conditions, Forster's theory of RET is no longer applicable and no theory of coherent RET advanced to date rivals the intuitive simplicity of Forster's theory. Here, we develop a framework for understanding RET that is based on classical electrodynamics but still captures the essence of the quantum coherence between the molecules. Our theory requires only a knowledge of the complex polarizabilities of the two molecules participating in the transfer as well as the distance between them. We compare our results to quantum mechanical calculations and show that the results agree quantitatively. PMID- 20949988 TI - An efficient method for computing steady state solutions with Gillespie's direct method. AB - Gillespie's direct method is a stochastic simulation algorithm that may be used to calculate the steady state solution of a chemically reacting system. Recently the all possible states method was introduced as a way of accelerating the convergence of the simulations. We demonstrate that while the all possible states (APS) method does reduce the number of required trajectories, it is actually much slower than the original algorithm for most problems. We introduce the elapsed time method, which reformulates the process of recording the species populations. The resulting algorithm yields the same results as the original method, but is more efficient, particularly for large models. In implementing the elapsed time method, we present robust methods for recording statistics and empirical probability distributions. We demonstrate how to use the histogram distance to estimate the error in steady state solutions. PMID- 20949989 TI - A transferable classical potential for the water molecule. AB - We developed a new model for the water molecule which contains only three Gaussian charges. Using the gas-phase geometry the dipole moment of the molecule matches, the quadrupole moment closely approximates the experimental values. The negative charge is connected by a harmonic spring to its gas-phase position. The polarized state is identified by the equality of the intermolecular electrostatic force and the spring force acting on the negative charge. In each timestep the instantaneous position of the massless negative charge is determined by iteration. Using the technique of Ewald summation, we derived expressions for the potential energy, the forces, and the pressure for Gaussian charges. The only properties to be fitted are the half-width values of the Gaussian charge distributions and the parameters of the nonelectrostatic repulsion-attraction potential. We determined the properties of gas-phase clusters up to six molecules, the internal energy and density of ambient water and hexagonal ice. We calculated the equilibrium density of ice VII as a function of pressure. As an additional test, we calculated the pair-correlation function, the isotherm compressibility, the heat capacity, and the self-diffusion coefficients for ambient water. As far as we know, this is the first classical model of water which is able to estimate both ends of the phase diagram, the high pressure ice VII, and the gas clusters of water with excellent accuracy. PMID- 20949990 TI - Simulation of loss mechanisms in organic solar cells: A description of the mesoscopic Monte Carlo technique and an evaluation of the first reaction method. AB - In this letter we evaluate the accuracy of the first reaction method (FRM) as commonly used to reduce the computational complexity of mesoscale Monte Carlo simulations of geminate recombination and the performance of organic photovoltaic devices. A wide range of carrier mobilities, degrees of energetic disorder, and applied electric field are considered. For the ranges of energetic disorder relevant for most polyfluorene, polythiophene, and alkoxy poly(phenylene vinylene) materials used in organic photovoltaics, the geminate separation efficiency predicted by the FRM agrees with the exact model to better than 2%. We additionally comment on the effects of equilibration on low-field geminate separation efficiency, and in doing so emphasize the importance of the energy at which geminate carriers are created upon their subsequent behavior. PMID- 20949991 TI - Basis set representation of the electron density at an atomic nucleus. AB - In this paper a detailed investigation of the basis set convergence for the calculation of relativistic electron densities at the position of finite-sized atomic nuclei is presented. The development of Gauss-type basis sets for such electron densities is reported and the effect of different contraction schemes is studied. Results are then presented for picture-change corrected calculations based on the Douglas-Kroll-Hess Hamiltonian. Moreover, the role of electron correlation, the effect of the numerical integration accuracy in density functional calculations, and the convergence with respect to the order of the Douglas-Kroll-Hess Hamiltonian and the picture-change-transformed property operator are studied. PMID- 20949992 TI - Analytic energy gradient in combined time-dependent density functional theory and polarizable force field calculation. AB - Formulas for evaluating analytic energy gradient are derived for combined time dependent density functional theory (TDDFT) and polarizable force field methods that incorporate dipole polarizability tensors and linearly induced point dipoles. The Z-vector method for determining relaxed one-particle difference density matrix in regular TDDFT methods is extended to include induced dipoles. The analytic gradient of the mutual polarization energy of the force field and the TDDFT excited state can be formulated by using the TDDFT difference density induced dipoles and the transition state density-induced dipoles. All the forces and torques involving induced dipoles can be efficiently evaluated using standard electrostatic formulas as if the induced dipoles were permanent dipoles. The formulas are given in the most general form and are applicable to various flavors of polarizable force fields. Implementation and tests with a polarizable five point water model show that the formulas are rigorous. The carbonyl vibration modes and infrared spectrum intensities of a cluster formed by acetone and two water molecules are studied. PMID- 20949994 TI - Negative ions of transition metal-halogen clusters. AB - A systematic density functional theory based study of the structure and spectroscopic properties of neutral and negatively charged MX(n) clusters formed by a transition metal atom M (M=Sc,Ti,V) and up to seven halogen atoms X (X=F,Cl,Br) has revealed a number of interesting features: (1) Halogen atoms are bound chemically to Sc, Ti, and V for n<=n(max), where the maximal valence n(max) equals to 3, 4, and 5 for Sc, Ti, and V, respectively. For n>n(max), two halogen atoms became dimerized in the neutral species, while dimerization begins at n=5, 6, and 7 for negatively charged clusters containing Sc, Ti, and V. (2) Magnetic moments of the transition metal atoms depend strongly on the number of halogen atoms in a cluster and the cluster charge. (3) The number of halogen atoms that can be attached to a metal atom exceeds the maximal formal valence of the metal atom. (4) The electron affinities of the neutral clusters abruptly rise at n=n(max), reaching values as high as 7 eV. The corresponding anions could be used in the synthesis of new salts, once appropriate counterions are identified. PMID- 20949993 TI - A Bayesian method for construction of Markov models to describe dynamics on various time-scales. AB - The dynamics of many biological processes of interest, such as the folding of a protein, are slow and complicated enough that a single molecular dynamics simulation trajectory of the entire process is difficult to obtain in any reasonable amount of time. Moreover, one such simulation may not be sufficient to develop an understanding of the mechanism of the process, and multiple simulations may be necessary. One approach to circumvent this computational barrier is the use of Markov state models. These models are useful because they can be constructed using data from a large number of shorter simulations instead of a single long simulation. This paper presents a new Bayesian method for the construction of Markov models from simulation data. A Markov model is specified by (tau,P,T), where tau is the mesoscopic time step, P is a partition of configuration space into mesostates, and T is an N(P)*N(P) transition rate matrix for transitions between the mesostates in one mesoscopic time step, where N(P) is the number of mesostates in P. The method presented here is different from previous Bayesian methods in several ways. (1) The method uses Bayesian analysis to determine the partition as well as the transition probabilities. (2) The method allows the construction of a Markov model for any chosen mesoscopic time scale tau. (3) It constructs Markov models for which the diagonal elements of T are all equal to or greater than 0.5. Such a model will be called a "consistent mesoscopic Markov model" (CMMM). Such models have important advantages for providing an understanding of the dynamics on a mesoscopic time-scale. The Bayesian method uses simulation data to find a posterior probability distribution for (P,T) for any chosen tau. This distribution can be regarded as the Bayesian probability that the kinetics observed in the atomistic simulation data on the mesoscopic time-scale tau was generated by the CMMM specified by (P,T). An optimization algorithm is used to find the most probable CMMM for the chosen mesoscopic time step. We applied this method of Markov model construction to several toy systems (random walks in one and two dimensions) as well as the dynamics of alanine dipeptide in water. The resulting Markov state models were indeed successful in capturing the dynamics of our test systems on a variety of mesoscopic time-scales. PMID- 20949995 TI - Electronic states of MgO: Spectroscopy, predissociation, and cold atomic Mg and O production. AB - We used multiconfigurational methods and a large basis set to compute the potential energy curves of the valence and valence-Rydberg electronic states of MgO molecule. New bound electronic states are found. Using these highly correlated wave functions, we evaluated their mutual spin-orbit couplings and transition moment integrals. For the bound electronic states of MgO, we deduced an accurate set of spectroscopic constants that agree remarkably well with experimental results. Moreover, our potentials, transition moments, and spin orbit coupling evolutions are incorporated into Fermi golden rule calculations to deduce the radiative lifetimes of MgO(B (1)Sigma(+)) rovibrational levels and the natural lifetimes of MgO(A (1)Pi) vibrational levels, where a good agreement is found with experimental values. Finally, we suggest new routes for the production of cold Mg and O atoms and cold MgO molecules. PMID- 20949996 TI - I(-)?CH(3)X (X=Cl,Br,I) photodetachment: The effect of electron-molecule interactions in cluster anion photodetachment spectra and angular distributions. AB - The electron kinetic energy dependence of the photoelectron spectra and angular distributions of I(-)?CH(3)X (X=Cl,Br,I) cluster anions are measured via velocity mapped imaging at wavelengths between 350 and 270 nm. Processes analogous to those encountered in free CH(3)X-electron interactions are revealed. In particular, the presence and energies of resonances associated with a low lying sigma(*) state have a marked effect on the results of I(-)?CH(3)X photoexcitation. These effects (vibrational excitation, product anion production, and alteration of the photoelectron angular distribution) are far more prominent for I(-)?CH(3)I. However, in the vicinity of the (2)P(1/2) threshold there is a sharp deviation in the (2)P(3/2) channel angular distribution and an enhancement of the (2)P(3/2) channel vibrational structure of all three cluster anions. These latter effects are specific to the cluster anion environment through the relaxation of the partner excited I atom and subsequent electronic autodetachment. PMID- 20949997 TI - Photoelectron spectroscopic study of the hydrated nucleoside anions: Uridine( )(H(2)O)(n=0-2), cytidine(-)(H(2)O)(n=0-2), and thymidine(-)(H(2)O)(n=0,1). AB - The hydrated nucleoside anions, uridine(-)(H(2)O)(n=0-2), cytidine(-)(H(2)O)(n=0 2), and thymidine(-)(H(2)O)(n=0,1), have been prepared in beams and studied by anion photoelectron spectroscopy in order to investigate the effects of a microhydrated environment on parent nucleoside anions. Vertical detachment energies (VDEs) were measured for all eight anions, and from these, estimates were made for five sequential anion hydration energies. Excellent agreement was found between our measured VDE value for thymidine(-)(H(2)O)(1) and its calculated value in the companion article by S. Kim and H. F. Schaefer III. PMID- 20949998 TI - Vertical detachment energies of anionic thymidine: Microhydration effects. AB - Density functional theory has been employed to investigate microhydration effects on the vertical detachment energy (VDE) of the thymidine anion by considering the various structures of its monohydrates. Structures were located using a random searching procedure. Among 14 distinct structures of the anionic thymidine monohydrate, the low-energy structures, in general, have the water molecule bound to the thymine base unit. The negative charge developed on the thymine moiety increases the strength of the intermolecular hydrogen bonding between the water and base units. The computed VDE values of the thymidine monohydrate anions are predicted to range from 0.67 to 1.60 eV and the lowest-energy structure has a VDE of 1.32 eV. The VDEs of the monohydrates of the thymidine anion, where the N(1)[Single Bond]H hydrogen of thymine has been replaced by a 2(')-deoxyribose ring, are greater by ~0.30 eV, compared to those of the monohydrates of the thymine anion. The results of the present study are in excellent agreement with the accompanying experimental results of Bowen and co-workers [J. Chem. Phys. 133, 144304 (2010)]. PMID- 20949999 TI - Global potential energy surface, vibrational spectrum, and reaction dynamics of the first excited (A (2)A(')) state of HO(2). AB - The authors report extensive high-level ab initio studies of the first excited (A (2)A(')) state of HO(2). A global potential energy surface (PES) was developed by spline-fitting 17 000 ab initio points at the internal contracted multireference configuration interaction (icMRCI) level with the AVQZ basis set. To ascertain the spectroscopic accuracy of the PES, the near-equilibrium region of the molecule was also investigated using three interpolating moving least-squares based PESs employing dynamically weighted icMRCI methods in the complete basis set limit. Vibrational energy levels on all four surfaces agree well with each other and a new assignment of some vibrational features is proposed. In addition, the dynamics of both the forward and reverse directions of the H+O(2)(a (1)Delta(g))<->OH+O reaction (J=0) were studied using an exact wave packet method. The reactions are found to be dominated by sharp resonances. PMID- 20950000 TI - A comparative computational study of hydrogen and lithium-bonded complexes. AB - A computational study of hydrogen-bonded complexes of F(3)CH and C1H and of lithium-bonded complexes of F(3)CLi and CILi, with small molecules such as N(2) and H(2)O was undertaken at the MP2/6-311++G(d,p) level of theory. Bond extensions and redshifts were obtained for the Cl[Single Bond]H bond in the ClH complexes, while bond contractions and blueshifts were obtained for the C[Single Bond]H bond in the F(3)CH complexes. By contrast, bond extensions and blueshifts were obtained for all of the lithium-bonded species. These results were rationalized using a model derived from perturbation theory. PMID- 20950001 TI - Quantum dynamics of dissociative chemisorption of CH(4) on Ni(111): Influence of the bending vibration. AB - Two-dimensional, three-dimensional, and four-dimensional quantum dynamic calculations are performed on the dissociative chemisorption of CH(4) on Ni(111) using the multiconfiguration time-dependent Hartree (MCTDH) method. The potential energy surface used for these calculations is 15-dimensional (15D) and was obtained with density functional theory for points which are concentrated in the region that is dynamically relevant to reaction. Many reduced dimensionality calculations were already performed on this system, but the molecule was generally treated as pseudodiatomic. The main improvement of our model is that we try to describe CH(4) as a polyatomic molecule by including a degree of freedom describing a bending vibration in our three-dimensional and four-dimensional models. Using a polyspherical coordinate system, a general expression for the 15D kinetic energy operator is derived, which discards all the singularities in the operator and includes rotational and Coriolis coupling. We use seven rigid constraints to fix the CH(3) umbrella of the molecule to its gas phase equilibrium geometry and to derive two-dimensional, three-dimensional, and four dimensional Hamiltonians, which were used in the MCTDH method. Only four degrees of freedom evolve strongly along the 15D minimum energy path: the distance of the center of mass of the molecule to the surface, the dissociative C[Single Bond]H bond distance, the polar orientation of the molecule, and the bending angle between the dissociative C[Single Bond]H bond and the umbrella. A selection of these coordinates is included in each of our models. The polar rotation is found to be important in determining the mode selective behavior of the reaction. Furthermore, our calculations are in good agreement with the finding of Xiang et al. [J. Chem. Phys. 117, 7698 (2002)] in their reduced dimensional calculation that the helicopter motion of the umbrella symmetry axis is less efficient than its cartwheel motion for promoting the reaction. The effect of pre-exciting the bend modes is qualitatively incorrect at higher energies, suggesting the necessity of including additional rotational and vibrational degrees of freedom in the model. PMID- 20950002 TI - Spin-orbit density functional and ab initio study of HgX(n) (X=F, Cl, Br, and I; n=1, 2, and 4). AB - Quantum chemical calculations of HgX(n) (X=F, Cl, Br, and I; n=1, 2, and 4) in the gas phase are performed using the density functional theory (DFT), two component spin-orbit (SO) DFT, and high-level ab initio method with relativistic effective core potentials (RECPs). Molecular geometries, vibrational frequencies, and various thermochemical energies are calculated and compared with available experimental results. We assess the performances of DFT functionals for calculating various molecular properties. The PBE0 functional is generally reasonable for the molecular geometries and the vibrational frequencies, but the M06 functional is more appropriate for estimating thermochemical energies. Both shape-consistent and energy-consistent RECPs correctly describe the SO effect. PMID- 20950003 TI - Sub-Doppler spectroscopy of mixed state levels in CH(2). AB - Perturbations in the 7(16) and 8(18) mixed singlet/triplet levels of a (1)A(1)(0,0,0) methylene, CH(2), have been reinvestigated by frequency-modulated laser sub-Doppler saturation spectroscopy. The hyperfine structure was completely resolved for both the predominantly singlet and the predominantly triplet components of these mixed rotational levels using b (1)B(1)-a (1)A(1) optical transitions near 12 200 cm(-1) with megahertz resolution. The mixing coefficients were obtained from the observed hyperfine splittings and a two-level deperturbation model. The analysis also determines the energy separation of the unperturbed zero-order levels and the unperturbed hyperfine splittings for the triplet perturbing levels 6(15) X (3)B(1)(0,3,0) and 9(37) X (3)B(1)(0,2,0). PMID- 20950004 TI - The electronic spectrum and photodissociation of dinitrogen tetroxide (N(2)O(4)): Multireference configuration interaction studies. AB - Multireference configuration interaction (MRCI) calculations were performed for vertical excitation energies and potential curves of N(2)O(4) in D(2h) symmetry using the TZVPP basis set with diffuse functions on the nitrogens. The strong absorption of N(2)O(4) around 185 nm is assigned to the transition from the ground state to 1 (1)B(1u) (sigma(O)->sigma(*) (N-N)) rather than 1 (1)B(2u) (pi(O)->pi(*) (NO(2) ),n->sigma(*) (N-N)), as previously assumed. (N(2)O(4) is placed in the yz-plane, with N-N along z.) Transition to 1 (1)B(1u) is calculated to have an oscillator strength f=0.71 and is z-polarized, in agreement with the experimental observations. Another state, 2 (1)B(2u), lies close by, however, at a much lower f-value. The weak absorption around 340 nm is assigned to 1 (1)B(3u). Excitation to 1 (1)B(2u) is calculated at 227 nm. There is no clear assignment of a state for the observed shoulder around 260 nm. TD-DFT (time dependent density functional theory) vertical excitation energies are close to MRCI values. MRCI singlet and triplet potential curves for the dissociation N(2)O(4)->2NO(2), combined with a table of NO(2) states correlating with those of N(2)O(4), indicate possible products of photodissociation at various wavelengths. The extensive literature on the photodissociation of N(2)O(4) is reviewed. DFT geometry optimizations have been performed on low-lying singlet and triplet states. PMID- 20950005 TI - Photodissociation of ozone in the Hartley band: Product state and angular distributions. AB - Product state properties from the photodissociation of ozone in the ultraviolet Hartley band are investigated by trajectory surface-hopping calculations. The diabatic B and R state potential energy and coupling surfaces of Schinke and McBane [J. Chem. Phys. 132, 044305 (2010)] are employed. The properties computed include rotational and vibrational distributions in both the singlet and triplet channels, the total internal energy distribution in the triplet channel, and the photodissociation anisotropy parameter beta in the singlet channel. A method for computing beta from trajectories computed in internal Jacobi coordinates is described. In the singlet channel, the vibrational distribution is in good agreement with the experimental results. The observed increase in beta with increasing photolysis wavelength is reproduced by the calculations and is attributed to the effects of the bending potential on the B state late in the fragmentation. The computed beta values are too high with respect to experiment, and the peaks j(max) of the singlet-channel rotational distributions are too low; these discrepancies are attributed to a too steep bending potential at long O-O distances. In the triplet channel, the main part of the internal energy distribution is described well by the calculations, although the detailed structures observed in the experiment are not reproduced. The experimental rotational distributions are well reproduced, although the maxima appear at slightly too high j. The triplet state product energy distributions are shown to depend largely on the distribution of hopping points onto the R state surface. A Landau-Zener model constructed as a function of the O(2) bond distance provides a good physical description of the two-state dynamics. The high internal energy O(2) products that cannot be attributed to the excitation of the Herzberg states remain unexplained. PMID- 20950006 TI - Molecular dynamics simulations for CO(2) absorption spectra. I. Line broadening and the far wing of the nu(3) infrared band. AB - Classical molecular dynamics simulations (CMDS) have been carried out for gaseous CO(2) starting from the intermolecular potential energy surface. Through calculations for a large number of molecules treated as rigid rotors, various autocorrelation functions (ACFs) are obtained together with probabilities of rotational changes. Those used in the present paper are the ACFs of the center of mass velocity and of the molecular orientation, and the conditional probability of a change of the angular speed. They enable calculations, respectively, of the mass diffusion coefficient, of the infrared (dipolar) band shape including the wings, and of individual line-broadening coefficients. It is shown that these calculations, free of any adjustable parameter, lead to good agreement with measured values. This is expected from previous studies for the mass diffusion coefficient and line-broadening coefficients, but it is, to our knowledge, the first demonstration of the interest of CMDS for the prediction of band wings. The present results thus open promising perspectives for the theoretical treatment of the difficult problem of far wings profiles. PMID- 20950007 TI - Nuclear motion in carbonyl sulfide induced by resonant core electron excitation. AB - The angular anisotropy for selected dissociation channels is measured at resonantly excited states of Sigma and Pi symmetries at the C and O K-shell ionization edges of carbonyl sulfide. While the kinetic energy released in the reaction is mainly independent of the excitation energy, the angular anisotropy and momentum correlation clearly show deformation of the OCS molecule in the C 1s(-1)pi(*1) state. The discovery of a two-body fragmentation channel SO(+)/C(+) with a well defined angular anisotropy indicates the rapid formation of the CSO isomeric species. PMID- 20950008 TI - Quantum dynamics of the S+OH->SO+H reaction. AB - First accurate quantum mechanical scattering calculations have been carried out for the S((3)P)+OH(X (2)Pi)->SO(X (3)Sigma(-))+H((2)S) reaction using a recent ab initio potential energy surface for the ground electronic state, X (2)A("), of HSO. Total and state-to-state reaction probabilities for a total angular momentum J=0 have been determined for collision energies up to 0.5 eV. A rate constant has been calculated by means of the J-shifting approach in the 10-400 K temperature range. Vibrational and rotational product distributions show no specific behavior and are consistent with a mixture of direct and indirect reaction mechanisms. PMID- 20950009 TI - Excited states and electronic spectra of extended tetraazaporphyrins. AB - Electronic excited states, electronic absorption, and magnetic circular dichroism (MCD) spectra of free-base tetraazaporphyrin (TAP), phthalocyanine (Pc), naphthalocyanine (Nc), and anthracocyanine (Ac) were studied by quantum chemical calculations using the symmetry-adapted cluster-configuration interaction (SAC CI) method. Not only optically allowed states including the Q- and B-bands but also optically forbidden states were calculated for transitions whose excitation energies were lower than 4.5 eV. The present SAC-CI calculations consistently assigned the absorption and MCD peaks as optically allowed pi->pi(*) excitations, although these calculations using double-zeta basis limit quantitative agreement and discussion. For Nc and Ac, excited states beyond the four-orbital model appeared in the low-energy region. The low-energy shifts of the Q-bands with the extension of molecular size were explained by the orbital energies. The splitting of the Q-bands decreases with extension of the molecular size. This feature was reproduced by the SAC-CI calculations but the configuration interaction with single excitations and time-dependent density functional theory calculations failed to reproduce this trend. Electron correlation in the excited states is important in reproducing this splitting of the Q-bands and in describing the energy difference between the B(2u) and B(3u) states of free-base porphyrins. PMID- 20950010 TI - Synchrotron vacuum ultraviolet radiation studies of the D (1)Pi(u) state of H(2). AB - The 3ppiD (1)Pi(u) state of the H(2) molecule was reinvestigated with different techniques at two synchrotron installations. The Fourier transform spectrometer in the vacuum ultraviolet wavelength range of the DESIRS beamline at the SOLEIL synchrotron was used for recording absorption spectra of the D (1)Pi(u) state at high resolution and high absolute accuracy, limited only by the Doppler contribution at 100 K. From these measurements, line positions were extracted, in particular, for the narrow resonances involving (1)Pi(u) (-) states, with an accuracy estimated at 0.06 cm(-1). The new data also closely match multichannel quantum defect calculations performed for the Pi(-) components observed via the narrow Q-lines. The Lambda-doubling in the D (1)Pi(u) state was determined up to v=17. The 10 m normal incidence scanning monochromator at the beamline U125/2 of the BESSY II synchrotron, combined with a home-built target chamber and equipped with a variety of detectors, was used to unravel information on ionization, dissociation, and intramolecular fluorescence decay for the D (1)Pi(u) vibrational series. The combined results yield accurate information on the characteristic Beutler-Fano profiles associated with the strongly predissociated Pi(u) (+) parity components of the D (1)Pi(u) levels. Values for the parameters describing the predissociation width as well as the Fano-q line shape parameters for the J=1 and J=2 rotational states were determined for the sequence of vibrational quantum numbers up to v=17. PMID- 20950011 TI - Equation of state and anharmonicity of carbon dioxide phase I up to 12 GPa and 800 K. AB - We present an extended investigation of phase I of carbon dioxide by x-ray diffraction and spectroscopic techniques at simultaneous high pressure and high temperature, up to 12 GPa and 800 K. Based on the present and literature data, we show that a Mie-Gruneisen-Debye model reproduces within experimental uncertainties the equation of state of CO(2) over the entire range of stability of phase I. Using infrared and Raman spectroscopy, we have determined the frequencies of the zone-center lattice modes as a function of pressure and temperature. We have then extracted the volume and temperature dependencies of the optical lattice mode frequencies and their respective Gruneisen parameters. We find a large difference between the thermodynamic Gruneisen parameter obtained from the P-V-T data and those associated with the optical lattice modes. This suggests, within the quasiharmonic approximation, that acoustic modes have a dominant contribution to the anharmonicity of the system. PMID- 20950012 TI - Thermodynamic data and modeling of the water and ammonia-water phase diagrams up to 2.2 GPa for planetary geophysics. AB - We present new experimental data on the liquidus of ice polymorphs in the H(2)O NH(3) system under pressure, and use all available data to develop a new thermodynamic model predicting the phase behavior in this system in the ranges (0 2.2 GPa; 175-360 K; 0-33 wt % NH(3)). Liquidus data have been obtained with a cryogenic optical sapphire-anvil cell coupled to a Raman spectrometer. We improve upon pre-existing thermodynamic formulations for the specific volumes and heat capacities of the solid and liquid phase in the pure H(2)O phase diagram to ensure applicability of the model in the low-temperature metastable domain down to 175 K. We compute the phase equilibria in the pure H(2)O system with this new model. Then we develop a pressure-temperature dependent activity model to describe the effect of ammonia on phase transitions. We show that aqueous ammonia solutions behave as regular solutions at low pressures, and as close-to-ideal solutions at pressure above 600 MPa. The computation of phase equilibria in the H(2)O-NH(3) system shows that ice III cannot exist at concentrations above 5-10 wt % NH(3) (depending on pressure), and ice V is not expected to form above 25% 27% NH(3). We eventually address the applications of this new model for thermal and evolution models of icy satellites. PMID- 20950013 TI - Volume of supercooled water under pressure and the liquid-liquid critical point. AB - The volume of water (H(2)O) was obtained at about 200-275 K and 40-400 MPa by using emulsified water. The plot of volume against temperature showed slightly concave-downward curvature at pressures higher than ~200 MPa. This is compatible with the liquid-liquid critical-point hypothesis, but hardly with the singularity free scenario. When the critical point is assumed to exist at ~50 MPa and ~223 K, the experimental volume and the derived compressibility are qualitatively described by the modified Fuentevilla-Anisimov scaling equation. PMID- 20950014 TI - Anomalous phase behavior in a model fluid with only one type of local structure. AB - We present evidence that the concurrent existence of two populations of particles with different effective diameters is not a prerequisite for the occurrence of anomalous phase behaviors in systems of particles interacting through spherically symmetric unbounded potentials. Our results show that an extremely weak softening of the interparticle repulsion, which yields a single nearest-neighbor separation, is able to originate a wide spectrum of unconventional features including reentrant melting, solid polymorphism, as well as thermodynamic, dynamic, and structural anomalies. These findings extend the possibility of anomalous phase behavior to a class of systems much broader than currently assumed. PMID- 20950015 TI - Nuclear momentum distribution in solid and liquid HF from ab initio calculation. AB - A calculation of nuclear momentum distribution of liquid and solid hydrogen fluoride was performed. In both systems, density functional theory generalized gradient approximation functional of Perdew, Burke, and Ernzerhof was used for the calculation: for liquid hydrogen fluoride, using an atom centered basis set for an isolated molecule with optimized geometry, and for solid hydrogen fluoride using plane-wave basis sets on optimized orthorhombic crystal cell. For liquid hydrogen fluoride, a semiclassical approach was adopted with the vibrational contribution to momentum distribution obtained from the density functional theory calculation and translational and rotational contributions calculated classically. Nuclear momentum distribution in the solid hydrogen fluoride was calculated entirely quantum mechanically using phonon dispersion and vibrational density of states calculated in the framework of plane-wave density functional theory. Theoretical results were contrasted with recently obtained results of Compton (deep inelastic) neutron scattering on liquid and solid hydrogen fluoride. In case of liquid hydrogen fluoride, almost a perfect agreement between theory and experiment was achieved within the harmonic Born-Oppenheimer approximation. For the solid system under investigation, the harmonic approximation leads to small (4%) overestimation of the square root of the second moment indicating that neutron Compton scattering technique is sensitive to proton delocalization due to hydrogen bonding in solid hydrogen fluoride. PMID- 20950016 TI - Excited state dynamics in solid and monomeric tetracene: The roles of superradiance and exciton fission. AB - The excited state dynamics in polycrystalline thin films of tetracene are studied using both picosecond fluorescence and femtosecond transient absorption. The solid-state results are compared with those obtained for monomeric tetracene in dilute solution. The room temperature solid-state fluorescence decays are consistent with earlier models that take into account exciton-exciton annihilation and exciton fission but with a reduced delayed fluorescence lifetime, ranging from 20-100 ns as opposed to 2 MUs or longer in single crystals. Femtosecond transient absorption measurements on the monomer in solution reveal several excited state absorption features that overlap the ground state bleach and stimulated emission signals. On longer timescales, the initially excited singlet state completely decays due to intersystem crossing, and the triplet state absorption superimposed on the bleach is observed, consistent with earlier flash photolysis experiments. In the solid-state, the transient absorption dynamics are dominated by a negative stimulated emission signal, decaying with a 9.2 ps time constant. The enhanced bleach and stimulated emission signals in the solid are attributed to a superradiant, delocalized S(1) state that rapidly fissions into triplets and can also generate a second superradiant state, most likely a crystal defect, that dominates the picosecond luminescence signal. The enhanced absorption strength of the S(0)->S(1) transition, along with the partially oriented nature of our polycrystalline films, obscures the weaker T(1)->T(N) absorption features. To confirm that triplets are the major species produced by relaxation of the initially excited state, the delayed fluorescence and ground state bleach recovery are compared. Their identical decays are consistent with triplet diffusion and recombination at trapping or defect sites. The results show that complications like exciton delocalization, the presence of luminescent defect sites, and crystallite orientation must be taken into account to fully describe the photophysical behavior of tetracene thin films. The experimental results are consistent with the traditional picture that tetracene's photodynamics are dominated by exciton fission and triplet recombination, but suggest that fission occurs within 10 ps, much more rapidly than previously believed. PMID- 20950017 TI - Formic and acetic acids in a nitrogen matrix: Enhanced stability of the higher energy conformer. AB - Formic acid (HCOOH, FA) and acetic acid (CH(3)COOH, AA) are studied in a nitrogen matrix. The infrared (IR) spectra of cis and trans conformers of these carboxylic acids (and also of the HCOOD isotopologue of FA) are reported and analyzed. The higher-energy cis conformer of these molecules is produced by narrowband near-IR excitation of the more stable trans conformer, and the cis-to-trans tunneling decay is evaluated spectroscopically. The tunneling process in both molecules is found to be substantially slower in a nitrogen matrix than in rare-gas matrices, the cis-form decay constants being approximately 55 and 600 times smaller in a nitrogen matrix than in an argon matrix, for FA and AA respectively. The stabilization of the higher-energy cis conformer is discussed in terms of specific interactions with nitrogen molecule binding with the OH group of the carboxylic acid. This model is in agreement with the observed differences in the IR spectra in nitrogen and argon matrices, in particular, the relative frequencies of the nuOH and tauCOH modes and the relative intensities of the nuOH and nuC=O bands. PMID- 20950018 TI - Dissociation of methane under high pressure. AB - Methane is an extremely important energy source with a great abundance in nature and plays a significant role in planetary physics, being one of the major constituents of giant planets Uranus and Neptune. The stable crystal forms of methane under extreme conditions are of great fundamental interest. Using the ab initio evolutionary algorithm for crystal structure prediction, we found three novel insulating molecular structures with P2(1)2(1)2(1), Pnma, and Cmcm space groups. Remarkably, under high pressure, methane becomes unstable and dissociates into ethane (C(2)H(6)) at 95 GPa, butane (C(4)H(10)) at 158 GPa, and further, carbon (diamond) and hydrogen above 287 GPa at zero temperature. We have computed the pressure-temperature phase diagram, which sheds light into the seemingly conflicting observations of the unusually low formation pressure of diamond at high temperature and the failure of experimental observation of dissociation at room temperature. Our results support the idea of diamond formation in the interiors of giant planets such as Neptune. PMID- 20950019 TI - Relaxation dynamics and ionic conductivity in a fragile plastic crystal. AB - We report a thorough characterization of the dielectric relaxation behavior and the ionic conductivity in the plastic-crystalline mixture of 60% succinonitrile and 40% glutaronitrile. The plastic phase can be easily supercooled and the relaxational behavior is investigated by broadband dielectric spectroscopy in the liquid, plastic crystalline, and glassy crystal phases. The alpha-relaxation found in the spectra is characterized in detail. A well-pronounced secondary and faint indications for a third relaxation process were found. The latter most likely is of Johari-Goldstein type. From the temperature dependence of the alpha relaxation time, a fragility parameter of 62 was determined. Thus, together with Freon112, this material stands out among all other plastic crystals by being a relatively fragile glass former. This finding provides strong support for an energy-landscape related explanation of the fragility of glass formers. In addition, unusually strong conductivity contributions were detected in the spectra exhibiting the typical features of ionic charge transport making this material a good basis for solid-state electrolytes. PMID- 20950020 TI - Analysis of localization sites for an excess electron in neutral methanol clusters using approximate pseudopotential quantum-mechanical calculations. AB - We have used a recently developed electron-methanol molecule pseudopotential in approximate quantum mechanical calculations to evaluate and statistically analyze the physical properties of an excess electron in the field of equilibrated neutral methanol clusters ((CH(3)OH)(n), n=50-500). The methanol clusters were generated in classical molecular dynamics simulations at nominal 100 and 200 K temperatures. Topological analysis of the neutral clusters indicates that methyl groups cover the surface of the clusters almost exclusively, while the associated hydroxyl groups point inside. Since the initial neutral clusters are lacking polarity on the surface and compact inside, the excess electron can barely attach to these structures. Nevertheless, most of the investigated cluster configurations do support weakly stabilized cluster anion states. We find that similarly to water clusters, the pre-existing instantaneous dipole moment of the neutral clusters binds the electron. The localizing electrons occupy diffuse, weakly bound surface states that largely engulf the cluster although their centers are located outside the cluster molecular frame. The initial localization of the excess electron is reflected in its larger radius compared to water due to the lack of free OH hydrogens on the cluster surface. The stabilization of the excess electron increases, while the radius decreases monotonically as the clusters grow in size. Stable, interior bound states of the excess electron are not observed to form neither in finite size methanol clusters nor in the equilibrium bulk. PMID- 20950021 TI - Quantum path integral simulation of isotope effects in the melting temperature of ice Ih. AB - The isotope effect in the melting temperature of ice Ih has been studied by free energy calculations within the path integral formulation of statistical mechanics. Free energy differences between isotopes are related to the dependence of their kinetic energy on the isotope mass. The water simulations were performed by using the q-TIP4P/F model, a point charge empirical potential that includes molecular flexibility and anharmonicity in the OH stretch of the water molecule. The reported melting temperature at ambient pressure of this model (T=251 K) increases by 6.5+/-0.5 and 8.2+/-0.5 K upon isotopic substitution of hydrogen by deuterium and tritium, respectively. These temperature shifts are larger than the experimental ones (3.8 and 4.5 K, respectively). In the classical limit, the melting temperature is nearly the same as that for tritiated ice. This unexpected behavior is rationalized by the coupling between intermolecular interactions and molecular flexibility. This coupling makes the kinetic energy of the OH stretching modes larger in the liquid than in the solid phase. However, the opposite behavior is found for intramolecular modes, which display larger kinetic energy in ice than in liquid water. PMID- 20950022 TI - Transition levels of defect centers in ZnO by hybrid functionals and localized basis set approach. AB - A hybrid density functional study based on a periodic approach with localized atomic orbital basis functions has been performed in order to compute the optical and thermodynamic transition levels between different charge states of defect impurities in bulk ZnO. The theoretical approach presented allows the accurate computation of transition levels starting from single particle Kohn-Sham eigenvalues. The results are compared to previous theoretical findings and with available experimental data for a variety of defects ranging from oxygen vacancies, zinc interstitials, and hydrogen and nitrogen impurities. We find that H and Zn impurities give rise to shallow levels; the oxygen vacancy is stable only in the neutral V(O) and doubly charged V(O) (2+) variants, while N-dopants act as deep acceptor levels. PMID- 20950023 TI - Sulfoxide stretching mode as a structural reporter via dual-frequency two dimensional infrared spectroscopy. AB - The S=O stretching mode in sulfoxides, having a frequency in the 950-1150 cm(-1) range, is tested as a structural label via dual-frequency two-dimensional infrared (2DIR) spectroscopy. The properties of this structural reporter are studied in several compounds, including (4,4(')-dimethyl-2,2(')-bipyridyl)(o methylsulfinylbenzoate) ruthenium II, [Ru(dmb)(2)(BzSO)](+), (RuBzSO), octylsulfinylpropionic acid (OSPA), and o- and p-methylsulfinyl-benzoic acid (oMSBA and pMSBA). The mode assignment in the fingerprint region for these compounds is made using a combination of density functional theory calculations and 2DIR and relaxation-assisted 2DIR (RA 2DIR) spectroscopies. The SO stretching mode frequency and IR intensity demonstrate substantial sensitivity to the molecular structure. Multiple cross peaks of the C=O and S=O stretching modes with modes in the fingerprint region (930-1450 cm(-1)) were recorded. The 2DIR and RA 2DIR spectra focusing at interactions of a high-frequency mode of a ligand with the modes in the fingerprint region provide a spectral fingerprint of a compound and help mode assignment in the often congested fingerprint region. The cross-peak amplitudes in oMSBA, pMSBA, and OSPA were compared with the theoretical predictions based on the computed values for the off-diagonal anharmonicities and a reasonable match is found. The SO stretching mode provides means for assigning other modes in the fingerprint region and constitutes a promising structural reporter for the 2DIR and RA 2DIR spectroscopy measurements. PMID- 20950024 TI - Curvature modulates the self-assembly of amphiphilic molecules. AB - In this work, we used lattice Monte Carlo simulations and theoretical model calculations to show how the self-assembly of adsorbed amphiphilic molecules is affected by the local curvature of solid surfaces. It is found that, beyond a critical curvature value, solid surface geometry governs the spatial ordering of aggregates and may induce the morphological transitions. The simulation results show how the curvature of solid surfaces modulates the distribution of aggregates: the anisotropy in local curvature along and perpendicular to the cylindrical surfaces tends to generate orientationally ordered cylindrical micelles. To account for the morphological transitions induced by the local curvature of solid surfaces, we constructed a theoretical model which includes the Helfrich bending energy, the deformation energy of aggregates induced by solid surfaces, and the adsorption energy. The model calculations indicate that on highly curved solid surfaces the bending energy for bilayer structure sharply increases with surface curvature, which in turn induces the morphological transition from bilayer to cylindrical structure. Our results suggest that the local curvature provides a means of controlling the spatial organization of amphiphilic molecules. PMID- 20950025 TI - Water adsorption isotherms on porous onionlike carbonaceous particles. Simulations with the grand canonical Monte Carlo method. AB - The grand canonical Monte Carlo method is used to simulate the adsorption isotherms of water molecules on different types of model soot particles. These soot models are constructed by first removing atoms from onion-fullerene structures in order to create randomly distributed pores inside the soot, and then performing molecular dynamics simulations, based on the reactive adaptive intermolecular reactive empirical bond order (AIREBO) description of the interaction between carbon atoms, to optimize the resulting structures. The obtained results clearly show that the main driving force of water adsorption on soot is the possibility of the formation of new water-water hydrogen bonds with the already adsorbed water molecules. The shape of the calculated water adsorption isotherms at 298 K strongly depends on the possible confinement of the water molecules in pores of the carbonaceous structure. We found that there are two important factors influencing the adsorption ability of soot. The first of these factors, dominating at low pressures, is the ability of the soot of accommodating the first adsorbed water molecules at strongly hydrophilic sites. The second factor concerns the size and shape of the pores, which should be such that the hydrogen bonding network of the water molecules filling them should be optimal. This second factor determines the adsorption properties at higher pressures. PMID- 20950026 TI - Investigation of antirelaxation coatings for alkali-metal vapor cells using surface science techniques. AB - Many technologies based on cells containing alkali-metal atomic vapor benefit from the use of antirelaxation surface coatings in order to preserve atomic spin polarization. In particular, paraffin has been used for this purpose for several decades and has been demonstrated to allow an atom to experience up to 10 000 collisions with the walls of its container without depolarizing, but the details of its operation remain poorly understood. We apply modern surface and bulk techniques to the study of paraffin coatings in order to characterize the properties that enable the effective preservation of alkali spin polarization. These methods include Fourier transform infrared spectroscopy, differential scanning calorimetry, atomic force microscopy, near-edge x-ray absorption fine structure spectroscopy, and x-ray photoelectron spectroscopy. We also compare the light-induced atomic desorption yields of several different paraffin materials. Experimental results include the determination that crystallinity of the coating material is unnecessary, and the detection of C[Double Bond]C double bonds present within a particular class of effective paraffin coatings. Further study should lead to the development of more robust paraffin antirelaxation coatings, as well as the design and synthesis of new classes of coating materials. PMID- 20950027 TI - Investigation on the orderly growth of thick zinc phthalocyanine films on Ag(100) surface. AB - The growth of zinc phthalocyanine (ZnPc) on Ag(100) surface from monolayer to multilayer was investigated by low-energy electron diffraction, x-ray diffraction, and high-resolution electron energy loss spectroscopy (HREELS). At monolayer coverage, ZnPc molecules form an ordered film with molecular planes parallel to the substrate. The same structure is maintained as the film thickness increases. HREELS analysis shows that intermolecular pi-pi interaction dominates during the film growth from monolayer to multilayer. The pi-d interaction between the adsorbates and the substrate is only applicable in the first adlayer. Stronger intermolecular-layer interaction is observed at higher coverages. PMID- 20950028 TI - Transport through a mixed-valence molecular transistor in the sequential tunneling regime: Theoretical insight from the two-site Peierls-Hubbard model. AB - Transport through a mixed-valence system in the sequential-tunneling region is investigated using the master equation method and a simple two-site Peierls Hubbard model that includes electron-phonon (e-p) coupling, electron hopping, and electron-electron (e-e) repulsion. The characteristics of Coulomb diamonds in the conductance spectra under three regimes are discussed. In the regime of zero e-p coupling, we found that the widths of Coulomb diamonds are dominated by the competition of electron-hopping and Coulomb repulsion. In the regime of weak and intermediate e-p coupling, by virtue of the normal-mode transformation we found that coupling to the symmetric-mode decreases the widths of Coulomb diamonds. In the regime of strong e-p coupling, an analytical expression for the widths of Coulomb diamonds can be derived using the small polaron transformation. The derived formula provides a new way to estimate e-e interactions and e-p couplings experimentally. PMID- 20950029 TI - Properties of alkali-halide salt solutions about polarizable nanoparticle solutes for different ion models. AB - We investigate the distributions of various salts about large hydrophobic polarizable solutes in aqueous electrolyte solutions. The solutes are modeled as nanometer-sized cylindrical objects, a scale relevant to biomolecules and nanomaterials, and particularly high aspect ratio nanoparticles. Interactions, including image charge forces arising from the finite polarizability of the solute, between explicit solvent/ions and the solute are computed explicitly using a molecular dynamics simulation methodology we have recently introduced. Comparisons are made between several salt species and different models of the force fields for each ionic component of the salt. We find evidence that both small cations, Li(+), and large anions, I(-), adsorb at hydrophobic interfaces. Our results indicate that the ion structure about the solute is strongly dependent on the force field investigated, suggesting that ion selectivity is quite sensitive to the respective parameters defining the ion's size and binding energy as well as to the polarizability of the solute. PMID- 20950030 TI - The possible equilibrium shapes of static pendant drops. AB - Analytical and numerical studies are carried out on the shapes of two-dimensional and axisymmetric pendant drops hanging under gravity from a solid surface. Drop shapes with both pinned and equilibrium contact angles are obtained naturally from a single boundary condition in the analytical energy optimization procedure. The numerical procedure also yields optimum energy shapes, satisfying Young's equation without the explicit imposition of a boundary condition at the plate. It is shown analytically that a static pendant two-dimensional drop can never be longer than 3.42 times the capillary length. A related finding is that a range of existing solutions for long two-dimensional drops correspond to unphysical drop shapes. Therefore, two-dimensional drops of small volume display only one static solution. In contrast, it is known that axisymmetric drops can display multiple solutions for a given volume. We demonstrate numerically that there is no limit to the height of multiple-lobed Kelvin drops, but the total volume is finite, with the volume of successive lobes forming a convergent series. The stability of such drops is in question, though. Drops of small volume can attain large heights. A bifurcation is found within the one-parameter space of Laplacian shapes, with a range of longer drops displaying a minimum in energy in the investigated space. Axisymmetric Kelvin drops exhibit an infinite number of bifurcations. PMID- 20950031 TI - DFT+U study of defects in bulk rutile TiO(2). AB - We present a systematic study of electronic gap states in defected titania using our implementation of the Hubbard-U approximation in the grid-based projector augmented wave density functional theory code, GPAW. The defects considered are Ti interstitials, O vacancies, and H dopants in the rutile phase of bulk titanium dioxide. We find that by applying a sufficiently large value for the Hubbard-U parameter of the Ti 3d states, the excess electrons localize spatially at the Ti sites and appear as states in the band gap. At U=2.5 eV, the position in energy of these gap states are in fair agreement with the experimental observations. In calculations with several excess electrons and U=2.5 eV, all of these end up in gap states that are spatially localized around specific Ti atoms, thus effectively creating one Ti(3+) ion per excess electron. An important result of this investigation is that regardless of which structural defect is the origin of the gap states, at U=2.5 eV, these states are found to have their mean energies within a few hundredths of an eV from 0.94 eV below the conduction band minimum. PMID- 20950032 TI - Transport of heat and mass in a two-phase mixture: From a continuous to a discontinuous description. AB - We present a theory that describes the transport properties of the interfacial region with respect to heat and mass transfer. Postulating the local Gibbs relation for a continuous description inside the interfacial region, we derive the description of the Gibbs surface in terms of excess densities and fluxes along the surface. We introduce overall interfacial resistances and conductances as the coefficients in the force-flux relations for the Gibbs surface. We derive relations between the local resistivities for the continuous description inside the interfacial region and the overall resistances of the surface for transport between the two phases for a mixture. It is shown that interfacial resistances depend among other things on the enthalpy profile across the interface. Since this variation is substantial, the coupling between heat and mass flow across the surface is also substantial. In particular, the surface puts up much more resistance to the heat and mass transfer than the homogeneous phases over a distance comparable to the thickness of the surface. This is the case not only for the pure heat conduction and diffusion but also for the cross effects such as thermal diffusion. For the excess fluxes along the surface and the corresponding thermodynamic forces, we derive expressions for excess conductances as integrals over the local conductivities along the surface. We also show that the curvature of the surface affects only the overall resistances for transport across the surface and not the excess conductivities along the surface. PMID- 20950033 TI - Investigation of methyl methacrylate-oligomer adsorbed on grooved substrate of different aspect ratios by coarse-grained configurational-bias Monte Carlo simulation. AB - The coarse-grained configurational-bias Monte Carlo simulation was used to investigate structural behaviors of methyl methacrylate (MMA)-oligomers adsorbed on grooved substrates with different aspect ratios. In this study, three types of chains are classified according to their positions relative to the groove. Types 1, 2, and 3 represent the entire MMA-oligomer within the groove, the MMA-oligomer partially within the groove, and the oligomer outside the groove, respectively. The orientational order parameters of types 1 and 2 oligomers decrease with the increase of groove width, but the orientational order parameter of type 3 oligomers is approximately equal to 0.1. In addition, observation of the orientational order parameters of type 1 oligomers interacting with the grooved substrate at different interaction strengths decrease with increasing the groove width. Furthermore, the orientational order parameters of type 1 oligomers within the narrowest (20 A) and the widest (35 A) groove with different depths were determined. For the narrowest groove, the arrangement of type 1 oligomers will be influenced by the groove width. However, in the case of the widest groove, the orientational order parameter of type 1 oligomers is approximately equal to 0.2. PMID- 20950034 TI - A two-temperature model of radiation damage in alpha-quartz. AB - Two-temperature models are used to represent the physics of the interaction between atoms and electrons during thermal transients such as radiation damage, laser heating, and cascade simulations. We introduce a two-temperature model applied to an insulator, alpha-quartz, to model heat deposition in a SiO(2) lattice. Our model of the SiO(2) electronic subsystem is based on quantum simulations of the electronic response in a SiO(2) repeat cell. We observe how the parametrization of the electronic subsystem impacts the degree of permanent amorphization of the lattice, especially compared to a metallic electronic subsystem. The parametrization of the insulator electronic subsystem has a significant effect on the amount of residual defects in the crystal after 10 ps. While recognizing that more development in the application of two-temperature models to insulators is needed, we argue that the inclusion of a simple electronic subsystem substantially improves the realism of such radiation damage simulations. PMID- 20950035 TI - The interaction of hybrid nanoparticles inserted within surfactant bilayers. AB - We determine by small-angle x-ray scattering the structure factor of hydrophobic particles inserted within lamellar surfactant phases for various particle concentrations. The data are then analyzed by numerically solving the Ornstein Zernicke equation, taking into account both the intra- and interlayer interactions. We find that particles within the same layer repel each other and that the interaction potential (taken as independent of the concentration) has a contact value of 2.2k(B)T and a range of about 10 A. If the amplitude is allowed to decrease with increasing concentration, the contact value in the dilute limit is about 5k(B)T for a similar range. PMID- 20950036 TI - Tilt grain boundaries in a diblock copolymer ordered nanocomposite lamellar phase. AB - A hybrid self-consistent field theory/density functional theory method is applied to predict tilt (kink) grain boundary structures between lamellar domains of a symmetric diblock copolymer with added spherical nanoparticles. Structures consistent with experimental observations are found and theoretical evidence is provided in support of a hypothesis regarding the positioning of nanoparticles. Some particle distributions are predicted for situations not yet examined by experiment. PMID- 20950037 TI - Stochastic entangled chain dynamics of dense polymer solutions. AB - We propose an adjustable-parameter-free, entangled chain dynamics model of dense polymer solutions. The model includes the self-consistent dynamics of molecular chains and solvent by describing the former via coarse-grained polymer dynamics that incorporate hydrodynamic interaction effects, and the latter via the forced Stokes equation. Real chain elasticity is modeled via the inclusion of a Pincus regime in the polymer's force-extension curve. Excluded volume effects are taken into account via the combined action of coarse-grained intermolecular potentials and explicit geometric tracking of chain entanglements. We demonstrate that entanglements are responsible for a new (compared to phantom chain dynamics), slow relaxation mode whose characteristic time scale agrees very well with experiment. Similarly good agreement between theory and experiment is also obtained for the equilibrium chain size. We develop methods for the solution of the model in periodic flow domains and apply them to the computation of entangled polymer solutions in equilibrium. We show that the number of entanglements Pi agrees well with the number of entanglements expected on the basis of tube theory, satisfactorily reproducing the latter's scaling of Pi with the polymer volume fraction phi. Our model predicts diminishing chain size with concentration, thus vindicating Flory's suggestion of excluded volume effects screening in dense solutions. The predicted scaling of chain size with phi is consistent with the heuristic, Flory theory based value. PMID- 20950038 TI - Many-body interactions and coarse-grained simulations of structure of nanoparticle-polymer melt mixtures. AB - We present a computational approach for coarse-grained simulations of nanoparticle-polymer melt mixtures. We first examine the accuracy of an effective one-component approach based on a pair interaction approximation to polymer mediated interactions, and demonstrate that even at low particle volume fractions, the polymer-mediated many-body interaction effects can prove significant in determining the structural characteristics of mixtures of nanoparticles and polymer melts. The origin of such effects is shown to arise from the extent of polymer perturbations resulting from the presence of the nanoparticles. To account for such effects, we propose a new simulation approach that employs a coarse-grained representation of the polymers to capture the many body corrections to the polymer-mediated pair interaction potentials. The results of the coarse-grained simulations are shown to be in good quantitative agreement with the reference simulations. The method developed in this article is proposed as a tractable approach to coarse-grain and effect computer simulations of atomistic descriptions of polymer-nanoparticle systems. PMID- 20950039 TI - Polymer-mediated spatial organization of nanoparticles in dense melts: Transferability and an effective one-component approach. AB - We study two problems in the framework of the integral equation theory of polymer mediated spatial organization of nanoparticles in dense melts motivated by multiscale simulation and many body physics issues. How nonspherical nanoparticle shape modifies polymer-induced interactions under dilute nanoparticle conditions is investigated over a range of primary particle sizes and interfacial cohesion strengths. Nonuniversal consequences of nonspherical shape are found for the pair correlation function on local scales and some qualitative differences on larger scales due primarily to intraparticle connectivity constraints. For a large enough nanoparticle site diameter, the potentials of mean force (PMF) for all shapes studied (sphere, rod, disk, compact tetrahedral cluster) exhibit linear scaling with the size ratio of nanoparticle to polymer monomer site diameter and quite good "transferability." The ability of a simple effective one-component approach, based on the dilute nanoparticle PMF as an effective pair-decomposable potential, to describe interparticle structure at nonzero volume fractions is also studied. Although not generally quantitatively accurate due to neglect of many body correlation effects, especially at high nanoparticle loadings and near contact separations, the simple approach captures rather well many aspects of the real space structure. The errors incurred depend systematically on whether interfacial cohesion strength results in contact aggregation, steric stabilization, or bridging. For the filler collective static structure factor, many body effects are weakest for local cage scale correlations and grow significantly at smaller wavevectors under depletion or bridging conditions. PMID- 20950040 TI - Rotational and spin viscosities of water: Application to nanofluidics. AB - In this paper we evaluate the rotational viscosity and the two spin viscosities for liquid water using equilibrium molecular dynamics. Water is modeled via the flexible SPC/Fw model where the Coulomb interactions are calculated via the Wolf method which enables the long simulation times required. We find that the rotational viscosity is independent of the temperature in the range from 284 to 319 K. The two spin viscosities, on the other hand, decrease with increasing temperature and are found to be two orders of magnitude larger than that estimated by Bonthuis et al. [Phys. Rev. Lett. 103, 144503 (2009)] We apply the results from molecular dynamics simulations to the extended Navier-Stokes equations that include the coupling between intrinsic angular momentum and linear momentum. For a flow driven by an external field the coupling will reduce the flow rate significantly for nanoscale geometries. The coupling also enables conversion of rotational electrical energy into fluid linear momentum and we find that in order to obtain measurable flow rates the electrical field strength must be in the order of 0.1 MV m(-1) and rotate with a frequency of more than 100 MHz. PMID- 20950041 TI - Nonlocal viscosity of polymer melts approaching their glassy state. AB - The nonlocal viscosity kernels of polymer melts have been determined by means of equilibrium molecular dynamics upon cooling toward the glass transition. Previous results for the temperature dependence of the self-diffusion coefficient and the value of the glass transition temperature are confirmed. We find that it is essential to include the attractive part of the interatomic potential in order to observe a strong glass transition. The width of the reciprocal space kernel decreases dramatically near the glass transition, being described by a deltalike function near and below the glass transition, leading to a very broad kernel in physical space. Thus, spatial nonlocality turns out to play an important role in polymeric fluids at temperatures near the glass transition temperature. PMID- 20950042 TI - Screening of charged spheroidal colloidal particles. AB - We study the effective screened electrostatic potential created by a spheroidal colloidal particle immersed in an electrolyte, within the mean field approximation, using Poisson-Boltzmann equation in its linear and nonlinear forms, and also beyond the mean field by means of Monte Carlo computer simulation. The anisotropic shape of the particle has a strong effect on the screened potential, even at large distances (compared to the Debye length) from it. To quantify this anisotropy effect, we focus our study on the dependence of the potential on the position of the observation point with respect with the orientation of the spheroidal particle. For several different boundary conditions (constant potential, or constant surface charge) we find that, at large distance, the potential is higher in the direction of the large axis of the spheroidal particle. PMID- 20950043 TI - A Nyquist analysis of glassy dynamics, aging, and discrete basins of attraction in a small system. AB - The process of attachment of a deformable polystyrene colloidal particle to a planar substrate shows features of slow relaxation and aging, typically observed in many-body disordered and glassy systems. This slow dynamics is attributed to the presence of polymeric tethers constituting a few internal degrees of freedom. The effects of these few degrees of freedom are revealed by a Nyquist analysis of the data that demonstrate the existence of only a few discernible basins of attraction as the system reaches the ground state and thus provides a minimal model of complexity and glassy dynamics. PMID- 20950044 TI - Entropic forces and directed alignment of hard squares in suspensions of rods and disks. AB - We use Monte Carlo simulations in two dimensions to study the depletion forces between two hard squares in a suspension of hard rods or disks. We determine the effects of size and concentration of rods and disks on the potential of mean force between the squares. Both rods and disks produce a short-range depletion attraction between the two squares. The depletion interaction can be strong enough to outweigh the (rotational) entropic repulsion between the squares at certain sizes and concentrations of the rods and disks. We also probe the relative orientation that two squares adopt as they approach each other and we observe rich behavior, in which the relative orientation depends on the size, concentration, and shape of the depletion agent. Simple models based on the ideas of Asakura and Oosawa [J. Chem. Phys. 22, 1255 (1954)] can explain trends in the potentials of mean force obtained from the simulations. PMID- 20950045 TI - The phase behavior, structure, and dynamics of rodlike mesogens with various flexibility using dissipative particle dynamics simulation. AB - We present a systematic dissipative particle dynamics (DPD) study on the phase behavior, structure, and dynamics of rodlike mesogens. In addition to a rigid fused-bead-chain model with RATTLE constraint method, we also construct a semirigid model in which the flexibility is controlled by the bending constant of k(phi). Using this notation, the rigid model has an infinite bending constant of k(phi)=infinity. Within the parameter space studied, both two kinds of models exhibit the nematic and smectic-A phases in addition to the isotropic and solid phases. All of the phase transitions are accompanied by the discontinuities in the thermodynamical, structural, and dynamical quantities and the hysteresis around the transition points, and are therefore first order. Note that the obtained solid state exhibits an in-layer tetragonal packing due to the high density. For the rigid model, the simulations show that the liquid crystal phases can be observed for mesogens with at least five beads and the nematic phase is the first one to appear. More importantly, the phase diagram of seven-bead-chain models is obtained as a function of k(phi) and temperature. It is found that decreasing the value of k(phi) reduces the anisotropy of molecular shape and the orientational ordering, and thereby shifts the liquid crystal phases to the lower temperature end of the phase diagram. Due to the different k(phi) dependence of phase transition temperatures, the nematic phase range exhibits a more marked narrowing than the smectic-A phase as k(phi) is reduced, implying that the flexibility has a destabilizing effect on the nematic and smectic-A phases. We also have investigated the anisotropic translational diffusion in liquid crystal phases and its temperature and flexibility dependence. In our study, we find that the phases formed, their statical and dynamic properties, as well as the transition properties are in close accord with those observations in real thermotropic liquid crystals. It is clear that both the rigid and semirigid models we used are valuable models with which to study the behavior of thermotropic liquid crystals using DPD algorithm. PMID- 20950046 TI - Water distributions in polystyrene-block-poly[styrene-g-poly(ethylene oxide)] block grafted copolymer system in aqueous solutions revealed by contrast variation small angle neutron scattering study. AB - We develop an experimental approach to analyze the water distribution around a core-shell micelle formed by polystyrene-block-poly[styrene-g-poly(ethylene oxide (PEO)] block copolymers in aqueous media at a fixed polymeric concentration of 10 mg/ml through contrast variation small angle neutron scattering (SANS) study. Through varying the D(2)O/H(2)O ratio, the scattering contributions from the water molecules and the micellar constituent components can be determined. Based on the commonly used core-shell model, a theoretical coherent scattering cross section incorporating the effect of water penetration is developed and used to analyze the SANS I(Q). We have successfully quantified the intramicellar water distribution and found that the overall micellar hydration level increases with the increase in the molecular weight of hydrophilic PEO side chains. Our work presents a practical experimental means for evaluating the intramacromolecular solvent distributions of general soft matter systems. PMID- 20950047 TI - Reduction of polymer surface tension by crystallized polymer nanoparticles. AB - Self-consistent field theory is applied to investigate the effects of crystallized polymer nanoparticles on polymer surface tension. It is predicted that the nanoparticles locate preferentially at the polymer surface and significantly reduce the surface tension, in agreement with experiment. In addition to the reduction of surface tension, the width of the polymer surface is found to narrow. The reduced width and surface tension are due to the smaller spatial extent of the nanoparticles compared to the polymer. This allows the interface to become less diffuse and so reduces the energies of interaction at the surface, which lowers the surface tension. The solubility of the surrounding solvent phase into the polymer melt is mostly unchanged, a very slight decrease being detectable. The solubility is constant because away from the interface, the system is homogeneous and the replacement of polymer with nanoparticles has little effect. PMID- 20950048 TI - Fractional protein dynamics seen by nuclear magnetic resonance spectroscopy: Relating molecular dynamics simulation and experiment. AB - We propose a fractional Brownian dynamics model for time correlation functions characterizing the internal dynamics of proteins probed by NMR relaxation spectroscopy. The time correlation functions are represented by a broad distribution of exponential functions which are characterized by two parameters. We show that the model describes well the restricted rotational motion of N-H vectors in the amide groups of lysozyme obtained from molecular dynamics simulation and that reliable predictions of experimental relaxation rates can be obtained on that basis. PMID- 20950049 TI - The susceptibility of alpha-helical secondary structure to steric strain: Coarse grained simulation of dendronized polypeptides. AB - The propensity of a peptide chain for adopting helical secondary structure can be modulated not only through the solvation properties of its side chains but also through their size and shape. Here we examine a coarse-grained model for dendronized polypeptides that focuses on the susceptibility of alpha-helical structure to the steric strain exerted by hydrophilic pendant groups. Undecorated molecules exhibit a pronounced transition from random coil to helix upon cooling [J. P. Kemp and J. Z. Y. Chen, Biomacromolecules 2, 389 (2001)]. As gauged by specific heat and by order parameters characterizing helicity at several length scales, this transition is quite robust to the introduction of first- and second generation dendron side chains. More highly branched side chains, however, reduce the entropy of compact states so severely that helical ordering is undetectable over the entire temperature range accessible to our importance sampling methods. Consistent with experimental observations for side chains comparable to those of our model in volume-excluding size and shape, we find the backbone of these third generation molecules to assume a distended rodlike state that is both stiff and achiral. PMID- 20950050 TI - On the hydration of the phosphocholine headgroup in aqueous solution. AB - The hydration of the phosphocholine headgroup in 1,2-dipropionyl-sn-glycero-3 phosphocholine (C(3)-PC) in solution has been determined by using neutron diffraction enhanced with isotopic substitution in combination with computer simulation techniques. The atomic scale hydration structure around this head group shows that both the -N(CH(3))(3) and -CH(2) portions of the choline headgroup are strongly associated with water, through a unique hydrogen bonding regime, where specifically a hydrogen bond from the C-H group to water and a strong association between the water oxygen and N(+) atom in solution have both been observed. In addition, both PO(4) oxygens (P=O) and C=O oxygens are oversaturated when compared to bulk water in that the average number of hydrogen bonds from water to both X=O oxygens is about 2.5 for each group. That water binds strongly to the glycerol groups and is suggestive that water may bind to these groups when phosophotidylcholine is embedded in a membrane bilayer. PMID- 20950052 TI - Note: The seeming disagreement between a recent Brownian-particle diffusion equation and a previous result: a clarification. PMID- 20950051 TI - Note: Collision-induced infrared absorption by gaseous deuterium. PMID- 20950054 TI - Erratum: "Dipolar sticky hard spheres within the Percus-Yevick approximation plus orientational linearization" [J. Chem. Phys. 133, 034511 (2010)]. PMID- 20950056 TI - 5-HT3 antagonists under development. AB - IMPORTANCE OF THE FIELD: The main therapeutic area of 5-HT(3) receptor antagonists is the treatment of chemotherapy-induced nausea and vomiting (CINV), which is the most common and distressing side effects of anticancer treatment. The second major clinical application of 5-HT(3) receptor antagonists is in the treatment of irritable bowel syndrome (IBS). 5-HT(3) antagonists have been widely used and found to decrease gut transit, increase fluid absorption and reduce pain. The uses of 5-HT(3) antagonists are expending to treatment of CNS diseases such as anxiety and sleep disorders as antipsychotics and so on. AREAS COVERED IN THIS REVIEW: The structures, in vitro activities, in vivo effects and some clinical data on 5-HT(3) receptor antagonists under development. WHAT THE READER WILL GAIN: Future research directions in 5-HT(3) antagonists based on the clinical trial data of the pipeline molecules. TAKE HOME MESSAGE: Most drug candidates in clinical trials were discovered in the early 1990s and their patent expiry is imminent. Acquiring intellectual properties of novel 5-HT(3) receptor antagonists with improved efficacies would provide a bright future. Particularly, as the current 5-HT(3) receptor antagonists are classified into only three representative structural families (one third are zacopride-like benzamides and the others are ondansteron-like tricyclic compounds and dolansetron-like bicyclic compounds), structurally diverse compound libraries need to be extensively investigated for identification of novel 5-HT(3) receptor antagonists. PMID- 20950057 TI - Evaluation of an occupational therapy mentorship program: effects on therapists' skills and family-centered behavior. AB - There is growing interest in understanding the usefulness of mentorship programs for children's rehabilitation service providers. This evaluation study examined the effects of an occupational therapy mentorship program on the skills and behaviors of 8 new and 17 experienced occupational therapists practicing at a regional children's rehabilitation center. Self- and peer-report measures of family-centered behavior, critical thinking ability, listening/interactive communication skill, and clinical behavior were collected before and after an 11 month facilitated, collaborative group mentorship intervention. Significant pre post changes associated with intervention were found on 9 of 12 outcome measures, including information provision, respectful treatment, self-confidence, and listening and clinical skill. Changes were not found on the more trait-like variables of open-mindedness, interpersonal sensitivity, and interpersonal skill. Experienced therapists had higher scores than new therapists on most variables, including family-centered behavior, listening skill, and clinical skill. Implications regarding the utility of mentorship programs in children's rehabilitation centers are discussed. PMID- 20950058 TI - Nonviral gene delivery to human ovarian cancer cells using arginine-grafted PAMAM dendrimer. AB - BACKGROUND: A specific and effective strategy is in demand to treat ovarian cancer successfully. Epidermal growth factor receptor (EGFR) is highly expressed in ovarian cancer, and thus EGFR antisense gene therapy can be a potential therapeutic strategy. METHOD: L-Arginine-grafted-polyamidoamine dendrimer (PAMAM Arg) has been reported to be a novel nonviral gene delivery carrier. Therefore, the ability of PAMAM-Arg in transferring a luciferase gene to ovarian carcinoma SK-OV3 cells has been examined, and the cytotoxicity of the cationic polymer has been investigated. In addition, the suppression of cell proliferation has been evaluated by transferring an EGFR antisense gene to SK-OV3 cells using PAMAM-Arg. Polyethyleneimine (PEI) 25K was used as a positive control. RESULTS: As a result, in vitro gene transfection efficiency of PAMAM-Arg was enhanced with increasing transfection time and N/P ratios. PAMAM-Arg transferred the luciferase gene into cells more efficiently than PEI. In addition, PAMAM-Arg was minimally toxic to the cells whereas PEI 25K was highly toxic. The polyplexes formed by the EGFR antisense gene and PAMAM-Arg significantly reduced thymidine incorporation into the cells suggesting the suppression of cancer cell proliferation. CONCLUSION: These results suggest that a PAMAM-Arg/EGFR antisense gene complex can be used as a safe and efficient therapeutic agent for cancer gene therapy. PMID- 20950059 TI - Nationally representative waist circumference percentiles in German adolescents aged 11.0-18.0 years. AB - OBJECTIVE: The aim of this study was to develop age- and sex-specific percentile curves for waist circumference (WC) in German adolescents. METHODS: A cross sectional population-based study (German Health Interview and Examination Survey for Children and Adolescents [KiGGS]) was carried out in a large nationally representative sample of 3 345 males and 3 221 females aged 11.0 to 18.0 years from May 2003 to May 2006. Smoothed percentile curves of WC were derived by the LMS method. RESULTS: Girls had lower WC values than boys at any age and percentile. WC increased with age in both boys and girls. The curves show a fairly linear pattern for males, but for females they begin to level off after the age of 13 years. CONCLUSIONS: The presented WC percentile curves are based on a representative sample of adolescents living in Germany and standardized measurements. We propose their use for clinical practice to monitor abdominal obesity in adolescents, although there is a need for future studies correlating cut-offs with health outcomes. The German curves could contribute to the feasibility of combining representative data from several countries to establish an international reference for WC. PMID- 20950060 TI - US health reform and value: hit or miss? PMID- 20950062 TI - Pharmacoeconomics of etravirine. AB - HIV infection, particularly multidrug-resistant HIV, continues to be a major societal and economic challenge worldwide. Etravirine, a new (US FDA approved in 2008) non-nucleoside reverse transcriptase inhibitor, has been shown to be very effective in treating patients who have failed prior antiretroviral therapy. Clinical studies demonstrated that etravirine in combination with other antiretrovirals achieved superior levels of undetectable plasma HIV RNA and CD4 cell count increases that led to reductions in risk of death and development of AIDS-defining illnesses when compared with placebo. Etravirine was also shown to be generally well tolerated, with favorable CNS and psychiatric tolerability profiles. In addition, etravirine in combination with other antiretrovirals has been shown to improve quality of life and quality-adjusted life expectancy. Economic evaluations showed that the addition of etravirine to a regimen was associated with lower costs per person with an undetectable viral load and lower hospital-related costs compared with placebo. PMID- 20950063 TI - Health. Happiness. Inequality. AB - At the beginning of June 2010, the conference 'Health. Happiness. Inequality. Modelling the Pathways between Income Inequality and Health' was held in Darmstadt, Germany. Invited speakers and presenters traveled from all over the world; and researchers from several different subdisciplines were represented at the conference. The common denominator of participants was an interest in how societal income inequality affects individual health and life satisfaction. New and fascinating research results were presented and participants engaged in many interesting discussions. PMID- 20950064 TI - Health Technology Assessment International 7th Annual Meeting: Dublin, Ireland, 6 9 June 2010. AB - A record number of delegates from industry, academia and health policy convened at the 7th Annual Meeting of Health Technology Assessment International (HTAi) which was held in Dublin, Ireland in June 2010. The theme of this year's meeting was 'Maximizing the Value of HTA'. The scientific program covered a broad range of topics from coverage with evidence development to timeliness of conducting HTAs, early engagement with stakeholders, value of information analysis, patient involvement and international collaboration. There was also a lively social program with the conference dinner held at the Guinness Storehouse. PMID- 20950065 TI - Cost-effectiveness of prostate cancer chemoprevention among high-risk men. AB - EVALUATION OF: Earnshaw SR, McDade CL, Black LK, Bell CF, Kattan MW. Cost effectiveness of 5-alpha reductase inhibitors for the prevention of prostate cancer in multiple patient populations. Pharmacoeconomics 28(6), 489-505 (2010). Chemoprevention with 5-alpha reductase inhibitors (5ARIs) has been shown in clinical trials to reduce the incidence of prostate cancer. Although avoiding or delaying a diagnosis of prostate cancer through chemoprevention is attractive, it is unknown whether 5ARI chemoprevention reduces the number of prostate cancer deaths. Prior cost-effectiveness studies have found the adoption of 5ARIs in the general population to not be cost effective owing to the high costs of 5ARIs and multiple years of treatment required before gains are realized. The current study examines the cost-effectiveness of 5ARIs for men with multiple risk factors, including an elevated prostate-specific antigen and a prior negative biopsy. The analysis consistently observes under multiple assumptions that chemoprevention in the subgroup of high-risk men is cost effective and represents a good value for money, while chemoprevention among men from the general population appears to not be cost effective. PMID- 20950066 TI - Patient-reported perceptions and safety behaviors in chemotherapy administration. AB - EVALUATION OF: Schwappach DL, Wernli M. Chemotherapy patients' perceptions of drug administration safety. J. Clin. Oncol. 28(17), 2896-2901 (2010). During the process of medication administration, patients can participate in their own care by engaging in error prevention behaviors. Patients' safety behaviors are important patient-reported outcomes that can reduce medication errors, and by it, improve treatment effectiveness and safety. This article discusses the exploratory study of patients' perceptions of chemotherapy drug administration safety and the association between patients' perceptions of risk, harm and staff safety practices with patients' safety behaviors. The authors found that patients are concerned and ready to engage in safety behaviors for preventing errors in chemotherapy administration. The study findings call for improved communication and collaboration between providers and patients in clinical practice to engage patients in their chemotherapy treatments in real-time, which can have a major impact on cost and quality of care delivered in cancer. PMID- 20950067 TI - Assessing quality of life in the eating disorders: the HeRQoLED-S. AB - EVALUATION OF: Las Hayas C, Quintana JM, Padierna JA, Bilbao A, Munoz P. Use of Rasch methodology to develop a short version of the Health Related Quality of Life for Eating Disorders questionnaire: a prospective study. Health Qual. Life Outcomes 8, 29 (2010). Quality of life has become of increasing interest for health professionals since the 1980s and is now incorporated into assessment, treatment and evaluation of many health interventions. Within the arena of eating disorders, adequate consideration of quality of life within treatment and research has been slower, but is now coming into line with wider physical and mental health fields. A number of eating disorder-specific measures have been developed that aim to assess perceived quality of life while also minimizing response bias, which can be attributable to the ego-syntonicity of the eating disorders. While these measures are of great importance, further work is still required to assess the reliability and validity of these scales and to adapt the current available measures to increase their suitability for incorporation into clinical and research protocols. The current discussed paper by Las Hayas et al. aims to evaluate the Health Related Quality of Life for the Eating Disorders - version 2 (HeRQoLEDv2) for reliability and validity, to develop a short form of this questionnaire, the Health Related Quality of Life for the Eating disorders - Short form (HeRQoLED-S) using Rasch methodology and to further assess the HeRQoLED-S for reliability and validity. The authors confirm their hypothesized internal structure of the scales and present evidence for the reliability of the short scale. However, the short measure should be subject to more rigorous analysis of its reliability and construct validity in order to provide evidence as to its relationship to quality of life as perceived by eating disorder individuals. PMID- 20950068 TI - Challenges in funding diabetes care: a health economic perspective. AB - Diabetes mellitus - especially Type 2 diabetes - represents a major threat to public health in nearly all countries worldwide. The number of patients with diabetes is expected to rise to over 438 million by the year 2030. As healthcare resources are considered limited, there is a need for prioritization among the different, existing therapeutic options available for treating or preventing diseases in a given healthcare system. This article will highlight five particular challenges for evaluating complex therapeutic approaches in diabetes care, introducing the health economic fundamentals of cost-effectiveness assessment and the different concepts to determine a cost-effectiveness threshold, with a special focus on the situation in low- and middle-income countries. PMID- 20950069 TI - Economic evaluation guidelines in Latin America: a current snapshot. AB - Economic evaluation guidelines are widespread in developed countries with fourth hurdle systems but as of yet not in Latin America. In the present article, a systematic search was conducted in order to retrieve regional guidelines in PubMed, Latin American and Caribbean Health Sciences Literature (LILACS) and the gray literature. Four national guidelines were found: Brazil, Colombia, Cuba and Mexico. We report a thorough review of these documents, as well as a comparison among them. We conclude that, despite some differences found, they are broadly similar, and are broadly in accordance with international documents. The existence of these documents, together with other experiences in the region that explicitly use economic evaluation information for health decision making clearly shows that this global tendency is gaining momentum in Latin America, although there is still a long way to go. In the near future we will be able to see if these documents were successfully used and applied for transparent and evidence based decision making. PMID- 20950070 TI - Priority setting in healthcare: towards guidelines for the program budgeting and marginal analysis framework. AB - Economists' approaches to priority setting focus on the principles of opportunity cost, marginal analysis and choice under scarcity. These approaches are based on the premise that it is possible to design a rational priority setting system that will produce legitimate changes in resource allocation. However, beyond issuing guidance at the national level, economic approaches to priority setting have had only a moderate impact in practice. In particular, local health service organizations - such as health authorities, health maintenance organizations, hospitals and healthcare trusts - have had difficulty implementing evidence from economic appraisals. Yet, in the context of making decisions between competing claims on scarce health service resources, economic tools and thinking have much to offer. The purpose of this article is to describe and discuss ten evidence based guidelines for the successful design and implementation of a program budgeting and marginal analysis (PBMA) priority setting exercise. PBMA is a framework that explicitly recognizes the need to balance pragmatic and ethical considerations with economic rationality when making resource allocation decisions. While the ten guidelines are drawn from the PBMA framework, they may be generalized across a range of economic approaches to priority setting. PMID- 20950071 TI - Health-state utility values in breast cancer. AB - Health-related quality of life is an important issue in the treatment of breast cancer and health-state utility values are essential for cost-utility analysis. A literature review was conducted to identify published values for common health states for breast cancer. In total, 13 databases were searched and 49 articles were identified providing 476 unique utility values. Where possible mean utility estimates were pooled using ordinary least squares with utilities clustered within study group and weighted by both number of respondents and inverse of the variance of each utility. Regressions included controls for disease state, utility assessment method and other features of study design. Utility values found in the review were summarized for six categories: screening-related states; preventative states; adverse events in breast cancer and its treatment; nonspecific breast cancer; metastatic breast cancer states; and early breast cancer states. The large number of values identified for metastatic breast cancer and early breast cancer states enabled data to be synthesized by meta-regression. Utilities were found to vary significantly between valuation methods and depending on who conducted the valuation. For metastatic breast cancer, values significantly varied by severity of condition, treatment and side-effects. Despite the numerous studies it is not feasible to generate a definitive list of health-state utility values that can be used in future economic evaluations owing to the complexity of the health states involved and the variety of methods used to obtain values. Future research into quality of life in breast cancer should make greater use of validated generic preference-based measures for which public preferences exist. PMID- 20950072 TI - Cost-effectiveness studies in radiation therapy. AB - The field of radiation therapy has made dramatic technical advances over the past 20 years. 3D conformal radiotherapy, intensity-modulated radiation therapy and proton beam therapy have all been developed in an attempt to improve the therapeutic ratio: higher cure rates with lower toxicity. Unfortunately, although the costs of radiation therapy are certainly increasing, it is unclear whether its clinical benefit has also improved. Cost-effectiveness analyses are designed to formally evaluate the cost of a treatment relative to an associated change in quality-adjusted survival. As the cost of oncologic care is increasing, it is critically important to assess the cost-effectiveness of radiation therapy. This article will describe the issues surrounding the delivery and cost of radiation therapy, and it will summarize the work that has been done to evaluate the use of cost-effectiveness in radiation oncology. PMID- 20950073 TI - Health outcome and economic measurement in breast cancer surgery: challenges and opportunities. AB - As breast cancer surgery techniques continue to advance, treatment options continue to increase, bringing with them increased scrutiny of health outcomes and healthcare cost. In addition, patients are becoming more involved in their own medical care and are demanding meaningful data to help them better understand expected outcomes. With these changes and advancements, there is a growing emphasis on evidence-based practice. In this article, we focus on scientific considerations, challenges to and opportunities for improving outcome measurement related to breast cancer surgery. There are two main messages from this article. First, until recently, rigorously developed specific patient-reported outcome (PRO) measures for breast cancer surgery patients have not been available for use. However, with the recent introduction of new PRO measures, such as the BREAST-Q, there is now good potential to collect useful outcome data on patient satisfaction and health-related quality of life, and to better understand the relative impact of different surgical procedures, decision making and clinical practice on patient outcome. Thus, PRO research using rigorously developed breast cancer surgery-specific measures is in its infancy, but growing steadily. Second, there is a great need but lack of specific health economic measures developed for use in breast cancer surgery research. In fact, research into the economic evaluation of breast cancer surgery is an area that has received less attention than that of PRO measure development, but there is good opportunity to expand this area of research in breast cancer surgery. Further studies are required to gain a clearer view of the role that generic preference and utility measures could play, how best to synthesize health-related quality of life and economic metrics data, and the potential use of new disease-specific tools. PMID- 20950074 TI - Walking speed and economic outcomes for walking-impaired patients with multiple sclerosis. AB - This article estimates the impact of walking speed (measured using the Timed 25 Foot Walk [T25FW]) on three economic outcomes: productivity (annual earnings), care burden (value per year) and quality of life (utility score). Empirical data are not available to directly measure these relationships. Therefore, this article develops indirect estimates by characterizing the impact of the T25FW on the Expanded Disability Status Scale (EDSS), and the impact of the EDSS on economic outcomes. Use of the EDSS as a bridge introduces uncertainty, which precludes robust quantification of the relationship between walking speed and economic outcomes. Nonetheless, the analysis provides plausible ranges for the magnitude of these relationships. PMID- 20950075 TI - Cost-effectiveness of community-based treatment of severe acute malnutrition in children. AB - Severe acute malnutrition affects 20 million children aged under 5 years old worldwide. Medical complications and death are common, but nutritional and medical treatment can result in good outcomes. Randomized trials of treatment after in-patient stabilization have shown community-based treatment to have similar outcomes to hospital-based treatment, at lower cost. Community-based ambulatory treatment, with in-patient care reserved for the most severe cases, is increasingly being implemented in Africa but has not been evaluated in randomized trials. Community-based treatment programs have shown favorable outcomes. Economic evaluations of community-based treatment have included cost analyses, cost and consequence analyses and decision analyses. Treatment costs have been consistently lower than for institution-based treatment. Costs of ambulatory community-based treatment of severe acute malnutrition have ranged between US$46 to $453 per child, depending on the type of care provided and the costing methods used. Recent studies have reported on costs and outcomes of similar large-scale African programs covering geographically defined populations, with ambulatory care for most children, and initial in-patient stabilization for the minority with most severe disease. In these studies the costs ranged from US$129 to $201 per child, and mortality rates ranged from 1.2 to 9.2%, depending on length of follow-up. A decision tree model based on such a program in Zambia estimated that community-based treatment of severe acute malnutrition in primary-care centers, with hospital access, cost US$203 per case treated, US$1760 per life saved, and US$53 per disability-adjusted life year gained, compared with no treatment. This latter cost per disability-adjusted life year gained suggests that community based treatment of severe acute malnutrition is cost effective compared with other priority health interventions in low-income countries, and compared with such countries' national incomes. PMID- 20950077 TI - Retinol binding protein 4 (RBP4) is primarily associated with adipose tissue mass in children. AB - OBJECTIVE: Retinol binding protein 4 (RBP4) is a novel adipocytokine that may link obesity and insulin resistance. We aimed to discriminate between primary and secondary associations of RBP4 with obesity and related disease. DESIGN: We applied clinical and experimental approaches to investigate the association of RBP4 levels with normal development, obesity, metabolic and cardiovascular parameters in 68 lean and 61 obese children. RESULTS: RBP4 significantly increased with age and pubertal development in healthy lean children. Obese children had significantly higher RBP4 levels compared with lean controls (30.5+/ 1.4 vs. 26.3+/-1.1 mg/L, P<0.05) and there was a clear association with BMI independent of age (r=0.33, P<0.0001). RBP4 levels correlated significantly with parameters of lipid and glucose metabolism, as well as cardiovascular parameters in univariate analyses. Multiple regression analyses confirmed the strong association of RBP4 with BMI z-score and age, while the association with most metabolic and cardiovascular parameters was abolished. To assess whether the association of RBP4 with obesity may be attributable to adipogenesis, we evaluated RBP4 expression and secretion during adipocyte differentiation using the human SGBS cell line. In preadipocytes, RBP4 mRNA expression was nearly undetectable but increased during differentiation up to approximately 1600-fold (P<0.05). Likewise, RBP4 secretion was restricted to mature adipocytes, further indicating that RBP4 is strongly related to differentiation of adipocytes. CONCLUSION: RBP4 is a marker of adipose tissue mass and obesity already evident in children. The association of RBP4 with metabolic and cardiovascular sequelae of obesity appears to be secondary to the underlying relationship wtih body fat. PMID- 20950078 TI - Why should we care? PMID- 20950079 TI - Cardiac standstill. PMID- 20950080 TI - Risk of ventriculostomy-related hemorrhage in patients with acutely ruptured aneurysms treated using stent-assisted coiling. AB - OBJECT: Intracranial stenting has improved the ability to treat wide-neck aneurysms via endovascular techniques. However, stent placement necessitates the use of antiplatelet agents, and the latter may complicate the treatment of patients with acutely ruptured aneurysms who demonstrate hydrocephalus and require ventriculostomy. Antiplatelet agents in this setting could increase the incidence of ventriculostomy-related hemorrhagic complications, but there are insufficient data in the medical literature to quantify this potential risk. The aim of this study was to directly quantify the risk of ventriculostomy-related hemorrhage in patients with acute aneurysmal subarachnoid hemorrhage treated with stent-assisted coiling. METHODS: The authors retrospectively identified 131 patients who underwent endovascular treatment for an acutely ruptured aneurysm as well as ventriculostomy or ventriculoperitoneal (VP) shunt placement. The rate of hemorrhagic complications associated with ventriculostomy or VP shunt insertion was compared between patients who underwent coiling without a stent (Group 1) and those who underwent stent-assisted coiling and dual antiplatelet therapy (Group 2). RESULTS: One hundred nine ventriculostomies or VP shunt placement procedures were performed in 91 patients in Group 1, and 50 procedures were undertaken in 40 patients in Group 2. The rates of radiographic hemorrhage and symptomatic hemorrhage were significantly higher in Group 2 (32% vs 14.7%, p = 0.02; and 8% vs 0.9%, p = 0.03, respectively). On multivariate analyses, Group 2 had 3.42 times the odds of a radiographic hemorrhage (95% CI 1.46-8.04, p = 0.0048) after adjusting for antiplatelet use prior to admission. CONCLUSIONS: The application of dual antiplatelet therapy in stent-assisted coiling of acutely ruptured aneurysms is associated with an increase in the risk of hemorrhagic complications following ventriculostomy or VP shunt placement, as compared with its use in a coiling procedure without a stent. PMID- 20950081 TI - Stereotactic depth electrode investigation of the insula in the evaluation of medically intractable epilepsy. AB - OBJECT: The authors describe their experience with stereotactic implantation of insular depth electrodes in patients with medically intractable epilepsy. METHODS: Between 2001 and 2009, 20 patients with epilepsy and suspected insular involvement during seizures underwent intracranial electrode array implantation at the authors' institution. All patients had either 1 or 2 insular depth electrodes placed as part of an intracranial array. RESULTS: A total of 29 insular depth electrodes were placed using a frontal oblique trajectory. Eleven patients had a single insular electrode placed and 8 patients had 2 insular electrodes placed unilaterally. One patient had bilateral insular electrodes implanted. Postoperative imaging demonstrated satisfactory placement in all but 1 instance, and there was no associated morbidity or mortality. Fourteen patients underwent a subsequent resection, involving the frontal lobe (9 patients), temporal lobe (4), or frontotemporal lobes (1), and of these, 11 currently have Engel Class I outcome. Two patients (10%) had seizures originating within the insula and another 5 patients (25%) demonstrated early specific insular involvement. Neither patient with an insular seizure focus went on to resection. All 5 of the patients with early specific insular involvement underwent an insula sparing resective procedure with Engel Class I outcome in all cases. CONCLUSIONS: Stereotactic placement of insular electrodes via a frontal oblique approach is a safe and efficient technique for investigating insular involvement in medically intractable epilepsy. The information obtained from insular recording can be valuable for appreciating the degree of insular contribution to seizures, allowing localization to the insula or clearer implication of other sites. PMID- 20950082 TI - Cardiac standstill for cerebral aneurysms in 103 patients: an update on the experience at the Barrow Neurological Institute. Clinical article. AB - OBJECT: The aim of this study was to clarify the surgical indications, risks, and long-term clinical outcomes associated with the use of deep hypothermic circulatory arrest for the surgical treatment of intracranial aneurysms. METHODS: The authors retrospectively reviewed 105 deep hypothermic circulatory arrest procedures performed in 103 patients (64 females and 39 males, with a mean age of 44.8 years) to treat 104 separate aneurysms. Patients' clinical histories, radiographs, and operative reports were evaluated. There were 97 posterior circulation aneurysms: at the basilar apex in 60 patients, midbasilar artery in 21, vertebrobasilar junction in 11, superior cerebellar artery in 4, and posterior cerebral artery in 1. Seven patients harbored anterior circulation aneurysms. Two additional patients harbored nonaneurysmal lesions. RESULTS: Perioperatively, 14 patients (14%) died. Five patients (5%) were lost to late follow-up. At a mean long-term follow-up of 9.7 years, 65 patients (63%) had the same or a better status after surgical intervention, 10 (10%) were worse, and 9 (9%) had died. There were 19 cases (18%) of permanent or severe complications. The combined rate of permanent treatment-related morbidity and mortality was 32%. The mean late follow-up Glasgow Outcome Scale score was 4, and the annual hemorrhage rate after microsurgical clipping during cardiac standstill was 0.5%/year. Ninety-two percent of patients required no further treatment of their aneurysm at the long-term follow-up. CONCLUSIONS: Cardiac standstill remains an important treatment option for a small subset of complex and giant posterior circulation aneurysms. Compared with the natural history of the disease, the risk associated with this procedure is acceptable. PMID- 20950083 TI - Gamma Knife surgery for brain metastases from colorectal cancer. Clinical article. AB - OBJECT: The outcomes after Gamma Knife surgery (GKS) were retrospectively analyzed in patients with brain metastases from radioresistant primary colorectal cancer to evaluate the efficacy of GKS and the prognostic factors for local tumor control and overall survival. METHODS: The authors reviewed the medical records of 152 patients with 616 tumors. The group included 102 men and 50 women aged 35 85 years (mean age 64.4 years), who underwent GKS for metastatic brain tumors from colorectal cancer between April 1992 and September 2008 at Yokohama Rosai Hospital. RESULTS: The mean prescription dose to the tumor margin was 18.5 Gy (range 8-30 Gy). The mean tumor volume at GKS was 2.0 cm(3) (range 0.004-10.0 cm(3)). The primary tumors were located in the colon in 88 patients and the rectum in 64. The median interval between the diagnosis of primary lesions and the diagnosis of brain metastases was 27 months (range 0-180 months). The median neuroradiological follow-up period after GKS was 3 months (mean 6.4 months, range 1-93 months). The local tumor growth control rate, based on MR imaging, was 91.2%. The significant factors for unfavorable local tumor growth control, based on multivariate analysis, were larger tumor volume (p = 0.001) and lower margin dose (p = 0.016). The median overall survival time was 6 months. Lower Karnofsky Performance Scale (KPS) score (p = 0.026) and the presence of extracranial metastases (p = 0.004) at first GKS were significantly correlated with poor overall survival period in multivariate analysis. The cause of death was systemic disease in 112 patients and neurological disease in 13 patients. Leptomeningeal carcinomatosis was significantly correlated with a shorter duration of neurological survival in multivariate analysis (p < 0.0001). CONCLUSIONS: Gamma Knife surgery is effective for suppression of local tumor growth in patients with brain metastases from radioresistant colorectal primary cancer. Therefore, clinical and radiological screening of intracranial metastases for patients with lower KPS scores and/or the presence of extracranial metastases as well as follow up examinations after GKS for brain metastases should be performed periodically in patients with colorectal cancer, because the neurological prognosis is improved by initial and repeat GKS for newly diagnosed or recurrent tumors leading to a prolonged high-quality survival period. PMID- 20950084 TI - Sir Victor Horsley's 19th century operations at the National Hospital for Neurology and Neurosurgery, Queen Square. AB - Although he was not the first man to operate on the brain, Sir Victor Horsley was the world's first surgeon appointed to a hospital post to perform brain surgery, which happened in 1886 at the National Hospital for Neurology and Neurosurgery, Queen Square, London. The authors examined the patient records between 1886 and 1899 and found 151 operations performed by Sir Victor Horsley at the National Hospital, including craniotomies, laminectomies, and nerve divisions. The authors present the outcome data and case illustrations of cerebral tumor resections and laminectomies from the nineteenth century. Outcomes and notable pioneering achievements are highlighted. PMID- 20950085 TI - Results with judicious modern neurosurgical management of parasagittal and falcine meningiomas. Clinical article. AB - OBJECT: The management of parasagittal and falcine meningiomas centers around the relationship between the tumor and the venous anatomy of the superior sagittal sinus (SSS) and the bridging veins. The present study aims to address surgical outcomes in a focused cohort of these patients for which there is not clinical equipoise between radiosurgery and transcranial resection. METHODS: The clinical outcomes of patients undergoing surgical removal of parasagittal and falcine meningiomas at the authors' institution over an 18-year period were analyzed. Analysis was limited to patients with large, symptomatic, or rapidly growing tumors, for whom radiosurgery was not a good option. Tumor control was assessed using Kaplan-Meier analysis, and specific attention was paid to the relationship between the tumor and the SSS, and its impact on tumor control and outcome. RESULTS: The authors identified 135 patients with large, symptomatic, and/or growing parasagittal/falcine meningiomas who underwent resection at their institution between 1991 and 2007. The median length of follow-up was 7.6 years (range 1.7-18.6 years). The SSS was found to be invaded in 61 of 135 cases. In 6 cases the sinus was completely occluded. In 33 of the remaining 55 cases, the tumor invading the sinus was able to be removed with simple microsurgical techniques. There was no difference in rates of tumor control in patients who received subtotal resection for a WHO Grade I tumor, followed by close observation, compared with those undergoing gross-total resection, primarily because no cases were observed in which the tumor remnant in the SSS demonstrated interval growth on serial imaging studies. Of the patients in this series, 19% experienced at least one neurological, medical, or surgical complication. CONCLUSIONS: Importantly, these data provide a more modern estimate of the expected outcomes that can be obtained with treatment of these tumors, in which a combination of image guidance, advanced microsurgical tools, and conformal radiation treatments is used. PMID- 20950086 TI - Progressive aneurysm development following hemodynamic insult. AB - OBJECT: Hemodynamic insult has been speculated to be a key factor in intracranial aneurysm formation; however, it is unclear whether a sustained insult is necessary. The authors examined whether aneurysmal degradation would continue despite the normalization of wall shear stress (WSS) by adaptive outward vascular remodeling. METHODS: Twenty-five rabbits underwent either sham operation (5 animals) or bilateral common carotid artery ligation (20 animals) to augment basilar artery (BA) flow. Basilar termini (BTs) were harvested at 5 days and 3, 12, and 27 weeks postoperation. Histological changes at the BTs were quantified using an aneurysm development score (ADS) wherein the luminal length of the vessel wall exhibiting internal elastic lamina (IEL) loss, media thinning (> 30% media loss), and bulging was multiplied by the percentage of media thinning divided by the BA diameter. This score and its component variables were evaluated over the specified time points and compared with the WSS time course obtained from multiple angiography and BA flow velocity measurements. RESULTS: Serial examination of histological sections from the ligation group (17 rabbits survived the procedure) demonstrated localized, progressive, degenerative, and aneurysmal changes at the BTs. Prominent IEL loss was observed in BT specimens from all ligated animals. Media thinning and luminal bulging significantly progressed over the 27-week follow-up. The composite ADS significantly increased over the study period, indicating progressive aneurysm development, although the WSS returned to preligation baseline values within 5 weeks of ligation. CONCLUSIONS: Hemodynamic insult can elicit a pathological vascular response leading to a self-sustaining aneurysmal remodeling that does not require persistence of the original inciting factor to continue its pathological progression. PMID- 20950088 TI - Radiosurgery for colorectal brain metastases. PMID- 20950087 TI - Recombinant adeno-associated virus type 2 pseudotypes: comparing safety, specificity, and transduction efficiency in the primate striatum. Laboratory investigation. AB - OBJECT: Although several clinical trials utilizing the adeno-associated virus (AAV) type 2 serotype 2 (2/2) are now underway, it is unclear whether this particular serotype offers any advantage over others in terms of safety or efficiency when delivered directly to the CNS. METHODS: Recombinant AAV2-green fluorescent protein (GFP) serotypes 2/1, 2/2, 2/5, and 2/8 were generated following standard triple transfection protocols (final yield 5.4 * 10(12) particles/ml). A total of 180 MUl of each solution was stereotactically infused, covering the entire rostrocaudal extent of the caudoputamen in 4 rhesus monkeys (Macaca mulatta) (3.0 +/- 0.5 kg). After 6 weeks' survival, the brain was formalin fixed, cut at 40 MUm, and stained with standard immunohistochemistry for anti-GFP, anticaspase-2, and cell-specific markers (anti-microtubule-associated protein-2 for neurons and anti-glial fibrillary acidic protein for glia). Unbiased stereological counting methods were used to determine cell number and striatal volume. RESULTS: The entire striatum of each animal contained GFP positive cells with significant labeling extending beyond the borders of the basal ganglia. No ischemic/necrotic, hemorrhagic, or neoplastic change was observed in any brain. Total infusate volumes were similar across the 4 serotypes. However, GFP-labeled cell density was markedly different. Adeno associated virus 2/1, 2/2, and 2/5 each labeled < 8000 cells/mm(3), whereas serotype 8 labeled > 21,000 cells, a 3- to 4-fold higher transduction efficiency. On the other hand, serotype 8 also labeled neurons and glia with equal affinity compared with neuronal specificities > 89% for the other serotypes. Moderate caspase-2 colabeling was noted in neurons immediately around the AAV2/1 injection tracts, but was not seen above the background anywhere in the brain following injections with serotypes 2, 5, or 8. CONCLUSIONS: Intrastriatal delivery of AAV2 yields the highest cell transduction efficiencies but lowest neuronal specificity for serotype 8 when compared with serotypes 1, 2, and 5. Only AAV2/1 revealed significant caspase-2 activation. Careful consideration of serotype-specific differences in AAV2 neurotropism, transduction efficiency, and potential toxicity may affect future human trials. PMID- 20950089 TI - Gamma Knife surgery for subependymal giant cell astrocytomas. Clinical article. AB - OBJECT: The authors report their experience of using Gamma Knife surgery (GKS) in patients with subependymal giant cell astrocytoma (SEGA). METHODS: Over a 20-year period, the authors identified 6 patients with SEGAs who were eligible for GKS. The median patient age was 16.5 years (range 7-55 years). In 4 patients, GKS was used as a primary management therapy. One patient underwent radiosurgery for recurrent tumors after prior resection, and in 1 patient GKS was used as an adjunct after subtotal resection. The median tumor volume at GKS was 2.75 cm(3) (range 0.7-5.9 cm(3)). A median radiation dose of 14 Gy (range 11-20 Gy) was delivered to the tumor margin. RESULTS: The median follow-up duration was 73 months (range 42-90 months). Overall local tumor control was achieved in 4 tumors (67%) with progression-free periods of 24, 42, 57, and 66 months. Three tumors regressed and one remained unchanged. In 2 patients the tumors progressed, and in 1 of these patients the lesion was managed by repeated GKS with subsequent tumor regression. The other relatively large tumor (5.9 cm(3)) was excised 9 months after GKS. The progression-free period for all GKS-managed tumors varied from 9 to 66 months. There were no cases of hydrocephalus or GKS-related morbidity. CONCLUSIONS: Gamma Knife surgery may be an additional minimally invasive management option for SEGA in a patient who harbors a small but progressively enlarging tumor when complete resection is not safely achievable. It may also benefit patients with a residual or recurrent tumor that has progressed after surgery. PMID- 20950090 TI - Natural course of intracranial arterial dissections. AB - OBJECT: Noninvasive neuroimaging techniques are increasingly identifying unruptured intracranial arterial dissections (IADs) at examination for headache or ischemic symptoms. Approximately 3% of cases of aneurysmal subarachnoid hemorrhage (SAH) are caused by IADs in Japan, but the natural history of unruptured IADs is not known. METHODS: Clinical data obtained in 190 patients with 206 IADs were retrospectively analyzed on the basis of long-time follow-up of geometry and clinical event. The IADs were divided into an unruptured group and SAH group depending on the patient's clinical status at the initial diagnosis. Day 0 was defined as the day preceding diagnosis of IAD-that is, the day of symptom onset. This was retrospectively determined from the clinical history. RESULTS: The 206 IADs included 98 unruptured lesions and 108 SAH. In both groups, the vertebral artery was the most frequent site. In the unruptured group, 93 IADs were followed for a mean of 3.44 years. The mean interval between symptom onset (Day 0) and neuroimaging diagnosis was 9.8 days. Subsequent geometry change was seen in 78 (83.9%) of 93 IADs. Major change was almost completed within 2 months, and complete normalization was seen on neuroimaging in 17 (18.3%) of 93 IADs, with the earliest on Day 15. Rupture of the IAD in the unruptured group occurred in only 1 patient on Day 11. In the SAH group, 84 of the 108 patients complained of preceding headache before onset of SAH. In 81 (96.4%) of the 84 patients, SAH occurred on Day 0-3 with the latest on Day 11. In all patients in the unruptured and SAH groups, the latest day of SAH from the onset of preceding headache was Day 11. CONCLUSIONS: Most IADs causing SAH bleed within a few days of occurrence. Most IADs that are unruptured already have little risk for bleeding at diagnosis because of the repair process. Intracranial arterial dissections may be much more common than previously thought, and the majority may occur and heal without symptom manifestation. PMID- 20950091 TI - Seroepidemiology of infection with Toxoplasma gondii in workers occupationally exposed to water, sewage, and soil in Durango, Mexico. AB - Water, sewage, and soil are potential sources of infection for Toxoplasma gondii. Therefore, we sought to determine the prevalence of T. gondii infection and associated characteristics in 61 plumbers, 203 construction workers, and 168 gardeners in Durango City, Mexico. Participants were tested for T. gondii IgG and IgM antibodies with the use of enzyme-linked immunoassays. In addition, sociodemographic, clinical, and behavioral characteristics from each participant were obtained. IgG T. gondii antibodies were found in 4 (6.6%) plumbers, 17 (8.4%) construction workers, and 10 (6.0%) gardeners; T. gondii IgM antibodies were found in 3 (1.5%) construction workers and 4 (2.4%) gardeners, but in none of the plumbers. In the total population, the prevalence of T. gondii infection was significantly higher in workers living in suburban areas, without education, workers that consumed chorizo, and those who suffered from any disease (P < 0.05). In gardeners, prevalence of infection was significantly higher in those with blood transfusion, and memory impairment (P < 0.05). Multivariate analysis showed that T. gondii infection was positively associated with consumption of unwashed fruits (adjusted odds ratio [OR] = 2.41; 95% confidence interval [CI]: 1.13-5.13), and with raising animals (adjusted OR = 2.53; 95% CI: 1.00-6.37). This is the first report of contributing factors for T. gondii infection in workers occupationally exposed to water, sewage, and soil in a Mexican city, and results will contribute to the design of optimal preventive measures. PMID- 20950092 TI - Host partitioning by parasites in an intertidal crustacean community. AB - Patterns of host use by parasites throughout a guild community of intermediate hosts can depend on several biological and ecological factors, including physiology, morphology, immunology, and behavior. We looked at parasite transmission in the intertidal crustacean community of Lower Portobello Bay, Dunedin, New Zealand, with the intent of: (1) mapping the flow of parasites throughout the major crustacean species, (2) identifying hosts that play the most important transmission role for each parasite, and (3) assessing the impact of parasitism on host populations. The most prevalent parasites found in 14 species of crustaceans (635 specimens) examined were the trematodes Maritrema novaezealandensis and Microphallus sp., the acanthocephalans Profilicollis spp., the nematode Ascarophis sp., and an acuariid nematode. Decapods were compatible hosts for M. novaezealandensis, while other crustaceans demonstrated lower host suitability as shown by high levels of melanized and immature parasite stages. Carapace thickness, gill morphology, and breathing style may contribute to the differential infection success of M. novaezealandensis and Microphallus sp. in the decapod species. Parasite-induced host mortality appears likely with M. novaezealandensis in the crabs Austrohelice crassa, Halicarcinus varius, Hemigrapsus sexdentatus, and Macrophthalmus hirtipes, and also with Microphallus sp. in A. crassa. Overall, the different parasite species make different use of available crustacean intermediate hosts and possibly contribute to intertidal community structure. PMID- 20950093 TI - Lice and ticks of the eastern rufous mouse lemur, Microcebus rufus, with descriptions of the male and third instar nymph of Lemurpediculus verruculosus (Phthiraptera: Anoplura). AB - Sucking lice and ticks were collected from live-trapped eastern rufous mouse lemurs, Microcebus rufus Geoffroy, in and around the periphery of Ranomafana National Park, southeastern Madagascar, from 2007 to 2009. Samples of 53 sucking lice (Insecta: Phthiraptera: Anoplura) and 28 hard ticks (Acari: Ixodidae) were collected from 36 lemur captures representing 26 different host individuals. All of the lice were Lemurpediculus verruculosus (Ward) (6 males, 46 females, 1 third instar nymph). Only the holotype female was known previously for this louse and the host was stated to be a "mouse lemur." Therefore, we describe the male and third instar nymph of L. verruculosus and confirm M. rufus as a host (possibly the only host) of this louse. All of the ticks were nymphs and consisted of 16 Haemaphysalis lemuris Hoogstraal, 11 Haemaphysalis sp., and 1 Ixodes sp. The last 2 ticks listed did not morphologically match any of the Madagascar Haemaphysalis or Ixodes ticks for which nymphal stages have been described. PMID- 20950094 TI - Distribution of Kroeyerina elongata (Kroyeriidae: Siphonostomatoida, Copepoda) in the olfactory sacs of the blue shark, Prionace glauca. AB - The infection pattern of Kroeyerina elongata (Kroyeriidae, Copepoda) in the olfactory sacs of the blue shark, Prionace glauca, was investigated using 4,722 copepods from 54 olfactory sacs. Copepod prevalence and mean intensity of infection per olfactory sac were 94.0 and 91.1%, respectively, and the most intensely infected olfactory sac and shark hosted 218 and 409 copepods, respectively. There were significant linear relationships between the number of female and total copepods per left olfactory sac and shark fork length as well as between the numbers of female, male, and total copepods per shark and mean olfactory sac width and cumulative olfactory sac width. Female copepods typically outnumbered males within olfactory sacs (mean intensity = 65.7 and 26.3, respectively), and no statistical differences were detected between the numbers of copepods inhabiting the left and right olfactory sacs. Copepods were not evenly distributed within olfactory sacs. Typically, female copepods occupied olfactory chambers located centrally along the length of the olfactory sac, while males infected lateral olfactory chambers nearest the naris. The orientation of most copepods (84.6%) suggested positive rheotaxis relative to the path of water through the olfactory sac. Within olfactory chambers, most mature females (68.2%) infected the first third of the peripheral excurrent channel and the adjacent fringe of olfactory lamellae, while most males (91.7%) infected the olfactory lamellae, and the 4 larval females collected were attached within the lamellar field and grasped by males. Based on the observed infection patterns and the pattern of water flow throughout the olfactory sac, a hypothesis regarding the life cycle of K. elongata is advanced wherein infective copepodids are swept into the olfactory sac from the surrounding sea and initially colonize the olfactory lamellae. Copepodids feed and mature among the olfactory lamellae, and adult males search for mates and copulate with young females among the olfactory lamellae. Inseminated females move to the peripheral excurrent channels to mature and produce ovisacs. Hatching ovisacs release free-swimming nauplii into the excurrent water flow to be swept into the milieu, where they can molt into infective copepodids that may infect new hosts. PMID- 20950095 TI - A new gyrodactylid species from Cobitis granoei (Rendahl) (Cobitidae) in central China. AB - Gyrodactylus granoei n. sp. (Monogenea: Gyrodactylidae) is described from the fins and body surface of the spine loach, Cobitis granoei (Rendahl) (Cobitidae), in central China. It resembles a suite of species from cyprinid and cobitid fishes that have short, compact hamuli, a ventral bar with no obvious anterolateral projections, a linguiform posterior membrane, a male copulatory organ with small hooks in multiple rows, a simple cylindrical dorsal bar, and short marginal hooks, with an expanded sickle heel. Of these, the new species resembles most closely Gyrodactylus micracanthus Hukuda, 1940 from Misgurnus anguillicaudatus (Cantor) (Cobitidae), but it is identified by the length of the hamuli and the morphology of dorsal and ventral bars. When searched using BLAST, sequence data (829 bp) spanning the ITS1, 5.8s, and ITS2 region did not return an identical match; close similarity (82-88%) was found with sequenced members of the subgenus Gyrodactylus. It is suggested that the new species is part of a freshwater lineage that has radiated successfully among cyprinid fishes in North America, Europe, and Asia, and some of their predator and amphibian neighbors. PMID- 20950096 TI - Long-term genetic stability and population dynamics of laboratory strains of Schistosoma mansoni. AB - Measures of genetic differentiation between populations are useful tools for understanding the long-term dynamics of parasite communities. We followed the allele frequencies of microsatellite markers in samples taken over a period of 16 yr from the Case Western Reserve University-Naval Medical Research Institute (CWRU-NMRI) laboratory strain of Schistosoma mansoni. DNA was isolated from pooled samples of adults, eggs, or cercariae collected at 46 time points and genotyped for 14 tri- or tetranucleotide microsatellite markers. For comparison, 2 S. mansoni reference strains (Biomedical Research Institute-NMRI, which has a common origin with the CWRU line, and PR-1) were analyzed over shorter periods of time. We observed that the long-term allele frequencies are generally stable in large laboratory populations of this parasite, and a high degree of similarity was observed between the allele frequencies of consecutive samples from different developmental stages. The CWRU strain, however, showed 2 periods of marked deviation from stability as demonstrated using genetic differentiation measures. The first period corresponds to an admixture event with the BRI strain in which a new equilibrium was established as the "migrants" became blended into the existing CWRU population, consistent with 23% admixture from BRI. The second corresponds to a period of genetic drift when the CWRU population size was greatly reduced with an accompanying loss in genetic diversity. Having demonstrated the utility of pooled samples for the genetic analysis of population dynamics in laboratory strains of schistosomes, this approach will be useful for analyzing field samples to determine the impact of schistosomiasis control programs on parasite population structure. Accounting only for the intensity or prevalence of parasite populations may fail to register significant changes in population structure that could have implications for resistance, morbidity, and the design of control measures. PMID- 20950097 TI - Relative clonal density of malaria parasites in mixed-genotype infections: validation of a technique using microsatellite markers for Plasmodium falciparum and P. mexicanum. AB - Quantifying the relative proportion of coexisting genotypes (clones) of a malaria parasite within its vertebrate host's blood would provide insights into critical features of the biology of the parasite, including competition among clones, gametocyte sex ratio, and virulence. However, no technique has been available to extract such data for natural parasite-host systems when the number of clones cycling in the overall parasite population is likely to be large. Recent studies find that data from genetic analyzer instruments for microsatellite markers allow measuring clonal proportions. We conducted a validation study for Plasmodium mexicanum and Plasmodium falciparum by mixing DNA from single-clone infections to simulate mixed infections of each species with known proportions of clones. Results for any mixture of DNA gave highly reproducible results. The relationship between known and measured relative proportions of clones was linear, with high regression r2 values. Known and measured clone proportions for simulated infections followed over time (mixtures) were compared with 3 methods: using uncorrected data, with uncorrected data and confidence intervals constructed from observed experimental error, and using a baseline mixture of equal proportions to calibrate all other results. All 3 methods demonstrated value in studies of mixed genotype infections sampled a single time or followed over time. Thus, the method should open new windows into the biology of malaria parasites. PMID- 20950098 TI - Intragenomic sequence variation of the ITS-1 region within a single flow cytometry-counted Cyclospora cayetanensis oocysts. AB - Cyclospora cayetanensis, a protozoan of emerging concern, causes self-limiting gastroenteritis in immune-competent hosts. It has been established that sequence variability exists in the first internal transcribed spacer region (ITS-1) of the ribosomal DNA operon from collections of oocysts obtained from individual or pooled fecal samples. To determine if single oocysts also exhibited ITS-1 sequence variability, DNA was extracted from individually flow-cytometry-counted oocysts. We determined that ITS-1 sequence variability exists at an individual genome level for C. cayetanensis and approached or exceeded the variability exhibited among oocyst collections. ITS-1 variability, at the genome level, reduces this region's utility for inferring relationships between strains. PMID- 20950099 TI - CpG stimulates protective immunity in Balb/cJ mice infected with larval Taenia crassiceps. AB - Balb/cJ mice infected in the peritoneal cavity with larval Taenia crassiceps fail to mount a protective immune response. In mice, inflammatory immune responses are believed to control larval reproduction, whereas antibody-mediated responses are believed to be permissive. In the present study, mice were treated with CpG oligodeoxynucleotides (CpG) to determine whether stimulation of the innate inflammatory response would confer increased resistance to larval growth. Female mice treated with CpG displayed a decrease in mean parasite burden by 54%, while male mice displayed a 73% reduction. Moreover, 5 of 12 CpG-treated male mice completely eliminated all larvae by 9 wk post-infection. In contrast, no female animals were found to be infection free. CpG treatment induced an increase in the transcript levels of tumor necrosis factor-alpha and inducible nitric oxide synthase (iNOS) from splenocytes and resulted in elevated levels of the proinflammatory molecules monocyte chemotactic protein (MCP)-1, MCP-3, and interleukin-6 at the site of infection. Additionally, CpG administration induced the enhanced recruitment of neutrophils and macrophages to the site of infection. The finding that both neutrophils and macrophages were recruited in significantly higher numbers in the male host as compared to the female host may explain the increased level of protection realized in male animals in response to CpG treatment. PMID- 20950100 TI - Vaccination with recombinant Leishmania donovani gamma-glutamylcysteine synthetase fusion protein protects against L. donovani infection. AB - Visceral leishmaniasis presents a serious health threat in many parts of the world. There is, therefore, an urgent need for an approved vaccine for clinical use to protect against infection. In this study, the ability of recombinant Leishmania donovani gamma-glutamyl cysteine synthetase protein (LdgammaGCS) alone or incorporated into a non-ionic surfactant vesicle (NIV) delivery system to protect against L. donovani infection was evaluated in a BALB/c mouse model. Immunization with LdgammaGCS alone or LdgammaGCS-NIV induced specific IgG1 and IgG2a antibodies compared to controls, with LdgammaGCS-NIV inducing significantly higher titers of both antibody classes (P < 0.05). Both formulations induced similar increases in splenocyte IFN-gamma production following ex vivo antigen stimulation with LdgammaGCS compared with cells from control mice (P < 0.05). Similar levels of protection against infection were induced by LdgammaGCS alone and LdgammaGCS-NIV, based on their ability to suppress liver parasite burdens compared to control values (P < 0.01), indicating that using a carrier system did not enhance the protective responses induced by the recombinant protein. The results of this study indicate that LdgammaGCS may be a useful component in a vaccine against L. donovani. PMID- 20950101 TI - Serological and parasitological prevalence of Toxoplasma gondii in wild birds from Colorado. AB - Ground-feeding birds are considered important in the epidemiology of Toxoplasma gondii because they serve as indicators of soil contamination by oocysts, and birds of prey are indicators of T. gondii prevalence in rodents and other small mammals. Cats excrete environmentally resistant oocysts after consuming tissues of T. gondii -infected birds. In the present study, sera and tissues from 382 wild birds from Colorado were tested for T. gondii infection. Antibodies to T. gondii were found in 38 birds with the use of the modified agglutination test (MAT, 1?25 titer). Tissues (brains, hearts) of 84 birds were bioassayed in mice. Viable T. gondii was isolated from 1 of 1 barn owl (Tyto alba), 1 of 5 American kestrels (Falco sparverius), 1 of 7 ferruginous hawks (Buteo regalis), 1 of 4 rough-legged hawks (Buteo lagopus), 2 of 13 Swainson's hawks (Buteo swainsoni), and 1 of 25 red-tailed hawks (Buteo jamaicensis). This is the first time T. gondii has been isolated from the barn owl, ferruginous hawk, rough-legged hawk, and Swainson's hawk. PMID- 20950103 TI - Helminth parasites in ringed seals (Pusa hispida) from Svalbard, Norway with special emphasis on nematodes: variation with age, sex, diet, and location of host. AB - Complete gastrointestinal tracts from 257 ringed seals (Pusa hispida) from Svalbard, Norway, were examined for helminth parasites. Three different helminth groups were recorded (acanthocephalans 61.1%; nematodes 38%; cestodes 0.9%). Acanthocephalans (Polymorphidae) and cestodes (Anophryocephalus and Diphyllobothrium sp(p)., as well as unidentified species, were confined to the intestines. The anisakid nematodes Phocascaris phocae, Pseudoterranova sp(p)., Anisakis sp(p)., and Phocascaris/Contracaecum sp(p). were recorded in both stomachs and the anterior part of the small intestines. The abundance of nematodes and acanthocephalans varied significantly with sampling location of the seal hosts. This is likely due to the relative prevalence of Arctic versus Atlantic water in the different fjord systems, which strongly influences the age class and species of fish available as prey for the seals. Adult male ringed seals had significantly higher abundances of nematodes than did adult females or juveniles. Adult males also had significantly higher abundances of acanthocephalans than did adult females, but were not significantly different from juveniles in this regard. Nematode abundance increased significantly with age of male hosts, but this trend was lacking in female seals. Infection parameters appeared to be related to differences in the age of polar cod (Boreogadus saida) exploited by male, female, and juvenile seals. PMID- 20950104 TI - Parasites found from the feces of Bornean orangutans in Danum Valley, Sabah, Malaysia, with a redescription of Pongobius hugoti and the description of a new species of Pongobius (Nematoda: Oxyuridae). AB - In order to obtain basic data on parasitic infections of Bornean orangutans, Pongo pygmaeus morio (Owen, 1837), in Danum Valley, Sabah, Malaysia, fecal examinations were conducted. Based on a total of 73 fecal samples from 25 individuals, cysts of Entamoeba coli, Entamoeba spp., and Chilomastix mesnili, cysts and trophozoites of Balantidium coli, and eggs of Trichuris sp. or spp., unknown strongylid(s), Strongyloides fuelleborni, and an unknown oxyurid, plus a rhabditoid larva of Strongyloides sp., were found. Mature and immature worms of Pongobius hugoti Barus et al., 2007 and Pongobius foitovae n. sp. (Oxyuridae: Enterobiinae) were recovered from fecal debris and described. Pongobius foitovae is readily distinguished from P. hugoti by having a much longer esophageal corpus, a longer and distally hooked spicule in males, and a more posteriorly positioned vulva in female. Presence of plural species of non- Enterobius pinworms is a remarkable feature of the orangutan-pinworm relationship, which may reflect speciation process of the orangutans, host switching, and coevolution by pinworms. PMID- 20950105 TI - Two new species of Sarcocystis (Apicomplexa: Sarcocystidae) infecting the wolverine (Gulo gulo) from Nunavut, Canada. AB - Infection with Sarcocystis species is common in many species of animals, but it has not yet been reported in wolverines (Gulo gulo). Histological sections of tongues from 41 wolverines in the Kitikmeot Region, Nunavut, Canada, were examined for sarcocysts. Sarcocysts were found in 33 (80.4%) wolverines. Two structurally distinct types of sarcocysts were found. Type A sarcocysts were thin (<1 um thick) walled. Ultrastructurally, the parasitophorous vacuolar membrane (Pvm) had minute undulations, but it lacked villar protrusions and was not invaginated into the granular layer. The bradyzoites were slender, about 5 * 1 um in size. Structurally, these sarcocysts were distinct from known species of Sarcocystis and possessed a novel 18S and ITS-1 sequence, sharing 98% and 78% sequence similarity with Sarcocystis canis . A new species name, Sarcocystis kalvikus, is proposed for type A sarcocysts. In contrast, type B sarcocysts had relatively thicker (about 2 um) cyst walls and larger bradyzoites, each about 10 * 2-3 um. Ultrastructurally, the Pvm on the sarcocyst wall had villar protrusions that were either mushroom-like or sloping. Molecular analysis identified a unique 18S and ITS-1 sequence that placed them in a clade within the Sarcocystidae. Based on histology, TEM, and genetic data, the new name, Sarcocystis kitikmeotensis, is proposed. Sarcocystis kalvikus was found in 14 (34.1%), S. kitikmeotensis was found in 7 (17%), and both species were found in 12 (29.2%) of 41 wolverines. PMID- 20950106 TI - Molecular characterization and phylogenetic analysis of Eimeria from turkeys and gamebirds: implications for evolutionary relationships in Galliform birds. AB - In order to determine the evolutionary relationships among Eimeria species that parasitize birds of the Galliformes, the 18s rDNA gene and a portion of the cytochrome oxidase subunit 1 (cox-1) were amplified from Eimeria species isolated from turkeys, chukars, and pheasants. The phylogenetic analysis of these sequences suggests that species infecting chickens are polyphyletic and, therefore, do not all share a direct common ancestor. Both the 18s rDNA and the cox-1 sequences indicate that Eimeria tenella and Eimeria necatrix are more closely related to Eimeria of turkeys and pheasants than to other species that infect the chicken. It is, therefore, likely that the chicken Eimeria spp. represent 2 separate ancestral colonizations of the gut, one of which comprises E. tenella and E. necatrix that infect the ceca, while the other includes Eimeria acervulina, Eimeria brunetti, Eimeria maxima, and Eimeria mitis, which infect the upper regions of the intestine. PMID- 20950107 TI - A new species of Philometra (Nematoda: Philometridae) from the sand perch Diplectrum formosum (Serranidae) off Florida, northern Gulf of Mexico. AB - A new nematode species, Philometra diplectri n. sp. (Philometridae), is described from male and female specimens found in unidentified tissues of head and anterior trunk (males) and subcutaneously in the mouth and under the operculum (females) of sand perch, Diplectrum formosum (Linnaeus) (Serranidae, Perciformes), from the northern Gulf of Mexico off Florida (Florida Middle Grounds). Based on light and scanning electron microscopy examination, the new species differs from other congeners parasitizing the subcutaneous tissues, fins, tissues of the buccal cavity, and gill covers or gill arches of marine and brackish-water fishes, mainly in having 8 conspicuously large cephalic papillae of the external circle, the absence of caudal projections, and the shape and small size of the anterior inflation of the esophagus in gravid females, and in possessing 5 pairs of caudal papillae and spicules 66-78 um long in males. Philometra diplectri is the first known species of this genus whose gravid females are parasitic in the head tissues of serranid fishes. PMID- 20950108 TI - Redescriptions of the nematodes Litomosoides patersoni (Mazza, 1928) (Onchocercidae) and Stilestrongylus stilesi Freitas, Lent, and Almeida, 1937 (Heligmonellidae) parasites of Holochilus chacarius (Rodentia, Cricetidae) from Salta, Argentina. AB - Two nematode species are redescribed from the type host species Holochilus chacarius Thomas (Rodentia, Cricetidae, Sigmodontinae) and from the type locality of 1 of them, i.e., Ingenio San Martin de Tabacal, Salta Province, Argentina. Rodents were deposited at the Coleccion Mamiferos Lillo, Tucuman, Argentina. Litomosoides patersoni (Mazza, 1928) (Onchocercidae) possesses a buccal capsule with irregular external walls, a buccal cavity smooth, becoming thinner near the oral opening, a complete set of head papillae, 3-6 pairs of cloacal papillae, and the " sigmodontis " type of spicules. Filarioids were found in 3 of 17 examined hosts. Stilestrongylus stilesi Freitas, Lent, and Almeida, 1937 (Heligmonellidae), whose description was based on male specimens, was found in all 17 of the examined hosts. Here, we describe the female and the synlophe of both sexes. Females are characterized by a short uterus with less than 25 eggs, short ovejector, short and conical tail, and the posterior extremity strongly invaginated in a cuticular expansion usually harboring 1 to several eggs. The synlophe is characterized by 29-31 sub-equal cuticular ridges at the mid-body, with single (in males) or double (in females) axis of orientation of the ridges. The present work validates and enlarges the original descriptions of both species and assigns the specimens from L. patersoni, recovered from the type locality and the type host species, as neotypes. PMID- 20950109 TI - Antibodies to Toxoplasma gondii and Neospora caninum in captive neotropical and exotic wild canids and felids. AB - This study was designed to detect antibodies to Toxoplasma gondii and Neospora caninum in wild captive carnivores maintained in Brazilian zoos. Blood samples were collected from 142 Brazilian wild felids and 19 exotic felids in zoos, and 3 European wolves (Canis lupus) and 94 Brazilian wild canids maintained in captivity in Brazilian zoos of Sao Paulo, Mato Grosso states and Federal District. One hundred and two (63.4%) and 70 (50.3%) of the 161 wild felids tested were seropositive for T. gondii and N. caninum by indirect immunofluorescent assay test (IFAT), respectively. Among sampled wild canids, 49 (50.5%) and 40 (41.2%) animals were seropositive for T. gondii and N. caninum antigens by IFAT, respectively. To our knowledge, this is the first serological detection of antibodies to N. caninum in Brazilian wild captive felids and bush dogs (Speothos venaticus (Lund)). PMID- 20950110 TI - Thaumatocotyle (Monogenea: Monocotylidae) from Dasyatidae (Elasmobranchii) of the North American Atlantic coast: current issues resolved. AB - The study of 4 dasyatid stingrays- Dasyatis centroura (Mitchill, 1815), D. americana Hildebrand and Schroeder, 1928, D. say (Lesueur, 1817), and D. sabina (Lesueur, 1824)-from the northwestern Atlantic and the Gulf of Mexico showed the presence of monocotylid monogeneans Thaumatocotyle Scott, 1904 in their nasal fossae. Specimens collected from D. centroura from the northern Atlantic were identified as T. dasybatis (MacCallum, 1916). This confirmed the incorrect type host attribution of D. pastinaca (Linnaeus, 1758), which does not occur in the geographic area where T. dasybatis was described. Monogeneans collected from D. americana and D. say in the western Atlantic and the Gulf of Mexico were identified as T. longicirrus Hargis, 1955 and T. retorta Hargis, 1955, respectively, which corresponds to the opposite hosts attributed for each parasite species compared with their original description in the Gulf of Mexico. The species T. roumillati de Buron and Euzet, 2005 described from D. sabina in the northwestern Atlantic is reported for the first time in D. sabina from the Gulf of Mexico. Results clarify confusion in the literature regarding the hosts and habitats of Thaumatocotyle from dasyatids of the western Atlantic and Gulf of Mexico and support the oioxenous specificity of these monogeneans as well as their specificity for the nasal fossae of their hosts. PMID- 20950111 TI - First isolation of Pseudocohnilembus persalinus (Ciliophora: Scuticociliatida) from freshwater-reared rainbow trout, Oncorhynchus mykiss. AB - Ciliated protists were isolated from the ovarian fluid of apparently healthy adult rainbow trout (Oncorhynchus mykiss) maintained in freshwater. The organism was identified as Pseudocohnilembus persalinus based on morphometric and morphological analysis of silver-stained specimens obtained from culture and on analysis of ribosomal RNA gene sequences. The cytochrome c oxidase subunit 1 gene sequence of this organism also was characterized. This ciliate has been reported previously as free living only in saline environments and as an endosymbiont in a marine teleost, the olive flounder (Paralichthys olivaceus). A cyst-like stage may have facilitated the novel occurrence of this organism as an endosymbiont in rainbow trout. PMID- 20950112 TI - Effects of Neospora caninum infection at mid-gestation on placenta in a pregnant mouse model. AB - Neospora caninum is one of the more-efficient transplacentally-transmitted organisms. The goal of the present study was to investigate the pathologic and immunologic changes that occur at the materno-fetal interphase in pregnant BALB/c mice infected with N. caninum at mid-gestation. Parasite DNA was detected in feto placentary units 3 days post-infection (PI). On day 7 PI, the DNA detection level and parasite burden were significantly higher in the placentas than in the fetuses, which may indicate that the parasite is mainly multiplying in the placenta during the initial infection. In the spleens of infected dams, we observed an increase in IFN-gamma, IL-10, and IL-4. However, only IL-4 was upregulated in placentas from the infected dams; this may enhance susceptibility to N. caninum at the materno-fetal interphase and favor transmission to the progeny. Finally, an increase in TNF-alpha expression in nested-PCR-positive placentas combined with necrosis may compromise the viability of the fetuses. PMID- 20950119 TI - 5-Fluorouracil/Leucovorin and arsenic trioxide for patients with refractory/relapsed colorectal carcinoma: a clinical experience. PMID- 20950120 TI - Higher comorbidity of depression and cardiovascular disease in women: a biopsychosocial perspective. AB - OBJECTIVES: The present paper aims at offering a synthesis of possible reasons of the higher comorbidity of cardiovascular disease (CVD) and depression in women from a biopsychosocial perspective. METHOD: The available literature is reviewed under sex/gender aspects related to the link between depression and CVD and common pathways to depression and CVD associated with chronic stress experiences including pathophysiological mechanisms and behavioural, cognitive, psychosocial and sociological risk factors/predictors. RESULTS: There is considerable evidence that greater exposure to chronic stressors in women, interpersonal stress responsiveness, and internalizing coping styles are associated with an elevated risk of CVD and/or depression through behavioural and pathophysiological mechanisms including alterations in HPA axis functioning and autonomic nervous system which appear to be specific for women. CONCLUSION: Women seem to be more strongly affected by psychosocial stressors related to CVD and depression as well as by direct and indirect effects of chronic stress compared to men. More evidence in understanding these differences within the biological, psychosocial and sociostructural determinants and pathways is essential for promoting women's health. PMID- 20950121 TI - A simple procedure for routine RNA extraction and miRNA array analyses from a single thyroid in vivo fine needle aspirate. AB - CONTEXT: microRNA (miRNA) expression profiling and classification of tissue obtained from fine-needle aspirates (FNA) could be a major improvement of the preoperative diagnosis of thyroid nodules. OBJECTIVE: Before this can be clinically implemented, a robust and non-toxic method for obtaining sufficient quantity and quality of RNA from single in vivo FNA has to be established. RNAlater is a non-toxic RNA-stabilizing agent. However, due to the high density of RNAlater, pelleting of the tissue samples is difficult, and results in low recovery of RNA that is insufficient for subsequent miRNA array expression analysis. We therefore developed a simple centrifugation method for capturing tissue stored in RNAlater on a 0.45-MUm filter. DESIGN: FNA from 24 patients with a solitary cold thyroid nodule was stored in Trizol, liquid nitrogen, or RNAlater. The tissue stored in RNAlater was either pelleted by centrifugation or captured on the 0.45-MUm filters. RNA was extracted using the Trizol method. To validate results, FNA from additional 30 patients were analyzed based on the modified RNAlater protocol. MAIN OUTCOME: Capturing FNA tissue samples on the filters increased the RNA yield 10 fold and maintained RNA purity, permitting miRNA array expression profiling and allowing comparable levels of known miRNA clusters regardless of preservation technique. Results were confirmed in an additional 30 patients. CONCLUSION: The modified RNAlater protocol is well suited for isolating RNA from single thyroid in vivo FNA in a clinical setting. Furthermore this permits shipping of FNA samples at room temperature from peripheral centers to a centralized array core facility. PMID- 20950123 TI - Crisis? What crisis? The need to develop academic capacity in general practice. PMID- 20950124 TI - A doctor close at hand: How GPs view their role in cancer care. AB - OBJECTIVE: To explore GPs' own views on their role in cancer care. DESIGN: Qualitative study based on semi-structured interviews. SETTING: Norwegian primary care. METHODS: The stories of 14 GPs concerning 18 patients were analyzed for core content and abstracted into general ideas, to create a broader sense of the experienced professional role. RESULTS: The GPs claimed to have an important role in cancer care. In our analysis, three main aspects of GPs' work emerged: first, as a flexible mediator, e.g. between the patient and the clinic, interpreting and translating; second, as an efficient "handyman", solving practical problems locally; and third, as a personal companion for the patient throughout the illness. CONCLUSION: The interviewed GPs see their place in cancer care as being close to their patients. In their many tasks we found three main aspects: the mediating, the practical, and the personal. PMID- 20950125 TI - Vascular function in obese children with non-alcoholic fatty liver disease. AB - OBJECTIVE: To test whether obese children with non-alcoholic fatty liver disease have impaired vascular function compared with obese children with normal liver fat content. METHODS: Obese children (n = 28, 16 males, mean age 10.9 +/- 0.7 years, body mass index [BMI] 31.9 +/- 4.5 kg/m(2)) with normal (HCLn) and increased hepatocellular lipid content (HCLi, 2.6 +/- 0.8 vs. 12.4 +/- 8.2%) were recruited, outcome measures being flow-mediated dilation of the brachial artery [FMD] measured by ultrasound, biochemical markers of inflammation (hs-CRP, hs IL6) and cell adhesion molecules [CAMs], hepatocellular lipids, visceral and subcutaneous fat quantified by nuclear magnetic resonance spectroscopy and imaging. RESULTS: HCLi and HCLn groups showed no significant differences in terms of age, gender, BMI, waist circumference and subcutaneous fat. Subjects in the HCLi group had significantly higher amounts of visceral fat and higher fasting glucose, insulin and triglyceride, but lower adiponectin levels and were more insulin resistant than their HCLn controls. Hepatic fat fraction (HFF) correlated positively with fasting plasma glucose, HOMA-IR, adiponectin, visceral fat, negatively with WBISI independent of BMI. HFF was not associated with subcutaneous fat, fasting insulin, FFA, HDL-C, TG, hs-CRP, hs-IL6, vCAM, iCAM, and FMD. HCLi patients had significantly higher serum levels of hs-CRP and hs-IL6 than HCLn controls. FMD and serum levels of vCAM and iCAM were comparable between groups. CONCLUSIONS: Obese children with simple steatosis rather than steatohepatitis seem to have intact vascular function. Further studies in obese children with different grades of NAFLD are warranted to elucidate the role of fatty liver as a marker of risk for future cardiovascular events. PMID- 20950126 TI - The number needed to treat for second-generation biologics when treating established rheumatoid arthritis: a systematic quantitative review of randomized controlled trials. AB - OBJECTIVE: To evaluate the number needed to treat (NNT) and the number needed to harm (NNH) of the second-generation biologics abatacept, certolizumab, golimumab, rituximab, and tocilizumab in patients with established rheumatoid arthritis (RA) taking concomitant methotrexate (MTX). METHODS: A systematic literature search of MEDLINE, EMBASE, Web of Science, and the Cochrane Register of Controlled Trials was conducted up to 1 November 2009. We selected any published randomized, double blind, MTX-controlled study including RA patients with a mean disease duration of at least 5 years before entering a pivotal trial on second-generation biological therapy. Studies eligible for inclusion involved patients, who had previously shown inadequate response to conventional disease-modifying anti-rheumatic drug (DMARD) therapy. Pre-specified binary outcomes were extracted with a preference for 1-year data (6-month data were used if no data were available for 1 year). Two reviewers independently extracted the data necessary to estimate the absolute measures in a non-responder intention-to-treat (ITT) analysis. RESULTS: Five randomized controlled trials, one for each of the drugs, were selected and data extracted according to published data at endpoint for American College of Rheumatology 50% (ACR50)-responding patients, and withdrawals due to adverse events. NNT ranged from four to six treated patients to achieve one ACR50 response, while withdrawals due to adverse events were few and non-significant compared to the placebo group, except for rituximab administered as 1000 mg. CONCLUSION: Comparable efficacy was shown by the five biological agents studied, with few adverse events. However, for rituximab, tocilizumab, and golimumab, only 6-month data were available, hampering the external validity with regard to long term efficacy and tolerability. A low dose (500 mg) of rituximab may be as effective as the recommended dose of 1000 mg. PMID- 20950127 TI - Prevalence and associations of hand pain in the community: results from a population-based study. AB - OBJECTIVES: To assess the prevalence and associations of hand symptoms in a community setting. METHODS: The North West Adelaide Health Study (NWAHS) is a longitudinal cohort study of people aged >= 18 years. Analysis was performed in participants who completed a telephone interview, a quality of life questionnaire [the 36-item short-form health survey, (SF-36)], and the Australian/Canadian (AUSCAN) Osteoarthritis (OA) Hand Index, and underwent grip strength measurement. RESULTS: Overall, 477 (13.7%) reported hand pain, aching, or stiffness. Of these, 169 (35.8%) had been diagnosed with hand arthritis. Women were more likely to have hand symptoms than men, as were those aged >= 50 years (p < 0.001). Hand symptoms were associated with lower quality of life scores (p < 0.05). Participants with hand arthritis had more severe pain, stiffness, and poorer physical functioning as reflected by higher AUSCAN scores. Grip strength was reduced in those with hand symptoms and hand arthritis (p < 0.05) and inversely associated with mean AUSCAN subscores and SF-36 physical functioning scores (p < 0.001). CONCLUSIONS: Hand symptoms were present in 14% of the population and were more common in women and those aged >= 50 years. Hand symptoms were associated with reduced grip strength and reduced quality of life. Hand arthritis was associated with higher AUSCAN scores. Hand symptoms and hand arthritis have a significant impact on physical functioning and quality of life. PMID- 20950128 TI - Assessment of dysphonia due to benign vocal fold lesions by acoustic and aerodynamic indices: a multivariate analysis. AB - The goal was to identify acoustic and aerodynamic indices that allow the discrimination of a benign organic dysphonic voice from a normal voice. Fifty three patients affected by dysphonia caused by vocal folds benign lesions, and a control group were subjected to maximum phonation time (MPT) measurements, GRB perceptual evaluations and acoustic/aerodynamic tests. All analyzed variables except the airflow variation coefficient were significantly different between the two groups. The unique significant factors in the discrimination between healthy and dysphonic subjects were the aerodynamic indices of MPT and Glottal efficiency index, and the acoustic index Shimmer. These results show that a combination of three parameters can discriminate a voice deviance and highlight the importance of a multidimensional assessment for objective voice evaluation. PMID- 20950129 TI - Role of GTP binding, isoprenylation, and the C-terminal alpha-helices in the inhibition of cell spreading by the interferon-induced GTPase, mouse guanylate binding protein-2. AB - Interferon-gamma pre-exposure inhibits Rac activation by either integrin engagement or platelet-derived growth factor treatment. Interferon-gamma does this by inducing expression of the large guanosine triphosphatase (GTPase) mouse guanylate-binding protein (mGBP-2). Inhibiting Rac results in the retardation of cell spreading. Analysis of variants of mGBP-2 containing amino acid substitutions in the guanosine triphosphate (GTP) binding domain suggests that GTP binding, and possibly dimerization, of mGBP-2 is necessary to inhibit cell spreading. However, isoprenylation is also required. Removal of the N-terminal GTP-binding globular domain from mGBP-2 yields a protein with only the extended C terminal alpha-helices that lacks enzymatic activity. The ability of the C terminal alpha-helices alone to inhibit cell spreading suggests that this is the domain that interacts with the downstream effectors of mGBP-2. Interestingly, mGBP-2 can inhibit cell spreading whether it is geranylgeranylated or farnesylated. This study begins to define the properties of mGBP-2 responsible for inhibiting cell spreading. PMID- 20950130 TI - The ISG56/IFIT1 gene family. AB - The ISG56/IFIT1 family of genes is clustered on human chromosome 10 and is comprised of 4 members, ISG56/IFIT1, ISG54/IFIT2, ISG60/IFIT3, and ISG58/IFIT5, whose homologs are evolutionarily conserved from mammals to amphibians. While these genes are normally silent in most cell types, their transcription is strongly induced by interferons, virus infection, and molecular patterns such as double-stranded RNA or lipopolysaccharides. The encoded P56 family proteins are characterized by multiple repeats of tetratricopeptide repeat helix-turn-helix motifs mediating a variety of protein-protein interactions, which result in a multitude of effects on cellular and viral functions, such as translation initiation, virus replication, double-stranded RNA signaling, cell migration, and proliferation. PMID- 20950131 TI - Curcumin's effect on intestinal inflammation and tumorigenesis in the ApcMin/+ mouse. AB - Curcumin's benefits on tumorigenesis are thought to be mediated by its antiinflammatory activity; however, these effects have not been well characterized in a mouse model of colon cancer. We examined the effects of curcumin on intestinal inflammation in the Apc(Min/+) mouse. Apc(Min/+) mice were given a placebo or curcumin (2%) diet from 4 to 18 weeks of age (n = 10/group). C57BL/6 mice were used as a wild-type control (n = 10/group). Intestines were analyzed for polyp burden (sections 1, 4, and 5) and for mRNA expression, and concentration of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, and chemokine ligand 2 (CCL2) (sections 2 and 3). Plasma was collected for concentration of CCL2. Curcumin decreased total intestinal polyps by 75% (P < 0.05) in all size categories [>2 mm (65%), 1-2 mm (72%), <1 mm (82%); P < 0.05]. mRNA expression of IL-1beta, IL-6, tumor necrosis factor-alpha, and CCL2 was elevated (P < 0.05) and curcumin blunted this increase (P < 0.05). Protein concentration of IL-1beta, IL-6 (section 3), and CCL2 was increased (P < 0.05) and curcumin reduced this response for IL-1beta (section 2) and CCL2 (P < 0.05). Curcumin also offset the increase in plasma CCL2 (P < 0.05). The benefits of curcumin in colon cancer may be at least in part mediated by its antiinflammatory activity. PMID- 20950132 TI - Characterization of the interferon-alpha response of pigs to the weaning stress. AB - The interferon (IFN)-alpha response of pigs to the stressing event of early weaning was investigated in a field trial. All the animals under study remained healthy and tested negative for common viral infections. However, a low-titered IFN-alpha response was detected in many sera by a bioassay on Madin-Darby bovine kidney (MDBK) cells on day +6 after weaning. Porcine IFN-alpha was unambiguously identified by a neutralization assay on a pool of IFN-alpha-positive sera. By gel filtration chromatography, the antiviral activity of sera on MDBK cells could be traced back to 3 components of apparent molecular mass 27/18/<14 kDa. Additional components of apparent molecular mass 58 and 41 kDa were revealed by ELISA in Nonidet P-40 lysates of peripheral blood mononuclear cells (PBMC). Also, many pigs tested positive in flow cytometry assays on PBMC for intracellular IFN alpha. The expression of porcine IFN-alpha genes was investigated by reverse transcriptase (RT) real-time polymerase chain reaction at days -1, +6, and +12 with regard to weaning in PBMC of 9 piglets. On days -1 and +12, IFN A5, A6, A12, as well as (in fewer pigs) A1, A7, A11, and A2 genes were shown to be expressed. On the contrary, none of the above genes was expressed on day +6, when plenty of pig sera were IFN-alpha-positive. Our results indicate that weaning causes the release of IFN-alpha and the transient shut-off of the corresponding gene transcriptions in PBMC. Interestingly, only IFN A9 gene transcription was shown in vitro to be virus induction-dependent. PMID- 20950133 TI - Retinoic acid-inducible gene-I-like receptors. AB - Retinoic acid-inducible gene-I (RIG-I), melanoma differentiation-associated 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2) form a family of DExD/H box RNA helicases. RIG-I-like receptors (RLRs) are expressed ubiquitously at low levels, and their expression is induced by treatment with type I interferon (IFN) or a viral infection. RLRs function as sensors for the detection of viral RNA (such as double-stranded RNA) in the cytoplasm to initiate antiviral responses by producing type I and type III IFNs. Unlike Toll-like receptors, which sense exogenous pathogen-associated molecular patterns, RLRs detect cytoplasmic viral RNA. Because RLRs are IFN-inducible viral sensors, they are critical in amplifying antiviral responses. PMID- 20950134 TI - Exhaled nitric oxide in children with allergic rhinitis and/or asthma: a relationship with bronchial hyperreactivity. AB - BACKGROUND: Nowadays, the measure of the fractional concentration of exhaled nitric oxide (FeNO) enables to assess airway inflammation during an office visit and there is international consensus on this testing methodology. The aim of this study was to evaluate whether FeNO measurement is predictable for bronchial hyperreactivity (BHR) in children with allergic rhinitis, asthma, or both. METHODS: Two hundred and eighty children with allergic rhinitis, allergic asthma, or both were evaluated. Bronchial function (FEV1 and FEF(25-75)), BHR (assessed by methacholine challenge), FeNO, and sensitizations were assessed. RESULTS: Bronchial function, BHR, and FeNO were significantly different in the three groups (p < .001). A strong inverse correlation between FeNO and BHR was found in patients with asthma and with asthma and rhinitis (r = -0.63 and r = -0.61, respectively). A cutoff of 32 ppb of FeNO was a predictive factor for BHR. CONCLUSIONS: This study highlights the relevance of FeNO as possible marker for BHR in allergic children and underlines the close link between upper and lower airways. PMID- 20950135 TI - Immunochromatographic assay for measurement of total IgE in tears, nasal mucus, and saliva of patients with allergic rhinoconjunctivitis. AB - OBJECTIVE: Measurement of total immunoglobulin E (IgE) is clinically important for the diagnosis of allergic diseases. The total serum IgE level is normally measured because of its widespread use and convenience, but little attention has been paid to the measurement of local IgE concentrations. We evaluated whether the measurement of local production of IgE in tears, saliva, and nasal mucus was useful for the diagnosis of allergic rhinoconjunctivitis. METHODS: A prospective, nonrandomized, cross-sectional study was conducted in 33 consecutive patients with seasonal allergic rhinoconjunctivitis (allergic group) and in 30 age- and sex-matched healthy control subjects (control group). The total IgE level was measured in tears, saliva, and nasal mucus from all subjects. Using a 4- or 5 point scale, symptoms (sneezing, rhinorrhea, nasal obstruction, ocular itching, and lacrimation) were assessed in each subject along with the activities of daily living (ADL) score and total symptom score for allergic conjunctivitis. RESULTS: Total IgE could be assayed within 10 minutes of collection in all samples. The scores for all symptoms were higher in the allergic group than in the control group (p < .00001). The IgE scores for tear fluid samples (p < .00001) and undiluted saliva (p = .00003) were significantly higher in the allergic group than in the control group. The total IgE score of tear fluid samples was strongly correlated with the severity of symptoms of allergic conjunctivitis, including ocular itching (r = 0.769, p < .00001), tearing (r = 0.560, p = .00035), and ocular symptom score (r = 0.329, p = .03452). On the contrary, the total IgE scores for both saliva and nasal mucus were correlated with the severity of rhinitis-related symptoms, including sneezing (saliva r = 0.897, p < .00001; nasal mucus r = 0.871, p = .00024), nose blowing (saliva r = 0.764, p < .00001; nasal mucus r = 0.829, p = .00080), and nasal obstruction (saliva r = 0.519, p = .00099; nasal mucus r = 0.745, p = .00429). The ADL score was correlated with the total IgE level in each specimen (tear r = 0.705, p < .00001; saliva r = 0.468, p = .00301; nasal mucus r = 0.479, p = .06816). CONCLUSIONS: These results suggest that local production of IgE is closely correlated with local allergic symptoms. This rapid test for the measurement of local IgE is easy to perform on an outpatient basis and may be helpful in the diagnosis of allergic rhinitis and conjunctivitis. PMID- 20950137 TI - Perforation of the cervix by the threads of a levonorgestrel-releasing intrauterine system: a case report. AB - Asymptomatic retraction of intrauterine device (IUD) threads into the cervical canal or uterine cavity is a common complication. We present the rare case of a 44-year-old woman with the threads protruding through an opening in the anterior cervical lip about 1 cm above the external cervical os. Despite this presentation, her management was straightforward. We review the literature and discuss the possible antecedents of the phenomenon in this patient. PMID- 20950136 TI - Gender and age disparities in the prevalence of Chlamydia infection among sexually active adults in the United States. AB - BACKGROUND: Chlamydia trachomatis (CT) causes a costly and potentially recurrent bacterial infection that accounts for a considerable proportion of sexually transmitted infections (STIs) in the United States. Disparities by gender and age group in CT prevalence have been reported previously. The current study evaluates demographic, socioeconomic, and behavioral risk and protective factors that may account for gender/age disparities in CT infections among sexually active young adults in the United States. METHODS: Secondary analyses were performing using the 1999-2006 National Health and Nutrition Examination Survey (NHANES) data. RESULTS: A total sample of 5611 adults, 20-39 years of age, who participated in the 1999-2006 NHANES, reported lifetime sexual experience, and had valid laboratory-based CT status, was analyzed. CT prevalence did not differ significantly by gender and was estimated to be 1.6%. It was slightly higher for people <25 years vs. those >=25 years of age; age disparities were reduced after controlling for demographic, socioeconomic, and behavioral characteristics. Among those <25 years, non-Hispanic blacks had a higher odds of CT infection compared with other groups. Among those >=25 years of age, not having had unprotected sex in the past month reduced the odds for CT infection, whereas non-Hispanic black race and never married status increased the odds for CT infection. CONCLUSIONS: Among sexually active adults, no gender disparities were observed in CT prevalence. Age group disparities were partly explained by personal characteristics associated with risk of STIs. PMID- 20950138 TI - Breast cancer in women with human immunodeficiency virus infection: pathological, clinical, and prognostic implications. AB - BACKGROUND: AIDS and breast cancer have become two important public health issues for women. Of interest is the prolonged survival of patients diagnosed with HIV infection as a result of the use of highly active antiretroviral therapy (HAART). With improved survival, we are likely to see more HIV-infected patients with breast cancer. METHODS: This study, which is a review of our experience at Harlem Hospital Center, New York, between 2000 and 2008, compared HIV-positive with HIV negative breast cancer patients, with attention to tumor size, stage, grade, molecular markers and lymphovascular invasion, treatment, and patient survival. RESULTS: Only 63 of 370 patients with breast carcinoma were tested for HIV, and 6 of the 63 women tested positive for HIV. We, therefore, compared the clinical features and tumor characteristics seen in the 6 HIV-infected women with those of the 57 HIV-seronegative breast cancer patients. We found no differences in presentation, median age, and tumor morphology in the two groups of patients. When the patients in our previous report on 5 HIV-positive breast cancer patients were added to the present group, the overall 5-year survival rate among the 11 HIV-infected patients was 75%. Of note is the finding that HIV infection in premenopausal women was not associated with aggressive breast cancer subtypes with poor survival outcome. CONCLUSIONS: These results demonstrate that histological subgroups and 5-year survival appear similar among HIV-positive breast cancer patients. PMID- 20950139 TI - Outcome analysis of fornix ruptures in 162 consecutive patients. AB - BACKGROUND: Fornix rupture is a potential urologic emergency. In most cases, ureteral stones represent the underlying cause. Management of a fornix rupture is not standardized. PATIENTS AND METHODS: In a retrospective analysis, we investigated 162 patients who had received a diagnosis of fornix rupture between 1994 and 2005. In all patients, the diagnosis was based on radiographic investigations with application of contrast media. We evaluated the parameters' underlying cause, associated symptoms, diagnostic and therapeutic procedures, and outcome in patients with a fornix rupture. RESULTS: There were 121 men and 41 women with a median age of 53 years (range 20-79 years). In 93.2% of patients, one or more symptoms were present at diagnosis. In 59.9% of cases, a ureteral stone was diagnosed; in 12.3%, the underlying cause was different; and in the remaining 27.8% of patients, no reason for a fornix rupture was found. In all patients, primary endoscopic therapy (96.3%) or insertion of a nephrostomy tube (3.7%) was performed. All patients had a bladder catheter inserted, and antibiotic treatment was given in 92% of patients. A renal or perirenal abscess or other secondary complications necessitating open operative revision did not develop in any patient. The retrospective manner is a limitation of our study. Comparison of subgroups may therefore be biased. CONCLUSIONS: Ureteral stones are the most frequent causes of a fornix rupture. With a low pressure system and antibiotic treatment, the outcome is excellent, and secondary complications can be effectively prevented. Parameters for conservative treatment are to be defined to reduce overtreatment of certain patients with a fornix rupture. PMID- 20950140 TI - Social participation of relatives post-stroke: the role of rehabilitation and related ethical issues. AB - PURPOSE: (1) Describe the challenges facing relatives of persons with stroke in accomplishing their daily activities and social roles (participation). (2) Reflect on the role of rehabilitation for relatives and ethical issues that may emerge following the adoption of a family-centred approach. METHOD: Review of the scientific literature in Medline (1996 to July 2009), Embase (1996 to July 2009) databases using keywords: stroke AND participation AND family OR spouse OR caregivers AND ethics AND burden. Selection criteria were as follows: study must examine the participation of relatives post-stroke (or equivalent concept such as burden), rehabilitation interventions for relatives post-stroke or ethical issues related to being a relative of a person with stroke. Articles not written in English or French were excluded. RESULTS: The sample comprised 17 scientific articles. According to five studies, social participation of relatives is characterised by increased responsibilities and a reduction in interpersonal relationships and leisure. In rehabilitation, there is no consensus regarding what should be done for relatives; guidelines exist but are not applied in practice. Little has been formally reported regarding ethical issues likely to emerge for relatives. CONCLUSIONS: The main impact of stroke is on social roles of relatives such as responsibilities, interpersonal relationships and leisure. The role of rehabilitation and related ethical issues needs further examination. PMID- 20950142 TI - When does coevolution promote diversification? AB - Coevolutionary interactions between species are thought to be an important cause of evolutionary diversification. Despite this general belief, little theoretical basis exists for distinguishing between the types of interactions that promote diversification and those types that have no effect or that even restrict it. Using analytical models and simulations of phenotypic evolution across a metapopulation, we show that coevolutionary interactions promote diversification when they impose a cost of phenotype matching, as is the case for competition or host-parasite antagonism. In contrast, classical coevolutionary arms races have no tendency to promote or inhibit diversification, and mutualistic interactions actually restrict diversification. Together with the results of recent phylogenetic and ecological studies, these results suggest that the causes of diversification in many coevolutionary systems may require reassessment. PMID- 20950141 TI - A small group aerobic exercise programme that reduces body weight is feasible in adults with severe chronic schizophrenia: a pilot study. AB - PURPOSE: To evaluate the feasibility and effects of an exercise programme on people with severe, chronic schizophrenia. METHOD: A single-group, pre-post pilot study incorporating a baseline familiarisation phase was followed by a 24-week, small-group aerobic exercise programme for up to 30-min each session, twice a week and a 30-min weekly walking session. Adherence was assessed by attendance, and by analysing the exercise supervisor's comments in a programme diary and in each participant's exercise logbook. Body weight, cardio-respiratory fitness (VO2 max), walking endurance (6-min walk test) and psychiatric symptoms (the Positive and Negative Syndrome Scale) were measured at each time point. RESULTS: Eight participants (6 men, 2 women; mean age 45 years, 9 months (SD 10 years, 1 month); mean body mass index 27.0 (SD 4.2)) attended a mean of 73% of the scheduled exercise sessions, and 83% of the walking sessions, with no adverse events and no dropouts. All participants displayed positive and negative behaviours during training sessions. There were significant reductions in weight (2.4%) and body mass index (2.2%), but no changes in other measures. CONCLUSIONS: It was feasible and safe to conduct a small-group aerobic exercise programme for adults with severe chronic schizophrenia that reduced body weight. PMID- 20950143 TI - Predator cognition permits imperfect coral snake mimicry. AB - Batesian mimicry is often imprecise. An underexplored explanation for imperfect mimicry is that predators might not be able to use all dimensions of prey phenotype to distinguish mimics from models and thus permit imperfect mimicry to persist. We conducted a field experiment to test whether or not predators can distinguish deadly coral snakes (Micrurus fulvius) from nonvenomous scarlet kingsnakes (Lampropeltis elapsoides). Although the two species closely resemble one another, the order of colored rings that encircle their bodies differs. Despite this imprecise mimicry, we found that L. elapsoides that match coral snakes in other respects are not under selection to match the ring order of their model. We suggest that L. elapsoides have evolved only those signals necessary to deceive predators. Generally, imperfect mimicry might suffice if it exploits limitations in predator cognitive abilities. PMID- 20950146 TI - Sequence analysis of the gag-pol gene of human immunodeficiency virus type 1 of intersubtype (B'/C) recombinant strain in Beijing, China. AB - Little is known about the molecular and biological properties of HIV-1 intersubtype B'/C in Beijing. To fill the gap, we sequenced and analyzed the gag pol genes from 39 HIV-1 B'/C recombinant infectors in Beijing, China during 2007. The results show that 36 CRF07_BC and 2 CRF08_BC isolates have a structural profile identical or nearly identical to CRF07_BC or CRF08_BC according to sequences in the gag-pol regions. The CRF07_BC circulating in injecting drug users (IDUs) and heterosexuals forms a diverse phylogenetic tree and most isolates from homosexuals cluster together. However, all the B'/C recombinant strains were remarkable for their low interpatient diversity in gag-pol genes (3.1, 3.0, and 2.2% for isolates from IDUs, heterosexuals, and homosexuals, respectively). We identified I7V, E91G, N242T, and K361R in the gag gene and R290I (HXB2 positions) in the pol gene as signature amino acid substitutions characteristic of HIV-1 CRF07_BC from the Beijing lineage. In addition, one new B'/C recombinant was detected. These results may contribute to an understanding of HIV-1 in Beijing. PMID- 20950147 TI - Drug resistance mutations in drug-naive HIV type 1 subtype C-infected individuals from rural Malawi. AB - In this preliminary study we show that in 2008, 3 years after antiretroviral therapy was introduced into the Karonga District, Malawi, a greater than expected number of drug-naive individuals have been infected with HIV-1 subtype C virus harboring major and minor drug resistance mutations (DRMs). From a sample size of 40 reverse transcriptase (RT) consensus sequences from drug-naive individuals we found five showing NRTI and four showing NNRTI mutations with one individual showing both. From 29 protease consensus sequences, again from drug-naive individuals, we found evidence of minor DRMs in three. Additional major and minor DRMs were found in clonal sequences from a number of individuals that were not present in the original consensus sequences. This clearly illustrates the importance of sequencing multiple HIV-1 variants from individuals to fully assess drug resistance. PMID- 20950148 TI - Molecular characterization of HIV type 1 among HIV-infected respondents in a cohort being prepared for HIV Phase III vaccine clinical trials, Western Kenya. AB - Kenya is one of the sub-Saharan African countries affected by HIV-1 infection and AIDS. We investigated HIV-1 genetic diversity in 130 individuals from Busia, Bungoma, and Kakamega in western Kenya as part of an HIV-1 vaccine feasibility study in preparation for Phase III efficacy clinical trials. After RNA extraction the partial gag (484 bp) and env (1297 bp) regions were amplified and directly sequenced. Phylogenetic analysis was done using MEGA version 4 and recombinants were identified using the jpHMM tool and phylogenetic analysis. HIV-1 sequences were amplified from 122 of the 130 samples, 118 (90.8%) from the gag region and 78 (60 %) from the env region and 74 samples (56.9%) from both the gag and env regions. Of these sequenced on both regions, 51.4% were subtype A, 9.4% subtype D, 1.4% subtype C, 4.1% subtype G, and 33.7% were discordant and thus possible recombinants, including A1/C, A1/D, A1/A2, and A2/C. The jpHMM tool indicated a further two samples with CD and BD breakpoints within the env gene and one within the gag gene (A1C). An additional sample had an A1D breakpoint in the gag gene, but the envelope was not amplified. HIV-1 subtype diversity in western Kenya should be considered in vaccines designed for clinical trials in this region and this genetic diversity should be continuously monitored. PMID- 20950150 TI - Partitioning the components of relative growth rate: how important is plant size variation? AB - Plant growth plays a key role in the functioning of the terrestrial biosphere, and there have been substantial efforts to understand why growth varies among species. To this end, a large number of experimental analyses have been undertaken; however, the emergent patterns between growth rate and its components are often contradictory. We believe that these conflicting results are a consequence of the way growth is measured. Growth is typically characterized by relative growth rate (RGR); however, RGR often declines as organisms get larger, making it difficult to compare species of different sizes. To overcome this problem, we advocate using nonlinear mixed-effects models so that RGR can be calculated at a standard size, and we present easily implemented methods for doing this. We then present new methods for analyzing the traditional components of RGR that explicitly allow for the fact that (log)(RGR) is the sum of its components. These methods provide an exact decomposition of the variance in (log)(RGR). Finally, we use simple analytical and simulation approaches to explore the effect of size variation on growth and its components and show that the relative importance of the components of RGR is influenced by the extent to which analyses standardize for plant size. PMID- 20950152 TI - Growth inhibition effect of beta-catenin small interfering RNA-mediated gene silencing on human colon carcinoma HT-29 cells. AB - The beta-catenin gene is a critical component of Wnt signaling pathway. Aberrant activation of Wnt/beta-catenin signaling and subsequent upregulation of beta catenin is related to enhancing cell proliferation and developing colon polyps and colon cancer. In the present study, the effect of beta-catenin knockdown on the growth and survival of the human colon cancer cell line HT-29 was investigated in vitro. The effect of knockdown of beta-catenin on cell proliferation was investigated by MTT assay and colony formation. The cell cycle distribution was investigated by flow cytometry. Apoptosis was measured by nuclear staining and flow cytometry. The change of beta-catenin and related proteins were determined by western blotting and immunofluorescence. The results showed that small interfering RNA directed against beta-catenin markedly inhibited the expression and nuclear translocation of beta-catenin and decreased the expression of known target genes such as cyclin D1 and c-myc; HT-29 cell proliferation was inhibited as indicated by growth reduction, cell cycle arrest in G0/G1 phase, and induction of apoptosis; and the inhibition of cell growth may be associated with switching off cyclin D1 and c-myc expression by small interfering RNA targeted against beta-catenin in colon cancer HT-29 cells. PMID- 20950151 TI - Adeno-associated virus serotype 8 gene transfer rescues a neonatal lethal murine model of propionic acidemia. AB - Propionic acidemia (PA) is an autosomal recessive disorder of metabolism caused by a deficiency of propionyl-coenzyme A carboxylase (PCC). Despite optimal dietary and cofactor therapy, PA patients still suffer from lethal metabolic instability and experience multisystemic complications. A murine model of PA (Pcca(-/-)) of animals that uniformly die within the first 48 hr of life was used to determine the efficacy of adeno-associated viral (AAV) gene transfer as a potential therapy for PA. An AAV serotype 8 (AAV8) vector was engineered to express the human PCCA cDNA and delivered to newborn mice via an intrahepatic injection. Greater than 64% of the Pcca(-/-) mice were rescued after AAV8 mediated gene transfer and survived until day of life 16 or beyond. Western analysis of liver extracts showed that PCC was completely absent from Pcca(-/-) mice but was restored to greater than wild-type levels after AAV gene therapy. The treated Pcca(-/-) mice also exhibited markedly reduced plasma levels of 2 methylcitrate compared with the untreated Pcca(-/-) mice, which indicates significant PCC enzymatic activity was provided by gene transfer. At the time of this report, the oldest treated Pcca(-/-) mice are over 6 months of age. In summary, AAV gene delivery of PCCA effectively rescues Pcca(-/-) mice from neonatal lethality and substantially ameliorates metabolic markers of the disease. These experiments demonstrate a gene transfer approach using AAV8 that might be used as a treatment for PA, a devastating and often lethal disorder desperately in need of new therapeutic options. PMID- 20950153 TI - Inhibitory effect of small interfering RNA targeting insulin-like growth factor-I receptor in ovarian cancer OVCAR3 cells. AB - AIM: Insulin-like growth factor-I receptor (IGF-IR) is widely overexpressed in a variety of human cancers including ovarian cancer. It plays an important role in cancer cell proliferation and tumor growth. In this study, small interfering RNA (siRNA) was used to silence IGF-IR gene expression in the human ovarian cancer cell line OVCAR3 and then its effects on proliferation, apoptosis, angiogenesis, and the growth of tumor cells in vitro and in nude mice were evaluated. METHODS: Three siRNA sequences for the IGF-IR gene were cloned into expression plasmids and transfected into OVCAR3 cells. The downregulation of IGF-IR expression at both mRNA and protein levels were detected by real-time polymerase chain reaction and western blot analysis. Cell proliferation inhibition rates were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Nude mice (n = 6 per group) were subcutaneously xenografted with 2 * 10(6) OVCAR3 cancer cells. Tumor growth, cellular proliferation (Ki-67 immunohistochemistry), apoptosis, and angiogenesis (CD31 immunohistochemistry) were compared for mice administered either IGF-IR-specific or negative control siRNA over 5 weeks. RESULTS: The mRNA and protein expression of IGF-IR was significantly decreased at 48 hours after transfection, leading to a potent suppression of tumor cell proliferation in vitro. The IGF-IR-specific siRNA dramatically suppressed tumor growth and cellular proliferation, as well as promoted tumor cellular apoptosis and inhibited angiogenesis in an OVCAR3 s.c. xenograft model. CONCLUSIONS: The siRNA targeting of IGF-IR can effectively inhibit the growth of ovarian cancer cells and may be used as a potent therapy. PMID- 20950154 TI - Menthol cigarette smoking and health, Florida 2007 BRFSS. AB - OBJECTIVE: To examine associations between menthol cigarette smoking and nicotine dependence, quit attempts, and physical and mental health. METHODS: Data were drawn from the 2007 Florida Behavioral Risk Factor Surveillance System (BRFSS) and a follow-up survey among current smokers (N = 3396). Univariate and multivariate logistic regression analyses were conducted. RESULTS: In multivariate analyses, menthol cigarette smoking was associated with women, African American and Hispanic race/ethnicity, and greater mental distress. CONCLUSIONS: Women, racial/ethnic minorities, and individuals reporting a greater frequency of mental distress are more likely to smoke menthol versus nonmenthol cigarettes. Implications for public health policy and cessation interventions are discussed. PMID- 20950149 TI - Southern Brazil HIV type 1 C expansion into the state of Sao Paulo, Brazil. AB - Abstract HIV diversity reflects multifactorial evolutionary forces, but monitoring subtype prevalence may provide clues to understanding the epidemic. In the Americas HIV-1 C is present at significant levels only in the southern states of Brazil. We describe in this study the presence of the HIV-1 C pol genome in 11.6% (95 CI 6-21%) of antiretroviral-naive individuals from Sao Paulo, the major city of South America, and 6.8% (95 CI 4-12%) from the second metropolitan area of the State of Sao Paulo, Brazil. Moreover, a significant growth trend of this subtype was documented among cases failing therapy in the area. Sequences were obtained by direct nested PCR from cDNA retrotranscribed from plasma RNA. Phylogenetic and amino acid signatures support an expansion from variants previously identified in southern Brazil. The evaluation of additional genomic regions (partial gag, envelope, and/or integrase) in samples with HIV-1 C at pol showed extensive recombination with clade B, observed in 47% of ARV-naive cases. The spread of HIV-1 C locally and to other areas of South America should be monitored as it may influence the dynamics of the epidemic. PMID- 20950155 TI - Self-control and health outcomes in a nationally representative sample. AB - OBJECTIVES: To explore the link between low self-control during adolescence and health problems in early adulthood. METHODS: Using data from the National Longitudinal Study of Adolescent Health, we examined the relationship between varying levels of self-control and the likelihood of being diagnosed with a variety of physical and brain-based health conditions. RESULTS: Results from logistic regression analyses indicated that subjects with lower levels of self control had significantly higher odds of being diagnosed with 9 of the 10 health outcomes. CONCLUSIONS: Targeting the development of self-control in childhood and adolescence may be valuable in preventing future health problems. PMID- 20950156 TI - Socioeconomic factors and health risk behaviors among adolescents. AB - OBJECTIVES: To examine relationships between a wide range of socioeconomic factors, race/ethnicity, and adolescent risk behaviors. METHODS: The Youth Asset Study (N = 1111) was used to examine multivariate relationships between sexual initiation, alcohol use, tobacco use, and drug use and 8 socioeconomic factors. RESULTS: Socioeconomic factors beyond income and parental education (eg, wealth) were associated with some health behaviors depending upon gender. However, we did not find that a wider range of factors helped us better understand racial/ethnic disparities. CONCLUSIONS: Even the more comprehensive set of socioeconomic factors considered may not accurately capture the underlying construct of adolescent SES. PMID- 20950157 TI - Predictors of retention of African American women in a walking program. AB - OBJECTIVE: To predict retention of African American women 6 months after initiating a community walking program. METHODS: Demographics, health status, cancer-related health behaviors, and network membership data from baseline wellness questionnaires of 1322 African American women participating in the walking program were analyzed using multivariate logistic regression models. RESULTS: Seventy-eight percent (n = 1032) of African American women were retained at 6 months. Network membership was the primary predictor of retention. CONCLUSIONS: Women affiliated with our comprehensive network, which provides ongoing cancer awareness, screening, and prevention programs to reduce cancer health disparities, were more likely to accomplish the first major milestone of the program. PMID- 20950158 TI - Stress-induced cardiovascular reactivity among African American smokers. AB - OBJECTIVES: To test for differences in stress-induced cardiovascular functioning among hypertensive and normotensive African American (AA) smokers. METHODS: Participants (n = 35) were exposed to both stress and neutral mood inductions. RESULTS: Repeated measures analyses of covariance produced a significant group x mood condition interaction for systolic blood pressure (P = .048), but not for diastolic blood pressure (P > .05). The most notable finding was that AA hypertensive smokers showed selectively greater elevations in their systolic responses compared with normotensive controls following the laboratory-induced stressor. CONCLUSIONS: Implications to an elevated risk of future cardiovascular disease among AA hypertensive smokers are discussed. PMID- 20950159 TI - Interactive social cognitive model of leisure-time physical activity in mid to late life. AB - OBJECTIVE: To examine the interactive effects of exercise identity (EI) and outcome expectations (OE) on constraints, constraint self-regulation, and leisure time physical activity (LTPA). METHODS: Surveyed a convenience sample of middle aged and older adults (N = 271) at a metropolitan park agency in the Midwest. RESULTS: The final reduced model predicted 24% of the variance in LTPA, including an indirect effect of EI x OE through intrapersonal constraints. CONCLUSION: Results suggest that these social cognitive factors are useful in understanding low to high-intensity LTPA and have implications for LTPA programs for adults aged 50 and older. PMID- 20950160 TI - Accelerometry and self-report in sedentary populations. AB - OBJECTIVES: To determine whether self-reported exercise duration and intensity matched accelerometer data in sedentary endometrial cancer survivors and age matched controls. METHODS: Participants were asked to wear an accelerometer and self-report exercise bouts, duration, and intensity for one week. Self-reported duration was compared with accelerometer data. RESULTS: Self-reported exercise bout duration matched accelerometer duration 93% for survivors and 99% for controls. Self-reported exercise-bout intensity matched accelerometer intensity 70% for survivors and 66% for controls. There were no significant differences between groups. CONCLUSIONS: Sedentary endometrial cancer survivors and controls self-reported duration and intensity of physical activity consistent with accelerometer data. PMID- 20950161 TI - Correlates of intergenerational and personal physical activity of parents. AB - OBJECTIVE: To compare the correlates of personal versus intergenerational leisure time physical activity of parents using the theory of planned behavior. METHODS: Participants were parents (n=126) with children between the ages of 2 and 12 years, and they completed a baseline questionnaire exploring intergenerational and personal activity. RESULTS: Perceived behavioral control and behavioral frequency were higher in intergenerational than personal activity. Affective attitude was higher for personal activity, and subjective norm was more important in intergenerational than personal intention. CONCLUSION: Future interventions may benefit from some specific targeting toward intergenerational or personal activity. PMID- 20950162 TI - Longitudinal analysis of weight perception and psychological factors in Chinese adolescents. AB - OBJECTIVES: To investigate associations of overweight status and perception with trajectories of psychological distress in adolescents. METHODS: Longitudinal data for 6970 Chinese adolescents were included. The multivariate curve-of-factor latent growth curve models were adopted to examine trajectories of psychological distress symptoms and associations with overweight status and perception. RESULTS: After controlling for actual overweight status, psychological distress symptoms were weakly but significantly associated with overweight perception (gamma = 0.08 for boys and gamma = 0.10 for girls, P < 0.05) and misperception (gamma = 0.06 for boys and gamma = 0.09 for girls, P < 0.05). DISCUSSION: Our findings help understanding associations of overweight perception and psychological well being of adolescents. PMID- 20950163 TI - Illness risk perceptions and trust: the association with blood pressure self measurement. AB - OBJECTIVE: To determine the prevalence of blood pressure selfmeasurement among those with hypertension and examine how this behavior may be associated with illness perceptions, risk perceptions, and attitudes about care. METHODS: Cross sectional data from a population-based study of cardiovascular disease (n = 656). RESULTS: The prevalence of self-measurement was 26.2%. Both above- and below average perceived risks of stroke were associated with a decreased likelihood of self-monitoring (OR = 0.36, 95% CI = 0.14-0.91; and OR = 0.16, 95% CI = 0.05-0.75 respectively). Completely trusting the medical system was associated with a decreased likelihood of self-monitoring (OR=0.47, 95% CI=0.22-0.99). CONCLUSION: Selfmonitoring can be influenced by illness risk perception and patient-physician trust. PMID- 20950164 TI - The mechanisms linking health literacy to behavior and health status. AB - OBJECTIVE: To examine the mechanisms linking health literacy to physical activity and self-reported health. METHODS: From 2005-2007, patients (N = 330) with hypertension were recruited from safety net clinics. Pathanalytic models tested the pathways linking health literacy to physical activity and self-reported health. RESULTS: There were significant paths from health literacy to knowledge (r = 0.22, P < 0.001), knowledge to self-efficacy (r = 0.13, P < 0.01), self efficacy to physical activity (r = 0.17, P < 0.01), and physical activity to health status (r = 0.17, P < 0.01). CONCLUSIONS: Health education interventions should be literacy sensitive and aim to enhance patient health knowledge and self efficacy to promote self-care behavior and desirable health outcomes. PMID- 20950165 TI - Teriparatide for bone loss in the jaw. PMID- 20950167 TI - Teriparatide therapy for alendronate-associated osteonecrosis of the jaw. PMID- 20950166 TI - Teriparatide and osseous regeneration in the oral cavity. AB - BACKGROUND: Intermittent administration of teriparatide, a drug composed of the first 34 amino acids of parathyroid hormone, has anabolic effects on bone. Although teriparatide has been evaluated for the treatment of osteoporosis and for the healing of fractures, clinical trials evaluating it for the treatment of osseous conditions of the oral cavity in humans are lacking. METHODS: A total of 40 patients with severe, chronic periodontitis underwent periodontal surgery and received daily injections of teriparatide (20 MUg) or placebo, along with oral calcium (1000 mg) and vitamin D (800 IU) supplementation, for 6 weeks. The patients were followed for 1 year. The primary outcome was a radiographic linear measurement of alveolar bone level. Secondary outcomes included clinical variables, bone turnover markers in serum and oral fluid, systemic bone mineral density, and quality of life. RESULTS: Radiographic linear resolution of osseous defects was significantly greater after teriparatide therapy than after placebo beginning at 6 months, with a mean linear gain in bone at 1 year of 29% as compared with 3% (P<0.001). Clinical improvement was greater in patients taking teriparatide than in those taking placebo, with a reduction in periodontal probing depth of 33% versus 20% (2.42 mm vs. 1.32 mm) and a gain in clinical attachment level of 22% versus 7% (1.58 mm vs. 0.42 mm) in target lesions at 1 year (P = 0.02 for both comparisons). No serious adverse events were reported; however, the number of patients in the study was small. No significant differences were noted with respect to the other variables that were assessed. CONCLUSIONS: Teriparatide, as compared with placebo, was associated with improved clinical outcomes, greater resolution of alveolar bone defects, and accelerated osseous wound healing in the oral cavity. Teriparatide may offer therapeutic potential for localized bone defects in the jaw. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00277706 .). PMID- 20950168 TI - Comparison of two infrared devices in their effectiveness in reducing symptoms associated with RLS. AB - This study was conducted to assess whether two kinds of near-infrared light devices, using different wavelengths and frequencies, impact symptoms associated with restless legs syndrome (RLS) differently. A recent randomized controlled study showed that symptoms associated with RLS can be diminished with near infrared light treatment for a limited time. We wanted to assess whether different wavelengths and frequencies had an impact on its effectiveness. Twenty five volunteers with symptoms of RLS were randomly assigned to either Anodyne(r) or HealthLightTM treatment. Both groups underwent 12 treatments with near infrared light, three times a week for 4 weeks. A validated RLS rating scale was used to track changes. The two groups were not different in reported symptoms at baseline (p=0.37) and after 4 weeks of treatment (p=0.88). There was a significant improvement of symptoms between week 0 and week 4 (p<0.001); the difference in change indicated virtually the same improvement between the two groups. Although the two near-infrared light devices used different wavelengths and frequencies and one device used additional red light, they both produced significant improvement in the symptoms associated with RLS after 4 weeks of treatment. PMID- 20950169 TI - Energetic costs and thermoregulation in northern fur seal (Callorhinus ursinus) pups: the importance of behavioral strategies for thermal balance in furred marine mammals. AB - Behavioral thermoregulation represents an important strategy for reducing energetic costs in thermally challenging environments, particularly among terrestrial vertebrates. Because of the cryptic lifestyle of aquatic species, the energetic benefits of such behaviors in marine endotherms have been much more difficult to demonstrate. In this study, I examined the importance of behavioral thermoregulation in the northern fur seal (Callorhinus ursinus) pup, a small bodied endotherm that spends prolonged periods at sea. The thermal neutral zones of three weaned male northern fur seal pups (body mass range = 11.8-12.8 kg) were determined by measuring resting metabolic rate using open-flow respirometry at water temperatures ranging from 2.5 degrees to 25.0 degrees C. Metabolic rate averaged 10.03 +/- 2.26 mL O2kg-1 min-1 for pups resting within their thermal neutral zone; lower critical temperature was 8.3 degrees +/- 2.5 degrees C , approximately 8 degrees C higher than the coldest sea surface temperatures encountered in northern Pacific waters. To determine whether behavioral strategies could mitigate this potential thermal limitation, I measured metabolic rate during grooming activities and the unique jughandling behavior of fur seals. Both sedentary grooming and active grooming resulted in significant increases in metabolic rate relative to rest (P = 0.001), and percent time spent grooming increased significantly at colder water temperatures (P < 0.001). Jughandling metabolic rate (12.71 +/- 2.73 mL O2kg-1 min -1) was significantly greater than resting rates at water temperatures within the thermal neutral zone (P < 0.05) but less than resting metabolism at colder water temperatures. These data indicate that behavioral strategies may help to mitigate thermal challenges faced by northern fur seal pups while resting at sea. PMID- 20950170 TI - The Mawrth Vallis region of Mars: A potential landing site for the Mars Science Laboratory (MSL) mission. AB - The primary objective of NASA's Mars Science Laboratory (MSL) mission, which will launch in 2011, is to characterize the habitability of a site on Mars through detailed analyses of the composition and geological context of surface materials. Within the framework of established mission goals, we have evaluated the value of a possible landing site in the Mawrth Vallis region of Mars that is targeted directly on some of the most geologically and astrobiologically enticing materials in the Solar System. The area around Mawrth Vallis contains a vast (>1 * 106 km2) deposit of phyllosilicate-rich, ancient, layered rocks. A thick (>150 m) stratigraphic section that exhibits spectral evidence for nontronite, montmorillonite, amorphous silica, kaolinite, saponite, other smectite clay minerals, ferrous mica, and sulfate minerals indicates a rich geological history that may have included multiple aqueous environments. Because phyllosilicates are strong indicators of ancient aqueous activity, and the preservation potential of biosignatures within sedimentary clay deposits is high, martian phyllosilicate deposits are desirable astrobiological targets. The proposed MSL landing site at Mawrth Vallis is located directly on the largest and most phyllosilicate-rich deposit on Mars and is therefore an excellent place to explore for evidence of life or habitability. PMID- 20950171 TI - Low-temperature ionizing radiation resistance of Deinococcus radiodurans and Antarctic Dry Valley bacteria. AB - The high flux of cosmic rays onto the unshielded surface of Mars poses a significant hazard to the survival of martian microbial life. Here, we determined the survival responses of several bacterial strains to ionizing radiation exposure while frozen at a low temperature characteristic of the martian near subsurface. Novel psychrotolerant bacterial strains were isolated from the Antarctic Dry Valleys, an environmental analogue of the martian surface, and identified by 16S rRNA gene phylogeny as representatives of Brevundimonas, Rhodococcus, and Pseudomonas genera. These isolates, in addition to the known radioresistant extremophile Deinococcus radiodurans, were exposed to gamma rays while frozen on dry ice (-79 degrees C). We found D. radiodurans to exhibit far greater radiation resistance when irradiated at -79 degrees C than was observed in similar studies performed at higher temperatures. This greater radiation resistance has important implications for the estimation of potential survival times of microorganisms near the martian surface. Furthermore, the most radiation resistant of these Dry Valley isolates, Brevundimonas sp. MV.7, was found to show 99% 16S rRNA gene similarity to contaminant bacteria discovered in clean rooms at both Kennedy and Johnson Space Centers and so is of prime concern to efforts in the planetary protection of Mars from our lander probes. Results from this experimental irradiation, combined with previous radiation modeling, indicate that Brevundimonas sp. MV.7 emplaced only 30 cm deep in martian dust could survive the cosmic radiation for up to 100,000 years before suffering 106 population reduction. PMID- 20950172 TI - Using the Internet to assess perceptions of patients with borderline personality disorder: what do patients want in the DSM-V? AB - OBJECTIVES: This study was an anonymous Internet survey of individuals currently diagnosed with borderline personality disorder (BPD), where participants gave opinions about BPD criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR), and suggested modifications for BPD criteria to appear in the DSM-V (5th edition). METHODS: Survey links were posted on 24 websites/Internet blogs that offered advice, education, or treatment of BPD. Demographic and clinical data pertaining to each participant were collected. Free-text responses were analyzed by frequencies of keywords and key phrases. RESULTS: A total of 1,832 responses were downloaded between March 7 and June 6, 2009, and 646 responses were analyzable. Results indicated that the majority of the DSM-IV-TR criteria appeared to capture what participants were experiencing, even though a significant percentage of participants felt that something was missing from the current criteria. A significant percentage of participants felt that BPD should be renamed in the DSM-V; some combination of "emotion(al)" and "(dys)regulation" was most commonly suggested to include in an alternative name. CONCLUSIONS: This Internet study highlighted the enthusiasm of individuals diagnosed with BPD to share their opinions on the DSM criteria with mental-health professionals. A significant percentage of participants in this study felt that BPD should be renamed in the DSM-V. Patient involvement during the DSM-V revision process remains controversial. PMID- 20950173 TI - College students' self-discrepancy on the Internet, from the perspectives of desktop practices, self-control, and academic training. AB - The self-discrepancy theory argues that perceived discrepancy between one's actual self and ideal self may induce anxiety, and that this in turn may motivate people to reduce or eliminate this perceived discrepancy by changing their behaviors. Based on this theory, this study investigated how college students perceived discrepancies between their actual and their reported ideal uses of the Internet. Their Internet use was examined on three levels: the grand level (i.e., hours spent online per week), the activity level (i.e., hours spent engaging in certain online activities per week), and the tool level (i.e., hours spent using certain Internet tools per week). Three particular factors were also selected for investigation: the participants' different desktop practices, levels of academic training, and exertions of self-control. The results indicate that the participants' perceptions of actual versus ideal discrepancies were shaped by the different levels (i.e., grand, activity, tool) of their Internet use. Additionally, this study shows that perceived self-discrepancy relating to the time that college students spend on the Internet may not be a problem in itself, but it may symbolize more profound psychological or behavioral factors that need to be addressed. PMID- 20950174 TI - Restorative effects of virtual nature settings. AB - Previous research regarding the potential benefits of exposing individuals to surrogate nature (photographs and videos) has found that such immersion results in restorative effects such as increased positive affect, decreased negative affect, and decreased stress. In the current experiment, we examined whether immersion in a virtual computer-generated nature setting could produce restorative effects. Twenty-two participants were equally divided between two conditions, while controlling for gender. In each condition, participants performed a stress-induction task, and were then immersed in virtual reality (VR) for 10 minutes. The control condition featured a slide show in VR, and the nature experimental condition featured an active exploration of a virtual forest. Participants in the nature condition were found to exhibit increased positive affect and decreased stress after immersion in VR when compared to those in the control condition. The results suggest that immersion in virtual nature settings has similar beneficial effects as exposure to surrogate nature. These results also suggest that VR can be used as a tool to study and understand restorative effects. PMID- 20950175 TI - Converting virtual community members into online buyers. AB - Although many online vendors have sponsored virtual communities (VCs) in the hope of reaping commercial benefits from it, not many have been successful in reaping commercial benefits from their VC. Online vendors can benefit greatly from having a VC, if the VC members can be converted into online buyers. This study examines the conversion of a VC member into an online buyer. Using a classical conditioning approach, this study finds that members' committed participation in the VC is the springboard for online vendors to convert VC members into online buyers. PMID- 20950176 TI - Body image in eating disorders: the influence of exposure to virtual-reality environments. AB - The aim of this article was to study the effect of virtual-reality exposure to situations that are emotionally significant for patients with eating disorders (ED) on the stability of body-image distortion and body-image dissatisfaction. A total of 85 ED patients and 108 non-ED students were randomly exposed to four experimental virtual environments: a kitchen with low-calorie food, a kitchen with high-calorie food, a restaurant with low-calorie food, and a restaurant with high-calorie food. In the interval between the presentation of each situation, body-image distortion and body-image dissatisfaction were assessed. Several 2 x 2 x 2 repeated measures analyses of variance (high-calorie vs. low-calorie food x presence vs. absence of people x ED group vs. control group) showed that ED participants had significantly higher levels of body-image distortion and body dissatisfaction after eating high-calorie food than after eating low-calorie food, while control participants reported a similar body image in all situations. The results suggest that body-image distortion and body-image dissatisfaction show both trait and state features. On the one hand, ED patients show a general predisposition to overestimate their body size and to feel more dissatisfied with their body image than controls. On the other hand, these body-image disturbances fluctuate when participants are exposed to virtual situations that are emotionally relevant for them. PMID- 20950177 TI - Gender differences and the effect of contextual features on game enjoyment and responses. AB - This article explores the effect of gender and contextual features on emotional reactions, identification toward game characters, and game enjoyment. Two aspects of contextual features are specifically examined: the moral justification of game characters and violence. An experiment was conducted by allowing participants to play either a morally justified character of a non-violent game, a morally justified character of a violent game, or a morally unjustified character of a violent game. The results show that participants felt less guilty and identified with the characters more when playing the morally justified characters of the non violent game. Furthermore, males and females demonstrate different patterns of enjoyment to different contextual features of video games. The implications of these findings and directions for future research are discussed. PMID- 20950178 TI - Impact of signals and experience on trust and trusting behavior. AB - Trust is an essential factor that drives virtual interaction and transactions on the Internet. Researchers have investigated the trust development process, and identified several important factors that form the basis for trust. This research combines the signal perspective and trust theory to examine the impact of market signals and past experience on trust formation and trusting behavior. Three market signals, including brand image, Web-site investment, and privacy policies, are identified and empirically tested to determine their impact on consumer trust. Based on 322 active Web users, the quantitative results suggest that brand image, Web-site investment, privacy policies, and past experience all positively impact trust formation. Furthermore, trust shows a positive effect on Web-site stickiness. Both theoretical and practical implications of the results are also offered. PMID- 20950179 TI - Virtual social interactions in social anxiety--the impact of sex, gaze, and interpersonal distance. AB - In social interactions, interpersonal distance between interaction partners plays an important role in determining the status of the relationship. Interpersonal distance is an important nonverbal behavior, and is used to regulate personal space in a complex interplay with other nonverbal behaviors such as eye gaze. In social anxiety, studies regarding the impact of interpersonal distance on within situation avoidance behavior are so far rare. Thus the present study aimed to scrutinize the relationship between gaze direction, sex, interpersonal distance, and social anxiety in social interactions. Social interactions were modeled in a virtual-reality (VR) environment, where 20 low and 19 high socially anxious women were confronted with approaching male and female characters, who stopped in front of the participant, either some distance away or close to them, and displayed either a direct or an averted gaze. Gaze and head movements, as well as heart rate, were measured as indices of avoidance behavior and fear reactions. High socially anxious participants showed a complex pattern of avoidance behavior: when the avatar was standing farther away, high socially anxious women avoided gaze contact with male avatars showing a direct gaze. Furthermore, they showed avoidance behavior (backward head movements) in response to male avatars showing a direct gaze, regardless of the interpersonal distance. Overall, the current study proved that VR social interactions might be a very useful tool for investigating avoidance behavior of socially anxious individuals in highly controlled situations. This might also be the first step in using VR social interactions in clinical protocols for the therapy of social anxiety disorder. PMID- 20950180 TI - Emotional responses during social information seeking on Facebook. AB - Based on existing research on social networking and information seeking, it was proposed that Facebook.com use could be conceptualized as serving two primary goals: passive social browsing (i.e., newsfeeds) and extractive social searching (i.e., friends' profiles). This study explored whether these categories adequately reflect Facebook use and whether they moderate physiological indicators of emotion. Thirty-six participants navigated Facebook.com while their on-screen activity and physiological responses associated with motivation and emotion were recorded. Results showed that the majority of screens encountered during Facebook use could be categorized as devoted to social browsing or social searching. Participants spent more time on social browsing than they spent on social searching. Skin-conductance data indicated that sympathetic activation diminished during the course of both social browsing and social searching. Facial EMG data indicated that participants experienced more pleasantness during the course of social searching than they experienced during social browsing. These results are discussed in terms of existing social-networking research and an evaluative space model of emotion. PMID- 20950181 TI - Designing appropriate blended courses: a students' perspective. AB - The computing education in Taiwan's vocational schools usually focuses on how to help students enhance their professional skills and pass certified examinations. In addition, due to national education policy and universities' regulations, pure online courses are not permitted in Taiwan. In order to design appropriate blended learning (BL) courses, the author explored the effects of web-mediated self-regulated learning (SRL) with variations in online class frequency on enhancing students' computing skills and their perspective of the blended courses. A total of 172 students, divided into four groups, participated in the experiment. The results showed that students in the SRL and BL group with five online classes had the highest scores for using a database management system (DBMS), and the highest pass rate on certified examinations. Students in this group also expressed their positive perspective on the arrangement of their blended course with the intervention of web-mediated SRL. PMID- 20950182 TI - "I feel more connected to the physically ideal mini me than the mirror-image mini me": theoretical implications of the "malleable self" for speculations on the effects of avatar creation on avatar-self connection in Wii. AB - What are the impacts of creating an avatar replicating the actual self versus an avatar projecting the ideal self on game players' avatar-self connection? This study leveraged an avatar-creating game (Mii Channel) within a video-game console (Wii) in a controlled, randomized study. The results of a two-group comparison (actual self-priming vs. ideal self-priming) between-subjects study (N = 76) demonstrated the significant main effect of self-priming via avatar (Mii) creation on avatar-self connection. Game players who were primed to create a Mii reflecting the ideal self felt greater avatar-self connection than those primed to create a replica Mii mirroring the actual self. Theoretical values and implications for a burgeoning body of research on the "malleable self" and the multidimensionality of the self-concept in avatar-based interactive media are discussed. PMID- 20950183 TI - Investigation of the computer experiences and attitudes of pre-service mathematics teachers: new evidence from Turkey. AB - This study aimed to investigate the experiences of pre-service mathematics (PSM) teachers with computers and their attitudes toward them. The Computer Attitude Scale, Computer Competency Survey, and Computer Use Information Form were administered to 180 Turkish PSM teachers. Results revealed that most PSM teachers used computers at home and at Internet cafes, and that their competency was generally intermediate and upper level. The study concludes that PSM teachers' attitudes about computers differ according to their years of study, computer ownership, level of computer competency, frequency of computer use, computer experience, and whether they had attended a computer-aided instruction course. However, computer attitudes were not affected by gender. PMID- 20950184 TI - Involving students in a blended course via teacher's initiation in Web-enhanced collaborative learning. AB - Teachers of application software in Taiwan have traditionally applied disjointed and out-of-context examples in their teaching, which usually result in ineffective learning outcomes. A Web-enhanced, collaborative learning approach was therefore adopted to help students become involved in a course more positively. Additionally, the teacher provided initiation, establishing the essential knowledge and required skills for students at the beginning of the course in order to help students climb the learning curve. The results showed that students who received Web-enhanced collaborative learning with initiation were significantly more involved than those who did not receive the initiation. Moreover, findings also revealed that the initiation contributed to significant increases in students' involvement at the end of the course. The implications for teachers, schools, and scholars who plan to provide Web-based learning for their students are also discussed. PMID- 20950185 TI - The role of structural characteristics in video-game play motivation: a Q methodology study. AB - Until recently, there has been very little naturalistic study of what gaming experiences are like, and how gaming fits into people's lives. Using a recently developed structural characteristic taxonomy of video games, this study examined the psycho-structural elements of computer games that motivate gamers to play them. Using Q-Sort methodology, 40 gamers participated in an online Q-sort task. Results identified six distinct types of gamers based on the factors generated: (a) story-driven solo gamers; (b) social gamers; (c) solo limited gamers; (d) hardcore online gamers; (e) solo control/identity gamers; and (f ) casual gamers. These gaming types are discussed, and a brief evaluation of similar and unique elements of the different types of gamer is also offered. The current study shows Q-methodology to be a relevant and applicable method in the psychological research of gaming. PMID- 20950186 TI - Virtual-reality distraction and cold-pressor pain tolerance: does avatar point of view matter? AB - This study tested the effects of distraction using virtual-reality (VR) technology on acute pain tolerance in young adults. Forty-one undergraduate students, aged 18-23 years, used a VR head-mounted display helmet, steering wheel, and foot pedal to play an auto racing video game while undergoing exposure to very cold water (cold pressor set at 1 degrees C). Two different game views were tested that were hypothesized to affect the degree to which participants felt "present" in the virtual environment: a first-person view, in which the participant saw the virtual environment through the eyes of the game character being manipulated; and a third-person view, in which the participant viewed the game character from a distance. The length of time participants tolerated the cold-water exposure (pain tolerance) under each distraction condition was compared to a baseline (no distraction) trial. Subjects also rated the degree to which they felt "present" in the virtual environment after each distraction trial. Results demonstrated that participants had significantly higher pain tolerance during both VR-distraction conditions relative to baseline (no distraction) trials. Although participants reported a greater sense of presence during the first-person condition than the third-person condition, pain-tolerance scores associated with the two distraction conditions did not differ. The types of VR applications in which presence may be more or less important are discussed. PMID- 20950189 TI - Comparison of the effect of three mechanical surface treatments on the repair bond strength of a laboratory composite. AB - OBJECTIVE: This study compared the effects of three mechanical surface treatments, including diamond bur, air-abrasion, and Er, Cr: YSGG laser on the repair bond strength of a laboratory composite resin. BACKGROUND DATA: A proper bonding must be created between the existing composite and the new one for successful repair. MATERIALS AND METHODS: Sixty cylindrical specimens of a laboratory composite resin (Gradia) were prepared and randomly divided into four groups (n = 15). Groups 2-4 were treated with diamond bur, air-abrasion, and Er, Cr: YSGG laser, respectively; group 1 was the control group, without any mechanical surface treatment. The topographical effects of different mechanical surface treatments were characterized by atomic force microscope. Silane and a bonding agent (Single Bond) were used in all of the groups before adding a direct resin composite. Then, the specimens were subjected to a shear bond strength test. Failure modes were evaluated under a stereomicroscope. All data were analyzed by one-way ANOVA and Tukey test at a significance level of p < 0.05. RESULTS: There were statistically significant differences in bond strengths between the groups (p < 0.0005). Differences in bond strengths between group 1 and the other groups were significant (p < 0.0005). Furthermore, there were significant differences in bond strengths between group 2 and groups 3 and 4 (p < 0.0005), while the bond strength differences between groups 3 and 4 were not significant. CONCLUSION: Based on the results of this study, Er, Cr: YSGG laser was confirmed to be as effective as air-abrasion for laboratory composite repair. PMID- 20950190 TI - Clinical evaluation of low-level laser treatment for recurring aphthous stomatitis. AB - OBJECTIVE: The aim of the present study was to assess the effect of low-level laser on the control of pain and the repair of recurring aphthous stomatitis (RAS). BACKGROUND: One of the most frequent pathologic conditions in the oral cavity is RAS. This multifactor immunologic inflammatory lesion causes patient discomfort, and treatment is controversial because of its unknown etiology. A number of treatment modalities have been proposed, but none is definitive. Low level laser treatment (LLLT) has been used for lesions of an inflammatory nature, not as an inhibitor of the process, but for its modulating action and reparative effect on tissues. MATERIALS AND METHODS: Twenty patients with RAS were divided into one group treated with a topical corticoid agent (n = 5) and another group treated with laser (n = 15). Group I received conventional treatment with triamcinolone acetonide 4 times per day. The patients in Group II received laser treatment with an InGaA1P diode laser with wavelength of 670 nm, 50 mW, 3 J/cm(2) per point in daily sessions (once per day) on consecutive days. Both treatments were applied until the disappearance of the lesions. All patients were evaluated on a daily basis, and the following clinical parameters were determined during each session: pain intensity before and after treatment and clinical measurement of lesion size. RESULTS: The results revealed that 75% of the patients reported a reduction in pain in the same session after laser treatment, and total regression of the lesion occurred after 4 days. Total regression in the corticoid group was from 5 to 7 days. CONCLUSION: The use of LLLT under the conditions administered in the present study demonstrated analgesic and healing effects with regard to RAS. PMID- 20950191 TI - Antimicrobial activity of doripenem and other carbapenems against gram-negative pathogens from Korea. AB - A total of 950 gram-negative bacterial isolates from patients with bacteremia and urinary tract infections were collected from tertiary-care hospitals in Korea. In vitro antimicrobial susceptibility testing was performed using broth microdilution test according to Clinical and Laboratory Standards Institute protocol. In general, carbapenems such as doripenem, imipenem, and meropenem were very active against Enterobacteriaceae, Moraxella catarrhalis, Pseudomonas aeruginosa, and Acinetobacter sp. isolates. Doripenem was more potent than imipenem against most Enterobacteriaceae species except Proteus spp. based on minimum inhibitory concentration (MIC)(50) and MIC(90). In addition, doripenem displayed similar activity to meropenem but was superior to imipenem against ceftazidime-resistant Enterobacteriaceae isolates. For P. aeruginosa and Acinetobacter spp. isolates, MIC(50)s of doripenem were 1 and 0.5 mg/L, respectively, which were the same with those of meropenem but two- to fourfold lower than those of imipenem (both 2 mg/L). On the basis of the in vitro data, we conclude that doripenem has equivalent or more activity than other carbapenems such as imipenem and meropenem against most gram-negative pathogens from Korea. Thus, doripenem may be a promising new antimicrobial agent for the treatment of infections caused by gram-negative pathogens in Korea. PMID- 20950192 TI - Susceptibility of Clostridium difficile toward antimicrobial agents used as feed additives for food animals. AB - A total of 65 toxigenic Clostridium difficile strains isolated from patients with antibiotic-associated diarrhea were tested for susceptibility to avilamycin, flavomycin, monensin, and salinomycin. Except for flavomycin the substances showed in vitro efficacy comparable to reports of the currently most commonly used drugs for treatment of C. difficile. This indicates that these old compounds may be useful for the treatment of C. difficile infections in man and perhaps for other bacterial causes of diarrhea. PMID- 20950193 TI - Solanum paniculatum L. leaf and fruit extracts: assessment of modulation of cytotoxicity and genotoxicity by micronucleus test in mice. AB - Solanum paniculatum L. is a plant species widespread throughout tropical America, especially in the Brazilian Savanna region. It is used in Brazil for culinary purposes and in folk medicine to treat liver and gastric dysfunctions, as well as hangovers. Previous studies with S. paniculatum ethanolic leaf extract (ELE) or ethanolic fruit extract (EFE) demonstrated that they have no genotoxic activity meant either in the micronucleus test in mice or in the phage induction SOS Inductest in bacterial strains; however, cytotoxicity was demonstrated in both tests. Because of the spread use of this plant as a therapeutic resource and food, the present study aimed at evaluating the modulator effects of S. paniculatum ELE or EFE against mitomycin C (MMC) using the mouse bone marrow micronucleus test. This short-term test was used to detect the acute effects of responsive erythropoiesis after 24- and 48-hour exposure periods. Swiss-Webster mice were orally treated with three different concentrations (100, 200, or 300 mg/kg) of ELE or EFE simultaneously with a single dose of MMC (4 mg/kg i.p.). Antigenotoxicity was evaluated using the frequency of micronucleated polychromatic erythrocytes (MNPCEs), whereas anticytotoxicity was assessed by the polychromatic/normochromatic erythrocyte ratio. Our results demonstrated that neither the ELE nor EFE of S. paniculatum protected cells against the cytotoxic action of MMC. Nevertheless, the present study showed the antimutagenic effect of ELE after a 24-hour treatment (reduction in the frequencies of MNPCEs after a 48 hour treatment with ELE can be due to toxicity) and no antimutagenic action of the EFE treatment against the aneugenic and/or clastogenic activities of MMC. PMID- 20950194 TI - BRAF status of follicular variant of papillary thyroid carcinoma and its relationship to its clinical and cytological features. AB - BACKGROUND: The cytological discrimination between benign and malignant follicular-patterned lesions of the thyroid can represent a diagnostic challenge, even for experienced pathologists. To attempt to clarify this diagnostic problem, we analyzed the BRAF status of thyroid tumors in a group of patients with follicular variant of papillary thyroid carcinoma (FVPTC) and its correlation with cytomorphological features. METHODS: The BRAF status was evaluated in a total of 187 patients in whom FVPTC was consecutively diagnosed by histology between January 2006 and January 2009. Each case had a previous fine-needle aspiration diagnosis classified according to the British Thyroid Association Guidelines categorized as inadequate (Thy1) (n = 19), benign (Thy2) (n = 19), follicular lesion and follicular lesion with atypia (Thy3) (n = 109), suspicious of PTC (Thy4) (n = 29), or malignant (Thy5) (n = 11). The first 68 cases were selected for a morphological study by a quantitative analysis of four cytological features (grooves, intranuclear cytoplasmatic inclusions, number of cells per high power field (400 *), and mean nuclear diameter) of the carcinomas. RESULTS: The BRAF status of each tumor was correlated with the cytological classes. 54.5% and 27.6% of Thy5 and Thy4, respectively, were BRAF-mutated, against 12.1% of follicular lesions and 9.3% of follicular lesion with atypia (Thy3). This comparison was statistically significative (p = 0.0017). Among the 68 cases selected for the cyto-morphological study, the BRAF status frequency was similar to that of the total case series. No significant differences were found correlating the cytological classes with the number of cells, the number of grooves, and the mean cell diameters. Only the number of intranuclear cytoplasmatic inclusions were associated (p < 0.05) with the Thy5 cytological class. CONCLUSIONS: BRAF is mutated in a low percentage of FVPTC, and most of these mutated cases are suspicious or positive on fine-needle aspiration. BRAF analysis is of limited value in the preoperative diagnosis of FVPTC. PMID- 20950195 TI - The 'difficult' nurse-patient relationship: development and evaluation of an e learning package. AB - Nurses in most clinical settings experience difficult 'nurse patient relationships' at various times. Attempts to describe and articulate how to manage such difficult relationships can be found, but often lay blame at the patient level and ultimately leave the nurse less confident to improve patient care. This study uses an action research approach in working with nurses in a generalist setting in developing an educational strategy that helped to improve their knowledge, skills and confidence in working within the 'difficult nurse patient relationship' paradigm. Through the experiential style learning methodology of scenario based learning and applying this via e-learning, an effective educational approach has been developed. Using a quasi-experimental design to evaluate the e-learning package, significant increases in knowledge, skill, confidence and reduced nurse stress as measured on the 'difficult patient stress scale' were shown. This approach allows nurses to reflect on their own behaviour and improve their ability to enhance patient care in difficult to manage nursing care situations. PMID- 20950196 TI - Clinicians' experiences of participating in an action research study. AB - The objective of this paper is to share our experiences of participating in an action research project designed to improve the care of older people at risk of delirium. The setting for the study and the subject of this paper was a busy medical ward in a 550 bed regional tertiary referral hospital located in New South Wales, Australia. The participants for the project and the authors of this paper include clinical nursing and allied health staff based on the ward at the time of the study. In the discussion that follows we outline details of the study, participatory action research (PAR), what we were asked to do to participate, our reasons for agreeing to participate, our expectations of the project, the group process, the PAR cycles: look, think and act, and the benefits and challenges of participating in the project. In conclusion we highlight the gains of participating in PAR and we make recommendations for the future. PMID- 20950197 TI - Beyond 'doing': Supporting clinical leadership and nursing practice in aged care through innovative models of care. AB - Contemporary health care environments are increasingly challenged by issues associated with the recruitment and retention of qualified nursing staff. This challenge is particularly felt by residential aged care providers, with registered nurse (RN) numbers already limited and resident acuity rapidly rising. As a result, aged care service providers are increasingly exploring creative and alternative models of care. This article details exploratory research into a pre existing, alternative model of care in a medium sized, regional residential aged care facility. Research findings suggest that the model of care is complex and multi-faceted and is an example of an integrated model of care. As a result of the implementation of this model of care a number of shifts have occurred in the practice experiences and clinical culture within this facility. Results suggest that the main benefits of this model are: (1) increased opportunities for RNs to engage in clinical leadership and proactive care management; (2) improved management and communication in relation to work processes and practices; and (3) enhanced recruitment and retention of both RNs and care workers. PMID- 20950198 TI - Doing clinical research: the challenges and benefits. AB - The need for research in practice is well documented within nursing and other health care disciplines. This acceptance is predicated on the belief that clinically applied research will inform and improve practice and health service delivery resulting in better outcomes for consumers and their families. Nurses, however, find doing clinical research challenging. This paper describes nurses' experiences of doing clinical research. The main challenges of doing clinical research arise from a culture that prioritises practice where nursing work is core business and there is the need to address immediate and short term goals. There are also problems associated with the use of research language amongst clinical nurses and ambiguity in relation to research role expectations. Lack of support and resources for doing research along with keeping up the momentum for a research project also pose significant challenges. The benefits of doing clinical nursing research include experiential learning that has the potential to lead to practice change and improved patient outcomes that are evidence based. PMID- 20950199 TI - EXEMPLAR: our shared experience of implementing action learning sets in an acute clinical nursing setting: approach taken and lessons learned. AB - Abstract This paper outlines the process employed by a Nurse Unit Manager and her senior nursing team to introduce action learning sets (ALSs) to the nursing staff of an inpatient medical unit. During the process, a workplace culture creative visioning exercise was also facilitated. A key finding of the exercise was that the process enabled others to act while challenging the process and encouraging the heart. Effective leadership enabled staff involved to foster growth. PMID- 20950200 TI - Plotting care: a modelling technique for visioning nursing practice in current and future contexts. AB - Health professionals in health-care organisations are frequently challenged to strategise their services, reshape patterns of care delivery and to adapt to changing environments. Relocation of services into new hospital buildings is one example of a situation that generates these challenges. In this paper the authors discuss an innovative modelling strategy that was employed to assist nurses to explore their current daily care practices, to visualise them in the context of proposed new buildings, and to work towards planning care in readiness for the new context. The modelling technique of 'plotting' is presented as a way of capturing the natural spatial-service wisdom that exists within teams, and assisting them to translate their knowledge of this to each other and to co operatively work towards a new clinical future. Plotting will be of use to health professionals, clinical leaders and educators who are interested in spatial analysis of care and other health service practices. PMID- 20950201 TI - Changing model of nursing care from individual patient allocation to team nursing in the acute inpatient environment. AB - Agreement was reached with 12 acute medical and surgical wards/units at Sydney's Prince of Wales Hospital to participate in a trial of team nursing (TN). Six units employed action research principles to undertake a change to a team nursing model and six remained with the pre-existing individual patient allocation (IPA) model. Task-based teaming was widely discarded by the team nursing units in favour of allocating patients within the team and introducing more supportive and communicative processes aimed at fostering responsibility sharing. Localised team based models of care arose in the change wards and were outlined, implemented and refined using social action research principles. A 12-month prospective experimental comparison of job satisfaction and staff retention between the TN and IPA groups indicated statistically significant job satisfaction benefits and practically important staff retention benefits associated with moving away from an IPA model of nursing care delivery towards a team-based model of care delivery. Perhaps not surprisingly, job satisfaction gains were most marked among new graduate nurses, who reported real benefits from a teaming inspired shift in model of care in the acute inpatient environment. PMID- 20950202 TI - An innovative approach to targeting pain in older people in the acute care setting. AB - This paper reports the findings of an exploratory pilot study which used mixed methods to determine (a) the feasibility of the study design for a larger multi site project and (b) whether a pain education promotion approach, termed 'Targeting Pain', using a multidisciplinary educational campaign and promotional media such as staff badges and ward signage, improves the detection and management of pain in older people in an acute care setting. Pre and post evaluation surveys and interviews were used to evaluate the approach. Findings showed an increase in pain assessment and documentation of pain by nursing staff, as well as an increase in the prescription of oral analgesics. However, the study indicated that the uptake regarding pain management from the education campaign was different between professional groups. Although there was a positive response by patients and staff to the use of staff badges, the ward signage failed to attract attention. The mixed methods approach used highlighted several areas that need to be improved for the next phase of the study. PMID- 20950203 TI - Improving the safety and efficacy of warfarin therapy in a metropolitan private hospital: a multidisciplinary practice improvement project. AB - BACKGROUND: Warfarin is a very complex, high risk therapy and one that carries the potential for severe adverse events. The aim of this project was to improve warfarin management through the application of the best available evidence. The project was undertaken in a 250 bed acute care metropolitan private hospital. INTERVENTIONS: A suite of evidence-based interventions were used including audit and feedback, patient and provider education, and decision support aides. MEASURES: This project used the ongoing collection of warfarin process and outcome clinical indicator data to measure improvement. RESULTS: Compliance with loading protocol increased by 12% (42-54%); patient education prior to discharge increased by 54% (31-85%); INRs > 5 decreased by 2.6% (3.7-1.1%); and abnormal bleeds fell by 1.2% (1.2-0%). CONCLUSION: This multifaceted suite of interventions was successful in influencing clinician behaviour and improving compliance with evidence-based warfarin guidelines. PMID- 20950204 TI - Clinical supervision of general nurses in a busy medical ward of a teaching hospital. AB - AIM: To implement and evaluate group clinical supervision (CS) for Associate Nurse Unit Managers (ANUMs) in a busy medical ward of a tertiary teaching hospital. Back-ground: Nursing work at managerial level is characterised by high stress, depersonalisation and burnout often leading to job dissatisfaction. CS was introduced as a strategy to reduce such issues, through reflection and sharing experiences. METHOD: Six ANUMs from an acute medical ward participated in weekly CS. The program was evaluated by a focus group conducted after six months to gather feedback about the ANUMs' experience of participating in CS. RESULTS: CS was viewed positively and five main themes emerged including Dedicated Time, I'm Not The Only One experiencing problems, Getting With The Program and having consistent approaches, Positive And Constructive Feedback, and That Word 'supervision'. CONCLUSIONS: CS provides senior nurses an opportunity to debrief, reflect and share common experiences and develop alternate approaches to problems. CS may offer managers a useful tool for retaining experienced senior nurses. PMID- 20950206 TI - Psychometric evaluation of an assessment of awareness using two different Rasch models. AB - OBJECTIVE: The aim of this study was to evaluate the psychometric properties of the Assessment of Awareness of Disability (AAD), applied to a sample of clients with a variety of diagnoses, using two different Rasch models. METHODS: The sample consisted of 245 clients admitted to occupational therapy services in Sweden. The psychometric properties of the AAD measures were analysed and compared using both Rasch partial credit (PCM) and rating scale (RSM) models. RESULTS: In relation to rating scale properties and person response validity, the RSM yielded better results. However, the PCM demonstrated better item goodness-of fit statistics than the RSM, supporting the internal scale validity of the AAD. Some systematic indications of sample-dependent misfit were also found in the data. CONCLUSION: The results support the validity of the AAD in a sample of clients with various diagnoses, although some limitations of the tool are addressed. The outcomes also demonstrate the importance of making cautious choices when selecting a Rasch model for investigating psychometric properties, as the choice has a substantial impact on the interpretation of the findings. PMID- 20950205 TI - Engaging clinicians in evidence based policy development: the case of nursing documentation. AB - A lack of consistent policy direction, revealed by a review of nursing and midwifery documentation, presented researchers with an opportunity to engage clinicians in the process of evidence based policy development. By utilising the framework informed by both practice development and the principles of evidence based practice, clinicians were taken through an education program and a series of activities to develop their skills in discerning how research evidence and other literature can inform policy development. The clinicians' involvement maximised their investment in the final policy. Clinicians synthesised all the evidence associated with nursing and midwifery documentation and produced a set of seven guiding principles that formed the basis of an area wide policy for nursing and midwifery documentation. The strength of this approach to policy development was that the clinician's experience ensured that the concerns of the clinicians were included in the policy. Difficulties in completing tasks outside meeting times were highlighted. PMID- 20950207 TI - Expression of Na-H exchanger-8 isoform is suppressed in experimental colitis in adult rat: lack of reversibility by dexamethasone. AB - OBJECTIVES: Mechanism of the apical transporter Na-H exchanger-8 (NHE-8) regulation was investigated by examining the effects of anti-inflammatory dexamethasone in experimental colitis. In addition, its localization was investigated in the lipid rich membrane domain called membrane rafts. MATERIAL AND METHODS: Colitis was induced by trinitrobenzene sulfonic acid (TNBS) and colon segments were removed from 5 day post-TNBS and used to estimate the levels of NHE-8 protein and mRNA using ECL western blot analysis and a competitive RT PCR method. Myeloperoxidase activity, malondialdehyde levels and histologic changes were evaluated. RESULTS: NHE-8 protein level was decreased in inflamed colon and was not reversed by dexamethasone. However, mRNA levels remained unchanged in inflamed colon. The levels of NHE-8 protein and mRNA were not significantly different in non-colitic control as compared to dexamethasone treated non-colitis. Elevation of myeloperoxidase activity, malondialdehyde and infiltration of inflammatory cells in inflamed colon were suppressed by dexamethasone treatment of colitis significantly. Furthermore, NHE-8 protein was not detected in the detergent resistant membrane (DRM) or lipid rafts, but was present in the detergent sensitive membrane (DRS) fractions. Actin showed its partition similar to NHE-8. On the contrary, NHE-3 was present in both DRM and DRS fractions. Flotillin-1 and caveolin were enriched in the fractions designated as lipid rafts. CONCLUSIONS: These findings demonstrate the suppression of NHE-8 protein in inflamed adult rat colon, which seems to be regulated post transcriptionally. Furthermore, the absence of NHE-8 in lipid rafts suggests its regulation independent of cAMP or recycling through endocytosis unlike NHE-3 isoform. PMID- 20950208 TI - Signet ring cell carcinoma of the ampulla of vater: a rare cause of acute pancreatitis. PMID- 20950209 TI - Endosonographic features of esophageal granular cell tumors using a high frequency catheter probe. AB - OBJECTIVE: Submucosal tumors (SMTs) are occasionally found in the esophagus during upper endoscopy. Granular cell tumors (GCTs) are reported to be the second most common esophageal mesenchymal tumors, after leiomyomas. Endoscopic ultrasonography (EUS) is an effective tool for predicting the histologic characteristics of SMTs by providing an accurate image of the layering structure of the esophagus, but it is hard to differentiate GCTs from submucosal leiomyomas accurately with conventional EUS. The aim of the present study was to characterize the EUS features of GCTs compared with those of submucosal leiomyomas using a high-frequency catheter probe EUS. MATERIAL AND METHODS: A total of 41 patients with GCTs or submucosal leiomyomas were included. All of the patients underwent EUS before histologic confirmation by endoscopic resection or biopsy. RESULTS: There were 14 GCTs in 12 patients and 30 leiomyomas in 29 patients. GCTs had a white-to-yellow surface color more frequently than leiomyomas. In comparison with the surrounding normal proper muscle layer, the echogenicity of the leiomyomas was similar to that of the surrounding muscle layer, but more than half of the GCTs were hyperechoic compared to the surrounding muscle layer. Unclear borders were observed more frequently in GCTs than in leiomyomas. The presence of at least two of these three features in a given tumor had a sensitivity of 85.7%, a specificity of 96.7%, and an accuracy of 93.2% for predicting GCTs. CONCLUSIONS: High-frequency probe EUS is helpful for differentiating esophageal GCTs from submucosal leiomyomas. PMID- 20950210 TI - Low prevalence of hereditary hemochromatosis in multiethnic populations in Northern Norway. AB - OBJECTIVE: Hereditary hemochromatosis has an autosomal recessive inheritance. The C282Y homozygosity is the most common genetic mutation in persons of Northern European descent. A screen of two multiethnic populations in Northern Norway was performed to investigate whether the prevalence of hereditary hemochromatosis was consistent with previous results in Northern Europe. MATERIAL AND METHODS: Participants in two population-based studies in Northern Norway were analyzed for serum ferritin (s-ferritin) and transferrin saturation. Participants with s ferritin or transferrin saturation above the reference limits in two separate blood samples were tested for three different HFE mutations, namely C282Y, H63D and S65. RESULTS: The estimated prevalence of the C282Y/C282Y mutation in the two municipalities studied was lower than in comparable studies in Norway. The prevalence was the lowest in the Sor-Varanger population (men 0.19% and women 0.22%), which also had the highest proportion of individuals with Sami and Kven affiliation. In Tromso, the prevalence was consistent with previous results in Norway. CONCLUSIONS: The prevalence of hereditary hemochromatosis is lower in multiethnic populations in Northern Norway than in previous studies from other parts of Norway. PMID- 20950211 TI - The protective effects of Lipoxin A4 during the early phase of severe acute pancreatitis in rats. AB - OBJECTIVE: Our aim was to investigate the protective effects of a Lipoxin A(4) analogue (LXA4) in the early phase of acute pancreatitis in rats. MATERIALS AND METHODS: Severe acute pancreatitis (SAP) was induced by injection of 5% sodium taurocholate into the pancreatic duct. Rats with SAP were treated with LXA4 (0.1 mg/kg), 10 min after the 5% sodium taurocholate injection, after which LXA4 was administrated every 8 hours, three times (LXA4 group). The sham group was only given the vehicle after operation. Plasma amylase activity, serum levels of interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-alpha) were measured at 4, 12, and 24 h after induction of SAP. The pancreatic index and histopathologic observations were evaluated and the expression of intercellular adhesion molecule-1 (ICAM-1) and NF-kappaB p65 in the pancreas, and the expression of ICAM-1 in the lungs were detected by immunohistochemistry. RESULTS: LXA4 treated rats had lower serum levels of TNF-alpha, IL-1, and IL-6 at all time points measured (p < 0.05), but significantly differed in plasma amylase activity only at 24 h as compared with the SAP group. The pancreatic index and the scores of pancreatitic histopathologic evaluations were lower in the LXA4 group as compared to the SAP group. Immunohistochemistry showed that LXA4 attenuated the expression of ICAM-1 and NF-kappaB p65 in the pancreas, as well as the expression of ICAM-1 in the lungs in animals with pancreatitis (p < 0.05). CONCLUSIONS: We demonstrate that LXA4 has protective effects in experimental SAP, which may be achieved by inhibiting the NF-kappaB signalling pathway, thereby reducing the production of proinflammatory cytokines. PMID- 20950212 TI - Weak association of the platelet-derived growth factor beta (PDGFB) and PDGF receptor beta (PDGFRB) genes with schizophrenia and schizoaffective disorder. AB - Schizophrenia is a severe neuropsychiatric disorder with diverse characterization of symptoms. Extensive research has been performed to elucidate the etiology of schizophrenia. One of the most convincing hypotheses comes from the dopaminergic system although none of the core genes has been consistently positive in association studies. OBJECTIVE: In this investigation, we explored the possibility that the genes for platelet-derived growth factor beta (PDGFB) and its receptor (PDGFRB) might play an important role in the development of schizophrenia based on previous reports pointing to their ability to interact with the dopamine D(2)/D(4) and NMDA receptors as well as their role in neurite outgrowth. METHODS: We investigated the association of variants around these genes with schizophrenia and schizoaffective disorder in 104 small nuclear families using the Sib-Transmission Disequilibrium Test (TDT-STDT). Furthermore, quantitative trait analysis using family-based association test was applied to determine possible association of age at onset (AAO). RESULTS: Allele G in PDGFRB(rs758588) was associated with AAO (P=0.019). An over-transmission of allele T in PDGFB(rs130650) polymorphism (P=0.043) and an over-transmission of allele A in PDGFRB(rs6865659) polymorphism (P=0.046) were observed. Furthermore, the combined TDT-STDT yielded consistent results. CONCLUSION: Overall, PDGFB and PDGFRB genes might play a role in the etiology of schizophrenia. PMID- 20950213 TI - Postmenopausal hormone therapy and lung cancer. AB - The latest recommendations on postmenopausal hormone therapy (HT) stress the need first to evaluate the individual benefits and risks and to prescribe the well informed patient only when the balance is most favorable. As a result of recent studies on the association of lung cancer with HT, this common malignancy was added to the list of potential serious adverse effects of HT. However, data show that estrogen alone does not carry a risk, whereas a combined estrogen + progestin (E + P) regimen may be associated with higher mortality in lung cancer patients. Women usually take HT in the early postmenopausal period and for several years only. No increase in risk was found in E + P users aged 50-59 years, nor for those who used HT for less than 5 years. The absolute numbers involved are in the order of less than one additional case of lung cancer in 1000 woman/years of hormone use. PMID- 20950214 TI - Unrestricted somatic stem cells: interaction with CD34+ cells in vitro and in vivo, expression of homing genes and exclusion of tumorigenic potential. AB - BACKGROUND AIMS: Transplantation of allogeneic hematopoietic stem cells (HSC) within the framework of hematologic oncology or inherited diseases may be associated with complications such as engraftment failure and long-term pancytopenia. HSC engraftment can be improved, for example by co-transplantation with mesenchymal stem cells (MSC). Recently, a new multipotent MSC line from umbilical cord blood, unrestricted somatic stem cells (USSC), has been described. It was demonstrated that USSC significantly support proliferation of HSC in an in vitro feeder layer assay. METHODS: A NOD/SCID mouse model was used to assess the effect of USSC on co-transplanted CD34(+) cells and look for the fate of transplanted USSC. The migration potential of USSC was studied in a Boyden chamber migration assay and in vivo. Quantitative real-time polymerase chain reaction (qRT-PCR) for CXCR4, CD44, LFA1, CD62L, VLA4, RAC2, VLA5A and RAC1 were performed. NMR1 nu/nu mice were used for a tumorigenicity test. RESULTS: After 4 weeks, homing of human cells (CD45(+)) to the bone marrow of NOD/SCID mice was significantly increased in mice co-transplanted with CD34(+) cells and USSC (median 30.9%, range 7-50%) compared with the CD34(+) cell-only control group (median 5.9%, range 3-10%; P = 0.004). Homing of USSC could not be shown in the bone marrow. A cell-cell contact was not required for the graft enhancing effect of USSC. An in vivo tumorigenicity assay showed no tumorigenic potential of USSC. CONCLUSIONS: This pre-clinical study clearly shows that USSC have an enhancing effect on engraftment of human CD34(+) cells. USSC are a safe graft adjunct. PMID- 20950215 TI - Real-time polymerase chain reaction followed by fast sequencing allows rapid genotyping of microbial pathogens. AB - In this study we describe a novel protocol for rapid molecular analysis of patient samples using a combination of real-time polymerase chain reaction (PCR) and Sanger sequencing. This would normally take 2 working days in the diagnostic laboratory, but using this protocol the process can be completed within 3 h using equipment normally found in the laboratory. The innovative steps in this protocol are the sequencing of the product generated in the diagnostic real-time PCR, addition of a sequencing tail to the PCR primer, which increases the quality of the sequence without loss of sensitivity or specificity, and optimization of the hands-on and instrument steps using modern reagents. The read length of the sequencing step is routinely 250 nucleotides, which is substantially longer than existing rapid sequencing methods, increasing the chances of covering several genetic markers within 1 analysis. As proof of the concept, we used the detection and genotyping of the intestinal parasite Giardia lamblia, but the protocol can be applied to any PCR and sequence-based analysis. PMID- 20950216 TI - Leukocyte myeloperoxidase and pathogenesis of the post-polio syndrome. PMID- 20950217 TI - Significant elevation of B cells at the acute stage in enterovirus 71-infected children with central nervous system involvement. AB - A feature of the large outbreak of human enterovirus 71 (EV71)-associated hand foot-and-mouth (HFMD) disease in China in 2008 was that severe cases presented with encephalitis. This study was performed to evaluate the immunophenotypic characteristics of patients with neurological involvement. Twenty-one patients with encephalitis and 14 with uncomplicated HFMD were recruited. Age-matched healthy volunteers were enrolled as controls. Peripheral lymphocyte subsets were analyzed by use of 3-colour flow cytometry, and the quantitative determination of plasma immunoglobulin (Ig) levels was also monitored. Comparisons between severe and mild cases demonstrated significant elevations of B cells and IgG levels and corresponding general decreases in natural killer (NK) cells and T lymphocytes in severe cases at the acute stage of infection (p < 0.01 for all). During the convalescent phase, rapid recoveries of B cells and IgG to the normal levels were observed, which appeared to be accompanied by an increase in EV71-specific neutralizing antibody titres. In summary, our data demonstrate that elevated B cells and IgG might be associated with neurological manifestations in EV71 infection. PMID- 20950219 TI - Use of cytokeratin 8 immunohistochemistry for assessing cell death after radiofrequency ablation of breast cancers. AB - The effects of minimally invasive therapies such as radiofrequency ablation (RFA) and laser induced thermal therapy on breast carcinoma lesions usually is assessed by NADH diaphorase enzyme histochemistry for cell viability. NADH staining requires frozen material, however, with its associated poor morphology. We aimed to validate cytokeratin 8 (CK 8) immunohistochemistry as an alternative that works on paraffin sections. RFA was performed ex vivo on 20 breast resections after surgery and in vivo in eight patients who underwent general anesthesia followed by immediate resection. After treatment, specimens were lamellated and the tumors were divided into two equal parts. One part was fixed in neutral buffered formaldehyde for routine histopathological evaluation using hematoxylin and eosin (H & E) staining and CK 8 immunostaining. The other section was snap frozen and stored at -80 degrees C for staining with NADH diaphorase. Both NADH diaphorase and CK 8 immunostaining demonstrated a clear and comparable demarcation between viable and nonviable tissues. The morphology of the CK 8 immunostained slides was much better, and fatty tissues could be judged readily by contrast to the NADH stained frozen sections, which had poor morphology and whose fatty parts were difficult to interpret. CK 8 immunohistochemistry seems to be well suited for assessing cell viability in breast tissue and for assessing the effects of RFA for breast cancer treatment. Because it can be applied to paraffin fixed material, it provides much better morphology than NADH staining and also can be applied to fatty tissues that usually are difficult to work up for frozen sections. Therefore, CK 8 immunohistochemistry may be preferred over NADH diaphorase staining for daily pathology practice for assessing the viability of breast carcinoma cells after RFA treatment. PMID- 20950220 TI - Toenail infection by Cladophialophora boppii. AB - Cladophialophora boppii is a black yeast-like fungus that up to now has been only rarely described as a cause of human infection and whose role as a pathogen was not established despite its repeated isolation and genetic identification in these reports. Here we report the first case of a verified toenail infection caused by this fungus in a woman without any systemic disease or evidence of immunodeficiency. Identical dark molds were isolated from the same toenail at three points of time. Species identification was performed by scrutinizing the isolates morphologic, physiologic and genetic characteristics which resulted in their identification as Cladophialophora boppii. Oral treatment with terbinafin plus topical ciclopiroxolamine was effective. PMID- 20950221 TI - Pathogenicity of Aspergillus fumigatus mutants assessed in Galleria mellonella matches that in mice. AB - Aspergillus fumigatus is a clinically important fungus with the ability to cause invasive aspergillosis with high mortality rates in immunocompromised patients and chronic pulmonary aspergillosis in immunocompetent individuals. Virulence of mutants has traditionally been assessed using mammalian hosts such as mice and rats and more recently the fruit fly, Drosophila melanogaster, demonstrated the potential to act as an in vivo host suitable for screening Aspergillus mutants. In this study using a larger thermotolerant invertebrate, Galleria mellonella, the virulence of individual gene deletants of Aspergillus fumigatus (cpcA, sidA, sidC, sidD, sidF and paba,) were compared to the parental and gene-replacement strains, if available. A range of infectious challenges consisting of from 3 * 10(3)-3 * 10(6) spores/larva was followed by observation of larval survival with mean survival time used as a surrogate of microbial pathogenicity. Mutants cpcA, sidA, sidF and paba were avirulent and sidC and sidD showed attenuated virulence. Virulence assessment in G. mellonella correlated closely with the historic data generated using mice and Drosophila. Pre-screening Aspergillus mutants using G. mellonella could significantly reduce the number of mammals required to assess changes in virulence. PMID- 20950222 TI - Degradation of fungal DNA in formalin-fixed paraffin-embedded sinus fungal balls hampers reliable sequence-based identification of fungi. AB - Identification of the etiologic agent responsible for sinus fungal ball (SFB) is rarely obtained due to either the culture of patient specimens not being ordered or if cultures were inoculated they proved to be negative. Obviously, this has a significant impact on the design of appropriate therapeutic strategies. We investigated whether paraffin-embedded (PE) tissues, the only materials often available, were suitable for the correct identification of the responsible fungi. We obtained PE tissues of SFB from 16 different patients who had risk factors for invasive fungal infections. DNA was extracted using an automated extractor and the internal transcribed spacer (ITS) sequenced following amplification with two sets of primers designed to amplify >300 bp fragments. This was attempted in parallel with a real-time quantitative PCR assay targeting Aspergillus spp. mitochondrial DNA designed to amplify <150 bp fragments. ITS sequencing succeeded in appropriately identifying the etiologic agents in 10 of the 16 samples (nine Aspergillus fumigatus, one Lewia spp.). In contrast, the <150 bp PCR assay amplified all specimens correctly except the one involving Lewia spp. If fungal identification is warranted to understand the pathophysiology of SFB and guide clinicians, we cannot rely only on ITS sequencing of the DNA obtained from PE tissues. The main reason is probably due to the fact that formalin prevents amplification of long DNA fragments and consequently, frozen or fresh tissues should be employed. PMID- 20950223 TI - Fatal invasive trichosporonosis due to Trichosporon loubieri in a patient with T lymphoblastic lymphoma. AB - This study describes the third known human case of an invasive infection caused by Trichosporon loubieri. The 21-year-old patient was suffering from a third relapse of T-lymphoblastic lymphoma and had been in pancytopenia for three months when she developed a blood trichosporonosis. The patient died 10 days later, despite intravenous voriconazole therapy. Final unequivocal identification of the strain was done using molecular biology tools. PMID- 20950224 TI - An open-label comparison of the efficacy and safety of certoparin versus unfractionated heparin for the prevention of thromboembolic complications in acutely ill medical patients: CERTAIN. AB - OBJECTIVE: Guidelines recommend low-dose unfractionated heparin (UFH) and low molecular-weight heparin for the prophylaxis of venous thromboembolism (VTE) in acutely ill medical patients. We report the findings of an open-label, active controlled, multicenter study in acutely ill medical patients comparing certoparin and UFH. RESEARCH DESIGN AND METHODS: Open-label, active-controlled, multicenter study. Patients received certoparin 3000 IU daily or UFH 7500 IU twice daily. MAIN OUTCOME MEASURES: The primary endpoint was a composite of symptomatic or asymptomatic proximal or distal deep vein thrombosis, symptomatic pulmonary embolism, or VTE-related death. RESULTS: 172 patients were randomized to UFH and 163 to certoparin for 8.5 +/- 2.1 days. The incidence of the primary endpoint was 18.0% in patients receiving UFH and 10.7% with certoparin [absolute difference -7.3; 95% confidence interval (CI) -16.9 to 2.3; p = 0.1353]. The incidence during follow-up was 2.6% in the UFH and 2.0% in the certoparin group (absolute difference -0.6; 95%CI -4.0 to 2.8; p = 0.7150). Major bleeding events occurred in three patients with UFH and one patient with certoparin. CONCLUSIONS: In acutely ill medical patients of at least 40 years of age, thromboprophylaxis with certoparin 3000 IU daily is effective and safe in comparison with 7500 IU twice daily UFH. PMID- 20950225 TI - TCP modelling - why is it important? PMID- 20950226 TI - Hypofractionated adjuvant whole breast radiotherapy: progress and prospects. AB - Published results of randomised trials involving >7000 women confirm the safety and efficacy of hypofractionated schedules of adjuvant radiotherapy for women with early breast cancer using fraction sizes between 2 and 3 Gy assuming appropriate downward adjustments to total dose. Unnecessary concerns relating to heart tolerance, suboptimal dose distribution and duration of follow up need not discourage the routine adoption of 15- or 16-fraction schedules in women treated by breast conservation surgery for early breast cancer. Regardless of fractionation regimen, dose escalation to the index quadrant in high risk subgroups will result in a greater relative increase in late adverse effects than tumour control, a therapeutic disadvantage that can only be overcome by exploiting a marked dose-volume effect. A 15-fraction schedule of whole breast radiotherapy is unlikely to represent the lower limits of hypofractionation, and the preliminary results of a 5-fraction regimen are encouraging. PMID- 20950227 TI - Analytical investigation of the possibility of parameter invariant TCP-based radiation therapy plan ranking. AB - PURPOSE: To analytically investigate the possibility of a parameter invariant ranking of radiotherapy (RT) plans based on comparing the tumor control probabilities (TCPs) produced by the competing plans for different values of the radiobiological model parameters determining the radiation response. METHOD: Individual TCP models based on the Single hit model of cell kill and on the linear-quadratic (LQ) model of cell damage, with and without repopulation, are considered. The tumor dose distributions in case of heterogeneous dose irradiation are described by a Gaussian distribution function on the basis of which a TCP expression is derived depending only on the mean dose to the tumor and its standard deviation and the TCP model parameters. RESULTS: It is shown that in case of homogeneous dose to the tumor the plan ranking in terms of TCP is parameter invariant. In case of heterogeneous dose to the tumor there are cases when the plan ranking is parameter invariant and cases when the parameter invariance is violated. An interesting dependence of the extent of the parameter invariance violation on the model of cell kill as well as on the size and repopulation rate of the tumor is noted. CONCLUSION: We conclude that in many cases RT plan ranking in terms of TCP is parameter invariant. However, since there exist cases where the parameter invariance is lost an investigation of the specific plans to be ranked should be performed applying the proposed approach. PMID- 20950228 TI - Bevacizumab for recurrent hemangioendothelioma. PMID- 20950229 TI - Magnetic resonance imaging of tumor necrosis. AB - BACKGROUND: The prognostic and predictive value of magnetic resonance (MR) investigations in clinical oncology may be improved by implementing strategies for discriminating between viable and necrotic tissue in tumors. The purpose of this preclinical study was to investigate whether the extent of necrosis in tumors can be assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and/or T(2)-weighted MR imaging. MATERIAL AND METHODS: Three amelanotic human melanoma xenograft lines differing substantially in tumor necrotic fraction, necrotic pattern, extracellular volume fraction, and blood perfusion were used as experimental models of human cancer. MRI was performed at 1.5 T and a spatial resolution of 0.23 * 0.47 * 2.0 mm(3). Gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA) was used as contrast agent. Plots of Gd-DTPA concentration versus time were generated for each voxel, and three parameters were calculated for each curve: the extracellular volume fraction (nu(e)), the final slope (a), and the Gd-DTPA concentration at one minute after the contrast administration (C(1min)). Parametric images of nu(e), a, C(1min), and the signal intensity in T(2)-weighted images (SI(T2W)) were compared with the histology of the imaged tissue. RESULTS: The nu(e), a, and C(1min) frequency distributions were significantly different for necrotic and viable tissue in all three tumor lines. By using adequate values of nu(e), a, and C(1min) to discriminate between necrotic and viable tissue, significant correlations were found between the fraction of necrotic tissue assessed by MRI and the fraction of necrotic tissue assessed by image analysis of histological preparations. On the other hand, the SI(T2W) frequency distributions did not differ significantly between necrotic and viable tissue in two of the three tumor lines. CONCLUSION: Necrotic regions in tumor tissue can be identified in parametric images derived from DCE-MRI series, whereas T(2)-weighted images are unsuitable for detection of tumor necrosis. PMID- 20950246 TI - Bilateral punctal-canalicular stenosis following photodynamic therapy for choroidal neovascularization. AB - Several medications have been reported to cause punctal-canalicular stenosis, such as mitomycin C, docetaxel, 5-fluorouracil, and isotretinoin. To our knowledge, there have been no cases of verteporfin-associated punctal-canalicular stenosis described in the literature. We hereby present such a case. PMID- 20950247 TI - Antimalarial cutaneous side effects: a study in 209 users. AB - BACKGROUND: Antimalarial agents are commonly used drugs that may have skin side effects. OBJECTIVE: To study the prevalence of cutaneous side effects in antimalarial users. METHODS: We studied the prevalence of cutaneous manifestations in 209 antimalarial users, 127 with systemic lupus erythematosus (SLE) and 82 with rheumatoid arthritis (RA). As control we included 200 patients from the gynecologic and ophthalmologic departments who did not have antimalarial use. Patients were submitted to a structured questionnaire for demographic data, type of antimalarial drug used, and treatment time as well as skin complaints. Physical examination was performed by a dermatologist. RESULTS: In 159 of 209 (76%) of the antimalarial users, there were cutaneous findings. The most frequent was xerosis, followed by skin hyperpigmentation and pruritus. In 4.8% of the antimalarial users, allergic reactions led to drug withdrawal. When comparing them with the control group, skin hyperpigmentation and xerosis were more prevalent (p < .0001 for both), but pruritus was not (p = .39). No relationship could be found between the skin side effects and ethnic background, gender, antimalarial type, or treatment duration. Hair depigmentation was more common in SLE patients than in RA patients. CONCLUSION: Cutaneous side effects in antimalarial users are frequent. Xerosis and hyperpigmentation are the most common findings. PMID- 20950248 TI - Sensitivity, predictive values, pretest-posttest probabilities, and likelihood ratios of presurgery clinical diagnosis of nonmelanoma skin cancers. AB - BACKGROUND: The precision of clinical diagnosis of skin tumors is not commonly measured and, therefore, very little is known about the diagnostic ability of clinicians. OBJECTIVE: This study aimed to compare clinical and histopathologic diagnoses of nonmelanoma skin cancers with regard to sensitivity, predictive values, pretest-posttest probabilities, and likelihood ratios. METHODS: Two hundred nineteen patients with 241 nonmelanoma skin cancers were enrolled in this study. Of these patients, 49.4% were female and 50.6% were male. The mean age +/- standard deviation (SD) was 63.66 +/- 16.44 years for the female patients and 64.77 +/- 14.88 years for the male patients. The mean duration of the lesions was 20.90 +/- 32.95 months. One hundred forty-eight (61.5%) of the lesions were diagnosed as basal cell carcinoma (BCC) and 93 (38.5%) were diagnosed as squamous cell carcinoma (SCC) histopathologically. RESULTS: Sensitivity, positive predictive value, and posttest probability were calculated as 75.96%, 87.77%, and 87.78% for BCC and 70.37%, 37.25%, and 37.20% for SCC, respectively. The correlation between clinical and histopathologic diagnoses was found to be higher in BCC. CONCLUSION: Knowledge of sensitivity, predictive values, likelihood ratios, and posttest probabilities may have implications for the management of skin cancers. To prevent unnecessary surgeries and achieve high diagnostic accuracies, multidisciplinary approaches are recommended. PMID- 20950249 TI - Contribution of intangible costs to the economic burden of multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is associated with a substantial economic burden resulting from direct medical costs associated with health and disability related resource utilization and indirect costs relating to reduced productivity. However, reduced health-related quality of life (HR-QOL) may be associated with additional costs, often termed 'intangible costs,' that should be considered as part of the economic burden from the societal or patient perspectives. OBJECTIVES: To review the contribution of intangible costs to the overall economic burden of MS. METHODS: Medline was searched through March 2010 for relevant articles that included the terms 'multiple sclerosis' in combination with 'intangible costs,' 'QALY,' 'quality-adjusted life year,' 'willingness-to pay,' and 'WTP.' Other than the restriction that the articles were published in English, there were no other exclusionary criteria for the search. Identified references were hand-searched to determine if intangible costs were estimated. RESULTS: Thirteen studies across ten countries were identified that estimated intangible costs based on the number of quality-adjusted life-years (QALYs) lost due to a reduction in HR-QOL multiplied by accepted willingness-to-pay (WTP) thresholds. Although absolute costs varied depending on thresholds used and year of evaluation, the intangible costs accounted for 17.5-47.8% of total costs of MS. Furthermore, evidence suggested intangible costs are positively correlated with worsening disability. The largest increase in intangible costs occurred at the transition between mild and moderate disability. However, since no value has been established as being acceptable to pay for a QALY, a limitation of these studies was their dependence on the definition of the WTP threshold. CONCLUSIONS: Intangible costs substantially add to the economic burden of MS. There is not only a need to further characterize these costs and incorporate them into economic studies, but also to determine how these costs can be reduced through appropriate management strategies. PMID- 20950250 TI - Feeding interventions for children with cerebral palsy: a review of the evidence. AB - AIM: To examine the evidence of the effectiveness of different feeding interventions for children with cerebral palsy. METHODS: A search of 12 electronic databases identified all relevant studies. For each study, the quality of the methods was assessed according to the study design. A total of 33 articles were retrieved, and 21 studies were included in the final analysis. RESULTS: Feeding interventions were separated into five main categories: oral sensorimotor facilitation, food consistency, positioning, oral appliances, and adaptive equipment. Five studies were randomized controlled trials. Outcomes were mainly reported on feeding safety and efficiency. One study documented positive results in height and weight change. Nineteen of the 21 studies presented positive outcomes in eating efficiency and/or safety. INTERPRETATION: Feeding interventions demonstrate potential benefits for children with cerebral palsy. However, the current level of evidence is poor, and empirical data are lacking. Methodologically, rigorous studies are required particularly investigating multimodal approaches. PMID- 20950251 TI - Expansion and hepatocytic differentiation of liver progenitor cells in vivo using a vascularized tissue engineering chamber in mice. AB - Current cell-based treatment alternatives to organ transplantation for liver failure remain unsatisfactory. Hepatocytes have a strong tendency to dedifferentiate and apoptose when isolated and maintained in culture. In contrast, liver progenitor cells (LPCs) are robust, easy to culture and have been shown to replace damaged hepatocytes in liver disease. In this study we investigate whether isolated LPCs can survive and differentiate toward mature hepatocytes in vivo when implanted into a heterotopic mouse tissue engineering chamber model. Healthy Balb/c mice and those put on a choline-deficient ethionin supplemented diet to induce chronic liver disease were implanted with a tissue engineering chamber based on the epigastric flow through pedicle model, containing either 1 * 10(6) LPCs suspended in Matrigel, or LPC-spheroids produced by preculture for 1 week in Matrigel. Four weeks after implantation the chamber contents were harvested. In all four groups, progenitor cells persisted in large numbers to 4 weeks and demonstrated evidence of considerable proliferation judged by Ki67-positive cells. Periodic acid Schiff staining demonstrated differentiation of some cells into mature hepatocytes. Constructs grown from LPC spheroids demonstrated considerably greater LPC survival than those from LPCs that were grown as monolayers and implanted as dissociated cells. The combined use of LPC spheroids and the vascularized chamber model could be the basis for a viable alternative to current treatments for chronic liver failure. PMID- 20950252 TI - A novel bioreactor for the dynamic stimulation and mechanical evaluation of multiple tissue-engineered constructs. AB - Systematic advancements in the field of musculoskeletal tissue engineering require clear communication about the mechanical environments that promote functional tissue growth. To support the rapid discovery of effective mechanostimulation protocols, this study developed and validated a mechanoactive transduction and evaluation bioreactor (MATE). The MATE provides independent and consistent mechanical loading of six specimens with minimal hardware. The six individual chambers accurately applied static and dynamic loads (1 and 10 Hz) in unconfined compression from 0.1 to 10 N. The material properties of poly(ethylene glycol) diacrylate hydrogels and bovine cartilage were measured by the bioreactor, and these values were within 10% of the values obtained from a standard single-chamber material testing system. The bioreactor was able to detect a 1-day 12% reduction (2 kPa) in equilibrium modulus after collagenase was added to six collagenase sensitive poly(ethylene glycol) diacrylate hydrogels (p = 0.03). By integrating dynamic stimulation and mechanical evaluation into a single batch-testing research platform, the MATE can efficiently map the biomechanical development of tissue-engineered constructs during long-term culture. PMID- 20950253 TI - Excision efficiency of radioguided occult lesion localization in reoperative thyroid and parathyroid surgery. AB - BACKGROUND: The purpose of this study was to investigate the efficiency of a radioguided occult lesion localization technique in reoperative thyroid and parathyroid procedures in patients who had undergone previous neck exploration for thyroid or parathyroid disease. METHODS: Twenty-one consecutive patients who were scheduled for reoperative thyroid or parathyroid surgery were studied. The indication for reoperation was recurrent papillary thyroid cancer (PTC) in eight patients, completion thyroidectomy for PTC in eight patients who had previously undergone a bilateral subtotal thyroidectomy, recurrent goiter in two patients, primary hyperparathyroidism in two patients, and recurrent parathyroid cancer in one patient. Ninety minutes before surgery, 0.1 mL of Technetium-99m (0.2 mCi) labeled macroaggregated albumin was injected directly into the lesion under ultrasonographic guidance. During surgery, a handheld gamma probe was used to localize and excise the lesions. The background and postexcisional site radioactivities were compared to confirm the completeness of each procedure. The radiation dose in the operating room environment, duration of surgery, and postoperative complication rates were evaluated in all patients. In patients with PTC, the change in serum thyroglobulin (Tg) following surgery was noted. RESULTS: Thirty lesions were marked and excised. The postexcisional bed gamma counts (610 +/- 141) were markedly decreased compared with the pre-excisional site counts (21,415.8 +/- 4993.4; p = 0.0001). The ratio of the postexcisional and background counts (4.6 +/- 4.3) was significantly lower than the ratio of the pre-excisional and background counts (173.7 +/- 156.4; p = 0.0001). The mean operation duration was 53.3 +/- 7.5 minutes. The dose absorbed by the hands of the surgeon was estimated as 0.07 +/- 0.02 and 0.15 +/- 0.05 millisievert/h when one or three lesions were marked, respectively. One patient developed postoperative transient hypoparathyroidism. After surgery, serum Tg levels dropped to <2 ng/mL in 86% (6/7) of the patients with PTC whose preoperative serum Tg was elevated. CONCLUSIONS: The radioguided occult lesion localization technique was efficient in the perioperative identification of thyroid and parathyroid tumors in patients who were undergoing reoperation for PTC and hyperparathyroidism. PMID- 20950254 TI - Patterns of iodine intake and urinary iodine concentrations during pregnancy and blood thyroid-stimulating hormone concentrations in the newborn progeny. AB - BACKGROUND: Appropriate maternal intake of iodine during pregnancy is essential for maternal thyroxine production and thyroid status of the fetus. It should be possible to enhance iodine intake during pregnancy by using iodine fortified salt or taking iodine supplements. In the present report we determined the status of iodine nutrition in pregnant women who were stratified on the basis of their history of taking or not taking iodized salt or iodine supplements. The study was performed in Toledo (Spain), a region in which prior studies have noted borderline iodine sufficiency. Iodine nutrition was assessed by measuring urinary iodine concentration (UIC) and neonatal thyrotropin (TSH). METHODS: UIC was measured in 525 pregnant women. They were grouped according to their history of iodine intake. Diet Group 1 patients (n = 69) did not take iodized salt or iodine supplements during pregnancy. Diet Group 2 patients (n = 75) took iodized salt but not iodine supplements during pregnancy. Diet Group 3 patients (n = 381) took iodine supplements during pregnancy. Plasma determinations included TSH, free thyroxine, thyroid peroxidase antibody, and thyroglobulin antibody. UIC was measured in a single urine sample from all the pregnant women. Neonatal TSH was measured in capillary spot blood from all the neonates as part of a screening for congenital metabolic abnormalities. RESULTS: The median UIC in all subjects was 164 MUg/L (interquartile range [IR]: 116-245). The median UICs in Diet Groups 1, 2, and 3 were 134.5 (IR: 90-196), 146 (IR: 103-205), and 183 (IR: 124-261) MUg/L, respectively (p = not significant [NS] for Diet Group 1 vs. 2; p < 0.01 for Diet Group 2 vs. 3; all other comparisons NS). The median (IR) TSH of the neonates in all Diet Groups was 1.0 (IR: 0.7-1.6) MUU/mL. Only 2 neonates had blood TSH concentrations >5 mU/L. Neonatal blood TSH concentrations were similar in all Diet Groups. CONCLUSIONS: In a region with a history of borderline iodine deficiency the UICs were below 150 MUg/L in a substantial percentage of pregnant women who did not take iodine supplements, regardless of whether or not they took iodized salt. Our results support the use of iodine supplements from the start of the pregnancy, or even before pregnancy in women who live in regions with a history of even small degrees of iodine deficiency. In addition, neonate TSH screening is not the best tool to assess whether the iodine status in populations is ideal. PMID- 20950255 TI - Postoperative hypocalcemia after thyroidectomy for Graves' disease. AB - BACKGROUND: It is believed that patients who undergo thyroidectomy for Graves' disease are more likely to experience postoperative hypocalcemia than patients undergoing total thyroidectomy for other indications. However, no study has directly compared these two groups of patients. The aim of this study was to determine whether there was an increased incidence or severity of postoperative hypocalcemia in patients who underwent thyroidectomy for Graves' disease. METHODS: An institutional review board-approved database was created of all patients who underwent thyroidectomy from 1998 to 2009 at the Johns Hopkins Hospital. There were a total of 68 patients with Graves' disease who underwent surgery. Fifty-five patients who underwent total thyroidectomy were randomly selected and served as control subjects. An analysis was conducted that examined potential covariates for postoperative hypocalcemia, including age, gender, ethnicity, preoperative alkaline phosphatase level, size of goiter, whether parathyroid tissue or glands were present in the specimen, and the reason the patient underwent surgery. Specific outcomes examined were calcium levels on postoperative day 1, whether or not patients experienced symptoms of hypocalcemia, whether or not Rocaltrol was required, the number of calcium tablets prescribed upon discharge, whether or not postoperative tetany occurred, and calcium levels 1 month after discharge. RESULTS: Each outcome was analyzed using a logistic regression. Graves' disease patients had a significantly (p value < 0.001) higher odds of greater number of calcium tablets prescribed upon discharge. Further, 6 of 68 patients with Graves' disease and no patient in the control group were readmitted with tetany (p = 0.033). There was a trend, though not significant, toward patients with Graves' disease having a higher prevalence of hypocalcemia the day after thyroidectomy and 1 month later. CONCLUSIONS: Patients with Graves' disease are more likely to require increased dosages of calcium as well as experience tetany postoperatively than patients undergoing total thyroidectomy for other indications. This suggests that patients operated upon for Graves' disease warrant close followup as both inpatients and outpatients for signs and symptoms of hypocalcemia. PMID- 20950256 TI - Recombinant human thyrotropin in thyroid remnant ablation with 131-iodine in high risk patients. AB - BACKGROUND: Most patients with well-differentiated thyroid cancer (WDTC) are first treated by total thyroidectomy followed by remnant ablation (RA) with (131)I. There are less data regarding the efficacy of recombinant human thyrotropin (rhTSH) for patients with WDTC at high risk of relapse than for low risk patients. This study compared the efficacies of rhTSH and thyroid hormone withdrawal (THW) to prepare patients at high risk of relapse for RA. METHODS: Post-thyroidectomy patients with WDTC and complete tumor resection (n = 275) were studied. They were at high risk of recurrence (tumor size >4 cm and/or extrathyroidal extension [pT3] and/or lymph node metastases), and they did not have antithyroglobulin (Tg) antibodies. Group A (n = 77) received 0.9 mg rhTSH for 2 consecutive days followed by RA on day 3. The remaining 198 patients (group B) were prepared by THW for 4 weeks. Patients in groups A and B received 3.7 or 5.5 GBq (131)I. RESULTS: The groups were similar in terms of gender, age, histology, TNM (tumor-node-metastases) stage, (131)I activity, and frequency of metastases on post-therapy whole-body scanning (RxWBS). Among patients without metastases on RxWBS, RA was successful (stimulated Tg <1 ng/mL and negative diagnostic whole body scan and neck ultrasonography) in 56 of 70 patients in group A (80%) and in 135 of 169 patients in group B (79.9%). Among patients with Tg >1 ng/mL immediately before RA, the comparable success rates were 68.4% and 67.4%, respectively. Among patients with metastases on the first RxWBS, no uptake was observed on the RxWBS 1 year later in 5 of 7 patients in group A (71.4%) and in 17 of 29 patients in group B (58.6%). The rhTSH stimulated serum Tg was <1 ng/mL in 3 of 5 and in 12 of 17 patients with a second negative RxWBS in groups A and B, respectively. Persistent disease (stimulated Tg >1 ng/mL and RxWBS continuing to show ectopic uptake) occurred in 2 of 7 patients in group A (28.5%) and in 12 of 29 patients in group B (41.3%). CONCLUSIONS: rhTSH is as effective as THW for RA in patients with WDTC who are at a high risk of relapse. PMID- 20950257 TI - Molecular characterization of human T cell leukemia virus type 1 subtypes in a group of infected individuals diagnosed in Portugal and Spain. AB - Over the past decade, Portugal and Spain received large numbers of immigrants from HTLV-1 endemic areas. Our aim was to investigate the diversity of subtypes circulating in these two countries and the introduction of new variants. We performed a molecular analysis of HTLV-1 strains in patients diagnosed since 1998. LTR and env proviral sequences from 26 individuals were analyzed to generate phylogenetic trees along with reference HTLV-1 subtypes from several geographic origins. Epidemiological and clinical data were recorded. Most subjects were immigrants (57.7%) from South America and Africa. All isolates belonged to the cosmopolitan A subtype. Most carried the transcontinental subgroup A, but five subjects carried subgroup D and one carried subgroup C, previously unreported in Europe. HTLV strains showed separate clusters linked to the patients' geographic origin. Although subjects with HTLV-1 infection tend not to be engaged in high-risk practices, silent dissemination of a broad diversity of HTLV-1 viruses may still occur. PMID- 20950258 TI - Antimetastatic activities and mechanisms of bisdioxopiperazine compounds. AB - Bisdioxopiperazine (Biz) compounds, including ICRF-154 and razoxane (ICRF-159, Raz), are anticancer agents developed in the UK specifically targeting tumor metastases. Further three bisdioxopiperazine derivatives, bimolane (Bim), probimane (Pro) and MST-16, have been synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, PR China after 1980. Since metastases, the prevailing deadliest pathologic feature of cancer in clinics, have been the main obstacle in cancer therapy, antimetastatic effects and mechanisms of Biz compounds are interesting and significant topics of all time for researchers undergoing the investigations of metastases biology, treatments and patho-physiology. This review addresses and highlights the different inhibitions against metastases in vivo and molecular mechanisms in vitro of Biz compounds especially relating to the inhibitions of tumor metastasis including pathways of inhibitions against angiogenesis, topoisomerase II, calmodulin, sialic acid, fibrinogen, cell-movement and so on. We argue hererin that the systematic exploration of antimetastatic activity and mechanisms of Biz compounds seems to be a shortcut for a final solution of cancer therapy in the future. PMID- 20950259 TI - Emerging therapeutic targets and agents for glioblastoma migrating cells. AB - Glioblastoma multiforme (GBM) is one of the most common and most aggressive types of primary brain tumors in humans. Even with aggressive surgical resections using state of the art preoperative and intraoperative neuroim-aging, along with the most recent techniques in radiotherapy and chemotherapy, the prognosis for GBM patients remains dismal. Survival after diagnosis is about 12-14 months. The tumor cells which already have migrated into normal brain tissue beyond the surgical resection margin account for the inability to effectively treat this tumor. Understanding how to control the migration of GBM cells is paramount to future therapies. In this review, we will focus on the emerging targets and agents which are being exploited to inhibit the migration of glioma cells in GBM. PMID- 20950260 TI - Combined patch containing salicylic acid and nicotinamide: role of drug interaction. AB - The aim of the present study was to formulate a combined patch containing salicylic (SA) acid and nicotinamide (NA), useful for the treatment of mild acne, and to verify their mutual effect on drug permeation and skin retention. The performance of the patch was tested in vitro in permeation experiments using pig ear skin as barrier. To better understand the data obtained from the film, permeation from solutions and isopropyl myristate/water partition coefficient were also determined. The results obtained in the present work suggest a mutual influence of NA and SA on their permeation across the skin from an innovative transdermal film. The partition coefficient obtained when the two molecules were simultaneously present was typically lower than the respective value obtained with NA and SA alone. PMID- 20950261 TI - Evaluation of Assam Bora rice starch as plasma volume expander by polymer analysis. AB - Water soluble polysaccharides are currently finding increasing use as a basis material for plasma volume expander. In clinical setting it is desirable to have a precise knowledge of steric and chemical structure, since these affect the pharmacokinetics and pharmacology of plasma volume expander. Branch component of starch amylopectin is very similar in structure to glycogen, the reserve polysaccharide of animal and therefore is liable to be compatible with body tissue. The knowledge of weight average molecular mass, degree of branching, osmotic pressure and coil dimension are essential, since low molecular mass do not have desirable effect and large molar mass have undesirable effect. Assam Bora rice starch was characterized by polymer analysis for use as plasma volume expander. Characterization involves the determination of FTIR spectra, degree of branching by H1 NMR, osmotic pressure by internal measurement technique, establishment of Mark-Houwink relationship and determination of Molecular weight viscosity relationship. PMID- 20950262 TI - Botulinum A toxin intravesical injections for painful bladder syndrome: impact upon pain, psychological functioning and Quality of Life. AB - INTRODUCTION: To assess the impact of intravesically injected botulinum A toxin (BoNT/A) upon bladder pain, urological complaints, symptoms of anxiety and depression, and Quality of Life (QoL) in patients with painful bladder symptoms (PBS) refractory to conventional treatment. PATIENTS AND METHODS: In this prospective study 14 patients received one injection of BoNT/A (200 U diluted in 20 ml 0.9% NaCl), under cystoscopic guidance. At pre- and 3 months post- treatment all patients underwent an urological assessment (voiding diary, urodynamics), a pain quantification on a visual analog scale (VAS), an evaluation with the 14-item Hamilton Anxiety Rating Scale (HAM-A) to assess symptoms of psychic and somatic anxiety, an evaluation with the Hamilton Depression Rating Scale (HAM-D) to assess depression, and the 36-item Medical Outcomes Study Short Form (SF-36) to assess QoL. Results. At pre-treatment all 14 patients had increased daytime and nighttime urinary frequency and high VAS scores. Nine patients had pathological HAM-A scores and all had pathological HAM-D scores. At the 3-month follow-up 10/14 patients reported a subjective improvement in pain. Mean VAS score, mean daytime and nighttime urinary frequency decreased significantly (p <0.01, <0.01 and <0.01, respectively). All domains in SF-36 and HAM-A significantly improved (p<0.01). All domains, except weight and sleep disorders, significantly improved in HAM-D, particularly somatoform symptoms (p<0.01), cognitive performance (p<0.01), and circadian variations (p<0.01). CONCLUSION: In patients with refractory PBS with symptoms of anxiety, depression and poor QoL, BoNT/A intravesical treatment reduced bladder pain, improved psychological functioning, and well-being. PMID- 20950263 TI - Biodistribution study using Egg Protein ELISA kit after administration of FITC labeled ovalbumin solution and its double liposomes in the in situ loop method, and its implication in oral immunization. AB - Ovalbumin (OVA) is often used as a model antigen, and its biodistribution is important for the induction of immunization, especially oral immunization. In this study, an allergic substance-detecting kit, Egg Protein ELISA kit, was applied to the investigation of the biodistribution of fluorescein isothiocyanate labeled ovalbumin (FITC-OVA). After FITC-OVA solution and its double liposomes were administered into the intestinal loop with one Peyer's patch, the biodistribution of FITC-OVA was examined with the Egg Protein ELISA kit. Each calibration was performed by fitting a quadratic curve to the observed ELISA response points. The ELISA response was almost the same between OVA and FITC-OVA. Similar ELISA response curves were obtained in Peyer's patch (PP) homogenate, spleen (SP) homogenate and plasma (PL). The concentration of FITC-OVA could be determined at 4 - 64 ng/ml for aqueous solution and SP homogenate and at 1 - 64 ng/ml for PP homogenate and PL. Thus, it was suggested that the ELISA kit should be useful for measurement of OVA biodistribution in an oral immunization study. After the administration of FITC-OVA solution and its double liposomes into the intestinal loop, the biodistribution of OVA-FITC in PP, SP and PL was investigated. The distributed amount was the greatest in PP. At the early time, the distributed amount in PP, SP and PL tended to be greater with FITC-OVA solution than the double liposomes. FITC-OVA was retained longer in PP with the double liposomes than FITC-OVA solution. The present results indicated that OVA could transfer well to PP and systemic circulation even with the solution dosage form in the loop method, probably because it was not exposed to harsh conditions such as a gastric fluid. Namely, it implied that the protection from gastric pH and enzyme by the double liposomes, which had been reported before, would be importantly associated with the promotion of immune induction. In addition, the double liposomes could retain OVA longer in PP, which might cause the enhancement of oral immunization. PMID- 20950265 TI - A timely review of state-of-the-art chronopharmaceuticals synchronized with biological rhythms. AB - Extensive research into circadian rhythms and their influence on biological systems has given rise to the science of chronobiology and subsequently chronotherapy, the science of delivering drugs in synchrony with biological rhythms. The field of chronotherapeutics paves the way for advances and complexities in current drug delivery technology. The ultimate goal of current chronopharmaceutical research strives to design ideal chronotherapeutic drug delivery systems that respond to such therapeutic needs. Considering the fact that physiological events such as heart rate, blood pressure, plasma concentration of hormones, plasma proteins and enzymes display constancy over time, drug delivery systems with constant release profiles have thus been favored. However, due to circadian rhythms, the conventional paradigm of constant drug delivery may not be what is needed. Instead, precisely timed drug delivery systems are required in order to correlate drug delivery with circadian rhythms to provide maximum therapeutic efficacy for chronotherapeutic diseases when most needed. The aim of this review paper is to outline the concepts in designing chronopharmaceuticals from a clinical viewpoint of major chronotherapeutic diseases such as asthma, allergic rhinitis, cardiovascular disorders, rheumatoid arthritis and cancer as well as relatively minor niche areas of interest such as in glaucoma, diabetes, immunity, pain, gastric ulcers, epilepsy and even HIV/AIDS that would require chronotherapy. In addition this review paper attempts to concisely assimilate and explicate the role of circadian rhythms in these various disease states and provide a focused overview of the current state-of-the-art in designing strategies for chronopharmaceutical formulations employed for treating chronotherapeutic diseases. PMID- 20950266 TI - Thermodynamics of drug nanoencapsulation: case study of phenytoin-poly (D, L lactide) nanocarrier. AB - In order to rationalize the nanoencapsulation process, a thermodynamic analysis allowed to predict the limit of a model drug (phenytoin, PHT) loading into poly (d, l-lactic acid) nanocarrier (PLA NC) prepared by solvent displacement method. The NC were characterized for size, morphology, thermal behavior and crystallography by dynamic light scattering, electron microscopies, differential scanning calorimetry, and powder X-ray diffraction, respectively. The drug loading, encapsulation efficiency (EE) and in vitro drug release profile were determined using high performance liquid chromatography. There was a logarithmic correlation between the partial molar free energy change based on the molecular descriptors and the drug / polymer weight (D/P) ratio predicting an equilibrium state at ratio= 0.29. This was consistent with experimental data as PHT appeared to be loaded either in crystalline or molecular/amorphous state within the PLA matrix with an average EE coefficient of 91.5%. Overall, the smallest PHT NC had a mean diameter of ~231 nm and was produced at the limiting D/P ratio of 0.33, using PHT: 18 mg, PLA: 60 mg and surfactant: 0.3%. The drug release occurred by diffusion following Higuchi model within 24 hours. These data suggested that thermodynamic analysis allows elucidating PHT encapsulation within PLA NC and may be useful in the rationale design of other macromolecular based-nanocarriers. PMID- 20950267 TI - Kinetics of vascular targeted monoclonal antibody. AB - PURPOSE: There is growing interest in delivery of drugs and radioisotopes with carriers designed to target molecular receptors in the vascular space. In contrast to targets outside of blood vessels, vascular receptors are easily accessed and tracer binding is not significantly impacted by the size of the targeted drug carrier. Although it is accepted that vascular targeting is very efficient, the kinetics of target binding in the vascular space immediately after injection has not been evaluated. MAb 201B accumulation in mouse lung, by virtue of its binding to thrombomodulin on lung endothelium, has been used as a model for imaging and vascular targeting. PROCEDURES: MAb 201B was radioiodinated with either (125)I comparing two different methods of radioiodination to assess label stability. MAb accumulation and retention were monitored after iv injection in normal BALB/c mice by standard biodistribution experiments, SPECT/CT. MAb radiolabeled with positron emitting (124)I was evaluated by dynamic microPET. RESULTS: The data show that lung uptake and kinetics of loss (t1/2~40 hrs) of (125)I MAb 201B was similar with two different radio-iodination methods. Loss of radioiodine was detected in sample radiolabeled using the chloramines T method, but only at later time points(24hrs). For very short time evaluations the more efficient chloramine T method was adopted for PET studies with (124)I. Lung uptake of (124)I MAb 201B occurred within seconds of injection as observed in dynamic microPET analysis with little (124)I MAb ever detected in the peripheral circulation. In contrast, distribution kinetics of control (124)I MAb 14 or (124)I MAb 201B that had been diluted with excess cold MAb demonstrated equilibration throughout the vascular space. CONCLUSION: Accumulation of MAb targeted to epitopes in the vascular space occurs very rapidly, is highly specific and very efficient. Drug delivery with vascular targeting agents can accommodate fast acting therapeutic agents including short half lived radioisotopes. PMID- 20950268 TI - Local delivery of minocycline hydrochloride: a therapeutic paradigm in periodontal diseases. AB - From the literature we can draw conclusions regarding the local use of minocycline in periodontal diseases. This review article attempts to evaluate the role of local delivery of minocycline HCl in the management of periodontal diseases. The efficacies of several local delivery devices of minocycline like minocycline films, strips, gels/ointment, microspheres and nanoparticles are discussed. The functional characteristics of local delivery devices of minocycline, their effectiveness as monotherapy, and comparison with scaling and root planning (SRP) are discussed in detail. Methods for the analysis of minocycline in various biological fluids, clinical trials and patents relevant to the local use of minocycline HCl in dental diseases have also been addressed in the article, conceptualizing the fact that direct application of minocycline into the diseased periodontal sulcus is an attractive treatment approach. PMID- 20950269 TI - Current approaches for drug delivery to central nervous system. AB - Brain, the center of the nervous system in all vertebrate, plays the most vital role in every function of human body. However, many neurodegenerative diseases, cancer and infections of the brain become more prevalent as populations become older. In spite of the major advances in neuroscience, many potential therapeutics are still unable to reach the central nervous system (CNS) due to the blood-brain barrier (BBB) which is formed by the tight junctions within the capillary endothelium of the vertebrate brain. This results in the capillary wall behaving as a continuous lipid bilayer and preventing the passage of polar and lipid insoluble substances. Several approaches for delivering drugs to the CNS have been developed to enhance the capacity of therapeutic molecules to cross the BBB by modifying the drug itself, or by coupling it to a vector for receptor mediated, carrier mediated or adsorption-mediated transcytosis. The current challenge is to develop drug delivery systems that ensure the safe and effective passage of drugs across the BBB. This review focuses on the strategies and approaches developed to enhance drug delivery to the CNS. PMID- 20950270 TI - The structure of CYP101D2 unveils a potential path for substrate entry into the active site. AB - The cytochrome P450 CYP101D2 from Novosphingobium aromaticivorans DSM12444 is closely related to CYP101D1 from the same bacterium and to P450cam (CYP101A1) from Pseudomonas putida. All three are capable of oxidizing camphor stereoselectively to 5-exo-hydroxycamphor. The crystal structure of CYP101D2 revealed that the likely ferredoxin-binding site on the proximal face is largely positively charged, similar to that of CYP101D1. However, both the native and camphor-soaked forms of CYP101D2 had open conformations with an access channel. In the active site of the camphor-soaked form, the camphor carbonyl interacted with the haem-iron-bound water. Two other potential camphor-binding sites were also identified from electron densities in the camphor-soaked structure: one located in the access channel, flanked by the B/C and F/G loops and the I helix, and the other in a cavity on the surface of the enzyme near the F helix side of the F/G loop. The observed open structures may be conformers of the CYP101D2 enzyme that enable the substrate to enter the buried active site via a conformational selection mechanism. The second and third binding sites may be intermediate locations of substrate entry and translocation into the active site, and provide insight into a multi-step substrate-binding mechanism. PMID- 20950271 TI - Spermine synthase activity affects the content of decarboxylated S adenosylmethionine. AB - dcAdoMet (decarboxylated S-adenosylmethionine) is an essential intermediate in the synthesis of polyamines. Its content is normally very low, amounting to less than 5% of that of S-adenosylmethionine itself. It was found that in mice lacking spermine synthase there was a large increase in dcAdoMet and that overexpression of spermine synthase reduced the amount of this nucleoside. There was also an increase in dcAdoMet in cells derived from patients with Snyder-Robinson syndrome, a rare X-linked recessive human disease caused by SMS gene mutations that greatly reduce the content of spermine synthase. These results suggest that there is an inverse relationship between the amount of spermine synthase protein and the content of dcAdoMet and raise the possibility that some of the abnormalities seen in mammals deficient in spermine synthase might be due to changes in dcAdoMet pools. PMID- 20950272 TI - Phosphorylation of bacterial-type phosphoenolpyruvate carboxylase at Ser425 provides a further tier of enzyme control in developing castor oil seeds. AB - PEPC [PEP (phosphoenolpyruvate) carboxylase] is a tightly controlled anaplerotic enzyme situated at a pivotal branch point of plant carbohydrate metabolism. Two distinct oligomeric PEPC classes were discovered in developing COS (castor oil seeds). Class-1 PEPC is a typical homotetramer of 107 kDa PTPC (plant-type PEPC) subunits, whereas the novel 910-kDa Class-2 PEPC hetero-octamer arises from a tight interaction between Class-1 PEPC and 118 kDa BTPC (bacterial-type PEPC) subunits. Mass spectrometric analysis of immunopurified COS BTPC indicated that it is subject to in vivo proline-directed phosphorylation at Ser425. We show that immunoblots probed with phosphorylation site-specific antibodies demonstrated that Ser425 phosphorylation is promoted during COS development, becoming maximal at stage IX (maturation phase) or in response to depodding. Kinetic analyses of a recombinant, chimaeric Class-2 PEPC containing phosphomimetic BTPC mutant subunits (S425D) indicated that Ser425 phosphorylation results in significant BTPC inhibition by: (i) increasing its Km(PEP) 3-fold, (ii) reducing its I50 (L malate and L-aspartate) values by 4.5- and 2.5-fold respectively, while (iii) decreasing its activity within the physiological pH range. The developmental pattern and kinetic influence of Ser425 BTPC phosphorylation is very distinct from the in vivo phosphorylation/activation of COS Class-1 PEPC's PTPC subunits at Ser11. Collectively, the results establish that BTPC's phospho-Ser425 content depends upon COS developmental and physiological status and that Ser425 phosphorylation attenuates the catalytic activity of BTPC subunits within a Class 2 PEPC complex. To the best of our knowledge, this study provides the first evidence for protein phosphorylation as a mechanism for the in vivo control of vascular plant BTPC activity. PMID- 20950273 TI - Complement 1q-binding protein inhibits the mitochondrial permeability transition pore and protects against oxidative stress-induced death. AB - Opening of the MPT (mitochondrial permeability transition) pore is a critical event in mitochondrial-mediated cell death. However, with the exception of CypD (cyclophilin D), the exact molecular composition of the MPT pore remains uncertain. C1qbp (complement 1q-binding protein) has recently been hypothesized to be an essential component of the MPT pore complex. To investigate whether C1qbp indeed plays a critical role in MPT and cell death, we conducted both gain of-function and loss-of-function experiments in MEFs (mouse embryonic fibroblasts). We first confirmed that C1qbp is a soluble protein that localizes to the mitochondrial matrix in mouse cells and tissues. Similarly, overexpression of C1qbp in MEFs using an adenovirus resulted in its exclusive localization to mitochondria. To our surprise, increased C1qbp protein levels actually suppressed H2O2-induced MPT and cell death. Antithetically, knockdown of endogenous C1qbp with siRNA (small interfering RNA) sensitized the MEFs to H2O2-induced MPT and cell death. Moreover, we found that C1qbp could directly bind to CypD. Therefore C1qbp appears to act as an endogenous inhibitor of the MPT pore, most likely through binding to CypD, and thus protects cells against oxidative stress. PMID- 20950274 TI - Mesohaem substitution reveals how haem electronic properties can influence the kinetic and catalytic parameters of neuronal NO synthase. AB - NOSs (NO synthases, EC 1.14.13.39) are haem-thiolate enzymes that catalyse a two step oxidation of L-arginine to generate NO. The structural and electronic features that regulate their NO synthesis activity are incompletely understood. To investigate how haem electronics govern the catalytic properties of NOS, we utilized a bacterial haem transporter protein to overexpress a mesohaem containing nNOS (neuronal NOS) and characterized the enzyme using a variety of techniques. Mesohaem-nNOS catalysed NO synthesis and retained a coupled NADPH consumption much like the wild-type enzyme. However, mesohaem-nNOS had a decreased rate of Fe(III) haem reduction and had increased rates for haem-dioxy transformation, Fe(III) haem-NO dissociation and Fe(II) haem-NO reaction with O2. These changes are largely related to the 48 mV decrease in haem midpoint potential that we measured for the bound mesohaem cofactor. Mesohaem nNOS displayed a significantly lower Vmax and KmO2 value for its NO synthesis activity compared with wild-type nNOS. Computer simulation showed that these altered catalytic behaviours of mesohaem-nNOS are consistent with the changes in the kinetic parameters. Taken together, the results of the present study reveal that several key kinetic parameters are sensitive to changes in haem electronics in nNOS, and show how these changes combine to alter its catalytic behaviour. PMID- 20950275 TI - Chinese herbal extracts (SK0506) as a potential candidate for the therapy of the metabolic syndrome. AB - The metabolic syndrome has reached epidemic proportions worldwide, but currently there is a lack of effective therapies for this multifactorial endocrine disease. TCM (traditional Chinese medicine) has been utilized to treat a wide variety of diseases for centuries in the People's Republic of China, subsequently becoming a promising source for the development of new therapeutic agents. Chinese medicinal herbs Gynostemma pentaphyllum, Coptis chinensis and Salvia miltiorrhiza have been shown to have anti-atherosclerotic and antidiabetic properties. In this study, we have investigated the metabolic effects of a mixture of these three herbal extracts (SK0506) in a rodent model of the metabolic syndrome induced by an HFD (high-fat diet). SD (Sprague-Dawley) rats that were fed on an HFD for 4 weeks gained 33% more weight compared with chow-fed rats (P<0.05). Four weeks treatment with SK0506 prevented weight gain with decreased visceral fat (P<0.01 compared with vehicle treatment). SK0506 also significantly reduced plasma triacylglycerols (triglycerides), NEFAs (non-esterified fatty acids) and cholesterol. SK0506 exerted similar effects to RSG (rosiglitazone) on impaired glucose intolerance. SK0506 also significantly enhanced glucose uptake and glycogen synthesis in adipose tissue during hyperinsulinaemic-euglycaemic clamp. Western blotting analysis revealed that SK0506 enhanced GLUT4 (glucose transporter 4) expression in adipose tissue, and RSG markedly up-regulated GLUT4 translocation in skeletal muscle. Overall, the present study has discovered that SK0506 can reverse several components of the metabolic syndrome primarily through acting on hyperlipidaemia and visceral obesity. The results from the present study suggest that it is worthwhile to conduct a randomized clinical trial to confirm the potential that SK0506 may be a new oral agent for treating the metabolic syndrome and preventing Type 2 diabetes. PMID- 20950276 TI - Stem cell-conditioned medium does not protect against kidney failure. AB - Paracrine secretion of mediators may be the main route by which stem cells protect against injuries. Stem cells commonly secrete different bioactive molecules. In this study, we examined the hypothesis that administration of conditioned media of stem cells can diminish the burden of kidney injury. A mouse model of cisplatin-induced nephropathy was developed to test the putative renoprotective effects of conditioned media of human umbilical cord blood USSCs (unrestricted somatic stem cells) as well as mouse bone marrow MSCs (mesenchymal stem cells). None of these two types of conditioned medium could protect against kidney failure in terms of serum urea and creatinine, histopathologic examinations and physical activity score. Neither MSC- nor USSC-conditioned media were effective in protecting against kidney injury in our study. Possible explanations for our observations are offered, and related literature is reviewed. PMID- 20950277 TI - SUMO modification selectively regulates transcriptional activity of peroxisome proliferator-activated receptor gamma in C2C12 myotubes. AB - PPAR (peroxisome-proliferator-activated receptor) gamma, a nuclear receptor, can be conjugated with SUMO (small ubiquitin-like modifier), which results in the negative regulation of its transcriptional activity. In the present study, we tested whether de-SUMOylation of PPARgamma affects the expression of PPARgamma target genes in mouse muscle cells and investigated the mechanism by which de SUMOylation increases PPARgamma transcriptional activity. We found that the SUMO specific protease SENP2 [SUMO1/sentrin/SMT3 (suppressor of mif two 3 homologue 1) specific peptidase 2] effectively de-SUMOylates PPARgamma-SUMO conjugates. Overexpression of SENP2 in C2C12 cells increased the expression of some PPARgamma target genes, such as FABP3 (fatty-acid-binding protein 3) and CD36 (fatty acid translocase), both in the absence and presence of rosiglitazone. In contrast, overexpression of SENP2 did not affect the expression of another PPARgamma target gene ADRP (adipose differentiation-related protein). De-SUMOylation of PPARgamma increased ChIP (chromatin immunoprecipitation) of both a recombinant PPRE (PPAR response element) and endogenous PPREs of the target genes CD36 and FABP3, but ChIP of the PPRE in the ADRP promoter was not affected by SENP2 overexpression. In conclusion, these results indicate that SENP2 de-SUMOylates PPARgamma in myotubes, and de-SUMOylation of PPARgamma selectively increases the expression of some PPARgamma target genes. PMID- 20950278 TI - Retinoic acid receptor-alpha signalling antagonizes both intracellular and extracellular amyloid-beta production and prevents neuronal cell death caused by amyloid-beta. AB - Alzheimer's disease (AD) is characterized by amyloid-beta (Abeta) deposition in the brain, neuronal cell loss and cognitive decline. We show here that retinoic acid receptor (RAR)alpha signalling in vitro can prevent both intracellular and extracellular Abeta accumulation. RARalpha signalling increases the expression of a disintegrin and metalloprotease 10, an alpha-secretase that processes the amyloid precursor protein into the non-amyloidic pathway, thus reducing Abeta production. We also show that RARalpha agonists are neuroprotective, as they prevent Abeta-induced neuronal cell death in cortical cultures. If RARalpha agonists are given to the Tg2576 mouse, the normal Abeta production in their brains is suppressed. In contrast, neither RARbeta nor gamma-agonists affect Abeta production or Abeta-mediated neuronal cell death. Therefore, RARalpha agonists have therapeutic potential for the treatment of AD. PMID- 20950279 TI - Physical exercise increases Notch activity, proliferation and cell cycle exit of type-3 progenitor cells in adult hippocampal neurogenesis. AB - In adult hippocampal neurogenesis of mice, the proliferation of precursor cells can be stimulated by voluntary exercise (wheel-running). Physical activity has an additional effect on late progenitor cells (type-3) by promoting cell survival and further maturation. Notch1 is a key regulator of various steps in neuronal development, including the inhibition of cell cycle exit and neuronal differentiation of neural stem cells, as well as promoting the survival and dendritic branching of newborn neurons. We here report that physical activity increased the proportion and absolute number of doublecortin(+) (DCX) type-2b and type-3 progenitor cells that showed an activated Notch1 pathway. In contrast, the fraction of dividing cells with nuclear Notch intracellular domain expression indicating an activated Notch pathway was not affected by physical exercise. We used double labeling with two halogenated thymidine analogs, iododeoxyuridine and chlorodeoxyuridine, to distinguish between cell cycle exit and continued division at the progenitor cell level. After 7 days of physical exercise, the proliferative activity of precursor cells was increased, whereas the proportion of type-2b/3 cells re-entering S-phase was reduced. Consistent with this observation, the proportion of DCX(+) cells that expressed the marker of postmitotic immature granule cells (calretinin) was enhanced. Running promotes both the proliferation and cell cycle exit of DCX(+) type-3 precursors, possibly by preferentially stimulating a last neurogenic cell division. These pro proliferative effects are independent of Notch1, whereas the running-induced survival and cell cycle exit of type-3 progenitor cells might by mediated by Notch1 activity. PMID- 20950280 TI - Gene expression analysis of the emergence of epileptiform activity after focal injection of kainic acid into mouse hippocampus. AB - We report gene profiling data on genomic processes underlying the progression towards recurrent seizures after injection of kainic acid (KA) into the mouse hippocampus. Focal injection enabled us to separate the effects of proepileptic stimuli initiated by KA injection. Both the injected and contralateral hippocampus participated in the status epilepticus. However, neuronal death induced by KA treatment was restricted to the injected hippocampus, although there was some contralateral axonal degeneration. We profiled gene expression changes in dorsal and ventral regions of both the injected and contralateral hippocampus. Changes were detected in the expression of 1526 transcripts in samples from three time-points: (i) during the KA-induced status epilepticus, (ii) at 2 weeks, before recurrent seizures emerged, and (iii) at 6 months after seizures emerged. Grouping genes with similar spatio-temporal changes revealed an early transcriptional response, strong immune, cell death and growth responses at 2 weeks and an activation of immune and extracellular matrix genes persisting at 6 months. Immunostaining for proteins coded by genes identified from array studies provided evidence for gliogenesis and suggested that the proteoglycan biglycan is synthesized by astrocytes and contributes to a glial scar. Gene changes at 6 months after KA injection were largely restricted to tissue from the injection site. This suggests that either recurrent seizures might depend on maintained processes including immune responses and changes in extracellular matrix proteins near the injection site or alternatively might result from processes, such as growth, distant from the injection site and terminated while seizures are maintained. PMID- 20950281 TI - Representations of visual proportions in the primate posterior parietal and prefrontal cortices. AB - The primate prefrontal (PFC) and posterior parietal cortices (PPC) have been shown to be cardinal structures in processing abstract absolute magnitudes, such as numerosity or length. The neuronal representation of quantity relations, however, remained largely elusive. Recent functional imaging studies in humans showed that blood flow changes systematically both in the PFC and the PPC as a function of relational distance between proportions. We investigated the response properties of single neurons in the lateral PFC and the inferior parietal lobule (IPL, area 7) in rhesus monkeys performing a lengths-proportion-discrimination task. Neurons in both areas shared many characteristics and showed peaked tuning functions with preferred proportions. However, a significantly higher percentage of neurons coding proportions was found in the PFC compared with the IPL. In agreement with human studies, our study shows that proportions are represented in the fronto-parietal network that has already been implicated for absolute magnitude processing. PMID- 20950282 TI - Cortical-evoked potentials reflect speech-in-noise perception in children. AB - Children are known to be particularly vulnerable to the effects of noise on speech perception, and it is commonly acknowledged that failure of central auditory processes can lead to these difficulties with speech-in-noise (SIN) perception. However, little is known about the mechanistic relationship between central processes and the perception of SIN. Our aims were twofold: to examine the effects of noise on the central encoding of speech through measurement of cortical event-related potentials and to examine the relationship between cortical processing and behavioral indices of SIN perception. We recorded cortical responses to the speech syllable [da] in quiet and multi-talker babble noise in 32 children with a broad range of SIN perception. Outcomes suggest inordinate effects of noise on auditory function in the bottom SIN perceivers compared with the top perceivers. The cortical amplitudes in the top SIN group remained stable between conditions, whereas amplitudes increased significantly in the bottom SIN group, suggesting a developmental central processing impairment in the bottom perceivers that may contribute to difficulties in encoding and perceiving speech in challenging listening environments. PMID- 20950283 TI - Dynamics of brain responses to phobic-related stimulation in specific phobia subtypes. AB - Very few studies have investigated to what extent different subtypes of specific phobia share the same underlying functional neuroanatomy. This study aims to investigate the potential differences in the anatomy and dynamics of the blood oxygen level-dependent (BOLD) responses associated with spider and blood injection-injury phobias. We used an event-related paradigm in 14 untreated spider phobics, 15 untreated blood-injection-injury phobics and 17 controls. Phobic images successfully induced distress only in phobic participants. Both phobic groups showed a similar pattern of heart rate increase following the presentation of phobic stimuli, this being different from controls. The presentation of phobic images induced activity within the same brain network in all participants, although the intensity of brain responses was significantly higher in phobics. Only blood-injection-injury phobics showed greater activity in the ventral prefrontal cortex compared with controls. This phobia group also presented a lower activity peak in the left amygdala compared with spider phobics. Importantly, looking at the dynamics of BOLD responses, both phobia groups showed a quicker time-to-peak in the right amygdala than controls, but only spider phobics also differed from controls in this parameter within the left amygdala. Considering these and previous findings, both phobia subtypes show very similar responses regarding their immediate reaction to phobia-related images, but critical differences in their sustained responses to these stimuli. These results highlight the importance of considering complex mental processes potentially associated with coping and emotion regulation processes, rather than exclusively focusing on primary neural responses to threat, when investigating fear and phobias. PMID- 20950284 TI - Parental support for newborn screening for cystic fibrosis. AB - AIM: To describe the attitudes among parents towards including cystic fibrosis (CF) in the newborn screening programme and towards the potential knowledge of their own carrier status. METHODS: A questionnaire with three to five response categories and an information leaflet was posted to 143 CF parents, 3 matched diabetes and 3 matched population parents, the response rate being 85%, 74% and 70%, respectively. Comparisons between groups were made with statistical tests for independent groups. RESULTS: Eighty-six percent of CF, 70% of diabetes and 77% of population parents were in favour of newborn screening for CF, 47%, 45% and 50%, respectively, wished to know their CF carrier status. The parental attitude was independent of the age of the child, as well as delay of diagnosis and well-being of the CF child at the time of diagnosis. Sixty percent of the CF parents experienced the diagnosis as delayed. CONCLUSION: Parents in Sweden support CF newborn screening. Half of the parents wanted to know their CF carrier status. PMID- 20950285 TI - A systematic meta-analytic review of evidence for the effectiveness of the 'Fast ForWord' language intervention program. AB - BACKGROUND: Fast ForWord is a suite of computer-based language intervention programs designed to improve children's reading and oral language skills. The programs are based on the hypothesis that oral language difficulties often arise from a rapid auditory temporal processing deficit that compromises the development of phonological representations. METHODS: A systematic review was designed, undertaken and reported using items from the PRISMA statement. A literature search was conducted using the terms 'Fast ForWord''Fast For Word''Fastforword' with no restriction on dates of publication. Following screening of (a) titles and abstracts and (b) full papers, using pre-established inclusion and exclusion criteria, six papers were identified as meeting the criteria for inclusion (randomised controlled trial (RCT) or matched group comparison studies with baseline equivalence published in refereed journals). Data extraction and analyses were carried out on reading and language outcome measures comparing the Fast ForWord intervention groups to both active and untreated control groups. RESULTS: Meta-analyses indicated that there was no significant effect of Fast ForWord on any outcome measure in comparison to active or untreated control groups. CONCLUSIONS: There is no evidence from the analysis carried out that Fast ForWord is effective as a treatment for children's oral language or reading difficulties. PMID- 20950286 TI - Witnessed violence and youth behavior problems: a multi-informant study. AB - Witnessed violence has significant negative consequences for youth behavior and mental health. However, many findings on the impact of witnessed violence have been based on a single informant. There is a general lack of consistency between caregiver and youth reports on both witnessed violence and behavioral problems. This study included data from both caregivers and youth and incorporated a multisource analytic approach to simultaneously examine the association between youth witnessed violence and externalizing and internalizing behavior problems. Data from 875 caregivers and 812 youth were collected as part of the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN). Findings showed that youth reported more witnessed violence than did their caregivers, and caregivers reported more externalizing and internalizing behavior problems than did youth. Further, the source of information had a significant impact on the association between witnessed violence and internalizing behaviors. These findings highlight the need to incorporate multiple sources and multi-informant analytic techniques to eliminate methodological limitations to understanding the effect of witnessed violence on youth behavioral problems. PMID- 20950287 TI - A dual-factor model of mental health: toward a more comprehensive understanding of youth functioning. AB - Traditional mental health models focus on psychological problems and distress; accordingly, health is viewed as the absence of illness or disability. In contrast, a dual-factor model of mental health incorporates both indicators of positive subjective well-being (SWB) and measures of psychopathological symptoms to comprehensively determine an individual's psychological adjustment. This study used such a dual-factor model to measure the mental health status of young adolescents. A total of 764 middle school students were classified into one of four distinct groups based on having high or low psychopathology and high or low SWB. Furthermore, group differences in student engagement, academic achievement, and environmental support for learning were investigated. Results demonstrated the existence of a traditionally neglected group of adolescents (low SWB and low psychopathology) who are nonetheless at risk for academic and behavior problems in school and who performed no better than the most troubled group of adolescents. Overall, both the presence of positive well-being and the absence of symptoms were necessary for ensuring the most advantageous school performance. These results highlight the importance of incorporating positive indicators of well-being along with traditional negative factors in more fully understanding relationships between individuals' mental health and educational outcomes. PMID- 20950288 TI - Factors associated with positive adjustment in siblings of children with severe emotional disturbance: the role of family resources and community life. AB - This study builds on the scant research involving siblings of children with severe emotional disturbances (SED) and examines: associations between adversity experiences and adjustment among 5- to 10-year-old siblings, and relations among family resources, community life, and sibling adjustment. Caregivers from 100 families completed standardized indicators of sibling adjustment and scales reflecting multiple contextual variables. Results document negative associations between stress exposure and sibling adjustment. Regression models also indicate positive associations between the caregiver-child relationship and broader family resources on sibling behavioral and emotional strengths, even after accounting for adversity experiences; adversity exposure was the prime correlate in regression models involving sibling oppositional behavior. Analyses also suggest that strain related to parenting a child with SED is associated with sibling adjustment. This work documents the needs of these siblings and their family systems and highlights the relevance of not only core proximal influences (e.g., child-caregiver relationship) but also elements of their broader contexts. Implications and recommendations are described, including the need to support plans of care that involve services, supports, or preventive strategies for these siblings. PMID- 20950289 TI - Family Connections: an approach for strengthening early care systems in facing depression and adversity. AB - Over a 4-year period, the authors worked in partnership with a large early care provider and a Head Start center to design and implement a systems-wide preventive program with the aim of increasing staff's capacity to deal with depression and related adversities in their encounters with families and children. The intervention consisted primarily of training sessions and mental health consultation. Staff interviews, focus groups, reports by consultants, observations by assessors, and documentation of staff use of sick time were used to assess program impact. Reports by staff showed that the intervention proved feasible to deliver and resulted in sustained parent, classroom, and teacher activities. Teachers were better able to deal with the challenges presented by parents and children. Results suggest that center-wide staff-focused training and consultation approaches deserve consideration. PMID- 20950290 TI - Ending child homelessness in America. AB - Approximately 1.5 million children experience homelessness in America each year. The current economic recession and staggering numbers of housing foreclosures have caused the numbers of homeless families to increase dramatically. The impact of homelessness on families and children is devastating. Without a place to call home, children are severely challenged by unpredictability, dislocation, and chaos. Homelessness and exposure to traumatic stresses place them at high risk for poor mental health outcomes. Despite the pressing needs of these children, federal policy during the last decade has focused primarily on chronically homeless adult individuals-to the exclusion of the families. In 2010, however, the U.S. Interagency Council on Homelessness issued a comprehensive plan to eradicate homelessness for all people through interagency collaboration and aligning mainstream services. A key goal is to prevent and end homelessness for families, youth, and children within 10 years. This policy-focused article describes several tools that can be used to help achieve this goal, including: general principles of care for serving homeless families and children; BSAFE-a promising practice that helps families access community-based services and supports; and the Campaign to End Child Homelessness aimed at action on behalf of homeless families and children at the national, state, and local levels. PMID- 20950291 TI - Leaving no children or families outside: the challenges of immigration. AB - This study addresses potentially stressful events that accompany the process of immigration for children and their families. Acculturation stress, combined with service disparities, may contribute to a higher risk for psychopathology among immigrant children and youth, as compared to their parents. Culturally informed, evidence-based treatment and preventive interventions that meet the mental health and cultural needs of immigrant children and families have the potential to minimize this higher risk of adverse mental health consequences. PMID- 20950292 TI - Communities that care for families: the LINC Model for enhancing individual, family, and community resilience. AB - The resilience of families and communities is inextricably linked. Their healthy functioning relies on a balance of stressors and resources. Both can be jeopardized by major challenges such as socioeconomic change or natural and man made disasters. Such events can cause increased incidences of physical and mental problems such as addiction, posttraumatic stress syndrome, and heart disease. Trauma breeds marginalization, abuse of power, and prejudice. How these stressors are handled is profoundly influenced by the degree of connectedness-attachment-to family and culture of origin. Connectedness can be enhanced by mobilizing support systems, facilitating access to resources, strengthening family, community and cultural ties, and fostering resilience. The LINC Model increases connectedness at the individual, family, and community levels. This article includes methods for designing interventions, studies and clinical vignettes that illustrate the application of the LINC Model, and examples of communities that have overcome major stress. PMID- 20950293 TI - Recycling: two big ideas in the care of older adults and other people with disabilities. PMID- 20950294 TI - How can government protect mental health amid a disaster? PMID- 20950295 TI - Jewish children hidden in France between 1940 and 1944: an analysis of their narratives today. AB - The psychology literature concerning Jewish children hidden during World War II appeared in 1991 and was predominantly American and Israeli. Nevertheless, few studies consider the specific and complex situation of the "hidden children." The present study broaches this theme. The aim of this research is to show the consequences of the cumulate trauma in adults whose trauma occurred when they were children; it also aims to show how the subjects cope with the trauma. This research used a qualitative methodology. A series of semistructured interviews on personal and psychological history was conducted with 35 Jewish people (21 women, 14 men; mean age = 74.9 years; range = 65-82 years) living in France and who had been hidden between 1940 and 1944 during the Occupation in France (except for 2 hidden in Belgium and the Netherlands). The current research identified specific traumas, intra- and intergenerational family disorders, and affiliation disturbances, as well as protective factors and ways of coping with the trauma. This research shows the impact of collective history on individual history, the experience of Jewish children who were hidden in France and who stayed in France following the Liberation presents specific features. PMID- 20950296 TI - Resilience in trauma-exposed refugees: the moderating effect of coping style on resilience variables. AB - Research with survivors of torture has generated considerable variability in prevalence rates of posttraumatic stress disorder (PTSD). Multiple risk and resilience factors may affect this variability, increasing or decreasing the likelihood of experiencing psychological distress. This study sought to investigate the effect of several such resilience factors, coping style, social support, cognitive appraisals, and social comparisons on PTSD symptom severity. Furthermore, this study examined whether coping style moderated the relationship between resilience variables and PTSD symptoms. Seventy-five torture survivors completed an intake interview and several self-report measures upon entry into a treatment program for survivors of torture. Results indicated that emotion focused coping styles significantly moderated the relationship between cognitive appraisal and social comparison variables and PTSD, and usually increased the likelihood of developing severe symptoms. These results indicate that the salience of resilience variables may differ depending on the individual's coping style, which present implications for clinical practice with torture survivors. PMID- 20950297 TI - Discrimination and mental health among Somali refugee adolescents: the role of acculturation and gender. AB - This study examines the role of social identity (acculturation and gender) in moderating the association between discrimination and Somali adolescent refugees' mental health. Participants were English-speaking Somali adolescent refugees between the ages of 11 and 20 (N = 135). Perceived discrimination, trauma history, posttraumatic stress disorder (PTSD), depressive symptoms, and behavioral acculturation were assessed in structured interviews. Fourteen in depth qualitative interviews and 3 focus groups were also conducted. Results indicated that discrimination was common and associated with worse mental health. For girls, greater Somali acculturation was associated with better mental health. Also, the association between discrimination and PTSD was less strong for girls who showed higher levels of Somali acculturation. For boys, greater American acculturation was associated with better mental health, and the association between discrimination and depression was less strong for boys with higher levels of American acculturation. PMID- 20950298 TI - Review of refugee mental health interventions following resettlement: best practices and recommendations. AB - There are increasing numbers of refugees worldwide, with approximately 16 million refugees in 2007 and over 2.5 million refugees resettled in the United States since the start of its humanitarian program. Psychologists and other health professionals who deliver mental health services for individuals from refugee backgrounds need to have confidence that the therapeutic interventions they employ are appropriate and effective for the clients with whom they work. The current review briefly surveys refugee research, examines empirical evaluations of therapeutic interventions in resettlement contexts, and provides recommendations for best practices and future directions in resettlement countries. The resettlement interventions found to be most effective typically target culturally homogeneous client samples and demonstrate moderate to large outcome effects on aspects of traumatic stress and anxiety reduction. Further evaluations of the array of psychotherapeutic, psychosocial, pharmacological, and other therapeutic approaches, including psychoeducational and community-based interventions that facilitate personal and community growth and change, are encouraged. There is a need for increased awareness, training and funding to implement longitudinal interventions that work collaboratively with clients from refugee backgrounds through the stages of resettlement. PMID- 20950299 TI - Acute stress disorder, depression, and tobacco use in disaster workers following 9/11. AB - Early posttraumatic psychiatric disorders have not been well studied in disaster workers. This study examined the rates of probable acute stress disorder (ASD), probable depression, increased tobacco use, and their associated risk factors in 9/11 World Trade Center disaster workers. Surveys were obtained from 90 disaster workers (e.g., medical personnel, police, firefighters, search and rescue) 2-3 weeks after 9/11. Nearly 15% of disaster workers had probable ASD and 26% had probable depression. Probable ASD and depression were highly related to functional impairment. The risk for ASD was increased for those with 9/11 specific disaster exposures, more pre-9/11 trauma exposures, and the peritraumatic dissociative symptom of altered sense of time. Disaster workers who were younger, non-White, or who had increasing numbers of peritraumatic dissociative symptoms were more likely to have probable depression. More than half of tobacco users increased their tobacco use after 9/11. Additionally, all tobacco users with probable ASD and almost all tobacco users with probable depression increased tobacco use. Rapid mobilization of resources for early screening and intervention and health promotion campaigns aimed at improving adverse health-related behaviors may be helpful for this high-risk group. PMID- 20950300 TI - Well-being in a deeply religious society in the shadows of war: results of a household survey of Kuwaitis. AB - The present study was designed to determine the current level and distribution of well-being among Kuwaiti citizens who have lived either in the middle or in the shadows of war since Kuwait was invaded by Iraq in August 1990. A measure of Kuwaiti well-being, the Kuwaiti Raha Scale, was developed and utilized as the primary indicator in the first National Household Survey (NHS) of well-being in Kuwait. The findings presented are part of an international program of research focusing on national trauma and mental health for which the Kuwaiti NHS was developed. From a population of 935,922 (2004), 830 households were randomly drawn, from which 487 were approached and 416 successfully recruited and surveyed. In contrast to prevailing views in the literature, level of well-being (Raha) was not associated with either educational attainment or wealth. Rather, the results indicate that well-being is more associated with health and religion. Implications of these findings for a new theory of well-being in a deeply religious society are offered along with suggestions for a program of research. The policy implications of the NHS are also discussed. PMID- 20950301 TI - Muslim families' understanding of, and reaction to, 'the war on terror'. AB - In multiethnic societies, the consequences of the war on terror (WOT) for Muslim youth are still not well understood and the school's role remains to be defined. This article documents the parent-child transmission of understanding and emotional reaction to the WOT in South Asian Muslim families in Montreal, Canada. For this qualitative study, the researchers interviewed 20 families. Results indicated that the families' emotional reactions and communication about these events were interlinked with family patterns of identity assignation. The majority of parents avoided talking with their children about the WOT and felt that these issues should not be discussed at school. Most children shared their parents' feelings of helplessness and familial patterns of identity assignation. Parents reporting a greater sense of agency displayed less avoidance, had a more complex vision of self and other, and favored the school's role in helping children make sense of these events. These results suggest that school interventions in neighborhoods strained by international tensions should emphasize immigrant parents' empowerment and provide spaces where their children feel comfortable expressing their concerns. PMID- 20950302 TI - When a parent goes to war: effects of parental deployment on very young children and implications for intervention. AB - Young children (birth through 5 years of age) are disproportionately represented in U.S. military families with a deployed parent. Because of their developmental capacity to deal with prolonged separation, young children can be especially vulnerable to stressors of parental deployment. Despite the resiliency of many military families, this type of separation can constitute a developmental crisis for a young child. Thus, the experience may compromise optimal child growth and development. This article reviews what is known about the effects of the military deployment cycle on young children, including attachment patterns, intense emotions, and behavioral changes and suggests an ecological approach for supporting military families with infants, toddlers, and preschoolers. Specifically, home-based family focused interventions seem to warrant the most serious consideration. PMID- 20950303 TI - Incidence and clinical significance of arterial injury in varicocele repair. AB - OBJECTIVE: * This study was performed to histologically determine the rate of arterial injury in varicocele ligation surgery and to determine the clinical significance of these arterial injuries. MATERIALS AND METHODS: * 41 men who underwent varicocele ligation surgery, and had segments of each ligated vessel examined histologically. * The patients were followed prospectively to determine the effect of arterial injury on surgical results and clinical complications. RESULTS: * Arterial ligation was identified in 6 of 41 patients (12%), and in 7 of 132 specimens (5%), which is higher than previous reports. * Arterial injury was not associated with testicular atrophy and there was no apparent effect of arterial injury on surgical outcome. CONCLUSION: * The rate of arterial injury during varicocele repair is higher than previously reported, but the clinical significance of these injuries appears to be limited. PMID- 20950304 TI - Do men with mild erectile dysfunction have the same risk factors as the general erectile dysfunction clinical trial population? AB - OBJECTIVE: * To compare the underlying risk for diseases associated with erectile dysfunction (ED; i.e. cardiovascular disease and diabetes) in a population of men with mild ED relative to a general ED clinical trial population. PATIENTS AND METHODS: * Men enrolled in a randomized, double-blind placebo-controlled (DBPC) trial of sildenafil for the treatment of mild ED were compared with a database of men enrolled in 67 of the manufacturer's other DBPC sildenafil trials. * The main outcome measures were baseline demographics, comorbidities and concomitant medications. RESULTS: * In both populations, most men were white, approximately one quarter were smokers, and most had an organic component to their ED etiology. * In the mild ED population (N = 176) versus the database population (N = 14,537), mean +/- sd (range) age was 50 +/- 12 (19-84) versus 55 +/- 11 (18-89) years, body mass index was 29 +/- 5 (20-48) versus 28 +/- 5 (11-64) kg/m2 and ED duration was 3.5 +/- 3.2 (< 1-18) versus 4.6 +/- 4.7 (< 1-45) years. * The prevalence of comorbidities associated with ED was similar (hypertension 26.1% (n = 46) vs 32.8%; diabetes mellitus 13.6% (n = 24) vs 22.1%; dyslipidemias 12.5% (n = 22) vs 11.7%; hypercholesterolemia 12.5% (n = 22) vs 9.5%; gastro-esophageal reflux disease 10.8% (n = 19) vs 6.0%; benign prostatic hyperplasia 9.7% (n = 17) vs 9.9%; depression 6.3% (n = 11) vs 5.6%; and anxiety 4.0% (n = 7) vs 1.6%), as was the rate of use of medications for those comorbidities. CONCLUSIONS: * Men with mild ED have similar risk factors to a general ED clinical trial population. Thus, mild ED is an important indicator of risk for underlying disease associated with ED. * Inquiry into ED should be part of routine clinical evaluation to facilitate rapid identification and early intervention. * Men complaining of mild ED should be evaluated adequately for underlying cardiovascular risk. PMID- 20950305 TI - No excess mortality after prostate biopsy: results from the European Randomized Study of Screening for Prostate Cancer. AB - OBJECTIVE: * To assess possible excess mortality associated with prostate biopsy among screening participants of the European Randomized Study of Screening for Prostate Cancer (ERSPC). PATIENTS AND METHODS: * From three centres in the ERSPC (Finland, The Netherlands and Sweden) 50,194 screened men aged 50.2-78.4 years were prospectively followed. A cohort of 12,959 first-time screening-positive men (i.e. with biopsy indication) was compared with another cohort of 37,235 first time screening-negative men. * Overall mortality rates (i.e. other cause than prostate cancer mortality) were calculated and the 120-day and 1-year cumulative mortality were calculated by the Kaplan-Meier method, with a log-rank test for statistical significance. * Incidence rate ratios (RR) and statistical significance were evaluated using Poisson regression analyses, adjusting for age, total PSA level, screening centre and whether a biopsy indication was present, or whether a biopsy was actually performed or not. RESULTS: * There was no statistically significant difference in cumulative 120-day other cause mortality between the two groups of men: 0.24% (95% CI, 0.17-0.34) for screening-positive men vs 0.24% (95% CI, 0.20-0.30) for screening-negative men (P= 0.96). This implied no excess mortality for screening-positive men. * Screening-positive men who were not biopsied (n= 1238) had a more than fourfold risk of other cause mortality during the first 120 days compared to screening-negative men: RR, 4.52 (95% CI, 2.63-7.74) (P < 0.001), adjusted for age, whereas men who were actually biopsied (n= 11,721) had half the risk: RR, 0.41 (95% CI, 0.23-0.73) (P= 0.002), adjusted for age. * Only 14/31 (45%) of the screening-positive men who died within 120 days were biopsied and none died as an obvious complication to the biopsy. CONCLUSION: * Prostate biopsy is not associated with excess mortality and fatal complications appear to be very rare. PMID- 20950306 TI - Bicalutamide monotherapy preserves bone mineral density, muscle strength and has significant health-related quality of life benefits for osteoporotic men with prostate cancer. AB - OBJECTIVES: * To evaluate changes in bone mineral density (BMD), body composition, muscle strength and health-related quality of life (HRQL) during bicalutamide (150 mg) monotherapy in osteoporotic patients with non-metastatic locally advanced prostate cancer. Osteoporosis is prevalent in men presenting with prostate cancer and also a common side effect of treatment with luteinizing hormone-releasing hormone agonists, which are associated with decreased BMD and loss of lean body mass and suppress testosterone, unlike bicalutamide, which results in an increase in serum testosterone and oestrogen levels. PATIENTS AND METHODS: * Forty-two men with non-metastatic locally advanced prostate cancer and osteoporosis (T-score <=-2.5) were treated with bicalutamide (150 mg) monotherapy. BMD was measured at baseline and 1 year. HRQL was assessed 3-monthly using the RAND 36-Item Health Survey and University of California Los Angeles Prostate Cancer Index questionnaires. Bone turnover markers, liver function tests, prostate-specific antigen, testosterone, oestradiol and haemoglobin were measured at baseline, at 3 weeks and 3-monthly thereafter. Arm anthropometry and dynamometry assessed fat mass, skeletal muscle mass and quadriceps strength. RESULTS: * BMD was maintained (+2.1% lumbar spine, +1.2% total hip and +1.1% forearm). Prostate-specific antigen decreased by 88% at 3 months. Testosterone and oestradiol had increased at 1 year by 58% and 42%, respectively. No increase in bone turnover markers was seen over 1 year. Quadriceps muscle strength was maintained. General and prostate cancer-specific HRQL were maintained throughout the study, with no significant reductions in physical or sexual function. Adverse events included breast pain and gynaecomastia. CONCLUSIONS: * Bicalutamide preserves BMD, muscle strength and HRQL in osteoporotic men with non-metastatic locally advanced prostate cancer. It provides an alternative to medical castration for well informed men at high fracture risk and those wishing to retain physical and sexual activity, with luteinizing hormone-releasing hormone agonists being reserved for those failing to respond or relapsing. PMID- 20950307 TI - Randomized, crossover study evaluating patient preference and the impact on quality of life of urisheaths vs absorbent products in incontinent men. AB - OBJECTIVE: * To evaluate the impact of urisheaths vs absorbent products (APs) on quality of life (QoL) in men with moderate to severe urinary incontinence (UI). PATIENTS AND METHODS: * A randomized, controlled, crossover trial in 61 outpatient adult men with stable, moderate to severe UI, with no concomitant faecal incontinence, was conducted from June 2007 to February 2009 in 14 urology centres. * Participants tested Conveen Optima urisheaths (Coloplast, Humlebaek, Denmark) with collecting bags and their usual AP in random order for 2 weeks each. * The impact of each on QoL was measured using the King's Health Questionnaire (KHQ) and the short form-12 acute questionnaire, and each patient's preference was recorded. * A 10-item patient questionnaire was also used to assess the product main advantages on an 11-point scale (0: worst; 10: best). A 72-h leakage diary was used to record the number and severity of leaks and daily product consumption. Safety was measured as the number of local adverse events. RESULTS: * All dimensions of the KHQ were scored lower with urisheaths, indicating an improvement in QoL. The greatest mean score reductions were in Limitations of Daily Activities (-10.24, P= 0.01) and Incontinence Impact (-7.05, P= 0.045). * The majority (69%) of patients preferred Conveen Optima urisheaths to their usual AP (P = 0.002). * Urisheaths scored significantly higher for all categories in the patient questionnaire (efficacy, self-image, odour management, discretion, skin integrity) except ease of use. * Safety was considered to be good. CONCLUSIONS: * Conveen Optima urisheaths showed a positive impact on QoL (according to the KHQ results) in moderate to severe incontinent men, who were long-term users of APs, and participants largely preferred urisheaths. * Conveen Optima urisheaths should be recommended to incontinent men in preference to APs. PMID- 20950308 TI - Percutaneous renal access training: content validation comparison between a live porcine and a virtual reality (VR) simulation model. AB - OBJECTIVE: * To compare the content validity (realism and usefulness) of percutaneous renal access (PRA) obtained on a live porcine model and a high fidelity computer-based surgical simulator (PERC Mentor, Simbionix; Lod, Israel) in our skills laboratory for trainees interested in PRA training, so as to determine which of the two is a more appropriate and effective training model. MATERIALS AND METHODS: * In all, 24 'experts' performed PRA in a live porcine model and using the PERC Mentor. * The porcine model access required a live anaesthetized pig with a pre-placed ureteric catheter. The access was done with flouroscopic guidance using a 22-G 'skinny' needle (Cook Medical, Bloomington, IN, USA). * Then the specific task of PRA using a similar case scenario was done using the PERC Mentor. * The experts rated the models using a questionnaire based on a 5-point Likert scale, consisting of 10- and three-items of realism and usefulness, respectively. RESULTS: * Of the 10 items of realism assessed, the porcine model was rated as better than the PERC Mentor for 'overall realism', 'movement of the kidney', 'tactile feedback of perinephric space', 'fluoroscopic realism' and 'complications encountered' (All P < 0.001). * It was inferior to the PERC Mentor for 'orientation to the flank', 'aspiration', 'repetitive performance' and 'organisational feasibility' (All P < 0.001). * 'Tactile feedback of successful access' was similar in both models (mean [sd] points, 4.24 [0.7] vs 4.6 [0.5]). * Of the three items of usefulness, 'overall usefulness' (4.6 [0.6] vs 4.65 [0.5]) and 'use as a training tool' (4.32 [0.5] vs 4.75 [0.4]) was similar; however, the porcine model was a much better assessment tool (P < 0.001). CONCLUSIONS: * Both models have relative advantages and disadvantages. The live porcine model is a more realistic assessment tool for PRA. The specific advantage of the PERC Mentor is of repetitive tasking and easier set up feasibility. * The overall usefulness was same for both the models. PMID- 20950309 TI - Laparoscopic extended pelvic lymph node dissection during radical cystectomy: technique and clinical outcomes. AB - OBJECTIVE: * To study the surgical techniques and clinical results of laparoscopic extended pelvic lymph node dissection during radical cystectomy. PATIENTS AND METHODS: * From July 2007 to October 2009, 43 patients with bladder carcinoma received laparoscopic radical cystectomy with extended pelvic lymphadenectomy and urinary diversion. * Pelvic lymph node dissection (PLND) was first performed within extended template. * The lower part of aorta and vena cava were isolated from the bifurcation of common iliac artery to the level of the inferior mesenteric artery. * The standard template PLND was continued along the external iliac vessels, internal iliac vessels and obturator nerve. The bladder was then removed laparoscopically and urinary diversion was performed. RESULTS: * All procedures were performed successfully and no open conversion occurred. The duration of the procedure for extended PLND was 90-185 min (mean 125 min) and total duration was 280-470 min (mean 329 min). * Intra-operative blood loss was 200-1500 mL (mean 325 mL) and eight cases received transfusion. Pathological study identified transitional cell carcinoma and a negative margin in all cases. A range of 19-53 lymph nodes were dissected in the patients with a mean of 31.3. * In total, 17 positive nodes were confirmed in 11 cases. Postoperative complications included two cases of bowel obstruction, two cases of mild urine leakage and 17 cases of lymphatic leakage. CONCLUSIONS: * Laparoscopic radical cystectomy with extended pelvic lymphadenectomy is indicated in selected patients with bladder cancer. * It is safe, minimally invasive and more lymph nodes can be retrieved with a higher success rate by extended pelvic lymphadenectomy. PMID- 20950310 TI - Novel methods for the diagnosis and treatment of ejaculatory duct obstruction. AB - OBJECTIVES: * To investigate a new method of vas deferens radiography for ejaculatory duct obstruction (EDO). * To evaluate the effect of a procedure involving dilation of the ejaculatory duct by F9 seminal vesicoscopy. PATIENTS AND METHODS: * Twenty-two patients with EDO were diagnosed using semen analysis, semen fructose measurement, transrectal ultrasonography (TRUS) and vas deferens radiography. * Of these, 18 patients were successfully treated by dilation of ejaculatory duct using F9 seminal vesicoscopy and four patients, whose treatment was unsuccessful, were treated by transurethral resection of the ejaculatory ducts (TURED). * All patients were followed up for at least 3 months after treatment. RESULTS: * Semen analyses in all 22 patients showed oligoasthenozoospermia or azoospermia, low semen volume (0-1.9 mL), low pH level (5.6-7.0) and absent or low semen fructose. TRUS and radiography showed pure dilated seminal vesicles on both sides in three patients, partial dilated seminal vesicles in one patient, dilation of both the ejaculatory duct and seminal vesicles in ten patients, dilated seminal vesicles and a prostatic cyst in four patients, and dilated ejaculatory duct or cystic lesions without dilated seminal vesicles in the remaining four patients. * At >3-month follow-up after dilation or TURED, the semen characteristics of 18 patients were improved and sperm were present in the semen in 13 cases. Normal semen analyses were found in 7 patients and 6 patients had conceived. * Voiding urethral radiography showed that no patients who had undergone dilation by seminal vesicoscopy had urine reflux into the ejaculatory duct. Only one patient showed urine reflux into the seminal vesicle after TURED. * All patients felt that their symptoms had improved after treatment. CONCLUSIONS: * The approach to vas deferens radiography using vas deferens aspiration has proved to be an effective and safe method for EDO diagnosis. * The procedure involving the dilation of the ejaculatory duct using F9 seminal vesicoscopy is equally effective but has fewer postoperative complications than TURED. PMID- 20950311 TI - Long-term oral treatment with BAY 41-2272 ameliorates impaired corpus cavernosum relaxations in a nitric oxide-deficient rat model. AB - OBJECTIVE: * To investigate the potential beneficial effects of 4-week oral treatment with 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1Hpyrazolo[3,4-b]pyridin-3 yl]-pyrimidin-4-ylamine (BAY 41-2272), a nitric oxide (NO)-independent soluble guanylate cyclase activator, on impaired rat corpus cavernosum relaxations in NO deficient rats. MATERIAL AND METHODS: * Male Wistar rats were divided into four groups: Control, N (G)-nitro-L- arginine methyl ester (L-NAME; 20 mg/rat/day), BAY 41-2272 (20 mg/kg/day) and L-NAME + BAY 41-2272. * Rats were treated with L NAME concomitantly with BAY 41-2272 for 4 weeks. * Concentration-response curves to acetylcholine (ACh) and sodium nitroprusside (SNP), along with the nitrergic relaxations (1-32 Hz) were obtained in rat corpus cavernosum (RaCC). * The RaCC contractile responses to the alpha1 -adrenoceptor agonist phenylephrine (PE) were obtained. RESULTS: * Acetylcholine (0.01-1000 umol/L) produced concentration dependent relaxing responses in RaCC that were significantly enhanced (P < 0.05) in BAY 41-2272-treated rats. * The ACh-induced relaxations were largely reduced in L-NAME-treated rats, and co-treatment with BAY 41-2272 failed to significantly modify these impaired relaxations. * The SNP-induced relaxations were modified neither by L-NAME nor by co-treatment with BAY 41-2272. * The nitrergic relaxations were significantly amplified in BAY 41-2272-treated rats (at 16 and 32 Hz). A significant reduction in the nitrergic relaxations was observed in L NAME-treated rats, an effect largely restored by co-treatment with BAY 41-2272. * The contractile RaCC responses produced by PE (0.001-100 umol/L) were significantly higher (P < 0.05) in L-NAME-treated rats, and co-treatment of L NAME with BAY 41-2272 nearly restored these enhanced contractile responses. CONCLUSION: * Four-week therapy with BAY 41-2272 prevents the impaired corpus cavernosum relaxations of rats treated chronically with L-NAME, indicating that accumulation of cyclic guanosine monophosphate into erectile tissue counteracts the NO deficiency. PMID- 20950312 TI - Detection of genotype recycling fraud in U.S. immigrants. AB - Relationship testing laboratories provide genetic evidence to support or refute claims of kinship between U.S. citizen petitioners and potential immigrant beneficiaries. One female beneficiary presented a male amelogenin type and alleles at 15 autosomal loci that were identical to an alleged brother's. Laboratory records showed that her alleged father had petitioned to have 15 children emigrate from Ghana. The petitioner's 15 paternity indices exceeded 105, but the children shared only four short tandem repeat (STR) profiles, suggesting fraudulent reuse of genotypes in this alleged pedigree (AP). To determine the extent of this "genotype recycling," I examined the laboratory's 555 APs from Ghana and 532 control APs from Nigeria. Seventeen Ghanaian APs (3.1%) but no Nigerian APs showed genotype recycling. Of 90 tested people in the 17 APs, 56 shared identical STR profiles with others in their AP. Of these 56 people, 10 were petitioners with unexpectedly high parentage indices. Seven of 56 had amelogenin types that disagreed with their declared genders. Database searches for identical multilocus genotypes in allegedly different people would best detect this fraud. PMID- 20950313 TI - Muscle contraction during electro-muscular incapacitation: A comparison between square-wave pulses and the TASER((r)) X26 Electronic control device. AB - Electronic control devices (including the Advanced TASER((r)) X26 model produced by TASER International) incapacitate individuals by causing muscle contractions. To provide information relevant to development of future potential devices, effects of monophasic square waves with different parameters were compared with those of the X26 electronic control device, using two animal models (frogs and swine). Pulse power, electrical pulse charge, pulse duration, and pulse repetition frequency affected muscle contraction. There was no difference in the charge required, between the square waveform and the X26 waveform, to cause approximately the same muscle-contraction response (in terms of the strength duration curve). Thus, on the basis of these initial studies, the detailed shape of a waveform may not be important in terms of generating electro-muscular incapacitation. More detailed studies, however, may be required to thoroughly test all potential waveforms to be considered for future use in ECDs. PMID- 20950314 TI - Acute arsenic poisoning: clinical, toxicological, histopathological, and forensic features. AB - This report describes a suicide case by acute arsenic intoxication via intravenous injection. A 30-year-old woman injected arsenic As (V) (sodium arseniate disodique: Disodium Hydrogena Arsenik RP) in a successful suicide attempt. Three hours following administration, the woman developed severe digestive symptoms. She was admitted to a hospital and transferred to the intensive care unit within 12 h of the massive administration of arsenic. Despite therapeutic efforts, over the next 2 h she developed multiorgan failure and died. A postmortem examination was performed. Pulmonary edema and congestion of liver were apparent. As (V) and As (III) were determined by high performance liquid chromatography and inductively coupled plasma mass spectrometry after mineralization of samples by concentrated nitric acid. Toxicological analysis revealed high concentrations of arsenic in biological fluids as well as in organs. Histopathological examination showed a typical indication of myocarditis. These findings were in agreement with acute arsenic poisoning. The symptoms developed by this young woman (intoxication by intravenous administration) were comparable to oral intoxication. The clinical signs, survival time, and administration type are discussed in light of the literature on acute and chronic arsenic poisoning. PMID- 20950315 TI - Myocardial hypertrophy induces carotid body hyperplasia. AB - The carotid bodies tend to enlarge after long-standing cardiopulmonary disease. Our objective was to investigate whether cardiac hypertrophy is associated with carotid body hyperplasia. Fifteen autopsy cases with combined left and right ventricular hypertrophy were examined and compared with two control groups (16 cases). The study involved a meticulous dissection of carotid bifurcations, thin serial sections, and morphometric analysis of carotid body volume and cell types (progenitor, dark, light, and sustentacular). There was a significant increase in sustentacular cells in all individuals with cardiac hypertrophy, which was not drug-induced, and accompanied by a similar increase in carotid body volume. Dark or light cell accumulation was detected focally and only in three instances. It appears that the generalized sustentacular cell hyperplasia is the result of long standing hypoxia, while a superimposed focal prominence of dark or light cells may be proliferative or metaplastic in nature and attributed to short-term hypoxia. PMID- 20950317 TI - The dynamic character of disguise behavior for text-based, mixed, and stylized signatures. AB - The aims of this study were to determine if dynamic parameters (duration, size, velocity, jerk, and pen pressure) differed for signing style (text-based, stylized, and mixed) and if signing style influences handwriting dynamics equally across three signature conditions (genuine, disguised, and auto-simulation). Ninety writers provided 10 genuine signatures, five disguised signatures, and five auto-simulated signatures. All 1800 signatures were collected using a digitizing tablet resulting in a database of each signature's dynamic characteristics. With genuine signatures, there were significant differences between styles for size, velocity, and pen pressure, and there were significant differences between genuine signatures and at least one of the un-natural signature conditions for all parameters. For velocity and size, these changes with condition were dependent on style. Changes with condition for the other parameters were similar for the three styles. This study shows that there are differences among natural signature styles and disguise behaviors that may be relevant in forensic signature examinations. PMID- 20950316 TI - Clinical effects and lethal and forensic aspects of propofol. AB - Propofol is a potent intravenous anesthetic agent that rapidly induces sedation and unconsciousness. The potential for propofol dependency, recreational use, and abuse has only recently been recognized, and several cases of accidental overdose and suicide have emerged. In addition, the first documented case of murder using propofol was reported a few months ago, and a high profile case of suspected homicide with propofol is currently under investigation. A number of analytical methods have been employed to detect and quantify propofol concentrations in biological specimens. The reported propofol-related deaths and postmortem blood and tissue levels are reviewed. Importantly, limitations of propofol detection are discussed, and future considerations are presented. Because propofol has the potential for diversion with lethal consequences, the forensic scientist must have a basic understanding of its clinical indications and uses, pharmacologic properties, and detection methods. In addition, medical institutions should develop systems to prevent and detect diversion of this potential drug of abuse. PMID- 20950318 TI - Plank fence penetration into automobiles-implications for prevention initiatives. AB - The wooden plank fence presents a deadly but unrecognized hazard to motorists. We hypothesize that fence plank injury is prevalent and results in significant morbidity and mortality. Databases of the University of Kentucky's Level I Trauma Center and the Fayette County Coroner were retrospectively analyzed over a 12 year period (1995-2006). One hundred and twenty-eight subjects were involved in vehicle contact with wooden plank fences. One hundred and twenty-three subjects were evaluated at the Emergency Department of our trauma center; 35 (27%) had a patient-plank interaction (PPI). Men (30/35) were more frequently involved (86%), and average age was 32.8 years. Thirty-two (91%) were drivers; 14/35 (40%) died from PPI-related injuries. The most common cause of death was blunt head trauma in 13 of these 14 fatally injured subjects (93%). This study provides new data underscoring the frequency, lethality, and economic consequences of this injury mechanism. Further research is needed to quantify the national prevalence of this problem and develop injury-mitigating strategies pertaining to roadway or fence design. PMID- 20950319 TI - Case series of completed suicides by burning over a 13-year period. AB - Suicide by burning is an extreme act that is uncommon in the United States and throughout the Western world. The characteristics of people who complete such acts are not well understood. To address this issue, we examined the death records of the King County Medical Examiner's Office in Washington State over the 13 years from 1996 to 2009. Twenty-five cases of suicide by burning were identified and used to characterize decedent demographics, circumstances of death, and motivating factors. Compared to other methods of suicide, burning demonstrated a significant overrepresentation of decedents who were women, 40-59 years of age, and Asian/Pacific Islander. They also tended to have previous psychiatric illness and/or substance abuse issues. Self-burning predominantly occurred at the decedent's residence with the intent of suicide given. There was no unifying theme in motivating factors. Together, these data represent the characteristics of people whose death is because of suicide by burning in King County, Washington. PMID- 20950320 TI - The 'break enter and die' syndrome may involve significant injury to major neck vessels. AB - Death from incised wounds of major vessels may occur during illegal entry of premises. Wounds are often relatively unimpressive having been caused by thin shards of glass. Alcohol and/or drugs have often been taken that have impaired coordination and contributed to a failure to take appropriate action. A 37-year old man slipped and fell while attempting to enter a house through a window that he had just broken. He was found dead surrounded by a large amount of blood. At autopsy, a single horizontal, deeply incised wound of the anterior neck was present with transection of the internal jugular veins bilaterally and the right common carotid artery. Toxicological studies were negative for alcohol and common drugs. Death was due to exsanguination and air embolism. This case demonstrates that the injuries sustained during such activities may be quite extensive and involve major neck vessels. Alcohol and drug intoxication are not necessarily involved. PMID- 20950321 TI - Mandibular ramus: an indicator for sex in fragmentary mandible. AB - Mandible is the hardest and most durable bone of the skull exhibiting a high degree of sexual dimorphism. Especially ramus of mandible is subjected to greater stress than any other bone of the skull because of the process of mastication. This study has been performed to establish the osteometric standards for practical use in forensic context over Indian population using mandibular ramus. The sample consists of 116 mandibles of Northern Indian population (M:F; 92:24, mean age 37.4 years), collected from the Department of Forensic Medicine, IMS, BHU, Varanasi. Osteometric informations about five metric parameters (coronoid height, projective height, condylar height, and maximum breadth and minimum breadth of ramus) were taken with sliding calipers. These parameters were subjected to different discriminant function analysis using SPSS 16.0. All parameters showed significant sexual dimorphism (p < 0.001 in all cases) with an overall accuracy of 80.2%, and coronoid height was the single best parameter providing an accuracy of 74.1%. PMID- 20950322 TI - Histological diagnosis of myocardial sarcoidosis in a fatal fall from a height. AB - The major issues of medico-legal relevance in fatal falls from a height are the manner of death and the reconstruction of the event. We present a peculiar case of a fatal fall from a height of about 9 m, involving a 27-year-old woman. At the death scene investigation, no suicide notes, housebreaking marks, or signs of fight were found, thus weakening both the suicide and homicide hypotheses. Combining circumstantial, autopsy and toxicology data, the kinematic analysis of the jump/fall, and the histological evidence of a myocardial sarcoidosis involving the left ventricle, we hypothesized that the young woman might have accidentally fallen from the window because of a sudden loss of consciousness related to cardiac disease undiagnosed during life. We believe that our brief report is a good example of the powerful additional information that histological investigations can offer for reconstructing the dynamics of the event in falls from a height and other traumatic fatalities. PMID- 20950323 TI - Expanded HIV screening in the United States: what will it cost government discretionary and entitlement programs? A budget impact analysis. AB - OBJECTIVE: The US Centers for Disease Control and Prevention (CDC) recently revised their HIV screening guidelines to promote testing and earlier entry to care. Prior analyses have examined the policy's cost-effectiveness but have not evaluated its impact on government budgets. METHODS: We used a simulation model of HIV screening, disease, and treatment to determine the budget impact of expanded HIV screening to US government discretionary, entitlement, and testing programs. We estimated total and incremental testing and treatment costs over a 5 year time horizon under current and expanded screening scenarios. We used CDC estimates of HIV prevalence and annual incidence, and considered variations in screening frequency, test return rates, linkage to care, test characteristics, and eligibility for government screening and treatment programs. RESULTS: Under current practice, 177,000 new HIV cases will be identified over 5 years. Expanded screening will identify an additional 46,000 cases at an incremental 5-year cost of $2.7 billion. The financial burden of expanded HIV screening will fall disproportionately on discretionary programs that fund care for newly identified patients and will not be offset by entitlement program savings. Testing will represent a small proportion (18%) of the total budget increase. Costs are sensitive to the frequency of screening and the proportion linked to care. CONCLUSIONS: The expanded HIV screening program will have a large downstream impact on government programs that fund HIV care. Expanded HIV screening will not meet early treatment goals unless government programs have sufficient budgets to expand testing and provide care for newly identified cases. PMID- 20950324 TI - Beneficial effects of electrostimulation contingencies on sustained attention and electrocortical activity. AB - INTRODUCTION: Chinese acupuncture therapy has been practiced for more than 3000 years. According to neuroimaging studies, electroacupuncture has been demonstrated to be effective via control of the frequency parameter of stimulation, based on the theory of frequency modulation of brain function. AIMS: To investigate the following: (1) possible sustained effects of acustimulation in improving perceptual sensitivity in attention by comparing before, during, and 5 min following stimulation; (2) relations between commission errors and the motor inhibition event-related potential (ERP) component measured with independent component analysis (ICA); (3) whether habituation would be demonstrated in the sham control group and would be militated by acustimulation in the experimental groups. RESULTS: Twenty-seven subjects were divided into three groups (n = 9). d Prime (d') derived from signal detection theory was used as an index of perceptual sensitivity in the visual continuous performance attention test. Increased d' was found during both alternating frequency (AE) and low frequency (LE) stimulation, but with no change in the sham control group (SE). However, only following AE was there a sustained poststimulation effect. Spatial filtration-based independent components (ICs) in the AE group revealed significantly decreased amplitudes of the motor inhibition ICs both during and poststimulation. There was a significant habituation effect from task repetition in the sham group with decreased amplitudes of ICs as follows: the visual comparison component difference between go (correct response) and nogo cues (correct withheld response), the P400 action monitoring and the working memory component in the nogo condition, and the passive auditory component on control trials. CONCLUSION: The results showed associations between acustimulation and improved perceptual sensitivity with sustained improvements following AE, but not LE stimulation. Improvements in commission errors in the AE group were related to the motor inhibition IC. The activational effects of acustimulation apparently attenuated the across-task habituation that characterized the control group. PMID- 20950325 TI - Electroacupuncture protected pyramidal cells in hippocampal CA1 region of vascular dementia rats by inhibiting the expression of p53 and Noxa. AB - AIM: Clinically electroacupuncture (EA) is proved an effective therapy for vascular dementia (VD), but their mechanisms remain uncertain. The aim of this study was to determine whether EA protects pyramidal cells from apoptosis in hippocampus of a VD rat model by inhibiting the expression of p53 and Noxa. METHODS: One month after a VD animal model was established by bilateral occlusion of common carotid arteries, EA treatment was given at "Baihui" (DU20), "Dazhui" (DU14), and "Shenshu" (BL23). The learning and memory ability was assessed by Morris water maze. Neuronal apoptosis in hippocampus was evaluated with hematoxylin-eosin (HE) staining, and the expression of p53 and Noxa was analyzed by confocal laser scanning microscope with immunofluorescence staining. RESULTS: Expressions of p53 and Noxa in the EA group and sham-operated group were less than in the VD model group (P < 0.01), and the expression of p53 was positively correlated to expression of Noxa in hippocampus of VD rats (r = 0.918, P < 0.01). EA treatment could reduce the amount of apoptotic neurons in hippocampal CA1 area of rats with VD. The average latency in the Morris water maze test was significantly shorter, and escape strategies improved from edge and random searches to more linear swim pathway in the EA group compared with the VD model group (P < 0.01). CONCLUSIONS: The increasing expressions of p53 and Noxa play important roles in the pathogenesis of VD. EA improves learning and memory ability and protects pyramidal cells from apoptosis by blocking expression of p53 and Noxa in the hippocampal CA1 region of VD rats. These results suggest a novel mechanism of EA treatment to VD. PMID- 20950326 TI - Asenapine: a review of acute and extension phase data in bipolar disorder. AB - The second generation atypical antipsychotic, asenapine (Saphris), was approved by the US FDA (August 2009) for the acute treatment of manic or mixed episodes with or without psychotic features associated with bipolar I disorder in adults as well as the acute treatment of schizophrenia. Asenapine exhibits a high affinity for and antagonism at several serotonergic (5-HT(2A-C), 5HT(5A), 5HT(6), 5HT(7)), dopaminergic (D(2), D(3)), alpha-adrenergic (alpha(1) and alpha(2)), and histaminergic (H1, H2) receptor subtypes. Asenapine is the first atypical antipsychotic formulated as a fast-dissolving, rapidly absorbed sublingual tablet. Asenapine was evaluated in adults with bipolar I disorder, manic or mixed episodes with or without psychotic features. Two identically designed 3-week registration trials confirmed the efficacy of asenapine relative to placebo in studies that included olanzapine as an active control. The placebo-subtracted rate of EPS (excluding akathisia) is 5% whereas the placebo-subtracted rate of akathisia was 2%. The placebo-subtracted rate of clinically significant weight gain (>=7%) with asenapine was approximately 5% during the 3-week acute mania trials. A 9- extension trial indicated that 19% of asenapine patients will experience clinically significant weight gain. Clinically significant metabolic abnormalities were not observed during the acute and/or extension trials. Asenapine can be associated with somnolence (asenapine 24%, placebo 6%) and does not appear to be associated with clinically significant changes in vital signs, laboratory parameters, or electrocardiographic changes. Bipolar depression and recurrence prevention studies are required to fully characterize this novel agent's position in the treatment of bipolar disorder. PMID- 20950327 TI - Nanoparticulate systems for drug delivery and targeting to the central nervous system. AB - Brain delivery is one of the major challenges for the neuropharmaceutical industry since an alarming increase in brain disease incidence is going on. Despite major advances in neuroscience, many potential therapeutic agents are denied access to the central nervous system (CNS) because of the existence of a physiological low permeable barrier, the blood-brain barrier (BBB). To obtain an improvement of drug CNS performance, sophisticated approaches such as nanoparticulate systems are rapidly developing. Many recent data demonstrate that drugs could be transported successfully into the brain using colloidal systems after i.v. injection by several mechanisms such as endocytosis or P-glycoprotein inhibition. This review summarizes the main brain targeted nanoparticulate carriers such as liposomes, lipid nanoparticles, polymeric nanoparticles, and micelles with great potential in drug delivery into the CNS. PMID- 20950328 TI - Role of spinal neurotransmitter receptors in itch: new insights into therapies and drug development. AB - Targets for antipruritic therapies are now expanding from the skin to the central nervous system. Recent studies demonstrate that various neuronal receptors in the spinal cord are involved in pruritus. The spinal opioid receptor is one of the best-known examples. Spinal administration of morphine is frequently accompanied by segmental pruritus. In addition to MU-opioid receptor antagonists, kappa opioid receptor agonists have recently come into usage as novel antipruritic drugs, and are expected to suppress certain subtypes of itch such as hemodialysis and cholestasis-associated itch that are difficult to treat with antihistamines. The gastrin-releasing peptide receptor in the superficial dorsal horn of the spinal cord has also received recent attention as a novel pathway of itch selective neural transmission. The NMDA glutamate receptor appears to be another potential target for the treatment of itch, especially in terms of central sensitization. The development of NMDA receptor antagonists with less undesirable side effects on the central nervous system might be beneficial for antipruritic therapies. Drugs suppressing presynaptic glutamate-release such as gabapentin and pregabalin also reportedly inhibit certain subtypes of itch such as brachioradial pruritus. Spinal receptors of other neuromediators such as bradykinin, substance P, serotonin, and histamine may also be potential targets for antipruritic therapies, given that most of these molecules interfere not only with pain, but also with itch transmission or regulation. Thus, the identification of itch specific receptors and understanding itch-related circuits in the spinal cord may be innovative strategies for the development of novel antipruritic drugs. PMID- 20950329 TI - Efficacy of rivastigmine on executive function in patients with Parkinson's disease dementia. AB - BACKGROUND AND OBJECTIVE: Rivastigmine is approved in the USA for the treatment of mild to moderate Alzheimer's disease and Parkinson's disease dementia (PDD). Executive function (EF) deficits are a core symptom of PDD. The current objective was to investigate the effects of rivastigmine capsules versus placebo on EF in PDD, focusing on secondary outcome measures from a large, international, randomized, double-blind, placebo-controlled, 24-week trial (EXPRESS, CENA713B2311). METHODS: Secondary outcomes included Delis-Kaplan Executive Function System (D-KEFS) measures of EF. Data from three D-KEFS subtests (Card Sorting, Letter Fluency, Color-Word Interference), plus the Symbol Digit Modalities Test were analyzed in the observed case (OC) population. Changes from baseline in the rivastigmine versus placebo groups were evaluated using the van Elteren test blocking for country. RESULTS: Of 541 patients in the EXPRESS study, 402, 71, 97, and 65 patients provided data for Letter Fluency, Card Sorting and Color-Word Interference subtests, and the Symbol Digit Modalities Test, respectively. On Letter Fluency, rivastigmine was associated with improvements in correct responses, set loss errors, and responses made (all P < 0.05), but not repetition errors. Higher Card Sorting recognition description score (P= 0.03), and more correct substitutions on the Symbol Digit Modalities Test (P= 0.02) were also recorded. CONCLUSION: Rivastigmine was associated with significant improvements over placebo on EF tests evaluating flexibility of thinking, problem solving and planning in patients with PDD. These findings support the hypothesis that rivastigmine may affect frontal subcortical circuits, which potentially contributes to observed clinical improvement associated with EF. PMID- 20950330 TI - Lacosamide and epilepsy. AB - We will review all available studies on the use of lacosamide in the treatment of partial-onset seizures. The available evidence includes two open-label studies and three randomized controlled trials evaluating the safety and efficacy of oral lacosamide. One open-label study and one randomized controlled trial evaluating the safety and tolerability of intravenous lacosamide was also identified. Lacosamide was found to be efficacious with significant reduction in seizure frequency dosed 400-600 mg daily. Moreover, its adverse drug effects were mild and infrequently reported in the literature. Findings suggest that lacosamide is an effective agent for adjunctive treatment of refractory partial-onset seizures. PMID- 20950331 TI - Survey of aspergillosis in non-neutropenic patients in Swiss teaching hospitals. AB - Invasive aspergillosis (IA) is a live-threatening opportunistic infection that is best described in haematological patients with prolonged neutropenia or graft versus-host disease. Data on IA in non-neutropenic patients are limited. The aim of this study was to establish the incidence, disease manifestations and outcome of IA in non-neutropenic patients diagnosed in five Swiss university hospitals during a 2-year period. Case identification was based on a comprehensive screening of hospital records. All cases of proven and probable IA were retrospectively analysed. Sixty-seven patients were analysed (median age 60 years; 76% male). Sixty-three per cent of cases were invasive pulmonary aspergillosis (IPA), and 17% of these were disseminated aspergillosis. The incidence of IPA was 1.2/10 000 admissions. Six of ten cases of extrapulmonary IA affected the brain. There were six cases of invasive rhinosinusitis, six cases of chronic pulmonary aspergillosis, and cases three of subacute pulmonary aspergillosis. The most frequent underlying condition of IA was corticosteroid treatment (57%), followed by chronic lung disease (48%), and intensive-care unit stays (43%). In 38% of patients with IPA, the diagnosis was established at autopsy. Old age was the only risk factor for post-mortem diagnosis, whereas previous solid organ transplantation and chronic lung disease were associated with lower odds of post-mortem diagnosis. The mortality rate was 57%. PMID- 20950333 TI - Liver X receptor agonist treatment promotes the migration of granule neurons during cerebellar development. AB - Liver X receptor alpha (LXRalpha) and beta (LXRbeta) are members of the nuclear receptor superfamily of ligand-activated transcription factors, and expressed in the CNS. We have previously demonstrated that LXRbeta is essential for migration of later-born neurons during cerebral cortex development, although the underlying mechanism is not clear. The cerebellum is organized in an exquisitely foliated structure with a simple layered cytoarchitecture and considered to be a good model to study morphogenesis of lamination and neuronal migration. Here, we found that T0901317, a potent LXR receptor agonist, administration to neonatal C57/BL6 mice, increased dendritic growth of Purkinje cell, although the appearance of the cerebellar cortex was not affected. We further demonstrated T0901317 treatment promoted the migration of granule neurons from the external granular layer to the internal granular layer during cerebellum development. Bergmann glial fibers serve as scaffolds for granule cells inward migration during cerebellum postnatal development. T0901317 treatment also inhibited premature differentiation of Bergmann glia during cerebellum development, which is related to the decreased levels of TGF-beta1 and Smad4 in the cerebellum. Taken together, our findings suggest that endogenous LXR affects differentiation process of Bergmann glia and subsequently leads to promote the migration of granule neurons. PMID- 20950332 TI - shRNA knockdown of guanylate cyclase 2e or cyclic nucleotide gated channel alpha 1 increases photoreceptor survival in a cGMP phosphodiesterase mouse model of retinitis pigmentosa. AB - In vertebrate rods, dark and light conditions produce changes in guanosine 3',5' cyclic monophosphate (cGMP) and calcium (Ca(2+) ) levels, which are regulated by the opposing function of several proteins. During the recovery of a bright flash, guanylate cyclase (GUCY) helps raise cGMP to levels that open cGMP-gated calcium sodium channels (CNG) to increase Na(+) and Ca(2+) influx in the outer segment. In contrast, light activates cGMP phosphodiesterase 6 (PDE6) causing rapid hydrolysis of cGMP, CNG closure, and reduced Na(+) and Ca(2+) levels. In Pde6b mouse models of retinitis pigmentosa (RP), photoreceptor death is preceded by abnormally high cGMP and Ca(2+) levels, likely because of continued synthesis of cGMP by guanylate cyclases and unregulated influx of Ca(2+) to toxic levels through CNG channels. To reverse the effects of Pde6b loss of function, we employed an shRNA knockdown approach to reduce the expression of Gucy2e or Cnga1 in Pde6b(H620Q) photoreceptors prior to degeneration. Gucy2e- or Cnga1-shRNA lentiviral-mediated knockdown GUCY2E and CNGA1 expression increase visual function and photoreceptor survival in Pde6b(H620Q) mice. We demonstrated that effective knockdown of GUCY2E and CNGA1 expression to counteract loss of PDE6 function may develop into a valuable approach for treating some patients with RP. PMID- 20950334 TI - Nicotine and cotinine increases the brain penetration of saquinavir in rat. AB - Endothelial tight junctions and efflux transporters of the blood-brain barrier (BBB) significantly limit brain accumulation of many drugs, including protease inhibitors such as saquinavir. The cholinergic agonist nicotine is one of the most commonly used drugs in the world and the incidence is even higher in the human immune deficiency virus population (~ 70%). We examined the ability of nicotine and its primary metabolite cotinine to modify brain uptake of saquinavir in rats. Both nicotine and cotinine at pharmacological concentrations matching those in smokers, increased brain saquinavir uptake by two fold. Co-perfusion with nicotinic receptor antagonists and passive permeability markers showed that the effect was not caused by receptor activation or BBB permeability disruption. Transport inhibition studies demonstrated that brain saquinavir uptake is limited by multiple efflux transporters, P-glycoprotein (P-gp), breast cancer resistance protein and multidrug resistance-associated protein. In situ perfusion and in vitro experiments using a classical P-gp substrate rhodamine 123 linked the effect of nicotine to inhibition of BBB P-gp transport. The effect was confirmed in vivo in chronic 14 day nicotine administration animals. These data suggest nicotine increases antiretroviral drug exposure to brain and may represent a significant in vivo drug-drug interaction at the BBB. Although this may slightly benefit CNS antiretroviral efficacy, it may also expose the brain to potential serious neurotoxicity. PMID- 20950336 TI - Differential roles of ERK1/2 and JNK in retinal development and degeneration. AB - Programmed cell death is well established as a key factor in the development of the vertebrate nervous system of which the retina is a unique sensory component. However, it is of utmost importance for the survival of post-mitotic tissues such as the retina that the execution of the cell death program is kept under stringent control once development is complete. This is exemplified by the many retinal dystrophies where aberrant apoptosis results in loss of distinct cell layers in the mature retina and often culminates in blindness. In this study, we report that the extracellular signal-regulated kinase (ERK1/2) pathway plays a key role in the regulation of apoptosis during retinal development. We show that as the retina matures, the emphasis shifts towards survival and ERK1/2 is activated resulting in phosphorylation of the potent BH3-only protein Bim(EL) and a dramatic decline in Bim(EL) expression via proteasomal degradation. We find that activation of ERK1/2 also occurs in response to injury in retinal explants. However, this is a transient response and appears to be overcome by Jun N terminal kinase activation resulting in induction of Bim(EL) mRNA and photoreceptor apoptosis. Our findings provide new insights into the intracellular pathways responsible for regulating apoptosis during neuronal development and degeneration. PMID- 20950337 TI - Modulation of mitochondria in the axon and soma of retinal ganglion cells in a rat glaucoma model. AB - Mitochondrial abnormality has been implicated in various models of retinal ganglion cell (RGC) degeneration. We investigated modulation of mitochondrial membrane permeability and apoptosis-inducing factor (AIF) translocation in a rat experimental glaucoma model. A decrease in MitoTracker-labeled mitochondria around the lamina area of the optic nerve was observed in the glaucomatous eye. Immunoblot analysis for axonal motor proteins showed that a significant decrease in kinesin 1 and myosin Va levels in the glaucomatous optic nerve. A significant decrease in mitochondrial thioredoxin 2 (Trx2) level was observed in the optic nerve after intraocular pressure (IOP) elevation. Translocation of AIF from the mitochondria to the axoplasm and nucleus was observed in the axon and cell body, respectively. Trx2 over-expression in the mitochondrial membrane of RGC-5 cells inhibited AIF translocation, resulting in cytoprotective effect against neurotoxicity induced by TNF-alpha/buthionine sulfoximine treatment. In vivo transfection was performed with EGFP-Trx2 plasmid and electroporation. Over expression of Trx2 in the retina and optic nerve indicated the protective effect against high IOP induced axonal degeneration. Thus, the decreased mitochondrial membrane potential and subsequent AIF translocation were involved in the glaucomatous neurodegeneration. Furthermore, modulation of mitochondria through the inhibition of AIF translocation may become a new treatment strategy for neurodegenerative disease, such as glaucoma. PMID- 20950335 TI - Mass-spectrometry based oxidative lipidomics and lipid imaging: applications in traumatic brain injury. AB - Lipids, particularly phospholipids, are fundamental to CNS tissue architecture and function. Endogenous polyunsaturated fatty acid chains of phospholipids possess cis-double bonds each separated by one methylene group. These phospholipids are very susceptible to free-radical attack and oxidative modifications. A combination of analytical methods including different versions of chromatography and mass spectrometry allows detailed information to be obtained on the content and distribution of lipids and their oxidation products thus constituting the newly emerging field of oxidative lipidomics. It is becoming evident that specific oxidative modifications of lipids are critical to a number of cellular functions, disease states and responses to oxidative stresses. Oxidative lipidomics is beginning to provide new mechanistic insights into traumatic brain injury which may have significant translational potential for development of therapies in acute CNS insults. In particular, selective oxidation of a mitochondria-specific phospholipid, cardiolipin, has been associated with the initiation and progression of apoptosis in injured neurons thus indicating new drug discovery targets. Furthermore, imaging mass spectrometry represents an exciting new opportunity for correlating maps of lipid profiles and their oxidation products with structure and neuropathology. This review is focused on these most recent advancements in the field of lipidomics and oxidative lipidomics based on the applications of mass spectrometry and imaging mass spectrometry as they relate to studies of phospholipids in traumatic brain injury. PMID- 20950338 TI - Prevalence and genetic diversity of pneumococcal serogroup 6 in Australia. AB - The prevalence of the newly discovered pneumococcal serotype 6C has increased in some countries since the introduction of seven-valent conjugate pneumococcal vaccine (PCV7). The distribution of invasive serogroup 6 serotypes, in Australia, including 6C and 6D, has not been reported previously. During the period 1999 to 2008, 6097 isolates were referred to the New South Wales Pneumococcal Reference Laboratory for serotyping. Of these, 847 were identified by Quellung reaction as belonging to serogroup 6 and 702 were available for further study. Serotypes were determined by serotype-specific PCR as follows: 6A, 197 (28.1%); 6B, 452 (64.4%); 6C, 52 (7.4%) and one 6D. The average numbers of invasive serogroup 6 isolates, per annum, fell from 62.2 before (2000-2005) to 49.7 after (2006-2008) the introduction of PCV7. The proportions of invasive 6B fell (from 72.4% to 47.3%, p 0.03), those of 6C rose (from 3.3% to 17%, p 0.02) significantly and those of 6A remained fairly constant (24.3% vs 27%, p 0.69) between the two periods. All 6C and 6D and selected 6A and 6B isolates were further characterized by multilocus sequence typing and sequence analysis of cps genes cpsA-cpsB (wzg-wzh) and wchA wciN(beta) -wciO, wciP. Results showed considerable diversity within serotype 6C, apparently as a result of both mutation and recombination. Sequence typing indicates that, in Australia, 6C has been largely derived from 6A. The genetic diversity and rapid increase in incidence of serotype 6C causing invasive pneumococcal disease has potential implications for vaccine efficacy. PMID- 20950339 TI - N-methyl-D-aspartate receptors are required for synaptic targeting of Alzheimer's toxic amyloid-beta peptide oligomers. AB - Soluble amyloid-beta peptide (Abeta) oligomers, known to accumulate in Alzheimer's disease brains, target excitatory post-synaptic terminals. This is thought to trigger synapse deterioration, a mechanism possibly underlying memory loss in early stage Alzheimer's disease. A major unknown is the identity of the receptor(s) targeted by oligomers at synapses. Because oligomers have been shown to interfere with N-methyl-d-aspartate receptor (NMDAR) function and trafficking, we hypothesized that NMDARs might be required for oligomer binding to synapses. An amplicon vector was used to knock-down NMDARs in mature hippocampal neurons in culture, yielding 90% reduction in dendritic NMDAR expression and blocking neuronal oxidative stress induced by Abeta oligomers, a pathological response that has been shown to be mediated by NMDARs. Remarkably, NMDAR knock-down abolished oligomer binding to dendrites, indicating that NMDARs are required for synaptic targeting of oligomers. Nevertheless, oligomers do not appear to bind directly to NMDARs as indicated by the fact that both oligomer-attacked and non attacked neurons exhibit similar surface levels of NMDARs. Furthermore, pre treatment of neurons with insulin down-regulates oligomer-binding sites in the absence of a parallel reduction in surface levels of NMDARs. Establishing that NMDARs are key components of the synaptic oligomer binding complex may illuminate the development of novel approaches to prevent synapse failure triggered by Abeta oligomers. PMID- 20950340 TI - Epoxyeicosatrienoic acids are endogenous regulators of vasoactive neuropeptide release from trigeminal ganglion neurons. AB - Epoxyeicosatrienoic acids (EETs) are bioactive eicosanoids produced from arachidonic acid by cytochrome P450 epoxygenases. We previously described the expression of cytochrome P450-2J epoxygenase in rat trigeminal ganglion neurons and that EETs signaling is involved in cerebrovascular dilation resulting from perivascular nerve stimulation. In this study, we evaluate the presence of the EETs signaling pathway in trigeminal ganglion neurons and their role in modulating the release of calcitonin gene-related peptide (CGRP) by trigeminal ganglion neurons. Liquid chromatography tandem mass spectrometry identified the presence of each of the four EETs regio-isomers within primary trigeminal ganglion neurons. Stimulation for 1 h with the transient receptor potential vanilloid-1 channel agonist capsaicin (100 nmol/L) or depolarizing K(+) (60 mmol/L) increased CGRP release as measured by ELISA. Stimulation-evoked CGRP release was attenuated by 30 min pre-treatment with the EETs antagonist 14,15 epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 10 MUmol/L). K(+) stimulation elevated CGRP release 2.9 +/- 0.3-fold above control levels, whereas in the presence of 14,15-EEZE K(+)-evoked CGRP release was significantly reduced to 1.1 +/- 0.2-fold above control release (p < 0.01 anova, n = 6). 14,15-EEZE likewise attenuated capsaicin-evoked CGRP release from trigeminal ganglion neurons (p < 0.05 anova, n = 6). Similarly, pre-treatment with the cytochrome P450 epoxygenase inhibitor attenuated stimulation-evoked CGRP release. These data demonstrate that EETs are endogenous constituents of rat trigeminal ganglion neurons and suggest that they may act as intracellular regulators of neuropeptide release, which may have important clinical implications for treatment of migraine, stroke and vasospasm after subarachnoid hemorrhage. PMID- 20950341 TI - Relationships between body mass index and short-circuit current in human duodenal and colonic mucosal biopsies. AB - AIM: Retrospectively, to investigate the relationship between body mass index (BMI) and basal electrogenic transport as measured by short-circuit current (SCC) in human duodenal and colonic mucosal biopsies. METHODS: The study included biopsies from mucosa of normal appearance in the sigmoid colon and/or distal duodenum. Patients were referred for routine endoscopy (predominantly for monosymptomatic abdominal pain) and had normal endoscopic findings. Biopsies were mounted in miniaturized Ussing chambers and basal SCC was recorded. Patients were divided into two groups on the basis of BMI (<=25 and >25 kg m-2). Statistical significance was assessed by the unpaired t-test or Wilcoxon rank-sum test. Correlation coefficients were calculated by Pearson product moment correlation. RESULTS: In colonic biopsies, basal SCC (mean +/- standard deviation) was significantly higher in 59 biopsies from 30 patients with low BMI than in 32 biopsies from 23 patients with high BMI (45 +/- 29 MUA cm-2 vs. 27 +/- 21 MUA cm 2, P = 0.016). In duodenal biopsies, mean basal SCC was numerically lower in 38 biopsies from 15 patients with low BMI than in 46 biopsies from 19 patients with high BMI (54 +/- 26 MUA cm-2 vs. 74 +/- 39 MUA cm-2, P = 0.069). The correlation coefficient between BMI and SCC was -0.26 (P = 0.06) in colonic biopsies and +0.44 (P = 0.001) in duodenal biopsies. CONCLUSION: Basal intestinal active electrogenic transport is related to BMI and this relationship may differ in different segments of the intestinal tract. PMID- 20950342 TI - Transient receptor potential ankyrin 1: emerging pharmacology and indications for cardiovascular biology. AB - Transient receptor potential anykrin 1 (TRPA1) is a member of the TRP superfamily, representing the sole member of the TRPA subfamily. It has many identified endogenous and exogenous agonists, comprising largely of chemical irritants and products of oxidative stress. Classically located on sensory neurone endings, TRPA1 has developed a strong presence in pain and inflammatory studies, where it is now becoming an intriguing clinical drug target. TRPA1 is increasingly recognized in a growing number of neuronal and non-neuronal locations with expanding expression and activity profiles providing evidence of a role for TRPA1 in other systems. Interest in discovering the pharmacological and functional roles of TRPA1 is increasing and diversifying into many areas. Historically, compounds now known as TRPA1 agonists have demonstrated cardiovascular activity, modulating activities in both the heart and the vasculature. Now TRPA1 has been identified as the receptor via which these compounds can act, these studies are being revisited and expanded on using current techniques. It is therefore timely to review the current knowledge of TRPA1 receptor presence and activities of relevance to the cardiovascular system, summarizing findings to date and identifying potential areas for future investigation. PMID- 20950343 TI - Does a low-pH microenvironment around phototrophic Fe(II) -oxidizing bacteria prevent cell encrustation by Fe(III) minerals? AB - Neutrophilic Fe(II) -oxidizing bacteria precipitate positively charged Fe(III) minerals that are expected to sorb to the negatively charged cell surface, leading to encrustation and thus limiting the cells' accessibility to substrates and nutrients. However, electron-microscopy analysis of phototrophic iron oxidizing Thiodictyon sp. strain F4 cells showed no encrustation, but mineral precipitation at a distance from the cell surface. In situ fluorescence microscopy analysis of F4 cells using a pH-sensitive fluorescent dye revealed a low cell surface pH (6.0 +/- 0.1) in contrast to the bulk pH (6.6 +/- 0.1). Biogeochemical modeling showed that the pH difference reduces Fe(III) sorption and Fe(III) precipitation rates at the cell surface, therefore directing mineral formation away from the cells. The results from this study therefore suggest that the establishment of a low cell surface pH could provide a mechanism for photoferrotrophs to successfully prevent Fe(III) mineral precipitation on the cell surface. PMID- 20950344 TI - Molecular profiling and identification of methanogenic archaeal species from rabbit caecum. AB - During a comparison of 16S rDNA PCR-denaturant gradient gel electrophoresis (DGGE) profiles of methanogenic archaea from rumen fluid, rabbit caecum and pig feces, a unique band common to all rabbit caecum samples was observed. DGGE profiling also showed that the methanogen community from the New Zealand White adult rabbits is different and less complex than the methanogen communities from the rumen and pig feces. Small subunit ribosomal gene sequences of methanogenic archaea were subsequently retrieved from the constructed rabbit caecum 16S rDNA gene library. Results of the phylogenetic analysis indicated that rabbit caecum is inhabited by members of the genus Methanobrevibacter and is possibly one species dominated, because all the retrieved sequences exhibited similarity values of 99% or higher. This species may well be a novel species of the genus Methanobrevibacter. It belongs to a distinct phylogenetic group containing Methanobrevibacter woesei, Methanobrevibacter thaueri and Methanobrevibacter gottschalkii strains isolated from animal feces, and Methanobrevibacter smithii from the predominating methanogen population of the human large bowel. PMID- 20950345 TI - Akt phosphorylates Sec24: new clues into the regulation of ER-to-Golgi trafficking. AB - Regulation of protein transport within the early secretory pathway is a relatively unexplored area. Here, we propose a new player in the control of protein transport from the endoplasmic reticulum (ER) to the Golgi. Akt is an important signaling kinase whose functioning is perturbed in diseases such as cancer and diabetes. We discovered that Akt phosphorylates Sec24, an essential coat protein II (COPII) component involved in mediating cargo selection for ER-to Golgi trafficking. We discuss how this finding may provide new insights into the regulation of protein transport. PMID- 20950346 TI - Lack of efficacy of low-dose spironolactone as adjunct treatment to conventional congestive heart failure treatment in dogs. AB - Aldosterone plays an important role in the pathophysiology of heart failure. Aldosterone receptor blockade has been shown to reduce morbidity and mortality in human patients with advanced congestive left ventricular heart failure. This study was designed to assess the efficacy and tolerance of long-term low-dose spironolactone when added to conventional heart failure treatment in dogs with advanced heart failure. Eighteen client-owned dogs with advanced congestive heart failure due to either degenerative valve disease (n=11) or dilated cardiomyopathy (n=7) were included in this prospective, placebo-controlled, double-blinded, randomized clinical study. After initial stabilization including furosemide, angiotensin-converting enzyme inhibitors, pimobendan and digoxin, spironolactone at a median dose of 0.52 mg/kg (range 0.49-0.8 mg/kg) once daily (n=9) or placebo (n=9) was added to the treatment, and the dogs were reassessed 3 and 6 months later. Clinical scoring, echocardiography, electrocardiogram, systolic blood pressure measurement, thoracic radiography, sodium, potassium, urea, creatinine, alanine aminotransferase, aldosterone and aminoterminal atrial natriuretic propeptide were assessed at baseline, 3 and 6 months. Survival times were not significantly different between the two treatment groups. Spironolactone was well tolerated when combined with conventional heart failure treatment. PMID- 20950347 TI - Antimicrobial disposition in pulmonary epithelial lining fluid of horses. Part I. Sulfadiazine and trimethoprim. AB - Sulfadiazine (SDZ) and trimethoprim (TMP) concentrations were examined in plasma and pulmonary epithelial lining fluid (PELF), following intravenous and oral administration and compared to minimum inhibitory concentrations (MICs) of common bacterial isolates from equine lower airway infections. SDZ/TMP (25/5 mg/kg) was administered intravenously, intragastric or per os to fed horses, and blood samples were collected before and 11 times, over 24 h, after administration. PELF samples were collected via a tampon device four times after drug administration and analysed for drug concentrations. Additionally, MICs of SDZ and TMP alone and in combination were determined in a selection of clinical respiratory isolates. Bioavailability was 74% for SDZ and 46% for TMP after paste administration in fed horses. The degree of penetration of SDZ and TMP into PELF, as described by AUC(PELF) /AUC(plasma) ratios, was 0.68 and 0.72, respectively, after intravenous administration. After oral administration, the degree of penetration for SDZ and TMP was 0.92 and 0.46, respectively. MIC measurements using SDZ/TMP ratios of 5:1 and 10:1 did not affect the interpretation of the results. The results indicate that clinically relevant drug concentrations of mainly TMP are difficult to maintain in PELF, especially after oral administration of SDZ/TMP. PMID- 20950348 TI - Antimicrobial disposition in pulmonary epithelial lining fluid of horses, part II. Doxycycline. AB - Doxycycline concentrations, following two types of oral administration to horses, in pulmonary epithelial lining fluid (PELF) were examined and compared to plasma concentrations. The oral bioavailability was estimated from plasma concentrations achieved after an intravenous study in two horses. Doxycycline (10 mg/kg) was administered either intragastric or as topdressing to nonfasted horses. Blood samples were collected for drug analysis, before and 11 times after administration during 24 h. PELF samples were collected by a tampon device four times after drug administration and analysed for doxycycline concentrations. Another two horses received doxycycline intravenously at a dose of 3 mg/kg and plasma was taken 14 times during a 24- h period. The oral bioavailability of doxycycline was calculated to 17% after intragastric administration and 6% after topdressing administration in nonfasted horses. The degree of penetration of doxycycline into PELF, as described by AUC(PELF) /AUC(plasma) ratios, was 0.87 after intragastric administration. The results indicate that clinically relevant doxycycline concentrations are possible to maintain in PELF after intragastric administration. Furthermore, if bioavailability could be enhanced for per os administration, doxycycline might be a valuable drug for the treatment of lower airway infections in horses. PMID- 20950349 TI - Pharmacokinetic-pharmacodynamic integration of orbifloxacin in Japanese quail (Coturnix japonica) following oral and intravenous administration. AB - The pharmacokinetics of single-dose administration of orbifloxacin were determined in Japanese quail (Coturnix japonica) at dosages of 5 mg/kg intravenous (i.v. n = 12) and 7.5 mg/kg oral (p.o.; n = 5), 10 mg/kg p.o. (n = 5), 15 mg/kg p.o. (n = 12) and 20 mg/kg p.o. (n = 5) via HPLC. Orbifloxacin minimal inhibitory concentrations (MICs) against 22 microbial isolates from various bird species were performed to calculate pharmacodynamic surrogate markers. The concentration-time data were analyzed using a naive pooled data (NPD) approach and compartmental and noncompartmental methods. Steady-state volume of distribution (Vd(ss)) and total body clearance (Cl) after i.v. administration were estimated to be 1.27 L/kg and 0.60 L/h.kg, respectively. Following 15 and 20 mg/kg p.o. dose, bioavailability was 102% and 117%, respectively. The harmonic mean of the corresponding terminal half-lives (T(1/2) lambda(z) ) across all the dose groups was 1.71 h. The C(max) /MIC(90) and AUC(0infinity24) /MIC(90) for the 15 and 20 mg/kg p.o. doses were >=5.22 and >=8.98, and >=25.80 and >=39.37 h, respectively. The results of this study suggest that 20 mg/kg orbifloxacin p.o. would be a rational daily dose to treat susceptible infections in Japanese quail not intended for food consumption. For more sensitive bacterial organisms, 15 mg/kg p.o. may also be effective. PMID- 20950350 TI - Involvement of breast cancer resistance protein (BCRP/ABCG2) in the secretion of danofloxacin into milk: interaction with ivermectin. AB - Danofloxacin, a veterinary fluoroquinolone antimicrobial drug, is actively secreted into milk by an as yet unknown mechanism. One of the main determinants of active drug secretion into milk is the transporter (BCRP/ABCG2). The main purpose was to determine whether danofloxacin is an in vitro substrate for Bcrp1/BCRP and to assess its involvement in danofloxacin secretion into milk. In addition, the role of potential drug-drug interactions in this process was assessed using ivermectin. Danofloxacin was transported in vitro by Bcrp1/BCRP, and ivermectin efficiently blocked this transport. Experiments with Bcrp1(-/-) mice showed no evidence of the involvement of Bcrp1 in plasma pharmacokinetics of danofloxacin. However, the milk concentration and milk-to-plasma ratio of danofloxacin were almost twofold higher in wild-type compared with Bcrp1(-/-) mice. The in vivo interaction with ivermectin was studied in sheep after co administration of danofloxacin (1.25 mg/kg, i.m.) and ivermectin (0.2 mg/kg, s.c.). Ivermectin had no significant effect on the plasma levels of danofloxacin but significantly decreased danofloxacin concentrations in milk by almost 40%. Concomitant administration of multiple drugs, often used in veterinary therapy, may not only affect their pharmacological activity but also their secretion into milk, because of potential drug-drug interactions mediated by BCRP. PMID- 20950351 TI - Pharmacokinetics and pharmacodynamics of three intravenous doses of yohimbine in the horse. AB - Yohimbine is an alpha 2 adrenergic receptor antagonist, which has been shown to counteract the CNS depressant effects of alpha 2 receptor agonists in a number of species. Recently, our laboratory identified yohimbine in the absence of detectable concentrations of an alpha 2 agonist in a regulatory sample collected from a horse racing in California. This coupled with anecdotal reports of CNS stimulation and documented reports of cardiovascular changes when administered in conjunction with an agonist led us to investigate the pharmacokinetics and pharmacodynamics of yohimbine when administered alone. Nine healthy adult horses received a single intravenous dose of 0.1, 0.2, and 0.4 mg/kg yohimbine. Blood samples were collected at time 0 (prior to drug administration) and at various times up to 24 h postdrug administration. Plasma samples were analyzed using liquid chromatography-mass spectrometry (LC-MS), and resulting data analyzed using both noncompartmental and compartmental analysis. Peak plasma concentrations were 106.0 +/- 28.9, 156.7 +/- 34.3, and 223.0 +/- 44.5 ng/mL for doses of 0.1, 0.2, and 0.4 mg/kg, respectively. Immediately following administration, two horses showed signs of sedation, one horse appeared excited, while the other six appeared behaviorally unaffected. Episodes of tachycardia were noted within minutes of administration for all horses at all doses; however, there was no correlation between behavioral responses and episodes of increased heart rate. Sixty-three percent of the horses (8, 6, and 4 of the 9 horses in the 0.1, 0.2, and 0.4 mg/kg dose groups, respectively) exhibited second-degree atrial ventricular conduction blocks and bradycardia prior to drug administration that transiently improved or disappeared upon administration of yohimbine. Gastrointestinal sounds were transiently increased following all doses. PMID- 20950352 TI - Ketoprofen in piglets: enantioselective pharmacokinetics, pharmacodynamics and PK/PD modelling. AB - The chiral pharmacokinetics and pharmacodynamics of ketoprofen were investigated in a placebo-controlled study in piglets after intramuscular administration of 6 mg/kg racemic ketoprofen. The absorption half-lives of both enantiomers were short, and S-ketoprofen predominated over R-ketoprofen in plasma. A kaolin induced inflammation model was used to evaluate the anti-inflammatory, antipyretic and analgesic effects of ketoprofen. Skin temperatures increased after the kaolin injection, but the effect of ketoprofen was small. No significant antipyretic effects could be detected, but body temperatures tended to be lower in the ketoprofen-treated piglets. Mechanical nociceptive threshold testing was used to evaluate the analgesic effects. The piglets in the ketoprofen treated group had significantly higher mechanical nociceptive thresholds compared to the piglets in the placebo group for 12-24 h following the treatment. Pharmacokinetic/pharmacodynamic modelling of the results from the mechanical nociceptive threshold testing gave a median IC(50) for S-ketoprofen of 26.7 MUg/mL and an IC(50) for R-ketoprofen of 1.6 MUg/mL. This indicates that R ketoprofen is a more potent analgesic than S-ketoprofen in piglets. Estimated ED(50) for racemic ketoprofen was 2.5 mg/kg. PMID- 20950353 TI - Comparative pharmacokinetics of intravenous cephalexin in pregnant, lactating, and nonpregnant, nonlactating goats. AB - The aims of this study were to describe and compare the pharmacokinetics of a single dose of cephalexin (10 mg/kg) after its intravenous (i.v.) administration to five goats in three different physiological status: nonpregnant nonlactating (NPNL), pregnant (P) and nonpregnant lactating (L). Blood samples were collected at predetermined times, and plasma concentrations of cephalexin were measured by microbiological assay. Relevant pharmacokinetic parameters were calculated using noncompartmental analysis. Statistical comparison was performed applying the nonparametric anova. No significant differences were found for cephalexin pharmacokinetic parameters between the L and the NPNL group. Median V(dss) was significantly lower in pregnant goats (0.09 [0.07-0.10] L/kg) compared with NPNL goats (0.16 [0.14-0.49] L/kg). Median total Cl and V(dz) were significantly lower in pregnant goats (0.25 [0.19-0.29] L/h.kg and 0.11 [0.10-0.13] L/kg, respectively) than in lactating goats (0.40 [0.32-0.57] L/h.kg and 0.20 [0.14 0.23] L/kg, respectively). Median AUC(0-infinity) was significantly higher in pregnant goats (37.79 [34.75-52.10] MUg.h/mL) than in lactating goats (25.11 [17.44-31.14] MUg.h/mL). Our study showed that even though some pharmacokinetic parameters of cephalexin are altered in pregnant and lactating goats, these differences are unlikely to be of clinical importance; therefore, no dose adjustment would be necessary during pregnancy and lactation. PMID- 20950354 TI - A physiologically based pharmacokinetic model for valnemulin in rats and extrapolation to pigs. AB - A flow-limited, physiologically based pharmacokinetic (PBPK) model for predicting the plasma and tissue concentrations of valnemulin after a single oral administration to rats was developed, and then the data were extrapolated to pigs so as to predict withdrawal interval in edible tissues. Blood/tissue pharmacokinetic data and blood/tissue partition coefficients for valnemulin in rats and pigs were collected experimentally. Absorption, distribution and elimination of the drug were characterized by a set of mass-balance equations. Model simulations were achieved using a commercially available software program. The rat PBPK model better predicted plasma and tissue concentrations. The correlation coefficients of the predicted and experimentally determined values for plasma, liver, kidney, lung and muscle were 0.96, 0.94, 0.96, 0.91 and 0.91, respectively. The rat model parameters were extrapolated to pigs to estimate valnemulin residue withdrawal interval in edible tissues. Correlation (R(2) ) between predicted and observed liver, kidney and muscle were 0.95, 0.97 and 0.99, respectively. Based on liver tissue residue profiles, the pig model estimated a withdrawal interval of 10 h under a multiple oral dosing schedule (5.0 mg/kg, twice daily for 7.5 days). PBPK models, such as this one, provide evidence of the usefulness in interspecies PK data extrapolation over a range of dosing scenarios and can be used to predict withdrawal interval in pigs. PMID- 20950355 TI - Experimental spinal cord injury in rats diminishes vagally-mediated gastric responses to cholecystokinin-8s. AB - BACKGROUND: We have shown recently that our model of experimental high-thoracic spinal cord injury (T3-SCI) mirrors the gastrointestinal clinical presentation of neurotrauma patients, whereby T3-SCI animals show diminished gastric emptying and dysmotility. In this study we used cholecystokinin as a model peptide to test the hypothesis that the T3-SCI induced gastroparesis is due, in part, to an impaired vagally-mediated response to gastrointestinal peptides. METHODS: We measured the responses to sulfated cholecystokinin (CCK-8s) in control and T3-SCI (3 or 21 days after injury) rats utilizing: (i) c-fos expression in the nucleus tractus solitarius (NTS) following peripherally administered CCK-8s; (ii) in vivo gastric tone and motility following unilateral microinjection of CCK-8s into the dorsal vagal complex (DVC); and (iii) whole cell recordings of glutamatergic synaptic inputs to NTS neurons. KEY RESULTS: Our results show that: (i) medullary c-fos expression in response to peripheral CCK-8s was significantly lower in T3-SCI rats 3 days after the injury, but recovered to control values at 3 weeks post SCI, (ii) Unilateral microinjection of CCK-8s in the DVC induced a profound gastric relaxation in control animals, but did not induce any response in T3-SCI rats at both 3 and 21 days after SCI, (iii) Perfusion with CCK-8s increased glutamatergic currents in 55% of NTS neurons from control rats, but failed to induce any response in NTS neurons from T3-SCI rats. CONCLUSIONS & INFERENCES: Our data indicate alterations of vagal responses to CCK-8s in T3-SCI rats that may reflect a generalized impairment of gastric vagal neurocircuitry, leading to a reduction of gastric functions after SCI. PMID- 20950356 TI - Rickettsial infections of dogs, horses and ticks in Juiz de Fora, southeastern Brazil, and isolation of Rickettsia rickettsii from Rhipicephalus sanguineus ticks. AB - The present study was performed in an area endemic for Brazilian spotted fever (BSF) in Juiz de Fora, state of Minas Gerais, Brazil, during the years 2007 and 2008, when fatal cases of BSF (caused by Rickettsia rickettsii) were reported. Adult ticks (Acari: Ixodidae) identified as Rhipicephalus sanguineus (Latreille) and Amblyomma cajennense (Fabricius) were collected from dogs and horses, respectively, and tested by polymerase chain reaction (PCR). Overall, 13.1% of the Rh. sanguineus ticks and none of the A. cajennense were found to be infected with R. rickettsii. Two isolates of R. rickettsii were successfully established in Vero cell culture from two Rh. sanguineus ticks. An indirect immunofluorescence assay (IFA) using R. rickettsii antigens detected blood serological reaction to R. rickettsii in 67.9% (53/78) of dogs and 41.0% (16/39) of horses living in the study area. Larval offspring from two Rh. sanguineus engorged females, naturally infected by R. rickettsii, were reared to adult stage in the laboratory. All active stages (larvae, nymphs, adults) remained 100% infected by R. rickettsii, which was efficiently transmitted to naive rabbits. Overall, the results of the present study indicate a potential risk for transmission of R. rickettsii to humans by Rh. sanguineus, an occurrence yet to be documented in Brazil. PMID- 20950357 TI - Changes in molecular composition of rat medial prefrontal cortex synapses during adolescent development. AB - Postnatal brain development continues throughout adolescence into young adulthood. In particular, synapse strengthening and elimination are prominent processes during adolescence. However, molecular data of this relatively late stage of synaptic development are sparse. In this study, we used iTRAQ (isobaric tag for relative and absolute quantification)-based proteomics and electron microscopy to investigate the molecular composition of a synaptic membrane fraction from adolescent postnatal day (P)34 and P44 and adult (P78) rat medial prefrontal cortex. Differential expression of proteins was most prominent between early adolescence and young adulthood (35%, P34-P78), with an over-representation of cell-membrane proteins during adolescent development (between P34 and P44), and synaptic vesicle proteins between late adolescence and young adulthood (P44 P78). Indicative of the critical period of development, we found that, between P34 and P44, a substantial number of proteins was differentially expressed (14%), much more than during the period after adolescence, i.e. between P44 and P78 (5%). A striking observation was the developmental non-stoichiometric regulation of distinct classes of proteins from the synaptic vesicle and the presynaptic release machinery. Electron microscopy demonstrated a small change in the number of docked vesicles between P34 and P44, but not in the total number of synaptic vesicles and in the size of the vesicle cluster. We conclude that the molecular composition of synapses, and more specifically the synaptic release machinery, of the medial prefrontal cortex changes drastically during adolescent development. PMID- 20950358 TI - Continuous and intermittent transcranial magnetic theta burst stimulation modify tactile learning performance and cortical protein expression in the rat differently. AB - Repetitive transcranial magnetic stimulation (rTMS) can modulate cortical excitability in a stimulus-frequency-dependent manner. Two kinds of theta burst stimulation (TBS) [intermittent TBS (iTBS) and continuous TBS (cTBS)] modulate human cortical excitability differently, with iTBS increasing it and cTBS decreasing it. In rats, we recently showed that this is accompanied by changes in the cortical expression of proteins related to the activity of inhibitory neurons. Expression levels of the calcium-binding protein parvalbumin (PV) and of the 67-kDa isoform of glutamic acid decarboxylase (GAD67) were strongly reduced following iTBS, but not cTBS, whereas both increased expression of the 65-kDa isoform of glutamic acid decarboxylase. In the present study, to investigate possible functional consequences, we applied iTBS and cTBS to rats learning a tactile discrimination task. Conscious rats received either verum or sham rTMS prior to the task. Finally, to investigate how rTMS and learning effects interact, protein expression was determined for cortical areas directly involved in the task and for those either not, or indirectly, involved. We found that iTBS, but not cTBS, improved learning and strongly reduced cortical PV and GAD67 expression. However, the combination of learning and iTBS prevented this effect in those cortical areas involved in the task, but not in unrelated areas. We conclude that the improved learning found following iTBS is a result of the interaction of two effects, possibly in a homeostatic manner: a general weakening of inhibition mediated by the fast-spiking interneurons, and re-established activity in those neurons specifically involved in the learning task, leading to enhanced contrast between learning-induced and background activity. PMID- 20950359 TI - Melatonin prevents hypertension and increased asymmetric dimethylarginine in young spontaneous hypertensive rats. AB - Nitric oxide (NO) deficiency is associated with development of hypertension. We examined whether melatonin protects against the blood pressure increase is because of the restoration of the NO pathway. Spontaneous hypertensive rats (SHR) and control normotensive Wistar Kyoto (WKY) rats aged 4 weeks were assigned to four groups (N=6 for each group): untreated SHR and WKY, melatonin-treated SHR and WKY. Melatonin-treated rats received 0.01% melatonin in drinking water for 8 wks. All rats were sacrificed at 12 wk of age. SHR had higher blood pressure than WKY, which melatonin prevented. Plasma asymmetric dimethylarginine (ADMA) levels were elevated in SHR, combined with a reduction in plasma L-arginine to ADMA ratio (AAR). In the kidney, L-arginine, ADMA, and AAR were not different between SHR and WKY rats, whereas L-citrulline level was increased in SHR. Melatonin decreased plasma ADMA level and restored plasma AAR. Renal dimethylarginine dimethylaminohydrolase (DDAH, ADMA-metabolizing enzyme) activity was lower in SHR than WKY rats, which melatonin therapy prevented. Also, melatonin elevated both L arginine and ADMA but reduced L-citrulline level in the kidney in SHR, which was associated with the prevention of reduced renal argininosuccinate lyase (ASL) expression in SHR. Moreover, melatonin reduced the degree of oxidative damaged DNA product, 8- hydroxydeoxyguanosine (8-OHdG) immunostaining in SHR. The observed antihypertensive effects of melatonin in young SHR are because of the restoration of the NO pathway by reduction of plasma ADMA, restoration of plasma AAR, preservation of renal L-Arg availability, and attenuation of oxidative stress. PMID- 20950361 TI - Intracytoplasmic adipophilin immunopositivity: a pitfall in the distinction of metastatic renal carcinoma from sebaceous carcinoma. PMID- 20950362 TI - The amazin' mets. PMID- 20950363 TI - Acquired elastotic hemangioma: ten cases with immunohistochemistry refuting a lymphatic origin in most lesions. PMID- 20950365 TI - Peripheral nerve regeneration in the MRL/MpJ ear wound model. AB - The MRL/MpJ mouse displays an accelerated ability to heal ear punch wounds without scar formation (whereas wounds on the dorsal surface of the trunk heal with scar formation), offering a rare opportunity for studying tissue regeneration in adult mammals. A blastema-like structure develops and subsequently the structure of the wounded ear is restored, including cartilage, skin, hair follicles and adipose tissue. We sought to assess if the MRL/MpJ strain also possessed an enhanced capacity for peripheral nerve regeneration. Female MRL/MpJ and C57BL/6 mice were wounded with a 2-mm excisional biopsy punch to the centre of each ear and two 4-mm excisional biopsy punches to the dorsal skin. Immunohistochemical dual staining of pan-neurofilament and CD31 markers was used to investigate reinnervation and vascularisation of both the dorsal surface of the trunk and ear wounds. The MRL/MpJ mouse ear exhibited a significantly (P > 0.01) higher density of regenerated nerves than C57BL/6 between 10 and 21 days post-wounding when the blastema-like structure was forming. Unlike dorsal skin wounds, nerve regeneration in the ear wound preceded vascularisation, recapitulating early mammalian development. Immunohistochemical data suggest that factors within the blastemal mesenchyme, such as aggrecan, may direct nerve regrowth in the regenerating ear tissue. PMID- 20950366 TI - Intraocular lens short wavelength light filtering. AB - There is increasing interest in the effects of reactive oxygen species ('free radicals') in ageing, both in the body overall and specifically in the eye. Cataract and age-related macular degeneration (AMD) are two major causes of blindness, with cataract accounting for 48 per cent of world blindness and AMD accounting for 8.7 per cent. Both cataract and AMD affect an older population (over 50 years of age) and while cataract is largely treatable provided resources are available, AMD is a common cause of untreatable, progressive visual loss. There is evidence that AMD is linked to exposure to short wavelength electromagnetic radiation, which includes ultraviolet, blue and violet wavelengths. The ageing crystalline lens provides some protection to the posterior pole because, as it yellows with age, its spectral absorption increasingly blocks the shorter wavelengths of light. Ultraviolet blocking intraocular lenses (IOLs) have been the standard of care for many years but a more recent trend is to include blue-blocking filters based on theoretical benefits. As these filters absorb part of the visible spectrum, they may affect visual function. This review looks at the risks and the benefits of filtering out short wavelength light in pseudophakic patients. PMID- 20950367 TI - Association of vascular endothelial growth factor gene polymorphisms with recurrent spontaneous abortion in Chinese Han women. AB - PROBLEM: An association of polymorphism -1154G/A (rs1570360) in vascular endothelial growth factor (VEGF) gene with idiopathic recurrent spontaneous abortion (RSA) has been found in Caucasians. The aim of this study was to examine the association of VEGF -1154 with RSA in a well-defined group of Chinese Han patients. METHOD OF STUDY: The VEGF -1154G/A genotype was detected by real-time PCR with TaqMan probes. The products were also subjected to gene sequence analysis to validate the PCR results. RESULTS: The allele frequencies of VEGF 1154G/A showed no significant difference between RSA patients and the normal controls (P = 0.183). The frequencies of VEGF -1154G/A genotypes were not significantly different between RSA patients and the normal controls (P = 0.228). CONCLUSION: Our study revealed that VEGF -1154G/A polymorphism was not associated with the susceptibility to RSA in Chinese Han women. PMID- 20950368 TI - An exploration of the lived experiences of individuals with relapsed multiple myeloma. AB - The experience of living with relapsed Multiple Myeloma (myeloma) for eight patients accessing treatment within a haematology unit in a large London hospital is explored in this study. Myeloma is recognised as incurable and is sometimes described as an 'incurable chronic disease' with a main treatment option of chemotherapy. Hermeneutic phenomenology was the methodology used in conducting the study and data were collected through open-ended, unstructured interviews. Findings suggest that living with relapsed myeloma in the context of a chronic illness causes an ever-shifting perspective between illness and wellness consequently maintaining a state of uncertainty. The patients in this study placed importance on the emotional aspect of their experience. Hope, intuitive knowing and a fighting spirit were expressed as required positive elements that enabled living with relapsed myeloma. These assisted in maintaining normality, coping with bad news and adjusting to the illness. Pervading through the themes was the need to control uncertainty. Having strong support from significant others provided something to live for and the necessary social support required to promote a new orientation to life. PMID- 20950370 TI - Overexpression of DeltaNp63alpha induces a stem cell phenotype in MCF7 breast carcinoma cell line through the Notch pathway. AB - To elucidate a role of DeltaNp63alpha in breast cancer, the expression levels of p63, estrogen receptor, progesterone receptor, p53, CK5, cerBb-2, and Notch1 were assayed in 50 clinical breast cancer specimens using immunochemistry. P63 was highly expressed in a subset of breast cancer with basal-like features. We then transfected MCF7 cells with DeltaNp63alpha plasmid, and assayed its cancer stem cell-like features after transfection. Overexpression of DeltaNp63alpha in MCF7 cells increased the percentage of CD24(-) CD44(+) subpopulation from 2.2+/-0.2% to 25.1+/-1.5% (P<0.05) and led to increased cancer cell proliferation, clonogenicity, anchorage-independent growth, and the incidence of xenograft grown in vivo. In addition, DeltaNp63alpha overexpressing cancer cells were more drug resistant. Further studies suggested DeltaNp63alpha-induced activation of the Notch pathway may play a role in these effects. Chromatin immunoprecipitation confirmed that DeltaNp63alpha could directly bind to Notch1. In clinical breast cancer specimens, the expression level of p63 was also found to positively correlate with the expression level of Notch1. Our results suggest that DeltaNp63alpha might serve as a tumor initiating transcription factor in breast cancer. PMID- 20950372 TI - Past and current tendency for facial flushing after a small dose of alcohol is a marker for increased risk of upper aerodigestive tract cancer in Japanese drinkers. PMID- 20950371 TI - Pilot study to relate clinical outcome in pancreatic carcinoma and angiogenic plasma factors/circulating mature/progenitor endothelial cells: Preliminary results. AB - Circulating endothelial cells (CEC) and bone marrow-derived endothelial progenitors (ECP) play important roles in tumor growth and have been proposed as non-invasive markers of angiogenesis. However, CEC and ECP levels have not been investigated in pancreatic carcinoma patients. Using four-color flow cytometry procedures, we evaluated the count of resting (rCEC) and activated (aCEC) endothelial cells and ECP in the peripheral blood of pancreatic carcinoma patients before and after chemotherapy, consisting of gemcitabine (GEM) alone or in combination with oxaliplatin (OX), or with 5-fluorouracil (5-FU). We also correlated CEC and ECP levels with plasma levels of relevant angiogenic factors, such as vascular endothelial growth factor (VEGF)-A, VEGF-D, angiopoietin (Angio) 1, and chemokine C-X-C motif ligand (CXCL)12, measured by ELISA, and with clinical features of pancreatic cancer. The aCEC, rCEC, ECP, and VEGF-A plasma levels were significantly higher in locally-advanced and metastatic patients than controls. Both ECP and VEGF-A levels correlated positively with disease stage and inversely with patient's overall survival. Measurements after the treatment course showed that VEGF-A plasma concentrations and ECP counts had decreased significantly. In particular, VEGF-A and rCEC were significantly down after treatment with GEM alone or in combination with OX. No significant differences in terms of circulating angiogenic factor or endothelial cell subtype levels were found between responders (patients entering partial remission or with stable disease) and non-responders (patients with progressive disease). The study provides insights into angiogenesis mechanisms in pancreatic carcinoma, for which anti-angiogenic targeting of VEGF-A and ECP could be of interest. PMID- 20950374 TI - Mammaglobin RT-qPCR for breast cancer metastasis detection in sentinel lymph nodes. PMID- 20950376 TI - Identification of disease-associated DNA methylation in intestinal tissues from patients with inflammatory bowel disease. AB - Overwhelming evidence supports the theory that inflammatory bowel disease (IBD) is caused by a complex interplay between genetic predispositions of multiple genes, combined with an abnormal interaction with environmental factors. It is becoming apparent that epigenetic factors can have a significant contribution in the pathogenesis of disease. Changes in the methylation state of IBD-associated genes could significantly alter levels of gene expression, potentially contributing to disease onset and progression. We have explored the role of DNA methylation in IBD pathogenesis. DNA methylation profiles (1505 CpG sites of 807 genes) of matched diseased (n = 26) and non-diseased (n = 26) intestinal tissues from 26 patients with IBD [Crohn's disease (CD) n = 9, ulcerative colitis (UC) n = 17] were profiled using the GoldenGateTM methylation assay. After an initial identification of a panel of 50 differentially methylated CpG sites from a training set (14 non-diseased and 14 diseased tissues) and subsequent validation with a testing set (12 non-diseased and 12 diseased tissues), we identified seven CpG sites that are differentially methylated in intestinal tissues of IBD patients. We have also identified changes in DNA methylation associated with the two major IBD subtypes, CD and UC. This study reports IBD-associated changes in DNA methylation in intestinal tissue, which may be disease subtype-specific. PMID- 20950377 TI - Two novel WTX mutations underscore the unpredictability of male survival in osteopathia striata with cranial sclerosis. AB - Osteopathia striata with cranial sclerosis (OMIM ##300373) is an X-linked dominant sclerosing bone dysplasia that presents in females with macrocephaly, cleft palate, mild learning disabilities, sclerosis of the long bones and skull, and longitudinal striations visible on radiographs of the long bones, pelvis, and scapulae. In males this entity is usually associated with foetal or neonatal lethality, because of severe heart defects and/or gastrointestinal malformations, and is often accompanied by bilateral fibula aplasia. Recently, the disease causing gene was identified as the WTX gene (FAM123B). Initially it was suggested that the mutations in the 5' region of the WTX gene are associated with male lethality. Mutation analysis in individuals of two families diagnosed with OSCS revealed two novel WTX mutations. In one family, the affected male is still alive in his teens. These mutations underline the unpredictability of male survival and suggest that WTX mutations should be considered in cases of male cranial sclerosis, even if striations are not present. An overview of all known mutations and their associated characteristics provide a valuable resource for the molecular analysis of OSCS. PMID- 20950378 TI - Telephone follow-up to improve glycaemic control in patients with Type 2 diabetes: systematic review and meta-analysis of controlled trials. AB - OBJECTIVE: To examine the impact of telephone follow-up interventions on glycaemic control in patients with Type 2 diabetes. METHODS: This was a systematic review and meta-analysis of randomized controlled trials using The Cochrane Library, including the Cochrane central register of controlled trials; MEDLINE, EMBASE, PsycINFO and CINHAL, together with citation searching. The included studies were randomized controlled trials examining the effect of a telephone follow-up intervention on glycaemic control in patients with Type 2 diabetes. All the included trials were subject to critical appraisal. Data were extracted on study design, characteristics of patients, exact nature of the telephone intervention and details of comparison. Pooled standardized effects were calculated for the primary outcome. Glycaemic control was measured by HbA(1c) . RESULTS: HbA(1c) levels reported in the reviewed studies were pooled using random effects models. The standardized effect of telephone follow-up was equivocal, with endpoint data showing weighted mean differences of -0.44 (95% CI 0.93 to 0.06) (Z = -1.72, P=0.08) in favour of the telephone follow-up intervention. Subgroup analysis of more intensive interventions (interactive follow-up with health professional plus automated follow-up or non-interactive follow-up) showed (n=1057) a significant benefit in favour of the treatment group, with a standardized mean difference of -0.84 (95% CI -1.67 to 0.0) (Z=1.97, P=0.05), indicating that more intensive (targeted) modes of follow-up may have better effects on glycaemic control. CONCLUSIONS: The analysis suggested that telephone follow-up interventions following a more intensive targeted approach could have a positive impact on glycaemic control for Type 2 diabetes. PMID- 20950379 TI - Effects of ethnicity on diabetes incidence and prevention: results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial. AB - AIMS: Risk of Type 2 diabetes varies by ethnicity, but whether ethnicity remains important among those who have impaired glucose tolerance or impaired fasting glucose is uncertain. Whether the effect of thiazolidinedione treatment on diabetes prevention in persons with non-diabetic dysglycaemia varies by ethnicity is also not known. We addressed these questions using data collected in the DREAM trial. METHODS: A 2-by-2 factorial double-blind randomized controlled trial to compare the effects of rosiglitazone and ramipril on the primary outcome of diabetes or death in persons meeting criteria for impaired glucose tolerance or impaired fasting glucose. The effect of these interventions by ethnicity was estimated using Cox regression analysis. RESULTS: Of 5269 adults, 2365 were randomly assigned to rosiglitzone and 2634 to placebo. South Asians showed a higher hazard for the primary outcome compared with Europeans (hazard ratio, 95% confidence interval 2.21, 1.41-3.47) adjusted for age, gender, BMI, waist-hip ratio and geographic region. A lesser increase in risk was seen in Black people (1.37, 1.04-1.81). A significant reduction in risk of the primary outcome with rosiglitazone treatment assignment was seen in all ethnic groups, but the treatment effect significantly differed by ethnicity (P=0.0242), with South Asians experiencing a smaller, and Latinos a larger preventive effect. CONCLUSIONS: Ethnicity is an important risk factor for Type 2 diabetes in dysglycaemic persons. All ethnic groups experienced a large significant reduction in diabetes risk because of rosiglitazone. The magnitude of this reduction differed by ethnicity. Given the post hoc nature of this analysis, further confirmation of these findings is needed. PMID- 20950380 TI - Trends of diabetes according to body mass index levels in Iran: results of the national Surveys of Risk Factors of Non-Communicable Diseases (1999-2007). AB - AIMS: The prevalence of diabetes is increasing dramatically worldwide. Less is known about whether this trend is similar among obese and lean individuals. METHODS: We analysed the data sets of three cross-sectional national surveys in adults aged 25-64 years: the National Health Survey-1999 (n=21,576), and the national Surveys of Risk Factors of Non-Communicable Diseases (SuRFNCD)-2005 (n=70,981) and SuRFNCD-2007 (n=4233). Diagnosed diabetes was ascertained, and height and weight were measured in all surveys. In SuRFNCD-2005 and SuRFNCD-2007, fasting plasma glucose was used to identify subjects with newly diagnosed diabetes (>= 7 mmol/l) and impaired fasting glucose (5.6 - 6.9 mmol/l) among individuals not reporting diabetes. RESULTS: The prevalence of diagnosed diabetes (after adjustment for age, sex and residential area) was 2.5, 4.0 and 4.6% in 1999, 2005 and 2007, respectively. The total prevalence of diabetes increased from 7.7% in 2005 to 8.7% in 2007, about half of which was attributed to newly diagnosed disease (in both surveys). The prevalence of diabetes increased in all categories of obesity, with the most evident trend being among subjects with body mass index <25 kg/m(2) . CONCLUSIONS: The prevalence of diabetes among Iranian adults has increased more than 1.8-fold in a period of only 8 years since 1999. This is the first report from Iran, and urgent measures need to be taken in order to prevent the progression and worsening of the problem and emergence of its undesired consequences. PMID- 20950381 TI - Alcohol drinking, the metabolic syndrome and diabetes in a population with high mean alcohol consumption. AB - AIMS: To investigate the relationship of alcohol consumption with the metabolic syndrome and diabetes in a population-based study with high mean alcohol consumption. Few data exist on these conditions in high-risk drinkers. METHODS: In 6172 adults aged 35-75 years, alcohol consumption was categorized as 0, 1-6, 7 13, 14-20, 21-27, 28-34 and >= 35 drinks/week or as non-drinkers (0), low-risk (1 13), medium-to-high-risk (14-34) and very-high-risk (>= 35) drinkers. Alcohol consumption was objectively confirmed by biochemical tests. In multivariate analysis, we assessed the relationship of alcohol consumption with adjusted prevalence of the metabolic syndrome, diabetes and insulin resistance, determined with the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Seventy-three per cent of participants consumed alcohol, 16% were medium-to-high risk drinkers and 2% very-high-risk drinkers. In multivariate analysis, the prevalence of the metabolic syndrome, diabetes and mean HOMA-IR decreased with low-risk drinking and increased with high-risk drinking. Adjusted prevalence of the metabolic syndrome was 24% in non-drinkers, 19% in low-risk (P<0.001 vs. non drinkers), 20% in medium-to-high-risk and 29% in very-high-risk drinkers (P=0.005 vs. low-risk). Adjusted prevalence of diabetes was 6.0% in non-drinkers, 3.6% in low-risk (P<0.001 vs. non-drinkers), 3.8% in medium-to-high-risk and 6.7% in very high-risk drinkers (P=0.046 vs. low-risk). Adjusted HOMA-IR was 2.47 in non drinkers, 2.14 in low-risk (P<0.001 vs. non-drinkers), 2.27 in medium-to-high risk and 2.53 in very-high-risk drinkers (P=0.04 vs. low-risk). These relationships did not differ according to beverage types. CONCLUSIONS: Alcohol has a U-shaped relationship with the metabolic syndrome, diabetes and HOMA-IR, without differences between beverage types. PMID- 20950382 TI - Hypoglycaemia increases aldosterone in a dose-dependent fashion. AB - AIMS: Intensive glycaemic control increases the incidence of hypoglycaemia. We sought to define the effects of hypoglycaemia on aldosterone, a hormone involved in cardiovascular injury and baroreflex impairment. METHODS: To contrast the effects of hypoglycaemia and euglycaemia on aldosterone and plasma renin activity, in Study 1, we assessed hormone levels in 13 subjects who participated in euglycaemic (5.0 mmol/l) and hypoglycaemic (2.8 mmol/l) hyperinsulinaemic clamp protocols in random order. To determine the relationship between aldosterone and the depth of hypoglycaemia, in Study 2, we assessed hormone levels in an additional 13 subjects who participated in a 3-h stepped hypoglycaemic hyperinsulinaemic clamp protocol; blood glucose was reduced in 0.55 mmol/l steps from 5.0 to 2.2 mmol/l. Subjects were healthy and consumed controlled sodium diets. RESULTS: In Study 1, aldosterone increased approximately 2.5-fold during hypoglycaemic hyperinsulinaemia, P<0.001, but did not rise with euglycaemic hyperinsulinaemia. Plasma renin activity increased during both hyperinsulinaemic clamps; however, the increase was greater during hypoglycaemia (Delta=1.5 +/- 0.2 ng ml(-1) h(-1) ) vs. euglycaemia (Delta=0.5 +/- 0.1 ng ml(-1) h(-1) ), P<0.005. In Study 2, aldosterone increased significantly at glucose levels of 2.8 mmol/l; this increase was amplified with glucose of 2.2 mmol/l. Aldosterone increases paralleled those of ACTH. CONCLUSIONS: Hypoglycaemia increases aldosterone in a dose-dependent fashion. This increase is likely attributable to activation of the renin-angiotensin-aldosterone system and increases in ACTH. Because aldosterone activation of the mineralocorticoid receptor is implicated in the pathophysiology of cardiovascular injury, including vascular dysfunction, inflammation, baroreflex impairment and cardiac arrhythmias, these findings may be of relevance in individuals who experience hypoglycaemia. PMID- 20950383 TI - The effect of increased ambulatory activity on markers of chronic low-grade inflammation: evidence from the PREPARE programme randomized controlled trial. AB - AIMS: To investigate whether an exercise intervention programme, with or without pedometer use, is effective at reducing chronic low-grade inflammation in those with impaired glucose tolerance. METHODS: Using baseline and 12-month data from the Pre-diabetes Risk Education and Physical Activity Recommendation and Encouragement (PREPARE) programme randomized controlled trial, we investigated whether the pedometer or the standard version of the PREPARE programme is associated with reduced chronic low-grade inflammation. Outcomes included interleukin-6, C-reactive protein, fasting and 2 h post-challenge glucose values and objectively measured ambulatory activity. RESULTS: Seventy-four participants (31% female; mean age, 65 years; body mass index, 29.3 +/- 4.8 kg/m(2) ) were included, of which 26 were in the control group and 24 were in each intervention group. At 12 months there was an increase in ambulatory activity of 1351 and 1849 steps/day in the standard and pedometer group, respectively, compared with control conditions; however, there was no significant change in markers of chronic low-grade inflammation. Across the pooled study sample, change in ambulatory activity was significantly correlated with change in interleukin-6 (r = -0.32, P = 0.01) after adjustment for group, age, sex, ethnicity, aspirin and statin medication, baseline body mass index and change in body mass index. Change in interleukin-6 was also significantly correlated with change in 2 h glucose after adjustment for the same variables (r = 0.26, P = 0.03). CONCLUSIONS: This study failed to show reductions in markers of chronic low-grade inflammation following an intervention that promoted modest increases in ambulatory activity; however, across the study sample, increased ambulatory activity was associated with reduced interleukin-6, independent of obesity. PMID- 20950384 TI - Cord blood telomere length, telomerase activity and inflammatory markers in pregnancies in women with diabetes or gestational diabetes. AB - AIMS: We tested the hypothesis that diabetes during pregnancy leads to chromosomal DNA damage and telomere attrition in the feto placental unit and cord blood, and provides evidence for intrauterine programming towards a senescent phenotype in the offspring. METHODS: We obtained cord blood from pregnant women with pregestational Type 1 diabetes (n=26), Type 2 diabetes (n=20) or gestational diabetes (n=71), and control subjects without diabetes (n=45, n=76 and n=81, respectively) matched for maternal and gestational age. We measured cord blood mononuclear cell telomere length, telomerase activity (a reverse transcriptase that limits telomere attrition), and concentrations of insulin, high-sensitivity C-reactive protein (hs-CRP) and soluble intercellular adhesion molecule-1 (sICAM 1). RESULTS: We found no significant differences between groups in cord blood telomere length in any nucleated cell type, or in hs-CRP or sICAM-1 concentrations, but telomerase activity was higher in cord blood from Type 1 (P<0.05) and gestational diabetes pregnancies (P<0.05), but not in Type 2 diabetes pregnancies. There were no significant relationships between glycaemic control, cord blood telomere length, telomerase activity or inflammatory markers in any group. CONCLUSIONS: We found no difference in cord blood telomere length in pregnancies of women with diabetes compared with control subjects, but higher cord blood telomerase activity in Type 1 and gestational diabetes. This may reflect upregulated telomere reverse transcriptase in response to in utero oxidative DNA and telomere damage. These observations are relevant to the hypothesis that diabetes during pregnancy leads to in utero preprogramming towards senescence in the offspring. PMID- 20950385 TI - Short-term metabolic change is associated with improvement in measures of diabetic neuropathy: a 1-year placebo cohort analysis. AB - AIMS: Randomized clinical trials have frequently shown improvement in diabetic sensorimotor polyneuropathy in placebo-treated participants, counter to the prevailing concept that it deteriorates with time. We aimed to determine the variables associated with this paradoxical nerve function improvement. METHODS: Participants with diabetic sensorimotor polyneuropathy randomized to placebo in a multi-centre, double-blind study were evaluated for the primary outcome of 1-year change in the summed sensory nerve conduction velocity of the bilateral sural and non-dominant median nerves. Association with clinical and biochemical variables measured at 13 time points were examined. RESULTS: The 134 participants had mild to moderate diabetic sensorimotor polyneuropathy of 4.6 years' duration and mean 1-year improvement of 2.0 +/- 8.0 m/s. Primary outcome measures were available for 122 participants (91%). In multivariate analyses, the change in HbA(1c) and serum triglycerides from baseline to 2 months demonstrated the strongest association, even independent of baseline and end-of-study levels. According to quintiles of change, we determined thresholds: participants with salutary improvement in HbA(1c) (exceeding a drop of -0.8%) or whose triglycerides did not increase (by 0.32 mmol/l or more) experienced significant improvement (2.9 m/s), while those with salutary levels of both these variables had an exaggerated improvement (5.1 m/s). In comparison, those with non-salutary changes in both variables experienced a loss of -4.9 m/s (ANOVA P=0.0014). CONCLUSIONS: In mild to moderate diabetic sensorimotor polyneuropathy, short-term improvements in glycaemic control and serum triglyceride levels have an independent, additive and durable effect on restoration of nerve function. PMID- 20950386 TI - Effects of saliva substitutes on oral status in patients with Type 2 diabetes. AB - AIMS: To assess oral status in a sample of Type 2 diabetic patients before and after therapy with saliva substitutes and oral status in a control group of diabetic patients who were not given saliva substitutes. METHODS: Salivary flow rate was determined in 134 patients (mean age 47.9 +/- 2.9 years) with Type 2 diabetes. Mean salivary rate was significantly low compared with a healthy control group. The sample of 134 patients was randomly divided into two groups of 67 people each. One group was given immunologically active salivary substitutes for 6 months, the other group was given nothing. Each patient of the two groups underwent a dental and periodontal examination at the beginning of the study and 6 months later. RESULTS: As regards carious teeth and teeth loss, there was no statistical difference between the first group after 6 months of treatment with salivary substitutes and the control group (P>0.01). Salivary substitutes did not significantly reduce the periodontal disease (P>0.01). In the group treated with salivary substitutes, after 6 months of therapy, the average dental plaque index decreased from 2.3 +/- 0.73 to 1.6 +/- 0.56, patients with gingivitis decreased from 66 to 43% and patients with positive yeast counts decreased from 60 to 37%. These differences were statistically significant (P<0.01). CONCLUSIONS: In Type 2 diabetes, in the case of hyposalivation, a therapy with immunologically active saliva substitutes can be of help in reducing the amount of plaque, gingivitis and positive yeast counts. PMID- 20950387 TI - Persistent individual tracking within overall improvement in HbA1c in a UK paediatric diabetes clinic over 15 years. AB - INTRODUCTION: There is some evidence of long-term tracking of HbA(1c) levels within diabetes centres, but little evidence of individual tracking. METHODS: HbA(1c) levels of children in the clinic over a period of 15 years were retrieved from the clinical chemistry laboratory information system. We measured the correlation of HbA(1c) between years (Spearman and Pearson rank correlation), as well as the relationship of HbA(1c) with age and the change over time in the clinic. RESULTS: Data were collected from 362 children and young people [158 female (44%)], aged 0-18 years (median 10.4 years), with 0-13.6 years of follow up (median 4.7 years). Mean HbA(1c) levels fell from 9.3 +/- 1.5% (78 +/- 16 mmol/mol) in 2001 to 8.1 +/- 1.3% (65 +/- 14 mmol/mol) in 2009 in those at least 6 months after diagnosis (P<0.0001). HbA(1c) levels gradually rise with increasing age. HbA(1c) levels from year to year are significantly correlated. This is better for adjacent than subsequent years, but there is a significant correlation up to 9 years from diagnosis. Only 4 of 49 children with a 6-month HbA(1c) level of 9% (75 mmol/mol) or more had a long-term (2-5 years) median HbA(1c) <8% (64 mmol/mol). CONCLUSIONS: HbA(1c) levels track in individuals within an improvement in overall clinic levels, suggesting that, if optimal control can be achieved in the first 6 months, it can persist for up to 9 years. PMID- 20950388 TI - Diabetes management of elective hospital admissions. AB - AIMS: At any given time, people with diabetes occupy approximately 10-20% of acute hospital beds. In addition, diabetes is associated with a greater length of stay. Patients undergoing elective procedures occupy approximately 50% of hospital beds. The aim of this 12-month project was to improve the quality of diabetes care for elective inpatients. The primary outcome measure was length of stay. METHODS: A team was established to improve the quality of care and reduce the length of stay of all patients admitted electively with diabetes. Specific areas of focus were surgical pre-assessment, planning the admission, post operative care and planning a safe discharge. A retrospective audit of all elective patients with a coded diagnosis of diabetes admitted between June 2008 and June 2009 was performed. RESULTS: Comparing the year of the project with the preceding year day-case rates for patients with diabetes increased by 34.8% for diabetes vs. 13.7% for the total hospital population (P for difference=0.048). There was a significant fall in diabetes length of stay of 0.34 days comparing 2008 and 2009 (P=0.040). Over the same period, we have shown a smaller reduction in length of stay for all other admissions of 0.08 days (p=0.039). CONCLUSION: A team specifically employed to focus on elective inpatient diabetes care have a significant impact on length of stay of this patient group with potential cost savings. PMID- 20950389 TI - Predictors of incident major depression in diabetic outpatients with subthreshold depression. AB - AIMS: The objective of the study was to determine rates and risks of major depression in diabetes outpatients with subthreshold depression. METHODS: This study is based on data of a stepped care-based intervention study in which diabetic patients with subthreshold depression were randomly allocated to low intensity stepped care, aimed at reducing depressive symptoms, or to care as usual. Patients had a baseline Center for Epidemiologic Studies Depression Scale (CES-D) score >= 16, but no baseline major depression according to the Mini International Neuropsychiatric Interview (MINI). Demographic, biological and psychological characteristics were collected at baseline. The MINI was used to determine whether participants had major depression during 2-year follow-up. Predictors of major depression were studied using logistic regression models. RESULTS: Of the 114 patients included at baseline, 73 patients were available at 2-year follow-up. The 2-year incidence of major depression was 42% (n=31). Higher baseline anxiety levels [odds ratio (OR)=1.25; 95% confidence interval (CI), 1.04 1.50; P=0.018] and depression severity levels (OR=1.09; 95% CI, 1.00-1.18; P=0.045) were predictors of incident major depression. Stepped care allocation was not related to incident major depression. In multivariable models, similar results were found. CONCLUSIONS: Having a higher baseline level of anxiety and depression appeared to be related to incident major depression during 2-year follow-up in diabetic patients with subthreshold depression. A stepped care intervention aimed at depression alone did not prevent the onset of depression in these patients. Besides level of depression, anxiety might be taken into account in the prevention of major depression in diabetic patients with subthreshold depression. PMID- 20950390 TI - Malignant melanoma misdiagnosed as a diabetic foot ulcer. PMID- 20950391 TI - Challenges in the management of a young child with Type 1 diabetes mellitus in a family of profoundly deaf parents. PMID- 20950392 TI - High prevalence of obstructive sleep apnoea syndrome in a Type 1 diabetic adult population: a pilot study. PMID- 20950393 TI - Medical student evaluation of clinical teaching sessions in diabetes and endocrinology: a quantitative analysis based on formatted feedback over 1 year. PMID- 20950394 TI - Clinical application of best practice guidelines for the genetic diagnosis of MODY2 and MODY3. PMID- 20950395 TI - Familial Simpson-Golabi-Behmel syndrome: studies of X-chromosome inactivation and clinical phenotypes in two female individuals with GPC3 mutations. AB - Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth/multiple congenital anomalies syndrome with an X-linked inheritance. Most cases of SGBS are attributed to mutations in the glypican 3-gene (GPC3), which is highly expressed in the mesodermal embryonic tissues and involves in a local growth regulation. Typical clinical features include pre/postnatal overgrowth, developmental delay, macrocephaly, characteristic facies with prominent eyes and macroglossia, diaphragmatic hernia, congenital heart defects, kidney anomalies, and skeletal anomalies. Obligate carrier females with GPC3 mutations are usually asymptomatic or with mild symptoms. It is thought that skewed X-inactivation is the underlining mechanism for the female patients to present with findings of SGBS. We identified three siblings with typical SGBS (two male and one female cases) and their mother with very mild symptoms in a family carrying c.256C>T (p.Arg86X) mutation in GPC3. X-inactivation studies on the androgen-receptor gene (AR) and the Fragile XE (FRAXE) gene were performed with blood, buccal swabs, and fibroblasts in the carrier females. The studies with blood showed moderately skewed X-inactivation with paternal X-chromosome being preferentially inactivated (71-80% inactivated) in the female patient with SGBS and no skewing was shown in the mother with very mild symptoms. The X-inactivation studies in the mother showed inactivation of the X-chromosome with the mutation by 57%. This suggests that loss of the functional GPC3 protein by 43% is closed to the threshold to develop the SGBS phenotype. Studies with buccal swabs and fibroblasts failed to show different X-inactivation patterns between the two female individuals. PMID- 20950396 TI - Family history, BRCA mutations and breast cancer in Vietnamese women. AB - The purpose of this report is to estimate the proportions of familial and hereditary breast cancers among unselected cases of breast cancer in Vietnam. Two hundred and ninety-two unselected cases of incident breast cancer were recruited from the National Cancer Hospital, Hanoi, the largest cancer centre in Vietnam. Family histories were collected for 292 cases and a DNA sample was obtained for 259 cases. DNA samples were screened for mutations in the large exons of BRCA1 and BRCA2 using the protein truncation test and by allele-specific testing for 17 founder mutations which have been reported in other Asian populations. Complete gene sequencing was performed on two cases of familial breast cancer. Seven of 292 cases reported a relative with breast cancer and one patient reported a relative with ovarian cancer. A pathogenic BRCA mutation was detected in 2 of 259 cases; one BRCA1 carrier was diagnosed at age 51 and one BRCA2 carrier was diagnosed at age 42. Neither case reported a relative with breast or ovarian cancer. A family history of breast cancer is very uncommon among Vietnamese breast cancer patients. The frequency of pathogenic BRCA mutations in Vietnamese breast cancer patients is among the lowest reported worldwide. PMID- 20950397 TI - The Renpenning syndrome spectrum: new clinical insights supported by 13 new PQBP1 mutated males. AB - Since the first reports of polyglutamine-binding protein 1 (PQBP1) mutations in Renpenning syndrome and related disorders, the spectrum of PQBP1-linked clinical manifestations has been outlined from rare published case reports. The phenotypic description is often obtained from medical archives, and therefore, heterogeneous. Moreover, some aspects such as brain imaging or cognitive and behavioral functioning are rarely described. In this study, 13 PQBP1-mutated French patients were subjected to a standardized clinical, cognitive and behavioral assessment. Physical measurements of their relatives were also collected. We report on a recognizable clinical and radiological phenotype. All patients presented with microcephaly, leanness and mild short stature, relative to familial measurements. Three new clinical features are described: upper back progressive muscular atrophy, metacarpophalangeal ankylosis of the thumb and velar dysfunction. The specific facial dysmorphic features included at least four of the following signs: long triangular face, large ridged nose, half-depilated eyebrows, dysplastic or protruding ears and rough slightly sparse hair. An over aged appearance was noticed in elderly patients. Cortical gyrification was normal based on available magnetic brain imaging of six patients. PQBP1-linked microcephaly (or Renpenning syndrome) is an X-linked mental retardation syndrome, which has clinically recognizable features. PMID- 20950398 TI - Aberrant PKD2 splicing due to a presumed novel missense mutation in autosomal dominant polycystic kidney disease. AB - Autosomal-dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder characterized by abnormal proliferation of renal tubular epithelium, leading to massive kidney enlargement and progressive chronic kidney disease. ADPKD is caused by mutations in PKD1 and PKD2 genes. Herein, we describe and characterize a novel missense mutation in the PKD2 gene (c.1320G>T) in a 41-year old White man with kidney cysts and a family history of ADPKD. This mutation abolishes a conserved acceptor splice site of intron 5, resulting in a premature termination following the addition of three aberrant amino acids (PKD2 p.L441C fsX4). We demonstrate that the aberrantly spliced transcript is found in substantial amounts in the patient's peripheral blood leukocytes (PBL), and show that this alternative splicing of exon 6 occurs, to a lesser magnitude, in other patients with ADPKD and in normal control individuals. The biological and clinical significance of this splice variant in ADPKD is currently unknown. PMID- 20950399 TI - An autosomal recessive syndrome of severe cognitive impairment, dysmorphic facies and skeletal abnormalities maps to the long arm of chromosome 17. AB - Cognitive impairment (CI) is one of the most challenging referrals to the clinical genetics service. The different algorithms proposed to assist in the molecular diagnosis of CI rest largely on the distinction between syndromic and non-syndromic forms. We have identified what appears to be a novel syndromic form of CI, the variable phenotype of which comprises severe CI, hirsutism, dysmorphic facies and skeletal abnormalities, and have mapped it to a single locus on chromosome 17q21.31-17q22 spanning 12.2 Mb. Two candidate genes, HOXB6 and PPP1R9B were sequenced but no pathogenic alterations were identified. This report adds to the growing list of autosomal recessive syndromic CI conditions and defines a linkage interval harboring a gene which probably plays a vital role in brain development. PMID- 20950400 TI - Significance levels in genome-wide interaction analysis (GWIA). AB - Interaction between genetic variants is hypothesized to be one of several putative explanations for the 'case of missing heritability.' Therefore, Genome Wide Interaction Analysis (GWIA) has recently gained substantial interest. GWIA is computationally challenging and respective power type I error studies are particularly difficult. Therefore, an accepted significance level for GWIA studies does not currently exist. It has been shown that for a GWAS single-marker analysis with n SNPs a correction for multiple testing with 1/2 . n is appropriate for populations of European ancestry. We speculated that for GWIA, correction by 1/4 . m should be appropriate, where m = n . (n- 1)/2 is the number of SNP pairs. We tried to verify this hypothesis using the INTERSNP program that implements interaction analysis and genome-wide Monte-Carlo (MC) simulation. Using a type I error study based on Illumina((r)) HumanHap 550 data, we were able to reproduce the published result for single-marker analysis. For GWIA using a test for allelic interaction, we show that correction with roughly 0.4 . m is appropriate, a number that is somewhat larger than that of our hypothesis. In summary, it can be stated that for an Illumina((r)) -type marker panel with 500,000 SNPs, an uncorrected P-value of 1.0 * 10-12 is needed to establish genome wide significance at the 0.05 level. PMID- 20950401 TI - Deferasirox administration for the treatment of non-transfusional iron overload in patients with thalassaemia intermedia. AB - Abnormal iron regulation in patients with thalassaemia intermedia may lead to iron overload even in the absence of transfusions. There are limited data on iron chelator use in patients with thalassaemia intermedia and no guidelines exist for the management of iron overload. We present data from 11 patients with thalassaemia intermedia treated with deferasirox (Exjade((r)) , 10-20 mg/kg/d) for 24 months. Liver iron concentration and serum ferritin levels significantly decreased over the first 12 months (P = 0.005) and continued to decrease over the remainder of the study (P = 0.005). This small-scale study indicated that deferasirox may be suitable for controlling iron levels in patients with thalassaemia intermedia. PMID- 20950402 TI - Increased phosphatidylserine exposure on the erythrocyte membrane in patients with polycythaemia vera. PMID- 20950403 TI - Autologous 111 In-labelled platelet sequestration studies in patients with primary immune thrombocytopenia (ITP) prior to splenectomy: a report from the United Kingdom ITP Registry. AB - While splenectomy is an effective therapy for primary immune thrombocytopenia (ITP), possible complications and observed non-complete response (CR) in one third of patients demonstrate the need for further research into potential pre surgical predictors of outcomes. Past investigations into platelet sequestration studies, a hypothesized predictive test, have adopted heterogeneous methods and varied widely with regard to power. By studying patients with primary ITP who underwent autologous (111) In-labelled platelet sequestration studies at Barts and The London NHS Trust between 1994 and 2008, we evaluated the effectiveness of sequestration site in predicting short, medium, and long-term CR (platelet count >100 * 10(9) /l) to splenectomy through multivariate (gender, age at splenectomy, and mean platelet lifespan) logistic regression modelling. In total, 256 patients with primary ITP underwent scans; 91 (35.5%) proceeded to splenectomy. Logistic regression revealed significant adjusted odds ratios for CR of 7.47 (95% confidence interval [CI], 1.89-29.43) at 1-3 months post-splenectomy, 4.85 (95% CI, 1.04-22.54) at 6-12 months post-splenectomy, and 5.39 (95% CI, 1.34-21.65) at last follow-up (median: 3.8 years [range: 0.5-13.1 years]) in patients with purely or predominantly splenic versus mixed or hepatic sequestration. These findings demonstrate the utility of autologous (111) In-labelled platelet sequestration studies as an adjunct predictive instrument prior to splenectomy. PMID- 20950404 TI - Prophylaxis in severe prothrombin deficiency. PMID- 20950405 TI - The impact of elective knee/hip replacement surgery and thromboprophylaxis with rivaroxaban or dalteparin on thrombin generation. AB - Total hip/knee replacement surgeries are associated with an increased risk of venous thromboembolism and post-operative thromboprophylaxis has become standard treatment. This study aimed to: (i) assess the impact of hip/knee replacement surgery on ex vivo thrombin generation (TG), prothrombin fragments 1 + 2 (F1 + 2), thrombin-antithrombin complexes (TAT) and D-dimer; (ii) compare the anticoagulant effects of dalteparin and rivaroxaban on TG 24 h after surgery. Haemostatic variables were assessed in plasma samples of 51 patients taken pre operatively, peri-operatively, and 24 h post-operatively. Prophylaxis, once a day, with dalteparin or rivaroxaban, starting 6-8 h post-operatively, was administered in 25 (14 knee/11 hip) and 26 patients (13 knee/13 hip) respectively. TG, F1 + 2, TAT and D-dimer increased during surgery. Dalteparin patients showed a variable TG response 24 h after surgery: conversely, the effect of rivaroxaban on TG was consistent across individuals. Good correlation was seen between rivaroxaban levels and TG-lag-time (rs = 0.46, P = 0.01); TG-time-to-Peak (rs = 0.53, P = 0.005); TG-peak-thrombin (rs = -0.59, P = 0.001); and TG-velocity index-rate (rs = -0.61, P = 0.0009). Patients who received rivaroxaban showed a greater decrease of TG, F1 + 2 and TAT (but not D-dimer) than those on dalteparin. TG increases during hip/knee replacement surgery. Rivaroxaban inhibits TG more than dalteparin at 24 h after surgery. PMID- 20950406 TI - HIV and HCV health beliefs in an inner-city community. AB - Chronic infection with the hepatitis C virus (HCV) is more prevalent than human immunodeficiency virus (HIV) infection, but more public health resources are allocated to HIV than to HCV. Given shared risk factors and epidemiology, we compared accuracy of health beliefs about HIV and HCV in an at-risk community. Between 2002 and 2003, we surveyed a random patient sample at a primary care clinic in New York. The survey was organized as domains of Common Sense Model of Self-Regulation: causes ('sharing needles'), timeline/consequences ('remains in body for life', 'causes cancer') and controllability ('I can avoid this illness', 'medications may cure this illness'). We compared differences in accuracy of beliefs about HIV and HCV and used multivariable linear regression to identify factors associated with relative accuracy of beliefs. One hundred and twenty-two subjects completed the survey (response rate 42%). Mean overall health belief accuracy was 12/15 questions (80%) for HIV vs 9/15 (60%) for HCV (P < 0.001). Belief accuracy was significantly different across all domains. Within the causes domain, 60% accurately believed sharing needles a risk factor for HCV compared to 92% for HIV (P < 0.001). Within the timeline/consequences domain, 42% accurately believed HCV results in lifelong infection compared to 89% for HIV (P < 0.001). Within the controllability domain, 25% accurately believed that there is a potential cure for HCV. Multivariable linear regression revealed female gender as significantly associated with greater health belief accuracy for HIV. Thus, study participants had significantly less accurate health beliefs about HCV than about HIV. Targeting inaccuracies might improve public health interventions to foster healthier behaviours and better hepatitis C outcomes. PMID- 20950407 TI - Extended treatment duration for treatment naive chronic hepatitis C genotype 1 late viral responders: a meta-analysis comparing 48 weeks vs 72 weeks of pegylated interferon and ribavirin. AB - Patients with genotype I chronic hepatitis C virus (HCV) infection with late virological response to therapy have low sustained viral response (SVR) with standard 48 weeks of therapy and may benefit from extended therapy. We performed a systematic review and meta-analysis of five studies to compare the outcome of 48 weeks vs 72 weeks treatment in treatment naive chronic hepatitis C genotype I patients with late virological response. The end of treatment response with extended 72 weeks of treatment compared to standard 48 weeks of treatment was similar 48% and 56%, respectively, with pooled odds ratio (OR) (0.85; 95% CI 0.52 1.37). However, the SVR rates were higher with 72 weeks of treatment compared to 48 weeks treatment 32%vs 25% with pooled OR of 1.67 in favour of extended duration therapy (95% CI 1.16-2.40). This was because of lower relapse rates with extended duration therapy (35%vs 55%) with OR of 0.39 in favour of 72 weeks therapy (95% CI 0.25-0.61). There was no heterogeneity. No publication bias was noted as assessed by Egger's test. Extending the treatment duration from 48 to 72 weeks in genotype 1 infected patients with late virological response improves SVR. Thus, therapy extension in genotype 1 late viral responders (LVR) may be a consideration to improve treatment response; however, the proportion of patients with LVR that might benefit from 72-week therapy appears to be small. PMID- 20950408 TI - Who uses nursing theory? A univariate descriptive analysis of five years' research articles. AB - BACKGROUND: Since the early 1950s, nursing leaders have worked diligently to build the Scientific Discipline of Nursing, integrating Theory, Research and Practice. Recently, the role of theory has again come into question, with some scientists claiming nurses are not using theory to guide their research, with which to improve practice. AIMS: The purposes of this descriptive study were to determine: (i) Were nursing scientists' research articles in leading nursing journals based on theory? (ii) If so, were the theories nursing theories or borrowed theories? (iii) Were the theories integrated into the studies, or were they used as organizing frameworks? METHODS: Research articles from seven top ISI journals were analysed, excluding regularly featured columns, meta-analyses, secondary analysis, case studies and literature reviews. The authors used King's dynamic Interacting system and Goal Attainment Theory as an organizing framework. They developed consensus on how to identify the integration of theory, searching the Title, Abstract, Aims, Methods, Discussion and Conclusion sections of each research article, whether quantitative or qualitative. RESULTS: Of 2857 articles published in the seven journals from 2002 to, and including, 2006, 2184 (76%) were research articles. Of the 837 (38%) authors who used theories, 460 (55%) used nursing theories, 377 (45%) used other theories: 776 (93%) of those who used theory integrated it into their studies, including qualitative studies, while 51 (7%) reported they used theory as an organizing framework for their studies. Closer analysis revealed theory principles were implicitly implied, even in research reports that did not explicitly report theory usage. CONCLUSIONS: Increasing numbers of nursing research articles (though not percentagewise) continue to be guided by theory, and not always by nursing theory. Newer nursing research methods may not explicitly state the use of nursing theory, though it is implicitly implied. PMID- 20950409 TI - Low pathogenic avian influenza (H7N1) transmission between wild ducks and domestic ducks. AB - This article describes a virological investigation in a mixed flock of ducks and geese following detection of avian influenza virus antibodies in domestic geese. Low pathogenic H7N1 was found in both domestic and wild birds, indicating that transmission of virus was likely to have taken place between these. The importance of implementing and maintaining appropriate biosecurity measures is re emphasized. PMID- 20950410 TI - Growth pattern and growth prediction of body height in children with mucopolysaccharidosis type II. AB - AIM: Our goal was to evaluate the level, degree and direction of deviation in the ontogenesis of patients with mucopolysaccharidosis type II (MPS II) in comparison with the healthy population. MATERIAL AND METHODS: The anthropometric data of a longitudinal study on 28 patients with MPS II, aged from 0.5 to 21 years, were used to analyse the general growth patterns in terms of height, weight and head circumference. The growth trend was assessed with the straight-line regression model. The mathematical structural growth model was used to evaluate the structure of body height growth. RESULTS: A statistically significant negative growth trend for all features was found. Analysis of development structure revealed an earlier onset of the adolescent growth spurt among healthy boys and a lower current velocity of growth than expected values. CONCLUSION: During the first 3 years of life, all observed anthropometric features grew faster than normal. They slowed down by the end of the third year and, in subsequent years, reached lower values when compared with the reference charts. The values obtained from the BTT model showed the structure of body height growth, with particular emphasis on the pubertal spurt, was significantly different from the reference charts. PMID- 20950411 TI - Optimal vitamin A and suboptimal vitamin D status are common in Iranian infants. AB - AIM: Investigation of serum concentrations of vitamins A and D in Iranian infants. METHODS: A descriptive cross-sectional study, investigating 7112 infants (15-23 months of age) from all regions of Iran, who attended health care centres from May 25 to June 2, 2001. Unequal clusters with unequal household sizes were sampled. Vitamin A and D levels were analysed with high-performance liquid chromatography. RESULTS: The mean (SD) concentration of vitamin A was 2.09 (0.83) MUmol/L. At a national level, 0.7% of the infants had a level indicating deficiency, and 0.5% of the infants had insufficient concentrations of vitamin A, defined as serum concentrations <0.35 and <0.7 MUmol/L retinol, respectively. A total of 88% of infants had optimal concentrations (>1.4 MUmol/L). The mean (SD) concentration of vitamin D was 61.3 (31.4) nmol/L. Deficiency was found in 2.8% of infants (<25 nmol/L), and insufficiency in 32.9% (<50 nmol/L). Suboptimal and optimal concentrations were found in 44% and 20%, representing 50-75 and >75 nmol/L, respectively. Girls had lower vitamin D concentrations than boys (p = 0.006). CONCLUSION: As in developed countries, vitamin A deficiency was rare in Iranian infants. Vitamin D deficiency was also rare, but 33% of infants had insufficient levels; this was more common in girls than boys. PMID- 20950412 TI - Meta-analysis of passive immunoprophylaxis in paediatric patients at risk of severe RSV infection. AB - AIM: To review respiratory syncytial virus (RSV), passive immunoprophylaxis (PI) trials and meta-analysis (MA). METHODS: A literature review. RESULTS: Two MA of PI were found. Overall 3927 patients were randomized. PI reduces RSV hospitalization in patients with bronchopulmonary dysplasia (RR 0.58; 95% CI 0.41, 0.82) and with acyanotic congenital heart disease (RR 0.29; 95% CI 0.14, 0.62). In patients with cyanotic heart disease or premature infants without bronchopulmonary dysplasia, results are inconclusive. Passive immunoprophylaxis has a null effect in mechanical ventilation and death. CONCLUSION: Passive immunoprophylaxis reduces RSV hospitalization in a subset of patients. However, it has no effect in harder endpoints of RSV disease severity. PMID- 20950413 TI - Further evidence for an involvement of nociceptin/orphanin FQ in the pathophysiology of Parkinson's disease: a behavioral and neurochemical study in reserpinized mice. AB - The contribution of nociceptin/orphanin FQ (N/OFQ) to reserpine-induced Parkinsonism was evaluated in mice. A battery of motor tests revealed that reserpine caused dose-dependent and long-lasting motor impairment. Endogenous N/OFQ sustained this response because N/OFQ peptide (NOP) receptor knockout (NOP( /-) ) mice were less susceptible to the hypokinetic action of reserpine than wild type (NOP(+/+) ) animals. Microdialysis revealed that reserpine elevated glutamate and reduced GABA levels in substantia nigra reticulata, and that resistance to reserpine in NOP(-/-) mice was accompanied by a milder increase in glutamate and lack of inhibition of GABA levels. To substantiate this genetic evidence, the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3 hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one (J-113397) simultaneously reduced akinesia and nigral glutamate levels in reserpinized NOP(+/+) mice, being ineffective in NOP(-/-) mice. Moreover, repeated J-113397 administration in reserpinized mice resulted in faster recovery of baseline motor performance which was, however, accompanied by a loss of acute antiakinetic response. The short-term beneficial effect of J-113397 was paralleled by normalization of nigral glutamate levels, whereas loss of acute response was paralleled by loss of the ability of J-113397 to inhibit glutamate levels. We conclude that endogenous N/OFQ contributes to reserpine-induced Parkinsonism, and that sustained NOP receptor blockade produces short-term motor improvement accompanied by normalization of nigral glutamate release. PMID- 20950414 TI - Reduced proteasomal activity contributes to the accumulation of carbonylated proteins in chronic experimental autoimmune encephalomyelitis. AB - We have recently shown that several carbonylated proteins, including glial fibrillary acidic protein, beta-actin and beta-tubulin, accumulate within cerebellar astrocytes during the chronic phase of myelin-oligodendrocyte glycoprotein (MOG)(35-55) peptide-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. As protein carbonyls cannot be repaired and there is less oxidative stress in chronic than in acute EAE, we hypothesized that the accumulation of carbonylated proteins in these animals may be due to a defect in the degradation of the modified proteins. Alternatively, oxidized proteins in chronic EAE mice may be more resistant to proteolysis. Using lipopolysaccharide-stimulated astrocytes and several protease inhibitors we identified the 20S proteasome as the proteolytic system responsible for the elimination of most oxidized proteins. We also discovered that the chymotrysin like and caspase-like activities of the 20S proteasome are impaired in chronic EAE, while the amount of proteasome was unchanged. Proteasome failure in these animals was confirmed by the build-up of ubiquitinated proteins, mostly within astrocytes. In a cell-free system, carbonylated proteins from EAE mice with acute and chronic disease seem to be equally sensitive to proteasomal degradation. Altogether, the results support the notion that diminished activity of the 20S proteasome is a major contributor to the accumulation of carbonylated proteins in astrocytes of chronic EAE mice. PMID- 20950415 TI - Insulin resistance and glycemic abnormalities are associated with deterioration of left ventricular diastolic function: a cross-sectional study. AB - BACKGROUND: Left ventricular diastolic dysfunction (LVDD) is considered a precursor of diabetic cardiomyopathy, while insulin resistance (IR) is a precursor of type 2 diabetes mellitus (T2DM) and independently predicts heart failure (HF). We assessed whether IR and abnormalities of the glucose metabolism are related to LVDD. METHODS: We included 208 patients with normal ejection fraction, 57 (27%) of whom had T2DM before inclusion. In subjects without T2DM, an oral glucose tolerance test (oGTT) was performed. IR was assessed using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). The lower limit of the top quartile of the HOMA-IR distribution (3.217) was chosen as threshold for IR. LVDD was verified according to current guidelines. RESULTS: IR was diagnosed in 38 (18%) patients without a history of diabetes. The prevalence of LVDD was 92% in subjects with IR vs. 72% in patients without IR (n = 113), respectively (p = 0.013). In the IR group, the early diastolic mitral inflow velocity (E) in relation to the early diastolic tissue Doppler velocity (averaged from the septal and lateral mitral annulus, E'av) ratio (E/E'av) was significantly higher compared to those without IR (9.8 [8.3-11.5] vs. 8.1 [6.6-11.0], p = 0.011). This finding remains significant when patients with IR and concomitant T2DM based on oGTT results were excluded (E/E'av ratio 9.8 [8.2-11.1)] in IR vs. 7.9 [6.5-10.5] in those without both IR and T2DM, p = 0.014). There were significant differences among patients with and without LVDD regarding the HOMA-IR (1.71 [1.04-3.88] vs. 1.09 [0.43-2.2], p = 0.003). The HOMA-IR was independently associated with LVDD on multivariate logistic regression analysis, a 1-unit increase in HOMA-IR value was associated with an odds ratio for prevalent LVDD of 2.1 (95% CI 1.3-3.1, p = 0.001). Furthermore, the E/E'av ratio increases along the glucose metabolism status from normal glucose metabolism (7.6 [6.2-10.1]) to impaired glucose tolerance (8.8 [7.4-11.0]) and T2DM (10.5 [8.1-13.2]), respectively (p < 0.001). CONCLUSIONS: Insulin resistance is independently associated with LVDD in subjects without overt T2DM. Patients with IR and glucose metabolism disorders might represent a target population to prevent the development of HF. Screening programs for glucose metabolism disturbances should address the assessment of diastolic function and probably IR. PMID- 20950416 TI - The role of concurrent chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma among endemic population: a meta-analysis of the phase III randomized trials. AB - BACKGROUND: The main objective of this meta-analysis was to determine the clinical benefit of concurrent chemoradiotherapy (CCRT) compared with radiation alone (RT) in the treatment of nasopharyngeal carcinoma (NPC) patients in endemic geographic areas. METHODS: Using a prospective meta-analysis protocol, two independent investigators reviewed the publications and extracted the data. Published randomized controlled trials (RCTs) in which patients with NPC in endemic areas were randomly assigned to receive CCRT or RT alone were included. RESULTS: Seven trials (totally 1608 patients) were eligible. Risk ratios (RRs) of 0.63 (95% CI, 0.50 to 0.80), 0.76 (95% CI, 0.61 to 0.93) and 0.74 (95% CI, 0.62 to 0.89) were observed for 2, 3 and 5 years OS respectively in favor of the CCRT group. The RRs were larger than that detected in the previously reported meta analyses (including both endemic and non-endemic), indicating that the relative benefit of survival was smaller than what considered before. CONCLUSIONS: This is the first meta-analysis of CCRT vs. RT alone in NPC treatment which included studies only done in endemic area. The results confirmed that CCRT was more beneficial compared with RT alone. However, the relative benefit of CCRT in endemic population might be less than that from previous meta-analyses. PMID- 20950417 TI - Dynamic functional modules in co-expressed protein interaction networks of dilated cardiomyopathy. AB - BACKGROUND: Molecular networks represent the backbone of molecular activity within cells and provide opportunities for understanding the mechanism of diseases. While protein-protein interaction data constitute static network maps, integration of condition-specific co-expression information provides clues to the dynamic features of these networks. Dilated cardiomyopathy is a leading cause of heart failure. Although previous studies have identified putative biomarkers or therapeutic targets for heart failure, the underlying molecular mechanism of dilated cardiomyopathy remains unclear. RESULTS: We developed a network-based comparative analysis approach that integrates protein-protein interactions with gene expression profiles and biological function annotations to reveal dynamic functional modules under different biological states. We found that hub proteins in condition-specific co-expressed protein interaction networks tended to be differentially expressed between biological states. Applying this method to a cohort of heart failure patients, we identified two functional modules that significantly emerged from the interaction networks. The dynamics of these modules between normal and disease states further suggest a potential molecular model of dilated cardiomyopathy. CONCLUSIONS: We propose a novel framework to analyze the interaction networks in different biological states. It successfully reveals network modules closely related to heart failure; more importantly, these network dynamics provide new insights into the cause of dilated cardiomyopathy. The revealed molecular modules might be used as potential drug targets and provide new directions for heart failure therapy. PMID- 20950418 TI - Canine and human gastrointestinal stromal tumors display similar mutations in c KIT exon 11. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are common mesenchymal neoplasms in the gastrointestinal tract of humans and dogs. Little is known about the pathogenesis of these tumors. This study evaluated the role of c-KIT in canine GISTs; specifically, we investigated activating mutations in exons 8, 9, 11, 13, and 17 of c-KIT and exons 12, 14, and 18 of platelet-derived growth factor receptor, alpha polypeptide (PDGFRA), all of which have been implicated in human GISTs. METHODS: Seventeen canine GISTs all confirmed to be positive for KIT immunostaining were studied. Exons 8, 9, 11, 13 and 17 of c-KIT and exons 12, 14, and 18 of PDGFRA, were amplified from DNA isolated from formalin-fixed paraffin embedded samples. RESULTS: Of these seventeen cases, six amplicons of exon 11 of c-KIT showed aberrant bands on gel electrophoresis. Sequencing of these amplicons revealed heterozygous in-frame deletions in six cases. The mutations include two different but overlapping six base pair deletions. Exons 8, 9, 13, and 17 of c KIT and exons 12, 14, and 18 of PDGFRA had no abnormalities detected by electrophoresis and sequencing did not reveal any mutations, other than synonymous single nucleotide polymorphisms (SNPs) found in exon 11 of c-KIT and exons 12 and 14 of PDGFRA. CONCLUSIONS: The deletion mutations detected in canine GISTs are similar to those previously found in the juxtamembrane domain of c-KIT in canine cutaneous mast cell tumors in our laboratory as well as to those reported in human GISTs. Interestingly, none of the other c-KIT or PDGFRA exons showed any abnormalities in our cases. This finding underlines the critical importance of c-KIT in the pathophysiology of canine GISTs. The expression of KIT and the identification of these activating mutations in c-KIT implicate KIT in the pathogenesis of these tumors. Our results indicate that mutations in c-KIT may be of prognostic significance and that targeting KIT may be a rational approach to treatment of these malignant tumors. This study further demonstrates that spontaneously occurring canine GISTs share molecular features with human GISTs and are an appropriate model for human GISTs. PMID- 20950419 TI - Characterization of exceptionally thermostable single-stranded DNA-binding proteins from Thermotoga maritima and Thermotoga neapolitana. AB - BACKGROUND: In recent years, there has been an increasing interest in SSBs because they find numerous applications in diverse molecular biology and analytical methods. RESULTS: We report the characterization of single-stranded DNA binding proteins (SSBs) from the thermophilic bacteria Thermotoga maritima (TmaSSB) and Thermotoga neapolitana (TneSSB). They are the smallest known bacterial SSB proteins, consisting of 141 and 142 amino acid residues with a calculated molecular mass of 16.30 and 16.58 kDa, respectively. The similarity between amino acid sequences of these proteins is very high: 90% identity and 95% similarity. Surprisingly, both TmaSSB and TneSSB possess a quite low sequence similarity to Escherichia coli SSB (36 and 35% identity, 55 and 56% similarity, respectively). They are functional as homotetramers containing one single stranded DNA binding domain (OB-fold) in each monomer. Agarose mobility assays indicated that the ssDNA-binding site for both proteins is salt independent, and fluorescence spectroscopy resulted in a size of 68 +/- 2 nucleotides. The half lives of TmaSSB and TneSSB were 10 h and 12 h at 100 degrees C, respectively. When analysed by differential scanning microcalorimetry (DSC) the melting temperature (Tm) was 109.3 degrees C and 112.5 degrees C for TmaSSB and TneSSB, respectively. CONCLUSION: The results showed that TmaSSB and TneSSB are the most thermostable SSB proteins identified to date, offering an attractive alternative to TaqSSB and TthSSB in molecular biology applications, especially with using high temperature e. g. polymerase chain reaction (PCR). PMID- 20950420 TI - Planctomycetes dominate biofilms on surfaces of the kelp Laminaria hyperborea. AB - BACKGROUND: Bacteria belonging to Planctomycetes display several unique morphological and genetic features and are found in a wide variety of habitats on earth. Their ecological roles in these habitats are still poorly understood. Planctomycetes have previously been detected throughout the year on surfaces of the kelp Laminaria hyperborea from southwestern Norway. We aimed to make a detailed investigation of the abundance and phylogenetic diversity of planctomycetes inhabiting these kelp surfaces. RESULTS: Planctomycetes accounted for 51-53% of the bacterial biofilm cells in July and September and 24% in February according to fluorescence in situ hybridization (FISH) results. Several separate planctomycetes lineages within Pirellulae, Planctomyces and OM190 were represented in 16S rRNA gene clone libraries and the most abundant clones belonged to yet uncultured lineages. In contrast to the abundance, the diversity of the planctomycete populations increased from July to February and was probably influenced by the aging of the kelp tissue. One planctomycete strain that was closely related to Rhodopirellula baltica was isolated using selective cultivation techniques. CONCLUSIONS: Biofilms on surfaces of L. hyperborea display an even higher proportion of planctomycetes compared to other investigated planctomycete-rich habitats such as open water, sandy sediments and peat bogs. The findings agree well with the hypothesis of the role of planctomycetes as degraders of sulfated polymeric carbon in the marine environment as kelps produce such substances. In addition, the abundant planctomycete populations on kelp surfaces and in association with other eukaryotes suggest that coexistence with eukaryotes may be a key feature of many planctomycete lifestyles. PMID- 20950421 TI - Increasing reports of non-tuberculous mycobacteria in England, Wales and Northern Ireland, 1995-2006. AB - BACKGROUND: Non-tuberculous mycobacteria have long been identified as capable of causing human disease and the number at risk, due to immune-suppression, is rising. Several reports have suggested incidence to be increasing, yet routine surveillance-based evidence is lacking. We investigated recent trends in, and the epidemiology of, non-tuberculous mycobacterial infections in England, Wales and Northern Ireland, 1995-2006. METHODS: Hospital laboratories voluntarily report non-tuberculous mycobacterial infections to the Health Protection Agency Centre for Infections. Details reported include age and sex of the patient, species, specimen type and source laboratory. All reports were analysed. RESULTS: The rate of non-tuberculous mycobacteria reports rose from 0.9 per 100,000 population in 1995 to 2.9 per 100,000 in 2006 (1608 reports). Increases were mainly in pulmonary specimens and people aged 60+ years. The most commonly reported species was Mycobacterium avium-intracellulare (43%); M. malmoense and M. kansasii were also commonly reported. M. gordonae showed the biggest increase over the study period rising from one report in 1995 to 153 in 2006. Clinical information was rarely reported. CONCLUSIONS: The number and rate of reports increased considerably between 1995 and 2006, primarily in older age groups and pulmonary specimens. Increases in some species are likely to be artefacts but real changes in more pathogenic species, some of which will require clinical care, should not be excluded. Enhanced surveillance is needed to understand the true epidemiology of these infections and their impact on human health. PMID- 20950422 TI - Extra-cellular release and blood diffusion of BART viral micro-RNAs produced by EBV-infected nasopharyngeal carcinoma cells. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is a human epithelial malignancy consistently associated with the Epstein-Barr virus. The viral genome is contained in the nuclei of all malignant cells with abundant transcription of a family of viral microRNAs called BART miRNAs. MicroRNAs are well known intra cellular regulatory elements of gene expression. In addition, they are often exported in the extra-cellular space and sometimes transferred in recipient cells distinct from the producer cells. Extra-cellular transport of the microRNAs is facilitated by various processes including association with protective proteins and packaging in secreted nanovesicles called exosomes. Presence of microRNAS produced by malignant cells has been reported in the blood and saliva of tumor bearing patients, especially patients diagnosed with glioblastoma or ovarian carcinoma. In this context, it was decided to investigate extra-cellular release of BART miRNAs by NPC cells and their possible detection in the blood of NPC patients. To address this question, we investigated by quantitative RT-PCR the status of 5 microRNAs from the BART family in exosomes released by NPC cells in vitro as well as in plasma samples from NPC xenografted nude mice and NPC patients. RESULTS: We report that the BART miRNAs are released in the extra cellular space by NPC cells being associated, at least to a large extent, with secreted exosomes. They are detected with a good selectivity in plasma samples from NPC xenografted nude mice as well as NPC patients. CONCLUSIONS: Viral BART miRNAs are secreted by NPC cells in vitro and in vivo. They have enough stability to diffuse from the tumor site to the peripheral blood. This study provides a basis to explore their potential as a source of novel tumor biomarkers and their possible role in communications between malignant and non-malignant cells. PMID- 20950423 TI - Categorisation of continuous risk factors in epidemiological publications: a survey of current practice. AB - BACKGROUND: Reports of observational epidemiological studies often categorise (group) continuous risk factor (exposure) variables. However, there has been little systematic assessment of how categorisation is practiced or reported in the literature and no extended guidelines for the practice have been identified. Thus, we assessed the nature of such practice in the epidemiological literature. Two months (December 2007 and January 2008) of five epidemiological and five general medical journals were reviewed. All articles that examined the relationship between continuous risk factors and health outcomes were surveyed using a standard proforma, with the focus on the primary risk factor. Using the survey results we provide illustrative examples and, combined with ideas from the broader literature and from experience, we offer guidelines for good practice. RESULTS: Of the 254 articles reviewed, 58 were included in our survey. Categorisation occurred in 50 (86%) of them. Of those, 42% also analysed the variable continuously and 24% considered alternative groupings. Most (78%) used 3 to 5 groups. No articles relied solely on dichotomisation, although it did feature prominently in 3 articles. The choice of group boundaries varied: 34% used quantiles, 18% equally spaced categories, 12% external criteria, 34% other approaches and 2% did not describe the approach used. Categorical risk estimates were most commonly (66%) presented as pairwise comparisons to a reference group, usually the highest or lowest (79%). Reporting of categorical analysis was mostly in tables; only 20% in figures. CONCLUSIONS: Categorical analyses of continuous risk factors are common. Accordingly, we provide recommendations for good practice. Key issues include pre-defining appropriate choice of groupings and analysis strategies, clear presentation of grouped findings in tables and figures, and drawing valid conclusions from categorical analyses, avoiding injudicious use of multiple alternative analyses. PMID- 20950424 TI - Analysis of conditional gene deletion using probe based Real-Time PCR. AB - BACKGROUND: Conditional gene deletion using Cre-lox recombination is frequently used in mouse genetics; however recombination is frequently incomplete, resulting in a mixture of cells containing the functional (2lox) allele and the truncated (1lox) allele. Conventional analysis of 1lox/2lox allele ratios using Southern Blotting is time consuming, requires relatively large amounts of DNA and has a low sensitivity. We therefore evaluated the utility of Real-Time PCR to measure 1lox/2lox allele ratios. RESULTS: We show that SYBR Green based Real-Time PCR analysis of 1lox/2lox allele ratios can generate erroneous peaks in the melting curve that are possibly caused by alternate hybridization products promoted by the palindromic loxP sequence motif. Since abnormal melting curves frequently contribute to dismissal of SYBR Green based data, we developed a convenient method with improved specificity that avoids such erroneous signals. Our data show that probe based Real-Time PCR, using a universal probe directed against the loxP site, can accurately detect small differences in 1lox/2lox allele ratios. We also validated this method in Fabpl4* at -132-Cre transgenic mice, measuring 1lox/2lox allele ratios that are in agreement with published data. Our Real-Time PCR protocol requires the use of one probe only for all reactions. Also the universal probe established in our assay is generally applicable to any experiment analyzing Cre-lox recombination efficiency, such that only primer sequences have to be adapted. CONCLUSIONS: Our data show that 1lox/2lox allele ratios are detected with high accuracy and high sensitivity with Real-Time PCR analysis using a probe directed against the loxP site. Due to the generally applicable probe the assay is conveniently adapted to all models of Cre-lox mediated gene deletion. PMID- 20950425 TI - T-RFPred: a nucleotide sequence size prediction tool for microbial community description based on terminal-restriction fragment length polymorphism chromatograms. AB - BACKGROUND: Terminal-Restriction Fragment Length Polymorphism (T-RFLP) is a technique used to analyze complex microbial communities. It allows for the quantification of unique or numerically dominant phylotypes in amplicon pools and it has been used primarily for comparisons between different communities. T RFPred, Terminal-Restriction Fragment Prediction, was developed to identify and assign taxonomic information to chromatogram peaks of a T-RFLP fingerprint for a more comprehensive description of microbial communities. The program estimates the expected fragment size of representative 16S rRNA gene sequences (either from a complementary clone library or from public databases) for a given primer and restriction enzyme(s) and provides candidate taxonomic assignments. RESULTS: To show the accuracy of the program, T-RFLP profiles of a marine bacterial community were described using artificial bacterioplankton clone libraries of sequences obtained from public databases. For all valid chromatogram peaks, a phylogenetic group could be assigned. CONCLUSIONS: T-RFPred offers enhanced functionality of T RFLP profile analysis over current available programs. In particular, it circumvents the need for full-length 16S rRNA gene sequences during taxonomic assignments of T-RF peaks. Thus, large 16S rRNA gene datasets from environmental studies, including metagenomes, or public databases can be used as the reference set. Furthermore, T-RFPred is useful in experimental design for the selection of primers as well as the type and number of restriction enzymes that will yield informative chromatograms from natural microbial communities. PMID- 20950426 TI - Mutational dynamics of murine angiogenin duplicates. AB - BACKGROUND: Angiogenin (Ang) is a protein involved in angiogenesis by inducing the formation of blood vessels. The biomedical importance of this protein has come from findings linking mutations in Ang to cancer progression and neurodegenerative diseases. These findings highlight the evolutionary constrain on Ang amino acid sequence. However, previous studies comparing human Angiogenin with homologs from other phylogenetically related organisms have led to the conclusion that Ang presents a striking variability. Whether this variability has an adaptive value per se remains elusive. Understanding why many functional Ang paralogs have been preserved in mouse and rat and identifying functional divergence mutations at these copies may explain the relationship between mutations and function. In spite of the importance of testing this hypothesis from the evolutionarily and biomedical perspectives, this remains yet unaccomplished. Here we test the main mutational dynamics driving the evolution and function of Ang paralogs in mammals. RESULTS: We analysed the phylogenetic asymmetries between the different Ang gene copies in mouse and rat in the context of vertebrate Ang phylogeny. This analysis shows strong evidence in support of accelerated evolution in some Ang murine copies (mAng). This acceleration is not due to non-functionalisation because constraints on amino acid replacements remain strong. We identify many of the amino acid sites involved in signal localization and nucleotide binding by Ang to have evolved under diversifying selection. Compensatory effects of many of the mutations at these paralogs and their key structural location in or nearby important functional regions support a possible functional shift (functional divergence) in many Ang copies. Similarities between 3D-structural models for mAng copies suggest that their divergence is mainly functional. CONCLUSIONS: We identify the main evolutionary dynamics shaping the variability of Angiogenin in vertebrates and highlight the plasticity of this protein after gene duplication. Our results suggest functional divergence among mAng paralogs. This puts forward mAng as a good system candidate for testing functional plasticity of such an important protein while stresses caution when using mouse as a model to infer the consequences of mutations in the single Ang copy of humans. PMID- 20950427 TI - Transforming growth factor beta family expression at the bovine feto-maternal interface. AB - BACKGROUND: Endometrial remodelling is necessary for implantation in all mammalian species. The TGF beta super-family plays a crucial role in this event in humans and mice. However, the role of TGF beta super-family members during implantation is still unclear in ruminants. In the present study, the spacio temporal expression of TGF beta super-family members including activin was explored in bovine trophoblasts and endometrial tissue during the peri implantation period in order to elucidate whether it is essential for promoting cell proliferation at the implantation site. METHODS: Gene expression in the fetal membrane and endometrium of the gravid and non-gravid horn around Day 35 of gestation were analyzed with a custom-made oligo-microarray in cattle. The expression of activin and its related genes was also analyzed with quantitative RT-PCR. Activin-like activity in trophoblastic tissue and BT-1 cells was examined using a fibroblast cell proliferation test and Western blotting. RESULTS: The expression of various TGF beta super-family related genes including activin was detected in trophoblasts and the endometrium in cattle. The most intensive activin expression was found in the gravid horn endometrium, and rather intense expression was detected in the non-gravid trophoblastic tissue. Extracts from the fetal membrane including trophoblasts and purified activin both stimulated fibroblast proliferation effectively, and activin was immunologically detected in BT-1 cells, which have trophoblastic features. CONCLUSIONS: Specific expression of the activin gene (gene name: inhibin beta A) was found in the gravid horn endometrium during peri-implantation. An activin-like molecule, which was derived from the endometrium and trophoblasts, stimulated the proliferation of fibroblast cells. These results suggested that as in other species, the activity of TGF beta super-family members including activin-like molecules plays a pivotal role in endometrial remodelling, which is an essential process in implantation and placentogenesis during the peri-implantation period in cattle. PMID- 20950428 TI - Sp1 acetylation is associated with loss of DNA binding at promoters associated with cell cycle arrest and cell death in a colon cell line. AB - Butyrate, a known histone deacetylase inhibitor (HDACi) and product of fibre fermentation, is postulated to mediate the protective effect of dietary fibre against colon cancer. The transcription factor Sp1 is a target of acetylation and is known to be associated with class I HDACs, including HDAC1. Sp1 is a ubiquitous transcription factor and Sp1-regulated genes include those involved in cell cycle regulation, apoptosis and lipogenesis: all major pathways in cancer development. The only known acetylated residue of Sp1 is lysine703 which resides in the DNA binding domain. Here we show that acetylated Sp1 loses p21- and bak promoter -binding function in vitro. Furthermore treatment with a panel of HDAC inhibitors showed clustering of activities for a subset of inhibitors, causing G2 cell cycle arrest, Sp1 acetylation, p21 and Bak over-expression, all with very similar EC50 concentrations. These HDACi activities were not distributed according to the molecular class of compound. In order to mimic loss of binding, an siRNA strategy was used to reduce Sp1 expression. This resulted in altered expression of multiple elements of the p53/p21 pathway. Taken together our data suggest a mechanistic model for the chemopreventive actions of butyrate in colon epithelial cells, and provide new insight into the differential activities some classes of HDAC inhibitors. PMID- 20950429 TI - Early clinical experience with volumetric modulated arc therapy in head and neck cancer patients. AB - BACKGROUND: To report about early clinical experience in radiation treatment of head and neck cancer of different sites and histology by volumetric modulated arcs with the RapidArc technology. METHODS: During 2009, 45 patients were treated at Istituto Clinico Humanitas with RapidArc (28 males and 17 females, median age 65 years). Of these, 78% received concomitant chemotherapy. Thirty-six patients were treated as exclusive curative intent (group A), three as postoperative curative intent (group B) and six with sinonasal tumours (group C). Dose prescription was at Planning Target Volumes (PTV) with simultaneous integrated boost: 54.45 Gy and 69.96 Gy in 33 fractions (group A); 54.45 Gy and 66 Gy in 33 fractions (group B) and 55 Gy in 25 fractions (group C). RESULTS: Concerning planning optimization strategies and constraints, as per PTV coverage, for all groups, D98% > 95% and V95% > 99%. As regards organs at risk, all planning objectives were respected, and this was correlated with observed acute toxicity rates. Only 28% of patients experienced G3 mucositis, 14% G3 dermitis 44% had G2 dysphagia. Nobody required feeding tubes to be placed during treatment. Acute toxicity is also related to chemotherapy. Two patients interrupted the course of radiotherapy because of a quick worsening of general clinical condition. CONCLUSIONS: These preliminary results stated that volumetric modulated arc therapy in locally advanced head and neck cancers is feasible and effective, with acceptable toxicities. PMID- 20950430 TI - RBP-J is not required for granule neuron progenitor development and medulloblastoma initiated by Hedgehog pathway activation in the external germinal layer. AB - BACKGROUND: The Notch signalling pathway plays crucial roles in neural development, functioning by preventing premature differentiation and promotion of glial cell fates. In the developing cerebellum Notch pathway components are expressed in granule neuron progenitors of the external germinal layer (EGL) but the precise function of Notch in these cells is unclear. The Hedgehog pathway is also crucial in cerebellar development, mainly via control of the cell cycle, and persistent activation of the pathways leads to the cerebellar tumour medulloblastoma. Interactions between Hedgehog and Notch have been reported in normal brain development as well as in Hedgehog pathway induced medulloblastoma but the molecular details of this interaction are not known and we investigate here the role of Notch signalling in the development of the EGL and the intersection between the two pathways in cerebellar granule neuron progenitors and in medulloblastoma. RESULTS: RBP-J is the major downstream effector of all four mammalian Notch receptors and the RBP-J conditional mouse facilitates inactivation of canonical Notch signals. Patched1 is a negative regulator of Hedgehog signalling and the Patched1 conditional mouse is widely used to activate Hedgehog signalling via Patched1 deletion in specific cell types. The conditional mouse lines were crossed with a Math1-Cre line to delete the two genes in granule neuron progenitors from embryonic day 10.5. While deletion of only Patched1 as well as Patched1 together with RBP-J leads to formation of medulloblastoma concomitant with disorganisation of cell layers, loss of RBP-J from granule neuron progenitors has no obvious effect on overall cerebellar morphology or differentiation and maturation of the different cerebellar cell types. CONCLUSIONS: Our results suggest that even though Notch signalling has been shown to play important roles in cerebellar development, signalling via RBP-J is surprisingly not required in granule neuron progenitors. Furthermore, RBP-J inactivation in these cells does not influence the formation of medulloblastoma initiated by Hedgehog pathway activation. This may suggest a requirement of Notch in cerebellar development at a different developmental stage or in a different cell type than examined here - for example, in the neural stem cells of the ventricular zone. In addition, it remains a possibility that, in granule neuron progenitors, Notch may signal via an alternative pathway without the requirement for RBP-J. PMID- 20950431 TI - Butyrate suppresses expression of neuropilin I in colorectal cell lines through inhibition of Sp1 transactivation. AB - BACKGROUND: Neuropilin is a transmembrane receptor for vascular endothelial growth factor (VEGF) and is expressed in normal endothelial cells and upregulated in cancer cells. Neuropilin-1 (NRP-1) has been shown to promote tumour cell migration and survival in colon cancer in response to VEGF binding. The expression profiles of neuropilins, associated co-receptors and known ligands have been mapped in three colorectal cell lines: Caco-2, HCT116 & HT29. We have previously shown that butyrate, a naturally occurring histone deacetylase inhibitor (HDACi) produced by fermentation of fibre in the colon, causes apoptosis of colon cancer cell lines. RESULTS: Here we demonstrate that butyrate down-regulates NRP-1 and VEGF at the mRNA and protein level in colorectal cancer cell lines. NRP-1 is a known transcriptional target of Sp1, whose activity is regulated by acetylation. NRP-1 down-regulation by butyrate was associated with decreased binding affinity of Sp1 for canonical Sp-binding sites in the NRP-1 promoter. siRNA-mediated knock-down of Sp1 implied that Sp1 may have strong DNA binding activity but weak transactivation potential. CONCLUSION: The downregulation of the key apoptotic and angiogenesis regulator NRP-1 by butyrate suggests a novel contributory mechanism to the chemopreventive effect of dietary fibre. PMID- 20950432 TI - A comparative analysis of HIV drug resistance interpretation based on short reverse transcriptase sequences versus full sequences. AB - BACKGROUND: As second-line antiretroviral treatment (ART) becomes more accessible in resource-limited settings (RLS), the need for more affordable monitoring tools such as point-of-care viral load assays and simplified genotypic HIV drug resistance (HIVDR) tests increases substantially. The prohibitive expenses of genotypic HIVDR assays could partly be addressed by focusing on a smaller region of the HIV reverse transcriptase gene (RT) that encompasses the majority of HIVDR mutations for people on ART in RLS. In this study, an in silico analysis of 125,329 RT sequences was performed to investigate the effect of submitting short RT sequences (codon 41 to 238) to the commonly used virco(r)TYPE and Stanford genotype interpretation tools. RESULTS: Pair-wise comparisons between full-length and short RT sequences were performed. Additionally, a non-inferiority approach with a concordance limit of 95% and two-sided 95% confidence intervals was used to demonstrate concordance between HIVDR calls based on full-length and short RT sequences.The results of this analysis showed that HIVDR interpretations based on full-length versus short RT sequences, using the Stanford algorithms, had concordance significantly above 95%. When using the virco(r)TYPE algorithm, similar concordance was demonstrated (>95%), but some differences were observed for d4T, AZT and TDF, where predictions were affected in more than 5% of the sequences. Most differences in interpretation, however, were due to shifts from fully susceptible to reduced susceptibility (d4T) or from reduced response to minimal response (AZT, TDF) or vice versa, as compared to the predicted full RT sequence. The virco(r)TYPE prediction uses many more mutations outside the RT 41 238 amino acid domain, which significantly contribute to the HIVDR prediction for these 3 antiretroviral agents. CONCLUSIONS: This study illustrates the acceptability of using a shortened RT sequences (codon 41-238) to obtain reliable genotype interpretations by virco(r)TYPE and Stanford algorithms. Implementation of this simplified protocol could significantly reduce the cost of both resistance testing and ARV treatment monitoring in RLS. PMID- 20950433 TI - Clinical, socio-demographic and radiological predictors of short-term outcome in rotator cuff disease. AB - BACKGROUND: Shoulder pain is common with rotator cuff disease as the most frequently used clinical diagnosis. There is a wide range of treatment options for this condition, but limited evidence to guide patients and clinicians in the choice of treatment strategy. The purpose of this study was to investigate possible prognostic factors of short-term outcome after corticosteroid injection for rotator cuff disease. METHODS: We performed analyses of data from 104 patients who had participated in a randomized controlled study. Socio demographic, clinical and radiographic baseline factors were assessed for association with outcome at six-weeks follow-up evaluated by Shoulder Pain and Disability Index (SPADI) and patient perceived outcome. Factors with significant univariate association were entered into multivariate linear and logistic regression analyses. RESULTS: In the multivariate analyses; a high SPADI score indicating pain and disability at follow-up was associated with decreasing age, male gender, high baseline pain and disability, being on sick-leave, and using regular pain medication. A successful patient perceived outcome was associated with not being on sick-leave, high active abduction, local corticosteroid injection and previous cortisone injections. Structural findings of rotator cuff tendon pathology on MRI and bursal exudation or thickening on ultrasonography did not contribute to the predictive model. CONCLUSIONS: Baseline characteristics were associated with outcome after corticosteroid injection in rotator cuff disease. Sick-leave was the best predictor of poor short-term outcome. TRIAL REGISTRATION: Clinical trials NCT00640575. PMID- 20950434 TI - Resuscitation fluid use in critically ill adults: an international cross sectional study in 391 intensive care units. AB - INTRODUCTION: Recent evidence suggests that choice of fluid used for resuscitation may influence mortality in critically ill patients. METHODS: We conducted a cross-sectional study in 391 intensive care units across 25 countries to describe the types of fluids administered during resuscitation episodes. We used generalized estimating equations to examine the association between patient, prescriber and geographic factors and the type of fluid administered (classified as crystalloid, colloid or blood products). RESULTS: During the 24-hour study period, 1,955 of 5,274 (37.1%) patients received resuscitation fluid during 4,488 resuscitation episodes. The main indications for administering crystalloid or colloid were impaired perfusion (1,526/3,419 (44.6%) of episodes), or to correct abnormal vital signs (1,189/3,419 (34.8%)). Overall, colloid was administered to more patients (1,234 (23.4%) versus 782 (14.8%)) and during more episodes (2,173 (48.4%) versus 1,468 (32.7%)) than crystalloid. After adjusting for patient and prescriber characteristics, practice varied significantly between countries with country being a strong independent determinant of the type of fluid prescribed. Compared to Canada where crystalloid, colloid and blood products were administered in 35.5%, 40.6% and 28.3% of resuscitation episodes respectively, odds ratios for the prescription of crystalloid in China, Great Britain and New Zealand were 0.46 (95% confidence interval (CI) 0.30 to 0.69), 0.18 (0.10 to 0.32) and 3.43 (1.71 to 6.84) respectively; odds ratios for the prescription of colloid in China, Great Britain and New Zealand were 1.72 (1.20 to 2.47), 4.72 (2.99 to 7.44) and 0.39 (0.21 to 0.74) respectively. In contrast, choice of fluid was not influenced by measures of illness severity (for example, Acute Physiology and Chronic Health Evaluation (APACHE) II score). CONCLUSIONS: Administration of resuscitation fluid is a common intervention in intensive care units and choice of fluid varies markedly between countries. Although colloid solutions are more expensive and may possibly be harmful in some patients, they were administered to more patients and during more resuscitation episodes than crystalloids were. PMID- 20950435 TI - Expression of the neuron-specific protein CHD5 is an independent marker of outcome in neuroblastoma. AB - BACKGROUND: The chromodomain, helicase DNA-binding protein 5 (CHD5) is a potential tumor suppressor gene located on chromosome 1p36, a region recurrently deleted in high risk neuroblastoma (NB). Previous data have shown that CHD5 mRNA is present in normal neural tissues and in low risk NB, nevertheless, the distribution of CHD5 protein has not been explored. The aim of this study was to investigate CHD5 protein expression as an immunohistochemical marker of outcome in NB. With this purpose, CHD5 protein expression was analyzed in normal neural tissues and neuroblastic tumors (NTs). CHD5 gene and protein expression was reexamined after induction chemotherapy in a subset of high risk tumors to identify potential changes reflecting tumor response. RESULTS: We provide evidence that CHD5 is a neuron-specific protein, absent in glial cells, with diverse expression amongst neuron types. Within NTs, CHD5 immunoreactivity was found restricted to differentiating neuroblasts and ganglion-like cells, and absent in undifferentiated neuroblasts and stromal Schwann cells. Correlation between protein and mRNA levels was found, suggesting transcriptional regulation of CHD5. An immunohistochemical analysis of 90 primary NTs highlighted a strong association of CHD5 expression with favorable prognostic variables (age at diagnosis <12 months, low clinical stage, and favorable histology; P < 0.001 for all), overall survival (OS) (P < 0.001) and event-free survival (EFS) (P < 0.001). Multivariate analysis showed that CHD5 prognostic value is independent of other clinical and biologically relevant parameters, and could therefore represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. The prognostic value of CHD5 was confirmed in an independent, blinded set of 32 NB tumors (P < 0.001).Reactivation of CHD5 expression after induction chemotherapy was observed mainly in those high risk tumors with induced tumor cell differentiation features. Remarkably, these NB tumors showed good clinical response and prolonged patient survival. CONCLUSIONS: The neuron-specific protein CHD5 may represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. Re-establishment of CHD5 expression induced by chemotherapy could be a surrogate marker of treatment response. PMID- 20950437 TI - Paediatric biepicondylar elbow fracture dislocation - a case report. AB - Paediatric elbow biepicondylar fracture dislocations are very rare injuries and have been only published in two independent case reviews. We report a case of 13 years old boy, who sustained this unusual injury after a fall on outstretched hand resulting in an unstable elbow fracture dislocation. Closed reduction was performed followed by delayed ORIF (Open Reduction and Internal Fixation) with K wires. Final follow-up at 14 weeks revealed a stable elbow and satisfactory function with full supination-pronation, range of motion from 0 degrees -120 degrees of flexion and normal muscle strength. This type of injury needs operative treatment and fixation to restore stability and return to normal or near normal elbow function. The method of fixation (screws or K wires) may depend on size and number of fracture fragments. PMID- 20950438 TI - QTLminer: identifying genes regulating quantitative traits. AB - BACKGROUND: Quantitative trait locus (QTL) mapping identifies genomic regions that likely contain genes regulating a quantitative trait. However, QTL regions may encompass tens to hundreds of genes. To find the most promising candidate genes that regulate the trait, the biologist typically collects information from multiple resources about the genes in the QTL interval. This process is very laborious and time consuming. RESULTS: QTLminer is a bioinformatics tool that automatically performs QTL region analysis. It is available in GeneNetwork and it integrates information such as gene annotation, gene expression and sequence polymorphisms for all the genes within a given genomic interval. CONCLUSIONS: QTLminer substantially speeds up discovery of the most promising candidate genes within a QTL region. PMID- 20950436 TI - Selective killing of human immunodeficiency virus infected cells by non nucleoside reverse transcriptase inhibitor-induced activation of HIV protease. AB - BACKGROUND: Current antiretroviral therapy against human immunodeficiency virus (HIV-1) reduces viral load and thereby prevents viral spread, but it cannot eradicate proviral genomes from infected cells. Cells in immunological sanctuaries as well as cells producing low levels of virus apparently contribute to a reservoir that maintains HIV persistence in the presence of highly active antiretroviral therapy. Thus, accelerated elimination of virus producing cells may represent a complementary strategy to control HIV infection. Here we sought to exploit HIV protease (PR) related cytotoxicity in order to develop a strategy for drug induced killing of HIV producing cells. PR processes the viral Gag and Gag-Pol polyproteins during virus maturation, but is also implicated in killing of virus producing cells through off-target cleavage of host proteins. It has been observed previously that micromolar concentrations of certain non-nucleoside reverse transcriptase inhibitors (NNRTIs) can stimulate intracellular PR activity, presumably by enhancing Gag-Pol dimerization. RESULTS: Using a newly developed cell-based assay we compared the degree of PR activation displayed by various NNRTIs. We identified inhibitors showing higher potency with respect to PR activation than previously described for NNRTIs, with the most potent compounds resulting in ~2-fold increase of the Gag processing signal at 250 nM. The degree of enhancement of intracellular Gag processing correlated with the compound's ability to enhance RT dimerization in a mammalian two-hybrid assay. Compounds were analyzed for their potential to mediate specific killing of chronically infected MT-4 cells. Levels of cytotoxicity on HIV infected cells determined for the different NNRTIs corresponded to the relative degree of drug induced intracellular PR activation, with CC50 values ranging from ~0.3 MUM to above the tested concentration range (10 MUM). Specific cytotoxicity was reverted by addition of PR inhibitors. Two of the most active compounds, VRX-480773 and GW 678248, were also tested in primary human cells and mediated cytotoxicity on HIV 1 infected peripheral blood mononuclear cells. CONCLUSION: These data present proof of concept for targeted drug induced elimination of HIV producing cells. While NNRTIs themselves may not be sufficiently potent for therapeutic application, the results provide a basis for the development of drugs exploiting this mechanism of action. PMID- 20950439 TI - Comparison of LPS-stimulated release of cytokines in punch versus transwell tissue culture systems of human gestational membranes. AB - BACKGROUND: Cytokine signaling within the amnionic, chorionic and decidual extraplacental gestational membranes plays an important role in membrane rupture and the timing of birth. The predominant in vitro explant culture system for evaluating cytokine induction in human gestational membranes has been the free floating biopsy punch culture. Punch systems have been used to investigate the impact of various toxicants, pharmaceuticals and genetic variation on expression of pro-inflammatory cytokines. More recently, a dual compartment transwell culture system has been developed that more closely mimics the intrauterine compartment. The current study compares these two systems with respect to release of pro- and anti-inflammatory cytokines in response to lipopolysaccharide (LPS), a model stimulant. METHODS: Tissue samples were exposed to 100 ng/ml LPS for 12 h and cytokines were measured by ELISA. Data are expressed as increase relative to non-treated controls. RESULTS: Levels of interleukin-6 increased in punch culture medium samples to a significantly greater extent (34.2 fold) compared with medium from transwell cultures in the amnion (6.6 fold) or choriodecidual (7.1 fold) compartments. Interleukin-8 also showed a significantly greater induction in punch (4.8 fold) than transwell amnion (1.6 fold) or choriodecidual (1.7 fold) samples. The anti-inflammatory interleukin-10 showed a significant difference between punch (36.5 fold) and transwell amnion (15.4 fold) samples, but no difference was observed between punch and transwell choriodecidual (28.5 fold) samples. Neither interleukin-1beta nor tumor necrosis factor-alpha (TNF-alpha) showed a significant difference between the punch and transwell samples. CONCLUSIONS: These results indicate that the pattern of LPS-stimulated cytokine release from gestational membranes in vitro depends on the culture system used, confounding comparisons of studies that use different gestational membrane culture systems to study inflammatory responses. PMID- 20950440 TI - An embryo-specific expressing TGF-beta family protein, growth-differentiation factor 3 (GDF3), augments progression of B16 melanoma. AB - Malignant tumor cells often express embryonic antigens which share the expression with embryonic stem (ES) cells. The embryonic antigens are usually encoded by ES cell-specific genes, a number of which are associated with tumorigenesis and/or tumor progression. We examined the expression of ES cell-specific genes in the mouse B16 melanoma cell line to identify the factors promoting tumorigenesis. We found that endogenous growth-differentiation factor 3 (GDF3) expression was induced in implant B16 tumor during tumor progression in syngenic C57BL/6 mice. B16 F10, a subline with a high metastatic potential, continuously expressed GDF3 while low metastatic B16 F1 expressed comparatively decreased levels of GDF3. Overexpression of GDF3 promoted growth of implanted melanoma B16 F1 and F10 in syngenic mice. Ectopic expression of GDF3 was accompanied by an increased level of production of CD24/CD44. Such a profile was reported to be characteristic of melanoma stem cell-like cells. GDF3 expression was observed in embryonal carcinomas, primary testicular germ cell tumors, seminomas and breast carcinomas. However, the role of GDF3 in these cancers remains undetermined. Overexpression of GDF3 did not affect the growth of mouse hepatoma high or low metastatic sublines G5 or G1, both of which do not express GDF3. Since GDF3-driven CD24 acts as a receptor for endogenous innate immune ligands that modulate cell proliferation, CD24 is an effective determinant of tumorigenesis in malignant cell transformation. Finally, our results support the view that GDF3 has the ability to induce progression of CD24-inducible melanoma in mice. PMID- 20950442 TI - Cost and mortality prediction using polymerase chain reaction pathogen detection in sepsis: evidence from three observational trials. AB - INTRODUCTION: Delays in adequate antimicrobial treatment contribute to high cost and mortality in sepsis. Polymerase chain reaction (PCR) assays are used alongside conventional cultures to accelerate the identification of microorganisms. We analyze the impact on medical outcomes and healthcare costs if improved adequacy of antimicrobial therapy is achieved by providing immediate coverage after positive PCR reports. METHODS: A mathematical prediction model describes the impact of PCR-based rapid adjustment of antimicrobial treatment. The model is applied to predict cost and medical outcomes for 221 sepsis episodes of 189 post-surgical and intensive care unit (ICU) sepsis patients with available PCR data from a prospective, observational trial of a multiplex PCR assay in five hospitals. While this trial demonstrated reduction of inadequate treatment days, data on outcomes associated with reduced inadequate initial antimicrobial treatment had to be obtained from two other, bigger, studies which involved 1,147 (thereof 316 inadequately treated) medical or surgical ICU patients. Our results are reported with the (5% to 95%) percentile ranges from Monte Carlo simulation in which the input parameters were randomly and independently varied according to their statistical characterization in the three underlying studies. The model allows predictions also for different patient groups or PCR assays. RESULTS: A total of 13.1% of PCR tests enabled earlier adequate treatment. We predict that cost for PCR testing (300 ?/test) can be fully recovered for patients above 717 ? (605 ? to 1,710 ?) daily treatment cost. A 2.6% (2.0 to 3.2%) absolute reduction of mortality is expected. Cost per incremental survivor calculates to 11,477 ? (9,321 ? to 14,977 ?) and incremental cost-effectiveness ratio to 3,107 ? (2,523 ? to 4,055 ?) per quality-adjusted life-year. Generally, for ICU patients with >25% incidence of inadequate empiric antimicrobial treatment, and at least 15% with a positive blood culture, PCR represents a cost-neutral adjunct method. CONCLUSIONS: Rapid PCR identification of microorganisms has the potential to become a cost-effective component for managing sepsis. The prediction model tested with data from three observational trials should be utilized as a framework to deepen insights when integrating more complementary data associated with utilization of molecular assays in the management of sepsis. PMID- 20950441 TI - Histopathology and biochemistry analysis of the interaction between sunitinib and paracetamol in mice. AB - BACKGROUND: Sunitinib, a tyrosine kinase inhibitor to treat GIST and mRCC may interact with paracetamol as both undergo P450 mediated biotransformation and P glycoprotein transport. This study evaluates the effects of sunitinib-paracetamol coadministration on liver and renal function biomarkers and liver, kidney, brain, heart and spleen histopathology. ICR male mice (n = 6 per group/dose) were administered saline (group-A) or paracetamol 500 mg/kg IP (group-B), or sunitinib at 25, 50, 80, 100, 140 mg/kg PO (group-C) or coadministered sunitinib at 25, 50, 80, 100, 140 mg/kg PO and paracetamol IP at fixed dose 500 mg/kg (group-D). Paracetamol was administered 15 min before sunitinib. Mice were sacrificed 4 h post sunitinib administration. RESULTS: Group-A serum ALT and AST levels were 14.29 +/- 2.31 U/L and 160.37 +/- 24.74 U/L respectively and increased to 249.6 +/- 222.7 U/L and 377.1 +/- 173.6 U/L respectively in group-B; group-C ALT and AST ranged 36.75-75.02 U/L and 204.4-290.3 U/L respectively. After paracetamol coadministration with low sunitinib doses (group-D), ALT and AST concentrations ranged 182.79-221.03 U/L and 259.7-264.4 U/L respectively, lower than group-B. Paracetamol coadministration with high sunitinib doses showed higher ALT and AST values (range 269.6-349.2 U/L and 430.2-540.3 U/L respectively), p < 0.05. Hepatic histopathology showed vascular congestion in group-B; mild congestion in group-C (but lesser than in group-B and D). In group-D, at low doses of sunitinib, lesser damage than in group-B occurred but larger changes including congestion were observed at high sunitinib doses. BUN levels were higher (p < 0.05) for group-B (33.81 +/- 5.68 mg/dL) and group-D (range 35.01 +/- 6.95 U/L to 52.85 +/- 12.53 U/L) compared to group-A (15.60 +/- 2.17 mg/dL) and group-C (range 17.50 +/- 1.25 U/L to 26.68 +/- 6.05 U/L). Creatinine remained unchanged. Renal congestion and necrosis was lower in group-C than group-B but was higher in group-D (p > 0.05). Mild cardiotoxicity occurred in groups B, C and D. Brain vascular congestion occurred at high doses of sunitinib administered alone or with paracetamol. Hepatic and renal biomarkers correlated with histopathology signs. CONCLUSIONS: Paracetamol and sunitinib coadministration may lead to dose dependent outcomes exhibiting mild hepatoprotective effect or increased hepatotoxicity. Sunitinib at high doses show renal, cardiac and brain toxicity. Liver and renal function monitoring is recommended. PMID- 20950443 TI - The multikinase inhibitor Sorafenib displays significant antiproliferative effects and induces apoptosis via caspase 3, 7 and PARP in B- and T-lymphoblastic cells. AB - BACKGROUND: Targeted therapy approaches have been successfully introduced into the treatment of several cancers. The multikinase inhibitor Sorafenib has antitumor activity in solid tumors and its effects on acute lymphoblastic leukemia (ALL) cells are still unclear. METHODS: ALL cell lines (SEM, RS4;11 and Jurkat) were treated with Sorafenib alone or in combination with cytarabine, doxorubicin or RAD001. Cell count, apoptosis and necrosis rates, cell cycle distribution, protein phosphorylation and metabolic activity were determined. RESULTS: Sorafenib inhibited the proliferation of ALL cells by cell cycle arrest accompanied by down-regulation of CyclinD3 and CDK4. Furthermore, Sorafenib initiated apoptosis by cleavage of caspases 3, 7 and PARP. Apoptosis and necrosis rates increased significantly with most pronounced effects after 96 h. Antiproliferative effects of Sorafenib were associated with a decreased phosphorylation of Akt (Ser473 and Thr308), FoxO3A (Thr32) and 4EBP-1 (Ser65 and Thr70) as early as 0.5 h after treatment. Synergistic effects were seen when Sorafenib was combined with other cytotoxic drugs or a mTOR inhibitor emphasizing the Sorafenib effect. CONCLUSION: Sorafenib displays significant antileukemic activity in vitro by inducing cell cycle arrest and apoptosis. Furthermore, it influences PI3K/Akt/mTOR signaling in ALL cells. PMID- 20950444 TI - Differences in hip morphology between the sexes in patients undergoing hip resurfacing. AB - There is limited morphological data on the sex differences between the commonly used pelvic parameters. This study analysed the CT scans of 100 consecutive Caucasian patients, 61 males and 39 females, undergoing hip resurfacing arthroplasty surgery for hip osteoarthritis in one institution.There were no sex differences in femoral torsion/anteversion, femoral neck angle and acetabular inclination. Males had a mean femoral torsion/anteversion of 8 degrees (range -5 to 26 degrees), a mean femoral neck angle of 129 degrees (range 119 to 138 degrees) and a mean acetabular inclination of 55 degrees (range 40 to 86 degrees). Females had a mean femoral torsion/anteversion of 9 degrees (range -2 to 31 degrees), a mean femoral neck angle of 128 degrees (range 121 to 138) and a mean acetabular inclination of 57 degrees (range 44 to 80 degrees). Females had a significantly greater acetabular version of 23 degrees (range 10 to 53) compared with 18 degrees in males (range 7 to 46 degrees (p = 0.02) and males had a significantly greater femoral offset of 55 mm (range 42 to 68 mm) compared with 48 mm (range 37 to 57 mm) in females (p = 0.00). There were no significant differences between measurements taken from each patient's right and left hips.These findings may be useful for the future design and the implantation of hip arthroplasty components. PMID- 20950445 TI - Human parvovirus PARV4 DNA in tissues from adult individuals: a comparison with human parvovirus B19 (B19V). AB - BACKGROUND: PARV4 is a new member of the Parvoviridae family not closely related to any of the known human parvoviruses. Viremia seems to be a hallmark of PARV4 infection and viral DNA persistence has been demonstrated in a few tissues. Till now, PARV4 has not been associated with any disease and its prevalence in human population has not been clearly established. This study was aimed to assess the tissue distribution and the ability to persist of PARV4 in comparison to parvovirus B19 (B19V). RESULTS: PARV4 and B19V DNA detection was carried out in various tissues of individuals without suspect of acute viral infection, by a real time PCR and a nested PCR, targeting the ORF2 and the ORF1 respectively. Low amount of PARV4 DNA was found frequently (>40%) in heart and liver of adults individuals, less frequently in lungs and kidneys (23,5 and 18% respectively) and was rare in bone marrow, skin and synovium samples (5,5%, 4% and 5%, respectively). By comparison, B19V DNA sequences were present in the same tissues with a higher frequency (significantly higher in myocardium, skin and bone marrow) except than in liver where the frequency was the same of PARV4 DNA and in plasma samples where B19V frequency was significantly lower than that of PARV4 CONCLUSIONS: The particular tropism of PARV4 for liver and heart, here emerged, suggests to focus further studies on these tissues as possible target for viral replication and on the possible role of PARV4 infection in liver and heart diseases. Neither bone marrow nor kidney seem to be a common target of viral replication. PMID- 20950446 TI - Discriminant analysis of principal components: a new method for the analysis of genetically structured populations. AB - BACKGROUND: The dramatic progress in sequencing technologies offers unprecedented prospects for deciphering the organization of natural populations in space and time. However, the size of the datasets generated also poses some daunting challenges. In particular, Bayesian clustering algorithms based on pre-defined population genetics models such as the STRUCTURE or BAPS software may not be able to cope with this unprecedented amount of data. Thus, there is a need for less computer-intensive approaches. Multivariate analyses seem particularly appealing as they are specifically devoted to extracting information from large datasets. Unfortunately, currently available multivariate methods still lack some essential features needed to study the genetic structure of natural populations. RESULTS: We introduce the Discriminant Analysis of Principal Components (DAPC), a multivariate method designed to identify and describe clusters of genetically related individuals. When group priors are lacking, DAPC uses sequential K-means and model selection to infer genetic clusters. Our approach allows extracting rich information from genetic data, providing assignment of individuals to groups, a visual assessment of between-population differentiation, and contribution of individual alleles to population structuring. We evaluate the performance of our method using simulated data, which were also analyzed using STRUCTURE as a benchmark. Additionally, we illustrate the method by analyzing microsatellite polymorphism in worldwide human populations and hemagglutinin gene sequence variation in seasonal influenza. CONCLUSIONS: Analysis of simulated data revealed that our approach performs generally better than STRUCTURE at characterizing population subdivision. The tools implemented in DAPC for the identification of clusters and graphical representation of between-group structures allow to unravel complex population structures. Our approach is also faster than Bayesian clustering algorithms by several orders of magnitude, and may be applicable to a wider range of datasets. PMID- 20950447 TI - Combinations of physiologic estrogens with xenoestrogens alter calcium and kinase responses, prolactin release, and membrane estrogen receptor trafficking in rat pituitary cells. AB - BACKGROUND: Xenoestrogens such as alkylphenols and the structurally related plastic byproduct bisphenol A have recently been shown to act potently via nongenomic signaling pathways and the membrane version of estrogen receptor alpha. Though the responses to these compounds are typically measured individually, they usually contaminate organisms that already have endogenous estrogens present. Therefore, we used quantitative medium-throughput screening assays to measure the effects of physiologic estrogens in combination with these xenoestrogens. METHODS: We studied the effects of low concentrations of endogenous estrogens (estradiol, estriol, and estrone) at 10 pM (representing pre development levels), and 1 nM (representing higher cycle-dependent and pregnancy levels) in combinations with the same levels of xenoestrogens in GH3/B6/F10 pituitary cells. These levels of xenoestrogens represent extremely low contamination levels. We monitored calcium entry into cells using Fura-2 fluorescence imaging of single cells. Prolactin release was measured by radio immunoassay. Extracellular-regulated kinase (1 and 2) phospho-activations and the levels of three estrogen receptors in the cell membrane (ERalpha, ERbeta, and GPER) were measured using a quantitative plate immunoassay of fixed cells either permeabilized or nonpermeabilized (respectively). RESULTS: All xenoestrogens caused responses at these concentrations, and had disruptive effects on the actions of physiologic estrogens. Xenoestrogens reduced the % of cells that responded to estradiol via calcium channel opening. They also inhibited the activation (phosphorylation) of extracellular-regulated kinases at some concentrations. They either inhibited or enhanced rapid prolactin release, depending upon concentration. These latter two dose-responses were nonmonotonic, a characteristic of nongenomic estrogenic responses. CONCLUSIONS: Responses mediated by endogenous estrogens representing different life stages are vulnerable to very low concentrations of these structurally related xenoestrogens. Because of their non-classical dose-responses, they must be studied in detail to pinpoint effective concentrations and the directions of response changes. PMID- 20950448 TI - Outer membrane protein a of Salmonella enterica serovar Typhimurium activates dendritic cells and enhances Th1 polarization. AB - BACKGROUND: Typhoid, which is caused by Salmonella enterica serovar Typhimurium, remains a major health concern worldwide. Multidrug-resistant strains of Salmonella have emerged which exhibit increased survivability and virulence, thus leading to increased morbidity. However, little is known about the protective immune response against this microorganism. The outer membrane protein (Omp)A of bacteria plays an important role in pathogenesis. RESULTS: We purified OmpA from S. enterica serovar Typhimurium (OmpA-sal) and characterized the role of OmpA-sal in promoting adaptive and innate immune responses. OmpA-sal functionally activated bone marrow-derived dendritic cells by augmenting expression of CD80, CD86, and major histocompatibility complex classes I and II. Interestingly, OmpA sal induced production of interferon-gamma from T cells in mixed lymphocyte reactions, thus indicating Th1-polarizing capacity. The expression of surface markers and cytokine production in dendritic cells was mediated by the TLR4 signaling pathway in a TLR4 Knock-out system. CONCLUSIONS: Our findings suggest that OmpA-sal modulates the adaptive immune responses to S. enterica serovar Typhimurium by activating dendritic cells and driving Th1 polarization, which are important properties to consider in the development of effective S. enterica serovar Typhimurium vaccines and immunotherapy adjuvant. PMID- 20950449 TI - A study protocol to evaluate the relationship between outdoor air pollution and pregnancy outcomes. AB - BACKGROUND: The present study protocol is designed to assess the relationship between outdoor air pollution and low birth weight and preterm births outcomes performing a semi-ecological analysis. Semi-ecological design studies are widely used to assess effects of air pollution in humans. In this type of analysis, health outcomes and covariates are measured in individuals and exposure assignments are usually based on air quality monitor stations. Therefore, estimating individual exposures are one of the major challenges when investigating these relationships with a semi-ecologic design. METHODS/DESIGN: Semi-ecologic study consisting of a retrospective cohort study with ecologic assignment of exposure is applied. Health outcomes and covariates are collected at Primary Health Care Center. Data from pregnant registry, clinical record and specific questionnaire administered orally to the mothers of children born in period 2007-2010 in Portuguese Alentejo Litoral region, are collected by the research team. Outdoor air pollution data are collected with a lichen diversity biomonitoring program, and individual pregnancy exposures are assessed with spatial geostatistical simulation, which provides the basis for uncertainty analysis of individual exposures. Awareness of outdoor air pollution uncertainty will improve validity of individual exposures assignments for further statistical analysis with multivariate regression models. DISCUSSION: Exposure misclassification is an issue of concern in semi-ecological design. In this study, personal exposures are assigned to each pregnant using geocoded addresses data. A stochastic simulation method is applied to lichen diversity values index measured at biomonitoring survey locations, in order to assess spatial uncertainty of lichen diversity value index at each geocoded address. These methods assume a model for spatial autocorrelation of exposure and provide a distribution of exposures in each study location. We believe that variability of simulated exposure values at geocoded addresses will improve knowledge on variability of exposures, improving therefore validity of individual exposures to input in posterior statistical analysis. PMID- 20950451 TI - Bee venom attenuates neuroinflammatory events and extends survival in amyotrophic lateral sclerosis models. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease affecting the central nervous system that is either sporadic or familial origin and causing the death of motor neurons. One of the genetic factors contributing to the etiology of ALS is mutant SOD1 (mtSOD1), which induces vulnerability of motor neurons through protein misfolding, mitochondrial dysfunction, oxidative damage, cytoskeletal abnormalities, defective axonal transport, glutamate excitotoxicity, inadequate growth factor signaling, and neuroinflammation. Bee venom has been used in the practice of Oriental medicine and evidence from the literature indicates that BV plays an anti-inflammatory or anti-nociceptive role against inflammatory reactions associated with arthritis and other inflammatory diseases. The purpose of the present study was to determine whether bee venom suppresses motor neuron loss and microglial cell activation in hSOD1G93A mutant mice. METHODS: Bee venom (BV) was bilaterally injected (subcutaneously) into a 14-week old (98 day old) male hSOD1G93A animal model at the Zusanli (ST36) acupoint, which is known to mediate an anti-inflammatory effect. For measurement of motor activity, rotarod test was performed and survival statistics were analyzed by Kaplan-Meier survival curves. The effects of BV treatment on anti neuroinflammation of hSOD1G93A mice were assessed via immunoreactions using Iba 1 as a microglia marker and TNF-alpha antibody. Activation of ERK, Akt, p38 MAP Kinase (MAPK), and caspase 3 proteins was evaluated by western blotting. RESULTS: BV-treated mutant hSOD1 transgenic mice showed a decrease in the expression levels of microglia marker and phospho-p38 MAPK in the spinal cord and brainstem. Interestingly, treatment of BV in symptomatic ALS animals improved motor activity and the median survival of the BV-treated group (139 +/- 3.5 days) was 18% greater than control group (117 +/- 3.1 days). Furthermore, we found that BV suppressed caspase-3 activity and blocked the defects of mitochondrial structure and cristae morphology in the lumbar spinal cord of hSOD1G93A mice at the symptomatic stage. CONCLUSION: From these findings, our research suggests BV could be a potential therapeutic agent for anti-neuroinflammatory effects in an animal model of ALS. PMID- 20950450 TI - Pdlim7 is required for maintenance of the mesenchymal/epidermal Fgf signaling feedback loop during zebrafish pectoral fin development. AB - BACKGROUND: Vertebrate limb development involves a reciprocal feedback loop between limb mesenchyme and the overlying apical ectodermal ridge (AER). Several gene pathways participate in this feedback loop, including Fgf signaling. In the forelimb lateral plate mesenchyme, Tbx5 activates Fgf10 expression, which in turn initiates and maintains the mesenchyme/AER Fgf signaling loop. Recent findings have revealed that Tbx5 transcriptional activity is regulated by dynamic nucleocytoplasmic shuttling and interaction with Pdlim7, a PDZ-LIM protein family member, along actin filaments. This Tbx5 regulation is critical in heart formation, but the coexpression of both proteins in other developing tissues suggests a broader functional role. RESULTS: Knock-down of Pdlim7 function leads to decreased pectoral fin cell proliferation resulting in a severely stunted fin phenotype. While early gene induction and patterning in the presumptive fin field appear normal, the pectoral fin precursor cells display compaction and migration defects between 18 and 24 hours post-fertilization (hpf). During fin growth fgf24 is sequentially expressed in the mesenchyme and then in the apical ectodermal ridge (AER). However, in pdlim7 antisense morpholino-treated embryos this switch of expression is prevented and fgf24 remains ectopically active in the mesenchymal cells. Along with the lack of fgf24 in the AER, other critical factors including fgf8 are reduced, suggesting signaling problems to the underlying mesenchyme. As a consequence of perturbed AER function in the absence of Pdlim7, pathway components in the fin mesenchyme are misregulated or absent, indicating a breakdown of the Fgf signaling feedback loop, which is ultimately responsible for the loss of fin outgrowth. CONCLUSION: This work provides the first evidence for the involvement of Pdlim7 in pectoral fin development. Proper fin outgrowth requires fgf24 downregulation in the fin mesenchyme with subsequent activation in the AER, and Pdlim7 appears to regulate this transition, potentially through Tbx5 regulation. By controlling Tbx5 subcellular localization and transcriptional activity and possibly additional yet unknown means, Pdlim7 is required for proper development of the heart and the fins. These new regulatory mechanisms may have important implications how we interpret Tbx5 function in congenital hand/heart syndromes in humans. PMID- 20950452 TI - Inferring gene regression networks with model trees. AB - BACKGROUND: Novel strategies are required in order to handle the huge amount of data produced by microarray technologies. To infer gene regulatory networks, the first step is to find direct regulatory relationships between genes building the so-called gene co-expression networks. They are typically generated using correlation statistics as pairwise similarity measures. Correlation-based methods are very useful in order to determine whether two genes have a strong global similarity but do not detect local similarities. RESULTS: We propose model trees as a method to identify gene interaction networks. While correlation-based methods analyze each pair of genes, in our approach we generate a single regression tree for each gene from the remaining genes. Finally, a graph from all the relationships among output and input genes is built taking into account whether the pair of genes is statistically significant. For this reason we apply a statistical procedure to control the false discovery rate. The performance of our approach, named REGNET, is experimentally tested on two well-known data sets: Saccharomyces Cerevisiae and E.coli data set. First, the biological coherence of the results are tested. Second the E.coli transcriptional network (in the Regulon database) is used as control to compare the results to that of a correlation based method. This experiment shows that REGNET performs more accurately at detecting true gene associations than the Pearson and Spearman zeroth and first order correlation-based methods. CONCLUSIONS: REGNET generates gene association networks from gene expression data, and differs from correlation-based methods in that the relationship between one gene and others is calculated simultaneously. Model trees are very useful techniques to estimate the numerical values for the target genes by linear regression functions. They are very often more precise than linear regression models because they can add just different linear regressions to separate areas of the search space favoring to infer localized similarities over a more global similarity. Furthermore, experimental results show the good performance of REGNET. PMID- 20950453 TI - Comparative transcriptomics among floral organs of the basal eudicot Eschscholzia californica as reference for floral evolutionary developmental studies. AB - BACKGROUND: Molecular genetic studies of floral development have concentrated on several core eudicots and grasses (monocots), which have canalized floral forms. Basal eudicots possess a wider range of floral morphologies than the core eudicots and grasses and can serve as an evolutionary link between core eudicots and monocots, and provide a reference for studies of other basal angiosperms. Recent advances in genomics have enabled researchers to profile gene activities during floral development, primarily in the eudicot Arabidopsis thaliana and the monocots rice and maize. However, our understanding of floral developmental processes among the basal eudicots remains limited. RESULTS: Using a recently generated expressed sequence tag (EST) set, we have designed an oligonucleotide microarray for the basal eudicot Eschscholzia californica (California poppy). We performed microarray experiments with an interwoven-loop design in order to characterize the E. californica floral transcriptome and to identify differentially expressed genes in flower buds with pre-meiotic and meiotic cells, four floral organs at preanthesis stages (sepals, petals, stamens and carpels), developing fruits, and leaves. CONCLUSIONS: Our results provide a foundation for comparative gene expression studies between eudicots and basal angiosperms. We identified whorl-specific gene expression patterns in E. californica and examined the floral expression of several gene families. Interestingly, most E. californica homologs of Arabidopsis genes important for flower development, except for genes encoding MADS-box transcription factors, show different expression patterns between the two species. Our comparative transcriptomics study highlights the unique evolutionary position of E. californica compared with basal angiosperms and core eudicots. PMID- 20950454 TI - Co-evolution of cancer microenvironment reveals distinctive patterns of gastric cancer invasion: laboratory evidence and clinical significance. AB - BACKGROUND: Cancer invasion results from constant interactions between cancer cells and their microenvironment. Major components of the cancer microenvironment are stromal cells, infiltrating inflammatory cells, collagens, matrix metalloproteinases (MMP) and newly formed blood vessels. This study was to determine the roles of MMP-9, MMP-2, type IV collagen, infiltrating macrophages and tumor microvessels in gastric cancer (GC) invasion and their clinico pathological significance. METHODS: Paraffin-embedded tissue sections from 37 GC patients were studied by Streptavidin-Peroxidase (SP) immunohistochemical technique to determine the levels of MMP-2, MMP-9, type IV collagen, macrophages infiltration and microvessel density (MVD). Different invasion patterns were delineated and their correlation with major clinico-pathological information was explored. RESULTS: MMP2 expression was higher in malignant gland compared to normal gland, especially nearby the basement membrane (BM). High densities of macrophages at the interface of cancer nests and stroma were found where BM integrity was destroyed. MMP2 expression was significantly increased in cases with recurrence and distant metastasis (P = 0.047 and 0.048, respectively). Infiltrating macrophages were correlated with serosa invasion (P = 0.011) and TNM stage (P = 0.001). MVD was higher in type IV collagen negative group compared to type IV collagen positive group (P = 0.026). MVD was related to infiltrating macrophages density (P = 0.040). Patients with negative MMP9 expression had better overall survival (OS) compared to those with positive MMP9 expression (Median OS 44.0 vs 13.5 mo, P = 0.036). Median OS was significantly longer in type IV collagen positive group than negative group (Median OS 25.5 vs 10.0 mo, P = 0.044). The cumulative OS rate was higher in low macrophages density group than in high macrophages density group (median OS 40.5 vs 13.0 mo, P = 0.056). Median OS was significantly longer in low MVD group than high MVD group (median OS 39.0 vs 8.5 mo, P = 0.001). The difference of disease-free survival (DFS) between low MVD group and high MVD group was not statistically significant (P = 0.260). Four typical patterns of cancer invasion were identified based on histological study of the cancer tissue, including Washing pattern, Ameba-like pattern, Spindle pattern and Linear pattern. CONCLUSIONS: Proteolytic enzymes MMP9, MMP2 and macrophages in stroma contribute to GC progression by facilitating the angiogenesis. Cancer invasion patterns may help predict GC metastasis. PMID- 20950455 TI - Route of administration for illicit prescription opioids: a comparison of rural and urban drug users. AB - BACKGROUND: Nonmedical prescription opioid use has emerged as a major public health concern in recent years, particularly in rural Appalachia. Little is known about the routes of administration (ROA) involved in nonmedical prescription opioid use among rural and urban drug users. The purpose of this study was to describe rural-urban differences in ROA for nonmedical prescription opioid use. METHODS: A purposive sample of 212 prescription drug users was recruited from a rural Appalachian county (n = 101) and a major metropolitan area (n = 111) in Kentucky. Consenting participants were given an interviewer-administered questionnaire examining sociodemographics, psychiatric disorders, and self reported nonmedical use and ROA (swallowing, snorting, injecting) for the following prescription drugs: buprenorphine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, OxyContin(r) and other oxycodone. RESULTS: Among urban participants, swallowing was the most common ROA, contrasting sharply with substance-specific variation in ROA among rural participants. Among rural participants, snorting was the most frequent ROA for hydrocodone, methadone, OxyContin(r), and oxycodone, while injection was most common for hydromorphone and morphine. In age-, gender-, and race-adjusted analyses, rural participants had significantly higher odds of snorting hydrocodone, OxyContin(r), and oxycodone than urban participants. Urban participants had significantly higher odds of swallowing hydrocodone and oxycodone than did rural participants. Notably, among rural participants, 67% of hydromorphone users and 63% of morphine users had injected the drugs. CONCLUSIONS: Alternative ROA are common among rural drug users. This finding has implications for rural substance abuse treatment and harm reduction, in which interventions should incorporate methods to prevent and reduce route-specific health complications of drug use. PMID- 20950456 TI - Primary and booster vaccination in Latin American children with a DTPw-HBV/Hib combination: a randomized controlled trial. AB - BACKGROUND: Diphtheria-tetanus-whole-cell pertussis (DTPw)-based combination vaccines are an attractive option to rapidly achieve high coverage and protection against other important pathogens, such as hepatitis B virus (HBV) and Haemophilus influenzae type B (Hib). To ensure adequate antigen supply, GlaxoSmithKline Biologicals has introduced a new DTPw antigen source and developed a new DTPw-HBV/Hib combination vaccine containing a reduced amount of Hib polyribosylribitol phosphate (PRP). This study was undertaken to compare the immunogenicity and reactogenicity of this new DTPw-HBV/Hib vaccine with a licensed DTPw-HBV/Hib vaccine (TritanrixTM-HBV/Hib). METHODS: This was a randomized, partially-blind, multicenter study in three countries in Latin America (Argentina, Chile and Nicaragua). Healthy children received either the new DTPw-HBV/Hib vaccine (1 of 3 lots; n = 439; double-blind) or TritanrixTM HBV/Hib (n = 146; single-blind) co-administered with oral poliovirus vaccine (OPV) at 2, 4 and 6 months, with a booster dose at 18-24 months. RESULTS: One month after the end of the 3-dose primary vaccination course, the new DTPw HBV/Hib vaccine was non-inferior to TritanrixTM-HBV/Hib in terms of seroprotection/vaccine response rates for all component antigens; >=97.3% and >=93.9% of subjects in the two groups, respectively, had seroprotective levels of antibodies against diphtheria, tetanus, hepatitis B and Hib and a vaccine response to the pertussis component. Persistence of antibodies against all vaccine antigens was comparable between groups, with marked increases in all antibody concentrations after booster administration in both groups. Both vaccines were generally well-tolerated as primary and booster doses. CONCLUSIONS: Results confirm the suitability of this new DTPw-HBV/Hib vaccine comprising antigens from a new source and a reduced PRP content for inclusion into routine childhood vaccination programs. TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT00332566. PMID- 20950457 TI - The immunogenicity and safety of a reduced PRP-content DTPw-HBV/Hib vaccine when administered according to the accelerated EPI schedule. AB - BACKGROUND: Combination vaccines improve coverage, compliance and effectively introduce new antigens to mass vaccination programmes. This was a phase III, observer-blind, randomized study of GSK Biologicals diphtheria-tetanus-whole cell pertussis vaccine combined with hepatitis B and Haemophilus influenzae type b vaccines, containing a reduced amount of polyribosyl-ribitol-phosphate (PRP) and a DTPw component manufactured at a different site (DTPw-HBV/Hib2.5 [Kft]). The primary aim of this study was to demonstrate that DTPw-HBV/Hib2.5 [Kft] was not inferior to the licensed DTPw-HBV/Hib (Tritanrix(tm)-HepB/Hiberix(tm)) vaccine or the DTPw-HBV/Hib2.5 vaccine, also containing a reduced amount of PRP, with respect to the immune response to the PRP antigen, when administered to healthy infants, according to the Expanded Programme for Immunization (EPI) schedule at 6, 10 and 14 weeks of age. METHODS: 299 healthy infants were randomised to receive either DTPw-HBV/Hib2.5 [Kft] DTPw-HBV/Hib2.5 or DTPw-HBV/Hib according to the 6-10-14 week EPI schedule. Blood samples were analysed prior to the first dose of study vaccine and one month after the third vaccine dose for the analysis of immune responses. Solicited local and general symptoms such as pain, redness and swelling at the injection site and drowsiness and fever, unsolicited symptoms (defined as any additional adverse event) and serious adverse events (SAEs) were recorded up to 20 weeks of age. RESULTS: One month after the third vaccine dose, 100% of subjects receiving DTPw-HBV/Hib2.5 [Kft] or DTPw-HBV/Hib and 98.8% of subjects receiving DTPw-HBV/Hib2.5 vaccine had seroprotective levels of anti-PRP antibodies (defined as anti-PRP antibody concentration >=0.15 MUg/ml). Seroprotective antibody concentrations were attained in over 98.9% of subjects for diphtheria, tetanus and hepatitis B. The vaccine response rate to pertussis antigen was at least 97.8% in each group. Overall, the DTPw-HBV/Hib2.5 [Kft] vaccine was well tolerated in healthy infants; no SAEs were reported in any group. CONCLUSIONS: The DTPw-HBV/Hib2.5 [Kft] vaccine was immunogenic and well tolerated when administered according to the EPI schedule to Indian infants. TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT00473668. PMID- 20950458 TI - A knowledge-based taxonomy of critical factors for adopting electronic health record systems by physicians: a systematic literature review. AB - BACKGROUND: The health care sector is an area of social and economic interest in several countries; therefore, there have been lots of efforts in the use of electronic health records. Nevertheless, there is evidence suggesting that these systems have not been adopted as it was expected, and although there are some proposals to support their adoption, the proposed support is not by means of information and communication technology which can provide automatic tools of support. The aim of this study is to identify the critical adoption factors for electronic health records by physicians and to use them as a guide to support their adoption process automatically. METHODS: This paper presents, based on the PRISMA statement, a systematic literature review in electronic databases with adoption studies of electronic health records published in English. Software applications that manage and process the data in the electronic health record have been considered, i.e.: computerized physician prescription, electronic medical records, and electronic capture of clinical data. Our review was conducted with the purpose of obtaining a taxonomy of the physicians main barriers for adopting electronic health records, that can be addressed by means of information and communication technology; in particular with the information technology roles of the knowledge management processes. Which take us to the question that we want to address in this work: "What are the critical adoption factors of electronic health records that can be supported by information and communication technology?". Reports from eight databases covering electronic health records adoption studies in the medical domain, in particular those focused on physicians, were analyzed. RESULTS: The review identifies two main issues: 1) a knowledge-based classification of critical factors for adopting electronic health records by physicians; and 2) the definition of a base for the design of a conceptual framework for supporting the design of knowledge-based systems, to assist the adoption process of electronic health records in an automatic fashion. From our review, six critical adoption factors have been identified: user attitude towards information systems, workflow impact, interoperability, technical support, communication among users, and expert support. The main limitation of the taxonomy is the different impact of the adoption factors of electronic health records reported by some studies depending on the type of practice, setting, or attention level; however, these features are a determinant aspect with regard to the adoption rate for the latter rather than the presence of a specific critical adoption factor. CONCLUSIONS: The critical adoption factors established here provide a sound theoretical basis for research to understand, support, and facilitate the adoption of electronic health records to physicians in benefit of patients. PMID- 20950459 TI - Inhibition of monocyte chemoattractant protein-1 prevents diaphragmatic inflammation and maintains contractile function during endotoxemia. AB - INTRODUCTION: Respiratory muscle weakness is common in sepsis patients. Proinflammatory mediators produced during sepsis have been implicated in diaphragmatic contractile dysfunction, but the role of chemokines has not been explored. This study addressed the role of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), in the pathogenesis of diaphragmatic inflammation and weakness during endotoxemia. METHODS: Mice were treated as follows (n = 6 per group): (a) saline, (b) endotoxin (25 MUg/g IP), (c) endotoxin + anti-MCP-1 antibody, and (d) endotoxin + isotype control antibody. Muscles were also exposed to recombinant MCP-1 in vivo and in vitro. Measurements were made of diaphragmatic force generation, leukocyte infiltration, and proinflammatory mediator (MCP-1, IL-1alpha, IL-1beta, IL-6, NF-kappaB) expression/activity. RESULTS: In vivo, endotoxin-treated mice showed a large decrease in diaphragmatic force, together with upregulation of MCP-1 and other cytokines, but without an increase in intramuscular leukocytes. Antibody neutralization of MCP-1 prevented the endotoxin-induced force loss and reduced expression of MCP-1, IL-1alpha, IL 1beta, and IL-6 in the diaphragm. MCP-1 treatment of nonseptic muscles also led to contractile weakness, and MCP-1 stimulated its own transcription independent of NF-kappaB activation in vitro. CONCLUSIONS: These results suggest that MCP-1 plays an important role in the pathogenesis of diaphragmatic weakness during sepsis by both direct and indirect mechanisms. We speculate that its immunomodulatory properties and ability to modify skeletal muscle function make MCP-1 a potential therapeutic target in critically ill patients with sepsis and associated respiratory muscle weakness. PMID- 20950460 TI - A Quick Test of cognitive speed is sensitive in detecting early treatment response in Alzheimer's disease. AB - INTRODUCTION: There is a great need for quick tests that identify treatment response in Alzheimer's disease (AD) to determine who benefits from the treatment. In this study, A Quick Test of cognitive speed (AQT) was compared with the mini-mental state examination (MMSE) in the evaluation of treatment outcome in AD. METHODS: 75 patients with mild to moderate AD at a memory clinic were assessed with AQT and the MMSE at a pretreatment visit, at baseline and after 8 weeks of treatment with cholinesterase inhibitors (ChEI) initiated at baseline. Changes in the mean test scores before and after treatment were compared, as well as the number of treatment responders detected by each test, according to a reliable change index (RCI). RESULTS: After 8 weeks of treatment, the AQT improvement, expressed as a percentage, was significantly greater than that of the MMSE (P = 0.026). According to the RCI, the cut-offs to define a responder were >=16 seconds improvement on AQT and >=3 points on the MMSE after 8 weeks. With these cut-offs, both tests falsely classified <=5% as responders during the pretreatment period. After 8 weeks of treatment, AQT detected significantly more responders than the MMSE (34% compared with 17%; P = 0.024). After 6 months of treatment, the 8-week AQT responders still showed a significantly better treatment response than the AQT nonresponders (22.3 seconds in mean difference; P < 0.001). CONCLUSIONS: AQT detects twice as many treatment responders as the MMSE. It seems that AQT can, already after 8 weeks, identify the AD patients who will continue to benefit from ChEI treatment. PMID- 20950461 TI - Women's experiences of sexual health when living with rheumatoid arthritis--an explorative qualitative study. AB - BACKGROUND: The ICF core sets for patients with Rheumatoid Arthritis (RA) acknowledge sexual function and intimate relationships as important since the patients' sexual health can be affected by the disease. About 36-70% of all RA patients experience a reduced sexual health, and their perceived problems are directly or indirectly caused by their disease. Physiotherapy is often used as non-pharmacological treatment for RA. Mobility treatment, pain reduction, and physical activities are often included in physiotherapy for patients with RA. The aim of the study was to explore sexual health in relation to physiotherapy in women living with RA. METHOD: An explorative qualitative interview study with a phenomenological approach was performed. The study consisted of ten interviews with women with RA. The analysis was performed according to Giorgi. RESULTS: The main theme that emerged in the material was that the body and the total life situation affected sexual health. Three categories were included in the theme: 1) sexual health - physical and psychological dimensions, 2) Impacts of RA, and 3) Possibilities to increase sexual health - does physiotherapy make a difference? CONCLUSIONS: Sexual health was affected by RA in different ways for the informants. Possibilities to improve sexual health were improved partner communication and physiotherapy. Physiotherapy can play an active role in improving sexual health for patients with RA. PMID- 20950462 TI - CD36 deficiency attenuates experimental mycobacterial infection. AB - BACKGROUND: Members of the CD36 scavenger receptor family have been implicated as sensors of microbial products that mediate phagocytosis and inflammation in response to a broad range of pathogens. We investigated the role of CD36 in host response to mycobacterial infection. METHODS: Experimental Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection in Cd36+/+ and Cd36-/- mice, and in vitro co-cultivation of M. tuberculosis, BCG and M. marinum with Cd36+/+ and Cd36 /-murine macrophages. RESULTS: Using an in vivo model of BCG infection in Cd36+/+ and Cd36-/- mice, we found that mycobacterial burden in liver and spleen is reduced (83% lower peak splenic colony forming units, p < 0.001), as well as the density of granulomas, and circulating tumor necrosis factor (TNF) levels in Cd36 /- animals. Intracellular growth of all three mycobacterial species was reduced in Cd36-/- relative to wild type Cd36+/+ macrophages in vitro. This difference was not attributable to alterations in mycobacterial uptake, macrophage viability, rate of macrophage apoptosis, production of reactive oxygen and/or nitrogen species, TNF or interleukin-10. Using an in vitro model designed to recapitulate cellular events implicated in mycobacterial infection and dissemination in vivo (i.e., phagocytosis of apoptotic macrophages containing mycobacteria), we demonstrated reduced recovery of viable mycobacteria within Cd36-/- macrophages. CONCLUSIONS: Together, these data indicate that CD36 deficiency confers resistance to mycobacterial infection. This observation is best explained by reduced intracellular survival of mycobacteria in the Cd36-/- macrophage and a role for CD36 in the cellular events involved in granuloma formation that promote early bacterial expansion and dissemination. PMID- 20950464 TI - What differences are detected by superiority trials or ruled out by noninferiority trials? A cross-sectional study on a random sample of two-hundred two-arms parallel group randomized clinical trials. AB - BACKGROUND: The smallest difference to be detected in superiority trials or the largest difference to be ruled out in noninferiority trials is a key determinant of sample size, but little guidance exists to help researchers in their choice. The objectives were to examine the distribution of differences that researchers aim to detect in clinical trials and to verify that those differences are smaller in noninferiority compared to superiority trials. METHODS: Cross-sectional study based on a random sample of two hundred two-arm, parallel group superiority (100) and noninferiority (100) randomized clinical trials published between 2004 and 2009 in 27 leading medical journals. The main outcome measure was the smallest difference in favor of the new treatment to be detected (superiority trials) or largest unfavorable difference to be ruled out (noninferiority trials) used for sample size computation, expressed as standardized difference in proportions, or standardized difference in means. Student t test and analysis of variance were used. RESULTS: The differences to be detected or ruled out varied considerably from one study to the next; e.g., for superiority trials, the standardized difference in means ranged from 0.007 to 0.87, and the standardized difference in proportions from 0.04 to 1.56. On average, superiority trials were designed to detect larger differences than noninferiority trials (standardized difference in proportions: mean 0.37 versus 0.27, P = 0.001; standardized difference in means: 0.56 versus 0.40, P = 0.006). Standardized differences were lower for mortality than for other outcomes, and lower in cardiovascular trials than in other research areas. CONCLUSIONS: Superiority trials are designed to detect larger differences than noninferiority trials are designed to rule out. The variability between studies is considerable and is partly explained by the type of outcome and the medical context. A more explicit and rational approach to choosing the difference to be detected or to be ruled out in clinical trials may be desirable. PMID- 20950465 TI - Biotechnology entrepreneurship--where no research has gone before. PMID- 20950463 TI - Units of plasticity in bacterial genomes: new insight from the comparative genomics of two bacteria interacting with invertebrates, Photorhabdus and Xenorhabdus. AB - BACKGROUND: Flexible genomes facilitate bacterial evolution and are classically organized into polymorphic strain-specific segments called regions of genomic plasticity (RGPs). Using a new web tool, RGPFinder, we investigated plasticity units in bacterial genomes, by exhaustive description of the RGPs in two Photorhabdus and two Xenorhabdus strains, belonging to the Enterobacteriaceae and interacting with invertebrates (insects and nematodes). RESULTS: RGPs account for about 60% of the genome in each of the four genomes studied. We classified RGPs into genomic islands (GIs), prophages and two new classes of RGP without the features of classical mobile genetic elements (MGEs) but harboring genes encoding enzymes catalyzing DNA recombination (RGPmob), or with no remarkable feature (RGPnone). These new classes accounted for most of the RGPs and are probably hypervariable regions, ancient MGEs with degraded mobilization machinery or non canonical MGEs for which the mobility mechanism has yet to be described. We provide evidence that not only the GIs and the prophages, but also RGPmob and RGPnone, have a mosaic structure consisting of modules. A module is a block of genes, 0.5 to 60 kb in length, displaying a conserved genomic organization among the different Enterobacteriaceae. Modules are functional units involved in host/environment interactions (22-31%), metabolism (22-27%), intracellular or intercellular DNA mobility (13-30%), drug resistance (4-5%) and antibiotic synthesis (3-6%). Finally, in silico comparisons and PCR multiplex analysis indicated that these modules served as plasticity units within the bacterial genome during genome speciation and as deletion units in clonal variants of Photorhabdus. CONCLUSIONS: This led us to consider the modules, rather than the entire RGP, as the true unit of plasticity in bacterial genomes, during both short-term and long-term genome evolution. PMID- 20950466 TI - Thoracoscopic resection of a paraaortic bronchogenic cyst. AB - Bronchogenic mediastinal cysts (BMC) represent 18% of primitive mediastinal tumors and the most frequent cystic lesions in this area. Nowadays, BMC are usually treated by VATS. However, the presence of major adhesions to vital structures is often considered as an unfavourable condition for thoracoscopic treatment. The authors report the thoracoscopic treatment of a BMC having dense adhesions to the aortic arch. Diagnosis and surgical treatment is described. Review of the literature and surgical options on this topic are discussed. PMID- 20950467 TI - Effect of a single acupuncture treatment on surgical wound healing in dogs: a randomized, single blinded, controlled pilot study. AB - BACKGROUND: The aim of the study was to investigate the effect of acupuncture on wound healing after soft tissue or orthopaedic surgery in dogs. METHODS: 29 dogs were submitted to soft tissue and/or orthopaedic surgeries. Five dogs had two surgical wounds each, so there were totally 34 wounds in the study. All owners received instructions for post operative care as well as antibiotic and pain treatment. The dogs were randomly assigned to treatment or control groups. Treated dogs received one dry needle acupuncture treatment right after surgery and the control group received no such treatment. A veterinary surgeon that was blinded to the treatment, evaluated the wounds at three and seven days after surgery in regard to oedema (scale 0-3), scabs (yes/no), exudate (yes/no), hematoma (yes/no), dermatitis (yes/no), and aspect of the wound (dry/humid). RESULTS: There was no significant difference between the treatment and control groups in the variables evaluated three and seven days after surgery. However, oedema reduced significantly in the group treated with acupuncture at seven days compared to three days after surgery, possibly due the fact that there was more oedema in the treatment group at day three (although this difference was nor significant between groups). CONCLUSIONS: The use of a single acupuncture treatment right after surgery in dogs did not appear to have any beneficial effects in surgical wound healing. PMID- 20950468 TI - New PRSS1 and common CFTR mutations in a child with acute recurrent pancreatitis, could be considered an "Hereditary" form of pancreatitis ? AB - BACKGROUND: acute recurrent pancreatitis is a complex multigenic disease, the diagnosis is even more difficult when this disease develops in a child. CASE PRESENTATION: a 6-years old boy, hospitalized with epigastric pain radiating to the back showed high serum levels of serum amylase, lipase, CRP and erythrosedimentation rate. Several similar milder episodes of pain, followed by quick recovery and complete disappearance of symptoms were reported during the previous 13 months. The child was medically treated and after 7 days with normal clinic and laboratory tests was discharged with a hypolipidic diet. All the known aetiologic hypotheses were excluded by anamnestic investigation, clinical observation and biochemical evaluation, whereas, anatomic abnormality were excluded by a secretin stimulated magnetic resonance (MRI). At the last follow-up visit, (11 months later), the child showed a normal body weight and anthropometric profile, without further abdominal pain. Mutation screening for coding regions of PRSS1, SPINK1, CFTR and the new hereditary pancreatitis associated chymotrypsin C (CTRC) genes showed a novel variation, c.541A > G (p.S181G), in the exon 4 of PRSS1 gene and the classical CF p.F508del mutation in the CFTR. Both mutations were present in his clinically normal mother and absent in the patient's father. CONCLUSIONS: this report extend the spectrum of PRSS1 mutations, however, the absence of family history of pancreatitis leaves the present case without the hallmark of the hereditary origin of pancreatitis. At the present knowledge it can be only stated that the combined genotype CFTR (F508del)/PRSS1 (S181G) is associated to a mild phenotype of acute recurrent pancreatitis in this child without any further conclusion on its pathogenetic role or prediction on the course of the disease. PMID- 20950469 TI - Large volume unresectable locally advanced non-small cell lung cancer: acute toxicity and initial outcome results with rapid arc. AB - BACKGROUND: To report acute toxicity, initial outcome results and planning therapeutic parameters in radiation treatment of advanced lung cancer (stage III) with volumetric modulated arcs using RapidArc (RA). METHODS: Twenty-four consecutive patients were treated with RA. All showed locally advanced non-small cell lung cancer with stage IIIA-IIIB and with large volumes (GTV:299 +/- 175 cm3, PTV:818 +/- 206 cm3). Dose prescription was 66Gy in 33 fractions to mean PTV. Delivery was performed with two partial arcs with a 6 MV photon beam. RESULTS: From a dosimetric point of view, RA allowed us to respect most planning objectives on target volumes and organs at risk. In particular: for GTV D1% = 105.6 +/- 1.7%, D99% = 96.7 +/- 1.8%, D5%-D95% = 6.3 +/- 1.4%; contra-lateral lung mean dose resulted in 13.7 +/- 3.9Gy, for spinal cord D1% = 39.5 +/- 4.0Gy, for heart V45Gy = 9.0 +/- 7.0Gy, for esophagus D1% = 67.4 +/- 2.2Gy. Delivery time was 133 +/- 7s. At three months partial remission > 50% was observed in 56% of patients. Acute toxicities at 3 months showed 91% with grade 1 and 9% with grade 2 esophageal toxicity; 18% presented grade 1 and 9% with grade 2 pneumonia; no grade 3 acute toxicity was observed. The short follow-up does not allow assessment of local control and progression free survival. CONCLUSIONS: RA proved to be a safe and advantageous treatment modality for NSCLC with large volumes. Long term observation of patients is needed to assess outcome and late toxicity. PMID- 20950470 TI - Genome-wide characterization of simple sequence repeats in cucumber (Cucumis sativus L.). AB - BACKGROUND: Cucumber, Cucumis sativus L. is an important vegetable crop worldwide. Until very recently, cucumber genetic and genomic resources, especially molecular markers, have been very limited, impeding progress of cucumber breeding efforts. Microsatellites are short tandemly repeated DNA sequences, which are frequently favored as genetic markers due to their high level of polymorphism and codominant inheritance. Data from previously characterized genomes has shown that these repeats vary in frequency, motif sequence, and genomic location across taxa. During the last year, the genomes of two cucumber genotypes were sequenced including the Chinese fresh market type inbred line '9930' and the North American pickling type inbred line 'Gy14'. These sequences provide a powerful tool for developing markers in a large scale. In this study, we surveyed and characterized the distribution and frequency of perfect microsatellites in 203 Mbp assembled Gy14 DNA sequences, representing 55% of its nuclear genome, and in cucumber EST sequences. Similar analyses were performed in genomic and EST data from seven other plant species, and the results were compared with those of cucumber. RESULTS: A total of 112,073 perfect repeats were detected in the Gy14 cucumber genome sequence, accounting for 0.9% of the assembled Gy14 genome, with an overall density of 551.9 SSRs/Mbp. While tetranucleotides were the most frequent microsatellites in genomic DNA sequence, dinucleotide repeats, which had more repeat units than any other SSR type, had the highest cumulative sequence length. Coding regions (ESTs) of the cucumber genome had fewer microsatellites compared to its genomic sequence, with trinucleotides predominating in EST sequences. AAG was the most frequent repeat in cucumber ESTs. Overall, AT-rich motifs prevailed in both genomic and EST data. Compared to the other species examined, cucumber genomic sequence had the highest density of SSRs (although comparable to the density of poplar, grapevine and rice), and was richest in AT dinucleotides. Using an electronic PCR strategy, we investigated the polymorphism between 9930 and Gy14 at 1,006 SSR loci, and found unexpectedly high degree of polymorphism (48.3%) between the two genotypes. The level of polymorphism seems to be positively associated with the number of repeat units in the microsatellite. The in silico PCR results were validated empirically in 660 of the 1,006 SSR loci. In addition, primer sequences for more than 83,000 newly-discovered cucumber microsatellites, and their exact positions in the Gy14 genome assembly were made publicly available. CONCLUSIONS: The cucumber genome is rich in microsatellites; AT and AAG are the most abundant repeat motifs in genomic and EST sequences of cucumber, respectively. Considering all the species investigated, some commonalities were noted, especially within the monocot and dicot groups, although the distribution of motifs and the frequency of certain repeats were characteristic of the species examined. The large number of SSR markers developed from this study should be a significant contribution to the cucurbit research community. PMID- 20950471 TI - Chyle leakage in port incision after video-assisted thoracoscopic surgery: case report. AB - A 26-year-old Asian male was found to have chyle leakage from the port incision after video-assisted thoracoscopic surgery (VATS) for excision of pulmonary bullae. The diagnosis was confirmed by oral intake of Sudan black and by lymphoscintigraphy. The leakage resolved after 5 days of restricted oral intake and total parenteral nutrition. No leakage recurred after return of oral intake. Possible explanations for the port incision chyle leakage are obstruction of the thoracic duct, which induced retrograde drainage of the lymphoid fluid, or an aberrant collateral branch of the thoracic duct in the chest wall. PMID- 20950473 TI - The effects of temperature on nitrous oxide and oxygen mixture homogeneity and stability. AB - BACKGROUND: For many long standing practices, the rationale for them is often lost as time passes. This is the situation with respect to the storage and handling of equimolar 50% nitrous oxide and 50% oxygen volume/volume (v/v) mixtures. METHODS: A review was undertaken of existing literature to examine the developmental history of nitrous oxide and oxygen mixtures for anesthesia and analgesia and to ascertain if sufficient bibliographic data was available to support the position that the contents of a cylinder of a 50%/50% volume/volume (v/v) mixture of nitrous oxide and oxygen is in a homogenous single gas phase in a filled cylinder under normal conditions of handling and storage and if justification could be found for the standard instructions given for handling before use. RESULTS: After ranking and removing duplicates, a total of fifteen articles were identified by the various search strategies and formed the basis of this literature review. Several studies were identified that confirmed that 50%/50% v/v mixture of nitrous oxide and oxygen is in a homogenous single gas phase in a filled cylinder under normal conditions of handling and storage. The effect of temperature on the change of phase of the nitrous oxide in this mixture was further examined by several authors. These studies demonstrated that although it is possible to cause condensation and phase separation by cooling the cylinder, by allowing the cylinder to rewarm to room temperature for at least 48 hours, preferably in a horizontal orientation, and inverting it three times before use, the cylinder consistently delivered the proper proportions of the component gases as a homogenous mixture. CONCLUSIONS: The contents of a cylinder of a 50%/50% volume/volume (v/v) mixture of nitrous oxide and oxygen is in a homogenous single gas phase in a filled cylinder under normal conditions of handling and storage. The standard instructions given for handling before are justified based on previously conducted studies. PMID- 20950472 TI - Prediction and analysis of the modular structure of cytochrome P450 monooxygenases. AB - BACKGROUND: Cytochrome P450 monooxygenases (CYPs) form a vast and diverse family of highly variable sequences. They catalyze a wide variety of oxidative reactions and are therefore of great relevance in drug development and biotechnological applications. Despite their differences in sequence and substrate specificity, the structures of CYPs are highly similar. Although being in research focus for years, factors mediating selectivity and activity remain vague. DESCRIPTION: This systematic comparison of CYPs based on the Cytochrome P450 Engineering Database (CYPED) involved sequence and structure analysis of more than 8000 sequences. 31 structures have been applied to generate a reliable structure-based HMM profile in order to predict structurally conserved regions. Therefore, it was possible to automatically transfer these modules on CYP sequences without any secondary structure information, to analyze substrate interacting residues and to compare interaction sites with redox partners. CONCLUSIONS: Functionally relevant structural sites of CYPs were predicted. Regions involved in substrate binding were analyzed in all sequences among the CYPED. For all CYPs that require a reductase, two reductase interaction sites were identified and classified according to their length. The newly gained insights promise an improvement of engineered enzyme properties for potential biotechnological application. The annotated sequences are accessible on the current version of the CYPED. The prediction tool can be applied to any CYP sequence via the web interface at http://www.cyped.uni-stuttgart.de/cgi-bin/strpred/dosecpred.pl. PMID- 20950474 TI - Exploratory factor analysis of self-reported symptoms in a large, population based military cohort. AB - BACKGROUND: US military engagements have consistently raised concern over the array of health outcomes experienced by service members postdeployment. Exploratory factor analysis has been used in studies of 1991 Gulf War-related illnesses, and may increase understanding of symptoms and health outcomes associated with current military conflicts in Iraq and Afghanistan. The objective of this study was to use exploratory factor analysis to describe the correlations among numerous physical and psychological symptoms in terms of a smaller number of unobserved variables or factors. METHODS: The Millennium Cohort Study collects extensive self-reported health data from a large, population-based military cohort, providing a unique opportunity to investigate the interrelationships of numerous physical and psychological symptoms among US military personnel. This study used data from the Millennium Cohort Study, a large, population-based military cohort. Exploratory factor analysis was used to examine the covariance structure of symptoms reported by approximately 50,000 cohort members during 2004 2006. Analyses incorporated 89 symptoms, including responses to several validated instruments embedded in the questionnaire. Techniques accommodated the categorical and sometimes incomplete nature of the survey data. RESULTS: A 14 factor model accounted for 60 percent of the total variance in symptoms data and included factors related to several physical, psychological, and behavioral constructs. A notable finding was that many factors appeared to load in accordance with symptom co-location within the survey instrument, highlighting the difficulty in disassociating the effects of question content, location, and response format on factor structure. CONCLUSIONS: This study demonstrates the potential strengths and weaknesses of exploratory factor analysis to heighten understanding of the complex associations among symptoms. Further research is needed to investigate the relationship between factor analytic results and survey structure, as well as to assess the relationship between factor scores and key exposure variables. PMID- 20950475 TI - A fast and cost-effective approach to develop and map EST-SSR markers: oak as a case study. AB - BACKGROUND: Expressed Sequence Tags (ESTs) are a source of simple sequence repeats (SSRs) that can be used to develop molecular markers for genetic studies. The availability of ESTs for Quercus robur and Quercus petraea provided a unique opportunity to develop microsatellite markers to accelerate research aimed at studying adaptation of these long-lived species to their environment. As a first step toward the construction of a SSR-based linkage map of oak for quantitative trait locus (QTL) mapping, we describe the mining and survey of EST-SSRs as well as a fast and cost-effective approach (bin mapping) to assign these markers to an approximate map position. We also compared the level of polymorphism between genomic and EST-derived SSRs and address the transferability of EST-SSRs in Castanea sativa (chestnut). RESULTS: A catalogue of 103,000 Sanger ESTs was assembled into 28,024 unigenes from which 18.6% presented one or more SSR motifs. More than 42% of these SSRs corresponded to trinucleotides. Primer pairs were designed for 748 putative unigenes. Overall 37.7% (283) were found to amplify a single polymorphic locus in a reference full-sib pedigree of Quercus robur. The usefulness of these loci for establishing a genetic map was assessed using a bin mapping approach. Bin maps were constructed for the male and female parental tree for which framework linkage maps based on AFLP markers were available. The bin set consisting of 14 highly informative offspring selected based on the number and position of crossover sites. The female and male maps comprised 44 and 37 bins, with an average bin length of 16.5 cM and 20.99 cM, respectively. A total of 256 EST-SSRs were assigned to bins and their map position was further validated by linkage mapping. EST-SSRs were found to be less polymorphic than genomic SSRs, but their transferability rate to chestnut, a phylogenetically related species to oak, was higher. CONCLUSION: We have generated a bin map for oak comprising 256 EST-SSRs. This resource constitutes a first step toward the establishment of a gene-based map for this genus that will facilitate the dissection of QTLs affecting complex traits of ecological importance. PMID- 20950476 TI - A phase 2 randomized, double-blind study of AMG 108, a fully human monoclonal antibody to IL-1R, in patients with rheumatoid arthritis. AB - INTRODUCTION: Preclinical work has suggested that IL-1 plays a critical role in the pathogenesis of rheumatoid arthritis (RA). The objective of the present study was to determine the effect of a long-acting IL-1 receptor inhibitor, AMG 108, in a double-blind, placebo-controlled, parallel-dosing study in patients with active RA who were receiving stable methotrexate (15 to 25 mg/week). METHODS: Patients were randomized equally to receive placebo or 50, 125, or 250 mg AMG 108 subcutaneously every 4 weeks for 6 months. The primary efficacy endpoint was a 20% improvement in the American College of Rheumatology response (ACR20) at week 24; other efficacy endpoints included the ACR50, the ACR70, and the RA disease activity score (28-joint count Disease Activity Score) responses, patient reported outcomes, and pharmacokinetic parameters. Safety endpoints included treatment-emergent adverse events (AEs), infectious AEs, serious AEs, serious infections, injection site reactions, laboratory abnormalities, and antibodies to AMG 108. RESULTS: Of 813 patients enrolled in the study, 204 patients were randomized to the 50 mg group, 203 to the 125 mg group, 203 to the 250 mg group, and 203 to placebo. At week 24, 40.4% of the 250 mg group, 36% of the 125 mg group, 30.9% of the 50 mg group, and 29.1% of the placebo group achieved an ACR20 (P = 0.022, 250 mg vs. placebo). Of the individual ACR components, numerical dose dependent improvements were only seen in tender joint counts, pain (visual analog scale), and the acute phase reactants, erythrocyte sedimentation rate and C reactive protein. No dose-related increase was observed in the incidence of treatment-emergent AEs. No deaths were reported, and the incidence of AEs and infections, serious AEs and infections, and withdrawals from study for safety were similar in the AMG 108 and placebo groups. CONCLUSIONS: This large double blind randomized trial with a long-acting IL-1 receptor blocker, AMG 108, is consistent with the experience of other IL-1 blockers, represents a definitive experiment showing that IL-1 inhibition provides only moderate symptomatic amelioration of arthritis activity in the majority of RA patients, and provides an answer to a question that has been discussed for many years in the rheumatologic community. TRIAL REGISTRATION: ClinicalTrials.gov NCT00293826. PMID- 20950477 TI - Serial interferon-gamma release assays during treatment of active tuberculosis in young adults. AB - BACKGROUND: The role of interferon-gamma release assay (IGRA) in monitoring responses to anti-tuberculosis (TB) treatment is not clear. We evaluated the results of the QuantiFERON-TB Gold In-tube (QFT-GIT) assay over time during the anti-TB treatment of adults with no underlying disease. METHODS: We enrolled soldiers who were newly diagnosed with active TB and admitted to the central referral military hospital in South Korea between May 1, 2008 and September 30, 2009. For each participant, we preformed QFT-GIT assay before treatment (baseline) and at 1, 3, and 6 months after initiating anti-TB medication. RESULTS: Of 67 eligible patients, 59 (88.1%) completed the study protocol. All participants were males who were human immunodeficiency virus (HIV)-negative and had no chronic diseases. Their median age was 21 years (range, 20-48). Initially, 57 (96.6%) patients had positive QFT-GIT results, and 53 (89.8%), 42 (71.2%), and 39 (66.1%) had positive QFT-GIT results at 1, 3, and 6 months, respectively. The IFN-gamma level at baseline was 5.31 +/- 5.34 IU/ml, and the levels at 1, 3, and 6 months were 3.95 +/- 4.30, 1.82 +/- 2.14, and 1.50 +/- 2.12 IU/ml, respectively. All patients had clinical and radiologic improvements after treatment and were cured. A lower IFN-gamma level, C-reactive protein >= 3 mg/dl, and the presence of fever (>= 38.3 degrees C) at diagnosis were associated with negative reversion of the QFT-GIT assay. CONCLUSION: Although the IFN-gamma level measured by QFT-GIT assay decreased after successful anti-TB treatment in most participants, less than half of them exhibited QFT-GIT reversion. Thus, the reversion to negativity of the QFT-GIT assay may not be a good surrogate for treatment response in otherwise healthy young patients with TB. PMID- 20950478 TI - Accuracy of direct genomic values in Holstein bulls and cows using subsets of SNP markers. AB - BACKGROUND: At the current price, the use of high-density single nucleotide polymorphisms (SNP) genotyping assays in genomic selection of dairy cattle is limited to applications involving elite sires and dams. The objective of this study was to evaluate the use of low-density assays to predict direct genomic value (DGV) on five milk production traits, an overall conformation trait, a survival index, and two profit index traits (APR, ASI). METHODS: Dense SNP genotypes were available for 42,576 SNP for 2,114 Holstein bulls and 510 cows. A subset of 1,847 bulls born between 1955 and 2004 was used as a training set to fit models with various sets of pre-selected SNP. A group of 297 bulls born between 2001 and 2004 and all cows born between 1992 and 2004 were used to evaluate the accuracy of DGV prediction. Ridge regression (RR) and partial least squares regression (PLSR) were used to derive prediction equations and to rank SNP based on the absolute value of the regression coefficients. Four alternative strategies were applied to select subset of SNP, namely: subsets of the highest ranked SNP for each individual trait, or a single subset of evenly spaced SNP, where SNP were selected based on their rank for ASI, APR or minor allele frequency within intervals of approximately equal length. RESULTS: RR and PLSR performed very similarly to predict DGV, with PLSR performing better for low density assays and RR for higher-density SNP sets. When using all SNP, DGV predictions for production traits, which have a higher heritability, were more accurate (0.52-0.64) than for survival (0.19-0.20), which has a low heritability. The gain in accuracy using subsets that included the highest ranked SNP for each trait was marginal (5-6%) over a common set of evenly spaced SNP when at least 3,000 SNP were used. Subsets containing 3,000 SNP provided more than 90% of the accuracy that could be achieved with a high-density assay for cows, and 80% of the high-density assay for young bulls. CONCLUSIONS: Accurate genomic evaluation of the broader bull and cow population can be achieved with a single genotyping assays containing ~ 3,000 to 5,000 evenly spaced SNP. PMID- 20950479 TI - Health literacy, health status, and healthcare utilization of Taiwanese adults: results from a national survey. AB - BACKGROUND: Low health literacy is considered a worldwide health threat. The purpose of this study is to assess the prevalence and socio-demographic covariates of low health literacy in Taiwanese adults and to investigate the relationships between health literacy and health status and health care utilization. METHODS: A national survey of 1493 adults was conducted in 2008. Health literacy was measured using the Mandarin Health Literacy Scale. Health status was measured based on self-rated physical and mental health. Health care utilization was measured based on self-reported outpatient clinic visits, emergency room visits, and hospitalizations. RESULTS: Approximately thirty percent of adults were found to have low (inadequate or marginal) health literacy. They tended to be older, have fewer years of schooling, lower household income, and reside in less populated areas. Inadequate health literacy was associated with poorer mental health (OR, 0.57; 95% CI, 0.35-0.91). No association was found between health literacy and health care utilization even after adjusting for other covariates. CONCLUSIONS: Low (inadequate and marginal) health literacy is prevalent in Taiwan. High prevalence of low health literacy is not necessarily indicative of the need for interventions. Systematic efforts to evaluate the impact of low health literacy on health outcomes in other countries would help to illuminate features of health care delivery and financing systems that may mitigate the adverse health effects of low health literacy. PMID- 20950481 TI - The implementation of DRG-based hospital reimbursement in Switzerland: A population-based perspective. AB - BACKGROUND: Switzerland introduces a DRG (Diagnosis Related Groups) based system for hospital financing in 2012 in order to increase efficiency and transparency of Swiss health care. DRG-based hospital reimbursement is not simultaneously realized in all Swiss cantons and several cantons already implemented DRG-based financing irrespective of the national agenda, a setting that provides an opportunity to compare the situation in different cantons. Effects of introducing DRGs anticipated for providers and insurers are relatively well known but it remains less clear what effects DRGs will have on served populations. The objective of the study is therefore to analyze differences of volume and major quality indicators of care between areas with or without DRG-based hospital reimbursement from a population based perspective. METHODS: Small area analysis of all hospitalizations in acute care hospitals and of all consultations reimbursed by mandatory basic health insurance for physicians in own practice during 2003-2007. RESULTS: The results show fewer hospitalizations and a relocation of resources to outpatient care in areas with DRG reimbursement. Overall burden of disease expressed as per capita DRG cost weights was almost identical between the two types of hospital reimbursement and no distinct temporal differences were detected in this respect. But the results show considerably higher 90-day rehospitalization rates in DRG areas. CONCLUSION: The study provides evidence of both desired and harmful effects related to the implementation of DRGs. Systematic monitoring of outcomes and quality of care are therefore essential elements to maintain in the Swiss health system after DRG's are implemented on a nationwide basis in 2012. PMID- 20950480 TI - Comparing de novo assemblers for 454 transcriptome data. AB - BACKGROUND: Roche 454 pyrosequencing has become a method of choice for generating transcriptome data from non-model organisms. Once the tens to hundreds of thousands of short (250-450 base) reads have been produced, it is important to correctly assemble these to estimate the sequence of all the transcripts. Most transcriptome assembly projects use only one program for assembling 454 pyrosequencing reads, but there is no evidence that the programs used to date are optimal. We have carried out a systematic comparison of five assemblers (CAP3, MIRA, Newbler, SeqMan and CLC) to establish best practices for transcriptome assemblies, using a new dataset from the parasitic nematode Litomosoides sigmodontis. RESULTS: Although no single assembler performed best on all our criteria, Newbler 2.5 gave longer contigs, better alignments to some reference sequences, and was fast and easy to use. SeqMan assemblies performed best on the criterion of recapitulating known transcripts, and had more novel sequence than the other assemblers, but generated an excess of small, redundant contigs. The remaining assemblers all performed almost as well, with the exception of Newbler 2.3 (the version currently used by most assembly projects), which generated assemblies that had significantly lower total length. As different assemblers use different underlying algorithms to generate contigs, we also explored merging of assemblies and found that the merged datasets not only aligned better to reference sequences than individual assemblies, but were also more consistent in the number and size of contigs. CONCLUSIONS: Transcriptome assemblies are smaller than genome assemblies and thus should be more computationally tractable, but are often harder because individual contigs can have highly variable read coverage. Comparing single assemblers, Newbler 2.5 performed best on our trial data set, but other assemblers were closely comparable. Combining differently optimal assemblies from different programs however gave a more credible final product, and this strategy is recommended. PMID- 20950482 TI - The tricarboxylic acid cycle in Shewanella oneidensis is independent of Fur and RyhB control. AB - BACKGROUND: It is well established in E. coli and Vibrio cholerae that strains harboring mutations in the ferric uptake regulator gene (fur) are unable to utilize tricarboxylic acid (TCA) compounds, due to the down-regulation of key TCA cycle enzymes, such as AcnA and SdhABCD. This down-regulation is mediated by a Fur-regulated small regulatory RNA named RyhB. It is unclear in the gamma proteobacterium S. oneidensis whether TCA is also regulated by Fur and RyhB. RESULTS: In the present study, we showed that a fur deletion mutant of S. oneidensis could utilize TCA compounds. Consistently, expression of the TCA cycle genes acnA and sdhA was not down-regulated in the mutant. To explore this observation further, we identified a ryhB gene in Shewanella species and experimentally demonstrated the gene expression. Further experiments suggested that RyhB was up-regulated in fur mutant, but that AcnA and SdhA were not controlled by RyhB. CONCLUSIONS: These cumulative results delineate an important difference of the Fur-RyhB regulatory cycle between S. oneidensis and other gamma proteobacteria. This work represents a step forward for understanding the unique regulation in S. oneidensis. PMID- 20950483 TI - Accurate peak list extraction from proteomic mass spectra for identification and profiling studies. AB - BACKGROUND: Mass spectrometry is an essential technique in proteomics both to identify the proteins of a biological sample and to compare proteomic profiles of different samples. In both cases, the main phase of the data analysis is the procedure to extract the significant features from a mass spectrum. Its final output is the so-called peak list which contains the mass, the charge and the intensity of every detected biomolecule. The main steps of the peak list extraction procedure are usually preprocessing, peak detection, peak selection, charge determination and monoisotoping operation. RESULTS: This paper describes an original algorithm for peak list extraction from low and high resolution mass spectra. It has been developed principally to improve the precision of peak extraction in comparison to other reference algorithms. It contains many innovative features among which a sophisticated method for managing the overlapping isotopic distributions. CONCLUSIONS: The performances of the basic version of the algorithm and of its optional functionalities have been evaluated in this paper on both SELDI-TOF, MALDI-TOF and ESI-FTICR ECD mass spectra. Executable files of MassSpec, a MATLAB implementation of the peak list extraction procedure for Windows and Linux systems, can be downloaded free of charge for nonprofit institutions from the following web site: http://aimed11.unipv.it/MassSpec. PMID- 20950484 TI - Anemia and chronic kidney disease are potential risk factors for mortality in stroke patients: a historic cohort study. AB - BACKGROUND: Chronic kidney disease (CKD) is associated to a higher stroke risk. Anemia is a common consequence of CKD, and is also a possible risk factor for cerebrovascular diseases. The purpose of this study was to examine if anemia and CKD are independent risk factors for mortality after stroke. METHODS: This historic cohort study was based on a stroke registry and included patients treated for a first clinical stroke in the stroke unit of one academic hospital over a three-year period. Mortality predictors comprised demographic characteristics, CKD, glomerular filtration rate (GFR), anemia and other stroke risk factors. GFR was estimated by means of the simplified Modification of Diet in Renal Disease formula. Renal function was assessed according to the Kidney Disease Outcomes Quality Initiative (K/DOQI)-CKD classification in five groups. A value of hemoglobin < 120 g/L in women and < 130 g/L in men on admission defined anemia. Kaplan-Meier survival curves and Cox models were used to describe and analyze one-year survival. RESULTS: Among 890 adult stroke patients, the mean (Standard Deviation) calculated GFR was 64.3 (17.8) ml/min/1.73 m2 and 17% had anemia. Eighty-two (10%) patients died during the first year after discharge. Among those, 50 (61%) had K/DOQI CKD stages 3 to 5 and 32 (39%) stages 1 or 2 (p < 0.001). Anemia was associated with an increased risk of death one year after discharge (p < 0.001). After adjustment for other factors, a higher hemoglobin level was independently associated with decreased mortality one year after discharge [hazard ratio (95% CI) 0.98 (0.97-1.00)]. CONCLUSIONS: Both CKD and anemia are frequent among stroke patients and are potential risk factors for decreased one-year survival. The inclusion of patients with a first-ever clinical stroke only and the determination of anemia based on one single measure, on admission, constitute limitations to the external validity. We should investigate if an early detection and management of both CKD and anemia could improve survival in stroke patients. PMID- 20950485 TI - Autoantibodies to muscarinic acetylcholine receptors found in patients with primary biliary cirrhosis. AB - BACKGROUND: Autoantibodies to the human muscarinic acetylcholine receptor of the M3 type (hmAchR M3) have been suggested to play an etiopathogenic role in Sjogren's syndrome. Primary biliary cirrhosis (PBC) often is associated with this syndrome. Therefore, we studied the co-presence of hmAchR M3 autoantibodies in patients with PBC. METHODS: Frequency of hmAchR M3 autoantibodies was assessed by Western blotting analysis as well as by an ELISA using a 25-mer peptide of the 2nd extracellular loop of hmAchR M3. Co-localization of hmAchR M3/PBC-specific autoantibodies was studied by confocal laser scanning microscopy. Finally, sera from patients with PBC as well as from healthy controls were tested. RESULTS: Western blotting analysis as well as results from ELISA testing revealed a significantly enhanced IgG reactivity in PBC patients in contrast to healthy controls. Co-localization of autoantibodies with the hmAchR M3 receptor-specific autoantibodies was observed in 10 out of 12 PBC-patients but none of the 5 healthy controls. Antibodies of the IgM type were not found to be affected. CONCLUSIONS: For the first time, our data demonstrate the presence of autoantibodies to the hmAchR M3 in PBC patients. These findings might contribute to the understanding of the pathogenesis of this disease. Further studies have to focus on the functionality of hmAchR M3 autoantibodies in PBC patients. PMID- 20950486 TI - Identification of expression QTL (eQTL) of genes expressed in porcine M. longissimus dorsi and associated with meat quality traits. AB - BACKGROUND: Genetic analysis of transcriptional profiles is a promising approach for identifying and dissecting the genetics of complex traits like meat performance. Accordingly, expression levels obtained by microarray analysis were taken as phenotypes in a linkage analysis to map eQTL. Moreover, expression levels were correlated with traits related to meat quality and principle components with high loadings of these traits. By using an up-to-date annotation and localization of the respective probe-sets, the integration of eQTL mapping data and information of trait correlated expression finally served to point to candidate genes for meat quality traits. RESULTS: Genome-wide transcriptional profiles of M. longissimus dorsi RNAs samples of 74 F2 animals of a pig resource population revealed 11,457 probe-sets representing genes expressed in the muscle. Linkage analysis of expression levels of these probe-sets provided 9,180 eQTL at the suggestive significance threshold of LOD > 2. We mapped 653 eQTL on the same chromosome as the corresponding gene and these were designated as 'putative cis eQTL'. In order to link eQTL to the traits of interest, probe-sets were addressed with relative transcript abundances that showed correlation with meat quality traits at p <= 0.05. Out of the 653 'putative cis-eQTL', 262 transcripts were correlated with at least one meat quality trait. Furthermore, association of expression levels with composite traits with high loadings for meat quality traits generated by principle component analysis were taken into account leading to a list of 85 genes exhibiting cis-eQTL and trait dependent expression. CONCLUSION: Holistic expression profiling was integrated with QTL analysis for meat quality traits. Correlations between transcript abundance and meat quality traits, combined with genetic positional information of eQTL allowed us to prioritise candidate genes for further study. PMID- 20950487 TI - Biological changes in auditory function following training in children with autism spectrum disorders. AB - BACKGROUND: Children with pervasive developmental disorders (PDD), such as children with autism spectrum disorders (ASD), often show auditory processing deficits related to their overarching language impairment. Auditory training programs such as Fast ForWord Language may potentially alleviate these deficits through training-induced improvements in auditory processing. METHODS: To assess the impact of auditory training on auditory function in children with ASD, brainstem and cortical responses to speech sounds presented in quiet and noise were collected from five children with ASD who completed Fast ForWord training. RESULTS: Relative to six control children with ASD who did not complete Fast ForWord, training-related changes were found in brainstem response timing (three children) and pitch-tracking (one child), and cortical response timing (all five children) after Fast ForWord use. CONCLUSIONS: These results provide an objective indication of the benefit of training on auditory function for some children with ASD. PMID- 20950488 TI - Investigation and improvement of DNA cleavage models of polyamide + Cu(II) nuclease + OOH- ligands bound to DNA. AB - BACKGROUND: Copper nucleases as a famous class of artificial metallonucleases have attracted considerable interest in relation to their diverse potentials not only as therapeutic agents but also in genomic researches. Copper nucleases present high efficient oxidative cleavage of DNA, in which DNA strand scission occurs generally after hydrogen atom abstracted from a sugar moiety. In order to achieve the selective cleavage of DNA sequences by copper nucleases, the DNA specific recognition agents of the Dervan-type hairpin and cyclic polyamides can be considered as proper carriers of copper nucleases. Investigation of the DNA cleavage selectivity of copper nucleases assisted by the hairpin and cyclic polyamides at the molecular level has not yet been elucidated. RESULTS: We carried out a series of molecular dynamics simulations for the nuclease [Cu(BPA)]2+ or [Cu(IDB)]2+ bound to the hairpin/cyclic polyamide and associated with DNA to investigate the selective DNA cleavage properties of Cu(II)-based artificial nucleases. The simulated results demonstrate that the DNA cleavage selectivity of the two nucleases assisted by the hairpin polyamide is improved efficiently. The [Cu(BPA)]2+ or [Cu(IDB)]2+ nuclease with a substrate OOH- bound to the hairpin polyamide can be stably located at the minor groove of DNA, and possibly abstracts H atom from the sugar of DNA. However, the DNA cleavage properties of the two nucleases assisted by the cyclic polyamide are significantly poor due to the rigidity of linking region between the cyclic polyamide and nuclease. With introduction of the flexible linker -CH2CH2CH2NH2, the modified cyclic polyamide can assist the two copper nucleases to improve the selective DNA cleavage properties efficiently. CONCLUSION: A flexible linker and a proper binding site of the polyamide-type recognition agents play an important role in improving the DNA cleavage selectivity of copper nucleases. Current investigations provide an insight into the DNA cleavage specificities of chemical nucleases assisted by an appropriate nucleic acid recognition agent. PMID- 20950489 TI - Precise pattern of recombination in serotonergic and hypothalamic neurons in a Pdx1-cre transgenic mouse line. AB - BACKGROUND: Multicellular organisms are characterized by a remarkable diversity of morphologically distinct and functionally specialized cell types. Transgenic techniques for the manipulation of gene expression in specific cellular populations are highly useful for elucidating the development and function of these cellular populations. Given notable similarities in developmental gene expression between pancreatic beta-cells and serotonergic neurons, we examined the pattern of Cre-mediated recombination in the nervous system of a widely used mouse line, Pdx1-cre (formal designation, Tg(Ipf1-cre)89.1Dam), in which the expression of Cre recombinase is driven by regulatory elements upstream of the pdx1 (pancreatic-duodenal homeobox 1) gene. METHODS: Single (hemizygous) transgenic mice of the pdx1-creCre/0 genotype were bred to single (hemizygous) transgenic reporter mice (Z/EG and rosa26R lines). Recombination pattern was examined in offspring using whole-mount and sectioned histological preparations at e9.5, e10.5, e11.5, e16.5 and adult developmental stages. RESULTS: In addition to the previously reported pancreatic recombination, recombination in the developing nervous system and inner ear formation was observed. In the central nervous system, we observed a highly specific pattern of recombination in neuronal progenitors in the ventral brainstem and diencephalon. In the rostral brainstem (r1-r2), recombination occurred in newborn serotonergic neurons. In the caudal brainstem, recombination occurred in non-serotonergic cells. In the adult, this resulted in reporter expression in the vast majority of forebrain-projecting serotonergic neurons (located in the dorsal and median raphe nuclei) but in none of the spinal cord-projecting serotonergic neurons of the caudal raphe nuclei. In the adult caudal brainstem, reporter expression was widespread in the inferior olive nucleus. In the adult hypothalamus, recombination was observed in the arcuate nucleus and dorsomedial hypothalamus. Recombination was not observed in any other region of the central nervous system. Neuronal expression of endogenous pdx1 was not observed. CONCLUSIONS: The Pdx1-cre mouse line, and the regulatory elements contained in the corresponding transgene, could be a valuable tool for targeted genetic manipulation of developing forebrain-projecting serotonergic neurons and several other unique neuronal sub-populations. These results suggest that investigators employing this mouse line for studies of pancreatic function should consider the possible contributions of central nervous system effects towards resulting phenotypes. PMID- 20950490 TI - The relationship between high density lipoprotein subclass profile and plasma lipids concentrations. AB - HDL particles possess multiple antiatherogenic activities and the identification and differentiation of individual HDL subclasses may be useful in documentation and understanding of metabolic changes of different HDL subclasses. The major plasma lipids exist and are transported in the form of lipoprotein complexes. Hence, alterations in plasma lipids levels can interfere with the composition, content, and distribution of plasma lipoprotein subclasses that affect atherosclerosis risk. The research review major discussed the relationship between plasma lipids levels and HDL subclasses distribution. The general shift toward smaller size of HDL particle size in HTG, HCL and MHL subjects, and the changes were more prominent with the elevation of TG and TC levels which imply that HDL maturation might be abnormal and RCT pathway might be weaken, and these changes were more seriously in MHL subjects. Plasma contents of small sized HDL particles significantly higher, whereas those of large sized HDL particles were significantly lower with elevation of TG/HDL-C and TC/HDL-C ratios. Increased in the TC/HDL-C ratio alone did not influence the distributions of HDL subclasses significantly when the TG/HDL-C ratio was low (TG/HDL-C <= 2.5). Hence, the TG/HDL-C ratio might be more sensitive to reflect the alteration of HDL subclass distribution than the TC/HDL-C ratio. In LDL-C/HDL-C <= 2.3 group, the pattern of distribution in HDL subclass was in agreement with the normolipidemic subjects. Moreover, considering the relative ease of measuring TC/HDL-C, TG/HDL-C and LDL C/HDL-C ratios, as opposed to measuring HDL subclasses, these 3 ratios together may be a good indicator of HDL subclass distribution. The protective effect of increased apoA-I levels against the reduction of HDL(2b) caused by elevated TG concentration. On one hand, plasma HDL-C and apoA-I appear to play a coordinated role in the assembly of HDL particles and the determination of their contents among the total subjects. On the other hand, the apoA-I level might be a more powerful factor than HDL-C to influence the distribution of HDL subclasses in hyperlipidemic subjects. At the same time, from point of HDL subclasses distribution, the plasma lipids, apos concentrations and apos ratios should be considered while assessing the CHD risk. Abnormality of HDL subclasses distribution may result in accelerated atherosclerosis, therapeutic normalization of attenuated antiatherogenic HDL function in terms of both particle number and distribution of HDL particles is the target of innovative pharmacological approaches to large-sized HDL particles rising, including enhanced apoA-I levels. PMID- 20950491 TI - Papillary fibroelastoma of the aortic valve--a case report and literature review. AB - The prevalence of primary cardiac tumour ranges from 0.0017-0.28% and papillary fibroelastoma is rare but not uncommon benign cardiac neoplasm. Currently, with the advent of higher-resolution imaging technology especially transoesophageal echocardiography such cases being recognized frequently. The clinical presentation of these tumours varies from asymptomatic to severe ischaemic or embolic complications. We herein, present a 50-year-old female patient with a papillary fibroelastoma of the aortic valve arising from the endocardium of the right coronary cusp very close to the commissure between the right and non coronary cusps. The patient presented with angina-like chest pain and was investigated using echocardiography and CT angiographic modalities in addition to the usual investigations. The differential diagnosis considered was a thrombus, myxoma, Lambl's excrescence and infective vegetation. The surgical management included a prompt resection of the tumour on cardiopulmonary bypass avoiding injury to the aortic valve. The patient recovered well. A review of the literature suggests that the cardiac papillary fibroelastoma is a rare but potentially treatable cause of embolic stroke and other fatal complications, therefore, a strong suspicion; appropriate use of imaging modality, preoperative anticoagulation and urgent surgical resection is warranted. Also, possibility of this diagnosis should be kept in mind while managing cardiac or valvular tumours. PMID- 20950492 TI - The global pediatric antiretroviral market: analyses of product availability and utilization reveal challenges for development of pediatric formulations and HIV/AIDS treatment in children. AB - BACKGROUND: Important advances in the development and production of quality certified pediatric antiretroviral (ARV) formulations have recently been made despite significant market disincentives for manufacturers. This progress resulted from lobbying and innovative interventions from HIV/AIDS activists, civil society organizations, and international organizations. Research on uptake and dispersion of these improved products across countries and international organizations has not been conducted but is needed to inform next steps towards improving child health. METHODS: We used information from the World Health Organization Prequalification Programme and the United States Food and Drug Administration to describe trends in quality-certification of pediatric formulations and used 7,989 donor-funded, pediatric ARV purchase transactions from 2002-2009 to measure uptake and dispersion of new pediatric ARV formulations across countries and programs. Prices for new pediatric ARV formulations were compared to alternative dosage forms. RESULTS: Fewer ARV options exist for HIV/AIDS treatment in children than adults. Before 2005, most pediatric ARVs were produced by innovator companies in single-component solid and liquid forms. Five 2-in1 and four 3-in-1 generic pediatric fixed-dose combinations (FDCs) in solid and dispersible forms have been quality-certified since 2005. Most (67%) of these were produced by one quality-certified manufacturer. Uptake of new pediatric FDCs outside of UNITAID is low. UNITAID accounted for 97-100% of 2008-2009 market volume. In total, 33 and 34 countries reported solid or dispersible FDC purchases in 2008 and 2009, respectively, but most purchases were made through UNITAID. Only three Global Fund country recipients reported purchase of these FDCs in 2008. Prices for pediatric FDCs were considerably lower than liquids but typically higher than half of an adult FDC. CONCLUSION: Pediatric ARV markets are more fragile than adult markets. Ensuring a long-term supply of quality, well adapted ARVs for children requires ongoing monitoring and improved understanding of global pediatric markets, including country-based research to explain and address low uptake of new, improved formulations. Continued innovation in pediatric ARV development may be threatened by outdated procurement practices failing to connect clinicians making prescribing decisions, supply chain staff dealing with logistics, donors, international organizations, and pharmaceutical manufacturers. Perceptions of global demand must be better informed by accurate estimates of actual country-level demand. PMID- 20950493 TI - The gastrointestinal nematode Trichostrongylus colubriformis down-regulates immune gene expression in migratory cells in afferent lymph. AB - BACKGROUND: Gastrointestinal nematode (GIN) infections are the predominant cause of economic losses in sheep. Infections are controlled almost exclusively by the use of anthelmintics which has lead to the selection of drug resistant nematode strains. An alternative control approach would be the induction of protective immunity to these parasites. This study exploits an ovine microarray biased towards immune genes, an artificially induced immunity model and the use of pseudo-afferent lymphatic cannulation to sample immune cells draining from the intestine, to investigate possible mechanisms involved in the development of immunity. RESULTS: During the development of immunity to, and a subsequent challenge infection with Trichostrongylus colubriformis, the transcript levels of 2603 genes of cells trafficking in afferent intestinal lymph were significantly modulated (P < 0.05). Of these, 188 genes were modulated more than 1.3-fold and involved in immune function. Overall, there was a clear trend for down-regulation of many genes involved in immune functions including antigen presentation, caveolar-mediated endocytosis and protein ubiquitination. The transcript levels of TNF receptor associated factor 5 (TRAF5), hemopexin (HPX), cysteine dioxygenase (CDO1), the major histocompatability complex Class II protein (HLA DMA), interleukin-18 binding protein (IL-18BP), ephrin A1 (EFNA1) and selenoprotein S (SELS) were modulated to the greatest degree. CONCLUSIONS: This report describes gene expression profiles of afferent lymph cells in sheep developing immunity to nematode infection. Results presented show a global down regulation of the expression of immune genes which may be reflective of the natural temporal response to nematode infections in livestock. PMID- 20950495 TI - Relationships between lexical and phonological development in young children. AB - Our understanding of the relationships between lexical and phonological development has been enhanced in recent years by increased interest in this area from language scientists, psychologists and phonologists. This review article provides a summary of research, highlighting similarities and differences across studies. It is suggested that the research falls into two categories with different goals and different methodological approaches: (1) child-centered studies that examine the influences active in the prelinguistic and early-word period, emphasizing individual developmental patterns and the active role played by the child; and (2) studies inspired by research on word processing in adults; these focus on the effects of the phonological and lexical characteristics of the ambient language on underlying representations and word learning in children. The article concludes with suggestions for integrating the findings from the two approaches and for future research. PMID- 20950494 TI - zTrap: zebrafish gene trap and enhancer trap database. AB - BACKGROUND: We have developed genetic methods in zebrafish by using the Tol2 transposable element; namely, transgenesis, gene trapping, enhancer trapping and the Gal4FF-UAS system. Gene trap constructs contain a splice acceptor and the GFP or Gal4FF (a modified version of the yeast Gal4 transcription activator) gene, and enhancer trap constructs contain the zebrafish hsp70l promoter and the GFP or Gal4FF gene. By performing genetic screens using these constructs, we have generated transgenic zebrafish that express GFP and Gal4FF in specific cells, tissues and organs. Gal4FF expression is visualized by creating double transgenic fish carrying a Gal4FF transgene and the GFP reporter gene placed downstream of the Gal4-recognition sequence (UAS). Further, the Gal4FF-expressing cells can be manipulated by mating with UAS effector fish. For instance, when fish expressing Gal4FF in specific neurons are crossed with the UAS:TeTxLC fish carrying the tetanus neurotoxin gene downstream of UAS, the neuronal activities are inhibited in the double transgenic fish. Thus, these transgenic fish are useful to study developmental biology and neurobiology. DESCRIPTION: To increase the usefulness of the transgenic fish resource, we developed a web-based database named zTrap http://kawakami.lab.nig.ac.jp/ztrap/. The zTrap database contains images of GFP and Gal4FF expression patterns, and genomic DNA sequences surrounding the integration sites of the gene trap and enhancer trap constructs. The integration sites are mapped onto the Ensembl zebrafish genome by in-house Blat analysis and can be viewed on the zTrap and Ensembl genome browsers. Furthermore, zTrap is equipped with the functionality to search these data for expression patterns and genomic loci of interest. zTrap contains the information about transgenic fish including UAS reporter and effector fish. CONCLUSION: zTrap is a useful resource to find gene trap and enhancer trap fish lines that express GFP and Gal4FF in desired patterns, and to find insertions of the gene trap and enhancer trap constructs that are located within or near genes of interest. These transgenic fish can be utilized to observe specific cell types during embryogenesis, to manipulate their functions, and to discover novel genes and cis-regulatory elements. Therefore, zTrap should facilitate studies on genomics, developmental biology and neurobiology utilizing the transgenic zebrafish resource. PMID- 20950496 TI - Phonology and lexicon in a cross-linguistic perspective: the importance of phonetics--a commentary on Stoel-Gammon's 'Relationships between lexical and phonological development in young children'. PMID- 20950497 TI - Stepping backwards in development: integrating developmental speech perception with lexical and phonological development--a commentary on Stoel-Gammon's 'Relationships between lexical and phonological development in young children'. PMID- 20950498 TI - Lexical and phonological development in children with childhood apraxia of speech -a commentary on Stoel-Gammon's 'Relationships between lexical and phonological development in young children'. PMID- 20950499 TI - Relationships between lexical and phonological development: a look at bilingual children--a commentary on Stoel-Gammon's 'Relationships between lexical and phonological development in young children'. AB - Stoel-Gammon (this issue) highlights the close and symbiotic association that exists between the lexical and phonological domains in early linguistic development. Her comprehensive review considers two bodies of literature: (1) child-centred studies; and (2) studies based on adult psycholinguistic research. Within the child-centred studies, both prelinguistic and early meaningful speech is examined. Stoel-Gammon organizes her review of child-centred studies around a series of postulates that capture the associations between lexical and phonological development and here she focuses primarily on normally developing children acquiring American English. My intention is not to question these postulates, which are based on established research findings, but to extend them beyond the limits of her review. In my commentary, I would like to explore the application of some of the stated postulates of the early meaningful speech period in children acquiring two or more languages. In so doing, I add a cross linguistic dimension to the discussion; a dimension that Stoel-Gammon would like to see pursued in future research on this topic. I also expand our understanding of lexical-phonological relationships by considering the potential for interaction in multiple lexical-phonological relationships. PMID- 20950500 TI - Differentiating word learning processes may yield new insights--a commentary on Stoel-Gammon's 'Relationships between lexical and phonological development in young children'. PMID- 20950501 TI - The role of production practice in lexical and phonological development--a commentary on Stoel-Gammon's 'Relationships between lexical and phonological development in young children'. AB - Carol Stoel-Gammon has made a real contribution in bringing together two fields that are not generally jointly addressed. Like Stoel-Gammon, we have long focused on individual differences in phonological development (e.g. Vihman, Ferguson & Elbert, 1986; Vihman, Boysson-Bardies, Durand & Sundberg, 1994; Keren-Portnoy, Majorano & Vihman, 2008). And like her, we have been closely concerned with the relationship between lexical and phonological learning. Accordingly, we will focus our discussion on two areas covered by Stoel-Gammon (this issue) on which our current work may shed some additional light. PMID- 20950503 TI - Interactions between lexical and phonological development: cross-linguistic and contextual considerations--a commentary on Stoel-Gammon's 'Relationships between lexical and phonological development in young children'. PMID- 20950502 TI - Lexicon-phonology relationships and dynamics of early language development--a commentary on Stoel-Gammon's 'Relationships between lexical and phonological development in young children'. PMID- 20950504 TI - Mechanisms linking phonological development to lexical development--a commentary on Stoel-Gammon's 'Relationships between lexical and phonological development in young children'. PMID- 20950505 TI - Bipolar input to melanopsin containing ganglion cells in primate retina. AB - Two morphological types of melanopsin-expressing ganglion cells have been described in primate retina. Both types show intrinsic light responses as well as rod- and cone-driven ON-type responses. Outer stratifying cells have their dendrites close to the inner nuclear layer (OFF sublamina); inner stratifying cells have their dendrites close to the ganglion cell layer (ON sublamina). Both inner and outer stratifying cells receive synaptic input via ribbon synapses, but the bipolar cell types providing this input have not been identified. Here, we addressed the question whether the diffuse (ON) cone bipolar type DB6 and/or rod bipolar cells contact melanopsin-expressing ganglion cells. Melanopsin containing ganglion cells in marmoset (Callithrix jacchus) and macaque (Macaca fascicularis) retinas were identified immunohistochemically; DB6 cells were labeled with antibodies against the carbohydrate epitope CD15, rod bipolar cells were labeled with antibodies against protein kinase C, and putative synapses between the two cells types were identified with antibodies against piccolo. For one inner cell, nearly all of the DB6 axon terminals that overlap with its dendrites in the two dimensional space show areas of close contact. In vertical sections, the large majority of the areas of close contact also contain a synaptic punctum, suggesting that DB6 cells contact inner melanopsin cells. The output from DB6 cells accounts for about 30% of synapses onto inner melanopsin cells. Synaptic contacts between rod bipolar axons and inner dendrites were not observed. In the OFF sublamina, about 10% of the DB6 axons are closely associated with dendrites of outer cells, and in about a third of these areas, axonal en passant synapses are detected. This result suggests that DB6 cells may also provide input to outer melanopsin cells. PMID- 20950506 TI - The relationship between worthlessness and mortality in a large cohort of Chinese elderly men. AB - BACKGROUND: This study explored the relationship between "worthlessness" and all cause non-suicide mortality in Chinese elderly men. METHODS: Data from interviews of 1999 men aged 65 years and over were collected. Clinically significant depressive symptoms were measured using the validated Chinese version of Geriatric Depression Scale. "Worthlessness" was defined by one of the 15 questions from the Geriatric Depression Scale with a yes/no response. All-cause mortality over six years was collected using data from the National Death Registry with adjudication by 4-monthly telephone interviews. Two men were excluded after suicide death. RESULTS: Age-adjusted mortality rates at five years were 44.3 and 23.9 per 1,000 person years for those who felt "worthless" and those did not, respectively. The adjusted relative risk for all-cause mortality associated with feeling worthless was 1.34 (95% CI: 1.02-1.76) after adjusting for potential confounders that included age, marital status, education, smoking, alcohol consumption, number of chronic diseases, self-rated health, body mass index, cognitive status, physical activity, occupation and maximum lifetime income. There was no statistically significant association between other depressive symptoms or overall depression and mortality. CONCLUSION: Worthlessness may be independently associated with all-cause mortality in Chinese elderly men. PMID- 20950507 TI - Development and evaluation of an educational intervention for general practitioners and staff caring for people with dementia living in residential facilities. AB - BACKGROUND: Despite high levels of participation in dementia education, general practitioners (GPs) and residential care facility (RCF) staff report perceived learning needs. Small group education, which is flexible, individualized, practical and case-based, is sought. We aimed to develop educational interventions for GPs and RCF staff tailored to meet their perceived educational needs. METHODS: We used a consultative process to develop education programs. A flexible program for RCF staff was developed in 30-minute blocks, which could be combined in sessions of different lengths. The RCF program aimed to facilitate sustainable change by engaging local "Dementia Champions". For GPs, face-to-face and self-directed packages were developed. We collected participant feedback to evaluate the program. RESULTS: GPs and RCF staff were recruited as part of a larger intervention study. Sixteen of the 27 GPs who were offered the dementia education participated. Two of the 16 GPs participated in both learning packages. A total of 45 GP feedback responses were received from 16 GPs: 28 out of 45 GPs (62%) reported that the participants' learning needs were entirely met. Eighteen of 19 facilities offered the intervention participated and 326 RCF staff attended one or more of the 94 RCF education sessions. Feedback was collected from 93 sessions: 1013 out of 1067 RCF staff feedback responses (95%) reported that the session met the participants' learning needs. Qualitative feedback was also strongly positive. CONCLUSION: Participants perceived the education programs as meeting their needs. Despite explicit attempts to provide flexible delivery options, overall participation rates remained low. PMID- 20950508 TI - "In the midnight hour": a case report of musical hallucinations with multiple etiological factors treated with lamotrigine. AB - We report the case of JW, a 66-year-old woman who presented with musical hallucinations and multiple etiological factors for these rare phenomena. We discuss these factors and the successful amelioration of her symptoms with lamotrigine. PMID- 20950509 TI - Hearing and ossicular chain preservation in cholesteatoma surgery. AB - OBJECTIVE: To assess the hearing changes associated with sacrificing an intact ossicular chain during cholesteatoma surgery. METHODS: We reviewed the operation notes of surgical procedures performed by the senior author between October 2000 and April 2006. Thirty-three cases were identified in which cholesteatoma surgery had been performed in the presence of a mobile, intact ossicular chain. One set of case notes was missing; therefore, 32 cases were included in the analysis. The ossicular chain was preserved in 17 cases (14 males and three females) and sacrificed in 15 (eight males and seven females). RESULTS: At the first post operative assessment, a median air-bone gap deterioration of 3.3 dB was seen in patients in whom the ossicular chain had been sacrificed, while a median air-bone gap improvement of 3.3 dB was seen in those in whom the chain had been preserved. However, multivariable logistic regression analysis suggested that this difference in hearing outcomes was due to pre-operative hearing status, and that preservation of the ossicular chain did not lead to a better outcome. CONCLUSIONS: In cholesteatoma surgery, there is at most a marginal benefit in preserving the ossicular chain. In the current study, the better hearing outcomes associated with preservation of the ossicular chain were accounted for by patients' better pre-operative hearing status. This study did not demonstrate a difference in residual disease rate, but was underpowered to do so. PMID- 20950510 TI - Squamous cell carcinoma of the thyroid gland: primary or secondary disease? AB - OBJECTIVE: To review the aetiopathogenesis, clinical characteristics, immunohistochemical profile, prognosis and treatment options for primary thyroid squamous cell carcinoma, and to compare it with squamous cell carcinoma metastatic to the thyroid, thus providing the reader with a framework for differentiating primary and secondary disease. METHOD: Review of English language literature from the past 25 years. SEARCH STRATEGY: A search of the Medline, Embase and Cochrane databases (April 1984 to April 2009) was undertaken to enable a comprehensive review. RESULTS: After applying strict criteria for the diagnosis of primary thyroid squamous cell carcinoma, 28 articles were identified reporting 84 cases. When reviewing secondary thyroid squamous cell carcinoma, we only analysed cases of squamous cell carcinoma metastatic to the thyroid gland, and found 28 articles reporting 78 cases. CONCLUSION: It is possible to differentiate between primary and secondary thyroid squamous cell carcinoma, on the basis of combined evidence from clinical examination and endoscopic, pathological and radiological evaluation. Such differentiation is important, as the prognosis for primary squamous cell carcinoma is uniformly poor irrespective of treatment, and the most suitable option may be supportive therapy. Treatment for secondary squamous cell carcinoma of the thyroid varies with the site and extent of spread of the primary tumour. PMID- 20950511 TI - Rigid endoscopic evaluation of conventional curettage adenoidectomy. AB - OBJECTIVES: To evaluate the results of conventional adenoidectomy, using rigid endoscopy of the nasopharynx, and to establish the role of such evaluation in facilitating complete adenoid removal via the curettage technique. DESIGN: Descriptive rigid endoscopic evaluation of the nasopharynx before and after adenoid curettage, and following subsequent endoscopy-assisted adenoidectomy. SETTING: Tertiary referral centre. PATIENTS: Forty-one consecutive children with symptomatic adenoid hypertrophy scheduled to undergo adenoidectomy. RESULTS: Rigid endoscopic evaluation indicated that conventional curettage, used alone, failed to completely remove adenoid tissue from the superomedial choanae and anterior vault in all cases; incomplete removal was also seen in other parts of the choanae (in 67.2 per cent of patients), the eustachian tube opening (63 per cent), the nasopharyngeal roof (61.78 per cent) and the fossa of Rosenmuller (61 per cent). Subsequent rigid endoscopy-assisted adenoidectomy successfully removed the residual adenoid tissue from all nasopharyngeal sites, except the eustachian tube opening in two cases. CONCLUSION: Conventional curettage adenoidectomy misses a substantial amount of adenoid tissue. Rigid endoscopy-assisted adenoidectomy improves this result by enabling localisation of any residual adenoid tissue. PMID- 20950513 TI - Spatial clustering of TB-infected cattle herds prior to and following proactive badger removal. AB - Bovine tuberculosis (TB) is primarily a disease of cattle. In both Ireland and the UK, badgers (Meles meles) are an important wildlife reservoir of infection. This paper examined the hypothesis that TB is spatially correlated in cattle herds, established the range of correlation and the effect, if any, of proactive badger removal on this. We also re-analysed data from the Four Area Project in Ireland, a large-scale intervention study aimed at assessing the effect of proactive badger culling on bovine TB incidence in cattle herds, taking possible spatial correlation into account. We established that infected herds are spatially correlated (the scale of spatial correlation is presented), but at a scale that varies with time and in different areas. Spatial correlation persists following proactive badger removal. PMID- 20950512 TI - Ear injuries sustained by British service personnel subjected to blast trauma. AB - OBJECTIVES: To describe the pattern of ear injuries sustained by all British servicemen serving in Iraq and Afghanistan between 2006 and 2009; to identify all servicemen evacuated to the Royal Centre for Defence Medicine following blast injury; to ascertain how many underwent otological assessment; and to calculate the incidence of hearing loss. DESIGN AND SETTING: A retrospective analysis of data obtained from the Joint Theatre Trauma Registry and the Defence Analytical and Statistics Agency, together with audiometry records from the University Hospitals Birmingham National Health Service Trust. RESULTS: Ear damage was present in 5 per cent of all British servicemen sustaining battle injuries. Tympanic membrane rupture occurred in 8 per cent of personnel evacuated with blast injuries. In 2006, 1 per cent of servicemen sustaining blast injury underwent audiography; this figure rose to 13 per cent in 2009. Fifty-three per cent of these audiograms were abnormal. CONCLUSION: The incidence of tympanic membrane rupture was higher than that found in previous conflicts. Otological assessment prior to and following military deployment is required to determine the incidence of ear injury amongst British servicemen following blast trauma. PMID- 20950514 TI - The evolution and distribution of phage ST160 within Salmonella enterica serotype Typhimurium. AB - Salmonellosis is an internationally important disease of mammals and birds. Unique epidemics in New Zealand in the recent past include two Salmonella serovars: Salmonella enterica subsp. enterica serovar Typhimurium definitive type (DT) 160 (S. Typhimurium DT160) and S. Brandenburg. Although not a major threat internationally, in New Zealand S. Typhimurium DT160 has been the most common serovar isolated from humans, and continues to cause significant losses in wildlife. We have identified DNA differences between the first New Zealand isolate of S. Typhimurium DT160 and the genome-sequenced strain, S. Typhimurium LT2. All the differences could be accounted for in one cryptic phage ST64B, and one novel P22-like phage, ST160. The majority of the ST160 genome is almost identical to phage SE1 but has two regions not found in SE1 which are identical to the P22-like phage ST64T, suggesting that ST160 evolved from SE1 via two recombination events with ST64T. All of the New Zealand isolates of DT160 were identical indicating the clonal spread of this particular Salmonella. Some overseas isolates of S. Typhimurium DT160 differed from the New Zealand strain and contained SE1 phage rather than ST160. ST160 was also identified in New Zealand isolates of S. Typhimurium DT74 and S. Typhimurium RDNC-April06 and in S. Typhimurium DT160 isolates from the USA. The emergence of S. Typhimurium DT160 as a significant pathogen in New Zealand is postulated to have occurred due to the sensitivity of the Salmonella strains to the ST160 phage when S. Typhimurium DT160 first arrived. PMID- 20950516 TI - Phylogenetic analysis of H and N2 genes of avian influenza viruses detected in Ireland between 2003 and 2007. AB - Phylogenetic analysis was performed on the haemagglutinin and neuraminidase subtype N2 genes of low-pathogenic avian influenza viruses (LPAIVs) detected in Ireland between 2003 and 2007. Nucleotide sequences were compared to previously published sequences from the National Centre for Biotechnology Information. Sequences from viruses of the same subtype isolated in different years were compared to examine the possibility that LPAIVs may have been maintained in Ireland from year to year. All viruses had closest identity with published sequences of European lineage, supporting the conclusion that LPAIVs had been introduced to Ireland by dabbling ducks that had migrated from Europe. The data suggested that different subtypes of virus had been introduced each year. However, there was evidence that some LPAIVs may have been maintained in the sedentary waterfowl population for consecutive seasons. Furthermore, almost identical H6 and H10 sequences with different N types were found in isolates from the same season, suggesting that reassortment had occurred. PMID- 20950515 TI - Salmonella enterica serovar Agona European outbreak associated with a food company. AB - We investigated an international outbreak of Salmonella Agona with a distinct PFGE pattern associated with an Irish Food company (company X) producing pre cooked meat products sold in various food outlet chains in Europe. The outbreak was first detected in Ireland. We undertook national and international case finding, food traceback and microbiological investigation of human, food and environmental samples. We undertook a matched case-control study on Irish cases. In total, 163 cases in seven European countries were laboratory-confirmed. Consumption of food from food outlet chains supplied by company X was significantly associated with being a confirmed case (mOR 18.3, 95% CI 2.2-149.2) in the case-control study. The outbreak strain was isolated from the company's pre-cooked meat products and production premises. Sufficient evidence was gathered to infer the vehicles of infection and sources of the outbreak and to justify the control measures taken, which were plant closure and food recall. PMID- 20950517 TI - Vulnerability in early life to changes in the rearing environment plays a crucial role in the aetiopathology of psychiatric disorders. AB - Adverse events early in life, including maternal separation and social isolation, profoundly affect brain development and adult behaviour and may contribute to the occurrence of psychiatric disorders such as schizophrenia and mood disorders in genetically predisposed individuals. The molecular mechanisms underlying these environmentally induced developmental adaptations are unclear and best evaluated in animal paradigms with translational salience. In this study, we examined the effects in mice of maternal separation and/or social isolation for 6 h/d between postnatal days 15 and 21 on performance during adulthood in the open-field, social interaction, elevated plus-maze, forced swimming, Y-maze, novel object recognition, conditioned fear-learning, prepulse inhibition, and locomotor activity tests, to investigate whether this animal model could show the phenotypes for schizophrenia and mood disorders. The stress of maternal separation and isolation led to adult behavioural deficits, activation of the hypothalamic-pituitary-adrenal axis, and decreases in the levels of norepinephrine and dopamine in the frontal cortex and metabolites of dopamine and serotonin in the amygdala, showing the involvement of endocrine and neuronal risk in behavioural deficits. The results suggest that the frontal cortex and amygdala undergo structural remodelling induced by the stress of maternal separation and isolation, which alters behavioural and physiological responses in adulthood, including anxiety, memory and other cognitive processes. Further, social isolation enhanced the behavioural dysfunctions induced by maternal separation. These findings indicate that maternal separation and social isolation early in life can lead to long-lasting abnormal behaviour and pathophysiological impairments including schizophrenia and mood disorders. PMID- 20950518 TI - When cues collide: children's sensitivity to letter- and meaning-patterns in spelling words in English. AB - In many learning situations, we need to determine to which cues to attend, particularly in cases when these cues conflict. These conflicts appear often in English orthography. In two experiments, we asked children to spell two-syllable words that varied on two dimensions: morphological and orthographic structure. In one set of these words, the two sources of information conflicted. Results of Experiment 1 suggest that seven- to nine-year-old children are sensitive to both orthographic and morphological dimensions of words, and that this dual sensitivity sometimes leads to correct spelling and sometimes to incorrect spelling. Results of Experiment 2 suggest that orthographic information dominates young (six-year-old) children's spelling, at least in a case when there is a strong orthographic regularity. Taken together, these experiments suggest that children are sensitive to the multiple dimensions of regularity in English orthography and that this sensitivity can lead to mistakes. PMID- 20950520 TI - Partnerships to improve community health, an interview with Professor David Kindig of MATCH. Interview by Fran Kritz. PMID- 20950521 TI - Challenges and opportunities for population health partnerships. PMID- 20950522 TI - Focusing on solid partnerships across multiple sectors for population health improvement. PMID- 20950523 TI - Improving public health system performance through multiorganizational partnerships. AB - Public health activities in the United States are delivered through multiple public and private organizations that vary widely in their resources, missions, and operations. Without strong coordination mechanisms, these delivery arrangements may perpetuate large gaps, inequities, and inefficiencies in public health activities. We examined evidence and uncertainties concerning the use of partnerships to improve the performance of the public health system, with a special focus on partnerships between public health agencies and health care organizations. We found that the types of partnerships likely to have the largest and most direct effects on population health are among the most difficult, and therefore least prevalent, forms of collaboration. High opportunity costs and weak and diffuse participation incentives hinder partnerships that focus on expanding effective prevention programs and policies. Targeted policy actions and leadership strategies are required to illuminate and enhance partnership incentives. PMID- 20950524 TI - Multisectoral lessons from healthy communities. AB - The healthy communities movement can provide insight into population health efforts in the United States, particularly in the context of recent health care reform. The movement has evolved from multisector partnerships that focused on improving the health, well-being, and quality of life for people and the social determinants of health to partnerships that focus more on chronic disease prevention, health equity, and environmental change. Evaluating the effects of community programs on population health has been challenging for a number of reasons. More metrics need to be developed for population health that will address inequities and focus policies on long-term health effects. PMID- 20950525 TI - Building multisectoral partnerships for population health and health equity. AB - Poor performance in achieving population health goals is well-noted - approximately 10% of public health measures tracked are met. Less well-understood is how to create conditions that produce these goals. This article examines some of the factors that contribute to this poor performance, such as lack of shared responsibility for outcomes, lack of cooperation and collaboration, and limited understanding of what works. It also considers challenges to engaging stakeholders at multiple ecologic levels in building collaborative partnerships for population health. Grounded in the Institute of Medicine framework for collaborative public health action, it outlines 12 key processes for effecting change and improvement, such as analyzing information, establishing a vision and mission, using strategic and action plans, developing effective leadership, documenting progress and using feedback, and making outcomes matter. The article concludes with recommendations for strengthening collaborative partnerships for population health and health equity. PMID- 20950526 TI - Multisector partnerships in population health improvement. AB - Many new initiatives for population health improvement feature partnerships of leaders and organizations across multiple sectors of society. The purpose of this article is to review 1) the rationale for such partnerships as an important, if not essential, tool for population health improvement; 2) key organizational and contextual factors that appear to be associated with effective multisector partnerships; and 3) the limited evidence regarding the effect of such partnerships on population health outcomes. We conclude that systems thinking - accounting for the collective effect of many actors and actions - is essential to organizing and sustaining efforts to improve population health, and to evaluating them. More research is needed to understand how and why multisector partnerships are formed and sustained and the conditions under which multisector partnerships are necessary or more effective than other strategies for population health improvement. Research on and evaluation of multisector partnerships also need to incorporate more standard measures of partnership contexts, characteristics, and strategies and adopt longitudinal and prospective designs to accelerate social learning in this area. Finally, studies of multisector partnerships must be alert to the value of such initiatives to individuals and communities apart from any direct and measurable impact on population health. PMID- 20950527 TI - Networks as a type of social entrepreneurship to advance population health. AB - A detailed case study from the field of social entrepreneurship is used to illustrate the network approach, which does not require more resources but rather makes better use of existing resources. Leaders in public health can use networks to overcome some of the barriers that inhibit the widespread adoption of a population health approach to community health. Public health leaders who embrace social entrepreneurship may be better able to accomplish their missions by building their networks rather than just their organizations. PMID- 20950528 TI - Improving population health: the business community imperative. AB - Information on the economic effect of poor population health is needed to engage the business community in population health improvement. In a competitive global market, the United States has high health care costs and poor outcomes (measured by such factors as healthy and productive lives) compared with other countries. US business needs to understand population health and not focus just on the health of employees at the worksite. We describe a long-term approach to population health, including incentives, and identify what is needed to engage business leadership in population health improvement. PMID- 20950529 TI - Designing Vermont's pay-for-population health system. AB - Vermont is developing a health care system that could offer a unique opportunity to test a new model for improving population health. Four lines of development converged for the system: 1) a published challenge to create a pay-for-population health system, 2) comprehensive state health reform legislation, 3) the Institute for Healthcare Improvement Triple Aim project, and 4) the concept of the accountable care organization (ACO). In phase 1 of pilot testing, 3 communities serving 10% of the population are using the system, which is based on the enhanced medical home model. Planning is under way for phase 2 of the pilot, ACOs that use incentives based on the Triple Aim goals. Vermont has created a conceptual framework for a community health system and identified some of the practical issues involved in implementing this framework. This article summarizes the design and implementation of the enhanced medical home pilots and the results of a feasibility study for the ACO pilots. It describes how one state is using a systematic approach to health care reform to overcome some of the implementation barriers to a pay-for-population health system. Vermont will continue to provide a statewide laboratory for a pay-for-population health system. PMID- 20950530 TI - The governance of standard-setting to improve health. AB - This article describes recent events in the governance of standard-setting for 2 areas of US health policy - states' decisions about which prescription drugs to cover under Medicaid and other public programs and making health an aspect of foreign policy - and whether these events offer lessons for policy making. In prescription drug coverage, methodologic advances in research that evaluates health services and the politics of restraining the rate of growth in health expenditures enabled policy makers in most states to establish new public processes for assessing and applying evidence about the effectiveness of competing drugs. Their counterparts in foreign policy, in contrast, made few changes in existing processes for choosing which interventions to support. The history of governance in each area of policy making for health explains the selection of standards to evaluate evidence about interventions and whether and how to use this evidence to guide policy. PMID- 20950531 TI - Observations and recommendations from the Mobilizing Action Toward Community Health (MATCH) expert meeting. PMID- 20950532 TI - Spontaneous diffusion of an effective skin cancer prevention program through Web based access to program materials. AB - INTRODUCTION: Little information exists about the diffusion of evidence-based interventions, a process that can occur naturally in organized networks with established communication channels. This article describes the diffusion of an effective skin cancer prevention program called Pool Cool through available Web based program materials. METHODS: We used self-administered surveys to collect information from program users about access to and use of Web-based program materials. We analyzed the content of e-mails sent to the official Pool Cool Web site to obtain qualitative information about spontaneous diffusion. RESULTS: Program users were dispersed throughout the United States, most often learning about the program through a Web site (32%), publication (26%), or colleague (19%). Most respondents (86%) reported that their pool provided educational activities at swimming lessons. The Leader's Guide (59%) and lesson cards (50%) were the most commonly downloaded materials, and most respondents reported using these core items sometimes, often, or always. Aluminum sun-safety signs were the least frequently used materials. A limited budget was the most commonly noted obstacle to sun-safety efforts at the pool (85%). Factors supporting sun safety at the pool centered around risk management (85%) and health of the pool staff (78%). CONCLUSION: Diffusion promotes the use of evidence-based health programs and can occur with and without systematic efforts. Strategies such as providing well-packaged, user-friendly program materials at low or no cost and strategic advertisement of the availability of program materials may increase program use and exposure. Furthermore, highlighting the benefits of the program can motivate potential program users. PMID- 20950533 TI - Training for and dissemination of the Nutrition Environment Measures Surveys (NEMS). AB - INTRODUCTION: Researchers believe that nutrition environments contribute to obesity and may explain some health disparities. The Nutrition Environment Measures Surveys (NEMS) are valid and reliable observational measures of the nutrition environment. This article describes the dissemination of the measures, including the development, implementation, and evaluation of training workshops, and a follow-up survey of training participants. METHODS: To disseminate the NEMS measures, we developed a 2-day intensive, participatory workshop. We used an immediate postcourse evaluation and a structured telephone follow-up interview to evaluate the workshops and the dissemination strategy. Topics included use of the NEMS measures, reactions to the workshops, and participants' training others on the measures. RESULTS: During the study period, 173 people participated in 14 workshops. Participants indicated a high level of satisfaction with the training workshops. Almost two-thirds of respondents reported using the measures to train an additional 292 people and to rate more than 3,000 food outlets. The measures have been used in diverse locations across the United States for various purposes. Respondents have reported NEMS results in peer-reviewed journals, master's theses, newspaper articles, and presentations. CONCLUSION: The NEMS measures are the only nutrition environment measures that have been packaged for distribution and widely disseminated. The measures fill a need in the worlds of research and community action, and dissemination was successful in accelerating diffusion and promoting adoption of the measures. The use of an ongoing, continual process to improve workshops and measures contributes to the usefulness of the surveys and accelerates their adoption and continued use. PMID- 20950534 TI - Association of workplace supports with active commuting. AB - INTRODUCTION: Active commuting is associated with a reduced risk of several chronic diseases, but few studies have considered institutional factors that influence it. We examined the association between cultural and physical workplace supports for active commuting and employee active commuting behavior. METHODS: Data were collected from employees (N = 375) in Manhattan, Kansas, via an online survey. Physical and cultural supports for active commuting in the workplace were measured separately. Active commuting frequency was dichotomized as 0 trips versus at least 1 trip per week by foot or bicycle. Binomial logistic regression was used to predict the likelihood of commuting actively at least once per week, according to the number and type of cultural and physical workplace supports. Analyses were conducted by sex and age and for the full sample. RESULTS: Among the full sample, employees who reported more physical and cultural supports in the workplace for active commuting were more likely to walk or bicycle to work at least once per week. Significant, positive relationships between cultural and physical supports and active commuting were observed for women but not for men. Both younger and older adults who reported 2 or more physical supports in the workplace were more likely to actively commute, but no relationship was observed for cultural supports. The most influential types of individual supports were perceiving that other coworkers actively commute and the presence of bicycle parking and a bicycle storage policy at the workplace. CONCLUSION: The presence of workplace physical and cultural supports is related to more active commuting behavior and may especially encourage active commuting among women. PMID- 20950535 TI - School and student characteristics associated with screen-time sedentary behavior among students in grades 5-8, Ontario, Canada, 2007-2008. AB - INTRODUCTION: We examined school and student characteristics associated with screen-time sedentary behavior. METHODS: We analyzed data collected from 2,449 students in grades 5 through 8 who attended 30 elementary schools in Ontario, Canada. We used multilevel logistic regression to examine the student- and school level factors associated with moderate and high screen-time sedentary behavior. RESULTS: Moderate screen time did not vary significantly across schools. Student characteristics significantly associated with moderate screen time were sex, number of friends who are active, and parental encouragement of physical activity. High screen time did vary significantly across schools; school-level differences accounted for 12% of the variability in the odds of a student reporting high screen time. Students who attended a school in the more advanced phase of emphasizing participation in physical activity through school programs were less likely to report high screen time compared with students who attended schools in the earlier phase for this school-level indicator. Student characteristics significantly associated with high screen time were sex, parental encouragement of physical activity, parental support of physical activity, and race/ethnicity. CONCLUSION: High levels of screen-time sedentary behavior are associated with both student characteristics and the characteristics of the school a student attends. Developing a better understanding of the school characteristics associated with sedentary behavior will be valuable for guiding the development of interventions to reduce sedentary behavior among youth populations. PMID- 20950536 TI - The influence of school policies on smoking prevalence among students in grades 5 9, Canada, 2004-2005. AB - INTRODUCTION: School characteristics may account for some of the variation in smoking prevalence among schools. The purpose of this study was to investigate the relationships between characteristics of school tobacco policies and school smoking prevalence. We also examined the relationship between these characteristics and individual smoking status. METHODS: Tobacco policy data were collected from schools in 10 Canadian provinces during the 2004-2005 school year. Written tobacco policies were collected from each school to examine policy intent, and school administrators were surveyed to assess policy enforcement. Students in grades 5 through 9 completed the Youth Smoking Survey to assess smoking behaviors and attitudes. We used negative binomial regression and multilevel logistic regression to predict the influence of school policies on smoking behavior at the school and student levels. RESULTS: School policies that explicitly stated purpose and goals predicted lower prevalence of smoking at the school and individual levels. Policies that prohibited smoking on school grounds at all times predicted lower smoking prevalence at the school level but not at the individual level. CONCLUSION: For maximum effectiveness, school smoking policies should clearly state a purpose and goals and should emphasize smoking prohibition. These policies can help reduce smoking prevalence among youths and are part of a comprehensive school approach to tobacco control. PMID- 20950537 TI - Implementing and disseminating an evidence-based program to prevent falls in older adults, Texas, 2007-2009. AB - INTRODUCTION: Falls are a public health problem for the growing population of older adults. We describe a statewide effort to implement and disseminate A Matter of Balance/Volunteer Lay Leader model, an evidence-based fall-prevention program. METHODS: We analyzed 2 secondary databases: 1) a centralized administrative data set to document implementation processes and structures for delivering the program and 2) a common set of outcome measures for assessing the effect of the program on older Texans. We used multivariate analyses to examine changes on key outcome variables, controlling for major covariates. RESULTS: From 2007 through 2009, we reached 3,092 older Texas residents. Program capacity was built by certifying 98 master trainers and 402 lay leaders and delivering the program in 227 classes through the Area Agency on Aging network. Immediate outcome results were positive, which indicates a pathway to promote more successful aging: 1) increases in falls efficacy, 2) improvements in overall physical activity levels, and 3) reductions in interference with everyday normal routines. CONCLUSION: Widespread dissemination of a program to prevent falls can promote active aging among people who would otherwise be at risk for a downward cycle of health and functionality. Creating partnerships among different delivery sectors is needed for building community infrastructure to enhance the health of older adults. PMID- 20950538 TI - An exploration into the determinants of noncommunicable diseases among rural-to urban migrants in periurban South Africa. AB - INTRODUCTION: Noncommunicable diseases are increasing in developing countries, exacerbated by growing urbanization. We examined the experiences and perceptions about noncommunicable diseases of people who migrated from rural areas to urban Cape Town, South Africa. METHODS: We conducted a qualitative study in an impoverished periurban township that has a noncommunicable disease prevention program, including health clubs. We used in-depth interviews, participatory reflection and action groups, and focus group discussions. RESULTS: Participants described changes in eating patterns and levels of physical activity. These changes were a result of socioeconomic and environmental constraints. However, respondents were not concerned about these changes. Despite hardships, they were pleased with their urban lifestyle. Furthermore, they approved of their weight gain because it signified dignity and respect. Participants who attended health clubs found them informative and socially and emotionally supportive. CONCLUSION: The study highlighted the complexity of the risk factors for noncommunicable diseases and the need to develop prevention strategies that extend beyond the traditional focus on diet and exercise. PMID- 20950539 TI - Making room for mental health in the medical home. AB - Discussions of health care reform emphasize the need for coordinated care, and evidence supports the effectiveness of medical home and integrated delivery system models. However, mental health often is left out of the discussion. Early intervention approaches for children and adolescents in primary care are important given the increased rates of detection of mental illness in youth. Most adults also receive treatment for mental illness from nonspecialists, underscoring the role for mental health in medical home models. Flexible models for coordinated care are needed for people with serious mental illness, who have high rates of comorbid medical problems. Programs implemented in the New York State public mental health system are examples of efforts to better coordinate medical and mental health services. PMID- 20950541 TI - [A multicenter randomized phase II trial of domestic product of rhG-CSF(Rui Xue Xin) in preventing leukopenia caused by chemotherapy in patients with lung cancer]. AB - BACKGROUND: To evaluate the effect and toxicity of the domestic product of rhG CSF (Rui Xue Xin) in preventing leukopenia caused by chemotherapy in patients with lung cancer. METHODS: 67 patients in multicenter were randomly devided into AB group and BA group. The first cycle was a trial cycle (chemotherapy plus injection of Rui Xue Xin) , and the second cycle was a control cycle (chemotherapy alone) in AB group. On the contrast , the first cycle was a control cycle , and the second cycle was a trial cycle in BA group. The changes of white blood cell (WBC) and absolute neutrophil counts (ANC) , and the side effect of Rui Xue Xin were observed and compared between the trial cycle and control cycle. RESULTS: Of the 67 patients , 6 cases were out of the trial because of patient compliance , and the another one case due to fever , and the other 61 cases could be used to analyze and to evaluate the effects and toxicity of Rui Xue Xin. The duration of leukopenia and neutropenia in cycle A was significantly shorter than that in cycle B ( P < 0. 01) . The nadirs of WBC and ANC following chemotherapy were remarkably higher in cycle A than those in cycle B ( P < 0. 01) . The incidence of chemotherapy delay due to WBC < 4. 0 *109 /L on the 21st day after chemotherapy in cycle A was also significantly lower than that in cycle B ( P < 0. 01) . The total rate of side effects of Rui Xue Xin was 26. 2 % , including pain and scleroma on the injection sites , weakness , fever. But , all of them were mild and didn't need to give any treatment. CONCLUSIONS: The results demonstrate that Rui Xue Xin is able to reduce the degree of leukopenia and neutropenia , and to shorten the duration of leukopenia and neutropenia caused by chemotherapy in patients with lung cancer. The toxicity is also slight. PMID- 20950542 TI - [Effects of exogenous wild-type p53 gene expression on sensitivity to chemotherapeutic agents in human lung cancer cell]. AB - BACKGROUND: To investigate the effects of exogenous wild-type p53 (wtp53) gene expression on sensitivity to chemotherapeutic agents with different mechanism of action in human lung cancer cells. METHODS: A human lung cancer cells line 801-D with point mutation of p53 was transfected with either constructed recombinant plasmid pEGFP-p53 , which expressed wtp53 or pEGFP vector. The expression of neo and wtp53 gene in anti-G418 clone , 801-D vector and 801-D-wtp53 , were detected by PCR. The functional activity of transfected wtp53 was demonstrated by partly 801-D apoptosis. 3 H-TdR uptake assay was taken for drug sensitivity measure according to standard procedures. Flow cytometry was employed to determine cell death. RESULTS: Sensitivity of 801-D-wtp53 to cisplatin and 5-fluorouracil was higher than that of 801-D vector by 9. 7 and 11. 4 fold respectively. There was no significant difference for other DNA-damaging agents and non-DNA-damaging agents , such as etoposide and adriamycin , vincristine and methylenum Caeruleum. Analysis of DNA ladder by gel electrophoresis and morphological observation showed cell necrosis characteristics. CONCLUSIONS: 801-D cell line shows a selective sensitization to DNA-damaging agents when exogenous wtp53 is expressed. The increased sensitivity to cisplatin by exogenous wtp53 expression may be through non-apoptosis pathway. This study results provide experimental bases for comprehensive treatment of lung cancer. PMID- 20950543 TI - [Expression of multidrug resistance gene and its reversion by cyclosporine in non small cell lung cancer]. AB - BACKGROUND: To investigate relation between the multidrug resistance gene (MDR1) expression and chemotherapeutic response for non-small cell lung cancer (NSCLC) and to evaluate the effect of cyclosporine (CsA) on reversion of MDR1. METHODS: Cancer tissue specimens and peripheral blood samples were collected from 46 patients with NSCLC. MDR1 was amplified in total RNA extracted from cancer cell specimens and peripheral blood lymphocyte (PBL) by RT-PCR assay. According to the result of detection , some MDR1-positive patients were treated with CsA and anticancer drugs (reverse group) , other MDR1-positive patients (positive control group) and MDR1-negative patients (negative control group) were treated with anticancer drugs alone. RESULTS: The MDR1 positive rate of cancer cells was 65. 2 %(30/ 46) , and of PBL was 58. 7 %(27/ 46) ; twenty-four cases were MDR1-positive both in cancer cells and PBL. The positive rate of patients with recurrence was 81. 3 %(26/ 32) ; of untreated patients was 28. 6 %(4/ 14) ; of patients with multi-cycle chemotherapy was 85. 7 %(24/ 28) ; of patients with non-chemotherapy was 33. 3 %(6/ 18) . The differences were significant ( P < 0. 01) . The response rate was 46. 7 %(7/ 15) in reverse group and 20 %(3/ 15) in positive control group and 37. 5 %(6/ 16) in negative control group. There were no significant differences in the toxicities and immunity changes except for hematological toxicity and impaired liver function between reverse group and other groups. CONCLUSIONS: RT-PCR examination of MDR1 expression is useful for predicting response to chemotherapy and prognosis in NSCLC patients. MDR1-positive is associated with poor prognosis. The reverse effect of CsA for expression of MDR1 requires further clinical study. PMID- 20950544 TI - [Expression of thrombospondin-1 and CD44 in human lung cancer tissues and their prognostic significance]. AB - BACKGROUND: To analyze the expression of CD44H , CD44V6 and TSP-1 in human lung cancer tissues and their prognostic significance. METHODS: A total of 112 lung cancer samples were examined for CD44H , CD44V6 and TSP-1 expression by immunohistochemical staining. Moreover , 25 cases out of them were detected for TSP-1 by RT-PCR assay simultaneously. RESULTS: Stronger expression of TSP-1 was demonstrated in adenocarcinomas (74. 36 %) as compared with squamous cell carcinomas (47. 17 % , P = 0. 03) and small cell lung cancer (35. 71 % , P = 0. 02) . All of small cell lung cancer had significantly low expression of CD44H and CD44V6. Adenocarcinomas (61. 54 %) showed stronger CD44H membranous expression than squamous cell carcinomas did (50. 94 % , P = 0. 036) . Whereas , squamous cell carcinomas (50. 94 %) showed stronger CD44V6 membranous expression than adenocarcinomas did (17. 95 % , P = 0. 003) . Kaplan-Meier survival statistical analysis for 100 cases with complete follow-up data indicated that there was no significant relationship among TSP-1 , CD44H , CD44V6 expression and overall survival rate. However , after stratifying by histopathological types , the overall survival rate of patients with low expression of TSP-1 was significantly higher than that of moderate/ high expression groups in adenocarcinomas (Log Rank= 0. 0163) . Immunohistochemical and RT-PCR technique were utilized in 25 out of 112 cases simultaneously. The accordance rate of the two methods was 84 % , and no significant difference was found between them. CONCLUSIONS: The expression of TSP-1 , CD44H and CD44V6 is significantly related to histopathological types. TSP-1 expression might be a prognostic indicator in lung adenocarcinoma. TSP-1 can be detected reliably in formalin-fixed , paraffin-embedded tissues by immunohistochemical method. PMID- 20950540 TI - Quality of systematic reviews of observational nontherapeutic studies. AB - INTRODUCTION: High-quality epidemiologic research is essential in reducing chronic diseases. We analyzed the quality of systematic reviews of observational nontherapeutic studies. METHODS: We searched several databases for systematic reviews of observational nontherapeutic studies that examined the prevalence of or risk factors for chronic diseases and were published in core clinical journals from 1966 through June 2008. We analyzed the quality of such reviews by using prespecified criteria and internal quality evaluation of the included studies. RESULTS: Of the 145 systematic reviews we found, fewer than half met each quality criterion; 49% reported study flow, 27% assessed gray literature, 2% abstracted sponsorship of individual studies, and none abstracted the disclosure of conflict of interest by the authors of individual studies. Planned, formal internal quality evaluation of included studies was reported in 37% of systematic reviews. The journal of publication, topic of review, sponsorship, and conflict of interest were not associated with better quality. Odds of formal internal quality evaluation (odds ratio [OR], 1.10 per year; 95% confidence interval [CI], 1.02 1.19) and either planned, formal internal quality evaluation or abstraction of quality criteria of included studies (OR, 1.17 per year; 95% CI, 1.08-1.26) increased over time, without positive trends in other quality criteria from 1990 through June 2008. Systematic reviews with internal quality evaluation did not meet other quality criteria more often than those that ignored the quality of included studies. CONCLUSION: Collaborative efforts from investigators and journal editors are needed to improve the quality of systematic reviews. PMID- 20950545 TI - [A study on the relationship between the expression of Bax gene products and prognosis in patients with human non-small cell lung cancer]. AB - BACKGROUND: To explore the relationship between the expression of Bax gene and oncogenesis , development and prognosis of lung cancer. METHODS: The expression level of Bax gene products was detected in 124 human non-small cell lung cancer by immunohistochemistry labelled-streptavidin-biotin methods. RESULTS: The expressional level of Bax products in lung cancer tissues (53. 76 %) was significantly lower than that in the normal tissues adjacent to lung cancer (75. 51 %) and normal lung tissues (74. 97 %) ( P < 0. 01) . The expressional level of Bax products was closely related with P-TNM stage , the size of primary tumor and lymph node metastasis ( P < 0. 01 or P < 0. 05) ; but not to histological classification , cell differentiation and site of the cancer , and age , sex of the patients and smoking or not ( P > 0. 05) . The five-year survival rate in patients with high Bax expression was significantly higher than that in patients with low Bax expression ( P < 0. 01) . CONCLUSIONS: Abnormal expression of Bax gene may play an important role in the oncogenesis , development and prognosis of lung cancer. Bax gene may be involved in the oncogenesis , development and metastasis of lung cancer. PMID- 20950546 TI - [Expression of MRP gene in non-small cell lung cancer and its significance]. AB - BACKGROUND: To investigate the effects of multi-drug resistance associated protein gene (MRP gene) overexpression on the prognosis of patients with non small cell lung cancer (NSCLC) . METHODS: Paraffin-embedded cancer tissues from 47 cases of NSCLC who had undergone radical resection were determined for expression of MRP gene mRNA by in situ hybridization combined with immunohistochemistry and all the patients had been followed up. RESULTS: All of 47 lung cancer specimen were found to have overexpression of MRP gene mRNA and the overexpression was closely related to survival time and recurrence or metastasis after surgery , but not to the clinical pathological factors. CONCLUSIONS: MRP gene is related with the prognosis of lung cancer patients and may be regarded as indicator to predict the prognosis and to choose suitable chemotherapy for non-small cell lung cancer patients. PMID- 20950547 TI - [153Sm-EDTMP in the treatment of bone metastasis of lung cancer]. AB - BACKGROUND: To explore the clinical effect of 153Sm-EDTMP therapy in the treatment of bone metastasis of lung cancer. METHODS: One hundred and ten patients with painful bone metastasis were entered into this study. The patients were administrated with two steps. At first , they were injected with tracer dose of 153Sm-EDTMP. After a series of index were calculated , such as urine discharge , bone uptake , cumulated skeletal activity , absorbed dose of red marrow and total dose , the second injection was given. RESULTS: Of 110 cases , 98 (89. 1 %) experienced pain relief with complete response in 38 cases and partial response in 60 ones. Pain relief occurred from 3 h to 4 weeks (7. 5 d +/-6. 3 d) . Duration of pain relief from single injection ranged from 2 to 4 weeks. Follow-up imaging studies were performed within 3 months. In 12 cases , metastatic foci disappeared completely (CR) , Karnofsky score increased by 20 , and analgesic were discontinued. In 20 patients , both number and diameter of metastatic foci decreased (PR) , with an improvement in Karnofsky score ranging from 10 to 15. There were significant decreases in WBC and platelet count found in 35 of 110 patients after therapy , however , blood cell counts returned to baseline within 1 to 3 months. CONCLUSIONS: 153Sm-EDTMP has proven to be a safe and effective therapy for bone pain in lung cancer , and often results in shrinkage or disappearance of metastatic foci. PMID- 20950548 TI - [Comparison between high-dose chemotherapy assisted with autologous peripheral blood stem cell and conventional chemotherapy in the treatment of small cell lung cancer]. AB - BACKGROUND: To compare the response and survival time of autologous peripheral blood stem cell assisted high-dose chemotherapy with conventional chemotherapy in treatment of small cell lung cancer (SCLC) and to access treatment-related toxicities of high-dose chemotherapy. METHODS: Twenty-seven patients with SCLC at age <= 65 yrs entered this study. Thirteen patients were given at high dose of cyclophosphamide (CTX,3. 0 g/ m(2) ) , etoposide (VP16 ,750 mg/ m(2) ) , carboplatin (CBP ,400 mg/ m(2) ) and cisplatin (DDP ,60 mg/ m(2) ) with autologous peripheral blood stem cell support by G-CSF (300mug/ d for 5 or 6 days) after one to three cycles of conventional chemotherapy with ifosfamide + vindesine + DDP ( IVP regimen) or ifosfamide + VP16 + DDP ( IEP regimen) or CTX+ VP16 + DDP (CEP regimen) . Forteen patients were given two courses of conventional chemotherapy with IVP or CEP or VP16 + DDP(EP regimen) . Patients in stage II and stage IIIA were given irradiation or surgical recection after chemotherapy and others by chemotherapy continuously. RESULTS: Response rate to conventional chemotherapy was 78. 6 % after one cycle and 85. 7 % after two cycles respectively , and that to high-dose chemotherapy was 100 %. The difference was not statistically significant ( P > 0. 05) . The survival time was 58 to 569 days for high-dose chemotherapy and 90 to 430 days for conventional chemotherapy respectively , and Log Rank test showed P < 0. 001. The main toxicity of high-dose chemotherapy was bone marrow suppression and all patients occured grade IV leukopenia and 61. 5 % occured grade IV thrombocytopenia , but they recovered in half month after stem cell transplantation and nobody died from high-dose chemotherapy. CONCLUSIONS: High-dose chemotherapy with support of autologous peripheral blood stem cell is an effective therapy for SCLC. Patients has higher response and longer survival time and less toxicity. PMID- 20950549 TI - [Survival and prognosis after pneumonectomy for non-small cell lung cancer (NSCLC) in the elderly]. AB - BACKGROUND: To study the probability and prognosis after pneumonectomy for NSCLC in the elderly. METHODS: From 1985 to 1995 , pneumonectomy was performed in 122 patients with non-small cell lung cancer. Of the 122 patients , 23 cases were 65 years old or older ( study group) and the other 99 cases were less than 65 years old. Five-year survival , operative complications and mortality , and change of lung functions before and after operation were compared between the two groups. Kaplan-meier method was used to analyzed the survival. RESULTS: The 5-year survival for the study group was similar to that for the control group (27. 56 % vs 30. 51 % , P > 0. 05) , but the mortality in the study group was significantly higher than that in the control group (13. 04 % vs 2. 02 % , P < 0. 05) . There was no significant difference between the pre-operative and post-operative lung function for both groups. CONCLUSIONS: Pneumonectomy in elderly patients with NSCLC appears to be applicable. However , it shoud be performed only in carefully selected patients because of the increased operative risk and death. PMID- 20950550 TI - [The multimodality therapeutic result of stage III patients with small cell lung cancer]. AB - BACKGROUND: To investigate the multimodality therapeutic result of stage III patients with small cell lung cancer. METHODS: The clinical data of 89 patients with small cell lung cancer in stage III, which were treated systematically with chemotherapy or radiotherapy-operation-chemotherapy-radiotherapy from 1983 to 1993 , were analysed retrospectively and compared to those of 66 control patients with small lung cancer in stage III, which were treated with chemotherapy or/ and radiotherapy in the same period. RESULTS: The 1- , 3- and 5-year survival rates in the multimodality therapy group were 75. 3 %(67/ 89) , 20. 2 %(18/ 89) and 9. 0 %(8/ 89) , and in the control group they were 48. 5 %(32/ 66) , 12. 1 %(8/ 66) and 0 ( P < 0. 01) . The 1- , 3- and 5-year survival rates for stage IIIA in the multimodality group were 86. 4 %(51/ 59) , 27. 1 %(16/ 59) and 13. 6 %(8/ 59) , and were 53. 3 %(16/ 30) , 6. 7 %(2/ 30) and 0 respectively ( P < 0. 01) for stage IIIB. For stage IIIA patients , the 5-year survival rates of radical resection and palliative resectoin were 18. 4 %(7/ 38) and 4. 8 %(10/ 21) respectively ( P < 0. 01) . For stage IIIB ,whether expanded or palliative resection ,no one survived over 5 years. The 1- , 3- and 5-year survival rates were 76. 3 %(29/ 38) , 18. 4 %(7/ 38) and 2. 6 %(1/ 38) for total pneumonectomy , and 80. 9 %(38/ 47) , 23. 4 %(11/47) and 12. 8 %(6/ 47) for lobectomy. Significant difference in 5-year survival rate was found between pneumonectomy and lobectomy group ( P < 0. 05) . CONCLUSIONS: The clinical TNM stage is the decisive factor influencing the survival rate. Multimodality therapy could improve the survival rate obviously. Radical resection is proper for stage IIIA patients ,but for stage IIIB , whether expanded or palliative resection , the long-term survival isn't satisfactory. So we should strictly choose candidates for surgery. PMID- 20950551 TI - [Mutational analysis of nm23-H1 gene in human lung cancer by polymerase chain reaction-single strand conformation polymorphism]. AB - BACKGROUND: To investigate the mutation of nm23 gene and its correlation with development , progression and metastasis of human lung cancer. METHODS: Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) was employed for mutational analysis of the five exons of nm23-H1 gene in 45 surgically resected lung cancer and 7 normal pulmonary tissues. RESULTS: In the examined DNA samples of pulmonary tissues , no homozygous loss of allele of nm23 H1 gene was observed. SSCP analysis revealed altered mobility of single stranded DNA of nm23-H1 exon 1 in one case of stage IIIB squamous cell pulmonary carcinoma with mediastinal lymphnode metastasis and malignant pleural effusion. CONCLUSIONS: The frequency of nm23-H1 gene mutation in its coding region is rare in lung cancer. Mutation of nm23-H1 gene might play a role in the progression and metastasis of lung cancer. PMID- 20950552 TI - [A study of paclitaxel on inhibiting effects and mechanisms for Lewis lung carcinoma]. AB - BACKGROUND: To research the inhibitory effect and mechanisms of paclitaxel on Lewis lung carcinoma (LLC) of C57BLP6 mice. METHODS: LLC cells were inoculated subcutaneously into C57BLP6 mice. Paclitaxel (10 mgPkg) was injected intraperitoneally in the treatment group for ten days. Then the growth and metastasis of LLC were observed and the apoptotic characteristics of LLC cells were detected by electron microscopy and flowcytes assay. RESULTS: The average weights of the tumors in treatment group and control group were (2. 833 +/-0. 074) g and (0. 588 +/-0. 040) g ( P < 0. 01) , the average numbers of lung metastasis were 5. 500 +/-0. 926 and 1. 167 +/-0. 753 ( P < 0. 01) , and the ratio of apoptosis of LLC cells were 9. 002 % and 25. 772 %( P < 0. 01) , respectively. Some typical apoptotic cells and apoptotic bodies were observed through electron microscope. CONCLUSIONS: Paclitaxel can effectively inhibit the growth , development and metastasis of the implanted LLC in C57BLP6 mice and it can induce apoptosis of the tumor cells apparently. PMID- 20950553 TI - [The nude mice model of human cryopreserved umbilical cord blood transplantation]. AB - BACKGROUND: To evaluate the hematopoietic potential of long-term cryopreserved human umbilical cord blood as well as the migration of the stem cells in nude mice. METHODS: Thirty lethally irradiated BALB/ C nu + mice were randomized into 3 groups. One group was injected cryopreserved human umbilical cord blood cells intravenously and one group was injected fresh cord blood and the other one was injected normal saline as control. The survival rates of mice and the successful transplantation evidence were observed and compared among three groups. The migration of the stem cells was analyzed by PCR and fluid cytometry. RESULTS: The survival rate of the cryopreserved group was much higher than that of the saline group , but there was no significant difference between the fresh group and the cryopreserved group. The evidence of human hematopoiesis was observed by PCR and fluid cytometry and lasted for at least 130 days. In addition , the migration of the cryopreserved stem cells was not the same as that of fresh cord blood , where human gene was hardly detected in liver and kidneys. CONCLUSIONS: Cryopreservation can keep the hematopoietic potential of cord blood for a long time , but may influence the adhesion molecular of the stem cells , hence influence the homing behavior of the stem cells. PMID- 20950554 TI - [Cellular and molecular mechanisms of memory]. AB - A defining characteristic of the brain is its remarkable capacity to undergo activity-dependent functional and morphological remodelling via mechanisms of plasticity that form the basis of our capacity to encode and retain memories. Today, it is generally accepted that one key neurobiological mechanism underlying the formation of memories reside in activity-driven modifications of synaptic strength and structural remodelling of neural networks activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation, a long-lasting activity-dependent form of synaptic strengthening, opened a new chapter in the study of the neurobiological substrate of memory in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular bases of learning and memory. To date, the key events in the cellular and molecular mechanisms underlying synaptic plasticity and memory formation are starting to be identified. They require the activation of specific receptors and of several molecular cascades to convert extracellular signals into persistent functional changes in neuronal connectivity. Accumulating evidence suggests that the rapid activation of neuronal gene programs is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. The recent developments in the search for the cellular and molecular mechanisms of memory storage are reviewed. PMID- 20950555 TI - [The hippocampus and the neural code of spatial memory]. AB - Recent work on the neural substrate of spatial memory strongly suggests the existence of a neuronal network dedicated to the coding of spatial information and allowing the subject to orient in space. This network includes place cells of the hippocampus, head direction cells which are found in several brain regions and particularly the post-subiculum, and grid cells in the entorhinal cortex. Several recently discovered features of place cell activity shed light on how the hippocampus contributes to memory construction. For instance, learning a novel environment relies on a dynamic population code in which place cell activity suddenly changes towards stable states built during previous experience. We briefly review these properties to show how they constrain the hippocampal memory code. PMID- 20950556 TI - [A new chapter in the field of memory: hippocampal neo-neurogenesis]. AB - The dogma according to which "once the development of the central nervous system ended, generation of neurons was impossible" has been challenged by the discovery that new neurons are created in specific regions of the adult mammalian brain. This discovery has been one of the most controversial of modern neuroscience. One of these regions is the dentate gyrus of the hippocampal formation, a key structure in memory. Here we will review our current knowledge on the role of adult hippocampal neurogenesis in memory and in the pathophysiology of memory. In particular we will review evidence showing that adult-born neurons are required for learning and memory and that an alteration of their production rate leads to memory impairments. We also discuss how neurogenesis is finely shaped by learning for the purpose of mnemonic information processing. PMID- 20950557 TI - [Epigenetics and memory]. AB - The epigenetic marking of chromatin in the brain has recently been recognized as an essential mechanism for brain functions such as learning and memory formation. It allows nerve cells not only to respond to environmental stimuli and modulate their profile of gene expression, but also to establish and maintain their own identity. The epigenetic code is conferred by a set of covalent modifications on the basic elements of chromatin, DNA and histone proteins. These changes are catalyzed by specific enzymes and mechanisms, which include DNA methylation, and post-translational modifications of histone proteins such as acetylation, phosphorylation, methylation and ubiquitination. They are both stable and highly dynamic, and are triggered during stimulation of neuronal circuits but can also persist thereafter. Their study in animal models has demonstrated their importance, and revealed some of their modes of function. PMID- 20950558 TI - [Contribution of sleep to learning and memory]. AB - A growing body of evidence indicates that sleep promotes memory consolidation. Although the first experimental evidence for this positive influence of sleep on memory was collected more than a century ago, the potential underlying neural mechanisms begins only to be conceptualized and experimentally characterized. A first hypothesis contrasted the influence of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep on declarative and procedural memories, respectively. As the understanding of the effects of sleep on memory consolidation during sleep progressed, the hypotheses were increasingly framed in terms of neural processes occurring with NREM and REM sleep, especially associated with phasic events such as slow waves, spindles or phasic REM sleep. This paper reviews two of these hypotheses: the synaptic downscaling and the systemic consolidation during non NREM sleep. PMID- 20950559 TI - [Neuroimaging in Alzheimer's disease: a synthesis and a contribution to the understanding of physiopathological mechanisms]. AB - Alzheimer's disease has become a major public health issue for occidental societies. Since animal models of Alzheimer's disease currently fail to perfectly mimic pathophysiological mechanisms or the manifestations of the disease, in vivo neuroimaging has a key role in better understanding the pathophysiology of Alzheimer's disease. The diversity of anatomical and functional neuroimaging techniques - anatomical (T1-MRI), functional (fMRI) and diffusion tensor imaging (DTI) via magnetic resonance imaging (MRI) as well as position emission tomography coupled to fluorodeoxyglucose ((18)FDG-PET) - offers a large possibility of investigation of brain alterations in Alzheimer's disease. These techniques have thus provided morphological and functional brain alterations mapping of Alzheimer's disease: on one hand grey matter atrophy first concerns the medial temporal lobe before extending to the temporal neocortex and then other neocortical areas; on the other hand, metabolic alterations are first located within the posterior cingulate cortex and then reach the temporo-parietal area as well as the prefrontal cortex, especially in its medial part. Assessments of white matter alterations with DTI have highlighted a variety of tract alterations including the cingulum bundle, a white matter tract connecting the medial temporal lobe to the posterior cingulate cortex. Finally fMRI activation studies have evidenced compensatory mechanisms through hyperactivations in Alzheimer's disease patients. Altogether these results have led to the hypothesis of two major pathophysiological mechanisms in Alzheimer's disease: on one hand compensatory mechanisms in regions where atrophy exceeds metabolic alterations, on the other disconnection between medial temporal lobe and posterior cingulate cortex through the cingulum bundle, accounting for higher metabolic than structural alterations in the posterior cingulate cortex. Our work has extensively contributed to this disconnection hypothesis thanks to the use of cross-sectional and longitudinal multi-modal neuroimaging approaches. It has underlined the relevance of distant over local mechanisms in the pathophysiology of Alzheimer's disease and offers new perspectives to the exploration of the neural bases of cognitive impairments in this disorder. PMID- 20950560 TI - [Physiopathology of autobiographical memory in aging: episodic and semantic distinction, clinical findings and neuroimaging studies]. AB - From an early age, autobiographical memory models our feeling of identity and continuity. It grows throughout lifetime with our experiences and is built up from general self-knowledge and specific memories. The study of autobiographical memory depicts the dynamic and reconstructive features of this type of long-term memory, combining both semantic and episodic aspects, its strength and fragility. In this article, we propose to illustrate the properties of autobiographical memory from the field of cognitive psychology, neuropsychology and neuroimaging research through the analysis of the mechanisms of disturbance in normal and Alzheimer's disease. We show that the cognitive and neural bases of autobiographical memory are distinct in both cases. In normal aging, autobiographical memory retrieval is mainly dependent on frontal/executive function and on sense of reexperiencing specific context connected to hippocampal regions regardless of memory remoteness. In Alzheimer's disease, autobiographical memory deficit, characterized by a Ribot's temporal gradient, is connected to different regions according to memory remoteness. Our functional neuroimaging results suggest that patients at the early stage can compensate for their massive deficit of episodic recent memories correlated to hippocampal alteration with over general remote memories related to prefrontal regions. On the whole, the research findings allowed initiating new autobiographical memory studies by comparing normal and pathological aging and developing cognitive methods of memory rehabilitation in patients based on preserved personal semantic capacity. PMID- 20950561 TI - [Memory and epilepsy]. AB - Medial temporal lobe epilepsy is a chronic neurological disease that begins in the early age and that is associated with frequent and disturbing memory deficits. Repeated seizures will lead to the formation of an epileptogenic network that may interfere with physiological neuronal networks and thus with normal brain function: by direct activation or indirectly by deactivation during a seizure, see for example the dreamy state or the ''deja vecu'' phenomenon during temporal seizures; by ictal or post-ictal inhibition, see for example ictal or post-ictal amnesia; by a repetitive and chronic modulation leading to a reorganization of the physiological neuronal networks. The study of these interactions between epileptic and physiological neural networks must lead to better explore the patient's memory and predict memory worsening before temporal lobe surgery and to better understand the reorganization of memory networks in chronic epilepsy. The goal is double: (1) improve the prediction of post operative memory worsening and guide rehabilitation in epileptic clinical practice; (2) improve the pathophysiological knowledge about memory processes. PMID- 20950562 TI - [Heterochromatin, a plastic component in the nucleus of Arabidopsis thaliana cells]. AB - The cytogenetic observation of the nucleus of Arabidopsis thaliana, a plant member of the brassicaceae family, reveals a simple organization of the nuclear content. Indeed, the nuclear volume is occupied by two distinct and easily distinguishable forms of chromatin: a large fraction of relatively decondensed and transcriptionnally active euchromatin surrounds about ten conspicuous regions, the chromocenters, which contain most repeated and highly condensed heterochromatic sequences. Remarkably, during the development of A. thaliana or when the plant is exposed to certain environmental variations, dramatic changes in the appearance, the size or the presence of the chromocenters occur. A number of cytogenetic studies have not only characterized the genomic sequences accommodated in the chromocenters, but have also established the dynamics of their assembly and disruption. Moreover, various endogenous and exogenous factors involved in the presence and the size of chromocenters were recently identified. Taken together, these studies carried out in A. thaliana suggest that heterochromatin is a truly "malleable" fraction of the genome whose dynamic organization is not controlled only by epigenetic marks and whose importance in nuclear function goes beyond merely grouping together non-coding genomic sequences. PMID- 20950563 TI - [Establishing transcriptional silencing of the X chromosome during early embryogenesis]. AB - Early development of female mammals is accompanied by transcriptional inactivation of one of their two X chromosomes. This process, known as X chromosome inactivation, relies on monoallelic activation of the Xist gene. Xist produces a non-coding RNA that can coat the chromosome from which it is transcribed in cis and trigger its silencing. How Xist expression is controlled and how it initiates transcriptional repression are central questions for our understanding of how this chromosome-wide monoallelic program is expressed. Several trans-acting factors have been identified as regulators of Xist expression. Interestingly, some Xist activators are encoded by the X chromosome itself, thereby efficiently promoting Xist expression in females (XX) but not in males (XY). Female cells also display transient physical pairing between their two X chromosomes at the level of their Xics (X inactivation centers) during the time window when X inactivation is initiated. It has been proposed that these pairing events may play a role in Xist activation and its monoallelic regulation. Xist RNA accumulates over the X chromosome from which it is expressed and rapidly triggers the exclusion of the transcription machinery. Genic sequences are initially located outside of this Xist RNA coated domain but as they become progressively silenced they are relocated into this silent nuclear compartment created by Xist. However genes are not all silenced with the same kinetics. Furthermore, some genes can escape X inactivation and remain located outside the Xist-coated compartment. Recent findings have revealed that young, active LINE-1 retrotransposons are expressed from the inactive X chromosome and may facilitate X inactivation, particularly in regions of the X that would otherwise be prone to escape. PMID- 20950564 TI - [Embryonic genome organization after fertilization in mammals]. AB - In mammals, the embryonic genome is first transcriptionally inactive after fertilization. Embryonic development is then strictly dependent on the maternally inherited RNA and proteins accumulated before ovulation and present in the oocyte cytoplasm. The onset of embryonic gene expression is initiated later during development, i.e. during the "embryonic genome activation (EGA)". EGA takes place at various preimplantation stages according to species and is dependent on the presence of the basal transcriptional machinery components but also on parental genomes reorganizations after fertilization. Indeed, during the first embryonic cycles, nuclei undergo intense remodeling that could be a key regulator of embryonic development. PMID- 20950565 TI - [Organization of the nucleus during cell differentiation in the mammary tissue]. AB - In many tissues, the features of cell nuclei are specific to their differentiated state, notably in terms of the nature and distribution of nuclear compartments and the position of chromosomes and genes. This spatial organization of the nucleus reveals domains that are differentially permissive for gene expression and may constitute an epigenetic mechanism that is involved in maintaining tissue specific expression profiles. The mammary gland is a complex tissue in which mammary epithelial cells (MECs), which synthesize and secrete milk components, interact with other cell types (myoepithelial cells, adipocytes) and the extracellular matrix. MECs cultures can to some extent recreate cell differentiation in vitro and have been used to follow the development and functional importance of nuclear organization. They have made it possible to show how hormonal stimulation can lead to a remodeling of nuclear domains and the repositioning of genes specific to the mammary gland, such as milk protein genes. By modulating the growth conditions of culture in order to replace cells in a microenvironment similar to that of mammary gland tissue, it should be possible to study the role of this cellular microenvironment in nuclear organization. PMID- 20950566 TI - [Heterochromatin compartments and gene silencing: human hematopoietic differentiation as a model study]. AB - In order to accomplish its differentiation program, the nucleus of a multipotent cell must be sequentially reprogrammed to acquire and maintain new gene expression patterns. When a stem cell is committed to differentiate towards a given lineage, global genome reprogramming involves both repression of non affiliated genes and selective activation of genes involved in the establishment of the lineage. Accumulating evidence indicates that lineage specific gene expression is determined not only by the availability of specific transcription factors, but also by epigenetic modifications including both local modifications of DNA and chromatin structure, as well as global topological changes in chromosomes and genes positioning in the nucleus. Combined, these different levels of gene regulation allow for fine controls that integrate environmental and intracellular signals to establish appropriate gene expression programs, and hence ultimately determine the identity of the cell. Therefore, epigenetic modifications most likely precede gene activation and play a critical role in the choices of a stem cell to continue to self-renew or to differentiate. However, the cause-effect relationship between chromatin structure, nuclear architecture and cell-fate decisions is still a matter of debate. The pericentromeric heterochromatin compartment will be presented as one of the best studied examples to understand the impact of and positioning of a gene on its transcription. We will set the influence of heterochromatin compartments in the context of hematopoietic differentiation of human multipotent progenitors. PMID- 20950567 TI - [Is an animal a person? And are scientists always rational animals?]. AB - An accumulation of scientific observations now challenges the idea that there is a huge difference between human beings and other animal species. There is no longer any need to assume that man possesses something special. Yet many scientists refuse to admit that this is so. As a result, they frequently express opinions that are both contrary to reality and flawed in their thinking. It is interesting to note that this shortage of logic is not due to a lack of knowledge (as would be a layperson's opinion), but sometimes due to a quest for precision. Some authors describe what appears to be well-controlled experiments but do not even envisage the most important skew. For example, the absence of social context for an animal whose social intelligence is being studied or ignoring the consequences of the taming or training process. The latter evidently encourages the animal to give the answer it thinks the experimenter wants, instead of actually trying to understand. In the end, it turns out that much incapacity attributed to animals is in fact incapacity on the part of the experimenter. PMID- 20950568 TI - [IGF and insulin signaling pathways in longevity]. AB - The role of the somatotropic hormone axis in mammalian longevity has been studied in diverse experimental models in vivo. This endocrine axis allows regulation of lifespan via metabolism modifications and oxidative stress defense mechanisms. Signaling can be altered at ligand, receptor or signal transduction molecule level through mutagenesis. Mutant mouse models affecting pituitary differentiation factors Prop-1 or Pit1, cognate receptors of GH, IGF or insulin, or receptor substrates IRS-1 or IRS-2 showed that regulation of the somatotropic endocrine axis is pivotal for maintaining an equilibrium between growth, metabolism, oxidative stress defense and longevity. Brain-specific gene inactivation of IGF-1R and IRS-2 resulted in similarly long-lived phenotypes indicating that control of longevity is possible by selectively targeting the brain. In addition to genetic modification, lifespan can be efficiently manipulated in mice by altering the environment, for instance by modifying caloric intake, or pharmacologically, as has been shown in a recent study about the effects of rapamycin on lifespan. Moreover, recent studies of the human genetics of aging revealed that mutations of IGF-1R and variants of FoxO3a are more frequent in certain centenarian cohorts. This suggested that these results are in principle transposable to humans. PMID- 20950569 TI - [Relevance of animal models in the study of human pathologies: a mouse model of Down syndrome]. AB - Animal models provide a simplified representation of biological systems impossible to study directly in the human being. Regarding genetic pathologies, mouse models are the most studied since they enable to reproduce in animals the mutation of the gene or genes responsible for the disease and to study the phenotypic consequences. Down syndrome is a genetic disorder arising from the presence of a third copy of the human chromosome 21 (Hsa21) and is characterized by different degrees of phenotypic alterations including morphological, cardiac, muscular, cerebral, motor and intellectual changes. This high phenotypic heterogeneity involves genetic and environmental effects, which are impossible to dissect out in human beings. Various models in mice have been developed in order to identify the genetic and neurobiological mechanisms responsible for Down syndrome. The Tc1 mouse is the most complete genetic animal model currently available to study Down syndrome, since it carries an almost complete Hsa 21. The behavioural and electrophysiological studies of this model reveal a great similarity between the animal phenotype and the Down syndrome symptomatology, consequently this model represents a powerful genetic tool with a potential to unravel the mechanisms underlying the deficiencies array characteristic of this human condition. In the long term, Tc1 mice will contribute to the development and the screening of new therapeutics, with the goal of improving all the impairments reported in Down syndrome. PMID- 20950570 TI - [Signal transduction in plants review and rectification--INTRODUCTION]. PMID- 20950571 TI - [Lipid signaling pathways in plants and their roles in response to water constraints]. AB - Plants are sessile organisms that have developed the capacity to detect slight variations of their environment. They are able to perceive these environmental signals and to transduce them by signaling pathways in order to trigger adaptative responses. Lipid signaling elements play a central role in these pathways in plants. A key element is phosphatidic acid (PA), which can be produced by two pathways. In the first one, phospholipids are hydrolysed by phospholipase D (PLD) to release PA. In the second one, PA is produced through the activity of phospholipase C (PLC) to produce diacylglycerol (DAG) which is then phosphorylated by DAG kinase (DAGK). The amount of PA in the cell is regulated by PA kinase, which phosphorylates PA to produce diacylglycerolpyrophosphate (DGPP), considered as a second messenger as well. PLCs play a dual role in cell signaling by regulating the amount of intracellular Ca(2+), another essential second messenger. Phosphoinositides, such as PI3P, PI4P and PI(4,5)P(2), are substrates of PLCs and PLDs and are considered as second messengers also. In this review, we present recent data regarding the specific features of these lipid signaling pathways in plant compared with other eukaryotes. PMID- 20950572 TI - [Plant calcium sensors in osmotic signaling]. AB - Calcium is an essential second messenger that mediates plant responses to developmental and environmental clues. Specific calcium signatures are sensed and decoded by diverse Ca(2+) sensors to induce appropriate downstream responses. Calmodulin is the most important and conserved Ca(2+) transducer in all eukaryotes. Additional plant-specific sensors are encoded by multigene families, i.e. calcineurin B-like and Ca(2+)-dependent protein kinases. Calcium binding induces structural conformational changes in Ca(2+) sensors, resulting in the modification of protein interaction or enzymatic activity. Activated Ca(2+) sensors subsequently regulate downstream targets which can be involved in signal transduction, like protein kinases and transcription factors, or in direct cell protection from stress damages, like ion transporters or detoxification enzymes. Ca(2+) plays an important role in osmotic signaling triggered by cold, drought and salinity. The multiplicity of plant calcium sensors associated with diverse cellular targets constitute a tightly regulated signaling network that induces specific stress responses to improve plant survival under unfavourable conditions. PMID- 20950573 TI - [Control of fertilization by self-incompatibility mechanisms]. AB - Flowering plants (angiosperms) are the most prevalent and evolutionarily advanced group of plants. Reproductive strategies that promote cross-fertilization have played an essential role in the success of angiosperms as they contribute to genetic variability among plant species. A major genetic barrier to self fertilization is self-incompatibility (SI), which allows female reproductive cells to discriminate between self- and non-self pollen and specifically reject self-pollen. In this review, we describe three SI mechanisms showing that different flowering plant families use distinct molecules for recognition of self as well as diverse biochemical pathways to arrest pollen tube growth. PMID- 20950574 TI - [Strigolactones, a novel class of plant hormones controlling branching]. AB - Plant architecture is a major trait for plant survival and plant fitness and has a huge influence on the agronomical value for most crops. The classical theory of apical dominance based on decapitation experiments suggested that two major plant hormones, auxin and cytokinins, were acting antagonistically on bud outgrowth to promote or repress branching. However this theory was challenged in the late 1930's by Snow who suggested the existence of a second messenger to auxin, as auxin was not acting directly to repress branching. The use of branching mutants in pea, Arabidopsis and rice led to the discovery of a new carotenoid-derived signal repressing branching. Genes involved in synthesis (RMS1, RMS5) as well as in response (RMS4) to this new signal have been identified and have given rise to a new model of the branching control. Two independent group have recently shown, one on pea, the other on rice, that strigolactones correspond to this novel signal which represses branching and to the secondary messenger in the theory of apical dominance. Strigolactones have been first identified for their role in germination of parasitic plants like Striga or Orobanche. They also play a critical role in the widespread association between 80% of plants and fungi, the arbuscular mycorrhizal symbiosis, as they are necessary for interaction between certain plants and fungi in the rhizosphere. PMID- 20950575 TI - [Passive immunotherapy today: brief history]. AB - Brief recall of the history of passive immunotherapy and its current importance. PMID- 20950576 TI - [Production of highly purified therapeutic immunoglobulins (HPTI): analysis of a purification process]. AB - Heterologous immunoglobulins have been used for more than a century for human therapeutic use. Introduction of fractionation and purification steps for the production of these heterologous immunoglobulins has allowed an improvement in their tolerance. Historically, the fractionation and purification steps consisted in one precipitation with 30% of ammonium sulfate followed by a hydrolysis with pepsin at acid pH. More recently, the addition of purification steps like ion exchange chromatography and the addition of viral safety steps like pasteurization have allowed to improve the purity of these products and to reduce the risk of adverse events. Today, the more efficient processes are able to reach a proportion of about 95% in F(ab')(2) fragments with less than 0.5% of aggregates and polymers ensuring an optimal safety profile of these products. PMID- 20950577 TI - [Emergency immunotherapy: snake and scorpion antivenoms]. AB - Passive immunotherapy was discovered in 1894. It is the only etiological treatment of envenomations by snakes or scorpions. Immunotherapy is based on administration of antibodies produced by an animal hyperimmunised against venom. Improvement of whole antivenomous sera was obtained, first by separating the antibodies from other components of blood plasma, then by using enzyme digestion of immunoglobulins G and, finally, by purifying the final product. Efficacy and also tolerance were significantly increased. Antivenom administration should be performed through the intravascular route to ensure better diffusion and to facilitate the complexion with the venom. The sale of antivenoms, in particular in Africa, is considerably reduced since about thirty years and is not in adequacy with the epidemiologic needs. In addition to the high cost of the current products, the difficulties of supplying, storage and use seem at the origin of this rejection by both the health staff and the victims who resort massively to traditional medicine. Whereas WHO reminds the rules of production and use of the antivenoms to producers and authorities in charge of drug regulations, it appears that the accessibility of the antivenoms depends on a concerted effort from all the actors, coordinated by health authorities: producers, distributers, manufacturers and public. Beyond technological improvements necessary in antivenom production, the strategy to be implemented must include the strict evaluation of the needs based on epidemiologic studies, the share of cost recovery between all the actors, and the optimization of the therapeutic protocol to make it applicable in remote health centres. Once confidence towards immunotherapy will be restored, mortality will be significantly reduced. PMID- 20950578 TI - [The use of passive rabies immunotherapy: from the past to the future]. AB - Rabies is a fatal disease transmitted by infected animals by bite, scratch, licking on broken skin or contamination of mucosis by saliva. The regimen of post exposure prophylaxis for people not previously vaccinated, that is currently recommended by WHO, consists of a combination of wound cleaning, active immunization and passive immunization when the exposure is of category 3. Most of the products available on the market, in particular human rabies immunoglobulins, highly purified equine rabies immunoglobulins and the derived F(ab')(2) fragments, are now characterized by high potency and safety. Although the interest of passive anti-rabies immunization was first demonstrated in the first half of the 20th century, there is still an inadequate supply of these products to the target populations mostly in developing countries. Therefore, it is urgent to set-up training and information actions for healthcare personnel on the need to use passive immunotherapy and the lack of adverse effects of the related products. For the future, we hope that a scale up of production and a lower price will improve the accessibility to these products. The development of new products based on monoclonal antibodies and molecular biology, and which may be cheaper, is promising. PMID- 20950579 TI - [Recombinant antibodies for medical protection against bioterrorism agents: the example of anthrax]. AB - Recombinant antibodies are a highly successful class of therapeutic molecules, they are well adapted for use against bio-weapons (BW) as they act immediately, are often synergistic with other therapeutic molecules, have a long half-life and are well tolerated. Anthrax is regarded at high risk of being used as BW, and its pathogenic properties depend on toxins, which might be neutralized by antibodies. These toxins are made of three different types of sub-units (PA, LF, EF). Several anti-PA have been developed, including an original approach by our team. We have developed an anti-LF, as recommended by experts. Our anti-PA antibody, and to a lesser extend our anti-LF antibody, will be presented here. PMID- 20950580 TI - [Guidelines for the production, control and regulation of snake antivenom immunoglobulins]. AB - Although frequent and severe, envenomations represent a neglected public health problem in most of the developing countries. Access to antivenoms is poor, mainly in Sub-Saharan Africa, and remains a major concern to World Health Organization (WHO). Since 2007, WHO committed international experts to propose guidelines aiming to improve the manufacture, quality control, registration and use of antivenoms. These guidelines, which will published soon, should promote access to antivenoms, and their use by health services, leading in the short term to a significant decrease of snakebite morbidity and mortality. PMID- 20950581 TI - Fused-core silica column ultra-performance liquid chromatography-ion trap tandem mass spectrometry for determination of global DNA methylation status. AB - Epigenetic modifications, such as DNA methylation, play key roles in transcriptional regulation of gene expression. More recently, global DNA methylation levels have been documented to be altered in several diseases, including cancer, and as the result of exposure to environmental toxicants. Based on the potential use of global DNA methylation status as a biomarker of disease status and exposure to environmental toxicants, we sought to develop a rapid, sensitive, and precise analytical method for the quantitative measurement of global DNA methylation status using ultra-performance liquid chromatography with detection by ion trap tandem mass spectrometry. Using a fused-core silica column, 2'-deoxyguanosine (2dG) and 5-methyl-2'-deoxycytidine (5mdC) were resolved in less than 1 min with detection limits of 0.54 and 1.47 fmol for 5mdC and 2dG, respectively. The accuracy of detection was 95% or higher, and the day-to-day coefficient of variation was found to be 3.8%. The method was validated by quantification of global DNA methylation status following treatment of cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine, which reduced DNA methylation from 3.1% in control cells to 1.1% in treated cells. The sensitivity and high throughput of this method rend it suitable for large-scale analysis of epidemiological and clinical DNA samples. PMID- 20950582 TI - A potential transcriptional regulator is out-of-frame translated from the metallothionein 2A messenger RNA. AB - In a number of yeast two-hybrid screens, we have found clones that contained parts of the human metallothionein 2A (MT2A) nucleotide sequence. All of these clones were out-of-frame relative to the MT2A coding sequence and activated the yeast reporters in the presence of the Gal4 DNA binding domain but irrespective of the bait protein. Reporter gene activation was abolished when activation domain and MT2A coding sequences were brought in-frame. In light of these findings, we evaluated all recently reported interactions with metallothioneins because our out-of-frame proline-rich protein might have been the actual interaction partner in some of these studies. PMID- 20950583 TI - Gel shift selection of translation enhancer sequences using messenger RNA display. AB - We designed a new approach for selection of translation enhancer sequences that enables efficient protein synthesis in cell-free systems. The selection is based on a gel shift assay of a messenger RNA (mRNA)-protein fusion product that is synthesized in a cell-free translation system using an mRNA display method. A library of randomized 20-nt-long sequences, with all possible combinations of the four nucleotides, upstream of a coding region was screened by successive rounds of screening in which the translation time of the succeeding round was reduced compared with the previous round. An efficient translation enhancer sequence capable of more rapid initiation of cell-free protein synthesis, with a minimal translation time of 5 min, than a natural longer enhancer sequence (Xenopus beta globin 5'UTR) was selected using rabbit reticulocyte extract as a model cell-free translation system. Furthermore, a successful screening of cap-independent translation enhancer sequence and a significant sequence similarity of the selected candidates validated the efficiency of the combined mRNA display and gel shift assay method for the rapid development of advanced cell-free translation systems. PMID- 20950584 TI - Adenine nucleotide translocase 2 is a key mitochondrial protein in cancer metabolism. AB - Adenine nucleotide translocase (ANT), a mitochondrial protein that facilitates the exchange of ADP and ATP across the mitochondrial inner membrane, plays an essential role in cellular energy metabolism. Human ANT presents four isoforms (ANT1-4), each with a specific expression depending on the nature of the tissue, cell type, developmental stage and status of cell proliferation. Thus, ANT1 is specific to muscle and brain tissues; ANT2 occurs mainly in proliferative, undifferentiated cells; ANT3 is ubiquitous; and ANT4 is found in germ cells. ANT1 and ANT3 export the ATP produced by oxidative phosphorylation (OxPhos) from the mitochondria into the cytosol while importing ADP. In contrast, the expression of ANT2, which is linked to the rate of glycolytic metabolism, is an important indicator of carcinogenesis. In fact, cancers are characterized by major metabolic changes that switch cells from the normally dual oxidative and glycolytic metabolisms to an almost exclusively glycolytic metabolism. When OxPhos activity is impaired, ANT2 imports glycolytically produced ATP into the mitochondria. In the mitochondrial matrix, the F1F0-ATPase complex hydrolyzes the ATP, pumping out a proton into the intermembrane space. The reverse operations of ANT2 and F1F0-ATPase under glycolytic conditions contribute to maintaining the mitochondrial membrane potential, ensuring cell survival and proliferation. Unlike the ANT1 and ANT3 isoforms, ANT2 is not pro-apoptotic and may therefore contribute to carcinogenesis. Since the expression of ANT2 is closely linked to the mitochondrial bioenergetics of tumors, it should be taken into account for individualizing cancer treatments and for the development of anticancer strategies. PMID- 20950585 TI - Inflammatory cytokines regulate microRNA-155 expression in human retinal pigment epithelial cells by activating JAK/STAT pathway. AB - Inflammatory response of the retinal pigment epithelium plays a critical role in the pathogenesis of retinal degenerative diseases such as age-related macular degeneration. Our previous studies have shown that human retinal pigment epithelial (HRPE) cells, established from adult donor eyes, respond to inflammatory cytokines by enhancing the expression of a number of cytokines and chemokines. To investigate the role of microRNA (miRNA) in regulating this response, we performed microarray analysis of miRNA expression in HRPE cells exposed to inflammatory cytokine mix (IFN-gamma+TNF-alpha+IL-1beta). Microarray analysis revealed ~11-fold increase in miR-155 expression, which was validated by real-time PCR analysis. The miR-155 expression was enhanced when the cells were treated individually with IFN-gamma, TNF-alpha or IL-1beta, but combinations of the cytokines exaggerated the effect. The increase in miR-155 expression by the inflammatory cytokines was associated with an increase in STAT1 activation as well as an increase in protein binding to putative STAT1 binding elements present in the MIR155 gene promoter region. All these activities were effectively blocked by JAK inhibitor 1. Our results show that the inflammatory cytokines increase miR 155 expression in human retinal pigment epithelial cells by activating the JAK/STAT signaling pathway. PMID- 20950586 TI - Induction of the Ras activator Son of Sevenless 1 by environmental pollutants mediates their effects on cellular proliferation. AB - TCDD (2,3,7,8-tetrachlorodibenzodioxin), a highly persistent environmental pollutant and a human carcinogen, is the ligand with the highest affinity for the Aryl Hydrocarbon Receptor (AhR) that induces via the AhR, xenobiotic metabolizing enzyme genes as well as several other genes. This pollutant elicits a variety of systemic toxic effects, which include cancer promotion and diverse cellular alterations that modify cell cycle progression and cell proliferation. Large scale studies have shown that the expression of Son of Sevenless 1 (SOS1), the main mediator of Ras activation, is one of the targets of dioxin in human cultured cells. In this study, we investigated the regulation of the previously uncharacterized SOS1 gene promoter by the AhR and its ligands in the human hepatocarcinoma cell line, HepG2. We found that several environmental pollutants (AhR ligands) induce SOS1 gene expression by increasing its transcription. Chromatin immunoprecipitation experiments demonstrated that the AhR binds directly and activates the SOS1 gene promoter. We also showed that dioxin treatment leads to an activated Ras-GTP state, to ERK activation and to accelerated cellular proliferation. All these effects were mediated by SOS1 induction as shown by knock down experiments. Our data indicate that dioxin induced cellular proliferation is mediated, at least partially, by SOS1 induction. Remarkably, our studies also suggest that SOS1 induction leads to functional effects similar to those elicited by the well-characterized oncogenic Ras mutations. PMID- 20950587 TI - alpha-Elapitoxin-Aa2a, a long-chain snake alpha-neurotoxin with potent actions on muscle (alpha1)(2)betagammadelta nicotinic receptors, lacks the classical high affinity for neuronal alpha7 nicotinic receptors. AB - In contrast to all classical long-chain alpha-neurotoxins possessing the critical fifth disulfide bond, alpha-elapitoxin-Aa2a (alpha-EPTX-Aa2a), a novel long-chain alpha-neurotoxin from the common death adder Acanthophis antarcticus, lacks affinity for neuronal alpha7-type nicotinic acetylcholine receptors (nAChRs). alpha-EPTX-Aa2a (8850Da; 0.1-1MUM) caused a concentration-dependent inhibition of indirect twitches, and blocked contractures to cholinergic agonists in the isolated chick biventer cervicis nerve-muscle preparation, consistent with a postsynaptic curaremimetic mode of action. alpha-EPTX-Aa2a (1-10nM) produced a potent pseudo-irreversible antagonism of chick muscle nAChRs, with an estimated pA(2) value of 8.311+/-0.031, which was not reversed by monovalent death adder antivenom. This is only 2.5-fold less potent than the prototypical long-chain alpha-neurotoxin, alpha-bungarotoxin. In contrast, alpha-EPTX-Aa2a produced complete, but weak, inhibition of (125)I-alpha-bungarotoxin binding to rat hippocampal alpha7 nAChRs (pK(I)=3.670), despite high sequence homology and similar mass to a wide range of long-chain alpha-neurotoxins. The mostly likely cause for the loss of alpha7 binding affinity is a leucine substitution, in loop II of alpha-EPTX-Aa2a, for the highly conserved Arg(33) in long-chain alpha neurotoxins. Arg(33) has been shown to be critical for both neuronal and muscle activity. Despite this substitution, alpha-EPTX-Aa2a retains high affinity for muscle (alpha1)(2)betagammadelta nAChRs. This is probably as a result of an Arg(29) residue, previously shown to be critical for muscle (alpha1)(2)betagammadelta nAChR affinity, and highly conserved across all short chain, but not long-chain, alpha-neurotoxins. alpha-EPTX-Aa2a therefore represents a novel atypical long-chain alpha-neurotoxin that includes a fifth disulfide but exhibits differential affinity for nAChR subtypes. PMID- 20950588 TI - Preferential localization of prostamide/prostaglandin F synthase in myelin sheaths of the central nervous system. AB - Prostaglandin (PG) F(2alpha) is a product of cyclooxygenase (COX)-catalyzed metabolism of arachidonic acid and exerts biological functions in various tissues. Prostaglandin ethanolamide (prostamide) F(2alpha) is a COX-2-catalyzed metabolite of arachidonoyl ethanolamide (anandamide) that induces pharmacological actions in ocular tissues. Although PGF(2alpha) is one of the most abundant prostaglandins in the brain, function of PGF(2alpha) in the central nervous system (CNS) has not been extensively investigated. Recently identified prostamide/PGF synthase catalyzes the reductions of prostamide H2 to prostamide F(2alpha) and PGH2 to PGF(2alpha), chiefly in the CNS. We examined tissue distribution of the enzyme in the CNS by immunohistochemistry, double immunofluorescence, and immuno-electron microscopy. We confirmed histological findings by immunofluorescence analyses of brain cell cultures. Prostamide/PGF synthase was expressed preferentially in the white matter bundles of the entire CNS of adult mice with less marked expression in neuronal cell bodies. The enzyme was colocalized with myelin basic protein (MBP) in myelin sheaths but not in axons. At the ultrastructural level, the enzyme was localized to myelin sheaths. Expression of the enzyme increased between P9 and P14 during the postnatal development, presumably in accordance with myelinogenesis. Cultured oligodendrocytes at 7 days in vitro expressed the enzyme in cytoplasmic processes where the enzyme was colocalized with MBP. Immunoreactivity for COX-2 was detected in white matter and cultured oligodendrocytes. Relatively selective localization of prostamide/PGF synthase suggests that myelin sheaths of the CNS may serve as the sites for producing prostamide F(2alpha) and/or PGF(2alpha), which may contribute to the formation and maintenance of central myelin. PMID- 20950590 TI - An fMRI study of neuronal interactions in face-selective areas of the brain. AB - Functionally activated sites usually have multiple specificities where coactivation is induced by inputs with different informational content. Using typical voxel-based functional mapping (univariate analysis), it is possible to show the presence of coactivation; however, it is not possible to distinguish whether coactivation occurs by independent or interactive processing units unless measurements are made at an extremely high spatial resolution. To address this problem, we have utilized the phenomenon of refractory suppression observable when two stimuli were given with a temporal separation of approximately 100 ms. This phenomenon is known to be noticeable in primary sensory areas. In this study, refractory suppression was investigated to determine its possible applications in higher functional sites. Two visual stimuli were presented in different hemifields, using a paradigm in which the first of the paired stimuli (face pictures) was placed in the left visual hemifield and the second stimulus was placed in the right hemifield. In this manner, the primary visual areas (V1) of the left and right hemispheres were independently activated. Along with independent activation in both V1, refractory suppression was indeed observed in higher functional areas, including the occipital and fusiform face areas in both hemispheres. PMID- 20950589 TI - Differential co-localization with choline acetyltransferase in nervus terminalis suggests functional differences for GnRH isoforms in bonnethead sharks (Sphyrna tiburo). AB - The nervus terminalis (NT) is a vertebrate cranial nerve whose function in adults is unknown. In bonnethead sharks, the nerve is anatomically independent of the olfactory system, with two major cell populations within one or more ganglia along its exposed length. Most cells are immunoreactive for either gonadotropin releasing hormone (GnRH) or RF-amide-like peptides. To define further the cell populations and connectivity, we used double-label immunocytochemistry with antisera to different isoforms of GnRH and to choline acetyltransferase (ChAT). The labeling patterns of two GnRH antisera revealed different populations of GnRH immunoreactive (ir) cell profiles in the NT ganglion. One antiserum labeled a large group of cells and fibers, which likely contain mammalian GnRH (GnRH-I) as described in previous studies and which were ChAT immunoreactive. The other antiserum labeled large club-like structures, which were anuclear, and a sparse number of fibers, but with no clear labeling of cell bodies in the ganglion. These club structures were choline acetyltrasferase (ChAT)-negative, and preabsorption control tests suggest they may contain chicken-GnRH-II (GnRH-II) or dogfish GnRH. The second major NT ganglion cell-type was immunoreactive for RF amides, which regulate GnRH release in other vertebrates, and may provide an intraganglionic influence on GnRH release. The immunocytochemical and anatomical differences between the two GnRH-immunoreactive profile types indicate possible functional differences for these isoforms in the NT. The club-like structures may be sites of GnRH release into the general circulation since these structures were observed near blood vessels and resembled structures seen in the median eminence of rats. PMID- 20950591 TI - Experiencing simultanagnosia through windowed viewing of complex social scenes. AB - Simultanagnosia is a disorder of visual attention, defined as an inability to see more than one object at once. It has been conceived as being due to a constriction of the visual "window" of attention, a metaphor that we examine in the present article. A simultanagnosic patient (SL) and two non-simultanagnosic control patients (KC and ES) described social scenes while their eye movements were monitored. These data were compared to a group of healthy subjects who described the same scenes under the same conditions as the patients, or through an aperture that restricted their vision to a small portion of the scene. Experiment 1 demonstrated that SL showed unusually low proportions of fixations to the eyes in social scenes, which contrasted with all other participants who demonstrated the standard preferential bias toward eyes. Experiments 2 and 3 revealed that when healthy participants viewed scenes through a window that was contingent on where they looked (Experiment 2) or where they moved a computer mouse (Experiment 3), their behavior closely mirrored that of patient SL. These findings suggest that a constricted window of visual processing has important consequences for how simultanagnosic patients explore their world. Our paradigm's capacity to mimic simultanagnosic behaviors while viewing complex scenes implies that it may be a valid way of modeling simultanagnosia in healthy individuals, providing a useful tool for future research. More broadly, our results support the thesis that people fixate the eyes in social scenes because they are informative to the meaning of the scene. PMID- 20950592 TI - Lentivirus-mediated transfer of MMP-9 shRNA provides neuroprotection following focal ischemic brain injury in rats. AB - Various studies on focal cerebral ischemic models have implicated the direct activation and expression of matrix metalloproteinases (MMPs), especially MMP-9, as a key orchestrator of blood-brain barrier (BBB) disruption. Moreover, studies have shown that MMP-9 siRNA can protect the BBB from ischemia/reperfusion injury. In the present study, we investigated the neuroprotective role of a lentivirus vector-mediated mmp-9shRNA following focal cerebral ischemia--specifically assessing whether LV-mmp9shRNA silencing of MMP-9 mRNA could ameliorate BBB disruption and in turn reduce vascular permeability, neuronal cell death, and neurobehavioral deficits. Treatment was given 2 weeks prior to surgery using a lentivirus-mediated vector. Surgery was conducted using the established middle cerebral artery occlusion (MCAO) model in rats, while outcomes were measured 24 h after injury. Our results demonstrated a significant reduction in brain infarction volume, brain water content, and neurobehavioral deficits following LV mmp9shRNA treatment. Additionally, Evans blue and IgG extravasation were reduced, MMP-9 mRNA expression was silenced, and Western blot analysis revealed a decreased expression of MMP-9 and VEGF with an increased expression of occludin and collagen IV in brain tissues. This suggests that successful delivery of LV mmp9shRNA may ameliorate ischemic brain injury by preserving structural integrity and improving functional outcome. PMID- 20950594 TI - Lead poisoning associated with Ayurvedic drug presenting as intestinal obstruction: a case report. AB - INTRODUCTION: Lead poisoning is most commonly caused by occupational exposure. It presents with a myriad of signs and symptoms ranging from mild anemia to frank encephalopathy, depending on the blood lead levels as well as the duration of exposure. Intake of herbal/Ayurvedic medicine may also lead to plumbism as heavy metals are often incorporated in such medications with the belief that such metals have medicinal properties. METHODS: We report a case of lead poisoning caused by Ayurvedic medication. The patient presented with symptoms of intestinal obstruction to the surgical casualty. RESULTS: The patient presented with symptoms that mimicked intestinal obstruction. No specific etiology could be determined. Serum lead levels were determined and diagnosis of lead poisoning ascertained. The lead content of the medicine was analyzed and it contained 30% w/w lead. CONCLUSIONS: The diagnosis of heavy metal poisoning consequent to intake of alternative medicine must be kept in mind when a patient presents with vague complaints. PMID- 20950593 TI - Methamphetamine potentiates behavioral and electrochemical responses after mild traumatic brain injury in mice. AB - We previously demonstrated that high doses of methamphetamine (MA) exacerbate damage induced by severe brain trauma. The purpose of the present study was to examine if MA, at low dosage, affected abnormalities in locomotor activity and dopamine turnover in a mouse model of mild traumatic brain injury (mTBI). Adult male CD1 mice were treated with MA (5 mg/kgi.p.) or vehicle 30-min prior to mTBI, conducted by dropping a 30 g metal weight onto the temporal skull, anterior the right ear. At 15 min after mTBI, animals were put into locomotor activity chambers for up to 72 h. During the first 3 h, mTBI alone, compared with vehicle control, did not alter total distance travelled. Treatment with MA significantly increased locomotor activity in the control animals during the first 3 h; mTBI reduced MA-induced hyperactivity. In contrast, at 2 and 3 days after injury, mTBI or MA alone reduced locomotor activity. Co-treatment with MA and mTBI further reduced this activity, suggesting a differential and temporal behavioral interaction between MA and mTBI during acute and subacute phases after injury. Dopamine and DOPAC levels in striatal tissue were analyzed using HPLC-ECD. At 1h after mTBI or injection, DA was not altered but DOPAC level and DOPAC/DA turnover ratios were significantly reduced. Co-treatment with MA further reduced the DOPAC/DA ratio. At 36 h after injury, mTBI increased tissue DA levels, but reduced DOPAC levels and DOPAC/DA ratios. Co-treatment with MA further reduced DOPAC/DA ratios in striatum. In conclusion, our data suggest that low dosage of MA worsens the suppression of locomotor responses and striatal dopamine turnover after mTBI. PMID- 20950595 TI - Measurement of B-type natriuretic peptide by two assays utilizing antibodies with different epitope specificity. AB - OBJECTIVES: To compare plasma BNP values determined by a conventional-type and a novel-type of BNP assays. DESIGN AND METHODS: Plasma samples (n=94) from HF patients were analyzed by the novel-type "Single Epitope Sandwich" (SES assay prototype) and the conventional-type Siemens ADVIA Centaur BNP assays. Both assays were calibrated using recombinant proBNP (expressed in E. coli). RESULTS: The SES assay measured 1.2- to 7.2-fold (2.1+/-0.9; mean, SD) greater BNP concentrations compared to the Siemens assay. A subset of six samples (6.4%) demonstrated the largest (3- to 7.2-fold higher) difference. CONCLUSIONS: The SES prototype assay appears to more accurately measure the absolute concentrations of BNP immunoreactive forms. PMID- 20950596 TI - Altered amino acid homeostasis and the development of fatigue by breast cancer radiotherapy patients: A pilot study. AB - OBJECTIVES: To examine altered amino acid homeostasis as a predisposing factor of fatigue in female radiotherapy breast cancer patients. DESIGN AND METHODS: Participants underwent breast-conserving surgery and adjuvant breast irradiation and were free from significant fatigue pre-radiotherapy. The Functional Assessment of Cancer Therapy fatigue subscale was used to assess fatigue pre- and post-radiotherapy. Blood biochemistry factors and urinary and plasma amino acid levels were measured. RESULTS: One third of 27 patients developed fatigue and were designated as the fatigued cohort. It was possible to differentiate between fatigued subjects pre- and post-radiotherapy based upon their urinary amino acid profiles. Univariate analysis supported altered amino acid homeostasis within the fatigued cohort. Urinary levels of histidine and alanine were increased pre radiotherapy whilst threonine, methionine, alanine, serine, asparagine and glutamine levels were higher after 5weeks of radiotherapy for the fatigued cohort. CONCLUSIONS: Fatigue was accompanied by altered amino acid homeostasis with increased amino acid excretion suggestive of a catabolic response. PMID- 20950597 TI - Application of serum protein fingerprint in diagnosis of coronary artery disease. AB - OBJECTIVES: The object of this study is to establish serum protein fingerprint models for early diagnosis and evaluation of luminal stenosis severity of CAD. DESIGN AND METHODS: A total of 189 samples were analyzed by surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS) coupled with CM10 chips and bioinformatics tools. RESULTS: Ten top-ranked proteins were selected as the potential fingerprints of pattern 1, which distinguishes patients with significant CAD (stenosis>=50%) from control individuals. Blind test was analyzed on the second day with a specificity of 79.3% and sensitivity of 78.3%. Pattern 2 distinguishes significant CAD from minimal CAD with luminal stenosis between 25% and 50%. The specificity and sensitivity of blind test for pattern 2 are 77.3% and 73.9%, respectively. CONCLUSIONS: The SELDI-TOF MS technique combined with bioinformatics approaches may be a novel noninvasive method which can not only facilitate the discovery of diagnostic models for CAD and its severity, but also provide a useful tool for molecular diagnosis. PMID- 20950598 TI - Zebrafish eve1 regulates the lateral and ventral fates of mesodermal progenitor cells at the onset of gastrulation. AB - Zebrafish eve1, a member of the even-skipped related gene family, is expressed initially in the animal pole of late blastula embryo and subsequently restricted to the ventral mesoderm of the gastrula embryo under the signaling control of bone morphogenetic protein (Bmp). Overexpression of eve1 in embryos results in similar ventralized phenotypes to that seen in embryos overexpressing Bmp, suggesting that Eve1 acts downstream of the Bmp signaling pathway to regulate the fate of mesodermal progenitor cells (MPCs). How eve1 functions in the normal development of MPCs is unknown. Using overexpression of a chimeric protein of Eve1 fused to the Gal4 activation domain and gene-knockdown approaches, we investigated the role of eve1 in MPC development of zebrafish embryos at early gastrulation. We find that Eve1 functions as a transcriptional repressor and is required for normal MPC development. The role of eve1 in MPCs requires the redundant and cooperative functions of Bmp-activated downstream homeobox genes, ved, vent and vox. Inhibition of eve1, ved, vent and vox in double and triple combinations results in dorsalized phenotypes. Furthermore, specific inhibition of eve1 and ved causes the expression of an ectopic patch of the brachyury ortholog no tail and leads to the formation of an ectopic tail. Our data show that Eve1 functions together with Ved, Vent and Vox in a transcriptional network to prevent the spread of anti-Bmp gene activity from the dorsal side, leading to the establishment of the Bmp gradient activity along the dorsoventral axis to induce distinct transcriptional outputs in MPCs to maintain the lateral and ventral MPC fates during gastrulation. PMID- 20950599 TI - Effect of a novel biphenyl compound, VMNS2e on ob/ob mice. AB - VMNS2e is a novel biphenyl compound, which in previous studies had showed most favourable interactions with the active site of protein tyrosine phosphatase 1B (PTP1B). The effect of acute and chronic treatment of VMNS2e (30mg/kg) was investigated in ob/ob mice. Plasma glucose was measured after acute administration of VMNS2e (30mg/kg) in both lean and ob/ob mice. In the chronic study, VMNS2e (30mg/kg) was given orally, once daily for 60days. Metformin (300mg/kg) was taken as standard therapy. Body weight, food intake and blood glucose was measured weekly while glycosylated hemoglobin A(1c) (HbA(1c)), insulin, triglyceride, total cholesterol, low density lipoprotein (LDL), fructosamine, non esterified fatty acid and organ weight were estimated after the completion of treatment period. Oral glucose tolerance test was performed on the last day of treatment. Liver and epididymal fat weights were taken. Acute dose of VMNS2e elicited an anti hyperglycemic effect. It reduced blood glucose by 14% (0.5h) and 35.6% (6h). Chronic VMNS2e treatment improved glucose tolerance by 25.3%. It decreased blood glucose levels. Hyperinsulinemia was reduced (19.6%). VMNS2e treatment had no significant effect on body weight and food consumption. VMNS2e treatment exhibited significant reduction (28.2%) in HbA(1c), plasma triglyceride (49%), LDL (24%) and fructosamine (13%) levels. VMNS2e treatment did not alter total cholesterol and non esterified fatty acid levels. Epididymal fat/body weight ratio was reduced (26.3%). VMNS2e exhibited both acute and chronic anti hyperglycemic effect, insulin sensitivity along with improvement in various lipid parameters and glycemic control. PMID- 20950601 TI - Diazoxide attenuates indomethacin-induced small intestinal damage in the rat. AB - ATP-sensitive potassium (K(ATP)) channel openers have been shown to protect against cellular damage in neurons, cardiac muscle, and kidney and to effectively reduce nonsteroidal anti-inflammatory drug (NSAID)-induced gastric damage in rats. We investigated the effects of K(ATP) channel opener diazoxide on small intestinal injury induced in rats by indomethacin administration. The effect of glibenclamide, a K(ATP) channel blocker, was also evaluated. Diazoxide (15, 45 and 135mg/kg) or glibenclamide (18mg/kg), were given by oral gavage 1h before and 6h after indomethacin treatment (20mg/kg p.o.). After 24h, macroscopic and histologic lesions, myeloperoxidase (MPO) activity and lipid peroxidation levels were evaluated. Diazoxide at 15mg/kg was ineffective, while at doses of 45mg/kg and 135mg/kg was able to significantly improve all damage parameters. Glibenclamide administration enhanced intestinal injury. These results show for the first time a beneficial effect of diazoxide in indomethacin-induced enteritis in the rat. Several mechanisms, such as oxidative phosphorylation uncoupling and hypermotility seem particularly important in NSAID-induced intestinal injury. Such events lead to increased mucosal permeability and to penetration of noxious lumen components, which ignite the inflammatory response. Since K(ATP) channel openers were shown to protect against mitochondrial damage, to reduce intercellular permeability and to relax smooth muscle, we suggest that diazoxide could exert its beneficial effects by one or more of these actions. PMID- 20950600 TI - Tetrahydrobiopterin analogues with NO-dependent pulmonary vasodilator properties. AB - Reduced NO levels due to the deficiency of tetrahydrobiopterin (BH(4)) contribute to impaired vasodilation in pulmonary hypertension. Due to the chemically unstable nature of BH(4), it was hypothesised that oxidatively stable analogues of BH(4) would be able to support NO synthesis to improve endothelial dysfunction in pulmonary hypertension. Two analogues of BH(4), namely 6-hydroxymethyl pterin (HMP) and 6-acetyl-7,7-dimethyl-7,8-dihydropterin (ADDP), were evaluated for vasodilator activity on precontracted rat pulmonary artery rings. ADDP was administered to pulmonary hypertensive rats, followed by measurement of pulmonary vascular resistance in perfused lungs and eNOS expression by immunohistochemistry. ADDP and HMP caused significant relaxation in vitro in rat pulmonary arteries depleted of BH(4) with a maximum relaxation at 0.3MUM (both P<0.05). Vasodilator activity of ADDP and HMP was completely abolished following preincubation with the NO synthase inhibitor, L-NAME. ADDP and HMP did not alter relaxation induced by carbachol or spermine NONOate. BH(4) itself did not produce relaxation. In rats receiving ADDP 14.1mg/kg/day, pulmonary vasodilation induced by calcium ionophore A23187 was augmented and eNOS immunoreactivity was increased. In conclusion, ADDP and HMP are two analogues of BH(4), which can act as oxidatively stable alternatives to BH(4) in causing NO-mediated vasorelaxation. Chronic treatment with ADDP resulted in improvement of NO mediated pulmonary artery dilation and enhanced expression of eNOS in the pulmonary vascular endothelium. Chemically stable analogues of BH(4) may be able to limit endothelial dysfunction in the pulmonary vasculature. PMID- 20950602 TI - Effects of quercetin on alpha9alpha10 nicotinic acetylcholine receptor-mediated ion currents. AB - Quercetin, one of the flavonoids, is a low molecular weight substance found in fruits and vegetables. Quercetin, like other flavonoids, has a wide range of neuropharmacological actions and antioxidant effects. The alpha9alpha10 nicotinic acetylcholine receptor is one of the numerous nicotinic acetylcholine receptors that exist as a heteropentameric form between efferent olivocochlear fibers and hair cells of the cochlea. In this study, we report the effects of quercetin on rat alpha9alpha10 nicotinic acetylcholine receptor-mediated ion currents using the two-electrode voltage-clamp technique. Treatment with acetylcholine evoked inward currents (I(ACh)) in oocytes heterologously expressing the alpha9alpha10 nicotinic acetylcholine receptor. Quercetin blocked I(ACh) in concentration dependent and reversible manners, and the blocking effect on I(ACh) was stronger with pre-application than co-application of quercetin. The half maximal inhibitory concentration (IC(50)) of quercetin was 45.4+/-10.1MUM. Quercetin mediated I(ACh) inhibition was not affected by acetylcholine concentration and was independent of membrane-holding potential. Although the inhibitory effect of quercetin was significantly attenuated in the absence of extracellular Ca(2+), the action of quercetin was independent of extracellular Ca(2+) concentration, indicating that the presence of extracellular Ca(2+) might be needed for quercetin-related effects and might play an important role in quercetin-mediated regulation of the alpha9alpha10 nicotinic acetylcholine receptor. These results indicate that quercetin-mediated regulation of the alpha9alpha10 nicotinic acetylcholine receptor could provide a molecular basis for quercetin actions at the cellular level. PMID- 20950603 TI - Agmatine modulates neuroadaptations of glutamate transmission in the nucleus accumbens of repeated morphine-treated rats. AB - It has been proved that agmatine inhibits opioid dependence, yet the neural mechanism remains unclear. In the present study, the effect of agmatine on the neuroadaptation of glutamate neurotransmission induced by morphine dependence, including changes of the extracellular glutamate level and glutamate receptors in the nucleus accumbens was investigated. We found that agmatine (2.5-20mg/kg, s.c.) inhibited development of morphine dependence, which was consistent with our previous report. In rats repeatedly treated with morphine, the glutamate level in the nucleus accumbens dialysate was markedly increased after naloxone precipitated withdrawal. When agmatine (20mg/kg, s.c.) was co-pretreated with morphine or was applied before naloxone-precipitated withdrawal, this elevation of the extracellular glutamate level was inhibited. In the synaptosome model, repeated morphine treatment and naloxone precipitation induced an increase in glutamate release, while agmatine (20mg/kg, s.c.) co-pretreated with morphine reversed the increase of glutamate release. However, neither morphine or agmatine treatment alone nor morphine and agmatine co-administration had any influence on [3H]-glutamate uptake. It indicated that the elevation of the glutamate level in the nucleus accumbens might be caused by the increase of glutamate release of synaptosome in the withdrawal conditions of morphine-dependent rat. Furthermore, agmatine concomitant treatment with morphine entirely abolished the up-regulation of the NR1 subunit of N-methyl-d-aspartate (NMDA) receptors in the nucleus accumbens in repeated morphine-treated rats. Taken together, the present study demonstrated that agmatine could modulate the neuroadaptations of glutamate transmission in the nucleus accumbens in the case of morphine dependence, including modulating extracellular glutamate concentration and NMDA receptor expression. PMID- 20950604 TI - Novel hexahydrocannabinol analogs as potential anti-cancer agents inhibit cell proliferation and tumor angiogenesis. AB - Both natural and synthetic cannabinoids have been shown to suppress the growth of tumor cells in culture and in animal models by affecting key signaling pathways including angiogenesis, a pivotal step in tumor growth, invasion, and metastasis. In our search for cannabinoid-like anticancer agents devoid of psychoactive side effects, we synthesized and evaluated the anti-angiogenic effects of a novel series of hexahydrocannabinol analogs. Among these, two analogs LYR-7 [(9S) 3,6,6,9-tetramethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-ol] and LYR-8 [(1-((9S)-1-hydroxy-6,6,9-trimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen 2-yl)ethanone)] were selected based on their anti-angiogenic activity and lack of binding affinity for cannabinoid receptors. Both LYR-7 and LYR-8 inhibited VEGF induced proliferation, migration, and capillary-like tube formation of HUVECs in a concentration-dependent manner. The inhibitory effect of the compounds on cell proliferation was more selective in endothelial cells than in breast cancer cells (MCF-7 and tamoxifen-resistant MCF-7). We also noted effective inhibition of VEGF induced new blood vessel formation by the compounds in the in vivo chick chorioallantoic membrane (CAM) assay. Furthermore, both LYR analogs potently inhibited VEGF production and NF-kappaB transcriptional activity in cancer cells. Additionally, LYR-7 or LYR-8 strongly inhibited breast cancer cell-induced angiogenesis and tumor growth. Together, these results suggest that novel synthetic hexahydrocannabinol analogs, LYR-7 and LYR-8, inhibit tumor growth by targeting VEGF-mediated angiogenesis signaling in endothelial cells and suppressing VEGF production and cancer cell growth. PMID- 20950605 TI - Downregulation of B lymphocyte stimulator expression by curcumin in B lymphocyte via suppressing nuclear translocation of NF-kappaB. AB - Overexpression of B lymphocyte stimulator (BLyS) is closely involved in the pathogenesis and progression of some autoimmune diseases. Curcumin, a pharmacologically safe agent, has been shown to possess potent anti-inflammatory properties. However, it is not clear whether curcumin affects the expression of BLyS. In this study, we report that curcumin inhibits the expression of BLyS and that a DNA-binding site for the transcriptional factor NF-kappaB in the BLyS promoter region is required for this regulation. Moreover, we find that curcumin reduces the DNA-binding activity of NF-kappaB to the BLyS promoter region and suppresses nuclear translocation of p65, suggesting that curcumin may suppress BLyS expression via negatively interfering with NF-kappaB signaling. These results suggest that curcumin may serve as a novel therapeutic agent in the treatment of autoimmune diseases by targeting BLyS. PMID- 20950606 TI - Pharmacological profile of AS1670542, a novel orally-active human thrombopoietin receptor agonist. AB - Eltrombopag, an orally-active small molecule thrombopoietin (TPO) receptor agonist, was used for the first time in 2008 to treat patients with chronic idiopathic thrombocytopenic purpura. Here, we investigated the pharmacological effect of a new orally-active small molecule TPO receptor agonist which may be effective in treating these patients. 50% effective concentration values for cell proliferation with AS1670542 or eltrombopag were 1.9 and 13nM, respectively, while those for megakaryocyte colony formation from human cord blood CD34(+) cells with AS1670542 or eltrombopag were 260 and 950nM, respectively. On Day 14 after the start of administration, AS1670542 significantly increased the number of human platelets in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice with transplanted human hematopoietic stem cells at 0.3 (P<0.05); in contrast, while administration of eltrombopag also increased the numbers of these platelets at 30mg/kg/day (P=0.058), no statistical significance was noted in the increase. Here, we identified AS1670542, a novel orally-active TPO receptor agonist which mimics the biological activity of TPO and may demonstrate greater in vitro and in vivo pharmacologically efficacy than eltrombopag. PMID- 20950607 TI - Hepatoprotective role of naringin on nickel-induced toxicity in male Wistar rats. AB - Aim of the present study was planned to determine the protective role of naringin in attenuating the toxicity induced by nickel sulfate in rat liver. In this investigation nickel sulfate (20mg/kg body weight) was administered intraperitoneally for 20days to induce toxicity. Naringin was administered orally (20, 40 and 80mg/kg body weight) for 20days with intraperitoneal administration of nickel sulfate. Liver injury was measured by the increased activities of serum hepatic enzymes namely aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma glutamyl transferase, lactate dehydrogenase and total bilirubin along with increased elevation of lipid peroxidation markers, thiobarbituric reactive acid substances, lipid hydroperoxides, protein carbonyl content and conjugated dienes. The toxic effect of nickel was also indicated by significantly decreased activities of enzymatic antioxidants like superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and glucose-6-phosphate dehydrogenase and non-enzymatic antioxidants like reduced glutathione, total sulfhydryl groups, vitamin C and vitamin E levels were significantly decreased. Naringin administered at a dose of 80mg/kg body weight significantly reversed the activities of hepatic marker enzymes, decreasing lipid peroxidative markers, increasing the antioxidant cascade and decreasing the nickel concentration in the liver. The effect at a dose of 80mg/kg body weight was more pronounced than that of other two doses (20 and 40mg/kg body weight). All these changes were supported by histopathological observations. These results clearly demonstrate that naringin has the potential in alleviating the toxic effects of nickel in rat liver. PMID- 20950608 TI - Extracellular signal-regulated kinases in pain of peripheral origin. AB - Activation of members of the family of enzymes known as extracellular signal regulated kinases (ERKs) is now known to be involved in the development and/or maintenance of the pain associated with many inflammatory conditions, such as herniated spinal disc pain, chronic inflammatory articular pain, and the pain associated with bladder inflammation. Moreover, ERKs are implicated in the development of neuropathic pain signs in animals which are subjected to the lumbar 5 spinal nerve ligation model and the chronic constriction injury model of neuropathic pain. The position has now been reached where all scientists working on pain subjects ought to be aware of the importance of ERKs, if only because certain of these enzymes are increasingly employed as experimental markers of nociceptive processing. Here, we introduce the reader, first, to the intracellular context in which these enzymes function. Thereafter, we consider the involvement of ERKs in mediating nociceptive signalling to the brain resulting from noxious stimuli at the periphery which will be interpreted by the brain as pain of peripheral origin. PMID- 20950609 TI - Overexpression of wild-type c-RET and zero prevalence of RET/PTC rearrangements are associated with papillary thyroid cancer (PTC) in Kuwait. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) is common in Kuwait. The activation of the RET oncogene by DNA rearrangement (RET/PTC) is known to have an important role in PTC carcinogenesis. However, the real frequency of the RET/PTC expression in PTC is variable between different studies. This study seeks to determine the prevalence of RET/PTC and to analyze the RET oncogene expression associated with PTC in Kuwait. METHODS: RET expression and DNA rearrangements (RET/PTC 1, RET/PTC 2 and RET/PTC 3) were studied by RT-PCR in different thyroid diseases. Results were confirmed by the Southern blot and by immunohistochemistry. Quantitative real-time PCR was used to determine the level of RET mRNA expression in PTCs. RESULTS: Wild-type (nonrearranged) c-RET oncogene was overexpressed in 60% of PTC cases and absent in follicular thyroid carcinoma (FTC), anaplastic thyroid carcinoma (ATC), follicular adenomas (FA) or normal thyroid. No RET/PTC rearrangement was detected in any sample. The c-RET expression in Hashimoto's thyroiditis and multinodular goiter was limited to follicular cells with PTC-like nuclear changes. CONCLUSIONS: The overexpression of wild-type c-RET is a characteristic molecular event of PTCs in Kuwait. The prevalence of RET/PTC is zero and among the lowest recorded in the world. PMID- 20950610 TI - The feasibility of Cep55/c10orf3 derived peptide vaccine therapy for colorectal carcinoma. AB - In our previous study, we demonstrated that a peptide derived from the novel centrosome residing protein Cep55/c10orf3 can be targeted by the cytotoxic T lymphocytes (CTLs) in peripheral blood mononuclear cells (PBMCs) of breast carcinoma patients. In this report, we evaluated the feasibility of cancer immunotherapy using Cep55/c10orf3 peptide for colorectal carcinoma (CRC). To evaluate the expression of Cep55/c10orf3 in CRC tissues, we performed immunohistochemical staining of using anti-Cep55/c10orf3 monoclonal antibody. Sixty-three percent cases showed weak positive for Cep55/c10orf3 in total 70 CRC cases. The Cep55/c10orf3 expression intention was collated with high histological grade of CRC. Thus, we hypothesized that Cep55/c10orf3 can also be the target of CTLs in CRC cases. We generated CTLs from PBMCs of human leukocyte antigen (HLA) A24-positive colorectal carcinoma patients using HLA-A24-restricted Cep55/c10orf3 peptides. Two of 6 colorectal cancer patients were reactive for the Cep55/c10orf3_193(10) peptide, which was the only immunogenic peptide in breast carcinoma patients. CTL clone specific for Cep55/c10orf3_193(10) recognized and lysed HLA-A24 (+) and Cep55/c10orf3 (+) colorectal carcinoma cell lines. In addition, 1 of 6 colorectal carcinoma patients was reactive for the Cep55/c10orf3_402(11) and Cep55/c10orf3_283(12) peptides, but not for Cep55/c10orf3_193(10) with the ELISPOT assay. These observations suggest that the antigenic peptide repertoire presented by HLA-A24 in colorectal carcinoma might be different from that in breast carcinoma. Thus, these peptide vaccination peptide mixture of Cep55/c10orf3_193(10), Cep55/c10orf3_402(11) and Cep55/c10orf3_283(12) might be more effective than a single peptide in the treatment of colorectal carcinoma patients. PMID- 20950611 TI - Structural and physiological responses to prolonged constant lighting in the cone rich retina of Arvicanthis ansorgei. AB - Cone photoreceptor death is a leading cause of blindness in industrialised countries. Despite this, there are few mammalian models available to study cone pathophysiology. The diurnal rodent Arvicanthis possesses a high cone percentage and ease of maintenance. We recently described the effect of ambient light conditions on cyclic disc shedding, and observed that 24 h of constant illumination ("LL") completely disrupted the normal rhythmic process and increased cone shedding fourfold. The current study was undertaken to see whether protracted constant illumination (7 days LL) would further perturb cone (and rod) turnover, and possibly lead to photoreceptor degeneration. Whereas control (cyclic lighting) retinas exhibited a typical early morning burst in phagosomes, LL retinas exhibited only low uniform numbers of rod and cone phagosomes across 24 h, with no peak of shedding at any time. Morphometric and immunohistochemical analyses of Arvicanthis retinas after 7 days LL (300 lux) showed no structural changes compared to control retinas. PMID- 20950612 TI - Sulfatide-mediated activation of type II natural killer T cells prevents hepatic ischemic reperfusion injury in mice. AB - BACKGROUND & AIMS: Hepatic ischemic reperfusion injury (IRI) is a major complication of liver transplantation and resectional hepatic surgeries. Natural killer T (NKT) cells predominate in liver, where they recognize lipid antigens bound to CD1d molecules. Type I NKT cells use a semi-invariant T-cell receptor and react with alpha-galactosylceramide; type II NKT cells use diverse T-cell receptors. Some type II NKT cells recognize the self-glycolipid sulfatide. It is not clear whether or how these distinct NKT cell subsets mediate hepatocellular damage after IRI. METHODS: We examined the roles of type I and type II NKT cells in mice with partial hepatic, warm ischemia, and reperfusion injury. RESULTS: Mice that lack type I NKT cells (Jalpha18-/-) were protected from hepatic IRI, indicated by reduced hepatocellular necrosis and serum levels of alanine aminotransferase. Sulfatide-mediated activation of type II NKT cells reduced interferon-gamma secretion by type I NKT cells and prevented IRI. Protection from hepatic IRI by sulfatide-mediated inactivation of type I NKT cells was associated with significant reductions in hepatic recruitment of myeloid cell subsets, especially the CD11b(+)Gr-1(int), Gr-1(-), and NK cells. CONCLUSIONS: In mice, subsets of NKT cells have opposing roles in hepatic IRI: type I NKT cells promote injury whereas sulfatide-reactive type II NKT cells protect against injury. CD1d activation of NKT cells is conserved from mice to human beings, so strategies to modify these processes might be developed to treat patients with hepatic reperfusion injury. PMID- 20950614 TI - Endoscopic ultrasonography-guided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts. AB - BACKGROUND & AIMS: Endoscopic ultrasonography (EUS)-guided interventions have been used to treat patients with cystic lesions of the pancreas (CLPs). We used EUS to guide injection and lavage of ethanol, followed by injection of paclitaxel, into cysts, and investigated treatment response and predictors. METHODS: Fifty-two patients were enrolled in the study using the following inclusion criteria: unilocular or oligolocular cysts, indeterminate cystic lesions that required EUS fine-needle aspiration, and cystic lesions that grew during the observation period. Forty-seven patients were followed up for more than 12 months and their outcomes were analyzed. RESULTS: The mean diameter of the CLPs was 31.8 mm (range, 17-68 mm) and the estimated volume was 14.09 mL (range, 1.16-68.74 mL). Twenty CLPs were oligolocular. The mean level of carcinoembryonic antigen was 463 ng/mL (range, 1-8190 ng/mL). The median follow up period was 21.7 months. A complete response was observed in 29 patients, a partial response in 6 patients, and persistent cysts in 12 patients. Four of 12 patients with persistent cysts underwent surgery. The histopathologic degree of epithelial ablation varied from 0% to 100%. Based on univariate analysis, EUS diameter and original volume predicted cyst resolution; in multivariate analysis, only original volume predicted resolution. Mild pancreatitis and splenic vein obliteration each occurred in 1 patient. CONCLUSIONS: EUS-guided injection and lavage of ethanol, followed by injection of paclitaxel, appears to be a safe method for treating pancreatic cysts; 62% of patients had complete resolution. Small cyst volume predicted complete resolution. PMID- 20950613 TI - Lack of commensal flora in Helicobacter pylori-infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia. AB - BACKGROUND & AIMS: Transgenic FVB/N insulin-gastrin (INS-GAS) mice have high circulating gastrin levels, and develop spontaneous atrophic gastritis and gastrointestinal intraepithelial neoplasia (GIN) with 80% prevalence 6 months after Helicobacter pylori infection. GIN is associated with gastric atrophy and achlorhydria, predisposing mice to nonhelicobacter microbiota overgrowth. We determined if germfree INS-GAS mice spontaneously develop GIN and if H pylori accelerates GIN in gnotobiotic INS-GAS mice. METHODS: We compared gastric lesions, levels of messenger RNA, serum inflammatory mediators, antibodies, and gastrin among germfree and H pylori-monoinfected INS-GAS mice. Microbiota composition of specific pathogen-free (SPF) INS-GAS mice was quantified by pyrosequencing. RESULTS: Germfree INS-GAS mice had mild hypergastrinemia but did not develop significant gastric lesions until 9 months old and did not develop GIN through 13 months. H pylori monoassociation caused progressive gastritis, epithelial defects, oxyntic atrophy, marked foveolar hyperplasia, dysplasia, and robust serum and tissue proinflammatory immune responses (particularly males) between 5 and 11 months postinfection (P<0.05, compared with germfree controls). Only 2 of 26 female, whereas 8 of 18 male, H pylori-infected INS-GAS mice developed low to high-grade GIN by 11 months postinfection. Stomachs of H pylori infected SPF male mice had significant reductions in Bacteroidetes and significant increases in Firmicutes. CONCLUSIONS: Gastric lesions take 13 months longer to develop in germfree INS-GAS mice than male SPF INS-GAS mice. H pylori monoassociation accelerated gastritis and GIN but caused less severe gastric lesions and delayed onset of GIN compared with H pylori-infected INS-GAS mice with complex gastric microbiota. Changes in gastric microbiota composition might promote GIN in achlorhydric stomachs of SPF mice. PMID- 20950615 TI - IL28B and the control of hepatitis C virus infection. AB - Treatment-induced control and spontaneous clearance of hepatitis C virus (HCV) infection are affected by various host factors. Polymorphisms in the region of the gene IL28B are associated with HCV clearance, implicating the gene product, interferon (IFN)-lambda3, in the immune response to HCV. Although it is not clear how the IL28B haplotype affects HCV clearance, IFN-lambda3 up-regulates interferon-stimulated genes, similar to IFN-alpha and IFN-beta but via a different receptor. There is also evidence that IFN-lambda3 affects the adaptive immune response. The IL28B genotype can be considered, along with other factors, in predicting patient responses to therapy with pegylated IFN-alpha and ribavirin. We review the genetic studies that uncovered the association between IL28B and HCV clearance, the biology of IFN-lambda3, the clinical implications of the genetic association, and areas of future research. PMID- 20950616 TI - An association between dietary arachidonic acid, measured in adipose tissue, and ulcerative colitis. AB - BACKGROUND & AIMS: Dietary arachidonic acid, an n-6 polyunsaturated fatty acid (n 6 PUFA), might be involved in the etiology of ulcerative colitis (UC). We performed a prospective cohort study to determine whether high levels of arachidonic acid in adipose tissue samples (which reflects dietary intake) are associated with UC. METHODS: We analyzed data collected from 57,053 men and women in the EPIC-Denmark Prospective Cohort Study from 1993 to 1997. Adipose tissue biopsy samples were collected from gluteal regions at the beginning of the study, the cohort was monitored over subsequent years, and participants who developed UC were identified. A subcohort of 2510 randomly selected participants were used as controls. Concentrations of arachidonic acid were measured in adipose tissue samples. In the analysis, arachidonic acid levels were divided into quartiles; relative risks (RR) were calculated and adjusted for smoking, use of aspirin and nonsteroidal anti-inflammatory drugs, and levels of n-3 PUFAs. RESULTS: A total of 34 subjects (56% men) developed incident UC at a median age of 58.8 years (range, 50.0-69.0 years). Those in the highest quartile for arachidonic acid concentrations in adipose tissue had an RR for UC of 4.16 (95% confidence interval [CI]: 1.56-11.04); a trend per 0.1% increase in arachidonic acid of 1.77 in RR was observed (95% CI: 1.38-2.27). The fraction attributed the highest levels of arachidonic acid was 40.3%. CONCLUSIONS: Individuals with the highest relative concentrations of arachidonic acid in adipose tissue have a significantly greater risk of developing UC. Dietary modifications might therefore prevent UC or reduce disease symptoms. PMID- 20950617 TI - Social environment affects testosterone level in captive male blue-black grassquits. AB - The challenge hypothesis proposes that testosterone (T) elevation above what is needed for breeding is associated with social factors, and males possibly modulate their hormonal response to variations in population density and sex ratio. We investigated the role of social environment in altering testosterone levels and aggression in a tropical, seasonally breeding grassquit (Volatinia jacarina). We exposed males to three social conditions during 1 year: all-males treatment (six males), mixed treatment (three males-three females), and paired treatment (one male-one female). We quantified aggressiveness among males and T plasma concentration for each individual in each treatment monthly. We found that more aggressive interactions occurred in the all-males treatment than in the mixed treatment. The data also revealed that, coincident with these behavioral changes, the patterns of T variation through time in each treatment were markedly different. The all-males treatment exhibited an early increase in T concentration, which was sustained for a lengthy period with two distinctive peaks, and subsequently declined sharply. The mixed treatment presented an intermediate pattern, with more gradual increase and decrease in T levels. At the other extreme, the paired treatment presented a later rise in T concentration. We conclude that the more competitive environment, with higher density of males, caused the early and higher elevation in T level, thus the presence of competitors may influence the decision of how much a male should invest in reproduction. We suggest that the male's perception of his social environment ultimately mediates hormonal production and alters his reproductive strategy. PMID- 20950619 TI - Arginine vasotocin neuronal phenotypes, telencephalic fiber varicosities, and social behavior in butterflyfishes (Chaetodontidae): potential similarities to birds and mammals. AB - The neuropeptide arginine vasopressin (AVP) influences many social behaviors through its action in the forebrain of mammals. However, the function of the homologous arginine vasotocin (AVT) in the forebrain of fishes, specifically the telencephalon remains unresolved. We tested whether the density of AVT immunoreactive (-ir) fiber varicosities, somata size or number of AVT-ir neuronal phenotypes within the forebrain were predictive of social behavior in reproductive males of seven species of butterflyfishes (family Chaetodontidae) in four phylogenetic clades. Similar to other fishes, the aggressive (often territorial) species in most cases had larger AVT-ir cells within the gigantocellular preoptic cell group. Linear discriminant function analyses demonstrated that the density of AVT-ir varicosities within homologous telencephalic nuclei to those important for social behavior in mammals and birds were predictive of aggressive behavior, social affiliations, and mating system. Of note, the density of AVT-ir varicosities within the ventral nucleus of the ventral telencephalon, thought to be homologous to the septum of other vertebrates, was the strongest predictor of aggressive behavior, social affiliation, and mating system. These results are consistent with the postulate that AVT within the telencephalon of fishes plays an important role in social behavior and may function in a similar manner to that of AVT/AVP in birds and mammals despite having cell populations solely within the preoptic area. PMID- 20950618 TI - Neural and hormonal mechanisms of reproductive-related arousal in fishes. AB - The major classes of chemicals and brain pathways involved in sexual arousal in mammals are well studied and are thought to be of an ancient, evolutionarily conserved origin. Here we discuss what is known of these neurochemicals and brain circuits in fishes, the oldest and most species-rich group of vertebrates from which tetrapods arose over 350 million years ago. Highlighted are case studies in vocal species where well-delineated sensory and motor pathways underlying reproductive-related behaviors illustrate the diversity and evolution of brain mechanisms driving sexual motivation between (and within) sexes. Also discussed are evolutionary insights from the neurobiology and reproductive behavior of elasmobranch fishes, the most ancient lineage of jawed vertebrates, which are remarkably similar in their reproductive biology to terrestrial mammals. PMID- 20950620 TI - Role of progesterone receptors during postpartum estrus in rats. AB - We studied the role of progesterone receptor (PR) in the display of female sexual behavior during postpartum estrus in rats. Adult female rats were treated with the PR antagonist, RU486 (1.25 and 5 mg), 3 h after parturition and sexual behavior was evaluated throughout the first postpartum day. Estradiol and progesterone serum levels changed during the first 24 h postpartum. The highest estradiol and progesterone levels were found at 9 and 12 h postpartum, respectively. The predominant PR isoform in the hypothalamus and the preoptic area was PR-A during postpartum day. The content of PR-A increased at 6 h postpartum in the hypothalamus and the preoptic area, and decreased in both regions at 9 h. PR-B content only increased in the preoptic area at 12 h postpartum. The highest display of lordotic and proceptive behaviors were found at 12 h postpartum. The treatment with 1.25 and 5 mg of RU486 respectively reduced lordosis by 61% and 92% at 12 h postpartum. These results suggest that PR is essential in the display of postpartum estrus in rats. PMID- 20950621 TI - Hormonal correlates of social status and courtship display in the cooperatively lekking lance-tailed manakin. AB - Though cooperative behavior has long been a focus of evolutionary biology, the proximate hormonal mechanisms underlying cooperative interactions remain poorly understood. Lance-tailed manakins (Chiroxiphia lanceolata) are tropical passerines that form long-term male-male partnerships and cooperate in paired male courtship displays. To elucidate patterns of natural hormonal variation in relation to cooperation and reproductive behavior, we examined circulating androgen levels of male lance-tailed manakins in relation to social status, display behavior, and time of year. We found significantly higher circulating androgen levels in alpha-ranked (breeding) males compared to non-alpha adult males in the population. Beta males, which participated in courtship displays but did not copulate, had androgen levels indistinguishable from those of unpaired adult males that never displayed for females, suggesting that an elevated concentration of plasma testosterone in tropical lekking birds may be associated primarily with copulatory behavior or other status-specific traits, and not the performance of courtship display. Androgens decreased throughout the breeding season for males of all status categories. Interestingly, alphas that displayed for females in the observation session prior to sampling had lower androgen levels than alphas that did not display for females. This pattern may result from female discrimination against alpha males at display areas with high levels of social conflict among males, as social disruption is linked to elevated testosterone in many species. However, recent change of a display partner was not related to alpha androgen levels. We discuss alternative explanations and the possible implications of these results, and generate several testable predictions for future investigations. PMID- 20950622 TI - How generalized CNS arousal strengthens sexual arousal (and vice versa). AB - Heightened states of generalized CNS arousal are proposed here to facilitate sexual arousal in both males and females. Genetic, pharmacologic and biophysical mechanisms by which this happens are reviewed. Moreover, stimulation of the genital epithelia, as triggers of sex behavior, is hypothesized to lead to a greater generalized arousal in a manner that intensifies sexual motivation. Finally, launched from histochemical studies intended to characterize cells in the genital epithelium, a surprising idea is proposed that links density of innervation with the efficiency of wound healing and with the capacity of that epithelium to stimulate generalized CNS arousal. Thus, bidirectional arousal related mechanisms that foster sexual behaviors are envisioned as follows: from specific to generalized (as with genital stimulation) and from generalized to specific. PMID- 20950623 TI - A KCR1 variant implicated in susceptibility to the long QT syndrome. AB - The acquired long QT syndrome (aLQTS) is frequently associated with extrinsic and intrinsic risk factors including therapeutic agents that inadvertently inhibit the KCNH2 K(+) channel that underlies the repolarizing I(Kr) current in the heart. Previous reports demonstrated that K(+) channel regulator 1 (KCR1) diminishes KCNH2 drug sensitivity and may protect susceptible patients from developing aLQTS. Here, we describe a novel variant of KCR1 (E33D) isolated from a patient with ventricular fibrillation and significant QT prolongation. We recorded the KCNH2 current (I(KCNH2)) from CHO-K1 cells transfected with KCNH2 plus wild type (WT) or mutant KCR1 cDNA, using whole cell patch-clamp techniques and assessed the development of I(KCNH2) inhibition in response to well characterized KCNH2 inhibitors. Unlike KCR1 WT, the E33D variant did not protect KCNH2 from the effects of class I antiarrhythmic drugs such as quinidine or class III antiarrhythmic drugs including dofetilide and sotalol. The remaining current of the KCNH2 WT+KCR1 E33D channel after 100 pulses in the presence of each drug was similar to that of KCNH2 alone. Simulated conditions of hypokalemia (1mM [K(+)](o)) produced no significant difference in the fraction of the current that was protected from dofetilide inhibition with KCR1 WT or E33D. The previously described alpha-glucosyltransferase activity of KCR1 was found to be compromised in KCR1 E33D in a yeast expression system. Our findings suggest that KCR1 genetic variations that diminish the ability of KCR1 to protect KCNH2 from inhibition by commonly used therapeutic agents constitute a risk factor for the aLQTS. PMID- 20950624 TI - Lysophosphatidylcholine enhances I(Ks) currents in cardiac myocytes through activation of G protein, PKC and Rho signaling pathways. AB - Lysophosphatidylcholine (LPC) is a bioactive phospholipid that accumulates rapidly in the ischemic myocardium. In recent years, it has been shown that some of the actions of LPC are mediated through the activation of the membrane G proteins. However, the precise mechanism(s) responsible for the LPC-related intracellular signaling in the regulation of cardiac ion channels are still poorly understood. The present study was undertaken to examine whether LPC regulates the slow component of the delayed rectifier K(+) current (I(Ks)) and, if so, what intracellular signals are important for this process. Isolated guinea pig cardiac myocytes were voltage-clamped using the whole-cell configuration of the patch-clamp method. The bath application of 1-palmitoyl lysophosphatidylcholine (LPC-16) concentration-dependently (EC(50)=0.7MUM) and reversibly increased I(Ks) in atrial cells, but failed to potentiate I(Ks) in ventricular myocytes. In contrast, 1-oleoyl-lysophosphatidylcholine (LPC-18:1) only produced a slight I(Ks) increase, and 1-caproyl-lysophosphatidylcholine (LPC 6) or the LPC-16 precursor (phosphatidylcholine) had no effect on I(Ks). Pretreatment of atrial cells with an antibody against the N-terminus of the G2A receptor significantly reduced the LPC-16-induced potentiation of I(Ks). The inhibition of heterotrimeric G protein, phospholipase C (PLC) and protein kinase C (PKC) significantly reduced LPC-16-induced enhancement of I(Ks). Moreover, the blockade of Rho and Rho-kinase by specific inhibitors also inhibited the activity of LPC-16. Immunohistochemical studies demonstrated that G2A was densely distributed in the plasma membrane of atrial myocytes. Therefore, the present study suggests that the activation of a G protein (probably Galpha(q)) by LPC-16 potentiates I(Ks) currents through the PLC-PKC and Rho-kinase pathways. PMID- 20950625 TI - Reversal of a mutator activity by a nearby fidelity-neutral substitution in the RB69 DNA polymerase binding pocket. AB - Phage RB69 B-family DNA polymerase is responsible for the overall high fidelity of RB69 DNA synthesis. Fidelity is compromised when conserved Tyr567, one of the residues that form the nascent polymerase base-pair binding pocket, is replaced by alanine. The Y567A mutator mutant has an enlarged binding pocket and can incorporate and extend mispairs efficiently. Ser565 is a nearby conserved residue that also contributes to the binding pocket, but a S565G replacement has only a small impact on DNA replication fidelity. When Y567A and S565G replacements were combined, mutator activity was strongly decreased compared to that with Y567A replacement alone. Analyses conducted both in vivo and in vitro revealed that, compared to Y567A replacement alone, the double mutant mainly reduced base substitution mutations and, to a lesser extent, frameshift mutations. The decrease in mutation rates was not due to increased exonuclease activity. Based on measurements of DNA binding affinity, mismatch insertion, and mismatch extension, we propose that the recovered fidelity of the double mutant may result, in part, from an increased dissociation of the enzyme from DNA, followed by the binding of the same or another polymerase molecule in either exonuclease mode or polymerase mode. An additional antimutagenic factor may be a structural alteration in the polymerase binding pocket described in this article. PMID- 20950626 TI - Evidence for amino acid roles in the chemistry of ATP hydrolysis in Escherichia coli Rho. AB - Many proteins that hydrolyze ATP or GTP have comparable amino acid residues for which specific roles have been proposed in a mechanism for the chemistry of hydrolysis. These roles include polarization by a glutamate residue of a water molecule for the attack on the gamma-phosphoryl group of the nucleotide, stabilization of the transition state by an arginine finger, discrimination between bound nucleoside triphosphate and diphosphate by a gamma sensor residue, and coordination by an aspartate of the Mg(2+) that accompanies the substrate nucleotide. We mutated four candidate residues for these roles in the Escherichia coli transcription termination factor Rho, E211, R366, R212, and D265, and characterized the resulting proteins for oligomerization state, ligand binding, RNA-dependent ATP hydrolysis, and, in rapid mix/chemical quench experiments, achievement of the chemistry step of hydrolysis. All four mutant proteins behaved as expected for Rhos lacking the proposed mechanistic roles. The results provide firm biochemical evidence in support of the proposed model for hydrolysis chemistry. PMID- 20950627 TI - Cysteine function governs its conservation and degeneration and restricts its utilization on protein surfaces. AB - Cysteine (Cys) is an enigmatic amino acid residue. Although one of the least abundant, it often occurs in the functional sites of proteins. Whereas free Cys is a polar amino acid, Cys in proteins is often buried, and its classification on the hydrophobicity scale is ambiguous. We hypothesized that the deviation of Cys residues from the properties of a free amino acid is due to their reactivity and addressed this possibility by examining Cys in large protein structure data sets. Compared to other amino acids, Cys was characterized by the most extreme conservation pattern, with the majority of Cys being either highly conserved or poorly conserved. In addition, clustering of Cys with another Cys residue was associated with high conservation, whereas exposure of Cys on protein surfaces was associated with low conservation. Moreover, although clustered Cys behaved as polar residues, isolated Cys was the most buried residue of all, in disagreement with known chemical properties of Cys. Thus, the anomalous hydrophobic behavior and conservation pattern of Cys can be explained by elimination of isolated Cys from protein surfaces during evolution and by clustering of other Cys residues. These findings indicate that Cys abundance is governed by Cys function in proteins rather than by the sheer chemical-physical properties of free amino acids, and suggest that a high tendency of Cys to be functionally active can considerably limit its abundance on protein surfaces. PMID- 20950628 TI - Loop analysis for pathogens: niche partitioning in the transmission graph for pathogens of the North American tick Ixodes scapularis. AB - In population biology, loop analysis is a method of decomposing a life cycle graph into life history pathways so as to compare the relative contributions of pathways to the population growth rate across species and populations. We apply loop analysis to the transmission graph of five pathogens known to infect the black-legged tick, Ixodes scapularis. In this context loops represent repeating chains of transmission that could maintain the pathogen. They hence represent completions of the life cycle, in much the same way as loops in a life cycle graph do for plants and animals. The loop analysis suggests the five pathogens fall into two distinct groups. Borellia burgdorferi, Babesia microti and Anaplasma phagocytophilum rely almost exclusively on a single loop representing transmission to susceptible larvae feeding on vertebrate hosts that were infected by nymphs. Borellia miyamotoi, in contrast, circulates among a separate set of host types and utilizes loops that are a mix of vertical transmission and horizontal transmission. For B. miyamotoi the main loop is from vertebrate hosts to susceptible nymphs, where the vertebrate hosts were infected by larvae that were infected from birth. The results for Powassan virus are similar to B. miyamotoi. The predicted impacts of the known variation in tick phenology between populations of I. scapularis in the Midwest and Northeast of the United States are hence markedly different for the two groups. All of these pathogens benefit, though, from synchronous activity of larvae and nymphs. PMID- 20950629 TI - Equivalent stiffness after glycosaminoglycan depletion in tendon--an ultra structural finite element model and corresponding experiments. AB - The glycosaminoglycan (GAG) side-chains of small leucine-rich proteoglycans have been postulated to mechanically cross-link adjacent collagen fibrils and contribute to tendon mechanics. Enzymatic depletion of tendon GAGs (chondroitin and dermatan sulfate) has emerged as a preferred method to experimentally assess this role. However, GAG removal is typically incomplete and the possibility remains that extant GAGs may remain mechanically functional. The current study specifically investigated the potential mechanical effect of the remaining GAGs after partial enzymatic digestion. A three-dimensional finite element model of tendon was created based upon the concept of proteoglycan mediated inter-fibril load sharing. Approximately 250 interacting, discontinuous collagen fibrils were modeled as having a length of 400 MUm, being composed of rod elements of length 67 nm and E-modulus 1 GPa connected in series. Spatial distribution and diameters of these idealized fibrils were derived from a representative cross-sectional electron micrograph of tendon. Rod element lengths corresponded to the collagen fibril D-Period, widely accepted to act as a binding site for decorin and biglycan, the most abundant proteoglycans in tendon. Each element node was connected to nodes of any neighboring fibrils within a radius of 100 nm, the slack length of unstretched chondroitin sulfate. These GAG cross-links were the sole mechanism for lateral load sharing among the discontinuous fibrils, and were modeled as bilinear spring elements. Simulation of tensile testing of tendon with complete cross-linking closely reproduced corresponding experiments on rat tail tendons. Random reduction of 80% of GAG cross-links (matched to a conservative estimate of enzymatic depletion efficacy) predicted a drop of 14% in tendon modulus. Corresponding mechanical properties derived from experiments on rat tail tendons treated in buffer with and without chondroitinase ABC were apparently unaffected, regardless of GAG depletion. Further tests for equivalence, conservatively based on effect size limits predicted by the model, confirmed equivalent stiffness between enzymatically depleted tendons and their native controls. Although the model predicts that relatively small quantities of GAGs acting as primary collagen cross-linking elements could provide mechanical integrity to the tendon, partial enzymatic depletion of GAGs should result in mechanical changes that are not reflected in analogous experimental testing. We thus conclude that GAG side chains of small leucine-rich proteoglycans are not a primary determinant of tensile mechanical behavior in mature rat tail tendons. PMID- 20950630 TI - A statistical model for red blood cell survival. AB - A statistical model for the survival time of red blood cells (RBCs) with a continuous distribution of cell lifespans is presented. The underlying distribution of RBC lifespans is derived from a probability density function with a bathtub-shaped hazard curve, and accounts for death of RBCs due to senescence (age-dependent increasing hazard rate) and random destruction (constant hazard), as well as for death due to initial or delayed failures and neocytolysis (equivalent to early red cell mortality). The model yields survival times similar to those of previously published studies of RBC survival and is easily amenable to inclusion of drug effects and haemolytic disorders. PMID- 20950632 TI - Deterioration of the memory for historic events in patients with mild cognitive impairment and early Alzheimer's disease. AB - Retrograde memory decline in Alzheimer's disease (AD) and mild cognitive impairment (MCI) has been evaluated using tests of past public knowledge, such as famous personalities and events, and tests of autobiographical memory. Reports of temporal gradients (TG) in retrograde amnesia have been inconclusive. Here, we compared the remembrance of famous historic events by patients with amnesic MCI and early AD using the newly developed Historic Events Test (HET). The HET demands knowledge about famous public events of the past 60 years divided into five time segments, and consists of three tasks, Recognition, Dating Accuracy, and Contextual Memory. In both patient groups, the performance was worse than in healthy controls. Memory performance of all time segments was uniformly affected by this kind of retrograde amnesia. There was no evidence of a TG, and memory decline was similar in all three tasks of the HET. In contrast, for the same patients tested at the same time, we had previously found a TG for autobiographical memory with better preservation of remote than recent memories (Leyhe, Muller, Milian, Eschweiler, & Saur, 2009). We propose that recall of more frequently retrieved remote autobiographical facts and incidents has become independent of the hippocampus, whereas more seldomly retrieved recent autobiographical memory and knowledge of famous events remain dependent on the hippocampus and will thereby be susceptible to the early neurodegenerative damage of the hippocampus in AD. Our assumption may reconcile the Cortical Reallocation Theory and the Multiple Trace Theory. PMID- 20950631 TI - Verapamil protects dopaminergic neuron damage through a novel anti-inflammatory mechanism by inhibition of microglial activation. AB - Verapamil has been shown to be neuroprotective in several acute neurotoxicity models due to blockade of calcium entry into neurons. However, the potential use of verapamil to treat chronic neurodegenerative diseases has not been reported. Using rat primary mesencephalic neuron/glia cultures, we report that verapamil significantly inhibited LPS-induced dopaminergic neurotoxicity in both pre- and post-treatment experiments. Reconstituted culture studies revealed that the presence of microglia was essential in verapamil-elicited neuroprotection. Mechanistic studies showed that decreased production of inflammatory mediators from LPS-stimulated microglia underlay neuroprotective property of verapamil. Further studies demonstrated that microglial NADPH oxidase (PHOX), the key superoxide-producing enzyme, but not calcium channel in neurons, is the site of action for the neuroprotective effect of verapamil. This conclusion was supported by the following two observations: 1) Verapamil failed to show protective effect on LPS-induced dopaminergic neurotoxicity in PHOX-deficient (deficient in the catalytic subunit of gp91(phox)) neuron/glia cultures; 2) Ligand binding studies showed that the binding of [(3)H]Verapamil onto gp91(phox) transfected COS7 cell membranes was higher than the non-transfected control. The calcium channel independent neuroprotective property of verapamil was further supported by the finding that R(+)-verapamil, a less active form in blocking calcium channel, showed the same potency in neuroprotection, inhibition of pro-inflammatory factors production and binding capacity to gp91(phox) membranes as R(-) verapamil, the active isomer of calcium channel blocker. In conclusion, our results demonstrate a new indication of verapamil-mediated neuroprotection through a calcium channel-independent pathway and provide a valuable avenue for the development of therapy for inflammation-related neurodegenerative diseases. PMID- 20950633 TI - Listening to the sound of silence: disfluent silent pauses in speech have consequences for listeners. AB - Silent pauses are a common form of disfluency in speech yet little attention has been paid to them in the psycholinguistic literature. The present paper investigates the consequences of such silences for listeners, using an Event Related Potential (ERP) paradigm. Participants heard utterances ending in predictable or unpredictable words, some of which included a disfluent silence before the target. In common with previous findings using er disfluencies, the N400 difference between predictable and unpredictable words was attenuated for the utterances that included silent pauses, suggesting a reduction in the relative processing benefit for predictable words. An earlier relative negativity, topographically distinct from the N400 effect and identifiable as a Phonological Mismatch Negativity (PMN), was found for fluent utterances only. This suggests that only in the fluent condition did participants perceive the phonology of unpredictable words to mismatch with their expectations. By contrast, for disfluent utterances only, unpredictable words gave rise to a late left frontal positivity, an effect previously observed following ers and disfluent repetitions. We suggest that this effect reflects the engagement of working memory processes that occurs when fluent speech is resumed. Using a surprise recognition memory test, we also show that listeners were more likely to recognise words which had been encountered after silent pauses, demonstrating that silence affects not only the process of language comprehension but also its eventual outcome. We argue that, from a listener's perspective, one critical feature of disfluency is the temporal delay which it adds to the speech signal. PMID- 20950635 TI - Signal transduction profile of chemical sensitisers in dendritic cells: an endpoint to be included in a cell-based in vitro alternative approach to hazard identification? AB - The development of non-animal testing methods for the assessment of skin sensitisation potential is an urgent challenge within the framework of existing and forthcoming legislation. Efforts have been made to replace current animal tests, but so far no alternative methods have been developed. It is widely recognised that alternatives to animal testing cannot be accomplished with a single approach, but rather will require the integration of results obtained from different in vitro and in silico assays. The argument subjacent to the development of in vitro dendritic cell (DC)-based assays is that sensitiser induced changes in the DC phenotype can be differentiated from those induced by irritants. This assumption is derived from the unique capacity of DC to convert environmental signals encountered at the skin into a receptor expression pattern (MHC class II molecules, co-stimulatory molecules, chemokine receptors) and a soluble mediator release profile that will stimulate T lymphocytes. Since signal transduction cascades precede changes in surface marker expression and cytokine/chemokine secretion, these phenotypic modifications are a consequence of a signal transduction profile that is specifically triggered by sensitisers and not by irritants. A limited number of studies have addressed this subject and the present review attempts to summarise and highlight all of the signalling pathways modulated by skin sensitisers and irritants. Furthermore, we conclude this review by focusing on the most promising strategies suitable for inclusion into a cell based in vitro alternative approach to hazard identification. PMID- 20950636 TI - Cytotoxicity of arsenic trioxide is enhanced by (-)-epigallocatechin-3-gallate via suppression of ferritin in cancer cells. AB - Arsenic trioxide (ATO) treatment is a useful therapy against human acute promyelocytic leukemia (APL), however, it concomitantly brings potential adverse consequences including serious side effect, human carcinogenicity and possible development of resistance. This investigation revealed that those problems might be relaxed by simultaneous application with (-)-epigallocatechin-3-gallate (EGCG), one of the major components from green tea. EGCG significantly lowered down the ATO concentration required for an effective control of APL cells, HL-60. The simultaneous treatment of ATO with EGCG induced a mitochondria-dependent apoptosis in HL-60 cells significantly, which accounted for more than 70% of the cell death in the treatment. The mechanism of apoptosis induction was elucidated. EGCG in HL-60 cells acted as a pro-oxidant enhancing intracellular hydrogen peroxide significantly. ATO, on the other hand, induced heme oxygenase-1 (HO-1) to catalyze heme degradation, thereby provided ferrous iron for EGCG-induced hydrogen peroxide to precede Fenton reaction, which in turn generated deleterious reactive oxygen species to damage cell. In addition, EGCG inhibited expression of ferritin, which supposedly to sequester harmful ferrous iron, thereby augmented the occurrence of Fenton reaction. This investigation also provided evidence that ATO, since mainly acted to induce HO-1 in simultaneous treatment with EGCG, could be replaced by other HO-1 inducer with much less human toxicity. Furthermore, several of our preliminary investigations revealed that the enhanced cytotoxicity induced by combining heme degradation and Fenton reaction is selectively toxic to malignant but not non-malignant cells. PMID- 20950638 TI - Phospholipase A2 inhibitors (betaPLIs) are encoded in the venom glands of Lachesis muta (Crotalinae, Viperidae) snakes. AB - Phospholipase A(2) inhibitors (PLIs) are glycoproteins secreted by snake liver into the circulating blood aiming the self-protection against toxic venom phospholipases A(2). In the present study, we describe the first complete nucleotide sequence of a betaPLI from venom glands of a New World snake, Lachesis muta. The deduced primary structure was compared to other known betaPLIs and recent literature findings of other possible roles of PLIs in snakes are discussed. PMID- 20950637 TI - Methanol exposure does not produce oxidatively damaged DNA in lung, liver or kidney of adult mice, rabbits or primates. AB - In vitro and in vivo genotoxicity tests indicate methanol (MeOH) is not mutagenic, but carcinogenic potential has been claimed in one controversial long term rodent cancer bioassay that has not been replicated. To determine whether MeOH could indirectly damage DNA via reactive oxygen species (ROS)-mediated mechanisms, we treated male CD-1 mice, New Zealand white rabbits and cynomolgus monkeys with MeOH (2.0 g/kg ip) and 6h later assessed oxidative damage to DNA, measured as 8-oxo-2'-deoxyguanosine (8-oxodG) by HPLC with electrochemical detection. We found no MeOH-dependent increases in 8-oxodG in lung, liver or kidney of any species. Chronic treatment of CD-1 mice with MeOH (2.0 g/kg ip) daily for 15 days also did not increase 8-oxodG levels in these organs. These results were corroborated in DNA repair-deficient oxoguanine glycosylase 1 (Ogg1) knockout (KO) mice, which accumulated 8-oxodG in lung, kidney and liver with age, but exhibited no increase following MeOH, despite a 2-fold increase in renal 8 oxodG in Ogg1 KO mice following treatment with a ROS-initiating positive control, the renal carcinogen potassium bromate (KBrO3; 100 mg/kg ip). These observations suggest that MeOH exposure does not promote the accumulation of oxidatively damaged DNA in lung, kidney or liver, and that environmental exposure to MeOH is unlikely to initiate carcinogenesis in these organs by DNA oxidation. PMID- 20950634 TI - Abnormal structure or function of the amygdala is a common component of neurodevelopmental disorders. AB - The amygdala, perhaps more than any other brain region, has been implicated in numerous neuropsychiatric and neurodevelopmental disorders. It is part of a system initially evolved to detect dangers in the environment and modulate subsequent responses, which can profoundly influence human behavior. If its threshold is set too low, normally benign aspects of the environment are perceived as dangers, interactions are limited, and anxiety may arise. If set too high, risk taking increases and inappropriate sociality may occur. Given that many neurodevelopmental disorders involve too little or too much anxiety or too little of too much social interaction, it is not surprising that the amygdala has been implicated in many of them. In this chapter, we begin by providing a brief overview of the phylogeny, ontogeny, and function of the amygdala and then appraise data from neurodevelopmental disorders which suggest amygdala dysregulation. We focus on neurodevelopmental disorders where there is evidence of amygdala dysregulation from postmortem studies, structural MRI analyses or functional MRI. However, the results are often disparate and it is not totally clear whether this is due to inherent heterogeneity or differences in methodology. Nonetheless, the amygdala is a common site for neuropathology in neurodevelopmental disorders and is therefore a potential target for therapeutics to alleviate associated symptoms. PMID- 20950639 TI - Developmental biology of the Brazilian 'Armed' spider Phoneutria nigriventer (Keyserling, 1891): microanatomical and molecular analysis of the embryonic stages. AB - Phoneutria (Ctenidae) is among the most dangerous venomous spiders in Brazil. Its venom is composed of a mixture of pharmacologically active components, some of which have been quite extensively studied due to their potentiality as models for new pharmaceutical drugs. Nevertheless, literature data on the venom-producing glands are very limited. In the present study, we follow the biological development of intra-cocoon stages of Phoneutria nigriventer spiders, mainly regarding the formation of the venomous apparatus and venom production. The results showed that the venom glands of Phoneutria are already present in the early 1st pre-larva stage. The venomous apparatus is completely formed in the larva, a stage that precedes the spider eclosion from the cocoon. At embryo stages, transcripts of a vertebrate-active neurotoxin (PhTx1) were shown to be present, as well as, unidentified venom proteins that were immunolabeled by anti venom antibodies. It seems that venom toxins play roles in the protection and survival of those early developmental stages of Phoneutria spiders. PMID- 20950640 TI - The impact of individually-tailored lifestyle advice in the colorectal cancer screening context: a randomised pilot study in North-West London. AB - OBJECTIVE: The screening context may provide a "teachable moment" for promoting health behaviours. The present study examined the impact on diet, alcohol and physical activity of providing individually-tailored advice in the context of flexible sigmoidoscopy (FS) screening. METHOD: Adults (n=365) aged 58-59 years who attended FS screening between 2006 and 2008 and had no abnormalities detected were randomised to one of three groups: (i) control (usual care); (ii) standard leaflet on healthy lifestyle; or (iii) standard leaflet plus brief, tailored feedback based on information from the pre-screening questionnaire. A 6-month follow-up questionnaire assessed group differences in fruit and vegetable consumption, alcohol intake and physical activity. RESULTS: More people in the tailored group were meeting the 5-a-day fruit and vegetable recommendation at 6 months (OR: 2.28, CI[1.09, 4.76]). For physical activity there was a non significant trend towards meeting current activity guidelines in the tailored group (OR: 1.26, CI[0.62, 2.55]). Alcohol intake was low overall and did not change in any group. CONCLUSION: Tailored advice given in the context of cancer screening may provide an opportunity to improve dietary behaviours. Further research is needed to determine whether screening provides a unique "teachable moment" or if similar effects can be achieved in other health settings. PMID- 20950641 TI - Cod cathelicidin: isolation of the mature peptide, cleavage site characterisation and developmental expression. AB - Cathelicidin antimicrobial peptides are multifunctional peptides that are important in the innate immune system of mammals. Cathelicidins have been identified in several fish species. In this study we have isolated cathelicidin from Atlantic cod (Gadus morhua) and identified the cleavage site from the cathelin propart. This is the first isolation of a cathelicidin from teleost fish. The mature cathelicidin was found to be a 67-residues peptide, highly cationic with a pI of 13. Reversed phase chromatographic fractions containing the purified peptide had pronounced antimicrobial activity and the activity of the mature peptide was confirmed using a synthetic peptide. We examined the expression of cathelicidin during cod larvae early development using real-time PCR and detected expression that varied in the course of the first 68 days post hatching (dph). Two groups of larvae having a different food regime were compared. Cathelicidin expression was found to differ between the two groups and this could be linked to their food input. The presence and rapid adjustment of cathelicidin expression in the larvae indicate that the immune system of cod is active from early on in development and responds to external stimuli by the production of antimicrobial peptides. PMID- 20950642 TI - Nucleotide sequence of the Serratia entomophila plasmid pADAP and the Serratia proteamaculans pU143 plasmid virulence associated region. AB - Some strains of Serratia entomophila and S. proteamaculans cause amber disease of the New Zealand grass grub Costelytra zealandica (Coleoptera: Scarabaeidae), an important pasture pest in New Zealand. The disease determinants of S. entomophila, are encoded on a 153,404-bp plasmid, termed pADAP for amber disease associated plasmid. The S. proteamaculans strain 143 (Sp143) exhibits an unusual pathotype, where only 60-70% of C. zealandica larvae infected with the bacterium succumb to disease. DNA sequence analysis of the Sp143 pU143 virulence associated region identified high DNA similarity to the pADAP sep virulence associated region, with DNA sequence variation in the sepA gene and the variable region of the sepC component. No pADAP anti-feeding prophage orthologue was detected in the Sp143 genome. The region of pADAP replication was cloned and found to replicate in S. entomophila but not in Escherichia coli. DNA sequence analysis of the plasmid pSG348 repA gene from the French isolate of Serratia grimesii, identified 93% DNA identity to the pADAP repA gene. A comparison of the pU143 virulence associated region with the completed pADAP nucleotide sequence is given. PMID- 20950643 TI - Social behavior and social stress in adolescence: a focus on animal models. AB - Adolescence is a transitional phase during which the juvenile develops into an independent adult individual. In this period in particular frontal cortical brain regions and related neural circuitry are structurally remodeled to a relatively high extent resulting in a refined connectivity and functionality of these brain regions in adulthood. In this review we aim to address the question whether a high structural neuronal plasticity during adolescence makes this developmental period particularly vulnerable to lasting detrimental effects of stress. To answer this question we focus on results from experimental animal research on behavioral, physiological and neurobiological consequences of stress during adolescence. There are indeed results from animal models on stress that confirm that adolescent stress can lastingly alter adult brain and behavior. Since many studies, however, have shown that long-lasting effects of stress also occur in other phases of life as the perinatal period and adulthood the data do not suggest that adolescents are particularly vulnerable to the negative consequences of stress. The outcome of many of the studies on adolescent stress also emphasizes the high resilience of adolescent animals to develop long-lasting psychopathological changes in behavior after being exposed to adolescent stress. PMID- 20950644 TI - There is more than the amygdala: potential threat assessment in the cingulate cortex. AB - Fear conditioning with its neurological basis in the amygdala and associated structures provides an important model of anxiety disorders. However, this review will argue for a distinction between fear-provoking immediate and anxiety provoking potential threats, with the amygdala processing immediate threats and the cingulate cortex (and insular) processing potential threats. Four independent but related literatures are reviewed to bolster this argument: (1) rodent remote contextual fear conditioning, (2) symptom provocation in obsessive compulsive disorder (OCD), (3) fMRI investigations of risk assessment, and (4) behavioural and neurological studies of precautionary reasoning. These four literatures converge in suggesting that the cingulate cortex (and in more specific instances the insula) underlie potential threat assessment, providing support for a number of recent models posting the existence of a separate potential threat system that is dysfunctional in obsessive compulsive disorder (e.g., Szechtman and Woody, 2004; Woody and Szechtman, 2011). PMID- 20950645 TI - Oseltamivir, zanamivir and amantadine in the prevention of influenza: a systematic review. AB - OBJECTIVE: To systematically review evidence relating to the clinical efficacy of oseltamivir, zanamivir and amantadine in the prevention of influenza. METHODS: RCTs evaluating these interventions in seasonal prophylaxis and post-exposure prophylaxis were identified using electronic bibliographic databases and handsearching of retrieved articles. RESULTS: Oseltamivir was effective in preventing symptomatic laboratory-confirmed influenza (SLCI) in seasonal prophylaxis in healthy adults and at-risk elderly subjects and in post-exposure prophylaxis within households of mixed composition. Post-exposure prophylaxis using oseltamivir for paediatric contacts was observed to prevent SLCI. Zanamivir prevented SLCI in seasonal prophylaxis in healthy adults, at-risk adults and adolescents and in post-exposure prophylaxis within mixed households, with a trend for seasonal and post-exposure preventative effects in elderly subjects. Evidence for amantadine prophylaxis across subgroups was very limited. However, amantadine prevented SLCI in seasonal prophylaxis in healthy adults and in outbreak control amongst adolescent subjects. Interventions were reported to be well tolerated by subjects, with a relatively low proportion of subjects experiencing drug-related adverse events and drug-related withdrawals. CONCLUSIONS: Evidence was identified for the efficacy of oseltamivir and zanamivir in preventing influenza in a range of population subgroups. The evidence base for amantadine was considerably more limited. PMID- 20950646 TI - Induced hypothermia in adult community-acquired bacterial meningitis--more than just a possibility? AB - We present the case series of adult community-acquired bacterial meningitis treated with hypothermia. The major criteria for therapeutic hypothermia (TH) was impaired carbon dioxide reactivity (CO(2)R) assessed by Transcranial Doppler (TCD). In patients without temporal acoustic window, minor criteria (optic nerve sheath diameter >= 6.0 mm plus GCS <= 8) were required. According to our, although limited experience, the use of mild hypothermia in selected patients with community-acquired bacterial meningitis accompanied with appropriate monitoring could be a promising treatment tool. PMID- 20950647 TI - The inflammasome regulatory pathway and infections: role in pathophysiology and clinical implications. AB - The innate immune system serves to generate immediate host defenses against pathogens. Advance in the mechanism of innate immunity has provided new insights into host-pathogen microbial interactions. The cytosolic multi-protein complex called the inflammasome, which regulates the caspase-1 dependent processing of inflammatory cytokines IL-1beta and IL-18, is critical for the innate defense against pathogens. We summarize the current knowledge regarding the regulatory functions of the inflammasome in the pathogenesis of infections by various microbes (e.g., bacteria, fungi, viruses, and protozoa), and discuss its potential application in a clinical setting. Understanding of the unique role of the inflammasome signaling pathway in initiating and regulating inflammation is pivotal for the development of innovative approaches to optimize management of these infections. PMID- 20950648 TI - Stem cell therapy for cardiovascular regeneration: the beginning or the end of all hearts' hopes. PMID- 20950649 TI - The cerebellar network: from structure to function and dynamics. AB - Since the discoveries of Camillo Golgi and Ramon y Cajal, the precise cellular organization of the cerebellum has inspired major computational theories, which have then influenced the scientific thought not only on the cerebellar function but also on the brain as a whole. However, six major issues revealing a discrepancy between morphologically inspired hypothesis and function have emerged. (1) The cerebellar granular layer does not simply operate a simple combinatorial decorrelation of the inputs but performs more complex non-linear spatio-temporal transformations and is endowed with synaptic plasticity. (2) Transmission along the ascending axon and parallel fibers does not lead to beam formation but rather to vertical columns of activation. (3) The olivo-cerebellar loop could perform complex timing operations rather than error detection and teaching. (4) Purkinje cell firing dynamics are much more complex than for a linear integrator and include pacemaking, burst-pause discharges, and bistable states in response to mossy and climbing fiber synaptic inputs. (5) Long-term synaptic plasticity is far more complex than traditional parallel fiber LTD and involves also other cerebellar synapses. (6) Oscillation and resonance could set up coherent cycles of activity designing a functional geometry that goes far beyond pre-wired anatomical circuits. These observations clearly show that structure is not sufficient to explain function and that a precise knowledge on dynamics is critical to understand how the cerebellar circuit operates. PMID- 20950650 TI - Rapid detection of drug-resistant mutations in hepatitis B virus by the PCR Invader assay. AB - Early detection of resistant mutations of hepatitis B virus (HBV) is important for patients on nucleos(t)ide analog therapy. An assay based on the PCR-Invader technology was developed to detect resistant mutations with high sensitivity. The assay specifically detects mutations at codons 180, 181, 184, 202, 204, and 250 of the HBV polymerase reverse transcriptase domain. These mutations result in resistance to lamivudine and entecavir. In mixtures of plasmids containing wild type and resistant mutants, fold-over-zero values for resistant mutations were detected in 2% of the total. Seventy-five serum samples from patients, whose treatment had been switched from lamivudine to entecavir, were examined by the PCR-Invader assay and direct sequencing. The PCR-Invader assay detected all resistant mutations that were detected by direct sequencing and even detected the presence of mutants that direct sequencing could not. Cloning sequencing confirmed those mutations found by the PCR-Invader assay and not by direct sequencing. The PCR-Invader assay is a useful tool for the early detection of drug-resistant mutations. PMID- 20950651 TI - Mathematical modelling of the mitochondrial apoptosis pathway. AB - Mitochondria are pivotal for cellular bioenergetics, but are also a core component of the cell death machinery. Hypothesis-driven research approaches have greatly advanced our understanding of the role of mitochondria in cell death and cell survival, but traditionally focus on a single gene or specific signalling pathway at a time. Predictions originating from these approaches become limited when signalling pathways show increased complexity and invariably include redundancies, feedback loops, anisotropies or compartmentalisation. By introducing methods from theoretical chemistry, control theory, and biophysics, computational models have provided new quantitative insights into cell decision processes and have led to an increased understanding of the key regulatory principles of apoptosis. In this review, we describe the currently applied modelling approaches, discuss the suitability of different modelling techniques, and evaluate their contribution to the understanding of the mitochondrial apoptosis pathway. This article is part of a Special Issue entitled Mitochondria: the deadly organelle. PMID- 20950652 TI - The crystal structures of human S100B in the zinc- and calcium-loaded state at three pH values reveal zinc ligand swapping. AB - S100B is a homodimeric zinc-, copper-, and calcium-binding protein of the family of EF-hand S100 proteins. Zn(2+) binding to S100B increases its affinity towards Ca(2+) as well as towards target peptides and proteins. Cu(2+) and Zn(2+) bind presumably to the same site in S100B. We determined the structures of human Zn(2+)- and Ca(2+)-loaded S100B at pH 6.5, pH 9, and pH 10 by X-ray crystallography at 1.5, 1.4, and 1.65A resolution, respectively. Two Zn(2+) ions are coordinated tetrahedrally at the dimer interface by His and Glu residues from both subunits. The crystal structures revealed that ligand swapping occurs for one of the four ligands in the Zn(2+)-binding sites. Whereas at pH 9, the Zn(2+) ions are coordinated by His15, His25, His 85', and His 90', at pH 6.5 and pH 10, His90' is replaced by Glu89'. The results document that the Zn(2+)-binding sites are flexible to accommodate other metal ions such as Cu(2+). Moreover, we characterized the structural changes upon Zn(2+) binding, which might lead to increased affinity towards Ca(2+) as well as towards target proteins. We observed that in Zn(2+)-Ca(2+)-loaded S100B the C-termini of helix IV adopt a distinct conformation. Zn(2+) binding induces a repositioning of residues Phe87 and Phe88, which are involved in target protein binding. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 20950653 TI - Mitochondrial longevity pathways. AB - Production of reactive oxygen species (ROS) is a tightly regulated process, and increased levels of ROS within mitochondria are the principal trigger not only for mitochondrial dysfunctions but, more in general, for the diseases associated with aging, thus representing a powerful signaling molecules. One of the key regulators of ROS production, mitochondrial dysfunction, and aging is the 66-kDa isoform of the growth factor adapter shc (p66(shc)) that is activated by stress and generates ROS within the mitochondria, driving cells to apoptosis. Accordingly, p66(shc) knockout animals are one of the best characterized genetic model of longevity. On the other hand, caloric restriction is the only non genetic mechanism that is shown to increase life span. Several studies have revealed a complex network of signaling pathways modulated by nutrients, such as IGF-1, TOR, sirtuins, AMP kinase, and PGC-1alpha that are connected and converge to inhibit oxidative stresses within the mitochondria. Animal models in which components of these signaling pathways are induced or silenced present a general phenotype characterized by the deceleration of the aging process. This review will summarize the main findings in the process that link mitochondria to longevity and the connections between the different signaling molecules involved in this intriguing relationship. PMID- 20950654 TI - DNA repair in organelles: Pathways, organization, regulation, relevance in disease and aging. AB - Both endogenous processes and exogenous physical and chemical sources generate deoxyribonucleic acid (DNA) damage in the nucleus and organelles of living cells. To prevent deleterious effects, damage is balanced by repair pathways. DNA repair was first documented for the nuclear compartment but evidence was subsequently extended to the organelles. Mitochondria and chloroplasts possess their own repair processes. These share a number of factors with the nucleus but also rely on original mechanisms. Base excision repair remains the best characterized. Repair is organized with the other DNA metabolism pathways in the organelle membrane-associated nucleoids. DNA repair in mitochondria is a regulated, stress responsive process. Organelle genomes do not encode DNA repair enzymes and translocation of nuclear-encoded repair proteins from the cytosol seems to be a major control mechanism. Finally, changes in the fidelity and efficiency of mitochondrial DNA repair are likely to be involved in DNA damage accumulation, disease and aging. The present review successively addresses these different issues. PMID- 20950657 TI - An integrative assessment of brain and body function 'at rest' in panic disorder: a combined quantitative EEG/autonomic function study. AB - We conducted a quantitative electroencephalographic (QEEG) and autonomic assessment of panic disorder (PD). The study samples comprised 52 individuals meeting DSM-IV criteria for PD (with or without agoraphobia) and 104 age-, gender , and handedness-matched controls. EEG data were acquired from 16 scalp sites during resting eyes-open (REO) and eyes-closed (REC) conditions, and spectral power was assessed within 4 frequency bands: theta, alpha-1, alpha-2, and beta. The main findings were an overall reduction of spectral power in PD, compared to controls (Group main effect, p=.011), which was most apparent during REC (Group Condition interaction, p=.014), and within the alpha-1 frequency band (8-11 Hz; Group Band interaction, p=.014). Alpha-1 desynchronization occurs in response to increases in non-specific information processing, and aspects of attention such as alertness. Other findings were region-specific alterations of spectral power at frontal and temporal scalp sites, including a frontal alpha-1 asymmetry (R16)Y(S/A/N/G)FGLGKR, with a strong bias for the codons UUU encoding for Phe and AAA for Lys, which can form strong Watson-Crick pairing in all peptides analyzed. The physical distance between these codons favor a loop structure from Ser/Ala-Phe to Lys-Arg. Other loop and hairpin loops were also inferred from the codon frequencies in the N-terminal motif, and the first amino acids from the C terminal motif, or the dibasic potential endoproteolytic cleavage site. Our results indicate that nucleotide frequencies and codon usage bias in FGLamide ASTs tend to favor mRNA folds in the codon sequence in the C-terminal active peptide core and at the dibasic potential endoproteolytic cleavage site. PMID- 20950663 TI - A new natural alpha-helical peptide from the venom of the scorpion Heterometrus petersii kills HCV. AB - Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. There is no vaccine available for HCV, and almost half of patients cannot be cured using standard combination therapy. Thus, new anti HCV strategies and drugs are urgently needed. Here, the gene encoding a new alpha helical peptide, Hp1090, was screened from the venomous gland cDNA library of the scorpion Heterometrus petersii. Structural analysis showed that Hp1090 is an amphipathic alpha-helical peptide. In vitro HCV RNA inhibitory assays indicated that Hp1090 peptide inhibited HCV infection with an IC(50) of 7.62 MUg/ml (5.0 MUM), whereas Hp1035 peptide, showing high homology to Hp1090, exhibited no anti HCV activity. Hp1090 acted as a viricide against HCV particles in vitro and prevented the initiation of HCV infection. Furthermore, this peptide interacted with HCV particles directly and rapidly permeabilized phospholipid membranes. Collectively, it seems that Hp1090 is virocidal for HCV in vitro, directly interacting with the viral membrane and decreasing the virus infectivity. These results suggest that Hp1090 could be considered an anti-HCV lead compound with virocidal mechanism that offers a potential therapeutic approach to HCV infection. Our work opens a new avenue for antiviral drug discovery in natural scorpion venom. PMID- 20950664 TI - Modulation of human bronchial epithelial cells by pneumococcal choline binding protein A. AB - Choline binding protein A (CbpA) is an important adhesin and a determinant of virulence for Streptococcus pneumoniae. Binding to epithelial cells of host mucosal surfaces by pneumococcal CbpA is essential for pneumococcus to initiate colonization and to trigger subsequent invasive pneumococcal infections. In this study, we examined the immunopathologic mechanisms for the activation of human bronchial epithelial cells by CbpA in pneumococcal infections. Adhesion molecules, cytokines, and chemokines were assessed by flow cytometry, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. Intracellular signaling molecules were investigated by enzyme-linked immunosorbent assay or transcription factor assay. CbpA could upregulate cell surface expression of adhesion molecule intercellular adhesion molecule-1 on human bronchial epithelial cells. CbpA could also induce the release of inflammatory cytokine interleukin-6, and chemokines CCL2, CXCL1, and CXCL8 from human bronchial epithelia cells. CbpA-mediated induction of these mediators was differentially regulated by extracellular signal-regulated kinase, c-Jun N-terminal protein kinase, p38-mitogen-activated protein kinase, and nuclear factor-kappaB pathways. CbpA was also found to participate in the induction of IL-6, CCL2, CXCL1, and CXCL8 in the airways of mice upon intranasal challenge with S. pneumoniae. Our study therefore suggests that pneumococcal CbpA plays an immunopathophysiologic role by activating human bronchial epithelial cells in pneumococcal infections. PMID- 20950665 TI - Studies on neurolathyrism in Ethiopia: dietary habits, perception of risks and prevention. AB - This study describes the correlation of traditional perceptions and dietary habits with the incidence of neurolathyrism to propose preventive measures. Therefore, 118 households of South Wollo and North Gondar (Amhara Regional State, Ethiopia), of which one third had at least one neurolathyrism affected member, were interviewed. Most of the affected families in this study had one neurolathyrism victim, being predominantly male and of younger age. The incidence among youngsters (boys and girls) was significantly correlated with the consumption of green unripe seeds (eshet), confirming this as a risk factor for developing neurolathyrism. The consumption of other popular grass pea preparations was not age related. Neurolathyrism patients did not attempt any medication as most people knew that neurolathyrism is incurable, but the consumption of grass pea was abandoned after developing the disease. The minority 'Woito' tribe was virtually unaffected. They were the only people reporting to consume fish which is rich in amino acids such as methionine and using metallic kitchen utensils in addition to clay pots. This observation points to the correlation between low neurolathyrism incidence and a better balanced diet as well as metallic kitchen utensils, suggesting a new approach for neurolathyrism prevention. PMID- 20950666 TI - A new tyrosine-specific chymotrypsin-like and angiotensin-degrading serine proteinase from Vipera lebetina snake venom. AB - Vipera lebetina venom contains different metallo- and serine proteinases that affect coagulation and fibrin(ogen)olysis. A novel serine proteinase from V. Lebetina venom having ChymoTrypsin Like Proteolytic activity (VLCTLP) was purified to homogeneity from the venom using Sephadex G-100sf, DEAE-cellulose, heparin-agarose and FPLC on Superdex 75 chromatographies. VLCTLP is a glycosylated serine proteinase with a molecular mass of 41926 Da. It reacts with N-acetyl-L-tyrosine ethyl ester (ATEE) but not with Suc-Ala-Ala-Pro-Phe-pNA or Suc-Ala-Ala-Pro-Leu-pNA. The complete amino acid sequence of the VLCTLP is deduced from the nucleotide sequence of the cDNA encoding this protein. The full length cDNA sequence of the VLCTLP encodes open reading frame of 257 amino acid residues that includes a putative signal peptide of 18 amino acids, a proposed activation peptide of six amino acid residues and serine proteinase of 233 amino acid residues. VLCTLP belongs to the S1 (chymotrypsin) subfamily of proteases. The multiple alignment of its deduced amino acid sequence showed structural similarity with other serine proteases from snake venoms. The protease weakly hydrolyses azocasein, Aalpha-chain and more slowly Bbeta-chain of fibrinogen. VLCTLP does not cleave fibrin and has no gelatinolytic activity. Specificity studies against peptide substrates (angiotensin I and II, oxidized insulin B chain, glucagon, fibrinogen fragments etc.) showed that VLCTLP catalysed the cleavage of peptide bonds after tyrosine residues. VLCTLP is the only purified and characterized serine proteinase from snake venoms that catalyses ATEE hydrolysis. We detected ATEE-hydrolysing activities also in 9 different Viperidae and Crotalidae venoms. PMID- 20950667 TI - Repairing injured peripheral nerves: Bridging the gap. AB - Peripheral nerve injuries that induce gaps larger than 1-2 cm require bridging strategies for repair. Autologous nerve grafts are still the gold standard for such interventions, although alternative treatments, as well as treatments to improve the therapeutic efficacy of autologous nerve grafting are generating increasing interest. Investigations are still mostly experimental, although some clinical studies have been undertaken. In this review, we aim to describe the developments in bridging technology which aim to replace the autograft. A multi disciplinary approach is of utmost importance to develop and optimise treatments of the most challenging peripheral nerve injuries. PMID- 20950669 TI - Modelling 18O2 and 16O2 unidirectional fluxes in plants: I. regulation of pre industrial atmosphere. AB - In closed systems, the O2) compensation point (Gamma0) was previously defined as the upper limit of O2 level, at a given CO2 level, above which plants cannot have positive carbon balance and survive. Studies with 18O2 measure the actual O2 uptake by photorespiration due to the dual function of Rubisco, the enzyme that fixes CO2 and takes O2 as an alternative substrate. One-step modelling of CO2 and O2 uptakes allows calculating a plant specificity factor (Sp) as the sum of the biochemical specificity of Rubisco and a biophysical specificity, function of the resistance to CO2 transfer from the atmosphere to Rubisco. The crossing points (Cx, Ox) are defined as CO2 and O2 concentrations for which O2 and CO2 uptakes are equal. It is observed that: (1) under the preindustrial atmosphere, photorespiration of C3 plants uses as much photochemical energy as photosynthesis, i.e. the Cx and Ox are equal or near the CO2 and O2 concentrations of that epoch; (2) contrarily to Gamma(C), a Gamma0 does not practically limit the plant growth, i.e. the plant net CO2 balance is positive up to very high O2 levels; (3) however, in a closed biosystem, Gamma0 exists; it is not the limit of plant growth, but the equilibrium point between photosynthesis and the opposite respiratory processes; (4) a reciprocal relationship exists between Gamma0 and Gamma(C), as unique functions of the respective CO2 and O2 concentrations and of Sp, this invalidates some results showing two different functions for Gamma0 and Gamma(C), and, consequently, the associated analyses related to greenhouse effects in the past; (5) the pre-industrial atmosphere levels of O2 and CO2 are the Gamma0 and Gamma(C) of the global bio-system. They are equal to or near the values of Cx and Ox of C3 plants, the majority of land plants in preindustrial period. We assume that the crossing points represent favourable feedback conditions for the biosphere-atmosphere equilibrium and could result from co-evolution of plants-atmosphere-climate. We suggest that the evolution of Rubisco and associated pathways is directed by an optimisation between photosynthesis and photorespiration. PMID- 20950670 TI - Modelling 18O2 and 16O2 unidirectional fluxes in plants: II. analysis of rubisco evolution. AB - The studies of Rubisco characteristics observed during plant evolution show that the variation of the Rubisco specificity factor only improved by two times from cyanobacteria to modern C3 plants. However we note important variations of the ratio between the maximum rates of oxygenation and carboxylation (V(O)/V(C)). Modelling in vivo 18O2 data in plant gas exchange shows that the oxygenation reaction of Rubisco plays a regulating role when the photochemical energy exceeds the carboxylation capacity. A protective index 'oxygenation capacity' is postulated, related to the ratio V(O)/V(C) of Rubisco, and hence to the sink energy effect of photorespiration. Analysing the trends of Rubisco parameters along the evolutionary scale, we show: (1) the increase of both V(C) and V(O); (2) the enhancement of CO2 affinity; and (3) the rise in oxygenation capacity at the expense of the CO2 specificity. Hence, the factors of evolutionary pressure have not only directed the enzyme towards a more efficient utilisation of CO2, but mainly to positively use the unavoidable great loss of energy and assimilated carbon in the process of photorespiration. These observations reinforce the hypothesis of plant-atmosphere co-evolution and of the complex role of Rubisco, which seems to be selected to develop both better CO2 affinity and oxygenation capacity. The latter increases the capacity of sink of photorespiration, in particular, during water stress or under high irradiance, the two conditions experienced by plants in terrestrial environments. These observations help to explain some handicaps of C4 plants, and the supremacy of CAM and C3 perennial higher plants in arid environments. PMID- 20950668 TI - Linking oligodendrocyte and myelin dysfunction to neurocircuitry abnormalities in schizophrenia. AB - Multiple lines of evidence in schizophrenia, from brain imaging, studies in postmortem brains, and genetic association studies, have implicated oligodendrocyte and myelin dysfunction in this disease. Recent studies suggest that oligodendrocyte and myelin dysfunction leads to changes in synaptic formation and function, which could lead to cognitive dysfunction, a core symptom of schizophrenia. Furthermore, there is accumulating data linking oligodendrocyte and myelin dysfunction with dopamine and glutamate abnormalities, both of which are found in schizophrenia. These findings implicate oligodendrocyte and myelin dysfunction as a primary change in schizophrenia, not only as secondary consequences of the illness or treatment. Strategies targeting oligodendrocyte and myelin abnormalities could therefore provide therapeutic opportunities for patients suffering from schizophrenia. PMID- 20950671 TI - Immunohistochemical localization of the neuropeptide S receptor in the rat central nervous system. AB - The neuropeptide S receptor (NPSR) is a G-protein coupled receptor that is potently activated by the linear 20 amino acid peptide, neuropeptide S (NPS). Central administration of NPS promotes arousal and anxiolytic-like effects in rodents, and fails to promote such effects in NPSR knockout animals or in the presence of NPSR-selective antagonists. In situ hybridization (ISH) studies in rat brain have revealed that the mRNAs encoding the NPS precursor and the NPS receptor are expressed at high levels in discrete regions of the rat CNS. The distribution of the NPSR protein in brain has not been reported due to a lack of available antibodies. We have generated and validated a NPSR-specific antibody and used it to determine the distribution of the NPSR in male Sprague-Dawley (SD) rat brain. The anti-NPSR antibody identified a single protein by Western blot with an estimated molecular weight of 65 kD, which was prevented by pre incubation of the antibody with the immunizing peptide. The protein distribution identified with this antibody in rat brain was consistent both with the mRNA distribution identified by in situ hybridization, and to the localization pattern identified by a second NPSR-specific antibody against a distinct NPSR epitope. NPSR protein was identified in the medial amygdala (MeA), substantia nigra pars compacta, subiculum, dorsal raphe, and several hypothalamic and thalamic regions. Additionally, NPSR protein was localized in the pyramidal cell layer of the ventral hippocampus, the medial habenula (MHb), and was widely distributed in the cortex. The distribution of NPSR protein provides further insight into the organization of the NPS system and may guide future studies on the role of the NPSR in brain. PMID- 20950672 TI - Regulation of synaptic strength by sphingosine 1-phosphate in the hippocampus. AB - Although the hippocampus is a brain region involved in short-term memory, the molecular mechanisms underlying memory formation are not completely understood. Here we show that sphingosine 1-phosphate (S1P) plays a pivotal role in the formation of memory. Addition of S1P to rat hippocampal slices increased the rate of AMPA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) recorded from the CA3 region of the hippocampus. In addition long-term potentiation (LTP) observed in the CA3 region was potently inhibited by a sphingosine kinase (SphK) inhibitor and this inhibition was fully reversed by S1P. LTP was impaired in hippocampal slices specifically in the CA3 region obtained from SphK1-knockout mice, which correlates well with the poor performance of these animals in the Morris water maze test. These results strongly suggest that SphK/S1P receptor signaling plays an important role in excitatory synaptic transmission in the CA3 region of hippocampus and has profound effects on hippocampal function such as spatial learning. PMID- 20950673 TI - Long-term exposure to high glucose induces changes in the content and distribution of some exocytotic proteins in cultured hippocampal neurons. AB - A few studies have reported the existence of depletion of synaptic vesicles, and changes in neurotransmitter release and in the content of exocytotic proteins in the hippocampus of diabetic rats. Recently, we found that diabetes alters the levels of synaptic proteins in hippocampal nerve terminals. Hyperglycemia is considered the main trigger of diabetic complications, although other factors, such as low insulin levels, also contribute to diabetes-induced changes. Thus, the aim of this work was to evaluate whether long-term elevated glucose per se, which mimics prolonged hyperglycemia, induces significant changes in the content and localization of synaptic proteins involved in exocytosis in hippocampal neurons. Hippocampal cell cultures were cultured for 14 days and were exposed to high glucose (50 mM) or mannitol (osmotic control; 25 mM plus 25 mM glucose), for 7 days. Cell viability and nuclear morphology were evaluated by MTT and Hoechst assays, respectively. The protein levels of vesicle-associated membrane protein-2 (VAMP-2), synaptosomal-associated protein-25 (SNAP-25), syntaxin-1, synapsin-1, synaptophysin, synaptotagmin-1, rabphilin 3a, and also of vesicular glutamate and GABA transporters (VGluT-1 and VGAT), were evaluated by immunoblotting, and its localization was analyzed by immunocytochemistry. The majority of the proteins were not affected. However, elevated glucose decreased the content of SNAP-25 and increased the content of synaptotagmin-1 and VGluT-1. Moreover, there was an accumulation of syntaxin-1, synaptotagmin-1 and VGluT-1 in the cell body of some hippocampal neurons exposed to high glucose. No changes were detected in mannitol treated cells. In conclusion, elevated glucose per se did not induce significant changes in the content of the majority of the synaptic proteins studied in hippocampal cultures, with the exception of SNAP-25, synaptotagmin-1 and VGluT-1. However, there was an accumulation of some proteins in cell bodies of hippocampal neurons exposed to elevated glucose, suggesting that the trafficking of these proteins to the synapse may be compromised. Moreover, these results also suggest that other factors, in addition to hyperglycemia, certainly contribute to alterations detected in synaptic proteins in diabetic animals. PMID- 20950674 TI - Genetic and histologic evidence implicates role of inflammation in traumatic brain injury-induced apoptosis in the rat cerebral cortex following moderate fluid percussion injury. AB - Traumatic brain injury (TBI) causes massive brain damage. However, the secondary injury and temporal sequence of events with multiple mechanisms after the insult has not been elucidated. Here, we examined the occurrence of apoptosis and a causal relationship between inflammation and apoptosis in the TBI brain. Following a lateral moderate fluid percussion injury model of TBI in adult rats, microarray analyses detected apparent changes in the expression levels of apoptosis-related genes which revealed time-dependent expression patterns for 23 genes in the lateral cortex. The upregulated 23 genes included inflammatory cytokines such as interleukin 1 (IL-1) alpha, IL-1beta, and tumor necrotic factor (TNF) which immediately increased at 3 h following the injury. Time-dependent gene expression profile analyses showed that apoptosis was subsequently induced following inflammation. These results taken together suggested changes in expression of apoptosis-related genes may be associated with inflammatory response. Accompanying this surge of cell death genes after TBI was a neurostructural pathologic hallmark of apoptosis characterized by leakage of cytochrome c into cytoplasm, DNA fragmentation and apoptotic cells in the lateral cortex of the impacted hemisphere. Caspase-3 positive cells in the TBI brain were initially sporadic after 3 h, but these apoptotic cells subsequently increased and populated the cerebral cortex at 6 and 12 h, and gradually reached a plateau by 48 h. Interestingly, the expression profile of CD68 macrophage labeled cells closely resembled that of apoptotic cells after TBI, including the role of inflammatory signaling pathway in the progression of apoptotic cell death. These results taken together suggest that TBI induced upregulation of apoptosis-related genes, concomitant with the detection of apoptotic brain pathology during the 3 48 h post-injury period, which may be likely mediated by inflammation. Therapies designed at abrogating apoptosis and/or inflammation may prove effective when initiated at this subacute TBI phase. PMID- 20950675 TI - Effect of bee venom acupuncture on methamphetamine-induced hyperactivity, hyperthermia and Fos expression in mice. AB - Acupuncture has been used to treat drug addiction by nicotine, alcohol, cocaine and morphine. This study was designed to investigate the effect of bee venom (BV) acupuncture on hyperactivity and hyperthermia induced by acute exposure to methamphetamine (METH, 1mg/kg, s.c.) in mice. Diluted BV (20MUl of 0.01, 0.1, 1 and 10mg/ml in saline, s.c.) was administered bilaterally into the Zusanli acupoint (ST36) or control points (SP9 or GB39 or tail base). BV injection into ST36 dose dependently reduced METH-induced hyperactivity and hyperthermia, while BV injection (1mg/ml) into control points did not produce these suppressive effects. METH injection significantly increased Fos expression in several brain regions including nucleus accumbens (NA), caudate putamen (CPU), ventral tegmental area (VTA), substantia nigra (SN) and locus coeruleus (LC). Interestingly, BV (1mg/ml) injection into ST36 further increased METH-induced Fos expression in NA (core and shell), SN and LC. When we performed sciatic denervation or combination treatment of BV and lidocaine (BV diluted in 5% lidocaine solution), the enhancement of Fos elevation by BV was completely blocked in the NA, SN and LC in METH-injected mice, indicating that BV-induced peripheral nerve stimulation played an important role in the BV effect. Furthermore, the effects of BV were completely blocked by the alpha2-adrenoceptor antagonist, idazoxan (3mg/kg, i.p.), but not by beta-adrenoceptor antagonist, propranolol (10mg/kg, i.p.). Taken together, these findings suggest that BV acupuncture into ST36 may modulate METH-induced hyperactivity, hyperthermia and Fos expression through activation of the peripheral nerve and the central alpha2 adrenergic activation. PMID- 20950677 TI - Translation efficiencies of synonymous codons for arginine differ dramatically and are not correlated with codon usage in chloroplasts. AB - Codon usage in chloroplast mRNAs is different from that in prokaryotic and cytosolic mRNAs. We previously devised an in vitro assay for translation efficiencies using synthetic mRNAs, and measured translation efficiencies of five synonymous codon groups in tobacco chloroplasts. Using this assay, we here report our analysis of four additional synonymous codon groups in tobacco chloroplasts. We found that translation efficiencies of three arginine codons AGA, CGU and CGA differ dramatically, ca. 10-fold difference although the three arginine codons possess similar codon usage. Translation of AGA is very high, while CGA is translated extremely low. CGA is used frequently in chloroplasts but rare in Escherichia coli. The single tRNA species reads two histidine codons (CAU and CAC) and this is also the case for two glutamic acid codons (GAA and GAG) and two arginine codons (GCU and GCA). Their translation efficiencies, however, differ significantly. These observations suggest that individual codons posses their intrinsic efficiencies. PMID- 20950676 TI - Future altruism: Social discounting of delayed rewards. AB - Social discounting assesses an individual's willingness to forgo an outcome for the self in lieu of a larger outcome for someone else. The purpose of the present research was to examine the effect of adding a common delay to outcomes in a binary choice, social discounting procedure. Based on the premise that both social and temporal distances are dimensions of psychological distance, we hypothesized that social discounting should decrease as a function of delay to the outcomes. Across two within-subject experiments, participants indicated preference between a hypothetical money reward for the self or for someone else. The outcomes were associated with no, short, and long delays. Both studies confirmed our hypothesis that adding any delay to the receipt of outcomes decreases social discounting, though no significant differences were observed between short and long delays. These results are discussed in the context of some existing literature on altruism. PMID- 20950678 TI - The structure of two CONSTANS-LIKE1 genes in potato and its wild relatives. AB - Day length controls development in many plants. In Arabidopsis thaliana, the CONSTANS (CO) gene has been firmly established as a key component in the photoperiodic pathway of floral transition; less is known about CONSTANS-LIKE1 (COL1) orthologues of this gene in Arabidopsis and several other species. The CONSTANS protein comprises two B-box-type zinc fingers, CCT domain, and a variable middle region (MR) which corresponds to exon 2 in the COL1 genes of Solanum species. Solanum COL1 proteins are over 85% identical within the genus and about 50% similar to Arabidopsis CO. Comparative COL1 analysis in several cultivated and wild Solanum species discerned two gene variants, which differed in the structures of exon 2 and introns 1 and 2. In exon 2, two variants were primarily discerned by the numbers of AAC/AAT and CAA/CAG repeats coding for polyasparagine and polyglutamine tracts in MR; therefore two variants were dubbed short and long COL1 genes (sCOL1 and lCOL1). However, intron 1 in lCOL1 was shorter than in sCOL1 due to three indels, whereas intron 2 in available COL1 sequences was represented by three different variants. The temporal profiles of sCOL1 and lCOL1 expression in tuberosum potato dramatically differed under short and long day, and the level of sCOL1 expression exceeded that of lSOL1 by an order of magnitude. Both sCOL1 and lCOL1 were found in each Solanum genome under study and in each individual plant, and the ratio of their copy numbers was not related to plant ploidy and photoperiodic response. Evidently the evolution of two COL1 genes preceded Solanum speciation, and the day-length response of diverse Solanum genotypes does not stem from the primary COL1 structure. PMID- 20950679 TI - Anti-inflammatory and antinociceptive effects of Arrabidaea brachypoda (DC.) Bureau roots. AB - AIM OF THE STUDY: Arrabidaea brachypoda (DC.) Bureau has been used to relieve general pain, painful joints and kidney stones in Brazilian folk medicine. Nevertheless, scientific information regarding this species is scarce; there are no reports related to its possible analgesic and anti-inflammatory effects. This study was aimed at evaluating the traditional use of Arrabidaea brachypoda root using in vivo inflammatory and nociceptive models. MATERIALS AND METHODS: Carrageenan-induced paw edema, peritonitis and fibrovascular tissue growth induced by s.c. cotton pellet implantation were used to investigate the anti inflammatory activity of Arrabidaea brachypoda roots ethanolic extract (AbEE) in rats. Formalin and acetic acid-induced writhing tests were used to investigate the antinociceptive activity in mice. High-performance liquid chromatography (HPLC) was used to determine the fingerprint chromatogram of AbEE. RESULTS: The AbEE at test doses of 30-300 mg/kg p.o. demonstrated anti-inflammatory effects. AbEE reduced paw edema induced by carrageenan, inhibited leukocyte recruitment into the peritoneal cavity and, in the model of chronic inflammation using the cotton pellet-induced fibrovascular tissue growth in rats, significantly inhibited the formation of granulomatous tissue. The extracts at test doses of 30 300 mg/kg p.o. clearly demonstrated antinociceptive activity, except during the first phase of the formalin test. The presence of quercetin and phenolic compounds in the extract Arrabidaea brachypoda was confirmed using HPLC. CONCLUSION: Arrabidaea brachypoda ethanol extract markedly demonstrated anti inflammatory action in rats and antinociceptive activity in mice, which supports the previous claims of traditional use. PMID- 20950680 TI - Medicinal plants in Baskoure, Kourittenga Province, Burkina Faso: an ethnobotanical study. AB - AIM OF THE STUDY: The majority of people living in Kourittenga Province, Burkina Faso, are highly dependent on medicinal plants for their daily health care. Knowledge on the use of medicinal plants by traditional healers is being seriously threatened, due to the fact that it is commonly transferred from one generation to another only verbally. Moreover, recent environmental changes, deforestation, and unsustainable rates of exploitation, represent a serious risk for plant species diversity. Thus, there is a need to record and document indigenous knowledge on medicinal plants in this country. The aim of this study was to report on the use of medicinal plants by traditional healers to treat human diseases in a rural area located in the East-Centre Region of Burkina Faso (Baskoure Area), which has not yet been studied from an ethnobotanical point of view. MATERIALS AND METHODS: The research was carried out over a period of 8 months, by means of open-ended and semi-structured interviews. A total of 41 traditional healers were interviewed, and group meetings were organised with family members and other local inhabitants having knowledge of traditional medicine. RESULTS: A total of 190 plant species were recorded. Most medicinal plants used to prepare concoctions were herbs, and leaves were the most frequently used parts. A high percentage of plants were used against gastrointestinal diseases and malaria, which are the prevalent diseases in the study area. The major source of remedies came from wild plants, indicating that cultivation of medicinal plants is not a common practice. CONCLUSIONS: Our study represents an inventory on medicinal plants used in a rural area of Burkina Faso, and confirms that wild plants are widely utilised as health remedies in this area. The collected data may help to avoid the loss of traditional knowledge on the use of medicinal plants detained by traditional healers, and represent the preliminary information required in view of a future phytochemical investigation on the most used plants. PMID- 20950681 TI - Metabolic changes in visual cortex of neonatal monocular enucleated rat: a proton magnetic resonance spectroscopy study. AB - Neonatal monocular enucleation (ME) is often employed to study the developmental mechanisms underlying visual perception and the cross-modal changes in the central nervous system caused by early loss of the visual input. However, underlying biochemical or metabolic mechanisms that accompany the morphological, physiological and behavioral changes after ME are not fully understood. Male Sprague-Dawley rats (N=14) were prepared and divided into 2 groups. The enucleated group (N=8) underwent right ME (right eye removal) at postnatal day 10, while the normal group (N=6) was intact and served as a control. Three weeks after ME, single voxel proton magnetic resonance spectroscopy ((1)H MRS) was performed over the visual cortex of each hemisphere in all animals with a point resolved spectroscopy (PRESS) sequence at 7 T. The taurine (Tau) and N acetylaspartate (NAA) levels were found to be significantly lower in the left visual cortex (contralateral to enucleated eye) for enucleated animals. Such metabolic changes measured in vivo likely reflected the cortical degeneration associated with the reduction of neurons, axon terminals and overall neuronal activity. This study also demonstrated that (1)H MRS approach has the potential to characterize neonatal ME and other developmental neuroplasticity models noninvasively for the biochemical and metabolic processes involved. PMID- 20950682 TI - Protective mechanism of quercetin and rutin on 2,2'-azobis(2 amidinopropane)dihydrochloride or Cu2+-induced oxidative stress in HepG2 cells. AB - Protective effects of quercetin and rutin against oxidative stress were evaluated using in vitro and intracellular antioxidant assay. Quercetin showed higher peroxyl and hydroxyl radical-scavenging activity in a dose-dependent manner than did rutin in oxygen-radical absorbance capacity (ORAC). At 10 and 100 MUM, quercetin had higher metal-chelating activity than rutin carrying rutinose at position C-3 and was also more efficient than rutin in reducing intracellular oxidative stress caused by peroxyl radicals and Cu(2+). The protective activities of 10 and 100 MUM quercetin against Cu(2+)-induced intracellular oxidation were 13.8% and 44.8%, respectively. Rutin showed no protective activity against Cu(2+) induced oxidative stress. Quercetin showed significantly lower intracellular Cu(2+)-chelating activity than did 1,10-phenanthroline but offered greater protection from Cu(2+)-induced oxidative stress. Thus, quercetin may diffuse through the cell membrane more efficiently than rutin because quercetin does not carry rutinose, is hydrophilic, and reduces Cu(2+)-induced oxidative stress by scavenging radicals instead of chelating with metal ions. PMID- 20950683 TI - Tributyltin (TBT) and dibutyltin (DBT) differently inhibit the mitochondrial Mg ATPase activity in mussel digestive gland. AB - Tri-n-butyltin (TBT) has long been considered as the most toxic among organotins, especially to membrane systems. The partially dealkylated derivative di-n butyltin (DBT) has up to now received poor attention and, whenever considered, shown to be less toxic than TBT except on the immune system. The present kinetic approach evidences that both TBT and DBT in vitro inhibit the Mg-ATPase in mussel digestive gland mitochondria by a different mechanism. DBT even displays a higher efficiency than TBT (IC(50)=0.32 MUM for TBT vs. 0.19 MUM for DBT) in inhibiting the enzyme hydrolytic activity. Differently from TBT which at high concentrations (>1 MUM) apparently decreases the oligomycin-sensitivity of the Mg-ATPase, DBT at any concentration tested does not affect the oligomycin sensitivity. TBT probably binds to F(0), either in the form of free enzyme or of enzyme-substrate complex (Ki=K'i), acting as non-competitive inhibitor with respect to the ATP substrate. Conversely DBT, which acts as uncompetitive inhibitor of ATP and as competitive inhibitor of Mg(2+) cofactor, may bind strongly to F(1) subunit, thus preventing ATP hydrolysis. The Mg-ATPase inhibition by both organotins warns against a potential threat to crucial cell energy metabolism processes even after years from contamination and partial TBT debutylation. PMID- 20950684 TI - Phospholipase D controls Dictyostelium development by regulating G protein signaling. AB - Dictyostelium discoideum cells normally exist as individual amoebae, but will enter a period of multicellular development upon starvation. The initial stages of development involve the aggregation of individual cells, using cAMP as a chemoattractant. Chemotaxis is initiated when cAMP binds to its receptor, cAR1, and activates the associated G protein, Galpha2betagamma. However, chemotaxis will not occur unless there is a high density of starving cells present, as measured by high levels of the secreted quorum sensing molecule, CMF. We previously demonstrated that cells lacking PldB bypass the need for CMF and can aggregate at low cell density, whereas cells overexpressing pldB do not aggregate even at high cell density. Here, we found that PldB controlled both cAMP chemotaxis and cell sorting. PldB was also required by CMF to regulate G protein signaling. Specifically, CMF used PldB, to regulate the dissociation of Galpha2 from Gbetagamma. Using fluorescence resonance energy transfer (FRET), we found that along with cAMP, CMF increased the dissociation of the G protein. In fact, CMF augmented the dissociation induced by cAMP. This augmentation was lost in cells lacking PldB. PldB appears to mediate the CMF signal through the production of phosphatidic acid, as exogenously added phosphatidic acid phenocopies overexpression of pldB. These results suggest that phospholipase D activity is required for CMF to alter the kinetics of cAMP-induced G protein signaling. PMID- 20950685 TI - Engineering polymer blend microparticles: an investigation into the influence of polymer blend distribution and interaction. AB - The aim of this work was to understand the influence of polymer interaction and distribution on drug release from microparticles fabricated from blends of polymers. Blends of pH dependent polymer (Eudragit S, soluble above pH 7) and pH independent polymer (Eudragit RL, Eudragit RS or ethylcellulose) were incorporated into prednisolone loaded microparticles using a novel emulsion solvent evaporation method. Microparticles fabricated from blends of Eudragit S and Eudragit RL or RS did not modify drug release compared to microparticles fabricated from Eudragit S alone. This can be attributed to the high degree of miscibility of Eudragit S with Eudragit RS or Eudragit RL within the microparticles as confirmed by glass transition temperature measurements and confocal laser scanning microscopy. In contrast, microparticles prepared from blends of Eudragit S (75%) and ethylcellulose (25%) extended the release of prednisolone at pH 7.4 (compared to Eudragit S microparticles). This change in release profile was related to the immiscibility of Eudragit S and ethylcellulose as assessed by thermal analysis, and confirmed by microscopy which showed pores within the microparticle structures following dissolution of the Eudragit S domains. The ability of water insoluble polymers to extend drug release from enteric polymer microparticles is dependent on the miscibility and interaction of the polymers. This knowledge is important in the design of pH responsive microparticles capable of extending drug release in the gastrointestinal tract. PMID- 20950686 TI - Infusion of Lin- bone marrow cells results in multilineage macrochimerism and skin allograft tolerance in minimally conditioned recipient mice. AB - Donor-specific immunological tolerance using high doses of donor bone marrow cells (BMC) has been demonstrated in mixed chimerism-based tolerance induction protocols; however, the development of graft versus host disease (GVHD) remains a risk. In the present study, we demonstrate that the infusion of low numbers of donor Lin(-) bone marrow cells (Lin(-) BMC) 7 days post allograft transplantation facilitates high level macrochimerism induction and graft tolerance. Full thickness BALB/c skin allografts were transplanted onto C57BL/6 mice. Mice were treated with anti-CD4 and anti-CD8 mAbs on day 0, +2, +5, +7 and +14 along with low dose busulfan on day +5. A low dose of highly purified Lin(-) BMC from BALB/c donor mice was infused on day +7. Chimerism and clonal cell deletion were evaluated using flow cytometry. Donor-specific tolerance was tested by donor and third-party skin grafting and mixed leukocyte reaction (MLR). Lin(-) BMC infusion with minimal immunosuppression led to stable, mixed, multilineage macrochimerism and long-term allograft survival (>300 days). Mixed donor-recipient macrochimerism was observed. Donor-reactive T cells were clonally deleted and a 130% increase in CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) was observed in the spleen. Tolerant mice subsequently accepted second donor, but not third-party (C3H), skin grafts and recipient splenocytes failed to react with allogeneic donor cells indicating donor-specific immunological tolerance was achieved. We conclude that the infusion of donor Lin(-) BMC without cytoreductive recipient conditioning can induce indefinite survival of skin allografts via mechanisms involving the establishment of a multilineage macrochimeric state principally through clonal deletion of alloreactive T cells and peripherally induced CD4(+)Foxp3(+) Tregs. PMID- 20950687 TI - Structure and composition of myelinated axons: a multimodal synchrotron spectro microscopy study. AB - We report elemental mappings on the sub-cellular level of myelinated sciatic neurons isolated from wild type mice, with high spatial resolution. The distribution of P, S, Cl, Na, K, Fe, Mn, Cu was imaged in freeze-dried as well as cryo-preserved specimen, using the recently developed cryogenic sample environment at beamline ID21 at the European Synchrotron Radiation Facility (ESRF). In addition, synchrotron radiation based Fourier transform infrared (FTIR) spectromicroscopy was used as a chemically sensitive imaging method. Finally single fiber diffraction in highly focused hard X-ray beams, and soft X ray microscopy and tomography in absorption contrast are demonstrated as novel techniques for the study of single nerve fibers. PMID- 20950688 TI - Transcription of T cell-related genes in teleost fish, and the European sea bass (Dicentrarchus labrax) as a model. AB - In recent years the cloning of genes coding for immuno-regulatory peptides, as well as the sequencing of genomes, provided fish immunologists with a growing amount of information on nucleotide sequences. Research is now also addressed in investigating the functional immunology counterpart of nucleotide sequence transcripts in various fish species. In this respect, studies on functional immunology of T cell activities are still at their beginning, and much work is needed to investigate T cell responses in teleost fish species. In this review we summarise the current knowledge on the group of genes coding for main T cell related peptides in fish, and the expression levels of these genes in organs and tissues. Particular attention is paid to European sea bass (Dicentrarchus labrax), a marine species in which some information on functional immunology has been obtained, and we reassume here the expression of some T cell-related genes in basal conditions. In addition, we provide original data showing that T cells purified from the intestinal mucosa of sea bass with a specific mAb, express transcripts for TRbeta, TRgamma, CD8alpha, and RAG-1, thus showing similarities with intra-epithelial leucocytes of mammals. PMID- 20950689 TI - Genetics of white matter development: a DTI study of 705 twins and their siblings aged 12 to 29. AB - White matter microstructure is under strong genetic control, yet it is largely unknown how genetic influences change from childhood into adulthood. In one of the largest brain mapping studies ever performed, we determined whether the genetic control over white matter architecture depends on age, sex, socioeconomic status (SES), and intelligence quotient (IQ). We assessed white matter integrity voxelwise using diffusion tensor imaging at high magnetic field (4-Tesla), in 705 twins and their siblings (age range 12-29; 290 M/415 F). White matter integrity was quantified using a widely accepted measure, fractional anisotropy (FA). We fitted gene-environment interaction models pointwise, to visualize brain regions where age, sex, SES and IQ modulate heritability of fiber integrity. We hypothesized that environmental factors would start to outweigh genetic factors during late childhood and adolescence. Genetic influences were greater in adolescence versus adulthood, and greater in males than in females. Socioeconomic status significantly interacted with genes that affect fiber integrity: heritability was higher in those with higher SES. In people with above-average IQ, genetic factors explained over 80% of the observed FA variability in the thalamus, genu, posterior internal capsule, and superior corona radiata. In those with below-average IQ, however, only around 40% FA variability in the same regions was attributable to genetic factors. Genes affect fiber integrity, but their effects vary with age, sex, SES and IQ. Gene-environment interactions are vital to consider in the search for specific genetic polymorphisms that affect brain integrity and connectivity. PMID- 20950690 TI - Phylogeny of the leafy liverwort Ptilidium: cryptic speciation and shared haplotypes between the Northern and Southern Hemispheres. AB - The small, phylogenetically isolated liverwort genus Ptilidium has been regarded as of cool-Gondwanic origin with the bipolar, terrestrial Ptilidium ciliare giving rise to the Northern Hemisphere epiphytes Ptilidium pulcherrimum and Ptilidium californicum. This hypothesis is examined using a dataset including three chloroplast DNA regions from 134 Ptilidium accessions and one accession each of its closest relatives Trichocoleopsis and Neotrichocolea. Maximum likelihood and parsimony analyses point to a close relationship between P. ciliare and P. pulcherrimum, whereas P. californicum is placed sister to the remainder of the genus, separated by a long branch. Haplotype analysis and our phylogeny indicate the presence of Southern Hemisphere haplotypes of P. ciliare in the Northern Hemisphere, and shared haplotypes of P. ciliare and P. pulcherrimum between Europe and North America. Based on our findings, we reject the Gondwana-scenario and propose recent long distance dispersal as an explanation for the bipolar disjunct range. Ptilidium ciliare is resolved as paraphyletic with P. pulcherrimum nested within it. An isolated Ptilidium lineage with the morphology of P. ciliare from the Himalaya region likely represents a hitherto unrecognized cryptic species. Ptilidium pulcherrimum splits into a Japanese clade and a clade with accessions from Europe and North America. PMID- 20950691 TI - Formalin fixation affects equilibrium partitioning of an ionic contrast agent microcomputed tomography (EPIC-MUCT) imaging of osteochondral samples. AB - OBJECTIVE: Equilibrium Partitioning of an Ionic Contrast agent with microcomputed tomography (EPIC-MUCT) is a non-invasive technique to quantify and visualize the three-dimensional distribution of glycosaminoglycans (GAGs) in fresh cartilage tissue. However, it is unclear whether this technique is applicable to already fixed tissues. Therefore, this study aimed at investigating whether formalin fixation of bovine cartilage affects X-ray attenuation, and thus the interpretation of EPIC-MUCT data. DESIGN: Osteochondral samples (n=24) were incubated with ioxaglate, an ionic contrast agent, for 22h prior to MUCT scanning. The samples were scanned in both formalin-fixed and fresh conditions. GAG content was measured using a biochemical assay and normalized to wet weight, dry weight, and water content to determine potential reasons for differences in X ray attenuation. RESULTS: The expected zonal distribution of contrast agent/GAGs was observed for both fixed and fresh cartilage specimens. However, despite no significant differences in GAG concentrations or physical properties between fixed and fresh samples, the average attenuation levels of formalin-fixed cartilage were 14.3% lower than in fresh samples. CONCLUSIONS: EPIC-MUCT is useful for three-dimensional visualization of GAGs in formalin-fixed cartilage. However, a significant reduction in X-ray attenuation for fixed (compared to fresh) cartilage must be taken into account and adjusted for accordingly when quantifying GAG concentrations using EPIC-MUCT. PMID- 20950692 TI - Simultaneous ultrasound measurement of articular cartilage and subchondral bone. AB - OBJECTIVE: In osteoarthritis (OA), subchondral sclerosis takes place during cartilage degeneration. High frequency ultrasound (12-55MHz) has been shown to diagnose degenerated articular cartilage, while 0.1-1MHz ultrasound has been applied for clinical characterization of bone and diagnostics of osteoporosis. The aim of the study is to investigate, for the first time, the feasibility of 5MHz ultrasound for simultaneous analysis of articular cartilage and subchondral bone. METHODS: Osteochondral samples (n=10) were prepared from fresh and visually normal bovine medial tibial plateaus. Acoustic properties of the cartilage and subchondral bone were measured with a scanning ultrasound system using the pulse echo geometry and compared with biomechanical, histological and compositional reference data. RESULTS: The apparent integrated backscatter (AIB) from internal cartilage showed significant partial correlations with hydroxyproline (Hypro) (r=0.58, P=0.000), water content (r=-0.52, P=0.001) and dynamic modulus (r=0.57, P=0.000) of the tissue. Weak but statistically significant correlation was found between the bone AIB and mineral density of the subchondral plate (r=-0.34, P=0.041). Topographical variations in cartilage thickness could be detected using ultrasound. Composition, thickness and mechanical properties of the cartilage varied significantly across the tibial plateau. For the calculated ultrasound parameters, the variation was significant only between a few locations. CONCLUSIONS: Pulse-echo ultrasound geometry at 5MHz was feasible for simultaneous measurement of the acoustic properties of articular cartilage and subchondral bone. However, the relationships between the ultrasound parameters and properties of cartilage and bone were not as strong as reported earlier in studies focusing only either on bone or cartilage. Simultaneous measurement of both tissues compromises, due to natural curvature of articulating surfaces, the perpendicularity of the incidence of the ultrasound pulse. Obviously, this source of uncertainty should be minimized in order to enable effective clinical use of ultrasound in simultaneous measurement of articular cartilage and subchondral bone. PMID- 20950693 TI - The effects of acute loading on T1rho and T2 relaxation times of tibiofemoral articular cartilage. AB - OBJECTIVE: To evaluate the effect of acute loading on healthy and osteoarthritic knee cartilage T(1rho) and T(2) relaxation times. DESIGN: Twenty subjects with radiographic evidence of osteoarthritis (OA) and 10 age-matched controls were enrolled. Magnetic resonance imaging (MRI) acquisition, including T(1rho) and T(2) map sequences were performed unloaded and loaded at 50% body mass. Cartilage masks were segmented semi-automatically on registered high-resolution spoiled gradient-echo (SPGR) images for each compartment (medial and lateral). Cartilage lesions were identified using a modified Whole Organ Magnetic Resonance Imaging Score (WORMS) score. Statistical differences were explored using separate two-way (group*loading condition) Analysis of Variance (ANOVA) using age as a covariate to evaluate the effects of loading on T(1rho) and T(2) relaxation times. RESULTS: A significant decrease in T(1rho) (44.5+/-3.8 vs 40.2+/-4.8ms for unloaded and loaded, respectively; P<0.001) and T(2) (31.8+/-3.8 vs 30.5+/-4.8ms for unloaded and loaded, respectively; P<0.001) relaxation times was observed in the medial compartment with loading while no differences were observed in the lateral compartment. This behavior occurred independent of WORMS score. Cartilage compartments with small focal lesions experienced greater T(1rho) change scores with loading when compared to cartilage without lesions or cartilage with larger defects (P=0.05). CONCLUSIONS: Acute loading resulted in a significant decrease in T(1rho) and T(2) relaxation times of the medial compartment, with greater change scores observed in cartilage regions with small focal lesions. These data suggest that changes of T(1rho) values with loading may be related to cartilage biomechanical properties (i.e., tissue elasticity) and may be a valuable tool for the scientist and clinician at identifying early cartilage disease. PMID- 20950694 TI - Accuracy of VA databases for diagnoses of knee replacement and hip replacement. AB - PURPOSE: To examine the validity of International Classification of Diseases Ninth Revision (ICD-9) and Current Procedural Terminology (CPT) codes for knee replacement and hip replacement in Veterans Affairs (VA) databases. METHODS: From a cohort of veterans who received health care at Minneapolis VA Medical Center and/or affiliated medical facilities, we obtained four random samples of 50 patients each with: neither hip nor knee replacement code, knee replacement code only, hip replacement code only and both knee and hip replacement codes. The gold standard was documentation of knee or hip replacement surgery in patient medical records. Accuracy of ICD-9 or CPT code for knee and hip replacement was assessed by calculating sensitivity, specificity, positive and negative predictive values (PPV and NPV). RESULTS: Of the 200 patients, medical records were available for 166:140 (70%) had complete medical records and 26 (13%) had incomplete medical records. Knee replacement codes were accurate with excellent PPV of 95%, sensitivity of 95%, specificity of 96% and NPV of 96%. Hip replacement codes were accurate with excellent PPV of 98%, sensitivity of 96%, specificity of 99% and NPV of 96%. Sensitivity analyses that included incomplete charts had little impact on these estimates. The procedure dates found in VA databases matched exactly with medical records in 96%. CONCLUSIONS: The ICD-9 and CPT codes for knee replacement and hip replacement in VA databases are valid. These codes may be used to identify cohorts of veterans with knee replacement and hip replacement for research studies. PMID- 20950695 TI - Does measurement of the anatomic axis consistently predict hip-knee-ankle angle (HKA) for knee alignment studies in osteoarthritis? Analysis of long limb radiographs from the multicenter osteoarthritis (MOST) study. AB - OBJECTIVE: Researchers commonly use the femoral shaft-tibial shaft angle (FS-TS) from knee radiographs to estimate the hip-knee-ankle angle (HKA) in studies examining risk factors for knee osteoarthritis (OA) incidence and progression. The objective of this study was to determine the relationship between HKA and FS TS, depending on the method of calculating FS-TS and the direction and degree of knee deformity. METHODS: 120 full-length digital radiographs were assigned, with 30 in each of four alignment groups (0.0 degrees -4.9 degrees , and >=5.0 degrees of varus and valgus), from a large cohort of persons with and at risk of knee OA. HKA and five measures of FS-TS (using progressively shorter shaft lengths) were obtained using Horizons Analysis Software, Orthopaedic Alignment & Imaging Systems Inc. (OAISYS). The offsets between HKA and the different versions of FS TS were calculated, with 95% confidence intervals (CIs). Pearson correlations were calculated. RESULTS: In varus limbs use of a shorter shaft length increased the offset between HKA and FS-TS from 5.1 degrees to 7.0 degrees . The opposite occurred with valgus limbs (from 5.0 degrees to 3.7 degrees ). Correlations between HKA and FS-TS for the whole sample of 120 individuals were excellent (r range 1.00-0.88). However, correlations for individual alignment groups were low to moderate, especially for the shortest-shaft FS-TS (r range 0.41-0.66). CONCLUSIONS: The offsets obtained using the shorter FS-TS measurements vary depending on direction and degree of knee deformity, and therefore may not provide reliable predictions for HKA We recommend that full-length radiographs be used whenever an accurate estimation of HKA is required, although broad categories of alignment can be estimated with FS-TS. PMID- 20950696 TI - HIF-2alpha as a possible therapeutic target of osteoarthritis. AB - OBJECTIVE: Endochondral ossification, a conversion process from nonvascularized and hypoxic cartilage to highly vascularized bone, plays a crucial role in osteoarthritis (OA) development as well as in physiological skeletal growth. We have shown that hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) is an extensive regulator of the endochondal ossification process. Here we review the possible signaling network regulating OA development on the axis of HIF 2alpha. METHODS: Peer reviewed publications published prior to August 2010 were searched in the Pubmed database. Articles that were relevant to HIF and molecular mechanisms of the endochondral ossification and OA were selected. RESULTS: As a trigger of OA, mechanical stress may induce the upstream NF-kappaB signal and HIF 2alpha expression in joint cartilage of mice and humans, which causes transactivation of endochondral ossification-related molecules with the most potent beta-subunit partner aryl hydrocarbon nuclear translocator-like (ARNTL). In contrast to HIF-2alpha, HIF-1alpha functions to maintain cartilage via a distinct mechanism, so that the shifting of the HIFs might possibly be involved in an OA pathogenesis. CONCLUSION: Signals on the HIF-2alpha axis from NF-kappaB signaling to the endochondral ossification-related molecules, possibly in combination with HIF-2alpha and ARNTL, may represent a rational therapeutic target for OA with minimal effects on physiological skeletal homeostasis. PMID- 20950697 TI - Functional adaptation of knee cartilage in asymptomatic female novice runners compared to sedentary controls. A longitudinal analysis using delayed Gadolinium Enhanced Magnetic Resonance Imaging of Cartilage (dGEMRIC). AB - OBJECTIVE: To longitudinally estimate the change in glycosaminoglycan content of knee cartilage in asymptomatic untrained female novice runners participating in a Start To Run program (STR) compared to sedentary controls. METHOD: Nine females enrolling in a 10-week STR and 10 sedentary controls participated voluntarily. Prior to and after the 10-week period, both groups were subjected to dGEMRIC imaging. dGEMRIC indices of knee cartilage were determined at baseline and for the change after the 10-week period in both groups. Based on a self-reported weekly log, physical activity change during the study was depicted as decreased, unchanged or increased. The Mann-Whitney U and Kruskal-Wallis tests were applied to test the hypotheses that dGEMRIC changes occurred between groups and according to physical activity changes respectively. RESULTS: No significant differences were established between groups for dGEMRIC indices at baseline (P=0.541). A significant positive change of the median dGEMRIC index in the runners group was demonstrated when compared to the controls [+11.66ms (95% CI: -25.29, 44.43) vs 9.56ms (95% CI: -29.55, 5.83), P=0.006]. The change in dGEMRIC index differed significantly according to physical activity change (P=0.014), showing an increase in dGEMRIC index with increasing physical activity. CONCLUSION: Since cartilage appears to positively respond to moderate running when compared to a sedentary lifestyle, this running scheme might be considered a valuable tool in osteoarthritis prevention strategies. Caution is warranted when applying these results to a wider population and to longer training periods. PMID- 20950698 TI - Identification of molecular markers for articular cartilage. AB - OBJECTIVE: The aim of the current study was to identify molecular markers for articular cartilage (AC) that can be used as tools for the quality control of tissue engineered (TE) cartilage. DESIGN: A genome-wide expression analysis was performed using RNA isolated from articular and growth plate (GP) cartilage, both extracted from the knee joints of 6 weeks old minipigs. After confirming the specific expression for selected genes by RT-PCR, these were used as molecular markers for the quality control of TE cartilage. RESULTS: Albeit several known chondrocyte markers were expressed to a similar extent in articular and GP cartilage, our genome-wide expression analysis led us to identify genes being selectively expressed in either GP or articular chondrocytes. These findings led us to perform a RT-PCR expression analysis for the corresponding genes to demonstrate the absence of GP-specific markers in TE cartilage, while common or AC markers were expressed. CONCLUSIONS: Taken together, these results provide important novel insights into chondrocyte biology in general and AC in particular. In addition, it is reasonable to speculate, that some of the identified genes play distinct roles in the regulation of articular chondrocyte differentiation and/or function, thereby raising the possibility that they may serve as targets for non-operative therapies of osteoarthritis (OA). PMID- 20950699 TI - Micro-CT quantification of subchondral endplate changes in intervertebral disc degeneration. AB - BACKGROUND: The intervertebral disc (IVD) is dependent on nutrient provision through a cartilage layer with underlying subchondral bone, analogous to joint cartilage. In the joint, subchondral bone remodeling has been associated with osteoarthritis (OA) progression due to compromised nutrient and gas diffusion and reduced structural support of the overlaying cartilage. However, subchondral bone changes in IVD degeneration have never been quantified before. OBJECTIVE: The aim of this study is to determine the subchondral bone changes at different stages of IVD degeneration by micro-CT. METHODS: Twenty-seven IVDs including the adjacent vertebral endplates were obtained at autopsy. Midsagittal slices, graded according the Thompson score, were scanned. Per scan 12 standardized cylindrical volumes of interest (VOI) were selected. Six VOIs contained the bony endplate and trabeculae (endplate VOIs) and six accompanying VOIs only contained trabecular bone (vertebral VOIs). Bone volume as percentage of the total volume (BV/TV) of the VOI, trabecular thickness (TrTh) and connectivity density (CD) were determined. RESULTS: An increase in BV/TV and TrTh was found in endplate VOIs of IVDs with higher Thompson score whereas these values remained stable or decreased in the vertebral VOIs. CONCLUSION: The increase in bone volume combined with the increase in TrTh in endplate VOIs strongly suggest that the subchondral endplate condenses to a more dense structure in degenerated IVDs. This may negatively influence the diffusion and nutrition of the IVD. The endplate differences between intact and mild degenerative IVDs (grade II) indicate an early association of subchondral endplate changes with IVD degeneration. PMID- 20950700 TI - The diverse sporulation characteristics of Clostridium difficile clinical isolates are not associated with type. AB - Clostridium difficile causes diarrhoeal diseases ranging from asymptomatic carriage to a fulminant, relapsing, and potentially fatal colitis. Endospore production plays a vital role in transmission of infection, and in order to cause disease these spores must then germinate and return to vegetative cell growth. Type BI/NAP1/027 strains of C. difficile have recently become highly represented among clinical isolates and are associated with increased disease severity. It has also been suggested that these 'epidemic' types generally sporulate more prolifically than 'non-epidemic' strains, although the few existing reports are inconclusive and encompass only a small number of isolates. In order to better understand any differences in sporulation rates between epidemic and non-epidemic C. difficile types, we analysed these characteristics using 14 C. difficile clinical isolates of a variety of types. Sporulation rates varied greatly between individual BI/NAP1/027 isolates, but this variation did not appear to be type associated. Furthermore, a number of BI/NAP1/027 spores appeared to form colonies with a lower frequency than specific non-BI/NAP1/027 strains. The data suggest that (i) careful experimental design is required in order to accurately quantify sporulation; and (ii) current evidence cannot link differences in sporulation rates with the disease severity of the BI/NAP1/027 type. PMID- 20950701 TI - Seroprotective titers against 2009 H1N1 influenza A virus after vaccination in allogeneic hematopoietic stem cell transplantation recipients. AB - Little data are available regarding the safety and immunologic response to pandemic H1N1 influenza vaccine in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). We measured serum antibody titers against A/California/7/2009 H1N1 using a hemagglutination inhibition assay in 82 allogeneic HSCT recipients who received the 2009 H1N1 vaccine between November 2009 and January 2010 after it became available at our institution. The median time between HSCT and vaccination was 19 months (range, 2.5-94 months), and the median time from vaccination to specimen collection was 56 days (range, 14-140 days). Seroprotective antibody titers (hemagglutination inhibition titer >=1:40) against 2009 H1N1 influenza A virus were detected in 51% of patients. The presence of chronic graft-versus-host disease and type of conditioning regimen did not affect the rate of detection of seroprotective titers after vaccination. Patients were more likely to have a seroprotective titer the farther away from HSCT they were (adjusted odds ratio, 1.79 per year; 95% confidence interval, 1.12 2.85). Rituximab administration in the year before vaccination was associated with a lack of seroprotective titer (adjusted odds ratio, 0.11; 95% confidence interval, 0.01-0.97). The vaccine was safe and well tolerated. Strategies are needed to improve the influenza vaccine response in this population, especially those receiving immunotherapy. PMID- 20950702 TI - Rituximab treatment for Epstein-Barr virus DNAemia after alternative-donor hematopoietic stem cell transplantation. AB - We report 55 patients undergoing an alternative-donor hematopoietic stem cell transplantation (HSCT) who developed Epstein-Barr virus (EBV) DNAemia, with >1000 EBV copies/10(5) peripheral blood mononuclear cells (PBMCs), and were treated with rituximab (375 mg/m(2)). The median patient age was 47 years (range, 20-65 years), and graft sources were mismatched family members (n = 4), unrelated donors (n = 46), and unrelated cord blood (n = 5). The conditioning regimen included antithymocyte globulin (ATG) in all patients. The median time to development of EBV DNAemia was day 27 post-HSCT (range, day 5 to day 242), with a median of 60 EBV copies/10(5) PBMCs (range, 1-5770 copies/10(5) PBMCs). The number of EBV copies was reduced to <1000/10(5) PBMCs on day +7 after initiation of rituximab therapy in 51% of the patients, on day +14 in 73% of the patients, and on +21 in 92% of the patients. Overall, 50 of 55 patients (91%) cleared EBV after one dose (n = 25) or more than one dose (n = 25) of rituximab. Factors predicting transplantation-related mortality (TRM) in multivariate analysis were a reduction to <1000 EBV copies/10(5) PBMCs by day +7 of treatment (relative risk [RR], 0.2; P = .01) and disease phase in remission (RR, 0.3; P = .05). TRM was 23% in the 40 patients with none or one of the negative predictors and 60% in the 15 patients with both negative predictors (P = .001). Of these latter 15 patients, 3 developed clinical posttransplantation lymphoproliferative disorder (PTLD). All 3 of these patients had a high EBV load on day +7 of rituximab therapy. This study confirms the effectiveness of rituximab in controlling EBV DNAemia in patients undergoing allogeneic HSCT. Patients with increasing EBV copies despite rituximab therapy are at high risk for EBV PTLD and may be considered for alternative therapies. PMID- 20950704 TI - [Splenic hyalohyphomycosis. Case report]. AB - Invasive aspergillosis is an important cause of morbidity and mortality in severely immunocompromised patients, especially those who are neutropenic or who have undergone bone marrow or solid-organ transplant. We report a case of hyalohyphomycosis morphologically suggestive of an Aspergillus spp. in a 22-year old patient with aplastic anaemia, treated with multiple transfusions and broad spectrum antibiotics. PMID- 20950703 TI - Regulation of sodium channel activity by phosphorylation. AB - Voltage-gated sodium channels carry the major inward current responsible for action potential depolarization in excitable cells as well as providing additional inward current that modulates overall excitability. Both their expression and function is under tight control of protein phosphorylation by specific kinases and phosphatases and this control is particular to each type of sodium channel. This article examines the impact and mechanism of phosphorylation for isoforms where it has been studied in detail in an attempt to delineate common features as well as differences. PMID- 20950705 TI - [A new case of rhinosporidiosis in Chile]. AB - BACKGROUND: Rhinosporidiosis is a chronic, granulomatous, and non-contagious infection, in which highly vascularized polyps (mainly present in the nasal cavity) appear. These polyps usually bleed easily. AIMS: To present the case of a 14 year-old male suffering from an obstruction and injury of the right nostril due to a polypoid shaped-lesion with a raspberry-like appearance. METHODS: A wide surgery resection of the base of the lesion was performed, as well as a standard histopathology procedure, including microscopic analysis with haematoxylin-eosin and Grocott staining. RESULTS AND CONCLUSIONS: The histopathology report indicated that the chronic inflammatory polyp was compatible with rhinosporidiosis. PMID- 20950706 TI - Skoulekia meningialis n. gen., n. sp. (Digenea: Aporocotylidae Odhner, 1912) a parasite surrounding the brain of the Mediterranean common two-banded seabream Diplodus vulgaris (Geoffroy Saint-Hilaire, 1817) (Teleostei: Sparidae): description, molecular phylogeny, habitat and pathology. AB - This study describes a new aporocotylid genus and species, Skoulekia meningialis n. gen., n. sp. which was detected in the ectomeningeal veins surrounding the optic lobes of the brain of the common two-banded seabream Diplodus vulgaris (Geoffroy Saint-Hilaire, 1817) from the Gulf of Valencia (Mediterranean Sea). A detailed morphological description of S. meningialis is provided, including drawings, measurements and scanning electron microscopy images as well as a phylogenetic study of S. meningialis and closely related taxa using DNA sequence data obtained from whole ITS2 and partial 18S and 28S rDNA regions. Morphology as well as molecular phylogeny strongly support the erection of a new genus and demonstrate its close relationship with the genera Psettarium (Goto & Ozaki, 1930) and Pearsonellum Overstreet & Koie, 1989. Skoulekia is the second aporocotylid genus described in the Sparidae, a family including economical important fishes. In contrast to the majority of the aporocotylids, which inhabit the heart or the blood vessels of the gills, S. meningialis inhabits the ectomeningeal veins surrounding the optic lobes. Eggs were found trapped within the gill vessels. Normally, blood fluke pathology is almost exclusively related to the eggs. However, in the case of S. meningialis, main histopathological alterations were related to the adult blood flukes which were found to cause mild localised meningitis. PMID- 20950707 TI - Hormone-sensitive lipase modulates adipose metabolism through PPARgamma. AB - Hormone-sensitive lipase (HSL) is rate limiting for diacylglycerol and cholesteryl ester hydrolysis in adipose tissue and essential for complete hormone stimulated lipolysis. Gene expression profiling in HSL-/- mice suggests that HSL is important for modulating adipogenesis and adipose metabolism. To test whether HSL is required for the supply of intrinsic ligands for PPARgamma for normal adipose differentiation, HSL-/- and wild-type (WT) littermates were fed normal chow (NC) and high-fat (HF) diets supplemented with or without rosiglitazone (200 mg/kg) for 16 weeks. Results show that supplementing rosiglitazone to an NC diet completely normalized the decreased body weight and adipose depots in HSL-/- mice. Additionally, rosiglitazone resulted in similar serum glucose, total cholesterol, FFA, and adiponectin values in WT and HSL-/- mice. Furthermore, rosiglitazone normalized the expression of genes involved in adipocyte differentiation, markers of adipocyte differentiation, and enzymes involved in triacylglycerol synthesis and metabolism, and cholesteryl ester homeostasis, in HSL-/- mice. Supplementing rosiglitazone to an HF diet resulted in improved glucose tolerance in both WT and HSL-/- animals and also partial normalization in HSL-/- mice of abnormal WAT gene expression, serum chemistries, organ and body weight changes. In vitro studies showed that adipocytes from WT animals can provide ligands for activation of PPARgamma and that activation is further boosted following lipolytic stimulation, whereas adipocytes from HSL-/- mice displayed attenuated activation of PPARgamma, with no change following lipolytic stimulation. These results suggest that one of the mechanisms by which HSL modulates adipose metabolism is by providing intrinsic ligands or pro-ligands for PPARgamma. PMID- 20950708 TI - Effect of beta-adrenergic stimulation on QT interval accommodation. AB - BACKGROUND: QT interval correction formulas are based on instantaneous heart rate (HR), but QT interval adaptation to sudden HR change occurs gradually. In humans, the QT interval has been reported to reach a new steady-state value in about 2 minutes. OBJECTIVE: This study sought to assess beta-adrenergic stimulation effects on QT interval response to HR change. METHODS: Ten subjects (42.1 +/- 15.3 years, 3 men) undergoing radiofrequency ablation of supraventricular tachycardia were studied. Atrial pacing for 5 minutes at an HR ranging from 60 to 140 beats/min was performed before and during dobutamine infusion (10 MUg/kg/min). The QT response to sudden HR change was evaluated. RESULTS: The QT response to sudden HR change consists of an immediate response (IR), followed by a gradual monoexponential course to the new steady-state value. Linear function results in inferior fit of QT adaptation course (P < .05 compared with exponential). The time constant of the exponential is approximately 1 minute (50.9 +/- 11.4 seconds). The IR magnitude is approximately 3% of the RR interval change (2.97% +/- 2.01%). Dobutamine shortens steady-state QT at given HR (from 301.8 +/- 11.2 ms to 290.6 +/- 13.2 ms at 120 beats/min; P < .001) and increases IR magnitude (to 13.28% +/- 8.99% of RR change; P < .01). During sinus rhythm, QT variability and QT variability index were significantly increased by dobutamine. CONCLUSION: QT adaptation has 2 distinct phases, which might have different mechanisms. The effect of beta-adrenergic stimulation on IR may increase QT variability by increasing the immediate response to HR variability. These results may be important in the assessment of drug effects on repolarization and for understanding of QT variability. PMID- 20950709 TI - Homozygous mutation in SCN5A associated with atrial quiescence, recalcitrant arrhythmias, and poor capture thresholds. PMID- 20950710 TI - Children are not just small adults. PMID- 20950711 TI - Exercise extreme caution when calling rare genetic variants novel arrhythmia syndrome susceptibility mutations. PMID- 20950712 TI - Microscopic systolic pressure alternans in human cardiomyopathy: noninvasive evaluation of a novel risk marker and correlation with microvolt T-wave alternans. AB - BACKGROUND: In patients with severe left ventricular (LV) dysfunction, visible pulsus alternans coincides with visible T-wave alternans (TWA), but a similar relationship has not been described for nonvisible microscopic systolic pressure alternans (MSPA) and microvolt TWA (MTWA). OBJECTIVE: The purpose of this study was to determine the prevalence of MSPA and its relationship to MTWA in patients with cardiomyopathy. METHODS: Using the spectral method, MSPA was measured from finger pressure during incremental atrial pacing and then validated against MSPA measured from the LV pressure in 12 patients. In 23 other patients with cardiomyopathy (LV ejection fraction <40%), noninvasive MSPA and MTWA were measured simultaneously during incremental atrial pacing. RESULTS: MSPA (<1 mm Hg) was detected in 80% of patients with cardiomyopathy and in 43% of controls. The presence of finger MSPA showed 100% positive concordance with LV MSPA; however, finger MSPA was 20% larger due to peripheral augmentation. Finger MSPA was highly concordant (96% positive concordance and 90% negative concordance) with MTWA. The magnitudes of MSPA and MTWA showed a linear correlation (R = 0.66, P <.001), and the k value, a measure of signal-to-noise ratio, was significantly larger for MSPA compared to MTWA (108 +/- 88 vs 24 +/- 48, P <.001). Premature beats resulted in concordant and coincident changes in MSPA and MTWA. During follow-up (454 +/- 274 days), 2 (8.6%) patients experienced ventricular tachycardia, and both manifested MSPA and MTWA during pacing at 600 ms. CONCLUSION: MSPA can be detected noninvasively in patients with cardiomyopathy and is coupled to MTWA, suggesting a common mechanism. The high signal-to-noise ratio of MSPA may provide a novel robust metric of sudden cardiac death risk in these patients. PMID- 20950713 TI - Comparison of voltage map-guided left atrial anterior wall ablation versus left lateral mitral isthmus ablation in patients with persistent atrial fibrillation. AB - BACKGROUND: Left lateral mitral isthmus (LLMI) ablation achieves a low percentage of bidirectional conduction block in atrial fibrillation (AF) ablation. OBJECTIVE: The purpose of this study was to investigate whether linear ablation through the lowest voltage area on the left atrial anterior wall (LAAW) can lead to better clinical outcomes compared to LLMI ablation. METHODS: We obtained high density three-dimensional (3D) voltage mapping (CARTO) of the LA in 29 patients with persistent AF and determined the area of low voltage. In the multicenter prospective study, clinical outcomes of LAAW (n = 100) and LLMI ablations (n = 100) were compared in patients with persistent AF (79.4% male, 59.4 +/- 10.6 years). RESULTS: (1) The low-voltage area consistently existed on LAAW and had a correlation with the LA-aorta contact area (R = 0.921, P <.0001). Mean voltage of LAAW was significantly lower than that of LLMI (P <.0001). (2) The length of LAAW ablation (37.9 +/- 3.4 mm vs 26.6 +/- 3.2 mm, P <.0001) was longer, but achievement of bidirectional block was higher (68.0% vs 32.0%, P = .0001) than in LLMI ablation. Mean duration of LAAW and LLMI ablations was 19.3 +/- 2.9 minutes and 18.2 +/- 3.7 minutes, respectively (P = .086). (3) During follow-up of 23.3 +/- 7.4 months, the recurrence rate of AF after LAAW ablation (26.0%) was significantly lower than that of LLMI ablation (41.0%, P = .021) after a single procedure. CONCLUSION: The voltage map is useful for guiding linear ablation in persistent AF patients. LAAW is the most frequent low-voltage area around the mitral annulus, and linear ablation along LAAW results in a better clinical outcome with a higher rate of bidirectional conduction block compared to LLMI ablation. PMID- 20950714 TI - Positive hemodynamic and clinical response to tri-left ventricular pacing in a nonresponder to traditional cardiac resynchronization therapy. PMID- 20950715 TI - FTIR 2D correlation spectroscopy of alpha1 and alpha2 fractions of an alkali pretreated gelatin. AB - An alkali-pretreated gelatin (pI~4.9) was fractionated by means of alcohol coacervation and semi-preparative gel chromatography. The thermal responses of the isolated alpha fractions, the coacervate and the total gelatin were investigated by 2D-correlation FTIR spectroscopy in the amide I band region (1600 1700 cm-1). The gelation temperature was the same for all examined samples (24.5 degrees C) while the melting temperature of the alpha2 fraction was lower (30 degrees C) than that of the other samples (32.5 degrees C). The 2D COS plots indicate that on cooling (gelation) the core sequence of conformational changes is the same for all samples. On heating, however, the alpha2 fraction deviates from the alpha1-containing samples and shows an earlier disappearance of the triple helix signal in the event sequence. The lower melting temperature (less thermostable gelatin gel) of the alpha2 fraction thus results from a different conformational cascade of the alpha2 chains upon melting. In all samples the initial conformational changes take place in the beta-turns, providing further evidence for the models proposed previously. PMID- 20950716 TI - Production and characterization of engineered alginate-based microparticles containing ECM powder for cell/tissue engineering applications. AB - A method for the production of engineered alginate-based microparticles, containing extracellular matrix and neonatal porcine Sertoli cells (SCs), is described. As a source for extracellular matrix, a powder form of isolated and purified urinary bladder matrix (UBM) was employed. We demonstrated that the incorporation of UBM does not significantly alter the morphological and dimensional characteristics of the microparticles. The alginate microparticles were used for SC encapsulation as an immunoprotective barrier for transplant purposes, while the co-entrapped UBM promoted retention of cell viability and function. These engineered microparticles could represent a novel approach to enhancing immunological acceptance and increasing the functional life-span of the entrapped cells for cell/tissue engineering applications. In this respect, it is noteworthy that isolated neonatal porcine SCs, administered alone in highly biocompatible microparticles, led to diabetes prevention and reversion in nonobese diabetic (NOD) mice. PMID- 20950717 TI - Clinical and molecular characterization of two patients with overlapping de novo microdeletions in 2p14-p15 and mild mental retardation. AB - Here, we present two patients with overlapping de novo microdeletions in chromosome 2p14-p15, mild mental retardation concerning especially language development, as well as mild dysmorphic features. Patient 1 also presented with generalized seizures, sensorineural hearing loss, and relative microcephaly. In patient 1, molecular karyotyping detected a 2.23-Mb deletion in chromosome 2p14 p15 including 11 known genes. The second patient, with a 2.84-Mb microdeletion containing 15 genes, was identified in the DECIPHER database. The two deleted regions overlap by a stretch of 1.6 Mb that contains 10 genes, several of which have functions in neuronal development. This report illustrates the power of databases such as DECIPHER and MRNET in assessing the pathogenicity of copy number variations (CNVs). PMID- 20950718 TI - Serum proteomics signature of cystic fibrosis patients: a complementary 2-DE and LC-MS/MS approach. AB - Complementary 2D-PAGE and 'shotgun' LC-MS/MS approaches were combined to identify medium and low-abundant proteins in sera of Cystic Fibrosis (CF) patients (mild or severe pulmonary disease) in comparison with healthy CF-carrier and non-CF carrier individuals aiming to gain deeper insights into the pathogenesis of this multifactorial genetic disease. 78 differentially expressed spots were identified from 2D-PAGE proteome profiling yielding 28 identifications and postulating the existence of post-translation modifications (PTM). The 'shotgun' approach highlighted altered levels of proteins actively involved in CF: abnormal tissue/airway remodeling, protease/antiprotease imbalance, innate immune dysfunction, chronic inflammation, nutritional imbalance and Pseudomonas aeruginosa colonization. Members of the apolipoproteins family (VDBP, ApoA-I, and ApoB) presented gradually lower expression from non-CF to CF-carrier individuals and from those to CF patients, results validated by an independent assay. The multifunctional enzyme NDKB was identified only in the CF group and independently validated by WB. Its functions account for ion sensor in epithelial cells, pancreatic secretion, neutrophil-mediated inflammation and energy production, highlighting its physiological significance in the context of CF. Complementary proteomics-based approaches are reliable tools to reveal pathways and circulating proteins actively involved in a heterogeneous disease such as CF. PMID- 20950719 TI - Foreword: skeletal complications of cancer. PMID- 20950721 TI - Clinical development of anti-RANKL therapies for treatment and prevention of bone metastasis. AB - The clinical sequelae from bone metastases, termed skeletal-related events, are among the most frequent and debilitating complications in patients with advanced cancer. Bone metastases are characterized by pathologically increased osteoclast activity, and accumulating evidence indicates that tumor cells interact within the bone to stimulate the RANK-RANK ligand (RANKL) pathway. RANKL is an essential mediator of osteoclast formation, function, and survival. Because of the central role of RANKL in cancer-induced bone destruction, the inhibition of RANKL has the potential to result in the reduction of pathologic bone resorption. Denosumab is a fully human monoclonal antibody specific for RANKL that inhibits the formation, activation, and survival of osteoclasts. This in turn decreases bone resorption and reduces cancer-induced bone destruction. As a result of its unique and specific mechanism of action, denosumab is being investigated for use in patients with advanced malignancies involving bone to prevent the occurrence of skeletal related events. PMID- 20950720 TI - Teriparatide therapy enhances devitalized femoral allograft osseointegration and biomechanics in a murine model. AB - Despite the remarkable healing potential of long bone fractures, traumatic injuries that result in critical defects require challenging reconstructive limb sparing surgery. While devitalized allografts are the gold standard for these procedures, they are prone to failure due to their limited osseointegration with the host. Thus, the quest for adjuvants to enhance allograft healing remains a priority for this unmet clinical need. To address this, we investigated the effects of daily systemic injections of 40 MUg/kg teriparatide (recombinant human parathyroid hormone) on the healing of devitalized allografts used to reconstruct critical femoral defects (4mm) in C57Bl/6 mice. The femurs were evaluated at 4 and 6 weeks using micro CT, histology, and torsion testing. Our findings demonstrated that teriparatide induced prolonged cartilage formation at the graft host junction at 4 weeks, which led to enhanced trabeculated bone callus formation and remarkable graft-host integration at 6-weeks. Moreover, we observed a significant 2-fold increase in normalized callus volume (1.04 +/- 0.3 vs. 0.54 +/- 0.14 mm3/mm; p < 0.005), and Union Ratio (0.28 +/- 0.07 vs. 0.13 +/- 0.09; p < 0.005), compared to saline treated controls at 6-weeks. Teriparatide treatment significantly increased the torsional rigidity (1175 +/- 311 versus 585 +/- 408 N.mm2) and yield torque (10.5 +/- 4.2 versus 6.8 +/- 5.5 N.mm) compared to controls. Interestingly, the Union Ratio correlated significantly with the yield torque and torsional rigidity (R2=0.59 and R2=0.77, p < 0.001, respectively). These results illustrate the remarkable potential of teriparatide as an adjuvant therapy for allograft repair in a mouse model of massive femoral defect reconstruction, and warrant further investigation in a larger animal model at longer time intervals to justify future clinical trials for PTH therapy in limb sparing reconstructive procedures. PMID- 20950722 TI - Hypoxia-inducible factor-1 is a positive regulator of Sox9 activity in femoral head osteonecrosis. AB - Legg-Calve-Perthes disease (LCPD) is a juvenile form of ischemic osteonecrosis of the femoral head leading to femoral head deformity and premature osteoarthritis. Femoral head osteonecrosis occurs due to blood supply disruption which results in hypoxic injury to the femoral head. Hypoxia-inducible factor-1 alpha (HIF-1alpha) is a master regulator of cellular response to hypoxia. A pig model of ischemic osteonecrosis of femoral head has been shown to have radiographic and histopathologic changes resembling LCPD. Our preliminary studies showed that the cartilage layer was thicker in the hypoxia group compared to the control group. The mechanism underlying this cartilage response is not known. To explore the hypoxia-induced downstream gene activity following the femoral head ischemia, porcine microarray analysis of gene profiles of chondrocytes from normal and ischemic femoral heads was performed. In the ischemic side, the expression of Sox9, a transcription factor required for chondrocyte differentiation, was upregulated along with HIF-1alpha. Expressions of Sox9 target genes, such as type II collagen and aggrecan, were also increased. Microarray results were confirmed by quantitative real-time RT-PCR. In addition, immunohistochemistry assay demonstrated that both HIF-1alpha and Sox9 were upregulated in chondrocytes in ischemic femoral heads compared with normal controls. To investigate the possible molecular mechanisms of hypoxia on Sox9 activity, we tested the effect of HIF 1alpha on Sox9 expression in vitro. We made a luciferase reporter construct driven by 2kb Sox9 promoter. Transient transfection assay showed that HIF-1alpha activated Sox9 promoter activity in a dose-dependent manner. Sox9 is known to activate type II collagen target gene expression. To test the effect of HIF 1alpha on Sox9-mediated transcription, HIF-1alpha was cotransfected with Sox9 in type II collagen reporter assay. Our results demonstrated that HIF-1alpha enhanced Sox9-mediated transcriptional activity. Moreover, coimmunoprecipitation assay showed that HIF-1alpha associated with Sox9 directly. Taken together, these findings indicate that HIF-1alpha activates Sox9 expression and enhances Sox9 mediated transcriptional activity and that HIF-1alpha physically interacts with Sox9. We speculate that HIF-1alpha upregulation of Sox9 activity may have a chondroprotective role following femoral head ischemia. PMID- 20950723 TI - In vivo micro-computed tomography allows direct three-dimensional quantification of both bone formation and bone resorption parameters using time-lapsed imaging. AB - Bone is a living tissue able to adapt its structure to external influences such as altered mechanical loading. This adaptation process is governed by two distinct cell types: bone-forming cells called osteoblasts and bone-resorbing cells called osteoclasts. It is therefore of particular interest to have quantitative access to the outcomes of bone formation and resorption separately. This article presents a non-invasive three-dimensional technique to directly extract bone formation and resorption parameters from time-lapsed in vivo micro computed tomography scans. This includes parameters such as Mineralizing Surface (MS), Mineral Apposition Rate (MAR), and Bone Formation Rate (BFR), which were defined in accordance to the current nomenclature of dynamic histomorphometry. Due to the time-lapsed and non-destructive nature of in vivo micro-computed tomography, not only formation but also resorption can now be assessed quantitatively and time-dependent parameters Eroded Surface (ES) as well as newly defined indices Mineral Resorption Rate (MRR) and Bone Resorption Rate (BRR) are introduced. For validation purposes, dynamic formation parameters were compared to the traditional quantitative measures of dynamic histomorphometry, where MAR correlated with R = 0.68 and MS with R = 0.78 (p < 0.05). Reproducibility was assessed in 8 samples that were scanned 5 times and errors ranged from 0.9% (MRR) to 6.6% (BRR). Furthermore, the new parameters were applied to a murine in vivo loading model. A comparison of directly extracted parameters between formation and resorption within each animal revealed that in the control group, i.e., during normal remodeling, MAR was significantly lower than MRR (p < 0.01), whereas MS compared to ES was significantly higher (p < 0.0001). This implies that normal remodeling seems to take place by many small formation packets and few but large resorption volumes. After 4 weeks of mechanical loading, newly extracted trabecular BFR and MS were significantly higher (p < 0.01) in the loading compared to the control group. At the same time, ES was significantly decreased (p < 0.01). This indicates that modeling induced by mechanical loading takes place primarily by increased area, not width of formation packets. With these results, we conclude that the non-invasive direct technique is well suited to extract dynamic bone morphometry parameters and eventually gain more insight into the processes of bone adaptation not only for formation but also resorption. PMID- 20950725 TI - Vitamin D deficiency influences histomorphometric features of bone in primary hyperparathyroidism. AB - INTRODUCTION: Vitamin D deficiency is common in patients with primary hyperparathyroidism (PHPT). The presence of low levels of vitamin D may affect the skeletal consequences of PHPT. METHODS: In this cross-sectional study, transiliac crest bone biopsies were performed after double tetracycline labeling in patients with mild PHPT and analyzed according to serum levels of 25 hydroxyvitamin D (25OHD). RESULTS: We studied 30 patients with mild PHPT (age 53 +/- 11 years; 67% women; calcium 11.1 +/- 1.0 mg/dl; PTH 149 +/- 129 pg/ml). Serum 25OHD levels were low in the majority of subjects (mean 21 +/- 11 ng/ml) and inversely associated with PTH (r = -0.69; p < 0.01). 25OHD levels were directly associated with cortical width (Ct.Wi; r = 0.46, p < 0.03) and trabecular separation (Tb.Sp; r = 0.41; p < 0.04), but inversely associated with cancellous bone volume (BV/TV; r = -0.39, p < 0.04). Subjects with 25OHD levels < 20 ng/ml (n = 14) and >= 20 ng/ml (n = 16) were compared. Groups did not differ by age, sex, menopausal status, serum calcium, creatinine, or 1,25(OH)2D. PTH was 1.8-fold higher in subjects with 25OHD < 20 (265 +/- 166 pg/ml vs. 95 +/- 50 pg/ml; p < 0.01). On histomorphometric analysis, those with low 25OHD had lower Ct.Wi (541 +/- 167 MUm vs. 712 +/- 200 MUm; p < 0.03). Conversely, measures of trabecular microarchitecture were better in those with lower 25OHD, with higher BV/TV (26.1 +/- 6.1% vs. 20.4 +/- 6.4%; p < 0.03), greater trabecular number (Tb.N: 2.0 +/- 0.4 mm-1 vs. 1.8 +/- 0.4 mm-1; p < 0.04) and lower Tb.Sp (371 +/- 90 MUm vs. 472 +/- 137 MUm; p < 0.04). There were no differences between the groups in bone remodeling indices. CONCLUSIONS: Low levels of 25OHD in patients with PHPT are associated with higher concentrations of PTH, greater catabolic effects in cortical bone and greater anabolic effects in trabecular bone. PMID- 20950726 TI - Resistance to vaccination: the attitudes and practices of primary healthcare workers confronting the H1N1 pandemic. AB - During the H1N1 pandemic, most healthcare workers in Turkey were not willing to take up the vaccine. This qualitative study aims to explore the factors that lead to vaccination resistance among a group of primary healthcare workers in Istanbul. Data were collected through focus group discussions. Thematic content analysis was conducted. All participants considered themselves at risk for infection, yet most of them were not vaccinated. Only persons with a "poor" immune system were considered by the respondents at risk for severe disease and death. Health personnel mostly did not realize their potential role in the transmission of influenza to patients. The decision of vaccination was dependent on the information source. The personnel who depended mainly on the media either did not accept vaccination or was undecided. They believed that the vaccine went through an accelerated authorization procedure. Yet the ones who accepted vaccination relied mostly on evidence-based sources and accessed information from the guidelines of the Ministry of Health, Professional Medical Associations and the World Health Organization. Social networks were also influential factors in the decision-making process. It is important to empower healthcare workers through supporting the skills of acquiring and using evidence-based information. This is particularly important for physicians who also serve as opinion leaders. PMID- 20950727 TI - Methodology of the sensitivity analysis used for modeling an infectious disease. AB - Mathematical models may be used to help clarify dynamics of several infectious diseases. Because of the complexity of some models and the high degree of uncertainty in estimating many parameters, the present study proposes a rigorous framework for sensitivity analyses of mathematical models using as example a model to assess varicella and herpes zoster incidence. Its main steps are to assess the uncertainty of the factors to be studied, to evaluate qualitatively and quantitatively the impacts of these factors on model results, and to conduct an univariate and multivariate sensitivity analysis. The application of this technique may have considerable utility in the analysis of a wide variety of complex biological and epidemiological models. PMID- 20950728 TI - Should I or shouldn't I: decision making, knowledge and behavioral effects of quadrivalent HPV vaccination in men who have sex with men. AB - Prior to FDA licensure in men, a surgical practice (SG) offered the quadrivalent HPV vaccine (qHPV) off-label to men who have sex with men (MSM). We administered a written or telephone survey to MSM to elicit drivers and barriers to vaccination, sexual behavior changes post-vaccination, and knowledge. 191 subjects enrolled: 68 refused qHPV, 71 received qHPV <1 year ago, and 52 received qHPV >1 year ago. History of HPV infection (86%, n=164) and level of HPV and qHPV knowledge were high, with a mean of 10.8 of 13 knowledge questions correct. Ninety-seven percent of participants understood that qHPV does not cure present infection or disease. MSM refused qHPV for reasons including cost and not FDA approved; prevention of future HPV infection was the paramount driver for immunization. Vaccination did not affect sexual behavior. PMID- 20950729 TI - Feasibility of single-shot H5N1 influenza vaccine in ferrets, macaques and rabbits. AB - The feasibility of a single-shot, low-dose vaccination against pandemic influenza was investigated. The immunogenicity and safety of whole inactivated, cell culture-derived H5N1 virus plus CoVaccine HTTM as adjuvant was tested in various animal species. In ferrets, doses of 4.0 and 7.5 MUg H5N1 (NIBRG-14; A/Vietnam/1194/04; clade 1) without adjuvant gave low geometric mean haemagglutination inhibition (HI) titres (GMTs) of 21-65 three weeks after intramuscular (IM) injection. The addition of 0.25-4 mg CoVaccine HTTM resulted in GMTs of 255-1470 corresponding with 4-25-fold increases. A second immunization caused GMTs of 8914-23,525 two weeks later, which confirmed strong priming. One out of 8 ferrets injected with antigen alone and 5 out of 32 ferrets injected with adjuvanted H5N1 demonstrated minimal transient, local reactions and two animals immunized with adjuvanted H5N1 exhibited increased body temperature one day after injection. In macaques, 5 MUg H5N1 with CoVaccine HTTM or aluminium hydroxide as adjuvant elicited GMTs of 172 and 11, respectively three weeks later. A second immunization resulted in GMTs of 1751 and 123, respectively four weeks later. Analysis of cross-reactivity of antibodies after the first immunization with NIBRG-14 adjuvanted plus CoVaccine HTTM revealed GMTs of 69 against NIBRG-23 (A/turkey/Turkey/1/05; clade 2.2) and 42 against IBCDC-RG-2 (A/Indonesia/5/05-like; clade 2.1.3) while titres with aluminium hydroxide were <10. After the second immunization with CoVaccine HTTM, GMT against NIBRG-23 was 599 and against IBCDC-RG-2 254, while those with aluminium hydroxide were 23 and 13, respectively. No local or systemic adverse events were detected in macaques. Safety of 5 MUg H5N1 plus 0, 2 or 4 mg CoVaccine HTTM was investigated in a repeated dose study in rabbits. Groups of 6 or 9 male and female animals were immunized IM three times at three week intervals. None of the animals exerted treatment-related adverse reactions during the study or at necropsy 3 or 4 days after treatment. We concluded that a low dose of whole inactivated influenza virus plus CoVaccine HTTM is a promising, single-shot vaccine against pandemic influenza. PMID- 20950730 TI - Significance of topoisomerase IIIbeta expression in breast ductal carcinomas: strong associations with disease-specific survival and metastasis. AB - Topoisomerases are ubiquitous nuclear enzymes that regulate DNA structure in eukaryotic cells. The role of topoisomerase IIIbeta, the newest member of the topoisomerase family, in the clinical outcome of breast cancer is still poorly understood. This study aims to investigate the immunoexpression of topoisomerase IIIbeta in breast cancer and its relationships with clinicopathologic features and immunohistochemical markers of prognostic significance in breast pathology. Using tissue microarrays containing 171 cases of primary invasive breast cancer, we analyzed the immunoexpression of topoisomerase IIIbeta, estrogen receptor, progesterone receptor, HER-2, BRCA-1, p53, and Ki67. Immunostaining for topoisomerase IIIbeta was found in 33.9% of breast carcinomas, and immunopositivity was correlated with distant metastasis (P = .036) and death (P = .006). Decreased expression of topoisomerase IIIbeta correlated with low expression of Ki67 (P < .001) and negativity for HER-2 (P < .001), BRCA-1 (P = .001), and p53 (P < .001). In the multivariate analysis, topoisomerase IIIbeta expression was a significant predictor of survival (hazard ratio, 3.006 [95% confidence interval, 1.582-5.715]; P = .001). In conclusion, topoisomerase IIIbeta expression can be a useful marker in assessing the prognosis of patients with breast cancer and is an independent predictor of survival. PMID- 20950731 TI - A randomized, double-blind, active-controlled, parallel-group pilot study to compare the efficacy and sedative effects of desloratadine 5 mg with levocetirizine 5 mg in the treatment of chronic idiopathic urticaria. PMID- 20950732 TI - Imatinib treatment of generalized localized scleroderma (morphea). PMID- 20950735 TI - Nodular melanomas associated with nevi. PMID- 20950736 TI - A noninvasive technique, reflectance confocal microscopy, for the characterization of melanocyte loss in untreated and treated vitiligo lesions. PMID- 20950737 TI - Recognizing psoriatic arthritis in the dermatology clinic. AB - Dermatologists care for patients with psoriasis in whom there exists an inherent risk of psoriatic arthritis, a condition with potential for causing joint damage and subsequent disability. Most patients have psoriasis for years before the development of psoriatic arthritis, and there may be a significant proportion of psoriasis patients with joint involvement that are cared for by the dermatologist. With the absence of a diagnostic measure, the criterion standard for recognizing or monitoring psoriatic arthritis remains the clinical assessment. Recognition of psoriatic arthritis in the psoriasis patient--and the dermatologist's ability to differentiate it from other types of arthritis- provide an opportunity to improve patient outcomes through early recognition and facilitation of intervention in collaboration with a rheumatologist. PMID- 20950738 TI - Mohs micrographic surgery at the Skin and Cancer Foundation Australia, 10 years later (1997 vs 2007). AB - BACKGROUND: Mohs micrographic surgery (MMS) provides a combination of high cure rate and tissue conservation. Epidemiologic factors and changes in techniques may affect the way MMS is performed. OBJECTIVE: We sought to evaluate changes over time in the type of patients and skin cancers that are treated using MMS, and the repairs used to close the defects. METHODS: We conducted a retrospective study on patients treated with MMS at the Skin and Cancer Foundation Australia, Westmead, in 1997 against those treated in 2007. Patient demographics (age, sex), pathology of tumor, anatomic site of the tumor, preoperative tumor size, postoperative defect size, and repair method were analyzed. RESULTS: There was a 260% increase in the number of procedures (596 in 1997 vs 1587 in 2007). The 2007 cohort was a little older (62 vs 64 years), but there were no differences in sex, anatomic site, rate of basal/squamous cell carcinoma, squamous cell carcinoma histologic subtypes, or preoperative tumor size. However, there were fewer superficial basal cell carcinomas, and the postoperative defect size was smaller in 2007 (P < .0001). There was also a decrease in the use of grafts and second-intention healing to close the defects and an increase in the number of side-to-side closures (P < .0001). LIMITATIONS: Retrospective study at one institution is a limitation. CONCLUSION: Although tumor size and the percentage of tumors in each anatomic site did not change over 10 years, the size of the defect created after MMS has become smaller. This reduction in defect size may explain why more defects are now repaired by side-to-side closure and flap repairs whereas fewer defects are repaired by skin grafting. PMID- 20950739 TI - Modifying the Burow's triangles of traditional transposition flaps for the repair of adjacent nasal defects. AB - BACKGROUND: Adjacent defects are commonly encountered during Mohs micrographic surgery for nasal skin cancers and often present a formidable reconstructive challenge. OBJECTIVE: This article will describe similar modifications of both the bilobed and nasolabial transposition flaps' Burow's triangles that allow for the repair of two adjacent defects of the distal nose using a single flap. METHODS: This is a report of two similar reconstructive cases after Mohs micrographic surgery requiring the repair of adjacent nasal defects. RESULTS: Both cases demonstrate the feasibility of this technique. LIMITATIONS: This technique is based on two case reports. CONCLUSIONS: Traditional transposition flaps' Burow's triangles can be effectively modified for the repair of properly selected adjacent wounds of the distal nose. PMID- 20950740 TI - P75 nerve growth factor receptor staining is superior to S100 in identifying spindle cell and desmoplastic melanoma. AB - BACKGROUND: Spindle cell melanoma (SCM) including desmoplastic melanoma (DM) is a rare variant of malignant melanoma that may present diagnostic difficulties particularly when staining with S100 is negative, weak, focal, or a combination of these. Conventional melanocytic markers in SCM are usually negative. OBJECTIVE: We sought to compare the staining of p75 nerve growth factor receptor (NGF-R) and S100 in SCMs. METHODS: We evaluated the staining of p75 NGF-R and S100 in 13 cases of SCMs: 3 SCMs without desmoplasia, 5 pure DMs, and 5 combined DMs with a conventional component. RESULTS: Staining with p75 NGF-R was positive in 13 of 13 (100%) cases of SCMs. In 3 cases the intensity of staining and the percentage of cells staining with this marker were greater than those with S100. One case of SCM was negative for S100 but demonstrated strong expression of p75 NGF-R. One case was focally and weakly positive with S100 but expressed strong positive staining with p75 NGF-R. Absence of staining with p75 NGF-R was noted in the conventional round cell component of two of 5 (40%) combined DMs whereas the same areas were strongly positive for human melanoma black (HMB)-45 and Melan-A. In 5 of 5 (100%) cases of combined DMs the desmoplastic component stained positive with p75 NGF-R, demonstrating an inverse relationship with the staining of conventional melanocytic markers. LIMITATIONS: Small study size was a limitation. CONCLUSION: p75 NGF-R exhibits superior staining characteristics and greater sensitivity in identifying SCM and DMs than S100. P75 NGF-R may be a useful diagnostic and ancillary stain in addition to S100. PMID- 20950741 TI - Treatment of cutaneous myiasis associated with scalp psoriasis in a 13-year-old girl with oral ivermectin. PMID- 20950742 TI - Dermatologists and the Internet. PMID- 20950743 TI - "Eruptive postoperative squamous cell carcinomas" or "hypertrophic lichen planus like reactions combined with infundibulocystic hyperplasia"? PMID- 20950744 TI - Percutaneous absorption of potent topical corticosteroids in patients with severe atopic dermatitis. PMID- 20950745 TI - JAAD Grand Rounds quiz. Chronic urticarial eruption. PMID- 20950746 TI - JAAD Grand Rounds quiz. Serpiginous eruption on the leg. PMID- 20950747 TI - JAAD Grand Rounds quiz. Reticulated rash on the anterior thighs. PMID- 20950748 TI - Power: staying charged when it matters. PMID- 20950753 TI - Clicks vs. bricks. PMID- 20950754 TI - Down & dirty: debunking decontamination. PMID- 20950756 TI - Humility: why do we kneel? PMID- 20950757 TI - No room to err: choosing adjunct airway devices in life-or-death moments. PMID- 20950759 TI - Jems 2010 salary & workplace survey: an employee's journey. AB - Keisha Johnson sits unusually straight in her chair and holds securely to her application packet. The waiting area is filled with other EMT and paramedic candidates applying for open positions at Page Paramedics, a not-for-profit ambulance service that partners with fire departments to provide emergency ALS transport. Keisha completed her paramedic program in the fall and worked for a small inter-facility transport service on nights and weekends while she went to school, but this would be her first paramedic position and chance to do traditional EMS work. PMID- 20950760 TI - Communication breakdown: EMS' struggle to get on the same wavelength. PMID- 20950761 TI - Lead the charge: keep your batteries functioning optimally for best patient care. PMID- 20950762 TI - Airway basics: five tips for better respiratory management. PMID- 20950764 TI - Zinc and cardiovascular disease. AB - Zinc is a vital element in maintaining the normal structure and physiology of cells. The fact that it has an important role in states of cardiovascular diseases has been studied and described by several research groups. It appears to have protective effects in coronary artery disease and cardiomyopathy. Intracellular zinc plays a critical role in the redox signaling pathway, whereby certain triggers such as ischemia and infarction lead to release of zinc from proteins and cause myocardial damage. In such states, replenishing with zinc has been shown to improve cardiac function and prevent further damage. Thus, the area of zinc homeostasis is emerging in cardiovascular disease research. The goal of this report is to review the current knowledge and suggest further avenues of research. PMID- 20950765 TI - Does methionine restriction cause hyperhomocysteinemia? PMID- 20950766 TI - Why routine intensive care unit admission after elective open infrarenal Abdominal Aortic Aneurysm repair is no longer an evidence based practice. AB - BACKGROUND: Elective open infrarenal Abdominal Aortic Aneurysm (AAA) repair is major surgery performed on high-risk patients. Routine ICU admission postoperatively is the current accepted standard of care. Few of these patients actually require a level of care that cannot be provided just as effectively in a surgical high dependency unit (HDU). Our aim was to determine, 'can high risk patients that will require ICU admission postoperatively be reliably identified preoperatively?'. METHODS: A retrospective analysis of all elective open infrarenal AAA repairs in our institution over a 3-year period was performed. The Estimation of Physiological Ability and Surgical Stress (E-PASS) model was used as our risk stratification tool for predicting post-operative morbidity. Renal function was also considered as a predictor of outcome, independent of the E PASS. RESULTS: 80% (n = 16) were admitted to ICU. Only 30% (n = 6) of the total study population necessitated intensive care. There were 9 complications in 7 patients in our study. The E-PASS comprehensive risk score (CRS)/Surgical stress score (SSS) were found to be significantly associated with the presence of a complication (p = 0.009)/(p = 0.032) respectively. Serum creatinine (p = 0.013) was similarly significantly associated with the presence of a complication. CONCLUSIONS: The E-PASS model possessing increasing external validity is an effective risk stratification tool in safely deciding the appropriate level of post-operative care for elective infrarenal AAA repairs. PMID- 20950767 TI - Diagnostic value of MR arthrogram in SLAP lesions of the shoulder. AB - BACKGROUND: Superior labrum anterior to posterior (SLAP) lesions are important cause of shoulder pain and instability. MR Arthrogram is key investigation for assessment of these lesions. We aimed this study to evaluate the diagnostic performance of MR Arthrogram in SLAP tears. MATERIALS AND METHODS: This was a retrospective study of 124 clinically diagnosed SLAP cases who had MR Arthrogram performed. Clinical, radiological and operative records were reviewed. MR Arthrogram findings were compared with arthroscopy. Those patients who did not undergo arthroscopy were not included in the final sensitivity analysis. RESULTS: Out of 124 cases, 54(43.54%) had normal MR Arthrogram, 32 (25.8%) had impingement or cuff related problems, 2 (1.61%) had Bankart lesions, and in 36 (29%) cases SLAP lesions were identified. Out of 54 patients with normal MR Arthrogram, 44 were discharged to physiotherapy and 10 underwent arthroscopy, showing SLAP lesion in one patient. Out of 32 patients with impingement or cuff problems, 19 were discharged to rehabilitation and 13 underwent surgery. Out of 36 patients with SLAP lesions, 5 recovered spontaneously, 5 were awaiting outpatient review and 26 underwent arthroscopy showing SLAP lesions in 22 cases. Overall, only 51 patients underwent arthroscopy. The MR Arthrogram was falsely positive in 4 cases (15.38%) and falsely negative in one case (3.84%). The sensitivity of MR Arthrogram was 95.6% (22/23), specificity 85.7% (24/28), positive predictive value 84.6% (22/26) and the negative predictive value was 96% (24/25). CONCLUSION: MR Arthrogram is a useful technique for the diagnosis and preoperative planning of suspected SLAP lesions. It may also save patients from unnecessary diagnostic arthroscopy. PMID- 20950768 TI - Age-specific incidence of hip fracture in the elderly: a healthy decline. AB - Hip fractures in the elderly are an important source of morbidity and mortality. The predicted increase in the number of hip fractures due to the increasing elderly population has not been universally observed. The purpose of this study was to examine the incidence of hip fractures over a twenty year period to determine if this rise is occurring in our region. All hip fractures from the unit over 20 years were identified. Population data for those over 65 in the catchment area of our hospital was acquired. The rate of fractures occurring each year relative to the population was determined. The results were split into age groups. There was a strong correlation between the population rise and number of fractures (p = 0.77). But there was no significant difference in the rate of fracture over time (p = 0.41). However, the average age at which fracture occurred increased by two years. In addition we show the overall trend in the rate of fractures decreases in the younger age groups and increases in the older age groups. Therefore, the predicted rapid increase in rate is not occurring. This probably reflects the strengthening of the economy in Ireland from the 1930's onwards, leading to a healthier population. PMID- 20950769 TI - An evaluation of Irish general surgical research publications from 2000 to 2009. AB - BACKGROUND: Maintaining a high standard of research, and being competitive in the funding application process requires a coordinated and focused research strategy. The first step in the formulation of such a strategy is the identification of those centres, and specifically those areas of study, in which Irish surgical research has previously performed strongly. The aim of this paper was to evaluate all surgical research produced in the Republic of Ireland in the first ten years of the new millennium. METHODS: All publications originating from adult Irish general surgical units between the years 2000-2009 were identified from Pubmed and Medline databases. All publications were examined for senior author, originating institute, theme, research model and publishing journal. RESULTS: There were a total of 590 publications in Irish general surgical units during the study period. The top publishing hospitals were Institution 1 (129:21%), Institution 2 (82:13.9%) and Institution 3 (81:13.7%). One hundred and thirty three papers were published in journals with impact factors > 4.5. Papers were more likely to be published in journals with impact factors > 4.5 if they came from Institution 1 (38 papers) p = 0.001, published on breast (50 papers) p < 0.001 or upper gastrointestinal topics (35 papers) p < 0.001, or published on bench research (76 papers) p < 0.001. Publications increased from the first half of the decade to the second, with the largest increases seen in Institution 1 (40 89), Institution 4 (21-42) and Institution 6 (11-37). CONCLUSIONS: Ireland continues to produce high quality surgical research, characterised by number of articles produced per 106 inhabitants. This study shows that the number of articles published in the second half of the decade almost doubled from 221 to 369 and that the mean journal impact factor for all articles published was 2.87. PMID- 20950770 TI - Is the structure of anatomy curriculum adequate for safe medical practice? AB - INTRODUCTION: Anatomy has been considered a core subject within the medical education curriculum. In the current setting of ever-changing diagnostic and treatment modalities, the opinion of both students and trainers is crucial for the design of an anatomy curriculum which fulfils the criteria required for safe medical practice. METHODS: Medical students, trainees and specialist trainee doctors and specialists from the London (England) area were surveyed to investigate the how curriculum changes have affected the relevance of anatomical knowledge to clinical practice and to identify recommendations for optimum teaching methods. The survey employed 5-point Likert scales and multiple-choice questions. Where the effect of training level was statistically significant (p < 0.05), post-hoc analysis was carried out using Mann-Whitney U tests. Significance levels were modified according to the Bonferroni method. RESULTS: Two hundred and twenty-eight individuals completed the survey giving a response rate of 53%. Medical students, trainees and specialists all agreed (mean Likert score 4.51, 4.79, 4.69 respectively) that knowledge of anatomy is important for medical practice. Most of the trainees (88.4%) and specialists (81.3%) used dissection to learn anatomy, but only 61.4% of medical students used this approach. Dissection was the most commonly recommended approach for learning anatomy across all the groups (41.7%-69.3%). CONCLUSIONS: Knowledge of anatomy is perceived to be important for safe clinical practice. Anatomy should be taught with other relevant system or clinical modules. Newer tools for anatomy teaching need further validation before incorporation into the curriculum. PMID- 20950771 TI - Therapeutic value and outcome of gastric access loops created during hepaticojejunostomy for iatrogenic bile duct injuries. AB - BACKGROUND AND PURPOSE: Hepaticojejunostomy is the reconstructive procedure performed for iatrogenic bile duct injuries. Anastomotic site stricture is the most significant complication of this operation. Revision surgery is associated with a significant morbidity and mortality. Creation of access to the anastomotic site facilitates the management of such strictures by minimal access techniques and reduces the need for revision surgery. This retrospective study aims to investigate the technical accessibility, usefulness, morbidity related to and the outcome of hepaticojejunostomy with gastric access loops performed as the treatment for iatrogenic bile duct injuries. METHODOLOGY: Twenty-seven consecutive patients who have undergone hepaticojejunostomy (including three revision surgeries and a re-revision surgery) with gastric access loops from July 2005 to October 2009 were followed up for clinical, biochemical, radiological and endoscopic evidence of anastomotic site occlusion and the need for intervention. Morbidity related to gastric access loops was assessed by dyspepsia disability score. RESULTS: Mean follow up was 35.4 (range 6-61) months. Three patients developed anastomotic strictures at 4, 22 and 5 months after hepaticojejunostomy and had successful endotherapy via the gastric access loop. They remain well at 33rd, 31st and 3rd months, respectively, following intervention. Based on the dyspepsia disability score none of the patients had symptomatic dyspepsia affecting daily activities. CONCLUSIONS: Gastric access loop is accessible and useful for stricture dilation and other endotherapeutic procedures. In the absence of significant symptoms related to bile reflux, gastric access loop could be considered as a useful and safe adjunct in the management of hepaticojejunostomy by surgeons especially in settings with limited facilities and expertise for radiological manipulations. PMID- 20950772 TI - Outcomes of emergency colectomy for fulminant Clostridium difficile colitis. AB - INTRODUCTION: Clostridium difficile has become increasingly a common cause of nosocomial infection with increasing antibiotic usage. Recently there has been an increase in the incidence of patients undergoing colectomy for fulminant C. difficile colitis (FCDC). Early surgical consultation is necessary to avoid delay in diagnosis. We present a retrospective review of the outcomes of colectomies for FCDC at our large district general hospital. MATERIALS AND METHODS: Over a twenty one month period, from January 2007 to September 2009, a total number of 20 patients underwent exploratory laparotomy for FCDC. A retrospective analysis of patients' case notes, was carried out retrieving all relevant. Data on haematology, biochemistry and imaging were extracted from the trust's on-line clinical databases. RESULTS: A total number of 528 diagnosed cases with C. difficile infection were identified. Of these, twenty patients underwent colectomy for FCDC (3.7%). All patients had received antibiotics prior to symptoms development. 45% of patients had multiple antibiotics. 35% of patients developed FCDC after having three doses of prophylactic antibiotic (Cefuroxime) for a surgical procedure. Time from referral to having surgery varied. Seventeen patients received subtotal colectomy and end ileostomy in a single operation. Mortality rate was 40%. CONCLUSION: Emergency colectomy for FCDC is associated with high mortality rate. The majority of patients who have significant co morbidities (75%) did not survive following emergency colectomy. Therefore, it is crucial to identify those patients early in their disease course before they progress into FCDC and organ failure. PMID- 20950773 TI - An automated assessment algorithm for micro-CT images of occlusal caries. AB - OBJECTIVES: To produce and test an algorithm to automatically quantify natural occlusal caries lesions in micro-computed tomography (micro-CT) scans of human teeth. METHODS: The algorithm presented divides the occlusal surface into regions of enamel and dentine by looking for sharp increases and decreases in radiopacity characteristic of step changes between materials. The accuracy of an automatic occlusal caries assessment based on these regions is assessed against serial histological assessment and manual examination of the same micro-CT images, using data from 68 previously scanned and sectioned teeth with varying levels of natural occlusal caries. RESULTS: Only three teeth were found to be free of caries by histology. The results of the automated analysis correlate well with histological assessment with a rho of 0.80 (p < 0.001), and with manual CT assessment with a rho of 0.85 (p < 0.001). The depth of dentine lesions correlated with histology with an intra-class correlation coefficient of 0.82 (p < 0.001; N = 45) and with manual assessment with an ICC of 0.93 (p < 0.001; N = 39). Micro-CT is found to generally underestimate caries compared to histological assessment. CONCLUSIONS: The algorithm presented can successfully segment micro CT scans into occlusal enamel and dentine regions, and the results show that the depths of dentine caries lesions can be accurately and objectively measured automatically using micro-CT. However, if enamel caries is to be accurately assessed by a computer, better scans will be required than those used here. PMID- 20950774 TI - Impact of surgeon volume on outcomes of rectal cancer surgery: a systematic review and meta-analysis. AB - AIM: To clarify the relationship between surgeon caseload and patient outcomes for patients undergoing rectal cancer surgery in order to inform debate about organisation of services. METHODS: We searched Medline and Embase for articles published up to March 2010, and included studies examining surgeon caseload and outcomes in rectal cancer patients treated after 1990. Outcomes considered were 30-day mortality, overall survival, anastomotic leak, local recurrence, permanent stoma and abdominoperineal excision rates. We assessed the risk of bias in included studies and performed random effects meta-analyses based on both unadjusted and casemix adjusted data. RESULTS: Eleven included studies enrolled 18,301 rectal cancer patients undergoing resective surgery. Unadjusted meta analysis showed a statistically significant benefit in favour of high volume surgeons for 30-day postoperative mortality (OR = 0.57, 95% CI: 0.43-0.77; based on three studies, 4809 patients) and overall survival (HR = 0.76, 95% CI 0.63 0.90; based on two studies, 1376 patients), although the former relationship was attenuated and non-significant when based on two studies (9685 patients) that adjusted for casemix (OR = 0.79, 95% CI: 0.59-1.06). Pooling of three studies (2202 patients) showed no significant relationship between surgeon volume and anastomotic leak rate. Permanent stoma formation was less likely for high volume surgeons (adjusted OR = 0.75, 95% CI: 0.64 to 0.88; based on two studies, 9685 patients) and APER rates were lower for high volume surgeons (unadjusted OR = 0.58, 95% CI: 0.45 to 0.76); based on six studies, 3921 participants. CONCLUSIONS: This review gives evidence that higher surgeon volume is associated with better overall survival, lower permanent stoma and APER rates. PMID- 20950775 TI - Patterns and management of vascular injuries in intravenous drug users: a literature review. AB - BACKGROUND: Intravenous drug use is becoming an increasing problem in today's society causing an enormous socio-economic burden. Any intravenous injection will carry a risk of vascular injury. However, this risk will be significantly increased with repeated injections. With ongoing injection drug misuse, individuals are at risk of serious complex vascular injuries that can masquerade as simple illnesses. METHODS: A comprehensive Medline search was conducted to identify key articles related to vascular injuries in intravenous drug users (IVDUs). RESULTS: Numerous arterial and venous injuries have been described as a result of intravenous drug use. This article reviews the literature to identify appropriate management of the peripheral vascular injuries encountered more and more often in this group of patients. Recommendations for investigation and treatment are made. CONCLUSION: Intravenous drug users are notoriously difficult to treat and present late in the course of their illnesses. Despite management problems, it is important to have a high index of suspicion for serious vascular problems. Education and awareness of both patients and health care professionals may lead to earlier diagnosis and treatment of these conditions which carry significant morbidity and mortality. PMID- 20950776 TI - Current issues in surgical education. PMID- 20950777 TI - Histone chaperone Jun dimerization protein 2 (JDP2): role in cellular senescence and aging. AB - Transcription factor Jun dimerization protein 2 (JDP2) binds directly to histones and DNA, and inhibits p300-mediated acetylation of core histones and reconstituted nucleosomes that contain JDP2-recognition DNA sequences. The region of JDP2 that encompasses its histone-binding domain and DNA-binding region is essential to inhibit histone acetylation by histone acetyltransferases. Moreover, assays of nucleosome assembly in vitro demonstrate that JDP2 also has histone chaperone activity. The mutation of the region responsible for inhibition of histone acetyltransferase activity within JDP2 eliminates repression of transcription from the c-jun promoter by JDP2, as well as JDP2-mediated inhibition of retinoic-acid-induced differentiation. Thus JDP2 plays a key role as a repressor of cell differentiation by regulating the expression of genes with an activator protein 1 (AP-1) site via inhibition of histone acetylation and/or assembly and disassembly of nucleosomes. Senescent cells show a series of alterations, including flatten and enlarged morphology, increase in nonspecific acidic beta-galactosidase activity, chromatin condensation, and changes in gene expression patterns. The onset and maintenance of senescence are regulated by two tumor suppressors, p53 and retinoblastoma proteins. The expression of p53 and retinoblastoma proteins is regulated by two distinct proteins, p16(Ink4a) and Arf, respectively, which are encoded by cdkn2a. JDP2 inhibits recruitment of the polycomb repressive complexes 1 and 2 (PRC-1 and PRC-2) to the promoter of the gene that encodes p16(Ink4a) and inhibits the methylation of lysine 27 of histone H3 (H3K27). The PRCs associate with the p16(Ink4a)/Arf locus in young proliferating cells and dissociate from it in senescent cells. Therefore, it seems that chromatin-remodeling factors that regulate association and dissociation of PRCs, and are controlled by JDP2, might play an important role in the senescence program. The molecular mechanisms that underlie the action of JDP2 in cellular aging and replicative senescence by mediating the dissociation of PRCs from the p16(Ink4a)/Arf locus are discussed. PMID- 20950778 TI - Efficacy and safety of the doxazosin gastrointestinal therapeutic system for the treatment of benign prostate hyperplasia. AB - This study was carried out to obtain information on the efficacy and safety of the controlled release formulation of the doxazosin Gastrointestinal Therapeutic System (GITS) in Taiwanese subjects with benign prostatic hyperplasia (BPH). Studies of doxazosin in Asian populations for this indication have lacked data particularly from Taiwan. This was an 8-week, post-marketing, open-label, non comparative study. Eighty male subjects (mean age=64 years) with BPH received doxazosin GITS 4 mg once daily. At week 4, subjects who achieved an increase in maximum urinary flow rate (Qmax) of >=3mL/s and a >=30% reduction in the total International Prostate Symptom Score (IPSS) continued on doxazosin GITS 4 mg for the remaining 4 weeks; all other subjects were up-titrated to 8 mg once daily. Change from baseline at weeks 4 and 8 (primary endpoint) in IPSS and Qmax was evaluated using two-sided paired t tests for the intent-to-treat population. Safety was assessed throughout the study. A total of 53 (66.3%) subjects completed the study. Baseline Qmax and IPSS were 10.7+3.4 mL/s and 20.6+5.4, respectively. At week 8, a significant increase from baseline in Qmax of 3.3+4.6 mL/s (95% confidence interval = 2.2-4.4, p< 0.001) and a significant decrease in total IPSS of -8.9 + 7.0 (95% confidence interval=-10.5 to -7.3, p< 0.001) was observed. The most common treatment-related adverse event was dizziness. Doxazosin GITS 4 mg per day (with an 8-mg titration step) effectively improved symptoms of BPH. The results from this study provide further information for clinicians on the use of doxazosin GITS for the treatment of BPH, particularly in Taiwanese patients. PMID- 20950779 TI - Comparison of left ventricular diastolic parameters between patients with and without significant mitral regurgitation. AB - Mitral regurgitation (MR) can affect left ventricular diastolic parameters because of interference with regurgitation flow. This study compared left ventricular diastolic parameters between patients with and without significant MR. The MR group included 57 consecutive patients with significant MR. Fifty seven age-, sex- and Tei index-matched patients without significant MR were selected as the reference group. Baseline characteristics and Tei index and its components were comparable between the MR and reference groups. The MR group had higher left atrial volume index, transmitral E wave velocity (E), ratio of E to transmitral A wave velocity, early diastolic mitral annular velocity (Ea), E/Ea, and ratio of E to isovolumic relaxation flow propagation velocity (IRFPV) (p <= 0.025), and lower E-wave deceleration time (p = 0.019) and late diastolic mitral annular velocity (p < 0.001). However, the two groups had similar IRFPV (p = 0.844). In conclusion, MR apparently affects E and Ea, but not IRFPV. IRFPV could potentially be a reliable relaxation parameter in patients with significant MR, but further confirmation by invasive studies is needed. PMID- 20950780 TI - Frontal function, disability and caregiver burden in elderly patients with major depressive disorder. AB - Caregivers of patients with late-life major depressive disorder experience a significant level of general caregiver burden. Disability in patients is possibly one of the origins of caregiver burden. Frontal lobe dysfunction might be the source of disability. This study investigated if frontal lobe dysfunction (body level) of patients with late-life major depressive disorder was associated with their disability (individual level), and if it led to a high level of caregiver burden (societal level). Thirty-four unselected pairs of caregivers and their family members with late-life major depressive disorder were recruited. Frontal Assessment Battery and Timed Instrumental Activities of Daily Living (TIADL) were used to assess patients' frontal function and disability, and Caregiver Burden Inventory was used to measure caregiver burden. Frontal Assessment Battery correlated with TIADL (r= -0.47; p<0.006). TIADL score was also associated with two subscales of the Caregiver Burden Inventory: social (r = 0.38, p=0.026) and time-dependent (r= 0.37, p= 0.033). This study supported the hypothesis that frontal lobe dysfunction in elderly patients with depression is associated with their disability in instrumental activities of daily living. Disability is related to social and time-dependent aspects of caregiver burden. Further studies to examine proposed cognitive interventions are suggested to reduce patient disability and caregiver burden. PMID- 20950781 TI - Intrarenal epidermal cyst. AB - Although renal cystic formations are seen frequently and arise with diverse symptoms, epidermal cyst is a very unusual cause of renal masses. A50-year-old woman was admitted to our clinic because of lumbar pain, hematuria and dysuria that lasted for 2 months. An atrophic and dysfunctional right kidney was identified. Transperitoneal laparoscopic simple nephrectomy was performed. Microscopic examination revealed typical findings of epidermoid cyst. According to the literature, intrarenal epidermal cysts are usually treated by nephrectomy because they cannot be differentiated from renal masses. To the best of our knowledge, this case report of an epidermoid cyst located in the renal parenchyma of a female patient is the first in the English-language literature. PMID- 20950782 TI - Metastatic gallbladder cancer presenting as a gingival tumor and deep neck infection. AB - Gallbladder cancer has an extremely poor prognosis because it is often diagnosed at an advanced stage. We describe a 63-year-old woman who was treated 4 years previously for gallbladder cancer, with laparoscopic cholecystectomy and secondary hepatectomy after presenting with acute cholecystitis and gallbladder rupture. At her second presentation, she had a left lower gingival tumor and deep neck infection. Incision and drainage and tumor biopsies were performed, and pathology at both sites revealed adenocarcinoma. Positron emission tomography revealed other tumors in the left breast and left lower lung field, which were both proven to be adenocarcinoma by biopsy. The patient's presentation with a metastatic oral tumor was rare. Although the incidence is very low, physicians should consider the possibility of metastatic cancer in a patient with a history of cancer, who presents with new oral tumor or deep neck infection. PMID- 20950783 TI - Primary ocular caruncular basal cell carcinoma in a Chinese patient. AB - Although basal cell carcinoma (BCC) is the most common eyelid neoplasm, BCC that originates from the lacrimal caruncle is extremely rare. To the best of our knowledge, only seven cases have been reported and here we report the first documented primary caruncular BCC in an Oriental patient. A 73-year-old Chinese man presented with a telangiectatic, multilobulated, pigmented tumor that measured 5*5 mm, which had arisen from the lacrimal caruncle of the left eye 3 months previously. The patient underwent tumor excision, and histopathological examination revealed BCC. He received adjuvant chemotherapy with intra-arterial methotrexate (30 mg/m(2)). A nodular pigmented BCC recurred in the bulbar conjunctiva close to the original tumor 3 months later, and he underwent a second excision. Bleomycin (8.5 mg/m(2) monthly) was added to the chemotherapy regimen, which was changed to fluorouracil (300 mg/m(2) monthly) 2 months later. The tumor did not recur during follow-up of 22 months. Malignant tumors of the caruncle are infrequent. BCC should be considered in the differential diagnosis of a pigmented caruncular lesion. PMID- 20950784 TI - Croup-induced postobstructive pulmonary edema. AB - Postobstructive pulmonary edema is life-threatening, and results from a sudden episode of upper airway obstruction. Croup is generally thought to be a benign condition, but occasionally it can develop into postobstructive pulmonary edema. We present a case of a 5-year-old boy with recurrent croup, who was diagnosed with postobstructive pulmonary edema. Our experience alerts pediatricians to this easily misdiagnosed disease. PMID- 20950786 TI - A genome-wide study reveals copy number variants exclusive to childhood obesity cases. AB - The prevalence of obesity in children and adults in the United States has increased dramatically over the past decade. Genomic copy number variations (CNVs) have been strongly implicated in subjects with extreme obesity and coexisting developmental delay. To complement these previous studies, we addressed CNVs in common childhood obesity by examining children with a BMI in the upper 5(th) percentile but excluding any subject greater than three standard deviations from the mean in order to reduce severe cases in the cohort. We performed a whole-genome CNV survey of our cohort of 1080 defined European American (EA) childhood obesity cases and 2500 lean controls (< 50(th) percentile BMI) who were genotyped with 550,000 SNP markers. Positive findings were evaluated in an independent African American (AA) cohort of 1479 childhood obesity cases and 1575 lean controls. We identified 17 CNV loci that were unique to at least three EA cases and were both previously unreported in the public domain and validated via quantitative PCR. Eight of these loci (47.1%) also replicated exclusively in AA cases (six deletions and two duplications). Replicated deletion loci consisted of EDIL3, S1PR5, FOXP2, TBCA, ABCB5, and ZPLD1, whereas replicated duplication loci consisted of KIF2B and ARL15. We also observed evidence for a deletion at the EPHA6-UNQ6114 locus when the AA cohort was investigated as a discovery set. Although these variants may be individually rare, our results indicate that CNVs contribute to the genetic susceptibility of common childhood obesity in subjects of both European and African ancestry. PMID- 20950787 TI - Infantile cerebral and cerebellar atrophy is associated with a mutation in the MED17 subunit of the transcription preinitiation mediator complex. AB - Primary microcephaly of postnatal onset is a feature of many neurological disorders, mostly associated with mental retardation, seizures, and spasticity, and it typically carries a grave prognosis. Five infants from four unrelated families of Caucasus Jewish origin presented soon after birth with spasticity, epilepsy, and profound psychomotor retardation. Head circumference percentiles declined, and brain MRI disclosed marked cereberal and cerebellar atrophy with severe myelination defect. A search for a common homozygous region revealed a 2.28 Mb genomic segment on chromosome 11 that encompassed 16 protein-coding genes. A missense mutation in one of them, MED17, segregated with the disease state in the families and was carried by four of 79 anonymous Caucasus Jews. A corresponding mutation in the homologous S.cerevisiae gene SRB4 inactivated the protein, according to complementation assays. Screening of MED17 in additional patients with similar clinical and radiologic findings revealed four more patients, all homozygous for the p.L371P mutation and all originating from Caucasus Jewish families. We conclude that the p. L371P mutation in MED17 is a founder mutation in the Caucasus Jewish community and that homozygosity for this mutation is associated with infantile cerebral and cerebellar atrophy with poor myelination. PMID- 20950788 TI - De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment. AB - Heterozygous mutations in FOXP2, which encodes a forkhead transcription factor, have been shown to cause developmental verbal dyspraxia and language impairment. FOXP2 and its closest homolog, FOXP1, are coexpressed in brain regions that are important for language and cooperatively regulate developmental processes, raising the possibility that FOXP1 may also be involved in developmental conditions that are associated with language impairment. In order to explore this possibility, we searched for mutations in FOXP1 in patients with intellectual disability (ID; mental retardation) and/or autism spectrum disorders (ASD). We first performed array-based genomic hybridization on sporadic nonsyndromic ID (NSID) (n = 30) or ASD (n = 80) cases. We identified a de novo intragenic deletion encompassing exons 4-14 of FOXP1 in a patient with NSID and autistic features. In addition, sequencing of all coding exons of FOXP1 in sporadic NSID (n = 110) or ASD (n = 135) cases, as well as in 570 controls, revealed the presence of a de novo nonsense mutation (c.1573C>T [p.R525X]) in the conserved forkhead DNA-binding domain in a patient with NSID and autism. Luciferase reporter assays showed that the p.R525X alteration disrupts the activity of the protein. Formal assessments revealed that both patients with de novo mutations in FOXP1 also show severe language impairment, mood lability with physical aggressiveness, and specific obsessions and compulsions. In conclusion, both FOXP1 and FOXP2 are associated with language impairment, but decrease of the former has a more global impact on brain development than that of the latter. PMID- 20950789 TI - Inflammatory cytokines and antioxidants in midtrimester amniotic fluid: correlation with pregnancy outcome. AB - OBJECTIVE: Elevated interleukin-6 (IL-6) level in midtrimester amniotic fluid is associated with preterm delivery. We hypothesized that, in patients with elevated IL-6, vitamin C and alpha-fetoprotein may provide protection from spontaneous preterm delivery through antioxidant functions. STUDY DESIGN: Antioxidant potential of alpha-fetoprotein was assessed in vitro. Amniotic fluid was collected from a prospective cohort of patients who underwent midtrimester amniocentesis. In patients with IL-6 >600 pg/mL, alpha-fetoprotein, vitamin C, tumor necrosis factor-alpha, tumor necrosis factor receptors, and antioxidant capacity were compared between subjects with spontaneous preterm and term deliveries. RESULTS: Alpha-fetoprotein demonstrated 75% the antioxidant capacity of albumin in vitro. Of 388 subjects, 73 women had elevated IL-6 levels. Among these subjects, alpha-fetoprotein, but not vitamin C, was significantly lower in 9 women with preterm birth. Antioxidant capacity correlated with vitamin C and tumor necrosis factor receptors, but not with alpha-fetoprotein or pregnancy outcome. CONCLUSION: Amniotic fluid alpha-fetoprotein, but not vitamin C, may protect against preterm birth in patients with elevated midtrimester IL-6 levels. PMID- 20950790 TI - Urogenital disorders in women with adjuvant endocrine therapy after early breast cancer. AB - OBJECTIVE: To investigate the prevalence of urogenital symptoms and vaginal atrophy in postmenopausal breast cancer patients on adjuvant endocrine therapy. STUDY DESIGN: A population-based, cross-sectional study on postmenopausal breast cancer patients on adjuvant endocrine treatment and age-matched control subjects. Vaginal atrophy was assessed by gynecologic examination and atrophy-related symptoms by validated questionnaires. RESULTS: In all, 57.6% of aromatase inhibitor-treated and 32.4% of tamoxifen-treated breast cancer patients rated at least 1 vaginal atrophy symptom as moderate/severe, which was significantly more common than in control subjects (P < .01). Aromatase inhibitor-treated patients more often had moderate or severe vaginal atrophy (P < .05), a more atrophic cytohormonal evaluation, and significantly higher vaginal pH (P < .05) than all control subjects, irrespective of hormonal use. CONCLUSION: Our findings indicate that the frequency of vaginal atrophy symptoms, particularly in aromatase inhibitor-treated women, might have been underestimated in previous clinical trials. PMID- 20950791 TI - Clinical and biochemical predictors of very preterm birth in twin-to-twin transfusion syndrome treated by fetoscopy. AB - OBJECTIVE: To evaluate pre- and postoperative predictors of preterm birth in twin to-twin transfusion syndrome treated with fetoscopic placental laser coagulation. STUDY DESIGN: Prospective cohort study (n = 166) assessing cervical length (pre and postoperatively), amniotic fluid interleukin-6, serum C-reactive protein and duration of surgery. Logistic regression was used to investigate associations with preterm delivery. RESULTS: Preterm delivery within 7 days, before 28.0 and 32.0 weeks occurred in 4.8%, 16.8%, and 28.9%, respectively. The only significant predictor of delivery within 7 days was postoperative cervical length (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.3-0.9). Concerning delivery before 32.0 weeks, preoperative cervical length (OR, 0.9; 95% CI, 0.8-1.0), and gestational age (OR, 0.8; 95% CI, 0.4-0.9) were independent risk factors but the association was weak. The presence of a single survivor after surgery was associated with a clear reduction of risk (OR, 0.3; 95% CI, 0.1-0.6). Inflammatory biomarkers and duration of surgery did not discriminate risk of prematurity. CONCLUSION: No strong preoperative predictive factor of preterm birth could be identified. A single survivor was a strong protective factor of very preterm birth. PMID- 20950792 TI - Countermeasures to prevent detection failure of a vehicle approaching on collision course. AB - OBJECTIVE: This study investigated causal factor of perceptual failure and possible countermeasure of crossing path crashes at clear-sighted unsignalised intersections. BACKGROUND: Crossing path crashes involving two vehicles at intersections are a common and serious problem, and perceptual failure has been identified as a predominant causal factor. Previous studies have showed that late detection of a crossing vehicle frequently occurs even when there are no visual obstructions, at such as rural intersections. METHOD: With using a fixed-based driving simulator, three experiments were performed to investigate a driver's ability to detect a periphery presented cross traffic while approaching an intersection. In Experiment 1, drivers' ability to detect crossing vehicles in their peripheral field of view was studied, both in conditions of vehicles following a collision and a non-collision trajectory. In Experiment 2, we examined whether abrupt appearance of a vehicle on collision course would improve detection performance. In Experiment 3, we tested potential of collision warning, if it affects voluntary visual scanning, improving the detection performance regarding hazards cross traffic. RESULTS: The results of Experiment 1 showed that vehicles on collision course vehicles were detected late. This suggested that the late detection could be related to the lack of motion visible in the peripheral view. In Experiment 2, it was found that abrupt appearance effect ("pop-up" from road side occluding furniture) improves detection performance of a crossing vehicle. The results of Experiment 3 demonstrated that cross traffic collision warnings were beneficial for preventing late detection responses by means of encouraging voluntary visual scanning. CONCLUSION: Less attention attractive visual properties of hazardous cross traffic attributed to mutual approaching course can cause recognition failure. Drivers' gaze shift to potential conflicting direction, either reflective or voluntary manner, is crucially important for preventing crossing path crashes at such as rural intersections. PMID- 20950793 TI - Molecular investigation of macrolide and Tetracycline resistances in oral bacteria isolated from Tunisian children. AB - OBJECTIVE: This study aims to investigate the antibiotic susceptibility of strains isolated from the oral cavity of Tunisian children. DESIGN: Strains were isolated from the oral cavity of Tunisian children (60 caries-actives and 30 caries-free). Molecular characterization was assessed by PCR assay to detect erythromycin methylase gene (ermB), macrolide efflux (mefI) and tetracycline resistance genes (tetM and tetO). RESULTS: A total of 21 species were isolated and identified. Antimicrobial susceptibility revealed that the resistance rate to antibiotics was as follow: erythromycin (22%), tetracycline (15.6%), cefotaxim, (7.3%), trimethoprim-sulfamethoxazol (37.6%), nitrofurantoine (2.8%), pristinamycin (17.4%), quinupristin-dalfopristin (15.6%), and rifampicin (3.7%). The majority of mefI positive strains (31.2%) were isolated from the carious children (n=34) in comparison with 8.25% from the control group (n=9). In addition, frequency of strains caring resistance genes were as follow: 12.84% for ermB, 9.17% for tetM and 27.52% for tetO from the carious children in comparison to 0.092%, 3.67% and 3.67% from the caries free group respectively. CONCLUSION: Multi-resistance strains towards macrolides and tetracycline were recorded. The majority of strains carrying antibiotics resistance genes were isolated from the caries active children. The presence of multi-resistant bacteria in the oral cavity can be the major cause of antibiotic prophylaxis failure in dental practise. PMID- 20950794 TI - Sigma receptor agonists: receptor binding and effects on mesolimbic dopamine neurotransmission assessed by microdialysis. AB - BACKGROUND: Subtypes of sigma (sigma) receptors, sigma1 and sigma2, can be pharmacologically distinguished, and each may be involved in substance-abuse disorders. sigma-Receptor antagonists block cocaine place conditioning and sigma receptor agonists are self-administered in rats that previously self-administered cocaine. Self-administration of abused drugs has been related to increased dopamine (DA) neurotransmission, however, sigma-receptor agonist effects on mesolimbic DA are not fully characterized. METHODS: Receptor-binding studies assessed affinities of sigma-receptor ligands for sigma-receptor subtypes and the DA transporter; effects on DA transmission in the rat nucleus accumbens shell were assessed using in vivo microdialysis. RESULTS: Cocaine (.1-1.0 mg/kg intravenous [IV]), the nonselective sigma(1/2)-receptor agonist DTG (1.0-5.6 mg/kg IV), and the selective sigma1-receptor agonist PRE-084 (.32-10 mg/kg IV) dose-dependently increased DA to ~275%, ~150%, and ~160% maxima, respectively. DTG-induced stimulation of DA was antagonized by the nonselective sigma(1/2) receptor antagonist BD 1008 (10 mg/kg intraperitoneal [IP]) and the preferential sigma2-receptor antagonist SN 79 (1-3 mg/kg IP), but not by the preferential sigma1-receptor antagonist, BD 1063 (10-30 mg/kg IP). Neither PRE-084 nor cocaine was antagonized by BD 1063 or BD 1008. CONCLUSIONS: sigma-Receptor agonists stimulated DA in a brain area critical for reinforcing effects of cocaine. DTG effects on DA appear to be mediated by sigma2-receptors rather than sigma1 receptors. However, DA stimulation by cocaine or PRE-084 does not likely involve sigma-receptors. The relatively low potency on DA transmission of the selective sigma1-receptor agonist, PRE-084, and its previously reported potent reinforcing effects, suggest a dopamine-independent reinforcing pathway that may contribute to substance-abuse disorders. PMID- 20950795 TI - The SNAP25 gene is linked to working memory capacity and maturation of the posterior cingulate cortex during childhood. AB - BACKGROUND: Working memory (WM) is the ability to retain task relevant information. This ability is important for a wide range of cognitive tasks, and WM deficits are a central cognitive impairment in neurodevelopment disorders such as attention-deficit/hyperactivity disorder (ADHD). Although WM capacity is known to be highly heritable, most genes involved remain unidentified. METHODS: Single nucleotide polymorphisms in genes previously associated with cognitive functions or ADHD were selected for genotyping. Associations of these with WM tasks were investigated in a community sample of 330 children and young adults. One single nucleotide polymorphisms was also investigated in an independent sample of 88 4 year-old children. Furthermore, association between brain structure and activity, as measured by magnetic resonance imaging techniques, and single nucleotide polymorphisms alleles were estimated in 88 participants. RESULTS: Genotype at rs363039, located in the gene coding for synaptosomal-associated protein, 25 kDa (SNAP25) was associated to WM capacity in both samples. Associations in the community sample were also found with measures of other cognitive functions. In addition, this polymorphism affected the gray matter and brain activity in the posterior cingulate cortex, an area included in the so-called default mode network previously correlated to regulation of attention and hypothesized to be implicated in ADHD. CONCLUSIONS: A novel gene-brain-behavior network was identified in which a genotype located in SNAP25 affects WM and has age-dependent effects on both brain structure and brain activity. Identifying such networks could be a key to better understanding cognitive development as well as some of its disorders. PMID- 20950796 TI - Candidate gene analysis of the human natural killer-1 carbohydrate pathway and perineuronal nets in schizophrenia: B3GAT2 is associated with disease risk and cortical surface area. AB - BACKGROUND: The Human Natural Killer-1 carbohydrate (HNK-1) is involved in neurodevelopment and synaptic plasticity. Extracellular matrix structures called perineuronal nets, condensed around subsets of neurons and proximal dendrites during brain maturation, regulate synaptic transmission and plasticity. METHODS: Ten genes of importance for HNK-1 biosynthesis (B3GAT1, B3GAT2, and CHST10) or for the formation of perineuronal nets (TNR, BCAN, NCAN, HAPLN1, HAPLN2, HAPLN3, and HAPLN4) were investigated for potential involvement in schizophrenia (SCZ) susceptibility, by genotyping 104 tagSNPs in the Scandinavian Collaboration on Psychiatric Etiology sample (849 cases; 1602 control subjects). Genome-wide association study imputation data from the European SGENE-plus sample (2663 cases; 13,498 control subjects) were used for comparison. The effect of SCZ risk alleles on brain structure was investigated in a Norwegian subset (98 cases; 177 control subjects) with structural magnetic resonance imaging data. RESULTS: Five single nucleotide polymorphisms (SNPs), located in two adjacent estimated linkage disequilibrium blocks in the first intron of beta-1,3-glucuronyltransferase 2 (B3GAT2), were nominally associated with SCZ (.004 <= P(empirical) <= .05). The rs2460691 was significantly associated in the comparison sample and in the meta analysis after correction for all 121 SNP/haplotype tests (P(raw) = 1 * 10(-4); P(corrected) = .018). Increased dosage of the rs2460691 SCZ risk allele was associated with decreased cortical area (p = .002) but not thickness or hippocampal volume. A second SNP (r(2) = .24 with rs10945275), which conferred the highest SCZ risk effect in the Norwegian subset, was also associated with cortical area. CONCLUSIONS: The present results suggest that effects on biosynthesis of the neuronal epitope HNK-1, through common B3GAT2 variation, could increase the risk of SCZ, possibly by decreasing cortical area. PMID- 20950797 TI - [Surgical site infection in a tertiary hospital. A prospective surveillance study (2001-2004)]. AB - INTRODUCTION: Surgical site infection (SSI) is a very common problem in hospital infection control. It represents a risk for the safety of the patient and therefore its reduction is a priority in Health Services. The aim of the study is to analyse the incidence of SSI in the surgical departments of a tertiary hospital. MATERIAL AND METHODS: A prospective cohort study was conducted on 14,455 patients admitted from January 2001 to December 2004. The cumulative incidence (CI) crude and adjusted for the National Nosocomial Infection Surveillance (NNIS) index and the incidence density (ID) of SSI were calculated. RESULTS: The CI of patients with SSI was 3.4% (95% CI: 3.0-3.7%), the CI of SSI was 3.5% and the observed ID was 0.28/100 surgical patients/day. Surgical units with the highest CI were maxillofacial (6%), gastrointestinal (5.3%) and cardiovascular (5.1%). Adjusting for length of stay, urology and paediatric surgery recorded the highest incidence rates, while ophthalmology and neurosurgery had the least. Colorectal surgery had the highest parameters (CI=10%; ID=0.57), followed by myocardial revascularisation and hip prosthesis. Among the surgical units and operative procedures assessed, the CI of SSI increased with the NNIS index. CONCLUSIONS: The CI and ID of SSI observed in this study were similar to those obtained in previous European surveillance projects, and lower than those recorded in our hospital in 1994 which reflects a higher level of vigilance and a higher awareness in applying control measures. PMID- 20950798 TI - Downgrading BIRADS 3 to BIRADS 2 category using a computer-aided microcalcification analysis and risk assessment system for early breast cancer. AB - This paper explores the potential of a computer-aided diagnosis system to discriminate the real benign microcalcifications among a specific subset of 109 patients with BIRADS 3 mammograms who had undergone biopsy, thus making it possible to downgrade them to BIRADS 2 category. The system detected and quantified critical features of microcalcifications and classified them on a risk percentage scale for malignancy. The system successfully detected all cancers. Nevertheless, it suggested biopsy for 11/15 atypical lesions. Finally, the system characterized as definitely benign (BIRADS 2) 29/88 benign lesions, previously assigned to BIRADS 3, and thus achieved a reduction of 33% in unnecessary biopsies. PMID- 20950799 TI - Changes in the initial slope of the QRS in ischemic patients and normal subjects undergoing scintigraphy with dipyridamole. AB - The effect of dipyridamole (Dp) on the linear portion of the first major deflection of the QRS in human electrocardiograms (which we refer to as Fslope) was investigated in the context of myocardial perfusion imaging (MPI), in normal subjects (NS, n=19) and in patients with cardiovascular ischemia (as manifested by a positive MPI scan, n=53). In the majority of participants, Fslope decreased (84% of 19 NS and 77% of 53 patients, p=0.69). The decrease in Fslope was more pronounced in patients with ST-T deviation as compared to those without (32.6+/ 24.5 vs. 22.4+/-23.1, p=0.24), and in patients vs. NS (24.9+/-23.5 vs. 19.6+/ 23.4, p=0.44). A change in Fslope is a sensitive (but not specific) measure for detecting the effect of Dp on the myocardium in the setting of scintigraphy. PMID- 20950800 TI - Accuracy of Medicare claims for identifying findings and procedures performed during colonoscopy. AB - BACKGROUND: Administrative claims data are frequently used for quality measurement. OBJECTIVE: To examine the accuracy of administrative claims for potential colonoscopy quality measures, including findings (polyp or tumor detection), procedures (biopsy or polypectomy), and incomplete colonoscopy. DESIGN: Cross-sectional study. PATIENTS: Patients age 65 and older undergoing colonoscopy in the Clinical Outcomes Research Initiative National Endoscopic Database in 2006. We linked colonoscopy records for these patients to Medicare colonoscopy claims by using patient age, sex, date of procedure, and performing provider's Unique Physician Identification Number. MAIN OUTCOME MEASUREMENTS: Sensitivity, specificity, positive and negative predictive values of the Medicare claims for potential quality measures, including colonoscopy findings and procedures. RESULTS: We linked Medicare colonoscopy claims to 15,168 of the 30,011 Clinical Outcomes Research Initiative colonoscopy records. Sensitivity of the claims for colon polyps was 93.4%, with a specificity of 97.8%. Sensitivity of claims for other diagnoses, including colorectal tumors was suboptimal, although specificity was high. In contrast, sensitivity of claims for procedures biopsy (with or without cautery) or polypectomy-was high (87.2%-97.6%), with specificity >97%. Claims had poor sensitivity for identification of incomplete colonoscopy. LIMITATIONS: Potential for inaccurate matching of colonoscopy records and Medicare claims. CONCLUSIONS: Medicare claims have high sensitivity and specificity for polyp detection, biopsy, and polypectomy at colonoscopy, but sensitivity is low for other diagnoses such as tumor detection and for incomplete colonoscopy. Caution is needed when using Medicare claims data for certain important quality measures, in particular tumor detection and incomplete colonoscopy. PMID- 20950802 TI - Ampulla of Vater metastasis from recurrent uterine cervix carcinoma presenting as groove pancreatitis. PMID- 20950801 TI - Dynamic patient position changes during colonoscope withdrawal increase adenoma detection: a randomized, crossover trial. AB - BACKGROUND: Colonoscopy has a miss rate for adenomas that may partly relate to poor visualization of the colonic surface. Dynamic position changes during colonoscope withdrawal can improve luminal distension. OBJECTIVE: To assess whether position changes also improve adenoma and polyp detection. DESIGN: Randomized crossover clinical trial. SETTING: Academic endoscopy unit. PATIENTS: This study involved 130 patients who presented for routine colonoscopy. INTERVENTION: Examination either entirely in the left lateral position followed by position changes (cecum to hepatic flexure, left lateral; transverse colon, supine; splenic flexure and descending colon, right lateral) or vice versa. After both examinations, polyps were removed for histopathology. MAIN OUTCOME MEASUREMENTS: Proportion of patients with >=1 polyp or adenoma detected between the hepatic flexure and the sigmoid-descending colon junction. Luminal distension was measured on a scale of 1 to 5: 1, total collapse; 5, fully distended. RESULTS: At least 1 adenoma was detected in 34% of patients in colon areas in which the patient position differed from left lateral (transverse colon, splenic flexure, descending colon) compared with 23% examined with the patient in the left lateral position alone (P = .01). At least 1 polyp was detected in 52% of patients with position changes versus 34% of patients examined in the left lateral position alone (P < .001). Adenoma and polyp detection were positively correlated with an improved distension score (correlation coefficient, 0.12; P < .001). Adenomas were detected in 16% of colon areas with adequate distension scores (4 and 5) compared with 7% of those with borderline or nondiagnostic scores (1-3; P < .001). LIMITATIONS: Single-operator study. CONCLUSION: Dynamic position changes during colonoscope withdrawal significantly improved polyp and adenoma detection. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00234650). PMID- 20950803 TI - The extent of overweight index in children and adolescents from Cracow, Poland (1971-2000). AB - Obesity indices describe the percentage of overweight and obese children in a given population but they do not show the extent to which the norms have been exceeded. The aim of this work was to determine the extent of overweight index (EOW), suggested by Jolliffe (2004a,b), by examining children and adolescents from Cracow in order to obtain information on overweight and obesity prevalence and on the amounts by which the BMI age- and sex-specific norms are exceeded, emphasising usefulness of EOW in population studies. The study material comprises three randomly selected groups, representative for Cracow: (1) measured in 1971 which includes 4090 individuals of both sexes and aged 7-19 years, (2) measured in 1983 with 6542 individuals aged 3-19 years and (3) measured in 2000 with 4524 boys and girls aged 3-19 years. The EOW index of overweight is a mean relative deviation from BMI threshold, assuming that for values lower than the threshold ones, the deviation amounts to zero. The EOW index values in boys increased from 0.9 in 1971 up to 2.2 in 2000 i.e. by 144%, indicating an increase of both prevalence of overweight and obesity and an increase of the amount by which the limits of overweight are exceeded. In girls the index also increased, though less dramatically, from 0.7 in 1971 to 1.5 in 2000 i.e. by 114%. An analysis of the results showed that the increasing prevalence of overweight and obesity in children and adolescents is accompanied by an increase of the amount by which the BMI threshold values are exceeded. PMID- 20950804 TI - Sex determination using the scapula in New Kingdom skeletons from Tell El-Amarna. AB - Both forensic and archaeological sciences use metric analysis of human skeletal remains for sex estimation of unknown individuals. Thomas Dwight first reported the utility of scapula metrics for sex estimation in 1894, and subsequent years have produced several techniques for sex estimation using scapula metrics. Levels of sexual dimorphism vary across time and space, making these methods not universally applicable. Novel discriminant functions for unique populations are thus necessary. The present study establishes metric standards for sex estimation for a New Kingdom Egyptian skeletal sample from Tell El-Amarna using scapular measurements. The sample for this research consists of 27 individuals (14 males; 13 females) whose sex estimate based on pelvic morphology is unambiguous. The five measurements showing the highest degree of sexual dimorphism (p<=0.001) are used in the discriminant functions reported here: maximum length of the scapula, maximum length of the scapular spine, breadth of the infraspinous body, height of the glenoid fossa, and breadth of the glenoid fossa. The overall leave one out, cross-validated accuracy for the five reported discriminant functions ranges from 84.0 to 88.0%; similar to accuracies reported for the femur and humerus. Functions combining multiple variables produce higher accuracies than those based on single measurements. The unique population of Amarna, being comprised of emigrants from throughout Egypt, suggests these discriminant functions will have utility for Amarna period sites across the spatial distances of Egypt, and possibly the temporal range of the New Kingdom as a whole. PMID- 20950805 TI - Matrix metalloproteases MMP-2 and MMP-9: are they early biomarkers of bone remodelling and healing after arthroscopic acromioplasty? AB - Arthroscopic acromioplasty, one of the most frequent procedures in shoulder surgery, can promote tissue healing process by the release of growth/angiogenic factors from the acromion. Matrix metalloproteinases MMP-2 and MMP-9 are involved in such process. The purpose of this study was to measure MMP-2 and MMP-9 levels in the articular fluid and in the peripheral blood of patients undergoing arthroscopic acromioplasty in order to better understand the local involvement of such factors in the healing process after surgical procedures. Concentrations of MMP-2 and MMP-9 in the subacromial space and peripheral blood collected shortly after surgery were determined by ELISA. MMP-2 and MMP-9 concentrations were measured in the subacromial fluid of 23 patients. In subacromial fluid, the levels between MMP-2 and MMP-9 did not reach statistical significance (127.15+/ 45.56 vs 149.41+/-53.61 pg/ml, respectively, p>0.05). Peripheral blood levels of MMP-2 (130.75+/-47.48 pg/ml) were comparable to the subacromial fluid ones (127.15+/-45.56 pg/ml) whereas MMP-9 level was higher in the subacromial space (149.41+/-53.61 pg/ml) than in the peripheral blood (67.61+/-12.62 pg/ml, p<0.001). This work suggests that the measurement of bone specific MMPs (MMP-2 and MMP-9) can be an useful tool to be monitored in parallel with growth factor levels and other bone turnover markers in order to evaluate the bone remodelling and tissue healing processes. This study suggests that the measurement of bone specific MMPs levels, in particular MMP-9, may evaluate the bone remodelling and healing after arthroscopic shoulder acromioplasty. PMID- 20950806 TI - Global perspectives on the professional doctorate. PMID- 20950807 TI - Psychometric properties of a Korean version of the summary of diabetes self-care activities measure. AB - BACKGROUND: The summary of diabetes self-care activities (SDSCA) questionnaire is one of the most widely used self-report instruments for measuring diabetes self management in adults. OBJECTIVES: This study aimed to examine the psychometric properties of a Korean version of the SDSCA questionnaire. METHODS: The 11-item English version of the SDSCA was translated into Korean following the standard translation methodology. The questionnaire was administered to 208 patients with type 2 diabetes. Exploratory and confirmatory factor analyses (EFA and CFA) were carried out for construct validity. Content validity index (CVI), internal consistency and a diabetes management self-efficacy scale (DMSES) were assessed. RESULTS: The CVI of a Korean version of the SDSCA was .83. The EFA yielded a 9 item measure with a four factor solution with the same labels for original scales. The results of CFA showed the goodness of fit in the 9-item Korean SDSCA version (SDSCA-K). The internal consistency of SDSCA-K was moderate (Cronbach's alpha=.69) and the positive correlation between the SDSCA-K and the DMSES was identified. CONCLUSION: The current study provides the initial psychometric properties of SDSCA-K modified to 9 items and supports SDSCA-K as a reliable and valid measure of diabetes self-management in Korean patients. PMID- 20950808 TI - Coronary bare metal stent implantation in homozygous LDL receptor deficient swine induces a neointimal formation pattern similar to humans. AB - INTRODUCTION: To date, most of all new developments in stent technologies are tested in normal animals. Although invaluable in the evaluation of device safety, the juvenile domestic swine (DS) do not follow the biological healing response occurring in humans following coronary stent implantation. By using a novel swine breed afflicted with familial hypercholesterolemia (FHS), we aimed to analyse the vascular response occurring following bare metal stent (BMS) implantation by comparing in vivo endovascular imaging and histological data. METHODS: A total of 26 swine were included in this study (12 FHS and 14 DS). Sixty eight BMS (FHS=28 versus DS=40) were implanted using a 10% overstretch ratio. Imaging evaluation (IVUS and OCT) was conducted in all animals at 30 (n=14) or 90 (n=12) days following stent implantation. After imaging, the stented coronary segments were harvested for histological evaluation. RESULTS: At 30 days, the degree of neointimal formation analysed by OCT (%AS=DS 21.9 +/- 10% versus FHS 25.4 +/- 12%; p=0.18) and histology (DS 24.6 +/- 10% versus FHS 23.58 +/- 10%; p=0.8) was similar between both animal groups. At 90 days, the degree of neointimal formation in the DS group decreased in all analysed variables (-40% in IVUS neointimal volume, -57% in OCT %AS, and -30% in %AS by histology) compared to the progression of neointimal formation observed in the FHS group (+29% in IVUS neointimal volume, +27% in OCT %AS and +43% in %AS by histology). CONCLUSION: The pattern of neointimal formation following BMS implantation in the FHS follows a progressive course that does not occur in the DS. Therefore, by providing a progressive neointimal biological response to BMS implantation, the FHS could serve as an ideal efficacy model for the validation of drug eluting stent technologies. PMID- 20950809 TI - Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine. AB - OBJECTIVE: Enzymatic degradation of the extracellular matrix is known to be powerful regulator of atherosclerosis. However, little is known about the enzymatic regulation of heparan sulfate proteoglycans (HSPGs) during the formation and progression of atherosclerotic plaques. METHODS AND RESULTS: Swine were rendered diabetic through streptozotocin injection and hyperlipidemic through a high fat diet. Arterial remodeling and local endothelial shear stress (ESS) were assessed using intravascular ultrasound, coronary angiography and computational fluid dynamics at weeks 23 and 30. Coronary arteries were harvested and 142 arterial subsegments were analyzed using histomorphologic staining, immunostaining and real time PCR. Heparanase staining and activity was increased in arterial segments with low ESS, in lesions with thin cap fibroatheroma (TCFA) morphology and in lesions with severely degraded internal elastic laminae. In addition, heparanase staining co-localized with staining for CD45 and MMP-2 within atherosclerotic plaques. Dual staining with gelatinase zymography and heparanase immunohistochemical staining demonstrated co-localization of matrix metalloprotease activity with heparanase staining. A heparanase enzymatic activity assay demonstrated increased activity in TCFA lesions, subsegments with low ESS and in macrophages treated with oxidized LDL or angiotensin II. CONCLUSIONS: Taken together, our results support a critical role for heparanase in the development of vulnerable plaques and suggest a novel therapeutic target for the treatment of atherosclerosis. PMID- 20950810 TI - Deficiency of macrophage migration inhibitory factor gene delays healing of the medial collateral ligament: a biomechanical and biological study. AB - The role played by macrophage migration inhibitory factor (MIF) in the process of wound healing is controversial. Besides, there have been no reports that investigated the expression or the role of MIF in the repair process after ligament injury. In this study, we hypothesized that the deficiency in MIF gene might delay ligament healing in mice. The aim of this study was to clarify this hypothesis using MIF gene-deficient mice (MIFKO) and murine model of injury to the medial collateral ligament (MCL). Biomechanical testing showed that the levels of mechanical properties were significantly lower in MIFKO than in wild type mice (WT) on day 28 after injury. Levels of matrix metalloproteinase (MMP)-2 and -13 mRNA in the healing tissue were significantly lower in MIFKO than in WT on day 28 and on day 7, respectively. Histologically, healing tissues in MIFKO exhibited prolonged hypertrophy, poor vascularity, and prolonged increase in cell number compared with those in WT. Taken together, it was suggested that MIFKO exhibited delayed healing of the MCL, which might be caused by lower mRNA expression of MMP-2 and -13. PMID- 20950811 TI - Adsorptive micro-extraction techniques--novel analytical tools for trace levels of polar solutes in aqueous media. AB - A novel enrichment technique, adsorptive MU-extraction (AMUE), is proposed for trace analysis of polar solutes in aqueous media. The preparation, stability tests and development of the analytical devices using two geometrical configurations, i.e. bar adsorptive MU-extraction (BAMUE) and multi-spheres adsorptive MU-extraction (MSAMUE) is fully discussed. From the several sorbent materials tested, activated carbons and polystyrene divinylbenzene phases demonstrated the best stability, robustness and to be the most suitable for analytical purposes. The application of both BAMUE and MSAMUE devices proved remarkable performance for the determination of trace levels of polar solutes and metabolites (e.g. pesticides, disinfection by-products, drugs of abuse and pharmaceuticals) in water matrices and biological fluids. By comparing AMUE techniques with stir bar sorptive extraction based on polydimethylsiloxane phase, great effectiveness is attained overcoming the limitations of the latter enrichment approach regarding the more polar solutes. Furthermore, convenient sensitivity and selectivity is reached through AMUE techniques, since the great advantage of this new analytical technology is the possibility to choose the most suitable sorbent to each particular type of application. The enrichment techniques proposed are cost-effective, easy to prepare and work-up, demonstrating robustness and to be a remarkable analytical tool for trace analysis of priority solutes in areas of recognized importance such as environment, forensic and other related life sciences. PMID- 20950812 TI - Screening of tetrodotoxin in puffers using gas chromatography-mass spectrometry. AB - Tetrodotoxin (TTX), a toxic compound found in some puffers can cause death to humans through consumption. We have developed a simplified method for the screening of TTX in puffers using GC-MS. A puffer tissue of 0.5g was treated with 5mL of 0.1% acetic acid, followed by alkaline hydrolysis, LLE or liquid-liquid extraction and N-methyl-N-TMS-trifluoroacetamide derivatization. The developed method used only a small sample and solvent, simplified LLE and derivatization procedures and short chromatographic analysis (8.2min). All of these contribute to cost-saving, enhanced sample throughput and high sensitivity of the screening assay. The developed method was validated and proved to be within the acceptable range. PMID- 20950813 TI - Solvent-free microwave-assisted extraction of fluoroquinolones from soil and liquid chromatography-fluorescence determination. AB - Presented hereafter is a novel method entailing solvent free microwave-assisted extraction (MAE) and HPLC equipped with Fluorimetric Detector (HPLC-FD) for the simultaneous determination at MUgkg(-1) concentration of eight fluoroquinolone antibiotics (FQs) (Ciprofloxacin, Danofloxacin, Enrofloxacin, Flerofloxacin, Levofloxacin, Marbofloxacin, Norfloxacin and Orbifloxacin) in agricultural soils. The extraction was quantitatively performed, in a single step, by using an aqueous solution containing Mg(II) as complexing agent, thus avoiding consumption of organic solvents. The optimal MAE conditions have been established through a chemometric approach by considering temperature, irradiation time and matrix moisture or solvent, as the most important recognized variables affecting the extraction yield. Satisfying recoveries (69-110%, spikes 0.03-0.5mgkg(-1)) were gained with a single MAE cycle of 20min, at 80 degrees C in 20% (w/v) Mg(NO(3))(2) solution as leaching agent. MAE-SPE recoveries at 10MUgkg(-1), concentration near method quantification limits (MQLs), were in the range 60-85%. Good repeatability and within-lab reproducibility were observed (both in the range 1-16%). The applicability of the method to real samples was assessed on natural contaminated soils. Compared to ultrasonic-assisted extraction (UAE), MAE was shown to be highly competitive in terms of extraction efficacy and analysis speed. PMID- 20950814 TI - Preparation of magnetic indole-3-acetic acid imprinted polymer beads with 4 vinylpyridine and beta-cyclodextrin as binary monomer via microwave heating initiated polymerization and their application to trace analysis of auxins in plant tissues. AB - Auxin is a crucial phytohormone for precise control of growth and development of plants. Due to its low concentration in plant tissues which are rich in interfering substances, the accurate determination of auxins remains a challenge. In this paper, a new strategy for isolation and enrichment of auxins from plant tissues was obtained by the magnetic molecularly imprinted polymer (mag-MIP) beads, which were prepared by microwave heating initiated suspension polymerization using indole-3-acetic acid (IAA) as template. In order to obtain higher selective recognition cavities, an enhanced imprinting method based on binary functional monomers, 4-vinylpyridine (4-VP) and beta-cyclodextrin (beta CD), was adopted for IAA imprinting. The morphological and magnetic characteristics of the mag-MIP beads were characterized by scanning electron microscopy, Fourier-transform infrared spectroscopy and vibrating sample magnetometry. A majority of resultant beads were within the size range of 80 150MUm. Porous surface morphology and good magnetic property were observed. Furthermore, the mag-MIP beads fabricated with 4-VP and beta-CD as binary functional monomers exhibited improved recognition ability to IAA, as compared with the mag-MIP beads prepared with the individual monomer separately. Competitive rebinding experiment results revealed that the mag-MIP beads exhibited a higher specific recognition for the template than the non-imprinted polymer (mag-NIP) beads. An extraction method by mag-MIP beads coupled with high performance liquid chromatography (HPLC) was developed for determination of IAA and indole-3-butyric acid (IBA) in plant tissues. Linear ranges for IAA and IBA were in the range of 7.00-100.0MUgL(-1) and 10.0-100.0MUgL(-1), and the detection limits were 3.9 and 7.4MUgL(-1), respectively. The analytical performance was also estimated by seedlings or immature embryos samples from three different plant tissues, pea, rice and wheat. Recoveries were in the range of 70.1-93.5%. The results show that the present imprinting method is a promising approach for preparation of selective adsorbents for sample preparation of auxin analysis in plant tissues. PMID- 20950815 TI - Streamlined pentafluorophenylpropyl column liquid chromatography-tandem quadrupole mass spectrometry and global (13)C-labeled internal standards improve performance for quantitative metabolomics in bacteria. AB - Streamlined quantitative metabolomics in central metabolism of bacteria would be greatly facilitated by a high-efficiency liquid chromatography (LC) method in conjunction with accurate quantitation. To achieve this goal, a methodology for LC-tandem quadrupole mass spectrometry (LC-MS/MS) involving a pentafluorophenylpropyl (PFPP) column and culture-derived global (13)C-labeled internal standards (I.Ss.) has been developed and compared to hydrophilic interaction liquid chromatography (HILIC)-MS/MS and published combined two dimensional gas chromatography and LC methods. All 50 tested metabolite standards from 5 classes (amino acids, carboxylic acids, nucleotides, acyl-CoAs and sugar phosphates) displayed good chromatographic separation and sensitivity on the PFPP column. In addition, many important critical pairs such as isomers/isobars (e.g. isoleucine/leucine, methylsuccinic acid/ethylmalonic acid and malonyl-CoA/3 hydroxybutyryl-CoA) and metabolites of similar structure (e.g. malate/fumarate) were resolved better on the PFPP than on the HILIC column. Compared to only one (13)C-labeled I.S., the addition of global (13)C-labeled I.Ss. improved quantitative linearity and accuracy. PFPP-MS/MS with global (13)C-labeled I.Ss. allowed the absolute quantitation of 42 metabolite pool sizes in Methylobacterium extorquens AM1. A comparison of metabolite level changes published previously for ethylamine (C2) versus succinate (C4) cultures of M. extorquens AM1 indicated a good consistency with the data obtained by PFPP-MS/MS, suggesting this single approach has the capability of providing comprehensive metabolite profiling similar to the combination of methods. The more accurate quantification obtained by this method forms a fundamental basis for flux measurements and can be used for metabolism modeling in bacteria in future studies. PMID- 20950816 TI - Mixed-mode and reversed-phase liquid chromatography-tandem mass spectrometry methodologies to study composition and base hydrolysis of polysorbate 20 and 80. AB - Polysorbate 20 (polyoxyethylenesorbitan monolaurate) and polysorbate 80 (polyoxyethylenesorbitan monooleate) used in protein drug formulations are complex mixtures that have been difficult to characterize. Here, two HPLC methods are used with evaporative light scattering detection (ELSD) and mass spectrometry (MS) to characterize polysorbate from commercial vendors. The first HPLC method used a mixed-mode stationary phase (Waters Oasis MAX, mixed-mode anion exchange and reversed-phase sorbent) with a step gradient to quantify both the total polyoxyethylene sorbitan ester and polyoxyethylene sorbitan (POE sorbitan, a non surfactant) in polysorbate. The results indicated POE sorbitan was present from 16.0 to 27.6 and 11.1 to 14.5% (w/w) in polysorbate 20 and 80, respectively. The second HPLC method used a reversed-phase stationary phase (Zorbax SB-300 C(8)) with a shallow gradient to separate, identify, and quantify the multiple ester species present in polysorbate. For all lots of polysorbate 20 analyzed, only 18 23% of the material was the expected structure, polyoxyethylenesorbitan monolaurate. Up to 40% and 70% (w/w) di- and triesters were found in polysorbate 20 and polysorbate 80 respectively. Likewise, polyoxyethylenesorbitan monooleate accounted for only 20% of polysorbate 80. A variability of 3-5% was observed for each ester species between multiple lots of polysorbate 20. The reversed-phase method was then used to determine the rate of hydrolysis for each polyoxyethylene sorbitan ester of polysorbate 20 in basic solution at room temperature. Increasing rates of hydrolysis were observed with decreasing aliphatic chain lengths in polysorbate 20. PMID- 20950817 TI - Rapid automated high performance liquid chromatography method for simultaneous determination of amino acids and biogenic amines in wine, fruit and honey. AB - This paper reports a new, simple, rapid and economical method for routine determination of 24 amino acids and biogenic amines in grapes and wine. No sample clean-up is required and total run time including column re-equilibration is less than 40min. Following automated in-loop automated pre-column derivatisation with an o-phthaldialdehyde, N-acetyl-l-cysteine reagent, compounds were separated on a 3mm*25cm C(18) column using a binary mobile phase. The method was validated in the range 0.25-10mg/l; repeatability was less than 3% RSD and the intermediate precision ranged from 2 to 7% RSD. The method was shown to be linear by the 'lack of fit' test and the accuracy was between 97 and 101%. The LLOQ varied between 10MUg/l for aspartic and glutamic acids, ethanolamine and GABA, and 100MUg/l for tyrosine, phenylalanine, putrescine and cadaverine. The method was applied to grapes, white wine, red wine, honey and three species of physalis fruit. Grapes and physalis fruit were crushed, sieved, centrifuged and diluted 1/20 and 1/100, respectively, for analysis; wines and honeys were simply diluted 10-fold. It was shown using this method that the amino acid content of grapes was strongly correlated with berry volume, moderately correlated with sugar concentration and inversely correlated with total acidity. PMID- 20950818 TI - Control of molecular weight of polystyrene using the reverse iodine transfer polymerization (RITP)-emulsion technique. AB - The RITP-emulsion polymerization of styrene in the presence of molecular iodine has been successfully performed using potassium persulfate (KPS) as an initiator and 1-hexadecanesulfonate as an emulsifier under argon atmosphere at 80 degrees C for 7 hrs in the absence of light. The effects of the iodine concentration, molar ratio between KPS and iodine, and solid contents on the molecular weight of polystyrene (PS) were studied. As the iodine concentration increased from 0.05 to 0.504 mmol under the fixed [KPS]/[I(2)] ratio at 4.5, the weight-average molecular weight of PS substantially decreased from 126,120 to 35,690 g/mol, the conversion increased from 85.0% to 95.2%, and the weight-average particle diameter decreased from 159 to 103 nm. In addition, as the ratio of [KPS]/[I(2)] increased from 0.5 to 6.0 at the fixed [I(2)] of 0.504 mmol, the weight-average molecular weight of PS decreased from 72,170 to 30,640 g/mol with high conversion between 81.7% and 96.5%. Moreover, when the styrene solid content increased from 10 to 40 wt.% at the fixed [KPS]/[I(2)] ratio of 4.5, the weight-average molecular weight of PS varied between 33,500 and 37,200 g/mol, the conversion varied between 94.9% and 89.7% and the weight-average diameter varied from 122 to 205 nm. Thus, the control of molecular weight of PS less than 100,000g/mol with high conversion (95%) and particle stability of up to 40 wt.% solid content were easily achieved through the usage of iodine with suitable ratio of [KPS]/[I(2)] in the RITP-emulsion polymerization technique, which is of great industrial importance. PMID- 20950819 TI - Supercritical CO2-ionic liquid mixtures for modification of organoclays. AB - The use of supercritical CO(2) as solvent in the modification of montmorillonite by imidazolium and phosphonium ionic liquids bearing long alkyl chains (C(18)) known for their excellent thermal stability is described. The objective is to combine the environmentally friendly character of ionic liquids and supercritical carbon dioxide for the organophilic treatment of lamellar silicates. Dialkyl imidazolium and alkyl phosphonium salts were synthesized to be used as new surfactants for cationic exchange of layered silicates. Then, the synthesized phosphonium (MMT-P) or imidazolium (MMT-I) modified montmorillonites, cationically exchanged under supercritical carbon dioxide with or without co solvent, have been analyzed by thermogravimetric analysis (TGA) and X-ray diffraction (XRD) and compared to montmorillonites treated by conventional cationic exchange. PMID- 20950821 TI - Effect of water and air-water interface on the structural modification of Ni arachidate Langmuir-Blodgett films. AB - Nickel arachidate (NiA) Langmuir-Blodgett (LB) films have been deposited on hydrophilic Si(0 0 1) substrates by three (up-down-up) and five (up-down-up-down up) strokes. During deposition, substrates were kept inside the water subphase for different times after each down stroke. Structural information of all the LB films have been obtained from X-ray reflectivity (XRR) studies. One and two symmetric monolayer (SML) was deposited on top of the asymmetric monolayer (AML) in three and five stokes respectively. All the preformed LB films were then used to go through the air-water interface with the same speed that was used at the time of film deposition. Structural information obtained from the XRR studies show that mainly the top layer density decreases after passing through the air water interface but the layered structure remains the same. Information obtained from both the XRR and atomic force microscopy (AFM) studies suggest that molecules peeled from the top SML layer do not reincorporate with the LB film through tail-tail hydrophobic interaction. Our study shows that NiA LB film has better stability compared with cadmium arachidate LB film inside the water subphase without forming any out-of-plane molecular reorganization. PMID- 20950820 TI - Formation of a silicato complex of zinc in aqueous solution and its accelerating effect on the formation of silica scales in cooling water systems. AB - This study elucidates the effect of zinc (Zn), which is an anticorrosive water additive, on the formation of silica scales from cooling water. In these experiments, the silica scales were analyzed by EPMA, and the results indicate that Zn is sorbed into the silica scales during formation. Measurements of the solubility of Zn(OH)(2) at various concentrations of silicic acid demonstrate that Zn is present as a silicato complex of Zn (SCZ) in cooling water. From adsorption experiments of the SCZ on silica and alumina, which are major components of the silica scales, it can be concluded that the SCZ accelerates the formation of silica scales from cooling water. PMID- 20950822 TI - DLVO interaction of colloidal particles with topographically and chemically heterogeneous surfaces. AB - The DLVO force and potential energy of interaction between microspheres and topographically and chemically heterogeneous surfaces in aqueous solution are computed using a modification of the surface element integration approach. The heterogeneous surface has an array of cylindrical pillars of varying height, diameter, and arrangement to model different nano-topographies. In agreement with previous studies, the nano-topography decreases the size of the potential energy barrier for unfavorable surfaces because the pillars limit the minimum separation distance. The influence of topography is significant even for pillars several nanometers high and is more pronounced if the surface potential of the pillar tops differs from that of the underlying surface. A new force- and energy averaging model is introduced as a simple method to compute the mean interaction energy or force between the particle and a heterogeneous surface, which differs significantly from a mean-field approach based on the average or nominal surface potential. Small variations in topography are found to remove large energy barriers to colloidal deposition. These results help explain the increased attraction of patchy surfaces towards particles relative to expectations based on typical DLVO calculations, which is particularly significant for surfaces with adsorbed polyelectrolytes. PMID- 20950824 TI - Cerebellar hyperactivity during smooth pursuit eye movements in bipolar disorder. AB - INTRODUCTION: Smooth pursuit eye movements (SPEM) are abnormal in individuals with schizophrenia and individuals with bipolar disorder. Functional imaging methods have revealed greater hippocampal activity and less frontotemporal, visual, and posterior cerebellar activity in individuals with schizophrenia when performing a SPEM task. The underlying neurobiology of SPEM deficits in bipolar disorder is unknown. METHODS: Functional magnetic resonance imaging at 3T was performed on fourteen subjects with bipolar disorder and 14 subjects without psychiatric illness during a block design SPEM task. Clinical measures were assessed on the day of testing and related to imaging measures. RESULTS: Subjects with bipolar disorder had greater hemodynamic response than control subjects in cerebellar vermis. Responses were associated with levels of depressive symptoms on the day of study. DISCUSSION: Increased cerebellar vermis activity during the smooth pursuit eye movement task in individuals with bipolar disorder further implicates cerebellar involvement in bipolar disorder. Increased hemodynamic response within the hippocampus was not seen in these individuals and may be a finding specific to schizophrenia. PMID- 20950823 TI - Personality disorders associated with full and partial posttraumatic stress disorder in the U.S. population: results from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. AB - BACKGROUND: While it is well known that personality disorders are associated with trauma exposure and PTSD, limited nationally representative data are available on DSM-IV personality disorders that co-occur with posttraumatic stress disorder (PTSD) and partial PTSD. METHODS: Face-to-face interviews were conducted with 34,653 adults participating in the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions. Logistic regression analyses controlling for sociodemographics and additional psychiatric comorbidity evaluated associations of PTSD and partial PTSD with personality disorders. RESULTS: Prevalence rates of lifetime PTSD and partial PTSD were 6.4% and 6.6%, respectively. After adjustment for sociodemographic characteristics and additional psychiatric comorbidity, respondents with full PTSD were more likely than trauma controls to meet criteria for schizotypal, narcissistic, and borderline personality disorders (ORs = 2.1 2.5); and respondents with partial PTSD were more likely than trauma controls to meet diagnostic criteria for borderline (OR = 2.0), schizotypal (OR = 1.8), and narcissistic (OR = 1.6) PDs. Women with PTSD were more likely than controls to have obsessive-compulsive PD. Women with partial PTSD were more likely than controls to have antisocial PD; and men with partial PTSD were less likely than women with partial PTSD to have avoidant PD. CONCLUSIONS: PTSD and partial PTSD are associated with borderline, schizotypal, and narcissistic personality disorders. Modestly higher rates of obsessive-compulsive PD were observed among women with full PTSD, and of antisocial PD among women with partial PTSD. PMID- 20950825 TI - Carbon monoxide releasing molecule-2 improves protamine-mediated hypocoagulation/hyperfibrinolysis in human plasma in vitro. AB - BACKGROUND: Protamine sulfate has been implicated as a possible cause of coagulopathy for over 20 y. Protamine has been demonstrated to decrease thrombin activity and to prolong bleeding. We tested the hypothesis that a new hemostatic agent, carbon monoxide releasing molecule-2 (tricarbonyldichlororuthenium (II) dimer; CORM-2), could attenuate protamine-mediated hypocoagulation/hyperfibrinolysis in plasma. METHODS: Normal plasma was exposed to 0, 12.5, 25, or 50 MUg/mL of protamine, with or without addition of 100 MUM CORM-2. Tissue factor was used to initiate coagulation, and tissue type plasminogen activator was added in some experiments. Additional experiments were performed wherein plasma was exposed to protamine combined with 0% or 30% dilution with normal saline, with or without CORM-2 addition. Thrombelastography was performed until either stable clot strength or clot lysis occurred. RESULTS: Protamine, in a concentration-dependent fashion, significantly prolonged the onset of coagulation, decreased the velocity of thrombus growth, and decreased clot strength in the absence or presence of tissue type plasminogen activator. Further, protamine significantly decreased the time to onset of fibrinolysis and decreased clot lysis time. CORM-2 exposure significantly diminished all aforementioned protamine-mediated effects on coagulation and fibrinolysis. Lastly, CORM-2 addition significantly increased the velocity of clot growth and strength in diluted, protamine-exposed plasma. CONCLUSIONS: CORM-2 attenuated protamine-mediated hypocoagulation/hyperfibrinolysis at clinically encountered concentrations. Additional preclinical investigation is warranted to determine if CORM-2 administration will be efficacious in diminishing coagulopathy caused by protamine. PMID- 20950826 TI - Reverse intestinal interposition: a model for living related small bowel transplantation? PMID- 20950827 TI - Impact of a new refrigerator for the preservation of whole blood. AB - BACKGROUND: A new refrigerating system has been recently developed, which can cool the inside of a material to the required temperature by frequently sensing the temperature of both the inside and the surface of the materials. The purpose of this study was to evaluate the usefulness of this new system in whole blood preservation. MATERIALS AND METHODS: Study 1 (human blood): Whole blood samples from healthy volunteers were anticoagulated with CPDA. The samples were divided into two groups. Group A, whole blood preserved in ordinary refrigerator and Group B, whole blood preserved in new refrigerator (4 degrees C, 15 wk). After preservation, ammonia, lactate, pH. and ATP levels were analyzed. Study 2 (rat experiment): Whole blood samples from male Wistar rats, stored in ordinary refrigerator (Group C) or new refrigerator (Group D). Whole blood was transfused after 8-wk storage and survival was compared. RESULTS: Study 1: The ammonia concentrations in Group B were significantly lower than those in Group A at 7 and 9 wk after preservation (P < 0.05). The lactate levels in Group B were significantly lower than those in Group A at 9 wk after preservation (P < 005). The pH levels in Group B were higher than those in Group A at 5 to 13 wk after preservation (P < 0.05). The ATP levels in Group B were higher than those in Group A at 5 to 13 wk after preservation. Study 2: In rat studies using blood transfusion in acute hemorrhagic shock model, survival rate in Group C was significantly higher than those in Group D (P < 0.05). CONCLUSIONS: Our new refrigerator is useful in preserving whole blood with good condition during preservation. PMID- 20950828 TI - TRPV1 agonist capsaicin attenuates lung ischemia-reperfusion injury in rabbits. AB - BACKGROUND: Capsaicin, a transient receptor potential vanilloid type 1 (TRPV1) agonist, was found to protect against myocardial and renal ischemia-reperfusion (IR) injury. This study was carried out to investigate the role of capsaicin in lung IR injury in vivo. METHODS: Forty male New Zealand rabbits were randomized into four groups (10 per group) as follows: sham group (sham thoracotomy), IR group (occlusion of the left pulmonary hilus for 1 h followed by reperfusion for 3 h), CAP (capsaicin) group (a bolus injection of CAP 5 min before ischemia), CPZ (capsazepine) group (a bolus injection of the TRPV1 antagonist CPZ 5 min before ischemia). Blood and lung tissue samples were obtained for blood gas and biochemical analyses, wet/dry weight ratio measurements, and histologic evaluation. Protein levels and neutrophils in the bronchoalveolar lavage fluid (BALF) were also measured. RESULTS: Pretreatment with capsaicin improved gas exchange function, decreased lung wet/dry ratio and protein levels and neutrophil counts in BALF, decreased lung malondialdehyde levels and myeloperoxidase activities, increased superoxide dismutase activities, along with an elevation of calcitonin gene-related peptide (CGRP) level (P < 0.05 versus IR group). Capsaicin also attenuated IR-induced pathological lesions. By contrast, capsazepine exacerbated gas exchange abnormality, increased pulmonary microvascular permeability, oxidative stress, neutrophils infiltration, and also revealed a decreased CGRP level (P < 0.05 versus IR group). CONCLUSION: Results from the present study show that capsaicin confers protection against lung IR injury. These protective effects seem to be closely related to the inhibition of inflammation and oxidative stress via the activation of TRPV1 and the release of CGRP. PMID- 20950829 TI - Eicosapentaenoic acid disrupts the balance between Tregs and IL-17+ T cells through PPARgamma nuclear receptor activation and protects cardiac allografts. AB - Eicosapentaenoic acid (EPA) is one of n-3 polyunsaturated fatty acids that possesses a wide array of anti-inflammatory effects but its effects, on transplantation in general and on Tregs and IL-17(+) T cells in particular, are not well studied. We treated recipient mice of heart transplantation with EPA and examined the effect of EPA on the ratio of Tregs/IL-17(+) T cells in an allogeneic heart transplant model. The hearts from BALB/c (H-2d) mice were transplanted into C57BL/6 (H-2b) mice, and the recipients were administered EPA (500 mg/kg/d, 250 mg/kg/d, or 100 mg/kg/d) from d 1 to 3 post-transplant. The survival of cardiac allografts in mice treated with EPA was significantly protracted. Further examination of donor hearts in EPA-treated group demonstrated that infiltrating Foxp3(+) T cells were increased, IL-17(+) T cells were decreased, and expression of PPARgamma was up-regulated. In mixed lymphocytes reaction (MLR), incubation with EPA significantly inhibited the proliferation of IL-17(+) T cells and promoted the proliferation of Tregs, while PPARgamma antagonists GW9662 could reverse the results. Our study demonstrated that EPA can effectively protect cardiac allografts and disrupt the balance between Tregs and IL-17(+) T cells in a murine model. This effect is partially mediated by PPARgamma nuclear receptor activation. PMID- 20950830 TI - Effects of seawater acidification on early development of the intertidal sea urchin Paracentrotus lividus (Lamarck 1816). AB - The effect of pH ranging from 8.0 to 6.8 (total scale - pH(T)) on fertilization, cleavage and larval development until pluteus stage was assessed in an intertidal temperate sea urchin. Gametes were obtained from adults collected in two contrasting tide pools, one showing a significant nocturnal pH decrease (lowest pH(T)=7.4) and another where pH was more stable (lowest pH(T)=7.8). The highest pH(T) at which significant effects on fertilization and cleavage were recorded was 7.6. On the contrary, larval development was only affected below pH(T) 7.4, a value equal or lower than that reported for several subtidal species. This suggests that sea urchins inhabiting stressful intertidal environments produce offspring that may better resist future ocean acidification. Moreover, at pH(T) 7.4, the fertilization rate of gametes whose progenitors came from the tide pool with higher pH decrease was significantly higher, indicating a possible acclimatization or adaptation of gametes to pH stress. PMID- 20950831 TI - Concentrations of 137Cs, 90Sr, 108m Ag, 239+240 Pu and atom ratio of 240Pu/239Pu in tanner crabs, Chionoecetes japonicus and Chionoecetes opilio collected around Japan. AB - The anthropogenic radionuclides, (137)Cs, (90)Sr, (108m)Ag, (239+240)Pu, were measured in two Chionoecetes species, red queen crab (Chionoecetes japonicus) and snow crab (Chionoecetes opilio) collected around Japan during 1996-2007. There was no increase in the concentrations of these radionuclides and no large variation of the atom ratio of (240)Pu/(239)Pu during this research period. These results indicated that the source of the radionuclides was not the radioactive wastes dumped by the former USSR and Russia and originated from past nuclear weapon tests. The higher atom ratio in the crab species than that from global fallout would be contributed by the Pacific Proving Grounds close-in fallout. The variability of the concentration of radionuclides in the crab species would result from the variability of the composition and quantity in the diet. However, the decrease in the concentration of radionuclides with sampling depth would depend on the concentration in the seawater and diet. PMID- 20950832 TI - [Musculoskeletal imaging case presented at the General Case Reading Session of the XXX National Congress of the Spanish Society of Diagnostic Imaging (SERAM), A Coruna. May 2010]. PMID- 20950833 TI - Removal of chromium (VI) from wastewater using bentonite-supported nanoscale zero valent iron. AB - Bentonite-supported nanoscale zero-valent iron (B-nZVI) was synthesized using liquid-phase reduction. The orthogonal method was used to evaluate the factors impacting Cr(VI) removal and this showed that the initial concentration of Cr(VI), pH, temperature, and B-nZVI loading were all importance factors. Characterization with scanning electron microscopy (SEM) validated the hypothesis that the presence of bentonite led to a decrease in aggregation of iron nanoparticles and a corresponding increase in the specific surface area (SSA) of the iron particles. B-nZVI with a 50% bentonite mass fraction had a SSA of 39.94 m(2)/g, while the SSA of nZVI and bentonite was 54.04 and 6.03 m(2)/g, respectively. X-ray diffraction (XRD) confirmed the existence of Fe(0) before the reaction and the presence of Fe(II), Fe(III) and Cr(III) after the reaction. Batch experiments revealed that the removal of Cr (VI) using B-nZVI was consistent with pseudo first-order reaction kinetics. Finally, B-nZVI was used to remediate electroplating wastewater with removal efficiencies for Cr, Pb and Cu > 90%. Reuse of B-nZVI after washing with ethylenediaminetetraacetic acid (EDTA) solution was possible but the capacity of B-nZVI for Cr(VI) removal decreased by approximately 70%. PMID- 20950834 TI - What affects public acceptance of recycled and desalinated water? AB - This paper identifies factors that are associated with higher levels of public acceptance for recycled and desalinated water. For the first time, a wide range of hypothesized factors, both of socio-demographic and psychographic nature, are included simultaneously. The key results, based on a survey study of about 3000 respondents are that: (1) drivers of the stated likelihood of using desalinated water differ somewhat from drivers of the stated likelihood of using recycled water; (2) positive perceptions of, and knowledge about, the respective water source are key drivers for the stated likelihood of usage; and (3) awareness of water scarcity, as well as prior experience with using water from alternative sources, increases the stated likelihood of use. Practical recommendations for public policy makers, such as key messages to be communicated to the public, are derived. PMID- 20950835 TI - Biocontrol of biomass bulking caused by Haliscomenobacter hydrossis using a newly isolated lytic bacteriophage. AB - This research demonstrates the first ever application of lytic bacteriophage (virus) mediated biocontrol of biomass bulking in the activated sludge process using Haliscomenobacter hydrossis as a model filamentous bacterium. Bacteriophages are viruses that specifically infect bacteria only. The lytic phage specifically infecting H. hydrossis was isolated from the mixed liquor of a local wastewater treatment plant. The isolated bacteriophage belongs to the Myoviridae family with a contractile tail (length-126 nm; diameter-18 nm) and icosahedral head (diameter-81 nm). Titer of the isolated phage with H. hydrossis was calculated to be 5.2 +/- 0.3 * 10(5) PFU/mL and burst size was found to be 105 +/- 7 PFU/infected cell. The phage was considerably stable after exposure to high temperature (42 degrees C) and pH between 5 and 8, emphasizing that it can withstand the seasonal/operational fluctuations under real-time applications. Phage to host (bacteria) ratio for the optimal infection was found to be 1:1000 with ~54% host death. The isolated phage showed no cross infectivity with other bacteria most commonly found in activated sludge systems, thus validating its suitability for biocontrol of filamentous bulking caused by H. hydrossis. Following the phage application, successful reduction in sludge volume index (SVI) from 155 to 105 was achieved, indicating improved biomass settling. The application of phage did not affect nutrient removal efficiency of the biomass, suggesting no collateral damage. Similar to phage therapy in medical applications, phage-mediated biocontrol holds a great potentiality for large scale applications as economic agent in the mitigation of several water, wastewater and environmental problems. Present study in this direction is a novel effort. PMID- 20950836 TI - Evaluation and improvement of total organic bromine analysis with respect to reductive property of activated carbon. AB - A collective parameter and a toxicity indicator for all the halogenated organic disinfection byproducts in a water sample is total organic halogen (TOX), which can be differentiated as total organic chlorine (TOCl), total organic bromine (TOBr) and total organic iodine. The TOX method involves concentration of organic halogens from water by adsorption onto activated carbon (AC). A previous study showed that a portion of TOCl can be reduced to chloride during the adsorption procedure, which can be minimized by ozonation of the AC. In this study, a portion of TOBr was sometimes found to be reduced by AC to bromide, and the reduction was generally less than that of corresponding TOCl. The results suggested that around 10% of brominated Suwannee River fulvic acid was reduced to bromide. However, some brominated amino compounds (especially glycylglycine, phenylalanine, and cytosine) were found to be more reactive with the AC. For the iodinated compounds studied, the reduction to iodide was not significant. The method for the TOBr measurement was improved by using ozonated AC when reduction occurred on the original AC. The improved method was also evaluated on treated wastewater and swimming pool water samples. PMID- 20950837 TI - Lack of correlation between enterococcal counts and the presence of human specific fecal markers in Mississippi creek and coastal waters. AB - The objective of this study was to determine whether statistically valid correlations could be shown between enterococcal counts of samples from creek and coastal sites and the presence of two molecular, library-independent markers that specify human and/or sewage pollution. Four hundred ninety samples were collected between August 2007 and April 2009 to determine enterococcal counts and the presence of genetic markers for the sewage indicator organisms Methanobrevibacter smithii and Bacteroidales. The presence of human/sewage markers and enterococcal counts were higher in creek samples than coastal samples, but the higher creek levels did not statistically correlate with the either enterococcal count or the presence of the markers present in coastal samples. Furthermore, there was no correlation between enterococcal counts in coastal samples and either marker at any of the beach sites tested. The results of this investigation in Mississippi coastal waters suggest that human/sewage markers are unlikely to correlate with enterococci counts in the nearshore environment and that enterococcal counts may be indicative of other animal or environmental sources. Additionally, a study comparing conventional gel electrophoresis with capillary electrophoresis did not convincingly establish that one method was better than the other in regard to the results obtained. The capillary method does allow reproducibility of results and the ability to analyze multiple samples in a short period of time; however, the operational expenditures exceed the cost of traditional gel electrophoresis. PMID- 20950838 TI - Demonstration of 20 pharmaceuticals and personal care products (PPCPs) as nitrosamine precursors during chloramine disinfection. AB - The worldwide detection of pharmaceuticals and personal care products (PPCPs) in the aquatic environment and drinking water has been a cause for concern in recent years. The possibility for concurrent formation of nitrosamine DBPs (disinfection by-products) during chloramine disinfection has become another significant concern for delivered drinking water quality because of their potent carcinogenicity. This study demonstrates that a group of PPCPs containing amine groups can serve as nitrosamine precursors during chloramine disinfection. Molar yields higher than 1% are observed for eight pharmaceuticals, with ranitidine showing the strongest potential to form N-nitrosodimethylamine (NDMA). The molar conversion increases with the Cl(2):N mass ratio, suggesting that dichloramine is relevant to the formation of NDMA from these precursors. Although the trace level of PPCPs in the environment suggests that they may not account for the majority of nitrosamine precursors during the disinfection process, this study demonstrates a connection between the transformation of PPCPs and the formation of nitrosamines during chloramine disinfection. This both expands the pool of potential nitrosamine precursors, and provides a possible link between the presence of trace levels of certain PPCPs in drinking water sources and potential adverse health effects. PMID- 20950839 TI - Temporal and spatial inhibitory effects of zinc and copper on wastewater biofilms from oxygen concentration profiles determined by microelectrodes. AB - To understand the temporal and spatial toxic effect of heavy metals on the microbial activities of biofilms, microelectrodes were used to measure the inhibitory oxygen (O(2)) concentration profiles resulted from the effects of zinc (Zn(2+)) and copper (Cu(2+)). Using the O(2) microprofiles as bases, the spatial distributions of net specific O(2) respiration were determined in biofilms with and without treatment of 5 mg/L Zn(2+) or 1 mg/L Cu(2+). Results show that microbial activities were inhibited only in the outer layer (~400 MUm) of the biofilms and bacteria present in the deeper sections of the biofilms became even more active. The inhibition caused by the heavy metals was evaluated by two methods. One was derived from the oxygen influx at the interface and the other was based on the integral of the oxygen consumption calculated from the entire O(2) profile. The two methods yielded significantly different results. We argue that the integral method results in more accurate assessment of toxicity than the surface flux determination. PMID- 20950840 TI - Monitoring treatments with unfractionated heparin: CTAD must be used instead of citrate as the anticoagulant solution when using partial-draw collection tubes. Results of a multicenter evaluation. AB - BACKGROUND: Sampling small volumes of blood may be necessary, particularly in pediatric patients, or in case of difficult or recurrent venipunctures. METHODS: Routine hemostasis test results evaluated in partial- and full-draw evacuated polymer tubes obtained in 4 centers were compared. RESULTS: No relevant discrepancy (Bland-Altman) was found between test results measured in partial- and full-draw tubes obtained from untreated patients and from patients on vitamin K-antagonist or low molecular weight heparin. In patients on unfractionated heparin (UFH), significantly lower anti-FXa activity [median=0.29IU/mL (range:0.04-1.15) vs. 0.39 (0.05-1.25), n=89, p<0.0001] and shorter aPTT were measured in partial-draw tubes. This discrepancy was likely to be related to the release of higher amounts of PF4 after increased platelet activation in partial draw tubes. As CTAD is known to counteract platelet activation, we then collected blood into partial-draw CTAD tube and full-draw citrate tube. Both in patients on UFH and in untreated patients, no relevant difference could be demonstrated for all studied parameters (Bland-Altman), including aPTT and anti-FXa activity, even if analytical comparison showed significantly higher anti-FXa activity in partial draw CTAD than in full-draw citrated tubes with a mean bias of 0.02 IU/mL, identical throughout the measuring range. CONCLUSIONS: These results suggest that samples collected into partial-draw citrate tubes allow accurate routine coagulation testingin all patients but those requiring UFH assessment,in which their use led to a significant underestimation ofanticoagulation. In such cases, partial-draw tubes containing CTAD could be validly used to monitor heparin therapy as well as to perform routine coagulation testing. PMID- 20950841 TI - Decreased fibrin network permeability and impaired fibrinolysis in the acute and convalescent phase of ischemic stroke. AB - INTRODUCTION: We investigated fibrin network permeability and fibrinolysis in the acute and convalescent phase of ischemic stroke. METHODS: 20 patients with a mean age of 74 years were studied in the acute (day 1) and convalescent phase (day 60) of ischemic stroke. 23 healthy individuals (controls) were also investigated. Fibrin formation in the samples was triggered by addition of tissue factor (1 pmol/L) and washed frozen-thawed platelets obtained from a healthy donor. The permeability constant (K(s)), which reflects fibrin network permeability, was then calculated from liquid flow measurements. A global assay newly developed in our group was also employed to determine the balance between fibrin formation ("Coagulation profile"; Cp) and fibrin degradation ("Fibrinolysis profile"; Fp) in the same samples. We also measured PAI-1 antigen and fibrinogen concentrations in plasma. RESULTS: As compared to controls, the stroke patients had lower Ks (lower fibrin network permeability) both on day 1 and on day 60 (p < 0.01 and p < 0.05, respectively). Fibrinolysis, assessed by Fp, was reduced on both day 1 and day 60 (p < 0.001, compared to controls), and PAI-1 concentrations were increased (p < 0.01 for both, compared to controls). Fibrin formation capacity in plasma (i.e. Cp) was increased in the acute phase (p < 0.05) but not in the convalescence, as compared to controls. CONCLUSION: The combination of a proneness to form a tighter fibrin network and impaired fibrinolysis is a feature of ischemic stroke that is present in both the acute and convalescent phase of the disease. PMID- 20950842 TI - Apical CD36 immunolocalization in human and porcine taste buds from circumvallate and foliate papillae. AB - CD36 is the receptor for long chain fatty acids (LCFA), and is expressed in lingual taste cells from rodents. In these animals, CD36 has been proposed to play an important role in oral detection of LCFA, and subsequently, determines their dietary fat preference. Humans also seem to detect LCFA in the oral cavity, however, information on the molecular mechanism of this human orosensory LCFA recognition is currently lacking. The aim of our study was to investigate whether CD36 is also expressed in lingual human and porcine taste buds cells. Using fluorescence immunohistochemistry, apical CD36 expression was revealed in human and porcine taste bud cells from circumvallate and foliate papillae. These data suggest CD36 as the putative orosensory receptor for dietary LCFA in human, and, therefore, may be involved in our preference for fatty foods. PMID- 20950843 TI - Effects of short-duration electromagnetic radiation on early postnatal neurogenesis in rats: Fos and NADPH-d histochemical studies. AB - The immediate effects of whole body electromagnetic radiation (EMR) were used to study postnatal neurogenesis in the subventricular zone (SVZ) and rostral migratory stream (RMS) of Wistar rats of both sexes. Newborn postnatal day 7 (P7) and young adult rats (P28) were exposed to pulsed electromagnetic fields (EMF) at a frequency of 2.45 GHz and mean power density of 2.8 mW/cm(2) for 2 h. Post irradiation changes were studied using immunohistochemical localization of Fos and NADPH-d. We found that short-duration exposure induces increased Fos immunoreactivity selectively in cells of the SVZ of P7 and P28 rats. There were no Fos positive cells visible within the RMS of irradiated rats. These findings indicate that some differences exist in prerequisites of proliferating cells between the SVZ and RMS regardless of the age of the rats. Short-duration exposure also caused praecox maturation of NADPH-d positive cells within the RMS of P7 rats. The NADPH-d positive cells appeared several days earlier than in age matched controls, and their number and morphology showed characteristics of adult rats. On the other hand, in the young adult P28 rats, EMR induced morphological signs typical of early postnatal age. These findings indicate that EMR causes age related changes in the production of nitric oxide (NO), which may lead to different courses of the proliferation cascade in newborn and young adult neurogenesis. PMID- 20950844 TI - Chewing gum has a stimulatory effect on bowel motility in patients after open or robotic radical cystectomy for bladder cancer: a prospective randomized comparative study. AB - OBJECTIVES: To determine whether chewing gum during the postoperative period facilitates the recovery of bowel function and has different efficacy according to operative method used in patients with radical cystectomy. METHODS: From July 2007 to September 2009, we randomized open radical cystectomy (ORC) patients into Group AI (ORC without gum chewing) and Group AII (ORC with gum chewing). Robot assisted radical cystectomy (RARC) patients were randomized into Group BI (RARC without gum chewing) and Group BII (RARC with gum chewing). RESULTS: A total of 32 ORC (17 Group AI and 15 Group AII) and 28 RARC (13 Group BI and 15 Group BII) patients were completed. The patient's perioperative data between the control (AI + BI) and chewing gum (AII + BII) group showed no differences. The median time to flatus and to bowel movement were significantly reduced in chewing gum group compared with the control patients: 57.1 vs. 69.5 hours 76.7 vs. 93.3 hours. In the ORC patients, decrease in time to flatus and bowel movement were observed in gum chewing (AII) group than control (AI) group: 64.3 vs. 80.3 hours 83.8 vs. 104.2 hours. In RARC patients, decrease in time to flatus and bowel movement were found in gum chewing (BII) group than control (BI) group: 48.8 vs. 60.3 hours 69.1 vs. 84.6 hours. No adverse effects were observed with chewing gum. CONCLUSIONS: Chewing gum had stimulatory effects on bowel motility after cystectomy and urinary diversion. Chewing gum was safe and could be used for postoperative ileus regardless of the operative method (ORC or RARC). PMID- 20950845 TI - Outcomes after radiation therapy with concurrent weekly platinum-based chemotherapy or every-3-4-week 5-fluorouracil-containing regimens for squamous cell carcinoma of the vulva. AB - OBJECTIVE: To compare outcomes in patients with squamous cell carcinoma (SCC) of the vulva treated with radiation (RT) and concurrent weekly platinum-based or every-3-4-week regimens containing 5-fluorouracil (5-FU). METHODS: Records of 44 patients with vulvar SCC treated with concurrent chemotherapy and radiation (chemoRT) from 1988 to 2008 were reviewed. Rates of disease-free survival (DFS), overall survival (OS), locoregional recurrence (LRR), and distant metastases (DM) were estimated using the Kaplan-Meier method. RESULTS: The median age was 63 years (range, 44-90), 84.1% of patients had ECOG performance status 0-1, and patients had FIGO Stage II (n=6), III (n=31), or IVA (n=7) disease. Patients were treated preoperatively (n=10), postoperatively (n=10), or without surgery (n=24). The median RT dose to the vulva was 50.2 Gray (range, 22-75). Concurrent chemotherapy regimens included weekly platinum (n=16) or every 3-4 week regimens with 5-FU as the backbone (n=28). With a median follow-up of 31.5 months, there was no significant difference in 2-year OS (74.5% vs. 70.0%; p=0.65), DFS (61.9% vs. 56.0%; p=0.85), LRR (31.3% vs. 32.9%; p=0.93), or DM (6.3% vs. 10.6%; p=0.81) between the weekly platinum and every-3-4-week 5-FU regimens. Twenty patients (45.4%) recurred: 16 LRR, 2 DM, and 2 with both. The clinical and pathologic complete response rates were 58.8% (20/34), and 53.8% (14/26), respectively. There was a higher proportion of grade 3 or higher acute non-skin toxicities in patients receiving every-3-4-week 5-FU (46.1% vs. 13.3%; p=0.07), but more grade 3 or higher skin toxicity in patients receiving weekly platinum (62.5% vs. 32.0%; p=0.01). CONCLUSION: OS, response rates, and recurrence rates were not significantly different after RT with concurrent weekly platinum-based versus every-3-4-week regimens containing 5-FU for vulvar SCC. PMID- 20950846 TI - Progranulin is a potential prognostic biomarker in advanced epithelial ovarian cancers. AB - OBJECTIVE: There are few validated relapse prediction biomarkers for epithelial ovarian cancer (EOC). We have shown progranulin (PGRN) and secretory leukocyte protease inhibitor (SLPI) are up regulated, overexpressed survival factors in EOC. We hypothesized they would predict presence of occult EOC. METHOD: PGRN, SLPI, and the known biomarker HE4 were measured in EOC patient plasma samples, prospectively collected every 3 months from initial remission until relapse. Clinical data and CA125 results were incorporated into statistical analyses. Exploratory Kaplan-Meier estimates, dividing markers at median values, evaluated association with progression-free survival (PFS) and overall survival (OS). Area under-the-curve (AUC) statistics were computed from receiver operating characteristic (ROC) curves to evaluate discrimination ability. A Cox proportional hazards model assessed the association between PFS, OS, and biomarkers, adjusting for clinical prognostic factors. RESULTS: Samples from 23 advanced stage EOC patients were evaluated. PGRN at 3 months was the only biomarker independently associated with PFS (P<0.0001) and OS (P<0.003). When used to predict progression by 18 months, sensitivity and specificity were 93% and 100%, respectively, with AUC=0.944. The Cox model hazard ratio for PFS, divided at 59 ng/ml by ROC analysis and adjusted for clinical factors, was 23.5 (95% CI: 2.49-220). Combinations with SLPI, HE4, and/or CA125 did not improve the model. CONCLUSIONS: We report pilot data indicating a potential independent association of PGRN on EOC patient PFS and OS. A validation study will be required to confirm this finding and to inform whether PGRN warrants evaluation as a potential screening biomarker. PMID- 20950847 TI - Quantification of intracellular HPV E6/E7 mRNA expression increases the specificity and positive predictive value of cervical cancer screening compared to HPV DNA. AB - OBJECTIVES: Current methods for HPV screening rely on the detection of L1 DNA from high risk genotypes (HRHPV). These assays have very high negative predictive values (~99%), however, the specificity and positive predictive value of HPV DNA tests for pre-cancerous and cancerous lesions (CIN 2+) is less than 50%. The purpose of this study was to compare HPV DNA with intracellular HPV E6, E7 mRNA quantification in an effort to improve the performance of cervical cancer screening. METHODS: Liquid-based cervical cytology specimens collected in either PreservCyt or SurePath were processed for routing cytology, HPV HRDNA detection by Hybrid Capture 2 and HPV E6, E7 mRNA quantification in cells using the same sample. We analyzed a total of 2049 samples including 73 with CIN 2, CIN 3, or squamous cell carcinoma by biopsy and 1694 samples from women with normal cytology. RESULTS: The positive predictive value of HPV E6, E7 mRNA quantification in cells for CIN2+ was 78% which was greater than HPV DNA alone (43%). The specificity of HPV E6, E7 mRNA quantification was 96% based on normal cytology compared to 82% for HC2 while the specificity of HPV E6, E7 mRNA quantification based on CIN 2- histology was 85% compared to 35% for HC2. CONCLUSIONS: With similar sensitivity and greater specificity/positive predictive value, HPV E6, E7 mRNA quantification in cells is an improvement over HPV DNA for cervical cancer screening. PMID- 20950848 TI - On being aware and accepting: a one-year longitudinal study into adolescent well being. AB - The nature and potential benefit of awareness and experiential acceptance in adolescence remains neglected and understudied. To address this gap in the literature, 776 students (50% female) in Grade 10 completed measures of mindfulness, emotional awareness, and experiential acceptance, as well as measures of major personality traits. To study prospective changes, assessments of emotional well-being were completed across a 1-year interval. Analyses revealed that "Acting with Awareness" (engaging fully in one's current activity with undivided attention), emotional awareness, and experiential acceptance where all linked to prosocial tendencies and uniquely predicted increases in well-being across the year. Observing experience (noticing, observing, and attending to a variety of stimuli) was correlated with positive and negative aspects of personality and did not predict changes in well-being. We discuss the implications for understanding awareness and acceptance in youth. PMID- 20950849 TI - Neonatal vitamin A supplementation and infant survival. PMID- 20950850 TI - Colloidal complexed silver and silver nanoparticles in extrapallial fluid of Mytilus edulis. AB - Metal transport in mollusk extrapallial fluid (EPF) that acts as a "bridge" between soft tissues and shell has surprisingly received little attention until now. Using ultrafiltration and radiotracer techniques we determined silver concentrations and speciation in the EPF of the blue mussel Mytilus edulis after short-term uptake and depuration laboratory experiments. Radiolabelled silver ((110m)Ag) was used in dissolved or nanoparticulate phases (AgNPs < 40 nm), with a similar low Ag concentration (total radioactive and cold Ag ~0.7 MUg/L) in a way that mussels could uptake radiotracers only from seawater. Our results indicated that silver nanoparticles were transported to the EPF of blue mussels at a level similar to the Ag ionic form. Bulk activity of radiolabelled silver in the EPF represented only up to 7% of the bulk activity measured in the whole mussels. The EPF extracted from mussels exposed to both treatments exhibited an Ag colloidal complexed form based on EPF ultrafiltration through a 3 kDa filter. This original study brings new insights to internal circulation of nanoparticles in living organisms and contributes to the international effort in studying the potential impacts of engineered nanomaterials on marine bivalves which play an essential role in coastal ecosystems, and are important contributors to human food supply from the sea. PMID- 20950851 TI - Biocompatibility of adhesive complex coacervates modeled after the sandcastle glue of Phragmatopoma californica for craniofacial reconstruction. AB - Craniofacial reconstruction would benefit from a degradable adhesive capable of holding bone fragments in three-dimensional alignment and gradually being replaced by new bone without loss of alignment or volume changes. Modeled after a natural adhesive secreted by the sandcastle worm, we studied the biocompatibility of adhesive complex coacervates in vitro and in vivo with two different rat calvarial models. We found that the adhesive was non-cytotoxic and supported the attachment, spreading, and migration of a commonly used osteoblastic cell line over the course of several days. In animal studies we found that the adhesive was capable of maintaining three-dimensional bone alignment in freely moving rats over a 12 week indwelling period. Histological evidence indicated that the adhesive was gradually resorbed and replaced by new bone that became lamellar across the defect without loss of alignment, changes in volume, or changes in the adjacent uninjured bone. The presence of inflammatory cells was consistent with what has been reported with other craniofacial fixation methods including metal plates, screws, tacks, calcium phosphate cements and cyanoacrylate adhesives. Collectively, the results suggest that the new bioadhesive formulation is degradable, osteoconductive and appears suitable for use in the reconstruction of craniofacial fractures. PMID- 20950852 TI - The regeneration of transected sciatic nerves of adult rats using chitosan nerve conduits seeded with bone marrow stromal cell-derived Schwann cells. AB - Autologous nerve grafts have been the 'gold standard' for treatment of peripheral nerve defects that exceed the critical gap length. To address issues of limited availability of donor nerves and donor site morbidity, we have fabricated chitosan conduits and seeded them with bone marrow stromal cell (BMSC)-derived Schwann cells as an alternative. The derived Schwann cells used were checked for fate commitment. The conduits were tested for efficacy in bridging the critical gap length of 12 mm in sciatic nerves of adult rats. By three months post operation, mid-shank circumference, nerve conduction velocity, average regenerated myelin area, and myelinated axon count, in nerves bridged with BMSC derived Schwann cells were similar to those treated with sciatic nerve-derived Schwann cells (p > 0.05) but significantly higher than those bridged with PBS filled conduits (p < 0.05). Evidence is thus provided in support of the use of chitosan conduits seeded with BMSC-derived Schwann cells to treat critical defects in peripheral nerves. This provides the basis to pursue BMSC as an autologous source of Schwann cells for transplantation therapy in larger animal species. PMID- 20950853 TI - Doxycycline hydrogels with reversible disulfide crosslinks for dermal wound healing of mustard injuries. AB - Doxycycline hydrogels containing reversible disulfide crosslinks were investigated for a dermal wound healing application. Nitrogen mustard (NM) was used as a surrogate to mimic the vesicant effects of the chemical warfare agent sulfur mustard. An 8-arm-poly(ethylene glycol) (PEG) polymer containing multiple thiol (-SH) groups was crosslinked using hydrogen peroxide (H(2)O(2) hydrogel) or 8-arm-S-thiopyridyl (S-TP hydrogel) to form a hydrogel in situ. Formulation additives (glycerin, PVP and PEG 600) were found to promote dermal hydrogel retention for up to 24 h. Hydrogels demonstrated high mechanical strength and a low degree of swelling (< 1.5%). Doxycycline release from the hydrogels was biphasic and sustained for up to 10-days in vitro. Doxycycline (8.5 mg/cm(3)) permeability through NM-exposed skin was elevated as compared to non vesicant treated controls at 24, 72 and 168 h post-exposure with peak permeability at 72 h. The decrease in doxycycline permeability at 168 h correlates to epidermal re epithelialization and wound healing. Histology studies of skin showed that doxycycline loaded (0.25% w/v) hydrogels provided improved wound healing response on NM-exposed skin as compared to untreated skin and skin treated with placebo hydrogels in an SKH-1 mouse model. In conclusion, PEG-based doxycycline hydrogels are promising for dermal wound healing application of mustard injuries. PMID- 20950854 TI - Incorporation of proteinase inhibitors into silk-based delivery devices for enhanced control of degradation and drug release. AB - Controlling the rate of silk degradation is critical to its potential use in biomedical applications, including drug delivery and tissue engineering. The effect of protease concentration on accelerating degradation, and the use of ethylenediamine tetraacetic acid (EDTA) on reducing rates of degradation and on drug release from silk-based drug carriers was studied. Increased rates of proteolysis resulted in increased dye release from silk carriers, while EDTA release from the silk carriers inhibited proteolysis. The sustained release of EDTA from silk carriers in combination with the release of the small molecule anti-convulsant adenosine was investigated in vitro. This combination of factors resulted in delayed release of adenosine by inhibiting proteolytic activity. These results introduce a promising strategy to control drug delivery through the regulation of silk degradation rate, achieved via manipulation of local proteolytic activity. This ability to modulate enzyme function could be applicable to a range of silk biomaterial formats as well as other biodegradable polymers where enzymatic functions control biomaterial degradation and drug release rates. PMID- 20950855 TI - The isolation of cell derived extracellular matrix constructs using sacrificial open-cell foams. AB - Extracellular matrix derived from human and animal tissues is being used to repair and reconstruct a variety of tissues clinically. The utility of such constructs is limited by the geometry, composition and constitutive properties of the tissue or organ from which the ECM is harvested. To address this limitation, we have developed an approach to isolate extracellular matrix in bulk from populations of living cells grown in culture on three-dimensional substrates. Human biopsy derived fibroblasts were seeded within open-cell foams and cultured in-vitro for periods up to three weeks, after which the synthetic component was removed by incubation in a water miscible solvent. After several wash steps and lyophilization, a white, lacy, multi-molecular construct was isolated. Tandem mass spectroscopy showed that it contained 22 extracellular matrix constituents, including such proteins and proteoglycans as collagen type I and type III, fibronectin, transforming growth factor beta, decorin and biglycan among others. On average 47 mg of construct was isolated for each gram of synthetic substrate initially seeded with cells. The biomaterial harvested from human tracheal fibroblasts had an elastic modulus (250 kPa) and a composition similar to that of human vocal fold tissue, and supported reseeding with human tracheal derived fibroblasts. An important finding was that the approach was useful in isolating ECM from a variety of cell lineages and developmental stages including skin fibroblasts, brain derived astrocytes and mesenchymal stem cells. The results, together with the archival literature, suggest that the approach can be used to produce a range of cell derived constructs with unique physical and chemical attributes for a variety of research and medical applications. PMID- 20950856 TI - Deportation of syncytial sprouts from the term human placenta. AB - Deportation of syncytial sprouts into the maternal circulation during early pregnancy is a well-accepted phenomenon. Whether the process continues throughout pregnancy has been more contentious. This study aimed to resolve the question through the study of serial sections derived from 5 normal term placentas. In each case, sprouts containing euchromatic nuclei were observed in the intervillous space, clearly detached from neighbouring villi. Deportation of sprouts therefore continues until term. PMID- 20950857 TI - Gender differences in internalizing problems among sexually abused early adolescents. AB - OBJECTIVE: The purpose of this study was twofold. First, we determined whether sexually abused adolescent boys or girls were more likely to have internalizing behavior scores in the clinical range. Second, after determining boys were more likely than girls to have an internalizing behavior problem, we tested whether this relationship would persist after several other variables were accounted for: characteristics of the sexual abuse, exposure to domestic violence, self efficacy, and their peer and caregiver relationships. METHODS: A national probability sample of children investigated by child protective services for child maltreatment was used. The sample consisted of 127 girls and 31 boys, ages 11-14. RESULTS: Sexually abused boys were more likely than girls to have an internalizing behavior problem in the clinical range even after controlling for several variables. Exposure to domestic violence, more severe sexual abuse, sexual abuse by a non-relative, and the amount of autonomy support provided by caregivers also increased the likelihood internalizing problem. CONCLUSIONS: During early adolescence, sexually abused boys may be more likely than sexually abused girls to have a clinically significant internalizing behavior problem. Researchers need to continue to investigate whether sexually abused boys are as likely as girls or more likely than girls to have an internalizing behavior problem in later adolescence. PRACTICE IMPLICATIONS: Internalizing symptoms warrant careful screening and assessment with sexually abused boys and girls who experience more intrusive sexual abuse, who are sexually abused by a non relative, who are exposed to domestic violence, and who receive lower autonomy support from their caregivers. PMID- 20950858 TI - Influence of Ca/Mg ratio on phytoextraction properties of Salix viminalis. II. Secretion of low molecular weight organic acids to the rhizosphere. AB - A hydroponic experiment in a phytotron was performed to investigate the effect of two different Ca/Mg ratios (4:1 and 1:10) and trace element ions (Cd, Cu, Pb and Zn) in solution on the efficiency of low molecular weight organic acid (LMWOA) formation in Salix viminalis rhizosphere. Depending on the Ca/Mg ratio and presence of selected trace elements at 0.5mM concentration, the amount and kind of LMWOAs in the rhizosphere were significantly affected. In physiological 4:1 Ca/Mg ratio the following complex of acids was observed: malonic (Pb, Zn), citric, lactic, maleic and succinic (Zn) acids. Under 1:10 Ca/Mg ratio, citric (Cd, Zn), maleic and succinic (Cd, Cu, Pb, Zn) acids were seen. Additionally, high accumulation of zinc and copper in all systems was observed, with the exception of those where one of the metals was at higher concentration. Summing up, the results indicate a significant role of LMWOAs in Salix phytoremediation abilities. Both effects can be modulated depending on the mutual Ca/Mg ratio. PMID- 20950859 TI - Magnetic resonance spectroscopy of a cerebral parasitic cyst. PMID- 20950860 TI - Dynamic perfusion-CT assessment of early changes in blood brain barrier permeability of acute ischaemic stroke patients. AB - BACKGROUND AND PURPOSE: Damage to the blood brain barrier (BBB) may lead to haemorrhagic transformation after ischaemic stroke. The purpose of this study was to evaluate the effect of patient characteristics and stroke severity on admission BBB permeability (BBBP) values measured with perfusion-CT (PCT) in acute ischaemic stroke patients. METHODS: We retrospectively identified 65 patients with proven ischaemic stroke admitted within 12 hours after symptom onset. Patients' charts were reviewed for demographic variables and vascular risk factors. The Patlak's model was applied to calculate BBBP values from the PCT data in the infarct core, penumbra and non-ischaemic tissue in the contralateral hemisphere. Mean BBBP values and their 95% confidence intervals (CI) were calculated in the different tissue types. Effects of demographic variables and risk factors on BBBP were analyzed using a multivariate, generalized estimating equations (GEE) model. RESULTS: BBBP values in the infarct core (mean [95%CI]: 2.48 [2.16-2.85]) and penumbra (2.48 [2.21-2.79]) were significantly higher than in non-ischaemic tissue (2.12 [1.88-2.39]). Multivariate analysis demonstrated that collateral filling has effect on BBBP. Less elevated BBBP values were associated with more than 50% collateral filling. CONCLUSIONS: BBBP values are increased in ischaemic brain tissue on the admission PCT scan of acute ischaemic stroke patients. Less abnormally elevated BBBP values were observed in patients with more than 50% collateral filling, possibly explaining why there is a relationship between more collateral filling and a lower incidence of haemorrhagic transformation. PMID- 20950861 TI - Regulatory B cells: evidence, developmental origin and population diversity. AB - The adaptive immune system has developed several highly effective mechanisms in order to avoid excessive or unwanted reactions and promote resolution of immune activation. An emerging, significant body of evidence indicates that B cells can actively modulate immune responses by mechanisms that do not directly involve the production of antibodies. B cells appear to have the capacity to both induce and suppress immune effector mechanisms and they exert these functions both by contact-dependent interactions and through the secretion of cytokines. In this review we will focus on the regulatory suppressive function of several recently described B cell populations, functionally defined "regulatory B cells" or Breg cells. We will first outline the evidence that has led to their identification and then we will summarize current hypotheses on their ontogeny and possible lineage relationship. PMID- 20950862 TI - Rate of non-adherence prior to upward dose titration in previously stable antidepressant users. AB - BACKGROUND: Non-adherence to antidepressant medications is a contributing factor to disease relapse and may result in needless increases in antidepressant dosing. METHODS: We analyzed de-identified patient claims data from Medco Health Solutions, Inc.'s information database and measured adherence as the medication possession ratio (MPR), with adequate adherence as MPR >=80%. Adherence was calculated for patients in whom antidepressants were dose escalated and who were on the same antidepressant medication for at least 180 days before the upward dosage titration. Statistical analysis was performed on subgroups comparing adherence with mail vs. retail channels, differences in age and gender, generic prescription vs. brand only, and prescription by psychiatrist vs. non psychiatrist. RESULTS: 29.7% of patients were non-adherent to their antidepressant medication during the 6 months prior to a prescribed increase in dosage. Non-adherence was significantly lower among patients using the Medco Therapeutic Resource Centers(r) mail order vs. retail channel. Younger age correlated with poorer adherence. Rates of non-adherence were also significantly greater among women, those receiving generic medications, and among patients with overall lower disease comorbidity. Adherence was not significantly impacted by prescription from a psychiatrist or a non-psychiatrist. LIMITATIONS: Retrospective design and use of an administrative patient claims database. CONCLUSIONS: Suboptimal medication adherence commonly precedes an upward dosage titration of antidepressant medications. Utilization of a mail order channel may improve adherence. Clinicians prescribing antidepressants should explore adherence issues carefully prior to recommending an increase in dosage. PMID- 20950863 TI - Optimal duration of combined psychotherapy and pharmacotherapy for patients with moderate and severe depression: a meta-analysis. AB - BACKGROUND: To investigate the most effective duration of combined psychotherapy and pharmacotherapy for achieving remission and preventing relapse in depressive patients as compared to pharmacotherapy alone. METHODS: A systematic review of English articles using PubMed, EMBASE, Web of Science, the Cochrane Library, and PsychINFO was performed in September 2009. Clinical studies comparing pharmacotherapy alone with pharmacotherapy in combination with a psychological intervention for depression treatment that reported response, remission or relapse as outcomes were included in the analysis. For each of the studies, clinical binary outcomes such as response, remission or relapse were extracted. RESULTS: All pooled analyses were based on random-effects models. Twenty-one article describing the influence of additional psychotherapy on remission and 15 articles reporting the influence on relapse in depression were included in the analysis. Patients receiving combined treatment experienced remission more often than those receiving pharmacotherapy alone, with the highest odds ratio OR, 2.36; 95% CI, 1.58-3.55 observed at 4months after commencing the treatment. Patients receiving pharmacotherapy alone also demonstrated a higher risk for relapse compared to those receiving combined treatment. LIMITATIONS: We restricted our search to only English language publications. Studies investigating relapse or recurrence rates are often of small size. CONCLUSION: Pharmacotherapy enhanced with psychotherapy is associated with a higher probability of remission and a lower risk of relapse, as compared to antidepressants alone for depression treatment. Receiving psychotherapy in both the acute and continuation phases is the most effective option. Further research is needed to investigate the influence of additional psychotherapy on different patients. PMID- 20950864 TI - Identification of post traumatic stress disorder and risk factors in military first responders 6 months after Wen Chuan earthquake in China. AB - BACKGROUND: Military personnel commonly serve as first responders to natural disasters. Our aim is to identify Post-Traumatic Stress Disorder (PTSD) and determine risk in military responders to the Wen Chuan earthquake. METHODS: Analyses were carried out on 1056 of the 1125 soldiers enrolled. In addition to social demographic characteristics, the Davidson Trauma Scale (DTS) and an Earthquake exposure screening scale were administered. RESULTS: PTSD prevalence was 6.53% (69 cases). Logistic regression indicated that intensity of traumatic exposure (odds ratio 6.46, 95% CI 4.47-9.32, p<0.001), not having received psychological counseling (odds ratio 3.28, 95% CI 1.31-8.20, p<0.02) and regular drinking (odds ratio 2.42, 95% CI 1.04-5.62, p<0.05) were significant predictors of PTSD. Being a single-child, not being raised by both parents and regular smoking also independently predicted PTSD if intensity of earthquake traumatic exposure was not included in the model. LIMITATIONS: The self-rated DTS was used to classify PTSD in this study and psychiatric co-morbidity outside of PTSD was not assessed in this sample. CONCLUSION: PTSD is a concern for Military disaster responders; to identify those with high risk of developing PTSD would be important and beneficial. PMID- 20950865 TI - Was Freud partly right on obsessive-compulsive disorder (OCD)? Investigation of latent aggression in OCD. AB - Inflated responsibility is increasingly regarded a pathogenetic mechanism in obsessive-compulsive disorder (OCD). In seeming contrast, there is mounting evidence that latent aggression is also elevated in OCD. Building upon psychodynamic theories that an altruistic facade including exaggerated concerns for others is partly a defense against latent aggression, evidence was recently obtained for high interpersonal ambivalence in OCD patients relative to psychiatric and healthy controls using a newly developed instrument entitled the Responsibility and Interpersonal Behaviors and Attitudes Questionnaire (RIBAQ). A total of 46 OCD patients and 23 healthy participants took part in the present study. OCD patients displayed a higher social responsibility than controls. At the same time, patients also disclosed more latent aggression/calculating behavior and interpersonal distrust. While the pathogenic role of latent aggression is still not fully uncovered, it may deserve more consideration in treatment in view of frequent tensions in the families of OCD patients. Longitudinal studies with at-risk sample are needed to assess the relationship between problems with anger expression as well as (exaggerated) moral standards in OCD. PMID- 20950867 TI - Gender differences in CNS autoimmunity induced by mimicry epitope for PLP 139-151 in SJL mice. AB - Development of multiple sclerosis (MS) is more prevalent in females than in males, but the underlying mechanisms are not clear. Microbial infections have been suspected as triggers of MS and it is not known whether gender differences in reactivity to environmental antigens contribute to the disease pathogenesis. We demonstrated that ACA 83-95, a mimicry epitope from Acanthamoeba castellanii for proteolipid protein (PLP) 139-151, induces clinical signs of encephalomyelitis in both male and female SJL mice. Conversely ACA 83-95-induced effector cells from males fail to induce disease in female mice. Although we found no gender differences in the frequencies of antigen-specific cells including cytokine production, PLP-specific cells induced with ACA 83-95 differed in T cell receptor vbeta usage from those induced with PLP 139-151. The data suggest that cross-reactive T cell expansion occurs similarly in both males and females, but their disease-inducing ability is influenced by gender. PMID- 20950866 TI - Enhanced neuronal expression of major histocompatibility complex class I leads to aberrations in neurodevelopment and neurorepair. AB - Mice deficient in classical major histocompatibility complex class I (MHCI) have aberrations in neurodevelopment. The consequences of upregulated neuronal MHCI expression have not been examined. We found that transgenic C57Bl/6 mice that are engineered to express higher levels of self-D(b) on their CNS neurons have alterations in their hippocampal morphology and retinogeniculate projections, as well as impaired neurorepair responses. Thus, enhanced neuronal classical MHCI expression can lead to aberrations in neural circuitry and neurorepair. These findings complement a growing body of knowledge concerning the neurobiological activities of MHCI and may have potential clinical relevance. PMID- 20950869 TI - Adjuvant-induced arthritis induces c-Fos chronically in neurons in the hippocampus. AB - Chronic pain, sickness behaviors, and cognitive decline are symptoms in rheumatoid arthritis. In the adjuvant-induced arthritis Lewis rat model, we examined the dynamics of c-Fos expression in the hippocampus, a brain region important for these symptoms. Brain sections were stained for c-Fos using immunohistochemistry. c-Fos-positive nuclei were counted in CA1, CA2, CA3 and the dentate gyrus of the dorsal hippocampi from rats receiving no treatment or base of-the-tail injections of (1 or 2) incomplete or complete Freund's adjuvant (low- or high-dose), (3), Mycobacterium butyricum cell wall suspended in saline, or (4) saline, and sacrificed 4, 14, 21, or 126days post-immunization. Disease severity was evaluated by dorsoplantar foot pad widths and X-ray analysis. We report sustained dose- and subfield-dependent c-Fos expression with arthritis, but transient expression in nonarthritic groups, suggesting long-term genomic changes in rheumatoid arthritis that may be causal for behavioral changes, adaptation to chronic pain and/or cognitive decline associated with disease. PMID- 20950870 TI - Infantile myofibroma of the nasal cavity; a case report and review of the literature. AB - Infantile myofibroma is the most common fibrous tumor of infancy. Although the etiology is unknown, some cases are associated with a genetic inheritance of variable penetrance. With a myriad of possible locations, the presenting symptoms and findings are highly variable making its diagnosis difficult. Worldwide, there have been close to three hundred reported cases. Approximately 90% of these cases presented before age 2 with over half present at birth. The incidence is likely to be greater as many asymptomatic or hidden lesions will regress prior to discovery. The following is a report on a 7 month old male diagnosed with an infantile myofibroma within his right nasal cavity originating from the anterior skull base. This case is unusual in both its symptom presentation as well as location of origin of this tumor. PMID- 20950868 TI - Induction of pregnancy during established EAE halts progression of CNS autoimmune injury via pregnancy-specific serum factors. AB - Multiple sclerosis (MS) is a demyelinating disease of the CNS involving T cell targeting of myelin antigens. During pregnancy, women with MS experience decreased relapses followed by a post partum disease flare. Using murine experimental autoimmune encephalomyelitis, we recapitulate pregnancy findings in both relapsing and progressive models. Pregnant mice produced less TNF-alpha, IL 17 and exhibited reduced CNS pathology relative to non-pregnant controls. Microparticles, called exosomes, shed into the blood during pregnancy were isolated and found to significantly suppress T cell activation relative to those from non-pregnant controls. These results demonstrate the immunosuppressive potential of pregnancy and serum-derived pregnancy exosomes. PMID- 20950871 TI - Comparison between symptoms and endoscopy in children with nasal obstruction. AB - OBJECTIVE: Nasal obstruction is a common symptom in childhood. It may be frequently observed in children with allergic rhinitis and/or adenoidal hypertrophy. However, its assessment is very difficult. The aim of the study was to compare the use of both a Face Related Scale (FRS), recorded by children and their parents, and a simplified Visual Analogue Scales (sVAS) with nasal endoscopy in children complaining nasal obstruction. METHODS: 121 children (75 males, mean age 7.5 years) were studied. FRS and sVAS for nasal obstruction and endoscopy were performed in all patients. RESULTS: A moderate correlation has been observed between FRS and sVAS and obstruction of nasal anterior segment (r=0.51 for FRS; r=0.52 for sVAS), a strong correlation was observed with nasal posterior segment (r=0.60 for FRS; r=0.61 for sVAS) assessed by endoscopy. However, parents' perception did not relate with objective parameters. CONCLUSIONS: This study suggests that assessment of FRS and sVAS for nasal obstruction may be used in clinical practice to approximately quantify this symptom in children. PMID- 20950872 TI - Improving door-to-balloon times in Asia for acute ST elevation myocardial infarction via direct activation by emergency physicians of percutaneous coronary intervention. PMID- 20950873 TI - Shedding light on intracoronary pathophysiology. AB - There is a new player in the field of interventional cardiology. It is optical coherence tomography (OCT), an imaging modality analogous to intravascular ultrasound (IVUS), but using light instead of sound. The paper by Yonetsu et al in this issue of the IJC is therefore of timely interest, as an illustration of where OCT evaluation of coronary pathophysiology is at present, and what the future might hold. PMID- 20950874 TI - Arrhythmia discrimination by physician and defibrillator: importance of atrial channel. AB - BACKGROUND: Many ICD carriers experience inappropriate shocks, but the relative merits of dual- /single-chamber devices for arrhythmia discrimination still remain unclear. We explored possible advantages of the atrial data provided by dual-chamber implantable defibrillators (ICD) for discrimination of real-life supraventricular/ventricular tachyarrhythmias (SVT/VT). METHODS: 100 dual-chamber traces from 24 ICD were blindly reviewed in dual-chamber and simulated single chamber (with/without discriminator data) reading modes by five electrophysiologists who determined chamber of origin and provided Likert-scale "confidence" ratings. We assessed 1) intra/interobserver concordance; 2) diagnostic accuracy, using expert diagnoses as a reference standard; 3) ROC curves of sensitivity/specificity of "likelihood perception" scores, generated by combining chamber-of-origin diagnostic judgments with Likert-scale "confidence" ratings. We also assessed diagnostic accuracy of automated discrimination by all possible dual-/single-chamber algorithm configurations. RESULTS: Interobserver concordance was "substantial" (modified Cohen kappa-test values for dual-/single chamber, 0.79/0.68); intraobserver concordance "almost complete" (kappa >= 0.89). Dual-chamber mode provided best diagnostic sensitivity/specificity (99%/92%) and highest reader confidence (p<0.001). Area under ROC curves of sensitivity/specificity values for the "likelihood perception" score (representing electrophysiologists' perceptions of the likelihood that an episode was of ventricular origin) was highest in dual-chamber mode (0.98 vs. 0.93 for both single-chamber modes; p<0.001). Regarding automated discrimination, all four dual-chamber configurations conferred 100% sensitivity (specificity values ranged 39%-88%), whereas single-chamber configurations appeared inferior (best sensitivity/specificity combination, 89%/64%). CONCLUSIONS: Availability of the atrial channel helps in reducing inappropriate ICD therapies by providing relevant advantages in terms of both appropriate cardiologist's post-hoc discrimination of SVT/VT (improving program tailoring) and automated arrhythmia discrimination. PMID- 20950875 TI - Epidemiological research and evidence based medicine: How do they fit and for whom. AB - Evidence based medicine involves using the best current information to inform patient care. In veterinary medicine, evidence based veterinary medicine (EBVM) has been discussed for about 15 years. Epidemiology and EBVM are closely linked and epidemiologists can provide crucial support for the practice of EBVM. The secondary literature which summarizes important research into more accessible and applied work could benefit from additional involvement by epidemiologists. Epidemiologists have a broad range of stakeholders for their work and should consider who the specific audience is and what the important endpoints are for that audience. More work on reporting guidelines for observational studies and on issues relating to external validity are needed to facilitate EBVM. Epidemiologists should consider teaching veterinary, graduate and post-graduate students how to perform EBVM. Getting credit for efforts which support EBVM can be difficult but creative presentation of work, publications and grants relating to EBVM should help. Quite a few veterinary journals are actively soliciting manuscripts relating to EBVM. PMID- 20950876 TI - Quality standards are needed for reporting of test accuracy studies for animal diseases. AB - The STARD statement (www.stard-statement.org) emphasizes complete and transparent reporting of key elements of test accuracy studies. Guidelines for authors in many biomedical journals recommend adherence to these standards but explicit recommendations by editors of veterinary journals are limited. Adherence to standards benefits end-users of tests including doctors, veterinarians and other healthcare professionals and the human and animal patients in which the tests are used. Reporting standards also provide a structured basis for researchers and graduate students to prepare manuscripts, and subsequently can be a useful adjunct to the peer-review process. This paper discusses the purpose of STARD and its possible modification for animal disease studies, variation in reporting and design quality in human and animal disease studies, use of a different instrument (QUADAS) for assessing methodological quality, and provides some recommendations for the future. Finally, the contributions of Dr. Hollis Erb to improvements in methodological and reporting qualities of test accuracy studies in Preventive Veterinary Medicine are described. PMID- 20950877 TI - A PathWayDiagram for introduction and prevention of Avian Influenza: Application to the Dutch poultry sector. AB - The introduction of Highly Pathogenic Avian Influenza (HPAI) viruses is a continuing threat to the poultry sector. In times of increased risk of introduction (e.g. because of HPAI outbreaks in neighbouring countries or trade partners), decision-makers face the question whether they should intensify current preventive measures or establish new ones. To support this, a qualitative decision tool in the form of a PathWayDiagram (PWD) is presented. The PWD includes theoretically possible pathways for introduction of HPAI in the domestic commercial poultry population together with corresponding preventive measures. Hence, the PWD is a systematic checklist focused on (1) possibilities of (increased risk of) introduction and (2) possible preventive measures. It can be used in a high-alert situation, when decision-makers have to act in a relatively short time to decide on and implement a coherent set of preventive measures covering the high-risk pathways involved. PMID- 20950878 TI - Patterns of care for brachytherapy in Europe: updated results. AB - OBJECTIVE: This descriptive survey evaluated brachytherapy (BT) practices and resources in the European area. This was a follow-up study to the original patterns of care for brachytherapy in Europe (PCBE). MATERIALS AND METHODS: A total of 1121 radiotherapy (RT) centres from 41 countries were asked to complete an online questionnaire on BT practices and resources. Countries with fewer than 50% of centres responding were excluded. Participating countries were divided into three groups based on gross domestic product (GDP); group I contained the countries with the highest GDP. RESULTS: The response rate was 56% (633/1121 centres) with 30/41 countries (73%) meeting the inclusion criteria. Sixty percent of reporting centres provided brachytherapy. Responding centres treated an average of 138 (+/-10, 1 SD) patients with BT; in group I, the mean was 110/centre, an increase of 18% from 2002. CT-dosimetry increased to 61% of centres vs. 33% in 2002. HDR (high-dose rate) BT was the most commonly reported technique (65% of centres). Most BT interventions were for gynaecological tumors (59% of all cases), followed by prostate (17%), breast (9%), lung/bronchus (3%), and esophagus tumors(2%). CONCLUSION: Gynaecological BT remains the most common application, although both prostate and breast BT have increased. CT-based dosimetry has become increasingly common since 2002. The use of HDR and PDR (pulsed-dose rate) techniques has increased markedly, while both LDR and MDR (medium-dose rate) have declined. PMID- 20950879 TI - A multi-institutional analysis comparing adjuvant and salvage radiation therapy for high-risk prostate cancer patients with undetectable PSA after prostatectomy. AB - BACKGROUND AND PURPOSE: In men with adverse pathology at the time of radical prostatectomy (RP), the most appropriate timing to administer radiotherapy (RT) remains a subject for debate. To determine whether salvage radiotherapy (SRT) upon early prostate-specific antigen (PSA) relapse is equivalent to immediate adjuvant radiotherapy (ART) post RP. MATERIAL AND METHODS: 130 patients receiving ART and 89 receiving SRT were identified. All had an undetectable PSA after RP. Homogeneous subgroups were built based on the status (+/-) of lymphatic invasion (LVI) and surgical margins (SM), to allow a comparison of ART and SRT. Biochemical disease-free survival (bDFS) was calculated from the date of surgery and from the end of RT. The multivariate analysis was performed using the Cox Proportional hazard model. RESULTS: In the SM-/LVI- and SM+/LVI- groups, SRT was a significant predictor of a decreased bDFS from the date of surgery, while in the SM+/LVI+ group, there was a trend towards significance. From the end of RT, SRT was also a significant predictor of a decreased bDFS in three patient groups: SM-/LVI-, SM+/LVI- and SM+/LVI+. Gleason score >7 showed to be another factor on multivariate analysis associated with decreased bDFS in the SM-/LVI- group, from the date of surgery and end of RT. Preoperative PSA was a significant predictor in the SM-/LVI- group from the date of RP only. CONCLUSIONS: Immediate ART post RP for patients with high risk features in the prostatectomy specimen significantly reduces bDFS after RP compared with early SRT upon PSA relapse. PMID- 20950880 TI - Determinants of variability in waiting times for radiotherapy in the treatment of breast cancer. AB - PURPOSE: To examine psycho-social and geographic determinants of delay in starting radiotherapy in early invasive breast cancer patients. MATERIAL AND METHODS: Waiting time was defined as the time elapsed until the beginning of radiotherapy, starting from the date of surgery (in absence of chemotherapy) or from the end of chemotherapy. RESULTS: Eight hundred and ninety six women aged 24 89 took part in the study. Mean waiting times were 52 days (sd=19) between surgery and radiotherapy and 31 days (sd=14) between chemotherapy and radiotherapy. Differences between radiotherapy centres (p<0.0001) accounted for 30% and 12%, respectively, of total variance in waiting times. Using a multivariate mixed analysis that took into account intra-centre correlation, the time between surgery and radiotherapy was shorter for young patients (p=0.020), those who had sought information about their illness (p=0.024) and those who had undergone surgery and radiotherapy in the same centre (p=0.021). On the other hand, no patient characteristic was associated with the time between chemotherapy and radiotherapy. CONCLUSION: Centre is the major factor that explained longer waiting times in radiotherapy, emphasising the structural hypothesis. It is important to pursue initiatives to improve the organization within radiotherapy centres and then to verify that these initiatives have succeeded in shortening waiting times. PMID- 20950881 TI - Linac-based stereotactic body radiation therapy for treatment of glomus jugulare tumors. AB - BACKGROUND: Glomus jugulare tumors are rare, typically benign, tumors that arise from the neural crest cells that are associated with the autonomic ganglia in and around the jugular bulb. Treatment options for glomus jugulare tumors include embolization followed by resection, fractionated external beam radiation therapy (EBRT), stereotactic radiosurgery (SRS), and/or stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: 18 patients were treated with linear accelerator based stereotactic body radiation therapy (SBRT) between May 2002 and November 2008. Fifteen patients (83%) had single glomus jugulare tumors and 3 patients had bilateral glomus jugulare tumors (although each of these patients had a single tumor targeted). The median tumor volume was 5.83 cm(3) (range, 0.32 35.47 cm(3)). Ten tumors (56%) were previously untreated, and 8 (44%) tumors were persistent after previous surgical resection. One patient had undergone previous EBRT and 2 patients were previously treated with Gamma Knife radiosurgery to the intracranial portion of their tumor, with planned SBRT to the extracranial portion 2-4 months later at our institution. The median prescribed dose was 20 Gy in 3 fractions (range: 16-25 Gy in 1-5 fx) to the 80% isodose line. The median prescription coverage of the tumor was 93.6% (range: 83-98.72%). RESULTS: Median follow-up for the entire cohort was 22 months. All the patients were alive at the time of the last follow-up with imaging available for review. The tumor was stable in 17 patients and decreased in size in one patient--yielding a local control rate of 100%. No patients experienced any new or worsening treatment related neurologic deficits. CONCLUSIONS: SBRT is a safe and efficacious treatment modality for glomus jugulare tumors. PMID- 20950882 TI - Adding external beam to intra-luminal brachytherapy improves palliation in obstructive squamous cell oesophageal cancer: a prospective multi-centre randomized trial of the International Atomic Energy Agency. AB - BACKGROUND: Whether the combination of high dose-rate brachytherapy (HDRBT) and External Beam Radiation Therapy (EBRT) is superior to HDRBT alone for the palliation of oesophageal cancer has only been explored in a previous IAEA pilot randomized trial. METHODS: Two hundred and nineteen patients were randomized to adding EBRT or not, after receiving two fractions of HDRBT within 1 week. Each HDRBT consisted of 8 Gy prescribed at 1cm from source centre. Patients randomized to EBRT received 30 Gy in 10 fractions. The primary outcome was dysphagia-relief experience (DRE). Additional outcomes included various scores, performance status, weight and adverse events. A majority of charts, imaging and radiotherapy plans were externally audited. RESULTS: Median follow-up was 197 days, with a median OS of 188 days and an 18% survival rate at 1 year. DRE was significantly improved with combined therapy, for an absolute benefit of +18% at 200 days from randomization (p=0.019). In longitudinal regression analyses, scores for dysphagia (p=0.00005), odynophagia (p=0.006), regurgitation (p=0.00005), chest pain (p=0.0038) and performance status (p=0.0015) were all significantly improved. In contrast, weight, toxicities and overall survival were not different between study arms. CONCLUSION: Symptom improvement occurs with the addition of EBRT to standard HDRBT. The combination is well tolerated and relatively safe. PMID- 20950883 TI - Effect evaluation of a Motivational Interviewing based counselling strategy in diabetes care. AB - AIM: The present study assessed the effects of a Motivational Interviewing (MI) based counselling training for nurses on clinical, behavioural and process outcomes among diabetes type 2 patients. METHODS: The study is an RCT with follow up measurements after 12 and 24 months. Thirty-three nurses and 584 patients participated. Nurses in the experimental condition received the training; control group nurses were trained after the study. The training consisted of two training sessions, two follow-up meetings, written feedback and three direct feedback sessions. Basic MI-principles and techniques and an MI-based counselling protocol were addressed. RESULTS: Results indicated disadvantageous effects on fat intake and HDL and advantageous effects on chance locus of control and knowledge. No effects were found on vegetable or fruit intake, physical activity, HbA1c, weight, blood pressure, total cholesterol, LDL, triglycerides, health care climate, quality of life or on self-efficacy. CONCLUSIONS: As in other MI studies, mixed results were found. It would be premature to recommend dissemination of MI in diabetes care. More studies are needed in real-world settings with health care professionals of the field instead of intensively trained MI interventionists. Knowledge should be gained about adequate training and factors contributing to the implementation of MI in daily practice. PMID- 20950885 TI - Cardiovascular risk prediction in adults with type 1 diabetes: the Fremantle Diabetes Study. AB - The performance of the Fremantle Diabetes Study cardiovascular risk equation, derived in 1240 individuals with type 2 diabetes, was assessed in a parallel cohort of 117 adults with type 1 diabetes. Despite significantly different phenotypic characteristics, the equation successfully identified adults with type 1 diabetes at increased cardiovascular risk. PMID- 20950884 TI - Prevalence and predictors of osteopenia and osteoporosis in postmenopausal Chinese women with type 2 diabetes. AB - AIMS: To determine the prevalence and biochemical/hormonal determinants of osteopenia/osteoporosis in postmenopausal Chinese women with type 2 diabetes. METHODS: This cross-sectional study was carried out in 890 postmenopausal women with type 2 diabetes and 689 age-matched non-diabetic women. Of the total subjects included in both groups were classified as obese (BMI >= 25 kg/m2) and non-obese (BMI< 25 kg/m2). Bone mineral density (BMD) at the sites (lumbar spine, femoral neck, and hip), obtained by dual X-ray absorptiometry and some other relevant clinical and laboratory indices of bone mineral metabolism were investigated. The prevalence of osteopenia and that of osteoporosis were evaluated. RESULTS: BMDs, T- and Z-scores at the total hip, femoral neck and ward's triangle were significantly lower in non-obese diabetic women than those in BMI-matched control subjects (P < 0.038). Obese diabetic patients and control subjects had similar BMDs and T- and Z-scores at various skeletal regions. Osteopenia/osteoporosis was more common at the hip and femoral neck in non-obese diabetic women than in obese diabetic women and control subjects (P = 0.026). On multiple linear regression analysis, which was adjusted for the sex hormone concentration, BMI, fasting insulin level, and serum osteocalcin were positively associated with BMDs at the hip and lumbar spine. Age, mean HbA1(c) levels, and NTx/Cr showed negative correlation (P < 0.0284) with BMD at the lumbar spine and femoral neck. CONCLUSIONS: Postmenopausal non-obese women with type 2 diabetes have lower BMD levels and higher osteopenia/osteoporosis rate than BMI-matched control subjects. Impaired bone formation may occur in Chinese postmenopausal women with type 2 diabetes. PMID- 20950886 TI - Serum 14-3-3; matrix metalloproteinases and their inhibitors' levels before and after cardiovascular surgery in diabetic and non-diabetic patients. AB - AIMS: We sought to assess the serum levels of the main extracellular matrix components before and after surgery in order to differentiate the response of diabetic patients to acute wounds from that of non-diabetic patients. METHODS: The serum levels of 14-3-3, Pro-MMP-1, MMP-3, and TIMP-1 were measured in diabetics (18 patients) and non-diabetics (22 patients) in samples obtained before a coronary artery bypass grafting operation and on the 1st, 3rd, and 5th postoperative days. RESULTS: The diabetics had higher serum levels of 14-3-3 both in the pre- and postoperative phases. Nevertheless, there was a postoperative drop in these amounts in all the patients. There was no difference in the serum levels of Pro-MMP-1 between the two groups. In addition, the serum levels of MMP 3 on the 3rd and 5th postoperative days and also TIMP-1 (inhibitor of both MMPs) on all postoperative days were higher in the diabetics. CONCLUSIONS: There was perfect synchronicity between the changes in the serum levels of these proteins and their functional nature in the injured tissue. Furthermore, the diabetic patients exhibited more changes in the levels of some of their extracellular enzymes in the wake of acute wounds; these changes were also traceable in the serum. PMID- 20950887 TI - Evolving strategies in the diagnosis of hepatocellular carcinoma. PMID- 20950888 TI - Outcomes of small-cell lung cancer patients treated with second-line chemotherapy: a multi-institutional retrospective analysis. AB - BACKGROUND: Patients with small-cell lung cancer (SCLC) that progress after first line chemotherapy have a poor prognosis and the evidence of a benefit from second line (SL) chemotherapy is limited. Patients relapsing or progressing more than 90 days after completion of first-line treatment are considered platinum sensitive and may be rechallenged with platinum-based chemotherapy. Topotecan is approved as SL treatment independent of time to progression. This retrospective analysis evaluates the clinical outcomes of SCLC patients who received SL chemotherapy after platinum-etoposide chemotherapy. PATIENTS AND METHODS: We retrospectively reviewed 161 patients who received SL chemotherapy for SCLC. Patients were divided into four subgroups by type of SL treatment: (1) platinum-based rechallenge; (2) anthracycline-based regimens; (3) topotecan; (4) other single agents. The endpoints were overall survival (OS), progression-free survival (PFS) and response rate (RR). Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis to investigate factors influencing survival. RESULTS: The median age was 63. There were 125 males and 36 females. Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0, 1 and 2 in 12.5%, 62.5% and 25% of patients, respectively. Platinum sensitive/platinum resistant/platinum refractory/unknown=121/29/3/8 patients. Median time to SL chemotherapy was 6.9 months. The median PFS from starting second-line treatment was 4.3 months and median OS was 5.8 months. The overall RR was 22.9%. There was a trend toward higher RR (34.5% vs 17.5%, p for trend: 0.06) and OS (9.2 months vs 5.8 months, p=0.08) for patients with sensitive disease who were rechallenged with platinum based chemotherapy. A multivariate analysis that adjusted for the time to SL treatment showed that a platinum-containing regimen achieves better RR, PFS and OS independently of the time to SL chemotherapy and that response to first-line treatment and PS at SL are the only independent prognostic factors. CONCLUSIONS: The outcome for second-line therapy for SCLC was poor and benefit appeared to be limited to those patients with good PS and rechallenged with platinum-based chemotherapy. Platinum-based rechallenge should be considered as a standard comparator in future randomized controlled trials of SL chemotherapy. PMID- 20950889 TI - The immune responses of central and effector memory BCG-specific CD4+ T cells in BCG-vaccinated PPD+ donors were modulated by Treg cells. AB - Most of the studies evaluating the function of tuberculosis (TB)-specific T cells were only based on the ability to produce cytokines, which may not fully reflect the function of T cells. In the present study, we confirmed that Bacille Calmette Guerin (BCG) could significantly induce cytokine production by CD4(+) T cells from BCG-vaccinated PPD(+) donors. In addition, CD4(+) T cells were activated, divided and proliferated in response to BCG stimulation. Phenotypic analysis showed that IFN-gamma(+)CD4(+) T cells displayed CD45RA(-)CCR7(+/-)CD62L(-), indicating that these CD4(+) T cells were central and effector memory cells. The analysis of cytokine profiles demonstrated that most of BCG-specific BrdU(+)CD4(+) T cells produced Th1 cytokines in response to polyclonal stimulation. In addition, we found that regulatory T cells (Treg) suppressed BCG induced proliferation and IFN-gamma production by memory CD4(+) T cells. The suppressive effects of Treg on BCG-specific responses of CD4(+) T cells could be partially reversed by blocking the production of IL-10. Taken together, our results demonstrated that functional central and effector memory BCG-specific CD4(+) T cells could be detected based on the activation, proliferation and division of these cells, and modulated by Treg in PBMCs from BCG-vaccinated PPD(+) donors. PMID- 20950890 TI - Proteomics analysis of rice seedling responses to ovine saliva. AB - Grazing is accompanied by a multitude of processes including wounding, saliva deposition, and defoliation. Previous studies have focused on the effects of the grazing or clipping intensity on plant regrowth, survival, and composition in the grassland. However, the impact of saliva deposition on plants is poorly understood. In this study, rice was used as a model plant to study the differentially expressed proteins after ovine saliva treatment. The shoots of 2 week-old seedlings were crosscut and the lower parts were daubed with ovine saliva at the cut surface. After 2, 6, 12 and 24h, proteomics analysis was performed using proteins extracted from the saliva-treated shoots. The results showed that proteins involved in multiple pathways were differentially expressed in response to ovine saliva, including catalase (CAT), peroxiredoxin (Prx), ATP synthase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and ribulose-1,5 bisphosphate carboxylase/oxygenase (RuBisCO). Moreover, real-time quantitative reverse-transcription-PCR (RT-PCR) data showed that most of the genes were also regulated at the transcript level. Our results indicate the ovine saliva induces an early response in the rice seedling by stress-related pathways. This study provides information about the response of rice seedlings to ovine saliva at the protein level. PMID- 20950891 TI - Increased expression of fructan 1-exohydrolase in rhizophores of Vernonia herbacea during sprouting and exposure to low temperature. AB - Rhizophores of Vernonia herbacea, an Asteraceae found in the Brazilian Cerrado, store high amounts of fructans that vary in composition over the phenological cycle. Fructan 1-exohydrolase (1-FEH) activity is detectable during the sprouting phase, mainly in the proximal regions of rhizophores, of plants induced to sprout by defoliation and/or cold storage. We found an increase in 1-FEH gene expression during natural and induced sprouting and further enhancement through low temperature treatment. Furthermore, a comparative analysis of 1-FEH gene expression in different regions of the rhizophores during the transition from dormancy to sprouting is presented. Transcripts were detected mainly in the proximal region, coinciding with high 1-FEH activity and a high concentration of free fructose. Low temperature promoted the accumulation of fructans of a low degree of polymerization (DP) and enhanced 1-FEH activity and gene expression. It is hypothesized that a set of 1-FEH proteins acts in two different ways during fructan mobilization: (1) by hydrolyzing fructo-oligosaccharides and polysaccharides in sprouting plants (naturally or induced) for carbon supply and (2) by hydrolyzing preferably fructo-polysaccharides under low temperature to maintain the oligosaccharide pool for plant cold acclimation. PMID- 20950892 TI - Investigation of the molecular mechanism of the blue-light-specific excitation energy quenching in the plant antenna complex LHCII. AB - Excitation of the major photosynthetic antenna complex of plants, LHCII, with blue light (470nm) provides an advantage to plants, as it gives rise to chlorophyll a fluorescence lifetimes shorter than with excitation with red light (635nm). This difference is particularly pronounced in fluorescence emission wavelengths longer than 715nm. Illumination of LHCII preparation with blue light additionally induces fluorescence quenching, which develops on a minute timescale. This effect is much less efficient when induced by red light, despite the equalized energy absorbed in both the spectral regions. Simultaneous analysis of the fluorescence and photoacoustic signals in LHCII demonstrated that the light-driven fluorescence quenching is not associated with an increase in heat emission. Instead, a reversible light-induced conformational transformation of the protein takes place, as demonstrated by the FTIR technique. These findings are discussed in terms of the blue-light-specific excitation energy quenching in LHCII, which may have photoprotective applications. PMID- 20950893 TI - Priming for JA-dependent defenses using hexanoic acid is an effective mechanism to protect Arabidopsis against B. cinerea. AB - Soil drench treatments with hexanoic acid can effectively protect Arabidopsis plants against Botrytis cinerea through a mechanism based on a stronger and faster accumulation of JA-dependent defenses. Plants impaired in ethylene, salicylic acid, abscisic acid or glutathion pathways showed intact protection by hexanoic acid upon B. cinerea infection. Accordingly, no significant changes in the SA marker gene PR-1 in either the SA or ABA hormone balance were observed in the infected and treated plants. In contrast, the JA signaling pathway showed dramatic changes after hexanoic acid treatment, mainly when the pathogen was present. The impaired JA mutants, jin1-2 and jar1, were unable to display hexanoic acid priming against the necrotroph. In addition, hexanoic acid-treated plants infected with B. cinerea showed priming in the expression of the PDF1.2, PR-4 and VSP1 genes implicated in the JA pathways. Moreover, JA and OPDA levels were primed at early stages by hexanoic acid. Treatments also stimulated increased callose accumulation in response to the pathogen. Although callose accumulation has proved an effective IR mechanism against B. cinerea, it is apparently not essential to express hexanoic acid-induced resistance (HxAc-IR) because the mutant pmr4.1 (callose synthesis defective mutant) is protected by treatment. We recently described how hexanoic acid treatments can protect tomato plants against B. cinerea by stimulating ABA-dependent callose deposition and by priming OPDA and JA-Ile production. We clearly demonstrate here that Hx-IR is a dependent plant species, since this acid protects Arabidopsis plants against the same necrotroph by priming JA-dependent defenses without enhancing callose accumulation. PMID- 20950894 TI - [Quality health care in an intensive care unit]. PMID- 20950895 TI - Novel conformationally restricted triazole derivatives with potent antifungal activity. AB - In continuation of our work on azole antifungal agents, a series of new conformationally restricted triazole derivatives possessing benzylpiperidin-4-yl methyl amino side chains were designed and synthesized. All the new azoles showed moderate to excellent in vitro antifungal activity against most of the tested pathogenic fungi. Several compounds (such as 12e, 12f, 12h and 12n) showed higher antifungal activity against Candida albicans than fluconazole. Moreover, compounds 12g-i also showed good activity against Aspergillus fumigatus with their MIC80 on the level of 1 MUg/mL. Flexible molecular docking was used to analyze the binding mode of the designed compounds. They interact with CACYP51 through hydrophobic and van der Waals interactions. PMID- 20950896 TI - Synthesis, antitrichinnellosis and antiprotozoal activity of some novel thieno[2,3-d]pyrimidin-4(3H)-ones containing benzimidazole ring. AB - Some novel thieno[2,3-d]pyrimidin-4(3H)-ones containing benzimidazol-2-yl thioethyl- and benzimidazol-2-yl-methanethioethyl moiety in second position of the pyrimidine ring were synthesized in order to determine their antitrichinellosis and antiprotozoal effects. The structures of the compounds were confirmed by IR, (1)H NMR and elemental analysis. The antiparasitic screening showed that the benzimidazole derivatives of thieno[2,3-d]pyrimidin 4(3H)-ones exhibited higher activity against Trichinella spiralis in vitro in comparison albendazole. The most active compound, 2-[2-(5-nitro-1H-benzimidazol-1 yl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one 22 revealed 95% activity at a dosage of 5 mg/kg mw after 24 h, while compounds 8 and 10 applied at the same dose showed efficacy of 90% after 48 h. The compound 2-{2 [(5(6)-nitro-1H-benzimidazol-2-yl)thio]ethyl}-5,6,7,8-tetrahydro[1] benzothieno[2,3-d]pyrimidin-4(3H)-one 11 exhibited 90% efficacy after 24 h. The pharmaco-therapeutic study in vivo on invaded with Lamblia muris white mice showed 100% effectiveness of the compounds 8, 10, 11, 13-15 and 22, 23 after five days-treatment course. PMID- 20950897 TI - Antiarrhythmic, serotonin antagonist and antianxiety activities of novel substituted thiophene derivatives synthesized from 2-amino-4,5,6,7-tetrahydro-N phenylbenzo[b]thiophene-3-carboxamide. AB - A series of novel thiophene derivatives 3-17 were synthesized by initial reactions of 2-amino-4,5,6,7-tetrahydro-N-phenylbenzo[b]thiophene-3-carboxamide 1 and 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carbonitrile 7 with different organic reagents. The structures of newly synthesized compounds were confirmed by IR, 1H NMR, MS spectral data and elemental analysis. Initially the acute toxicity of the compounds was assayed via the determination of their LD50. All the compounds were screened for their antiarrhythmic, serotonin antagonist and antianexiety activities and they showed high activity compared with procaine amide, lidocaine, diazepam and buspirone as positive controls. The detailed synthesis, spectroscopic data, LD50 and pharmacological activities of the synthesized compounds were reported. PMID- 20950899 TI - Incidence and predictors of eating disability among nursing home residents with middle-stage dementia. AB - BACKGROUND & AIMS: Inability to feed oneself is documented in people with Alzheimer disease, however little research has differentiated between eating disability due to dementia and eating disability due to factors other than dementia that may be remediable (i.e. 'excess disability'). The study aim was to estimate the incidence and identify the predictors of eating disability due to dementia and to excess disability. METHOD: In a one year, prospective cohort study of 120 nursing homes residents with middle-stage dementia, ability to eat was monitored fortnightly. Potential predictors of disability were assessed using survival analysis. RESULTS: The estimated incidence of eating disability was 40.8% (95% confidence interval (CI): 32.7%-50.2%). Half of this was attributed to causes other than dementia (23.6%; 95% CI: 16.6%-33.0%). Predictors of eating disability included more advanced dementia (hazard ratio (HR): 2.6, 95% CI: 1.4 to 4.8), more comorbidities (HR: 2.4; 95% CI: 1.3 to 4.3), and less supportive environments (HR: 2.0; 95% CI: 1.1 to 3.6). There were no statistically significant predictors of excess disability. CONCLUSIONS: Approximately half of the eating disability was not due to dementia. Eating disability may be minimized by treating comorbidities and creating supportive social and physical nursing home environments. PMID- 20950898 TI - Design, synthesis and structure-activity relationship study of novel pyrazole based heterocycles as potential antitumor agents. AB - The versatile hitherto unreported 3-[(E)-3-(dimethylamino)acryloyl]-1,5-diphenyl 1H-pyrazole-4-carbonitrile (3) was prepared via the reaction of 3-acetyl-1,5 diphenyl-1H-pyrazole-4-carbonitrile (1) with dimethylformamid-dimethylacetal (DMF DMA). The latter product and 3-((E)-3-morpholin-4-yl-acryloyl)-1,5-diphenyl-1H pyrazole-4-carbonitrile (4) underwent regioselective 1,3-dipolar cycloaddition with nitrilimines to afford the corresponding pyrazole derivatives. In vivo anti estrogenic activity and acute toxicity after single oral dose of the newly synthesized compounds were evaluated. In vitro disease-oriented primary antitumor screening utilizing 14 cell lines of breast and ovarian tumor subpanels has been also carried out. All tested compounds showed anti-estrogenic properties equipotent or superior to the reference drug, letrozole. 3-[3-(4-Cyano-1,5 diphenyl-1H-pyrazole-3-yl)-1-(4-methylphenyl)-1H-pyrazole-4-carbonyl]-1,5 diphenyl-1H-pyrazole-4-carbonitrile (27c) and 3-(3-acetyl-1-phenyl-1H-pyrazole-4 carbonyl)-1,5-diphenyl-1H-pyrazole-4-carbonitrile (8a) showed a significant cytotoxic activity in a nanomolar range against certain types of breast and ovarian tumors with tolerable toxicity. PMID- 20950900 TI - Side plate fixation vs. intramedullary nailing in an unstable medial femoral neck fracture model: A comparative biomechanical study. AB - BACKGROUND: The objective of this study was to investigate primary stability of the proximal femoral nailing antirotation for the indication of unstable medial femoral neck fractures. The device was compared to the dynamic hip screw blade, which is a "gold standard" in the treatment of proximal femoral fractures. METHODS: Six pairs of human cadaver femurs were tested in a cyclic loading model with loads up to 200 N, 400 N, 600 N, 800 N, and 1000 N, respectively. Iliotibial tract was simulated by a chain that applied forces on the greater trochanter during loading. In vitro combined axial and bending loads were applied. Angular displacements during loading were recorded in all directions, and loads to failure were recorded. FINDINGS: For the cyclic loading test no statistically significant differences between the two groups could be detected. Specimens fixed with the dynamic hip screw blade showed higher displacements in the varus direction at 400 N and 600 N, in the external rotation at 200 N, 400 N and 600 N, and in the anterior direction at 400 N. Load to failure revealed no statistical difference between the two implants. INTERPRETATION: The proximal femoral nailing antirotation achieves primary stability comparable to the dynamic hip screw blade. The proximal femoral nailing antirotation combines the biomechanical favorable concept of intramedullary fixation with a minimally invasive surgical technique, which theoretically may be advantageous in clinical use. Further biomechanical studies are required to clarify to what extent the results of the present study can be transferred to the clinical situation. PMID- 20950901 TI - Alterations in joint kinematics during walking following hamstring and patellar tendon anterior cruciate ligament reconstruction surgery. AB - BACKGROUND: Previous research has shown that patients with anterior cruciate ligament reconstruction have altered movement patterns in the reconstructed knee during walking. In the sagittal plane, graft specific changes in knee joint motion have been reported between hamstring and patellar tendon anterior cruciate ligament reconstruction grafts. This study examined the secondary planes of movement during walking in anterior cruciate ligament reconstructed knees to evaluate the influences of graft type (hamstring or patellar tendon) and control condition (control group or contralateral knee). METHODS: In 54 participants (18 patellar tendon graft, 18 hamstring graft and 18 controls) varus-valgus and internal-external rotation was measured during level walking in a gait laboratory at mean of 10 months after surgery. All patients had undergone primary unilateral anterior cruciate ligament reconstruction within 12 months of injury. FINDINGS: For internal-external rotation there was no difference between the graft types and both patient groups had reduced internal rotation (an external rotation offset) and reduced internal rotation range when compared to the control group and contralateral knee. For 31 of 36 patients, internal rotation values were less than the control group mean. The hamstring group had reduced varus rotation compared to both the patellar tendon and control groups, but not when compared to the contralateral knee. INTERPRETATION: The results show that there are differences in tibial rotation during walking in anterior cruciate ligament reconstructed knees compared to both the contralateral knee and uninjured control group. These kinematic alterations may relate to the high incidence of knee osteoarthritis observed in this population over time. Reduced varus in the hamstring group may relate to the graft harvest. PMID- 20950903 TI - Contact stresses in a patient-specific unicompartmental knee replacement. AB - BACKGROUND: Unicompartmental knee replacement has gained popularity in recent times, showing improved success rates. The main reasons for the failure of unicompartmental knee replacement are the wear of the polyethylene bearing, aseptic loosening and wear in the opposite compartment. The contact stresses involved are significant contributing factors to these causes of failure. METHODS: In this study, a patient-specific unicompartmental knee replacement is proposed using a methodology based on neural network modeling of a database of healthy knee geometries. This custom implant was then compared to two conventional implant designs in terms of contact stress in a validated finite element model. FINDINGS: The custom implant experienced lower contact stresses at the tibio-femoral joint compared to a fixed-bearing design and also displayed more uniform stress distribution at the bone-implant interface than any of the other implant designs. INTERPRETATION: Custom unicompartmental knee replacements therefore have the potential of providing good contact stress distribution, preserve bone stock and could be more anatomically accurate. PMID- 20950902 TI - Differences in posture-movement changes induced by repetitive arm motion in healthy and shoulder-injured individuals. AB - BACKGROUND: Neck/Shoulder pain is linked to movement repetition, awkward postures, prolonged maintenance of static postures, and muscular fatigue. Studies have examined the influence of pain and fatigue on movement characteristics, but few reported multi-dimensional adaptations to movement repetition. We compared the adaptations measured in three-dimensions during a repetitive reaching task in persons with chronic neck/shoulder pain and healthy subjects. METHODS: A shoulder injured group (intensity >3/10, duration >3 consecutive months) and an age-sex matched control group (n=16 in each) performed a repetitive reaching task to voluntary termination. Kinematics, kinetics, heart rate and muscle activity were recorded throughout. Power output on a 10-s pushing/pulling task was assessed pre and post-reaching. Group comparisons were made in absolute time and at task end. FINDINGS: Control subjects performed the task 55% longer than the pain group; yet, both groups demonstrated task-related increased heart rate (6 beats per minute) and decreased power output (6 W). Throughout the task, the pain group demonstrated: higher supraspinatus activity, and less elbow flexion and endpoint movement. The control group increased movement amplitude of the endpoint, elbow, and shoulder, while the pain group moved the shoulder less and increased center of mass excursion to maintain the task. INTERPRETATION: Both groups adapted to the task in unique ways. The control group continually increased elbow and endpoint range of motion, bringing the arm closer to the targets, possibly to prolong task performance. The pain group used a fixed, en block arm strategy, likely to reduce the load on the injured structures; however, this may place other structures at risk for pain and injury. PMID- 20950904 TI - Functional and biomechanical characteristics of foot disease in chronic gout: A case-control study. AB - OBJECTIVES: despite the predilection of gout to the feet, the impact of gout on foot function and biomechanics is currently unknown. The aim of this study was to describe the effects of chronic gout upon function and selected biomechanical parameters associated with gait. METHODS: twenty-five patients with a history of gout were compared with 25 age and gender matched control participants with no history of gout or other forms of arthritis. General function, foot specific disease activity and lower limb activities were determined using the Health Assessment Questionnaire, Foot Function Index (pain domain), and Leeds Foot Impact Scale respectively. Each patient also underwent a gait assessment that included plantar pressure measurements and an evaluation of temporal-spatial gait parameters. FINDINGS: patients with chronic gout had higher levels of general and foot-specific disability, pain and impairment (P <=0.001). Significantly lower peak plantar pressures were observed in the hallux of patients with chronic gout (P <=0.05). Significantly higher pressure-time integrals were observed in the cases at the midfoot (P <=0.05), but lower values were observed at the hallux (P <=0.05). Patients with chronic gout walked slower, with longer step and stride lengths compared to the controls. INTERPRETATION: patients with chronic gout experience pain and disability associated with their feet. Different toe-off strategies may account for functional changes and pain associated with foot problems in chronic gout. PMID- 20950905 TI - DIC: which laboratory tests are most useful. AB - In patients with disseminated intravascular coagulation (DIC) a variety of altered coagulation parameters may be detectable, such as thrombocytopenia, prolonged global coagulation times, reduced levels of coagulation inhibitors, or high levels of fibrin split products. In addition, more sophisticated tests for activation of individual factors or pathways of coagulation may point to specific involvement of these components in the pathogenesis of the disorder. There is not a single test, however, that is sufficiently accurate to establish or reject a diagnosis of DIC. Nevertheless, a combination of widely available tests may be helpful in making the diagnosis of DIC and can also be helpful to guide in the selection of DIC patients that require specific, often expensive, interventions in the coagulation system. More recently developed dynamic algorithms, assessing changes in coagulation parameters over sequential days, could further increase the diagnostic accuracy for DIC and may be helpful to detect early stages of coagulopathy potentially evolving into DIC. PMID- 20950906 TI - Discursive gaps in the implementation of public health policy guidelines in India: the case of HIV testing. AB - The implementation of standardized policy guidelines for care of diseases of public health importance has emerged as a subject of concern in low and middle income countries (LMIC) globally. We conducted an empirical research study using the interpretive policy analysis approach to diagnose reasons for gaps in the implementation of national guidelines for HIV testing in Indian hospitals. Forty six in-depth interviews were conducted with actors involved in policy implementation processes in five states of India, including practitioners, health administrators, policy-planners and donors. We found that actors' divergences from their putative roles in implementation were underpinned by their inhabitation of discrete 'systems of meaning' - frameworks for perceiving policy problems, acting and making decisions. Key gaps in policy implementation included conflicts between different actors' ideals of performance of core tasks and conformance with policy, and problems in communicating policy ideas across systems of meaning. These 'discursive' gaps were compounded by the lack of avenues for intellectual intercourse and by unaccounted interrelationships of power between implementing actors. Our findings demonstrate the importance of thinking beyond short-sighted ideals of aligning frontline practices with global policymakers' intentions. Recognising the deliberative nature of implementation, and strengthening discourse and communications between involved actors may be critical to the success of public health policies in Indian and comparable LMIC settings. Effective policy implementation in the long term also necessitates enhancing practitioners' contributions to the policy process, and equipping country public health functionaries to actualize their policy leadership roles. PMID- 20950907 TI - Scottish mortality rates 2000-2002 by deprivation and small area population mobility. AB - Despite recent increases in life expectancy, inequalities in mortality in Scotland have been widening. Previous research has suggested that one of the potential drivers of geographical inequalities in health is the process of selective migration. Although support for the effect of selective migration on widening geographic inequalities in health has been mixed, several studies have shown that people in good health move away from deprived areas while people in poor health move towards more deprived areas. In this paper, we examine mortality rates in Scotland by area deprivation and population mobility. Previous research in Scotland has shown that the relationship between population mobility and migration disappears once deprivation is accounted for. However, the authors measure population mobility over a longer time period than we do here and at a different geographical level. We consider small area population mobility on the basis of moves made in the year prior to the 2001 Scottish census. Areas were classified as one of four types: decreasing, increasing or stable (with high or low turnover). Mortality rates, calculated for the period 2000-2002, were found to be highest in deprived areas that had declined in population over the previous year. In the most deprived quintile, the causes of death contributing disproportionately to the excess mortality in decreasing areas were causes linked to alcohol and drug use, suicides and assault. Focussing on those individuals in the most deprived areas who live in areas that are declining in population could help to reduce widening inequalities for these causes of death. This work shows the extent to which population migration can influence small areas over a relatively short time period and gives some insight into potential factors, not measured by traditional indices of area level deprivation, which may lead to differences in the health status of areas. PMID- 20950908 TI - Using a neural network for mining interpretable relationships of West Nile risk factors. AB - The West Nile Virus (WNV) is an infectious disease spreading rapidly throughout the United States, causing illness among thousands of birds, animals, and humans. Yet, we only have a rudimentary understanding of how the mosquito-borne virus operates in complex avian-human environmental systems. The four broad categories of risk factors underlying WNV incidences are: environmental (temperature, precipitation, wetlands), socioeconomic (housing age), built-environment (catch basins, ditches), and existing mosquito abatement policies. This research first built a model incorporating the non-linear relationship between WNV incidences and hypothesized risk factors and second, identified important factor(s) whose management would result in effective disease prevention and containment. The research was conducted in the Metropolitan area of Minnesota, which had experienced significant WNV outbreaks from 2002. Computational neural network (CNN) modeling was used to understand the occurrence of WNV infected dead birds because of their ability to capture complex relationships with higher accuracy than linear models. Further a detailed interpretation technique, based on weights and biases of the network, provided a means for extracting relationships between risk factors and disease occurrence. Five risk factors: proximity to bogs, lakes, temperature, housing age, and developed medium density land cover class, were selected by the model. The detailed interpretation indicated that temperature, age of houses, and developed medium density land cover were positively related, and distance to bogs and lakes were negatively related to the incidence of WNV. This paper provides both applied and methodological contributions to the field of health geography. The relationships between the risk factors and disease occurrence could contribute to vector control strategies such as targeted insecticide spraying near bogs and lakes, mosquito control treatments for older houses, and extensive mapping, inspection, and treatments of catch basins. The proposed interpretation technique expanded the role of CNN models in health sciences as both predictive and explanatory tools. PMID- 20950909 TI - Feasibility of conical biodegradable polyurethane foam for closure of oroantral communications. AB - PURPOSE: To assess the feasibility of a conically shaped biodegradable polyurethane (PU) foam for closure of oroantral communications (OACs). PATIENTS AND METHODS: In 10 consecutive patients, fresh OACs (present for <24 hours) were closed with PU foam. Standardized evaluations were performed at 2 and 8 weeks after closure of the OAC. Success was considered permanent closure of the OAC. RESULTS: No complications were observed in 7 of the 10 patients. Of the other 3 patients, 1 developed a maxillary sinusitis that was successfully managed with antibiotics and the OAC recurred in 2 patients. CONCLUSIONS: Permanent closure of the OAC using PU foam was accomplished in 8 of 10 patients. The results obtained in the present study were more favorable than in a previous feasibility study. Therefore, the alterations in the treatment protocol were maintained for additional research of this new and straightforward treatment strategy. In general, closure of OACs with biodegradable PU foam is feasible and has the potential to make surgical treatment unnecessary for a large number of patients with OACs. PMID- 20950910 TI - Ossifying fibromyxoid tumor of head and neck region: case report and systematic review of literature. PMID- 20950911 TI - The relationship of glycemic control to the outcomes of dental extractions. AB - PURPOSE: The aim of this study was to determine whether glycemic control influences healing after tooth extractions. MATERIALS AND METHODS: We enrolled 115 diabetic patients who required dental extractions in this prospective observer-blinded study. Epithelialization of extraction sites was assessed relative to the patient's history, non-fasting blood glucose levels, and glycosylated hemoglobin levels. RESULTS: Of 115 patients, 78 had 1- and 2-week follow-up data. There was no statistically significant difference in the rate of postextraction epithelialization between diabetic patients based on preoperative blood glucose levels, hemoglobin A1c levels, or patient history. Only the size of the extraction site at days 0 and 7 was predictive of future epithelialization. CONCLUSIONS: Glycemic control did not influence postextraction healing in diabetic patients. Recommendations for management of the diabetic patient requiring extractions are discussed. PMID- 20950912 TI - Paradoxical reaction following administration of a benzodiazepine. PMID- 20950913 TI - Lateral cortical bone thickness of human mandibles in region of mental foramen. AB - PURPOSE: We sought to verify the cortical thickness and presence of tooth roots and inferior alveolar canal where miniplates are placed using the Champy technique to treat parasymphyseal fractures between the canine and premolar. We also studied these anatomic features at the same level anteriorly and posteriorly to the mental foramen. MATERIALS AND METHODS: A total of 80 dry, normal adult dentate human hemimandibles (40 male and 40 female) were studied. Verification was performed at 3 levels-above (S), below (I), and at the same height as the mental foramen (F). At each level, the thickness and proximity of the tooth roots and inferior alveolar canal were checked at 4 points; two anteriorly (4.5 and 9 mm) and 2 posteriorly (4.5 and 9 mm) to the mental foramen. RESULTS: The cortical bone was significantly thicker at level F (Fa2, 2.37 mm; Fa1, 2.43 mm; Fp1, 2.86 mm; Fp2, 2.89 mm) than the corresponding level S points (Sa2, 2.00 mm; Sa1, 2.11 mm; Sp1, 2.30 mm; Sp2, 2.45 mm) and level I points (Ia2, 2.11 mm; Ia1, 2.17 mm; Ip1, 2.39 mm; Ip2, 2.43 mm). Regarding the thickness and risk of injury, no difference was found between the points at levels S and I, where the miniplates are normally fixed with monocortical screws. No relationship was seen between the points at level F and the tooth roots or inferior alveolar canal. In contrast, a relationship between the points at level S and the tooth root and between the points at level I and the inferior alveolar canal was found. CONCLUSIONS: Above and below the mental foramen, the cortical bone for miniscrew anchorage was up to 3 mm thick. At the level of the foramen, the cortical plate will provide better anchorage and the insertion of miniscrews will be free of any risk of injuring the tooth roots or inferior alveolar canal. PMID- 20950914 TI - Comparative study of effect of single and multiple suture techniques on inflammatory complications after third molar surgery. AB - PURPOSE: Pain, swelling, and trismus are the most common complications associated with third molar surgery. Several methods of alleviation of these complications have been described. The effect of single and multiple suture techniques on these complications was compared in the present study. PATIENTS AND METHODS: All consecutive patients 18 years of age or older who had been referred for surgical extraction of their impacted teeth between January and December 2007 at the maxillofacial unit of the Aminu Kano Teaching Hospital were recruited and randomized into 2 groups. All selected participants underwent surgical extraction of their impacted teeth by the same surgeon under local anesthesia. The flaps in 1 group were closed by multiple sutures and those in the second group were closed by a single suture. Pain, swelling, and trismus were evaluated at postoperative days 1, 2, 3, 5, and 7. Descriptive and comparative statistical analyses were performed, and the results are presented. Significance was set at P < .05. RESULTS: A total of 50 subjects participated in the present study. Both groups were comparable in terms of the age distribution (multiple suture group, 26.0 +/- 4.73 years; single suture group, 25.8 +/- 4.28 years, P = .755), difficulty index (multiple suture group, 5.0 +/- 1.68; single suture group, 4.9 +/- 4.79; P = .935), duration of surgery (multiple suture group, 29. 7 +/- 6.11 minutes; single suture group, 30.0 +/- 6.04 minutes; P = .835), and baseline parameters such as facial width (multiple suture group, 10.0 +/- 1.32 cm; single suture group, 9.8 +/- 0.37 cm; P = .115), mouth opening (multiple suture group, 4.5 +/- 1.32 cm, single suture group, 4.8 +/- 0.26 cm; P = .165), and preoperative pain, which was 0 in both groups. Other comparable variables included impaction type (P = .210) and indication for surgery (P = .278). A statistically significant difference was found in the level of pain at postoperative days 1, 2, and 3 (P < .05). A similar significant difference was found in swelling and trismus (P < .05). At days 5 and 7, no significant differences were found between the 2 groups for all parameters of pain, swelling, and trismus (P > .05). CONCLUSION: Our study had a comparable distribution of age, gender, and operative variables, such as the pattern of impaction, preoperative difficulty index, and operative time between patients undergoing the 2 methods of closure. With that, our results have shown that the single suture closure technique was better than the multiple suture technique with regard to postoperative pain, swelling, and trismus. PMID- 20950915 TI - Psychological impact of third molar surgery: a 1-month prospective study. AB - PURPOSE: To prospectively examine the psychological impact of surgical third molar removal, and to identify possible psychological risk factors for the development of dental anxiety and symptoms of psychological trauma. MATERIALS AND METHODS: Patients (N = 71) scheduled for surgical mandibular third molar removal were assessed regarding operative and psychological variables immediately postoperatively and at 1-week and 1-month follow-up. RESULTS: The emotional impact of the surgical procedure appeared to be modest. Only a small proportion of respondents reported a significant increase in dental anxiety or posttraumatic stress (4.3%) at 1-month follow-up. CONCLUSIONS: The results suggest that surgical removal of a third molar by use of local anesthesia, without sedation or general anesthesia, has minimal impact on the development of dental anxiety or symptoms of psychological trauma. Replication of the findings in samples with higher preoperative anxiety levels and with other types of surgical procedures is warranted. PMID- 20950916 TI - Gaze-evoked amaurosis--post reconstruction of orbital floor fracture with a bone graft: case report. PMID- 20950917 TI - Is dental treatment of an infected tooth a risk factor for locally invasive spread of infection? AB - PURPOSE: To determine the impact of antecedent dental procedures and dental health on the course of odontogenic maxillofacial infections requiring hospital care. PATIENTS AND METHODS: In this retrospective cohort study in a referral center, we evaluated medical records and panoramic radiographs of all patients admitted because of odontogenic maxillofacial infection (n = 84). The predictor variables were preceding dental treatment, antimicrobial therapy, and dental health. The outcome variables comprised infection parameters, length of stay, need for intensive care, and management during hospitalization. RESULTS: The mean age of the patients was 43.2 +/- 16.5 years and 60% were men. Dental procedure preceded the spread of the infection in 49 cases (58%): endodontic treatment (n = 22), tooth extraction (n = 19), and minor first aid (n = 8). Twenty-seven patients had not received any dental or antimicrobial treatment in the recent past. Antimicrobial treatment alone had been given to 8 patients. Patients without preceding treatment had the highest C-reactive protein levels on admission and at maximum (P = .020 and P = .011) and the highest white blood cell counts on admission (P = .011). Their length of stay was also longer, and they needed intensive care more often than the other patients. Maximum C-reactive protein levels and white blood cell counts between treatment groups did not significantly differ from each other. CONCLUSIONS: The systemic response to the infection was strongest and the course of the infection most severe in the absence of preceding dental treatment and in patients with poor dental health. All types of dental treatment contributed to a less severe course of infection. PMID- 20950918 TI - Treatment of mandibular fractures via transoral 2.0-mm miniplate fixation with 2 weeks of maxillomandibular fixation: a retrospective study. AB - PURPOSE: The intraoral approach for placement of fixation plates for treatment of mandibular fracture has several advantages over the extraoral approach, including lower morbidity and avoidance of nerve VII injury. If this method were shown to be effective in contributing to a low percentage of postoperative complications, especially infection, nonunion, and need for plate removal, this would be a method of choice in treatment of such injuries, especially in dark-skinned or keloid-forming patients. MATERIALS AND METHODS: This was a retrospective study of 337 fractures of the angle, body, and parasymphyseal regions of the mandible treated at St Barnabas Hospital (Bronx, NY), a level I trauma center, from 2001 to 2006. RESULTS: The percentage of such complications was 1%. CONCLUSION: This method is very useful in the treatment of these injuries. PMID- 20950919 TI - ERP evidence of early cross-modal links between auditory selective attention and visuo-spatial memory. AB - Previous dual-task research pairing complex visual tasks involving non-spatial cognitive processes during dichotic listening have shown effects on the late component (Ndl) of the negative difference selective attention waveform but no effects on the early (Nde) response suggesting that the Ndl, but not the Nde, is affected by non-spatial processing in a dual-task. Thus to further explore the nature of this dissociation and whether the Nd waveform is affected by spatial processing; fourteen adult participants performed auditory dichotic listening in conjunction with visuo-spatial memory in a cross-modal dual-task paradigm. The results showed that the visuo-spatial memory task decreased both the Nde and Ndl waveforms, and also attenuated P300 and increased its latency. This pattern of results suggests that: (1) the Nde reflects a memory trace that is shared with vision when the information is spatial in nature, and (2) P300 latency appears to be influenced by the discriminability of stimuli underlying the Nde and Ndl memory trace. PMID- 20950920 TI - [Difficult necks. Diagnosis and treatment. Retrospective study of 145 cases using the method of Feldman]. AB - To identify a neck as difficult seems an easy thing. Nevertheless, we must admit that various clinical situations are represented under this single designation. A clinical and anatomical classification is proposed regarding the surgical strategy presented in this paper. Predominant tissue laxity and predominant fat accumulation are presented as progressive forms. Short platysma muscles and low hyoid bones are presented as constitutional. According to this classification, 145 patients among 438 facial rejuvenations were designated as difficult necks. The surgical strategy was intended, in each case, to address the underlying anatomical features, using a short incision system. A combination of wide skin undermining, fat removal under direct vision and corset platysmaplasty was performed in the 145 patients between November 2003 and May 2008. The average age was 59 years old and medium follow-up at 22 months. There was only 2% of secondary touch up for aesthetic reasons. Difficult necks, as described in this article, responded adequately to the present protocol. The postoperative results on the neck were consistent with the rest of the rejuvenated face and stood the test of time. PMID- 20950921 TI - [Buccal mucosal graft for the treatment of urethral stricture]. AB - INTRODUCTION: The indication of the buccal mucosal graft for urethroplasty has evolved over recent years. The ease of its harvesting, availability, and immunohistological properties, as well as its satisfactory results, has made the buccal mucosal graft the current procedure of choice. We report a case of use of a buccal mucosal graft to treat an urethral stricture correction. CASE REPORT: A 48-year-old man underwent a buccal mucosal graft for post-infectious urethral stricture correction. An inner right cheek graft of 50 * 30 mm was harvested and inserted into place after complete excision of the stricture. Postoperative evolution was satisfactory with no pain at the 5th day, resumption of normal diet at the 12th day, a significant improvement of peak flow rate at the 21st day. Follow-up examination at the 7th week revealed a mouth opening to 40 mm with complete healing. DISCUSSION: Buccal mucosal graft has currently the highest success rate compared to other surgical techniques as full thickness skin graft from hair or graft of bladder mucosa. Its harvesting can be single or multiple, however care must be taken as regards Stenon's duct and to the labial commissure. The complications of the donor site are infrequent and can be characterized by numbness and limited mouth opening. Tissues that contain immunohistological properties, which are similar to those of the urothelium, buccal mucosal graft, have become the gold standard for this type of correction. PMID- 20950922 TI - Post-resuscitation myocardial microcirculatory dysfunction is ameliorated with eptifibatide. AB - BACKGROUND: The post-cardiac arrest syndrome includes a decline in myocardial microcirculation function. Inhibition of the platelet IIb/IIIa glycoprotein receptor has improved myocardial microvascular function post-percutaneous coronary intervention. Therefore, we evaluated such inhibition with eptifibatide for its effect on myocardial microcirculation function post-cardiac arrest and resuscitation. METHODS: Four groups of swine were studied in a prospective, randomized, blinded, placebo-controlled protocol including; eptifibatide administered during CPR (Group 1, n=5), after resuscitation (Group 2, n=4), during and after resuscitation (Group 3, n=5), or placebo (Group 4, n=10). CPR was initiated following 12min of untreated VF. Those successfully resuscitated were studied during a 4-h post-resuscitation period. Coronary flow reserve, a measure of microcirculation function (in the absence of coronary obstruction), as well as parameters of left ventricular systolic and diastolic function, were measured pre-arrest and serially post-resuscitation. RESULTS: Coronary flow reserve was preserved during the post-resuscitation period, indicating normal microcirculatory function in the eptifibatide-treated animals, but not in the placebo-treated group. However, LV function declined equally in both groups during the first 4h after cardiac arrest. CONCLUSION: Inhibition of platelet IIb/IIIa glycoprotein receptors with eptifibatide post-resuscitation prevented myocardial microcirculation dysfunction. Left ventricular dysfunction post resuscitation was not improved with eptifibatide, and perhaps transiently worse at 30min post-resuscitation. Post-cardiac arrest ventricular dysfunction may require a multi-modality treatment strategy for successful prevention or amelioration. PMID- 20950923 TI - Use of independent component analysis for reducing CPR artefacts in human emergency ECGs. AB - AIM: We applied independent component analysis (ICA) to cardiopulmonary resuscitation (CPR)-corrupted human multichannel emergency ECGs with the aim of reconstructing the original ECGs. MATERIALS: Two ICA algorithms (EFICA and JADE) were selected. Data for ICA were acquired by simultaneously recording eight ECG channels during CPR on a porcine model. The algorithms' reconstruction performance was assessed by the Spearman correlation coefficient (SCC) and the shock advice algorithm of an AED. We then compared the performance of EFICA with the established second-channel adaptive matching pursuit method (AF). RESULTS: ICA was applied to 918 corrupted ECG multichannel signals. The sensitivity of the AED's shock/no-shock decision increased from 93.5% (corrupted signal) to 99.5/99.8% (JADE/EFICA) in the selected independent component; specificity increased from 50.5% to 78.9/83.2% (JADE/EFICA). The SCCs comparing the reconstructed with the original signal (JADE: 0.75+/-0.15; EFICA: 0.76+/-0.15, n=918) were significantly higher than for the corrupted signal vs. the original (0.52+/-0.22). The SCC is significantly higher (p<0.01) using EFICA than AF (EFICA: 0.75+/-0.16; AF: 0.72+/-0.19, n=718). For all signals at all SNR levels, specificity did not differ significantly between EFICA (83.6%) and AF (80.2%). EFICA proved to be superior especially at low corruption levels (SNR<-5dB). Sensitivity was above 99.5% for both algorithms. CONCLUSION: We have demonstrated that CPR artefacts in the emergency ECG can be reduced using ICA. EFICA and JADE are at least as successful in this regard as are other published algorithms. In particular, non-shockable signals with low SNRs (<-5dB) are reconstructed significantly better (p=0.01) with EFICA than with AF. PMID- 20950924 TI - Airborne pollen calendar of Salamanca, Spain, 2000-2007. AB - BACKGROUND: The determination of pollen types and their proportions in the atmosphere of relevant urban areas have increasingly been evaluated in different regions. The final goal has been to elaborate a pollen calendar, providing data about the occurrence of pollen grains in the air, thus permitting medical treatment and prophylaxis. METHODS: An aerobiological study was carried out in the atmosphere of the city of Salamanca, Spain, during eight years (2000-2007) by means of a Hirst type volumetric spore trap. A pollen calendar was elaborated following exponential classes obtained from 10-day average concentrations of the main pollen types. RESULTS: Mean annual pollen index was 16,916, coming from 72 different types of pollen. During the studied period, an increase of annual pollen levels was registered by means of regression analysis index. The most important types of pollen were Quercus, Poaceae, Cupressaceae, Olea, and Plantago. Arboreal pollen grains (62.7%) were more represented in airborne pollen spectrum than non-arboreal pollen (37.3%). Airborne pollen levels were particularly high between April and July, showing the highest values in May and June. CONCLUSIONS: In aerobiological terms Poaceae pollen seems to be a major risk for potential sensitised individuals due to its known allergenicity and its high atmospheric concentrations between late spring and early summer, followed by Cupressaceae, Olea and Platanus pollen grains, and taking into account the possible role of Fraxinus and Quercus in early spring allergenic courses and in processes of cross-sensitivity, respectively. PMID- 20950925 TI - Gynaecological surgical training in the operating room: an exploratory study. AB - OBJECTIVE: One of the challenging goals of gynaecological education is preparing trainees for independent practice of surgery. Research, however, on how to acquire surgical skills in the operating room safely, effectively and efficiently is scarce. We performed this study to explore trainers' and trainees' mutual expectations concerning operative training, to identify key aspects for improving learning and teaching in the operating theatre. STUDY DESIGN: We conducted a focus group study in different teaching hospitals in The Netherlands. Three focus groups were composed of gynaecology consultants representing over half of the training hospitals in The Netherlands. Four groups were composed of gynaecology trainees at different stages of training, from university and non-university hospitals and of both sexes. The interviews were recorded, transcribed verbatim and entered into qualitative data analysis software and two researchers performed a thematic analysis. RESULTS: Teaching and learning in the operating theatre are complicated by the dynamics of trainer-trainee interaction, which are fraught with potentially conflicting interests. Trainer and trainee have to consider each other's interests, while their primary concern must be patient safety. Trainers want to feel in control and trainees want to be given a free hand within a safe atmosphere. Structuring of the teaching and learning process appears to hold the key to creating positive dynamics between trainer, trainee and their responsibility towards the patient. Structuring can be achieved before, during and after an operation. Before the operation both trainer and trainee can take the initiative to talk about learning objectives, plan of action, and task allocation. During the operation, the trainee can verbalise actions before actually performing them. This makes trainee actions predictable, enhances trainer confidence and thus may increase the trainee's chance of actually performing (a portion of) a procedure. After the operation, both trainer and trainee can initiate an evaluation the trainee's performance. CONCLUSION: Interaction between trainer and trainee is complicated by their shared responsibility towards the patient. Structured interactions before, during and after operations appear to offer opportunities for improving learning and teaching in the operating theatre. PMID- 20950926 TI - Influence of parameters on the heterogeneous photocatalytic degradation of pesticides and phenolic contaminants in wastewater: a short review. AB - In recent years, the application of heterogeneous photocatalytic water purification processes has gained wide attention due to its effectiveness in degrading and mineralizing the recalcitrant organic compounds as well as the possibility of utilizing the solar UV and visible-light spectrum. This paper aims to review and summarize the recent works on the titanium dioxide (TiO(2)) photocatalytic oxidation of pesticides and phenolic compounds, predominant in storm and wastewater effluents. The effects of various operating parameters on the photocatalytic degradation of pesticides and phenols are discussed. Results reported here suggest that the photocatalytic degradation of organic compounds depends on the type and composition of the photocatalyst and, light intensity, initial substrate concentration, amount of catalyst, pH of the reaction medium, ionic components in water, solvent types, oxidizing agents/electron acceptors, catalyst application mode, and calcination temperature in the water environment. A substantial amount of research has focused on the enhancement of TiO(2) photocatalysis by modification with metal, non-metal and ion doping. Recent developments in TiO(2) photocatalysis for the degradation of various pesticides and phenols are also highlighted in this review. It is evident from the literature survey that photocatalysis has good potential to remove a variety of organic pollutants. However, there is still a need to determine the practical utility of this technique on a commercial scale. PMID- 20950927 TI - Real-time qualitative ultrasound elastography of cervical lymph nodes in routine clinical practice: interobserver agreement and correlation with malignancy. AB - To evaluate real-time qualitative ultrasound (US) elastography for cervical lymphadenopathy in routine clinical practice, 74 nodes (37 malignant, 37 benign) in 74 patients undergoing sonography underwent US elastography prior to fine needle aspiration for cytology. Dynamic cine loops of elasticity imaging displayed using a chromatic-scale were qualitatively scored by three independent observers for the proportion of stiff areas from ES1-4 (soft to stiff). There was fair to good interobserver agreement as indicated by weighted kappa (kappa) statistic from 0.374 to 0.738. Median ES for benign and malignant nodes were 2 and 3 respectively. ES was higher in malignant nodes (p = 0.0003-0.0049, Mann Whitney U tests) although areas under receiver operating characteristic curves (0.68-0.74) indicated suboptimal discrimination. The optimal discriminatory cut off, ES > 2, achieved only 62.2% sensitivity, 83.8% specificity and 73% accuracy for malignancy. Improvements in reliability and accuracy of real-time qualitative ultrasound elastography are required for it to be adopted into routine clinical practice. PMID- 20950928 TI - Mechanical stimulation improves survival in random-pattern skin flaps in rats. AB - This was a study on the effects of 3-MHz ultrasound at 16- and 100-Hz pulse repetition frequencies on angiogenesis and viability of random-pattern skin flaps in rats. A cranially-based dorsal skin flap was raised in 60 EPM-Wistar rats, which were randomly divided into four groups: control, sham, 16-Hz and 100-Hz groups. The mean percentage of necrosis was as follows: control, 42% +/- 13%; sham, 18% +/- 13%; 16-Hz group, 13% +/- 10%; and 100-Hz group, 15% +/- 7%, with significant differences between the control and the other groups (p < 0.001). The mean vascular density was as follows: control, 5% +/- 2%; sham, 7% +/- 2%; 16-Hz group, 21% +/- 4%; and 100-Hz group, 24% +/- 10%, with significant differences between control and ultrasound groups, and between the sham and ultrasound groups (p < 0.001). Both ultrasound treatments (16- and 100-Hz PRFs) induced angiogenesis, and sham and ultrasound treatments improved viability of random pattern skin flaps in rats. PMID- 20950929 TI - Three-dimensional modeling of the dynamics of therapeutic ultrasound contrast agents. AB - A 3-D thick-shell contrast agent dynamics model was developed by coupling a finite volume Navier-Stokes solver and a potential boundary element method flow solver to simulate the dynamics of thick-shelled contrast agents subjected to pressure waves. The 3-D model was validated using a spherical thick-shell model validated by experimental observations. We then used this model to study shell break-up during nonspherical deformations resulting from multiple contrast agent interaction or the presence of a nearby solid wall. Our simulations indicate that the thick viscous shell resists the contrast agent from forming a re-entrant jet, as normally observed for an air bubble oscillating near a solid wall. Instead, the shell thickness varies significantly from location to location during the dynamics, and this could lead to shell break-up caused by local shell thinning and stretching. PMID- 20950930 TI - Color Doppler twinkling artifacts from gallstones: in vitro analysis regarding their compositions and architectures. AB - The purpose of our study was to investigate the relationship between a twinkling artifact and the biochemical compositions of gallstones in phantom experiments. Fifty-two gallstones surgically extracted from 26 patients (26 cholesterol, 12 brown pigment and 14 black pigment stones) were included in the phantom study. Color Doppler sonography was performed to evaluate the occurrence of a twinkling artifact behind the stones. The artifacts were graded from grade 0 (no artifact) to grade 3 (very strong artifact). Micro computed tomography (CT) images were obtained to analyze the internal architecture and external surface of the stones. A total of 20 of 26 cholesterol stones (77%) produced grade 2 or 3 artifacts, whereas almost all the black pigment stones and more than half of the brown pigment stones produced no artifacts or grade 1 artifacts (p = 0.0010). The sensitivity and specificity of grade 2 or greater artifacts for cholesterol stones were 76.9% and 76.9%, respectively. The composition of the stones was strongly correlated with the internal shape on the micro CT image. Cholesterol stones with rough surfaces did not show stronger intensities of the artifacts than those with smooth surfaces (p > 0.05). In conclusion, most of the prominent artifacts arose from cholesterol stones having radial or radial-concentric internal architectures, whereas the black pigment stones mostly produced little artifact. PMID- 20950931 TI - Regional myocardial function and response to acute afterload increase in chronically anemic fetal sheep: evaluation by two-dimensional strain echocardiography. AB - We hypothesized that in chronic fetal anemia, remodeling of the myocardium is related to abnormalities in regional wall motion and acutely increased afterload further disturbs myocardial strain. Chronic anemia was induced in one fetus of each of seven sheep twin pregnancies. The fetuses were studied by two-dimensional (2-D) strain echocardiography at baseline and during increased afterload via angiotensin II (AT II) infusion. At baseline, the peak systolic longitudinal, radial and circumferential strains in the left ventricular lateral wall in anemic fetuses were lower than those in the controls (all p<0.05). During AT II, the circumferential strain of right ventricular free wall decreased significantly both in the control and anemic fetuses. Left ventricular free wall systolic strains were not affected by AT II. Fetal myocardial remodeling in chronic anemia decreases left ventricular systolic free wall strains. The myocardial adaptation does not change ventricular responses to acutely increased afterload. PMID- 20950932 TI - Low-intensity pulsed ultrasound produced an increase of osteogenic genes expression during the process of bone healing in rats. AB - The aim of this study was to measure the temporal expression of osteogenic genes during the process of bone healing in low-intensity pulsed ultrasound (LIPUS) treated bone defects by means of histopathologic and real-time polymerase chain reaction (PCR) analysis. Animals were randomly distributed into two groups (n = 30): control group (bone defect without treatment) and LIPUS treated (bone defect treated with LIPUS). On days 7, 13 and 25 postinjury, 10 rats per group were sacrificed. Rats were treated with a 30 mW/cm(2) LIPUS. The results pointed out intense new bone formation surrounded by highly vascularized connective tissue presenting a slight osteogenic activity, with primary bone deposition was observed in the group exposed to LIPUS in the intermediary (13 days) and late stages of repair (25 days) in the treated animals. In addition, quantitative real time polymerase chain reaction (RT-qPCR) showed an upregulation of bone morphogenetic protein 4 (BMP4), osteocalcin and Runx2 genes 7 days after the surgery. In the intermediary period, there was no increase in the expression. The expression of alkaline phosphatase, BMP4 and Runx2 was significantly increased at the last period. Our results indicate that LIPUS therapy improves bone repair in rats and upregulated osteogenic genes, mainly at the late stages of recovery. PMID- 20950933 TI - Transcranial ultrasound perfusion imaging and perfusion-MRI--a pilot study on the evaluation of cerebral perfusion in severe carotid artery stenosis. AB - Severe internal carotid artery stenosis can cause constriction of cerebral perfusion. Different techniques of measuring brain perfusion are currently available. Ultrasound perfusion imaging (UPI) can differentiate hypoperfused and nonperfused cerebral tissue. Aim of this study was to compare the value of UPI and perfusion-weighted magnetic resonance imaging (pw-MRI) in the evaluation of cerebral perfusion in patients with severe internal carotid artery stenosis. Ten patients with severe internal carotid artery stenosis were included. UPI was performed with phase-inversion-harmonic-imaging and bolus application of contrast media for semiquantitative analysis of time-intensity curves. Time-to-peak intensity (TPI) values were compared with time-to-peak maps of pw-MRI examinations in predefined regions-of-interest (ROI). Further, a comparison of pre- and postoperative UPI data was performed in selected cases. Seven of 10 patients could be evaluated. Eighty ROIs were used for the comparison of UPI and pw-MRI, 37 ROIs were used for pre- and 36 ROIs for postoperative comparison of UPI data. There was no delay in any MRI ROI. In UPI, there were relevant delays in seven of 37 ROIs (18.9%) before and in nine of 36 ROIs (25.0%) after surgery. Eleven of these 16 ROIs (68.8%) were in the inner border zone. Compared with the established pw-MRI technique, UPI described possible subtle perfusion delays mainly of the inner border zone. These preliminary results suggest a possible diagnostic power of UPI as a noninvasive tool for the detection of hemodynamic relevance in severe internal carotid artery disease. PMID- 20950934 TI - Noninvasive fetal lung maturity prediction based on ultrasonic gray level histogram width. AB - The aim of this work was to noninvasively predict fetal lung immaturity with the ultrasonic gray level histogram width (GLHW), a form of clinical tissue characterization. The study included 22 fetuses in which infant respiratory distress syndrome (IRDS) developed post-delivery, and 25 fetuses without IRDS development. Independent receiver operating characteristic (ROC) analysis of fetal lung-to-liver GLHW ratios, fetal weights, gestational ages and the product of GLHW ratios by gestational ages for this cohort indicated that optimal thresholds for these parameters to differentiate immature from mature were 0.94, 1.750 g, 31 weeks and 29, respectively. With the optimal decision threshold of 0.94, the GLHW ratio provided sensitivity and specificity of 0.86 and 0.72, respectively. The corresponding values for gestational age were 0.77 and 0.68, 0.77 and 0.60 for fetal weight versus 0.96 and 0.72 for the product of GLHW ratio by fetal age, which was comparable with invasive amniotic fluid tests. The areas under the ROC curve for these parameters were 0.82, 0.82, 0.70 and 0.91. We found that GLHW is a noninvasive, stable and reliable measure of fetal lung maturity using commercial scanners. PMID- 20950935 TI - On the synthesis of sample volumes for real-time spectral Doppler ultrasound simulation. AB - A variety of methods for simulating the ultrasound field produced by transducers are currently used in ultrasound imaging system design. However, simulations can be time-consuming, making them difficult to apply in real-time environments when the observation field changes rapidly with time. This is particularly true for interactive real-time Doppler and B-mode ultrasound simulators designed for use as training tools. In this paper, it is demonstrated that the use of a distribution of monopole sources can be used to simulate the field from a phased linear array and the accuracy should be sufficient for simulating pulsed spectral Doppler. Very good agreement can be achieved in comparison with that obtained by a more exact method and, because of the simplicity of the calculations, real-time simulations of flow in the arterial system becomes possible. Specifically, quantitative measurements were made and compared against an analytic solution for the case of a piston transducer and against Field II for the phased array. The root-mean-square error shows that it is possible to achieve 10% or less error for the latter case. For comparable conditions, the computational speed for the transmit field of phased array using the Field II method as compared with the monopole approach was found to be at least an order of magnitude faster. It is pointed out that the simplicity of the monopole approach provides the opportunity for a further order of magnitude gain. Our findings can have direct application on the simulation of spectral Doppler and other ultrasound techniques for the purpose of teaching and training. PMID- 20950936 TI - In vitro studies and safety assessment of Doppler ultrasound as a diagnostic tool in rhinosinusitis. AB - We have previously proposed the use of Doppler ultrasound to noninvasively stage a sinus infection. In this study, we first investigated the acoustic properties of nonpurulent and mucopurulent sinus secretions. The density, viscosity, speed of sound and attenuation of 18 samples of sinus fluid were examined. We then assessed the safety of the method by determining the temperature increase when ultrasound is transmitted through a bone sample of the same thickness as the anterior wall of the maxillary sinus. As a measure of the probability to generate acoustic streaming, we determined the ratio of sound attenuation over the viscosity of the sinus fluid and compared this with the value obtained from acoustic streaming measurements on a model system. The results indicated that detectable levels of acoustic streaming can be generated in serous sinus fluid, which has a low viscosity, but is very unlikely in mucopurulent secretions. The attenuation of the mucopurulent sinus fluid was 10 times higher than that of the serous cyst fluid, but the viscosity of the mucopurulent secretion was a thousand times higher than that of serous fluid. The safety experiments gave a temperature increase of the bone of <1.5 degrees C at I(spta) of 640 mW/cm(2), below the temperature increase considered to be harmful by the World Federation for Ultrasound in Medicine and Biology. PMID- 20950937 TI - Transvaginal natural orifice transluminal endoscopic surgery-assisted minilaparoscopic nephrectomy: a step towards scarless surgery. AB - The feasibility of a transvaginal hybrid natural orifice transluminal endoscopic surgery (NOTES) nephrectomy has already been demonstrated using standard laparoscopic ports through the abdominal wall. We evaluated the feasibility of a transvaginal NOTES-assisted minilaparoscopic nephrectomy (mLN). The patient is positioned in a semilumbotomy position with legs separated to allow for vaginal access. A 3.5-mm port is placed at the umbilicus for a 30 degrees laparoscope; two 3.5-mm ports are placed in the flank in the same location as for a standard transperitoneal nephrectomy; and a 12-mm port is placed through the vagina, perforating the vaginal wall. Kidney dissection is performed following the steps of a traditional nephrectomy. The renal pedicle is dissected and secured with Hem o-Lok clips through the vaginal access port. The specimen is then extracted through an extended incision in the posterior wall of the vagina. We treated five patients. The average operative time was 120 min, blood loss was 160 ml, and no complications were recorded. Our initial experience suggests that transvaginal NOTES-assisted mLN is feasible and appears to be safe. It is simpler than a pure NOTES procedure and ensures excellent cosmetic results. PMID- 20950938 TI - Factor XIII deficiency related recurrent spontaneous intracerebral hemorrhage: a case and literature review. AB - Spontaneous intracerebral hemorrhage (ICH) in young adults under 50 years of age is an uncommon occurrence associated with considerable morbidity and mortality. The differential diagnosis of ICH in this population differs from that of older individuals and includes vascular, toxic, inflammatory, oncologic, infectious and hematologic conditions. We present a case based observation of a spontaneous and recurrent ICH in a 25-year-old female secondary to undetected Factor XIII (FXIII) deficiency with no prior associated stigmata of hematologic disturbance admitted to a tertiary care neuroscience intensive care unit (NICU). Our patient was admitted after spontaneous development of left thalamic hemorrhage with ventricular extension. Initial management included external drain placement (EVD) and fresh frozen plasma administration. Diagnostic evaluation was unrevealing including CT angiography, magnetic resonance imaging (MRI) with venography, conventional cerebral angiogram, and hematologic and rheumatologic screens. Our patient recovered but represented 6 months later with five foci of spontaneous ICH. She underwent vascular, infectious, oncologic, hematologic, and rheumatologic evaluations. She expired secondary to ICH expansion with uncal herniation. The results of our investigation revealed markedly diminished FXIII activity. The pathophysiology, diagnosis and treatment of this disease are reviewed. FXIII deficiency should be considered in a case of cryptogenic ICH presenting with multifocal, recurrent ICH and a normal coagulation profile. Early diagnosis and initiation of factor replacement therapy offer the best strategies to reduce the morbidities associated with this disease. PMID- 20950939 TI - The biochemical response to different Cr and Cd concentrations in soils amended with organic wastes. AB - The effects of adding municipal solid waste (MSW) or poultry manure (PM) on the biochemical properties of a soil polluted with Cr and Cd were studied. Soil was mixed with Cr(NO(3))(3) and Cd(NO(3))(2) to give three concentrations (0, 100, and 250 mg Cr kg(-1) and 0, 100, and 250 mg Cd kg(-1)) in the soil, which was then treated with MSW at a rate of 10% or PM at a rate of 7.6%. The pH and biochemical parameters were measured at 0 and 120 days. An unamended and no polluted soil was used as control. Compared with the non-polluted soil, for the 250 mg Cd kg(-1) treatment the microbial biomass-C, dehydrogenase, urease, beta glucosidase, phosphatase, and arylsulphatase activities decreases 23%, 26.2%, 36%, 34.8%, 18.4%, and 15.8%, respectively, whereas for 250 mg Cr kg(-1) treatment the biochemical parameters were slightly lowest than for 250 mg Cd kg( 1) treatment. For 250 mg Cr kg(-1) soil+250 mg Cd kg(-1) soil treatment, the inhibition percentages of the biochemical parameters increased. After the application of organic wastes in Cr+Cd polluted soil, the inhibition of biochemical properties was greater with the MSW amendment than with PM, possibly due to its higher humic acid concentration. PMID- 20950940 TI - N-terminal pro-atrial natriuretic peptide response to acute exercise in depressed patients and healthy controls. AB - BACKGROUND: The dysfunction of hypothalamic-pituitary-adrenal (HPA) axis in major depression includes hyperactivity and reduced feedback inhibition. Atrial natriuretic peptide (ANP) is able to reduce the HPA-axis response to stress and has an anxiolytic effect in rodents and humans. We hypothesized that patients with depression would have an attenuated N-terminal proANP (NT-proANP) response to acute exercise compared to healthy controls. Secondly, we aimed to assess the effect of antidepressants on NT-proANP response to acute exercise. METHODS: We examined 132 outpatients with mild to moderate depression (ICD-10) and 44 healthy controls, group matched for age, sex, and BMI. We used an incremental bicycle ergometer test as a physical stressor. Blood samples were drawn at rest, at exhaustion, and 15, 30, and 60 min post-exercise. RESULTS: The NT-proANP response to physical exercise differed between depressed subjects and healthy controls (group*time; F(4,162.9)=10.92; p<0.001). The increase from rest to VO(2max) was 0.98 (SD 0.8) and 1.96 nmol/l (SD 1.1), respectively, for depressed subjects and healthy controls (mean diff: 0.98 nmol/l; 95% CI 0.7-1.3; t=6.63; df=170; p<0.001). The increase in NT-proANP from rest to peak VO(2max) was 1.27 (SD 1.0) and 0.84 nmol/l (SD 0.6), respectively, for unmedicated and medicated patients (mean diff: 0.42 nmol/l; 95% CI 0.1-0.8; t=2.56; df=128; p=0.01). CONCLUSION: We observed an attenuated NT-proANP response to acute physical stress in depressed patients. Antidepressants were associated with an independent suppressive effect on the NT-proANP response. PMID- 20950941 TI - Chronotype and diurnal cortisol profile in working women: differences between work and leisure days. AB - The influence of chronotype on the diurnal profile of salivary cortisol was examined in a sample of 187 healthy women: 21 evening chronotype, 24 morning chronotype and 142 intermediate chronotype. Saliva samples were collected at waking, 30 min post-awakening, at 1000 h, 1200 h, 1500 h, 1700 h and at bedtime on one work and one leisure day. Several components of the diurnal profile were examined including the cortisol awakening response, the total cortisol output and the diurnal profile on both the work and the leisure day, a significant main effect of time emerged (both p<0.01). After adjustment for age, smoking status, self-rated health, time of waking, and sleep problems, no effect of chronotype was evident for cortisol in the evening, the cortisol awakening response, or total cortisol output over the working day. However, on the leisure day, total cortisol output was greater in evening-types than intermediate or morning-types, after adjustment for covariates (p=0.029). The present data indicate that chronotype has a limited impact on the diurnal cortisol profile of healthy women, and may be somewhat impervious to individual preferences for morning or evening activity. PMID- 20950942 TI - High-glycolytic cancers and their interplay with the body's glucose demand and supply cycle. AB - Many difficult-to-treat solid cancer tumours and metastases have high-glucose uptake, usually under hypoxic conditions. Hypoxic tumours suppress the immune system and are insensitive to traditional chemoradiotherapies. The only therapy usually available is surgical resection. However, with widespread metastases, surgery often becomes unviable. Surgery in itself can also result in metastasis. The need for investigating adjuvant treatments is obvious. Here we investigate whether the high-glucose uptake of hypoxic tumours could lead to such a treatment. Before any treatment can be hypothesised, it is crucial to understand how this glycolytic cancer phenotype fits in with the normal body's blood glucose cycle. The brain creates the healthy body's largest demand for blood glucose (BG) and ensures a very high level of control on in vivo supply. It is hypothesised that, through somatic evolution, high-glycolytic cancer cells opportunistically tap into this very stable energy environment. It is shown that therapies which target the glycolytic cancers' high BG needs cannot be developed without addressing the brain's energy needs. Based on this knowledge, and to initiate thinking on potential BG therapies, a first attempt is made at hypotheses for potential control of the in vivo brain demand as well as the available in vivo BG. The aim is to adversely affect primary as well as metastatic tumours without damaging brain and innocent bystander cells. PMID- 20950943 TI - Ovarian malignant mixed mullerian tumor with primitive neuroectodermal differentiation: case report with review of the literature. AB - Ovarian malignant mixed mullarian tumor (OMMMT) is a rare and aggressive tumor of the female genital tract, occurring mainly in elderly women. Stage of disease is the most important predictor for survival with no prognostic effect, yet, of heterologous elements. Rare case reports described the peculiar presence of primitive neuroectodermal tissue among other heterologous elements in these tumors. Attractive designations, such as teratoid carcinosarcoma, were set by some authors to describe this subset of lesions, where it was considered a primary neuroectodermal tumor capable of multilineage differentiation. We here report a case of OMMMT in an elderly woman with focal primitive neuroectodermal differentiation as the sole heterologous element, and review the controversy on this topic in the literature. PMID- 20950944 TI - Stereotactic body radiotherapy reirradiation for recurrent epidural spinal metastases. AB - PURPOSE: When patients show progression after conventional fractionated radiation for spine metastasis, further radiation and surgery may not be options. Stereotactic body radiotherapy (SBRT) has been successfully used in treatment of the spine and may be applicable in these cases. We report the use of SBRT for 60 consecutive patients (81 lesions) who had radiological progressive spine metastasis with epidural involvement after previous radiation for spine metastasis. METHODS AND MATERIALS: SBRT was used with fiducial and vertebral anatomy-based targeting. The radiation dose was prescribed based on the extent of spinal canal involvement; the dose was 8 Gy*3=24 Gy when the tumor did not touch the spinal cord and 5 to 6 Gyx5=25 to 30 Gy when the tumor abutted the cord. The cord surface received up to the prescription dose with no hot spots in the cord. RESULTS: The median overall survival was 11 months, and the median progression free survival was 9 months. Overall, 93% of patients had stable or improved disease while 7% of patients showed disease progression; 65% of patients had pain relief. There was no significant toxicity other than fatigue. CONCLUSIONS: SBRT is feasible and appears to be an effective treatment modality for reirradiation after conventional palliative radiation fails for spine metastasis patients. PMID- 20950945 TI - Widespread dependence of backup NHEJ on growth state: ramifications for the use of DNA-PK inhibitors. AB - PURPOSE: The backup pathway of nonhomologous end joining (B-NHEJ) enables cells to process DNA double-strand breaks (DSBs) when the DNA-PK-dependent pathway of NHEJ (D-NHEJ) is compromised. Our previous results show marked reduction in the activity of B-NHEJ when LIG4(-/-) mouse embryo fibroblasts (MEFs) cease to grow and enter a plateau phase. The dependence of B-NHEJ on growth state is substantially stronger than that of D-NHEJ and points to regulatory mechanisms or processing determinants that require elucidation. Because the different D-NHEJ mutants show phenotypes distinct in their details, it is necessary to characterize the dependence of their DSB repair capacity on growth state and to explore species-specific responses. METHODS AND MATERIALS: DSB repair was measured in cells of different genetic background from various species using pulsed-field gel electrophoresis, or the formation of gamma-H2AX foci, at different stages of growth. RESULTS: Using pulsed-field gel electrophoresis, we report a marked reduction of B-NHEJ during the plateau phase of growth in KU and XRCC4, mouse or Chinese hamster, mutants. Notably, this reduction is only marginal in DNA-PKcs-deficient cells. However, reduced B-NHEJ is also observed in repair proficient, plateau-phase cells after treatment with DNA-PK inhibitors. The reduction of B-NHEJ activity in the plateau phase of growth does not derive from the reduced expression of participating proteins, is detectable by gamma H2AX foci analysis, and leads to enhanced cell killing. CONCLUSIONS: These results further document the marked dependence on growth state of an essential DSB repair pathway and show the general nature of the effect. Molecular characterization of the mechanism underlying this response will help to optimize the administration of DNA repair inhibitors as adjuvants in radiation therapy. PMID- 20950946 TI - Gamma knife radiosurgery for choroidal hemangioma. AB - PURPOSE: Patients with choroidal hemangioma (CH), a benign ocular hamartoma, frequently presents with visual disturbance as a result of exudative retinal detachment (RD), which originates in subretinal fluid accumulation. We report our experience using the Leksell Gamma Knife in the management of symptomatic CH. METHODS AND MATERIALS: Seven patients with symptomatic CH (circumscribed form in 3 patients and diffuse form in 4) were treated with the Leksell Gamma Knife at our institution during a 7-year period. All patients presented with exudative RD involving the macula that resulted in severe visual deterioration. The prescription dose to the target margin was 10 Gy in all cases. The mean tumor volume receiving the prescription dose was 536 mm3 (range, 151-1,057). The clinical data were analyzed in a retrospective fashion after a mean follow-up of 34.4 months (range, 9-76). RESULTS: The resolution of exudative RD was achieved within 6 months, and the visual acuity of the affected eye had improved at the latest follow-up examination (p=.018) in all patients. No recurrence of exudative RD occurred. Thinning of the CHs was observed in most patients; however, symptomatic radiation toxicity had not developed in any of the patients. CONCLUSION: Symptomatic CHs can be safely and effectively managed with Gamma Knife radiosurgery using a marginal dose of 10 Gy. PMID- 20950947 TI - A comparison of out-of-field dose and its constituent components for intensity modulated radiation therapy versus conformal radiation therapy: implications for carcinogenesis. AB - PURPOSE: To investigate differences in scatter and leakage between 6-MV intensity modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3DCRT); to describe the relative contributions of internal patient scatter, collimator scatter, and head leakage; and to discuss implications for second cancer induction. METHODS AND MATERIALS: Dose was measured at increasing distances from the field edge in a water bath with a sloping wall (1) under full scatter conditions, (2) with the field edge abutting but outside the bath to prevent internal (water) scatter, and (3) with the beam aperture plugged to reflect leakage only. RESULTS: Internal patient scatter from IMRT is 11% lower than 3DCRT, but collimator scatter and head leakage are five and three times higher, respectively. Ultimately, total scattered dose is 80% higher with IMRT; however this difference is small in absolute terms, being 0.14% of prescribed dose. Secondary dose from 3DCRT is mostly due to internal patient scatter, which contributes 70% of the total and predominates until 25 cm from the field edge. For IMRT, however, machine scatter/leakage is the dominant source, contributing 65% of the secondary dose. Internal scatter predominates for just the first 10 cm from field edge, collimator scatter for the next 10 cm, and head leakage thereafter. CONCLUSIONS: Out-of-field dose is 80% higher with IMRT, but differences are tiny in absolute terms. Reductions in internal patient scatter with IMRT are outweighed by increased machine scatter and leakage, at least for small fields. Reductions from IMRT in dose to tissues within the portals and in internal scatter, which predominates close to the field edge, means that calculations based solely on dose to distant tissues may overestimate carcinogenic risks. PMID- 20950948 TI - Proton beam therapy as a nonsurgical approach to mucosal melanoma of the head and neck: a pilot study. AB - PURPOSE: The aim of this pilot study was to assess the clinical benefit of proton beam therapy for mucosal melanoma of the head and neck. METHODS AND MATERIALS: Patients with mucosal melanoma of the head and neck with histologically confirmed malignant melanoma and N0 and M0 disease were enrolled. Proton therapy was delivered three times per week with a planned total dose of 60 Gy equivalents (GyE) in 15 fractions. RESULTS: Fourteen consecutive patients were enrolled from January 2004 through February 2008. Patient characteristics were as follows: median age 73 years old (range, 56 to 79 years); male/female ratio, 7/7; and T stage 1/2/3/4, 3/2/0/9. All patients were able to receive the full dose of proton therapy. The most common acute toxicities were mucositis (grade 3, 21%) and mild dermatitis (grade 3, 0%). As for late toxicity, 2 patients had a unilateral decrease in visual acuity, although blindness did not occur. No treatment-related deaths occurred throughout the study. Initial local control rate was 85.7%, and, with a median follow-up period of 36.7 months, median progression-free survival was 25.1 months, and 3-year overall survival rates were 58.0%. The most frequent site of first failure was cervical lymph nodes (6 patients), followed by local failure in 1 patient and lung metastases in 1 patient. On follow-up, 5 patients died of disease, 4 died due to cachexia caused by distant metastases, and 1 patient by carotid artery perforation cause by lymph nodes metastases. CONCLUSIONS: Proton beam radiotherapy showed promising local control benefits and would benefit from ongoing clinical study. PMID- 20950949 TI - Dose reduction study in vaginal balloon packing filled with contrast for HDR brachytherapy treatment. AB - PURPOSE: Vaginal balloon packing is a means to displace organs at risk during high dose rate brachytherapy of the uterine cervix. We tested the hypothesis that contrast-filled vaginal balloon packing reduces radiation dose to organs at risk, such as the bladder and rectum, in comparison to water- or air-filled balloons. METHODS AND MATERIALS: In a phantom study, semispherical vaginal packing balloons were filled with air, saline solution, and contrast agents. A high dose rate iridium-192 source was placed on the anterior surface of the balloon, and the diode detector was placed on the posterior surface. Dose ratios were taken with each material in the balloon. Monte Carlo (MC) simulations, by use of the MC computer program DOSXYZnrc, were performed to study dose reduction vs. balloon size and contrast material, including commercially available iodine- and gadolinium-based contrast agents. RESULTS: Measured dose ratios on the phantom with the balloon radius of 3.4 cm were 0.922 +/- 0.002 for contrast/saline solution and 0.808 +/- 0.001 for contrast/air. The corresponding ratios by MC simulations were 0.895 +/- 0.010 and 0.781 +/- 0.010. The iodine concentration in the contrast was 23.3% by weight. The dose reduction of contrast-filled balloon ranges from 6% to 15% compared with water-filled balloon and 11% to 26% compared with air-filled balloon, with a balloon size range between 1.4 and 3.8 cm, and iodine concentration in contrast of 24.9%. The dose reduction was proportional to the contrast agent concentration. The gadolinium-based contrast agents showed less dose reduction because of much lower concentrations in their solutions. CONCLUSIONS: The dose to the posterior wall of the bladder and the anterior wall of the rectum can be reduced if the vaginal balloon is filled with contrast agent in comparison to vaginal balloons filled with saline solution or air. PMID- 20950950 TI - Treatment effects and sequelae of radiation therapy for orbital mucosa-associated lymphoid tissue lymphoma. AB - PURPOSE: Among extranodal lymphomas, orbital mucosa-associated lymphoid tissue (MALT) lymphoma is a relatively rare presentation. We performed a review to ascertain treatment efficacy and toxicity of radiation therapy for orbital MALT lymphoma. We also evaluated changes in visual acuity after irradiation. METHODS AND MATERIALS: Thirty patients with orbital MALT lymphoma underwent radiation therapy with curative intent. Clinical stages at diagnosis were stage IEA in 29 patients and stage IIEA in 1 patient. Total doses of 28.8 to 45.8 Gy (median, 30 Gy) in 15 to 26 fractions (median, 16 fractions) were delivered to the tumors. RESULTS: All irradiated tumors were controlled during the follow-up period of 2 to 157 months (median, 35 months) after treatment. Two patients had relapses that arose in the cervical lymph node and the ipsilateral palpebral conjunctiva outside the radiation field at 15 and 67 months after treatment, respectively. The 5-year local progression-free and relapse-free rates were 100% and 96%, respectively. All 30 patients are presently alive; the overall and relapse-free survival rates at 5 years were 100% and 96%, respectively. Although 5 patients developed cataracts of grade 2 at 8 to 45 months after irradiation, they underwent intraocular lens implantation, and their eyesight recovered. Additionally, there was no marked deterioration in the visual acuity of patients due to irradiation, with the exception of cataracts. No therapy-related toxicity of grade 3 or greater was observed. CONCLUSIONS: Radiation therapy was effective and safe for patients with orbital MALT lymphoma. Although some patients developed cataracts after irradiation, visual acuity was well preserved. PMID- 20950951 TI - Differences in radiation dosimetry and anorectal function testing imply that anorectal symptoms may arise from different anatomic substrates. AB - PURPOSE: To explore the influence of functional changes and dosimetric parameters on specific incontinence-related anorectal complaints after prostate external beam radiotherapy and to estimate dose-effect relations for the anal wall and rectal wall. METHODS AND MATERIALS: Sixty patients, irradiated for localized prostate cancer, underwent anorectal manometry and barostat measurements to evaluate anal pressures, rectal capacity, and rectal sensory functions. In addition, 30 untreated men were analyzed as a control group. In 36 irradiated patients, the anal wall and rectal wall were retrospectively delineated on planning computed tomography scans, and dosimetric parameters were retrieved from the treatment plans. Functional and dosimetric parameters were compared between patients with and without complaints, focusing on urgency, incontinence, and frequency. RESULTS: After external beam radiotherapy, reduced anal pressures and tolerated rectal volumes were observed, irrespective of complaints. Patients with urgency and/or incontinence showed significantly lower anal resting pressures (mean 38 and 39 vs. 49 and 50 mm Hg) and lower tolerated rectal pressures (mean 28 and 28 vs. 33 and 34 mm Hg), compared to patients without these complaints. In patients with frequency, almost all rectal parameters were reduced. Several dosimetric parameters to the anal wall and rectal wall were predictive for urgency (e.g., anal D(mean)>38 Gy), whereas some anal wall parameters correlated to incontinence and no dose-effect relation for frequency was found. CONCLUSIONS: Anorectal function deteriorates after external beam radiotherapy. Different incontinence-related complaints show specific anorectal dysfunctions, suggesting different anatomic and pathophysiologic substrates: urgency and incontinence seem to originate from both anal wall and rectal wall, whereas frequency seems associated with rectal wall dysfunction. Also, dose-effect relations differed between these complaints. This implies that anal wall and rectal wall should be considered separate organs in radiotherapy planning. PMID- 20950952 TI - Retrospective study of palliative radiotherapy in newly diagnosed head and neck carcinoma. AB - PURPOSE: To examine the patterns of care, outcomes, and prognostic factors for patients with head-and-neck cancer (HNC) treated with palliative radiotherapy (RT). METHODS AND MATERIALS: An institutional HNC anthology and electronic patient records were used to identify patients with previously untreated HNC of mucosal or salivary gland origin who underwent palliative RT at our institution between July 2003 and June 2008. Overall survival was determined from the start date of RT to either the date of death or the date of last follow-up for living patients. The data were censored if the subject was either lost to follow-up or had not been seen for follow-up at our institution for >=4 months. RESULTS: We identified 148 eligible patients. The median age was 72 years (range, 19-94). Of the 148 patients, 12 had Stage II-III, 39 Stage IVA, 36 Stage IVB, and 54 Stage IVC; for 7 patients, the stage was unknown. Oropharyngeal primary cancer (40) was the most common primary site. The Eastern Cooperative Oncology Group performance status was 0 in 15, 1 in 69, 2 in 40, 3 in 19, and 4 in 5 patients. The Adult Co morbidity Evaluation-27 scale was 0 in 33, 1 in 47, 2 in 44, and 3 in 21. The median radiation dose was 50 Gy (range, 2-70), the median fraction number was 20 (range, 1-40), and the median total treatment time (including breaks) was 29 days (range, 1-80). At analysis, 108 patients (73%) had died, 20 (13.5%) were alive, and 20 (13.5%) had been censored. The median follow-up was 4.8 months, and the median survival time was 5.2 months. Information on the treatment response was available for 103 patients (70%). On multivariate analysis, the radiation dose was an independent predictor of both overall survival (hazard ratio 0.97, 95% confidence interval 0.96-0.99, p <.01) and treatment response (odds ratio 1.05, 95% confidence interval 1.01-1.08, p <.01). CONCLUSION: For patients considered unsuitable for curative RT, the radiation dose might be an independent predictive factor for both overall survival and treatment response. Additional research is required to more effectively select those patients who might benefit from more aggressive treatment. PMID- 20950953 TI - Atypical clinical behavior of p16-confirmed HPV-related oropharyngeal squamous cell carcinoma treated with radical radiotherapy. AB - PURPOSE: To report atypical clinical behavior observed in human papillomavirus (HPV)-related oropharyngeal carcinoma (OPC) treated with radiotherapy. METHODS AND MATERIALS: A retrospective cohort study was conducted for all newly diagnosed OPC cases treated with radiotherapy on July 1, 2003 to April 30, 2009. HPV positivity was determined by p16 immunostaining in tumors. The incidence of additional malignancies and the pattern of distant metastases (DMs) were compared between the HPV-positive (HPV+) and HPV-negative (HPV-) cohorts. RESULTS: HPV status was evaluated in 318 of 613 consecutive OPC cases (52%), showing 236 HPV+ and 82 HPV- patients. Compared with HPV-, HPV+ cases were less likely to have additional malignancies (prior: 11% vs. 20%, p = 0.038; synchronous: 1% vs. 9%, p = 0.001; metachronous: 6% vs. 16%, p = 0.003). Whereas the majority (10 of 12) of HPV- additional head-and-neck (HN) mucosal malignancies were in the oral cavity, there was none (0 of 7) in the HPV+ cohort (p < 0.001). HPV+ synchronous HN second primaries (SPs) were in the supraglottis, post-cricoid, and nasopharynx; metachronous HN SPs were in the glottis, supraglottis, and ethmoid plus glottis/post-cricoid region. All SPs that could be tested were HPV+. There was no difference in DM rate (10% vs. 15%, p = 0.272), but HPV+ DMs were more likely to involve multiple organs (46% vs. 0%, p = 0.005) and unusual sites. CONCLUSIONS: This study reports atypical clinical behavior seen in HPV+ OPC, including multicentric lesions in HN mucosa and DM to multiple organs and unusual sites. The frequency of these events is low, but they may have clinical implications. The routine assessment of HPV status for all OPC is warranted. PMID- 20950954 TI - Patient selection and activity planning guide for selective internal radiotherapy with yttrium-90 resin microspheres. AB - PURPOSE: Selective internal radiotherapy (SIRT) with yttrium-90 ((90)Y) resin microspheres can improve the clinical outcomes for selected patients with inoperable liver cancer. This technique involves intra-arterial delivery of beta emitting microspheres into hepatocellular carcinomas or liver metastases while sparing uninvolved structures. Its unique mode of action, including both (90)Y brachytherapy and embolization of neoplastic microvasculature, necessitates activity planning methods specific to SIRT. METHODS AND MATERIALS: A panel of clinicians experienced in (90)Y resin microsphere SIRT was convened to integrate clinical experience with the published data to propose an activity planning pathway for radioembolization. RESULTS: Accurate planning is essential to minimize potentially fatal sequelae such as radiation-induced liver disease while delivering tumoricidal (90)Y activity. Planning methods have included empiric dosing according to degree of tumor involvement, empiric dosing adjusted for the body surface area, and partition model calculations using Medical Internal Radiation Dose principles. It has been recommended that at least two of these methods be compared when calculating the microsphere activity for each patient. CONCLUSIONS: Many factors inform (90)Y resin microsphere SIRT activity planning, including the therapeutic intent, tissue and vasculature imaging, tumor and uninvolved liver characteristics, previous therapies, and localization of the microsphere infusion. The influence of each of these factors has been discussed. PMID- 20950955 TI - Ductal carcinoma in situ with microinvasion: prognostic implications, long-term outcomes, and role of axillary evaluation. AB - PURPOSE: To compare the clinical-pathologic features and long-term outcomes for women with ductal carcinoma in situ (DCIS) vs. DCIS with microinvasion (DCISM) treated with breast conservation therapy (BCT), to assess the impact of microinvasion. PATIENTS AND METHODS: A total of 393 patients with DCIS/DCISM from our database were analyzed to assess differences in clinical-pathologic features and outcomes for the two cohorts. RESULTS: The median follow-up was 8.94 years, and the mean age was 55.8 years for the entire group. The DCISM cohort was comprised of 72 of 393 patients (18.3%). Surgical evaluation of the axilla was performed in 58.3% (n = 42) of DCISM vs. 18.1% (n = 58) of DCIS, with only 1 of 42 DCISM (2.3%) vs. 0 of 58 DCIS with axillary metastasis. Surgical axillary evaluation was not an independent predictor of local-regional relapse (LRR), distant relapse-free survival (DRFS), or overall survival (OS) in Cox proportional hazards analysis (p > 0.05). For the DCIS vs. DCISM groups, respectively, the 10-year breast relapse-free survival was 89.0% vs. 90.7% (p = 0.36), DRFS was 98.5% vs. 97.9% (p = 0.78), and OS was 93.2% vs. 95.7% (p = 0.95). The presence of microinvasion did not correlate with LRR, age, presentation, race, family history, margin status, and use of adjuvant hormonal therapy (all p > 0.05). In univariate analysis, pathology (DCIS vs. DCISM) was not an independent predictor of LRR (hazard ratio [HR], 1.58; 95% confidence interval [CI], 0.58-4.30; p = 0.36), DRFS (HR, 0.72; 95% CI, 0.07-6.95; p = 0.77), or OS (HR, 1.03; 95% CI, 0.28-3.82; p = 0.95). CONCLUSIONS: Our data imply that the natural history of DCISM closely resembles that of DCIS, with a low incidence of local-regional and distant failures. On the basis of our large dataset, the incidence of axillary metastasis in DCISM appears to be small and not appear to correlate to outcomes, and thus, microinvasion alone should not be the sole criterion for more aggressive treatment. PMID- 20950956 TI - Four-dimensional positron emission tomography: implications for dose painting of high-uptake regions. AB - PURPOSE: To investigate the behavior of tumor subvolumes of high [18F] fluorodeoxyglucose (FDG) uptake as seen on clinical four-dimensional (4D) FDG positron emission tomography (PET) scans. METHODS AND MATERIALS: Four-dimensional FDG-PET/computed tomography scans from 13 patients taken before radiotherapy were available. The analysis was focused on regions of high uptake that are potential dose-painting targets. A total of 17 lesions (primary tumors and lymph nodes) were analyzed. On each one of the five phases of the 4D scan a classification algorithm was applied to obtain the region of highest uptake and segment the tumor volume. We looked at the behavior of both the high-uptake subvolume, called "Boost," and the segmented tumor volume, called "Target." We measured several quantities that characterize the Target and Boost volumes and quantified correlations between them. RESULTS: The behavior of the Target could not always predict the behavior of the Boost. The shape deformation of the Boost regions was on average 133% higher than that of the Target. The gross to internal target volume expansion was on average 27.4% for the Target and 64% for the Boost, a statistically significant difference (p < 0.05). Finally, the inhale-to-exhale phase (20%) had the highest shape deformation for the Boost regions. CONCLUSIONS: A complex relationship between the measured quantities for the Boost and Target volumes is revealed. The results suggest that in cases in which advanced therapy techniques such as dose painting are being used, a close examination of the 4D PET scan should be performed. PMID- 20950957 TI - Reduction of radiation-induced vascular nitrosative stress by the vitamin E analog gamma-tocotrienol: evidence of a role for tetrahydrobiopterin. AB - PURPOSE: The vitamin E analog gamma-tocotrienol (GT3) is a powerful radioprotector. GT3 reduces postradiation vascular peroxynitrite production, an effect dependent on inhibition of hydroxy-methylglutaryl-coenzyme A reductase. Hydroxy-methylglutaryl-coenzyme A reductase inhibitors mediate their pleiotropic effects via endothelial nitric oxide synthase that requires the cofactor tetrahydrobiopterin (BH4). This study investigated the effects of radiation on BH4 bioavailability and of GT3 on BH4 metabolism. METHODS AND MATERIALS: Mice were exposed to 8.5 Gy of total body irradiation (TBI). Lung BH4 and total biopterin concentrations were measured 0, 3.5, 7, 14, and 21 days after TBI by use of differential oxidation followed by high-performance liquid chromatography. The effect of exogenous GT3 and BH4 treatment on postradiation vascular oxidative stress and bone marrow colony-forming units were assessed in vivo. The effect of GT3 on endothelial cell apoptosis and endothelial expression of guanosine triphosphate (GTP) cyclohydrolase 1 (GTPCH), GTPCH feedback regulatory protein (GFRP), GFRP transcription, GFRP protein levels, and GFRP-GTPCH protein binding was determined in vitro. RESULTS: Compared with baseline levels, lung BH4 concentrations decreased by 24% at 3.5 days after TBI, an effect that was reversed by GT3. At 14 and 21 days after TBI, compensatory increases in BH4 (58% and 80%, respectively) were observed. Relative to vehicle-treated controls, both GT3 and BH4 supplementation reduced postirradiation vascular peroxynitrite production at 3.5 days (by 66% and 33%, respectively), and BH4 resulted in a 68% increase in bone marrow colony-forming units. GT3 ameliorated endothelial cell apoptosis and reduced endothelial GFRP protein levels and GFRP-GTPCH binding by decreasing transcription of the GFRP gene. CONCLUSIONS: BH4 bioavailability is reduced in the early postradiation phase. Exogenous administration of BH4 reduces postirradiation vascular oxidative stress. GT3 potently reduces the expression of GFRP, one of the key regulatory proteins in the BH4 pathway, and may thus exert some of its beneficial effects on postradiation free radical production partly by counteracting the decrease in BH4. PMID- 20950958 TI - A treatment planning method for sequentially combining radiopharmaceutical therapy and external radiation therapy. AB - PURPOSE: Effective cancer treatment generally requires combination therapy. The combination of external beam therapy (XRT) with radiopharmaceutical therapy (RPT) requires accurate three-dimensional dose calculations to avoid toxicity and evaluate efficacy. We have developed and tested a treatment planning method, using the patient-specific three-dimensional dosimetry package 3D-RD, for sequentially combined RPT/XRT therapy designed to limit toxicity to organs at risk. METHODS AND MATERIALS: The biologic effective dose (BED) was used to translate voxelized RPT absorbed dose (D(RPT)) values into a normalized total dose (or equivalent 2-Gy-fraction XRT absorbed dose), NTD(RPT) map. The BED was calculated numerically using an algorithmic approach, which enabled a more accurate calculation of BED and NTD(RPT). A treatment plan from the combined Samarium-153 and external beam was designed that would deliver a tumoricidal dose while delivering no more than 50 Gy of NTD(sum) to the spinal cord of a patient with a paraspinal tumor. RESULTS: The average voxel NTD(RPT) to tumor from RPT was 22.6 Gy (range, 1-85 Gy); the maximum spinal cord voxel NTD(RPT) from RPT was 6.8 Gy. The combined therapy NTD(sum) to tumor was 71.5 Gy (range, 40-135 Gy) for a maximum voxel spinal cord NTD(sum) equal to the maximum tolerated dose of 50 Gy. CONCLUSIONS: A method that enables real-time treatment planning of combined RPT-XRT has been developed. By implementing a more generalized conversion between the dose values from the two modalities and an activity-based treatment of partial volume effects, the reliability of combination therapy treatment planning has been expanded. PMID- 20950959 TI - Radical external beam radiotherapy for clinically localized prostate cancer in Japan: changing trends in the patterns of care process survey. AB - PURPOSE: To delineate changing trends in radical external beam radiotherapy (EBRT) for prostate cancer in Japan. METHODS AND MATERIALS: Data from 841 patients with clinically localized prostate cancer treated with EBRT in the Japanese Patterns of Care Study (PCS) from 1996 to 2005 were analyzed. RESULTS: Significant increases in the proportions of patients with stage T1 to T2 disease and decrease in prostate-specific antigen values were observed. Also, there were significant increases in the percentages of patients treated with radiotherapy by their own choice. Median radiation doses were 65.0 Gy and 68.4 Gy from 1996 to 1998 and from 1999 to 2001, respectively, increasing to 70 Gy from 2003 to 2005. Moreover, conformal therapy was more frequently used from 2003 to 2005 (84.9%) than from 1996 to 1998 (49.1%) and from 1999 to 2001 (50.2%). On the other hand, the percentage of patients receiving hormone therapy from 2003 to 2005 (81.1%) was almost the same as that from 1996 to 1998 (86.3%) and from 1999 to 2001 (89.7%). Compared with the PCS in the United States, patient characteristics and patterns of treatments from 2003 to 2005 have become more similar to those in the United States than those from 1996 to 1998 and those from 1999 to 2001. CONCLUSIONS: This study indicates a trend toward increasing numbers of patients with early-stage disease and increasing proportions of patients treated with higher radiation doses with advanced equipment among Japanese prostate cancer patients treated with EBRT during 1996 to 2005 survey periods. Patterns of care for prostate cancer in Japan are becoming more similar to those in the United States. PMID- 20950960 TI - Hypofractionated whole-breast radiotherapy for women with early breast cancer: myths and realities. PMID- 20950961 TI - Quality assurance of 4D-CT scan techniques in multicenter phase III trial of surgery versus stereotactic radiotherapy (radiosurgery or surgery for operable early stage (stage 1A) non-small-cell lung cancer [ROSEL] study). AB - PURPOSE: To determine the accuracy of four-dimensional computed tomography (4D CT) scanning techniques in institutions participating in a Phase III trial of surgery vs. stereotactic radiotherapy (SBRT) for lung cancer. METHODS AND MATERIALS: All 9 centers performed a 4D-CT scan of a motion phantom (Quasar, Modus Medical Devices) in accordance with their in-house imaging protocol for SBRT. A cylindrical cedar wood insert with plastic spheres of 15 mm (o15) and 30 mm (o30) diameter was moved in a cosine-based pattern, with an extended period in the exhale position to mimic the actual breathing motion. A range of motion of R = 15 and R = 25 mm and breathing period of T = 3 and T = 6 s were used. Positional and volumetric imaging accuracy was analyzed using Pinnacle version 8.1* at various breathing phases, including the mid-ventilation phase and maximal intensity projections of the spheres. RESULTS: Imaging using eight CT scanners (Philips, Siemens, GE) and one positron emission tomography-CT scanner (Institution 3, Siemens) was investigated. The imaging protocols varied widely among the institutions. No strong correlation was found between the specific scan protocol parameters and the observed results. Deviations in the maximal intensity projection volumes averaged 1.9% (starting phase of the breathing cycle [o]15, R = 15), 12.3% (o15, R = 25), and -0.9% (o30, R = 15). The end-expiration volume deviations (13.4%, o15 and 2.5%, o30), were, on average, smaller than the end inspiration deviations (20.7%, o15 and 4.5%, o30), which, in turn, were smaller than the mid-ventilation deviations (32.6%, o15 and 8.0%, o30). A slightly larger variation in the mid-ventilation origin position was observed (mean, -0.2 mm; range, -3.6-4.2) than in the maximal intensity projection origin position (mean, 0.1 mm; range, -2.5-2.5). The range of motion was generally underestimated (mean, -1.5 mm; range, -5.5-1). CONCLUSIONS: Notable differences were seen in the 4D-CT imaging protocols for SBRT among centers. However, the observed deviations in target volumes were generally small. They were slightly larger for the mid ventilation phases and smallest for the end-expiration phases. Steps to optimize and standardize the 4D-CT scanning protocols for SBRT are desirable. PMID- 20950962 TI - Tocopherol succinate: modulation of antioxidant enzymes and oncogene expression, and hematopoietic recovery. AB - PURPOSE: A class of naturally occurring isoforms of tocopherol (tocols) was shown to have varying degrees of protection when administered before radiation exposure. We recently demonstrated that alpha-tocopherol succinate (TS) is a potential radiation prophylactic agent. Our objective in this study was to further investigate the mechanism of action of TS in mice exposed to (60)Co gamma radiation. METHODS AND MATERIALS: We evaluated the effects of TS on expression of antioxidant enzymes and oncogenes by quantitative RT-PCR in bone marrow cells of (60)Co gamma-irradiated mice. Further, we tested the ability of TS to rescue and repopulate hematopoietic stem cells by analyzing bone marrow cellularity and spleen colony forming unit in spleen of TS-injected and irradiated mice. RESULTS: Our results demonstrate that TS modulated the expression of antioxidant enzymes and inhibited expression of oncogenes in irradiated mice at different time points. TS also increased colony forming unit-spleen numbers and bone marrow cellularity in irradiated mice. CONCLUSIONS: Results provide additional support for the observed radioprotective efficacy of TS and insight into mechanisms. PMID- 20950963 TI - Fibroblast growth factor 2--a predictor of outcome for patients irradiated for stage II-III non-small-cell lung cancer. AB - PURPOSE: The prognostic value of the tumor cell expression of the fibroblast growth factor 2 (FGF-2) in patients with non-small-cell lung cancer (NSCLC) is unclear. The present study investigated the effect of tumor cell expression of FGF-2 on the outcome of 60 patients irradiated for Stage II-III NSCLC. METHODS AND MATERIALS: The effect of FGF-2 expression and 13 additional factors on locoregional control (LRC), metastasis-free survival (MFS), and overall survival (OS) were retrospectively evaluated. These additional factors included age, gender, Karnofsky performance status, histologic type, histologic grade, T and N category, American Joint Committee on Cancer stage, surgery, chemotherapy, pack years, smoking during radiotherapy, and hemoglobin during radiotherapy. Locoregional failure was identified by endoscopy or computed tomography. Univariate analyses were performed with the Kaplan-Meier method and the Wilcoxon test and multivariate analyses with the Cox proportional hazard model. RESULTS: On univariate analysis, improved LRC was associated with surgery (p = .017), greater hemoglobin levels (p = .036), and FGF-2 negativity (p <.001). On multivariate analysis of LRC, surgery (relative risk [RR], 2.44; p = .037), and FGF-2 expression (RR, 5.06; p <.001) maintained significance. On univariate analysis, improved MFS was associated with squamous cell carcinoma (p = .020), greater hemoglobin levels (p = .007), and FGF-2 negativity (p = .001). On multivariate analysis of MFS, the hemoglobin levels (RR, 2.65; p = .019) and FGF 2 expression (RR, 3.05; p = .004) were significant. On univariate analysis, improved OS was associated with a lower N category (p = .048), greater hemoglobin levels (p <.001), and FGF-2 negativity (p <.001). On multivariate analysis of OS, greater hemoglobin levels (RR, 4.62; p = .002) and FGF-2 expression (RR, 3.25; p = .002) maintained significance. CONCLUSIONS: Tumor cell expression of FGF-2 appeared to be an independent negative predictor of LRC, MFS, and OS. PMID- 20950964 TI - [High-level HCG in non-gravidic situations: About two cases]. AB - Ovarian dysgerminoma is the most common germinal tumor in women; however, a lot of different symptoms can lead to its diagnosis. In the two cases reported here, misdiagnosis of ectopic pregnancy was first done because of inappropriate secretion of HCG by the tumor. These two cases point out the particularity of dysgerminoma with its various secretion capacity. Conversely, facing a raised level of HCG in non-gravidic situation, physicians have to consider different gynaecological and extragynaecological hypothesis. PMID- 20950965 TI - Initiation to drug injection among street youth: a gender-based analysis. AB - OBJECTIVE(S): To estimate the incidence rate of initiation into drug injection and to identify predictors of initiation into drug injection separately among street girls and boys. DESIGN: Data from two consecutive prospective street youth cohort studies (1995-2001 and 2001-2005) were used to conduct these analyses, stratified by gender. METHODS: Data were collected using semi-annual interviewer administered questionnaires. Variables from the following domains were considered in Cox regression models: socio-demographic characteristics, early and current substance abuse, marginalization, childhood traumatic sexual events and injection exposure. RESULTS: Of the 946 youth who had never injected drugs at study entry, 86.4% completed at least two questionnaires representing 243 girls and 574 boys. Incidence rates of injection of 7.0 and 5.9 per 100 person-years were observed among these girls and boys respectively. Among girls, cocaine or crack use (adjusted hazard ratio (AHR)=1.97), heroin use (AHR=2.86), homelessness (AHR=2.49) and hanging out regularly with people who inject (AHR=4.46) all independently increased risk of first injection. Among boys, age decreased risk of initiating injection (AHR=0.90/year), while cocaine or crack use (AHR=2.14), heroin use (AHR=3.56), homelessness before age 16 (AHR=1.68), incest or rape before age 14 (AHR=1.98) and hanging out regularly with people who inject (AHR=1.66) all independently increased this risk. CONCLUSIONS: Our findings suggest similar rates of initiation among girls and boys; however, factors associated with initiation vary by gender. This might lead to the design of more effective programs to prevent initiation into drug injection. PMID- 20950966 TI - Auditory processing during sleep in preterm infants: An event related potential study. AB - Auditory processing during sleep was investigated in premature infants by auditory event related potentials (AERPs). Twenty-six premature infants (mean GA 30 week- range 25-35) admitted to a neonatal intensive care unit were studied, prior to discharge, in active and quiet sleep at a mean post-conceptional age of 35 weeks. Infant state was determined by behavioral observation according to standard criteria. An auditory odd-ball paradigm was used with frequently occurring 'standard' tones at 1000Hz and infrequent 'deviant' tones at 2000Hz. Waveforms were recorded at Fz, Cz, Pz, T3 and T4 scalp locations. Measurements were performed in 18 patients because 8 preterm infants were excluded since they had less than the required artifact-free deviant trials in each sleep state. The responses to standard tones were equally recorded in both active and quiet sleep, but auditory responses to deviant tones consisting of an increased frontal negativity in the time period from 200 to 300ms after the stimulus were recorded only in active sleep. A significant effect of electrode placement, for frontal location by sleep condition and sleep condition by 50ms time windows was shown by repeated measures analyses of variance. The significance of these findings on evoked potential methodology in preterm infants admitted to neonatal intensive care unit is discussed. PMID- 20950967 TI - Do neonatologists limit parental decision-making authority? A Canadian perspective. AB - BACKGROUND: According to the principles of family-centered care, fully informed parents and health care professionals are partners in the care of sick neonates. AIM: The aim of this study was to assess the attitudes of Canadian neonatologists towards the authority of parents to make life-and-death decisions for their babies. STUDY DESIGN: We interviewed 121 (74%) of the 164 practicing neonatologists in Canada (June 2004-March 2005), using scripted open-ended questions and common clinical scenarios. Data analysis employed interpretive description methodology. MAIN OUTCOME MEASURE: The main outcome measure was the intention of neonatologists to limit parental life-and-death decision-making authority, when they disagree with parental decisions. RESULTS: Neonatologists' self-rated respect for parental decision-making authority was 8/10. Most neonatologists thought that parents should be either primary decision-makers or part of the decision-making team. Fifty-six percent of neonatologists would limit parental decision-making authority if the parents' decision is not in the baby's "best interest". In response to common neonatal severe illness scenarios, up to 18% of neonatologists said they would limit parental decision-making, even if the chance of intact survival is very poor. For clinical scenarios with equally poor long-term outcomes, neonatologists were more likely to comply with parental wishes early in the life of a baby, particularly with documented brain injury. CONCLUSIONS: Canadian neonatologists espouse high regard for parental decision making authority, but are prepared to limit parental authority if the parents' decision is not thought to be in the baby's best interest. Although neonatologists advise parents that treatment can be started at birth, and stopped later, this was only for early severe brain injury. PMID- 20950968 TI - Endometrial expression of leptin receptor and members of the growth hormone Insulin-like growth factor system throughout the estrous cycle in heifers. AB - The growth hormone (GH)-insulin-like growth factor (IGF) system is expressed in bovine uterus during the estrous cycle and early pregnancy and is acknowledged to play an important role in regulating the development of the embryo and uterus. The leptin receptor (LEPR) is also expressed in the bovine uterus although it is not known whether its expression varies during the estrous cycle. In this study, the expression of the IGF-I and -II, the type 1 IGF receptor (IGF-1R), GH receptor (GHR) and LEPR transcripts was determined on endometrial transcervical biopsies collected on days 0 (estrus), 5, 12 and 19 of the cow estrous cycle (n=8). The expression of mRNA was determined by RT real time PCR using ribosomal protein L19 as a housekeeping gene. It has been demonstrated for the first time that LEPR mRNA is expressed in the bovine uterus throughout the estrous cycle and that it presents a cycle-dependent variation, with higher levels observed during the luteal phase. The expression of IGF-I mRNA was greatest at estrus and day 5 (100%), and decreased on days 12 and 19 to 47% and 35% of the initial values. IGF II mRNA increased on day 12 and decreased sharply thereafter (to one-third of day 12 values). Interestingly, IGF-1R showed the same pattern as IGF-II: increased 50% on day 12 compared to values at estrus and presented a sharp decrease on day 19. The expression of GHR transcript was greatest at estrus and on day 5 and progressively decreased thereafter. These results show that the GH-IGF system components are distinctively regulated during the estrous cycle suggesting that modulation of the IGF system may influence uterine activity during this period. The increase in the uterine sensitivity to IGFs during the late luteal phase - as demonstrated by the increased IGF-1R expression - concomitant with the increased IGF-II mRNA expression may reinforce the role of IGF-II during early pregnancy. Moreover, leptin is also likely to play roles during early embryo development. PMID- 20950969 TI - Older men's knowledge about osteoporosis and educational interventions to increase osteoporosis knowledge in older men: a systematic review. AB - OBJECTIVE: The prevalence of osteoporosis and low bone density in men over the age of 65 is approximately 45%. The public health response to a disease affecting almost half of a given population includes assessment of knowledge and design of educational interventions in order to improve screening and prevention. The aim of this systematic review is two fold. We aim to describe older men's knowledge about the osteoporosis disease process, risk factors, and prevention. Second, we examine educational interventions designed to increase older men's knowledge about osteoporosis. METHODS: Computerized literature searches were performed with multiple databases including Academic Search Premier, CINAHL, MEDLINE, SocINDEX, and Psychology and Behavioral Sciences Collection. Studies were considered if they included men aged 50 years or older, included a measure of osteoporosis knowledge and/or had an intervention designed to change osteoporosis knowledge and/or lifestyle risk factors for osteoporosis. RESULTS: Thirteen studies were included in the review. Nine of the studies were cross-sectional studies on men's knowledge of osteoporosis. All of the studies found that men have minimal knowledge of the osteoporosis disease process, risk factors, and prevention. Four studies focused on education about osteoporosis. Educational interventions were found to increase initiation of calcium supplementation and knowledge about osteoporosis prevention. CONCLUSION: Older men know remarkably little about the osteoporosis disease process, risk factors for the disease, or prevention. Education has the potential to improve this situation. Unfortunately, so few clinical trials have occurred that the best method for improving men's knowledge cannot be stated. Future studies examining knowledge and education of osteoporosis for men need to use validated instruments with a focus on risk factors pertinent to men. PMID- 20950970 TI - The role of the forensic odontologist in disaster victim identification: lessons for management. AB - Forensic odontologists are involved in all phases of disaster victim identification (DVI). The failure of DVI management to embed odontology teams within all phases of the investigation and to include them in management decisions throughout the operation may lead to delays in the reconciliation process and could possibly compromise the integrity of the DVI investigation. In the case study presented, trained and experienced teams of forensic odontologists were not utilised to full capacity in all phases of the investigation. The complexity of the initial scene investigation was not identified resulting in the incomplete recovery of all remains. The scene had to be re-examined on three subsequent occasions. The post-mortem examination of the remains had to be deferred until all subsequent material had been collected. The collection of all ante-mortem dental records was not undertaken, resulting in transcription information that was incomplete and compromised. As a result, the reconciliation (formal identification) of the deceased became problematic because of the compounded errors in all phases of this DVI investigation and the resulting odontological report of identification could have jeopardized the integrity of the entire DVI process. Following a review of this case and the recognition of possible areas of omission in the management of the investigation a strategy to address these problems is proposed. PMID- 20950971 TI - Restless Leg Syndrome in ADHD children: levetiracetam as a reasonable therapeutic option. AB - The comorbidity of Attention Deficit Hyperactivity Disorder (ADHD) with sleep disorders has been extensively studied. In particular, Restless Legs Syndrome (RLS) appears to be consistently more frequent in children with ADHD. Several papers also draw attention to the frequent occurrence of epileptic seizures and EEG abnormalities in ADHD children. We performed a preliminary open label study to evaluate the efficacy of Levetiracetam (LEV) to ameliorate the sleep pattern and reduce RLS symptoms in children with a complex comorbidity between Attention Deficit Hyperactivity Disorder (ADHD), RLS and focal interictal epileptic discharges (IEDs) on EEG. We recruited seven children (all males, aged between 5 and 12years) who fulfilled the following criteria: ADHD diagnosis combined subtype; presence of idiopathic RLS; and presence of focal IEDs on EEG. All children were given LEV at a starting dose of approximately 10-20mg/kg/day followed by 10mg/kg/day incrementing at 1-week intervals up to 50-60mg/kg/day given in two separate doses. At a 3 and 6month follow-up, all children showed significant improvement (p<0.05) in global International RLS Rating Scale (IRLS RS). Parents' reports revealed improved sleep quality with fewer awakenings and restorative sleep in their children. LEV was well tolerated and no major side effects were reported. With an accessory report we observed the reduction of epileptiform EEG activity during sleep. In most patients (6 on 7) the discharges completely disappeared; in the last patient epileptiform EEG activity was significantly reduced. These children may represent a subgroup of ADHD patients in which the hyperactivity and attention difficulties might be aggravated by sleep disturbances and by IEDs. LEV could represent a therapeutic option for these comorbid conditions. PMID- 20950972 TI - Complication risk of endovascular embolization for cerebral arteriovenous malformation. AB - OBJECTIVE: The embolic agents currently used for the treatment of AVMs are n butyl cyanoacrylate (NBCA) and ethylene-vinyl alcohol copolymer (ONYX). The purpose of this study was to examine the overall NBCA and ONYX embolization related complication rate. METHODS: We retrospectively reviewed 147 consecutive patients with cerebral AVMs treated mainly with endovascular NBCA and ONYX embolization. Demographics, including age, sex, presenting symptoms, and angiographic factors including AVM size, deep venous drainage, and involvement of eloquent cortex were recorded. Number of pedicles embolized, the obliteration rate, and any complications were recorded. Complications were classified as the following: bleeding and ischemic complications. The ischemic complications were also classified as transient neurologic deficit, and permanent deficits. Modified Rankin Scale (mRS) scores were collected pre- and postembolization on all patients. Univariate regression analysis of determinants of complications was performed. RESULTS: We reviewed 147 patients with BAVM (58.5% male; mean age+/-SD at treatment: 27.5+/-11.1 years) treated with endovascular embolization. Two hundred twenty embolization, 144 NBCA and 76 ONYX embolizations were performed. Complete obliteration of BAVMs were achieved in 29 patients (19.7%). Additional gamma-knife radiosurgery were performed for 32 (21.8%) patients. There were 5 Spetzler-Martin grade I (3.4%), 20 grade II (13.6%), 54 grade III (36.7%), 44 grade IV (30%), and 24 grade V (16.3%) AVMs. There were a total of 7 (4.8% per patient, 3.2% per procedure) complications. There were bleeding complications in 2 patients (1.4% per patient, 0.9% per procedure), transient neurologic deficits in 4 (2.7% per patient, 1.8% per procedure) and 1 permanent deficit (0.7% per patient, 0.5% per procedure). Of the 147 patients, 141 (95.9%) were mRS 0-2, 6 (4.1%) were mRS=3 at discharge. Univariate analysis of risk factors for embolic agent showed that ONYX was not significantly associated with complications (X2=0.3, P>0.5). CONCLUSIONS: Embolization of brain AVMs is safe, 95.9% of patients had excellent or good outcomes at discharge after AVM embolization using liquid embolic agents, with a complication rate of 4.8%. ONYX embolization was not associated a higher rate of complications comparing with NBCA embolization. PMID- 20950973 TI - Bladder paraganglioma in adults: MR appearance in four patients. AB - PURPOSE: To document the magnetic resonance imaging (MRI) characteristics of paraganglioma of the urinary bladder in adults. MATERIALS AND METHODS: The MRI findings and clinical features of pathologically-proven bladder paraganglioma in four patients (three men, one woman; age range, 39-62 years; mean age, 46.8 years) were reviewed retrospectively. All patients underwent MRI in a 1.5 T instrument. The MRI features of the lesions were analyzed, with emphasis on the size, shape, location, margin, signal intensity, degree of MRI enhancement, and apparent diffusion coefficient (ADC) values. RESULTS: The bladder paragangliomas were located in the posterior vesicle wall (n=2), in the dome of the bladder wall (n=1), or the inferoanterior wall (n=1). On MR images, the tumors were round (n=1) or oval-shaped (n=3) and all exhibited well-circumscribed margins and broad based attachment to the bladder wall. On T1-weighted images, the lesions demonstrated homogeneous hyperintensity (n=4) compared to the gluteus maximus muscle; while on T2-weighted images, they showed slight hyperintensity (n=4). On contrast-enhanced MR images, all lesions showed intense enhancement. On diffusion weighted imaging (DWI), the lesions showed hyperintensity (n=4) and the mean ADC value was 0.973*10(-3) mm2/s. CONCLUSION: Bladder pheochromocytoma appears as a round or oval-shaped intensely enhancing lesion with T1 hyperintensity; these characteristics may facilitate the preoperative determination. PMID- 20950974 TI - Normal cranial bone marrow MR imaging pattern with age-related ADC value distribution. AB - OBJECTIVE: To determine MRI appearances of normal age-related cranial bone marrow and the relationship between MRI patterns and apparent diffusion coefficient (ADC) values. METHODS: Five hundred subjects were divided into seven groups based on ages. Cranial bone marrow MRI patterns were performed based on different thickness of the diploe and signal intensity distribution characteristics. ADC values of the frontal, parietal, occipital and temporal bones on DWI were measured and calculated. Correlations between ages and ADC values, between patterns and ADC values, as well as the distribution of ADC values were analyzed. RESULTS: Normal cranial bone marrow was divided into four types and six subtypes, Type I, II, III and IV, which had positive correlation with age increasing (chi2=266.36, P<0.01). The ADC values of normal parietal and occipital bone marrow showed significant negative correlation with age growing (r=-0.561 and 0.622, P<0.01), while there were no significant differences of that with age increasing in frontal and temporal bone marrow (P>0.05). In addition, there was significant negative correlation between the ADC values and MRI patterns in the normal parietal and occipital bones (r=-0.691 and -0.750, P<0.01). CONCLUSION: The combination of MRI features and ADC values changes in different cranial bones showed significant correlation with age increasing. Familiar with the MRI appearance of the normal bone marrow conversion pattern in different age group and their ADC value will aid the diagnosis and differential of the cranial bone pathology. PMID- 20950975 TI - Plain radiographic evaluation of children with obstructive adenoids. AB - BACKGROUND: There are several methods of evaluating adenoidal size pre operatively. Plain nasopharyngeal radiography is a common investigative modality: it has been advocated, and also condemned. AIM: This study was intended to assess nasopharyngeal airway obstruction by the adenoids using plain X-rays; and also to find correlation if any, with the symptomatology. METHODS: This is a retrospective study carried out between January and December 2008. The case notes and plain X-rays of the nasopharynx of 34 paediatric patients with clinical features of obstructive adenoids were analyzed. RESULTS: A total of 34 children were studied, 22 (64.7%) were males and 12 (35.3%) were females. Their ages ranged between 7 months and 10 years: mean age was 3.55 years, standard deviation 2.723. Majority (67.6%) of the children were in the age group 0-4 years. The lowest symptomatology assessment score was 0 and the highest was 3. Children 4 years and below had the highest symptomatology scores. The minimum adenoidal nasopharyngeal ratio was 0.35 and the maximum was 0.94. There was no significant difference in the mean adenoidal-nasopharyngeal ratio of males and females (t=0.407; p=0.692). Many (75.0%) of the children with moderate to severe nasopharyngeal airway obstruction by the adenoids were in the age bracket 0-4 years. The lowest adenoidal-nasopharyngeal ratio score was 0 and the highest was 3. Children 4 years and below had the highest adenoidal-nasopharyngeal ratio scores. There was a very weak nonsignificant correlation between the symptomatology assessment score and the radiological assessment score (r=0.168; p=0.375). CONCLUSION: The adenoidal-nasopharyngeal ratio is reliable in assessing the nasopharyngeal airway in children with obstructive adenoids. PMID- 20950976 TI - Health complaints among nurses working near MRI scanners--a descriptive pilot study. AB - A questionnaire-based descriptive pilot study was conducted among all nurses routinely working with MRI in the Northern part of Sweden to provide an indication of the self-reported prevalence of health complaints related to working with MRI systems. Fifty-nine nurses (88% response rate), with on average 8 (+/-6) years experience with MRI scanning procedures, returned the questionnaire. In total, 9 nurses (15%) reported regularly experiencing at least one of the health complaints (1-5% for specific health complaints) attributed to arise or be aggravated by their presence in the MRI scanning room. Stratification of the results indicated that reporting of adverse symptoms was not related to the level of occupational workload/stress. However, reporting of health complaints was related to the strength of the magnet(s) the nurses worked with, with 57% of symptoms reported by those nurses working with the strongest systems (both 1.5 and 3T scanners in this population). Although this descriptive study did not include a control population and was based on self-reporting of health complaints, these data indicate that the prevalence of reported health complaints is not related to perceived work load or occupational stress, but does confirm data from other occupational sectors and indicates that the prevalence of adverse health complaints increases with the strength of the MRI system for nurses as well. PMID- 20950977 TI - Radiofrequency ablation for recurrent intrahepatic cholangiocarcinoma after curative resection. AB - OBJECTIVE: Percutaneous radiofrequency ablation (RFA) has shown efficacy in patients with recurrent hepatocellular carcinoma, but has not been well documented in patients with recurrent intrahepatic cholangiocarcinoma (ICC). We therefore evaluated the long-term survival and safety of percutaneous RFA for patients with recurrent ICC after curative resection. MATERIALS AND METHODS: A total of 20 patients with 29 recurrent ICCs underwent ultrasound-guided percutaneous RFA. All patients had undergone curative resection of the primary ICC. Tumor size ranged from 0.7 cm to 4.4 cm in maximum dimension (mean, 1.9 cm; median, 1.5 cm). RESULTS: The technical effectiveness rate of RFA was 97% (28/29) of recurrent ICCs. Mean local tumor progression-free survival was 39.8 months, and the cumulative local tumor progression-free 6 month and 1, 2, and 4 year survival rates were 93%, 74%, 74%, and 74%, respectively. Median overall survival after RFA was 27.4 months and the cumulative overall 6 month and 1, 2, and 4 year survival rates were 95%, 70%, 60%, and 21%, respectively. There were two major complications (one liver abscess and one biliary stricture, 7% per treatment) during the follow-up, but no procedure-related deaths. CONCLUSION: RFA is safe and provides successful local tumor control in patients with recurrent ICC after curative resection. RFA for recurrent ICC resulted in a median overall survival rate of 27.4 months after RFA in the present series. PMID- 20950978 TI - Accuracy of automatic airway morphometry in computed tomography-correlation of radiological-pathological findings. AB - OBJECTIVES: Airway morphology shows characteristic changes in different pathologies. This study assesses the accuracy of a current automatic airway assessment technique by correlating CT images of porcine airways to histological slices of the same localization. MATERIALS AND METHODS: Four isolated and ventilated porcine lungs were frozen in a liquid nitrogen bath and examined with a CT scanner (MDCT). This technique both preserved normal radiomorphological appearance and made it possible to slice the specimens for histological examination for subsequent correlation. The parameters wall thickness (WT), wall percentage (WP), and total diameter (TD) were assessed by computer-aided measurement of the MDCT images using an integral-based method (IBM) and by manually measuring the histological slices with an electronic caliper. RESULTS: The radiological-pathological correlation could be performed for 16 localizations. Mean relative errors for WT, WP, and TD were 11%, 5.6%, and 8.5%, respectively. Correlation was very high with coefficients r of 0.951 for WT, 0.916 for WP, and 0.987 for TD. CONCLUSIONS: Our results are comparable to previously described errors in phantom correlations but are the first proof of ex vivo feasibility. Thus, by applying this freezing technique to MDCT data of diseased, explanted lungs and by combination with the IBM, further experiments can be performed to explore the effects of airway pathology on radiological morphology. PMID- 20950979 TI - Bombiscardovia coagulans gen. nov., sp. nov., a new member of the family Bifidobacteriaceae isolated from the digestive tract of bumblebees. AB - One hundred and eighty-seven fructose-6-phosphate phosphoketolase positive strains were isolated from the digestive tract of three different bumblebee species. Analyses of the partial 16S rRNA gene sequences of the representative strains showed only 92.8% and 92.5% similarity to Bifidobacterium coryneforme YIT 4092(T) and Bifidobacterium indicum JCM 1302(T), 92.2% similarity to Alloscardovia omnicolens CCUG 18650 and slightly reduced similarity of 91% to other members of the family Bifidobacteriaceae. On the other hand, analyses of the partial heat-shock protein 60 (hsp60) gene sequence revealed that the proposed type strain BLAPIII-AGV(T) was affiliated only to the 60 kDa chaperonin sequence of uncultured bacteria from human vagina (79-80%) and the hsp60 gene sequence of A. omnicolens CCUG 31649(T) (75.5%). The peptidoglycan type was A4alpha with an l-Lys-d-Asp interpeptide bridge. The polar lipids contained diphosphatidylglycerol, an unknown phospholipid, six glycolipids and two phosphoglycolipids. The major fatty acids were C(18:1), C(20:0) and C(18:0). These and other analyses indicated that the isolates represented a new genus within the family Bifidobacteriaceae. This observation was further substantiated by determination of the DNA G+C contents (46.1-47.1 mol%). Affinity of the strains to some scardovial genera (Aeriscardovia, Alloscardovia and Metascardovia) was also confirmed by their ability to grow under aerobic conditions. Besides the above mentioned differences, Bombiscardovia coagulans was found to differ from all scardovial genera in the ability to grow at temperatures as low as 5 degrees C, which was another major phenotypically different characteristic of this new member of the family Bifidobacteriaceae. Hence, on the basis of phylogenetic analyses using partial 16S rRNA and hsp60 gene sequence data, and the temperature related phenotypic difference, we propose a novel taxa, B. coagulans gen. nov., sp. nov. (type strain=BLAPIII-AGV(T)=DSM 22924(T)=ATCC BAA-1568(T)). PMID- 20950980 TI - The percutaneous ventricular assist device in severe refractory cardiogenic shock. AB - OBJECTIVES: We evaluated the efficacy and safety of the percutaneous ventricular assist device (pVAD) in patients in severe refractory cardiogenic shock (SRCS) despite intra-aortic balloon pump (IABP) and/or high-dose vasopressor support. BACKGROUND: SRCS is associated with substantial mortality despite IABP counterpulsation. Until recently, there was no rapid, minimally invasive means of providing increased hemodynamic support in SRCS. METHODS: A total of 117 patients with SRCS implanted with TandemHeart pVAD (CardiacAssist, Inc., Pittsburgh, Pennsylvania) were studied, of whom 56 patients (47.9%) underwent active cardiopulmonary resuscitation immediately before or at the time of implantation. Data was collected regarding clinical characteristics, hemodynamics, and laboratory values. RESULTS: Eighty patients had ischemic and 37 patients had nonischemic cardiomyopathy. The average duration of support was 5.8 +/- 4.75 days. After implantation, the cardiac index improved from median 0.52 (interquartile range [IQR]: 0.8) l/(min.m(2)) to 3.0 (IQR:0.9) l/(min.m(2)) (p < 0.001). The systolic blood pressure and mixed venous oxygen saturation increased from 75 (IQR:15) mm Hg to 100 (IQR:15) mm Hg (p < 0.001) and 49 (IQR:11.5) to 69.3 (IQR:10) (p < 0.001), respectively. The urine output increased from 70.7 (IQR: 70) ml/day to 1,200 (IQR: 1,620) ml/day (p < 0.001). The pulmonary capillary wedge pressure, lactic acid level, and creatinine level decreased, respectively, from 31.53 +/- 10.2 mm Hg to 17.29 +/- 10.82 mm Hg (p < 0.001), 24.5 (IQR: 74.25) mg/dl to 11 (IQR: 92) mg/dl (p < 0.001), and 1.5 (IQR: 0.95) mg/dl to 1.2 (IQR: 0.9) mg/dl (p = 0.009). The mortality rates at 30 days and 6 months were 40.2% and 45.3%, respectively. CONCLUSIONS: The pVAD rapidly reversed the terminal hemodynamic compromise seen in patients with SRCS refractory to IABP and vasopressor support. PMID- 20950982 TI - Higher glucose on admission is associated with need for angioembolization in stable pelvic fracture. AB - BACKGROUND: Angioembolization is an effective adjunct to the management of retroperitoneal hemorrhage in pelvic fractures. Most patients with stable-type pelvic fracture are treated conservatively. However, in some stable pelvic fracture cases, patients should receive angioembolization for hemostasis upon incidental finding of contrast extravasation on computed tomography (CT). In this study, we attempted to define the characteristics of patients with stable pelvic fracture requiring angioembolization. METHODS: We retrospectively reviewed the charts of patients with pelvic fractures between January 2005 and November 2009. We focused on stable pelvic fracture patients with contrast extravasation on CT who then received angioembolization. The demographics, Injury Severity Score (ISS), Abbreviated Injury Scale score, and the blood glucose levels on admission were analyzed. RESULTS: In total, 334 patients were enrolled. Patients with higher blood glucose level on admission with stable pelvic fracture had a higher rate of angioembolization. Furthermore, these patients presented with a higher Abbreviated Injury Scale score and ISS. CONCLUSIONS: In patients with stable pelvic fracture, higher blood glucose level on admission was associated with a higher likelihood of needing angioembolization. Blood glucose level should be checked during the initial survey of a pelvic fracture, and greater attention should be given to patients with higher blood glucose level or with an ISS of 25 or greater, even when the imaging study only reveals a stable pelvic fracture. PMID- 20950983 TI - Renal failure in a patient with postpolio syndrome and a normal creatinine level. AB - Patients with renal failure who are taking trimethoprim have an increased risk of developing hyperkalemia, which can cause muscle weakness. In patients with postpolio syndrome, a normal creatinine level could be abnormally high, renal failure is possible because of lack of creatinine production, and the muscle weakness from resultant hyperkalemia could be more severe because of their underlying condition. This abnormally high creatinine level has been termed from this point relative renal failure. The objective of the study was to review a case in which relative renal failure and hyperkalemia caused muscle weakness that manifested as shortness of breath and confusion with electrocardiographic changes. A dehydrated patient with relative renal failure and postpolio syndrome had taken trimethoprim-sulfamethoxazole that caused symptomatic hyperkalemia. The patient presented with muscle weakness, shortness of breath, and confusion, with her postpolio syndrome compounding the situation and likely making the muscle weakness more severe. A patient on trimethoprim with renal failure is at an increased risk of developing hyperkalemia. Patients with postpolio syndrome could have severe muscle weakness from the hyperkalemia and could have renal failure even with a normal creatinine level. This case report will remind treating physicians to evaluate such patients for hyperkalemia if they present with muscle weakness, especially if the patient has renal failure and is on trimethoprim. PMID- 20950984 TI - Computed tomography scan utilization in emergency departments: a multi-state analysis. AB - BACKGROUND: Increased utilization of computed tomography (CT) in emergency departments (EDs) has become a concern due to its expense and the potential risks associated with radiation exposure. OBJECTIVE: To describe the predictors of CT utilization based on patient, provider, and ED characteristics. METHODS: There were 3,217,396 ED patient visits during a 12-month period that were included in this retrospective analysis of a database from a single billing company that included 227 EDs in 41 states. Data were collected between January 1, 2006 and December 31, 2006 and included patient visit information, CT use for each patient visit, patient demographics, ED provider information, and ED volume. RESULTS: The CT utilization rate was 16.7% (95% confidence interval [CI] 16.7-16.8%) for adults, whereas in pediatric patients (< 18 years of age) it was 5.3% (95% CI 5.3 5.4%). The adult CT utilization rate ranged from 11.3% (95% CI 11.2-11.4%) at age 20-29 years to 24.6% (95% CI 24.5-24.8%) for those>65 years of age. For the admitted patients, the CT utilization rate was 27.8% (95% CI 27.6-27.9%); for the patients transferred out of the hospital, the CT utilization rate was 23.2% (95% CI 22.9-23.6%). Discharged patients had a rate of 11.3% (95% CI 11.2-11.3%) and patients who left against medical advice had a scan rate of 20.2% (95% CI 19.6 20.7%). The CT utilization rate was 9.3% (95% CI 9.2-9.4%) in EDs with<20,000 annual visits and increased to 17.8% (95% CI 17.7-17.9%) in EDs with volumes of>40,000. The CT utilization rate was 16.1% (95% CI 16.1-16.2%) for emergency medicine boarded physicians vs. 11.3% (95% CI 11.3-11.4%) for non-emergency medicine boarded physicians. CONCLUSIONS: CT utilization by EDs seems to vary by a number of parameters, including patient age, ED volume, training background of the provider, and disposition status of the patient. PMID- 20950985 TI - Children of the new reproductive technologies: social and genetic parenthood. AB - OBJECTIVE: To review empirical studies on families created by new reproductive technologies (NRT) in which only one parent has a genetic link to the child. METHODOLOGY: Literature search was conducted among computerized databases. Inclusion criteria were that studies should focus on childrearing or parenting, as well as on the psychological adjustment of children in: heterosexual families formed through artificial insemination with donated semen (AID), single-mother AID families, oocyte-donation families, planned lesbian-mother families, planned gay-father families, and partial surrogacy families. RESULTS: Compared to natural conception parents, parents in these NRT families have better relationships with their children, and their children are functioning well. CONCLUSION: Although several studies show that parents in NRT families are more emotionally involved in their parenting than are parents in naturally conceived families, no empirical evidence was found that the psychological adjustment of children in NRT families differs from that of their counterparts in natural-conception families. PRACTICAL IMPLICATION: The results inform counselors and infertile couples that concerns regarding the use of NRT in relation to negative consequences for the parent child relationship or the psychological adjustment of the child are till now unfounded. PMID- 20950986 TI - Anterosuperior labral tear without biceps anchor involvement: a subtle isolated cause of a painful shoulder. AB - PURPOSE: The purposes of this study were to determine common clinical symptoms related to an anterosuperior labral tear without biceps anchor involvement and to establish the outcome of arthroscopic management of this injury. METHODS: In our database of arthroscopic procedures we identified 23 patients with an isolated anterosuperior labral tear. The mean age at the time of surgery was 38.3 +/- 6.8 years (range, 18 to 59 years). The preoperative clinical diagnosis varied, but an anterosuperior labral isolated lesion was not detected before surgery. The diagnosis of anterosuperior labral tear was made arthroscopically, and the lesion was fixed with a suture anchor technique, by use of 1 single bioabsorbable anchor. Patients were reviewed after a minimum of 2.5 years of follow-up. Clinical outcome was evaluated with the Rowe score, American Shoulder and Elbow Surgeons score, Simple Shoulder Test score, and visual analog scale score. RESULTS: History, clinical examination, and preoperative imaging usually failed to indicate the presence of an isolated anterosuperior labral tear as the cause of shoulder pain in our patients. Repair of the labral lesions yielded good to excellent results with normalization of the range of motion and a significant improvement in shoulder scores (Rowe, American Shoulder and Elbow Surgeons, Simple Shoulder Test, and visual analog scale). CONCLUSIONS: Isolated tears of the anterosuperior labrum represent a subtle cause of shoulder pain and dysfunction. The lesion is very difficult to diagnose clinically. Arthroscopic repair is a reliable procedure providing a good outcome in terms of pain relief, patient satisfaction, and shoulder scores. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 20950988 TI - Biomechanical comparison of acromioclavicular joint reconstructions using coracoclavicular tendon grafts with and without coracoacromial ligament transfer. AB - PURPOSE: The purpose of this study was to compare the initial strength of acromioclavicular joint reconstructions using coracoclavicular (CC) tendon grafts with and without coracoacromial (CA) ligament transfers. METHODS: Two different acromioclavicular joint reconstructions were performed in 7 matched pairs of cadaveric shoulders. Paired shoulders were repaired with either a hamstring allograft CC reconstruction (group 1) or a hamstring allograft CC reconstruction plus a CA ligament transfer (group 2). Intact specimens and then reconstructions were cycled from 0 to 100 N at 1 Hz for 100 cycles in a superior direction, and displacements were recorded. Finally, the stiffness of the reconstructions and the ultimate load to failure were recorded. RESULTS: Superior displacement of the reconstructions after cyclic loading was 4.43 +/- 1.82 mm in group 1 and 3.75 +/- 1.56 mm in group 2 (P = .38). Ultimate load after load to failure was 970.3 +/- 361.03 N in group 1 and 952.7 +/- 296.89 N in group 2 (P = .94). Finally, stiffness of the reconstructions was 50.6 +/- 6.14 N/mm in group 1 and 65.6 +/- 18.45 N/mm in group 2 (P = .12). CONCLUSIONS: The addition of a transfer of the CA ligament to an acromioclavicular joint reconstruction with a CC hamstring graft does not appear to significantly improve its overall initial biomechanical strength. CLINICAL RELEVANCE: These data suggest that a CA ligament transfer may add very little to a CC tendon graft reconstruction augmented with high-strength suture with regard to initial, time zero displacement and strength. PMID- 20950987 TI - Combined arthroscopic and radiation synovectomy of the knee joint in rheumatoid arthritis: 14-year follow-up. AB - PURPOSE: To investigate the long-term outcome of combined arthroscopic and radiation synovectomy of the knee joint in early cases of rheumatoid arthritis (RA) with regard to knee function and the need for surgical re-interventions. METHODS: Between 1993 and 1997, a consecutive series of 38 RA patients with therapy-refractory synovitis of the knee joint and only mild cartilage lesions (not exceeding Outerbridge grade II at surgery) were treated with combined arthroscopic and radiation synovectomy. Knee function was assessed preoperatively; at 6 months, 1 year, and 5 years; and finally, at a mean of 14 years with 4 different functional scores. A Kaplan-Meier survival curve was calculated with "any re-intervention" and "total knee arthroplasty" as endpoints. RESULTS: Of 38 knees, 32 were available for the final 14-year follow-up with a total of 22 re-interventions: intra-articular steroid injection (n = 3), arthroscopic (n = 2) or radiation (n = 1) re-synovectomy, and total knee arthroplasty (n = 16). The remaining 10 patients with no re-intervention showed knee function not significantly different from the postoperative state. With any surgical re-intervention as the endpoint, the survival rate was 84% at 5 years (95% confidence interval [CI], 67.0% to 86.7%), 44% at 10 years (95% CI, 26.7% to 60.0%), and 32% at the 14-year assessment (95% CI, 16.0% to 49.3%). With total knee arthroplasty as the endpoint, the joint survival rate was 88.5% at 5 years (95% CI, 68.5% to 96.2%), 53.9% at 10 years (95% CI, 33.3% to 71.6%), and 39.6% at 14 years (95% CI, 18.9% to 48.6%). CONCLUSIONS: Combined arthroscopic and radiation synovectomy leads to a stable improvement of knee function for a minimum of 5 years, but surgical re-interventions were frequently observed at the 14-year assessment and challenge the long-term benefit of the procedure. Patients with no interventions had a significantly shorter history of disease (7 v 11 years). LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 20950989 TI - Computer-navigated surgery in anterior cruciate ligament reconstruction: are radiographic outcomes better than conventional surgery? AB - PURPOSE: The use of computer navigation systems in anterior cruciate ligament (ACL) has been the subject of debate. However, there is a lack of systematic review to analyze the radiographic outcomes after computer-navigated ACL reconstruction. METHODS: We searched, in duplicate, Medline, Embase, and Web of Science databases for randomized controlled trials (RCTs)/quasi-RCTs comparing conventional versus computer-navigated ACL reconstruction. Two reviewers independently extracted the data. Radiographic outcomes reported in a majority of included trials were meta-analyzed using the Mantel-Haenszel test statistic. RESULTS: After applying our eligibility criteria, we had 5 trials for systematic review and data synthesis. There was no evidence of statistical heterogeneity between all included studies. Both navigated and conventional ACL reconstructions placed the tibial tunnel in acceptable positions. The risk of notch impingement was reduced in the navigated group in comparison with the conventional group. CONCLUSIONS: A computer navigation systems may reduce variation from optimal graft alignment and notch impingement. However, there is a need for further high quality studies with long-term follow-up, so as to prove the clinical significance of these findings. LEVEL OF EVIDENCE: Level II, systematic review of randomized controlled trials. PMID- 20950990 TI - Does an educational strategy based on systematic preoperative assessment of simplified Apfel's score decrease postoperative nausea and vomiting? AB - BACKGROUND AND OBJECTIVE: Postoperative nausea and vomiting (PONV) is a frequent and unpleasant side effect occurring after anaesthesia and surgery. In the present study, we hypothesized that an educational strategy based on systematic preoperative assessment of the simplified Apfel's score decreased the incidence of PONV in a population of adult surgical patients. METHODS: All consecutive patients admitted in the postanaesthesia care unit (PACU) for elective surgery under general anaesthesia were included and PONV occurring in the PACU recorded. An educational strategy consisting in printing the items allowing calculation of the simplified Apfel's score on the records of the preanaesthetic visit, and encouraging anaesthetists to measure and record it was set up. Meetings dedicated to PONV prevention by emphasis on the current guidelines were regularly organized. The primary endpoint was the incidence of PONV occurring in the PACU. RESULTS: One hundred and ninety-one patients were included during the control period (08/01/07 to 28/02/07) and 193 after the educational strategy (01/03/07 to 30/04/07). The incidence of PONV was decreased in the second period from 19.37% to 11.4% (p=0.0340). The rate of administration of intraoperative prophylactic anti-emetics in high-risk groups increased from 36.4% to 52.8% (p=0.049). The prescription rate of anti-emetic prophylaxis correlated with the PONV risk derived from the simplified Apfel's score in the second period of the study (p=0.1415 before, vs. p=0.0005 after). CONCLUSION: An educational strategy based on systematic preoperative measurement and recording of the simplified Apfel's score is efficient to decrease markedly the incidence of PONV in a population of adult surgical patients. PMID- 20950991 TI - WITHDRAWN: Oxidative stress in aging: Theoretical outcomes and clinical evidences in humans. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.biomag.2011.03.001. The duplicate article has therefore been withdrawn. PMID- 20950992 TI - WITHDRAWN: Sodium butyrate protects against myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein in rats. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 20950993 TI - WITHDRAWN: Study on tolerance to ischemia-reperfusion injury and protection of ischemic preconditioning of type 1 diabetes rat heart. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.biomag.2010.09.004. The duplicate article has therefore been withdrawn. PMID- 20950994 TI - WITHDRAWN: Simvastatin prevents decreased SERCA2a activity in non-ischemic heart failure in rabbits via inhibition of beta-adrenergic signaling. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.biomag.2010.09.003. The duplicate article has therefore been withdrawn. PMID- 20950995 TI - WITHDRAWN: Neuroendocrine axes function in healthy aging: Evaluation of predictive and manipulable blood serum indexes. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.biomag.2010.09.002. The duplicate article has therefore been withdrawn. PMID- 20950996 TI - Thermal damage and tracker-pin track infection in computer-navigated total knee arthroplasty. AB - Choice of pins, drills, and drilling technique can result in heat generation leading to thermal necrosis of bone. This has been reported frequently in internal as well as in external fixation. This publication is the first report of a patient having osteomyelitis of the proximal tibia due to thermal necrosis following tracker pin placement in computer-navigated total knee arthroplasty. PMID- 20950997 TI - A novel joint-processing adaptive nonlinear equalizer using a modular recurrent neural network for chaotic communication systems. AB - To eliminate nonlinear channel distortion in chaotic communication systems, a novel joint-processing adaptive nonlinear equalizer based on a pipelined recurrent neural network (JPRNN) is proposed, using a modified real-time recurrent learning (RTRL) algorithm. Furthermore, an adaptive amplitude RTRL algorithm is adopted to overcome the deteriorating effect introduced by the nesting process. Computer simulations illustrate that the proposed equalizer outperforms the pipelined recurrent neural network (PRNN) and recurrent neural network (RNN) equalizers. PMID- 20950998 TI - Delay-distribution-dependent state estimation for discrete-time stochastic neural networks with random delay. AB - This paper is concerned with the state estimation problem for a class of discrete time stochastic neural networks (DSNNs) with random delays. The effect of both variation range and distribution probability of the time delay are taken into account in the proposed approach. The stochastic disturbances are described in terms of a Brownian motion and the time-varying delay is characterized by introducing a Bernoulli stochastic variable. By employing a Lyapunov-Krasovskii functional, sufficient delay-distribution-dependent conditions are established in terms of linear matrix inequalities (LMIs) that guarantee the existence of the state estimator which can be checked readily by the Matlab toolbox. The main feature of the results obtained in this paper is that they are dependent on not only the bound but also the distribution probability of the time delay, and we obtain a larger allowance variation range of the delay, hence our results are less conservative than the traditional delay-independent ones. One example is given to illustrate the effectiveness of the proposed result. PMID- 20950999 TI - Annular tilt as a screening test for right ventricular enlargement in patients with tetralogy of fallot. AB - BACKGROUND: Right ventricular end-diastolic volume (RVEDV) greater than 150 mL/m2 is a risk factor for sudden death in patients with tetralogy of Fallot (TOF) after repair. Because of its anterior placement and abnormal geometry, two dimensional echocardiography is limited to a qualitative assessment of RVEDV. Cardiac magnetic resonance imaging (CMRI) and computed tomography angiography (CTA) are the accepted standards for quantifying RVEDV. This study evaluated the ability of a novel echocardiographic measure, the right ventricular annular tilt (RVAT), to identify patients with increased RVEDV. METHODS: All patients with repaired TOF with an echocardiogram and CMRI or CTA were included in this retrospective study. The RVAT was determined by measuring the angle of the tricuspid valve plane relative to the mitral valve plane at end-diastole in the apical 4-chamber view in study (n = 38) and age-matched control (n = 74) patients. The RVEDV measurements were obtained by CMRI (n = 32) or CTA (n = 6). The study and control patients' ages were no different (11.3 and 11.8 years, P = .73). RESULTS: The study group RVAT was significantly higher than the control group RVAT (17.4 vs. 0.1 degrees; P < .0001). RVAT values greater than 20 degrees had a mean RVEDV of 166 +/- 60 mL/m2, whereas RVAT less than 20 degrees had a mean RVEDV of 122 +/- 25 mL/m2 (P = .0370). Receiver operating characteristic analysis demonstrated an RVAT of 17.9 degrees as the cutoff for predicting a RVEDV of greater than 150 mL/m2 with a sensitivity of 75% and specificity of 73% (area under the curve = 0.76; confidence interval, 0.56-0.96; P = .0063). Intraclass correlation analysis demonstrated minimal interobserver and intraobserver variability when measuring RVAT (0.99 and 0.92). CONCLUSION: An RVAT less than 20 degrees is associated with an RVEDV less than 150 mL/m2. RVAT is a useful echocardiographic technique for detecting increased RVEDV in patients with TOF and may help discern which patients should undergo RVEDV quantification by CMRI or CTA. PMID- 20951000 TI - Detection of coronary artery disease by combined assessment of wall motion, myocardial perfusion and coronary flow reserve: a multiparametric contrast stress echocardiography study. AB - BACKGROUND: Wall motion (WM), Doppler-derived measurement of the coronary flow reserve (CFR) in the left anterior descending coronary artery (LAD), and myocardial perfusion imaging (MPI) can be sequentially assessed during dipyridamole stress echocardiography. Data regarding the relative diagnostic value of each of these parameters when assessed during the same examination in patients with suspected coronary artery disease (CAD) are lacking. METHODS: Dipyridamole stress echocardiography was performed in 400 patients at two centers, before the performance of clinically indicated coronary angiography. The diagnostic accuracy of WM, CFR-LAD, combined WM and CFR-LAD, and MPI was measured in comparison with quantitative angiographic results. RESULTS: For CAD defined as >= 1 stenosis >50%, MPI had the highest sensitivity (96%), lowest specificity (66%), and highest accuracy (86%); WM and CFR-LAD had the highest specificities (85% and 80%), lowest sensitivities (63% and 66%), and lowest overall accuracies (70% and 71%). Combined WM and CFR-LAD obtained intermediate values for both sensitivity (84%) and specificity (71%) and the second best accuracy (80%). For CAD defined as >70% stenosis, MPI, combined WM and CFR-LAD, and WM obtained similar accuracies (P = NS), but WM showed the best balance of sensitivity (73%) and specificity (73%), with the highest Youden index. CONCLUSIONS: MPI had the highest sensitivity and accuracy for the detection of CAD > 50% during dipyridamole stress echocardiography, despite showing the lowest specificity among tested parameters. Standalone WM and combined WM and CFR-LAD were not significantly inferior in terms of overall accuracy when CAD > 70% was the diagnostic end point. The addition of MPI or CFR-LAD to standard WM assessment allows the detection of milder CAD. PMID- 20951001 TI - Wegener's granuloma harbors B lymphocytes with specificities against a proinflammatory transmembrane protein and a tetraspanin. AB - Wegener's granulomatosis (WG) is a severe autoimmune disorder ranging from localized granulomatous disease to generalised anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. A previous analysis of immunoglobulin heavy chain genes derived from tissue, i.e. Wegener's granuloma indicated selection and affinity maturation towards local antigen(s). The current study focused on determining the specificity of immunoglobulins from distinct B lymphocytes out of Wegener's granuloma. Four pairs of variable region immunoglobulin light and heavy chain genes, isolated before, were recombinantly expressed using the baculovirus/insect cell system. These immunoglobulins were then analysed for their antigenic target employing a protein macroarray based upon a human fetal brain tissue cDNA expression library. The lysosomal transmembrane protein 9B, a key regulator for TNFalpha activation, was identified as the putative antigenic target of two immunoglobulins and a tetraspanin, which might play a role in leukocyte activation and motility, was identified as the putative antigenic target of another one. Recombinant monoclonal antibodies out of Wegener's granuloma represent a new tool aiding in elucidation of its and WG immunopathogenesis. PMID- 20951002 TI - Validation of reaction time as a measure of cognitive function and quality of life in healthy subjects and patients. AB - OBJECTIVE: Malnutrition is a common problem in hospitalized patients and is related to decreased cognitive function and impaired quality of life (QoL). We investigated the validity of reaction time as a simple bedside tool for measuring cognitive function in healthy subjects and patients, and additionally the relationships with QoL and malnutrition in patients. METHODS: Healthy subjects (N = 130) were assessed for simple and complex reaction time and cognitive function (Addenbrooke cognitive examination, ACE). Patients (N = 70) were assessed for simple and complex reaction time, cognitive function (ACE), and QoL (short-form health survey) (N = 40). RESULTS: Reaction time was related to cognitive function in both healthy subjects and patients. Reaction time was inversely related to the physical component summary of QoL in patients (r = -0.42, P < 0.001). Five of eight QoL scales and the mental component summary of QoL were significantly lower in malnourished patients. Reaction time and ACE were impaired in patients compared to healthy subjects, but not further impaired in malnourished patients. CONCLUSION: Simple reaction time test is related to cognitive function in healthy subjects and patients and to QoL in patients. Complex reaction time test is related to more components of cognitive function. Thus, simple and complex reaction time tests could serve as bedside measurements reflecting, respectively, QoL or cognitive function. PMID- 20951003 TI - Ingestion of a high-molecular-weight hydrothermally modified waxy maize starch alters metabolic responses to prolonged exercise in trained cyclists. AB - OBJECTIVE: We examined whether the ingestion of a hydrothermally modified starch (HMS) would alter metabolic and hormonal responses to prolonged cycling compared with maltodextrin (MAL). METHODS: Nine male cyclists (30 +/- 2 y, 79.2 +/- 2.1 kg, 4.7 +/- 0.1 L of O(2)/min, 7.5 +/- 1.3 y training) fasted 10 h before cycling for 150 min at 70% peak oxygen consumption and completing a cycling-to-exhaustion trial at 100% peak oxygen consumption. Participants ingested 1g/kg of HMS or MAL 30 min before and within 10 min of completing the bout. Blood samples were provided every 15 min before, during, and 90 min after exercise. Expired gases were collected every 30 min during exercise. In a crossover, randomized, and double-blind fashion, identical testing was completed 1 wk later. RESULTS: Primary findings from this study were that 1) increases in serum glucose were greater during MAL (peak 9.5 mM) versus HMS (peak 7.4 mM, P <= 0.01), 2) insulin levels were significantly lower during HMS (peak 2.5 MUIU/mL) versus MAL (peak 20.3 MUIU/mL, P < 0.001), and 3) HMS was associated with greater fat breakdown as indicated by the increased serum non-esterified fatty acids (P < 0.01) and glycerol levels (P < 0.05). CONCLUSION: Ingestion of a low-glycemic HMS before prolonged cycling exercise blunted the initial spike in serum glucose and insulin and increased the breakdown in fat compared with MAL. PMID- 20951004 TI - Comparative anticonvulsant efficacy in the corneal kindled mouse model of partial epilepsy: Correlation with other seizure and epilepsy models. AB - Chronic electrical stimulation via corneal electrodes can rapidly yield large numbers of kindled mice with a seizure phenotype reflective of secondarily generalized partial seizures. The corneal kindled mouse model has been found to be a highly sensitive and efficient screening model for antiepileptic drug (AED) discovery. The present study further evaluates the utility of the corneal kindled mouse model as a tool for rapid screening of investigational AEDs. Results obtained with nine AEDs (valproic acid, lamotrigine, phenytoin, carbamazepine, levetiracetam, vigabatrin, topiramate, tiagabine, and ezogabine) with varying mechanisms of action and clinical spectrums, as well as six investigational compounds were evaluated in the corneal kindled mouse. ED(50) values are compared to those obtained in the hippocampal kindled rat, the mouse maximal electroshock (MES) model, the 6Hz partial psychomotor seizure model, and the subcutaneous pentylenetetrazol (scPTZ) test. The results obtained in the corneal kindled mouse demonstrate a positive correlation with those attained employing established preclinical models: MES (r2 = 0.9511), scPTZ (r2 = 0.9697), 6Hz (r2 = 0.9519), and hippocampal kindling (r2 = 0.9037). The demonstrated predictive ability of the corneal kindled mouse model supports its use in the early evaluation of investigational AEDs. PMID- 20951005 TI - Poly(D,L-lactide-co-glycolide)/hydroxyapatite core-shell nanospheres. Part 1: A multifunctional system for controlled drug delivery. AB - Biodegradable poly(d,l-lactide-co-glycolide) (PLGA) and bioactive hydroxyapatite (HAp) are selected for the formation of a multifunctional system with the specific core-shell structure to be applied as a carrier of a drug. As a result, both components of PLGA/HAp core-shells are able to capture one part of the drug. Polymeric shells consisting of small nanospheres up to 20nm in size act as a matrix in which one part of the drug is dispersed. In the same time, ceramic cores are formed of rod-like hydroxyapatite particles at the surface of which another part of the drug is adsorbed onto the interface between the polymer and the ceramics. The content of the loaded drug, as well as the selected solvent/non solvent system, have a crucial influence on the resulting PLGA/HAp morphology and, finally, unimodal distribution of core-shells is obtained. The redistribution of the drug between the organic and inorganic parts of the material is expected to provide an interesting contribution to the kinetics of the drug release resulting in non-typical two-step drug release. PMID- 20951006 TI - Poly(D,L-lactide-co-glycolide)/hydroxyapatite core-shell nanosphere. Part 2: Simultaneous release of a drug and a prodrug (clindamycin and clindamycin phosphate). AB - The novel concept of a simultaneous, controlled release of a drug and a prodrug with different physico-chemical properties was applied in order to prolong the release period of antibiotics and estimate their high local concentrations, which are the necessary preconditions for the treatment of some chronic infection diseases. For this purpose poly(D,L-lactide-co-glycolide)/hydroxyapatite (PLGA/HAp) core-shell nanostructures were used as the carrier of clindamycin base, as a drug, and clindamycin-2-phosphate, as a prodrug model. As a result, a two-step release was observed: the controlled release of the more soluble phosphate form and the sustained release of the less-soluble base form of clindamycin, resulting in a high overall concentration of the released drug during the period of 30 days in vitro. The HAp phase within the PLGA core-shells, applied as a drug carrier, delayed the process of the degradation of the polymer; however, the presence of the drug affected the process of degradation and this influence was the dominant factor in the control over the degradation of the polymer phase of PLGA/HAp and the consequent kinetics of the drug release. PMID- 20951007 TI - A novel water-in-ionic liquid microemulsion and its interfacial effect on the activity of laccase. AB - It is of great significance to develop an appropriate water-in-ionic liquid (W/IL) microemulsion suitable for the expression of the catalytic activity of a given enzyme. In this paper, the phase diagram of a new AOT/Triton X 100/H(2)O/[Bmim][PF(6)] pseudo ternary system is presented. With the aid of nonionic surfactant Triton X-100, AOT could be dissolved in hydrophobic ionic liquid [Bmim][PF(6)], forming a large single phase microemulsion region. The water-in-[Bmim][PF(6)] (W/IL) microemulsion domain was identified electrochemically by using K(3)Fe(CN)(6) as a probe. The existence of W/IL microemulsions was demonstrated spectrophotometrically by using CoCl(2) as a probe. New evidences from the FTIR spectroscopic study, which was first introduced to the W/IL microemulsion by substituting D(2)O for H(2)O to eliminate the spectral interference, demonstrated that there existed bulk water at larger omega(0) values (omega(0) was defined as the molar ratio of water to the total surfactant) in the W/IL microemulsion, which had remained unclear before. In addition to the inorganic salts, biomacromolecule laccase could be solubilized in the W/IL microemulsion. The laccase hosted in the microemulsion exhibited a catalytic activity and the activity could be regulated by the composition of the interfacial membrane. PMID- 20951008 TI - Single, binary and multi-component adsorption of some anions and heavy metals on environmentally friendly Carpobrotus edulis plant. AB - A low-cost adsorbent and environmentally friendly adsorbent from Carpobrotus edulis plant was used for the removal of NO(3)(-), H(2)PO(4)(-), Pb(2+) and Cd(2+) ions from single, binary and multi-component systems. The efficiency of the adsorbent was studied using batch adsorption technique under different experimental conditions by varying parameters such as pH, initial concentration and contact time. In single component systems, the dried C. edulis has the highest affinity for Pb(2+), followed by NO(3)(-), Cd(2+) and H(2)PO(4)(-), with adsorption capacities of 175mg/g, 125mg/g, 28mg/g and 26mg/g, respectively. These results showed that the adsorption of NO(3)(-) and H(2)PO(4)(-) ions from single and binary component systems can be successfully described by Langmuir and Freundlich isotherms. Freundlich adsorption model, showed the best fit to the single and binary experimental adsorption data. These results also indicated that the adsorption yield of Pb(2+) ion was reduced by the presence of Cd(2+) ion in binary metal mixture. The competitive adsorption of NO(3)(-), H(2)PO(4)(-), Pb(2+) and Cd(2+) ions on dried C. edulis plant shows that NO(3)(-) and H(2)PO(4)(-) anions are able to adsorb on different free binding sites and Pb(2+) and Cd(2+) cations are able to adsorb on the same active sites of C. edulis particles. The dried C. edulis was found to be efficient in removing nitrate, phosphate, cadmium and lead from aqueous solution as compared to other adsorbents already used for the removal of these ions. PMID- 20951009 TI - Enhancing percutaneous delivery of methotrexate using different types of surfactants. AB - Regarding the potential severe toxicity associated with systemic administration of methotrexate (MTX), a topical formulation might be of greater utility for the treatment of psoriasis and other hyperproliferative skin disorders. One of the presumed reasons for the lack of clinical activity of topical methotrexate in psoriasis is insufficient percutaneous penetration necessary to inhibit epidermal DNA synthesis. The present study was undertaken to prepare a formulation to enhance skin penetration of MTX. For this mean, topical gel formulations were prepared and evaluated for MTX percutaneous absorption using rat skin and standard Franz diffusion cells. For enhancing percutaneous absorption, three surfactants (anionic, cationic and nonionic) were incorporated into formulations with different concentrations. Finally salicylic acid as a keratolytic material was added for more enhancement effect. The results showed that SLS (sodium lauryl sulphate) and alkyl benzyl dimethyl chloride did not show significant enhancement effect on the penetration of MTX. Transcutol was able to enhance transdermal absorption of MTX and the higher enhancement ratio was obtained with 2% (w/w) concentration of transcutol. Addition of salicylic acid increased this ratio. Prepared formulation containing transcutol 2% (w/w) and salicylic acid 6% (w/w) showed higher enhancement property and could be used clinically for local treatment of psoriasis. PMID- 20951010 TI - [Multicenter validation of the clinical dehydration scale for children]. AB - INTRODUCTION: Dehydration is an important complication for sick children. The Clinical Dehydration Scale for children (CDS) measures dehydration based on 4 clinical signs: general appearance, eyes, saliva, and tears. OBJECTIVE: To validate the association between the CDS and markers of dehydration in children aged 1 month to 5 years visiting emergency departments (EDs) for vomiting and/or diarrhea. METHOD: An international prospective cohort study conducted in 3 university-affiliated EDs in 2009. Participants were a convenience sample of children aged 1-60 months presenting to the ED for acute vomiting and/or diarrhea. Following triage, a research nurse obtained informed consent and evaluated dehydration using the CDS. A few days after recovery, another research assistant weighed participants at home. The primary outcome was the percentage of dehydration calculated by the difference in weight at first evaluation and after recovery. Secondary outcomes included proportion of blood test measurements, intravenous use, hospitalization, and inter-rater agreement. RESULTS: During the study period, 264 children were recruited and data regarding weight and dehydration scores were complete for 219 (83%). According to the CDS, 88 had no dehydration, 159 some dehydration, and 15 moderate or severe dehydration. A Chi square test showed a statistical association between CDS and weight gain, the occurrence of blood tests, intravenous rehydration, hospitalization, and abnormal plasmatic bicarbonate. Good inter-rater correlation was found among participants (linear weighted Kappa score of 0.65; (95% CI, 0.43-0.87). CONCLUSION: CDS categories correlate with markers of dehydration for young children complaining of vomiting and/or diarrhea in the ED. PMID- 20951011 TI - [Vitamin D revisited: a cornerstone of health?]. AB - There is a recent renewed interest in vitamin D metabolism and pathophysiology, due to its recent description as a hormone with a positive impact on global health rather than a strictly bone hormone: vitamin D could be a protective factor against infection, autoimmunity, cardiovascular morbidity, and cancer. By contrast, vitamin D deficiency appears to be increasingly frequent worldwide. We propose a review of these new aspects of vitamin D metabolism, with a focus on vitamin D status in a local pediatric cohort. There is an urgent need for revisiting current guidelines on vitamin D supplementation and for closely monitoring serum vitamin D in children with chronic diseases, i.e., at greater risk of cardiovascular impairment, bone morbidity, infectious disease, and acute inflammation. PMID- 20951012 TI - Synchronous chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck using capecitabine: a single-centre, open-label, single-group phase II study. AB - AIM: To evaluate the efficacy of concurrent oral capecitabine with accelerated hypofractionated radical radiotherapy in locally advanced squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: Between 2001 and 2004, 50 patients with stage III/IV SCCHN (0 to 2 performance status) were enrolled into this study. The capecitabine dose was between 450 and 550 mg/m(2) twice daily, continuously for 28 days. The radiotherapy dose was 5500 cGy in 20 fractions over 4 weeks. No intensity-modulated radiation was used. We evaluated the complete response rate, toxicity, locoregional control, overall survival, disease-free survival and cancer-specific survival. RESULTS: The median age was 55 (range 38 76) years; 72% had stage IV disease. The median follow-up was 6 years on the 30 surviving patients. Eighty-two per cent of patients completed the course of capecitabine and 94% completed prescribed radiotherapy. There were no treatment related deaths, grade 3/4 haematological or renal toxicity. Five patients developed drug-related grade 3/4 acute toxicity (cardiac, skin, bowel); 47 developed grade 3/4 mucositis from chemoradiotherapy. Twenty-two (44%) patients required tube feeding and the tube dependency rate at 1 year was 6%. The complete response rate at 3 months was 90% (45/50 patients). Relapse occurred in 17/50 (34%) patients by 5 years. The locoregional control, overall survival, cancer specific survival and disease-free survival rates at 3 years were 78, 72, 82 and 62%, respectively, and at 5 years were 72, 64, 75 and 56%, respectively. CONCLUSION: This schedule of synchronous capecitabine for locally advanced SCCHN is well tolerated. The local control in this series compares favourably with other synchronous chemoradiotherapy reports. Chronic dysphagia and tube dependence is uncommon with this approach. Capecitabine as targeted therapy given with each fraction of radiotherapy and administered orally may have significant advantages over intravenous, 3 weekly cisplatin. PMID- 20951013 TI - NICE guidance, but who does the work? PMID- 20951014 TI - Association of circulating visfatin concentrations with insulin resistance and low-grade inflammation after dietary energy restriction in Spanish obese non diabetic women: role of body composition changes. AB - BACKGROUND AND AIMS: To assess the influence of body composition changes on circulating serum visfatin after following 12 weeks of energy restricted diet intervention. We also examined the possible role of visfatin in glucose metabolism and in obesity-associated low-grade inflammation. METHODS AND RESULTS: A total of 78 obese (BMI 34.0 +/- 2.8 kg/m2) women aged 36.7+/-7 y volunteered to participate in the study. We measured by DXA body fat mass (FM) and lean mass (LM). Fasting serum visfatin, glucose, insulin, adiponectin, leptin, IL-1beta, IL 6, IL-8, TNF-alpha and CRP concentrations were analyzed before and after the intervention and HOMA and QUIKI indexes were calculated. Mean weight loss 7.7 +/- 3.0 kg and HOMA decreased in 24 +/- 35%. Serum visfatin concentration change was negatively associated with LM difference (P < 0.05), whereas no significant relationship was observed with FM changes after energy restricted diet intervention. Changes in circulating serum visfatin levels were significantly and inversely associated with HOMA-IR (P < 0.01) and positively with QUICKI index (P < 0.02) after energy restricted diet intervention, regardless of achieved body weight loss. We did not find any significant association between changes in visfatin levels and IL-1beta, IL-6, IL-8, TNF-alpha and CRP levels after dietary intervention (all P > 0.2). CONCLUSION: Circulating visfatin concentration is associated with sensitivity improvement achieved after energy restricted diet intervention induced weight loss. Furthermore, LM changes could be an influencing factor on visfatin concentrations and consequently, on the improvement of insulin sensitivity after weight loss in obese non-diabetic women. Our findings did not provide any evidence for a role of visfatin increase on low-grade inflammation after weight loss. PMID- 20951015 TI - Three-dimensional surface models of detailed lumbosacral structures reconstructed from the Visible Korean. AB - Unlike volume models, surface models representing hollow, three-dimensional images have a small file size; allowing them to be displayed, rotated, and modified in real time. Therefore, surface models of lumbosacral structures can be effectively used for interactive simulation of, e.g., virtual lumbar puncture, virtual surgery of herniated lumbar discs, and virtual epidural anesthesia. In this paper, we present surface models of extensive lumbosacral structures which can be used in medical simulation systems. One-hundred and thirty-eight chosen structures included the spinal cord, lumbar and sacral nerves, vertebrae, intervertebral discs, ligaments, muscles, arteries, and skin. The structures were outlined in the sectioned images from the Visible Korean. From these outlined images, serial outlines of each structure were stacked. Adopting commercial software (3D-DOCTOR, Maya), an advanced surface reconstruction technique was applied to create a surface model of the structure. In the surface models, we observed the anatomical relationships of the lumbosacral structures (e.g., cauda equina and ligaments) in detail. Additionally, the portions of some spinal nerves that could not be outlined were drawn and added to the surface models. These constructed models will hopefully facilitate development of high quality medical simulation of the lumbosacral region. PMID- 20951016 TI - Antigen presentation in immunity to murine malaria. AB - Understanding the initiation of cellular immune responses during blood-stage malaria infection is essential for the development of an effective vaccine that improves upon the naturally acquired immune response and induces rapid and long lasting protection against disease. Recent studies have identified the dendritic cell (DC) subtypes responsible for priming Plasmodium-specific T cells that mediate protection and/or pathology during blood-stage infection. Significant progress has also been made towards understanding DC recognition of Plasmodium parasites through engagement of TLR signalling pathways, as well as the potential for non-TLR ligands to mediate Plasmodium-induced suppression of DC antigen presentation. PMID- 20951017 TI - The prevalence of asthma and COPD in Italy: a practice-based study. AB - We conducted a population-based cross-sectional epidemiologic survey of asthma and COPD in an adult representative national sample using information obtained from the Health Search Database owned by the Italian College of General Practitioners. General Practitioners who had a list of patient population of 909,638 individuals (429,962 men and 479,676 women; man/woman ratio [M/WR]: 0.89) >= 14 years old at the end of December 2009 were selected to be representatives of the whole Italian population. Cases of asthma and COPD were identified on the basis of the ICD-9 codes. The total sample included 55,500 (6.10% of the entire population; 5.49% of men and 6.64% of women; M/WR: 0.74) subjects suffering from asthma and 25,762 (2.83% of the entire population; 3.51% of men and 2.23% of women; M/WR: 1.41) subjects suffering from COPD. The asthma/COPD ratio in general population was 2.16. The odds ratio (OR) was chosen because asthma and COPD had a prevalence less than 10%. The OR of developing asthma decreased with age both in men and women, but in the first group of age (15-34 years) it was higher in men vs. women (1.69 vs. 1.00) although it became lower than 1 from 35 years old and up in men and from 75 years old and up in women. On the contrary, the OR of developing COPD became higher than 1 from 55 years old and up both in men and in women and progressively increased with age (in the group 75-84 years, it was 6.16 in men and 4.07 in women, respectively). PMID- 20951018 TI - Community based physiotherapeutic exercise in COPD self-management: a randomised controlled trial. AB - Little is known about effects of community-based physiotherapeutic exercise programmes incorporated in COPD self-management programmes. In a randomised trial, the effect of such a programme (COPE-active) on exercise capacity and various secondary outcomes including daily activity as a marker of behaviour change was evaluated. All patients attended four 2-h self-management sessions. In addition the intervention group participated in the COPE-active programme offered by physiotherapists of private practices, consisting of a 6-month "compulsory" period (3 sessions/week) and subsequently a 5-month "optional" period (2 sessions/week). Because COPE-active was intended to change behaviour with regard to exercise, one session/week in both periods consisted of unsupervised home based exercise training. Of 153 patients, 74 intervention and 68 control patients completed the one-year follow-up. Statistically significant between-group differences in incremental shuttle walk test-distance (35.1 m; 95% CI (8.4; 61.8)) and daily activity (1190 steps/day; 95% CI (256; 2125)) were found in favour of the intervention group. Over the 12-month period a significant difference of the chronic respiratory questionnaire (CRQ) dyspnoea-score (0.33 points; 95% CI (0.01; 0.64)) and a non-significant difference of the endurance shuttle walk test (135 m (95% CI (-29; 298)) was found. No differences were found in the other CRQ-components, anxiety and depression scores and percentage of fat free mass. This study demonstrates that a community-based reactivation programme improves exercise capacity in patients with moderately to severe COPD. Even more important, the programme improves actual daily activity after one-year which indicates behaviour change with regard to daily exercise. Registered trail number: ISRCTN81447311. PMID- 20951019 TI - Epigenetic regulation of germ cell differentiation. AB - Germ cells and somatic cells have the identical genome. However, unlike the mortal fate of somatic cells, germ cells have the unique ability to differentiate into gametes that retain totipotency and produce an entire organism upon fertilization. The processes by which germ cells differentiate into gametes, and those by which gametes become embryos, involve dramatic cellular differentiation accompanied by drastic changes in gene expression, which are tightly regulated by genetic circuitries as well as epigenetic mechanisms. Epigenetic regulation refers to heritable changes in gene expression that are not due to changes in primary DNA sequence. The past decade has witnessed an ever-increasing understanding of epigenetic regulation in many different cell types/tissues during embryonic development and adult homeostasis. In this review, we focus on recent discoveries of epigenetic regulation of germ cell differentiation in various metazoan model organisms, including worms, flies, and mammals. PMID- 20951020 TI - Caloric restriction reduces IgA levels and modifies cytokine mRNA expression in mouse small intestine. AB - The aim of this study was to determine the effect of caloric restriction (CR) in mouse small intestine on the production and secretion of immunoglobulin (Ig) A, the population of lymphocytes in the lamina propria, and the expression of cytokines that mediate and regulate innate and adaptive immunity. One group of young Balb/c mice was fed ad libitum, while the CR group was fed ad libitum and fasted on alternate days. When mice were six months old, IgA levels in the proximal small intestine were quantified by enzyme-linked immunosorbent assay, while the number of IgA containing cells, CD4(+) T cells and CD8(+) T cells in the duodenal mucosa was determined by immunohistochemistry. Furthermore, the expression of several intestinal cytokines, the genes for alpha-chain IgA, and the polymeric Ig receptor (pIgR) were analyzed by real-time polymerase chain reaction. CR decreased the levels of IgA in the intestine, apparently a consequence of a reduced number of IgA(+) cells in the lamina propria that decrease the production and secretion of this Ig, and a reduced secretion of S IgA into the bile, which in turn discharges into the proximal intestine. Contrarily, CR increased the expression of genes for alpha-chain IgA, and the pIgR, indicating that transport of IgA was not a key factor in the decrease of this Ig. Additionally, CR modified the expression of genes for tumor necrosis factor-alpha, interferon-gamma, tumor growth factor-beta, interleukin (IL)-2 and IL-10, all of which regulate the synthesis of IgA and pIgR, the inflammatory response, and the immune response in the intestine. PMID- 20951021 TI - The inhibition of angiogenesis and tumor growth by denbinobin is associated with the blocking of insulin-like growth factor-1 receptor signaling. AB - Denbinobin, which is a phenanthraquinone derivative present in the stems of Ephemerantha lonchophylla, has been demonstrated to display antitumor activity. Recent reports suggest that the enhanced activity of insulin-like growth factor-1 receptor (IGF-1R) is closely associated with tumor angiogenesis and growth. This study aims at investigating the roles of denbinobin in suppressing these effects and at further elucidating the underlying molecular mechanisms. In the present study, we used an in vivo xenograft model antitumor and the Matrigel implant assays to show that denbinobin suppresses lung adenocarcinoma A549 growth and microvessel formation. Additionally, crystal violet and capillary-like tube formation assays indicated that denbinobin selectively inhibits insulin-like growth factor-1 (IGF-1)-induced proliferation (GI50=1.3*10-8 M) and tube formation of human umbilical vascular endothelial cells (HUVECs) without influencing the effect of epidermal growth factor; vascular endothelial growth factor and basic fibroblast growth factor. Furthermore, denbinobin inhibited the IGF-1-induced migration of HUVECs in a concentration-dependent fashion. Western blotting and immunoprecipitation demonstrated that denbinobin causes more efficient inhibition of IGF-1-induced activation of IGF-1R and its downstream signaling targets, including , extracellular signal-regulated kinase, Akt, mTOR, p70S6K, 4EBP and cyclin D1. All of our results provide evidences that denbinobin suppresses the activation of IGF-1R and its downstream signaling pathway, which leads to the inhibition of angiogenesis. Our findings suggest that denbinobin may be a novel IGF-1R kinase inhibitor and has potential therapeutic abilities for angiogenesis-related diseases such as cancer. PMID- 20951022 TI - Stress-strain response of plastic waste mixed soil. AB - Recycling plastic waste from water bottles has become one of the major challenges worldwide. The present study provides an approach for the use plastic waste as reinforcement material in soil. The experimental results in the form of stress strain-pore water pressure response are presented. Based on experimental test results, it is observed that the strength of soil is improved and compressibility reduced significantly with addition of a small percentage of plastic waste to the soil. The use of the improvement in strength and compressibility response due to inclusion of plastic waste can be advantageously used in bearing capacity improvement and settlement reduction in the design of shallow foundations. PMID- 20951023 TI - Microbial biosensors: a review. AB - A microbial biosensor is an analytical device which integrates microorganism(s) with a physical transducer to generate a measurable signal proportional to the concentration of analytes. In recent years, a large number of microbial biosensors have been developed for environmental, food, and biomedical applications. Starting with the discussion of various sensing techniques commonly used in microbial biosensing, this review article concentrates on the summarization of the recent progress in the fabrication and application of microbial biosensors based on amperometry, potentiometry, conductometry, voltammetry, microbial fuel cell, fluorescence, bioluminescence, and colorimetry, respectively. Prospective strategies for the design of future microbial biosensors will also be discussed. PMID- 20951024 TI - Hybrid isoprenoid secondary metabolite production in terrestrial and marine actinomycetes. AB - Terpenoids are among the most ubiquitous and diverse secondary metabolites observed in nature. Although actinomycete bacteria are one of the primary sources of microbially derived secondary metabolites, they rarely produce compounds in this biosynthetic class. The terpenoid secondary metabolites that have been discovered from actinomycetes are often in the form of biosynthetic hybrids called hybrid isoprenoids (HIs). HIs include significant structural diversity and biological activity and thus are important targets for natural product discovery. Recent screening of marine actinomycetes has led to the discovery of a new lineage that is enriched in the production of biologically active HI secondary metabolites. These strains represent a promising resource for natural product discovery and provide unique opportunities to study the evolutionary history and ecological functions of an unusual group of secondary metabolites. PMID- 20951025 TI - Reliability of the intelligent stretching device for ankle stiffness measurements in healthy individuals. AB - BACKGROUND: A number of devices have been developed to measure joint stiffness. This study investigated the reliability of the Intelligent (Intel) stretch device to measure bilateral ankle joint stiffness during passive range of motion (ROM). METHODS: The reliability of the device was investigated based on torque and angle by establishing the consistency of measurements between examiners on different testing days. In addition, demographic variables were analyzed to investigate the degree of stiffness. Forty-six gender-matched subjects completed the test. RESULTS: The reliability ICC2(,)1 coefficient of ankle stiffness between-day for both examiners was 0.77 for the right ankle and 0.76 for the left ankle with a 0.05 standard error of measurement (SEM) for ankle stiffness for the right side and 0.04 for the left side. The ICC values of the two examiners were also high based on Chronbach's alpha (0.87 and 0.86). Among the demographic variables, gender (F=35.25, p=0.001) and body weight (F=23.55, p=0.001) were the most important factors in determining ankle joint stiffness. DISCUSSION: The results of this study indicated that dorsiflexion and plantarflexion measurements obtained by the Intel stretch device are reproducible and consistent. In addition, ankle stiffness was significantly different based on gender and body weight to develop and/or maintain ankle function. These results may help to identify ankle stiffness factors that will lead to more efficient rehabilitation programs and injury prevention strategies. PMID- 20951026 TI - Recognition of nuclear targeting signals by Karyopherin-beta proteins. AB - The Karyopherin-beta family of nuclear transport factors mediates the majority of nucleocytoplasmic transport. Although each of the 19 Karyopherin-betas transports unique sets of cargos, only three classes of nuclear localization and export signals, or NLSs and NESs, have been characterized. The short basic classical-NLS was first discovered in the 1980s and their karyopherin-bound structures were first reported more than 10 years ago. More recently, structural and biophysical studies of Karyopherin-beta2-cargo complexes led to definition of the complex and diverse PY-NLS. Structural knowledge of the leucine-rich NES is finally available more than 10 years after the discovery of its recognition by the exportin CRM1. We review recent findings relating to how these three classes of nuclear targeting signals are recognized by their Karyopherin-beta nuclear transport factors. PMID- 20951027 TI - The mechanism of signal transduction by two-component systems. AB - Two-component systems, composed of a homodimeric histidine kinase (HK) and a response regulator (RR), are major signal transduction devices in bacteria. Typically the signal triggers HK autophosphorylation at one His residue, followed by phosphoryl transfer from the phospho-His to an Asp residue in the RR. Signal extinction frequently involves phospho-RR dephosphorylation by a phosphatase activity of the HK. Our understanding of these reactions and of the determinants of partner specificity among HK-RR couples has been greatly increased by recent crystal structures and biochemical experiments on HK-RR complexes. Cis autophosphorylation (one subunit phosphorylates itself) occurs in some HKs while trans-autophosphorylation takes place in others. We review and integrate this new information, discuss the mechanism of the three reactions and propose a model for transmembrane signaling by these systems. PMID- 20951030 TI - Thermal degradation mechanisms of wood under inert and oxidative environments using DAEM methods. AB - The pyrolytic behavior of wood is investigated under inert and oxidative conditions. The TGA experiment is given a temperature variation from 323 to 1173 K by setting the heating rate between 5 and 40 K/min. The results of DTG curves show that the hemicellulose shoulder peak for birch is more visible under inert atmosphere due to the higher content of reactive xylan-based hemicellulose (mannan-based for pine). When oxygen presents, thermal reactivity of biomass (especially the cellulose) is greatly enhanced due to the acceleration of mass loss in the first stage, and complex reactions occur simultaneously in the second stage when char and lignin oxidize. A new kinetic model is employed for biomass pyrolysis, namely the distributed activation energy model (DAEM). Under inert atmosphere, the distributed activation energy for the two species is found to be increased from 180 to 220 kJ/mol at the solid conversion of 10-85% with the high correlation coefficient. Under oxidative atmosphere, the distributed activation energy is about 175-235 kJ/mol at the solid conversion of 10-65% and 300-770 kJ/mol at the solid conversion of 70-95% with the low correlation coefficient (below 0.90). Comparatively, the activation energy obtained from established global kinetic model is correspondingly lower than that from DAEM under both inert and oxidative environments, giving relatively higher correlation coefficient (more than 0.96). The results imply that the DAEM is not suitable for oxidative pyrolysis of biomass (especially for the second mass loss stage in air), but it could represent the intrinsic mechanism of thermal decomposition of wood under nitrogen better than global kinetic model when it is applicable. PMID- 20951029 TI - Production and selected fuel properties of biodiesel from promising non-edible oils: Euphorbia lathyris L., Sapium sebiferum L. and Jatropha curcas L. AB - A comparative study on the composition, biodiesel production and fuel properties of non-edible oils from Euphorbia lathyris L. (EL), Sapium sebiferum L. (SS), and Jatropha curcas L. (JC) was conducted. Under optimal conditions, the FAME content and yield of the three oils were greater than 97.5 wt.% and 84.0%, respectively. The best biodiesel was produced from EL due to its high monounsaturation (82.66 wt.%, Cn: 1), low polyunsaturation (6.49 wt.%, Cn: 2, 3) and appropriate proportion of saturated components (8.78 wt.%, Cn: 0). Namely, EL biodiesel possessed a cetane number of 59.6, an oxidation stability of 10.4 h and a cold filter plug point of -11 degrees C. However, the cetane number (40.2) and oxidative stability (0.8 h) of dewaxed SS kernel oil (DSSK) biodiesel were low due to the high polyunsaturation (72.79 wt.%). In general, the results suggest that E. lathyris L. is a promising species for biodiesel feedstock. PMID- 20951028 TI - A role for flexible loops in enzyme catalysis. AB - Triosephosphate isomerase (TIM), glycerol 3-phosphate dehydrogenase, and orotidine 5'-monophosphate decarboxylase each use the binding energy from the interaction of phosphite dianion with a flexible phosphate gripper loop to activate a second, phosphodianion-truncated, substrate towards enzyme-catalyzed proton transfer, hydride transfer, and decarboxylation, respectively. Studies on TIM suggest that the most important general effect of loop closure over the substrate phosphodianion, and the associated conformational changes, is to extrude water from the enzyme active site. This should cause a decrease in the effective active-site dielectric constant, and an increase in transition state stabilization from enhanced electrostatic interactions with polar amino acid side chains. The most important specific effect of these conformational changes is to increase the basicity of the carboxylate side chain of the active site glutamate base by its placement in a 'hydrophobic cage'. PMID- 20951031 TI - Rapid estimation of nutrients in chicken manure during plant-field composting using physicochemical properties. AB - Regression equations which relate livestock and poultry manure nutrient content to its several physicochemical properties have been reported by previous researchers. This study explores the feasibility and efficiency to determine the nutrients (TN; TP; TK; Cu and Zn) in chicken manure during composting using physicochemical properties (pH, EC and DM), and compares the performances of regression equations in this study with those in the literature. The results show that DM is the best predictor to construct the single linear regressions for all the nutrients (R2>=0.84, p<0.001). In addition, the multiple linear regression equations based on DM and pH are all notable. These findings show the potential of physicochemical models for TN, TP, TK, Cu and Zn with more convenience and rapidness, but further research is needed to develop better models with higher accuracy for the above and other more nutrients. PMID- 20951032 TI - Modelling N mineralization from bovine manure and sewage sludge composts. AB - Nitrogen mineralization kinetics were compared in three different soils (pH values: 5.2, 7.1 and 8.6) when treated with bovine manure (BM) and sewage sludge (SS) composts. The soil-compost mixtures were kept at a controlled moisture content of 60% of their water holding capacity (WHC) and were incubated in the dark at 25 degrees C for 2 years. Five mathematical models were compared (simple exponential, double exponential, special model, hyperbolic and parabolic), using as experimental data the mineralized N accumulated during 360 and 720 days of incubation. The results showed that the best fit for describing the mineralization of organic N from the compost after 1 year of experimentation was obtained with the simple exponential model. However, the special model showed the best fit for data from 2 years of incubation and thus better reflected organic N mineralization over a longer time-span. This suggested that the organic N in the two composts was made up of two organic pools of different degrees of stability. PMID- 20951033 TI - Design, synthesis and SAR of a novel series of benzimidazoles as potent NPY Y5 antagonists. AB - A novel class of benzimidazole NPY Y5 receptor antagonists was prepared exploiting a privileged spirocarbamate moiety. The structure-activity relationship of this series and efforts to achieve a profile suitable for further development and an appropriate pharmacokinetic profile in rat are described. Optimisation led to the identification of the brain penetrant, orally bioavailable Y5 antagonist 9b which significantly inhibited the food intake induced by a Y5 selective agonist with a minimal effective dose of 30mg/kg po. PMID- 20951034 TI - Synthesis of new 4-aminoquinolines and quinoline-acridine hybrids as antimalarial agents. AB - Despite emergence of resistance to CQ and other 4-aminoquinoline drugs in most of the endemic regions, research findings provide considerable support that there is still significant potential to discover new affordable, safe, and efficacious 4 aminoquinoline antimalarials. In present study, new side chain modified 4 aminoquinoline derivatives and quinoline-acridine hybrids were synthesized and evaluated in vitro against NF 54 strain of Plasmodium falciparum. Among the evaluated compounds, compound 17 (MIC=0.125 MUg/mL) was equipotent to standard drug CQ (MIC=0.125 MUg/mL) and compound 21 (MIC=0.031 MUg/mL) was four times more potent than CQ. Compound 17 showed the curative response to all the treated swiss mice infected with CQ-resistant N-67 strain of Plasmodium yoelii at the doses 50 mg/kg and 25 mg/kg for four days by intraperitoneal route and was found to be orally active at the dose of 100 mg/kg for four days. The promising antimalarial potency of compound 17 highlights the significance of exploring the privileged 4 aminoquinoline class for new antimalarials. PMID- 20951035 TI - Neo-tanshinlactone inspired synthesis, in vitro evaluation of novel substituted benzocoumarin derivatives as potent anti-breast cancer agents. AB - A small library of novel benzocoumarin derivatives based on naturally occurring neo-tanshinlactone scaffold was constructed and their antiproliferative activities against breast cancer cells MCF-7 and MDA-MB-231 were evaluated. A number of derivatives showed good anti-breast cancer activity, in some cases higher to that of the reference compound tamoxifen. In particular, benzocoumarins Bc-5, Bc-8 and Bc-9 strongly inhibited the proliferation of MCF-7 cancer cell line with the IC(50) values of 3.8, 7.9 and 6.5 MUM, respectively. The compounds were capable of inducing nuclear fragmentation, cell cycle arrest and caspase dependent apoptosis in MCF-7 cell lines. In addition, these derivatives were devoid of cytotoxic effect against normal osteoblast cells. These synthetic benzocoumarins hold promises for developing safer alternative to the existing anti-breast cancer agents. PMID- 20951036 TI - Synthesis and SAR of 4-aryl-1-(indazol-5-yl)pyridin-2(1H)ones as MCH-1 antagonists for the treatment of obesity. AB - A new series of 4-aryl-1-(indazol-5-yl)pyridin-2(1H)ones possessing MCH-1 receptor antagonism is presented. Suzuki coupling of boronic acids with key triflate 6 allowed rapid generation of a range of analogs. The SAR of the MCH-1 receptor was explored with a variety of aryl and heterocyclic moieties. Selected compounds were studied in a five-day diet induced obese mouse model to evaluate their potential use as weight loss agents. PMID- 20951037 TI - Substituted spiro [2.3'] oxindolespiro [3.2"]-5,6-dimethoxy-indane-1"-one pyrrolidine analogue as inhibitors of acetylcholinesterase. AB - Series of pyrolidine analogues were synthesized and examined as acetylcholinesterase (AChE) inhibitors. Among the compounds, compounds 4k and 6k were the most potent inhibitors of the series. Compound 4k, showed potent inhibitory activity against acetyl cholinesterase enzyme with IC(50) 0.10 MUmol/L. Pyrolidine analogues might be potential acetyl cholinesterase agents for AD. PMID- 20951038 TI - Small molecule inhibitors of hantavirus infection. AB - Hantaviruses use alpha(v)beta(3) integrins on the surface of human host cells as a gateway to invasion, hence compounds that target this receptor may be used as antiviral agents. To accomplish this aim, new peptidomimetic compounds were selected based on similarity to a cyclic peptide known to bind the alpha(v)beta(3) receptor. This first round of biological screening identified peptidomimetic molecules which were effective hantavirus inhibitors in the low micromolar range, two thousand times more potent than the original cyclic peptide. Pharmacophore models were built to broaden the structural diversity of the second set of compounds screened. Structure-activity relationships (SAR) were drawn from the entire dataset. Further characterization by dose-response studies revealed that three compounds had potency in the nanomolar range. Selectivity assays with a panel of hantaviruses supported the mechanism of inhibition by targeting the alpha(v)beta(3) receptor, through the beta(3) integrin. PMID- 20951039 TI - Synthesis and structure-activity relationships of tyrosine-based inhibitors of autotaxin (ATX). AB - Autotaxin (ATX) is a secreted soluble enzyme that generates lysophosphatidic acid (LPA) through its lysophospholipase D activity. Because of LPA's role in neoplastic diseases, ATX is an attractive therapeutic target due to its involvement in LPA biosynthesis. Here we describe the SAR of ATX inhibitor, VPC8a202, and apply this SAR knowledge towards developing a high potency inhibitor. We found that electron density in the pyridine region greatly influences activity of our inhibitors at ATX. PMID- 20951040 TI - Congenital fibre type disproportion associated with mutations in the tropomyosin 3 (TPM3) gene mimicking congenital myasthenia. AB - Congenital myopathy with fibre type disproportion (CFTD) has been associated with mutations in ACTA1, SEPN1, RYR1 and TPM3 genes. We report the clinico pathological and electrophysiological features of 2 unrelated cases with heterozygous TPM3 mutation. Case 1 is a 19-year-old lady who presented with motor delay in infancy, respiratory failure in early teens requiring non-invasive ventilation despite being ambulant, ptosis, axial more than proximal weakness and scoliosis. Case 2 is a 7-year-old boy with hypotonia, feeding difficulties, motor delay and scoliosis, also requiring non-invasive ventilation while ambulant. Muscle biopsies in both cases showed fibre type disproportion. Muscle MRI (Case 1) showed mild uniformly increased interstitial tissue in and around the muscles. Sequencing of TPM3 in case 1 revealed a previously described heterozygous c.503G > A(pArg168His) missense variant in exon 5 and a novel heterozygous missense mutation c.521A > C(pGlu174Ala), also in exon 5, in case 2. A mild abnormality in the single fibre EMG was documented on electrophysiology in both cases. These cases highlight the neuromuscular transmission defect in CFTD secondary to TPM3 mutations. PMID- 20951041 TI - Co-occurrence of amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease type 2A in a patient with a novel mutation in the mitofusin-2 gene. AB - Mitofusin-2 gene (MFN2) mutations cause Charcot-Marie-Tooth type 2A (CMT2A), sometimes complicated by additional features such as optic atrophy, hearing loss, upper motor neuron signs and cerebral white-matter abnormalities. Here we report, for the first time, the occurrence of motor neuron disease, consistent with amyotrophic lateral sclerosis (ALS), in a 62-year-old woman affected by early onset slowly progressive CMT2A, due to a novel MFN2 mutation. After age 60, rate of disease progression changed and she rapidly developed generalised muscle wasting, weakness, and fasciculations, together with dysarthria and dysphagia. Clinical features, EMG findings, and fast progression were consistent with ALS superimposed on CMT. PMID- 20951042 TI - Developmental defects and neuromuscular alterations due to mitofusin 2 gene (MFN2) silencing in zebrafish: a new model for Charcot-Marie-Tooth type 2A neuropathy. AB - The development of new animal models is a crucial step in determining the pathological mechanism underlying neurodegenerative diseases and is essential for the development of effective therapies. We have investigated the zebrafish (Danio rerio) as a new model to study CMT2A, a peripheral neuropathy characterized by the selective loss of motor neurons, caused by mutations of mitofusin 2 gene. Using a knock-down approach, we provide evidence that during embryonic development, mitofusin 2 loss of function is responsible of several morphological defects and motility impairment. Immunohistochemical investigations, revealing the presence of severe alterations in both motor neurons and muscles fibres, indicated the central role played by MFN2 in axonal and neuromuscular development. Finally, we demonstrated the ability of human MFN2 to balance the downregulation of endogenous mfn2 in zebrafish, further supporting the conserved function of the MFN2 gene. These results highlight the essential role of mitofusin 2 in the motor axon development and demonstrate the potential of zebrafish as a suitable and complementary platform for dissecting pathogenetic mechanisms of MFN2 mutations in vivo. PMID- 20951043 TI - Structural long-term changes at mushroom body input synapses. AB - How does the sensory environment shape circuit organization in higher brain centers? Here we have addressed the dependence on activity of a defined circuit within the mushroom body of adult Drosophila. This is a brain region receiving olfactory information and involved in long-term associative memory formation. The main mushroom body input region, named the calyx, undergoes volumetric changes correlated with alterations of experience. However, the underlying modifications at the cellular level remained unclear. Within the calyx, the clawed dendritic endings of mushroom body Kenyon cells form microglomeruli, distinct synaptic complexes with the presynaptic boutons of olfactory projection neurons. We developed tools for high-resolution imaging of pre- and postsynaptic compartments of defined calycal microglomeruli. Here we show that preventing firing of action potentials or synaptic transmission in a small, identified fraction of projection neurons causes alterations in the size, number, and active zone density of the microglomeruli formed by these neurons. These data provide clear evidence for activity-dependent organization of a circuit within the adult brain of the fly. PMID- 20951044 TI - Effectively reducing sensory eye dominance with a push-pull perceptual learning protocol. AB - Much knowledge of sensory cortical plasticity is gleaned from perceptual learning studies that improve visual performance [1-7]. Although the improvements are likely caused by modifications of excitatory and inhibitory neural networks, most studies were not primarily designed to differentiate their relative contributions. Here we designed a novel push-pull training protocol to reduce sensory eye dominance (SED), a condition that is mainly caused by unbalanced interocular inhibition [8-10]. During the training, an attention cue presented to the weak eye precedes the binocular competitive stimulation. The cue stimulates the weak eye (push) while causing interocular inhibition of the strong eye (pull). We found that this push-pull protocol reduces SED (shifts the balance toward the weak eye) and improves stereopsis more so than the push-only protocol, which solely stimulates the weak eye without inhibiting the strong eye. The stronger learning effect with the push-pull training than the push-only training underscores the crucial involvement of a putative inhibitory mechanism in sensory plasticity. The design principle of the push-pull protocol can potentially lend itself as an effective, noninvasive treatment of amblyopia. PMID- 20951045 TI - 14-3-3 coordinates microtubules, Rac, and myosin II to control cell mechanics and cytokinesis. AB - BACKGROUND: During cytokinesis, regulatory signals are presumed to emanate from the mitotic spindle. However, what these signals are and how they lead to the spatiotemporal changes in the cortex structure, mechanics, and regional contractility are not well understood in any system. RESULTS: To investigate pathways that link the microtubule network to the cortical changes that promote cytokinesis, we used chemical genetics in Dictyostelium to identify genetic suppressors of nocodazole, a microtubule depolymerizer. We identified 14-3-3 and found that it is enriched in the cortex, helps maintain steady-state microtubule length, contributes to normal cortical tension, modulates actin wave formation, and controls the symmetry and kinetics of cleavage furrow contractility during cytokinesis. Furthermore, 14-3-3 acts downstream of a Rac small GTPase (RacE), associates with myosin II heavy chain, and is needed to promote myosin II bipolar thick filament remodeling. CONCLUSIONS: 14-3-3 connects microtubules, Rac, and myosin II to control several aspects of cortical dynamics, mechanics, and cytokinesis cell shape change. Furthermore, 14-3-3 interacts directly with myosin II heavy chain to promote bipolar thick filament remodeling and distribution. Overall, 14-3-3 appears to integrate several critical cytoskeletal elements that drive two important processes-cytokinesis cell shape change and cell mechanics. PMID- 20951046 TI - LIN-14 inhibition of LIN-12 contributes to precision and timing of C. elegans vulval fate patterning. AB - Studies of C. elegans vulval development have illuminated mechanisms underlying cell fate specification and elucidated intercellular signaling pathways [1]. The vulval precursor cells (VPCs) are spatially patterned during the L3 stage by the EGFR-Ras-MAPK-mediated inductive signal and the LIN-12/Notch-mediated lateral signal. The pattern is both precise and robust [2] because of crosstalk between these pathways [3]. Signaling is also regulated temporally, because constitutive activation of the spatial patterning pathways does not alter the timing of VPC fate specification [4, 5]. The heterochronic genes, including the microRNA lin-4 and its target lin-14, constitute a temporal control mechanism used in different contexts [6-8]. We find that lin-4 specifically controls the activity of LIN 12/Notch through lin-14, but not other known targets, and that persistent lin-14 blocks LIN-12 activity without interfering with the key events of LIN-12/Notch signal transduction. In the L2 stage, there is sufficient lin-14 activity to inhibit constitutive lin-12. Our results suggest that lin-4 and lin-14 contribute to spatial patterning through temporal gating of LIN-12. We propose that in the L2 stage, lin-14 sets a high threshold for LIN-12 activation to help prevent premature activation of LIN-12 by ligands expressed in other cells in the vicinity, thereby contributing to the precision and robustness of VPC fate patterning. PMID- 20951047 TI - Encoding of motor skill in the corticomuscular system of musicians. AB - How motor skills are stored in the nervous system represents a fundamental question in neuroscience. Although musical motor skills are associated with a variety of adaptations [1-3], it remains unclear how these changes are linked to the known superior motor performance of expert musicians. Here we establish a direct and specific relationship between the functional organization of the corticomuscular system and skilled musical performance. Principal component analysis was used to identify joint correlation patterns in finger movements evoked by transcranial magnetic stimulation over the primary motor cortex while subjects were at rest. Linear combinations of a selected subset of these patterns were used to reconstruct active instrumental playing or grasping movements. Reconstruction quality of instrumental playing was superior in skilled musicians compared to musically untrained subjects, displayed taxonomic specificity for the trained movement repertoire, and correlated with the cumulated long-term training exposure, but not with the recent past training history. In violinists, the reconstruction quality of grasping movements correlated negatively with the long term training history of violin playing. Our results indicate that experience dependent motor skills are specifically encoded in the functional organization of the primary motor cortex and its efferent system and are consistent with a model of skill coding by a modular neuronal architecture [4]. PMID- 20951048 TI - Reproductive timing alters population connectivity in marine metapopulations. AB - Populations of most marine organisms are connected by the dispersal of larval stages, with profound implications for marine conservation. Because of the extreme effort needed to empirically measure larval exchange, multispecies conservation efforts must estimate connectivity by extrapolation using taxonomy, adult distribution, life history, behavior, or phenology. Using a 6-year record of connectivity realized through trace-elemental fingerprinting of larval shells, we document the seasonal and interannual variability of larval exchange for two congeneric mussel species with overlapping but distinct distribution, life history, and reproduction timing. We reveal consistent autumn poleward movement and spring equatorward movement for both species, coincident with near-shore surface currents. However, because the major reproductive seasons differ, the dominant source-sink dynamics of these two congeneric species are nearly opposite. Consideration of present and future reproductive timing as altered by climate change is crucial to marine connectivity and conservation, especially for the numerous coastal areas subject to seasonal current reversals. PMID- 20951049 TI - Physcomitrella patens auxin-resistant mutants affect conserved elements of an auxin-signaling pathway. AB - Auxin regulates most aspects of flowering-plant growth and development, including key developmental innovations that evolved within the vascular plant lineage after diverging from a bryophyte-like ancestor nearly 500 million years ago. Recent studies in Arabidopsis indicate that auxin acts by directly binding the TIR1 subunit of the SCF(TIR1) ubiquitin ligase; this binding results in degradation of the Aux/IAA transcriptional repressors and de-repression of auxin responsive genes. Little is known, however, about the mechanism of auxin action in other plants. To characterize auxin signaling in a nonflowering plant, we utilized the genetically tractable moss Physcomitrella patens. We used a candidate-gene approach to show that previously identified auxin-resistant mutants of P. patens harbor mutations in Aux/IAA genes. Furthermore, we show that the moss Aux/IAA proteins interact with Arabidopsis TIR1 moss homologs called PpAFB and that a reduction in PpAFB levels results in a phenotype similar to that of the auxin-resistant mutants. Our results indicate that the molecular mechanism of auxin perception is conserved in land plants despite vast differences in the role auxin plays in different plant lineages. PMID- 20951050 TI - Registered nurse and health care chaplains experiences of providing the family support person role during family witnessed resuscitation. AB - OBJECTIVE: To provide an in-depth exploration regarding the Registered Nurse (RN) and Healthcare Chaplains' (HCC) perspective of the role of the family support person (FSP) during family witnessed resuscitation (FWR). RESEARCH METHODOLOGY/DESIGN: A phenomenological approach utilising in-depth interviews were undertaken outside of the work setting. A purposive sample of 4 RN's and 3 HCC were recruited from four sites within the United Kingdom. All interviews were tape recorded, transcribed verbatim and analysed utilising Husserl's framework. FINDINGS: Seven key themes emerged which included assessment, managing choice, navigating the setting, on-going commentary, coming to terms with death, conflicts and support. CONCLUSIONS: This study has provided an insight regarding the intense clinical engagement associated with the role of the FSP and highlighted the importance of this role for family member's optimal care and support. It is vital that adequate professional development is instigated and that support mechanisms are in place for those health care professionals (HCP) undertaking this role in order to help family members through this difficult experience. PMID- 20951051 TI - Intra-operative navigation of knee kinematics and the influence of osteoarthritis. AB - Intra-operative assessment of knee kinematics should optimise implantation of total knee arthroplasties. The purpose of this work was to validate the data delivered by an adapted navigation system in 10 healthy cadaver knees and to investigate the kinematics of 10 osteoarthritic (OA) knees in patients undergoing total knee replacement. The system displayed the magnitude of axial rotation, the position of the instantaneous centre of axial rotation and the displacements of the condyles. Successive cycles from full extension to 140 degrees of flexion in the same knee produced a mean external rotation of 20 degrees +/- 10 degrees , which was correlated to knee flexion (r=0.6 +/- 0.2 in healthy knees, r=0.8 +/- 0.2 in OA knees). The centre of axial rotation migrated posteriorly an average of 8.2mm in both groups. The posterior displacements were 4 mm +/- 5 mm in healthy and 5 mm +/- 6 mm in OA knees for the medial condyle, and 21 mm +/- 9 mm in healthy and 21 mm +/- 10 mm in OA knees for the lateral condyle. The medial condyle lifted off beyond 110 degrees of flexion. Results in healthy knees were consistent with those reported in the current literature. The kinematics of healthy and of OA knees with an intact anterior cruciate ligament did not differ significantly. PMID- 20951052 TI - Study on boron-film thermal neutron converter prepared by pulsed laser deposition. AB - The boron film converter used in the position-sensitive thermal neutron detector is discussed and the method of preparing this converter layer via Pulsed Laser Deposition (PLD) is introduced. The morphology and the composition were studied by Scanning Electron Microscopy (SEM) and X-ray Photoelectron Spectroscopy (XPS). Both boron and boride existed on the layer surface. It was shown that the energy intensity of laser beam and the substrate temperature both had an important influence on the surface morphology of the film. PMID- 20951053 TI - Role of the Ca-pectates on the accumulation of heavy metals in the root apoplasm. AB - In order to better understand the processes that regulate the accumulation in the apoplasm of heavy metals and their mobilization by the plant metabolites it is essential to study the mechanisms that regulate the interactions between metal ions and pectins. In such a context, the sorption of Cd(II), Zn(II), Cu(II) and Pb(II) from single and multi-metal solutions, by a Ca-polygalacturonate gel with a degree of esterification of 18.0 (PGAM(1)) and 65.5% (PGAM(2)) was studied in the 3.0-6.0 pH range in the presence of CaCl(2) 2.5mM. The sorption of Cr(III) from single metal solution was also considered. The results show that the amount of each metal ion sorbed increases with increasing the initial metal ion concentration and pH. The data from the single metal solution tests show that at pH 6.0 the affinity of the metal ions towards the PGAM(1) matrix follows the order: Cr(III)>Cu(II)?Pb(II)?Zn(II)?Cd(II). The simultaneous sorption of the bivalent metal ions by the PGAM(1) gels indicates that Pb(II) is selectively sorbed. The FT-IR spectra show that the carboxylate groups are mainly responsible for the metal ion coordination. The ability of PGAM(2) to accumulate Cr(III), Cu(II), and Pb(II) was lower than that found in the PGAM(1) systems whereas the sorption of Zn(II) and Cd(II) was negligible. PMID- 20951054 TI - Selenium protects sorghum leaves from oxidative damage under high temperature stress by enhancing antioxidant defense system. AB - Oxidative stress is commonly induced when plants are grown under high temperature (HT) stress conditions. Selenium often acts as an antioxidant in plants; however, its role under HT-induced oxidative stress is not definite. We hypothesize that selenium application can partly alleviate HT-induced oxidative stress and negative impacts of HT on physiology, growth and yield of grain sorghum [Sorghum bicolor (L.) Moench]. Objectives of this study were to investigate the effects of selenium on (a) leaf photosynthesis, membrane stability and antioxidant enzymes activity and (b) grain yield and yield components of grain sorghum plants grown under HT stress in controlled environments. Plants were grown under optimal temperature (OT; 32/22 degrees C daytime maximum/nighttime minimum) from sowing to 63 days after sowing (DAS). All plants were foliar sprayed with sodium selenate (75mgL(-1)) at 63 DAS, and HT stress (40/30 degrees C) was imposed from 65 DAS through maturity. Data on physiological, biochemical and yield traits were measured. High temperature stress decreased chlorophyll content, chlorophyll a fluorescence, photosynthetic rate and antioxidant enzyme activities and increased oxidant production and membrane damage. Decreased antioxidant defense under HT stress resulted in lower grain yield compared with OT. Application of selenium decreased membrane damage by enhancing antioxidant defense resulting in higher grain yield. The increase in antioxidant enzyme activities and decrease in reactive oxygen species (ROS) content by selenium was greater in HT than in OT. The present study suggests that selenium can play a protective role during HT stress by enhancing the antioxidant defense system. PMID- 20951055 TI - Glycolytic enzymatic activities in developing seeds involved in the differences between standard and low oil content sunflowers (Helianthus annuus L.). AB - As opposed to other oilseeds, developing sunflower seeds do not accumulate starch initially. They rely on the sucrose that comes from the mother plant to synthesise lipid precursors. Glycolysis is the principal source of carbon skeletons and reducing power for lipid biosynthesis. In this work, glycolytic initial metabolites and enzyme activities from developing seed of two different sunflower lines, of high and low oil content, were compared during storage lipid synthesis. These two lines showed different kinetic lipid accumulation in the developing embryos. Fatty acids levels during the initial and final stage of lipid synthesis were higher in CAS-6 than in ZEN-8. The analysis of the photosynthate and sugars content suggests that, although the hexoses levels were quite similar in both lines, the amount of sucrose produced by the mother plant and available for lipid synthesis was higher in CAS-6. Although, a smaller amount of sucrose is available in the ZEN-8 line, its seeds maintain the levels of intermediate sugars in the initial steps of glycolysis due to an increase in the levels of the invertase, hexokinase and phosphoglucose isomerase activities in ZEN-8, with respect to CAS-6. Also, a readjustment in the final part of this metabolic route took place, with the activities of phosphoglycerate kinase and enolase in CAS-6 being higher, allowing increased synthesis of phosphoenolpiruvate, the intermediate carbon donor for fatty acid synthesis. In addition, recently, it has been shown that Arabidopsis mutants with a lower fat content in their seeds have a higher amount of sucrose. These data together point to these last two enzymatic activities, phosphoglycerate kinase and enolase, as being responsible for the lower fat content in the ZEN-8 line. PMID- 20951056 TI - Mapping of an anthocyanin-regulating MYB transcription factor and its expression in red and green pear, Pyrus communis. AB - 'Max Red Bartlett' is a red bud mutation of the yellow pear (Pyrus communis L.) cultivar 'Williams' (known as 'Bartlett' in North America). Anthocyanins are the most important pigments for red colour in fruits. Synthesis of anthocyanins is mediated by a number of well-characterized enzymes that include chalcone synthase (CHS), flavanone-3-hydroxylase (F3H), dihydroflavonol-4-reductase (DFR), anthocyanidin synthase (ANS), and UDP-glucose:flavonoid-3-O-glucosyltransferase (UFGT). Expression of the genes encoding these five enzymes was examined in pear fruit skin in order to elucidate the molecular mechanism for red coloration. In addition, the gene PcMYB10, encoding an R2R3 MYB transcription factor involved in anthocyanin biosynthetic pathway regulation, was isolated from both 'Williams' and 'Max Red Bartlett'. Analysis of the deduced amino acid sequence suggests that this gene is an ortholog of anthocyanin regulators known in other plant species. Its expression level was significantly higher in 'Max Red Bartlett' (red pear) compared with the original yellow variety 'Williams'. Although the map position of PcMYB10 corresponds to that of MdMYBa and MdMYB10, which control pigmentation of apple fruit skin, PcMYB10 is not directly responsible for red versus yellow colour in the two pear varieties, as the mutation underlying this difference maps to a different region of the pear genome. PMID- 20951057 TI - Australia's health care reform agenda: implications for the nurses' role in chronic heart failure management. AB - INTRODUCTION: The importance of the nursing role in chronic heart failure (CHF) management is increasingly recognised. With the recent release of the National Health and Hospitals Reform Commission (NHHRC) report in Australia, a review of nursing roles in CHF management is timely and appropriate. AIM: This paper aims to discuss the implications of the NHHRC report and nursing roles in the context of CHF management in Australia. METHOD: The electronic databases, Thomson Rheuters Web of Knowledge, Scopus and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), were searched using keywords including; "heart failure", "management", "Australia" and "nursing". In addition policy documents were reviewed including statements and reports from key professional organisations and Government Departments to identify issues impacting on nursing roles in CHF management. RESULTS: There is a growing need for the prevention and control of chronic conditions, such as CHF. This involves an increasing emphasis on specialist cardiovascular nurses in community based settings, both in outreach and inreach health service models. This review has highlighted the need to base nursing roles on evidence based principles and identify the importance of the nursing role in coordinating and managing CHF care in both independent and collaborative practice settings. CONCLUSION: The importance of the nursing role in early chronic disease symptom recognition and implementing strategies to prevent further deterioration of individuals is crucial to improving health outcomes. Consideration should be given to ensure that evidence based principles are adopted in models of nursing care. PMID- 20951058 TI - Clinical usefulness of a novel C1q assay to detect immunoglobulin G antibodies capable of fixing complement in sensitized pediatric heart transplant patients. AB - BACKGROUND: Donor-specific antibodies (DSA) against human leukocyte antigens complicate transplantation with the potential for acute antibody-mediated rejection (AMR). Complement-fixing antibodies are required to initiate the complement cascade. Not all DSAs, however, can fix complement. METHODS: A novel C1q assay was developed to detect the sub-set of immunoglobulin G (IgG) antibodies capable of fixing complement. Sera from 18 pediatric heart transplant patients were analyzed for DSAs using a Luminex platform (Luminex Inc, Austin, TX) and commercially available single-antigen bead assay kits. Biopsy specimens were assessed for AMR using histopathologic criteria and immunohistochemical staining. RESULTS: During the study period, 5 patients had AMR; of these, 2 were C1q virtual crossmatch positive (VXM+) and had persistent C1q DSAs after transplant, and 3 were C1q VXM- but antibody developed immediately after transplant. A positive C1q assay in the immediate post-transplant period had a positive predictive value (PPV) of 100% and a negative predictive value (NPV) of 100%, with 100% sensitivity and 100% specificity (Fisher exact p = 0.001). Of 11 patients who were IgG VXM+, 5 had AMR; the IgG VXM had a PPV of 45% and NPV of 100%, with 100% sensitivity and 54% specificity (Fisher exact p = 0.101). CONCLUSIONS: The C1q assay can detect a sub-set of antibodies capable of fixing complement and predicts AMR early after transplant. Avoiding only the donor antigens that would be recognized by the C1q assay may accelerate time to transplant by expansion of the donor pool and potentially allows transplantation of previously "incompatible" organs. PMID- 20951059 TI - Memory, autonoetic consciousness, and the self. AB - Memory is a general attribute of living species, whose diversification reflects both evolutionary and developmental processes. Episodic-autobiographical memory (EAM) is regarded as the highest human ontogenetic achievement and as probably being uniquely human. EAM, autonoetic consciousness and the self are intimately linked, grounding, supporting and enriching each other's development and cohesiveness. Their development is influenced by the socio-cultural-linguistic environment in which an individual grows up or lives. On the other hand, through language, textualization and social exchange, all three elements leak into the world and participate to the dynamic shaping and re-shaping of the cultural scaffolding of the self, mental time traveling and EAM formation. Deficits in self-related processing, autonetic consciousness, emotional processing and mental time traveling can all lead to or co-occur with EAM disturbances, as we illustrate by findings from EAM impairments associated with neurological or psychiatric disorders. PMID- 20951060 TI - Relationship between self-reported shoulder function/quality of life, body mass index, and other contributing factors in patients awaiting rotator cuff repair surgery. AB - HYPOTHESES: We hypothesized that body mass index (BMI) would be negatively associated with self-reported shoulder function/pain. A second objective was to investigate the significance of other potential contributing factors: age, sex, smoking status, tear size, and workers' compensation (WC) involvement. METHODS: In this retrospective cohort study, consecutive patients who underwent arthroscopic rotator cuff repair surgery between 2002 and 2007 were reviewed. Preoperative American Shoulder and Elbow Society (ASES) and Simple Shoulder Test (SST) scores were compared with regard to age, sex, height, weight, smoking status, WC status, and rotator cuff tear size. RESULTS: Fifty-four patients were enrolled in this study. At a level of significance of P < .05, BMI showed no correlation with preoperative SST or ASES scores. WC status was negatively correlated with ASES scores. Female sex, WC status, and smoking were each negatively correlated with SST scores. The regression model predictive of preoperative SST scores included sex, WC status, and smoking status. WC status was predictive of ASES scores. DISCUSSION: To our knowledge, this is the first study to examine BMI as a contributing factor in the magnitude of pain and level of function in patients with chronic rotator cuff tears. Our data suggest that there is no impact of BMI on function/pain. The inter-relationships between factors such as BMI, sex, age, and others are complex, and further study is needed to fully establish that there is no effect. CONCLUSION: Our hypothesis that BMI is negatively related to magnitude of pain/level of function was not supported. Factors found to be related were sex, WC involvement, and smoking. PMID- 20951061 TI - Does objective shoulder impairment explain patient-reported functional outcome? A study of proximal humerus fractures. AB - HYPOTHESIS: Following a healed proximal humerus fracture, patient-reported outcome is predicted by objective physical examination findings. Range of motion and strength thresholds can correctly identify subjects with normal functioning shoulders. METHODS: Subjects were age >=55 years with a healed proximal humerus fracture. Impairment was measured with a focused physical examination of the shoulder; patient-reported outcome was assessed using 4 outcome questionnaires. Linear regression was used to determine how well variations in shoulder impairment explain differences in patient-reported outcomes. ROC curves were constructed to determine the physical examination thresholds that would correctly identify normally functioning shoulders. RESULTS: Thirty-one subjects with a mean age of 70 +/- 8 years participated. The mean patient-reported outcome scores were: DASH 21 +/- 19, ASES 82 +/- 17, SST 8 +/- 3, and Oxford 20 +/- 8. The linear regression analysis suggests that shoulder impairment explains 38% of the Oxford, 50% of the DASH, 58% of the SST, and 70% of the ASES variance. Abduction strength was a significant predictor for all functional outcomes. Based on ROC analysis, forward flexion had the best discriminatory ability for identifying normally functioning shoulders (area under curve, 0.93). A threshold of 120 degrees forward flexion correctly classified 90% of the shoulders. CONCLUSION: Range of motion and strength thresholds can identify subjects with normal shoulder function. A discordance between shoulder impairment and patient-reported outcome has been demonstrated and further work to identify patient, injury, or treatment factors to minimize this discrepancy is still needed. PMID- 20951062 TI - Treatment of supra- and intra-articular fractures of the distal humerus with the LCP Distal Humerus Plate: a 2-year follow-up. AB - BACKGROUND: The LCP Distal Humerus Plate (DHP) system represents an angular stable fixation system consisting of 2 anatomically pre-shaped orthogonal plates intended for the treatment of fractures of the distal humerus. The purpose of this retrospective study was to evaluate the clinical and radiologic outcome after a minimum follow-up of 2 years after open reduction and fixation of distal humeral fractures with this device. METHODS: Twenty-two consecutive patients with distal humeral fractures were treated with the DHP system between January 2004 and June 2006. Of these, 16 could be clinically and radiologically evaluated after a mean follow-up of 30.5 months. Follow-up included anteroposterior and lateral radiographs; assessment of range of motion; pain according to a VAS; Disabilities of the Arm, Shoulder and Hand score; and Mayo Elbow Performance Score. RESULTS: All fractures showed satisfactory articular reduction. One patient showed preoperative sensory ulnar neuropathy, which recovered incompletely, and two patients showed sensory ulnar neuropathy postoperatively, requiring revision surgery in one patient. Mean range of motion was as follows: flexion, 129 degrees ; extension, -16 degrees ; pronation, 82 degrees ; and supination, 71 degrees . The mean visual analog scale score was 1 point; the mean Disabilities of the Arm, Shoulder and Hand score, 23.3 points; and the mean Mayo Elbow Performance Score, 84.7 points. CONCLUSION: The DHP system represents a valuable tool to perform internal fixation of complex fractures of the distal humerus. In contrast to conventional plating, we did not observe any case of secondary fracture displacement, even in elderly patients with potentially reduced bone mass. The multiple angular stable point fixation also of small distal fragments seems to be effective in the application of this system. PMID- 20951063 TI - Patient reported activities after shoulder replacement: total and hemiarthroplasty. AB - HYPOTHESIS/BACKGROUND: The indication to perform a shoulder arthroplasty is guided in part by a patient's intended level of activity after surgery. What level of activity should be safely recommended, and, presently, patient reported activity level is unknown. The purpose of this study was to define and compare the self-reported activities of patients following shoulder arthroplasty either total (TSA) or hemiarthroplasty (HA). METHODS: Two groups of 75 patients each following TSA or HA were matched by age, sex, operative side, timing from surgery, and state of residence. A mailed questionnaire asked patients to report on their level of pain, motion, strength, and choice of 72 different activities. Reported activities were classified as low demand, intermediate demand, or high demand. RESULTS: Ninety-nine patients completed the survey, 52 in the TSA group (average age 62 years; 30F:22M), and 47 in the HA group (average age 62 years; 27F:20M). No difference on a pain scale was reported between groups. Better results were reported in the TSA group in forward flexion (P = .006), internal rotation (P = .04), and strength (P = .04). The most commonly reported activities in each category were: low demand (eg, cooking), medium demand (eg, gardening), and high demand (eg, snow shoveling). For each activity there was no significant difference between groups. DISCUSSION/CONCLUSION: Conventional thinking that HA provides for more activity is not supported by patient-reported activities when compared with TSA. Patients following TSA reported better motion and strength and were equally as active as the HA group. PMID- 20951064 TI - A reproducible and practical method for documenting the position of the humeral head center relative to the scapula on standardized plain radiographs. AB - BACKGROUND: Recent articles in this journal showed the clinical importance of the position of the humeral head center in relation to the glenoid. However, the precision, reproducibility, and sensitivity of this and other methods of documenting the head center position have not been evaluated in detail. MATERIALS AND METHODS: We used templates to fit a coordinate system to the scapular anatomy visible on standardized radiographs. Two observers then used these templates to measure the position of the head center relative to this coordinate system on 25 normal shoulder radiographs and on 25 radiographs of shoulders with cuff tear arthropathy (CTA). RESULTS: Head center measurements had excellent precision. Normal shoulder radiographs showed a consistent head center position (0.7 +/- 1.7 mm medial and 0.6 +/- 1.3 mm inferior to the coordinate origin on the anteroposterior view and 0.1 +/- 1.3 mm medial and 0.0 +/- 1.3 mm anterior to the coordinate origin on the axillary view). The head center of CTA shoulder radiographs was 10.18 +/- 5.16 mm above the coordinate origin on the anteroposterior view, significantly different from that for the normal shoulder radiographs (P < .001). DISCUSSION: The relative position of the humeral head center to the scapula determines the resting length and the moment arms of the scapulohumeral muscles. Correlation of shoulder function with the head center position may provide insights into both shoulder pathomechanics and the optimization of shoulder arthroplasty. CONCLUSION: This practical technique showed a high degree of precision and reproducibility for normal and CTA shoulder radiographs as well as a high level of discrimination between these two groups. PMID- 20951065 TI - Balloon cells in the dentate gyrus in hippocampal sclerosis associated with non herpetic acute limbic encephalitis. AB - The presence of balloon cells, a pathognomonic cellular feature of focal cortical dysplasia type IIB, in a background of hippocampal sclerosis is rare. Here we report the surgical pathologic features of the hippocampus resected from a 32 year-old woman with mesial temporal lobe epilepsy and a precipitating history of non-herpetic acute limbic encephalitis. Histologically, the resected specimen showed features of hippocampal sclerosis with granule cell dispersion. Characteristically, many balloon cells, immunoreactive for nestin, vimentin, glial fibrillary acidic protein (GFAP), GFAP-delta and CD34, were observed in the molecular and granule cell layers of the dentate gyrus. In the present case hippocampal sclerosis was an apparently acquired alteration, rather than a result of maldevelopment. The appearance of balloon cells raises questions regarding their origin and morphogenesis. PMID- 20951066 TI - Epilepsy surgery of posterior quadrant dysplasia in the first year of life: experience of a single centre with long term follow-up. AB - Posterior quadrant dysplasia (PQD) is a rare variant of cortical dysplasia involving the posterior regions of a single hemisphere. It is always associated with early onset, refractory epilepsy often characterized by a "catastrophic" evolution. The experience on its surgical management during the first year of life is limited to sporadic, isolated cases. Between 2002 and 2005, four children less than one-year-old and affected by drug-resistant epilepsy associated with PQD were admitted to our Institution and underwent surgical treatment. One patient remained seizure-free during all the follow-up (Engel I). The remaining three children showed a recurrence of the seizures, requiring subsequent surgical procedures in two cases. In one case (Engel II), the seizure control has been obtained thanks to pharmacological treatment. The other two patients respectively had only a partial (Engel III) and a less relevant reduction of the number of seizures (Engel IV). Both the epileptic and the neuropsychological outcome of our series were significantly influenced by persistent contralateral interictal anomalies rather than by the timing of the surgical procedure. Unpredictable results should be expected in this kind of patients if there is the detection of contralateral independent epileptiform activities on the EEG at diagnosis. Parents and relatives should be aware of the results' variability, even though a reduction of seizures may be expected, enabling an easier handling of the child's condition. PMID- 20951067 TI - A 6-month prospective study on efficacy safety and QOL profiles of extended release formulation of valproate in patients with epilepsy. AB - The goals of this study were to evaluate the efficacy, safety, and quality of life profiles of ER formulation of valproate in patients with epilepsy. This was a prospective, multicentre, open-lable study. Patients with a definite diagnosis of epilepsy were included and prescribed the ER formulation of valproate as initial or add-on therapy for 6 months. Efficacy and safety re-evaluation procedures were performed at 1 (V1), 3 (V2), and 6 months (V3) after enrollment. A QOLIE-31 inventory was used to assess the quality of life before and after the 6-month treatment. Nine hundred and fifty-eight patients with diagnosis of epilepsy were included in the analysis. The mean of seizure frequency at baseline was 8.56 per month. The median maintenance dose of the ER valproate was 750 mg per day. The number of seizure attacks per month was significantly decreased at the last visit compared to baseline by 88.3%. Patients improved quality of life in the fields of 'seizure worry' (P=0.000), 'overall quality of life' (P=0.000), 'social function' (P<0.01), and 'Question 31' (P=0.000), but showed decreased 'energy' (P=0.000). In the early phase of treatment, the main adverse effects included drowsiness, dizziness, and anorexia. By 6 months of treatment, weight gain, alopecia, and tremor were most frequently reported. The results of the present study demonstrated that patients receiving ER valproate as add-on or mono therapy for 6 months exhibited significantly greater median percent reductions from baseline in seizure frequency for all seizure types, and significantly higher responder rates and higher seizure freedom rates, with good tolerance and improved quality of life. PMID- 20951068 TI - Intravital imaging reveals distinct dynamics for natural killer and CD8(+) T cells during tumor regression. AB - Recognition of NKG2D ligands by natural killer (NK) cells plays an important role during antitumoral responses. To address how NKG2D engagement affects intratumoral NK cell dynamics, we performed intravital microscopy in a Rae-1beta expressing solid tumor. This NKG2D ligand drove NK cell accumulation, activation, and motility within the tumor. NK cells established mainly dynamic contacts with their targets during tumor regression. In sharp contrast, cytotoxic T lymphocytes (CTLs) formed stable contacts in tumors expressing their cognate antigen. Similar behaviors were observed during effector functions in lymph nodes. In vitro, contacts between NK cells and their targets were cytotoxic but did not elicit sustained calcium influx nor adhesion, whereas CTL contact stability was critically dependent on extracellular calcium entry. Altogether, our results offer mechanistic insight into how NK cells and CTLs can exert cytotoxic activity with remarkably different contact dynamics. PMID- 20951069 TI - The house of questionnaires now has a bedroom, but what is the house's floorplan? PMID- 20951070 TI - Computational analysis of water residence on ceramide and sphingomyelin bilayer membranes. AB - Many physical chemical properties of lipid membranes, for example, the thickness, phase state, order parameter, and fluidity, can be understood straightforwardly. Water residence on a membrane is, however, an exception. To tackle this problem, we have performed molecular dynamics simulations of the distribution of water normal to the surface of several lipid membranes and from this deduced the associated water residence time. Our analysis of the results clearly indicates that lipid membranes have hydration shells on their surface, just as a solute in an aqueous solution does, and that the water residence time can be estimated from the potential for the mean force field derived from the distribution function of the water. We have done this atomic-scale analysis for ceramide bilayers and contrasted the calculation results with those for sphingomyelin bilayers, revealing that sphingomyelin bilayers can retain water molecules longer than ceramide bilayers and that the total number of water molecules retained on the membrane surface of sphingomyelin is larger than that for ceramide. In addition, we find that not only polar atoms of lipid molecules, such as oxygen, but also non-polar atoms, such as carbon, influence the motion of water on the membranes. PMID- 20951071 TI - Structures and spectroscopic properties of nonperipherally and peripherally substituted metal-free phthalocyanines: a substitution effect study based on density functional theory calculations. AB - The molecular structures, molecular orbitals, atomic charges, electronic absorption spectra, and infrared (IR) and Raman spectra of a series of substituted metal-free phthalocyanine compounds with four (1, 3, 5, 7) or eight (2, 4, 6, 8) methoxyl (1, 2, 5, 6) or methylthio groups (3, 4, 7, 8) on the nonperipheral (1-4) or peripheral positions (5-8) of the phthalocyanine ring are studied by density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. The calculated structural parameters and simulated electronic absorption and IR spectra are compared with the X-ray crystallography structures and the experimentally observed electronic absorption and IR spectra of the similar molecules, and good agreement between the calculated and experimental results is found. The substitution of the methoxyl or methylthio groups at the nonperipheral positions of the phthalocyanine ring has obvious effects on the molecular structure and spectroscopic properties of the metal-free phthalocyanine. Nonperipheral substitution has a more significant influence than peripheral substitution. The substitution effect increases with an increase in the number of substituents. The methylthio group shows more significant influence than the methoxyl group, despite the stronger electron-donating property of the methoxyl group than the methylthio group. The octa-methylthio-substituted metal free phthalocyanine compounds have nonplanar structures whose low-lying occupied molecular orbitals and electronic absorption spectra are significantly changed by the substituents. The present systematical study will be helpful for understanding the relationship between structures and properties in phthalocyanine compounds and designing phthalocyanines with typical properties. PMID- 20951072 TI - Clinical implementation of total skin electron beam (TSEB) therapy: a review of the relevant literature. AB - Total skin electron beam therapy has been in medical service since the middle of the last century in order to confront rare skin malignancies. Since then various techniques have been developed, all aiming at better clinical results in conjunction with less post-irradiation complications. In this article every available technique is presented in addition to physical parameters of technique establishment and common dose fractionation. This study also revealed the preference of the majority of institutes the last 20 years in "six dual field technique" at a high dose rate, which is a safe and effective treatment. PMID- 20951073 TI - SCA in Korea and its regional distribution: a multicenter analysis. PMID- 20951074 TI - Scapular positioning and motor control in children and adults: a laboratory study using clinical measures. AB - INTRODUCTION: The scapular muscular system is the major determinant of scapular positioning. In addition, strength and muscular endurance develops from childhood through adolescence. It is not known whether differences in scapular positioning and motor control between adults and children may exist. METHODS: Ninety-two shoulders of 46 adults (mean = 39.4; 18-86 years; SD = 22.5), and 116 shoulders of 59 children (mean = 11.6; 6-17 years; SD = 3.5), were included in the study. Scapular positioning data were collected using a clinical assessment protocol including visual observation of titling and winging, measurement of forward shoulder posture, measurement of scapular upward rotation, and the Kinetic Medial Rotation Test (KMRT). RESULTS: The observation protocol for scapular winging and tilting did not show significant differences between adults and children. After controlling for height, forward shoulder posture (relaxed (0.28 cm/cm (0.06) vs. 0.31 cm/cm (0.07) and retracted (0.15 cm/cm (0.05) vs. 0.20 cm/cm (0.06)) were significantly smaller in children than in adults (P < 0.01). In addition, children showed greater scapular upward rotation (18.6 degrees ; SD 9.6 degrees ) than adults (14.5 degrees ; SD 10.9 degrees ) at 90 degrees shoulder abduction. No significant differences were seen between children (19% positive test) and adults (24% positive test) using the KMRT. CONCLUSION: Children and adults show significant but small differences in scapular upward rotation and forward shoulder posture. These data provide useful reference values using a clinical protocol. PMID- 20951075 TI - Robust statistical shape models for MRI bone segmentation in presence of small field of view. AB - Accurate bone modeling from medical images is essential in the diagnosis and treatment of patients because it supports the detection of abnormal bone morphology, which is often responsible for many musculoskeletal diseases (MSDs) of human articulations. In a clinical setting, images of the suspected joints are acquired in a high resolution but with a small field of view (FOV) in order to maximize the image quality while reducing acquisition time. However bones are only partially visible in such small FOVs. This presents difficult challenges in automated bone segmentation and thus limits the application of sophisticated algorithms such as statistical shape models (SSM), which have been generally proven to be an efficient technique for bone segmentation. Indeed, the reduced image information affects the initialization and evolution of these deformable model-based approaches. In this paper, we present a robust multi-resolution SSM algorithm with an adapted initialization to address the segmentation of MRI bone images acquired in small FOVs for modeling and computer-aided diagnosis. Our innovation stems from the derivation of a robust SSM based on complete and corrupted shapes, as well as from a simultaneous optimization of transformation and shape parameters to yield an efficient initialization technique. We demonstrate our segmentation algorithm using 86 clinical MRI images of the femur and hip bones. These images have a varied resolution and limited FOVs. The results of our segmentation (e.g., average distance error of 1.12 +/- 0.46 mm) are within the needs of image-based clinical diagnosis. PMID- 20951076 TI - A curvelet-based patient-specific prior for accurate multi-modal brain image rigid registration. AB - We present a new non-uniform sampling method for the accurate estimation of mutual information in multi-modal brain image rigid registration. Most existing density estimators used for mutual information computation incorrectly assume that the intensity of each voxel is independent from its neighborhood. Our method uses the 3D Fast Discrete Curvelet Transform to reduce the sampled voxels' interdependency by sampling voxels that are less dependent on their neighborhood, and thus provide a more accurate estimation of the mutual information and a more accurate registration. The main advantages of our method over other non-uniform sampling schemes are that: (1) it provides more accurate estimation of the image statistics with fewer samples; (2) it is less sensitive to the variability of anatomical structures shapes, orientations, and sizes, and; (3) it yields more accurate registration results. Extensive evaluation on 1000 synthetic registrations between T1 and T2-weighted clinical MRI images and 20 real clinical registrations of brain CT images to Proton Density (PD) and T1 and T2-weighted MRI images from the public RIRE database show the effectiveness of our method. Our method has the lowest mean registration errors recorded to date for CT-MR image registration in the RIRE website for methods tested on more than five datasets. These results indicate that our sampling scheme can be used to achieve more accurate multi-modal registration required for image guided therapy and surgery. PMID- 20951077 TI - A role for COX2-derived PGE2 and PGE2-receptor subtypes in head and neck squamous carcinoma cell proliferation. AB - The overexpression of cyclooxygenase (COX)-2 is a frequent event in squamous cell carcinomas of the head and neck (HNSCC), and non-steroidal anti-inflammatory drugs, which are potent inhibitors of COX-1 and COX-2, exert chemopreventive effects on HNSCC cancer development. COX-2 promotes the release of the pro inflammatory mediator prostaglandin E2 (PGE2), which acts on its cell surface G protein-coupled receptors EP1, EP2, EP3, and EP4. Here, we investigated the role of PGE2 and its receptors in cellular proliferation in HNSCC. The expression of COX-2 and EP1-4 was examined in immortalized oral epithelial cells and in a representative panel of HNSCC cell lines, and based on these data EP1-EP3 and COX 2 expression were evaluated by immunohistochemistry in a large clinical sample collection using HNSCC tissue microarrays. The ability of selective COX-2 inhibition to block PGE2 secretion was measured by ELISA specific assays. The effects of PGE2 on cell proliferation were evaluated using PGE2, its stable analog, and EP2 and EP3-specific synthetic agonists. The results presented here show that HNSCC tumoral lesions and their derived cell lines constitutively express COX-2 and the EP1, EP2 and EP3 receptors for PGE2. HNSCC cells secrete PGE2, which can be suppressed by low concentrations of COX-2 selective inhibitors, without inhibiting cell proliferation. Exogenously added stable PGE2 and EP3-specific agonists induce DNA synthesis in all HNSCC cell lines tested. Overall, our study supports the emerging notion that PGE2 produced in the tumor microenvironment by the overexpression of COX-2 in tumoral and inflammatory cells may promote the growth of HNSCC cells in an autocrine and paracrine fashion by acting on PGE2 receptors that are widely expressed in most HNSCC cancer cells. In particular, our findings suggest that EP3 receptor may play a more prominent role in HNSCC cell growth promotion, thus providing a rationale for the future evaluation of this PGE2 receptor as a target for HNSCC prevention strategies. PMID- 20951078 TI - Protein localization by recognition of membrane curvature. AB - Bacteria often sort proteins to specific subcellular locations, but many of the chemical beacons that specify those sites and subsequently recruit proteins have not been identified. Recent reports suggest that some bacterial proteins localize to specific subcellular sites by recognizing either convex or concave membrane curvature. Thus, degrees of membrane curvature, dictated by the shape of the cell, can define a geometric cue for the recruitment of curvature-sensing proteins. PMID- 20951079 TI - Effects of nucleoid-associated proteins on bacterial chromosome structure and gene expression. AB - Bacterial nucleoid-associated proteins play a key role in the organisation, replication, segregation, repair and expression of bacterial chromosomes. Here, we review some recent progress in our understanding of the effects of these proteins on DNA and their biological role, focussing mainly on Escherichia coli and its chromosome. Certain nucleoid-associated proteins also regulate transcription initiation at specific promoters, and work in concert with dedicated transcription factors to regulate gene expression in response to growth phase and environmental change. Some specific examples, involving the E. coli IHF and Fis proteins, that illustrate new principles, are described in detail. PMID- 20951080 TI - The introduction of a diagnostic decision support system (DXplainTM) into the workflow of a teaching hospital service can decrease the cost of service for diagnostically challenging Diagnostic Related Groups (DRGs). AB - BACKGROUND: In an era of short inpatient stays, residents may overlook relevant elements of the differential diagnosis as they try to evaluate and treat patients. However, if a resident's first principal diagnosis is wrong, the patient's appropriate evaluation and treatment may take longer, cost more, and lead to worse outcomes. A diagnostic decision support system may lead to the generation of a broader differential diagnosis that more often includes the correct diagnosis, permitting a shorter, more effective, and less costly hospital stay. METHODS: We provided residents on General Medicine services access to DXplain, an established computer-based diagnostic decision support system, for 6 months. We compared charges and cost of service for diagnostically challenging cases seen during the fourth through sixth month of access to DXplain (intervention period) to control cases seen in the 6 months before the system was made available. RESULTS: 564 cases were identified as diagnostically challenging by our criteria during the intervention period along with 1173 cases during the control period. Total charges were $1281 lower (p=.006), Medicare Part A charges $1032 lower (p=0.006) and cost of service $990 lower (p=0.001) per admission in the intervention cases than in control cases. CONCLUSIONS: Using DXplain on all diagnostically challenging cases might save our medical center over $2,000,000 a year on the General Medicine Services alone. Using clinical diagnostic decision support systems may improve quality and decrease cost substantially at teaching hospitals. PMID- 20951081 TI - Updating clinical knowledge: an evaluation of current information alerting services. AB - PURPOSE: Clinicians are overwhelmed by the sheer magnitude of new clinical information that is available on a daily basis. Despite the availability of information tools for finding this information and for updating clinical knowledge, no study has examined the quality of current information alerting services. METHODS: We developed a 7-item checklist based on the principles of evidence-based medicine and assessed content validity with experts and face validity with practicing clinicians and clinician researchers. A list of clinical information updating tools (push tools) was generated in a systematic fashion and the checklist was used to rate the quality of these tools by two independent raters. Prior to rating all instruments, the raters were trained to achieve good agreement (>80%) by applying the checklist to two sets of three randomly selected tools. Descriptive statistics were used to describe the quality of the identified tools and inter-rater reliability was assessed using Intraclass Correlation (ICC). RESULTS: Eighteen tools were identified using our systematic search. The average quality of these tools was 2.72 (range 0-7). Only two tools met all suggested criteria for quality. Inter-rater reliability for the 7-item checklist was .82 (ICC). CONCLUSIONS: We developed a checklist that can be used to reliably assess the quality of clinical information updating tools. We found many shortcomings in currently available clinical knowledge updating tools. Ideally, these tools will evolve in the direction of applying basic evidence-based medicine principles to new medical information in order to increase their usefulness to clinicians. PMID- 20951082 TI - The MITRE Identification Scrubber Toolkit: design, training, and assessment. AB - PURPOSE: Medical records must often be stripped of patient identifiers, or de identified, before being shared. De-identification by humans is time-consuming, and existing software is limited in its generality. The open source MITRE Identification Scrubber Toolkit (MIST) provides an environment to support rapid tailoring of automated de-identification to different document types, using automatically learned classifiers to de-identify and protect sensitive information. METHODS: MIST was evaluated with four classes of patient records from the Vanderbilt University Medical Center: discharge summaries, laboratory reports, letters, and order summaries. We trained and tested MIST on each class of record separately, as well as on pooled sets of records. We measured precision, recall, F-measure and accuracy at the word level for the detection of patient identifiers as designated by the HIPAA Safe Harbor Rule. RESULTS: MIST was applied to medical records that differed in the amounts and types of protected health information (PHI): lab reports contained only two types of PHI (dates, names) compared to discharge summaries, which were much richer. Performance of the de-identification tool depended on record class; F-measure results were 0.996 for order summaries, 0.996 for discharge summaries, 0.943 for letters and 0.934 for laboratory reports. Experiments suggest the tool requires several hundred training exemplars to reach an F-measure of at least 0.9. CONCLUSIONS: The MIST toolkit makes possible the rapid tailoring of automated de identification to particular document types and supports the transition of the de identification software to medical end users, avoiding the need for developers to have access to original medical records. We are making the MIST toolkit available under an open source license to encourage its application to diverse data sets at multiple institutions. PMID- 20951084 TI - Increasing the efficiency of neonatal MEG measurements by alternating auditory and tactile stimulation. AB - OBJECTIVE: To evaluate the possible effect of intervening auditory stimulation on somatosensory evoked magnetic fields in newborns. METHODS: We recorded auditory and tactile evoked responses with magnetoencephalography (MEG) from two groups of healthy newborns. One group (n=11) received only tactile stimuli to the index finger, the other (n=11) received alternating tactile and auditory (vowel [a:] with 300-ms duration) stimuli. The interval between subsequent tactile stimuli was always 2 s. We analyzed the equivalent current dipoles (ECDs) of the main auditory and somatosensory responses. RESULTS: The ECDs of the tactile responses agreed with activation of the primary somatosensory cortex at ~60 ms and the secondary somatosensory region at ~200 ms. The source of the auditory response (~250 ms) was clearly distinct from those to tactile stimulation and in line with auditory cortex activation. The intervening auditory stimulation did not affect the strength, latency, or location of the ECDs of the tactile responses. CONCLUSIONS: Auditory and tactile MEG responses from newborns can be obtained in one measurement session. SIGNIFICANCE: The alternating stimulation can be used to shorten the total measurement time and/or to improve the signal to noise ratio by collecting more data. PMID- 20951085 TI - CFTR-dependent susceptibility of the cystic fibrosis-host to Pseudomonas aeruginosa. AB - Cystic fibrosis is the most common autosomal recessive disorder in western countries. The disease is characterized by recurrent and chronic infections of the lung in particular with Pseudomonas aeruginosa, Staphylococcus aureus, Burkholderia cepacia, and Haemophilus influenzae. Albeit intensive research in the last years, the molecular mechanisms causing the high susceptibility of cystic fibrosis patients to bacterial infections are still unknown. Animal models provided important novel information on the pathophysiology of cystic fibrosis and mimicked many of the pathological findings in humans, for instance chronic inflammation and increased infection susceptibility. These animal models were recently employed to identify several proteins and lipids that are critically involved in the pathophysiology of cystic fibrosis. Thus, several studies identified death receptors, caveolin proteins, membrane rafts, and alterations of the ceramide metabolism with an accumulation of ceramide in cystic fibrosis lungs to be critically involved in the infection susceptibility, the chronic inflammation, and the reduced mucociliary clearance in cystic fibrosis. PMID- 20951086 TI - Murine models of acute and chronic lung infection with cystic fibrosis pathogens. AB - Animal models of acute and chronic infection, along with mice genetically modified for the Cftr gene, are a key asset in cystic fibrosis (CF) research. Despite some limitations, these models provide valuable resources to mimic the initial and progressive bronchopulmonary infection typical of CF patients. The following review summarizes the strengths and weaknesses of different types of animal models with a major emphasis placed on the significant species differences between mice and humans. Murine models of acute and chronic lung infection with Pseudomonas aeruginosa, Burkholderia cenocepacia, Staphylococcus aureus, and Haemophilus influenzae have been used to study the molecular mechanisms underlying the pathogen virulence and host defense. In addition, they have provided insights in the potential of vaccination to restrict infectious exacerbations, the activity of antibiotics, and the effectiveness of anti inflammatory therapy in reducing lung damage. Indeed, animal models of infection should allow the validation of future therapeutic interventions for lung infections in patients with CF. PMID- 20951087 TI - Clonal epidemiology of Pseudomonas aeruginosa in cystic fibrosis. AB - The basic defect in cystic fibrosis (CF) predisposes to chronic bacterial airway infections, particularly with Pseudomonas aeruginosa. Airway infections with P. aeruginosa in individuals with CF are unique in that they chronically affect a host who is immunocompetent in terms of cellular and humoral responses but is immunocompromised by impaired airway clearance. The initially acquired P. aeruginosa clone typically persists for many years in the patients' airways and thereby diversifies by de novo point mutations and the composition of its accessory genome. Co-colonizations with 2 or more clones are preferentially observed during the first 3 years of colonization. Upper and lower airways are commonly colonized by the same clone suggesting that the sinuses are the reservoir and gateway for the colonization of the lower airways. Early antipseudomonal chemotherapy has an 80% chance to eradicate the P. aeruginosa clone. This regimen introduced in the late 1980s has shifted the median age of the onset of chronic airways colonization with P. aeruginosa from school age to early adulthood at the most successful CF centres. The measures to prevent and to treat the Pseudomonas infections in CF have been considerably improved during the last 20 years. Highly transmissible epidemic strains, however, that emerge within a clonal lineage remain a major, still unresolved health threat for the CF community. PMID- 20951088 TI - Research is needed on the use of cognitive enhancer drugs in sport. PMID- 20951089 TI - Burnout syndrome in surgical oncology and general surgery nurses: a cross sectional study. AB - PURPOSE: The occurrence of burnout syndrome is strongly associated with and modulated by multiple personality and environmental factors. In Poland, nurses experience a discrepancy between the demands, expectations and social status of the position of their profession and low salaries. Such a situation provokes frustration and depression, and further leads to problems of adaptation including burnout syndrome. The aim of this study was to evaluate the occurrence of burnout syndrome among nurses working in general surgery and surgical oncology specialties. METHODS: The study was designed as a cross-sectional questionnaire survey. It was undertaken in the largest Hospital in the Pomeranian region of Poland. The participants included 60 nurses working in two departments: General Surgery and Surgical Oncology. The study was based upon an anonymous self-test composed of a questionnaire and three psychological measures: Maslach Burnout Inventory (MBI), Psychological Burden Scale and a self-constructed questionnaire on job satisfaction. RESULTS: Intensity of burnout syndrome was significantly higher among oncology nurses than among surgical ones. There was also a strong but not significant trend towards higher Psychological Burden Scale in the group of oncology nurses. CONCLUSIONS: The study revealed a high degree of emotional burden and burnout in nurses working in the study hospital suggesting that nurses are at great occupational risk. The findings of the study provide evidence of the potential need to restructure the system and suggest that nurses need more control of their work including a higher degree of involvement in clinical decision-making. PMID- 20951090 TI - The meaning and significance of routine follow-up in lung cancer - a qualitative study of patients' experiences and interpretations. AB - PURPOSE: Questions have been raised about the benefits of routine follow-up for patients with lung cancer and a number of studies have now explored alternative models of care for this patient group. This study explores the experiences of lung cancer patients attending routine follow-up and illustrates factors which might influence patients' interpretations of the meaning and significance of follow-up. METHOD: This qualitative study was undertaken to gain insight into patients' experiences of attending routine follow-up clinics after treatment completion. A purposive sample of ten patients was interviewed, including patients of both genders, different lung cancer types, treatment intent, treatment received, performance status and experience of follow-up. RESULTS: Analysis of the transcripts revealed patients' confidence and faith in their consultants and the importance of having a connection with the oncology department. The meaning and significance of follow-up is constructed by what they bring to the consultation (anxiety, vulnerability, uncertainty, symptoms) as well as what happens within that consultation (reassurance, relief, encouragement). Although some participants were anxious about attending, all express expectation and desire for follow-up to continue. Many were, however, prepared to consider nurse-led follow-up. CONCLUSION: Although small, this study highlights the significance that patients with lung cancer attach to attending follow-up clinics and the need to consider patients' experiences in the design of future follow-up care and also consideration should be given to complementary and innovative approaches to follow-up. PMID- 20951091 TI - Genetics of lung-cancer susceptibility. AB - Lung cancer is the most common form of cancer death worldwide. Although reduction of tobacco consumption remains the most appropriate strategy to reduce lung cancer burden, identification of genes involved in the cause of disease could contribute to further understanding of the underlying mechanisms, and eventually lead to additional prevention strategies and targeted treatments. Common gene variants involved in lung cancer have been recently identified through large, collaborative, genome-wide association studies. These studies identified three separate loci that are associated with lung cancer (5p15, 6p21, and 15q25) and include genes that regulate acetylcholine nicotinic receptors and telomerase production. However, much about genetic risk remains to be discovered, and rarer gene variants, such as those of the CHEK2 gene, likely account for most of the remaining risk. There is also a need for studies that investigate how genetic susceptibility is associated with clinical outcome measures, including treatment response and tumour relapse. PMID- 20951093 TI - Computation of mutual information from Hidden Markov Models. AB - Understanding evolution at the sequence level is one of the major research visions of bioinformatics. To this end, several abstract models--such as Hidden Markov Models--and several quantitative measures--such as the mutual information- have been introduced, thoroughly investigated, and applied to several concrete studies in molecular biology. With this contribution we want to undertake a first step to merge these approaches (models and measures) for easy and immediate computation, e.g. for a database of a large number of externally fitted models (such as PFAM). Being able to compute such measures is of paramount importance in data mining, model development, and model comparison. Here we describe how one can efficiently compute the mutual information of a homogenous Hidden Markov Model orders of magnitude faster than with a naive, straight-forward approach. In addition, our algorithm avoids sampling issues of real-world sequences, thus allowing for direct comparison of various models. We applied the method to genomic sequences and discuss properties as well as convergence issues. PMID- 20951092 TI - Innate immune cell populations function as initiators and effectors in Th2 cytokine responses. AB - The recent identification of previously unrecognized innate cell populations, termed natural helper cells (NHCs), multi-potent progenitor type 2 (MPP(type2)) cells, nuocytes, and innate type 2 helper (Ih2) cells has provided new insights into our understanding of the cellular mechanisms that lead to the development of CD4(+) Th2 cell-dependent immunity and/or inflammation at mucosal sites. In this review, we focus on the functional significance, similarities, and differences between NHCs, MPP(type2) cells, nuocytes and Ih2 cells. All four cell populations are activated by interleukin (IL)-25 and/or IL-33 and are capable of promoting Th2 cytokine responses. Collectively, the identification of these cell populations might illuminate ancient evolutionary conserved pathways that are involved in the development of Th2 cytokine responses, and could be of benefit in the development of therapeutic approaches that target helminth infections and allergic diseases. PMID- 20951094 TI - The predictive value of the first postnatal ultrasound in children with antenatal hydronephrosis. AB - OBJECTIVE: To evaluate the effectiveness of the first postnatal ultrasound (US) in predicting the final postnatal diagnosis using a database of children followed prospectively for antenatal hydronephrosis, and to compare these findings with a systematic review of the literature. METHODS: The study involved 1441 children who had their radiological evaluation between 3 and 60 days of life, including an US, performed at our institution in 1998-2006. Univariate and multivariate analyses were performed. A systematic review of articles on prenatal hydronephrosis resulted in 31 studies with 2202 patients who met the inclusion criteria for analysis. RESULTS: 62.0% of renal units (RUs) had transient or non obstructive hydronephrosis. Increasing degree of hydronephrosis correlated with increased risk of urological pathologies (from 29.6% RUs in the mild group to 96.3% RUs in the severe group). A systematic review of the literature indicated very poor quality data, but the findings appeared to be concordant with those from our patient population. CONCLUSION: The findings from this study will help to quantify the incidence of postnatal pathology based upon the first postnatal US parameters. This information is useful for counseling and for determining which postnatal radiological tests will be necessary. PMID- 20951095 TI - Evolution and prognosis value of intrarenal reflux. AB - PURPOSE: The aim of this study was to evaluate the prognostic significance of intrarenal reflux (IRR) regarding urinary tract infection (UTI), renal scarring and spontaneous resolution after 3 years of follow up. PATIENTS AND METHODS: 33 patients (42 refluxing units) with IRR were compared to 27 children (44 refluxing units) with high-grade vesicoureteral reflux (VUR) without IRR (controls) matched for gender, age and VUR grade. All patients received antibiotic prophylaxis during observation and antireflux surgery was performed in children with recurrent UTI. DMSA scan was performed at study entry, and 18 and 36 months. RESULTS: DMSA scores at entry showed a higher proportion of moderate and severe damage in the IRR group (25/42) compared to the control group (16/44) (Chi squared, P < 0.03). During follow up the incidence of UTI was similar in the two groups, as well as the stability of DMSA scintigraphy and the rate of spontaneous disappearance of the reflux. A similar proportion of patients underwent surgery (18/33 patients with IRR and 13/27 control patients; Chi squared, not significant). CONCLUSIONS: Under medical management, the prognosis for IRR is not different from high-grade VUR without IRR. The presence of IRR does not justify more aggressive management than a high-grade VUR without IRR. PMID- 20951096 TI - Specific cytokine patterns of pulmonary tuberculosis in Central Africa. AB - Different cytokines have been suggested to be involved in the pathogenesis of pulmonary tuberculosis (TB). The frequencies of Mycobacterium tuberculosis (MTB) specific CD4(+) and CD8(+) T cells, CD4(+)CD25(+) Forkhead Box Protein (FoxP)3(+) T cells, interleukin (IL)-6, interferon (IFN)-gamma, Tumor necrosis factor (TNF) alpha, transforming growth factor (TGF)-beta and IL-10 were assessed in HIV negative, pulmonary tuberculosis (TB) patients (n=30) and in healthy controls (n=23) in Gabon. Peripheral blood mononuclear cells (PBMC) were stimulated with purified protein derivative (PPD) and early secretory antigenic target-6 (ESAT 6). In patients, a pronounced pro-inflammatory cytokine response with highly significant increased levels of IL-6 and TNF-alpha accompanied by increased TGF beta was detectable. Differences in IFN-gamma responses between patients and healthy individuals were less pronounced than expected. FoxP3 expression did not differ between groups. A distinct cytokine pattern is associated with active pulmonary TB in patients from Central Africa. PMID- 20951097 TI - Posterior unilateral pedicle subtraction osteotomy of hemivertebra for correction of the adolescent congenital spinal deformity. AB - BACKGROUND CONTEXT: The treatment of adolescent congenital deformity (late diagnosed congenital deformity) is still unknown. The best candidates for hemivertebra excision are young patients, typically between 4 and 6 years of age. Partial excision may be feasible for older children. PURPOSE: The purpose of this study was to assess the effect of unilateral pedicle subtraction osteotomy of hemivertebra for correction of the adolescent congenital spinal deformity. STUDY DESIGN: Retrospective analysis. PATIENT SAMPLE: Twelve patients with adolescent congenital deformity who underwent posterior unilateral pedicle subtraction osteotomy and correction were evaluated. Mean age at the time of surgery was 17 years. OUTCOME MEASURES: The charts, standing full-length posteroanterior and lateral view radiographs, and functional measures were reviewed. METHODS: For evaluation of surgical effectiveness, comparative analysis of the parameters of the total main curve, the segmental curve, the compensatory cranial and caudal curves, the segmental kyphosis, and the trunk shift before and after operation and at the most recent follow-up was done. RESULTS: The mean follow-up period was 40.5 months. Mean Cobb angles of the total main curve and the segmental curve were, respectively, 47.5 degrees and 43.8 degrees before surgery, 23.7 degrees and 16.5 degrees after surgery, and 22.6 degrees and 17 degrees at the last follow-up. The angle of segmental kyphosis was 11.8 degrees before surgery, 6.2 degrees after surgery, and 7.8 degrees (range, -30 degrees to 26 degrees ) at the final follow-up. The mean final global lordosis was within the normal range. No neurologic deficit occurred. Solid fusion was achieved for all cases. CONCLUSIONS: Unilateral pedicle subtraction osteotomy with instrumentation from a posterior-only approach is indicated in older teenagers for an adolescent congenital spinal deformity. Compared with hemivertebra excision, corrective surgery with hemivertebra osteotomy has a lower intraoperative blood loss and shorter operation time. PMID- 20951098 TI - Glucagon-like peptide 1 and the brain: central actions-central sources? AB - Glucagon-like peptide 1(GLP-1) is both an incretin released postprandially from the gut and a neuropeptide produced by select brainstem neurons. Its principal role is in the control of metabolic and cardiovascular functions, acting both in the periphery and within the central nervous system (CNS). Specifically, GLP-1 functions that involve the CNS include the suppression of food intake, the regulation of glucose homeostasis and the modulation of heart rate and blood pressure. Thus far, relatively little is known about the exact interplay between gut-derived and neuronally-produced GLP-1. This is partially due to the difficulty of identifying and targeting GLP-1 producing cells in vitro. This obstacle has recently been overcome by the generation of transgenic mice with fluorescently-tagged GLP-1 cells (mGLU-YFP mice). This review revisits what has been discovered about the central actions of GLP-1 during the past decade and puts it into context of the emerging findings from the mGLU-YFP mice. PMID- 20951099 TI - Budding yeast Mph1 promotes sister chromatid interactions by a mechanism involving strand invasion. AB - Stalling of replication forks at lesions is a serious threat to genomic integrity and cell viability. Cells have developed a variety of pathways that allow continuation of synthesis, including translesion synthesis, postreplication repair and homologous recombination. We have devised a sensitive genetic system for detection of sister chromatid interactions in Saccharomyces cerevisiae. A 266bp sequence duplication in the KanMX4 module was generated and reversions were scored via G418 resistant colonies. Both 4-NQO induced and spontaneous reversions are strictly dependent on RAD52. Damage-induced reversions are also largely dependent on RAD51. Thus, most damage-induced events require a strand invasion step. Induced reversions were not affected in rev3 mutants and partially reduced in rad30 mutants indicating an involvement of Pol eta. In cells lacking Mph1, a member of the FANCM family of DNA helicases, that has been implicated in a pathway for fork reactivation involving homologous recombination, damage-induced events are significantly reduced. Together with the spontaneous mutator phenotype of mph1 mutants this data strongly suggest that Mph1 has an additional function in recombination besides its previously described ability to disrupt D-loops. We propose that Mph1 promotes D-loop formation. PMID- 20951100 TI - Determination of PF-04928473 in human plasma using liquid chromatography with tandem mass spectrometry. AB - A simple, rapid and sensitive liquid chromatography/tandem mass spectrometric (LC/MS/MS) analytical method was developed for quantification of Hsp90 inhibitor PF-04928473 in human plasma, following administration of its prodrug, PF 04929113. Sample processing involved protein precipitation by addition of 0.4 mL of methanol containing internal standard (PF-04972487) to 50 MUL volume of plasma sample. Chromatographic separation of PF-04928473 and PF-04972487 was achieved on a Phenomenex(r)) Luna C18(2) (2.0 mm x 50 mm, 5 MUm) column using a gradient elution method with mobile phase solvents: methanol containing 0.1% formic acid and 0.1% formic acid at a flow rate of 0.25 mL/min. Detection was performed in electrospray positive ionization mode, monitoring the ion transitions from m/z 465.1->350.1 (PF-04928473) and m/z 447.0->329.1 (PF-04972487). The retention times for PF-04928473 and PF-04972487 were 1.86 and 2.85 min, respectively. Calibration curves were generated in the range of 2-2000 ng/mL. The accuracy and precision ranged from 94.1 to 99.0% and 86.7 to 97.6%, respectively, which were calculated using quality control samples of three different concentrations analyzed in quintuplicate on four different days. PMID- 20951101 TI - An automated packed protein G micro-pipette tip assay for rapid quantification of polyclonal antibodies in ovine serum. AB - The demands on the biopharmaceutical sector to expedite process development have instigated the deployment of micro-biochemical engineering techniques to acquire manufacturing insight with extremely small sample volumes. In conjunction with automated liquid handlers, this permits the simultaneous evaluation of multiple operating conditions and reduces manual intervention. For these benefits to be sustained, novel ways are now required to accelerate analysis and so prevent this becoming a throughput bottleneck. For example, although Protein G HPLC is used to quantify antibody titres in bioprocess feedstocks, it can be time-consuming owing to the serial nature of its application. Although commercial options are available that can process many samples simultaneously, these require separate, potentially expensive instruments. A more integrated approach is desirable wherein the assay is implemented directly on a robot. This article describes a high-throughput alternative to antibody HPLC analysis which uses an eight-channel liquid handler to control pipette tips packed with 40 MUL of Protein G affinity matrix. The linearity, range, limit of detection, specificity and precision of the method were established, with results showing that antibody was detected reliably and specifically between 0.10 and 1.00 mg/mL. Subsequently, the technique was used to quantify the antibody titre in ovine serum, which is used as feed material by BTG PLC for manufacturing FDA-approved polyclonal bio therapeutics. The mean concentration determined by the tips was comparable to that found by HPLC, but the tip method delivered its results in less than 40% of the time and with the potential for further, substantial time-savings possible by using higher capacity robots. PMID- 20951102 TI - Simultaneous determination of triclabendazole and its metabolites in bovine and goat tissues by liquid chromatography-tandem mass spectrometry. AB - A sensitive liquid chromatography-tandem mass spectrometry method for the simultaneous determination of triclabendazole, its main metabolites (triclabendazole sulphone and triclabendazole sulphoxide) and a marker residue (ketotriclabendazole) in bovine and goat muscle, liver, and kidney samples is developed and validated. Analyte extraction from samples is effectively performed using liquid-liquid extraction by acetonitrile. Chromatographic separation is performed on a C18 reversed-phase column with gradient elution. The analytes are detected by tandem quadrupole mass spectrometry after positive electrospray ionization by multiple reaction monitoring. The limits of detection for analytes are found to be 0.25-2.5 MUg/kg in muscle tissues and 1-10 MUg/kg in liver and kidney tissues, respectively. The recoveries of edible bovine and goat tissues range from 84.9% to 109.5% when spiked at different levels with analytes, with relative standard deviations generally below 12.8%. PMID- 20951103 TI - Modeling the long term health outcomes and cost-effectiveness of two interventions promoting fruit and vegetable intake among schoolchildren. AB - This study provides an example on how to assess the cost-effectiveness of a nation wide implementation of two school-based interventions promoting fruit and vegetable intake among primary schoolchildren in the Netherlands compared to 'no intervention' and to each other. Data collection using self-report questionnaires in both studies was conducted between 2003 and 2005. Effects of the intervention in terms of fruit and vegetable intake were assessed and epidemiological modeling (conducted in 2008) was used to estimate the number of disability-adjusted life years gained over the lifetime of all 10 years old in the Netherlands. We assumed 30% of the effect on consumption was permanent. Incremental cost effectiveness ratios (ICER) and net monetary benefits (NMB) were estimated and one-way and probabilistic sensitivity analyses were conducted. The ICER for the Pro Children intervention in comparison with no intervention was estimated at ?5728/DALY and the ICER for the Schoolgruiten intervention in comparison with no intervention at ?10,674/DALY. Using the Dutch per capita income as a decision threshold (?19,600) the probability that the Pro Children intervention was cost-effective in comparison with no intervention was 80% and that the Schoolgruiten intervention was cost-effective in comparison with no intervention was 68%. The Pro Children had a 70% chance of being dominant over the Schoolgruiten intervention in terms of cost-effectiveness. The current cost-effectiveness model shows that both the Pro Children intervention and the Schoolgruiten intervention were cost-effective in comparison with no intervention. Extensive sensitivity analyses showed that the conclusions were sensitive to the discount rate and the proportion of effects that remains lifelong. PMID- 20951104 TI - [Erythropoietin in neonates]. PMID- 20951106 TI - Rhomboid flap with multiple Z-plasty for treatment of hypertrophic scar on the pubic area. AB - The pubic area is prone to the development of hypertrophic scars; however, few studies have reported on the valid means of treating hypertrophic scars affecting this area. We have recently devised a new operative procedure, 'rhomboid flap with multiple Z-plasty', for the treatment of this condition. For this operative procedure, the defect after resection of the scarred tissue in the pubic area is first covered with a rhomboid flap elevated from the hypogastric area, followed by applying multiple Z-plasty to the suture wound of the donor site. By avoiding excessive suturing of the defect in the pubic area, and by covering the defect with a rhomboid flap, the tension on the wound margin can be sufficiently reduced. This is followed by multiple Z-plasty for the longitudinal wound of the hypogastric area, erasing all suture lines perpendicular to the natural folds. Here, we report two cases that underwent this procedure with favourable outcomes. PMID- 20951105 TI - Tunnelised inferiorly based preauricular flap repair of antitragus and concha after basal cell carcinoma excision: case report. AB - Ear reconstruction represents a challenge for plastic and reconstructive surgeons because of the complex anatomy of the ear. Reconstructive techniques vary, depending on both the location and extent of defects. This report describes a new option for antitragus and concha reconstruction after excision of skin malignancies. PMID- 20951107 TI - Abdominoplasty: to inform about TRAM flaps or not? PMID- 20951108 TI - Vital and functional outcomes of the first-ever hemispheric stroke, epidemiological comparative study between Kunming (China) and Limoges (France). AB - BACKGROUND: Clinical outcomes and socioeconomic consequences after a stroke may differ between regions. METHODS: One cohort was established prospectively in Kunming (China) to compare with a cohort of 156 stroke patients included in Limoges (France). During 1 year, patients hospitalized within 48 hours for a first-ever hemispheric stroke were included. Demographic data and neurocardiovascular risk factors were registered. Hemiplegia was evaluated. Functional outcome was assessed using the Barthel Index (BI) after 3 months. RESULTS: One hundred and eighteen patients were included in Kunming. Patients of Kunming were younger (61.4 +/- 13.4 vs 72.3 +/- 14.6 years in Limoges, P<0.0001), more involved in professional activity (36.4% vs 12.8%, P<0.0001). Survival analysis indicated that mortality did not differ between cohorts, but independently predicted by coma at the 2nd day (HR=9.33, 95% CI [4.39, 19.78]) and age>70 years (HR=6.29, 95% CI [2.36, 16.59]). Despite a better baseline BI for patients of Kunming (50.0 +/- 34.9 vs 37.4 +/- 34.2, P=0.0031), after adjustment for confusing, patients in Limoges had a 2.11 OR 95% CI [1.03, 4.31]) to reach a BI>80 at 3 months. CONCLUSIONS: Functional recovery for patients of Kunming was not as good as expected. The socioeconomic consequences of stroke in Kunming are significant as they involved younger subjects who were still in work. PMID- 20951109 TI - Ambulatory groin and ventral hernia repair. AB - OBJECTIVE: Ambulatory surgery is not commonly practiced in France today. The aim of this study was to prospectively evaluate the feasibility of ambulatory hernia repair in a consecutive series of unselected patients. PATIENTS AND METHODS: From June 2008 to October 2009, 257 patients (238 men and 19 women, median age 65 years) were treated in a same-day surgery unit for 270 hernias (244 groin hernias, 25 ventral hernias and one Spiegelian hernia). RESULTS: For groin hernia, the techniques included the totally extraperitoneal repair (TEP) in 108 cases, the transinguinal preperitoneal (TIPP) approach in 106 cases and other alternative techniques in 30 cases; for ventral hernias, the technique was an open suture in 20 cases, an open prosthetic repair in four cases and laparoscopic repair in one case. Anesthesia was general in 145 cases, local in 121 cases and spinal in four cases. Repair was completed in a same-day surgery setting in 242 (89.6%) cases; hospital stay greater than 23 hours was planned for 21 (7.8%) patients while non-programmed hospitalizations were necessary for seven (2.6%) patients. There were two (0.7%) readmissions and nine (3.3%) benign postoperative complications. CONCLUSION: These results suggest that groin and ventral hernia repair can be performed in an outpatient setting in nearly 90% of unselected patients. PMID- 20951110 TI - Enhancing electro-transformation competency of recalcitrant Bacillus amyloliquefaciens by combining cell-wall weakening and cell-membrane fluidity disturbing. AB - Bacillus amyloliquefaciens has been a major workhorse for the production of a variety of commercially important enzymes and metabolites for the past decades. Some subspecies of this bacterium are recalcitrant to exogenous DNA, and transformation with plasmid DNA is usually less efficient, thereby limiting the genetic manipulation of the recalcitrant species. In this work, a methodology based on electro-transformation has been developed, in which the cells were grown in a semicomplex hypertonic medium, cell walls were weakened by adding glycine (Gly) and DL-threonine (DL-Thr), and the cell-membrane fluidity was elevated by supplementing Tween 80. After optimization of the cell-loosening recipe by response surface methodology (RSM), the transformation efficiency reached 1.13 +/ 0.34 * 10(7) cfu/MUg syngeneic pUB110 DNA in a low conductivity electroporation buffer. Moreover, by temporary heat inactivation of the host restriction enzyme, a transformation efficiency of 8.94 +/- 0.77 * 10(5) cfu/MUg DNA was achieved with xenogeneic shuttle plasmids, a 10(3)-fold increase compared to that reported previously. The optimized protocol was also applicable to other recalcitrant B. amyloliquefaciens strains used in this study. This work could shed light on the functional genomics and subsequent strain improvement of the recalcitrant Bacillus, which are difficult to be transformed using conventional methods. PMID- 20951111 TI - Saline and buffers minimize the action of interfering factors in the bacterial endotoxins test. AB - The bacterial endotoxins test (BET) is the most sensitive assay for measuring endotoxin levels in solution. However, it is difficult to quantify endotoxin levels in some solutions because unknown interfering factors may inhibit or enhance the Limulus amebocyte lysate (LAL) coagulation reaction. We investigated the mechanisms of this interference and found that interference can be reduced or totally suppressed by preparing sample solutions in saline, Dulbecco's phosphate buffered saline (D-PBS), N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), or 2-amino-2-hydroxymethyl-1,3-propanediol (Tris) buffers. We examined the inhibitory effect on the interfering action of various reagents. The reagents examined were classified into two groups: a weak interference and a strong interference group. The interference of the strong interference group was suppressed by adding endotoxin and the test factors to LAL individually. Endotoxin peaks analyzed by gel-filtration HPLC disappeared in the presence of interfering factors. When buffers were used to prepare sample solutions instead of water, endotoxin peaks were maintained and interference with LAL reaction was suppressed. These results indicate that for the strong interference group, interference of the LAL reaction was a direct consequence of interfering factors binding to endotoxin. This alters endotoxin complexation, but this effect may be suppressed by preparing solutions in saline or other buffers instead of in water. PMID- 20951112 TI - Microfluidic immunosensor with gold nanoparticle platform for the determination of immunoglobulin G anti-Echinococcus granulosus antibodies. AB - This article describes a microfluidic immunosensor, developed for the detection of IgG antibodies specific to Echinococcus granulosus in human serum samples, which represents an alternative tool that can be used for the immunodiagnosis of hydatidosis in an automated way. Our device consists of a Plexiglas system with a central channel and a gold electrode. For immobilization of the E. granulosus antigen, a gold electrode was modified with the incorporation of gold nanoparticles. Immobilized antigen was allowed to react with IgG-anti-E. granulosus antibodies in samples, and these were quantified by horseradish peroxidase (HRP) enzyme-labeled secondary antibodies specific to human IgG using catechol (Q) as enzymatic mediator. HRP in the presence of hydrogen peroxide (H(2)O(2)) catalyzes the oxidation of Q to o-benzoquinone (P). The electrochemical reduction back to Q was detected on the gold electrode (AuE) at 0.15 V. The current obtained was proportional to the activity of the enzyme and to the concentration of antibodies of interest. The detection limit for electrochemical detection was 0.091 ng ml(-1), and the within- and between-assay coefficients of variation were below 6.7%. The proposed system presents many benefits, the more relevant are: reduced complexity and costs that are considered as the most wanted features for the clinical-immunodiagnostic field. PMID- 20951113 TI - Direct quantification of mitochondrial DNA and its 4.9-kb common deletion without DNA purification. AB - Quantitative analysis of mitochondrial DNA (mtDNA) and its common deletion (CD) are sensitive and early markers for mitochondrial mutations and suffering. However, the use of purified DNA can lead to quantification errors because of variable DNA extraction yields due to the significant differences in size and structure between genomic DNA (gDNA) and mtDNA. We report a real-time qPCR-based protocol directly on tissue lysate, without DNA extraction. This method, which allows both absolute and relative measure, increases the measuring accuracy of the mtDNA/gDNA ratio and leads to reliable and more reproducible results when measuring the deleted/total mtDNA ratio. PMID- 20951114 TI - Direct evidence for a phenylalanine site in the regulatory domain of phenylalanine hydroxylase. AB - The hydroxylation of phenylalanine to tyrosine by the liver enzyme phenylalanine hydroxylase is regulated by the level of phenylalanine. Whether there is a distinct allosteric binding site for phenylalanine outside of the active site has been unclear. The enzyme contains an N-terminal regulatory domain that extends through Thr117. The regulatory domain of rat phenylalanine hydroxylase was expressed in Escherichia coli. The purified protein behaves as a dimer on a gel filtration column. In the presence of phenylalanine, the protein elutes earlier from the column, consistent with a conformational change in the presence of the amino acid. No change in elution is seen in the presence of the non-activating amino acid proline. 1H-15N HSQC NMR spectra were obtained of the 15N-labeled protein alone and in the presence of phenylalanine or proline. A subset of the peaks in the spectrum exhibits chemical shift perturbation in the presence of phenylalanine, consistent with binding of phenylalanine at a specific site. No change in the NMR spectrum is seen in the presence of proline. These results establish that the regulatory domain of phenylalanine hydroxylase can bind phenylalanine, consistent with the presence of an allosteric site for the amino acid. PMID- 20951115 TI - Differences and similarities in binding of pyruvate and L-lactate in the active site of M4 and H4 isoforms of human lactate dehydrogenase. AB - We present QM/MM calculations that show differences in geometries of active sites of M(4) and H(4) isoforms of human LDH ligated with oxamate, pyruvate or L lactate. As the consequence of these differences, binding isotope effects of the methyl hydrogen atoms of pyruvate and l-lactate may be used to experimentally distinguish these isoforms. Based on the FEP calculations we argue that L-lactate is a better candidate for the experimental studies. Our calculations of energies of interactions of ligands with the active site residues provide explanation for the observed experimentally sensitivity to inhibition of the M(4) isoenzyme isoform and pinpoint the differences to interactions of the ligand with the histidine residue. We conclude that pyruvate interacts much stronger in the active site of H(4) than M(4) isoform and that the latter interactions are weaker than with water molecules in the aqueous solution. PMID- 20951116 TI - Stimulation of Na+/K+ ATPase activity and Na+ coupled glucose transport by beta catenin. AB - beta-Catenin is a multifunctional protein stimulating as oncogenic transcription factor several genes important for cell proliferation. beta-Catenin-regulated genes include the serum- and glucocorticoid-inducible kinase SGK1, which is known to stimulate a variety of transport systems. The present study explored the possibility that beta-catenin influences membrane transport. To this end, beta catenin was expressed in Xenopus oocytes with or without SGLT1 and electrogenic transport determined by dual electrode voltage clamp. As a result, expression of beta-catenin significantly enhanced the ouabain-sensitive current of the endogeneous Na(+)/K(+)-ATPase. Inhibition of vesicle trafficking by brefeldin A revealed that the stimulatory effect of beta-catenin on the endogenous Na(+)/K(+) ATPase was not due to enhanced stability of the pump protein in the cell membrane. Expression of beta-catenin further enhanced glucose-induced current (Ig) in SGLT1-expressing oocytes. In the absence of SGLT1 Ig was negligible irrespective of beta-catenin expression. The stimulating effect of beta-catenin on both Na(+)/K(+) ATPase and SGLT1 activity was observed even in the presence of actinomycin D, an inhibitor of transcription. The experiments disclose a completely novel function of beta-catenin, i.e. the regulation of transport. PMID- 20951117 TI - A harpin-induced ethylene-responsive factor regulates plant growth and responses to biotic and abiotic stresses. AB - Harpin protein induces disease resistance in diverse plant species. Transcriptome study of tomato (Solanum lycopersicum) genome indicated that harpin activated cellular events of transcription regulation, signaling transduction, stress response, membrane transporting, photosynthesis and cell wall biosynthesis. Among the harpin-induced genes, the expression of tomato ethylene-response factor 5 (designated as SlERF5) was induced to the highest level. The amino acid sequence of SlERF5 was closely related to that of CaEREBP-C4, NtERF4 and NsERF4. Overexpression of SlERF5 in Arabidopsis thaliana activated a large number of genes involved in signaling pathways of disease resistance, redox system, abiotic response and protein phosphorylation. Seedlings of transgenic plants exhibited hypersensitive response to exogenous ABA and increased tolerance to salt stress. In summary, the results of this study suggest that SlERF5 is a transcription activator for genes involved in the responses to ABA, biotic and abiotic stress. Thus, harpin may exert its effect on plant growth and defense response through activation of SlERF5 transcription factors. PMID- 20951118 TI - Sclerostin-erbB-3 interactions: modulation of erbB-3 activity by sclerostin. AB - To gain insights into the mechanism of action of sclerostin, a protein that regulates bone mass, we performed yeast two-hybrid analyses using human SOST (sclerostin) cDNA cloned into pGBKT7 DNA-binding domain vector as a bait, and a normalized, high-complexity, universal cDNA library in a GAL4 activating domain vector. We identified an interaction between sclerostin and the carboxyl-terminal portion of the receptor tyrosine-protein kinase erbB-3. To determine the biological relevance of this interaction, we treated MC3T3-E1 mouse osteoblast cells transfected with either a SOST expression plasmid or a control vector, with recombinant heregulin/neuregulin. Phospho-p44/42 (Thr202/Tyr204) MAPK was assessed in heregulin/neuregulin treated cells. We observed an increase in phospho-p44/42 (Thr202/Tyr204) MAPK concentrations in SOST transfected cells but not in cells transfected with a control vector, thus demonstrating a modulatory effect of sclerostin on heregulin/neuregulin signaling in osteoblasts. The data demonstrate that sclerostin functions in part, by modulating the activity of erbB 3. PMID- 20951119 TI - Targeting maladaptive glutathione responses in lung disease. AB - The lung is unique being exposed directly to the atmospheric environment containing xenobiotics, pathogens, and other agents which are continuously inhaled on a daily basis. Additionally, the lung is exposed to higher ambient oxygen levels which can promote the formation of a complex number of reactive oxygen and nitrogen species. Due to this constant barrage of potential damaging agents, the lung has developed a high degree of plasticity in dealing with ever changing conditions. In the present commentary, we will focus on glutathione (GSH) as a key antioxidant in the lung airways and discuss mechanisms by which the lung uses GSH to adapt to its rapidly changing environment. We will then examine the evidence on how defective and inadequate adaptive responses can lead to lung injury, inflammation and disease. Lastly, we will examine some of the recent attempts to alter lung GSH levels with therapies in a number of human lung diseases and discuss some of the limitations of such approaches. PMID- 20951120 TI - Ameliorative potential of S-allyl cysteine on oxidative stress in STZ induced diabetic rats. AB - Increased oxidative stress and impaired antioxidant defense mechanism are important factors in the pathogenesis and progression of diabetes mellitus and other oxidant-related diseases. The present study was undertaken to evaluate the possible protective effects of S-allyl cysteine (SAC) against oxidative stress in streptozotocin (STZ) induced diabetic rats. SAC was administered orally for 45 days to control and STZ induced diabetic rats. The effects of SAC on glucose, plasma insulin, thiobarbituric acid reactive substances (TBARS), hydroperoxide, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), oxidized glutathione (GSSG) and GSH/GSSG ratio were studied. The levels of glucose, TBARS, hydroperoxide, and GSSG were increased significantly whereas the levels of plasma insulin, reduced glutathione, GSH/GSSG ratio, superoxide dismutase, catalase and GPx were decreased in STZ induced diabetic rats. Administration of SAC to diabetic rats showed a decrease in plasma glucose, TBARS, hydroperoxide and GSSG. In addition, the levels of plasma insulin, superoxide dismutase, catalase, GPx and reduced glutathione (GSH) were increased in SAC treated diabetic rats. The above findings were supported by histological observations of the liver and kidney. The antioxidant effect of SAC was compared with glyclazide, a well-known antioxidant and antihyperglycemic drug. The present study indicates that the SAC possesses a significant favorable effect on antioxidant defense system in addition to its antidiabetic effect. PMID- 20951121 TI - The serum levels of Receptor Activator of Nuclear Factor-kappaB Ligand, bone specific alkaline phosphatase, osteocalcin and osteoprotegerin do not correlate with the radiographically assessed severity of idiopathic hip and knee osteoarthritis. AB - OBJECTIVES: Determination of the serum levels of Receptor Activator of Nuclear Factor-Kappab Ligand, bone-specific alkaline phosphatase, osteocalcin and osteoprotegerin in patients suffering from osteoarthritis of varying severity and healthy controls and correlation of these results with the patients' age and the radiographically assessed severity of the disease. DESIGN AND METHODS: Patients suffering from hip (n=58) or knee (n=117) osteoarthritis and matched controls (n=19) were enrolled in this study. Patients underwent physical examination and standard radiographic evaluation before blood sampling. RESULTS: The serum levels of osteoprotegerin were positively correlated with age in all groups, whereas those of osteocalcin in the 'knee' group only. Osteoarthritis' severity and location did not have a statistically significant impact on the mean serum level of any marker in both groups. CONCLUSIONS: Based on our results, none of the studied markers can serve as a surrogate for radiographic imaging in patients suffering from hip and knee osteoarthritis. PMID- 20951122 TI - The effect of cysteine and glutathione on sperm and oxidative stress parameters of post-thawed bull semen. AB - The aim of this study was to determine the effects of antioxidants such as reduced glutathione (GSH) and cysteine in Laiciphose(r) extender on semen parameters, fertilizing ability, lipid peroxidation (LPO) level and glutathione peroxidise (GPx) activity of post-thawed bull semen. Totally 54 ejaculates of three bulls were used in the study. Five groups, namely; GSH (0.5 and 2 mM), cysteine (5 and 10 mM) and control group, were conducted to test the antioxidants in Laiciphose(r). Insemination doses were processed that each 0.25-mL straw contained 15 x 106 sperm. The addition of antioxidants did not present any significant effect on the percentages of post-thaw sperm morphology (acrosome and total abnormalities), subjective, CASA and progressive motilities, as well as sperm motility characteristics (VAP, VSL, VCL, LIN and ALH), compared to the control groups (P > 0.05). GSH 0.5mM (55.5+/-7.38%) and cysteine 10 mM (48+/ 5.65%) led to lower rates of DNA damage, compared to control (P < 0.05). As regards to MDA level, cysteine at 10 mM dose gave the highest level (4.99+/-0.44 nmol/L) (P < 0.001). GPx activity was demonstrated to be higher level upon the addition of 5 mM cysteine when compared to the other groups (P < 0.05). With respect to fertility results based on 60-day non-returns, the supplementation of antioxidants did not present significant differences (P > 0.05). The results of this study may provide an useful information for the future studies in this area. So, further studies could be suggested to achieve better information in terms of the DNA damage and fertilizing capacity of bull sperm frozen with effective antioxidants. PMID- 20951123 TI - Resveratrol protects human keratinocytes HaCaT cells from UVA-induced oxidative stress damage by downregulating Keap1 expression. AB - Ultraviolet radiation A (UVA)-induced oxidative stress is recognized as an important factor in the development of skin carcinogenesis. Resveratrol is demonstrated to possess remarkable antioxidant activity in the organism. The aim of this study was to investigate the protective role of resveratrol in human keratinocytes (HaCaT) against UVA-induced oxidative damage and the possible mechanism of the translocation of NF-E2-related factor-2 (Nrf2) into the nucleus. The HaCaT cells were UVA-irradiated and the effects of resveratrol on cell viability, reactive oxygen species generation and membrane-lipid peroxidation were measured. The proteins and mRNA of Nrf2 and Kelch-like-ECH-associated protein 1 (Keap1) were determined by immunofluorescence staining, Western blot and quantitative PCR, respectively. UVA exposure led to a decrease in viability and an increase in reactive oxygen species generation in HaCaT cells. Resveratrol could effectively increase the viability of HaCaT cells after UVA exposure and protect them from UVA-induced oxidative stress. Moreover, resveratrol increased the level of Nrf2 protein and facilitated Nrf2 accumulation in the nucleus; as a result, the activity of antioxidant enzymes was also upregulated. The main finding was that Keap1 protein, a repressor of Nrf2 in the cytoplasm, was clearly decreased by resveratrol treatment 12h and beyond though the level of Keap1 mRNA still increased. Our results suggest that resveratrol can degrade Keap1 protein and facilitate Nrf2 accumulation in the nucleus, thereby protecting HaCaT cells from UVA-induced oxidative stress. Resveratrol could be a more useful natural medicine for the protection of epidermal cells from UVA-induced damage. PMID- 20951124 TI - Differential effects of two major neurosteroids on cerebellar and cortical GABA(A) receptor binding and function. AB - Cerebellar and cerebrocortical A-type gamma-aminobutyric acid (GABA(A)) receptors were examined in mice and rats. In wild-type mouse cerebellum, the agonists GABA and gaboxadol exerted heterogeneous displacement of [(3)H]ethynylbicycloorthobenzoate (EBOB) binding with nanomolar and submicromolar affinities. In mouse cerebella lacking alpha6 subunits (alpha6KO), nanomolar displacement by GABA agonists was absent, while micromolar displacement was potentiated to 12-fold by 0.3MUM 5alpha-tetrahydrodeoxycorticosterone (5alpha THDOC). In alpha6KO cerebellum, 60% of [(3)H]EBOB binding was neurosteroid insensitive, while 5alpha-THDOC elicited enhancement with EC(50)=150nM instead of nanomolar displacement. In conclusion, nanomolar displacement of cerebellar [(3)H]EBOB binding by GABA agonists and neurosteroids can be attributed to GABA(A) receptors containing alpha6 and delta subunits. In contrast, [(3)H]EBOB binding to rat cerebral cortex was affected by allopregnanolone and 5alpha-THDOC in bidirectional manner with nanomolar enhancement (EC(50) ~80nM) and micromolar displacement. Nonequilibrium binding conditions with decreased incubation time tripled the maximal enhancement of [(3)H]EBOB binding by 5alpha-THDOC. 5beta THDOC enhanced the cortical [(3)H]EBOB binding with EC(50) ~0.5MUM and it attenuated bidirectional modulation by 5alpha-THDOC. Allopregnanolone and 5alpha THDOC produced biphasic enhancements of chloride currents elicited by 1MUM GABA in cerebellar granule cells, for 5alpha-THDOC with EC(50,1) ~16nM and EC(50,2) ~1.3MUM. Differences in peak current enhancements in the absence minus presence of 0.1mM furosemide corresponding to alpha6betadelta GABA(A) receptors were augmented only by micromolar 5alpha-THDOC while the difference curve for allopregnanolone was polyphasic as without furosemide. Consequently, these neurosteroids differentially affected the binding and function of various GABA(A) receptor populations. PMID- 20951125 TI - Gly-Ala-Gly-Val-Gly-Tyr, a novel synthetic peptide, improves glucose transport and exerts beneficial lipid metabolic effects in 3T3-L1 adipoctyes. AB - Recently, it has been demonstrated that fibroin and fibroin-derived peptides enhances insulin sensitivity and glucose metabolism in adipocytes. Here, we show that a synthetic hexapeptide Gly-Ala-Gly-Val-Gly-Tyr (GAGVGY) derived from repetitive amino acid sequence of fibroin improves glucose transport and exerts beneficial lipid metabolic effects in 3T3-L1 adipocytes. GAGVGY increases both basal and insulin-stimulated glucose uptake through enhancement of GLUT1 expression and PI 3-K-dependent GLUT4 translocation, respectively. GAGVGY treatment also led to a significant reduction in the expression of lipogenic genes including sterol regulatory element binding protein-1c (SREBP1c), peroxisome proliferator-activated receptor-gamma (PPARgamma), and fatty acid synthase (FAS) in mature 3T3-L1 adipocytes, which was corroborated with decreased lipid accumulation by GAGVGY treatment. Additionally, in cells undergoing differentiation, mRNA levels of adipogenic genes including PPARgamma and CCAAT/enhancer binding protein alpha (C/EBPalpha), stearoyl-CoA desaturase 1 (SCD1), and FAS were suppressed by GAGVGY. Furthermore, GAGVGY increased AMP activated protein kinase (AMPK) phosphorylation and adiponectin secretion in 3T3 L1 adipocytes. The latter effect was supported with evidence showing increased AMPK activation in C2C12 myocytes treated with 3T3-L1-adipocyte-conditioned medium. Together, our data suggest that GAGVGY has multiple beneficial effects on glucose and lipid metabolism, and would control hyperglycemia without the adverse effect of weight gain. PMID- 20951126 TI - Activation of p38 MAPK by damnacanthal mediates apoptosis in SKHep 1 cells through the DR5/TRAIL and TNFR1/TNF-alpha and p53 pathways. AB - The effect of the natural compound damnacanthal from Morinda citrifolia on SKHep 1 cell growth regulation was investigated. Treatment of SKHep 1 cells with damnacanthal for 24h indicated a dose-dependent antiproliferative activity. Damnacanthal seems to be selective for tumor cell lines, since there is only minimal toxicity against normal hepatocyte cells (FL83B). This is first demonstration that damnacanthal-mediated apoptosis involves the sustained activation of the p38 MAPK pathway, leading to the transcription of the death receptor family genes encoding DR5/TRAIL and TNF-R1/TNF-alpha genes as well as the p53-regulated Bax gene. The damnacanthal-mediated expression of DR5/TRAIL and TNF-R1/TNF-alpha results in caspase 8 activation, leading to Bid cleavage. In turn, activated Bid, acting with p53-regulated Bax, leads to cytochrome c released from mitochondria into the cytoplasm. Combined activation of the death receptors and mitochondrial pathways results in activation of the downstream effecter caspase 3, leading to cleavage of PARP. TRAIL- and TNF-alpha-mediated damnacanthal-induced apoptosis could be suppressed by treatment with caspase inhibitors as well as soluble death receptors Fc:DR5 and Fc:TNF-R1 chimera. Taken together, this study provided first evidence demonstrating that TRAIL-, TNF-alpha , and p53-mediated damnacanthal-induced apoptosis require the activation of p38 MAPK and mitochondrion-mediated caspase-dependent pathways. PMID- 20951127 TI - Psoralidin inhibits LPS-induced iNOS expression via repressing Syk-mediated activation of PI3K-IKK-IkappaB signaling pathways. AB - Psoralidin has been reported to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production, but the mechanisms of the action remain unclear. Thus, the impact of psoralidin on signaling pathways known to be implicated in NO synthesis was explored in LPS-activated RAW264.7 macrophages by using RT-PCR and Western blotting. Consistent with NO inhibition, psoralidin suppressed LPS-induced expression of inducible NO synthase (iNOS) by abolishing IkappaB kinase (IKK) phosphorylation, IkappaB degradation and nuclear factor kappaB (NF-kappaB) nuclear translocation without effecting mitogen-activated protein kinases (MAPKs) phosphorylation. Exposure to wortmannin abrogated IKK/IkappaB/NF-kappaB-mediated iNOS expression, suggesting activation of such a signal pathway might also be phosphoinositide-3-kinase (PI3K) dependent. By using Src inhibitor PP2, Janus kinase 2 (JAK-2) inhibitor AG490, Bruton's tyrosine kinase (Btk) inhibitor LFM A13 and spleen tyrosine kinase (Syk) inhibitor piceatannol, the results showed that piceatannol clearly repressed NO production more potently than the other inhibitors. Furthermore, piceatannol significantly repressed LPS-induced PI3K/Akt phosphorylation and the downstream IKK/IkappaB activation, suggesting that Syk is an upstream key regulator in the activation of PI3K/Akt-mediated signaling. In fact, transfection with siRNA targeting Syk obviously reduced iNOS expression. Interestingly, LPS-induced phosphorylations of Syk and PI3K-p85 were both significantly blunted by psoralidin treatment. The present results show that interfering with Syk-mediated PI3K phosphorylation might contribute to the NO inhibitory effect of psoralidin via blocking IKK/IkappaB signaling propagation in LPS-stimulated RAW 264.7 macrophages. PMID- 20951129 TI - Suppression of nitric oxide synthesis by L-NAME reverses the beneficial effects of pioglitazone on scopolamine-induced memory impairment in mice. AB - Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma (PPARgamma), which is widely used in treatment of type 2 diabetes, has shown some therapeutic effect in Alzheimer's disease. In this study, effects of acute pioglitazone on acquisition, consolidation and retrieval of memory, and also the involvement of nitric oxide (NO) in the effects of pioglitazone on spatial recognition memory has been investigated in a two-trial recognition Y-maze test and passive avoidance in mice. Memory impairment was induced by scopolamine (1mg/kg, i.p.). Pioglitazone (10 and 20mg/kg, p.o.) was administrated prior to either acquisition, consolidation or retention trials, while L-NAME (N-nitro-l arginine methyl ester), a non-specific NO synthase inhibitor, was administered (10mg/kg, i.p.) 30min before each trial. RESULTS: 1) pioglitazone improved the acquisition of recognition spatial memory-impaired by scopolamine; L-NAME dramatically reversed improving effects of pioglitazone on memory acquisition; 2) pioglitazone did not change the consolidation of spatial memory, impaired by scopolamine; 3) pioglitazone improved the retrieval of spatial memory and L-NAME did not alter the beneficial effect of pioglitazone; 4) pioglitazone did not affect scopolamine-induced cognitive impairments in the passive avoidance test. The present study demonstrates the beneficial effect of acute pioglitazone administration on acquisition and retrieval of scopolamine-induced cognitive deficits. This effect was reversed only in acquisition phase by nitric oxide synthase inhibitor, L-NAME, therefore, it could be concluded that NO might be involved in the pioglitazone beneficial effect of spatial memory acquisition. PMID- 20951128 TI - Tetrahydroxystilbene glucoside, a plant-derived cognitive enhancer, promotes hippocampal synaptic plasticity. AB - Plant or food derived polyphenols have received a great deal of attention due to their biological properties including anti-oxidative effects, neuroprotection and memory enhancement. Here, we investigated the roles of 2,3,5,4' tetrahydroxystilbene-2-O-beta-d-glucoside (TSG), an active component of the rhizome extracted from Polygonum multiflorum, in the regulation of hippocampal synaptic plasticity in normal mice as well as the underlying mechanisms. It was shown that TSG promoted the differentiation of PC12 cells and increased the intracellular calcium level in hippocampal neurons. TSG facilitated high frequency stimulation (HFS)-induced hippocampal long-term potentiation (LTP) in a bell-shaped manner. The facilitation of LTP induction by TSG required calcium/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal regulated kinase (ERK) activation. Taken together, our data demonstrate that TSG promotes LTP induction and this effect may contribute to the enhancement of learning and memory seen in animal models. PMID- 20951130 TI - The glucagon-like peptide 1 receptor agonist exendin-4 improves reference memory performance and decreases immobility in the forced swim test. AB - We have earlier shown that the glucagon-like peptide 1 receptor agonist exendin-4 stimulates neurogenesis in the subventricular zone and excerts anti-parkinsonian behavior. The aim of this study was to assess the effects of exendin-4 treatment on hippocampus-associated cognitive and mood-related behavior in adult rodents. To investigate potential effects of exendin-4 on hippocampal function, radial maze and forced swim test were employed. The time necessary to solve a radial maze task and the duration of immobility in the forced swim test were significantly reduced compared to respective vehicle groups if the animals had received exendin-4 during 1-2weeks before testing. In contrast to the positive control imipramine, single administration of exendin-4 1h before the challenge in the forced swim test had no effect. Immunohistochemical analysis showed that the incorporation of bromodeoxyuridine, a marker for DNA synthesis, as well as doublecortin expression was increased in the hippocampal dentate gyrus following chronic treatment with exendin-4 compared to vehicle-treated controls. The neurogenic effect of exendin-4 on hippocampus was confirmed by quantitative PCR showing an upregulation of mRNA expression for Ki-67, doublecortin and Mash-1. Since exendin-4 significantly improves hippocampus-associated behavior in adult rodents, it may be a candidate for alleviation of mood and cognitive disorders. PMID- 20951131 TI - Crocetin prevents retinal degeneration induced by oxidative and endoplasmic reticulum stresses via inhibition of caspase activity. AB - Crocetin is a carotenoid that is the aglicone of crocin, which are found in saffron stigmas (Crocus sativus L.) and gardenia fruit (Gardenia jasminoides Ellis). In this study, we investigated the effects of crocetin on retinal damage. To examine whether crocetin affects stress pathways, we investigated intracellular oxidation induced by reactive oxygen species, expression of endoplasmic reticulum (ER) stress-related proteins, disruption of the mitochondrial membrane potential (DeltaPsi(m)), and caspases activation. In vitro, we employed cultured retinal ganglion cells (RGC-5, a mouse ganglion cell line transformed using E1A virus). Cell damage was induced by tunicamycin or hydrogen peroxide (H(2)O(2)) exposure. Crocetin at a concentration of 3MUM showed the inhibitory effect of 50-60% against tunicamycin- and H(2)O(2)-induced cell death and inhibited increase in caspase-3 and -9 activity. Moreover, crocetin inhibited the enzymatic activity of caspase-9 in a cell-free system. In vivo, retinal damage in mice was induced by exposure to white light at 8000lx for 3h after dark adaptation. Photoreceptor damage was evaluated by measuring the outer nuclear layer thickness at 5days after light exposure and recording the electroretinogram (ERG). Retinal cell damage was also detected with Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining at 48h after light exposure. Crocetin at 100mg/kg, p.o. significantly inhibited photoreceptor degeneration and retinal dysfunction and halved the expression of TUNEL-positive cells. These results indicate that crocetin has protective effects against retinal damage in vitro and in vivo, suggesting that the mechanism may inhibit increase in caspase-3 and -9 activities after retinal damage. PMID- 20951132 TI - Extracellular engagement of ADAM12 induces clusters of invadopodia with localized ectodomain shedding activity. AB - Invadopodia are dynamic actin structures at the cell surface that degrade extracellular matrix and act as sites of signal transduction. The biogenesis of invadopodia, including the mechanisms regulating their formation, composition, and turnover is not entirely understood. Here, we demonstrate that antibody ligation of ADAM12, a transmembrane disintegrin and metalloprotease, resulted in the rapid accumulation of invadopodia with extracellular matrix-degrading capacity in epithelial cells expressing the alphavbeta3 integrin and active c-Src kinase. The induction of invadopodia clusters required an intact c-Src interaction site in the ADAM12 cytoplasmic domain, but was independent of the catalytic activity of ADAM12. Caveolin-1 and transmembrane protease MMP14/MT1-MMP were both present in the ADAM12-induced clusters of invadopodia, and cholesterol depletion prevented their formation, suggesting that lipid-raft microdomains are involved in the process. Importantly, our data demonstrate that ADAM12-mediated ectodomain shedding of epidermal growth factor receptor ligands can occur within these invadopodia. Such localized growth factor signalling offers an interesting novel biological concept highly relevant to the properties of carcinoma cells, which often show upregulated ADAM12 and beta3 integrin expression, together with high levels of c-Src kinase activity. PMID- 20951134 TI - A conserved gene cluster as a putative functional unit in insect innate immunity. AB - The Nimrod gene superfamily is an important component of the innate immune response. The majority of its member genes are located in close proximity within the Drosophila melanogaster genome and they lie in a larger conserved cluster ("Nimrod cluster"), made up of non-related groups (families, superfamilies) of genes. This cluster has been a part of the Arthropod genomes for about 300-350 million years. The available data suggest that the Nimrod cluster is a functional module of the insect innate immune response. PMID- 20951135 TI - The rank product method with two samples. AB - Breitling et al. (2004) introduced a statistical technique, the rank product method, for detecting differentially regulated genes in replicated microarray experiments. The technique has achieved widespread acceptance and is now used more broadly, in such diverse fields as RNAi analysis, proteomics, and machine learning. In this note, we extend the rank product method to the two sample setting, provide distribution theory attending the rank product method in this setting, and give numerical details for implementing the method. PMID- 20951133 TI - Cellular inhibitor of apoptosis 1 (cIAP-1) degradation by caspase 8 during TNF related apoptosis-inducing ligand (TRAIL)-induced apoptosis. AB - TNF-related apoptosis-inducing ligand (TRAIL) is a potential chemotherapeutic agent with high selectivity for malignant cells. Many tumors, however, are resistant to TRAIL cytotoxicity. Although cellular inhibitors of apoptosis 1 and 2 (cIAP-1 and -2) are often over-expressed in cancers, their role in mediating TRAIL resistance remains unclear. Here, we demonstrate that TRAIL-induced apoptosis of liver cancer cells is associated with degradation of cIAP-1 and X linked IAP (XIAP), whereas cIAP-2 remains unchanged. Lower concentrations of TRAIL causing minimal or no apoptosis do not alter cIAP-1 or XIAP protein levels. Silencing of cIAP-1 expression, but not XIAP or cIAP-2, as well as co-treatment with a second mitochondrial activator of caspases (SMAC) mimetic (which results in rapid depletion of cIAP-1), sensitizes the cells to TRAIL. TRAIL-induced loss of cIAP-1 and XIAP requires caspase activity. In particular, caspase 8 knockdown stabilizes both cIAP-1 and XIAP, while caspase 9 knockdown prevents XIAP, but not cIAP-1 degradation. Cell-free experiments confirmed cIAP-1 is a substrate for caspase 8, with likely multiple cleavage sites. These results suggest that TRAIL mediated apoptosis proceeds through caspase 8-dependent degradation of cIAP-1. Targeted depletion of cIAP-1 by SMAC mimetics in conjunction with TRAIL may be beneficial for the treatment of human hepatobiliary malignancies. PMID- 20951136 TI - Site-specific cleavage of the 40S ribosomal subunit reveals eukaryote-specific ribosomal protein S28 in the subunit head. AB - After resolving the crystal structure of the prokaryotic ribosome, mapping the proteins in the eukaryotic ribosome is a challenging task. We applied RNase H digestion to split the human 40S ribosomal subunit into head and body parts. Mass spectrometry of the proteins in the 40S subunit head revealed the presence of eukaryote-specific ribosomal protein S28e. Recombinant S28e was capable of specific binding to the 3' major domain of the 18S rRNA (K(a)=8.0+/-0.5*10(9) M( 1)). We conclude that S28e has a binding site on the 18S rRNA within the 40S subunit head. PMID- 20951138 TI - Sumoylation by Ubc9 regulates the stem cell compartment and structure and function of the intestinal epithelium in mice. AB - BACKGROUND & AIMS: Small ubiquitin-like modifiers (SUMOs) are attached to other proteins to regulate their function (sumoylation). We investigated the role of Ubc9, which covalently attaches SUMOs to proteins, in the gastrointestinal tract of adult mice. METHODS: We investigated the effects of decreased sumoylation in adult mammals by generating mice with an inducible knockout (by injection of 4 hydroxytamoxifen) of the E2 enzyme Ubc9 (Ubc9fl/-/ROSA26-CreERT2 mice). We analyzed the phenotypes using a range of histologic techniques. RESULTS: Loss of Ubc9 from adult mice primarily affected the small intestine. Ubc9fl/-/ROSA26 CreERT2 mice died within 6 days of 4-hydroxytamoxifen injection, losing 20% or less of their body weight and developing severe diarrhea on the second day after injection. Surprisingly, other epithelial tissues appeared to be unaffected at that stage. Decreased sumoylation led to the depletion of the intestinal proliferative compartment and to the rapid disappearance of stem cells. Sumoylation was required to separate the proliferative and differentiated compartments from the crypt and control differentiation and function of the secretory lineage. Sumoylation was required for nucleus positioning and polarized organization of actin in the enterocytes. Loss of sumoylation caused detachment of the enterocytes from the basal lamina, as observed in tissue fragility diseases. We identified the intermediate filament keratin 8 as a SUMO substrate in epithelial cells. CONCLUSIONS: Sumoylation maintains intestinal stem cells and the architecture, mechanical stability, and function of the intestinal epithelium of mice. PMID- 20951139 TI - Diseases of commercially exploited crustaceans: cross-cutting issues for global fisheries and aquaculture. PMID- 20951137 TI - Colitis and intestinal inflammation in IL10-/- mice results from IL-13Ralpha2 mediated attenuation of IL-13 activity. AB - BACKGROUND & AIMS: The cytokine interleukin (IL)-10 is required to maintain immune homeostasis in the gastrointestinal tract. IL-10 null mice spontaneously develop colitis or are more susceptible to induction of colitis by infections, drugs, and autoimmune reactions. IL-13 regulates inflammatory conditions; its activity might be compromised by the IL-13 decoy receptor (IL-13Ralpha2). METHODS: We examined the roles of IL-13 and IL-13Ralpha2 in intestinal inflammation in mice. To study the function of IL-13Ralpha2, il10(-/-) mice were crossed with il13ralpha2(-/-) to generate il10(-/-)il13ralpha2(-/-) double knockout (dKO) mice. Colitis was induced with the gastrointestinal toxin piroxicam or Trichuris muris infection. RESULTS: Induction of colitis by interferon (IFN)-gamma or IL-17 in IL-10 null mice requires IL-13Ralpha2. Following exposure of il10(-/-) mice to piroxicam or infection with T muris, production of IL-13Ralpha2 increased, resulting in decreased IL-13 bioactivity and increased inflammation in response to IFN-gamma or IL-17A. In contrast to il10(-/-) mice, dKO mice were resistant to piroxicam-induced colitis; they also developed less severe colitis during chronic infection with T muris infection. In both models, resistance to IFN-gamma and IL-17-mediated intestinal inflammation was associated with increased IL-13 activity. Susceptibility to colitis was restored when the dKO mice were injected with monoclonal antibodies against IL 13, confirming its protective role. CONCLUSIONS: Colitis and intestinal inflammation in IL10(-/-) mice results from IL-13Ralpha2-mediated attenuation of IL-13 activity. In the absence of IL-13Ralpha2, IL-13 suppresses proinflammatory Th1 and Th17 responses. Reagents that block the IL-13 decoy receptor IL-13Ralpha2 might be developed for inflammatory bowel disease associated with increased levels of IFN-gamma and IL-17. PMID- 20951140 TI - Delineation of the complement receptor type 2-C3d complex by site-directed mutagenesis and molecular docking. AB - The interactions between the complement receptor type 2 (CR2) and the C3 complement fragments C3d, C3dg, and iC3b are essential for the initiation of a normal immune response. A crystal-derived structure of the two N-terminal short consensus repeat (SCR1-2) domains of CR2 in complex with C3d has previously been elucidated. However, a number of biochemical and biophysical studies targeting both CR2 and C3d appear to be in conflict with these structural data. Previous mutagenesis and heteronuclear NMR spectroscopy studies directed toward the C3d binding site on CR2 have indicated that the CR2-C3d cocrystal structure may represent an encounter/intermediate or nonphysiological complex. With regard to the CR2-binding site on C3d, mutagenesis studies by Isenman and coworkers [Isenman, D. E., Leung, E., Mackay, J. D., Bagby, S. & van den Elsen, J. M. H. (2010). Mutational analyses reveal that the staphylococcal immune evasion molecule Sbi and complement receptor 2 (CR2) share overlapping contact residues on C3d: Implications for the controversy regarding the CR2/C3d cocrystal structure. J. Immunol. 184, 1946-1955] have implicated an electronegative "concave" surface on C3d in the binding process. This surface is discrete from the CR2-C3d interface identified in the crystal structure. We generated a total of 18 mutations targeting the two (X-ray crystallographic- and mutagenesis-based) proposed CR2 SCR1-2 binding sites on C3d. Using ELISA analyses, we were able to assess binding of mutant forms of C3d to CR2. Mutations directed toward the concave surface of C3d result in substantially compromised CR2 binding. By contrast, targeting the CR2-C3d interface identified in the cocrystal structure and the surrounding area results in significantly lower levels of disruption in binding. Molecular modeling approaches used to investigate disparities between the biochemical data and the X-ray structure of the CR2-C3d cocrystal result in highest-scoring solutions in which CR2 SCR1-2 is docked within the concave surface of C3d. PMID- 20951141 TI - Size-independent and noncooperative recognition of dsRNA by the Rice stripe virus RNA silencing suppressor NS3. AB - Plant and animal viruses employ diverse suppressor proteins to thwart the host antiviral reaction of RNA silencing. Many suppressors bind dsRNA with different size specificity. Here, we examine the dsRNA recognition mechanism of the Rice stripe virus NS3 suppressor using quantitative biochemical approaches, as well as mutagenesis and suppression activity analyses in plants. We show that dimeric NS3 is a size-independent, rather than small interfering RNA-specific, dsRNA-binding protein that recognizes a minimum of 9 bp and can bind to long dsRNA with two or more copies. Global analysis using a combinatorial approach reveals that NS3 dimer has an occluded site size of ~ 13 bp on dsRNA, an intrinsic binding constant of 1 * 10(8) M(-1), and virtually no binding cooperativity. This lack of cooperativity suggests that NS3 is not geared to target long dsRNA. The larger site size of NS3, compared with its interacting size, indicates that the NS3 structure has a border region that has no direct contact with dsRNA but occludes a ~ 4-bp region from binding. We also develop a method to correct the border effect of ligand by extending the lattice length. In addition, we find that NS3 recognizes the helical structure and 2'-hydroxyl group of dsRNA with moderate specificity. Analysis of dsRNA-binding mutants suggests that silencing of the suppression activity of NS3 is mechanistically related to its dsRNA binding ability. PMID- 20951143 TI - A matrix computational approach to kinesin neck linker extension. AB - Kinesin stepping requires both tethered diffusion of the free head and conformational changes driven by the chemical state of the motor. We present a numerical method using matrix representations of approximating Markov chains and renewal theory to compute important experimental quantities for models that include both tethered diffusion and chemical transitions. Explicitly modeling the tethered diffusion allows for exploration of the model under perturbation of the neck linker; comparisons are made between the computed models and in vitro assays. PMID- 20951142 TI - Crystal structures of the glutamate receptor ion channel GluK3 and GluK5 amino terminal domains. AB - Ionotropic glutamate receptors (iGluRs) mediate the majority of fast excitatory synaptic neurotransmission in the central nervous system. The selective assembly of iGluRs into AMPA, kainate, and N-methyl-d-aspartic acid (NMDA) receptor subtypes is regulated by their extracellular amino-terminal domains (ATDs). Kainate receptors are further classified into low-affinity receptor families (GluK1-GluK3) and high-affinity receptor families (GluK4-GluK5) based on their affinity for the neurotoxin kainic acid. These two families share a 42% sequence identity for the intact receptor but only a 27% sequence identity at the level of ATD. We have determined for the first time the high-resolution crystal structures of GluK3 and GluK5 ATDs, both of which crystallize as dimers but with a strikingly different dimer assembly at the R1 interface. By contrast, for both GluK3 and GluK5, the R2 domain dimer assembly is similar to those reported previously for other non-NMDA iGluRs. This observation is consistent with the reports that GluK4-GluK5 cannot form functional homomeric ion channels and require obligate coassembly with GluK1-GluK3. Our analysis also reveals that the relative orientation of domains R1 and R2 in individual non-NMDA receptor ATDs varies by up to 10 degrees , in contrast to the 50 degrees difference reported for the NMDA receptor GluN2B subunit. This restricted domain movement in non-NMDA receptor ATDs seems to result both from extensive intramolecular contacts between domain R1 and domain R2 and from their assembly as dimers, which interact at both R1 and R2 domains. Our results provide the first insights into the structure and function of GluK4-GluK5, the least understood family of iGluRs. PMID- 20951144 TI - Mathematical modeling of allergy and specific immunotherapy: Th1-Th2-Treg interactions. AB - Regulatory T cells (Treg) have recently been identified as playing a central role in the immune response to allergens and during allergen-specific immunotherapy. We have extended our previous mathematical model describing the nonlinear dynamics of Th1-Th2 regulation by including Treg cells and their major cytokines. We hypothesize that immunotherapy mainly acts on the T cell level and that the decisive process can be regarded as a dynamical phenomenon. The model consists of nonlinear differential equations which describe the proliferation and mutual suppression of different T cell subsets. The old version of the model was based upon the Th1-Th2 paradigm and is successful in describing the "Th1-Th2 switch" which was considered to be the decisive event during specific immunotherapy. In recent years, however, the Th1-Th2 paradigm has been questioned and therefore, we have investigated a modified model in order to account for the influence of a regulatory T cell type. We examined the extended model by means of numerical simulations and analytical methods. As the modified model is more complex, we had to develop new methods to portray its characteristics. The concept of stable manifolds of fixed points of a stroboscobic map turned out to be especially important. We found that when including regulatory T cells, our model can describe the events in allergen-specific immunotherapy more accurately. Our results suggest that the decisive effect of immunotherapy, the increased proliferation of Treg and suppression of Th2 cells, crucially depends on the administration of high dose injections in short intervals right before the maintenance phase sets in. Empirical protocols could therefore be improved by optimizing this step of therapy. PMID- 20951146 TI - Curative effects of hydrogen sulfide against acetaminophen-induced hepatotoxicity in mice. AB - AIMS: Hydrogen sulfide (H(2)S), an endogenous gaseous mediator, plays an important role in regulation of many physiological and pathological processes. On the other hand, acetaminophen overdose is a major cause of drug-induced liver failure. The aim of this study therefore is to evaluate the possible curative effects of H(2)S against acetaminophen-induced hepatotoxicity. MAIN METHODS: Male Swiss mice were treated with sodium hydrogen sulfide, a H(2)S donor, 30 min after acetaminophen administration. N-acetylcysteine, a therapeutic antidote, was used as a reference drug. KEY FINDINGS: H(2)S treatment resulted in hepatocurative effects as evident by a significant decrease in serum alanine aminotransferase and hepatic malondialdehyde and nitric oxide levels, with a concurrent increase in hepatic glutathione content compared to acetaminophen-treated group. H(2)S did not alter catalase activity. Additionally, immunohistochemical analysis demonstrated that H(2)S treatment markedly reduced tumor necrosis factor-alpha expression, while expression of cyclooxygenase-2 was markedly enhanced with nuclear localization into hepatocytes. The curative effects of H(2)S were confirmed by liver histopathological examination and were maintained in the presence of glibenclamide, an antagonist of ATP-sensitive potassium (K(ATP)) channels. SIGNIFICANCE: H(2)S treatment markedly alleviates acetaminophen hepatotoxicity in mice possibly, in part, through anti-oxidative and anti inflammatory effects but not likely to be coupled with activation of K(ATP) channels. The hepatocurative effects of H(2)S are comparable to N-acetylcysteine. Hence, H(2)S has a potential therapeutic value for treatment of acetaminophen hepatotoxicity. PMID- 20951147 TI - Beneficial effect of risedronate on arterial thickening and stiffening with a reciprocal relationship to its effect on bone mass in female osteoporosis patients: a longitudinal study. AB - AIMS: A longitudinal study was performed to examine the effect of risedronate on arterial thickening and stiffening in postmenopausal female osteoporosis patients. MAIN METHODS: Patients treated with risedronate (2.5mg/day) (n=33) and those that did not receive risedronate (n=30, control group) were monitored over a 1-year period. Bone metabolic markers, bone mineral density (BMD) of the femur neck (FN), brachial-ankle pulse wave velocity (baPWV), and intima-media thickness at the carotid artery (CA-IMT) were measured. KEY FINDINGS: At baseline, there was no significant difference in blood pressure, serum lipid profiles, FN BMD, baPWV and CA-IMT between the risedronate-treated patients and the controls. Baseline levels of FN BMD were significantly negatively correlated with those of CA-IMT and baPWV. During the study, FN BMD increased significantly in the risedronate group (p=0.0097), but decreased significantly in the control group (p=0.0013). BaPWV and CA-IMT did not change significantly in the risedronate group, but both increased significantly in the control group. The percentage change in FN BMD over the study period showed a significant negative correlation with those for baPWV (r=-0.294, p=0.0262) and CA-IMT (r=-0.305, p=0.0234) in all subjects (risedronate-treated patients and controls). SIGNIFICANCE: In addition to increasing BMD, risedronate significantly suppressed the progression of arterial thickening and stiffening in postmenopausal osteoporotic patients over one year. These changes may indirectly be due to the effect of risedronate on bone. PMID- 20951145 TI - A prospective on drug abuse-associated epigenetics and HIV-1 replication. AB - Drugs of abuse serve as cofactors to susceptibility to HIV infection and disease progression. Although clinical reports indicate association between HIV/AIDS and drug use, the molecular mechanism of infection susceptibility and disease progression remains unclear. Drugs such as cocaine exert their addictive effects in part by epigenetic mechanisms. Given that epigenetic modifications play an important role in HIV-1 life cycle, it is essential to unravel whether drug abuse associated epigenetic changes may contribute to HIV/AIDS. In this article we will provide a prospective on the impact of epigenetic mechanisms on HIV-1 life cycle. PMID- 20951150 TI - A legacy of discovery: from monoamines to GABA. AB - Seldom does a single individual have such a profound effect on the development of a scientific discipline as Erminio Costa had on neuropharmacology. During nearly sixty years of research, Costa and his collaborators helped established many of the basic principles of the pharmacodynamic actions of psychotherapeutics. His contributions range from defining basic neurochemical, physiological and behavioral properties of neurotransmitters and their receptors, to the development of novel theories for drug discovery. Outlined in this report is a portion of his work relating to the involvement of monoamines and GABA in mediating the symptoms of neuropsychiatric disorders and as targets for drug therapies. These studies were selected for review because of their influence on my own work and as an illustration of his logical and insightful approach to research and his clever use of techniques and technologies. Given the significance of his work, the legions of scientist who collaborated with him, and those inspired by his reports, his research will continue to have an impact as long as there is a search for new therapeutics to alleviate the pain and suffering associated with neurological and psychiatric disorders. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 20951151 TI - Comparison of voluntary and foraging running wheel activity on food demand in mice. AB - The effects of running wheel activity on food intake and meal patterns were measured under several cost conditions for food in CD1 mice. In a first experiment, voluntary wheel running activity increased daily food intake relative to a sedentary group, and runners consumed bigger but fewer meals. Although they ate more, runners had significantly lower body fat than sedentary mice. In a second experiment, running was used as an approach cost and food access was contingent on running wheel activity. Mice were able to emit more wheel revolution responses compared to a condition in which nose poking was the approach response. In both voluntary and foraging running protocols mice had inelastic demand functions compared to the non-running groups. When running was voluntary (experiment 1), the day-night cycle for activity was more pronounced compared to when running was a foraging or approach activity (experiment 2). PMID- 20951148 TI - Sex differences in kappa opioid pharmacology. AB - In recent years it has become apparent that sex is a major factor involved in modulating the pharmacological effects of exogenous opioids. The kappa opioid receptor (KOPR) system is a potential therapeutic target for pain, mood disorders and addiction. In humans mixed KOPR/MOPR ligands have been found to produce greater analgesia in women than men. In contrast, in animals, selective KOPR agonists have been found to produce greater antinociceptive effects in males than females. Collectively, the studies indicate that the direction and magnitude of sex differences of KOPR-mediated antinociception/analgesia are dependent on species, strain, ligand and pain model examined. Of interest, and less studied, is whether sex differences in other KOPR-mediated effects exist. In the studies conducted thus far, greater effects of KOPR agonists in males have been found in neuroprotection against stroke and suppression of food intake behavior. On the other hand, greater effects of KOPR agonists were found in females in mediation of prolactin release. In modulation of drugs of abuse, sex differences in KOPR effects were observed but appear to be dependent on the drug examined. The mechanism(s) underlying sex differences in KOPR-mediated effects may be mediated by sex chromosomes, gonadal hormonal influence on organization (circuitry) and/or acute hormonal influence on KOPR expression, distribution and localization. In light of the diverse pharmacology of KOPR we discuss the need for future studies characterizing the sexual dimorphism of KOPR neural circuitry and in examining other behaviors and processes that are modulated by the KOPR. PMID- 20951149 TI - Persistent anxiolytic affects after chronic administration of the CRF1 receptor antagonist R121919 in rats. AB - Corticotropin-releasing factor (CRF) functions as one of the major mediators of the mammalian stress response and appears to play a key role in the pathophysiology of mood and anxiety disorders. Small molecule CRF1 receptor antagonists may represent a novel form of pharmacotherapy for these disorders. The therapeutic success of CRF1 receptor antagonists will depend, in part, upon whether tolerance develops to the actions of these compounds and whether appropriate patterns of HPA axis function is maintained. This study evaluated the effects of long term (~4 week) treatment with the CRF1 receptor antagonist R121919, on CRF receptor function, HPA axis activity, behavioral measures, adrenal gland size, and body weight gain. Animals treated with 20 mg/kg/day of R121919 spent significantly more time in the open field in a defensive withdrawal test (138+/-36s for R121919 vs 52+/-12s for vehicle, p=0.01). No significant effect of chronic CRF1 receptor blockade on basal ACTH or corticosterone concentrations were detected, nor were significant changes detected in an elevated plus maze test. Both vehicle- and R121919- treated rats showed increases in AUC and peak ACTH and corticosterone concentrations following air puff startle stress, without any overall group differences, although a clear but non significant attenuation in HPA axis response was observable in R121919 treated animals. Chronic CRF1 receptor blockade increased CRF peptide mRNA expression in the PVN and decreased CRF peptide mRNA expression in the central nucleus of the amygdala. Overall our results suggest that anxiolytic effects of chronic CRF1 receptor antagonism persist following chronic administration without significant attenuation of the HPA axis's ability to mount a stress response. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 20951152 TI - Orexins in the midline thalamus are involved in the expression of conditioned place aversion to morphine withdrawal. AB - Previous studies have implicated the bed nucleus of the stria terminalis, central nucleus of the amygdala and the shell of the nucleus accumbens (collectively called the extended amygdala) as playing an important role in mediating the aversive emotion associated with opioid withdrawal. The paraventricular nucleus of the thalamus (PVT) provides a very dense input to the extended amygdala, and the PVT is densely innervated by orexin neurons, which appear to be involved in producing some of the physical and emotional effects associated with morphine withdrawal. In the present study, we confirm that the PVT is densely innervated by orexin fibers, whereas the regions of the extended amygdala associated with the effects of morphine withdrawal are poorly innervated. Microinjections of the orexin-1 receptor (OX1R) antagonist SB334867 or the orexin-2 receptor (OX2R) antagonist TCSOX229 at doses of 5.0 or 15.0 microg into the PVT region did not affect the acquisition of the conditioned place aversion (CPA) nor the physical effects produced by naloxone-precipitated morphine withdrawal. In contrast, microinjections of TCSOX229 (15.0 microg) in the PVT region significantly attenuated the expression of naloxone-induced CPA while microinjections of SB334867 at the same dose had no effect. The results from these experiments indicate a role for OX2R in the PVT on the expression of CPA associated with morphine withdrawal. Orexins may mediate the aversive effects of morphine withdrawal by engaging the extended amygdala indirectly through the action of orexins on the PVT. PMID- 20951153 TI - Enhanced testosterone levels affect singing motivation but not song structure and amplitude in Bengalese finches. AB - Song is a fundamental component of territory defense and mate attraction in birds, and androgens (like testosterone) are known to play a key role in controlling it. However, little is known about how differences in testosterone levels between males translate into inter-individual song variation. Indeed, testosterone could affect both the motivation to sing and the structure of song itself. Here, we tested whether experimentally elevated testosterone levels in adult Bengalese finches (Lonchura striata var. domestica), an oscine bird species, have an activational effect on 1) song performance, and 2) song structure. Our results show that testosterone-treated males, in contrast to sham control males, sang more when confronted with a female. Other performance-related traits, however, such as latency to sing and song amplitude, were not affected. Testosterone-treated males also showed no differences in our two measures of song structure: fundamental element frequency and mean song frequency. Because song structure is known to be organizationally affected by testosterone, our results, synthesized together with findings from the current literature, suggest that in oscine birds, song contains multiple messages about the signaler's hormonal status. First, song performance may reflect current hormonal condition, and second, song structure may reflect the past hormonal state. PMID- 20951154 TI - Mercuric ions inhibit mitogen-activated protein kinase dephosphorylation by inducing reactive oxygen species. AB - Mercury intoxication profoundly affects the immune system, in particular, signal transduction of immune cells. However, the mechanism of the interaction of mercury with cellular signaling pathways, such as mitogen activated protein kinases (MAPK), remains elusive. Therefore, the objective of this study is to investigate three potential ways in which Hg(2+) ions could inhibit MAPK dephosphorylation in the human T-cell line Jurkat: (1) by direct binding to phosphatases; (2) by releasing cellular zinc (Zn(2+)); and (3) by inducing reactive oxygen species (ROS). Hg(2+) causes production of ROS, measured by dihydrorhodamine 123, and triggers ROS-mediated Zn(2+) release, detected with FluoZin-3. Yet, phosphatase-inhibition is not mediated by binding of Zn(2+) or Hg(2+). Rather, phosphatases are inactivated by at least two forms of thiol oxidation; initial inhibition is reversible with reducing agents such as Tris(2 carboxyethyl)phosphine. Prolonged inhibition leads to non-reversible phosphatase oxidation, presumably oxidizing the cysteine thiol to sulfinic- or sulfonic acid. Notably, phosphatases are a particularly sensitive target for Hg(2+)-induced oxidation, because phosphatase activity is inhibited at concentrations of Hg(2+) that have only minor impact on over all thiol oxidation. This phosphatase inhibition results in augmented, ROS-dependent MAPK phosphorylation. MAPK are important regulators of T-cell function, and MAPK-activation by inhibition of phosphatases seems to be one of the molecular mechanisms by which mercury affects the immune system. PMID- 20951155 TI - Spectral sensitivity of the photointrinsic iris in the red-eared slider turtle (Trachemys scripta elegans). AB - Our goal in this study was to examine the red-eared slider turtle for a photomechanical response (PMR) and define its spectral sensitivity. Pupils of enucleated eyes constricted to light by ~11%, which was one-third the response measured in alert behaving turtles at ~33%. Rates of constriction in enucleated eyes that were measured by time constants (1.44-3.70 min) were similar to those measured in turtles at 1.97 min. Dilation recovery rates during dark adaptation for enucleated eyes were predicted using line equations and computed times for reaching maximum sizes between 26 and 44 min. Times were comparable to the measures in turtles where maximum pupil size occurred within 40 min and possessed a time constant of 12.78 min. Hill equations were used to derive irradiance threshold values from enucleated hemisected eyes and then plot a spectral sensitivity curve. The analysis of the slopes and maximum responses revealed contribution from at least two different photopigments, one with a peak at 410 nm and another with a peak at 480 nm. Fits by template equations suggest that contractions are triggered by multiple photopigments in the iris including an opsin-based visual pigment and some other novel photopigment, or a cryptochrome with an absorbance spectrum significantly different from that used in our model. In addition to being regulated by retinal feedback via parasympathetic nervous pathways, the results support that the iris musculature is photointrinsically responsive. In the turtle, the control of its direct pupillary light response (dPLR) includes photoreceptive mechanisms occurring both in its iris and in its retina. PMID- 20951156 TI - Converging evidence for diverging pathways: neuropsychology and psychophysics tell the same story. AB - In 1992, Goodale and Milner proposed the existence of a dedicated visuomotor control system that allows for the control of action without the need for conscious perception of the target object's form. The 'action and perception hypothesis' was motivated in large part by the surprising observation of spared visuomotor abilities in D.F., a patient with a severe deficit in visual form perception attributable to a lesion concentrated in the lateral occipital complex of the ventral stream. When D.F. reaches out to grasp an object, her hand posture in flight reflects the size, shape, and orientation of the object, despite the fact that she is unable to report those same object features. Nevertheless, there are systematic limits to her spared ability to grasp objects: her performance sharply deteriorates for objects defined by second-order contrast, objects whose principal axis of orientation is ambiguous, objects removed from view before the onset of the action, and objects seen without cues to absolute distance. At the same time, a considerable body of psychophysical evidence from healthy observers has accumulated that is consistent with the idea of a dedicated visuomotor control system that is independent of perceptual influence. Although some of this evidence is controversial, we will argue that, on balance, there is good agreement between the psychophysical and neuropsychological data - and that the action and perception hypothesis is still alive and well. PMID- 20951157 TI - Spatial and temporal stimulus variants for multifocal pupillography of the central visual field. AB - Multifocal pupillographic objective perimetry (mfPOP) has the advantage of being a non-invasive, objective method for measuring up to 88 visual field responses from both eyes concurrently within 5min. To date mfPOP has been used to assess the peripheral visual field. Here we examine the practicality of mfPOP for testing the macular region of the visual field. This study examines variations in temporal presentation rate, spatial stimulus layout and luminance intensity in a group of normal subjects to determine the optimal parameters for achieving high signal to noise ratios for a macular version of mfPOP. Responses to multifocal stimuli comprising 24 or 44 stimulus regions per eye were measured dichoptically achieving median signal to noise ratios of 2.47 z-score units. Long stimulus presentation intervals combined with 24 region non-overlapping layouts produced the largest contraction amplitudes and shortest response delays. PMID- 20951158 TI - Endogenous nitric oxide enhances the light-response of cones during light adaptation in the rat retina. AB - The electroretinogram (ERG) is a non-invasive indicator of retinal function. Light flashes evoke a cornea-negative a-wave followed by a cornea-positive b wave. Light-adaptation is known to increase the amplitude of cone-dependent b waves. To identify the underlying mechanism, we recorded rat cone photoresponses in situ, using intravitreally-injected glutamate to block synaptic transmission and intense paired-flash stimuli to isolate cone a-waves. Steady adapting illumination caused a progressive increase in cone a-wave amplitude, which was suppressed in a dose-dependent manner by intravitreal CPTIO, a nitric oxide scavenger. We conclude that light-adaptation causes release of nitric oxide, which enhances the cone photoresponse. PMID- 20951159 TI - Circulating leptin levels are associated with increased craving to smoke in abstinent smokers. AB - The adipocyte hormone leptin regulates satiety and energy expenditure. Recent evidence suggests that leptin is associated with increased craving for alcohol and with shorter length of abstinence during alcohol treatment. This study examined leptin's associations with craving for cigarettes and smoking relapse among smokers interested in cessation. Participants (32 smokers; 14 women) attended a laboratory session 24h following their designated quit day where circulating leptin levels and craving for smoking were assessed. Other measures of withdrawal symptoms, affect, physical symptoms, as well as neuroendocrine and cardiovascular measures were collected before and after performing two stress tasks (public speaking and cognitive tasks). High circulating leptin levels were associated with increased craving, withdrawal symptoms, negative affect, physical symptoms, and reduced positive affect. Circulating leptin levels were not related to cardiovascular and neuroendocrine measures, responses to acute stressors, or to smoking relapse. These results indicate that circulating leptin is a promising biological marker of craving for smoking and warrant further investigation of the links between appetite regulation and nicotine dependence. PMID- 20951161 TI - Using pentobarbital to assess the sensitivity and independence of response-bout parameters in two mouse strains. AB - A recently developed model posits that a bout of operant responding comprises three different components: bout initiation rate, within-bout response rate and bout length. Each parameter is thought to be affected by different classes of variables. Pentobarbital was used to assess the independence and sensitivity of these parameters in two mouse strains, BALB/c and C57BL/6, selected because of their different behavioral characteristics. With or without a running wheel present, BALB/c and C57BL/6 mice nose-poked under a Percentile 10:0.5 schedule designed to select high response rates while holding reinforcement rate constant. Baseline rates of nose-poking were higher for BALB/c mice than for C57BL/6 mice, but no strain difference occurred in baseline distance run. Nose-poking occurred at a higher rate when the wheel was absent from the chamber for both strains, and this was due to longer bout lengths and higher bout initiation rates. Nose-poke rates were increased by the 5.6-17 mg/kg doses of pentobarbital, especially in C57BL/6 mice. Pentobarbital only decreased running. No strain differences in pentobarbital sensitivity were observed for running. Whether reinforcement was extrinsic or intrinsic to the response was hypothesized to influence pentobarbital's effects. The different bout parameters helped dissect pentobarbital's effects and were selectively affected by pentobarbital. PMID- 20951162 TI - 5-fluorouracil loaded fibrinogen nanoparticles for cancer drug delivery applications. AB - In this study, 5-flurouracil loaded fibrinogen nanoparticles (5-FU-FNPs) were prepared by two step coacervation method using calcium chloride as cross-linker. The prepared nanoparticles were characterized using DLS, SEM, AFM, FT-IR, TG/DTA and XRD studies. Particle size of 5-FU-FNPs was found to be 150-200 nm. The loading efficiency (LE) and in vitro drug release was studied using UV spectrophotometer. The LE of FNPs was found to be ~90%. The cytotoxicity studies showed 5-FU-FNPs were toxic to MCF7, PC3 and KB cells while they are comparatively non toxic to L929 cells. Cellular uptake of Rhodamine 123 conjugated 5-FU-FNPs was also studied. Cell uptake studies demonstrated that the nanoparticles are inside the cells. These results indicated that FNPs could be useful for cancer drug delivery. PMID- 20951160 TI - An acetaldehyde-sequestering agent inhibits appetitive reinforcement and behavioral stimulation induced by ethanol in preweanling rats. AB - Ethanol's motivational consequences have been related to the actions of acetaldehyde, a metabolic product of ethanol oxidation. The present study assessed the role of acetaldehyde in the motivational effects of ethanol on preweanling rats. In Experiment 1 pups (postnatal days 13-14, PD 13-14) were given systemic administration of D-penicillamine (DP, a drug that sequesters acetaldehyde: 0, 25, 50 or 75 mg/kg) before pairings of 1.0 g/kg ethanol and a rough surface (sandpaper, conditioned stimulus, CS). At test, pups given sandpaper-ethanol pairings exhibited greater preference for the CS than unpaired controls, but this preference was not expressed by pups given DP. Pre-training administration of 25 or 50 mg/kg DP completely blocked the expression of ethanol mediated appetitive conditioning. D-penicillamine did not alter blood ethanol levels. Subsequent experiments revealed that ethanol-induced activation was blocked by central (intra-cisterna magna injections, volume: 1 MUl, dose: 0 or 75 MUg) but not systemic treatment with DP (0, 25, 50 or 75 mg/kg; ip). These results indicate that: (a) preweanling rats are sensitive to the reinforcing effect of ethanol, and (b) that this effect is associated with the motor activating effect of the drug. These effects seem to be mediated by the first metabolite of ethanol, acetaldehyde. PMID- 20951164 TI - Effects of cardiac pulsation in diffusion tensor imaging of the rat brain. AB - The purpose of this study was to investigate the effects of cardiac pulsation in diffusion tensor imaging (DTI) of the rat brain. DTI data were acquired either with or without different cardiac gating delays. For each case, two sets of identical DTI data were acquired for a bootstrap analysis to measure the uncertainty in estimating mean diffusivity (MD), fractional anisotropy (FA) and the primary eigenvector direction. The 95% confidence interval of the primary eigenvectors was substantially reduced (21-25%) when cardiac gating with triggering delay of 70 ms (~half of R-R peak duration) was used in comparison to studies without gating or when gating with a triggering delay of 0 ms was used. Standard deviations of MD and FA estimates were also reduced by 12-26% and 13 24%, respectively. For voxels with mean FA values larger than 0.15 and smaller than 0.95, the decrease in CI and standard deviations of MD and FA by cardiac gating with triggering delay of 70 ms were significant (p < 0.05). These results demonstrate the importance of cardiac gating in acquisition of in vivo high resolution DTI data. PMID- 20951163 TI - Human, mouse or rat? Species authentication of glioma-derived cell cultures. AB - Cell culture and the use of cell lines are often fundamental requirements in basic scientific research. It is of the utmost importance for researchers to ensure that the cell lines in use have a well defined origin and are routinely re analysed to highlight possible areas of contamination. In this preliminary study species specific primers were designed to easily distinguish between human, mouse and rat DNA with standard agarose gel electrophoresis. Inter-species contamination is often the most common form of contamination experienced, with the most common of cell lines in use being of human, mouse and rat derivation. A PCR-based assay was therefore developed to ensure an accurate, quick and cost effective means of determining any cell line contamination which could be easily executed on a routine basis. Furthermore, this simple PCR is able to identify the species in the inter-species mixture of DNA and therefore provides a valuable tool for the authentication of human cell lines. PMID- 20951165 TI - The validation of a real-time RT-PCR assay which detects influenza A and types simultaneously for influenza A H1N1 (2009) and oseltamivir-resistant (H275Y) influenza A H1N1 (2009). AB - Influenza A H1N1 (2009) was declared by the World Health Organisation (WHO) as the first influenza pandemic of the 21st century. Rapid detection of influenza A and differentiation of influenza A H1N1 (2009) and seasonal influenza A is beneficial. In addition the rapid detection of antiviral resistant strains of influenza A H1N1 (2009) would be useful for clinicians to allow for change to an effective treatment at a much earlier stage if resistance is found. It was the aim of this study to develop a real-time RT-PCR that can detect all influenza A viruses and type simultaneously for influenza A H1N1 (2009) and oseltamivir resistant (H275Y) influenza A H1N1 (2009). This multiplex assay will allow laboratories to screen respiratory samples for all types of influenza A, influenza A H1N1 (2009) virus and oseltamivir resistant (H275Y) influenza A H1N1 (2009) virus in a rapid and cost effective format, ensuring that typing methods for seasonal and avian viruses are used on a smaller subset of samples. Since most virology laboratories already offer a molecular service for influenza A this assay could easily be implemented into most areas at little cost therefore increasing local access to resistance testing. PMID- 20951166 TI - Rapid detection of Newcastle disease virus replication in embryonated chicken eggs using quantitative real time polymerase chain reaction. AB - Newcastle disease virus (NDV), an avian paramyxovirus, is an economically important disease of poultry globally. Rapid methods to detect and differentiate the virus are important to curtail the spread of this virus. Nucleic acid based detection methods are routinely employed for diagnosis that suffer from the disadvantage of failure to discriminate viable virus and non-infectious genome. However, virus isolation remains the gold standard for diagnosis of field outbreaks. The sensitivity of virus isolation was combined with nucleic acid based detection methods so that the time taken for confirmatory diagnosis could be considerably reduced while increasing sensitivity. Quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) and conventional RT-PCR techniques were compared for the detection of NDV genome replication in 9-11-day old embryonated chicken eggs (ECE) using the nucleoprotein (NP) gene of the virus as a target. The results suggest that at least two to fourfold increase in cycle threshold (C(t)) values over the baseline C(t) value of samples lacking infectious virus, would indicate live NDV replication. The limit of detection of NDV replication using qRT-PCR was 1*10(4.0) mean embryo infective doses (EID(50)). The earliest time point when live virus replication was detectable by qRT-PCR or RT-PCR was 30h post-inoculation in ECE. PMID- 20951167 TI - Development of a polyprobe to detect six viroids of pome and stone fruit trees. AB - A simple and sensitive dot blot hybridization assay using a digoxigenin-labeled cRNA polyprobe was developed for the simultaneous detection of six viroids that infect pome and stone fruit trees. The polyprobe was constructed by cloning sequentially partial sequences of each viroid into a single vector, with run-off transcription driven by the T7 promoter. All six viroids were detectable within a dilution range of 5(-3) to 5(-4) in total nucleic acid extracts from infected trees. Individual trees were co-inoculated to create mixed infections and all four pome fruit viroids and both stone fruit viroids could be detected in pear and peach trees, respectively, using the polyprobe. The results of the assays using the polyprobe were comparable to those using single probes. The methods were validated by testing geographically diverse isolates of viroids, as well as field samples from several collections in the US. The assay offers a rapid, reliable and cost-effective approach to the simultaneous detection of six fruit trees viroids and has the potential for routine use in quarantine, certification, and plant genebank programs where many samples are tested and distributed worldwide. PMID- 20951168 TI - Cholesterol is important for a post-adsorption step in the entry process of transmissible gastroenteritis virus. AB - Cholesterol is a major constituent of detergent-resistant membrane microdomains (DRMs). We localized transmissible gastroenteritis virus (TGEV) spike (S) protein in DRMs in the viral envelope. Though S protein was not solubilized by cold non ionic detergents, this behavior was unchanged when cholesterol was depleted from viral membrane by methyl-beta-cyclodextrin (MbetaCD) and the protein did not comigrate with cellular DRM marker proteins in flotation analyses. Therefore, the S protein is not anchored in the viral membrane DRMs as they are known to occur in the plasma membrane. Cholesterol depletion from viral membrane may not affect the adsorption process as neither the sialic acid binding activity nor the binding to aminopeptidase N was reduced post-MbetaCD treatment. Reduced infectivity of cholesterol-depleted TGEV was observed only when the adsorption process occurred at 37 degrees C but not when the virus was applied at 4 degrees C. Cholesterol is important for a post-adsorption step, allowing membrane rearrangements that facilitate virus entry. PMID- 20951169 TI - Cellular FLIP(L) plays a survival role and regulates morphogenesis in breast epithelial cells. AB - Strong evidences support the inhibitory activity of cellular FLICE-inhibitory protein (FLIP) in the apoptotic signalling by death receptors in tumor cells. However, little is known about the role of FLIP in the regulation of apoptosis in non-transformed cells. In this report, we demonstrate that FLIP(L) plays an important role as a survival protein in non-transformed breast epithelial cells. Silencing of FLIP(L) by siRNA methodology enhances TRAIL-R2 expression and activates a caspase-dependent cell death process in breast epithelial cells. This cell death requires the expression of TRAIL, TRAIL-R2, FADD and procaspase-8 proteins. A mitochondria-operated apoptotic pathway is partially required for FLIP(L) siRNA-induced apoptosis. Interestingly, FLIP(L) silencing markedly abrogates formation of acinus-like structures in a three-dimensional basement membrane culture model (3D) of the human mammary MCF-10A cell line through a caspase-8 dependent process. Furthermore, over-expression of FLIP(L) in MCF-10A cells delayed lumen formation in 3D cultures. Our results highlight the central role of FLIP in maintaining breast epithelial cell viability and suggest that the mechanisms regulating FLIP levels should be finely controlled to prevent unwanted cell demise. PMID- 20951170 TI - Validation of DNA and RNA real-time assays for food analysis using the hilA gene of Salmonella enterica serovars. AB - In Europe, alternative methods for the detection of food-borne pathogens can be used instead of the standard ISO/CEN reference protocol, if validated according to the protocol outlined in ISO 16140, 2003. In this study, the performance of two novel methods for the detection of Salmonella sp. using real-time PCR technology in tandem with an adapted two-step enrichment protocol were assessed and validated against a reference culture method, ISO 6579, 2004. The DNA and RNA real-time PCR assays amplified a 270 bp region of the hilA gene of Salmonella enterica serovars, and incorporated an internal amplification control (IAC) which was co-amplified with the hilA gene to monitor potential PCR inhibitors and ensure successful amplification. The inclusivity and exclusivity of the hilA primer set was examined for both the DNA and RNA methods and detected the 30 S. enterica serovars but not the 30 non-salmonellae strains. The inoculation of meat carcass swabs with five different S. enterica serovars at five different inocula, indicated both PCR methods were able to detect between 1 and 10 CFU per carcass swab. The real-time DNA PCR assay performed as well as the traditional cultural method in detecting Salmonella sp. in artificially contaminated salad, chocolate, fish and cheese samples. The relative accuracy, relative sensitivity and relative specificity of the DNA PCR real-time method were determined to be 98.5, 98.1 and 100%, respectively. The DNA method was further validated in a collaborative inter laboratory trial according to ISO 16140, 2003. The validated methods provide an accurate means for the rapid detection and tracking of S. enterica serovars giving equivalent results to the standard method within three days, thus providing an alternative testing method to the reference microbiological method. The real-time PCR methodology not only offers significant time-saving advantages compared to traditional methods, it can also be applied to a wide range of samples types. PMID- 20951171 TI - Rapid multiple-locus variable-number tandem-repeats analysis of Shigella spp. using multicolour capillary electrophoresis. AB - The multiple-locus variable-number tandem-repeats analysis (MLVA) method for genotyping has proven to be a fast and reliable typing tool in several bacterial species. MLVA is in our laboratory the routine typing method for Salmonella enterica subsp. enterica serovar Typhimurium, Escherichia coli (two assays), Listeria monocytogenes and Yersinia enterocolitica. The gram-negative invasive enteropathogenic bacterium Shigella is the most common cause of bacillary dysentery (shigellosis) worldwide, and is a global human health problem. It was of great interest to develop a rapid and robust MLVA-assay for this important pathogen. Though not common in Norway, we do receive isolates mostly associated with foreign travel and thus an outbreak may be possible. The resulting MLVA assay is based on seven polymorphous VNTRs found by search in the published genomes of all Shigella species. The assay is fast (one multiplexed PCR reaction), robust and show high divergence among the Shigellae. A total of 235 Shigella spp. were typed with 194 distinct MLVA-genotypes. An outbreak cluster of Shigella sonnei was additionally identified during manuscript preparation. PMID- 20951172 TI - The small ribosomal protein S12P gene rpsL as an efficient positive selection marker in allelic exchange mutation systems for Corynebacterium glutamicum. AB - We report that the mutant rpsL K43R in streptomycin-resistant and lysine producing Corynebacterium glutamicum is responsible for streptomycin resistance. In addition, we describe its effective application in gene modification in C. glutamicum. PMID- 20951173 TI - Genotyping of Brazilian Erysipelothrix spp. strains by amplified fragment length polymorphism. AB - One hundred and fifty-one Erysipelothrix spp. isolates from diseased and carrier swine from Brazil were identified by PCR, submitted to serotyping and analyzed by amplified fragment length polymorphism with a single enzyme (AFLP). Reference strains from Australia and the United Kingdom were also examined. The 151 strains were classified into 18 different serotypes (1a, 1b, 2a, 2b, 4, 5, 6, 7, 8, 10, 11, 12, 15, 17, 19, 21, 24 and 25), being serotype 2b the most frequent (39.7%). By associating serotyping and PCR results, it was possible to identify 146 strains as E. rhusiopathiae and five strains as E. tonsillarum. Despite the fact that for this genus AFLP did not cluster all isolates according to serotype, origin, disease or isolation data, the execution of the technique was easy and fast, demonstrating high discriminatory power. The results produced by the AFLP analysis of Erysipelothrix spp. could also support its use as a discriminatory tool for E. rhusiopathiae and E. tonsillarum species. PMID- 20951174 TI - Differential predictive power of self report and implicit measures on behavioural and physiological fear responses to spiders. AB - In this study, we investigated to what extent indirect measures predict behavioural and physiological fear responses towards spiders. Implicit attitudes towards spiders were assessed using an implicit association test and attentional bias towards spiders was assessed using a dot probe task and a disengagement task. Results showed that a self report measure of fear for spiders, but not the indirect measures predicted avoidance behaviour. The indirect measures but not the self report measure predicted changes in heart rate in response to the presentation of a spider. These results suggest that indirect measures may be useful in predicting and understanding fear responses that are not easily voluntarily controlled. PMID- 20951175 TI - Porcine reproductive and respiratory syndrome virus: an update on an emerging and re-emerging viral disease of swine. AB - Recognized in the late 1980s in North America and Europe the syndrome that caused reproductive and respiratory problems in swine was initially called "mystery swine disease" and is now termed "porcine reproductive and respiratory syndrome (PRRS)". In the early 1990 s an arterivirus, referred to as PRRS virus (PRRSV), was determined to be the etiologic agent of this disease. Since then research has progressed substantially. Most recently "porcine high fever disease" was reported in China starting in 2006 with PRRSV being a critical virus associated with high morbidity and mortality (20%) associated with this syndrome which in 2010 is still causing severe pathology in pigs in China, with spread to Vietnam and Cambodia. This volume contains a series of reviews that highlight the virus, its pathogenesis, epidemiology, immunology, vaccinology and host genetic control. This paper provides a brief historical review of PRRS and the associated PRRSV. It presents areas of research gaps that inhibit current progress towards PRRS elimination through production of effective vaccines and current plans for PRRS elimination or eradication programs. It is hoped that this discussion will stimulate further collaboration between researchers and swine veterinarians throughout the world to provide answers that enhance our understanding of PRRS and PRRSV in an effort to eliminate this economically important disease. PMID- 20951176 TI - Helicoverpa armigera single nucleocapsid nucleopolyhedrovirus ORF51 is a ChaB homologous gene involved in budded virus production and DNA replication. AB - The baculovirus ChaB proteins are conserved in all completely sequenced Lepidopteran NPVs and are annotated as putative DNA binding proteins. Here we investigated Helicoverpa armigera single nucleocapsid nucleopolyhedrovirus (HearNPV) ORF51 (ha51), one of the ChaB homologues in HearNPV. 5'-RACE revealed that Ha51 is transcribed from a conventional early promoter transcriptional initiator motif (CATT) located at 159nt upstream of ATG. RT-PCR confirmed that ha51 is an early transcribed gene. To study the function of Ha51 in the life cycle of HearNPV, Ha51 knockout and repair bacmids were generated by homologous recombination in Escherichia coli. Growth curve and DNA replication analyses showed that the levels of budded virus (BV) production and viral DNA accumulation were significantly higher in cells infected with Ha51 null virus than those infected with wild-type bacmid derived virus. Electron microscopy revealed that polyhedra formation was not affected by the deletion of Ha51. Bioassay demonstrated that the Ha51-deleted virus had similar oral infectivity as the wild type and rescued virus. Western blot analyses suggested that HA51 is a component of the nucleocapsid of BV and occlusion-derived virus as well as the envelope of BV. Immunofluorescence microscopy showed that HA51 protein is mainly localized in the cytoplasm of infected cells. Taken together, our results indicate that, unlike previously characterized baculovirual ChaB genes, Ha51 is involved in viral DNA replication and BV production and is transcribed in the early stage of infection. PMID- 20951177 TI - The therapeutic equivalence of complex drugs. AB - When the patent of a small molecule drug expires generics may be introduced. They are considered therapeutically equivalent once pharmaceutical equivalence (i.e. identical active substances) and bioequivalence (i.e. comparable pharmacokinetics) have been established in a cross-over volunteer study. However this generic paradigm cannot be applied to complex drugs as biologics and a number of other therapeutic modalities. For copies of biologics the European Medicine Agency and other regulatory agencies have introduced a new regulatory biosimilar pathway which mandates clinical trials to show therapeutic equivalence. However for other complex drugs such as the iron-carbohydrate drugs, low molecular weight heparins (LMWHs), liposomal drugs and the glatiramoids regulatory guidance is still mostly lacking. In this paper we will discuss (therapeutic) experience obtained so far with these different classes of 'complex drugs' and their specifics to provide scientific arguments and criteria for consideration for a regulatory framework for the market authorization for these type of drugs. PMID- 20951178 TI - Survey results on the use of the tissue cross-reactivity immunohistochemistry assay. AB - A multinational pharmaceutical and biotechnology company survey was conducted to gain a better understanding of the use and value of the tissue cross-reactivity (TCR) assay in the development of biotherapeutic molecules. The majority of the molecules did not use TCR data as the only basis for determining species selection for toxicity studies (73%). For 95% of the molecules, the TCR data had no impact on the development strategy. For 2% of the molecules (1/56), TCR data was the sole source of information indicating a potential risk to patients. Unexpected or off-target binding was seen with 35% of the molecules, with the majority of this binding occurring in the CNS and reproductive organs. Tissues that were known or presumed to contain the target stained positively in 22% and 10% of molecules tested in non-human primate and human tissues, respectively. Tissues that were known or presumed to lack the target were negative for staining in 39% and 50% of molecules for non-human primate and human tissue, respectively. For 5% (6/110) of all the molecules, companies stated that toxicities would have been missed in animal studies or the clinic (i.e., not identified by clinical signs, histopathology, etc.) if the TCR studies had not been performed. PMID- 20951179 TI - Genotoxicity and subchronic toxicity evaluation of Active Hexose Correlated Compound (AHCC). AB - Active Hexose Correlated Compound (AHCC), a mushroom extract rich in alpha-1,4 linked glucans, is associated with immunostimulatory effects. AHCC is used in Japan as a dietary supplement to boost immune function and it also is purported to improve the symptoms of cancer and liver disease patients. A series of toxicological studies were conducted on a freeze dried preparation of AHCC (AHCC FD) to further develop the body of evidence supporting the safety of this ingredient. AHCC-FD was not mutagenic to Salmonella typhimurium and did not exhibit clastogenicity in a mouse micronucleus assay. In a 90-day study, Sprague Dawley rats were administered 1000, 3000, or 6000 mg/kg body weight/day by gavage. No changes attributable to AHCC-FD treatment were observed in overall condition, body weight, food consumption, ophthalmology findings, hematology and clinical chemistry parameters, and absolute and relative organ weights. Changes in urinary pH values observed in high-dose animals and mid-dose females were considered physiological rather than adverse effects given the acidic nature of AHCC-FD. Urinary protein also was increased in the same dose groups. As this finding was associated with decreased urinary pH and no evidence of kidney dysfunction was observed, it was considered of no toxicological significance. Histopathological changes related to AHCC-FD administration were observed in the limiting ridge of the stomach and in the liver of the high-dose group. The NOAEL was considered to be 3000 mg/kg body weight/day. PMID- 20951180 TI - In vitro antioxidant and inhibitory potential of Terminalia bellerica and Emblica officinalis fruits against LDL oxidation and key enzymes linked to type 2 diabetes. AB - The present study evaluated the free radical scavenging capacity and antioxidant potential of different solvent extracts (Hexane (HE), ethyl acetate (EA), methanol (ME), 70% methanol (MW) and Water (WA)) of Terminalia bellerica (TB) and Emblica officinalis (EB) fruits. Methanol extract (ME) of TB and EB fruits exhibited maximum scavenging activity against DPPH, superoxide, hydroxyl and nitric oxide radicals. Cell based antioxidant activity was assayed by flow cytometry using DCFH-DA as probe. Methanol extracts were also screened for their antidiabetic activity via inhibition of alpha-amylase, alpha-glucosidase and antiglycation assays. Results showed that ME of TB and EB can act as potent alpha amylase and alpha-glucosidase inhibitor. Significant antiglycation activity also confirms the therapeutic potential of these extracts against diabetes. Both the extracts significantly inhibited the oxidation of LDL under in vitro conditions. Liquid chromatography-mass spectroscopy (LC-MS) analysis revealed that methanol extract of TB and EB contains ellagic acid and ascorbic acid as the major compound respectively. PMID- 20951181 TI - Differential effects of indirubin and 2,3,7,8-tetrachlorodibenzo-p-dioxin on the aryl hydrocarbon receptor (AhR) signalling in liver progenitor cells. AB - In the present study, we investigated the effects of potential endogenous ligand indirubin on the aryl hydrocarbon receptor (AhR) signalling, with a focus on the AhR-dependent gene expression and cell cycle progression in rat liver progenitor cells, and compared them with the effects of a model toxic AhR ligand, 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). The low (picomolar and nanomolar) doses of indirubin, corresponding to expected endogenous levels, induced a transient translocation of AhR to the nucleus, while high (micromolar) doses induced a long term AhR nuclear translocation, followed by its degradation, similar to the effects of TCDD. Whereas high doses of indirubin recruited AhR/ARNT1 dimer to rat Cyp1a1 promoter, the low doses did not induce its DNA binding, as revealed by the chromatin immunoprecipitation assay. This corresponded with the fact that the micromolar doses of indirubin significantly increased Cyp1a1/1b1 mRNA in a way similar to TCDD, while the low doses of indirubin were only poor inducers of Cyp1a1/1b1 expression. Comparable patterns of expression were observed also for other AhR gene targets, such as Nqo1 and Nrf2. Also, only micromolar doses of indirubin were able to mimic the effects of TCDD on cell cycle and proliferation of liver progenitor cells or hepatoma cells. Nevertheless, indirubin at low concentrations may have unique effects on gene expression in non-tumorigenic cells. Although both TCDD and the high doses of indirubin repressed plakoglobin (Jup) expression, the picomolar doses of indirubin, unlike the equimolar doses of TCDD, increased mRNA levels of this important desmosomal and adherens junctions constituent. These present data suggest that the outcome of AhR activation induced by indirubin at concentrations expected in vivo may differ from the AhR signalling triggered by exogenous toxic ligands, such as TCDD. PMID- 20951182 TI - Construction and immunogenicity of a recombinant fowlpox vaccine coexpressing S1 glycoprotein of infectious bronchitis virus and chicken IL-18. AB - Infectious bronchitis virus (IBV) poses a major threat to the chicken industry worldwide. In this study, we developed a recombinant fowlpox virus (rFPV) vaccine expressing the IBV S1 gene and chicken interleukin-18 gene (IL-18), rFPV-S1/IL18. Recombinant plasmid pSY-S1/IL18 was constructed by cloning chicken IL-18 into fowlpox virus transfer plasmid containing S1 gene and transfected into the chicken embryo fibroblasts cell pre-infected with S-FPV-017 to generate rFPV S1/IL18. Expression of the recombinant proteins was confirmed by RT-PCR and IFA. We also constructed the recombinant fowlpox virus rFPV-S1 without IL-18. One-day old chickens were vaccinated by wing-web puncture with the two rFPVs, and the induced humoral and cellular responses were evaluated. There was a significant difference in ELISA antibody levels (P<0.05) elicited by either rFPV-S1 or rFPV S1/IL18. The ratios of CD4(+) to CD8(+) in chickens immunized with rFPV-S1/IL18 were significantly higher (P<0.05) than in those immunized with rFPV-S1. All chickens immunized with rFPV-S1/IL18 were completely protected (20/20) after challenge with the virulent IBV HN99 strain 43 days after immunization, while only 15 out of 20 of the chickens immunized with the rFPV-S1 were protected. Our results show that the protective efficacy of the rFPV-S1 vaccine could be enhanced significantly by simultaneous expression of IL-18. PMID- 20951183 TI - The anti-MMP activity of benzalkonium chloride. AB - OBJECTIVE: This study evaluated the ability of benzalkonium chloride (BAC) to bind to dentine and to inhibit soluble recombinant MMPs and bound dentine matrix metalloproteinases (MMPs). METHODS: Dentine powder was prepared from extracted human molars. Half was left mineralized; the other half was completely demineralized. The binding of BAC to dentine powder was followed by measuring changes in the supernatant concentration using UV spectrometry. The inhibitory effects of BAC on rhMMP-2, -8 and -9 were followed using a commercially available in vitro proteolytic assay. Matrix-bound endogenous MMP-activity was evaluated in completely demineralized beams. Each beam was either dipped into BAC and then dropped into 1 mL of a complete medium (CM) or they were placed in 1 mL of CM containing BAC for 30 days. After 30 days, changes in the dry mass of the beams or in the hydroxyproline (HYP) content of hydrolysates of the media were quantitated as indirect measures of matrix collagen hydrolysis by MMPs. RESULTS: Demineralized dentine powder took up 10-times more BAC than did mineralized powder. Water rinsing removed about 50% of the bound BAC, whilst rinsing with 0.5M NaCl removed more than 90% of the bound BAC. BAC concentrations 0.5wt% produced 100% inhibition of soluble recombinant MMP-2, -8 or -9, and inhibited matrix-bound MMPs between 55 and 66% when measured as mass loss or 76-81% when measured as solubilization of collagen peptide fragments. CONCLUSIONS: BAC is effective at inhibiting both soluble recombinant MMPs and matrix-bound dentine MMPs in the absence of resins. PMID- 20951184 TI - Oral bacterial deactivation using a low-temperature atmospheric argon plasma brush. AB - OBJECTIVE: To study the plasma treatment effects on deactivation effectiveness of oral bacteria. METHODS: A low temperature atmospheric argon plasma brush were used to study the oral bacterial deactivation effects in terms of plasma conditions, plasma exposure time, and bacterial supporting media. Oral bacteria of Streptococcus mutans and Lactobacillus acidophilus with an initial bacterial population density between 1.0*10(8) and 5.0*10(8)cfu/ml were seeded on various media and their survivability with plasma exposure was examined. Scanning electron microscopy was used to examine the morphological changes of the plasma treated bacteria. Optical absorption was used to determine the leakage of intracellular proteins and DNAs of the plasma treated bacteria. RESULTS: The experimental data indicated that the argon atmospheric plasma brush was very effective in deactivating oral bacteria. The plasma exposure time for a 99.9999% cell reduction was less than 15s for S. mutans and within 5 min for L. acidophilus. It was found that the plasma deactivation efficiency was also dependent on the bacterial supporting media. With plasma exposure, significant damages to bacterial cell structures were observed with both bacterium species. Leakage of intracellular proteins and DNAs after plasma exposure was observed through monitoring the absorbance peaks at wavelengths of 280 nm and 260 nm, respectively. CONCLUSION: The experimental results from this study indicated that low temperature atmospheric plasma treatment was very effective in deactivation of oral bacteria and could be a promising technique in various dental clinical applications such as bacterial disinfection and caries early prevention. PMID- 20951185 TI - Post-ischemic activation of protein kinase C epsilon protects the hippocampus from cerebral ischemic injury via alterations in cerebral blood flow. AB - Protein kinase C (PKC) is a family of serine/threonine-isozymes that are involved in many signaling events in normal and disease states. Previous studies from our lab have demonstrated that EPKC plays a pivotal role in neuroprotection induced by ischemic preconditioning. However, the role of EPKC during and after brain ischemia is not clearly defined. Therefore, in the present study, we tested the hypothesis that activation of EPKC during an ischemic event is neuroprotective. Furthermore, other studies have demonstrated that EPKC mediates cerebral ischemic tolerance in the rat brain by decreasing vascular tone. Thus, we also tested the effects of EPKC activation during ischemia on cerebral blood flow (CBF). We found that psiE-Receptors for Activated C Kinase (RACK), a EPKC-selective peptide activator, injected intravenously 30min before induction of global cerebral ischemia conferred neuroprotection in the CA1 region of the rat hippocampus. Moreover, measurements of CBF before, during, and after cerebral ischemia revealed a significant reduction in the reperfusion phase of rats pretreated with psiERACK as compared to Tat peptide (vehicle). Our results suggest that EPKC can protect the rat brain against ischemic damage by regulating CBF. Thus, EPKC may be one of the treatment modalities against ischemic injury. PMID- 20951186 TI - Response of astrocytes and microglia/macrophages to brain injury after bone marrow stromal cell transplantation: a quantitative study. AB - The aim of the present study was to investigate the effects of intracerebral and intravenous administration of bone marrow stromal cells (BMSCs) on cellular activity in the injured brain. Female Wistar rats were subjected to cerebral cortex injury followed by the injection of BMSCs or saline, directly to the injured site or to the tail vein. Lectin histochemistry and glial fibrillary acidic protein immunohistochemistry were used to analyze the number of microglia/macrophages and astrocytes in the injured cerebral cortex, respectively. BMSC treatment affected cell response to brain injury. The effects of BMSC action were dependent on the site of their administration. The intravenous injection of BMSCs noticeably increased the number of microglia/macrophages in the injured brain. Intracerebral transplantation of BMSCs significantly enhanced the number of astrocytes, and in a less degree caused changes in the number of microglia/macrophages. The results suggest that BMSCs can affect the restorative processes in the injured brain through stimulation of the cellular response to injury. PMID- 20951188 TI - Cytochrome P450 1 enzyme inhibition and anticancer potential of chromene amides from Amyris plumieri. AB - Cytochrome P450 (CYP) enzyme inhibitory properties of six chromenylated amide compounds (CAs) from Amyris plumieri are described. Inhibition of CYP microsomes (CYP1A1, CYP1A2, CYP1B1, CYP2D6, CYP3A4 and CYP2C19) was monitored using a fluorescent assay. Potent inhibition was found against CYP1A1 with IC(50) and K(i) for CA1 (acetamide), being the lowest at 1.547 +/- 1.0 MUM and 0.37 MUM respectively, displaying non-competitive kinetics. The selectivity for CYP1A1 was increased in CA3 (butanamide), which also exhibited cytotoxicity against breast cancer cells, MCF7 with an IC(50) of 47.46 +/- 1.62 MUM. Structure-activity relationship studies provide insight at a molecular level for CAs with implications in chemoprevention and chemotherapy. PMID- 20951187 TI - Granulocyte-colony stimulating factor (G-CSF) enhances recovery in mouse model of Parkinson's disease. AB - INTRODUCTION: Granulocyte-colony stimulating factor (G-CSF) is used routinely in clinical practice for the treatment of neutropenia and to increase generation of hematopoietic stem cells in bone marrow donors. A growing body of literature on the neurotrophic effects of G-CSF has led to clinical trials in stroke, Alzheimer's disease (AD) and Parkinson's disease (PD). OBJECTIVES: The primary objective of this study was to determine if G-CSF administration would rescue the nigro-striatal system and restore locomotor function after completion of a sub acute course of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration (30mg/kg i.p. for 5 days) in 12 month-old mice. A secondary aim was to determine if G-CSF affects the neuro-inflammatory response by modulating microglial activation in striatum and midbrain. RESULTS: MPTP-treated mice were impaired on the rotometer test after the last dose of the toxicant and remained impaired until euthanasia. MPTP-treated mice that were given an 8-day regimen of G-CSF starting 2 days after the last dose of toxicant enhanced motor performance compared to the MPTP alone group. MPTP treatment depleted striatal DA (DA) levels; G-CSF given after MPTP resulted in a partial, significant repletion of DA levels. Total microglial burden in the striatum was increased significantly in MPTP-treated mice and was reduced after G-CSF rescue. CONCLUSION: G-CSF enhances recovery of DA nigro-striatal function from MPTP toxicity in part by modulating the microglial response to injury. The G-CSF receptor may provide a novel target for modifying the disease process in Parkinson's disease. PMID- 20951189 TI - Expression divergence of TaMBD2 homoeologous genes encoding methyl CpG-binding domain proteins in wheat (Triticum aestivum L.). AB - Most hexaploid wheat genes are present as triplicate homoeologs derived from the ancestral species. Previously, we isolated six wheat cDNAs with open reading frame, encoding methyl CpG-binding domain proteins (MBDs). In this study, the genomic and cDNA sequences of three TaMBD2 homoeologous genes were obtained and mapped on chromosomes 5A, 5B and 5D, respectively. These sequences showed a very high conservation in the coding region and the exon/intron structure, but the cDNA sequences are distinguishable by a 9-bp insertion in coding region and a size polymorphism in the 3'-untranslated region (UTR). The expression patterns of each homeologous gene in different tissues of various developmental stages and in response to abiotic stress were analyzed by using real-time PCR. Relative mRNA abundance of the three homoeologs varied considerably in different developmental stages from seedling to developing seeds. Most notably, TaMBD2-5B and TaMBD2-5D were highly responsive to salt stress and TaMBD2-5B was specifically upregulated by low temperature in the seedling leaves. These results provide further evidence for the expression variation of genes duplicated in allopolyploids. Moreover, the variation of TaMBD2 homoeologous gene expression in response to environmental stress may enable plants to better cope with stresses in their natural environments. PMID- 20951190 TI - Functional conservation and divergence of duplicated insulin-like growth factor 2 genes in grass carp (Ctenopharyngodon idellus). AB - Insulin-like growth factor 2 (IGF2) is a potent mitogenic and survival factor involved in the regulation of growth, development and reproduction in animals. Only one IGF2 gene exists in mammals. Recently, two igf2 genes have been identified in zebrafish, which presumably resulted from gene duplication. However, sequence information of duplicated igf2s and their functional regulation in other teleost fish is still unknown. Here, we report the identification of two igf2 cDNAs in grass carp, Ctenopharyngodon idellus. Like their human ortholog, grass carp igf2a and igf2b mRNAs encoded two structurally distinct mature IGF peptides. Both of them were detected by RT-PCR throughout embryogenesis. Ubiquitous expression of igf2b mRNAs was observed in embryos, whereas igf2a mRNAs were expressed mainly in the notochord and brain with in situ hybridization. In adult fish, igf2b mRNAs were transcribed in multiple tissues, whereas igf2a mRNAs were detected mainly in the liver. Hepatic levels of igf2a and igf2b transcripts were both up-regulated by growth hormone injection. Furthermore, the levels of hepatic igf2a and igf2b mRNAs decreased significantly during starvation and were rebounded rapidly after re-feeding. Our results suggest that duplicated igf2 genes have evolved divergent yet played an overlapping biological role in regulating grass carp growth and development. PMID- 20951191 TI - Timing of cochlear responses inferred from frequency-threshold tuning curves of auditory-nerve fibers. AB - Links between frequency tuning and timing were explored in the responses to sound of auditory-nerve fibers. Synthetic transfer functions were constructed by combining filter functions, derived via minimum-phase computations from average frequency-threshold tuning curves of chinchilla auditory-nerve fibers with high spontaneous activity (Temchin et al., 2008), and signal-front delays specified by the latencies of basilar-membrane and auditory-nerve fiber responses to intense clicks (Temchin et al., 2005). The transfer functions predict several features of the phase-frequency curves of cochlear responses to tones, including their shape transitions in the regions with characteristic frequencies of 1 kHz and 3-4 kHz (Temchin and Ruggero, 2010). The transfer functions also predict the shapes of cochlear impulse responses, including the polarities of their frequency sweeps and their transition at characteristic frequencies around 1 kHz. Predictions are especially accurate for characteristic frequencies <1 kHz. PMID- 20951192 TI - Meta-analysis of the clinical value of Astragalus membranaceus in diabetic nephropathy. AB - AIM OF STUDY: Nowadays diabetic nephropathy (DN) has become a serious problem. Astragalus membranaceus is a traditional herb used for thousands of years in China and East Asia for kidney disease. In modern medicine, Astragalus shows significant renal protective effect in DN. We aimed to systematically review the randomized and semi-randomized control trials to ascertain its role in the treatment of DN. MATERIALS AND METHODS: PUBMED, MEDLINE, Chinese journal full test database (CJFD), Chinese biological and medical database were searched by computer and manual searching. Two assessors independently reviewed each trial. 25 studies comprising 21 RCTs and 4 CCTs were involved including 1804 patients (945 in treatment group and 859 in control group). RESULTS AND CONCLUSIONS: Astragalus injection had more therapeutic effect in DN patients including renal protective effect (BUN, SCr, CCr and urine protein) and systemic state improvement (serum albumin level) compared with the control group. ETHNOPHARMACOLOGICAL RELEVANCE: This study investigates the effect of Astragalus in DN patients. It suggests that although of unknown bioactive ingredients and mechanism of renal protection, the role of Astragalus in the treatment of DN can be disclosed and of profound significance. PMID- 20951193 TI - Antinociceptive activity of Quillaja saponaria Mol. saponin extract, quillaic acid and derivatives in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Quillaja saponaria bark contains a high percentage of triterpene saponins and has been used for centuries as a cleansing and analgesic agent in Chilean folk medicine. AIM OF THE STUDY: The topical and systemic analgesic effects of a commercial partially purified saponin extract, 3beta,16alpha-dihydroxy-23-oxoolean-12-en-28-oic acid (quillaic acid), methyl 3beta,16alpha-dihydroxy-23-oxoolean-12-en-28-oate and methyl 4-nor-3,16 dioxoolean-12-en-28-oate. MATERIALS AND METHODS: The samples were assessed in mice using the topical tail-flick and i.p. hot-plate tests, respectively. RESULTS: All the samples showed activity in both analgesic tests in a dose dependent manner. The most active against tail flick test was commercial partially purified saponin extract (EC50 27.9 mg%, w/v) and more than the ibuprofen sodium. On hot-plate test, methyl 4-nor-3, 16-dioxoolean-12-en-28-oate was the most active (ED50 12.2 mg/kg) and more than the ibuprofen sodium. CONCLUSIONS: The results of the present study demonstrated that Quillaja saponaria saponins, quillaic acid, its methyl ester, and one of the oxidized derivatives of the latter, elicit dose-dependent antinociceptive effects in two murine thermal models. PMID- 20951194 TI - Proteomic analysis of plasma proteins in Japanese semisuper centenarians. AB - We performed proteomic analysis of plasma proteins in Japanese semisuper centenarians (SSCs) (>105 years) and young controls (20-39 years), and found that 18 protein spots were altered in the plasma of SSCs. From peptide mass fingerprinting following in-gel digestion, it was demonstrated that paraoxonase/arylesterase 1 (PON 1) and apolipoprotein E were decreased, while haptoglobin beta-chain, alpha(1)-microglobulin, and clusterin precursor were increased in SSCs. Interestingly, proteins related to oxidative stress, PON1, haptoglobin, alpha(1)-microglobulin, and clusterin, were altered in SSCs. These results suggest that systemic redox regulation is important for the longevity of SSCs. Overall, proteomics analysis is a powerful technique to search for useful biomarkers for future studies in gerontology and to characterize the individual proteins associated with successful aging of SSCs. PMID- 20951195 TI - Association of a common LAMA5 variant with anthropometric and metabolic traits in an Italian cohort of healthy elderly subjects. AB - Laminins are large heterotrimeric glycoproteins found in basement membranes where they play an essential role in cell-matrix adhesion, migration, growth, and differentiation of various cell types. Previous work reported that a genetic variant located within the intron 1 of LAMA5 (rs659822) was associated with anthropometric traits and HDL-cholesterol levels in a cohort of premenopausal women. The present study aimed to investigate the effect of LAMA5 rs659822 on anthropometric traits, lipid profile, and fasting glucose levels in an Italian cohort of 667 healthy elderly subjects (aged 64-107years). We also tested for association between these traits and the single nucleotide polymorphism (SNP) rs13043313, which was previously shown to control variation in LAMA5 transcript abundance in the liver of Caucasians. In age- and gender-adjusted linear regression analyses, we did not find association of rs13043313 with any of the traits. However, under an additive model, the minor C-allele of LAMA5 rs659822 was associated with shorter stature (p = 0.007) and higher fasting glucose levels (p = 0.02). Moreover, subjects homozygous for the C-allele showed on average 6% and 10% lower total cholesterol (p = 0.034) and LDL-cholesterol (p = 0.016) levels, respectively, than those carrying at least one T allele, assuming a recessive model. Finally, in analyses stratified by age groups (age range 64-89 and 90-107 years), we found that the C-allele was additively associated with increased body weight (p = 0.018) in the age group 64-89 years, whereas no association was found in the age group 90-107 years. In conclusion, this study provides evidence that LAMA5 rs659822 regulates anthropometric and metabolic traits in elderly people. Future studies are warranted to replicate these findings in independent and larger populations and to investigate whether rs659822 is the causal variant responsible for the observed associations. PMID- 20951196 TI - A comprehensive assessment of methods for de-novo reverse-engineering of genome scale regulatory networks. AB - De-novo reverse-engineering of genome-scale regulatory networks is an increasingly important objective for biological and translational research. While many methods have been recently developed for this task, their absolute and relative performance remains poorly understood. The present study conducts a rigorous performance assessment of 32 computational methods/variants for de-novo reverse-engineering of genome-scale regulatory networks by benchmarking these methods in 15 high-quality datasets and gold-standards of experimentally verified mechanistic knowledge. The results of this study show that some methods need to be substantially improved upon, while others should be used routinely. Our results also demonstrate that several univariate methods provide a "gatekeeper" performance threshold that should be applied when method developers assess the performance of their novel multivariate algorithms. Finally, the results of this study can be used to show practical utility and to establish guidelines for everyday use of reverse-engineering algorithms, aiming towards creation of automated data-analysis protocols and software systems. PMID- 20951197 TI - Comparative genomic study of protein disulfide isomerases from photosynthetic organisms. AB - Protein disulfide isomerases (PDIs) are eukaryotic oxidoreductases essential for oxidative protein folding. Their diversity in photosynthetic organisms was assessed by analyzing 24 sequenced genomes belonging to algal, lycophyte, bryophyte and angiosperm phyla. This phylogenetic analysis led to an updated classification into 9 classes (PDI-A to -F, -L, -M and -S) which differed by the number of Trx domains and the presence of additional domains (D, COPII, J and ARMET). From an evolutionary perspective, the distribution and protein architecture of PDIs differ considerably between algae and terrestrial plants, 5 PDI classes are common whereas 1 is specific to terrestrial plants and 3 to algae. Some algal PDI-Fs possess selenocysteine residues. The PDI family is larger in mammals (19 members in human) than in land plants (around 10 members) and Saccharomyces cerevisiae (5 members). However, PDIs from photosynthetic organisms display an important structural and functional diversity considering their association to specific protein domains. PMID- 20951198 TI - Data-mining of the Meloidogyne incognita degradome and comparative analysis of proteases in nematodes. AB - Proteases perform essential physiological functions in all living organisms. In parasitic helminths, they are of particular importance for tissue penetration, digestion of host tissues for nutrition, and evasion of host immune responses. The recent availability of the genome sequence of the nematode Meloidogyne incognita has allowed the analysis of the protease repertoire of this major crop pathogen. The M. incognita degradome consists of at least 334 proteases that are distributed into 43 families of the five known catalytic classes. Expression profiling identified protease genes with a differential transcript level between eggs and infective juveniles. Comparing the M. incognita degradome with those of five other nematodes showed discrepancies in the distribution of some protease families, including large expansion in some families, that could reflect specific aspects of the parasitic lifestyle of this organism. This comparative study should provide a framework for deciphering the diversity of protease-mediated functions in nematodes. PMID- 20951199 TI - Collagen type IV nephropathy: genetic heterogeneity examinations in affected Hungarian families. AB - The Col4A3, Col4A4 and Col4A5 collagen type IV genes are found to be mutated in Col IV nephropathy. In males with a mutation in the Col4A5 gene (X-linked Alport syndrome: XL-AS), progressive renal disease always develops. Female carriers with a mutation in the Col4A5 gene can develop thin basement membrane nephropathy (TBMN). Males and females who carry 1 Col4A3 or Col4A4 mutation usually manifest TBMN with nonprogressive hematuria. In the event of 2 Col4A3 or Col4A4 gene mutations, the autosomal recessive AS will develop. We examined the cosegregation pattern of hematuria in 20 families. The renal biopsies led to diagnoses of AS in 7 families, and of TBMN in 6 families. In 7 others, the diagnosis of familial hematuria (FHU) was based on the clinical symptoms. Markers of the ColA3/Col4A4 and Col4A5 loci (Col4A3: CA11 and D2S401; Col4A4: HaeIII/RFLP; and Col4A5: DXS456, 2B6 and 2B20) were used to assess their linkage to the clinical symptoms and morphological alterations. Maximum likelihood and the FASTLINK version of the linkage program were applied to compute logarithm of the odds (LOD) scores. A linkage to the Col4A3/Col4A4 genes was identified in 5 families (FHU in 3, AS in 2 families, 25%, LOD score range: 0.20-3.51). The XL-AS pattern of inheritance seemed likely with Col4A5 in 9 families (45%, LOD: 0.43-4.20); we found 4 disease causative mutations by high-resolution melting curve analysis (LC480) and sequencing in this group. In 2 FHU families, the linkage to chromosomes 2 and X was precluded. Knowledge of the genetic background of Col IV nephropathy is essential to avoid the misdiagnosis of FHU and early AS. The allele frequencies, heterozygosity content and polymorphism information content of the applied STR markers on unrelated Hungarian normal and affected chromosomes 2 and X were also calculated. PMID- 20951200 TI - A new Pharmaceutical Aerosol Deposition Device on Cell Cultures (PADDOCC) to evaluate pulmonary drug absorption for metered dose dry powder formulations. AB - Absorption studies with aerosol formulation delivered by metered dose inhalers across cell- and tissue-based in vitro models of the pulmonary epithelia are not trivial due to the complexity of the processes involved: (i) aerosol generation and deposition, (ii) drug release from the carrier, and (iii) absorption across the epithelial air-blood barrier. In contrast to the intestinal mucosa, pulmonary epithelia are only covered by a thin film of lining fluid. Submersed cell culture systems would not allow to studying the deposition of aerosol particles and their effects on this delicate epithelial tissue. We developed a new Pharmaceutical Aerosol Deposition Device on Cell Cultures (PADDOCC) to mimic the inhalation of a single metered aerosol dose and its subsequent deposition on filter-grown pulmonary epithelial cell monolayers exposed to an air-liquid interface. The reproducibility of deposition of these dry powder aerosols and subsequent drug transport across Calu-3 monolayers with commercially available dry powder inhalers containing salbutamol sulphate or budesonide could be demonstrated. In the context of developing new dry powder aerosol formulations, PADDOCC appears as a useful tool, allowing reducing animal testing and faster translation into clinical trials. PMID- 20951201 TI - Clonal overgrowth of esophageal smooth muscle cells in diffuse leiomyomatosis Alport syndrome caused by partial deletion in COL4A5 and COL4A6 genes. AB - This is a study of a patient who manifests all of the features of a diffuse leiomyomatosis-Alport syndrome (DL-ATS), and her two-year-old son who has already been diagnosed with Alport syndrome. Fourteen years ago, the patient underwent a partial esophageal resection followed by a replacement with jejunum. Recently, she underwent a surgical resection of the esophagus due to esophageal dysfunction. Genetic analyses of COL4A5 and COL4A6 on the X-chromosome were efficiently performed using the genomic DNA of her son. We have identified a novel deletion of 194-kb in length, encompassing COL4A5-COL4A6 promoters as well as nearly the entire large intron 1 of COL4A5 and intron 2 of COL4A6. To uncover the relationship of the esophagus-specific occurrence of the tumor and the expression of those genes, immunohistochemical analyses of type IV collagen alpha chains were conducted in the non-affected individuals. The esophageal smooth muscle-specific expression of alpha5(IV) and alpha6(IV) chains in the gastrointestinal tract was observed. Moreover, CAG repeat analysis of the androgen receptor gene and an immunohistochemical analysis in the leiomyoma revealed clonal overgrowth of the cells which received X-inactivation on the non affected allele. These results may suggest that the dominant effect was caused by the partial deletion of the esophageal smooth muscle-specific genes, COL4A5 and COL4A6. PMID- 20951202 TI - Dysfunctional tendon collagen fibrillogenesis in collagen VI null mice. AB - Tendons are composed of fibroblasts and collagen fibrils. The fibrils are organized uniaxially and grouped together into fibers. Collagen VI is a non fibrillar collagen expressed in developing and adult tendons. Human collagen VI mutations result in muscular dystrophy, joint hyperlaxity and contractures. The purpose of this study is to determine the functional roles of collagen VI in tendon matrix assembly. During tendon development, collagen VI was expressed throughout the extracellular matrix, but enriched around fibroblasts and their processes. To analyze the functional roles of collagen VI a mouse model with a targeted inactivation of Col6a1 gene was utilized. Ultrastructural analysis of Col6a1-/- versus wild type tendons demonstrated disorganized extracellular micro domains and associated collagen fibers in the Col6a1-/- tendon. In Col6a1-/- tendons, fibril structure and diameter distribution were abnormal compared to wild type controls. The diameter distributions were shifted significantly toward the smaller diameters in Col6a1-/- tendons compared to controls. An analysis of fibril density (number/MUm(2)) demonstrated a ~2.5 fold increase in the Col6a1-/- versus wild type tendons. In addition, the fibril arrangement and structure were aberrant in the peri-cellular regions of Col6a1-/- tendons with frequent very large fibrils and twisted fibrils observed restricted to this region. The biomechanical properties were analyzed in mature tendons. A significant decrease in cross-sectional area was observed. The percent relaxation, maximum load, maximum stress, stiffness and modulus were analyzed and Col6a1-/- tendons demonstrated a significant reduction in maximum load and stiffness compared to wild type tendons. An increase in matrix metalloproteinase activity was suggested in the absence of collagen VI. This suggests alterations in tenocyte expression due to disruption of cell-matrix interactions. The changes in expression may result in alterations in the peri-cellular environment. In addition, the absence of collagen VI may alter the sequestering of regulatory molecules such as leucine rich proteoglycans. These changes would result in dysfunctional regulation of tendon fibrillogenesis indirectly mediated by collagen VI. PMID- 20951203 TI - DT56a (Femarelle), contrary to estradiol-17beta, is effective in human derived female osteoblasts in hyperglycemic condition. AB - We have reported previously, that female-derived cultured osteoblasts (hObs) responded to DT56a (Femarelle) measured by the stimulation of creatine kinase specific activity (CK), which is a marker for hormone responsiveness and (3)[H] thymidine incorporation into DNA (DNA synthesis). Since the skeletal protective effects of estrogens are not discernable in hyperglycemic diabetic women, we sought to analyze the effect of estrogenic compounds on CK and DNA synthesis in hObs when grown in high glucose concentration (HG). Cells were grown either in normal glucose (NG) (4.5g/L; 22mM) or HG (9.0g/L; 44mM) for 7 days. HG increased constitutive CK but, the response of CK activity and DNA synthesis to estradiol 17beta (E(2)) treatment was reduced. In contrary, DT56a was found to be active (as measured by CK activity and DNA synthesis) in both NG and HG. HG decreases the hormonal responsiveness and might block important effects of estrogenic compounds, most likely contributing to their decreased skeletal preserving properties in hyperglycemic women. In hObs from post-menopausal women grown in HG, ERs mRNA expressions were unchanged. On the other hand, in hObs from pre menopausal women HG increased ERs mRNA expressions. Since DT56a unlike E(2) is active in HG environment as well as in normal glucose, it may be an effective bone restoring agent in diabetic post-menopausal women. PMID- 20951204 TI - Monitoring of CD38high expression in peripheral blood CD8+ lymphocytes in patients after kidney transplantation as a marker of cytomegalovirus infection. AB - BACKGROUND: Cytomegalovirus (CMV) infection is a life-threatening complication after solid organ transplantation. It usually appears in the first months after transplantation as a consequence of immunosuppression. The goal of this study was to evaluate the clinical significance of CD38(high)/CD3(+)8(+) percentages in the detection of CMV infection in patients after kidney transplantation. METHODS: In this retrospective study, 269 patients were monitored 2-3 months after renal transplantation for the percentage of CD38(high)/CD3(+)8(+) lymphocytes estimated by flow cytometry and for the number of CMV DNA copies in peripheral blood using a real-time polymerase chain reaction. RESULTS: CMV infection was diagnosed in 12 (4.5%) patients between the 31st and 63rd days after transplantation, and all of them had percentages of CD38(high)/CD3(+)8(+) T lymphocytes above 20%. In 4 of them, CMV DNAemia in peripheral blood was not detected, and 2 of these suffered from tissue-invasive CMV disease. In 7 patients with CMV DNAemia, the CD38(high)/CD3(+)8(+) T lymphocyte percentage did not exceed 20%, and these patients did not develop CMV infection requiring antiviral treatment. In 23 additional patients, a CD38(high)/CD3(+)CD8(+) percentage above 20% was recorded without CMV DNAemia. All of the remaining 234 patients never exceeded the arbitrary limit of 20%. The estimated sensitivity and specificity were 100% and 91% using clinical decision on the presence of CMV infection as a reference value, respectively. The estimated negative predictive value was 100%; however, the estimated positive predictive value was quite low (34%). CONCLUSIONS: The CD38(high)/CD3(+)8(+) lymphocyte percentage seems to be a useful additional diagnostic marker for CMV infection in patients after kidney transplantation, especially when patients are in the risk of a tissue-invasive disease when CMV DNA copies may not be detectable in peripheral blood. PMID- 20951205 TI - Both cytoplasmic and nuclear accumulations of the protein are neurotoxic in Drosophila models of TDP-43 proteinopathies. AB - Recently, the TAR DNA-binding protein-43 (TDP-43) has been identified as a major constituent of nuclear and/or cytoplasmic ubiquitin-positive inclusions in patient with amyotrophic lateral sclerosis or frontotemporal lobar degeneration. Pathological proteins are abnormally hyperphosphorylated and partially cleaved to generate C-terminal fragments. In this issue, we addressed the mechanism underlying TDP-43 toxicity in vivo, using Drosophila as an experimental model. We developed new Drosophila transgenic models expressing different variants of full length human TDP-43 proteins presenting different subcellular localizations: a wild-type form of hTDP-43 and two mutants forms of the protein, hTDP-43mutNLS and hTDP43mutNES, which lack nuclear localization signals (NLS) and nuclear export signals (NES), respectively. Using an inducible GAL4 system, we found that both nuclear and cytoplasmic accumulations of TDP-43 in adult neurons lead to reduction of lifespan in Drosophila, the gradient of toxicity being hTDP-43>hTDP 43mutNLS>hTDP43mutNES. This toxicity occurs regardless of inclusions formation. In the other hand, in retina, muscle and glial cells, only the accumulation of cytoplasmic species of TDP-43 was toxic. Biochemical data showed that human TDP 43 proteins expressed in adult fly neurons are abnormally phosphorylated on the disease-specific Ser409/Ser410 site and processed. In conclusion, our data show that TDP-43 expression in flies recapitulates several biochemical key features of human TDP-43 proteinopathies, including abnormal phosphorylation on a disease specific site and processing of the protein. Moreover, our TDP-43 Drosophila models indicate that distinct pathways of TDP-43 toxicity might operate depending on the cell type. PMID- 20951206 TI - Increased vesicular glutamate transporter expression causes excitotoxic neurodegeneration. AB - Increases in vesicular glutamate transporter (VGLUT) levels are observed after a variety of insults including hypoxic injury, stress, methamphetamine treatment, and in genetic seizure models. Such overexpression can cause an increase in the amount of glutamate released from each vesicle, but it is unknown whether this is sufficient to induce excitotoxic neurodegeneration. Here we show that overexpression of the Drosophila vesicular glutamate transporter (DVGLUT) leads to excess glutamate release, with some vesicles releasing several times the normal amount of glutamate. Increased DVGLUT expression also leads to an age dependent loss of motor function and shortened lifespan, accompanied by a progressive neurodegeneration in the postsynaptic targets of the DVGLUT overexpressing neurons. The early onset lethality, behavioral deficits, and neuronal pathology require overexpression of a functional DVGLUT transgene. Thus overexpression of DVGLUT is sufficient to generate excitotoxic neuropathological phenotypes and therefore reducing VGLUT levels after nervous system injury or stress may mitigate further damage. PMID- 20951207 TI - Striatal Abeta peptide deposition mirrors dementia and differentiates DLB and PDD from other parkinsonian syndromes. AB - Recent neuropathological studies have described widespread amyloid-beta peptide (Abeta) deposition in the striatum of patients with Lewy body disorders, particularly in Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). However, positron emission tomography (PET) studies using the [(11)C]PIB ligand, binding to Abeta deposits, detects significant striatal pathology only in DLB and not in PDD. Employing immunohistochemistry, we examined striatal Abeta deposition in the caudate nucleus and putamen of 52 PD, 41 PDD, 14 DLB, 7 multiple system atrophy (MSA) and 14 progressive supranuclear palsy (PSP) cases in relation to the presence of dementia. PD, MSA and PSP cases showed little or no Abeta pathology in the striatum. In contrast, both PDD and DLB cases demonstrated significantly greater Abeta deposition in the striatum when compared to PD, MSA and PSP groups. We conclude that striatal Abeta pathology is common in both PDD and DLB and may reflect the development of dementia in these conditions. More detailed examination of the morphology of the Abeta pathology suggests that it is the presence of cored amyloid plaques in DLB, but not PDD, that underlies the differences seen in PET imaging. PMID- 20951208 TI - Morphological and functional alterations in the substantia nigra pars compacta of the Mecp2-null mouse. AB - Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the MECP2 gene, in which older patients often develop parkinsonian features. Although Mecp2 has been shown to modulate the catecholaminergic metabolism of the RTT mouse model, little is known about the central dopaminergic neurons. Here we found that the progression of the motor dysfunction in the Mecp2-deficient mouse becomes more severe between 4 and 9 weeks of age. We then studied the phenotype of the dopaminergic neurons of the substantia nigra pars compacta (SNpc). We found a major reduction in the number of tyrosine hydroxylase (Th)-expressing neurons, as well as a reduction in their soma size, by 5 weeks of age. We showed that this deficit is not due to apoptosis and that the remaining neurons express a mature dopaminergic phenotype. A reduction in the Th-staining intensity was also found in the caudate-putamen (CPu), the main dopaminergic target for SNpc. We found that the amount of activated-Th (pSer40-Th) is slightly reduced at 5 weeks of age in the Mecp2-deficient mouse, but that this amount is affected more importantly by 9 weeks of age. Neurochemical measurements revealed a significant reduction of dopamine content at 5 and 9 weeks of age in the CPu whereas SNpc contents were preserved. Finally, we found that chronic L-Dopa treatment improved the motor deficits previously identified. Altogether, our findings demonstrate that Mecp2-deficiency induces nigrostriatal deficits, and they offer a new perspective to better understand the origin of motor dysfunction in RTT. PMID- 20951209 TI - Endothelium-dependent vasomotor effects of telmisartan in isolated rat femoral arteries. AB - AT(1) receptor antagonists (ARBs) are drugs widely used for preventing and/or treating major cardiovascular diseases. Some of these drugs also show AT(1) receptor-independent effects that may have patho-physiological significance, such as Peroxisome Proliferator-Activated Receptors gamma (PPARgamma) stimulation. Here we investigated the effect of telmisartan (that also stimulates PPARgamma) on vasomotor responses of femoral arteries isolated from rat, in comparison to losartan. Femoral artery segments were mounted in a wire myograph and challenged with cumulative concentrations of phenylephrine (PE) and acetylcholine (ACh) after 30-min incubation in the absence or presence of 30 MUM telmisartan or 30 MUM losartan. Vasomotor responses were not significantly changed by losartan, whereas telmisartan reduced vasoconstriction to PE and increased vasodilatation to ACh. Incubation with 0.1 mM N(G)-nitro-l-arginine abolished relaxation to ACh in untreated controls as well as in losartan-treated preparations, but did not in telmisartan-treated preparations (were 20% relaxation subsisted); this residual relaxing effect was abolished by indomethacin and by endothelium removal. Incubation with 30 MUM GW9662 (PPARgamma antagonist), 10 MUM PD123319 (AT(2) antagonist) or 30 MUM A779 (angiotensin(1-7)/Mas antagonist) did not change the effect of telmisartan on vasomotor responses in preparations with intact endothelium. We conclude that telmisartan modifies constriction and dilatation of isolated arteries in an endothelium-dependent manner, involving both nitric oxide and prostanoid production. The present effect of telmisartan, however, does not seem to involve PPARgamma, AT(2) or angiotensin(1-7)/Mas. PMID- 20951212 TI - Characterization of an oxidative stress response regulator, homologous to Escherichia coli OxyR, from the phytopathogen Xylella fastidiosa. AB - The OxyR oxidative stress transcriptional regulator is a DNA-binding protein that belongs to the LysR-type transcriptional regulators (LTTR) family. It has the ability to sense oxidative species inside the cell and to trigger the cell's response, activating the transcription of genes involved in scavenging oxidative species. In the present study, we have overexpressed, purified and characterized the predicted OxyR homologue (orf xf1273) of the phytopathogen Xylella fastidiosa. This bacterium is the causal agent of citrus variegated chlorosis (CVC) disease caused by the 9a5c strain, resulting in economic and social losses. The secondary structure of the recombinant protein was analyzed by circular dichroism. Gel filtration showed that XfoxyR is a dimer in solution. Gel shift assays indicated that it does bind to its own predicted promoter under in vitro conditions. However, considering our control experiment we cannot state that this interaction occurs in vivo. Functional complementation assays indicated that xfoxyR is able to restore the oxidative stress response in an oxyr knockout Escherichia coli strain. These results show that the predicted orfxf1273 codes for a transcriptional regulator, homologous to E. coli OxyR, involved in the oxidative stress response. This may be important for X. fastidiosa to overcome the defense mechanisms of its host during the infection and colonization processes. PMID- 20951213 TI - A strategy for high-level expression of a single-chain variable fragment against TNFalpha by subcloning antibody variable regions from the phage display vector pCANTAB 5E into pBV220. AB - A phage display single-chain variable fragment (scFv) library against TNFalpha was constructed using a recombinant phage antibody system (RPAS). The cloned scFv gene was introduced into the phage display vector pCANTAB 5E and expressed in Escherichia coli (E. coli) with a yield of up to 0.15 mg/l of total protein. With the attempt to improve the expression level of TNF-scFv, a strategy was established for subcloning the scFv gene from pCANTAB 5E into the plasmid pBV220. Under the control of a highly efficient tandem P(R)P(L) promoter system, scFv production was increased to 30% of total protein as inclusion bodies. After extraction from the cell pellet by sonication, the inclusion bodies were solubilized and denatured in the presence of 8M urea. Purification of denatured scFv was performed using nickel column chromatography followed by renaturation. The purity and activity of the refolded scFv were confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blotting and by an enzyme-linked immunoabsorbent assay (ELISA). The results reveal that the overall yield of bioactive TNF-scFv from E. coli flask cultures was more than 45 mg/l culture medium and 15 mg/g wet weight cells. The renatured scFv exhibited binding activity similarly to soluble scFv. In conclusion we developed a method to over express TNF-scFv, which have biological function after purification and renaturation. PMID- 20951211 TI - Tetracycline compounds with non-antimicrobial organ protective properties: possible mechanisms of action. AB - Tetracyclines were developed as a result of the screening of soil samples for antibiotics. The first(t) of these compounds, chlortetracycline, was introduced in 1947. Tetracyclines were found to be highly effective against various pathogens including rickettsiae, as well as both gram-positive and gram-negative bacteria, thus becoming the first class of broad-spectrum antibiotics. Many other interesting properties, unrelated to their antibiotic activity, have been identified for tetracyclines which have led to widely divergent experimental and clinical uses. For example, tetracyclines are also an effective anti-malarial drug. Minocycline, which can readily cross cell membranes, is known to be a potent anti-apoptotic agent. Another tetracycline, doxycycline is known to exert anti-protease activities. Doxycycline can inhibit matrix metalloproteinases which contribute to tissue destruction activities in diseases such as periodontitis. A large body of literature has provided additional evidence for the "beneficial" actions of tetracyclines, including their ability to act as reactive oxygen species scavengers and anti-inflammatory agents. This review provides a summary of tetracycline's multiple mechanisms of action as a means to understand their beneficial effects. PMID- 20951214 TI - Baculoviral expression and characterization of human recombinant PGCP in the form of an active mature dimer and an inactive precursor protein. AB - The human-blood plasma glutamate carboxypeptidase (PGCP) is a proteinase that acts on the unsubstituted N- and C-termini of dipeptides. It has been suggested that this PGCP is involved in the release of thyroxine. Furthermore, research has suggested that its activity is up-regulated in hepatitis-C-virus-infected patients with hepatocellular carcinoma. In this study expressed human PGCP in the baculovirus expression system was produced by a Sf9 insect cell line with aim to prepare sufficient amounts of active recombinant enzyme for a subsequent biological characterization. Recombinant PGCP was expressed and secreted into the medium in the form of an inactive proenzyme. It was gradually converted into an active form in the medium after three days, with the highest expression of the active form on day six. The protein was sequentially purified by a combination of various liquid chromatographies, such as hydroxyapatite, ion exchange, and gel chromatography, and as final step with affinity chromatography on Phe-Leu Sepharose. The human PGCP was purified as an active enzyme in the dimer form and as inactive precursor protein. The dipeptidase activity was confirmed by measuring the hydrolysis of the Ser-Met dipeptide at a slightly acidic pH. PMID- 20951215 TI - Emotional perception: meta-analyses of face and natural scene processing. AB - Functional imaging studies of emotional processing typically contain neutral control conditions that serve to remove simple effects of visual perception, thus revealing the additional emotional process. Here we seek to identify similarities and differences across 100 studies of emotional face processing and 57 studies of emotional scene processing, using a coordinate-based meta-analysis technique. The overlay of significant meta-analyses resulted in extensive overlap in clusters, coupled with offset and unique clusters of reliable activity. The area of greatest overlap is the amygdala, followed by regions of medial prefrontal cortex, inferior frontal/orbitofrontal cortex, inferior temporal cortex, and extrastriate occipital cortex. Emotional face-specific clusters were identified in regions known to be involved in face processing, including anterior fusiform gyrus and middle temporal gyrus, and emotional scene studies were uniquely associated with lateral occipital cortex, as well as pulvinar and the medial dorsal nucleus of the thalamus. One global result of the meta-analysis reveals that a class of visual stimuli (faces vs. scenes) has a considerable impact on the resulting emotion effects, even after removing the basic visual perception effects through subtractive contrasts. Pure effects of emotion may thus be difficult to remove for the particular class of stimuli employed in an experimental paradigm. Whether a researcher chooses to tightly control the various elements of the emotional stimuli, as with posed face photographs, or allow variety and environmental realism into their evocative stimuli, as with natural scenes, will depend on the desired generalizability of their results. PMID- 20951216 TI - Entropy-based analysis for diffusion anisotropy mapping of healthy and myelopathic spinal cord. AB - The present study utilized diffusion MR imaging and fractional anisotropy (FA) mapping to delineate the microstructure of spinal cord. The concept of Shannon entropy was introduced to analyze the complex microstructure of healthy and injured spinal cords based on FA map. A total of 30 volunteers were recruited in this study with informed consent, including 13 healthy adult subjects (group A, 25+/-3 years), 12 healthy elderly subjects (group B, 53+/-7 years) and 5 cervical spondylotic myelopathy (CSM) patients (group C, 53+/-15 years). Diffusion MRI images of cervical spinal cord were taken using pulsed gradient spin-echo-echo planar imaging (SE-EPI) sequence with a 3T MR system. The region of interest was defined to cover the spinal cord in FA maps. The Shannon entropy of FA values of voxels in the cord was calculated as well as the average FA values. The significant differences were determined among three groups using one-way ANOVA and post-hoc test. As compared with adult and elderly healthy subjects, the entropy of whole spinal cord was significantly lower in CSM patients (group A: 6.07+/-0.18; B: 6.01+/-0.23; C: 5.32+/-0.44; p<0.05). Whereas there were no significant difference in FA values among groups (group A: 0.62+/-0.08; B: 0.64+/ 0.09; C: 0.64+/-0.12). In CSM patients, there was a loss of architectural structural complexity in the cervical spinal cord tissue as noted by the lower Shannon entropy value. It indicated the potential application of entropy-based analysis for the diagnosis of the severity of chronic compressive spinal cord injuries, i.e. CSM. PMID- 20951217 TI - In vivo mapping of brain myo-inositol. AB - Myo-Inositol (MI) is one of the most abundant metabolites in the human brain located mainly in glial cells and functions as an osmolyte. The concentration of MI is altered in many brain disorders including Alzheimer's disease and brain tumors. Currently available magnetic resonance spectroscopy (MRS) methods for measuring MI are limited to low spatial resolution. Here, we demonstrate that the hydroxyl protons on MI exhibit chemical exchange with bulk water and saturation of these protons leads to reduction in bulk water signal through a mechanism known as chemical exchange saturation transfer (CEST). The hydroxyl proton exchange rate (k=600 s(-1)) is determined to be in the slow to intermediate exchange regime on the NMR time scale (chemical shift (?omega)>k), suggesting that the CEST effect of MI (MICEST) can be imaged at high fields such as 7 T (?omega=1.2*10(3)rad/s) and 9.4 T (?omega=1.6*10(3) rad/s). Using optimized imaging parameters, concentration dependent broad CEST asymmetry between ~0.2 and 1.5 ppm with a peak at ~0.6 ppm from bulk water was observed. Further, it is demonstrated that MICEST detection is feasible in the human brain at ultra high fields (7 T) without exceeding the allowed limits on radiofrequency specific absorption rate. Results from healthy human volunteers (N=5) showed significantly higher (p=0.03) MICEST effect from white matter (5.2+/-0.5%) compared to gray matter (4.3+/-0.5%). The mean coefficient of variations for intra-subject MICEST contrast in WM and GM were 0.49 and 0.58 respectively. Potential overlap of CEST signals from other brain metabolites with the observed MICEST map is discussed. This noninvasive approach potentially opens the way to image MI in vivo and to monitor its alteration in many disease conditions. PMID- 20951219 TI - Short-term memory capacity (7 +/- 2) predicted by theta to gamma cycle length ratio. AB - The number of items that can be held in human short-term memory (STM) is limited to 7 (+/- 2) elements. Lisman and Idiart's theoretical model of STM proposes that this value depends on the number of gamma cycles that can fit in one theta cycle. Previous studies on animals and humans provided support for this hypothesis but direct evidence from human EEG scalp recordings has not previously been reported. We recorded spontaneous EEG activity from 17 participants and measured their verbal STM capacity with a modified digit span task from the Wechsler battery. The strong and positive correlation we found between verbal STM capacity and theta/gamma cycle length ratio thus provides a direct argument in favor of this STM theoretical model. In this study we also demonstrated a new method for assessing individual theta and gamma frequencies by detecting functional coupling between these oscillations. PMID- 20951218 TI - Phylogenetic analysis of New Zealand earthworms (Oligochaeta: Megascolecidae) reveals ancient clades and cryptic taxonomic diversity. AB - We have constructed the first ever phylogeny for the New Zealand earthworm fauna (Megascolecinae and Acanthodrilinae) including representatives from other major continental regions. Bayesian and maximum likelihood phylogenetic trees were constructed from 427 base pairs from the mitochondrial large subunit (16S) rRNA gene and 661 base pairs from the nuclear large subunit (28S) rRNA gene. Within the Acanthodrilinae we were able to identify a number of well-supported clades that were restricted to continental landmasses. Estimates of nodal support for these major clades were generally high, but relationships among clades were poorly resolved. The phylogenetic analyses revealed several independent lineages in New Zealand, some of which had a comparable phylogenetic depth to monophyletic groups sampled from Madagascar, Africa, North America and Australia. These results are consistent with at least some of these clades having inhabited New Zealand since rifting from Gondwana in the Late Cretaceous. Within the New Zealand Acanthodrilinae, major clades tended to be restricted to specific regions of New Zealand, with the central North Island and Cook Strait representing major biogeographic boundaries. Our field surveys of New Zealand and subsequent identification has also revealed extensive cryptic taxonomic diversity with approximately 48 new species sampled in addition to the 199 species recognized by previous authors. Our results indicate that further survey and taxonomic work is required to establish a foundation for future biogeographic and ecological research on this vitally important component of the New Zealand biota. PMID- 20951220 TI - Critical roles of mecamylamine-sensitive mushroom body neurons in insect olfactory learning. AB - In insects, cholinergic neurons are thought to transmit olfactory conditioned stimulus (CS) to the sites for associating the CS with unconditioned stimulus (US), but the types of acetylcholine (ACh) receptor used by neurons participating in the association have not been determined. In cockroaches, a type of nicotinic ACh receptor specifically antagonized by mecamylamine (MEC) has been characterized. Here we investigated the roles of neurons possessing MEC-sensitive ACh receptors (MEC-sensitive neurons) in olfactory conditioning of salivation, monitored by changes in activities of salivary neurons, in cockroaches. Local and bilateral microinjection of MEC into each of the three olfactory centers, antennal lobes, calyces of the mushroom bodies and lateral protocerebra, impaired olfactory responses of salivary neurons, indicating that MEC-sensitive neurons in all olfactory centers participate in pathways mediating olfactory responses of salivary neurons. Conditioning of olfactory CS with sucrose US was impaired by injection of MEC into the antennal lobes or calyces, i.e., conditioned responses were absent even after recovery from MEC injection, suggesting that the CS-US association occurs in MEC-sensitive neurons in calyces (most probably Kenyon cells) or in neurons in downstream pathways. In contrast, conditioned responses appeared after recovery from MEC injection into the lateral protocerebra, suggesting that MEC-sensitive neurons in the lateral protocerebra are downstream of the association sites. Since lateral protocerebra are major termination areas of mushroom body efferent neurons, we suggest that input synapses of MEC sensitive Kenyon cells, or their output synapses upon mushroom body efferent neurons, are the sites for CS-US association for conditioning of salivation. PMID- 20951221 TI - dsRNA-induced expression of thymic stromal lymphopoietin (TSLP) in asthmatic epithelial cells is inhibited by a small airway relaxant. AB - RATIONALE: Thymic Stromal Lymphopoietin (TSLP) is considered a hub cytokine that activates dendritic cells and T-cells producing asthma-like Th2-inflammation. Viral stimuli, a major cause of asthma exacerbations, have been shown to induce overexpression of TSLP in asthmatic epithelium. Capsazepine has multiple effects and is of interest because it relaxes human small airways. Here we have explored effects of capsazepine on viral surrogate (dsRNA)-induced TSLP and other cytokines (TNF-alpha, IL-8) in human bronchial epithelial cells (HBEC) from healthy and asthmatic donors. METHODS: HBEC obtained from healthy and asthmatic subjects were grown and stimulated with dsRNA. Cells pre-treated with capsazepine (3-30 MUM), dexamethasone (0.1-10 MUM) or an IkappaB-kinase inhibitor (PS1145, 30 MUM) were also exposed to dsRNA (10 MUg/ml). Cells and supernatants were harvested for analyses of gene expression (RT-qPCR) and protein production (ELISA,Western blot). RESULTS: dsRNA-induced TSLP, TNF-alpha, and IL-8 in asthmatic and non-asthmatic HBEC. Dexamethasone attenuated gene expression and protein release whereas capsazepine dose-dependently, and similar to a non relaxant NFkB inhibitor (PS1145), completely inhibited dsRNA-induced TSLP and TNF alpha in both healthy and asthmatic HBEC. Capsazepine reduced dsRNA-induced IL-8 and it prevented dsRNA-induced loss of the NF-kappaB repressor protein IkBalpha. CONCLUSION: Additional to its human small airway relaxant effects we now demonstrate that capsazepine has potent anti-inflammatory effects on viral stimulus-induced cytokines in HBEC from healthy as well as asthmatic donors. Based on these data we suggest that exploration of structure-activity amongst the multifaceted capsazepinoids is warranted in search for compounds of therapeutic value in viral-induced, steroid-resistant asthma. PMID- 20951222 TI - Epigenetic regulation on the 5'-proximal CpG island of human porcine endogenous retrovirus subgroup A receptor 2/GPR172B. AB - Porcine endogenous retroviruses (PERVs) have been considered one of the major risks of xenotransplantation from pigs to humans. PERV-A efficiently utilizes human PERV-A receptor 2 (HuPAR-2)/GPR172B to infect human cells; however, there has been no study on the regulation mechanisms of HuPAR-2/GPR172B expression. In this study, we examined the expression of HuPAR-2/GPR172B from the standpoint of epigenetic regulation and discussed the risks of PERV-A infection in xenotransplantation. Quantitative real-time RT-PCR revealed that HuPAR-2 mRNA was preferentially expressed in placental tissue, whereas it was highly suppressed in BeWo cells (a human choriocarcinoma cell line) and HEK293 cells. A CpG island containing the HuPAR-2 transcription starting site was identified by in silico analysis. The DNA methylation ratio (the relative quantity of methylcytosine to total cytosine) and histone modification (H3K9me3) levels in the CpG island measured by bisulfite genomic sequencing and ChIP assay, respectively, were inversely correlated with the mRNA levels. Both HuPAR-2 mRNA and HuPAR-2 protein were up-regulated in HEK293 cells by inhibiting DNA methylation and histone deacetylation. Additionally, promoter/enhancer activities within the CpG island were suppressed by in vitro DNA methylation. Our results demonstrated that epigenetic modification regulates HuPAR-2 expression. PMID- 20951223 TI - Migratory responses of leukocytes infected with Toxoplasma gondii. AB - Recently, monocytic cells were suggested to systemically transport Toxoplasma tachyzoites during acute infection in mice. The mechanism underlying this shuttling function may partly be explained by dramatically enhanced host-cell motility upon parasite invasion. Here, we report that infection of human and murine macrophages in vitro resulted in augmented migration across a transwell membrane, linked to host-cell differentiation and to the parasite genotype. The hypermotility phenotype was absent in infected monocytes, NK, B or T-cells. In contrast to previous observations with dendritic cells, adoptive transfer of infected macrophages or lymphocytes did not exacerbate infection in mice compared to inoculation with free parasites. PMID- 20951224 TI - Interactions between Batrachochytrium dendrobatidis and its amphibian hosts: a review of pathogenesis and immunity. AB - The fungus Batrachochytrium dendrobatidis (Bd) causes a lethal skin disease of amphibians, chytridiomycosis, which has caused catastrophic amphibian die-offs around the world. This review provides a summary of host characteristics, pathogen characteristics and host-pathogen responses to infection that are important for understanding disease development. PMID- 20951226 TI - Mechanisms involved in lung cancer development in COPD. AB - Lung cancer and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality worldwide. They share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by the incidence of these diseases in only a fraction of smokers. COPD is also a major independent risk factor for lung carcinoma, among long-term smokers. Smokers with COPD also have a higher risk of developing a specific histological subtype of non-small cell lung cancer termed squamous cell carcinoma. For these reasons the focus of this review is on the potential pathogenic molecular links between tobacco smoking-related COPD and squamous cell carcinoma. We believe that we need to promote more studies on the molecular and cellular pathobiology of smokers with premalignant bronchial lesions of the squamous cell lung carcinoma compared with a control group of smokers with and without COPD to unravel the complex molecular interactions between COPD and early squamous cell lung carcinoma. These studies should also look at younger healthy smokers in combination with risk models of lung cancer and COPD. Overall these studies may allow the discovery of new molecular targets of the early carcinogenesis process that in the foreseeable future may render the early diagnosis and treatment, and may be even the prevention, of invasive squamous cell lung carcinoma a reality. PMID- 20951225 TI - SIV infection in natural hosts: resolution of immune activation during the acute to-chronic transition phase. AB - SIV-infected natural hosts do not progress to clinical AIDS yet display high viral replication and an acute immunologic response similar to pathogenic SIV/HIV infections. During chronic SIV infection, natural hosts suppress their immune activation, whereas pathogenic hosts display a highly activated immune state. Here, we review natural host SIV infections with an emphasis on specific immune cells and their contribution to the transition from the acute-to-chronic phases of infection. PMID- 20951227 TI - Exposure to low environmental levels of benzene: evaluation of micronucleus frequencies and S-phenylmercapturic acid excretion in relation to polymorphisms in genes encoding metabolic enzymes. AB - An integrated approach based on environmental and biological monitoring, including the analysis of biomarkers of exposure [excretion of S phenylmercapturic acid (S-PMA)], early biological effects [micronucleus (MN) frequency] and susceptibility (genetic polymorphisms), was applied to characterize benzene exposure in a group of 70 traffic policemen and 40 employees of the city of Bologna, Italy. Median personal benzene exposure was 6.55-fold higher for traffic policemen than for controls (P<0.0001). This higher exposure was confirmed by a significant, 2.53-fold higher S-PMA excretion in traffic policemen compared with that observed for indoor workers (P<0.0001). Median MN frequency was also significantly higher in policemen compared with indoor workers (P=0.001), emphasizing the genotoxic effect potentially associated with benzene exposure. With regard to biomarkers of susceptibility, the analysis revealed that high epoxide hydrolase (mEH) (predicted) enzyme activity was significantly correlated with a lower median MN frequency (P=0.003). A gene-gender interaction was observed for the glutathione-S-transferase M1 (GSTM1) genotype. The GSTM1 null genotype was associated with a significantly higher median MN frequency in men, not in women. Statistical analysis did not reveal any association between the presence of the protective allele, pushing the pathway towards benzene detoxification, and MN frequency or S-PMA excretion. Even though there are some limitations in the study, our results indicate that policemen are exposed to higher levels of benzene than individuals spending most of the time indoors. This higher exposure may contribute to DNA damage, suggesting an increase health risk from traffic benzene emission. Finally, a more comprehensive study is warranted in order to better elucidate the involvement of EPHX1 genotypes combination in benzene genotoxicity. PMID- 20951228 TI - Zoonotic Brugia pahangi filariasis in a suburbia of Kuala Lumpur City, Malaysia. AB - Five local Malaysian patients with clinical manifestations consistent with lymphatic filariasis were referred to our medical centre between 2003 and 2006. Although no microfilariae (mf) were detected in their nocturnal blood samples, all were diagnosed to have lymphatic filariasis on the basis of clinical findings and positive serology results. PCR on their blood samples revealed that two of the patients were infected with Brugia pahangi, an animal filarial worm hitherto not known to cause human disease in the natural environment. All the patients were successfully treated with anti-filarial drugs: four patients were treated with a combination of diethylcarbamazine (DEC) and albendazole, and one with doxycycline. Four of them were residents of Petaling Jaya, a residential suburbia located 10 km southwest of Kuala Lumpur city, Malaysia. The fifth patient was a frequent visitor of the suburbia. This suburbia has no history or record of B. malayi infection. The most likely vector of the worm was Armigeres subalbatus as extensive entomological surveys within the suburbia revealed only adult females of this mosquito species were infected with B. pahangi larvae. Wild monkeys caught in the suburbia were free from B. pahangi mf, but domestic cats were mf positive. This suggests that infected cats might be the source of the zoonotic infection in the suburbia. PMID- 20951229 TI - Does atorvastatin induce aortic smooth muscle cell apoptosis in vivo? AB - It has been reported that HMG-CoA reductase inhibitors such as atorvastatin induce vascular smooth muscle cell (SMC) apoptosis in vitro. However, this effect remains to be demonstrated in vivo. The present studies were designed to test the ability of atorvastatin to induce SMC apoptosis in vivo, using the spontaneously hypertensive rat (SHR) as a well-known reference model of SMC apoptosis induction in vivo by cardiovascular drugs including the calcium channel blocker amlodipine. Atorvastatin was administered to SHR for 3 or 6 weeks either alone or together with amlodipine, a drug combination clinically available to patients. Primary endpoints included aortic medial hypertrophy and aortic SMC hyperplasia, internucleosomal DNA fragmentation and expression of the apoptosis regulatory proteins Bax and Bcl-2. The SHR aorta showed no evidence of SMC apoptosis induction by atorvastatin, even at the high dose of 50 mg kg(-1) day(-1), although the statin significantly reduced oxidative stress after 3 weeks and blood pressure after 6 weeks of administration. Amlodipine-induced regression of aortic hypertophy and aortic SMC hyperplasia were dose- and time-dependent, but there was no interaction between atorvastatin and amlodipine in modulating the primary endpoints. These results do not support the notion that atorvastatin induces SMC apoptosis in the aortic media in vivo. PMID- 20951230 TI - Anti-arthritic effects of chlorogenic acid in interleukin-1beta-induced rabbit chondrocytes and a rabbit osteoarthritis model. AB - Cartilage degradation is one of the pathological changes of osteoarthritis (OA), and accumulating evidence suggests an excess of matrix metalloproteinases (MMPs) plays a role in this cartilage breakdown. Here, we investigated the effects of chlorogenic acid (CGA) on the mRNA and protein expression of MMPs in interleukin (IL)-1beta-induced rabbit chondrocytes and evaluated the in vivo effects of CGA in experimental OA induced by anterior cruciate ligament transection (ACLT) in rabbits. Using quantitative real-time PCR and ELISA to investigate the expression levels of MMP-1, MMP-3, MMP-13, and tissue inhibitors of metalloproteinase-1(TIMP 1) in IL-1beta-induced rabbit chondrocytes, we showed that CGA inhibits the expression of these MMPs while increasing TIMP-1 expression, at both the mRNA and protein levels. In addition, IL-1beta-induced activation of nuclear factor kappa B (NF-kappaB) and the degradation of inhibitor of kappaB (IkappaB)-alpha were suppressed by CGA. In rabbits, CGA decreased cartilage degradation as assessed by morphological and histological analyses. The down-regulation of MMP-1, MMP-3, and MMP-13 expression and up-regulation of TIMP-1 expression were also detected in CGA-treated cartilage compared with vehicle-treated cartilage, confirming these findings in an in vivo model. Taken together, these findings indicate that CGA may be considered as a possible candidate agent in the treatment of OA. PMID- 20951231 TI - Biventricular pacing in hypertrophic obstructive cardiomyopathy: a pilot study. AB - BACKGROUND: Right ventricular apex pacing for gradient reduction in hypertrophic obstructive cardiomyopathy (HOCM) with severe left ventricular (LV) obstruction has yielded conflicting results. OBJECTIVE: The purpose of this study was to assess the feasibility and effectiveness of biventricular pacing in HOCM. METHODS: Transvenous biventricular pacing was attempted in 12 severely symptomatic HOCM patients. Optimal intervals were programmed after implant. Echocardiographic LV pressure gradient and synchrony were assessed. LV lead implantation was successful in 9 patients. Optimal pacing mode was biventricular in 6 patients, left ventricular only in 2 patients, and right ventricular only in 1 patient. RESULTS: Functional capacity and quality of life progressively improved. New York Heart Association functional class decreased from 3.2 +/- 0.4 at baseline to 1.9 +/- 0.3 at 3 months and to 1.4 +/- 0.5 at 1 year (P <.05); 6 minute walk test increased from 349 +/- 116 m at baseline to 454 +/- 144 m at 3 months and to 517 +/- 206 m (P <.05); and quality of life increased from 54 +/- 16 points at baseline to 28 +/- 13 points at 3 months and 27 +/- 15 points at 1 year (P <.05). There was also a progressive reduction in LV gradient from 74 +/- 23 mmHg at baseline to 50 +/- 27 mmHg acutely, 40 +/- 26 mmHg at 3 months, and 28 +/- 17 mmHg at 1 year (P <.05). Gradient reduction was associated with diminished peak longitudinal displacement of the LV septum and earlier displacement of the lateral wall. A progressive reduction of LV mass was observed, from 356 +/- 110 g at baseline to 315 +/- 70 g at 3 months (P = .13) and to 284 +/- 42 g at 1 year (P <.05). CONCLUSION: Biventricular pacing is feasible and usually the best configuration for gradient reduction in HOCM. Biventricular pacing reduces LV hypertrophy. PMID- 20951232 TI - A combined gene and cell therapy approach for restoration of conduction. AB - BACKGROUND: Abnormal conduction underlies both bradyarrhythmias and re-entrant tachyarrhythmias. However, no practical way exists for restoring or improving conduction in areas of conduction slowing or block. OBJECTIVE: This study sought to test the feasibility of a novel strategy for conduction repair using genetically engineered cells designed to form biological "conducting cables." METHODS: An in vitro model of conduction block was established using spatially separated, spontaneously contracting, nonsynchronized human embryonic stem cell derived cardiomyocytes clusters. Immunostaining, dye transfer, intracellular recordings, and multielectrode array (MEA) studies were performed to evaluate the ability of genetically engineered HEK293 cells, expressing the SCN5A-encoded Na(+) channel, to couple with cultured cardiomyocytes and to synchronize their electrical activity. RESULTS: Connexin-43 immunostaining and calcein dye-transfer experiments confirmed the formation of functional gap junctions between the engineered cells and neighboring cardiomyocytes. MEA and intracellular recordings were performed to assess the ability of the engineered cells to restore conduction in the co-cultures. Synchronization was defined by establishment of fixed local activation time differences between the cardiomyocytes clusters and convergence of their activation cycle lengths. Nontransfected control cells were able to induce synchronization between cardiomyocytes clusters separated by distances up to 300 MUm (n = 21). In contrast, the Na(+) channel-expressing cells synchronized contractions between clusters separated by up to 1,050 MUm, the longest distance studied (n = 23). Finally, engineered cells expressing the voltage-sensitive K(v)1.3 potassium channel prevented synchronization at any distance. CONCLUSION: Genetically engineered cells, transfected to express Na(+) channels, can form biological conducting cables bridging and coupling spatially separated cardiomyocytes. This novel cell therapy approach might be useful for the development of therapeutic strategies for both bradyarrhythmias and tachyarrhythmias. PMID- 20951233 TI - The ECG: the old ally for a better selection of preventive ICD treatment? PMID- 20951235 TI - Innovative service delivery for secondary prevention of PTSD in at-risk OIF-OEF service men and women. AB - Service personnel involved in Operation Enduring Freedom/Operation Iraqi Freedom are at high risk for trauma-related physical injury and emotional problems, including posttraumatic stress disorder (PTSD) and major depression. Although evidence-based psychotherapies are increasingly available and effective in treating symptoms of PTSD, a large number of service personnel are reluctant to seek mental health treatments due to both perceived stigma associated with these treatments and geographically-based barriers to care at specialized treatment facilities. The present investigation evaluates an innovation in service delivery designed to address these concerns. Specifically, we are comparing exposure-based therapy for PTSD delivered via traditional, in-person settings to the same exposure-based treatment delivered via telehealth technology. The proposed project is a prospective, randomized repeated measures design with two treatment groups (telehealth and in-person) assessed at pre-treatment, mid-treatment, post treatment and 3- and 12-month follow-up points. Outcome measures ascertain longer term effects of the treatments on three domains: clinical, process, and economic. Non-inferiority and superiority analyses will be conducted to determine symptom changes between pre-treatment, post-treatment, and follow-up time points between the two treatment conditions. The study will determine whether an exposure therapy for PTSD delivered via telehealth is at least as successful as the same exposure-based therapy delivered in-person in treating the symptoms of PTSD in both subthreshold and fully diagnosed cases. PMID- 20951234 TI - Validation of a risk-assessment scale and a risk-adapted monitoring plan for academic clinical research studies--the Pre-Optimon study. AB - CONTEXT: Good Clinical Practice regulates monitoring activities in clinical research. Due to question and design diversity, and limited resources, on-site monitoring is often less intensive in the academic context, and variable. Standardization is needed, and relies on definition and validation of tools accounting for risk. OBJECTIVE: To define, and validate tools, to implement a risk-based monitoring strategy for academic clinical research. METHODS: Working groups of experienced professionals searched the literature, and built a consensus risk-assessment scale (RAS), and a risk-adapted monitoring plan (RAMP). We allocated 200 protocols to 49 assessors. We assessed the RAS relevance vs. a visual analogue scale (VAS), and its reproducibility through Kraemer's kappa, and intraclass correlation coefficient (ICC) from a random proportional odds model. We identified sources of disagreement through a logistic regression. We described assessors' difficulties during assessment. We applied the RAMP to 10 protocols per risk level, and rated its feasibility (0 = easy to 4 = impossible). RESULTS: RAS and RAMP were defined in 4 levels. RAS relevance was good: RAS-risk levels were evenly distributed on VAS-risk (0.6, 2.6, 5.6, and 7.9). Reproducibility was moderate to good: kappa=0.48, ICC=0.70. Major disagreements (36%) arose from decision-makers, rather than hands-on managers. Most difficulties occurred in ill written protocols (17%). RAMP was easily feasible for most protocols (mean score: 0.2 to 0.9). We proposed a standard synopsis for evaluation purpose. CONCLUSION: We defined, and validated risk-based tools. This risk-adapted strategy will be compared to an intensive one in a randomized trial, Optimon, to define a standard of practice for academic clinical research. PMID- 20951236 TI - Experiences of families with a child, adolescent, or young adult with neurofibromatosis type 1 and plexiform neurofibroma evaluated for clinical trials participation at the National Cancer Institute. AB - BACKGROUND: With increasing knowledge of the molecular pathways contributing to the progression of neurofibromatosis type 1 (NF1)-related plexiform neurofibroma (PN), the number of clinical trials for PNs has increased. However, little is known about the experiences of families with children with NF1 participating in clinical trials. METHOD: A 47-item anonymous survey, designed to assess experiences in research, was sent to parents with a child with NF1 and PNs who was evaluated at the National Cancer Institute (NCI) for a clinical trial. RESULTS: Sixty-four (85%) parents completed the paper or online questionnaire. Fifty-nine percent of the children were male; 44% were 11 years or older upon enrollment. Most parents reported understanding the purpose of the study, possible side effects, and their right to withdraw. Of respondents whose child had participated in a placebo-controlled trial, 100% said they understood the reason for the placebo at least somewhat. Seventy-four percent felt that study participation helped their child; most would "definitely" or "probably" participate in a future study, including a placebo-controlled trial, and particularly those assessing cognitive functioning or pain. Overall satisfaction with participation was high and correlated with fewer transportation problems, fewer study-related financial difficulties, and fewer school problems for the child (ps<.05). CONCLUSIONS: Most parents of children with NF1 who participated in research at the NCI reported a positive impact and would participate in future studies. Respondents identified several areas for improvement. This report may help plan future studies to optimize experiences of children and their families enrolled in clinical trials. PMID- 20951237 TI - Tuberculosis transmission in Northwest of Iran: using MIRU-VNTR, ETR-VNTR and IS6110-RFLP methods. AB - Tuberculosis is the main cause for adults' death from a single infectious agent killing about 2 million people every year. Identifying the source of transmission infection is necessary to decrease tuberculosis. In this study we used IS6110 RFLP, MIRU-VNTR and ETR-VNTR methods to determine transmission dynamic of tuberculosis in Northwest of Iran from March 2004 to March 2005. 156 culture positive isolates (51 from Orumieh and 105 from Tabriz) were collected. IS6110 RFLP was done by standardized method and MIRU-VNTR was done by 12 primers specific for 12 MIRU-VNTR loci by polymerase chain reaction and ETR was carried out by primers specific for ETR-A, ETR-B and ETR-C as well. Genetic relationship analyses were performed by MVSP software and MIRU-VNTRplus website. The results revealed that the copy number of IS6110 in isolates ranged from 0 to 17. One hundred and seven unique patterns and 16 shared patterns by 2-10 isolates were determined by IS6110-RFLP, and 116 distinct patterns were identified by MIRU-VNTR including 21 clustered patterns and 95 unique patterns. Having combined MIRU-VNTR and ETR-VNTR data, we increased the discriminatory power of typing method, thus 25 clusters were identified. Loci 10, 26, 40 in MIRU and ETR-A were highly discriminatory. Distribution of lineages in our study according to tentative data in MIRU-VNTRplus database was multi-matches 9.09%, Bovis 9.74%, S 8.44%, New-1 0.65%, Uganda I 0.65%, Haarlem 0.65%, Cameroon 0.65% and X 0.65%. The minimum estimate for tuberculosis proportion due to transmission was 20.1% with IS6110 RFLP and was 18.8% with MIRU and ETR. In conclusion, tuberculosis sanitation status in northwest of Iran due to minimum estimate of tuberculosis transmission was satisfactory, and the reactivation of tuberculosis was responsible for more than 80% of new tuberculosis. According to the results and drawbacks of IS6110 RFLP method we strongly recommend MIRU-VNTRplus ETR-VNTR as an easy, reliable, reproducible and highly discriminatory power method. PMID- 20951238 TI - High CR1 level and related polymorphic variants are associated with cerebral malaria in eastern-India. AB - The complement receptor 1 (CR1/CD35) protein acts as the major rosetting receptor in Plasmodium falciparum infection and several genetic variants of CR1 gene have been shown to be associated with quantitative expression of erythrocyte CR1 (E CR1) level. However, CR1 level and gene polymorphisms exhibit differences in clinical manifestation of malaria in regions of varying disease endemicity. The result of the present study which analyzed three SNPs (intron 27 HindIIIA>T, exon 22 3650 A>G, and exon 33 5507 C>G) of the CR1 gene in Orissa, a hyperendemic state in eastern-India showed that a significantly increased risk for cerebral malaria (CM) was associated with AA genotype of both intron 27 and exon 22 when compared with mild, severe malaria anemia (SMA) and CM+SMA group respectively. Further, the overall haplotype analysis for all the three loci showed predominantly two major haplotypes 'AAC' coding for higher expression of CR1 and 'TGG' haplotype coding for low expression of CR1 level with the former haplotype being significantly associated with CM (P value<0.00619 after Bonferroni correction) compared to mild malaria. The 'TGG' haplotype was proportionately more in SMA cases compared to mild malaria though statistically not significant. These findings suggest that the mild malaria group had an intermediate level of E CR1 and extremely low or high levels of CR1 can cause severity in malaria. Further large scale studies in different endemic regions are needed to explain the epidemiological differences between E-CR1 expression and clinical manifestation of malaria which may contribute to the understanding of malaria pathogenesis. PMID- 20951239 TI - Prevalence of metabolic syndrome in primary antiphospholipid syndrome patients. AB - OBJECTIVE: To estimate the prevalence of metabolic syndrome (MetS) in patients with primary antiphospholipid syndrome (PAPS). PATIENTS AND METHODS: Cross sectional study of PAPS patients from the outpatient clinic. MetS was based on three international definitions: World Health Organization (WHO), Adult Treatment Panel III (ATP III), or International Diabetes Federation (IDF). Clinical history and laboratory investigations, including insulin levels, lipid profile, glucose, and CRP, anthropometric and blood pressure measurements, were evaluated. Descriptive statistics was used. Kappa statistics examined the agreement between MetS definitions. RESULTS: 58 PAPS patients were studied, mean age 42.14+/-11.62, 9 men, 49 women. The most frequent cardiovascular risk (CVR) factors were hypertriglyceridemia, low HDL cholesterol levels, and visceral obesity. Prevalence of MetS was 17.2% according to WHO, 34.5% according to ATP III and 37.9% according to IDF criteria. MetS according to ATP III and WHO criteria was similar to the general population (34.5% vs. 36.8%) (17.2% vs. 13.6%), and lower according to IDF definition (37.9% vs. 49.8%). CONCLUSIONS: This study shows a high prevalence of MetS in PAPS patients, similar to that in the general population and other autoimmune diseases. Identification of MetS is very important to indicate preventive strategies and reduce cardiovascular morbidity and mortality in PAPS. PMID- 20951240 TI - Autoimmunity in hepatitis C virus carriers: involvement of ferritin and prolactin. AB - BACKGROUND: Ferritin and prolactin have been associated with active autoimmune diseases as systemic lupus erythematosus and autoantibody production, but have been little studied in viral infections that present autoimmunity. OBJECTIVE: To investigate the association of these two autoimmune mediators with the presence of cryoglobulinaemia and non-organ-specific autoantibodies (RF, SMA, beta2GPI IgA antibody and ANA) in Brazilian individuals chronically infected with hepatitis C virus (HCV). METHODS: Ninety-nine patients were evaluated. Ferritin and prolactin levels were determined by chemiluminescent immunoassays. RESULTS: Hyperprolactinemia was found in 10 (six men and four women) out of 99 (10.1%) hepatitis C patients. Thirty-eight out of 99 (38.4%) HCV carriers had hyperferritinemia (median level 385ng/mL). Neither hyperprolactinemia nor hyperferritinemia was associated with cryoglobulinaemia or non-organ-specific autoantibodies (p>.05). There was an association between hyperprolactinemia and the infection with HCV genotype 3 (p<.01). Ferritin and ALT levels were correlated (p<.05). CONCLUSION: Our results suggest that neither prolactin nor ferritin is involved with the extra-hepatic manifestation of autoimmunity observed in HCV carriers. PMID- 20951241 TI - A novel extracellular protease from Pseudomonas aeruginosa MCM B-327: enzyme production and its partial characterization. AB - The focus of this study was on production, purification and characterization of dehairing protease from Pseudomonas aeruginosa MCM B-327, isolated from vermicompost pit soil. Optimum protease activity, 395 U mL(-1), was observed in the medium containing soybean meal and tryptone, at pH 7 and 30 degrees C. The crude enzyme exhibited dehairing activity. As compared to chemical method, enzymatic method of dehairing showed reduction in COD, TDS and TSS by 34.28%, 37.32% and 51.58%, respectively. Zymogram of crude enzyme on native-PAGE presented two bands with protease activity of molecular weights of 56 and 67 kDa. Both proteases showed dehairing activity. Out of these, 56kDa protease (PA02) was purified 3.05-folds with 2.71% recovery. The enzyme was active in pH range 7-9 and temperature 20-50 degrees C with optimum pH of 8 and temperature 35 degrees C. Moreover, the enzyme activity of PA02 protease was not strongly inhibited by specific inhibitor showing the novel nature of enzyme compared to serine, cysteine, aspartyl and metalloproteases. Kinetic studies indicated that substrate specificity of PA02 protease was towards various natural and synthetic proteolytic substrates but inactive against collagen and keratin. These findings suggest protease secreted by P. aeruginosa MCM B-327 may have application in dehairing for environment-friendly leather processing. PMID- 20951242 TI - PKCalpha suppresses osteoblastic differentiation. AB - Protein kinase C (PKC) plays an essential role in cellular signal transduction for mediating a variety of biological functions. There are 11 PKC isoforms and these isoforms are believed to play distinct roles in cells. Although the role of individual isoforms of PKC has been investigated in many fields, little is known about the role of PKC in osteoblastic differentiation. Here, we investigated which isoforms of PKC are involved in osteoblastic differentiation of the mouse preosteoblastic cell line MC3T3-E1. Treatment with Go6976, an inhibitor of PKCalpha and PKCbetaI, increased alkaline phosphatase (ALP) activity as well as gene expression of ALP and Osteocalcin (OCN), and enhanced calcification of the extracellular matrix. Concurrently, osteoblastic cell proliferation decreased at a concentration of 1.0 MUM. In contrast, a PKCbeta inhibitor, which inhibits PKCbetaI and PKCbetaII, did not significantly affect osteoblastic differentiation or cell proliferation. Knockdown of PKCalpha using MC3T3-E1 cells transfected with siRNA also induced an increase in ALP activity and in gene expression of ALP and OCN. In contrast, overexpression of wild-type PKCalpha decreased ALP activity and attenuated osteoblastic differentiation markers including ALP and OCN, but promoted cell proliferation. Taken together, our results indicate that PKCalpha suppresses osteoblastic differentiation, but promotes osteoblastic cell proliferation. These results imply that PKCalpha may have a pivotal role in cell signaling that modulates the differentiation and proliferation of osteoblasts. PMID- 20951243 TI - Prediction of hip and hand fractures in older persons with or without a diagnosis of periodontitis. AB - PURPOSE: In a prospective study, we assessed if a diagnosis of osteoporosis and periodontitis could predict hip and hand fractures in older persons. MATERIALS AND METHODS: Bone density was assessed by a Densitometer. Periodontitis was defined by evidence of alveolar bone loss. RESULTS: 788 Caucasians (52.4% women, overall mean age: 76 years, S.D.+/- 9.0, range: 62 to 96) were enrolled and 7.4% had a hip/hand fracture in 3 years. Calcaneus PIXI T-values < -1.6 identified osteoporosis in 28.2% of the older persons predicting a hip/hand fracture with an odds ratio of 3.3:1 (95% CI: 1.9, 5.7, p < 0.001). Older persons with osteoporosis had more severe periodontitis (p < 0.01). Periodontitis defined by >= 30% of sites with >= 5 mm distance between the cemento-enamel junction (CEJ) and bone level (ABL) was found in 18.7% of the older persons predicting a hip/hand fracture with an odds ratio of 1.8:1 (95% CI: 1.0, 3.3, p < 0.05). Adjusted for age, the odds ratio of a hip/hand fracture in older persons with osteoporosis (PIXI T-value < -2.5) and periodontitis was 12.2:1 (95% CI: 3.5, 42.3, p < 0.001). CONCLUSIONS: Older persons with osteoporosis and periodontitis have an increased risk for hip/hand fractures. PMID- 20951244 TI - Off-pump coronary artery bypass grafting: for the many or the few? PMID- 20951245 TI - Robotic pulmonary lobectomy--the future and probably should remain so. PMID- 20951246 TI - The Society of Thoracic Surgeons National Adult Cardiac Database: a continuing commitment to excellence. PMID- 20951247 TI - Data entry and data accuracy. PMID- 20951248 TI - Should asymptomatic enlarged thymus glands be resected? AB - OBJECTIVE: Patients frequently have an "enlarged thymus" incidentally identified on imaging. We sought to determine whether thymectomy is appropriate in patients with diffusely enlarged thymus glands. METHODS: A retrospective review was conducted of patients undergoing thymectomy without myasthenia gravis at 1 institution over 15 years. RESULTS: Of 117 patients undergoing thymectomy, 109 patients had complete data. Thirty-six had a gland judged by the surgeon to be diffusely enlarged, and 73 had a discrete mass. Of the 36 diffusely enlarged thymus glands, 18 (50%) occurred in patients with no symptoms referable to the thymus. No patient (0/18; 0%) with an asymptomatic diffusely enlarged thymus gland had a pathologic diagnosis that would have required resection (8 normal; 10 "hyperplasia"). Of the 18 symptomatic patients with diffusely enlarged glands, 4 (22.2%) harbored lymphoma, but none harbored thymoma or other tumor (P < .05; symptomatic vs asymptomatic). Of the 73 patients with discrete masses, 45 (61.6%) were symptomatic, and both the symptomatic and asymptomatic patients had a high rate of pathologic diagnoses that represented an indication for resection (53.3% and 42.8%, respectively, harbored thymoma or other tumor). Of the 25 (of 109) patients initially having a diagnosis of thymic hyperplasia, only 3 (12%) had true follicular hyperplasia on re-review of the pathologic condition. Interestingly, an autoimmune disorder developed in 2 (67%) of these 3 patients on long-term follow-up. CONCLUSIONS: Asymptomatic patients with diffusely enlarged thymus glands can be followed up expectantly because they have a negligible incidence of significant thymic disease; symptomatic patients with diffusely enlarged thymus glands may have lymphoma, so biopsy is appropriate. Half of patients with a discrete mass have tumors requiring resection; imaging advances would be useful to better differentiate among patients within this group. PMID- 20951250 TI - Analysis of clamping versus cutting of T3 sympathetic nerve for severe palmar hyperhidrosis. AB - OBJECTIVES: Endoscopic thoracic sympathectomy can predictably eliminate the disabling symptoms of palmar hyperhidrosis. Debate has ensued over competing techniques, in particular, cutting versus clamping of the sympathetic chain. We subjectively assessed the sweat severity in different areas of the body and evaluated changes in the quality of life in patients undergoing either the cutting or clamping technique. METHODS: Patients examined between June 2003 and March 2007 were asked to quantify the severity of their symptoms before and after endoscopic thoracic sympathectomy. The interviews were conducted approximately 1 year after the procedure. Only the patients undergoing sympathectomy at the T3 level for a chief complaint of palmar hyperhidrosis were included in the analysis (n = 152). In 45% of these patients, clamping of the sympathetic chain was performed, and the remaining 55% had the chain cut. RESULTS: After surgery, no patients had continued excessive sweating of the hands. Of all the patients, 95% were satisfied with the results after the cutting procedure and 97% were satisfied after clamping. No difference was seen in any outcome between the patients undergoing clamping versus cutting of the sympathetic chain, including sweating on the hands, face, armpits, feet, trunk, and thighs or in the quality of life. CONCLUSIONS: We found high rates of success and patient satisfaction when T3 sympathectomy was performed for palmar hyperhidrosis, with no differences found between the cutting and clamping techniques. PMID- 20951252 TI - Superior nationwide outcomes of endovascular versus open repair for isolated descending thoracic aortic aneurysm in 11,669 patients. AB - OBJECTIVES: Thoracic endovascular aneurysm repair (TEVAR) was introduced in 2005 to treat descending thoracic aortic aneurysms. Little is known about TEVAR's nationwide effect on patient outcomes. We evaluated nationwide data regarding the short-term outcomes of TEVAR and open aortic repair (OAR) procedures performed in the United States during a 2-year period. METHODS: From the Nationwide Inpatient Sample data, we identified patients who had undergone surgery for an isolated descending thoracic aortic aneurysm from 2006 to 2007. Patients with aneurysm rupture, aortic dissection, vasculitis, connective tissue disorders, or concomitant aneurysms in other aortic segments were excluded. Of the remaining 11,669 patients, 9106 had undergone conventional OAR and 2563 had undergone TEVAR. Hierarchic regression analysis was used to assess the effect of TEVAR versus OAR after adjusting for confounding factors. The primary outcomes were mortality and the hospital length of stay (LOS). The secondary outcomes were the discharge status, morbidity, and hospital charges. RESULTS: The patients who had undergone TEVAR were older (69.5 +/- 12.7 vs 60.2 +/- 14.2 years; P < .001) and had higher Deyo comorbidity scores (4.6 +/- 1.8 vs 3.3 +/- 1.8; P < .001). The unadjusted LOS was shorter for the TEVAR patients (7.7 +/- 11 vs 8.8 +/- 7.9 days), but the unadjusted mortality was similar (TEVAR 2.3% vs OAR 2.3%; P = 1.0). The proportion of nonelective interventions was similar between the 2 groups (TEVAR 15.9% vs OAR 15.8%; P = .9). The TEVAR and OAR techniques produced similar risk-adjusted mortality rates; however, the TEVAR patients had 60% fewer complications overall (odds ratio, 0.39; P < .001) and a shorter LOS (by 1.3 days). The TEVAR patients' hospital charges were greater by $6713 (95% confidence interval $1869 to $11,556; P < .001). However, the TEVAR patients were 4 times more likely to have a routine discharge to home. CONCLUSIONS: The nationwide data on TEVAR for descending thoracic aortic aneurysms have associated this procedure with better in-hospital outcomes than OAR, even though TEVAR was selectively performed in patients who were almost 1 decade older than the OAR patients. Compared with OAR, TEVAR was associated with a shorter hospital LOS and fewer complications but significantly greater hospital charges. PMID- 20951254 TI - Identifying patients at particular risk of injury during repeat sternotomy: analysis of 2555 cardiac reoperations. AB - OBJECTIVES: A variety of protective strategies during repeat sternotomy been proposed; however, it remains unclear for which patients they are warranted. METHODS: We identified adults undergoing repeat median sternotomy for routine cardiac surgery at our institution between January 1, 1996, and December 31, 2007. The operative notes and perioperative outcomes were reviewed. RESULTS: Of the 2555 patients, 1537 (60%) had undergone previous coronary artery bypass grafting, 700 (27%) previous mitral valve surgery, and 643 (25%) previous aortic valve replacement (AVR). Sixty-one patients (2%) had prior mediastinal radiotherapy, and 424 (17%) had more than one previous sternotomy. In 231 patients, 267 injuries (9.0%) occurred. Injury occurred during sternotomy in 87 patients (33%) and during prepump dissection in 135 (51%). The hospital mortality rate was 6.5% among those without injury and 18.5% among those with injury (P < .001); when injury occurred during sternal division, the mortality rate was 25%. Injuries were more common after previous coronary artery bypass grafting (11% with previous coronary artery bypass grafting vs 7% without, P = .0012) but not previous AVR, mitral valve surgery, or aortic surgery. Injury was also more common when the current operation was AVR (10% with AVR vs 8% without, P = .04) or aortic surgery (14% vs 8%, P = .004). On multivariate analysis, previous radiotherapy (odds ratio, 4.9), a greater number of previous sternotomies (odds ratio 1.7), and a patent internal thoracic artery (odds ratio, 1.8) predicted injury. Injury was an independent risk factor of hospital death (odds ratio, 2.6). CONCLUSIONS: Particular attention to protective strategies should be considered during reoperative sternotomy among patients with multiple previous sternotomies, previous mediastinal radiotherapy, and those with patent internal thoracic artery grafts. PMID- 20951256 TI - Persistent risk of subsequent procedures and mortality in patients after interrupted aortic arch repair: a Congenital Heart Surgeons' Society study. AB - OBJECTIVE: Multiple subsequent procedures directed at the arch and/or the left ventricular outflow tract are frequently required after interrupted aortic arch repair. We the investigated patterns and factors associated with these subsequent procedures and mortality. METHODS: We reviewed the data from 447 patients with interrupted aortic arch at 33 institutions enrolled from 1987 to 1997. We classified the subsequent procedures by type (catheter-based or surgical) and focus (arch, left ventricular outflow tract, and "other" cardiovascular lesions). We used competing risks and modulated renewal analysis to explore subsequent procedures. RESULTS: There were 158 subsequent arch and 100 left ventricular outflow tract procedures. Freedom from death at 21 years was 60% overall. The risk of additional subsequent arch procedures decreased after the first subsequent arch procedure in the acute phase, but did not significantly change in the chronic phase. The risk of additional subsequent left ventricular outflow tract procedures increased after the first subsequent left ventricular outflow tract procedure in the chronic phase. The risk factors for subsequent arch procedures and mortality, but not for subsequent outflow track procedures, were related in a complex way to previous procedures and their timing. CONCLUSIONS: Interrupted aortic arch is a chronic disease in which patients often undergo multiple subsequent procedures with persistent risk for additional intervention and mortality. The risk factors are related to the nature and timing of previous procedures and to the morphology and details of the index procedure. Interrupted aortic arch should be considered a chronic disorder. PMID- 20951258 TI - In situ pericardial extracardiac lateral tunnel Fontan operation: fifteen-year experience. AB - BACKGROUND: The study purpose is to evaluate the long-term outcome of the in situ pericardial extracardiac lateral tunnel Fontan operation. METHODS: From June 1994 to August 2009, 160 patients with single ventricle (boys, n = 96, 60%, median age = 39 months, mean weight 15.5 kg) underwent the pedicled pericardial extracardiac lateral tunnel operation. Patients' charts were reviewed for perioperative and long-term follow-up data, outcome, and mortality. The potential growth of these tunnels was evaluated. RESULTS: The main diagnoses included tricuspid atresia (n = 44, 27%); double-outlet right ventricle (n = 29, 18%), and hypoplastic left heart syndrome (n = 26, 16%). The mean follow-up was 6.5 +/- 3.7 years (range: 0.1-15 years). There were 2 (1.3%) operative and 6 (3.7%) late deaths. Actuarial survival at 14 years was 93%. Early complications included prolonged effusions (n = 35, 22%), chylothorax (n = 5, 3.1%), readmissions (n = 35, 22%), cerebrovascular accidents (n = 8, 5%), contralateral phrenic nerve palsy (n = 1, 0.8%), and transient arrhythmias (n = 5, 3.1%). No pacemaker was needed. Late complications included tunnel stenosis (n = 3, 1.8%) managed with balloon dilatation and stenting in 2 patients and surgical revision in 1; tunnel thrombosis (n = 2, 1.2%) causing death in both patients; and protein losing enteropathy (n = 4, 2.5%). Follow-up echocardiography of 10 patients showed laminar flow, no turbulence/gradient at the inferior vena cava and mid-tunnel levels. The diameter indexed to body surface area showed growth, reduction, or no change depending on flow demands. CONCLUSIONS: The construction of the extracardiac lateral tunnel Fontan conduit using viable pedicled pericardium is a relatively simple, durable, and safe operation. Long-term follow-up confirms low morbidity and mortality. Fenestration is unnecessary in most patients. This viable tunnel adapts to physiologic flow demands. PMID- 20951260 TI - Thromboelastometrically guided transfusion protocol during aortic surgery with circulatory arrest: a prospective, randomized trial. AB - OBJECTIVE: Aortic surgical procedures requiring hypothermic circulatory arrest are associated with altered hemostasis and increased bleeding. In a randomized clinical trial, we evaluated effects of thromboelastometrically guided algorithm on transfusion requirements. METHODS: Fifty-six consecutive patients (25 with acute type A dissection) undergoing aortic surgery with hypothermic circulatory arrest were enrolled in a randomized trial during a 6-month period. Patients were randomly allocated to treatment group (n = 27) with thromboelastometrically guided transfusion algorithm or control group (n = 29) with routine transfusion practices (clinical judgment-guided transfusion followed by transfusion according to coagulation test results). Primary end point was cumulative allogeneic blood units (red blood cells, fresh-frozen plasma, and platelets) transfused. RESULTS: Transfusion of allogeneic blood was significantly reduced in the thromboelastometry group: median 9.0 units (interquartile range, 2.0-30.0 units) versus. 16.0 units (9.0-23.0 units, P = .02). Most significant decrease was in the use of fresh-frozen plasma (3.0 units, 0-12.0 units, vs 8.0 units, 4.0-18.0 units, P = .005). Postoperative blood loss (890 mL/d, 600-1250 mL/d vs 950 mL/d, 650-1400 mL/d, p = 0.5) and rate of surgical re-exploration (19% vs 24%, P = .7) were similar between groups. Thromboelastometrically guided algorithm significantly decreased need for massive perioperative transfusion (odds ratio, 0.45; 95% confidence interval, 0.2-0.9; P = .03) in multivariable logistic regression analysis. CONCLUSIONS: Thromboelastometrically guided transfusion is associated with a decreased use of allogeneic blood units and reduced incidence of massive transfusion in patients undergoing aortic surgery with circulatory arrest. PMID- 20951262 TI - Pericardial, pleural, and diaphragmatic endometriosis. PMID- 20951261 TI - Spliced stromal cell-derived factor-1alpha analog stimulates endothelial progenitor cell migration and improves cardiac function in a dose-dependent manner after myocardial infarction. AB - OBJECTIVES: Stromal cell-derived factor (SDF)-1alpha is a potent endogenous endothelial progenitor cell (EPC) chemokine and key angiogenic precursor. Recombinant SDF-1alpha has been demonstrated to improve neovasculogenesis and cardiac function after myocardial infarction (MI) but SDF-1alpha is a bulky protein with a short half-life. Small peptide analogs might provide translational advantages, including ease of synthesis, low manufacturing costs, and the potential to control delivery within tissues using engineered biomaterials. We hypothesized that a minimized peptide analog of SDF-1alpha, designed by splicing the N-terminus (activation and binding) and C-terminus (extracellular stabilization) with a truncated amino acid linker, would induce EPC migration and preserve ventricular function after MI. METHODS: EPC migration was first determined in vitro using a Boyden chamber assay. For in vivo analysis, male rats (n = 48) underwent left anterior descending coronary artery ligation. At infarction, the rats were randomized into 4 groups and received peri-infarct intramyocardial injections of saline, 3 MUg/kg of SDF-1alpha, 3 MUg/kg of spliced SDF analog, or 6 MUg/kg spliced SDF analog. After 4 weeks, the rats underwent closed chest pressure volume conductance catheter analysis. RESULTS: EPCs showed significantly increased migration when placed in both a recombinant SDF-1alpha and spliced SDF analog gradient. The rats treated with spliced SDF analog at MI demonstrated a significant dose-dependent improvement in end-diastolic pressure, stroke volume, ejection fraction, cardiac output, and stroke work compared with the control rats. CONCLUSIONS: A spliced peptide analog of SDF-1alpha containing both the N- and C- termini of the native protein induced EPC migration, improved ventricular function after acute MI, and provided translational advantages compared with recombinant human SDF-1alpha. PMID- 20951264 TI - Relation between hemodynamic behavior and occurrence of early stenotic failure of bioprostheses. PMID- 20951265 TI - Anticoagulation after bioprosthetic aortic valve replacement. PMID- 20951266 TI - Surgical versus endovascular treatment for type B aortic dissections. PMID- 20951268 TI - Decision making in ischemic cardiomyopathy: is the Cleveland Clinic model valid? PMID- 20951269 TI - Preface: Psychiatry for the internist. PMID- 20951270 TI - An approach to collaborative care and consultation: interviewing, cultural competence, and enhancing rapport and adherence. AB - Although changes in the US health care system promote a population-based approach, increases in population diversity emphasize the need for culturally competent, patient-centered, participatory care. Despite this perceived conflict, the global view has improved the recognition of mental health issues as a driver of overall health as well as health care spending. This recognition, along with the many forces that keep mental health care in the primary care sector, actually encourages the development of collaborative models that capitalize on the primary care provider's opportunity to leverage their rapport with the patient to improve access to, and comfort with, specialty mental health services. Engaging patients in their own path to recovery or well-being improves engagement in, and adherence to, the treatment plan and ultimately improves outcomes. PMID- 20951271 TI - An approach to the patient in crisis: assessments of the risk of suicide and violence. AB - Suicide is one of the leading causes of death in the United States and is defined as intentional self-harm with the intent of causing death. Various mental disorders may be a cause for increased violence. This article outlines the elements of the risk assessment (for harm to self and/or others) in patients in crisis and addresses which contributing factors may be modifiable. This article also proposes a practical framework for the management of risk regarding suicide and violence. PMID- 20951272 TI - An approach to the patient with cognitive impairment: delirium and dementia. AB - Patients with cognitive impairment can be divided into 2 broad groups: those with chronic cognitive decline (most likely diagnosable with a dementia) and those with acute cognitive changes (most likely experiencing a delirium). However, diagnosis in clinical practice is far more complicated than it is in textbooks. Perhaps the greatest hurdle in evaluating the cognitively impaired patient is the clarification of a cohesive history. Unfortunately, the cognitively impaired patient is most often unable to provide such a history, and in the absence of a reliable family member, friend, or caregiver to fill in the gaps, diagnostic clarity can be difficult to achieve. This article outlines the broad diagnostic spectra of delirium and dementia, reviews current understanding of their pathogenesis, and discusses useful diagnostic and therapeutic techniques. PMID- 20951273 TI - An approach to the patient with dysregulated mood: major depression and bipolar disorder. AB - Major depressive disorder (MDD) and bipolar disorder are chronic relapsing remitting illnesses whose effects on mood, behavior, and thinking exact a heavy toll on patients' physical and mental health and on their capacity for satisfying relationships and employment. In the inpatient setting, these affective illnesses and their treatments can complicate the diagnosis, course, therapy, and prognosis of numerous medical conditions. In this article, the authors discuss a general approach for general internists, family practitioners, and other primary care providers to follow in caring for patients with suspected MDD or bipolar disorder. PMID- 20951274 TI - An approach to the patient with anxiety. AB - Patients seen in primary care and in specialty medical settings often have prominent anxiety. This article presents the epidemiology, etiology, manifestations, and treatment of anxiety disorders. PMID- 20951275 TI - An approach to the psychopharmacologic care of patients: antidepressants, antipsychotics, anxiolytics, mood stabilizers, and natural remedies. AB - The number of safe and effective medication treatments for psychiatric illness has expanded substantially over the past 10 to 15 years. Knowing when and how to prescribe psychotropics--and knowing which medication to prescribe--can be challenging, but with knowledge of some basic principles, this task can be performed adeptly by physicians of all specialties. In this article, the authors discuss basic principles of psychopharmacology and outline an approach to using several commonly prescribed classes of medications. PMID- 20951276 TI - An approach to the psychosocial treatment of the medically ill patient. AB - This article discusses some of the practices of psychosocial treatment. Broadly speaking, these practices include an emphasis on the doctor-patient relationship, the creation of a sound and lasting alliance, and the experience of trust and partnership that the physician fosters in helping the patient to negotiate the complex and uniquely individual experience of being ill. An argument is proposed that unless practitioners of medicine are mindful of the threats to the way they would like and are expected by their patients to practice medicine, they are unlikely to endorse changes actively or to pass the need for these changes onto the next generation of physicians. In this sense, keeping these concerns alive and the subject of ongoing discussion is crucial to the ongoing conceptualization of what it means to be a doctor. PMID- 20951277 TI - An approach to the patient with substance use and abuse. AB - Substance use is ubiquitous among medically ill patients. The 2008 National Survey on Drug Abuse and Health survey estimated that 20.1 million Americans aged 12 years or older (8% of the US population) had used an illicit drug during the preceding month. Some licit substances also create havoc. The survey found that slightly more than half (56%) of Americans reported being current drinkers of alcohol. A total of 6.2 million (2.5%) Americans used prescription-type psychotherapeutic drugs for nonmedical purposes and 70.9 million Americans (or 28.4%) used tobacco during the survey period. Substance abuse problems were diagnosed in up to 36% of medically hospitalized patients for whom a psychiatric consultation was requested. Given how prevalent the use of substances is among the medically ill and their potential effect on comorbid medical conditions, it is important for physicians to be mindful of their prevalence and presentation. This article covers the presenting symptoms of intoxication and withdrawal states, addresses the acute management of the most commonly encountered substances, and summarizes all others in a table. PMID- 20951278 TI - An approach to the patient with multiple physical symptoms or chronic disease. AB - Doctors diagnose and treat disease; illness is the experience of, and response to, a disease by patients and the people in their lives. Discrepancies between disease and illness (eg, adjustment to the sick role, treatment-related difficulties, denial of medical illness, and psychiatric comorbidity) are prevalent, as are somatoform disorders and other conditions in which patients are invested in being understood as medically ill. This article reviews suggestions for physicians' responses to these patients and their dilemmas. PMID- 20951279 TI - An approach to symptoms at the interface of medicine and psychiatry: pain, insomnia, weight loss and anorexia, fatigue and forgetfulness, and sexual dysfunction. AB - Primary care physicians commonly deal with patients who present with a somatic complaint for which no clear organic etiology can be found. This article discusses how a psychiatrist thinks about somatic symptoms (eg, pain, insomnia, weight loss and loss of appetite, fatigue and forgetfulness, sexual dysfunction) in a patient who might have depression. The management of a patient in whom no satisfactory medical or psychiatric diagnosis can be made is also reviewed briefly. PMID- 20951280 TI - An approach to selected legal issues: confidentiality, mandatory reporting, abuse and neglect, informed consent, capacity decisions, boundary issues, and malpractice claims. AB - Medical practice occurs within a legal and regulatory context. This article covers several of the legal issues that frequently arise in the general medical setting. While this article provides an overview of approaches to informed consent, boundary issues, and malpractice claims, it is critical for clinicians to be familiar with the specific requirements and standards in the jurisdictions in which they practice. As a general rule, it is most important that physicians recognize that the best way to avoid legal problems is to be aware of legal requirements in the jurisdictions in which they practice, but to think clinically and not legally in the provision of consistent and sound clinical care to their patients. PMID- 20951281 TI - An approach to the patient with organ failure: transplantation and end-of-life treatment decisions. AB - Organ transplantation offers an opportunity for extended survival and enhanced quality of life to patients with end-stage organ disease. Significant challenges are associated with both pre- and post-transplantation care, however, that require awareness of psychiatric issues in this patient population. Ventricular assist devices have added another dimension to patient care and to quality-of life considerations. Unfortunately, effective incorporation of palliative care and end-of-life discussions is frequently overlooked during caretaking of these patients. PMID- 20951282 TI - Effect of working length measurement by electronic apex locator or radiography on the adequacy of final working length: a randomized clinical trial. AB - INTRODUCTION: Obtaining a correct working length is critical to the success of endodontic therapy. The aim of this clinical study was to compare the effect of working length determination using electronic apex locator or working length radiograph on the length adequacy of final working length as well as the final obturation. METHODS: A total of 84 patients with 188 canals were randomized into two groups; in group 1, the working length was determined by working length radiograph, whereas in group 2, it was determined by the Raypex5 electronic apex locator (VDW, Munich, Germany). Length adequacy was assessed in each group for master cone and final obturation radiography and categorized into short, acceptable, and over cases. RESULTS: There was no statistically significant difference between the rates of acceptable (master cone radiography: group 1 = 82.1% and group 2 = 90.4%; final radiography: group 1 = 85.7% and group 2 = 90.4%) and short cases (master cone radiography: group 1 = 7.1% and group 2 = 8.7%; final radiography: group 1 = 1.2% and group 2 = 1%) between the two groups. Over cases in master cone radiography were significantly more in group 1 (10.7%) than group 2 (1%) (chi2, p = 0.00). However, this category did not show a significant difference for final obturation between group 1 (13.1%) and group 2 (8.7%). CONCLUSION: The results of endodontic treatment using the Raypex5 electronic apex locator are quite comparable, if not superior, to radiographic length measurement regarding the rates of acceptable and short cases. Furthermore, in addition to reducing the radiographic exposure, electronic apex locators are superior in reducing overestimation of the root canal length. PMID- 20951283 TI - Outcome of endodontic surgery: a meta-analysis of the literature--part 1: Comparison of traditional root-end surgery and endodontic microsurgery. AB - INTRODUCTION: The aim of this study was to investigate the outcome of root-end surgery. The specific outcome of traditional root-end surgery (TRS) versus endodontic microsurgery (EMS) and the probability of success for comparison of the 2 techniques were determined by means of meta-analysis and systematic review of the literature. METHODS: An intensive search of the literature was conducted to identify longitudinal studies evaluating the outcome of root-end surgery. Three electronic databases (Medline, Embase, and PubMed) were searched to identify human studies from 1966 to October 2009 in 5 different languages (English, French, German, Italian, and Spanish). Relevant articles and review papers were searched for cross-references. Five pertinent journals (Journal of Endodontics, International Endodontic Journal, Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics, Journal of Oral and Maxillofacial Surgery, International Journal of Oral and Maxillofacial Surgery) were individually searched back to 1975. Three independent reviewers (S.S., M.K., and F.S.) assessed the abstracts of all articles that were found according to predefined inclusion and exclusion criteria. Relevant articles were acquired in full-text form, and raw data were extracted independently by each reviewer. Qualifying papers were assigned to group TRS or group EMS. Weighted pooled success rates and relative risk assessment between TRS and EMS were calculated. A comparison between the groups was made by using a random effects model. RESULTS: Ninety-eight articles were identified and obtained for final analysis. In total, 21 studies qualified (12 for TRS [n = 925] and 9 for EMS [n = 699]) according to the inclusion and exclusion criteria. Weighted pooled success rates calculated from extracted raw data showed 59% positive outcome for TRS (95% confidence interval, 0.55-0.6308) and 94% for EMS (95% confidence interval, 0.8889-0.9816). This difference was statistically significant (P < .0005). The relative risk ratio showed that the probability of success for EMS was 1.58 times the probability of success for TRS. CONCLUSIONS: The use of microsurgical techniques is superior in achieving predictably high success rates for root-end surgery when compared with traditional techniques. PMID- 20951284 TI - Clinical investigation of the efficacy of chemomechanical preparation with rotary nickel-titanium files for removal of endotoxin from primarily infected root canals. AB - INTRODUCTION: This clinical study was conducted to investigate the ability of chemomechanical preparation with 2.5% NaOCl + 17% ethylenediaminetetraacetic acid (EDTA) and rotary nickel-titanium (NiTi) system in removing endotoxin from primary root canal infection with apical periodontitis. METHODS: Twenty-one root canals with necrotic pulps were selected. Samples were collected before (s1) and after chemomechanical preparation (s2). The limulus amebocyte lysate (LAL) assay was used to quantify endotoxins. RESULTS: The LAL assay indicated that endotoxins were present in 100% of the root canals investigated (19/19) before (s1) and after chemomechanical preparation (s2). Analyses of the quantitative data revealed that the endotoxin content was significantly reduced at s2 (98.06%) compared with that at s1 (P < .05). CONCLUSIONS: Our findings indicate that chemomechanical preparation with 2.5% NaOCl + 17% EDTA and rotary NiTi files was effective in reducing endotoxin load in the root canal infection from primarily infected teeth with apical periodontitis. PMID- 20951285 TI - A prospective, randomized, double-blind comparison of the anesthetic efficacy of two percent lidocaine with 1:100,000 epinephrine and three percent mepivacaine in the maxillary high tuberosity second division nerve block. AB - INTRODUCTION: The purpose of this prospective, randomized, double-blind study was to compare the anesthetic efficacy of 2% lidocaine with 1:100,000 epinephrine and 3% mepivacaine in the maxillary high tuberosity second division nerve block. METHODS: Fifty subjects randomly received maxillary high tuberosity second division nerve blocks by using 3.6 mL of 2% lidocaine with 1:100,000 epinephrine and 3.6 mL of 3% mepivacaine at 2 separate appointments spaced at least 1 week apart. The anterior, premolar, and molar teeth were pulp tested in 4-minute cycles for a total of 60 minutes. Success was defined as no subject response to 2 consecutive 80 readings with the electric pulp tester. RESULTS AND CONCLUSIONS: The high tuberosity approach to the maxillary second division nerve block with both anesthetic formulations resulted in a high success rate (92%-98%) for the first and second molars. Approximately 76%-78% of the second premolars were anesthetized with both anesthetic formulations. Both anesthetic formulations were ineffective for the anterior teeth and first premolars. The use of 3% mepivacaine provided a significantly shorter duration of pulpal anesthesia than 2% lidocaine with 1:100,000 epinephrine in the molars and premolars. PMID- 20951286 TI - Histologic assessment of human pulp response to capping with mineral trioxide aggregate and a novel endodontic cement. AB - INTRODUCTION: This study was conducted to compare human pulp response to mineral trioxide aggregate (MTA) and a novel endodontic cement (NEC) when used as pulp capping materials after a time period of 2 and 8 weeks. METHODS: Thirty-two premolar teeth that were scheduled for extraction for orthodontic reasons were exposed and capped with either MTA or NEC. Half of the specimens underwent extraction and histologic analysis after 2 weeks, and the remaining half were assessed after 8 weeks. Each slide was graded histologically according to the morphology of the dentinal bridge, thickness of the dentinal bridge, presence of odontoblast cells, and inflammation of the pulp. RESULTS: Both MTA and NEC showed significantly better pulp response after 8 weeks compared with 2 weeks, with a thicker and more tubular pattern of the dentinal bridge, less pulp inflammation, and a palisade pattern of odontoblast cells. Although MTA and NEC groups had no significant difference in each measure in both time intervals, NEC induced a thicker dentinal bridge with less pulp inflammation at both 2 weeks and 8 weeks, compared with MTA. CONCLUSIONS: MTA and NEC showed similar biocompatibility and favorable response in pulp capping treatment and inducing the formation of the dentinal bridge. PMID- 20951287 TI - Comparison of the debridement efficacy of the EndoVac irrigation system and conventional needle root canal irrigation in vivo. AB - INTRODUCTION: The purpose of this study was to compare the debridement efficacy of EndoVac irrigation versus conventional needle irrigation in vivo. METHODS: Seven adult patients with a total of 22 matched pairs of single-canaled vital teeth with fully formed apices were recruited. Canals were instrumented to a master apical file size #40/.04 taper. One tooth from each matched pair was irrigated by using the EndoVac system. The other tooth was irrigated by conventional needle irrigation. Five additional teeth were used as positive controls. A #10 K-file was inserted into the control canals to determine working length (WL), with no other instrumentation or irrigation performed to confirm the presence of debris. The teeth were extracted, fixed, and decalcified. Six histologic slides each 6 MUm thick were made from sections at 1 and 3 mm from WL and stained. The slide with the most debris was photographed at each level for each tooth. A Wilcoxon signed rank test was used to compare the percentage of debris remaining in the canals between the 2 irrigation techniques. RESULTS: The median amount of debris remaining at 1 mm was 0.05% for the EndoVac group and 0.12% for the conventional irrigation group (P < .05). The median amount of debris remaining at 3 mm was 0.09% for the EndoVac group and 0.07% for the conventional needle irrigation group (P > .05). CONCLUSIONS: EndoVac irrigation resulted in significantly less debris at 1 mm from WL compared with conventional needle irrigation. There was no significant difference at the 3-mm level. PMID- 20951288 TI - Evaluation of the root and canal morphology of mandibular first permanent molars in a western Chinese population by cone-beam computed tomography. AB - INTRODUCTION: The purpose of this study was to evaluate the root and canal morphology of mandibular first permanent molars in a western Chinese population by using cone-beam computed tomography (CBCT). METHODS: In this study, 558 samples were examined by CBCT. Details of sex, tooth position, the number of roots and canals, and the canal configuration were recorded. The root canal configuration was categorized and compared according to Vertucci's criteria. RESULTS: Overall, 51.4% of the mandibular first permanent molars examined had four canals, and 25.8% had a separate distolingual root. In 48.1% of these, the fourth canal was in the separate distolingual root. In the two-rooted mandibular first permanent molars, 93.9% of the mesial root canals were of type IV, and 62.9% of the distal root canals were of type I. In the three-rooted samples, 94.4% of the mesial root canals were of type IV, and 98.6% of the distobuccal and 100% of the distolingual root canals were of type I. In addition, there was a higher incidence of three-rooted mandibular first permanent molars on the left side than on the right, but this relationship was not significantly correlated with sex. CONCLUSIONS: Mandibular first permanent molars commonly have four canals and a higher prevalence for a separated distolingual canal in a western Chinese population. PMID- 20951289 TI - Distribution of Porphyromonas gingivalis fimA genotypes in chronic apical periodontitis associated with symptoms. AB - INTRODUCTION: Porphyromonas gingivalis (P. gingivalis) is an anaerobic bacterium involved in root canal infections whose fimbriae are classified into six genotypes (types I-V and Ib) based on nucleotide sequence. Accumulated evidence suggests there is significant association between P. gingivalis and some clinical symptoms of periodontal diseases. The present study aims to determine the prevalence of P. gingivalis fimA genotypes in apical periodontitis and to investigate the correlation between P. gingivalis fimA genotypes and clinical symptoms. METHODS: Samples were obtained from 158 infected root canals with apical periodontitis. DNA was extracted and analyzed with a polymerase chain reaction-based identification assay. Odds ratios, 95% confidence intervals, and contingency coefficient were calculated for associating the fimA-specific genes with clinical symptoms. RESULTS: P. gingivalis was detected in 39.9% of the inflected root canal samples and was found in 44.5% of P. gingivalis-positive specimens with symptoms. Types II (69.4%) were the most frequent in the symptomatic cases followed by type IV (32.7%). The occurrence of type I (64.3%) was significantly higher than any other genotypes in the asymptomatic apical periodontitis, whereas type II and type Ib were not identified. Statistical analysis revealed that the occurrences of types II, IV, and Ib fimA were associated with greater risk of clinical signs (swelling, sinus tract, or intracanal exudates) than type I. CONCLUSIONS: Results from this study reinforce the association between P. gingivalis-specific fimA genotypic clones and apical periodontitis, indicating that fimA genotypes (types II, IV, and Ib) were related to the etiology of symptomatic periradicular diseases. PMID- 20951290 TI - Treponema species detected in infected root canals and acute apical abscess exudates. AB - INTRODUCTION: Different microbial communities have been associated with acute endodontic infections. The majority of the microorganisms are as yet uncultivable or difficult to grow under current laboratory conditions. Treponema species are strict anaerobic bacteria that are involved in several oral diseases. The aim of this study was to detect the presence of Treponema species in infected root canals (RCs) and exudates related to acute apical abscesses (AAAs) as well as to determine positive association between targeted species and clinical signs/symptoms. METHODS: Paired samples of infected RCs and AAAs were collected from 20 subjects. Nested polymerase chain reaction assay with species-specific primers for 16S rDNA and downstream intergenic spacer region was used for microbial detection. The frequency of species and statistical associations between species and signs/symptoms of endodontic origin as well as their simultaneous detection in both milieus were investigated. RESULTS: The most frequently detected species were T. socranskii (RC, 17/20; AAA, 15/20), T. denticola (RC, 8/20; AAA, 11/20); T. medium (RC, 6/20; AAA, 9/20); and T. amylovorum (RC, 5/20; AAA, 9/20). Positive correlation was found for simultaneous presence of T. denticola in both RCs and AAAs (p = 0.01). Positive association was observed between T. medium and T. vincentii (p = .037). No positive statistical association was observed between the targeted species and signs/symptoms. CONCLUSIONS: The high incidence of Treponema species in RC and AAA samples from the same tooth indicated that they are important pathogens in acute endodontic infections. PMID- 20951291 TI - Hypertension and dental periapical condition. AB - INTRODUCTION: The purpose of this study was to investigate the prevalence of apical periodontitis and endodontic treatment in hypertensive patients and control subjects without hypertension. METHODS: In a cross-sectional study, the records of 40 hypertensive patients and 51 control subjects were examined. Periapical status of all teeth was assessed by using the periapical index score. RESULTS: Apical periodontitis in 1 or more teeth was found in 75% of hypertensive patients and in 61% of control subjects (P = .15; odds ratio, 1.94; 95% confidence interval, 0.78-4.81). One or more root-filled teeth were found in 45% and 39% of hypertensive and control subjects, respectively (P > .0.5). Among hypertensive patients 5.2% of the teeth had apical periodontitis, whereas in the control subjects 4.2% of teeth were affected (P > .05). The percentages of root filled teeth in the study and control groups were 3.1% and 1.8%, respectively (P > .05). Among hypertensive patients 65% of root-filled teeth had apical periodontitis, whereas in the control subjects 43% of the root-filled teeth were associated with apical periodontitis (P > .05). CONCLUSIONS: The prevalence of apical periodontitis and endodontic treatment was not significantly different in hypertensive patients compared with control subjects without hypertension. PMID- 20951292 TI - Effects of morphogen and scaffold porogen on the differentiation of dental pulp stem cells. AB - INTRODUCTION: Dental pulp tissue engineering is an emerging field that can potentially have a major impact on oral health. However, the source of morphogens required for stem cell differentiation into odontoblasts and the scaffold characteristics that are more conducive to odontoblastic differentiation are still unclear. This study investigated the effect of dentin and scaffold porogen on the differentiation of human dental pulp stem cells (DPSCs) into odontoblasts. METHODS: Poly-L-lactic acid (PLLA) scaffolds were prepared in pulp chambers of extracted human third molars using salt crystals or gelatin spheres as porogen. DPSCs seeded in tooth slice/scaffolds or control scaffolds (without tooth slice) were either cultured in vitro or implanted subcutaneously in immunodefficient mice. RESULTS: DPSCs seeded in tooth slice/scaffolds but not in control scaffolds expressed putative odontoblastic markers (DMP-1, DSPP, and MEPE) in vitro and in vivo. DPSCs seeded in tooth/slice scaffolds presented lower proliferation rates than in control scaffolds between 7 and 21 days (p < 0.05). DPSCs seeded in tooth slice/scaffolds and transplanted into mice generated a tissue with morphological characteristics similar to those of human dental pulps. Scaffolds generated with gelatin or salt porogen resulted in similar DPSC proliferation. The porogen type had a relatively modest impact on the expression of the markers of odontoblastic differentiation. CONCLUSIONS: Collectively, this work shows that dentin-related morphogens are important for the differentiation of DPSC into odontoblasts and for the engineering of dental pulp-like tissues and suggest that environmental cues influence DPSC behavior and differentiation potential. PMID- 20951293 TI - Food-borne enterococci integrate into oral biofilm: an in vivo study. AB - INTRODUCTION: Enterococci, particularly Enterococcus faecalis, are still a primary concern in endodontic infections. To date, enterococci have been considered to be only transiently present in the oral cavity. The aim of this study was to examine whether different enterococci from food are able to reside in oral biofilm. METHODS: Six healthy volunteers wore dental splints loaded with enamel slabs. After 3 days, the volunteers consumed cheese containing enterococci. The fate of the enterococci was analyzed by culture technique and 16S rRNA gene sequencing. All isolates were characterized genotypically by macrorestriction analysis (SmaI) and pulsed-field gel electrophoresis. E. faecalis was also analyzed by using fluorescent in situ hybridization (FISH). RESULTS: E. faecalis, E. faecium, E. avium, and E. durans were detected in the initial biofilm after 2 hours, as well as in the 5-day-old oral biofilm. E. faecalis, E. faecium, and E. avium isolated from the initial biofilm and from the 5-day-old biofilm, as well as those isolated from cheese, showed genetic homogeneity. E. faecium and E. avium had integrated into a pre-existing 3-day-old biofilm. No genetic similarity between E. durans strains isolated from cheese and those from the initial and 5-day-old oral biofilm was detected. E. faecalis was also detected in the oral biofilm by using FISH. CONCLUSIONS: Food-borne enterococci, particularly E. faecalis, might not only be transient but could also survive in the oral biofilm and become a source for endodontic infections. Moreover, genotypic analysis is required to study the source of oral enterococci. PMID- 20951294 TI - Bacterial viability in starved and revitalized biofilms: comparison of viability staining and direct culture. AB - OBJECTIVES: The aim of this study was to enumerate viable bacteria at different growth stages of a multispecies oral biofilm and to compare results obtained with the LIVE/DEAD BacLight Kit (Molecular Probes, Eugene, OR) with those from culturing and plate counting (colony-forming unit counts [CFUs]). METHODS: The multispecies biofilm was grown from plaque bacteria on collagen-coated hydroxyapatite disks in brain-heart infusion broth for 3 weeks (phase I) with a weekly addition of new nutrients. This was followed by a 9-week nutrient deprivation phase (phase II); after which, the biofilm was reactived again by weekly additions of fresh BHI medium for 4 weeks (phase III). The number and proportion of live bacteria in biofilm was assessed by culturing and by confocal laser scanning microscopy using a LIVE/DEAD viability stain throughout the experiment. RESULTS: The CFU counts dropped more than four logarithmic steps during phase II. However, viability staining by LIVE/DEAD stain indicated only a 25% drop in viability. The CFU counts increased during phase III, but it took 4 weeks for them to return close to the original CFU numbers. Cell viability, as indicated by the staining, improved from 75% close to the original 100%. CONCLUSIONS: Bacteria in the multispecies biofilm grown under nutrient deprivation became viable but nonculturable but could be brought back to a culturable state after reestablishing sufficient access to nutrients. The results indicate that viability staining better reflected true viability of the biofilm bacteria than culturing during the long starvation phase. The result of this study may have an impact on the interpretation of cultural studies on root canal microbiology/biofilms in vivo. PMID- 20951295 TI - Effects of fibroblast growth factor-2 on the expression and regulation of chemokines in human dental pulp cells. AB - BACKGROUND: Fibroblast growth factor-2 (FGF-2) participates in both hematopoiesis and osteogenesis; however, the effects of FGF-2 on chemokines during odontoblastic differentiation have not been reported. This study investigated whether human dental pulp cells (HDPCs) treated with FGF-2 could express chemokines during differentiation into odontoblastic cells and sought to identify its underlying mechanism of action. METHODS: To analyze differentiation, we measured alkaline phosphatase (ALP) activity, calcified nodule formation by alizarin red staining, and marker RNA (mRNA) expression by reverse-transcriptase polymerase chain reaction (RT-PCR). Expression of chemokines, such as interleukin 6 (IL-6), IL-8, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP-3alpha, were evaluated by RT PCR. RESULTS: ALP activity, the mineralization, and mRNA expression for odontoblastic markers were enhanced by FGF-2 in HDPCs. FGF-2 also up-regulated the expression of IL-6, IL-8, MCP-1, MIP-1alpha, and MIP-3alpha mRNAs, which were attenuated by inhibitors of p38, ERK1/2 and p38 MAP kinases, protein kinase C, phosphoinositide-3 kinase, and NF-kappaB. CONCLUSION: Taken together, these data suggest that FGF-2 plays a role not only as a differentiation inducing factor in the injury repair processes of pulpal tissue but also as a positive regulator of chemokine expression, which may help in tissue engineering and pulp regeneration using HDPCs. However, the fate of odontoblastic or osteoblastic differentiation, effective local delivery for FGF-2, interaction of chemotatic and odontogenic factors, and other limitations will need to be overcome before a major modality for the treatment of pulp disease. PMID- 20951296 TI - Gene expression profiling concerning mineralization in human dental pulp cells treated with mineral trioxide aggregate. AB - INTRODUCTION: This study investigated changes in gene expressions related to mineralization when mineral trioxide aggregate (MTA) is applied in vitro to human dental pulp cells (HDPCs). METHODS: MTA in a Teflon tube (diameter 10 mm, height 2 mm) was applied to HDPCs. Empty tube-applied HDPCs were used as negative control. Total RNA was extracted at 6, 24, and 72 hours after MTA application for microarray analysis. The results were confirmed selectively by performing reverse transcriptase-polymerase chain reaction for genes that showed changes of more than 2-fold or less than half. RESULTS: Of the 24,546 genes, 109 genes were up regulated more than 2-fold (eg, THBS1, VCAN, BHLHB2, FN1, COL10A1, TUFT1, and HMOX1), and 69 genes were down-regulated below 50% (eg, DCN, SOCS2, and IL8). CONCLUSIONS: These results suggest that rather than being a bio-inert material, MTA affects pulp cells in various ways. MTA appears to affect mineralization and induces slight inflammation and protective role against slight inflammation. PMID- 20951297 TI - Effect of mineral trioxide aggregate on mesenchymal stem cells. AB - INTRODUCTION: Mineral trioxide aggregate (MTA) is known to stimulate the hard tissue repair process. The purpose of this study was to evaluate the ability of MTA to support the adhesion, proliferation, and migration of human bone marrow derived mesenchymal stem cells (hMSCs). METHODS: White ProRoot MTA and white Portland cement were mixed and left to set 24 hours. MSCs were cultured on the samples and observed after 24 hours by confocal laser scanning microscopy (CLSM) by using the cytoskeleton marker CellTracker. Cell proliferation was evaluated by means of alamar blue assay in the presence and absence of differentiation medium during a period of 28 days, and cells seeded on polystyrene culture wells were the control. To assess the effect on migratory ability of hMSCs, a transwell migration assay was performed for 18 hours, positioning MTA and Portland cement in 6-well plates and the cells in 8-MUm pore inserts. RESULTS: hMSCs observed under CLSM showed attachment and spread activity on the upper surface of the MTA. Cell proliferation was significantly higher on MTA than on Portland cement. A rate proliferation increase of the MTA group compared with the control was observed after 14 days in presence of basic medium, whereas the same effect was reached after 21 days in presence of differentiation medium. Moreover, MTA was able to enhance cell migration significantly more than Portland cement. CONCLUSIONS: Our findings suggest that MTA was able to assist hMSC adhesion, growth, and migration. PMID- 20951298 TI - In vitro cytocompatibility of N-acetylcysteine-supplemented dentin bonding agents. AB - INTRODUCTION: Cytotoxic resin components of dentin bonding agents are known to cause oxidative damage and suppress odontogenic differentiation of dental pulp cells. Because antioxidants were found to protect cells from cytotoxicity of resin monomers in previous studies, we investigated the effect of N acetylcysteine (NAC) on cytotoxicity and anti-differentiation activity of bonding agents. METHODS: Human dental pulp cells were treated with the extracts of dentin bonding agents (Prime & Bond NT, Adper Single Bond, and Dentin Cement), and then cell viability, alkaline phosphatase (ALP) activity, and matrix mineralization were observed. To assess the effects of NAC, NAC was directly added into culture media or mixed with bonding agents before extraction. Release of NAC from bonding agents was also observed by high-performance liquid chromatography. RESULTS: NAC enhanced ALP activity and mRNA expression of dentin sialophosphoprotein gene, whereas extracts of dentin bonding agents inhibited the induction of ALP activity. When the cells were treated with extracts of the bonding agents, the NAC in the culture media reduced the cytotoxicity of the bonding agents. When NAC was incorporated into bonding agents, a protective effect was only seen for Prime & Bond NT containing more than 1% NAC. The disruption of ALP activity and matrix mineralization in pulp cells was partially reversed by NAC only in Prime & Bond NT-treated cells. High-performance liquid chromatography analysis of NAC showed that the amount of NAC effluxed from Prime & Bond NT was not greater than that effluxed from Adper Single Bond. CONCLUSIONS: NAC was useful for reversing cytotoxicity and anti-differentiation effects of Prime & Bond NT on human dental pulp cells. PMID- 20951299 TI - Biocompatibility of accelerated mineral trioxide aggregate in a rat model. AB - INTRODUCTION: The purpose of this study was to evaluate the biocompatibility of gray mineral trioxide aggregate (MTA) mixed with selected accelerants by examining the inflammatory response through histological analysis after implantation into rat mandibles. METHODS: Sixty rats were randomly divided into experimental groups of calcium chloride (CaCl2), calcium nitrite/nitrate (CaN/N), or calcium formate (CaF) mixed with MTA and compared with controls of MTA mixed with sterile water (MTA control) and unfilled osteotomies. Material was implanted into an osteotomy prepared between the roots of the mandibular molars and the incisors in the mandible. After 2 or 8 weeks, tissues were collected and processed for hematoxylin and eosin staining and light microscopic evaluation. Blinded evaluators graded the inflammatory response along the MTA-bone interface on an ordinal scale. Data were analyzed using the Kruskal-Wallis test, and interobserver agreement was determined by the kappa analysis. RESULTS: Interobserver agreement was good with kappa = 0.72. No statistically significant differences were noted between experimental and control groups at the 2-week time point (p > 0.05). At this time, all groups displayed a range of inflammatory responses from none to severe with mostly mild to moderate reactions. At the 8 week time point, the inflammatory reaction of CaF mixed with MTA was statistically different from the controls (p = 0.03). CaCl2 and CaN/N were not statistically different from the controls, and the MTA control displayed no inflammation at this time point. CONCLUSIONS: The findings of this study indicate that MTA mixed with accelerants may be a biocompatible alternative when a rapid set is indicated clinically. PMID- 20951300 TI - Push-out bond strength of mineral trioxide aggregate in the presence of alkaline pH. AB - INTRODUCTION: The aim of this study was to evaluate the effect of a range of alkaline pH values on the push-out strength of white mineral trioxide aggregate (WMTA). METHODS: The standardized lumens of root slices prepared from extracted single-rooted human teeth were filled with white ProRoot MTA. The specimens were then randomly divided into 4 groups (n = 20) and wrapped in pieces of gauze soaked in synthetic tissue fluid (STF) (pH, 7.4) and STF buffered in potassium hydroxide at pH values of 8.4, 9.4, or 10.4. The samples were incubated for 3 days at 37 degrees C. The push-out bond strengths were then measured by using a universal testing machine. Failure modes after the push-out test were examined under a light microscope at *40 magnification. The data were analyzed by using one-way analysis of variance and Tukey post hoc tests. RESULTS: The greatest (9.46 +/- 0.63 MPa) and lowest (5.68 +/- 0.83 MPa) mean push-out bond strengths were observed after exposure to pH values of 8.4 and 10.4, respectively. There were significant differences between the groups (P = .001). The bond failure was adhesive for all experimental groups. CONCLUSIONS: Push-out bond strength of WMTA could be influenced by different alkaline pH values. PMID- 20951301 TI - Ability of chemomechanical preparation with either rotary instruments or self adjusting file to disinfect oval-shaped root canals. AB - INTRODUCTION: Oval-shaped root canals might represent a great challenge for proper disinfection. This study compared the capability of a newly developed instrument, the self-adjusting file (SAF), and rotary nickel-titanium (NiTi) instrumentation to eliminate Enterococcus faecalis populations from long oval root canals of extracted human teeth. As a secondary purpose, the ability of a modification in sampling technique to recover bacteria lodged in recesses of oval canals was evaluated. METHODS: Long oval canals from mandibular incisors and maxillary second premolars were infected with E. faecalis (ATCC 29212) for 30 days and then randomly distributed into 2 experimental groups. In group 1, canals were prepared up to a 40/04 rotary BioRaCe instrument by using irrigation with NaviTip needles; in group 2, canals were prepared by using the SAF system with continuous irrigation. NaOCl and ethylenediaminetetraacetic acid were used as irrigants. Bacteriologic samples were taken before (S1) and after preparation (S2a and S2b). RESULTS: Reduction in the bacterial populations was highly significant in both groups (P < .001). Preparation of long oval canals with the SAF was significantly more effective than rotary NiTi instrumentation in reducing intracanal E. faecalis counts (P = .01). Frequency of positive cultures in S2 samples was 11 of 20 (55%) for rotary instrumentation and 4 of 20 (20%) for SAF instrumentation (P = .048). S2b samples (modified method) yielded more positive samples than S2a (12/40 vs 5/40), but this difference reached no statistical significance (P > .05). CONCLUSIONS: The SAF system was significantly more effective than rotary NiTi instrumentation used with syringe/needle irrigation in disinfecting long oval root canals in vitro. A modified sampling technique might be necessary for oval canals. PMID- 20951302 TI - Three-dimensional morphologic analysis of isthmuses in the mesial roots of mandibular molars. AB - INTRODUCTION: The purpose of this study was to investigate the three-dimensional (3-D) morphology of isthmuses in the mesial roots of mandibular molars. METHODS: One hundred twenty-six extracted mandibular molars including 70 first molars (MFMs) and 56 second molars (MSMs) from a Chinese population were scanned by micro-computed tomography, and the apical 5 mm of the root canals with or without isthmuses was reconstructed with 3D-Doctor software. Each reconstructed isthmus model was assigned to 1 of the following 4 categories: sheet connection, separate, mix, and cannular connection. The length of the isthmus (L(i)) and the distance from the bottom of the isthmus to apex (D(ba)) were measured and analyzed. RESULTS: The incidence of an isthmus in the apical 5 mm of the mesial roots was 85%. MFMs had more isthmuses with separate type and mixed type, whereas MSMs had more isthmuses with sheet connections. The L(i) and D(ba) in mandibular molars were 2.331 mm and 1.850 mm, respectively. CONCLUSIONS: MFMs present different anatomical features of isthmuses in the apical part of the mesial roots than MSMs. PMID- 20951303 TI - Heat release, time required, and cleaning ability of MTwo R and ProTaper universal retreatment systems in the removal of filling material. AB - INTRODUCTION: This ex vivo study evaluated the heat release, time required, and cleaning efficacy of MTwo (VDW, Munich, Germany) and ProTaper Universal Retreatment systems (Dentsply/Maillefer, Ballaigues, Switzerland) and hand instrumentation in the removal of filling material. METHODS: Sixty single-rooted human teeth with a single straight canal were obturated with gutta-percha and zinc oxide and eugenol-based cement and randomly allocated to 3 groups (n = 20). After 30-day storage at 37 degrees C and 100% humidity, the root fillings were removed using ProTaper UR, MTwo R, or hand files. Heat release, time required, and cleaning efficacy data were analyzed statistically (analysis of variance and the Tukey test, alpha = 0.05). RESULTS: None of the techniques removed the root fillings completely. Filling material removal with ProTaper UR was faster but caused more heat release. Mtwo R produced less heat release than the other techniques but was the least efficient in removing gutta-percha/sealer. CONCLUSIONS: ProTaper UR and MTwo R caused the greatest and lowest temperature increase on root surface, respectively; regardless of the type of instrument, more heat was released in the cervical third. Pro Taper UR needed less time to remove fillings than MTwo R. All techniques left filling debris in the root canals. PMID- 20951304 TI - Bactericidal activity of stabilized chlorine dioxide as an endodontic irrigant in a polymicrobial biofilm tooth model system. AB - INTRODUCTION: The purpose of this study was to determine bactericidal efficacy of 0.04% stabilized chlorine dioxide, 3% sodium hypochlorite, 2% chlorhexidine gluconate, and sterile distilled water in a polymicrobial biofilm model. METHODS: Roots of 35 permanent bovine incisors had pulps extirpated, and their apical size and root length were standardized. Teeth were coated with mucin, inoculated with standardized suspensions of Streptococcus sanguinis, Actinomyces viscosus, Fusobacterium nucleatum, Peptostreptococcus micros, and Prevotella nigrescens and incubated anaerobically. Teeth were randomly divided into four groups and rinsed for 3 minutes with 15 mL of irrigant. Biofilms were harvested and spiral-plated on selective media. Numbers of bacteria in the harvested biofilms was determined via the standard spiral-plating methodology. Treatment groups were evaluated using the nonparametric Kruskal-Wallis procedure. Pair-wise comparisons among the four groups and five organisms were made using the Wilcoxon-Mann-Whitney procedure. Adjustments for multiple comparisons were made using the Holm method with p < 0.05. RESULTS: Results provide strong evidence of a significant difference in levels of bactericidal activity associated with the type of irrigant for all five bacterial species tested. Levels of bactericidal activity were significantly higher for the NaOCl group than for the stabilized chlorine dioxide (ClO2) group for S. sanguinis, A. viscosus, and P. nigrescens. Results for F. nucleatum and P. micros were not significant after the adjustment for multiple comparisons. CONCLUSIONS: The triple-inoculation bovine tooth model system is a robust, consistent, and reproducible model system to study polymicrobial biofilms. It should be used with the knowledge expansion of biofilm structure and function as well as the development of antimicrobial protocols. PMID- 20951305 TI - Diagnostic ability of a cone-beam computed tomography scan to assess longitudinal root fractures in prosthetically treated teeth. AB - INTRODUCTION: This study evaluated the influence of cast-gold posts on the diagnostic ability of a cone beam computed tomography (CBCT) system in assessing longitudinal root fractures. In addition, the influence of gutta-percha and variations in voxel resolution were assessed. METHODS: One hundred eighty endodontically prepared teeth were divided into 3 experimental and 3 control groups and placed in a dry human skull. The teeth in the experimental groups were artificially fractured. Certain experimental and control groups were filled with gutta-percha cones. Other experimental and control groups were filled with cast gold posts. All the teeth were viewed by using a tomography scan with 2 voxel resolution protocols (0.3-mm and 0.2-mm). A calibrated examiner, blinded to the protocol, assessed the images by using the nominated scan software. RESULTS: The kappa values obtained for intraobserver reproducibility were 0.84 and 0.93 for 0.3-mm and 0.2-mm voxel resolution, respectively. The presence of gutta-percha or posts reduced the overall sensitivity and specificity in both voxel resolutions, but with no significant association. The CBCT specificity values were similar and did not depend on the voxel resolution adopted. In contrast, the sensitivity values were significantly higher for 0.2-mm voxel resolution in nonfilled (P < .05), gutta-percha (P < .001), and overall (P < .001) groups. CONCLUSIONS: The CBCT diagnostic ability was not influenced by the presence of posts or gutta percha, and the 0.3-mm voxel resolution images were demonstrated not to be a reliable protocol for the investigation of longitudinal root fractures. PMID- 20951306 TI - Effects of pH on surface hardness and microstructure of mineral trioxide aggregate and Aureoseal: an in vitro study. AB - INTRODUCTION: The aim of the study was to evaluate the surface hardness and the morphologic microstructure of white mineral trioxide aggregate (WMTA) and Aureoseal in acid environment. METHODS: WMTA and Aureoseal were mixed and packed into 64 cylindrical stainless steel molds. Thirty-two of each group were exposed to pH values of 4.4 and 7.4, respectively, for 7 days. Four specimens, 2 exposed to acid pH and 2 exposed to pH of 7.4, were prepared for evaluation under scanning electron microscope by using scattered electron (SE) and backscattered electron (BSE) detectors. Vickers surface hardnesses were measured in the remaining 60 samples. RESULTS: The mean surface hardness values +/- standard deviation were 37.54 +/- 1.52 and 30.24 +/- 1.47 for WMTA and 40.63 +/- 1.35 and 28.67 +/- 1.07 for Aureoseal after exposure to pH values of 7.4 and 4.4, respectively. WMTA showed higher hardness values in acid environment than Aureoseal, which showed the highest microhardness at pH values of 7.4. The SE detector revealed crystal formation on the WMTA surface at pH values of 7.4 and 4.4. In the WMTA specimens the BSE detector showed more unhydrated structures at pH values of 4.4 than at 7.4. The SE detector did not reveal crystal formation on the Aureoseal specimens at pH 7.4 and 4.4. BSE detection showed amorphous microstructures in the Aureoseal specimens treated in the pH 4.4 acid environment. CONCLUSIONS: There was significant interaction between the cements and the environments where the cements hardened. PMID- 20951307 TI - An evaluation of the effect of pulsed ultrasound on the cleaning efficacy of passive ultrasonic irrigation. AB - INTRODUCTION: Multiple activations of the irrigant by using pulsed ultrasound may enhance the removal of dentin debris because of repeated acceleration of the irrigant. The aim of this study was to evaluate the effect of pulsed ultrasound on passive ultrasonic irrigation (PUI) in its ability to remove artificially placed dentin debris from a simulated apical oval extension within standardized root canals. METHODS: Each of 20 in vitro root canal models with a standard groove in the apical portion of one canal wall filled with dentin debris received PUI repeatedly, either without pulsation (group 1) or with pulsation (730 milliseconds on/100 milliseconds off in group 2, 400 milliseconds on/400 milliseconds off in group 3, and 100 milliseconds on/670 milliseconds off in group 4), corresponding to duty cycles of 100%, 88%, 50%, and 13%, respectively. After each irrigation procedure, the amount of dentin debris in the groove was evaluated by taking photographs of the groove and scoring. The irrigation procedures were also visualized in vitro using high-speed imaging performed in glass root canal models. RESULTS: The debris score was significantly lower only in group 3 (p = 0.023). The in vitro visualization showed increased streaming and cavitation during the start-up phase of each pulse. CONCLUSIONS: PUI with a pulsation pattern of 400 milliseconds on/400 milliseconds off and a duty cycle of 50% is more effective in removing dentin debris from a simulated apical oval extension in standardized root canals than continuous ultrasonic activation. Duty cycles of 13% and 88% showed no difference compared with continuous oscillation. PMID- 20951308 TI - Analysis of temperature rise and the use of coolants in the dissipation of ultrasonic heat buildup during post removal. AB - INTRODUCTION: This study was designed to calculate probabilities for tissue injury and to measure effectiveness of various coolant strategies in countering heat buildup produced by dry ultrasonic vibration during post removal. METHODS: A simulated biological model was used to evaluate the cooling efficacy of a common refrigerant spray, water spray, and air spray in the recovery of post temperatures deep within the root canal space. The data set consisted of cervical and apical measures of temperature increase at 1-second intervals from baseline during continuous ultrasonic instrumentation until a 10 degrees C increase in temperature at the cervical site was registered, wherein instrumentation ceased, and the teeth were allowed to cool under ambient conditions or with the assistance of 4 coolant methods. RESULTS: Data were analyzed with analysis of variance by using the independent variables of time of ultrasonic application (10, 15, 20 seconds) and cooling method. In addition to the customary means, standard deviations, and analysis of variance tests, analyses were conducted to determine probabilities that procedures would reach or exceed the 10 degrees C threshold. Both instrumentation time and cooling agent effects were significant at P <.0001. CONCLUSIONS: Under the conditions of this study, it was shown that injurious heat transfer occurs in less than 1 minute during dry ultrasonic instrumentation of metallic posts. Cycles of short instrumentation times with active coolants were effective in reducing the probability of tissue damage when teeth were instrumented dry. With as little as 20 seconds of continuous dry ultrasonic instrumentation, the consequences of thermal buildup to an individual tooth might contribute to an injurious clinical outcome. PMID- 20951309 TI - Suboptimal debridement quality produced by the single-file F2 ProTaper technique in oval-shaped canals. AB - INTRODUCTION: The aim of this study was to determine whether the debridement quality of the single-file F2 ProTaper instrumentation technique is comparable to a full conventional ProTaper sequence in both round and oval-shaped root canals. METHODS: Fifty-four recently extracted vital lower incisors were instrumented with either a full range of ProTaper Universal instruments in rotary motion (group 1) or with the single-file F2 ProTaper technique in reciprocating motion (group 2). Teeth were previously classified as round or oval-shaped by means of bidirectional radiographs, resulting in 24 round canals, 24 oval canals, and 12 controls. After instrumentation, the roots were demineralized, and the apical 3 mm was multi-sliced and processed for histologic examination. The percentage of residual pulp tissue (PRPT) was calculated with the aid of image analysis software. Univariate analysis of variance was used to verify the variables influencing PRPT. RESULTS: Both canal shape and technique significantly influenced PRPT (P < .05). Oval-shaped canals displayed much more PRPT than round canals in both techniques (P < .05). The difference in PRPT between the techniques depended on the root canal shape, since a significant interaction between canal shape and technique was observed (P < .05). Group 1 displayed considerably less PRPT in oval canals than group 2 (P < .05), whereas in round canals no significant difference was found between the 2 techniques (P > .05). CONCLUSIONS: The single-file F2 ProTaper technique displayed similar PRPT to the full range of ProTaper instruments in round canals. However, the debridement quality of the single-file F2 ProTaper technique was suboptimal in oval canals. PMID- 20951310 TI - Endodontic management of supernumerary tooth fused with maxillary first molar by using cone-beam computed tomography. AB - INTRODUCTION: Fusion is a rare occurrence, and its definitive diagnosis is of prime importance for successful root canal treatment. This case report discusses the endodontic management of a supernumerary tooth fused with a right maxillary first molar by using cone-beam computed tomography (CBCT). METHODS: Nonsurgical endodontic retreatment was performed on the supernumerary tooth. A communication between the maxillary first molar and the supernumerary tooth was repaired by using flowable resin. RESULTS: After 1 year of follow-up, there were no clinical symptoms, and the maxillary first molar remained vital. Recall radiographs and CBCT showed satisfactory healing of the periapical pathosis. CONCLUSIONS: Proper diagnosis and treatment planning for endodontic management of fused teeth by using CBCT can ensure predictable and successful results. PMID- 20951311 TI - Multiple bilateral taurodontism. A case report. AB - INTRODUCTION: Taurodontism is a morphologic change characterized by wide pulp chambers, displaced toward the apical floor of the tooth and short roots. OBJECTIVE: To describe the characteristics of multiple bilateral taurodontism in a female patient. CASE REPORT: A 13-year-old female patient evaluated for ectopic eruption of the lower right canine. Physical examination revealed no alteration or apparent mental retardation. Intraoral exam detected multiple carious lesions. Periapical and panoramic X-rays revealed short roots and wide and elongated pulp chambers in the second upper and lower molars. Taurodontism was determined in 2, 15, 18, and 31. CONCLUSION: Findings emphasize the importance of radiographic assessment for diagnosing taurodontism, which might present unusual characteristics, such as multiple and bilateral appearance. The absence of a syndrome should not be used to rule out the possible manifestation of this morphologic variation. PMID- 20951312 TI - The epigenetics of (hereditary) colorectal cancer. AB - In the last decade, it has become apparent that not only DNA sequence variations but also epigenetic modifications may contribute to disease, including cancer. These epigenetic modifications involve histone modification including acetylation and methylation, DNA methylation, and chromatin remodeling. One of the best characterized epigenetic changes is aberrant methylation of cytosines that occur in so-called CpG islands. DNA hypomethylation, prevalent as a genome-wide event, usually occurs in more advanced stages of tumor development. In contrast, DNA hypermethylation is often observed as a discrete, targeted event within tumor cells, resulting in specific loss of gene expression. Interestingly, it was found that sporadic and inherited cancers may exhibit similar DNA methylation patterns, and many genes that are mutated in familial cancers have also been found to be hypermethylated, mutated, or deleted in sporadic cancers. In this review, we will focus on DNA methylation events as heritable epimutations predisposing to colorectal cancer development. PMID- 20951313 TI - Somatic mutations of signaling genes in non-small-cell lung cancer. AB - Lung cancer is the leading cause of cancer-related deaths, with non-small-cell lung cancer (NSCLC) accounting for approximately 85% of cases. A significant proportion of NSCLC cases are not diagnosed until a late stage, when aggressive treatments are required but often prolong survival only modestly. Recent advances in molecular characterization of NSCLC have enabled identification of numerous cell growth and proliferation pathways that are disrupted in these tumors. This knowledge has provided insight into the mechanisms of tumor development in various histologic subtypes of NSCLC and has pointed the way toward targeted treatment strategies. In this review, we highlight literature findings of somatic mutations in genes involved in cell growth and proliferation that are commonly found in the various subtypes of NSCLC, and we discuss how these findings may relate to treatment strategies. PMID- 20951314 TI - NUT midline carcinoma. AB - NUT midline carcinoma (NMC) is a rare, aggressive human cancer, genetically defined by rearrangements of the gene NUT (HUGO symbol: C15orf55). In the majority (~75%) of NMCs, most of the coding sequence of NUT on chromosome 15q14 is fused with BRD4 creating chimeric genes that encode BRD-NUT fusion proteins. In the remaining cases, NUT is fused to BRD3 or an unknown partner gene; these tumors are termed NUT-variant. Diagnosis of NMC is made by demonstration of expression of the NUT-fusion protein using a monoclonal antibody to NUT for immunohistochemistry, and confirmation of the fusion (BRD-NUT or NUT-variant) by fluorescent in situ hybridization or reverse transcriptase-polymerase chain reaction. BRD-NUT functions to block cellular differentiation and promote uncontrolled growth of carcinoma cells. Because the reagents and expertise required to diagnose NMC are not available in most laboratories, and because of incomplete awareness of this disease, NMC is frequently undiagnosed or misdiagnosed, and its actual prevalence is unknown. NUT midline carcinoma does not arise from any specific tissue type or organ. It presents as a poorly differentiated carcinoma originating from midline locations such as the head, neck or mediastinum. Although rare, NMCs occur throughout life, and advanced local disease is frequently accompanied by distant hematogenous metastases. There still is no effective treatment for NMC, there are no guidelines, and current approaches to treatment are based on discussions among a few oncologists who each have had a single experience treating this disease. PMID- 20951315 TI - Cytogenetic and molecular events in adenoma and well-differentiated thyroid follicular-cell neoplasia. AB - In spite of its simple organization, the thyroid gland can give rise to a wide spectrum of neoplasms, ranging from innocuous to highly malignant lesions. Approximately 94% of the malignancies is represented by well-differentiated thyroid carcinoma originating from follicular cells. These neoplasms are divided into two main categories, papillary thyroid carcinoma and follicular thyroid carcinoma. Despite their origin from the same type of cells, the two neoplasias show different biological behavior and a different set of genetic features, including specific cytogenetic patterns. Thyroid adenoma is the benign counterpart of follicular carcinoma. No benign counterpart of papillary carcinoma has yet been identified. The chromosomes of thyroid nodules have been investigated since 1965, and different cytogenetic subgroups have been recognized, some of which show structural chromosomal rearrangements. These structural changes lead to the formation of fusion genes RET-PTC, TRK(-T), and BRAF-AKAP9, which originate as a result of intrachromosomal or interchromosomal rearrangements and are found in papillary thyroid carcinoma. Fusion genes involving PPARgamma are caused mainly by translocations and are characteristic of follicular neoplastic tissue. Radiation exposure and the particular architectural arrangement of chromatin regions in which the affected genes lie during interphase are thought to favor the formation of fusion genes in papillary thyroid carcinoma and possibly also in follicular thyroid carcinoma. PMID- 20951316 TI - Solid tumors associated with multiple endocrine neoplasias. AB - We present an update on molecular and clinical genetics of solid tumors associated with the various multiple endocrine neoplasias (MEN) syndromes. MEN type 1 (MEN1) describes the association of pituitary, parathyroid, and pancreatic islet cell tumors with a variety of many other lesions. MEN type 2 (MEN2) conditions represent at least four different syndromes that associate pheochromocytoma with medullary thyroid carcinoma, hyperparathyroidism, and a number of other manifestations. Other pheochromocytoma-associated syndromes include von Hippel-Lindau disease; neurofibromatosis 1; the recently defined paraganglioma syndromes type 1, 3, and 4; Carney-Stratakis syndrome; and the Carney triad. Carney-Stratakis syndrome is characterized by the association of paragangliomas and familial gastrointestinal stromal tumors. In the Carney triad, patients can manifest gastrointestinal stromal tumors, lung chondroma, paraganglioma, adrenal adenoma and pheochromocytoma, esophageal leiomyoma, and other conditions. The Carney complex is yet another form of MEN that is characterized by skin tumors and pigmented lesions, myxomas, schwannomas, and various endocrine neoplasias. PMID- 20951317 TI - The 'omics' of cancer. AB - After the first draft sequence of the human genome was announced by the International Human Genome Sequencing Consortium and Celera Genomics in February 2001, this and subsequent sequences have been instrumental for the systematic analysis of various human genomes, including the cancer genome. Now we are moving into an era in which comprehensive sequence-based information on vast numbers of tumors can be obtained. Such information can provide novel and detailed perspectives on how individual tumors develop. As a corollary, this information can be used to generate novel diagnostic and prognostic markers and to design novel therapeutic strategies. Because these advances are moving rapidly, any state-of-the-art overview is likely to be outdated before it reaches publication. Nevertheless, data presented at the 12th European Workshop on Cytogenetics and Molecular Genetics of Solid Tumors, held June 3-6, 2010, at Nijmegen in The Netherlands, and of which the abstracts are included in this special issue of Cancer Genetics and Cytogenetics, may provide a basis for such an overview. Although one nowadays hears talk of the post-genome era, we are in fact still very much within the genome era; indeed, most of the work presented at the workshop dealt with the cancer genome. Other emerging areas were also addressed, however, including the cancer epigenome, the cancer transcriptome, and the cancer fragilome. PMID- 20951318 TI - A doughnut in the heart: peculiar finding of a giant coronary artery aneurysm with coronary arteriovenous fistula. PMID- 20951319 TI - Medical and surgical treatment of acute right ventricular failure. AB - Acute right ventricular (RV) failure is a frequent and serious clinical challenge in the intensive care unit. It is usually seen as a consequence of left ventricular failure, pulmonary embolism, pulmonary hypertension, sepsis, acute lung injury or after cardiothoracic surgery. The presence of acute RV failure not only carries substantial morbidity and mortality, but also complicates the use of commonly used treatment strategies in critically ill patients. In contrast to the left ventricle, the RV remains relatively understudied, and investigations of the treatment of isolated RV failure are rare and usually limited to nonrandomized observations. We searched PubMed for papers in the English language by using the search words right ventricle, right ventricular failure, pulmonary hypertension, sepsis, shock, acute lung injury, cardiothoracic surgery, mechanical ventilation, vasopressors, inotropes, and pulmonary vasodilators. These were used in various combinations. We read the abstracts of the relevant titles to confirm their relevance, and the full papers were then extracted. References from extracted papers were checked for any additional relevant papers. This review summarizes the general measures, ventilation strategies, vasoactive substances, and surgical as well as mechanical approaches that are currently used or actively investigated in the treatment of the acutely failing RV. PMID- 20951320 TI - Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy. AB - OBJECTIVES: The purpose of this study was to investigate the long-term outcome after elective percutaneous coronary intervention in low-risk patients screened for aspirin and/or clopidogrel responsiveness in the 3T/2R (Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel) trial. BACKGROUND: The impact of aspirin and/or clopidogrel poor response on long-term outcome is debated. METHODS: Aspirin and clopidogrel response was measured with the VerifyNow system aspirin and P2Y12 assays. After percutaneous coronary intervention (PCI), death, stroke, and myocardial infarction were assessed up to 1 year. RESULTS: Overall, 1,277 patients were screened, and 826 (65%) were treated with PCI. In all, 124 patients were found to be aspirin poor responders, and there were 179 clopidogrel poor responders (totally, 278 poor responders). The 1-year end point was significantly higher in poor responders as compared to full responders (15.8% vs. 8.6%, p=0.002), which is principally due to more myocardial infarction occurrence. At multivariable analysis, clopidogrel poor response emerged as an independent predictor (hazard ratio: 1.15, 95% confidence interval: 1.03 to 1.28). Receiver-operator characteristic analysis identifies<=23 of percentage of platelet inhibition and >=208 of P2Y12 reactivity units as optimal cut offs to predict 1-year end point. Excluding periprocedural events, also peri-PCI myocardial infarction, which is strongly related to aspirin/clopidogrel poor response, was an independent predictor (hazard ratio: 1.25, 95% confidence interval: 1.14 to 1.37). Glycoprotein IIb/IIIa inhibitor administration reduces this risk in poor responders (21.2% vs. 34.7%, p=0.02), but not in full responders (6.3% vs. 6.5%, p=0.8). CONCLUSIONS: Poor response to clopidogrel is an independent predictor of periprocedural myocardial infarction and worse 1-year outcome in low-risk patients undergoing PCI, whereas poor response to aspirin failed to predict a worse outcome. Contrary to what was observed in poor responders, glycoprotein IIb/IIa inhibitor therapy failed to provide a benefit in aspirin and/or clopidogrel full responders. PMID- 20951321 TI - Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency catheter ablation: a randomized controlled trial. AB - OBJECTIVES: We sought to clarify the efficacy of corticosteroid therapy for preventing atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI). BACKGROUND: The inflammatory process may cause acute AF recurrence after PVI. However, no studies have examined the relationship between corticosteroid administration and AF recurrence after PVI. METHODS: A total of 125 patients with paroxysmal AF were randomized to receive either corticosteroids (corticosteroid group) or a placebo (placebo group). In the corticosteroid group, intravenous hydrocortisone (2 mg/kg) was given the day of the procedure, and oral prednisolone (0.5 mg/kg/day) was administered for 3 days after the PVI. The body temperature and high-sensitivity C-reactive protein level were measured before and on each of the first 3 days after ablation. RESULTS: The prevalence of immediate AF recurrence (<=3 days after the PVI) was significantly lower in the corticosteroid group (7%) than in the placebo group (31%). The maximum body temperature and C-reactive protein during the initial 3 days after ablation and the increase in the body temperature and C-reactive protein level from baseline were significantly lower in the corticosteroid group than in the placebo group. Corticosteroid treatment did not decrease AF recurrences between 4 and 30 days after ablation. The AF-free rate at 14 months post-ablation was greater in the corticosteroid group (85%) than in the placebo group (71%, p=0.032 by the log rank test). CONCLUSIONS: Transient use of small amounts of corticosteroids shortly after AF ablation may be effective and safe for preventing not only immediate AF recurrences but also AF recurrences during the mid-term follow-up period after PVI. PMID- 20951322 TI - Corticosteroid therapy after catheter ablation of atrial fibrillation for an authentic "blanking period". PMID- 20951323 TI - Cardiorespiratory fitness is related to the risk of sudden cardiac death: a population-based follow-up study. AB - OBJECTIVES: Our aim was to examine the relation of cardiorespiratory fitness with sudden cardiac death (SCD) in a population-based sample of men. BACKGROUND: Very limited information is available about the role of cardiorespiratory fitness in the prediction of SCD. METHODS: This population study was based on 2,368 men 42 to 60 years of age. Cardiorespiratory fitness was defined by using respiratory gas exchange analyzer and maximal workload during cycle ergometer exercise test. RESULTS: During the 17-year follow-up, there were 146 SCDs. As a continuous variable, 1 metabolic equivalent (MET) increment in cardiorespiratory fitness was related to a decrease of 22% in the risk of SCD (relative risk: 0.78, 95% confidence interval: 0.71 to 0.84, p<0.001). In addition to cardiorespiratory fitness, ischemic ST-segment depression during exercise testing, smoking, systolic blood pressure, prevalent coronary heart disease, family history of coronary heart disease, and type 2 diabetes mellitus were related to the risk of SCD. The Harrell C-index for the total model discrimination was 0.767, while cardiorespiratory fitness provides modest improvement (from 0.760 to 0.767) in the risk prediction when added with all other risk factors. The integrated discrimination improvement was 0.0087 (p=0.018, relative integrated discrimination improvement 0.11) when cardiorespiratory fitness was added in the model. However, the net reclassification index (-0.018) was not statistically significantly improved (p=0.703). CONCLUSIONS: Cardiorespiratory fitness is a predictor of SCD in addition to that predicted by conventional risk factors. There was a slight improvement in the level of discrimination, although the net reclassification index did not change while using cardiorespiratory fitness with conventional risk factors. PMID- 20951324 TI - Risk stratification for sudden cardiac death: a puzzle beyond p values. PMID- 20951325 TI - Follow-up after pulmonary valve replacement in adults with tetralogy of Fallot: association between QRS duration and outcome. AB - OBJECTIVES: The aim of this study was to analyze whether QRS duration, before and after pulmonary valve replacement (PVR), is related to long-term outcome in patients with tetralogy of Fallot (TOF). BACKGROUND: Key factors that determine outcome after PVR in adult TOF patients are largely unknown. Recognition of such factors assists the identification of patients at increased risk of adverse events. METHODS: Adults who previously underwent total correction for TOF (n=90; age 31.4+/-10.3 years) and required PVR for pulmonary regurgitation were included. The QRS duration was measured pre-operatively and 6 months after PVR. The post-operative changes in QRS duration were calculated. Adverse events (death, re-PVR, ventricular tachycardia, and symptomatic heart failure) were noted during follow-up. RESULTS: During 5.5+/-3.5 years of follow-up, 13 adverse events occurred. The 5-year event-free survival rate was 76% for patients with a pre-operative QRS duration>180 ms and 90% in patients with a QRS duration<=180 ms (p=0.037). For patients with a post-operative QRS duration>180 ms, 5-year event free survival was 71%, whereas it was 91% for patients with a post-operative QRS duration<=180 ms (p=0.004). After multivariate correction, a post-operative QRS duration>180 ms (hazard ratio: 3.685, 95% confidence interval: 1.104 to 12.304, p<0.05) and the absence of a reduction in QRS duration post-PVR (hazard ratio: 6.767, 95% confidence interval: 1.704 to 26.878, p<0.01), was significantly associated with adverse outcome. CONCLUSIONS: Severe QRS prolongation, before or after PVR, and the absence of a reduction in QRS duration after PVR, are major determinants of adverse outcome during long-term follow-up of patients with TOF. PMID- 20951326 TI - Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis. AB - OBJECTIVES: Four variants (K60N, Q128R, G202R, and A592E) in the nebulette gene were identified in patients with dilated cardiomyopathy (DCM) and endocardial fibroelastosis. We sought to determine if these mutations are cardiomyopathy causing. BACKGROUND: Nebulette aligns thin filaments and connects them with the myocardial Z-disk, playing a role in mechanosensation. METHODS: We generated transgenic mice with cardiac-restricted overexpression of human wild-type or mutant nebulette. Chimera and transgenic mice were examined at 4, 6, and 12 months of age by echocardiography and cardiac magnetic resonance imaging. The hearts from embryos and adult mice were assessed by histopathologic, immunohistochemical, ultrastructural, and protein analyses. Rat H9C2 cardiomyoblasts with transient expression of nebulette underwent cyclic mechanical strain. RESULTS: We identified lethal cardiac structural abnormalities in mutant embryonic hearts (K60N and Q128R). Founders of the mutant mouse lines developed DCM with severe heart failure. An irregular localization pattern for nebulette and impaired desmin expression were noted in the proband and chimeric Q128R mice. Mutant G202R and A592E mice exhibited left ventricular dilation and impaired function with specific changes in I-band and Z-disk proteins by 6 months of age. The mutations modulated distribution of nebulette in the sarcomere and Z disk during stretch of H9C2 cells. CONCLUSIONS: Nebulette is a new susceptibility gene for endocardial fibroelastosis and DCM. Different mutations in nebulette trigger specific mechanisms, converging to a common pathological cascade leading to endocardial fibroelastosis and DCM. PMID- 20951327 TI - Nebulette mutations in cardiac remodeling: big effects from a small mechanosensor. PMID- 20951328 TI - The ankle-brachial index and incident cardiovascular events in the MESA (Multi Ethnic Study of Atherosclerosis). AB - OBJECTIVES: The purpose of this study was to examine the association of both a low and a high ankle-brachial index (ABI) with incident cardiovascular events in a multiethnic cohort. BACKGROUND: Abnormal ABIs, both low and high, are associated with elevated cardiovascular disease (CVD) risk. However, it is unknown whether this association is consistent across different ethnic groups, and whether it is independent of both newer biomarkers and other measures of subclinical atherosclerotic CVD. METHODS: A total of 6,647 non-Hispanic white, African-American, Hispanic, and Chinese men and women age 45 to 84 years from free-living populations in 6 U.S. field centers and free of clinical CVD at baseline had extensive measures of traditional and newer biomarker risk factors, and measures of subclinical CVD, including the ABI. Incident CVD, defined as coronary disease, stroke, or other atherosclerotic CVD death, was determined over a mean follow-up of 5.3 years. RESULTS: Both a low (<1.00) and a high (>=1.40) ABI were associated with incident CVD events. Sex- and ethnic-specific analyses showed consistent results. Hazard ratios were 1.77 (p<0.001) for a low and 1.85 (p=0.050) for a high ABI after adjustment for both traditional and newer biomarker CVD risk factors, and the ABI significantly improved risk discrimination. Further adjustment for coronary artery calcium score, common and internal carotid intimal medial thickness, and major electrocardiographic abnormalities only modestly attenuated these hazard ratios. CONCLUSIONS: In this study, both a low and a high ABI were associated with elevated CVD risk in persons free of known CVD, independent of standard and novel risk factors, and independent of other measures of subclinical CVD. Further research should address the cost effectiveness of measuring the ABI in targeted population groups. PMID- 20951329 TI - Accessory mitral valve associated with mitral cleft, bicuspid aortic valve, and aortic coarctation. PMID- 20951330 TI - A question of central importance. PMID- 20951331 TI - Battlescarred: subgroup or selection bias? PMID- 20951333 TI - "Social" robots are psychological agents for infants: a test of gaze following. AB - Gaze following is a key component of human social cognition. Gaze following directs attention to areas of high information value and accelerates social, causal, and cultural learning. An issue for both robotic and infant learning is whose gaze to follow. The hypothesis tested in this study is that infants use information derived from an entity's interactions with other agents as evidence about whether that entity is a perceiver. A robot was programmed so that it could engage in communicative, imitative exchanges with an adult experimenter. Infants who saw the robot act in this social-communicative fashion were more likely to follow its line of regard than those without such experience. Infants use prior experience with the robot's interactions as evidence that the robot is a psychological agent that can see. Infants want to look at what the robot is seeing, and thus shift their visual attention to the external target. PMID- 20951334 TI - Detecting contingencies: an infomax approach. AB - The ability to detect social contingencies plays an important role in the social and emotional development of infants. Analyzing this problem from a computational perspective may provide important clues for understanding social development, as well as for the synthesis of social behavior in robots. In this paper, we show that the turn-taking behaviors observed in infants during contingency detection situations are tuned to optimally gather information as to whether a person is responsive to them. We show that simple reinforcement learning mechanisms can explain how infants acquire these efficient contingency detection schemas. The key is to use the reduction of uncertainty (information gain) as a reward signal. The result is an interesting form of learning in which the learner rewards itself for conducting actions that help reduce its own sense of uncertainty. This paper illustrates the possibilities of an emerging area of computer science and engineering that focuses on the computational understanding of human behavior and on its synthesis in robots. We believe that the theory of stochastic optimal control will play a key role providing a formal mathematical foundation for this newly emerging discipline. PMID- 20951335 TI - Social gating and pedagogy: mechanisms for learning and implications for robotics. AB - It seems self-evident that human responsiveness to social input enhances learning, yet the details of the social forces at play are only beginning to come into focus. Recent research on language and cognitive development in preschoolers and infants illuminates mechanisms such as social gating and natural pedagogy, and specific ways in which they benefit learning. We review such advances and consider implications of this research for designing robotic systems that can harness the power of social forces for learning. PMID- 20951336 TI - A pilot study of the epilepsy risk awareness checklist (ERAC) in people with epilepsy and learning disabilities. AB - PURPOSE: People with epilepsy are at risk of injury, and protection from potential dangers must be balanced against the need for autonomy. We developed an epilepsy risk awareness checklist (ERAC) as a tool to assess potential risks of epilepsy and related injuries, aiming to improve management strategies. It was designed for use by specialist nurses (in learning disability and epilepsy), as there was no existing tool for this. This study refined and tested this checklist in patients with epilepsy and learning disability in a range of community settings. METHOD: We used quantitative and qualitative measures to devise and revise the tool. Eleven qualified learning disability nurses completed the ERAC in three patients each (33 patients) using a purposive sampling method. They provided quantitative and qualitative feedback through questionnaires and interviews, and an expert panel reviewed and commented on the checklist. RESULTS: The checklist was revised through the evaluation process. All eleven nurses concluded that they would use the tool again. CONCLUSION: The epilepsy risk awareness checklist (ERAC) provides a measure of risk, and this study suggests that it is a useful tool in the care of people with learning disability and epilepsy. A larger scale study is planned. PMID- 20951337 TI - Transient global amnesia with post-hyperventilation temporal sharp waves--a case report. AB - We report a 55-year-old woman, who presented with transient amnesia for 7h following underwater swimming. There was no evidence of neurological disturbance except global amnesia. Sharp waves in both temporal regions were registered during the initial EEG recording, which was accentuated by hyperventilation. Right hippocampal high signal intensity was observed in DWI performed 56 h after symptom onset. The sharp waves were all disappeared on follow-up EEG recordings. PMID- 20951338 TI - Thoracic aortic dissection - beyond the acute problem. PMID- 20951339 TI - Linc-ing Long noncoding RNAs and enhancer function. AB - Enhancers are distal regulatory sequences that control gene expression in development. Orom et al. now report in Cell that some long noncoding RNAs have functional properties of enhancers. Known enhancers are also transcribed in cells in which they are active, suggesting that noncoding RNAs are integral to enhancer action. PMID- 20951340 TI - How the sea squirt nucleus tells mesoderm not to be endoderm. AB - Sea squirts are simple invertebrate chordates. In this issue of Developmental Cell, Takatori et al. show nuclear migration within ascidian mesendodermal cells enables polarized localization of Not mRNA, which encodes a homeobox protein that distinguishes mesoderm from endoderm fates. The link between nuclear migration and mRNA localization suggests exciting parallels with protostomes. PMID- 20951341 TI - Stem cell fate in proliferating tissues: equal odds in a game of chance. AB - Quantitative lineage tracing reveals stem cell fate in vivo. A new study in a recent issue of Cell shows intestinal crypt stem cells are functionally equivalent, with equal odds of differentiation. Differentiating stem cells are replaced by the symmetric division of adjacent stem cells. PMID- 20951342 TI - The hippo signaling pathway in development and cancer. AB - First discovered in Drosophila, the Hippo signaling pathway is a conserved regulator of organ size. Central to this pathway is a kinase cascade leading from the tumor suppressor Hippo (Mst1 and Mst2 in mammals) to the oncoprotein Yki (YAP and TAZ in mammals), a transcriptional coactivator of target genes involved in cell proliferation and survival. Here, I review recent progress in elucidating the molecular mechanism and physiological function of Hippo signaling in Drosophila and mammals. These studies suggest that the core Hippo kinase cascade integrates multiple upstream inputs, enabling dynamic regulation of tissue homeostasis in animal development and physiology. PMID- 20951343 TI - Evidence for a growth-stabilizing regulatory feedback mechanism between Myc and Yorkie, the Drosophila homolog of Yap. AB - An understanding of how animal size is controlled requires knowledge of how positive and negative growth regulatory signals are balanced and integrated within cells. Here we demonstrate that the activities of the conserved growth promoting transcription factor Myc and the tumor-suppressing Hippo pathway are codependent during growth of Drosophila imaginal discs. We find that Yorkie (Yki), the Drosophila homolog of the Hippo pathway transducer, Yap, regulates the transcription of Myc, and that Myc functions as a critical cellular growth effector of the pathway. We demonstrate that in turn, Myc regulates the expression of Yki as a function of its own cellular level, such that high levels of Myc repress Yki expression through both transcriptional and posttranscriptional mechanisms. We propose that the codependent regulatory relationship functionally coordinates the cellular activities of Yki and Myc and provides a mechanism of growth control that regulates organ size and has broad implications for cancer. PMID- 20951344 TI - Regulation of TCF3 by Wnt-dependent phosphorylation during vertebrate axis specification. AB - A commonly accepted model of Wnt/beta-catenin signaling involves target gene activation by a complex of beta-catenin with a T-cell factor (TCF) family member. TCF3 is a transcriptional repressor that has been implicated in Wnt signaling and plays key roles in embryonic axis specification and stem cell differentiation. Here we demonstrate that Wnt proteins stimulate TCF3 phosphorylation in gastrulating Xenopus embryos and mammalian cells. This phosphorylation event involves beta-catenin-mediated recruitment of homeodomain-interacting protein kinase 2 (HIPK2) to TCF3 and culminates in the dissociation of TCF3 from a target gene promoter. Mutated TCF3 proteins resistant to Wnt-dependent phosphorylation function as constitutive inhibitors of Wnt-mediated activation of Vent2 and Cdx4 during anteroposterior axis specification. These findings reveal an alternative in vivo mechanism of Wnt signaling that involves TCF3 phosphorylation and subsequent derepression of target genes and link this molecular event to a specific developmental process. PMID- 20951346 TI - Jiraiya attenuates BMP signaling by interfering with type II BMP receptors in neuroectodermal patterning. AB - During embryogenesis, bone morphogenetic protein (BMP) signaling needs to be finely tuned in a locally restricted manner. Here, we report a cell-intrinsic mode of BMP response control executed by the membrane protein Jiraiya. In the Xenopus embryo, zygotic Jiraiya, expressed exclusively in the neuroectoderm, is essential and sufficient for limiting dorsal neural development, which is dependent on BMP signals. In animal cap assays, Jiraiya selectively and cell autonomously inhibits BMP signaling, while Jiraiya's knockdown enhances the signaling. In the cell, Jiraiya selectively forms a complex with type II BMP receptor (BMPRII) and downregulates the cell surface localization of functional BMPRII. This functional interaction with Jiraiya depends on the unique tail domain of BMPRII, and, in particular, the conserved EVNNNG motif, the function of which has been unknown. Thus, Jiraiya represents a cell-intrinsic cutoff mechanism for dynamic responsiveness to BMP signals via subtype-selective receptor control. PMID- 20951345 TI - Zfp521 is a target gene and key effector of parathyroid hormone-related peptide signaling in growth plate chondrocytes. AB - In the growth plate, the interplay between parathyroid hormone-related peptide (PTHrP) and Indian hedgehog (Ihh) signaling tightly regulates chondrocyte proliferation and differentiation during longitudinal bone growth. We found that PTHrP increases the expression of Zfp521, a zinc finger transcriptional coregulator, in prehypertrophic chondrocytes. Mice with chondrocyte-targeted deletion of Zfp521 resembled PTHrP(-/-) and chondrocyte-specific PTHR1(-/-) mice, with decreased chondrocyte proliferation, early hypertrophic transition, and reduced growth plate thickness. Deleting Zfp521 increased expression of Runx2 and Runx2 target genes, and decreased Cyclin D1 and Bcl-2 expression while increasing Caspase-3 activation and apoptosis. Zfp521 associated with Runx2 in chondrocytes, antagonizing its activity via an HDAC4-dependent mechanism. PTHrP failed to upregulate Cyclin D1 and to antagonize Runx2, Ihh, and collagen X expression when Zfp521 was absent. Thus, Zfp521 is an important PTHrP target gene that regulates growth plate chondrocyte proliferation and differentiation. PMID- 20951347 TI - Drosophila SPARC is a self-protective signal expressed by loser cells during cell competition. AB - During development and aging, animals suffer insults that modify the fitness of individual cells. In Drosophila, the elimination of viable but suboptimal cells is mediated by cell competition, ensuring that these cells do not accumulate during development. In addition, certain genes such as the Drosophila homolog of human c-myc (dmyc) are able to transform cells into supercompetitors, which eliminate neighboring wild-type cells by apoptosis and overproliferate, leaving total cell numbers unchanged. Here we have identified Drosophila Sparc as an early marker transcriptionally upregulated in loser cells that provides a transient protection by inhibiting Caspase activation in outcompeted cells. Overall, we describe the unexpected existence of a physiological mechanism that counteracts cell competition during development. PMID- 20951349 TI - Segregation of germ layer fates by nuclear migration-dependent localization of Not mRNA. AB - An important step in early embryonic development is the allocation and segregation of germ layer fates into distinct embryonic regions. However, the mechanism that segregates the mesendoderm into mesoderm and endoderm fates remains largely unknown in most animals. Here, using ascidians, a primitive chordate, we show that these fates are segregated by partitioning of asymmetrically localized Not mRNA from the mesendoderm cell to its mesodermal daughter. Migration of the mesendoderm cell nucleus to the future mesoderm forming region, release of Not mRNA from the nucleus, Wnt5alpha-dependent local retention of the mRNA, and subsequent repositioning of the mitotic spindle to the center of the cell are each required for the asymmetric localization and partitioning of Not mRNA. Our results show that nuclear migration plays an unexpected role in asymmetric cell divisions that segregate germ layer fates in chordate embryos. PMID- 20951348 TI - Integrin-linked kinase controls microtubule dynamics required for plasma membrane targeting of caveolae. AB - Caveolae are specialized compartments of the plasma membrane that are involved in signaling, endocytosis, and cholesterol transport. Their formation requires the transport of caveolin-1 to the plasma membrane, but the molecular mechanisms regulating the transport are largely unknown. Here, we identify a critical role for adhesion-mediated signaling through beta1 integrins and integrin-linked kinase (ILK) in caveolae formation. Mice lacking beta1 integrins or ILK in keratinocytes have dramatically reduced numbers of plasma membrane caveolae in vivo, which is due to impaired transport of caveolin-1-containing vesicles along microtubules (MT) to the plasma membrane. Mechanistically, ILK promotes the recruitment of the F-actin binding protein IQGAP1 to the cell cortex, which, in turn, cooperates with its effector mDia1 to locally stabilize MTs and to allow stable insertion of caveolae into the plasma membrane. Our results assign an important role to the integrin/ILK complex for caveolar trafficking to the cell surface. PMID- 20951350 TI - A Mec1- and PP4-dependent checkpoint couples centromere pairing to meiotic recombination. AB - The faithful alignment of homologous chromosomes during meiotic prophase requires the coordination of DNA double-strand break (DSB) repair with large-scale chromosome reorganization. Here we identify the phosphatase PP4 (Pph3/Psy2) as a mediator of this process in Saccharomyces cerevisiae. In pp4 mutants, early stages of crossover repair and homology-independent pairing of centromeres are coordinately blocked. We traced the loss of centromere pairing to the persistent phosphorylation of the chromosomal protein Zip1 on serine 75. Zip1-S75 is a consensus site for the ATR-like checkpoint kinase Mec1, and centromere pairing is restored in mec1 mutants. Importantly, Zip1-S75 phosphorylation does not alter chromosome synapsis or DSB repair, indicating that Mec1 separates centromere pairing from the other functions of Zip1. The centromeric localization and persistent activity of PP4 during meiotic prophase suggest a model whereby Zip1 S75 phosphorylation dynamically destabilizes homology-independent centromere pairing in response to recombination initiation, thereby coupling meiotic chromosome dynamics to DSB repair. PMID- 20951352 TI - A strand-specific burst in transcription of pericentric satellites is required for chromocenter formation and early mouse development. AB - At the time of fertilization, the paternal genome lacks the typical configuration and marks characteristic of pericentric heterochromatin. It is thus essential to understand the dynamics of this region during early development, its importance during that time period and how a somatic configuration is attained. Here, we show that pericentric satellites undergo a transient peak in expression precisely at the time of chromocenter formation. This transcription is regulated in a strand-specific manner in time and space and is strongly biased by the parental asymmetry. The transcriptional upregulation follows a developmental clock, yet when replication is blocked chromocenter formation is impeded. Furthermore, interference with major satellite transcripts using locked nucleic acid (LNA)-DNA gapmers results in developmental arrest before completion of chromocenter formation. We conclude that the exquisite strand-specific expression dynamics at major satellites during the 2-cell stage, with both up and downregulation, are necessary events for proper chromocenter organization and developmental progression. PMID- 20951351 TI - The mammalian doublesex homolog DMRT1 is a transcriptional gatekeeper that controls the mitosis versus meiosis decision in male germ cells. AB - The switch from mitosis to meiosis is a unique feature of germ cell development. In mammals, meiotic initiation requires retinoic acid (RA), which activates meiotic inducers, including Stra8, but how the switch to meiosis is controlled in male germ cells (spermatogonia) remains poorly understood. Here we examine the role of the Doublesex-related transcription factor DMRT1 in adult spermatogenesis using conditional gene targeting in the mouse. Loss of Dmrt1 causes spermatogonia to precociously exit the spermatogonial program and enter meiosis. Therefore, DMRT1 determines whether male germ cells undergo mitosis and spermatogonial differentiation or meiosis. Loss of Dmrt1 in spermatogonia also disrupts cyclical gene expression in Sertoli cells. DMRT1 acts in spermatogonia to restrict RA responsiveness, directly repress Stra8 transcription, and activate transcription of the spermatogonial differentiation factor Sohlh1, thereby preventing meiosis and promoting spermatogonial development. By coordinating spermatogonial development and mitotic amplification with meiosis, DMRT1 allows abundant, continuous production of sperm. PMID- 20951353 TI - Intrauterine illicit substance exposure. PMID- 20951354 TI - Tourette syndrome in children: an updated review. AB - Tourette syndrome (TS) is a common neuropsychiatric disorder in children characterized by multiple motor and vocal tics that fluctuate in severity and lasting for at least 1 year. Boys are more commonly affected than girls. Symptoms usually begin with simple motor or vocal tics which then evolve into more complex motor and vocal tics over time. Premonitory sensory urges are common in children over the age of 8 years, and these urges help distinguish tics from symptoms of other movement disorders. Common comorbidities of TS include attention deficit hyperactivity disorder, obsessive-compulsive disorder and learning difficulties. Several genes have been assessed as candidate genes for TS; environmental factors such as stress and streptococcal infections might also contribute to its etiology. The pathophysiology of TS mainly involves dysfunction of basal ganglia related circuits and hyperactive dopaminergic innervations. A thorough history assessment and neurological examination are important for the correct diagnosis and differentiation from other movement disorders. Treatment for TS should focus on improving the patient's social functioning, minimizing the impairment from cormobid disorders, and controlling tics, if they are severe. Commonly used medications for TS include a2-adrenergic agonists and atypical neuroleptics. Habit reversal therapy is an effective option for TS, and repetitive transcranial magnetic stimulation may be a promising approach for severe cases. PMID- 20951355 TI - Low seroprevalence of parvovirus B19 in Taiwanese children and young adults. AB - BACKGROUND: This study aimed to evaluate the prevalence of parvovirus B19 antibodies in children and young adults aged=30 years old in Taiwan. METHODS: Stored serum samples from healthy volunteers aged 1-29 years in Taipei were randomly selected and tested for antiparvovirus B19 immunoglobulin G by enzyme immunoassay. RESULTS: A total of 277 serum samples were tested. The overall seroprevalence of parvovirus B19 in Taiwanese children and young adults was 23.1% (64/277) in 2004. The positive rate increased slightly with age; it ranged from 15.0% in those aged 1-4 years to 30.8% in those aged 25-29 years (trend test, p=0.01). The age-adjusted anti-B19 immunoglobulin G seropositive rate was slightly higher in males (27.8%) than in females (18.8%; adjusted odds ratio: 0.56; 95% confidence interval: 0.32-0.99). CONCLUSION: Most children and young adults in Taipei City are not immune to parvovirus B19, suggesting that no parvovirus B19 epidemic has occurred in the last few decades. PMID- 20951356 TI - Duodenal derotation and extent tapering jejunoplasty as primary repair for neonates with high jejunal atresia. AB - BACKGROUND: The dilated bowel segment usually involves the entire jejunum, as well as the duodenum in patients with high jejunal atresia. Classical approaches with a limited tapering enteroplasty and anastomosis frequently fail to restore intestinal function. A novel technique using duodenal derotation and extent tapering jejunoplasty (DDETJ) is reported here. METHODS: Infants with high jejunal atresia within 10 cm of the ligament of Treitz treated with DDETJ over a 3-year period were reviewed. The entire dilated duodenum and jejunum were visualized after duodenal derotation. A longitudinal extensive tapering resection of dilated bowel with Endo GIA stapler was performed to fashion as a tube and anastomosed to the distal jejunum. RESULTS: Five female infants underwent this procedure over a 3-year period. Four infants underwent primary DDETJ, while one with associated multiple atresias had previously undergone limited tapering jejunoplasty, but was unable to tolerate oral feeding. DDETJ was performed 4 weeks later. There were no postoperative complications, and all patients tolerated feeding within 14 days. Follow-up lasted from 2 to 18 months. CONCLUSION: In very proximal high atresia, the extent of tapering is limited by the proximity of the ligament of Treitz. Duodenal derotation provides better access to the high atresia. The results of this limited experience suggest that the DDETJ procedure could provide an alternative therapy in patients with high jejunal atresia. PMID- 20951357 TI - Comparison of the Global Initiative for Asthma guideline-based Asthma Control Measure and the Childhood Asthma Control Test in evaluating asthma control in children. AB - BACKGROUND: Reliable assessment of asthma control is essential for effective treatment. While several validated tools for assessing asthma control in children are currently available, few studies have evaluated the correlations between different asthma control measures in children. This study aimed to determine the correlations between the Childhood Asthma Control Test (C-ACT) and the Global Initiative for Asthma (GINA) guideline-based asthma control measure (ACM) with lung function parameters in children with asthma. METHODS: Sixty-three children aged 6-11 years with mild-intermittent to severe-persistent asthma were evaluated. They completed the C-ACT, the GINA guideline-based assessment and lung function tests with the help of their caregivers. RESULTS: C-ACT scores and GINA guideline-based ACM were positively correlated. The average C-ACT scores for children with controlled, partly controlled and uncontrolled asthma according to the GINA guidelines were 24.4+/-0.3, 22.8+/-0.6 and 21.3+/-1.0 (mean+/-SE), respectively. High C-ACT scores were also noted in children with uncontrolled asthma based on the GINA guidelines. The GINA guideline-based ACM was correlated with spot spirometry parameters (forced vital capacity, forced expiratory volume in 1 second, and maximal mid-expiratory flow). Conversely, the C-ACT score was not correlated with these spirometry parameters. CONCLUSIONS: The C-ACT may overestimate asthma control in certain circumstances. For children with poorly controlled asthma or poor symptom perception, more frequent visits and serial pulmonary function tests are recommended. PMID- 20951358 TI - Infant with in utero ketamine exposure: quantitative measurement of residual dosage in hair. AB - BACKGROUND: The drug ketamine is frequently abused for recreational use in Asia, but few studies in humans have focused on the effects of ketamine exposure during pregnancy on the health of neonates. Here, we report a neonate whose mother was suspected of ketamine abuse during pregnancy. The case was confirmed by testing hair samples of the neonate. METHODS: Hair samples of the neonate were taken on the first day of referral. Levels of common drugs of abuse in Asia were measured in the hair sample by gas chromatography-mass spectrometry using our previously reported method with modifications. This method was developed and validated to simultaneously quantify levels of amphetamine, ketamine and opiate in human hair. RESULTS: The neonate was a female baby, born full term, with a low birth weight of 2250 g. Very high levels of ketamine were detected in the neonate's hair, even though the mother stated that she had stopped abusing ketamine during the early stage of pregnancy. The neonate suffered from general hypotonia; moderate cerebral dysfunction was found by electroencephalography. Fortunately, her hypotonia improved gradually within 21 days. CONCLUSION: This is the first report of ketamine exposure during late pregnancy detected by hair testing. We noted several clinical features in this case, including the infant being small for gestational age, intrauterine growth retardation, remarkable hypotonia, and poor reflex responses. Although the mother denied the use of ketamine during the late stage of her pregnancy, significant amount of ketamine and norketamine was still found in hair samples (only 2 cm long and 25 mg) from the infant. PMID- 20951359 TI - Epidemiology of childhood intussusception and determinants of recurrence and operation: analysis of national health insurance data between 1998 and 2007 in Taiwan. AB - BACKGROUND: To study the epidemiology of childhood intussusception and risk factors of recurrence and operation based on a nationwide data. METHODS: Children with hospitalization due to intussusception (ICD9: 560.0) between 1998 and 2007 were identified from a national health insurance database. The incidence was calculated by age, sex, calendar year and month of admission. Recurrence and operation rates, duration and costs of hospitalization were analyzed. RESULTS: A total of 8217 intussusception-related hospitalizations were identified in 7541 children. The incidence of intussusception peaked between 3 and 36 months of age. Male -to-female incidence rate ratio increased from 1.31 in the first year to 2.52 in the ninth year of life. The overall recurrence and operation rates were 7.9% and 24.9%, respectively. In children less than 1 year old, the recurrence rate was 10.1%, which decreased to 5.3% in children over 3 years old. Multiple logistic regression analysis showed that children receiving operation had a significantly lower risk of recurrence with an odds ratio (95% confidence interval) of 0.31 (0.24-0.41) after controlling for age and sex. There are significantly more cases occurring during the warmer months between May and October compared to the cooler months between November and April. CONCLUSIONS: There was a male predominance of intussusception with a dynamic male-to-female incidence rate ratio. Children under 1 year of age have the highest recurrence and operation rates. Seasonal variation of intussusception was suspected in Taiwan. PMID- 20951360 TI - Ocular findings in a case of trisomy 18 with variant of Dandy-Walker syndrome. AB - Trisomy 18 is the second most common chromosomal syndrome and has multiple dysmorphic features. However, ocular findings in trisomy 18 are rarely reported. Retinal folds are the most common ocular finding described to date, although retinal hypopigmentation, dysplasia, and areas of hemorrhage and gliosis are also found in trisomy 18. Dandy-Walker syndrome is a brain malformation that has been reported in association with numerous chromosomal abnormalities, although it has rarely been reported in association with trisomy 18. Here, we present a case of trisomy 18 with ocular pathology and variant of Dandy-Walker syndrome, a combination that has not previously been reported. PMID- 20951361 TI - Intramuscular hemangioma of the temporalis muscle with incidental finding of bilateral symmetric calcification of the basal ganglia: a case report. AB - We report an 11-year-old boy whose brain computed tomography findings incidentally revealed bilateral basal ganglia calcification. He was symptom-free and had no abnormal neurological findings. He was diagnosed with Fahr's disease based on radiological findings and after excluding other etiologies such as infection, metabolic disorders, congenital malformation and malignancies. Most of the reported cases display an autosomal dominant mode of inheritance. Although Fahr's disease is a rare cause of basal ganglia calcification in children, this disease should be considered in children with a family history of neuropsychiatric disorders. PMID- 20951362 TI - Psychogenic urinary retention in children: a case report. AB - Psychogenic urinary retention occurs relatively infrequently in children and is less common than in adults. The influence of psychogenic factors on voiding generally results in an irritative syndrome, but rarely in urinary retention. A definitive diagnosis is established by excluding other pathological conditions. Evaluation includes urine culture, renal echography, spine magnetic resonance imaging, voiding cysto-urethrography, intravenous pyelography, and uroflowmetry. Here, we report on a 6-year-old girl with a 1-month history of voiding difficulty. Urology studies, including urine culture, revealed Escherichia coli, which was not present in preadmission urine cultures. Renal ultrasound and radiological images showed no gross abnormalities or vesicoureteral reflux, but uroflowmetry showed a low flow rate with residual urine. The results of imaging studies and pediatric psychiatric consultation led to a diagnosis of psychogenic urinary retention combined with urinary tract infection. Urinary rehabilitation included intermittent catheterization, bladder training, and supportive psychotherapy, after which the patient recovered and was discharged. PMID- 20951363 TI - Cushing's disease in children: report of three cases. AB - Cushing's disease is rare in children and adolescents. We report the clinical presentations of three children with Cushing's disease. All three exhibited the typical symptoms and signs of weight gain and growth retardation. Tw o also demonstrated personality changes, hypertension and hypokalemia, the last of these being rarely reported in patients with Cushing's disease. Lack of diurnal changes in serum cortisol levels was the most common biochemical finding. Serum cortisol levels were suppressed by low-dose dexamethasone in one patient, which is not typical for patients with Cushing's disease. Imaging studies are essential for localizing the tumor. Transsphenoidal surgery remains the treatment of choice, and pituitary irradiation should be considered for those patients whose tumors cannot be totally removed. Careful follow-up of these patients with awareness of the possibilities of relapse and the complications of hypopituitarism is indicated. PMID- 20951364 TI - An unfortunate change of heart. PMID- 20951365 TI - A rapid decline. PMID- 20951367 TI - Serious ups and downs. PMID- 20951366 TI - Portrait of a methanol-intoxicated brain. PMID- 20951368 TI - A study on embarrassment associated with product use. AB - User interactions with products or systems can produce positive feelings, e.g. pleasing, encouraging or challenging; or negative ones, e.g. annoying, depressing or even abusive. This study attempted to explore reasons for negative emotions associated with product use by probing into the embarrassing emotions aroused in a product-use situation. The results showed that the embarrassment associated with product use was caused by two constructs: losing control of the product and inappropriate operation. Both of the two constructs have impacts on embarrassing emotions; however, the structural model showed that for the embarrassment associated with product use, inappropriate operation stands out as a more significant construct than losing control of the product. Users tended to blame themselves for the embarrassing situation, believing that the embarrassment was a result of their improper use of the product or carelessness. PMID- 20951369 TI - Calcitonin gene-related peptide- and adrenomedullin-induced facilitation of calcium current in submandibular ganglion. AB - OBJECTIVE: The control of saliva secretion is mainly under parasympathetic control. The submandibular ganglion (SMG) is a parasympathetic ganglion which receives inputs from preganglionic cholinergic neurons, and innervates the submandibular salivary gland to control saliva secretion. The aim of this study was to investigate if adrenomedullin (ADM) and/or calcitonin gene-related peptide (CGRP) modulate voltage-dependent calcium channel (VDCCs) current (I(Ca)) in SMG. DESIGN: The profile of CGRP and ADM actions in SMG was studied using the whole cell configuration of the patch-clamp technique. RESULTS: Both ADM and CGRP facilitated I(Ca). These facilitations were attenuated by intracellular dialysis of the anti-Galpha(s)-protein and pretreatment of SQ22536 (an adenylate cyclase inhibitor). CONCLUSIONS: ADM and CGRP facilitates VDCCs mediated by Galpha(s) protein and adenylate cyclase in SMG. PMID- 20951370 TI - Sustained elevation of serum interleukin-6 and relative insensitivity to hydrocortisone differentiates posttraumatic stress disorder with and without depression. AB - BACKGROUND: Elevated levels of proinflammatory cytokines, especially interleukin 6 (IL-6), can mediate the greater risk for cardiovascular disease in individuals with posttraumatic stress disorder (PTSD), particularly in those with comorbid major depressive disorder (MDD). However, IL-6 levels are not consistently elevated in either PTSD or MDD. Although PTSD is associated with supersensitivity to glucocorticoids; prior studies have not evaluated the effect of comorbid MDD. METHODS: Serum IL-6 levels were measured hourly between 7:00 pm and 7:00 am in individuals with PTSD with comorbid MDD (PTSD + MDD) (n = 9) and compared with those with PTSD without MDD (PTSD - MDD) (n = 9) and nontraumatized healthy control subjects (n = 14). Group differences in serum IL-6, plasma adrenocorticotropic hormone (ACTH), and plasma cortisol response to 30 mg of intravenous hydrocortisone were evaluated using linear mixed models. RESULTS: Only subjects with PTSD + MDD exhibited higher, overnight serum IL-6 levels compared with individuals with PTSD - MDD (p < .01) and healthy control subjects (p < .001). Peak overnight IL-6 levels positively correlated with severity of PTSD (r = .56, p < .01) and depressive symptoms (r = .54, p < .01). Hydrocortisone administration significantly reduced IL-6 levels in both PTSD groups; however, IL-6 levels in PTSD + MDD were higher than both PTSD - MDD (p < .05) and healthy control subjects (p < .01). Following hydrocortisone administration, there was a greater reduction in levels of ACTH in PTSD - MDD compared with control subjects (p < .01). CONCLUSIONS: Sustained elevations of overnight IL-6 levels and relatively decreased sensitivity to hydrocortisone distinguish PTSD + MDD from PTSD - MDD. Novel strategies that decrease IL-6 levels offer a new direction in the prevention and treatment of PTSD and associated comorbid medical illnesses. PMID- 20951371 TI - Endoplasmic reticulum stress drives a regulatory phenotype in human T-cell clones. AB - T cells alter their functional phenotype during the evolution of an immune response (intra-lineage differentiation), but the driving forces to this plastic intra-lineage differentiation are poorly understood. The endoplasmic reticulum (ER) stress response is a possible critical event for the initial T cell differentiation upon antigen recognition. Here we studied the relationship between ER and Il-10 transcription in human Treg clones. The induction of ER stress with a canonical stressor, thapsigargin, enhances Il-10 transcription. Salubrinal, a small molecule inhibitor of the eukaryotic translation initiation factor 2alpha (eIF2alpha) dephosphporylation, dramatically inhibits it. Il-10 transcription is also enhanced by exogenous TNFalpha. These results disclose a role for ER stress in driving T cell plasticity. PMID- 20951372 TI - An automatic patient-specific seizure onset detection method in intracranial EEG based on incremental nonlinear dimensionality reduction. AB - Epileptic seizure features always include the morphology and spatial distribution of nonlinear waveforms in the electroencephalographic (EEG) signals. In this study, we propose a novel incremental learning scheme based on nonlinear dimensionality reduction for automatic patient-specific seizure onset detection. The method allows for identification of seizure onset times in long-term EEG signals acquired from epileptic patients. Firstly, a nonlinear dimensionality reduction (NDR) method called local tangent space alignment (LTSA) is used to reduce the dimensionality of available initial feature sets extracted with continuous wavelet transform (CWT). One-dimensional manifold which reflects the intrinsic dynamics of seizure onset is obtained. For each patient, IEEG recordings containing one seizure onset is sufficient to train the initial one dimensional manifold. Secondly, an unsupervised incremental learning scheme is proposed to update the initial manifold when the unlabelled EEG segments flow in sequentially. The incremental learning scheme can cluster the new coming samples into the trained patterns (containing or not containing seizure onsets). Intracranial EEG recordings from 21 patients with duration of 193.8h and 82 seizures are used for the evaluation of the method. Average sensitivity of 98.8%, average uninteresting false positive rate of 0.24/h, average interesting false positives rate of 0.25/h, and average detection delay of 10.8s are obtained. Our method offers simple, accurate training with less human intervening and can be well used in off-line seizure detection. The unsupervised incremental learning scheme has the potential in identifying novel IEEG classes (different onset patterns) within the data. PMID- 20951373 TI - The development of a tele-monitoring system for physiological parameters based on the B/S model. AB - The development of a new physiological multi-parameter remote monitoring system is based on the B/S model. The system consists of a server monitoring center, Internet network and PC-based multi-parameter monitors. Using the B/S model, the clients can browse web pages via the server monitoring center and download and install ActiveX controls. The physiological multi-parameters are collected, displayed and remotely transmitted. The experimental results show that the system is stable, reliable and operates in real time. The system is suitable for use in physiological multi-parameter remote monitoring for family and community healthcare. PMID- 20951374 TI - [Initial experience with a new manual device for aspiration of intracoronary thrombus "ELIMINATE"]. PMID- 20951375 TI - Comparison of a reusable with a disposable vessel-sealing device in a sheep model: efficacy and costs. AB - OBJECTIVE: To compare the efficacy of the new reusable vessel-sealing device MarSeal (KLS Martin, Tuttlingen, Germany) with the conventional standard disposable LigaSure device (Covidien-Valleylab, Boulder, CO) in an in vivo animal model. DESIGN: Prospective animal study. SETTING: Center of Experimental Surgery at a university hospital. ANIMALS: Thirteen sheep. INTERVENTION(S): The carotid and femoral arteries were dissected bilaterally and sealed randomly with MarSeal unilaterally and consecutively with LigaSure contralaterally in vivo. Afterward the burst pressure was determined for each artery. MAIN OUTCOME MEASURE(S): Sealing time, failure rate, and burst pressure. RESULT(S): The mean diameter of all arteries sealed did not differ significantly between the two groups (MarSeal 5.40 mm vs. LigaSure 5.35 mm). The mean sealing time was significantly shorter with use of the reusable device (MarSeal 5.2 seconds vs. LigaSure 9.1 seconds). We did not find a significant difference in sealing failure rates between the groups (MarSeal 7.0% vs. LigaSure 9.1%). In addition, analysis of mean burst pressure did not reveal a significant difference between the different devices (MarSeal 429 mm Hg vs. LigaSure 484 mm Hg). There was no significant difference with respect to lateral thermal damage (MarSeal 0.91 cm vs. LigaSure 0.93 cm). CONCLUSION(S): In our in vivo animal study, the new reusable MarSeal device appears to be equivalently effective for vessel sealing when compared with the conventional disposable LigaSure device. PMID- 20951376 TI - Pregnancy after rebiopsy and vitrification of blastocysts following allele dropout after day 3 biopsy. AB - OBJECTIVE: To report a clinical pregnancy after rebiopsy and vitrification of blastocysts following allele dropout (ADO) of biopsied day 3 embryos. DESIGN: Case report. SETTING: Private center. PATIENT(S): Thirty-year-old woman and her 33-year-old husband who carries the single-gene condition paraganglioma. INTERVENTION(S): In vitro fertilization with day 3 embryo biopsy-ET-blastocyst biopsy and vitrification-subsequent frozen ET cycle. MAIN OUTCOME MEASURE(S): Results from preimplantation genetic diagnosis and pregnancy results after fresh and frozen ETs. RESULT(S): Nineteen oocytes were retrieved of which 13 were mature and 12 fertilized. Eleven embryos were biopsied on day 3: two were normal, five were affected, and four exhibited ADO. The two normal blastocysts were transferred, and three of the ADO blastocysts were biopsied and sent for reanalysis. The biopsied blastocysts were vitrified. No pregnancy resulted from the fresh ET. One of the biopsied blastocysts was normal, one received no result, and one exhibited ADO. A singleton clinical pregnancy resulted from a subsequent frozen ET of the thawed biopsied normal blastocyst. CONCLUSION(S): Rebiopsy and vitrification of blastocysts could be used in cases of ADO or lack of results after day 3 embryo biopsy. PMID- 20951377 TI - Hidden mosaicism for a structural chromosome rearrangement: a rare explanation for recurrent miscarriages and affected offspring? AB - We found maternal mosaicism for an unbalanced chromosome rearrangement in a woman with recurrent chromosome rearrangements in the offspring. Hidden mosaicism may be a previously underestimated explanation for recurrent miscarriages and/or affected offspring, and preimplantation genetic diagnosis can be used to verify germinal mosaicism, to evaluate the recurrence risk, and to provide a possibility to achieve a normal pregnancy. PMID- 20951378 TI - Distal femur fractures of the elderly--different treatment options in a biomechanical comparison. AB - BACKGROUND: Fractures of the distal femur, especially in the elderly patient, are an unsolved problem in orthopaedic and trauma surgery. Poor bone stock quality caused by osteoporosis often results in bad implant anchorage in the distal part with a high risk of secondary failures such as cutout. This study investigates the biomechanical characteristics of four implants with different distal locking options under quasi-static torsional and cyclic axial loading. Therefore, an osteoporotic bone model simulating severe osteoporotic conditions was used. METHODS: Four different implants (T2 intramedullary nail, supracondylar nail (SCN), distal femoral nail (DFN) and the AxSOS angular stable plate) with different distal locking options were instrumented using an osteoporotic bone model. Five specimens per implant and per loading type (torsional and axial) were used. Mechanical testing was performed under physiologic loading conditions. First, a torsional test was performed in internal and external rotation (10 Nm), with a new specimen; a stepwise cyclic axial loading was conducted until failure of the construct. FINDINGS: For torsional loading, the lowest range of motion (ROM) and neutral zone (NZ) was found for the AxSOS plate construct. The SCN and T2 constructs showed similar results, and the highest ROM and NZ were found for the constructs treated with the DFN. Axial stiffness was highest for SCN constructs and in the same range for DFN and T2. The lowest stiffness showed in the AxSOS plate constructs with 47% of SCN stiffness. Under cyclic axial loading, the SCN constructs showed the highest number of cycles to failure, followed by AxSOS (70%), DFN (69%) and T2 (48%). INTERPRETATION: In conclusion of this biomechanical study, we can clinically suggest that, if, in general, torsional stability is required (e.g., for bedridden patients) the AxSOS plate will be sufficient. By contrast, the findings of this study support the fact that the SCN should be considered for mobile patients where early postoperative mobilisation for rehabilitation is desired. PMID- 20951379 TI - Reliability and validity of the Spanish version of the TAPQOL: a health-related quality of life (HRQOL) instrument for 1- to 5-year-old children. AB - OBJECTIVES: To evaluate the reliability, and construct validity of the Spanish version of the TNO-AZL preschool children quality of life (TAPQOL). METHODS: A consecutive sample of children (3 months to 5 years old) was recruited from primary care centers and two teaching hospitals in Spain. The TAPQOL and a set of questions related to their child's health status were administered to parents. Clinical diagnoses were collected from clinical records. Principal component analysis (PCA) with varimax rotation was used to analyze the instrument's structure. Effect size (ES) and analysis of variance (ANOVA) were used to analyze differences between subgroups known to be in poor health compared to the healthy subgroup. RESULTS: A total of 228 children participated in the study (response rate=95%). Ten of the 12 scales showed more than 30% ceiling effect. All dimensions except one had Cronbach's alpha coefficients greater than 0.7. PCA explained 75% of the variance. Healthy children in general had better scores than the other subgroups. Children at risk of poor health outcomes and those with respiratory problems scored lower in several scales than the healthy subgroup. CONCLUSIONS: Although the Spanish TAPQOL shows a non-negligible ceiling effect, it seems to be a reliable and valid instrument for Spanish infants and toddlers, and with similar psychometric characteristics to the original version. Future studies should try to improve questionnaire's structure and assess its sensitivity to change. PMID- 20951380 TI - Assessment of coronary plaque characteristics by optical coherence tomography in patients with diabetes mellitus complicated with unstable angina pectoris. AB - BACKGROUND: Diabetic patients are characterised by poorer prognosis and more cardiovascular complications compared with non-diabetic patients, which may be due to metabolic abnormalities and atherosclerotic plaque characteristics. METHODS: Patients with unstable angina pectoris were enrolled in the study and divided into diabetes mellitus (DM) (patients, n=25; plaques, n=42) and non-DM (patients, n=53; plaques, n=65) groups according to their DM history. Optical coherence tomography (OCT) examinations were performed on all patients, and images were analysed by two independent investigators. Fibrous cap thickness was measured at the thinnest point of each plaque. The presence of plaque disruption, dissection, erosion, thrombosis and calcification were also noted. RESULTS: Calcified plaques in the DM group were significantly greater than those in the non-DM group (42.9% vs. 23.1%; p=0.03). Thin-cap fibroatheroma (TCFA) were detected, and no significant difference was found in the frequencies (42.9% vs. 52.3%; p=0.34) and fibrous cap thickness (57.08 +/- 6.20 MUm vs. 56.11 +/- 9.23 MUm, p=0.74) between the DM and non-DM groups. Thrombus and plaque erosion were similar in the two groups, but the frequency of dissection in the DM group was greater than that in the non-DM group (21.4% vs. 7.7%, p=0.04). The high sensitivity C-reactive protein between the two groups was similar (0.44 +/- 0.20mg/dl vs. 0.46 +/- 0.15 mg/dl, p=0.83). CONCLUSION: Higher calcification and dissection were detected in diabetic patients with unstable angina pectoris, and the difference in coronary plaque characteristics can explain the difference in clinical prognoses between DM and non-DM patients. PMID- 20951382 TI - 'Contributions of individual muscles to hip joint contact force in normal walking' by T.A. Correa, K.M. Crossley, H.J. Kim and M.G. Pandy. PMID- 20951381 TI - Resistin, exercise capacity, and inducible ischemia in patients with stable coronary heart disease: data from the Heart and Soul study. AB - OBJECTIVE: Resistin is an adipocytokine involved in insulin resistance, inflammation, and atherosclerosis. Its role in the development and progression of coronary heart disease (CHD) is not yet well-characterized. We performed a cross sectional study to evaluate the association between serum resistin levels, exercise capacity, and exercise-induced cardiac ischemia among patients with stable CHD. METHODS AND RESULTS: We measured serum resistin concentrations and determined treadmill exercise capacity and inducible ischemia by stress echocardiography in 899 outpatients with documented CHD. Of these, 215 (24%) had poor exercise capacity (<5 metabolic equivalent tasks), and 217 (24%) had inducible ischemia. As compared with participants who had resistin levels in the lowest quartile, those with resistin levels in the highest quartile were more likely to have poor exercise capacity (33% versus 16%, odds ratio [OR] 2.68, P<0.0001) and inducible ischemia (30% versus 17%, OR 2.08, P=0.001). Both associations remained robust after adjusting for numerous clinical risk factors, metabolic variables, and markers of insulin resistance (poor exercise capacity adjusted OR 1.73, P=0.04; inducible ischemia adjusted OR 1.82, P=0.01). However, further adjustments for C-reactive protein, interleukin-6, and tumor necrosis factor-alpha eliminated the association with poor exercise capacity (adjusted OR 1.50, P=0.14) and substantially weakened the association with inducible ischemia (adjusted OR 1.72, P=0.03). CONCLUSIONS: Elevated serum resistin is associated with poor exercise capacity and exercise-induced cardiac ischemia in patients with stable coronary disease. Adjustment for inflammatory markers attenuated these associations, suggesting a possible role for resistin in inflammation and CHD pathophysiology. PMID- 20951383 TI - Effect of bioparticle size on dispersion and retention in monolithic and perfusive beds. AB - Single-component pulse response studies were used to compare the retention and transport behavior of small molecules, proteins, and a virus on commercially available monolithic and perfusive ion-exchangers. Temporal distortion and extra column effects were corrected for using a simple algorithm based on the method of moments. It was found that temporal distortion is inversely related to the number of theoretical plates. With increasing bioparticle size, retention increased and the transition from a non-eluting to a non-adsorbing state with increasing ionic strength became more abrupt. Both of these observations are qualitatively explained by calculations of particle-surface electrostatic attractive energy. Calculations also suggest that, for sufficiently large bioparticles, such as viruses or cells, hydrodynamic drag can promote elution. Under non-adsorbing conditions, plate height increased only weakly with flow rate and the skew remained unchanged. With increasing retention, plate height increased dramatically for proteins. Plate height was scaled by permeability rather than bead diameter to enable comparison among different stationary phases. PMID- 20951384 TI - Role of surface roughness and lubricant film thickness in nanolubrication of sliding components in adaptive optics. AB - Integrated microprojectors are being developed to project a large image on any surface chosen by users. For a laser-based microprojector, a piezo-electric based adaptive optics unit is adopted in the green laser architecture. Nanolubrication of adaptive optics sliding components is needed to reduce wear and for smooth operation. Mobile lubricant film thickness needs to be optimized for a given interface with a certain surface roughness to minimize stiction/friction and maximize durability. In this paper, the role of roughness and film thickness on adhesion, friction, and wear of the interface is studied. The results and associated mechanisms are presented. PMID- 20951385 TI - Cognitive abilities and clinical variables in bipolar I depressed and euthymic patients and controls. AB - BACKGROUND: While studies demonstrated that bipolar patients (BP) display cognitive deficits during mood episodes and remission, little is known about the clinical influences underlying these deficits. The aim of this study was to compare the performance of euthymic and depressed BPs and non-affective/psychotic disorder controls at several cognitive tasks, exploring which clinical variables influenced the performance of these subtests. It is hypothesized that the cognitive deficits in rank order are: depressed BPs > euthymic BPs > controls. METHODS: Sixty-five bipolar-I outpatients and thirty-four controls were assessed by the Brazilian version of the Wechsler Adult Intelligence Scale, Third Edition (WAIS-III). BPs were divided into depressed and euthymics, and these two groups were then compared to non-affective/psychotic disorder controls. RESULTS: For 12 of 14 subtest scores, comparisons yielded statistically significant (p < 0.05) between-group differences, including three subtests of attention and working memory (Digit Span and its two subtests) with both depressed and euthymic BPs, compared to controls, displaying significantly worse performance, and six subtests of visual and working memory with depressed (but not euthymic) BPs performing worse than controls. For all subtests, comparisons of depressed and euthymic patients' scores were non-significant. Performance on several subtests was negatively predicted by the severity of the disorder in both patient groups. LIMITATIONS: The cross-sectional design of the study, as well as confounding effects of medications and co-morbidities. CONCLUSIONS: The fact that the impairment of cognitive performance of both groups of patients is influenced by the severity of the illness is consistent with the literature. PMID- 20951387 TI - Transient "sicca syndrome" during phenobarbital treatment. AB - Even after the introduction of new antiepileptic drugs, phenobarbital continues to be largely used in the treatment of epilepsy. We report the case of a 59-year old woman with focal seizures with secondary generalization, treated with phenobarbital with normal serum levels. After thirty days she showed Sjogren-like symptoms, which resolved after the replaced of phenobarbital with oxcarbazepine. Although many antiepileptic drugs are known to induce autoimmune disorders, a "Sicca Syndrome" has never been reported as an adverse effect of phenobarbital. We think this case report leads to take into consideration the possibility of a drug-induced disorder whenever patients treated with barbiturates develop symptoms suggestive of Sjogren's Syndrome. PMID- 20951386 TI - Dysbindin (DTNBP1)--a role in psychotic depression? AB - Previous studies yielded evidence for dysbindin (DTNBP1) to impact the pathogenesis of schizophrenia on the one hand and affective disorders such as bipolar or major depressive disorder (MDD) on the other. Thus, in the present study we investigated whether DTNBP1 variation was associated with psychotic depression as a severe clinical manifestation of MDD possibly constituting an overlapping phenotype between affective disorders and schizophrenia. A sample of 243 Caucasian inpatients with MDD (SCID-I) was genotyped for 12 SNPs spanning 92% of the DTNBP1 gene region. Differences in DTNBP1 genotype distributions across diagnostic subgroups of psychotic (N = 131) vs. non-psychotic depression were estimated by Pearson Chi(2) test and logistic regression analyses adjusted for age, gender, Beck Depression Inventory (BDI) and the Global Assessment of Functioning Scale (GAF). Overall, patients with psychotic depression presented with higher BDI and lower GAF scores expressing a higher severity of the illness as compared to depressed patients without psychotic features. Four DTNBP1 SNPs, particularly rs1997679 and rs9370822, and the corresponding haplotypes, respectively, were found to be significantly associated with the risk of psychotic depression in an allele-dose fashion. In summary, the present results provide preliminary support for dysbindin (DTNBP1) gene variation, particularly SNPs rs1997679 and rs9370822, to be associated with the clinical phenotype of psychotic depression suggesting a possible neurobiological mechanism for an intermediate trait on the continuum between affective disorders and schizophrenia. PMID- 20951388 TI - Genetic association of PICALM polymorphisms with Alzheimer's disease in Han Chinese. AB - PICALM might play an important role in AD pathology through participating in altering synaptic vesicle cycling or APP endocytosis. A recent genome-wide study (GWAS) identified a single nucleotide polymorphism (SNP) rs3851179 in the 5' to the PICALM gene strongly associated with Alzheimer's disease (AD) in Caucasians. In order to assess the involvement of the PICALM polymorphism in the risk of developing late-onset AD (LOAD), we analyzed the genotype and allele distributions of these three polymorphisms in 609 Han Chinese subjects. Our data showed no significant association between the PICALM rs3851179 polymorphism and LOAD (genotype distribution: P=0.43; allele frequency: P=0.25, odds ratio=0.87, 95% confidence interval=0.68 to 1.10), even after statistical adjustment for age, gender and apolipoprotein E (APOE) status. Our results suggest that the PICALM polymorphism may not play a major role in the development of LOAD in the Han Chinese population. PMID- 20951389 TI - Should buttresses and sealants be used to manage pulmonary parenchymal air leaks? PMID- 20951390 TI - Redo aortic valve surgery: Influence of prosthetic valve endocarditis on outcomes. AB - OBJECTIVE: Compared with reoperative aortic valve replacement for nonendocarditic causes, the contemporary risk and long-term outcomes of reoperation for aortic prosthetic valve endocarditis are ill-defined. METHODS: Between December 1994 and April 2008, 313 patients underwent reoperative aortic valve replacement, of whom 152 (48.6%) had prosthetic valve endocarditis. Mean follow-up was 6.5 +/- 0.4 years and 97.4% complete. RESULTS: Patients with prosthetic valve endocarditis were older with a higher risk profile. The overall hospital mortality was 15.3% (n = 48) (prosthetic valve endocarditis vs nonendocarditis: 24.3%, n = 37, vs 6.8%, n = 11; P < .001). Independent predictors of perioperative mortality for prosthetic valve endocarditis were sepsis (odds ratio [OR], 6.5; 95% confidence interval [CI], 2.0-21.0; P < .01), ejection fraction less than 30% (OR, 5.8; 95% CI, 1.3-25.0; P = .02), concomitant coronary artery bypass grafting (OR, 3.3; 95% CI, 1.1-9.8; P = .03), and aortic root abscess (OR, 2.7; 95% CI, 1.2-6.4; P = .02), and for the nonendocarditis group were concomitant coronary artery bypass grafting (OR, 8.1; 95% CI, 2.0-33.0; P < .01), and mitral valve surgery (OR, 4.8; 95% CI, 1.3-17.9; P = .02). The 1-, 3-, 5-, and 10-year survivals for patients with and without prosthetic valve endocarditis were 52% +/- 4% versus 82% +/- 3%, 43% +/- 5% versus 73% +/- 4%, 37% +/- 5% versus 63% +/- 5%, and 31% +/- 7% versus 56% +/- 8%, respectively (log rank < 0.001). Predictors of long-term mortality in prosthetic valve endocarditis were sepsis (OR, 3.1; 95% CI, 1.5-4.5; P < .01) and unstable preoperative status (OR, 1.8; 95% CI, 1.2-3.5; P = .04), whereas in nonendocarditis patients the only predictor was New York Heart Association class IV (OR, 2.5; 95% CI, 2.8-7.4; P < .01). Five-year actuarial freedom from endocarditis was 80% +/- 0.3% versus 95% +/- 0.6% (prosthetic valve endocarditis cersus nonendocarditis; P = .002). CONCLUSIONS: Despite contemporary therapy, reoperation for aortic prosthetic valve endocarditis is still associated with relatively high perioperative mortality and limited long-term survival. PMID- 20951391 TI - Is cardiac diagnosis a predictor of neurodevelopmental outcome after cardiac surgery in infancy? AB - OBJECTIVES: To determine whether a cardiac diagnosis is a predictor of neurodevelopmental outcomes after infant cardiac surgery. METHODS: Infants with ventricular septal defect (VSD), tetralogy of Fallot (TOF), transposition of the great arteries (TGA), and hypoplastic left heart syndrome (HLHS) in a study of apolipoprotein E (APOE) polymorphisms, and neurodevelopmental outcome underwent neurodevelopmental and genetic evaluation at 4 years of age. The domains tested included cognition, language, speech, memory, executive function, visual-motor, fine motor, and reading and math skills. RESULTS: Testing was completed in 178 patients with normal genetic evaluations: VSD (n = 26), TOF (n = 44), TGA (n = 41), and HLHS (n = 67). No differences were found in gestational age, ethnicity, APOE genotype, socioeconomic status, or maternal education among groups. Patient age at the first surgery was significantly lower for patients with TGA and HLHS compared with those with TOF and VSD. The postoperative length of stay was significantly longer for HLHS than all other groups and for TGA compared with TOF and VSD. HLHS correlated significantly with the use of deep hypothermic circulatory arrest and multiple operations. The mean scores for each domain were within normal limits for all groups. Compared with the other patients, those with HLHS had significantly lower scores for cognition, fine motor skills, executive function, and math skills. No significant differences were found among the TGA, TOF or VSD patients for any domain. Significant impairments in at least 1 domain were identified in 8% (2/25) of patients with VSD, 20% (8/41) with TOF, 17% (7/41) with TGA, and 18% (12/65) with HLHS. After correction for the demographic, preoperative, and operative variables, no significant differences were found among the groups for any domain. CONCLUSIONS: The mean scores for the neurodevelopmental outcomes domains tested were in the normal range for preschool children with no recognized genetic syndromes after surgery for VSD, TOF, TGA, and HLHS. In each diagnostic group, the number of children with impairments in at least 1 domain increased compared with the general population. Unadjusted neurodevelopmental outcomes for HLHS were lower for cognition, fine motor skills, executive function, and math skills compared with the other patients. After correction for the demographic, preoperative, and operative variables, no significant differences were found among the groups for any domain. The specific cardiac diagnosis determines a large portion of the variation in these covariates. Therefore, although HLHS did predict for poorer outcomes in some domains, it did not add predictive power to the other factors considered. PMID- 20951393 TI - Inorganic and methylmercury: do they transfer along a tropical coastal food web? AB - Methylmercury (MeHg) and inorganic mercury (Hg(inorg)) were evaluated in the water of a Brazilian estuary, with two size classes of plankton and seven fish species of different feeding habits. Water partition coefficients (PCs) in microplankton were fourfold higher for MeHg than for Hg(inorg); and water PCs in mesoplankton were 26 times higher for MeHg than Hg(inorg). Difference between microplankton and mesoplankton MeHg bioaccumulation factor (BAF) was higher (0.60 log units) than Hg(inorg) BAF (0.24 log units), indicating that trophic transfer of MeHg between planktonic organisms is more efficient than Hg(inorg) transference. MeHg concentrations, proportion of mercury as MeHg and its biotransference factors (BTFs) in the microplankton, mesoplankton and fish increased with increasing trophic level while biotic concentrations of Hg(inorg) and proportion of mercury as Hg(inorg) decreased thus indicating that MeHg was indeed the biomagnified species of mercury. MeHg reflected the vertical trophic guilds distribution, due to the fact that the top predator fish presented the highest concentration (0.77 MUg g(-1)d.w.), followed by the less voracious species (0.43 MUg g(-1)d.w.); while planktivorous fish presented the lowest concentrations (0.044 MUg g(-1)d.w.). Hg(inorg) did not present the same behavior. Results suggest that feeding habits and trophic guild are important parameters, influencing biotransference and biomagnification processes. PMID- 20951394 TI - [Practical aspects for the assessment of clinical trials with prophylactic vaccines against infectious diseases]. PMID- 20951395 TI - Up-regulation of hepatic low-density lipoprotein receptor-related protein 1: a possible novel mechanism of antiatherogenic activity of hydroxymethylglutaryl coenzyme A reductase inhibitor Atorvastatin and hepatic LRP1 expression. AB - Low-density lipoprotein receptor-related protein 1 (LRP1) binds to apolipoprotein E and serves as a receptor for remnant lipoproteins in the liver, thus playing an important role in clearing these atherogenic particles. In this study, we investigated the effect of atorvastatin, a hydroxymethylglutaryl-coenzyme A reductase inhibitor, on hepatic LRP1 expression. We used HepG2 and Hep3B cells for in vitro study, and Otsuka Long-Evans Tokushima fatty and Sprague-Dawley rats for in vivo study. We used relatively high pharmacologic dose of atorvastatin in this study (in vitro, 0.5 MUmol/L in culture media, for 48 hours; in vivo, 20 mg/[kg d], for 6 weeks). Atorvastatin increased LRP1 and low-density lipoprotein (LDL) receptor expression in HepG2 and Hep3B cells and induced hepatic LRP1 and LDL receptor expression in chow diet-fed Sprague-Dawley rats and high-fat diet fed Otsuka Long-Evans Tokushima fatty rats. Atorvastatin decreased intracellular sterol level and increased the amount of the nuclear form of sterol response element-binding protein-2 (SREBP-2) in both HepG2 and Hep3B cells as well as in two animal models. Treatment of HepG2 cells with LDL increased intracellular sterol level and reduced LRP1, LDL receptor, and SREBP-2. When SREBP-2 in HepG2 cells was knocked down by small interfering RNA, the induction of LRP1 expression by atorvastatin did not take place. In conclusion, up-regulation of hepatic LRP1 might be a novel mechanism by which statin treatment decreases remnant lipoproteins. In addition, SREBP-2 acts as a mediator of atorvastatin-induced up regulation of hepatic LRP1. Future studies using standard doses of atorvastatin in humans are needed to elucidate clinical relevance of these findings. PMID- 20951396 TI - [Ultrasound-guided interventional procedures in the musculoskeletal system]. AB - Ultrasonography is the most appropriate tool for interventional procedures in the musculoskeletal system when the lesion is visible on ultrasonography. Procedures performed under ultrasonographic guidance include: taking biopsies; draining abscesses; bursitis; hematomas or muscle tears; treating cystic lesions; diagnostic or therapeutic arthrocentesis; injecting substances into joints or lesions; aspirating calcium deposits and extracting foreign bodies. Although some of these procedures are often carried out without imaging guidance, ultrasonographic guidance improves their efficacy. Drainage can be performed with catheters or needles and makes it possible to avoid more aggressive treatments in most cases. Urokinase is useful for draining hematomas or fibrinous collections. Injecting corticoids is useful in the treatment of synovial cysts, Baker's cyst, tendinitis, and non-infective arthritis. Calcifying tendinitis of the shoulder can be treated effectively with percutaneous calcium lavage. PMID- 20951397 TI - [Neuroimaging case presented at the General Case Reading Session of the XXX National Congress of the SERAM, A Coruna. May 2010]. PMID- 20951398 TI - Calcium phosphate coupled Newcastle disease vaccine elicits humoral and cell mediated immune responses in chickens. AB - Calcium phosphate (CaP) particles were coupled with inactivated Newcastle disease virus (NDV) vaccine. The surface morphology of CaP particles coupled to NDV was found to be spherical, smooth and with a tendency to agglomerate. The mean (+/- SE) size of CaP particles was found 557.44 +/- 18.62 nm. The mean percent encapsulation efficiency of CaP particles coupled to NDV assessed based on total protein content and haemagglutination (HA) activity in eluate was found to be 10.72 +/- 0.89 and 12.50 +/- 2.09, respectively. The humoral and cell mediated immune responses induced by CaP coupled NDV vaccine were assessed in comparison to a commercial live vaccine (RDV 'F'). CaP coupled NDV vaccine elicited prolonged haemagglutination inhibition (HI) and enzyme linked immunosorbent assay (ELISA) titres in the serum even at fourth and fifth week post-vaccination (PV), unlike RDV 'F' inoculated chickens whose titres declined to insignificant levels by this time. CaP coupled NDV vaccine could stimulate HI antibodies in tracheal washings and tears from second and first week PV, respectively. IgA ELISA antibodies were also seen in tracheal washings of these birds from third week PV and in tears from second week PV. CaP coupled NDV vaccine elicited cell mediated immune responses (CMI) from two to four weeks PV. The stimulation indices obtained after stimulation with specific antigen was not significantly different between CaP coupled antigen and live NDV virus except on first week PV. However, CaP coupled antigen did not cause suppression of lympo proliferation as indicated by statistically similar responses to mitogen, concanavalin A between the two groups. Overall, CaP coupled NDV vaccine elicited stronger and prolonged immune responses in comparison to the commercial live vaccine. No increase in the serum calcium and phosphorous levels were seen in CaP coupled NDV vaccine inoculated chickens. PMID- 20951399 TI - Communication failure in the operating room. AB - BACKGROUND: Communication errors contribute to the occurrence of adverse events in various domains of health care. Recent studies surveying perceptions of communication in the operating room have found disparities in the perceived quality of communication among members of the operating room team. Our aim was to characterize the nature of communication failures observed in the operating room and to assess whether a Team Training curriculum had any impact on observed communication errors. METHODS: Intraoperative observation was performed and communication errors were identified according to predetermined criteria. Observed errors were classified according to the type of error, subject matter, and observed effect. RESULTS: Seventy-six communication failures were observed over 150 hours of observation. Overall, communication errors relating to equipment and keeping team members informed of the progress of an operation comprised 36% and 24% of all observed communication errors, respectively. Prior to the introduction of a Team Training curriculum, 56 errors were observed over 76 hours (rate,737 errors per hour; standard error, 0.098). After Team Training, 20 errors over 74 hours were observed (rate .270 errors per hour; standard error, 0.060; P < .001). CONCLUSION: Communication failures related most frequently to equipment and keeping team members updated as to the progress of an operation. These failures can lead to procedural delay and inefficiencies. A program that teaches teamwork and communication skills is one strategy that may improve communication among members of the operating room team. PMID- 20951400 TI - Virus neutralising activity of African fruit bat (Eidolon helvum) sera against emerging lyssaviruses. AB - It is likely that phylogroup 2 lyssaviruses circulate within bat reservoirs. We adapted a pseudotype (pt) neutralisation assay (PNA) to a multiplex format enabling serosurveillance for Lagos bat virus (LBV), Mokola virus (MOKV) and West Caucasian bat virus (WCBV) in a potential reservoir, the African straw-coloured fruit bat, Eidolon helvum. Highly correlated titres were observed between single and multiplex PNAs using ptLBV and ptMOKV (r=0.97, p<0.0001), validating its use for bat serosurveillance. Of the bat serum samples screened 56% neutralised ptLBV, 27% ptMOKV and 1% ptWCBV. Mean VNAb titres were 1:266, 1:35 and 1:7 against ptLBV, ptMOKV and ptWCBV respectively. The high seroprevalence estimates suggest that the infection rate of LBV in E. helvum remains high enough to persist in this species. This supports the hypothesis that LBV is endemic in Ghanaian E. helvum and we speculate that LBV may have co-evolved with African megachiroptera. PMID- 20951401 TI - Implications of land disturbance on drinking water treatability in a changing climate: demonstrating the need for "source water supply and protection" strategies. AB - Forests form the critical source water areas for downstream drinking water supplies in many parts of the world, including the Rocky Mountain regions of North America. Large scale natural disturbances from wildfire and severe insect infestation are more likely because of warming climate and can significantly impact water quality downstream of forested headwaters regions. To investigate potential implications of changing climate and wildfire on drinking water treatment, the 2003 Lost Creek Wildfire in Alberta, Canada was studied. Four years of comprehensive hydrology and water quality data from seven watersheds were evaluated and synthesized to assess the implications of wildfire and post fire intervention (salvage-logging) on downstream drinking water treatment. The 95th percentile turbidity and DOC remained low in streams draining unburned watersheds (5.1 NTU, 3.8 mg/L), even during periods of potential treatment challenge (e.g., stormflows, spring freshet); in contrast, they were elevated in streams draining burned (15.3 NTU, 4.6 mg/L) and salvage-logged (18.8 NTU, 9.9 mg/L) watersheds. Persistent increases in these parameters and observed increases in other contaminants such as nutrients, heavy metals, and chlorophyll-a in discharge from burned and salvage-logged watersheds present important economic and operational challenges for water treatment; most notably, a potential increased dependence on solids and DOC removal processes. Many traditional source water protection strategies would fail to adequately identify and evaluate many of the significant wildfire- and post-fire management-associated implications to drinking water "treatability"; accordingly, it is proposed that "source water supply and protection strategies" should be developed to consider a suppliers' ability to provide adequate quantities of potable water to meet demand by addressing all aspects of drinking water "supply" (i.e., quantity, timing of availability, and quality) and their relationship to "treatability" in response to land disturbance. PMID- 20951402 TI - Dietary exposure of rainbow trout to 8:2 and 10:2 fluorotelomer alcohols and perfluorooctanesulfonamide: Uptake, transformation and elimination. AB - The bioaccumulation of perfluorooctanesulfonamide (PFOSA) and two fluorotelomer alcohols (8:2 FTOH, 10:2 FTOH) by rainbow trout (Oncorhynchus mykiss) through dietary exposure, including depuration rates and metabolism was investigated. Concentrations in the spiked feed ranged from 10.9 MUg g-1 wet weight (wet wt) for PFOSA and 6.7 MUg g-1 wet wt for 8:2 FTOH to 5.0 MUg g-1 wet wt for 10:2 FTOH. Trout was fed at 1.5% body weight per day for 30 d and depuration was followed for up to 30 d following previously published dietary exposure protocols. Perfluorooctanesulfonate (PFOS) was the major perfluoroalkylsulfonate (PFSA) detected in fish following dietary exposure to PFOSA. Half-lives of PFOS and PFOSA were 16.9 +/- 2.5 and 6.0 +/- 0.4 d, respectively. A biomagnification factor (BMF) of 0.023 was calculated for PFOSA which indicates that dietary exposure to PFOSA does not result in biomagnification in the rainbow trout. PFOS had a BMF of 0.08. The fluorotelomer saturated acids (8:2 FTCA, 10:2 FTCA) and fluorotelomer unsaturated acids (8:2 FTUCA, 10:2 FTUCA) were the major products detected in rainbow trout following dietary exposure to 8:2 FTOH and 10:2 FTOH, respectively. Half-lives were 3.7 +/- 0.4, 2.1 +/- 0.5, 3.3, and 1.3 d for 10:2 FTCA, 10:2 FTUCA, 8:2 FTCA, and 8:2 FTUCA, respectively. Small amounts of perfluorooctanoate (PFOA) and perfluorodecanoate (PFDA) were also detected in the FTOH exposed fish. PMID- 20951403 TI - Accumulation of organochlorine contaminants in loggerhead sea turtles, Caretta caretta, from the eastern Adriatic Sea. AB - We analyzed 15 polychlorinated biphenyls (PCBs) and five organochlorine pesticides (OCPs) in fat tissue of 27 loggerhead sea turtles (Caretta caretta) from eastern Adriatic Sea with the curved carapace length ranging from 25.0 to 84.5 cm. The PCB profile was dominated by hexa- and hepta-chlorinated congeners, with PCB-153 (median: 114.9 ng g-1 wet mass), PCB-138 (80.0 ng g-1 w.m.), and PCB 180 (26.7 ng g-1 w.m.) detected with the highest levels. Toxic mono-ortho congeners PCB-118, PCB-105 and PCB-180 with dioxin-like toxicity were found in > 70% samples. 4,4'-DDE (81.0 ng g-1 w.m.) prevailed the OCP signature, accounting for 80% of the total DDTs. A significant increasing trend in accumulation with size was found for PCB-52 (r(s) = 0.512, p < 0.01) and PCB-114 (r(s) = 0.421, p < 0.05). Comparison of our results with organochlorine contaminant (OC) pattern in some prey taxa suggest that contamination occurs primarily through the food web, with biomagnification factors of 0.14-6.99 which were positively correlated with the octanol-water partition coefficient (logK(ow); p < 0.05). This study, based upon a fairly large sample size collected mostly from incidentally captured animals over a short time period (June 2001-November 2002), present a temporal snapshot of OC contamination in wild, free-ranging loggerheads from Adriatic feeding grounds and provide a baseline for monitoring the regional OC trends in this endangered species. PMID- 20951404 TI - Dietary exposure to PCBs based on food consumption survey and food basket analysis at Taizhou, China--the world's major site for recycling transformers. AB - The levels of PCBs in different types of food (fish, shellfish, meat, rice, vegetables, and fruits) were analyzed to determine the dietary intake of 37 PCBs for local residents and e-waste workers (all lactating mothers) at Taizhou (China), a major electronic waste scrapping center, in particular for recycling transformers. The exposure to PCBs through dietary intake in Taizhou was estimated at 92.79 ngkg(-1)d(-1), contributed by consumption of freshwater fish (28%), rice (28%), meat (17%), shellfish (9%), vegetables (8%), egg (4%) and marine fish (2%). With regards to WHO-PCB-TEQ values, freshwater fish (40%), shellfish (24%), duck liver (18%) and rice (12%) were the main dietary sources with total daily intake (9.78 pg WHO-PCB-TEQ kg(-1)d(-1)), exceeding the FAO/WHO Tolerable Daily Intake (70 pg TEQkg(-1)body(-1)wt(-1)month(-1)). PMID- 20951405 TI - Urinary and serum metabolites of di-n-pentyl phthalate in rats. AB - Di-n-pentyl phthalate (DPP) is used mainly as a plasticizer in nitrocellulose. At high doses, DPP acts as a potent testicular toxicant in rats. We administered a single oral dose of 500 mg kg(-1)bw of DPP to adult female Sprague-Dawley rats (N=9) and collected 24-h urine samples 1d before and 24- and 48-h after DPP was administered to tentatively identify DPP metabolites that could be used as exposure biomarkers. At necropsy, 48 h after dosing, we also collected serum. The metabolites were extracted from urine or serum, resolved with high performance liquid chromatography, and detected by mass spectrometry. Two DPP metabolites, phthalic acid (PA) and mono(3-carboxypropyl) phthalate (MCPP), were identified by using authentic standards, whereas mono-n-pentyl phthalate (MPP), mono(4 oxopentyl) phthalate (MOPP), mono(4-hydroxypentyl) phthalate (MHPP), mono(4 carboxybutyl) phthalate (MCBP), mono(2-carboxyethyl) phthalate (MCEP), and mono-n pentenyl phthalate (MPeP) were identified based on their full scan mass spectrometric fragmentation pattern. The omega-1 oxidation product, MHPP, was the predominant urinary metabolite of DPP. The median urinary concentrations (MUg mL( 1)) of the metabolites in the first 24h urine collection after DPP administration were 993 (MHPP), 168 (MCBP), 0.2 (MCEP), 222 (MPP), 47 (MOPP), 26 (PA), 16 (MPeP), and 9 (MCPP); the concentrations of metabolites in the second 24 h urine collection after DPP administration were significantly lower than in the first collection. We identified some urinary metabolic products in the serum, but at much lower levels than in urine. Because of the similarities in metabolism of phthalates between rats and humans, based on our results and the fact that MHPP can only be formed from the metabolism of DPP, MHPP would be the most adequate DPP exposure biomarker for human exposure assessment. Nonetheless, based on the urinary levels of MHPP, our preliminary data suggest that human exposure to DPP in the United States is rather limited. PMID- 20951406 TI - Mycelial growth and solid-state fermentation of lignocellulosic waste by white rot fungus Phanerochaete chrysosporium under lead stress. AB - Lignocellulosic biomass is an abundant renewable resource difficult to degrade. Its bioconversion plays important roles in carbon cycles in nature, which may be influenced by heavy metals in environment. Mycelial growth and the degradation of lignocellulosic waste by lignin-degrading fungus Phanerochaete chrysosporium under lead stress were studied. It was shown that P. chrysosporium could grow in liquid media with 400 mg L-1 Pb(II), and mycelial dry weight was reduced by 54% compared to the control. Yellow mycelia in irregular short-strip shape formed in Pb-containing media, whereas the control showed ivory-white regular mycelial pellets. Two possible responses to Pb stress were: dense hyphae, and secretion from mycelia to resist Pb. During solid-state fermentation of straw, fungal colonization capability under Pb stress was positively correlated with the removal efficiency of soluble-exchangeable Pb when its content was higher than 8.2 mg kg-1 dry mass. Carboxymethyl cellulase activity and cellulose degradation were inhibited at different Pb concentrations, whereas low Pb concentrations increased xylanase and ligninolytic enzyme activities and the hemicellulose and lignin degradation. Cluster analyses indicated that Pb had similar effects on the different microbial indexes related to lignin and hemicellulose degradation. The present findings will advance the understandings of lignocellulose degradation by fungi under Pb pollution, which could provide useful references for developing metal-polluted waste biotreatment technology. PMID- 20951407 TI - When humans chew bones. PMID- 20951408 TI - A methodological investigation of hominoid craniodental morphology and phylogenetics. AB - The evolutionary relationships of extant great apes and humans have been largely resolved by molecular studies, yet morphology-based phylogenetic analyses continue to provide conflicting results. In order to further investigate this discrepancy we present bootstrap clade support of morphological data based on two quantitative datasets, one dataset consisting of linear measurements of the whole skull from 5 hominoid genera and the second dataset consisting of 3D landmark data from the temporal bone of 5 hominoid genera, including 11 sub-species. Using similar protocols for both datasets, we were able to 1) compare distance-based phylogenetic methods to cladistic parsimony of quantitative data converted into discrete character states, 2) vary outgroup choice to observe its effect on phylogenetic inference, and 3) analyse male and female data separately to observe the effect of sexual dimorphism on phylogenies. Phylogenetic analysis was sensitive to methodological decisions, particularly outgroup selection, where designation of Pongo as an outgroup and removal of Hylobates resulted in greater congruence with the proposed molecular phylogeny. The performance of distance based methods also justifies their use in phylogenetic analysis of morphological data. It is clear from our analyses that hominoid phylogenetics ought not to be used as an example of conflict between the morphological and molecular, but as an example of how outgroup and methodological choices can affect the outcome of phylogenetic analysis. PMID- 20951409 TI - Temporal variability of nitrate transport through hydrological response during flood events within a large agricultural catchment in south-west France. AB - The temporal variability of nitrate transport was monitored continuously in a large agricultural catchment, the 1110km(2) Save catchment in south-west France, from January 2007 to June 2009. The overall aim was to analyse the temporal transport of nitrate through hydrological response during flood events in the catchment. Nitrate loads and hysteresis were also analysed and the relationships between nitrate and hydro-climatological variables within flood events were determined. During the study period, 19 flood events were analysed using extensive datasets obtained by manual and automatic sampling. The maximum NO(3)( ) concentration during flood varied from 8.2mgl(-1) to 41.1mgl(-1) with flood discharge from 6.75m(3)s(-1) to 112.60m(3)s(-1). The annual NO(3)(-) loads in 2007 and 2008 amounted to 2514t and 3047t, respectively, with average specific yield of 2.5tkm(-12)yr(-1). The temporal transport of nitrate loads during different seasonal flood events varied from 12t to 909t. Nitrate transport during flood events amounted to 1600t (64% of annual load; 16% of annual duration) in 2007 and 1872t (62% of annual load; 20% of annual duration) in 2008. The level of peak discharge during flood events did not control peak nitrate concentrations, since similar nitrate peaks were produced by different peak discharges. Statistically strong correlations were found between nitrate transport and total precipitation, flood duration, peak discharge and total water yield. These four variables may be the main factors controlling nitrate export from the Save catchment. The relationship between nitrate and discharge (hysteresis patterns) investigated through flood events in this study was mainly dominated by anticlockwise behaviour. PMID- 20951410 TI - A roadmap for development of sustainable E-waste management system in India. AB - The problem of E-waste has forced Environmental agencies of many countries to innovate, develop and adopt environmentally sound options and strategies for E waste management, with a view to mitigate and control the ever growing threat of E-waste to the environment and human health. E-waste management is given the top priority in many developed countries, but in rapid developing countries like India, it is difficult to completely adopt or replicate the E-waste management system in developed countries due to many country specific issues viz. socio economic conditions, lack of infrastructure, absence of appropriate legislations for E-waste, approach and commitments of the concerned, etc. This paper presents a review and assessment of the E-waste management system of developed as well as developing countries with a special emphasis on Switzerland, which is the first country in the world to have established and implemented a formal E-waste management system and has recycled 11kg/capita of WEEE against the target of 4kg/capita set by EU. And based on the discussions of various approaches, laws, legislations, practices of different countries, a road map for the development of sustainable and effective E-waste management system in India for ensuring environment, as well as, occupational safety and health, is proposed. PMID- 20951411 TI - Occurrence of neuropeptides and tyrosine hydroxylase in the olfactory epithelium of the lesser-spotted catshark (Scyliorhinus canicula Linnaeus, 1758). AB - Immunohistochemical studies using antisera against various neuropeptides (Substance P, vasoactive intestinal polypeptide, and cholecystokinin octapeptide) and tyrosine hydroxylase revealed both olfactory sensory neuron (OSN) polymorphisms and transepithelial-subepithelial nerves in the olfactory epithelium of the cartilaginous fish, Scyliorhinus canicula. This study provides the first evidence of three morphological types of OSNs within the olfactory epithelium of cartilaginous fish that are similar to those found in the teleosts. In fishes there is evidence that OSNs differ functionally, including their differential olfactory bulb projections and molecular properties. The Substance P positive olfactory neurons in S. canicula may have a separate bulbar projection site that is not known, but may indicate a characteristic found in olfactory neuron subtypes in both lampreys and teleost fish. Numerous Substance P immunopositive nerves are found at the base of and in the olfactory epithelium. Some of them were observed to extend outwards almost reaching the epithelial surface. Their presumptive origin from the trigeminal nerve and their interrelationship with chemosensory cells in the nasal passages of vertebrates are discussed. PMID- 20951412 TI - Assessment of overactive bladder symptoms: comparison of 3-day bladder diary and the overactive bladder symptoms score. AB - OBJECTIVES: To compare the Overactive Bladder Symptom Score (OABSS) and a bladder diary as a tool for assessing symptoms of overactive bladder (OAB). METHODS: Treatment-naive OAB patients received an antimuscarinic agent, solifenacin. At baseline and 12 weeks after treatment, patients completed a 3-day bladder diary and the OABSS. Relationships between the 2 methods were evaluated by comparison of changes after treatment, agreement between variables and correlation between changes. RESULTS: In total, 79 patients (42 male and 37 female, mean age 71.1 years) were included in the analysis. Statistically significant improvements were noted for all the OABSS and the corresponding diary variables. The effect size (ES) was largest for the OABSS urgency score (2.00), followed by the OABSS total score (1.54), and then by the diary urgency score (0.92). All of the ESs for the OABSS, except daytime frequency, were larger than those of the corresponding diary variables. The standard response means followed a similar pattern to the ESs. A fairly good agreement between OABSS items and the corresponding diary variables was found at baseline and 12 weeks (kappa coefficient, 0.33-0.80). High correlations (Spearman's rho, >= 0.5) between changes in OABSS items and the corresponding diary variables were found for urgency incontinence and night-time frequency. CONCLUSIONS: The OABSS is highly sensitive to treatment-related changes of OAB symptoms. Because of its simplicity and dependability, the OABSS can be an alternative to a bladder diary for symptom and efficacy assessment in daily clinical practice. PMID- 20951413 TI - Ventral longitudinal stricturotomy and transversal closure: the Heineke-Mikulicz principle in urethroplasty. AB - OBJECTIVES: To describe the Heineke-Mikulicz principle in urethral surgery and to evaluate preliminary surgical and functional outcomes of this technique. METHODS: Ten patients (of a cohort of more than 400 patients treated with urethroplasty during a 7-year period) with a urethral stricture were treated using the Heineke Mikulicz principle: a ventral longitudinal stricturotomy was performed with transversal closure of the urethra. Only patients with a short (<1 cm), not too narrow or fibrotic stricture at the bulbar urethra or fossa navicularis were considered as appropriate candidates. At closure of the study, all patients were sent a questionnaire about the functional outcome of the procedures. This included questions about postoperative shortening, chordee, postvoid dribbling, ejaculatory disturbances, erectile dysfunction, and penile sensitivity. RESULTS: Mean follow-up was 46.6 months (range: 15-79 months). There were no immediate or early postoperative complications. Nine of 10 patients (90%) were successfully treated. On the questionnaire, 1 patient reported mild postoperative chordee and shortening, and 1 patient complained of postvoid dribbling. None of the sexually active patients reported ejaculatory disturbances, erectile dysfunction, or diminished penile sensitivity. CONCLUSIONS: The preliminary surgical and functional results with the Heineke-Mikulicz principle are promising. Larger cohorts of patients are needed for further evaluation. PMID- 20951414 TI - SIU Scholarship: Dr. Sachit Sharma. PMID- 20951415 TI - Cone beam computed tomography: an assessment of renal image quality and applicability for percutaneous renal cryotherapy in a swine model. AB - OBJECTIVES: To assess cone bean computed tomography (CBCT) for renal imaging in a phantom model, ex vivo kidney and an in vivo porcine percutaneous renal cyroablation (PRC). CBCT provides 3-dimensional sectional imaging without the space requirements, repositioning, and expenditure of computed tomography (CT). METHODS: CBCT was focused on a radiological phantom with electron density of renal tissue and visualization was recorded. The ability of CBCT to image an ex vivo kidney in a water bath, with and without contrast, was then evaluated. An in vivo porcine animal model was then used to perform PRC and the scanner was evaluated in regard to image of the kidneys, a fiber-agarose pseudotumor, and guidance of the cryoprobe. RESULTS: Qualitative assessment of phantom images revealed sufficient contrast between the renal tissue and water densities. Images of the ex vivo porcine kidneys without contrast revealed limited renal architecture, whereas retrograde contrast revealed 3D images of renal shape and vascular/collecting system architecture visible in axial and sagittal planes. Noncontrast imaging facilitated precise needle guidance but was inadequate to consistently visualize ice-ball formation during cryoablation. At necropsy, all tumors were encompassed by the cryolesion with >1-cm margins, except for 1 pseudotumor that had been placed extracapsularly. CONCLUSIONS: CBCT is an imaging modality capable of excellent spatial resolution and soft-tissue sensitivity in a radiographic phantom and ex vivo and in situ porcine renal models. Based on our preliminary results, further refinements in image quality are required to improve soft tissue visualization to be applied to percutaneous renal cryoablation. PMID- 20951416 TI - Radiological treatment of renal artery occlusion after blunt abdominal trauma in a pediatric patient: is it never too late? AB - A 15-year-old boy was severely injured in a motor vehicle accident. A blunt abdominal trauma resulted in multiple lesions requiring urgent surgical treatment. Seven days after the trauma, renal Doppler sonography showed absence of arterial signal in the left kidney hilum. Selective renal angiography was performed, showing localized aneurysmatic dilatation in the principal branch of the left renal artery with interruption of renal parenchyma blood flow. Stent graft placement resulted in the resumption of a normal perfusion. After long-term follow-up, symmetric renal function has been demonstrated. Our results confirmed the efficacy of endovascular treatment in the management of pediatric patients with renal artery occlusion after blunt abdominal trauma. The outcome appeared excellent even after a prolonged period of renal ischemia. PMID- 20951417 TI - Altered expression and localization of estrogen receptors alpha and beta in the testes of a cryptorchid rat model. AB - OBJECTIVES: To assess the involvement of estrogen in spermatogenesis, we evaluated the expression of estrogen receptors (ERs) alpha (ERalpha) and beta (ERbeta) in the cryptorchid testes in model rats exposed to flutamide during the fetal stage. METHODS: Cryptorchid model rats were produced by administering flutamide to pregnant Sprague-Dawley rats. To evaluate the sequential change in the expression of ERalpha and ERbeta genes, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was performed using specific primers. Immunohistochemistry with ERalpha and ERbeta antibodies was performed, and the results were evaluated to determine the influences of orchiopexy. RESULTS: Real time RT-PCR revealed that ERalpha expression in control testes increases with growth and peaks value at 7 weeks and significantly decreases in cryptorchid testes. ERbeta expression was low, and there were no significant differences between both the cryptorchid and control testes groups. Immunohistochemistry revealed that ERalpha protein was present in the spermatids and Sertoli cells of descended testes, and that this protein was strongly expressed in the Leydig cells of cryptorchid testes. ERbeta was detected in multiple cells in both groups. After orchiopexy, ERalpha expression was detected in the spermatids of cryptorchid testes. CONCLUSIONS: Spermatogenesis in cryptorchid rats is disrupted. Because the expression of ERbeta was unchanged in both control and cryptorchid testes, we supposed that alteration in ERalpha levels is more closely related to spermatogenic failure than ERbeta levels in the cryptorchid testes. We considered that increased expression of ERalpha in Leydig cells of cryptorchid testes is associated with estradiol level in the testicular tissue, and androgen estrogen imbalance deteriorates spermatogenesis in cryptorchidism. PMID- 20951418 TI - Trends in the medical management of urolithiasis: a comparison of general urologists and endourology specialists. AB - OBJECTIVES: To determine whether there are differences in the medical and dietary recommendations given to stone formers between urologists that subspecialize in endourology and general urologists. METHODS: A 10 question on-line survey was sent via e-mail to members of the North Central Section (NCS) of the American Urological Association and the Endourological Society (ES). RESULTS: A total of 206 surveys were completed by members of the NCS and 122 surveys were completed by members of the ES. Of the ES members, 75% were in academic practice versus 21% of NCS members (P < .01). Urologists in both groups performed their own medical management (88% ES, 83% NCS) and believed that they were able to provide effective dietary recommendations (73% ES, 72% NCS). Most urologists in both groups performed 24-hour urine and serum studies in recurrent stone formers (68% ES, 73% NCS) as opposed to all stone formers (17% ES, 18% NCS). Members of both groups recommended low salt intake to all stone formers (68% ES, 61% NCS) or only calcium stone formers (18% ES, 29% NCS; P = .03). A higher percentage of urologists from the ES recommended low animal protein intake to all stone formers than urologists from the NCS (69% ES, 47% NCS; P < .05). CONCLUSIONS: Urologists from both the NCS and the ES, despite differences in the type of practice, subspecialty interest in endourology and geographic location of practice, have similar medical and nutritional practices when counseling patients in the prevention of stone disease. PMID- 20951419 TI - T(H)2 heterogeneity: Does function follow form? AB - T(H)2 immune responses are required for the 2 fundamental pathological processes characteristic of allergic disease: IgE-mediated hypersensitivity and eosinophilic inflammation. The 3 established T(H)2 cytokines, IL-4, IL-5, and IL 13, each play a nonredundant role in allergic disease pathology. The recent explosion of T(H) subpopulations combined with the wide availability of polychromatic cytokine staining has facilitated the discovery of T(H)2 lineage heterogeneity. In this article we review T(H)2 heterogeneity and ask the following question: At what point do these subpopulations graduate from in vitro curiosities to immunologically robust therapeutic targets? We propose criteria to establish a T-cell subset as a biologically relevant entity and address the evidence to support these T(H)2 subpopulations having a unique function or specific contribution to allergic pathology or host defense. PMID- 20951420 TI - Spatially resolved assessments of composite shrinkage in MOD restorations using a digital-image-correlation technique. AB - OBJECTIVES: To analyze the influence of cavity geometry and lining materials in MOD composite restorations by characterizing the polymerization shrinkage and cusp deflection. METHODS: Eighty intact molars with similar sizes were collected and randomly divided into eight groups. MOD cavities with various widths and depths were prepared on these teeth: Group I, 2((W)) * 2((D)) mm; Group II, 4((W)) * 2((D)) mm; Groups III, IIIf, IIIg, 2((W)) * 4((D)) mm; and Groups IV, IVf, IVg, 4((W)) * 4((D)) mm. In Groups IIIf and IVf, flowable composite liner was placed prior to composite restoration, while glass-ionomer liner was used in Groups IIIg and IVg. Deformations of restorations resulted from composite shrinkage were recorded for 30 min following light irradiation using a digital image-correlation (DIC) method to subpixel level. The displacements at the boundaries of the restorations were analyzed using one-way ANOVA and the post hoc test at a 5% significance level. The correlation between the geometric factors and the displacements was also analyzed. RESULTS: The inward displacements on free surfaces were greater than those on the bonded surfaces. Groups with flowable composite linings showed greater amount of displacements on free and bonded surfaces compared to the unlined and glass ionomer lining groups. The correlation analysis showed that the free surface shrinkage was related with the cavity width and C-factor, while cusp deflections were correlated with the cavity depth and the cusp compliance. SIGNIFICANCE: The DIC technique measures composite shrinkage on different boundaries of restorations to facilitate the investigation of polymerization kinetics. Using flowable composite lining and increased cusp depth may aggravate the cusp flexure. PMID- 20951421 TI - Curing hepatitis C with pills: a step toward global control. PMID- 20951422 TI - Chest-compression-only versus standard cardiopulmonary resuscitation: a meta analysis. AB - BACKGROUND: In out-of-hospital cardiac arrest, dispatcher-assisted chest compression-only bystander CPR might be superior to standard bystander CPR (chest compression plus rescue ventilation), but trial findings have not shown significantly improved outcomes. We aimed to establish the association of chest compression-only CPR with survival in patients with out-of-hospital cardiac arrest. METHODS: Medline and Embase were systematically reviewed for studies published between January, 1985, and August, 2010, in which chest-compression only bystander CPR was compared with standard bystander CPR for adult patients with out-of-hospital cardiac arrest. In the primary meta-analysis, we included trials in which patients were randomly allocated to receive one of the two CPR techniques, according to dispatcher instructions; and in the secondary meta analysis, we included observational cohort studies of chest-compression-only CPR. All studies had to supply survival data. The primary outcome was survival to hospital discharge. A fixed-effects model was used for both meta-analyses because of an absence of heterogeneity among the studies (I(2)=0%). FINDINGS: In the primary meta-analysis, pooled data from three randomised trials showed that chest compression-only CPR was associated with improved chance of survival compared with standard CPR (14% [211/1500] vs 12% [178/1531]; risk ratio 1.22, 95% CI 1.01 1.46). The absolute increase in survival was 2.4% (95% CI 0.1-4.9), and the number needed to treat was 41 (95% CI 20-1250). In the secondary meta-analysis of seven observational cohort studies, no difference was recorded between the two CPR techniques (8% [223/2731] vs 8% [863/11 152]; risk ratio 0.96, 95% CI 0.83 1.11). INTERPRETATION: For adults with out-of-hospital cardiac arrest, instructions to bystanders from emergency medical services dispatch should focus on chest-compression-only CPR. FUNDING: US National Institutes of Health and American Heart Association. PMID- 20951423 TI - Dispatcher-assisted bystander CPR: a KISS for a kiss. PMID- 20951424 TI - Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. AB - BACKGROUND: Present interferon-based standard of care treatment for chronic hepatitis C virus (HCV) infection is limited by both efficacy and tolerability. We assessed the safety, tolerability, and antiviral activity of an all-oral combination treatment with two experimental anti-HCV drugs-RG7128, a nucleoside polymerase inhibitor; and danoprevir, an NS3/4A protease inhibitor-in patients with chronic HCV infection. METHODS: Patients from six centres in New Zealand and Australia who were chronically infected with HCV genotype 1 received up to 13 days oral combination treatment with RG7128 (500 mg or 1000 mg twice daily) and danoprevir (100 mg or 200 mg every 8 h or 600 mg or 900 mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or web response system to either active treatment or placebo. Patients were separately randomly assigned within each cohort with a block size that reflected the number of patients in the cohort and the ratio of treatment to placebo. The random allocation schedule was computer generated. Dose escalation was started in HCV treatment-naive patients; standard of care treatment-experienced patients, including previous null responders, were enrolled in higher-dose danoprevir cohorts. Investigators, personnel at the study centre, and patients were masked to treatment allocation. However, the pharmacist who prepared the doses, personnel involved in pharmacokinetic sample analyses, statisticians who prepared data summaries, and the clinical pharmacologists who reviewed the data before deciding to initiate dosing in the next cohort were not masked to treatment allocation. The primary outcome was change in HCV RNA concentration from baseline to day 14 in patients who received 13 days of combination treatment. All patients who completed treatment with the study drugs were included in the analyses. This study is registered with ClinicalTrials.gov, NCT00801255. FINDINGS: 88 patients were randomly assigned to a study drug treatment regimen (n=74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n=14, all of whom received at least one dose). The median change in HCV RNA concentration from baseline to day 14 ranged from -3.7 to -5.2 log(10) IU/mL in the cohorts that received 13 days of combination treatment. At the highest combination doses tested (1000 mg RG7128 and 900 mg danoprevir twice daily), the median change in HCV RNA concentration from baseline to day 14 was -5.1 log(10) IU/mL (IQR -5.6 to -4.7) in treatment-naive patients and -4.9 log(10) IU/mL in previous standard of care null responders (-5.2 to -4.5) compared with an increase of 0.1 log(10) IU/mL in the placebo group. The combination of RG7128 and danoprevir was well tolerated with no treatment-related serious or severe adverse events, no grade 3 or 4 changes in laboratory parameters, and no safety-related treatment discontinuations. INTERPRETATION: This oral combination of a nucleoside analogue polymerase inhibitor and protease inhibitor holds promise as an interferon-free treatment for chronic HCV. FUNDING: Roche Palo Alto. PMID- 20951425 TI - A serum-resistant polyamidoamine-based polypeptide dendrimer for gene transfection. AB - A serum tolerant polycation gene vector, G(2) PAMAM-PGlu-G(1) PAMAMs (ALA), was designed, synthesized, characterized and evaluated. A honeycomb-like molecular structure model for mechanistic explanation of ALA was postulated and discussed. Designed as a star-shaped polyamidoamine (PAMAM)-based polypeptide dendrimer through peptide bond linkages, ALA was with non-toxic low generation G(2) PAMAM (G(2)) as its central core, polyglutamate (PGlu)s as its star-shaped backbone branches and G(1) PAMAM (G(1))s as its branch grafts and peripheral terminals. IR, (1)H NMR demonstrated its successful combination. As a gene carrier, ALA exhibited good DNA binding and condensation capacity with particle size (approximately 87 nm for N/P 40, approximately 170 nm for N/P 30) and zeta potential (approximately 16 mV for N/P 30-40), negligible cytotoxicity, exciting serum tolerant capacity and significant serum-promoted (serum-containing 56.6%>serum-free 32.7%), cell line dependent (Hek 293 > Bel 7402 > Hela), incubation period dependent (38 h > 18 h > 12 h > 9 h > 4 h > 2 h > 1 h) and sustained (peak transfection appeared at 30 h incubation) transfection efficiency. The presence of serum had not only no inhibition on, but also prominent promotion to, the transfection activity of ALA. All above features differentiated ALA clearly from most other serum-inhibitive nonviral gene carriers, and proved ALA the promising and challenging potential efficient gene vector for practical clinical application. PMID- 20951426 TI - Evaluation of gel spun silk-based biomaterials in a murine model of bladder augmentation. AB - Currently, gastrointestinal segments are considered the gold standard for bladder reconstructive procedures. However, significant complications including chronic urinary tract infection, metabolic abnormalities, urinary stone formation, bowel dysfunction, and secondary malignancies are associated with this approach. Biomaterials derived from silk fibroin may represent a superior alternative due their robust mechanical properties, biodegradable features, and processing plasticity. In the present study, we evaluated the efficacy of a gel spun silk based matrix for bladder augmentation in a murine model. Over the course of 70 d implantation period, H&E and Masson's trichrome (MTS) analysis revealed that silk matrices were capable of supporting both urothelial and smooth muscle regeneration at the defect site. Prominent uroplakin and contractile protein expression (alpha-actin, calponin, and SM22alpha) was evident by immunohistochemical analysis demonstrating maturation of the reconstituted bladder wall compartments. Gel spun silk matrices also elicited a minimal acute inflammatory reaction following 70 d of bladder integration, in contrast to parallel assessments of small intestinal submucosa (SIS) and poly-glycolic acid (PGA) matrices which routinely promoted evidence of fibrosis and chronic inflammatory responses. Voided stain on paper analysis revealed that silk augmented animals displayed similar voiding patterns in comparison to non surgical controls by 42 d of implantation. In addition, cystometric evaluations of augmented bladders at 70 d post-op demonstrated that silk scaffolds supported significant increases in bladder capacity and voided volume while maintaining similar degrees of compliance relative to the control group. These results provide evidence for the utility of gel spun silk-based matrices for functional bladder tissue engineering applications. PMID- 20951427 TI - The allo-epi-endothelial lining of the intervillous space. AB - An unusual monolayer of cells lines the interface between the basal plate and the intervillous space in human term placenta but not the chorionic villi. Our recent descriptions of it are based on advanced microscopy, phenotyping and cytogenetic approaches. The papers show that the layer is partly epithelial (ectoderm) and partly endothelial (mesoderm): it is partly derived from the fetus and partly from the mother. This first accurate description of a naturally occurring human allo-epi-endothelium (monolayer of cells derived from two embryological germ layers and two individuals) is of interest in anatomy, obstetrics and gynaecology, developmental biology, histology and immunology. The most extensive evidence for this mosaic applies to the intervillous space lining layer of the basal plate where the endothelial proportion is of the order of 50%; it extends throughout central, intermediate and peripheral parts of the basal plate and is a consistent feature of the intervillous space lining of the chorionic plate also. Its presence lining chorionic plate is noteworthy as it includes the furthest parts of the sinus from the supplying and draining vessels which are endothelial lined. PMID- 20951428 TI - Placental effects of systemic tumour necrosis factor-alpha in an animal model of gestational diabetes mellitus. AB - BACKGROUND: Gestational diabetes mellitus (GDM) may adversely affect fetoplacental interaction. Numerous reports demonstrate that GDM women have increased circulating tumour necrosis factor-alpha (TNF), a pro-apoptotic peptide. OBJECTIVE: To examine whether implantation site apoptosis is increased by exogenous TNF in mice heterozygous for a defective leptin receptor (db/+), a GDM animal model. STUDY DESIGN: Implantation sites were studied at gestational day (gd)18.5 in 3 groups: saline-treated wild-type (wt) and db/+ mice, and TNF treated db/+ mice. Saline or TNF (total dose 4 MUg) was administered by miniosmotic pump from gd11.5. Immunostaining for cleaved caspase-3, PAS and cytokeratin was performed for quantification of apoptotic cells, uterine natural killer (uNK) cells, and trophoblast invasion, respectively. The mRNA expression of TNF and TNF-induced apoptotic markers in placenta and mesometrial triangle (MT) was measured by quantitative RT-PCR. RESULTS: The implantation sites from saline-treated wt and db/+ mice showed comparable numbers of apoptotic cells and uNK cells. Compared with the saline-treated groups, TNF-treated db/+ dams had less fetuses; the placental labyrinth and trophospongium contained more apoptotic cells; and the MT contained a higher total number of uNK cells including more cells intensely stained for cleaved caspase-3 as well as cells with negative staining. Trophoblast invasion was shallower in db/+ than in wt mice (14% and 30% of total invasion into MT, respectively) but this was not affected by TNF. The mRNA expression of TNF and apoptotic markers was comparable in the 3 groups. CONCLUSIONS: TNF treatment in db/+ mice raises the number of apoptotic cells in the placenta, and appears to increase the retention of uNK cells in the MT. Db/+ mice demonstrate shallower trophoblast invasion which is unaffected by exogenous TNF. PMID- 20951429 TI - Physiological changes in maternal cortisol do not alter expression of growth related genes in the ovine placenta. AB - OBJECTIVES: The aim of this study was to investigate the effect of cortisol on growth-related genes in the ovine placenta. STUDY DESIGN: Ewes carrying singleton pregnancies were operated on between 112 and 116 days of gestation (115 +/- 0.4, term = 147 days) and randomly assigned into three groups: six control animals, five ewes that were administered cortisol by continuous intravenous infusion (1 mg/kg/day, high cortisol), and five ewes that were adrenalectomized and replaced with 0.5-0.6 mg cortisol/kg/day and 3 MUg aldosterone/kg/day to produce cortisol concentrations equivalent to pre-pregnancy values (low cortisol). At necropsy (130 +/- 0.2 days of gestation), placental tissue was frozen and stored at -80 degrees C for mRNA analysis. MAIN OUTCOME MEASURES: To assess potential molecular mechanisms by which cortisol alters placental structure and function and fetal growth. RESULTS: Cortisol levels did not significantly affect 11beta hydroxysteroid dehydrogenase 1 and 2 enzymes, glucocorticoid receptor, mineralocorticoid receptor and angiotensin II receptor, type 1 (AT1R) expression levels. Gene expression levels of AT2R were increased in the high cortisol group for type B placentomes. There was little effect of cortisol on the insulin-like growth factor (IGF) axis. There was significantly more IGF-I mRNA in B versus A type and more IGFBP-2 mRNA in B and C type versus A type placentomes regardless of treatment (p < 0.05). CONCLUSIONS: These data suggest that cortisol increases placental AT2R expression at high concentrations whereas it has little effect on the placental IGF axis. PMID- 20951430 TI - Ubiquitin-proteasome system profiling in acute leukemias and its clinical relevance. AB - The ubiquitin-proteasome system (UPS) plays a major role in the homeostasis of cellular protein. We demonstrate that each of the major hematologic diseases (AML, ALL, and MDS) has a specific and different plasma profile of UPS protein and enzymatic activities. While high levels of proteasome and ubiquitin proteins and enzymatic activities are detected in the plasma samples from patients, normalizing enzymatic activities, show that each proteasome has lower enzymatic activities in these diseases as compared with normal controls. Proteasome protein levels in AML are strong predictor of survival independently of cytogenetics, performance status and age. The Ch-L activity when normalized to the level of proteasome protein show significant negative correlation with survival in ALL. PMID- 20951431 TI - The influence of soil properties on the toxicity of molybdenum to three species of soil invertebrates. AB - Mo toxicity to earthworms (Eisenia andrei), Collembola (Folsomia candida) and enchytraeids (Enchytraeus crypticus) was determined in 10 European soils and a standard artificial soil, freshly spiked with Na(2)MoO(4), after 28 days exposure. Mo affected survival only in three low pH sandy soils; in all other soils LC50 was >3200 mg Mo/kg dry soil. EC50 values for the reproduction toxicity of Mo were 129-2378 mg/kg for earthworms, 72->3396 mg/kg for Collembola, and 301 >2820 mg/kg for enchytraeids. Variation in toxicity among soils could not be explained by differences in available (pore water, water and 0.01 M CaCl(2) extractable) Mo concentrations. Clay content best predicted the EC50 for Mo toxicity to earthworms, while toxicity of Mo for enchytraeids was best described by soil pH. For Collembola no relationships could be derived due to the absence of toxicity in most soils. Soil properties had a strong but species-specific effect on Mo toxicity to soil invertebrates. PMID- 20951432 TI - Optimization of cow dung spiked pre-consumer processing vegetable waste for vermicomposting using Eisenia fetida. AB - This paper reports the optimization of cow dung (CD) spiked pre-consumer processing vegetable waste (PPVW) for vermicomposting using Eisenia fetida in a laboratory scale study. Vermicomposting process decreased carbon and organic matter concentration and increased N, P and K content in the vermicompost. The C:N ratio was decreased by 45-69% in different vermireactors indicating stabilization of the waste. The heavy metal content was within permissible limits of their application in agricultural soils. It has been concluded from the results that addition of PPVW up to 40% with CD can produce a good quality vermicompost. Whereas, growth and fecundity of E. fetida was best when reared in 20% PPVW+80% CD feed mixture. However, higher percentages of PPVW in different vermireactors significantly affected the growth and fecundity of worms. PMID- 20951433 TI - Mercury and lead: assessing the toxic effects on growth and metal accumulation by Lemna minor. AB - Lemna minor L. was used to investigate the toxic effects of Pb and Hg either alone or in various binary mixtures under the static test conditions. A full strength Jacob culture medium was used for the long-term cultivation of duckweeds and the experiments. Tests were run for 4 and 7 days. The EC(50) values for Pb was estimated as 6.8 +/- 0.2 mg L(-1) and 5.5 +/- 0.1 mg L(-1) for a 4 and a 7 day test periods, respectively. Hg was much more toxic than Pb with the EC(50) of 0.64 +/- 0.03 mg L(-1) (4 days) and 0.48 +/- 0.02 mg L(-1) (7 days). The amounts of Pb uptake by the plants were determined by atomic absorption spectrometer (AAS). The cold vapor AAS-technique (CV-AAS) was used for Hg determination. The interactive effect between Pb and Hg on growth was evaluated as additive on the basis of statistical data analysis. However, an antagonistic interaction was observed on the metal accumulation efficiency. PMID- 20951434 TI - Constrained confidence intervals in time series studies of mortality and air pollution. AB - This paper focuses on constrained confidence intervals in the context of environmental time series studies where one seeks to ascertain the effects of ambient air pollution on human mortality. If the regression parameter representing such effects is non-negative, corresponding to a belief that more pollution cannot be beneficial, a desirable goal is to produce a constrained confidence interval for the parameter which is entirely non-negative. We show how this goal can be achieved using the method of tail functions. The proposed methodology is illustrated by the application to an environmental study of 100 cities in the United States involving regressions of mortality counts on levels of particulate matter air pollution. The large number of constrained CIs that contain zero is an indication that for the majority of the 100 cities there is not enough evidence to conclude a positive association between air pollution and mortality. PMID- 20951435 TI - High concentrations of polybrominated diphenylethers (PBDEs) in breast adipose tissue of California women. AB - We measured major PBDEs and PCBs in breast adipose tissues of California women participating in a breast cancer study in the late 1990s. Samples were analyzed using gas chromatography with electron impact ionization and tandem mass spectrometry detection. The congener profile observed was: BDE47>BDE99>BDE153>BDE100>BDE154 and PCB153>PCB180>PCB138>PCB118. Whereas high correlations were observed within each chemical class, very weak correlations appeared between classes, pointing to different exposure pathways. Weak negative associations were observed for PBDE congeners and age. Our PBDE data are among the highest reported, exceeding data from the National Health and Nutrition Examination Survey and consistent with the high use of PBDEs in California. These data may be helpful in establishing a baseline for PBDE body burdens to gauge changes over time as a result of restrictions in the use of PBDE formulations. PMID- 20951436 TI - The role of perceptual and cognitive processes in addition-subtraction studies with 5-month-old infants. AB - After a brief familiarization period to either one or two toys 5-month-olds gave a clear preference for perceptually novel displays, suggesting that replicable findings of greater looking at an unexpected arithmetic outcome in addition/subtraction experiments cannot easily be attributed to simple familiarity preferences. PMID- 20951437 TI - Specifying the role of function in infant categorization. AB - Research demonstrates that object functions facilitate artifact categorization in infancy. To explicate the nature and magnitude of this effect, 16-month-olds participated in three studies. In Experiment 1, categorization was facilitated more by object functions than by distinctive motions, suggesting that the motion properties of function cannot fully explain its influence. In Experiment 2, infants failed to categorize when each category exemplar performed a different function, thus revealing the importance of shared functionality in facilitating categorization. In Experiment 3, infants were tested after each new exemplar was introduced. When object functions were provided during training, infants were more likely to appropriately extend the novel categories on the very first trial. This suggests that function reduces the need for exposure to multiple exemplars in forming categories. Together, these findings confirm the conceptual nature of the facilitative effect of function on early categorization. PMID- 20951438 TI - Cross-sectional and longitudinal relations between affective instability and depression. AB - BACKGROUND: There is a growing recognition that emotional traits are important for understanding many mental health disorders, including major depressive disorder (MDD). The present research examined (a) the relation between MDD and the emotional trait of affective instability, and (b) whether individual facets of affective instability, affect intensity and affect variability, exhibited unique relations with anhedonic depression. METHODS: In Study 1, affective instability and MDD were both assessed via clinical interviews in an adult community sample (n=288). In Studies 2 and 3, the relations between anhedonic depression and affect variability and affect intensity were assessed cross sectionally using self-report measures in a college student sample (n=142; Study 2) and a female community sample (n=101; Study 3). Study 3 also prospectively examined whether affect variability and/or intensity predicted changes in anhedonic depression over two months. RESULTS: In Study 1, affective instability and MDD were significantly associated, even after excluding individuals experiencing a current major depressive episode. In Studies 2 and 3, affect variability but not affect intensity was significantly, positively associated with anhedonic depression. In Study 3, affect variability but not affect intensity prospectively predicted increases in anhedonic depression. LIMITATIONS: Future studies should assess the entire Bipolar Disorder spectrum and utilize event sampling, permitting the examination of other facets of affective instability (e.g., temporal dependency) and address other limitations of retrospective measures (e.g., recall bias). CONCLUSIONS: These findings suggest that affective instability and particularly affect variability are associated with MDD and anhedonic depression. The tendency to experience frequent fluctuations in mood may constitute an important risk factor for depression. PMID- 20951439 TI - Characterisation of plasma acute phase protein concentrations in a high health boar herd. AB - Acute phase proteins (APP) are used as markers of inflammation and sub-clinical disease and are considered potential biomarkers for pig health and welfare. However, reference ranges for their baseline concentrations are necessary before their use can be considered in routine herd health. In this study, C-reactive protein (CRP), haptoglobin (Hp), pig-major acute-phase protein (Pig-MAP) and transthyretin (TTR) baseline concentrations were determined in boars from a high health commercial herd and differences between seven commercial breeding lines within the herd were investigated. Reference ranges of 3.6-183 mg/L for CRP, 0.01 1.31 g/L for Hp, 0.32-2.9 g/L for Pig-MAP and 174-610 mg/L for TTR were found. Correlations were determined between Hp and CRP, Hp and Pig-MAP and CRP and Pig MAP. Additionally, significant differences were found among the concentrations of CRP, Pig-MAP and TTR in seven commercial breeding lines. PMID- 20951440 TI - Establishment of a quantitative ELISA for the measurement of allergen-specific IgE in dogs using anti-IgE antibody cross-reactive to mouse and dog IgE. AB - As IgE plays a pivotal role in type I hypersensitivity-mediated allergic diseases, it is valuable to measure absolute quantity of serum antigen-specific IgE for clinical and research purposes. Here we describe a novel ELISA system that enables quantification of antigen-specific IgE in ng/ml in dogs. A newly developed monoclonal antibody (CRE-DM) was shown to recognize canine and mouse IgE equally in a dose dependent manner, but it did not recognize canine IgG. The reactivity of CRE-DM to canine IgE was also confirmed by an inhibition ELISA using canine IgE as an inhibitor and the maximum inhibition rate was 91.3%. In order to know whether canine IgE specific to an allergen could be quantitatively measured with an ELISA using CRE-DM, we established a quantitative ELISA that could measure canine IgE recognizing Cry j 1, one of the major allergens of Japanese cedar pollen. In this ELISA, a standard curve was created by using concentration-predetermined Cry j 1-specific monoclonal mouse IgE. According to the standard curve, the concentration of Cry j 1-specific IgE in dogs that were experimentally sensitized to Japanese cedar pollen could be calculated and determined in ng/ml. The specificity of the Cry j 1-specific IgE ELISA using CRE DM was also confirmed by inhibition ELISA using canine IgE as an inhibitor and the inhibition rate was 97.0%. Reproducibility of the ELISA in three independent assays was determined using groups of pooled canine sera whose Cry j 1-IgE titers ranged from 155.9 to 888.2 ng/ml. Intra- and inter-assay reproducibility was determined with coefficient of variation ranging between 3.1-5.2% and 2.2-8.0%, respectively. These results demonstrated that the ELISA utilizing CRE-DM was a specific, reliable and robust new laboratory test that could quantify absolute amount of antigen-specific IgE in canine serum. The ELISA will serve as a useful tool in the clinics to evaluate the change of serum IgE titers during anti allergic treatments as well as during seasonal fluctuation of allergen exposure. PMID- 20951441 TI - Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis. AB - Anti-NMDA-receptor encephalitis is a severe, treatable and potentially reversible disorder presenting with memory deficits, psychiatric symptoms and seizures. Initially described in young patients with ovarian teratoma, the disease is meanwhile increasingly recognized also in women without tumours, in men and in children. The presence of anti-glutamate receptor (type NMDA) autoantibodies in serum or cerebrospinal fluid is specific for this novel and widely underdiagnosed disorder. Early recognition is crucial since prognosis largely depends on adequate immunotherapy and, in paraneoplastic cases, complete tumour removal. Indirect immunofluorescence using NMDA-type glutamate receptors recombinantly expressed in human cells is a highly competent method for diagnosing anti-NMDA receptor encephalitis. PMID- 20951442 TI - Atypical locations of retropharyngeal abscess: beware of the normal lateral soft tissue neck X-ray. AB - Retropharyngeal abscesses (RPA) are uncommon but potentially lethal deep neck space infections, over 95% of which occur in children under six years of age. Without a high index of suspicion, early recognition and prompt intervention, catastrophic consequences can ensue, and mortality can be as high as 60% if jugular vein thrombosis or mediastinitis occurs. While older children may have specific complaints referable to the pharynx, infants and young children may present with vague symptoms. To date, a lot of emphasis continues to be placed on the importance of lateral soft tissue neck X-ray in the diagnosis and management of patients with suspected retropharyngeal abscesses; and lateral neck X-ray has been cited as the most useful radiological view of the laryngopharynx. While we recognise the role of lateral neck X-rays in retropharyngeal and other upper airway pathologies, we present three case series in which lateral neck X-rays were normal and diagnosis was made only after CT scanning. These three cases were unusual as the abscesses were located high in the naso-pharynx making them impossible to detect on the lateral soft tissue neck X-rays and this underscores the need for high index of suspicion and prompt CT or MRI scanning, in any child with symptoms or signs suggestive of a possible retropharyngeal abscess. PMID- 20951443 TI - Efficacy of manual jet ventilation using Manujet III for bronchoscopic airway foreign body removal in children. AB - OBJECTIVES: To evaluate the efficacy of a manual jet ventilation device for bronchoscopic removal of foreign bodies in children. METHODS: 360 children aged from 10 months to 12 years old undergoing rigid bronchoscopy for airway foreign body (FB) removal from February 2005 to June 2009 were included in the study. Patients were randomly divided into three groups of 120 patients per group (S, P and J). In group S, anesthesia was induced with propofol and gamma hydroxybutyrate sodium and maintained by intermittent bolus administration of propofol; the patients were breathing spontaneously throughout the procedure. In group P, anesthesia was induced with propofol (4-5 mg/kg), fentanyl (1-2 MUg/kg) and succinylcholine (2 mg/kg). Mechanical ventilation was performed through the side arm of the rigid bronchoscope. In group J, the patient received propofol, fentanyl and succinylcholine as the same doses administered in group P, and manual jet ventilation was performed by using the Manujet III device. Condition for insertion of bronchoscope, occurrence of hypoxemia, successful rate of FB removal, the duration of the operation, the time of emergence and recovery from anesthesia, and perioperative complications (adverse events) were recorded. RESULTS: Groups P and J had significantly higher rates of successful bronchoscope insertion (P<0.05), significantly higher success rates for FB removal (P<0.05), and lower incidences of hypoxemia during intra- and post-operative periods when compared with group S. Perioperative complications were lower (P<0.05), duration of operation was shorter, and emergence from anesthesia was faster (P<0.05) in groups P and J when compared with group S. Incidences of hypoxemia were lower in Group J when compared with Group P (P<0.05). CONCLUSION: This study confirmed the safety and efficacy of performing manual jet ventilation with Manujet III in foreign body removal by rigid bronchoscopy in children. PMID- 20951444 TI - Differences in leisure activities between children with allergic rhinitis and healthy peers. AB - OBJECTIVE: The symptoms of allergic rhinitis (AR) are frequently evoked when individuals with AR perform daily activities. Thus, AR may interfere the optimal participation in daily life, negatively impact the patient's productivity and quality of life (QOL). While most studies refer to adult with AR, this pilot study examined participation of children with AR as expressed in their daily activity preferences. METHODS: Participants were 31 children with AR and 31 healthy children, aged 5-11 years. All children completed the Preference for Activities of Children (PAC). RESULTS: Children with AR showed significantly lower preference to participate in skill-based, social and informal activities, as compared to their healthy peers (F(7,53)=2.61, p=0.02, ES-eta(2)=0.27). Children with AR showed 5-20% lower preference to participate in activity than their typical peers. CONCLUSIONS: AR may negatively impact children's preference to participate in daily activities. Treatment of children with AR should consider a multi-disciplinary intervention for encouraging their optimal development, improve their well-being and QOL. PMID- 20951445 TI - Utility of routine postoperative chest radiography in pediatric tracheostomy. AB - OBJECTIVES: Routine chest radiography following pediatric tracheostomy is commonly performed in order to evaluate for air-tracking complications. Routine chest radiography affords disadvantages of radiation exposure and cost. The primary objective of this study was to determine the utility of routine postoperative chest radiography following tracheostomy in pediatric patients. Secondary objectives were to compare the rates of postoperative complications by various patient and surgeon characteristics. METHODS: All infants and children 18 years of age or less (n=421) who underwent tracheostomy at a single tertiary-care medical center from January 2000 to April 2009 were included in the study. A combination of data obtained from billing and administrative systems and review of electronic medical records were recorded and compiled in a database for statistical analysis. RESULTS: Three air-tracking complications (2 pneumothoraces and 1 pneumomediastinum) were identified in our population of 421 pediatric patients, for an incidence of 0.71% (95% CI: 0.1-2.0%). No significant relationships were found between the incidence of air-tracking complication and surgical specialty, patient age, or type of procedure (elective, urgent/emergent). CONCLUSIONS: Our study identified a low rate of pneumothorax and pneumomediastinum following pediatric tracheostomy. In all three cases, the pneumothorax was suspected clinically. This finding suggests that postoperative chest radiography should be reserved for cases where there is suspicion of a complication on the basis of intraoperative findings or clinical parameters. PMID- 20951446 TI - Research into the therapeutic roles of two-pore-domain potassium channels. AB - The K(2P) potassium channels are responsible for the background conductance observed in several tissues. Their ubiquitous localization and thus their potential implications in diseases have led to increased research on these channels over the last few years. In this review, we outline different aspects of the research on K(2P) channels and highlight some of the latest discoveries in this area. We focus on research into K(2P) channels as potential therapeutic targets in ischemia/hypoxia, depression, memory disorders, pain, cardiovascular disease and disorders of the immune system. We address the challenge of developing novel pharmacological compounds to target these channels. We also discuss the regulation of expression of the K(2P) gene in health and disease, as well as the value of assessing the expression of K(2P) channels as potential biomarkers of disease. PMID- 20951447 TI - Changing expectations: Do journals drive methodological changes? Should they? AB - "Yes" to both questions. I believe that journals can, should, and do drive methodological changes. However, it is not a unilateral responsibility; authors and teachers also must be drivers of improvements. There are multiple ways that journals drive change: Journals promote new concepts and methods in study design and data analysis by publishing them-giving the new methodologies voice and credibility after peer review. Journals further promote new methodologies by asking authors to adhere to the newest appropriate best methods (relying heavily on advice from reviewers). Journals enforce methodological quality standards through their review processes and by asking authors to adhere to recognized, published guidelines for the information that should be included in manuscripts. I summarized what I consider to be the key features of 15 of the statements of guidelines. Now that good guidelines (e.g., CONSORT, STROBE, STARD, PRISMA, REFLECT-LFS) are available on so many topics, I recommend that we require these as minimum reporting standards so that the information content of papers is forced to be high. The guidelines should make is easier for reviewers and editors to make sure nothing was overlooked in the review process, and make it easier for authors to see the minimum standards and their justifications. It should be a positively reinforcing system. Authors develop these new concepts and methods, use the guidelines, and cooperate in good faith with the journals to which their manuscripts are submitted. Some authors also become reviewers and further contribute to the process. Good teachers offer the next academic generations both the best current concepts and practices and the understanding that improvements will come along and must be considered for adoption. I made six recommendations regarding reporting guidelines. PMID- 20951448 TI - Reporting guidelines for primary research: Saying what you did. AB - Reporting guidelines aim to facilitate publication of a full and accurate description of research conducted. The motivations for a full and accurate description of research is to enable reproduction of the study, assessment of bias, extraction of data from the study, and to fulfill an ethical obligation to maximize the utility of research findings. Many reporting guidelines exist and most are based on a specific study design such as randomized controlled trials (CONSORT statement) and observational studies (STROBE statement). The REFLECT statement focuses on randomized control trials in livestock and food safety studies. The REFLECT statement has increased emphasis on conveying information about animal housing, group level allocation and challenge studies. Guidelines can be used by authors, reviewers and editors to provide readers with a full and accurate description of the work conducted. PMID- 20951449 TI - Voice after radiotherapy of the larynx carcinoma. AB - BACKGROUND: The study presents the evaluation of the phonatory function of the larynx after radiotherapy. The research covered the patients from the rural areas of Poland who revealed neoplastic changes in the glottis area. MATERIAL AND METHODS: The test group consisted of 45 men aged 41-78 years with the carcinoma of the larynx with T1 and T2 progression types of cancer, according to the TNM classification. The analysis of laryngeal tone was performed with the digital analyzer Kay Elemetrics Model CSL 4300 and Multi Dimensional Voice Program (MDVP). A stroboscopic test in all the patients with T1 progression revealed the reduction of vibrations. RESULTS: The acoustic analysis of the voice in the pre treatment group as compared with the control group allowed for differentiation of the following parameters of a definitely pathologic character: Jita, Jitter, RAP, PPQ, vFo, Shimmer, APQ, vAm, NHR, VTI, SPI, and DUV. CONCLUSIONS: In the acoustic analysis of voice in the post-radiotherapy group, the following parameters reached values close to the norm: JITA, JITT, RAP, PPQ, vF0, vAM, DUV, and Schimmer dB. PMID- 20951450 TI - Analysis of second malignancies after modern radiotherapy versus prostatectomy for localized prostate cancer. AB - PURPOSE: To clarify the risk of developing second primary cancers (SPCs) after radiotherapy (RT) versus prostatectomy for localized prostate cancer (PCa) in the modern era. METHODS: The RT cohort consisted of 2120 patients matched on a 1:1 basis with surgical patients according to age and follow-up time. RT techniques consisted of conventional or two-dimensional RT (2DRT, 36%), three-dimensional conformal RT and/or intensity modulated RT (3DCRT/IMRT, 29%), brachytherapy (BT, 16%), and a combination of 2DRT and BT (BT boost, 19%). RESULTS: The overall SPC risk was not significantly different between the matched-pair (HR 1.14, 95% CI 0.94-1.39), but the risk became significant >5years or >10years after RT (HR 1.86, 95% CI 1.36-2.55; HR 4.94, 95% CI 2.18-11.2, respectively). The most significant sites of increased risk were bladder, lymphoproliferative, and sarcoma. Of the different RT techniques, only 2DRT was associated with a significantly higher risk (HR 1.76, 95% CI 1.32-2.35), but not BT boost (HR 0.83, 95% CI 0.50-1.38), 3DCRT/IMRT (HR 0.81, 95% CI 0.55-1.21), or BT (HR 0.53, 95% CI 0.28-1.01). CONCLUSIONS: Radiation-related SPC risk varies depending on the RT technique and may be reduced by using BT, BT boost, or 3DCRT/IMRT. PMID- 20951451 TI - Use of lymphoscintigraphy in radiation treatment of primary breast cancer in the context of lymphedema risk reduction. AB - PURPOSE: The goal of this study was to determine the feasibility of SPECT/CT scintigraphic method for mapping lymphatic drainage for radiation therapy of breast cancer. MATERIALS AND METHODS: Thirty-six patients were enrolled in a SPECT/CT lymphoscintigraphy study. (99m)Tc sulfur colloid (1mCi) was injected intradermally in the ipsilateral arm. After 5-8h post-injection, the SPECT/CT scans were taken and analyzed on a GE eNTRGRA system. The SPECT/CT images were co registered in the treatment planning system (TPS). The original treatment plan was recreated for nodal dosimetry. Intensity modulated radiation therapy (IMRT) planning was performed for reducing lymph node dose for reducing arm lymphedema. RESULTS: The number of lymph nodes varied from 0 to 10 with a mean value of 3.4+/ 5.4 nodes. The location of nodes varied in the axillary, supraclavicular, and breast regions depending upon the surgical procedure and the extent of the disease. The prescribed radiation dose to the breast varied from 45 to 50.4Gy depending on the disease pattern in 32 evaluated patients having CT data. The dose to lymph nodes varied from 0 to 61.8Gy depending upon the location and the radiation technique used. SPECT/CT study in conjunction with IMRT plan showed that it is possible to decrease nodal dose and thereby potentially reduce the risk of developing arm lymphedema. CONCLUSIONS: The SPECT/CT device provides a novel method to map the lymph nodes in the radiation treatment fields that could be used to tailor the radiation dose. PMID- 20951452 TI - Malignant mucosal melanoma treated with carbon ion radiotherapy with concurrent chemotherapy: prognostic value of pretreatment apparent diffusion coefficient (ADC). AB - BACKGROUND AND PURPOSE: To evaluate the potential of apparent diffusion coefficient (ADC) value before carbon ion radiotherapy (C-ion RT) for malignant mucosal melanoma (MMM) to predict prognosis. MATERIALS AND METHODS: We recruited 37 patients with MMM in the head and neck treated by C-ion RT with concomitant chemotherapy. Univariate and multivariate analyses of minimum ADC, mean ADC, tumor volume, age, PS, and gender were performed to identify prognostic factors. RESULTS: The 3-year local control rate, distant metastasis-free survival rate and overall survival rate of all patients were 81.1%, 37.6% and 65.3%, respectively, with a median follow-up period of 19.0 months. In univariate analyses, lower minimum ADC (<=0.6380 * 10(-3) mm(2)/s) and lower mean ADC (<=1.1523 * 10(-3) mm(2)/s) were unfavorable prognostic factors for distant metastasis (p=0.029 and p=0.014, respectively), and lower minimum ADC was an unfavorable prognostic factor for overall survival (p=0.019). However, there was no significant prognostic factor of local control including ADC value. In multivariate analyses, only minimum ADC was selected as a prognostic factor of distant metastasis-free survival and overall survival (p=0.015 and p=0.006, respectively). CONCLUSION: Minimum ADC can be a prognostic factor of MMM in the head and neck after C-ion RT. PMID- 20951453 TI - Cardiopulmonary morbidity and quality of life in non-small cell lung cancer patients treated with or without postoperative radiotherapy. AB - AIM: To prospectively assess the cardiopulmonary morbidity and quality of life in patients with non-small cell lung cancer (NSCLC) treated with postoperative radiotherapy (PORT) in comparison to those not receiving PORT. MATERIALS AND METHODS: From 2003 to 2007, 291 patients entered the study; 171 pN2 patients received 3D-planned PORT (PORT group), 120 pN1 patients (non-PORT group) did not. One month after surgery, all patients completed EORTC QLQ C-30 questionnaire and had pulmonary function tests (PFT); cardiopulmonary symptoms were assessed by modified LENT-SOM scale. Two years later, disease-free patients repeated the same examinations. The differences between baseline values and values recorded at two years in QLQ, LENT-SOM and the PFT of the two groups were compared. RESULTS: In the whole cohort, the rate of non-cancer related deaths was 5.3% and 5.0% in PORT and non-PORT group, respectively. Ninety-five patients (47 - PORT group, 48 - non PORT group) were included into the final analysis. The differences in the QLQ and cardiopulmonary function (LENT/SOM, PFT) between both groups were insignificant. The forced expiratory volume in one second was on average 12.2% and 1.3% better in the PORT and the non-PORT group, respectively, p=0.2. CONCLUSIONS: Our findings support the hypothesis about insignificant morbidity of 3D-planned PORT. PMID- 20951454 TI - In vitro screening of probiotics and synbiotics according to anti-inflammatory and anti-proliferative effects. AB - There is emerging evidence of the efficiency of probiotic, prebiotic and synbiotic treatments in inflammatory bowel diseases (IBDs) and one of their long term complications, colorectal cancer (CRC). In this study, various strains of probiotic lactic acid bacteria, prebiotic glucooligosaccharides (GOS) or a synbiotic combination of the two were screened for anti-inflammatory and anti proliferative effects in different in vitro models in the context of such diseases. To mimic IBD response to Gram negative bacteria, HT-29 cells were sensitised to inflammatory response to lipopolysaccharide (LPS) by IFNgamma which increased expression of TLR4, the LPS biosensor, and were then treated by probiotics, prebiotics and synbiotics. Secreted IL-8 and activated NF-kappaB were monitored as inflammation biomarkers. A selection of active strains were then subjected to a second inflammatory cell culture model consisting of inflammatory activated transgenic Caco-2 cells transfected by a reporter gene under the control of NF-kappaB inducible promoter. Quantification of reporter gene expression allowed us to demonstrate some probiotic inhibitory properties or to confirm such characteristics in two different models. Proliferation of cancerous HT-29 cells was monitored by XTT assay. Only three probiotic strains induced a proliferation decrease, but with a lack of reproducibility. Binary or ternary probiotic associations, complemented or not by prebiotic GOS, significantly decreased proliferation, especially with a synbiotic association of Bifidobacterium breve, Lactococcus lactis and oligoalternan, a GOS. This combination was selected for the following experiments. We showed the involvement of both bacterial and carbohydrate compounds of this synbiotic in the observed effect by dose range tests. We demonstrated that this decrease in proliferation may be due to an induction of a differentiated phenotype, as shown by the up regulation of intestinal alkaline phosphatase, a biomarker of differentiation, monitored by real-time RT-PCR in HT-29 cells treated by the selected synbiotics. Thus, this study demonstrates the ability of probiotics to exert anti inflammatory effects and shows some anti-proliferative characteristics for a specific synbiotics. These products should be further evaluated in animal models to confirm the in vitro results. PMID- 20951455 TI - Antimicrobial properties of chitosan and mode of action: a state of the art review. AB - Owing to its high biodegradability, and nontoxicity and antimicrobial properties, chitosan is widely-used as an antimicrobial agent either alone or blended with other natural polymers. To broaden chitosan's antimicrobial applicability, comprehensive knowledge of its activity is necessary. The paper reviews the current trend of investigation on antimicrobial activities of chitosan and its mode of action. Chitosan-mediated inhibition is affected by several factors can be classified into four types as intrinsic, environmental, microorganism and physical state, according to their respective roles. In this review, different physical states are comparatively discussed. Mode of antimicrobial action is discussed in parts of the active compound (chitosan) and the target (microorganisms) collectively and independently in same complex. Finally, the general antimicrobial applications of chitosan and perspectives about future studies in this field are considered. PMID- 20951456 TI - A proteomic approach to cold acclimation of Staphylococcus aureus CECT 976 grown at room and human body temperatures. AB - Staphylococcus aureus is an important pathogenic microorganism that has been associated with serious infection problems in different fields, from food to clinic. In the present study, we have taken into account that the main reservoirs of this microorganism are the human body and some parts of food processing plants, which have normal temperatures of around 37 and 25 degrees C, respectively. It can be expected that S. aureus must acclimate its metabolism to colder temperatures before growing in food matrices. Since temperature abuse for foods occurs at approximately 12 degrees C, it is expected that S. aureus must acclimate its metabolism to colder temperatures before growing in food. For this reason, we have performed a proteomic comparison between exponential- and stationary-phase cultures of S. aureus CECT 976 acclimated to 12 degrees C after growing at 25 degrees C or 37 degrees C. The analysis led to the identification of two different protein patterns associated with cold acclimation, denominated pattern A and pattern B. The first was characteristic of cultures at stationary phase of growth, grown at 25 degrees C and acclimated to 12 degrees C. The second appeared in the rest of experimental cases. Pattern A was distinguished by the presence of glycolytic proteins, whereas pattern B was differentiated by the presence of general stress and regulatory proteins. Pattern A was related through physiological experiments with a cross-resistance to acid pH, whereas pattern B conferred resistance to nisin. This prompted us to conclude that both molecular strategies could be valid, in vivo, for the process of acclimation of S. aureus to cold temperatures. PMID- 20951457 TI - Modelling Salmonella concentration throughout the pork supply chain by considering growth and survival in fluctuating conditions of temperature, pH and a(w). AB - We aim to predict the population density of Salmonella spp. through the pork supply chain under dynamic environmental conditions (pH, a(w) and temperature) that fluctuate from growth to survival/slow inactivation. To do this, the dependence of the probability of growth, and of the growth and inactivation rate on the temperature, pH and a(w) were modelled. Probabilistic and kinetic measurements, i.e. growth and survival curves, were collected from the ComBase database (www.combase.cc). Conditions at which selected data used to fit the models were generated covered wide ranges that are relevant to the pork supply chain. Probabilistic and kinetic models were combined to give predictions on the concentration of Salmonella spp. at any stage of the pork supply chain under fluctuating pH, a(w) and/or temperature. Models were implemented in a user friendly computing tool freely available from http://www.ifr.ac.uk/safety/SalmonellaPredictions/. This program provides estimates on the population dynamics of Salmonella spp. at any stage of the pork supply chain and its predictive performance has been validated in several pork products. PMID- 20951458 TI - Study of adherence comes to the treatment of chronic hepatitis B. PMID- 20951459 TI - Microarchitecture of the liver: a jigsaw puzzle. PMID- 20951460 TI - Distance and socioeconomic status as a health service predictor on the periphery in the southern region of Israel. AB - This research focuses on the accessibility of health-services to the population in the southern region of Israel, comparing accessibility within the periphery. The objective was to study whether there is a correlation between the number of patient visits to specialist-clinics to the geographical distance from the patient's home and the patient's socioeconomic-status. The population of the study was patients insured by the Clalit HMO, the major health-provider on the periphery in Israel's southern region who visited the Soroka University Medical Center's (SUMC) out-patient specialist-clinics between 2000 and 2005. The specialist-clinics in the study were divided into five categories: (1) pediatrics (2) orthopedics (3) audio lab (4) sleep lab; (5) geriatrics. The dependent variable-the number of patients' visits to clinics was analyzed (parametric and non-parametric) according to a set of independent variables: (1) population size, (2) age-distribution (3) gender (4) size of family, (5) vehicles per household, (6) socioeconomic level (by percentiles) (7) distance from the Beer-Sheva (site of the SUMC clinics) in terms of concentric geographical rings (distance and time travel). Results show that the distance from Beer-Sheva and the socioeconomic level of patients' town (by percentiles) has a negative correlation to the number of visits. That is, patients who live further away or are from higher socio economical percentiles, frequent specialist-clinics less. In order to be effective (equality of availability and accessibility), a health system in the periphery must build programs that take into consideration the needs of specific localities, such as distance to the health services, and the patient's socioeconomic level. PMID- 20951461 TI - Estimating drowning deaths in Northern Iran using capture-recapture method. AB - BACKGROUND: Descriptive epidemiological study has shown that drowning is a problem health in low and middle income countries. To analyze records of drowning deaths from two injury registry systems, to ascertain a true estimate of drowning mortality, it can help to follow up drowning prevention policy. METHODS: This study uses capture-recapture methods to arrive at a more accurate estimate of the number of drowning events occurring over a one-year period in Guilan and Mazandran Provinces, in northern Iran. Records from the Iran's Forensic Medical System and Death Registry System were compared, using five matching approaches based on various combinations of the following variables: gender, place of drowning, date of death, victim age, name, region of residence, and/or place of residence. RESULTS: The results revealed that the estimated number of drowning cases in the study population is much higher than official figures, ranging from 5.26 to 8.25 per 100,000 residents compared to the national figure of 4.5 per 100,000. The completeness of Death Registry System records for drowning was 70% of corrected estimates while the completeness of records from Forensic Medicine was 54.4%. CONCLUSION: We conclude that the use of capture-recapture methodology may provide better accuracy in measuring drowning events. This method may also help reduce bias in the estimate of incidence rates and comparison of different populations. PMID- 20951462 TI - Critical reasoning on causal inference in genome-wide linkage and association studies. AB - Genome-wide linkage and association studies of tens of thousands of clinical and molecular traits are currently underway, offering rich data for inferring causality between traits and genetic variation. However, the inference process is based on discovering subtle patterns in the correlation between traits and is therefore challenging and could create a flood of untrustworthy causal inferences. Here we introduce the concerns and show that they are already valid in simple scenarios of two traits linked to or associated with the same genomic region. We argue that more comprehensive analysis and Bayesian reasoning are needed and that these can overcome some of the pitfalls, although not in every conceivable case. We conclude that causal inference methods can still be of use in the iterative process of mathematical modeling and biological validation. PMID- 20951463 TI - GPU-accelerated elastic 3D image registration for intra-surgical applications. AB - Local motion within intra-patient biomedical images can be compensated by using elastic image registration. The application of B-spline based elastic registration during interventional treatment is seriously hampered by its considerable computation time. The graphics processing unit (GPU) can be used to accelerate the calculation of such elastic registrations by using its parallel processing power, and by employing the hardwired tri-linear interpolation capabilities in order to efficiently perform the cubic B-spline evaluation. In this article it is shown that the similarity measure and its derivatives also can be calculated on the GPU, using a two pass approach. On average a speedup factor 50 compared to a straight-forward CPU implementation was reached. PMID- 20951465 TI - Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. AB - Management of patients with lung cancer continues to pose a considerable challenge to today's oncologist. While treatment may be curative in the early stages of the disease, the majority of patients are not diagnosed until the tumor has progressed beyond the primary site. Most patients face an intensive and invasive treatment regimen comprising surgery, radiotherapy, or chemotherapy, or combinations thereof depending on disease stage/performance status. Most will require chemotherapy even if their initial surgery is potentially curative; for those with advanced disease, chemotherapy may be their only treatment option. Moreover, the majority of patients will require multiple lines of therapy as their cancer cells acquire resistance to the chemotherapeutic agents to which they are exposed. Resistance to current chemotherapeutics available for the management of non-small cell lung cancer (NSCLC) represents one of the most significant barriers to improving long-term outcomes for this vulnerable patient group. Future management may lie in individualizing therapy through careful selection of appropriate agents based on the likelihood of response and the development of resistance. A number of biomarkers are emerging that predict response to current therapeutics; work is ongoing to develop appropriate algorithms based on such markers to guide treatment selection. In addition, novel chemotherapeutics are in development including new platinum analogs such as picoplatin (a cisplatin analog), ABT-751 (a sulfonamide) and tubulin binding agents (TBAs) such as the epothilones, providing hope for the future. PMID- 20951464 TI - Sex differences in susceptibility to PAHs is an intrinsic property of human lung adenocarcinoma cells. AB - Recent epidemiological studies have disputed whether females are at increased risk of lung cancer compared to males. However, several molecular studies are in support of an increased susceptibility to tobacco smoke carcinogens among females. Our earlier findings suggest that women display higher levels of smoking induced bulky/hydrophobic DNA adducts which may be related to an increased expression of CYP1A1 in their lungs, compared to men. In this in vitro study, 11 lung adenocarcinoma cell lines, 6 of male and 5 of female origin, were exposed to benzo[a]pyrene, cigarette smoke condensate (CSC), or vehicle control. Subsequent expression analysis of genes in the polycyclic aromatic hydrocarbon bioactivation pathway was conducted with Real-Time RT-PCR. DNA adducts were measured in benzo[a]pyrene-exposed cells by 32P-postlabelling analysis, and CYP1 activity was measured by EROD assay. Analysis of benzo[a]pyrene-DNA adducts showed higher levels of adducts in cell lines from women compared to cell lines from men (p=0.03). The results also revealed significant sex differences in CYP1A1 gene expression, both in untreated cells (p=0.03), and in cells exposed to benzo[a]pyrene (p=0.017) and cigarette smoke condensate (p=0.0043). In CSC exposed cells, significantly higher levels of CYP1 activity was found in cell lines of female origin (p=0.049). These results are in support of the previously published in vivo data, providing evidence for a higher susceptibility to PAH of women's lungs. PMID- 20951466 TI - S-1 is an active anticancer agent for advanced thymic carcinoma. AB - BACKGROUND: Thymic carcinoma is a rare intrathoracic malignant tumor, and the prognosis for patients with advanced stage of the disease is poor. However, no definitive chemotherapeutic regimen has been established for advanced thymic carcinoma in front-line settings. The efficacy and benefit of second-line or salvage chemotherapy are also unknown, as few cases or case series have been reported. PATIENTS AND METHODS: We evaluated the efficacy and toxicity of S-1 monotherapy with S-1, a novel oral fluoropyrimidine agent, as salvage therapy in four consecutive patients with previously treated advanced thymic carcinoma from January, 2008 to May, 2010. RESULTS: Two patients achieved stable disease, and two achieved partial response. Median progression-free survival was 8.1 months. Hematological toxicity was mild, but gastrointestinal toxicity led to discontinuation in two of four patients. CONCLUSIONS: We concluded that oral S-1 monotherapy is useful as second-line or later chemotherapy in previously treated patients with advanced thymic carcinoma and is a potential alternative choice for patients who cannot tolerate platinum-containing treatments. PMID- 20951467 TI - SIGN-R1, a C-type lectin, binds to Bip/GRP78 and this interaction mediates the regurgitation of T-cell-independent type 2 antigen dextran through the endoplasmic reticulum. AB - Capsular polysaccharides of Streptococcus pneumoniae are representative T-cell independent type 2 (TI-2) antigens, frequently causing serious infections in children, the elderly, and immunocompromised patients. However, the detailed mechanism of this immune escape by CPSs is poorly understood. To pursue this question, polysaccharide dextran, ligand of SIGN-R1 as well as an appropriate model of the immunogenicity of many TI-2 polysaccharide antigens was used. SIGN R1 bound to binding immunoglobulin protein (BiP), a well-characterized endoplasmic reticulum (ER) chaperone, primarily in non-ER compartments. Interestingly, SIGN-R1(+) macrophages in the MZ showed high expression of BiP, implying an important role of SIGN-R1 binding to BiP in vivo. To our surprise, dextran is rapidly transported into the ER and subsequently regurgitated out of cells in vitro or in vivo. BiP down-regulation in SIGN-R1 transfectant reduced the regurgitation of dextran, causing the accumulation of dextran in the ER. Therefore, these results demonstrated the first example to describe the intracellular trafficking and the regurgitation of TI-2 antigen dextran, suggesting the novel pathway of TI-2 antigen presentation to immune cells. PMID- 20951468 TI - A DREB gene from Limonium bicolor mediates molecular and physiological responses to copper stress in transgenic tobacco. AB - The DRE-binding (DREB) transcription factors play an important role in regulating stress-related genes. In the present study, a novel DREB gene (LbDREB) from Limonium bicolor was cloned. To characterize the function of DREB in heavy metal stress tolerance, LbDREB-transformed tobacco plants were generated and subjected to CuSO(4) stress. Analysis of the role of LbDREB in tolerance to copper stress in transgenic tobacco showed that overexpression of LbDREB increased the contents of soluble protein and proline, and elevated the ratio of K to Na under CuSO(4) stress. Moreover, overexpression of LbDREB can up-regulate some stress-related genes, including Cu/Zn superoxide dismutase (Cu/Zn SOD), peroxidases (PODs), late embryogenesis abundant (LEA), and lipid transfer proteins (LTP). These results suggest that LbDREB can enhance plant copper tolerance by up-regulating a series of stress-related genes, thereby mediating physiological processes associated with stress tolerance in plants. PMID- 20951469 TI - Phosphatidic acid production in chitosan-elicited tomato cells, via both phospholipase D and phospholipase C/diacylglycerol kinase, requires nitric oxide. AB - Nitric oxide (NO) and the lipid second messenger phosphatidic acid (PA) are involved in plant defense responses during plant-pathogen interactions. NO has been shown to be involved in the induction of PA production in response to the pathogen associated molecular pattern (PAMP) xylanase in tomato cells. It was shown that NO is critical for PA production induced via phospholipase C (PLC) in concerted action with diacylglycerol kinase (DGK) but not for the xylanase induced PA via phospholipase D (PLD). In order to study whether this is a general phenomenon during PAMP perception or if it is particular for xylanase, we studied the effect of the PAMP chitosan in tomato cell suspensions. We observed a rapid NO production in tomato cells treated with chitosan. Chitosan induced the formation of PA by activating both PLD and PLC/DGK. The activation of either phospholipase-mediated signaling pathway was inhibited in cells treated with the NO scavenger cPTIO. This indicates that NO is required for PA generation via both the PLD and PLC/DGK pathway during plant defense response in chitosan elicited cells. Responses downstream PA were studied. PLC inhibitors neomycin and U73122 inhibited chitosan-induced ROS production. Differences between xylanase and chitosan-induced phospholipid signaling pathways are discussed. PMID- 20951470 TI - Mimicking disinfection and drying of biofilms in contaminated endoscopes. AB - The effects of peracetic acid-based (PAA) disinfectant with, and without, additional drying on Candida albicans, Candida parapsilosis, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, isolated from contaminated flexible endoscopes, in single- and dual-species biofilms were studied. Biofilms were prepared in sterile tissue culture polystyrene 96-well microtitre plates and were quantified using the tetrazolium salt (MTT) reduction assay and by counting colony-forming yeasts and bacteria from 10-fold serial biofilm dilutions on agar plates. An in vitro biofilm model was applied to mimic the biofilm formation inside the endoscope channels and to imitate the disinfection and drying procedures used for reprocessing of flexible endoscopes. The PAA-based disinfectant was effective against bacteria and yeasts in the planktonic and biofilm states directly after treatment, but allowed regrowth of all biofilms if the drying procedure was skipped. No biofilm regrowth occurred in wells after a drying procedure in all single- and dual-species biofilms. Routine cleaning procedures do not remove biofilm reliably from endoscope channels if the accurate drying procedure is not applied. This may explain the failure of decontamination during endoscope reprocessing. PMID- 20951471 TI - Costs of nosocomial pneumonia caused by meticillin-resistant Staphylococcus aureus. AB - Nosocomial infections with meticillin-resistant Staphylococcus aureus (MRSA) lead to increased health and economic costs. The purpose of this study was to determine costs for nosocomial MRSA pneumonia compared with meticillin susceptible S. aureus (MSSA) pneumonia. A case-control study was conducted with patients who acquired nosocomial pneumonia with either MRSA or MSSA between January 2005 and December 2007. Patients were matched for age, severity of underlying disease, stay on intensive care units and non-intensive care units, admission and discharge within the same year, and in-hospital stay at least as long as that of cases before MRSA pneumonia. Our analysis includes 82 patients (41 cases, 41 controls). The overall costs for patients with nosocomial MRSA pneumonia were significantly higher than for patients with MSSA pneumonia (?60,684 vs ?38,731; P=0.01). The attributable costs for MRSA pneumonia per patient were ?17,282 (P<0.001). The financial loss was higher for patients with MRSA pneumonia than for patients with MSSA pneumonia (?11,704 vs ?2,662; P=0.002). More cases died than controls while in the hospital (13 vs 1 death, P<0.001). Hospital personnel should be aware of the attributable costs of MRSA pneumonia, and should implement control measures to prevent MRSA transmission. PMID- 20951472 TI - Prudent use of antimicrobial agents: not just for humans. PMID- 20951473 TI - Design, synthesis and inhibitory activity against Mycobacterium tuberculosis thymidine monophosphate kinase of acyclic nucleoside analogues with a distal imidazoquinolinone. AB - Thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKmt) has been proposed as an attractive target in the search of new agents to fight against tuberculosis. We recently reported that thymine derivatives carrying a naphtholactam or naphthosultam moiety at position 4 of a (Z)-butenyl chain inhibit TMPKmt in the subMUM range. Here we describe the replacement of the planar naphtholactam and naphthosultam rings in our identified hits by 5,6 dihydro-1H-imidazo[4,5,1-ij]quinolinones and a 5,6-dihydro-1H,4H-1,2,5 thiadiazolo[4,3,2-ij]quinoline-2,2-dioxide where the planarity has been broken. Interestingly, these non-planar compounds were similarly potent against the target enzyme than their aromatic analogues, suggesting a bioisosteric behavior that may also be applied to other biologically active compounds. The synthesis of the different targeted imidazoquinolinones has been successfully performed via a hypervalent iodide mediated oxidative cyclization of N-methoxyureas catalized by bis(trifluoroacetoxy)iodobenzene (PIFA) expanding the reported use of this reagent for the synthesis of differently substituted imidazoquinolinones. PMID- 20951474 TI - [Management of candidemia and invasive candidiasis]. AB - Candida species is the fourth most common cause of bloodstream infection and is the leading cause of invasive fungal infection among hospitalized patients. Acute disseminated candidiasis remains a life-threatening disease that now occurs mainly in intensive care units hospitalized patients. Delay in treatment of Candida bloodstream infections could be minimized by the development of more rapid and sensitive diagnostic techniques for the identification of Candida bloodstream infections. Current guidelines for the management of invasive candidiasis recommend fluconazole or an echinocandin as the primary therapeutic option. The optimal choice of the antifungal agent should depend on local epidemiology, prior antifungal therapy and patient's characteristics. PMID- 20951475 TI - [Sarcoidosis: What's new in 2010 for internists?]. PMID- 20951476 TI - Using psychodynamic small group work in nurse education: closing the theory practice gap? AB - This paper illustrates the role of psychodynamic small group work in integrating theory and practice for nursing students. Psychodynamic work with individual patients and small staff groups is established in some areas of medical and nursing practice although not widely used in general nursing. Clinical material which was brought to two group supervision sessions by student nurses on clinical placement is presented in this paper and discussed using a psychodynamic perspective. A critical review of psychodynamic small group work and a position paper is presented in this paper to argue that using a psychodynamic approach in nurse education may address the theory-practice gap for student nurses by allowing them to reflect on the emotional issues arising in clinical placements. The paper illustrates how supervision can assist students to integrate theory and practice. It is suggested that reflecting on feelings in small group work with student nurses with a tutor or supervisor who works psychodynamically may help students integrate their theoretical and practical learning. Understanding the theory-practice gap from a psychodynamic perspective may help nurse tutors in their personal tutor work to integrate theoretical and practical learning for students and thereby support students in providing good quality care for their patients. PMID- 20951477 TI - Soil radium, soil gas radon and indoor radon empirical relationships to assist in post-closure impact assessment related to near-surface radioactive waste disposal. AB - Least squares (LS), Theil's (TS) and weighted total least squares (WTLS) regression analysis methods are used to develop empirical relationships between radium in the ground, radon in soil and radon in dwellings to assist in the post closure assessment of indoor radon related to near-surface radioactive waste disposal at the Low Level Waste Repository in England. The data sets used are (i) estimated 226Ra in the < 2 mm fraction of topsoils (eRa226) derived from equivalent uranium (eU) from airborne gamma spectrometry data, (ii) eRa226 derived from measurements of uranium in soil geochemical samples, (iii) soil gas radon and (iv) indoor radon data. For models comparing indoor radon and (i) eRa226 derived from airborne eU data and (ii) soil gas radon data, some of the geological groupings have significant slopes. For these groupings there is reasonable agreement in slope and intercept between the three regression analysis methods (LS, TS and WTLS). Relationships between radon in dwellings and radium in the ground or radon in soil differ depending on the characteristics of the underlying geological units, with more permeable units having steeper slopes and higher indoor radon concentrations for a given radium or soil gas radon concentration in the ground. The regression models comparing indoor radon with soil gas radon have intercepts close to 5 Bq m-3 whilst the intercepts for those comparing indoor radon with eRa226 from airborne eU vary from about 20 Bq m-3 for a moderately permeable geological unit to about 40 Bq m-3 for highly permeable limestone, implying unrealistically high contributions to indoor radon from sources other than the ground. An intercept value of 5 Bq m-3 is assumed as an appropriate mean value for the UK for sources of indoor radon other than radon from the ground, based on examination of UK data. Comparison with published data used to derive an average indoor radon: soil 226Ra ratio shows that whereas the published data are generally clustered with no obvious correlation, the data from this study have substantially different relationships depending largely on the permeability of the underlying geology. Models for the relatively impermeable geological units plot parallel to the average indoor radon: soil 226Ra model but with lower indoor radon: soil 226Ra ratios, whilst the models for the permeable geological units plot parallel to the average indoor radon: soil 226Ra model but with higher than average indoor radon: soil 226Ra ratios. PMID- 20951478 TI - Multiple schwannomas in the oral floor: case report. AB - We present a case of multiple schwannomas of the oral floor in a 62-year-old man, which met the diagnostic criteria of schwannomatosis. PMID- 20951479 TI - Removal of broken screws using a hollow rubber tube (Nelaton catheter). PMID- 20951480 TI - Waste water treatment plants as sources of polyfluorinated compounds, polybrominated diphenyl ethers and musk fragrances to ambient air. AB - To investigate waste water treatment plants (WWTPs) as sources of polyfluorinated compounds (PFCs), polybrominated diphenyl ethers (PBDEs) and synthetic musk fragrances to the atmosphere, air samples were simultaneously taken at two WWTPs and two reference sites using high volume samplers. Contaminants were accumulated on glass fiber filters and PUF/XAD-2/PUF cartridges, extracted compound-dependent by MTBE/acetone, methanol, or hexane/acetone and detected by GC-MS or HPLC-MS/MS. Total (gas+particle phase) concentrations ranged from 97 to 1004 pg m(-3) (neutral PFCs), 0.923-0.999) when compared to the physical measurements (ICC; 0.964-0.999). Only one CBCT measurement (t-g) and one Di3D measurement (t-sn left) had a mean AE of more than 1.5mm. There are clear potential benefits of using 3D measurements appose to direct measurements in the assessment of facial deformities. Measurements recorded by the three 3D systems appeared to be both sufficiently accurate and reliable enough for research and clinical use. PMID- 20951518 TI - Autopsy and genetic diagnosis of 21-hydroxylase deficiency with bilateral testicular tumors in a case under no medication for over one year. AB - The autopsy findings of an adult patient with 21-hydroxylase deficiency are presented. Genetic analysis of the 21-hydroxylase gene (CYP21A2) was performed for accurate diagnosis of congenital adrenal hyperplasia (CAH), and bilateral testicular tumors were characterized. We report a 29-year-old Japanese man who was diagnosed with CAH (21-hydroxylase deficiency) in infancy and had continued steroid therapy until the age of 28. However, for more than one year, he had not been treated for CAH and was found dead. In the medico-legal autopsy findings, both adrenal glands were enlarged, and hypertrophy of adrenal cortices and bilateral testicular tumors positive for melan-A were observed. Genomic DNA was prepared from cervical lymph nodes collected during autopsy, and CYP21A2 was PCR amplified and sequenced directly using newly designed primers. From the morphological findings, the bilateral testicular tumors were considered to be adrenogenital syndrome (TTAGS). Through the whole sequence of CYP21A2, the intron 2 splice mutation (656)A to (656)G was found. TTAGS were thought to be adrenal rests enlarged by ACTH stimulus. From the autopsy findings and the result of genetic analysis, he was diagnosed with the salt-wasting form of 21-hydroxylase deficiency and his cause of death was presumed to be heart failure based on abnormal electrolytes. PMID- 20951520 TI - 99mTc-DPD-SPECT/CT predicts the outcome of imaging-guided diagnostic anaesthetic injections: a prospective cohort study. AB - PURPOSE: We hypothesized that bone SPECT combined with multiplanar reconstructed CT can identify and target the pain-inducing focus in the foot and can be used to successfully guide anaesthetic infiltrations. Therefore we prospectively investigated feasibility and predictive value of bone SPECT/CT for image guided diagnostic infiltrations in patients with chronic foot pain. METHODS: All patients received a standardized bone SPECT/CT of both feet. The scintigraphically most active structures were subsequently infiltrated with local anaesthetics under CT-guidance. The pre- and post-infiltration pain intensity was measured using the visual analogue scale (VAS). Then, we assessed (i) the agreement on pain originating structures determined by standard clinical assessment versus SPECT/CT and (ii) the predictive value of SPECT-CT in groups with and without agreement. RESULTS: 27 of 30 participants reported a pain reduction on VAS of 50% or more, resulting in a response rate of 90%. When assessing the agreement on pain initiating structures determined by standard clinical assessment versus SPECT/CT, we found a disagreement in 16 of 30 (53%) cases. Particularly, disagreement appeared in all 9 participants with symptoms located in the mid-foot (100%). In participants with hind-foot pathology, disagreement was found in 7 of 21 cases (33%). CONCLUSION: The present study shows the feasibility of 99mTc-DPD-SPECT/CT guided infiltration of osseous structures of patients with chronic foot pain. 99mTc-DPD-SPECT/CT had a higher predictive value on the clinical outcome than the clinical assessment. In the clinical setting 99mTc-DPD-SPECT/CT might overrule the clinical assessment in case of disagreement on the target lesion. PMID- 20951519 TI - Measurement of renal volume using respiratory-gated MRI in subjects without known kidney disease: intraobserver, interobserver, and interstudy reproducibility. AB - OBJECTIVE: Since renal volume is to be considered in managing renal diseases, a reproducible technique is needed. Our aim was to estimate intraobserver, interobserver, and interstudy reproducibility of renal volume measurement in subjects without known kidney disease using magnetic resonance (MR) imaging. MATERIALS AND METHODS: We studied 20 patients (age range 33-82 years) without known renal disease using 1.5-T MR imaging with a respiratory-gated two dimensional coronal balanced steady state free precession sequence. Each patient repeated the study after 1h. Two readers independently segmented the area of both kidneys of the first study, subtracting cysts. After 1 week, the first reader segmented the second study and repeated the segmentation of the first study. The volume of each kidney was obtained by multiplying the renal area on each slice by the slice thickness and summing all the partial volumes. Reproducibility was assessed by Bland-Altman and Wilcoxon statistics. The coefficient of repeatability (CoR) was summed to the absolute value of bias; the ratio between this sum and the mean of the two data sets was used as a measure of variability while its complement to 100% was used as a measure of reproducibility. RESULTS: Acquisition time was 2-3 min. Segmentation time was 20-25 min. Intraobserver variability results in a CoR of 7 ml and in a reproducibility of 95%, interobserver variability 8.8-9.8 ml and 87-88%, interstudy variability 9.8-10.6 ml and 91-93%, respectively. Considering both the effect of observer and the repetition of the study, the reproducibility was 83-87%. CONCLUSION: Renal volume measurement by MR imaging is highly reproducible. PMID- 20951521 TI - Unsupervised MRI segmentation of brain tissues using a local linear model and level set. AB - Real-world magnetic resonance imaging of the brain is affected by intensity nonuniformity (INU) phenomena which makes it difficult to fully automate the segmentation process. This difficult task is accomplished in this work by using a new method with two original features: (1) each brain tissue class is locally modeled using a local linear region representative, which allows us to account for the INU in an implicit way and to more accurately position the region's boundaries; and (2) the region models are embedded in the level set framework, so that the spatial coherence of the segmentation can be controlled in a natural way. Our new method has been tested on the ground-truthed Internet Brain Segmentation Repository (IBSR) database and gave promising results, with Tanimoto indexes ranging from 0.61 to 0.79 for the classification of the white matter and from 0.72 to 0.84 for the gray matter. To our knowledge, this is the first time a region-based level set model has been used to perform the segmentation of real world MRI brain scans with convincing results. PMID- 20951522 TI - Characterization of mediastinal lymphadenopathy with diffusion-weighted imaging. AB - PURPOSE: To predict malignancy of mediastinal lymphadenopathy with diffusion weighted imaging. MATERIAL AND METHODS: A prospective study was conducted on 35 patients with mediastinal lymphadenopathy (28 malignant and seven benign nodes). They underwent echoplanar diffusion-weighted magnetic resonance imaging of the mediastinum with b-factors of 0, 300 and 600 s/mm(2). The apparent diffusion coefficient (ADC) values of the mediastinal lymph nodes were calculated. The ADC values were correlated with the biopsy results and statistical analysis was done. A value of P<.05 was considered significant. RESULTS: The mean ADC value of malignant mediastinal lymphadenopathy (1.06+/-0.3*10(-3) mm(2)/s) was significantly lower (P=.001) than that of benign lymphadenopathy (2.39+/-0.7*10( 3) mm(2)/s). There was an insignificant difference in the ADC values between metastatic and lymphomatous mediastinal lymph nodes (P=.32) as well as within benign nodes (P=.07). When an ADC value of 1.85*10(-3) mm(2)/s was used as a threshold value for differentiating malignant mediastinal nodes from benign nodes, the best results were obtained with an accuracy of 83.9%, a sensitivity of 96.4%, a specificity of 71.4%, a negative predictive value of 95.2% and a positive predictive value of 77.1%. The area under the curve was 0.98. CONCLUSION: Diffusion weighted magnetic resonance imaging is a promising noninvasive imaging modality that can be used for characterization of mediastinal lymphadenopathy and differentiation of malignant from benign mediastinal lymph nodes. PMID- 20951525 TI - Letter to "Management of motorcycle accident-related blunt hepatic injury-a different strategy". PMID- 20951524 TI - Effects of therapeutic hypothermia on coagulopathy and microcirculation after cardiopulmonary resuscitation in rabbits. AB - OBJECTIVE: The aim of this study was to investigate the effects of therapeutic hypothermia (TH) on coagulopathy and cerebral microcirculation disorder after cardiopulmonary resuscitation (CPR) in rabbits. METHODS: Cardiac ventricular fibrillation was induced by alternating current in 24 New Zealand rabbits, and hypothermia was induced by surface cooling or normothermia (NT) was maintained for 12 hours after the return of spontaneous circulation (ROSC). Several physiologic indexes were measured before CPR and at 4, 8, and 12 hours after ROSC. The microcirculation flow in the cerebral cortex was measured with a PERIMED Multichannel Laser Doppler system (Perimid, Sweden), and glomerular fibrin deposition was determined by microscopy. RESULTS: Compared with the NT group, the prothrombin time, activated partial thromboplastin time, and international normalized ratio in the TH group were increased; there were no differences in anti-thrombin-III, protein C, and d-dimer indexes. The microcirculation flow in the cerebral cortex before CPR and after ROSC at 4, 8, and 12 hours was 401.60 +/- 11.76, 258.86 +/- 34.58, 317.59 +/- 23.36, and 371.98 +/- 5.79 mL/min, respectively, in the NT group, and 398.18 +/- 12.91, 336.19 +/- 19.27, 347.76 +/- 13.80, and 383.78 +/- 3.29 mL/min, respectively, in the TH group. There were apparent disparities at each checkpoint after ROSC in these 2 groups (4 hours: P = .001; 8 hours: P = .011; 12 hours: P = .009). The Pearson correlation test showed that the microcirculation flow in the cerebral cortex was positively correlated with activated partial thromboplastin time after ROSC (4 hours: r = 0.503, P = .033; 8 hours: r = 0.565, P = .035; 12 hours: r = 0.774, P = .009), but not with other coagulation parameters. CONCLUSIONS: Therapeutic hypothermia might cause coagulant dysfunction but concomitantly improves the microcirculation flow in the cerebral cortex, which might be an effect of TH that results in cerebral protection. PMID- 20951527 TI - Short- vs long-axis approach to ultrasound-guided peripheral intravenous access: a prospective randomized study. AB - OBJECTIVE: The objective of the study was to determine if the short-axis approach and long-axis approach to ultrasound-guided peripheral intravenous access (USGPIV) differ in success rate, catheter insertion time, and number of needle sticks. METHODS: A convenience sample of emergency department patients aged 18 to 65 years with difficult IV access (2 or more failed landmark attempts) was prospectively randomized to short-axis or long-axis USGPIV. Time from skin puncture to catheter insertion (insertion time) and number of needle sticks were recorded. Number of needle sticks and insertion time were compared using Mann Whitney U tests. RESULTS: Forty subjects were enrolled; 20 were randomized to the short-axis and 20 to the long-axis approach. Success rate was 95% (19/20; 95% confidence interval, 85%-100%) in the short-axis group compared with 85% (17/20; 95% confidence interval, 69%-100%) in the long-axis group. All 3 subjects with failed IV placement in the long-axis group had successful rescue USGPIV placement in short axis. Median insertion time was 34 seconds (interquartile range, 35 seconds) for the short-axis group compared with 91 seconds (interquartile range, 59 seconds) for the long-axis group (P = .02). Mean number of needle sticks was 1.5 (+/-SD 0.7) in the short-axis group compared with 1.4 (+/-SD 0.7) in the long axis group (P = .82). CONCLUSIONS: Short-axis USGPIV technique required less insertion time than the long-axis technique. Success rate was higher in the short axis group, but this difference was not statistically significant. However, all of the failed IVs in the long axis were rescued successfully in short axis. PMID- 20951526 TI - Dental pain as a risk factor for accidental acetaminophen overdose: a case control study. AB - Patients frequent take acetaminophen to treat dental pain. One previous study found a high rate of overuse of nonprescription analgesics in an emergency dental clinic. OBJECTIVES: The purpose of this study is to determine if patients with dental pain are more likely to be treated for accidental acetaminophen poisoning than patients with other types of pain. METHODS: We conducted a case-control study at 2 urban hospitals. Cases were identified by chart review of patients who required treatment for accidental acetaminophen poisoning. Controls were self reported acetaminophen users taking therapeutic doses identified during a survey of emergency department patients. For our primary analysis, the reason for taking acetaminophen was categorized as dental pain or not dental pain. Our primary outcome was the odds ratio of accidental overdose to therapeutic users after adjustment for age, sex, alcoholism, and use of combination products using logistic regression. RESULTS: We identified 73 cases of accidental acetaminophen poisoning and 201 therapeutic users. Fourteen accidental overdose patients and 4 therapeutic users reported using acetaminophen for dental pain. The adjusted odds ratio for accidental overdose due to dental pain compared with other reasons for use was 12.8 (95% confidence interval, 4.2-47.6). CONCLUSIONS: We found that patients with dental pain are at increased risk to accidentally overdose on acetaminophen compared with patients taking acetaminophen for other reasons. Emergency physicians should carefully question patients with dental pain about overuse of analgesics. PMID- 20951528 TI - Out-of-hospital use of an automated chest compression device: facilitating access to extracorporeal life support or non-heart-beating organ procurement. AB - OBJECTIVE: The aim of the study was to assess the ease-of-use, safety, and usefulness of an automated external chest compression device for cardiopulmonary resuscitation. METHODS: Adults with out-of-hospital cardiac arrest (OHCA) were included prospectively. The emergency medical services (EMS) in a large suburb northeast of Paris (France) recorded data for standard criteria for EMS care for CA and specific criteria on device use-application time, ease of application and use (visual analog scale score: 0, impossible; 5, very easy), technical incidents, and clinical complications. RESULTS: We attended 4868 OHCA patients (January 2005 to April 2010) and used the device in 285 patients (6%) (212 males [74%], 73 females [26%]; median age, 56 [43-70] years). Results (medians with 25 75 percentiles) were as follows: time to apply device, 30 seconds (20-60); ease of application and activation, 5 (4-5) and 5 (5-5), respectively; duration of use, 30 (20-41) minutes; return to spontaneous circulation (ROSC), 76 patients (27%); and time to ROSC, 19 (12-32) minutes after placement. Twenty-seven patients (9%) with refractory CA benefited from extracorporeal life support. Overall, 32 patients were alive after 24 hours, 11 at 7 days, and 3 at 1 month. An additional 23 patients (8%) with refractory CA were selected for non-heart beating kidney procurement. Ten patients were used to harvest kidneys and 15 were transplanted. There were 21 technical incidents (7%) and 19 clinical complications (7%). CONCLUSION: The device was easy to use in routine emergency practice and of particular value in facilitating access to extracorporeal life support or non-heart-beating organ procurement. These uses should be itemized in all OHCA studies. PMID- 20951529 TI - Neck collar used in treatment of victims of urban motorcycle accidents: over- or underprotection? AB - BACKGROUND: Cervical collar brace protection of the cervical spine at the scene of the incident is the first priority for emergency medical technicians treating patients who have sustained trauma. However, there is still controversy between over- or underprotection. The objective of this study was to survey the cervical spine injury of lightweight motorcycle accident victims and further evaluate the neck collar protection policy. MATERIALS AND METHODS: We retrospectively reviewed patients who sustained lightweight motorcycle injuries, assumed to have been at a low velocity, with incidence of cervical spine damage, from a single medical center's trauma registration from 2008 to 2009. Patients were divided into 2 groups: those who were immobilized by cervical collar brace and those who were not. RESULTS: Of the 8633 motorcycle crash victims, 63 patients had cervical spine injury. The average of the injury severity score in these patients was 14.31 +/- 8.25. There was no significant correlation of cervical spine injury between the patients who had had the neck collar applied and those who had not (chi(2), P = .896). The length of stay in intensive care unit was longer in the patients who had the neck collar applied, but the total hospital length of stay was not statistically different to the patients who did not have the neck collar applied. CONCLUSION: The incidence of cervical spinal injuries in the urban area lightweight motorcyclists is very low. Prehospital protocol for application of a cervical collar brace to people who have sustained a lightweight motorcycle accident in the urban area should be revised to avoid unnecessary restraint and possible complications. PMID- 20951530 TI - Jugular venous distension on ultrasound: sensitivity and specificity for heart failure in patients with dyspnea. AB - BACKGROUND: Accurately diagnosing congestive heart failure (CHF) in patients with dyspnea can be difficult because clinical history and physical examination are often nondiagnostic and may be inaccurate, especially when patients have complicated comorbid conditions. OBJECTIVE: To prospectively assess jugular venous distension on ultrasound (JVD-US) performed by emergency physicians for identifying CHF on echocardiography by the department of cardiology (C-ECHO) in patients with dyspnea. MEASUREMENTS: This was a secondary analysis of a previously collected data set from a prospective study of JVD-US in ED patients with dyspnea due to suspected CHF. C-ECHO results were obtained and used as the criterion standard. RESULTS: Jugular venous distension on ultrasound had a sensitivity of 99% (95% confidence interval [CI], 92.2%-100%), specificity of 59% (95% CI, 40.9%-74.4%), positive likelihood ratio of 2.4 (95% CI, 1.6-3.6), and negative likelihood ratio of 0.01 (95% CI, 0.0007-0.20) for identifying CHF on C ECHO in patients with dyspnea. CONCLUSION: This initial study suggests that JVD US by emergency physicians is predictive of CHF using echocardiography performed by the department of cardiology as the criterion standard. PMID- 20951531 TI - The Denver Seizure Score: anion gap metabolic acidosis predicts generalized seizure. AB - OBJECTIVES: Anion gap (AG) and serum bicarbonate concentration (BICARB) may help confirm a diagnosis of seizure in an unwitnessed collapse; however, little data exist to support this practice. Our objective was to assess the association between AG metabolic acidosis and generalized seizure and to derive a simple score to predict seizure. METHODS: This was a case-control study at an urban teaching hospital. Patients transported to our emergency department with witnessed loss of consciousness and final confirmed diagnoses of generalized seizure (cases) or syncope (controls) were eligible for enrollment. Multivariable logistic regression analysis was used to model associations between AG, BICARB, and seizure. RESULTS: In 49 cases and 40 controls, patients in the seizure group were more likely to have a lower median BICARB (17 [range, 14-34] vs 23 [range, 20-24], P < .0001) and a higher median AG (22 [range, 9-42] vs 13 [range, 7-21], P < .0001). The Denver Seizure Score was defined, using regression coefficient weighting, as the Delta BICARB plus twice the Delta AG [(24 - BICARB) + (2*(AG - 12))]. The score ranged from -16 to +74 and identified patients as low likelihood (score <0), moderate likelihood (score 0-20), or high likelihood (score >20), with 21% (95% confidence interval [CI], 5%-51%), 40% (95% CI, 26%-56%), and 96% (95% CI, 82%-100%) being categorized as seizure, respectively. CONCLUSIONS: Anion gap metabolic acidosis is associated with generalized seizure. A Denver Seizure Score greater than 20 predicts generalized seizure in the emergency department and may be useful for differentiating patients with unwitnessed loss of consciousness. PMID- 20951532 TI - Emergency tracheal intubation using the Airtraq laryngoscope during chest compression. PMID- 20951533 TI - Clinical predictors of Enterobacter bacteremia among patients admitted to the ED. AB - OBJECTIVES: This study was performed to evaluate clinical features of community onset Enterobacter bacteremia and determine the risk factors for Enterobacter bacteremia among patients admitted to the emergency department. METHODS: A post hoc analysis of a nationwide surveillance database of bacteremia was performed. A total of 53 patients with community-onset Enterobacter bacteremia were compared with 882 patients with Escherichia coli bacteremia. RESULTS: As for the underlying disease, solid tumor was more likely common in Enterobacter bacteremia than in E. coli bacteremia (39.6% [21/53] vs 19.7% [174/882], P < .001). Neutropenia, indwelling urinary catheter, and tube insertion were significantly more common in Enterobacter bacteremia than in E. coli bacteremia (all Ps < .05). As for the site of infection, lung and abdomen were more likely common in Enterobacter bacteremia than in E. coli bacteremia, whereas urinary tract was less likely frequent in Enterobacter bacteremia than in E. coli bacteremia (all Ps < .05). In the multivariate analysis, pneumonia, tube insertion, solid tumor, and health care-associated infection were found to be significantly associated with Enterobacter bacteremia (all Ps < .05). CONCLUSIONS: Enterobacter species were important pathogens among community-onset gram-negative bacteremia, in association with health care-associated infections. Pneumonia, tube insertion, solid tumor, and health care-associated infections were found to be significantly associated with Enterobacter bacteremia. PMID- 20951534 TI - The emergency computed tomography as important modality for early diagnosis of Fournier gangrene. PMID- 20951536 TI - Critical appraisal of the Carotid Duplex Consensus criteria in the diagnosis of carotid artery stenosis. AB - BACKGROUND: Clinicians have relied on published institutional experience for interpreting carotid duplex ultrasound studies (CDUS). This study will validate the ultrasound imaging consensus criteria published in 2003. METHODS: The CDUS and angiography results of 376 carotid arteries were analyzed. Receiver-operating characteristic (ROCs) curves were used to compare peak systolic velocities (PSVs), end-diastolic velocities (EDVs) of the internal carotid artery (ICA), and ICA/common carotid (CCA) ratios in detecting < 50%, 50% to 69% (ICA PSV of 125 230 cm/s), and 70% to 99% (PSV of >= 230 cm/s) stenosis according to the consensus criteria. RESULTS: The consensus criteria uses a PSV of 125 to 230 cm/s for detecting angiographic stenosis of 50% to 69%, which has a sensitivity of 93%, specificity of 68%, and overall accuracy of 85%. A PSV of >= 230 cm/s for >= 70% stenosis had a sensitivity of 99%, specificity of 86%, and overall accuracy of 95%. ROC curves showed that the ICA PSV was significantly better (area under the curve [AUC], 0.97) than EDV (AUC, 0.94) or ICA/CCA ratio (AUC, 0.84; P = .036) in detecting >= 70% stenosis and >= 50% stenosis. Pearson correlations showed a statistical difference between the correlation of PSV with angiography (0.833; 95% confidence interval [CI], 0.8-0.86), EDV with angiography (0.755; 95% CI, 0.71-0.80), and ICA/CCA systolic ratio with angiography (0.601; 95% CI, 0.53 0.66; P < .0001) in detecting 70% to 99% stenosis. Adding the EDV values or the ratios to the PSV values did not improve accuracy. The consensus criteria for diagnosing 50% to 69% stenosis can be significantly improved by using an ICA PSV of 140 to 230 cm/s, with a sensitivity of 94%, specificity of 92%, and overall accuracy of 92%. CONCLUSIONS: The consensus criteria can be accurately used for diagnosing >= 70% stenosis; however, the accuracy can be improved for detecting 50% to 69% stenosis if the ICA PSV is changed to 140 to < 230 cm/s. PMID- 20951537 TI - Quality assurance in colonoscopy for colorectal cancer diagnosis. AB - Colonoscopy can prevent colorectal cancer, but its effectiveness is diminished by operator-dependent factors. Therefore, quality assurance programs should be implemented in all colonoscopy practices. Adherence to quality performance measures varies among different countries, and physicians seem reluctant to adopt them. We provide an overview of the existing guidelines for colonoscopy quality assurance, and a summary of the quality control initiatives in Belgium and the surrounding countries. PMID- 20951538 TI - Partial-thickness tears of the gluteus medius: rationale and technique for trans tendinous endoscopic repair. AB - Tears in the gluteus medius and minimus tendons, often misdiagnosed as trochanteric bursitis, have recently emerged as an important cause of recalcitrant greater trochanter pain syndrome. Advances in endoscopic surgery of the hip have created opportunities to better evaluate and treat pathology in the peritrochanteric compartment. We reviewed the literature on trochanteric pain syndrome and gluteus medius tendon injuries. Existing techniques for endoscopic and open gluteus tendon repair and potential challenges in restoration of abductor function were analyzed. Partial-thickness undersurface tears of the gluteus medius were identified as a common pathologic entity. Although these tears are otherwise analogous to partial-thickness tears of the rotator cuff, the lack of arthroscopic access to the deep side of the gluteus medius tendon represents a unique technical challenge. To address the difficulty in visualizing and thus repairing undersurface tears of the gluteus medius, a novel endoscopic trans-tendinous repair technique was developed. The purposes of this article are to review the anatomy, pathology, and existing repair techniques of gluteus medius tendon tears and to describe the rationale and surgical steps for endoscopic trans-tendinous repair. PMID- 20951539 TI - WITHDRAWN: Altered oxidative stress indexes related to disease progression marker in human immunodeficiency virus infected patients with antiretroviral therapy. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.biomag.2010.09.001. The duplicate article has therefore been withdrawn. PMID- 20951540 TI - [Letter on the article: "How to explore iron-deficiency anemia"]. PMID- 20951541 TI - The value of amphotericin B in the treatment of invasive fungal infections. AB - Over the last 20 years, there has been an increase in the total number of invasive fungal infections (IFIs) and in infections caused by rare and emerging pathogens. This is due in part to the growing population of immunocompromised patients at risk of developing fungal infections. Three classes of antifungal agents are widely used for the treatment of systemic fungal infections: polyenes, azoles, and echinocandins. Polyenes were the first antifungal agents developed and have a long-standing history in the treatment of IFIs. The use of conventional amphotericin B has been limited because of toxic side effects, which have been reduced by the lipid formulations of amphotericin B. Treatment options for invasive mycoses have expanded with the recent introduction of the second generation triazoles (voriconazole and posaconazole) and the echinocandins (caspofungin, micafungin, anidulafungin). Despite the increased number of antifungal drugs, resistance issues present a problem in the treatment of IFIs. Although some fungal pathogens display innate resistance, others have developed resistance secondary to selective pressure. This article briefly reviews the changing epidemiology of fungal infections and associated risk factors, resistance issues with commonly administered antifungal agents, and treatment options for IFIs, with a focus on polyenes. PMID- 20951542 TI - The temporal relationship between anxiety disorders and urinary incontinence among community-dwelling adults. AB - OBJECTIVE: The purpose of this paper was to carefully examine the temporal relationships between anxiety disorders and urinary incontinence among community dwelling adults. METHOD: In all, 1071 persons aged 30 and over were the continuing participants in a population-based longitudinal study of community dwelling adults. Participants were classified as incontinent if any uncontrolled urine loss within the 12 months prior to the interview was reported. Condition specific functional loss secondary to urinary incontinence was further assessed based on a series of questions relating directly to participants' inability to engage in certain activities due to their urinary incontinence. Anxiety disorders were assessed with standardized interviews keyed to the diagnostic criteria. RESULTS: In multivariate models that controlled for potentially influential characteristics the association between urinary incontinence with condition specific functional loss and newly-incident anxiety disorders was statistically significant (adjusted relative odds (RO)=2.55, 95% confidence interval (CI) [1.05, 6.20]). CONCLUSIONS: Urinary incontinence with condition-specific functional loss predicted onset of newly-incident anxiety disorders among community-dwelling adults. PMID- 20951544 TI - Over-selectivity as a learned response. AB - An experiment investigated the effects of different levels of task complexity in pre-training on over-selectivity in a subsequent match-to-sample (MTS) task. Twenty human participants were divided into two groups; exposed either to a 3 element, or a 9-element, compound stimulus as a sample during MTS training. After the completion of training, both groups were tested on an MTS task using a novel 6-element compound sample stimulus. The level of over-selectivity at test was influenced by the training. Specifically, the group exposed to a more complex (9 element) training task displayed higher levels of over-selectivity at test than the group with a less complex training task. The results suggest that over selectivity may be a learned response to complex situations, and are discussed with respect to theories and treatments for over-selectivity. PMID- 20951543 TI - Multicomponent behavioral treatment for chronic combat-related posttraumatic stress disorder: a randomized controlled trial. AB - This study examined the efficacy of a multicomponent cognitive-behavioral therapy, Trauma Management Therapy, which combines exposure therapy and social emotional rehabilitation, to exposure therapy only in a group of male combat veterans with chronic posttraumatic stress disorder (PTSD). Thirty-five male Vietnam veterans with PTSD were randomly assigned to receive either Trauma Management Therapy (TMT) or Exposure Therapy Only (EXP). Participants were assessed at pre-treatment, mid-treatment, and post-treatment. Primary clinical outcomes were reduction of PTSD symptoms and improved social emotional functioning. Results indicated that veterans in both conditions showed statistically significant and clinically meaningful reductions in PTSD symptoms from pre- to post-treatment, though consistent with a priori hypotheses there were no group differences on PTSD variables. However, compared to the EXP group, participants in the TMT group showed increased frequency in social activities and greater time spent in social activities. These changes occurred from mid treatment (after completion of exposure therapy) to post-treatment (after completion of the social emotional rehabilitation component); supporting the hypothesis that TMT alone would result in improved social functioning. Although the TMT group also had a significant decrease in episodes of physical rage, that change occurred prior to introduction of the social emotional component of TMT. This study demonstrates efficacy of exposure therapy for treating the core symptoms of PTSD among combat veterans with a severe and chronic form of this disorder. Moreover, multi-component CBT shows promise for improving social functioning beyond that provided by exposure therapy alone, particularly by increasing social engagement/interpersonal functioning in a cohort of veterans with severe and chronic PTSD. PMID- 20951545 TI - Coincidence of homophone spelling errors and attention problems in schoolchildren: a survey study. AB - This article examines the relationship between writing and attention problems and hypothesizes that homophone spelling errors coincide with attention deficits. We analyze specific types of attention deficits, which may contribute to Attention Deficits Hyperactivity Disorder (ADHD); rather than studying ADHD, however, we focus on the inattention dimension of behavior. Our methodology was to develop a survey study for exploring the coincidence of homophone errors and attention problems in schoolchildren. Two sets of parent-questionnaires characterizing individually types of Chinese handwriting errors and behavioral problems in schoolchildren were developed by the research team. Our participants were 491 Taiwanese children from the first to fifth grades in an elementary school in Taipei; they all used traditional Chinese as their primary written language of communication. Based on the ratings of the parent-questionnaires, two groups with proficient and non-proficient homophonic writing were formed. One consisted of children known to have made heterographic homophone errors (words with correct pronunciation but different spellings). The other (control group) consisted of children known to be proficient in Chinese homophone spellings. In each group, there were 54 boy and girl pupils, matched by gender, age, school and grade. A significant correlation was found between attention deficits and homophone errors. This survey study confirms our hypothesis and strengthens a currently underdeveloped theory in the literature of handwriting that attention impairments play an important role in the production of homophone errors. PMID- 20951546 TI - Effect of geographical and ethnic variation on Dysphonia Severity Index: a study of Indian population. AB - Dysphonia Severity Index (DSI) is a widely used multiparametric approach to objectively quantify the voice quality. Few research groups have investigated the test-retest, interobserver variability, and influence of age and gender. They have also verified the application of DSI in various voice rehabilitation conditions. However, all these studies have been conducted on European population. There is a possibility of variation in the basic parameters of DSI across geographical and ethnic groups. Hence, the present study evaluated DSI in Indian population. One hundred twenty voluntary participants (60 males, 60 females) who had G(0) on the Grade, Roughness, Breathiness, Aesthenia, Strain (GRBAS) scale participated in the study (age range of 18-25 years, M=21.8, standard deviation=2.7). Maximum phonation time (MPT), frequency intensity, and jitter measurements were made using CSL 4500 (Kay Elemetrics, Pine Brook, NJ). Results showed noticeable difference between Indian and European population on MPT, Highest frequency (F(0)-High), and DSI values. Significant gender difference was also observed on MPT and F(0)-High. Test-retest reliability showed >95% for all the parameters. The MPT decrement lead to a reduction in the overall DSI value in both the genders. These results of the study caution voice professionals to reinvestigate and establish their own norms for their geographical and ethnic groups. PMID- 20951547 TI - Vocal fold vibration and phonation start in aspirated, unaspirated, and staccato onset. AB - OBJECTIVES/HYPOTHESES: Singers learn to produce well-controlled tone onsets by accurate synchronization of glottal adduction and buildup of subglottal pressure. Spectrographic analyses have shown that the higher spectrum partials are present also at the vowel onset in classically trained singers' performances. Such partials are produced by a sharp discontinuity in the waveform of the transglottal airflow, presumably produced by vocal fold collision. STUDY DESIGN: After hearing a prompt series of a triad pattern, six singer subjects sang the same triad pattern on the vowel /i/ (1) preceded by an aspirated /p/, (2) preceded by an unaspirated /p/, and (3) without any preceding consonant in staccato. METHODS: Using high-speed imaging we examined the initiation of vocal fold vibration in aspirated and unaspirated productions of the consonant /p/ as well as in the staccato tones. RESULTS: The number vibrations failing to produce vocal fold collision were significantly higher in the aspirated /p/ than in the unaspirated /p/ and in the staccato tones. High frequency ripple in the audio waveform was significantly delayed in the aspirated /p/. CONCLUSIONS: Initiation of vocal fold collision and the appearance of high-frequency ripple in the vowel /i/ are slightly delayed in aspirated productions of a preceding consonant /p/. PMID- 20951548 TI - Classification of the classical male singing voice using long-term average spectrum. AB - OBJECTIVES/HYPOTHESIS: Singing-voice classification is often considered the cornerstone of a classical singer's identity. Traditionally, classification has been a highly subjective, nonstandardized process. As a result, misclassification of the singing voice is thought to be common, especially in young singers. Long term average spectrum (LTAS) average is an objective measurement that could be used to classify a singer's voice. The purpose of this study was to determine the relationship of LTAS with singing-voice classification. STUDY DESIGN: Descriptive between-subject study. METHODS: Nine professional classical male singers performed the "Star Spangled Banner" in a comfortable key of their choice. LTAS was calculated for the first two phrases, the remainder of the song, and the entire song. The overall LTAS averages of each sample as well as the physiological and singing ranges were compared with self-reported singing-voice classification. RESULTS: Voice classification and overall LTAS average were moderately correlated, but the strength of the correlation varied with each sample. The strongest correlation was with the entire song. Voice classification and singing range were strongly correlated. CONCLUSIONS: LTAS remains a promising tool to aid in singing-voice classification. However, how to best use LTAS in classification remains unclear because of the influence of sample length and phonetic and pitch content on LTAS. PMID- 20951549 TI - Voice and laryngeal configuration of men with unilateral vocal fold paralysis before and after medialization. AB - AIM: To describe the laryngeal configuration and the voice of male patients diagnosed with unilateral vocal fold paralysis (UVFP) before and after medialization. METHODS: A retrospective study involving the collection of data from medical records of 142 patients diagnosed with UVFP from January 2003 to April 2009, submitted to auditory-perceptual assessment of voices and visual perception of laryngeal images before and after medialization. RESULTS: The study included data from 24 male patients, with an average of 60.7 years, who underwent three surgical medialization techniques (injection of hyaluronic acid, type I thyroplasty, and injection of Teflon). Before treatment, the position of the paralyzed vocal fold was seen to have a significant influence to the passing of the healthy vocal fold beyond the midline and on the overall degree of dysphonia. After treatment, the complete glottic closure; the free margin of the linear vocal fold; paralyzed vocal fold in the median position, reduction of hoarseness, roughness and breathiness (more frequently mild), and asthenia (more frequently normal and mild); tension and instability (more frequency normal); and a decrease in the overall degree of dysphonia were found to be significant. CONCLUSION: The position of the paralyzed vocal fold influences the position of the healthy vocal fold in relation to the midline and the overall degree of dysphonia. All three treatments improved the glottic configuration and the voice of patients with UVFP. PMID- 20951550 TI - Voice characteristics in adults with neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder caused by mutations in the NF1 gene, which is located at the long arm of chromosome 17. Major characteristics include multiple cafe-au-lait spots and neurofibromas. Voice abnormalities have been reported to occur in this patient group. However, most studies relied on subjective measurements only. The present study reports the results of an objective voice assessment based on a multiparameter approach in 22 adults with NF1. Aerodynamic measurements, voice range profiles, acoustic voice quality and intonation measurements, and dysphonia severity indices were obtained and compared with data from a control group, consisting of 22 healthy adults. It was found that NF1 patients show a poorer overall voice quality compared with controls. Particularly, a reduction of vital capacity and limitations in laryngeal possibilities with respect to frequency and intensity were observed in the NF1 group. PMID- 20951551 TI - Ex vivo canine vocal fold lamina propria rehydration after varying dehydration levels. AB - OBJECTIVES: To examine the recoverability of canine vocal fold (VF) lamina propria (LP) on rehydration from varying dehydration levels. STUDY DESIGN: Open, controlled experimental trial. METHODS: The VF LP was excised en bloc using a scalpel from 10 canine larynges, providing 20 tissue samples. The initial volume of each sample was measured. Ten samples were dehydrated to 30% by mass and the other 10 samples to 70%. Each sample was rehydrated in 0.9% saline until the mass stabilized. The liquid mass and volume fractions, liquid:solid mass and volume ratios, and the fractions of the original tissue masses and volumes were calculated. RESULTS: All calculated parameters were significantly different between 30% and 70% dehydration recovery, with all parameters lesser in the 70% dehydration treatment group. Half of the tissue samples subjected to 30% dehydration fully recovered to their original volumes, whereas only one of the 10 samples subjected to 70% dehydration fully recovered its volume. CONCLUSIONS: The level of attainable rehydration recovery of VF LP tissue in an ex vivo setting depends on the level of dehydration. The results correspond to the biphasic theory and may be used to help model the biomechanical and physiological properties of VF LP tissue during rehydration. PMID- 20951552 TI - A comparison of the VHI, VHI-10, and V-RQOL for measuring the effect of botox therapy in adductor spasmodic dysphonia. AB - BACKGROUND: Although disease-specific quality-of-life (QOL) instruments are an invaluable outcome measure in spasmodic dysphonia, there is no consensus on which QOL instrument should be used. OBJECTIVE: To determine the responsiveness of the Voice Handicap Index (VHI), Voice Handicap Index-10 (VHI-10), and Voice-Related Quality of Life (V-RQOL) to the treatment effect of botulinum toxin (Botox) in adductor spasmodic dysphonia (ADSD). SETTING: Stanford University Voice and Swallowing Center. DESIGN: Prospective case series (level of evidence=4). METHODS: Consecutive ADSD patients with a stable Botox dose-response relationship were recruited prospectively. VHI, VHI-10, and V-RQOL scores were obtained pretreatment and during the middle third of the posttreatment injection cycle. RESULTS: Thrity-seven patients completed the follow-up. The average total Botox dose was 0.88 units. The average follow-up time after injection was 7.84 weeks. The pretreatment QOL scores reflected the burden of the disease. All the three instruments were highly correlated in subscale and total scores. After treatment, all three instruments showed significant improvement. CONCLUSION: The VHI, VHI 10, and V-RQOL all reflected the morbidity associated with ADSD and were significantly responsive to the effect of Botox therapy. The choice of instrument should be based on physician preference. PMID- 20951553 TI - Temporomandibular joint synovial chondromatosis with a traumatic etiology. AB - Synovial chondromatosis (SC) is a metaplastic disorder characterized by the formation of cartilaginous nodules inside the articular space. SC is uncommon in the temporomandibular joint (TMJ). A few reports suggest a correlation between a traumatic episode and the development of SC. The authors describe the diagnosis, treatment and follow-up of a patient with unilateral SC of the left TMJ in conjunction with bony resorption on the mandibular condyle and a clear traumatic etiology. They review and comment on previous reports in the literature. PMID- 20951554 TI - Impact of reduced left atrial functions on diagnosis of paroxysmal atrial fibrillation: results from analysis of time-left atrial volume curve determined by two-dimensional speckle tracking. AB - BACKGROUND: Atrial fibrillation is commonly associated with impaired reservoir and booster functions of the left atrium (LA). Recent advances in two-dimensional speckle tracking technique (2DST) enabled automatic analysis of the time-LA volume curve representing these functions. Our objective was to evaluate LA function in patients with or without paroxysmal atrial fibrillation (PAF) using 2DST. METHODS: We studied 111 patients (68 men, age 62 +/- 16 years) with (n = 53) or without (n = 58) PAF. After constructing time-LA volume curves from the apical four and two chamber views (iE33, Philips with QLAB 6.0, Philips Medical Systems, Bothell, WA, USA), maximal LA volume (LAVmax), preatrial contraction LA volume (LAVpreA), and minimum LA volume (LAVmin) were obtained. Then, LA reservoir volume (ARV=LAVmax-LAVmin) and active emptying volume (AEV=LAVpreA LAVmin) were calculated to determine ARV/LAVmax as reservoir function and AEV/LAVpreA as booster pump function. RESULTS: PAF was associated with greater LAVmax than that in controls (80 +/- 21 ml versus 65 +/- 16 ml, p < 0.001) and with reduced reservoir and booster functions (ARV/LAVmax 46 +/- 9% versus 52 +/- 7%; AEV/LAVpreA 29 +/- 10% versus 36 +/- 6%, p < 0.001). Multivariate logistic analysis demonstrated that ARV/LAVmax and AEV/LAVpreA were closely associated with the existence of PAF. CONCLUSION: These results demonstrate that the present 2DST enables determining LA reservoir and booster functions, providing insights into the diagnosis of PAF. PMID- 20951555 TI - Vigabatrin-induced peripheral visual field defects in patients with refractory partial epilepsy. AB - PURPOSE: Vigabatrin can cause retinopathy, resulting in bilateral visual field constriction. Previous analyses of results from a prospective, observational study assessing vigabatrin-induced visual field constriction (described below) employed a partially subjective interpretation of static perimetery. To affirm these previous findings through more objective, quantitative methodology, we now report data from a subset analysis of refractory partial epilepsy patients in the study who underwent Goldmann kinetic perimetry. METHODS: Patients aged >= 8 years with refractory partial seizures were enrolled and grouped: those receiving vigabatrin for >= 6 months (Group I); those who had received vigabatrin for >= 6 months and then had discontinued for >= 6 months (Group II); and those naive to vigabatrin (Group III). Patients underwent static or kinetic perimetry, or both, every 4-6 months for <= 3 years. For kinetic perimetry, the temporal and nasal visual fields were measured along the horizontal meridian with the largest (V4e, IV4e) and smallest (I2e, I1e) isopters, respectively. RESULTS: Of 735 patients enrolled, 341 had Goldmann perimetry data. Of these, 258 received vigabatrin. Sixteen percent of vigabatrin-exposed patients had moderate visual field defects (30-60 degrees retained temporal vision), and 3% had severe defects (< 30 degrees retained temporal vision). Visual function questionnaire results indicated a weak correlation between visual field constriction severity and visual symptoms. CONCLUSIONS: These results affirm both an analysis of the same study based primarily on static perimetry and findings from cross-sectional studies. The present analysis verifies that visual field constriction, when it occurs, is most often mild or moderate and is not associated with symptoms of abnormal visual function. The clinical decision to prescribe vigabatrin should be based on a benefit-risk analysis for each individual patient. PMID- 20951556 TI - Absolute spike frequency and etiology predict the surgical outcome in epilepsy due to amygdala lesions. AB - PURPOSE: To identify surgical prognostic factors for temporal lobe epilepsy (TLE) due to amygdala lesions. METHODS: We included 42 patients (mean age: 31.4 +/- 11) who underwent presurgical evaluation including long-term video-EEG and in whom the high-resolution MRI showed amygdala lesions without hippocampal abnormalities. All patients had apical temporal lobe resection without hippocampectomy. We distinguished patients with frequent spikes (spike frequency >= 60/h) and with non-frequent spikes (< 60 spikes/h). RESULTS: At the 2-year postoperative evaluation, 30 patients (71%) were seizure-free. The presence of infrequent spikes (p = 0.013), tumor on the MRI (p = 0.027), and no epilepsy history in the family (p = 0.027) were independently associated with 2-year seizure-free outcome. Of 33 patients with infrequent spikes, 79% became seizure free, while of 9 patients with frequent spikes only 4 had a favorable surgical outcome (44%). CONCLUSION: In TLE patients due to amygdala lesions, high spike frequency and family history of epilepsy predicted an unfavorable, while tumoral etiology a favorable outcome after apical temporal lobe resection without hippocampectomy. Seventy-one percent of patients with amygdalar epilepsy who underwent this novel type of epilepsy surgery became seizure-free. This is comparable with results of "classical" anterior temporal lobe resections where hippocampus is NOT spared. Moreover, the surgical outcome may be predictable. PMID- 20951557 TI - Estimation of an optimal chemotherapy utilisation rate for primary malignant brain tumours: an evidence-based benchmark for cancer care. AB - AIMS: The optimal chemotherapy utilisation rate can serve as a benchmark to assess the quality of cancer care. The aim of this study was to determine the optimal proportion of patients with primary malignant brain tumours for whom there was evidence that they should receive chemotherapy at least once. MATERIALS AND METHODS: An optimal chemotherapy utilisation tree was constructed using indications for chemotherapy identified from evidence-based treatment guidelines. Data on the proportion of patient and tumour-related attributes for which chemotherapy was indicated were obtained and merged with the treatment indications to calculate an optimal chemotherapy utilisation rate. This optimal rate was compared with reported actual rates of chemotherapy utilisation. RESULTS: Chemotherapy is indicated at least once, either as an initial treatment or at recurrence (in those who have not previously received chemotherapy), in 72% of all patients with primary malignant brain tumours. No recent published data on actual chemotherapy utilisation rates were identified for comparison with the optimal rate. CONCLUSION: The optimal chemotherapy utilisation rate can serve as an evidence-based benchmark in the planning and evaluation of chemotherapy services for brain cancer. There are no recent published patterns of care studies that report on chemotherapy utilisation rates for primary malignant brain tumours; future research should focus on filling this gap. PMID- 20951558 TI - Mammary gland proliferation in female rats: effects of the estrous cycle, pseudo pregnancy and age. AB - Assessment of mammary gland proliferation in rats is an important endpoint in preclinical safety studies of pharmaceutical compounds. However, existing data on mammary gland proliferation in rats during the estrous cycle is conflicting, and it is unknown whether mammary gland proliferation differs between young and mature female virgin rats. Additionally, it is unclear which of the commonly applied markers of proliferating cells that is optimal for assessment of rat mammary gland proliferation. In this study the caudal thoracic, the abdominal and the cranial inguinal (i.e., the 3rd the 4th and the 5th) mammary gland were collected from 29 young and 26 mature non-treated, virgin female Sprague Dawley rats. Estrous cycle stage was determined from repeated vaginal smears and histological examination of the reproductive organs. Proliferation of mammary epithelium was assessed by immunohistochemistry using three markers: PCNA, Ki67, and BrdU. Proliferation of the mammary epithelium occurred mainly in the terminal end buds in the young animals. Epithelial proliferation was significantly increased during metestrus compared to the other phases. Mammary gland proliferation in pseudo-pregnant females was increased compared to proestrus, estrus and diestrus, but not metestrus. Except during estrus no difference in mammary gland proliferation was observed between young and mature female rats, and no significant differences was observed between different mammary glands. The percentages of PCNA-, Ki67- and BrdU-positive epithelial cells were significantly correlated. In conclusion, the variation in normal proliferation between estrous cycle stages and animals with an irregular estrous cycle should be considered in toxico-pathological studies of mammary gland proliferation. PMID- 20951559 TI - Arrangement of collagen fibers in the wall of the main gastrocnemius venous trunk in humans. AB - The main gastrocnemius trunk (MGT) drains all of the blood from the network formed by the gastrocnemius veins that emerge from the gastrocnemius muscle. Twenty MGTs were used (nine medial and eleven lateral), from male human cadavers of mean age 31.42+/-10.93 years, fixed in 10% formalin solution. The aim of this study was to analyze the arrangement of the bundles of collagen fibers in the wall of the MGT. Sections were stained using Masson's trichrome and picrosirius red solutions and were examined under a polarizing microscope. The bundles of collagen fibers in the wall of the MGT were seen to be arranged in a continuous three-dimensional network, in which bundles crossing in two fundamentally opposite directions formed meshes that, along with the bundles themselves, decreased in size from the tunica adventitia to the tunica intima. These findings may contribute towards understanding the state of functional adaptation of the MGT to responses of dilatation, distensibility and increased venous pressure, in normal and pathological situations. PMID- 20951560 TI - Report on the 4th International FESTEM Symposium on "Recent advances in trace element research: From experiments to nutritional and clinical applications in humans" (Saint Petersburg, Russia, June 09-12th, 2010). PMID- 20951561 TI - Pro: the treatment of the granulomatous response is beneficial in acute sarcoidosis. PMID- 20951562 TI - The proglycation effect of caffeic acid leads to the elevation of oxidative stress and inflammation in monocytes, macrophages and vascular endothelial cells. AB - In this study, the effects of phenolic acids [caffeic acid (CA), ferulic acid, m coumaric acid, and chlorogenic acid] on methylglyoxal (MG)-induced protein glycation were investigated in vitro. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and advanced glycation end products (AGEs)-specific fluorescence showed that MG-mediated protein modification was enhanced dose-dependently by CA (P<.05), whereas alpha-lipoic acid, glutathione and EDTA inhibited these changes. Electron paramagnetic resonance spectra showed that CA increased reactive oxygen species (ROS) production during glycation, suggesting the proglycation mechanism of CA is associated with its pro-oxidative properties. Additionally, fetal bovine serum (FBS) was utilized as the source of target proteins for evaluating the effects of CA in cells. Differential glycation of FBS samples was performed by incubating FBS with MG, CA or aminoguanidine (AG, an AGE inhibitor). FBS incubated with MG and CA (MG/CA-FBS) evoked the greatest deleterious responses, as follows: (1) inducing proinflammatory tumor necrosis factor (TNF)-alpha and interleukin-1beta expression and ROS production in monocytic THP-1 cells, (2) stimulating TNF-alpha secretion in RAW 264.7 macrophages and (3) causing oxidative DNA damage and inducing the expression of receptor for AGEs (RAGE), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 in human umbilical vein endothelial cells. Furthermore, adhesion and transendothelial migration of monocytes were also significantly increased by MG/CA-FBS treatment compared to MG-FBS (P<.05). In conclusion, our data show that CA exhibits pro-oxidative and pro-glycative effects during the glycation process, suggesting a detrimental role for CA under high-glycotoxin conditions. PMID- 20951563 TI - Eicosapentaenoic acid decreases expression of anandamide synthesis enzyme and cannabinoid receptor 2 in osteoblast-like cells. AB - Anandamide (AEA) is an endogenous agonist for the cannabinoid receptor 2 (CB2) which is expressed in osteoblasts. Arachidonic acid (AA) is the precursor for AEA and dietary n-3 polyunsaturated fatty acids (PUFA) are known to reduce the concentrations of AA in tissues and cells. Therefore, we hypothesized that n-3 PUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which reduce AA in cells, could lower AEA in osteoblasts by altering enzyme expression of the endocannabinoid (EC) system. MC3T3-E1 osteoblast-like cells were grown for 6, 10, 15, 20, 25 or 30 days in osteogenic medium. Osteoblasts were treated with 10 MUM of AA, EPA, DHA, oleic acid (OA) or EPA+DHA (5 MUM each) for 72 h prior to their collection for measurement of mRNA and alkaline phosphatase (ALP) activity. Compared to vehicle control, osteoblasts treated with AA had higher levels of AA and n-6 PUFA while those treated with EPA and DHA had lower n-6 but higher n-3 PUFA. Independent of the fatty acid treatments, osteoblasts matured normally as evidenced by ALP activity. N-acyl phosphatidylethanolamine-selective phospholipase D (NAPE-PLD), fatty acid amide hydrolase (FAAH) and CB2 mRNA expression were higher at 20 days compared to 10 days. NAPE-PLD and CB2 mRNA was lower in osteoblasts treated with EPA compared to all other groups. Thus, mRNA expression for NAPE-PLD, FAAH, and CB2 increased during osteoblast maturation and EPA reduced mRNA for NAPE-PLD and CB2 receptor. In conclusion, EPA lowered mRNA levels for proteins of the EC system and mRNA for AEA synthesis/degradation is reported in osteoblasts. PMID- 20951564 TI - Comparison of mass balance, energy consumption and cost of composting facilities for different types of organic waste. AB - Mass balance, energy consumption and cost are basic pieces of information necessary for selecting a waste management technology. In this study, composting facilities that treat different types of organic waste were studied by questionnaire survey and via a chemical analysis of material collected at the facilities. The mass balance was calculated on a dry weight basis because the moisture content of organic waste was very high. Even though the ratio of bulking material to total input varied in the range 0-65% on a dry basis, the carbon and ash content, carbon/nitrogen ratio, heavy metal content and inorganic nutrients in the compost were clearly influenced by the different characteristics of the input waste. The use of bulking material was not correlated with ash or elemental content in the compost. The operating costs were categorised into two groups. There was some economy of scale for wages and maintenance cost, but the costs for electricity and fuel were proportional to the amount of waste. Differences in operating costs can be explained by differences in the process characteristics. PMID- 20951565 TI - Gold coated ferric oxide nanoparticles based disposable magnetic genosensors for the detection of DNA hybridization processes. AB - In this article, a disposable magnetic DNA sensor using an enzymatic amplification strategy for the detection of specific hybridization processes, based on the coupling of streptavidin-peroxidase to biotinylated target sequences, has been developed. A thiolated 19-mer capture probe was attached to gold coated ferric oxide nanoparticles and hybridization with the biotinylated target was allowed to proceed. Then, a streptavidin-peroxide was attached to the biotinylated target and the resulting modified gold coated ferric oxide nanoparticles were captured by a magnetic field on the surface of a home-made carbon screen printed electrode (SPE). Using hydroquinone as a mediator, a square wave voltammetric procedure was chosen to detect the hybridization process after the addition of hydrogen peroxide. Different aspects concerning the assay protocol and nanoparticles fabrication were optimized in order to improve the sensitivity of the developed methodology. A low detection limit (31 pM) with good stability (RSD=7.04%, n=10) was obtained without the need of polymerase chain reaction (PCR) amplification. PMID- 20951566 TI - New trends in instrumental design for surface plasmon resonance-based biosensors. AB - Surface plasmon resonance (SPR)-based biosensing is one of the most advanced label free, real time detection technologies. Numerous research groups with divergent scientific backgrounds have investigated the application of SPR biosensors and studied the fundamental aspects of surface plasmon polaritons that led to new, related instrumentation. As a result, this field continues to be at the forefront of evolving sensing technology. This review emphasizes the new developments in the field of SPR-related instrumentation including optical platforms, chips design, nanoscale approach and new materials. The current tendencies in SPR-based biosensing are identified and the future direction of SPR biosensor technology is broadly discussed. PMID- 20951567 TI - Real-time detection of DNA hybridization on microarray using a CCD-based imaging system equipped with a rotated microlens array disk. AB - This work describes a novel charge-coupled device (CCD)-based imaging system (MB Biochip ReaderTM) for real-time detection of DNA hybridization to DNA microarrays. The MB Biochip ReaderTM consisted of a laser light source (532 nm), a microlens array for generation of a multi-beam laser, and a CCD for 2-D signal imaging. The MB Biochip ReaderTM with a rotated microlens array, allowed large field imaging (6.2 mm * 7.6 mm with 6.45 MUm resolution) with fast time resolution at 0.2 s without speckle noise. Furthermore, real-time detection of DNA hybridization, which is sufficient to obtain accurate data from tens of thousands of array element per field, was successfully performed without the need for laser scanning. The performance of the MB Biochip ReaderTM for DNA microarray imaging was similar to the commercially available photomultiplier tube (PMT) based microarray scanner, ScanArray Lite. The system potentially could be applied toward real-time analysis in many other fluorescent techniques in addition to real-time DNA microarray analysis. PMID- 20951568 TI - Highly stable enzyme precipitate coatings and their electrochemical applications. AB - This paper describes highly stable enzyme precipitate coatings (EPCs) on electrospun polymer nanofibers and carbon nanotubes (CNTs), and their potential applications in the development of highly sensitive biosensors and high-powered biofuel cells. EPCs of glucose oxidase (GOx) were prepared by precipitating GOx molecules in the presence of ammonium sulfate, then cross-linking the precipitated GOx aggregates on covalently attached enzyme molecules on the surface of nanomaterials. EPCs-GOx not only improved enzyme loading, but also retained high enzyme stability. For example, EPC-GOx on CNTs showed a 50 times higher activity per unit weight of CNTs than the conventional approach of covalent attachment, and its initial activity was maintained with negligible loss for 200 days. EPC-GOx on CNTs was entrapped by Nafion to prepare enzyme electrodes for glucose sensors and biofuel cells. The EPC-GOx electrode showed a higher sensitivity and a lower detection limit than an electrode prepared with covalently attached GOx (CA-GOx). The CA-GOx electrode showed an 80% drop in sensitivity after thermal treatment at 50 degrees C for 4 h, while the EPC-GOx electrode maintained its high sensitivity with negligible decrease under the same conditions. The use of EPC-GOx as the anode of a biofuel cell improved the power density, which was also stable even after thermal treatment of the enzyme anode at 50 degrees C. The excellent stability of the EPC-GOx electrode together with its high current output create new potential for the practical applications of enzyme-based glucose sensors and biofuel cells. PMID- 20951569 TI - An assessment of peripheral vascular disease in patients with diabetic foot ulcer. AB - BACKGROUND: Peripheral vascular disease (PVD) is a chronic limb ischaemia caused by atherosclerosis of the peripheral arteries. Diabetes mellitus is a risk factor for this disease. The most common symptom of PVD is muscle pain in the lower limbs on exercise. In diabetes, pain perception may be blunted by the presence of peripheral neuropathy. Therefore, a patient with diabetes and PVD is more likely to present with an ischaemic ulcer or gangrene than a patient without diabetes. The use of ankle-brachial-pressure index (ABI) in the clinic and bedside provide a measure of blood flow to the ankle. This could help early detection, initiate early therapy and may thus reduce the risk of critical limb ischaemia and limb loss. OBJECTIVE: The purpose of this study is to evaluate the occurrence of peripheral vascular disease using ankle-brachial index in diabetic patients with and without foot ulcers and the risk factors associated with diabetic foot ulcer (DFU). METHOD: This prospective study involved all type 2 DM patients with foot ulcer (DFU population) and those without foot ulcers (non-DFU population) seen in our hospital. Their demographic, clinical and laboratory parameters were noted and documented. Measurement of ABI was done using a portable hand held Doppler and ankle pressures<0.9 is suggestive of PVD. RESULTS: A total of 74 patients were recruited. Males were 42 (56.8%) and females were 32 (43.2%). The mean age of the patients was 62.89+/-10.66 years and the duration of diabetes was 7.61+/ 7.57 years. Forty-six (62.2%) presented with foot ulcer while 28 (37.8%) were without foot ulcer. Patients with PVD represented by ABI<0.9 was DFU 31(76.4%) while in non-DFU it was 10 (13.4%). Multivariant analysis of variables associated with DFU in those with ABI<0.9 showed correlation with tobacco use r=.235, p=0.044; duration of diabetes r=-.427; p=0.001; and systolic blood pressure r= .301; p=0.009. DISCUSSION: The occurrence of PVD determined by the absence of >2 pulses by palpation alone and using ABI was 25.7% and 55.4% respectively. This suggests that assessment by palpation is subjective while the use of Doppler is quantitative and more reliable. DFU patients with PVD showed a significant correlation with tobacco use, duration of diabetes and systolic blood pressure but not with dyslipidaemia. CONCLUSION: This study shows that these patients had risk factors for PVD. The use of hand held Doppler will aid early diagnosis of critical limb at risk of loss and help to prevent and reduce the high rate of limb loss in our patients. PMID- 20951570 TI - The early results of minimally invasive technique for hallux valgus repair. PMID- 20951571 TI - S-Adenosylmethionine-dependent radical-based modification of biological macromolecules. AB - Proteins and RNA molecules enjoy a variety of chemically complex post translational and post-transcriptional modifications. The chemistry at work in these reactions, which was considered to be exclusively ionic in nature has recently been shown to depend on radical mechanisms in some cases. The overwhelming majority of these radical-based reactions are catalyzed by 'Radical SAM' enzymes. This review article highlights mechanistic and structural aspects of this class of reactions and indicates important research directions to be addressed. PMID- 20951572 TI - Substrate activation by iron superoxo intermediates. AB - A growing number of non-heme-iron oxygenases and oxidases catalyze reactions for which the well-established mechanistic paradigm involving a single C-H-bond cleaving intermediate of the Fe(IV)-oxo (ferryl) type [1(*)] is insufficient to explain the chemistry. It is becoming clear that, in several of these cases, Fe(III)-superoxide complexes formed by simple addition of O(2) to the reduced [Fe(II)] cofactor initiate substrate oxidation by abstracting hydrogen [2,3(*)]. This substrate-oxidizing entry route into high-valent-iron intermediates makes possible an array of complex and elegant oxidation reactions without the consumption of valuable reducing equivalents. Examples of this novel mechanistic strategy are discussed with the goal of bringing forth unifying principles. PMID- 20951573 TI - Thirsty plants and beyond: structural mechanisms of abscisic acid perception and signaling. AB - Abscisic acid (ABA) is a plant hormone with important functions in stress protection and physiology. Recently, the PYR/PYL/RCAR family of intracellular ABA receptors was identified. These receptors directly link ABA perception to a canonical ABA signaling pathway, in which ABA-bound receptors bind and inhibit type 2C phosphatases. High resolution crystal structures of members of this family have been solved in all relevant states: as apo receptors, bound to ABA, and as receptor-ABA-phosphatase complexes. Together, these structures provide a detailed gate-latch-lock mechanism of ABA recognition, receptor-PP2C interaction, and inhibition of the PP2C phosphatase activity and provide a basis for the design of synthetic ABA agonists for stress protection of crop plants. PMID- 20951574 TI - Relationship between changes in haemoglobin A1C and prostate-specific antigen in healthy men. AB - BACKGROUND: Although many studies have shown an inverse relationship between diabetes and prostate cancer, it still remains unclear why diabetes may reduce the risk of prostate cancer. An inverse association between haemoglobin A(1C) (HbA(1C)) and prostate-specific antigen (PSA) also has been reported in previous studies that assessed the association cross-sectionally. To fully understand the relationship between diabetes and prostate cancer, it is essential to examine the association in a longitudinal design. The effect of plasma volume should also be considered in examining the PSA level. The aim of this study was to determine whether changes in HbA(1C) were associated with PSA levels, independent of plasma volume changes, as indicated by haematocrit and weight. METHODS: We investigated 5917 Japanese men aged 50 and over who visited St. Luke's International Hospital, Tokyo for routine health check-ups in 2006 and 2007. We performed a multiple linear regression analysis to examine any association between changes in HbA(1C) and PSA over 1 year. RESULTS: Adjusting for age, body mass index at baseline and changes in weight and haematocrit, the increases in HbA(1C) and PSA were concordant (5.7% increase per 1-unit HbA(1C) change; 95% confidence interval, 2.8 8.5%; p<0.001). CONCLUSIONS: In contrast to previous cross-sectional observations showing an inverse association between HbA(1C) and PSA, longitudinal observations suggest a positive association between the two. Further studies are needed to investigate the association between diabetes and prostate cancer. PMID- 20951576 TI - Numerical simulation of mechanical mixing in high solid anaerobic digester. AB - Computational fluid dynamics (CFD) was employed to study mixing performance in high solid anaerobic digester (HSAD) with A-310 impeller and helical ribbon. A mathematical model was constructed to assess flow fields. Good agreement of the model results with experimental data was obtained for the A-310 impeller. A systematic comparison for the interrelationship of power number, flow number and Reynolds number was simulated in a digester with less than 5% TS and 10% TS (total solids). The simulation results suggested a great potential for using the helical ribbon mixer in the mixing of high solids digester. The results also provided quantitative confirmation for minimum power consumption in HSAD and the effect of share rate on bio-structure. PMID- 20951575 TI - Serum CCL2 and serum TNF-alpha--two new biomarkers predict bone invasion, post treatment distant metastasis and poor overall survival in nasopharyngeal carcinoma. AB - PURPOSE: To evaluate the prognostic potential of serum CCL2 (sCCL2) and serum TNF alpha (sTNF-alpha) in nasopharyngeal carcinoma (NPC) before treatment by analysing the expression of these two markers. EXPERIMENTAL DESIGN: Both sCCL2 and sTNF-alpha were prospectively detected in 297 NPC patients with enzyme-linked immunosorbent assay (ELISA) before treatment. The correlations between sCCL2 level or sTNF-alpha level and patient's survival were evaluated. RESULTS: For sCCL2, the 5-year overall survival (OS) and 5-year distant metastasis-free survival (DMFS) of high expression group and low expression group were 64% versus 81% and 67% versus 84% (P < 0.05), respectively. For sTNF-alpha, the 5-year OS and 5-year DMFS of high expression group and low expression group were 62% versus 79% and 66% versus 82% (P < 0.05), respectively. The 5-year OS and 5-year DMFS for both positive patients, one marker positive patient and both negative patients were 53% versus 77% versus 85% and 58% versus 80% versus 86% (P < 0.05), respectively. Concentrations of sCCL2 and sTNF-alpha in patients with large skull base invasion were higher than those without or with small skull invasion (P < 0.05). Patients who developed bone metastasis alone after radical treatment had higher pre-treatment concentrations of sCCL2 and sTNF-alpha than those without metastasis (P < 0.001). Multifactorial Cox regression analyses demonstrated that T/N/M classification, chemotherapy, sCCL2 level and sTNF-alpha level were independent predictors of OS and DMFS of NPC patients. CONCLUSION: High expression levels of sCCL2 and sTNF-alpha predict bone invasion, post-treatment distant metastasis and poor overall survival in NPC patients. PMID- 20951577 TI - Esterification of acidified oil with methanol by SPES/PES catalytic membrane. AB - A sulfonated polyethersulfone (SPES)/polyethersulfone (PES) blend catalytic membrane was prepared and used as a heterogeneous catalyst in the esterification of the acidified oil (acid value 153 mg KOH/g) with methanol for producing biodiesel. The results showed that the free fatty acids conversion reached 97.6% using SPES/PES catalytic membrane under the optimal esterification conditions. Meanwhile, the SPES/PES membrane with 20.3% degree of sulfonation showed a good catalytic stability. A pseudo-homogeneous kinetic model was established. The results indicated that the reaction rate constant increased with increasing methanol/acidified oil molar ratio, the loading of catalytic membrane and reaction temperature. The reaction order was 2 and the activation energy decreased from 74.65 to 21.07 kJ/mol with increasing catalytic membrane loading from 0 to 0.135 meq/g(oil). It implies that the esterification is not diffusively controlled but kinetically controlled. The predicted results were in good agreement with the experimental data. PMID- 20951578 TI - Composting domestic sewage sludge with natural zeolites in a rotary drum reactor. AB - This work aimed the influence of zeolites addition on a sludge-straw composting process using a pilot-scale rotary drum reactor. The type and concentration of three commercial natural zeolites were considered: a mordenite and two clinoptilolites (Klinolith and Zeocat). Mordenite caused the greatest carbon removal (58%), while the clinoptilolites halved losses of ammonium. All zeolites removed 100% of Ni, Cr, Pb, and significant amounts (more than 60%) of Cu, Zn and Hg. Zeocat displayed the greatest retention of ammonium and metals, and retention efficiencies increased as Zeocat concentration increased. The addition of 10% Zeocat produced compost compliant with Spanish regulations. Zeolites were separated from the final compost, and leaching studies suggested that zeolites leachates contained very low metals concentrations (<1 mg/kg). Thus, the final compost could be applied directly to soil, or metal-polluted zeolites could be separated from the compost prior to application. The different options have been discussed. PMID- 20951579 TI - Anaerobic co-digestion of desugared molasses with cow manure; focusing on sodium and potassium inhibition. AB - Desugared molasses (DM), a syrup residue from beet-molasses, was investigated for biogas production in both batch and in continuously-stirred tank reactor (CSTR) experiments. DM contained 2-3 times higher concentration of ions than normal molasses, which could inhibit the biogas process. The effect of sodium and potassium concentration on biogas production from manure was also investigated. Fifty percent inhibition occurred at sodium and potassium concentration of 11 and 28 g/L, respectively. The reactor experiments were carried out to investigate the biogas production from DM under different dilutions with water and co-digestion with manure. Stable operation at maximum methane yield of 300 mL-CH4/gVS-added was obtained at a mixture of 5% DM in cow manure. The biogas process was inhibited at DM concentrations higher than 15%. Manure was a good base substrate for co-digestion, and a stable anaerobic digestion could be achieved by co digesting DM with manure at the concentration below 15% DM. PMID- 20951580 TI - Plants for waste water treatment--effects of heavy metals on the detoxification system of Typha latifolia. AB - Upon treatment with Cd and As cattail (Typha latifolia) showed induced catalase, monodehydroascorbate reductase and ascorbate peroxidase activities in leaves but strong inhibition in rhizomes. Peroxidase activity in leaves of the same plants was inhibited whereas linear increase was detected after Cd treatment in rhizomes. Glutathione S-transferase measurements resulted in identical effects of the trace elements on the substrates CDNB, DCNB, NBC, NBoC, fluorodifen. When GST was assayed with the model substrate DCNB, a different pattern of activity was observed, with strongly increasing activities at increasing HM concentrations. Consequently, to improve the success rates, future phytoremediation plans need to preselect plant species with high antioxidative enzyme activities and an alert GST pattern capable of detoxifying an array of organic xenobiotics. PMID- 20951581 TI - Conjugation of laccase from the white rot fungus Trametes versicolor to chitosan and its utilization for the elimination of triclosan. AB - A commercial laccase from Trametes versicolor was conjugated with biopolymer chitosan using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) as the cross-linking agent. Laccase-chitosan conjugation strategies were tested using different molar ratios of glucosamine monomer/protein with different molar excess ratios of EDC relative to laccase. Immobilization techniques were developed to improve the stability against thermal and chemical denaturation, storage and reusability of this biocatalyst. The conjugation resulted in a solid biocatalyst with an apparent laccase activity of +/-626 U/g, 12 and 60 folds higher in the conjugation efficiency of biocatalyst relative to the immobilized and free laccase activity respectively when compared with zero EDC/laccase ratio used in conjugation solution. The conjugated laccases formed successfully eliminated the emerging pollutant triclosan (TCS) from aqueous solutions, having a higher potential to transform TCS than free laccase. UPLC-QTOF results indicate the formation of TCS oligomers. Furthermore, they are the first evidence of direct dechlorination of TCS mediated by the oxidative action of laccases. PMID- 20951582 TI - Oleanane-type triterpenoids from Panax stipuleanatus and their anticancer activities. AB - One newly (1) and 10 known oleanane-type triterpenoids (2-11) were isolated from the methanol extract of Panax stipuleanatus rhizomes. Based on their spectroscopic data, these compounds were identified as spinasaponin A methyl ester (1), pesudoginsenoside RP(1) methyl ester (2), spinasaponin A 28-O glucoside (3), pseudoginsenoside RT(1) methyl ester (4), pseudoginsenoside RT(1) (5), stipuleanoside R(2) methyl ester (6), stipuleanoside R(2) (7), araloside A methyl ester (8), 3-O-beta-D-glucopyranosyl (1->3)-beta-D-glucuronopyranoside-28 O-beta-D-glucopyranosyl oleanolic acid methyl ester (9), 3-O-beta-D-xylopyranosyl (1->2)-beta-D-glucopyranosyl-28-O-beta-D-glucopyranosyl oleanolic acid (10), and chikusetsusaponin IVa (11). When the cytotoxic activities of the isolated compounds were evaluated, compound 1 exhibited significant cytotoxic activity with IC(50) values of 4.44 and 0.63 MUM against HL-60 (leukemia) and HCT-116 (colon cancer) cell lines, respectively. Compound 2 showed potent cytotoxicity with an IC(50) of 6.50 MUM against HCT-116, whereas it was less cytotoxic against HL-60 (IC(50)=41.45 MUM). After HL-60 and HCT-116 were treated with compounds 1 and 2, increased production of apoptotic bodies was observed. Furthermore, compounds 1 and 2 in HCT-116 cells activated intrinsic and extrinsic apoptosis pathways by upregulating DR-5 and Bax, downregulating Bcl-2, activating caspase 9, and cleaving poly-ADP-ribose polymerase (PARP). We also observed the activation of ERK1/2 MAPK by both compounds in the HCT-116 cells. Together, compounds 1 and 2 might induce intrinsic and extrinsic apoptosis pathways through the activation of the ERK1/2 MAPK pathway in HCT-116 colon cancer cells. Structure-activity relationship analysis indicated that a carboxyl group at position-28 is potentially responsible for the cytotoxic effects. PMID- 20951583 TI - Antimalarial histone deacetylase inhibitors containing cinnamate or NSAID components. AB - Malaria is the most lethal parasite-mediated tropical infectious disease, killing 1-2 million people each year. An emerging drug target is the enzyme Plasmodium falciparum histone deacetylase 1 (PfHDAC1). We report 26 compounds designed to bind the zinc and exterior surface around the entrance to the active site of PfHDAC1, 16 displaying potent in vitro antimalarial activity (IC(50)<100 nM) against P. falciparum. Selected compounds were shown to cause hyperacetylation of P. falciparum histones and be >10-fold more cytotoxic towards P. falciparum than a normal human cell type (NFF). Twenty-two inhibitors feature cinnamic acid derivatives or non-steroidal anti-inflammatory drugs (NSAIDs) as HDAC-binding components. A homology model of PfHDAC1 enzyme gives new insights to interactions likely made by some of these inhibitors. Results support PfHDAC1 as a promising new antimalarial drug target. PMID- 20951584 TI - 5-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4 dihydro-2(1H)-quinolinones: dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors. Part 3. AB - 5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4 dihydro-2(1H)-quinolinones have been identified with different combinations of 5 HT(1) autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at targets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different pharmacological profiles in a range of animal behavioral and disease models. PMID- 20951585 TI - WITHDRAWN: Anti-proliferative effects of compounds from the fruit peel of Wisteria floribunda on vascular smooth muscle cells. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 20951586 TI - Adjuvant oral etoposide plus cisplatin (EoP) following sequential doxorubicin/cyclophosphamide (AC) and docetaxel (T) in early breast cancer patients with 4 or more positive lymph nodes (10 years follow-up). AB - BACKGROUND AND OBJECTIVES: Previous reports suggest that including cisplatin plus etoposide in the adjuvant treatment may improve the outcomes in patients with early breast cancer. PATIENTS AND METHODS: Forty-one patients with early breast cancer and 4 or more positive lymph nodes were treated with 3 cycles of EoP (oral etoposide plus cisplatin) in addition to 3 cycles of AC (doxorubicin plus cyclophosphamide) and 3 cycles of T (docetaxel) (Group 1). Toxicity and survival results were compared to those with similar disease characteristics who were treated with 4 cycles of AC plus 4 cycles of T (Group 2) during the same period. RESULTS: There were no long-term side effects related to EoP. While median disease-free and overall survivals were not reached in Group 1, they were 107 +/- 13 (p = 0.387) months and 123 +/- 5 months (p = 0.618) in Group 2. Likewise 10 year disease-free survivals (DFS) were 59.3% and 44.7% respectively. CONCLUSIONS: The trend towards improvement in survival with adjuvant AC + T + EoP when compared to AC + T needs to be studied in randomized trial. PMID- 20951587 TI - Kinetochores' gripping feat: conformational wave or biased diffusion? AB - Climbing up a cliff while the rope unravels underneath your fingers does not sound like a well-planned adventure. Yet chromosomes face a similar challenge during each cell division. Their alignment and accurate segregation depends on staying attached to the assembling and disassembling tips of microtubule fibers. This coupling is mediated by kinetochores, intricate machines that attach chromosomes to an ever-changing microtubule substrate. Two models for kinetochore microtubule coupling were proposed a quarter century ago: conformational wave and biased diffusion. These models differ in their predictions for how coupling is performed and regulated. The availability of purified kinetochore proteins has enabled biochemical and biophysical analyses of the kinetochore-microtubule interface. Here, we discuss what these studies reveal about the contributions of each model. PMID- 20951588 TI - The Nebulin family: an actin support group. AB - Nebulin, a giant, actin-binding protein, is the largest member of a family of proteins (including N-RAP, nebulette, lasp-1 and lasp-2) that are assembled in a variety of cytoskeletal structures, and expressed in different tissues. For decades, nebulin has been thought to act as a molecular ruler, specifying the precise length of actin filaments in skeletal muscle. However, emerging evidence suggests that nebulin should not be viewed as a ruler but as an actin filament stabilizer required for length maintenance. Nebulin has also been implicated recently in an array of regulatory functions independent of its role in actin filament length regulation. In this review, we discuss the current evolutionary, biochemical, and functional data for the nebulin family of proteins - a family whose members, both large and small, function as cytoskeletal scaffolds and stabilizers. PMID- 20951589 TI - The role of chromatin structure in cell migration. AB - Chromatin dynamics play a major role in regulating genetic processes. Now, accumulating data suggest that chromatin structure may also affect the mechanical properties of the nucleus and cell migration. Global chromatin organization appears to modulate the shape, the size and the stiffness of the nucleus. Directed-cell migration, which often requires nuclear reshaping to allow passage of cells through narrow openings, is dependent not only on changes in cytoskeletal elements but also on global chromatin condensation. Conceivably, during cell migration a physical link between the chromatin and the cytoskeleton facilitates coordinated structural changes in these two components. Thus, in addition to regulating genetic processes, we suggest that alterations in chromatin structure could facilitate cellular reorganizations necessary for efficient migration. PMID- 20951590 TI - Assessment of postural asymmetry in mild to moderate Parkinson's disease. AB - Asymmetry of symptoms of Parkinson's disease is clinically most evident for appendicular impairments. For axial impairments such as freezing of gait, asymmetry is less obvious. To date, asymmetries in balance control in PD patients have seldom been studied. Therefore, in this study we investigated whether postural control can be asymmetrically affected in mild to moderate PD patients. Seventeen PD patients were instructed to stand as still and symmetrically as possible on a dual force-plate during two trials. Dynamic postural asymmetry was assessed by comparing the centre-of-pressure velocities between both legs. Results showed that four patients (24%) had dynamic postural asymmetry, even after correcting for weight-bearing asymmetry. Hence, this study suggests that postural control can be asymmetrical in early PD. However, future studies should investigate the prevalence of dynamic postural asymmetry, in a larger group of PD patients. It should also be further investigated whether this approach can be used as a tool to support the initial diagnosis or monitor disease progression, or as an outcome measure for interventions aimed at improving balance in PD. PMID- 20951591 TI - Age-related changes in the performance of forward reach. AB - Aging is widely considered to be associated with limited balance capacity. It is not clear if forward reach ability is also affected by aging. The purpose of this study was to determine if aging was associated with reduced ability of forward reach or changes in movement patterns. Thirty-three young and 31 older adults were instructed to reach forward as far as possible without losing balance. A motion analysis system was used to record the body kinematics to calculate the joint angle and estimate the motion of center of mass (COM) using a five-segment model. Reach distance (measured from the finger marker), COM displacement, and the distance that the COM exceeded the 2nd toe marker (COM-toe) were used to represent reach performance. The movement patterns were classified as hip, ankle or mixed strategies based upon joint kinematics. It was found that the initial location of the COM was significantly more anterior in the older adults. Older adults were found to have significantly smaller COM displacement and greater hip flexion, but did not differ from young adults in reach distance or COM-toe. Older adults overwhelmingly adopted a hip strategy, but none adopted an ankle strategy. The distribution of the different strategies also differed significantly between groups. These findings suggest that aging appears to be associated with modifications in movement patterns, but not necessarily with a reduction in the ability to approach the boundary of stability. Clinically, balance training for older adults may include the exploration and instruction of atypical movement patterns. PMID- 20951592 TI - Unraveling type III secretion systems in the highly versatile Burkholderia pseudomallei. AB - Burkholderia pseudomallei is a highly versatile pathogen capable of infecting many species of animals and plants. It is the causative agent of melioidosis, a medically important infectious disease in humans with a wide spectrum of disease manifestations. Its versatility as a pathogen is reflected in its huge 7.2Mb genome and the many virulence mechanisms it possesses, including three different type III secretion systems (T3SSs). Recent elucidation of the regulatory network of T3SS3 and the characterization of several T3SS proteins have enabled us to construct a model of the B. pseudomallei T3SS3 apparatus and evaluate the role it plays in disease pathogenesis. PMID- 20951593 TI - Identification by high-throughput screening of inhibitors of Schistosoma mansoni NAD(+) catabolizing enzyme. AB - Schistosomiasis is a major tropical parasitic disease. For its treatment, praziquantel remains the only effective drug available and the dependence on this sole chemotherapy emphasizes the urgent need for new drugs to control this neglected disease. In this context, the newly characterized Schistosoma mansoni NAD(+) catabolizing enzyme (SmNACE) represents a potentially attractive drug target. This potent NAD(+)glycohydrolase, which is localized to the outer surface (tegument) of the adult parasite, is presumably involved in the parasite survival by manipulating the host's immune regulatory pathways. In an effort to identify SmNACE inhibitors, we have developed a sensitive and robust fluorometric high throughput screening assay. The implementation of this assay to the screening of a highly diverse academic chemical library of 14,300 molecules yielded, after secondary assays and generation of dose-response curves, the identification of two natural product inhibitors, cyanidin and delphinidin. These confirmed hits inhibit SmNACE with IC(50) values in the low micromolar range. To rationalize the structure-activity relationship, several related flavonoids were tested, thereby leading to the identification of 15 additional natural product inhibitors. A selection of representative flavonoid inhibitors indicated that although they also inhibit the homologous human CD38, a selectivity in favor of SmNACE could be reached. Docking studies indicated that these inhibitors mimic the binding mode of the enzyme substrate NAD(+) and suggested the pharmacophoric features required for SmNACE active site recognition. PMID- 20951594 TI - Tuning hydrophobicity of highly cationic tetradecameric Gramicidin S analogues using adamantane amino acids. AB - Ring extended Gramicidin S analogues containing adamantane amino acids and six cationic residues were designed and evaluated. Systematic replacement of the hydrophobic residues with adamantane amino acids resulted in a small set of compounds with varying amphipathic character. It was found that the amphipathicity of these compounds is correlated to their biological activity. Several bacterial strains including MRSA strains were shown to be killed by the novel peptides. The most potent antibacterial peptides are tetradecameric GS analogues containing six positives charges and two adamantane moieties. PMID- 20951595 TI - Ligand-based virtual screening and ADME-tox guided approach to identify triazolo quinoxalines as folate cycle inhibitors. AB - In the process of drug discovery the lead-identification phase may be critical due to the likely poor safety profile of the candidates, causing the delay or even the abandonment of a certain project. Nowadays, combining molecular modeling and in vivo cellular evaluation can help to identify compounds with an enhanced safety profile. Previously, two quinoxalines have been identified as inhibitors of the folate-dependent proteins belonging to the thymidylate synthase cycle. Unfortunately, cytotoxic activity against a panel of cisplatin(cDDP)-sensitive ovarian carcinoma cell lines and their resistant counterparts was coupled with toxicity to non-tumorigenic Vero cells. Here we describe the application of a ligand-based virtual screening, and several [1,2,4]triazolo[4,3-a]quinoxalines were optimized to improve their ADME-tox profile. The resulting 4 (trifluoromethyl)-1-p-tolyl-[1,2,4]triazolo[4,3-a]quinoxaline (24), which interferes intracellularly with DHFR and TS reducing the protein levels like 5 FU, but without inducing TS ternary complex formation, was 2-times less toxic in vitro than cisplatin and 5-FU. PMID- 20951596 TI - An in situ electrochemical soft X-ray spectromicroscopy investigation of Fe galvanically coupled to Au. AB - In this paper we report a pioneering electrochemical study of the galvanic coupling of Au and Fe in neutral aqueous solutions containing sulphate and fluoride ions, carried out by synchrotron-based in situ soft X-ray imaging and X ray absorption microspectroscopy. The investigation was performed at the TwinMic X-ray Microscopy station at Elettra synchrotron facility combining X-ray imaging with MU-XAS with sub-micron lateral resolution. Using a purposely developed model thin-layer wet cell the morphology and chemical evolution of Fe electrodes in contact with aqueous solutions containing Na2SO4 and NaF have been investigated. The obtained results shed light on fundamental aspects regarding stability of Fe based metallic bipolar plates in different electrochemical environments, an important issue for durability of polymer-electrolyte fuel cells. Imaging morphological features typical of the relevant electrochemical processes with chemical contrast, yields details on the spatial distribution and speciation of Fe resulting from corrosion of the Fe electrodes in the working fuel cells. PMID- 20951597 TI - Effects of additives and templates on calcium carbonate mineralization in vitro. AB - The review focuses on the effects of several important additives and templates controlling the calcium carbonate crystals formation and the complexity of the crystal morphologies in vitro. Additives include soluble matrices extracted from shells and pearls, amino-acids, magnesium ions and collagen among others. Templates include modified single crystal silicon, natural biominerals among others. Mechanisms proposed to explain the phenomena are not systematic, further studies are necessary to explain how organic matrices mediate calcium carbonate mineralization. PMID- 20951598 TI - Biochemical and structural characterization of recombinant hyoscyamine 6beta hydroxylase from Datura metel L. AB - Hyoscyamine 6beta-hydroxylase (H6H; EC 1.14.11.11), an important enzyme in the biosynthesis of tropane alkaloids, catalyzes the hydroxylation of hyoscyamine to give 6beta-hydroxyhyoscyamine and its epoxidation in the biosynthetic pathway leading to scopolamine. Datura metel produces scopolamine as the predominant tropane alkaloid. The cDNA encoding H6H from D. metel (DmH6H) was cloned, heterologously expressed and biochemically characterized. The purified recombinant His-tagged H6H from D. metel (DmrH6H) was capable of converting hyoscyamine to scopolamine. The functionally expressed DmrH6H was confirmed by HPLC and ESI-MS verification of the products, 6beta-hydroxyhyoscyamine and its derivative, scopolamine; the DmrH6H epoxidase activity was low compared to the hydroxylase activity. The K(m) values for both the substrates, hyoscyamine and 2 oxoglutarate, were 50MUM each. The CD (circular dichroism) spectrum of the DmrH6H indicated a preponderance of alpha-helicity in the secondary structure. From the fluorescence studies, Stern-Volmer constants for hyoscyamine and 2-oxoglutarate were found to be 0.14M(-1) and 0.56M(-1), respectively. These data suggested that the binding of the substrates, hyoscyamine and 2-oxoglutarate, to the enzyme induced significant conformational changes. PMID- 20951599 TI - Isolation and characterization of novel plant growth promoting Micrococcus sp NII 0909 and its interaction with cowpea. AB - A phosphate-solubilizing bacterial strain NII-0909 isolated from the Western ghat forest soil in India was identified as Micrococcus sp on the basis of phenotypic characteristics, carbon source utilization pattern, fatty acid methyl esters analysis, and 16S rRNA gene sequence. The strain exhibited the plant growth promoting attributes of phosphate solubilization, auxin production, 1 aminocyclopropane-1-carboxylate deaminase activity, and siderophore production. It was able to solubilize (122.4MUg of Ca(3)PO(4) ml(-1)), and produce IAA (109MUgml(-1)) at 30 degrees C. P-solubilizing activity of the strain NII-0909 was associated with the release of organic acids and a drop in the pH of the NBRIP medium. HPLC analysis detected two organic acids in the course of P solubilization. A significant increase in the growth of cow pea was recorded for inoculations under controlled conditions. Scanning electron microscopic study revealed the root colonization of strain on cow pea seedlings. These results demonstrate that isolates NII-0909 has the promising PGPR attributes to be develop as a biofertilizer to enhance soil fertility and promote the plant growth. PMID- 20951600 TI - Indolyl-3-butyric acid-induced Arabidopsis stomatal opening mediated by 3',5' cyclic guanosine-monophosphate. AB - It has been pharmacologically suggested that 3',5'-cyclic guanosine-monophosphate (cGMP) mediates indolyl-3-butyric acid (IBA)-induced stomatal opening. In Arabidopsis thaliana (L.) Heynh., such investigations compared the wild type (Columbia and Ws ecotypes) to mutants knockout for either GTP-binding protein (G protein) alpha subunit 1 (gpa1-4), putative G protein-coupled receptor 1 (gcr1 5), calcineurin B-like isoform 1 (cbl1) or 9 (cbl9), or the NADPH oxidases AtrbohD and AtrbohF (atrbohD/F). Stomatal opening to IBA or the permeant cGMP analogue, 8-bromo-cGMP (8-Br-cGMP) was abolished in the atrbohD/F mutant. The IBA response was fully or partially suppressed, respectively, in the gcr1-5 mutant, or the gpa1-4 and cbl1 mutants. In the cbl9 mutant, the response to IBA or 8-Br cGMP, respectively, was partially or fully suppressed. Phenylarsine oxide (PAO) affected the IBA response, which the cbl1 mutant overlapped or the gpa1-4 and cbl9 mutants increased up to 100% inhibition. 6-anilino-5,8-quinolinedione, mas17, the (Rp)-diastereomer of 8-bromo-3',5'-cyclic guanosine monophosphorothioate (Rp-8-Br-cGMPS), nicotinamide, ruthenium red (RRed), 1,2 bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), cyclosporine A (CsA) and FK506 converged to affect the IBA response, which the gpa1-4 and cbl9 mutants overlapped or the cbl1 mutant and PAO increased up to 100% inhibition. Rp 8-Br-cGMPS, nicotinamide, RRed, BAPTA, CsA or FK506 paralled the cbl9 and atrbohD/F mutants to abolish the 8-Br-cGMP response. Based on so far revealed features of these mutants and pharmacological compounds, these results confirmed cGMP as a Ca(2+)-mobilizing second messenger for apoplastic auxin whose perception and transduction would implicate a seven-transmembrane receptor - G protein - guanylyl cyclase unit at the guard cell plasma membrane. PMID- 20951601 TI - Clinicopathological study of p-T1aN0M0 non-small-cell lung cancer, as defined in the seventh edition of the TNM classification of malignant tumors. AB - OBJECTIVE: The seventh edition of the TNM Classification of Malignant Tumours was published in 2009. The present study was conducted to investigate the clinicopathological features of p-T1aN0M0 non-small-cell lung cancer, which is the earliest stage defined in the new tumor, node, metastasis (TNM) classification, in relation to patient prognosis. METHODS: We retrospectively studied 162 patients, who underwent surgical resection at our institution for p T1aN0M0 non-small-cell lung cancer, as re-categorized in the seventh TNM classification. Univariate and multivariate analyses of disease-free survival were performed. RESULTS: The mean tumor size was 13.2 +/- 4.7 mm. The maximum tumor diameter was >10 mm in 104 cases (64.6%), and <= 10 mm in 58 (35.4%). The median follow-up period was 44.5 months. Univariate analysis showed that the 5 year disease-free survival rate of patients with and without preoperative serum carcinoembryonic antigen elevation was 50.8% and 95.1% (P<0.0001), respectively, that of patients with and without blood vessel or lymphatic invasion was 40.0% and 95.8% (positive vs negative, P<0.0001), respectively, and that of patients aged >= 70 years and <70 years was 86.8% and 96.1% (P=0.014), respectively. Multivariate analysis including these three clinicopathologic factors demonstrated that preoperative elevation of the carcinoembryonic antigen level and blood vessel or lymphatic invasion were independent prognostic factors. CONCLUSION: In patients with p-T1aN0M0 non-small-cell lung cancer, an elevated preoperative carcinoembryonic antigen level and blood vessel or lymphatic invasion tend to affect prognosis to a greater degree than tumor size. Therefore, the efficacy of adjuvant chemotherapy for these patients should be evaluated in clinical trials. PMID- 20951602 TI - Usefulness of [18F]fluoro-2-deoxy-D-glucose positron emission tomography for predicting the World Health Organization malignancy grade of thymic epithelial tumors. AB - OBJECTIVE: The objective of this study was to investigate whether the maximum standardized uptake value (SUVmax) determined using positron emission tomography with [(18)F]fluoro-2-deoxy-D-glucose ((18)FDG-PET) can predict the grade of malignancy of thymic epithelial tumors based on the World Health Organization (WHO) classification. METHODS: We retrospectively analyzed 13 patients with thymic epithelial tumors, who underwent (18)FDG-PET examination before treatment. The patients were subdivided into a thymoma group and a thymic carcinoma group, and the two were compared clinicopathologically. RESULTS: There were six men and seven women, ranging in age from 36 to 78 years (mean, 58.8 +/- 13.3 years). Mean tumor size was 47.3 +/- 26.0mm, and the WHO classification was type A in two patients, type AB in none, type B1 in one, type B2 in three, type B3 in two, and thymic carcinoma in five. Thus, eight patients had thymoma and five had thymic carcinoma. The Masaoka stage was I in four patients, II in four, III in three, and IV in two. Mean pre-treatment SUVmax for the tumors overall was 5.24 +/- 3.10, with a range of 1.73-11.21. Mean SUVmax in the thymic carcinoma group was 8.15 +/- 7.88, and that in the thymoma group was 3.43 +/- 2.19, the difference being significant (P = 0.002). CONCLUSIONS: A significant relationship was observed between SUVmax and morphological classification by the WHO system for this cohort of thymic epithelial tumors. Pre-treatment SUVmax may be useful for differentiating thymoma from thymic carcinoma. PMID- 20951603 TI - Photosensitive materials and potential of photocurrent mediated tissue regeneration. AB - Photocurrent therapy with participation of light and electrical stimulations could be an innovative and promising approach in regenerative medicine, especially for skin and nerve regeneration. Photocurrent is generated when light irradiates on a photosensitive device, and with more and more types of photosensitive materials being synthesized, photocurrent could be applied for enhanced regeneration of tissue. Photosensitive scaffolds such as composite poly (3-hexylthiophene)/polycaprolactone (P3HT/PCL) nanofibers are fabricated by electrospinning process in our lab for skin regeneration in presence of applied photocurrent. This review article discuss on the various in vitro, in vivo and clinical studies that utilized the principle of 'electrotherapy' and 'phototherapy' for regenerative medicine and evaluates the potential application of photocurrent in regenerative medicine. We conclude that photocurrent therapy will play an important role in regenerative medicine. PMID- 20951605 TI - Transthoracic echocardiographic simulator: normal and the abnormal. PMID- 20951604 TI - Therapeutic strategies and mechanisms of tumorigenesis of HER2-overexpressing breast cancer. AB - The receptor tyrosine kinase HER2 is overexpressed in approximately 25% of breast cancers. HER2 acts as a signal amplifier for its siblings, namely three different transmembrane receptors that collectively bind with 11 distinct growth factors of the EGF family. Thus, overexpression of HER2 confers aggressive invasive growth in preclinical models and in patients. Specific therapies targeting HER2 include monoclonal antibodies, antibody-drug conjugates, small molecule tyrosine kinase inhibitors, as well as heat shock protein and sheddase inhibitors. Two of these drugs have shown impressive - yet mostly transient - efficacy in patients with HER2 overexpressing breast cancer. We highlight the biological roles of HER2 in breast cancer progression, and overview the available therapeutic armamentarium directed against this receptor-kinase molecule. Focusing on the mechanisms that confer resistance to individual HER2 targeting agents, we envisage therapeutic approaches to delay or overcome the evolvement of resistance in patients. PMID- 20951606 TI - The pharmacokinetics of ropivacaine in elderly patients undergoing nerve stimulator-guided thoracic paravertebral block. PMID- 20951607 TI - Cerebral oximetry-guided antegrade cerebral perfusion in aortic arch surgery. PMID- 20951608 TI - The nested neural hierarchy and the self. AB - In spite of enormous recent interest in the neurobiology of the self, we currently have no global models of the brain that explain how its anatomical structure, connectivity, and physiological functioning create a unified self. In this article I present a triadic neurohierarchical model of the self that proposes that the self can be understood as the product of three hierarchical anatomical systems: The interoself system, the integrative self system, and the exterosensorimotor system. An analysis of these three systems and their functional features indicates that the neural hierarchy possesses features of both non-nested and nested hierarchies that are necessary for the creation of a unified consciousness and self. These functional properties also make the central nervous system a biologically unique entity unlike anything else in nature. PMID- 20951609 TI - Biomechanical consequences of humeral component malpositioning after anatomical total shoulder arthroplasty. AB - HYPOTHESIS: We hypothesized that the malpositioning of the humeral component can preclude the long-term success of anatomical total shoulder arthroplasty. The goal of this study was to evaluate the mechanical consequences of superior and inferior malpositioning of the humeral head. MATERIALS AND METHODS: A numerical musculoskeletal model of the shoulder joint allowing natural humeral head translation was used to simulate a loaded abduction movement controlled by muscular activation. An inferior and superior malpositioning of 5 mm were compared to an optimal positioning. Impingements, articular contact pattern, and cement stress were evaluated. RESULTS: Inferior malpositioning of the humeral head induced impingement and limited the abduction level, while superior malpositioning increased the subluxation risk. Both inferior and superior malpositioning increased the stress level within the cement mantle. DISCUSSION: This numerical study highlights the importance of an anatomical reconstruction of the glenohumeral surfaces for the success rate of anatomical total shoulder arthroplasty. PMID- 20951610 TI - Medial perforation of the glenoid neck following SLAP repair places the suprascapular nerve at risk: a cadaveric study. AB - BACKGROUND: Although suprascapular nerve injury after SLAP (superior labrum anterior to posterior) repair has rarely been reported, the direction of anchor insertion is toward the suprascapular nerve. The purpose of this study was to evaluate the risk of suprascapular nerve injury during the drilling and anchor insertion for anterior SLAP repair. MATERIALS AND METHODS: Twelve cadaveric shoulders were mounted in a lateral decubitus position (to mimic actual surgery) and 1 suture anchor for anterior SLAP repair was inserted arthroscopically from the anterior portal at 00:30-1:00 o'clock in right shoulders (11-11:30 in left). Then, cadaveric shoulders were dissected to determine the pathway of suprascapular nerve, the location of suture anchor, and anchor perforation of the glenoid wall. Distances from suprascapular nerve to suture anchor tips (which perforated medial cortex of glenoid)-that is, nerve-anchor interval (NAI)--were measured. Glenoid widths and heights were also measured to evaluate the correlation between glenoid areas and NAI. Depth of drilling was also determined. RESULTS: All suture anchors perforated the glenoid wall. Mean drill depth was 14.2 (+/-2.8) mm and mean NAI was 3.1 (+/-2.7) mm. In 4 shoulders, suture anchor tips contacted the suprascapular nerve. The mean height of the glenoid surface was 30.0 mm (+/-2.5), its mean width was 22.9 mm (+/-1.9), and its mean area was 2164.3 mm(2) (+/-334.1). No correlation was found between glenoid areas and NAI (P = .277). CONCLUSION: Suprascapular nerve lies very close to drilling sites and suture anchors during arthroscopic anterior SLAP repair. The present study cautions that care should be taken when anterior anchors are being inserted. PMID- 20951611 TI - Usefulness of video-EEG monitoring in children. AB - Video-EEG monitoring (v-EEG) was originally restricted to the evaluation for epilepsy surgery. It is now widely available and often utilized to clarify the nature of paroxysmal events or to identify the epileptic syndrome. It is important to define carefully the diagnostic value of this high-cost and time consuming procedure. Few data on children are available. In this study, we have evaluated the utility of this procedure and the factors leading to a successful recording in children. We retrospectively reviewed 380 v-EEG done in 320 children. The rate of event detection was 59%. The v-EEG recorded a seizure in 40% (n=150), a non-epileptic event in 19% (n=73), and both seizure and non epileptic events in 3% (n=11). Only 9% remained without diagnosis after v-EEG. The frequency of the usual events was the only factor contributing to a successful recording. This procedure confirmed the diagnosis of epilepsy in 43% of patients but excluded it in 25% of them. In children with epilepsy, the v-EEG allowed to define a new syndrome (30% of patients) or to improve clinical description and to identify the origin of the seizures (30%). The treatments were modified in 66% of patients following the v-EEG. Continuous video-EEG monitoring is an efficient and valuable procedure in the diagnosis and management of epilepsy and paroxysmal disorders in children. PMID- 20951612 TI - 64-slice CT perfusion imaging of pancreatic adenocarcinoma and mass-forming chronic pancreatitis. AB - RATIONALE AND OBJECTIVES: To investigate 64 computed tomography (CT) perfusion imaging features of patients with pancreatic cancer and mass-forming chronic pancreatitis. MATERIALS AND METHODS: Between January 2003 and April 2010, 234 patients with pancreatic mass underwent 64-CT perfusion imaging. Among them, the histopathological results of 64 patients were proven to be pancreatic adenocarcinoma and 15 patients were proven to be mass-forming chronic pancreatitis. Additionally, CT perfusion imaging was performed in 33 healthy volunteers served as controls. The slice data were processed using CT perfusion software. Perfusion parameters including time density curve, blood flow, blood volume, permeability, peak enhancement, and time to peak were recorded. RESULTS: Blood flow was 77% lower in patients with pancreatic adenocarcinoma than in controls, 48% lower in patients with mass-forming chronic pancreatitis than in controls, and 56% lower in patients with pancreatic adenocarcinoma than with mass forming chronic pancreatitis (P < .016). Blood volume was 65% lower in pancreatic adenocarcinoma than in controls, 27% lower in mass-forming chronic pancreatitis than in controls, and 53% lower in cancer than mass-forming chronic pancreatitis (P < .016). Permeability was 559% higher in pancreatic adenocarcinoma than in controls, 821% higher in mass-forming chronic pancreatitis than in controls, and 28% lower in cancer than mass-forming chronic pancreatitis (P < .016). Peak enhancement was 27% lower and time to peak 23% longer in pancreatic adenocarcinoma than mass-forming chronic pancreatitis (P < .016). Time-density curve showed the peak of mass-forming chronic pancreatitis is earlier and higher than that of pancreatic adenocarcinoma, and the peak of mass-forming chronic pancreatitis is later and lower than that of controls. CONCLUSION: CT perfusion imaging can provide additional quantitative hemodynamic information of pancreatic adenocarcinoma and mass-forming chronic pancreatitis. PMID- 20951613 TI - Rupture in small abdominal aortic aneurysms: beyond the rates.... PMID- 20951614 TI - High-resolution magnetic resonance imaging-based biomechanical stress analysis of carotid atheroma: a comparison of single transient ischaemic attack, recurrent transient ischaemic attacks, non-disabling stroke and asymptomatic patient groups. AB - BACKGROUND: Vulnerable carotid plaques are associated with cerebrovascular ischaemic events. High-resolution magnetic resonance (MR) imaging not only allows the morphological assessment of such plaques, but also provides geometrical data, which can be used for biomechanical stress analysis. We assess its utility to assess the plaque stress profiles of symptomatic (transient ischaemic attack (TIA) and non-disabling stroke) and asymptomatic patients. METHODS: A total of 70 consecutive patients with confirmed underlying carotid artery disease underwent carotid MR imaging of their carotid artery in a 1.5-T MR system using a standard carotid atheroma imaging protocol. MR images were manually segmented for different plaque components and used for biomechanical stress analysis. The maximum critical stress (M-CStress) for various clinical groups was determined and compared. RESULTS: M-CStress of symptomatic plaques (n = 45) was significantly higher than for asymptomatic plaques (n = 25) (median (interquartile range (IQR): 275 kPa (190-390) vs. 165 kPa (120-200), p = 0.0001)). Within the symptomatic group, no M-CStress differences were present between the TIA (n = 30) and stroke (n = 15) patients (260 kPa (190-370) vs. 295 kPa (200-510), p = 0.31). Within the TIA patient cohort, those who had presented with recurrent TIAs (n = 6) had significantly higher stresses than patients who had suffered a single episode (n = 24) (425 kPa (285-580) vs. 250 kPa (180-310), p = 0.001). CONCLUSIONS: Symptomatic carotid plaques, particularly those associated with recurrent TIAs, have high biomechanical stresses. As there is pre existing evidence to suggest that high biomechanical stresses are associated with plaque vulnerability, MR-imaging-based stress analysis has the potential to identify high-risk patients with vulnerable plaques. PMID- 20951615 TI - In response to Prof. M.J. Gough's second comment on SCAMICOS. PMID- 20951616 TI - Sudden unexpected death in epilepsy (SUDEP) and sleep. AB - The risk of sudden unexpected death is considered to be notably higher in patients with epilepsy with respect to the general population. Sudden unexpected death in epilepsy (SUDEP) is probably caused by the peri-ictal concurrence of a number of different predisposing and precipitating factors. Among these, the presence of a seizure before the fatal event is the only feature that seems to be constantly present. Different mechanisms, namely cardiac arrhythmias, respiratory dysfunctions, dysregulation of systemic or cerebral circulation have been suggested as potential physiopathological mechanisms. Moreover, clinical data seem to suggest that SUDEP could occur preferentially during sleep. In order to assess a possible relationship between sleep and SUDEP, we have analyzed studies in which sufficient information about the circumstances of deaths was available. Our analysis confirms that the relationship between sleep and SUDEP is not given by chance as the percentage of possible sleep-related SUDEP is higher than 40% in the majority of studies. We will discuss the possible longstanding and precipitating mechanisms involved in the interaction between sleep and epilepsy likely to favour SUDEP occurrence. In this perspective, possible preventive measures will be hypothesized. PMID- 20951617 TI - Expectations modulate long-term heat pain habituation. AB - Habituation to pain was shown to be a complex mechanism involving the pain encoding regions and the antinociceptive system in the brain. Pain perception can be modulated by cognitive factors; however it is unclear whether cognitive factors also influence habituation to pain. We used an established experimental design with repetitive moderate painful heat stimulation over eight consecutive days. Thirty-seven healthy subjects were recruited and assigned to four different groups: The first group (n=10) was instructed that pain perception over time will habituate; the second group (n=9) that pain will increase; the third group (n=8) was instructed that pain will remain stable over the 8 days of pain stimulation and the fourth group (n=10) was not given any specific information and served as a control group. We found that the control group habituated as described before. However, it was abolished in the second (sensitize) and third (stable) group, but was very strongly demonstrated in the first (habituation) group. In this group, habituation tended to be increased as compared to the control group. In conclusion, our findings highlight the importance of context information in pain studies and contribute to our knowledge about pain processing and behaviour. PMID- 20951619 TI - Identification of compound heterozygous mutations in GNPTG in three siblings of a Chinese family with mucolipidosis type III gamma. AB - Mucolipidosis III gamma is an autosomal recessive disorder with defective phosphorylation and trafficking of lysosomal enzymes. In a Chinese family with three siblings, linkage analysis revealed positive linkage of the family to GNPTG. Direct DNA sequence analysis identified two novel compound heterozygous mutations, c.471delC in exon 7 and IVS4-1G>C, in three patients. The two mutations cause frameshift and abnormal splicing, respectively, and represent the first series of GNPTG mutations in the Chinese population. PMID- 20951618 TI - On the measurement of 15N-{1H} nuclear Overhauser effects. 2. Effects of the saturation scheme and water signal suppression. AB - Measurement of steady-state (15)N-{(1)H} nuclear Overhauser effects forms a cornerstone of most methods to determine protein backbone dynamics from spin relaxation data, since it is the most reliable probe of very fast motions on the ps-ns timescale. We have, in two previous publications (J. Magn. Reson. 192 (2008) 302-313; J. Am. Chem. Soc. 131 (2009) 6048-6049) reevaluated spin-dynamics during steady-state (or "saturated") and reference experiments, both of which are required to determine the NOE ratio. Here we assess the performance of several windowed and windowless sequences to achieve effective saturation of protons in steady-state experiments. We also evaluate the influence of the residual water signal due to radiation damping on the NOE ratio. We suggest a recipe that allows one to determine steady-state (15)N-{(1)H} NOE's without artifacts and with the highest possible accuracy. PMID- 20951620 TI - Sensitivity and specificity of the World Health Organization pertussis clinical case definition. AB - OBJECTIVES: Bordetella pertussis continues to circulate even in countries with good childhood vaccination coverage. This study was undertaken to define the relationship between documented disease and the clinical criteria proposed by the World Health Organization (WHO). METHODS: Nasopharyngeal swab samples were collected from previously healthy 6-14-year-old school children in Tehran, presenting with persistent cough of at least 2- week duration. Specimens were examined for Bordetella pertussis and Bordetella parapertussis by culture and polymerase chain reaction (PCR). RESULTS: Out of 6601 students, 328 (5.0%) had been coughing for at least 2 weeks. Of these children with cough, 182 (55.5%) experienced whooping, 194 (59.1%) suffered a paroxysmal cough, and 73 (22.3%) had post-tussive vomiting. Twenty-one (6.4%) samples tested positive for B. pertussis and six (1.8%) for B. parapertussis by PCR. Culture of four (1.2%) specimens was positive for B. pertussis. In comparison to PCR, the sensitivity and the specificity of the WHO clinical criteria (year 2000) were 95.2% and 15.0%, respectively. CONCLUSIONS: Pertussis remains one of the etiologies of prolonged cough, even in communities with high immunization in children. The specificity of the WHO criteria is low in diagnosing pertussis compared with PCR. PMID- 20951621 TI - Waist circumference and mortality: impact of associated risk factors. AB - AIM: This study was designed to evaluate the risks of all-cause and cardiovascular mortality in subjects with large waist circumferences, with or without associated risk factors, and to determine whether or not waist circumference might identify high-risk subjects. METHODS: The population included 55,800 men (aged 52.1 +/- 8.2 years) and 28,937 women (aged 54.2 +/- 9.1 years) who had undergone a health checkup at the Preventive and Clinical Investigations Centre between January 1999 and December 2004 with a mean follow-up of 4.7 +/- 1.7 years. An increased waist circumference was defined as those in the last quintile of distribution. Mortality risk for each waist-circumference quintile, with or without associated risk factors (hypertension, diabetes, elevated LDL cholesterol), was evaluated using Cox's regression models, including age, gender, tobacco and alcohol consumption, and physical activity. RESULTS: The percentage of subjects with hypertension, diabetes and raised LDL cholesterol levels increased from the first waist-circumference quintile to the last. After adjusting for variables, all-cause mortality risk did not increase significantly with large waist circumference only (HR: 1.19 [0.84-1.68]), but was significantly higher when an increased waist circumference was associated with at least one risk factor (HR=1.58 [1.26-1.98]; 3.70 [2.05-6.68] for three risk factors). Similar results were observed for cardiovascular mortality (HR: 0.85 [0.19-3.68] with only large waist circumference and 3.56 [2.05-6.57] when waist circumference was associated with at least one risk factor). CONCLUSION: In a population with low-to-moderate mortality risk, waist circumference alone did not identify high risk subjects, thus suggesting that a more global approach is necessary. PMID- 20951622 TI - A comparative microanatomical study on cross-sections of superficial branch of radial nerve in proximal and distal parts of the forearm: a cadaveric study. AB - PURPOSE OF STUDY: Changes in peripheral nerve anatomy with age may be the cause for poor prognosis after nerve repair in elderly cases. The aim of the present study is to find out and compare the cross-sectional microanatomy as well as age related changes in the non-fascicular components of superficial branch of radial nerve at cubital fossa (SBRN-1) and above wrist (SBRN-2). METHODS: Thirty-eight fresh human (14 male and five female) cadaveric SBRN-1 and SBRN-2 were collected from both sides of 19 cadavers and study has been performed at different magnifications after routine histological (Masson's trichrome stain) processing was done for morphometric analysis (total cross-sectional area [Asc], fascicular area [Af], non-Af [Anonf], adipose [FAT] area and non-adipose area [nFAT]). RESULTS: SBRN-1 and SBRN-2 belonged to polyfascicular type and showed difference in amount of connective and adipose tissues in Anonf. The number of fascicles in SBRN-1 ranged from 2 to 6 (3.66+/-0.21, mean+/-SEM) and in SBRN-2 ranged from 7.5 to 11.5 (9.24+/-0.26). On comparing the percentage level of adipose tissue (FAT) in total cross-section area (Asc) and in Anonf of SBRN-1 and SBRN-2, the level of adipose tissue was increased with age. CONCLUSIONS: The amount of adipose tissue in SBRN-1 and SBRN-2 Anonf was found to be high in most of the elderly cases. On comparison, there was not much difference between SBRN-1 and SBRN-2, but, the fascicle count was found to be increasing gradually from proximal to distal part of the SBRN. PMID- 20951623 TI - Is there any treatment for inflammatory amyloidosis? PMID- 20951624 TI - Kinetics of sono-photooxidative degradation of poly(alkyl methacrylate)s. AB - The mechano-chemical degradation of poly(methyl methacrylate) (PMMA), poly(ethyl methacrylate) (PEMA) and poly(n-butyl methacrylate) (PBMA) using ultrasound (US), ultraviolet (UV) radiation and a photoinitiator (benzoin) has been investigated. The degradation of the polymers was monitored using the reduction in number average molecular weight (M(n)) and polydispersity (PDI). A degradation mechanism that included the decomposition of the initiator, generation of polymer radicals by the hydrogen abstraction of initiator radicals, reversible chain transfer between stable polymer and polymer radicals was proposed. The mechanism assumed mid-point chain scission due to US and random scission due to UV radiation. A series of experiments with different initial M(n) of the polymers were performed and the results indicated that, irrespective of the initial PDI, the PDI during the sono-photooxidative degradation evolved to a steady state value of 1.6+/-0.05 for all the polymers. This steady state evolution of PDI was successfully predicted by the continuous distribution kinetics model. The rate coefficients of polymer scission due to US and UV exhibited a linear increase and decrease with the size of the alkyl group of the poly(alkyl methacrylate)s, respectively. PMID- 20951625 TI - Effect of ultrasound on the activity of alliinase from fresh garlic. AB - Alliinase is a homodimeric glycoprotein found most often in genus Allium plants. In this study, alliinase was purified from fresh garlic by using ammonium sulfate precipitation and gel filtration on a Sephacryl S-200 column. Homogeneity of the purified protein with a molecular weight of 54,000 Da was confirmed by SDS-PAGE. The effect of ultrasound on the alliinase activity was further studied. The optimal parameters for stimulating the alliinase activity were as follows: ultrasonic intensity, 0.5 W/cm(2) and ultrasonic frequency, 40 kHz. Under the optimal conditions, ultrasonic irradiation did not affect the enzyme's optimal temperature and pH, and improved its thermal stability. The low frequency and mild intensity ultrasound could increase the alliinase activity about 47.1%. Under ultrasound, the alliinase activity was inhibited by exogenous pyridoxal 5' phosphate (PLP) and K(+), and obviously enhanced by Fe(2+). However, PLP and both of the metal ions showed opposite effects in the absence of ultrasound. Ultrasound could retard or slow down the inhibitory effect of l-cysteine on the alliinase activity. These results indicated that the activity of alliinase from fresh garlic might be enhanced by the low frequency and mild intensity ultrasound. PMID- 20951626 TI - Fluid load support and contact mechanics of hemiarthroplasty in the natural hip joint. AB - The articular cartilage covering the ends of the bones of diarthrodial synovial joints is thought to have evolved so that the loads are transferred under different and complex conditions, with a very high degree of efficiency and without compromising the structural integrity of the tissue for the life of an individual. These loading conditions stem from different activities such as walking, and standing. The integrity of cartilage may however become compromised due to congenital disease, arthritis or trauma. Hemiarthroplasty is a potentially conservative treatment when only the femoral cartilage is affected as in case of femoral neck fractures. In hemiarthroplasty, a metallic femoral prosthesis is used to articulate against the natural acetabular cartilage. It has also been hypothesized that biphasic lubrication is the predominant mechanism protecting the cartilage through a very high fluid load support which lowers friction. This may be altered due to hemiarthroplasty and have a direct effect on the frictional shear stresses and potentially cartilage degradation and wear. This study modelled nine activities of daily living and investigated the contact mechanics of a hip joint with a hemiarthroplasty, focussing particularly on the role of the fluid phase. It was shown that in most of the activities studied the peak contact stresses and peak fluid pressures were in the superior dome or lateral roof of the acetabulum. Total fluid load support was very high (~90%) in most of the activities which would shield the solid phase from being subjected to very high contact stresses. This was dependent not only on the load magnitude but also the direction and hence on the location of the contact area with respect to the cartilage coverage. Lower fluid load support was found when the contact area was nearer the edges where the fluid drained easily. PMID- 20951627 TI - Perceived environmental risk as a predictor of teenage motherhood in a British population. AB - Previous studies have shown that strong relationships exist between deprived environments and teenage motherhood. However, such studies have predominantly identified deprivation using neighbourhood-wide measures of socio-economic status. Few studies of teenage parenthood have examined how individuals perceive their environment and the importance of this perception on reproductive behaviour and timing. Using data collected from a sample of women living the county of Gloucestershire, UK, this paper explores the predictive value of two methods of assessing the environment: (1) the structural component-deprivation at the neighbourhood level and (2) the individual's subjective experience of her pre pregnancy environment, when examining how the wider environmental context can influence the decision of becoming a teenage mother. The results indicate that a woman's perception of her neighbourhood of residence at the time she conceived, her perceived environmental risk, may be a more discriminating predictor of teenage motherhood than deprivation measured by ward economic and deprivation indicators. PMID- 20951628 TI - "What if": the use of biomechanical models for understanding and treating upper extremity musculoskeletal disorders. AB - To aid understanding of the working of the upper extremity, several musculoskeletal models of the shoulder and arm have been developed. These models comprise the full shoulder girdle, which implies that the thoracohumeral link is formed by a scapular and clavicular segment. These models are based upon limited anatomical parameter sets and work on the assumption of a general control principle. Upper Extremity models have proven to be useful for different categories of applications, such as quantification of the load on musculoskeletal structures, or the evaluation of changes in the musculoskeletal structure on function and mechanical integrity ("what if" questions). Although these models are increasingly used, validation has long been a difficult issue. With the development of instrumented endoprostheses, a new method for model validation has come within reach. Up till now results have indicated that to obtain 'true' force values, models should be scaled, and should allow for cocontraction. Musculoskeletal models will be finding their way in education and in clinical decision making. On the longer run individualized models might become important for application to individual patients, although scaling will for some time remain a difficult issue. PMID- 20951629 TI - A strain energy filter for 3D vessel enhancement with application to pulmonary CT images. AB - The traditional Hessian-related vessel filters often suffer from detecting complex structures like bifurcations due to an over-simplified cylindrical model. To solve this problem, we present a shape-tuned strain energy density function to measure vessel likelihood in 3D medical images. This method is initially inspired by established stress-strain principles in mechanics. By considering the Hessian matrix as a stress tensor, the three invariants from orthogonal tensor decomposition are used independently or combined to formulate distinctive functions for vascular shape discrimination, brightness contrast and structure strength measuring. Moreover, a mathematical description of Hessian eigenvalues for general vessel shapes is obtained, based on an intensity continuity assumption, and a relative Hessian strength term is presented to ensure the dominance of second-order derivatives as well as suppress undesired step-edges. Finally, we adopt the multi-scale scheme to find an optimal solution through scale space. The proposed method is validated in experiments with a digital phantom and non-contrast-enhanced pulmonary CT data. It is shown that our model performed more effectively in enhancing vessel bifurcations and preserving details, compared to three existing filters. PMID- 20951630 TI - The critical role of retrieval practice in long-term retention. AB - Learning is usually thought to occur during episodes of studying, whereas retrieval of information on testing simply serves to assess what was learned. We review research that contradicts this traditional view by demonstrating that retrieval practice is actually a powerful mnemonic enhancer, often producing large gains in long-term retention relative to repeated studying. Retrieval practice is often effective even without feedback (i.e. giving the correct answer), but feedback enhances the benefits of testing. In addition, retrieval practice promotes the acquisition of knowledge that can be flexibly retrieved and transferred to different contexts. The power of retrieval practice in consolidating memories has important implications for both the study of memory and its application to educational practice. PMID- 20951631 TI - A manifold of spatial maps in the brain. AB - Two neural systems are known to encode self-location in the brain: Place cells in the hippocampus encode unique locations in unique environments, whereas grid cells, border cells and head-direction cells in the parahippocampal cortex provide a universal metric for mapping positions and directions in all environments. These systems have traditionally been studied in very simple environments; however, natural environments are compartmentalized, nested and variable in time. Recent studies indicate that hippocampal and entorhinal spatial maps reflect this complexity. The maps fragment into interconnected, rapidly changing and tightly coordinated submaps. Plurality, fast dynamics and dynamic grouping are optimal for a brain system thought to exploit large pools of stored information to guide behavior on a second-by-second time frame in the animal's natural habitat. PMID- 20951632 TI - Interaction study of pioglitazone with albumin by fluorescence spectroscopy and molecular docking. AB - Pioglitazone is a medicine of thiazolidinedione (TZD) class with hypoglycemic (antihyperglycemic, antidiabetic) action. Pioglitazone binding to human serum albumin (HSA) was investigated at different temperatures (290, 300 and 310 K) by fluorescence spectroscopic method. Molecular docking study was also carried out besides the experiments. Experimental results revealed that pioglitazone have an ability to quench the intrinsic fluorescence of HSA tryptophan through a static quenching procedure. The binding constant was determined using Stern-Volmer modified equation and energy transfer mechanisms of quenching were discussed. Thermodynamic parameters were also calculated according to enthalpy changes dependence on different temperatures. According to the theoretical and experimental results, hydrogen bonding was found to play a major role in the interaction of pioglitazone with HSA. PMID- 20951633 TI - Palladium(II) and platinum(II) derivatives of benzothiazoline ligands: Synthesis, characterization, antimicrobial and antispermatogenic activity. AB - A series of Pd(II) and Pt(II) complexes with two N(?)S donor ligands, 5-chloro-3 (indolin-2-one)benzothiazoline and 6-nitro-3-(indolin-2-one)benzothiazoline, have been synthesized by the reaction of metal chlorides (PdCl2 and PtCl2) with ligands in 1:2 molar ratios. All the synthesized compounds were characterized by elemental analyses, melting point determinations and a combination of electronic, IR, 1H NMR and 13C NMR spectroscopic techniques for structure elucidation. In order to evaluate the effect of metal ions upon chelation, both the ligands and their complexes have been screened for their antimicrobial activity against the various pathogenic bacterial and fungal strains. The metal complexes have shown to be more antimicrobial against the microbial species as compared to free ligands. One of the ligands, 5-chloro-3-(indolin-2-one)benzothiazoline and its corresponding palladium and platinum complexes have been tested for their antifertility activity in male albino rats. The marked reduction in sperm motility and density resulted in infertility by 62-90%. Significant alterations were found in biochemical parameters of reproductive organs in treated animals as compared to control group. It is concluded that all these effects may finally impair the fertility of male rats. PMID- 20951634 TI - Misspellings in drug information system queries: characteristics of drug name spelling errors and strategies for their prevention. AB - INTRODUCTION: Efficient search for and finding drugs is essential for electronic drug information systems which, for their part, are prerequisites for computerized physician order entry systems and clinical decision support with the potential to prevent medication errors. Search failures would be critical: they may delay or even prohibit prescription processes or timely retrieval of vital drug information. We analyzed spelling-correction and error characteristics in drug searches and the suitability of auto-completion as prevention strategy. METHODS: A blank entry field was presented to the user for unbiased queries in a web-based drug information system containing >105,000 brand names and active ingredients accessible from all 5500 computers of the Heidelberg University Hospital. The system was equipped with an error-tolerant search. Misspelled but found drug names confirmed by users were aligned by dynamic programming algorithms, opposing misspelled and correct names letter by letter. We analyzed the ratios of correctly and incorrectly spelled but found drugs, frequencies of characters, and their position in misspelled search words. RESULTS: Without error tolerant search, no results were found in 17.5% of all queries. Users confirmed 31% of all results found with phonetic error-correction support. Sixteen percent of all spelling errors were letters in close proximity to the correct letter on keyboards. On average, 7% of the initial letters in misspelled words contained errors. CONCLUSION: Drug information systems should be equipped with error tolerant algorithms to reduce search failures. Drug initial letters are also error-prone, thus auto-completion is not a sufficient error-prevention strategy and needs additional support by error-tolerant algorithms. PMID- 20951635 TI - Cervicovaginal shedding of hepatitis C viral RNA is associated with the presence of menstrual or other blood in cervicovaginal fluids. AB - BACKGROUND: The role of sexual activity in hepatitis C virus (HCV) transmission remains controversial. Studies to date have not explored the relationship between HCV shedding in cervicovaginal fluids and the presence of menstrual or other blood. OBJECTIVES: Since cross-sectional studies may underestimate the prevalence of viral shedding, we performed a 56-day longitudinal study of cervical HCV shedding. STUDY DESIGN: Women self-collected cervicovaginal swabs for 56 consecutive days, while keeping a diary of menses and genital symptoms. Swabs were tested for HCV RNA and cellular DNA by quantitative PCR, and hemoglobin by spectrophotometry. RESULTS: Sixteen women contributed a total of 701 cervicovaginal swabs (mean collection period 48 days, range 18-56). Detection of HCV RNA was associated with detection of hemoglobin. Premenopausal women were more likely than post-menopausal women to have HCV RNA detected in cervicovaginal fluids. For premenopausal women, detection of HCV RNA was more likely during menstruation (OR=56.4) or when hemoglobin was detected in cervicovaginal fluids, even if menstruation was not occurring (OR=35.4). No woman post-hysterectomy had HCV RNA detected in cervicovaginal fluids on any day, regardless of whether hemoglobin was detected. CONCLUSIONS: Our findings are consistent with a low likelihood of sexual transmission of HCV. The results suggest that shedding of HCV RNA in the female genital tract is associated with the presence of blood, and requires the presence of a cervix. Clinicians should consider advising premenopausal women who are concerned about transmitting infection that infectivity may increase during menstruation. PMID- 20951636 TI - Anti-Tax antibody levels in asymptomatic carriers, oligosymptomatic carriers, patients with rheumatologic disease or with HAM/TSP do not correlate with HTLV-1 proviral load. AB - BACKGROUND: HTLV-1 infects millions of people around the world and induces myelopathy (HAM/TSP), adult T-cell leukemia (ATL) or other inflammatory or rheumatologic diseases. The host-virus interaction causes asymptomatic carriers to develop HAM/TSP. Biomarkers are needed to predict patients who are at risk for HAM/TSP. Tax is highly immunogenic and is a major target protein recognized by cytotoxic T lymphocytes. Anti-Tax antibodies are involved in HAM/TSP pathogenesis. OBJECTIVES: To assess anti-Tax IgG reactivity with a flow cytometry assay (FCA) using an infection/transfection system with Vaccinia virus and pLW44/Tax-expressing Tax and to correlate the anti-Tax response and the HTLV-1 proviral load. STUDY DESIGN: : We enrolled 81 individuals: 9 HTLV-1 seronegative (NP) and 72 HTLV-1 positive (23 HTLV-1 asymptomatic carriers (AC), 12 oligosymptomatic patients (OL), 7 with rheumatologic diseases (DR) and 30 with HAM/TSP (HT)). Anti-Tax reactivity was assessed by FCA, and HTLV-1 proviral load was measured with real time PCR. RESULTS: The HT and DR groups showed greater anti-Tax IgG reactivity (p<0.001 and p<0.05 comparing HT to the OL and AC group, respectively; p<0.05 comparing DR to the OL group), and the reactivity in the DR+HT group was significantly different when compared to the AC group (p<0.05) and to the OL group (p<0.001). The proviral load was higher in the HT group compared to the OL (p<0.001) and in the HT+DR group compared to OL (p<0.001). There was no correlation between anti-Tax IgG reactivity and proviral load in any of the HTLV-1-infected groups. CONCLUSION: These findings suggest that although anti-Tax IgG reactivity and the HTLV-1 proviral load are important markers of the development of HTLV-1-associated diseases, their levels are not correlated. PMID- 20951637 TI - A woman with suspected subacute sclerosing panencephalitis (SSPE). PMID- 20951638 TI - Anaerobic physiology of Pseudomonas aeruginosa in the cystic fibrosis lung. AB - During chronic infection of the cystic fibrosis (CF) lung, Pseudomonas aeruginosa grows and persists in a microaerobic to anaerobic environment. P. aeruginosa is well adapted to thrive under such conditions and contains multiple enzyme systems for energy generation under oxygen-restricted or even anaerobic conditions. Recent data confirm a heterogeneous environment in the CF lung and indicate that P. aeruginosa induces enzyme systems for microaerobic growth but also denitrification and fermentative pathways. Moreover, stress response systems as universal stress proteins enhance survival under anaerobic energy starvation conditions. Growth in these oxygen-limited environments induces a drastic physiological change in P. aeruginosa, like increased alginate production and alterations in the outer membrane, which contribute to an increased antibiotic tolerance. PMID- 20951639 TI - Biological functions of GCS3, a novel plasminogen-binding protein of Streptococcus dysgalactiae ssp. equisimilis. AB - Increasing awareness of the relevance of Streptococcus dysgalactiae ssp. equisimilis as a human pathogen motivates the analysis of its pathomechanisms. One of the mechanisms that increases infectivity and dissemination of several streptococcal species is the recruitment and subsequent activation of host plasminogen on the streptococcal surface. This study identified GCS3 as a novel plasminogen-binding M protein of S. dysgalactiae ssp. equisimilis and revealed a difference in the mode of binding as compared to the plasminogen-binding protein PAM of S. pyogenes. In contrast to PAM, GCS3 did not bind to the kringle 1-3 region of plasminogen. Despite this difference, GCS3 exerts the same function of recruiting plasminogen to the streptococcal surface, which can be activated by streptokinase and host plasminogen activators to serve as a spreading factor. Moreover, we demonstrate a role of GCS3 in plasminogen-dependent streptococcal adherence to human pharyngeal cells (cell line Detroit 562) that indicates an additional function of the protein as an adhesin in the oral cavity. PMID- 20951640 TI - In silico comparison of Yersinia pestis and Yersinia pseudotuberculosis transcriptomes reveals a higher expression level of crucial virulence determinants in the plague bacillus. AB - Although Yersinia pestis and Yersinia pseudotuberculosis are genetically very similar (97% nucleotide sequence identity for most of the chromosomal genes), they exhibit very different patterns of infection. Y. pestis causes plague which is usually fatal in the absence of treatment, whereas Y. pseudotuberculosis generally triggers non-life-threatening intestinal symptoms. This drastic difference in pathogenicity may result from the acquisition of a few species specific genes, but also from differences in their transcriptional regulation networks. In this study, we performed an in silico comparative whole-genome transcriptome analysis of Y. pestis and Y. pseudotuberculosis grown in parallel under 8 distinct conditions to determine whether they exhibit differences in their regulatory networks. In this analysis, 304 genes common to both species were found to display significant inter-species differences in transcriptional levels, with 91% of them being more expressed in Y. pestis. Remarkably, 3 major virulence determinants conserved in the 2 species (the pYV virulence plasmid, the High Pathogenicity Island, and the ail locus) were among the genes more expressed in Y. pestis. Furthermore, the induction at 37 degrees C of pYV-borne genes was considerably greater in Y. pestis than in Y. pseudotuberculosis. Conversely, the rovA transcriptional regulator gene was more transcribed in Y. pseudotuberculosis. We also performed a clustering analysis of the transcriptome data of both Y. pestis and Y. pseudotuberculosis, which allowed to group genes according to their expression profiles. This analysis identified groups of genes with unknown functions which, based on regulation patterns similar to those of known virulence genes, are potential new virulence determinants in Y. pestis. In conclusion, this is the first comparative analysis at the whole-genome level of the transcription profiles of Y. pestis and Y. pseudotuberculosis. Our results suggest that the higher pathogenicity of the plague bacillus may not only result from the acquisition of new genetic material, but also from a higher expression level of common crucial virulence genes. This in silico analysis thus opens new avenues for investigating Y. pestis gain of pathogenicity and new potential virulence factors. PMID- 20951641 TI - A multiresistance megaplasmid pLG1 bearing a hylEfm genomic island in hospital Enterococcus faecium isolates. AB - Enterococcus faecium is considered to be a nosocomial pathogen with increasing medical importance. The putative virulence factor, hyl(Efm), encoding a putative hyaluronidase, is enriched among the hospital-associated polyclonal subpopulation of E. faecium.. The hyl(Efm) gene is described to be part of a genomic island and was recently identified to be plasmid-located. Here, we present a description of the structure, localization, and distribution of the putative pathogenicity factor hyl(Efm) and its putative island among 39 clinical isolates and elucidate the composition and host range of pLG1, a hyl(Efm) multiresistance plasmid of approximately 281.02kb. The hyl(Efm) gene was located within a 17,824-bp element highly similar to the putative genomic island (GI) structure that had been previously described. This genomic region was conserved among 39 hyl(Efm) positive strains with variation in a specific region downstream of hyl(Efm) in 18 strains. The putative hyl(Efm) was located on large plasmids (150-350kb) in 37 strains. pLG1 could be horizontally transferred into four different E. faecium recipient strains (n=4) but not into E. faecalis (n=3). Sequencing of pLG1 resolved putative plasmid replication, conjugation, and maintenance determinants as well as a pilin gene cluster, carbon uptake and utilization genes, heavy metal and antibiotic resistance clusters. The hyl(Efm) transferable plasmid pLG1 bears additional putative pathogenicity factors and antibiotic resistance genes. These findings suggest horizontal gene transfer of virulence factors and antibiotic resistance gene clusters by a single genetic event (conjugative transfer) which might be triggered by heavy antibiotic use common in health care units where E. faecium is increasingly prevalent. PMID- 20951642 TI - Regulation of specific target genes and biological responses by estrogen receptor subtype agonists. AB - Estrogenic effects are mediated through two estrogen receptor (ER) subtypes, ERalpha and ERbeta. Estrogens are the most commonly prescribed drugs to treat menopausal conditions, but by non-selectively triggering both ERalpha and ERbeta pathways in different tissues they can cause serious adverse effects. The different sizes of the binding pockets and sequences of their activation function domains indicate that ERalpha and ERbeta should have different specificities for ligands and biological responses that can be exploited for designing safer and more selective estrogens. ERalpha and ERbeta regulate different genes by binding to different regulatory elements and recruiting different transcription and chromatin remodeling factors that are expressed in a cell-specific manner. ERalpha-selective and ERbeta-selective agonists have been identified that demonstrate that the two ERs produce distinct biological effects. ERalpha and ERbeta agonists are a promising new approach for treating specific conditions associated with menopause. PMID- 20951643 TI - Protein dynamics: dancing on an ever-changing free energy stage. PMID- 20951644 TI - From protein folding to protein function and biomolecular binding by energy landscape theory. AB - Protein folding and function are inherently linked sharing a joined funneled energy landscape. In this theoretical framework, the integration of simulations, structural information, and sequence data has led to quantitatively explore, understand, and predict biomolecular binding and recognition, key processes in pharmacology, as a natural extension of the selective self-binding found in protein folding. Computer simulations based on these principles have made valuable contributions to understanding protein and RNA folding, protein-protein interactions, and protein-metabolite/RNA-metabolite interactions. PMID- 20951645 TI - Synthesis of artificial lymphoid tissue with immunological function. AB - The ability to generate functional artificial lymphoid tissue to induce specific immunity at ectopic sites could offer a potential breakthrough for treatment of diseases such as cancer and severe infection using immunotherapy. Artificial lymphoid tissue could also offer an informative tool to study further lymphoid tissue development and function in vivo. Here, we review the process of secondary and tertiary lymphoid organization, of which an understanding is essential for artificial lymphoid tissue synthesis. Using this knowledge, we consider the combination of cell types, soluble factors and scaffold properties that will enable proper accumulation and organization of lymphocytes into tissue grafts. Recent success in in vivo induction of artificial lymphoid tissue are also considered. PMID- 20951646 TI - The quality of on-line communication in a national learning programme for newly qualified nurses, midwives and allied health professionals. AB - Asynchronous communication has become the dominant mode of on-line instruction and has been incorporated into Flying Start NHS, an on-line programme for newly qualified NMAHPs in the transition phase from student to registered practitioner. On-line programmes have a number of objectives including the delivery of educational materials and the development of on-line communities. This study sought to provide a direct and objective understanding of the quality of the on line community within Flying Start NHS and give an indication of areas of strength and weakness. The study used mixed methods including a Gricean analysis of on-line communication focusing on quantity, quality, relevance, and manner, and a thematic analysis of communication content. There was little evidence that students engaged in the type of interactive communication essential for creating on-line learning communities. The majority of postings related to progression through Flying Start. The small number of communications which did begin to engage with the learning materials were limited with little evidence of the development of critical debate. Analysis of the qualitative data indicates that the period of transition continues to be stressful with Flying Start NHS being undertaken concurrently with local CPD being seen as duplication of effort. PMID- 20951647 TI - Incidence of red-cell alloimmunization due to non-anti-D antibodies during pregnancy: an experience from Turkey. AB - Antigen D incompatibility between mother and fetus is the most frequent cause of red-cell alloimmunization. However there are surface antigens capable of producing hemolytic disease other than antigen D. Populational antigen frequencies may be country specific. The aim of this retrospective study was to evaluate the incidence of red-cell alloimmunization due to non-anti-D antibodies during pregnancy. We evaluated the indirect antiglobulin test results of 535 pregnant women performed between March 2003 and 2009. The incidence of non-anti-D antibodies was found 1.21%, similar with reported in literature, but the spectrum of non-anti-D antibodies was different from other countries. PMID- 20951648 TI - Successful use of maternal blood in the management of severe hemolytic disease of the fetus and newborn due to anti-Kp(b). AB - BACKGROUND: The incidence of hemolytic disease of the fetus and newborn (HDFN) has decreased since the introduction of Rh immunoglobulin prophylaxis in Rh(D) negative pregnant women. Thus, the relative incidence of rare alloantibody related HDFN has increased. The lack of available maternally matched red blood cells for transfusion in these cases may create management difficulties. CASE: We report a case of anti-Kp(b) HDFN. Severe fetal anemia required intrauterine transfusion. Difficulty in obtaining Kp(b)-negative blood necessitated using the mother's donated RBCs. CONCLUSION: Severe HDFN with rare antibodies can be managed successfully using maternal blood. PMID- 20951649 TI - Alterations of circulating endothelial cells after apheresis in patients with sickle cell disease: a potential clue for restoration of pathophysiology. AB - OBJECTIVES: The potential influence of automated red cell exchange (ARCE) on endothelial activation is not well established. This study was intended to assess whether ARCE influences circulating endothelial cells (CECs) in patients with sickle cell disease. BACKGROUND: Automated red cell exchange (ARCE) has been used to protect the patient from complications of sickle cell disease. However, the expected benefits vary in different patients. CECs reflect endothelial activation. We hypothesize that suppression of endothelial activation may be an important mechanism of ARCE. METHODS: The study included 20 patients with sickle cell disease who underwent 30 apheresis procedures. We used flow cytometry to directly compare pre- and post-apheresis CEC number (prior to ARCE and 5 days after ARCE) during the steady state and painful crisis. We also determined if independent variables (the level of plasma nitrite concentration, the percentage of circulating hemoglobin S, and painful crisis) significantly contributed to the CEC level. RESULTS: The mean CEC number decreased (P = 0.04), while progenitor CECs did not change in patients with sickle cell disease after ARCE compared with pre-ARCE values (P>0.05). Clinical factors such as the volume of replacement fluid and the citrate infusion rate did not correlate with post-apheresis CECsand progenitor CEC numbers. The independent variables were not significantly associated with CEC and progenitor CEC numbers. CONCLUSIONS: ARCE can alter the CEC number, suggesting the possibility of suppression of endothelial activation. This may highlight the efficacy of ARCE for prevention or management of sickle cell vaso-occlusive crisis. PMID- 20951650 TI - Goal-directed hemostatic resuscitation for massively bleeding patients: the Copenhagen concept. AB - BACKGROUND: Continued hemorrhage remains a major cause of mortality in massively transfused patients, many of whom develop coagulopathy. A review of transfusion practice for these patients at our hospital revealed that a significant proportion received suboptimal transfusion therapy. Survivors had higher platelets count than non-survivors. METHODS: For massively transfused patients with hemodynamic instability, we introduced the concept of transfusion packages comprising five units of red blood cells, five units of fresh frozen plasma and two units of platelet concentrates. Thrombelastogram analysis was validated for routine laboratory use and implemented in the blood bank for monitoring coagulopathy and guiding transfusion therapy. Anaesthetists at our hospital were trained in functional haemostasis management based on analysis of thrombelastograms. RESULTS: Intraoperative administration of transfusion packages for patients operated on for a ruptured abdominal aortic aneurysm was associated with a reduction in mortality from 56% to 34% (p = 0.02). When comparing massively transfused patients treated with hemostatic control resuscitation, i.e., transfusion package therapy during hemodynamic instability and thromboelastogram--monitored and guided transfusion therapy, with controls treated in accordance with existing transfusion guidelines, mortality was reduced from 31% to 20% (p = 0.002). CONCLUSION: The initiative from the blood bank, i.e., transfusion packages for patients with uncontrollable bleeding and based on the thromboelastogram when hemodynamic control is established, has improved the transfusion practice and survival in massively transfused patients at our hospital. PMID- 20951651 TI - Nocturnal epileptiform EEG discharges, nocturnal epileptic seizures, and language impairments in children: review of the literature. AB - This review addresses the effect on language function of nocturnal epileptiform EEG discharges and nocturnal epileptic seizures in children. In clinical practice, language impairment is frequently reported in association with nocturnal epileptiform activity. Vice versa, nocturnal epileptiform EEG abnormalities are a common finding in children with specific language impairment. We suggest a spectrum that is characterized by nocturnal epileptiform activity and language impairment ranging from specific language impairment to rolandic epilepsy, nocturnal frontal lobe epilepsy, electrical status epilepticus of sleep, and Landau-Kleffner syndrome. In this spectrum, children with specific language impairment have the best outcome, and children with electrical status epilepticus of sleep or Landau-Kleffner syndrome, the worst. The exact nature of this relationship and the factors causing this spectrum are unknown. We suggest that nocturnal epileptiform EEG discharges and nocturnal epileptic seizures during development will cause or contribute to diseased neuronal networks involving language. The diseased neuronal networks are less efficient compared with normal neuronal networks. This disorganization may cause language impairments. PMID- 20951652 TI - On the mutagenicity of homologous recombination and double-strand break repair in bacteriophage. AB - The double-strand break (DSB) repair via homologous recombination is generally construed as a high-fidelity process. However, some molecular genetic observations show that the recombination and the recombinational DSB repair may be mutagenic and even highly mutagenic. Here we developed an effective and precise method for studying the fidelity of DSB repair in vivo by combining DSBs produced site-specifically by the SegC endonuclease with the famous advantages of the recombination analysis of bacteriophage T4 rII mutants. The method is based on the comparison of the rate of reversion of rII mutation in the presence and in the absence of a DSB repair event initiated in the proximity of the mutation. We observed that DSB repair may moderately (up to 6-fold) increase the apparent reversion frequency, the effect of being dependent on the mutation structure. We also studied the effect of the T4 recombinase deficiency (amber mutation in the uvsX gene) on the fidelity of DSB repair. We observed that DSBs are still repaired via homologous recombination in the uvsX mutants, and the apparent fidelity of this repair is higher than that seen in the wild-type background. The mutator effect of the DSB repair may look unexpected given that most of the normal DNA synthesis in bacteriophage T4 is performed via a recombination dependent replication (RDR) pathway, which is thought to be indistinguishable from DSB repair. There are three possible explanations for the observed mutagenicity of DSB repair: (1) the origin-dependent (early) DNA replication may be more accurate than the RDR; (2) the step of replication initiation may be more mutagenic than the process of elongation; and (3) the apparent mutagenicity may just reflect some non-randomness in the pool of replicating DNA, i.e., preferential replication of the sequences already involved in replication. We discuss the DSB repair pathway in the absence of UvsX recombinase. PMID- 20951653 TI - Factors that influence telomeric oxidative base damage and repair by DNA glycosylase OGG1. AB - Telomeres are nucleoprotein complexes at the ends of linear chromosomes in eukaryotes, and are essential in preventing chromosome termini from being recognized as broken DNA ends. Telomere shortening has been linked to cellular senescence and human aging, with oxidative stress as a major contributing factor. 7,8-Dihydro-8-oxogaunine (8-oxodG) is one of the most abundant oxidative guanine lesions, and 8-oxoguanine DNA glycosylase (OGG1) is involved in its removal. In this study, we examined if telomeric DNA is particularly susceptible to oxidative base damage and if telomere-specific factors affect the incision of oxidized guanines by OGG1. We demonstrated that telomeric TTAGGG repeats were more prone to oxidative base damage and repaired less efficiently than non-telomeric TG repeats in vivo. We also showed that the 8-oxodG-incision activity of OGG1 is similar in telomeric and non-telomeric double-stranded substrates. In addition, telomere repeat binding factors TRF1 and TRF2 do not impair OGG1 incision activity. Yet, 8-oxodG in some telomere structures (e.g., fork-opening, 3' overhang, and D-loop) were less effectively excised by OGG1, depending upon its position in these substrates. Collectively, our data indicate that the sequence context of telomere repeats and certain telomere configurations may contribute to telomere vulnerability to oxidative DNA damage processing. PMID- 20951654 TI - Determination of 17 illicit drugs in oral fluid using isotope dilution ultra-high performance liquid chromatography/tandem mass spectrometry with three atmospheric pressure ionizations. AB - The collection of oral fluid for drug testing is easy and non-invasive. This study developed a drug testing method using ultra-high performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS) in selected-reaction monitoring (SRM) mode. We tested the method on the analysis of four opiates and their metabolites, five amphetamines, flunitrazepam and its two metabolites, and cocaine and its four metabolites in oral fluid. 100-MUL samples of oral fluid were diluted with twice the amount of water then spiked with isotope-labeled internal standards. After the samples had undergone high-speed centrifugation for 20 min, we analyzed the supernatant. The recovery of the sample preparation ranged from 81 to 108%. We compared the performance of electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI) and atmospheric pressure photoionization (APPI). The ion suppression of most analytes on ESI (28-78%) was lower than that of APCI and APPI. A post-column flow split (5:1) did not reduce the matrix effect on ESI. Direct APPI performed better than dopant-assisted APPI using toluene. ESI, APCI and APPI limits of quantitation mostly ranged from 0.11 to 1.9 ng/mL, 0.02 to 2.2 ng/mL and 0.02 to 2.1 ng/mL, respectively, but were much higher on amphetamine and ecgonine methyl ester (about 2.7-4.7 ng/mL, 8.7-14 ng/mL, and 10-19 ng/mL, respectively). Most of the bias percentages (accuracy) and relative standard deviations (precision) on spiked samples were below 15%. This method greatly simplifies the process of sample preparation and shortens the chromatographic time to only 7.5 min per run and is able to detect analytes at sub-ppb levels. PMID- 20951655 TI - [Primary hyperparathyroidism due to parathyroid carcinoma]. PMID- 20951656 TI - [Early administration of erythropoietin in the extreme premature, a risk factor for retinopathy of prematurity?]. AB - INTRODUCTION: Erythropoietin (EPO) stimulates angiogenesis and may favour the appearance of retinopathy of prematurity (ROP). The objective was to determine if EPO+Fe administered from the 5th day of life could be an independent risk factor for ROP appearance and its severity. PATIENTS AND METHOD: The study included 718 preterm newborns with a birth weight <=1,500g or a gestational age <=32 weeks (and 6 days), admitted between 2001 and 2008. During these years, the target SaO2 was between 88% and 93%. EPO treatment began at 5-7 days of life, with a dose of 250 UI/Kg, 3 times a week, subcutaneously, together with Fe, 5-6mg/kg/day, both until 34 weeks of corrected age or discharge. RESULTS: A total of 493 preterms (68.7%) did not have ROP, 139 (19.4%) had a grade 1 ROP, 50 (7.0%) a grade 2 ROP and 36 (5.0%) a grade 3 ROP. Laser therapy was required by 27 severe ROP was associated with lower birth weight and gestational age, more neonatal morbidity and a more aggressive treatment (duration of oxygen supplements or mechanical ventilation, number of blood transfusions). Risk factors independently and significantly associated with any ROP grade were: lower birth weight, no caesarean section, EPO administration and need for blood transfusion. EPO administration increased the risk of ROP by 2.4, but this only happened in case of grade 1 ROP (OR: 5.50). CONCLUSIONS: EPO+Fe administration is associated and perhaps stimulates the appearance of grade 1 ROP. PMID- 20951657 TI - Early clinical experience of hyaluronic acid gel for breast enhancement. AB - BACKGROUND: An increasing number of women are seeking minimally-invasive procedures to enhance the shape and volume of their breasts. Early, limited use of MacrolaneTM suggests it is a promising agent for non-surgical breast enhancement. OBJECTIVE: To assess the safety and efficacy of MacrolaneTM in non surgical breast enhancement. METHODS: A prospective report of 194 women presenting for non-surgical breast enhancement at London Bridge Plastic Surgery between November 2007 and August 2009. RESULTS: SAFETY: Adverse events were reported in a total of 21.1% of patients. Minor adverse events (12%) were mainly confined to product migration, lumpiness, scar pigmentation and breast pain. All events were of mild to moderate intensity and resolved promptly without any additional treatment. Major adverse events (8.7%) included infection, capsular contracture, early resorption and product removal. EFFICACY: EFFICACY of treatment was assessed by patients using the five-point Global Esthetic Improvement Scale (GEIS). Patient satisfaction with treatment was consistently high with a mean score>=3.3 at all time points during follow-up. Patient-assessed GEIS indicated that some degree of improvement was seen by all (100%) patients at all time points up to and including 12 months irrespective of whether they had been re-treated. At the time of analysis, follow-up data are available for 45% of patients at 12 months, with 19% of all patients presenting for re-treatment with MacrolaneTM to date and 5.7% going on to have breast implants. CONCLUSION: This review represents the largest European clinical experience with MacrolaneTM for breast enhancement. It shows that MacrolaneTM can provide satisfactory improvement in breast shape. It is associated with high patient satisfaction, and provides a long-lasting result. Follow-up to data have been adequate to identify early complications; however, further follow-up is required to monitor long-term outcomes. The impact of HA on breast cancer remains inconclusive to date. PMID- 20951658 TI - The outcome of reduction mammaplasty remains stable at 2-5 years' follow-up: a prospective study. AB - PURPOSE: Several randomised studies have proved the effectiveness of reduction mammaplasty in short-term follow-up. However, medium-term prospective follow-up studies are rare. Therefore, a prospective study was conducted to assess the medium-term results and to see whether there are any changes in the intervention effect during the first years. METHODS: A total of 73 patients were operated on between January 2005 and March 2007. Patients completed the 15D health-related quality-of-life questionnaire, The Finnish Breast-Associated Symptoms (FBAS) questionnaire and Raitasalo's modification of the short form of the Beck Depression Inventory (RBDI). In July 2009, follow-up data was collected by postal mail. RESULTS: As many as 62 patients (85%) agreed to participate in the study and returned the follow-up data. Non-responders did not differ from responders in baseline characteristics. Mean follow-up time was 4.0 years (range, 2.3-4.6). Preoperatively, patients had significantly inferior quality of life when compared with the age-standardised population (p < 0.001). This health burden was removed after reduction mammaplasty. At follow-up, patients had significantly better quality of life, less breast-associated symptoms, less depression and anxiety and better self-esteem when compared with the preoperative situation (p < 0.001). CONCLUSIONS: Reduction mammaplasty results in remarkable alleviation in breast associated and psychological symptoms, and improvement in quality of life. This remains clearly significant and stable at 2-5 years follow-up. PMID- 20951659 TI - Determination of the variables affecting mixed MiniFilerTM DNA profiles. AB - The interpretation of mixed DNA profiles presents additional challenges for the forensic scientist. There has been a broad based call for transparency in the process of interpretation of all evidence including mixed DNA profiles. This interpretation is greatly facilitated by a sound understanding of the variability in peak heights for the two peaks of a heterozygote, in the sizes of stutter peaks and in the variability in peak heights across loci. This study examines single source and mixed DNA profiles to assess this variability. The relative variability in peak height between the two peaks of a heterozygote and in the peak heights across loci becomes greater as the peaks themselves become smaller. This is consistent with findings from other multiplexes. This variability appears larger in the MiniFilerTM system at 30 cycles than, for example, in the IdentifilerTM system at 28 cycles and this difference is largely explained by the two extra cycles of amplification. Stutter peaks appear no larger in the MiniFilerTM system at 30 cycles than in the IdentifilerTM system at 28 cycles. PMID- 20951660 TI - Human embryonic stem cells and derived contractile embryoid bodies are susceptible to Coxsakievirus B infection and respond to interferon Ibeta treatment. AB - We studied the susceptibility of human embryonic stem cells and derived contractile embryoid bodies from WAO9, HUES-5 and HUES-16 cell lines to Coxsackievirus B infection. After validating stem cell-like properties and cardiac phenotype, Coxsackievirus B receptors CAR and DAF, as well as type I interferon receptors were detected in all cell lines and differentiation stages studied. Real-time PCR analysis showed that CAR mRNA levels were 3.4-fold higher in undifferentiated cells, while DAF transcript levels were 2.78-fold more abundant in differentiated cultures (P<0.05). All cell lines were susceptible to Coxsackievirus serotypes B1-5 infection as shown by RT-PCR detection of viral RNA, immunofluorescence detection of viral protein and infectivity titration of cell culture supernatants resulting in cell death. Supernatants infectivity titers 24-48 h post-infection ranged from 105-106 plaque forming units (PFU)/ml, the highest titers were detected in undifferentiated cells. Cell viability detected by a colorimetric assay, showed inverse correlation with infectivity titers of cell culture supernatants. Treatment with 100 U of interferon Ibeta significantly reduced viral replication and associated cell death during a 24-48 h observation period, as detected by reduced infectivity titers in the supernatants and increased cell viability by a colorimetric assay, respectively. We propose human embryonic stem cell and derived contractile embryoid bodies as a valid model to study cardiac Coxsackievirus B infection. PMID- 20951661 TI - Laparoscopic left colectomy for cancer. PMID- 20951662 TI - Benign osteoblastoma in an unusual mastoid location. AB - INTRODUCTION: Benign osteoblastoma (OB) is an unusual primary bone tumor. The preferred locations are the posterior arch of vertebrae and long bones. We report herein an extremely rare location of an OB in the mastoid process of the temporal bone. CASE REPORT: A 22-year-old woman presented with painful left retro auricular swelling. Computed tomography features were suggestive of an aggressive osteolytic lesion of the left mastoid. The pathologic examination of bone curettage material revealed a benign OB. A complete resection of the tumor was performed later, with no evidence of recurrence at 1 year. DISCUSSION/CONCLUSION: To our knowledge, this is the 14th reported case of OB confined to the mastoid process of temporal bone. Its histological diagnosis can be difficult and osteosarcoma is its principal differential diagnosis. Although generally regarded as benign, OB has potential for recurrence and local invasion. As such, complete resection, whenever possible, is preferred over conventional curettage. PMID- 20951663 TI - Vibratory properties of maxillary dentition in maxillectomy patients wearing metal framework obturator prostheses with three different metal materials. AB - PURPOSE: The purpose of this study was to evaluate the vibratory properties of maxillary dentition in maxillectomy patients wearing metal framework obturator prostheses with three different material types of metal frameworks and to determine the optimal type by applying in vivo modal analysis. METHODS: The three metal framework obturator prostheses using gold alloy, cobalt-chromium alloy and titanium alloy were fabricated for four maxillectomy patients, whose shapes were almost the same for each patient. All patients were classified into Aramany's Class II. The transfer functions of the maxillary dentition with and without obturator prostheses were measured to obtain the natural frequency, modal shape and damping ratio. A forced response simulation was carried out, in which an impact assuming occlusal force was applied to the lateral segment teeth on the non-defect side, and the maximum displacements of the measurement points were calculated. RESULTS: As for the natural frequency, wearing the obturator prostheses caused reduction of the natural frequency of the maxillary dentition. The modal shapes of titanium alloy obturator prostheses showed the strongest splint-like effect and were concluded to be the most preferable. The damping ratio of titanium alloy obturator prostheses was significantly higher than cobalt chromium obturator prostheses. The maximum displacement of gold alloy obturator prostheses was significantly the highest of all. CONCLUSION: From the viewpoint of preserving abutments and remaining teeth, we conclude that titanium alloy is a more preferable material than gold alloy and cobalt-chromium alloy for the metal frameworks of metal framework obturator prostheses. PMID- 20951664 TI - Chewing-induced regional brain activity in edentulous patients who received mandibular implant-supported overdentures: a preliminary report. AB - PURPOSE: We used functional magnetic resonance imaging (fMRI) to investigate the change in brain regional activity during gum chewing when edentulous subjects switched from mandibular complete dentures to implant-supported removable overdentures. METHODS: Four edentulous patients (3 males and 1 female, aged 64 to 79 years) participated in the study. All subjects received a set of new maxillary and mandibular complete dentures (CD), followed by a maxillary complete denture and a new mandibular implant-supported removable overdentures (IOD). A 3-T fMRI scanner produced images of the regional brain activity for each subject that showed changes in the blood-oxygenation-level-dependent (BOLD) contrast in the axial orientation during gum-chewing with CD and IOD. RESULTS: Region-of-interest analysis showed that IOD treatment significantly suppressed chewing-induced brain activity in the prefrontal cortex. The chewing-induced brain activities in the primary sensorimotor cortex and cerebellum tended to decrease with IOD treatment, however they did not reach to significance level. There was no change in brain activity in the supplementary motor area, thalamus and insula between gum chewing with CD and IOD. Group comparison using statistical parametrical mapping further showed that, within the prefrontal cortex, the neural activity of the frontal pole significantly decreased during gum-chewing with IOD when compared to that with CD (P<0.05). CONCLUSION: Despite the limitation of a small sample size, these results suggest that the gum-chewing task in elderly edentulous patients resulted in differential neural activity in the frontal pole within the prefrontal cortex between the 2 prosthodontic therapies-mandibular CD and IOD. PMID- 20951665 TI - Synthetic nanoparticle vaccines produced by layer-by-layer assembly of artificial biofilms induce potent protective T-cell and antibody responses in vivo. AB - Nanoparticle vaccines induce potent immune responses in the absence of conventional adjuvant due to the recognition by immune cells of the particle structures, which mimic natural pathogens such as viruses and bacteria. Nanoparticle vaccines were fabricated by constructing artificial biofilms using layer-by-layer (LbL) deposition of oppositely charged polypeptides and target designed peptides on CaCO(3) cores. LbL nanoparticles were efficiently internalized by dendritic cells in vitro by a mechanism that was at least partially phagocytic, and induced DC maturation without triggering secretion of inflammatory cytokines. LbL nanoparticle delivery of designed peptides to DC resulted in potent cross-presentation to CD8+ T-cells and more efficient presentation to CD4+ T-cells compared to presentation of soluble peptide. A single immunization of mice with LbL nanoparticles containing designed peptide induced vigorous T-cell responses characterized by a balanced effector (IFNgamma) and Th2 (IL-4) ELISPOT profile and in vivo CTL activity. Mice immunized with LbL nanoparticles bearing ovalbumin-derived designed peptides were protected from challenge with Listeria monocytogenes ectopically expressing ovalbumin, confirming the relevance of the CTL/effector T-cell responses. LbL nanoparticles also elicited antibody responses to the target epitope but not to the matrix components of the nanoparticle, avoiding the vector or carrier affect that hampers utility of other vaccine platforms. The potency and efficacy of LbL nanoparticles administered in aqueous suspension without adjuvant or other formulation additive, and the absence of immune responses to the matrix components, suggest that this strategy may be useful in producing novel vaccines against multiple diseases. PMID- 20951666 TI - Biodistribution, persistence and lack of integration of a multigene HIV vaccine delivered by needle-free intradermal injection and electroporation. AB - It is likely that gene-based vaccines will enter the human vaccine area soon. A few veterinary vaccines employing this concept have already been licensed, and a multitude of clinical trials against infectious diseases or different forms of cancer are ongoing. Highly important when developing novel vaccines are the safety aspects and also new adjuvants and delivery techniques needs to be carefully investigated so that they meet all short- and long-term safety requirements. One novel in vivo delivery method for plasmid vaccines is electroporation, which is the application of short pulses of electric current immediately after, and at the site of, an injection of a genetic vaccine. This method has been shown to significantly augment the transfection efficacy and the subsequent vaccine-specific immune responses. However, the dramatic increase in delivery efficacy offered by electroporation has raised concerns of potential increase in the risk of integration of plasmid DNA into the host genome. Here, we demonstrate the safety and lack of integration after immunization with a high dose of a multigene HIV-1 vaccine delivered intradermally using the needle free device Biojector 2000 together with electroporation using Derma VaxTM DNA Vaccine Skin Delivery System. We demonstrate that plasmids persist in the skin at the site of injection for at least four months after immunization. However, no association between plasmid DNA and genomic DNA could be detected as analyzed by qPCR following field inversion gel electrophoresis separating heavy and light DNA fractions. We will shortly initiate a phase I clinical trial in which healthy volunteers will be immunized with this multiplasmid HIV-1 vaccine using a combination of the delivery methods jet-injection and intradermal electroporation. PMID- 20951667 TI - Modulation of T lymphocyte and eosinophil functions in vitro by natural tetranortriterpenoids isolated from Carapa guianensis Aublet. AB - We have previously described the anti-allergic activities of a pooled fraction of tetranortriterpenoids (TNTPs) containing 6alpha-acetoxygedunin, 7-deacetoxy-7 oxogedunin, andirobin and methyl angolensate isolated from the seeds of Carapa guianensis. In the present study, we performed in vitro studies in order to elucidate the mechanisms by which TNTPs present their anti-allergic effects and to identify the bioactive compound(s) present in such fraction. Here, we show that in vitro incubation of eosinophils with the pooled TNTP fraction, as well as with each one of the five isolated tetranortriterpenoids, impaired the adhesion of eosinophils to tumor necrosis factor-alpha (TNF-alpha)-primed tEND.1 endothelial cells. Furthermore, the individual or pooled TNTPs impaired CCL11/eotaxin-mediated chemotaxis. By contrast, pooled TNTPs failed to inhibit adhesion and chemotaxis of T lymphocytes. However, TNTPs were able to impair anti CD3 monoclonal antibody-induced T cell proliferation and the expression of CD25 and CD69. These data suggest that TNTPs prevent T cell activation. Pretreatment of splenocytes with the pooled TNTP fraction, as well as with each one of the five isolated TNTPs, inhibited ovalbumin (OVA)-induced in vitro production of interleukin-2, chemokine (C-C motif) ligand 11 (CCL11) and regulated on activation normal T cell expressed and secreted (RANTES, also known as CCL5). TNTPs (except 6alpha-acetoxygedunin) also impaired nuclear factor-kappaB (NFkappaB) nuclear translocation in OVA-challenged splenocytes. Taken together, these results demonstrate that the anti-allergic effects of TNTPs isolated from C. guianensis might rely on their ability to inhibit eosinophil migration, as well as the activation of T lymphocytes, which is shared by the five isolated TNTPs. PMID- 20951668 TI - Immunohematopoietic modulation by oral beta-1,3-glucan in mice infected with Listeria monocytogenes. AB - In this study we demonstrated that the oral administration of beta-1,3-glucan (Imunoglucan(r)) protects mice from a lethal dose of Listeria monocytogenes (LM) when administered prophylactically for 10 days at the doses of 150 and 300 mg/kg, with survival rates up to 40%. These doses also prevented the myelosuppression and the splenomegaly caused by a sublethal infection with LM, due to increased numbers of granulocyte-macrophage progenitors (CFU-GM) in the bone marrow. Investigation of the production of colony-stimulating factors revealed an increased colony-stimulating activity (CSA) in the serum of infected mice pre treated with Imunoglucan(r). The treatment also restored the reduced ability of stromal cells to display myeloid progenitors in long-term bone marrow cultures (LTBMC) and up-regulated IL-6 and IL-1alpha production by these cells in the infected mice, which was consistent with higher number of non-adherent cells. Additional studies to investigate the levels of interferon-gamma (INF-gamma) in the supernatant of splenocyte cultures demonstrated a further increase in the level of this cytokine in infected-treated mice, compared to infected controls. In all cases, no differences were observed between the responses of the two optimal biologically effective doses. In contrast, no significant changes were produced by the treatment with the 50mg/kg dose. In addition, no changes were observed in normal mice treated with the three doses used. All together our results suggest that orally given Imunoglucan(r) indirectly modulates immune activity and probably disengages Listeria induced suppression of these responses by inducing a higher reserve of myeloid progenitors in the bone marrow in consequence of biologically active cytokine release (CSFs, IL-1alpha, IL-6, and INF-gamma). PMID- 20951669 TI - Expression of TLR-4 and -2 in peripheral mononuclear cells in renal transplant patients with TLR-4 gene polymorphism. AB - INTRODUCTION: TLR-4 has also been identified as a receptor for endogenous alarmins, which are increased post transplantation. TLR-4 has also been associated with a polymorphism that could impact graft outcome. OBJECTIVE: To assess the expression of TLR-4 in kidney transplant patients carrying or not a polymorphism. METHODS: TLR-4 polymorphism (A299G/T399I) was studied in 200 renal transplant patients. Healthy volunteers were also enrolled as control group. The polymorphism analysis was performed using restriction enzymes technique (RFLP). Functionality of TLR-4 polymorphism was assessed in samples from controls by quantification of TNF-alpha after LPS stimulus. TLR-4 and -2 expressions were also analyzed by flow cytometry. RESULTS: TLR-4 polymorphism was present in 8.5% of renal transplant patients. This polymorphism was associated with impairment in TNF-alpha secretion. In general, in renal transplant patients, TLR-4 expression in monocytes and in neutrophils was lower than in health volunteers. TLR-2 and TLR-4 expressions in healthy volunteers with A299G/T399I TLR-4 polymorphism was higher than in wild-type genotype healthy volunteers (p<0.01 and p<0.05, respectively), and also higher than A299G/T399I TLR-4 polymorphism renal transplant patients (p<0.05). TLR-2 expression on neutrophils in wild-type genotype renal transplant patients was higher compared to wild-type genotype healthy volunteers, and was also higher in relation to A299G/T399I kidney transplanted patients (p<0.01). CONCLUSION: Stable renal transplant patients with TLR-4 polymorphism have a lower expression of TLR-4 and TLR-2 receptors in peripheral mononuclear cells, which ultimately indicate a less responsiveness for alarmins. PMID- 20951670 TI - An activated medium with high durability and low nonspecific adsorption: application to protein A chromatography. AB - Activated media allow the user to easily synthesize a variety of affinity media. We have developed a novel activated medium based on porous silica modified with phosphorylcholine (PC) and N-hydroxysuccinimide (NHS) groups for the purpose of high-throughput purification and reducing nonspecific protein adsorption. The PC groups function as suppressors of nonspecific protein adsorption, whereas the NHS groups are able to covalently bind to the primary amino groups of ligands. Because protein A affinity medium is the most frequently used affinity medium, we prepared protein A media in which a recombinant protein A was bound to the NHS groups of the activated media and evaluated its utility. After optimizing various factors in the synthetic process, the resultant protein A medium showed improved durability at a high flow rate over 300 purification cycles and reduced nonspecific protein adsorption compared with commercially available protein A media. PMID- 20951671 TI - Visible wavelength spectrophotometric assays of L-aspartate and D-aspartate using hyperthermophilic enzyme systems. AB - Methods with which to simply and rapidly assay L-aspartate (L-Asp) and D aspartate (D-Asp) would be highly useful for physiological research and for nutritional and clinical analyses. Levels of L- and D-Asp in food and cell extracts are currently determined using high-performance liquid chromatography. However, this method is time-consuming and expensive. Here we describe a simple and specific method for using an L-aspartate dehydrogenase (L-AspDH) system to colorimetrically assay L-Asp and a system of three hyperthermophilic enzymes- aspartate racemase (AspR), L-AspDH, and L-aspartate oxidase (L-AO)--to assay D Asp. In the former, the reaction rate of nicotinamide adenine dinucleotide (NAD(+))-dependent L-AspDH was measured based on increases in the absorbance at 438 nm, reflecting formation of formazan from water-soluble tetrazolium-1 (WST 1), using 1-methoxy-5-methylphenazinum methyl sulfate (mPMS) as a redox mediator. In the latter, D-Asp was measured after first removing L-Asp in the sample solution with L-AO. The remaining D-Asp was then changed to L-Asp using racemase, and the newly formed L-Asp was assayed calorimetrically using NAD(+)-dependent aspartate dehydrogenase as described above. This method enables simple and rapid spectrophotometric determination of 1 to 100 MUM L- and D-Asp in the assay systems. In addition, methods were applicable to the L- and D-Asp determinations in some living cells and foods. PMID- 20951672 TI - How the N-terminal extremity of Saccharomyces cerevisiae IF1 interacts with ATP synthase: a kinetic approach. AB - The N-terminal part of the inhibitory peptide IF1 interacts with the central gamma subunit of mitochondrial isolated extrinsic part of ATP synthase in the inhibited complex (J.R. Gledhill, M.G. Montgomery, G.W. Leslie, J.E. Walker, 2007). To explore its role in the different steps of IF1 binding, kinetics of inhibition of the isolated and membrane-bound enzymes were investigated using Saccharomyces cerevisiae IF1 derivatives modified in N-terminal extremity. First, we studied peptides truncated in Nter up to the amino acid immediately preceding Phe17, a well-conserved residue thought to play a key role. These deletions did not affect or even improve the access of IF1 to its target. They decreased the stability of the inhibited complex but much less than previously proposed. We also mutated IF1-Phe17 and found this amino acid not mandatory for the inhibitory effect. The most striking finding came from experiments in which PsaE, a 8 kDa globular-like protein, was attached in Nter of IF1. Unexpectedly, such a modification did not appreciably affect the rate of IF1 binding. Taken together, these data show that IF1-Nter plays no role in the recognition step but contributes to stabilize the inhibited complex. Moreover, the data obtained using chimeric PsaE-IF1 suggest that before binding IF1 presents to the enzyme with its middle part facing a catalytic interface and its Nter extremity folded in the opposite direction. PMID- 20951673 TI - Biochemical and biophysical characterization of succinate: quinone reductase from Thermus thermophilus. AB - Enzymes serving as respiratory complex II belong to the succinate:quinone oxidoreductases superfamily that comprises succinate:quinone reductases (SQRs) and quinol:fumarate reductases. The SQR from the extreme thermophile Thermus thermophilus has been isolated, identified and purified to homogeneity. It consists of four polypeptides with apparent molecular masses of 64, 27, 14 and 15kDa, corresponding to SdhA (flavoprotein), SdhB (iron-sulfur protein), SdhC and SdhD (membrane anchor proteins), respectively. The existence of [2Fe-2S], [4Fe 4S] and [3Fe-4S] iron-sulfur clusters within the purified protein was confirmed by electron paramagnetic resonance spectroscopy which also revealed a previously unnoticed influence of the substrate on the signal corresponding to the [2Fe-2S] cluster. The enzyme contains two heme b cofactors of reduction midpoint potentials of -20mV and -160mV for b(H) and b(L), respectively. Circular dichroism and blue-native polyacrylamide gel electrophoresis revealed that the enzyme forms a trimer with a predominantly helical fold. The optimum temperature for succinate dehydrogenase activity is 70 degrees C, which is in agreement with the optimum growth temperature of T. thermophilus. Inhibition studies confirmed sensitivity of the enzyme to the classical inhibitors of the active site, as there are sodium malonate, sodium diethyl oxaloacetate and 3-nitropropionic acid. Activity measurements in the presence of the semiquinone analog, nonyl-4 hydroxyquinoline-N-oxide (NQNO) showed that the membrane part of the enzyme is functionally connected to the active site. Steady-state kinetic measurements showed that the enzyme displays standard Michaelis-Menten kinetics at a low temperature (30 degrees C) with a K(M) for succinate of 0.21mM but exhibits deviation from it at a higher temperature (70 degrees C). This is the first example of complex II with such a kinetic behavior suggesting positive cooperativity with k' of 0.39mM and Hill coefficient of 2.105. While the crystal structures of several SQORs are already available, no crystal structure of type A SQOR has been elucidated to date. Here we present for the first time a detailed biophysical and biochemical study of type A SQOR-a significant step towards understanding its structure-function relationship. PMID- 20951674 TI - Solution- and solid-state NMR studies of GPCRs and their ligands. AB - G protein-coupled receptors (GPCRs) represent one of the major targets of new drugs on the market given their roles as key membrane receptors in many cellular signalling pathways. Structure-based drug design has potential to be the most reliable method for novel drug discovery. Unfortunately, GPCR-ligand crystallisation for X-ray diffraction studies is very difficult to achieve. However, solution- and solid-state NMR approaches have been developed and have provided new insights, particularly focussing on the study of protein-ligand interactions which are vital for drug discovery. This review provides an introduction for new investigators of GPCRs/ligand interactions using NMR spectroscopy. The guidelines for choosing a system for efficient isotope labelling of GPCRs and their ligands for NMR studies will be presented, along with an overview of the different sample environments suitable for generation of high resolution structural information from NMR spectra. PMID- 20951675 TI - Tryptophan orientations in membrane-bound gramicidin and melittin-a comparative linear dichroism study on transmembrane and surface-bound peptides. AB - In the search for methods to study structure and function of membrane-associated proteins and peptides flow linear dichroism, LD, spectroscopy has emerged as a promising technique. Using shear-aligned lipid vesicles, conformations and binding geometries of membrane-bound bio-macromolecules can be assessed. Here we investigate anchoring properties and specific orientations of tryptophan relative to the peptide backbone and to the membrane normal for the model peptides gramicidin and melittin. We have monitored the conformational change associated with the refolding of non-channel gramicidin into its channel form, and quantitatively determined the average orientations of its tryptophan transition moments, suggesting that these residues adopt a well-defined orientation at the membrane interface. An important conclusion regards the structural variation of gramicidin between these two distinct transmembrane forms. Whilst circular dichroism (CD) spectra, as has been reported before, vary strongly between the two forms suggesting their structures might be quite different, the LD results clearly evidence both the peptide backbone orientation and tryptophan side-chain positioning to be very similar. The latter are oriented in accord with what is expected from their role to anchor peptide termini to the membrane surface. The variations in CD could be due to, the in LD observed, minor shifts in mutual orientation and distance between neighbouring tryptophans sensitively determining their exciton interactions. Our data dispute that the non-channel form of membrane-bound gramicidin would be any of the intertwined forms often observed in crystal as the positioning of tryptophans along the peptide axis would not be compatible with the strong interfacial positioning observed here. The general role of tryptophans as interfacial anchors is further assessed for melittin whose conformation shows considerable angular spread, consistent with a carpet model of its mechanism for induced membrane leakage, and a predominantly surface-aligned membrane orientation governed by amphipathic interactions. PMID- 20951676 TI - Excessive ingestion of long-chain polyunsaturated fatty acids during developmental stage causes strain- and sex-dependent eye abnormalities in mice. AB - The eyes are rich in long-chain polyunsaturated fatty acids (LC-PUFAs) such as arachidonic acid [ARA; 20:4 (n-6)] and docosahexaenoic acid [DHA; 22:6 (n-3)]. Despite their abundance in the eyes, ARA and DHA cannot be sufficiently synthesized de novo in mammals. During gestation, eye development is exceptionally rapid, and substantial amounts of LC-PUFAs are needed to ensure proper eye development. Here, we studied the influences of dietary LC-PUFAs in dams (C57BL/6 and C3H/He) on the eye morphogenesis and organogenesis of their pups. Intriguingly, fetuses and newborn mice from C57BL/6 dams fed an LC-PUFA (particularly ARA)-enriched diet displayed a much higher incidence of eye abnormalities such as microphthalmia (small eye) and corneal opacity than those from dams fed an LC-PUFA-poor diet. The effects of LC-PUFAs on eye anomalies were evident only in the female pups of C57BL/6 inbred mice, not in those of C3H/He mice or male C57BL/6 mice. These results demonstrate a gene-by-environment (GxE) interaction in eye development in mice. Furthermore, our molecular analysis suggested the potential roles of Pitx3 and Pax6 in the above interaction involving ARA. PMID- 20951677 TI - Cell-specific regulation of Fas exon 6 splicing mediated by Hu antigen R. AB - The differential expression levels of T-cell intracellular antigens (TIA) and Hu antigen R (HuR) are concomitant with a splicing switch in apoptosis receptor Fas in HCT-116 cells. Thus, overexpression and knockdown of HuR led to Fas exon 6 skipping and inclusion, respectively. These results suggest that the TIA and HuR cellular ratio influences cell-type specific Fas exon 6 splicing pattern. PMID- 20951678 TI - The E3 ubiquitin ligase WWP1 regulates DeltaNp63-dependent transcription through Lys63 linkages. AB - The transcription factor p63, a member of the p53 family, plays a crucial role in epithelial development and tumorigenesis through the regulation of epithelial progenitor cell proliferation, differentiation and apoptosis. Similarly to p53, p63 activity is regulated by post-translational modifications, including ubiquitylation. Here, we report that the WWP1 E3 ubiquitin ligase binds specifically to DeltaNp63 isoform but it does not trigger DeltaNp63 proteasome dependent degradation. Accordingly, we found that WWP1-dependent ubiquitylation of DeltaNp63 occurs through the formation of Lys63-linked poly-ubiquitin chains. Importantly, we found that WWP1 is able to increase DeltaNp63-dependent transcription and depletion of WWP1 in human primary keratinocytes induces cell cycle arrest. All together these results indicate that WWP1 regulates DeltaNp63 transcriptional activity, acting thus as a potential regulator of the proliferation and survival of epithelial-derived cells. PMID- 20951679 TI - Activation of VPAC1 receptors aggravates early atherosclerosis in hypercholesterolemic apolipoprotein E-deficient mice. AB - OBJECTIVE: Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide widely expressed in the body and binding three types of receptors: VPAC(1)-R, VPAC(2)-R and PAC(1)-R. Based on beneficial effects of VIP and VPAC(1)-R agonists in mouse models of several chronic inflammatory disorders, we hypothesized that activation of VIP receptors would prevent atherosclerosis development in apolipoprotein E deficient mice. METHODS AND RESULTS: Contrary to our hypothesis, administration of a VPAC(1)-R agonist, (Ala(11,22,28))-VIP aggravated atherosclerotic lesion development in the aortic root of these mice compared to control mice. This was accompanied by a significant increase in the expression of MHC class II protein I A(b), and suggests enhanced inflammatory activity in the vessel wall. The amount of macrophage-specific CD68 staining as well as serum cholesterol and triglyceride levels did not change as a result of the (Ala(11,22,28))-VIP treatment, i.e. the treatment resulted in significant changes in lipid accumulation in the lesions without changing the number of macrophages or systemic lipid levels. Interestingly, administration of VIP did not alter the course of the disease. CONCLUSION: Despite beneficial effects in murine models of several inflammatory disorders, VPAC(1)-R activation aggravates atherosclerotic lesion formation in apolipoprotein E-deficient mice through enhanced inflammatory activity in the vessel wall. PMID- 20951680 TI - PPARgamma activates ABCA1 gene transcription but reduces the level of ABCA1 protein in HepG2 cells. AB - Synthesis of ABCA1 protein in liver is necessary for high-density lipoproteins (HDL) formation in mammals. Nuclear receptor PPARgamma is known as activator of ABCA1 expression, but details of PPARgamma-mediated regulation of ABCA1 at both transcriptional and post-transcriptional levels in hepatocytes have not still been well elucidated. In this study we have shown, that PPARgamma activates ABCA1 gene transcription in human hepatoma cells HepG2 through increasing of LXRbeta binding with promoter region of ABCA1 gene. Treatment of HepG2 cells with PPARgamma agonist GW1929 leads to dissociation of LXRbeta from ABCA1/LXRbeta complex and to nuclear translocation of this nuclear receptor resulting in reduction of ABCA1 protein level 24h after treatment. Inhibition of protein kinases MEK1/2 abolishes PPARgamma-mediated dissociation of LXRbeta from ABCA1/LXRbeta complex, but does not block PPARgamma-dependent down-regulation of ABCA1 protein in HepG2 cells. These data suggest that PPARgamma may be important for regulation of the level of hepatic ABCA1 protein and indicate the new interplays between PPARgamma, LXRbeta and MEK1/2 in regulation of ABCA1 mRNA and protein expression. PMID- 20951681 TI - Characterization of voltage-activated ionic currents in the GnRH-containing terminalis nerve in transgenic zebrafish. AB - The terminalis nerve (TN) is in a class of cranial nerves that plays important roles in animal development, physiology and behavior. Here, we report a study on the characterization of voltage-activated ionic currents in GnRH-containing TN cells in zebrafish. The experiments were performed using acutely dissociated TN cells from the transgenic zebrafish Tg (GnRH-3::GFP). In the transgenic zebrafish, the TN cells express GFP under the transcriptional control of the zebrafish GnRH-3 promoter. In all of the GnRH-containing TN cells examined, we recorded both low-voltage-activated (LVA) and high-voltage-activated (HVA) calcium current (I(Ca)). The characteristics of the I(Ca) were similar to those described in other zebrafish cell types. However, the distribution patterns of the currents in the GnRH-containing TN cells were different in comparison to the distribution of the currents in other cell types. In addition, we characterized TTX-sensitive sodium current (I(Na)) and 4AP-sensitive and TEA-resistant potassium current (I(K)). The characteristics of voltage-activated I(Na) and I(K) in the GnRH-containing TN cells were similar to those described in other zebrafish cell types. Together, the data from this study revealed the electrophysiological properties of the GnRH-containing TN cells, thereby providing insight on the regulatory mechanisms of TN-signaling in animal physiology. PMID- 20951682 TI - Effects of GABA agonist and antagonist injections into the oculomotor vermis on horizontal saccades. AB - The oculomotor vermis (OMV) of the cerebellum is necessary for the generation of the accurate rapid eye movements called saccades. Large lesions of the midline cerebellar cortex involving the OMV cause saccades to become hypometric and more variable. However, saccades were not examined immediately after these lesions so the interpretation of the resulting deficits might have been contaminated by some adaptation to the saccade dysmetria. Therefore, to better understand the contribution of the OMV to normal saccades, we impaired its operation locally by injecting small amounts of either an agonist or antagonist of gamma-aminobutyric acid (GABA), which is a ubiquitous neurotransmitter throughout the cerebellar cortex. Muscimol, a GABA agonist, inactivated part of the OMV, whereas bicuculline, an antagonist, disinhibited it. Muscimol caused all ipsiversive horizontal saccades from 5 to 30 degrees to become hypometric. In contrast, bicuculline produced an amplitude-dependent dysmetria: ipsiversive horizontal saccades elicited by target steps <10 degrees became hypometric, whereas those in response to larger steps became hypermetric. At the transition target amplitude, saccade amplitudes were quite variable with some being hypo- and others hypermetric. After most injections of either agent, saccades had lower peak velocities and longer durations than pre-injection saccades of the same amplitude. The longer durations were associated with a prolongation of the deceleration phase. Both agents produced inconsistent effects on contraversive saccades. These results establish that the oculomotor vermis helps control the characteristics of normal ipsiversive saccades and that GABAergic inhibitory processes are a crucial part of this process. PMID- 20951683 TI - Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus. AB - Gonadotropin-releasing hormone (GnRH) secretion has two modes of release in mammalian species; the surge mode and the pulse mode. The surge mode, which is required for the induction of the preovulatory gonadotropin discharge in most species, is induced by the positive feedback of estrogen secreted by the mature ovarian follicle. The pulse mode of GnRH secretion stimulates tonic luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion which drives folliculogenesis, spermatogenesis and steroidogenesis and is negatively fine tuned by estrogen or androgen. The GnRH pulse-generating mechanism is sensitive to environmental cues, such as photoperiod, nutrition and stress surge-generating mechanism is relatively emancipated from these environmental cues. The present article first provides a brief historical background to the work that led to the concept of the GnRH pulse generator: a hypothalamic network that is central to our understanding of the regulation of reproduction. We then discuss possible neurobiological mechanisms underlying GnRH pulse generation, and conclude by proposing that kisspeptin neurons in the arcuate nucleus are key players in this regard. PMID- 20951684 TI - Synergism of human amnion-derived multipotent progenitor (AMP) cells and a collagen scaffold in promoting brain wound recovery: pre-clinical studies in an experimental model of penetrating ballistic-like brain injury. AB - One of the histopathological consequences of a penetrating ballistic brain injury is the formation of a permanent cavity. In a previous study using the penetrating ballistic-like brain injury (PBBI) model, engrafted human amnion-derived multipotent progenitor (AMP) cells failed to survive when injected directly in the injury tract, suggesting that the cell survival requires a supportive matrix. In this study, we seated AMP cells in a collagen-based scaffold, injected into the injury core, and investigated cell survival and neuroprotection following PBBI. AMP cells suspended in AMP cell conditioned medium (ACCS) or in a liquefied collagen matrix were injected immediately after a PBBI along the penetrating injury tract. Injured control rats received only liquefied collagen matrix. All animals were allowed to survive two weeks. Consistent with our previous results, AMP cells suspended in ACCS failed to survive; likewise, no collagen was identified at the injury site when injected alone. In contrast, both AMP cells and the collagen were preserved in the injury cavity when injected together. In addition, AMP cells/collagen treatment preserved some apparent brain tissue in the injury cavity, and there was measurable infiltration of endogenous neural progenitor cells and astrocytes into the preserved brain tissue. AMP cells were also found to have migrated into the subventricular zone and the corpus callosum. Moreover, the AMP cell/collagen treatment significantly attenuated the PBBI induced axonal degeneration in the corpus callosum and ipsilateral thalamus and improved motor impairment on rotarod performance. Overall, collagen-based scaffold provided a supportive matrix for AMP cell survival, migration, and neuroprotection. PMID- 20951685 TI - Neuroprotective effects of curcumin on 6-hydroxydopamine-induced Parkinsonism in rats: behavioral, neurochemical and immunohistochemical studies. AB - Curcumin, the active principle of turmeric used in Indian curry is known for its antitumor, antioxidant, antiarthritic, anti-ischemic and anti-inflammatory properties and might inhibit the accumulation of destructive beta-amyloid in the brains of Alzheimer's disease patients. A Parkinsonian model in rats was developed by giving 6-hydroxydopamine (10 MUg/2 MUl in 0.1% ascorbic acid-saline) in the right striatum. After 3 weeks of lesioning, the behavior activities (rotarod, narrow beam test, grip test and contra-lateral rotations) were increased in a lesioned group as compared to a sham group and these activities were protected significantly with the pretreatment of curcumin. A significant protection on lipid peroxidation, glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase, tyrosine hydroxylase and D(2) receptor binding was observed in the striatum of lesioned group animals pretreated with 80 mg/kg body weight of curcumin for 21 days as compared to lesion group animals. No significant alterations on behavior and biochemical parameters were observed in sham group animals and the animals of sham group pretreated with curcumin. This study indicates that curcumin, which is an important ingredient of diet in India and also used in various systems of indigenous medicine, is helpful in preventing Parkinsonism and has therapeutic potential in combating this devastating neurologic disorder. PMID- 20951686 TI - Ranking antioxidants based on their effect on human serum lipids peroxidation. AB - Evaluation of the activity of antioxidants is commonly based on measurements of the effect of a specific antioxidant on redox reactions conducted in a solution. Given the difference between reactions that occur in homogeneous solutions and those that occur at lipid-water interfaces, as in biological membranes and lipoproteins, the relevance of the commonly-used assays (such as TEAC and ORAC) to the antioxidative activity in biological systems is questionable. The aim of the present investigation is to develop a more relevant assay. Based on our results, we propose an assay based on prolongation of the lag preceding fast peroxidation of serum lipids. The assay employs our previously developed procedure for determination of susceptibility of serum lipids to peroxidation. The effect of antioxidants is expressed in terms of the relative prolongation of the lag preceding peroxidation. It can be considered reliable because it is only marginally dependent on the specific sera used for the assay. The resultant ranking of antioxidants may be expressed either as the relative prolongation of the lag per 1MUM of antioxidant or as the concentration of antioxidant required to double the lag. As expected, the observed ranking order is very different from that reported for TEAC or ORAC assays, undermining the relevance of these assays for oxidation that occurs at interfaces. PMID- 20951687 TI - Crystal structure and microstructure of cholesteryl oleyl carbonate. AB - The crystal structure as well as the microstructure, i.e., size and strain, of crystallites of cholesteryl oleyl carbonate was determined from X-ray powder diffraction data. The X-ray line broadening was analyzed through the refinement of TCH-pseudo-Voigt function parameters (isotropic effects) and the refinement of multipolar functions, i.e., symmetrized cubic harmonics (anisotropic effects). The crystal structure turns out to be primitive monoclinic, space group Pc, type I monolayer having two molecules per unit cell with parameters: a=18.921+/ 0.006A, b=12.952+/-0.003A, c=9.276+/-0.002A and beta=91.32+/-0.03 degrees . The average size of a well ground specimen of crystallites was 60nm. The average micro-strain, e.g., 45*10(-4) has been tentatively attributed to fatty chain conformational disorder. The unit cell parameters, including the lamellar thickness, of COC crystal is very closely similar to those of another, structurally similar cholesterol ester, e.g., cholesteryl oleate (CO) crystal, space group P2(1), type II monolayer. Type I monolayer structure has been established for COC on the basis of the intensity calculations of the XRD profiles of both CO and COC. The dipolar and structural disorder in a 4:1 molar, binary mixture of CO and COC can be accommodated in an induced smectic phase with a lamellar thickness, which is nearly equal to that of pure CO or pure COC. PMID- 20951688 TI - Urinary NGAL measurement: biological variation and ratio to creatinine. PMID- 20951689 TI - Differential expression of genes in retinoblastoma. AB - Retinoblastoma is a pediatric eye tumor that serves as a paradigm for understanding the genetic basis of cancer. Mutations and/or epigenetic alterations inactivating both alleles of the retinoblastoma gene (RB) are associated with retinoblastoma. There are many other genes which express differentially in the preneoplastic retinal cells after RB loss, as cells progress to form tumors. These genetic changes and the pathways involved can provide valuable insight into the development and progression of this cancer. Conventional molecular and genetic methods for studying cancer are limited to the analysis of one locus at a time. A cluster of genes that are regulated together can be identified by DNA microarray, and the functional relationships can uncover new aspects of cancer biology. Meta analysis is an important tool for the identification and validation of differentially expressed genes to increase power in clinical and biological studies across different sets of data. Recently, meta analysis approaches have been applied to large collections of microarray datasets to investigate molecular commonalities of multiple cancer types not only to find the common molecular pathways in tumor development but also to compare the individual datasets to other cancer datasets to identify new sets of genes. The outcome of these analyses might accelerate the application of basic research findings into daily clinical practice through translational research and may have an impact on foreseeing the clinical outcome, predicting tumor response to specific therapy, identification of new prognostic biomarkers, discovering targets for the development of novel therapies and providing further insights. These and related research efforts reveal novel data that enhance our understanding of the biology of retinoblastoma. These observations may facilitate new therapeutic approaches to further decrease the morbidity and mortality associated with retinoblastoma and other more common forms of cancer. PMID- 20951690 TI - Lack of association between cellular repressor of E1A-stimulated genes (CREG) [corrected] polymorphisms and coronary artery disease in the Han population of North China. AB - BACKGROUND: Phenotypic switching of smooth muscle cells (SMCs) plays a critical role in the pathogenesis of atherosclerotic lesions such as coronary artery disease (CAD). Accumulating evidence demonstrates that a cellular repressor of E1A-stimulated genes (CREG) plays a role in the maintenance of the mature phenotype of vascular SMCs. We assessed the possible association between CREG and CAD in the Han population of North China. METHODS: The promoter region of CREG by direct sequencing was conducted in 48 subjects. Then SNP rs2995073 and another 4 tagSNPs (rs4657669, rs3767443, rs16859185, and rs3753921) were selected for the association study. All five selected SNPs were determined in 1161 patients with angiographically proven CAD and 960 controls with normal coronary angiograms to investigate the possible involvement of CREG in CAD. RESULTS: Genotype frequencies of the 5 polymorphisms were similarly distributed between CAD group and controls (P>0.05). Further haplotype analysis also found no significant differences in the distributions between CAD group and controls (P>0.05). CONCLUSION: This study did not show an association between common variants of CREG and CAD in the northern Chinese Han population. PMID- 20951691 TI - Measurement of serum remnant-like lipoprotein particle-triglyceride (RLP-TG) and RLP-TG/total TG ratio using highly sensitive triglyceride assay reagent. AB - BACKGROUND: Serum concentration of remnant-like lipoprotein particles (RLP) have been measured by cholesterol as RLP-C for clinical diagnostic purpose. However, the measurement of TG in RLP and the ratio of RLP-TG/total TG has not been well established. METHOD: Highly sensitive triglyceride assay reagent (TG-EX) was used for RLP-TG assay and compared with the previously used TG reagent (Determiner LTGII). Sera in health check-up populations, cardiovascular disease, diabetes and oral fat load cases were used for the evaluation of the new RLP-TG assay. Serum TC, TG, HDL-C, LDL-C and RLP-C concentrations were also determined in above cases. RESULTS: The detection limit of new RLP-TG using TG-EX was 2.0mg/dl. The within-run imprecision (n=10) was CV=3.0% (RLP-TG: 4.1 mg +/- 0.7 mg/dl), CV = 1.4% (RLP-TG: 42.0 +/- 0.6 mg/dl) and CV=0.5% (RLP-TG: 100.6 +/- 0.6 mg/dl). Cut off value (75 percentile) of RLP-TG determined in the fasting Japanese population was 13.1mg/dl in men and 9.9 mg/dl in women. In patients with metabolic syndrome, cardiovascular disease and diabetes, RLP-TG levels were significantly higher than those in normal control subjects. RLP-TG levels increased significantly after an oral fat load and the ratio of RLP-TG/total TG increased > 3-fold compared to the ratio in the fasting state. Approximately 80% of TG increased after an oral fat load was TG derived from remnant lipoproteins. CONCLUSION: Normal range of plasma RLP-TG in the fasting Japanese population was first determined using a highly sensitive TG assay reagent. RLP-TG was shown to be higher in cases with metabolic syndrome, cardiovascular disease, etc and a better marker than RLP-C for the measurement of postprandial remnant lipoproteins, together with total TG for RLP TG/total TG ratio. PMID- 20951692 TI - Genetically-defined lineage tracing of Nkx2.2-expressing cells in chick spinal cord. AB - In the spinal cord, generation of oligodendrocytes (OLs) is totally dependent on the presence of Olig2, a basic helix-loop-helix transcription factor. However, it also requires Nkx2.2 for its generation, whose expression follows the expression of Olig2. Although it is believed that oligodendrocytes originate from the pMN domain, Nkx2.2 is present in the p3 domain located ventral to the pMN domain. According to recent reports, it is possible that oligodendrocytes are directly derived from the p3 domain in addition to the pMN domain in the chick spinal cord. We examined this hypothesis in this paper. To analyze OL development in the spinal cord, chick embryos are widely used for genetic modification by electroporation or for transplantation experiments, because it is relatively easy to manipulate them compared with mouse embryos. However, genetic modification by electroporation is not appropriate for glial development analyses because glia proliferate vigorously before maturation. In order to overcome these problems, we established a novel method to permanently introduce exogenous gene into a specific cell type. We introduced the CAT1 gene, a murine retroviral receptor, by electroporation followed by injection of murine retrovirus. By using this method, we successfully transduced murine retrovirus into the chick neural tube. We analyzed cell lineage from the p3 domain by restricting CAT1 expression by Nkx2.2 enhancer and found that most of the labeled cells became OLs when the cells were labeled at cE4. Moreover, the labeled OLs were found throughout the white matter in the spinal cord including the most dorsal spinal cord. Thus p3 domain directly generates spinal cord OLs in the chick spinal cord. PMID- 20951693 TI - PTEN inhibitors cause a negative inotropic and chronotropic effect in mice. AB - Inactivation of phosphatase and tensin homologue deleted on chromosome ten (PTEN) decreases cardiac contractility under basal conditions and induces cardioprotection against ischemia-reperfusion injury. However, the pharmacological effect of PTEN inhibitors on cardiac contractility has not been studied before. In the present study, we investigated the hypothesis that PTEN inhibition decreases cardiac contractility in mice. We first exposed isolated mouse hearts to the PTEN inhibitor bpV(phen) (40MUM), the phosphoinositide-3 kinase inhibitor wortmannin (1MUM), and the PTEN-resistant PIP3 analog 3 phosphorothioate-PtdIns(3,4,5)P3 (3-PT-PTP, 0.5MUM) for 10min. Left ventricular pressure was measured by a Mikro-tip pressure catheter. We then inhibited PTEN in mice by intra-peritoneal injection of VO-OHpic (10MUg/kg) 30min before ischemia and then exposed them to 30min of ischemia and 120min of reperfusion. At the end of the experiments, hearts were isolated for measurement of myocardial infarct size by 1.5% triphenyltetrazolium chloride. Left ventricular systolic pressure and heart rate were significantly decreased by bpV(phen). Consistent with the result, the maximal rate of left ventricular pressure increase or decrease was significantly decreased by bpV(phen). 3-PT-PIP3 mimicked the effect of bpV(phen), and the opposite effect on cardiac contractility was seen with wortmannin. Moreover, inhibition of PTEN in vivo by VO-OHpic decreased left ventricular systolic pressure and heart rate before ischemia, but resulted in an increase in cardiac functional recovery and a decrease in myocardial infarct size after ischemia-reperfusion. In conclusion, PTEN inhibition causes a negative inotropic and chronotropic effect while inducing cardioprotection against ischemia reperfusion injury. PMID- 20951694 TI - A role for adenosine A(1) receptor blockade in the ability of caffeine to promote MDMA "Ecstasy"-induced striatal dopamine release. AB - Co-administration of caffeine profoundly enhances the acute toxicity of 3,4 methylenedioxymethamphetamine (MDMA) in rats. The aim of this study was to determine the ability of caffeine to impact upon MDMA-induced dopamine release in superfused brain tissue slices as a contributing factor to this drug interaction. MDMA (100 and 300MUM) induced a dose-dependent increase in dopamine release in striatal and hypothalamic tissue slices preloaded with [(3)H] dopamine (1MUM). Caffeine (100MUM) also induced dopamine release in the striatum and hypothalamus, albeit to a much lesser extent than MDMA. When striatal tissue slices were superfused with MDMA (30MUM) in combination with caffeine (30MUM), caffeine enhanced MDMA-induced dopamine release, provoking a greater response than that obtained following either caffeine or MDMA applications alone. The synergistic effects in the striatum were not observed in hypothalamic slices. As adenosine A(1) receptors are, one of the main pharmacological targets of caffeine, which are known to play an important role in the regulation of dopamine release, their role in the modulation of MDMA-induced dopamine release was investigated. 1MUM 8 cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific A(1) antagonist, like caffeine, enhanced MDMA-induced dopamine release from striatal slices while 1MUM 2,chloro-N(6)-cyclopentyladenosine (CCPA), a selective adenosine A(1) receptor agonist, attenuated this. Treatment with either SCH 58261, a selective A(2A) receptor antagonist, or rolipram, a selective PDE-4 inhibitor, failed to reproduce a caffeine-like effect on MDMA-induced dopamine release. These results suggest that caffeine regulates MDMA-induced dopamine release in striatal tissue slices, via inhibition of adenosine A(1) receptors. PMID- 20951695 TI - Clonidine inhibits itch-related response through stimulation of alpha(2) adrenoceptors in the spinal cord in mice. AB - The present study investigated whether clonidine - an alpha(2)-adrenoceptor agonist known to relieve pain - is able to suppress itch-related behavior in mice. An intraplantar injection of serotonin induced biting (an itch-related response), which was inhibited by intraperitoneal and intrathecal, but not intraplantar or intracisternal, clonidine injections. The effect of intrathecal clonidine was inhibited by intrathecal injections of phentolamine (a non selective alpha-adrenoceptor antagonist) and yohimbine (a selective alpha(2) adrenoceptor antagonist), but not by prazosin (a selective alpha(1)-adrenoceptor antagonist). The effect of intraperitoneal clonidine was also inhibited by intrathecal yohimbine. These results suggest that clonidine is an effective antipruritic agent and that the effect is mainly mediated by the stimulation of alpha(2)-adrenoceptors in the dorsal horn. PMID- 20951696 TI - Histamine H(1) antagonist treatment with pyrilamine reduces nicotine self administration in rats. AB - Nicotine has been definitively shown to be critically involved in the neural bases of tobacco addiction. However, nicotine releases a wide variety of neurotransmitters. Nicotine-induced dopamine release has been shown to play a key role in facilitating nicotine self-administration. Other transmitter systems may also play important roles in the pharmacological effects of nicotine and may provide important leads for combating nicotine self-administration. Clozapine, an antipsychotic drug, which blocks a variety of different transmitter receptors including serotonin 5HT(2) and histamine H(1) receptors, has been found to decrease smoking. Previously we found that the serotonin 5HT(2) antagonist, ketanserin, significantly reduced nicotine self-administration. In the current study, we assessed histamine H(1) receptor interaction with nicotine self administration. Young adult female Sprague-Dawley rats were fitted with IV catheters and trained to self-administer nicotine (0.03mg/kg/infusion). Acute doses of 40mg/kg of pyrilamine, a histamine H(1) antagonist, significantly reduced nicotine self-administration. We also found that repeated injections (20mg/kg) or chronic infusion via osmotic minipumps (50mg/kg/day) of pyrilamine also significantly decreased nicotine self-administration. The peripherally restricted H(1) antagonist ebastine was ineffective in reducing nicotine self administration, pointing to central H(1) receptor blockade as key for the effectiveness of pyrilamine. H(1) antagonists may be a promising avenue to explore for new treatments to aid smoking cessation. PMID- 20951697 TI - Fluconazole inhibits hERG K(+) channel by direct block and disruption of protein trafficking. AB - Fluconazole, a commonly used azole antifungal drug, can induce QT prolongation, which may lead to Torsades de Pointes and sudden death. To investigate the arrhythmogenic side effects of fluconazole, we studied the effect of fluconazole on human ether-a-go-go-related gene (hERG) K(+) channels (wild type, Y652A and F656C) expressed in human embryonic kidney (HEK293) cells using a whole-cell patch clamp technique, Western blot analysis and confocal microscopy. Fluconazole inhibited wild type hERG currents in a concentration-dependent manner, with a half-maximum block concentration (IC(50)) of 48.2+/-9.4MUM. Fluconazole did not change other channel kinetics (activation and steady-state inactivation) of hERG channel. Mutations in drug- binding sites (Y652A or F656C) of the hERG channel significantly attenuated the hERG current blockade by fluconazole. In addition, fluconazole inhibited the trafficking of hERG protein by Western blot analysis and confocal microscopy, respectively. These findings indicate that fluconazole may cause acquired long QT syndrome (LQTS) via a direct inhibition of hERG current and by disrupting hERG protein trafficking, and the mutations Y652 and F656 may be obligatory determinants in inhibition of hERG current for fluconazole. PMID- 20951698 TI - Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice. AB - BACKGROUND & AIMS: The limited clinical response observed in many patients with colorectal cancer may be related to the presence of chemoresistant colorectal cancer stem cells (CRC-SCs). Bone morphogenetic protein 4 (BMP4) promotes the differentiation of normal colonic stem cells. We investigated whether BMP4 might be used to induce differentiation of CRC-SCs and for therapeutic purposes. METHODS: CRC-SCs were isolated from 25 tumor samples based on expression of CD133 or using a selection culture medium. BMP4 expression and activity on CRC-SCs were evaluated in vitro; progeny of the stem cells were evaluated by immunofluorescence, immunoblot, and flow cytometry analyses. The potential therapeutic effect of BMP4 was assessed in immunocompromised mice after injection of CRC-SCs that responded to chemotherapy (n = 4) or that did not (n = 2). RESULTS: CRC-SCs did not express BMP4 whereas differentiated cells did. Recombinant BMP4 promoted differentiation and apoptosis of CRC-SCs in 12 of 15 independent experiments; this effect did not depend on Small Mothers against decapentaplegic (Smad)4 expression level or microsatellite stability. BMP4 activated the canonical and noncanonical BMP signaling pathways, including phosphoInositide 3-kinase (PI3K) and PKB (protein kinase B)/AKT. Mutations in PI3K or loss of Phosphatase and Tensin homolog (PTEN) in Smad4-defective tumors made CRC-SCs unresponsive to BMP4. Administration of BMP4 to immunocompromised mice with tumors that arose from CRC-SCs increased the antitumor effects of 5 fluorouracil and oxaliplatin. CONCLUSIONS: BMP4 promotes terminal differentiation, apoptosis, and chemosensitization of CRC-SCs in tumors that do not have simultaneous mutations in Smad4 and constitutive activation of PI3K. BMP4 might be developed as a therapeutic agent against cancer stem cells in advanced colorectal tumors. PMID- 20951699 TI - The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2. AB - BACKGROUND & AIMS: We investigated mechanisms of hepatocellular carcinoma (HCC) metastasis and identified an antimetastatic microRNA (miRNA), miR-139, that is down-regulated in human HCC samples. METHODS: Effects of stable and transient expression of miRNA-139 and its inhibitors were studied in the human HCC cell lines SMMC-7721 and BEL7402; cells were analyzed for migration and invasion. Liver samples from patients with metastatic HCC were analyzed for levels of miRNA 139; data were compared with survival data using the Kaplan-Meier method and compared between groups by the log-rank test. Tumor formation and metastasis from human HCC MHCC97L cells that did or did not express miR-139 were analyzed in mice. RESULTS: Down-regulation of miR-139 in HCC was associated significantly with poor prognosis of patients and features of metastatic tumors, including venous invasion, microsatellite formation, absence of tumor encapsulation, and reduced differentiation. miR-139 expression was reduced in metastatic HCC tumors compared with primary tumors. Overexpression of miR-139 in HCC cells significantly reduced cell migration and invasion in vitro and the incidence and severity of lung metastasis from orthotopic liver tumors in mice. miR-139 interacted with the 3' untranslated region of Rho-kinase 2 (ROCK2) and reduced its expression in HCC cells. Levels of miR-139 were correlated inversely with ROCK2 protein in human HCC samples. Overexpression of miR-139 did not inhibit HCC cell motility when ROCK2 was knocked down. CONCLUSIONS: The microRNA miR-139 interacts with ROCK2 and reduces its expression in HCC cells. Down-regulation of miR-139 increased the invasive abilities of HCC cells in vitro and HCC metastasis in vivo. Expression of miR-139 is reduced in human metastatic HCC samples and correlates with prognosis. PMID- 20951700 TI - Preovulatory follicle dynamics and ovulatory efficiency in sows with thrifty genotype and leptin resistance due to leptin receptor gene polymorphisms (Iberian pig). AB - This study compares follicular function and ovulatory efficiency in 20 sows with obesity/leptin resistance genotype (Iberian pig) and 20 females of lean commercial crosses (Large White * Landrace; LW*L). Estrous cycle was synchronized with progestagens; ovulation was induced with eCG and hCG, in half of the females of each group, to determine its effect. In females of both breeds not treated with gonadotropins, the number of follicles larger than 4.9 mm and the estradiol secretion increased throughout the follicular phase (P<0.05); estradiol values were similar at estrus detection (22.5+/-1.2 vs. 26.5+/-0.6 pg/ml respectively, for Iberian and LW*L sows). Moreover, ovulation rate was higher in Iberian pigs (15.3+/-1.3 CLs) than in LW*L (10.2+/-1.3 CLs; P<0.05), with mean progesterone values being 18.1+/-0.7 ng/ml in Iberian and 16.8+/-0.6 ng/ml in LW*L pigs. Thus, the preovulatory follicular growth and the ovulatory efficiency seem not to be the main limiting factors for reproductive efficiency in Iberian swine. The gonadotropins induced a significant increase, when compared to untreated females (P<0.05), in the number of follicles larger than 4.9 mm growing throughout the follicular phase; however, estradiol values at estrus were lower (P<0.05) in both breeds (9.2+/-0.7 pg/ml in Iberian vs. 8.6+/-0.8 pg/ml in LW*L), when compared with the nontreated animals, which suggests defective follicular function after gonadotropin stimulation. There were also no differences between genotypes in ovulation rate (15.2+/-1.3 vs. 12.7+/-1.8) and progesterone secretion (21.2+/-0.8 ng/ml in Iberian and 20.9+/-0.7 ng/ml in LW*L sows) in the treated animals. In conclusion, the current findings indicate that preovulatory follicular growth and ovulatory efficiency are not main limiting factors for prolificacy in a pig model of leptin resistance and obesity. PMID- 20951701 TI - Dolphins as animal models for type 2 diabetes: sustained, post-prandial hyperglycemia and hyperinsulinemia. AB - There is currently no known natural animal model that fully complements type 2 diabetes in humans. Criteria for a true natural animal model include the presence of a fasting hyperglycemia, evidence of insulin resistance, and pathologies matching that reported in humans. To investigate the bottlenose dolphin (Tursiops truncatus) as a comparative model for type 2 diabetes in humans, hourly plasma and urine chemistry changes, including glucose, were analyzed among five healthy, adult dolphins for 24 h following ingestion of 2.5-3.5 kg of mackerel or 2-3 L of 10% dextrose in ionosol. Fasting and 2 h post-prandial insulin levels were also determined among five adult dolphins to assess the presence of hyperinsulinemia. Finally, a case-control study compared insulin and glucagon levels among dolphins with and without iron overload, a condition associated with insulin resistance in humans. Both protein and dextrose meals caused significant increases in plasma glucose during the 0-5 h post-prandial period; dolphins fed dextrose demonstrated a sustained hyperglycemia lasting 5-10 h. Fasting plasma insulin levels among healthy dolphins mimicked those found in humans with some insulin resistance. Dolphins with hemochromatosis had higher post-prandial plasma insulin levels compared to controls. We conclude that bottlenose dolphins can demonstrate metabolic responses consistent with type 2 diabetes, specifically sustained hyperglycemia and hyperinsulinemia. Understanding more about how and why dolphins have a diabetes-like metabolism may provide new research avenues for diabetes in humans. PMID- 20951702 TI - Association analysis between variants in bovine NPY gene and growth traits in Nanyang cattle (Bos tarus). AB - Neuropeptide Y (NPY) is one of the most potent orexigenic factors that is implicated in the control of feeding behavior and energy homeostasis. Four Chinese indigenous cattle breeds (n=338) were used to detect single nucleotide polymorphisms (SNPs) in the coding regions with their intron-exon boundaries and the proximal flanking regions of NPY gene by PCR-SSCP and DNA sequencing. Five novel SNPs (38017 C>G, 34240 C>A, 34168 G>A, 32463 A>C and 32302 C>G) were identified. Polymorphisms of P3 lous in NPY gene, containing SNP4 and SNP5, were associated with body length and chest girth in Nanyang cattle aged 6, 12 and 18 months (P<0.05), but they had no significant effect on the two growth traits in Nanyang cattle aged 24 months (P>0.05). The results open a new field of study and extend the spectrum of genetic variation of the bovine NPY gene, which might contribute to cattle genetic resources and breeding. PMID- 20951703 TI - Effects of sex steroids on aromatase mRNA expression in the male and female quail brain. AB - Castrated male quail display intense male-typical copulatory behavior in response to exogenous testosterone but ovariectomized females do not. The behavior of males is largely mediated by the central aromatization of testosterone into estradiol. The lack of behavioral response in females could result from a lower rate of aromatization. This is probably not the case because although the enzymatic sex difference is clearly present in gonadally intact sexually mature birds, it is not reliably found in gonadectomized birds treated with testosterone, in which the behavioral sex difference is always observed. We previously discovered that the higher aromatase activity in sexually mature males as compared to females is not associated with major differences in aromatase mRNA density. A reverse sex difference (females>males) was even detected in the bed nucleus of the stria terminalis. We analyzed here by in situ hybridization histochemistry the density of aromatase mRNA in gonadectomized male and female quail that were or were not exposed to a steroid profile typical of their sex. Testosterone and ovarian steroids (presumably estradiol) increased aromatase mRNA concentration in males and females respectively but mRNA density was similar in both sexes. A reverse sex difference in aromatase mRNA density (females>males) was detected in the bed nucleus of subjects exposed to sex steroids. Together these data suggest that although the induction of aromatase activity by testosterone corresponds to an increased transcription of the enzyme, the sex difference in enzymatic activity results largely from post-transcriptional controls that remain to be identified. PMID- 20951704 TI - Ex vivo simulation of leukocyte function: stimulation of specific subset of leukocytes in whole blood followed by the measurement of function-associated mRNAs. AB - In order to characterize a wide spectrum of leukocyte functions with clinically applicable procedures, 0.06 ml each of heparinized whole blood was stimulated in triplicate for 4h with phytohemagglutinin (T cell stimulator), heat aggregated IgG (IgG Fc receptor stimulator), lipopolysaccharide (toll-like receptor (TLR)-4 stimulator), zymosan (TLR-2 stimulator), monoclonal antibody against T-cell receptor alpha/beta chain, recombinant interleukin-2, and solvent controls, then 32 different leukocyte function-associated mRNAs were quantified by the method reported previously (Mitsuhashi et al. Clin. Chem. 2006). Two control genes (beta actin, beta-2-microglobulin) were not affected by these stimulations, whereas the induction of CCL chemokines-2, 4, 8, 20, CXCL chemokines-3, 10, interleukin (IL) 8 (markers of leukocyte accumulation/recruit), granzyme B, perforin 1, tumor necrosis factor superfamily-1, 2, 5, 14, 15, CD16 (markers of cell killing), IL10, transforming growth factor beta 1 (humoral factors of immune suppression), forkhead box P3, CD25, arginase (cellular markers of immune suppression), IL2, IL4, interferon-gamma, IL17 (markers of various subsets of T helper cells), granulocyte-macrophage colony-stimulating factor (marker of antigen presenting cells), immunoglobulin heavy locus (marker of B-cells), vascular endothelial growth factor (marker of angiogenesis), pro-opiomelanocortin (marker of local pain), and CD11a mRNA (marker of leukocyte adherence to endothelium) were identified by these stimulations. The blood volume in this assay was 1.44 ml, and 4 h' incubation in whole blood was physiological. Using triplicate aliquots of whole blood for both stimulant and solvent control, statistical conclusion was drawn for each stimulant for each mRNA. The method introduced in this study will be a new paradigm for clinical cellular immunology. PMID- 20951705 TI - Expression and roles of Cav1.3 (alpha1D) L-type Ca2+ channel in atrioventricular node automaticity. AB - Atrioventricular node (AV node) is the hub where electrical input from the atria is propagated and conveyed to the ventricles. Despite its strategic position and role in governing impulse conduction between atria and ventricles, there is paucity of data regarding the contribution of specific ion channels to the function of the AV node. Here, we examined the roles of Ca(v)1.3 L-type Ca(2+) channel in AV node by taking advantage of a mouse model with null mutation of Ca(v)1.3 (Ca(v)1.3(-/-)). Ca(v)1.3 null mutant mice show evidence of AV node dysfunction with AV block, suggesting the tissue-specific function of the Ca(v)1.3 channel. In keeping with this assertion, we demonstrate that Ca(v)1.3 isoform is highly expressed in the isolated AV node cells. Furthermore, AV node isolated from Ca(v)1.3 null mutant mice show a significant decrease in the firing frequency of spontaneous action potentials suggesting that Ca(v)1.3 L-type Ca(2+) channel plays significant roles in the automaticity of the AV node. Because of the distinct voltage-dependence of Ca(v)1.2 and Ca(v)1.3 Ca(2+) channels, Ca(v)1.2 alone does not suffice to maintain normal AV node function. Ca(v)1.3 currents activate at more hyperpolarizing voltage compared to Ca(v)1.2 currents. Consequently, Ca(v)1.2 Ca(2+) channel cannot functionally substitute for Ca(v)1.3 isoform in the AV node of Ca(v)1.3 null mutant mice. Thus, our study demonstrates that the distinct biophysical properties of Ca(v)1.3 Ca(2+) channel play critical roles in the firing frequency of AV node tissues. PMID- 20951707 TI - A rare example of lock-and-key RNA recognition. PMID- 20951706 TI - SAM recognition and conformational switching mechanism in the Bacillus subtilis yitJ S box/SAM-I riboswitch. AB - S-box (SAM-I) riboswitches are a widespread class of riboswitches involved in the regulation of sulfur metabolism in Gram-positive bacteria. We report here the 3.0 A crystal structure of the aptamer domain of the Bacillus subtilis yitJ S-box (SAM-I) riboswitch bound to S-adenosyl-L-methionine (SAM). The RNA folds into two sets of helical stacks spatially arranged by tertiary interactions including a K turn and a pseudoknot at a four-way junction. The tertiary structure is further stabilized by metal coordination, extensive ribose zipper interactions, and SAM mediated tertiary interactions. Despite structural differences in the peripheral regions, the SAM-binding core of the B. subtilis yitJ riboswitch is virtually superimposable with the previously determined Thermoanaerobacter tengcongensis yitJ riboswitch structure, suggesting that a highly conserved ligand-recognition mechanism is utilized by all S-box riboswitches. SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) chemical probing analysis further revealed that the alternative base-pairing element in the expression platform controls the conformational switching process. In the absence of SAM, the apo yitJ aptamer domain folds predominantly into a pre-binding conformation that resembles, but is not identical with, the SAM-bound state. We propose that SAM enters the ligand-binding site through the "J1/2-J3/4" gate and "locks" down the SAM-bound conformation through an induced-fit mechanism. Temperature-dependent SHAPE revealed that the tertiary interaction-stabilized SAM-binding core is extremely stable, likely due to the cooperative RNA folding behavior. Mutational studies revealed that certain modifications in the SAM-binding region result in loss of SAM binding and constitutive termination, which suggests that these mutations lock the RNA into a form that resembles the SAM-bound form in the absence of SAM. PMID- 20951708 TI - Phosphatidylinositol-4,5-bisphosphate promotes budding yeast septin filament assembly and organization. AB - Septins are a conserved family of GTP-binding proteins that assemble into symmetric linear heterooligomeric complexes, which in turn are able to polymerize into apolar filaments and higher-order structures. In budding yeast (Saccharomyces cerevisiae) and other eukaryotes, proper septin organization is essential for processes that involve membrane remodeling, such as the execution of cytokinesis. In yeast, four septin subunits form a Cdc11-Cdc12-Cdc3-Cdc10 Cdc10-Cdc3-Cdc12-Cdc11 heterooctameric rod that polymerizes into filaments thought to form a collar around the bud neck in close contact with the inner surface of the plasma membrane. To explore septin-membrane interactions, we examined the effect of lipid monolayers on septin organization at the ultrastructural level using electron microscopy. Using this methodology, we have acquired new insights into the potential effect of septin-membrane interactions on filament assembly and, more specifically, on the role of phosphoinositides. Our studies demonstrate that budding yeast septins interact specifically with phosphatidylinositol-4,5-bisphosphate (PIP2) and indicate that the N terminus of Cdc10 makes a major contribution to the interaction of septin filaments with PIP2. Furthermore, we found that the presence of PIP2 promotes filament polymerization and organization on monolayers, even under conditions that prevent filament formation in solution or for mutants that prevent filament formation in solution. In the extreme case of septin complexes lacking the normally terminal subunit Cdc11 or the normally central Cdc10 doublet, the combination of the PIP2 containing monolayer and nucleotide permitted filament formation in vitro via atypical Cdc12-Cdc12 and Cdc3-Cdc3 interactions, respectively. PMID- 20951709 TI - Double dissociation between familiarity and recollection in Parkinson's disease as a function of encoding tasks. AB - Parkinson's disease (PD) is associated with episodic memory deficits, but their exact nature is unclear. Some dual-process studies have suggested that recollection is impaired and familiarity is spared in PD, yet others have found the opposite. Our goal was to investigate these memory processes in PD and determine whether the inconsistency among existing findings is related to differences in encoding conditions. We used a process-dissociation procedure with word pairs to estimate familiarity and recollection. In Experiment 1, we used a directed, deep, relational encoding condition (i.e., sentence generation), and in Experiment 2, we contrasted this encoding condition with a shallower, non directed encoding condition (i.e., read condition). We found a double dissociation as a function of the encoding task: In the sentence generation encoding condition, recollection was impaired in the PD patients, but familiarity was spared. In contrast, in the read encoding condition, there was no group difference in recollection, but familiarity was impaired in the PD group. Within subject comparisons revealed that both control and PD participants benefitted from the provision of a directed, deep relational encoding strategy. However, this benefit was manifested as an increase in recollection in the controls, but an increase in familiarity in the PD patients. These findings help to reconcile the extant literature and suggest that episodic memory deficits in PD are two fold, involving: (1) difficulties instantiating encoding strategies independently, leading to deficits in familiarity, and (2) impaired recollection when encoding strategies are equated across groups. Our results highlight the importance of controlling encoding conditions between groups and of taking account of other variables that may influence the participants' performance, such as deficits associated with normal aging, which may mask deficits in neurodegenerative diseases in particular situations. More generally, our study raises the possibility that deficits in recollection or familiarity in patient populations are not immutably linked to the structure that is affected, as is typically assumed, but that such deficits may interact with type of encoding, and possibly with the nature of the retrieval process. PMID- 20951710 TI - Sound before meaning: word learning in autistic disorders. AB - Successful word learning depends on the integration of phonological and semantic information with social cues provided by interlocutors. How then, do children with autism spectrum disorders (ASDs) learn new words when social impairments pervade? We recorded the eye-movements of verbally-able children with ASD and their typical peers while completing a word learning task in a social context. We assessed learning of semantic and phonological features immediately after learning and again four weeks later. Eye-movement data revealed that both groups could follow social cues, but that typically developing children were more sensitive to the social informativeness of gaze cues. In contrast, children with ASD were more successful than peers at mapping phonological forms to novel referents; however, this advantage was not maintained over time. Typical children showed clear consolidation of learning both semantic and phonological information, children with ASD did not. These results provide unique evidence of qualitative differences in word learning and consolidation and elucidate the different mechanisms underlying the unusual nature of autistic language. PMID- 20951711 TI - Sex differences in sensorimotor mu rhythms during selective attentional processing. AB - We used magnetoencephalography to investigate the effect of directed attention on sensorimotor mu (8-12 Hz) response (mu reactivity) to non-painful electrical stimulation of the median nerve in healthy adults. Mu desynchronization in the 10 12 Hz bandwidth is typically observed during higher-order cognitive functions including selective attentional processing of sensorimotor information (Pfurtscheller, Neuper, & Krauz, 2000). We found attention-related sex differences in mu reactivity, with females showing (i) prolonged mu desynchrony when attending to somatosensory stimuli, (ii) attentional modulation of the mu response based on whether attention was directed towards or away from somatosensory stimuli, which was absent in males, and (iii) a trend for greater neuronal excitability of the primary somatosensory region suggesting greater physiological responsiveness to sensory stimulation overall. Our findings suggest sex differences in attentional control strategies when processing somatosensory stimuli, whose salience may be greater for females. These sex differences in attention to somatosensory stimuli may help elucidate the well-documented sex biases in pain processing wherein females typically report greater sensitivity to experimental and clinical pain. PMID- 20951712 TI - Smoking modulates language lateralization in a sex-specific way. AB - Smoking affects a widespread network of neuronal functions by altering the properties of acetylcholinergic transmission. Recent studies show that nicotine consumption affects ascending auditory pathways and alters auditory attention, particularly in men. Here we show that smoking affects language lateralization in a sex-specific way. We assessed brain asymmetries of 90 healthy, right-handed participants using a classic consonant-vowel syllable dichotic listening paradigm in a 2*3 experimental design with sex (male, female) and smoking status (non smoker, light smoker, heavy smoker) as between-subject factors. Our results revealed that male smokers had a significantly less lateralized response pattern compared to the other groups due to a decreased response rate of their right ear. This finding suggests a group-specific impairment of the speech dominant left hemisphere. In addition, decreased overall response accuracy was observed in male smokers compared to the other experimental groups. Similar adverse effects of smoking were not detected in women. Further, a significant negative correlation was detected between the severity of nicotine dependency and response accuracy in male but not in female smokers. Taken together, these results show that smoking modulates functional brain lateralization significantly and in a sexually dimorphic manner. Given that some psychiatric disorders have been associated with altered brain asymmetries and increased smoking prevalence, nicotinergic effects need to be specifically investigated in this context in future studies. PMID- 20951713 TI - Effects of acute alcohol intoxication on verbal memory in young men as a function of time of day. AB - This experiment examined whether the time of day of alcohol administration influences alcohol metabolism and the impact of alcohol on verbal memory. It was hypothesized that circadian fluctuations in endogenous levels of testosterone in young men would differentially affect blood alcohol levels, which would consequently impair their memory performance to a different degree. Participants were administered alcohol or placebo drinks either at 8am or 6pm and recall of 4 prose passages was examined. The results indicated that recall declined for subjects administered alcohol but time of day did not moderate these effects. Nevertheless, generally alcohol breath levels changed in the predicted direction as a function of the time of the day with higher levels recorded in the morning and lower levels in the afternoon. The results suggested that observed differences in breath alcohol levels may be influenced by differences in endogenous levels of testosterone, but the effect of this presumed interaction on verbal memory appears inconclusive. PMID- 20951714 TI - Resistance of male Sprague-Dawley rats to sucrose-induced obesity: effects of 18 methoxycoronaridine. AB - Evidence suggests that the development of obesity in males and females might be mediated by distinct mechanisms, warranting different treatment approaches. In previous studies from this laboratory, a high sucrose diet induced excessive weight gain in female Sprague-Dawley rats and administration of a selective antagonist of alpha3beta4 nicotinic receptors, 18-methoxycoronaridine (18-MC), prevented this form of obesity. In the present study similar parameters were studied in male rats by using an identical experimental protocol. The effects of repeated administration of 18-MC on body weight gain, deposition of fat, consummatory behavior and biochemical markers of obesity in male rats were also assessed. In contrast to females, males consuming ad libitum quantities of sucrose solution (30%) in combination with normal chow did not become obese; they did not gain excessive weight nor show excessive fat deposition. Repeated administration of 18-MC (20mg/kg, i.p.) attenuated weight gain in both sucrose consuming and control animals without altering food or fluid intake. The present results indicate that males and females are differentially responsive to high carbohydrate-diet obesity. Such gender disparities could be secondary to sex specific alterations in cholinergic mechanisms of feeding and body weight regulation. PMID- 20951716 TI - Involvement of monoaminergic systems in the antidepressant-like effect of nobiletin. AB - Nobiletin isolated from citrus peels up-regulates synaptic transmission and improves memory impairment in rodents. This study investigated the antidepressant like effect of nobiletin in the forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the monoaminergic mechanisms involved in the antidepressant-like effect of nobiletin in mice were also assessed. Nobiletin (25, 50 and 100mg/kg, p.o.) decreased the immobility time in both the FST and TST without locomotor alterations in the open-field test (OFT). The anti-immobility effect of nobiletin (50mg/kg, p.o.) was completely prevented by the pretreatment of mice with WAY 100635 (0.1mg/kg, s.c., a serotonin 5-HT(1A) receptor antagonist), cyproheptadine (3mg/kg, i.p., a serotonin 5-HT(2) receptor antagonist), prazosin (62.5MUg/kg, i.p., an alpha(1)-adrenoceptor antagonist), SCH23390 (0.05mg/kg, s.c., a dopamine D(1) receptor antagonist) or sulpiride (50mg/kg, i.p., a dopamine D(2) receptor antagonist). On the other hand, the pretreatment of mice with yohimbine (1mg/kg, i.p., an alpha(2)-adrenoceptor antagonist) or propranolol (5mg/kg, i.p., a beta-adrenoceptor antagonist) did not block the antidepressant-like effect of nobiletin in the TST. Taken together, the data demonstrated that nobiletin produced an antidepressant-like effect that seems to be dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems. Thus, the present study suggests the therapeutic potential of this dietary flavonoid for the treatment of depression. PMID- 20951717 TI - Synthesis of new symmetrical bis-steroidal pyrazine analogues from diosgenin. AB - New symmetrical bis-steroidal pyrazine dimers that are cephalostatins/ritterazines analogues have been prepared easily from a cheap, readily available natural steroid (diosgenin). These dimers were obtained by classical, condensation of alpha-amino ketones in order to construct the pyrazine rings. The three dimers differ in the functionalized diosgenin: (25R) 5alpha,6beta-dihydroxy-5alpha-spirosta-3-one, (25R)-4,5alpha-epoxy-5beta-spirosta 3,6-dione and (25R)-5alpha-hydroxy-5alpha-spirosta-3,6-dione respectively. PMID- 20951718 TI - Autoregulation of cholesterol synthesis: physiologic and pathophysiologic consequences. AB - Autoregulation of cholesterol synthesis focuses on the 19 metabolic steps from lanosterol to cholesterol. Although synchronization of their rates of synthesis in all tissues was the paradigm, a known exception occurs in the ovary where a local increase in a sterol intermediate, FF-MAS (follicular fluid meiosis activating sterol), activates meiosis during oocyte maturation. Mutations in the genes that govern synchronization cause an increase in sterol intermediates that follow an alternate, oxysterol, pathway of metabolism. Experimental models in animals imply that oxysterol metabolites are determinants of the dysmorphism that occurs during fetal development in these genetic diseases. These few examples may portend a much broader role for sterol intermediates and their novel oxysterol metabolites in physiologic and pathophysiologic processes. PMID- 20951715 TI - Prenatal and postnatal ethanol experiences modulate consumption of the drug in rat pups, without impairment in the granular cell layer of the main olfactory bulb. AB - The effect of moderate exposure to ethanol during late gestation was studied in terms of its interaction with moderate exposure during nursing from an intoxicated dam. A further issue was whether behavioral effects of ethanol, especially the enhanced ethanol intake known to occur after moderate ethanol prenatally or during nursing, depend upon teratological effects that may include death of neurons in the main olfactory bulb (MOB). During gestational days 17-20 rats were given 0, 1 or 2g/kg ethanol doses intragastrically (i.g.). After parturition these dams were given a dose of 2.5g/kg ethanol i.g. each day and allowed to perform regular nursing activities. During postnatal days (PDs) 15 and 16, ethanol intake of pups was assessed along with aspects of their general activity. In a second experiment pups given the same prenatal treatment as above were tested for blood ethanol concentration (BEC) in response to an ethanol challenge on PD6. A third experiment (Experiment 2b) assessed stereologically the number of cells in the granular cell layer of the MOB on PD7, as a function of analogous pre- and postnatal ethanol exposures. Results revealed that ethanol intake during the third postnatal week was increased by prenatal as well as postnatal ethanol exposure, with a few interesting qualifications. For instance, pups given 1g/kg prenatally did not have increased ethanol intake unless they also had experienced ethanol during nursing. There were no effects of ethanol on either BECs or conventional teratology (cell number). This increases the viability of an explanation of the effects of prenatal and early postnatal ethanol on later ethanol intake in terms of learning and memory. PMID- 20951719 TI - Saccadic eye movements and perceptual judgments reveal a shared visual representation that is increasingly accurate over time. AB - Although there is evidence to suggest visual illusions affect perceptual judgments more than actions, many studies have failed to detect task-dependant dissociations. In two experiments we attempt to resolve the contradiction by exploring the time-course of visual illusion effects on both saccadic eye movements and perceptual judgments, using the Judd illusion. The results showed that, regardless of whether a saccadic response or a perceptual judgement was made, the illusory bias was larger when responses were based on less information, that is, when saccadic latencies were short, or display duration was brief. The time-course of the effect was similar for both the saccadic responses and perceptual judgements, suggesting that both modes may be driven by a shared visual representation. Changes in the strength of the illusion over time also highlight the importance of controlling for the latency of different response systems when evaluating possible dissociations between them. PMID- 20951720 TI - Surface boundaries do not constrain a depth aftereffect. AB - We investigated whether a depth aftereffect is better explained in a surface based organization of depth representation (Nakayama & Shimojo, 1992), where depth is represented in conjunction with surface features, rather than a coordinate-based organization, where depth is represented in conjunction with spatial position. Observers adapted to a stereogram depicting a surface with reference plane and were tested with a surface with either the same contour or position as the adaptation surface. The aftereffect did not depend on test surface position or contour. Thus, a depth aftereffect can be caused by a mechanism that does not depend on grouping by surface contour or position. PMID- 20951721 TI - Overlapping spatiotemporal patterns of regulatory gene expression are required for neuronal progenitors to specify retinal ganglion cell fate. AB - Retinal progenitor cells (RPCs) are programmed early in development to acquire the competence for specifying the seven retinal cell types. Acquiring competence is a complex spatiotemporal process that is still only vaguely understood. Here, our objective was to more fully understand the mechanisms by which RPCs become competent for specifying a retinal ganglion cell (RGC) fate. RGCs are the first retinal cell type to differentiate and their abnormal development leads to apoptosis and optic nerve degeneration. Previous work demonstrated that the paired domain factor Pax6 and the bHLH factor Atoh7 are required for RPCs to specify RGCs. RGC commitment is marked by the expression of the Pou domain factor Pou4f2 and the Lim domain factor Isl1. We show that three RPC subpopulations can specify RGCs: Atoh7-expressing RPCs, Neurod1-expressing RPCs, and Atoh7-Neurod1 expressing RPCs. All three RPC subpopulations were highly interspersed throughout retinal development, although each subpopulation maintained a distinct temporal pattern. Most, but not all, RPCs from each subpopulation were postmitotic. Atoh7 Neurod1 double knockout mice were generated and double-mutant retinas revealed an unexpected role for Neurod1 in specifying RGC fate. We conclude that RPCs have a complex regulatory gene expression program in which they acquire competence using highly integrated mechanisms. PMID- 20951724 TI - Public perceptions of cardiovascular risk factors in Croatia: the PERCRO survey. AB - OBJECTIVE: Since there are almost no data about the perceptions and attitudes of the general public concerning risk factors for cardiovascular diseases (CVD) this survey was performed. METHOD: Face-to-face interviews were conducted based upon a questionnaire with 883 members of the general population from different parts of Croatia in October-November 2008. RESULTS: 36.1% of them correctly identified CVD as the leading cause of death but the most feared disease was cancer (40.0%). CVD was on the second place with only 21.6%. 30.9% was aware that elevated LDL cholesterol increases CVD risk but 49.0% knew that high HDL-cholesterol is beneficial. 43.3% knew their total cholesterol (TC) value and 74.4% knew their blood pressure (BP). 30.9% knew what their target TC should be and 33.9% knew what their target BP should be. The knowledge about TC and BP target values was positively associated with higher educational level. 53.2% of the general public reported that they have never discussed any CVD risk factor with their physician. CONCLUSION: These data suggest insufficient awareness of CVD risk factors in general population and a need for improved promotion of CVD prevention. To achieve this people and physicians should be motivated by the health authorities and/or insurance companies. PMID- 20951722 TI - Binocular vision. AB - This essay reviews major developments - empirical and theoretical - in the field of binocular vision during the last 25years. We limit our survey primarily to work on human stereopsis, binocular rivalry and binocular contrast summation, with discussion where relevant of single-unit neurophysiology and human brain imaging. We identify several key controversies that have stimulated important work on these problems. In the case of stereopsis those controversies include position vs. phase encoding of disparity, dependence of disparity limits on spatial scale, role of occlusion in binocular depth and surface perception, and motion in 3D. In the case of binocular rivalry, controversies include eye vs. stimulus rivalry, role of "top-down" influences on rivalry dynamics, and the interaction of binocular rivalry and stereopsis. Concerning binocular contrast summation, the essay focuses on two representative models that highlight the evolving complexity in this field of study. PMID- 20951725 TI - Microwave assisted synthesis of polyacrylamide grafted starch (St-g-PAM) and its applicability as flocculant for water treatment. AB - Polyacrylamide grafted starch (St-g-PAM) was made by a novel method of synthesis, involving combination of microwave radiation and a chemical free radical initiator (ceric ammonium nitrate) to initiate grafting reaction. This method (microwave assisted synthesis) is quick, highly reliable, reproducible and yields high quality product as compared to the conventional method (which uses a chemical free radical initiator alone to initiate the grafting reaction).The St-g PAM grades synthesized were characterized by various physicochemical techniques. Further, its application as flocculant for wastewater treatment was investigated. PMID- 20951726 TI - Characterization and gene expression of transcription factors, PU.1 and C/EBPalpha driving transcription from the tumor necrosis factor alpha promoter in Japanese flounder, Paralichthys olivaceus. AB - Both PU.1 and C/EBPalpha transcription factors play important roles in myeloid development and inflammatory response. These transcripts were cloned from the Japanese flounder (Paralichthys olivaceus) and were highly conserved with those of other vertebrates. PU.1 mRNA was mainly expressed in lymphoid tissues while C/EBPalpha mRNA was widely expressed in all tissues examined. Higher levels of PU.1 mRNA were expressed in the IgM(+) cells of both PBL and KL, while C/EBPalpha expression was higher only in the IgM(-) cells of KL. The expression of C/EBPalpha mRNA was induced only in KL stimulated with LPS. Interestingly, PU.1 mRNA expression was induced by Edwardsiella tarda, whereas the expression of C/EBPalpha mRNA was induced by Streptococcus iniae infection. Both PU.1 and C/EBPalpha drove transcription from the LPS-responsive region of the Japanese flounder TNFalpha gene, suggesting that both PU.1 and C/EBPalpha induced by bacterial infection are involved in inflammation mediated through TNFalpha expression. PMID- 20951728 TI - Surveillance of shigellosis by real-time PCR suggests underestimation of shigellosis prevalence by culture-based methods in a population of rural China. AB - INTRODUCTION: Shigellosis is a leading public health issue in China, especially in Children under 5 years of age. The disease burden of shigellosis is usually underestimated by conventional culture. In this study, real-time PCR was applied to detect Shigella infection in parallel with routine culture, to investigate the true burden of disease caused by Shigella spp. METHODS: Rectal swab specimens of 39 Shigella culture positive and 298 Shigella culture negative patients from a population-based surveillance study were selected randomly. Real-time PCR targeting the invasion plasmid antigen H gene sequence (ipaH) was used to detect DNA sequences characteristic for Shigella spp. RESULTS: ipaH were detected in 174 of 298 (58%) randomly selected Shigella culture negative specimens and in 38 of 39 (97%) Shigella culture positive specimens (p < 0.001). Among 10 variables, culture results was the strongest predictive factor (OR = 15.5; 95% CI: 2.0 119.0), followed by a clinical presentation of diarrhea with fever (OR = 2.8; 95% CI: 1.2-6.2), epidemic season (OR = 2.4; 95% CI: 1.4-4.3), and female gender (OR = 1.8; 95% CI: 1.1-3.0). CONCLUSION: The high detection rate of ipaH in culture negative specimens through use of real-time PCR suggests that earlier estimates of shigellosis burden measured by conventional culture may have underestimated the true disease burden. PMID- 20951723 TI - The genetics of sex differences in brain and behavior. AB - Biological differences between men and women contribute to many sex-specific illnesses and disorders. Historically, it was argued that such differences were largely, if not exclusively, due to gonadal hormone secretions. However, emerging research has shown that some differences are mediated by mechanisms other than the action of these hormone secretions and in particular by products of genes located on the X and Y chromosomes, which we refer to as direct genetic effects. This paper reviews the evidence for direct genetic effects in behavioral and brain sex differences. We highlight the 'four core genotypes' model and sex differences in the midbrain dopaminergic system, specifically focusing on the role of Sry. We also discuss novel research being done on unique populations including people attracted to the same sex and people with a cross-gender identity. As science continues to advance our understanding of biological sex differences, a new field is emerging that is aimed at better addressing the needs of both sexes: gender-based biology and medicine. Ultimately, the study of the biological basis for sex differences will improve healthcare for both men and women. PMID- 20951729 TI - Isolation and characterization of an imported extremely-resistant Pseudomonas aeruginosa producing three different extended-spectrum beta-lactamases and hyperproducing two multidrug-efflux pumps. PMID- 20951727 TI - Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. AB - Schizophrenia is a severe mental illness that afflicts nearly 1% of the world's population. One of the cardinal pathological features of schizophrenia is perturbation in synaptic connectivity. Although the etiology of schizophrenia is unknown, it appears to be a developmental disorder involving the interaction of a potentially large number of risk genes, with no one gene producing a strong effect except rare, highly penetrant copy number variants. The purpose of this review is to detail how putative schizophrenia risk genes (DISC-1, neuregulin/ErbB4, dysbindin, Akt1, BDNF, and the NMDA receptor) are involved in regulating neuroplasticity and how alterations in their expression may contribute to the disconnectivity observed in schizophrenia. Moreover, this review highlights how many of these risk genes converge to regulate common neurotransmitter systems and signaling pathways. Future studies aimed at elucidating the functions of these risk genes will provide new insights into the pathophysiology of schizophrenia and will likely lead to the nomination of novel therapeutic targets for restoring proper synaptic connectivity in the brain in schizophrenia and related disorders. PMID- 20951733 TI - F2-isoprostane formation, measurement and interpretation: the role of exercise. AB - The level of F2-isoprostanes (F2-IsoP) in blood or urine is widely regarded as the reference marker for the assessment of oxidative stress. As a result, nowadays, F2-IsoP is the most frequently measured oxidative stress marker. Nevertheless, determining F2-IsoP is a challenging task and the measurement is neither free of mishaps nor straightforward. This review presents for the first time the effect of acute and chronic exercise on F2-IsoP levels in plasma, urine and skeletal muscle, placing emphasis on the origin, the methodological caveats and the interpretation of F2-IsoP alterations. From data analysis, the following effects of exercise have emerged: (i) acute exercise clearly increases F2-IsoP levels in plasma and this effect is generally short-lived, (ii) acute exercise and increased contractile activity markedly increase F2-IsoP levels in skeletal muscle, (iii) chronic exercise exhibits trend for decreased F2-IsoP levels in urine but further research is needed. Theoretically, it seems that significant amounts of F2-IsoP can be produced not only from phospholipids but from neutral lipids as well. The origin of F2-IsoP detected in plasma and urine (as done by almost all studies in humans) remains controversial, as a multitude of tissues (including skeletal muscle and plasma) can independently produce F2-IsoP. PMID- 20951734 TI - Medium-throughput computer aided micro-island method to assay embryonic dopaminergic neuron cultures in vitro. AB - In Parkinson's disease (PD) midbrain dopaminergic (DA) neurons degenerate and die, causing loss of motor function. Currently no therapies exist to ameliorate neurodegeneration or to restore DA neurons, although neurotrophic factors (NTFs) are promising leads. Prior in vivo studies the NTFs are routinely assessed in vitro by quantifying the survival of DA neurons from embryonic rodent midbrain cultures. Current in vitro methods are limited in terms of assay reliability, arduous workflow, low throughput, low statistical power and may obscure detection of molecules with minor yet critically important therapeutic effects. We have developed a medium-throughput, micro-island culture method. It permits analysis of 10-12 data points from a single embryo - several fold more than any previously published method - and enables comparisons of DA neurons from a single gene knockout (KO) embryo. It is computer-aided, improves statistical power and decreases the number of animals and workload per experiment. This method enhances testing capabilities of NTFs and other factors, and enables small scale screening of chemical drug libraries. We have validated the method by confirming the known effects of glial cell line-derived neurotrophic factor (GDNF) and neurturin (NRTN), and demonstrated additive effects via simultaneous addition of GDNF and heparin binding growth associated molecule (HB-GAM). We also show for the first time that DA neurons isolated from GDNF receptor RET-deficient mice are still GDNF responsive, suggesting the presence of an alternative non-RET receptor for GDNF in the DA system. Finally, the method can be adapted for analyses of other low abundance neuronal systems. PMID- 20951730 TI - Chronic alcohol neuroadaptation and stress contribute to susceptibility for alcohol craving and relapse. AB - Alcoholism is a chronic relapsing disorder. Major characteristics observed in alcoholics during an initial period of alcohol abstinence are altered physiological functions and a negative emotional state. Evidence suggests that a persistent, cumulative adaptation involving a kindling/allostasis-like process occurs during the course of repeated chronic alcohol exposures that is critical for the negative symptoms observed during alcohol withdrawal. Basic studies have provided evidence for specific neurotransmitters within identified brain sites being responsible for the negative emotion induced by the persistent cumulative adaptation following intermittent-alcohol exposures. After an extended period of abstinence, the cumulative alcohol adaptation increases susceptibility to stress- and alcohol cue-induced negative symptoms and alcohol seeking, both of which can facilitate excessive ingestion of alcohol. In the alcoholic, stressful imagery and alcohol cues alter physiological responses, enhance negative emotion, and induce craving. Brain fMRI imaging following stress and alcohol cues has documented neural changes in specific brain regions of alcoholics not observed in social drinkers. Such altered activity in brain of abstinent alcoholics to stress and alcohol cues is consistent with a continuing ethanol adaptation being responsible. Therapies in alcoholics found to block responses to stress and alcohol cues would presumably be potential treatments by which susceptibility for continued alcohol abuse can be reduced. By continuing to define the neurobiological basis of the sustained alcohol adaptation critical for the increased susceptibility of alcoholics to stress and alcohol cues that facilitate craving, a new era is expected to evolve in which the high rate of relapse in alcoholism is minimized. PMID- 20951735 TI - Recovery of motor function after stroke: a polymyography-based analysis. AB - We present a method for assessing muscle activation patterns during goal-directed movement. We present a cohort study from a randomized clinical trial that followed the recovery of motor function during and after intensive gait training, assisted by sensor-driven, four-channel electrical stimulation. The instrument that we developed allows for the simultaneous recordings of up to 16 channels that are wirelessly sent to a host computer, which then provides feedback to the subject. The inputs to the portable instrument support electromyography (EMG) amplifiers, inertial sensors and goniometers. We show that this method is sensitive enough to show changes in muscle activation patterns in stroke patients before and after gait training (four weeks, five days a week, 30 min daily). We also show that the recovery decreases the differences between patterns of muscle activities (e.g., levels of muscle activations and median frequencies) assessed in hemiplegic and healthy subjects. This method allows for the analysis of muscle contributions and activation patterns; therefore, it might be possible to better understand the physiology behind the recovery of function. This EMG analysis provides a quantification of recovery that is a valuable addition to other measures, such as the Fugl-Meyer score, the Berg-Balance score, gait speed, and the symmetry index. PMID- 20951732 TI - The impact of redox and thiol status on the bone marrow: Pharmacological intervention strategies. AB - Imbalances in cancer cell redox homeostasis provide a platform for new opportunities in the development of anticancer drugs. The control of severe dose limiting toxicities associated with redox regulation, including myelosuppression and immunosuppression, remains a challenge. Recent evidence implicates a critical role for redox regulation and thiol balance in pathways that control myeloproliferation, hematopoietic progenitor cell mobilization, and immune response. Hematopoietic stem cell (HSC) self-renewal and differentiation are dependent upon levels of intracellular reactive oxygen species (ROS) and niche microenvironments. Redox status and the equilibrium of free thiol:disulfide couples are important in modulating immune response and lymphocyte activation, proliferation and differentiation. This subject matter is the focus of the present review. The potential of redox modulating chemotherapeutics as myeloproliferative and immunomodulatory agents is also covered. PMID- 20951731 TI - Regulation of monoamine transporters: Role of transporter phosphorylation. AB - Presynaptic biogenic amine transporters mediate reuptake of released amines from the synapse, thus regulating serotonin, dopamine and norepinephrine neurotransmission. Medications utilized in the treatment of depression, attention deficit-hyperactivity disorder and other psychiatric disorders possess high affinity for amine transporters. In addition, amine transporters are targets for psychostimulants. Altered expression of biogenic amine transporters has long been implicated in several psychiatric and degenerative disorders. Therefore, appropriate regulation and maintenance of biogenic amine transporter activity is critical for the maintenance of normal amine homoeostasis. Accumulating evidence suggests that cellular protein kinases and phosphatases regulate amine transporter expression, activity, trafficking and degradation. Amine transporters are phosphoproteins that undergo dynamic control under the influence of various kinase and phosphatase activities. This review presents a brief overview of the role of amine transporter phosphorylation in the regulation of amine transport in the normal and diseased brain. Understanding the molecular mechanisms by which phosphorylation events affect amine transporter activity is essential for understanding the contribution of transporter phosphorylation to the regulation of monoamine neurotransmission and for identifying potential new targets for the treatment of various brain diseases. PMID- 20951737 TI - In vivo simultaneous intra- and extracellular potassium recordings using a micro optrode. AB - This technique proposes a new approach to correlate intra- and extracellular variations of the ionic concentrations in vivo by means of tapered optical waveguides coupled to standard electrophysiological electrodes to monitor in vivo simultaneously the intracellular and extracellular K(+) concentration as well as the neighboring field potential. The optical fibers were tapered to a final diameter of approximately 10 MUm and were used to guide the excitation light deep into the tissue and to collect the fluorescence emanating from the intracellular milieu. This fiber was coupled to a double barrel ion-sensitive electrode forming a micro-optrode with a final diameter around 15 MUm. The method was successfully used to record the intracellular K(+) evolution with the fluorescent indicator PBFI during three states: normal sleep-like patterns, paroxysmal seizures, and coma. While we could not disclose any phasic fluctuations of the intracellular K(+) during normal sleep patterns, they were clearly present during seizures and coma. In the majority of cases (58%), paroxysmal discharges were associated with positive variations of the intracellular fluorescence of 62+/-5% corresponding to extracellular K(+) increases of 2.04+/-0.4 mM. In the remaining cases (42%) intracellular K(+) dropped by 44.4+/-12% for an extracellular K(+) increase of 2.62+/-0.47 mM. We suggest that this differential behavior might reflect different cellular populations (glia vs. neurons, respectively). Comatose states were accompanied by an extracellular drop of K(+) of 1.31+/-0.13 mM, which was reflected, in all cases, by an intracellular K(+) increase of 39+/-4%. PMID- 20951736 TI - A reliable microinjectrode system for use in behaving monkeys. AB - We describe a modified system for the precise delivery of small volumes of drugs to brain sites of behaving monkeys during simultaneous single-neuron electrophysiology. The system combines a conventional microelectrode for recording single neurons and a small gauge microsyringe in a durable design. It incorporates newly available microfluidic components to achieve high-precision fluidic control. The system is inexpensive, reusable and easy to fabricate; it minimizes neural tissue damage and achieves reliable single-neuron recordings at the injection site. PMID- 20951739 TI - Culturing conditions determine neuronal and glial excitability. AB - The cultivation of pure neuronal cultures is considered advantageous for the investigation of cell-type specific responses (such as transmitter release and also pharmacological agents), however, divergent results are a likely consequence of media modifications and culture composition. Using Fura-2 based imaging techniques, we here set out to compare calcium responses of rat hippocampal neurones and glia to excitatory stimulation with l-glutamate in different culture types and media. Neurones in neurone-enriched cultures had increased responses to 10 MUM and 100 MUM l-glutamate (+43 and 45%, respectively; p's< 0.001) and a slower recovery compared to mixed cultures, indicating heightened excitability. In matured (15-20 days in vitro) mixed cultures, neuronal responder rates were suppressed in a neurone-supportive medium (Neurobasal-A, NB: 65%) compared to a general-purpose medium (supplemented minimal essential medium, MEM: 96%). Glial response size in contrast did not differ greatly in isolated or mixed cultures maintained in MEM, but responder rates were suppressed in both culture types in NB (e.g. 10 MUM l-glutamate responders in mixed cultures: 29% in NB, 71% in MEM). This indicates that medium composition is more important for glial excitability than the presence of neurones, whereas the presence of glia has an important impact on neuronal excitability. Therefore, careful consideration of culturing conditions is crucial for interpretation and comparison of experimental results. Especially for investigations of toxicity and neuroprotection mixed cultures may be more physiologically relevant over isolated cultures as they comprise aspects of mutual influences between glia and neurones. PMID- 20951740 TI - Expression profiles of novel cell surface molecules on B-cell subsets and plasma cells as analyzed by flow cytometry. AB - Cell surface molecules are present on several lymphocyte subsets and are differentially expressed during lymphocyte development and activation. Human Leukocyte Differentiation Antigen (HLDA) Workshops have played an essential role in the identification and characterization of the molecules found in the membrane of hematopoietic cells. In the present study, the reactivities of sixty-five monoclonal antibodies (mAbs) submitted to the HLDA9 Workshop were tested. A multicolor flow cytometric analysis was performed in order to determine the expression profiles of these proteins on peripheral blood lymphocytes, hematopoietic cell lines, and tonsil B-cells. The following B-cell subsets were assessed: mature naive, pre-germinal center, germinal center, unswitched and switched memory, plasmablasts, and plasma cells. Immunohistochemical analysis on formalin-fixed paraffin-embedded tonsils was also carried out. Remarkably, a large group of immunoglobulin family inhibitory cell surface molecules were observed on several distinct B-cell subsets including: CD152 (CTLA4), CD170 (Siglec-5), CD272 (BTLA), CD305 (LAIR1), CD307d (FCRL4), and CD329 (Siglec-9). The following molecules were also found to be differentially expressed on B-cell subsets (CD80, CD185 (CXCR5), CD196 (CCR6), CD270 (TNFRSF14), CD307a-c (FCRL1-3), CD319 (SLAMF7) and CD362 (SDC2)) or delineated B-cell subpopulations (CD126 (IL 6R), CD255 (TNFSF12), CD264 (TNFRSF10D), CD267 (TNFRSF13B) and CD329 (Siglec-9)). Of these, only CD307a, CD307b, and CD307d presented a B-cell-specific expression pattern. Our results show that several of these molecules are capable of further subdividing the known B-cell subsets and, in fact, may represent new markers for research, diagnosis, and eventually targets for the treatment of B-cell malignancies and autoimmune diseases. PMID- 20951738 TI - Convection-enhanced delivery and systemic mannitol increase gene product distribution of AAV vectors 5, 8, and 9 and increase gene product in the adult mouse brain. AB - The use of recombinant adeno-associated viral (rAAV) vectors as a means of gene delivery to the central nervous system has emerged as a potentially viable method for the treatment of several types of degenerative brain diseases. However, a limitation of typical intracranial injections into the adult brain parenchyma is the relatively restricted distribution of the delivered gene to large brain regions such as the cortex, presumably due to confined dispersion of the injected particles. Optimizing the administration techniques to maximize gene distribution and gene expression is an important step in developing gene therapy studies. Here, we have found additive increases in distribution when 3 methods to increase brain distribution of rAAV were combined. The convection enhanced delivery (CED) method with the step-design cannula was used to deliver rAAV vector serotypes 5, 8 and 9 encoding GFP into the hippocampus of the mouse brain. While the CED method improved distribution of all 3 serotypes, the combination of rAAV9 and CED was particularly effective. Systemic mannitol administration, which reduces intracranial pressure, also further expanded distribution of GFP expression, in particular, increased expression on the contralateral hippocampi. These data suggest that combining advanced injection techniques with newer rAAV serotypes greatly improves viral vector distribution, which could have significant benefits for implementation of gene therapy strategies. PMID- 20951741 TI - New monoclonal antibodies against B-cell antigens: possible new strategies for diagnosis of primary cutaneous B-cell lymphomas. AB - Reactivities of the monoclonal antibodies (mAbs) of the 9th Human Leukocyte Differentiation Antigen Workshop, in order to define specific antigenic expression of the primary cutaneous B-cell lymphomas (PC-BCL), were analyzed by immunohistology on human tonsil and on PC-BCL, such as follicular centre B-cell lymphomas (FCL), marginal zone lymphomas (MZL) and diffuse large B-cells lymphomas leg-type (DLBL-LT). We identified some subgroups of mAbs that were exclusively or preferentially positive in one lymphoma cell type: the PC-FCL subgroup of mAbs includes PD1/CD279, GCET-1, hFCRL1/CD307a, FCRL2/CD307b, CXCR5/CD185, B7-DC/CD273, MRC/CD200, CD130, CXCR4/CD184, Siglec-5/14, CD150, on the other hand subgroup of mAbs in PC-MZL includes BTLA/CD272, BLIMP-1, hCD38. No specific subgroup of mAbs was found to label PC-DLBCL. This study may be useful to better define specific antigen profile of different PC-BCL entities leading to a correct diagnosis. PMID- 20951742 TI - Mutual benefits of B-ALL and HLDA/HCDM HLDA 9th Barcelona 2010. AB - The B-cell panel of the ninth HLDA was applied in a multicentre fashion to cryopreserved cells from 46 patients with acute lymphoblastic leukemia. The reagents were aliquoted and shipped to volunteer participants from the French Groupe d'Etude Immunologique des Leucemies (GEIL). All samples were tested in flow cytometry, and the results collected as of the strength of labeling of the leukemic clone as negative, weak or strong. Among the 64 antibodies tested, the strongest and most frequent staining was observed for CD305 (LAIR), CD229 (Ly9), CD200 (OX-2) and, to a lesser extent, CD361 (EVI2b). Details of the observations, and information about the molecules tested are provided in the manuscript as well as a summary table. PMID- 20951743 TI - Development and validation of a lateral flow immunoassay using colloidal gold for the identification of serotype-specific foot-and-mouth disease virus O, A and Asia 1. AB - A lateral flow immunoassay (LFI) was developed to identify and diagnose foot-and mouth disease virus (FMDV) serotypes O, A and Asia 1. Antibodies obtained from rabbits and guinea pigs immunized with cell-culture-adapted virus strains (O/CHA/99, A/GS/LX/66, Asia 1/CHN/05) and suckling-mouse adapted virus strains (O/AV99(L), A/AV88(L), Asia 1/YNBS/58) were used as capture antibodies. The diagnostic kit included three immunochromatographic strips of types O, A and Asia 1, and the type-specific results were confirmed by color on the test lines of the three strips. The LFI was evaluated using epithelial and vesicular samples (n=396) prepared from current and historical field samples (provide by the National Foot-and-Mouth Disease Reference Laboratory of China at Lanzhou Veterinary Research Institute). Negative samples (n=95) were collected from healthy animals. The diagnostic sensitivity of the LFI for FMDV serotypes O, A and Asia 1 was 88.3% compared to 89.7% obtained by the reference method of indirect-sandwich ELISA. The sensitivity of the LFI for FMDV type Asia 1 was higher at 92.1% compared to 90.5% for the ELISA. The specificity of the LFI was 97.1% compared with 97.4%. PMID- 20951744 TI - Implementation and validation of a sensitive PCR detection method in the eradication campaign against Aleutian mink disease virus. AB - Aleutian mink disease virus (AMDV) is a severe progressive disease causing multiple different clinical syndromes in mink. In Denmark, the disease is notifiable and under official control. The control programme, based on serological screening, has confined successfully AMDV to the northern part of Denmark. However, re-infections and new introductions of virus into farms require a confirmatory virological test to verify the positive test results of single animals and ultimately to investigate disease transmission. A one step PCR amplifying a 374-base fragment of the NS1 gene of AMDV was compared to the counter-current immune electrophoresis (CIE) routinely used in the serological screening programme. Mink organs (n=299) obtained from 55 recently infected farms and 8 non-infected farms from 2008 to 2010 were tested by PCR, and the results were found to have a high correlation with the serological status of the mink. The relative diagnostic sensitivity of the PCR was 94.7%, and the relative diagnostic specificity was 97.9% when read in parallel with the CIE. PCR positive samples were sequenced and phylogenetic analysis revealed high similarity within the analysed AMDV strains and to AMDV strains described previously. PMID- 20951745 TI - A new method for detection of pandemic influenza virus using High Resolution Melting analysis of the neuraminidase gene. AB - Diagnostic methods based upon exclusive detection of haemagglutinin do not detect sequence variation in other gene segments of the Influenza A virus. A complementary approach is described based upon high-resolution melting curve analysis of the neuraminidase gene, an approach with the potential ability to detect small changes in the neuraminidase sequence without the need for specific probes. PMID- 20951746 TI - Nigericin is a potent inhibitor of the early stage of vaccinia virus replication. AB - Poxviruses remain a significant public health concern due to their potential use as bioterrorist agents and the spread of animal borne poxviruses, such as monkeypox virus, to humans. Thus, the identification of small molecule inhibitors of poxvirus replication is warranted. Vaccinia virus is the prototypic member of the Orthopoxvirus genus, which also includes variola and monkeypox virus. In this study, we demonstrate that the carboxylic ionophore nigericin is a potent inhibitor of vaccinia virus replication in several human cell lines. In HeLa cells, we found that the 50% inhibitory concentration of nigericin against vaccinia virus was 7.9 nM, with a selectivity index of 1038. We present data demonstrating that nigericin targets vaccinia virus replication at a post-entry stage. While nigericin moderately inhibits both early vaccinia gene transcription and translation, viral DNA replication and intermediate and late gene expression are severely compromised in the presence of nigericin. Our results demonstrate that nigericin has the potential to be further developed into an effective antiviral to treat poxvirus infections. PMID- 20951747 TI - Differential infectious entry of human influenza A/NWS/33 virus (H1N1) in mammalian kidney cells. AB - In this report we focused our interest on the early events of the replication cycle of NWS/33 human influenza A (NWS) virus in MDCK (canine), LLC-MK2 (simian), and NSK (swine) kidney cells, with different susceptibility upon infection. We have previously demonstrated that actin organization induces restriction to viral replication during the early stages of NWS virus infection in simian kidney cells. To explore how cell endocytic mechanisms are hijacked by NWS virus and may modulate the outcome of viral infection, the effect of drugs affecting selectively the entry via clathrin-coated pits, caveolar/raft-dependent endocytosis and macropinocytosis was analyzed. Results point to critical differences in terms of internalization pathways exploited by NWS virus to enter the examined cell models. Moreover, we show that some ways of entry do not allow an effective virus internalization, depending on the cell type. Understanding how specific cell functions/components may regulate early phases of viral replication allows us to deepen our knowledge on influenza virus infection and provides new insights for anti-viral researches. PMID- 20951749 TI - Nanoemulsion improves the oral absorption of candesartan cilexetil in rats: Performance and mechanism. AB - Candesartan cilexetil (CC), an inactive prodrug of candesartan, was rapidly hydrolyzed into active candesartan during absorption in the gastrointestinal (GI) tract to achieve antihypertensive effects. However, CC exhibited incomplete intestinal absorption with low oral bioavailability due to its poor aqueous solubility. In this work, a novel CC loaded nanoemulsion (CCN) was designed to improve the intestinal absorption. CCN was prepared by a modified emulsification solvent evaporation technique. The physicochemical characteristics of CCN were characterized, and the intestinal absorption was investigated as well. The experimental results indicated that CCN was nanometer-sized droplets (35.5+/ 5.9nm) with negative potential (-6.45+/-0.36mV), and the absorption of CCN was significantly improved in total intestinal tract compared with free CC solution. Moreover, CCN could be internalized into the enterocytes by clathrin-mediated endocytosis pathway, and thereafter transported into systemic circulation via both portal vein and lymphatic pathway. The concentration of active candesartan in rat plasma was determined by LC-MS-MS method. The experimental results showed that the area under the concentration-time curve (AUC(0-t)) of candesartan was improved over 10-fold after CC was incorporated into CCN. The overall results implicated that the nanoemulsion was very effective for enhancing the oral absorption of insoluble CC, and CCN showed the great potential for clinical application. PMID- 20951748 TI - Viral RNA silencing suppressors (RSS): novel strategy of viruses to ablate the host RNA interference (RNAi) defense system. AB - Pathogenic viruses have developed a molecular defense arsenal for their survival by counteracting the host anti-viral system known as RNA interference (RNAi). Cellular RNAi, in addition to regulating gene expression through microRNAs, also serves as a barrier against invasive foreign nucleic acids. RNAi is conserved across the biological species, including plants, animals and invertebrates. Viruses in turn, have evolved mechanisms that can counteract this anti-viral defense of the host. Recent studies of mammalian viruses exhibiting RNA silencing suppressor (RSS) activity have further advanced our understanding of RNAi in terms of host-virus interactions. Viral proteins and non-coding viral RNAs can inhibit the RNAi (miRNA/siRNA) pathway through different mechanisms. Mammalian viruses having dsRNA-binding regions and GW/WG motifs appear to have a high chance of conferring RSS activity. Although, RSSs of plant and invertebrate viruses have been well characterized, mammalian viral RSSs still need in-depth investigations to present the concrete evidences supporting their RNAi ablation characteristics. The information presented in this review together with any perspective research should help to predict and identify the RSS activity-endowed new viral proteins that could be the potential targets for designing novel anti viral therapeutics. PMID- 20951750 TI - Ultrasound activation of TiO2 in melanoma tumors. AB - Sonodynamic therapy (SDT) is a new modality using ultrasound (US) to activate certain chemical sensitizers for cancer therapy. In this study, the effect of US combined with a nanoparticle titanium dioxide (TiO(2)) on melanoma cell was investigated in vitro and in vivo. Melanoma cells (C32) were irradiated with US in the presence and/or absence of TiO(2). Cell viability was measured immediately after US irradiation (1MHz, 0.5 and 1.0W/cm(2) for 10s). The effect of the combination of TiO(2) and US exposure (1MHz, 1.0W/cm(2), 2 min duration) on subcutaneously implanted C32 solid tumors in mice were investigated by measuring tumor volume regression. The cell viability was significantly decreased only after US irradiation in the presence of TiO(2). In vivo results showed significant inhibition of tumor growth in groups treated with TiO(2) and US. To our knowledge, this is the first report to demonstrate the cell killing effect of TiO(2) nanoparticles under the irradiation US in vitro and in vivo. PMID- 20951751 TI - Development of novel therapeutic strategy by regulating the nuclear hormone receptors. Preface. PMID- 20951752 TI - Miracle fruit improves sweetness of a low-calorie dessert without promoting subsequent energy compensation. AB - This study sought to determine if miracle fruit enhances sweetness and acceptability of a sour, low-sugar dessert, and reduces energy intake. Subjects (n=13) completed four trials in a randomized cross over design. Subjects ate standardized breakfast and lunch. Lunch was followed by lemon juice based popsicles that were either normal, sucrose sweetened (854J) popsicles (REG) or a sour, low-sugar (142J) version (DIET) with or without miracle fruit administration preceding consumption. Energy consumption for the remainder of the day was measured by weighed food intake. Popsicles were evaluated for acceptability using a 9-point hedonic scale; sweetness and fullness were assessed by visual analog scales. Subjects rated DIET as sweeter when consumed after miracle fruit (58 +/- 36 mm vs. 29 +/- 38 mm); however, there was no difference in hedonic preference. Subjects did not detect a difference in sweetness for REG compared to DIET with miracle fruit. Consumption of DIET with miracle fruit produced lower energy intake compared to REG with (-1017 +/- 1022J) and without ( 955 +/- 1302J) miracle fruit. Thus, miracle fruit can enhance the sweetness of a low sugar dessert while limiting energy intake in comparison to a higher calorie, sucrose-sweetened popsicles. PMID- 20951754 TI - Cancer transmissibility across HLA barriers between immunocompetent individuals: rare but not impossible. AB - The axiom of human leukocyte incompatibility (HLA) incompatibility has always led scientists to consider cancer transmission between HLA-different individuals impossible. In fact, cancer transmission between individuals represents a frightening possibility in animal populations with limited HLA diversity or for rare cancers exploiting downregulation of HLA expression. We review here evidence from nonhuman models and settings for interhuman transmission. PMID- 20951753 TI - Association of IL-6 and IL-6R gene polymorphisms with susceptibility to respiratory tract infections in young Finnish men. AB - Interleukin-1 (IL-6) is an important mediator of inflammatory response in the respiratory tract during an infection, and the action of IL-6 is mediated by an IL-6 receptor. Several polymorphisms in the IL-6 and IL-6R genes have been associated with different inflammatory disease states. We studied the association between 2 IL-6 (IL6A and IL6B) and 5 IL-6R gene polymorphisms (IL6R1 to IL6R5) and respiratory infections in 511 Finnish military recruits whose respiratory infectious episodes were followed during 6 months of service. A promoter polymorphism of the IL-6R gene, IL6R1 (-183G/A), and two intron 1 polymorphisms, IL6R2 (A/G) and IL6R3 (T/A), were associated with infections. The strongest associations were found for the IL6R1 and IL6R2 polymorphisms, which were in the same linkage disequilibrium block. Conscripts with the A/A (IL6R1), G/G (IL6R2), and A/A (IL6R3) genotypes had an increased risk for respiratory infections during service as follows: odds ratio (OR) 1.72, 95% confidence interval (CI) 1.35-2.19; OR 1.66, 95% CI 1.23-2.26; and OR 1.23, 95% CI 0.98-1.55, respectively. IL-6 gene polymorphism IL6A (-174C/G) was associated with infections only in combination with an IL-6R polymorphism. Our data suggest that polymorphisms in the 5' area of the IL-6R gene may be associated with increased susceptibility to respiratory infections. PMID- 20951755 TI - Effect of multiple activation stimuli on the generation of Th1-polarizing dendritic cells. AB - It was originally reported that only a small fraction of total matured dendritic cells (DCs) produced interleukin (IL)-12, but it has never been determined whether different combinations of activating signals now shown to maximize secreted IL-12 do so through increasing output by the same IL-12 producers, or by recruiting additional cytokine-secreting cells. We therefore tested all combinations of bacterial lipopolysaccharide (LPS) (TLR4 ligand), R848 (TLR8 ligand), interferon (IFN)-gamma, and CD40L for activating human monocyte-derived dendritic cells (DC), and determined by intracellular flow cytometry that enhanced IL-12 secretion was accomplished in large part by markedly increasing the proportion of cells producing IL-12, with the triple and quadruple combinations recruiting the most DC. This optimization requirement for multiple signals was not reflected in differential Toll-like receptor (TLR) expression by the cells. Interestingly, DCs activated with single TLR ligands plus IFN-gamma were capable of responding with a second burst of IL-12 upon later CD40L stimulation, whereas DCs activated with R848 plus LPS were not, despite the trend of the latter for superior polarization of naive T cells toward IFN-gamma secreting Th1. These results have implications for the biology of IL-12-secreting DCs and choice of activation regimen for prospective use in DC-based immunotherapy. PMID- 20951756 TI - Development of quantitative structure-activity relationship (QSAR) models to predict the carcinogenic potency of chemicals. II. Using oral slope factor as a measure of carcinogenic potency. AB - The overall risk associated with exposure to a chemical is determined by combining quantitative estimates of exposure to the chemical with their known health effects. For chemicals that cause carcinogenicity, oral slope factors (OSFs) and inhalation unit risks are used to quantitatively estimate the carcinogenic potency or the risk associated with exposure to the chemical by oral or inhalation route, respectively. Frequently, there is a lack of animal or human studies in the literature to determine OSFs. This study aims to circumvent this problem by developing quantitative structure-activity relationship (QSAR) models to predict the OSFs of chemicals. The OSFs of 70 chemicals based on male/female human, rat, and mouse bioassay data were obtained from the United States Environmental Protection Agency's Integrated Risk Information System (IRIS) database. A global QSAR model that considered all 70 chemicals as well as species and/or sex-specific QSARs were developed in this study. Study results indicate that the species and sex-specific QSARs (r(2)>0.8, q(2)>0.7) had a better predictive abilities than the global QSAR developed using data from all species and sexes (r(2)=0.77, q(2)=0.73). The QSARs developed in this study were externally validated, and demonstrated reasonable predictive abilities. PMID- 20951757 TI - Neuropsychological functions in Han Chinese patients in Taiwan with bipolar II disorder comorbid and not comorbid with alcohol abuse/alcohol dependence disorder. AB - OBJECTIVE: Studies exploring neuropsychological functions of bipolar disorder (BP) specifically include patients comorbid with alcohol abuse (AB), alcohol dependence (AD), or both (AB/AD). Contradictory assessments of neuropsychological impairment may be caused by not excluding the confounding effects of comorbid AB/AD. Most of the literature discusses BP without subtyping, which overlooks that BP-II may be a valid diagnosis different from BP-I. Because neuropsychological functions are involved in overall BP-II outcomes, we hypothesized that the neuropsychological functions of patients with BP-II comorbid with AD (BP(+AD)) are significantly different from and more impaired than those of patients with BP-II not comorbid with AD (BP(-AD)). METHODS: Using DSM-IV criteria, the study included 69 patients with BP-II (19 with BP(+AD); 28 with BP(-AD)) and 22 healthy controls compared using a battery of neuropsychological tests that assessed memory, psychomotor speed, and certain aspects of frontal executive function. All BP-II patients were in an inter episode period (a period of remission between states of mania, hypomania, and depression). RESULTS: BP(+AD) patients had lower scores than did BP(-AD) patients and controls in verbal memory, visual memory, attention, psychomotor speed, and executive function. Working memory was poorer for BP(+AD) than BP(-AD) patients and for both BP groups than for controls. CONCLUSIONS: BP(+AD) patients manifested wide neuropsychological dysfunctions, and BP(-AD) patients showed a reduction in working memory, which suggested that working memory might be related to a history of BP-II. Neuropsychological dysfunctions seemed more strongly associated with AB/AD than with BP-II in inter-episode periods. PMID- 20951758 TI - Predictors of compulsory admission in schizophrenia-spectrum patients: excitement, insight, emotion perception. AB - PURPOSE: We explored socio-demographic and clinical variables associated with compulsory admissions (CA) compared with voluntary admissions in schizophrenia spectrum patients; moreover, we investigated the ability of excitement, emotion perception, and lack of insight to predict CA. METHODS: 119 consecutive schizophrenia-spectrum patients admitted to the Servizio Psichiatrico di Diagnosi e Cura (SPDC = PES = psychiatric emergency service) of the Department of Neuroscience and Mental Health-San Giovanni Battista Hospital of Turin in the period between December 2007 and December 2009 were enrolled in the study. A backward stepwise logistic regression was used to test factors contributing to CA. RESULTS: CA rate in our sample was 28.5%. Previous CAs, drop-out, severity of illness, positive symptoms, excitement, emotion perception, and insight were significantly different in CA patients compared to voluntary ones. After backward selection of variables, three variables predicted CA in our sample: excitement, impaired emotion perception and lesser insight. Finally, the effect of excitement on CA status seemed partially mediated by emotion perception, the prediction model accounting for 53.8% of the variance of CA status. Conversely, insight seemed not to be a mediator of excitement on CA. IMPLICATIONS: Understanding CA patterns in special populations represents a first step towards improving clinical decision-making and developing appropriate interventions and service provision. PMID- 20951759 TI - The cooked meat-derived mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5 b]pyridine promotes invasive behaviour of breast cancer cells. AB - The cooked meat derived genotoxic carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5 b]pyridine (PhIP) induces cancer of the colon, prostate and mammary gland when fed to rats. Epidemiology studies link these tumours to a Western diet and exposure to heterocyclic amines such as PhIP. We have shown that PhIP is also potently estrogenic and have proposed that this hormonal activity contributes to its target site carcinogenicity. We now postulate that the estrogenic properties of PhIP influence metastatic potential. We have used an in vitro assay for cell invasion based upon digestion and migration through a reconstituted basement membrane model. Zymography and immunoblotting were used to confirm PhIP-mediated changes associated with induction of the invasive phenotype. Treatment of the mammary cancer cell lines MCF-7 and T47D with PhIP induces cells to digest and migrate through a reconstituted basement membrane. The response was dose dependent, observed at sub-nanomolar concentrations of PhIP and was inhibited by the antiestrogen ICI 182,780. The PhIP-induced invasive phenotype was associated with expression of cathepsin D, cyclooxygenase-2 and matrix metalloproteinase activity. These findings emphasise the range and potency of the biological activities associated with this cooked meat product and mechanistically support the tissue-specific carcinogenicity of the chemical. PMID- 20951760 TI - Mapping the eosinophil cationic protein antimicrobial activity by chemical and enzymatic cleavage. AB - The eosinophil cationic protein (ECP) is a human antimicrobial protein involved in the host immune defense that belongs to the pancreatic RNase A family. ECP displays a wide range of antipathogen activities. The protein is highly cationic and its bactericidal activity is dependant on both cationic and hydrophobic surface exposed residues. Previous studies on ECP by site-directed mutagenesis indicated that the RNase activity is not essential for its bactericidal activity. To further understand the ECP bactericidal mechanism, we have applied enzymatic and chemical limited cleavage to search for active sequence determinants. Following a search for potential peptidases we selected the Lys-endoproteinase, which cleaves the ECP polypeptide at the carboxyl side of its unique Lys residue, releasing the N-terminal fragment (0-38). Chemical digestion using cyanogen bromide released several complementary peptides at the protein N-terminus. Interestingly, ECP treatment with cyanogen bromide represents a new example of selective chemical cleavage at the carboxyl side of not only Met but also Trp residues. Recombinant ECP was denatured and carboxyamidomethylated prior to enzymatic and chemical cleavage. Irreversible denaturation abolishes the protein bactericidal activity. The characterization of the digestion products by both enzymatic and chemical approaches identifies a region at the protein N-terminus, from residues 11 to 35, that retains the bactericidal activity. The most active fragment, ECP(0-38), is further compared to ECP derived synthetic peptides. The region includes previously identified stretches related to lipopolysaccharide binding and bacteria agglutination. The results contribute to define the shortest ECP minimized version that would retain its antimicrobial properties. The data suggest that the antimicrobial RNase can provide a scaffold for the selective release of cytotoxic peptides. PMID- 20951761 TI - Estimating daytime ecosystem respiration from eddy-flux data. AB - To understand what governs the patterns of net ecosystem exchange of CO2, an understanding of factors influencing the component fluxes, ecosystem respiration and gross primary production is needed. In the present paper, we introduce an alternative method for estimating daytime ecosystem respiration based on whole ecosystem fluxes from a linear regression of photosynthetic photon flux density data vs. daytime net ecosystem exchange data at forest ecosystem level. This method is based on the principles of the Kok-method applied at leaf level for estimating daytime respiration. We demonstrate the method with field data and provide a discussion of the limitations of the method. PMID- 20951762 TI - PS II model based analysis of transient fluorescence yield measured on whole leaves of Arabidopsis thaliana after excitation with light flashes of different energies. AB - Our recently presented PS II model (Belyaeva et al., 2008) was improved in order to permit a consistent simulation of Single Flash Induced Transient Fluorescence Yield (SFITFY) traces that were earlier measured by Steffen et al. (2005) on whole leaves of Arabidopsis (A.) thaliana at four different energies of the actinic flash. As the essential modification, the shape of the actinic flash was explicitly taken into account assuming that an exponentially decaying rate simulates the time dependent excitation of PS II by the 10 ns actinic flash. The maximum amplitude of this excitation exceeds that of the measuring light by 9 orders of magnitude. A very good fit of the SFITFY data was achieved in the time domain from 100 ns to 10s for all actinic flash energies (the maximum energy of 7.5 * 1016 photons/(cm2flash) is set to 100%, the relative energies of weaker actinic flashes were of ~8%, 4%, ~1%). Our model allows the calculation and visualization of the transient PS II redox state populations ranging from the dark adapted state, via excitation energy and electron transfer steps induced by pulse excitation, followed by final relaxation into the stationary state eventually attained under the measuring light. It turned out that the rate constants of electron transfer steps are invariant to intensity of the actinic laser flash. In marked contrast, an increase of the actinic flash energy by more than two orders of magnitude from 5.4*1014 photons/(cm2flash) to 7.5*1016 photons/(cm2flash), leads to an increase of the extent of fluorescence quenching due to carotenoid triplet (3Car) formation by a factor of 14 and of the recombination reaction between reduced primary pheophytin (Phe(-)) and P680(+) by a factor of 3 while the heat dissipation in the antenna complex remains virtually constant. The modified PS II model offers new opportunities to compare electron transfer and dissipative parameters for different species (e.g. for the green algae and the higher plant) under varying illumination conditions. PMID- 20951763 TI - Measurements of neuron soma size and density in rat dorsal striatum, nucleus accumbens core and nucleus accumbens shell: differences between striatal region and brain hemisphere, but not sex. AB - Both hemispheric bias and sex differences exist in striatal-mediated behaviors and pathologies. The extent to which these dimorphisms can be attributed to an underlying neuroanatomical difference is unclear. We therefore quantified neuron soma size and density in the dorsal striatum (CPu) as well as the core (AcbC) and shell (AcbS) subregions of the nucleus accumbens to determine whether these anatomical measurements differ by region, hemisphere, or sex in adult Sprague Dawley rats. Neuron soma size was larger in the CPu than the AcbC or AcbS. Neuron density was greatest in the AcbS, intermediate in the AcbC, and least dense in the CPu. CPu neuron density was greater in the left in comparison to the right hemisphere. No attribute was sexually dimorphic. These results provide the first evidence that hemispheric bias in the striatum and striatal-mediated behaviors can be attributed to a lateralization in neuronal density within the CPu. In contrast, sexual dimorphisms appear mediated by factors other than gross anatomical differences. PMID- 20951765 TI - Neural substrates in color processing: a comparison between painting majors and non-majors. AB - Although several studies provide evidence of differences in the neural mechanisms of art professionals and non-professionals, little is known about the neural mechanism differences between painting professionals/majors and non professionals/non-majors during color processing. For the first time, we compared functional activation patterns, functional connectivity during both color naming and passive color viewing, and gray-matter density in 12 painting majors and 12 controls through both functional and structural magnetic resonance imaging techniques. Inter-group comparisons revealed that the painting majors showed more activation in the color selective areas and increased correlation between left V4 and the left ventral lateral prefrontal cortex during color naming. In contrast, the controls exhibited stronger activity in the Broca's area during color naming. Moreover, increased gray matter density in the left V4 complex was found when the painting majors were compared to the controls. This study demonstrates that the left V4 complex shows both functional and structural differences between painting majors and non-majors. In addition, the results suggest the reorganization of the brain circuit underlying lexical retrieval during color naming in the anterior regions of the painting major group. PMID- 20951764 TI - High cerebrospinal tau levels are associated with the rs242557 tau gene variant and low cerebrospinal beta-amyloid in Parkinson disease. AB - Cerebrospinal fluid (CSF) tau and phospho-tau levels have been associated with certain tau gene variants and low CSF amyloid-beta (Abeta) levels in Alzheimer disease (AD), constituting potential biomarkers of molecular mechanisms underlying neurodegeneration. We aimed to assess whether such CSF-genetic endophenotypes are also present in Parkinson disease (PD). CSF tau, phospho-tau and Abeta levels were obtained from 38 PD patients (19 with dementia) using specific ELISA techniques. All cases were genotyped for a series of tau gene polymorphisms (rs1880753, rs1880756, rs1800547, rs1467967, rs242557, rs2471738 and rs7521). The A-allele rs242557 polymorphism was the only tau gene variant significantly associated with higher CSF tau and phospho-tau levels, under both dominant and dose-response model. This association depended on the presence of dementia, and was only observed in individuals with low (<500pg/mL) CSF Abeta levels. Such genetic-CSF endophenotypes are probably a reflection of the presence of AD-like molecular changes in part of PD patients in the setting of dementia. PMID- 20951766 TI - Effect of anxiety on antero-posterior postural stability in patients with dizziness. AB - The purpose of this study was to investigate the effect of anxiety on the postural stability of a variety of dizzy patients during upright standing. To address this issue, 54 patients complaining of dizziness were enrolled in this study. The degree of anxiety in patients was evaluated on the basis of a routine vestibular examination together with their dizziness handicap inventory (DHI) scores as well as the hospital anxiety and depression scale (HADS). The patients were divided into 3 groups. If there was no vestibular dysfunction, they were defined as psychogenic (PSY) (N=16). The remaining subjects were further divided on the basis of their HADS score. If the score of A (anxiety) was less than 5, they are defined as organic (ORG) (N=25), and the rest were defined as a combination of psychogenic and organic (PSY+ORG) (N=13). Posturographic measurements were performed in a quiet and stable standing position on a force platform, as one of the vestibular examinations. The total length, the area of body sway, and the ratio of maximum perturbation of antero-posterior axis (A/P ratio) were registered. Spectrum analyses of the left-right axis and antero posterior axis were also performed by using the fast Fourier transform (FFT) method of body sway. We found a significant correlation between anxiety and postural instability in the antero-posterior axis in all subjects as a group and in either group PSY or PSY+ORG. However, no significant correlation was found in group ORG. Using power spectrum analysis (FFT), we identified 3 frequency components of postural sway: group A (0.02-0.21Hz), group B (0.22-2.01Hz), and group C (2.01-10Hz). Statistical significance of the data was examined by ANOVA. Group C reflected somatosensory inputs, and group A reflected vestibular inputs. The power of group C decreased in the high anxiety group, whereas the power of group A increased in the high anxiety group. These phenomena disappeared in the eyes-closed condition. Our study shows that the effect of visual input on vestibular and somatosensory input is affected by anxiety. In conclusion, our results indicate that anxiety affects the postural perturbation in the antero posterior axis and that anxiety possibly affects the interactions of visual inputs with vestibular and somatosensory inputs in the maintenance of postural balance in patients complaining of dizziness. PMID- 20951767 TI - LINGO1 rs9652490 variant in Parkinson disease patients. AB - Essential tremor (ET) has been hypothesized to be a risk factor for the development of Parkinson disease (PD). Recently, rs9652490 variant in the leucine rich repeat and Ig domain containing 1 gene (LINGO1) was found to be associated with ET susceptibility. To evaluate whether the same variant is associated also with PD susceptibility, we investigated the association between the LINGO1 rs9652490 variant and PD phenotype in Caucasian and Chinese PD subjects. We found no significant differences in genotypic and allele distribution between patients and control subjects (chi(2)=1.931, p=0.381 for genotypic distribution; chi(2)=0.001, p=0.973 for allele distribution), suggesting this variant is not associated with PD. PMID- 20951768 TI - The arcuate nucleus as a circumventricular organ in the mouse. AB - The present study searched for morphological correlates of the permeability of the ventromedial arcuate nucleus of the mouse to blood-borne proteins. First, we determined that highly permeable microvessels are detected in the ventromedial arcuate nucleus using a rat monoclonal antibody to a mouse-specific endothelial phenotype (clone MECA32) recently recognized as a marker of endothelial fenestral diaphragms and previously shown to label circumventricular organs. Second, in the mild conditions of tissue fixation mandatory for use of MECA32, we observed that after a rapid vascular flush with saline, endogenous immunoglobulins are especially retained in circumventricular organs and ventromedial arcuate nucleus. The ventromedial arcuate nucleus thus shares features in common with classical circumventricular organs. PMID- 20951769 TI - NFkappaB/p53 crosstalk-a promising new therapeutic target. AB - The transcription factors p53 and NFkappaB determine cellular fate and are involved in the pathogenesis of most-if not all-cancers. The crosstalk between these transcription factors becomes increasingly appreciated as an important mechanism operative during all stages of tumorigenesis, metastasis, and immunological surveillance. In this review, we summarize molecular mechanisms regulating cross-signaling between p53 and NFkappaB proteins and how dysregulated interactions between p53 and NFkappaB family members contribute to oncogenesis. We furthermore analyze how such signaling modules represent targets for the design of novel intervention strategies using established compounds and powerful combination therapies. PMID- 20951770 TI - Histone lysine methylation and demethylation pathways in cancer. AB - The genetic changes leading to the development of human cancer are accompanied by alterations in the structure and modification status of chromatin, which represent powerful regulatory mechanisms for gene expression and genome stability. These epigenetic alterations have sparked interest into deciphering the regulatory pathways and function of post-translational modifications of histones during the initiation and progression of cancer. In this review we describe and summarize the current knowledge of several histone lysine methyltransferase and demethylase pathways relevant to cancer. Mechanistic insight into histone modifications will pave the way for the development and therapeutic application of "epidrugs" in cancer. PMID- 20951771 TI - Enhanced excitatory and reduced inhibitory synaptic transmission contribute to persistent pain-induced neuronal hyper-responsiveness in anterior cingulate cortex. AB - The anterior cingulate cortex (ACC) has been demonstrated to play an important role in the affective dimension of pain. Although much evidence has pointed to an increased excitatory synaptic transmission in the ACC in some of the pathological pain state, the inhibitory synaptic transmission in this process has not been well studied. Also, the overall changes of excitatory and inhibitory synaptic transmission have not been comparatively studied in an animal model displaying both long-term persistent nociception and hyperalgesia. Here we used patch clamp recordings in ACC brain slices to observe the changes in synaptic transmission in a pain model induced by peripheral bee venom injection. First, we show that, comparing with those of naive and saline controlled rats, there was a significant increase in spike frequency in ACC neurons harvested from rats after 2 h period of peripheral persistent painful stimuli. Second, it is further shown that the frequency, amplitude and half-width were all increased in spontaneous excitatory post-synaptic currents (sEPSCs), while the amplitude of spontaneous inhibitory post-synaptic currents (sIPSCs) was decreased. The recordings of miniature post synaptic currents demonstrate an increase in frequency of miniature excitatory post-synaptic currents (mEPSCs) and a decrease in both frequency and amplitude of miniature inhibitory post-synaptic currents (mIPSCs) in rats' ACC slice of bee venom treatment. Taken together, the present results demonstrate an unparalleled change between excitatory and inhibitory synaptic transmission in the ACC under a state of peripheral persistent nociception that might be underlying mechanisms of the excessive excitability of the ACC neurons. We propose that the painful stimuli when lasts or becomes persistent may cause a disruption of the balance between excitatory and inhibitory synaptic transmission that can contribute to the functional change in the ACC. PMID- 20951772 TI - Distribution of transient receptor potential vanilloid 1 channel-expressing nerve fibers in mouse rectal and colonic enteric nervous system: relationship to peptidergic and nitrergic neurons. AB - In the gut, transient receptor potential vanilloid (TRPV) 1 activation leads to release of neurotransmitters such as neuropeptides and nitric oxide. However, the distribution of TRPV1 nerve fibers and neurotransmitters released form sensory nerve endings in the enteric nervous system are currently not well understood. The present study investigated the immunohistochemical distribution of TRPV1 channels, sensory neuropeptides, and nitric oxide and their co-localization in mouse large intestine. Numerous TRPV1 and calcitonin gene-related peptide (CGRP) immunoreactivities were detected, mainly in the mucosa, submucosal layer, and myenteric plexus. Abundant substance P (SP), neurokinin A (NKA), and neuronal nitric oxide synthase (nNOS)-immunoreactivity were revealed in muscle layers. Motor function studies of circular and longitudinal muscles found that contractile responses to capsaicin in the rectum were most sensitive among the rectum, and distal, transverse, and proximal colon. Double labeling studies were carried out in horizontal sections of mouse rectum. TRPV1/protein gene product (PGP)9.5 double labeled axons were observed, but PGP9.5 and neuronal nuclear protein immunopositive cell bodies did not express TRPV1 immunoreactivity in the myenteric plexus. In the mucosa, submucosal layer, deep muscular plexus, circular muscle, myenteric plexus and longitudinal muscle layer, TRPV1 nerve fibers were found to contain CGRP, SP and nNOS. SP and NKA were almost entirely colocalized at the axons and cell bodies in all layers. Double labeling with c-Kit revealed that TRPV1 nerve fibers localized adjacent to the interstitial cells of Cajal (ICC). These results suggest that the TRPV1-expressing nerve and its neurotransmitters regulate various functions of the large intestine. PMID- 20951773 TI - Foxp4 is essential in maintenance of Purkinje cell dendritic arborization in the mouse cerebellum. AB - Purkinje cells (PCs) are one of the principal neurons in the cerebellar cortex that play a central role in the coordination of fine-tuning body movement and balance. To acquire normal cerebellum function, PCs develop extensive dendritic arbors that establish synaptic connections with the parallel fibers of granule cells to form the proper neuronal circuitry. Therefore, dendritic arborization of PCs is an important developmental step to construct the mature neural network in the cerebellum. However, the genetic control of this process is not fully understood. In this study, Foxp4, a forkhead transcription factor that is expressed specifically in migrating and mature PCs of cerebellum from embryonic stages to adulthood, was knocked down by small interfering RNA (siRNA) in organotypic cerebellar slice culture. When Foxp4 expression was knocked down at postnatal day 5 (P5), no abnormalities for early dendritic remodeling of PCs were observed. However, when Foxp4 was knocked down in P10 cerebellar slices, the organization of PC dendritic arbors was highly impaired, leaving hypoplastic but non-apoptotic cell bodies. The radial alignment of Bergmann glial fibers that associated with PC dendrites was also lost. These results suggest that Foxp4 is dispensable for the early PC dendrite outgrowth, but is essential for the maintenance of PC dendritic arborization and subsequent association with Bergmann glial fibers. PMID- 20951774 TI - Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2. AB - Inheritance of the APOE4 allele is a well established genetic risk factor linked to the development of late onset Alzheimer's disease. As the major lipid transport protein in the central nervous system, apolipoprotein (apo) E plays an important role in the assembly and maintenance of synaptic connections. Our previous work showed that 7 month old human apoE4 targeted replacement (TR) mice displayed significant synaptic deficits in the principal neurons of the lateral amygdala, a region that is critical for memory formation and also one of the primary regions affected in Alzheimer's disease, compared to apoE3 TR mice. In the current study, we determined how age and varying APOE genotype affect synaptic integrity of amygdala neurons by comparing electrophysiological and morphometric properties in C57BL6, apoE knockout, and human apoE3, E4 and E2/4 TR mice at 1 month and 7 months. The apoE4 TR mice exhibited the lowest level of excitatory synaptic activity and dendritic arbor compared to other cohorts at both ages, and became progressively worse by 7 months. In contrast, the apoE3 TR mice exhibited the highest synaptic activity and dendritic arbor of all cohorts at both ages. C57BL6 mice displayed virtually identical synaptic activity to apoE3 TR mice at 1 month; however this activity decreased by 7 months. ApoE knockout mice exhibited a similar synaptic activity profile with apoE4 TR mice at 7 months. Consistent with previous reports that APOE2 confers protection, the apoE4-dependent deficits in excitatory activity were significantly attenuated in apoE2/4 TR mice at both ages. These findings demonstrate that expression of human apoE4 contributes to functional deficits in the amygdala very early in development and may be responsible for altering neuronal circuitry that eventually leads to cognitive and affective disorders later in life. PMID- 20951775 TI - Age-related decline in sensory processing for locomotion and interception. AB - The ability to control locomotion through the environment and to intercept, or avoid objects is fundamental to the survival of all locomotor species. The extent to which this control relies upon optic flow, visual direction cues or non-visual sensory inputs has long been debated. Here we look at the use of sensory information in young and middle-aged participants using a locomotor-driven interceptive task. Both groups of participants were asked to produce forward displacements in more or less impoverished environments by manipulating a joystick and to regulate, if necessary, their displacement velocity so as to intercept approaching targets. We show that the displacements produced by the middle-aged participants were more nonlinear in comparison with young participants. The errors in the middle-aged group can be accounted for by a constant bearing angle (CBA) model that incorporates a decrease in the sensitivity of sensory detection with advancing age. The implications of this study to a better understanding of the mechanisms underlying the detection of the rate of change in bearing angle are discussed. PMID- 20951776 TI - Transcription factor Sox11b is involved in spinal cord regeneration in adult zebrafish. AB - Adult zebrafish have the ability to recover from spinal cord injury and exhibit re-growth of descending axons from the brainstem to the spinal cord. We performed gene expression analysis using microarray to find damage-induced genes after spinal cord injury, and found that Sox11b mRNA is up-regulated at 11 days after injury. However, the functional relevance of Sox11b for regeneration is not known. Here, we report that the up-regulation of Sox11b mRNA after spinal cord injury is mainly localized in ependymal cells lining the central canal and in newly differentiating neuronal precursors or immature neurons. Using an in vivo morpholino-based gene knockout approach, we demonstrate that Sox11b is essential for locomotor recovery after spinal cord injury. In the injured spinal cord, expression of the neural stem cell associated gene Nestin, and the proneural gene Ascl1a (Mash1a), which are involved in the self-renewal and cell fate specification of endogenous neural stem cells, respectively, is regulated by Sox11b. Our data indicate that Sox11b promotes neuronal determination of endogenous stem cells and regenerative neurogenesis following spinal cord injury in the adult zebrafish. Enhancing Sox11b expression to promote proliferation and neurogenic determination of endogenous neural stem cells after injury may be a promising strategy in restorative therapy after spinal cord injury in mammals. PMID- 20951777 TI - Crystal structure of the cysteine protease inhibitor 2 from Entamoeba histolytica: functional convergence of a common protein fold. AB - Cysteine proteases (CP) are key pathogenesis and virulence determinants of protozoan parasites. Entamoeba histolytica contains at least 50 cysteine proteases; however, only three (EhCP1, EhCP2 and EhCP5) are responsible for approximately 90% of the cysteine protease activity in this parasite. CPs are expressed as inactive zymogens. Because the processed proteases are potentially cytotoxic, protozoan parasites have developed mechanisms to regulate their activity. Inhibitors of cysteine proteases (ICP) of the chagasin-like inhibitor family (MEROPS family I42) were recently identified in bacteria and protozoan parasites. E. histolytica contains two ICP-encoding genes of the chagasin-like inhibitor family. EhICP1 localizes to the cytosol, whereas EhICP2 is targeted to phagosomes. Herein, we report two crystal structures of EhICP2. The overall structure of EhICP2 consists of eight beta-strands and closely resembles the immunoglobulin fold. A comparison between the two crystal forms of EhICP2 indicates that the conserved BC, DE and FG loops form a flexible wedge that may block the active site of CPs. The positively charged surface of the wedge-forming loops in EhICP2 contrasts with the neutral surface of the wedge-forming loops in chagasin. We postulate that the flexibility and positive charge observed in the DE and FG loops of EhICP2 may be important to facilitate the initial binding of this inhibitor to the battery of CPs present in E. histolytica. PMID- 20951778 TI - Nanostructured lipid carrier (NLC) coated with Chitosan Oligosaccharides and its potential use in ocular drug delivery system. AB - The objective of the present investigation was to explore the potential of the Chitosan Oligosaccharides (COS)-coated NLC (nanostructured lipid carrier) for ocular drug delivery. NLC loaded with flurbiprofen was prepared by melt ultrasonic method and then coated with COS with a molecular weight of 3000 6000kDa. After coating, the particles reflected spherical morphology with smooth surface under transmission electron microscope (TEM) analysis and a changed zeta potential from -0.446mV to +20.7mV. The ocular bioadhesion property was evaluated by Gamma scintigraphic technique, revealing that the clearance of the formulations labeled with radioactive 99(m)Tc-DTPA was significantly delayed in the presence of COS, and the AUC of the COS-coated formulation had a 7.7-fold increase comparing with non-coated ones. Additionally, enhanced transcorneal penetration was achieved by using the COS coating with a corresponding apparent permeability coefficients (P(app)) which had a 2.4-fold increase comparing with the reference. Consequently, COS coating modified the properties of NLCs and presented a series of notable advantages in ophthalmic application. PMID- 20951779 TI - Stimuli-responsive magnetic particles for biomedical applications. AB - In recent years, magnetic nanoparticles have been studied due to their potential applications as magnetic carriers in biomedical area. These materials have been increasingly exploited as efficient delivery vectors, leading to opportunities of use as magnetic resonance imaging (MRI) agents, mediators of hyperthermia cancer treatment and in targeted therapies. Much attention has been also focused on "smart" polymers, which are able to respond to environmental changes, such as changes in the temperature and pH. In this context, this article reviews the state-of-the art in stimuli-responsive magnetic systems for biomedical applications. The paper describes different types of stimuli-sensitive systems, mainly temperature- and pH sensitive polymers, the combination of this characteristic with magnetic properties and, finally, it gives an account of their preparation methods. The article also discusses the main in vivo biomedical applications of such materials. A survey of the recent literature on various stimuli-responsive magnetic gels in biomedical applications is also included. PMID- 20951780 TI - Characterization of the developed antimicrobial urological catheters. AB - Antimicrobial urological catheters were developed by the mixed, covalent and non covalent binding of sparfloxacin (SPA) to heparin (HP) film which was first deposited on the latex surface of biomaterial. The SPA-HP modified surface was characterized by SEM analysis and ATR-Fourier transform infrared spectroscopy. For the antimicrobial prevention, SPA as an antibiotic with a broad antimicrobial spectrum was chosen. Antimicrobial activity of antibiotic-modified catheter against Staphylococcus aureus, Staphylococcus epidermidis and Escherichia coli strains was assessed using various procedures. On the basis of the inhibition zone and diffusion assays the efficacy around the modified catheters was demonstrated. The test samples clearly showed an antibacterial activity against all tested bacterial stains for a least one month. Inhibition of the bacterial colonization on the modified catheter surface was proved by the biofilm test. Antimicrobial activity of SPA-treated catheter surface was also quantitatively evaluated according to standard method of ISO based on JIS. The R-values were found to be higher than 3.8. The performed research indicated that the immobilization of SPA on the catheter surface by means of the mixed-type bonds resulted in stable antibacterial protection of the urological catheters for a long time. PMID- 20951781 TI - Nano spray drying: a novel method for preparing protein nanoparticles for protein therapy. AB - There has been an increasing interest in the development of protein nanotherapeutics for diseases such as cancer, diabetes and asthma. Spray drying with prior micro mixing is commonly used to obtain these powders. However, the separation and collection of protein nanoparticles with conventional spray dryer setups has been known to be extremely challenging due to its typical low collection efficiency for fine particles less than 2MUm. To date, there has been no feasible approach to produce these protein nanoparticles in a single step and with high yield (>70%). In this study, we explored the feasibility of the novel Nano Spray Dryer B-90 (equipped with a vibrating mesh spray technology and an electrostatic particle collector) for the production of bovine serum albumin (BSA) nanoparticles. A statistical experimental design method (Taguchi method based on three levels, five variables L(18) orthogonal array robust design) was implemented to study the effect of and optimize the experimental conditions of: (1) spray mesh size, (2) BSA solution concentration, (3) surfactant concentration, (4) drying air flow rate and (5) inlet temperature on: (1) size and (2) morphology (axial ratio). Particle size and morphology were predominantly influenced by the spray mesh size and surfactant concentration, respectively. The drying air flow rate and inlet temperature had minimal impact. Optimized production of smooth spherical nanoparticles (median size: 460+/-10nm, axial ratio: 1.03+/-0.00, span 1.03+/-0.03, yield: 72+/-4%) was achieved using the 4MUm spray mesh at BSA concentration of 0.1% (w/v), surfactant concentration of 0.05% (w/v), drying flow rate of 150L/min and inlet temperature of 120 degrees C. The Nano Spray Dryer B-90 thus offers a new, simple and alternative approach for the production of protein nanoparticles suited for a variety of drug delivery applications. PMID- 20951782 TI - Thermal analysis: a further step in characterizing solid forms obtained by screening crystallization of an API. AB - Phase and habit selection is a very important step in the early stages of pharmaceutical development of new APIs. In this paper, we show how observation, diffraction and thermal analysis are complementary methods of solid habit and phase characterization. At the end of phase screening of an API several habits and phases can be discriminated by microscopy, XRPD or Raman spectroscopy. Using thermal methods here allows us to separate the 12 phases discriminated by XRPD into: anhydrous, monohydrate, organic monosolvate and heterosolvate phases. PMID- 20951783 TI - Antitumoral activity of camptothecin-loaded nanoparticles in 9L rat glioma model. AB - Camptothecin (CPT), a plant alkaloid, is a potent anticancer drug in cell culture studies but it is clinically inactive due to rapid hydrolysis under physiological conditions. The drug exists in two forms depending on the pH value, an active lactone form at pH below 5 and an inactive carboxylate form at basic pH and this is a reversible reaction. In this study, nanoparticulate delivery systems were developed with either amphiphilic cyclodextrins, poly(lactide-co-glycolide) or poly-E-caprolactone in order to maintain the active lactone form and prevent the drug from hydrolysis. All nanoparticles were prepared with nanoprecipitation technique. Mean particle sizes were 130-280nm and surface charges were negative. The encapsulation efficiency was significantly higher for amphiphilic cyclodextrin nanoparticles when compared to polymeric nanoparticles. Nanoparticle formulations based on cyclodextrins showed a controlled release profile extended up to 12 days. 6-O-Capro-beta-cyclodextrin (1.44MUg/60MUL CPT) and concentrated 6 O-Capro-beta-cyclodextrin (2.88MUg/60MUL CPT) nanoparticles significantly modified the growth or lethality of the 9L gliomas, since the median survival time was 26 days for the untreated group and between 27 and 33 days for amphiphilic cyclodextrin nanoparticle groups. These results indicate that, CPT loaded amphiphilic cyclodextrin nanoparticles may provide a promising carrier system for the effective delivery of CPT in comparison to polymeric analogues. PMID- 20951784 TI - Protective effect of panaxatriol saponins extracted from Panax notoginseng against MPTP-induced neurotoxicity in vivo. AB - AIM OF THE STUDY: Panaxatriol saponins (PTS), the main constituents extracted from Panax notoginseng, a Chinese herbal medicine, has been shown to be an effective agent on various diseases. Our previous study has demonstrated that PTS is an inducer of thioredoxin-1 (Trx-1) and has a possible potential as a therapeutic agent for Parkinson's disease (PD). However, the effect of PTS on 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in vivo is unknown. MATERIALS AND METHODS: Using locomotor activity test and traction test, we detected the effect of PTS on MPTP-induced behavioral impairment. Tyrosine hydroxylase, Trx-1, cyclooxygenase-2, pro-caspase-9, pro-caspase-12 and caspase-3 expressions in the anatomical region of substantia nigra pars compacta (SNc) were tested by Western blot. RESULTS: PTS provided neuroprotection against the loss of dopaminergic neurons and behavioral impairment caused by MPTP. MPTP induced neuronal death in the SNc was suppressed by PTS through increasing Trx-1 expression, suppressing cyclooxygenase-2 over-expression and inhibiting mitochondria-mediated apoptosis. CONCLUSIONS: PTS, an inducer of Trx-1, has pluripharmacological properties in the protection against PD including enhancing antioxidant activity, acting as neurotrophic factor, modulating inflammation and inhibiting mitochondria-mediated apoptosis. PMID- 20951785 TI - Systemic exposure of quercetin after administration of feng-liao-chang-wei-kang granules to rats. AB - AIM OF STUDY: The objective of this study was to observe the systemic exposure of quercetin (QCT) including its free and total concentration in rat blood samples following a single p.o. dose of feng-liao-chang-wei-kang granules (FLCWKG). MATERIALS AND METHODS: Six male rats were given the FLCHKG and the serial blood samples were collected. Fully or partially validated LC/MS/MS methods were developed to analyze the resulting biosamples. Various pharmacokinetic (PK) parameters were estimated from the plasma concentration versus time data using non-compartmental methods. RESULTS: Both methods for analysis of the free and total QCT plasma concentration are sensitive, specific, accurate and reliable. The PK parameters of free QCT after administration of FLCWKG, in comparison with total concentration, show a lower C(max) (32.4+/-8.2 ng/ml versus 164+/-49 ng/ml), a lower AUC(0->infinity) (39.3+/-6.9 ng/ml h versus 313+/-16 ng/ml h), a shorter T(max) (0.17+/-0.00 h versus 0.83+/-1.01 h) and a similar t(1/2) (3.90+/ 0.88 h versus 3.10+/-1.94 h), MRT(0->t) (2.27+/-0.10 h versus 2.86+/-0.41 h). CONCLUSIONS: Free QCT was quickly absorbed from gastrointestinal tract and circulated in blood at quite low concentration. The circulating flavonoids originating from this formula were dominantly conjugated derivatives. PMID- 20951786 TI - Antimicrobial and cytotoxic activities of medicinal plants of the Brazilian cerrado, using Brazilian cachaca as extractor liquid. AB - ETHNOPHARMACOLOGICAL IMPORTANCE: Many species of plants in the Brazilian cerrado (savanna) are widely used in ethnomedicine. However, the safety and effectiveness of medicinal plants used in communities with little or no access to manufactured drugs should be evaluated. AIM OF THE STUDY: Evaluate the antimicrobial and cytotoxic activities of extracts from eight plant species, obtained using Brazilian cachaca as the extractor liquid. MATERIALS AND METHODS: The extracts were tested against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, Candida parapsilosis, promastigote forms of Leishmania amazonensis, and poliovirus. In addition, cytotoxic activity was assayed in Vero cells and in human erythrocytes. RESULTS: The plant species Curatella americana, Sclerolobium aureum, and Plathymenia reticulata showed the best activity against yeasts, especially the crude extract of C. americana and its ethyl-acetate fraction. Kielmeyera lathrophyton showed a minimum inhibitory concentration of 250 MUg/ml against S. aureus, and was inactive against gram negative bacteria. The extract obtained from Annona coriacea showed the best activity against the promastigote forms of Leishmania amazonensis (IC(50)=175 MUg/ml). Only C. americana showed potential for antipoliovirus activity. The concentrations of the crude extracts that showed toxicity to VERO cells had CC(50) between 31 and 470 MUg/ml, and the lyophilized Brazilian cachaca showed a CC(50) of 307 MUg/ml. None of the extracts showed toxicity against human erythrocytes. CONCLUSIONS: Among the plant species studied, C. americana proved to be effective against microorganisms, especially as an antifungal. The results will help in the search for alternative drugs to be used in pharmacotherapy, and will contribute to establish safe and effective use of phytomedicines in the treatment of infectious diseases. PMID- 20951787 TI - Renal toxicity caused by oral use of medicinal plants: the yacon example. AB - AIM OF THE STUDY: Yacon [Smallanthus sonchifolius (Poepp. & Endl.) H. Robinson, Asteraceae] is an Andean species that has traditionally been used as an anti diabetic herb in several countries around the world, including Brazil. Its hypoglycaemic action has recently been demonstrated in normal and diabetic rats. However, studies about the safety of prolonged oral consumption of yacon leaf extracts are lacking. Thus, this work was undertaken to evaluate the repeated dose toxicity of three extracts from yacon leaves: the aqueous extract (AE) prepared as a tea infusion; the leaf-rinse extract (LRE), which is rich in sesquiterpene lactones (STLs); and a polar extract from leaves without trichomes, or polar extract (PE), which lacks STLs but is rich in chlorogenic acids (CGAs). MATERIALS AND METHODS: The major classes of the compounds were confirmed in each extract by IR spectra and HPLC-UV-DAD profiling as well as comparison to standard compounds. The toxicity of each extract was evaluated in a repeated-dose toxicity study in Wistar rats for 90 days. RESULTS: The PE was rich in CGAs, but we did not detect any STLs. The AE and LRE showed the presence of STLs. The polar extract caused alterations in some biochemical parameters, but the animals did not show signs of behavioural toxicity or serious lesions in organs. Alterations of specific biochemical parameters in the blood (creatinine 7.0 mg/dL, glucose 212.0 mg/dL, albumin 2.8 g/dL) of rats treated with AE (10, 50 and 100 mg/kg) and LRE (10 and 100 mg/kg) pointed to renal damage, which was confirmed by histological analysis of the kidneys. CONCLUSIONS: The renal damage was associated with increased blood glucose levels after prolonged oral administration of the AE. This observation suggested that the hypoglycaemic effect observed after treatment for 30 days in an earlier study is reversible and was likely the result of renal injury caused by the toxicity of yacon. Because STLs were detected in both AE and LRE, there is strong evidence that these terpenoids are the main toxic compounds in the leaves of the yacon. Based on our results, we do not recommend the oral use of yacon leaves to treat diabetes. PMID- 20951788 TI - Effects on neuroendocrinoimmune network of Lizhong Pill in the reserpine induced rats with spleen deficiency in traditional Chinese medicine. AB - AIM OF THE STUDY: Lizhong Pill, composed of radix Ginseng (Panax ginseng C.A. Meyer), rhizoma Zingiberis (Zingiber officinale Roscoe), rhizoma Atractylodis Macrocephalae (Atractylodes macrocephala Koidz.) and radix Glycytthizae (Glycyrrhiza uralensis Fisch.), is a classical herbal product for curing spleen deficiency in traditional Chinese medicine (TCM), and reserpine treated rats show similar signs to TCM spleen deficiency pattern. This paper is aimed to explore the regulatory effect on neuroendocrinoimmune network by Lizhong Pill in reserpine induced TCM spleen deficiency rats. MATERIALS AND METHODS: 100 healthy adult male SD rats, with a mean weight of 200 g, were randomly divided into five groups in average: control group, reserpine treated group, atropine treated group, treatment groups with Lizhong Pill at high dose and low dose (equal to the dosage of crude drugs for 4 g/kg/d and 8 g/kg/d). Rats in reserpine treated group were induced by intraperitoneal injection of reserpine at 0.5 mg/kgd for 4 weeks. The levels of IL-1, IL-6 and gastrin were measured with radioimmunoassay, TNF alpha and IFN-gamma in serum were measured with ELISA, the level of vasoactive intestinal peptide (VIP) and substance P (SP) in small intestine were determined with radioimmunoassay, and the TNF-alpha and TGF-beta positive cells in small intestine were detected by immunohistological staining. Data were analyzed with SAS 9.1 software package. RESULTS: The rats in reserpine treated group, body weight, concentrations of IFN-gamma, IL-1 and TNF-alpha in serum, expression of TGF-beta in small intestine, VIP in small intestine decreased (P<0.05), and the level of IL-6 in serum, expression of TNF-alpha, SP in small intestine and gastrin were increased (P<0.05). Administration of Lizhong Pill at high dose could increase the body weights at day 21, and the weights of rats in Lizhong Pill groups were much higher compared to reserpine treated group. At high dose of Lizhong Pill could increase the level of TNF-alpha in serum. Lizhong Pill at high dose and low dose could reverse the changes of IL-1, IL-6 and IFN-gamma, gastrin, expression of TGF-beta and TNF-alpha, VIP and SP in small intestine. CONCLUSIONS: The rats treated with reserpine, with similar signs to TCM spleen deficiency, show neuroendocrinoimmune disorders, and the restoration of the neuroendocrinoimmune disorders might be the part of mechanism of Lizhong Pill for reinforcing TCM spleen deficiency. PMID- 20951789 TI - Orally administered mycelial culture of Phellinus linteus exhibits antitumor effects in hepatoma cell-bearing mice. AB - AIM OF THE STUDY: The aim of this study was to evaluate the anticancer effect of a mycelial culture from Phellinus linteus PL-7 (MCPL-7) and to elucidate its potential mechanism in vivo. MATERIALS AND METHODS: SCID CB-17 mice received a transplant of Hep3B cells followed by daily MCPL-7 administrations for 8 weeks. Following tumor implantation, groups C-E were subcutaneously administered 50 mg/kg, 100 mg/kg, or 250 mg/kg MCPL-7 powder per day, respectively, for 8 weeks. Groups A and B received saline solution subcutaneously for 8 weeks. RESULTS: MCPL 7 administration induced a significant reduction in tumor size and was associated with a significant increase in T cell numbers; IL-12, IFN-gamma and TNF-alpha secretion; NK cell activity; and phagocytic ability. Therefore, increased numbers of CD4(+) cells could have been caused by greater numbers of dendritic cells and macrophages in the spleen. Furthermore, the activation of dendritic cells and macrophages resulted in increased IL-12 secretion, which could upregulate NK cell activation. The increased secretion of IL-12, IFN-gamma, and TNF-alpha enhanced the activity and phagocytic ability of NK cells. Thus, MCPL-7 may provide a potential therapeutic approach for both immunomodulatory and antitumor effects. PMID- 20951791 TI - Mild stress facilitates learning and exercise improves retention in aged mice. AB - While chronic or severe stress generally has negative consequences in the brain, moderate stress has been shown to facilitate learning in young animals. It is unknown if stress facilitates or impairs learning in an aged animal. In this study, the effect of mild stress on learning and task retention (1 week later) was assessed in young and aged mice. In addition, because exercise can counteract negative effects of stress and facilitate learning, the effect of 1 week of voluntary exercise on task retention was assessed. Regulation of the learning/memory related genes BDNF exon VI, synapsin, MAPK, and CRFR1 were also examined in the hippocampus using real-time PCR. Results of this study demonstrate that mild stress 24h prior to the learning test improved performance in aged, but not young animals. However, exercise for 1 week between tests improved the performance of both groups of animals in the retention task. In aged, but not young animals, all four genes increased significantly after exercise. Thus, in aged animals mild stress facilitates learning and the retention of this task is improved by voluntary exercise. PMID- 20951790 TI - Effects of chronic fentanyl administration on physical performance of aged rats. AB - There is growing concern over the increasing use of opioids to treat chronic pain in the elderly primarily because of the potential increased sensitivity to the adverse side effects. Here, we use a preclinical model (male Brown Norway X F344 rats aged 12, 18, 24, and 30 months) to describe the outcome of chronic fentanyl administration (1.0mg/kg/day) on various physiological and behavioral measures. Continuous fentanyl administration resulted in an initial decrease in food consumption, followed by the development of tolerance to this effect over a 4 week period and a subsequent increase in food consumption during withdrawal. This change in food consumption was associated with decreases in body weight (predominantly due to a loss of fat mass) that was maintained through early withdrawal. After 1 month of withdrawal, only the 12-month old animals had fully regained body weight. Fentanyl administration resulted in a decrease in grip strength and an increase in locomotor activity that did not differ across age groups. There was no effect of fentanyl administration on rotarod performance. These results demonstrate that while there is a delayed recovery of body mass with age, the observed changes in behavioral responses are uniform across ages. PMID- 20951792 TI - IL-23 modulated myelin-specific T cells induce EAE via an IFNgamma driven, IL-17 independent pathway. AB - Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS) mediated by myelin-reactive CD4(+) T cells. An unresolved issue that has important clinical implications concerns the cytokines produced by myelin-reactive T cells that determine their pathogenicity. Initially, IL-12 polarized, IFNgamma producing Th1 cells were thought to be essential for the development of EAE. More recently, IL-23 polarized, IL-17 producing Th17 cells have been highlighted as critical encephalitogenic effectors. There is growing evidence that parallel autoimmune pathways can result in common clinical and histopathological endpoints. In the current study, we describe a form of EAE induced by the transfer of IL-23 modulated CD4(+) T cells into IL-17 receptor (IL-17R) deficient hosts. We found that IL-23 stimulates myelin-reactive T cells to produce both IFNgamma and IL-17. Surprisingly, in this model the development of EAE is IFNgamma dependent. Our findings illustrate a novel mechanism by which IL-23 promotes encephalitogenicity and they further expand the spectrum of autoreactive T cells capable of mediating inflammatory demyelinating disease of the CNS. PMID- 20951793 TI - Cytokine levels in the blood may distinguish suicide attempters from depressed patients. AB - Elevated plasma cytokines is a common finding in Major Depressive Disorder (MDD), although not consistent. It is currently not known whether the inflammatory changes are confined to any specific subgroup of depressive patients. We here analyzed three inflammatory markers in suicidal and non-suicidal depressed patients, as well as healthy controls. Plasma interleukin (IL)-2, IL-6 and tumor necrosis factor (TNF)-alpha were measured in 47 suicide attempters, 17 non suicidal depressed patients and 16 healthy controls. Study participants were evaluated using the Comprehensive Psychopathological Rating Scale (CPRS) with subscales for anxiety and degree of depression, as well as the Suicide Assessment Scale (SUAS). We found increased levels of IL-6 and TNF-alpha as well as decreased IL-2 concentrations in suicide attempters compared to non-suicidal depressed patients and healthy controls. The results were adjusted for potential confounders of cytokine expression, such as age, sex, body mass index (BMI), degree of depression, anxiety, personality disturbance, abuse and type of medication. These results demonstrate for the first time that suicidal patients display a distinct peripheral blood cytokine profile compared to non-suicidal depressed patients. Thus, our study provides further support for a role of inflammation in the pathophysiology of suicidality. PMID- 20951794 TI - CD14 and TRIF govern distinct responsiveness and responses in mouse microglial TLR4 challenges by structural variants of LPS. AB - Toll-like receptor (TLR) 4 responds to a range of agonists in infection and injury, but is best known for the recognition of bacterial lipopolysaccharides (LPS). Assembly in heterologous receptor complexes as well as signaling through both MyD88 and TRIF adaptor proteins, as unmatched by other TLRs, could underlie its versatile response options, probably also in a cell type-dependent manner. We show that microglia, the CNS macrophages, react to diverse LPS variants, including smooth (S) and rough (R) LPS chemotypes, with cytokine/chemokine induction, MHC I expression and suppression of myelin phagocytosis. The TLR4 co receptor CD14 was shown in peritoneal macrophages to be essential for S-LPS effects and the link of both S- and R-LPS to TRIF signaling. In contrast, cd14(-/ ) microglia readily respond to S- and R-LPS, suggesting an a priori high(er) sensitivity to both chemotypes, while CD14 confers increased S- and R-LPS potencies and compensates for their differences. Importantly, CD14 controls the magnitude and shapes the profile of cyto/chemokine production, this influence being itself regulated by critical LPS concentrations. Comparing reactive phenotypes of microglia with deficiencies in CD14, MyD88 and TRIF (cd14(-/-), myd88(-/-), and trif(lps2)), we found that distinct signaling routes organize for individual functions in either concerted or non-redundant fashion and that CD14 has contributions beyond the link to TRIF. Modulation of response profiles by key cytokines finally reveals that the microglial TLR4 can differentiate between the class of LPS structures and a self-derived agonist, fibronectin. It thus proves as a sophisticated decision maker in infectious and non-infectious CNS challenges. PMID- 20951795 TI - Differential effects of p,p'-DDE on testis and liver mitochondria: implications for reproductive toxicology. AB - The release of environmental contaminants can contribute to impaired male fertility. The bioenergetics of isolated liver mitochondria have been used as a toxicological indicator, an inexpensive first line model to screen possible effects of several substances. Here we report the effects of 2,2-bis(4 chlorophenyl)-1,1-dichloro-ethylene (DDE) on the bioenergetical parameters of testicular mitochondria. A significant decrease in repolarization potential (after a phosphorylative cycle), state 3 respiration and uncoupled respiration, with a concomitant increase in lag phase was found, demonstrating a decrease in mitochondrial function. Importantly, there was also a clear increase in maximum potential in DDE-treated testis mitochondria, which was not mirrored by more commonly used liver mitochondria. Indeed, comparative studies showed that testis and liver mitochondria have strikingly different sensitivities and patterns of response to DDE, indicating that testis mitochondria should be used as a primary toxicological model for a proper evaluation of putative effects of environmental toxicants on the bioenergetics of spermatogenesis and male fertility. PMID- 20951796 TI - Exposure of neonatal female rats to bisphenol A disrupts hypothalamic LHRH pre mRNA processing and estrogen receptor alpha expression in nuclei controlling estrous cyclicity. AB - This study examines the effects of neonatal exposure to the endocrine disruptor bisphenol A (BPA) on the neural network that controls estrous cyclicity. From postnatal day 1 (PND1) to PND7, female pups were injected with vehicle (control) or BPA (BPA.05: 0.05mg/kg-d, BPA20: 20mg/kg-d). At PND100 BPA.05-females showed alterations in estrous cyclicity and BPA20-females were incapable of producing an estradiol-induced LH surge. By real-time PCR we determined that hypothalamic expression of mature LH-releasing hormone (LHRH) mRNA was increased in BPA.05 and decreased in BPA20-females. Furthermore, unprocessed intron A-containing LHRH RNA was decreased in the cytoplasm of hypothalamic cells of both groups. Immunohistochemistry revealed that estrogen receptor alpha protein was up regulated in anteroventral periventricular and down-regulated in arcuate nucleus of both groups. Our results show that BPA permanently disrupts hypothalamic LHRH pre-mRNA processing and steroid receptors expression in nuclei that control estrous cyclicity in adult rats. PMID- 20951797 TI - Neonatal exposure to genistein adversely impacts the ontogeny of hypothalamic kisspeptin signaling pathways and ovarian development in the peripubertal female rat. AB - Neonatal exposure to estrogenic endocrine disrupting compounds (EDCs) can advance pubertal onset and induce premature anestrous in female rats. It was recently discovered that hypothalamic kisspeptin (KISS) signaling pathways are sexually dimorphic and regulate both the timing of pubertal onset and estrous cyclicity. Thus we hypothesized that disrupted sex specific ontogeny of KISS signaling pathways might be a mechanism underlying these EDC effects. We first established the sex specific development of KISS gene expression, cell number and neural fiber density across peripuberty in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC), hypothesizing that the sexually dimorphic aspects of KISS signaling would be most vulnerable to EDCs. We next exposed female rats to the phytoestrogen genistein (GEN, 1 or 10 mg/kg bw), estradiol benzoate (EB, 10 MUg), or vehicle from post natal day (P) 0-3 via subcutaneous (sc) injection. Animals were sacrificed on either P21, 24, 28, or 33 (n=5-14 per group at each age). Vaginal opening was significantly advanced by EB and the higher dose of GEN compared to control animals and was accompanied by lower numbers of KISS immunoreactive fibers in the AVPV and ARC. Ovarian morphology was also assessed in all age groups for the presence of multiple oocyte follicles (MOFs). The number of MOFs decreased over time in each group, and none were observed in control animals by P24. MOFs were still present, however, in the EB and 10 mg/kg GEN groups beyond P24 indicating a disruption in the timing of ovarian development. PMID- 20951798 TI - Akt1 protects against germ cell apoptosis in the postnatal mouse testis following lactational exposure to 6-N-propylthiouracil. AB - Exposure to 6-propyl-2-thio-uracil (PTU), a neonatal goitrogen, leads to increased testis size and sperm production in rodents. Akt1, a gene involved in cell survival and proliferation is also phosphorylated by thyroxine (T(4)). Therefore, we examined the requirement for Akt1 in germ cell survival following PTU-induced hypothyroidism. Experiments were performed using Akt1+/+, Akt1+/-, and Akt1-/- mice. PTU was administered (0.01% w/v) via the drinking water of dams from birth to PND21. At PND15, T(4) serum levels were similar in all control groups, and significantly lower in all exposed groups with a dramatic decrease in Akt1-/- mice. PTU-exposed Akt1-/- testes displayed smaller tubules, increased apoptosis, delayed lumen formation, and increased inhibin B and AMH mRNA. Relative adult testis weights were similar in all exposure groups; however, no increase in daily sperm production was observed in PTU-exposed Akt1-/- mice. In conclusion, Akt1 contributes to the effects of thyroid hormone on postnatal testis development. PMID- 20951799 TI - Molecular bases of thioredoxin and thioredoxin reductase-mediated prooxidant actions of (-)-epigallocatechin-3-gallate. AB - Thioredoxin (Trx) and thioredoxin reductase (TrxR) function as antioxidant and anti-apoptotic proteins, which are often up-regulated in drug-resistant cancer cells. (-)-epigallocatechin-3-gallate (EGCG) is a naturally occurring antioxidant in green tea, but also exhibits prooxidant and apoptosis-inducing properties. We have previously showed a linkage between EGCG-induced inactivation of TrxR and decreased cell survival, revealing TrxR as a new target of EGCG. However, the molecular events underlying the importance of Trx/TrxR in EGCG-induced cytotoxicity remain unclear. Here, we show that the crosstalk between EGCG and Trx/TrxR occurred in a redox-dependent manner, and EGCG induced inactivation of Trx/TrxR in parallel with increased ROS levels in HeLa cells. Moreover, EGCG displayed great reactivity with Cys/Sec residues that have low pK(a) values. The structure of EGCG suggests that its quinone form would readily react with thiolate and selenolate nucleophiles. Using mass spectrometry, we have demonstrated the formation of EGCG-Trx1 (Cys(32)) and EGCG-TrxR (Cys/Sec) conjugates, confirming that EGCG quinone specifically conjugates with active-site Cys(32) in Trx or C-terminal Cys/Selenocysteine (Sec) couple in TrxR under conditions where Trx/TrxR are reduced. Non-reduced form of Trx/TrxR could escape from EGCG inhibition. These data reveal a potential mechanism for enhancing EGCG induced cancer cell death by the NADPH-dependent reduction of Trx/TrxR. PMID- 20951800 TI - Compensatory effects in the PI3K/PTEN/AKT signaling network following receptor tyrosine kinase inhibition. AB - Overcoming de novo and acquired resistance to anticancer drugs that target signaling networks is a formidable challenge for drug design and effective cancer therapy. Understanding the mechanisms by which this resistance arises may offer a route to addressing the insensitivity of signaling networks to drug intervention and restore the efficacy of anticancer therapy. Extending our recent work identifying PTEN as a key regulator of Herceptin sensitivity, we present an integrated theoretical and experimental approach to study the compensatory mechanisms within the PI3K/PTEN/AKT signaling network that afford resistance to receptor tyrosine kinase (RTK) inhibition by anti-HER2 monoclonal antibodies. In a computational model representing the dynamics of the signaling network, we define a single control parameter that encapsulates the balance of activities of the enzymes involved in the PI3K/PTEN/AKT cycle. By varying this control parameter we are able to demonstrate both distinct dynamic regimes of behavior of the signaling network and the transitions between those regimes. We demonstrate resistance, sensitivity, and suppression of RTK signals by the signaling network. Through model analysis we link the sensitivity-to-resistance transition to specific compensatory mechanisms within the signaling network. We study this transition in detail theoretically by variation of activities of PTEN, PI3K, AKT enzymes, and use the results to inform experiments that perturb the signaling network using combinatorial inhibition of RTK, PTEN, and PI3K enzymes in human ovarian carcinoma cell lines. We find good alignment between theoretical predictions and experimental results. We discuss the application of the results to the challenges of hypersensitivity of the signaling network to RTK signals, suppression of drug resistance, and efficacy of drug combinations in anticancer therapy. PMID- 20951801 TI - NOTCH1 missense alleles associated with left ventricular outflow tract defects exhibit impaired receptor processing and defective EMT. AB - Notch signaling is essential for proper cardiac development. We recently identified missense variants in the NOTCH1 receptor in patients with diverse left ventricular outflow tract (LVOT) malformations (NOTCH1(G661S) and NOTCH1(A683T)) that reduce ligand-induced Notch signaling. Here, we examine the molecular mechanisms that contribute to reduced signaling and perturbed development. We find that NOTCH1(A683T) exhibits reduced S1 cleavage due to impaired trafficking through the endoplasmic reticulum (ER). This observation is consistent with improper localization of the variant receptor to the ER and decreased presentation at the cell surface. In contrast, the nearby mutation NOTCH1(G661S) exhibits reduced cell-surface presentation in the absence of overt folding or trafficking defects. To examine the implications of these variants in disease pathogenesis, we investigated their effect on epithelial-to-mesenchymal transition (EMT), a critical process for development of the outflow tract. We find that these LVOT-associated NOTCH1 alleles can contribute to defective EMT in endothelial cell lines through impaired induction of Snail and Hes family members. These data represent the first description of a molecular mechanism underlying NOTCH1 mutations in individuals with LVOT malformations, and have important implications regarding the functional contribution of these alleles to a complex set of developmental defects. PMID- 20951802 TI - A historical perspective on the collaboration between psychoanalysis and neuroscience. AB - The aim of this article is to present and discuss the connections between psychoanalysis and neuroscience from a historical viewpoint. We start by examining how Sigmund Freud can be viewed as a pioneer in the interaction between these two fields. Freud was himself a neurologist and had maintained an interest in biology as he developed the key concepts of psychoanalysis. His ideas regarding psychosomatics are described. We will also explore how the concept of drive is essential to the connection between psychoanalysis and neuroscience. Then, we describe several key actors and historical events and characters at the interface of these two fields, namely Sandor Rado Lawrence S. Kubie and Mc Culloch, the debates that took place during the Macy conferences, as well as the positions of Jacques Lacan, George L. Engel, and Eric Kandel. Finally, we present a synthesis of the main fields in which the connections between psychoanalysis and neuroscience are already fruitful, and those where they should be developed: the classification of mental diseases, the link between the scientific and psychic dimensions, therapeutics, the organization of the body, intersubjectivity, the subjective division and ambivalence, as well as transferential effects like such as the placebo and nocebo effects. In the conclusion, we advocate several strategic alliances and underscore the complementarity between rigorous scientific experimentation and the individualized psychoanalytic approach. PMID- 20951803 TI - PKC activator therapeutic for mild traumatic brain injury in mice. AB - Traumatic brain injury (TBI) is a frequent consequence of vehicle, sport and war related injuries. More than 90% of TBI patients suffer mild injury (mTBI). However, the pathologies underlying the disease are poorly understood and treatment modalities are limited. We report here that in mice, the potent PKC activator bryostatin1 protects against mTBI induced learning and memory deficits and reduction in pre-synaptic synaptophysin and post-synaptic spinophylin immunostaining. An effective treatment has to start within the first 8h after injury, and includes 5 * i.p. injections over a period of 14 days. The treatment is dose dependent. Exploring the effects of the repeated bryostatin1 treatment on the processing of the amyloid precursor protein, we found that the treatment induced an increase in the putative alpha-secretase ADAM10 and a reduction in beta-secretase activities. Both these effects could contribute towards a reduction in beta-amyloid production. These results suggest that bryostatin1 protects against mTBI cognitive and synaptic sequela by rescuing synapses, which is possibly mediated by an increase in ADAM10 and a decrease in BACE1 activity. Since bryostatin1 has already been extensively used in clinical trials as an anti cancer drug, its potential as a remedy for the short- and long-term TBI sequelae is quite promising. PMID- 20951804 TI - Antimicrobial and non-antimicrobial tetracyclines in human cancer trials. AB - Tetracyclines are capable of inhibiting mammalian collagenases by non antimicrobial mechanisms. Because collagenases and other matrix metalloproteinases have been linked to cancer pathogenesis, this property of tetracycline's has led to speculation that these drugs could be used to slow tumor growth, invasion and metastasis in neoplasms that overly express these enzymes. The FDA has already approved two tetracycline derivates for treatment of chronic inflammatory periodontal disease and chronic inflammatory skin disease. Here we review the efforts to determine the efficacy of tetracyclines as chemotherapeutics in human cancer trials. While the majority of clinical trials have yielded disappointing results, tetracyclines have been shown to be generally well tolerated and have significant anti-proliferative effects in certain cancer types. In particular the chemically modified tetracycline derivative COL-3 (also known as CMT-3) has been shown to cause dramatic improvement in the tumor burden of patients with Kaposi Sarcoma. The experience using tetracyclines as chemotherapeutics is relatively limited, but further success is possible if future trials are focused on specific cancer subtypes that are known to rely heavily on collagenases and other matrix metalloproteinases for their pathogenesis. PMID- 20951807 TI - Production of functional recombinant bovine trypsin in transgenic rice cell suspension cultures. AB - A synthetic bovine trypsinogen (sbTrypsinogen) was synthesized on the basis of rice-optimized codon usage via an overlap PCR strategy, prior to being expressed under the control of the sucrose starvation-inducible rice alpha-amylase 3D (RAmy3D) promoter. Secretion of trypsin into the culture medium was achieved by using the existing signal peptide. The plant expression vector was introduced into rice calli (Oryza sativa L. cv. Dongjin), mediated by Agrobacterium tumefaciens. The integration of the sbTrypsinogen gene into the chromosome of the transgenic rice callus was verified via genomic DNA PCR amplification, and sbTrypsin expression in transgenic rice suspension cells was confirmed via Northern blot analysis. Western blot analysis detected glycosylated proteins in the culture medium, having masses from 24 to 26 kDa, following induction by sugar starvation. Proteolytic activity of the rice-derived trypsin was confirmed by gelatin zymogram, and was similar to that of the commercial bovine-produced trypsin. The yields of sbTrypsin that accumulated in the transgenic rice cell suspension medium were 15 mg/L at 5 days after sugar starvation. PMID- 20951806 TI - Passenger mutations as a marker of clonal cell lineages in emerging neoplasia. AB - Cancer arises as the result of a natural selection process among cells of the body, favoring lineages bearing somatic mutations that bestow them with a proliferative advantage. Of the thousands of mutations within a tumor, only a small fraction functionally drive its growth; the vast majority are mere passengers of minimal biological consequence. Yet the presence of any mutation, independent of its role in facilitating proliferation, tags a cell's clonal descendants in a manner that allows them to be distinguished from unrelated cells. Such markers of cell lineage can be used to identify the abnormal proliferative signature of neoplastic clonal evolution, even at a stage which predates morphologically recognizable dysplasia. This article focuses on molecular techniques for assessing cellular clonality in humans with an emphasis on how they may be used for early detection of tumorigenic processes. We discuss historical as well as contemporary approaches and consider ways in which powerful new genomic technologies might be harnessed to develop a future generation of early cancer diagnostics. PMID- 20951808 TI - Heparin cofactor II (RbHCII) from rock bream (Oplegnathus fasciatus): molecular characterization, cloning and expression analysis. AB - Heparin cofactor (HCII) is a serine protease inhibitor (SPI), and plays important physiological roles in various biological events including hemostasis. The gene encoding the HCII was isolated from GS-FLXTM genomic data of rock bream (Oplegnathus fasciatus), designated as RbHCII. The RbHCII (1950 bp) consists of a 1512 bp open reading frame (ORF) encoding 504 amino acids (aa), with a signal peptide of 19 aa residues. The predicted molecular mass and the estimated isoelectric point of RbHCII were 58 kDa and 5.9, respectively. The deduced aa sequence of RbHCII displayed a characteristic serpin domain and a serpin signature motif (FTVDQPFLFLI). RbHCII demonstrated homology with vertebrate HCIIs and the greatest degree of similarity (90.1%) was observed with Gasterosteus aculeatus HCII. Various functional domains including the reactive center loop (RCL), glycosaminoglycan (GAG) and thrombin binding sites and acidic repeats of human and RbHCII were found to be orthologs through the molecular modeling studies. Phylogenetic analysis revealed that RbHCII belongs to the clade D serpins, and is closely related to the clade A members. Constitutive expression of RbHCII mRNA was detected at different levels in various tissues in a tissue specific manner. Interestingly, RbHCII transcription was significantly downregulated (p < 0.05) in liver after challenge with lipopolysaccharide (LPS), Edwardsiella tarda and rock bream iridovirus (RBIV). However, after the immune challenges, RbHCII showed a significant downregulation in blood tissue only at the late-phase of investigation. The recombinant RbHCII (rRbHCII) was overexpressed in Rosetta-gami (DE3) cells and purified using the pMALTM system. The rRbHCII inhibited thrombin and chymotrypsin in a dose-dependent manner. Remarkably, heparin was found to be an enhancer of RbHCII's thrombin-inhibitory activity. Correlating the heparin-dependent thrombin-inhibition activity of RbHCII with its temporal downregulation against immune stimulants, it could be suggested that it is not only involved in the blood coagulation cascade, but also plays an incognito role in immune modulation. PMID- 20951809 TI - Molecular characterization of a mollusk chicken-type lysozyme gene from Haliotis discus hannai Ino, and the antimicrobial activity of its recombinant protein. AB - A chicken-type lysozyme was obtained and characterized from the abalone Haliotis discus hannai Ino (HdLysC). The full-length cDNA of HdLysC was 586 bp, and it contained an open reading frame of 441 bp, encoding a 147-amino acid protein with a calculated molecular mass of 15.64 kDa and an isoelectric point of 4.87. The amino acid sequence of HdLysC possessed all conserved features critical for the fundamental structure and function of c-type lysozymes, including the two catalytic residues, Glu54 and Asp70. The genomic length of HdLysC was 2865 bp, with four exons interrupted by three introns. The genomic structure of HdLysC was more similar to vertebrates than invertebrates. Many putative transcription factor binding sites involved in the immune system and cancer were found in the promoter region of HdLysC. Quantitative real-time RT-PCR detected HdLysC expression in all examined tissues, as well as in an expression profile of abalone gills challenged with bacteria Vibrio anguillarum. HdLysC transcripts were found to be most abundantly expressed in mantles, and weakly expressed in hemocytes, and increased expression of HdLysC also observed after bacterial stimulation. HdLysC was expressed in Escherichia coli, and the recombinant protein showed bacteriolytic activity against both Gram-positive and Gram negative bacteria. Of the Vibrio species tested, more effective activity was detected against V. anguillarum. PMID- 20951811 TI - A new gene family of single fibrinogen domain lectins in Mytilus. AB - In molluscs haemolymph lectins bearing fibrinogen-like domain (FREP) act as immune pattern-recognition receptors. A full-length cDNAs of MytFREP1 and MytFREP2 cloned from haemocytes of blue mussel Mytilus edulis encoded putative polypeptides of 230 and 241 amino acids. Both polypeptides consist of signal peptide and C-terminal fibrinogen-like domain. Immune functions of these molecules may be extrapolated from the close-related and functionally characterized lectin AiFREP from bay scallop, Argopecten irradians. However, immune challenge experiments with zymosan particles, Escherichia coli bacterium and cercariae of Himasthla elongata (Trematoda) failed to modulate MytFREP1 and MytFREP2 mRNA expression in M. edulis haemocytes. Hypothetically, it argues into rather high specificity of mechanisms triggering a differential expression of MytFREP genes. The search in the EST database revealed orthologous copies for described genes and portion of relatively similar genes from two close-related mytilids, Mytilus galloprovincialis and Mytilus californianus. We document the new multigene family of FREPs from bivalves of genus Mytilus. MytFREP family currently represented by 2 genes from M. edulis, 4 genes from M. californianus and 7 genes from M. galloprovincialis. PMID- 20951805 TI - DNA replication fidelity and cancer. AB - Cancer is fueled by mutations and driven by adaptive selection. Normal cells avoid deleterious mutations by replicating their genomes with extraordinary accuracy. Here we review the pathways governing DNA replication fidelity and discuss evidence implicating replication errors (point mutation instability or PIN) in carcinogenesis. PMID- 20951810 TI - Changes in complement responses in Gilthead seabream (Sparus aurata) and European seabass (Dicentrarchus labrax) under crowding stress, plus viral and bacterial challenges. AB - Gilthead seabream (Sparus aurata) and European seabass (Dicentrarchus labrax) were subjected to either experimental infection with Photobacterium damselae subsp. piscicida or Nodavirus after a period of 2 weeks of crowding in which fish were subjected to a 5-fold increase in density (10-50 kg/m(3)). Samples were obtained before the crowding period (0 h or control) and at 24h and 72 h after crowding from both groups of infected fish. The Complement haemolytic activity and the expression of the C3 gene were evaluated in blood and liver samples respectively. The bacteriolytic and lysozyme activities were also assessed. The results showed that Complement haemolytic activity was reduced at 72 h with both bacteria and virus in high density Gilthead seabream, and a similar increase was observed at low density. Bacteriolytic activity under both bacterial and viral challenges for both species was increased at 24h, under low density. At high density, the bacterial challenge did not induce significant changes. C3 mRNA abundance was substantially increased after pathogen treatments in low density groups at 24h but no significant changes were detected at high densities. These results support the idea of the suppressor effect of stressors on the immune system since a reduction of Complement activity under virus and high density, or lack of response in C3 expression under high density were observed. PMID- 20951812 TI - Source localization of event-related potentials to pitch change mapped onto age appropriate MRIs at 6 months of age. AB - Auditory event-related potentials (ERPs) have been used to understand how the brain processes auditory input, and to track developmental change in sensory systems. Localizing ERP generators can provide invaluable insights into how and where auditory information is processed. However, age-appropriate infant brain templates have not been available to aid such developmental mapping. In this study, auditory change detection responses of brain ERPs were examined in 6-month old infants using discrete and distributed source localization methods mapped onto age-appropriate magnetic resonance images. Infants received a passive oddball paradigm using fast-rate non-linguistic auditory stimuli (tone doublets) with the deviant incorporating a pitch change for the second tone. Data was processed using two different high-pass filters. When a 0.5 Hz filter was used, the response to the pitch change was a large frontocentral positive component. When a 3 Hz filter was applied, two temporally consecutive components associated with change detection were seen: one with negative voltage, and another with positive voltage over frontocentral areas. Both components were localized close to the auditory cortex with an additional source near to the anterior cingulate cortex. The sources for the negative response had a more tangential orientation relative to the supratemporal plane compared to the positive response, which showed a more lateral, oblique orientation. The results described here suggest that at 6 months of age infants generate similar response patterns and use analogous cortical areas to that of adults to detect changes in the auditory environment. Moreover, the source locations and orientations, together with waveform topography and morphology provide evidence in infants for feature specific change detection followed by involuntary switching of attention. PMID- 20951813 TI - Characterization of cardiac repolarization in the Gottingen minipig. AB - INTRODUCTION: The minipig represents an attractive experimental animal within cardiovascular research due to its extensive similarities to the human heart in terms of anatomy and physiology. Although minipigs have been used for cardiovascular research for decades no thorough characterization of the minipig cardiac electrophysiology has been performed. Therefore, we have for the first time characterized the minipig cardiac repolarization in a series of experiments ranging from mRNA quantification to in vivo studies. METHODS: Gottingen minipigs were used throughout the study. Cardiac mRNA quantification was performed using quantitative PCR methods. For ex vivo experiments, hearts were excised using cardioplegic procedures and Langendorff and microelectrode action potential recordings were performed. Effects of temperature in vivo were recorded in anesthetized animals. RESULTS: On the mRNA level the expression profile of major cardiac ion channel proteins in both atria and ventricle was very similar to what has been reported for humans. In both intact isolated heart and isolated endocardial strips the I(Kr) blocker dofetilide increased action potential duration (APD). The I(Ks) blocker HMR1556 increased APD and triangulation only when I(Kr) was blocked with dofetilide. In the presence of I(Kr) and I(Ks) blockade a reduction of [K+](e) resulted in a marked increase in APD(90) in isolated hearts. I(K1) blockade with Ba2+ increased APD in whole heart and isolated endocardium. In isolated endocardium, beta-adrenergic stimulation with isoprenaline resulted in an increase in APD and potential amplitude but a decrease in triangulation. There was a rate-dependent decrease in APD in both whole heart and isolated endocardium. In vivo and ex vivo investigations revealed a negative correlation between temperature and duration of cardiac repolarization. DISCUSSION: Our results point toward the minipig being a promising species for cardiac safety research. PMID- 20951814 TI - What is a good patient reported outcome after total hip replacement? AB - OBJECTIVES: There is an increasing movement to collect and report patient reported outcome measures (PROM's) following total hip replacement (THR). In the UK, the procedure specific PROM of choice is the Oxford Hip Score (OHS). It is currently unclear how to use this information to determine outcome following surgery. The aim of this study was to define a threshold for the OHS that is correlated with patient satisfaction. DESIGN: Prospective cohort study. SETTING: A district general hospital (St. Helier Hospital, Carshalton, UK). PARTICIPANTS: 799 patients receiving THR from 1995 to 2004. MAIN OUTCOME MEASURES: At 12 and 24 months after surgery patients were asked if they were satisfied with surgery and completed the OHS. Receiver operating characteristic (ROC) analyses were used to identify thresholds of follow-up OHS, which best discriminated patient satisfaction. Analyses were stratified by age, sex, body mass index (BMI), baseline OHS and patient expectations. RESULTS: 91.9% of patients were satisfied with THR at 12 months (92.8% at 24 months). Using the ROC technique, the OHS at 12 months associated with patient satisfaction was 38 and at 24 months 33. The OHS at 24 months associated with satisfaction was higher in those with highest tertile of baseline OHS (30, 33, 43 respectively), and lowest tertile of BMI. CONCLUSIONS: We have identified a value of the OHS that predicts patient satisfaction 12-24 months following THR within a standard clinical setting. However, this threshold is markedly influenced by pre-operative OHS and should be stratified accordingly. PMID- 20951815 TI - Probiotic properties of Lactobacillus strains isolated from the feces of breast fed infants and Taiwanese pickled cabbage. AB - This study assessed potential probiotic Lactobacillus strains isolated from the feces of breast-fed infants and from Taiwanese pickled cabbage for their possible use in probiotic fermented foods by evaluating their (i) in vitro adhesive ability, resistance to biotic stress, resistance to pathogenic bacteria, and production of beta-galactosidase; (ii) milk technological properties; and (iii) in vivo adhesive ability, intestinal survival and microbial changes during and after treatment. Five Lactobacillus isolates identified as Lactobacillus reuteri F03, Lactobacillus paracasei F08, Lactobacillus rhamnosus F14, Lactobacillus plantarum C06, and Lactobacillus acidophilus C11 that showed resistance to gastric juice and bile salts were selected for further evaluation of their probiotic properties. All the strains demonstrated the ability to adhere to Caco 2 cells, particularly, strain L. plantarum C06 and L. reuteri F03 showed satisfactory abilities, which were similar to that of the reference strain L. rhamnosus GG. The strains L. paracasei F08 and L. acidophilus C11 had the highest beta-galactosidase activity. Most of the strains were resistant to aminoglycosides and vancomycin but sensitive to ampicillin, erythromycin, and penicillin. All the 5 strains elicited antibacterial activity against both Gram positive (Bacillus cereus, Listeria monocytogenes and Staphylococcus aureus) and negative (Escherichia coli and Salmonella enterica) pathogens. Moreover, the strains L. reuteri F03, L. paracasei F08, and L. plantarum C06 could grow rapidly in milk without nutrient supplementation and reached 108 cfu/mL after 24 h of fermentation at 37 degrees C. The viable cell counts of the 3 strains remained above 107 cfu/mL after 21 d of storage at 4 degrees C. In the animal feeding trial, the number of intestinal lactobacilli increased significantly after administration of milk fermented with the 3 strains, and the counts of fecal coliforms and Clostridium perfringens were markedly reduced. Lactobacillus strains could also survive in the ileal intestinal tissue of the treated rats. Technologically interesting Lactobacillus isolates may be used in the future as probiotic starter cultures for manufacturing novel fermented foods. PMID- 20951816 TI - Anaerobe/aerobe environmental flux determines protein expression profiles of Bacteroides fragilis, a redox pathogen. AB - The oxidation-reduction (redox) of the environment characterizes the Bacteroides fragilis pathogenic potential. Previously, using 3D confocal laser scanning microscopy, the bacteria prepared from cultures grown under oxidizing conditions (Eh(7)ca. + 100 mV) were able to penetrate into Hela cell monolayers. In contrast, when grown under reducing conditions (Eh(7)ca. - 60 mV), there were no bacteria evident within Hela cells. The influence of the anaerobe/aerobe environmental flux during the process of the anaerobe infection could be significant. In B. fragilis peritonitis, this may depend on the occurrence of aerobiosis as opposed to anaerobiosis. To this end, three clinical B. fragilis strains, two infectious and one non-infectious, were grown under oxidizing and reducing conditions; then, the outer membrane protein expressions derived from these strains were assessed, following sarcosyl extraction and SDS-PAGE. The differences between the protein profiles from these strains when cultured under oxidizing and reducing conditions were found to be statistically significant for the two infectious strains, but not for the non-infectious strain. OMP profiles under aerobic conditions compared to anaerobic conditions exhibited products with a range of apparent molecular weights suggestive of unique participation in the interaction with the host cell. PMID- 20951817 TI - 5-azacytidine as salvage treatment in relapsed myeloid tumors after allogeneic bone marrow transplantation. AB - Relapse after allogeneic blood or marrow transplantation carries a very poor prognosis. Current strategies for management that include donor lymphocyte infusions (DLIs) and salvage chemotherapies are usually toxic and ineffective. Here we report the outcome of 10 patients with myeloid malignancies that received 5-azacytidine after a failed allogeneic bone marrow transplant. Of the 10 patients, 6 achieved a complete remission, 1 had stable disease, and 3 progressed after a median of 6 cycles administered. Only 1 patient has died (of disease progression), and no flares of graft-versus-host disease (GVHD) were observed with 5-azacytidine. As of latest follow-up, the median overall survival (OS) for the group was 422.5 days (127-1411). These results further suggest that 5 azacytidine is an active agent after failing an allogeneic bone marrow transplant, and prospective studies are warranted. PMID- 20951818 TI - 25-hydroxy vitamin D deficiency following pediatric hematopoietic stem cell transplant. AB - Children may be at increased risk for vitamin D deficiency following HSCT because of lack of sun exposure, the recommended use of sunscreen, dietary insufficiency, malabsorption, and the use of certain medications. We prospectively assessed the prevalence of and risk factors for 25-hydroxy (25-OH) vitamin D deficiency in 67 patients transplanted at our institution. 25-OH vitamin D levels were checked during 3 separate 4-week periods in the spring, autumn, and winter. Subjects were <2 years following transplant and/or being treated for chronic graft-versus-host disease (cGVHD). Levels less than 20 ng/mL were considered deficient, and those less than 30 ng/mL were considered insufficient. The mean 25-OH vitamin D level was 22.8 ng/mL (range: 7-46.2). A total of 80.6% (confidence interval [CI] 69.1% 89.3%) of patients had a level less than the lower limit of the institutional normal range. The deficiency rate was 37.3% (CI 25.8%-50%). The mean parathyroid hormone (PTH) level was 77.5 (SD = 80.5). There was no correlation between 25-OH vitamin D and PTH levels. We evaluated potential risk factors for 25-OH vitamin D deficiency including age, season of testing, sun exposure, sunscreen use, use of steroid or calcineurin inhibitor, race, and dairy intake. In multivariate logistic regression, only older age was found to be a risk factor for deficiency (P = .004). Patients with deficient levels were treated with 50,000 IU of ergocalciferol once weekly for 6 weeks. A postrepletion 25-OH level was available for 22 patients. The majority of repleted patients had a normal posttreatment level (63.6%). The postsupplementation level corrected into the insufficient range for 31.8% of patients and 4.6% remained deficient. Vitamin D insufficiency and deficiency are common following HSCT. Further investigation into potential risk factors and the appropriate supplementation for these patients is warranted. PMID- 20951819 TI - Donor cell leukemia: a review. AB - Relapse of acute leukemia following hematopoietic stem cell transplantation (HSCT) usually represents return of an original disease clone, having evaded eradication by pretransplant chemo-/radiotherapy, conditioning, or posttransplant graft-versus-leukemia (GVL) effect. Rarely, acute leukemia can develop de novo in engrafted cells of donor origin. Donor cell leukemia (DCL) was first recognized in 1971, but for many years, the paucity of reported cases suggested it to be a rare phenomenon. However, in recent years, an upsurge in reported cases (in parallel with advances in molecular chimerism monitoring) suggest that it may be significantly more common than previously appreciated; emerging evidence suggests that DCL might represent up to 5% of all posttransplant leukemia "relapses." Recognition of DCL is important for several reasons. Donor-derivation of the leukemic clone has implications when selecting appropriate therapy, because seeking to enhance an allogeneic GVL effect would intuitively not have the same role as in standard recipient-derived relapses. There are also broader implications for donor selection and workup, particularly given the growing popularity of nonmyeloblative HSCT and corresponding rising age of the potential donor pool. Identification of DCL raises potential concerns over future health of the donor, posing ethical dilemmas regarding responsibilities toward donor notification (particularly in the context of cord blood transplantation). The entity of DCL is also of research interest, because it might provide a unique human model for studying the mechanisms of leukemogenesis in vivo. This review presents and collates all reported cases of DCL, and discusses the various strategies, controversies, and pitfalls when investigating origin of posttransplant relapse. Putative etiologic factors and mechanisms are proposed, and attempts made to address the difficult ethical questions posed by discovery of donor-derived malignancy within a HSCT recipient. PMID- 20951820 TI - Eighth Annual International Umbilical Cord Blood Transplantation Symposium, San Francisco, California, June 3-5, 2010. PMID- 20951821 TI - Novel cord blood transplant therapies. PMID- 20951822 TI - Lead genetic studies in Dictyostelium discoideum and translational studies in human cells demonstrate that sphingolipids are key regulators of sensitivity to cisplatin and other anticancer drugs. AB - A Dictyostelium discoideum mutant with a disruption in the sphingosine-1 phosphate (S-1-P) lyase gene was obtained in an unbiased genetic analysis, using random insertional mutagenesis, for mutants with increased resistance to the widely used cancer chemotherapeutic drug cisplatin. This finding opened the way to extensive studies in both D. discoideum and human cells on the role and mechanism of action of the bioactive sphingolipids S-1-P and ceramide in regulating the response to chemotherapeutic drugs. These studies showed that the levels of activities of the sphingolipid metabolizing enzymes S-1-P lyase, sphingosine kinase and ceramide synthase, affect whether a cell dies or lives in the presence of specific drugs. The demonstration that multiple enzymes of this biochemical pathway were involved in regulating drug sensitivity provided new opportunities to test whether pharmacological intervention might increase sensitivity. Thus it is of considerable clinical significance that pharmacological inhibition of sphingosine kinase synergistically sensitizes cells to cisplatin, both in D. discoideum and human cells. Linkage to the p38 MAP kinase and protein kinase C (PKC) signaling pathways has been demonstrated. This work demonstrates the utility of D. discoideum as a lead genetic system to interrogate molecular mechanisms controlling the sensitivity of tumor cells to chemotherapeutic agents and for determining novel ways of increasing efficacy. The D. discoideum system could be easily adapted to a high throughput screen for novel chemotherapeutic agents. PMID- 20951823 TI - GTPases involved in vesicular trafficking: structures and mechanisms. AB - Several types of GTPases play important roles in intracellular vesicular transport. These include the Rab and Arf families of the Ras superfamily, which are key regulators of several steps in the overall process. The basic structural and mechanistic properties of these proteins and their interactions with partner proteins and membranes are reviewed and compared in this article. PMID- 20951825 TI - STAT3 in tissue fibrosis: is there a role in the lung? AB - Fibrosis is defined as an excessive deposition of connective tissue components that results in the destruction of normal tissue architecture and compromises organ function. When fibrosis occurs in the major organs such as the lung, for example in idiopathic pulmonary fibrosis, it inevitably leads to organ failure and premature death of the afflicted individual. Current evidence suggests that fibrosis initially develops along the same pathway as normal wound healing, although there is chronic progression of the disease without resolution, suggesting the control of intracellular processes that occur during wound healing is disturbed. It follows then that determining where this control is lost is key to preventing and treating this condition. The IL-6 cytokine family is a group of pleiotropic cytokines produced by a variety of cells in response to inflammatory stimuli. These cytokines are grouped together on the basis of overlapping functions, and common usage of gp130 as part of their multimeric receptor complexes. Activation of these receptor complexes results in the recruitment and phosphorylation of the latent transcription factor STAT-3 which induces a gene program involved in cell differentiation and proliferation. STAT3 also induces expression of a number of inhibitors including SOCS-3. In this manuscript we review the available literature on the IL-6/gp-130 family of cytokines and their role in regulating fibrosis. Despite a large number of studies in mouse models as well as human cells in vitro, the role of these cytokines or STAT3 activated by other cytokines in the development of fibrosis remains unclear. PMID- 20951826 TI - Metabolic physiology in age related macular degeneration. AB - Ischemia and hypoxia have been implicated in the pathophysiology of age related macular degeneration (AMD). This has mostly been based on studies on choroidal perfusion, which is not the only contributor to retinal hypoxia found in AMD eyes. Other features of AMD may also interfere with retinal oxygen metabolism including confluent drusen, serous or hemorrhagic retinal detachment, retinal edema and vitreoretinal adhesion. Each of these features contributes to retinal hypoxia: the drusen and retinal elevation by increasing the distance between the choriocapillaris and retina; vitreoretinal adhesion by reducing diffusion and convection of oxygen towards and vascular endothelial growth factor (VEGF) away from hypoxic retinal areas. Hypoxia-inducible-factor is known to exist in subretinal neovascularization and hypoxia is the main stimulus for the production of VEGF. Each feature may not by itself create enough hypoxia and VEGF accumulation to stimulate wet AMD, but they may combine to do so. Choroidal ischemia in AMD has been demonstrated by many researchers, using different technologies. Choroidal ischemia obviously decreases oxygen delivery to the outer retina. Confluent drusen, thickening of Bruch's membrane and any detachment of retina or retinal pigment epithelium, increases the distance between the choriocapillaris and the retina and thereby reduces the oxygen flux from the choroid to the outer retina according to Fick's law of diffusion. Retinal elevation and choroidal ischemia may combine forces to reduce choroidal oxygen delivery to the outer retina, produce retinal hypoxia. Hypoxia leads to production of VEGF leading to neovascularization and tissue edema. A vicious cycle may develop, where VEGF production increases effusion, retinal detachment and edema, further increasing hypoxia and VEGF production. Adhesion of the viscous posterior vitreous cortex to the retina maintains a barrier to diffusion and convection currents in the vitreous cavity according to the laws of Fick's, Stokes-Einstein and Hagen-Poiseuille. If the vitreous is detached from the surface of the retina, the low viscosity fluid transports oxygen and nutrients towards an ischemic area of the retina, and cytokines away from the retina, at a faster rate than through attached vitreous gel. Vitreoretinal adhesion can exacerbate retinal hypoxia and accumulation of cytokines, such as VEGF. Vitreoretinal traction can also cause hypoxia by retinal elevation. Conceivably, the basic features of AMD, drusen, choroidal ischemia, and vitreoretinal adhesion are independently determined by genetics and environment and may combine in variable proportions. If the resulting hypoxia and consequent VEGF accumulation crosses a threshold, this will trigger effusion and neovascularization. PMID- 20951824 TI - Acute effect of a high nitrate diet on brain perfusion in older adults. AB - AIMS: Poor blood flow and hypoxia/ischemia contribute to many disease states and may also be a factor in the decline of physical and cognitive function in aging. Nitrite has been discovered to be a vasodilator that is preferentially harnessed in hypoxia. Thus, both infused and inhaled nitrite are being studied as therapeutic agents for a variety of diseases. In addition, nitrite derived from nitrate in the diet has been shown to decrease blood pressure and improve exercise performance. Thus, dietary nitrate may also be important when increased blood flow in hypoxic or ischemic areas is indicated. These conditions could include age-associated dementia and cognitive decline. The goal of this study was to determine if dietary nitrate would increase cerebral blood flow in older adults. METHODS AND RESULTS: In this investigation we administered a high vs. low nitrate diet to older adults (74.7+/-6.9 years) and measured cerebral perfusion using arterial spin labeling magnetic resonance imaging. We found that the high nitrate diet did not alter global cerebral perfusion, but did lead to increased regional cerebral perfusion in frontal lobe white matter, especially between the dorsolateral prefrontal cortex and anterior cingulate cortex. CONCLUSION: These results suggest that dietary nitrate may be useful in improving regional brain perfusion in older adults in critical brain areas known to be involved in executive functioning. PMID- 20951827 TI - Calcium- and integrin-binding protein 1 regulates microtubule organization and centrosome segregation through polo like kinase 3 during cell cycle progression. AB - Polo-like kinases (Plks) are a family of serine/threonine protein kinases that are involved in the regulation of the various stages of the cell cycle. Plk2 and Plk3, two members of this family, are known to interact with calcium- and integrin-binding protein 1 (CIB1). Activity of both Plk2 and Plk3 is inhibited by CIB1 in a calcium-dependent manner. However, the physiological consequences of this inhibition are not known. Here, we show that overexpression of CIB1 inhibits T47D cell proliferation. Overexpression of CIB1 or knockdown of Plk3 using shRNA produced a multinucleated phenotype in T47D cells. This phenotype was not cancer cell specific, since it also occurred in normal cells. The cells overexpressing CIB1 appear to undergo proper nuclear division, but are unable to complete the process of cytokinesis, thus forming large multinucleated cells. Both CIB1 overexpression and Plk3 knockdown disrupted microtubule organization and centrosomal segregation, which may have led to incomplete cytokinesis. The observed effect of CIB1 overexpression is not due to the inhibition of Plk2 by CIB1. Plk3 and CIB1 both colocalize at the centrosomes, however, localization of CIB1 is dependent on the expression of Plk3. Furthermore, expression of Plk3 blocks the multinucleated phenotype induced by expression of CIB1 in these cells. These results suggest that CIB1 tightly regulates Plk3 activity during cell division and that either over- or underexpression results in a multinucleated phenotype. PMID- 20951828 TI - Per arborem ad astra: morphological adaptations to exploiting the woody habitat in the early evolution of Hymenoptera. AB - We survey morphological features of larval and adult wasps that undergo their entire larval development inside wood and interpret them in view of the lifestyle. The evolution of some of the characters is explored by mapping them on a recently published phylogeny of Hymenoptera. Based on this phylogeny, it is reasonable to assume that wood-living wasps evolved from a xylophagous/mycetophagous stage as displayed by woodwasps to a carnivorous/parasitoid lifestyle, preying on woodboring insect larvae. The latter mode of life is probably ancestral to the Apocrita which comprise the majority of the order; they share this lifestyle with their sister group, the Orussidae. However, most apocritan wasps have radiated into other habitats, the Orussidae and Stephanidae apparently being the only taxa that have retained the ancestral lifestyle of carnivorous wasps. Other apocritan lineages associated with wood (e.g., Aulacidae, Megalyridae, basal Cynipoidea and some Ichneumonoidea and Chalcidoidea) possibly entered this habitat secondarily and independently acquired morphological traits associated with it. The woody habitat was occupied by Hymenoptera during a crucial stage in their evolution where the transition from the phytophagous to carnivorous lifestyle took place. The anatomy of both larva and adults was extensively transformed in the process. PMID- 20951829 TI - Outpatient physician billing data for age and setting specific syndromic surveillance of influenza-like illnesses. AB - Syndromic surveillance is a novel automated approach to monitoring influenza activity, but there is no consensus regarding the most informative data sources for use within such a system. By comparing physician billing data from Quebec, Canada and hospital admission records, we assessed the timeliness of medical visits for influenza-like illnesses (ILI) to two types of outpatient healthcare settings. Overall, ILI visits by children aged 5-17 years at community-based settings were the most strongly correlated with hospital admissions and gave the greatest lead over hospital admissions. However, a degree of year-to-year variation suggests that syndromic surveillance of influenza should not focus on just a single subgroup. These findings reveal the richness of these real-time data for epidemic monitoring and demonstrate the flexibility of syndromic surveillance. By using real-time data, an evolving epidemic can be rapidly characterized by its epidemiological patterns, which is not possible with traditional surveillance systems. PMID- 20951830 TI - Safety for patients with celiac disease of baked goods made of wheat flour hydrolyzed during food processing. AB - BACKGROUND & AIMS: Celiac disease (CD) is characterized by an inflammatory response to wheat gluten, rye, and barley proteins. Fermentation of wheat flour with sourdough lactobacilli and fungal proteases decreases the concentration of gluten. We evaluated the safety of daily administration of baked goods made from this hydrolyzed form of wheat flour to patients with CD. METHODS: Patients were randomly assigned to consumption of 200 g per day of natural flour baked goods (NFBG) (80,127 ppm gluten; n = 6), extensively hydrolyzed flour baked goods (S1BG) (2480 ppm residual gluten; n = 2), or fully hydrolyzed baked goods (S2BG) (8 ppm residual gluten; n = 5) for 60 days. RESULTS: Two of the 6 patients who consumed NFBG discontinued the challenge because of symptoms; all had increased levels of anti-tissue transglutaminase (tTG) antibodies and small bowel deterioration. The 2 patients who ate the S1BG goods had no clinical complaints but developed subtotal atrophy. The 5 patients who ate the S2BG had no clinical complaints; their levels of anti-tTG antibodies did not increase, and their Marsh grades of small intestinal mucosa did not change. CONCLUSIONS: A 60-day diet of baked goods made from hydrolyzed wheat flour, manufactured with sourdough lactobacilli and fungal proteases, was not toxic to patients with CD. A combined analysis of serologic, morphometric, and immunohistochemical parameters is the most accurate method to assess new therapies for this disorder. PMID- 20951831 TI - Colonoscopy and diminutive polyps: hot or cold biopsy or snare? Do I send to pathology? PMID- 20951832 TI - Evidence of persistent cognitive impairment after resolution of overt hepatic encephalopathy. AB - BACKGROUND & AIMS: The Inhibitory Control Test has been proposed as a tool to detect the persistence of cognitive defects after the resolution of overt hepatic encephalopathy (OHE). We tested learning abilities of cirrhotic patients using the Psychometric Hepatic Encephalopathy Score (PHES). METHODS: One hundred six cirrhotic patients who agreed to be examined twice within 3 days were studied using the PHES. Twenty-seven patients had previous OHE; of the remaining 79 patients, 34 were affected by minimal HE and 45 were normal. RESULTS: Among patients without previous OHE, PHESs significantly improved at the second examination; this learning effect was present in the patients with or without minimal HE. To the contrary, learning ability was lost in patients with previous OHE. Even among the 8 patients with history of HE and normal PHESs in the first examination, repeated testing showed a lack of learning capacity. CONCLUSIONS: HE is not a fully reversible condition. Residual cognitive impairments should be evaluated by specific tests, based on patients' learning capacities. PMID- 20951833 TI - Percutaneous cholecystostomy as a bridge to definitive endoscopic gallbladder stent placement. AB - BACKGROUND & AIMS: Percutaneous cholecystostomy (PC) is an effective treatment for acute cholecystitis (AC) in patients who are poor surgical candidates, although it is generally used as a bridge to cholecystectomy, given its long-term risks, the need for repeated procedures, and patient dissatisfaction. Ongoing patient comorbidity, however, might preclude cholecystectomy after recovery from the acute illness. METHODS: Four patients with AC who were poor immediate and long-term candidates for cholecystectomy underwent PC as primary therapy for AC, followed by endoscopic placement of a transpapillary gallbladder stent as definitive long-term management. RESULTS: All 4 patients were successfully treated for AC with PC. After recovery, the patients underwent endoscopic gallbladder stent placement and removal of the PC. In 2 cases, endoscopic transpapillary access to the gallbladder was facilitated by advancing a guidewire through the cholecystostomy tract into the duodenum. All patients had favorable outcomes. CONCLUSIONS: PC as a bridge to permanent therapy with endoscopic gallbladder stenting appears to be a viable strategy in the management of patients with AC who are poor immediate and long-term candidates for cholecystectomy. PMID- 20951834 TI - To B(iopsy) or not to B(iopsy) .... PMID- 20951835 TI - Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease. AB - BACKGROUND & AIMS: Few data are available on effects of biologic therapies in patients more than 65 years old with inflammatory bowel disease (IBD). We evaluated the risk and benefits of therapy with tumor necrosis factor (TNF) inhibitors in these patients. METHODS: We collected data from patients with IBD treated with infliximab (n = 2475) and adalimumab (n = 604) from 2000 to 2009 at 16 tertiary centers. Ninety-five patients (3%) were more than 65 years old (52 men; 37 with ulcerative colitis and 58 with Crohn's disease; 78 treated with infliximab and 17 with adalimumab). The control group comprised 190 patients 65 years old or younger who were treated with both biologics and 190 patients older than 65 years who were treated with other drugs. The primary end points were severe infection, cancer, or death. RESULTS: Among patients more than 65 years old who received infliximab and adalimumab, 11% developed severe infections, 3% developed neoplasms, and 10% died. No variable was associated with severe infection or death. Among control patients more than 65 years old, 0.5% developed severe infections, 2% developed cancer, and 2% died. Among control patients less than 65 years old, 2.6% developed severe infections, none developed tumors, and 1% died. CONCLUSIONS: Patients older than 65 years treated with TNF inhibitors for IBD have a high rate of severe infections and mortality compared with younger patients or patients of the same age that did not receive these therapeutics. The effects of anti-TNF agents in older patients with IBD should be more thoroughly investigated, because these patients have higher mortality related to hospitalization than younger patients. PMID- 20951836 TI - Wegener's granulomatosis presenting with colonic ulcerations. PMID- 20951837 TI - Image of the month. Asymptomatic dilatation of the intrahepatic biliary tree due to thrombosed pericholedochal varices (portal biliopathy). PMID- 20951838 TI - Epidemiology, mechanisms, and management of diabetic gastroparesis. AB - Recent evidence of the significant impact of gastroparesis on morbidity and mortality mandates optimized management of this condition. Gastroparesis affects nutritional state, and in diabetics it has deleterious effects on glycemic control and secondary effects on organs that increase mortality. First-line treatments include restoration of nutrition and medications (prokinetic and antiemetic). We review the epidemiology, pathophysiology, impact, natural history, time trends, and treatment of gastroparesis, focusing on diabetic gastroparesis. We discuss pros and cons of current treatment options, including metoclopramide. Second-line therapeutic approaches include surgery, venting gastrostomy or jejunostomy, and gastric electrical stimulation; most of these were developed based on results from open-label trials. New therapeutic strategies for gastroparesis include drugs that target the underlying defects, prokinetic agents such as 5-hydroxytryptamine agonists that do not appear to have cardiac or vascular effects, ghrelin agonists, approaches to pace the stomach, and stem cell therapies. PMID- 20951839 TI - Early adenocarcinoma of the esophagus - clinical relevance of depth of infiltration into the submucosa. PMID- 20951840 TI - A novel algorithm to define infection tendencies in H1N1 cases in Mainland China. AB - Incidences of H1N1 viral infections in Mainland China are collected by the Ministry of Health, the People's Republic of China. The number of confirmed cases and the timing of these outbreaks from May 13 to July 22, 2009 were obtained and subjected to a novel mathematical model to simulate the infection profile (time vs number). The model was predicated upon the grey prediction theory which allows assignment of future trends using limited numbers of data points. During the period of our analysis, the number of confirmed H1N1 cases in Mainland China increased from 1 to 1772. The efficiency of our model to simulate these data points was evaluated using Sum of squares of error (SSE), Relative standard error (RSE), Mean absolute deviation (MAD) and Average relative error (ARE). Results from these analyses were compared to similar calculations based upon the grey prediction algorithm. Using our equation, defined herein as equation D-R, results showed that SSE=6742.00, RSE=10.69, MAD=7.07, ARE=2.47% were all consistent with the D-R algorithm performing well in the estimation of future trends of H1N1 cases in Mainland China. Calculations using the grey theory had no predictive value [ARE for GM(1,1)=-104.63%]. To validate this algorithm, we performed a second analysis using new data obtained from cases reported to the WHO and CDC in the US between April 26 and June 8, 2009. In like manner, the model was equally predictive. The success of the D-R mathematical model suggests that it may have broader application to other viral infections among the human population in China and may be modified for application to other regions of the world. PMID- 20951841 TI - Molecular characterization of the Hepatitis B virus genotypes in Colombia: a Bayesian inference on the genotype F. AB - Hepatitis B is a worldwide health problem affecting about 2 billion people and more than 350 million are chronic carriers of the virus. Nine HBV genotypes (A to I) have been described. The geographical distribution of HBV genotypes is not completely understood due to the limited number of samples from some parts of the world. One such example is Colombia, in which few studies have described the HBV genotypes. In this study, we characterized HBV genotypes in 143 HBsAg-positive volunteer blood donors from Colombia. A fragment of 1306 bp partially comprising HBsAg and the DNA polymerase coding regions (S/POL) was amplified and sequenced. Bayesian phylogenetic analyses were conducted using the Markov Chain Monte Carlo (MCMC) approach to obtain the maximum clade credibility (MCC) tree using BEAST v.1.5.3. Of all samples, 68 were positive and 52 were successfully sequenced. Genotype F was the most prevalent in this population (77%) - subgenotypes F3 (75%) and F1b (2%). Genotype G (7.7%) and subgenotype A2 (15.3%) were also found. Genotype G sequence analysis suggests distinct introductions of this genotype in the country. Furthermore, we estimated the time of the most recent common ancestor (TMRCA) for each HBV/F subgenotype and also for Colombian F3 sequences using two different datasets: (i) 77 sequences comprising 1306 bp of S/POL region and (ii) 283 sequences comprising 681 bp of S/POL region. We also used two other previously estimated evolutionary rates: (i) 2.60 * 10(-4)s/s/y and (ii) 1.5 * 10(-5)s/s/y. Here we report the HBV genotypes circulating in Colombia and estimated the TMRCA for the four different subgenotypes of genotype F. PMID- 20951842 TI - Lattice strains and load partitioning in bovine trabecular bone. AB - Microdamage and failure mechanisms have been well characterized in bovine trabecular bone. However, little is known about how elastic strains develop in the apatite crystals of the trabecular struts and their relationship with different deformation mechanisms. In this study, wide-angle high-energy synchrotron X-ray diffraction has been used to determine bulk elastic strains under in situ compression. Dehydrated bone is compared to hydrated bone in terms of their response to load. During compression, load is initially borne by trabeculae aligned parallel to loading direction with non-parallel trabeculae deforming by bending. Ineffective load partitioning is noted in dehydrated bone whereas hydrated bone behaves like a plastically yielding foam. PMID- 20951843 TI - Preparation of 3-D scaffolds in the SiO2-P2O5 system with tailored hierarchical meso-macroporosity. AB - Herein we report for the first time the synthesis of three-dimensional scaffolds in the binary system SiO2-P2O5 exhibiting different scales of porosity: (i) highly ordered mesopores with diameters of ca. 4 nm; (ii) macropores with diameters in the 30-80 MUm range with interconnections of ca. 2-4 and 8-9 MUm; and (iii) ultra-large macropores of ca. 400 MUm. The hierarchical porosity of the resulting scaffolds makes them suitable for bone tissue engineering applications. The chemical nature and mesoporosity of these matrices would allow these scaffolds to act as local controlled delivery systems of biologically active molecules, such as certain drugs to treat bone pathologies. The synthetic method consists of the combination of a single-step sol-gel route in the presence of a surfactant as the mesostructure directing agent and a biomacromolecular polymer such as methylcellulose as the macrostructure template followed by rapid prototyping technique. An exhaustive study of the aging process as well as of the rheological properties of the slurry after methylcellulose addition has been carried out to obtain hierarchical meso-macroporosity. This study allows the establishment of the time period in which the slurry presents appropriate viscosity to be extruded during the rapid prototyping once the ink is prepared. The setting up of this manufacture process at the laboratory level is important from the industrial point of view when the large-scale production of scaffolds for bone tissue repair and regeneration is targeted. PMID- 20951844 TI - Intussusception in adults: institutional review. AB - OBJECTIVE: The objectives were to review adult intussusception (AI), its diagnosis and treatment. BACKGROUND DATA: Intussusception is a different entity in adults than it is in children. AI represents 1% of all bowel obstructions, 5% of all intussusceptions. METHODS: The records of all patients, 18 years and older, with the postoperative diagnosis of intussusception at the B.P.K.I.H.S during the years 2003-2009 were reviewed retrospectively. RESULTS: In six years, there were thirty-eight patients of surgically proven AI. The patients' mean age was 49.6 years, M:F ratio was 1.3:1. Intestinal obstructions of various extents were the commonest presentation in twenty-seven patients (71%). There were 42% enteric, 32% ileocolic and 26% colonic AI. The diagnostic accuracy of the ultrasonography was 78.5%, CT scan was 90% and colonoscopy was 100%. The pathological lesions were found in 94% of AI. Among the pathological lesion, enteric have 62% benign, 38% malignant, ileocolic have 50% benign, 50% malignant, and in colocolic 70% malignant, 30% benign. In enteric AI, 68% were reduced successfully, 25% reduction was not attempted. Of ileocolic AI, 58.3% were reduced successfully, 41.6% had resection without reduction. Of colocolic AI, 30% of them were reduced successfully before resection, 70% had resection without reduction. CONCLUSIONS: AI is a rare entity and requires a high index of suspicion. CT scanning proved to be the most useful diagnostic radiologic method. Colonoscopy is most accurate in ileocolic and colonic AI. The treatment of adult intussusception is surgical. Our review supports that small-bowel intussusception should be reduced before resection if the underlying etiology is suspected to be benign or if the resection required without reduction is deemed to be massive. Large bowel should generally be resected without reduction because pathology is mostly malignant. PMID- 20951845 TI - New cases and refinement of the critical region in the 1q41q42 microdeletion syndrome. AB - Microdeletions of 1q41q42 have recently been classified as a syndrome. Features include significant developmental delay and characteristic dysmorphic features as well as cleft palate, clubfeet, seizures, and short stature in some individuals, with a clinical diagnosis of Fryns syndrome in two individuals with congenital diaphragmatic hernia at the severe end of the spectrum. The gene DISP1, which is involved in sonic hedgehog signaling, has been proposed as a candidate for the midline defects in this syndrome. We undertook a genotype-phenotype analysis of seven previously unreported individuals with deletions of 1q41q42 that range from 777 kb to 6.87 Mb. Three of the individuals in our cohort do not display the major features of the syndrome and have more proximal deletions that only overlap with the previously described 1q41q42 smallest region of overlap (SRO) at DISP1. One individual with several features of the syndrome has a more distal deletion that excludes DISP1. The three remaining individuals have larger deletions that include the entire SRO and demonstrate features of the microdeletion syndrome. Confounding genotype-phenotype correlations, one of the small deletions involving DISP1 was inherited from a phenotypically normal parent. DISP1 haploinsufficiency may not be solely responsible for the major features of 1q41q42 microdeletion syndrome, and other genes in the SRO likely play a role in the phenotype. Additionally, some features present in a minority of individuals, such as Pelger Huet anomaly, may be attributed to deletions of genes outside of the SRO. PMID- 20951846 TI - "4D Biology for health and disease" workshop report. AB - The "4D Biology Workshop for Health and Disease", held on 16-17th of March 2010 in Brussels, aimed at finding the best organising principles for large-scale proteomics, interactomics and structural genomics/biology initiatives, and setting the vision for future high-throughput research and large-scale data gathering in biological and medical science. Major conclusions of the workshop include the following. (i) Development of new technologies and approaches to data analysis is crucial. Biophysical methods should be developed that span a broad range of time/spatial resolution and characterise structures and kinetics of interactions. Mathematics, physics, computational and engineering tools need to be used more in biology and new tools need to be developed. (ii) Database efforts need to focus on improved definitions of ontologies and standards so that system scale data and associated metadata can be understood and shared efficiently. (iii) Research infrastructures should play a key role in fostering multidisciplinary research, maximising knowledge exchange between disciplines and facilitating access to diverse technologies. (iv) Understanding disease on a molecular level is crucial. System approaches may represent a new paradigm in the search for biomarkers and new targets in human disease. (v) Appropriate education and training should be provided to help efficient exchange of knowledge between theoreticians, experimental biologists and clinicians. These conclusions provide a strong basis for creating major possibilities in advancing research and clinical applications towards personalised medicine. PMID- 20951847 TI - Production of diacylglycerols from glycerol monooleate and ethyl oleate through free and immobilized lipase-catalyzed consecutive reactions. AB - The ability of free and immobilized lipase on the production of diacylglycerols (DAG) by transesterification of glycerol monooleate (GMO) and ethyl oleate was investigated. Among three free lipases such as lipase G (Penicillium cyclopium), lipase AK (Pseudomonas fluorescens) and lipase PS (Pseudomonas cepacia), lipase PS exhibited the highest DAG productivity, and the DAG content gradually increased up to 24 hours reaction and then remained steady. The comparative result for DAG productivity between free lipase PS and immobilized lipases (lipase PS-D and Lipozyme RM IM) during nine times of 24 hours reaction indicated that total DAG production was higher in immobilized lipase PS-D (183.5mM) and Lipozyme RM IM (309.5mM) than free lipase PS (122.0mM) at the first reaction, and that the DAG production rate was reduced by consecutive reactions, in which more sn-1,3-DAG was synthesized than sn-1,2-DAG. During the consecutive reactions, the activity of lipase PS was relatively steady by showing similar DAG content, whereas DAG production of lipase PS-D and Lipozyme RM IM was gradually decreased to 69.9 and 167.1mM at 9th reaction, respectively, resulting in 62% and 46% reduced production when compared with 1st reaction. Interestingly, from 7th reaction lipase PS produced more DAG than immobilized lipase PS-D, and exhibited a stable activity for DAG production. Therefore, the present study suggested that DAG productivity between GMO and ethyl oleate was higher in immobilized lipases than free lipases, but the activity was reduced with repeated uses. PMID- 20951848 TI - Identification of diacylglycerol and triacylglycerol containing 11,12,13 trihydroxy-9,14-octadecadienoic acid in castor oil. AB - Castor oil has many industrial uses. Molecular species of acylglycerols containing monohydroxy, dihydroxy and trihydroxy fatty acids in castor oil have been reported. We report here the identification of acylglycerols containing a triOH18:2 fatty acid in castor oil. The structure of this novel fatty acid was proposed as 11,12,13-trihydroxy-9,14-octadecadienoic acid by the mass spectrometry of the lithiated adducts of acylglycerols in the HPLC fractions of castor oil. The fragmentation pathways of the lithiated adduct of 11,12,13 trihydroxy-9,14-octadecadienoic acid were proposed. We also proposed the biosynthetic pathways of polyhydroxy fatty acids in castor. PMID- 20951849 TI - MacroRNA underdogs in a microRNA world: evolutionary, regulatory, and biomedical significance of mammalian long non-protein-coding RNA. AB - The central dogma of molecular biology relegates RNAs to the role of "messengers" of genetic information, with proteins as the end products that perform key roles as regulators and effectors of biological processes. Notable exceptions include non-protein-coding RNAs, which function as adaptors (tRNAs) and ribosomal components (rRNAs) during translation, as well as in splicing (snRNAs) and RNA maturation including editing (snoRNAs). Genome and transcriptome projects have revealed, however, a significant number, rivaling the protein-coding transcripts, of non-protein-coding RNAs not related to these previously characterized transcript classes. Non-protein-coding RNA research has primarily focused on microRNAs, a small subclass of non-protein-coding RNAs, and their regulatory roles in gene expression, and these findings have been reviewed extensively. Here, we turn our attention to the larger, in number and size, long non-coding RNAs (lncRNAs), and review their evolutionary complexity and the growing evidence for their diverse mechanisms of action and functional roles in basic molecular and cellular biology and in human disease. In contrast to the focus on in-silico and expression studies in existing lncRNA literature, we emphasize direct evidence for lncRNA function, presenting experimental approaches and strategies for systematic characterization of lncRNA activities, with applications to known gene regulatory networks and diseases. PMID- 20951850 TI - Contrast-enhanced micro-computed tomography of fatigue microdamage accumulation in human cortical bone. AB - Conventional methods used to image and quantify microdamage accumulation in bone are limited to histological sections, which are inherently invasive, destructive, two-dimensional, and tedious. These limitations inhibit investigation of microdamage accumulation with respect to volumetric spatial variation in mechanical loading, bone mineral density, and microarchitecture. Therefore, the objective of this study was to investigate non-destructive, three-dimensional (3 D) detection of microdamage accumulation in human cortical bone using contrast enhanced micro-computed tomography (micro-CT), and to validate micro-CT measurements against conventional histological methods. Unloaded controls and specimens loaded in cyclic uniaxial tension to a 5% and 10% reduction in secant modulus were labeled with a precipitated BaSO4 stain for micro-CT and basic fuchsin for histomorphometry. Linear microcracks were similarly labeled by BaSO4 and basic fuchsin as shown by backscattered electron microscopy and light microscopy, respectively. The higher X-ray attenuation of BaSO4 relative to the bone extracellular matrix provided enhanced contrast for the detection of damage that was otherwise not able to be detected by micro-CT prior to staining. Therefore, contrast-enhanced micro-CT was able to nondestructively detect the presence, 3-D spatial location, and accumulation of fatigue microdamage in human cortical bone specimens in vitro. Microdamage accumulation was quantified on segmented micro-CT reconstructions as the ratio of BaSO4 stain volume (SV) to total bone volume (BV). The amount of microdamage measured by both micro-CT (SV/BV) and histomorphometry (Cr.N, Cr.Dn, Cr.S.Dn) progressively increased from unloaded controls to specimens loaded to a 5% and 10% reduction in secant modulus (p < 0.001). Group means for micro-CT measurements of damage accumulation were strongly correlated to those using histomorphometry (p < 0.05), validating the new methods. Limitations of the new methods in the present study included that the precipitated BaSO4 stain was non-specific and non-biocompatible, and that micro-CT measurements exhibited greater variability compared to conventional histology. Nonetheless, contrast-enhanced micro-CT enabled non-destructive imaging and 3-D spatial information, which are not possible using conventional histological methods. PMID- 20951851 TI - Rapid ultraviolet monitoring of multiple psychotropic drugs with a renewable microfluidic device. AB - A rapid method for sensitive ultraviolet detection of multiple psychotropic drugs in human plasma was developed on a low-cost and expediently fabricated hybrid microfluidic device. The device was composed of one fused-silica capillary with a sampling fracture, a poly(methyl methacrylate) board with four reservoirs, and a printed circuit board. At the optimal separation and detection conditions, the baseline separation of three kinds of psychotropic drugs including barbiturates (phenobarbital and barbital), benzodiazepines (nitrazepam, clonazepam, chlordiazepoxide, alprazolam and diazepam) and tricyclic antidepressant drugs (amitriptyline) was achieved within 200 s with separation efficiency up to 3.80 * 10(5) plates m(-1). The linear ranges for ultraviolet detection were from 2.0 to 1000.0 MUg mL(-1) for chlordiazepoxide and 1.0 to 1000.0 MUg mL(-1) for other seven drugs. Combining with solid-phase extraction, this novel protocol could successfully be used to screen naturally existing psychotropic drugs in a known human plasma sample. The minimum detectable concentration was down to 27 ng mL( 1) for phenobarbital spiked in plasma. This work provided a promising way to initially screen different psychotropic drugs with high resolution, rapid separation and low-cost. PMID- 20951852 TI - Glow discharge analysis of nanostructured materials and nanolayers--a review. AB - Advances in instrumentation and the parallel development of proper analytical methodologies have fuelled an extraordinary growth of analytical applications with glow discharge (GD) techniques. In fact, GDs with detection by optical emission spectrometry (OES) and mass spectrometry (MS) have become today, fast, comparatively simple, and reliable tools for materials analytical characterization at the nanoscale. A critical description of latest advances and presently available GD-OES and GD-MS instrumentation (commercial, prototype and laboratory equipments) is carried out here. Analytical strategies developed for the analysis at the surface and for concentration depth profile analysis of thin and ultrathin layers with GDs are also discussed. Finally, selected representative applications and trends of GD-OES and GD-MS techniques for the nanometer range analysis (e.g. nanolayers, two-dimension nanostructured materials and molecular depth profiling of polymer-based coatings) are briefly described, confirming the increasing analytical value of GD-OES and GD-MS techniques in the nanotechnology field. PMID- 20951853 TI - Analytical applications of photoinduced chemiluminescence in flow systems--a review. AB - In this review, the recent evolution and the state of the art of photochemical reactions coupled with chemiluminescence processes are presented. Different chemiluminescence systems have been considered together with suitable photochemical derivatization processes that can affect either the analyte of interest or even the chemiluminogenic reagent, producing some derivatives able to participate more efficiently in the CL reactions and enhancing the CL emission. The on-line integration of the photochemical reactions as well as the coupling of this resulting photoinduced chemiluminescence (PICL) method with dynamic analytical systems, such as flow injection analysis, liquid or gas chromatography and capillary electrophoresis, have been discussed. Important applications of PICL have been proposed in environmental, pharmaceutical and food analysis. PMID- 20951854 TI - Analytical potential of mid-infrared detection in capillary electrophoresis and liquid chromatography: a review. AB - Literature published in the last decade concerning the use of mid-infrared spectrometry as a detection system in separation techniques employing a liquid mobile phase is reviewed. In addition to the continued use of isocratic liquid chromatographic (LC) techniques, advances in chemometric data evaluation techniques now allow the use of gradient techniques on a routine basis, thus significantly broadening the range of possible applications of LC-IR. The general trend towards miniaturized separation systems was also followed for mid-IR detection where two key developments are of special importance. Firstly, concerning on-line detection the advent of micro-fabricated flow-cells with inner volumes of only a few nL for transmission as well as attenuated total reflection measurements enabled on-line mid-IR detection in capillary LC and opened the path for the first successful realization of on-line mid-IR detection in capillary zone electrophoresis as well as micellar electrokinetic chromatography. Secondly, concerning off-line detection the use of micro-flow through dispensers now enables to concentrate eluting analytes on dried spots sized a few tens of micrometers, thus matching the dimensions for sensitive detection by mid-IR microscopy. Finally in an attempt to increase detection sensitivity of on-line mid-IR detection, mid-IR quantum cascade lasers have been used. Applications cover the field of food analysis, environmental analysis and the characterization of explosives among others. Best detection sensitivities for on-line and off-line detection have been achieved in miniaturized systems and are in the order of 50 ng and 2 ng on column, respectively. PMID- 20951855 TI - Determination of endpoint of procedure for radix rehmanniae steamed based on ultraviolet spectrophotometry combination with continuous wavelet transform and kernel independent component analysis. AB - A method for determination of the endpoint of the procedure for radix rehmanniae steamed was proposed based on UV spectrophotometry combination with continuous wavelet transform and kernel independent component analysis (UV-CWT-KICA). In the proposed method, the raw UV spectra of the rehmanniae samples during steamed procedure were measured. The raw UV spectral data were firstly pretreated by CWT for elimination of the noise signal and enrichment of the spectral resolution, then the independent components (ICs) were estimated from the mixed CWT coefficient matrix. The results show that the ICs are chemical significance with their relative concentrations gradually decreasing or increasing during the first steamed period, and the endpoint of the steamed procedure can be determined by inspection of the relative concentration profiles, at which the ICs should be approached maximum or minimum. Furthermore, the estimated ICs of rehmanniae samples from different areas or with different grades are similar, and the relative concentration of the similar ICs in different groups are increasing or decreasing before the first 14 h, and nearly steady or some decreasing after 16 h. Based on the variations of the relative concentration profiles of the ICs, the endpoint of the steamed procedure can be determined as 15 h, while that determined by sensory analysis is 14-20 h. The proposed UV-CWT-KICA method can avoid the higher deviations of the endpoints that were determined by sensory analysis. It provides an alternative approach for determination of the endpoint of the procedure for processing traditional Chinese medicine (TCM). PMID- 20951856 TI - Evaluation of ultrasound-assisted extraction as sample pre-treatment for quantitative determination of rare earth elements in marine biological tissues by inductively coupled plasma-mass spectrometry. AB - In this work, the determination of rare earth elements (REEs), i.e. Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu in marine biological tissues by inductively coupled-mass spectrometry (ICP-MS) after a sample preparation method based on ultrasound-assisted extraction (UAE) is described. The suitability of the extracts for ICP-MS measurements was evaluated. For that, studies were focused on the following issues: (i) use of clean up of extracts with a C18 cartridge for non-polar solid phase extraction; (ii) use of different internal standards; (iii) signal drift caused by changes in the nebulization efficiency and salt deposition on the cones during the analysis. The signal drift produced by direct introduction of biological extracts in the instrument was evaluated using a calibration verification standard for bracketing (standard-sample bracketing, SSB) and cumulative sum (CUSUM) control charts. Parameters influencing extraction such as extractant composition, mass-to-volume ratio, particle size, sonication time and sonication amplitude were optimized. Diluted single acids (HNO(3) and HCl) and mixtures (HNO(3)+HCl) were evaluated for improving the extraction efficiency. Quantitative recoveries for REEs were achieved using 5 mL of 3% (v/v) HNO(3)+2% (v/v) HCl, particle size <200 MUm, 3 min of sonication time and 50% of sonication amplitude. Precision, expressed as relative standard deviation from three independent extractions, ranged from 0.1 to 8%. In general, LODs were improved by a factor of 5 in comparison with those obtained after microwave-assisted digestion (MAD). The accuracy of the method was evaluated using the CRM BCR-668 (mussel tissue). Different seafood samples of common consumption were analyzed by ICP-MS after UAE and MAD. PMID- 20951857 TI - Application of ultrasound-assisted surfactant-enhanced emulsification microextraction for the determination of some organophosphorus pesticides in water samples. AB - An ultrasound-assisted surfactant-enhanced emulsification microextraction (UASEME) was developed as a new approach for the extraction of organophosphorus pesticides (OPs) in water samples prior to high-performance liquid chromatography with diode array detection (HPLC-DAD). The use of a surfactant as an emulsifier in the UASEME method could enhance the dispersion of water-immiscible extraction solvent into aqueous phase and is favorable for the mass-transfer of the analytes from aqueous phase to the organic phase. Several variables that affect the extraction efficiency, including the kind and volume of the extraction solvent, the type and concentration of the surfactant, salt addition, ultrasound emulsification time and temperature, were investigated and optimized. Under the optimum experimental conditions, the calibration curve was linear in the concentration range from 1 to 200 ng mL(-1) for the seven OPs (isocarbophos, phosmet, parathion, parathion-methyl, fenitrothion, fonofos and phoxim), with the correlation coefficients (r) varying from 0.9973 to 0.9998. High enrichment factors were achieved ranging from 210 to 242. The established UASEME-HPLC-DAD method has been successfully applied for the determination of the OPs in real water samples. The limits of detection were in the range between 0.1 and 0.3 ng mL(-1). The recoveries of the target analytes over the three spiked concentration levels of the compounds (10, 50, and 100 ng mL(-1), respectively) in rain, reservoir and well water samples were between 83% and 106% with the relative standard deviations varying from 3.3% to 5.6%. PMID- 20951858 TI - Simultaneous pressurized enzymatic hydrolysis extraction and clean up for arsenic speciation in seafood samples before high performance liquid chromatography inductively coupled plasma-mass spectrometry determination. AB - The feasibility of pressurized conditions to assist enzymatic hydrolysis of seafood tissues for arsenic speciation was novelty studied. A simultaneous in situ (in cell) clean-up procedure was also optimized, which speeds up the whole sample treatment. Arsenic species (As(III), MMA, DMA, As(V), AsB and AsC) were released from dried seafood tissues using pepsin as a protease, and the arsenic species were separated/quantified by anion exchange high performance liquid chromatography (HPLC) coupled to inductively coupled plasma-mass spectrometry (ICP-MS). Variables inherent to the enzymatic activity (pH, temperature and ionic strength), the amount of enzyme (pepsin), and factors affecting pressurization (pressure, static time, number of cycles and amount of dispersing agent, C-18) were fully evaluated. Pressurized assisted enzymatic hydrolysis (PAEH) with pepsin can be finished after few minutes (two cycles of 2 min each one plus 3 min to reach the hydrolysis temperature of 50 degrees C). A total sample solubilisation is not achieved after the procedure, however it is efficient enough for breaking down certain bonds of bio-molecules and for releasing arsenic species. The developed method has been found to be precise (RSDs lower than 6% for As(III), DMA and As(V); and 3% for AsB) and sensitive (LOQs of 18.1, 36.2, 35.7, 28.6, 20.6 and 22.5 ng/g for As(III), MMA, DMA, As(V), AsB and AsC, respectively). The optimized methodology was successfully applied to different certified reference materials (DORM-2 and BCR 627) which offer certified AsB and DMA contents, and also to different seafood products (mollusks, white fishes and cold water fishes). PMID- 20951859 TI - Miniaturized salting-out liquid-liquid extraction of sulfonamides from different matrices. AB - Salting-out liquid-liquid extraction (LLE) uses water-miscible organic solvents as the extractants. The principle of it is based on the phase separation of water miscible organic solvents from the aqueous solutions in the presence of high concentration of salts. As an effort to miniaturization, in the present study, a 1-mL syringe was employed as the phase separation device for salting-out LLE. Once the phase separation occurred, the upper layer could be narrowed into the needle tip by pushing the plunger; thus, the collection of the upper layer solvent was convenient. By miniaturization, the consumption of organic solvent was decreased as low as possible. Four sulfonamides were used as model analytes. The optimal salting-out parameters were as follows. 150 MUL of acetonitrile was added to the 500 MUL of sample solution containing 300 mg mL(-1) sodium chloride at a pH of 6.5. This procedure afforded a convenient, fast and cost-saving operation with good cleanup ability for the model analytes. It showed promising applications for different matrices. Herein, food (honey), environmental water (river water) and biological fluid (human urine) were investigated. Satisfactory results were obtained. An additional bonus of this sample preparation method is that, owing to its water-miscible nature, the extraction solvent is compatible with various analytical systems, like gas chromatography, high-performance liquid chromatography and capillary electrophoresis. PMID- 20951860 TI - Voltage effects on the nanoelectrospray characteristics in fully voltage controlled atomisation of gold nanocolloids. AB - The voltage effects on fully voltage-controlled nanoelectrospraying of aqueous gold nanocolloids were investigated. In the nanoelectrospray using 30 MUm nozzle, with an increasing of voltage two stable spray regimes of pulsating and cone-jet mode were clearly observed by a combination of current measurement and fast imaging technology. In this nanoelectrospray uniquely determined by the electrical field voltage the current-voltage characteristics were analysed and evaluated based on an equivalent circuit method. At high field in cone-jet regime all the equivalent resistances derived by fitting appear close to a value of 0.53 +/- 0.03 GOmega, showing independence to the conductivity of the nanocolloids. In low field pulsating regime a high pulsation frequency up to 100 kHz with relatively stable current pulse was exhibited in all the gold nanocolloids. A linear relationship between the DC components in the pulsating current and the voltage was found and the DC equivalent resistance obtained from the fitting varies between 0.90 and 1.47 GOmega. A strong correlation between the pulsating properties and the conductivity of the colloids was identified. PMID- 20951861 TI - Enhancement of deoxyribonucleic acid microarray performance using post hybridization signal amplification. AB - Microarray performance depends upon the ability to screen samples against a vast array of probes with the appropriate sensitivity and selectivity. While these factors are significantly influenced by probe design, they are also subject to the particular detection methodology and reagents employed. Herein we describe the incorporation of super avidin-biotin system (SABS) and secondary enzymatic enhancement (SEE) as post-hybridization signal amplification techniques to improve the sensitivity of oligonucleotide microarrays. To these ends, we tested these methods on electrochemically interrogated arrays using both purified influenza A PCR products and randomly amplified genomic Francisella tularensis DNA as targets. While SABS treatment did not improve sensitivity for CombiMatrix ElectraSense((r)) arrays using purified influenza A cDNA, chip sensitivity was improved 10-fold for randomly amplified targets. SEE improved performance to a greater degree and was able to lower the detection limits 10-fold for influenza A and 100-fold for F. tularensis DNA. These results indicate the promising capability of post-hybridization amplification techniques for enhancing microarray performance. PMID- 20951862 TI - A reversed phase high performance liquid chromatography method for the determination of fumonisins B1 and B2 in food and feed using monolithic column and positive confirmation by liquid chromatography/tandem mass spectrometry. AB - The development of a reversed phase high performance liquid chromatography fluorescence method for the determination of the mycotoxins fumonisin B(1) and fumonisin B(2) by using silica-based monolithic column is described. The samples were first extracted using acetonitrile:water (50:50, v/v) and purified by using a C(18) solid phase extraction-based clean-up column. Then, pre-column derivatization for the analyte using ortho-phthaldialdehyde in the presence of 2 mercaptoethanol was carried out. The developed method involved optimization of mobile phase composition using methanol and phosphate buffer, injection volume, temperature and flow rate. The liquid chromatographic separation was performed using a reversed phase Chromolith((r)) RP-18e column (100 mm * 4.6 mm) at 30 degrees C and eluted with a mobile phase of a mixture of methanol and phosphate buffer pH 3.35 (78:22, v/v) at a flow rate of 1.0 mL min(-1). The fumonisins separation was achieved in about 4 min, compared to approximately 20 min by using a C(18) particle-packed column. The fluorescence excitation and emission were at 335 nm and 440 nm, respectively. The limits of detections were 0.01-0.04 MUg g( 1) fumonisin B(1) and fumonisin B(2), respectively. Good recoveries were found for spiked samples (0.1, 0.5, 1.5 MUg g(-1) fumonisins B(1) and B(2)), ranging from 84.0 to 106.0% for fumonisin B(1) and from 81.0 to 103.0% for fumonisin B(2). Fifty-three samples were analyzed including 39 food and feeds and 14 inoculated corn and rice. Results show that 12.8% of the food and feed samples were contaminated with fumonisin B(1) (range, 0.01-0.51 MUg g(-1)) and fumonisin B(2) (0.05 MUg g(-1)). The total fumonisins in these samples however, do not exceed the legal limits established by the European Union of 0.8 MUg g(-1). Of the 14 inoculated samples, 57.1% contained fumonisin B(1) (0.16-41.0 MUg g(-1)) and fumonisin B(2) (range, 0.22-50.0 MUg g(-1)). Positive confirmation of selected samples was carried out using liquid chromatography-tandem mass spectrometry, using triple quadrupole analyzer and operated in the multiple reaction monitoring mode. PMID- 20951863 TI - Commentary on "vacuum-assisted closure in severe abdominal sepsis with or without retention sutured sequential fascial closure: a clinical trial". PMID- 20951864 TI - Refinements in perioperative beta blocker use for patients undergoing elective abdominal aortic aneurysm repair. PMID- 20951866 TI - Response to "tertiary hyperparathyroidism: is less than a subtotal resection ever appropriate? A study on long-term outcomes". PMID- 20951868 TI - Recent developments in understanding dengue virus replication. AB - Dengue is the most important cause of mosquito-borne virus diseases in tropical and subtropical regions in the world. Severe clinical outcomes such as dengue hemorrhagic fever and dengue shock syndrome are potentially fatal. The epidemiology of dengue has undergone profound changes in recent years, due to several factors such as expansion of the geographical distribution of the insect vector, increase in traveling, and demographic pressure. As a consequence, the incidence of dengue has increased dramatically. Since mosquito control has not been successful and since no vaccine or antiviral treatment is available, new approaches to this problem are needed. Consequently, an in-depth understanding of the molecular and cellular biology of the virus should be helpful to design efficient strategies for the control of dengue. Here, we review the recently acquired knowledge on the molecular and cell biology of the dengue virus life cycle based on newly developed molecular biology technologies. PMID- 20951870 TI - Influenza vaccines: the good, the bad, and the eggs. AB - Outbreaks of influenza A viruses continue to cause morbidity and mortality worldwide. The global disease burden of influenza is substantial. While antiviral therapies are available, influenza vaccines are the mainstay of efforts to reduce the substantial health burden from seasonal influenza. Inactivated influenza vaccines have been available since the 1940s, with live attenuated, cold-adapted vaccines becoming available in the United States in 2003. In spite of the successes, more research is needed to develop more effective seasonal influenza vaccines that provide long-lasting immunity and broad protection against strains that differ antigenically from vaccine viruses. This review introduces the virus and its disease, the current state of seasonal and pandemic influenza vaccines, and the challenges we face in the future. PMID- 20951869 TI - Evolution of human papillomavirus carcinogenicity. AB - Members of the Alphapapillomavirus genus are the causative agent for virtually all cases of cervical cancer. However, strains (commonly referred to as types) within this genus span the entire range of pathogenicity from highly carcinogenic (e.g., HPV16, odds ratio = 281.9, responsible for 50% of all cervical cancers), moderately carcinogenic (e.g., HPV31) to not carcinogenic (e.g., HPV71). The persistent expression of the viral oncoproteins (E6 and E7) from HPV16 has been shown to be necessary and sufficient to transform primary human keratinocytes in vitro. A plethora of functions have been described for both oncoproteins, and through functional comparisons between HPV16 and HPV6, a subset of these functions have been suggested to be oncogenic. However, extrapolating functional differences from these comparisons is unlikely to tease apart the fine details. In this review, we argue that a thorough understanding of the molecular mechanisms differentiating oncogenic from nononcogenic types should be obtained by performing functional assays in an evolutionary and epidemiological framework. We continue by interpreting some recent results using this paradigm and end by suggesting directions for future inquiries. PMID- 20951872 TI - Involvement of the plant nucleolus in virus and viroid infections: parallels with animal pathosystems. AB - The nucleolus is a dynamic subnuclear body with roles in ribosome subunit biogenesis, mediation of cell-stress responses, and regulation of cell growth. An increasing number of reports reveal that similar to the proteins of animal viruses, many plant virus proteins localize in the nucleolus to divert host nucleolar proteins from their natural functions in order to exert novel role(s) in the virus infection cycle. This chapter will highlight studies showing how plant viruses recruit nucleolar functions to facilitate virus translation and replication, virus movement and assembly of virus-specific ribonucleoprotein (RNP) particles, and to counteract plant host defense responses. Plant viruses also provide a valuable tool to gain new insights into novel nucleolar functions and processes. Investigating the interactions between plant viruses and the nucleolus will facilitate the design of novel strategies to control plant virus infections. PMID- 20951873 TI - A critical look at critical care. PMID- 20951874 TI - The Global Fund: a bleak future ahead. PMID- 20951875 TI - Mental health: WHO minds the GAP. PMID- 20951871 TI - Innate host barriers to viral trafficking and population diversity: lessons learned from poliovirus. AB - Poliovirus is an error-prone enteric virus spread by the fecal-oral route and rarely invades the central nervous system (CNS). However, in the rare instances when poliovirus invades the CNS, the resulting damage to motor neurons is striking and often permanent. In the prevaccine era, it is likely that most individuals within an epidemic community were infected; however, only 0.5% of infected individuals developed paralytic poliomyelitis. Paralytic poliomyelitis terrified the public and initiated a huge research effort, which was rewarded with two outstanding vaccines. During research to develop the vaccines, many questions were asked: Why did certain people develop paralysis? How does the virus move from the gut to the CNS? What limits viral trafficking to the CNS in the vast majority of infected individuals? Despite over 100 years of poliovirus research, many of these questions remain unanswered. The goal of this chapter is to review our knowledge of how poliovirus moves within and between hosts, how host barriers limit viral movement, how viral population dynamics impact viral fitness and virulence, and to offer hypotheses to explain the rare incidence of paralytic poliovirus disease. PMID- 20951876 TI - Time for a bold new vision at the Stop TB Partnership. PMID- 20951877 TI - Rural MBBS degree in India. PMID- 20951879 TI - Robert Edwards: Nobel Prize for father of in-vitro fertilisation. PMID- 20951880 TI - Editorials about home birth--proceed with caution. PMID- 20951881 TI - Editorials about home birth--proceed with caution. PMID- 20951882 TI - Editorials about home birth--proceed with caution. PMID- 20951883 TI - High-dose allopurinol in patients with stable angina pectoris. PMID- 20951884 TI - High-dose allopurinol in patients with stable angina pectoris. PMID- 20951885 TI - Editorials about home birth--proceed with caution. PMID- 20951887 TI - High-dose allopurinol in patients with stable angina pectoris. PMID- 20951889 TI - Was it really hepatic hydrothorax? PMID- 20951890 TI - Testiculopathy and vitamin D insufficiency. PMID- 20951891 TI - Putting patients above politics. PMID- 20951892 TI - Can we increase male involvement in AIDS treatment? PMID- 20951893 TI - Delirious deficiency. PMID- 20951895 TI - Understanding stability of the distal radioulnar joint through an understanding of its anatomy. AB - The authors describe the anatomy of the distal radioulnar joint (DRUJ) and delineate the importance of viewing this joint as part of the whole forearm. The osseous congruity and ligamentous integrity is of essence for the stability of the DRUJ, according to the principles of tensegrity. The neuromuscular control and possible proprioceptive function of the DRUJ are also outlined. PMID- 20951896 TI - Imaging the distal radioulnar joint. AB - Imaging the DRUJ requires knowledge of the complex bony, muscular, and ligamentous anatomy that contribute to this unique joint. Standard well positioned radiography is always the appropriate first step in any imaging evaluation of the wrist. High-resolution MRI of the wrist, preferably performed at 3T, helps to delineate the important ligamentous structures relevant to the DRUJ and ulnar wrist, whether the joint is unstable or not. The presence of instability on physical examination is an indication for dynamic CT evaluation. Close attention to technique, no matter what the modality of choice, offers the best chance for success in providing added value with imaging. Finally, communication between the radiologist and hand surgeon allows the advanced imaging examinations to be tailored to the specific clinical problem for the most effective use of resources for each individual patient. PMID- 20951897 TI - Surgical approaches to the distal radioulnar joint. AB - For the distal radioulnar joint (DRUJ) to be stable, not only do the articulating surfaces need to be congruent and well aligned but also the capsule and ligaments need to be mechanically and sensorially competent. According to recent investigations, ligaments should not be regarded as simple static structures maintaining articular alignment but as complex arrangements of collagen fibers containing mechanoreceptors, which are able to generate neural reflexes aiming at a more efficient and a more definitive muscular stabilization. By careful planning and meticulous execution of surgical incisions to approach the DRUJ, the nerve endings innervating the capsule and DRUJ ligaments may be safeguarded, thus preserving the proprioceptive function of the joint. PMID- 20951898 TI - Arthroscopic and open repair of the TFCC. AB - Injury to the triangular fibrocartilage complex is the most common cause of ulnar sided wrist pain. This functionally related complex of anatomic structures can be a source of pain secondary to acute injury or chronic degeneration. Strategies for the treatment of these injuries involve determining the anatomic location of the tear, the presence of associated distal radioulnar joint instability, and the presence of associated degenerative changes. Surgical management with open and arthroscopic techniques have been described, both with successful results. PMID- 20951899 TI - Longitudinal split tears of the ulnotriquetral ligament. AB - Unlike tears of the peripheral triangular fibrocartilage or avulsions of the distal radioulnar ligaments, longitudinal split tears of the ulnotriquetral (UT) ligament do not cause any instability to the distal radioulnar joint or the ulnocarpal articulation. It is mainly a pain syndrome that can be incapacitating. However, because the UT ligament arises from the palmar radioulnar ligament of the triangular fibrocartilage complex (TFCC), it is by definition, an injury of the TFCC. The purpose of this article is to describe the cause of chronic ulnar wrist pain arising from a longitudinal split tear of the UT ligament. PMID- 20951900 TI - Acute dislocations of the distal radioulnar joint and distal ulna fractures. AB - This article reviews acute dislocations of the distal radioulnar joint (DRUJ) and distal ulna fractures. Acute dislocations can occur in isolation or in association with a fracture to the distal radius, radial metadiaphysis (Galeazzi fracture), or radial head (Essex-Lopresti injury). Distal ulna fractures may occur in isolation or in combination with a distal radius fracture. Both injury patterns are associated with high energy. Outcomes are predicated on anatomic reduction and restoration of the stability of the DRUJ. PMID- 20951901 TI - The management of chronic distal radioulnar instability. AB - The stabilizing constraints of the distal radioulnar joint (DRUJ) include its bony geometry and the surrounding soft tissue support. Given the shallow nature of the sigmoid notch, reconstruction of the palmar and dorsal ligamentous sleeve provides the best solution for restoring stability in cases of chronic DRUJ instability. The pertinent anatomy, indications, contraindications, soft tissue stabilizing procedures, and rehabilitation for the management of chronic DRUJ instability are highlighted in this review. PMID- 20951902 TI - Salvage of failed distal radioulnar joint reconstruction. AB - In the patient in whom primary distal radioulnar joint surgery has failed, consideration must be given to the anatomy and biomechanics of the native joint; how this has been disrupted by injury, disease, and previous trauma; and what is required to reconstruct the joint. The forearm relies on a congruent condylar cam of the distal ulna, with intact soft tissue restraints for normal biomechanics. Surgical reconstruction using tendon graft, autologous bone graft, allograft interposition, and prosthetic reconstruction are discussed in this article. If these procedures fail, then salvage procedures including wide excision of the ulna or one-bone forearm can be performed. PMID- 20951903 TI - Management of injuries to the interosseous membrane. AB - Injury to the interosseous membrane of the forearm typically occurs in conjunction with disruption of the radial head and the distal radioulnar joint. Frequently, the true extent of injury is not initially appreciated, and patients may develop longitudinal instability of the forearm, with wrist pain, forearm discomfort, and instability. This article outlines various treatment strategies, which include considerations at the wrist, forearm, and elbow. PMID- 20951904 TI - Ulnar impaction. AB - Ulnar impaction syndrome is a common source of ulnar-sided wrist pain. It is a degenerative condition that occurs secondary to excessive load across the ulnocarpal joint, resulting in a spectrum of pathologic changes and symptoms. It may occur in any wrist but is usually associated with positive ulnar variance, whether congenital or acquired. The diagnosis of ulnar impaction syndrome is made by clinical examination and is supported by radiographic studies. Surgery is indicated if nonoperative treatment fails. Although a number of alternatives exist, the 2 primary surgical options are ulnar-shortening osteotomy or partial resection of the distal dome of the ulna (wafer procedure). This article discusses the etiology of ulnar impaction syndrome, and its diagnosis and treatment. PMID- 20951905 TI - The Sauve-Kapandji procedure: indications and tips for surgical success. AB - Arthrodesis is the most reliable and durable surgical procedure for the treatment of a joint disorder, with the main disadvantage of loss of motion of the fused joint. The distal radioulnar joint can be arthrodesed, while forearm pronation and supination are maintained or even improved by creating a pseudoarthrosis of the ulna just proximal to the arthrodesis. This is known as the Sauve-Kapandji procedure. This procedure is not void of possible complications, such as nonunion or delayed union of the arthrodesis, fibrous or osseous union at the pseudoarthrosis, and painful instability at the proximal ulna stump. All of these can be prevented if a careful surgical technique is used. PMID- 20951906 TI - Periprosthetic bone resorption and sigmoid notch erosion around ulnar head implants: a concern? AB - Metallic ulnar head implants have been proposed not only to solve symptomatic radioulnar impingement after Darrach or Sauve-Kapandji procedures, but also to prevent such an impingement when treating arthritic distal radioulnar joint. This article prospectively analyzes a series of ulnar head implants with special reference to bone resorption at the prosthesis collar and erosion of the sigmoid notch of the distal radius at an average follow-up of 32 months (minimum 24 months). PMID- 20951907 TI - The management of congenital and acquired problems of the distal radioulnar joint in children. AB - Pain in the ulnar aspect of the pediatric wrist is an uncommon problem; however, when pain does occur it is usually the result of antecedent bony trauma or an underlying skeletal abnormality, which may lead to ulnar-sided wrist pain of varying etiology. The clinician must to be able to identify these entities within the pediatric wrist in order to make the appropriate diagnosis and plan for surgical intervention to prevent ongoing damage to the distal radioulnar joint (DRUJ). This article reviews the etiology, clinical presentation, and treatment strategies for the management of the unique problems that can affect the pediatric and adolescent DRUJ. PMID- 20951908 TI - Clinical pharmacology of gastrointestinal and liver disease. Preface. PMID- 20951909 TI - New pharmacologic approaches in gastroesophageal reflux disease. AB - This article highlights current and emerging pharmacological treatments for gastroesophageal reflux disease (GERD), opportunities for improving medical treatment, the extent to which improvements may be achieved with current therapy, and where new therapies may be required. These issues are discussed in the context of current thinking on the pathogenesis of GERD and its various manifestations and on the pharmacologic basis of current treatments. PMID- 20951910 TI - The pharmacological therapy of non-variceal upper gastrointestinal bleeding. AB - The modern management of patients with upper gastrointestinal bleeding includes, in selected patients, the performance of timely multimodal endoscopic hemostasis followed by profound acid suppression. This article discusses the available data on the use of antisecretory regimens in the management of patients with bleeding peptic ulcers, which are a major cause of non-variceal upper gastrointestinal bleeding, and briefly addresses other medications used in this acute setting. The most important clinically relevant data are presented, favoring fully published articles. PMID- 20951911 TI - Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention. AB - Increasing life expectancy in developed countries has led to a growing prevalence of arthritic disorders, which has been accompanied by increasing prescriptions for nonsteroidal antiinflammatory drugs (NSAIDs). These are the most widely used agents for musculoskeletal and arthritic conditions. Although NSAIDs are effective, their use is associated with a broad spectrum of adverse reactions in the liver, kidney, cardiovascular system, skin, and gut. Gastrointestinal (GI) side effects are the most common. The dilemma for the physician prescribing NSAIDs is, therefore, to maintain the antiinflammatory and analgesic benefits, while reducing or preventing GI side effects. The challenge is to develop safer NSAIDs by shifting from a focus on GI toxicity to the increasingly more appreciated cardiovascular toxicity. PMID- 20951912 TI - Pharmacologic aspects of eradication therapy for Helicobacter pylori Infection. AB - The commonly used regimens for the eradication of Helicobacter pylori infection consist of administration of proton pump inhibitors (PPIs) and 1 to 3 antimicrobial agents, such as amoxicillin, clarithromycin, metronidazole, fluoroquinolone, or tetracycline. Each agent has its own pharmacologic characteristics. PPIs are metabolized by cytochrome P450 2C19 (CYP2C19), which is polymorphic. CYP2C19 genotypic differences in the pharmacokinetics and pharmacodynamics of PPIs influence the eradication rates of H pylori infection by PPI-containing regimens. Amoxicillin is a time-dependent antibiotic, whereas clarithromycin, metronidazole, tetracycline, and fluoroquinolone are not. The plasma half-life of antimicrobial agents also differs among these antibiotics. To achieve consistently high eradication rates, the eradication regimens must be designed based on a good understanding of the resistance patterns of the bacteria and the pharmacologic characteristics of the agents used for H pylori eradication therapy. PMID- 20951913 TI - Current medical treatments of dyspepsia and irritable bowel syndrome. AB - Dyspepsia is a highly prevalent condition characterized by symptoms originating in the gastroduodenal region without underlying organic disorder. Treatment modalities include acid-suppressive drugs, gastroprokinetic drugs, Helicobacter pylori eradication therapy, tricyclic antidepressants, and psychological therapies. Irritable bowel syndrome is a multifactorial, lower functional gastrointestinal disorder involving disturbances of the brain-gut axis. The pathophysiology provides the basis for pharmacotherapy: abnormal gastrointestinal motor functions, visceral hypersensitivity, psychosocial factors, intraluminal changes, and mucosal immune activation. Medications targeting chronic constipation or diarrhea may also relieve irritable bowel syndrome. Novel approaches to treatment require approval, and promising agents are guanylate cyclase cagonists, atypical benzodiazepines, antibiotics, immune modulators, and probiotics. PMID- 20951914 TI - Pharmacological management of diarrhea. AB - According to the World Health Organization, there are approximately 2 billion annual cases of diarrhea worldwide. Diarrhea is the leading cause of death in children younger than 5 years and kills 1.5 million children each year. It is especially prevalent in the developing world, where mortality is related to dehydration, electrolyte disturbance, and the resultant acidosis, and in 2001, it accounted for 1.78 million deaths (3.7% of total deaths) in low- and middle income countries. However, diarrhea is also a common problem in the developed world, with 211 million to 375 million episodes of infectious diarrheal illnesses in the United States annually, resulting in 73 million physician consultations, 1.8 million hospitalizations, and 3100 deaths. Furthermore, 4% to 5% of the Western population suffers from chronic diarrhea. Given the high prevalence of diarrhea, research has been directed at learning more about the cellular mechanisms underlying diarrheal illnesses in order to develop new medications directed at novel cellular targets. These cellular mechanisms and targets are discussed in this article. PMID- 20951915 TI - Pharmacologic management of chronic constipation. AB - Chronic constipation is a common digestive problem in North America, with significant psychosocioeconomic implications. Dietary and lifestyle measures and low-cost traditional over-the-counter laxatives are usually the first line of therapy but help only half of the patients. Several newer agents that act by increasing colonic peristalsis, altering colonic secretion, and/or antagonizing enteric opioid receptors have been developed that are effective in treating constipation and its related symptoms as well as improving quality of life. This article focuses on the pharmacology of traditional and newer agents for the treatment of constipation. PMID- 20951917 TI - Tumor necrosis factor-alpha monoclonal antibodies in the treatment of inflammatory bowel disease: clinical practice pharmacology. AB - In the last 10 years, anti-tumor necrosis factor (TNF)-alpha therapy has become a cornerstone in the management of autoimmune diseases. Clinical trial data have consistently found that infliximab, adalimumab, and recently certolizumab pegol offer therapeutic benefits to patients with inflammatory bowel diseases (Crohn's disease and ulcerative colitis). Recent understanding on how these monoclonal antibodies evoke changes at the physiological and molecular levels have provided insights into disease pathogenesis and helped to identify new targets for future drug therapy. With increased experience in the use of these anti-TNF-alpha antibodies the long-term safety data, use in pregnancy have become available. This article provides an overview of the current knowledge regarding anti-TNF alpha therapies for clinicians caring for patients with Crohn's disease and ulcerative colitis. PMID- 20951918 TI - Clinical pharmacology of 5-ASA compounds in inflammatory bowel disease. AB - Mesalamine has been the first-line of therapy in patients with inflammatory bowel disease (IBD) since the 1960s. This article serves as a review of the different 5 aminosalicylic acid compounds, release formulations, use and dosing in the treatment of IBD, in particular ulcerative colitis. PMID- 20951916 TI - The safety of drugs used in acid-related disorders and functional gastrointestinal disorders. AB - Medicines are frequently used in the management of acid-related disorders and functional gastrointestinal disorders. With the exception of complicated peptic ulcer disease, these disorders are not associated with appreciable mortality. Drug treatments have consequently been held to the highest standards of safety. Some medicines have been withdrawn or restricted based on assessments and perceptions of risk. However, the risk of serious toxicity is low for most of the agents discussed in this article. Assessments are made of the safety and adverse event profiles of certain drug classes and, where appropriate, individual medicines. For conditions with a low risk of mortality or serious morbidity, clinicians need to balance the risks of potential adverse events with the anticipated benefits of a successful outcome of specific drug treatment. PMID- 20951919 TI - Targeted therapeutic agents for colorectal cancer. AB - The treatment of colorectal cancer (CRC) has evolved substantially during the past decade with the advent of molecular targeted therapies. Inhibitors to the vascular endothelial growth factor and epidermal growth factor receptor (EGFR) pathways have been shown to enhance the efficacy of cytotoxic chemotherapy in patients with advanced CRC, and anti-EGFR antibodies demonstrate modest activity as monotherapeutic agents. These biologic agents have improved patient outcomes and survival and have been incorporated into routine clinical practice establishing a new standard of care. Molecular markers have recently been adopted into clinical practice with the finding that the KRAS oncogene is a predictive biomarker for anti-EGFR therapy, whereby the therapeutic benefit of anti-EGFR treatment is restricted to tumors with wild-type KRAS. The use of molecular targeted agents has fewer yet more specific toxicities compared with conventional cytotoxic drugs and enables a more personalized approach to cancer therapy. In contrast to the results for advanced CRC, targeted therapies have not shown a benefit in the adjuvant setting for patients with resected colon cancer. The goal of this review is to provide an update on the medical management of CRC, with a focus on the use of targeted therapy. PMID- 20951921 TI - The gastrointestinal complications of oncologic therapy. AB - A spectrum of oncologic treatments including chemotherapy, radiotherapy, and molecular targeted therapies is available to combat cancer. These treatments are associated with adverse effects in several organ systems including the gastrointestinal (GI) tract. The immunocompromised state induced by oncologic therapy is also an important contributing factor underlying GI complications. This review discusses common GI complications that can result from cancer therapy. The pathologic mechanisms underlying each complication and the pharmacology of the agents used to treat these complications are discussed. PMID- 20951920 TI - New pharmacologic therapies for gastroenteropancreatic neuroendocrine tumors. AB - Successful treatment of unresectable and metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) requires the thoughtful choice of systemic therapy as a component of a multidisciplinary therapeutic approach. The role of somatostatin analogues is established in symptom relief, but the efficacy of interferon and radiopeptide targeted therapy is not clear. The utility of a variety of tyrosine kinase and antiangiogenic agents is variable and under investigation, whereas the role of cytotoxic chemotherapy in poorly differentiated GEP-NETs is accepted. Overall, the ideal treatment of more indolent tumors is less certain. Reassessments of the GEP-NET pathology classification has provided improved logic for the role of a variety of agents, whereas the precise positioning of many new agents that target molecular pathways of angiogenesis and proliferation is under examination. This article describes the current options for systemic therapy for GEP-NETs within the framework of the current World Health Organization classification system. PMID- 20951922 TI - Pharmacokinetics and pharmacodynamics of peginterferon and ribavirin: implications for clinical efficacy in the treatment of chronic hepatitis C. AB - The pharmacokinetics and pharmacodynamics of standard interferon alfa-2a and interferon alfa-2b are substantially altered by pegylation. The size, geometry, and site of attachment of the PEG moiety affect the pharmacokinetics and pharmacodynamics as evidenced by the different absorption, volume of distribution, and clearance of the linear 12-kDa peginterferon alfa-2b and the branched 40-kDa peginterferon alfa-2a. Despite these differences, the clinical efficacy, safety, and tolerability of the 2 peginterferons are similar. However, evidence exists that peginterferon alfa-2 plus ribavirin is associated with small but significantly higher sustained virological response rates compared with peginterferon alfa-2b. This article discusses the pharmacokinetics and pharmacodynamics of the 2 peginterferons and their combination with ribavirin. PMID- 20951923 TI - New pharmacologic therapies in chronic hepatitis B. AB - Approximately 350 million persons worldwide are chronically infected with hepatitis B, which can result in cirrhosis, liver failure, and hepatocellular carcinoma. Currently, 2 interferons and 5 nucleos(t)ide analogues have been approved for the treatment of chronic hepatitis B (CHB). This article discusses the mechanisms of action, pharmacokinetics, optimal dose, clinical efficacy, and side effects of medications used for the treatment of CHB. PMID- 20951925 TI - Therapeutic potential of peroxisome proliferator-activated receptors in chronic inflammation and colorectal cancer. AB - Peroxisome proliferatoreactivated receptors (PPARs) are members of the nuclear hormone receptor superfamily and have been implicated in a variety of physiologic and pathologic processes, such as nutrient metabolism, energy homeostasis, inflammation, and cancer. This article highlights breakthroughs in our understanding of the potential roles of PPARs in inflammatory bowel disease and colorectal cancer. PPARs might hold the key to some of the questions that are pertinent to the pathophysiology of inflammatory diseases and colorectal cancer and could possibly serve as drug targets for new antiinflammatory therapeutic and anticancer agents. PMID- 20951927 TI - Pharmabiotic manipulation of the microbiota in gastrointestinal disorders, from rationale to reality. AB - The viewpoints of enthusiasts and skeptics in relation to the role of probiotics should not be allowed to distract clinicians from the bigger issue, which is the pivotal role of the microbiota in the protection against many disorders and in the pathogenesis of others. However, all probiotics, like all bacteria, are not created equal, and therapeutic deployment in a generic sense is as absurd as the administration of pills or tablets without regard for the nature of the active ingredient and the intended effect. The rationale for therapeutic manipulation or supplementation of the microbiota is sound in conditions where the intestinal ecosystem is poorly developed, such as in low birth weight neonates, or where it is profoundly disturbed, such as after broad-spectrum antibiotics. In other conditions, such as irritable bowel disorder (IBD), the efficacy of some, but not all, probiotics has been a welcome surprise. However, the impact of probiotics is likely to be modest and is probably more complicated in IBD. In choosing a probiotic strategy, clinicians should adhere to the principles of evidence-based therapeutics. These include: selection from a reputable supplier, with appropriate documentation of contents and shelf life; anticipation of strain specific effects; avoidance of cocktails without documentation of the activities of each ingredient with absence of interstrain antagonism; and published evidence of efficacy from clinical trials. PMID- 20951924 TI - Clinical pharmacology of portal hypertension. AB - Portal hypertension is an increase in pressure in the portal vein and its tributaries. It is defined as a portal pressure gradient (the difference in pressure between the portal vein and the hepatic veins) greater than 5 mm Hg. Although this gradient defines portal hypertension, a gradient of 10 mm Hg or greater defines clinically significant portal hypertension, because this pressure gradient predicts the development of varices, decompensation of cirrhosis, and hepatocellular carcinoma. The most direct consequence of portal hypertension is the development of gastroesophageal varices that may rupture and lead to the development of variceal hemorrhage. This article reviews the pathophysiologic bases of the different pharmacologic treatments for portal hypertension in patients with cirrhosis and places them in the context of the natural history of varices and variceal hemorrhage. PMID- 20951926 TI - New pharmacologic therapies in gastrointestinal disease. AB - Many gastrointestinal diseases remain poorly responsive to therapies, and even in the cases of conditions for which there are many effective drugs, there is still considerable room for improvement. This article is focused on drugs for digestive disorders that have entered the marketplace recently, or are expected to reach the marketplace within the next 1 to 2 years. Although advances have been made in understanding gastrointestinal motility, visceral pain, mucosal inflammation, and tissue repair, the major gastrointestinal diseases remain as significant therapeutic challenges. PMID- 20951928 TI - [Single-port in urology]. AB - Single-port transumbilical laparoscopy has emerged as an attempt to further enhance cosmetic benefits and reduce morbidity of minimally invasive surgery. Within a short span, several clinical reports have emerged in the urologic literature. As this field is poised to move forward, a complete understanding of its evolution and current status seems imperative. We have summarized and reviewed the history of Single-Port across surgical disciplines. This review emphasizes nomenclature, surgical technique, instrumentation, and perioperative outcomes. EVIDENCE ACQUISITION: Using the National Library of Medicine database, the English language literature was reviewed for the past 40 years. Keyword searches included scarless, scar free, single-port/trocar/incision, laparoendoscopic single site surgery intraumbilical, and transumbilical. Within the bibliography of selected references, additional sources were retrieved. EVIDENCE SYNTHESIS: The major findings and surgical techniques described in these papers, are summarized in a chronological and subject-grouped manner. CONCLUSIONS: Single-port has made its initial forays into laparoscopic surgery. Ongoing refinement in technique and instrumentation is likely to expand its future role. PMID- 20951929 TI - [Treatment of the lower urinary tract symptoms secondary to benign prostatic hyperplasia by phosphodiesterase type 5 inhibitors. Review article]. AB - CONTEXT: In aging males, there is an increased prevalence of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) whose affect significantly their quality of life. LUTS would represent for ED an independent risk factor. Some treatment of LUTS have undesirable effects on the erectile function. The phosphodiesterase type 5 inhibitors (IPDE 5) revolutionized the treatment of ED. Several recent clinical studies evaluated the effect daily treatment by IPDE 5 on the LUTS secondary to BPH among patients with or without ED. MATERIALS AND METHODS: we searched Medline for the peer-reviewed articles in English published, pertaining to findings of potential interest supporting a role of IPDE5 in LUTS due to BHP. The keywords used were: benign prostatic hyperplasia; cyclic nucleotide phosphodiesterase type 5; lower urinary tract symptoms; erectile dysfunction. RESULTS: Generally, daily treatment with IPDE 5 improves the LUTS secondary to BPH as well as in both the storage and voiding domains of the international prostate symptom score (IPPS) and in quality of life questionnaire. It was not observed adverse events. CONCLUSION: The first results of the use of IPDE 5 in the LUTS treatment secondary to the HBP seem promising. However, a direct comparison of efficacy of IPDE 5 and alpha-blockers or 5-alpha-reductase inhibitors is not yet available. The mechanism(s) of action(s) of these compounds in this indication remain difficult to affirm even if new hypotheses can be formulated. PMID- 20951930 TI - [Contribution of curative and preventive embolization for renal angiomyolipomas treatment]. AB - OBJECTIVE: The purpose of this study was to present the role of embolization in the treatment of kidney angiomyolipomas (AML), for preventive care or in case of bleeding. METHODS: From March 1995 to March 2007, 22 AML in 21 patients (16 women and five men, mean age 38 years) were embolized: five AML were treated for hemorrhagic shock emergency and 16 were preventive embolization. Eight AML were discovered incidentally and nine patients had pain or hematuria. The average size of AML was 70 mm (20 to 130 mm). The embolization was performed with coils or embospheres. RESULTS: Three patients have not been embolized because of renal failure catheterization. The embolization was effective in 100% of patients treated in emergency. The six patients cared for gross hematuria and pain were asymptomatic after embolization. The average tumor size reduction was 32% with a mean time of 53.2 months (five to 101 months). Three patients (14%) have benefited from surgery remotely. CONCLUSION: Embolization is the best technique for treating bleeding secondary to AML. In preventive treatment or symptomatic, AML embolization is a treatment to offer before considering surgery. PMID- 20951931 TI - [Impact of low-dose CT in the diagnosis and treatment of renal colic in emergency department]. AB - OBJECTIVE: To evaluate the diagnostic performance and the benefit in terms of management of low-dose CT for the imaging assessment of renal colic (CN) emergencies. PATIENTS AND METHODS: Two hundred and ninety-one patients admitted to emergency for CN were included in this study. Eighty-seven had a low-dose CT and 40 an ASP and an ultrasound (ASPE). Different parameters evaluating the diagnostic performance and efficiency of care were compared between the two groups. The quantitative and qualitative variables were compared by Student t test and chi(2) test, respectively. RESULTS: CT and ASPE confirmed the diagnosis of CN in 76% and 54% of patients, respectively (p=0.013). The average lengths of stay were 408 minutes versus 520 (p=0.013) in group scanner and ASPE, respectively. The scan was obtained more rapidly (139 min versus 224, p=0.002). There were more requests for expert advice (30% versus 20%, p=0.18) and gestures endo-urology (9.5% versus 5%, p=0.31) in the CT group compared to the group ASPE. Finally, the patients in the scanner have less painful recurrences (6% versus 12.5%, p=0.18) and fewer imaging examinations of second-line (0% versus 30%, p<0.001). CONCLUSION: The low dose CT has been more efficient than the couple ASPE for a CN diagnosis. It optimizes the management of emergency patients by reducing their length of stay, waiting time and the rate of second consultation. PMID- 20951932 TI - [Does robotics improve laparoscopic radical prostatectomy in complex surgical cases?]. AB - The radical prostatectomy is the main treatment prostate cancer in young men. However in difficult cases, another therapeutic option is often suggested. OBJECTIVE: Evaluation of the quality of the anastomosis in complex surgical cases by comparing laparoscopic radical prostatectomy (LRP) to robotic assisted radical prostatectomy (RLRP). MATERIAL: From March 2004 to August 2009, 397 patients underwent radical prostatectomy: 176 LRP and 221 RLRP consecutively by the same surgeon. Antecedents that might have complicated dissection were analyzed: prostatic volume over 80 cc, previous inguinal hernia repair with mesh, previous pelvic surgery, body mass index over 30 and previous trans-urethral resection of prostate. RESULTS: In a preoperative mode, there was no significant difference between the two groups. A multivariable analysis of the quality of the anastomosis turned to the advantage of the robot (OR=2.56 [95 %CI: 1.28-5.25]), specifically for difficult cases (Odd Ratio=7.736 [95 %CI: 2.689-22.254]). CONCLUSION: The use of the robot improved the quality of the anastomosis for patients that might have raised technical issues. PMID- 20951933 TI - [Prospective monocentric evaluation of bladder tumor targeting by Hexvix(r) fluorescence: preliminary results]. AB - PURPOSE: Prospective evaluation of bladder tumor targeting by Hexvix((r)) fluorescence. PATIENT AND METHODS: From September 2008 to September 2009, 28 patients have been evaluated using Hexvix((r)) technique (blue light) for typically papillary bladder tumor or suspected bladder tumor. Clinical and pathological data have been collected and patients have been classified using EORTC score. RESULTS: From the 28 patients, 14 have been identified with bladder cancer (31 tumors) and 90 samples have shown positive fluorescence in blue light. Compared to white light, four additional tumors have been diagnosed by Hexvix((r)) for three patients (p=NS): two cis, one LMP, one pTa low grade. The false positive rate for Hexvix((r)) was 65.5 versus 58.5% for white light. EORTC score for bladder cancer was associated with better bladder cancer targeting by Hexvix((r)) (p<0.05). CONCLUSION: In our experience, Hexvix((r)) targeting was associated with better diagnosis for bladder cancer. Thirteen percent of new positive samples have been found for 10.7% of patients. In our study false positive rate is a critical point (65.5%). EORTC score for recurrence and progression might allow to select patients to be targeted by Hexvix((r)). PMID- 20951934 TI - [Assessment of cancer RCP meetings in Rhone-Alpes: a survey on the ground]. AB - The results of a local survey sent to urologists, oncologists and radiotherapeutists working in Rhone-Alpes have been reported to assess the value of multidisciplinary oncological meetings (RCP) in Urology. The results of this short study have been analyzed and compared to the national results published by the Inspection Generale des Affaires Sociales report. Meanwhile, we have created a professional electronic directory collecting all RCP of Rhone-Alpes, which will be accessible soon. PMID- 20951935 TI - [Torsion of spermatic cord: can we trust a previous orchidopexy? A case report with loss of a single testis with medico-legal issue]. AB - The authors report the case of a patient aged of 27 years who presented in the past a testicular torsion with loss of the ipsilateral testis and fixation of the contralateral one. Ten years later, he presented with pain on the remaining testis, which evolved to necrosis, and led to a second orchidectomy. In retrospective, it appears that the assumption that the testis had been adequately fixed ten years earlier led to the loss of the remaining testis. We thus recommend an urgent surgical exploration when facing a suspicion of spermatic cord torsion, regardless of previous history of orchidopexy. PMID- 20951936 TI - [Pelvic kystic schwannoma evoking a tumor of the right seminal vesicle]. AB - We present the case of a pelvic schwannoma in a 36 year old man. It was discovered by chance during the medical assessment of a prostatitis. A computed tomography scan and magnetic resonance imaging revealed a 8 centimeters cystic pelvic tumor, closed to the right seminal vesicle. The patient underwent a transrectal ultrasound-guided biopsy, which showed a proliferation of neural peripheric cells with nuclear abnormalities. A tumorectomy was performed by laparotomy. The histological study diagnosed a benign cystic schwannoma. The patient was free of disease 12 months postoperatively. PMID- 20951937 TI - MicroRNA biogenesis takes another single hit from microsatellite instability. AB - In this issue of Cancer Cell, Melo et al. show that mutation of a single allele of the Exportin-5 gene (XPO5) suffices to depress microRNA (miRNA) levels and promote tumorigenesis. Thus, XPO5 joins the ranks of DICER and TRBP as a haploinsufficient tumor suppressor in the miRNA biogenesis pathway. PMID- 20951938 TI - T-lineage lymphoblastic lymphoma and leukemia-a MASSive problem. AB - T cell precursor malignancies may present as T-lymphoblastic lymphoma (T-LBL) with marked enlargement of lymph nodes or acute T-lymphoblastic leukemia (T-ALL) with little lymph node enlargement. In this issue of Cancer Cell, Feng et al. show that dysregulation of BCL2, AKT signaling, and cell adhesion pathways are hallmarks of T-LBL. PMID- 20951939 TI - Epigenetics and microRNAs combine to modulate the MDM2/p53 axis in myeloma. AB - Avoiding the inhibitory effects of p53 on cell growth is important for tumor progression. In this issue of Cancer Cell, Picchiorri et al. describe epigenetic silencing of MDM2-targeting microRNAs in multiple myeloma (MM), which generally appears to have intact p53 function. This provides the rationale for microRNA targeted therapy for MM. PMID- 20951940 TI - BRAF inhibitor unveils its potential against advanced melanoma. AB - Unresponsiveness to therapy is a hallmark feature of advanced metastatic melanoma. However, the discovery of BRAF-activating mutations in approximately 50% of human melanomas has provided an attractive therapeutic target. Here, we discuss two recent publications focusing on the mutant BRAF kinase inhibitor PLX4032 that validate oncogene-targeted melanoma therapy. PMID- 20951941 TI - A genetic defect in exportin-5 traps precursor microRNAs in the nucleus of cancer cells. AB - The global impairment of mature microRNAs (miRNAs) is emerging as a common feature of human tumors. One interesting scenario is that defects in the nuclear export of precursor miRNAs (pre-miRNAs) might occur in transformed cells. Exportin 5 (XPO5) mediates pre-miRNA nuclear export and herein we demonstrate the presence of XPO5-inactivating mutations in a subset of human tumors with microsatellite instability. The XPO5 genetic defect traps pre-miRNAs in the nucleus, reduces miRNA processing, and diminishes miRNA-target inhibition. The XPO5 mutant form lacks a C-terminal region that contributes to the formation of the pre-miRNA/XPO5/Ran-GTP ternary complex and pre-miRNAs accumulate in the nucleus. Most importantly, the restoration of XPO5 functions reverses the impaired export of pre-miRNAs and has tumor-suppressor features. PMID- 20951942 TI - Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. AB - Epigenetic alterations have been increasingly implicated in oncogenesis. Analysis of Drosophila mutants suggests that Polycomb and SWI/SNF complexes can serve antagonistic developmental roles. However, the relevance of this relationship to human disease is unclear. Here, we have investigated functional relationships between these epigenetic regulators in oncogenic transformation. Mechanistically, we show that loss of the SNF5 tumor suppressor leads to elevated expression of the Polycomb gene EZH2 and that Polycomb targets are broadly H3K27-trimethylated and repressed in SNF5-deficient fibroblasts and cancers. Further, we show antagonism between SNF5 and EZH2 in the regulation of stem cell-associated programs and that Snf5 loss activates those programs. Finally, using conditional mouse models, we show that inactivation of Ezh2 blocks tumor formation driven by Snf5 loss. PMID- 20951943 TI - Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase. AB - Cyclin D1 elicits transcriptional effects through inactivation of the retinoblastoma protein and direct association with transcriptional regulators. The current work reveals a molecular relationship between cyclin D1/CDK4 kinase and protein arginine methyltransferase 5 (PRMT5), an enzyme associated with histone methylation and transcriptional repression. Primary tumors of a mouse lymphoma model exhibit increased PRMT5 methyltransferase activity and histone arginine methylation. Analyses demonstrate that MEP50, a PRMT5 coregulatory factor, is a CDK4 substrate, and phosphorylation increases PRMT5/MEP50 activity. Increased PRMT5 activity mediates key events associated with cyclin D1-dependent neoplastic growth, including CUL4 repression, CDT1 overexpression, and DNA rereplication. Importantly, human cancers harboring mutations in Fbx4, the cyclin D1 E3 ligase, exhibit nuclear cyclin D1 accumulation and increased PRMT5 activity. PMID- 20951944 TI - Myeloid leukemia development in c-Cbl RING finger mutant mice is dependent on FLT3 signaling. AB - Although myeloid leukemias are primarily caused by leukemic stem cells, the molecular basis of their transformation remains largely unknown. Here, by analyzing mice with a mutation in the RING finger domain of c-Cbl, we show that the E3 ubiquitin ligase activity of c-Cbl is required to restrict myeloid leukemia development. These mice develop a myeloproliferative disease which progresses to leukemia and involves hematopoietic progenitors that exhibit augmented FLT3 signaling. Suppressing this signaling through matings with FLT3 ligand knockout mice prevents leukemia development. We also observe enhanced c Kit, Akt and Erk activity, and deregulated expression of leukemia-associated transcription factors in hematopoietic progenitors. The characterization of these perturbations provides direction for therapeutics that may aid the treatment of patients with c-Cbl mutations. PMID- 20951945 TI - T-lymphoblastic lymphoma cells express high levels of BCL2, S1P1, and ICAM1, leading to a blockade of tumor cell intravasation. AB - The molecular events underlying the progression of T-lymphoblastic lymphoma (T LBL) to acute T-lymphoblastic leukemia (T-ALL) remain elusive. In our zebrafish model, concomitant overexpression of bcl-2 with Myc accelerated T-LBL onset while inhibiting progression to T-ALL. The T-LBL cells failed to invade the vasculature and showed evidence of increased homotypic cell-cell adhesion and autophagy. Further analysis using clinical biopsy specimens revealed autophagy and increased levels of BCL2, S1P1, and ICAM1 in human T-LBL compared with T-ALL. Inhibition of S1P1 signaling in T-LBL cells led to decreased homotypic adhesion in vitro and increased tumor cell intravasation in vivo. Thus, blockade of intravasation and hematologic dissemination in T-LBL is due to elevated S1P1 signaling, increased expression of ICAM1, and augmented homotypic cell-cell adhesion. PMID- 20951946 TI - Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. AB - In multiple myeloma (MM), an incurable B cell neoplasm, mutation or deletion of p53 is rarely detected at diagnosis. Using small-molecule inhibitors of MDM2, we provide evidence that miR-192, 194, and 215, which are downregulated in a subset of newly diagnosed MMs, can be transcriptionally activated by p53 and then modulate MDM2 expression. Furthermore, ectopic re-expression of these miRNAs in MM cells increases the therapeutic action of MDM2 inhibitors in vitro and in vivo by enhancing their p53-activating effects. In addition, miR-192 and 215 target the IGF pathway, preventing enhanced migration of plasma cells into bone marrow. The results suggest that these miRNAs are positive regulators of p53 and that their downregulation plays a key role in MM development. PMID- 20951948 TI - [Viral induced bronchiolitis and genetics]. PMID- 20951947 TI - Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage. AB - Microtubule inhibitors are important cancer drugs that induce mitotic arrest by activating the spindle assembly checkpoint (SAC), which, in turn, inhibits the ubiquitin ligase activity of the anaphase-promoting complex (APC). Here, we report a small molecule, tosyl-L-arginine methyl ester (TAME), which binds to the APC and prevents its activation by Cdc20 and Cdh1. A prodrug of TAME arrests cells in metaphase without perturbing the spindle, but nonetheless the arrest is dependent on the SAC. Metaphase arrest induced by a proteasome inhibitor is also SAC dependent, suggesting that APC-dependent proteolysis is required to inactivate the SAC. We propose that mutual antagonism between the APC and the SAC yields a positive feedback loop that amplifies the ability of TAME to induce mitotic arrest. PMID- 20951949 TI - [In-utero antiretroviral exposure and mitochondrial toxicity in a cohort of uninfected infants born to HIV-1-infected women]. AB - INTRODUCTION: In this study, we attempt to find out the percentage of uninfected infants born to HIV-infected women and exposed in-utero and perinatally to Antiretroviral Treatment (ART) that show high lactate levels, or any other mitochondrial damage markers (such as hypertransaminasaemia or hyperamylasaemia), during the first three months of age. We shall also establish whether certain drugs used in-utero are associated with higher lactate, transaminase or amylase levels. METHODS: We analysed the available data from 623 uninfected infants born in the Spanish FIPSE cohort that were born in the period 2000-2005. The normal values for lactate, transaminases and amylase were set according to AIDS Clinical Groups Trials toxicity tables for infants. RESULTS: The percentages of children with high lactate levels at 0.5; 1.5 and 3 months of age were 48%, 51.4% and 43% among those infants with available data. Respectively, the percentages of children with high AST values were 13.2; 10.4 and 17.2%. The values for high ALT were 3.3%; 3.4% and 5%. The percentages for hyperamylasaemia were 0%; 0.6% and 2.6%. We found no significant difference among the drugs used in utero for the four analysed biochemical markers along the first three months of age. CONCLUSIONS: We have found a high proportion of hyperlactataemia among infants exposed in-utero to ART, as shown in other cohorts of similar characteristics. No morbidity or mortality was communicated to the cohort analysis group. No ART drug among those used in-utero was statistically associated with a higher proportion of high lactate levels in these infants. PMID- 20951950 TI - [Process optimization in the hospital--more than a method from the "quality diminution--work ethic"]. PMID- 20951951 TI - [Process optimisation: from theory to practical implementation]. AB - Today process optimisation is an indispensable approach to mastering the current challenges of modern health care management. The objective is to design business processes free of defects and free of waste as well as their monitoring and controlling with meaningful test statistics. Based on the identification of essential key performance indicators, key success factors and value cash generators two basic approaches to process optimisation, which are well established and widely used in the industry, are now being implemented in the health care sector as well: Lean Management and Six Sigma. PMID- 20951952 TI - [Process orientation as a tool of strategic approaches to corporate governance and integrated management systems]. AB - The concept of general process orientation as an instrument of organisation development is the core principle of quality management philosophy, i.e. the learning organisation. Accordingly, prestigious quality awards and certification systems focus on process configuration and continual improvement. In German health care organisations, particularly in hospitals, this general process orientation has not been widely implemented yet - despite enormous change dynamics and the requirements of both quality and economic efficiency of health care processes. But based on a consistent process architecture that considers key processes as well as management and support processes, the strategy of excellent health service provision including quality, safety and transparency can be realised in daily operative work. The core elements of quality (e.g., evidence based medicine), patient safety and risk management, environmental management, health and safety at work can be embedded in daily health care processes as an integrated management system (the "all in one system" principle). Sustainable advantages and benefits for patients, staff, and the organisation will result: stable, high-quality, efficient, and indicator-based health care processes. Hospitals with their broad variety of complex health care procedures should now exploit the full potential of total process orientation. PMID- 20951953 TI - [Working together with the staff to implement change: leadership and responsibilities]. AB - Top-down process optimisation, i.e. the adjustment of hospital treatment and care processes in terms of a best possible resource utilisation straight from the desk of the managing director, is doomed to fail. Instead, the employees' "creative potential" should be used in order to implement change not over the heads of, but hand in hand with staff members, which sets high demands on managing directors and requires a new understanding and concept of leadership. In order to promote more staff independence, management by objectives plays an essential role. PMID- 20951954 TI - [Process optimisation in hospitals: from process to business organisation]. AB - Apart from a multidimensional quality definition and the understanding of quality as a company-wide challenge, a third essential element of quality management is prevention. Thus, company quality policy has to be prevention-oriented and requires both customer and process orientation as important prerequisites. Process orientation especially focuses on the critical analyses of work flows as a condition for identifying early intervention options which, in turn, may influence the result. Developing a business organisation requires the definition of criteria for space planning, room assignment and room integration in consideration of both medical and economic aspects and the architectural concept. Specific experiences will be demonstrated as a case study using the example of a new building in the midst of the Carl Gustav Carus University Hospital in Dresden, the Diagnostic Centre for Internal Medicine and Neurology. The hospital management placed an order to develop a sustainable as well as feasible business organisation for all the different departments. The idea was to create a medical centre where maximum use was made of all planned spaces and resources on the basis of target processes which had to be defined and agreed upon with all the persons concerned. In a next step all the personal, space and operational resources required were assigned. The success of management in all industries, including the health care sector, crucially depends on the translation of ideas into practice, among them the critical factor of sustainability. In this context, the support by the management as a role model, a formal frame for the respective project group and the definition of controlling via defined indicators have special importance. The example of the Diagnostic Centre for Internal Medicine and Neurology demonstrates that the result of changed processes may release a cultural change where competition can be replaced by cooperation step by step. PMID- 20951955 TI - [Case study: Operating department reorganization in a hospital of maximal care and greater standards--a current challenge]. PMID- 20951956 TI - [Improvement of medical processes with Six Sigma - practicable zero-defect quality in preparation for surgery]. AB - Six Sigma is an innovative management- approach to reach practicable zero- defect quality in medical service processes. The Six Sigma principle utilizes strategies, which are based on quantitative measurements and which seek to optimize processes, limit deviations or dispersion from the target process. Hence, Six Sigma aims to eliminate errors or quality problems of all kinds. A pilot project to optimize the preparation for neurosurgery could now show that the Six Sigma method enhanced patient safety in medical care, while at the same time disturbances in the hospital processes and failure costs could be avoided. All six defined safety relevant quality indicators were significantly improved by changes in the workflow by using a standardized process- and patient- oriented approach. Certain defined quality standards such as a 100% complete surgical preparation at start of surgery and the required initial contact of the surgeon with the patient/ surgical record on the eve of surgery could be fulfilled within the range of practical zero- defect quality. Likewise, the degree of completion of the surgical record by 4 p.m. on the eve of surgery and their quality could be improved by a factor of 170 and 16, respectively, at sigma values of 4.43 and 4.38. The other two safety quality indicators "non-communicated changes in the OR schedule" and the "completeness of the OR- schedule by 12:30 a.m. on the day before surgery" also show an impressive improvement by a factor of 2.8 and 7.7, respectively, corresponding with sigma values of 3.34 and 3.51. The results of this pilot project demonstrate that the Six Sigma method is eminently suitable for improving quality of medical processes. In our experience this methodology is suitable, even for complex clinical processes with a variety of stakeholders. In particular, in processes in which patient safety plays a key role, the objective of achieving a zero- defect quality is reasonable and should definitely be aspirated. PMID- 20951957 TI - [Case study: change by means of speech-- a physician with conversation about "Change Talk"]. PMID- 20951958 TI - [Sex role orientation and interdisciplinary co-operation]. AB - Interdisciplinary collaboration between nurses and physicians contributes to optimal patient outcomes. Both insufficient knowledge of each other's roles and competencies and the power position of physicians impede nurse-physician collaboration. Health care managers play an important role in the promotion of nurse-physician collaboration. Leadership is associated with masculine traits, but female attributes are crucial in social relationships. Austrian health care management students (n=141, response rate: 93 %) rated themselves, the typical nurse and the typical physician with respect to masculine and feminine traits using the Bem sex-role-inventory (BSRI). The respondents saw themselves as equally masculine and feminine (androgynous self-concept); nurses were rated as significantly more masculine than feminine, whereas physicians were described as masculine sex-typed and significantly less feminine than nurses. For health care managers who also have to promote interdisciplinary collaboration an androgynous self-concept can be regarded as advantageous. They need to reflect on their ideas about nurses and physicians in order to manage the challenge of promoting interprofessional co-operation. PMID- 20951959 TI - [An analysis of the effectiveness of external quality assurance programmes using changes in quality indicators of individual hospitals]. AB - Judging the effectiveness of external quality assurance programmes by comparing current performance with unadjusted regional or national crude averages is misleading because the influence of the actual size of the populations under consideration as well as the variance of performance between hospitals is underestimated. Not only do these artefacts lead to a general overestimation of changes in regional averages. They also may lead to a ranking confounded by regional size. An assessment at unit level circumvents these difficulties. The differential grading of degree of departure of a unit's performance from national targets available from funnel plots allows, in addition, for the discrimination between effects due to the monitoring institution and achievements attributable to the hospital under surveillance. A central role is played by the scoring system adopted for evaluating incremental changes of performance indicator values in successive years. The following proposal is intended to both assist the assessment of effectiveness of quality assurance programmes and identify areas requiring urgent improvement. Bavarian quality assurance data (BAQ 1995) are used to illustrate the method. PMID- 20951960 TI - [Lack of evidence of benefit - using the example of low dose rate brachytherapy for the treatment of localised prostate carcinoma]. AB - The appraisal of new diagnostics or therapies performed by the Federal Joint Committee in Germany often reveals a dramatic lack of evidence of the benefit of such medical treatments. For example, the evaluation of low dose rate brachytherapy used to treat men with local prostate cancer demonstrates that controlled trials still need to be conducted to ensure evidence-based patient care. In Germany, legal incentives are missing to regularly assess the benefits of medical devices and operative techniques. For the sake of patient safety there is an urgent need for a change in law in order to initiate a systematic evaluation of these new medical technologies before their widespread use. PMID- 20951961 TI - [2. National symposium for quality management in health care delivery--cost limits in health--better quality?]. PMID- 20951962 TI - A virus takes an "L" turn to find its receptor. AB - Virus-receptor interaction represents a crucial step during virus entry. In this issue of Cell Host & Microbe, Neu et al. (2010) identify a receptor motif that engages JC virus, a human polyomavirus known to cause progressive multifocal leukoencephalopathy in immunocompromised individuals. PMID- 20951963 TI - MicroRNAs and LPS: developing a relationship in the neonatal gut. AB - Upon birth, the intestine converts from a sterile environment to a home for commensal microorganisms. How immune homeostasis is maintained during this transition is not well understood. Here, Chassin et al. (2010) demonstrate that microRNA-146a regulates the responsiveness of intestinal epithelial cells during microbial colonization of the neonatal intestine. PMID- 20951964 TI - Parasite protein kinases: at home and abroad. AB - Two studies identify protein kinases of parasitic protists with roles in either their own development or the control of the behavior of their host cell. PMID- 20951965 TI - Structure-function analysis of the human JC polyomavirus establishes the LSTc pentasaccharide as a functional receptor motif. AB - The human JC polyomavirus (JCV) causes a fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML), in immunocompromised individuals. Current treatment options for PML are inadequate. Sialylated oligosaccharides and the serotonin receptor are known to be necessary for JCV entry, but the molecular interactions underlying JCV attachment remain unknown. Using glycan array screening and viral infectivity assays, we identify a linear sialylated pentasaccharide with the sequence NeuNAc-alpha2,6-Gal-beta1,4-GlcNAc-beta1,3-Gal beta1,4-Glc (LSTc) present on host glycoproteins and glycolipids as a specific JCV recognition motif. The crystal structure of the JCV capsid protein VP1 was solved alone and in complex with LSTc. It reveals extensive interactions with the terminal sialic acid of the LSTc motif and specific recognition of an extended conformation of LSTc. Mutations in the JCV oligosaccharide-binding sites abolish cell attachment, viral spread, and infectivity, further validating the importance of this interaction. Our findings provide a powerful platform for the development of antiviral compounds. PMID- 20951967 TI - Cholesterol lipids of Borrelia burgdorferi form lipid rafts and are required for the bactericidal activity of a complement-independent antibody. AB - Borrelia burgdorferi, the agent of Lyme disease, is unusual as it contains free cholesterol and cholesterol glycolipids. It is also susceptible to complement independent bactericidal antibodies, such as CB2, a monoclonal IgG1 against outer surface protein B (OspB). We find that the bactericidal action of CB2 requires the presence of cholesterol glycolipids and cholesterol. Ultrastructural, biochemical, and biophysical analysis revealed that the bacterial cholesterol glycolipids exist as lipid raft-like microdomains in the outer membrane of cultured and mouse-derived B. burgdorferi and in model membranes from B. burgdorferi lipids. The order and size of the microdomains are temperature sensitive and correlate with the bactericidal activity of CB2. This study demonstrates the existence of cholesterol-containing lipid raft-like microdomains in a prokaryote, and we suggest that the temperature dependence of B. burgdorferi lipid raft organization may have significant implications in the transmission cycle of the spirochetes which are exposed to a range of temperatures. PMID- 20951966 TI - Nature and duration of growth factor signaling through receptor tyrosine kinases regulates HSV-1 latency in neurons. AB - Herpes simplex virus-1 (HSV-1) establishes life-long latency in peripheral neurons where productive replication is suppressed. While periodic reactivation results in virus production, the molecular basis of neuronal latency remains incompletely understood. Using a primary neuronal culture system of HSV-1 latency and reactivation, we show that continuous signaling through the phosphatidylinositol 3-kinase (PI3-K) pathway triggered by nerve growth factor (NGF)-binding to the TrkA receptor tyrosine kinase (RTK) is instrumental in maintaining latent HSV-1. The PI3-K p110alpha catalytic subunit, but not the beta or delta isoforms, is specifically required to activate 3-phosphoinositide dependent protein kinase-1 (PDK1) and sustain latency. Disrupting this pathway leads to virus reactivation. EGF and GDNF, two other growth factors capable of activating PI3-K and PDK1 but that differ from NGF in their ability to persistently activate Akt, do not fully support HSV-1 latency. Thus, the nature of RTK signaling is a critical host parameter that regulates the HSV-1 latent lytic switch. PMID- 20951968 TI - Functional dissection of the apicomplexan glideosome molecular architecture. AB - The glideosome of apicomplexan parasites is an actin- and myosin-based machine located at the pellicle, between the plasma membrane (PM) and inner membrane complex (IMC), that powers parasite motility, migration, and host cell invasion and egress. It is composed of myosin A, its light chain MLC1, and two gliding associated proteins, GAP50 and GAP45. We identify GAP40, a polytopic protein of the IMC, as an additional glideosome component and show that GAP45 is anchored to the PM and IMC via its N- and C-terminal extremities, respectively. While the C terminal region of GAP45 recruits MLC1-MyoA to the IMC, the N-terminal acylation and coiled-coil domain preserve pellicle integrity during invasion. GAP45 is essential for gliding, invasion, and egress. The orthologous Plasmodium falciparum GAP45 can fulfill this dual function, as shown by transgenera complementation, whereas the coccidian GAP45 homolog (designated here as) GAP70 specifically recruits the glideosome to the apical cap of the parasite. PMID- 20951969 TI - miR-146a mediates protective innate immune tolerance in the neonate intestine. AB - After birth, the intestinal mucosa undergoes a dramatic transition from a sterile protected site to an environmentally exposed and permanently colonized surface. The mechanisms that facilitate this transition are ill defined. Here, we demonstrate that microRNA-146a-mediated translational repression and proteolytic degradation of the essential Toll-like receptor (TLR) signaling molecule interleukin 1 receptor associated kinase 1 (IRAK1) is sufficient to induce intestinal epithelial innate immune tolerance and provide protection from bacteria-induced epithelial damage in neonates. Despite low IRAK1 protein levels, continuous TLR4- and IRAK1-dependent signal transduction induced by intraepithelial endotoxin persistence during the neonatal period maintains tolerance through sustained miR-146a expression. Strikingly, it additionally facilitates transcription of a distinct set of genes involved in cell survival, differentiation, and homeostasis. Thus, our results identify the underlying molecular mechanisms of intestinal epithelial innate immune tolerance during the neonatal period and characterize tolerance as an active condition involved in the establishment of intestinal mucosal homeostasis. PMID- 20951970 TI - A mouse model for the human pathogen Salmonella typhi. AB - Salmonella enterica serovar Typhi (S. Typhi) causes typhoid fever, a life threatening human disease. The lack of animal models due to S. Typhi's strict human host specificity has hindered its study and vaccine development. We find that immunodeficient Rag2(-/-) gammac(-/-) mice engrafted with human fetal liver hematopoietic stem and progenitor cells are able to support S. Typhi replication and persistent infection. A S. Typhi mutant in a gene required for virulence in humans was unable to replicate in these mice. Another mutant unable to produce typhoid toxin exhibited increased replication, suggesting a role for this toxin in the establishment of persistent infection. Furthermore, infected animals mounted human innate and adaptive immune responses to S. Typhi, resulting in the production of cytokines and pathogen-specific antibodies. We expect that this mouse model will be a useful resource for understanding S. Typhi pathogenesis and for evaluating potential vaccine candidates against typhoid fever. PMID- 20951971 TI - The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission. AB - Although eukaryotic protein kinases (ePKs) contribute to many cellular processes, only three Plasmodium falciparum ePKs have thus far been identified as essential for parasite asexual blood stage development. To identify pathways essential for parasite transmission between their mammalian host and mosquito vector, we undertook a systematic functional analysis of ePKs in the genetically tractable rodent parasite Plasmodium berghei. Modeling domain signatures of conventional ePKs identified 66 putative Plasmodium ePKs. Kinomes are highly conserved between Plasmodium species. Using reverse genetics, we show that 23 ePKs are redundant for asexual erythrocytic parasite development in mice. Phenotyping mutants at four life cycle stages in Anopheles stephensi mosquitoes revealed functional clusters of kinases required for sexual development and sporogony. Roles for a putative SR protein kinase (SRPK) in microgamete formation, a conserved regulator of clathrin uncoating (GAK) in ookinete formation, and a likely regulator of energy metabolism (SNF1/KIN) in sporozoite development were identified. PMID- 20951972 TI - Features associated with foveal retinal detachment in myopic macular retinoschisis. AB - PURPOSE: To determine the retinal features seen on enhanced spectral-domain optical coherence tomography (SD-OCT) associated with foveal retinal detachment in eyes with myopic macular retinoschisis. DESIGN: Retrospective case series. METHODS: We reviewed fundus photographs and conventional and enhanced SD-OCT images of 21 eyes of 19 patients with myopic macular retinoschisis. Features seen on enhanced SD-OCT images were identified and compared between eyes with and without foveal detachment. RESULTS: On enhanced SD-OCT images, the retinoschisis in the outer retina was accompanied by splitting in the inner plexiform layer (IPL) in 11 eyes (50.0%) and a detachment of the inner limiting membrane (ILM) in 11 eyes (50.0%) in the superior and/or inferior peripheral macula; 9 eyes (42.9%) had both features. Multiple columnar structures were seen throughout the outer retinoschisis in 20 of 21 eyes (95.2%), and in ILM detachment/IPL retinoschisis in all eyes. Thirteen eyes had or progressed to a foveal detachment; an ILM detachment developed in 10 eyes (76.9%) with a foveal detachment and in 1 eye (12.5%) without a foveal detachment (P = .008). IPL retinoschisis was detected in 8 eyes (61.5%) with a foveal detachment and 3 eyes (37.5%) without a foveal detachment, but this difference was not significant. CONCLUSIONS: An ILM detachment in the superior and/or inferior peripheral macula was associated with a foveal retinal detachment in highly myopic eyes with macular retinoschisis. This feature may indicate strong tractional forces on the ILM that are transmitted to the outer retina through the dense columnar structures, resulting in a foveal retinal detachment. PMID- 20951973 TI - The impact of eyeglasses on vision-related quality of life in American Indian/Alaska Natives. AB - PURPOSE: To determine the change in vision-related quality-of-life scores after providing eyeglasses to American Indian/Alaska Natives with undercorrected refractive error. STUDY DESIGN: Prospective, comparative (nonrandomized) interventional study. METHODS: We compared a group with undercorrected refractive error to a control group who did not need a change in eyeglasses. Undercorrected refractive error was defined as distance visual acuity 20/40 or worse in the better-seeing eye that could be improved by at least 2 lines in Snellen visual acuity. Intervention was the provision of new glasses to the undercorrected refractive error group members, based on results of manifest refraction. The main outcome measures were the differences in the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) scores from baseline (Time 1) to the time after providing eyeglasses (Time 2). RESULTS: The NEI VFQ-25 median Composite score at Time 1 was significantly lower in those with undercorrected refractive error when compared to the control group (75 vs 92, P = .001). The median Composite score for the undercorrected refractive error group improved to 96 (P < .001) at Time 2 when compared to Time 1, while the control group remained stable at 93 (P = .417). The undercorrected refractive error group showed significantly greater improvement than the control group in 8 of 12 subscale scores and in the overall Composite score (all P values <= .05). A multivariate linear regression analysis, which controlled for differences in age, percent self identified American Indian/Alaskan Native, and best-corrected visual acuity between the undercorrected refractive error and control group, showed eyeglasses to be significantly associated with improvement in NEI VFQ-25 composite score. CONCLUSION: Visual impairment from undercorrected refractive error is common in American Indian/Alaskan Natives. Providing eyeglasses results in a large, significant increase in vision-related quality of life. PMID- 20951974 TI - Retinal thickness in the offspring of diabetic pregnancies. AB - PURPOSE: To compare macular and peripapillary retinal nerve fiber layer (RNFL) thickness in children from diabetic compared with nondiabetic pregnancy. DESIGN: Cross-sectional study. METHODS: As part of the Sydney Myopia Study, 2367 children from grade 7 (age range 11.1 to 14.4 years) completed detailed ocular examinations during 2004-2005. Examination included determination of best corrected visual acuity (logarithm of minimal angle of resolution) and autorefraction after cycloplegia. Axial length was measured using noncontact interferometry. Optical coherence tomography (OCT) was performed using Stratus OCT through dilated pupils. Participants and parents completed comprehensive questionnaires including questions on birth parameters and medical history. RESULTS: There were 1741 and 1687 children with adequate-quality RNFL and macular scans respectively, who had complete examination and questionnaire data. There were 57 children from diabetic pregnancies who had both RNFL and macular scans. Children from diabetic pregnancies had significantly thinner inner (264.9 MUm vs 270.2 MUm, P = .007) and outer (231.9 MUm vs 238.6 MUm, P = .0001) macular thickness and macular volume (6.75 mm(3) vs 6.92 mm(3), P = .0003) compared with children from nondiabetic pregnancies. However, central macular thickness, foveal minimum thickness, and RNFL parameters were not significantly different between the 2 groups. CONCLUSION: Diabetes during pregnancy is associated with changes in retinal morphology in the offspring. Thinning of the pericentral macular parameters was evident in Stratus OCT scans of children from diabetic pregnancies. These findings suggest the possibility that maternal diabetes impacts on the development of the retina. PMID- 20951975 TI - Thickness mapping of retinal layers by spectral-domain optical coherence tomography. AB - PURPOSE: To report normal baseline thickness maps for 6 retinal layers generated by segmentation of spectral-domain optical coherence tomography (SD-OCT) images in normal subjects. Intersubject thickness variability and thickness variations in 9 macular sectors were established. DESIGN: Prospective cross-sectional study. MATERIALS AND METHODS: SD-OCT imaging was performed in 15 normal subjects. Nineteen SD-OCT images were acquired, encompassing a 6 * 5-mm retinal area, centered on the fovea. Each image was analyzed using an automated segmentation algorithm to derive thickness profiles of 6 retinal layers. Thickness data obtained from all scans were combined to generate thickness maps of 6 retinal layers: nerve fiber layer, ganglion cell layer + inner plexiform layer, inner nuclear layer, outer plexiform layer, outer nuclear layer + photoreceptor inner segments, and photoreceptor outer segments. Mean and standard deviation of thickness measurements were calculated in 9 macular sectors and 6 retinal layers. Intersubject and intrasector thickness variations were established based on standard deviation of measurements. RESULTS: Minimum and maximum thickness of the nerve fiber layer were observed in the foveal and nasal perifoveal areas, respectively. The largest thickness variation among subjects and intrasector variability were observed in perifoveal areas. Thickness of the ganglion cell layer + inner plexiform layer and intersubject thickness variability were largest in parafoveal areas. The inner nuclear layer thickness was relatively constant in parafoveal and perifoveal areas and intrasector thickness variations were largest in the foveal area. The outer plexiform layer thickness was relatively constant in foveal and parafoveal areas and higher than in perifoveal areas. Intersubject thickness variability in inner nuclear layer and outer plexiform layer was relatively uniform in all macular sectors. The outer nuclear layer + photoreceptor inner segments thickness map displayed maximum thickness in the foveal area and intersubject thickness variability was largest superior to the fovea. Thickness of the photoreceptor outer segments layer, thickness variations among subjects, and intrasector thickness variability were relatively constant. There was a significant correlation between total retinal thickness derived by thickness mapping and SD-OCT commercial software. CONCLUSION: Normal thickness maps for 6 retinal layers were generated and thickness variations among subjects and macular areas were assessed. This technique is promising for investigating thickness changes attributable to disease in specific retinal layers and macular areas. PMID- 20951976 TI - Factors influencing the reliability of autorefractometry after LASIK for myopia and myopic astigmatism. AB - PURPOSE: To study the factors influencing the reliability (accuracy) of autorefractometry before and after laser in situ keratomileusis (LASIK) for myopia and myopic astigmatism. DESIGN: Retrospective case series. METHODS: A total of 250 consecutive eyes (132 patients, mean age 37 years) were included from the Department of Ophthalmology, J.W. Goethe University, Frankfurt, Germany. The mean preoperative spherical equivalent of the subjective refraction (SR) was 6.59 diopters (D) (-1.38 to -15.13). The patient data were reviewed before and 1 month after LASIK, including SR, objective automated refraction (AR), and visual acuity. Subgroup analysis was performed with regard to the preoperative myopia and the excimer laser optical zone (OZ). The Holm-Sidak and Wilcoxon matched pairs tests were used for statistical analysis. RESULTS: The correlation coefficient between AR und SR is r = 0.98 before LASIK versus r = 0.79 afterwards (P < .001). The mean difference between the spherical equivalents (DSE) is +0.13 +/- 0.51 D preoperatively versus -0.30 +/- 0.58 D after LASIK (P < .001). With a small optical zone size (5.0-5.5 mm) the postoperative difference is -0.61 D, versus -0.36 D for OZ 5.6-6.0, versus -0.16 for OZ 6.1-7.0 mm. With a rising preoperative amount of myopia, the postoperative AR results become increasingly more myopic than the SR. CONCLUSIONS: Following LASIK, autorefractometry is less accurate than in nonoperated eyes. The reliability of the AR is influenced by the OZ and the preoperative amount of myopia, with a small OZ and high myopia resulting in a greater difference between AR and SR and with the AR determining more myopic results. PMID- 20951977 TI - Immunohistochemical expression of DNA methyltransferases 1, 3a and 3b in oral leukoplakias and squamous cell carcinomas. AB - Over-expression of DNA methyltransferases DNMT1, DNMT3a and DNMT3b has been reported in various cancers and precancerous lesions. OBJECTIVE: To investigate DNMT1, DNMT3a and DNMT3b enzymes in oral squamous cell carcinoma (SCC) and leukoplakia, and their relationship with histopathologic/clinical parameters. STUDY DESIGN: Immunohistochemistry was carried out to evaluate the three DNMTs in 60 samples of oral SCC and 37 samples of oral leukoplakia. RESULTS: DNMT3a immunoreactivity in the three groups of oral SCC (39.8%) was significantly higher than in control (22.6%) (ANOVA, Student-Newman-Keuls test, P<0.05), but not when compared to oral leukoplakia groups (28.2%). For DNMT1 and DNMT3b, there were no statistically significant differences between oral SCC groups (65% and 74.7%), oral leukoplakia groups (68.3% and 70.9%) and control (65.4% and 76.5%). There was a significantly higher mean percentage of DNMT1 immunoreactivity in non smokers (ANOVA, P=0.048), and a higher DNMT3a immunoreactivity in alcohol users (ANOVA, P=0.01). CONCLUSIONS: Higher DNMT3a immunopositivity may be associated with oral SCC and alcohol use, whilst lower levels of DNMT1 may be related with smoking habit. However, there was a significantly higher mean percentage of DNMT1 immunoreactivity in non-smokers (ANOVA, P=0.048), and a higher DNMT3a immunoreactivity in alcohol users (ANOVA, P=0.010). PMID- 20951978 TI - Decrease of prefrontal metabolism after subthalamic stimulation in obsessive compulsive disorder: a positron emission tomography study. AB - BACKGROUND: High-frequency bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is a promising treatment in refractory obsessive-compulsive disorder (OCD). METHOD: Using the crossover, randomized, and double-blind procedure adopted by the STOC study, 10 patients treated with high-frequency bilateral STN DBS underwent am 18-fluorodeoxyglucose positron emission tomography (PET) investigation to highlight the neural substratum of this therapeutic approach. RESULTS: The median Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores for all 10 patients were 31 (minimum = 18, maximum = 36) with "Off Stimulation" status and 19 (minimum = 0, maximum = 30) with "On-Stimulation" status (p = .05). The OCD patients in Off-Stimulation status showed a hypermetabolism in the right frontal middle and superior gyri, right parietal lobe, postcentral gyrus, and bilateral putamen compared with healthy control subjects. A significant decrease in cerebral metabolism was observed in the left cingulate gyrus and the left frontal medial gyrus in On-Stimulation conditions compared with Off-Stimulation conditions. In addition, the improvement assessed by Y-BOCS scores during the On-Stimulation conditions was positively correlated with PET signal changes at the boundary of the orbitofrontal cortex and the medial prefrontal cortex, between PET signal changes and the Y-BOCS scores modifications in On-Stimulation status. CONCLUSION: This study suggests that the therapeutic effect of STN DBS is related to a decrease in prefrontal cortex metabolism. PMID- 20951979 TI - Reduced cortical thickness as an outcome of differential sensitivity to environmental risks in schizophrenia. AB - BACKGROUND: The etiology of schizophrenia is thought to involve differential likely genetically mediated-sensitivity to environmental exposures. However, examination of differential sensitivity in models of psychopathologic constructs is subject to bias because psychopathology itself may distort exposure assessment. The use of neuroimaging phenotypes, conversely, may provide unbiased evidence for differential sensitivity to environmental exposures. This study examined the impact of two environmental exposures associated with both schizophrenia and magnetic resonance imaging (MRI) cerebral alterations in models of cerebral cortical thickness. METHODS: T1-weighted MRI scans were acquired from 88 patients with schizophrenia, 98 healthy siblings at higher than average genetic risk for schizophrenia, and 87 control subjects. Freesurfer software was used to measure cortical thickness for 68 brain regions. Associations between 1) cortical thickness and 2) cannabis use and developmental trauma were examined. RESULTS: A significant group * developmental trauma interaction (chi(2) = 9.65, p = .01), as well as a significant group * cannabis interaction (chi(2) = 6.04, p = .05) was apparent, indicating differential sensitivity of the patient group, which displayed stronger reductions of cortical thickness for both exposures. A similar pattern was found in the sibling-control comparison for cannabis. For developmental trauma, siblings did not differ from control subjects, displaying an increase in cortical thickness with higher levels of trauma. CONCLUSIONS: The findings suggest that schizophrenia and its genetic liability are associated with differential cerebral cortical sensitivity to developmental environmental exposures such as cannabis. Gene-environment interactions may underlie some of the brain alterations observed in patients with schizophrenia and their relatives. PMID- 20951980 TI - Abnormal cingulate and prefrontal cortical neurochemistry in major depression after electroconvulsive therapy. AB - BACKGROUND: Metabolic changes after electroconvulsive therapy (ECT) have been described in depressed patients, but results are heterogeneous. To determine the concentrations of N-acetyl-aspartate (NAA), choline-containing compounds, creatine + phosphocreatine (tCr), and glutamate in the left dorsolateral prefrontal cortex (DLPFC) and left anterior cingulum of depressed patients before and after ECT, we used proton magnetic resonance spectroscopy. METHODS: Metabolite concentrations in the DLPFC and anterior cingulum were determined in 25 patients with major depressive disorder (MDD) and 27 healthy control subjects using the point resolved spectroscopy sequence. Neuropsychological and clinical parameters were determined before and after nine sessions of right unilateral ultrabrief pulse ECT. RESULTS: In the cingulum, baseline glutamate and NAA levels were decreased in depressed patients. High glutamate at baseline predicted a greater treatment response. After ECT, increased NAA levels were observed in responders to treatment and tCr levels were significantly decreased across all depressive patients. In the left DLPFC, NAA levels were significantly decreased in responders to ECT compared with nonresponders. Autobiographic memory was deteriorated in all patients after ECT. CONCLUSIONS: Low glutamatergic state in depressive patients emphasizes the role of dysfunctional glutamatergic neurotransmission in the pathophysiology of MDD. The low NAA level at baseline in the patients supports neurodegenerative changes in MDD. N-acetyl-aspartate levels might serve as early surrogate marker for dynamic metabolic changes due to ECT, reflecting both neuroprotection and lowered neuronal viability. The tCr decrease in the cingulum suggests altered mitochondrial energy metabolism. PMID- 20951981 TI - The kinetics of p-nitrophenyl-beta-D-cellobioside hydrolysis and transglycosylation by Thermobifida fusca Cel5Acd. AB - The hydrolysis of p-nitrophenyl-beta-1,4-cellobioside (pNP-G2) by the catalytic domain of the retaining-family 5-2 endocellulase Cel5A from Thermobifida fusca (Cel5Acd) was studied. The dominant reaction pathway involves hydrolysis of the aglyconic bond, producing cellobiose (G2) and a 'reporter' species p-nitrophenol (pNP), which was monitored spectrophotometrically to track the reaction. We also detected the production of cellotriose (G3) and p-nitrophenyl-glucoside (pNP-G1), confirming the presence of a competing transglycosylation pathway. We use a mechanistic model of hydrolysis and transglycosylation to derive an expression for the rate of pNP-formation as a function of enzyme concentration, substrate concentration, and several lumped kinetics parameters. The derivation assumes that the quasi-steady-state assumption (QSSA) applies for three intermediate species in the mechanism; we determine conditions under which this assumption is rigorously justified. We integrate the rate expression and compare its integral form to pNP-versus-time data collected for a range of enzyme and substrate concentrations. The integral comparison gives a stringent test of the mechanistic model, and it serves to quantify the lumped kinetics parameters with good statistical precision, particularly a previously unidentified parameter that determines the selectivity of hydrolysis versus transglycosylation. The integrated rate expression accounts well for pNP-versus-time data under all circumstances we have investigated. PMID- 20951982 TI - The computational model to predict accurately inhibitory activity for inhibitors towards CYP3A4. AB - The cytochrome P450 (CYP) is a superfamily of enzymes with oxidative function responsible for the metabolism of xenobiotics especially drug metabolism. CYP3A4, an extensive studied CYP isoform, plays crucial role in the metabolism of structurally diverse drugs. Furthermore, the drug-drug interaction resulted from the inhibition of CYP3A4 activity is of extreme importance for the treatment of disease and the development of new drug. In this study, using the method of the support vector machine (SVM) and three descriptors selected from the 153 descriptors we construct the models that can predict accurately the inhibitory effect of a compound on the activity of CYP3A4. By optimizing the parameters related to SVM, the cross validation correlation efficient of the model can achieve 0.71, which is higher than those of other models obtained using Artifical Neutral Network (ANN) and Partial least square (PLS) methods to our knowledge, and thus our model can present the important application in assessment of the potential toxicity of a drug as well as prediction of drug-drug interactions. PMID- 20951983 TI - [Information resources in medicine: present and future trends]. AB - We are immersed in a new paradigm for scientific information access that, in the future, will be only be available and transmitted in electronic format. The concept of using internet as information storage has changed, with emphasis on its interactivity and possibility to share contents. The Web 2.0 has revolutionized the way of internet is understood, promoting the participation of those who access it, collaborating in its construction per se through intuitive and easy-to-use tools. Medicine 2.0 means supposes the participation of the user in the design, selection and evaluation of the contents. The future of access to information is through Medicine 2.0 services. The aim of this paper is to review the tools and instruments available for health care professionals to access scientific information, with special emphasis on web 2.0 tools. PMID- 20951984 TI - Imaging of endometriosis with computerized tomography colonography. AB - We demonstrate the use of computerized tomography colonography for the imaging of intestinal endometriosis to facilitate preoperative management in our hospital setting. PMID- 20951985 TI - Wide percutaneous access to pancreatic necrosis with self-expandable stent: new application (with video). PMID- 20951986 TI - Intralesional steroid injection after endoscopic balloon dilation in pediatric Crohn's disease with stricture: a prospective, randomized, double-blind, controlled trial. AB - BACKGROUND: Endoscopic balloon dilation (EBD) is an attractive conservative therapy for Crohn's disease (CD) with stricture; however, its long-term efficacy has been questioned because many patients require more dilations or postdilation surgery. Most reports are retrospective, and no pediatric data are available. OBJECTIVE: To assess the effectiveness of corticosteroid intralesional injection after EBD in preventing stricture recurrence. DESIGN: Single-center prospective, randomized, double-blind, controlled trial. SETTING: Tertiary-referral university hospital. PATIENTS: Between November 2005 and January 2009, 29 pediatric patients with stricturing CD were enrolled. INTERVENTIONS: Enrolled patients were randomized to receive intrastricture injection of corticosteroid (CS) (n = 15) or placebo (n = 14) after EBD. Patients were followed clinically via small intestine contrast US and intestinal magnetic resonance imaging at 1, 3, 6, and 12 months; all underwent colonoscopy 12 months after dilation. MAIN OUTCOME MEASUREMENTS: Time free of repeat dilation and time free of surgery in the 2 groups. RESULTS: One of the 15 patients receiving CS required redilation, whereas the latter was needed in 5 of the 14 placebo patients; surgery was needed in 4 of the placebo patients, but in none of those receiving CS. The 2 groups statistically differed in the time free of redilation (P = .04) as well as for time free of surgery after EBD (P = .02), which were worse in the placebo group compared with the CS group. There were no significant differences in baseline demographics between the 2 groups. LIMITATIONS: Sample size, participation bias, and short-term follow-up. CONCLUSION: In pediatric CD with stricture, intralesional CS injection after EBD is an effective strategy for reducing the need both for redilation and surgery. PMID- 20951987 TI - Temporary self-expandable metal stent placement for treatment of post sphincterotomy bleeding. AB - BACKGROUND: Endoscopic sphincterotomy (ES) is a basic technique for performing therapeutic interventions during ERCP. Bleeding after ES is a recognized complication and can be difficult to treat. OBJECTIVE: To evaluate the role of temporary placement of fully covered self-expandable metal stents (SEMSs) for the treatment of difficult-to-control post-ES hemorrhage. DESIGN: Retrospective case series. SETTING: Interventional endoscopy unit at a tertiary care referral hospital. PATIENTS: Five patients treated with temporary SEMSs for difficult-to control post-ES hemorrhage. INTERVENTIONS: ERCP with placement of fully covered, biliary SEMSs and subsequent stent removal within 8 weeks. MAIN OUTCOME MEASUREMENTS: Technical success of SEMS placement, clinical success with hemostasis, complications related to SEMS placement and removal. RESULTS: Five patients were treated with temporary fully covered SEMSs for post-ES hemorrhage over an 8-month period. Hemostasis was achieved in all patients. Within 8 weeks of the procedure, the SEMSs were easily removed in 3 patients; the SEMSs had spontaneously migrated without incident in the other 2. No other complications were seen. LIMITATIONS: Retrospective series with a small number of patients. CONCLUSIONS: Temporary placement of fully covered SEMSs across the biliary orifice seems to be an effective treatment for post-ES hemorrhage. However, stent migration is a concern and may limit this therapy in certain settings. PMID- 20951988 TI - A new partially covered metal stent for palliation of malignant dysphagia: a prospective follow-up study. AB - BACKGROUND: Metal stents are frequently used for palliation of malignant dysphagia. Recently, a new stent design, the partially covered Wallflex stent (Boston Scientific, Natick, Mass), has been introduced. OBJECTIVE: To determine clinical effectiveness and safety of the esophageal Wallflex stent for the palliation of dysphagia. DESIGN: A prospective follow-up study evaluating a new stent design. SETTING: Three tertiary-care referral centers. PATIENTS: This study involved 37 patients with cancer of the esophagus or gastric cardia. INTERVENTIONS: Stent placement. MAIN OUTCOME MEASUREMENTS: Data were collected regarding technical and clinical outcome, complications, recurrent dysphagia, and survival. RESULTS: A total of 37 patients (median age, 67 years; range, 48-84 years; 22 men [59%]) had a Wallflex stent placed. Stent placement was technically successful in all but 1 patient. Dysphagia improved from a median dysphagia score of 3 (ability to swallow liquids only) to 1 (ability to eat some solid foods) 4 weeks after stent placement. Major complications occurred in 3 patients (8%; pneumonia in 1, severe pain in 2), and 1 patient (3%) died from a complication (pneumonia). Minor complications included mild retrosternal pain in 10 patients (27%) and regurgitation in 7 patients (19%). In total, 8 patients (22%) developed recurrent dysphagia because of stent migration (n = 2 [6%]), food impaction (n = 2 [6%]), or tissue ingrowth or overgrowth (n = 4 [10%]). LIMITATIONS: Nonrandomized study design. CONCLUSIONS: Placement of a partially covered Wallflex stent is safe and effective for the palliation of malignant dysphagia, with migration and tissue in- and overgrowth rates comparable to those of similarly designed stents. Retrosternal pain may occur more often with this stent than with other stent designs. PMID- 20951989 TI - Endoscopic closure of GI fistulae by using an over-the-scope clip (with videos). AB - BACKGROUND: Preclinical studies have demonstrated the over-the-scope clip (OTSC) to be feasible and safe for closure of gastric, duodenal, and colonic perforations. A retrospective clinical study demonstrated the feasibility and preliminary safety of the OTSC for the treatment of GI bleeding and closure of acute GI perforations. OBJECTIVE: Because the OTSC allows rapid and easy endoscopic organ wall closure, we hypothesized that it might be a useful tool to close GI fistulae. DESIGN: Case series. SETTING: Academic medical center. PATIENTS: Four consecutive patients with GI fistulae. INTERVENTIONS: In all patients, a 12-mm OTSC, in combination with the dedicated twin grasper, anchor device, or endoscopic suction, was used to facilitate endoscopic closure. MAIN OUTCOME MEASUREMENTS: In 2 cases, OTSCs allowed complete closure of a posttraumatic esophagopulmonary fistula and a chronic gastrocutaneous fistula. Leak tests and follow-up examination demonstrated complete leakproof closures. In 1 esophagopulmonary fistula and 1 jejunocutaneous fistula, the initial closure attempts using OTSCs were not successful because of chronic fibrotic changes and scarring at the fistula site. Both OTSCs were removed by using an endoscopic grasping forceps. The mean procedure time was 54 minutes (range 24-93 minutes). There were no procedure-related complications. LIMITATIONS: Small sample size. CONCLUSIONS: The OTSC seems to be a feasible device to close chronic fistulae of the GI tract. It can achieve leakproof, full-thickness closure of transmural defects. Nevertheless, in circumstances of severe fibrosis and scarring, complete incorporation of the defect into the applicator cap and successful OTSC application might not be possible. PMID- 20951990 TI - Relationship between haematoma in femoral neck fractures contamination and early postoperative prosthetic joint infection. AB - INTRODUCTION: Prosthetic joint infection (PJI) after femoral neck fracture is associated with a higher mortality, morbidity and economic costs. Although is well known that the presence of a post surgical haematoma is associated with infection, in our knowledge there are no articles evaluating the contamination of the femoral neck fracture haematoma and the possible relationship with early postoperative PJI. The aim of our study was to evaluate the prevalence of positive cultures from haematoma in patients with femoral neck fracture and the relationship with early PJI. METHODS: A prospective observational study was performed. All patients who underwent hiphemiarthroplasty for a femoral neck fracture from April'08 to February'09 were included. Three samples were taken just after the arthrotomy, a tissue sample, a swab of haematoma and blood of haematoma inoculated into blood culture flasks. Patients received the standard prophylaxis. RESULTS: A total of 109 patients were treated during this period in our center, 16 were excluded for mistakes during taking samples or for receiving extra antibiotic treatment after or before the surgery of the fracture. In 29 patients (31.2%) one or more intraoperative cultures were positive. Four patients developed an early PJI caused by Gram-negative bacilli (GNB) in all cases. The early PJI rate in the group of patients with negative intraopertive cultures was 3.1% while in the group with one or more positive cultures was 6.9% (p = 0.3). In 3 cases the haematoma was contaminated with a GNB. The PJI rate inpatients with intraoperative cultures positive for a GNB was 66.6% (2/3) while in the group of patients without a GNB the infection rate was 2.2% (2/89, p = 0.004, Fisher exact test). Furthermore in these two patients the microorganism that caused the PJI was the same that had been isolated from the haematoma. CONCLUSION: The haematoma in femoral neck fractures was contaminated in 31.2% of cases before surgery. The contamination of the haematoma with a GNB was associated with a higher risk of early postoperative PJI. PMID- 20951992 TI - Percutaneous techniques in the treatment of osteoporotic, traumatic and neoplastic fractures of thoraco-lumbar spine: our institutional experience. AB - Fifty-eight (30 females) patients with a mean age of 55 were treated in our institution with minimal invasive surgery techniques for osteoporotic, traumatic and neoplastic fractures of the thoraco-lumbar spine. All patients completed pre operatively and post-operatively the VAS score (0-10, 10 being the worst state for pain) as well as the Oswestry low back pain disability questionnaire at 3, 12, 24 and 36 months intervals. Overall the VAS score was reduced from 7.8 points pre-operatively, to 2.1 points at the 36 month follow up. Oswestry disability score improved from a pre-operative severe disability to moderate disability at 3 months up to a minimum disability at 36 months. The minimally invasive surgical techniques can significantly improve clinical outcomes by preventing many of the drawbacks associated with open approaches whilst also allowing to associate other methods such as coblation, vertebroplasty, interbody fusion that can be complementary to vertebral fixation. PMID- 20951991 TI - Late recovery of sciatic nerve palsy at twelve years following pelvis fracture. PMID- 20951993 TI - Influence of counter-ions on the self-assembly of ZrO2 nanodisks. AB - In three strong inorganic acidic conditions (HNO(3), HCl and H(2)SO(4)), we have prepared a series of air-water interfacial zirconium dioxide (ZrO(2)) films at normal temperature via a self-assembly technique, by using dodecylbenzenesulfonic acid (DBSA) as template and Zr(OC(4)H(9))(4) as precursor. X-ray diffraction (XRD), transmission electron microscope (TEM), UV-vis and fluorescence spectra have been used to characterize the ZrO(2) films. Results show that a number of worm-like mesoporous nanodisks and ambiguously mesoporous nanodisks are observed in the ZrO(2) films with NO(3)(-) and SO(4)(2-) counter-ions, respectively. Remarkably, a great many perfect target-like multiring nanodisks are obtained in the ZrO(2) sample with Cl(-) counter-ion. The self-assembly mechanism for ZrO(2) nanodisks has been purposely discussed. A model based on the structural changes with respect to the influence of counter-ions on the self-assembly of ZrO(2) nanodisks is therefore proposed. In addition, the structural changes for the ZrO(2) films self-assembled at a higher temperature have been discussed in combination with the influence of counter-ions. PMID- 20951994 TI - Minimising reversion, using seawater and magnesium chloride, caused by the dissolution of tricalcium aluminate hexahydrate. AB - The increase in pH and aluminium concentration after the neutralisation of bauxite refinery residues is commonly known as reversion. This investigation reports the extent of reversion in synthetic supernatant liquor and possible methods to reduce reversion. This work is based on bauxite refinery residues produced from alumina refineries, where reversion is a real life situation in neutralised refinery residues. Tricalcium aluminate hexahydrate, a common phase in bauxite refinery residues, has been found to cause reversion. It has been established that reductions in both pH and aluminium from the seawater neutralisation process are due to the formation of 'Bayer' hydrotalcite Mg(7)Al(2)(OH)(18)(CO(3)(2-),SO(4)(2-)).xH(2)O. This is the primary mechanism involved in the removal of aluminium from solution. Increasing the volume of seawater used for the neutralisation process minimises the extent of reversion for both synthetic supernatant liquor and red mud slurry. The addition of MgCl(2).6H(2)O also showed a reduction in reversion and confirmed that the decrease in aluminium and hydroxyl ions is due to the formation of Bayer hydrotalcite and not simply a dilution effect. PMID- 20951995 TI - Facile patterning of upconversion NaYF4:Yb,Er nanoparticles. AB - Different kinds of highly ordered patterns of NaYF(4):Yb,Er nanoparticles on gold substrates were fabricated using a simple method combining micro-contact printing and "breath figures" techniques. Ordered arrays of water droplets were first formed in the hydrophilic regions of patterned self-assembled monolayers (SAMs). This was subsequently submerged in a chloroform solution of NaYF(4):Yb,Er nanoparticles. The particles were spontaneously assembled at the interface of chloroform/water droplet surface, leading to different kinds of uniform patterns after solvent evaporation. The structures of NaYF(4):Yb,Er particles patterns depended on the dimension of the substrate, the concentration of the NaYF(4):Yb,Er nanoparticles and the water condensation process. PMID- 20951996 TI - Chinese children's evaluations of white lies: weighing the consequences for recipients. AB - This research examined how Chinese children make moral judgments about lie telling and truth telling when facing a "white lie" or "politeness" dilemma in which telling a blunt truth is likely to hurt the feelings of another. We examined the possibility that the judgments of participants (7-11 years of age, N=240) would differ as a function of the social context in which communication takes place. The expected social consequences were manipulated systematically in two studies. In Study 1, participants rated truth telling more negatively and rated lie telling more positively in a public situation where telling a blunt truth is especially likely to have negative social consequences. In Study 2, participants rated truth telling more positively and rated lie telling more negatively in a situation where accurate information is likely to be helpful for the recipient to achieve future success. Both studies showed that with increased age, children's evaluations became significantly influenced by the social context, with the strongest effects being seen among the 11-year-olds. These results suggest that Chinese children learn to take anticipated social consequences into account when making moral judgments about the appropriateness of telling a blunt truth versus lying to protect the feelings of another. PMID- 20951997 TI - Antidepressant effects, of magnetic seizure therapy and electroconvulsive therapy, in treatment-resistant depression. AB - Major depression is a common mental health problem and associated with significant morbidity and mortality, including impaired social and physical functioning and increased risk for suicide. Electroconvulsive therapy (ECT) is highly efficacious in treatment-resistant depressive disorders, but cognitive side effects are frequently associated with the treatment. Magnetic seizure therapy (MST) is a form of convulsive therapy, using magnetic fields in order to induce therapeutic seizures. First studies suggested that cognitive side effects of MST, including postictal recovery time, are more benign than those resulting from ECT treatment. In this open-label study we tested the hypothesis that MST is associated with clinically significant antidepressant effects in treatment resistant depression (TRD) as an add-on therapy to a controlled pharmacotherapy. Twenty patients suffering from TRD were randomly assigned to receive either MST or ECT starting from July 2006 until November 2008. Primary outcome measure was antidepressant response assessed by Montgomery Asberg Depression Scale. Secondary outcome measures included Hamilton Depression Rating Scale, Hamilton Anxiety Scale, Beck Depression Inventory and 90-Item Symptom Checklist. Antidepressant response (improvement of 50% in MADRS ratings) was statistically significant and of similar size in both treatment groups. Cognitive side effects were observed in neither group. Characteristics in MST- and ECT-induced seizures were comparable, especially regarding ictal activity and postictal suppression. Thus, MST may be a potential alternative to ECT if efficacy and safety are validated in larger clinical trials. PMID- 20951998 TI - Investigation of tumor-peritoneal interactions in the pathogenesis of peritoneal metastases using a novel ex vivo peritoneal model. AB - BACKGROUND: Peritoneal metastasis occurs in up to 30% of patients with gastric cancer. The aim of this experimental study is to develop and validate a novel ex vivo model of the human peritoneum to better identify factors involved in the development of peritoneal metastasis in order to improve its management and prognosis. METHODS: Peritoneal discs harvested from hernia sacs obtained at inguinal hernia surgery were suspended in media using Teflon rings. Viability of the tissue was investigated using MTS assay, light and scanning electron microscopy (LM and SEM) over 72 h. To assess validity of the model, phenotypic changes in tumor cells were investigated. Changes in matrix metalloproteinases (MMP)-2 and -9 activities in HGC and AGS gastric adenocarcinoma cells after co culture were investigated using zymography. Modulation of tumor cell adhesion to peritoneum after exposure to heparin was assessed using a fluorometric adhesion assay. Analysis was performed using Kruskal-Wallis for multiple comparisons and Mann-Witney U for comparisons between each group. RESULTS: MTS assay showed reduced viability after 72 h (P = 0.047, compared with 24 h). Mesothelial cell loss at 48 h was demonstrated by LM and SEM, confirming peritoneal viability for at least 24 h after tissue harvesting. Zymography confirmed increased MMP2 and -9 activities in tumor cells and peritoneal tissue during co-culture compared with controls, and heparin significantly reduced tumor cell adherence (P = 0.04), as observed in published in vivo models. CONCLUSION: A validated complete model of peritoneum was developed that has shown potential to determine realistic mechanisms of peritoneal metastasis. PMID- 20951999 TI - A new treatment era in multiple sclerosis: clinical applications of new concepts. AB - Several clinical courses have been defined in multiple sclerosis (MS), but uncertainty remains as to whether they reflect different neuropathological mechanisms. Two recent concepts have emerged which could influence the treatment strategy adopted in MS: inflammation drives axonal damage; disability progression in MS follows a two-stage process. PMID- 20952000 TI - Grafts are unnecessary for proximal bulbar reconstruction. AB - PURPOSE: We compared our experience with the reconstruction of proximal vs distal bulbar stricture to assess the role of excision and primary anastomosis vs graft procedures at each site. MATERIALS AND METHODS: We reviewed all urethroplasties done by a single surgeon during a 2-year period. Data analyzed included patient history and demographics, operative details, stricture length and site, and clinical outcome. The proximal bulbar urethra was defined as the segment within 5 cm of the membranous urethra and the distal bulb was defined as the adjoining segment extending to the penoscrotal junction. Cases involving the pendulous or posterior urethra were excluded from study. RESULTS: Of 210 urethroplasties from 2007 to 2009, 112 were done for bulbar strictures, including 72 (64%) for proximal bulbar strictures. All 72 cases were treated with excision and primary anastomosis. Median stricture length was 2 cm (range 1 to 5), although 31 of 72 strictures (43%) were of intermediate length (2.5 to 5 cm). Recurrence developed in 1 case (1.4%). Distal bulbar strictures in 40 of the 112 cases (36%) were treated predominantly with substitution urethroplasty in 36 (90%), and with excision and primary anastomosis in 4 (10%). Median stricture length was 3.75 cm (range 1.5 to 20). We noted intermediate length stricture in 18 of 40 cases (45%) and recurrence in 11 (28%). Of intermediate length strictures recurrence was much rarer after excision and primary anastomosis than after graft procedures (1 of 33 or 3.0% vs 6 of 16 or 38%, p<0.05). CONCLUSIONS: Location is critical when selecting an appropriate technique for bulbar urethral reconstruction. Excision and primary anastomosis are superior to grafts in the proximal bulb. Grafts are often unnecessary for reconstructing proximal bulbar strictures 5 cm or less. PMID- 20952001 TI - Urodynamic studies are recommended in children with central nervous system tumors regardless of location. AB - PURPOSE: Neurogenic bladder dysfunction is a frequent occurrence in association with neoplasms involving the central nervous system. We determine whether tumor location in children with central nervous system neoplasms correlates with specific patterns of urodynamic abnormalities, alleviating the need for urodynamic investigations in these patients. MATERIALS AND METHODS: A total of 62 children with the diagnosis of a central nervous system neoplasm underwent urodynamic investigation after treatment between 1994 and 2004. Patient demographics, tumor location and etiology were assessed. Urodynamic variables recorded included bladder capacity, early and late compliance, voiding pressure and post-void residual volume. For comparative analysis patients were grouped according to central nervous system level of involvement. Statistical analysis was performed, with p<0.05 considered significant. RESULTS: Mean+/-SD patient age at urodynamic evaluation was 10.6+/-7 years. Tumor was located intracranially in 21% of patients and in the spinal cord in 79% (cervical/thoracic in 27%, lumbar in 27%, sacral in 47%). There was no correlation between tumor location and any specific bladder dynamic parameter (p>0.05). Similarly there were no significant differences in urodynamic findings in patients with intracranial vs extracranial tumors, or in those with sacral vs suprasacral involvement. CONCLUSIONS: Abnormalities in urodynamic parameters in children with a central nervous system tumor cannot be predicted based on the location of tumor involvement. Therefore, urodynamic evaluation is appropriate in all patients with neoplastic involvement of the central nervous system, regardless of the tumor location, for best management of lower urinary tract function. PMID- 20952002 TI - Retropubic bulbourethral sling for post-prostatectomy male incontinence: 2-year followup. AB - PURPOSE: Post-prostatectomy incontinence is usually due to sphincter damage as a complication of prostatectomy but may result from other causes. The intermediate term outcome of the retropubic bulbourethral sling is presented. MATERIALS AND METHODS: Included in study were 40 men with post-prostatectomy incontinence who used 5 or greater pads daily for protection. All patients had undergone prostatectomy, including transurethral resection in 17, holmium laser enucleation in 3, and open retropubic and radical prostatectomy in 12 and 8, respectively. Preoperatively voiding cystourethrogram and urodynamics were done in all men as applicable. A bulbourethral sling was prepared from polypropylene mesh. Suspension was achieved using size zero nylon sutures to fix the mesh in front of the rectus sheath. Patients were followed at 1 week, 3 and 6 months, and semiannually thereafter. RESULTS: Median incontinence duration was 3 years (range 0.5 to 14). Concomitant surgery was done in 11 men (27.5%), 34 (85%) were dry at 24-month followup and 10 (25%) underwent retightening at 3 to 6 months. Urodynamics showed no significant change in filling or voiding parameters. The increase in maximum urethral closure pressure and functional urethral length was not statistically significant. CONCLUSIONS: The described retropubic bulbourethral sling is a viable option for severe male incontinence with a satisfactory cure rate at intermediate followup. It is adjustable and cost effective. PMID- 20952003 TI - Botulinum toxin-A injections into neurogenic overactive bladder--to include or exclude the trigone? A prospective, randomized, controlled trial. AB - PURPOSE: The short-term outcomes of initial detrusor injections vs combined detrusor-trigone botulinum toxin-A injections were determined in patients with spinal cord injury-neurogenic detrusor overactivity. MATERIALS AND METHODS: Adults with refractory spinal cord injury-neurogenic detrusor overactivity who strictly discontinued anticholinergics were recruited for the study. At a 1:1 ratio patients randomly received 300 U botulinum toxin-A intradetrusor injections excluding the trigone (detrusor arm) or 200 U intradetrusor plus 100 U intratrigonal injections (combined arm). Study end points were determination of the impact on incontinence episodes, complete dryness, quality of life, reusing anticholinergics, maximum detrusor pressure, reflex volume, maximum cystometric capacity, vesicoureteral reflux and adverse events. Patients were evaluated at baseline, and 2, 8, 12 and 18 weeks after injection. Statistical significance was considered at p<0.05. RESULTS: Analysis included 18 patients per arm with no significant baseline differences. On within group analysis all parameters improved significantly compared to baseline. On between group analysis in the detrusor vs the combined arm at week 8 incontinence decreased by 52.4% vs 80.9% (number needed to treat 1.91 vs 1.23 patients, p<0.001), complete dryness was achieved in 33.3% vs 66.7% of patients (number needed to treat 3 vs 1.5, p<0.001) and quality of life score was decreased by 46.76% vs 48.13% (number needed to treat 2.14 vs 2.08, p<0.44). The absolute difference was 60% vs 82.5% for reflex volume (p<0.001), 66.2% vs 68.4% for maximum cystometric capacity (p<0.22) and 42.3% vs -41.9% for maximum detrusor pressure (p<0.21). At week 18 anticholinergics were needed again in 9 (50%) and 4 patients (22.2%) patients, respectively. No patient showed new or upgraded vesicoureteral reflux or reported significant adverse events. CONCLUSIONS: In the short term all parameters improved significantly in each arm. The superiority of including rather than excluding the trigone was significant. PMID- 20952004 TI - A noninvasive, motility independent, sperm sorting method and technology to identify and retrieve individual viable nonmotile sperm for intracytoplasmic sperm injection. AB - PURPOSE: For intracytoplasmic sperm injection in the absence of sperm motility it can be virtually impossible to distinguish viable from nonviable sperm. A reliable means to identify viable nonmotile sperm is needed and would likely improve the intracytoplasmic sperm injection success rate. Optoelectronic tweezers are a new technology that uses light induced dielectrophoresis fields to distinguish individual live cells from dead cells. We assessed the ability of optoelectronic tweezers to distinguish viable from nonviable individual nonmotile human sperm. MATERIALS AND METHODS: Fresh semen specimens from 6 healthy men were suspended in an isotonic sucrose/dextrose solution and incubated with 0.4% trypan blue dye (Sigma-Aldrich(r)). Within 15 minutes we randomly selected 5 motile and 50 nonmotile sperm, including 25 trypan negative, followed by 25 trypan positive sperm, under 200* magnification for optoelectronic tweezers assay. We recorded the individual sperm response (attraction or repulsion) to the optoelectronic tweezer field and trypan staining status. RESULTS: From each subject 55 unwashed sperm were individually assayed for a total of 330. All motile sperm were attracted to optoelectronic tweezers. Of 150 trypan negative (viable) sperm 132 (88%) were attracted to the optoelectronic tweezer field with 0.88 sensitivity (95% CI 0.82-0.93) vs that of the trypan blue assay. All 150 trypan positive (nonviable) sperm were repulsed by or neutral to the optoelectronic tweezer field with 1.0 specificity (95% CI 0.98-1.00) vs that of the trypan blue assay. Type I error equaled 0 and overall assay agreement was 94%. CONCLUSIONS: The optoelectronic tweezer assay can distinguish viable from nonviable nonmotile viable sperm with sensitivity comparable to that of the trypan blue assay and equal specificity. Optoelectronic tweezers are a promising means of selecting sperm for intracytoplasmic sperm injection. PMID- 20952005 TI - Transurethral enucleation and resection of prostate in patients with benign prostatic hyperplasia by plasma kinetics. AB - PURPOSE: We evaluated transurethral enucleation and resection of the prostate in patients with urinary symptoms due to benign prostatic hyperplasia using the PlasmakineticTM system. MATERIALS AND METHODS: We retrospectively analyzed the records of 1,100 patients who underwent transurethral enucleation and resection of the prostate between January 2003 and February 2009 at our institution. We assessed the International Prostate Symptom Score, quality of life score, peak flow rate and post-void residual urine volume preoperatively, 1, 3, 6 and 12 months postoperatively, and yearly thereafter. Enucleation and resection time, enucleated tissue weight, catheterization time, hospital stay and long-term complications were recorded. RESULTS: No patient had significant blood loss or signs of the transurethral resection syndrome. Mean+/-SD patient age was 66.7+/ 7.3 years and mean followup was 4.3 years. Mean preoperative prostate weight was 67.7+/-12 gm (range 35 to 256), mean enucleation time was 15.5 minutes (range 10 to 38), mean resection time was 46 minutes (range 20 to 65) and mean resected tissue weight was 42.8+/-7.7 gm (range 23 to 219). Mean catheter time was 1.8+/ 0.4 days and mean hospital stay was 5.3+/-2.3 days. Transurethral enucleation and resection of the prostate induced significant, pronounced, immediate and lasting improvement in the International Prostate Symptom Score, quality of life, maximum urinary flow and post-void residual urine volume. Postoperative complications included meatal stenosis in 9 cases, incontinence in 56, urethral stricture in 12 and bladder neck contracture in 10. CONCLUSIONS: Transurethral enucleation and resection of the prostate appears to be the modern alternative to transurethral resection of the prostate and open prostatectomy for bladder outlet obstruction due to benign prostatic hyperplasia. It may be done in glands up to 250 gm. PMID- 20952006 TI - Assessing urological complications of radiation therapy and surgical approaches for repair. PMID- 20952007 TI - Contralateral ureteroscopy performed at percutaneous nephrolithotomy: a unique evaluation of stone-free rates. AB - PURPOSE: Immediate stone-free rates of ureteroscopy are rarely reported. To establish accurate stone-free rates after ureteroscopy we assessed the safety and success of ureteroscopy for patients undergoing the procedure at contralateral percutaneous nephrolithotomy. MATERIALS AND METHODS: From our prospectively collected, institutional review board approved, percutaneous nephrolithotomy database we identified patients who underwent contralateral ureteroscopy for urolithiasis at percutaneous nephrolithotomy from December 2001 to December 2008. Stone-free status was assessed with noncontrast computerized tomography on postoperative day 1. RESULTS: A total of 65 patients underwent ureteroscopy for urolithiasis at contralateral percutaneous nephrolithotomy. There were 63 patients available for review who had noncontrast computerized tomography on postoperative day 1. Immediate stone-free status was achieved after ureteroscopy in 37 of 63 patients (58.7%). The remaining 26 patients (41.3%) demonstrated a residual stone burden. Of these patients with residual stones after ureteroscopy 65.4% (17 of 26) had residual fragments of 1 to 3 mm and 34.6% (9 of 26) had residual stones larger than 3 mm. Three patients (4.8%) underwent repeat ureteroscopy at secondary percutaneous nephrolithotomy. There was no association of stone composition, patient age, stone location, gender or surgical complications with residual fragments (p>0.05). CONCLUSIONS: Based on noncontrast computerized tomography 58.7% of patients who underwent ureteroscopy were rendered immediately stone-free. When residual passable stone fragments less than 3 mm were included the success rate increased to 85.7%. We found no association between characteristics of patients, stones or procedures and residual fragments. PMID- 20952008 TI - The effectiveness of shock wave lithotripters: a case matched comparison. AB - PURPOSE: We compared the results of shock wave lithotripsy with a newer electromagnetic lithotripter to those of an electrohydraulic lithotripter using identical treatment and followup criteria. MATERIALS AND METHODS: We performed a case matched comparison of 8,565 patients treated from 2003 to 2007 using the Medstone STSTM and the Modulith(r) SLX machines, matching for stone size, location and patient body mass index. The outcome of interest was treatment success in producing stone-free status. We report treatment characteristics, such as stone site and size, gating and final stone-free rate. Significance was considered at p<0.05. RESULTS: Overall Modulith SLX and Medstone STS stone-free rates were equivalent (61.1% and 64.5%, respectively, p=0.0664). Matching and logistic regression results showed that differences in the stone-free rate were insignificant for all stones (p>0.7592), lower pole kidney stones (p=0.9659) and ureteral stones (p=0.6409). Medstone STS performed better than Modulith SLX only for distal ureteral stones (83.63% vs 66.67%, p=0.0154). The rate of post lithotripsy secondary procedures was equivalent (p=0.2079). The difference was insignificant for harder stones (p=0.2988). CONCLUSIONS: Shock wave lithotripsy is equally effective using Medstone STS and Modulith SLX for different stone sizes and most stone sites. Shock wave lithotripsy is more successful for lower ureteral stones using the Medstone STS. To our knowledge this is the first study comparing these 2 commonly used lithotripters. PMID- 20952009 TI - Quality of life in adults with bladder exstrophy-epispadias complex. AB - PURPOSE: We evaluated quality of life in adults with bladder exstrophy-epispadias complex to improve patient and parent counseling. MATERIALS AND METHODS: We evaluated quality of life in a multicenter study using the SF-36(r) Medical Outcome Study questionnaire and a local questionnaire. A total of 47 patients born in 1957 to 1990 were followed due to bladder exstrophy-epispadias complex at the 4 participating hospitals. RESULTS: Nine women and 16 men were included in analysis, including 15 who underwent staged reconstruction for bladder exstrophy epispadias complex and 10 who underwent primary or secondary urinary diversion. Nine patients were married and 2 were in a long-term partnership. A total of 22 patients achieved a high school degree with examination success and 17 worked full time. Six women and 12 men achieved penetrative intercourse. A total of 13 children were born to 3 women and 7 men. Quality of life scores in our patients were less than the norm based scores on 2 of the 8 health concepts, including limitations in physical activity due to health problems and general health perception. Results were statistically different among patients depending on dryness, voiding and urinary reconstruction/diversion. Patient scores did not differ in regard to gender, number of interventions, sexual life, cosmesis or renal function. CONCLUSIONS: Patient scores were less than norm based scores on only 2 health concepts and patients were generally well integrated into society. Urinary diversion was usually well tolerated. It remains a therapeutic option when incontinence interferes with social life or renal function is compromised. PMID- 20952010 TI - Annual surgical caseload and open radical prostatectomy outcomes: improving temporal trends. AB - PURPOSE: Radical prostatectomy is the standard of care for localized prostate cancer. Numerous previous reports show the relationship between surgical experience and various outcomes. We examined the effect of surgical experience on complications and transfusion rates, and determined individual surgeon annual caseload trends in a contemporary radical prostatectomy cohort. MATERIALS AND METHODS: We analyzed annual caseload temporal trends in 34,803 patients who underwent surgery between 1999 and 2008 in Florida. Logistic regression models controlled for clustering among surgeons addressed the relationship of surgical experience, defined as the number of radical prostatectomies done since January 1, 1999 until each radical prostatectomy, with complications and transfusions. RESULTS: During the study period the proportion of surgeons in the high annual caseload tertile (24 radical prostatectomies or greater yearly) and the proportion of patients treated by those surgeons increased from 5% to 10% and from 20% to 55%, respectively. Conversely complication and transfusion rates decreased from 14.3% to 9.2% and 12.6% to 6.9%, respectively. Radical prostatectomies done by surgeons in the high surgical experience tertile (86 or greater radical prostatectomies) decreased the risk of any complication by 33% and of any transfusion by 30% vs those in patients operated on by surgeons in the low surgical experience tertile (27 or fewer radical prostatectomies). CONCLUSIONS: The proportion of surgeons in the high annual caseload tertile and the proportion of patients treated by these surgeons steadily increased during the last decade. Complication and transfusion rates decreased with time. The implications of these encouraging findings may result in improved outcomes in patients with surgically managed prostate cancer. PMID- 20952011 TI - A prospective early history of incident interstitial cystitis/painful bladder syndrome. AB - PURPOSE: The longitudinal history of interstitial cystitis/painful bladder syndrome has been studied infrequently. In a national sample of incident cases we assessed changes in symptoms during the first several years of interstitial cystitis/painful bladder syndrome. MATERIALS AND METHODS: We recruited 312 women with a history of interstitial cystitis/painful bladder syndrome symptoms of 12 months or less and interviewed them by telephone at baseline, and 6, 12, 18, 24, 36 and 48 months later. We queried symptoms in the last week and interval medication use. Individual and composite symptom categories were constructed. RESULTS: The median history of symptoms at study enrollment was 9 months. Median followup was 33 months after onset. The 57 study withdrawals (18%) were not substantively different than those remaining in followup. Many cases of severe and moderate interstitial cystitis/painful bladder syndrome at enrollment improved with time. As followup progressed, increasing proportions reported improvement while decreasing proportions reported symptom worsening. Of the women 27 (9%) reported at least temporary symptom remission. CONCLUSIONS: Of 304 women with incident interstitial cystitis/painful bladder syndrome 35% reported improvement from baseline in symptoms at last followup a median of 33 months after onset. However, the disappearance of all symptoms at any followup was uncommon. PMID- 20952012 TI - Skeletal muscle involvement by limited Gleason score 6 adenocarcinoma of the prostate on needle biopsy is not associated with adverse findings at radical prostatectomy. AB - PURPOSE: Skeletal muscle involvement by prostate cancer is considered to be ambiguous for extraprostatic extension when it is found at the apex, where benign prostatic glands naturally blend with the skeletal muscle of the rhabdosphincter. We investigated the significance of skeletal muscle involvement by cancer in needle biopsies in predicting adverse outcomes at radical prostatectomy. MATERIALS AND METHODS: From 2000 to 2009, we retrospectively identified 40 cases with Gleason score 6 adenocarcinoma involving up to 20% of 1 core, with skeletal muscle involvement. Outcomes of radical prostatectomy were compared with a control group of 82 cases with the same parameters without skeletal muscle involvement from the same period. RESULTS: In radical prostatectomy specimens Gleason score greater than 6, extraprostatic extension and positive margins were found in 15.0%, 7.5% and 12.5% of patients in the study group, compared to 20.7%, 11.0% and 4.9% of patients in the control group, respectively. No statistically significant differences were found between cases with or without skeletal muscle involvement on needle biopsy. The apical margin was the only positive margin in 4 of 5 study group cases with positive margins. In contrast, positive margins were randomly distributed in the control group. CONCLUSIONS: Limited cancer involvement of skeletal muscle in biopsy specimens should not be used as a contraindication for radical prostatectomy for otherwise resectable prostate cancer as most patients have organ confined disease and negative margins. However, care must be taken during division of the dorsal vein complex to avoid a positive margin on the anterior apex of the prostate. PMID- 20952013 TI - Efficacy and safety of onabotulinumtoxinA for idiopathic overactive bladder: a double-blind, placebo controlled, randomized, dose ranging trial. AB - PURPOSE: Treatment options for patients with overactive bladder refractory to anticholinergics are limited. We assessed the dose response across a range of doses of onabotulinumtoxinA (BOTOX(r)) in patients with idiopathic overactive bladder and urinary urgency incontinence whose symptoms were not adequately managed with anticholinergics. MATERIALS AND METHODS: In a phase 2, multicenter, randomized, double-blind study, 313 patients with idiopathic overactive bladder and urinary urgency incontinence experiencing 8 or more urinary urgency incontinence episodes a week and 8 or more micturitions daily at baseline received 50, 100, 150, 200 or 300 U intradetrusor onabotulinumtoxinA, or placebo. Symptoms were recorded using a 7-day bladder diary. The primary efficacy variable was weekly urinary urgency incontinence episodes and the primary end point was week 12. RESULTS: Demographics and baseline characteristics were balanced across the treatment groups. Durable efficacy was observed for all onabotulinumtoxinA dose groups of 100 U or greater for primary and secondary efficacy measures, including the proportion of incontinence-free patients. When the dose response curves were analyzed, doses greater than 150 U contributed minimal additional or clinically relevant improvement in symptoms. This finding was also reflected in health related quality of life assessments. Dose dependent changes in post-void residual urine volume were observed and the use of clean intermittent catheterization was also dose dependent. The only adverse events significantly greater with onabotulinumtoxinA than with placebo were urinary tract infection and urinary retention. CONCLUSIONS: OnabotulinumtoxinA at doses of 100 U or greater demonstrated durable efficacy in the management of idiopathic overactive bladder and urinary urgency incontinence. A dose of 100 U may be the dose that appropriately balances the symptom benefits with the post-void residual urine volume related safety profile. PMID- 20952014 TI - Factors associated with quality of life in women undergoing surgery for stress urinary incontinence. AB - PURPOSE: We determined the association of clinicodemographic factors with urinary incontinence related quality of life in women undergoing surgery for stress urinary incontinence, and compared the incontinence specific Incontinence Impact Questionnaire and the International Consultation on Incontinence Questionnaire. Secondary objectives were to evaluate the contributions of incontinence severity and sexual function on quality of life. MATERIALS AND METHODS: We used baseline data on 597 women in the Trial of Mid-Urethral Slings. Tested quality of life correlates included health status and history, sexual function, and urinary incontinence type, severity and bother. RESULTS: On each questionnaire lower quality of life was associated with younger age, higher body mass index, more stress urinary incontinence symptoms, and more severe and bothersome urinary incontinence symptoms. Each measure identified factors associated with lower quality of life that were not identified by the other, including Hispanic ethnicity, poor health status and more urge urinary incontinence symptoms on the Incontinence Impact Questionnaire, and prior urinary incontinence treatment and more urinary incontinence episodes daily on the International Consultation on Incontinence Questionnaire. Sexually active women had similar quality of life as well as increased incontinence episodes on each questionnaire and more sexual dysfunction on the Incontinence Impact Questionnaire only. CONCLUSIONS: In women planning stress urinary incontinence surgery quality of life is associated with nonurinary incontinence factors, and with the type, severity and degree of urinary incontinence symptom bother. Many factors are associated with quality of life as measured by the Incontinence Impact Questionnaire and the International Consultation on Incontinence Questionnaire. However, more nonurinary incontinence factors were associated with quality of life when measured by the former than by the latter. More than 1 scale may be needed to evaluate quality of life after treatment for stress urinary incontinence. PMID- 20952015 TI - Botox(r) in urology--will it become standard of care for urge urinary incontinence? PMID- 20952016 TI - In vivo determination of urinary stone composition using dual energy computerized tomography with advanced post-acquisition processing. AB - PURPOSE: We assessed whether dual energy computerized tomography with advanced post-image processing can accurately differentiate urinary calculi composition in vivo. MATERIALS AND METHODS: A total of 25 patients scheduled to undergo ureteroscopic/percutaneous nephrolithotomy were prospectively identified. Dual energy computerized tomography was performed using 64-slice multidetector computerized tomography. Novel post-processing (DECTSlope) used pixel by pixel analyses to generate data sets grayscale encoding ratios of relative differences in attenuation of low (DECT80 kVp) and high energy (DECT140 kVp) series. Surgical extraction and Fourier spectroscopy resulted in 82 calculi. Of these stones 51 showed minor admixtures (uric acid, ammonium urate, struvite, calcium oxalate monohydrate and brushite) and 31 were polycrystalline (mixtures of calcium oxalate monohydrate/dihydrate and calcium phosphate). Analyses identified stone clusters of equal composition and distinct attenuation descriptors on DECT140 kVp, DECT80 kVp and DECTSlope. Iterative cross-validation of the 3 dual energy computerized tomography data sets was used to identify characteristic attenuation limits for each stone type. RESULTS: Attenuatio profiles showed substantial overlap among various stones on DECT140 kVp (uric acid 427.3+/-168.1 HU, ammonium urate 429.9+/-99.7 HU, struvite 480.2+/-123.5 HU, calcium oxalate monohydrate 852.4+/-301.4 HU, brushite 863.7+/-180.1 HU and polycrystalline 858.1+/-210.5 HU) and on DECT80 kVp (uric acid 493.6+/-182.8 HU, ammonium urate 591.5+/-157.9 HU, struvite 712.4+/-173.9 HU, calcium oxalate monohydrate 1,240.5+/-494.7 HU, brushite 1,532.1+/-273.1 HU and polycrystalline 1,358.7+/-316.8 HU). Statistically spectral separation was not sufficient to characterize stones unambiguously based on DECT140 kVp/DECT80 kVp attenuation. Analysis of attenuation showed sufficient spectral separation on DECTSlope (uric acid 14.9+/ 10.9 U, ammonium urate 56.1+/-1.8 U, struvite 42.7+/-1.4 U, calcium oxalate monohydrate 62.8+/-1.8 U and brushite 113.2+/-5.3 U). Polycrystalline stones (51.8+/-3.7 U) overlapped with struvite and ammonium urate stones. This overlap was resolved as all struvite/ammonium urate stones measured 900 HU or less and all polycrystalline stones measured more than 900 HU on DECT80 kVp. CONCLUSIONS: Dual energy computerized tomography with novel post-processing allows accurate discrimination among main subtypes of urinary calculi in vivo and, thus, may have implications in determining the optimum clinical treatment of urinary calculi from a noninvasive, preoperative radiological assessment. PMID- 20952017 TI - The delivery of prostate cancer care in the United States: implications for delivery system reform. AB - PURPOSE: Since health care in the United States is fragmented and expensive, 1 reform option focuses on improving care coordination as in the medical home model. To better understand care coordination in the context of prostate cancer we examined how the delivery of prostate cancer care is partitioned across primary care providers and specialists. MATERIALS AND METHODS: We identified 105,961 patients diagnosed with prostate cancer between 1992 and 2005 using Surveillance, Epidemiology and End Results-Medicare data. We assigned all health care for prostate cancer and nonprostate cancer diagnoses by provider specialty across 3 distinct phases of care, including initial, continuing care and end of life. We then identified service types and proportions of care across specialties. RESULTS: Urologists provided most prostate cancer care (45.2%). Radiation oncologist involvement decreased from 27.4% of claims in the initial phase to 5.5% and 5.7% in the continuing care and end of life phases, respectively. Conversely medical oncology and to a lesser degree primary care captured a greater percent of ongoing prostate cancer care. In patients with prostate cancer 7,120,343 of 36,837,904 services (19.3%) were directly related to prostate cancer care. Primary care providers were responsible for 47% of overall health care in men with prostate cancer. CONCLUSIONS: Urologists provided most prostate cancer care while primary care providers were responsible for most overall health care in men with prostate cancer. In light of current reforms directed at improving care coordination urologists serve as a logical starting point to improve care delivery in the broader context of a medical home. PMID- 20952018 TI - Malignancy and augmentation--how worried should we be? PMID- 20952019 TI - Use of the UPOINT chronic prostatitis/chronic pelvic pain syndrome classification in European patient cohorts: sexual function domain improves correlations. AB - PURPOSE: Patients with chronic prostatitis-chronic pelvic pain syndrome are difficult to treat due to the unknown etiology and complex clinical presentation. Clinical phenotyping may better correlate with multimodal treatment concepts than a current diagnosis. We evaluated a novel clinical phenotyping system in a database of patients with chronic prostatitis-chronic pelvic pain syndrome at 2 European institutions and correlated it with patient symptoms. We also investigated the addition of a sexual dysfunction domain in regard to symptom correlation and system internal consistency. MATERIALS AND METHODS: We retrospectively classified 937 patients from Milan, Italy, and 290 from Giessen, Germany, with chronic prostatitis-chronic pelvic pain syndrome into a 6-domain phenotyping system, consisting of urinary, psychosocial, organ specific, infection, neurological and muscle tenderness domains, termed UPOINT. Symptom severity was assessed by the National Institutes of Health Chronic Prostatitis Symptom Index and the International Prostate Symptom Score. RESULTS: There was significant correlation between the number of positive UPOINT domains and Chronic Prostatitis Symptom Index/International Prostate Symptom Score symptoms in the total and Italian cohorts but not in the German cohort. After adding a sexual dysfunction domain to create the modified UPOINTS system phenotypic domains also correlated significantly with Chronic Prostatitis Symptom Index symptoms in the German cohort. CONCLUSIONS: Consistency of the UPOINT chronic prostatitis-chronic pelvic pain syndrome clinical phenotyping system was generally confirmed by our study and further refined by adding a sexual dysfunction domain. The treatment effect of clinical phenotyping with UPOINT(S) must be extensively evaluated in prospective treatment studies. PMID- 20952020 TI - Cardiovascular safety of degarelix: results from a 12-month, comparative, randomized, open label, parallel group phase III trial in patients with prostate cancer. AB - PURPOSE: We assessed the cardiovascular safety profile of degarelix, a new gonadotropin-releasing hormone antagonist. MATERIALS AND METHODS: This is the first report to our knowledge on cardiovascular safety data from a completed 1 year randomized controlled trial of leuprolide acetate vs degarelix. Outcomes considered in these analyses included the QT interval by central reading and analysis, and cardiovascular adverse events. On multivariate analyses relationships between selected baseline factors and cardiovascular events were evaluated. RESULTS: There were no significant differences between treatment groups for mean change in Fridericia's correction of QT during the trial. Markedly abnormal Fridericia's correction of QT values (500 milliseconds or greater) were observed in only a small number of subjects by treatment group, that is 2 (less than 1%) in the pooled degarelix group and 2 (1%) in the leuprolide group. Supraventricular arrhythmias were the most common type of arrhythmias, affecting 2% of subjects in the pooled degarelix group and 4% in the leuprolide group. Other arrhythmias occurred in 1% or less of subjects by treatment group. The most frequently reported cardiac disorder was ischemic heart disease, which occurred in 4% of subjects treated with degarelix and 10% of those on leuprolide. Cox proportional hazard ratio estimates for selected baseline covariates showed a significantly increased risk of cardiovascular events by age (p=0.0459) and systolic blood pressure (p=0.0061). CONCLUSIONS: In men with prostate cancer degarelix and leuprolide have similar cardiovascular safety profiles. These observations suggest that the cardiovascular events associated with both agents result from hypogonadism rather than a direct drug effect. PMID- 20952021 TI - Testosterone and androgen receptor in human nephrolithiasis. AB - PURPOSE: We investigated the relationship of kidney calculi with plasma free and total testosterone, and androgen receptor up-regulation in the kidneys of men with nephrolithiasis. MATERIALS AND METHODS: Male patients with kidney stone and healthy men were included in the study. Blood was collected in a tube containing 2% heparin in the morning. Total and free serum testosterone was measured by enzyme linked immunosorbent assay. All patients underwent percutaneous nephrostolithotomy. At the end of the procedure ultrasound guided puncture biopsy was done to acquire kidney tissue. Normal kidney tissue obtained at autopsy served as the control. Androgen receptor was detected in kidney tissue by immunohistochemistry. Stone composition was analyzed in each patient. RESULTS: The study included 37 male patients 22 to 39 years old and 31 healthy men 24 to 37 years old. All calculi were composed of calcium oxalate monohydrate or calcium oxalate dihydrate and a few also contained protein or uric acid. Mean+/-SD serum total and free testosterone was 13.29+/-4.79 ng/ml and 63.23+/-28.58 pg/ml in patients, and 7.30+/-0.82 ng/ml and 35.59+/-24.91 pg/ml in healthy men, respectively (each p<0.001). Immunohistochemistry revealed androgen receptor up regulation in the kidneys of patients with nephrolithiasis. CONCLUSIONS: Our data suggest the important role of enhanced androgen signaling in human nephrolithiasis. PMID- 20952022 TI - The learning curve for laparoscopic radical prostatectomy: an international multicenter study. AB - PURPOSE: It is not yet possible to estimate the number of cases required for a beginner to become expert in laparoscopic radical prostatectomy. We estimated the learning curve of laparoscopic radical prostatectomy for positive surgical margins compared to a published learning curve for open radical prostatectomy. MATERIALS AND METHODS: We reviewed records from 8,544 consecutive patients with prostate cancer treated laparoscopically by 51 surgeons at 14 academic institutions in Europe and the United States. The probability of a positive surgical margin was calculated as a function of surgeon experience with adjustment for pathological stage, Gleason score and prostate specific antigen. A second model incorporated prior experience with open radical prostatectomy and surgeon generation. RESULTS: Positive surgical margins occurred in 1,862 patients (22%). There was an apparent improvement in surgical margin rates up to a plateau at 200 to 250 surgeries. Changes in margin rates once this plateau was reached were relatively minimal relative to the CIs. The absolute risk difference for 10 vs 250 prior surgeries was 4.8% (95% CI 1.5, 8.5). Neither surgeon generation nor prior open radical prostatectomy experience was statistically significant when added to the model. The rate of decrease in positive surgical margins was more rapid in the open vs laparoscopic learning curve. CONCLUSIONS: The learning curve for surgical margins after laparoscopic radical prostatectomy plateaus at approximately 200 to 250 cases. Prior open experience and surgeon generation do not improve the margin rate, suggesting that the rate is primarily a function of specifically laparoscopic training and experience. PMID- 20952023 TI - Persistent vesicourethral anastomotic leak after radical prostatectomy: a novel endoscopic solution. AB - PURPOSE: A vesicourethral anastomotic leak after radical prostatectomy is a common postoperative sequela. Rarely additional intervention is required for a persistent or high output urinary leak. We describe a novel solution to this uncommon complication. MATERIALS AND METHODS: With the patient under general or spinal anesthesia the technique included 19Fr rigid cystoscopy in a partially distended bladder and insertion of 5Fr Single J(r) ureteral stents over a hydrophilic guidewire under fluoroscopic guidance. The 2 stents were exteriorized via the urethra beside an 18Fr Foley catheter. We monitored urine output and the relative amount of leak. The Jackson-Pratt drains were removed after leakage decreased to 50 ml or less per day. All patients underwent cystogram to ascertain leak resolution before stent removal. Time to continence was estimated using Kaplan-Meier analysis. RESULTS: Seven of 1,480 patients (0.5%) required intervention for a prolonged or high output anastomotic leak after radical prostatectomy. Mean time from surgery to stent insertion was 6.2 days (range 2 to 12). Stents were retained an average of 9 days (range 6 to 11), enabling complete resolution of the leak within a mean+/-SD of 1.8+/-0.9 days. Median time to recovery of urinary continence was 20+/-1.7 weeks. CONCLUSIONS: Temporary urinary diversion with exteriorized ureteral stents via the urethra is a safe, effective solution for a prolonged or high output anastomotic leak after radical prostatectomy. Recovery of urinary continence may be delayed in this setting but long-term urinary function appears to be unaffected in most patients. PMID- 20952024 TI - Early complications of cystectomy after high dose pelvic radiation. AB - PURPOSE: Radical cystectomy in patients with a history of pelvic radiation therapy is often a challenging and morbid procedure. We report early complication rates in patients undergoing cystectomy and urinary diversion after high dose pelvic radiation. MATERIALS AND METHODS: From 1983 to 2008, 2,629 patients underwent cystectomy with urinary diversion at a single institution. Of these patients 148 received 60 Gy or greater pelvic radiation therapy before surgery. Patient medical records were retrospectively reviewed and any complication within 90 days of surgery was graded using the Clavien-Dindo system. RESULTS: Median patient age was 74 years with a median American Society of Anesthesiologists score of 3. Patients received a median of 70 Gy pelvic radiation therapy a median of 2.3 years before surgery. Urinary diversions performed were ileal conduit in 65 patients (43.9%), continent cutaneous pouch in 35 (23.6%) and orthotopic neobladder in 48 (32.4%). A total of 335 early complications were identified. The highest grade complication was 0 in 23% of the patients, grade 1 in 12.2%, grade 2 in 32.4%, grade 3 in 18.9%, grade 4 in 7.4% and grade 5 in 6.1%. Age older than 65 years and American Society of Anesthesiologists score were statistically significant predictors of postoperative complications (p=0.0264 and p=0.0252, respectively). The type of urinary diversion did not significantly affect the grade distribution or number of early complications per patient (p=0.7444 and p=0.1807, respectively). CONCLUSIONS: The early complication rate using a standardized reporting system in patients undergoing radical cystectomy after radiation therapy is higher than previously published in nonirradiated subjects. Age and American Society of Anesthesiologists score but not urinary diversion type were associated with early complications in this population. PMID- 20952025 TI - Salvage spiral sling techniques: alternatives to manage disabling recurrent urinary incontinence in females. AB - PURPOSE: Females with recurrent stress urinary incontinence after anti incontinence surgery represent a therapeutic challenge. In our experience and that of others standard sling procedures have occasionally failed to correct these problems. We determined the effectiveness of various spiral sling techniques used in these cases to manage pipe stem urethras in which conventional slings had failed. MATERIALS AND METHODS: Between January 2007 and July 2008 we evaluated 30 female patients with persistent stress urinary incontinence after multiple failed anti-incontinence procedures. Preoperative and postoperative evaluation consisted of history, physical examination, number of pads, Stamey score and quality of life questionnaires. RESULTS: We followed 28 patients a minimum of 15 months (range 15 to 18). Mean patient age was 60 years (range 36 to 84). At presentation patients had undergone a mean of 3.5 prior vaginal procedures (range 1 to 6) and used a mean of 7 pads daily (range 3 to 12). Of the patients 21 received a synthetic spiral sling, 5 received an autologous spiral sling (rectus fascia in 3 and fascia lata in 2) and 3 received a lateral spiral sling. Mean pad use decreased to 0.9 daily (range 0 to 2, p<0.05). Postoperative mean Stamey score decreased from 2.6 to 0.3 (p<0.05). Complications included unilateral vesical perforation in 3 patients with a contralateral lateral spiral sling. The overall success rate was 72%. CONCLUSIONS: Salvage spiral sling techniques are a satisfactory alternative treatment for refractory stress urinary incontinence. When synthetic material cannot be used, autologous tissue can provide similar results. When the bladder is perforated unilaterally, a lateral spiral sling can be used on the contralateral side. PMID- 20952026 TI - Masculinity is dangerous to your health. PMID- 20952027 TI - Ductal adenocarcinoma of the prostate: increased mortality risk and decreased serum prostate specific antigen. AB - PURPOSE: The clinical significance of ductal prostatic carcinoma is not well defined. In a population based cancer registry we identified a large group of patients with ductal carcinoma to characterize the impact of the ductal subtype on presentation and survival in men with prostate cancer. MATERIALS AND METHODS: We used a national cancer registry to identify incident cases of ductal and acinar adenocarcinoma from 1996 to 2006. We analyzed clinicopathological variables and performed Cox multivariate survival analysis. Prostate specific antigen values were available for 2004 to 2006 and used to assess differences in Gleason grade and serum prostate specific antigen between ductal and acinar cancer cases at diagnosis. RESULTS: We identified 442,881 acinar and 371 ductal cases. Ductal cases were more likely to present with distant disease (12% vs 4%, p <0.001) and be poorly differentiated (50% vs 32%, p <0.001). Ductal histology was associated with a 30% decrease in geometric mean prostate specific antigen (adjusted coefficient 0.7, 95% CI 0.6-0.8) and more than 2-fold increased odds of prostate specific antigen less than 4.0 ng/ml (OR 2.4, 95% CI 1.4-4.0) independent of other clinicopathological variables. In men with nondistant disease at diagnosis ductal histology was associated with 2.2-fold (CI 1.4-3.5) increased disease specific mortality. CONCLUSIONS: In what is to our knowledge the largest series of this histological subtype ductal cancer cases were more likely to present with advanced stage cancer and lower prostate specific antigen, suggesting that timely disease detection is a significant challenge. Also, men with locoregional disease were more likely to die of the disease. PMID- 20952028 TI - Androgen receptor CAG repeat length and association with prostate cancer risk: results from the prostate cancer prevention trial. AB - PURPOSE: We investigated the association between the length of the polymorphic trinucleotide CAG microsatellite repeats in exon 1 of the AR gene and the risk of prostate cancer. MATERIALS AND METHODS: This is a nested case-control study of 1,159 cases and 1,353 controls from the Prostate Cancer Prevention Trial, a randomized, placebo controlled trial testing whether the 5alpha-reductase inhibitor finasteride could decrease the 7-year prevalence of prostate cancer. During the course of the trial men underwent annual digital rectal examination and prostate specific antigen measurement. Prostate biopsy was recommended in all men with abnormal digital rectal examination or finasteride adjusted prostate specific antigen greater than 4.0 ng/ml. Cases were drawn from men with biopsy determined prostate cancer identified by for cause or end of study biopsy. Controls were selected from men who completed the end of study biopsy. RESULTS: Mean CAG repeat length did not differ between cases and controls. The frequency distribution of cases and controls for the AR CAG repeat length was similar. There were no significant associations of CAG repeat length with prostate cancer risk when stratified by treatment arm (finasteride or placebo), or when combined. There was also no significant association between CAG repeat length and the risk of low or high grade prostate cancer. CONCLUSIONS: There is no association of AR CAG repeat length with prostate cancer risk. Knowledge of AR CAG repeat length provides no clinically useful information to predict prostate cancer risk. PMID- 20952029 TI - Xenogenic extracellular matrices as potential biomaterials for interposition grafting in urological surgery. AB - PURPOSE: The field of tissue engineering focuses on developing strategies for reconstructing injured, diseased, and congenitally absent tissues and organs. During the last decade urologists have benefited from remodeling and regenerative properties of bioscaffolds derived from xenogenic extracellular matrices. We comprehensively reviewed the current literature on structural and functional characteristics of xenogenic extracellular matrix grafting since it was first described in urological surgery. We also reviewed the clinical limitations, and assessed the potential for safe and effective urological application of extracellular matrix grafting in place of autogenous tissue. MATERIALS AND METHODS: We performed literature searches for English language publications using the PubMed(r) and MEDLINE(r) databases. Keywords included "xenogenic," "extracellular matrix" and "genitourinary tract applications." A total of 112 articles were scrutinized, of which 50 were suitable for review based on clinical relevance and importance of content. RESULTS: Since the mid 1990s xenogenic extracellular matrices have been used to successfully treat a number of pathological conditions that affect the upper and lower genitourinary tract. They are typically prepared from porcine organs such as small intestine and bladder. These organs are harvested and subjected to decellularization and sterilization techniques before surgical implantation. Bioinductive growth factors that are retained during the preparation process induce constructive tissue remodeling as the extracellular matrix is simultaneously degraded and excreted. However, recent documented concerns over durability, decreased mechanical strength and residual porcine DNA after preparation techniques have temporarily hampered the potential of extracellular matrices as a reliable replacement for genitourinary tract structures. CONCLUSIONS: Extracellular matrices are a useful alternative for successfully treating a number of urological conditions that affect the genitourinary tract. However, clinical concerns regarding mechanical limitations and biosafety need to be addressed before their long-term role in reconstructive urological surgery can be clearly established. PMID- 20952030 TI - Imaging use among employed and self-employed urologists. AB - PURPOSE: Compared to physicians paid on salary (ie employed), those who own their practice (ie self-employed) derive financial benefit from providing more care. Whether the volume based incentives of ownership influence physician use of other ancillary services, like diagnostic imaging, remains unknown. We explored this possibility among urologists. MATERIALS AND METHODS: We used data from the National Ambulatory Medical Care Survey (2006 to 2007) to identify outpatient urology visits. We determined whether the urologist who was responsible for the encounter was employed or self-employed. We calculated the proportion of visits at which imaging was ordered, and we evaluated for a difference between visits directed by employed vs self-employed urologists. We used multivariable logistic regression to measure the relationship between urologist employment status and imaging use, adjusting for patient, provider and practice level characteristics. RESULTS: More than 1 in 5 urology visits resulted in imaging. While imaging use did not vary by measurable patient or practice level characteristics, self employed urologists ordered imaging more often than employed urologists (24.2% vs 13.2%, respectively, p<0.001). In fact, the odds of a patient receiving imaging were almost 2-fold greater if seen by a self-employed urologist (OR 1.84, 95% CI 1.18-2.87). On stratified analysis an independent association between employment status and imaging use was observed for urolithiasis (OR 4.76, 95% CI 1.30-17.4) and hematuria visits (OR 5.52, 95% CI 1.23-24.8). CONCLUSIONS: Compared with employed urologists, those who are self-employed have more resource intense practice styles with respect to imaging use. PMID- 20952031 TI - Concordance of near infrared spectroscopy with pressure flow studies in men with lower urinary tract symptoms. AB - PURPOSE: Near infrared spectroscopy is a technology with the potential to diagnose bladder outlet obstruction noninvasively. We investigated the correlation between the near infrared spectroscopy algorithm classification of obstructed or unobstructed (based on near infrared spectroscopy pattern, maximum flow rate and post-void residual) and pressure flow studies in men with lower urinary tract symptoms. We also assessed whether the near infrared spectroscopy pattern itself, independent of the near infrared spectroscopy algorithm (which also includes maximum flow rate and post-void residual urine), correlates with bladder outlet obstruction. MATERIALS AND METHODS: Subjects simultaneously underwent urodynamics and near infrared spectroscopy evaluation. Bladder outlet obstruction classification was based on the International Continence Society nomogram. The near infrared spectroscopy algorithm was evaluated against the comparable noninvasive algorithms with receiver operating characteristic curves. For significance the Mann-Whitney U test was used with p<0.05 considered significant. RESULTS: Of 42 subjects 33 (79%) had evaluable data. Area under the curve was 0.484 for the near infrared spectroscopy algorithm relative to pressure flow diagnosis. A downward near infrared spectroscopy pattern is associated with obstruction whereas an upward pattern is associated with nonobstruction. Of 26 patients with urodynamic bladder outlet obstruction 9 (35%) had a downward, 4 (15%) a flat and 13 (50%) an upward near infrared spectroscopy pattern. Of 7 unobstructed cases 4 (57%) had a downward, 1 (14%) a flat and 2 (29%) an upward near infrared spectroscopy pattern. CONCLUSIONS: The near infrared spectroscopy algorithm had a 0.484 AUC for diagnosing bladder outlet obstruction. The near infrared spectroscopy pattern component itself did not correlate strongly. The near infrared spectroscopy algorithm does not appear to provide substantial clinical usefulness in diagnosing bladder outlet obstruction in men with lower urinary tract symptoms. More studies are needed to further define and validate uses for near infrared spectroscopy in urology. PMID- 20952032 TI - Joint AUA/SUNA white paper on reprocessing of flexible cystoscopes. AB - PURPOSE: Numerous federal bodies and professional societies have produced guidelines and standards for the reprocessing of endoscopes, but few specifically address the reprocessing of cystoscopes. MATERIALS AND METHODS: This document presents a summary of the current recommendations for reprocessing flexible cystoscopes, and highlights particular aspects of instrument reprocessing that are unique to cystoscopy. RESULTS: Cystoscopes are classified as "semi-critical" devices. Such devices require high-level disinfection or sterilization between patients. High-level disinfection differs from sterilization in that high-level disinfection does not kill large numbers of bacterial spores, while sterilization involves the complete destruction of all microbial life. In the office setting, high-level disinfection (using glutaraldehyde or another chemical disinfectant) is commonly employed for the reprocessing of flexible cystoscopes. During high level disinfection, standard reprocessing steps should be followed to prevent contamination of the cystoscope between uses. These include precleaning, leak testing, cleaning, disinfection, rinsing, and drying. Recommended "soak times" for glutaraldehyde vary from 20 to 45 minutes, depending upon the degree to which these steps are followed. If no precleaning is performed, a 45-minute glutaraldehyde soak is required to achieve high-level disinfection. Conversely, a 20-minute soak is adequate to achieve high-level disinfection if recommended reprocessing steps are followed prior to immersion in the glutaraldehyde. One chemical disinfectant (ortho-phthalaldehyde) has been associated with anaphylaxis in bladder cancer patients, and should be avoided in these patients. CONCLUSIONS: This white paper provides a concise reference document for the reprocessing of flexible cystoscopes. In addition, references and links to more comprehensive resources are provided. This document may be useful for clinicians and others who are in search of guidance in this area. PMID- 20952034 TI - Factors affecting patient radiation exposure during percutaneous nephrolithotomy. AB - PURPOSE: We identified patient and stone characteristics that may contribute to increased radiation exposure during percutaneous nephrolithotomy and offer technique modifications to limit the radiation dose. MATERIAL AND METHODS: We reviewed the records of 96 patients who underwent percutaneous nephrolithotomy in the last 2 years. The effective radiation dose was calculated using accepted conversion tables. We performed multivariate linear regression to determine the association of the effective radiation dose with specific patient, stone and procedural characteristics. RESULTS: Mean+/-SD patient age was 51.5+/-13.4 years and 62.5% of the patients were female. Median body mass index was 32.0+/-9.7 kg/m2 (range 16.2 to 59.6) and the median stone burden was 4 cm2. Increased body mass index (p<0.001), higher stone burden (p=0.013), stone nonbranched configuration (p=0.002) and a greater number of percutaneous access tracts (p=0.040) were significantly associated with an increased effective radiation dose. Specifically obese patients with a body mass index of 30 to 39.9 kg/m2 had a more than 2-fold increase in the mean adjusted effective radiation dose and morbidly obese patients with a body mass index of 40 kg/m2 or greater had a greater than 3-fold increase vs that in normal weight patients with a body mass index of less than 25 kg/m2 (6.49 and 9.13 mSv, respectively, vs 2.66, p<0.001). Other stone specific parameters, including site and composition, percutaneous access site and estimated blood loss were not associated with the effective radiation dose. CONCLUSIONS: Patients with higher body mass index, greater stone burden, nonbranched stones and multiple nephrostomy access tracts are at risk for increased radiation exposure during percutaneous nephrolithotomy. Urologists must seek alternative strategies to minimize radiation exposure, such as tighter collimation to the region of interest, judicious use of magnification and the acquisition of as few images as possible during stone removal. PMID- 20952033 TI - Contemporary clinical epidemiology of renal cell carcinoma: insight from a population based case-control study. AB - PURPOSE: To clarify the contemporary clinical epidemiology of renal cell carcinoma we present trends in clinical presentation and treatment in patients enrolled in a population based case-control study. MATERIALS AND METHODS: The National Cancer Institute performed a population based case-control study in metropolitan Detroit and Chicago from 2002 through 2007. In 1,136 patients with renal cell carcinoma who consented to an epidemiological interview and medical record review we ascertained detailed information on social and medical history, methods of renal cell carcinoma detection and diagnosis, cancer severity and treatment(s) received. From these data we assessed the demographic and cancer specific characteristics of study cases, and trends in clinical presentation, diagnosis and treatment. RESULTS: Most patients with renal cell carcinoma had localized or regional tumors, including 52% with tumors 4 cm or less. The proportion of asymptomatic cases increased from 35% in 2002 to 50% in 2007 (p<0.001). Hypertension and diabetes were common in patients (58% and 17%, respectively) and 24% had at least 2 significant comorbid conditions at cancer diagnosis. While the use of laparoscopic surgery increased with time (p<0.001), fewer than 1/5 patients underwent nephron sparing surgery. CONCLUSIONS: The proportion of patients presenting with small, asymptomatic renal cell carcinoma continues to increase. Most of these cases are still treated with radical nephrectomy, although increasingly via a laparoscopic approach. Since most patients with small renal cell carcinomas have 1 or more renal function relevant comorbidities, there is an imperative to increase the use of nephron sparing surgery. PMID- 20952035 TI - An exploratory study of endorectal magnetic resonance imaging and spectroscopy of the prostate as preoperative predictive biomarkers of biochemical relapse after radical prostatectomy. AB - PURPOSE: Radical prostatectomy has significant side effects. Preoperative information predicting its long-term outcome would be valuable to patients and physicians. We determined whether pretreatment endorectal magnetic resonance imaging/magnetic resonance spectroscopic imaging predicts biochemical recurrence after radical prostatectomy. MATERIALS AND METHODS: Of 202 patients who underwent endorectal magnetic resonance imaging/magnetic resonance spectroscopic imaging from January 2000 to December 2002 before radical prostatectomy 130 satisfied study inclusion criteria and were included in analysis. We compared imaging factors with potential predictive capability to biochemical recurrence data, including magnetic resonance imaging risk score based on local disease extent and magnetic resonance spectroscopic imaging index lesion characteristics, such as the number of voxels and degree of metabolic abnormality (magnetic resonance spectroscopic imaging grade). We evaluated associations of these imaging variables with time to biochemical recurrence by Cox proportional hazards regression adjusted for known predictors of biochemical recurrence, such as stage, grade and prostate specific antigen. RESULTS: At a median 68-month followup there were 26 biochemical failures. Risk score, lesion volume and high grade voxels each correlated with time to biochemical recurrence. In a model combining clinical parameters risk score, lesion volume and at least 1 high grade voxel the magnetic resonance spectroscopic imaging variables remained significant but the magnetic resonance imaging score dropped out. CONCLUSIONS: Index lesion volume on magnetic resonance spectroscopic imaging and high grade magnetic resonance spectroscopic imaging voxels correlate with time to biochemical recurrence after radical prostatectomy even when adjusted for clinical data. Results suggest the preoperative predictive usefulness of endorectal magnetic resonance imaging/magnetic resonance spectroscopic imaging in patients considering radical prostatectomy. PMID- 20952036 TI - Management of surgical and radiation induced rectourethral fistulas with an interposition muscle flap and selective buccal mucosal onlay graft. AB - PURPOSE: Rectourethral fistulas are a rare but devastating complication of pelvic surgery and radiation. We review, analyze and describe the management and outcomes of nonradiated and radiation/ablation induced rectourethral fistulas during a consecutive 12-year period. MATERIALS AND METHODS: We performed a retrospective review of patients undergoing rectourethral fistula repair between January 1, 1998 and December 31, 2009. Patient demographics as well as preoperative, operative and postoperative data were obtained. All rectourethral fistulas were repaired using an anterior transperineal approach with a muscle interposition flap and selective use of a buccal mucosal graft urethral patch onlay. RESULTS: A total of 74 patients with rectourethral fistulas underwent repair with an anterior perineal approach and muscle interposition flap (68 gracilis muscle interposition flaps, 6 other muscle interposition flaps). We compared 35 nonradiated and 39 radiated/ablation induced rectourethral fistulas. Concurrent urethral strictures were present in 11% of nonradiated and 28% of radiated/ablation rectourethral fistulas. At a mean followup of 20 months 100% of nonradiated rectourethral fistulas were closed with 1 procedure while 84% of radiated/ablation rectourethral fistulas were closed in a single stage. Of the patients with nonradiated rectourethral fistulas 97% had the bowel undiverted. Of those undiverted cases 100% were without bowel complication. Of the patients with radiated/ablation rectourethral fistulas 31% required permanent fecal diversion. CONCLUSIONS: Successful rectourethral fistula closure can be achieved for nonradiated (100%) and radiation/ablation (84%) rectourethral fistulas using a standard anterior perineal approach with an interposition muscle flap and selective use of buccal mucosal graft, providing a standard for rectourethral fistula repair. Even the most complex radiation/ablation rectourethral fistula can be repaired avoiding permanent urinary and fecal diversion. PMID- 20952037 TI - Understanding the barriers to the dissemination of medical expulsive therapy. AB - PURPOSE: Increasing trial evidence suggests that a course of medical expulsive therapy is warranted for patients with ureteral stones who are amenable to conservative treatment, and that this efficacious process of care is underused. To better understand the barriers to the dissemination of medical expulsive therapy we analyzed health care claims of working age adults with urinary stone disease. MATERIALS AND METHODS: Using MarketScan(r) data (2002 to 2006) we identified patients with urinary stone disease who were treated in the emergency department. We characterized differences between patients who were prescribed medical expulsive therapy and those who were not. After assigning patients to their principal providers we determined how much of the variation in medical expulsive therapy prescribing rates was attributable to patient vs provider level factors. RESULTS: A total of 79,688 patients were seen for an acute stone episode. They received care from 12,328 providers. In general those patients prescribed medical expulsive therapy tended to be older (p<0.001) and were more likely male (p<0.001). A higher percentage of medical expulsive therapy recipients were salaried (p=0.003) and had full-time employment (p<0.001). Of the unexplained variation in medical expulsive therapy prescription 21% was accounted for by unmeasured provider factors and patient odds of receiving medical expulsive therapy were 5-fold higher if seen by a urologist (OR 4.94, 95% CI 2.96 8.28, p<0.001). CONCLUSIONS: These data reveal that the provider seen for an episode of renal colic substantially determines whether the patient will receive medical expulsive therapy. As such, an educational intervention directed toward emergency department physicians might hasten the uptake of medical expulsive therapy within the broader medical community. PMID- 20952038 TI - PCDD/Fs in sediments of Central Vietnam coastal lagoons: in search of TCDD. AB - Samples from nine Central Vietnam coastal lagoons, together with three soils and sediments collected in two freshwater reservoirs of the Thua Thien-Hue province, were analysed for polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). Total concentrations are low, from 192 to 2912 pg g(-1) and depth profiles in Tam Giang-Cau Hai (TG-CH) sediment cores show only minor changes over time in PCDD/F input and composition. Octachloro dibenzo-p-dioxin (OCDD) is the prevailing congener (approximately 90%), indicating combustion as the main PCDD/F source to these coastal systems, whereas natural formation might be partly responsible for the presence at depth. 2,3,7,8-Tetrachloro dibenzo-p-dioxin (TCDD), largely sprayed together with Agent Orange over the study areas during the war (1961 1971), is absent or very low. This result supports the hypothesis of strong degradation soon after spraying. Multivariate statistical analyses account for the presence of local, short-range sources as observed in the northern part of the TG-CH lagoon. PMID- 20952039 TI - Proteomics - The key to understanding systems biology of Arabidopsis trichomes. AB - Every multicellular organism consists of numerous organs, tissues and specific cell types. To gain detailed knowledge about the morphogenesis of these complex structures, it is inevitable to advance biochemical analyses to ultimate spatial and temporal resolution since individual cell types contribute differently to the overall performance of living objects. Single cell sampling combined with systems biological approaches was recently applied to investigations of Arabidopsis thaliana trichomes (leaf hairs). These are single celled structures that provide ideal model systems to address various aspects of plant cell development and differentiation at the level of individual cells. A previously suggested function of trichomes in plant stress responses could thus be confirmed. Furthermore, trichome-specific "omics" data collected in several laboratories are mutually conclusive which demonstrates the applicability of systems biological approaches at the single cell level. PMID- 20952040 TI - Sebestenoids A-D, BACE1 inhibitors from Cordia sebestena. AB - Bioassay-guided fractionation of an extract prepared from the fruits of Cordia sebestena led to the isolation of sebestenoids A-D (1-4). Their structures were elucidated on the basis of extensive NMR experiments and mass spectroscopic measurements. Compounds 1-4 exhibited moderate inhibition of the aspartic protease BACE1. PMID- 20952041 TI - Biosynthesis of jasmonic acid in a plant pathogenic fungus, Lasiodiplodia theobromae. AB - Jasmonic acid (JA) is a plant hormone that plays an important role in a wide variety of plant physiological processes. The plant pathogenic fungus, Lasiodiplodia theobromae also produces JA; however, its biosynthesis in this fungus has yet to be explored. Administration of [1-(13)C] and [2-(13)C] NaOAc into L. theobromae established that JA in this fungus originates from a fatty acid synthetic pathway. The methyl ester of 12-oxo-phytodienoic acid (OPDA) was detected in the culture extracts of L. theobromae by GC-MS analysis. This finding indicates the presence of OPDA (a known intermediate of JA biosynthesis in plants) in L. theobromae. (2)H NMR spectroscopic data of JA produced by L. theobromae with the incorporation of [9,10,12,13,15,16-(2)H(6)] linolenic acid showed that five deuterium atoms remained intact. In plants, this is speculated to arise from JA being produced by the octadecanoid pathway. However, the observed stereoselectivity of the cyclopentenone olefin reduction in L. theobromae was opposite to that observed in plants. These data suggest that JA biosynthesis in L. theobromae is similar to that in plants, but differing in the facial selectivity of the enone reduction. PMID- 20952042 TI - Towards eradication: three years after the tsunami of 2004, has malaria transmission been eliminated from the island of Simeulue? AB - The island of Simeulue was the first landfall of the tsunami of December 2004. The tsunami destroyed many villages on the island, leaving one third of the population homeless. Malaria is endemic in Simeulue and an epidemic was reported to have occurred three months prior to the tsunami. Information concerning malaria was, however, not easily available. The earthquakes related to the tsunami may have created extensive potential breeding sites of Anopheles sundaicus, the probable vector, and increased vulnerability of the human population; a possibility of increased transmission made a further outbreak possible. Consequently, subsequent to the tsunami, considerable amounts of aid, including anti-malarial measures such as insecticide treated mosquito-nets, were deployed on the island. A series of island-wide cross-sectional surveys were conducted in 2005-2007 to determine whether these had had any effect on malaria prevalence. Larval sampling, and CDC light-trap and landing collections of hungry mosquitoes were also undertaken. The results indicate that despite the continuing presence of potential vectors in some places the anti-malaria measures introduced following the tsunami have controlled, and may be close to eliminating, malaria from the island. PMID- 20952043 TI - Are native naiads more tolerant to pollution than exotic freshwater bivalve species? An hypothesis tested using physiological responses of three species transplanted to mercury contaminated sites in the Ebro River (NE, Spain). AB - In the lower Ebro River exist the paradoxical convergence of relatively well preserved river dynamics with the historical presence of a chloralkali plant with a long history of mercury discharges and the recent invasion of foreign bivalves species. Here we performed a comparative study on two alien bivalves, the Zebra mussel and the Asian clam (Dreissena polymorpha and Corbicula fluminea), and one protected species of naiads (Psilunio littoralis), which is the most common species of the freshwater mussel assemblages in this river. Individuals of the three species were transplanted to three sites that included a clean unpolluted upstream site, a contaminated location next to the mercury source and a downstream one. The study focused on digestive gland antioxidant and oxidative stress responses such as antioxidant enzymes, glutathione S transferase, glutathione levels, metallothionein proteins, DNA strand breaks and lipid peroxidation levels. Results evidenced interspecies differences on accumulation levels of mercury, antioxidant defensive systems and oxidative tissue damage. The naiad species, despite of accumulating more mercury showed the greatest antioxidant defensive potential, which was characterized by having high constitutive activities of glutathione S transferase and inducible activities and levels of key antioxidant enzymes and glutathione. Exposed individuals of C. fluminea had moderate levels of metal accumulation, the highest activities of antioxidant enzymes but also high levels of lipid peroxidation. D. polymorpha mussels showed the lowest levels of mercury but the lowest antioxidant responses and consequently the highest levels of oxidative injuries in the DNA and of mortality. Our results support the hypothesis that naiad species might be more tolerant to pollution than exotic species. PMID- 20952044 TI - Effect of short-chain organic acids and pH on the behaviors of pyrene in soil water system. AB - The effects of five short-chain organic acids (SCOAs) on the behaviors of pyrene in soil-water system were investigated. The influences of the quantity and species of organic acids, pH, and soil dissolved organic matter were considered. The results showed the presence of SCOAs inhibited the adsorption and promoted the desorption of pyrene in the following order: citric acid>oxalic acid>tartaric acid>lactic acid>acetic acid. The decreased extents of pyrene adsorption performance enhanced with increasing SCOA concentrations, while the decreasing rate became less pronounced at high SCOA concentrations. In the presence of organic acids, the adsorption ability of pyrene decreased with increasing pH. However, there was a slight increase of pyrene adsorption with the addition of oxalic acid, tartaric acid and citric acid above pH 8. The capacity for pyrene retention differentiated significantly between the soils with and without dissolved organic matter. The presence of SCOAs was also favorable for the decrease of pyrene adsorption on soil without dissolved organic matter. The results of this study have important implications for the remediation of persistent organic pollutants in soil and groundwater. PMID- 20952045 TI - Effect of fluorescent silica nanoparticles in embryo and larva of Oryzias latipes: sonic effect in nanoparticle dispersion. AB - We characterized fluorescent silica nanoparticles (FNPs), which had been applied in many biological systems, in fish embryo rearing media (ERM) solution and evaluated the potential toxicity to the early development of Oryzias latipes embryos. Distribution of FNPs in embryos and larvae of O. latipes was studied by fluorescent and confocal laser scanning microscopic studies. Embryos exposed to three different concentrations of FNPs in stirred or sonicated ERM solutions were observed up to 2d after hatching. FNPs had a negligible effect on the hatchability of O. latipes embryos; however, compared to controls, more than 30% of eggs were abnormal in 10 and 50 mg FN P L(-1) solutions. We found that the toxic effect was increased in sonicated FNP solution, which seems to be related with the dissolution of FNPs in ERM solutions that could be accelerated by sonication. Further study found that the CaCl2 included in ERM solution might enhance the dissolution of the FNPs and the silicate ion released from FNPs partially contributed to larval toxicity. This study showed that some nanoparticles may not be stable in biological fluids even if they are stable in water. Dissolution factors such as sonication and cellular components should be considered in biological application of nanoparticles. PMID- 20952046 TI - The bony labyrinth of the early platyrrhine primate Chilecebus. AB - We document the morphology of the bony labyrinth of Chilecebus carrascoensis, one of the best preserved early platyrrhines known, based on high resolution CT scanning and 3D digital reconstruction. The cochlea is low and conical in form, as in other anthropoids, but has only 2.5 spiral turns. When the allometric relationship with body mass is considered, cochlear size is similar to that in extant primates. The relative size of the semicircular canals, which is well within the range of other primates, indicates that Chilecebus carrascoensis was probably not as agile in its locomotion as other small-bodied platyrrhines such as Leontopithecus rosalia, Saguinus oedipus, and Callithrix jacchus, but it probably was not a suspensory acrobat or a slow climber. The proportion, shape, and orientation of the semicircular canals in Chilecebus carrascoensis also mirror that typically seen in extant primates. However, no single variable can be used for predicting the locomotor pattern in Chilecebus carrascoensis. Based on Principle Component Analysis (PCA) scores we calculated rescaled Euclidean distances for various taxa; primates with similar locomotor patterns tend to share shorter distances. Results for Chilecebus carrascoensis underscore its general resemblance to living quadrupedal primate taxa, but it is not positioned especially near any single living taxon. PMID- 20952047 TI - Multivariate analysis of the geochemistry and mineralogy of soils along two continental-scale transects in North America. AB - Soils collected in 2004 along two North American continental-scale transects were subjected to geochemical and mineralogical analyses. In previous interpretations of these analyses, data were expressed in weight percent and parts per million, and thus were subject to the effect of the constant-sum phenomenon. In a new approach to the data, this effect was removed by using centered log-ratio transformations to 'open' the mineralogical and geochemical arrays. Multivariate analyses, including principal component and linear discriminant analyses, of the centered log-ratio data reveal the effects of soil-forming processes, including soil parent material, weathering, and soil age, at the continental-scale of the data arrays that were not readily apparent in the more conventionally presented data. Linear discriminant analysis of the data arrays indicates that the majority of the soil samples collected along the transects can be more successfully classified with Level 1 ecological regional-scale classification by the soil geochemistry than soil mineralogy. A primary objective of this study is to discover and describe, in a parsimonious way, geochemical processes that are both independent and inter-dependent and manifested through compositional data including estimates of the elements and corresponding mineralogy. PMID- 20952050 TI - The processing of consonants and vowels during letter identity and letter position assignment in visual-word recognition: an ERP study. AB - Recent research suggests that there is a processing distinction between consonants and vowels in visual-word recognition. Here we conjointly examine the time course of consonants and vowels in processes of letter identity and letter position assignment. Event related potentials (ERPs) were recorded while participants read words and pseudowords in a lexical decision task. The stimuli were displayed under different conditions in a masked priming paradigm with a 50 ms SOA: (i) identity/baseline condition e.g., chocolate-CHOCOLATE); (ii) vowels delayed condition (e.g., choc_l_te-CHOCOLATE); (iii) consonants-delayed condition (cho_o_ate-CHOCOLATE); (iv) consonants-transposed condition (cholocate CHOCOLATE); (v) vowels-transposed condition (chocalote-CHOCOLATE), and (vi) unrelated condition (editorial-CHOCOLATE). Results showed earlier ERP effects and longer reaction times for the delayed-letter compared to the transposed-letter conditions. Furthermore, at early stages of processing, consonants may play a greater role during letter identity processing. Differences between vowels and consonants regarding letter position assignment are discussed in terms of a later phonological level involved in lexical retrieval. PMID- 20952049 TI - The non-steroidal anti-inflammatory drug diclofenac is readily biodegradable in agricultural soils. AB - Diclofenac, 2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetic acid, is an important non-steroidal anti-inflammatory drug widely used for human and animals to reduce inflammation and pain. Diclofenac could potentially reach agricultural lands through the application of municipal biosolids or wastewater, and in the absence of any environmental fate data, we evaluated its persistence in agricultural soils incubated in the laboratory. (14)C-Diclofenac was rapidly mineralized without a lag when added to soils varying widely in texture (sandy loam, loam, clay loam). Over a range of temperature and moisture conditions extractable (14)C diclofenac residues decreased with half lives <5days. No extractable transformation products were detectable by HPLC. Diclofenac mineralization in the loam soil was abolished by heat sterilization. Addition of biosolids to sterile or non-sterile soil did not accelerate the dissipation of diclofenac. These findings indicate that diclofenac is readily biodegradable in agricultural soils. PMID- 20952048 TI - A combined ecological and epidemiologic investigation of metal exposures amongst Indigenous peoples near the Marlin Mine in Western Guatemala. AB - In August 2009 a combined epidemiological and ecological pilot study was conducted to investigate allegations of human rights abuses in the form of exposures to toxic metals experienced by mine workers and Indigenous Mam Mayan near the Marlin Mine in Guatemala. In the human study there were no differences in blood and urine metals when comparing five mine workers with eighteen non-mine workers, and there were no discernible relationships between metal exposures and self-reported health measures in any study group. On the other hand, individuals residing closest to the mine had significantly higher levels of certain metals (urinary mercury, copper, arsenic, and zinc) when compared to those living further away. The levels of blood aluminum, manganese, and cobalt were elevated in comparison to established normal ranges in many individuals; however, there was no apparent relationship to proximity to the mine or occupation, and thus are of unclear significance. In the ecological study, several metals (aluminum, manganese, and cobalt) were found significantly elevated in the river water and sediment sites directly below the mine when compared to sites elsewhere. When the human and ecological results are combined, they suggest that exposures to certain metals may be elevated in sites near the mine but it is not clear if the current magnitude of these elevations poses a significant threat to health. The authors conclude that more robust studies are needed while parallel efforts to minimize the ecological and human impacts of mining proceed. This is critical particularly as the impact of the exposures found could be greatly magnified by expected increases in mining activity over time, synergistic toxicity between metals, and susceptibility for the young and those with pre-existing disease. PMID- 20952051 TI - Clinical performance of a hybrid resin composite with and without an intermediate layer of flowable resin composite: a 7-year evaluation. AB - OBJECTIVE: The objective of this prospective clinical follow up was to evaluate the long term clinical performance of a hybrid resin composite in Class II restorations with and without intermediate layer of flowable resin composite. METHODS: Each participant received at least two, as similar as possible, Class II restorations of the hybrid resin composite. One resin composite restoration of each pair (59) was chosen at random to be restored with an intermediary layer with flowable resin composite. The other was restored without. The 118 restorations were evaluated using slightly modified USPHS criteria at baseline and then yearly during 7 years. RESULTS: Four drop outs were registered during the 7-year follow up (2 with and 2 without flowable) restorations. A prediction of the caries risk showed that 18 of the evaluated 46 patients were considered as high risk patients. Seventeen failures were observed, 8 in restorations with and 9 in restorations without an intermediate layer of flowable resin composite, resulting in a 14.9% failure rate after 7 years. The main reasons for failure were: fracture of resin composite (8), secondary caries (4) and cusp fracture (3). No statistical difference was seen between restorations restored with and without flowable layer. CONCLUSION: The hybrid resin composite showed a good clinical performance during the 7-year evaluation. The use of flowable resin composite as an intermediate layer did not result in improved effectiveness of the Class II restorations. PMID- 20952052 TI - Associations among sleep problems, learning difficulties and substance use in adolescence. AB - This study investigated the relationships among sleep problems, learning difficulties and substance use in adolescence. Previous research suggests that these variables share an association with executive functioning deficits, and are intertwined. The sample comprised 427 adolescents (M age = 16 years) attending remedial schools and 276 adolescents (M age = 15 years) attending a mainstream school in Cape Town, South Africa. Participants completed anonymous self-report questionnaires. Results indicated that adolescents without learning difficulties were more likely to use tobacco, methamphetamine and cannabis, whereas those with learning difficulties engaged in more inhalant use. Adolescents who had more sleep problems were more likely to use tobacco, alcohol, methamphetamine, cannabis, inhalants, cocaine, ecstasy and any other illegal drug. Adolescents with learning difficulties had more sleep problems than those without learning difficulties. However, sleep problems remained independently associated with tobacco, cannabis and inhalant use when learning difficulties were taken into account. PMID- 20952053 TI - Trust, autonomy and relationships: the help-seeking preferences of young people in secondary level schools in London (UK). AB - Help-seeking among young people is complicated, often determined vicariously by the ability of adults, family or professionals, to recognize, and respond to, their difficulties. We know very little about the complex concerns of teenage young people and how they impact on help-seeking preferences. We aimed to ascertain the help-seeking preferences for a range of mental health problems among adolescents attending schools in an inner-city area of London. In particular we sought to examine the relationship between such adolescents and their family doctor. Using a mixed methods approach we explored help-seeking attitudes of young people. Emotional and mental health problems are not seen by young people as the domain of General practitioners. Moreover, there is a worrying lack of confidence and trust placed in family doctor and other professionals by young people. Young people do not tend easily to trust adults to help them with emotional difficulties. PMID- 20952054 TI - Toward modeling the bone marrow niche using scaffold-based 3D culture systems. AB - In the bone marrow, specialized microenvironments, called niches, regulate hematopoietic stem cell (HSC) maintenance and function through a complex crosstalk between different cell types. Although in vivo studies have been instrumental to elucidate some of the mechanisms by which niches exert their function, the establishment of an in vitro model that recapitulates the fundamental interactions of the niche components in a controlled setting would be of great benefit. We have previously shown that freshly harvested bone marrow- or adipose tissue-derived cells can be cultured under perfusion within porous scaffolds, allowing the formation of an organized 3D stromal tissue, composed by mesenchymal and endothelial progenitors and able to support hematopoiesis. Here we describe 3D scaffold-based perfusion systems as potential models to reconstruct ex vivo the bone marrow stem cell niche. We discuss how several culture parameters, including scaffold properties, cellular makeup and molecular signals, can be varied and controlled to investigate the role of specific cues in affecting HSC fate. We then provide a perspective of how the system could be exploited to improve stem cell-based therapies and how the model can be extended toward the engineering of other specialized stromal niches. PMID- 20952055 TI - The effect of protein structure on their controlled release from an injectable peptide hydrogel. AB - Hydrogel materials are promising vehicles for the delivery of protein therapeutics. Proteins can impart physical interactions, both steric and electrostatic in nature, that influence their release from a given gel network. Here, model proteins of varying hydrodynamic diameter and charge are directly encapsulated and their release studied from electropositive fibrillar hydrogels prepared from the self-assembling peptide, MAX8. Hydrogelation of MAX8 can be triggered in the presence of proteins for their direct encapsulation with neither effect on protein structure nor the hydrogel's mechanical properties. Bulk release of the encapsulated proteins from the hydrogels was assessed for a month time period at 37 degrees C before and after syringe delivery of the loaded gels to determine the influence of the protein structure on release. Release of positively charged and neutral proteins was largely governed by the sterics imposed by the network. Conversely, negatively charged proteins interacted strongly with the positively charged fibrillar network, greatly restricting their release to <10% of the initial protein load. Partition and retention studies indicated that electrostatic interactions dictate the amount of protein available for release. Importantly, when protein encapsulated gels were delivered via syringe, the release profiles of the macromolecules show the similar trends as those observed for non-sheared gels. This study demonstrates that proteins can be directly encapsulated in self assembled MAX8 hydrogels, which can then be syringe delivered to a site where subsequent release is controlled by protein structure. PMID- 20952056 TI - Natural killer cells and HLA-G expression in the basal decidua of human placenta adhesiva. AB - Retained placenta is caused by abnormal adherence of the placenta to the uterine wall, leading to delayed expulsion of the placenta and causing postpartum haemorrhage. The mildest form of retained placenta is the placenta adhesiva (PA), of which the cause is unknown. The aim of our study was to explore possible differences in immune response in the basal decidua between PA and control placentas (CP). We performed a descriptive analysis of immunohistochemical differences in 17 PA and 10 CP. Our results show that in PA the amount of uterine natural killer (uNK) cells is significantly reduced (0.2 uNK cell/standardised area) as compared to CP (9.8 uNK cell/standardised area, p < 0.001) whereas the number of trophoblast cells and the expression of HLA-G by trophoblast are similar in the decidua of PA and CP. We speculate that adequate numbers of uNK cells in the basal decidua are needed for normal expulsion of the placenta. PMID- 20952057 TI - Does a picture of the human placenta predict the future? PMID- 20952058 TI - Fully-automated image processing software to analyze calcium traces in populations of single cells. AB - Advances in fluorescence live cell imaging over the last decade have revolutionized cell biology by providing access to single-cell information in space and time. One current limitation of live-cell imaging is the lack of automated procedures to analyze single-cell data in large cell populations. Most commercially available image processing softwares do not have built-in image segmentation tools that can automatically and accurately extract single-cell data in a time series. Consequently, individual cells are usually identified manually, a process which is time consuming and inherently low-throughput. We have developed a MATLAB-based image segmentation algorithm that reliably detects individual cells in dense populations and measures their fluorescence intensity over time. To demonstrate the value of this algorithm, we measured store-operated calcium entry (SOCE) in hundreds of individual cells. Rapid access to single-cell calcium signals in large populations allowed us to precisely determine the relationship between SOCE activity and STIM1 levels, a key component of SOCE. Our image processing tool can in principle be applied to a wide range of live-cell imaging modalities and cell-based drug screening platforms. PMID- 20952059 TI - Significance of AF4-MLL reciprocal fusion in t(4;11) leukemias? PMID- 20952060 TI - Chronic myelogenous leukemia cells convert to myofibroblasts in vitro: effect of vascular endothelial growth factor on development of the microenvironment. AB - To elucidate the biological characteristics of chronic myelogenous leukemia (CML) cells, we observed morphological and functional changes of CML cells during primary long-term culture, in which their morphology changed to that of myofibroblasts with similar molecular characteristics to the parental CML cells including BCR-ABL fusion gene, and produced cytokines such as granulocyte colony stimulating factor, interleukin-6, and vascular endothelial growth factor (VEGF) A. When cultured on the CML-derived myofibroblasts, parental non-adherent CML cells significantly proliferated. When anti-VEGF-A-neutralizing antibody was added to the cultures, non-adherent CML cell proliferation was significantly inhibited. These observations indicate that CML cells can convert their morphology and function to adherent myofibroblasts, and produce a significant amount of cytokine to give a growth-promotion activity to CML cells. PMID- 20952061 TI - Can grapefruit juice decrease the cost of imatinib for the treatment of chronic myelogenous leukemia? PMID- 20952062 TI - Cryptic IGH/BCL2 rearrangements with variant FISH patterns in follicular lymphoma. AB - Follicular lymphoma (FL) is one of the most common non-Hodgkin lymphomas (NHL). Translocation t(14;18)(q32;q21) involving IGH and BCL2 genes represents its genetic hallmark. We present six cases of a series of 75 well diagnosed FL patients in which variant fluorescence in situ hybridization (FISH) patterns for this rearrangement were found. Moreover, G-banding cytogenetics and polymerase chain reaction (PCR) methods were unable to detect t(14;18)(q32;q21). According to our results, FISH is the best technique to define variant rearrangements of IGH/BCL2 genes and is important to detect it in cases with non-conclusive FL characteristics to avoid misdiagnosis with other NHL. PMID- 20952063 TI - The impact of bortezomib on the risk of thrombosis in multiple myeloma. PMID- 20952064 TI - Characterization of pathogen-specific expression of host immune response genes in Anaplasma and Mycobacterium species infected ruminants. AB - Anaplasma and Mycobacterium species are among the most prevalent bacterial pathogens in European red deer (Cervus elaphus) in south-central Spain and are known to modify gene expression in ruminants. In this study, we used microarray hybridization and real-time RT-PCR analyses to characterize global gene expression profiles in red deer in response to Anaplasma ovis and A. ovis/Mycobacterium bovis/Mycobacterium avium sub. paratuberculosis (MAP) infections, compare the expression of immune response genes between red deer infected with A. ovis, M. bovis and A. ovis/M. bovis/MAP, and characterize the differential expression of immune response genes identified in red deer in cattle infected with M. bovis and Anaplasma marginale. Global gene differential expression in A. ovis- and A. ovis/M. bovis/MAP-infected deer resulted in the modification of common and pathogen-specific cellular biological processes. The differential expression of host immune response genes showed pathogen and host specific signatures and the effect of infection with multiple pathogens on deer immune response. These results suggested that intracellular bacteria from Anaplasma and Mycobacterium genera produce similar genes expression patterns in infected ruminants. However, pathogen and host-specific differences could contribute to disease diagnosis and treatment in ruminants. PMID- 20952065 TI - Hemispheral brain atrophy without leptomeningeal malformation in an adult with neurocutaneous overlap syndrome. PMID- 20952066 TI - [Central nervous system involvement in systemic diseases: Spectrum of MRI findings]. AB - Central nervous system (CNS) involvement in systemic disease (SD) is unusual. MRI features of such lesions are unfamiliar to most radiologists. The diagnosis of SD is still based on clinical features and laboratory findings but some characteristic MRI findings exist for each SD: micronodular leptomeningeal enhancement in sarcoidosis, diffuse or focal pachymeningeal involvement in Wegener disease, dentate nuclei and brain stem lesions in Langerhans cell histiocytosis, meningeal masses, dentate nuclei lesions and periarterial infiltration in Erdheim-Chester disease, meningeal masses in Rosai-Dorfman disease, veinular pontic lesions and cerebral vein thrombosis in Behcet, supratentorial microvascular lesions in lupus and antiphospholipid and Gougerot Sjogren syndrome. In this work, we explain, describe and illustrate the most characteristic MRI findings for each disease. PMID- 20952067 TI - Dealing with mentally ill domestic violence perpetrators: A therapeutic jurisprudence judicial model. AB - People suffering from mental illness are increasingly referred to the domestic violence court. Yet the typical diversion programs available, including batterer's intervention programs, are inappropriate for those with serious mental illness. As a result, the Miami-Dade Domestic Violence Court has developed a new approach for dealing with this population that applies mental health court techniques in domestic violence court. This article will describe and discuss this pioneering model. It also will situate this model within the context of other problem-solving courts and discuss how the court uses principles and approaches of therapeutic jurisprudence. The paper presents some preliminary data that describe the social and legal characteristics of 20 defendants in the Domestic Violence Mental Health Court followed over a two year period between 2005 and 2007. PMID- 20952068 TI - Several current-use, non-PBDE brominated flame retardants are highly bioaccumulative: evidence from field determined bioaccumulation factors. AB - With the phaseout of brominated flame retardants (BFRs) polybrominated diphenyl ethers (PBDEs), some non-PBDE BFRs have prompted to be alternatives to the discontinued PBDEs. To assess the bioaccumulation potential of these chemicals, field bioaccumulation factors (BAFs) for several non-PBDE BFRs including hexabromocyclododecanes (HBCDs), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), pentabromotoluene (PBT), pentabromoethylbenzene (PBEB), and hexabromobenzene (HBB), were determined in the aquatic species from a natural pond in an electronic waste recycling site in South China. The log BAFs ranged 2.58-6.01, 3.24-5.58, 3.44-5.98, 2.85-5.98, 3.32-6.08, 2.04-4.77, 2.72-4.09 and 3.31-5.54 for alpha-HBCD, beta-HBCD, gamma-HBCD, ?HBCDs, BTBPE, PBT, PBEB, and HBB, respectively. The log BAF values for HBCD isomers, BTBPE, and HBB were greater than 3.7 (corresponding BAF value 5000) in most of the investigated species, demonstrating their highly bioaccumulative properties. alpha-, beta-, and gamma HBCDs, BTBPE, and HBB appeared comparable or had even greater BAFs compared to PBDE congeners with similar K(OW), suggesting that these BFRs may have a potentially high environmental risk. The BAFs for the given BFR compound were largely variable between species, due to the species-specific feeding ecology, trophic level, and metabolic capacity for these pollutants. Positive linear relationships between log BAF and log K(OW) (r2 = 0.59, p = 0.04), and molecular weight (r2 = 0.54, p = 0.06) of non-PBDE BFRs were observed in the species with low trophic level (Chinese mysterysnail), suggesting that the chemical's physicochemical properties also played key roles in the bioaccumulation processes. PMID- 20952069 TI - Pesticide exposure among pregnant women in Jerusalem, Israel: results of a pilot study. AB - BACKGROUND: Pesticides have been shown to disrupt neurodevelopment in laboratory animals and in human populations. To date, there have been no studies on exposure to pesticides in pregnant women in Israel, despite reports of widespread exposure in other populations of pregnant women and the importance of evaluating exposure in this susceptible sub-population. METHODS: We measured urinary concentrations of organophosphorus (OP) insecticide metabolites and plasma concentrations of OP and other pesticides in 20 pregnant women, recruited in Jerusalem, Israel in 2006, and collected questionnaire data on demographic factors and consumer habits from these women. We compared geometric mean concentrations in subgroups using the Mann-Whitney U-test for independent samples. We compared creatinine-adjusted OP pesticide metabolite concentrations, as well as plasma pesticide concentrations, with other populations of pregnant women. RESULTS: Creatinine adjusted total dimethyl (DM) metabolite concentrations were between 4 and 6 times higher in this population compared to other populations of pregnant women in the United States while total diethyl (DE) metabolite concentrations were lower. Dimethylphosphate (DMP) was detected in 74% of the urine samples whereas dimethylthiophosphate (DMTP) was detected in 90% of the urine samples. The carbamate bendiocarb was detected in 89% of the plasma samples, while the OP insecticide chlorpyrifos was detected in 42% of the samples. Mean plasma concentrations of bendiocarb and chlorpyrifos in our sample were 4.4 and 3.9 times higher, respectively, than that of an urban minority cohort from New York City. Twelve women (63%) reported using some form of household pest control during their pregnancy and five (26%) reported using household pest control during the past month. Women with a graduate degree had significantly higher geometric mean concentrations of total urinary DM metabolite concentrations compared to other women (P=0.006). Finally, one woman in the study had exceptionally high concentrations of DMP, DMTP, DMDTP compared to the other women in the study, despite reporting no current occupational exposure to OP pesticides and no other significant exposure sources. CONCLUSIONS: Pregnant women in the Jerusalem area are exposed to OP pesticides and to the carbamate pesticide bendiocarb. It is unclear why total DM metabolites concentrations were much higher in this population compared to other populations of pregnant women in the United States and Netherlands. Finally, the finding of very high DM metabolite concentrations in one woman who reported being moved from her regular laboratory work to administrative work upon becoming pregnant, raises questions about the adequacy of measures to protect pregnant women from pesticide exposures during pregnancy. PMID- 20952071 TI - Non-classical binding of a polyreactive alpha-type anti-idiotypic antibody to B cells. AB - Detailed information on the immunological relevance of alpha-type anti-idiotypic antibodies is lacking after more than 30 years since Jerne postulated his Idiotypic Network Theory. The B7Y33 mutant is a mouse-human chimeric version of the B7 MAb, a polyreactive alpha-type anti-idiotypic antibody, generated against an anti-GM2 ganglioside IgM Ab1 antibody. It retained the unusual self-binding activity and multispecificity of the parental murine antibody, being able to recognize several anti-ganglioside IgM antibodies as well as non-immunoglobulin antigens. Previous work with the murine B7 MAb suggested that this antibody might have immunoregulatory properties, and therefore we investigated the possible interaction of B7Y33 with immune cells. We found that B7Y33 binds to human and murine B lymphocytes. Inhibition assays using flow cytometry indicated that this antibody is capable of binding the Fc gamma receptor II (FcgammaRII). The recognition of FcgammaRII-expressing K562, Raji and Daudi human cell lines, together with the capability of inhibiting the binding of an anti-human FcgammaRII antibody to these cells, suggest that B7Y33 interacts with both the FcgammaRIIa and FcgammaRIIb isoforms. We evaluated the contribution to the binding of different surface-exposed residues at the top of the heavy chain variable region (VH) CDR loops through the construction of mutants with substitutions in the three conventional VH CDRs (HCDRs) and the "HCDR4", located in the framework 3 (HFR3). In addition, we assessed the involvement of the Fc region by performing key mutations in the CH2 domain. Furthermore, chimeric hybrid molecules were obtained by combining the B7Y33 heavy chain with unrelated light chains. Our results indicate that the multispecificity and self-binding properties of B7Y33 are not linked to its recognition of B lineage cells, and that this phenomenon occurs in a non-classical way with the participation of both the variable and constant regions of the antibody. Two possible models for this interaction are proposed, with B7Y33 binding to two FcgammaRIIb molecules through the Fc and Fv regions, or simultaneously to FcgammaRIIb and another unknown antigen on B cells. The FcgammaRIIb has recently received great attention as an attractive target for therapies directed to B lymphocytes. The recognition of peripheral B lymphocytes from B cell chronic lymphocytic leukemia (B-CLL) patients by B7Y33 suggests its potential application for the treatment of B cell malignancies. PMID- 20952070 TI - Dynamic DNA methylation patterns across the mouse and human IL10 genes during CD4+ T cell activation; influence of IL-27. AB - IL-10 plays a critical role in controlling inflammation and the anti-inflammatory functions of IL-10 are regulated based on its coordinated expression from various cellular sources, most notably T cells. Although nearly all CD4+ subpopulations can express IL-10, surprisingly little is known about the molecular mechanisms which control IL-10 induction, particularly in humans. To examine the regulation of human IL-10 expression, we created the hIL10BAC transgenic mouse. As previously reported, we observed conservation of myeloid-derived IL-10 expression but found that human IL-10 was only weakly expressed in splenic CD4+ T cells from hIL10BAC mice. Since DNA methylation is an important determinant of gene expression profiles, we assessed the patterns of DNA methylation in the human and mouse IL10 genes in naive and activated CD4+ T cells. Across mouse and human IL10 there were no obvious patterns of CpG methylation in naive CD4+ T cells following polyclonal activation. Overall however, the human IL10 gene had significantly higher levels of DNA methylation. Interestingly, coculture with the IL-10 inducing cytokine IL-27 lead to a site-specific reduction in methylation of the mouse but not human IL10 gene. Demethylation was specifically localized to an intronic site adjacent to a known regulatory region. Our findings indicate that while the mouse and human IL10 genes undergo variable changes in DNA methylation during CD4+ T cell activation, IL-27 appears to influence DNA methylation in a particular intronic region thus associating with IL-10 expression. PMID- 20952072 TI - Does postnatal depression screening work? Throwing out the bathwater, keeping the baby. AB - BACKGROUND: Rates of help-seeking for Postnatal Depression (PND) are generally low and population screening has the potential to increase diagnosis rates. Of central importance is the screening instrument's Positive Predictive Value (PPV), which is itself influenced by the prevalence of the condition. When PPV exceeds prevalence, screening defines a screen-positive group with a higher prevalence to which diagnostic-stage procedures can be targeted, a necessary component of a screening program's potential for cost-effectiveness. METHODS: Employing the best available estimates of the prevalence of PND we applied Bayes' Theorem to map the parameter space for the Positive Predictive Value of the Edinburgh Postnatal Depression Scale (EPDS) across a realistic range of values. Only seven methodologically comparable validation studies are available for major depression and/or minor depression. RESULTS: Screening with the EPDS always facilitated an increase in identification rates, over the key range of prevalence values. The EPDS defined a sub-group with prevalence between 5-fold and 17-fold greater than the general population. A central estimate of PPV (at a prevalence of 6.8%) was 62%. LIMITATIONS: Few high-quality data are available for analysis and therefore better estimates, of both PND prevalence and of screening accuracy, in the populations where screening takes place are needed. CONCLUSIONS: Our estimates of PPV indicate that population screening with an instrument at least as accurate as the EPDS could successfully increase the number of cases identified and, therefore, treatment rates. Comparisons with the performance of physical health screening programs appear favourable. Appropriate training for health professionals is essential to minimize potential harms, and following all positive screening results with a formal diagnostic procedure is likely to be useful both clinically and in terms of health system costs. PMID- 20952073 TI - Frontolimbic responses to emotional faces in young people at familial risk of depression. AB - BACKGROUND: The processing of aversive stimuli in patients with major depression is associated with increased neural activity in limbic areas while the activity in cortical regulatory regions is diminished. The aim of the present study was to examine whether related neural abnormalities might be present in young people at increased familial risk of depression but with no personal history of illness. METHODS: We used a block designed functional magnetic resonance imaging to measure the neural responses to a task involving the matching of emotional facial expressions in 29 young people (age 16-21 years) who had a biological parent with a history of major depression, and 30 age- and gender-matched controls. RESULTS: Relative to the controls, the participants with increased familial risk of depression (FH) had diminished responses in left dorsolateral prefrontal cortex (DLPFC) to the presentation of fearful faces while the activity in the amygdala did not distinguish the groups. LIMITATIONS: FH participants had more depressive symptomatology than the controls. Their FH status was based on self-report. CONCLUSIONS: Young people at increased familial risk of depression show evidence of decreased cortical regulation of aversive stimuli. Further studies will be needed to ascertain if this abnormality might predispose to the eventual development of clinical depression. PMID- 20952074 TI - Lifting the shroud on depression and premature mortality: a 49-year follow-up study. AB - Numerous studies have shown higher rates of death from natural causes in the years immediately following an episode of clinical depression. The longer term relationship of depression to excess mortality is less clear because relatively few studies have followed the same cohort of patients for more than 10 years. The present paper reports on the findings following the same cohort of patients 49 years after discharge. METHOD: Patients who were diagnosed with depression in the Chichester/Salisbury Catchment Area Study were followed for 49 years. The incidence of death from natural causes in the clinical population was compared with population rates adjusted for age and sex. RESULTS: The results suggest that clinical depression may have enduring effects on physical health that emerge later in life, the significance of which have so far remained undetected. Further analyses of death rates by age and sex suggest that: a.) Depression has a stronger impact on mortality among women. b.) Excess mortality starts to emerge at an earlier age among women. DISCUSSION: Because prior studies of depression and mortality have typically followed patients for fewer than 25 years, the long term impact of major depression has remained undetected. The results are consistent with the view that depression has a negative impact on health that spans multiple decades. LIMITATIONS: The association between mortality and depression could arise if prolonged treatment with antidepressant medication increases mortality. The association found between depression and mortality might also reflect differences in the quality of medical care that is provided to clinically depressed individuals. The present study does not control for factors that are confounded with depression (e.g., diet, exercise), nor does it utilize a matched control group. CONCLUSION: The pathways linking depression and mortality are likely to be complex and multifactorial in nature. The major implication of the present work is to suggest that such pathways link depression with long-term, as well as short-term differences in mortality. PMID- 20952075 TI - Functional analysis of the mannose-binding lectin complement pathway in normal pregnancy and preeclampsia. AB - Preeclampsia is a severe complication of pregnancy characterized by hypertension and proteinuria developing after midgestation. Previous studies have shown increased complement activation in normal and preeclamptic pregnancies. We aimed to investigate the role of the mannose-binding lectin pathway in the initiation of pathological complement activation observed in patients with preeclampsia. The study included 60 preeclamptic patients, 60 healthy pregnant women and 56 healthy non-pregnant women. Functional activity of the complex of mannose-binding lectin and mannose-binding lectin-associated serine protease 2 (MBL-MASP2 complex) was determined by ELISA. Circulating levels of complement components and C-reactive protein (CRP) were also measured. MBL-MASP2 activity was significantly higher in healthy pregnant than non-pregnant women. However, increased activity of the MBL MASP2 complex in preeclamptic patients was not observed, compared to healthy pregnant women. MBL-MASP2 activity showed no relationship with either the levels of complement parameters, or with the clinical data and level of CRP in patients with preeclampsia. In conclusion, the complement system is activated with increased terminal complex formation in the third trimester of normal human pregnancy, and is further activated in preeclampsia as shown by the elevated amounts of activation markers. The activity of MBL-MASP2 is also increased in normal pregnancy, to the same level seen in preeclampsia. In our study, no relationship between MBL-MASP2 activity and extent of complement activation was observed in preeclampsia. We tentatively conclude, albeit without an evaluation of local placental concentrations, that the mannose-binding lectin pathway may play only a minor role in pathological complement activation during preeclampsia. PMID- 20952076 TI - Comparison of characteristics of suicide attempters with schizophrenia spectrum disorders and those with mood disorders in Japan. AB - Suicidality in patients with schizophrenia is high. To clarify the characteristics of suicidal behavior in patients with schizophrenia, we investigated suicide attempters with schizophrenia spectrum disorders in comparison with patients with mood disorders. One hundred patients with schizophrenia spectrum disorders and 155 patients with mood disorders admitted to an emergency department after a suicide attempt were interviewed in detail on items concerning 1) demographic characteristics, 2) previous suicidal behavior, and 3) index suicidal behavior. Differences between the two groups were subsequently analyzed. Patients with schizophrenia spectrum disorders showed a lower incidence of previous deliberate self-harm, and a higher incidence of a subsequent suicide attempt more than 1 year after the previous suicide attempt as well as a higher lethality of index suicide attempt compared to patients with mood disorders. Furthermore, the most common motive for making a suicide attempt in patients with schizophrenia spectrum disorders was having a mental problem. This study revealed the factors associated with suicide attempts among Japanese patients with schizophrenia spectrum disorders, and the nature of these factors makes it difficult to predict future attempts. This makes clear the importance of continuous long-term follow-up with careful attention to the mental symptoms and psychological burden for such patients. PMID- 20952077 TI - Uptake and effects of manufactured silver nanoparticles in rainbow trout (Oncorhynchus mykiss) gill cells. AB - Nanoparticles are already widely used in technology, medicine and consumer products, but there are limited data on their effects on the aquatic environment. In this study the uptake and effect of citrate (AgNP(CIT)) and polyvinylpyrrolidone (AgNP(PVP)) coated manufactured silver nanoparticles, as well as AgNO(3) (Ag(+)) were tested using primary gill cells of rainbow trout (Oncorhynchus mykiss). Prior to use, the nanoparticles were characterized for size, surface charge and aggregation behavior. Gill cells were cultured either as monolayers on solid support, or as multilayers on a permeable support cell culturing system, enabling transport studies. The uptake of silver nanoparticles and Ag(+) after exposure to 10 mg L(-1) was determined with microscopical methods and inductively coupled plasma mass spectrometry (ICP-MS). Cytotoxicity, in terms of membrane integrity, as well as oxidative stress (depletion of reduced glutathione) was tested at silver concentrations ranging from 0.1 mg L(-1) to 10 mg L(-1). Results show that AgNP(CIT) nanoparticles are readily taken up into gill cell monolayers while uptake was less for AgNP(PVP). In contrast, it appears that the slightly smaller AgNP(PVP) were transported through cultured multilayers to a higher extent, with transport rates generally being in the ng cm(-2) range for 48 h exposures. Transport rates for all exposures were dependent on the epithelial tightness. Moderate cytotoxic effects were seen for all silver treatments. Levels of reduced glutathione were elevated in contrast to control groups, pointing on a possible overcompensation reaction. Taken together silver nanoparticles were taken up into cells and did cause silver transport over cultured epithelial layers with uptake and transport rates being different for the two nanoparticle species. All silver treatments had measurable effects on cell viability. PMID- 20952078 TI - Acute toxicity, accumulation and tissue distribution of copper in the blue crab Callinectes sapidus acclimated to different salinities: in vivo and in vitro studies. AB - In vivo and in vitro studies were performed to evaluate acute toxicity, organ specific distribution, and tissue accumulation of copper in Callinectes sapidus acclimated to two different experimental salinities (2 and 30 ppt). Blue crabs were quite tolerant to copper. Acute dissolved copper toxicity (96-h LC(50) and its corresponding 95% confident interval) was higher at salinity 2 ppt (5.3 (3.50 8.05) MUM Cu) than at 30 ppt (53.0 (27.39-102.52) MUM Cu). The difference between salinities can be completely explained based on the water chemistry because it disappeared when 96-h LC(50) values were expressed as the free Cu(2+) ion (3.1 (1.93-4.95) MUM free Cu at 2 ppt versus 5.6 (2.33-13.37) MUM free Cu at 30 ppt) or the Cu(2+) activity (1.4 (0.88-2.26) MUM Cu activity at 2 ppt versus 1.7 (0.71 4.07) MUM Cu activity at 30 ppt). The relationships between gill Cu burden and % mortality were very similar at 2 and 30 ppt, in accord with the Biotic Ligand Model. In vivo experiments showed that copper concentration in the hemolymph is not dependent on metal concentration in the surrounding medium at either experimental salinity. They also showed that copper flux into the gills is higher than into other tissues analyzed, and that anterior and posterior gills are similarly important sites of copper accumulation at both experimental salinities. In vitro experiments with isolated-perfused gills showed that there is a positive relationship between copper accumulation in this tissue and the metal concentration in the incubation media for both anterior and posterior gills. A similar result was observed at both low and high salinities. Furthermore, in vitro experiments showed that copper accumulation in posterior gills is also positively and strongly dependent on the incubation time with copper. Gill copper accumulation occurred at a lower rate in the first 2h of metal exposure, increasing markedly after this "steady-state" period. This finding was corroborated by a significant increase in copper influx to the gill perfusate (corresponding to crab hemolymph) after this time, measured using (64)Cu. In vivo, after uptake from solution, (64)Cu was primarily accumulated in the gills and the rest of the body rather than in the hemolymph, hepatopancreas, or other internal tissues. Overall, the present findings indicate that gills are a key target organ for copper accumulation, as well as an important biological barrier against the excessive uptake of copper into the hemolymph and the subsequent distribution of this metal to internal organs of the blue crab. PMID- 20952079 TI - Is employer-based health insurance a barrier to entrepreneurship? AB - The focus on employer-provided health insurance in the United States may restrict business creation. We address the limited research on the topic of "entrepreneurship lock" by using recent panel data from matched Current Population Surveys. We use difference-in-difference models to estimate the interaction between having a spouse with employer-based health insurance and potential demand for health care. We find evidence of a larger negative effect of health insurance demand on business creation for those without spousal coverage than for those with spousal coverage. We also take a new approach in the literature to examine the question of whether employer-based health insurance discourages business creation by exploiting the discontinuity created at age 65 through the qualification for Medicare. Using a novel procedure of identifying age in months from matched monthly CPS data, we compare the probability of business ownership among male workers in the months just before turning age 65 and in the months just after turning age 65. We find that business ownership rates increase from just under age 65 to just over age 65, whereas we find no change in business ownership rates from just before to just after for other ages 55-75. We also do not find evidence from the previous literature and additional estimates that other confounding factors such as retirement, partial retirement, social security and pension eligibility are responsible for the increase in business ownership in the month individuals turn 65. Our estimates provide some evidence that "entrepreneurship lock" exists, which raises concerns that the bundling of health insurance and employment may create an inefficient level of business creation. PMID- 20952080 TI - Price adjustment in the hospital sector. AB - We analyse the properties of optimal price adjustment to hospitals when no lump sum transfers are allowed and when prices differ to reflect observable exogenous differences in costs. We find that: (a) when the marginal benefit from treatment is decreasing and the cost function is the power function, price adjustment for hospitals with higher costs is positive but partial; if the marginal benefit is constant, the price is identical across providers; (b) if the cost function is exponential or it is separable in monetary and non-monetary costs (and linear in monetary costs), price adjustment is positive even when the marginal benefit is constant; (c) higher inequality aversion of the purchaser increases concentration in prices and lowers concentration in quantities; (d) if some dimensions of costs are private information, a higher correlation between the observable and unobservable cost component increases the optimal price for providers whose observable costs are above the average. PMID- 20952081 TI - Judging the 'passability' of dynamic gaps in a virtual rugby environment. AB - Affordances have recently been proposed as a guiding principle in perception action research in sport (Fajen, Riley, & Turvey, 2009). In the present study, perception of the 'passability' affordance of a gap between two approaching defenders in rugby is explored. A simplified rugby gap closure scenario was created using immersive, interactive virtual reality technology where 14 novice participants (attacker) judged the passability of the gap between two virtual defenders via a perceptual judgment (button press) task. The scenario was modeled according to tau theory (Lee, 1976) and a psychophysical function was fitted to the response data. Results revealed that a tau-based informational quantity could account for 82% of the variance in the data. Findings suggest that the passability affordance in this case, is defined by this variable and participants were able to use it in order to inform prospective judgments as to passability. These findings contribute to our understanding of affordances and how they may be defined in this particular sporting scenario; however, some limitations regarding methodology, such as decoupling perception and action are also acknowledged. PMID- 20952082 TI - Detection of changes in the cellular composition of Salmonella enterica serovar Typhimurium in the presence of antimicrobial compound(s) of Lactobacillus strains using Fourier transform infrared spectroscopy. AB - It was previously established that Lactobacillus fermentum ACA-DC 179, Lactobacillus plantarum ACA-DC 287 and Lactobacillus plantarum ACA-DC 2350 exhibit antimicrobial activity against Salmonella enterica serovar Typhimurium. In order to further investigate the killing effect of these microorganisms against Salmonella cells, we employed Fourier transform infrared spectroscopy (FT IR). Salmonella cells were incubated with different concentrated lactobacilli supernatants and their FT-IR spectra were recorded. The second derivative transformation of the original spectra revealed changes in spectral regions corresponding to absorptions of major cellular constituents (e.g. cell wall, cell membrane, and proteins of the cell) among the Salmonella cells treated with the supernatants and those treated with the control samples. Principal component analysis of the second derivative transformed spectra showed that the yet unidentified antimicrobial compound(s) produced by the lactobacilli tested clearly interfered with the fatty acids of the cell membrane, as well as the polysaccharides of the cell wall in Salmonella cells, pointing towards a dual killing mode. Our study shed light for the first time in the anti-Salmonella activity of the particular Lactobacillus strains. PMID- 20952083 TI - Focus. What is the significance of hepatitis E as a public health threat in the industrialized countries? Hepatitis E virus infection in Italy. PMID- 20952085 TI - Inhibition of mammalian target of rapamycin: two goals with one shot? PMID- 20952084 TI - Dysadherin can enhance tumorigenesis by conferring properties of stem-like cells to hepatocellular carcinoma cells. AB - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is associated with a high potential for metastasis and disease recurrence, even after surgical resection. The cancer stem cell (CSC) hypothesis proposes that CSCs are responsible for chemo-resistance, recurrence, and metastasis. Dysadherin is a prognostic indicator of metastasis and poor survival in many different cancer types. In this study, we investigated the possible link between dysadherin and CSC in HCC. METHODS: We analyzed the functional implications of dysadherin on cancer stemness by modification of the dysadherin gene in HCC cell lines. RESULTS: The transfection of dysadherin cDNA into the liver cancer cell line PLC/PRF/5 enhanced the properties of CSCs, including anti-apoptosis, their sphere-forming ability, side population phenotype, and tumor initiation ability in vivo. Furthermore, knockdown of dysadherin in the liver cancer cell line SK-Hep1 suppressed its stem cell-like properties. CONCLUSIONS: These results show that dysadherin give rise to properties of CSC in HCC. Therefore, these findings suggest that dysadherin may be a potential molecular prognostic marker of HCC and may aid in the development of more effective therapies. PMID- 20952086 TI - Prevalence and lifetime healthcare cost of cerebral palsy in South Korea. AB - OBJECTIVES: This study examined the prevalence of cerebral palsy (CP) in South Korea, and the attributable lifetime medical cost according to physiological types and extent of involvement. METHODS: The number of medical service use and medical cost of CP were obtained from the national health insurance review and assessment (HIRA) service. The prevalence was calculated from the number of five year-old patients who used medical services between 2004 and 2008. The lifetime medical cost of CP was calculated from the data and discount rate of 3%. RESULTS: The prevalence of CP in South Korea was 2.6 per 1000 children. The attributable lifetime medical cost of CP in South Korea was calculated to be 26,383 US dollars, which is 1.8 times the basic lifetime medical cost of the general population (14,579 US dollars). Spastic CP showed the highest attributable medical cost, followed by dyskinetic and ataxic CP. Spastic diplegia showed 1.4 times of the attributable lifetime medical cost of spastic hemiplegia. CONCLUSIONS: The prevalence of CP in South Korea is comparable to that in other countries. CP is a disease with wide range of clinical features, and the medical cost according to the physiological types and extent of involvement should be considered. PMID- 20952087 TI - Angiosarcoma of the lung: 2 cases report and literature reviewed. AB - Angiosarcoma is a kind of malignant tumors derived from vascular endothelial cell. Its incidence rate is very low. Pulmonary angiosarcomas are usually secondary tumors, and primary cases are less than 20 so far. Here we presented two cases of angiosarcoma involved the lung, and we only confirmed case 2 as a primary pulmonary angiosarcoma. The clinical characteristics, diagnosis, treatment options and prognosis of pulmonary angiosarcoma were reviewed in this article too. PMID- 20952088 TI - Adaptation genomics: the next generation. AB - Understanding the genetics of how organisms adapt to changing environments is a fundamental topic in modern evolutionary ecology. The field is currently progressing rapidly because of advances in genomics technologies, especially DNA sequencing. The aim of this review is to first briefly summarise how next generation sequencing (NGS) has transformed our ability to identify the genes underpinning adaptation. We then demonstrate how the application of these genomic tools to ecological model species means that we can start addressing some of the questions that have puzzled ecological geneticists for decades such as: How many genes are involved in adaptation? What types of genetic variation are responsible for adaptation? Does adaptation utilise pre-existing genetic variation or does it require new mutations to arise following an environmental change? PMID- 20952089 TI - Species differences in responses to captivity: stress, welfare and the comparative method. AB - Approximately 26 billion animals, spanning over 10 000 species, are kept on farms and in zoos, conservation breeding centers, research laboratories and households. Captive animals are often healthier, longer-lived and more fecund than free living conspecifics, but for some species the opposite is true. Captivity is a very long way from the ideal 'common garden' often assumed by evolutionary and ecological researchers using data for captive animals. The use of comparative methods to investigate the fundamental biological causes of these species differences would help to improve husbandry and enclosure design, and might even reveal relationships between susceptibilities to poor captive welfare and susceptibilities to anthropogenic threat in the wild. Studies of these species differences could also inspire and facilitate 'evo-mecho' research into the functions of behavioral control mechanisms. PMID- 20952090 TI - Swarm intelligence in plant roots. PMID- 20952091 TI - The reactive transport of trichloroethene is influenced by residence time and microbial numbers. AB - The dechlorination rate in a flow-through porous matrix can be described by the species specific dechlorination rate observed in a liquid batch unless mass transport limitations prevail. This hypothesis was examined by comparing dechlorination rates in liquid batch with that in column experiments at various flow rates (3-9-12 cm day(-1)). Columns were loaded with an inoculated sand and eluted with a medium containing 1mM trichloroethene (TCE) for 247 days. Dechlorination in the column treatments increased with decreasing flow rate, illustrating the effect of the longer residence time. Zeroth order TCE or cis-DCE degradation rates were 4-7 folds larger in columns than in corresponding batch systems which could be explained by the higher measured Geobacter and Dehalococcoides numbers per unit pore volume in the columns. The microbial numbers also explained the variability in dechlorination rate among flow rate treatments marked by a large elution of the dechlorinating species' yield as flow increased. Stop flow events did not reveal mass transport limitations for dechlorination. We conclude that flow rate effects on reactive transport of TCE in this coarse sand are explained by residence time and by microbial transport and that mass transport limitations in this porous matrix are limited. PMID- 20952093 TI - The cortactin-binding domain of WIP is essential for podosome formation and extracellular matrix degradation by murine dendritic cells. AB - In immature dendritic cells (DCs) podosomes form and turn over behind the leading edge of migrating cells. The Arp2/3 complex activator Wiskott-Aldrich Syndrome Protein (WASP) localises to the actin core of forming podosomes together with WASP-Interacting Protein (WIP). A second weaker Arp2/3 activator, cortactin, is also found at podosomes where it has been proposed to participate in matrix metalloproteinase (MMP) secretion. We have previously shown that WIP(-/-) DCs are unable to make podosomes. WIP binds to cortactin and in this report we address whether WIP regulates cortactin-mediated MMP activity. Using DCs derived from splenic murine precursors, we found that wild-type cells were able to localise MMPs at podosomes where matrix degradation takes place. In contrast, WIP(-/-) DCs remain able to synthesise MMPs but do not degrade the extracellular matrix. Infection of WIP KO DCs with lentivirus expressing WIP restored both podosome formation and their ability to degrade the extracellular matrix, implicating WIP induced podosomes as foci of functional MMP location. When WIP KO DCs were infected with a mutant form of WIP lacking the cortactin-binding domain (WIPDelta110-170) DCs were only able to elaborate disorganised podosomes that were unable to support MMP-mediated matrix degradation. Taken together, these results suggest a role for WIP not only in WASP-mediated actin polymerisation and podosome formation, but also in cortactin-mediated extracellular matrix degradation by MMPs. PMID- 20952095 TI - [Superior eyelid phtiriasis]. PMID- 20952094 TI - Metabolic response in roots of Prunus rootstocks submitted to iron chlorosis. AB - Iron deficiency induces several responses to iron shortage in plants. Metabolic changes occur to sustain the increased iron uptake capacity of Fe-deficient plants. We evaluated the metabolic changes of three Prunus rootstocks submitted to iron chlorosis and their different responses for tolerance using measurements of metabolites and enzymatic activities. The more tolerant rootstocks Adesoto (Prunus insititia) and GF 677 (Prunus amygdalus*Prunus persica), and the more sensitive Barrier (P. persica*Prunus davidiana) were grown hydroponically in iron sufficient and -deficient conditions over two weeks. Sugar, organic and amino acid concentrations of root tips were determined after two weeks of iron shortage by proton nuclear magnetic resonance spectroscopy of extracts. Complementary analyses of organic acids were performed by liquid chromatography coupled to mass spectrometry. The major soluble sugars found were glucose and sucrose. The major organic acids were malic and citric acids, and the major amino acid was asparagine. Iron deficiency increased root sucrose, total organic and amino acid concentrations and phosphoenolpyruvate carboxylase activity. After two weeks of iron deficiency, the malic, citric and succinic acid concentrations increased in the three rootstocks, although no significant differences were found among genotypes with different tolerance to iron chlorosis. The tolerant rootstock Adesoto showed higher total organic and amino acid concentrations. In contrast, the susceptible rootstock Barrier showed lower total amino acid concentration and phosphoenolpyruvate carboxylase activity values. These results suggest that the induction of this enzyme activity under iron deficiency, as previously shown in herbaceous plants, indicates the tolerance level of rootstocks to iron chlorosis. The analysis of other metabolic parameters, such as organic and amino acid concentrations, provides complementary information for selection of genotypes tolerant to iron chlorosis. PMID- 20952096 TI - Screening to select patients carrying extended-spectrum beta-lactamase-producing Enterobacteriaceae for isolation in Flemish intensive care units: a Swiss cheese strategy? PMID- 20952097 TI - Transporting clinical tools to new settings: cultural adaptation and validation of the Emergency Severity Index in German. AB - STUDY OBJECTIVE: To date, no German triage tool with proven reliability and validity exists. The goal of this project is to translate and culturally adapt the Emergency Severity Index (ESI) and to assess reliability and validity of the German version. METHODS: The ESI was translated following principles recommended for the translation and cultural adaptation of instruments. We performed a prospective, single-center cohort study. Reliability was assessed by calculating Cohen's weighted kappa for agreement of 2 experts who reviewed the triage nurses' notes. To assess validity, associations of the number of resources, hospitalization, admission to intensive care, length of stay, and mortality with the assigned ESI level were investigated. RESULTS: Only small cultural adaptations had to be made during the translation process. Interrater agreement was high (kappa(w) = 0.985) in a sample of 125 patients. For the assessment of validity, a sample of 2,114 patients was used. Spearman's rank correlation coefficient between ESI category and number of resources was rho = -0.567. The association (Kendall's tau) between ESI category and disposition, and hospitalization was tau = -0.429 and tau = -0.453, respectively. The areas under the curves for the predictive ability of the ESI for hospitalization in general and hospitalization to an ICU were 0.788 and 0.856, respectively. The association between emergency department length of stay and ESI category was also significant (Kruskal-Wallis chi2 = 450.8; df = 4; P < .001). Furthermore, the association between ESI category and survival probability was significant (log-rank chi2 = 36.06; df = 3; P < .001). CONCLUSION: Translation of the ESI following guidelines was feasible and resulted in a reliable and valid German version. PMID- 20952098 TI - Short-term outcomes after Fab antivenom therapy for severe crotaline snakebite. AB - STUDY OBJECTIVES: We seek to determine the short-term outcomes associated with the use of Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) therapy for severe crotaline snake envenomation and to better define the incidence of hypersensitivity reactions associated with FabAV use. METHODS: We conducted a multicenter observational case series study of patients who received FabAV at 17 US hospitals in 2002 to 2004. A 7-point score incorporating local, systemic, and hematologic venom effects was used to grade envenomation severity before and after FabAV therapy. The primary outcome for response to therapy was the change in overall envenomation severity after FabAV administration. The primary safety outcomes were the rates of immediate hypersensitivity reactions and serum sickness. RESULTS: The outcome-evaluable population included 209 patients, of whom 28 had severe envenomation. All severely envenomated patients improved after receiving FabAV. The median severity scores of severely envenomated patients were 5 (interquartile range [IQR] 5 to 5) before FabAV, 1 (IQR 1 to 2) at the last FabAV loading dose, and 1 (IQR 0 to 1) at the last clinical observation. The proportion of patients with progressive pain, progressive swelling, cardiovascular effects, respiratory effects, neurologic effects, gastrointestinal effects, coagulopathy, and thrombocytopenia all improved after FabAV therapy. The safety population included 247 patients. Immediate hypersensitivity reactions were reported in 6.1% (95% confidence interval 3.4% to 9.8%) of patients. Serum sickness was reported in 5% (95% confidence interval 0.6% to 17%) of patients with a minimum of 6 days of follow-up after the last dose of FabAV. CONCLUSION: FabAV therapy is associated with clinical improvement in severe crotaline snake envenomation. Immediate hypersensitivity and serum sickness rates may be less than described in the FabAV prescribing information. PMID- 20952099 TI - Reperfusion is delayed beyond guideline recommendations in patients requiring interhospital helicopter transfer for treatment of ST-segment elevation myocardial infarction. AB - STUDY OBJECTIVE: Early reperfusion portends better outcomes for ST-segment elevation myocardial infarction (STEMI) patients. This investigation estimates the proportions of STEMI patients transported by a hospital-based helicopter emergency medical services (EMS) system who meet the goals of 90-minute door-to balloon time for percutaneous coronary intervention or 30-minute door-to-needle time for fibrinolysis. METHODS: This was a multicenter, retrospective chart review of STEMI patients flown by a hospital-based helicopter service in 2007. Included patients were transferred from an emergency department (ED) to a cardiac catheterization laboratory for primary or rescue percutaneous coronary intervention. Out-of-hospital, ED, and inpatient records were reviewed to determine door-to-balloon time and door-to-needle time. Data were abstracted with a priori definitions and criteria. RESULTS: There were 179 subjects from 16 referring and 6 receiving hospitals. Mean age was 58 years, 68% were men, and 86% were white. One hundred forty subjects were transferred for primary percutaneous coronary intervention, of whom 29 had no intervention during catheterization. For subjects with intervention, door-to-balloon time exceeded 90 minutes in 107 of 111 cases (97%). Median door-to-balloon time was 131 minutes (interquartile range 114 to 158 minutes). Thirty-nine subjects (21%) received fibrinolytics before transfer, and 19 of 39 (49%) received fibrinolytics within 30 minutes. Median door-to-needle time was 31 minutes (interquartile range 23 to 45 minutes). CONCLUSION: In this study, STEMI patients presenting to non-percutaneous coronary intervention facilities who are transferred to a percutaneous coronary intervention-capable hospital by helicopter EMS do not commonly receive fibrinolysis and rarely achieve percutaneous coronary intervention within 90 minutes. In similar settings, primary fibrinolysis should be considered while strategies to reduce the time required for subsequent interventional care are explored. PMID- 20952100 TI - The time dependence of antithrombin initiation in patients with non-ST-segment elevation acute coronary syndromes: subgroup analysis from the ACUITY trial. AB - STUDY OBJECTIVE: Antithrombins are among standard treatment agents for patients with non-ST-segment elevation acute coronary syndromes. We aimed to determine the association between time from emergency department (ED) presentation to treatment with an antithrombin and adverse cardiac events. METHODS: The study cohort was a subgroup of the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial, enrolled from March 1, 2005, to December 5, 2005. The ACUITY trial enrolled patients with moderate- and high-risk non-ST-segment elevation acute coronary syndromes and who were undergoing an early invasive strategy (<72 hours from randomization). All patients received an antithrombin (unfractionated heparin, low-molecular-weight heparin, or bivalirudin), in addition to other agents. A formal ED case report form was introduced in March 2005. Time from presentation to antithrombin initiation was evaluated as a continuous variable in hours. The endpoints were defined as major ischemic events (death, myocardial infarction, unplanned revascularization) or major bleeding within 30 days, or inhospital major bleeding. Logistic regression was used to adjust for demographics, severity of disease, comorbidities, and treatment differences. RESULTS: Of the 2,722 patients enrolled with an ED case report form, complete time data were available in 2,632 (96%). Median time to antithrombin administration was 4.87 hours (interquartile range 2.67 to 9.83). After multivariable analysis, there was no association of major ischemic events with log time (hours) to antithrombin treatment (adjusted odds ratio [OR] 0.99; 95% confidence interval [CI] 0.97 to 1.01). There was an increase in major bleeding at 30 days and inhospital major bleeding complications with longer log time (hours) to antithrombin initiation (adjusted OR 1.44, 95% CI 1.15 to 1.80; OR 1.43, 95% CI 1.13 to 1.83, respectively). CONCLUSION: In this study of patients with non-ST-segment elevation acute coronary syndromes who were undergoing an early invasive management strategy, we were unable to demonstrate an association between adverse ischemic outcomes with the timing of antithrombin administration. However, there was an increase in bleeding outcomes as time to antithrombin administration increased. PMID- 20952101 TI - Evidence-based emergency medicine. Does this patient have a hemorrhagic stroke? PMID- 20952102 TI - [Outbreak of follicular conjunctivitis caused by adenovirus in a geriatric centre]. AB - INTRODUCTION: Adenovirus serotype 4a is a respiratory virus that occasionally causes conjunctivitis. This paper describes an outbreak of follicular conjunctivitis that occurred in a geriatric centre. MATERIAL AND METHODS: Outbreak description and epidemiological research through a survey. For the microbiological study conjunctival swabs were collected using viral and bacterial transport media. Adenovirus was detected by real-time polymerase chain reaction. The serotype was determined by sequencing of a fragment of the hexon and E1 genes. RESULTS: In autumn 2008 an outbreak of follicular conjunctivitis caused by adenovirus serotype 4a was detected. Twenty three percent 23% (69/300) of residents and 5% (9/180) of workers in a geriatric centre in Gipuzkoa were affected. The clinical symptoms were of prolonged duration (11+/-5 days). The temporal association of the cases suggested transmission from person to person. The sanitary measures established (asepsis and frequent hand washing, cleaning and disinfection of objects and surfaces) were effective, interrupting the transmission of the disease within a short period of time. CONCLUSION: Rapid detection, identification of the causative agent and implementing appropriate control measures can significantly reduce the impact on both health and economic costs of these outbreaks. PMID- 20952103 TI - Efficient synthesis of (6-deoxy-glycopyranosid-6-yl) sulfone derivatives and their effect on Ca2+-ATPase. AB - Synthesis of a series of novel (6-deoxy-glycopyranosid-6-yl) sulfone derivatives has been achieved using a general synthetic strategy. Yields were excellent in every case. The synthetic compounds were evaluated for their biological potential against Ca2+-ATPase, an important enzyme involves in transporting Ca2+ across the cell membranes. PMID- 20952105 TI - Secret study: a new concept in continuing professional education. AB - Formal post-registration continuing professional education (CPE) has been explored previously, however, not from the perspectives of perioperative nurses. Using a descriptive qualitative approach, interviews were conducted with 23 perioperative nurses who had recent experience of formal university-based study. Analysis of interview transcripts revealed the extent to which participants revealed their CPE lay on a continuum; some told all colleagues they were studying ('public study') whilst others told no-one ('secret study'). These decisions appeared to relate to the cultural discourse of their workplace, participants' academic confidence, and potential ramifications of failure. The concept of 'secret study' has not previously been explored, but is of significance to both nurses and educators: further research is required to indicate transferability of these findings outside of perioperative care. PMID- 20952104 TI - [Alzheimer's and related diseases: toward earlier and more accurate diagnosis]. AB - Because of population ageing, the prevalence of Alzheimer's disease (AD), the most common cause of dementia, increases progressively. This condition is now considered as a public health priority. New disease modifying therapeutic strategies could be available in the next few years that would necessitate an accurate and early diagnosis of the disease. Recently developed diagnostic tools are being assessed. Development of structural brain imaging allows to measure the hippocampus volume. Metabolic imaging can assess a broad range of functional parameters such as cerebral blood flow and dopaminergic activity with single photon emission computed tomography, cerebral glucose metabolism and cerebral amyloid burden with positron emission tomography. Those imaging methods are under evaluation to appreciate cerebral abnormalities that may occur earlier than structural ones. Cerebrospinal fluid biomarkers, in particular amyloid and tau peptides, allow us to look at in vivo biochemical cerebral changes related to AD, before possible serum biomarkers. Studies are under way to confirm the relevance of these new diagnostic tools. It will help us to improve evaluation of patients with AD or related diseases. PMID- 20952106 TI - Phospholipid fatty acid biomarkers in a freshwater periphyton community exposed to uranium: discovery by non-linear statistical learning. AB - Phospholipid fatty acids (PLFA) have been widely used to characterize environmental microbial communities, generating community profiles that can distinguish phylogenetic or functional groups within the community. The poor specificity of organism groups with fatty acid biomarkers in the classic PLFA microorganism associations is a confounding factor in many of the statistical classification/clustering approaches traditionally used to interpret PLFA profiles. In this paper we demonstrate that non-linear statistical learning methods, such as a support vector machine (SVM), can more accurately find patterns related to uranyl nitrate exposure in a freshwater periphyton community than linear methods, such as partial least squares discriminant analysis. In addition, probabilistic models of exposure can be derived from the identified lipid biomarkers to demonstrate the potential model-based approach that could be used in remediation. The SVM probability model separates dose groups at accuracies of ~87.0%, ~71.4%, ~87.5%, and 100% for the four groups; Control (non amended system), low dose (amended at 10 MUg UL-1), medium dose (amended at 100 MUg UL-1), and high dose (500 MUg UL-1). The SVM model achieved an overall cross validated classification accuracy of ~87% in contrast to ~59% for the best linear classifier. PMID- 20952107 TI - A regulatory perspective on the radiological impact of NORM industries: the case of the Spanish phosphate industry. AB - Radioactive and chemical risks coexist in NORM industries although they are usually addressed separately by regulations. The European Union (EU) has developed extensive legislation concerning both matters, which has been diversely reflected in national policies. We consider the case of the Spanish phosphate industry and analyse to which extent regulatory mandates have reduced the historical and ongoing radiological impact on the environment of phosphate facilities. Although no specific radiological constraints on effluent monitoring and release or on waste disposal have yet been imposed on NORM industries in Spain, other environmental regulations have achieved a substantial reduction on the phosphate industry impact. Nevertheless, a more efficient control could be established by eliminating the current conceptual and practical separation of chemical and radioactive risks in NORM industries. We highlight research needs to accomplish so and propose shorter-term measures that require active cooperation among the regulatory bodies involved. PMID- 20952108 TI - Pre-surgical mapping of cutaneous non-melanoma carcinoma using topical methyl aminolevulinic acid. PMID- 20952109 TI - Outcomes of percutaneous endoscopic gastrostomy and radiologically inserted gastrostomy in patients with head and neck cancer: a systematic review. AB - Enteral feeding is an essential part of the management of patients with a history of treatment of head and neck cancer. There are three main types of feeding gastrostomy: surgical, percutaneous endoscopic gastrostomy (PEG), and radiologically inserted gastrostomy (RIG). The associations between serious complications (such as mortality, peritonitis, and infection) and these procedures in this group of patients is the topic of this systematic review. PMID- 20952110 TI - Effects of a pushing intervention on pain, fatigue and birthing experiences among Taiwanese women during the second stage of labour. AB - OBJECTIVES: To evaluate maternal labour pain, fatigue, duration of the second stage of labour, the women's bearing-down experiences and the newborn infant Apgar scores when spontaneous pushing is used in an upright position. DESIGN: Quasi-experimental study. SETTING: Medical centre in Taichung, Taiwan. PARTICIPANTS: 66 Women giving birth at the hospital, with 33 primigravidas assigned to each group. INTERVENTIONS: During the second stage of labour, the women in the experimental group pushed from an upright position and were given support to push spontaneously; the women in the control group pushed from a supine position and were supported via Valsalva pushing. OUTCOME MEASURES: Pain scores were recorded at two evaluation time points: at 10 cm of cervical dilation and one hour after the first pain score evaluation. One to four hours after childbirth, the trained nurses collected the fatigue and pushing experience scores. FINDINGS: The women in the experimental group had a lower pain index (5.67 versus 7.15, p = 0.01), lower feelings of fatigue post birth (53.91 versus 69.39, p < 0.001), a shorter duration of the second stage of labour (91.0 versus 145.97, p = 0.02) and more positive labour experiences (39.88 versus 29.64, p < 0.001) compared with the control group. There was no significant difference in the Apgar score for newborn infants during either the first minute (7.70 versus 7.73, p = 0.72) or the fifth minute (8.91 versus 8.94, p = 0.64). KEY CONCLUSIONS: The pushing intervention during the second stage of labour lessened pain and fatigue, shortened the pushing time and enhanced the pushing experience. IMPLICATIONS FOR PRACTICE: Pushing interventions can yield increased satisfaction levels for women giving birth. PMID- 20952111 TI - Finite element model of the proximal femur under consideration of the hip centralizing forces of the iliotibial tract. AB - BACKGROUND: the aim of our investigations was the development of a finite element model of the hip joint under consideration of the hip centralizing forces of the iliotibial tract within different femoral neck angles and its influence to the centralizing of the femoral head to the acetabulum. METHODS: for the development of the finite element model of the femur and the iliotibial tract we utilized the program IDEAS 3D as well as the material/lengthening characteristics of the iliotibial tract. In the following step we developed a hip joint model with different centrum-collum-diaphysis-angles of 115 degrees , 128 degrees and 155 degrees for determination of the IT force and the consequential force on the femoral head. FINDINGS: with a coxa vara the force on the femoral head in relation to the physiological centrum-collum-diaphysis-angle and the coxa valga decreased (115 degrees =1601N, 128 degrees =2360N, and 155 degrees =2422N). On the other side the hip centralizing forces of the iliotibial tract within a coxa vara increased in comparison to 128 degrees (physiological) and 155 degrees (valga) (115 degrees =997N, 128 degrees =655,5N, and 155 degrees =438N). Within a coxa valga a higher compressive force on the femoral head and with a coxa vara a decreasing compressive force on the femoral head occurred. INTERPRETATION: the clinical relevance consists in the predictability of an increasing or decreasing band wiring effect of the iliotibial tract in reliance to the centrum-collum diaphysis-angle of the femoral neck and its importance for the displacement osteotomy of the growing hip. PMID- 20952112 TI - The influence of pH and organic matter content in paddy soil on heavy metal availability and their uptake by rice plants. AB - The experiments were done to investigate the effect of soil pH and organic matter content on EDTA-extractable heavy metal contents in soils and heavy metal concentrations in rice straw and grains. EDTA-extractable Cr contents in soils and concentrations in rice tissues were negatively correlated with soil pH, but positively correlated with organic matter content. The combination of soil pH and organic matter content would produce the more precise regression models for estimation of EDTA-Cu, Pb and Zn contents in soils, demonstrating the distinct effect of the two factors on the availability of these heavy metals in soils. Soil pH greatly affected heavy metal concentrations in rice plants. Furthermore, inclusion of other soil properties in the stepwise regression analysis improved the regression models for predicting straw Fe and grain Zn concentrations, indicating that other soil properties should be taken into consideration for precise predicting of heavy metal concentrations in rice plants. PMID- 20952113 TI - Molecular effects and bioaccumulation of levonorgestrel in the non-target organism Dreissena polymorpha. AB - Bioaccumulation and effects of the contraceptive hormone levonorgestrel were examined in the non-target organism Dreissena polymorpha. Molecular biomarkers of biotransformation, elimination, antioxidant defence and protein damage were analyzed after exposure to increasing concentrations of levonorgestrel in a flow through system. The lowest concentration (0.312 MUg L(-1)) was 100-fold bioconcentrated within four days. A decrease of the bioconcentration factor was observed within one week for the highest test concentrations (3.12 and 6.24 MUg L(-1)) suggesting enhanced excretory processes. The immediate mRNA up-regulation of pi class glutathione S-transferase proved that phase II biotransformation processes were induced. Disturbance of fundamental cell functions was assumed since the aryl hydrocarbon receptor has been permanently down-regulated. mRNA up regulation of P-glycoprotein, superoxide dismutase and metallothioneine suggested enhanced elimination processes and ongoing oxidative stress. mRNA up-regulation of heat shock protein 70 in mussels exposed to the two highest concentrations clearly indicated impacts on protein damage. PMID- 20952115 TI - Acellular dermal graft augmentation of primary palatoplasty: case report and review of the literature. PMID- 20952114 TI - Transcriptional response of stress genes to metal exposure in zebra mussel larvae and adults. AB - Development of stress markers for the invader freshwater zebra mussel (Dreissena polymorpha) is of great interest for both conservation and biomonitoring purposes. Gene expression profiles of several putative or already established gene expression stress markers (Metallothionein, Superoxide dismutase, Catalase, Glutathione S transferase, Glutathione peroxidase, Cytochrome c oxidase, the multixenobiotic resistance P-gp1, and heat shock proteins HSP70 and HSP90) were analyzed by quantitative Real-Time PCR in adults and pediveliger larvae after exposure to metals (Hg, Cu, Cd). A defined pattern of coordinated responses to metal exposure and, presumably, to oxidative stress was observed in gills and digestive gland from adults. A similar, albeit partial response was observed in larvae, indicating an early development of stress-related gene responses in zebra mussel. The tools developed in this study may be useful both for future control strategies and for the use of zebra mussel as sentinel species in water courses with stable populations. PMID- 20952116 TI - Orthognathic surgery dilemma: increasing access. AB - With the national decline in orthognathic surgery procedures being performed, the specialty must entertain methods of increasing access to this critical service. This report explores the reasons for the decline and the strategies we have used to enhance access in our community. PMID- 20952117 TI - [Primitive neuroendocrine cancer of the breast. Post-traumatic discovery of a man]. AB - We report a primitive neuroendocrine breast tumor (NET) in a male. This situation is uncommon by its mode of discovery. We have treated a 74-year-old man with a lesion in the left areola initially considered as an organized hematoma due to a severe trauma. The ablation was performed by direct access under local anesthesia. The analysis of the piece has showed a NET of the breast due to the positivity of the neuroendocrine, cytokeratin and hormone markers. No other NET lesion was found, excluding the secondary origin of the breast tumor. Complementary therapies associated mastectomy, lymphadenectomy, hormonotherapy. Male breast cancer is rare. NET are exceptional, only a dozen of male NET is reported. These tumors affect a specific population and have a better prognosis than infiltrating ductal carcinoma. In our case, no causal link can be demonstrated between trauma and tumor microenvironment necessary for the growth of quiescent cancer cells. PMID- 20952118 TI - [Breast reconstruction with superior gluteal artery perforator (SGAP) flap without intraoperative setup change. About eight cases]. AB - INTRODUCTION: The superior gluteal artery perforator flap (SGAP) typically requires a peroperative change of the patient's position that increase the duration time of the procedure and the hospitalization. The aim of this study is to present our serie of eight consecutive SGAP flaps without setup change, and to precise the surgical technique we used. PATIENTS AND METHODS: This is a retrospective series of eight consecutive SGAP flaps performed between September 2001 and March 2010. All these flaps were performed without peroperative setup change. We studied the number of perforators used and their origins, the type of recipient vessels, the duration time of the procedure and the hospitalization. We also analyzed the morphological and functional outcomes for the donor site. RESULTS: All eight flaps were raised on a single septo-cutaneous perforator located between the gluteus maximus and gluteus medius muscles. The internal mammary vessels were chosen as recipients in all cases. The average duration time of the operation was 6 hours and 5 minutes. We report one flap loss. No functional or morphological complications were reported on the donor site. The morphological results on the reconstructed breast were satisfactory or very satisfactory in most cases. CONCLUSION: A satisfying breast reconstruction can be achieved with the SGAP flap without changing setup. The use of the septo cutaneous branch between the gluteus maximus and gluteus medius muscles lengthens the pedicle and reduces the surgery time by facilitating the dissection. SGAP is therefore another autologous technique for breast reconstruction with low morbidity, when a DIEP flap cannot be harvested. PMID- 20952119 TI - [Clinical and cardiovascular characteristics of patients with obstructive sleep apnoeas without excessive daytime sleepiness]. AB - OBJECTIVES: To investigate whether patients with obstructive sleep apnoea (OSA) without excessive daytime sleepiness (EDS) have cardiovascular problems and different clinical characteristics from OSA with EDS. METHODS: Two groups of patients were compared retrospectively, one without EDS (Epworth <11) and another control group with EDS (Epworth>10), adjusted for sex, age, body mass index (BMI) and apnoea-hypopnoea index (AHI). The diurnal and nocturnal symptoms of OSA were analysed along with, polysomnography variables, prevalence of hypertension, diabetes mellitus, hyperlipaemia and history of previous cardiovascular events. A logistic regression was performed adjusted for multiple confounding factors to identify the variables associated with OSA without EDS. RESULTS: A total of 166 patients without EDS were studied (Epworth 7.2+/-2.4) and 295 with EDS (Epworth 14.5+/-2.5). In the adjusted multivariate logistic regression, OSA without EDS is independently associated with a feeling of restful sleep (95% CI: 1.70 to 3.93), less intellectual deterioration (95% CI: 0.30 to 0.95) and less effective sleep (95% CI: 0.96 to 0.99). No differences were found as regards prevalence of cardiovascular comorbidity, previous cardiovascular events, sleep structure or nocturnal clinical symptoms of OSA. When the patients who were in the extreme quartiles of the Epworth scale were analysed, the results obtained were equivalent to those of the whole series, with only intellectual deterioration disappearing from the final model. CONCLUSIONS: After adjusting for confounding variables, OSA without EDS has a similar prevalence of cardiovascular comorbidities and less diurnal symptoms than OSA with EDS. PMID- 20952120 TI - [Secondary amyloidosis with renal involvement in an adult patient with cystic fibrosis]. PMID- 20952121 TI - An unusual presentation of follicular lymphoma. PMID- 20952122 TI - Cytochromes: Reactivity of the "dark side" of the heme. AB - Ligand binding to the heme distal side is a paradigm of heme-protein biochemistry, the proximal axial ligand being in most cases a His residue. NO binds to the ferrous heme-Fe-atom giving rise to hexa-coordinated adducts (as in myoglobin and hemoglobin) with His and NO as proximal and distal axial ligands, respectively, or to penta-coordinated adducts (as in soluble guanylate cyclase) with NO as the axial distal ligand. Recently, the ferrous derivative of Alcaligenes xylosoxidans cytochrome c' (Axcyt c') and of cardiolipin-bound horse heart cytochrome c (CL-hhcyt c) have been reported to bind NO to the "dark side" of the heme (i.e., as the proximal axial ligand) replacing the endogenous ligand His. Conversely, CL-free hhcyt c behaves as ferrous myoglobin by binding NO to the heme distal side, keeping His as the proximal axial ligand. Moreover, the ferrous derivative of CL-hhcyt c binds CO at the heme distal side, the proximal axial ligand being His. Furthermore, CL-hhcyt c shows peroxidase activity. In contrast, CL-free hhcyt c does not bind CO and does not show peroxidase activity. This suggests that heme-proteins may utilize both sides of the heme for ligand discrimination, which appears to be modulated allosterically. Here, structural and functional aspects of NO binding to ferrous Axcyt c' and (CL-)hhcyt c are reviewed. PMID- 20952123 TI - Primary tumor response to targeted agents in patients with metastatic renal cell carcinoma. AB - BACKGROUND: The recent development of multiple targeted agents for metastatic renal cell carcinoma (mRCC) has changed the treatment paradigm; hence the benefit and optimal timing of cytoreductive nephrectomy is being reevaluated. OBJECTIVE: To determine primary tumor response to treatment with targeted agents in patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS: We reviewed the clinical and radiographic data of all mRCC patients seen at our institution between November 2004 and December 2009 without prior systemic treatment who received targeted therapy with their primary tumor in situ. MEASUREMENTS: Two independent reviewers measured the diameter of primary and metastatic tumors at baseline and subsequent scans, using Response Evaluation Criteria Solid Tumors (RECIST) v.1.1 to assess disease response. RESULTS AND LIMITATIONS: We identified 168 consecutive patients with a median 15 mo of follow-up and a median maximum tumor diameter of 9.6 cm. Median maximum primary tumor response was -7.1% (interquartile range: -14.0 to 0.1). A total of 61 patients had multiple studies available for evaluation. In 43 patients with <10% decrease in primary tumor within in the first 60 d, median maximum response was -7.2% at 154 d versus -24.5% maximum response at 174.5 d for 18 patients with >=10% decrease in primary tumor during the initial 60 d. CONCLUSIONS: Decrease in primary tumor diameter >30% while on targeted therapy for mRCC is rare, with most patients demonstrating minimal or no decrease in primary tumor diameter. Early response predicts a better overall primary tumor response. PMID- 20952124 TI - The anatomical relation between the superior sagittal sinus and the sagittal suture with surgical considerations. AB - OBJECTIVE: Localization of superior sagittal sinus before craniotomy is very crucial to prevent the complications of surgery. The goal of this study was to verify the anatomical relationship between the sagittal suture and the superior sagittal sinus (SSS). METHODS: Fifty adult cadavers were included in this descriptive analytic study. The length of sagittal suture and the width of sagittal suture and SSS were measured in three points: (bregma), (lambda) and midpoint of sagittal suture. Anatomical relationship between SSS and sagittal suture was analyzed. RESULTS: Superior sagittal sinus was deviated to the right side of the sagittal suture in 54% of cases at bregma and 64% of cases at the midpoint of sagittal suture and lambda. SSS was located at the right side of sagittal suture about 3.5mm at bregma, 4.5mm at midpoint of sagittal suture and 5.7 mm at lambda. The right transverse sinus was dominant in 76% of cases. No gender-associated difference was noticed. CONCLUSION: Our study demonstrates that SSS is deviated to the right side of sagittal suture in the majority of cases. Maximum deviation of SSS to the right side is about 10mm. Neurosurgeons are advised to be aware of this anatomical relation while operating around SSS. PMID- 20952125 TI - Rheological characterization of xanthan suspensions of nanoscale iron for injection in porous media. AB - Nanoscale zerovalent iron (NZVI) represents one of the most interesting reagents for the remediation of contaminated aquifers, but its application is hindered by a lack of colloidal stability. Prior studies have shown that nanoscale iron slurries can be successfully stabilized against aggregation and sedimentation through dispersion in xanthan solutions; thus, further research was carried out by focusing on the flow behavior of xanthan-modified NVZI suspensions. This work aims at understanding the rheological properties of NZVI-xanthan suspensions, which have been extensively tested under two different flow conditions: simple shear flow and flow through a porous medium. According to both experimental approaches, the suspensions show a shear thinning behavior that is dependent on iron concentration. These rheological properties are explained by referring to the microstructure of the colloidal system. Flow equations have been formulated and solved in radial coordinates in order to demonstrate the feasibility of such suspensions in field scale applications. PMID- 20952126 TI - Characterization and genomic analysis of a highly chromate resistant and reducing bacterial strain Lysinibacillus fusiformis ZC1. AB - Lysinibacillus fusiformis ZC1 isolated from chromium (Cr) contaminated wastewater of a metal electroplating factory displayed high chromate [Cr(VI)] resistance with a minimal inhibitory concentration (MIC) of 60mM in R2A medium. L. fusiformis ZC1 showed resistances to multiple metals (Cu, Ni, Co, Hg, Cd and Ag) and a metalloid (As). This bacterium exhibited an extremely rapid Cr(VI) reduction capability. It almost completely reduced 1mM K(2)CrO(4) in 12h. The Cr(VI) reduction ability of L. fusiformis ZC1 was enhanced by sodium acetate and NADH. By whole genome sequence analysis, strain ZC1 was found to contain large numbers of metal(loid) resistance genes. Specifically, a chrA gene encoding a putative chromate transporter conferring chromate resistance was identified. The chromate resistance was constitutive in both phenotypic and gene expression analyses. Furthermore, we found a yieF gene and several genes encoding reductases that were possibly involved in chromate reduction. Expression of adjacent putative chromate reduction related genes, nitR and yieF, was found to be constitutive. The large numbers of NADH-dependent chromate reductase genes may be responsible for the rapid chromate reduction in order to detoxify Cr(VI) and survive in the harsh wastewater environment. PMID- 20952127 TI - Effect of nutrients on the biodegradation of tributyltin (TBT) by alginate immobilized microalga, Chlorella vulgaris, in natural river water. AB - The removal and degradation of tributyltin (TBT) by alginate immobilized Chlorella vulgaris has been evidenced in our previously published work. The present study was further to investigate the effect of spiked nutrient concentrations on the TBT removal capacity and degradation in the same alginate immobilized C. vulgaris. During the 14-d experiment, compared to the control (natural river water), the spiked nutrient groups (50% or 100% nutrients of the commercial Bristol medium as the reference, marked as 1/2N or 1N) showed more rapid cell proliferation of microalgae and higher TBT removal rate. Moreover, significantly more TBT was adsorbed onto the alginate matrix, but less TBT was taken up by the algal cells of the nutrient groups than that of the control. Mass balance data showed that TBT was lost as inorganic tin in the highest degree in 1N group, followed by 1/2N group and the least was in the control, but the relative abundance of the intermediate products of debutylation (dibutyltin and monobutyltin) were comparable among three groups. In conclusion, the addition of nutrients in contaminated water stimulated the growth and physiological activity of C. vulgaris immobilized in alginate beads and improved its TBT degradation efficiency. PMID- 20952128 TI - Genotoxic evaluation of the non-halogenated disinfection by-products nitrosodimethylamine and nitrosodiethylamine. AB - Disinfection by-products (DBPs) are chemicals that are produced as a result of chlorine being added to water for disinfection. As well as the halogenated DBPs, N-nitrosamines have recently been identified as DBPs, especially when amines and ammonia ions are present in raw water. In this work, the genotoxicity of two nitrosamines, namely nitrosodimethylamine (NDMA) and nitrosodiethylamine (NDEA), has been studied in cultured human cells. To evaluate their genotoxic potential two assays were used, the comet assay and the micronucleus test. The comet assay measures the induction of single and double-strand breaks, and also reveals the induced oxidative DNA damage by using endoIII and FPG enzymes. Chromosomal damage was evaluated by means of the cytokinesis-blocked micronucleus test. The results of the comet assay show that both compounds are slightly genotoxic but only at high concentrations, NDEA being more effective than NDMA. Enzyme treatments revealed that only NDEA was able to produce increased levels of oxidized bases, mainly in purine sites. The results obtained in the micronucleus assay, which measures the capacity of the tested agents to induce clastogenic and/or aneugenic effects, are negative for both of the nitrosamines evaluated, either using TK6 cells or human peripheral blood lymphocytes. Taking into account the very high concentrations needed to produce DNA damage, our data suggest a low, if existent, genotoxic risk associated with the presence of these compounds in drinking water. PMID- 20952129 TI - Magnetic Fe(2)MO(4) (M:Fe, Mn) activated carbons: fabrication, characterization and heterogeneous Fenton oxidation of methyl orange. AB - We present a simple and efficient method for the fabrication of magnetic Fe(2)MO(4) (M:Fe and Mn) activated carbons (Fe(2)MO(4)/AC-H, M:Fe and Mn) by impregnating the activated carbon with simultaneous magnetic precursor and carbon modifying agent followed by calcination. The obtained samples were characterized by nitrogen adsorption isotherms, X-ray diffraction (XRD), scanning electron microscopy (SEM) and vibrating sample magnetometer (VSM), and the catalytic activity in heterogeneous Fenton oxidation of methyl orange (MO) was evaluated. The resulting Fe(2)MnO(4)/AC-H showed higher catalytic activity in the methyl orange oxidation than Fe(3)O(4)/AC-H. The effect of operational parameters (pH, catalyst loading H(2)O(2) dosage and initial MO concentration) on degradation performance of the oxidation process was investigated. Stability and reusability of selected catalyst were also tested. PMID- 20952130 TI - Understanding chronic pain in older adults: abdominal fat is where it is at. PMID- 20952131 TI - Risk of cardiac dysfunction with trastuzumab in breast cancer patients: a meta analysis. AB - BACKGROUND: Trastuzumab is used widely for the treatment of early and advanced breast cancer. However, concerns have arisen regarding its cardiac toxicity. We did a systematic review and meta-analysis of published randomized controlled trials (RCTs) to assess the overall risk of cardiac dysfunction associated with trastuzumab treatment. METHODS: We searched PubMed and Web of Science (January 1966-July 2009) and American Society of Clinical Oncology conferences held (January 2000-July 2009) for relevant articles and abstracts. Summary incidence rates, relative risks (RRs), and 95% confident intervals (CIs) were calculated using a fixed-effects or random-effects model. RESULTS: 11,882 patients from 10 RCTs were included for analysis. The incidences of LVEF decrease and congestive heart failure (CHF) were 7.5% (95% CI 4.2-13.1) and 1.9% (95% CI 1.0-3.8) among patients receiving trastuzumab. Trastuzumab significantly increased the risk of LVEF decrease (RR = 2.13, 95% CI, 1.31-3.49; p = 0.003). In addition, it significantly increased the risk of CHF (RR = 4.19, 95% CI 2.73-6.42; p < 0.00001). The increased risk of CHF was observed in patients with early stage (RR = 4.05, 95% CI 2.49-6.58; p < 0.00001) as well as metastatic disease (RR = 4.75, 95% CI 1.93-11.71; p = 0.0007). Furthermore, trastuzumab significantly increased the risk of CHF (RR = 4.27, 95% CI 2.75-6.61, p < 0.00001) in patients receiving anthracycline-based chemotherapy, but not in patients receiving non-anthracycline chemotherapy (RR = 2.42, 95% CI 0.36-16.19, p = 0.36). CONCLUSION: The addition of trastuzumab to anthracycline-based chemotherapy significantly increase the risk of cardiac dysfunction in breast cancer patients. Further studies are recommended for non-anthracycline chemotherapy. PMID- 20952133 TI - Concentration of biologically active polyamines in meat and liver of sheep and lambs after slaughter and their changes in mutton during storage and cooking. AB - Putrescine (PUT), spermidine (SPD) and spermine (SPM) concentrations using a UPLC method, in chilled mutton, lamb and livers 24 h after slaughter were determined. PUT concentrations were quantifiable only in some samples. Mean SPD concentrations were 4-6, 13.5 and 16.8 mg kg-1 in the meats, sheep and lamb livers, respectively. The respective SPM concentrations were 17-25, 128 and 79 mg kg-1. SPD and SPM losses of about one fifth and half of the initial level, respectively, were apparent in mutton loins stored at -18 degrees C for 6 months. Significant losses of SPD and SPM were found in mutton loins stored aerobically, vacuum-packaged or in a modified atmosphere at +2 degrees C. Boiling and stewing of mutton legs caused SPD and SPM losses of about 40% and roasting of about 60% of the initial content. PMID- 20952132 TI - Major depressive disorder, generalised anxiety disorder, and their comorbidity: associations with cortisol in the Vietnam Experience Study. AB - OBJECTIVES: The aim of these analyses was to examine the association of cortisol, dehydroepiandrosterone sulphate (DHEAS), and the cortisol:DHEAS ratio with the diagnoses of major depressive disorder (MDD), generalised anxiety disorder (GAD), and their comorbidity. DESIGN: This was a cross-sectional study. METHODS: Participants were 4256 Vietnam era US army veterans. From military service files, telephone interviews, and a medical examination, occupational, socio-demographic, and health data were collected. One-year prevalence of MDD and GAD was determined through a diagnostic interview schedule based on the DSM-IV criteria. Contemporary morning fasted cortisol and DHEAS concentrations were determined. Analyses of covariance were run, first with adjustment for age and then additionally adjusting for a range of candidate confounders. RESULTS: In fully adjusted analyses, there was evidence of lower basal cortisol levels in individuals with MDD and co-morbid MDD and GAD than those with GAD alone or no diagnosis. CONCLUSION: This suggests that MDD and its comorbidity can also be characterised by low as well as high cortisol levels. A profitable line of future research might be to examine cortisol and DHEAS levels in more representative samples including older participants and women with and without MDD, GAD, and other psychiatric diagnoses. PMID- 20952134 TI - Solitary intrapulmonary cystic lymphangioma in an infant: a case report with literature review. AB - Lymphangioma rarely presents as a solitary pulmonary lesion. We encountered a case of solitary cystic lymphangioma and present its clinicopathologic and immunohistochemical findings. A 2-month-old boy was referred to the hospital after developing a persistent cough. Chest X-ray showed a large cyst in the right lung. Under the preoperative diagnosis of bronchogenic cyst, he underwent right lower lobectomy at the age of 11 months. The resected specimen contained a 5.5-cm septate cystic lesion. Microscopically, the lesion consisted of a large cystic space and interconnected slit-like spaces surrounding bronchovascular islands. The cyst was lined by a monolayer of flat cells with focal multinucleated giant cells. Immunohistochemically, the cells lining the cystic lesion were positive for D2-40, Prox1, CD34, and CD31, and weakly positive for VEGFR-3, but were negative for AE1/3, HMB45, VEGF-A, VFGF-C, VEGFR-1. Differential diagnoses included lobar or interstitial emphysema, bronchogenic cyst, congenital pulmonary airway malformation and alveolar adenoma. D2-40 and Prox1 were useful in differentiation and in determining the extent of the lesion. A review of the literature found only 15 cases of solitary pulmonary lymphangioma. In younger patients, the lesions tend to occupy more of the lung. Focal giant cell reaction has not been described in the reported papers. PMID- 20952135 TI - Treating options for deaf children. AB - BACKGROUND/AIM: Although already established for metabolic diseases, universal screening programs for hearing have not been widely applied, despite the high incidence of profound congenital hearing loss. The present paper aims to review the current knowledge on the available treatment options for deaf infants. DATA SYNTHESIS: The acquisition of spoken language is a time-dependent process. For a child to become linguistically competent, some form of linguistic input should be present as early as possible in his/her life. Although objective audiological methods have certain weaknesses, their combination can give an accurate diagnosis in most of the cases. Later on, behavioural audiometry should confirm the diagnosis. Additional disabilities also need to be considered, although such assessments may be difficult in very young children. Congenital deafness should be managed by a multidisciplinary team (MDT). Affected infants should be bilaterally fitted with hearing aids, no later than three months after birth. They should be monitored and if they are not progressing linguistically, cochlear implantation (CI) should be considered after thorough preoperative assessment. Following CI, the vast majority of congenitally deaf children develop significant speech perception and production abilities over time. Age-at-intervention and oral communication, are the most important determinants of outcomes. Realistic parental expectations are also essential. The continuous support of a dedicated pediatric CI program, in collaboration with local professionals, and community members, are also necessary to achieve a successful outcome. CONCLUSION: Congenitally deaf children should be detected early, and referred timely for the process of auditory rehabilitation to be initiated. Strong support by community members, and professional bodies, can maximize the future earnings of pediatric auditory rehabilitation with hearing aids and cochlear implants. PMID- 20952136 TI - Anaesthesia for urgent and emergency surgery. AB - The general principles that guide a pediatric anesthesiologist in the care of a newborn needing urgent and emergent neonatal surgery are reviewed. These include careful evaluation and assessment of the newborn including a detailed prenatal history. A brief review of neonatal physiology including the development of the autonomic nervous system and the development of nociceptive pathways is discussed and how important it is to suppress the stress response to surgical intervention in order to improve surgical outcomes. Most of the current general anesthetics have been associated with anesthetic neurotoxicity in juvenile mammals and several epidemiologic studies in human infants and toddlers have linked surgery occurring in the first 3 years of life with neurocognitive delays in school age children. These concerns are discussed in this paper. Practical considerations about neonatal intubation, line placement and intraoperative fluid management are also reviewed. And the anesthetic management of specific neonatal conditions such as congenital diaphragmatic hernias, transesophageal fistulas, gastroschisis and omphaloceles, necrotizing enterocolitis and meningomyeloceles is examined. PMID- 20952137 TI - Neonatal brain tumours - a review. AB - Brain tumors in infants (under the age of 1 yr) are mercifully rare. Nonetheless, neonatal tumours present a treatment challenge to those involved. Surgery can be technically challenging, if possible at all, and the sensitivity of the developing nervous system to the side-effects of radio- and chemotherapy has limited their utility as adjunctive treatments. The risk/benefit equation in the planning of treatment of neonatal tumours using these modalities is further complicated by the fact that these tumours are often histologically benign, of large dimensions, but are often situated in locations that lead to a fatal outcome. This review article seeks to provide guidance on the management of neonatal patients and infants up to 1 year of age with brain tumours based on evidence from the literature. PMID- 20952138 TI - Fracture of the neck structures in suicidal hangings: a retrospective study on contributing variables. AB - INTRODUCTION: Several factors may play a role in the development of fractures of the neck structures in hanging. It has been repetitively demonstrated that the incidence of fractures increases with age. The role of other variables is less clear, different studies presenting contradictory results on the role of gender, the type of suspension, or the type of ligature. However, most of these studies evaluated these factors independently of the age of the victims. Considering that age is probably the most important factor in the development of neck structure fractures, all other contributing factors should be studied in relation to age. The aim of the present study is to evaluate the role of contributing factors to the development of neck structure fractures, taking age categories into account. MATERIALS AND METHODS: A total of 206 cases were analysed for the presence and localization of thyroid fracture. For each case, the following information was also compiled: the presence and localization of other neck structure fractures, gender and age, height and weight, body mass index (BMI) type of suspension (complete or incomplete), type of ligature used (rope, wire, clothes, sheet or lace) and localization of the knot (anterior, right, left or posterior). RESULTS: The incidence of neck structure fractures increased with age (chi(2)=21.85; p<.001) and is significantly higher in male victims (31.4%) compared to female victims (11.8%) (chi(2)=5.41; p=.02). The incidence of fractures varied significantly with the height (t=2.19; p=.031; D=.33), weight (t=4.38; p<.001; D=.89) and BMI (t=3.84; p<.001; D=.60). The incidence of fractures did not vary significantly with the type of suspension (i.e. complete hanging with feet off the ground or incomplete hanging with body parts partially supporting the weight of the body) (chi(2)=3.12; p=.077; Phi=.077) and the type of ligature (i.e. narrow vs wide) (chi(2)=.05; p=.828; Phi=.015). However, when taking the age of the victims into account, a different picture was revealed: in individuals aged 40 years or more, victims with complete suspension of the body presented with a significantly higher incidence of fractures (63.2%) compared to victims with incomplete suspension (31.0%) (chi(2)=6.79; p=.009; Phi=.318). CONCLUSION: Several variables contribute to the development of neck structure fractures in hanging. Age is probably the most important one. Other contributing factors are gender, height, weight, BMI and the type of suspension. PMID- 20952139 TI - An algorithm for sparse MRI reconstruction by Schatten p-norm minimization. AB - In recent years, there has been a concerted effort to reduce the MR scan time. Signal processing research aims at reducing the scan time by acquiring less K space data. The image is reconstructed from the subsampled K-space data by employing compressed sensing (CS)-based reconstruction techniques. In this article, we propose an alternative approach to CS-based reconstruction. The proposed approach exploits the rank deficiency of the MR images to reconstruct the image. This requires minimizing the rank of the image matrix subject to data constraints, which is unfortunately a nondeterministic polynomial time (NP) hard problem. Therefore we propose to replace the NP hard rank minimization problem by its nonconvex surrogate - Schatten p-norm minimization. The same approach can be used for denoising MR images as well. Since there is no algorithm to solve the Schatten p-norm minimization problem, we derive an efficient first-order algorithm. Experiments on MR brain scans show that the reconstruction and denoising accuracy from our method is at par with that of CS-based methods. Our proposed method is considerably faster than CS-based methods. PMID- 20952140 TI - Separation and structural elucidation of a novel analogue of vardenafil included as an adulterant in a dietary supplement by liquid chromatography-electrospray ionization mass spectrometry, infrared spectroscopy and nuclear magnetic resonance spectroscopy. AB - MEGATON, a dietary supplement, was analyzed in order to detect PDE-5 inhibitors and their analogues. A new analogue of vardenafil could be detected by high performance liquid chromatography (HPLC) analysis with a photodiode array detector (PDA). This compound was compared with sildenafil, tadalafil, and vardenafil as well as their structurally modified analogues such as hongdenafil and homosildenafil. The structure of this compound was elucidated by mass spectrometry (MS), infrared (IR) spectroscopy and one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy. When compared with vardenafil to verify the structural difference, this compound had an acetyl group instead of a sulfonyl group in the pyrazolopyrimidine portion without any substitution in the piperazine ring of the molecule. This compound was identified as 2-(2-ethoxy-5-(2 (4-ethylpiperazin-1-yl)acetyl)phenyl)-5-methyl-7-propyl-imidazo(5,1-f) (1,2,4)triazin-4(3H)-one, which is also called acetylvardenafil. PMID- 20952141 TI - Stability indicating ion chromatography method for the simultaneous determination of ibandronate sodium drug substance and its impurities. AB - A simple and sensitive ion chromatography method has been developed for the simultaneous assay of ibandronate sodium drug substance and the determination of its impurities. The separation was achieved on AllsepTM anion column 150 mm * 4.6 mm, 7 MUm particle diameter. The mobile phase consisted of 1% (v/v) aqueous formic acid and acetone 98:2% (v/v); flow rate 1.0 ml min(-1) at ambient temperature. The analytes were monitored by conductometric detector. The drug substance was subjected to stress conditions of hydrolysis, oxidation, photolytic, thermal and humidity degradation. Considerable degradation was achieved only under oxidative conditions. Mass balance was demonstrated in all stress conditions. The method was validated for specificity, precision, linearity, solution stability and accuracy. The limits of detection (LOD) and limits of quantification (LOQ) for impurities were in the range of 0.36-0.80 MUg ml(-1) and 1.00-2.40 MUg ml(-1), respectively. For ibandronate LOD was 38 MUg ml( 1) and LOQ was 113 MUg ml(-1). The average recoveries for impurities and ibandronate were in the range of 99.0-103.1% and the method can be successfully applied for the routine analysis of ibandronate sodium drug substance. PMID- 20952142 TI - Skills training after night shift work enables acquisition of endovascular technical skills on a virtual reality simulator. AB - BACKGROUND: Adoption of residents' working time restrictions potentially undermines surgical training by reduction of operating room exposure. Simulation has been proposed as a way to acquire necessary skills in a laboratory environment but remains difficult to incorporate into training schedules. This study assessed whether residents working successive nights could acquire endovascular skills similar to colleagues working day shifts. METHODS: This prospective observational cohort study recruited 20 junior residents, divided into day shift and night shift groups by their respective call schedule. After initial cognitive skills training, a validated renal artery stent module on an endovascular simulator was completed over a series of seven sequential shifts during 1 week. The primary outcome measure was serial technical skill assessments. Secondary measures comprised assessments of activity, cognitive performance, introspective fatigue, quality, and quantity of preceding sleep. RESULTS: Both groups demonstrated significant learning curves for total time at the first session median vs seventh session median (181 vs 564 seconds [P < .001]; night, 1399 vs 572 [P < .001]), fluoroscopy time (day, 702 vs 308 seconds, [P < .001]; night, 669 vs 313 [P < .001]), and contrast volume (day, 29 vs 13 mL [P < .001]; night, 40 vs 16 [P < .001]). Residents working day shifts reached plateau 1 day earlier in the above measures vs those on night duty. The night shift group walked more steps (P < .001), reviewed more patients (P < .001), performed worse on all cognitive assessments (P < .05), slept less (P < .05), had poorer quality of sleep (P = .001), and was more fatigued (P < .001) than the day shift group. Acquired skill was retained a week after completion of shifts. CONCLUSION: Technical skills training after night shift work enables acquisition of endovascular technical skills, although it takes longer than after day shift training. This study provides evidence for program directors to organize simulation-based training schedules for residents on night shift rotations. PMID- 20952143 TI - Existing trauma and critical care scoring systems underestimate mortality among vascular trauma patients. AB - BACKGROUND: The impact of vascular injuries on patient mortality has not been well evaluated in multi-trauma patients. This study seeks to determine (1) whether the presence of vascular trauma negatively affects outcome compared with nonvascular trauma (NVT) and (2) the utility of existing severity scoring systems in predicting mortality among vascular trauma (VT) patients. METHODS: A retrospective review of our trauma database from January 2005 to December 2007 was conducted. Demographics, Injury Severity Scores (ISS), Revised Trauma Scores (RTS), Trauma Score-Injury Severity Scores (TRISS), Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, and mortality rates were compared. Control patients were selected from a matching cohort based on ISS. Comparisons were made between groups based on the above scoring systems. Statistical analysis used chi(2) analysis and Student t-tests. RESULTS: Fifty VT and 50 NVT patients were identified with no significant differences in age, gender, mechanism of injury, ISS, RTS, or TRISS. The mean APACHE II score was higher in VT compared with NVT (12.3 vs 8.8, P < .05). Overall mortality was higher in VT compared with NVT but did not reach statistical significance (24% vs 11.8%, P = .108). VT patients with RTS score >5 had a higher mortality rate (26% vs 2.2%, P = .007). VT patients with an ISS score >24 had a higher mortality compared with NVT patients (61% vs 28.6%, P = .04). VT patients with an APACHE II score <14 also had a higher mortality rate (18.2% vs 0%, P = .007). Finally, VT patients with a TRISS probability of survival of >80% had a higher mortality rate (13.9% vs 0%, P = .05). CONCLUSIONS: In multi-trauma patients, the presence of vascular injury was associated with increased mortality in less severely injured patients based on the RTS, TRISS, and APACHE II scores. These scoring systems underestimated mortality in patients with vascular trauma. Level of care and future trauma algorithms should be adjusted in the presence of vascular trauma. PMID- 20952144 TI - Total laparoscopic renal artery bypass for restenosis after failed percutaneous transluminal renal stenting. AB - OBJECTIVE: The purpose of this article was to report our experience of the repair of renal artery restenosis after percutaneous transluminal renal angioplasty (PTRA) using a total laparoscopic technique without robotic assistance. METHODS: Between February 2005 and October 2009, we performed six total laparoscopic aortorenal artery bypasses for restenosis after failed PTRA. All these patients had recurrent hypertension with renal insufficiency. RESULTS: The mean operative time was 246 minutes (range, 200-310 minutes). The mean warm renal ischemic time was 28 minutes (range, 22-35 minutes). All patients received a prosthetic graft interposition. The estimated surgical blood loss was 980 mL (range, 500-1400 mL). No conversion was observed and no in-hospital deaths occurred. There was no severe postoperative morbidity. Postoperative serum creatinine levels raised in all patients but all returned to baseline before discharge. Median length of postoperative hospital stay was 6 days (range, 4-8 days). Median follow-up was 13 months (range, 7-19 months). Color Doppler ultrasound scan examination and computed tomography (CT) with injection of contrast media showed patency of all bypasses. Hypertension was improved in all patients but renal insufficiency remained unchanged. CONCLUSION: Total laparoscopic renal artery bypass is feasible and safe in patients after failed PTRA. This approach may reduce the morbidity of open repair but is technically demanding and necessitates a large previous experience in total laparoscopic aortic surgery. PMID- 20952145 TI - Allograft anterior cruciate ligament reconstruction in the young, active patient: Tegner activity level and failure rate. AB - PURPOSE: The purpose was to analyze outcomes of nonirradiated, fresh-frozen bone patellar tendon-bone (BPTB) allograft anterior cruciate ligament (ACL) reconstruction in patients aged under 40 years with regard to activity level (Tegner score). METHODS: Between 1993 and 2005, 111 patients, aged under 40 years, underwent primary, nonirradiated, fresh-frozen BPTB allograft ACL reconstruction and were retrospectively reviewed. Follow-up was limited to a minimum of 24 months. Patients with concomitant ligament injuries and previous surgeries were excluded. Seventy-eight patients met the inclusion criterion and were available for follow-up. Four hundred eleven patients had BPTB autograft ACL reconstructions and comprised the control group. Failure of the graft was defined as repeat ACL reconstruction because of reinjury or graft failure, 2+ Lachman (no endpoint), any pivot shift, and/or 5-mm side-to-side KT-1000 difference (MEDmetric, San Diego, CA) or greater. Initial examinations, surgical findings, and follow-up examinations were prospectively entered into a computerized relational database. The results were assessed by both objective and subjective measures. RESULTS: High-activity allograft patients had a 2.6- to 4.2-fold increase in the probability of graft failure compared with low-activity BPTB allograft patients and low- and high-activity BPTB autograft patients. Patients undergoing BPTB autograft reconstruction reported significantly fewer problems on a visual analog scale and scored significantly higher on the postoperative Tegner activity scale than patients undergoing allograft reconstruction. CONCLUSIONS: The active allograft group is 2.6 to 4.2 times more likely to fail compared with low-activity allografts and low- and high-activity autografts. We conclude that fresh-frozen BPTB allografts should not be used in young patients who have a high Tegner activity score because of their higher risk of failure. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 20952146 TI - Human chondrocyte viability after treatment with local anesthetic and/or magnesium: results from an in vitro study. AB - PURPOSE: We aimed to assess the effect on chondrocyte viability of adding magnesium to a variety of commonly available local anesthetic agents. METHODS: Human chondrocytes were grown under standard culture conditions. Cells were exposed to a local anesthetic agent with the addition of magnesium (10%, 20%, or 50%). Cells were also exposed to the varying concentrations of magnesium and 0.9% saline solution. Untreated cells served as controls. The CellTiter 96 AQueous One Solution Cell Proliferation Assay was used to assess for cell viability 24 hours after exposure. One-way analysis of variance was used to test for statistical significance. RESULTS: Magnesium sulfate alone was no more toxic than normal saline solution (P > .3) compared with untreated cells. The addition of magnesium to the local anesthetic agents resulted in greater cell viability than when cells were treated with a local anesthetic alone (lidocaine [P = .033], levobupivacaine [P = .007], bupivacaine [P < .001], and ropivacaine [P < .001]). CONCLUSIONS: Our findings support the use of magnesium either alone or in combination with a local anesthetic rather than a local anesthetic alone, and this represents a potential strategy for the reduction of chondrocyte toxicity associated with intra articular local anesthetic administration after arthroscopy. CLINICAL RELEVANCE: The addition of magnesium to a local anesthetic results in a reduced toxic effect to the articular chondrocyte. This may represent a potential approach to intra articular analgesia. PMID- 20952147 TI - Correlation between the 2-dimensional notch width and the 3-dimensional notch volume: a cadaveric study. AB - PURPOSE: The purpose of this study was to compare the size of the entrance of the notch, as measured arthroscopically (2-dimensionally), with the volume of the notch as measured by use of computed tomography (CT) (3-dimensionally). METHODS: For 20 cadaveric knees, the dimensions of the notch entrance were measured arthroscopically, and the notch volume was measured by use of CT. The correlation between the size of the notch entrance and the notch volume was calculated. Intraobserver reliability and interobserver reliability of the arthroscopic and CT measurements were tested. RESULTS: The Pearson correlation coefficients between CT-assessed notch volume and arthroscopically assessed notch height and width at the bottom, middle, and top of the notch were 0.603, 0.506, 0.551, and 0.642, respectively. The intraobserver reliability and interobserver reliability of the arthroscopic measurements were above 0.962 and 0.819, respectively, and 0.983 and 0.975, respectively, for the CT measurements. CONCLUSIONS: There were only moderate correlations between arthroscopic notch measurements and notch volume. Both the arthroscopic and CT measurements proved highly reliable. CLINICAL RELEVANCE: The moderate correlation between 2-dimensional and 3 dimensional notch measurements warrants caution concerning the use of either measurement for assessing risk for anterior cruciate ligament injury or as justification for notchplasty until studies between the relation of 3-dimensional notch volume and anterior cruciate ligament injury are conducted. PMID- 20952148 TI - Femoral cross-pin safety in anterior cruciate ligament reconstruction as a function of femoral tunnel position and insertion angle. AB - PURPOSE: To compare femoral cross-pin guidewire insertion at differing angles to identify "safe zones" relative to saphenous nerve, popliteus tendon, fibular collateral ligament, peroneal nerve, and femoral artery/vein locations between transtibial and medial-portal femoral tunnel drilling methods. METHODS: Five paired cadaveric knees were randomly assigned to a transtibial or medial-portal femoral (anatomic) tunnel drilling group. Guidewires were inserted at differing frontal plane angles (+10 degrees , 0 degrees , -10 degrees , and -20 degrees ). Distances between the guidewire and the anatomic structure of interest were measured with an electronic caliper. RESULTS: Two-way analysis of variance showed that guidewire angle, not tunnel drilling method, created significant differences between guidewire-saphenous nerve (P < .001) and guidewire-femoral artery/vein (P < .001) distances. The +10 degrees angle showed a shorter guidewire-saphenous nerve distance than the 0 degrees , -10 degrees , and -20 degrees angles. The +10 degrees angle also showed a shorter guidewire-femoral artery/vein distance than the -10 degrees and -20 degrees angles, and the 0 degrees insertion angle created a shorter guidewire-femoral artery/vein distance than the -10 degrees and -20 degrees angles. Fisher exact tests showed that guidewires inserted at a +10 degrees angle showed a greater incidence of safe-zone violations for the saphenous nerve (P = .04) and femoral artery/vein (P < .0001). CONCLUSIONS: Insertion angle, not tunnel drilling method, influenced saphenous nerve and femoral artery/vein injury risk. At the +10 degrees angle, the saphenous nerve and femoral artery/vein are at greater risk for surgically induced injury. Guidewire insertion at -10 degrees or -20 degrees angles should increase concerns about potential popliteus tendon and fibular collateral ligament injury. CLINICAL RELEVANCE: Insertion angle, not tunnel drilling method, influenced saphenous nerve and femoral artery/vein injury risk. PMID- 20952150 TI - Three-dimensional assessment of cam engagement in femoroacetabular impingement. AB - PURPOSE: The purpose of our study was to 3-dimensionally assess cam engagement in male patients with symptomatic femoroacetabular impingement during motion. METHODS: A total of 13 hips with cam-type impingement were investigated. Patient anatomy and clinical range of motion were determined. After 3-dimensional segmentation and reconstruction, the dynamic behavior of the cam lesion was investigated for the previously analyzed motions. RESULTS: Important differences in the pattern of cam engagement were noticed. Abutment of the cam lesion and the acetabular cartilage was observed in flexion in 7 hips (54%) and in abduction in 11 hips (84%). Internal rotation with the hip in 90 degrees of flexion caused intrusion of the cam lesion into the joint in 10 of the investigated cases (77%). Neutral rotation did not cause any conflict between the cam lesion and acetabulum for the measured range of motion. A similar area in the anterosuperior quadrant of the acetabulum appeared to be involved in the different motions that were analyzed. CONCLUSIONS: Typically, during internal rotation in 90 degrees of flexion, the centromedial portion of the cam lesion was found to abut against the anterosuperior quadrant of the acetabular cartilage. During abduction and flexion, this appeared to be the lateral and medial portions of the cam lesion, respectively. All motions causing cam intrusion appeared to focus on the same cartilage area of the acetabulum in its anterosuperior quadrant. PMID- 20952149 TI - A computed tomography scan assessment of synthetic multiphase polymer scaffolds used for osteochondral defect repair. AB - PURPOSE: To evaluate the radiographic response of a synthetic multiphase implant at various intervals after implantation and assess the nature of bone ingrowth into the implant location. METHODS: Patients undergoing autologous osteochondral transplantation for full-thickness condylar defects with the donor sites filled by use of a synthetic implant were evaluated by computed tomography (CT) scan for the density at both donor and recipient sites. Hounsfield unit (HU) readings were obtained at the synthetic implant, transplanted autograft plug, soft-tissue, cancellous bone, and cortical bone sites. The implant site material was graded by an established ossification quality score (range, 1 to 4). RESULTS: Nine patients underwent CT scans at intervals ranging from 2 to 63 months after surgery. This sequence of images tracked the potential development of bone ingrowth activity. Postoperative imaging confirmed complete autograft bone plug healing. The synthetic implant site CT scans showed a drop in density from 84 HU at 4 months to 19 HU by 13 months (fibrous scar density). The ossification quality score for all synthetic implants was 1 (tract filled with soft-tissue density) instead of 4 (cancellous bone). The transplanted autograft plug densities were consistent with and completely incorporated into the adjacent cancellous bone. CONCLUSIONS: The synthetic multiphase implant showed no evidence of bone ingrowth, osteoconductivity, or ossification. The implant density declined over time to that of fibrous scar. This synthetic plug does not provide subchondral structural support for any tissue that grows over it. This study does not support the use of this implant for the primary repair of articular cartilage lesions. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 20952151 TI - The safe zone for TransFix fixation in anterior cruciate ligament reconstruction using the anteromedial portal technique. AB - PURPOSE: The risk of neurovascular injury is inherent to cross-pin femoral fixation for anterior cruciate ligament reconstruction and has not been evaluated using the anteromedial portal technique; therefore, we determined a safe zone of cross-pin drill angles. METHODS: Five cadaveric midthigh to midknee specimens underwent anterior cruciate ligament reconstruction by use of the anteromedial portal to drill the femoral tunnel and a cross-pin femoral fixation system. Guide pins were passed through the femur at -40 degrees , -20 degrees , 0 degrees , and +20 degrees , with 0 degrees being the coronal plane bisecting the femoral shaft, negative angles when the guide pin started posteriorly, and positive angles when the guide pin started anteriorly. Distances between the guide pin and saphenous nerve, femoral artery, and peroneal nerve were measured. The neurovascular structures were considered safe if the guide pin did not pass within 10 mm of the structures. RESULTS: The mean distance from pin to saphenous nerve was 74, 61, 21, and 24 mm at -40 degrees , -20 degrees , 0 degrees , and +20 degrees , respectively; pin to femoral artery was 100, 85, 59, and 51 mm, respectively; and pin to peroneal nerve was 40, 50, 65, and 76 mm, respectively. The safe zone for the saphenous nerve was violated at 0 degrees and +20 degrees in 2 of 5 knees, and the safe zone for the femoral artery was violated at +20 degrees in 2 of 5 knees. CONCLUSIONS: We have shown that a 20 degrees safe zone of rotational angles about the axis of the femoral tunnel, from -40 degrees to 20 degrees , minimizes the risk of damage to the saphenous nerve, femoral artery, and peroneal nerve. CLINICAL RELEVANCE: Intraoperative guide-pin angle measurement can be made in reference to the coronal plane of the femur to guide safe drilling of the TransFix guide pin (Arthrex, Naples, FL). PMID- 20952152 TI - Arthroscopic resection of dorsal wrist ganglia: 114 cases with minimum follow-up of 2 years. AB - PURPOSE: The objective of this study was to review the results of arthroscopic resection of dorsal wrist ganglion (DWG), as well as to describe the senior author's technique and technical details to minimize potential complications. METHODS: Between September 1999 and May 2004, 114 patients underwent arthroscopic resection of DWG with a minimum follow-up of 24 months. We describe the surgical technique and discuss our results and complications. RESULTS: A total of 114 patients (87 female patients and 27 male patients) with a mean age of 33.1 years were treated with our operative technique. The symptoms at presentation were unsightly appearance in 63 (55.2%), pain in 33 (28.9%), and both unsightly appearance and pain in 18 (15.8%). The patients presented between 1 and 96 months before surgery (mean, 17.81 months). Of the patients, 66 (57.9%) had been treated previously with nonsurgical modalities (aspiration) and 1 had undergone open surgery. The origin of the DWG was more commonly related to the midcarpal joint (85 patients [74.6%]). Our surgery brought about a significant improvement in flexion and extension after surgery (P < .005). Similarly, our surgery brought about a significant improvement in grip strength (P < .005). In patients with preoperative pain, treatment also showed a significant impact. At 2 years' follow up, there were 14 recurrences (12.3%), diagnosed at a mean of 16.86 months after surgery (range, 2 to 25 months). Complications were identified in 6 patients (5.26%), and the mean time off work was 11 days, with a majority of patients returning in less than 1 week. CONCLUSIONS: Arthroscopic DWG resection showed an improvement in functional measurements in addition to relief of pain in a significant proportion of patients. Complications related to the operative technique did not cause any significant long-term functional deficit. The recurrence rate was 12.3%, and patient satisfaction was high. Arthroscopic technique allows patients to use their hand immediately. The results of this study support the use of arthroscopy as primary treatment for DWG resection. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 20952153 TI - Posterior cruciate ligament tibial insertion anatomy and implications for tibial tunnel placement. AB - PURPOSE: The purposes of this study were (1) to predict the tibial insertion of the posterior cruciate ligament (PCL) and posterior cortex that aligned with the tibial tunnel (PCTT) by use of 2-dimensional plain radiographs by evaluating the relation between plain radiograph and computed tomography (CT) images and (2) to determine the safe angle of the tibial guide for preventing breakage of the posterior cortex. METHODS: In 10 fresh cadaveric tibias, the soft tissues were dissected and the tibial footprint of the PCL was identified. The insertion of the PCL, the longest distance from the PCTT to the posterior cortex that aligned with the tibial plateau (PCTP), and the possible maximum angle of the tibial guide to the most posteriorly positioned cortical line were measured from simple anteroposterior (AP) and lateral radiographs, as well as CT. RESULTS: The mean tibial insertion of the PCL from the joint line was located between 5.9 +/- 1.1 and 17.4 +/- 2.4 mm on the simple AP radiographs and between 2.2 +/- 1.2 and 12.3 +/- 1.5 mm on the simple lateral radiographs (P = .005). The PCL insertion was from the posterior 48% of the area of the posterior intercondylar fossa to the posterior cortex. The longest distance from the PCTT to the PCTP was 10.8 +/- 2.2 mm. The maximum angle of the tibial guide to the PCTT possible on CT and the PCTP on lateral radiographs was 52 degrees +/- 5 degrees and 62 degrees +/- 4.5 degrees , respectively (P = .005). CONCLUSIONS: The mean tibial insertion of the PCL from the joint line was located higher on the lateral radiographs than on the AP radiographs, and the PCL insertion was in the posterior 48% of the area of the PCL fovea to the posterior cortex. The maximum possible angle of the tibial guide to the PCTT based on CT was 52 degrees . Therefore the angle of the tibial guide pin must be limited for tibial footprint reconstruction to prevent posterior wall breakage. CLINICAL RELEVANCE: Increasing the tibial guide angle may have some advantages, but there is a limit because of posterior wall breakage. PMID- 20952154 TI - The effect of storage medium tonicity on osteochondral autograft plug diameter. AB - PURPOSE: The purpose of this study was to investigate the effect of differing storage medium on osteochondral plug diameter. METHODS: Four storage conditions were evaluated: air, hypotonic solution (sterile water), isotonic saline solution (0.9% sodium chloride), and hypertonic saline solution (3.0% sodium chloride). Four osteochondral plugs were acquired (4.5-mm harvesting system) from each of 10 fresh calf femurs and randomized to 1 of 4 storage media (N = 40). Micro-computed tomography was used to evaluate the precise diameter of each plug. After a time 0 scan, each plug was placed in a designated storage medium and rescanned at 3 time points over approximately 1 hour. A region of interest was identified from approximately 1 to 6 mm proximal to the tidemark. Custom software automatically calculated the diameter of each plug. RESULTS: The time 0 plug diameter (mean +/- 95% confidence interval) for all specimens was 4.66 +/- 0.01 mm. There were no significant differences between any of the groups at the baseline scan. There were also no significant differences between the time 0 and subsequent scans of the unsubmerged specimens. However, all of the liquid solutions (hypertonic, isotonic, and hypotonic) resulted in a significant increase in diameter from their baseline scans (P < .05), indicating that a cause may be increased extracellular matrix fluid pressure. CONCLUSIONS: Placing an osteochondral plug in a liquid solution increased the diameter of the subchondral bone. Size increase from the storage medium appeared to level off within 14 minutes after placement in solution. CLINICAL RELEVANCE: Increases in diameter of the plug may alter the ease of insertion of the graft, possibly increasing contact pressure on cartilage during plug implantation. PMID- 20952155 TI - Multifocal intraocular lenses for unilateral cataract in children. AB - PURPOSE: To evaluate the implantation of apodized diffractive multifocal intraocular lenses (IOLs) in children with unilateral cataract. SETTING: Ophthalmology Service, Hospital Clinico Lozano Blesa, Zaragoza, Spain. DESIGN: Prospective clinical study. METHODS: Five children between 4 and 6 years of age with unilateral cataract had cataract extraction and implantation of an apodized diffractive multifocal IOL (AcrySof Restor SN60D3). Phacoaspiration was accompanied by posterior capsulorhexis followed by an anterior vitrectomy. Uncorrected distance (UDVA), corrected distance (CDVA), and corrected near (CNVA) visual acuities; binocular function using the Worth 4-dot test and the TNO stereotest; and subjective symptoms such as glare and halos were evaluated over 21 months of follow-up. RESULTS: At the final follow-up visit, the mean UDVA was 0.45 +/- 0.149 logMAR and the mean CDVA was 0.30 +/- 0.06 logMAR with 20/32 in 3 eyes, 20/50 in 1 eye, and 20/63 in 1 eye. The mean CNVA was 0.10 +/- 0.05 logMAR (about 20/25) with J1 in 2 eyes, J2 in 1 eye, J3 in 1 eye, and J4 in 1 eye. The stereoacuity was 120 seconds of arc (arcsec) in 2 patients, 240 arcsec in 1 patient, 1980 arcsec in 1 patient, and nonexistent in 1 patient. The Worth 4-dot test showed that 4 patients had fusion. None of the 5 patients complained about halos or glare. No IOL decentration was observed in any patient. CONCLUSION: Implantation of an apodized multifocal IOL seems to be a satisfactory alternative to monofocal pseudophakia in children with unilateral cataract. PMID- 20952156 TI - The prevalence of dental anxiety across previous distressing experiences. AB - AIMS: To compare the prevalence of high dental anxiety across a variety of past distressing experiences with a previously reported Dutch sample. METHOD: University students from the UK (N=1024) completed an online survey containing; the Modified Dental Anxiety Scale, and the Level of Exposure-Dental Experiences Questionnaire (LOE-DEQ). Adjusted odds ratios (OR) were calculated to assess the association of self-reported distressing experiences and dental anxiety. RESULTS: The percentage of respondents with high dental anxiety (HDA) (total MDAS score>=19) was 11.2%. Significant prevalence of HDA across several distressing experiences was shown in both UK and Dutch samples notably: extreme helplessness during dental treatment, lack of understanding of the dentist and extreme embarrassment during dental treatment. There were little or no effects of non dental trauma, with the exception of sexual abuse in the UK sample. CONCLUSIONS: Trauma from various past experiences may be implicated in an increased risk of high dental anxiety. PMID- 20952157 TI - How much change is true change? The smallest detectable difference of the Preschool Imitation and Praxis Scale (PIPS) in preschoolers with intellectual disabilities of heterogeneous aetiology. AB - The teaching of imitation skills is often the first step in interventions for young learners with intellectual disabilities. The main goal of this study was to determine the smallest detectable difference (SDD) at 95% confidence of the Preschool Imitation and Praxis Scale (PIPS) in preschoolers with intellectual disabilities. Two raters independently scored videotapes of the imitation performance of 44 preschoolers (27 with Down syndrome, 10 with Non-Specific Mental Retardation and 7 with Low-functioning Autism) between 13 and 58 months of age (mean age 39.6 months, SD 11.9 months). Results revealed that the PIPS demonstrated acceptable interrater reliability on item level (weighted kappa values ranged from 0.52 to 0.96) and scale level (ICC = 0.986; 95% CI: 0.975 0.993). The SDD of the PIPS was 7.2%, indicating that the change score rated by different raters for an individual child with an intellectual disability is valid and that the PIPS can be used by early interventionists and researchers as an outcome measure to determine children's maturation or improvement. PMID- 20952158 TI - Predictors of early-onset permanent hearing loss in malnourished infants in Sub Saharan Africa. AB - The objective of this study was to determine the predictors of early-onset permanent hearing loss (EPHL) among undernourished infants in a low-income country where routine screening for developmental disabilities in early childhood is currently unattainable. All infants attending four community-based clinics for routine immunization who met the criteria for undernutrition by the Growth Standards of the World Health Organization (WHO) based on weight-for-age, weight for-length and body-mass-index-for-age were enlisted. EPHL was determined after two-stage screening with transient-evoked otoacoustic emissions, automated auditory brainstem response and diagnostic evaluation. Factors predictive of EPHL were explored with multivariable logistic regression analysis. Some 39 (1.7%) infants from 2254 undernourished infants were confirmed with hearing loss (>30 dB HL). Bilateral EPHL was mild in 7 (17.9%) and moderate-to-profound in 26 (66.7%). EPHL was unilateral in 6 (15.4%). Multiparity, chronological age of more than 30 days, the absence of skilled attendant at birth and severe neonatal jaundice were associated with an increased risk of EPHL while having a Christian mother and exclusive breast feeding had protective effect against EPHL. EPHL is highly prevalent among undernourished infants and associated with modifiable risk factors that can be addressed at the community-level and used as a basis for targeted intervention in resource-poor countries. PMID- 20952159 TI - Towards the automatic study of the vocal tract from magnetic resonance images. AB - Over the last few decades, researchers have been investigating the mechanisms involved in speech production. Image analysis can be a valuable aid in the understanding of the morphology of the vocal tract. The application of magnetic resonance imaging to study these mechanisms has been proven to be reliable and safe. We have applied deformable models in magnetic resonance images to conduct an automatic study of the vocal tract; mainly, to evaluate the shape of the vocal tract in the articulation of some European Portuguese sounds, and then to successfully automatically segment the vocal tract's shape in new images. Thus, a point distribution model has been built from a set of magnetic resonance images acquired during artificially sustained articulations of 21 sounds, which successfully extracts the main characteristics of the movements of the vocal tract. The combination of that statistical shape model with the gray levels of its points is subsequently used to build active shape models and active appearance models. Those models have then been used to segment the modeled vocal tract into new images in a successful and automatic manner. The computational models have thus been revealed to be useful for the specific area of speech simulation and rehabilitation, namely to simulate and recognize the compensatory movements of the articulators during speech production. PMID- 20952160 TI - Severity of contracture and self-reported disability in patients with Dupuytren's contracture referred for surgery. AB - The purpose of the study was to explore the relationship between preoperative flexion contracture (FC) and self-reported disability in patients undergoing surgical release by fasciectomy or dermofasciectomy. The study design used was a prospective observational study: Dupuytren's disease (DD) is a fibroproliferative disorder of the palmar fascia and may lead to functional deficits requiring surgical intervention. Outcomes are usually reported using digital range of motion although recent studies have also included patient-rated outcome measures with the extensively validated Disabilities of the Arm, Shoulder, and Hand (DASH) Questionnaire commonly used. One hundred fifty-four patients consecutively enrolled in a prospective randomized trial were assessed before surgery for active range of movement using goniometry and self-reported functioning using DASH questionnaire. The small finger was affected in 69% of patients with a mean FC of 77.8 degrees (standard deviation=43.5 degrees ). The mean DASH score was 16 points (range, 0-62). The correlation between severity of FC in all four fingers and DASH was weak (r=0.264, p=0.001). At individual digital level, the correlation between FC and DASH was weak in the index (r=0.26), middle (r=0.28), and ring (r=0.21) fingers but almost absent in the small finger (r=0.07). These results show that the relationship between severity of FC and functional disability measured by the DASH questionnaire appear to be very weak or even absent. LEVEL OF EVIDENCE: Level III prospective cohort study. PMID- 20952161 TI - Measurement of right ventricular mechanical synchrony in children using tissue Doppler velocity and two-dimensional strain imaging. AB - BACKGROUND: Right ventricular (RV) mechanical dyssynchrony may be associated with RV dysfunction. The aim of this study was to investigate the feasibility of measuring RV synchrony in normal children using Doppler tissue imaging and two dimensional speckle tracking. METHODS: The RV delay (difference in time to peak velocity or two-dimensional strain between the RV lateral wall and the interventricular septum) and standard deviation of time to peak velocity or strain were measured and corrected for heart rate. Intraobserver and interobserver reliabilities were analyzed. RESULTS: One hundred three children were studied. RV delay analysis was feasible in 95% by Doppler tissue imaging and in 63% by two-dimensional speckle tracking (99% and 84% when imaging was adequate). The mean +/- 2 standard deviations RV delay by either method was <70 msec or <8% of the cardiac cycle in systole and <65 msec or <7% of the cardiac cycle in diastole. Intraobserver and interobserver variability showed small absolute differences but high variability because delays were either positive or negative. CONCLUSION: This study establishes the feasibility of the measurement of RV mechanical synchrony in normal children aged 3 to 18 years. PMID- 20952162 TI - Results from simulated data sets: probabilistic record linkage outperforms deterministic record linkage. AB - OBJECTIVE: To gain insight into the performance of deterministic record linkage (DRL) vs. probabilistic record linkage (PRL) strategies under different conditions by varying the frequency of registration errors and the amount of discriminating power. STUDY DESIGN AND SETTING: A simulation study in which data characteristics were varied to create a range of realistic linkage scenarios. For each scenario, we compared the number of misclassifications (number of false nonlinks and false links) made by the different linking strategies: deterministic full, deterministic N-1, and probabilistic. RESULTS: The full deterministic strategy produced the lowest number of false positive links but at the expense of missing considerable numbers of matches dependent on the error rate of the linking variables. The probabilistic strategy outperformed the deterministic strategy (full or N-1) across all scenarios. A deterministic strategy can match the performance of a probabilistic approach providing that the decision about which disagreements should be tolerated is made correctly. This requires a priori knowledge about the quality of all linking variables, whereas this information is inherently generated by a probabilistic strategy. CONCLUSION: PRL is more flexible and provides data about the quality of the linkage process that in turn can minimize the degree of linking errors, given the data provided. PMID- 20952163 TI - Versatility of full thickness skin-subcutaneous fat grafts as interpositional material in the management of temporomandibular joint ankylosis. AB - The authors present a review of seven patients (eight joints) with temporomandibular ankylosis treated between 2007 and 2008. The aim of this retrospective study was to present the experience of using full thickness skin subcutaneous fat grafts, harvested from the patient's abdomen as interpositional material after gap arthroplasty. All patients presented with osseous ankylosis and were graded according to Topazian's classification. Postoperative follow up ranged from 12 to 24 months. Maximal inter-incisal opening (MIO) on presentation ranged from 0 to 8mm, which stabilized to 27-44mm at follow up. There was no evidence of re-ankylosis. This study found merit in the use of autogenous full thickness skin-subcutaneous fat graft as an interpositional material for up to 2 years following ankylosis release. PMID- 20952164 TI - Antimicrobial chemotherapy and lung microdialysis: a review. AB - Pneumonia is a form of lung infection that may be caused by various micro organisms. The predominant site of infection in pneumonia is debatable. Advances in the fields of diagnostic and therapeutic medicine have had a less than optimal effect on the outcome of pneumonia and one of the many causes is likely to be inadequate antimicrobial concentrations at the site of infection in lung tissue. Traditional antimicrobial therapy guidelines are based on indirect modelling from blood antimicrobial levels. However, studies both in humans and animals have shown the fallacy of this concept in various tissues. Many different methods have been employed to study lung tissue antimicrobial levels with limited success, and each has limitations that diminish their utility. An emerging technique being used to study the pharmacokinetics of antimicrobial agents in lung tissue is microdialysis. Development of microdialysis catheters, along with improvement in analytical techniques, has improved the accuracy of the data. Unfortunately, very few studies have reported the use of microdialysis in lung tissue, and even fewer antimicrobial classes have been studied. These studies generally suggest that this technique is a safe and effective way of assessing the pharmacokinetics of antimicrobial agents in lung tissue. Further descriptive studies need to be conducted to study the pharmacokinetics and pharmacodynamics of different antimicrobial classes in lung tissue. Data emanating from these studies could inform decisions for appropriate dosing schedules of antimicrobial agents in pneumonia. PMID- 20952165 TI - Probing interfacial interactions of bacteria on metal nanoparticles and substrates with different surface properties. AB - This report describes the findings of an investigation of interfacial interactions of bacteria (Pseudomonas aeruginosa) on metal nanoparticles and substrates with different surface properties. In addition to the antibacterial activity of metal nanoparticles, the results of atomic force microscopy (AFM) probing of the interfacial interactions of P. aeruginosa on flat substrates with different surface properties, including a hydrophilic mica and a hydrophobic highly ordered pyrolytic graphite (HOPG), and with different nanoparticle patterns are the focus of this discussion. AFM imaging data revealed that the interaction of the hydrophilic mica surface with P. aeruginosa keeps the cell outer membrane relatively 'rigid'. The cell outline is largely retained even under the condition of dense packing on the surface. In contrast, the interaction of the hydrophobic HOPG surface renders the cell outer membrane relatively 'soft'. This soft nature maximises its contact area with the substrate so that the cell outline is altered to fill intercell voids. Demonstration of the viability of creating a nanoparticle-patterned AFM imaging platform in which the assembled nanoparticles inactivate bacteria whereas the bottom substrate promotes bacterial adhesion may find applications in high-throughput screening or assays of bacterial adhesion and antibacterial activity of metal nanoparticles. PMID- 20952167 TI - [Dermatofibrosarcoma protuberans in children]. AB - Dermatofibrosarcoma protuberans (DFSP) is a relatively rare skin neoplasm. Usually affecting adults, the incidence in children is even less frequent. Through a report of three pediatric cases of DFSP, we describe the particularities of this tumor in children. Three boys aged 8, 9, and 15 years presented with a firm nodular skin lesion of the trunk, varying in size from 1 to 5 cm. No previous trauma event had occurred. Diagnosis was confirmed in all cases by immunohistological study. Surgical excision was performed in all cases. No recurrence was evident during the follow-up period of, respectively, 15, 36, and 49 months. The DFSP is an infiltrative tumor of intermediate malignancy, with a limited potential for metastasis (<5%) but a high rate of local recurrence (>= 50%). The incidence in children is even less frequent. In children, its seemingly benign clinical appearance may explain delays in diagnosis; the majority of lesions affect the extremities, suggesting a potential role-played by injury. In our observations, however, as in adults, the trunk was the site of occurrence. Despite the uncertain pathogenesis of this tumor, the finding of certain characteristic histopathological features helps establish an accurate diagnosis. As in adults, surgical treatment with large surgical margins remains the best practice for children with DFSP, directly affecting the prognosis. PMID- 20952166 TI - Maturation of limbic regions in Asperger syndrome: a preliminary study using proton magnetic resonance spectroscopy and structural magnetic resonance imaging. AB - People with autistic spectrum disorders (ASD, including Asperger syndrome) may have developmental abnormalities in the amygdala-hippocampal complex (AHC). However, in vivo, age-related comparisons of both volume and neuronal integrity of the AHC have not yet been carried out in people with Asperger syndrome (AS) versus controls. We compared structure and metabolic activity of the right AHC of 22 individuals with AS and 22 healthy controls aged 10-50 years and examined the effects of age between groups. We used structural magnetic resonance imaging (sMRI) to measure the volume of the AHC, and magnetic resonance spectroscopy ((1)H-MRS) to measure concentrations of N-acetyl aspartate (NAA), creatine+phosphocreatine (Cr+PCr), myo-inositol (mI) and choline (Cho). The bulk volume of the amygdala and the hippocampus did not differ significantly between groups, but there was a significant difference in the effect of age on the hippocampus in controls. Compared with controls, young (but not older) people with AS had a significantly higher AHC concentration of NAA and a significantly higher NAA/Cr ratio. People with AS, but not controls, had a significant age related reduction in NAA and the NAA/Cr ratio. Also, in people with AS, but not controls, there was a significant relationship between concentrations of choline and age so that choline concentrations reduced with age. We therefore suggest that people with AS have significant differences in neuronal and lipid membrane integrity and maturation of the AHC. PMID- 20952169 TI - Carboplatin chemotherapy in patients with recurrent high-grade glioma. AB - AIMS: To investigate the efficacy of carboplatin chemotherapy in patients with recurrent high-grade glioma (HGG) who had received at least two previous lines of chemotherapy. MATERIALS AND METHODS: Case notes of patients who had received chemotherapy with carboplatin for recurrent HGG between June 2005 and July 2008 were reviewed. Baseline characteristics and outcomes after treatment were recorded. RESULTS: Twenty-six patients received carboplatin as third- or fourth line chemotherapy for recurrent HGG (grade III glioma n=8; grade IV glioma n=18). The median number of cycles completed was 2.5. The most common reasons for discontinuing treatment were progressive disease and death (n=19; 73%). Three patients (12%) had a partial response, five (19%) had stable disease and 18 (69%) had progressive disease. Six month progression-free survival was 23% (25% in patients with grade III glioma and 22% in patients with grade IV glioma). The median time to disease progression from the first treatment with carboplatin was 9.0 weeks. The median survival was 19.4 weeks (27.9 weeks for patients with grade III glioma and 8.1 weeks for patients with grade IV glioma). Among patients with either stable disease or a partial response, the median survival was 42.4 weeks compared with 11.7 weeks in patients with progressive disease (hazard ratio for death with progressive disease on treatment: 5.02; 95% confidence interval 1.64 15.4; P=0.005). Carboplatin was well tolerated overall. CONCLUSIONS: Single-agent carboplatin has modest activity in patients with recurrent HGG who have received at least two lines of chemotherapy. The overall time to progression is short and over two-thirds of patients had to discontinue treatment due to progressive disease. Among the small proportion of patients achieving stable disease or a partial response to treatment, the median survival is improved. More effective but well tolerated regimens are required for this patient population. PMID- 20952170 TI - Inhibition of acetylcholinesterase activities and some pro-oxidant induced lipid peroxidation in rat brain by two varieties of ginger (Zingiber officinale). AB - Ginger has been reportedly used for the management or treatment of Alzheimer's disease in folklore medicine. Therefore, this study sought to investigate the inhibitory effects of water extractable phytochemicals of red and white ginger on acetylcholinesterase activities, and sodium nitroprusside (SNP) and quinolinic acid (QA)-induced lipid peroxidation in rat brain -in vitro. Both extracts inhibited acetylcholinesterase (AChE) activities in a dose-dependent manner; however, white ginger had higher acetylcholinesterase inhibitory activity than red ginger. Combination of the ginger inhibited acetylcholinesterase activities synergistically. Furthermore, SNP and QA caused a significant increase in the malondialdehyde (MDA) contents of the brain; however, the extracts significantly decrease the SNP and QA elevated brain MDA contents in a dose-dependent manner. Nevertheless, there was no significant difference (P>0.05) in the inhibition of the SNP and QA-induced lipid peroxidation by both extracts. The inhibitory effect of ginger extracts on acetylcholinesterase activities and some prooxidants induced lipid peroxidation in rat's brain could be attributed to the presence of phytochemicals such as flavonoids, tannins, alkaloids and terpenoids. Therefore, some possible mechanism by which ginger extracts exert anti-Alzheimer properties could be through the inhibition of acetylcholinesterase activities and prevention of lipid peroxidation in the brain. PMID- 20952171 TI - Ontogenetic differences in the feeding biomechanics of oviparous and viviparous caecilians (Lissamphibia: Gymnophiona). AB - Caecilians have a unique dual jaw-closing system in that jaw closure is driven by the ancestral jaw-closing muscles (mm. levatores mandibulae) plus a secondarily recruited hyobranchial muscle (m. interhyoideus posterior). There is a variety of feeding habits (suction feeding, skin feeding, intrauterine scraping, and biting) during ontogeny that relate to reproductive modes in different caecilian species. This study examines the cranial biomechanics of caecilians in the suction-feeding larva of Ichthyophis cf. kohtaoensis, in the embryo and juvenile of the skin feeding Boulengerula taitana, and in a newborn of the intrauterine feeder Typhlonectes natans. A lever arm model was applied to calculate effective mechanical advantages of jaw-closing muscles over gape angles and to predict total bite force in developing caecilians. In I. cf. kohtaoensis, Notable differences were found in the larval jaw-closing system compared to that of the adult. The suction-feeding larva of I. cf. kohtaoensis has comparatively large mm. levatores mandibulae that insert with an acute muscle fiber angle to the lower jaw and a m. interhyoideus posterior that has its optimal leverage at small gape angles. Conversely, the skin-feeding juvenile of B. taitana and the neonate T. natans are very similar in the feeding parameters considered herein compared to adult caecilians. Some ontogenetic variation in the feeding system of B. taitana before the onset of feeding was present. This study contributes to our understanding of the functional demands that feeding habits put on the development of cranial structures. PMID- 20952172 TI - Differential roles of internal and terminal double bonds in docosahexaenoic acid: Comparative study of cytotoxicity of polyunsaturated fatty acids to HT-29 human colorectal tumor cell line. AB - The role of the double bonds in docosahexaenoic acid (22:6(Delta4,7,10,13,16,19); DHA) in cytotoxic lipid peroxidation was studied in a superoxide dismutase defective human colorectal tumor cell line, HT-29. In a conventional culture, DHA and other polyunsaturated fatty acids (PUFAs) were found to induce acute lipid peroxidation and subsequent cell death. PUFAs that lack one or both the terminal double bonds (Delta19 and Delta4) but share Delta7,10,13,16 such as 22:5(Delta7,10,13,16,19), 22:5(Delta4,7,10,13,16), and 22:4(Delta7,10,13,16) were more effective than DHA. Lipid peroxidation and cell death were completely inhibited, except by 22:4(Delta7,10,13,16) when radical-mediated reactions were suppressed by culturing cells in 2% O(2) in the presence of vitamin E. DHA and C22:5 PUFAs but not 22:4(Delta7,10,13,16) were efficiently incorporated in phosphatidylinositol, regardless of the culturing conditions. These and other results suggested that the internal unsaturations Delta7,10,13,16 were sensitive to lipid peroxidation, whereas the terminal ones Delta19 and Delta4 appeared to be involved in assimilation into phospholipids. PMID- 20952173 TI - NK cells: elusive participants in transplantation immunity and tolerance. AB - NK cells constitute an innate MHC class I-reactive lymphoid population that rapidly responds to infection, injury, or cell distress. In the transplant field, NK cells have most often been associated with pro-inflammatory immunity resulting in the exacerbation of allograft injury. Despite this general view of NK cell reactivity, it has been challenging to assign unambiguous obligate roles for NK cells in the allograft response. While recent reports continue to provide evidence supporting a role for NK cells in promoting both acute and chronic rejection, there are also a growing number of studies that illustrate an alternative role for NK cells in promoting allograft survival and tolerance. This review addresses the plasticity of NK responses in transplantation by suggesting specific 'checkpoints' whereby NK cells can either enhance or inhibit the allograft response in vivo. PMID- 20952174 TI - Prevalence of COPD in Copenhagen. AB - INTRODUCTION: COPD is a leading cause of death worldwide; however, prevalence estimates have varied considerably in previous studies. This study aimed to determine the prevalence and severity of COPD in Copenhagen using data from the 4th examination of The Copenhagen City Heart Study, to investigate the relationship between tobacco consumption and COPD, and to characterize the subjects with COPD with regard to BMI, dyspnoea, treatment with respiratory medication and co-morbidities. METHODS: 6236 people participated. All non asthmatic participants aged 35 years or older with adequate lung function data were included for the final prevalence analyses (n = 5,299). COPD staging was done according to the GOLD criteria. RESULTS: The overall prevalence of COPD was 17.4%. The prevalence increased with age and was higher among males. 6.2% had mild COPD, 9.2% had moderate COPD, and 2.0% had severe or very severe COPD. Tobacco consumption was closely linked to both prevalence and disease severity. Subjects with COPD had lower mean Body Mass Index (BMI) and more frequently a BMI < 21 kg/m(2). Dyspnoea was correlated to lung function but a substantial number of participants with severe COPD experienced no dyspnoea. Only a minority of subjects with COPD received pulmonary medication. COPD was associated with cardiovascular disease and cancer. CONCLUSION: The prevalence of COPD in Denmark is among the highest in the world. It is closely correlated to smoking and age. It is accompanied by substantial co-morbidity and it is grossly under treated. PMID- 20952175 TI - Lycopene inhibits proinflammatory cytokine and chemokine expression in adipose tissue. AB - Obesity is associated with a low-grade inflammation which is correlated with an increased secretion of pro-inflammatory cytokines and chemokines by adipose tissue, suspected to contribute to the development of insulin resistance. Because lycopene is mostly stored in adipose tissue and possesses anti-inflammatory properties, we hypothesize that lycopene could reduce the production of proinflammatory markers in adipose tissue. In agreement with this hypothesis, we observed a decrease of inflammatory markers such as IL-6, MCP-1 and IL-1beta at both the mRNA and protein level when explants of epididymal adipose tissue from mice fed with a high-fat diet were incubated with lycopene ex vivo. The same effect was reproduced with explants of adipose tissue preincubated in lycopene and then subjected to TNFalpha stimulation. The contribution of adipocytes and preadipocytes was evaluated. In both preadipocytes and differentiated 3T3-L1 adipocytes, lycopene preincubation for 24 h decreased the TNFalpha-mediated induction of IL-6 and MCP-1. Finally, the same results were reproduced with human adipocyte primary cultures. The molecular mechanism was also studied. In transient transfections, a decrease of the luciferase gene reporter under control of NF-kappaB responsive element was observed for cells incubated in the presence of lycopene and TNFalpha compared to TNFalpha alone. The involvement of the NF kappaB pathway was confirmed by the modulation of IKKalpha/beta phosphorylation by lycopene. Altogether, these results showed for the first time a limiting effect of lycopene on adipose tissue proinflammatory cytokine and chemokine production. Such an effect could prevent or limit the prevalence of obesity associated pathologies, such as insulin resistance. PMID- 20952176 TI - "It's not rocket science, what I do": Self-directed harm reduction strategies among drug using ethno-racially diverse gay and bisexual men. AB - BACKGROUND: Research on harm reduction has typically focused on broad-based or organisational strategies such as needle exchange and opiate substitute programmes. Less attention has been paid to the self-directed harm reduction practices of substance users themselves. Few studies have focused on sexual minority populations such as gay and bisexual men and fewer still on the marginalised groups that constitute these populations. This paper identifies self directed harm reduction strategies among substance using ethno-racially diverse gay and bisexual men. METHODS: This article presents findings from the Party Drugs Study in Toronto's gay dance club scene, a community-based qualitative study in Toronto, Canada. We present a thematic analysis of interviews with 43 gay and bisexual men from diverse ethno-racial backgrounds about their substance use in the gay dance club scene. FINDINGS: We identify five self-directed harm reduction strategies: rationing, controlling or avoiding mixing, controlling quality, maintaining a healthy lifestyle, and following guidelines during substance use. CONCLUSIONS: We discuss our findings in relation to prior research and to critical theory. We suggest that drug users' awareness of possible harm, and their personal investment in harm reduction, constitute a viable platform from which community-based and public health organisations may promote and strengthen harm reduction among gay and bisexual men from ethno-racially diverse backgrounds. PMID- 20952177 TI - Application of fuzzy logic and sensitivity analysis for soil contamination hazard classification. AB - The present article is aimed at illustrating a methodology for a rapid and effective assessment of pollution hazard connected with the presence of uncontrolled landfills. In particular, by means of a fuzzy approach, the criterion adopted allowed a comparison of the results obtained from a cross analysis of some intrinsic characteristics of the single landfills and the territory where they are located. Their identification shows the most relevant environmental problem. Therefore, we have classified each site within a hazard scale enabling us to understand which one requires to be checked more urgently, to do instrumental surveys and, if needed, to do restoration and reclamation. Moreover, the sensitivity analysis we carried out allowed us to identify which is the best membership function belonging and which is the best defuzzification method. That is, in particular, the trapezoidal function and the centroid method. The proposed fuzzy approach, supported by the sensitivity analysis, has revealed to be an important tool for supporting decisions, in order to optimise technical and economic resources. PMID- 20952178 TI - Property-close source separation of hazardous waste and waste electrical and electronic equipment--a Swedish case study. AB - Through an agreement with EEE producers, Swedish municipalities are responsible for collection of hazardous waste and waste electrical and electronic equipment (WEEE). In most Swedish municipalities, collection of these waste fractions is concentrated to waste recycling centres where households can source-separate and deposit hazardous waste and WEEE free of charge. However, the centres are often located on the outskirts of city centres and cars are needed in order to use the facilities in most cases. A full-scale experiment was performed in a residential area in southern Sweden to evaluate effects of a system for property-close source separation of hazardous waste and WEEE. After the system was introduced, results show a clear reduction in the amount of hazardous waste and WEEE disposed of incorrectly amongst residual waste or dry recyclables. The systems resulted in a source separation ratio of 70 wt% for hazardous waste and 76 wt% in the case of WEEE. Results show that households in the study area were willing to increase source separation of hazardous waste and WEEE when accessibility was improved and that this and similar collection systems can play an important role in building up increasingly sustainable solid waste management systems. PMID- 20952179 TI - Ultrasensitive electrochemical strategy for NT-proBNP detection with gold nanochains and horseradish peroxidase complex amplification. AB - A novel electrochemical immunosensor for sensitive detection of cardiac biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) is fabricated based on the nanostructural gold and carbon nanotubes composite as desirable platform for the capture antibodies immobilization and gold nanochains (AuNCs) and horseradish peroxidase (HRP) complex labeled secondary antibodies (AuNCs-HRP-Ab(2)) for signal amplification. The gold nanochains were prepared by the employment of L ascorbic acid (AA) as a mediator and template. With the surface area enhancement by nanostructural gold functionalized carbon nanotubes composite, the amount of immobilized primary antibodies (Ab(1)) can be enhanced. More importantly, enhanced sensitivity can be achieved by introducing the multibioconjugates of AuNCs-HRP-Ab(2) onto the electrode surface through "sandwich" immunoreactions. The linear range extended from 0.02 to 100 ng/mL with a correlation coefficient of R=0.997 and a limit of detection reaching 6 pg/mL at a signal-to-noise ratio of 3:1, which is well below the commonly accepted concentration threshold (0.1 ng/mL) used in clinical diagnosis. The specificity, regeneration and stability test demonstrated the feasibility of the developed immunoassay, which gives the attractive characteristics to be a candidate for the detection of NT-proBNP and other proteins of interest in both fundamental and applied research. PMID- 20952180 TI - DNA hybridization sensor based on pentacene thin film transistor. AB - A DNA hybridization sensor using pentacene thin film transistors (TFTs) is an excellent candidate for disposable sensor applications due to their low-cost fabrication process and fast detection. We fabricated pentacene TFTs on glass substrate for the sensing of DNA hybridization. The ss-DNA (polyA/polyT) or ds DNA (polyA/polyT hybrid) were immobilized directly on the surface of the pentacene, producing a dramatic change in the electrical properties of the devices. The electrical characteristics of devices were studied as a function of DNA immobilization, single-stranded vs. double-stranded DNA, DNA length and concentration. The TFT device was further tested for detection of lambda-phage genomic DNA using probe hybridization. Based on these results, we propose that a "label-free" detection technique for DNA hybridization is possible through direct measurement of electrical properties of DNA-immobilized pentacene TFTs. PMID- 20952181 TI - Macromolecule diffusion and confinement in prokaryotic cells. AB - We review recent observations on the mobility of macromolecules and their spatial organization in live bacterial cells. We outline the major fluorescence microscopy-based methods to determine the mobility and thus the diffusion coefficients (D) of molecules, which is not trivial in small cells. The extremely high macromolecule crowding of prokaryotes is used to rationalize the reported lower diffusion coefficients as compared to eukaryotes, and we speculate on the nature of the barriers for diffusion observed for proteins (and mRNAs) in vivo. Building on in vitro experiments and modeling studies, we evaluate the size dependence of diffusion coefficients for macromolecules in vivo, in case of both water-soluble and integral membrane proteins. We comment on the possibilities of anomalous diffusion and provide examples where the macromolecule mobility may be limiting biological processes. PMID- 20952182 TI - Plantar fasciitis and impaired vision: A case report. AB - We report a case of acute bilateral central serous chorioretinopathy in a patient who received a local injection of triamcinolone for the treatment of plantar fasciitis. Central serous chorioretinopathy is a serious, though rare, ocular complication of steroid treatment and it may occur even when the steroid is administered at a site as remote from the eye as the foot. This case report highlights the need for greater awareness of this complication amongst all medical personnel who prescribe steroids. It is advisable that patients, undergoing steroid treatment for any cause, be alerted to the risk of sudden visual impairment. PMID- 20952183 TI - Evolution of brain-computer interface: action potentials, local field potentials and electrocorticograms. AB - Brain computer interfaces (BCIs) were originally developed to give severely motor impaired patients a method to communicate and interact with their environment. Initially most BCI systems were based on non-invasive electroencephalographic recordings from the surface of the scalp. To increase control speed, accuracy and complexity, researchers began utilizing invasive recording modalities. BCIs using multi-single unit action potentials have provided elegant multi-dimensional control of both computer cursors and robotic limbs in the last few years. However, long-term stability issues with single-unit arrays has lead researchers to investigate other invasive recording modalities such as high-frequency local field potentials and electrocorticography (ECoG). Although ECoG originally evolved as a replacement for single-unit BCIs, it has come full circle to become an effective tool for studying cortical neurophysiology. PMID- 20952184 TI - Keeping neural progenitor cells on a short leash during Drosophila neurogenesis. AB - The developmental potential of stem cells and progenitor cells must be functionally distinguished to ensure the generation of diverse cell types while maintaining the stem cell pool throughout the lifetime of an organism. In contrast to stem cells, progenitor cells possess restricted developmental potential, allowing them to give rise to only a limited number of post-mitotic progeny. Failure to establish or maintain restricted progenitor cell potential can perturb tissue development and homeostasis, and probably contributes to tumor initiation. Recent studies using the developing fruit fly Drosophila larval brain have provided molecular insight into how the developmental potential is restricted in neural progenitor cells. PMID- 20952185 TI - Enhanced production of validamycin A by H2O2-induced reactive oxygen species in fermentation of Streptomyces hygroscopicus 5008. AB - A novel fermentation strategy to enhance antibiotics production was demonstrated by inducing reactive oxygen species (ROS), and validamycin A (VAL-A) production by Streptomyces hygroscopicus 5008 in agro-industrial residues containing medium was taken as an example. By optimizing H2O2 amount and addition time, the intracellular ROS level was increased, and VAL-A production titer was enhanced by 40% on day 4 when 25 MUM H2O2 was added at 8th h of fermentation. Addition of diphenyleneiodonium chloride (ROS inhibitor) reduced the H2O2 induction effect. The transcription level of eight VAL-A structure genes was enhanced by ROS, and activities of glucose-6-phosphate dehydrogenase and ValG enzyme were increased while glyceraldehyde 3-phosphate dehydrogenase activity was inhibited. This work demonstrated that ROS induction was a useful strategy for VAL-A fermentation, and the information on gene transcription and enzyme activities may be helpful to further understanding the mechanism of ROS effect on the antibiotic biosynthesis. PMID- 20952186 TI - Effects of struvite formation and nitratation promotion on nitrogenous emissions such as NH3, N2O and NO during swine manure composting. AB - To reduce nitrogenous emissions from composting, two different countermeasures were applied simultaneously in swine manure composting. One was forming struvite by adding Mg and P at the start of composting, and the other was to promote nitratation (nitrite being oxidized nitrate) by adding nitrite-oxidizing bacteria after the thermophilic phase of composting. In the laboratory- and mid-scale composting experiments, 25-43% of NH3, 52-80% of N2O and 96-99% of NO emissions were reduced. From the nitrogen balance, it was revealed that the struvite formation reduced not only NH3, but also other nitrogenous emissions except N2O. The amount of total nitrogen losses was reduced by 60% by the two combined countermeasures, against 51% by the struvite formation alone. However, the nitratation promotion dissolved struvite crystals due to the pH decline, diminishing the effect of struvite as a slow-release fertilizer. PMID- 20952187 TI - Kinetics of sequential reaction of hydrolysis and sugar degradation of rice husk in ethanol production: effect of catalyst concentration. AB - This study focuses on kinetics of rice husk hydrolysis using sulfuric acid catalyst to produce sugars. The experiments were conducted at various catalyst concentrations. It turned out that during hydrolysis, degradation of sugars was encountered. The kinetics was expressed with both homogeneous and heterogeneous models. At catalyst concentration of higher than 0.44 N, heterogeneous model works better than homogeneous model, while at the lower, both models work well. In the heterogeneous model, it is observed that the mass transfer of sulfuric acid in the particles and the hydrolysis reaction control the rate of hydrolysis. The mass transfer can be described by Fick's law with the effective diffusivity of 1.4*10(-11) cm2/s, while the hydrolysis and sugar degradation rate constants follow Arrhenius equations. In addition, it was experimentally observed that the sugars produced can be converted to ethanol by fermentation using yeast. PMID- 20952188 TI - Estimation of a novel method to produce bio-oil from sewage sludge by microwave pyrolysis with the consideration of efficiency and safety. AB - This paper presented a feasible method to produce bio-oil from sewage sludge by microwave pyrolysis. The results showed that oils derived under 400 W obtained an attractive yield (49.8 wt.%) with favorable characteristics such as high calorific value (35.0 MJ/kg), low density (929 kg/m3) and preferable chemical composition (29.5 wt.% of monoaromatics). A model to study the relationship between microwave power and mass balance of product fractions was developed, and the results indicated that the power range of the highest transforming efficiency for organics in sludge into oils was 400-600 W, the subsequent increase of power to the range of 600-800 W favored gases formation at the expense of oils, and increase of power to above 800 W led to the conversion of solids into gases, while oils remained unchanged. The analysis of sulfur and nitrogen compounds in oils showed that bio-oil should be extracted before being used as fuel. PMID- 20952189 TI - Substrate inhibition during bio-filtration of TCE using diazotrophic bacterial community. AB - The kinetics of biodegradation of TCE in the biofilter packed with wood charcoal and inoculated with diazotrophic bacterial community had been investigated. Use of Michaelis-Menten type model showed that substrate inhibition was present in the system. The kinetic model proposed by Edwards (1970) was used to calculate kinetic parameters-maximum elimination capacity (EC(max)), substrate constant (K(s)), and inhibition constant (K(I)). The model fitted well with the experimental data and the EC(max) was found to be in the range of 10.8-6.1 g/m(3) h. The K(s) values depended upon substrate concentration and ranged from 0.024 to 0.043 g/m(3) indicating the high affinity of diazotrophs for TCE. The K(I) values were low and nearly constant (0.011-0.015 g/m(3)) indicating a moderate substrate inhibition. PMID- 20952191 TI - Detoxification of corn stover prehydrolyzate by trialkylamine extraction to improve the ethanol production with Pichia stipitis CBS 5776. AB - In order to realize the separated ethanol fermentation of glucose and xylose, prehydrolysis of corn stover with sulfuric acid at moderate temperature was applied, while inhibitors were produced inevitably. A complex extraction was adopted to detoxify the prehydrolyzate before fermentation to ethanol with Pichia stipitis CBS 5776. The best proportion of mixed extractant was 30% trialkylamine 50% n-octanol -20% kerosene. Detoxification results indicated that 73.3% of acetic acid, 45.7% of 5-hydroxymethylfurfural and 100% of furfural could be removed. Compared with the undetoxified prehydrolyzate, the fermentability of the detoxified prehydrolyzate was significantly improved. After 48 h fermentation of the detoxified prehydrolyzate containing 7.80 g/l of glucose and 52.8 g/l of xylose, the sugar utilization ratio was 93.2%; the ethanol concentration reached its peak value of 21.8 g/l, which was corresponding to 82.3% of the theoretical value. PMID- 20952190 TI - Improving the remaining activity of lignocellulolytic enzymes by membrane entrapment. AB - The production of bioethanol by the conversion of lignocellulosic waste has attracted much interest in recent years because of its low cost and great potential availability. However, the high cost of the enzyme required for this conversion is often considered to be the major bottleneck in the commercial lignocellulosic ethanol industry. In this work, the hydrolysis of rice straw by free and entrapped lignocellulolytic enzymes (cellulase, xylanase and laccase) was carried out at pH 5.5 and 37 degrees C. The hydrolysis of rice straw by enzymes entrapped in a membrane produced a higher monosaccharide content: 601.05 mg/g rice straw for entrapped enzymes vs. 465.46 mg/g rice straw for free enzymes. This study has shown that enzyme entrapment is an important technique for the efficient use and reuse of enzymes in industrial applications and also for the rapid separation of saccharide products from the reaction medium, thus improving the remaining enzymatic activities. PMID- 20952192 TI - Influence of fermentation by-products on the purification of ethanol from water using pervaporation. AB - Pervaporation is claimed to be a promising separation technique for the purification of ethanol from fermentation broths during bio-ethanol production. In this study, influence of fermentation by-products on the purification of ethanol from water during hydrophobic pervaporation was investigated. Sugars and salts were found to increase the membrane performance. Reason for this was a change in vapor/liquid equilibrium. 2,3-butanediol decreased the ethanol flux and selectivity factor, while glycerol exhibited no effect. This was explained by a strong sorption of butanediol into PDMS and no sorption of glycerol. Due to the presence of carboxylic acids, hydrophobicity degree of the Pervap 4060 membrane decreased, which resulted in an irreversible increase in water flux and decrease in separation performance. These observations suggested the presence of silicalite-based fillers in the membrane. When the pH was raised to a value above the dissociation constant, no changes in hydrophobicity degree and membrane performance were found. PMID- 20952193 TI - Electricity generation and microbial community response to substrate changes in microbial fuel cell. AB - The effect of substrate changes on the performance and microbial community of two chamber microbial fuel cells (MFCs) was investigated in this study. The MFCs enriched with a single substrate (e.g., acetate, glucose, or butyrate) had different acclimatization capability to substrate changes. The MFC enriched with glucose showed rapid and higher power generation, when glucose was switched with acetate or butyrate. However, the MFC enriched with acetate needed a longer adaptation time for utilizing glucose. Microbial community was also changed when the substrate was changed. Clostridium and Bacilli of phylum Firmicutes were detected in acetate-enriched MFCs after switching to glucose. By contrast, Firmicutes completely disappeared and Geobacter-like species were specifically enriched in glucose-enriched MFCs after feeding acetate to the reactor. This study further suggests that the type of substrate fed to MFC is a very important parameter for reactor performance and microbial community, and significantly affects power generation in MFCs. PMID- 20952194 TI - C-11 diamino cryptolepine derivatives NSC748392, NSC748393, and NSC748394: anticancer profile and G-quadruplex stabilization. AB - G-Quadruplex DNA ligands are promising novel anticancer agents with potentially fewer side effects and greater selectivity than standard anticancer drugs. However, the design of G-quadruplex ligands remains challenging since known chemical features increasing selectivity have often compromised drugability. Three C-11 diamino cryptolepine derivatives, with significant chemical differences between the side chains, low cytotoxicity to mammalian non-tumor cells (Vero cells) and drug-like properties, were selected for anticancer drug screening in the NCI Developmental Therapeutics Program. The three compounds showed good in vitro anticancer profiles with GI(50) averages at sub-micromolar concentrations (0.32-0.78 MUM), cytostatic effects (TGI) at micromolar concentrations (1.3-6.9 MUM) and moderate cytotoxic effects to cancer cells (LC(50)) also at micromolar concentrations (4.7-33 MUM), but only the compound with a linear alkylamine side chain (NSC748393) showed a good score in the in vivo anticancer Hollow Fiber assay. compare analysis of growth inhibition profile of NSC748393 suggested a multi-target mechanism. G-Quadruplex DNA binding affinity and selectivity studies by FRET-melting assays showed that NSC748392 and NSC478393, with aliphatic amine side chains, are good G-quadruplex ligands but not selective, whereas a C-11 aromatic side chain, as in NSC748394, increases selectivity although with decreasing binding affinity. Overall, NSC748393 can be considered a lead molecule for the design of effective but more selective anticancer drugs targeting telomeric G-quadruplexes. PMID- 20952195 TI - Tetrahydrocarboline analogs as MCH-1 antagonists. AB - A new series of tetrahydrocarbolines with potent MCH-1 antagonist activity were synthesized, using a conformationally constrained design approach towards optimizing pharmacokinetic properties. Two compounds from this series were progressed to a 5-day diet-induced obesity mouse screening model to evaluate their potential as weight loss agents. Both compounds produced a highly significant reduction in weight, which was attributed to their improved pharmacokinetic profile. PMID- 20952196 TI - Pyrimidinylmethylphenyl glucoside as novel C-aryl glucoside SGLT2 inhibitors. AB - Novel C-aryl glucoside SGLT2 inhibitors containing pyrimidine motif were designed and synthesized for biological evaluation. Among the compounds assayed, pyrimidine containing methylthio moiety 11 g demonstrated the best in vitro inhibitory activity against SGLT2 in this series to date (IC(50)=10.7 nM). PMID- 20952197 TI - A single, low, oral dose of a 5-carbon-linked trioxane dimer orthoester plus mefloquine cures malaria-infected mice. AB - Four 5-carbon-linked trioxane dimer orthoesters (6a-6d) have been prepared in 4 or 5 chemical steps from the natural trioxane artemisinin (1). When administered orally to malaria-infected mice using a single dose of only 6 mg/kg body weight along with 18 mg/kg of mefloquine hydrochloride, trioxane dimer orthoester sulfone 6d completely and safely cured the mice; after 30 days, the cured mice showed no detectable parasitemia, gained at least as much weight as the control mice (no infection), and behaved normally. PMID- 20952198 TI - Speed- and cane-related alterations in gait parameters in individuals with multiple sclerosis. AB - Previous literature reporting gait parameters in the MS population has largely focused on preferred walking speed without the use of an assistive device. However, these data may not fully represent daily activity, as individuals with MS vary their speed or use a cane when walking. In this exploratory study, 11 MS participants and 13 controls walked at both maximal and preferred speed for a distance of 25-feet. Participants with MS that used a cane daily (n=6) were asked to complete additional trials with their cane. When walking unassisted at both speeds, MS participants displayed significantly reduced velocity, cadence, stride length, step length ratio, single support and swing time, as well as increased double support and stance time compared to controls. Cane use resulted in significantly higher velocities when walking at maximal speeds, and showed significantly improved variability, gait asymmetry, and bilateral coordination at preferred walking speed. In conclusion, the use of a cane may significantly improve gait for individuals with MS. Furthermore, gait parameters should be measured at both maximal and preferred speeds, with and without a cane, as its use may mask underlying gait impairment. PMID- 20952199 TI - Naphthylchalcones induce apoptosis and caspase activation in a leukemia cell line: The relationship between mitochondrial damage, oxidative stress, and cell death. AB - In this study, we investigated the effects of 24 chalcone derivatives from 2 naphthylacetophenone toward a lymphoblastic leukemia cell line (L1210). Three compounds, called R7, R13, and R15, presented concentration- and time-dependent cytotoxicity and induced cellular death by apoptosis via mitochondrial injury and oxidative stress. The effects of these compounds appear to occur through different mechanisms because R13 and R7 induced a greater disturbance of mitochondrial potential, and all compounds induced disturbances of cellular ATP content and increased caspase-3 activity before cellular death. These compounds also interfered with antioxidant enzymes activities and GSH content through different mechanisms. PMID- 20952200 TI - Tip enhanced Raman scattering with adiabatic plasmon focusing tips. AB - Tip-Enhanced Raman spectroscopy (TERS) is a promising microscopy technique which combines, in principle, outstanding spatial resolution with a detailed chemical analysis of the sample. However, as yet, it is not routinely used although an increasing number of research groups are becoming more actively involved in the field. Among the several reasons which can explain the relatively low usage of TERS, the lack of reproducibility of tips as field enhancers is probably the most critical. Here we propose and demonstrate a TERS microscope which uses photonic engineered tips. These tips are based on standard silicon nitride atomic force microscope (AFM) cantilevers. A photonic crystal together with a plasmonic waveguide focuses the Raman excitation laser to the apex of the waveguide, enabling a photon confinement equivalent to the radius of curvature of the nanofabricated tip. These tips were successfully applied here in both AFM imaging and high resolution Raman spectroscopy. The new tips produced AFM imaging performances comparable with the best AFM commercial tips. Moreover, we demonstrate that the photonic crystal combined with the plasmonic waveguide acts effectively as a localized near field emitter. PMID- 20952201 TI - Controlled synthesis and biomolecular probe application of gold nanoparticles. AB - In addition to their optical properties, the ability of gold nanoparticles (Au NPs) to generate table immobilization of biomolecules, whilst retaining their bioactivities is a major advantage to apply them as biosensors. Optical biosensors using Au NPs are simple, fast and reliable and, recently, they have been moving from laboratory study to the point of practical use. The optical properties of Au NPs strongly depend on their size, shape, degree of aggregation and the functional groups on their surface. Rapid advances in the field of nanotechnology offer us a great opportunity to develop the controllable synthesis and modification of Au NPs as well as to study on their properties and applications. The size-controlled growth of Au NPs requires the isotropic growth on the surface of Au nuclei whereas anisotropic growth will induce the formation of Au NPs of varying shape. Functionalized Au NPs provide sensitive and selective biosensors for the detection of many targets, including metal ions, small organic compounds, protein, DNA, RNA and cell based on their optical, electrical or electrochemical signals. In this review, we will discuss the size- and shape controlled growth and functionalization of Au NPs to obtain Au nanoprobes. The basis of the optical detection of Au nanoprobes and their applications in nucleic acid, protein detection and cell imaging are also introduced. PMID- 20952202 TI - Quantification of metals in river water using a portable EDXRF system. AB - This work identified, quantified, and presents results for metals in water using a portable energy dispersive X-ray fluorescence (EDXRF) system. It was possible to quantify the following range of concentrations in mg L(-1): Ca(0.043-0.021), Ti(0.137-0.014), Mn(0.052-0.008), Fe(1.66-0.035), Ni(0.012-0.010), Cu(0.010 0.007), Zn(0.070-0.007), and Pb(1.01-0.85). The final conclusion is that in 4h of field work it was possible to prepare, measure, and analyze 14 membranes. PMID- 20952203 TI - The impact of preoperative body mass index on respiratory complications after pneumonectomy for non-small-cell lung cancer. Results from a series of 154 consecutive standard pneumonectomies. AB - OBJECTIVE: Although it may seem intuitive that obesity is an additional risk factor for surgical patients, few studies have correlated this condition with lung cancer resection. The only data currently available suggest that obesity does not increase the rate of complications after anatomic resection for non small-cell lung cancer (NSCLC). METHODS: We enrolled 154 consecutive patients undergoing standard pneumonectomy for NSCLC at the Department of Thoracic Surgery of the European Institute of Oncology from January 2004 to April 2008. To determine the influence of preoperative body mass index (BMI) on postoperative complications, patients were classified into two groups: (1) BMI >= 25 kg m-2; n = 93 (60.4%); and (2) BMI < 25 kg m-2; n = 61 (39.6%). Data on sex, age, cigarette smoking, preoperative albumin, total proteins and creatinine values, forced expiratory volume in 1s percentage (FEV1%), diffusion lung capacity for carbon monoxide/alveolar volume percentage (DLCO/AV%) and histology and pathological stage were collected. Information on total postoperative complications, 30-day mortality rate, specific pulmonary and cardiac complications, intensive care unit (ICU) admission and hospital stay was collected and analysed for the BMI group. RESULTS: Among the 154 operated patients, 30 (19.5%) were women with a mean age of 63.4 years (range: 36-82). As many as 136 (88.3%) patients were smokers or former smokers; 80 patients (51.9%) received presurgical treatment. A total of 64 (41.6%) right pneumonectomy procedures were performed. Mean +/- SD for preoperative variables were FEV1%: 83.5 +/- 19.2, DLCO/AV: 85.4% +/- 20.3, albumin: 4.07 +/- 0.44 g dl(-1), total proteins: 7.23 +/- 0.59 g dl-1, creatinine: 0.81 +/- 0.23 mg dl-1. Ten patients died within the first 30 days (30-day mortality: 6.5%). The male sex was significantly more prevalent in the high BMI group (p=0.039). The preoperative mean creatinine value was significantly higher in the high BMI group (0.86 mg dl( 1) vs 0.75 mg dl-1, p=0.002) and preoperative DLCO/AV values were better in the high BMI group than in the BMI group < 25 kg m-2 (79.9 vs 88.8, p = 0.009). The high BMI group had a higher incidence of respiratory complications (21.5% vs 4.9% p = 0.005, odds ratio (OR) = 5.3, 95% confidence interval (CI): 1.5, 18.7). No significant differences were observed between the two groups regarding ICU admission, hospital stay, 30-day mortality and total and specific cardiac complications. CONCLUSIONS: The risk of respiratory complications in patients with BMI higher than 25 kg m-2 undergoing pneumonectomy for lung cancer is 5.3 times higher than that of patients with BMI < 25 kg m-2. Thoracic surgeons and anaesthesiologists should be aware of this information before planning elective pneumonectomy in overweight and especially in obese patients. PMID- 20952204 TI - Comparison of a minimized perfusion circuit versus conventional cardiopulmonary bypass. PMID- 20952205 TI - Re: How to perform a haemodialysis using the arterial and venous lines of an extracorporeal life support. PMID- 20952206 TI - Pericardial patch anterior leaflet extension in rheumatic mitral insufficiency. AB - This report describes a technique for anterior leaflet extension using an autologous pericardial patch in patients suffering from rheumatic mitral regurgitation. The technique has recently evolved and now enables us to correct both vertical and transversal fibrotic leaflet retraction. PMID- 20952207 TI - Epigenetic regulation of V(D)J recombination. PMID- 20952208 TI - Advances in aortic valve repair: focus on functional approach, clinical outcomes, and central role of echocardiography. AB - The surgical classification of aortic regurgitation (AR) is based on cusp mobility. Based on this classification, there are 3 classes of AR: type I is defined as normal cusp mobility, type II is defined as excessive cusp mobility, and type III is defined as restricted cusp mobility. Patients often have multiple coexisting mechanisms. Because aortic valve (AV) repair is safe, effective, and durable, it likely will become a mainstream surgical option for the management of significant AR, even in the setting of a bicuspid valve. Intraoperative transesophageal echocardiography has a central role at all stages in AV repair. Before cardiopulmonary bypass, it can accurately diagnose the mechanism of AR to guide operative strategy for successful repair. After separation from cardiopulmonary bypass, it can comprehensively evaluate the AV repair, including the likelihood that the repair will be durable in the long-term. Important echocardiographic predictors of a durable AV repair include the absence of AR, cusp coaptation above the annular plane, a coaptation length >4 mm, and an effective cusp height >8 mm. The clinical applicability of AV repair continues to expand and likely will evolve into a mainstream surgical therapy for AR, including minimally invasive techniques. PMID- 20952209 TI - New-onset graft dysfunction after heart transplantation--incidence and mechanism related outcomes. AB - BACKGROUND: Graft dysfunction (GD) after heart transplantation (HTx) is a major cause of morbidity and mortality. The impact of different pathophysiologic mechanisms on outcome is unknown. In this large, single-center study we aimed to assess the incidence of GD and compare the outcomes with different histopathologic mechanisms of rejection. METHODS: We analyzed a data set of 1,099 consecutive patients after their HTx at Columbia University Medical Center between January 1994 and March 2008, and identified all patients hospitalized with new-onset GD. Based on the histopathologic data, patients were divided into GD-unexplained (Group-GD-U), GD-antibody-mediated rejection (Group-GD-AMR), GD cardiac allograft vasculopathy (Group-GD-CAV) and GD-acute cellular rejection (Group-GD-ACR) groups. We compared the in-hospital and 3-, 6- and 12-month mortality across these groups using the chi-square test. We also compared the 3-, 6- and 12-month survival curves across groups using the log-rank test. RESULTS: Of 126 patients (12%) identified with GD, complete histology data were available for 100 patients. There were 21, 20, 27 and 32 patients identified in Group-GD-U, Group-GD-AMR, Group-GD-CAV and Group-GD-ACR, respectively. The in-hospital mortality rates were 52%, 20%, 15% and 6%, respectively. The in-hospital mortality rate was significantly higher in Group-GD-U compared with all other groups (p = 0.0006). The 3-, 6- and 12-month survival rate was also significantly lower in Group-GD-U compared with all other groups. CONCLUSION: A significant proportion of patients presenting with new-onset GD have unexplained histopathology. Unexplained GD is associated with a significantly higher mortality rate. New diagnostic tools are necessary to better understand and detect/predict this malignant phenotype. PMID- 20952210 TI - Expression of extra domain A containing fibronectin in chronic cardiac allograft rejection. AB - BACKGROUND: Cardiac allograft vasculopathy (CAV) and fibrosis are important in chronic cardiac allograft rejection. The aim of our study was to analyze the up regulation of extra domain A (ED-A) containing fibronectin (ED-A(+) Fn) in cardiac allografts after heterotopic rat heart transplantation using a human recombinant antibody applicable for targeted drug delivery. METHODS: Cardiac allografts were subjected to immunofluorescence double labelling procedures combining a human recombinant small immunoprotein (SIP) format antibody recognizing ED-A(+) Fn (F8) with antibodies recognizing CD31, ASMA or CD45. Protein expression levels of ED-A(+) Fn were measured by quantitative confocal laser scanning microscopy and messenger RNA expression levels by real-time reverse-transcription polymerase chain reaction. RESULTS: A distinct re expression of ED-A(+) Fn was detectable with the F8 antibody, especially in vessel structures exhibiting CAV and in fibrotic areas. ED-A(+) Fn protein deposition but not messenger RNA expression levels increased with rising rejection grade (p <= 0.001). There were clear co-localizations of ED-A(+) Fn and alpha-smooth muscle actin in vessels and in fibrotic areas. CONCLUSIONS: We could show first that ED-A(+) Fn is expressed in rat cardiac allografts in association with CAV and cardiac fibrosis. The protein is detectable with the human recombinant antibody F8 usable for targeted drug delivery to the side of disease. Second, protein expression levels increase with rising rejection grade. Thus, ED A(+) Fn might be usable to monitor and target CAV as well as fibrosis after heart transplantation. PMID- 20952211 TI - BK virus in heart transplant recipients: a prospective study. PMID- 20952212 TI - Neuropathologies of the self: clinical and anatomical features. AB - The neuropathologies of the self (NPS) are disorders of the self and identity that occur in association with neuropathology and include perturbations of the bodily, relational, and narrative self. Right, especially medial-frontal and orbitofrontal lesions, are associated with these conditions. The ego disequilibrium theory proposes this brain pathology causes a disturbance of ego boundaries and functions and the emergence of developmentally immature styles of thought, ego functioning, and psychological defenses including denial, projection, splitting, and fantasy that the NPS patient has in common with the child. I hypothesize that during brain development between approximately ages 3 and 7 immature defensive functions and fantasies tend to be replaced by mature defenses and the inhibition of fantasy a process that depends upon maturational processes within the right hemisphere. I propose a four-tiered model of the NPS that emphasizes a multifactorial approach and includes both negative and positive, bottom up and top down, and neuropsychological and psychological factors. PMID- 20952213 TI - Dissociative tendencies and right-hemisphere processing load: effects on vigilance performance. AB - The present study was designed to explore the relationship between self-reported dissociative experiences and performance in tasks eliciting right-hemisphere processing load. Thirty-four participants (10 men and 24 women) performed a vigilance task in two conditions: with task-irrelevant negative-arousing pictures and task-irrelevant neutral pictures. Dissociation was assessed with the Dissociative Experience Scale. Consistent with theories positing right-hemisphere deregulation in high non-clinical dissociators, dissociative experiences correlated with greater vigilance decrement only in the negative picture condition. As both the vigilance task and negative picture processing are right lateralized, this result provides support for a right-hemisphere dysfunction in high dissociators, at least in negative conditions. PMID- 20952214 TI - Endomyocardial nodular calcification as a cause of heart failure. AB - Massive cardiac calcification is rare, occurring in association with chronic diseases or more commonly with previous myocardial infarction. We present an intriguing case of massive myocardial calcification of the left ventricle in a young patient with restrictive cardiomyopathy and progressive heart failure who required transplantation. The patient's history and clinical presentation did not reveal the etiology of the myocardial calcification. PMID- 20952215 TI - Sodium valproate and highly active antiretroviral therapy in HIV positive patients who develop new onset seizures. AB - Recurrent seizures may occur in up to 11% of HIV positive patients. The aetiology of the seizures includes opportunistic infections, neoplasia, HIV itself, metabolic derangements and drugs. Apart from treating the cause of the seizures, the challenge is to use the appropriate anticonvulsant drug (AED) to avoid potentially adverse drug-drug interactions in patients who are on concurrent highly active antiretroviral therapy (HAART). Initial recommendations were that the newer AEDs should preferably be used because of their simpler pharmacokinetics. We report on our experience with the use sodium valproate (SV) in eight patients who were on concurrent HAART. There were two males and six females with a mean age of 34.1 years. The mean dose of SV was 1075 mg per day. Seizure control was excellent, the CD4 count improved and there was successful viral suppression in all patients. This small study showed that SV was safe and effective. It is also relatively inexpensive compared to the newer AEDs - an important consideration in resource poor settings. PMID- 20952216 TI - Rupture rates of small abdominal aortic aneurysms: a systematic review of the literature. AB - BACKGROUND: Small aneurysms of the abdominal aorta (3.0-5.5 cm in diameter) often are managed by regular surveillance, rather than surgery, because the risk of surgery is considered to outweigh the risk of aneurysm rupture. The risk of small aneurysm rupture is considered to be low. The purpose of this review is to summarise the reported estimates of small aneurysm rupture rates. METHODS AND FINDINGS: We conducted a systematic review of the literature published before 2010 and identified 54 potentially eligible reports. Detailed review of these studies showed that both ascertainment of rupture, patient follow-up and causes of death were poorly reported: diagnostic criteria for rupture were never reported. There were only 14 studies from which rupture rates (as ruptures per 100 person-years) were available. These 14 published studies included 9779 patients (89% male) over the time period 1976-2006 but only 7 of these studies provided rupture rates specifically for the diameter range 3.0-5.5 cm, which ranged from 0 to 1.61 ruptures per 100 person-years. CONCLUSIONS: Rupture rates of small abdominal aortic aneurysms would appear to be low, but most studies have been poorly reported and did not have clear ascertainment and diagnostic criteria for aneurysm rupture. PMID- 20952217 TI - The VIRTUE Registry of type B thoracic dissections--study design and early results. AB - INTRODUCTION: Endovascular procedures for repair of Type B aortic dissection have become increasingly common and are often considered to be first line therapy for acute complicated dissections. The long term durability of these repairs is largely undefined. METHODS: The Virtue Registry is a prospective, non-randomised, multi centre European Clinical Registry designed to inform on the clinical and morphological outcomes of 100 patients with Type B aortic dissection treated with the Medtronic Valiant thoracic stent graft. Patients with acute, sub-acute and chronic Type B dissections will be prospectively followed for three years. Clinical outcomes and aortic morphology will be defined. RESULTS: Fifty patients had an acute dissection, 24 a sub-acute dissection and 26 a chronic lesion. The 30-day mortality for the acute, sub-acute and chronic lesions was 8%, 0% and 0%. The in hospital composite outcome (mortality, stroke or paraplegia) for the three groups was 16%, 0% and 3.8% respectively. The effect of left subclavian artery (LSCA) revascularisation was defined with the composite endpoint of patients with a covered, non-revascularised LSCA being 20% as compared to 5.8% in the covered, revascularised group. CONCLUSION: The early outcomes for the treatment of Type B aortic dissection are reported in the Virtue Registry. Longer term follow-up is planned to report on clinical and morphological outcomes up to 36 months post procedure. PMID- 20952218 TI - Correlation between transcription factor Snail1 expression and prognosis in adenoid cystic carcinoma of salivary gland. AB - OBJECTIVE: Transcription factor Snail1 has a central role in induction of epithelial-mesenchymal transition (EMT). The aim of the present study was to study the association of Snail1 expression with clinicopathologic factors and prognosis in adenoid cystic carcinoma (ACC) of salivary gland. STUDY DESIGN: Demographic variables and primary tumor site, dates of diagnoses, perineural invasion, local regional recurrence, and distant metastasis of 121 cases of salivary ACC were retrieved. The Snail1 expression of all these cases was examined by immunohistochemical methods. The association between Snail1 expression and clinicopathologic variables was analyzed using chi-square test, and the prognostic factors were examined by univariate and multivariate analyses. RESULTS: Our data demonstrated that the positive expression of Snail1 was observed in 58.68% (71/121) of cases. Snail1 expression was significantly associated with histologic pattern, perineural invasion, local regional recurrence, and distant metastasis of patients with ACC (P < .05). And Snail1 expression, local regional recurrence, and distant metastasis were independent and significant prognostic factors in all patients. CONCLUSION: Snail1 may play an important role in the invasion and metastasis of ACC, and Snail1 has the potential for being a strong prognosis indicator at presentation of ACC patients. PMID- 20952219 TI - The detection accuracies for proximal caries by cone-beam computerized tomography, film, and phosphor plates. AB - OBJECTIVES: To evaluate the accuracy of cone-beam computerized tomography (CBCT) for the detection of noncavitated proximal caries and to compare the detection accuracies of 2 CBCT imaging systems with those based on plain-film radiographs and phosphor-plate images. STUDY DESIGN: Test radiographs of 39 noncavitated unrestored human permanent teeth were obtained with film, phosphor-plate, ProMax 3D, and Kodak 9000 3D imaging systems. Seven observers used a 5-level scale to evaluate test images for the presence of proximal caries. With histologic examination serving as the reference standard, observer performances were assessed with receiver operating characteristic (ROC) curves, and the areas under the ROC curves (A(z) values) for the observers, and modalities were analyzed with a repeated-measures analysis of variance. RESULTS: The mean A(z) values for film, phosphor plates, ProMax 3D, and Kodak 9000 3D imaging systems were 0.541, 0.523, 0.528, and 0.525, respectively (P = .763). CONCLUSION: For detecting subtle noncavitated proximal caries, the detection accuracy with the CBCT images was little better than chance performance and was similar to that with phosphor plate and film-based intraoral images. PMID- 20952220 TI - Effective radiation dose of ProMax 3D cone-beam computerized tomography scanner with different dental protocols. AB - OBJECTIVES: The aim of this study was to compare effective doses resulting from different scan protocols for cone-beam computerized tomography (CBCT) using International Commission on Radiological Protection (ICRP) 1990 and 2007 calculations of dose. STUDY DESIGN: Average tissue-absorbed dose, equivalent dose, and effective dose for a ProMax 3D CBCT with different dental protocols were calculated using thermoluminescent dosimeter chips in a human equivalent phantom. Effective doses were derived using ICRP 1990 and the superseding 2007 recommendations. RESULTS: Effective doses (ICRP 2007) for default patient sizes from small to large ranged from 102 to 298 MUSv. The coefficient of determination (R(2)) between tube current and effective dose (ICRP 2007) was 0.90. When scanning with lower resolution settings, the effective doses were reduced significantly (P < .05). CONCLUSIONS: ProMax 3D can provide a wide range of radiation dose levels. Reduction in radiation dose can be achieved when using lower settings of exposure parameters. PMID- 20952221 TI - Methemoglobinemia secondary to over-the-counter Anbesol. AB - BACKGROUND: Methemoglobinemia is a potentially lethal condition which may result from exposure to benzocaine. It must be treated promptly, because it may cause a significant decrease in oxygen delivery to tissues and organs. CASE DESCRIPTION: A 39-year-old caucasian man presented to the emergency department (ED) with dental pain. After a review of systems and a dental exam, an oxygen saturation of 90% was noted. The patient reported no previous cardiac or pulmonary pathology, but did report using a large amount of over-the-counter Anbesol. A second oxygen saturation measurement had fallen to 87%. An arterial blood gas sample was taken, and the patient was found to have high levels of methemoglobin. He was transferred to the critical care ED and treated with 2 mg/kg intravenous methylene blue. CLINICAL IMPLICATIONS: Dentists must be aware of the possible lethal effects of benzocaine toxicity, including methemoglobinemia. It is important to recognize the signs and symptoms and act in a judicious manner. PMID- 20952222 TI - Histomorphometric analysis of different latency periods effect on new bone obtained by periosteal distraction: an experimental study in the rabbit model. AB - OBJECTIVES: The aim of this study was to evaluate the effects of latency period on the bone formation after periosteal distraction. For this purpose, a rabbit model was developed and histologic and histomorphometric analyses were conducted. STUDY DESIGN: Periosteal distractors were custom designed and built from stainless steel. Rabbits were divided into 2 groups of 18 each according to the duration of latency period. In group 1, the latency period was 7 days, and in group 2 it was 1 day. Distraction was performed by activating the distractor 0.25 mm twice per day. A periosteal distraction of 7.0 mm was achieved after a distraction period of 10 days. Both groups were divided to 3 subgroups according to the rabbits being killed on the 15th, 30th, or 60th day of the consolidation period. Histologic and histomorphometric analyses were performed to evaluate the bone formation. RESULTS: In the histologic evaluation, new bone formation was observed on the lateral side of the mandible of all the rabbits. Histomorphometric measurements revealed that the mean area of newly formed bone formation was 2.62 cm(2) in group 1 and 3.26 cm(2) in group 2. CONCLUSIONS: Periosteal distraction osteogenesis is a viable method in acquired and congenital alveolar ridge defects, resulting in new bone formation. Newly formed bone can be obtained by periosteal distraction osteogenesis applying different latency periods. PMID- 20952223 TI - CROOMA, complication rates of operatively treated mandibular fractures, paramedian and body. AB - INTRODUCTION: This retrospective study comprises an exploratory analysis of 10 years of surgical treatment of symphysis (S) and parasymphysis/body (P/B). Correlations of complications, as well as dependencies of surgical concepts, are investigated. MATERIALS AND METHODS: All surgically treated patients in the period of 1995 to 2005 with at least one mandibular fracture mesial to the mandibular angle were included in this study. A total of 63 patients (46 men, 17 women) with 63 symphysis fractures were included and 497 patients (369 men, 128 women) with 553 P/B were included; 99.27% (549) of these fractures were included in the study, 4 had to be dismissed because of inconclusive documentation. RESULTS: Of patients with P/B, 96.04% were successfully treated with 1 open reduction, 3.76% had 2, and 0.20% had 3 surgeries. Of the surgically treated patients, 75.77% (416) were completely free of complications, whereas the other 24.23% of the P/B showed 1 or more complications. The main complication was mild nerve damage (24.8%). Osteosynthesis failure rate (OFR) was 2.4% (7 of 298) for 2 miniplates, 5.7% (3 of 53) for 1 tension screw, and 8.4% (9 of 107) for 1 miniplate. Regarding OFR, 2 miniplates showed to be superior in a Fisher exact test (P = .018, adjusted P = .132). Symphysis fractures were completely free of complications in 81.8% and showed 2 major complications, i.e., 1 severe nerve damage and 1 osteosynthesis failure. DISCUSSION: This study has the limitations of a retrospective study. CONCLUSION: A high success rate of open reduction and osteosynthesis with 2 miniplates can be guaranteed. PMID- 20952224 TI - Osteomyelitis after bilateral sagittal split osteotomy: case report and a review of the management. AB - OBJECTIVES: The purpose of this paper is to report a case of osteomyelitis following a bilateral sagittal split osteotomy in a patient who underwent 2-jaw surgery. A review of the management of osteomyelitis is included, with a discussion of implications for the reconstruction of the mandible after treatment for osteomyelitis. STUDY DESIGN: A case of a rapidly progressing osteomyelitis is presented with a detailed review of the management of osteomyelitis, using this case to illustrate key points of management. RESULTS: In a very short period of time the patient lost a significant portion of the left side of her mandible. The actual management that she underwent, as well as some of the controversies that are present with the treatment of osteomyelitis, is discussed. CONCLUSION: Although osteomyelitis of the mandible usually is seen after odontogenic infections and trauma, it can occur in patients undergoing elective osteotomies. When recognized, it should be aggressively treated. PMID- 20952225 TI - Simvastatin-loaded porous implant surfaces stimulate preosteoblasts differentiation: an in vitro study. AB - OBJECTIVE: Recent studies demonstrate that simvastatin stimulates bone formation, suggesting the potential application in dental implantology. In this study, our lab developed a simvastatin-loaded titanium porous surface. The aim was to investigate the effect of simvastatin-loaded titanium surfaces on the promotion of osteogenesis in preosteoblasts (MC3T3-E1) in vitro. STUDY DESIGN: The control group consisted of cells cultured on titanium disks without any intervention for different time intervals (4, 7, and 14 days), and the experimental groups (simvastatin-loaded groups) consisted of cells cultured on titanium disks that were preincubated in varying concentration (10(-7) mol/L, 10(-6) mol/L, 10(-5) mol/L, and 10(-4) mol/L) of simvastatin for the same time intervals of the control group. Alkaline phosphatase (ALP) activity, type I collagen synthesis, and osteocalcin release were used to measure the cellular osteoblastic activities. RESULTS: All simvastatin-loaded groups showed increased ALP activity compared with the control group at every time point, especially the 10(-7) mol/L group, which significantly increased the activity almost fourfold at 4 days (P < .05). In the type I collagen synthesis assay, all simvastatin-loaded groups showed an increase, and the effect was inverse dose dependent (maximal at 10(-7) mol/L). This stimulatory effect of simvastatin was also observed in the osteocalcin release assay (P < .05; at 10(-7) mol/L, 10(-6) mol/L, maximal at 10( 7) mol/L). CONCLUSION: These results indicate that simvastatin-loaded porous implant surfaces promote accelerated osteogenic differentiation of preosteoblasts, which have the potential to improve the nature of osseointegration. PMID- 20952226 TI - Lymphoepithelioma-like carcinoma of head and neck skin: a systematic analysis of 11 cases and review of literature. AB - Lymphoepithelioma-like carcinoma of the skin (LELCS) is a rare tumor of unknown etiology, low malignant potential, and microscopic resemblance to undifferentiated nasopharyngeal carcinoma. Clinically, it presents as a flesh colored firm nodule or plaque on the face, scalp, or shoulder of middle-aged to elderly individuals. Histologically, LELCS is composed of islands of enlarged epithelial cells with large vesicular nuclei surrounded and permeated by a dense lymphoplasmacytic infiltrate. LELCS exhibits immunoreactivity with high-molecular weight cytokeratins and epithelial membrane antigen, indicating the epithelial origin. The differential diagnosis includes basal cell carcinoma, squamous cell carcinoma, lymphoma, pseudolymphoma, and Merkel cell carcinoma. We report 11 cases of LELCS of the head and neck region with discussion of the clinical, histopathologic, immunohistochemical, and therapeutic aspects of this rare cutaneous neoplasm. In addition, we systematically review and compare the findings with the previously published cases of LELCS. This study is the largest case series of LELCS reported in the English-language literature. It attempts to more clearly define the diagnostic criteria for LELCS. Its histomorphologic and immunophenotypic features help distinguish this tumor from similar-appearing malignancies, including metastatic nasopharyngeal carcinoma. PMID- 20952227 TI - Up-regulation of EGF receptor and its ligands, AREG, EREG, and HB-EGF in oral lichen planus. AB - OBJECTIVE: This study aimed to investigate the roles of the epidermal growth factor receptor (EGFR) family members and their ligands in oral lichen planus (OLP). STUDY DESIGN: The expressions of 4 EGFR-like receptors and 6 EGF-like ligands were measured in OLP tissues from 10 patients and compared with the levels in normal oral mucosa (NOM) from 10 healthy donors. RESULTS: Of the receptors, only EGFR mRNA and protein were more highly expressed in OLP compared with NOM tissues. Regarding the ligands, the mRNAs of amphiregulin (AREG), epiregulin (EREG), and heparin-binding EGF-like growth factor (HB-EGF) were more highly expressed in OLP compared with NOM tissues. These ligands were strongly expressed by infiltrating lamina propria lymphocytes as well as epithelial keratinocytes in OLP lesions, as shown by immunohistochemistry. CONCLUSIONS: The enhanced EGFR expression on the keratinocytes in OLP lesions and the up regulation of EGF-like ligands in keratinocytes and infiltrating mononuclear cells could contribute to the carcinogenesis and pathogenesis of OLP. PMID- 20952228 TI - Prevention of relapse following intraoral vertical ramus osteotomy mandibular setback: can coronoidotomy help? AB - OBJECTIVE: Relapse after intraoral vertical ramus osteotomy (IVRO) is a subject of debate. The impact of the temporalis muscle on relapse has led to modifications, including liberating the temporalis muscle from the coronoid process or removing the coronoid process itself. The objective of this study was to evaluate the effect of coronoidotomy in preventing relapse after IVRO. STUDY DESIGN: Fifty-six patients with mandibular prognathism, selected for IRVO, were studied within a 21-month period. These patients were randomly divided into 2 groups. The patients were matched regarding cephalometric norms. The case group underwent the IVRO plus coronoidotomy, whereas the control group underwent the simple IVRO. Relapse ratio within the first year was compared between groups. Significant relapse was defined as relapse >30% of the primary setback. RESULTS: Twenty-seven patients in the study group and 29 patients in the control group were followed. The mean relapse ratio 1 year after surgery in B, menton, and pogonion points were greater in control subjects. The mean relapse ratio for ANB and SNB angle 1 year after surgery compared with the primary setback ratio was more in control subjects. CONCLUSION: This study suggests that IVRO along with coronoidotomy was slightly better than IVRO without coronoidotomy for treatment of mandibular prognathism. PMID- 20952229 TI - Anatomy of impacted lower third molars evaluated by computerized tomography: is there an indication for 3-dimensional imaging? AB - OBJECTIVE: Surgical removal of impacted third molar is one of the most frequent procedures in oral surgery. Today 3-dimensional (3D) imaging is occasionally used. The aim of this study was to describe and estimate the frequencies of anatomic variations of lower third molars in patients with panoramic findings at high risk for inferior alveolar nerve (IAN) injury. STUDY DESIGN: The investigators designed and implemented a retrospective cases series study with a study population composed of patients presenting with an impacted lower third molar with projection of the tooth over the full width of the IAN in panoramic radiograph and, therefore, 3D imaging before a planned surgical removal. Spatial relationship to the IAN, type of angulation, root configuration and maturation were primary study variables. Descriptive statistics were computed for all variables. RESULTS: A total of 707 wisdom teeth in 472 patients (54% female, 46% male) were evaluated. A close relationship to the IAN was seen in 69.7%, and in 45.1% the diameter of the mandibular canal was reduced. In 52.8% the IAN was vestibular and in 37.3% lingual to the roots; there were 9.9% with an inter- or intraroot course. Most teeth had 1 or 2 roots (86.7%), but 13.3% had >=3 roots. Mesial angulation was the main type (40.2%), followed by vertical (29%), horizontal (13.9%), distal (10.2%), and transverse (6.8%) positions. CONCLUSION: Based on the range of variations in the course of the nerve and the number of roots the authors recommend 3D imaging before surgical removal of a lower third molar that shows signs of a close relationship to the IAN. PMID- 20952230 TI - Development of pediatric sleep questionnaires as diagnostic or epidemiological tools: a brief review of dos and don'ts. AB - Questionnaires are a useful and extensively used tool in clinical sleep medicine and in sleep research. The number of sleep questionnaires targeting the pediatric age range has tremendously increased in recent years, and with such explosion in the number of instruments, their heterogeneity has become all the more apparent. Here, we explore the theoretical and pragmatic processes required for instrument design and development, i.e., how any questionnaire, inventory, log, or diary should be created and evaluated, and also provide illustrative examples to further underline the potential pitfalls that are inherently embedded in every step of tool development. PMID- 20952231 TI - Identification of stable and oestrus cycle-independent housekeeping genes in the rat mammary gland and other tissues. AB - The function and development of the rat mammary gland is dependent on the oestrus cycle. Normalization of gene expression in mammary gland samples assessed by quantitative RT-PCR therefore requires housekeeping genes (HKGs) which are stably expressed during the oestrus cycle. mRNA expression of 10 HKGs was measured in the rat mammary gland at different phases of the oestrus cycle. In addition, mRNA expression of the HKGs was measured in a panel of other rat tissues comprising laser microdissected mammary gland alveolar lobules and interlobular connective tissue and macrodissected mammary gland, liver, skeletal muscle, colon and ovary samples. Expression and ranking of HKGs varied between tissues and oestrus cycle phases and several HKGs were necessary for normalization between samples. In the mammary gland samples, three HKGs (Sdha, Tbp, and Atp5b) were identified as the optimal combination of stably expressed genes across oestrus cycle phases. For normalization between samples from the entire panel of rat tissues, eight HKGs (Rps18, Eef1a1, B2m, Actb, Tbp, Hprt, Pgk1, and Sdha) were identified as the optimal combination. These HKGs are of general relevance for studies comparing gene expression between different rat tissues. PMID- 20952232 TI - IPAP-HSQMBC: measurement of long-range heteronuclear coupling constants from spin state selective multiplets. AB - A new NMR approach is proposed for the measurement of long-range heteronuclear coupling constants ((n)J(XH), n>1) in natural abundance molecules. Two complementary in-phase (IP) and anti-phase (AP) data are separately recorded from a modified HSQMBC experiment and then added/subtracted to provide spin-state selective alpha/beta-HSQMBC spectra. The magnitude of (n)J(XH) can be directly determined by simple analysis of the relative displacement between alpha- and beta-cross-peaks. The robustness of this IPAP-HSQMBC experiment is evaluated experimentally and by simulation using a variety of different conditions. Important aspects such as signal intensity dependence and presence of unwanted cross-talk effects are discussed and examples on the measurement of small proton carbon ((n)J(CH)) and proton-nitrogen ((n)J(NH)) coupling constants are provided. PMID- 20952233 TI - Prediction of toxicity and data exploratory analysis of estrogen-active endocrine disruptors using counter-propagation artificial neural networks. AB - In this work, a novel algorithm for optimization of counter-propagation artificial neural networks has been used for development of quantitative structure-activity relationships model for prediction of the estrogenic activity of endocrine-disrupting chemicals. The search for the best model was performed using genetic algorithms. Genetic algorithms were used not only for selection of the most suitable descriptors for modeling, but also for automatic adjustment of their relative importance. Using our recently developed algorithm for automatic adjustment of the relative importance of the input variables, we have developed simple models with very good generalization performances using only few interpretable descriptors. One of the developed models is in details discussed in this article. The simplicity of the chosen descriptors and their relative importance for this model helped us in performing a detailed data exploratory analysis which gave us an insight in the structural features required for the activity of the estrogenic endocrine-disrupting chemicals. PMID- 20952234 TI - Leishmaniasis, an emerging infection in travelers. AB - Leishmaniasis is a vector-borne protozoan infection with a wide clinical spectrum, which ranges from asymptomatic infection to fatal visceral leishmaniasis. A review of the recent literature indicates a sharp increase in imported leishmaniasis cases in developed, non-endemic countries over the last decade, in association with increasing international tourism, military operations, and the influx of immigrants from endemic countries. South America is the main area for the acquisition of cutaneous leishmaniasis, and adventure travelers on long-term trips in highly-endemic forested areas are at particular risk. Popular Mediterranean destinations are emerging as the main areas of acquisition of visceral leishmaniasis for European travelers. Leishmaniasis should be considered in patients presenting with a compatible clinical syndrome and a history of travel to an endemic area, even if this occurred several months or years ago. Appropriate counseling should be provided to adventure travelers, military personnel, researchers, and other groups of travelers likely to be exposed to sandflies in endemic areas. PMID- 20952235 TI - Geographical variation in human papillomavirus prevalence in Mexican women with normal cytology. AB - OBJECTIVE: To determine the prevalence of human papillomavirus (HPV) infection and genotype distribution in Mexican women with similar lifestyles from two geographical regions who receive medical care from the Mexican Navy Health System, and to identify the associated sociodemographic and reproductive characteristics. METHODS: Cervical swabs from 671 women, beneficiaries of the Mexican Navy Health System, from two distinct southern coast regions of Mexico, were analyzed. Data were obtained regarding sociodemographic variables and sexual and reproductive history. For HPV detection and typing, PCR with general primers and direct sequencing were performed on extracted DNA. Association with clinical variables was evaluated. RESULTS: Most patients had a normal cytology or low grade intraepithelial neoplasia. A high prevalence of HPV was found (43.6%), with a significant difference between the two regions studied from the southwest Pacific coast of Mexico (37.6% in Acapulco, Guerrero vs. 49.7% in Lazaro Cardenas, Michoacan). Some differences were also found associated to HPV type distribution, particularly related to genotypes 18, 58, and 53. Factors influencing these differences could not be identified with the analysis of typical risk factors linked to the acquisition of an HPV infection. CONCLUSIONS: Regional differences in HPV prevalence and distribution show an apparent geographic boundary between the studied populations that deserves further analysis, taking into account other factors such as those related to the sexual partners. PMID- 20952236 TI - Immunofluorescence assay in India for confirmation of HIV-1 infection using a T cell line infected with defective HIV-1. AB - BACKGROUND: In India, the enzyme immunoassay (EIA)/rapid test is used for screening and confirmatory antibody testing of HIV infection, and all HIV reactive samples are further confirmed by two other rapid tests working on different principles; however, Western blotting (WB) and immunofluorescence (IF) assays are not routinely performed in this country. METHODS: A total of 2104 sera from Indian subjects were tested for the presence of HIV-1 antibody using EIA/rapid tests, according to the guidelines of the National AIDS Control Organization of India, and were also subjected to IF test using L-2 cells persistently infected with defective HIV-1. WB and a nested reverse transcriptase polymerase chain reaction (RT-PCR) were performed on discrepant samples. RESULTS: IF results were 100% concordant with EIA/rapid tests for 212 HIV-1-positive samples and 1889 HIV-1-negative samples. Interestingly, three (0.14%) samples negative by EIA/rapid tests were weakly or moderately positive (1+/2+) by IF test. All three of these samples were confirmed to be negative by WB (reactive with Gag/Pol, but not with Env), but positive by RT-PCR with primers targeting the C2-V5 fragment of the env gene. These three samples were from individuals who voluntarily reported for HIV testing because of high-risk practices, and they may have been at an early stage of HIV infection. CONCLUSIONS: These results confirm that the IF test using L-2 cells is a sensitive and specific alternative method for confirmation of HIV-1 infection and could be included in the diagnostic algorithm in reference laboratories in developing countries. PMID- 20952237 TI - The largest outbreak of hand; foot and mouth disease in Singapore in 2008: the role of enterovirus 71 and coxsackievirus A strains. AB - BACKGROUND: During 2008, Singapore experienced its largest ever outbreak of hand, foot and mouth disease (HFMD), resulting in 29686 cases, including four cases of encephalitis and one fatality. METHODS: A total of 51 clinical specimens from 43 patients with suspected HFMD at the National University Hospital, Singapore were collected for virus isolation and identification by reverse transcription polymerase chain reaction (RT-PCR) and sequencing. RESULTS: Enteroviruses were identified in 34 samples (66.7%), with 11 samples (21.6%) being positive for enterovirus 71 (EV71). Other non-EV71 enteroviruses (including coxsackievirus A4, A6, A10, and A16) were identified in 23 samples (45.1%). The most prevalent virus serotypes were CA6, CA10, and EV71. CA6 and CA10 accounted for 35.3% of all HFMD cases, which may explain the high transmissibility and low fatality that characterized this unprecedented epidemic associated with relatively mild disease. Phylogenetic analyses of 10 circulating EV71 strains indicated that they belonged to two subgenogroups, i.e., B5 (80%) and C2 (20%). The VP1 sequences of the 2008 EV71 strains also exhibited continuous mutations during the outbreak, reflecting the relatively high mutation rate of the EV71 capsid protein, which may have implications for future vaccine development. CONCLUSIONS: A safe and effective vaccine against EV71 is certainly warranted in view of its potential neurovirulence and its role in HFMD epidemics of recurring frequency with resultant fatalities in Asia, as well as other parts of the world. PMID- 20952238 TI - Genetic analysis of the rhabdomyolysis-associated genes in forensic autopsy cases of methamphetamine abusers. AB - Methamphetamine (MA) use sometimes causes rhabdomyolysis, which has been associated with mortality. We analyzed potential rhabdomyolysis-susceptibility genes from autopsy samples of 18 methamphetamine abusers. We examined mutations in the ryanodine receptor 1 (RYR 1), carnitine palmitoyltransferase II (CPT II), very long-chain acyl-CoA dehydrogenase (VLCAD), and cytochrome P450 (CYP) 2D6 genes. Different RYR1 mutations that caused amino acid substitutions ((612)Ala>Thr and (4295)Ala>Val) were identified in 2 cases. In the CPT II gene, there was a new mutation ((545)Glu>Ala) in 1 case and there were mutations that did not change activity in 17 cases. In the VLCAD gene, there were mutations that did not change activity in 6 cases. In the CYP2D6 gene, homozygosity for CYP2D6*10, which is associated with significantly reduced metabolic activity, was found in 3 cases, while 2 cases carried a different previously unreported missense mutation ((344)Arg>Gln and (48)His>Tyr). RYR1 mutations and the new CPT II mutation identified in this study were not observed in a control group. Eighteen cases that were genetically analyzed were also investigated immunohistochemically to diagnose the possibility of rhabdomyolysis. However, there were no significant mutations that reduced enzyme activity in the suspected cases of rhabdomyolysis. These data suggested no obvious relationship between the genetic mutations observed in this study and rhabdomyolysis. PMID- 20952239 TI - Comments on "Interpreting Y chromosome STR haplotype mixture". PMID- 20952240 TI - Efficacy of extended kinship analyses utilizing commercial STR kit in establishing personal identification. AB - Unprecedented fidelity and specificity have afforded DNA testing its long reigning status as the gold standard for establishing personal identification. While the method itself is flawless, forensic experts have undoubtedly stumbled across challenging cases in which no reference samples for an unknown person (UP) are available for comparison. In such cases, experts often must resort to an assortment of kinship analyses-primarily those involving alleged parents or children of a UP-to establish personal identification. The present study derives likelihood ratio (LR) distributions from an extensive series of kinship simulations and places actual data, obtained from 120 cases in which personal identification of a UP was established via kinship analyses, to a comprehensive comparison in order to evaluate the efficacy of kinship assessments in establishing personal identification. A commercially available AmpFlSTR Identifiler kit was used to obtain DNA profiles. UP DNAs were extracted and isolated from fingernail (n=87), cardiac blood (24), carpal bone (7) and tooth (2). Buccal cells were procured from alleged kin (AK) for subsequent kinship analyses. In 72 cases 1-3 alleged children were available for comparison; in 46 cases, one or both alleged parents were available; and in the final 2 cases (involving a pair of bodies discovered together in a dwelling), their alleged children were typed for comparison. For each case a LR was calculated based on the DNA typing results. Interestingly, we found that the median LR observed in the actual cases virtually mirrored those of the simulations. With exception to 2 cases in which a silent allele was observed at D19S433, biological relatives showed a LR greater than 100 and in these cases, kinship between the UP and AK were further supported by additional forms of evidence. We show here that in the vast majority of identification cases where direct reference samples are unavailable for a UP, kinship analyses referring to alleged parents/children and using 15 standard loci is more than capable of establishing the identification of a UP. However, discretion should be advised for silent alleles which-albeit rare are known to occur at loci such as D19S433, along with other mutations which could render a deceivingly reduced LR. PMID- 20952241 TI - A preliminary biomechanical study of a novel carbon-fibre hip implant versus standard metallic hip implants. AB - Total hip arthroplasty is a widespread surgical approach for treating severe osteoarthritis of the human hip. Aseptic loosening of standard metallic hip implants due to stress shielding and bone loss has motivated the development of new materials for hip prostheses. Numerically, a three-dimensional finite element (FE) model that mimicked hip implants was used to compare a new hip stem to two commercially available implants. The hip implants simulated were a novel CF/PA12 carbon-fibre polyamide-based composite hip stem, the Exeter hip stem (Stryker, Mahwah, NJ, USA), and the Omnifit Eon (Stryker, Mahwah, NJ, USA). A virtual axial load of 3 kN was applied to the FE model. Strain and stress distributions were computed. Experimentally, the three hip stems had their distal portions rigidly mounted and had strain gauges placed along the surface at 3 medial and 3 lateral locations. Axial loads of 3 kN were applied. Measurements of axial stiffness and strain were taken and compared to FE analysis. The overall linear correlation between FE model versus experimental strains showed reasonable results for the lines-of-best-fit for the Composite (Pearson R(2)=0.69, slope=0.82), Exeter (Pearson R(2)=0.78, slope=0.59), and Omnifit (Pearson R(2)=0.66, slope=0.45), with some divergence for the most distal strain locations. From FE analysis, the von Mises stress range for the Composite stem was much lower than that in the Omnifit and Exeter implants by 200% and 45%, respectively. The preliminary experiments showed that the Composite stem stiffness (1982 N/mm) was lower than the metallic hip stem stiffnesses (Exeter, 2460 N/mm; Omnifit, 2543 N/mm). This is the first assessment of stress, strain, and stiffness of the CF/PA12 carbon fibre hip stem compared to standard commercially-available devices. PMID- 20952242 TI - Calibration of the finite element model of a lumbar functional spinal unit using an optimization technique based on differential evolution. AB - The development of a finite element model of the lumbar spine usually involves choosing among available alternatives to decide which values should be assigned to the material properties of the different spinal structures. Furthermore, the model has to be validated so that a reasonable approximation to the mechanical response of the lumbar spine is achieved. One approach for choosing such material properties involves calibrating the model by choosing the properties that produce the best fit with the in vitro mechanical response of the lumbar spine. This study proposes the use of an optimization method based on differential evolution to calibrate the finite element model of a functional spinal unit. Calibration was performed using reported in vitro data on the mechanical response of an intact lumbar functional unit and its successive reduced stages after the dissection of ligaments, facet joints, vertebral arch and nucleus pulposus. The loading conditions in the study were pure moments in flexion, extension, lateral bending and axial rotation. Considering all dissection stages and loading conditions, the maximum difference in vertebral rotation between the in vitro data and the model results was only 1.24 degrees . Other model results such as facet loads and annulus fibrosus behavior also correlated well with reported data. PMID- 20952243 TI - Measurement of patient-centered outcomes in Parkinson's disease: what do patients really want from their treatment? AB - BACKGROUND: Parkinson's disease (PD) impacts several domains of functioning, some of which may be neglected when designing treatment or evaluating outcome using current clinical standards. We therefore argue that taking the patients' perspectives of their condition may allow for a more in-depth assessment of patient goals and subsequent tailoring of care. METHODS: One hundred and forty eight patients with idiopathic PD completed a modified version of the Patient Centered Outcomes Questionnaire (PCOQ-PD), to evaluate treatment success and expectations from the patient's perspective across 10 motor and non-motor functional domains. We also examined patient subgroups based on importance of improvement in various domains. RESULTS: Patients' ratings suggested there was substantial variation in functional interference that was generally unrelated to demographic variables. On average, across all domains, patients indicated a 50.32% reduction in symptoms would be successful (range = 40.63-58.23%), regardless of treatment experience. Change scores between patients' usual levels of symptom interference and their treatment success levels suggested a greater degree of change was desired in motor versus non-motor domains (p < 0.05). Finally, cluster analyses revealed two patient subgroups based on overall importance of improvement (High vs. Low Importance Endorsement). Notably, the two groups differed in self-reported usual symptom levels despite having similar clinical severity. CONCLUSIONS: We empirically examined treatment success from the PD patient's view as opposed to clinician judgment alone, thereby broadening the set of criteria by which to evaluate outcome. Findings from this exploratory study may guide future treatment emphases and guide patient-provider communication via clarification of patient-defined success. PMID- 20952244 TI - Manual or exercise therapy for long-standing adductor-related groin pain: a randomised controlled clinical trial. AB - HYPOTHESIS: A multi-modal treatment program (MMT) is more effective than exercise therapy (ET) for the treatment of long-standing adductor-related groin pain. STUDY DESIGN: Single blinded, prospective, randomised controlled trial. METHODS: PATIENTS: Athletes with pain at the proximal insertion of the adductor muscles on palpation and resisted adduction for at least two months. INTERVENTIONS: ET: a home-based ET and a structured return to running program with instruction on three occasions from a sports physical therapist. MMT: Heat, Van den Akker manual therapy followed by stretching and a return to running program. PRIMARY OUTCOME: time to return to full sports participation. SECONDARY OUTCOME MEASURES: objective outcome score and the visual analogue pain score during sports activities. Outcome was assessed at 0, 6, 16 and 24 weeks. RESULTS: Athletes who received MMT returned to sports quicker (12.8 weeks, SD 6.0) than athletes in the ET group (17.3 weeks, SD 4.4. p = 0.043). Only 50-55% of athletes in both groups made a full return to sports. There was no difference between the groups in objective outcome (p = 0.72) or VAS during sports (p = 0.12). CONCLUSIONS: The multi-modal program resulted in a significantly quicker return to sports than ET plus return to running but neither treatment was very effective. PMID- 20952245 TI - Chemically modified antibodies as diagnostic imaging agents. AB - Notable new applications of antibodies for imaging involve genetically extracting the essential molecular recognition properties of an antibody, and in some cases enhancing them by mutation, before protein expression. The classic paradigm of intravenous administration of a labeled antibody to image not only its target but also its metabolism can be improved on. Protocols involving molecular targeting with an engineered unlabeled protein derived from an antibody, followed by capture of a small probe molecule that provides a signal, are being developed to a high level of utility. This is accompanied by new strategies for probe capture such as irreversible binding, incorporation of engineered enzyme active sites, and antibody-ligand systems that generate a signal only upon binding or uptake. PMID- 20952246 TI - Cytokeratin 8/18 monoclonal antibody is dissimilar to anti-cytokeratin CAM 5.2 reagent--Comment on: "Oral metastatic hepatocellular carcinoma: A changing demographic in Europe and North America. Immunohistochemical advances in the microscopic diagnosis. Oral Oncol. 2010 Aug 20 [Epub ahead of print]". PMID- 20952247 TI - Transcriptional repression of DLEC1 associates with the depth of tumor invasion in oral squamous cell carcinoma. AB - The objective of this study was to clarify the expression and epigenetic regulation of DLEC1, a candidate tumor suppressor gene (TSG) located at 3p21.3 p22, in oral squamous cell carcinoma (OSCC) and the clinical relevance of its down-expression. Quantitative RT-PCR was performed to exam the expression level of DLEC1 in matched OSCC and normal oral samples from 57 prospectively enrolled patients (with additional matched leukoplakia samples from 9 patients). We defined DLEC1 down-expression as a 2-fold decrease in expression of DLEC1 between normal tissues and tumors, and determined its correlation with clinical characteristics. Methylation-specific PCR (MSP) and bisulfite sequencing were used to evaluate the promoter methylation status of DLEC1 in 19 OSCC, 19 oral leukoplakia (OL), and 17 normal oral tissues. A statistically significant association between DLEC1 down-expression and invasive depth of OSCC was observed (P=0.026). Besides, expression of DLEC1 decreased sequentially from normal tissues to OL and then to OSCC (P<0.05), which was inversely correlated with methylation status of the DLEC1 promoter. Promoter methylation of DLEC1 increased progressively among normal tissues, OL, and OSCC, as revealed by MSP, and confirmed by sequencing. Treatment of OSCC cell lines with 5-aza-2'-deoxycytidine (5-Aza-dC) reversed the methylation and restored DLEC1 expression. Our results demonstrating that down-expression and promoter methylation of DLEC1 increased from normal tissues to premalignancies and then to malignancies. Furthermore, its transcriptional repression is associated with the depth of tumor invasion. PMID- 20952248 TI - Comment on "Acute toxicity of three versus two courses of cisplatin for radiochemotherapy of locally advanced squamous cell carcinoma of the head and neck (SCCHN): a matched pair analysis", by Rades et coll. PMID- 20952249 TI - Childhood myocarditis and parvovirus B19 genotypes. AB - BACKGROUND: Human parvovirus B19 (PVB19) infection is occasionally associated with acute myocarditis. Three cases of children with PVB19 virus-associated myocarditis occurred in a very short period and the same geographical region. OBJECTIVE: To elucidate if virological factors could be responsible for determining the course of infection, a molecular epidemiologic investigation was performed. STUDY DESIGN: The diagnosis of myocarditis was established by histology or echocardiography. In the three cases, the PVB19 DNA was detected in different samples. Eight different regions were amplified by PCR using a high fidelity Taq polymerase and sequenced on both strands. Phylogenetic analyses were performed. First, the genotypes of the PVB19 strains were determined, then the intra-patient viral variability was analysed by sequencing PVB19 detected in different specimens sampled from the same patient at the same moment. RESULTS: Nearly complete sequences of the PVB19 virus (4265nt) were obtained from different samples in the three patients. The phylogenetic analyses showed that PVB19 strains identified clustered with genotype 1a PVB19 strains referenced in GenBank. When compared to the referenced strain NC_000883, the number of substitutions (transitions and transversions) were as follows: 58 for Caen.FRA/19.09, 74 for Caen.FRA/21.09 and 60 for Caen.FRA/24.09. The strains isolated from the same patient showed 100% of similarity. CONCLUSIONS: Viral myocarditis is a frequently unrecognized cause of post-inflammatory cardiomyopathy. The detailed molecular analyses do not give rise to virological markers associated with myocarditis in these children. PMID- 20952250 TI - High plasma mid-regional pro-adrenomedullin levels in children with severe dengue virus infections. AB - BACKGROUND: Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is characterized by hemorrhage, plasma leakage and shock. Adrenomedullin and vasopressin are vaso-active hormones that mediate endothelial permeability, vascular tone and water balance and may therefore play a role during DHF/DSS. Adrenomedullin reduces endothelial permeability and has vasodilatory properties, while vasopressin is a potent vasoconstrictor with anti-diuretic effects. OBJECTIVES: To determine mid-regional pro-adrenomedullin (MR-proADM) and copeptin, which are reliable and stable markers for adrenomedullin and vasopressin response, respectively, and relate their plasma concentrations to outcome and markers of plasma leakage in Indonesian children with DHF and DSS. STUDY DESIGN: In this observational cohort study Indonesian children with DHF/DSS were enrolled. On study days 0 and 2, plasma MR-proADM and copeptin concentrations as well as parameters of plasma leakage were determined. Plasma MR proADM and copeptin concentrations were compared to values of healthy controls. RESULTS: MR-proADM was increased in both DHF (n=43) and DSS (n=28) vs. controls (n=17), with median (IQR) values of 0.47 (0.40-0.68), 0.56 (0.44-1.00) vs. 0.22 (0.19-0.29) nmol/L, respectively. Additionally, MR-proADM correlated with signs of increased vascular leakage such as low albumin and increased pleural effusion. Copeptin concentrations showed no significant changes as compared to controls. CONCLUSIONS: MR-proADM concentrations are elevated in children with DHF and DSS and correlate with the severity of plasma leakage, in contrast to copeptin concentrations. We speculate that adrenomedullin has a functional role in limiting endothelial hyperpermeability during DHF/DSS. Finally, MR-proADM may be a candidate biomarker to predict development of DHF/DSS. PMID- 20952251 TI - Stenotrophomonas maltophilia strains from cystic fibrosis patients: genomic variability and molecular characterization of some virulence determinants. AB - The genetic relatedness of 52 Stenotrophomonas maltophilia strains, collected from various environmental and clinical sources, including cystic fibrosis (CF) patients, as well as the presence and the expression of some virulence-associated genes were studied. Pulsed-field gel electrophoresis (PFGE) analysis identified 47 profiles and three clusters of isolates with an identical PFGE pattern considered to be indistinguishable strains. Restriction fragment length polymorphism of the gyrB gene grouped the 52 strains into nine different profiles. Most CF clinical isolates (29 out of 41) showed profile 1, while the analysis of the hypervariable regions of the 16S rRNA gene revealed five distinct allelic variations, with the majority of CF isolates (23 out of 41) belonging to sequence group 1. Furthermore, the strains were characterized for motility and expression of virulence-associated genes, including genes encoding type-1 fimbriae, proteases (StmPr1 and StmPr2) and esterase. All S. maltophilia strains exhibited a very broad range of swimming and twitching motility, while none showed swarming motility. A complete smf-1 gene was PCR-amplified only from clinically derived S. maltophilia strains. Finally, the virulence of representative S. maltophilia strains impaired in the expression of proteases and esterase activities was evaluated by infecting larvae of the wax moth Galleria mellonella. The results obtained strongly indicate that the major extracellular protease StmPr1 may be a relevant virulence factor of S. maltophilia. PMID- 20952252 TI - Adjuvant therapy with methylene blue in the treatment of right ventricular failure after pulmonary embolectomy. AB - Severe pulmonary embolism often leads to right ventricular failure after surgical embolectomy secondary to ischaemia reperfusion injury and acute lung injury (ALI). Acute right ventricular dysfunction is traditionally treated with inotropes and vasopressors to maintain cardiac output and coronary perfusion as well as selective pulmonary vasodilators to provide right ventricular afterload reduction. We report the first case of utilisation of methylene (MB) in a patient with acute right ventricular failure and vasoplegic shock after surgical pulmonary embolectomy. PMID- 20952253 TI - Evaluation of bone marrow examinations performed by an advanced nurse practitioner: an extended role within a haematology service. AB - PURPOSE: Traditionally, medical personnel have undertaken bone marrow (BM) examination. However, specially trained nurses in advanced practice roles are increasingly undertaking this role. This paper presents the findings from an audit of BM examinations undertaken by an advanced nurse practitioner (ANP) at a regional haematology specialist centre. METHODS: The audit evaluated the quality of BM examinations performed by the ANP over the past two years (September 2007 September 2009). Over the two year period, 324 BM examinations were performed at the centre of which 156 (48.1%) were performed by the ANP. A random sample of 30 BM examinations undertaken by the ANP were analysed by the consultant haematologist. RESULTS: All 30 BM examinations undertaken by the ANP were sufficient for diagnosis. CONCLUSIONS: The ANP is capable and competent to obtain BM samples which are of a sufficient quality to permit diagnosis. PMID- 20952254 TI - Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. AB - BACKGROUND: Knowledge about the distribution of human papillomavirus (HPV) genotypes in invasive cervical cancer is crucial to guide the introduction of prophylactic vaccines. We aimed to provide novel and comprehensive data about the worldwide genotype distribution in patients with invasive cervical cancer. METHODS: Paraffin-embedded samples of histologically confirmed cases of invasive cervical cancer were collected from 38 countries in Europe, North America, central South America, Africa, Asia, and Oceania. Inclusion criteria were a pathological confirmation of a primary invasive cervical cancer of epithelial origin in the tissue sample selected for analysis of HPV DNA, and information about the year of diagnosis. HPV detection was done by use of PCR with SPF-10 broad-spectrum primers followed by DNA enzyme immunoassay and genotyping with a reverse hybridisation line probe assay. Sequence analysis was done to characterise HPV-positive samples with unknown HPV types. Data analyses included algorithms of multiple infections to estimate type-specific relative contributions. FINDINGS: 22,661 paraffin-embedded samples were obtained from 14,249 women. 10,575 cases of invasive cervical cancer were included in the study, and 8977 (85%) of these were positive for HPV DNA. The most common HPV types were 16, 18, 31, 33, 35, 45, 52, and 58 with a combined worldwide relative contribution of 8196 of 8977 (91%, 95% CI 90-92). HPV types 16 and 18 were detected in 6357 of 8977 of cases (71%, 70-72) of invasive cervical cancer. HPV types 16, 18, and 45 were detected in 443 of 470 cases (94%, 92-96) of cervical adenocarcinomas. Unknown HPV types that were identified with sequence analysis were 26, 30, 61, 67, 69, 82, and 91 in 103 (1%) of 8977 cases of invasive cervical cancer. Women with invasive cervical cancers related to HPV types 16, 18, or 45 presented at a younger mean age than did those with other HPV types (50.0 years [49.6-50.4], 48.2 years [47.3-49.2], 46.8 years [46.6-48.1], and 55.5 years [54.9-56.1], respectively). INTERPRETATION: To our knowledge, this study is the largest assessment of HPV genotypes to date. HPV types 16, 18, 31, 33, 35, 45, 52, and 58 should be given priority when the cross-protective effects of current vaccines are assessed, and for formulation of recommendations for the use of second-generation polyvalent HPV vaccines. Our results also suggest that type specific high-risk HPV-DNA-based screening tests and protocols should focus on HPV types 16, 18, and 45. PMID- 20952255 TI - HPV genotypes: implications for worldwide cervical cancer screening and vaccination. PMID- 20952257 TI - Infectious causes of encephalitis. PMID- 20952256 TI - Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. AB - BACKGROUND: Encephalitis has many causes, but for most patients the cause is unknown. We aimed to establish the cause and identify the clinical differences between causes in patients with encephalitis in England. METHODS: Patients of all ages and with symptoms suggestive of encephalitis were actively recruited for 2 years (staged start between October, 2005, and November, 2006) from 24 hospitals by clinical staff. Systematic laboratory testing included PCR and antibody assays for all commonly recognised causes of infectious encephalitis, investigation for less commonly recognised causes in immunocompromised patients, and testing for travel-related causes if indicated. We also tested for non-infectious causes for acute encephalitis including autoimmunity. A multidisciplinary expert team reviewed clinical presentation and hospital tests and directed further investigations. Patients were followed up for 6 months after discharge from hospital. FINDINGS: We identified 203 patients with encephalitis. Median age was 30 years (range 0-87). 86 patients (42%, 95% CI 35-49) had infectious causes, including 38 (19%, 14-25) herpes simplex virus, ten (5%, 2-9) varicella zoster virus, and ten (5%, 2-9) Mycobacterium tuberculosis; 75 (37%, 30-44) had unknown causes. 42 patients (21%, 15-27) had acute immune-mediated encephalitis. 24 patients (12%, 8-17) died, with higher case fatality for infections from M tuberculosis (three patients; 30%, 7-65) and varicella zoster virus (two patients; 20%, 2-56). The 16 patients with antibody-associated encephalitis had the worst outcome of all groups-nine (56%, 30-80) either died or had severe disabilities. Patients who died were more likely to be immunocompromised than were those who survived (OR = 3.44). INTERPRETATION: Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Extensive testing substantially reduced the proportion with unknown cause, but the proportion of cases with unknown cause was higher than that for any specific identified cause. FUNDING: The Policy Research Programme, Department of Health, UK. PMID- 20952258 TI - A stochastic evolution model for residue Insertion-Deletion Independent from Substitution. AB - We develop here a new class of stochastic models of gene evolution based on residue Insertion-Deletion Independent from Substitution (IDIS). Indeed, in contrast to all existing evolution models, insertions and deletions are modeled here by a concept in population dynamics. Therefore, they are not only independent from each other, but also independent from the substitution process. After a separate stochastic analysis of the substitution and the insertion deletion processes, we obtain a matrix differential equation combining these two processes defining the IDIS model. By deriving a general solution, we give an analytical expression of the residue occurrence probability at evolution time t as a function of a substitution rate matrix, an insertion rate vector, a deletion rate and an initial residue probability vector. Various mathematical properties of the IDIS model in relation with time t are derived: time scale, time step, time inversion and sequence length. Particular expressions of the nucleotide occurrence probability at time t are given for classical substitution rate matrices in various biological contexts: equal insertion rate, insertion-deletion only and substitution only. All these expressions can be directly used for biological evolutionary applications. The IDIS model shows a strongly different stochastic behavior from the classical substitution only model when compared on a gene dataset. Indeed, by considering three processes of residue insertion, deletion and substitution independently from each other, it allows a more realistic representation of gene evolution and opens new directions and applications in this research field. PMID- 20952259 TI - Food insecurity is associated with acculturation and social networks in Puerto Rican households. AB - OBJECTIVE: To examine whether acculturation and social networks influence household food insecurity in an inner-city Puerto Rican community. METHODS: A survey was administered to 200 low-income female Puerto Rican caregivers with at least 1 child 12-72 months old living in Hartford, CT. Food insecurity was measured with the Radimer/Cornell Hunger Scale. Multivariate logistic regression analyses were used to identify food insecurity risk factors. RESULTS: Significant food insecurity risk factors included: being unemployed (odds ratio: 2.69), being single (2.34), being born in the United States (2.68), speaking only Spanish (3.15), planning to return to Puerto Rico (4.58), almost never/never attending Hispanic cultural events (6.85), and food stamps lasting less than a month (7.74). CONCLUSIONS AND IMPLICATIONS: Low levels of acculturation, lack of social networks, and poor food stamps management skills may influence household food insecurity. PMID- 20952261 TI - The art of forecasting and the impact of forecasts: The case of chronic hepatitis C. PMID- 20952260 TI - Bypass of N2-ethylguanine by human DNA polymerase kappa. AB - The efficiency and fidelity of nucleotide incorporation and next-base extension by DNA polymerase (pol) kappa past N(2)-ethyl-Gua were measured using steady state and rapid kinetic analyses. DNA pol kappa incorporated nucleotides and extended 3' termini opposite N(2)-ethyl-Gua with measured efficiencies and fidelities similar to that opposite Gua indicating a role for DNA pol kappa at the insertion and extension steps of N(2)-ethyl-Gua bypass. The DNA pol kappa was maximally activated to similar levels by a twenty-fold lower concentration of Mn(2+) compared to Mg(2+). In addition, the steady state analysis indicated that high fidelity DNA pol kappa-catalyzed N(2)-ethyl-Gua bypass is Mg(2+)-dependent. Strikingly, Mn(2+) activation of DNA pol kappa resulted in a dramatically lower efficiency of correct nucleotide incorporation opposite both N(2)-ethyl-Gua and Gua compared to that detected upon Mg(2+) activation. This effect is largely governed by diminished correct nucleotide binding as indicated by the high K(m) values for dCTP insertion opposite N(2)-ethyl-Gua and Gua with Mn(2+) activation. A rapid kinetic analysis showed diminished burst amplitudes in the presence of Mn(2+) compared to Mg(2+) indicating that DNA pol kappa preferentially utilizes Mg(2+) activation. These kinetic data support a DNA pol kappa wobble base pairing mechanism for dCTP incorporation opposite N(2)-ethyl-Gua. Furthermore, the dramatically different polymerization efficiencies of the Y-family DNA pols kappa and iota in the presence of Mn(2+) suggest a metal ion-dependent regulation in coordinating the activities of these DNA pols during translesion synthesis. PMID- 20952262 TI - Preserved liver function, portal thrombosis and absence of oesophageal varices are risk factors for metastasis of hepatocellular carcinoma. AB - BACKGROUND: Extrahepatic metastases represent a major obstacle for further improving prognosis of hepatocellular carcinoma. AIM: To assess clinical predictors of extrahepatic metastases in a large cohort followed in a single centre. METHODS: We evaluated clinical files of 520 consecutive patients with hepatocellular carcinoma admitted from 1994 to 2002 to our Liver Unit. The following risk factors were assessed: age, gender, hepatitis viruses, alcohol, diabetes, size, number and differentiation of hepatocellular carcinoma, percutaneous biopsy, portal thrombosis, alpha-fetoprotein, Child-Pugh, Cancer Liver Italian Program and Model for End-stage Liver Disease scores, Barcelona Clinic Liver Cancer classification, varices, hepatocellular carcinoma treatment. RESULTS: Extrahepatic metastases were detected in 55/520 patients (10.5%) after 0 72 months (median 15, CI 3-20) from initial evaluation. Lower bilirubin, INR, Child-Pugh and Model for End-stage Liver Disease scores, higher alpha-feto protein levels, portal thrombosis and absence of oesophageal varices were all associated with distant metastases at univariate analysis. Absence of oesophageal varices and portal thrombosis resulted as independent predictors (P = 0.0003 and P = 0.004, respectively) on multivariate logistic regression. Patients with metastases showed poorer survival (3 months) than total hepatocellular carcinoma population (26 months). CONCLUSIONS: Extrahepatic metastases of hepatocellular carcinoma are rare but significantly impair prognosis. Extrahepatic metastases were more frequent in patients with well preserved liver function. Absence of oesophageal varices and presence of portal thrombosis were the strongest risk factors. PMID- 20952263 TI - Gender roles, eating pathology, and body dissatisfaction in men: a meta-analysis. AB - The current study reviewed relationships between gender roles and (a) eating pathology, (b) body dissatisfaction, and (c) muscle dissatisfaction among men via meta-analysis. Moderators of sexual orientation and type of gender role measure were also investigated. Results revealed the relationship between femininity and eating and body-related variables did not significantly differ from zero. Sexual orientation moderated the relationship between femininity and muscle dissatisfaction (i.e., femininity was negatively related to muscle dissatisfaction for heterosexual but not gay men). Masculinity was negatively associated with eating pathology and body dissatisfaction. Type of masculinity measure moderated the relationship between masculinity and body dissatisfaction (i.e., trait-based measures produced a negative association, multidimensional measures yielded nonsignificant relationships). Type of masculinity measure produced a cross-over interaction when examining muscle dissatisfaction (i.e., trait-based instruments yielded a negative association and multidimensional instruments revealed a positive relationship). Findings highlight the salience of masculinity in men's eating and body concerns. PMID- 20952264 TI - Reconstruction of a four-quadrant full-thickness abdominal wall defect after removal and debridement of an infected mesh hernioplasty. AB - This case-report shows our experience with a patient, who underwent mesh hernioplasty followed by infection of the mesh and full-thickness loss of the abdominal wall after debridement due to necrosis. The anamnesis included generalised arteriosclerosis, chronic nicotine and alcohol abuse and recurring wound-healing disorders after surgical procedures. The initial infection was treated by radical debridement, targeted antibiotics and V.A.C.((r)) Therapy. After this, a staged plastic reconstructive procedure with four pedicled flaps was performed. The functional integrity of the abdominal wall was completely re established. The patient was able to continue her occupation as a facility manager. Although the use of free flaps is very common in modern plastic and reconstructive surgery, procedures such as pedicled flaps still have their significance for special indications. In this case, a full recovery of the abdominal wall with autologous tissue was successful under difficult vascular conditions by using local flaps. PMID- 20952265 TI - Microsatellite based ovine parentage testing to identify the source responsible for the killing of an endangered species. AB - In this study, we present an animal forensic genetics case in which we applied ovine microsatellite based parentage testing to the resolution of an act against protected wildlife. The aim was to identify the origin of the animal responsible for the death of an Egyptian vulture (Neophron percnopterus) that had been poisoned through consumption of a Latxa Blond Face breed lamb. Thus, we carried out a 22 microsatellite based parentage test in order to identify the parents of the lamb in the flock which grazes in the same place where the vulture's remains were found. Multiple parentage analysis revealed two possible parents, one ewe and one ram, with a combined paternity/maternity index (PI) higher than 9.09E9 and a likelihood (W) value of 99.9999%, assuming 50% probability a priori. This result confirmed the flock of origin of the poisoned lamb and shows that the microsatellite panel described herein is a potentially useful tool for the resolution of animal forensic cases. PMID- 20952266 TI - An investigation of the robustness of the consensus method of interpreting low template DNA profiles. AB - Forensic STR profiles generated from low-template DNA samples are more noticeably subject to effects such as allele dropout, contamination with spurious alleles ('drop-in') and proportionally larger stutter. The profiles obtained are frequently partial, and are challenging to interpret. Specifically, interpretation guidelines which are used when the template DNA is in the optimal range for the STR test kit in use must be adapted to the low-template regime. A commonly used approach to such modified interpretation is known as the 'consensus' or 'biological' method, and relies on replication to achieve reliable results. We have carried out a study to assess the robustness of the consensus method as applied to SGM Plus((r)) STR profiles obtained after applying a set of post-PCR purification methods together known as DNA SenCE, and report the results here. Multiple repeat analysis of DNA at five template quantities (ranging between 5pg and 100pg) and from five single donors, was carried out, and the resulting profiles were used to produce consensus profiles using several different evaluation criteria. Our aim was to determine whether the consensus profiles produced are conservative, that is, that the alleles reported are associated with the donor and that drop-in is reduced or eliminated. To this end, the alleles in the consensus profiles were compared with those of the donors, and the degree of concordance determined. The results suggest that increasingly stringent requirements for the number of times an allele must be observed in a set of repeat runs do, as expected, reduce the effect of drop-in, but also reduce the evidential value of the consensus profiles. However, the former is reduced to a much greater extent than the latter, resulting in a relative increase in profile information content versus drop-in peak risk with increased stringency. We also found that approximately half of the non-donor peaks appearing in consensus profiles were in -4 stutter positions for donor alleles present in the same profile, suggesting that many of these so-called drop-in alleles are, in fact, large stutter peaks rather than 'true' drop-in. Nevertheless, the appearance of non-donor peaks in a profile, including what are assumed to be oversized stutter peaks, appears to be an essentially random event. PMID- 20952267 TI - Influence of clinical and gait analysis experience on reliability of observational gait analysis (Edinburgh Gait Score Reliability). AB - OBJECTIVES: Treatment complexity of cerebral palsy (CP) patients imposes outcome evaluation studies, which may include objective technical analysis and more subjective functional evaluation. The Edinburgh Gait Score (EGS) was proposed as an additive or alternative when complex instrumented three-dimensional gait analysis is not available. Our purposes were to apply a translated EGS to standard video recordings of independent walking spastic diplegic CP patients, to evaluate its intraobserver and interobserver reliability with respect to gait analysis familiar and not familiar observers. METHODS: Ten standard video recordings acquired during routine clinical gait analysis were examined by eight observers gait analysis interpretation experienced or not, out of various specialities, two times with a two weeks interval. Kappa statistics and intraclass correlation coefficient were calculated. RESULTS: Better reliability was observed for foot and knee scores than in proximal segments with significant differences between stance and swing phase. Significantly better results in gait analysis trained observers underlines the importance to either be used to clinical gait analysis interpretation, or to benefit of video analysis training before observational scoring. CONCLUSION: Visual evaluation may be used for outcome studies to explore clinical changes in CP patients over time and may be associated to other validated evaluation tools. PMID- 20952268 TI - Fem1b antigen in the stool of ApcMin mice as a biomarker of early Wnt signaling activation in intestinal neoplasia. AB - BACKGROUND: Colorectal cancer is preventable by early detection and removal of precursor lesions. Central to early stages of colorectal neoplasia is activation of Wnt signaling, usually due to inactivation of the Apc tumor suppressor gene for which there is an established animal model, the Apc(Min) mouse. Immunodetection in stool of proteins up-regulated by aberrant Wnt signaling, within intestinal epithelial cells shed into the lumen, could be a rational approach to identify biomarkers of early intestinal neoplasia. Fem1b gene expression is up-regulated, following inactivation of Apc, in mouse intestinal epithelium. METHODS: We initially screened pooled random stool samples by immunoblotting and found that we could detect, in Apc(Min) mice but not wild-type mice, a fragment of Fem1b protein with an antibody (Li-50) directed against an epitope near the middle of the protein, but not with antibodies directed against N-terminus or C-terminus epitopes. We then evaluated freshly voided individual stool samples collected on four consecutive days from four each of male and female Apc(Min) mice and their wild-type littermates. RESULTS: The Fem1b antigen was detected with the Li-50 antibody in 15/16 samples from male Apc(Min) mice compared to 0/16 samples from male wild-type mice, and in 5/16 samples from female Apc(Min) mice compared to 0/16 samples from female wild-type mice. CONCLUSIONS: This study provides proof-of-principle that fragments of proteins, whose expression is increased by aberrant Wnt signaling early in intestinal neoplasia, can be immunodetected in stool. Excreted Fem1b protein fragments may be a useful biomarker for epithelial Wnt signaling and early intestinal neoplasia. PMID- 20952269 TI - The accuracy of cancer mortality statistics based on death certificates in the United States. AB - BACKGROUND: One measure of the accuracy of cancer mortality statistics is the concordance between cancer defined as the underlying cause of death from death certificates and cancer diagnoses recorded in central, population-based cancer registries. Previous studies of such concordance are outdated. OBJECTIVE: To characterize the accuracy of cancer mortality statistics from the concordance between cancer cause of death and primary cancer site at diagnosis. DESIGN: Central cancer registry records from California, Colorado, and Idaho in the U.S. were linked with state vital statistics data and evaluated by demographic and tumor information across 79 site categories. A retrospective arm (confirmation rate per 100 deaths) compared death certificate data from 2002 to 2004 with cancer registry diagnoses from 1993 to 2004, while a prospective arm (detection rate per 100 deaths) compared cancer registry diagnoses from 1993 to 1995 with death certificate data from 1993 to 2004 by International Statistical Classification of Diseases and Related Health Problems (ICD) version used to code deaths. RESULTS: With n=265,863 deaths where cancer was recorded as the underlying cause based on the death certificate, the overall confirmation rate for ICD-10 was 82.8% (95% confidence interval [CI], 82.6-83.0%), the overall detection rate for ICD-10 was 81.0% (95% CI, 80.4-81.6%), and the overall detection rate for ICD-9 was 85.0% (95% CI, 84.8-85.2%). These rates varied across primary sites, where some rates were <50%, some were 95% or greater, and notable differences between confirmation and detection rates were observed. CONCLUSIONS: Important unique information on the quality of cancer mortality data obtained from death certificates is provided. In addition, information is provided for future studies of the concordance of primary cancer site between population-based cancer registry data and data from death certificates, particularly underlying causes of death coded in ICD-10. PMID- 20952270 TI - Terminal ligature of inferior thyroid artery branches during total thyroidectomy for multinodular goiter is associated with higher postoperative calcium and PTH levels. AB - PURPOSE: To evaluate the impact of truncal versus terminal branch ligature of the inferior thyroid artery (ITA) on postoperative calcium and PTH plasma levels in patients undergoing total thyroidectomy for multinodular goiter. METHODS: A prospective randomized study was performed comparing a group of patients that underwent either truncal ligature of the ITA (group 1) or terminal ligature of ITA branches (group 2). RESULTS: A series of 126 consecutive patients with non toxic euthyroid multinodular goiter underwent total thyroidectomy. Truncal ligature of the ITA was performed in 63 patients (group 1) and terminal branch ITA ligature in 63 patients (group 2). Postoperative ionized serum calcium (mmol/L) at 24 hours was significantly lower in group 1 than in group 2 patients (1.22 +/- 0.06 vs. 1.25 +/- 0.05, P<0.05) and at 48 hours (1.20 +/- 0.05 vs. 1.23 +/- 0.05, P<0.05). Mean postoperative PTH levels (pg/mL) at 4 hours after thyroidectomy were significantly lower in group 1 than in group 2 patients (22.32 +/- 11.64 vs. 25.82 +/- 12.87, P=0.044). Mean hospital stay (hours) was higher in group 1 than in group 2 patients (87.47 +/- 41.04 vs. 70.34 +/- 24.82, P<0.05). CONCLUSION: This study shows that terminal ligature of ITA branches during total thyroidectomy for multinodular goiter is associated with higher mean postoperative calcium and PTH levels, and shorter hospital stay. However, no significant difference in terms of permanent hypoparathyroidism was observed between the two groups. PMID- 20952271 TI - B-cell lymphoma of the mandible. AB - INTRODUCTION: Primary malignant lymphoma of the mandible is rare. It is frequently mistaken for a dental lesion, delaying diagnosis. We here report a case of mandibular lymphoma and present the clinical and radiological characteristics and means of treatment of this pathology. CASE REPORT: A 17-year old woman consulted for right facial tumefaction with 1 year's evolution. Clinical examination found a mass facing the horizontal branch of the mandible, extending to the right parotid region without cutaneous involvement. CT and MRI showed a large expansive process of mandibular origin with parotid, temporal and intracranial extension. Biopsy indicated large B-cell lymphoma. The patient showed good evolution 2 years after chemotherapy. CONCLUSION: Lymphoma is the second most frequent form of head and neck tumor, after epidermoid carcinoma. Only 0.6% of locations are mandibular, almost always consisting of B-cell lymphoma. They are often initially misdiagnosed as a dental pathology. Complete remission after chemotherapy ranges from 60 to 80% at 1 year. PMID- 20952272 TI - What role does the blood brain barrier play in acute mountain sickness? AB - As high altitude travel increases, acute mountain sickness (AMS) and life threatening high altitude cerebral oedema (HACE) are becoming more prevalent. Acute mountain sickness occurs in 45% of lowlanders above 4250 m. Predisposing factors are still unknown and its development is more complex than the original "tight fit" hypothesis. This review examines evidence relating to a possible role of the blood brain barrier in AMS as suggested by MRI studies. Underlying mechanisms may involve vascular endothelial growth factor and free radicals in addition to increases in hydrostatic pressure. An increased understanding is important in advising patients planning high altitude adventures. Current studies have linked increased blood brain barrier permeability to high altitude cerebral oedema, but the role of the blood brain barrier in acute mountain sickness is less clear; varied symptoms include headache. MRI shows vasogenic oedema occurs in high altitude cerebral oedema, suggesting blood brain barrier permeability increases, and acute mountain sickness typically precedes high altitude cerebral oedema. Hypoxia leads to increased hydrostatic pressure, and blood brain barrier permeability has been shown to increase in stroke patients. Vascular endothelial growth factor is upregulated in hypoxia, and may increase blood brain barrier permeability. PMID- 20952273 TI - Combined tubular adenocarcinoma and hepatoid adenocarcinoma arising in Barrett esophagus. AB - Hepatoid adenocarcinoma arising in the esophagus is extremely rare. To date, there are only 3 cases in the world English literature. We report the fourth case here. A 76-year-old Japanese man was admitted to our hospital because of the deterioration of nephritic syndrome. He presented with chest burn, and the endoscopic examination of upper digestive tract disclosed the tumor in the lower esophagus. The subtotal esophagectomy was undertaken because of esophageal cancer. The postoperative histologic examination showed the finding of combined tubular adenocarcinoma and hepatoid adenocarcinoma arising in Barrett esophagus. Immunohistochemically, hepatoid adenocarcinoma cells were positive for a fetoprotein, hepatocyte, a1-antitrypsin, a1-antichymotrypsin, and CDX2, but negative for MUC5AC and MUC6. Esophageal hepatoid adenocarcinoma seems to be closely associated with Barrett esophagus and show the intestinal phenotype rather than gastric phenotype. PMID- 20952274 TI - Primary squamous carcinoma of the ovary likely arising from a monodermal cystic mucinous teratoma. AB - We present a 58-year-old woman with primary squamous carcinoma of the ovary likely arising from a monodermal cystic mucinous teratoma. Noninvolved ovary showed no Brenner tumor, endometriosis, transitional carcinoma, endometrioid adenocarcinoma, or typical multigerm layer classic mature teratoma. Moreover, no other primary site was possible because there were no prior or concomitant squamous carcinomas, or history of cervical intraepithelial neoplasia. The tumor showed strong positivity for p63 and CK5/6, reactivity that also extended from the squamous carcinoma into the basal-cell lining of the mucinous cyst of a likely monodermal teratoma. This basal-cell pattern was absent in a series of conventional benign and borderline cystic mucinous cystadenomas of the ovary, but clearly present in the mucinous cysts part of mature teratomas. We present this as a unique case of squamous carcinoma likely arising from a monodermal cystic mucinous teratoma. Moreover, we submit that the p63 and CK5/6 staining pattern may help to differentiate monodermal cystic mucinous teratoma from conventional cystic mucinous tumors. PMID- 20952275 TI - Endometrioid carcinoma with a low-grade spindle cell component: a tumor resembling an adnexal tumor of probable Wolffian origin. AB - Endometrioid carcinoma is known to have many histopathologic variants, which may cause diagnostic difficulty. One rare variant resembles Wolffian adnexal tumor (female adnexal tumor of probable Wolffian origin). This pattern can produce a significant solid component within the tumor. Once the true endometrioid nature of the tumor is recognized, the tumor can appear deceptively high grade by International Federation of Gynecology and Obstetrics grading criteria, which take into account the percentage of the tumor showing solid growth. The English language literature on this variant is scant, and its behavior is not well documented. We present a case of ovarian endometrioid carcinoma with a Wolffian adnexal tumor pattern that recurred 19 years after the original surgery; and the patient continues to remain well without evidence of disease 1 year following her second surgery, that is, 20 years of indolent behavior. This long clinical course shows evidence for low-grade behavior for this tumor. PMID- 20952276 TI - Epithelioid malignant peripheral nerve sheath tumor of the uterine corpus. AB - Epithelioid variant of a malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma. Rarer still is its occurrence at uncommon sites like the uterine corpus where an index of suspicion for this diagnosis is extremely low. Herein, we report a rare case of a uterine epithelioid MPNST in a young girl who underwent a total abdominal hysterectomy for a uterine tumor that was initially diagnosed as an undifferentiated sarcoma and whose paraffin blocks were submitted to us for review. Biopsy sections showed a malignant tumor, predominantly composed of polygonal cells, including "rhabdoid" forms with conspicuous mitoses. On immunohistochemistry, tumor cells were diffusely positive for vimentin and S 100 and negative for smooth muscle actin, desmin, myogenin cytokeratin, epithelial membrane antigen, melan A, HMB-45, CD10, glial fibrillary acid protein inhibin, synaptophysin, chromogranin, MIC2, FLI-1, and neuron-specific enolase. Diagnosis of an epithelioid MPNST was offered. The case is presented in view of its rarity and also to highlight the value of immunohistochemistry in objectively identifying unusual sarcomas at uncommon sites. PMID- 20952277 TI - Plasmablastic lymphoma of the oral cavity in an HIV-negative patient. AB - Plasmablastic lymphoma (PBL) is a rare, highly aggressive lymphoma typified by immunoblast-like cells with abundant basophilic cytoplasm and paranuclear hof. It shows absent expression of CD45 and CD20. In contrast, it displays a constant reaction with CD138 and VS38c. It may be easily misinterpreted as some other lymphoma. An exhaustive integration of clinical, morphologic, phenotypic, and molecular features is important to exclude misdiagnosis and inappropriate treatment. We report a case of HIV-negative PBL arising on the left areas of posterior teeth mucosa of a 58-year-old man. Immunohistochemically, the tumor cell was immunoreactive for CD138, VS38c, VEGF, and vimentin; Ki-67 showed a high proliferation rate. Epstein-Barr virus (in situ hybridization) was nonreactive, and IgH gene rearrangement was identified by polymerase chain reaction amplification products. A diagnosis of PBL was rendered. PMID- 20952278 TI - A unique case of an indolent CD56-positive T-cell lymphoproliferative disorder of the gastrointestinal tract: a lesion potentially misdiagnosed as natural killer/T cell lymphoma. AB - Primary intestinal natural killer (NK)/T-cell lymphoma (nasal-type) and enteropathy-associated T-cell lymphoma, type II, are CD56-positive lymphoproliferative disorders with very poor survival rates. We report a long surviving patient with a CD56-positive T-cell lymphoproliferative disorder of the gastrointestinal tract that presented as vomiting, diarrhea, weight loss, and pain. This patient was referred to the university hospital as a case of peripheral T-cell lymphoma due to this CD56-positive lymphocyte population. There was no evidence of enteropathy; and the infiltrates were negative for CD8, Epstein-Barr virus, and T-cell receptor gene rearrangement. Despite its persistence for 8 years, the clinical course has remained indolent. This report confirms that patients may rarely present with a CD56-positive NK/T-cell-like proliferation of the gastrointestinal tract, yet follow an indolent clinical course. Thus, all pathologic features of enteropathy-associated T-cell lymphoma or NK/T-cell lymphoma should be present before making this diagnosis and exposing the patient to toxic chemotherapy. PMID- 20952279 TI - WITHDRAWN: Syringoma: the clear cell variant made clearer. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 20952280 TI - Bilateral renal tumors; conventional clear cell carcinoma and contralateral t(6;11)/t(X;17)-like tumor Histomorphologic, immunohistochemical, ultrastructural and molecular genetic studies including the report of a novel mutation in the VHL gene. AB - A 34-year-old pregnant woman with bilateral kidney tumors 9.5 and 2.5 cm in maximum diameter is presented. The larger tumor was clear renal cell carcinoma. The smaller contralateral tumor was focally HMB45 positive and had unusual histomorphology, including features resembling clear renal cell carcinoma with features of both t(6;11)- and t(X;17)/ASPL-TFE3 carcinomas. This tumor displayed a complex karyotype. A novel germ line mutation in the VHL gene (c.439A>G/p.I147V) was also identified in this patient. PMID- 20952281 TI - Familial gastrointestinal stromal tumor with germ line mutation of the juxtamembrane domain of the KIT gene observed in relatively young women. AB - Familial gastrointestinal stromal tumor (GIST) is an extremely rare autosomal dominant disorder, and approximately 20 families have been reported to date. In this article, we present one additional family. A 25-year-old Japanese woman presented with abdominal pain, and subsequent image analyses disclosed multiple tumors measuring 12 cm in maximum diameter in the lower digestive tract. The postoperative histologic examination showed multiple GISTs and diffuse hyperplasia of interstitial cells of Cajal. Her mother had a history of GIST in the digestive tract. Three members of this family including her younger sister and mother had cutaneous hyperpigmentation of external genitalia and axilla. Their DNA samples showed identical missense mutation at exon 11 in the juxtamembrane domain of the KIT gene, and this mutation site was considered to be a hot spot in familial GIST. One year after, her younger sister suffered from multiple GISTs in the digestive tract at the age of 25 years. To correctly diagnose familial GIST, mutual information should be exchanged among clinicians, pathologists, and molecular scientists. PMID- 20952282 TI - Amphicrine carcinoma of the liver. AB - Amphicrine tumors are defined by evidence of both glandular and neuroendocrine differentiation in the same cell. These are extremely rare tumors, with only scattered case reports in the pancreas and stomach. We here report a case of amphicrine carcinoma occurring in apparent isolation in the liver. The tumor was characterized by signet ring cell morphology, mucicarmine, and periodic acid Schiff with diastase (PASD) positivity, and expression of chromogranin, synaptophysin, villin, and CDX2. No other tumor was identified by radiological or endoscopic examination of the gastrointestinal tract. The patient is disease-free 22 months after the resection. We speculate that this represents the first reported occurrence of primary amphicrine carcinoma of the liver. PMID- 20952283 TI - Adamantinoma with plasmacytoid features: expanding the spectrum of a diagnostically challenging entity. AB - Adamantinoma is a rare neoplasm that characteristically involves the tibia. In many instances, typical location within the tibia, very slow course, and a typical radiographic appearance can strongly suggest the correct diagnosis. We present a case that has both unusual radiographic findings and uncharacteristic histology. In this case, radiologic imaging showed a poorly defined lytic lesion within the distal, lateral tibia extending to the joint with central necrosis, overlying periosteal reaction and possible tumor spread into soft tissue. The histology of this lesion showed pronounced vascularity and surrounding large neoplastic cells with plasmacytoid morphology. The combination of these features led to an initial misdiagnosis as metastatic carcinoma from unknown primary. PMID- 20952284 TI - Hematolymphoid malignancies with intraocular intravascular involvement: report of 2 cases. AB - The interaction between the endothelium and malignant hematolymphoid cells within vessels of the eye can result in focal or diffuse intravascular pathology. As a result, correlation of these findings with specific clinical and ophthalmologic features can vary. We review the ophthalmic findings in two cases of hematolymphoid malignancies limited to the intravascular space and review published literature on this topic. In cases of intravascular large B-cell lymphoma, underexpression of beta1-integrin and intercellular adhesion molecule-1 by the cells of intravascular large B-cell lymphoma results in diffuse ocular vascular involvement. The widespread degree of intravascular involvement correlates with clinical ophthalmologic findings and may lead to retinal and choroidal detachment that is observed postmortem. Conversely, in the context of acute leukemia, induced overexpression of certain adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) in the endothelium of certain vascular beds may result in leukostasis with only selective (choroidal) ocular vessel involvement. As a result of only focal vascular activation and adhesion in the orbit, the gross findings in these cases are minimal and may not correlate with clinical ophthalmologic findings. PMID- 20952285 TI - Botryoid odontogenic cyst: a clinicopathologic study of 10 cases. AB - Botryoid odontogenic cyst is a rare multilocular variant of lateral periodontal cysts. In this study, a series of 10 cases of botryoid odontogenic cysts retrieved from the archives of the Postgraduation Program in Oral Pathology, Federal University of Rio Grande do Norte (Brazil), were reviewed for epidemiologic data, clinical presentation, radiographic and histopathologic characteristics, treatment, and recurrence. PMID- 20952286 TI - Clear cell papillary renal cell carcinoma and clear cell renal cell carcinoma arising in acquired cystic disease of the kidney: an immunohistochemical and genetic study. AB - Clear cell papillary renal cell carcinoma (RCC) is a recently established disease entity. However, there are few reports on genetic study of this entity. We report such a case with focus on genetic study. A 57-year-old Japanese man was found to have 3 renal tumors. Histologically, two tumors showed findings of clear cell RCC; and the other tumor showed findings of clear cell papillary RCC that was characterized by papillary growth pattern of neoplastic cells in cystic space with purely clear cell cytology. Immunohistochemically, tumor cells of clear cell papillary RCC were diffusely positive for PAX2 and cytokeratin 7, but negative for CD10, RCC Ma, and AMACR. In fluorescence in situ hybridization study for one clear cell papillary RCC, we detected polysomy for chromosome 7 and monosomy for chromosomes 17, 16, and 20. In addition, we detected mutation of VHL gene in clear cell RCC, but found no VHL gene mutation in clear cell papillary RCC. Finally, our results provide further evidence that clear cell papillary RCC may be both morphologically and genetically distinct entity from clear cell RCC and papillary RCC. PMID- 20952287 TI - A new translocation between chromosomes 6 and 9 helps to establish diagnosis of renal oncocytoma. AB - Renal oncocytomas are benign epithelial tumors of the kidney. Histologically, they resemble certain malignant renal tumors, such as chromophobe renal cell carcinoma and the eosinophilic or granular form of clear cell renal carcinoma. It is, therefore, important to be able to differentiate among these tumors. Cytogenetic analysis is an important adjunct to the diagnosis of renal tumors, as the various subtypes have specific acquired chromosome abnormalities. Oncocytomas present either with loss of chromosome 1 and a sex chromosome, or with recurring translocations involving chromosome 11. We describe 2 patients with renal oncocytoma and a new translocation between chromosomes 6 and 9. The tumors in both patients were histologically virtually identical. The t(6;9)(p21;p23) may be a new translocation associated with renal oncocytomas. PMID- 20952288 TI - Malignant mixed mullerian tumor of primary peritoneal origin. AB - The aim of this study was to describe 2 cases of primary peritoneal malignant mixed mullerian tumor (MMMT). Two patients with primary peritoneal MMMT were examined for their clinical and pathologic features. We describe 2 cases of primary peritoneal MMMT in which the carcinomatous and mesenchymal components were readily identifiable, predominantly involving the peritoneum, with no ovarian involvement. The peritoneum and ovaries, with their common embryologic origin, likely account for the peritoneum's ability to undergo a similar malignant transformation, with the resultant genesis of an MMMT of peritoneal origin. PMID- 20952289 TI - Malignant pulmonary epithelioid hemangioendothelioma with hilar lymph node metastasis. AB - Few cases each of malignant pulmonary epithelioid hemangioendothelioma (PEH) and PEH with lymph node metastasis have been reported. Here we report a case of PEH with lymph node metastasis. A Japanese woman was found to have a 2-cm-diameter mass with small satellite nodules in the right upper lobe of the lung. Microscopic examination revealed solid destructive growth of the main tumor, with epithelioid cells showing cytologic atypia and 3 mitotic figures per 10 high power fields. Some of the tumor cells had intracytoplasmic lumina that appeared as vacuoles. These lumina were negative for alcian blue and periodic acid Schiff, and contained erythrocytes. However, erythrocytes were seen more frequently within small but distinct vascular channels that were arranged diffusely in the periphery of the main tumor. Other satellite nodules showed conventional PEH morphology. In hilar lymph nodes, the tumor cells resembled those of the main tumor. The vascular origin of the main tumor and satellite nodules was demonstrated by positive immunoreactivity for some endothelial markers. Although the diagnostic features of malignant PEH are not clear, those for PEH in other organs have included nuclear atypia, many mitoses, presence of necrosis, large tumor size, and spindle cell proliferation. The present case met these criteria, except for large tumor size and spindle cell proliferation. In conclusion, atypical cytologic features, the presence of necrosis, a high Ki-67 labeling index, and accompanying nodules of conventional PEH in the same pulmonary lobe suggest that this case was a malignant PEH with hilar lymph node metastasis. PMID- 20952290 TI - Clear cell renal cell carcinoma with focal renal angiomyoadenomatous tumor-like area. AB - Recently, renal angiomyoadenomatous tumor (RAT) has been identified. However, there are no descriptions about clear cell renal cell carcinoma (RCC) with focal RAT-like features. A 33-year-old Japanese man was found to have a tumor in the left kidney. Macroscopically, the tumor extended into the perinephric fat tissue, and the cut surface showed the yellowish color. The histologic examination of the tumor consisted of 2 components of clear cell RCC and RAT-like area. The RAT-like area showed the admixture of epithelial cells with basophilic or clear cytoplasm and stromal component containing leiomyomatous stroma, fine capillary network, and pericytic network. Immunohistochemically, epithelial neoplastic cells in RAT like area were diffusely positive for CD10 and RCC Ma. G-band karyotype showed the structural abnormality of chromosome 3 and both components of clear cell RCC and RAT-like area revealed the identical VHL gene mutation. Finally, pathologists should pay attention to the presence of clear cell RCC focally resembling RAT. PMID- 20952291 TI - Reticular and microcystic schwannoma: a distinctive tumor of the gastrointestinal tract. AB - Reticular/microcystic schwannoma is a rare variant of schwannoma with a predilection for viscera, especially the gastrointestinal tract. Of the 9 cases reported thus far, 7 have occurred in female patients. The average age of presentation is 67 years. They are usually small, asymptomatic lesions ranging in size from 0.85 to 2.2 cm with a mean size of 1.35 cm. They usually occur in the stomach, small bowel, and proximal large intestine. It differs from usual schwannomas of the gastrointestinal tract by lacking the peripheral cuff of lymphocytes. The histologic appearance of slender bipolar spindle cells in a lace like reticular pattern set within a myxoid stroma raises a wide differential diagnosis including gastrointestinal stromal tumor, perineurioma, and in more epithelioid examples, even carcinoma. Awareness of the entity and an immunohistochemical panel of markers will ensure that the correct diagnosis is made. PMID- 20952292 TI - Osteosarcoma after radiotherapy for prostate cancer. AB - Postradiation sarcomas are long-term complications of radiation treatment of various forms of cancer. Osteosarcoma, specifically, occurring in patients with a history of prostate cancer is rare; but with high-dose radiotherapy now an accepted standard of care for localized prostate adenocarcinoma, it should be considered in the clinical setting of patients presenting with potential remote disease relapse. We describe an osteosarcoma of the pubic ramus in a patient previously treated 10 years prior with radiation therapy for prostate cancer. Because of the long latency period, the appearance of lytic bone lesions with soft tissue components in pelvic bony structures may mimic recurrent/metastatic prostate adenocarcinoma. The prognosis of patients developing osteosarcoma after radiotherapy for prostate cancer is similar to other radiation-induced osteosarcomas occurring in the axial skeleton, with a 50% overall mortality within the first year after diagnosis. PMID- 20952293 TI - Histiocytoid carcinoma of the male breast. AB - Histiocytoid carcinoma of the breast is a rare tumor with approximately 30 cases reported, all occurring in female patients. We report the first case of histiocytoid breast carcinoma in a male patient. A 68-year-old man presented with a 2.5-cm breast mass. Microscopic examination of the needle core biopsy revealed a diffuse (lobular type) infiltration of tumor cells as angulated clusters, linear arrangements, small nests, and individual cells; there was no duct formation. The nuclei were round-oval and hyperchromatic with inconspicuous nucleoli and finely dispersed chromatin. The cytoplasm was abundant, was amphophilic, and ranged from granular to vacuolated. A subset of tumor cells contained periodic acid Schiff-positive cytoplasmic material, which was largely but incompletely removed by diastase treatment. There was minimal nuclear pleomorphism, and mitotic figures were inconspicuous. The intervening stroma was densely fibrotic, and the tumor infiltrated among tightly packed collagen bundles. Immunohistochemistry was positive for estrogen receptor, progesterone receptor, androgen receptor, vimentin, epithelial membrane antigen, and pan cytokeratin. The tumor was negative for CK7, CAM5.2, 34BE12, AE1/AE3, GCDFP-15 (BRST-2), E-cadherin, and CD68. The mastectomy resection demonstrated similar histologic findings. Sentinel lymph node biopsy was negative. The morphology of this tumor is similar to that described for histiocytoid carcinoma of the female breast, a rare entity. Such tumors are felt to be variants of lobular carcinomas, which is supported by diffuse infiltrative growth, loss of E-cadherin expression, and strong ER positivity. We believe our case to be the first reported example of histiocytoid carcinoma in a male breast. PMID- 20952294 TI - Mixed cortical adenoma and composite pheochromocytoma-ganglioneuroma: an unusual corticomedullary tumor of the adrenal gland. AB - Adrenal neoplasms composed of more than one cell type and demonstrating a mixed histologic appearance are exceedingly rare. We report the clinical and pathologic features of a morphologically distinctive tumor of the adrenal gland composed of cortical, chromaffin, and neural cells. Histologically, the tumor consisted of intermixed areas of proliferating cortical cells resembling adrenal cortical adenoma, neoplastic chromaffin cells consistent with pheochromocytoma, and a ganglioneuromatous stroma. The presence of the cortical, medullary, and neural components within the tumor was confirmed by immunohistochemical studies. The present case serves to broaden the morphologic spectrum of mixed tumors that may be encountered in the adrenal gland. PMID- 20952295 TI - Papillary carcinoma with diffuse papillomatosis of gallbladder and cystic duct. AB - Biliary papillomatosis and papillary carcinoma are rare tumors of biliary tract; and because of their morphologic similarities, papillomatosis-papillary carcinoma sequel has been proposed. We report an unusual case of polypoid minimally invasive papillary carcinoma located at the junction between cystic and common bile ducts, complicated with biliary papillomatosis of gallbladder and cystic duct, showing focal areas of malignant change. Intrahepatic ducts, hepatic ducts, and distal common bile duct were spared. Both papillomatosis and papillary carcinoma showed areas of high p53 and p21 expression with high proliferative index. Patient is still alive for 4 years without evidence of disease after modified Whipple operation. Possible pathogenetic mechanisms are further discussed. PMID- 20952296 TI - Sinonasal teratocarcinosarcoma with yolk sac elements: a neoplasm of somatic or germ cell origin? AB - Sinonasal teratocarcinosarcoma is an uncommon, aggressive, morphologically heterogenous tumor composed of cells derived from the 3 somatic layers. A histogenetic origin from a multipotential adult somatic stem cell with divergent differentiation has been favored over a germ cell origin. This assumption has been based on the lack of germ cell elements and, until recently, the absence of demonstrable amplification of 12p. We report a case that exhibited foci of yolk sac elements with papillary structures and intracytoplasmic periodic acid-Schiff positive, diastase-resistant, alpha-fetoprotein-positive, hyaline globules. An expanded area of undifferentiated cells, likely precursor cells, in the basal layer of the overlying mucosal epithelium transitions into and merges with the immature epithelial, neuroepithelial, and mesenchymal components. These previously unreported histomorphological features support the hypothesis that this tumor is a teratomatous tumor arising from pluripotent embryonic stem cells in the basal layer of the sinonasal epithelium. That notion is further supported by fluorescence in situ hybridization cytogenetic analysis, which showed a distinct subpopulation of the tumor cells with an extra copy of chromosome 12p13. PMID- 20952297 TI - Extraskeletal osteosarcoma of abdominal wall in a child. AB - Compared with osteosarcoma of bone, extraskeletal osteosarcoma is rare and accounts for approximately 1% to 2 % of all soft tissue sarcomas. Osteosarcoma arising in soft tissues is exceedingly rare in children. The tumor most often affects older adults, involves the lower extremity, responds poorly to chemotherapy, and carries a grave prognosis. The authors describe a 4-year-old girl with an extraskeletal osteosarcoma in the lateral abdominal wall. PMID- 20952298 TI - Blue nevus of the colorectal mucosa. AB - The blue nevus is a well-described benign melanocytic proliferation that generally occurs on the skin. Infrequently, blue nevi are found on mucosal surfaces. The most common location for mucosal blue nevi is the oral mucosa, with reported cases in the sinonasal mucosa and genital tract, as well as in other locations. To our knowledge, blue nevi of the rectal mucosa have not been described. Here, we describe a case of blue nevus arising in the rectal mucosa. Blue nevi are benign melanocytic proliferations with the potential for malignant transformation and should be included in the differential diagnosis of pigmented mucosal lesions of the rectum. PMID- 20952299 TI - Clear cell carcinoma of the ovary mimicking struma ovarii and carcinoid tumor. AB - Clear cell carcinomas are considered as high-grade tumor often with poor prognosis. We describe 2 cases of clear cell carcinomas of the ovary mimicking benign or less aggressive tumors encountered in the female genital track. The first case is mimicking a benign monodermal teratoma, the so-called struma ovarii, and the second mimicking a carcinoid tumor. PMID- 20952300 TI - Low-grade fibromyxoid sarcoma metastatic to the prostate. AB - Spindle cell tumors of the prostate are rare and mostly primary. We report a case of retroperitoneal sarcoma, which is a low-grade fibromyxoid sarcoma involving the prostate secondarily by metastasis. The patient was a 44-year-old man who presented with progressing abdominal pain. Computed tomography showed a large retroperitoneal mass. The patient underwent surgical resection. Intraoperatively, a second smaller mass was identified in the pelvis and was left untouched. The resected retroperitoneal specimen and prostate transrectal needle biopsies taken afterward showed the same mesenchymal tumor. Radical cystoprostatectomy was performed. Metatatic tumor involving the prostate, bilateral seminal vesicles, and base of the urinary bladder was found. Microscopic examination revealed typical histomorphologic features of low-grade fibromyxoid sarcoma. The patient is without evidence of disease 3 years postoperatively. This case is the first documentation of metastatic sarcoma to the prostate and expands the list of malignant mesenchymal neoplasms that may involve this organ. PMID- 20952301 TI - Sialolipoma of minor salivary glands. AB - Sialolipoma is a recently described histologic variant of lipoma and is characterized by well-demarcated proliferation of mature adipocytes with secondary entrapment of salivary gland elements. These tumors have been observed in both the major and minor salivary glands, with more than 20 cases being reported in the English literature. In general, the clinical presentation of sialolipomas of the minor salivary glands suggests a diagnostic hypothesis of salivary gland lesions, commonly neoplasms. In the major salivary glands, the clinical features suggest either a salivary gland neoplasm or a lipoma. Surgical excision is the treatment of choice for sialolipomas, with no reports of recurrence or malignant transformation. The present article reports 4 additional cases of sialolipoma, all of them affecting the minor salivary glands, and reviews the literature regarding clinicopathologic aspects, differential diagnosis, and therapeutic management of this recently recognized histologic variant of lipoma. PMID- 20952302 TI - Cytokeratin-, calponin-, and p63-positive chondroblastoma with extensive soft tissue involvement and vascular invasion: a potential diagnostic dilemma. PMID- 20952303 TI - Epithelioid melanoma of the rectum: reappraisal of a deceptive microscopic simulator. AB - We report 2 cases of rectal melanoma. The patients were a 48-year-old man and an 88-year-old woman. In both cases, the tumor presented as polypoid and necrotic masses, making initial diagnostic assessment difficult because of the regressive tissue changes. Microscopically, tumors were mostly composed of epithelioid, highly atypical cells mimicking poorly differentiated carcinoma or large cell lymphoma. Tumor cells were negative for keratin, leukocyte common antigen, and epithelial membrane antigen and positive for S100 protein and several melanoma markers, although in endoscopic biopsy specimens, the positive reaction was focal due to the limited viable tissue. One patient was treated with abdominoperineal resection. Pathologic examination of the surgical specimen revealed a polypoid mass infiltrating the muscle coat of the rectum. Local lymph nodes contained metastatic deposits. Microscopic examination of the rectal mucosa adjacent to the infiltrating neoplasm revealed colonization of the intestinal crypts by atypical melanocytes. This patient is alive 1 year after surgery with no evidence of recurrent disease. The other case was not deemed amenable to radical surgery because of the patient's advanced age and evidence of diffuse metastatic disease. She was alive 6 months after the initial diagnosis but was lost to follow-up. Data indicate that the diagnosis of melanoma, although feasible in large resection specimens, may be problematic in endoscopic biopsy, especially when only small tissue fragments are available and tumor regression hampers the accuracy of immunohistochemical stains. Documentation of intracryptic atypical melanocytes in nonneoplastic mucosa conceptually corroborates claims that rectal melanoma is related to preinvasive precursors as in cutaneous melanoma. PMID- 20952311 TI - Comments on "effect of vergence adaptation on convergence accommodation: model simulations". PMID- 20952315 TI - A Presidential Patent [Patents]. AB - There is only one U.S. president who is also a patentee. One might guess that the president is Thomas Jefferson, who invented many things and considered himself to be an inventor. Or, we might guess George Washington whose work as a surveyor and planter, not to mention commander-in-chief of the army, brought him into contact with the latest technology of the 18th century. PMID- 20952320 TI - Environmentally robust motion detection for video surveillance. AB - Most video surveillance systems require to manually set a motion detection sensitivity level to generate motion alarms. The performance of motion detection algorithms, embedded in closed circuit television (CCTV) camera and digital video recorder (DVR), usually depends upon the preselected motion sensitivity level, which is expected to work in all environmental conditions. Due to the preselected sensitivity level, false alarms and detection failures usually exist in video surveillance systems. The proposed motion detection model based upon variational energy provides a robust detection method at various illumination changes and noise levels of image sequences without tuning any parameter manually. We analyze the structure mathematically and demonstrate the effectiveness of the proposed model with numerous experiments in various environmental conditions. Due to the compact structure and efficiency of the proposed model, it could be implemented in a small embedded system. PMID- 20952323 TI - Modeling and percept of transcorneal electrical stimulation in humans. AB - Retinal activation via transcorneal electrical stimulation (TcES) in normal humans was investigated by comparing subject perception, model predictions, and brain activation patterns. The preferential location of retinal stimulation was predicted from 3-D admittance modeling. Visual cortex activation was measured using positron emission tomography (PET) and (18)F-fluorodeoxyglucose (FDG). Two different corneal electrodes were investigated: DTL-Plus and ERG-Jet. Modeling results predicted preferential stimulation of the peripheral, inferior, nasal retina during right eye TcES using DTL-Plus, but more extensive activation of peripheral, nasal hemiretina using ERG-Jet. The results from human FDG PET study using both corneal electrodes showed areas of visual cortex activation that consistently corresponded with the reported phosphene percept and modeling predictions. ERG-Jet was able to generate brighter phosphene percept than DTL Plus and elicited retinotopically mapped primary visual cortex activation. This study demonstrates that admittance modeling and PET imaging consistently predict the perceived location of electrically elicited phosphenes produced during TcES. PMID- 20952324 TI - Magnetically controllable gastrointestinal steering of video capsules. AB - Wireless capsule endoscopy (WCE) allows for comfortable video explorations of the gastrointestinal (GI) tract, with special indication for the small bowel. In the other segments of the GI tract also accessible to probe gastroscopy and colonscopy, WCE still exhibits poorer diagnostic efficacy. Its main drawback is the impossibility of controlling the capsule movement, which is randomly driven by peristalsis and gravity. To solve this problem, magnetic maneuvering has recently become a thrust research area. Here, we report the first demonstration of accurate robotic steering and noninvasive 3-D localization of a magnetically enabled sample of the most common video capsule (PillCam, Given Imaging Ltd, Israel) within each of the main regions of the GI tract (esophagus, stomach, small bowel, and colon) in vivo, in a domestic pig model. Moreover, we demonstrate how this is readily achievable with a robotic magnetic navigation system (Niobe, Stereotaxis, Inc, USA) already used for cardiovascular clinical procedures. The capsule was freely and safely moved with omnidirectional steering accuracy of 1 degrees , and was tracked in real time through fluoroscopic imaging, which also allowed for 3-D localization with an error of 1 mm. The accuracy of steering and localization enabled by the Stereotaxis system and its clinical accessibility world wide may allow for immediate and broad usage in this new application. This anticipates magnetically steerable WCE as a near-term reality. The instrumentation should be used with the next generations of video capsules, intrinsically magnetic and capable of real-time optical-image visualization, which are expected to reach the market soon. PMID- 20952325 TI - Parametric shape representation by a deformable NURBS model for cardiac functional measurements. AB - This paper proposes a method of parametric representation and functional measurement of 3-D cardiac shapes in a deformable nonuniform rational B-splines (NURBS) model. This representation makes it very easy to automatically evaluate the functional parameters and myocardial kinetics of the heart, since quantitative analysis can be followed in a simple way. In the model, local deformation and motion on the cardiac shape are expressed in adjustable parameters. Especially, an effective integral algorithm is used for volumetric measurement of a NURBS shape since the volume is the most basic parameter in cardiac functional analysis. This method promises the numerical computation to be very convenient, efficient, and accurate, in comparison with traditional methods. Practical experiments are carried out, and results show that the algorithm can get satisfactory measurement accuracy and efficiency. The parametric NURBS model in cylindrical coordinates is not only very suitable to fit the anatomical surfaces of a cardiac shape, but also easy for geometric transformation and nonrigid registration, and able to represent local dynamics and kinetics, and thus, can easily be applied for quantitative and functional analysis of the heart. PMID- 20952326 TI - Iris center corneal reflection method for gaze tracking using visible light. AB - Very few attempts, if any, have been made to use visible light in corneal reflection approaches to the problem of gaze tracking. The reasons usually given to justify the limited application of this type of illumination are that the required image features are less accurately depicted, and that visible light may disturb the user. The aim of this paper is to show that it is possible to overcome these difficulties and build an accurate and robust gaze tracker under these circumstances. For this purpose, visible light is used to obtain the corneal reflection or glint in a way analogous to the well-known pupil center corneal reflection technique. Due to the lack of contrast, the center of the iris is tracked instead of the center of the pupil. The experiments performed in our laboratory have shown very satisfactory results, allowing free-head movement and no need of recalibration. PMID- 20952327 TI - Estimation of lung's air volume and its variations throughout respiratory CT image sequences. AB - A respiratory image-sequence-segmentation technique is introduced based on a novel image-sequence analysis. The proposed technique is capable of segmenting the lung's air and its soft tissues followed by estimating the lung's air volume and its variations throughout the image sequence. Accurate estimation of these two parameters is very important in many applications related to lung disease diagnosis and treatment systems (e.g., brachytherapy), where the parameters are either the variables of interest themselves or are dependent/independent variables. The concept of the proposed technique involves using the image sequence's combined histogram to obtain a reasonable initial guess for the lung's air segmentation thresholds. This is followed by an optimization process to find the optimum threshold values that best satisfy the lung's air mass conservation and tissue incompressibility principles. These threshold values are consequently applied to estimate the lung's air volume and its variations throughout respiratory Computed Tomography (CT) image sequences. Ex vivo experiments were conducted on porcine left lungs in order to demonstrate the performance of the proposed technique. The proposed method was initially validated using a breath hold CT image sequence with known air volumes inside the lung, where results show that the proposed technique outperforms single-histogram-based methods. This was followed by demonstrating the proposed technique's application in a 4-D-CT respiratory sequence, where the air volume inside the lung was unknown. Consistency of the obtained results in the latter experiment with tissue near incompressibility principle was validated. The results indicate a very good ability of the proposed method for estimating the lung's air volume and its variations in a respiratory image sequence. PMID- 20952328 TI - Advancements in noncontact, multiparameter physiological measurements using a webcam. AB - We present a simple, low-cost method for measuring multiple physiological parameters using a basic webcam. By applying independent component analysis on the color channels in video recordings, we extracted the blood volume pulse from the facial regions. Heart rate (HR), respiratory rate, and HR variability (HRV, an index for cardiac autonomic activity) were subsequently quantified and compared to corresponding measurements using Food and Drug Administration approved sensors. High degrees of agreement were achieved between the measurements across all physiological parameters. This technology has significant potential for advancing personal health care and telemedicine. PMID- 20952329 TI - Automatic optic disc detection from retinal images by a line operator. AB - Under the framework of computer-aided eye disease diagnosis, this paper presents an automatic optic disc (OD) detection technique. The proposed technique makes use of the unique circular brightness structure associated with the OD, i.e., the OD usually has a circular shape and is brighter than the surrounding pixels whose intensity becomes darker gradually with their distances from the OD center. A line operator is designed to capture such circular brightness structure, which evaluates the image brightness variation along multiple line segments of specific orientations that pass through each retinal image pixel. The orientation of the line segment with the minimum/maximum variation has specific pattern that can be used to locate the OD accurately. The proposed technique has been tested over four public datasets that include 130, 89, 40, and 81 images of healthy and pathological retinas, respectively. Experiments show that the designed line operator is tolerant to different types of retinal lesion and imaging artifacts, and an average OD detection accuracy of 97.4% is obtained. PMID- 20952330 TI - A Web-based system for the quantitative and reproducible assessment of clinical indexes from the retinal vasculature. AB - A novel system for the vascular tree identification and the quantitative estimation of arteriolar venular ratio clinical index in retinal fundus images is presented. The system is composed of a module for automatic vascular tracking, an interactive editing interface to correct errors and set the required parameters of analysis, and a module for the computation of clinical indexes. The system was organized as a client-server structure to allow clinicians and researchers from all over the world to work remotely. The system was evaluated by three graders analyzing 30 fundus images. The evaluation of the Pearson's correlation coefficient and p-value of a paired t-test for each pair of graders demonstrates the high reproducibility of the measures provided by the system. PMID- 20952331 TI - Segmentation of intra-retinal layers from optical coherence tomography images using an active contour approach. AB - Optical coherence tomography (OCT) is a noninvasive, depth-resolved imaging modality that has become a prominent ophthalmic diagnostic technique. We present a semi-automated segmentation algorithm to detect intra-retinal layers in OCT images acquired from rodent models of retinal degeneration. We adapt Chan-Vese's energy-minimizing active contours without edges for the OCT images, which suffer from low contrast and are highly corrupted by noise. A multiphase framework with a circular shape prior is adopted in order to model the boundaries of retinal layers and estimate the shape parameters using least squares. We use a contextual scheme to balance the weight of different terms in the energy functional. The results from various synthetic experiments and segmentation results on OCT images of rats are presented, demonstrating the strength of our method to detect the desired retinal layers with sufficient accuracy even in the presence of intensity inhomogeneity resulting from blood vessels. Our algorithm achieved an average Dice similarity coefficient of 0.84 over all segmented retinal layers, and of 0.94 for the combined nerve fiber layer, ganglion cell layer, and inner plexiform layer which are the critical layers for glaucomatous degeneration. PMID- 20952333 TI - Performance analysis of a new real-time elastographic time constant estimator. AB - New elastographic techniques such as poroelastography and viscoelasticity imaging aim at imaging the temporal mechanical behavior of tissues. These techniques usually involve the use of curve fitting methods being applied to noisy data to estimate new elastographic parameters. As of today, however, current elastographic implementations of poroelastography and viscoelasticity imaging methods are in general too slow and not optimized for clinical applications. Furthermore, image quality performance of these new elastographic techniques is still largely unknown due to a paucity of data and the lack of systematic studies that analyze their performance limitations. In this paper, we propose a new elastographic time constant (TC) estimator, which is based on the use of the least square error (LSE) curve-fitting method and the Levenberg-Marquardt (LM) optimization rule as applied to noisy elastographic data obtained from a material in a creep-type experiment. The algorithm is executed on a massively parallel general purpose graphics processing unit (GPGPU) to achieve real-time performance. The estimator's performance is analyzed using simulations. Experimental results obtained from poroelastic phantoms are presented as a proof of principle of the new estimator's technical applicability on real experimental data. The results of this study demonstrate that the newly proposed elastographic estimator can produce highly accurate and sensitive elastographic TC estimates in real-time and at high signal-to-noise ratios. PMID- 20952332 TI - Mosaic decomposition: an electronic cleansing method for inhomogeneously tagged regions in noncathartic CT colonography. AB - Electronic cleansing (EC) is a method that segments fecal material tagged by an X ray-opaque oral contrast agent in computed tomographic colonography (CTC) images, and effectively removes the material for digitally cleansing the colon. In this study, we developed a novel EC method, called mosaic decomposition (MD), for reduction of the artifacts due to incomplete cleansing of inhomogeneously tagged fecal material in CTC images, especially in noncathartic CTC images. In our approach, the entire colonic region, including the residual fecal regions, was first decomposed into a set of local homogeneous regions, called tiles, after application of a 3-D watershed transform to the CTC images. Each tile was then subjected to a single-class support vector machine (SVM) classifier for soft tissue discrimination. The feature set of the soft-tissue SVM classifier was selected by a genetic algorithm (GA). A scalar index, called a soft-tissue likelihood, is formulated for differentiation of the soft-tissue tiles from those of other materials. Then, EC based on MD, called MD-cleansing, is performed by first initializing of the level-set front with the classified tagged regions; the front is then evolved by use of a speed function that was designed, based on the soft-tissue index, to reserve the submerged soft-tissue structures while suppressing the residual fecal regions. The performance of the MD-cleansing method was evaluated by use of a phantom and of clinical cases. In the phantom evaluation, our MD-cleansing was trained with the supine (prone) scan and tested on the prone (supine) scan, respectively. In both cases, the sensitivity and specificity of classification were 100%. The average cleansing ratio was 90.6%, and the soft-tissue preservation ratio was 97.6%. In the clinical evaluation, 10 noncathartic CTC cases (20 scans) were collected, and the ground truth of a total of 2095 tiles was established by manual assignment of a material class to each tile. Five cases were randomly selected for training GA/SVM, and the remaining five cases were used for testing. The overall sensitivity and specificity of the proposed classification scheme were 97.1% and 85.3%, respectively, and the accuracy was 94.6%. The area under the ROC curve (Az) was 0.96. Our results indicated that the use of MD-cleansing substantially improved the effectiveness of our EC method in the reduction of incomplete cleansing artifacts. PMID- 20952334 TI - Regularized image reconstruction algorithms for dual-isotope myocardial perfusion SPECT (MPS) imaging using a cross-tracer prior. AB - In simultaneous dual-isotope myocardial perfusion SPECT (MPS) imaging, data are simultaneously acquired to determine the distributions of two radioactive isotopes. The goal of this work was to develop penalized maximum likelihood (PML) algorithms for a novel cross-tracer prior that exploits the fact that the two images reconstructed from simultaneous dual-isotope MPS projection data are perfectly registered in space. We first formulated the simultaneous dual-isotope MPS reconstruction problem as a joint estimation problem. A cross-tracer prior that couples voxel values on both images was then proposed. We developed an iterative algorithm to reconstruct the MPS images that converges to the maximum a posteriori solution for this prior based on separable surrogate functions. To accelerate the convergence, we developed a fast algorithm for the cross-tracer prior based on the complete data OS-EM (COSEM) framework. The proposed algorithm was compared qualitatively and quantitatively to a single-tracer version of the prior that did not include the cross-tracer term. Quantitative evaluations included comparisons of mean and standard deviation images as well as assessment of image fidelity using the mean square error. We also evaluated the cross tracer prior using a three-class observer study with respect to the three-class MPS diagnostic task, i.e., classifying patients as having either no defect, reversible defect, or fixed defects. For this study, a comparison with conventional ordered subsets-expectation maximization (OS-EM) reconstruction with postfiltering was performed. The comparisons to the single-tracer prior demonstrated similar resolution for areas of the image with large intensity changes and reduced noise in uniform regions. The cross-tracer prior was also superior to the single-tracer version in terms of restoring image fidelity. Results of the three-class observer study showed that the proposed cross-tracer prior and the convergent algorithms improved the image quality of dual-isotope MPS images compared to OS-EM. PMID- 20952335 TI - A novel model-based 3D +time left ventricular segmentation technique. AB - A common approach to model-based segmentation is to assume a top-down modelling strategy. However, this is not feasible for complex 3D +time structures, such as the cardiac left ventricle, due to increased training requirements, aligning difficulties and local minima in resulting models. As our main contribution, we present an alternate bottom-up modelling approach. By combining the variation captured in multiple dimensionally-targeted models at segmentation-time we create a scalable segmentation framework that does not suffer from the "curse of dimensionality." Our second contribution involves a flexible contour coupling technique that allows our segmentation method to adapt to unseen contour configurations outside the training set. This is used to identify the endo- and epicardium contours of the left ventricle by coupling them at segmentation-time, instead of at model-time. We apply our approach to 33 3D +time cardiac MRI datasets and perform comprehensive evaluation against several state-of-the-art works. Quantitative evaluation illustrates that our method requires significantly less training than state-of-the-art model-based methods, while maintaining or improving segmentation accuracy. PMID- 20952336 TI - Total Bregman divergence and its applications to DTI analysis. AB - Divergence measures provide a means to measure the pairwise dissimilarity between "objects," e.g., vectors and probability density functions (pdfs). Kullback Leibler (KL) divergence and the square loss (SL) function are two examples of commonly used dissimilarity measures which along with others belong to the family of Bregman divergences (BD). In this paper, we present a novel divergence dubbed the Total Bregman divergence (TBD), which is intrinsically robust to outliers, a very desirable property in many applications. Further, we derive the TBD center, called the t-center (using the l(1)-norm), for a population of positive definite matrices in closed form and show that it is invariant to transformation from the special linear group. This t-center, which is also robust to outliers, is then used in tensor interpolation as well as in an active contour based piecewise constant segmentation of a diffusion tensor magnetic resonance image (DT-MRI). Additionally, we derive the piecewise smooth active contour model for segmentation of DT-MRI using the TBD and present several comparative results on real data. PMID- 20952337 TI - A new method for volume segmentation of PET images, based on possibility theory. AB - 18F-fluorodeoxyglucose positron emission tomography (18FDG PET) has become an essential technique in oncology. Accurate segmentation and uptake quantification are crucial in order to enable objective follow-up, the optimization of radiotherapy planning, and therapeutic evaluation. We have designed and evaluated a new, nearly automatic and operator-independent segmentation approach. This incorporated possibility theory, in order to take into account the uncertainty and inaccuracy inherent in the image. The approach remained independent of PET facilities since it did not require any preliminary calibration. Good results were obtained from phantom images [percent error =18.38% (mean) +/- 9.72% (standard deviation)]. Results on simulated and anatomopathological data sets were quantified using different similarity measures and showed the method was efficient (simulated images: Dice index =82.18% +/- 13.53% for SUV =2.5 ). The approach could, therefore, be an efficient and robust tool for uptake volume segmentation, and lead to new indicators for measuring volume of interest activity. PMID- 20952338 TI - Robust curve clustering based on a multivariate t-distribution model. AB - This brief presents a curve clustering technique based on a new multivariate model. Instead of the usual Gaussian random effect model, our method uses the multivariate t-distribution model which has better robustness to outliers and noise. In our method, we use the B-spline curve to model curve data and apply the mixed-effects model to capture the randomness and covariance of all curves within the same cluster. After fitting the B-spline-based mixed-effects model to the proposed multivariate t -distribution, we derive an expectation-maximization algorithm for estimating the parameters of the model, and apply the proposed approach to the simulated data and the real dataset. The experimental results show that our model yields better clustering results when compared to the conventional Gaussian random effect model. PMID- 20952339 TI - Leveraging social system networks in ubiquitous high-data-rate health systems. AB - Social system networks with high data rates and limited storage will discard data if the system cannot connect and upload the data to a central server. We address the challenge of limited storage capacity in mobile health systems during network partitions with a heuristic that achieves efficiency in storage capacity by modifying the granularity of the medical data during long intercontact periods. Patterns in the connectivity, reception rate, distance, and location are extracted from the social system network and leveraged in the global algorithm and online heuristic. In the global algorithm, the stochastic nature of the data is modeled with maximum likelihood estimation based on the distribution of the reception rates. In the online heuristic, the correlation between system position and the reception rate is combined with patterns in human mobility to estimate the intracontact and intercontact time. The online heuristic performs well with a low data loss of 2.1%-6.1%. PMID- 20952340 TI - Apnea MedAssist: real-time sleep apnea monitor using single-lead ECG. AB - We have developed a low-cost, real-time sleep apnea monitoring system ''Apnea MedAssist" for recognizing obstructive sleep apnea episodes with a high degree of accuracy for both home and clinical care applications. The fully automated system uses patient's single channel nocturnal ECG to extract feature sets, and uses the support vector classifier (SVC) to detect apnea episodes. "Apnea MedAssist" is implemented on Android operating system (OS) based smartphones, uses either the general adult subject-independent SVC model or subject-dependent SVC model, and achieves a classification F-measure of 90% and a sensitivity of 96% for the subject-independent SVC. The real-time capability comes from the use of 1-min segments of ECG epochs for feature extraction and classification. The reduced complexity of "Apnea MedAssist" comes from efficient optimization of the ECG processing, and use of techniques to reduce SVC model complexity by reducing the dimension of feature set from ECG and ECG-derived respiration signals and by reducing the number of support vectors. PMID- 20952341 TI - Fall detection with multiple cameras: an occlusion-resistant method based on 3-D silhouette vertical distribution. AB - According to the demographic evolution in industrialized countries, more and more elderly people will experience falls at home and will require emergency services. The main problem comes from fall-prone elderly living alone at home. To resolve this lack of safety, we propose a new method to detect falls at home, based on a multiple-cameras network for reconstructing the 3-D shape of people. Fall events are detected by analyzing the volume distribution along the vertical axis, and an alarm is triggered when the major part of this distribution is abnormally near the floor during a predefined period of time, which implies that a person has fallen on the floor. This method was validated with videos of a healthy subject who performed 24 realistic scenarios showing 22 fall events and 24 cofounding events (11 crouching position, 9 sitting position, and 4 lying on a sofa position) under several camera configurations, and achieved 99.7% sensitivity and specificity or better with four cameras or more. A real-time implementation using a graphic processing unit (GPU) reached 10 frames per second (fps) with 8 cameras, and 16 fps with 3 cameras. PMID- 20952342 TI - A hybrid clustering method for ROI delineation in small-animal dynamic PET images: application to the automatic estimation of FDG input functions. AB - Tracer kinetic modeling with dynamic positron emission tomography (PET) requires a plasma time-activity curve (PTAC) as an input function. Several image-derived input function (IDIF) methods that rely on drawing the region of interest (ROI) in large vascular structures have been proposed to overcome the problems caused by the invasive approach for obtaining the PTAC, especially for small-animal studies. However, the manual placement of ROIs for estimating IDIF is subjective and labor-intensive, making it an undesirable and unreliable process. In this paper, we propose a novel hybrid clustering method (HCM) that objectively delineates ROIs in dynamic PET images for the estimation of IDIFs, and demonstrate its application to the mouse PET studies acquired with [ (18)F]Fluoro 2-deoxy-2-D-glucose (FDG). We begin our HCM using k-means clustering for background removal. We then model the time-activity curves using polynomial regression mixture models in curve clustering for heart structure detection. The hierarchical clustering is finally applied for ROI refinements. The HCM achieved accurate ROI delineation in both computer simulations and experimental mouse studies. In the mouse studies, the predicted IDIF had a high correlation with the gold standard, the PTAC derived from the invasive blood samples. The results indicate that the proposed HCM has a great potential in ROI delineation for automatic estimation of IDIF in dynamic FDG-PET studies. PMID- 20952343 TI - Automated detection of cell nuclei in pap smear images using morphological reconstruction and clustering. AB - In this paper, we present a fully automated method for cell nuclei detection in Pap smear images. The locations of the candidate nuclei centroids in the image are detected with morphological analysis and they are refined in a second step, which incorporates a priori knowledge about the circumference of each nucleus. The elimination of the undesirable artifacts is achieved in two steps: the application of a distance-dependent rule on the resulted centroids; and the application of classification algorithms. In our method, we have examined the performance of an unsupervised (fuzzy C-means) and a supervised (support vector machines) classification technique. In both classification techniques, the effect of the refinement step improves the performance of the clustering algorithm. The proposed method was evaluated using 38 cytological images of conventional Pap smears containing 5617 recognized squamous epithelial cells. The results are very promising, even in the case of images with high degree of cell overlapping. PMID- 20952344 TI - Upslope walking with a powered knee and ankle prosthesis: initial results with an amputee subject. AB - This paper extends a previously developed level- ground walking control methodology to enable an above knee amputee to walk up slopes using a powered knee and ankle prosthesis. Experimental results corresponding to walking on level ground and two different slope angles (5 ( degrees ) and 10 ( degrees )) with the powered prosthesis using the control method are compared to walking under the same conditions with a passive prosthesis. The data indicate that the powered prosthesis with the upslope walking controller is able to reproduce several kinematic characteristics of healthy upslope walking that the passive prosthesis does not (such as knee flexion after heel strike and a powered ankle plantarflexion during push-off). Finally, results are shown that demonstrate the ability of the prosthesis to generate a slope estimate, which is in turn utilized to adapt the underlying control parameters to the corresponding slope. PMID- 20952345 TI - Safety and efficacy after switch to a saquinavir-containing antiretroviral regimen in protease inhibitor pretreated HIV-positive patients. AB - OBJECTIVE: the RAINBOW survey is a multinational observational study assessing the tolerability and efficacy of ritonavir-boosted saquinavir (SQV/r), using the 500 mg film-coated SQV formulation, in routine clinical practice. This analysis presents data from the German subgroup of protease inhibitor (PI)-pretreated, but SQV-naive patients. METHODS: multicenter, prospective, open-label, 48 week cohort study. Efficacy assessments included the proportion of patients with HIV-1 RNA <50 and <400 copies/mL and changes in CD4 cell count from baseline to week 48. Tolerability assessments included changes in liver enzymes and lipid levels from baseline to week 48. RESULTS: a total of 426 patients were included in the analysis. The proportion of patients with HIV RNA levels <50 copies/mL at week 48 was 60.3 % (compared with 31.7% at switch to SQV/r) (intent-to-treat, last observation carried forward analysis). After 48 weeks, median CD4 count increased by +61 cells/mm3 from baseline (p<0.01) and 60.3% of patients achieved HIV-1 RNA <50 copies/mL. Median changes in fasting triglyceride levels (stratified according to baseline level) at week 48 were: +14 mg/dL (IQR -8; 57) for patients with baseline triglyceride <200 mg/dL; -50 mg/dL (IQR -139; 0) for baseline triglyceride 200-750 mg/dL, and -656 mg/dL (IQR -1024; 0) for baseline triglyceride >750 mg/dL (p<0.01 for all). Median changes in fasting total cholesterol (TC) levels (stratified according to baseline) were +16 mg/dL (IQR 3; 43) for patients with baseline TC <200 mg/dL (p<0.01), -3 mg/dL (IQR -25; 25) for baseline TC 200-300 mg/dL (p = 0.4), and -47 mg/dL (IQR -87; -4) for baseline TC >300 mg/dL (p<0.01). No significant changes in liver enzymes or bilirubin were observed. SQV treatment was discontinued in 22% of patients, 6% due to side effects. CONCLUSIONS: these data confirm the efficacy and tolerability of SQV/r in PI-experienced, SQV-naive patients treated in a real-life clinical setting. Of particular relevance are the improvements in triglycerides and TC levels observed in patients with baseline grade III-IV elevations. PMID- 20952346 TI - Simian virus 40 inhibits differentiation and maturation of rhesus macaque DC SIGN(+) dendritic cells. AB - Dendritic cells (DC) are the initiators and modulators of the immune responses. Some species of pathogenic microorganisms have developed immune evasion strategies by controlling antigen presentation function of DC. Simian virus 40 (SV40) is a DNA tumor virus of rhesus monkey origin. It can induce cell transformation and tumorigenesis in many vertebrate species, but often causes no visible effects and persists as a latent infection in rhesus monkeys under natural conditions. To investigate the interaction between SV40 and rhesus monkey DC, rhesus monkey peripheral blood monocyte-derived DC were induced using recombinant human Interleukin-4 (rhIL-4) and infective SV40, the phenotype and function of DC-specific intracellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN)(+) DC were analyzed by flow cytometry (FCM) and mixed lymphocyte reaction (MLR). Results showed that SV40 can down-regulate the expression of CD83 and CD86 on DC and impair DC-induced activation of T cell proliferation. These findings suggest that SV40 might also cause immune suppression by influencing differentiation and maturation of DC. PMID- 20952347 TI - Prospective observational study for perioperative volume replacement with 6% HES 130/0,42, 4% gelatin and 6% HES 200/0,5 in cardiac surgery. AB - BACKGROUND: the constantly growing amount of different kinds of colloid fluids necessitates comparative investigations with regards to the safety and effectivity in clinical use of these preparations. Hence we compared three colloid fluids in an observational study. The objective was the exploration of the influence of these three colloids on blood coagulation, hemodynamics and renal function of the cardiac surgical patient. METHODS: we included 90 patients undergoing an elective open-heart surgery with the use of the heart-lung machine and observed them consecutively. Group 1 [gelatin 4% (n = 30)], Group 2 [HES 200/0,5 (n = 30)] and Group 3 [HES 130/0,42 (n = 30)]. We measured the perioperative volume replacement, the administration of blood- and coagulation products, the application of catecholamines, the renal function, blood gas and the platelet aggregation using multiplate electrode analyzer (Multiplate, Dynabyte medical, Munich, Germany). RESULTS: the gelatin-group needed significantly more norepinephrine than the HES 130/0.42 group. The responsible surgeon considered the blood coagulation in the HES 200/0.5 group most frequently as impaired. Furthermore we saw a significant decrease in platelet function in the HES 200/0.5 group when performing the multiplate-analysis (ADP-and COL-test). HES 130/0.4 as well as gelatin 4% showed no significant change in platelet function. The gelatin-group and the HES 200/0.5 needed significantly more aprotinine than the HES 130/0.4 group. We saw no significant difference with regards to administration of blood and coagulation products between the three groups. The urinary excretion during the intervention was significantly higher in the HES 200/0.5 group and in the gelatin group than in the HES 130/0.4 group. CONCLUSIONS: our results confirm the lower stabilizing effect of gelatin on circulation during fluid resuscitation. The blood coagulation was mostly impaired due to HES 200/0.5 confirmed by the multiplate(r)-analysis as well as by different clinical findings. PMID- 20952348 TI - MIS approach for diverticula of the esophagus. AB - PURPOSE: diverticula of the esophagus represent a rare pathological entity. Distinct classifications of the disease imply different surgical concepts. Surgery should be reserved for symptomatic patients only. Minimally invasive surgery (MIS) for treatment of esophageal diverticula encompasses rigid and flexible intraluminal endoscopy, thoracoscopy and laparoscopy. We here give an overview on the pathogenesis of esophageal diverticula, the minimally invasive surgical techniques for treatment and the recent literature. Additionally, we present our own experience with MIS for midthoracic diverticula. METHODS: we analyzed the cases of patients who underwent MIS for midthoracic diverticula with regard to preoperative symptoms, perioperative and follow-up data. RESULTS: three patients (two female, one male, age 79, 78 and 59 years) received thoracoscopic surgery for midthoracic diverticula. All patients reported of dysphagia and regurgitation. In two patients pH-investigation showed pathological reflux but manometry was normal in all patients. Operating time was 205, 135 and 141 minutes. We performed intraoperative intraluminal endoscopy in all patients. There were no intraoperative complications and although no surgical complications occured postoperatively one patient developed pneumonia which advanced to sepsis and lethal multi organ failure. Upon follow-up the two patients did not have recurrent diverticula or a recurrence of previous symptoms. CONCLUSIONS: surgery for diverticular disease of the esophagus has been associated with high rates of morbidity and mortality. Despite the lethal non-surgical complication we encountered, with regard to recent publications minimally invasive apporaches to treat patients with symptomatic esophageal diverticula entail lower rates of complications with better long term results in comparison to open surgery. PMID- 20952349 TI - Cellular locations of proteinases and association with vesicles in Porphyromonas gingivalis. AB - We found that locations of arginine-specific gingipain (RGP) in the cellular fractions in the crude extract, envelope, vesicles, and culture supernatants were 48%, 16%, 17%, and 31%, respectively, and the corresponding values of lysine specific gingipain (KGP) were 47%, 10%, 7%, and 36%, respectively. Although the molecular mass of RGP in the culture supernatant had been determined as 43 kDa, and that of KGP had been as 48 kDa, molecular masses of both proteinases solubilized from the vesicles were estimated to be over 1,500 kDa, since they eluted in the void volume of the column in the gel filtration on Sephacryl S-300. There was no reduction of molecular size by the following treatment with SDS, high-concentration NaCl, or urea. Interestingly, the occurrence of the macromolecular forms could not observed in other enzymes tested such as monopeptidyl, dipeptidyl, and tripeptidyl peptidases, as well as alkaline phosphatase. Therefore, occurrence of the macromolecular forms may be restricted to the proteinases. When the vesicle and culture supernatants containing free RGP and KGP were mixed and incubated, neither RGP nor KGP seemed to bind to vesicles. RGP bound to the vesicle was found to be more stable to heat treatment than the free form, suggesting that association of RGP with the vesicle caused heat stability of this enzyme. PMID- 20952350 TI - Alexithymia, emotion processing and social anxiety in adults with ADHD. AB - OBJECTIVE: given sparse research on the issue, this study sought to shed light upon the interactions of alexithymia, emotion processing, and social anxiety in adults with attention-deficit hyperactivity disorder (ADHD). SUBJECTS AND METHODS: 73 German adults with ADHD according to DSM-IV diagnostic criteria participated. We used the Toronto Alexithymia Scale (TAS-20) to assess alexithymia, the Social Phobia Scale (SPS) and the Social Interaction Anxiety Scale (SIAS) to assess different features of social anxiety, and we applied the German "Experience of Emotions Scalerdquor; (SEE) to measure emotion processing. RESULTS: 40% of the sample were found to meet the DSM-IV criteria of social anxiety disorder, and about 22% were highly alexithymic according to a TAS-20 total score >= 61; however, the mean TAS-20 total score of 50.94 +/- 9.3 was not much higher than in community samples. Alexithymic traits emerged to be closely linked to emotion processing problems, particularly 'difficulty accepting own emotions', and to social anxiety features. DISCUSSION/CONCLUSION: our findings suggest interactions of alexithymia, emotion processing dysfunction, and social anxiety in adults with ADHD, which may entail the therapeutic implication to thoroughly instruct these patients to identify, accept, communicate, and regulate their emotions to aid reducing interaction anxiety. PMID- 20952352 TI - High-dose intravenous immunoglobulins in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis in Chinese patients: a retrospective study of 82 cases. AB - Stevens-Johnson Syndrome (SJS) and Toxic epidermal necrolysis (TEN) are drug induced diseases with a low incidence but high mortality. While there is no standard treatment, corticosteroids and intravenous immunoglobulin (IVIG) therapy have been widely used, with controversy. Our objective was to summarize the etiology and therapeutic regimen of SJS or TEN in 82 hospitalized patients in China. A retrospective study was performed on 82 patients who were diagnosed with SJS or TEN and hospitalized in Peking Union Medical College Hospital from July 1994 to August 2009. Of them, 24 were treated with IVIG plus corticosteroids (IVIG group) and the other 58 were treated with corticosteroids only (corticosteroids group). SCORTEN was used to evaluate the severity and prognosis of the patients. The efficacy of therapeutic modalities was assessed by the following parameters: starting and the maximum dose of corticosteroids, cumulative dose of corticosteroids before tapering, cumulative dose of IVIG, days of corticosteroid application before its tapering and the hospitalization days. The common agents triggering SJS/TEN in these patients were non-steroidal anti inflammatory drugs (31 cases), anti-epileptics (18 cases), antibiotics (14 cases), antipodagrics (4 cases), sulfanilamides (4 cases) and others (11 cases), respectively. Carbamazepine was the most common drug, and induced 15 cases of SJS/TEN. The SCORTEN was significantly higher in the IVIG group than that in the corticosteroid group (2.0 +/- 1.7 vs 0.8 +/- 1.0, P = 0.001). Whereas no differences were observed between the two groups in the parameters including starting and maximum dose of corticosteroids, cumulative dose and the number of application days of corticosteroids before tapering and hospitalization days. However, in patients whose SCORTEN scores were 2, application of IVIG and corticosteroids shortened the duration of hospitalization from 26.4 +/- 9.5 d to 18.1 +/- 5.3 d (P < 0.05). No significant difference was observed in the incidence of complications between the two groups (54.2% vs 39.7%, P > 0.05). The actual mortalities were 12.5% in the IVIG group and 3.4% in corticosteroid group respectively, which were significantly lower than the predicted values (22.0% and 7.2%, respectively). Standardized mortality ratio (SMR) analysis showed a trend to a lower actual mortality (not significant) with corticosteroid treatment than the predicted mortality (SMR = 0.480; 95% CI: 0.075-1.923) and combination therapy had a tendency to reduce the mortality (not significant) rate of TEN (SMR = 0.569; 95% CI: 0.318-1.910). No significant difference in SMR was found between the two groups (P = 0.1474). Survival analysis showed that a favorable overall survival was associated with younger age (P = 0.0405). Our data indicated that early application of corticosteroids presented beneficial effects on SJS/TEN, and that combination therapy of corticosteroids and IVIG achieved a better therapeutic effect than the administration of corticosteroids alone. We recommend early treatment with IVIG at total doses of more than 2 g/kg in SJS/TEN patients whose SCORTEN are higher than 0. PMID- 20952353 TI - Accentuated cortico-cortical evoked potentials in neocortical epilepsy in areas of ictal onset. AB - OBJECTIVE: To determine whether patients with neocortical epilepsy show evidence for increased excitability measured by cortico-cortical evoked potentials (CCEPs) in ictal-onset regions. METHODS: In patients undergoing intracranial recordings with subdural electrodes for epilepsy surgery, we measured amplitudes, latencies, and stimulus thresholds of CCEPs near ictal onset zones (iCCEPs), and compared with adjacent neocortex not associated with ictal EEG (nCCEP). CCEP amplitude and latency measurements were made with each stimulation site, using graded stimulation intensities. RESULTS: Ten patients were included in this study. CCEPs were recorded in eight of 10 patients. The first negative (N1) iCCEP amplitude was higher than that of nCCEP in seven of the eight patients. In the group analysis, this difference was statistically significant. In three of these patients, the difference was individually significant. In one patient, the amplitude was higher in nCCEP than iCCEP and the area selected as nCCEP was within primary eloquent cortex. There was no significant difference seen in latency changes or stimulus threshold. CONCLUSIONS: Accentuated CCEP amplitudes near ictal onset zones could reflect an increased excitability of the cortex associated with the epileptogenic zone in some patients with neocortical epilepsy. The response of the neocortex to low-frequency stimulation may vary depending on the presence or absence of intrinsic epileptogenicity. PMID- 20952351 TI - Fulminant staphylococcus lugdunensis septicaemia following a pelvic varicella zoster virus infection in an immune-deficient patient: a case report. AB - INTRODUCTION: the deadly threat of systemic infections with coagulase negative Staphylococcus lugdunensis despite an appropriate antibiotic therapy has only recently been recognized. The predominant infectious focus observed so far is left-sided native heart valve endocarditis, but bone and soft tissue infections, septicaemia and vascular catheter-related bloodstream infections have also been reported. We present a patient with a fatal Staphylococcus lugdunensis septicaemia following zoster bacterial superinfection of the pelvic region. case presentation: a 71-year old male diagnosed with IgG kappa plasmocytoma presented with a conspicuous weight loss, a hypercalcaemic crisis and acute renal failure. After initiation of haemodialysis treatment his condition improved rapidly. However, he developed a varicella-zoster virus infection of the twelfth thoracic dermatome requiring intravenous acyclovir treatment. Four days later the patient presented with a fulminant septicaemia. Despite an early intravenous antibiotic therapy with ciprofloxacin, piperacillin/combactam and vancomycin the patient died within 48 hours, shortly before the infective isolate was identified as Staphylococcus lugdunensis by polymerase chain reaction. CONCLUSION: despite S. lugdunensis belonging to the family of coagulase-negative staphylococci with an usually low virulence, infections with S. lugdunensis may be associated with an aggressive course and high mortality. This is the first report on a Staphylococcus lugdunensis septicaemia following a zoster bacterial superinfection of the pelvic region. PMID- 20952355 TI - Optimal positioning in the detection of inferior wall infarct size with myocardial perfusion scintigraphy: prone vs. supine. AB - OBJECTIVE: The prone position is commonly utilized to reduce false positive perfusion defects because this position overcomes the diaphragmatic inferior wall attenuation in single-photon emission computerized tomography (SPECT) studies. We investigated whether the prone position had an important advantage over the supine position in determining the severity and extent of infarct in patients with acute inferior myocardial infarction (MI). METHODS: Twenty-nine male patients (mean age 61 +/- 10 years) with acute inferior MI were enrolled in the cross-sectional study. After injection of thallium-201 (201Tl) under resting conditions, redistribution SPECT imaging was twicely performed in each subject, in both the supine and prone positions, consecutively. The extent and severity scores of the perfusion defects were calculated from the sum of individual segment scores. Myocardial infarction size was also evaluated using peak cardiac troponin T (cTnT) levels. Wilcoxon rank and Spearman's rank correlation tests were used for statistical analyses of data. RESULTS: For the supine vs. prone positions, the median defect severity scores were 8 (4-13) vs. 5 (0.5-8.5) and the defect extent scores were 4 (3-5.5) vs. 3 (0.5-4.5), respectively. Both perfusion defect scores in the prone position were significantly lower than those in the supine position (p=0.001). The mean peak cTnT level during hospitalization was 7.2 +/- 3.9 ug/l. Peak cTnT levels were correlated with all SPECT parameters. However, the correlation was greater in the prone position (defect severity: r=0.712, p=0.001) (defect extent: r=0.790, p=0.001) than in the supine position (defect severity: r=0.495, p=0.01) (defect extent: r=0.481, p=0.01). CONCLUSION: In patients with inferior MI, the SPECT results revealed a significant difference between the supine and prone images. The perfusion extent and severity scores of SPECT in the inferior wall with prone imaging correlates better with the peak troponin compared to the supine position. Comparative studies that use advanced imaging tools are needed to verify our present findings. PMID- 20952354 TI - [Reliability and validity of the Turkish version of the Chronic Heart Failure Questionnaire]. AB - OBJECTIVE: Any disease specific Health Related Quality of Life Instrument for Chronic Heart Failure (CHF) is lacking in Turkey. The aim of this study is to adapt the Chronic Heart Failure Questionnaire (CHQ) into Turkish and probe the reliability and validity of this questionnaire. METHODS: There are four dimensions of this 20 items scale. These dimensions are: dyspnea (5 items), fatigue (4 items), emotional status (7 items) and mastery (4 items). Response options were evaluated using a 7 -point Likert type scale. Quality of life (QOL) improves as the score increases. A total of 205 CHF patients hospitalized in the Department of Cardiology of Ege University hospital were enrolled in this study. The CHQ was applied to the patients twice with a wash-out period of 15 days. Confirmatory approach was used during the reliability and validity analysis. Cronbach alpha test was used for the reliability analysis. Confirmatory factor analysis (CFA) was used for the construct validity testing. NYHA classification for testing the criterion validity; SF-36 and WHOQOL-100 General Health and QOL facet for convergent validity testing of the Turkish version of the CHQ were used. Responsiveness to change was evaluated by Effect Size analysis by using test-retest data. RESULTS: The range of Cronbach alpha values is 0.72-0.94. A considerable ceiling and floor effects were observed for the dyspnea dimension of the scale but no problematic items were observed for the entire scale. The CFA results supported the original four factors scale structure. Criterion and construct validity rebuts were satisfactory. Effect sizes obtained among dimensions of the CHQ were between 0.13 and 0.56. CONCLUSION: Overall results revealed that Turkish version of the CHQ is a reliable and valid instrument to be used for the evaluation of CHF patients. PMID- 20952356 TI - [Value of interatrial conduction time and P wave dispersion in the prediction of atrial fibrillation following coronary bypass surgery]. AB - OBJECTIVE: This prospective observational study investigated predictive power of interatrial conduction time (IACT) and P wave dispersion (PWD), in addition to other atrial fibrillation (AF) predictors, in patients undergoing coronary artery bypass surgery (CABG). METHODS: Eighty-one patients undergoing CABG were enrolled. Before surgery, IACT and PWD were measured. Time interval from electrocardiographic P wave to echocardiographic transmitral a wave was defined as IACT. Rhythm monitorization was used for AF detection. Continuous and categorical data were compared with independent samples t test and Chi-square statistics. Multiple logistic regression analysis was used to identify independent AF predictors. RESULTS: During a follow-up period of 6.4 +/- 2.1 days, AF developed in 14 patients (17%). There were no significant differences between patients with or without AF according to age, gender, number of bypass grafts, cross-clamp duration, systolic function, and left atrial diameter. Significantly increased PWD and IACT were found in AF group (PWD: 37 +/- 9 ms vs 24 +/- 8 ms, p=0.005 and IACT: 129 +/- 11 ms vs 117 +/- 11 ms, p=0.01) as compared to group without AF. Increased PWD (OR 1.17; 95% CI 1.04-1.31; p=0.02), absence of beta-blocker treatment (OR 8.88; 95% CI 1.62-48.45; p=0.01), diabetes (DM) and hypertension (HT) combination (OR 1.45; 95% CI 1.15-4.22; p=0.01) were independent AF predictors. However, IACT predictive power had borderline significance (OR 1.03; 95% CI 0.95-1.12; p=0.06). CONCLUSION: Increased PWD, absence of beta-blocker therapy, HT-DM combination were independent AF predictors following CABG. There was significant difference between groups according to IACT, however predictive value of IACT was nonsignificant. Other studies are needed to establish predictive power of IACT. PMID- 20952357 TI - The preserved autonomic functions may provide the asymptomatic clinical status in heart failure despite advanced left ventricular systolic dysfunction. AB - OBJECTIVE: Autonomic dysfunction is an important marker of prognosis in congestive heart failure (CHF) and may determine the symptoms and progression of CHF. The aim of our study was to investigate whether preserved autonomic function assessed by heart rate variability (HRV) analyses is related to absence of CHF symptoms despite prominently reduced systolic function. METHODS: The study had a cross-sectional observational design. Fifty patients with left ventricular ejection fraction (EF) below 40% were enrolled. The patients were divided into two groups according to their CHF symptomatic status as Group 1 (NYHA functional class I, asymptomatic group) and Group 2 (NYHA functional class >= II, symptomatic group). Plasma C-reactive protein (CRP), N-terminal proB-type natriuretic peptide (NT-proBNP) levels, echocardiographic parameters and HRV indices were measured while the patients were clinically stable in each group. Possible factors associated with the development of CHF symptoms were assessed by using multiple regression analysis. RESULTS: Baseline clinical characteristics and left ventricular EF were similar in the two groups. Serum CRP (15 +/- 21 vs 7 +/- 18 mg/L, p=0.011) and NT-proBNP levels (1935 +/- 1088 vs 1249 +/- 1083 pg/mL, p=0.020) were significantly higher in symptomatic group. The HRV parameters (SDNN: 78 +/- 57 vs 122 +/- 42 ms, p=0.001; SDANN: 65 +/- 55 vs 84 +/- 38 ms, p=0.024; SDNNi: 36 +/- 41 vs 70 +/- 46 ms, p<0.001; triangular index [Ti]: 17 +/- 12 vs 32 +/- 14, p<0.001) were also significantly depressed in symptomatic group. When multiple regression analysis was performed, only HRV indices of autonomic function were significantly associated with the asymptomatic status (SDNN, OR: 1.016, 95%CI: 1.002-1.031, p=0.028; SDNNi, OR: 1.030, 95%CI: 1.008-1.052, p=0.006; TI, OR: 1.088, 95%CI: 1.019-1.161, p=0.011). CONCLUSION: Preserved autonomic functions were shown to be associated with absence of CHF symptoms independently of angiotensin converting enzyme inhibitor/angiotensin receptor blocker's treatment and BNP levels and may be protective against the development of CHF symptoms despite advanced left ventricular systolic dysfunction. PMID- 20952359 TI - Shared decision making, self-determination and psychiatric rehabilitation. PMID- 20952358 TI - [The relation between exercise-induced myocardial ischemia and high-sensitive C reactive protein and neopterin levels]. AB - OBJECTIVE: High sensitivity C-reactive protein (hsCRP) and neopterin are associated with atherosclerosis. We aimed to evaluate the association between hsCRP and neopterin, and myocardial ischemia during exercise stress test (EST) in patients with stable angina pectoris (SAP) and to assess the predictive value of these mediators in obstructive coronary artery disease. METHODS: Forty-five patients with SAP were included in this prospective observational study. EST- positive group included 23 patients (15 males, mean age 54 +/- 10 years) and EST negative group-22 patients (14 males, mean age 52 +/- 9 years). In each patient, blood samples were obtained 1 hour before and 30 minutes after EST. In EST positive group, coronary angiography was performed to determine the presence and severity of coronary artery lesions as assessed by Gensini score. Statistical analysis was performed using Chi-square, unpaired t, Mann-Whitney U and Wilcoxon rank tests. Logistic regression analysis was used to establish the predictive value of tests. RESULTS: Before EST, hsCRP and neopterin levels were similar between the two groups, however, hsCRP levels were higher in EST-positive group after EST (p=0.03). There was no significant difference between the two groups with respect to neopterin levels after EST (p=0.4). In EST-positive group, EST resulted in significant increases in both hsCRP and neopterin levels (from 3.8 +/ 2.8 mg/L to 4.3 +/- 3.1 mg/L, p=0.001; from 8.7 +/- 4.0 nmol/L to 13.1 +/- 10.0 nmol/L, p=0.001, respectively). In EST-negative group only neopterin levels significantly increased after EST (from 6.9 +/- 1.8 nmol/L to 9.0 +/- 3.9 nmol/L, p=0.001). No relation was observed between the obstructive coronary lesions and the levels of hsCRP or neopterin at any point. CONCLUSION: In SAP patients, independent with the existence of obstructive coronary lesion, elevated levels of hsCRP after EST might be an indicator of immune activation caused by myocardial ischemia. PMID- 20952361 TI - The fierce urgency of now. PMID- 20952360 TI - Letter to the editor. PMID- 20952362 TI - Early outcomes and lessons learned from a study of the Building Recovery of Individual Dreams and Goals through Education and Support (BRIDGES) program in Tennessee. AB - OBJECTIVE: Peer-led education interventions have the potential to provide mental health consumers with the knowledge, skills and support they need to live successful and rewarding self-determined lives. However, few studies have explored whether and how these interventions enhance recovery. This study addresses this knowledge gap by examining changes among 160 participants in the Building Recovery of Individual Dreams and Goals (BRIDGES) education program. BRIDGES is a peer-led 8-week course taught by trained instructors who publicly disclose the fact that they are in recovery from mental illness. METHOD: Structured interviews assessing recovery outcomes were conducted with participants in the month prior to their receipt of BRIDGES, and immediately after receipt of the intervention. Paired t-tests were conducted to examine changes in psychiatric symptoms, hopefulness, social support, self-advocacy, empowerment, adaptive coping, and recovery pre-receipt and post-receipt of BRIDGES. RESULTS: Post-receipt of BRIDGES, participants reported significantly fewer psychiatric symptoms, decreased use of maladaptive coping behaviors, and increased feelings of hopefulness, self-advocacy, empowerment, and recovery. CONCLUSIONS: These promising early results from our ongoing study of BRIDGES suggest that peer-led education interventions are a valuable resource. Additional research is needed to better understand the effectiveness of these interventions, including potential long-term post-program participation benefits. PMID- 20952363 TI - Promoting self-determination and financial security through innovative asset building approaches. AB - TOPIC: Studies indicate that asset development programs such as Individual Development Accounts (IDAs) can enhance the economic security of low-income populations; however, only a handful of asset development programs have been implemented specifically to serve people with psychiatric disabilities, and larger programs have not collected disability-specific information. PURPOSE: The purpose of this article is to increase our knowledge about the use of IDAs to enhance self-determination and recovery for people with psychiatric disabilities. SOURCES USED: Background information about IDAs is presented followed by case studies of two IDA programs that serve people with psychiatric disabilities. CONCLUSIONS: The use of IDA programs in enhancing self-determination among people with psychiatric disabilities is discussed, along with barriers and future directions. PMID- 20952364 TI - Developing the evidence base for peer-led services: changes among participants following Wellness Recovery Action Planning (WRAP) education in two statewide initiatives. AB - OBJECTIVE: The purpose of this analysis was to evaluate the outcomes of two statewide initiatives in Vermont and Minnesota, in which self-management of mental illness was taught by peers to people in mental health recovery using Wellness Recovery Action Planning (WRAP). METHODS: Pre-post comparisons were made of reports from 381 participants (147 in Vermont and 234 in Minnesota) on a survey instrument that assessed three dimensions of self-management: 1) attitudes, such as hope for recovery and responsibility for one's own wellness; 2) knowledge, regarding topics such as early warning signs of decompensation and symptom triggers; and 3) skills, such as identification of a social support network and use of wellness tools. RESULTS: Significant positive changes in self management attitudes, skills and behaviors were observed on 76% of items completed by Vermont participants (13 of 17 survey items), and 85% of items completed by Minnesota participants (11 of 13 items). In both states, participants reported significant increases in: 1) their hopefulness for their own recovery; 2) awareness of their own early warning signs of decompensation; 3) use of wellness tools in their daily routine; 4) awareness of their own symptom triggers; 5) having a crisis plan in place; 6) having a plan for dealing with symptoms; 7) having a social support system; and 8) ability to take responsibility for their own wellness. CONCLUSIONS: Given the rapid growth of this intervention in the U.S. and internationally, these results contribute to the evidence base for peer-led services, and suggest that more rigorous investigations are warranted in the future. PMID- 20952365 TI - Cultural competency in peer-run programs: results of a web survey and implications for future practice. AB - OBJECTIVE: The study explored perceptions of adults with psychiatric disabilities regarding cultural competency of peer-run mental health support groups and programs. METHODS: Web survey respondents were recruited via mental health list servs, web sites, newsletters, emails, and word of mouth. A total of 527 peers were surveyed about cultural competency barriers facing peer-run programs; common reasons for not using peer services; and strategies to engage diverse communities. RESULTS: Both multicultural and Caucasian respondents agreed that lack of funding and staff education about diversity were barriers to cultural competency in peer programs. Multicultural respondents were more likely than whites to feel that both the recognition of the need for and interest in attending cultural competency training is lacking in peer programs, as well as information about the diverse composition of peer program memberships. Among those who had never participated in peer support, people of color were more likely than whites to endorse feeling they would not belong and believing their languages would not be spoken in peer programs. Whites, on the other hand, were more likely to cite a preference for professional over peer support, while nearly half of both groups indicated that the main reason for non-attendance is a lack of knowledge about peer programs. Qualitative results highlighted successful outreach and engagement strategies. CONCLUSIONS: Study findings informed development of a cultural competency tool that was pilot-tested among peer-run programs. Given the importance of peer support in recovery, these findings suggest the need for additional research on cultural competency in peer programs. PMID- 20952366 TI - The recovery education in the academy program: transforming academic curricula with the principles of recovery and self-determination. AB - TOPIC: This article describes a curricular transformation initiative, the Recovery Education in the Academy Program (REAP), spearheaded by the University of Illinois at Chicago's National Research and Training Center on Psychiatric Disability. PURPOSE: REAP is designed to integrate principles of recovery, self determination, and other evidence-based practices for people with psychiatric disabilities into medical, social, and behavioral sciences curricula. The principles on which the curricula transformation efforts are based, the instructional activities employed, early outcomes of the endeavor, and future plans for replication are delineated. SOURCES USED: As described in this paper, REAP builds on a theoretical framework derived from the evidence-based literature, multiple technical reports, and curricular initiatives, including the Institute of Medicine, the Annapolis Coalition for Behavioral Workforce Development, and the Final Report of President's New Freedom Commission on Mental Health. CONCLUSIONS: REAP has delivered state-of-the-science education to over 1,000 trainees, including medical students, psychiatry residents, psychology and social work interns, and rehabilitation counselors, pre/post-doctoral students and professionals within a variety of academic settings. REAP serves as a replicable structure to successfully integrate recovery education into existing, accredited academic programs and curricula using the parameters outlined by multiple experts and stakeholders. Barriers to curricular transformation and strategies to overcome these barriers are highlighted. PMID- 20952367 TI - Participatory action research to establish self-directed care for mental health recovery in Texas. AB - OBJECTIVE: This article describes a public-academic collaboration between a university research center and the Texas state mental health authority to design and evaluate a unique "money follows the person" model called self-directed care (SDC). SDC programs give participants control over public funds to purchase services and supports for their own recovery. METHODS: Through a participatory action research process, the project combined use of evidence-based practice and community consensus as a tool for system change. RESULTS: The story of this effort and the program that resulted are described, along with quantitative and qualitative data from the project's start-up phase. CONCLUSIONS: Lessons learned about the importance of community collaboration are discussed in light of the current emphasis on public mental health system transformation through alternative financing mechanisms. PMID- 20952368 TI - Building capacity in social service agencies to employ peer providers. AB - OBJECTIVE: While there is evidence that peer providers are valuable to service delivery teams, the agencies where they work face difficulties in fulfilling the potential of including peers on staff effectively. The purpose of this article is to report findings of a pilot test of a workplace strategy that promoted inclusion of peer providers at social service agencies by building organizational capacity to support people with mental health conditions in peer provider roles. The strategy included training, goal setting and ongoing consultation. METHODS: Seventy-one peer, non-peer and supervisory staff participated from 6 agencies over a one year period. Goal attainment scaling and data from in-depth interviews about perceptions of differences in the ways in which staff are supported, administered prior to and after the consultation period, were used to assess strategy impact. RESULTS: Most frequently staff set goals to respond to role conflict or a lack of support. Staff that met or exceeded their goals utilized the formal structure of consultation to improve communication among themselves, had leadership that sanctioned changes and felt that their participation was of value to the organization and contributed to their individual development. Strategy participation promoted inclusion by initiating changes to policies and practices that devalued the peer provider role, increased skill sets, and formalized lines of communication for sharing information and understanding related to peer providers. CONCLUSIONS: Findings demonstrate that a strategy of training, goal setting and consultation can positively affect perceptions of inclusion, and promote implementation of practices associated with inclusive workplaces. PMID- 20952369 TI - Recovery orientation of treatment, consumer empowerment, and satisfaction with services: a mediational model. AB - OBJECTIVE: This study explores the relationship between the recovery orientation of treatment and subjective experiences of consumer empowerment and satisfaction with services for individuals with severe and persistent mental illness. METHODS: Instruments measuring perceptions of empowerment, recovery orientation of treatment, and satisfaction with services were administered to 45 participants enrolled in two demographically similar mental health treatment programs in Tampa, Florida - a community mental health center and an Assertive Community Treatment team. Analyses were conducted according to traditional mediation models. Empowerment was expected to mediate the relationship between the recovery orientation of treatment and consumer satisfaction with services. RESULTS: A recovery-based treatment orientation significantly predicted both consumer empowerment and satisfaction with services. Empowerment mediated the relationship between treatment orientation and consumer satisfaction. CONCLUSIONS: These preliminary findings highlight the impact of the recovery orientation of treatment on empowerment and satisfaction with services among individuals with severe and persistent mental illness. PMID- 20952370 TI - Living a dream: using the Individual Development Account (IDA) to support financial independence. PMID- 20952371 TI - Inaccurate self-assessments. PMID- 20952373 TI - Lipid-lowering treatment to the end? A review of observational studies and RCTs on cholesterol and mortality in 80+-year olds. AB - People aged 80 or older are the fastest growing population in high-income countries. One of the most common causes of death among the elderly is the cardiovascular disease (CVD). Lipid-lowering treatment is common, e.g. one-third of 75-84-year-old Swedes are treated with statins. The assumption that hypercholesterolaemia is a risk factor at the highest ages seems to be based on extrapolation from younger adults. A review of observational studies shows a trend where all-cause mortality was highest when total cholesterol (TC) was lowest ('a reverse J-shaped' association between TC and all-cause mortality). Low TC (<5.5 mmol/l) is associated with the highest mortality rate in 80+-year olds. No clear optimal level of TC was identified. A review of the few randomised controlled trials including 80+-year olds did not provide evidence of an effect of lipid-lowering treatment on total mortality in 80+-year-old people. There is not sufficient data to recommend anything regarding initiation or continuation of lipid-lowering treatment for the population aged 80+, with known CVD, and it is even possible that statins may increase all-cause mortality in this group of elderly individuals without CVD. PMID- 20952374 TI - Orthostatic intolerance in the heat: are the alpha-adrenergic receptors the culprit? PMID- 20952375 TI - MicroRNAs and exercise-induced skeletal muscle adaptations. PMID- 20952376 TI - Altered microvascular control of exercising skeletal muscle blood flow: the unfortunate male? PMID- 20952377 TI - What the left and right anterior fusiform gyri tell us about semantic memory. AB - The study of patients with semantic dementia, a variant of frontotemporal lobar degeneration, has emerged over the last two decades as an important lesion model for studying human semantic memory. Although it is well-known that semantic dementia is associated with temporal lobe degeneration, controversy remains over whether the semantic deficit is due to diffuse temporal lobe damage, damage to only a sub-region of the temporal lobe or even less severe damage elsewhere in the brain. The manner in which the right and left temporal lobes contribute to semantic knowledge is also not fully elucidated. In this study we used unbiased imaging analyses to correlate resting cerebral glucose metabolism and behavioural scores in tests of verbal and non-verbal semantic memory. In addition, a region of interest analysis was performed to evaluate the role of severely hypometabolic areas. The best, indeed the only, strong predictor of semantic scores across a set of 21 patients with frontotemporal lobar degeneration with semantic impairment was degree of hypometabolism in the anterior fusiform region subjacent to the head and body of the hippocampus. As hypometabolism in the patients' rostral fusiform was even more extreme than the abnormality in other regions with putative semantic relevance, such as the temporal poles, the significant fusiform correlations cannot be attributed to floor-level function in these other regions. More detailed analysis demonstrated more selective correlations: left anterior fusiform function predicted performance on two expressive verbal tasks, whereas right anterior fusiform metabolism predicted performance on a non-verbal test of associative semantic knowledge. This pattern was further supported by an additional behavioural study performed on a wider cohort of patients with semantic dementia, in which the patients with more extensive right-temporal atrophy (when matched on degree of naming deficit to a set of cases with more extensive left temporal atrophy) were significantly more impaired on the test of non-verbal semantics. Our preferred interpretation of this laterality effect involves differential strength of connectivity between different regions of a widespread semantic network in the human brain. PMID- 20952378 TI - Taking both sides: do unilateral anterior temporal lobe lesions disrupt semantic memory? AB - The most selective disorder of central conceptual knowledge arises in semantic dementia, a degenerative condition associated with bilateral atrophy of the inferior and polar regions of the temporal lobes. Likewise, semantic impairment in both herpes simplex virus encephalitis and Alzheimer's disease is typically associated with bilateral, anterior temporal pathology. These findings suggest that conceptual representations are supported via an interconnected, bilateral, anterior temporal network and that it may take damage to both sides to produce an unequivocal deficit of central semantic memory. We tested and supported this hypothesis by investigating a case series of 20 patients with unilateral temporal damage (following vascular accident or resection for tumour or epilepsy), utilizing a test battery that is sensitive to semantic impairment in semantic dementia. Only 1/20 of the cases, with a unilateral left lesion, exhibited even a mild impairment on the receptive semantic measures. On the expressive semantic tests of naming and fluency, average performance was worse in the left- than right-unilateral cases, but even in this domain, only one left-lesion case had scores consistently more than two standard deviations below control means. These results fit with recent parallel explorations of semantic function using repetitive transcranial magnetic stimulation as well as functional imaging in stroke aphasic and neurologically intact participants. The evidence suggests that both left and right anterior temporal lobe regions contribute to the representation of semantic memory and together may form a relatively damage resistant, robust system for this critical aspect of higher cognition. PMID- 20952380 TI - Adaptation of motor function after spinal cord injury: novel insights into spinal shock. AB - The mechanisms underlying spinal shock have not been clearly defined. At present, clinical assessment remains the mainstay to describe progression through spinal shock following traumatic spinal cord injury. However, nerve excitability studies in combination with conventional nerve conduction and clinical assessments have the potential to investigate spinal shock at the level of the peripheral axon. Therefore, peripheral motor axon excitability was prospectively and systematically evaluated in more than 400 studies of 11 patients admitted to hospital after traumatic spinal cord injury, with cord lesions above T9 (nine cervical, two thoracic). Recordings commenced within 15 days of admission from the median nerve to abductor pollicis brevis in the upper limb and the common peroneal nerve to tibialis anterior in both lower limbs, and were continued until patient discharge from hospital. Excitability was assessed using threshold tracking techniques and recordings were compared with data from healthy controls. In addition, concurrent clinical measures of strength, serum electrolytes and nerve conduction were collected. High threshold stimulus-response relationships were apparent from the early phase of spinal shock that coincided with depolarization-like features that reached a peak on Day 16.9 (+/- 2.7 standard error) for the common peroneal nerve and Day 11.8 (+/- 2.0 standard error) for the median nerve. Overall, changes in the common peroneal nerve were of greater magnitude than for the median nerve. For both nerves, the most significant changes were in threshold electrotonus, which was 'fanned in', and during the recovery cycle superexcitability was reduced (P < 0.001). However, refractoriness was increased only for the common peroneal nerve (P < 0.05). Changes in the spinal injured cohort could not be explained on the basis of an isolated common peroneal nerve palsy. By the time patients with spinal injury were discharged from hospital between Days 68 and 215, excitability for upper and lower limbs had returned towards normative values, but not for all parameters. Electrolyte levels and results for nerve conduction studies remained within normal limits throughout the period of admission. Contrary to prevailing opinion, these data demonstrate that significant changes in peripheral motor axonal excitability occur early during spinal shock, with subsequent further deterioration in axonal function, before recovery ensues. PMID- 20952379 TI - Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. AB - Pontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P < 0.0005) between TSEN54 mutations and a dragonfly-like cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. Mutations in TSEN54 are clinically associated with dyskinesia and/or dystonia and variable degrees of spasticity, in some cases with pure generalized spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype of more perinatal symptoms, ventilator dependency and early death. In addition, we present ten new mutations in TSEN54, TSEN2 and RARS2. Furthermore, we show that pontocerebellar hypoplasia type 1 together with elevated cerebrospinal fluid lactate may be caused by RARS2 mutations. PMID- 20952381 TI - OPA1 mutations impair mitochondrial function in both pure and complicated dominant optic atrophy. PMID- 20952382 TI - Deficiency of a transmembrane prolyl 4-hydroxylase in the zebrafish leads to basement membrane defects and compromised kidney function. AB - Prolyl 4-hydroxylases (P4Hs) catalyze the hydroxylation of collagens and hypoxia inducible factor (HIF)-alpha subunits. We studied the zebrafish homologue of the recently characterized human transmembrane P4H (P4H-TM) that can hydroxylate HIF alpha, but not collagens, in vitro and influence HIF-alpha levels in cellulo. The zebrafish P4H-TM mRNA had its highest expression in the eye and brain and lower levels in other tissues, including the kidney. Morpholino knockdown of P4H-TM in embryos resulted in a reduction in the size of the eye and head and morphological alterations in the head from 2 days postfertilization onward. In addition, pericardial edema, regarded as a sign of kidney dysfunction, developed from 3 days postfertilization onward. The phenotype was dependent on the P4H-TM catalytic activity because similar results were obtained with morpholinos targeting either translation initiation or catalytic residues of the enzyme. Structural and functional analyses of the morphant pronephric kidneys revealed fragmented glomerular basement membranes (BMs), disorganized podocyte foot processes, and severely compromised pronephric kidney function leading to proteinuria. The opacity of the eye lens was increased due to the presence of extra nuclei and deposits, and the structure of the lens capsule BM was altered. Our data suggest that P4H-TM catalytic activity is required for the proper development of the glomerular and lens capsule BMs. Many HIF target genes were induced in the P4H-TM-deficient morphants, but the observed phenotype is not likely to be mediated at least solely via the HIF pathway, and thus P4H-TM probably has additional, as yet unknown, substrates. PMID- 20952383 TI - Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways. AB - Sclerostin is expressed by osteocytes and has catabolic effects on bone. It has been shown to antagonize bone morphogenetic protein (BMP) and/or Wnt activity, although at present the underlying mechanisms are unclear. Consistent with previous findings, Sclerostin opposed direct Wnt3a-induced but not direct BMP7 induced responses when both ligand and antagonist were provided exogenously to cells. However, we found that when both proteins are expressed in the same cell, sclerostin can antagonize BMP signaling directly by inhibiting BMP7 secretion. Sclerostin interacts with both the BMP7 mature domain and pro-domain, leading to intracellular retention and proteasomal degradation of BMP7. Analysis of sclerostin knock-out mice revealed an inhibitory action of sclerostin on Wnt signaling in both osteoblasts and osteocytes in cortical and cancellous bones. BMP7 signaling was predominantly inhibited by sclerostin in osteocytes of the calcaneus and the cortical bone of the tibia. Our results suggest that sclerostin exerts its potent bone catabolic effects by antagonizing Wnt signaling in a paracrine and autocrine manner and antagonizing BMP signaling selectively in the osteocytes that synthesize simultaneously both sclerostin and BMP7 proteins. PMID- 20952384 TI - Reactive oxygen species generated by NADPH oxidase 2 and 4 are required for chondrogenic differentiation. AB - Although generation of reactive oxygen species (ROS) by NADPH oxidases (Nox) is thought to be important for signal transduction in nonphagocytic cells, little is known of the role ROS plays in chondrogenesis. We therefore examined the possible contribution of ROS generation to chondrogenesis using both ATDC5 cells and primary chondrocytes derived from mouse embryos. The intracellular level of ROS was increased during the differentiation process, which was then blocked by treatment with the ROS scavenger N-acetylcysteine. Expression of Nox1 and Nox2 was increased upon differentiation of ATDC5 cells and primary mouse chondrocytes, whereas that of Nox4, which was relatively high initially, was decreased gradually during chondrogenesis. In developing limb, Nox1 and Nox2 were highly expressed in prehypertrophic and hypertrophic chondrocytes. However, Nox4 was highly expressed in proliferating chondrocytes and prehypertrophic chondrocytes. Depletion of Nox2 or Nox4 expression by RNA interference blocked both ROS generation and differentiation of ATDC5 cells, whereas depletion of Nox1 had no such effect. We also found that ATDC5 cells depleted of Nox2 or Nox4 underwent apoptosis. Further, inhibition of Akt phosphorylation along with subsequent activation of ERK was observed in the cells. Finally, depletion of Nox2 or Nox4 inhibited the accumulation of proteoglycan in primary chondrocytes. Taken together, our data suggest that ROS generated by Nox2 or Nox4 are essential for survival and differentiation in the early stage of chondrogenesis. PMID- 20952385 TI - Brain endothelial cells produce amyloid {beta} from amyloid precursor protein 770 and preferentially secrete the O-glycosylated form. AB - Deposition of amyloid beta (Abeta) in the brain is closely associated with Alzheimer disease (AD). Abeta is generated from amyloid precursor protein (APP) by the actions of beta- and gamma-secretases. In addition to Abeta deposition in the brain parenchyma, deposition of Abeta in cerebral vessel walls, termed cerebral amyloid angiopathy, is observed in more than 80% of AD individuals. The mechanism for how Abeta accumulates in blood vessels remains largely unknown. In the present study, we show that brain endothelial cells expressed APP770, a differently spliced APP mRNA isoform from neuronal APP695, and produced Abeta40 and Abeta42. Furthermore, we found that the endothelial APP770 had sialylated core 1 type O-glycans. Interestingly, Omicron-glycosylated APP770 was preferentially processed by both alpha- and beta-cleavage and secreted into the media, suggesting that O-glycosylation and APP processing involved related pathways. By immunostaining human brain sections with an anti-APP770 antibody, we found that APP770 was expressed in vascular endothelial cells. Because we were able to detect O-glycosylated sAPP770beta in human cerebrospinal fluid, this unique soluble APP770beta has the potential to serve as a marker for cortical dementias such as AD and vascular dementia. PMID- 20952386 TI - Interaction of Escherichia coli RNA polymerase sigma70 subunit with promoter elements in the context of free sigma70, RNA polymerase holoenzyme, and the beta' sigma70 complex. AB - Promoter recognition by RNA polymerase is a key point in gene expression and a target of regulation. Bacterial RNA polymerase binds promoters in the form of the holoenzyme, with the sigma specificity subunit being primarily responsible for promoter recognition. Free sigma, however, does not recognize promoter DNA, and it has been proposed that the intrinsic DNA binding ability is masked in free sigma but becomes unmasked in the holoenzyme. Here, we use a newly developed fluorescent assay to quantitatively study the interactions of free sigma(70) from Escherichia coli, the beta'-sigma complex, and the sigma(70) RNA polymerase (RNAP) holoenzyme with non-template strand of the open promoter complex transcription bubble in the context of model non-template oligonucleotides and fork junction templates. We show that sigma(70), free or in the context of the holoenzyme, recognizes the -10 promoter element with the same efficiency and specificity. The result implies that there is no need to invoke a conformational change in sigma for recognition of the -10 element in the single-stranded form. In the holoenzyme, weak but specific interactions of sigma are increased by contacts with DNA downstream of the -10 element. We further show that region 1 of sigma(70) is required for stronger interaction with non-template oligonucleotides in the holoenzyme but not in free sigma. Finally, we show that binding of the beta' RNAP subunit is sufficient to allow specific recognition of the TG motif of the extended -10 promoter element by sigma(70). The new fluorescent assay, which we call a protein beacon assay, will be instrumental in quantitative dissection of fine details of RNAP interactions with promoters. PMID- 20952387 TI - C1q/TNF-related protein-3 (CTRP3), a novel adipokine that regulates hepatic glucose output. AB - Adipose tissue-derived adipokines play important roles in controlling systemic insulin sensitivity and energy balance. Our recent efforts to identify novel metabolic mediators produced by adipose tissue have led to the discovery of a highly conserved family of secreted proteins, designated as C1q/TNF-related proteins 1-10 (CTRP1 to -10). However, physiological functions regulated by CTRPs are largely unknown. Here we provide the first in vivo functional characterization of CTRP3. We show that circulating levels of CTRP3 are inversely correlated with leptin levels; CTRP3 increases with fasting, decreases in diet induced obese mice with high leptin levels, and increases in leptin-deficient ob/ob mice. A modest 3-fold elevation of plasma CTRP3 levels by recombinant protein administration is sufficient to lower glucose levels in normal and insulin-resistant ob/ob mice, without altering insulin or adiponectin levels. The glucose-lowering effect in mice is linked to activation of the Akt signaling pathway in liver and a marked suppression of hepatic gluconeogenic gene expression. Consistent with its effects in mice, CTRP3 acts directly and independently of insulin to regulate gluconeogenesis in cultured hepatocytes. In humans, alternative splicing generates two circulating CTRP3 isoforms differing in size and glycosylation pattern. The two human proteins form hetero-oligomers, an association that does not require interdisulfide bond formation and appears to protect the longer isoform from proteolytic cleavage. Recombinant human CTRP3 also reduces glucose output in hepatocytes by suppressing gluconeogenic enzyme expression. This study provides the first functional evidence linking CTRP3 to hepatic glucose metabolism and establishes CTRP3 as a novel adipokine. PMID- 20952388 TI - Molecular association of the Arabidopsis ETR1 ethylene receptor and a regulator of ethylene signaling, RTE1. AB - The plant hormone ethylene plays important roles in growth and development. Ethylene is perceived by a family of membrane-bound receptors that actively repress ethylene responses. When the receptors bind ethylene, their signaling is shut off, activating responses. REVERSION-TO-ETHYLENE SENSITIVITY (RTE1) encodes a novel membrane protein conserved in plants and metazoans. Genetic analyses in Arabidopsis thaliana suggest that RTE1 promotes the signaling state of the ethylene receptor ETR1 through the ETR1 N-terminal domain. RTE1 and ETR1 have been shown to co-localize to the endoplasmic reticulum (ER) and Golgi apparatus in Arabidopsis. Here, we demonstrate a physical association of RTE1 and ETR1 using in vivo and in vitro methods. Interaction of RTE1 and ETR1 was revealed in vivo by bimolecular fluorescence complementation (BiFC) in a tobacco cell transient assay and in stably transformed Arabidopsis. The association was also observed using a truncated version of ETR1 comprising the N terminus (amino acids 1-349). Interaction of RTE1 and ETR1 was confirmed by co-immunoprecipitation from Arabidopsis. The interaction occurs with high affinity (K(d), 117 nM) based on tryptophan fluorescence spectroscopy using purified recombinant RTE1 and a tryptophan-less version of purified recombinant ETR1. An amino acid substitution (C161Y) in RTE1 that is known to confer an ETR1 loss-of-function phenotype correspondingly gives a nearly 12-fold increase in the dissociation constant (K(d), 1.38 MUM). These findings indicate that a high affinity association of RTE1 and ETR1 is important in the regulation of ETR1. PMID- 20952389 TI - Moonlighting glutamate formiminotransferases can functionally replace 5 formyltetrahydrofolate cycloligase. AB - 5-Formyltetrahydrofolate (5-CHO-THF) is formed by a side reaction of serine hydroxymethyltransferase. Unlike other folates, it is not a one-carbon donor but a potent inhibitor of folate enzymes and must therefore be metabolized. Only 5 CHO-THF cycloligase (5-FCL) is generally considered to do this. However, comparative genomic analysis indicated (i) that certain prokaryotes lack 5-FCL, implying that they have an alternative 5-CHO-THF-metabolizing enzyme, and (ii) that the histidine breakdown enzyme glutamate formiminotransferase (FT) might moonlight in this role. A functional complementation assay for 5-CHO-THF metabolism was developed in Escherichia coli, based on deleting the gene encoding 5-FCL (ygfA). The deletion mutant accumulated 5-CHO-THF and, with glycine as sole nitrogen source, showed a growth defect; both phenotypes were complemented by bacterial or archaeal genes encoding FT. Furthermore, utilization of supplied 5 CHO-THF by Streptococcus pyogenes was shown to require expression of the native FT. Recombinant bacterial and archaeal FTs catalyzed formyl transfer from 5-CHO THF to glutamate, with k(cat) values of 0.1-1.2 min(-1) and K(m) values for 5-CHO THF and glutamate of 0.4-5 MUM and 0.03-1 mM, respectively. Although the formyltransferase activities of these proteins were far lower than their formiminotransferase activities, the K(m) values for both substrates relative to their intracellular levels in prokaryotes are consistent with significant in vivo flux through the formyltransferase reaction. Collectively, these data indicate that FTs functionally replace 5-FCL in certain prokaryotes. PMID- 20952390 TI - Vibrio cholerae ParE2 poisons DNA gyrase via a mechanism distinct from other gyrase inhibitors. AB - DNA gyrase is an essential bacterial enzyme required for the maintenance of chromosomal DNA topology. This enzyme is the target of several protein toxins encoded in toxin-antitoxin (TA) loci as well as of man-made antibiotics such as quinolones. The genome of Vibrio cholerae, the cause of cholera, contains three putative TA loci that exhibit modest similarity to the RK2 plasmid-borne parDE TA locus, which is thought to target gyrase although its mechanism of action is uncharacterized. Here we investigated the V. cholerae parDE2 locus. We found that this locus encodes a functional proteic TA pair that is active in Escherichia coli as well as V. cholerae. ParD2 co-purified with ParE2 and interacted with it directly. Unlike many other antitoxins, ParD2 could prevent but not reverse ParE2 toxicity. ParE2, like the unrelated F-encoded toxin CcdB and quinolones, targeted the GyrA subunit and stalled the DNA-gyrase cleavage complex. However, in contrast to other gyrase poisons, ParE2 toxicity required ATP, and it interfered with gyrase-dependent DNA supercoiling but not DNA relaxation. ParE2 did not bind GyrA fragments bound by CcdB and quinolones, and a set of strains resistant to a variety of known gyrase inhibitors all exhibited sensitivity to ParE2. Together, our findings suggest that ParE2 and presumably its many plasmid- and chromosome encoded homologues inhibit gyrase in a different manner than previously described agents. PMID- 20952391 TI - State-dependent regulation of cystic fibrosis transmembrane conductance regulator (CFTR) gating by a high affinity Fe3+ bridge between the regulatory domain and cytoplasmic loop 3. AB - The unique regulatory (R) domain differentiates the human CFTR channel from other ATP-binding cassette transporters and exerts multiple effects on channel function. However, the underlying mechanisms are unclear. Here, an intracellular high affinity (2.3 * 10(-19) M) Fe(3+) bridge is reported as a novel approach to regulating channel gating. It inhibited CFTR activity by primarily reducing an open probability and an opening rate, and inhibition was reversed by EDTA and phenanthroline. His-950, His-954, Cys-832, His-775, and Asp-836 were found essential for inhibition and phosphorylated Ser-768 may enhance Fe(3+) binding. More importantly, inhibition by Fe(3+) was state-dependent. Sensitivity to Fe(3+) was reduced when the channel was locked in an open state by AMP-PNP. Similarly, a K978C mutation from cytoplasmic loop 3 (CL3), which promotes ATP-independent channel opening, greatly weakened inhibition by Fe(3+) no matter whether NBD2 was present or not. Therefore, although ATP binding-induced dimerization of NBD1-NBD2 is required for channel gating, regulation of CFTR activity by Fe(3+) may involve an interaction between the R domain and CL3. These findings may support proximity of the R domain to the cytoplasmic loops. They also suggest that Fe(3+) homeostasis may play a critical role in regulating pathophysiological CFTR activity because dysregulation of this protein causes cystic fibrosis, secretary diarrhea, and infertility. PMID- 20952392 TI - Specific binding of red blood cells to endothelial cells is regulated by nonadsorbing macromolecules. AB - Abnormal adhesion of red blood cells to the endothelium has been linked to the pathophysiology of several diseases associated with vascular disorders. Various biochemical changes, including phosphatidylserine exposure on the outer membrane of red blood cells as well as plasma protein levels, have been identified as being likely to play a key role, but the detailed interplay between plasma factors and cellular factors remains unknown. It has been proposed that the adhesion-promoting effect of plasma proteins originates from ligand interaction, but evidence substantiating this assumption is often missing. In this work, we identified an alternative pathway by demonstrating that nonadsorbing macromolecules can also have a marked impact on the adhesion efficiency of red blood cells with enhanced phosphatidylserine exposure to endothelial cells. It is concluded that this adhesion-promoting effect originates from macromolecular depletion interaction and thereby presents an alternative mechanism by which plasma proteins could regulate cell-cell interactions. These findings should thus be of potential value for a detailed understanding of the pathophysiology of diseases associated with vascular complications and might be applicable to a wide range of cell-cell interactions in plasma or plasma-like media. PMID- 20952394 TI - Preventing broken Borrelia telomeres: ResT couples dual hairpin telomere formation with product release. AB - Spirochetes of the genus Borrelia include the tick-transmitted causative agents of Lyme disease and relapsing fever. They possess unusual genomes composed mainly of linear replicons terminated by closed DNA hairpins. Hairpin telomeres are formed from inverted repeat replicated telomere junctions (rTels) by the telomere resolvase ResT. ResT uses a reaction mechanism similar to that of the type IB topoisomerases and tyrosine recombinases. ResT can catalyze three distinct reactions: telomere resolution, telomere fusion, and Holliday junction (HJ) formation. HJ formation is known to occur only in the context of a synapsed pair of rTels. To test whether telomere resolution was synapsis-dependent, we performed experiments with rTel substrates immobilized on streptavidin-coated beads. We report that telomere resolution by ResT is synapsis-independent, indicating that alternative complexes are formed for telomere resolution and HJ formation. We also present evidence that dual hairpin telomere formation precedes product release. This mechanism of telomere resolution prevents the appearance of broken telomeres. We compare and contrast this mechanism with that proposed for TelK, the telomere resolvase of phiKO2. PMID- 20952393 TI - Substrate channeling in mammalian base excision repair pathways: passing the baton. AB - The current model for base excision repair (BER) involves two general sub pathways termed single-nucleotide BER and long patch BER that are distinguished by their repair patch sizes and the enzymes/co-factors involved. Both sub pathways involve a series of sequential steps from initiation to completion of repair. The BER sub-pathways are designed to sequester the various intermediates, passing them along from one step to the next without allowing these toxic molecules to trigger cell cycle arrest, necrotic cell death, or apoptosis. Although a variety of DNA-protein and protein-protein interactions are known for the BER intermediates and enzymes/co-factors, the molecular mechanisms accounting for step-to-step coordination are not well understood. In the present study we designed an in vitro assay to explore the question of whether there is a channeling or "hand-off" of the repair intermediates during BER in vitro. The results show that when BER enzymes are pre-bound to the initial single-nucleotide BER intermediate, the DNA is channeled from apurinic/apyrimidinic endonuclease 1 to DNA polymerase beta and then to DNA ligase. In the long patch BER subpathway, where the 5'-end of the incised strand is blocked, the intermediate after DNA polymerase beta gap filling is not channeled to the subsequent enzyme, flap endonuclease 1. Instead, flap endonuclease 1 must recognize and bind to the intermediate in competition with other molecules. PMID- 20952395 TI - Individual lysine acetylations on the N terminus of Saccharomyces cerevisiae H2A.Z are highly but not differentially regulated. AB - The multi-functional histone variant Htz1 (Saccharomyces cerevisiae H2A.Z) is acetylated on up to four N-terminal lysines at positions 3, 8, 10, and 14. It has thus been posited that specific acetylated forms of the histone could regulate distinct roles. Antibodies against Htz1-K8(Ac), -K10(Ac), and -K14(Ac) show that all three modifications are added by Esa1 acetyltransferase and removed by Hda1 deacetylase. Completely unacetylatable htz1 alleles exhibit widespread interactions in genome scale genetic screening. However, singly mutated (e.g. htz1-K8R) or singly acetylable (e.g. the triple mutant htz1-K3R/K10R/K14R) alleles show no significant defects in these analyses. This suggests that the N terminal acetylations on Htz1 are internally redundant. Further supporting this proposal, each acetylation decays with similar kinetics when Htz1 transcription is repressed, and proteomic screening did not find a single condition in which one Htz1(Ac) was differentially regulated. However, whereas the individual acetylations on Htz1 may be redundant, they are not dispensable. Completely unacetylatable htz1 alleles display genetic interactions and phenotypes in common with and distinct from htz1Delta. In addition, each Htz1 N-terminal lysine is deacetylated by Hda1 in response to benomyl and reacetylated when this agent is removed. Such active regulation suggests that acetylation plays a significant role in Htz1 function. PMID- 20952396 TI - A phosphorylation switch regulates the transcriptional activation of cell cycle regulator p21 by histone deacetylase inhibitors. AB - Histone deacetylase inhibitors induce cell cycle arrest and apoptosis in tumor cells and are, therefore, promising anti-cancer drugs. The cyclin-dependent kinase inhibitor p21 is activated in histone deacetylase (HDAC) inhibitor-treated tumor cells, and its growth-inhibitory function contributes to the anti tumorigenic effect of HDAC inhibitors. We show here that induction of p21 by trichostatin A involves MAP kinase signaling. Activation of the MAP kinase signaling pathway by growth factors or stress signals results in histone H3 serine 10 phosphorylation at the p21 promoter and is crucial for acetylation of the neighboring lysine 14 and recruitment of activated RNA polymerase II in response to trichostatin A treatment. In non-induced cells, the protein phosphatase PP2A is associated with the p21 gene and counteracts its activation. Induction of p21 is linked to simultaneous acetylation and phosphorylation of histone H3. The dual modification mark H3S10phK14ac at the activated p21 promoter is recognized by the phospho-binding protein 14-3-3zeta, which protects the phosphoacetylation mark from being processed by PP2A. Taken together we have revealed a cross-talk of reversible phosphorylation and acetylation signals that controls the activation of p21 by HDAC inhibitors and identify the phosphatase PP2A as chromatin-associated transcriptional repressor in mammalian cells. PMID- 20952397 TI - Health systems strengthening: a common classification and framework for investment analysis. AB - Significant scale-up of donors' investments in health systems strengthening (HSS), and the increased application of harmonization mechanisms for jointly channelling donor resources in countries, necessitate the development of a common framework for tracking donors' HSS expenditures. Such a framework would make it possible to comparatively analyse donors' contributions to strengthening specific aspects of countries' health systems in multi-donor-supported HSS environments. Four pre-requisite factors are required for developing such a framework: (i) harmonization of conceptual and operational understanding of what constitutes HSS; (ii) development of a common set of criteria to define health expenditures as contributors to HSS; (iii) development of a common HSS classification system; and (iv) harmonization of HSS programmatic and financial data to allow for inter agency comparative analyses. Building on the analysis of these aspects, the paper proposes a framework for tracking donors' investments in HSS, as a departure point for further discussions aimed at developing a commonly agreed approach. Comparative analysis of financial allocations by the Global Fund to Fight AIDS, Tuberculosis and Malaria and the GAVI Alliance for HSS, as an illustrative example of applying the proposed framework in practice, is also presented. PMID- 20952398 TI - CancerResource: a comprehensive database of cancer-relevant proteins and compound interactions supported by experimental knowledge. AB - During the development of methods for cancer diagnosis and treatment, a vast amount of information is generated. Novel cancer target proteins have been identified and many compounds that activate or inhibit cancer-relevant target genes have been developed. This knowledge is based on an immense number of experimentally validated compound-target interactions in the literature, and excerpts from literature text mining are spread over numerous data sources. Our own analysis shows that the overlap between important existing repositories such as Comparative Toxicogenomics Database (CTD), Therapeutic Target Database (TTD), Pharmacogenomics Knowledge Base (PharmGKB) and DrugBank as well as between our own literature mining for cancer-annotated entries is surprisingly small. In order to provide an easy overview of interaction data, it is essential to integrate this information into a single, comprehensive data repository. Here, we present CancerResource, a database that integrates cancer-relevant relationships of compounds and targets from (i) our own literature mining and (ii) external resources complemented with (iii) essential experimental and supporting information on genes and cellular effects. In order to facilitate an overview of existing and supporting information, a series of novel information connections have been established. CancerResource addresses the spectrum of research on compound-target interactions in natural sciences as well as in individualized medicine; CancerResource is available at: http://bioinformatics.charite.de/cancerresource/. PMID- 20952399 TI - Quantifying the energetic contributions of desolvation and pi-electron density during translesion DNA synthesis. AB - This report examines the molecular mechanism by which high-fidelity DNA polymerases select nucleotides during the replication of an abasic site, a non instructional DNA lesion. This was accomplished by synthesizing several unique 5 substituted indolyl 2'-deoxyribose triphosphates and defining their kinetic parameters for incorporation opposite an abasic site to interrogate the contributions of pi-electron density and solvation energies. In general, the K(d, app) values for hydrophobic non-natural nucleotides are ~10-fold lower than those measured for isosteric hydrophilic analogs. In addition, k(pol) values for nucleotides that contain less pi-electron densities are slower than isosteric analogs possessing higher degrees of pi-electron density. The differences in kinetic parameters were used to quantify the energetic contributions of desolvation and pi-electron density on nucleotide binding and polymerization rate constant. We demonstrate that analogs lacking hydrogen-bonding capabilities act as chain terminators of translesion DNA replication while analogs with hydrogen bonding functional groups are extended when paired opposite an abasic site. Collectively, the data indicate that the efficiency of nucleotide incorporation opposite an abasic site is controlled by energies associated with nucleobase desolvation and pi-electron stacking interactions whereas elongation beyond the lesion is achieved through a combination of base-stacking and hydrogen-bonding interactions. PMID- 20952400 TI - KUPS: constructing datasets of interacting and non-interacting protein pairs with associated attributions. AB - KUPS (The University of Kansas Proteomics Service) provides high-quality protein protein interaction (PPI) data for researchers developing and evaluating computational models for predicting PPIs by allowing users to construct ready-to use data sets of interacting protein pairs (IPPs), non-interacting protein pairs (NIPs) and associated features. Multiple filters and options allow the user to control the make-up of the IPPs and NIPs as well as the quality of the resultant data sets. Each data set is built from the overall database, which includes 185 446 IPPs and ~1.5 billion NIPs from five primary databases: IntAct, HPRD, MINT, UniProt and the Gene Ontology. The IPP set can be set to specific model organisms, interaction types and experimental evidence. The NIP set can be generated using four different strategies, which can alleviate biased estimation problems. Lastly, multiple features can be provided for all of the IPP and NIP pairs. Additionally, KUPS provides two benchmark data sets to help researchers compare their algorithms to existing approaches. KUPS is freely available at http://www.ittc.ku.edu/chenlab. PMID- 20952401 TI - PAIR: the predicted Arabidopsis interactome resource. AB - The predicted Arabidopsis interactome resource (PAIR, http://www.cls.zju.edu.cn/pair/), comprised of 5990 experimentally reported molecular interactions in Arabidopsis thaliana together with 145,494 predicted interactions, is currently the most comprehensive data set of the Arabidopsis interactome with high reliability. PAIR predicts interactions by a fine-tuned support vector machine model that integrates indirect evidences for interaction, such as gene co-expressions, domain interactions, shared GO annotations, co localizations, phylogenetic profile similarities and homologous interactions in other organisms (interologs). These predictions were expected to cover 24% of the entire Arabidopsis interactome, and their reliability was estimated to be 44%. Two independent example data sets were used to rigorously validate the prediction accuracy. PAIR features a user-friendly query interface, providing rich annotation on the relationships between two proteins. A graphical interaction network browser has also been integrated into the PAIR web interface to facilitate mining of specific pathways. PMID- 20952402 TI - Temperature dependence of DNA persistence length. AB - We have determined the temperature dependence of DNA persistence length, a, using two different methods. The first approach was based on measuring the j-factors of short DNA fragments at various temperatures. Fitting the measured j-factors by the theoretical equation allowed us to obtain the values of a for temperatures between 5 degrees C and 42 degrees C. The second approach was based on measuring the equilibrium distribution of the linking number between the strands of circular DNA at different temperatures. The major contribution into the distribution variance comes from the fluctuations of DNA writhe in the nicked circular molecules which are specified by the value of a. The computation-based analysis of the measured variances was used to obtain the values of a for temperatures up to 60 degrees C. We found a good agreement between the results obtained by these two methods. Our data show that DNA persistence length strongly depends on temperature and accounting for this dependence is important in quantitative comparison between experimental results obtained at different temperatures. PMID- 20952403 TI - Chromatin and DNA methylation dynamics during retinoic acid-induced RET gene transcriptional activation in neuroblastoma cells. AB - Although it is well known that RET gene is strongly activated by retinoic acid (RA) in neuroblastoma cells, the mechanisms underlying such activation are still poorly understood. Here we show that a complex series of molecular events, that include modifications of both chromatin and DNA methylation state, accompany RA mediated RET activation. Our results indicate that the primary epigenetic determinants of RA-induced RET activation differ between enhancer and promoter regions. At promoter region, the main mark of RET activation was the increase of H3K4me3 levels while no significant changes of the methylation state of H3K27 and H3K9 were observed. At RET enhancer region a bipartite chromatin domain was detected in unstimulated cells and a prompt demethylation of H3K27me3 marked RET gene activation upon RA exposure. Moreover, ChIP experiments demonstrated that EZH2 and MeCP2 repressor complexes were associated to the heavily methylated enhancer region in the absence of RA while both complexes were displaced during RA stimulation. Finally, our data show that a demethylation of a specific CpG site at the enhancer region could favor the displacement of MeCP2 from the heavily methylated RET enhancer region providing a novel potential mechanism for transcriptional regulation of methylated RA-regulated loci. PMID- 20952405 TI - COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. AB - COSMIC (http://www.sanger.ac.uk/cosmic) curates comprehensive information on somatic mutations in human cancer. Release v48 (July 2010) describes over 136,000 coding mutations in almost 542,000 tumour samples; of the 18,490 genes documented, 4803 (26%) have one or more mutations. Full scientific literature curations are available on 83 major cancer genes and 49 fusion gene pairs (19 new cancer genes and 30 new fusion pairs this year) and this number is continually increasing. Key amongst these is TP53, now available through a collaboration with the IARC p53 database. In addition to data from the Cancer Genome Project (CGP) at the Sanger Institute, UK, and The Cancer Genome Atlas project (TCGA), large systematic screens are also now curated. Major website upgrades now make these data much more mineable, with many new selection filters and graphics. A Biomart is now available allowing more automated data mining and integration with other biological databases. Annotation of genomic features has become a significant focus; COSMIC has begun curating full-genome resequencing experiments, developing new web pages, export formats and graphics styles. With all genomic information recently updated to GRCh37, COSMIC integrates many diverse types of mutation information and is making much closer links with Ensembl and other data resources. PMID- 20952404 TI - An RNA degradosome assembly in Caulobacter crescentus. AB - In many bacterial species, the multi-enzyme RNA degradosome assembly makes key contributions to RNA metabolism. Powering the turnover of RNA and the processing of structural precursors, the RNA degradosome has differential activities on a spectrum of transcripts and contributes to gene regulation at a global level. Here, we report the isolation and characterization of an RNA degradosome assembly from the alpha-proteobacterium Caulobacter crescentus, which is a model organism for studying morphological development and cell-cycle progression. The principal components of the C. crescentus degradosome are the endoribonuclease RNase E, the exoribonuclease polynucleotide phosphorylase (PNPase), a DEAD-box RNA helicase and the Krebs cycle enzyme aconitase. PNPase and aconitase associate with specific segments in the C-terminal domain of RNase E that are predicted to have structural propensity. These recognition 'microdomains' punctuate structurally an extensive region that is otherwise predicted to be natively disordered. Finally, we observe that the abundance of RNase E varies through the cell cycle, with maxima at morphological differentiation and cell division. This variation may contribute to the program of gene expression during cell division. PMID- 20952406 TI - OMPdb: a database of {beta}-barrel outer membrane proteins from Gram-negative bacteria. AB - We describe here OMPdb, which is currently the most complete and comprehensive collection of integral beta-barrel outer membrane proteins from Gram-negative bacteria. The database currently contains 69,354 proteins, which are classified into 85 families, based mainly on structural and functional criteria. Although OMPdb follows the annotation scheme of Pfam, many of the families included in the database were not previously described or annotated in other publicly available databases. There are also cross-references to other databases, references to the literature and annotation for sequence features, like transmembrane segments and signal peptides. Furthermore, via the web interface, the user can not only browse the available data, but submit advanced text searches and run BLAST queries against the database protein sequences or domain searches against the collection of profile Hidden Markov Models that represent each family's domain organization as well. The database is freely accessible for academic users at http://bioinformatics.biol.uoa.gr/OMPdb and we expect it to be useful for genome wide analyses, comparative genomics as well as for providing training and test sets for predictive algorithms regarding transmembrane beta-barrels. PMID- 20952407 TI - NIASGBdb: NIAS Genebank databases for genetic resources and plant disease information. AB - The National Institute of Agrobiological Sciences (NIAS) is implementing the NIAS Genebank Project for conservation and promotion of agrobiological genetic resources to contribute to the development and utilization of agriculture and agricultural products. The project's databases (NIASGBdb; http://www.gene.affrc.go.jp/databases_en.php) consist of a genetic resource database and a plant diseases database, linked by a web retrieval database. The genetic resources database has plant and microorganism search systems to provide information on research materials, including passport and evaluation data for genetic resources with the desired properties. To facilitate genetic diversity research, several NIAS Core Collections have been developed. The NIAS Rice (Oryza sativa) Core Collection of Japanese Landraces contains information on simple sequence repeat (SSR) polymorphisms. SSR marker information for azuki bean (Vigna angularis) and black gram (V. mungo) and DNA sequence data from some selected Japanese strains of the genus Fusarium are also available. A database of plant diseases in Japan has been developed based on the listing of common names of plant diseases compiled by the Phytopathological Society of Japan. Relevant plant and microorganism genetic resources are associated with the plant disease names by the web retrieval database and can be obtained from the NIAS Genebank for research or educational purposes. PMID- 20952408 TI - Ab initio identification of transcription start sites in the Rhesus macaque genome by histone modification and RNA-Seq. AB - Rhesus macaque is a widely used primate model organism. Its genome annotations are however still largely comparative computational predictions derived mainly from human genes, which precludes studies on the macaque-specific genes, gene isoforms or their regulations. Here we took advantage of histone H3 lysine 4 trimethylation (H3K4me3)'s ability to mark transcription start sites (TSSs) and the recently developed ChIP-Seq and RNA-Seq technology to survey the transcript structures. We generated 14,013,757 sequence tags by H3K4me3 ChIP-Seq and obtained 17,322,358 paired end reads for mRNA, and 10,698,419 short reads for sRNA from the macaque brain. By integrating these data with genomic sequence features and extending and improving a state-of-the-art TSS prediction algorithm, we ab initio predicted and verified 17,933 of previously electronically annotated TSSs at 500-bp resolution. We also predicted approximately 10,000 novel TSSs. These provide an important rich resource for close examination of the species specific transcript structures and transcription regulations in the Rhesus macaque genome. Our approach exemplifies a relatively inexpensive way to generate a reasonably reliable TSS map for a large genome. It may serve as a guiding example for similar genome annotation efforts targeted at other model organisms. PMID- 20952409 TI - Amphiphilic block copolymers enhance the cellular uptake of DNA molecules through a facilitated plasma membrane transport. AB - Amphiphilic block copolymers have been developed recently for their efficient, in vivo transfection activities in various tissues. Surprisingly, we observed that amphiphilic block copolymers such as Lutrol(r) do not allow the transfection of cultured cells in vitro, suggesting that the cell environment is strongly involved in their mechanism of action. In an in vitro model mimicking the in vivo situation we showed that pre-treatment of cells with Lutrol(r), prior to their incubation with DNA molecules in the presence of cationic lipid, resulted in higher levels of reporter gene expression. We also showed that this improvement in transfection efficiency associated with the presence of Lutrol(r) was observed irrespective of the plasmid promoter. Considering the various steps that could be improved by Lutrol(r), we concluded that the nucleic acids molecule internalization step is the most important barrier affected by Lutrol(r). Microscopic examination of transfected cells pre-treated with Lutrol(r) confirmed that more plasmid DNA copies were internalized. Absence of cationic lipid did not impair Lutrol(r)-mediated DNA internalization, but critically impaired endosomal escape. Our results strongly suggest that in vivo, Lutrol(r) improves transfection by a physicochemical mechanism, leading to cellular uptake enhancement through a direct delivery into the cytoplasm, and not via endosomal pathways. PMID- 20952410 TI - SuperSweet--a resource on natural and artificial sweetening agents. AB - A vast number of sweet tasting molecules are known, encompassing small compounds, carbohydrates, d-amino acids and large proteins. Carbohydrates play a particularly big role in human diet. The replacement of sugars in food with artificial sweeteners is common and is a general approach to prevent cavities, obesity and associated diseases such as diabetes and hyperlipidemia. Knowledge about the molecular basis of taste may reveal new strategies to overcome diet induced diseases. In this context, the design of safe, low-calorie sweeteners is particularly important. Here, we provide a comprehensive collection of carbohydrates, artificial sweeteners and other sweet tasting agents like proteins and peptides. Additionally, structural information and properties such as number of calories, therapeutic annotations and a sweetness-index are stored in SuperSweet. Currently, the database consists of more than 8000 sweet molecules. Moreover, the database provides a modeled 3D structure of the sweet taste receptor and binding poses of the small sweet molecules. These binding poses provide hints for the design of new sweeteners. A user-friendly graphical interface allows similarity searching, visualization of docked sweeteners into the receptor etc. A sweetener classification tree and browsing features allow quick requests to be made to the database. The database is freely available at: http://bioinformatics.charite.de/sweet/. PMID- 20952411 TI - ParameciumDB in 2011: new tools and new data for functional and comparative genomics of the model ciliate Paramecium tetraurelia. AB - ParameciumDB is a community model organism database built with the GMOD toolkit to integrate the genome and biology of the ciliate Paramecium tetraurelia. Over the last four years, post-genomic data from proteome and transcriptome studies has been incorporated along with predicted orthologs in 33 species, annotations from the community and publications from the scientific literature. Available tools include BioMart for complex queries, GBrowse2 for genome browsing, the Apollo genome editor for expert curation of gene models, a Blast server, a motif finder, and a wiki for protocols, nomenclature guidelines and other documentation. In-house tools have been developed for ontology browsing and evaluation of off-target RNAi matches. Now ready for next-generation deep sequencing data and the genomes of other Paramecium species, this open-access resource is available at http://paramecium.cgm.cnrs-gif.fr. PMID- 20952412 TI - A retrospective study of cryptosporidial diarrhea in a region with high HIV prevalence. AB - This retrospective study describes 63 patients <18 years of age presenting with cryptosporidial diarrhea to Tygerberg Children's' Hospital, a referral centre in the Western Cape, South Africa, from June 2004 through May 2005. Their mean age was 18.7 months (SD 17 months). Of the patients, 39 (62%) were male and 13 (20.6%) were HIV infected. Most children (57%) presented during the hot dry months of the year (December to March) and the majority (75%) of them required hospitalization. HIV-infected children were hospitalized for longer duration (median 18 days) than HIV-uninfected children (median 8.5 days). Four HIV infected children (30.7%) died vs. four who were either HIV uninfected or of unknown status (p = 0.049). Seven of the children who died were malnourished. The CD4 count of HIV-infected children who died was 416 * 109) l-1 compared with 1269 * 109 l-1 (p = 0.1) for uninfected children. Cryptosporidium is an important cause of diarrhea among younger children in the Western Cape, which occurs more frequently during the dry months of the year and has a worse outcome in HIV infected children. PMID- 20952413 TI - Length-dependent tension in the failing heart and the efficacy of cardiac resynchronization therapy. AB - AIMS: Cardiac resynchronization therapy (CRT) has emerged as one of the few effective and safe treatments for heart failure. However, identifying patients that will benefit from CRT remains controversial. The dependence of CRT efficacy on organ and cellular scale mechanisms was investigated in a patient-specific computer model to identify novel patient selection criteria. METHODS AND RESULTS: A biophysically based patient-specific coupled electromechanics heart model has been developed which links the cellular and sub-cellular mechanisms which regulate cardiac function to the whole organ function observed clinically before and after CRT. A sensitivity analysis of the model identified lack of length dependence of tension regulation within the sarcomere as a significant contributor to the efficacy of CRT. Further simulation analysis demonstrated that in the whole heart, length-dependent tension development is key not only for the beat-to-beat regulation of stroke volume (Frank-Starling mechanism), but also the homogenization of tension development and strain. CONCLUSIONS: In individuals with effective Frank-Starling mechanism, the length dependence of tension facilitates the homogenization of stress and strain. This can result in synchronous contraction despite asynchronous electrical activation. In these individuals, synchronizing electrical activation through CRT may have minimal benefit. PMID- 20952414 TI - The detection of the nitrite reductase and NO-generating properties of haemoglobin by mitochondrial inhibition. AB - AIMS: Nitrite (NO2-), now regarded as an endocrine reserve of nitric oxide (NO), is bioactivated by nitrite reductase enzymes to mediate physiological responses. In blood, haemoglobin (Hb) catalyses nitrite reduction through a reaction modulated by haem redox potential and oxygen saturation, resulting in maximal NO production around the Hb P50. Although physiological studies demonstrate that Hb catalysed nitrite reduction mediates cyclic guanosine monophosphate (cGMP) dependent vasodilation, the NO-scavenging effects of Hb raise questions about how NO generated from this reaction escapes the Hb molecule to signal at distant targets. Here, we characterize the NO-generating properties of Hb using the cGMP independent and NO-dependent inhibition of mitochondrial cytochrome c oxidase. METHODS AND RESULTS: Using a novel technique to measure respiratory inhibition of isolated rat mitochondria, we provide evidence that the reduction of nitrite by intact red blood cells (RBCs) and Hb generates NO, which inhibits mitochondrial respiration. We show that allosteric modulators, which reduce the haem redox potential and stabilize the R state of Hb, regulate the ability of this reaction to inhibit respiration. Finally, we find that the rate of NO generation increases with the rate of Hb deoxygenation, explained by an increase in the proportion of partially deoxygenated R-state tetramers, which convert nitrite to NO more rapidly. CONCLUSION: These data reveal redox and allosteric mechanisms that control Hb-mediated nitrite reduction and regulation of mitochondrial function, and support a role for Hb-catalysed nitrite reduction in hypoxic vasodilation. PMID- 20952415 TI - Regulation of the cardiac sodium channel Nav1.5 by utrophin in dystrophin deficient mice. AB - AIMS: Duchenne muscular dystrophy (DMD) is a severe striated muscle disease due to the absence of dystrophin. Dystrophin deficiency results in dysfunctional sodium channels and conduction abnormalities in hearts of mdx mice. Disease progression in the mdx mouse only modestly reflects that of DMD patients, possibly due to utrophin up-regulation. Here, we investigated mice deficient in both dystrophin and utrophin [double knockout (DKO)] to assess the role of utrophin in the regulation of the cardiac sodium channel (Na(v)1.5) in mdx mice. METHODS AND RESULTS: Co-immunoprecipitation studies in HEK293 cells showed that utrophin interacts with Na(v)1.5 via syntrophin proteins, an interaction abolished by deletion of the PDZ (PSD-95, Dlg, and Zona occludens) domain-binding motif of Na(v)1.5. We also provide evidence for such interaction in mouse heart using Na(v)1.5 C-terminus fusion proteins. In hearts of DKO mice, Na(v)1.5 protein levels were decreased by 25 +/- 8%, together with a 42 +/- 12% reduction of syntrophins compared with mdx, where utrophin was up-regulated by 52 +/- 9% compared with C57BL/10 control mice. Sodium current was found to be reduced by 41 +/- 5% in DKO cardiomyocytes compared with mdx, representing a loss of 63 +/- 3% when compared with C57BL/10 wild-type control mice. Decreased Na(v)1.5 protein and current in DKO were reflected in a significant slowing of 27 +/- 6% of maximal upstroke velocity of the cardiac action potential compared with mdx. CONCLUSION: Utrophin plays a central role in the regulation of Na(v)1.5 in mdx mice. These findings provide support for therapeutic strategies aimed at overexpressing utrophin in the hopes of reducing cardiac pathology in DMD patients. PMID- 20952417 TI - In vitro susceptibility of Actinobaculum schaalii to 12 antimicrobial agents and molecular analysis of fluoroquinolone resistance. AB - OBJECTIVES: To assess the in vitro susceptibility of Actinobaculum schaalii to 12 antimicrobial agents as well as to dissect the genetic basis of fluoroquinolone resistance. METHODS: Forty-eight human clinical isolates of A. schaalii collected in Switzerland and France were studied. Each isolate was identified by 16S rRNA sequencing. MICs of amoxicillin, ceftriaxone, gentamicin, vancomycin, clindamycin, linezolid, ciprofloxacin, levofloxacin, moxifloxacin, co trimoxazole, nitrofurantoin and metronidazole were determined using the Etest method. Interpretation of results was made according to EUCAST clinical breakpoints. The quinolone-resistance-determining regions (QRDRs) of gyrA and parC genes were also identified and sequence analysis was performed for all 48 strains. RESULTS: All isolates were susceptible to amoxicillin, ceftriaxone, gentamicin, clindamycin (except three), vancomycin, linezolid and nitrofurantoin, whereas 100% and 85% were resistant to ciprofloxacin/metronidazole and co trimoxazole, respectively. Greater than or equal to 90% of isolates were susceptible to the other tested fluoroquinolones, and only one strain was highly resistant to levofloxacin (MIC >=32 mg/L) and moxifloxacin (MIC 8 mg/L). All isolates that were susceptible or low-level resistant to levofloxacin/moxifloxacin (n = 47) showed identical GyrA and ParC amino acid QRDR sequences. In contrast, the isolate exhibiting high-level resistance to levofloxacin and moxifloxacin possessed a unique mutation in GyrA, Ala83Val (Escherichia coli numbering), whereas no mutation was present in ParC. CONCLUSIONS: When an infection caused by A. schaalii is suspected, there is a risk of clinical failure by treating with ciprofloxacin or co-trimoxazole, and beta-lactams should be preferred. In addition, acquired resistance to fluoroquinolones more active against Gram-positive bacteria is possible. PMID- 20952416 TI - The potential role of the red blood cell in nitrite-dependent regulation of blood flow. AB - Nitrite was once thought to have little physiological relevance. However, nitrite is now being increasingly recognized as a therapeutic or possibly even physiological precursor of nitric oxide (NO) that is utilized when needed to increase blood flow. It is likely that different mechanisms for nitrite bioconversion occur in different tissues, but in the vascular system, there is evidence that erythrocyte haemoglobin (Hb) is responsible for the oxygen dependent reduction of nitrite to modulate blood flow. Here, we review the complex chemical interactions of Hb and nitrite and discuss evidence supporting its role in vasodilation. We also discuss ongoing work focused on defining the precise mechanisms for export of NO activity from red blood cells and of other pathways that may mediate nitrite-dependent vasodilation. PMID- 20952418 TI - Tribal ethnicity and CYP2B6 genetics in Ugandan and Zimbabwean populations in the UK: implications for efavirenz dosing in HIV infection. AB - OBJECTIVES: To determine differences in CYP2B6 loss of function (LoF) single nucleotide polymorphisms (SNPs) and haplotypes between Zimbabweans and Ugandans, and within Ugandan populations (Bantu and Nilotic). METHODS: Genetic epidemiological study enrolling adult black African Ugandan and Zimbabwean patients attending a UK HIV-1 clinic, irrespective of antiretroviral therapy status. Genomic DNA was extracted from whole blood and the presence of CYP2B6 alleles was determined by direct sequencing of all nine exons of the CYP2B6 gene. Blood was also collected, where appropriate, for determination of efavirenz concentrations. Frequency of SNPs in all patients and LoF haplotype frequencies were calculated. The relationship between the number of LoF haplotype alleles possessed and efavirenz trough concentration (ETC) was determined. RESULTS: Thirty-six Zimbabweans and 74 Ugandans (58 Bantu and 16 Nilotic) were recruited. The definite haplotypes determined were *6, *18, *20 and *27 as LoF and *4 as gain of function. Among those with definite genotypes, the frequency of LoF alleles was 65% [95% confidence interval (95% CI): 51-80] of Zimbabweans versus 22% (95% CI: 12-31) of Ugandan Bantus (P = 10(-6)) and versus 39% (95% CI: 14-64) of Ugandan Nilotics (P = 0.09). Among the 19 patients with definite genotype and with available ETCs, log ETCs were associated with a greater number of LoF haplotype alleles [848 ng/mL (n = 12), 1069 ng/mL (n = 4) and 1813 ng/mL (n = 3) for 0, 1 or 2 LoF haplotypes, respectively (P = 0.016)]. CONCLUSIONS: Among Zimbabweans, LoF haplotypes constitute the majority of CYP2B6 alleles and are significantly higher in prevalence compared with Ugandans. Frequencies of LoF haplotypes and SNPs in Ugandan Nilotics appear to lie between those of Zimbabweans and Ugandan Bantus. These findings may have relevance to pharmacokinetics and dosing of efavirenz in African populations. PMID- 20952419 TI - In vitro antimicrobial activities of capuramycin analogues against non tuberculous mycobacteria. AB - OBJECTIVES: To determine antibacterial activity of capuramycin analogues SQ997, SQ922, SQ641 and RKS2244 against several non-tuberculous mycobacteria (NTM). METHODS: In vitro antibiotic activities, i.e. MIC, MBC, rate of killing and synergistic interaction with other antibiotics, were evaluated. RESULTS: SQ641 was the most active compound against all the NTM species studied. The MIC of SQ641 was <=0.06-4 mg/L for Mycobacterium avium complex (MAC; n = 20), 0.125-2 mg/L for M. avium paratuberculosis (MAP; n = 9), 0.125-2 mg/L for Mycobacterium kansasii (MKN;n = 2), 0.25-1 mg/L for Mycobacterium abscessus (MAB; n = 11), 4 mg/L for Mycobacterium smegmatis (MSMG; n = 1), and 1 and 8 mg/L for Mycobacterium ulcerans (MUL; n = 1), by microdilution and agar dilution methods, respectively. SQ641 was bactericidal against NTM, with an MBC/MIC ratio of 1 to 32, and killed all mycobacteria faster than positive control drugs for each strain. In chequerboard titrations, SQ641 was synergistic with ethambutol against both MAC and MSMG, and was synergistic with streptomycin and rifabutin against MAB. CONCLUSIONS: In vitro, SQ641 was the most potent of the capuramycin analogues against all NTM tested, both laboratory and clinical strains. PMID- 20952420 TI - Different versions of the right answer: the importance of measurement uncertainty in radiation dosimetry. AB - The performance of radiation dosemeters that are issued by approved individual monitoring services generally meet international standards, with typical results within a few tens of per cent of the reference value. Experienced dosimetry practitioners will understand the uncertainties and treat monitoring results with due caution. However, where different technologies (for example, where passive and electronic dosemeters) are used side by side, apparent disagreements can arise. These apparent disagreements between different systems can be significant, and dosimetrists must be prepared to help in addressing the issues that result. PMID- 20952421 TI - RD20, a stress-inducible caleosin, participates in stomatal control, transpiration and drought tolerance in Arabidopsis thaliana. AB - Plants overcome water deficit conditions by combining molecular, biochemical and morphological changes. At the molecular level, many stress-responsive genes have been isolated, but knowledge of their physiological functions remains fragmentary. Here, we report data for RD20, a stress-inducible Arabidopsis gene that belongs to the caleosin family. As for other caleosins, we showed that RD20 localized to oil bodies. Although caleosins are thought to play a role in the degradation of lipids during seed germination, induction of RD20 by dehydration, salt stress and ABA suggests that RD20 might be involved in processes other than germination. Using plants carrying the promoter RD20::uidA construct, we show that RD20 is expressed in leaves, guard cells and flowers, but not in root or in mature seeds. Water deficit triggers a transient increase in RD20 expression in leaves that appeared predominantly dependent on ABA signaling. To assess the biological significance of these data, a functional analysis using rd20 knock-out and overexpressing complemented lines cultivated either in standard or in water deficit conditions was performed. The rd20 knock-out plants present a higher transpiration rate that correlates with enhanced stomatal opening and a reduced tolerance to drought as compared with the wild type. These results support a role for RD20 in drought tolerance through stomatal control under water deficit conditions. PMID- 20952422 TI - Relaxin family peptides in the male reproductive system--a critical appraisal. AB - The human genome project has identified, besides ovarian relaxin (RLN), six other relaxin-like molecules (RLN3, H1-RLN, INSL3-6), most of which appear to be expressed in the testis and/or male reproductive system, together with four different G-protein-coupled receptors responsive to one or other of these peptides. Earlier work on relaxin in the male assumed the simplistic hypothesis of only a single relaxin-like entity. This review systematically examines the expression and physiology of relaxin-like molecules in the male reproductive system in order to reappraise the importance of this hormone system for male reproductive function. Although there are important species differences, only INSL3 and INSL6 appear to be generally expressed at a moderately high level within the testis, whereas ovarian RLN is consistently a major secretory product of the prostate epithelium. However, all members of this relaxin-like family appear to be expressed also at a low level in different organs of the male reproductive system, suggesting possible autocrine/paracrine effects. The four receptors (RXFP1-4) for these peptides are also expressed to differing levels in both somatic and seminiferous compartments of the testis and in the prostate, supporting relevant functions for most members of this interesting peptide family. Recent studies of relaxin family peptides in prostate pathology highlight their functional importance in the clinical context as potential causative, diagnostic and therapeutic agents and warrant more specific and detailed studies of their roles also in regard to male fertility and other aspects of male reproductive function. PMID- 20952424 TI - Acute haemodynamic effects of increase in paced heart rate in heart failure patients recorded with an implantable haemodynamic monitor. AB - AIMS: The aim of this study was to investigate the acute effects of different biventricularly paced heart rates (pHRs) on right ventricular (RV) haemodynamics in heart failure (HF) patients with an implantable haemodynamic monitor (IHM). METHODS AND RESULTS: At rest, seven pHRs, range 60-120 bpm (steps of 10), were randomly programmed and maintained for 60 s in 10 patients (male, 65+/-12 years, New York Heart Association II-III). Right ventricular systolic (RVSP) and diastolic pressures, estimated pulmonary artery diastolic (ePAD) pressure, and RV+dP/dt were recorded beat-to-beat using the IHM. Cardiac output (CO) was estimated from the RV pressure waveforms and arterial blood pressure was measured (Portapres(r)). To compare the haemodynamic effects of increased pHR at rest to that of spontaneous, sinus-driven heart rate (HR) increase, patients also performed a symptom-limited bicycle exercise. At rest, RV+dP/dt increased significantly with elevated pHR (P, main effect, <0.001), whereas filling pressures (ePAD and RVSP) decreased significantly in the range 60-100 bpm (P<0.03 and P<0.003, respectively) but tended to increase or level out at pHRs>00 bpm. At a pHR of 100 bpm, ePAD was 1.4 mmHg lower compared with 60 bpm (P<0.01). Cardiac output increased gradually with elevated pHR at rest (P<0.001). Both total peripheral and estimated pulmonary arterial resistance significantly decreased with increased pHR. During exercise-induced maximum HR increase, RV+dP/dt, ePAD, and CO were all significantly higher compared with the corresponding pHR at rest. CONCLUSION: During cardiac resynchronization therapy in HF patients, the force frequency relationship is present in the RV, as increasing the pHR in the range 60-100 bpm results in decreased filling pressures and increased CO. PMID- 20952425 TI - Mechanical thrombectomy of an infected deep venous thrombosis: a novel technique of source control in sepsis. AB - A young i.v. drug abuser presented with an extensive iliofemoral deep vein thrombosis and signs of severe sepsis. Subsequent investigations revealed multiple septic emboli in his lungs originating from infected thrombus in his leg. Despite systemic anti-coagulation and appropriate parenteral antibiotics, he continued to show signs of worsening acute infection. Percutaneous mechanical thrombectomy was performed successfully and resulted in an immediate improvement in his condition. In this report, we discuss the novel use of this technique for source control in a patient with septic shock secondary to infected thrombus. PMID- 20952426 TI - Transtracheal jet ventilation in 50 patients with severe airway compromise and stridor. AB - BACKGROUND: Management of the airway is difficult in patients with pharyngeal or laryngeal pathology caused by malignancy, extensive surgery, or radiotherapy scarring, particularly when undergoing pharyngolaryngeal surgery. Tracheal intubation, with or without fibreoptic guidance, is often impractical because of the severe glottic stenosis and primary tracheostomy under local anaesthesia has been the preferred technique. However, complication rates as high as 30% have been reported after primary tracheostomy and there is the potential for long-term morbidity. High-frequency jet ventilation (HFJV) has several advantages over other techniques in the management of the difficult airway and can be delivered by supraglottic and infraglottic routes. To date, no large series has described the use of transtracheal HFJV (TTHFJV) in adult patients with stridor and critical airway obstruction. METHODS: We report a prospective, descriptive audit of the safe use of TTHFJV in patients with severe airway compromise and stridor undergoing pharyngolaryngeal surgery (50 consecutive procedures in 44 patients). RESULTS: TTHFJV was successful in all 50 cases. There were no major complications and the incidence of minor complications was 20% with no subsequent morbidity. CONCLUSIONS: We attribute this low incidence to the use of an automated jet ventilator with airway pressure monitoring and control, and the alteration of ventilator parameters by an experienced anaesthetist. PMID- 20952429 TI - Opioid-induced hyperalgesia: pain hurts? PMID- 20952427 TI - Randomized controlled trial comparing morphine or clonidine with bupivacaine for caudal analgesia in children undergoing upper abdominal surgery. AB - BACKGROUND: Various additives have been used to increase the duration of analgesia provided by bupivacaine administered by single-shot caudal injection in children. METHODS: A prospective, randomized, double-blind controlled study in 50 ASA I-II children (34 boys and 16 girls) aged 1-6 yr undergoing upper abdominal surgery was conducted. Patients were divided into two groups to receive either morphine 30 ug kg-1 (MB) or clonidine 2 ug kg-1 (CB) in bupivacaine 0.2% (1.25 ml kg-1) for caudal analgesia. The duration of analgesia (FLACC scale) and sedation and side-effects such as vomiting, itching, respiratory depression, hypotension, and bradycardia were observed. RESULTS: The mean duration of analgesia was 16.5 (3.6) h in the CB group compared with 10.2 (2.3) h (P<0.01) in the MB group. Subjects who received clonidine (CB) were sedated for longer [7.1 (0.8) h] compared with the MB group [3.8 (0.7) h; P<0.01]. Vomiting was observed in 4% and 12% of subjects in the CB and MB groups, respectively. Sixteen per cent of subjects reported itching in the MB group (P=0.03), and none in the CB group. No hypotension, bradycardia, or respiratory depression was observed in any subjects. CONCLUSIONS: Caudal clonidine 2 ug kg-1 in bupivacaine 0.2% provides a longer duration of analgesia and sedation compared with caudal morphine 30 ug kg-1 in bupivacaine 0.2% without significant side-effects in children undergoing upper abdominal surgery. PMID- 20952430 TI - Cormack-Lehane classification revisited. PMID- 20952431 TI - Critical incident reporting and learning. PMID- 20952432 TI - Obstruction of a reinforced oral tracheal tube. PMID- 20952433 TI - Rapid awaking after administration of neostigmine in an elderly neurosurgical patient with prolonged recovery from general anaesthesia. PMID- 20952434 TI - Automated perioperative QT monitoring in a patient with long QT syndrome 2. PMID- 20952435 TI - Spinal anaesthesia guided by computed tomography scan in a patient with severe post-polio sequelae. PMID- 20952436 TI - The relevance of protein-protein interactions for p53 function: the CPE contribution. AB - The relevance of p53 as a tumour suppressor is evident from the fact that more than 50% of the human cancers hold mutations in the gene coding for p53, and of the remaining cancers a considerable number have alterations in the p53 pathway. From its discovery 30 years ago, the importance of p53 as an essential transcription factor for tumour suppression has become clear. More recently, new and seemingly diverse roles of p53 have been discovered. It soon became clear that protein-protein interactions play an important role in the regulation of the p53 function at different levels. Here we review the contribution by Prof. Fersht and his group towards understanding the basis and functional relevance of p53 protein-protein interactions, and the important role that protein science, biophysics and structural biology have played in the science produced in the Centre for Protein Engineering over the years. PMID- 20952437 TI - Sequence and structural analysis of two designed proteins with 88% identity adopting different folds. AB - Protein folding is a natural phenomenon by which a sequence of amino acids folds into a unique functional three-dimensional structure. Although the sequence code that governs folding remains a mystery, one can identify key inter-residue contacts responsible for a given topology. In nature, there are many pairs of proteins of a given length that share little or no sequence identity. Similarly, there are many proteins that share a common topology but lack significant evidence of homology. In order to tackle this problem, protein engineering studies have been used to determine the minimal number of amino acid residues that codes for a particular fold. In recent years, the coupling of theoretical models and experiments in the study of protein folding has resulted in providing some fruitful clues. He et al. have designed two proteins with 88% sequence identity, which adopt different folds and functions. In this work, we have systematically analysed these two proteins by performing pentapeptide search, secondary structure predictions, variation in inter-residue interactions and residue-residue pair preferences, surrounding hydrophobicity computations, conformational switching and energy computations. We conclude that the local secondary structural preference of the two designed proteins at the Nand C terminal ends to adopt either coil or strand conformation may be a crucial factor in adopting the different folds. Early on during the process of folding, both proteins may choose different energetically favourable pathways to attain the different folds. PMID- 20952438 TI - Gender differences in smoking experience and cessation: do wealth and education matter equally for women and men in Serbia? AB - BACKGROUND: Although nowadays smoking is less popular, one-third of adults in Serbia still smoke regularly. The aim of this study was to analyze associations of smoking experience and quitting with gender and socio-economic status. METHODS: Cross-sectional, population-based nationally representative household survey (Health Survey, 2006). Age- and multivariate-adjusted logistic regression analyses were used to analyze predictors of smoking experience and cessation. RESULTS: Of 12 365 interviewed, 51.1% used to smoke: current smokers accounted for 36.8% and former smokers for 14.3%. Higher educated women were more prone to smoking [secondary school: odds ratio (OR), 1.75; 95% confidence interval (CI), 1.52-2.01; university degree: OR, 1.53; 95% CI, 1.26-1.86], whereas for men the opposite was observed (university degree: OR, 0.72; 95% CI, 0.60-0.86). Education also was 'pro-quitting' factor (university degree: OR, 1.46; 95% CI, 1.07-1.99 for women; university degree: OR, 1.61; 95% CI, 1.23-1.80 for men). To quit smoking, wealth status was gradually more important for women, while just the richest men were more likely to quit smoking (OR, 1.45; 95% CI, 1.09-1.93). CONCLUSION: The poorest women in Serbia and the least educated men are those least likely to quit smoking, which indicates that ability to quit is predicted by socio-economic status. PMID- 20952439 TI - The pathogenesis of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an appalling prognosis. The failure of anti-inflammatory therapies coupled with the observation that deranged epithelium overlies proliferative myofibroblasts to form the fibroblastic focus has lead to the emerging concept that IPF is a disease of deregulated epithelial-mesenchymal crosstalk. IPF is triggered by an as yet unidentified alveolar injury that leads to activation of transforming growth factor-beta (TGF-beta) and alveolar basement membrane disruption. In the presence of persisting injurious pathways, or disrupted repair pathways, activated TGF-beta can lead to enhanced epithelial apoptosis and epithelial-to mesenchymal transition (EMT) as well as fibroblast, and fibrocyte, transformation into myofibroblasts which are resistant to apoptosis. The resulting deposition of excess disrupted matrix by these myofibroblasts leads to the development of IPF. PMID- 20952440 TI - A case of benign, multiple metastases. PMID- 20952441 TI - Takayasu arteritis: severe consequences of delayed diagnosis. PMID- 20952443 TI - Current organic waste recycling and the potential for local recycling through urban agriculture in Metro Manila. AB - Using the solid waste management programmes of three barangays (the smallest unit of local government in the Philippines) in Quezon City, Metro Manila, as a case study, this research aimed to further the development of efficient organic waste recycling systems through the promotion of urban agricultural activities on green and vacant spaces. First, the quantity of organic waste and compost produced through ongoing barangay projects was measured. The amount of compost that could potentially be utilized on farmland and vacant land within the barangays was then identified to determine the possibility of a local recycling system. The results indicate that, at present, securing buyers for compost is difficult and, therefore, most compost is distributed to large neighbouring farm villages. However, the present analysis of potential compost use within the barangay demonstrates that a more local compost recycling system is indeed feasible. PMID- 20952444 TI - Bioconversion of herbal industry waste into vermicompost using an epigeic earthworm Eudrilus eugeniae. AB - The aim of the present study was to investigate the potential of bioconversion of industrial herbal waste to vermicompost using Eudrilus eugeniae. Vermibeds were made using a mixture of herbal waste and cowdung (1 : 1) in comparison with the use of cowdung alone as substrate, resulting in vermicomposts 1 and 2, respectively. Different parameters were studied and it was observed that the nutrient profile of vermicompost 1 strongly influenced the growth of pea (Pisum sativum) and marigold plant (Tagetus erectus). The dry and fresh weight of shoots and roots, number of flowers, total yield in terms of fruit showed significant increase with vermicompost 1. Furthermore, vermicompost 1 (herbal waste and cow dung as substrate) resulted in a significant reduction in TOC by 58% in comparison with vermicompost 2 (cowdung as substrate). The C : N ratio was less than 20 in vermicompost 1 as well as in vermicompost 2, which indicated an advanced degree of stabilization and mineralization. The ability of earthworms to survive, grow and breed in the vermibed fed with the herbal waste indicates the sustainability and efficiency of a heterogeneous kind of organic waste. The results of the study suggested that bulk industrial herbal waste can be utilized as a substrate for vermicomposting and this can be proposed as an alternative for waste disposal in a clean green manner, promoting the concept of organic farming. PMID- 20952445 TI - Time limits? Reflecting and responding to time barriers for healthy, active living in Australia. AB - Lack of time is the main reason people say they do not exercise or use public transport, so addressing time barriers is essential to achieving health promotion goals. Our aim was to investigate how time barriers are viewed by the people who develop programs to increase physical activity or use active transport. We studied five interventions and explored the interplay between views and strategies. Some views emphasized personal choice and attitudes, and strategies to address time barriers were focused on changing personal priorities or perceptions. Other views emphasized social-structural sources of time pressures, and provided pragmatic ideas to free up time. The most nuanced strategies to address time barriers were employed by programs that researched and solicited the views of potential participants. Two initiatives re-shaped their campaigns to incorporate ways to save time, and framed exercise or active transport as a means to achieve other, pressing, priorities. Time shortages also posed problems for one intervention that relied on the unpaid time of volunteers. Time-sensitive health and active transport interventions are needed, and the methods and approaches we describe could serve as useful, preliminary models. PMID- 20952446 TI - Poor effect of guideline-based treatment of restless legs syndrome in clinical practice. PMID- 20952448 TI - Living and coping with Parkinson's disease: perceptions of informal carers. AB - A review of the literature highlights the important role informal carers play in the provision of palliative care in the community. In order to explore the caring experience of relatives with Parkinson's Disease (PD), interviews were conducted with 26 informal family caregivers. Interviews were taped, transcribed and subjected to content analysis. All caregivers were spouses, the majority female (n = 17) and all were responsible for providing physical, social and emotional care in the home. Although they viewed care giving as their role and duty, the results highlight the widespread burden of providing care on the emotional and physical health of the caregivers. The financial implications for providing care were outlined, with many reporting difficulty in accessing benefits. From the point of diagnosis, which had a huge emotional impact on relatives and carers, carers did not feel health professionals integrated them within the caring journey. Since diagnosis, carers commented on the lack of continued and coordinated care plans for relatives, resulting in symptoms being mismanaged and care opportunities for relatives and carers missed. Stereotypes of the meaning and timing of palliative care were common with many viewing it as being synonymous with cancer and not applicable to a person with PD. As the well-being of the informal carer directly influences the care of the person with PD, support interventions are required to relieve their burden, maximize outcomes and ensure targeting of services. PMID- 20952447 TI - ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease. AB - Huntington's disease (HD) is an inherited, progressive and ultimately fatal neurodegenerative disorder that is characterized by psychiatric, cognitive and motor symptoms. Among the pathways implicated in HD are those involving mitogen activated protein kinase signaling and particularly the Ras-extracellular signal regulated kinase (ERK) cascade. Studies in both cells and animal models suggest that ERK activation might provide a novel therapeutic target for the treatment of HD but compounds that specifically activate ERK are few. To test the hypothesis that pharmaceutical activation of ERK might be protective for HD, a polyphenol, fisetin, which was previously shown to activate the Ras-ERK cascade, was tested in three different models of HD: PC12 cells expressing mutant Httex1 under the control of an inducible promoter, Drosophila expressing mutant Httex1 and the R6/2 mouse model of HD. The results indicate that fisetin can reduce the impact of mutant huntingtin in each of these disease models. Prompted by this observation, we determined that the related polyphenol, resveratrol, also activates ERK and is protective in HD models. Notably, although more than a dozen small molecule inhibitors of ERK activation are in clinical trials, very few small molecule activators of ERK signaling are reported. Thus, fisetin, resveratrol and related compounds might be useful for the treatment of HD by virtue of their unique ability to activate ERK. PMID- 20952449 TI - Evaluation of the established non-MHC multiple sclerosis loci in an Indian population. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating neurodegenerative disorder with a strong genetic component. OBJECTIVE: The prevalence of MS in India is low compared with white populations of Northern European descent. METHODS: In order to ascertain whether disease susceptibility genes are the same across different populations, we completed the first investigation in the Indian MS population of 15 MS loci outside of the major histocompatibility (MHC) region that were previously identified and validated with MS susceptibility through genome-wide association and replication studies in white populations. RESULTS: In total, 197 Indian patients and 197 unrelated controls were analyzed. The most associated single nucleotide polymorphism (SNP) within this study was rs6897932 in the IL7R gene, which showed a strong protective effect in this data set (rs 6897932, OR = 0.5543, 95% CI = 0.37-0.78, p = 0.0009727). Two other SNPs were nominally associated with MS in this dataset, namely CLEC16A rs 12708716 (p = 0.0082, OR = 1.478, 95% CI = 1.106-1.975) and CD226 rs763361 (p = 0.03971, OR = 1.353, CI = 1.014-1.805). For the majority of the remaining SNPs (7/14), the trend for association was in the same direction as in previous studies in the white population. CONCLUSIONS: Although the power of this study was limited, our preliminary data suggest that disease susceptibility genes in MS in the Indian population may be similar to those of western populations. PMID- 20952450 TI - Development of an in vitro model to investigate joint ochronosis in alkaptonuria. AB - OBJECTIVES: Alkaptonuria (AKU) is a genetic disorder caused by lack of the enzyme responsible for breaking down homogentisic acid (HGA), an intermediate in tyrosine metabolism. HGA is deposited as a polymer, termed ochronotic pigment, in collagenous tissues. Pigmentation is progressive over many years, leading to CTDs including severe arthropathies. To investigate the mechanism of pigmentation and to determine how it leads to arthropathy, we aimed to develop an in vitro model of ochronosis. METHODS: Osteosarcoma cell lines MG63, SaOS-2 and TE85 were cultured in medium containing HGA from 0.1 MUM to 1 mM. Cultures were examined by light microscopy and transmission electron microscopy, and Schmorl's stain was used to detect pigment deposits in vitro, following the observation that this stain identifies ochronotic pigment in AKU tissues. The effects of HGA on cell growth and collagen synthesis were also determined. RESULTS: There was a dose related deposition of pigment in cells and associated matrix from 33 MUM to 0.33 mM HGA. Pigmentation in vitro was much more rapid than in vivo, indicating that protective mechanisms exist in tissues in situ. Pigment deposition was dependent on the presence of cells and was observed at HGA concentrations that were not toxic. There was an inhibition of cell growth and a stimulation of type I collagen synthesis up to 0.33 mM HGA, but severe cell toxicity at 1 mM HGA. CONCLUSION: We have developed an in vitro model of ochronosis that should contribute to understanding joint destruction in AKU and to the aetiology of OA. PMID- 20952451 TI - Cardioprotective effect of lemon grass as evidenced by biochemical and histopathological changes in experimentally induced cardiotoxicity. AB - Isoproterenol is a synthetic catecholamine found to cause toxicity leading to severe stress in the myocardium of experimental animals. The aim of the present study is to evaluate the cardioprotective effect of Cymbopogon citratus, which is used as a culinary item and commonly known as lemon grass (LG), in isoproterenol induced cardiotoxicity. Male Wistar albino rats were segregated into five different groups as follows. Groups I and II rats were treated with vehicle. Groups III and IV rats were treated with 100 and 200 mg/kg b.wt. of LG. Group V with 100 mg/kg b.wt. of vitamin E. Myocardial necrosis was induced in Groups II, III, IV and V on 58(th) and 59(th) day using isoproterenol at a dose of 85 mg/kg twice at 24-hour interval. Animals were sacrificed on the 60( th) day. LG pretreatment exhibited cardioprotective activity as evidenced by decreased activity of cardiac markers in serum and increased the same in heart homogenate (p < 0.05). LG administration decreased the toxic events of lipid peroxidation (TBARS) in both serum and heart tissue, by increasing the level of enzymatic antioxidants and non-enzymatic antioxidants significantly in both heart homogenate and serum sample (p < 0.05). The histopathological observations also revealed that the cardioprotective effect of LG extract was observed at a dose of 200 mg/kg b.wt. The results of the present study reveal that LG is cardioprotective and antilipid peroxidative by increasing various antioxidants at a dose of 200 mg/kg b.wt., which is comparable with that of vitamin E. PMID- 20952452 TI - Fulminant hepatic failure in woman with iron and non-steroidal anti-inflammatory drug intoxication. AB - A 17-year-old, previously healthy female ingested 16,000 mg iron sulphate (96.15 mg of iron ions per kg of b.wt.) with a suicidal intent. The patient was admitted to a toxicology unit 10 hours after the drug ingestion. Serum iron concentration at admission was 2351 MUg% (421.0 MUmol/L). In the course of the intoxication, hemorrhagic gastritis, renal insufficiency and increasing signs of fulminant hepatic failure complicated with coagulopathy and encephalopathy were observed. Treatment with deferoxamine was started immediately after admission to the hospital and continued for 15 hours until the serum concentration of iron decreased to 145 MUg% (25.9 MUmol/L). Patient was qualified for liver transplant, therefore albumin dialysis as a bridge to liver transplantation was performed. In spite of two procedures of albumin dialysis using the Prometheus system, deep coma, shock and respiratory insufficiency developed. The patient died 80 hours after iron ingestion. In the presented case, the ingestion of a very high dose of iron and late introduction of deferoxamine treatment contributed to fulminant liver failure and fatal outcome of the intoxication. PMID- 20952454 TI - Treatment with paroxetine, but not amitriptyline, lowers levels of lipoprotein(a) in patients with major depression. AB - High lipoprotein(a) (Lp(a)) levels constitute a major risk factor for vascular mortality. Major depression also increases the risk of cardiovascular disease. We measured the concentrations of Lp(a) in depressed patients and controls and studied the effects of antidepressant treatment and treatment outcome. Lp(a) levels were analysed at baseline in 35 in-patients with DSM-IV major depression who were then treated in a randomized double-blind manner with amitriptyline (n = 14) or paroxetine (n = 21), as well as in 33 healthy controls. Lp(a) levels were re-assessed after 4 weeks of treatment. We found a significant decrease in Lp(a) in patients treated with paroxetine, but not in those treated with amitriptyline. Our results suggest that antidepressant treatment with paroxetine might contribute to a decrease in vascular mortality risk irrespective of treatment outcome. PMID- 20952453 TI - The incidence and associated risk factors for sudden unexplained death in psychiatric in-patients in England and Wales. AB - Clinical characteristics and risk factors associated with sudden unexplained death (SUD) in the psychiatric population are unclear. Psychiatric in-patients (England, Wales) who met criteria for SUD were identified (1 March 1999-31 December 2005). Cases were matched with controls (in-patients alive on the day a SUD occurred). Data were collected via questionnaires. Some 283 cases of SUD were identified (41 annually), with a rate of 2.33/10,000 mental health admissions (in England). Electrocardiograms were not routine, cardiopulmonary resuscitation equipment was sometimes unavailable, attempts to resuscitate patients were carried out on one-half of all patients and post mortems/inquiries were not routine. Restraint and seclusion were uncommon. Risk factors included: benzodiazepines (odds ratio (OR): 1.83); >= 2 antipsychotics (OR: 2.35); promazine (OR: 4.02); diazepam (OR: 1.71); clozapine (OR: 2.10); cardiovascular disease (OR: 2.00); respiratory disease (OR: 1.98); diagnosis of dementia (OR: 2.08). Venlafaxine and a diagnosis of affective disorder were associated with reduced ORs (OR: 0.42; OR: 0.65). SUD is relatively rare, although it is more common in older patients and males. Prevention measures may include safer prescribing of antipsychotics and improved physical health care. The contribution of restraint or seclusion to SUD in individual cases is unclear. A uniform definition of SUD may help to identify contributing factors. PMID- 20952455 TI - Effect of isolation rearing on the expression of AMPA glutamate receptors in the hippocampal formation. AB - Reduced glutamatergic signaling may contribute to cognitive dysfunction in schizophrenia. Glutamatergic synapses might be the site of primary abnormalities in this disorder with the dopaminergic changes being secondary to altered glutamatergic transmission. Isolation rearing of rats from weaning has been used as an experimental model for affective disorders like schizophrenia. In this immunohistochemistry study we evaluate the changes in the expression of GluR1 and GluR2 AMPA receptors in the hippocampus, amygdala and entorhinal cortex induced by isolation rearing. Two groups of Wistar rats (grouped and isolated, n = 6/each) were used. Isolation rearing induced a significant decrease in GluR1- and GluR2-immunopositive cells in the hippocampus. For GluR1 the reduction was 31% in the hilus of dentate gyrus (p = 0.02) and 47% in CA3 (p = 0.002). For GluR2 the reduction was 52% in the hilus of dentate gyrus (p < 0.0001) and 29% in CA1 (p = 0.002). Isolation rearing induced a non-significant decrease in GluR1 immunopositive cells in the basolateral amygdala (p = 0.066) while no alteration was found in the lateral nucleus (p = 0.657). For GluR2 no changes were induced by isolation in both nuclei of the amygdala. In the entorhinal cortex no apparent difference was seen in GluR1- or GluR2-immunopositive cells when isolated reared rats were compared to grouped rats. The results suggest that isolation rearing from weaning induces changes on the expression of AMPA glutamate receptors in the hippocampus similar to those reported for postmortem human brains with schizophrenia. These findings also contribute to additional evidence for using isolation rearing of rats from weaning as an animal model for schizophrenia. PMID- 20952456 TI - Discriminative stimulus, subject-rated and cardiovascular effects of cocaine alone and in combination with aripiprazole in humans. AB - Aripiprazole is a dopamine D(2) receptor partial agonist undergoing evaluation as a pharmacotherapy for stimulant-use disorders. Acutely administered aripiprazole attenuates the discriminative stimulus and other behavioral effects of d amphetamine in humans; however, whether aripiprazole attenuates the effects of more commonly abused stimulants is unknown. The aim of this experiment was to assess the discriminative stimulus, subject-rated and cardiovascular effects of oral cocaine alone and following acute administration of aripiprazole in humans. Eight cocaine-dependent subjects learned to discriminate 150 mg cocaine from placebo. After acquiring the discrimination, the effects of cocaine (0, 25, 50, 100 and 200 mg) administered alone and in combination with aripiprazole (15 mg) were determined. Significant effects of cocaine were observed for the drug discrimination task, stimulant-like subject-rated effects and heart rate. Limited effects of aripiprazole were revealed. However, for most measures, fewer doses of cocaine were significantly greater than placebo when combined with aripiprazole, suggesting a reduction in the discriminative stimulus, self-reported and cardiovascular effects of cocaine. These data are consistent with previous studies that have tested acutely administered aripiprazole in combination with d amphetamine and suggest that the ability of aripiprazole to modify stimulant effects is a function of the duration of treatment (acute vs. chronic). PMID- 20952457 TI - Paternal age at birth of first child and risk of schizophrenia. AB - OBJECTIVE: Greater paternal age is associated with increased risk of schizophrenia, and it has been hypothesized that de novo mutations in paternal germ cells are responsible for this association. An alternative hypothesis is that selection into late fatherhood accompanies a predisposition to schizophrenia. However, direct evidence of either hypothesis is lacking. If de novo mutations are responsible, greater paternal age at conception should increase the risk of schizophrenia. Conversely, if selection into late fatherhood is responsible for the association, greater age at which the father had his first child should increase the risk of schizophrenia. The authors aimed to distinguish between these two measures of paternal age. METHOD: A total of 2.2 million people born in Denmark between 1955 and 1992 were followed up until first diagnosis with schizophrenia. Incidence rate ratios were estimated in a Cox regression. RESULTS: Among second- or later-born children, greater paternal age increased the risk of schizophrenia. However, when paternal age at the time of the father's first child was accounted for, the risk of schizophrenia did not depend on paternal age at the birth of later children. In contrast, the risk of schizophrenia increased significantly with increasing paternal age at the time of the father's first child. CONCLUSIONS: Factors related to greater paternal age when the father's first child was born, and not the father's age at conception of later children, are responsible for the association between paternal age and the risk of schizophrenia. These findings do not support the de novo mutation hypothesis. PMID- 20952458 TI - Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome. AB - OBJECTIVE: Research is increasingly linking autism spectrum disorders and other neurodevelopmental disorders to synaptic abnormalities ("synaptopathies"). PSD-95 (postsynaptic density-95, DLG4) orchestrates protein-protein interactions at excitatory synapses and is a major functional bridge interconnecting a neurexinneuroligin-SHANK pathway implicated in autism spectrum disorders. METHOD: The authors characterized behavioral, dendritic, and molecular phenotypic abnormalities relevant to autism spectrum disorders in mice with PSD-95 deletion (Dlg4-(/)-). The data from mice led to the identification of single-nucleotide polymorphisms (SNPs) in human DLG4 and the examination of associations between these variants and neural signatures of Williams' syndrome in a normal population, using functional and structural neuroimaging. RESULTS: Dlg4-(/)- showed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses. Dlg4-(/)- had subtle dysmorphology of amygdala dendritic spines and altered forebrain expression of various synaptic genes, including Cyln2, which regulates cytoskeletal dynamics and is a candidate gene for Williams' syndrome. A signifi-cant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling, both of which characterize Williams' syndrome. CONCLUSIONS: These findings demonstrate that DLG4 gene disruption in mice produces a complex range of behavioral and molecular abnormalities relevant to autism spectrum disorders and Williams' syndrome. The study provides an initial link between human DLG4 gene variation and key neural endophenotypes of Williams' syndrome and perhaps corticoamygdala regulation of emotional and social processes more generally. PMID- 20952459 TI - Cortical activations during auditory verbal hallucinations in schizophrenia: a coordinate-based meta-analysis. AB - OBJECTIVE: Auditory verbal hallucinations (AVHs) constitute severe, incapacitating symptoms of schizophrenia. Despite increasing interest in the functional exploration of AVHs, the available findings remain difficult to integrate because of their considerable variability. The authors' aim was to perform a robust quantitative review of existing functional data in order to elucidate consistent patterns observed during the emergence of AVHs and to orient new pathophysiological models of hallucinations. METHOD: Ten positron emission tomography or functional magnetic resonance imaging studies were selected for the meta-analysis after systematic review. A total of 68 patients with schizophrenia spectrum disorders experiencing AVHs during scanning were included. According to a random-effects activation likelihood estimation algorithm, stereotaxic coordinates of 129 foci, reported as significant in the source studies, were extracted and computed to estimate the brain locations most consistently associated with AVHs across studies (cluster-extent threshold: 200 mm3). RESULTS: Patients experiencing AVHs demonstrated significantly increased activation likelihoods in a bilateral neural network, including the Broca's area (activation likelihood estimation=1.84*10-3), anterior insula (1.78*10-3), precentral gyrus (1.46*10-3), frontal operculum (1.29*10-3), middle and superior temporal gyri (1.59*10-3), inferior parietal lobule (1.33*10-3), and hippocampus/parahippocampal region (1.90*10-3). CONCLUSIONS: This meta-analysis demonstrated that experiencing AVHs is associated with increased activity in fronto-temporal areas involved in speech generation and speech perception, but also within the medial temporal lobe, a structure notably involved in verbal memory. Such findings support a model for AVHs in which aberrant cortical activations emerge within a distributed network involved at different levels of complexity in the brain architecture. Critical future directions are considered. PMID- 20952460 TI - Childhood trauma and children's emerging psychotic symptoms: A genetically sensitive longitudinal cohort study. AB - OBJECTIVE: Using longitudinal and prospective measures of trauma during childhood, the authors assessed the risk of developing psychotic symptoms associated with maltreatment, bullying, and accidents in a nationally representative U.K. cohort of young twins. METHOD: Data were from the Environmental Risk Longitudinal Twin Study, which follows 2,232 twin children and their families. Mothers were interviewed during home visits when children were ages 5, 7, 10, and 12 on whether the children had experienced maltreatment by an adult, bullying by peers, or involvement in an accident. At age 12, children were asked about bullying experiences and psychotic symptoms. Children's reports of psychotic symptoms were verified by clinicians. RESULTS: Children who experienced mal-treatment by an adult (relative risk=3.16, 95% CI=1.92-5.19) or bullying by peers (relative risk=2.47, 95% CI=1.74-3.52) were more likely to report psychotic symptoms at age 12 than were children who did not experience such traumatic events. The higher risk for psychotic symptoms was observed whether these events occurred early in life or later in childhood. The risk associated with childhood trauma remained significant in analyses controlling for children's gender, socioeconomic deprivation, and IQ; for children's early symptoms of internalizing or externalizing problems; and for children's genetic liability to developing psychosis. In contrast, the risk associated with accidents was small (relative risk=1.47, 95% CI=1.02-2.13) and inconsistent across ages. CONCLUSIONS: Trauma characterized by intention to harm is associated with children's reports of psychotic symptoms. Clinicians working with children who report early symptoms of psychosis should inquire about traumatic events such as maltreatment and bullying. PMID- 20952461 TI - The structure of genetic and environmental risk factors for syndromal and subsyndromal common DSM-IV axis I and all axis II disorders. AB - OBJECTIVE: The authors sought to clarify the structure of the genetic and environmental risk factors for 22 DSM-IV disorders: 12 common axis I disorders and all 10 axis II disorders. METHOD: The authors examined syndromal and subsyndromal axis I diagnoses and five categories reflecting number of endorsed criteria for axis II disorders in 2,111 personally interviewed young adult members of the Norwegian Institute of Public Health Twin Panel. RESULTS: Four correlated genetic factors were identified: axis I internalizing, axis II internalizing, axis I externalizing, and axis II externalizing. Factors 1 and 2 and factors 3 and 4 were moderately correlated, supporting the importance of the internalizing-externalizing distinction. Five disorders had substantial loadings on two factors: borderline personality disorder (factors 3 and 4), somatoform disorder (factors 1 and 2), paranoid and dependent personality disorders (factors 2 and 4), and eating disorders (factors 1 and 4). Three correlated environmental factors were identified: axis II disorders, axis I internalizing disorders, and externalizing disorders versus anxiety disorders. CONCLUSIONS: Common axis I and II psychiatric disorders have a coherent underlying genetic structure that reflects two major dimensions: internalizing versus externalizing, and axis I versus axis II. The underlying structure of environmental influences is quite different. The organization of common psychiatric disorders into coherent groups results largely from genetic, not environmental, factors. These results should be interpreted in the context of unavoidable limitations of current statistical methods applied to this number of diagnostic categories. PMID- 20952462 TI - Tocilizumab for rheumatoid arthritis: a Cochrane systematic review. AB - OBJECTIVE: to compare the benefit and safety of tocilizumab to placebo in patients with rheumatoid arthritis (RA). METHODS: we searched multiple databases for published randomized or controlled clinical trials comparing benefit and safety of tocilizumab to placebo, disease-modifying antirheumatic drugs (DMARD), or other biologics. For dichotomous outcomes, we calculated the relative risk, and for continuous outcomes, the mean difference. RESULTS: eight randomized controlled trials were included in this systematic review, with 3334 participants, 2233 treated with tocilizumab and 1101 controls. The US and Canadian approved dose of tocilizumab, 8 mg/kg every 4 weeks, was given to 1561 participants. In patients taking concomitant methotrexate, compared to placebo, patients treated with approved dose of tocilizumab were substantially and statistically significantly more likely than placebo to achieve the American College of Rheumatology 50 (absolute percentage, 38.8% vs 9.6%, respectively; RR 3.2, 95% CI 2.7, 3.7); Disease Activity Score remission (30.5% vs 2.7%; RR 8.7, 95% CI 6.3, 11.8); and a clinically meaningful decrease in Health Assessment Questionnaire (HAQ)/Modified HAQ scores (60.5% vs 34%; RR 1.8, 95% CI 1.6, 1.9). There were no substantive statistically significant differences in serious adverse effects (0.8% vs 0.7%; RR 1.2, 95% CI 0.8, 1.6) or withdrawals due to adverse events (4.9% vs 3.7%; RR 1.4, 95% CI 0.9, 2.1); however, tocilizumab treated patients were significantly more likely to have any adverse event (74% vs 65%; RR 1.05, 95% CI 1.03, 1.07); elevation in the ratio of low-density lipoprotein to high-density lipoprotein cholesterol (HDL; 20% vs 12%; RR 1.7, 95% CI 1.2, 2.2); and increase in the ratio of total to HDL cholesterol (12% vs 7%; RR 1.7, 95% CI 1.2, 2.6); and they were less likely to withdraw from treatment for any reason (8.1% vs 14.9%; RR 0.6, 95% CI 0.5, 0.8). CONCLUSION: at the approved dose of 8 mg/kg every 4 weeks, tocilizumab in combination with methotrexate/DMARD is beneficial in decreasing RA disease activity and improving function. Tocilizumab treatment was associated with a significant increase in cholesterol levels and occurrence of any adverse event, but not serious adverse events. Larger safety studies are needed to address these safety concerns. PMID- 20952463 TI - Association of IgA Anti-beta2 glycoprotein I with clinical and laboratory manifestations of systemic lupus erythematosus. AB - OBJECTIVE: IgA isotypes of anticardiolipin and anti-beta(2) glycoprotein I (anti beta(2)-GPI) are omitted from the revised antiphospholipid syndrome (APS) classification criteria. Multiple studies have found a high prevalence of IgA anti-beta(2)-GPI in systemic lupus erythematosus (SLE). We determined the frequency and associations of IgA anti-beta(2)-GPI in a cohort of patients with SLE. METHODS: anti-beta(2)-GPI was measured in 796 patients with SLE (93% women, 53% white, 38% African American, mean age 45 yrs). IgA anti-beta(2)-GPI (> 20 phospholipid units) was found in 20%. Using a cohort database, associations with cumulative thrombotic and other manifestations were determined. RESULTS: of patients with SLE who demonstrated IgA anti-beta(2)-GPI positivity, about 6% had transient ischemic attack (p = 0.070), 4% had superficial thrombophlebitis (p = 0.647), 20% had deep venous thrombosis (p = 0.003), 4% had other venous thrombosis (p = 0.827), 12% had stroke (p = 0.050), and 1% had myocardial infarction (p = 0.397). CONCLUSION: IgG anti-beta(2)-GPI has the strongest association with thrombosis in SLE. However, IgA anti-beta(2)-GPI was more strongly associated with deep venous thrombosis and with stroke than was IgM. These results indicate that assessment of IgA anti-beta(2)-GPI is associated with thrombosis in SLE, and that the classification criteria for APS should be revised to include IgA anti-beta(2)-GPI in patients with SLE. PMID- 20952464 TI - Increased prevalence of metabolic syndrome associated with rheumatoid arthritis in patients without clinical cardiovascular disease. AB - OBJECTIVE: to examine whether patients with rheumatoid arthritis (RA) with no overt cardiovascular disease (CVD) have a higher prevalence of metabolic syndrome (MetS) than subjects without RA or CVD. We also examined whether RA disease characteristics are associated with the presence of MetS in RA patients without CVD. METHODS: subjects from a population-based cohort of patients who fulfilled 1987 American College of Rheumatology criteria for RA between January 1, 1980, and December 31, 2007, were compared to non-RA subjects from the same population. All subjects with any history of CVD were excluded. Waist circumference, body mass index (BMI), and blood pressure were measured during the study visit. Data on CVD, lipids, and glucose measures were ascertained from medical records. MetS was defined using NCEP/ATP III criteria. Differences between the 2 cohorts were examined using logistic regression models adjusted for age and sex. RESULTS: the study included 232 RA subjects without CVD and 1241 non-RA subjects without CVD. RA patients were significantly more likely to have increased waist circumference and elevated blood pressure than non-RA subjects, even though BMI was similar in both groups. Significantly more RA patients were classified as having MetS. In RA patients, MetS was associated with Health Assessment Questionnaire Disability Index, large-joint swelling, and uric acid levels, but not with C-reactive protein or RA therapies. CONCLUSION: among subjects with no history of CVD, patients with RA are more likely to have MetS than non-RA subjects. MetS in patients with RA was associated with some measures of disease activity. PMID- 20952465 TI - Cytokines and regulatory T cells in rheumatoid arthritis and their relationship with response to corticosteroids. AB - OBJECTIVE: To analyze circulating cytokines and regulatory T cells (Treg) in patients with rheumatoid arthritis (RA) of different durations, and their association with functional interleukin 10 (IL-10) and tumor necrosis factor alpha (TNF-alpha) genotypes in patients treated with corticosteroids. METHODS: Serum levels of IL-6, IL-10, IL-17, IL-18, TNF-alpha, and transforming growth factor-beta (TGF-beta) were quantified in 196 patients and 61 healthy controls. Percentage of CD4+CD25high cells was determined by flow cytometry and Foxp3 expression by real-time reverse-transcription polymerase chain reaction. Data were related to clinical measurements and presence of the genotype -1082GG IL-10/ 308GG TNF-alpha, previously associated with good response to corticosteroids. RESULTS: Levels of TNF-alpha, IL-6, and IL-18 were significantly higher in patients compared to controls, while TGF-beta and IL-10 were lower. Serum samples of patients at disease onset (n = 32) had increased IL-6 and decreased TGF-beta, but there were no differences in other cytokines. These patients also presented a higher percentage of CD4+CD25high cells than those with established disease, although no significant differences were detected in Foxp3. Patients under corticosteroid treatment who were carriers of the good responder genotype had higher levels of TGF-beta, Foxp3, and Treg compared to patients with other genotypes, while relatively lower levels of TNF-alpha and IL-17 were observed. CONCLUSION: Patients at onset of RA present fewer alterations in cytokine levels and Treg than those with longer disease duration, supporting the role of disease progression in subsequent changes. The antiinflammatory balance observed in high IL-10/low TNF-alpha patients treated with prednisone supports the use of these genetic polymorphisms as predictors of response to corticosteroid therapy. PMID- 20952466 TI - Serum and urinary cell-free MiR-146a and MiR-155 in patients with systemic lupus erythematosus. AB - OBJECTIVE: Recent studies showed that micro-RNA play important roles in the pathogenesis of autoimmune diseases. We studied the levels of miR-146a and miR 155 in the serum and urinary supernatant of patients with systemic lupus erythematosus (SLE). METHODS: The serum and urinary supernatant levels of miR 146a and miR-155 were determined by real-time quantitative polymerase chain reaction in 40 patients with SLE and 30 healthy controls. RESULTS: Compared to controls, serum miR-146a and miR-155 levels were lower, and the urinary level of miR-146a was higher, in SLE. Estimated glomerular filtration rate (eGFR) correlated with both serum miR-146a (r = 0.519, p = 0.001) and miR-155 (r = 0.384, p = 0.014). Serum miR-146a inversely correlated with proteinuria (r = 0.341, p = 0.031) and the SLE Disease Activity Index (r = -0.465, p = 0.003). Serum miR-146a and miR-155 levels also correlated with red blood cell count, platelet count, and lymphocyte count. After treatment with calcitriol for 6 months, serum miR-146a level of SLE patients increased significantly (p < 0.001), and its change inversely correlated with the level of calcium-phosphate product (r = -0.466, p = 0.003). CONCLUSION: The results suggested that serum miR-146a and miR-155 participate in the pathophysiology of SLE and might be used as biomarkers of SLE. PMID- 20952467 TI - Whole-blood gene expression profiling in ankylosing spondylitis shows upregulation of toll-like receptor 4 and 5. AB - OBJECTIVE: to identify differentially expressed genes in peripheral blood cells (PBC) of patients with ankylosing spondylitis (AS) relative to healthy controls and controls with systemic inflammation. METHODS: we investigated PBC samples of 16 patients with AS and 14 matched controls, in addition to systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) samples utilizing Illumina Human Ref-8 BeadChips. Candidate genes were confirmed using quantitative PCR. Subsequently, these genes were also validated in a separate sample of 27 patients with AS [before and after anti-tumor necrosis factor (anti-TNF) treatment] and 27 matched controls. RESULTS: we identified 83 differentially expressed transcripts between AS patients and controls. This gene list was filtered through the lists of differentially expressed transcripts in SLE and SSc, which resulted in identification of 52 uniquely dysregulated transcripts in AS. Many of the differentially expressed genes belonged to Toll-like receptor (TLR) and related pathways. TLR4 and TLR5 were the only dysregulated TLR subtypes among AS patients. We confirmed the overexpression of TLR4 and TLR5 in AS patients in comparison to controls (p = 0.012 and p = 0.006, respectively) and SLE (p = 0.002, p = 0.008) using quantitative PCR in the same sample. Similarly, TLR4 (p = 0.007) and TLR5 (p = 0.012) were significantly upregulated among the AS patients before anti-TNF treatment in the confirmatory sample. TLR4 (p = 0.002) and TLR5 (p = 0.025) decreased significantly after anti-TNF treatment. CONCLUSION: PBC gene expression profiling in AS shows an upregulation of TLR4 and TLR5. This supports the importance of TLR subtypes in the pathogenesis of AS that are responsible for the immune response to Gram-negative bacteria. PMID- 20952468 TI - Informing response criteria for psoriatic arthritis (PsA). II: Further considerations and a proposal--the PsA joint activity index. AB - OBJECTIVE: To develop a recommended measure of response for use in psoriatic arthritis (PsA) clinical trials and observational cohort studies reflecting joint involvement. METHODS: Previously, we used data from phase III randomized placebo controlled trials of anti-tumor necrosis factor (TNF) agents to determine models, based primarily on statistical considerations but with some clinical input when necessary, that best distinguish drug-treated from placebo-treated patients. For the same data, we examine response criteria currently used for PsA and logistic regression models based on the individual components of these response criteria. Comparison with our previously developed models, based primarily on statistical consideration, is made. RESULTS: A simplified score, the PsA Joint Activity Index (PsAJAI), based on components of the ACR30, performed better than the ACR20 and PsARC, and comparable to our previously developed models. The PsAJAI is a weighted sum of 30% improvement in core measures with weights of 2 given to the joint count measure, the C-reactive protein laboratory measure, and the physician global assessment of disease activity measure. Weights of 1 should be given to the remaining 30% improvement measures including pain, patient global assessment of disease activity, and the Health Assessment Questionnaire. CONCLUSION: We recommend the PsAJAI be used as an outcome measure for assessing joint disease response in PsA clinical trials. PMID- 20952469 TI - Adalimumab improves sleep and sleep quality in patients with active ankylosing spondylitis. AB - OBJECTIVE: fatigue and sleep problems are significant in patients with ankylosing spondylitis (AS). This subanalysis of the RHAPSODY study (Review of Safety and Effectiveness with Adalimumab in Patients with Active Ankylosing Spondylitis) was conducted to evaluate the effect of adalimumab on sleep in patients with active AS. METHODS: all patients (n = 1250) had active AS and received adalimumab 40 mg every other week during the 12-week open-label treatment period. Sleep was assessed by the Medical Outcomes Study Sleep Scale (MOS-SS) at screening and Weeks 6, 12, and 20 (optional continuation period). Effect sizes were calculated to determine clinical significance. Paired Student t tests compared the change in the MOS-SS domains from Week 12 to baseline. Correlation coefficients were calculated to determine the relationship between change in sleep domains and other Week 12 clinical and patient-reported outcomes (Bath AS Disease Activity Index, C-reactive protein, nocturnal pain, total back pain, Bath AS Functional Index, patient's global assessment of disease activity, morning stiffness, Short Form-36 Health Survey, and Work Productivity and Activity Impairment questionnaire components). RESULTS: at week 12, adalimumab significantly improved sleep in each of the MOS-SS domains (p < 0.001). Effect sizes for 3 of the 6 domains (disturbance, -0.69; adequacy, 0.55; somnolence, -0.52) and both sleep problems indices (Index I, -0.68; Index II, -0.77) were moderate, suggesting clinical significance. Change in the MOS-SS Sleep Problem Index II was moderately correlated with change in most clinical and patient-reported outcomes. Sleep improvements were similar in patients with and without radiographically advanced AS. CONCLUSION: adalimumab improves overall sleep and sleep quality in patients with active AS. PMID- 20952470 TI - Relative clinical influence of clinical, laboratory, and radiological investigations in early arthritis on the diagnosis of rheumatoid arthritis. Data from the French Early Arthritis Cohort ESPOIR. AB - OBJECTIVE: To evaluate the relative level of influence of usual investigations in early arthritis on the diagnosis of rheumatoid arthritis (RA). METHODS: PATIENTS: those included in the ESPOIR early arthritis cohort, a national cohort of patients with grade >= 2 synovitis for > 6 weeks and < 6 months. The diagnostic properties of variables assessed at baseline were measured against the diagnosis of RA defined by American College of Rheumatology criteria (at any timepoint between inclusion and 12-month followup) and expert opinion. Various models, including (1) clinical data; (2) clinical + radiographic data (plain radiographs); (3) addition of rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide (anti-CCP); and (4) addition of HLA-DR typing, were assessed by comparing areas under the curves for ROC curves. RESULTS: Of 731 patients studied, 372 (50.9%) satisfied criteria for RA at 1 year. In univariate analysis, sensitivity was highest for distal articular presentation (94.6%), presence of IgM RF (69.4%), pain on metatarso-phalangeal squeeze test (66.1%), and presence of anti-CCP (65.6%); whereas specificity was highest for nodules (100%), HLA typing: shared-epitope double dose (95.9%), radiographic erosions (86.5%), and anti-CCP antibodies (86.4%). The most efficient model included swollen joint count, morning stiffness, erosions, RF, and anti-CCP. Adding rheumatoid nodules, C-reactive protein, or HLA-DR information was not contributive. CONCLUSION: In addition to the clinical variables and radiographs, RF and/or anti-CCP are the single variables of interest that are contributive for the diagnosis of RA. PMID- 20952471 TI - Is physical activity a risk factor for primary knee or hip replacement due to osteoarthritis? A prospective cohort study. AB - OBJECTIVE: To estimate prospectively any association between measures of physical activity and the risk of either primary knee or hip replacement due to osteoarthritis (OA). METHODS: Eligible subjects (n = 39,023) were selected from participants in a prospective cohort study recruited 1990-1994. Primary knee and hip replacement for OA during 2001-2005 was determined by linking the cohort records to the National Joint Replacement Registry. A total physical activity level was computed, incorporating both intensity and frequency for different forms of physical activity obtained by questionnaire at baseline attendance. RESULTS: There was a dose-response relationship between total physical activity level and the risk of primary knee replacement [hazards ratio (HR) 1.04, 95% CI 1.01-1.07 for an increase of 1 level in total physical activity]. Although vigorous activity frequency was associated with an increased risk of primary knee replacement (HR 1.42, 95% CI 1.08-1.86) for 1-2 times/week and HR 1.24 (95% CI 0.90-1.71) for >= 3 times/week), the p for trend was marginal (continuous HR 1.08, 95% CI 1.00-1.16, p = 0.05). The frequency of less vigorous activity or walking was not associated with the risk of primary knee replacement, nor was any measure of physical activity associated with the risk of primary hip replacement. CONCLUSION: Increasing levels of total physical activity are positively associated with the risk of primary knee but not hip replacement due to OA. Physical activity might affect the knee and hip joints differently depending on the preexisting health status and anatomy of the joint, as well as the sort of physical activity performed. PMID- 20952472 TI - An audit of Behcet's syndrome research: a 10-year survey. AB - OBJECTIVE: data suggest that the use of disease control groups and proper use of power calculations were neglected in published reports. We surveyed these and other methodological shortcomings in reports published within the last decade about one specific topic, Behcet's syndrome. We reason that recognizing such methodological shortcomings will lead to better quality clinical and basic science articles. METHODS: articles published in the 15 highest impact factor journals on rheumatology, ophthalmology, dermatology, and general medicine between January 1999 and January 2009 were searched for original reports on Behcet's syndrome. Study designs (study types and time element), control groups, demographic data, use of power calculations, and reporting of negative results were specifically tabulated. RESULTS: most studies on Behcet's syndrome were cross-sectional (83%). Prospective longitudinal studies were few (7%). In a considerable proportion of papers (21%), some basic demographic data were missing. Power calculations were rare (3%) even in randomized controlled trials and were not considered at all in clinical hypothesis-testing. Disease control groups were present in slightly over half of clinical and laboratory original research, while just 13% of genetic association studies included disease controls. Only 12% of all reports concerned mainly negative outcomes. CONCLUSION: a considerable number of the published research articles have methodological weaknesses. The generalizability of what we observed in Behcet's syndrome to other research topics needs to be formally studied. PMID- 20952473 TI - Mycophenolate mofetil for induction treatment of lupus nephritis: a systematic review and metaanalysis. AB - OBJECTIVE: to systematically review the efficacy and safety of mycophenolic acid and mycophenolate mofetil (MMF) compared to cyclophosphamide (CYC) for the induction treatment of lupus nephritis (LN). METHODS: medline, Embase, the Cochrane Center Register of Controlled Trials, and abstracts presented in major international conferences were searched for randomized controlled trials. The primary outcome was renal remission (complete, partial, and overall) and secondary outcomes were adverse events during study period and longterm followup data. Data were compared between groups and relative risk (RR) and 95% CI were calculated. RESULTS: four trials of a total of 618 patients were included. MMF was not superior to CYC for renal remission (partial RR 0.94, 95% CI 0.80 to 1.12; complete RR 0.67, 95% CI 0.35 to 1.28, and overall RR 0.89, 95% CI 0.71 to 1.10). There was a significant reduction in alopecia (RR 5.77, 95% CI 1.56 to 21.38) and amenorrhea (RR 6.64, 95% CI 2.00 to 22.07) with the use of MMF compared to CYC. These results should be interpreted with caution given the width of the CI. There was no significant difference for infections, leukopenia, gastrointestinal symptoms, herpes zoster, endstage renal disease, and death among groups during study period and longterm followup data. CONCLUSION: we could not show that MMF is superior to CYC for the induction treatment of LN. Patients treated with MMF showed reduced risk of certain side effects. MMF can be used as an alternative to CYC for the induction treatment of LN. PMID- 20952474 TI - Treatment with tiludronic acid helps reduce the development of experimental osteoarthritis lesions in dogs with anterior cruciate ligament transection followed by reconstructive surgery: a 1-year study with quantitative magnetic resonance imaging. AB - OBJECTIVE: to investigate over a 1-year period in dogs that underwent extracapsular stabilization surgery (ECS) following anterior cruciate ligament (ACL) transection: whether reconstructive surgery could prevent osteoarthritis (OA) progression and whether treatment with the bisphosphonate tiludronic acid (TA) could improve the chronic evolution of OA structural changes. METHODS: ACL transection was performed on dogs on Day 0 and ECS on Day 28. Dogs were randomly divided into 2 groups: 15 received placebo and 16 were treated with TA (2 mg/kg subcutaneous injection) on Days 14, 28, 56, and 84. Magnetic resonance images were acquired on Days -10, 26, 91, 210, and 357, and cartilage volume was quantified. At sacrifice (Day 364), cartilage from femoral condyles and tibial plateaus was macroscopically and histologically evaluated. Expression levels of MMP-1, -3, -13, ADAMTS-4, -5, BMP-2, FGF-2, IGF-1, TGF-beta1, collagen type II, and aggrecan were determined using real-time RT-PCR. RESULTS: the loss of cartilage volume observed after ACL transection stabilized following ECS. Thereafter, a gradual gain occurred, with the cartilage volume loss on the tibial plateaus reduced at Day 91 (p < 0.02) and Day 210 (p < 0.001) in the TA-treated dogs. At sacrifice, TA-treated dogs presented a reduction in the severity of macroscopic (p = 0.03 for plateaus) and histologic (p = 0.07 for plateaus) cartilage lesions, had a better preserved collagen network, and showed decreased MMP-13 (p = 0.04), MMP-1 and MMP-3 levels. CONCLUSION: our findings indicate that in dogs with ACL transection, ECS greatly prevents development of cartilage volume loss. Treatment with TA provided an additional benefit of reducing the development of OA lesions. PMID- 20952475 TI - Prevalence of vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. AB - OBJECTIVE: 25-hydroxy-vitamin D (25-OH-D) insufficiency/deficiency is increasingly prevalent and has been associated with many chronic diseases, including rheumatoid arthritis (RA). Our purpose was to define the prevalence and associations of 25-OH-D insufficiency/deficiency in a cohort of US veterans with RA. METHODS: vitamin D status (25-OH-D) was assessed in patients with RA using radioimmunoassay on banked plasma collected at enrollment. Insufficiency was defined as concentrations < 30 ng/ml and deficiency as < 20 ng/ml. Associations of 25-OH-D insufficiency/deficiency with patient characteristics obtained at enrollment were examined using multivariate logistic regression, adjusting for age, sex, season of enrollment, and race. RESULTS: patients (850 men, 76% Caucasian) had a mean (SD) age of 64 (SD 11.3) years. The prevalences of 25-OH-D insufficiency and deficiency were 84% and 43%, respectively. After multivariate adjustment, both insufficiency and deficiency were more common with anti-cyclic citrullinated peptide antibody positivity and non-Caucasian race, and in the absence of vitamin D supplementation. 25-OH-D deficiency, but not insufficiency, was independently associated with higher tender joint counts and highly sensitive C-reactive protein levels. CONCLUSION: in a predominantly elderly, male RA population, 25-OH-D insufficiency was highly prevalent. With the increasing adverse health outcomes associated with hypovitaminosis D, screening and supplementation, particularly among minority, seropositive patients with RA, should be performed routinely. PMID- 20952476 TI - Prognostic factors of radiological damage in rheumatoid arthritis: a 10-year retrospective study. AB - OBJECTIVE: to describe the longterm clinical and radiological outcomes in rheumatoid arthritis (RA) in a cohort in northwestern Greece; and to investigate predictive factors of radiological damage at the 10-year followup in patients with RA. METHODS: we studied the disease course and outcome of 144 patients with RA and radiographs of the hands and wrists available at baseline and at 10 years. Baseline measurements and time-averaged measures of swollen joint count (SJC) and inflammatory markers [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)] were tested in univariate analysis, and then those presenting a statistically significant association with either Larsen score at 10 years or annual progression rate were included in 2 logistic regression models in order to determine relevant independent prognostic factors. RESULTS: a significant clinical improvement was noted, associated with a decrease of inflammatory markers along the timepoints. Larsen score and the number of erosive joints were increased. In the univariate analysis, both final Larsen score at 10 years and accelerated annual radiological progression rate were significantly associated with baseline radiographic measurements (Larsen score and number of erosive joints), the presence of autoantibodies [anticyclic citrullinated peptide antibodies (anti-CCP) and rheumatoid factor of IgA and IgM isotype], disease duration, and time-averaged measures of ESR, CRP, and SJC. In the logistic regression analysis, the baseline Larsen score, anti-CCP antibodies, and time averaged CRP presented significant and independent associations with Larsen score at 10 years. An accelerated annual radiological progression rate was also predicted by baseline Larsen score and time-averaged measures of SJC and CRP. CONCLUSION: despite clinical improvement, the radiologic progression of RA continues over time, because of the underlying inflammatory process. Baseline radiographic damage, anti-CCP antibodies, and time-averaged CRP constitute the main predictive factors of poor radiologic outcome in the long term. PMID- 20952477 TI - Pain-specific beliefs and pain experience in children with juvenile idiopathic arthritis: a longitudinal study. AB - OBJECTIVE: to assess longitudinal associations between pain-specific health beliefs and pain in children with juvenile idiopathic arthritis (JIA), and to compare a selected group of patients with high pain and low disease activity (high-pain patients) with the remaining group. METHODS: forty-seven children with JIA, aged 7-15 years, completed the children's version of the Survey of Pain Attitudes (SOPA-C) and a 3-week pain diary at study entry (T1) and in a followup study 2 years later (T2). Parents also rated the Childhood Health Assessment Questionnaire (CHAQ), and an arthritis activity score was calculated each time. Second-order principal component analysis was conducted to reduce the number of independent variables. Regression analysis of the dependent measure was performed. The use of health beliefs was compared using t test for independent samples. RESULTS: T1 health beliefs predicted 7% of the variance in T2 pain scores after controlling for T1 pain, CHAQ, and disease activity. At T2, statistical differences were found between the scores of the high-pain group and the rest of the group for the health belief subscales of disability (mean +/- SD 2.7 +/- 0.5 and 2.2 +/- 0.7, respectively) and harm (mean +/- SD 3.8 +/- 0.8 and 3.3 +/- 0.6). CONCLUSION: our findings suggest that pain beliefs are influential on the longitudinal course of pain in children with JIA. Dysfunctional health beliefs in patients with high pain seem to be stable over time. PMID- 20952478 TI - Rheumatoid arthritis disease-modifying antirheumatic drug intervention and utilization study: safety and etanercept utilization analyses from the RADIUS 1 and RADIUS 2 registries. AB - OBJECTIVE: to report the rates of serious adverse events (SAE), serious infectious events (SIE), and events of medical interest (EMI) in patients receiving etanercept; to identify the risk factors for SAE, SIE, and EMI; and to report time to switching from etanercept therapy, reasons for switching, and time to restarting treatment with etanercept in patients with rheumatoid arthritis (RA) in US clinical practice. METHODS: adults >= 18 years of age who fulfilled the 1987 American Rheumatism Association criteria for RA were eligible for enrollment in 2 prospective, 5-year, multicenter, observational registries. RADIUS 1 (Rheumatoid Arthritis DMARD Intervention and Utilization Study) enrolled patients with RA who required a change in treatment [either an addition or a switch of a biologic or nonbiologic disease-modifying antirheumatic drug (DMARD)]. In RADIUS 2, patients with RA were required to start etanercept therapy at entry. Patients were seen at a frequency determined by their rheumatologist. RADIUS 1 and RADIUS 2 were registered under the US National Institutes of Health ClinicalTrials.gov identifiers NCT00116714 and NCT00116727, respectively. RESULTS: in these patients, SAE, SIE, and EMI occurred at rates comparable to those seen in clinical trials. No unexpected safety signals were observed. Rates for SAE, SIE, and EMI in etanercept-treated patients were comparable to rates observed in patients receiving methotrexate monotherapy and did not increase with greater exposure to etanercept therapy. CONCLUSION: the RADIUS registries provide a better understanding of the safety of etanercept in patients with RA in the US practice setting. PMID- 20952479 TI - Systemic vasculitis in patients with hepatitis C virus infection with and without detectable mixed cryoglobulinemia. AB - OBJECTIVE: to describe hepatitis C virus (HCV)-related systemic vasculitis in patients without detectable mixed cryoglobulinemia (MC) and to compare them to typical cases of HCV-MC vasculitis. METHODS: twelve HCV RNA+ patients with histologically proven vasculitis in the absence of detectable MC (cases) were retrospectively compared with 48 HCV RNA+ patients with MC vasculitis (controls). Each case was matched with 4 controls for age and sex. RESULTS: the main epidemiological and virologic features were similar between cases and controls. No clinical difference was found, except for lower rates of arthralgias (33% vs 71%; p = 0.02) and purpura (50% vs 83%; p = 0.03) in cases. Cases showed higher mean serum C3 (1.17 +/- 0.21 vs 0.93 +/- 0.23 g/l; p = 0.01) and median C4 levels (0.25 vs 0.04 g/l; p < 0.001), lower median serum IgM levels (0.6 vs 1.9 g/l; p < 0.001), and lower rates of rheumatoid factor positivity (8% vs 82%; p < 0.001) than controls. The main histologic features were similar between cases and controls. Immunofluorescence analysis of skin biopsy from 1 case revealed perivascular deposits of C3 and IgA. After treatment, overall clinical response of vasculitis (75% vs 83%) and sustained virological response (40% vs 64%; p = 0.3) were similar between cases and controls, except for higher complete clinical response (42% vs 73%; p = 0.05) in controls. CONCLUSION: HCV-related systemic vasculitis may occur in the absence of detectable MC. Our findings suggest that such vasculitis probably results from immune complex-mediated mechanisms, and that the therapeutic management of such vasculitis should be similar to that of HCV-MC vasculitis. PMID- 20952480 TI - Is it necessary to combine detection of anticitrullinated protein antibodies in the diagnosis of rheumatoid arthritis? AB - OBJECTIVE: Antibodies against citrulline-containing epitopes, such as antiperinuclear factor (APF), antikeratin antibodies (AKA), antifilaggrin antibodies, and anticyclic citrullinated peptide (anti-CCP) antibodies, are specific in rheumatoid arthritis (RA). Detection of APF, AKA, and anti-CCP has been widely used in clinical practice. However, studies on combined detection of these anti citrullinated protein antibodies (ACPA) in the significance of diagnosing RA have been limited. We aimed to detect APF, AKA, and anti-CCP antibodies and to evaluate the significance of combined detection of these ACPA in RA. METHODS: A total of 551 patients with arthritic disorders, 304 with RA and 247 with other rheumatic diseases, were selected at the Department of Rheumatology and Immunology during the past 2 years. AKA and APF were tested by indirect immunofluorescence assay. Anti-CCP was detected using the second generation ELISA kit. RESULTS: The sensitivities of anti-CCP, AKA, and APF tests for RA were 76.2%, 43.4%, and 34.5%, respectively, while the specificities were 96.0%, 98.4%, and 99.6%. The combination of anti-CCP, AKA, and APF positivity had the highest specificity (100%), but it yielded a low sensitivity (28.3%). When 2 of the 3 ACPA were positive, the sensitivity and specificity were 48.4% and 99.2%, respectively. When either anti-CCP or AKA or APF was positive, sensitivity increased to 77.3%, but specificity decreased to 94.7%. CONCLUSION: Anti-CCP was the most valuable marker in the diagnosis of RA, among the 3 ACPA. Combined detection of anti-CCP, AKA, and APF did not increase the diagnostic capability for RA. PMID- 20952481 TI - Multiple levels of gene regulation mediate differentiation of the intracellular pathogen Leishmania. AB - For many years, mRNA abundance has been used as the surrogate measure of gene expression in biological systems. However, recent genome-scale analyses in both bacteria and eukaryotes have revealed that mRNA levels correlate with steady state protein abundance for only 50-70% of genes, indicating that translation and post-translation processes also play important roles in determining gene expression. What is not yet clear is whether dynamic processes such as cell cycle progression, differentiation, or response to environmental changes change the relationship between mRNA and protein abundance. Here, we describe a systems approach to interrogate promastigote-to-amastigote differentiation in the obligatory intracellular parasitic protozoan Leishmania donovani. Our results indicate that regulation of mRNA levels plays a major role early in the differentiation process, while translation and post-translational regulation are more important in the latter part. In addition, it appears that the differentiation signal causes a transient global increase in the rate of protein synthesis, which is subsequently down-regulated by phosphorylation of alpha subunit of translation initiation factor 2. Thus, Leishmania dynamically changes the relationship between mRNA and protein abundance as it adapts to new environmental circumstances. It is likely that similar mechanisms play a more important role than previously recognized in regulation of gene expression in other organisms. PMID- 20952482 TI - A series of D-amino acid oxidase inhibitors specifically prevents and reverses formalin-induced tonic pain in rats. AB - We have found that mutation of D-amino acid oxidase (DAO) diminished formalin induced tonic pain. The present research further studied the analgesic effects of a series of DAO inhibitors in this model. 5-Chlorobenzo[d]isoxazol-3-ol (CBIO), 4H-thieno[3,2-b]pyrrole-5-carboxylic acid (compound 8), 5-methylpyrazole-3 carboxylic acid (AS057278), sodium benzoate, and 4-nitro-3-pyrazole carboxylic acid (NPCA) inhibited rat spinal cord-derived DAO activity in a concentration dependent manner, with maximal inhibition of 100% and potency rank of CBIO > compound 8 > AS057278 > sodium benzoate > NPCA. In rats, intrathecal injections of CBIO, compound 8, AS057278, and sodium benzoate but not NPCA specifically prevented formalin-induced tonic pain but not acute nociception, with the same potency order as in the DAO activity assay. The highly potent analgesia of DAO inhibitors was evidenced by CBIO, which prevented 50% pain at 0.06 MUg, approximately 5-fold the potency of morphine. CBIO given after formalin challenge also reversed the established pain state to the same degree as prevention. The antihyperalgesic potencies of these DAO inhibitors were highly correlated to their inhibitions of spinal DAO activity. Maximum inhibition of pain by these compounds was approximately 60%, comparable with that of the N-methyl-D-aspartic acid receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten 5,10-imine maleate (MK-801), suggesting that a larger portion of formalin-induced tonic pain is "DAO-sensitive," whereas the remaining 40% of tonic pain and acute nociception is "DAO-insensitive." These findings, combined with our previous DAO gene mutation and induction results, indicate spinal DAO mediates both induction and maintenance of formalin-induced tonic pain and further validate spinal DAO as a novel and efficacious target molecule for the treatment of chronic pain. PMID- 20952484 TI - FYX-051: a novel and potent hybrid-type inhibitor of xanthine oxidoreductase. AB - 4-[5-(Pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (FYX-051) is a potent inhibitor of bovine milk xanthine oxidoreductase (XOR). Steady-state kinetics study showed that it initially behaved as a competitive-type inhibitor with a K(i) value of 5.7 * 10(-9) M, then after a few minutes it formed a tight complex with XOR via a Mo-oxygen-carbon atom covalent linkage, as reported previously (Proc Natl Acad Sci USA 101:7931-7936, 2004). Thus, FYX-051 is a hybrid-type inhibitor exhibiting both structure- and mechanism-based inhibition. The FYX-051-XOR complex decomposed with a half-life of 20.4 h, but the enzyme activity did not fully recover. This was found to be caused by XOR-mediated conversion of FYX-051 to 4-[5-(2-hydroxypyridin-4-yl)-1H-1,2,4-triazol-3 yl]pyridine-2-carbonitrile (2-hydroxy-FYX-051), as well as formation of 6-hydroxy 4-[5-(2-hydroxypyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (dihydroxy-FYX-051) and 4-[5-(2,6-dihydroxypyridin-4-yl)-1H-1,2,4-triazol-3-yl]-6 hydroxypyridine-2-carbonitrile (trihydroxy-FYX-051) during prolonged incubation for up to 72 h. A distinct charge-transfer band was observed concomitantly with the formation of the trihydroxy-FYX-051-XOR complex. Crystallographic analysis of the charge-transfer complex indicated that a Mo-nitrogen-carbon bond was formed between molybdenum of XOR and the nitrile group of trihydroxy-FYX-051. FYX-051 showed a potent and long-lasting hypouricemic effect in a rat model of potassium oxonate-induced hyperuricemia, and it seems to be a promising candidate for the clinical treatment of hyperuricemia. PMID- 20952483 TI - The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brain. AB - ATP-binding cassette transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) have been shown to work in concert to restrict brain penetration of several tyrosine kinase inhibitors. It has been reported that P-gp is dominant in limiting transport of many dual P-gp/BCRP substrates across the blood-brain barrier (BBB). This study investigated the influence of P-gp and BCRP on the central nervous system (CNS) penetration of sorafenib, a multitargeted tyrosine kinase inhibitor currently being evaluated in clinical trials for glioma. In vitro studies showed that BCRP has a high affinity for sorafenib. Sorafenib inhibited P-gp, but did not seem to be a P-gp substrate in vitro. CNS distribution studies showed that transport of sorafenib to the brain was restricted because of active efflux at the BBB. The brain-to-plasma equilibrium distribution coefficient (area under the concentration-time profiles for plasma/area under the concentration-time profiles for brain) was 0.06 in wild type mice. Steady-state brain-to-plasma concentration ratio of sorafenib was approximately 0.36 +/- 0.056 in the Bcrp1(-/-) mice, 0.11 +/- 0.021 in the Mdr1a/b(-/-) mice, and 0.91 +/- 0.29 in the Mdr1a/b(-/-)Bcrp1(-/-) mice compared with 0.094 +/- 0.007 in the wild-type mice. Sorafenib brain-to-plasma ratios increased on coadministration of the dual P-gp/BCRP inhibitor elacridar such that the ratio in wild-type mice (0.76 +/- 0.24), Bcrp1(-/-) mice (1.03 +/- 0.33), Mdr1a/b(-/-) mice (1.3 +/- 0.29), and Mdr1a/b(-/-)Bcrp1(-/-) mice (0.73 +/- 0.35) were not significantly different. This study shows that BCRP and P-gp together restrict the brain distribution of sorafenib with BCRP playing a dominant role in the efflux of sorafenib at the BBB. These findings are clinically relevant to chemotherapy in glioma if restricted drug delivery to the invasive tumor cells results in decreased efficacy. PMID- 20952488 TI - Effects of graded heat stress on global left ventricular function and twist mechanics at rest and during exercise in healthy humans. AB - Increased left ventricular (LV) twist and untwisting (LV twist mechanics) contribute to the maintenance of stroke volume during passive heat stress. However, it remains unknown whether changes in LV twist mechanics are related to the magnitude of heat stress and whether performing exercise during heat stress alters this response. We examined global LV function and LV twist mechanics in 10 healthy men at baseline and three progressive levels of heat stress, at rest and during knee-extensor exercise. At rest, heat stress increased cardiac output and reduced end-diastolic volume and end-systolic volume, whilst stroke volume and mean arterial pressure (MAP) were maintained. Left ventricular twist and untwisting velocity also increased from baseline to severe heat stress (from 10.6 +/- 3.3 to 15.1 +/- 5.2 deg and from -123 +/- 55 to -210 +/- 49 deg s(-1), respectively, both P < 0.01) and correlated significantly with body temperature, heart rate and LV volumes (P < 0.05). Similar to resting conditions, progressive heat stress during exercise increased cardiac output and reduced end-diastolic volume and end-systolic volume with a maintained stroke volume. However, MAP declined (P < 0.01) and there was no significant change in LV twist and untwisting velocity, resulting in non-significant relationships between twist mechanics and systemic responses. In conclusion, LV twist mechanics increase proportionally with the magnitude of heat stress at rest. However, there is no increase in LV twist and untwisting velocity from control exercise to severe heat stress during exercise despite a significant increase in body temperatures and cardiac output. We, therefore, suggest that the maintenance of stroke volume in the combined conditions of heat stress and small muscle mass exercise may be further facilitated by other peripheral factors, such as the continuous decline in MAP. PMID- 20952489 TI - Diet-induced obesity alters signalling pathways and induces atrophy and apoptosis in skeletal muscle in a prediabetic rat model. AB - Pro-inflammatory and stress-activated signalling pathways are important role players in the pathogenesis of obesity and insulin resistance. Obesity and type II diabetes are associated with chronic, low-grade inflammation and elevated tumour necrosis factor-alpha (TNF-alpha) levels. There is increasing evidence that TNF-alpha may play a critical role in skeletal muscle atrophy. However, the effects of obesity-induced insulin resistance on these signalling pathways are poorly understood in skeletal muscle. Therefore, the present study addressed the effects of obesity-induced insulin resistance on the activity of the ubiquitin ligases, nuclear factor-B, p38 MAPK and phosphoinositide 3-kinase signalling pathways in the gastrocnemius muscle and compared these with muscle of standard chow-fed control rats. Male Wistar rats were randomly allocated to a control diet group (standard commercial chow; 60% carbohydrates, 30% protein and 10% fat) or a cafeteria diet group (65% carbohydrates, 19% protein and 16% fat) for 16 weeks. Blood analysis was conducted to determine the impact of the model of obesity on circulating insulin, glucose, free fatty acids, TNF-alpha and angiotensin II concentrations. The experimental animals were 18% heavier and had 68% greater visceral fat mass than their control counterparts and were dyslipidaemic. Significant increases in the ubiquitin ligase and MuRF-1, as well as in caspase-3 and poly-ADP-ribose polymerase cleavage were observed in the muscle of obese animals compared with the control rats. We propose that dyslipidaemia may be a mechanism for the activation of inflammatory/stress-activated signalling pathways in obesity and type II diabetes, which will lead to apoptosis and atrophy in skeletal muscle. PMID- 20952490 TI - Acute vagal modulation of electrophysiology of the atrial and pulmonary veins increases vulnerability to atrial fibrillation. AB - Vagal activity is thought to influence atrial electrophysiological properties and play a role in the initiation and maintenance of atrial fibrillation (AF). We evaluated the effects of acute vagal stimulation on atrial conduction, refractoriness of atrial and pulmonary veins (PVs) and inducibility of AF. An open-chest epicardial approach was performed in New Zealand White rabbits with preserved autonomic innervation. Atrial electrograms were obtained with four unipolar electrodes placed epicardially along the atria (n = 22) and an electrode adapted to the proximal left PV (n = 10). The cervical vagus nerve was stimulated with bipolar platinum electrodes (20 Hz). Epicardial activation was recorded in sinus rhythm, and effective refractory periods (ERPs), dispersion of refractoriness and conduction times from high-lateral right atrium (RA) to high lateral left atrium (LA) and PVs assessed at baseline and during vagal stimulation. Burst pacing (50 Hz, 10 s), alone or combined with vagal stimulation, was applied to the right (RAA) and left atrial appendage (LAA) and PVs to induce AF. At baseline, ERPs were lower in PVs than in LA and LAA, but did not differ significantly from RA and RAA, and there was a significant delay in the conduction time from RA to PVs compared with the activation time from RA to LA (P < 0.01). During vagal stimulation, ERP decreased significantly at all sites, without significant differences in the dispersion of refractoriness, and the atrial conduction times changed from 39 +/- 19 to 49 +/- 9 ms (RA to PVs; n.s.) and from 14 +/- 7 to 28 +/- 12 ms (RA to LA; P = 0.01). Induction of AF was reproducible in 50% of cases with 50 Hz and in 82% with 50 Hz combined with vagal stimulation (P < 0.05). During vagal stimulation, AF cycle length decreased at all sites, and AF duration changed from 1.0 +/- 0.9 to 14.0 +/- 10.0 s (P < 0.01), with documentation of PV tachycardia in three cases. In 70% of the animals, AF ceased immediately after interruption of vagal stimulation. We conclude that in the intact rabbit heart, vagal activity prolongs interatrial conduction and shortens atrial and PV ERP, contributing to the vulnerability to the induction and maintenance of AF. This model may be useful in the assessment of the autonomic influence in the mechanisms underlying AF. PMID- 20952491 TI - Is best interests a relevant decision making standard for enrolling non capacitated subjects into clinical research? AB - The 'best interests' decision making standard is used in clinical care to make necessary health decisions for non-capacitated individuals for whom neither explicit nor inferred wishes are known. It has been also widely acknowledged as a basis for enrolling some non-capacitated adults into clinical research such as emergency, critical care, and dementia research. However, the best interests standard requires that choices provide the highest net benefit of available options, and clinical research rarely meets this criterion. In the context of modern norms of bioethics, the best interests standard rarely supports surrogate consent for research and should not be accepted as a routine provision. PMID- 20952492 TI - Religion and discussion of end-of-life care: the hunt for the hidden confounder must begin. PMID- 20952493 TI - Ethics in systematic reviews. AB - Since its introduction by the Nuremberg Code and the Declaration of Helsinki, the place held by ethics in biomedical research has been continuously increasing in importance. The past 30 years have also seen exponential growth in the number of biomedical articles published. A systematic review of the literature is the scientific way of synthesising a plethora of information, by exhaustively searching out and objectively analysing the studies dealing with a given issue. However, the question of ethics in systematic reviews is rarely touched upon. This could lead to some drawbacks, as systematic reviews may contain studies with ethical insufficiencies, may be a possible way to publish unethical research and may also be prone to conflict of interest. Finally, informed consent given for an original study is not necessarily still valid at the systematic review level. There is no doubt that routine ethical assessment in systematic reviews would help to improve the ethical and methodological quality of studies in general. However, ethical issues change so much with time and location, and are so broad in scope and in context that it appears illusory to search for a universal, internationally accepted standard for ethical assessment in systematic reviews. Some simple suggestions could nevertheless be drawn from the present reflection and are discussed in the paper. PMID- 20952494 TI - Linking lung function and inflammatory responses in ventilator-induced lung injury. AB - Despite decades of research, the mechanisms of ventilator-induced lung injury are poorly understood. We used strain-dependent responses to mechanical ventilation in mice to identify associations between mechanical and inflammatory responses in the lung. BALB/c, C57BL/6, and 129/Sv mice were ventilated using a protective [low tidal volume and moderate positive end-expiratory pressure (PEEP) and recruitment maneuvers] or injurious (high tidal volume and zero PEEP) ventilation strategy. Lung mechanics and lung volume were monitored using the forced oscillation technique and plethysmography, respectively. Inflammation was assessed by measuring numbers of inflammatory cells, cytokine (IL-6, IL-1beta, and TNF-alpha) levels, and protein content of the BAL. Principal components factor analysis was used to identify independent associations between lung function and inflammation. Mechanical and inflammatory responses in the lung were dependent on ventilation strategy and mouse strain. Three factors were identified linking 1) pulmonary edema, protein leak, and macrophages, 2) atelectasis, IL-6, and TNF-alpha, and 3) IL-1beta and neutrophils, which were independent of responses in lung mechanics. This approach has allowed us to identify specific inflammatory responses that are independently associated with overstretch of the lung parenchyma and loss of lung volume. These data provide critical insight into the mechanical responses in the lung that drive local inflammation in ventilator induced lung injury and the basis for future mechanistic studies in this field. PMID- 20952495 TI - Keratinocyte growth factor improves alveolar barrier function: keeping claudins in line. PMID- 20952496 TI - MAPK signaling pathways regulate IL-8 mRNA stability and IL-8 protein expression in cystic fibrosis lung epithelial cell lines. AB - Cystic fibrosis (CF) is characterized by a massive proinflammatory phenotype in the lung, caused by mutations in the CFTR gene. IL-8 and other proinflammatory mediators are elevated in the CF airway, and the immediate mechanism may depend on disease-specific stabilization of IL-8 mRNA in CF lung epithelial cells. MAPK signaling pathways impact directly on IL-8 protein expression in CF cells, and we have hypothesized that the mechanism may also involve stabilization of the IL-8 mRNA. To test this hypothesis, we have examined the effects of pharmacological and molecular inhibitors of p38, and downstream MK2, ERK1/2, and JNK, on stability of IL-8 mRNA in CF lung epithelial cells. We previously showed that tristetraprolin (TTP) was constitutively low in CF and that raising TTP destabilized the IL-8 mRNA. We therefore also tested these effects on CF lung epithelial cells stably expressing TTP. TTP binds to AU-rich elements in the 3' UTR of the IL-8 mRNA. We find that inhibition of p38 and ERK1/2 reduces the stability of IL-8 mRNA in parental CF cells. However, neither intervention further lowers TTP-dependent destabilization of IL-8 mRNA. By contrast, inhibition of the JNK-2 pathway has no effect on IL-8 mRNA stability in parental CF cell, but rather increases the stability of the message in cells expressing high levels of TTP. However, we find that inhibition of ERK1/2 or p38 leads to suppression of the effect of JNK-2 inhibition on IL-8 mRNA stability. These data thus lend support to our hypothesis that constitutive MAPK signaling and proteasomal activity might also contribute, along with aberrantly lower TTP, to the proinflammatory phenotype in CF lung epithelial cells by increasing IL-8 mRNA stability and IL-8 protein expression. PMID- 20952497 TI - Signaling pathways leading to phosphorylation of Akt and GSK-3beta by activation of cloned human and rat cerebral D2and D3 receptors. AB - Although dopamine (DA) regulates the serine/threonine kinase Akt and its downstream substrate glycogen synthase kinase-3beta (GSK-3beta), the direct influence of dopaminergic receptors remains poorly characterized. Short-term incubation of Chinese hamster ovary (CHO)-expressed human (h)D(2L) and hD3) receptors with DA (maximal effect, 5-10 min) phosphorylated Akt (Thr308 and Ser473) and GSK-3beta (Ser9), actions blocked by the selective D2 and D3 antagonists, 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole (L741,626) and (3aR,9bS)-N[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4 c]pyrrole-2-yl)-butyl] (4-phenyl)benzamide (S33084), respectively. Similar findings were acquired with the specific D2/D3 receptor agonist quinelorane, which also enhanced (10 min after administration) levels of p-Akt and p-GSK-3beta in rat nucleus accumbens, an action blocked by the D2/D3 receptor antagonist raclopride. Akt and GSK-3beta phosphorylation mediated via CHO-expressed hD(2L) and hD3 receptors was prevented by pertussis toxin and by inhibitors of insulin like growth factor-1 receptors as well as phosphatidylinositol 3-kinase and Src. Likewise, chelation of intracellular Ca2+ and interference with an "atypical" phorbol ester-insensitive protein kinase C (PKC) abolished recruitment of Akt and GSK-3beta. Inactivation of PKCMU blocked Akt and GSK-3beta phosphorylation at hD(2L) receptors. However, blockade of conventional PKC isoforms attenuated the actions of DA at hD3 receptors only. Furthermore, phospholipase C (PLC), calmodulin, and Akt inhibitors abolished DA-induced GSK-3beta phosphorylation by hD3 receptors, whereas phosphorylation by hD(2L) receptors partially involved calmodulin, Akt, and extracellular signal-regulated kinase (ERK) 1/2. In conclusion, at both hD(2L) and hD3 receptors, DA elicited a G(i/o)- and Ca2+/calmodulin-dependent phosphorylation of Akt and GSK-3beta via transactivation of insulin-like growth factor 1 receptor. However, significant differences were seen regarding the involvement of PLC, calmodulin, and ERK1/2. PMID- 20952498 TI - Endocannabinoid overload. AB - The signaling capacity of endogenous cannabinoids ("endocannabinoids") is tightly regulated by degradative enzymes. This Perspective highlights a research article in this issue (p. 996) in which the authors show that genetic disruption of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG), causes marked elevations in 2-AG levels that lead to desensitization of brain cannabinoid receptors. These findings highlight the central role that MAGL plays in endocannabinoid metabolism in vivo and reveal that excessive 2-AG signaling can lead to functional antagonism of the brain cannabinoid system. PMID- 20952499 TI - Strict sex-specific mtDNA segregation in the germ line of the DUI species Venerupis philippinarum (Bivalvia: Veneridae). AB - Doubly Uniparental Inheritance (DUI) is one of the most striking exceptions to the common rule of standard maternal inheritance of metazoan mitochondria. In DUI, two mitochondrial genomes are present, showing different transmission routes, one through eggs (F-type) and the other through sperm (M-type). In this paper, we report results from a multiplex real-time quantitative polymerase chain reaction analysis on the Manila clam Venerupis philippinarum (formerly Tapes philippinarum). We quantified M- and F-types in somatic tissues, gonads, and gametes. Nuclear and external reference sequences were used, and the whole experimental process was designed to avoid any possible cross-contamination. In most male somatic tissues, the M-type is largely predominant: This suggests that the processes separating sex-linked mitochondrial DNAs (mtDNAs) in somatic tissues are less precise than in other DUI species. In the germ line, we evidenced a strict sex-specific mtDNA segregation because both sperm and eggs do carry exclusively M- and F-types, respectively, an observation that is in contrast with a previous analysis on Mytilus galloprovincialis. More precisely, whereas two mtDNAs are present in the whole gonad, only the sex-specific one is detected in gametes. Because of this, we propose that the mtDNA transmission is achieved through a three-checkpoint process in V. philippinarum. The cytological mechanisms of male mitochondria segregation in males and degradation in females during the embryo development (here named Checkpoint #1 and Checkpoint #2) are already well known for DUI species; a Checkpoint #3 would act when primordial germ cells (PGCs) are first formed and would work in both males and females. We believe that Checkpoint #3 is a mere variation of the "mitochondrial bottleneck" in species with standard maternal inheritance, established when their PGCs separate during embryo cleavage. PMID- 20952500 TI - Effective population size is positively correlated with levels of adaptive divergence among annual sunflowers. AB - The role of adaptation in the divergence of lineages has long been a central question in evolutionary biology, and as multilocus sequence data sets have become available for a wide range of taxa, empirical estimates of levels of adaptive molecular evolution are increasingly common. Estimates vary widely among taxa, with high levels of adaptive evolution in Drosophila, bacteria, and viruses but very little evidence of widespread adaptive evolution in hominids. Although estimates in plants are more limited, some recent work has suggested that rates of adaptive evolution in a range of plant taxa are surprisingly low and that there is little association between adaptive evolution and effective population size in contrast to patterns seen in other taxa. Here, we analyze data from 35 loci for six sunflower species that vary dramatically in effective population size. We find that rates of adaptive evolution are positively correlated with effective population size in these species, with a significant fraction of amino acid substitutions driven by positive selection in the species with the largest effective population sizes but little or no evidence of adaptive evolution in species with smaller effective population sizes. Although other factors likely contribute as well, in sunflowers effective population size appears to be an important determinant of rates of adaptive evolution. PMID- 20952501 TI - In vitro screening for population variability in chemical toxicity. AB - Immortalized human lymphoblastoid cell lines have been used to demonstrate that it is possible to use an in vitro model system to identify genetic factors that affect responses to xenobiotics. To extend the application of such studies to investigative toxicology by assessing interindividual and population-wide variability and heritability of chemical-induced toxicity phenotypes, we have used cell lines from the Centre d'Etude du Polymorphisme Humain (CEPH) trios assembled by the HapMap Consortium. Our goal is to aid in the development of predictive in vitro genetics-anchored models of chemical-induced toxicity. Cell lines from the CEPH trios were exposed to three concentrations of 14 environmental chemicals. We assessed ATP production and caspase-3/7 activity 24 h after treatment. Replicate analyses were used to evaluate experimental variability and classify responses. We show that variability of response across the cell lines exists for some, but not all, chemicals, with perfluorooctanoic acid (PFOA) and phenobarbital eliciting the greatest degree of interindividual variability. Although the data for the chemicals used here do not show evidence for broad-sense heritability of toxicity response phenotypes, substantial cell line variation was found, and candidate genetic factors contributing to the variability in response to PFOA were investigated using genome-wide association analysis. The approach of screening chemicals for toxicity in a genetically defined yet diverse in vitro human cell-based system is potentially useful for identification of chemicals that may pose a highest risk, the extent of within species variability in the population, and genetic loci of interest that potentially contribute to chemical susceptibility. PMID- 20952502 TI - The impact of dose rate on ethylene glycol developmental toxicity and pharmacokinetics in pregnant CD rats. AB - High-dose bolus exposure of rats to ethylene glycol (EG) causes developmental toxicity mediated by a metabolite, glycolic acid (GA), whose levels increase disproportionately when its metabolism is saturated. However, low-level exposures that do not saturate GA metabolism have a low potential for developmental effects. Toward the goal of developing EG risk assessments based on internal dose metrics, this study examined the differences between fast (bolus) and slow (continuous infusion) dose-rate exposures to EG on developmental outcome and pharmacokinetics. Time-mated female CD rats received sc bolus injections of 0, 1000, or 2000 mg/kg/day of EG on gestation day (GD) 6-15 once daily, whereas three corresponding groups were given the same daily doses as an infusion administered continuously from GD 6-15 via an sc implantable pump. In the sc bolus groups, increases in 11 fetal malformations (major defects) and 12 variations (minor alterations) were seen at the 2000 mg/kg/day dose level, whereas increases in 2 malformations and 2 variations occurred at 1000 mg/kg/day. In contrast, equivalent daily doses of EG given slowly via infusion did not cause any developmental effects. A pharmacokinetics time course was then conducted to compare GD 11-12 kinetics from oral bolus (gavage) exposure versus sc infusion of EG. Although dose rate had a modest impact (8- to 11-fold difference) on peak EG levels, peak levels of GA in maternal blood, kidney, embryo, and exocoelomic fluid were 59, 100, 49, and 56 times higher, respectively, following gavage versus the same dose given by infusion. These data illustrate how high-dose bolus exposure to EG causes a dramatic shift to nonlinear GA kinetics, an event which is highly unlikely to occur following exposures to humans associated with consumer and worker uses. PMID- 20952504 TI - In vivo doses of acrylamide and glycidamide in humans after intake of acrylamide rich food. AB - For assessment of cancer risk from acrylamide (AA) exposure through food, the relation between intake from food in humans and the in vivo doses (area under the concentration-time curve, AUC) of AA (AUC-AA) and of its genotoxic metabolite glycidamide (GA) (AUC-GA) is used as a basis for extrapolation between exposure levels and between species. In this study, AA-rich foods were given to nonsmokers: a high intake of 11 MUg AA/kg body weight (bw) and day for 4 days or an extra (medium) intake of 2.5 MUg AA/kg bw and day for a month. Hemoglobin (Hb) adduct levels from AA and GA, measured in blood samples donated before and after exposures, were used for calculation of AUC-AA and AUC-GA using reaction rate constants for the adduct formation measured in vitro. Both AA- and GA-adduct levels increased about twofold after the periods with enhanced intake. AUC for the high and medium groups, respectively, in nanomolar hours per microgram AA per kilogram bw, was for AA 212 and 120 and for GA 49 and 21. The AA intake in the high group was better controlled and used for comparisons with other data. The AUCs per exposure dose obtained in the present human study (high group) are in agreement with those previously obtained at 10(2) times higher exposure levels in humans. Furthermore, the values of AUC-AA and AUC-GA are five and two times higher, respectively, than the corresponding values for F344 rats exposed to AA at levels as in published cancer bioassays. PMID- 20952503 TI - The long winding road toward understanding the molecular mechanisms for B-cell suppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. AB - Suppression of humoral immune responses by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was first reported in the mid-1970s. Since this initial observation, much effort has been devoted by many laboratories toward elucidation of the cellular and molecular mechanisms responsible for the profound impairment of humoral immune responses by TCDD, which is characterized by decreased B cell to plasma cell differentiation and suppression of immunoglobulin production. These efforts have led to a significant body of research demonstrating a direct effect of TCDD on B-cell maturation and function as well as a requisite but as yet undefined role of the aryl hydrocarbon receptor (AhR) in these effects. Likewise, a number of molecular targets putatively involved in mediating B-cell dysfunction by TCDD, and other AhR ligands, have been identified. However, our current understanding has primarily relied on findings from mouse models, and the translation of this knowledge to effects on human B cells and humoral immunity in humans is less clear. Therefore, a current challenge is to determine how TCDD and the AhR affect human B cells. Efforts have been made in this direction but continued progress in developing adequate human models is needed. An in-depth discussion of these advances and limitations in elucidating the cellular and molecular mechanisms putatively involved in the suppression of B-cell function by TCDD as well as the implications on human diseases associated in epidemiological studies with exposure to TCDD and dioxin-like compounds is the primary focus of this review. PMID- 20952505 TI - Genomic deregulation during metastasis of renal cell carcinoma implements a myofibroblast-like program of gene expression. AB - Clear cell renal cell carcinoma (RCC) is the most common and invasive adult kidney cancer. The genetic and biological mechanisms that drive metastatic spread of RCC remain largely unknown. We have investigated the molecular signatures and underlying genomic aberrations associated with RCC metastasis, using an approach that combines a human xenograft model; expression profiling of RNA, DNA, and microRNA (miRNA); functional verification; and clinical validation. We show that increased metastatic activity is associated with acquisition of a myofibroblast like signature in both tumor cell lines and in metastatic tumor biopsies. Our results also show that the mesenchymal trait did not provide an invasive advantage to the metastatic tumor cells. We further show that some of the constituents of the mesenchymal signature, including the expression of the well characterized myofibroblastic marker S100A4, are functionally relevant. Epigenetic silencing and miRNA-induced expression changes accounted for the change in expression of a significant number of genes, including S100A4, in the myofibroblastic signature; however, DNA copy number variation did not affect the same set of genes. These findings provide evidence that widespread genetic and epigenetic alterations can lead directly to global deregulation of gene expression and contribute to the development or progression of RCC metastasis culminating in a highly malignant myofibroblast-like cell. PMID- 20952506 TI - Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene. AB - Genetic rearrangements of the anaplastic lymphoma kinase (ALK) kinase occur in 3% to 13% of non-small cell lung cancer patients and rarely coexist with KRASor EGFR mutations. To evaluate potential treatment strategies for lung cancers driven by an activated EML4-ALK chimeric oncogene, we generated a genetically engineered mouse model that phenocopies the human disease where this rearranged gene arises. In this model, the ALK kinase inhibitor TAE684 produced greater tumor regression and improved overall survival compared with carboplatin and paclitaxel, representing clinical standard of care. 18F-FDG-PET-CT scans revealed almost complete inhibition of tumor metabolic activity within 24 hours of TAE684 exposure. In contrast, combined inhibition of the PI3K/AKT and MEK/ERK1/2 pathways did not result in significant tumor regression. We identified EML4-ALK in complex with multiple cellular chaperones including HSP90. In support of a functional reliance, treatment with geldanamycin-based HSP90 inhibitors resulted in rapid degradation of EML4-ALK in vitro and substantial, albeit transient, tumor regression in vivo. Taken together, our findings define a murine model that offers a reliable platform for the preclinical comparison of combinatorial treatment approaches for lung cancer characterized by ALK rearrangement. PMID- 20952508 TI - HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. AB - Molecular and cellular mechanisms underlying resistance/low responsiveness to antiangiogenic compounds are under extensive investigations. Both populations of tumor and stroma (nontumor compartment) seem to contribute in inherent/acquired resistance to antiangiogenic therapy. Here, investigating in vivo efficacy of sunitinib in experimental models resulted in the identification of tumors that were resistant/sensitive to the therapy. Analysis of tumor protein lysates indicated a greater concentration of hepatocyte growth factor (HGF) in resistant tumors than in sensitive ones. In addition, using flow cytometry, c-Met expression was found to be significantly higher in endothelial cells than in tumor cells, suggesting that HGF might target the vascular endothelial cells in resistant tumors. Combination of sunitinib and a selective c-Met inhibitor significantly inhibited tumor growth compared with sunitinib or c-Met inhibitor alone in resistant tumors. Histology and in vitro analyses suggested that combination treatment mainly targeted the vasculature in the resistant tumors. Conversely, systemic injection of HGF in the sensitive tumor models conferred resistance to sunitinib through maintenance of tumor angiogenesis. In conclusion, our study indicates a role for HGF/c-Met pathway in development of resistance to antiangiogenic therapy and suggests a potential strategy to circumvent resistance to vascular endothelial growth factor receptor tyrosine kinase inhibitor in the clinic. PMID- 20952507 TI - p53 status in stromal fibroblasts modulates tumor growth in an SDF1-dependent manner. AB - The p53 tumor suppressor exerts a variety of cell-autonomous effects that are aimed to thwart tumor development. In addition, however, there is growing evidence for cell nonautonomous tumor suppressor effects of p53. In the present study, we investigated the impact of stromal p53 on tumor growth. Specifically, we found that ablation of p53 in fibroblasts enabled them to promote more efficiently the growth of tumors initiated by PC3 prostate cancer-derived cells. This stimulatory effect was dependent on the increased expression of the chemokine SDF-1 in the p53-deficient fibroblasts. Notably, fibroblasts harboring mutant p53 protein were more effective than p53-null fibroblasts in promoting tumor growth. The presence of either p53-null or p53-mutant fibroblasts led also to a markedly elevated rate of metastatic spread of the PC3 tumors. These findings implicate p53 in a cell nonautonomous tumor suppressor role within stromal fibroblasts, through suppressing the production of tumor stimulatory factors by these cells. Moreover, expression of mutant p53 by tumor stroma fibroblasts might exert a gain of function effect, further accelerating tumor development. PMID- 20952509 TI - Transcription factor NF-Y induces apoptosis in cells expressing wild-type p53 through E2F1 upregulation and p53 activation. AB - The CCAAT-binding transcription factor NF-Y plays a central role in regulating cellular proliferation by controlling the expression of genes required for cell cycle progression such as cyclin A, cyclin B1, cyclin B2, cdc25A, cdc25C, and cdk1. Here we show that unrestricted NF-Y activity leads to apoptosis in an E2F1- and wild-type p53 (wtp53)-dependent manner. Unrestricted NF-Y activity induced an increase in E2F1 mRNA and protein levels. Furthermore, NF-Y directly bound the E2F1 promoter and this correlated with the appearance of open chromatin marks. The ability of NF-Y to induce apoptosis was impaired in cells lacking E2F1 and wtp53. Moreover, NF-Y overexpression elicited phosphorylation of wt p53Ser18 in an E2F1-dependent manner. Our findings establish that NF-Y acts upstream of E2F1 in p53-mediated apoptosis. PMID- 20952510 TI - Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting leukotriene A4hydrolase. AB - The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4'-trihydroxy-trans -stilbene) is a well-known polyphenolic compound of red wine with cancer chemopreventive activity. However, the basis for this activity is unclear. We studied leukotriene A(4) hydrolase (LTA(4)H) as a relevant target in pancreatic cancer. LTA(4)H knockdown limited the formation of leukotriene B(4) (LTB(4)), the enzymatic product of LTA(4)H, and suppressed anchorage-independent growth of pancreatic cancer cells. An in silico shape similarity algorithm predicted that LTA(4)H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA(4)H in vitro and in cells and suppressed proliferation and anchorage independent growth of pancreatic cancer by inhibiting LTB(4) production and expression of the LTB(4) receptor 1 (BLT(1)). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA(4)H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA(4)H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA(4)H activity. Our findings identify LTA(4)H as a functionally important target for mediating the anticancer properties of resveratrol. PMID- 20952511 TI - p57Kip2 is a downstream effector of BCR-ABL kinase inhibitors in chronic myelogenous leukemia cells. AB - Chronic myelogenous leukemia (CML) is characterized by the expression of BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show that BCR-ABL-positive CML cell lines treated with imatinib (STI571) undergo G1 cell cycle arrest associated with the accumulation of p57(Kip)2, a cyclin-dependent kinase inhibitor (CKI). Interestingly, p57(Kip)2 increase precedes the reported STI571-dependent upregulation of p27(Kip)1. A number of complementary approaches allow the demonstration that p57(Kip)2 buildup is due to the transcriptional activation of CDKN1C, the p57(Kip)2-encoding gene, while neither p57(Kip)2 half-life elongation nor its cell relocalization were observed. We also identified a heretofore undescribed pattern of p57(Kip)2 phosphorylated isoforms which, however, did not change in response to STI571 cell treatment. The imatinib-dependent p57(Kip)2 upregulation occurs only in STI571-responsive cells, while the CKI accumulation was not evidenced in an imatinib-resistant clone. Nilotinib and dasatinib (second generation BCR-ABL inhibitors), at concentrations comparable to those used in therapy, increase the CKI but do not affect p27(Kip)1 level. Finally, CD34(+) cells from CML patients display a clear imatinib-dependent p57(Kip)2 upregulation, which was not observed in CD34(+) cells from control subjects. In conclusion, our study points to p57(Kip)2 as a novel and precocious effector of BCR-ABL targeting drugs. PMID- 20952513 TI - Pathologically decreased miR-26a antagonizes apoptosis and facilitates carcinogenesis by targeting MTDH and EZH2 in breast cancer. AB - The role of miR-26a in carcinogenesis appears to be a complicated one, in the sense that both oncogenic and tumor suppressive effects were reported in cancers such as glioblastoma and hepatocellular carcinoma, respectively. Here, we report for the first time that miR-26a is downregulated in breast cancer specimens and cell lines and its transient transfection initiates apoptosis of breast cancer cell line MCF7 cells. Furthermore, retrovirus-delivered miR-26a impairs the in vitro colony forming and in vivo tumor-loading ability of MCF7 cells. Subsequently, MTDH and EZH2 are identified as two direct targets of miR-26a and they are significantly upregulated in breast cancer. MCF7 xenografts with exogenous miR-26a show that a decrease in expression of both MTDH and EZH2 is accompanied by an increase in apoptosis. Moreover, knockdown of MTDH causes apoptosis while reexpression of MTDH partially reverses the proapoptotic effect of miR-26a in MCF7 cells. Our findings suggest that miR-26a functionally antagonizes human breast carcinogenesis by targeting MTDH and EZH2. PMID- 20952514 TI - A prospective evaluation of the biochemical, metabolic, hormonal and structural bone changes associated with bortezomib response in multiple myeloma patients. AB - We prospectively evaluated the bone changes associated with proteasome inhibition using single agent bortezomib in relapsed or refractory myeloma patients. Ten patients received bortezomib 1.3 mg/m(2) per days 1, 4, 8 and 11 for three 21-day cycles, and 6 patients received 1 mg/m(2) per day with the same schedule. Bone architecture and metabolism changes were assessed by bone markers, micro-CT, bone histomorphometry, tetracycline labeling and serum parathormone levels. Bone parameter variations were compared by response to treatment. Microarchitectural changes were observed in all evaluable responsive patients. Bone alkaline phosphatase changes were associated with disease response (>=PR vs. others P=0.03 cycle 1, day 11) serum parathormone levels were also significantly increased (P=0.04 on days 11, 21, 33) in responding individuals. This study demonstrates that the myeloma control produced by proteasome inhibition is associated with bone changes and to a discrete pattern of hormonal variation. PMID- 20952512 TI - RAD51C: a novel cancer susceptibility gene is linked to Fanconi anemia and breast cancer. AB - Germline mutations in many of the genes that are involved in homologous recombination (HR)-mediated DNA double-strand break repair (DSBR) are associated with various human genetic disorders and cancer. RAD51 and RAD51 paralogs are important for HR and in the maintenance of genome stability. Despite the identification of five RAD51 paralogs over a decade ago, the molecular mechanism(s) by which RAD51 paralogs regulate HR and genome maintenance remains obscure. In addition to the known roles of RAD51C in early and late stages of HR, it also contributes to activation of the checkpoint kinase CHK2. One recent study identifies biallelic mutation in RAD51C leading to Fanconi anemia-like disorder. Whereas a second study reports monoallelic mutation in RAD51C associated with increased risk of breast and ovarian cancer. These reports show RAD51C is a cancer susceptibility gene. In this review, we focus on describing the functions of RAD51C in HR, DNA damage signaling and as a tumor suppressor with an emphasis on the new roles of RAD51C unveiled by these reports. PMID- 20952515 TI - Iron overload induces BMP6 expression in the liver but not in the duodenum. AB - BACKGROUND: The bone morphogenetic protein BMP6 regulates hepcidin production by the liver. However, it is not yet known whether BMP6 derives from the liver itself or from other sources such as the small intestine, as has been recently suggested. This study was aimed at investigating the source of BMP6 further. DESIGN AND METHODS: We used three different strains of mice (C57BL/6, DBA/2, and 129/Sv) with iron overload induced either by an iron-enriched diet or by inactivation of the Hfe gene. We examined Bmp6 expression at both the mRNA (by quantitative PCR) and protein (by immunohistochemistry and Western blotting analyses) levels. RESULTS: We showed that iron overload induces Bmp6 mRNA expression in the liver but not in the duodenum of these mice. Bmp6 is also detected by immunohistochemistry in liver tissue sections of mice with iron overload induced either by an iron-enriched diet or by inactivation of the Hfe gene, but not in liver tissue sections from iron-loaded Bmp6-deficient mice. Bmp6 in the duodenum was below immunodetection threshold, thus confirming quantitative PCR data. Lack of specificity of available antibodies together with slight heterogeneity between 129 substrains may account for the differences with previously published data. CONCLUSIONS: Our data strongly support the importance of liver BMP6 for regulation of iron metabolism. Indeed, they demonstrate that intestinal Bmp6 expression is modulated by iron neither at the mRNA nor at the protein level. PMID- 20952516 TI - The mammalian target of rapamycin inhibitor RAD001 (everolimus) synergizes with chemotherapeutic agents, ionizing radiation and proteasome inhibitors in pre-B acute lymphocytic leukemia. AB - BACKGROUND: Despite incremental improvements in outcomes for patients with acute lymphoblastic leukemia, significant numbers of patients still die from this disease. Mammalian target of rapamycin inhibitors have shown potential in vitro and in vivo as therapeutic agents against a range of tumors including acute lymphoblastic leukemia. DESIGN AND METHODS: Flow cytometry was used to evaluate drug-induced cell death in acute lymphoblastic leukemia cell lines and patients' samples. Human xenografts in immunocompromised mice were used to assess the in vivo effects of selected combinations. Pharmacological inhibitors and lentiviral small interfering ribonucleic acid knock-down of p53 were used to investigate the mechanism of cell killing involved. RESULTS: Synergistic interactions between RAD001 and cytotoxic agents were demonstrated in vitro and in vivo, with increased caspase-dependent killing. RAD001 suppressed p53 and p21 responses, while suppression of p53 did not prevent killing, indicating p53 independence. RAD001 and cytotoxic agents activated the JUN N-terminal kinase pathway and the combination further increased JUN N-terminal kinase activation. JUN N-terminal kinase inhibition reduced synergistic cell killing by cytotoxic agents and RAD001 in pre-B acute lymphoblastic leukemia cell lines and patients' samples. Bortezomib and MG132, which activate the JUN N-terminal kinase pathway, also synergized with RAD001 in killing pre-B acute lymphoblastic leukemia cells. Killing was greater when RAD001 was combined with proteasome inhibitors than with cytotoxic drugs. CONCLUSIONS: These observations suggest that combining mammalian target of rapamycin inhibitors with conventional chemotherapy or selected novel agents has the potential to improve clinical responses in patients with pre-B acute lymphoblastic leukemia. PMID- 20952517 TI - Liposomal cytarabine is effective and tolerable in the treatment of central nervous system relapse of acute lymphoblastic leukemia and very aggressive lymphoma. AB - BACKGROUND: Treatment of central nervous system relapse in adult acute lymphoblastic leukemia is a challenge and outcome is poor. Liposomal cytarabine has a prolonged half-life and, given intrathecally, has produced high response rates in patients with central nervous system relapse of non-Hodgkin's lymphoma. The aim of this study was to evaluate the efficacy and tolerability of liposomal cytarabine in central nervous system relapse of acute lymphoblastic leukemia or Burkitt's lymphoma/leukemia. DESIGN AND METHODS: Liposomal cytarabine (50 mg) was given intrathecally together with systemic or intrathecal dexamethasone once every 2 weeks in a phase II European trial. The primary end-point, cytological response in the cerebrospinal fluid after one or two cycles, was evaluated at the time of next treatment. RESULTS: Nineteen heavily pretreated patients (median age, 53 years; range 24-76 years) were evaluable: 14 with acute lymphoblastic leukemia and 5 with Burkitt's lymphoma/leukemia). Complete cytological remission as best response after two cycles of liposomal cytarabine was confirmed in 74% of the patients: 86% of those with acute lymphoblastic leukemia and 40% of those with Burkitt's lymphoma/leukemia). Nine of the 14 patients who achieved complete remission relapsed after a median of 7 months. The median overall survival was 11 months. Adverse events were observed in 89% of the patients (57% of cycles). Grade III-IV events with potential correlation to liposomal cytarabine occurred in 32% of the patients. The most frequent adverse event was headache. One patient developed severe neurological complications with loss of vision and a conus syndrome. CONCLUSIONS: Overall, liposomal cytarabine showed excellent antileukemic activity. Toxicity was acceptable but appeared to increase with the number of cycles. Future evaluation in prophylaxis is of interest. PMID- 20952519 TI - Chromosome fragility in dairy cows exposed to dioxins and dioxin-like PCBs. AB - In this study, we compared cross-bred dairy cows in the Susa Valley (Piedmont, northern Italy), reared either near a high-temperature steel production plant (Farms A and B) or in an industry-free area (control). Exposed cows (n = 36) were selected based on mean bulk milk toxic equivalent values of polychlorodibenzodioxins (PCDDs) and dioxin-like (DL) polychlorobiphenyls (PCBs) and polychlorodibenzofurans (PCDFs) equal to 18.56 pg/g fat and 8.56 pg/g of fat in dairy cows from Farms A and B, respectively, exceeding both those permitted by the legislation in force (6 pg/g fat PCDDs and DL-PCDFs/PCBs), and those measured in dairy cows (n = 19) of the farm used as control (1.75 pg/g of fat PCDDs and DL PCDFs/PCBs). Two types of peripheral blood cell cultures were performed: without (normal cultures for the chromosome abnormality (CA)-test: gaps, chromatid breaks, chromosome breaks and fragments) and with addition of bromodeoxyuridine [for the sister chromatid exchange (SCE)-test]. Both tests revealed a significant (P <= 0.05) higher chromosome fragility in the exposed cattle compared to controls: CA/cell mean values (without gaps) were 0.65 +/- 0.91, 0.51 +/- 0.81 and 0.13 +/- 0.39 in Farms A, B and controls, respectively, while SCE/cell mean values were 7.00 +/- 2.88, 6.39 +/- 2.80 and 5.29 +/- 2.51. Although the role of other pollutants (e.g. heavy metals) in the genesis of the recorded chromosome alterations cannot be ruled out, our results confirm the findings of previous research into dioxin-exposed sheep. PMID- 20952518 TI - Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. AB - Background Sorafenib is a multi-kinase inhibitor with activity against fms-like tyrosine kinase 3 with internal tandem duplication mutation and Raf kinase among others. A phase I dose escalation study of sorafenib was conducted in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. DESIGN AND METHODS: Fifty patients received one of two different schedules; Schedule "A": once or twice daily, five days per week, every week for a 21 day cycle, and Schedule "B": once or twice daily, for 14 days every 21 days. Dose limiting toxicities were grade 3/4 hypertension, hyperbilirubinemia, and amylase elevation. The recommended phase II dose in hematologic malignancies is 400 mg twice daily for both schedules. RESULTS: Complete remissions or complete remissions with incomplete recovery of platelets were achieved in 5 (10%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Significant reduction in bone marrow and/or peripheral blood blasts was seen in an additional 17 (34%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Eleven of these responses (including 3 complete remissions/complete remissions with incomplete recovery) lasted for 2 cycles or beyond. In conclusion, sorafenib is active and well tolerated in acute myelogenous leukemia with fms-like tyrosine kinase 3 internal tandem duplication mutation. Conclusions Additional studies of sorafenib in patients with acute myelogenous leukemia, particularly those with fms-like tyrosine kinase 3 internal tandem duplication, are warranted, including sorafenib-based combinations. (ClinicalTrials.gov Identifier: NCT00217646). PMID- 20952521 TI - Product versus additive model for studying artificial insemination results in several livestock populations. AB - Two models can be used for studying binary results of AI. The additive threshold model proposes an underlying variable as summing the environmental and genetic effects from the 2 individuals involved in the mating, and the product threshold model assumes that the conditional probability of AI success is the product of the probabilities of success of 2 unobserved binary phenotypes (one is the male fertility; the other is the female fertility). The purpose of this paper is to compare the predictive ability of the product and the additive threshold models for studying AI results and to compare results obtained with the 2 models in 3 different species: cattle, sheep, and rabbits. Results showed that the predictive ability of the product model is similar to the additive model in sheep and rabbits but worst in cattle (percentage of wrong prediction = 42, 27, and 35% in the additive model; 43, 28, and 47% in the product model in sheep, rabbits, and cattle, respectively). Even when the 2 models have similar performance, they differed in their EBV (for instance, Pearson correlation between EBV predicted with the 2 models = 0.46 in sheep for male fertility). The product model can determine which sex is responsible for an AI failure. In sheep, the female was the responsible in 94% of the cases and male in 2% of them; in rabbits, the female was the responsible in 54% of the cases and the male in 39% of them. Different estimates of probabilities for male and female fertility success obtained with the product model in the 3 species suggest that male and female fertilities behave differently depending on the species and the uniqueness of the data sets. Although product model seems to provide additional information in the fertility process, further research is needed to understand the worst performance of the product model in cattle. PMID- 20952520 TI - miR-200a Prevents renal fibrogenesis through repression of TGF-beta2 expression. AB - OBJECTIVE: Progressive fibrosis in the diabetic kidney is driven and sustained by a diverse range of profibrotic factors. This study examines the critical role of microRNAs (miRNAs) in the regulation of the key fibrotic mediators, TGF-beta1 and TGF-beta2. RESEARCH DESIGN AND METHODS: Rat proximal-tubular epithelial cells (NRK52E) were treated with TGF-beta1 and TGF-beta2 for 3 days, and expression of markers of epithelial-to-mesenchymal transition (EMT) and fibrogenesis were assessed by RT-PCR and Western blotting. The expression of miR-141 and miR-200a was also assessed, as was their role as translational repressors of TGF-beta signaling. Finally, these pathways were explored in two different mouse models, representing early and advanced diabetic nephropathy. RESULTS: Both TGF-beta1 and TGF-beta2 induced EMT and fibrogenesis in NRK52E cells. TGF-beta1 and TGF-beta2 also downregulated expression of miR-200a. The importance of these changes was demonstrated by the finding that ectopic expression miR-200a downregulated smad-3 activity and the expression of matrix proteins and prevented TGF-beta-dependent EMT. miR-200a also downregulated the expression of TGF-beta2, via direct interaction with the 3' untranslated region of TGF-beta2. The renal expression of miR-141 and miR-200a was also reduced in mouse models representing early and advanced kidney disease. CONCLUSIONS: miR-200a and miR-141 significantly impact on the development and progression of TGF-beta-dependent EMT and fibrosis in vitro and in vivo. These miRNAs appear to be intricately involved in fibrogenesis, both as downstream mediators of TGF-beta signaling and as components of feedback regulation, and as such represent important new targets for the prevention of progressive kidney disease in the context of diabetes. PMID- 20952522 TI - Feeding behavior and ruminal acidosis in beef cattle offered a total mixed ration or dietary components separately. AB - Eighty continental crossbred beef heifers (414.9 +/- 37.9 kg of BW), 16 of which were ruminally cannulated, were used in a 52-d experiment with a generalized randomized block design, to assess if self-selection of dietary ingredients modulates ruminal pH and improves rumen function of feedlot finishing cattle. Treatments were total mixed ration [TMR; 85% barley grain (BG), 10% corn silage (CS), 5% supplement]; or free-choice (self-selection; FC) diets of barley grain and corn silage (BGCS), barley grain and wheat distillers grain (BGDG), or corn silage and wheat distillers grain (CSDG). Heifers were housed in groups of 10 in 8 pens equipped with the GrowSafe System (Airdrie, AB, Canada) enabling feed intake and feeding behavior to be continuously monitored. Two cannulated heifers were randomly assigned to each pen and equipped with indwelling pH probes for continuous measurement of ruminal pH during 4 periods (d 1 to 4, d 7 to 14, d 21 to 28, and d 42 to 49). Rumen fluid samples were collected from cannulated heifers on d 7 and 42 before feed delivery, and on d 4 and 49 at 2 h post-feed delivery for determination of VFA. Heifers fed the TMR had shorter (P = 0.01) and smaller (P = 0.03) meals than those fed the FC diets. Cattle fed BGCS and BGDG increased (P < 0.01) intake of BG over time by up to 80 and 70%, respectively. Increased consumption of BG arose from an increase (P < 0.01) in eating rate over the same (P > 0.10) feeding time, which was accompanied by an increase (P < 0.05) in eating rate but a decrease (P < 0.05) in feeding time of either CS or DG. Even with increased BG consumption, ruminal pH and VFA profiles were not different (P > 0.10) among FC diets or compared with the TMR. Cattle fed FC CSDG consumed DG at 60% of dietary DM over the trial, resulting in greater (P < 0.05) mean ruminal pH and acetate-to-propionate ratio and less (P < 0.05) area under the curve than those given the other FC diets or the TMR. Finishing feedlot cattle fed FC diets containing BG self-regulate intake of diets that have a similar composition, intake level, and ruminal fermentation profile to those fed a TMR. PMID- 20952523 TI - Cloning of avian G(0)/G(1) switch gene 2 genes and developmental and nutritional regulation of G(0)/G(1) switch gene 2 in chicken adipose tissue. AB - Adipose triglyceride lipase (ATGL), a newly identified lipase, is a rate-limiting enzyme for triglyceride hydrolysis in adipocytes. The regulatory proteins involved in ATGL-mediated lipolysis in fat tissue are not fully identified and understood. The G(0)/G(1) switch gene 2 (G0S2) is an inhibitor of ATGL activity by interacting with ATGL through the hydrophobic domain of G0S2. Here, for the first time, we have cloned the coding sequence of G0S2 cDNA for the chicken, turkey, and quail. Sequence comparisons with mammals revealed that the avian G0S2 also have a conserved hydrophobic domain. Avian G0S2 is predominantly expressed in adipose tissues relative to other tested tissues. Within the adipose tissue, G0S2 is expressed 20-fold greater in the adipocyte than in the stromal-vascular (SV) fraction (P < 0.001). Expression of G0S2 mRNA gradually increased during differentiation of chicken adipocytes in culture (P < 0.05). However, there is G0S2 expression in embryonic adipose tissue, SV fraction, and primary preadipocytes before confluence that generally have an increased capacity of cell proliferation, which indicates it has an important role in adipocyte differentiation rather than proliferation. For a better understanding of how G0S2 responds to environmental stimuli, chickens were fasted for 24 h and then refed. Expression of G0S2 in adipose tissue was dramatically decreased (P < 0.05) in the chickens and quail after a 24-h fasting period, and increased to the control level after refeeding. In contrast to G0S2 expression, ATGL expression was induced (P < 0.05) after the 24-h fasting period and rapidly returned to the control level during the refeeding period. These data indicate that changes in lipolytic activities of adipose tissue in vivo can be regulated by G0S2 expression, as an inhibitor of ATGL. PMID- 20952524 TI - Cardiovascular performance of adult breeding sows fails to obey allometric scaling laws. AB - In view of the remarkable decrease of the relative heart weight (HW) and the relative blood volume in growing pigs, we investigated whether HW, cardiac output (CO), and stroke volume (SV) of modern growing pigs are proportional to BW, as predicted by allometric scaling laws: HW (or CO or SV) = a.BW(b), in which a and b are constants, and constant b is a multiple of 0.25 (quarter-power scaling law). Specifically, we tested the hypothesis that both HW and CO scale with BW to the power of 0.75 (HW or CO = a.BW(0.75)) and SV scales with BW to the power of 1.00 (SV = a.BW(1.0)). For this purpose, 2 groups of pigs (group 1, consisting of 157 pigs of 50 +/- 1 kg; group 2, consisting of 45 pigs of 268 +/- 18 kg) were surgically instrumented with a flow probe or a thermodilution dilution catheter, under open-chest anesthetized conditions to measure CO and SV, after which HW was determined. The 95% confidence intervals of power-coefficient b for HW were 0.74 to 0.80, encompassing the predicted value of 0.75, suggesting that HW increased proportionally with BW, as predicted by the allometric scaling laws. In contrast, the 95% confidence intervals of power-coefficient b for CO and SV as measured with flow probes were 0.40 to 0.56 and 0.39 to 0.61, respectively, and values obtained with the thermodilution technique were 0.34 to 0.53 and 0.40 to 0.62, respectively. Thus, the 95% confidence limits failed to encompass the predicted values of b for CO and SV of 0.75 and 1.0, respectively. In conclusion, although adult breeding sows display normal heart growth, cardiac performance appears to be disproportionately low for BW. This raises concern regarding the health status of adult breeding sows. PMID- 20952526 TI - Relative bioavailability of phosphorus in inorganic phosphorus sources fed to growing pigs. AB - The relative bioavailability of P in 5 sources of inorganic P was determined using growing pigs. The 5 sources of inorganic P were dicalcium phosphate (DCP), monocalcium phosphate (MCP) containing 50% MCP (MCP50), MCP containing 70% MCP (MCP70), MCP containing 100% MCP (MCP100), and monosodium phosphate (MSP). A total of 11 diets were formulated. The basal diet was formulated to contain 0.10% P, and 10 additional diets were formulated by adding 0.07 or 0.14% P from each of the 5 P sources to the basal diet. Growing pigs (n = 44; initial BW: 16.8 +/- 4.3 kg) were individually housed and randomly allotted to the 11 experimental diets. Feed was provided on an ad libitum basis throughout the 28-d experimental period. At the conclusion of the experiment, all pigs were killed, and 4 bones (i.e., the third and fourth metacarpals on both front feet) were harvested. Bone-breaking strength, bone ash, and Ca and P concentrations were determined. The concentration of bone ash increased (P < 0.05) as MCP50, MCP70, MCP100, or MSP were added to the basal diet, and the concentration of bone P also increased (P < 0.05) as MCP70, MCP100, or MSP were added to the basal diet. The relative bioavailability of P in each of the feed phosphates was determined using slope ratio methodologies based on breaking strength, and expressed relative to MSP. The slope of the regression line for diets containing MSP or MCP100 was steeper (P < 0.05) than the slope for pigs fed the diet containing DCP, but not different (P > 0.05) from that of pigs fed diets supplemented with MCP50 or MCP70. In conclusion, P in MSP and MCP100 is more bioavailable than P in DCP, but there were no differences within MCP sources. PMID- 20952525 TI - Comparison of a wheat-based diet supplemented with purified {beta}-glucans, with an oat-based diet on nutrient digestibility, nitrogen utilization, distal gastrointestinal tract composition, and manure odor and ammonia emissions from finishing pigs. AB - It was hypothesized that supplementation of an oat-extracted mixed-linkage (1 -> 3), (1 -> 4)-beta-d-glucan (beta-glucans) to a wheat-based diet may beneficially mitigate manure odor and ammonia emissions associated with intensive pig production, without depressing nutrient digestibility as has been observed with oat-based diets. An experiment was conducted to investigate the effect of dietary beta-glucan source and the inclusion of an enzyme composite containing beta glucanase on energy and nutrient digestibility, N utilization, distal gastrointestinal tract (GIT) fermentation, and manure emissions from finisher boars. Twenty-eight boars (BW = 74.2 +/- 3.6 kg) were assigned to 1 of 4 dietary treatments (n = 7/treatment): 1) an oat-based diet (oat), 2) an oat diet + enzyme composite (OE), 3) a wheat-based diet + purified beta-glucans (WG), and 4) a wheat-based diet + purified beta-glucans + enzyme composite. The wheat-based diets containing purified beta-glucans were formulated to contain concentrations of total beta-glucans comparable with the oat-based diet. Consumption of the WG diet resulted in a greater digestibility of GE (P = 0.001) and an increase in the urine:feces N excretion ratio (P = 0.049) compared with the oat diet. In the distal GIT, pigs offered the WG diet contained fewer bifidobacteria (P = 0.027) and lactobacilli (P = 0.050) compared with the oat diet. Pigs offered the WG diet had increased manure odor emissions compared with the oat diet (P = 0.023). In conclusion, although supplementing wheat-based diets with extracted oat-beta glucan did not reduce nutrient digestibility, there was a negligible effect in beneficially influencing manure emissions from pigs when compared with a conventional oat formulation. PMID- 20952527 TI - The effect of different postweaning altrenogest treatments of primiparous sows on follicular development, pregnancy rates, and litter sizes. AB - This study investigated follicular development during and after postweaning altrenogest treatment of primiparous sows in relation to subsequent reproductive performance. Primiparous sows (n = 259) were randomly assigned at weaning (d 0) to 1 of 4 groups: control (no altrenogest, n = 71), RU4 (20 mg of altrenogest from d -1 to 2, n = 62), RU8 (20 mg of altrenogest from d -1 to 6, n = 65), or RU15 (20 mg of altrenogest from d -1 to 13, n = 61). Average follicular size (measured by ultrasound) increased during altrenogest treatment and resulted in larger follicles at the start of the follicular phase for RU4, RU8, and RU15 compared with controls (5.3 +/- 0.9, 5.5 +/- 1.3, 5.1 +/- 1.2, and 3.4 +/- 0.6 mm, respectively; P < 0.0001). Farrowing rate was greater in RU15 (95%) than in RU8 (76%; P = 0.04). The RU15 group also had more piglets (2 to 3 more piglets total born and born alive; P < 0.05) than the other treatment groups. Follicular development at weaning clearly affected reproductive performance. At weaning, average follicular size: small (<3.5 mm), medium (3.5 to 4.5 mm), or large (>= 4.5 mm), was associated with farrowing rates of 86, 78, and 48%, respectively (P < 0.001). Sows with large follicles at weaning had low farrowing rates (71%) in RU4, very low farrowing rates (22%) in RU8, but normal farrowing rates in RU15 (83%). In conclusion, this study showed that 15 d of postweaning altrenogest treatment of primiparous sows may allow follicle turnover in sows that had large follicles at weaning and that this was associated with an improved reproductive performance. It also showed that shorter treatment with altrenogest (4 or 8 d) is beneficial for sows with small follicles at weaning, but is not recommendable for sows with large follicles at weaning. PMID- 20952528 TI - A comparison of bovine seminal quality assessments using different viewing chambers with a computer-assisted semen analyzer. AB - Computer-assisted sperm analysis of fresh and frozen-thawed bovine sperm requires proper handling and preparation, and the type of slide used in the assessment is critical if the resultant data are to be useful quality control measurements. In the present study, 4 different slide viewing chambers, a Makler chamber, a clean slide-coverslip, or a 2- or 4-cell chamber Leja slide, were compared with assess their utility in providing reliable measurements of sperm motility variables. A Hamilton-Thorne IVOS Computer-Assisted Semen Analyzer (CASA) was the instrument used to determine sperm measurements utilizing the 4 different chambers. Fifty eight different freeze batches of bovine semen that had been collected from 47 bulls at 7 sites that sex-sort sperm using Sexing Technologies sorting criteria were incorporated into the trial. Neither the percentage of motile sperm nor the percentage of progressively motile sperm differed for the Makler chamber vs. slide-coverslip comparisons. Similarly, total and progressively motile sperm did not differ between the 2- and 4-cell chambered Leja slides. However, total and progressive motility of sperm determined with the Makler chamber and slide coverslip were greater (P < 0.0001) than motilities recorded by the 2- or 4-cell chambered Leja slides. Based on the results, the type of viewing chamber can affect the range of sperm motility values when CASA is used for quality control evaluations of thawed, cryopreserved sex-sorted sperm samples. PMID- 20952529 TI - Effect of dietary inorganic sulfur level on growth performance, fecal composition, and measures of inflammation and sulfate-reducing bacteria in the intestine of growing pigs. AB - Two experiments investigated the impact of dietary inorganic S on growth performance, intestinal inflammation, fecal composition, and the presence of sulfate-reducing bacteria (SRB). In Exp. 1, individually housed pigs (n = 42; 13.8 kg) were fed diets containing 2,300 or 2,100 mg/kg of S for 24 d. Decreasing dietary S had no effect on ADG, ADFI, or G:F. In Exp. 2, pigs (n = 64; 13.3 kg) were fed diets containing 0, 0.625, 1.25, 2.5, or 5.0% CaSO(4), thereby increasing dietary S from 2,900 to 12,100 mg/kg. Two additional diets were fed to confirm the lack of an impact due to feeding low dietary S on pig performance and to determine if the increased Ca and P content in the diets containing CaSO(4) had an impact on growth performance. Pigs were fed for 35 d. Ileal tissue, ileal mucosa, and colon tissue were harvested from pigs fed the 0 and 5% CaSO(4) diets (low-S and high-S, respectively) to determine the impact of dietary S on inflammation-related mRNA, activity of mucosal alkaline phosphatase and sucrase, and pathways of inflammatory activation. Real-time PCR was used to quantify SRB in ileal and colon digesta samples and feces. Fecal pH, sulfide, and ammonia concentrations were also determined. There was no impact on growth performance in pigs fed the diet reduced in dietary S or by the increase of dietary Ca and P. Increasing dietary S from 2,900 to 12,100 mg/kg had a linear (P < 0.01) effect on ADG and a cubic effect (P < 0.05) on ADFI and G:F. Real-time reverse transcription PCR analysis revealed that pigs fed high-S increased (P < 0.05) the relative abundance of intracellular adhesion molecule-1, tumor necrosis factor alpha, and suppressor of cytokine signaling-3 mRNA, and tended (P = 0.09) to increase the relative abundance of IL-6 mRNA in ileal tissue. Likewise, pigs fed high-S had reduced (P < 0.05) abundance of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha and increased (P < 0.05) phospho-p44/p42 mitogen-activated protein kinase in ileal tissue, but there was no effect of dietary S on mucosal alkaline phosphatase or sucrase activity. Pigs fed the high-S diet had decreased (P < 0.05) total bacteria in ileal digesta, but increased (P < 0.05) prevalence of SRB in colon contents. Fecal sulfide was increased (P < 0.05) and fecal pH was deceased (P < 0.05) in pigs fed high-S. The data indicate that growing pigs can tolerate relatively high amounts of dietary inorganic S, but high dietary S content alters inflammatory mediators and intestinal bacteria. PMID- 20952530 TI - Adipogenic differentiation state-specific gene expression as related to bovine carcass adiposity. AB - Genetic regulation of the site of fat deposition is not well defined. The objective of this study was to investigate adipogenic differentiation state specific gene expression in feedlot cattle (>75% Angus; <25% Simmental parentage) of varying adipose accretion patterns. Four groups of 4 steers were selected via ultrasound for the following adipose tissue characteristics: low subcutaneous-low intramuscular (LSQ-LIM), low subcutaneous-high intramuscular (LSQ-HIM), high subcutaneous-low intramuscular (HSQ-LIM), and high subcutaneous-high intramuscular (HSQ-HIM). Adipose tissue from the subcutaneous (SQ) and intramuscular (IM) depots was collected at slaughter. The relative expression of adipogenic genes was evaluated using quantitative PCR. Data were analyzed using the mixed model of SAS, and gene expression data were analyzed using covariate analysis with ribosomal protein L19 as the covariate. No interactions (P > 0.10) were observed between IM and SQ adipose tissue depots for any of the variables measured. Therefore, only the main effects of high and low accretion within a depot and the effects of depot are reported. Steers with LIM had smaller mean diameter IM adipocytes (P < 0.001) than HIM steers. Steers with HSQ had larger mean diameter SQ adipocytes (P < 0.001) than LSQ. However, there were no differences (P > 0.10) in any of the genes measured due to high or low adipose accretion. Preadipogenic delta-like kinase1 mRNA was greater in the IM than the SQ adipose tissue; conversely, differentiating and adipogenic genes, lipoprotein lipase, PPARgamma, fatty acid synthetase, and fatty acid binding protein 4 were greater (P < 0.001) in the SQ than the IM depot. Intramuscular adipocytes were smaller than SQ adipocytes and had greater expression of the preadipogenic gene, indicating that more hyperplasia was occurring. Meanwhile, SQ adipose tissue contained much larger (P < 0.001) adipocytes that had a greater expression (P < 0.001) of differentiating and adipogenic genes than did the IM adipose tissue, indicating more cells were undergoing differentiation and hypertrophy. Adipogenic differentiation state-specific gene expression was not different in cattle with various phenotypes, but adipogenesis in the SQ and IM adipose tissues seems to occur independently. PMID- 20952531 TI - Ruminant Nutrition Symposium: Role of fermentation acid absorption in the regulation of ruminal pH. AB - Highly fermentable diets are rapidly converted to organic acids [i.e., short chain fatty acids (SCFA) and lactic acid] within the rumen. The resulting release of protons can constitute a challenge to the ruminal ecosystem and animal health. Health disturbances, resulting from acidogenic diets, are classified as subacute and acute acidosis based on the degree of ruminal pH depression. Although increased acid production is a nutritionally desired effect of increased concentrate feeding, the accumulation of protons in the rumen is not. Consequently, mechanisms of proton removal and their quantitative importance are of major interest. Saliva buffers (i.e., bicarbonate, phosphate) have long been identified as important mechanisms for ruminal proton removal. An even larger proportion of protons appears to be removed from the rumen by SCFA absorption across the ruminal epithelium, making efficiency of SCFA absorption a key determinant for the individual susceptibility to subacute ruminal acidosis. Proceeding initially from a model of exclusively diffusional absorption of fermentation acids, several protein-dependent mechanisms have been discovered over the last 2 decades. Although the molecular identity of these proteins is mostly uncertain, apical acetate absorption is mediated, to a major degree, via acetate-bicarbonate exchange in addition to another nitrate-sensitive, bicarbonate-independent transport mechanism and lipophilic diffusion. Propionate and butyrate also show partially bicarbonate-dependent transport modes. Basolateral efflux of SCFA and their metabolites has to be mediated primarily by proteins and probably involves the monocarboxylate transporter (MCT1) and anion channels. Although the ruminal epithelium removes a large fraction of protons from the rumen, it also recycles protons to the rumen via apical sodium-proton exchanger, NHE. The latter is stimulated by ruminal SCFA absorption and salivary Na(+) secretion and protects epithelial integrity. Finally, SCFA absorption also accelerates urea transport into the rumen, which via ammonium recycling, may remove protons from rumen to the blood. Ammonium absorption into the blood is also stimulated by luminal SCFA. It is suggested that the interacting transport processes for SCFA, urea, and ammonia represent evolutionary adaptations of ruminants to actively coordinate energy fermentation, protein assimilation, and pH regulation in the rumen. PMID- 20952532 TI - Building p53. AB - The intricacies of p53 regulation just got more complex. While much is known about the transcriptional regulation of p53 target genes, Chen and Kastan (pp. 2146-2156) uncovered a new mechanism regarding the making of the p53 protein itself. In the October 1, 2010, issue of Genes & Development, they introduced us to a novel mechanism of p53 translational control, by which a 5'-3' cap independent, poly(A)-independent, RNA-RNA interaction enhances p53 translation by binding the ribosomal protein RPL26 following DNA damage. Oligonucleotides designed against this 5'-3' untranslated region (UTR) duplex disrupted the binding of RPL26 to p53 mRNA and reduced p53 synthesis and, therefore, function. This study reveals an alternate mechanism of translational control to regulate p53 levels. PMID- 20952533 TI - Evidence for and against regional differences in neural stem and progenitor cells of the CNS. AB - Neural stem and progenitor cells (NSCs) give rise to the cellular diversity of the CNS. There is evidence both for and against differences in these cells based on the region of the brain in which they reside. Primary brain tumors mimic many aspects of NSC behavior. Recent data suggest that some of the variability in glioma biology may be, in part, a reflection of regional differences in the NSCs from which they arise. In this issue of Genes & Development, Lee and colleagues (pp. 2317-2329) examine how NF1 regulates NSC proliferation and glial differentiation in the brainstem and cortex of the postnatal mouse brain. PMID- 20952535 TI - Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes. AB - Noncoding RNAs are important components of regulatory networks controlling the epigenetic state of chromatin. We analyzed the role of pRNA (promoter-associated RNA), a noncoding RNA that is complementary to the rDNA promoter, in mediating de novo CpG methylation of rRNA genes (rDNA). We show that pRNA interacts with the target site of the transcription factor TTF-I, forming a DNA:RNA triplex that is specifically recognized by the DNA methyltransferase DNMT3b. The results reveal a compelling new mechanism of RNA-dependent DNA methylation, suggesting that recruitment of DNMT3b by DNA:RNA triplexes may be a common and generally used pathway in epigenetic regulation. PMID- 20952534 TI - Induced pluripotency: history, mechanisms, and applications. AB - The generation of induced pluripotent stem cells (iPSCs) from somatic cells demonstrated that adult mammalian cells can be reprogrammed to a pluripotent state by the enforced expression of a few embryonic transcription factors. This discovery has raised fundamental questions about the mechanisms by which transcription factors influence the epigenetic conformation and differentiation potential of cells during reprogramming and normal development. In addition, iPSC technology has provided researchers with a unique tool to derive disease-specific stem cells for the study and possible treatment of degenerative disorders with autologous cells. In this review, we summarize the progress that has been made in the iPSC field over the last 4 years, with an emphasis on understanding the mechanisms of cellular reprogramming and its potential applications in cell therapy. PMID- 20952536 TI - Control of melanocyte differentiation by a MITF-PDE4D3 homeostatic circuit. AB - Cyclic AMP (cAMP) is a ubiquitous second messenger that regulates a variety of biological processes. The magnitude and duration of cAMP expression are regulated by both production and hydrolysis. Melanocyte-stimulating hormone (MSH) plays a crucial role in pigment cell differentiation via cAMP-regulated expression of the master transcription factor MITF. We report the identification of phosphodiesterase 4D3 as a direct target of the MSH/cAMP/MITF pathway. This creates a negative feedback loop that induces refractoriness to chronic stimulation of the cAMP pathway in melanocytes. This homeostatic pathway highlights a potent mechanism controlling melanocyte differentiation that may be amenable to pharmacologic manipulation for skin cancer prevention. PMID- 20952538 TI - Error-prone polyploid mitosis during normal Drosophila development. AB - Endopolyploidy arises during normal development in many species when cells undergo endocycles-variant cell cycles in which DNA replicates but daughter cells do not form. Normally, polyploid cells do not divide mitotically after initiating endocycles; hence, little is known about their mitotic competence. However, polyploid cells are found in many tumors, and the enhanced chromosomal instability of polyploid cells in culture suggests that such cells contribute to tumor aneuploidy. Here, we describe a novel polyploid Drosophila cell type that undergoes normal mitotic cycles as part of a remodeling process that forms the adult rectal papillae. Similar polyploid mitotic divisions, but not depolyploidizing divisions, were observed during adult ileum development in the mosquito Culex pipiens. Extended anaphases, chromosome bridges, and lagging chromosomes were frequent during these polyploid divisions, despite normal expression of cell cycle regulators. Our results show that the switch to endocycles during development is not irreversible, but argue that the polyploid mitotic cycle is inherently error-prone, and that polyploid mitoses may help destabilize the cancer genome. PMID- 20952537 TI - Sept4/ARTS is required for stem cell apoptosis and tumor suppression. AB - Inhibitor of Apoptosis Proteins (IAPs) are frequently overexpressed in tumors and have become promising targets for developing anti-cancer drugs. IAPs can be inhibited by natural antagonists, but a physiological requirement of mammalian IAP antagonists remains to be established. Here we show that deletion of the mouse Sept4 gene, which encodes the IAP antagonist ARTS, promotes tumor development. Sept4-null mice have increased numbers of hematopoietic stem and progenitor cells, elevated XIAP protein, increased resistance to cell death, and accelerated tumor development in an EMU-Myc background. These phenotypes are partially suppressed by inactivation of XIAP. Our results suggest that apoptosis plays an important role as a frontline defense against cancer by restricting the number of normal stem cells. PMID- 20952539 TI - CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1. AB - Drosophila contains one (dCDK12) and humans contain two (hCDK12 and hCDK13) proteins that are the closest evolutionary relatives of yeast Ctk1, the catalytic subunit of the major elongation-phase C-terminal repeat domain (CTD) kinase in Saccharomyces cerevisiae, CTDK-I. However, until now, neither CDK12 nor CDK13 has been demonstrated to be a bona fide CTD kinase. Using Drosophila, we demonstrate that dCDK12 (CG7597) is a transcription-associated CTD kinase, the ortholog of yCtk1. Fluorescence microscopy reveals that the distribution of dCDK12 on formaldehyde-fixed polytene chromosomes is virtually identical to that of hyperphosphorylated RNA polymerase II (RNAPII), but is distinct from that of P TEFb (dCDK9 + dCyclin T). Chromatin immunoprecipitation (ChIP) experiments confirm that dCDK12 is present on the transcribed regions of active Drosophila genes. Compared with P-TEFb, dCDK12 amounts are lower at the 5' end and higher in the middle and at the 3' end of genes (both normalized to RNAPII). Appropriately, Drosophila dCDK12 purified from nuclear extracts manifests CTD kinase activity in vitro. Intriguingly, we find that cyclin K is associated with purified dCDK12, implicating it as the cyclin subunit of this CTD kinase. Most importantly, we demonstrate that RNAi knockdown of dCDK12 in S2 cells alters the phosphorylation state of the CTD, reducing its Ser2 phosphorylation levels. Similarly, in human HeLa cells, we show that hCDK13 purified from nuclear extracts displays CTD kinase activity in vitro, as anticipated. Also, we find that chimeric (yeast/human) versions of Ctk1 containing the kinase homology domains of hCDK12/13 (or hCDK9) are functional in yeast cells (and also in vitro); using this system, we show that a bur1(ts) mutant is rescued more efficiently by a hCDK9 chimera than by a hCDK13 chimera, suggesting the following orthology relationships: Bur1 <-> CDK9 and Ctk1 <-> CDK12/13. Finally, we show that siRNA knockdown of hCDK12 in HeLa cells results in alterations in the CTD phosphorylation state. Our findings demonstrate that metazoan CDK12 and CDK13 are CTD kinases, and that CDK12 is orthologous to yeast Ctk1. PMID- 20952540 TI - CREB mediates brain serotonin regulation of bone mass through its expression in ventromedial hypothalamic neurons. AB - Serotonin is a bioamine regulating bone mass accrual differently depending on its site of synthesis. It decreases accrual when synthesized in the gut, and increases it when synthesized in the brain. The signal transduction events elicited by gut-derived serotonin once it binds to the Htr1b receptor present on osteoblasts have been identified and culminate in cAMP response element-binding protein (CREB) regulation of osteoblast proliferation. In contrast, we do not know how brain-derived serotonin favors bone mass accrual following its binding to the Htr2c receptor on neurons of the hypothalamic ventromedial nucleus (VMH). We show here--through gene expression analysis, serotonin treatment of wild-type and Htr2c(-/-) hypothalamic explants, and cell-specific gene deletion in the mouse--that, following its binding to the Htr2c receptor on VMH neurons, serotonin uses a calmodulin kinase (CaMK)-dependent signaling cascade involving CaMKKbeta and CaMKIV to decrease the sympathetic tone and increase bone mass accrual. We further show that the transcriptional mediator of these events is CREB, whose phosphorylation on Ser 133 is increased by CaMKIV following serotonin treatment of hypothalamic explants. A microarray experiment identified two genes necessary for optimum sympathetic activity whose expression is regulated by CREB. These results provide a molecular understanding of how serotonin signals in hypothalamic neurons to regulate bone mass accrual and identify CREB as a critical determinant of this function, although through different mechanisms depending on the cell type, neuron, or osteoblast in which it is expressed. PMID- 20952541 TI - Actinomadura apis sp. nov., isolated from a honey bee (Apis mellifera) hive, and the reclassification of Actinomadura cremea subsp. rifamycini Gauze et al. 1987 as Actinomadura rifamycini (Gauze et al. 1987) sp. nov., comb. nov. AB - A Gram-reaction-positive aerobic actinomycete, designated strain IM17-1(T), was isolated from a honey bee (Apis mellifera) hive in Chiang Mai Province, Thailand. The strain formed a branched substrate mycelium and mature aerial mycelium bore short chains of arthrospores with warty surfaces. The cell wall contained meso 2,6-diaminopimelic acid (cell-wall type III) and the whole cell sugars were fucose, galactose, glucose, madurose, mannose and ribose. The major isoprenoid quinone was hexahydrogenated menaquinone with nine isoprene units and the predominant cellular fatty acids were C16:0 (33.8 %), C18:1omega9c (32.7 %), summed feature 3 (C16:1omega7c and/or iso-C15:0 2-OH) (8.7 %) and 10-methyl C18:0 (8.2 %). The phospholipids were diphosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannosides. These morphological and chemotaxonomic characteristics were consistent with the classification of IM17-1(T) within the genus Actinomadura. Based on 16S rRNA gene sequence analysis, strain IM17-1(T) was closely related to the type strains of Actinomadura cremea subsp. cremea (98.1 %) and Actinomadura cremea subsp. rifamycini (98.6 %); however, it represented a distinct phylogenetic lineage from the other species within this genus. The unique genetic characteristics were reaffirmed by low levels of DNA DNA relatedness between strain IM17-1(T) and the two most closely related type strains, A. cremea subsp. cremea JCM 3308(T) (56.5+/-4.9 %) and A. cremea subsp. rifamycini JCM 3309(T) (31.0+/-22.6 %), and further supported the proposal of IM17-1(T) as a novel species. Strain IM17-1(T) ( = JCM 16576(T) = TISTR 1980(T)) thus represents a novel species of the genus Actinomadura, for which the name Actinomadura apis sp. nov. is proposed. In addition, the genotypic and phenotypic data suggested the reclassification of Actinomadura cremea subsp. rifamycini Gauze et al. 1987 as a separate species, Actinomadura rifamycini sp. nov., comb. nov. PMID- 20952542 TI - Ochrobactrum pecoris sp. nov., isolated from farm animals. AB - Two Gram-negative, rod-shaped, non-spore-forming strains, designated 08RB2639(T) and 08RB2781-1, were isolated from a sheep (Ovis aries) and a domestic boar (Sus scrofa domestica), respectively. By 16S rRNA gene sequencing, the isolates revealed identical sequences and were shown to belong to the Alphaproteobacteria. They exhibited 97.8 % 16S rRNA gene sequence similarity with Ochrobactrum rhizosphaerae PR17(T), O. pituitosum CCUG 50899(T), O. tritici SCII24(T) and O. haematophilum CCUG 38531(T) and 97.4 % sequence similarity with O. cytisi ESC1(T), O. anthropi LMG 3331(T) and O. lupini LUP21(T). The recA gene sequences of the two isolates showed only minor differences (99.5 % recA sequence similarity), and strain 08RB2639(T) exhibited the highest recA sequence similarity with Ochrobactrum intermedium CCUG 24694(T) (91.3 %). The quinone system was ubiquinone Q-10, with minor amounts of Q-9 and Q-11, the major polyamines were spermidine, putrescine and sym-homospermidine and the major lipids were phosphatidylethanolamine, phosphatidylmonomethylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and phosphatidylcholine, with moderate amounts of the Ochrobactrum-specific unidentified aminolipid AL2. The major fatty acids (>20 %) were C18:1omega7c and C19:0 cyclo omega8c. These traits were in excellent agreement with the assignment of the isolates to the genus Ochrobactrum. DNA-DNA relatedness and physiological and biochemical tests allowed genotypic and phenotypic differentiation from other members of the genus Ochrobactrum. Hence, it is concluded that the isolates represent a novel species, for which the name Ochrobactrum pecoris sp. nov. is proposed (type strain 08RB2639(T) = DSM 23868(T) = CCUG 60088(T) = CCM 7822(T)). PMID- 20952543 TI - Candidimonas nitroreducens gen. nov., sp. nov. and Candidimonas humi sp. nov., isolated from sewage sludge compost. AB - Two bacterial strains (SC-089(T) and SC-092(T)) isolated from sewage sludge compost were characterized by using a polyphasic approach. The isolates were Gram negative short rods, catalase- and oxidase-positive, and showed good growth at 30 degrees C, at pH 7 and with 1 % (w/v) NaCl. Ubiquinone 8 was the major respiratory quinone, and phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol were amongst the major polar lipids. On the basis of 16S rRNA gene sequence analysis, the strains were observed to be members of the family Alcaligenaceae, but could not be identified as members of any validly described genus. The low levels of 16S rRNA gene sequence similarity to other recognized taxa, together with comparative analysis of phenotypic traits and chemotaxonomic markers, supported the proposal of a new genus within the family Alcaligenaceae, for which the name Candidimonas gen. nov. is proposed. Strains SC 089(T) and SC-092(T), which shared 99.1 % 16S rRNA gene sequence similarity, could be differentiated at the phenotypic level, and DNA-DNA hybridization results supported their identification as representing distinct species. The names proposed for these novel species are Candidimonas nitroreducens sp. nov. (type strain, SC-089(T) = LMG 24812(T) = CCUG 55806(T)) and Candidimonas humi sp. nov. (type strain, SC-092(T) = LMG 24813(T) = CCUG 55807(T)). PMID- 20952544 TI - Rhodotorula bloemfonteinensis sp. nov., Rhodotorula eucalyptica sp. nov., Rhodotorula orientis sp. nov. and Rhodotorula pini sp. nov., yeasts isolated from monoterpene-rich environments. AB - Recent rDNA sequencing of 25 isolates from a previous study, during which limonene-utilizing yeasts were isolated from monoterpene-rich environments by using 1,4-disubstituted cyclohexanes as sole carbon sources, led to the identification of four hitherto unknown Rhodotorula species. Analyses of the 26S rDNA D1/D2 region as well as the internal transcribed spacer (ITS) domain indicated that two isolates (CBS 8499(T) and CBS 10736) were identical and were closely related to Rhodotorula cycloclastica, a previously described limonene utilizing yeast. These novel isolates differed from known yeast species and could be distinguished from R. cycloclastica by standard physiological tests. The other three isolates represent three novel Rhodotorula species, closely related to Sporobolomyces magnisporus. These three species could also be distinguished from other Rhodotorula species by standard physiological tests. Based on these results, we suggest that the new isolates represent novel species, for which the names Rhodotorula eucalyptica sp. nov. (type strain CBS 8499(T) = NRRL Y 48408(T)), Rhodotorula pini sp. nov. (type strain CBS 10735(T) = NRRL Y 48410(T)), Rhodotorula bloemfonteinensis sp. nov. (type strain CBS 8598(T) = NRRL Y-48407(T)) and Rhodotorula orientis sp. nov. (type strain CBS 8594(T) = NRRL Y-48719(T)) are proposed. R. eucalyptica and R. pini can also utilize limonene. PMID- 20952545 TI - Tistrella bauzanensis sp. nov., isolated from soil. AB - A Gram-reaction-negative, strictly aerobic, motile, rod-shaped bacterium, designated strain BZ78(T), was isolated from soil from an industrial site. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain BZ78(T) belonged to the family Rhodospirillaceae and formed a coherent cluster with the type strain of Tistrella mobilis (98.3 % pairwise similarity). The predominant cellular fatty acids of strain BZ78(T) were C18:1omega7c (58.3 %), C19:0omega8c cyclo (11.5 %), C18:1 2-OH (10.9 %) and C14:0 3-OH (6.4 %). The predominant ubiquinone was Q-10. The genomic DNA G+C content of strain BZ78(T) was 65.8 mol%. On the basis of phenotypic characteristics, phylogenetic analysis and DNA-DNA relatedness data, strain BZ78(T) is considered to represent a novel species of the genus Tistrella, for which the name Tistrella bauzanensis sp. nov. is proposed. The type strain is BZ78(T) ( = DSM 22817(T) = CGMCC 1.10188(T) = LMG 26047(T)). PMID- 20952546 TI - Pandoraea oxalativorans sp. nov., Pandoraea faecigallinarum sp. nov. and Pandoraea vervacti sp. nov., isolated from oxalate-enriched culture. AB - Five isolates, designated TA2, TA4, TA25(T), KOx(T) and NS15(T) were isolated in previous studies by enrichment in mineral medium with potassium oxalate as the sole carbon source and were characterized using a polyphasic approach. The isolates were Gram-reaction-negative, aerobic, non-spore-forming rods. Phylogenetic analyses based on 16S rRNA and DNA gyrase B subunit (gyrB) gene sequences confirmed that the isolates belonged to the genus Pandoraea and were most closely related to Pandoraea sputorum and Pandoraea pnomenusa (97.2-99.7 % 16S rRNA gene sequence similarity). The isolates could be differentiated from their closest relatives on the basis of several phenotypic characteristics. The major cellular fatty acid profiles of the isolates comprised C16:0, C18:1omega7c, C17:0 cyclo and summed feature 3 (C16:1omega7c and/or iso-C15:0 2-OH). On the basis of DNA-DNA hybridization studies and phylogenetic analyses, the isolates represent three novel species within the genus Pandoraea, for which the names Pandoraea oxalativorans sp. nov. (TA25(T) = NBRC 106091(T) = CCM 7677(T) = DSM 23570(T)), Pandoraea faecigallinarum sp. nov. (KOx(T) = NBRC 106092(T) = CCM 2766(T) = DSM 23572(T)) and Pandoraea vervacti sp. nov. (NS15(T) = NBRC 106088(T) = CCM 7667(T) = DSM 23571(T)) are proposed. PMID- 20952547 TI - Achromobacter marplatensis sp. nov., isolated from a pentachlorophenol contaminated soil. AB - A polyphasic taxonomic approach was applied to the study of a Gram-negative bacterium (B2(T)) isolated from soil by selective enrichment with pentachlorophenol. 16S rRNA gene sequence analysis of strain B2(T) showed that the strain belongs to the genus Achromobacter within the Betaproteobacteria. The 16S rRNA gene sequence displayed more than 99 % similarity to the sequences of the type strains of all species of Achromobacter, with the highest sequence similarity to those of Achromobacter spanius CCM 7183(T) and A. piechaudii CCM 2986(T) (99.8 %). On the basis of phylogenetic analysis, genomic DNA-DNA relatedness and phenotypic characteristics, including chemotaxonomic (cellular fatty acid profile) analysis, a novel species is proposed, Achromobacter marplatensis sp. nov., with the type strain B2(T) ( = CCM 7608(T) = CCUG 56371(T) = CECT 7342(T)). PMID- 20952548 TI - Salarchaeum japonicum gen. nov., sp. nov., an aerobic, extremely halophilic member of the Archaea isolated from commercial salt. AB - Strain YSM-79(T) was isolated from commercial salt made from seawater in Yonaguni island, Okinawa, Japan. The strain is an aerobic, Gram-negative, chemo organotrophic and extremely halophilic archaeon. Cells are short rods that lyse in distilled water. Growth occurs at 1.5-5.3 M NaCl (optimum 2.5-3.0 M), pH 5.0 8.8 (optimum pH 5.2-6.3) and 20-55 degrees C (optimum 40 degrees C). Mg2+ is required for growth, with maximum growth at 200-300 mM Mg2+. Polar lipid analysis revealed the presence of phosphatidylglycerol, phosphatidylglycerophosphate methyl ester, sulfated diglycosyl diether-1 and five unidentified glycolipids. The G+C content of the DNA was 64 mol%. On the basis of 16S rRNA gene sequence analysis, strain YSM-79(T) was determined to be a member of the family Halobacteriaceae, with the closest related genus being Halobacterium (94 % sequence identity). In addition, the rpoB' gene sequence of strain YSM-79(T) had <88 % sequence similarity to those of other members of the family Halobacteriaceae. The results of phenotypic, chemotaxonomic and phylogenetic analysis suggested that strain YSM-79(T) should be placed in a new genus, Salarchaeum gen. nov., as a representative of Salarchaeum japonicum sp. nov. The type strain is YSM-79(T) ( = JCM 16327(T) = CECT 7563(T)). PMID- 20952549 TI - Lysobacter korlensis sp. nov. and Lysobacter bugurensis sp. nov., isolated from soil. AB - Two Gram-reaction-negative, rod-shaped, gliding, yellow-pigmented bacterial strains, designated ZLD-17(T) and ZLD-29(T), were isolated from arid soil samples collected from Xinjiang Province, north-west China, and subjected to analysis using a polyphasic taxonomic approach. Both novel strains required 1.0-2.0 % (w/v) sea salts for optimal growth. Phylogenetic analysis based on 16S rRNA gene sequences indicated that these two strains belong to the genus Lysobacter within the class Gammaproteobacteria. Strain ZLD-17(T) showed highest 16S rRNA gene sequence similarities to Lysobacter capsici KCTC 22007(T) (96.9 %), Lysobacter spongiicola DSM 21749(T) (96.8 %) and Lysobacter koreensis KCTC 12204(T) (96.8 %), whereas strain ZLD-29(T) showed highest sequence similarities to Lysobacter niastensis DSM 18481(T) (96.0 %) and Lysobacter enzymogenes DSM 2043(T) (95.9 %). 16S rRNA gene sequence similarity between ZLD-17(T) and ZLD-29(T) was 96.1 %. The DNA G+C contents of strains ZLD-17(T) and ZLD-29(T) were 67.9 and 68.2 mol%, respectively. The major cellular fatty acids of both strains were summed feature 3 (iso-C15:0 2-OH and/or C16:1omega7c), iso-C17:1omega9c, iso-C16:0, C16:0 and iso-C11:0 3-OH; their predominant isoprenoid quinone was Q-8 and their major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. Based on their phenotypic characteristics, phylogenetic position as determined by 16S rRNA gene sequence analysis and chemotaxonomic data, strains ZLD-17(T) ( = CCTCC AB 207174(T) = KCTC 23076(T)) and ZLD-29(T) ( = CCTCC AB 207175(T) = KCTC 23077(T)) represent two novel species of the genus Lysobacter, for which the names Lysobacter korlensis sp. nov. and Lysobacter bugurensis sp. nov. are proposed, respectively. PMID- 20952550 TI - Dietzia alimentaria sp. nov., isolated from a traditional Korean food. AB - An actinobacterial strain, designated 72(T), was isolated from a traditional salt fermented seafood in Korea. Colonies were coral red and cells were Gram-reaction positive, non-motile rods. Strain 72(T) grew with 0-10 % (w/v) NaCl, at pH 7-10 and at 15-37 degrees C. Optimum growth conditions were 2 % NaCl, pH 7.0 and 30 degrees C. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that strain 72(T) belonged to the genus Dietzia. The major cellular fatty acids (>5 %) were C16:0, summed feature 3 (comprising C16:1omega6c and/or C16:1omega7c), 10-methyl C18:0, C17:0, C19:0 and C18:1omega9c. 16S rRNA gene sequence analysis and DNA-DNA hybridization, coupled with physiological and biochemical tests, revealed genotypic and phenotypic differences between strain 72(T) and other members of the genus Dietzia. Based on these data, strain 72(T) represents a novel species, for which the name Dietzia alimentaria sp. nov. is proposed. The type strain is 72(T) ( = JCM 16360(T) = KACC 21126(T)). PMID- 20952551 TI - Inhibition of human sterol Delta7-reductase and other postlanosterol enzymes by LK-980, a novel inhibitor of cholesterol synthesis. AB - Novel potential inhibitors of the postsqualene portion of cholesterol synthesis were screened in HepG2 cells. 2-(4-Phenethylpiperazin-1-yl)-1-(pyridine-3 yl)ethanol (LK-980) was identified as a prospective compound and was characterized further in cultures of human primary hepatocytes from seven donors. In vitro kinetic measurements show that the half-life of LK-980 is at least 4.3 h. LK-980 does not induce CYP3A4 mRNA nor enzyme activity. Target prediction was performed by gas chromatography-mass spectrometry, allowing simultaneous separation and quantification of nine late cholesterol intermediates. Experiments indicated that human sterol Delta(7)-reductase (DHCR7) is the major target of LK 980 (34-fold increase of 7-dehydrocholesterol), whereas human sterol Delta(14) reductase (DHCR14), human sterol Delta(24)-reductase (DHCR24), and human sterol C5-desaturase (SC5DL) represent minor targets. In the absence of purified enzymes, we used the mathematical model of cholesterol synthesis to evaluate whether indeed more than a single enzyme is inhibited. In silico inhibition of only DHCR7 modifies the flux of cholesterol intermediates, resulting in a sterol profile that does not support experimental data. Partial inhibition of the DHCR14, DHCR24, and SC5DL steps, in addition to DHCR7, supports the experimental sterol profile. In conclusion, we provide experimental and computational evidence that LK-980, a novel inhibitor from the late portion of cholesterol synthesis, inhibits primarily DHCR7 and to a lesser extent three other enzymes from this pathway. PMID- 20952552 TI - Application of quantitative NMR in pharmacological evaluation of biologically generated metabolites: implications in drug discovery. AB - It is important to gain an understanding of the pharmacological activities of metabolite(s) of compounds in development, especially if they are found in systemic circulation in humans. Pharmacological evaluation of metabolites is normally conducted with synthetic standards, which become available during various stages of drug development. However, the synthesis of metabolite standards may be protracted, taking anywhere from several weeks to months to be completed. This often slows down early pharmacological evaluation of metabolites. Once a metabolite(s) is found to possess comparable (or greater) pharmacological activity than the parent compound, additional studies are performed to better understand the implications of circulating pharmacologically active metabolite(s). To conduct some of these studies as early as possible without slowing the progression of a compound in development is important, especially if critical go or no-go decisions impinge on the outcomes from these studies. Early pharmacological evaluation of significant metabolites is hereby proposed to be conducted in the drug discovery stage so that all pertinent studies and information can be gathered in a timely manner for decision-making. It is suggested that these major metabolites be isolated, either from biological or chemical sources, and quantified appropriately. For biologically generated metabolites, NMR is proposed as the tool of choice to quantitate these metabolites before their evaluation in pharmacological assays. For metabolites that have the same UV characteristics as the parent compound, quantitation can be conducted using UV spectroscopy instead of NMR. In this article, we propose a strategy that could be used to determine the pharmacological activities of metabolites isolated in submilligram quantities. PMID- 20952553 TI - Does exposure to coal dust prevent or cause lung cancer? PMID- 20952554 TI - Exposure to brominated trihalomethanes in drinking water and reproductive outcomes. AB - OBJECTIVES: Exposure to disinfection by-products (DBPs) during pregnancy has been associated with adverse birth outcomes. We evaluated exposure to DBPs through ingestion, inhalation and dermal absorption among pregnant women in Crete, in relation to birth weight and gestational age. METHODS: The mother-child birth cohort in Crete ('Rhea' study) enrolled 1359 pregnant women at the third month of pregnancy (2007-2008), residents in the prefecture of Heraklion. Exposures were assessed through three questionnaires administered during pregnancy requesting extensive information on personal water-related habits. Tap water samples were collected in representative mother homes on the basis of detailed water distribution patterns, and were analysed for major DBPs including trihalomethanes (THMs). Logistic and linear regression models were applied. RESULTS: Pregnant women reported a high consumption of bottled water at home (76%) and work (96%). More than half the women (59%) washed dishes by hand, nearly all women (94%) took showers rather than baths (1%), and only 2% attended a swimming pool. THM levels were low (<20 MUg/l) with a high proportion of brominated compounds. When using quantitative estimates of residential exposure, we found no association with low birth weight (LBW, OR 0.7, 95% CI 0.4 to 1.4), small for gestational age for weight (SGAweight, OR 1.1, 95% CI 0.6 to 2.2) and preterm delivery (OR 0.8, 95% CI 0.5 to 1.3). Similar results were observed when taking into account uptake of THMs through all exposure routes. CONCLUSIONS: We found no evidence for an increased risk of LBW, SGA and preterm delivery at the relatively low level exposure to THMs and particularly brominated THMs in Cretan drinking water. PMID- 20952555 TI - Cohort mortality study of workers at seven beryllium processing plants: update and associations with cumulative and maximum exposure. AB - OBJECTIVES: To extend follow-up of cause-specific mortality in workers at seven beryllium processing plants and to estimate associations between mortality risk and beryllium exposure. METHODS: 9199 workers were followed for mortality from 1940 through 2005. Standardised mortality ratios (SMRs) were estimated based on US population comparisons for lung, nervous system and urinary tract cancers, chronic obstructive pulmonary disease (COPD), chronic kidney disease, and categories containing chronic beryllium disease (CBD) and cor pulmonale. Associations with maximum and cumulative exposure were calculated for a subset of the workers. RESULTS: Overall mortality in the cohort compared with the US population was elevated for lung cancer (SMR 1.17; 95% CI 1.08 to 1.28), COPD (SMR 1.23; 95% CI 1.13 to 1.32), and the categories containing CBD (SMR 7.80; 95% CI 6.26 to 9.60) and cor pulmonale (SMR 1.17; 95% CI 1.08 to 1.26). Mortality rates for most diseases of interest increased with time-since-hire. For the category including CBD, rates were substantially elevated compared to the US population across all exposure groups. Workers whose maximum beryllium exposure was >= 10 MUg/m(3) had higher rates of lung cancer, urinary tract cancer, COPD and the category containing cor pulmonale than workers with lower exposure. Significant positive trends with cumulative exposure were observed for nervous system cancers (p = 0.0006) and, when short-term workers were excluded, lung cancer (p = 0.01), urinary tract cancer (p = 0.003) and COPD (p < 0.0001). CONCLUSION: These findings reaffirm that lung cancer and CBD, and suggest that COPD and nervous system and urinary tract cancers, are related to beryllium exposure. Cigarette smoking and exposure to other lung carcinogens are unlikely to explain these elevations. PMID- 20952556 TI - Traffic-related air pollution and incident asthma in a high-risk birth cohort. AB - OBJECTIVES: The risk of incident asthma and bronchial hyper-reactivity associated with early life exposure to traffic-related air pollution has not been fully elucidated. We aimed to evaluate the hypothesis that the risk of new onset asthma is positively associated with early exposure to traffic-related air pollution in a well-characterised high-risk birth cohort. METHODS: Infants at high-risk for asthma were recruited for an intervention study. Birth year exposures to NO, NO(2), black carbon and PM(2.5) were estimated by land use regression. At 7 years of age, asthma was assessed by a paediatric allergist and bronchial hyper reactivity was measured by methacholine challenge. Associations between exposures and outcomes were analysed by stepwise multiple logistic regression, adjusted for potential confounding variables. RESULTS: Exposure estimates were available for 184 children; 23 were diagnosed with asthma and 68 with bronchial hyper reactivity. The IQR (4.1 MUg/m(3)) of birth year PM(2.5) was associated with a significantly increased risk of asthma (OR 3.1, 95% CI 1.3 to 7.4) and with a trend to increased risk of bronchial hyper-reactivity. Similar findings were noted in association with NO and NO(2), while black carbon did not appear to confer increased risk. CONCLUSION: Modest elevations in exposure to some traffic related air pollutants during the year of birth are associated with new onset asthma assessed at age 7. That significant associations were revealed in spite of a limited sample size emphasises the strengths of a high-risk birth cohort model, along with individual air pollution exposure estimates and well-characterised data on covariates and outcomes. PMID- 20952557 TI - Medical surveillance programme for diisocyanate exposure. AB - OBJECTIVES: Surveillance programmes for occupational asthma should reduce the severity of asthma both at the time of diagnosis and after removal from exposure as well as costs related to functional impairment. The aim of this study was to compare the severity and cost of diisocyanate-induced occupational asthma in workers participating in a surveillance programme and in twice the number of workers diagnosed after being referred by their physician. METHODS: Answers to a self-administered questionnaire led to possible referral for further assessment that included methacholine testing and specific inhalation challenges as the gold standard for confirming occupational asthma. Results Of the 2897 workers who participated, 182 (6.3%) had a positive questionnaire. 79/182 (43%) were referred for further medical assessment and 20 had confirmed occupational asthma by specific inhalation testing. At the time of diagnosis, the 20 screened subjects had a mean PC(20) of 3.35 mg/ml as compared to 1.50 mg/ml (p = 0.05) in the 66 controls. Two years after diagnosis and removal from exposure, the 20 subjects screened had a mean PC(20) of 4.81 mg/ml compared to 1.67 mg/ml (p = 0.03) in controls. Clinical remission occurred in 34% of the screened group compared to 16% of the control group (p = 0.02). The median costs for functional impairment were $C11,900 in screened subjects and $C19,600 in controls (p = 0.04). CONCLUSIONS: Subjects with occupational asthma screened by a medical surveillance programme have a better outcome both at the time of diagnosis and 2 years after removal from exposure, with lower compensation costs compared to controls. PMID- 20952558 TI - Impact of a direct access occupational physiotherapy treatment service. AB - BACKGROUND: Musculoskeletal disorders (MSDs) cause significant morbidity and absence from work for both manual and sedentary occupations. AIMS: To examine the impact of a direct access physiotherapy treatment service in an occupational setting. METHODS: This was a pilot study carried out as a service audit. Physiotherapy patients were assessed pre- and post-treatment using the work function score (WFS), a visual analogue scale for pain (VASP) and adjusted clinical score (ACS). Self-report questionnaires were completed on sickness absence, attendance at work and the World Health Organization (five) Well-being Index. RESULTS: There were 231 participants. Patient improvement was reported in WFS (63%), ACS (84%) and VASP (94%). Compared with those who had one or two sessions, improvement was most likely after three to four sessions for WFS [odds ratio (OR): 4.5; 95% confidence interval: 1.4-14.3, P < 0.05], VASP (OR: 32.2; 95% confidence interval: 3.5-294.2, P < 0.01) and five to six sessions for ACS (OR: 6.9; 95% confidence interval: 1.9-25.9, P < 0.01). While the self-reported questionnaire response rate was low at 29%, respondents indicated that there was potential to reduce and prevent sickness absence and improve mental well-being. CONCLUSIONS: Brief physiotherapy treatment for MSDs may have the potential to improve not only clinical status and pain as expected but also work function, psychological well-being and sickness absence. Further research is warranted to confirm these positive impacts and to endorse physiotherapy as an effective intervention in occupational settings and a useful component in rehabilitation and 'Fit for Work' programmes. PMID- 20952559 TI - Health consequences of pipe versus cigarette smoking. AB - OBJECTIVES: To estimate the risk of dying from all causes and from specified smoking-related diseases in men who were exclusive daily pipe smokers at two consecutive examinations, and in men who switched from smoking cigarettes only to pipe only. DESIGN: A prospective cohort study. SETTING: Three counties in Norway. PARTICIPANTS: 16, 932 men, aged 20-49, screened for cardiovascular disease risk factors in the mid-1970s, re-screened after 3-13 years, and followed throughout 2007. OUTCOMES: Absolute mortality and relative risks adjusted for confounding variables, of dying from all causes and ischaemic heart disease, stroke, cardiovascular disease, lung cancer and other smoking-related cancer. RESULTS: Altogether, the men were observed for 403, 327 years, and during the observation period, 4933 deaths occurred. With sustained never smokers as reference, the sustained smokers of a pipe only had adjusted relative risk (95% CI), of dying from any cause that was 1.99 (1.73 to 2.27). At comparable tobacco consumption, no significant difference in risk between pipe and cigarette smokers appeared. As to survival, no difference was found between sustained smokers of a pipe only and of cigarettes only. Men who switched from cigarettes only to pipe only had a risk which was not significantly different from the risk in sustained smokers of cigarettes only. CONCLUSIONS: Between pipe and cigarette smokers, no or only minor differences were found in mortality from any cause and the specified smoking-related diseases. Pipe smoking is not safer than cigarette smoking. PMID- 20952560 TI - Relationship between the Chinese tobacco industry and academic institutions in China. AB - OBJECTIVE: To investigate the relationship between the Chinese tobacco industry and academic institutions in China. METHODS: We searched online databases of journal articles published in both Chinese and English for academic institutions in China conducting research with or sponsored by Chinese tobacco companies. We also searched the websites of tobacco companies, their affiliated institutions and academic institutions for reports of collaborations. RESULTS: The Chinese tobacco industry, in addition to its own strong tobacco research capacity, maintains close ties with an extensive network of academic research institutions and universities to provide both research and training. The Chinese tobacco industry relies heavily upon academic researchers to advance its research agenda and such reliance has grown over time. Most research deals with farming, manufacturing and management issues, but research on 'reduced harm' and health effects has increased from 1% of projects in 1983-1987 to 4% in 2003-2007. CONCLUSIONS: Chinese academic institutions should consider the fact that engagement with the tobacco industry, particularly on issues related to health or promotion of tobacco products, could damage their reputations, a concern that has led many leading Western universities to eschew relationships with the tobacco industry. To the extent that the Chinese tobacco industry's involvement in academic institutions affects tobacco control policy making; it violates Article 5.3 of Framework Convention on Tobacco Control, which China ratified in 2005. PMID- 20952563 TI - Criminal trial highlights Queensland's "archaic" abortion law. PMID- 20952561 TI - Behavioral/lifestyle and immunologic factors associated with HPV infection among women older than 45 years. AB - BACKGROUND: Cervical human papilloma virus (HPV) detection increases after menopause, but its determinants need clarification. METHODS: In a case-control study nested within a 10,049 women cohort, we evaluated women 45 to 75 years old who acquired HPV infection and were HPV positive 5 to 6 years after enrollment (N = 252), and HPV-negative women as matched controls (N = 265). Detailed sexual behavior and cellular immune response were investigated. Odds ratios (OR) and attributable fractions were estimated. RESULTS: Women with 2+ lifetime partners had 1.7-fold (95% CI = 1.1-2.7) higher risk than monogamous women, with similar findings if their partners had other partners. Women with 2+ partners after last HPV-negative result had the highest risk (OR = 3.9; 95% CI = 1.2-12.4 compared with 0-1 partners). Weaker immune response to HPV-16 virus-like particles increased risk (OR = 1.7; 95% CI = 1.1-2.7 comparing lowest to highest tertile). Among women with no sexual activity in the period before HPV appearance, reduced immune response to phytohemagglutinin was the only determinant (OR = 2.9; 95% CI = 0.94-8.8). Twenty-one percent of infections were explained by recent sexual behavior, 21% by past sexual behavior, and 12% by reduced immune response. CONCLUSIONS: New infections among older women may result from sexual activity of women and/or their partners or reappearance of past (latent) infections possibly related to weakened immune response. IMPACT: HPV infections among older women are associated with current and past sexual exposures and possibly with immune senescence. The risk of cancer from these infections is likely to be low but could not be fully evaluated in the context of this study. PMID- 20952564 TI - White mother given mixed race sperm in IVF loses compensation claim. PMID- 20952566 TI - Genome of Helicobacter pylori strain 908. AB - Helicobacter pylori is a genetically diverse and coevolved pathogen inhabiting human gastric niches and leading to a spectrum of gastric diseases in susceptible populations. We describe the genome sequence of H. pylori 908, which was originally isolated from an African patient living in France who suffered with recrudescent duodenal ulcer disease. The strain was found to be phylogenetically related to H. pylori J99, and its comparative analysis revealed several specific genome features and novel insertion-deletion and substitution events. The genome sequence revealed several strain-specific deletions and/or gain of genes exclusively present in HP908 compared with different sequenced genomes already available in the public domain. Comparative and functional genomics of HP908 and its subclones will be important in understanding genomic plasticity and the capacity to colonize and persist in a changing host environment. PMID- 20952567 TI - Genome sequence of the biocontrol agent Pantoea vagans strain C9-1. AB - Pantoea vagans is a Gram-negative enterobacterial plant epiphyte of a broad range of plants. Here we report the 4.89-Mb genome sequence of P. vagans strain C9-1 (formerly Pantoea agglomerans), which is commercially registered for biological control of fire blight, a disease of pear and apple trees caused by Erwinia amylovora. PMID- 20952568 TI - Genomic island 2 is an unstable genetic element contributing to Brucella lipopolysaccharide spontaneous smooth-to-rough dissociation. AB - Brucella is a Gram-negative bacterium that causes a worldwide-distributed zoonosis. The genus includes smooth (S) and rough (R) species that differ in the presence or absence, respectively, of the O-polysaccharide of lipopolysaccharide. In S brucellae, the O-polysaccharide is a critical diagnostic antigen and a virulence determinant. However, S brucellae spontaneously dissociate into R forms, a problem in antigen and S vaccine production. Spontaneous R mutants of Brucella abortus, Brucella melitensis, and Brucella suis carried the chromosomal scar corresponding to genomic island 2 (GI-2) excision, an event causing the loss of the wboA and wboB O-polysaccharide genes, and the predicted excised circular intermediate was identified in B. abortus, B. melitensis, and B. suis cultures. Moreover, disruption of a putative phage integrase gene in B. abortus GI-2 caused a reduction in O-polysaccharide loss rates under conditions promoting S-R dissociation. However, spontaneous R mutants not carrying the GI-2 scar were also detected. These results demonstrate that the phage integrase-related GI-2 excision is a cause of S-R brucella dissociation and that other undescribed mechanisms must also be involved. In the R Brucella species, previous works have shown that Brucella ovis but not Brucella canis lacks GI-2, and a chromosomal scar identical to those in R mutants was observed. These results suggest that the phage integrase-promoted GI-2 excision played a role in B. ovis speciation and are consistent with other evidence, suggesting that this species and B. canis have emerged as two independent lineages. PMID- 20952569 TI - Genome sequence of Leuconostoc argentinum KCTC 3773. AB - Leuconostoc argentinum is one of the most prevalent lactic acid bacteria present during the manufacturing process of kimchi, the best-known traditional Korean dish. Here, we present the draft genome sequence of type strain KCTC 3773 of Leuconostoc argentinum (1,720,683 bp, with a G+C content of 42.9%), which consists of 98 large contigs (>100 bp in size). PMID- 20952570 TI - Shining a light on an opportunistic pathogen. PMID- 20952572 TI - Sighting the alien within: a new look at Bdellovibrio. PMID- 20952571 TI - Genome sequence of the obligate methanotroph Methylosinus trichosporium strain OB3b. AB - Methylosinus trichosporium OB3b (for "oddball" strain 3b) is an obligate aerobic methane-oxidizing alphaproteobacterium that was originally isolated in 1970 by Roger Whittenbury and colleagues. This strain has since been used extensively to elucidate the structure and function of several key enzymes of methane oxidation, including both particulate and soluble methane monooxygenase (sMMO) and the extracellular copper chelator methanobactin. In particular, the catalytic properties of soluble methane monooxygenase from M. trichosporium OB3b have been well characterized in context with biodegradation of recalcitrant hydrocarbons, such as trichloroethylene. The sequence of the M. trichosporium OB3b genome is the first reported from a member of the Methylocystaceae family in the order Rhizobiales. PMID- 20952573 TI - BglJ-RcsB heterodimers relieve repression of the Escherichia coli bgl operon by H NS. AB - RcsB is the response regulator of the complex Rcs two-component system, which senses perturbations in the outer membrane and peptidoglycan layer. BglJ is a transcriptional regulator whose constitutive expression causes activation of the H-NS- and StpA-repressed bgl (aryl-beta,D-glucoside) operon in Escherichia coli. RcsB and BglJ both belong to the LuxR-type family of transcriptional regulators with a characteristic C-terminal DNA-binding domain. Here, we show that BglJ and RcsB interact and form heterodimers that presumably bind upstream of the bgl promoter, as suggested by mutation of a sequence motif related to the consensus sequence for RcsA-RcsB heterodimers. Heterodimerization of BglJ-RcsB and relief of H-NS-mediated repression of bgl by BglJ-RcsB are apparently independent of RcsB phosphorylation. In addition, we show that LeuO, a pleiotropic LysR-type transcriptional regulator, likewise binds to the bgl upstream regulatory region and relieves repression of bgl independently of BglJ-RcsB. Thus, LeuO can affect bgl directly, as shown here, and indirectly by activating the H-NS-repressed yjjQ bglJ operon, as shown previously. Taken together, heterodimer formation of RcsB and BglJ expands the role of the Rcs two-component system and the network of regulators affecting the bgl promoter. PMID- 20952574 TI - Expression of the Streptomyces coelicolor SoxR regulon is intimately linked with actinorhodin production. AB - The [2Fe-2S]-containing transcription factor SoxR is conserved in diverse bacteria. SoxR is traditionally known as the regulator of a global oxidative stress response in Escherichia coli, but recent studies suggest that this function may be restricted to enteric bacteria. In the vast majority of nonenterics, SoxR is predicted to mediate a response to endogenously produced redox-active metabolites. We have examined the regulation and function of the SoxR regulon in the model antibiotic-producing filamentous bacterium Streptomyces coelicolor. Unlike the E. coli soxR deletion mutant, the S. coelicolor equivalent is not hypersensitive to oxidants, indicating that SoxR does not potentiate antioxidant defense in the latter. SoxR regulates five genes in S. coelicolor, including those encoding a putative ABC transporter, two oxidoreductases, a monooxygenase, and a possible NAD-dependent epimerase/dehydratase. Expression of these genes depends on the production of the benzochromanequinone antibiotic actinorhodin and requires intact [2Fe-2S] clusters in SoxR. These data indicate that actinorhodin, or a redox-active precursor, modulates SoxR activity in S. coelicolor to stimulate the production of a membrane transporter and proteins with homology to actinorhodin-tailoring enzymes. While the role of SoxR in S. coelicolor remains under investigation, these studies support the notion that SoxR has been adapted to perform distinct physiological functions to serve the needs of organisms that occupy different ecological niches and face different environmental challenges. PMID- 20952575 TI - DosS responds to a reduced electron transport system to induce the Mycobacterium tuberculosis DosR regulon. AB - The DosR regulon in Mycobacterium tuberculosis is involved in respiration limiting conditions, its induction is controlled by two histidine kinases, DosS and DosT, and recent experimental evidence indicates DosS senses either molecular oxygen or a redox change. Under aerobic conditions, induction of the DosR regulon by DosS, but not DosT, was observed after the addition of ascorbate, a powerful cytochrome c reductant, demonstrating that DosS responds to a redox signal even in the presence of high oxygen tension. During hypoxic conditions, regulon induction was attenuated by treatment with compounds that occluded electron flow into the menaquinone pool or decreased the size of the menaquinone pool itself. Increased regulon expression during hypoxia was observed when exogenous menaquinone was added, demonstrating that the menaquinone pool is a limiting factor in regulon induction. Taken together, these data demonstrate that a reduced menaquinone pool directly or indirectly triggers induction of the DosR regulon via DosS. Biochemical analysis of menaquinones upon entry into hypoxic/anaerobic conditions demonstrated the disappearance of the unsaturated species and low-level maintenance of the mono-saturated menaquinone. Relative to the unsaturated form, an analog of the saturated form is better able to induce signaling via DosS and rescue inhibition of menaquinone synthesis and is less toxic. The menaquinone pool is central to the electron transport system (ETS) and therefore provides a mechanistic link between the respiratory state of the bacilli and DosS signaling. Although this report demonstrates that DosS responds to a reduced ETS, it does not rule out a role for oxygen in silencing signaling. PMID- 20952576 TI - The putative assembly factor CcoH is stably associated with the cbb3-type cytochrome oxidase. AB - Cytochrome oxidases are perfect model substrates for analyzing the assembly of multisubunit complexes because the need for cofactor incorporation adds an additional level of complexity to their assembly. cbb(3)-type cytochrome c oxidases (cbb(3)-Cox) consist of the catalytic subunit CcoN, the membrane-bound c type cytochrome subunits CcoO and CcoP, and the CcoQ subunit, which is required for cbb(3)-Cox stability. Biogenesis of cbb(3)-Cox proceeds via CcoQP and CcoNO subcomplexes, which assemble into the active cbb(3)-Cox. Most bacteria expressing cbb(3)-Cox also contain the ccoGHIS genes, which encode putative cbb(3)-Cox assembly factors. Their exact function, however, has remained unknown. Here we analyzed the role of CcoH in cbb(3)-Cox assembly and showed that CcoH is a single spanning-membrane protein with an N-terminus-out-C-terminus-in (N(out)-C(in)) topology. In its absence, neither the fully assembled cbb(3)-Cox nor the CcoQP or CcoNO subcomplex was detectable. By chemical cross-linking, we demonstrated that CcoH binds primarily via its transmembrane domain to the CcoP subunit of cbb(3) Cox. A second hydrophobic stretch, which is located at the C terminus of CcoH, appears not to be required for contacting CcoP, but deleting it prevents the formation of the active cbb(3)-Cox. This suggests that the second hydrophobic domain is required for merging the CcoNO and CcoPQ subcomplexes into the active cbb(3)-Cox. Surprisingly, CcoH does not seem to interact only transiently with the cbb(3)-Cox but appears to stay tightly associated with the active, fully assembled complex. Thus, CcoH behaves more like a bona fide subunit of the cbb(3) Cox than an assembly factor per se. PMID- 20952577 TI - Biochemical characterization of individual components of the Allochromatium vinosum DsrMKJOP transmembrane complex aids understanding of complex function in vivo. AB - The DsrMKJOP transmembrane complex has a most important function in dissimilatory sulfur metabolism and consists of cytoplasmic, periplasmic, and membrane integral proteins carrying FeS centers and b- and c-type cytochromes as cofactors. In this study, the complex was isolated from the purple sulfur bacterium Allochromatium vinosum and individual components were characterized as recombinant proteins. The two integral membrane proteins DsrM and DsrP were successfully produced in Escherichia coli C43(DE3) and C41(DE3), respectively. DsrM was identified as a diheme cytochrome b, and the two hemes were found to be in low-spin state. Their midpoint redox potentials were determined to be +60 and +110 mV. Although no hemes were predicted for DsrP, it was also clearly identified as a b-type cytochrome. To the best of our knowledge, this is the first time that heme binding has been experimentally proven for a member of the NrfD protein family. Both cytochromes were partly reduced after addition of a menaquinol analogue, suggesting interaction with quinones in vivo. DsrO and DsrK were both experimentally proven to be FeS-containing proteins. In addition, DsrK was shown to be membrane associated, and we propose a monotopic membrane anchoring for this protein. Coelution assays provide support for the proposed interaction of DsrK with the soluble cytoplasmic protein DsrC, which might be its substrate. A model for the function of DsrMKJOP in the purple sulfur bacterium A. vinosum is presented. PMID- 20952578 TI - Role of porins in iron uptake by Mycobacterium smegmatis. AB - Many bacteria rely on siderophores to extract iron from the environment. However, acquisition of iron-loaded siderophores is dependent on high-affinity uptake systems that are not produced under high-iron conditions. The fact that bacteria are able to maintain iron homeostasis in the absence of siderophores indicates that alternative iron acquisition systems exist. It has been speculated that such low-affinity uptake of iron in Gram-negative bacteria includes diffusion of iron ions or chelates across the outer membrane through porins. The outer membrane of the saprophytic Mycobacterium smegmatis contains the Msp family of porins, which enable the diffusion of small and hydrophilic solutes, such as monosaccharides, amino acids, and phosphate. However, it is unknown how cations cross the outer membrane of mycobacteria. Here, we show that the Msp porins of M. smegmatis are involved in the acquisition of soluble iron under high-iron conditions. Uptake of ferric ions by a triple porin mutant was reduced compared to wild-type (wt) M. smegmatis. An intracellular iron reporter indicated that derepression of iron responsive genes occurs at higher iron concentrations in the porin mutant. This was consistent with the finding that the porin mutant produced more siderophores under low-iron conditions than wt M. smegmatis. In contrast, uptake of the exochelin MS, the main siderophore of M. smegmatis, was not affected by the lack of porins, indicating that a specific outer membrane siderophore receptor exists. These results provide, to our knowledge, the first experimental evidence that general porins are indeed the outer membrane conduit of low-affinity iron acquisition systems in bacteria. PMID- 20952579 TI - Instability of ackA (acetate kinase) mutations and their effects on acetyl phosphate and ATP amounts in Streptococcus pneumoniae D39. AB - Acetyl phosphate (AcP) is a small-molecule metabolite that can act as a phosphoryl group donor for response regulators of two-component systems (TCSs). The serious human respiratory pathogen Streptococcus pneumoniae (pneumococcus) synthesizes AcP by the conventional pathway involving phosphotransacetylase and acetate kinase, encoded by pta and ackA, respectively. In addition, pneumococcus synthesizes copious amounts of AcP and hydrogen peroxide (H(2)O(2)) by pyruvate oxidase, which is encoded by spxB. To assess possible roles of AcP in pneumococcal TCS regulation and metabolism, we constructed strains with combinations of spxB, pta, and ackA mutations and determined their effects on ATP, AcP, and H(2)O(2) production. Unexpectedly, DeltaackA mutants were unstable and readily accumulated primary suppressor mutations in spxB or its positive regulator, spxR, thereby reducing H(2)O(2) and AcP levels, and secondary capsule mutations in cps2E or cps2C. DeltaackA DeltaspxB mutants contained half the cellular amount of ATP as a DeltaspxB or spxB(+) strain. Acetate addition and anaerobic growth experiments suggested decreased ATP, rather than increased AcP, as a reason that DeltaackA mutants accumulated spxB or spxR suppressors, although experimental manipulation of the AcP amount was limited. This finding and other considerations suggest that coping with endogenously produced H(2)O(2) may require energy. Starting with a DeltaspxB mutant, we constructed Deltapta, DeltaackA, and Deltapta DeltaackA mutants. Epistasis and microarray experiment results were consistent with a role for the SpxB-Pta-AckA pathway in expression of the regulons controlled by the WalRK(Spn), CiaRH(Spn), and LiaSR(Spn) TCSs involved in sensing cell wall status. However, AcP likely does not play a physiological role in TCS sensing in S. pneumoniae. PMID- 20952580 TI - Hal4 and Hal5 protein kinases are required for general control of carbon and nitrogen uptake and metabolism. AB - The yeast protein kinases Sat4/Hal4 and Hal5 are required for the plasma membrane stability of the K(+) transporter Trk1 and some amino acid and glucose permeases. The transcriptomic analysis presented here indicates alterations in the general control of the metabolism of both nitrogen and carbon. Accordingly, we observed reduced uptake of methionine and leucine in the hal4 hal5 mutant. This decrease correlates with activation of the Gcn2-Gcn4 pathway, as measured by expression of the lacZ gene under the control of the GCN4 promoter. However, with the exception of methionine biosynthetic genes, few amino acid biosynthetic genes are induced in the hal4 hal5 mutant, whereas several genes involved in amino acid catabolism are repressed. Concerning glucose metabolism, we found that this mutant exhibits derepression of respiratory genes in the presence of glucose, leading to an increased activity of mitochondrial enzymes, as measured by succinate dehydrogenase (SDH) activity. In addition, the reduced glucose consumption in the hal4 hal5 mutant correlates with a more acidic intracellular pH and with low activity of the plasma membrane H(+)-ATPase. As a compensatory mechanism for the low glycolytic rate, the hal4 hal5 mutant overexpresses the HXT4 high-affinity glucose transporter and the hexokinase genes. These results indicate that the hal4 hal5 mutant presents defects in the general control of nitrogen and carbon metabolism, which correlate with reduced transport of amino acids and glucose, respectively. A more acidic intracellular pH may contribute to some defects of this mutant. PMID- 20952581 TI - A mutant defective in sexual development produces aseptate ascogonia. AB - The transition from the vegetative to the sexual cycle in filamentous ascomycetes is initiated with the formation of ascogonia. Here, we describe a novel type of sterile mutant from Sordaria macrospora with a defect in ascogonial septum formation. This mutant, named pro22, produces only small, defective protoperithecia and carries a point mutation in a gene encoding a protein that is highly conserved throughout eukaryotes. Sequence analyses revealed three putative transmembrane domains and a C-terminal domain of unknown function. Live-cell imaging showed that PRO22 is predominantly localized in the dynamic tubular and vesicular vacuolar network of the peripheral colony region close to growing hyphal tips and in ascogonia; it is absent from the large spherical vacuoles in the vegetative hyphae of the subperipheral region of the colony. This points to a specific role of PRO22 in the tubular and vesicular vacuolar network, and the loss of intercalary septation in ascogonia suggests that PRO22 functions during the initiation of sexual development. PMID- 20952582 TI - Functional characterization of a new member of the Cdk9 family in Aspergillus nidulans. AB - Cdk9-like kinases in complex with T-type cyclins are essential components of the eukaryotic transcription elongation machinery. The full spectrum of Cdk9/cyclin T targets, as well as the specific consequences of phosphorylations, is still largely undefined. We identify and characterize here a Cdk9 kinase (PtkA) in the filamentous ascomycete Aspergillus nidulans. Deletion of ptkA had a lethal effect in later stages of vegetative growth and completely impeded asexual development. Overexpression of ptkA affected directionality of polarized growth and the initiation of new branching sites. A green fluorescent protein-tagged PtkA version localized inside the nucleus during interphase, supporting a role of PtkA in transcription elongation, as observed in other organisms. We also identified a putative cyclin T homolog, PchA, in the A. nidulans genome and confirmed its interaction with PtkA in vivo. Surprisingly, the Pcl-like cyclin PclA, previously described to be involved in asexual development, was also found to interact with PtkA, indicating a possible role of PtkA in linking transcriptional activity with development and/or morphogenesis in A. nidulans. This is the first report of a Cdk9 kinase interacting with a Pcl-like cyclin, revealing interesting new aspects about the involvement of this Cdk-subfamily in differential gene expression. PMID- 20952583 TI - Metformin use and mortality in ambulatory patients with diabetes and heart failure. AB - BACKGROUND: Despite the common coexistence of diabetes and heart failure (HF), the optimal medial treatment of diabetes in HF patients has not been well studied. We sought to compare the association between metformin use and clinical outcomes in a cohort of ambulatory patients with diabetes and established HF. METHODS AND RESULTS: Using propensity score-matched samples, we examined the association between metformin use and the risk of death or risk of hospitalization in a national cohort of 6185 patients with HF and diabetes treated in ambulatory clinics at Veteran Affairs medical centers. In this cohort, 1561 (25.2%) patients were treated with metformin. At 2 years of follow-up, death occurred in 246 (15.8%) patients receiving metformin and in 1177 (25.5%) patients not receiving metformin (P<0.001). In the propensity score-matched analysis (n=2874), death occurred in 232 (16.1%) patients receiving metformin compared with 285 (19.8%) patients not receiving metformin (hazard ratio, 0.76; 95% confidence interval, 0.63 to 0.92; P<0.01). In propensity score-matched analyses, HF hospitalization or total hospitalization rates were not significantly different between individuals treated with metformin compared with those not treated with metformin (hazard ratio, 0.93; 95% confidence interval, 0.74 to 1.18; and hazard ratio, 0.94; 95% confidence interval, 0.83 to 1.07, respectively). CONCLUSIONS: Metformin therapy was associated with lower rates of mortality in ambulatory patients with diabetes and HF. Future prospective studies are necessary to define the optimal therapy for diabetic patients with HF. PMID- 20952584 TI - Autoimmunity to desmocollin 3 in pemphigus vulgaris. AB - Pemphigus vulgaris is a blistering disease associated with autoantibodies to the desmosomal adhesion protein, desmoglein 3. Genetic deficiency of desmoglein 3 in mice mimics autoimmunity to desmoglein 3 in pemphigus vulgaris, with mucosal dominant blistering in the suprabasal layer of the epidermis. Mice with an epidermal-specific deletion of desmocollin 3, the other major desmosomal cadherin isoform expressed in the basal epidermis, develop suprabasal blisters in skin that are histologically identical to those observed in pemphigus vulgaris, suggesting that desmocollin 3 might be a target of autoantibodies in some pemphigus vulgaris patients. We now demonstrate that desmocollin 3 is an autoantigen in pemphigus vulgaris, illustrated in a patient with mucosal-dominant blistering. Six of 38 pemphigus vulgaris and one of 85 normal serum samples immunoprecipitate desmocollin 3 (P = 0.003). Incubation of patient IgG with human keratinocytes causes loss of intercellular adhesion, and adsorption with recombinant desmocollin 3 specifically prevents this pathogenic effect. Additionally, anti-desmocollin 3 sera cause loss of keratinocyte cell surface desmocollin 3, but not desmoglein 3 by immunofluorescence, indicating distinct cellular pathogenic effects in anti-desmocollin and anti-desmoglein pemphigus, despite their identical clinical presentations. These data demonstrate that desmocollin 3 is a pathogenic autoantigen in pemphigus vulgaris and suggest that pemphigus vulgaris is a histological reaction pattern that may result from autoimmunity to desmoglein 3, desmocollin 3, or both desmosomal cadherins. PMID- 20952585 TI - The alternative and terminal pathways of complement mediate post-traumatic spinal cord inflammation and injury. AB - Complement is implicated in the inflammatory response and the secondary neuronal damage that occurs after traumatic spinal cord injury (SCI). Complement can be activated by the classical, lectin, or alternative pathways, all of which share a common terminal pathway that culminates in formation of the cytolytic membrane attack complex (MAC). Here, we investigated the role of the alternative and terminal complement pathways in SCI. Mice deficient in the alternative pathway protein factor B (fB) were protected from traumatic SCI in terms of reduced tissue damage and demyelination, reduced inflammatory cell infiltrate, and improved functional recovery. In a clinically relevant paradigm, treatment of mice with an anti-fB mAb resulted in similarly improved outcomes. These improvements were associated with decreased C3 and fB deposition. On the other hand, deficiency of CD59, an inhibitor of the membrane attack complex, resulted in significantly increased injury and impaired functional recovery compared to wild-type mice. Increased injury in CD59-deficient mice was associated with increased MAC deposition, while levels of C3 and fB were unaffected. These data indicate key roles for the alternative and terminal complement pathways in the pathophysiology of SCI. Considering a previous study demonstrating an important role for the classical pathway in promoting SCI, it is likely that the alternative pathway plays a critical role in amplifying classical pathway initiated complement activation. PMID- 20952586 TI - Targeted modulation of the neuroinflammatory response after spinal cord injury: the ongoing quest for the "holy grail". AB - This Commentary discusses the role of inflammation after spinal cord injury. PMID- 20952587 TI - Angiopoietin-like 4 interacts with integrins beta1 and beta5 to modulate keratinocyte migration. AB - Adipose tissue secretes adipocytokines for energy homeostasis, but recent evidence indicates that some adipocytokines also have a profound local impact on wound healing. Upon skin injury, keratinocytes use various signaling molecules to promote reepithelialization for efficient wound closure. In this study, we identify a novel function of adipocytokine angiopoietin-like 4 (ANGPTL4) in keratinocytes during wound healing through the control of both integrin-mediated signaling and internalization. Using two different in vivo models based on topical immuno-neutralization of ANGPTL4 as well as ablation of the ANGPTL4 gene, we show that ANGPTL4-deficient mice exhibit delayed wound reepithelialization with impaired keratinocyte migration. Human keratinocytes in which endogenous ANGPTL4 expression was suppressed by either siRNA or a neutralizing antibody show impaired migration associated with diminished integrin-mediated signaling. Importantly, we identify integrins beta1 and beta5, but not beta3, as novel binding partners of ANGPTL4. ANGPTL4-bound integrin beta1 activated the FAK-Src PAK1 signaling pathway, which is important for cell migration. The findings presented herein reveal an unpredicted role of ANGPTL4 during wound healing and demonstrate how ANGPTL4 stimulates intracellular signaling mechanisms to coordinate cellular behavior. Our findings provide insight into a novel cell migration control mechanism and underscore the physiological importance of the modulation of integrin activity in cancer metastasis. PMID- 20952588 TI - PTP1B suppresses prolactin activation of Stat5 in breast cancer cells. AB - Basal levels of nuclear localized, tyrosine phosphorylated Stat5 are present in healthy human breast epithelia. In contrast, Stat5 phosphorylation is frequently lost during breast cancer progression, a finding that correlates with loss of histological differentiation and poor patient prognosis. Identifying the mechanisms underlying loss of Stat5 phosphorylation could provide novel targets for breast cancer therapy. Pervanadate, a general tyrosine phosphatase inhibitor, revealed marked phosphatase regulation of Stat5 activity in breast cancer cells. Lentiviral-mediated shRNA allowed specific examination of the regulatory role of five tyrosine phosphatases (PTP1B, TC-PTP, SHP1, SHP2, and VHR), previously implicated in Stat5 regulation in various systems. Enhanced and sustained prolactin-induced Stat5 tyrosine phosphorylation was observed in T47D and MCF7 breast cancer cells selectively in response to PTP1B depletion. Conversely, PTP1B overexpression suppressed prolactin-induced Stat5 tyrosine phosphorylation. Furthermore, PTP1B knockdown increased Stat5 reporter gene activity. Mechanistically, PTP1B suppression of Stat5 phosphorylation was mediated, at least in part, through inhibitory dephosphorylation of the Stat5 tyrosine kinase, Jak2. PTP1B knockdown enhanced sensitivity of T47D cells to prolactin phosphorylation of Stat5 by reducing the EC(50) from 7.2 nmol/L to 2.5 nmol/L. Immunohistochemical analyses of two independent clinical breast cancer materials revealed significant negative correlations between levels of active Stat5 and PTP1B, but not TC-PTP. Collectively, our data implicate PTP1B as an important negative regulator of Stat5 phosphorylation in invasive breast cancer. PMID- 20952589 TI - Prognostic significance of Sox4 expression in human cutaneous melanoma and its role in cell migration and invasion. AB - The Sox4 transcription factor is involved in various cellular processes, such as embryonic development and differentiation. Deregulated expression of Sox4 in several human cancers has been reported to date, but its role in melanoma is unknown. We explored the role of Sox4 in melanoma pathogenesis in vivo and in vitro. Using tissue microarray, we evaluated Sox4 expression in 180 melanocytic lesions and investigated its role in melanoma cell migration and invasion. Sox4 expression was remarkably reduced in metastatic melanoma compared with dysplastic nevi (P < 0.05) and primary melanoma (P < 0.01). This reduction was correlated with a poorer disease-specific survival of melanoma patients (P = 0.039). Multivariate Cox regression analysis revealed that reduced Sox4 expression is an independent prognostic factor (P = 0.049). Knockdown of Sox4 enhanced melanoma cell invasion, migration, and stress fiber formation. The increased migration and invasion on Sox4 knockdown depends on the presence of nuclear factor (NF)-kappaB p50 and is abrogated when p50 is knocked down. We further observed inhibition of NF-kappaB p50 transcription by Sox4, in addition to a reverse pattern of expression of Sox4 and NF-kappaB p50 in different stages of melanocytic lesions. Our results suggest that Sox4 regulates melanoma cell migration and invasion in an NF-kappaB p50-dependent manner and may serve as a prognostic marker and potential therapeutic target for human melanoma. PMID- 20952590 TI - Effects of hypoxia-inducible factor-1alpha overexpression in pregnant mice: possible implications for preeclampsia and intrauterine growth restriction. AB - Preeclampsia and intrauterine growth restriction (IUGR) are pregnancy-specific disorders that share a common pathophysiology. Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that plays an important role in placental development. HIF-1alpha is elevated in preeclamptic placentas and induces soluble vascular endothelial growth factor receptor-1 (sFLT-1), a central factor in preeclampsia and IUGR pathogenesis. Our objective was to investigate the effects of HIF-1alpha overexpression on pregnancy in mice. C57BL/6J pregnant mice were systemically administered either adenovirus expressing stabilized HIF-1alpha (cytomegalovirus [CMV]-HIF), luciferase control (CMV-Luc), or saline on gestational day 8. Pregnant mice overexpressing HIF-1alpha had significantly elevated blood pressure and proteinuria compared with pregnant controls. HIF 1alpha mice showed fetal IUGR, decreased placental weights, and histopathological placental abnormalities compared with control mice. Glomerular endotheliosis, the hallmark lesion of preeclampsia, was demonstrated in the kidneys of these mice relative to the normal histology in control mice. Moreover, liver enzyme levels were significantly elevated, whereas complete blood counts revealed significant anemia and thrombocytopenia in CMV-HIF mice compared with controls. Blood smears confirmed microangiopathic hemolytic anemia in CMV-HIF mice, consistent with HELLP (hemolysis, elevated liver enzymes, and low platelets)-like syndrome. CMV HIF mice showed elevation in serum sFLT-1 and soluble endoglin, providing a mechanistic explanation for the observations. Collectively, our results suggest a possible role for HIF-1alpha in the pathogenesis of both preeclampsia and IUGR. PMID- 20952591 TI - Activation of OX40 augments Th17 cytokine expression and antigen-specific uveitis. AB - Uveitis is a major and common cause of visual disability. Recent studies have shown that Th17 cells are implicated in the pathogenesis of this serious intraocular disorder. Activated T cells express an inducible costimulatory molecule called OX40, and OX40 in turn promotes the activation and proliferation of these lymphocytes. Nevertheless, it is unclear whether OX40 plays a vital role in enhancing the effector function of Th17 cells as well as the severity of uveitis. In this study, we demonstrated an increase of OX40 transcription in ovalbumin-induced uveitis, whereas anti-OX40L antibody substantially inhibited the antigen-specific ocular inflammation. Next, results from flow cytometry showed that activated Th17 cells expressed OX40, and OX40-activating antibody significantly augmented the production of Th17 cytokines in vitro. To validate the impact of OX40 in vivo, we stimulated ovalbumin-specific T cells with the OX40-activating antibody. Compared to donor cells without OX40 activation, adoptive transfer of OX40-stimulated lymphocytes elicited more severe ocular inflammation. Furthermore, an interleukin-17-neutralizing antibody attenuated OX40-mediated uveitis. In conclusion, our findings suggest that activation of OX40 augments Th17 cell function and thereby contributes to ocular inflammation. This study thus enhances our knowledge of costimulatory molecule-mediated immunopathological mechanisms of uveitis and suggests a future therapeutic strategy to treat uveitis by the targeting of OX40. PMID- 20952592 TI - Tumorigenic potential of mononucleated small cells of Hodgkin lymphoma cell lines. AB - Tumor cells with tumorigenic potential are limited to a small cell population known as cancer stem cells (CSCs). CSCs yield both CSCs and non-CSCs, whereas non CSCs do not yield CSCs. CSCs have not been identified in any malignant lymphomas. Hodgkin lymphoma (HL) is a mostly B-cell neoplasm that can be diagnosed by the presence of multinucleated (Reed-Sternberg; RS) cells admixed with Hodgkin cells with distinct nucleoli and various inflammatory cells. Here, the tumorigenic potential of cells with a single nucleus (S) and cells with multiple nuclei (M), which may be equivalent to Hodgkin and RS cells, respectively, was examined in HL cell lines L1236 and L428. Cultures of single S cells yielded both S and M cells, whereas M cell cultures yielded only M cells. When either cultured in methylcellulose or inoculated into NOD/SCID mice, the colony number and tumor size were both larger in S than in M cells. Concentrations of intracellular reactive oxygen species (ROS) were at low levels in a portion of S cells that abundantly expressed FoxO3a, a transcription factor that regulates ROS-degrading enzymes. In clinical samples of HL, FoxO3a was expressed in mononuclear Hodgkin cells but not in multinucleated RS cells. These findings suggest that smaller cells or Hodgkin cells that show low-ROS concentrations and high FoxO3a expression levels might be candidates for HL CSCs. PMID- 20952593 TI - Development of sporadic microsatellite instability in colorectal tumors involves hypermethylation at methylated-in-tumor loci in adenoma. AB - Microsatellite instability (MSI) and genomic hypermethylation of methylated-in tumor (MINT) loci are both strong prognostic indicators in a subgroup of patients with sporadic colorectal cancer (CRC). The present study was designed to determine whether the methylation of MINT loci during the progression of adenoma to CRC is related to MSI in CRC cases. Methylation index (MI) was measured by absolute quantitative assessment of methylated alleles at seven MINT loci in primary CRC with contiguous adenomatous and normal tissues of 79 patients. Results were then validated in primary CRC tissues from an independent group of 54 patients. Increased MI of both MINT loci 1 and 31 was significantly associated with MSI in CRC and was specific for adenoma. Total MI and the number of methylated loci were threefold (P=0.02) and fivefold (P=0.004) higher, respectively, in adenomas associated with microsatellite-stable CRC versus microsatellite-unstable CRC. MINT MI was found to be correlated with mismatch repair protein expression, MSI, BRAF (V600E) mutation status, mut-L homologue 1 methylation status, and disease-specific survival in the second independent validation group of patients. MI of specific MINT loci may be prognostic indicators of colorectal adenomas that will develop into sporadic microsatellite unstable CRCs. Increased MINT locus methylation appears to precede MSI and may have utility in defining clinical pathology in the absence of features of malignant invasive tumors. PMID- 20952594 TI - Angiopoietin-2-driven vascular remodeling in airway inflammation. AB - Vascular remodeling is a feature of chronic inflammation during which capillaries transform into venules that expand the region of the vasculature in which leakage and leukocyte emigration both occur. Recently, we found that angiopoietin/Tie2 receptor signaling drives the transformation of capillaries into venules at an early stage of the sustained inflammatory response in the airways of mice infected with Mycoplasma pulmonis. However, the precise contributions of both angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) are not clear. In this study, we sought to determine the contribution of Ang2 to this vascular remodeling. Ang2 mRNA expression levels increased and phosphorylated Tie2 immunoreactivity in mucosal blood vessels decreased, indicative of diminished receptor signaling after infection. Selective inhibition of Ang2 throughout the infection by administration of either of two distinct function-blocking antibodies reduced the suppression of Tie2 phosphorylation and decreased the remodeling of mucosal capillaries into venules, the amount of leukocyte influx, and disease severity. These findings are consistent with Ang2 acting as an antagonist of Tie2 receptors and the reduction of Tie2 phosphorylation in endothelial cells rendering the vasculature more responsive to cytokines that promote both vascular remodeling and the consequences of inflammation after M. pulmonis infection. By blocking such changes, Ang2 inhibitors may prove beneficial in the treatment of sustained inflammation in which vascular remodeling, leakage, and leukocyte influx contribute to its pathophysiology. PMID- 20952595 TI - Alcohol consumption over time and risk of lymphoid malignancies in the California Teachers Study cohort. AB - Several previous studies found inverse associations between alcohol consumption and risk of non-Hodgkin lymphoma (NHL) and multiple myeloma. However, most studies were retrospective, and few distinguished former drinkers or infrequent drinkers from consistent nondrinkers. Therefore, the authors investigated whether history of alcohol drinking affected risks of NHL and multiple myeloma among 102,721 eligible women in the California Teachers Study, a prospective cohort study in which 496 women were diagnosed with B-cell NHL and 101 were diagnosed with multiple myeloma between 1995-1996 and December 31, 2007. Incidence rate ratios and 95% confidence intervals were estimated using Cox proportional hazards regression. Risk of all types of B-cell NHL combined or multiple myeloma was not associated with self-reported past consumption of alcohol, beer, wine, or liquor at ages 18-22 years, at ages 30-35 years, or during the year before baseline. NHL subtypes were inconsistently associated with alcohol intake. However, women who were former alcohol drinkers at baseline were at elevated risk of overall B-cell NHL (rate ratio = 1.46, 95% confidence interval: 1.08, 1.97) and follicular lymphoma (rate ratio = 1.81, 95% confidence interval: 1.00, 3.28). The higher risk among former drinkers emphasizes the importance of classifying both current and past alcohol consumption and suggests that factors related to quitting drinking, rather than alcohol itself, may increase B-cell NHL risk. PMID- 20952597 TI - Phylogenetic relationships of 3/3 and 2/2 hemoglobins in Archaeplastida genomes to bacterial and other eukaryote hemoglobins. AB - Land plants and algae form a supergroup, the Archaeplastida, believed to be monophyletic. We report the results of an analysis of the phylogeny of putative globins in the currently available genomes to bacterial and other eukaryote hemoglobins (Hbs). Archaeplastida genomes have 3/3 and 2/2 Hbs, with the land plant genomes having group 2 2/2 Hbs, except for the unexpected occurrence of two group 1 2/2 Hbs in Ricinus communis. Bayesian analysis shows that plant 3/3 Hbs are related to vertebrate neuroglobins and bacterial flavohemoglobins (FHbs). We sought to define the bacterial groups, whose ancestors shared the precursors of Archaeplastida Hbs, via Bayesian and neighbor-joining analyses based on COBALT alignment of representative sets of bacterial 3/3 FHb-like globins and group 1 and 2 2/2 Hbs with the corresponding Archaeplastida Hbs. The results suggest that the Archaeplastida 3/3 and group 1 2/2 Hbs could have originated from the horizontal gene transfers (HGTs) that accompanied the two generally accepted endosymbioses of a proteobacterium and a cyanobacterium with a eukaryote ancestor. In contrast, the origin of the group 2 2/2 Hbs unexpectedly appears to involve HGT from a bacterium ancestral to Chloroflexi, Deinococcales, Bacilli, and Actinomycetes. Furthermore, although intron positions and phases are mostly conserved among the land plant 3/3 and 2/2 globin genes, introns are absent in the algal 3/3 genes and intron positions and phases are highly variable in their 2/2 genes. Thus, introns are irrelevant to globin evolution in Archaeplastida. PMID- 20952596 TI - Comparison of dual-energy x-ray absorptiometric and anthropometric measures of adiposity in relation to adiposity-related biologic factors. AB - Dual-energy x-ray absorptiometry (DXA) can provide accurate measurements of body composition. Few studies have compared the relative validity of DXA measures with anthropometric measures such as body mass index (BMI) and waist circumference (WC). The authors compared correlations of DXA measurements of total fat mass and fat mass percent in the whole body and trunk, BMI, and WC with obesity-related biologic factors, including blood pressure and levels of plasma lipids, C reactive protein, and fasting insulin and glucose, among 8,773 adults in the National Health and Nutrition Examination Survey (1999-2004). Overall, the magnitudes of correlations of BMI and WC with the obesity-related biologic factors were similar to those of fat mass or fat mass percent in the whole body and trunk, respectively. These observations were largely consistent across different age, gender, and ethnic groups. In addition, in both men and women, BMI and WC demonstrated similar abilities to distinguish between participants with and without the metabolic syndrome in comparison with corresponding DXA measurements. These data indicate that the validity of simple anthropometric measures such as BMI and WC is comparable to that of DXA measurements of fat mass and fat mass percent, as evaluated by their associations with obesity-related biomarkers and prevalence of metabolic syndrome. PMID- 20952598 TI - End-of-treatment but not interim PET scan predicts outcome in nonbulky limited stage Hodgkin's lymphoma. AB - BACKGROUND: Early interim positron emission tomography (PET) scans appear powerfully predictive of outcome in Hodgkin's lymphoma (HL), particularly in advanced-stage disease where it has been predominantly studied. The prognostic value of interim PET in limited-stage patients with nonbulky disease has not been well established. PATIENTS AND METHODS: Ninety-six patients with nonbulky limited stage HL were identified who had interim and end-of-treatment PET scans. Response rate, overall survival (OS), and progression-free survival (PFS) were calculated. RESULTS: Four-year PFS and OS for the entire cohort were 88% and 97%, respectively. Interim PET did not predict outcome, with PFS in positive and negative patients 87% versus 91% (P=0.57), respectively. End-of-treatment PET result was predictive of outcome, with PFS of 94% in end PET-negative patients versus 54% in end PET-positive patients (P<0.0001). Four-year OS was 100% in end PET-negative patients and 84% in end PET-positive patients (P<0.0001). CONCLUSIONS: Interim PET scans were not predictive of outcome, compared with scans carried out at completion of therapy. End-of-treatment PET was highly predictive of PFS and OS, regardless of interim PET result. In this low-risk patient population, even patients with interim positive PET scans show a favorable prognosis. PMID- 20952599 TI - Incidence of thyroid cancer in Italy, 1991-2005: time trends and age-period cohort effects. AB - BACKGROUND: In Italy, some of the highest incidence rates (IRs) of thyroid cancer (TC) worldwide have been reported. PATIENTS AND METHODS: TC cases <85 years of age reported to Italian cancer registries during 1991-2005 were included. Age standardized IRs were computed for all TC and age-period-cohort effects were estimated for papillary TC. RESULTS: IRs of TC were twofold higher in 2001-2005 than in 1991-1995 (18 and 8 per 100,000 women, 6 and 3 per 100,000 men, respectively). Increases were similar in the two sexes and nearly exclusively due to papillary TC. Increases of papillary TC by birth cohort were found in both sexes and among all age groups between 20 and 79 years. Age-period-cohort models showed a strong period effect in both sexes (rate ratio for 2001-2009 versus 1991 1995 = 2.5 in women and 2.3 in men), although IRs peaked at an earlier age in women (45-49 years) than men (65-69 years). CONCLUSION: The strength of the period effect in both sexes and the earlier onset in women than men strongly implicated increased medical surveillance in the upward trends of papillary TC incidence in Italy. The consequences of the current intense search for TC on morbidity and possible overtreatment, especially among young women, should be carefully evaluated. PMID- 20952600 TI - Determinants of heavy cigarette smoking: are there differences in men and women? Results from the population-based MONICA/KORA Augsburg surveys. AB - INTRODUCTION: Heavy cigarette smoking is more frequent in men than in women. So far, little is known whether this sex-specific difference in cigarette consumption is modified by age at smoking onset, sociodemographical, and lifestyle factors. Therefore, we aimed to identify sex-specific characteristics associated with heavy daily cigarette smoking. METHODS: The study population consisted of 3,178 daily smokers aged 25-74 years from the population-based MONICA/KORA Augsburg surveys conducted between 1984 and 1995. Subjects consuming at least 20 cigarettes daily were defined as heavy smokers. Multivariate logistic regression was used to identify sociodemographical, smoking-related, and lifestyle characteristics of heavy smokers. RESULTS: A number of 1,576 subjects (49.6%) were identified as heavy smokers. Men were significantly more often heavy smokers than women with the exception of those women who have started smoking at an early age. Multivariate logistic regression revealed early age at smoking onset determines heavy smoking in women but not in men. While younger age at study examination and low educational level was associated with heavy smoking in men only, current employment was associated with heavy smoking in women only. Moreover, living alone, high alcohol or coffee consumption, and low physical leisure activity were associated with heavy smoking behavior in both sexes. Survey, obesity and parental history of smoking showed no association with heavy smoking. CONCLUSIONS: The present study revealed sex-specific differences in heavy smoking by age at smoking onset, which was not shown before so far. These findings should be further investigated and addressed in future prevention campaigns. PMID- 20952601 TI - Risk and risk management for Australian sex workers. AB - In this article, we address the experiences of female sex workers in urban Australia through analysis of interviews using a feminist approach. Although many previous studies have been conducted, our focus was on the voices of sex workers in an area that was rapidly gentrifying, leading to local community tensions. Intensive analysis of interview transcripts was employed to derive thematic codes for understanding how the women viewed and managed everyday risk in sex work. They were well aware of the health risks associated with sex work. For women working on premises, domain separation between sex work and other life domains was an important management strategy for maintaining self-esteem. For women working on the street, instincts honed by years of dangerous work provided a measure of safety. Our findings have implications for health and other agencies dealing with sex workers in situations in which community pressure is exerted to move sex workers away from the area. PMID- 20952602 TI - Alternative families in recovery: fictive kin relationships among residents of sober living homes. AB - Sober living homes are group residences for people attempting to maintain abstinence from alcohol and drugs in a mutually supportive setting. Residents typically develop strong psychological and economic ties and have been referred to as "alternative families," thus evoking the anthropological concept of fictive kinship. We analyzed data from seven focus groups with sober living home residents to assess the prevalence and functions of fictive kinship in these settings. Results suggest that residents created kinship by exchanging various types of support, and by incorporating other residents into existing family relationships, particularly in homes where there were children. Residents perceived fictive kin as more supportive than actual kin, encouraging them toward greater individuation, in contrast with family backgrounds that were sometimes described as stifling. These accounts of the therapeutic qualities of fictive kin in sober living homes could inform the work of fair housing advocates and other community stakeholders. PMID- 20952603 TI - "It's one of the better drugs to use": perceptions of cocaine use among gay and bisexual Asian American men. AB - Research on drug use among gay and bisexual men has primarily focused on examining the link between drug use- most notably, methamphetamine-sexual practices, and risk of HIV transmission. Drawing on in-depth qualitative data from 40 interviews with gay and bisexual Asian American men, we examine perceptions and meanings associated with cocaine use in the San Francisco Bay Area gay community. We found that the participants, in contrast to their negative perceptions of methamphetamine use, believed that cocaine enhanced sociability and was acceptable for use in most social situations. Furthermore, participants perceived little connection between cocaine use and risky sexual practices, emphasizing the drug's safety relative to other illicit substances. Based on these findings, we suggest that an increase in the favorability of cocaine use might be an unintended consequence of methamphetamine prevention campaigns targeting the gay community, with their emphasis on the harmful effects of drug use, unsafe sex, and HIV risk. PMID- 20952604 TI - Commentary on an article by R.W. Draeger, MD, et al.: "Corticosteroids as an adjunct to antibiotics and surgical drainage for the treatment of pyogenic flexor tenosynovitis". PMID- 20952605 TI - Corticosteroids as an adjunct to antibiotics and surgical drainage for the treatment of pyogenic flexor tenosynovitis. AB - BACKGROUND: Many similarities exist between pyogenic flexor tenosynovitis and other closed-space infections such as septic arthritis. Previous studies have demonstrated that corticosteroids in conjunction with antibiotics considerably improve treatment outcomes in patients with septic arthritis. Using a chicken model, we investigated whether or not corticosteroids in combination with antibiotics and/or surgical drainage could minimize the loss of range of motion typically associated with pyogenic flexor tenosynovitis. METHODS: We inoculated the flexor tendon sheath of the right long toe of broiler chickens with Staphylococcus aureus (American Type Culture Collection 29523 NA) (6 * 10(9) colony-forming units/mL) and twenty-four hours later administered one of six treatments to groups of fourteen or fifteen chickens. Treatment combinations included systemic or intrasynovial antibiotics, surgical drainage with catheter irrigation or no surgical drainage, and local corticosteroid injections or no corticosteroid injections. Measurements of active digital flexion at the proximal and middle interphalangeal joints were performed before inoculation and treatment and at seven, fourteen, and twenty-eight days after treatment. Flexion measurements were compared between groups as well as with similar measurements in the contralateral, uninfected, control long toe. RESULTS: At twenty-eight days, two of three groups treated with locally administered corticosteroids and the group treated with intrasynovial antibiotics alone (without surgery) regained significantly more active flexion in comparison with chickens treated with systemic antibiotics and surgical drainage (the current standard of care). Pooled data revealed that the corticosteroid-treated groups regained significantly more active flexion at all post-treatment time points. CONCLUSIONS: Our data support the hypothesis that adding locally administered corticosteroids to the treatment regimen for pyogenic flexor tenosynovitis in a chicken model can significantly decrease loss of motion resulting from the infection. Furthermore, locally administered antibiotics may be effective for the treatment of pyogenic flexor tenosynovitis. PMID- 20952606 TI - Comparison between standard and high-flexion posterior-stabilized rotating platform mobile-bearing total knee arthroplasties: a randomized controlled study. AB - BACKGROUND: A high-flexion posterior-stabilized rotating-platform mobile-bearing prosthesis was designed in an attempt to improve the range of motion after total knee arthroplasty without compromising the theoretical advantages of the posterior-stabilized rotating-platform mobile-bearing system. The aim of this study was to compare the outcomes of standard and high-flexion posterior stabilized rotating-platform mobile-bearing total knee arthroplasties. METHODS: One hundred and seventy knees were randomly allocated to receive either a standard (n = 85) or a high-flexion (n = 85) posterior-stabilized rotating platform mobile-bearing prosthesis and were followed prospectively for a minimum of two years. Ranges of motion, functional outcomes determined with use of standard scoring systems, and radiographic measurements were assessed. In addition, patients' abilities to perform activities requiring deep knee flexion and patient satisfaction were evaluated with use of questionnaires. RESULTS: The average postoperative maximal flexion was 130 degrees for the knees with the standard design and 128 degrees for those with the high-flexion design, and the difference was not significant. The two prosthetic designs also did not differ significantly with regard to the Knee Society scores; Hospital for Special Surgery (HSS) scores; or the scores on the pain, stiffness, and function subscales of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). In addition, the numbers of knees able to perform deep-flexion-related activities and the rates of patient satisfaction were similar in the two study groups. CONCLUSIONS: This prospective randomized study revealed no significant differences between standard and high-flexion posterior-stabilized rotating platform mobile-bearing total knee prostheses in terms of clinical or radiographic outcomes or range of motion at a minimum of two years postoperatively. PMID- 20952607 TI - Nitric oxide metabolites in goldfish under normoxic and hypoxic conditions. AB - Nitric oxide (NO), produced by nitric oxide synthases (NOS enzymes), regulates multiple physiological functions in animals. NO exerts its effects by binding to iron (Fe) of heme groups (exemplified by the activation of soluble guanylyl cyclase) and by S-nitrosylation of proteins - and it is metabolized to nitrite and nitrate. Nitrite is used as a marker for NOS activity but it is also a NO donor that can be activated by various cellular proteins under hypoxic conditions. Here, we report the first systematic study of NO metabolites (nitrite, nitrate, S-nitroso, N-nitroso and Fe-nitrosyl compounds) in multiple tissues of a non-mammalian vertebrate (goldfish) under normoxic and hypoxic conditions. NO metabolites were measured in blood (plasma and red cells) and heart, brain, gill, liver, kidney and skeletal muscle, using highly sensitive reductive chemiluminescence. The severity of the chosen hypoxia levels was assessed from metabolic and respiratory variables. In normoxic goldfish, the concentrations of NO metabolites in plasma and tissues were comparable with values reported in mammals, indicative of similar NOS activity. Exposure to hypoxia [at P(O2) (partial pressure of O2) values close to and below the critical P(O2)] for two days caused large decreases in plasma nitrite and nitrate, which suggests reduced NOS activity and increased nitrite/nitrate utilization or loss. Tissue NO metabolites were largely maintained at their tissue-specific values under hypoxia, pointing at nitrite transfer from extracellular to intracellular compartments and cellular NO generation from nitrite. The data highlights the preference of goldfish to defend intracellular NO homeostasis during hypoxia. PMID- 20952608 TI - The role of serotonin in the enhancement of long-term memory resulting from predator detection in Lymnaea. AB - Serotonergic systems play important roles in modulating stress-induced arousal and vigilance behaviours. The pond snail, Lymnaea, shows multiple defensive vigilance behaviours in response to the stress associated with predator detection. Predator detection elicited by crayfish effluent (CE), increases the time to re-emerge from the shell and enhances the shadow withdrawal response. More importantly, in Lymnaea, CE enhances the ability to form long-term memory (LTM). We investigated the role of the serotonergic system in these anti-predator responses in Lymnaea. Using a serotonin-receptor antagonist, mianserin, we found that two defensive vigilance behaviours (e.g. increasing the time to re-emerge from their shell and shadow response) elicited by CE were not observed when the serotonergic system was disrupted. Also, methysergide, another serotonin antagonist, blocked the enhanced LTM formation after training in CE. Importantly, mianserin did not alter LTM formation in pond water (PW). These data suggest that a serotonergic system is activated only when Lymnaea detect a predator. When snails were trained in CE using a training procedure that in PW produces a 24-h LTM, a more persistent form of LTM (5 days) occurred. This more persistent form of LTM was abolished after mianserin treatment. Increasing 5-HT levels in the snail by the injection of 5-HT was also associated with enhanced LTM formation. Lastly, we tested whether the osphradium is implicated in CE detection and subsequent enhanced formation of LTM. Cutting the osphradial nerve to the CNS resulted in the loss of the ability to form enhanced LTM in CE. Together, these findings support the hypothesis that the serotonergic system plays a key role in modulating the predator-induced stress responses in Lymnaea. PMID- 20952609 TI - Arboreal locomotion in rats - the challenge of maintaining stability. AB - Arboreal locomotion has mainly been looked at to date in the context of investigations into the specialization of primates and other 'arboreally adapted' animals. The feat of moving on branches as small or smaller than the body's diameter was tested in rats (Rattus norvegicus) as they moved on horizontal poles of different diameters. The data were compared with data pertaining to terrestrial locomotion. We investigated three-dimensional kinematics and dynamics using biplanar cineradiography with simultaneous substrate reaction force (SRF) measurements. As predicted, rats flexed fore- and hindlimbs and reduced vertical forces during pole locomotion. In addition, the orientation of the mediolateral substrate reaction force resultant (SRR) and impulses switched from lateral to medial. In order to maintain stability during arboreal locomotion, lateral spine movements increased. We propose that the combination of lateral sequence gaits, similar travel speed of the animals and similar contact times, higher or similar peak vertical forces as well as similar mediolateral impulses in forelimbs and hindlimbs are typical of clawed mammals moving on thin supports. Clawed mammals and primates share the reduction of vertical oscillations and side-to-side fluctuations, a crouched posture as well as the increase in lateral spine movements. We conclude that these features are behavioral adaptations caused by the biomechanical constraints of small branch locomotion, regardless of the way they make contact with the substrate. PMID- 20952610 TI - Olfactory modulation of flight in Drosophila is sensitive, selective and rapid. AB - Freely flying Drosophila melanogaster respond to odors by increasing their flight speed and turning upwind. Both these flight behaviors can be recapitulated in a tethered fly, which permits the odor stimulus to be precisely controlled. In this study, we investigated the relationship between these behaviors and odor-evoked activity in primary sensory neurons. First, we verified that these behaviors are abolished by mutations that silence olfactory receptor neurons (ORNs). We also found that antennal mechanosensors in Johnston's organ are required to guide upwind turns. Flight responses to an odor depend on the identity of the ORNs that are active, meaning that these behaviors involve odor discrimination and not just odor detection. Flight modulation can begin rapidly (within about 85 ms) after the onset of olfactory transduction. Moreover, just a handful of spikes in a single ORN type is sufficient to trigger these behaviors. Finally, we found that the upwind turn is triggered independently from the increase in wingbeat frequency, implying that ORN signals diverge to activate two independent and parallel motor commands. Together, our results show that odor-evoked flight modulations are rapid and sensitive responses to specific patterns of sensory neuron activity. This makes these behaviors a useful paradigm for studying the relationship between sensory neuron activity and behavioral decision-making in a simple and genetically tractable organism. PMID- 20952611 TI - The catecholamine release-inhibitory peptide catestatin (chromogranin A344-363) modulates myocardial function in fish. AB - Catestatin (CST), the 21-amino acid, cationic and hydrophobic peptide proteolytically derived from the ubiquitous chromogranin A (CgA), is an endogenous inhibitor of catecholamine release, a potent vasodilator in vivo and an anti-hypertensive agent in mammals, including humans. Recently, we discovered that CST also functions as an important negative modulator of heart performance in frog and rat. To gain an evolutionary perspective on CST cardiotropism in fish, we analysed the influence of bovine CST (CgA344-364) on the eel heart, as well as the eventual species-specific mechanisms of its myocardial action. Experiments were carried out on fresh-water eels (Anguilla anguilla L.) using an electrically paced isolated working heart preparation. Stroke volume and stroke work were used as measures of ventricular performance. Under basal conditions, CST (from 11 nmol l-1 to 165 nmol l-1) caused a concentration-dependent negative inotropism, which was abolished by inhibitors of either beta1/beta2 (propranolol) or beta3 (SR59230) adrenergic receptors, or by G(i/o) protein (PTx) or nitric oxide synthase (L-NMMA), or guanylate cyclase (ODQ) blockers. This suggests a beta-adrenergic receptor-G(i/o) protein-NO-cGMP-dependent mechanism. By contrast, the CST-induced cardio-suppression was not influenced by atropine, unspecific muscarinic antagonist, thus excluding cholinergic receptor involvement. CST also counteracted the adrenergic (isoproterenol)-mediated positive inotropism. Under increased preload (i.e. Frank-Starling response) conditions, CST induced a significant increase of the Frank-Starling response, which was blocked by L-NMMA and thapsigargin, but independent from guanylate cyclase. In conclusion, this is the first report in fish that CST modulates myocardial performance under basal, as well as under increased preload, conditions and counteracts the adrenergic mediated positive inotropism, which strikingly supports the evolutionary significance and establishes the cardioactive role of this peptide. PMID- 20952612 TI - Green fluorescent protein regulation in the coral Acropora yongei during photoacclimation. AB - Reef-building corals inhabit high light environments and are dependent on photosynthetic endosymbiotic dinoflagellates for nutrition. While photoacclimation responses of the dinoflagellates to changes in illumination are well understood, host photoacclimation strategies are poorly known. This study investigated fluorescent protein expression in the shallow-water coral Acropora yongei during a 30 day laboratory photoacclimation experiment in the context of its dinoflagellate symbionts. Green fluorescent protein (GFP) concentration measured by Western blotting changed reversibly with light intensity. The first 15 days of the photoacclimation experiment led to a ~1.6 times increase in GFP concentration for high light corals (900 MUmol quanta m-2 s-1) and a ~4 times decrease in GFP concentration for low light corals (30 MUmol quanta m-2 s-1) compared with medium light corals (300 MUmol quanta m-2 s-1). Green fluorescence increased ~1.9 times in high light corals and decreased ~1.9 times in low light corals compared with medium light corals. GFP concentration and green fluorescence intensity were significantly correlated. Typical photoacclimation responses in the dinoflagellates were observed including changes in density, photosynthetic pigment concentration and photosynthetic efficiency. Although fluorescent proteins are ubiquitous and abundant in scleractinian corals, their functions remain ambiguous. These results suggest that scleractinian corals regulate GFP to modulate the internal light environment and support the hypothesis that GFP has a photoprotective function. The success of photoprotection and photoacclimation strategies, in addition to stress responses, will be critical to the fate of scleractinian corals exposed to climate change and other stressors. PMID- 20952613 TI - The consequences of reversible gill remodelling on ammonia excretion in goldfish (Carassius auratus). AB - Goldfish acclimated to cold water (e.g. 7 degrees C) experience a marked reduction in functional lamellar surface area owing to the proliferation of an interlamellar cell mass (ILCM), a phenomenon termed gill remodelling. The goal of the present study was to assess the consequences of the reduced functional surface area on the capacity of goldfish to excrete ammonia. Despite the expected impact of ambient temperature on functional surface area, fish acclimated to 7 degrees C and 25 degrees C exhibited similar rates of ammonia excretion (J(net,amm)); the Q10 values for fed and starved fish were 1.07 and 1.20, respectively. To control for possible temperature-related differences in rates of endogenous ammonia production, J(net,amm) was determined at the two acclimation temperatures after loading fish with 1.12 MUmol g-1 of NH4Cl. In the 3 h post injection period, J(net,amm) was elevated to a greater extent in the 25 degrees C fish. To estimate the potential contribution of increased ventilation and cardiac output to ammonia clearance in the warmer fish, the ammonia loading experiment was repeated on the 7 degrees C fish immediately after they were exercised to exhaustion. The rate of excretion of ammonia was significantly increased in the exercised 7 degrees C fish (presumably experiencing increased ventilation and cardiac output for at least some of the measurement period) suggesting that differences in external and internal convection may at least partially explain the enhanced capacity of the 25 degrees C fish to clear the ammonia load. To more specifically assess the contribution of the different functional surface areas on the differing rates of ammonia clearance at the two acclimation temperatures, the 7 degrees C fish were exposed for 7 days to hypoxia (P(O2)=10 mmHg=1.33 kPa), a treatment known to cause the disappearance of the ILCM. The results demonstrated that the hypoxia-associated loss of the ILCM was accompanied by a significant increase in the rate of ammonia clearance in the 7 degrees C fish when returned to normoxic conditions. To determine whether compensatory changes in the ammonia transporting proteins might be contributing to sustaining J(net,amm) under conditions of reduced functional lamellar surface area, the relative expression and branchial distribution of four Rh proteins were assessed by western blotting and immunocytochemistry. Although the relative expression of the Rh proteins was unaffected by acclimation temperature, there did appear to be a change in the spatial distribution of Rhag, Rhbg and Rhcg1. Specifically, these three Rh proteins (and to a lesser extent Rhcg2) appeared to localize in cells on the outer edge of the ILCM that were enriched with Na(+)/K(+)-ATPase. Thus, we suggest that despite the impediment to ammonia excretion imposed by the ILCM, goldfish acclimated to 7 degrees C are able to sustain normal rates of excretion owing to the redistribution of ammonia transporting cells. PMID- 20952614 TI - The control of breathing in goldfish (Carassius auratus) experiencing thermally induced gill remodelling. AB - At temperatures below 15 degrees C the gill lamellae of goldfish (Carassius auratus) are largely covered by an interlamellar cell mass (ILCM) which decreases the functional surface area of the gill. The presence of the ILCM in goldfish acclimated to cold water conceivably could lead to a covering of the neuroepithelial cells (NECs), which are believed to be important for sensing ambient O2 and CO2 levels. In this study we tested the hypothesis that goldfish with covered lamellae (and presumably fewer NECs exposed to the water) exhibit a decreased capacity to hyperventilate in response to hypoxic stimuli. Measurements of ventilation amplitude and frequency were performed during exposure to acute hypoxia (P(w(O2))=30 mmHg) or following injections of the O2 chemoreceptor stimulant NaCN into the buccal cavity or caudal vein of fish acclimated to 25 degrees C (uncovered lamellae) or 7 degrees C (covered lamellae) to stimulate predominantly the externally or internally oriented NECs, respectively. The results demonstrated no significant differences in the response to hypoxia, with each group exhibiting similar percentage increases in ventilation amplitude (90 91%) and frequency (34-43%). Similarly, with the exception of a rightward shift of the ventilation frequency dose-response in the fish acclimated to 7 degrees C, there were no significant differences between the two groups of fish in the ED(50) values. These findings suggest that goldfish with covered lamellae retain the capacity to sense external hypoxic stimuli. Using immunohistochemistry to identify serotonin-enriched NECs, it was demonstrated that the presence of the ILCM results in the NECs being redistributed towards the distal regions of the lamellae. In 25 degrees C-acclimated fish, the NECs were distributed evenly along the length of the lamellae with 53+/-3% of them in the distal half, whereas in fish acclimated to 7 degrees C, 83+/-5% of the NECs were confined to the distal half. Using the neuronal marker antibody ZN-12, it was demonstrated that the NECs at the distal edges of the lamellae are innervated by nerve fibres. Thus, it is hypothesised that the capacity to sense external hypoxic stimuli in goldfish acclimated to cold water is maintained despite the increasing coverage of the gill epithelial surfaces because of a redistribution of innervated NECs to the exposed distal regions of the lamellae. PMID- 20952615 TI - Look and touch: multimodal sensory control of flower inspection movements in the nocturnal hawkmoth Manduca sexta. AB - A crucial stage in the interaction between pollinators and plants is the moment of physical contact between them, known as flower inspection, or handling. Floral guides - conspicuous colour markings, or structural features of flower corollas - have been shown to be important in the inspecting behaviour of many insects, particularly in diurnal species. For the nocturnal hawkmoth Manduca sexta tactile input has an important role in flower inspection, but there is no knowledge about the use of visual floral guides in this behaviour. I carried out a series of experiments to first, evaluate the putative role of floral guides during flower inspection and second, to explore how simultaneous tactile and visual guides could influence this behaviour. Results show that visual floral guides affect flower inspection by M. sexta. Moths confine proboscis placement to areas of higher light reflectance regardless of their chromaticity, but do not appear to show movements in any particular direction within these areas. I also recorded inspection times, finding that moths can learn to inspect flowers more efficiently when visual floral guides are available. Additionally, I found that some visual floral guides can affect the body orientation that moths adopt while hovering in front of horizontal models. Finally, when presented with flower models offering both visual and tactile guides, the former influenced proboscis placement, whereas the latter controlled proboscis movements. Results show that innate inspection behaviour is under multimodal sensory control, consistent with other components of the foraging task. Fine scale inspection movements (elicited by diverse floral traits) and the tight adjustment between the morphology of pollinators and flowers appear to be adaptively integrated, facilitating reward assessment and effective pollen transfer. PMID- 20952616 TI - Response properties of crayfish antennules to hydrodynamic stimuli: functional differences in the lateral and medial flagella. AB - Antennules have been reported to influence localization of distant food odors, sex discrimination, and agonistic and social behaviors of decapod crustaceans. Although olfaction by the antennules is largely recognized, information on the sensitivity of antennules to hydrodynamic stimuli has been scant. In red swamp crayfish Procambarus clarkii antennules, mechanosensory setae outnumber the chemosensory setae. We studied the mechanosensitivity of crayfish antennules by recording neural activities from isolated antennules in response to sinusoidal dipole stimuli. Both the lateral and the medial flagellum of the antennules responded to hydrodynamic stimuli, although the medial flagellum showed more sensitivity at frequencies higher than 60 Hz. The most dominant setae present on the stimulated site were the simple setal type. Although both lateral and medial flagella are capable of detecting chemical and hydrodynamic cues, results from neural responses, morphological observations and antennular behavior observations indicate that the lateral flagellum of P. clarkii functions as an olfactory organ whereas the medial flagellum complements as a hydrodynamic receptor. It appears that in crayfish antennular sensory processing, crayfish simultaneously use chemical and hydrodynamic information. We have compared our data with the threshold of fish lateral line to the same stimuli and we discuss probable similarities in response properties. PMID- 20952617 TI - Cardiac responses to anoxia in the Pacific hagfish, Eptatretus stoutii. AB - In the absence of any previous study of the cardiac status of hagfishes during prolonged anoxia and because of their propensity for oxygen-depleted environments, the present study tested the hypothesis that the Pacific hagfish Eptatretus stoutii maintains cardiac performance during prolonged anoxia. Heart rate was halved from the routine value of 10.4+/-1.3 beats min-1 by the sixth hour of an anoxic period and then remained stable for a further 30 h. Cardiac stroke volume increased from routine (1.3+/-0.1 ml kg-1) to partially compensate the anoxic bradycardia, such that cardiac output decreased by only 33% from the routine value of 12.3+/-0.9 ml min-1 kg-1. Cardiac power output decreased by only 25% from the routine value of 0.26+/-0.02 mW g-1. During recovery from prolonged anoxia, cardiac output and heart rate increased to peak values within 1.5 h. Thus, the Pacific hagfish should be acknowledged as hypoxic tolerant in terms of its ability to maintain around 70% of their normoxic cardiac performance during prolonged anoxia. This is only the second fish species to be so classified. PMID- 20952618 TI - Changes in materials properties explain the effects of humidity on gecko adhesion. AB - Geckos owe their remarkable stickiness to millions of dry setae on their toes, and the mechanism of adhesion in gecko setae has been the topic of scientific scrutiny for over two centuries. Previously, we demonstrated that van der Waals forces are sufficient for strong adhesion and friction in gecko setae, and that water-based capillary adhesion is not required. However, recent studies demonstrated that adhesion increases with relative humidity (RH) and proposed that surface hydration and capillary water bridge formation is important or even necessary. In this study, we confirmed a significant effect of RH on gecko adhesion, but rejected the capillary adhesion hypothesis. While contact forces of isolated tokay gecko setal arrays increased with humidity, the increase was similar on hydrophobic and hydrophilic surfaces, inconsistent with a capillary mechanism. Contact forces increased with RH even at high shear rates, where capillary bridge formation is too slow to affect adhesion. How then can a humidity-related increase in adhesion and friction be explained? The effect of RH on the mechanical properties of setal beta-keratin has escaped consideration until now. We discovered that an increase in RH softens setae and increases viscoelastic damping, which increases adhesion. Changes in setal materials properties, not capillary forces, fully explain humidity-enhanced adhesion, and van der Waals forces remain the only empirically supported mechanism of adhesion in geckos. PMID- 20952619 TI - Zebrafish take their cue from temperature but not photoperiod for the seasonal plasticity of thermal performance. AB - Organisms adjust to seasonal variability in the environment by responding to cues that indicate environmental change. As most studies of seasonal phenotypic plasticity test only the effect of a single environmental cue, how animals may integrate information from multiple cues to fine-tune plastic responses remains largely unknown. We examined the interaction between correlated (seasonally matching) and conflicting (seasonally opposite) temperature and photoperiod cues on the acclimation of performance traits in male zebrafish, Danio rerio. We acclimated fish for 8 weeks and then tested the change in thermal dependence of maximum burst swimming and feeding rate between 8 and 38 degrees C. We predicted that correlated environmental cues should induce a greater acclimation response than uncorrelated cues. However, we found that only temperature was important for the seasonal acclimation of performance traits in zebrafish. Thermal acclimation shifted the thermal performance curve of both traits. For maximum burst swimming, performance increased for each group near the acclimation temperature and reduced in environments that were far from their acclimation temperature. The feeding rate of cold-acclimated zebrafish was reduced across the test temperature range compared with that of warm-acclimated fish. Our study is the first that has found no effect of the covariation between temperature and photoperiod acclimation cues on locomotor performance in fishes. Our results support the intuitive idea that photoperiod may be a less important seasonal cue for animals living at lower latitudes. PMID- 20952620 TI - Posterior lymph heart function in two species of anurans: analysis based on both in vivo pressure-volume relationships by conductance manometry and ultrasound. AB - Rhinella marina and Lithobates catesbeianus have known differences in the capacity to mobilize lymph to stabilize blood volume following dehydration and hemorrhage. The purpose of these experiments was to assess whether there are interspecific differences in basic lymph heart functions. The end diastolic volumes of posterior lymph hearts averaged 10.8 MUl kg-1 in R. marina and 7.9 10.8 MUl kg-1 in L. catesbeianus by conductance manometry, and 9-32 MUl kg-1 in R. marina by ultrasound techniques, which correlated with body mass. Stroke volumes were approximately 20% of end diastolic volumes in both species. Peak systolic pressures and stroke work were correlated with the index of contractility (dP/dt(max)) in both species. Stroke volume was correlated to stroke work but not peak systolic pressure, end diastolic volume or end diastolic pressure indicating the preload variables do not seem to determine stroke volume as would be predicted from Starling considerations of the blood heart. Renal portal elastance (end systolic pressure/stroke volume) an afterload index did not differ interspecifically, and was equivalent to values for systemic flow indices from mice of equivalent ventricular volume. These data, taken together with predictions derived from mammalian models on the effect of high resistance indicate afterload (renal portal pressure), may be important determinants of posterior lymph heart stroke volume. The shape of the pressure-volume loop is different from an idealized version previously reported, and is influenced by end diastolic volume. Our data indicate that increasing end diastolic pressure and volume can influence the loop shape but not the stroke volume. This indicates that lymph hearts do not behave in a Starling Law manner with increased preload volume. PMID- 20952621 TI - Decreased echolocation performance following high-frequency hearing loss in the false killer whale (Pseudorca crassidens). AB - Toothed whales and dolphins possess a hypertrophied auditory system that allows for the production and hearing of ultrasonic signals. Although the fossil record provides information on the evolution of the auditory structures found in extant odontocetes, it cannot provide information on the evolutionary pressures leading to the hypertrophied auditory system. Investigating the effect of hearing loss may provide evidence for the reason for the development of high-frequency hearing in echolocating animals by demonstrating how high-frequency hearing assists in the functioning echolocation system. The discrimination abilities of a false killer whale (Pseudorca crassidens) were measured prior to and after documented high-frequency hearing loss. In 1992, the subject had good hearing and could hear at frequencies up to 100 kHz. In 2008, the subject had lost hearing at frequencies above 40 kHz. First in 1992, and then again in 2008, the subject performed an identical echolocation task, discriminating between machined hollow aluminum cylinder targets of differing wall thickness. Performances were recorded for individual target differences and compared between both experimental years. Performances on individual targets dropped between 1992 and 2008, with a maximum performance reduction of 36.1%. These data indicate that, with a loss in high frequency hearing, there was a concomitant reduction in echolocation discrimination ability, and suggest that the development of a hypertrophied auditory system capable of hearing at ultrasonic frequencies evolved in response to pressures for fine-scale echolocation discrimination. PMID- 20952622 TI - Putative pacemakers of crayfish show clock proteins interlocked with circadian oscillations. AB - Although the molecular mechanisms that control circadian rhythms in many animals, particularly in the fly, are well known, molecular and biochemical studies addressing the location and function of the proteins and genes contributing to the cycling of the clock in crayfish Procambarus clarkii are scarce. In this study, we investigated whether three proteins that interact in the feedback loop of the molecular clock described for Drosophila are expressed in the putative circadian pacemakers of crayfish retina, eyestalk and brain and whether their expression cycles in a manner consistent with elements of the circadian clock. Here we identified PER, TIM and CLK immunoreactivity in the cytoplasm and nucleus of cells located in the retina as well as in clusters of cells and neuropils of the optic ganglia, lateral protocerebrum and brain. Brain clusters 6, 10, 9 and 11, in particular, showed Per, Tim and Clk-like immunoreactivity at the perikarya and nucleus, and these antigens colocalized at Zeitgeber time (ZT) 0 and/or ZT 12. A biochemical assay demonstrated circadian functionality of Per, Tim and Clk proteins. Both in the eyestalk and in the brain, these proteins demonstrated apparent daily and circadian rhythms. The presence and colocalization of these clock proteins in the cytoplasm and/or nucleus of several cells of retina, optic lobe and brain, depending on time, as well as their circadian oscillations, suggest interactions between positive and negative transcription factors and clock proteins similar to those forming the feedback loop of the canonical model proposed for different animals. PMID- 20952623 TI - The impact of glide phases on the trackability of hydrodynamic trails in harbour seals (Phoca vitulina). AB - The mystacial vibrissae of harbour seals (Phoca vitulina) constitute a highly sensitive hydrodynamic receptor system enabling the seals to detect and follow hydrodynamic trails. In the wild, hydrodynamic trails, as generated by swimming fish, consist of cyclic burst-and-glide phases, associated with various differences in the physical parameters of the trail. Here, we investigated the impact of glide phases on the trackability of differently aged hydrodynamic trails in a harbour seal. As fish are not easily trained to swim certain paths with predetermined burst-and-glide phases, the respective hydrodynamic trails were generated using a remote-controlled miniature submarine. Gliding phases in hydrodynamic trails had a negative impact on the trackability when trails were 15 s old. The seal lost the generated trails more often within the transition zones, when the submarine switched from a burst to a glide moving pattern. Hydrodynamic parameter analysis (particle image velocimetry) revealed that the smaller dimensions and faster decay of hydrodynamic trails generated by the gliding submarine are responsible for the impaired success of the seal tracking the gliding phase. Furthermore, the change of gross water flow generated by the submarine from a rearwards-directed stream in the burst phase to a water flow passively dragged behind the submarine during gliding might influence the ability of the seal to follow the trail as this might cause a weaker deflection of the vibrissae. The possible ecological implications of intermittent swimming behaviour in fish for piscivorous predators are discussed. PMID- 20952624 TI - Flight behaviour of the hawkmoth Manduca sexta towards unimodal and multimodal targets. AB - Here, we analyse the flight behaviour of the hawkmoth Manduca sexta while it approaches three different artificial flower stimuli: a clearly visible blue flower, an invisible scented flower and a flower that is both visible and scented. By tracking the moths in fine temporal detail, we find that flight towards an artificial flower differs depending on whether the stimulus is unimodal (either visual or olfactory) or multimodal (both visual and olfactory). In all three cases, the moth reduces its speed as it nears the target but the speed is higher overall when the visual stimulus is not present. Visual feedback, as well as the concentration gradient of the odour, is used to guide the moths towards the stimulus. The main difference in flight behaviour between an approach towards a visual and a multimodal stimulus is that the olfactory information makes the moths turn more rapidly towards the multimodal stimulus. We also find that moths extend their proboscises in front of a clearly visible feeder independent of whether an odour is present. In contrast, a scented transparent artificial flower only occasionally triggers this response. PMID- 20952625 TI - Sound detection by the longfin squid (Loligo pealeii) studied with auditory evoked potentials: sensitivity to low-frequency particle motion and not pressure. AB - Although hearing has been described for many underwater species, there is much debate regarding if and how cephalopods detect sound. Here we quantify the acoustic sensitivity of the longfin squid (Loligo pealeii) using near-field acoustic and shaker-generated acceleration stimuli. Sound field pressure and particle motion components were measured from 30 to 10,000 Hz and acceleration stimuli were measured from 20 to 1000 Hz. Responses were determined using auditory evoked potentials (AEPs) with electrodes placed near the statocysts. Evoked potentials were generated by both stimuli and consisted of two wave types: (1) rapid stimulus-following waves, and (2) slower, high-amplitude waves, similar to some fish AEPs. Responses were obtained between 30 and 500 Hz with lowest thresholds between 100 and 200 Hz. At the best frequencies, AEP amplitudes were often >20 MUV. Evoked potentials were extinguished at all frequencies if (1) water temperatures were less than 8 degrees C, (2) statocysts were ablated, or (3) recording electrodes were placed in locations other than near the statocysts. Both the AEP response characteristics and the range of responses suggest that squid detect sound similarly to most fish, with the statocyst acting as an accelerometer through which squid detect the particle motion component of a sound field. The modality and frequency range indicate that squid probably detect acoustic particle motion stimuli from both predators and prey as well as low frequency environmental sound signatures that may aid navigation. PMID- 20952626 TI - Imaging fertilization in flowering plants, not so abominable after all. AB - Although the discovery of double fertilization in flowering plants took place at the end of the nineteenth century little progress had been made in understanding the cellular and molecular mechanisms involved until the end of the twentieth century. After attempts to study fertilization with isolated male and female gametes, researchers turned to Arabidopsis thaliana as a model for genetic analysis and in vivo imaging. The development of confocal imaging and fluorescent proteins, coupled with new molecular insights into cell fate specification of plant gametes, allowed the development of robust markers for cells participating in double fertilization. These markers enabled the imaging of double fertilization in vivo in Arabidopsis. These studies have been coupled with the identification and molecular characterization of genes controlling fertilization in Arabidopsis. Live imaging has already provided new insights on sperm cell delivery, the equivalence of the fate of the sperm cells, gamete fusion, and re initiation of the zygotic life. This review covers these topics and outlines many important aspects of double fertilization that remain unknown. PMID- 20952627 TI - Raising yield potential of wheat. III. Optimizing partitioning to grain while maintaining lodging resistance. AB - A substantial increase in grain yield potential is required, along with better use of water and fertilizer, to ensure food security and environmental protection in future decades. For improvements in photosynthetic capacity to result in additional wheat yield, extra assimilates must be partitioned to developing spikes and grains and/or potential grain weight increased to accommodate the extra assimilates. At the same time, improvement in dry matter partitioning to spikes should ensure that it does not increase stem or root lodging. It is therefore crucial that improvements in structural and reproductive aspects of growth accompany increases in photosynthesis to enhance the net agronomic benefits of genetic modifications. In this article, six complementary approaches are proposed, namely: (i) optimizing developmental pattern to maximize spike fertility and grain number, (ii) optimizing spike growth to maximize grain number and dry matter harvest index, (iii) improving spike fertility through desensitizing floret abortion to environmental cues, (iv) improving potential grain size and grain filling, and (v) improving lodging resistance. Since many of the traits tackled in these approaches interact strongly, an integrative modelling approach is also proposed, to (vi) identify any trade-offs between key traits, hence to define target ideotypes in quantitative terms. The potential for genetic dissection of key traits via quantitative trait loci analysis is discussed for the efficient deployment of existing variation in breeding programmes. These proposals should maximize returns in food production from investments in increased crop biomass by increasing spike fertility, grain number per unit area and harvest index whilst optimizing the trade-offs with potential grain weight and lodging resistance. PMID- 20952628 TI - Regulation of flowering time and floral patterning by miR172. AB - Since the discovery of miRNAs in plants it has become clear that they are central to the regulation of many aspects of plant development and responses to the environment. miR172 regulates expression of a small group of AP2-like transcription factors in an evolutionarily ancient interaction. miR172 functions in regulating the transitions between developmental stages and in specifying floral organ identity. These two roles are conserved across monocotyledons and dicotyledons. Investigations into the roles of miR172 and its targets in phase changes in the model plant Arabidopsis have illustrated that this process is governed by complex regulatory systems. In addition to its conserved roles, miR172 has also acquired specialized species-specific functions in other aspects of plant development such as cleistogamy and tuberization. PMID- 20952629 TI - Raising yield potential of wheat. I. Overview of a consortium approach and breeding strategies. AB - Theoretical considerations suggest that wheat yield potential could be increased by up to 50% through the genetic improvement of radiation use efficiency (RUE). However, to achieve agronomic impacts, structural and reproductive aspects of the crop must be improved in parallel. A Wheat Yield Consortium (WYC) has been convened that fosters linkage between ongoing research platforms in order to develop a cohesive portfolio of activities that will maximize the probability of impact in farmers' fields. Attempts to increase RUE will focus on improving the performance and regulation of Rubisco, introduction of C(4)-like traits such as CO(2)-concentrating mechanisms, improvement of light interception, and improvement of photosynthesis at the spike and whole canopy levels. For extra photo-assimilates to translate into increased grain yield, reproductive aspects of growth must be tailored to a range of agro-ecosystems to ensure that stable expression of a high harvest index (HI) is achieved. Adequate partitioning among plant organs will be critical to achieve favourable expression of HI, and to ensure that plants with heavier grain have strong enough stems and roots to avoid lodging. Trait-based hybridization strategies will aim to achieve their simultaneous expression in elite agronomic backgrounds, and wide crossing will be employed to augment genetic diversity where needed; for example, to introduce traits for improving RUE from wild species or C(4) crops. Genomic selection approaches will be employed, especially for difficult-to-phenotype traits. Genome wide selection will be evaluated and is likely to complement crossing of complex but complementary traits by identifying favourable allele combinations among progeny. Products will be delivered to national wheat programmes worldwide via well-established international nursery systems and are expected to make a significant contribution to global food security. PMID- 20952630 TI - Genetics, phosphorus availability, and herbivore-derived induction as sources of phenotypic variation of leaf volatile terpenes in a pine species. AB - Oleoresin produced and stored in pine tree leaves provides direct resistance to herbivores, while leaf volatile terpenes (LVT) in the resin are also powerful airborne infochemicals. Resin concentration and profile show considerable spatial and temporal phenotypic variation within and among pine populations. LVT biochemistry is known to be under genetic control, and although LVT should be plastic to diverse abiotic and biotic environmental factors such as nutrient availability and herbivore attack, little is known about their relative contributions and interactive effects. The aim of this paper was to clarify whether reduced phosphorus availability could increase the LVT concentration and affect the expression of herbivore-derived induced defences, and how plasticity would contribute to the phenotypic variation of LVT. The constitutive and methyl jasmonate (MeJa) induced LVT concentration and profile were analysed in 17 half sib Pinus pinaster families growing under two levels of P-availability (complete and P-limited fertilization). Individual terpene concentrations showed large additive genetic variation, which was more pronounced in the control than in MeJa induced pines. MeJa application did not affect the LVT concentration, but significantly modified the LVT profile by depleting the alpha-pinene content and reducing the sesquiterpene fraction. Low P-availability strongly reduced plant growth and foliar nutrient concentrations, but did not affect LVT concentration and profile, and did not interact with MeJa-induction. Results indicate a strong homeostasis of LVT concentration to P-availability, and minor changes in the LVT profile due to MeJa-induction. Genetic variation appears to be the main source of phenotypic variation affecting the LVT concentration in this pine species. PMID- 20952631 TI - Association of single-nucleotide polymorphisms from 17 candidate genes with baseline symptom-limited exercise test duration and decrease in duration over 20 years: the Coronary Artery Risk Development in Young Adults (CARDIA) fitness study. AB - BACKGROUND: It is not known whether the genes involved with endurance performance during young adulthood are also involved with changes in performance. We examined the associations of gene variants with symptom-limited exercise test duration at baseline and decrease in duration over 20 years. METHODS AND RESULTS: A total of 3783 (1835 black, 1948 white) and 2335 (1035 black, 1300 white) participants from the Coronary Artery Risk Development in Young Adults study were included in the baseline and 20-year models, respectively. Two hundred seventeen single nucleotide polymorphisms (SNPs) in black participants and 171 in white participants from 17 genes were genotyped. In blacks, 5 SNPs in the ATP1A2, HIF1A, NOS3, and PPARGC1A loci tended to be associated (P<0.05) with baseline duration in a multivariate regression model. Blacks (n=99) with at least 4 of the most-favorable genotypes at these loci had an ~2-minute longer baseline duration than those with only 2 such genotypes (P<0.0001). In whites, the HIF1A rs1957757 and PPARGC1A rs3774909 markers tended to be associated with baseline duration, but the association of a multimarker construct of the most-favorable genotypes at both SNPs with baseline duration was not statistically significant. In whites, 4 SNPs in the AGT, AMPD1, ANG, and PPARGC1A loci tended to be associated with decrease in exercise duration over 20 years, and those with all 4 favorable genotypes (n=40) had a 0.8-minute less decline in duration compared with those with none or 1 (n=232) (P<0.0001). CONCLUSIONS: In multimarker constructs, alleles at genes related to skeletal muscle Na(+)/K(+) transport, hypoxia, and mitochondrial metabolism are associated with symptom-limited exercise test duration over time in adults. PMID- 20952632 TI - Effects on locomotion, muscle, bone, and blood induced by a combination therapy eliciting weight-bearing stepping in nonassisted spinal cord-transected mice. AB - BACKGROUND: The health benefits associated with physical activity-based rehabilitation in patients with no lower-extremity motor function after a spinal cord injury (SCI) is uncertain. METHODS: The authors assessed signs of efficacy, safety, and utility associated with a novel pharmacological combination therapy to activate central pattern generator (CPG) activity and corresponding locomotor activity in complete thoracic Th9/10-transected mice. RESULTS: Subcutaneous administration 4 times per week for 1 month of 1.5 mg/kg buspirone, 1.5 mg/kg apomorphine, 12.5 mg/kg benserazide, and 50 mg/kg L-DOPA induced episodes of weight-bearing stepping on a treadmill in nonassisted paraplegic mice for 45 minute sessions. Hindlimb muscle cross-sectional area and fiber area values as well as several blood cell constituent levels assessed at 30 days postinjury were positively affected by the combination therapy, as compared with controls. Episodes of locomotion remained effective on each treatment. Femoral bone mineral density loss was not prevented by triple therapy. CONCLUSION: Although translation of these findings needs further experimentation, similar pharmacological activation of the CPG offers a novel therapeutic target to provide some health benefits in motor-complete SCI patients. PMID- 20952633 TI - Posterolateral surface electrical stimulation of abdominal expiratory muscles to enhance cough in spinal cord injury. AB - BACKGROUND: Spinal cord injury (SCI) patients have respiratory complications because of abdominal muscle weakness and paralysis, which impair the ability to cough. OBJECTIVE: This study aims to enhance cough in high-level SCI subjects (n = 11, SCI at or above T6) using surface electrical stimulation of the abdominal muscles via 2 pairs of posterolaterally placed electrodes. METHODS: From total lung capacity, subjects performed maximum expiratory pressure (MEP) efforts against a closed airway and voluntary cough efforts. Both efforts were performed with and without superimposed trains of electrical stimulation (50 Hz, 1 second) at a submaximal intensity set to evoke a gastric pressure (P(ga)) of 40 cm H(2)O at functional residual capacity. RESULTS: In the MEP effort, stimulation increased the maximal P(ga) (from 21.4 +/- 7.0 to 59.0 +/- 5.7 cm H(2)O) and esophageal pressure (P(es); 47.2 +/- 11.7 to 65.6 +/- 13.6 cm H(2)O). During the cough efforts, stimulation increased P(ga) (19.5 +/- 6.0 to 57.9 +/- 7.0 cm H(2)O) and P(es) (31.2 +/- 8.7 to 56.6 +/- 10.5 cm H(2)O). The increased expiratory pressures during cough efforts with stimulation increased peak expiratory flow (PEF, by 36% +/- 5%), mean expiratory flow (by 80% +/- 8%), and expired lung volume (by 41% +/- 16%). In every subject, superimposed electrical stimulation improved peak expiratory flow during cough efforts (by 0.99 +/- 0.12 L/s; range, 0.41-1.80 L/s). Wearing an abdominal binder did not improve stimulated cough flows or pressures. CONCLUSIONS: The increases in P(ga) and PEF with electrical stimulation using the novel posterolateral electrode placement are 2 to 3 times greater than improvements reported in other studies. This suggests that posterolateral electrical stimulation of abdominal muscles is a simple noninvasive way to enhance cough in individuals with SCI. PMID- 20952634 TI - Functional isolation within the cerebral cortex in the vegetative state: a nonlinear method to predict clinical outcomes. AB - BACKGROUND: Establishing prognosis in patients in a persistent vegetative state (VS) is still challenging. Neural networks underlying consciousness may be regarded as complex systems whose outputs show a degree of unpredictability experimentally quantifiable by means of nonlinear parameters such as approximate entropy (ApEn). OBJECTIVE: The authors propose that the VS might be the result of derangement of the above neural networks, with an ensuing decrease in complexity and mutual interconnectivity: this might lead to a functional isolation within the cerebral cortex and to a reduction in the chaotic behavior of its outputs, with monotony taking the place of unpredictability. To test this hypothesis, the authors investigated whether nonlinear dynamics methods applied to electroencephalography (EEG) recordings may be able to predict outcomes. METHODS: A total of 38 vegetative patients and 40 matched healthy controls were investigated. At admission, all patients were assessed by means of the Extended Glasgow Outcomes Coma Scale (E-GOS) and the Coma Recovery Scale-Revised (CRS-R). At the same time an EEG recording was performed and used for time series analysis and ApEn computation. Patients were clinically reassessed at 6 months from the first evaluation. RESULTS: Mean ApEn values (0.73, standard deviation [SD] = 0.12 vs 0.97, SD = 0.02; P < .001) were lower in patients than in controls. Patients with the lowest ApEn values either died (n = 14) or remained in a VS (n = 12), whereas patients with the highest ApEn values became minimally conscious (n = 5) or showed partial (n = 4) or full recovery (n = 3). CONCLUSIONS: These findings suggest that dynamic correlates of neural residual complexity might help in predicting outcomes in vegetative patients. PMID- 20952635 TI - Functional analyses of caffeic acid O-Methyltransferase and Cinnamoyl-CoA reductase genes from perennial ryegrass (Lolium perenne). AB - Cinnamoyl CoA-reductase (CCR) and caffeic acid O-methyltransferase (COMT) catalyze key steps in the biosynthesis of monolignols, which serve as building blocks in the formation of plant lignin. We identified candidate genes encoding these two enzymes in perennial ryegrass (Lolium perenne) and show that the spatio temporal expression patterns of these genes in planta correlate well with the developmental profile of lignin deposition. Downregulation of CCR1 and caffeic acid O-methyltransferase 1 (OMT1) using an RNA interference-mediated silencing strategy caused dramatic changes in lignin level and composition in transgenic perennial ryegrass plants grown under both glasshouse and field conditions. In CCR1-deficient perennial ryegrass plants, metabolic profiling indicates the redirection of intermediates both within and beyond the core phenylpropanoid pathway. The combined results strongly support a key role for the OMT1 gene product in the biosynthesis of both syringyl- and guaiacyl-lignin subunits in perennial ryegrass. Both field-grown OMT1-deficient and CCR1-deficient perennial ryegrass plants showed enhanced digestibility without obvious detrimental effects on either plant fitness or biomass production. This highlights the potential of metabolic engineering not only to enhance the forage quality of grasses but also to produce optimal feedstock plants for biofuel production. PMID- 20952636 TI - Arabidopsis VASCULAR-RELATED NAC-DOMAIN6 directly regulates the genes that govern programmed cell death and secondary wall formation during xylem differentiation. AB - Xylem consists of three types of cells: tracheary elements (TEs), parenchyma cells, and fiber cells. TE differentiation includes two essential processes, programmed cell death (PCD) and secondary cell wall formation. These two processes are tightly coupled. However, little is known about the molecular mechanisms underlying these processes. Here, we show that VASCULAR-RELATED NAC DOMAIN6 (VND6), a master regulator of TEs, regulates some of the downstream genes involved in these processes in a coordinated manner. We first identified genes that are expressed downstream of VND6 but not downstream of SECONDARY WALL ASSOCIATED NAC DOMAIN PROTEIN1 (SND1), a master regulator of xylem fiber cells, using transformed suspension culture cells in microarray experiments. We found that VND6 and SND1 governed distinct aspects of xylem formation, whereas they regulated a number of genes in common, specifically those related to secondary cell wall formation. Genes involved in TE-specific PCD were upregulated only by VND6. Moreover, we revealed that VND6 directly regulated genes that harbor a TE specific cis-element, TERE, in their promoters. Thus, we found that VND6 is a direct regulator of genes related to PCD as well as to secondary wall formation. PMID- 20952637 TI - Antiglycation effects of carnosine and other compounds on the long-term survival of Escherichia coli. AB - Glycation, or nonenzymatic glycosylation, is a chemical reaction between reactive carbonyl-containing compounds and biomolecules containing free amino groups. Carbonyl-containing compounds include reducing sugars such as glucose or fructose, carbohydrate-derived compounds such as methylglyoxal and glyoxal, and nonsugars such as polyunsaturated fatty acids. The latter group includes molecules such as proteins, DNA, and amino lipids. Glycation-induced damage to these biomolecules has been shown to be a contributing factor in human disorders such as Alzheimer's disease, atherosclerosis, and cataracts and in diabetic complications. Glycation also affects Escherichia coli under standard laboratory conditions, leading to a decline in bacterial population density and long-term survival. Here we have shown that as E. coli aged in batch culture, the amount of carboxymethyl lysine, an advanced glycation end product, accumulated over time and that this accumulation was affected by the addition of glucose to the culture medium. The addition of excess glucose or methylglyoxal to the culture medium resulted in a dose-dependent loss of cell viability. We have also demonstrated that glyoxylase enzyme GloA plays a role in cell survival during glycation stress. In addition, we have provided evidence that carnosine, folic acid, and aminoguanidine inhibit glycation in prokaryotes. These agents may also prove to be beneficial to eukaryotes since the chemical processes of glycation are similar in these two domains of life. PMID- 20952639 TI - Potential of the melanophore pigment response for detection of bacterial toxicity. AB - Chromatophore cells have been investigated as potential biodetectors for function based detection of chemically and biologically toxic substances. Oncorhynchus tshawytscha (chinook salmon) melanophores, a chromatophore cell type containing brown pigment, rapidly detect the salmonid pathogens Aeromonas salmonicida, Yersinia ruckeri, and Flavobacterium psychrophilum and the human pathogen Bacillus cereus. PMID- 20952638 TI - Antibiotic-resistant Escherichia coli bacteria, including strains with genes encoding the extended-spectrum beta-lactamase and QnrS, in waterbirds on the Baltic Sea Coast of Poland. AB - Individual cloacal swabs of mallards (Anas platyrhynchos) and of herring gulls (Larus argentatus), as well as samples of waterbird feces obtained in 2008 and 2009, were cultivated for Escherichia coli. Isolates of E. coli were tested for susceptibilities to 12 antimicrobial agents by the disk diffusion method. Moreover, the samples were subcultivated on MacConkey agar (MCA) containing cefotaxime (2 mg liter(-1)) to detect E. coli with extended-spectrum beta lactamase (ESBL) and subsequently on MCA supplemented with ciprofloxacin (0.05 mg liter(-1)) and MCA with nalidixic acid (20 mg liter(-1)) to isolate fluoroquinolone-resistant E. coli. PCR was used to detect specific antibiotic resistance genes. We found 9 E. coli isolates producing ESBL with bla genes: bla(CTX-M-1) (6 isolates), bla(CTX-M-9) plus bla(TEM-1b) (1 isolate), bla(CTX-M 15) plus bla(OXA-1) (1 isolate), and bla(SHV-12) (1 isolate). In the isolate with bla(CTX-M-15), the gene aac(6)-Ib-cr was also detected. The bla genes were harbored by transferable plasmids of the IncN and IncI1 groups. Nine quinolone resistant E. coli isolates with qnrS genes were found and characterized. The gene qnrS was associated with a Tn3-like transposon on the IncX1 plasmid together with bla(TEM-1) in two isolates. The gene qnrS was also harbored by conjugative plasmids of the IncN and IncX2 groups. Even if populations of wild birds are not directly influenced by antibiotic practice, we have demonstrated that antibiotic resistant E. coli strains, including strains with various ESBL and qnrS genes, are found in the feces of wild birds on the coast of the Baltic Sea in Poland. PMID- 20952640 TI - Antibiotic manipulation of intestinal microbiota to identify microbes associated with Campylobacter jejuni exclusion in poultry. AB - The ability of various subsets of poultry intestinal microbiota to protect turkeys from colonization by Campylobacter jejuni was investigated. Community subsets were generated in vivo by inoculation of day-old poults with the cecal contents of a Campylobacter-free adult turkey, followed by treatment with one antimicrobial, either virginiamycin, enrofloxacin, neomycin, or vancomycin. The C. jejuni loads of the enrofloxacin-, neomycin-, and vancomycin-derived communities were decreased by 1 log, 2 logs, and 4 logs, respectively. Examination of the constituents of the derived communities via the array-based method oligonucleotide fingerprinting of rRNA genes detected a subtype of Megamonas hypermegale specific to the C. jejuni-suppressive treatments. PMID- 20952641 TI - Characterization of the protocatechuate 4,5-cleavage pathway operon in Comamonas sp. strain E6 and discovery of a novel pathway gene. AB - The protocatechuate (PCA) 4,5-cleavage (PCA45) pathway is the essential catabolic route for the degradation of various aromatic acids in the genus Comamonas. All of the PCA45 pathway genes, orf1-pmdKEFDABC, as well as another PCA 4,5 dioxygenase gene, pmdA(II)B(II), were isolated from a phthalate-degrading bacterium, Comamonas sp. strain E6. Disruption of pmdB and pmdD in E6, which code for the beta subunit of PCA 4,5-dioxygenase and 2-pyrone-4,6-dicarboxylate (PDC) hydrolase, respectively, resulted in a growth defect on PCA, indicating that these genes are essential for the growth of E6 on PCA. On the other hand, inactivation of pmdB(II) did not affect the growth of E6 on PCA. Disruption of pmdK, which is related to a 4-hydroxybenzoate/PCA transporter of Pseudomonas putida, resulted in growth retardation on PCA. The insertional inactivation of orf1 in E6, whose deduced amino acid sequence has no similarity with proteins of known function, led to the complete loss of growth on PCA and the accumulation of PDC and 4-oxalomesaconate (OMA) from PCA. These results indicated the involvement of orf1 in the PCA45 pathway, and this gene, designated pmdU, was suggested to code for OMA tautomerase. Reverse transcription-PCR analysis suggested that the pmdUKEFDABC genes constitute an operon. The transcription start site of the pmd operon was mapped at 167 nucleotides upstream of the initiation codon of pmdU. The pmd promoter activity was enhanced 20-fold when the cells were grown in the presence of PCA. Inducers of the pmd operon were found to be PCA and PDC, but PDC was the more effective inducer. PMID- 20952642 TI - Construction of a single-chain variable-fragment antibody against the superantigen Staphylococcal enterotoxin B. AB - Staphylococcal food poisoning (SFP) is one of the most prevalent causes of food borne illness throughout the world. SFP is caused by 21 different types of staphylococcal enterotoxins produced by Staphylococcus aureus. Among these, staphylococcal enterotoxin B (SEB) is the most potent toxin and is a listed biological warfare (BW) agent. Therefore, development of immunological reagents for detection of SEB is of the utmost importance. High-affinity and specific monoclonal antibodies are being used for detection of SEB, but hybridoma clones tend to lose their antibody-secreting ability over time. This problem can be overcome by the use of recombinant antibodies produced in a bacterial system. In the present investigation, genes from a hybridoma clone encoding monoclonal antibody against SEB were immortalized using antibody phage display technology. A murine phage display library containing single-chain variable-fragment (ScFv) antibody genes was constructed in a pCANTAB 5E phagemid vector. Phage particles displaying ScFv were rescued by reinfection of helper phage followed by four rounds of biopanning for selection of SEB binding ScFv antibody fragments by using phage enzyme-linked immunosorbent assay (ELISA). Soluble SEB-ScFv antibodies were characterized from one of the clones showing high affinity for SEB. The anti-SEB ScFv antibody was highly specific, and its affinity constant was 3.16 nM as determined by surface plasmon resonance (SPR). These results demonstrate that the recombinant antibody constructed by immortalizing the antibody genes from a hybridoma clone is useful for immunodetection of SEB. PMID- 20952643 TI - Accumulation of non-superoxide anion reactive oxygen species mediates nitrogen limited alcoholic fermentation by Saccharomyces cerevisiae. AB - Throughout alcoholic fermentation, nitrogen depletion is one of the most important environmental stresses that can negatively affect the yeast metabolic activity and ultimately leads to fermentation arrest. Thus, the identification of the underlying effects and biomarkers of nitrogen limitation is valuable for controlling, and therefore optimizing, alcoholic fermentation. In this study, reactive oxygen species (ROS), plasma membrane integrity, and cell cycle were evaluated in a wine strain of Saccharomyces cerevisiae during alcoholic fermentation in nitrogen-limiting medium under anaerobic conditions. The results indicated that nitrogen limitation leads to an increase in ROS and that the superoxide anion is a minor component of the ROS, but there is increased activity of both Sod2p and Cta1p. Associated with these effects was a decrease in plasma membrane integrity and a persistent cell cycle arrest at G(0)/G(1) phases. Moreover, under these conditions it appears that autophagy, evaluated by ATG8 expression, is induced, suggesting that this mechanism is essential for cell survival but does not prevent the cell cycle arrest observed in slow fermentation. Conversely, nitrogen refeeding allowed cells to reenter cell cycle by decreasing ROS generation and autophagy. Altogether, the results provide new insights on the understanding of wine fermentations under nitrogen-limiting conditions and further indicate that ROS accumulation, evaluated by the MitoTracker Red dye CM-H(2)XRos, and plasma membrane integrity could be useful as predictive markers of fermentation problems. PMID- 20952644 TI - Occurrence, survival, and persistence of human adenoviruses and F-specific RNA phages in raw groundwater. AB - Detection of specific genetic markers can rapidly identify the presence of enteric viruses in groundwater. However, comparison of stability characteristics between genetic and infectivity markers is necessary to better interpret molecular data. Human adenovirus serotype 2 (HAdV2), in conjunction with MS2 phages or GA phages, was spiked into raw groundwater microcosms. Viral stability was periodically assessed by both infectivity and real-time PCR methods. The results of this yearlong study suggest that adenoviruses have the most stable persistence profile and an ability to survive for a long time in groundwater. According to a linear regression model, infectivity reductions of HAdV2 ranged from 0.0076 log(10)/day (4 degrees C) to 0.0279 log(10)/day (20 degrees C) and were significantly lower than those observed for phages. No adenoviral genome degradation was observed at 4 degrees C, and the reduction was estimated at 0.0036 log(10)/day at 20 degrees C. Occurrence study showed that DNA of human adenoviruses could be observed in groundwater from a confined aquifer (7 of the 60 samples were positive by real-time PCR), while no fecal indicators were detected. In agreement with the persistence of genetic markers, the presence of adenoviral DNA in groundwater may be misleading in term of health risk, especially in the absence of information on the infective status. PMID- 20952645 TI - Determination of the effects of medium composition on the monochloramine disinfection kinetics of Nitrosomonas europaea by the propidium monoazide quantitative PCR and Live/Dead BacLight methods. AB - Various medium compositions (phosphate, 1 to 50 mM; ionic strength, 2.8 to 150 meq/liter) significantly affected Nitrosomonas europaea monochloramine disinfection kinetics, as determined by the Live/Dead BacLight (LD) and propidium monoazide quantitative PCR (PMA-qPCR) methods (lag coefficient, 37 to 490 [LD] and 91 to 490 [PMA-qPCR] mg.min/liter; Chick-Watson rate constant, 4.0 * 10(-3) to 9.3 * 10(-3) [LD] and 1.6 * 10(-3) to 9.6 * 10(-3) [PMA-qPCR] liter/mg.min). Two competing effects may account for the variation in disinfection kinetic parameters: (i) increasing kinetics (disinfection rate constant [k] increased, lag coefficient [b] decreased) with increasing phosphate concentration and (ii) decreasing kinetics (k decreased, b increased) with increasing ionic strength. The results support development of a standard medium for evaluating disinfection kinetics in drinking water. PMID- 20952646 TI - Diversity and mobility of integrative and conjugative elements in bovine isolates of Streptococcus agalactiae, S. dysgalactiae subsp. dysgalactiae, and S. uberis. AB - Bovine isolates of Streptococcus agalactiae (n = 76), Streptococcus dysgalactiae subsp. dysgalactiae (n = 32), and Streptococcus uberis (n = 101) were analyzed for the presence of different integrative and conjugative elements (ICEs) and their association with macrolide, lincosamide, and tetracycline resistance. The diversity of the isolates included in this study was demonstrated by multilocus sequence typing for S. agalactiae and pulsed-field gel electrophoresis for S. dysgalactiae and S. uberis. Most of the erythromycin-resistant strains carry an ermB gene. Five strains of S. uberis that are resistant to lincomycin but susceptible to erythromycin carry the lin(B) gene, and one has both linB and lnuD genes. In contrast to S. uberis, most of the S. agalactiae and S. dysgalactiae tetracycline-resistant isolates carry a tet(M) gene. A tet(S) gene was also detected in the three species. A Tn916-related element was detected in 30 to 50% of the tetracycline-resistant strains in the three species. Tetracycline resistance was successfully transferred by conjugation to an S. agalactiae strain. Most of the isolates carry an ICE integrated in the rplL gene. In addition, half of the S. agalactiae isolates have an ICE integrated in a tRNA lysine (tRNA(Lys)) gene. Such an element is also present in 20% of the isolates of S. dysgalactiae and S. uberis. A circular form of these ICEs was detected in all of the isolates tested, indicating that these genetic elements are mobile. These ICEs could thus also be a vehicle for horizontal gene transfer between streptococci of animal and/or human origin. PMID- 20952647 TI - Associations between the presence of virulence determinants and the epidemiology and ecology of zoonotic Escherichia coli. AB - The severity of human infection with pathogenic Escherichia coli depends on two major virulence determinants (eae and stx) that, respectively, produce intimin and Shiga toxin. In cattle, both may enhance colonization, but whether this increases fitness by enhancing cattle-to-cattle transmission in the field is unknown. In E. coli O157, the almost uniform presence of the virulence determinants in cattle isolates prevents comparative analysis. The availability to this study of extensive non-O157 E. coli data, with much greater diversity in carriage of virulence determinants, provides the opportunity to gain insight into their potential impact on transmission. Dynamic models were used to simulate expected prevalence distributions for serogroups O26 and O103. Transmission parameters were estimated by fitting model outputs to prevalence data from Scottish cattle using a Bayesian Markov chain Monte Carlo (MCMC) approach. Despite similar prevalence distributions for O26 and O103, their transmission dynamics were distinct. Serogroup O26 strains appear well adapted to the cattle host. The dynamics are characterized by a basic reproduction ratio (R(0)) of >1 (allowing sustained cattle-to-cattle transmission), a relatively low transmission rate from environmental reservoirs, and substantial association with eae on transmission. The presence of stx(2) was associated with reduced transmission. In contrast, serogroup O103 appears better adapted to the noncattle environment, characterized by an R(0) value of <1 for plausible test sensitivities, a significantly higher transmission rate from noncattle sources than serogroup O26, and an absence of fitness benefits associated with the carriage of eae. Thus, the association of eae with enhanced transmission depends on the E. coli serogroup. Our results suggest that the capacity of E. coli strains to derive fitness benefits from virulence determinants influences the prevalence in the cattle population and the ecology and epidemiology of the host organism. PMID- 20952649 TI - Response of nursery pigs to a synbiotic preparation of starch and an anti Escherichia coli K88 probiotic. AB - Postweaning diarrhea in pigs is frequently caused by enterotoxigenic Escherichia coli K88 (ETEC). The aim of this study was to test the efficacy of E. coli probiotics (PRO) in young pigs challenged with E. coli K88. We also tested the synbiotic interaction with raw potato starch (RPS), which can be used as a prebiotic. Forty 17-day-old weaned piglets were randomly assigned to four treatments: treatment 1, positive-control diet (C), no probiotics or RPS but containing in-feed antibiotics; treatment 2, probiotic (PRO), no feed antibiotics plus a 50:50 mixture of probiotic E. coli strains UM-2 and UM-7; treatment 3, 14% RPS, no antibiotics (RPS); treatment 4, 14% RPS plus a 50:50 mixture of probiotic E. coli strains UM-2 and UM-7, no antibiotics (PRO-RPS). The pigs were challenged with pathogenic E. coli K88 strains on day 7 of the experiment (24-day-old pigs) and euthanized on day 10 of the experiment (35-day-old pigs). Probiotic and pathogenic E. coli strains were enumerated by selective enrichment on antibiotics, and microbial community analysis was conducted using terminal restriction length polymorphism analysis (T-RFLP) of 16S rRNA genes. The combination of raw potato starch and the probiotic had a beneficial effect on piglet growth performance and resulted in a reduction of diarrhea and increased microbial diversity in the gut. We conclude that the use of E. coli probiotic strains against E. coli K88 in the presence of raw potato starch is effective in reducing the negative effects of ETEC in a piglet challenge model. PMID- 20952648 TI - Both leaf properties and microbe-microbe interactions influence within-species variation in bacterial population diversity and structure in the lettuce (Lactuca Species) phyllosphere. AB - Morphological and chemical differences between plant genera influence phyllosphere microbial populations, but the factors driving within-species variation in phyllosphere populations are poorly understood. Twenty-six lettuce accessions were used to investigate factors controlling within-species variation in phyllosphere bacterial populations. Morphological and physiochemical characteristics of the plants were compared, and bacterial community structure and diversity were investigated using terminal restriction fragment length polymorphism (T-RFLP) profiling and 16S rRNA gene clone libraries. Plant morphology and levels of soluble carbohydrates, calcium, and phenolic compounds (which have long been associated with plant responses to biotic stress) were found to significantly influence bacterial community structure. Clone libraries from three representative accessions were found to be significantly different in terms of both sequence differences and the bacterial genera represented. All three libraries were dominated by Pseudomonas species and the Enterobacteriaceae family. Significant differences in the relative proportions of genera in the Enterobacteriaceae were detected between lettuce accessions. Two such genera (Erwinia and Enterobacter) showed significant variation between the accessions and revealed microbe-microbe interactions. We conclude that both leaf surface properties and microbial interactions are important in determining the structure and diversity of the phyllosphere bacterial community. PMID- 20952650 TI - Biodegradation of a biocide (Cu-N-cyclohexyldiazenium dioxide) component of a wood preservative by a defined soil bacterial community. AB - The wood protection industry has refined their products from chrome-, copper-, and arsenate-based wood preservatives toward solely copper-based preservatives in combination with organic biocides. One of these is Cu-HDO, containing the chelation product of copper and N-cyclohexyldiazenium dioxide (HDO). In this study, the fate of isotope-labeled ((13)C) and nonlabeled ((12)C) Cu-HDO incorporated in wood sawdust mixed with soil was investigated. HDO concentration was monitored by high-pressure liquid chromatography. The total carbon and the delta(13)C content of respired CO(2), as well as of the soil-wood-sawdust mixture, were determined with an elemental analyzer-isotopic ratio mass spectrometer. The concentration of HDO decreased significantly after 105 days of incubation, and after 24 days the (13)CO(2) concentration respired from soil increased steadily to a maximum after 64 days of incubation. Phospholipid fatty acid-stable isotope probing (PFA-SIP) analysis revealed that the dominant PFAs C(19:0)d8,9, C(18:0), C(18:1)omega7, C(18:2)omega6,9, C(17:1)d7,8, C(16:0), and C(16:1)omega7 were highly enriched in their delta(13)C content. Moreover, RNA-SIP identified members of the phylum Acidobacteria and the genera Phenylobacterium and Comamonas that were assimilating carbon from HDO exclusively. Cu-HDO as part of a wood preservative effectively decreased fungal wood decay and overall microbial respiration from soil. In turn, a defined bacterial community was stimulated that was able to metabolize HDO completely. PMID- 20952651 TI - Effects of engineered cerium oxide nanoparticles on bacterial growth and viability. AB - Interest in engineered nanostructures has risen in recent years due to their use in energy conservation strategies and biomedicine. To ensure prudent development and use of nanomaterials, the fate and effects of such engineered structures on the environment should be understood. Interactions of nanomaterials with environmental microorganisms are inevitable, but the general consequences of such interactions remain unclear, due to a lack of standard methods for assessing such interactions. Therefore, we have initiated a multianalytical approach to understand the interactions of synthesized nanoparticles with bacterial systems. These efforts are focused initially on cerium oxide nanoparticles and model bacteria in order to evaluate characterization procedures and the possible fate of such materials in the environment. The growth and viability of the Gram negative species Escherichia coli and Shewanella oneidensis, a metal-reducing bacterium, and the Gram-positive species Bacillus subtilis were examined relative to cerium oxide particle size, growth media, pH, and dosage. A hydrothermal synthesis approach was used to prepare cerium oxide nanoparticles of defined sizes in order to eliminate complications originating from the use of organic solvents and surfactants. Bactericidal effects were determined from MIC and CFU measurements, disk diffusion tests, and live/dead assays. For E. coli and B. subtilis, clear strain- and size-dependent inhibition was observed, whereas S. oneidensis appeared to be unaffected by the particles. Transmission electron microscopy along with microarray-based transcriptional profiling was used to understand the response mechanism of the bacteria. Use of multiple analytical approaches adds confidence to toxicity assessments, while the use of different bacterial systems highlights the potential wide-ranging effects of nanomaterial interactions in the environment. PMID- 20952652 TI - Activation of a silent fungal polyketide biosynthesis pathway through regulatory cross talk with a cryptic nonribosomal peptide synthetase gene cluster. AB - Filamentous fungi produce numerous natural products that constitute a consistent source of potential drug leads, yet it seems that the majority of natural products are overlooked since most biosynthesis gene clusters are silent under standard cultivation conditions. Screening secondary metabolite genes of the model fungus Aspergillus nidulans, we noted a silent gene cluster on chromosome II comprising two nonribosomal peptide synthetase (NRPS) genes, inpA and inpB, flanked by a regulatory gene that we named scpR for secondary metabolism cross pathway regulator. The induced expression of the scpR gene using the promoter of the alcohol dehydrogenase AlcA led to the transcriptional activation of both the endogenous scpR gene and the NRPS genes. Surprisingly, metabolic profiling of the supernatant of mycelia overexpressing scpR revealed the production of the polyketide asperfuranone. Through transcriptome analysis we found that another silent secondary metabolite gene cluster located on chromosome VIII coding for asperfuranone biosynthesis was specifically induced. Quantitative reverse transcription-PCR proved the transcription not only of the corresponding polyketide synthase (PKS) biosynthesis genes, afoE and afoG, but also of their activator, afoA, under alcAp-scpR-inducing conditions. To exclude the possibility that the product of the inp cluster induced the asperfuranone gene cluster, a strain carrying a deletion of the NRPS gene inpB and, in addition, the alcAp-scpR overexpression cassette was generated. In this strain, under inducing conditions, transcripts of the biosynthesis genes of both the NRPS-containing gene cluster inp and the asperfuranone gene cluster except gene inpB were detected. Moreover, the existence of the polyketide product asperfuranone indicates that the transcription factor ScpR controls the expression of the asperfuranone biosynthesis gene cluster. This expression as well as the biosynthesis of asperfuranone was abolished after the deletion of the asperfuranone activator gene afoA, indicating that ScpR binds to the afoA promoter. To the best of our knowledge, this is the first report of regulatory cross talk between two biosynthesis gene clusters located on different chromosomes. PMID- 20952653 TI - Agrobacterium tumefaciens-mediated transformation for investigation of somatic recombination in the fungal pathogen Armillaria mellea. AB - Armillaria root disease is one of the most damaging timber and fruit tree diseases in the world. Despite its economic importance, many basic questions about the biology of the causal fungi, Armillaria spp., are unanswered. For example, Armillaria undergoes matings between diploid and haploid mycelia, which can result in a recombinant diploid without meiosis. Evidence of such somatic recombination in natural populations suggests that this reproductive mode may affect the pathogen's ecology. Investigations of the mechanisms and adaptive consequences of somatic recombination are, however, hampered by the lack of a method to reliably synthesize somatic recombinants. Here we report the first genetic transformation system for the genus Armillaria. We transformed A. mellea with selective markers for use in diploid-haploid matings to reliably synthesize somatic recombinants. This was accomplished with Agrobacterium tumefaciens carrying pBGgHg, which carries the hygromycin phosphotransferase gene (hph). hph was integrated into transformants, as evidenced by serial transfer to selective media, PCR, reverse transcription-PCR (RT-PCR), and Southern hybridization. Nuclear and mitochondrial markers were developed to genotype synthesized mycelia. In matings between a wild-type diploid and hygromycin-resistant haploids (transgenic), we identified recombinant, hygromycin-resistant diploids and, additionally, hygromycin-resistant triploids, all with the mitochondrial haplotype of the haploid partner. Our approach created no mycelium in which the haploid nucleus was replaced by the diploid nucleus, the typical outcome of diploid-haploid matings in Armillaria. This genetic transformation system, in combination with new markers to track chromosomal and cytoplasmic inheritance in A. mellea, will advance research aimed at characterizing the significance of somatic recombination in the ecology of this important fungus. PMID- 20952654 TI - Does aqueous fullerene inhibit the growth of Saccharomyces cerevisiae or Escherichia coli? AB - Studies reporting on potentially toxic interactions between aqueous fullerene nanoparticles (nC(60)) and microorganisms have been contradictory. When known confounding factors were avoided, growth yields of Saccharomyces cerevisiae and Escherichia coli cultured in the presence and absence of independently prepared lots of underivatized nC(60) were found not to be significantly different. PMID- 20952655 TI - Mullerian inhibiting substance preferentially inhibits stem/progenitors in human ovarian cancer cell lines compared with chemotherapeutics. AB - Cancer stem cells are proposed to be tumor-initiating cells capable of tumorigenesis, recurrence, metastasis, and drug resistance, and, like somatic stem cells, are thought to be capable of unlimited self-renewal and, when stimulated, proliferation and differentiation. Here we select cells by expression of a panel of markers to enrich for a population with stem cell-like characteristics. A panel of eight was initially selected from 95 human cell surface antigens as each was shared among human ovarian primary cancers, ovarian cancer cell lines, and normal fimbria. A total of 150 combinations of markers were reduced to a panel of three--CD44, CD24, and Epcam--which selected, in three ovarian cancer cell lines, those cells which best formed colonies. Cells expressing CD44, CD24, and Epcam exhibited stem cell characteristics of shorter tumor-free intervals in vivo after limiting dilution, and enhanced migration in invasion assays in vitro. Also, doxorubicin, cisplatin, and paclitaxel increased this enriched population which, conversely, was significantly inhibited by Mullerian inhibiting substance (MIS) or the MIS mimetic SP600125. These findings demonstrate that flow cytometry can be used to detect a population which shows differential drug sensitivity, and imply that treatment of patients can be individualized to target both stem/progenitor cell enriched and nonenriched subpopulations. The findings also suggest that this population, amenable to isolation by flow cytometry, can be used to screen for novel treatment paradigms, including biologic agents such as MIS, which will improve outcomes for patients with ovarian cancer. PMID- 20952656 TI - Crystal structure of Spot 14, a modulator of fatty acid synthesis. AB - Spot 14 (S14) is a protein that is abundantly expressed in lipogenic tissues and is regulated in a manner similar to other enzymes involved in fatty acid synthesis. Deletion of S14 in mice decreased lipid synthesis in lactating mammary tissue, but the mechanism of S14's action is unknown. Here we present the crystal structure of S14 to 2.65 A and biochemical data showing that S14 can form heterodimers with MIG12. MIG12 modulates fatty acid synthesis by inducing the polymerization and activity of acetyl-CoA carboxylase, the first committed enzymatic reaction in the fatty acid synthesis pathway. Coexpression of S14 and MIG12 leads to heterodimers and reduced acetyl-CoA carboxylase polymerization and activity. The structure of S14 suggests a mechanism whereby heterodimer formation with MIG12 attenuates the ability of MIG12 to activate ACC. PMID- 20952657 TI - NKG2A inhibits NKG2C effector functions of gammadelta T cells: implications in health and disease. AB - The CD94/NKG2 complex is expressed on T and NK lymphocytes. CD94 molecules covalently associate to activating or inhibitory NKG2 molecules, and their expression finely tunes cell responses. Human gammadelta T cells express several NKRs. Expression of these receptors is confined to the cytolytic Vdelta2 subset, which coexpresses the FcgammaRIII CD16 and CD45RA and has been defined as Vgamma9Vdelta2 T(EMRA) cells. We show that the CD94/NKG2C complex, associated with KARAP/DAP12, is fully functional in gammadelta T cells, as determined by measuring IFN-gamma production, T cell proliferation, and cytolytic activity by gammadelta lymphocytes. In contrast, NKG2A expression was found on all gammadelta T cell memory subsets, suggesting a crucial role of the inhibitory signal provided by this receptor on gammadelta T cell responses. Moreover, we found Vgamma9Vdelta2 T(EMRA), NK, and CD8+ alphabeta T cells coexpressing NKG2A and NKG2C receptors. Functional experiments showed that the inhibitory signal mediated by the NKG2A receptor prevails when double-positive cells are activated. Finally, NKG2A expression on gammadelta LDGL correlates with asymptomatic pathology, even in the presence of NKG2C coexpression, whereas in symptomatic patients affected by severe disease, the inhibitory NKG2A receptor is absent, and a variety of activatory NKRs was found. We propose that the silent behavior of gammadelta cells in LDGL patients is a result of effective inhibitory HLA class I receptors. PMID- 20952658 TI - The biological paths of IL-1 family members IL-18 and IL-33. AB - Cytokines are key mediators of the immune system, and few have been more thoroughly studied than those of the IL-1 family. IL-1alpha and IL-1beta are the founding members and now celebrate 25 years since their cloning. In that time, IL 1-directed research has illuminated many aspects of cytokine biology and innate immunity. The family is now recognized to include 11 total members, including IL 18 and IL-33, which are the topic of this review. These two inflammatory cytokines are expressed broadly, and their actions influence a variety of physiologic responses involved in inflammation and immunity. The purpose of this article is not to provide an exhaustive review of IL-18 and IL-33 but rather, to summarize what is known about their key functions and to provide perspective on their similarities and differences. PMID- 20952660 TI - Foxp3+IL-17+ T cells promote development of cancer-initiating cells in colorectal cancer. AB - The pathogenesis of CRC remains to be further understood. This study was designed to elucidate the role of Foxp3+IL-17+ T cells in the pathogenesis of CRC. Surgically removed CRC tissue was collected from 12 patients with CRC. The frequency and cytokine profile of Foxp3+IL-17+ T cells in CRC were examined by flow cytometry. Chemokine CXCL11 was examined in CRC tissue by Western blotting. Treg chemotaxis was examined in a transwell system. The effect of Foxp3+IL-17+ T cells on induction of cancer-initiating cells was examined; the latter's Akt and MAPK activities and colony formation were examined afterward. Abundant Foxp3+IL 17+ T cells were detected in CRC tissue that expresses high levels of TGF-beta, CXCR3, CCR6, and RORgammat. High levels of CXCL11 were detected in CRC tissue derived CD68+ cells, which had a strong chemotactic effect on Foxp3+ Tregs. Hypoxia induced the expression of IL-17 in Foxp3+ Tregs; Foxp3+IL-17+ T cells were capable of inducing CRC-associated cell markers in BMMo and drove the cells to be cancer-initiating cells. High levels of phosphorylated Akt and MAPK were detected in the induced cancer-initiation cells; the latter has the capability to form a colony. CRC tissue-derived Foxp3+IL-17+ cells have the capacity to induce cancer-initiating cells. PMID- 20952661 TI - Heart rate reduction with ivabradine prevents the global phenotype of left ventricular remodeling. AB - The aim of this study was to investigate the effect of chronic heart rate (HR) reduction with the hyperpolarization-activated current inhibitor ivabradine on the global phenotype of left ventricular (LV) remodeling in a ligated rat model. Seven days after coronary artery ligation, Wistar rats received ivabradine (10 mg . kg(-1) . day(-1) administered in drinking water) [myocardial infarction + ivabradine (MI+IVA), n = 22] or vehicle only (drinking water) (MI, n = 20) for 90 days. A sham group (n = 20) was included for model validation. MI+IVA rats had 12% lower HR (P < 0.01), improved LV volumes, 15% higher LV ejection fraction (LVEF, P < 0.01) than MI rats, and 33% reductions in both plasma atrial natriuretic peptide (ANP, P = 0.052) and cardiac hydroxyproline. Using patch clamp, action potential duration was reduced and transient outward current density increased (P < 0.05). Cardiac energy metabolism was also improved (+33% creatine phosphate, P < 0.001; +15% ATP; and +9% energy charge, P < 0.05). Significant correlations were found between HR and parameters of cardiac metabolism, ANP, and LVEF (all P < 0.05). The HR-reducing properties of ivabradine prevent changes in the global phenotype of LV remodeling in the rat, optimize energy consumption, and avoid electrophysiological and structural remodeling. PMID- 20952659 TI - Opioid-induced chemokine expression requires NF-kappaB activity: the role of PKCzeta. AB - Opioid receptor agonists induce broad immunomodulatory activity, which substantially alters host defense and the inflammatory response. Previous studies have shown that the MOR selective agonist DAMGO has the capacity to increase the expression of the proinflammatory chemokines CCL2, CCL5, and CXCL10 in human PBMCs. NF-kappaB is a transcription factor that plays a pivotal role in innate and adaptive immune responses. We report that NF-kappaB is a vital player in the DAMGO-induced, MOR-mediated regulation of chemokine expression. Results show that NF-kappaB inhibitors prevent the induction of CCL2 expression in response to DAMGO administration and that the NF-kappaB subunit, p65, is phosphorylated at serine residues 311 and 536 in response to MOR activation. Furthermore, we demonstrate that PKCzeta is phosphorylated following DAMGO-induced MOR activation, and this kinase is essential for NF-kappaB activation as well as CCL2 expression and transcriptional activity. Finally, ChIP analysis shows that DAMGO administration induces binding of p65 to the enhancer region of the CCL2 promoter. These data are consistent with the notion that MOR activation promotes a proinflammatory response, which involves NF-kappaB activation. Our results also suggest a significant and novel role for PKCzeta as an essential participant in the MOR-mediated regulation of proinflammatory chemokine expression. PMID- 20952662 TI - Intrathecal PACAP-38 causes increases in sympathetic nerve activity and heart rate but not blood pressure in the spontaneously hypertensive rat. AB - The rostral ventrolateral medulla contains presympathetic neurons that project monosynaptically to sympathetic preganglionic neurons (SPN) in the spinal cord and are essential for the tonic and reflex control of the cardiovascular system. SPN directly innervate the adrenal medulla and, via postganglionic axons, affect the heart, kidneys, and blood vessels to alter sympathetic outflow and hence blood pressure. Over 80% of bulbospinal, catecholaminergic (C1) neurons contain pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA. Activation of PACAP receptors with intrathecal infusion of PACAP-38 causes a robust, prolonged elevation in sympathetic tone. Given that a common feature of most forms of hypertension is elevated sympathetic tone, this study aimed to determine in the spontaneously hypertensive rat (SHR) and the Wistar Kyoto rat (normotensive control) 1) the proportion of C1 neurons containing PACAP mRNA and 2) responsiveness to intrathecal PACAP-38. We further investigated whether intrathecal infusion of the PACAP antagonist, PACAP(6-38), reduces the hypertension in the SHR. The principal findings are that 1) the proportion of PACAP mRNA-containing C1 neurons is not different between normotensive and hypertensive rats, 2) intrathecal PACAP-38 causes a strain-dependent, sustained sympathoexcitation and tachycardia with variable effects on mean arterial pressure in normotensive and hypertensive rats, and 3) PACAP(6-38) effectively attenuated the effects of intrathecal PACAP-38, but had no effect alone, on any baseline variables. This finding indicates that PACAP-38 is not tonically released in the spinal cord of rats. A role for PACAP in hypertension in conscious rats remains to be determined. PMID- 20952664 TI - Altered hemodynamic regulation and reflex control during exercise and recovery in obese boys. AB - The aims of the present study were to assess in obese and lean boys 1) the hemodynamic responses and baroreflex sensitivity (BRS) to isometric handgrip exercise (HG) and recovery and 2) the muscle metaboreflex-induced blood pressure response and the variables that determine this response. Twenty-seven boys (14 obese and 13 lean boys, body mass index: 29.2 +/- 0.9 vs. 18.9 +/- 0.3 kg/m(2), respectively) participated. The testing protocol involved 3 min of baseline, 3 min of HG (30% maximum voluntary contraction), 3 min of circulatory occlusion, and 3 min of recovery. The same protocol was repeated without occlusion. At baseline, no differences were detected between groups in beat-to-beat arterial pressure (AP), heart rate (HR), and BRS; however, obese boys had higher stroke volume and lower total peripheral resistance than lean boys (P < 0.05). During HG, lean boys exhibited higher HR and lower BRS compared with their obese counterparts. In lean boys, BRS decreased during HG compared with baseline, whereas in obese boys, it was not significantly modified. In lean boys, TPR was elevated during HG and declined after exercise, whereas in obese boys, TPR did not significantly decrease after exercise cessation. In the postexercise period, BRS in lean boys returned to baseline, whereas an overshoot was observed in obese boys. Postexercise BRS was correlated with body mass index (R = 0.56, P < 0.05). Although the metaboreflex-induced increase in AP was similar between obese and lean children, it was achieved via different mechanisms: in lean children, total peripheral resistance was the main contributor to AP maintenance during the metaboreflex, whereas in obese children, stroke volume significantly contributed to AP maintenance during the metaboreflex. In conclusion, obese normotensive children demonstrated altered cardiovascular hemodynamics and reflex control during exercise and recovery. PMID- 20952663 TI - Microinjections of urocortin1 into the nucleus ambiguus of the rat elicit bradycardia. AB - Urocortins are members of the hypothalamic corticotropin-releasing factor (CRF) peptide family. Urocortin1 (UCN1) mRNA has been reported to be expressed in the brainstem neurons. The present investigation was carried out to test the hypothesis that microinjections of UCN1 into the nucleus ambiguus (nAmb) may elicit cardiac effects. Urethane-anesthetized, artificially ventilated, adult male Wistar rats, weighing between 300-350 g, were used. nAmb was identified by microinjections of l-glutamate (5 mM, 30 nl). Microinjections (30 nl) of different concentrations (0.062, 0.125, 0.25, and 0.5 mM) of UCN1 into the nAmb elicited bradycardic responses (26.5 +/- 1, 30.1 +/- 1.7, 46.9 +/- 1.7, and 40.3 +/- 2.6 beats/min, respectively). These heart rate responses were not accompanied by significant changes in mean arterial pressure. The bradycardic responses to maximally effective concentration of UCN1 (0.25 mM) were significantly (P < 0.05) attenuated by prior microinjections of a selective antagonist (NBI 27914, 1.5 mM) for CRF type 1 receptor (CRF1R). Prior microinjections of ionotropic glutamate receptor (iGLUR) antagonists [d-(-)-2-amino-7-phosphono-heptanoic acid and 2,3 dioxo-6-nitro-1,2,3,4-tetrahydrobenzo-(f)quinoxaline-7-sulfonamide disodium] also attenuated the bradycardia elicited by UCN1 microinjections into the nAmb. Microinjections of NBI 27914 (1.5 mM) into the nAmb did not alter baroreflex responses. Bilateral vagotomy abolished the bradycardic responses to microinjections of UCN1 into the nAmb. These results indicated that 1) microinjections of UCN1 into the nAmb elicited bradycardia, 2) the bradycardia was vagally mediated, 3) activation of CRF1Rs in the nAmb was responsible for the actions of UCN1, and 4) activation of iGLURs in the nAmb also participated in the bradycardia elicited by UCN1. PMID- 20952665 TI - A novel approach to in vivo mitral valve stress analysis. AB - Three-dimensional (3-D) echocardiography allows the generation of anatomically correct and time-resolved geometric mitral valve (MV) models. However, as imaged in vivo, the MV assumes its systolic geometric configuration only when loaded. Customarily, finite element analysis (FEA) is used to predict material stress and strain fields rendered by applying a load on an initially unloaded model. Therefore, this study endeavors to provide a framework for the application of in vivo MV geometry and FEA to MV physiology, pathophysiology, and surgical repair. We hypothesize that in vivo MV geometry can be reasonably used as a surrogate for the unloaded valve in computational (FEA) simulations, yielding reasonable and meaningful stress and strain magnitudes and distributions. Three experiments were undertaken to demonstrate that the MV leaflets are relatively nondeformed during systolic loading: 1) leaflet strain in vivo was measured using sonomicrometry in an ovine model, 2) hybrid models of normal human MVs as constructed using transesophageal real-time 3-D echocardiography (rt-3DE) were repeatedly loaded using FEA, and 3) serial rt-3DE images of normal human MVs were used to construct models at end diastole and end isovolumic contraction to detect any deformation during isovolumic contraction. The average linear strain associated with isovolumic contraction was 0.02 +/- 0.01, measured in vivo with sonomicrometry. Repeated loading of the hybrid normal human MV demonstrated little change in stress or geometry: peak von Mises stress changed by <4% at all locations on the anterior and posterior leaflets. Finally, the in vivo human MV deformed minimally during isovolumic contraction, as measured by the mean absolute difference calculated over the surfaces of both leaflets between serial MV models: 0.53 +/- 0.19 mm. FEA modeling of MV models derived from in vivo high-resolution truly 3-D imaging is reasonable and useful for stress prediction in MV pathologies and repairs. PMID- 20952666 TI - Mice expressing ouabain-sensitive alpha1-Na,K-ATPase have increased susceptibility to pressure overload-induced cardiac hypertrophy. AB - The Na,K-ATPase is a ubiquitous transmembrane pump and a specific receptor for cardiac glycosides such as ouabain and digoxin, which are used in the management of congestive heart failure (CHF). A potential role for these so-called endogenous cardiotonic steroids (CS) has been explored, and it has become apparent that such compounds are elevated and may play an important role in a variety of physiological and pathophysiological conditions such as hypertension and CHF. Recent evidence suggests that the Na,K-ATPase may act as a signal transducer upon CS binding and induce nonproliferative cardiac growth, implicating a role for endogenous CS in the development of cardiac hypertrophy and progressive failure of the heart. In the present study, we tested whether hypertrophic responses to pressure overload would be altered in mutant mice that specifically express ouabain-sensitive or ouabain-resistant alpha1- and alpha2 Na,K-ATPase subunits, as follows: alpha1-resistant, alpha2-resistant (alpha1(R/R)alpha2(R/R)); alpha1-sensitive, alpha2-resistant (alpha1(S/S)alpha2(R/R)); and alpha1-resistant, alpha2-sensitive (alpha1(R/R)alpha2(S/S), wild-type). In alpha1(S/S)alpha2(R/R) mice, pressure overload by transverse aortic coarctation induced severe left ventricular (LV) hypertrophy with extensive perivascular and replacement fibrosis at only 4 wk. Responses in alpha1(R/R)alpha2(S/S) and alpha1(R/R)alpha2(R/R) mice were comparatively mild. Mutant alpha1(S/S)alpha2(R/R) mice also had LV dilatation and depressed LV systolic contractile function by 4 wk of pressure overload. In separate experiments, chronic Digibind treatment prevented the rapid progression of cardiac hypertrophy and fibrosis in alpha1(S/S)alpha2(R/R) mice. These data demonstrate that mice with a ouabain-sensitive alpha1-Na,K-ATPase subunit have a dramatic susceptibility to the development of cardiac hypertrophy, and failure from LV pressure overload and provide evidence for the involvement of endogenous CS in this process. PMID- 20952667 TI - Minor contribution of cytosolic Ca2+ transients to the pacemaker rhythm in guinea pig sinoatrial node cells. AB - The question of the extent to which cytosolic Ca(2+) affects sinoatrial node pacemaker activity has been discussed for decades. We examined this issue by analyzing two mathematical pacemaker models, based on the "Ca(2+) clock" (C) and "membrane clock" (M) hypotheses, together with patch-clamp experiments in isolated guinea pig sinoatrial node cells. By applying lead potential analysis to the models, the C mechanism, which is dependent on potentiation of Na(+)/Ca(2+) exchange current via spontaneous Ca(2+) release from the sarcoplasmic reticulum (SR) during diastole, was found to overlap M mechanisms in the C model. Rapid suppression of pacemaker rhythm was observed in the C model by chelating intracellular Ca(2+), whereas the M model was unaffected. Experimental rupturing of the perforated-patch membrane to allow rapid equilibration of the cytosol with 10 mM BAPTA pipette solution, however, failed to decrease the rate of spontaneous action potential within ~30 s, whereas contraction ceased within ~3 s. The spontaneous rhythm also remained intact within a few minutes when SR Ca(2+) dynamics were acutely disrupted using high doses of SR blockers. These experimental results suggested that rapid disruption of normal Ca(2+) dynamics would not markedly affect spontaneous activity. Experimental prolongation of the action potentials, as well as slowing of the Ca(2+)-mediated inactivation of the L-type Ca(2+) currents induced by BAPTA, were well explained by assuming Ca(2+) chelation, even in the proximity of the channel pore in addition to the bulk cytosol in the M model. Taken together, the experimental and model findings strongly suggest that the C mechanism explicitly described by the C model can hardly be applied to guinea pig sinoatrial node cells. The possible involvement of L-type Ca(2+) current rundown induced secondarily through inhibition of Ca(2+)/calmodulin kinase II and/or Ca(2+)-stimulated adenylyl cyclase was discussed as underlying the disruption of spontaneous activity after prolonged intracellular Ca(2+) concentration reduction for >5 min. PMID- 20952668 TI - Assessment of collateral artery function and growth in a pig model of stepwise coronary occlusion. AB - Therapeutic stimulation of collateral artery growth is a promising approach for treatment of cardiovascular diseases. Unfortunately, translation into clinical practice yet remains cumbersome. Cardiovascular physiology and anatomy are major determinants of vascular growth processes. Hence, large-animal models are needed to improve clinical translatability of preclinical research. Furthermore, acute complete occlusions are mostly applied in experimental research, whereas stepwise occlusions are more often observed in human disease. We developed a model of coronary collateral artery growth in which 1) the artery is occluded in a step wise approach, and 2) effects of local treatment can be measured individually for each supplying coronary vessel. A hemodynamically relevant stenosis was created by implantation of a tapered stent at day 0 (d0) in the left circumflex artery (LCX), followed by complete arterial occlusion at day 14 (d14). Fluorescent microspheres were injected for demarcation of perfusion territories at each time point. Three and four weeks after induction of stenosis, collateral conductance measurements were performed for each coronary artery separately using differently labeled fluorescent microspheres. Postmortem angiography after acute LCX occlusion confirmed the presence of preexistent coronary anastomoses in the pig. The tapered stent created a hemodynamically significant stenosis immediately postplacement (fractional flow reserve, 0.70 +/- 0.03). Between day 21 and 28, collateral conductance significantly increased in both the left anterior descending (LAD) and the right coronary artery (RCA)-supplied, collateral dependent territories (LAD d21, 0.77 +/- 0.14; LAD d28, 1.35 +/- 0.12; RCA d21, 0.88 +/- 0.29; RCA d28, 1.70 +/- 0.16 ml . min(-1) . g(-1) . 100 mmHg(-1)), indicating collateral artery growth. We here describe a new translational minimally invasive model of coronary collateral artery growth in pigs, according to a defined protocol of LCX-stenosis and subsequent occlusion, allowing preclinical evaluation of arteriogenic therapies. PMID- 20952669 TI - Endothelial FGF receptor signaling accelerates atherosclerosis. AB - Members of the fibroblast growth factor (FGF) family have been clinically applied to the treatment of ischemic diseases because of their strong angiogenic actions. Although tissue ischemia is predominantly caused by atherosclerosis, the roles of endothelial FGF receptors (FGF-Rs) in atherosclerosis remain obscure. We generated endothelial cell (EC)-targeted constitutively active FGF-R2 overexpressing mice, using the Tie2 promoter (Tie2-FGF-R2-Tg), and crossed them with apolipoprotein E (ApoE)-deficient mice (ApoE-KO) to generate Tie2-FGF-R2 Tg/ApoE-deficient mice (Tie2-FGF-R2-Tg/ApoE-KO). After being fed a Western diet for 8 wk, the Tie2-FGF-R2-Tg/ApoE-KO demonstrated 2.0-fold greater atherosclerotic lesion area on the luminal surfaces of the aortas than the ApoE KO (P < 0.01). The level of p21(Cip1) protein, a cell cycle inhibitor, in the FGF R2-overexpressing EC was 2.5-fold greater than that in the wild-type (WT) EC at the baseline (P < 0.01). FGF-R2 overexpression in the EC resulted in increased expression of VCAM-1 and ICAM-1, acceleration of apoptosis, and decreased proliferative activity, all of which were normalized by small interfering RNA (siRNA)-mediated knockdown of p21(Cip1) (75% reduction in protein level, P < 0.01). Furthermore, the expression of PDGF-B and Egr-1, a PDGF/p21(Cip1) inducible transcription factor, in the aortic endothelium of Tie2-FGF-R2-Tg/ApoE KO was significantly greater than that in ApoE-KO. The proliferation of vascular smooth muscle cells in the aortic media of Tie2-FGF-R2-Tg/ApoE-KO was 2.0-fold higher than that in ApoE-KO (P < 0.01). Thus our study reveals that endothelial FGF-R2 signaling aggravates atherosclerosis by promoting p21(Cip1)-mediated EC dysfunction and cautions against the use of FGF for therapeutic angiogenesis in the setting of atherosclerosis. PMID- 20952670 TI - Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. AB - Endothelial dysfunction is now considered an important early event in the development of atherosclerosis, which precedes gross morphological signs and clinical symptoms. The assessment of flow-mediated dilation (FMD) was introduced almost 20 years ago as a noninvasive approach to examine vasodilator function in vivo. FMD is widely believed to reflect endothelium-dependent and largely nitric oxide-mediated arterial function and has been used as a surrogate marker of vascular health. This noninvasive technique has been used to compare groups of subjects and to evaluate the impact of interventions within individuals. Despite its widespread adoption, there is considerable variability between studies with respect to the protocols applied, methods of analysis, and interpretation of results. Moreover, differences in methodological approaches have important impacts on the response magnitude, can result in spurious data interpretation, and limit the comparability of outcomes between studies. This review results from a collegial discussion between physiologists with the purpose of developing considered guidelines. The contributors represent several distinct research groups that have independently worked to advance the evidence base for improvement of the technical approaches to FMD measurement and analysis. The outcome is a series of recommendations on the basis of review and critical appraisal of recent physiological studies, pertaining to the most appropriate methods to assess FMD in humans. PMID- 20952671 TI - Circadian regulation of cardiovascular function: a role for vasoactive intestinal peptide. AB - The circadian system, driven by the suprachiasmatic nucleus (SCN), regulates properties of cardiovascular function. The dysfunction of this timing system can result in cardiac pathology. The neuropeptide vasoactive intestinal peptide (VIP) is crucial for circadian rhythms in a number of biological processes including SCN electrical activity and wheel running behavior. Anatomic evidence indicates that SCN neurons expressing VIP are well positioned to drive circadian regulation of cardiac function through interactions with the autonomic centers. In this study, we tested the hypothesis that loss of VIP would result in circadian deficits in heart rate (HR) and clock gene expression in cardiac tissue. We implanted radiotelemetry devices into VIP-deficient mice and wild-type (WT) controls and continuously recorded HR, body temperature, and cage activity in freely moving mice. Under light-dark conditions, VIP-deficient mice displayed weak rhythms in HR, body temperature, and cage activity, with onsets that were advanced in phase compared with WT mice. Similarly, clock gene expression in cardiac tissue was rhythmic but phase advanced in mutant mice. In constant darkness, the normal circadian rhythms in HR were lost in VIP-deficient mice; however, most mutant mice continued to exhibit circadian rhythms of body temperature with shortened free-running period. The loss of VIP altered, but did not abolish, autonomic regulation of HR. Analysis of the echocardiograms did not find any evidence for a loss of cardiac function in VIP-deficient mice, and the size of the hearts did not differ between genotypes. These results demonstrate that VIP is an important regulator of physiological circadian rhythmicity in the heart. PMID- 20952672 TI - Sensory transduction of the ischemic myocardium. PMID- 20952673 TI - A critical function of Th17 proinflammatory cells in the development of atherosclerotic plaque in mice. AB - Considerable evidence supports that the CD4(+) T cell-mediated immune response contributes to the development of atherosclerotic plaque. However, the effects of Th17 cells on atherosclerosis are not thoroughly understood. In this study, we evaluated the production and function of Th17 and Th1 cells in atherosclerotic susceptible ApoE(-/-) mice. We observed that the proportion of Th17 cells, as well as Th1, increased in atherosclerotic ApoE(-/-) mice compared with nonatherosclerotic wild-type littermates. In ApoE(-/-) mice with atherosclerosis, the expression of IL-17 and retinoic acid-related orphan receptor gammat was substantially higher in the arterial wall with plaque than in the arterial wall without plaque. Increased Th17 cells were associated with the magnitude of atherosclerotic plaque in ApoE(-/-) mice. Importantly, treatment of ApoE(-/-) mice with neutralizing anti-IL-17 Ab dramatically inhibited the development of atherosclerotic plaque, whereas rIL-17 application significantly promoted the formation of atherosclerotic plaque. These data demonstrate that Th17 cells play a critical role in atherosclerotic plaque formation in mice, which may have implications in patients with atherosclerosis. PMID- 20952674 TI - Generation and differentiation of IL-17-producing CD4+ T cells in malignant pleural effusion. AB - IL-17-producing CD4(+) T (Th17) cells have been found to be increased in some human cancers; however, the possible implication of Th17 cells in regulating antitumor responses in malignant pleural effusion (MPE) remains to be elucidated. In the current study, distribution and phenotypic features of Th17 cells in both MPE and peripheral blood from patients with lung cancer were determined by flow cytometry or double immunofluorescence staining. The impacts of cytokines on Th17 cell generation and differentiation were explored. The chemoattractant activity of chemokines CCL20 and CCL22 for Th17 cells in vitro was also observed. It was found that the increased Th17 cells could be found in MPE compared with blood. The in vitro experiments showed that IL-1beta, IL-6, IL-23, or their various combinations could promote Th17 cell generation and differentiation from naive CD4(+) T cells. MPE was chemotactic for Th17 cells, and this activity was partly blocked by anti-CCL20 and/or CCL22 Abs. Our data also showed that the accumulation of Th17 cells in MPE predicted improved patient survival. It could be concluded that the overrepresentation of Th17 cells in MPE might be due to Th17 cell differentiation and expansion stimulated by pleural proinflammatory cytokines and to recruitment of Th17 cells from peripheral blood induced by pleural chemokines CCL20 and CCL22. Furthermore, the accumulation of Th17 cells in MPE predicted improved patient survival. These data provide the basis for developing immune-boosting strategies based on ridding the cancer patient of this cell population. PMID- 20952675 TI - Innate immune activation during Salmonella infection initiates extramedullary erythropoiesis and splenomegaly. AB - Systemic Salmonella infection commonly induces prolonged splenomegaly in murine or human hosts. Although this increase in splenic cellularity is often assumed to be due to the recruitment and expansion of leukocytes, the actual cause of splenomegaly remains unclear. We monitored spleen cell populations during Salmonella infection and found that the most prominent increase is found in the erythroid compartment. At the peak of infection, the majority of spleen cells are immature CD71(-)Ter119(+) reticulocytes, indicating that massive erythropoiesis occurs in response to Salmonella infection. Indeed, this increase in RBC precursors corresponded with marked elevation of serum erythropoietin (EPO). Furthermore, the increase in RBC precursors and EPO production required innate immune signaling mediated by Myd88/TRIF. Neutralization of EPO substantially reduced the immature RBC population in the spleen and allowed a modest increase in host control of infection. These data indicate that early innate immunity to Salmonella initiates marked splenic erythropoiesis and may hinder bacterial clearance. PMID- 20952676 TI - The rapid induction of HLA-E is essential for the survival of antigen-activated naive CD4 T cells from attack by NK cells. AB - Increasing evidence shows that NK cells regulate adaptive immunity, but the underlying mechanisms are not well understood. In this study, we show that activated human NK cells suppress autologous naive CD4 T cell proliferation in response to allogeneic dendritic cells (DCs) by selectively killing Ag-activated T cells. Naive CD4 T cells, which were initially resistant to NK cell-mediated cytotoxicity, became substantially susceptible to NK cells within a day after priming with DCs. Ag-activated T cells showed various degrees of susceptibility to NK cells. After 1 d of priming with LPS-matured DCs, T cells were less susceptible to NK cells than were T cells primed with TNF-alpha-matured DCs. Subsequently at day 3, Ag-activated T cells regained resistance to NK cells. The level of HLA-E expression on Ag-activated T cells was closely correlated with resistance to NK cells. HLA-E was highly expressed at day 1 by T cells primed with LPS-matured DCs but not by T cells primed with TNF-alpha-matured DCs. An Ab blockade revealed a critical role for the HLA-E-NKG2A interaction in the protection of Ag-activated T cells from NK cells. Collectively, this study demonstrates that NK cells impact adaptive immunity through the finely controlled kinetics of HLA-E expression on T cells. Thus, HLA-E may be a new target for immunoregulation. PMID- 20952677 TI - BLT2 Is upregulated in allergen-stimulated mast cells and mediates the synthesis of Th2 cytokines. AB - Mast cells are effector cells that mediate the allergic response through Ag stimulation of IgE bound to FcepsilonRI. In allergic reactions, cross-linking of the surface receptors for IgE on mast cells results in the synthesis of Th2 cytokines such as IL-4 and IL-13, which are critical for the initiation and progression of the allergic response. Despite the important roles of these cytokines, the signaling mechanism by which Ag stimulation mediates the production of IL-4 and IL-13 in mast cells is not clearly understood. In the present study, we found that Ag-stimulated bone marrow-derived mast cells (BMMCs) highly upregulated the expression of BLT2, a leukotriene B(4) receptor, and that blockade of BLT2 with the specific antagonist LY255283 or small interfering RNA knockdown completely abolished the production of Th2 cytokines. Furthermore, BMMCs overexpressing BLT2 showed significantly enhanced production of Th2 cytokines compared with wild-type BMMCs. Additionally, we found that the generation of Nox1-derived reactive oxygen species occurs downstream of BLT2, thus mediating the synthesis of Th2 cytokines. Taken together, our results suggest that the BLT2-Nox1-reactive oxygen species cascade is a previously unsuspected mediatory signaling mechanism to Th2 cytokine production in Ag stimulated BMMCs, thus contributing to allergic response. PMID- 20952678 TI - Contributions of edema factor and protective antigen to the induction of protective immunity by Bacillus anthracis edema toxin as an intranasal adjuvant. AB - We have shown that intranasal coapplication of Bacillus anthracis protective Ag (PA) together with a B. anthracis edema factor (EF) mutant having reduced adenylate cyclase activity (i.e., EF-S414N) enhances anti-PA Ab responses, but also acts as a mucosal adjuvant for coadministered unrelated Ags. To elucidate the role of edema toxin (EdTx) components in its adjuvanticity, we examined how a PA mutant lacking the ability to bind EF (PA-U7) or another mutant that allows the cellular uptake of EF, but fails to efficiently mediate its translocation into the cytosol (PA-dFF), would affect EdTx-induced adaptive immunity. Native EdTx promotes costimulatory molecule expression by macrophages and B lymphocytes, and a broad spectrum of cytokine responses by cervical lymph node cells in vitro. These effects were reduced or abrogated when cells were treated with EF plus PA dFF, or PA-U7 instead of PA. We also intranasally immunized groups of mice with a recombinant fusion protein of Yersinia pestis F1 and LcrV Ags (F1-V) together with EdTx variants consisting of wild-type or mutants PA and EF. Analysis of serum and mucosal Ab responses against F1-V or EdTx components (i.e., PA and EF) revealed no adjuvant activity in mice that received PA-U7 instead of PA. In contrast, coimmunization with PA-dFF enhanced serum Ab responses. Finally, immunization with native PA and an EF mutant lacking adenylate cyclase activity (EF-K346R) failed to enhance Ab responses. In summary, a fully functional PA and a minimum of adenylate cyclase activity are needed for EdTx to act as a mucosal adjuvant. PMID- 20952679 TI - Impaired apoptotic cell clearance in the germinal center by Mer-deficient tingible body macrophages leads to enhanced antibody-forming cell and germinal center responses. AB - Germinal centers (GCs) are specialized microenvironments that generate high affinity Ab-forming cells (AFCs) and memory B cells. Many B cells undergo apoptosis during B cell clonal selection in GCs. Although the factors that regulate the AFC and GC responses are not precisely understood, it is widely believed that dysregulated AFCs and GCs contribute to autoimmunity. The Mer receptor tyrosine kinase (Mer) facilitates macrophage clearance of apoptotic cells. The Tyro-3, Axl, and Mer receptors, including Mer, suppress TLRs and cytokine-mediated inflammatory responses. We report in this study that tingible body macrophages (TBMphis) in GCs express Mer. Compared to C57BL/6 (B6) controls, Mer-deficient (Mer(-/-)) mice had significantly higher AFC, GC, and Th1-skewed IgG2 Ab (especially IgG2c) responses against the T cell-dependent Ag (4-hydroxy-3 nitrophenyl) acetyl-chicken gamma globulin. Mer(-/-) mice had a significantly higher percentage of GC B cells on days 9, 14, and 21 postimmunization compared with B6 controls. Significantly increased numbers of apoptotic cells accumulated in Mer(-/-) GCs than in B6 GCs, whereas the number of TBMphis remained similar in both strains. Our data are the first, to our knowledge, to demonstrate a critical role for Mer in GC apoptotic cell clearance by TBMphis and have interesting implications for Mer in the regulation of B cell tolerance operative in the AFC and GC pathways. PMID- 20952680 TI - The protein tyrosine phosphatase SHP-1 modulates the suppressive activity of regulatory T cells. AB - The importance of regulatory T cells (Tregs) for immune tolerance is well recognized, yet the signaling molecules influencing their suppressive activity are relatively poorly understood. In this article, through in vivo studies and complementary ex vivo studies, we make several important observations. First, we identify the cytoplasmic tyrosine phosphatase Src homology region 2 domain containing phosphatase 1 (SHP-1) as an endogenous brake and modifier of the suppressive ability of Tregs; consistent with this notion, loss of SHP-1 expression strongly augments the ability of Tregs to suppress inflammation in a mouse model. Second, specific pharmacological inhibition of SHP-1 enzymatic activity via the cancer drug sodium stibogluconate potently augmented Treg suppressor activity both in vivo and ex vivo. Finally, through a quantitative imaging approach, we directly demonstrate that Tregs prevent the activation of conventional T cells and that SHP-1-deficient Tregs are more efficient suppressors. Collectively, our data reveal SHP-1 as a critical modifier of Treg function and a potential therapeutic target for augmenting Treg-mediated suppression in certain disease states. PMID- 20952681 TI - Endothelin-1-induced macrophage inflammatory protein-1beta expression in monocytic cells involves hypoxia-inducible factor-1alpha and AP-1 and is negatively regulated by microRNA-195. AB - Patients with sickle cell disease (SCD) exhibit a chronic inflammatory state manifested by leukocytosis and increased circulating levels of proinflammatory cytochemokines. Our studies show that placenta growth factor levels are high in SCD, and placental growth factor induces the release of the vasoconstrictor endothelin-1 (ET-1) from pulmonary microvascular endothelial cells. In this study, we observed that ET-1 increased the expression of the chemokines MIP-1beta or CCL4. ET-1-induced MIP-1beta mRNA expression in THP-1 cells and human peripheral blood monocytes occurred via the activation of PI3K, NADPH oxidase, p38 MAPK, and JNK-1 but not JNK-2. ET-1-induced MIP-1beta expression involved hypoxia-inducible factor-1alpha (HIF-1alpha), independent of hypoxia, as demonstrated by silencing with HIF-1alpha small interfering RNA, EMSA, and chromatin immunoprecipitation analysis. ET-1-induced MIP-1beta promoter luciferase activity was attenuated when any of the five hypoxia-response elements, AP-1, or NF-kappaB binding motifs in the proximal MIP-1beta promoter ( 1053/+43 bp) were mutated. Furthermore, ET-1 significantly downregulated the expression of a key microRNA, microRNA-195a, which showed a complementary binding site in the 3' untranslated region of MIP-1beta mRNA. Moreover, ET-1-induced MIP 1beta mRNA expression in either THP-1 cells or peripheral blood monocytes was reduced upon expression of microRNA-195a. Conversely, transfection of monocytes with anti-microRNA-195a oligonucleotide augmented several-fold ET-1-induced MIP 1beta expression. Taken together, these studies showed that ET-1-mediated MIP 1beta gene expression is regulated via hypoxia-response elements, AP-1, and NF kappaB cis-binding elements in its promoter and negatively regulated by microRNA 195, which targets the 3' untranslated region of MIP-1beta RNA. These studies provide what we believe are new avenues, based on targets of HIF-1alpha and microRNAs, for ameliorating inflammation in SCD. PMID- 20952682 TI - A ligand for CD5 is CD5. AB - Recognition by scavenger receptor cysteine-rich domains on membrane proteins regulates innate and adaptive immune responses. Two receptors expressed primarily on T cells, CD5 and CD6, are linked genetically and are structurally similar, both containing three scavenger receptor cysteine-rich domains in their extracellular regions. A specific cell surface interaction for CD5 has been difficult to define at the molecular level because of the susceptibility of CD5 protein to denaturation. By using soluble CD5 purified at neutral pH to preserve biological activity, we show that CD5 mediates species-specific homophilic interactions. CD5 domain 1 only is involved in the interaction. CD5 mAbs that have functional effects in humans, rats, and mice block homophilic binding. Ag specific responses by mouse T cells in vitro were increased when engagement of human CD5 domain 1 was inhibited by mutation or by IgG or Fab fragment from a CD5 mAb. This showed that homophilic binding results in productive engagement. Enhancement of polyclonal immune responses of rat lymph node cells by a Fab fragment from a CD5 mAb shown to block homophilic interactions provided evidence that the extracellular region of CD5 regulates inhibition in normal cells. These biochemical and in vitro functional assays provide evidence that the extracellular region of CD5 regulates immunity through species-specific homophilic interactions. PMID- 20952683 TI - A role for lymphotoxin in primary Sjogren's disease. AB - The etiology of salivary gland injury in primary Sjogren's disease is not well understood. We have previously described a mouse model of Sjogren's disease, IL 14alpha transgenic (IL14alphaTG) mice, which reproduces many of the features of the human disease. We now demonstrate a critical role for lymphotoxin alpha (LTA) in the pathogenesis of Sjogren's disease in IL14alphaTG mice. IL14alphaTG mice express LTA mRNA in their salivary glands and spleen and produce soluble LTA protein in their salivary secretions. When IL14alphaTG mice were crossed with LTA(-/-) mice, the IL14alphaTG.LTA(-/-) mice retained normal salivary gland secretions and did not develop either lymphocytic infiltration of their salivary glands or secondary lymphomas. However, both IL14alphaTG and IL14alphaTG.LTA(-/-) mice produced similar amounts of IFN-alpha and had similar deposition of autoantibodies in their salivary glands. Both IL14alpha and IL14alpha/LTA(-/-) mice had similar B cell responses to T-dependent and T-independent Ags, L selectin expression, and expression of RelA, RelB, and NF-kappaB2 in their spleens. These studies suggest that LTA plays a critical role in the local rather than systemic inflammatory process of Sjogren's disease. Furthermore, local production of soluble LTA in the salivary glands of IL14alphaTG mice is necessary for the development of overt Sjogren's disease. Autoantibody deposition alone is not sufficient to produce salivary gland dysfunction. We also demonstrate that LTA is increased in the salivary gland secretions and sera of patients with Sjogren's disease, further strengthening the biological relevance of the IL14alphaTG model to understanding the pathogenesis of human disease. PMID- 20952684 TI - Role of the P2Y12 receptor in the modulation of murine dendritic cell function by ADP. AB - The effects of ADP on the biology of dendritic cells have been studied much less than those of ATP or adenosine. In this study, we showed that adenosine-5'-O-(2 thiodiphosphate) (ADPbetaS) induced intracellular Ca(2+) transients in murine dendritic cells (DCs). This effect was abolished by AR-C69931MX, a dual P2Y(12) and P2Y(13) receptor antagonist. RT-PCR experiments revealed the expression of both P2Y(12) and P2Y(13) mRNA in DCs. The Ca(2+) response to ADPbetaS was maintained in P2Y(13)-deficient DCs, whereas it was abolished completely in P2Y(12)(-/-) DCs. ADPbetaS stimulated FITC-dextran and OVA capture in murine DCs through macropinocytosis, and this effect was abolished in P2Y(12)(-/-) DCs. ADPbetaS had a similar effect on FITC-dextran uptake by human monocyte-derived DCs. OVA loading in the presence of ADPbetaS increased the capacity of DCs to stimulate OVA-specific T cells, whereas ADPbetaS had no effect on the ability of DCs to stimulate allogeneic T cells. Moreover, after immunization against OVA, the serum level of anti-OVA IgG1 was significantly lower in P2Y(12)(-/-) mice than that in wild-type controls. In conclusion, we have shown that the P2Y(12) receptor is expressed in murine DCs and that its activation increased Ag endocytosis by DCs with subsequent enhancement of specific T cell activation. PMID- 20952685 TI - Mast cell fibroblastoid differentiation mediated by airway smooth muscle in asthma. AB - Mast cell microlocalization to the airway smooth muscle (ASM) bundle is a key feature of asthma, but whether these mast cells have an altered phenotype is uncertain. In this paper, we report that in vivo, mast cells within the ASM bundle, in contrast to mast cells in the bronchial submucosa, commonly expressed fibroblast markers and the number of these cells was closely related to the degree of airway hyperresponsiveness. In vitro human lung mast cells and mast cell lines cultured with fibronectin or with primary human ASM cells acquired typical fibroblastic markers and morphology. This differentiation toward a fibroblastoid phenotype was mediated by ASM-derived extracellular matrix proteins, independent of cell adhesion molecule-1, and was attenuated by alpha5beta1 blockade. Fibroblastoid mast cells demonstrated increased chymase expression and activation with exaggerated spontaneous histamine release. Together these data indicate that in asthma, ASM-derived extracellular matrix proteins mediate human mast cell transition to a fibroblastoid phenotype, suggesting that this may be pivotal in the development of airway dysfunction in asthma. PMID- 20952686 TI - The M cell-targeting ligand promotes antigen delivery and induces antigen specific immune responses in mucosal vaccination. AB - Oral mucosal immunization can induce protective immunity in both systemic compartments and the mucosa. Successful mucosal immunization depends on Ag delivery to the mucosal immune induction site. The high transcytotic activity of M cells within the mucosa makes these cells attractive targets for mucosal Ag delivery, although it remains unclear whether delivery of Ag to M cells only can guarantee the induction of effective immune responses. In this study, we evaluated the ability of an M cell-targeting ligand with adjuvant activity to induce immunity against ligand-fused Ag. We selected M cell-targeting ligands through biopanning of a phage display library against differentiated in vitro M like cells and produced the recombinant Ags fused to the selected ligands using the model Ag. One of the selected peptide ligands, Co1, promoted the binding of ligand-fused Ag to mouse Peyer's patch M cells and human M-like cells that had been defined by binding with the M cell-specific and anti-GP2 Abs. In addition, Co1 ligand enhanced the uptake of fused Ag by immunogenic tissue in an ex vivo loop assay and in vivo oral administration experiments. After oral administration, the ligand-fused Ag enhanced immune responses against the fused Ag compared with those of the control Ag without ligand. In addition, this use of the ligand supported a skewed Th2-type immune response against the fused Ag. Collectively, these results suggest that the ligand selected through biopanning against cultured M-like cells could be used as an adjuvant for targeted Ag delivery into the mucosal immune system to enhance immune induction. PMID- 20952687 TI - Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. AB - Acute graft-versus-host disease (aGVHD) is associated with high risk of morbidity and mortality and is a common complication after double umbilical cord blood (UCB) transplantation. To reduce these risks, we established a method of CD4(+)CD25(+)FoxP3(+) T regulatory cell (Treg) enrichment from cryopreserved UCB followed by a 18 (+) 1-day expansion culture including anti-CD3/anti-CD28 antibody-coated beads and recombinant human interleukin-2. In a "first-in-human" clinical trial, we evaluated the safety profile of UCB Treg in 23 patients. Patients received a dose of 0.1-30 * 10(5)UCB Treg/kg after double UCB transplantation. The targeted Treg dose was achieved in 74% of cultures, with all products being suppressive in vitro (median 86% suppression at a 1:4 ratio). No infusional toxicities were observed. After infusion, UCB Treg could be detected for 14 days, with the greatest proportion of circulating CD4(+)CD127(-)FoxP3(+) cells observed on day (+)2. Compared with identically treated 108 historical controls without Treg, there was a reduced incidence of grade II-IV aGVHD (43% vs 61%, P = .05) with no deleterious effect on risks of infection, relapse, or early mortality. These results set the stage for a definitive study of UCB Treg to determine its potency in preventing allogeneic aGVHD. This study is registered at http://www.clinicaltrials.gov as NCT00602693. PMID- 20952688 TI - Hypoxia inhibits senescence and maintains mesenchymal stem cell properties through down-regulation of E2A-p21 by HIF-TWIST. AB - Although low-density culture provides an efficient method for rapid expansion of human mesenchymal stem cells (MSCs), MSCs enriched by this method undergo senescence and lose their stem cell properties, which could be preserved by combining low-density and hypoxic culture. The mechanism was mediated through direct down-regulation of E2A-p21 by the hypoxia-inducible factor-1alpha (HIF 1alpha)-TWIST axis. Expansion under normoxia induced E2A and p21 expression, which were abrogated by overexpression of TWIST, whereas siRNA against TWIST up regulated E2A and p21 in hypoxic cells. Furthermore, siRNA against p21 in normoxic cells enhanced proliferation and increased differentiation potential, whereas overexpression of p21 in hypoxic cells induced a decrease in proliferation and a loss of differentiation capacity. More importantly, MSCs expanded under hypoxic conditions by up to 100 population doublings, exhibited telomerase activity with maintained telomere length, normal karyotyping, and intact genetic integrity, and did not form tumors. These results support low density hypoxic culture as a method for efficiently expanding MSCs without losing stem cell properties or increasing tumorigenicity. PMID- 20952689 TI - Cytokine polymorphisms in Th1/Th2 pathway genes, body mass index, and risk of non Hodgkin lymphoma. AB - We conducted a population-based, case-control study in Connecticut women to test the hypothesis that genetic variations in Th1 and Th2 cytokine genes modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL). Compared with those with BMI less than 25 kg/m(2), women with BMI more than or equal to 25 kg/m(2) had 50% to 90% increased risk of NHL among women who carried IFNGR2 (rs9808753) AA, IL5 (rs2069812) CT/TT, IL7R (rs1494555) AA, and TNF (rs1799724) CC genotypes, but no increased risk among women with IFNGR2 AG/GG, IL5 CC, IL7R AG/GG, and TNF CT/TT genotypes. A significant interaction with BMI was only observed for IFNGR2 (rs9808753 P(forinteraction) = .034) and IL7R (rs1494555 P(forinteraction) = .016) for NHL overall; IL7R (rs1494555 P(forinteraction) = .016) and TNF (1799724 P(forinteraction) = .031) for B-cell lymphoma; and IL5 (rs2069812 P(forinteraction) = .034) for T-cell lymphoma. After stratification by common B-cell lymphoma subtypes, a significant interaction was observed for IFNGR2 (rs9808753 P(forinteraction) = .006), IL13 (rs20541 P(forinteraction) = .019), and IL7R (rs1494555 P(forinteraction) = .012) for marginal zone B-cell lymphoma; IL7R (rs1494555 P(forinteraction) = .017) for small lymphocytic lymphoma/chronic lymphocytic leukemia; and IL12A (rs568408 P(forinteraction) = .013) and TNF (1799724 P(forinteraction) = .04) for follicular lymphoma. The results suggest that common genetic variation in Th1/Th2 pathway genes may modify the association between BMI and NHL risk. PMID- 20952690 TI - AKAP9 regulation of microtubule dynamics promotes Epac1-induced endothelial barrier properties. AB - Adhesive forces at endothelial cell-cell borders maintain vascular integrity. cAMP enhances barrier properties and controls cellular processes through protein kinase A bound to A-kinase anchoring proteins (AKAPs). It also activates exchange protein directly activated by cAMP (Epac1), an exchange factor for Ras-related protein 1 (Rap1) GTPases that promotes cadherin- and integrin-mediated adhesion through effects on the actin cytoskeleton. We demonstrate that AKAP9 facilitates the microtubule polymerization rate in endothelial cells, interacts with Epac1, and is required for Epac1-stimulated microtubule growth. AKAP9 is not required for maintaining barrier properties under steady-state conditions. Rather, it is essential when the cell is challenged to make new adhesive contacts, as is the case when Epac activation enhances barrier function through a mechanism that, surprisingly, requires integrin adhesion at cell-cell contacts. In the present study, defects in Epac-induced responses in AKAP9-silenced cells were evident despite an intact Epac-induced increase in Rap activation, cortical actin, and vascular endothelial-cadherin adhesion. We describe a pathway that integrates Epac-mediated signals with AKAP9-dependent microtubule dynamics to coordinate integrins at lateral borders. PMID- 20952692 TI - Effects of calcium diet supplements on egg strength in conventional and furnished cages, and effects of 2 different nest floor materials. AB - Several studies have demonstrated a greater incidence of cracked eggs in furnished than in conventional cages. Hens kept in furnished cages may have greater bone strength, so they may lay eggs with weaker shells because they may utilize more calcium for bone mineralization and less for shell formation. The effects of increased dietary calcium content were therefore studied in 3-hen conventional and 8-hen furnished cages. In addition, the effects of 2 different nest floor materials were studied in furnished cages. A total of 1,216 Lohmann Selected Leghorn hens were housed in either furnished or conventional cages and offered either the normal calcium supplementation used in commercial diets (37 to 40 g of calcium/kg) or increased calcium supplementation (44 to 50 g of calcium/kg) consisting of added limestone for 3 consecutive feeding phases of 20, 16, and 16 wk. Dietary calcium had similar effects in both cage systems. Greater limestone supplementation increased the laying rate (P < 0.05). Increased dietary limestone had no significant effects on egg quality, and no effects on tibia breaking strength or specific gravity were observed. The laying rate was higher in conventional than in furnished cages (P < 0.05), but there was no significant difference between the cage types in terms of total egg mass produced. The cage type had no effect on tibia-breaking strength. However, the specific gravity and ash content of tibias were higher in hens kept in furnished than in conventional cages (P < 0.001). Based on this study, the weakening of eggshells in furnished cages is not caused by a possible calcium shortage resulting from high bone mineralization. PMID- 20952691 TI - Opposing roles for HIF-1alpha and HIF-2alpha in the regulation of angiogenesis by mononuclear phagocytes. AB - Macrophages contribute to tumor growth through the secretion of the proangiogenic molecule vascular endothelial growth factor (VEGF). We previously observed that monocytes treated with the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) produce a soluble form of the VEGF receptor-1 (sVEGFR-1), which neutralizes VEGF biologic activity. The VEGF and VEGFR-1 promoters both contain a hypoxia regulatory element, which binds the hypoxia-inducible factor (HIF) transcription factors under hypoxic conditions. Based on this observation, we examined VEGF and sVEGFR-1 production from monocytes cultured at various O(2) concentrations. The amount of sVEGFR-1 production observed from GM-CSF-treated monocytes increased with decreasing levels of O(2). This sVEGFR-1 was biologically active and sequestered VEGF. To evaluate the role of the HIFs in sVEGFR-1 production, we used macrophages with a genetic deletion of HIF-1alpha. HIF-1alpha(-/-) macrophages cultured with GM-CSF at hypoxia secreted diminished amounts of VEGF compared with HIF-1alpha(+/+) macrophages, whereas sVEGFR-1 secretion was unaffected. In contrast, siRNA-mediated knockdown of HIF-2alpha inhibited the production of sVEGFR-1 in response to GM-CSF and low O(2), whereas VEGF production was unaffected. These studies suggest that hypoxia, generally thought to promote angiogenesis, can induce antiangiogenic behavior from macrophages within a GM-CSF-rich environment. Furthermore, these results suggest specific and independent roles for HIF-1alpha and HIF-2alpha in hypoxic macrophages. PMID- 20952693 TI - Effects of a premolt calcium and low-energy molt program on laying hen behavior and heterophil-to-lymphocyte ratios. AB - The objectives of this study were to compare the behaviors, postures, and heterophil-to-lymphocyte ratios (H:L) of laying hens housed in a cage system when offered a Ca premolt treatment and low-energy molt diets vs. a traditional feed withdrawal (FW) treatment during and after molt. A total of 144 Hy-Line W-36 hens (85 wk of age), housed 3 hens/cage (413 cm(2)/hen), were used. Hens were allotted to treatments according to a randomized complete block design, with the cage location and initial BW as the blocking criteria. Six treatments were compared in a 2 * 3 factorial arrangement with 2 Ca premolt treatments (fine or coarse) and 3 low-energy molt diets (FW, soybean hulls, or wheat middlings). The 2 Ca premolt treatments differed only in Ca particle size (fine was 0.14 mm and coarse was 2.27 mm mean diameter). Two postures and 5 behaviors were recorded and H:L was measured. Data were analyzed using the MIXED procedure of SAS, with P < 0.05 considered significant. There were no differences in behaviors, postures, or H:L during the premolt baseline period. The Ca premolt treatment had no carryover effects during or after molt for behaviors or postures. During molt, hens in the FW treatment were more active, and they ate and drank less compared with hens fed soybean hulls or wheat middlings, but there were no differences in aggression, nonnutritive pecking, or sitting. Drinking and aggression during and after molt were not different, but hens postmolt engaged in more sitting and feeding and less activity, nonnutritive pecking, and preening compared with during molt. There were no differences in H:L during or after molt. In conclusion, a Ca premolt treatment did not affect the behavior of the laying hen. The low-energy molt diets did not adversely affect behavior compared with FW and did not increase H:L; therefore, they could be useful alternatives for inducing molt in laying hens. PMID- 20952694 TI - Effect of light intensity on broiler production, processing characteristics, and welfare. AB - Manipulation of light intensity is an important management tool affecting broiler production and well being. Despite considerable research on light intensity, there is still a debate on the optimum level to be used for intensively housed broilers. Two trials were conducted with the objective of investigating the effect of light intensity, within the practical levels at confinement barns (1, 10, 20, and 40 lx), on production, processing characteristics, and welfare of broilers raised to 35 d of age. Each light intensity treatment was replicated in 2 environmentally controlled rooms in each trial with 950 Ross * Ross 308 chicks per room. Data were analyzed as a randomized complete block design with trial serving as a block. All chicks were exposed to 40 lx of light intensity and 23 h of light for the first 7 d followed by treatment light intensity and 17 h of day length thereafter. Body weight and feed consumption were determined at 7, 14, and 35 d of age. At the end of each trial, 60 birds per treatment were processed to determine the detailed meat yield. Skeletal and footpad and ocular health were monitored at 31 and 32 d of age, respectively. Body weight, feed consumption, feed:gain ratio, and mortality were unaffected by light intensity. Carcass, thigh, and drum yield as a percentage of live weight decreased linearly with increasing light intensity. The 1 lx treatment resulted in heavier wings as a percentage of live weight. Light intensity had no effect on skeletal health, but ulcerative footpad lesions decreased linearly with increasing light intensity. Birds exposed to the 1 lx treatment had heavier and larger eyes. In conclusion, light intensity did not affect broiler production and mortality but did affect carcass characteristics. The 1 lx light intensity treatment had a negative effect on broiler welfare as demonstrated by increased ulcerative footpad lesions and eye size. PMID- 20952695 TI - Inheritance of hatchability in broiler chickens and its relationship to egg quality traits. AB - The first objective of this study on broiler breeders was to investigate the genetic basis of variability in hatchability over age using a longitudinal model. Weekly percentage hatch of fertile and hatch of set eggs were available for 23,250 dams mated to 3,106 sires of the same age between the 28th and 54th week of life. Hatch of set was very highly correlated with fertility and showed a similar pattern through lay. There was a genetic contribution of the dam but not the sire to hatch of fertile; its heritability was about 6% from peak lay onward but lower earlier. The second objective was to investigate the relationship between hatchability and internal and external egg quality traits measured at 48 wk of age. These traits, specific gravity, weight loss, egg weight, and Haugh units, had moderate to high heritabilities, 0.53, 0.38, 0.65, and 0.38, respectively. Parameters of the genetic trend in weekly hatchability (mean and persistency) were significantly correlated with these egg quality traits, suggesting that in a bulk mating situation in which individual recording of hatchability is not possible, these quality traits could provide some indication on the trend in flock hatchability. PMID- 20952697 TI - Genetic interrelationships among phosphorus, nitrogen, calcium, and energy bioavailability in a growing chicken population. AB - A random-mating population was used to study the genetic interrelationship between phytate P (PPB), Ca (CaB), N (NB), and energy bioavailability (EB), BW at 4 wk of age, relative growth (RG), and feed conversion ratio (FCR). Heritability estimates for PPB, CaB, NB, and EB were 0.09, 0.13, 0.16, and 0.10, respectively, and those of BW, RG, and FCR were 0.66, 0.15, and 0.10, respectively. Genetic correlations between PPB and BW, and FCR were moderate and negative, suggesting that improvement in PPB will impair growth. The genetic correlations between PPB and CaB, and EB and RG were positive and moderate, indicating that improvement in PPB would also lead to improved CaB, EB, and RG. Energy bioavailability was positively correlated with CaB, NB, PPB, and BW. Even though the genetic correlation between EB and the other traits measured, except RG and FCR, ranged from low to moderate, improving the ability of birds to utilize caloric energy in the feed would consequently improve PPB as well as growth. Improving PPB would reduce the amount of P in excreta and provide an additional savings if exogenous phytase were not added to poultry feed. The genetic correlation between PPB and NB was low but positive, whereas NB had a positive genetic correlation with BW. Therefore, selecting on NB will result in positive correlated responses in BW and PPB. Improving PPB and NB will not only improve productivity, but also reduce the polluting effects of P and N on the environment. PMID- 20952696 TI - Genetic epistasis analysis of 10 peroxisome proliferator-activated receptor gamma correlated genes in broiler lines divergently selected for abdominal fat content. AB - Chicken peroxisome proliferator-activated receptor gamma (PPARgamma), which is highly expressed in adipose tissues, is a key factor in fat accumulation in the abdominal fat pad. In this study, association and pairwise epistasis analyses were performed for all the polymorphisms detected in PPARgamma and for 9 genes from PPARgamma-correlated lipid metabolic pathways for abdominal fat weight (AFW) in 10th-generation populations of Northeast Agricultural University broiler lines divergently selected for abdominal fat content. Epistatic networks were then reconstructed with the identified epistatic effects. Single-marker association analyses showed that 5 of the 20 screened polymorphisms were significantly associated with AFW (P < 0.05), and CCAAT/enhancer-binding protein alpha (C/EBPalpha) c.552G>A was 1 of the 5 significant loci. Pairwise interaction analyses showed that 15 pairs of polymorphisms reached a significance level of P < 2.64 * 10(-4) (adjusted by Bonferroni correction) in the lean line, 41 pairs reached significance in the fat line, and 7 pairs reached significance in both lines. Interestingly, many other loci interacted with C/EBPalpha c.552G>A in both lines. In epistatic network analyses, C/EBPalpha c.552G>A seemed to behave as a hub for the epistatic network in both lines. All these results revealed that the genetic architecture of C/EBPalpha c.552G>A for AFW seemed to be an apparent individual main-effect QTL but that it could be dissected into a genetic epistatic network. Our results suggest that C/EBPalpha c.552G>A might be the most important locus contributing to phenotypic variation in AFW among all the polymorphisms detected in this study. PMID- 20952698 TI - The effect of frizzle gene and dwarf gene on reproductive performance of broiler breeder dams under high and normal ambient temperatures. AB - In 3 experimental runs, the influence of genotype * temperature interactions on the reproductive traits (sexual maturity, egg production, fertility, hatchability, and chick production) of hens of a broiler breeder dam line carrying major genes for dwarfism (dw-) and frizzle (F) was investigated. In experiments 1 and 2, the hens were caged individually under hot (30 degrees C) and temperate (19 degrees C) temperatures, from wk 18 to 72 of age, whereas in experiment 3, hens were kept under moderate temperature (24 degrees C). Hens in experiment 1 were heterozygous for the frizzle gene, and those in experiments 2 and 3 were homozygous, both with and without the dwarf gene. Hens without the above-mentioned major genes (ffDw-) served as control lines. In experiment 1, the frizzle gene (Ff) had no significant effect on sexual maturity, egg production, fertility, hatchability, and chick number under the 2 environmental conditions. In experiment 2, there was a significant interaction between feathering genotype (FF) and environmental temperature for all traits except sexual maturity. Under heat stress, there was a distinct reduction in all reproductive traits except sexual maturity for normally feathered hens compared with frizzle-feathered hens, whereas under temperate conditions, egg production and number of chicks of the FF genotype were reduced and sexual maturity was delayed. In experiments 1 and 2, the dw- gene showed a depressive effect on the growth of hens. In experiment 1, the interaction between dwarf genotype and environmental temperature for egg production was significant. Under temperate conditions, the egg production of dwarf hens was inferior to that of normally sized birds, whereas under hot temperatures, the egg production of the 2 body sizes did not differ. In experiment 2, for sexual maturity, egg production and fertility locus * locus interactions could be determined. The genotype combining the 2 major genes (FFdw ) proved to be inferior to the normally feathered dwarf type (ffdw-) for laying performance but superior in fertility. Under the conditions in experiment 3, the egg production of dwarf birds was significant reduced. PMID- 20952699 TI - Development and evaluation of candidate recombinant Salmonella-vectored Salmonella vaccines. AB - Attenuated Salmonella Enteriditis (DeltaSE) recombinant vaccine vectors incorporating a Salmonella flagellar filament protein (fliC) subunit, a putative cell-mediated epitope, for expression of the lamB gene (encoding a maltose outer membrane porin), with or without co-expression of a putative immune-enhancing CD154 oligopeptide, were developed and compared with wild-type Salmonella Enteriditis (experiments 1 and 2) or the attenuated DeltaSE empty vector (experiment 3) as initial vaccine candidates against Salmonella infection. A total of 3 experiments were performed to assess the infection and clearance rate of each of these constructs. Each construct or Salmonella Enteriditis was orally administered to broiler chicks at day of hatch by oral gavage (~10(8) cfu/chick). In experiments 1 to 3, liver-spleen and cecal tonsils were removed aseptically for recovery of wild-type Salmonella Enteriditis or DeltaSE mutants. These experiments suggested that cell surface expression of fliC alone markedly increased the clearance rate of the vector at or before 21d postvaccination in all 3 experiments. In a fourth experiment, broilers were vaccinated with one of the vaccine constructs or the DeltaSE empty vector and then challenged with wild type Salmonella Typhimurium. At 19 d posthatch, 16 d postinfection, neither candidate protected against challenge significantly better than the DeltaSE empty vector, although there was significantly less Salmonella recovered from vaccinated chickens as compared with nonvaccinated controls. These experiments indicate that these experimental vaccines did not protect against heterologous challenge or enhance clearance after Salmonella Typhimurium challenge; as such, their value as vaccines is limited. The increased clearance of the candidate vaccines, particularly the vector expressing fliC alone, may have value in that the fliC epitope may decrease the clearance time of other recombinant vectored Salmonella vaccines. PMID- 20952700 TI - Evaluation of the efficacy of yeast extract in reducing intestinal Clostridium perfringens levels in broiler chickens. AB - The etiological agent of necrotic enteritis is Clostridium perfringens. Traditionally, necrotic enteritis is controlled with in-feed antibiotics. However, increasing consumer demand for drug-free poultry has fostered the search for nonantibiotic alternatives. Yeast extract contain nucleotides that are immunomodulatory and also essential for cellular functions. An experiment was conducted to evaluate the efficacy of NuPro yeast extract (Alltech Inc., Nicholasville, KY) in reducing intestinal C. perfringens levels in broiler chickens. One hundred ninety-two 1-d-old male broiler chicks were obtained and randomly assigned to 6 treatments in a battery cage trial. Treatment 1 consisted of chicks fed a corn-soybean meal basal diet (BD) without added bacitracin methylene disalicylate or NuPro. Treatment 2 consisted of chicks fed BD into which bacitracin methylene disalicylate was added at 0.055 g/kg. Treatment 3 consisted of chicks fed BD supplemented with NuPro at a 2% level for the first 10 d of the experiment. Treatments 4 (PX), 5, and 6 (PN) consisted of chicks that were challenged with 3 mL of the C. perfringens inoculum (~10(7) cfu/mL) on d 14, 15, and 16 of the experiment and fed diets similar to treatments 1, 2, and 3, respectively. On d 1 and 7 postchallenge, intestinal C. perfringens levels, lesion scores, and alkaline phosphatase activity were assessed. On d 1 postchallenge, C. perfringens level in treatment 5 (2.09 log(10) cfu/g) was lower (P < 0.05) compared with the PX treatment (4.71 log(10) cfu/g) but similar to the PN treatment (2.98 log(10) cfu/g). A similar trend was observed on d 7 postchallenge. NuPro supplementation enhanced alkaline phosphatase activity (P < 0.05) in C. perfringens-challenged chicks and appeared to reduce intestinal lesion scores. Although dietary supplementation of NuPro in the PN treatment reduced C. perfringens levels by 1.73 and 0.68 log(10) cfu/g compared with the PX treatment on d 1 and 7 postchallenge, respectively, these reductions were not significant. Extending the period of NuPro supplementation beyond the first 10 d of life should be considered for achieving significant reduction in intestinal C. perfringensg levels. PMID- 20952701 TI - Detection of reticuloendotheliosis virus as a contaminant of fowl pox vaccines. AB - This study was designed to detect reticuloendotheliosis virus (REV) as a contaminant in fowl pox vaccines. A total of 30 fowl pox vaccine samples were examined for the presence of REV using both in vitro and in vivo methods. In in vitro testing, the fowl pox vaccine samples were inoculated into chicken embryo fibroblast cultures prepared from specific-pathogen-free embryonated chicken eggs, and the cultures were examined using PCR to detect REV. In in vivo testing, each fowl pox vaccine sample was inoculated into 5-d-old specific-pathogen-free chicks, which were kept under observation for up to 12 wk postinoculation; serum samples were collected at 15, 30, and 45 d postinoculation for the detection of REV-specific antibodies using ELISA. Tissue samples were collected at 8 and 12 wk postinoculation for histopathological examination. Of the tested vaccines, only one imported vaccine sample tested positive for REV using PCR. Serum samples collected from chicks infected with the PCR-positive vaccine batch also tested positive for REV-specific antibodies using ELISA. Histopathological examination of the liver, spleen, and bursa of Fabricius demonstrated the presence of tumor cells in these organs, confirming the results obtained using PCR and ELISA, and indicating that the sample was contaminated with REV. These data clearly indicate that the screening of all commercial poultry vaccines for viruses is an important factor in assuring the biosafety of animal vaccines. PMID- 20952702 TI - Effects of honeybee venom supplementation in drinking water on growth performance of broiler chickens. AB - The effects of water supplementation of bee venom (BV) on performance, antioxidant activity, and liver function in Arbor Acres broiler chickens were investigated. Hence, 3 experimental treatment groups (control, 0.5 mg/L of BV, and 1 mg/L of BV) were allocated to 3 replicates of 5,000 one-day-old chicks each. The control group was kept on tap water, whereas the other 2 groups were supplied water supplemented with 0.5 and 1 mg of BV, respectively, per liter of drinking water. Broilers were provided ad libitum access to feed for the experimental period of 1 to 28 d of age. Supplementing drinking water with BV significantly increased BW gain at 28 d of age (P < 0.05). The average daily weight gain from d 1 to 28 was increased for birds supplemented with BV compared with control birds. The increase in BW gain was more pronounced with supplementation of 1 mg/L of BV compared with 0.5 mg/L of BV. An improved feed intake was noted in groups supplemented with BV as compared with control chicks. Liver function enzymes, aspartate aminotransferase, and alanine aminotransferase activities including total cholesterol, total protein, albumin, and globulin were not changed by BV supplementation. Tap water supplementation of BV did not alter the number of leukocytes, erythrocytes, heterophils, and lymphocytes. However, the antioxidative activities estimated as a superoxide dismutase-like activity of broiler chicks supplemented with BV was significantly increased (P < 0.05) in comparison with those without BV supplementation. These data indicate a possibility of better broiler performance through BV supplementation under conditions of severe stressful challenges the newly born chicks encounter. PMID- 20952703 TI - Efficacy of a lactylate on production performance and intestinal health of broilers during a subclinical Clostridium perfringens infection. AB - Clostridium perfringens, an alpha-toxin producing gram-positive bacterium, is an enteric pathogen for poultry. Because subclinical C. perfringens infections often result in damage of the intestinal mucosa, decreased nutrient digestion, and poor performance, efforts should be taken to find an effective strategy that controls overgrowth of C. perfringens. For this purpose, the efficacy of a sodium lauroyl lactylate (LauL) as a feed additive to prevent C. perfringens colonization in broilers was determined. First, the effect of LauL was compared with capric and lauric mono- and diglycerides (MDG) and capric and lauric free fatty acids in Clostridium-infected chickens. Clostridial lesion scoring at d 16 showed that MDG and LauL were both effective in reducing the severity of lesions. When taking into account results on BW gain and mortality, LauL was more effective than MDG. For this reason, a dose response study was made to determine the optimal dietary dosage of LauL. In this experiment, it was shown that a LauL dose higher than 0.15% should be used to expect positive effects on lesion severity and mortality. None of the LauL doses led to a significant better response on growth performance. In a third trial, efficacy of LauL was compared with commercial products that limit bacterial activity in the intestinal tract (Aromabiotic Poul 60) or coccidiosis (chemical coccidiostat, Clinacox). None of the products were able to reduce the number or severity of lesions, and no effect on production performance was observed. Thus, despite the clear positive effect seen in experiment 1, and in experiment 2 with LauL doses higher than 0.15%, supplementing this lactylate to the diet does not consistently reduce C. perfringens colonization in broiler chickens because no such effects were observed in experiment 3. These results, however, provide a scientific basis for future studies to further investigate lactylates as potential additives to reduce the severity of necrotic enteritis in broilers in a C. perfringens challenge model. PMID- 20952704 TI - Humoral and cellular immune responses in adult geese induced by an inactivated vaccine against new type gosling viral enteritis virus. AB - To assess the immunogenicity of an inactivated new type gosling viral enteritis virus (NGVEV) vaccine, we investigated 3 different doses of the inactivated vaccine and the inactivated vaccine in conjunction with 3 different doses of recombinant goose interleukin-2 (rGoIL-2) adjuvant. A virus concentration of 10(5) 50% embryo infective dose/mL was subcutaneously inoculated into adult geese divided into 6 groups. The dynamic changes of the humoral and cellular immunity responses elicited by the vaccines in the adult geese postvaccination (PV) were investigated using ELISA, virus neutralization test, and lymphocyte proliferation assay. The clearance of virus from the intestines of geese (175 d PV) was studied by histopathological examination and indirect immunofluorescence assay after virulent NGVEV challenge. This study showed that the inactivated NGVEV vaccine elicits strong humoral and cellular responses in the vaccinated adult geese. The absorbance values of specific anti-NGVEV antibodies, the neutralization antibody titer, and the lymphocyte proliferation index rapidly increased, peaked at about 28 d PV, progressed to the plateau stage, and then decreased slightly. The rGoIL 2 adjuvant enhanced the immune response, and this adjuvant in conjunction with the inactivated NGVEV vaccine induces a significantly higher specific anti-NGVEV antibody absorbance value, neutralization antibody titer, and lymphocyte proliferation index than the non-adjuvant-inactivated NGVEV vaccine (P < 0.05). The inactivated NGVEV vaccine conferred adequate efficient ability to clear NGVEV in vaccinated geese even in the last phase of the vaccination period (175 d PV). The inactivated NGVEV vaccine (0.5 mL/goose) with 1,000 units of rGoIL-2 adjuvant/goose is the most effective dose, thereby eliciting the strongest humoral and cellular immunity responses and providing the most efficacious clearance of NGVEV in vivo. PMID- 20952705 TI - Chicken chemokine receptors in T cells isolated from lymphoid organs and in splenocytes cultured with concanavalin A. AB - Chemokine receptors guide immune cells to specific organs during health and disease. The mRNA content of the chemokine receptors CCR2, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CXCR4, CXCR5, and CX3CR1 in CD4(+) cells (T-helper cells) isolated from blood, bursa, cecal tonsil, spleen, and thymus and in CD8(+) cells (T-cytotoxic cells) isolated from blood, cecal tonsil, spleen, and thymus were investigated. The CD4(+) cells isolated from thymus had the highest amount of CCR7 and CCR8 mRNA. The CD4(+) cells isolated from bursa, cecal tonsil, and thymus had the highest amount of CCR5 mRNA. The CD4(+) cells isolated from cecal tonsils had the highest amount of CCR9 mRNA. The CD4(+) cells isolated from bursa and thymus had the highest amount of CXCR5 mRNA. The CD8(+) cells isolated from cecal tonsil had the highest mRNA amount of all receptors studied except CCR9 and CX3CR1. The CD4(+) cells treated with concanavalin A had increased CCR2, CCR4, CCR7, CCR8, and CXCR5 mRNA amounts at 24 h of stimulation. The CD8(+) cells treated with concanavalin A had increased CCR4 mRNA at 72 h, increased CCR6 mRNA at 24 h, and decreased CCR8 and CXCR4 mRNA at 24 h of stimulation. PMID- 20952706 TI - Molecular characterization of chicken infectious anemia viruses detected from breeder and broiler chickens in South Korea. AB - In South Korea, 32 sequences of chicken infectious anemia virus (CIAV) from various flocks of breeder and commercial chickens were genetically characterized for the first time. Phylogenetic analysis of the viral protein 1 gene, including a hypervariable region of the CIAV genome, indicated that Korean CIAV strains were separated into groups II, IIIa, and IIIb. Strains were commonly identified in great-grandparent and grandparent breeder farms as well as commercial chicken farms. In the field, CIAV strains from breeder farms had no clinical effects, but commercial farm strains were associated with depression, growth retardation, and anemia regardless of the group from which the strain originated. In addition, we identified 7 CIAV genomes that were similar to vaccine strains from vaccinated and unvaccinated breeder flocks. These data suggest that further studies on pathogenicity and vaccine efficacy against the different CIAV group are needed, along with continuous CIAV surveillance and genetic analysis at breeder farms. PMID- 20952707 TI - Effect of dietary fat sources on fatty acid deposition and lipid metabolism in broiler chickens. AB - The hypothesis tested was that dietary vegetable fats rich in saturated fatty acids, when compared with a vegetable oil rich in linoleic acid, increase fat deposition in broiler chickens and affect synthesis or oxidation, or both, of individual fatty acids. Diets with native sunflower oil (SO), a 50:50 mix of hydrogenated and native SO, palm oil, and randomized palm oil were fed to broiler chickens. Intake of digestible fat and fatty acids, whole body fatty acid deposition, hepatic fatty acid profile, and hepatic enzyme activities involved in fatty acid oxidation and synthesis were measured. The fat deposition:digestible fat intake ratio was significantly lower for the SO group in comparison with the groups fed the vegetable fats rich in saturated fatty acids. The difference between digestible intake and deposition of C18:2, reflecting its maximum disappearance rate, was highest for the SO group and lowest for the palm oil- and randomized palm oil-fed birds. The calculated minimal rate of de novo synthesis of monounsaturated fatty acids (MUFA), calculated as deposition minus digestible intake, was more than 50% lower for the SO group than for the other 3 dietary groups. Based on the fatty acid profiles in the liver, it would appear that increasing contents of C18:2 decrease the desaturation of saturated fatty acids into MUFA. It is concluded that a diet rich in C18:2 in comparison with different kinds of vegetable saturated fatty acids decreases the deposition of fat, especially of MUFA. It appears to be caused by a higher beta-oxidation and a reduced de novo synthesis of MUFA, but this conclusion is not fully supported by the measured activities of enzymes involved in fatty acid synthesis and oxidation. PMID- 20952708 TI - Yolk sac nutrient composition and fat uptake in late-term embryos in eggs from young and old broiler breeder hens. AB - In the present study, we examined the composition, amount, and uptake of yolk nutrients [fat, protein, water, and carbohydrates (COH)] during incubation of eggs from 30- and 50-wk-old broiler breeder hens. Eggs were sampled at embryonic d 0 (fresh eggs), 13, 15, 17, 19, and 21 (hatch). Egg, embryo, yolk content, and yolk sac membrane were weighed, and the yolk sac (YS; i.e., yolk content + yolk sac membrane) composition was analyzed. From 30 to 50 wk of age, the albumen weight increased by 13.3%, whereas the yolk increased by more than 40%. The proportion of fat in the fresh yolk of the 30-wk-old group was 23.8% compared with 27.4% in the 50-wk-old group, whereas the proportion of protein was 17.9% compared with 15.6%, respectively. During incubation, results indicated that water and protein infiltrated from other egg compartments to the YS. Accordingly, the calculated change in the content of water and protein between fresh yolk and sampled YS does not represent the true uptake of these components from the YS to the embryo, and only fat uptake from the YS can be accurately estimated. By embryonic d 15, fat uptake relative to embryo weight was lower in the 30-wk-old group than in the 50-wk-old group. However, by embryonic d 21, embryos of both groups reached similar relative fat uptake, suggesting that to hatch, embryos must attain a certain amount of fat as a source of energy for the hatching process. The amount of COH in the YS increased similarly during incubation in eggs from hens of both ages, reaching a peak at embryonic d 19, suggesting COH synthesis in the YS. At hatch, the amount of protein, water, and COH in the residual YS, relative to the weight of the yolk-free chick, was similar in eggs from young and old hens. However, chicks from the younger hens had less fat in the YS for their immediate posthatch nutrition compared with those from the older hens. PMID- 20952709 TI - Is there a relationship between the kinetics of lipoprotein lipase activity after a meal and the susceptibility to hepatic steatosis development in ducks? AB - The difference in the ability of Pekin and Muscovy ducks to develop hepatic steatosis could result from a different peripheral lipoprotein lipase (LPL) activity, which hydrolyses triacylglycerol secreted by the liver. We studied the kinetics of plasma LPL activity in response to a meal at different ages in Pekin and Muscovy ducks. For that purpose, blood samples were taken at 5, 9, 12, 13, and 14 wk of age just before and 1, 2, 4, and 8 h after a meal. To release LPL into general circulation, an i.v. injection of heparin (400 IU/kg of BW) was administered 10 min before blood collection. For that reason, different ducks per genotype were used for each point of measurement (n = 6). Plasma LPL activity measured before the meal was negatively correlated with the weight of the fatty liver measured in the same ducks at 14 wk of age (r = -0.58, P < 0.001). Plasma triacylglycerol level measured before the meal was negatively correlated with plasma LPL activity measured in the same ducks (r = -0.31, P = 0.025) and was negatively correlated with plasma LPL activity measured in the same ducks for each age and each timing (r = -0.39, P < 0.001). At 14 wk of age for Muscovy and Pekin ducks, we observed that a high plasma LPL activity (>200 IU/L of plasma) corresponded to a relatively low development of fatty liver (190 g) induced by overfeeding, whereas a low plasma LPL activity (<150 IU/L of plasma) corresponded to a high propensity to develop fatty liver (470 g). In conclusion, plasma LPL activity measured just before the meal during the rearing period could be used as a marker of hepatic steatosis development during the overfeeding period. PMID- 20952710 TI - Cytochrome P450 enzymes involved in the metabolism of aflatoxin B1 in chickens and quail. AB - A study was conducted to identify the cytochrome P450 (CYP, CYP450) enzyme orthologs involved in the bioactivation of aflatoxin B(1) (AFB(1)) into the highly toxic metabolite known as aflatoxin-8,9-epoxide (AFBO) in quail and chicken hepatic microsomes. The strategies used included the use of specific CYP450 inhibitors and the correlation of prototype substrate activities with AFBO production. Additionally, the presence of the enzymes was qualitatively determined using an immunoblotting technique. The results showed that both quail and chicken microsomes have CYP1A1, CYP1A2, CYP2A6, and CYP3A4 enzymatic activity. A strong relationship between CYP1A1 and CYP2A6 activities and AFB(1) bioactivation was found in both species. Inhibition studies provided more evidence for the role of CYP2A6 in the bioactivation of AFB(1). The immunoblot results showed clear bands for the CYP2A6 and CYP3A4 orthologs in both species. The results of the present study indicate that CYP2A6 and, to a lesser extent, CYP1A1 are responsible for the bioactivation of AFB(1) into AFBO in both quail and chicken hepatic microsomes. PMID- 20952711 TI - Influence of egg warming during storage and hypercapnic incubation on egg characteristics, embryonic development, hatchability, and chick quality. AB - Negative effects of prolonged egg storage on hatchability and chick quality may be caused by changes in the embryo or in the egg characteristics, or by both. The aim of this experiment was to investigate whether prestorage incubation (PSI), frequent warming during storage (FW), or hypercapnic incubation (HI) during the first 5 d of incubation affect egg characteristics, embryonic development, hatchability, and chick quality. The experiment had a 2 * 2 * 2 randomized design: PSI (yes-no), FW (yes-no), and HI (yes-no). All eggs were stored for 15 d at 16 degrees C and 75% RH. On the second day after oviposition, half of the eggs were incubated for 7 h (PSI). During storage, half of the eggs were warmed 6 times for 30 min in water at 37.8 degrees C (FW). During the first 5 d of incubation, the CO(2) concentration in the incubator was maintained between 0.70 and 0.80% (HI) or increased from 0.05 to 0.20% (control). Prestorage incubation and FW increased the stage of embryonic development and the number of viable embryonic cells, but these treatments did not have a pronounced effect on egg characteristics, hatchability, or chick quality. Hypercapnic incubation decreased total albumen pH, which was measured at 18, 42, 66, and 90 h of incubation, and the percentage of eggs classified as infertile (Delta = 1.2%). In contrast, HI retarded embryonic development, decreased hatchability of fertile eggs by 1.3%, but did not affect chick quality. We conclude that both PSI and FW did not improve hatchability and chick quality, although the stage of embryonic development and the number of viable embryonic cells increased due to the treatments. Hypercapnic incubation decreased total albumen pH, which may be related to the increased number of embryos that continued their development at the onset of incubation. Because HI retarded further embryonic development and decreased hatchability, long-term stored embryos were probably sensitive to the CO(2) concentration of 0.70 to 0.80% between 48 and 72 h of incubation. PMID- 20952712 TI - Effects of lipid sources in the diet of laying hens on the fatty acid profiles of egg yolks. AB - The effects of different dietary lipids on the fatty acid profiles of eggs produced by 20- and 54-wk-old Dekalb laying hens were investigated. The 4 treatments were based on the lipid source added to the diet: soybean oil, sunflower oil, linseed oil, or control (no added oil). The experimental design was a simple random-sample design using a 4 * 2 factorial arrangement (4 treatments and 2 ages). The fatty acid composition of the yolks of eggs produced by the laying hens was analyzed. The fatty acid profiles found in the egg yolks were the same as those provided in each diet. Eggs laid by hens fed the diet containing soybean oil had a large amount of n-6 polyunsaturated fatty acids (PUFA), whereas eggs laid by hens fed the diet containing linseed oil had the highest percentage of n-3 PUFA. A decrease in PUFA deposition in egg yolks was observed as the laying hens got older. Eggs of hens fed the diet containing linseed oil presented an n-6:n-3 ratio of 2.01 in younger chickens and 2.17 in older ones. The trans fat percentages found in the egg yolks of all treatments were very low. It was concluded that the quantity of fatty acids present in the egg yolk may be altered according to the source of lipids in the diets; the addition of linseed oil to the ration of laying hens resulted in the production of n-3-enriched eggs and excellent n-6:n-3 ratios, and the egg yolks had insignificant amounts of trans fat, irrespective of the different lipid sources added to the diets or the age of the chickens. PMID- 20952713 TI - Ergosterol as an indicator of the presence of microscopic fungi in eggs for human consumption produced in different husbandry systems. AB - Ergosterol (ERG) content, being an indicator of fungal biomass, was analyzed in samples of eggshell, egg white, and egg yolk from eggs from farms with intensive management systems of layer hens (i.e., cage and litter housing). Moreover, analogous samples were analyzed from eggs from farms in the western central part of Poland, where layer hens were kept in the organic system. In all samples, the highest ERG concentration was found in shells and the lowest in egg white, whereas ERG was not found in egg yolk. When comparing investigated housing systems, a higher concentration of the analyzed metabolite was detected in eggs from litter housing than in eggs from cage housing. Concentrations of ERG in samples of eggs from organic husbandry were highly varied, ranging from 2.44 to 42.67 mg/kg in shells and from 0.28 to 16.11 mg/kg in egg white. PMID- 20952714 TI - Age affects the laying performance and egg hatchability of red-legged partridges (Alectoris rufa) in captivity. AB - Red-legged partridge breeders are frequently reared in captivity with the aim of producing fertile eggs and chicks. However, little is known regarding the role of breeder age on fertility and egg production performance. Therefore, we investigated the effects of breeder age on egg size and shape, flock reproductive performance, fertility, hatchability, and embryonic mortality. In experiment 1, the effects of breeders' age on fertility, hatchability of eggs, and embryo mortality were evaluated. We found that partridge breeder age significantly affected the onset of egg laying, egg production, number and proportion of settable eggs, hatchability, and fertility. Specifically, 1-yr-old females laid their first egg 1 wk later than 2, 3, or 4-yr-old birds. Furthermore, 2-yr-old females produced a significantly higher number of settable and fertile eggs than other females (53.0 vs. 46.4 to 48.5) and had a lower incidence of embryo mortality. In experiment 2, we examined the effects of breeder age, egg size, and egg shape on egg hatchability. We found that small eggs (<17.6 g) had a significantly lower hatchability than medium (17.6 to 18.9 g) or large eggs (>18.9 g). However, we did not observe any significant correlation between egg shape and hatchability. These results suggest that red-legged partridge breeders attain maximum reproductive capacity at 2 yr of age and produce fewer eggs with lower weight and hatchability thereafter. PMID- 20952715 TI - Disinfection of eggshells using ultraviolet light and hydrogen peroxide independently and in combination. AB - Poor hatchability can occur due to eggshell bacterial contamination, which can be decreased by UV light or H(2)O(2) alone. However, antimicrobial effects of these 2 treatments combined, as well as optimum length of UV exposure, are not known. Therefore, the objectives of this study were to determine the optimum length of UV exposure for maximum bacterial reduction and to determine if a greater bacterial reduction would occur using a combination of UV and H(2)O(2) compared with either treatment alone. The first experiment was conducted to determine the optimum length of UV exposure by exposing eggs to 4, 8, 16, and 32 min of UV. Three experiments were also conducted to determine what concentration of H(2)O(2) in combination with UV exposure would yield maximum bacterial reduction. For experiment 2, treatments consisted of a control and UV alone as well as 0, 1, 2, and 3% H(2)O(2) alone and in combination with UV for 8 min. In experiment 3, treatments consisted of a control, UV alone, 3% H(2)O(2) alone, as well as 0, 0.5, 1, 1.5, 2, 2.5, and 3% H(2)O(2) in combination with UV for 8 min. Experiment 4 used 10 treatments including a control and 1.5, 2, and 2.5% H(2)O(2) at UV exposure times of 2, 4, and 8 min for each H(2)O(2) concentration. Results indicated that every control eggshell contained bacteria, resulting in an average bacterial count of 4 log cfu/egg. Exposure to UV alone for 8 min yielded significant bacterial reductions without excessive egg heating. When administered independently, H(2)O(2) and UV each reduced eggshell bacterial counts by 2 log cfu/egg. The combination of 1.5% H(2)O(2) and UV for 8 min reduced bacterial counts by a maximum of 3 log cfu/egg, with only 35% of the eggs positive for bacteria. Because bacterial contamination was further reduced by using a combination of UV and H(2)O(2), it is possible that hatchability and chick quality of breeder eggs might be improved by such treatments. PMID- 20952716 TI - Prediction of body composition by total body electrical conductivity technique is affected by fat reserves of Japanese quail. AB - The effect of fat accumulation on the prediction of in vivo body composition by a total body electrical conductivity (TOBEC) technique was evaluated using Japanese quail at 2 life periods (0 to 21 d and 28 to 70 d of age) that differ significantly in the fatness of birds. In total, 119 quail of 14 age categories were weighed and scanned by the TOBEC analyzer, and their carcasses were subjected to chemical analysis. The prediction equations for chemical composition (percentage of water, lipids, and lean tissue) and body masses (weight of body, water, lipids, and lean tissue) were obtained by linear regression analysis. The equations involved the E-value as the independent variable. In both growth phases, a high accuracy of estimation was found for the total body, lean, and water masses (0.85 <= R(2) <= 0.98), whereas a low accuracy of estimation was observed for percentages of lipids, lean tissue, and water (0.27 <= R(2) <= 0.64). Most of the variables showed a worse estimation in the late than in the early growth phase; the maximum difference was observed for the lipid mass (R(2) = 0.35 vs. 0.90, respectively). The correlations between analyzed variables and the residual error distributions of regression models demonstrated that the lower power of the models in the late versus early growth phase may be attributed to an enhanced fat accumulation in sexually mature birds. Their high fat reserves considerably decrease body hydration, which negatively influences the estimation of body composition based upon the TOBEC procedure. PMID- 20952717 TI - An economic analysis of a methionine source comparison response model. AB - Methionine is the first-limiting amino acid in corn and soybean meal-based poultry diets. Therefore, its supplementation level is of primary economic importance to poultry production. The responses to the methionine sources dl methionine (DLM) and methionine-hydroxy analog-free acid (HMTBA) have been compared using various methodologies. The so-called common plateau nonlinear model has been used to estimate relative bioavailabilities of the sources. This model has a coefficient that is used as a single value to compare the relative bioavailabilities of the sources for independent technical parameters like gain and feed efficiency. This model was used previously in a meta-analysis of published experiments and found 79 and 81% relative biological efficiencies of HMTBA for DLM for ADG and feed utilization efficiency, respectively. Because different sources would have different optimal feeding levels to maximize profits, we demonstrate the challenge of calculating a single optimal level for the different methionine sources. Further, we apply an economic analysis to results of the previous meta-analysis to demonstrate that the relative values of HMTBA and DLM for BW and ADG are between 81 and 86%, depending on the value of a broiler and the costs of feed and DLM. PMID- 20952718 TI - Analysis of ordered categorical data with threshold models exemplified by plumage damage scores from laying hens differing in their genotype and rearing environment. AB - Plumage damage scores (PDS) were assessed in laying hens of 2 genotypes (Lohmann Tradition and Lohmann Silver) at the 45th and 70th weeks of age, with scores ranging from zero (no damage) to 6 (completely denuded). This ordinally scaled categorical characteristic was recorded from different body regions of 365 hens that had experienced different housing environments (2 enrichment levels) during their rearing and laying periods. The so-called threshold model is an option for analyzing repeated ordered categorical data from individual animals. This model represents a generalized linear mixed model if the linear predictor additionally includes the animal as a random effect. This paper is intended to fill the gap between the theoretical aspects of generalized linear mixed models and their practical application in animal science. A cumulative probit model was adapted for analyzing plumage damage. The variation among birds was considered as a random effect for the analysis of cumulative probabilities. The numerical implementation of the methodology was done based on the NLMIXED procedure of the SAS statistical program. A threshold model with inhomogeneous residual variances for the latent variable was used because less plumage damages were observed up to the 45th week of age compared to the 70th week of age. Differences in PDS were evident between genotypes, age, and enrichment levels during housing periods. However, neither of the 2 enriched environments proved consistent superiority or inferiority across all traits. Major plumage damage (PDS larger than or equal to 5) was observed for the breast region in 56.6% of all birds with the Lohmann Tradition genotype and in 34.4% with the Lohmann Silver genotype when we look at the mean over all treatments. The most severe plumage damage was observed at the 70th week of age for the traits breast and housing environment without additional enrichment. PMID- 20952719 TI - The integration of broiler chicken threonine responses data into neural network models. AB - In making general recommendations for amino acids, researchers might survey various published data on the responses of poultry to amino acids. In this way, the use of appropriate mathematical and statistical approaches may help researchers draw appropriate conclusions. The purpose of this study was to develop artificial neural network (ANN)-based models to analyze data on the responses of broiler chickens [ADG and feed conversion ratio (FCR)] to protein and threonine from 21 to 42 d of age. A data set containing 92 dose-response treatments was extracted from the literature, compiled, and entered into the training and testing sets of the ANN models. The constructed models were subjected to a process of sensitivity analysis to evaluate the relative importance of the effects of dietary protein and threonine on ADG and FCR. Optimal values for the input variables (protein and threonine requirements) to maximize ADG and minimize FCR in birds were obtained by using the ANN models with an optimization algorithm. Based on the calculated goodness of fit criteria, it appeared that the platform of ANN-based models with the sensitivity analysis and optimization algorithms was an efficient tool for integrating published data on the responses of broiler chickens to threonine. The analyses of ANN models for ADG and FCR based on the compiled data set suggested that the dietary protein concentration was more important than the threonine concentration. The optimization algorithm revealed that diets containing 18.69% protein and 0.73% threonine could lead to optimal ADG, whereas the optimal FCR could be achieved with diets containing 18.71% protein and 0.75% threonine. PMID- 20952720 TI - Assessment of a food microbiology senior undergraduate course as a potential food safety distance education course for poultry science majors. AB - Distance education courses have become popular due to the increased number of commuter students as well as people already in the workforce who need further education for advancement within their careers. A graduate-level Web-based course entitled Special Topics-Poultry Food Safety Microbiology was developed from an existing senior undergraduate advanced food microbiology course in the Poultry Science Department at Texas A&M University. Conversion of standard lecture material into a distance education course can provide unique challenges to maintain comparable course content in an asynchronous manner. The overall objective for this course was to examine bacterial activities including ecology in food, animals, raw and processed meat, eggs, and human pathogenesis. Students were surveyed at the end of the class and the majority agreed that they would be willing to take the course as an online course, although they were not willing to pay an extra fee for an online course. The majority of students used the online version of the course as a supplement to the classroom rather than as a substitute. PMID- 20952721 TI - Colorectal hamartomatous polyposis and ganglioneuromatosis in a dog. AB - A 5-month-old female Great Dane puppy was treated for hematochezia, tenesmus, and rectal prolapse by resection of a 10-cm-long segment of colon and rectum. Grossly, the colorectal segment had diffuse mucosal and submucosal thickening with multiple polypoid nodules. The histologic diagnosis was colorectal hamartomatous polyps with ganglioneuromatosis. Duplication of PTEN was detected by quantitative multiplex polymerase chain reaction testing. The presence of 2 hamartomatous colorectal lesions with PTEN mutation is similar to human Cowden syndrome. PMID- 20952722 TI - Germinal matrix hemorrhage in Zellweger syndrome. AB - A term male newborn was noted to have severe diffuse hypotonia, hyporeflexia, hepatosplenomegaly, and characteristic abnormal facies of Zellweger syndrome, the diagnosis of which was confirmed by identification of 2 mutations including Nt2098insT, a frameshift with premature stop codon in exon 13, as well as a novel second mutation at Nt3038G->A (Arg1013His) on skin fibroblast testing. His brain magnetic resonance imaging (MRI) demonstrated bilateral germinolytic cysts with unilateral hemorrhagic transformation. Germinolytic cysts are one of the characteristic radiographic features of Zellweger syndrome, but germinal matrix hemorrhage has never been reported. Germinal matrix hemorrhage is common in premature infants, but found in only 4% of normal term infants. Germinal matrix hemorrhage was seen in a case of Zellweger syndrome with a novel mutation. PMID- 20952723 TI - The relationship between parental concerns and final diagnosis in children with developmental delay. AB - Parental concern is a useful screening approach for early detection of children with developmental delay. We investigated the relationships among parental concerns, functional impairment, and final diagnosis of children (n = 273) with developmental delays. Of these, motor, language, and global delay were most common. Parental concerns, especially in language and motor development, were good predictors of children with language or motor delay, and provided reliable information for detection of children with delays in these domains. Parents were less likely to identify children with cognitive problems, global delay, or associated behavioral problems. Co-occurrence of developmental disorders was also recognized, especially in children with global delay. We conclude that parental concerns are useful information for detection of specific developmental problems in children. Because co-occurrence of developmental disorders is common, their early recognition would be helpful for better care of these children. PMID- 20952724 TI - Review. Colon cancer vaccines: an update. AB - Despite advances in research and treatment modalities, colorectal cancer still accounts for around half a million deaths yearly worldwide. Traditional and even newer pharmaceutical therapeutic regimens are limited in terms of tolerance, efficacy and cross-resistance. Additional non-cross resistant therapies with non overlapping toxicities are needed to improve the outcome for patients with colorectal cancer. Cancer vaccines, designed to activate immune effectors (T cells and antibodies) to prevent recurrence or treat advanced cancers, have now demonstrated clinical benefit in prostate cancer and lymphoma. Because immune effector infiltration into colon tumours is associated with improved clinical outcome, vaccines intended to activate immune responses against colon cancer have generated significant interest. This review discusses data supportive of the immune responsiveness of colorectal cancer, as well as the current status of colon cancer vaccines under development including those based on whole tumour cells or lysates, peptide or protein antigens, anti-idiotype antibodies, viral vectors, and dendritic cells. We also discuss challenges to colon cancer vaccine development, such as tumour associated mechanisms for immune evasion, and how future strategies may address these challenges. PMID- 20952725 TI - Uterus cryopreservation in the sheep: one step closer to uterus transplantation. AB - BACKGROUND: Uterus transplantation is the only way for women with no functional uterus to become pregnant. However, the technique is limited by the fact that an aggressive immunosuppression is necessary in order to avoid rejection of the graft. For better chances of finding a matching organ, which would minimize the immunosuppressive therapy, the establishment of cryobanks with a large number of uteri would be helpful. The aim of this study was to evaluate the feasibility to cryopreserve sheep uteri and to review the literature in this exciting new field of uterus cryopreservation and transplantation. MATERIAL AND METHODS: Ten sheep uteri were frozen either with slow cooling after perfusion with 10% dimethylsulfoxide, or without perfusion and the contractile ability was compared with that of fresh uteri. RESULTS: All perfused uteri showed contractions after thawing, similar to those of the non-frozen uteri. CONCLUSION: This study shows that the perfusion of sheep uterus with a cryoprotectant prior to slow freezing allows the cryopreservation of the whole organ and maintains the functionality of the organ after thawing. The perfused sheep uterus provides an experimental model for further investigations with other cryoprotective agents and freezing protocols. PMID- 20952726 TI - Thrombogenicity of sirolimus-eluting stents and bare metal stents: evaluation in the early phase after stent implantation. AB - BACKGROUND: Thrombogenicitiy of drug-eluting stents is a matter of controversial debate. The aim of this study was to evaluate the thrombogenicity of sirolimus eluting stents (SES) compared to bare metal stents (BMS) in a standardised in vitro model. MATERIALS AND METHODS: Nine SES and nine BMS were implanted in tubing loops and nine loops without stent served as controls. Initially and after 90 minutes of blood circulation in a modified chandler loop model, thrombin antithrombin III complex (TAT), PMN-elastase, factor XIIa, SC5b-9, sP-selectin and platelet count were measured. Expression of CD62P, CD45/41 and PAC-1 on platelets were determined by flow cytometry. RESULTS: After 90 minutes, platelet count decreased significantly in the loops with BMS and SES (p<0.05). Levels of TAT, PMN-elastase and SC5b-9 were significantly elevated after 90 minutes in all loops (p<0.05). sP-selectin significantly increased in the loops with BMS and SES after 90 minutes. No significant changes occurred in any flow cytometric data. Platelet count, sP-selectin, TAT, PMN-elastase, SC5b-9, CD62P, CD41/CD45 and PAC 1 showed no significant difference between BMS and SES. CONCLUSION: These data provide evidence that there is no difference in thrombogenicity of BMS and SES in the in vitro model. PMID- 20952727 TI - The effect of voluntarily ingested buprenorphine on rats subjected to surgically induced global cerebral ischaemia. AB - The effect of perioperatively administered buprenorphine analgesia on rats subjected to surgically induced global ischaemia was assessed. Rats supplied with buprenorphine, mixed in nut paste for voluntary ingestion, displayed significant reductions in postoperative excretions of faecal corticosterone, in both magnitude and variance. This is indicative of lowered stress levels and less inter-animal metabolic variation. Although corticosterone has been reported to modulate the extent of cerebral damage, histology of coronal sections exhibited no differences in the extent of the ischaemia in buprenorphine-treated and untreated animals. A part from a slightly higher hyperthermia immediately after surgery and typical opiate-associated behaviour, the buprenorphine treatment had no apparent adverse effects on the experimental model. In contrast, the analgesic treatment improved the model by minimizing stress-associated confounding variables in the experimental animals. PMID- 20952728 TI - uPA, uPAR and TGFbeta1 expression during early and late post myocardial infarction period in rat myocardium. AB - The expression patterns of transforming growth factor beta 1 (TGFbeta1), urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR) were analysed after artery ligation-induced myocardial infarction (MI) in the rat myocardium. uPA and uPAR expressions were significantly increased both at transcriptional and protein level during early phase post MI period (uPA at 1 hour and uPAR at 24 hours post infarction). TGFbeta1 mRNA expression profile revealed a significant increase of TGFbeta1 expression from day 4 up to 8 weeks post infarction. These data suggest that the need for an increasing TGFbeta1 bioavailability during the post-infarction period in rat myocardium is achieved in the early post MI period by an increased expression of uPA/uPAR proteolytic system (indirect activation of latent TGFbeta1) and in the late post MI period by direct regulation of TGFbeta1 expression. It is therefore concluded that differential regulation of the TGFbeta1 bioavailability may be a crucial step of the repair mechanisms during the post MI infarction period in the rat myocardium. PMID- 20952729 TI - CD95 and TNFalpha-induced apoptosis in liver metastases of colorectal carcinoma. AB - BACKGROUND: Therapeutic options in patients with metastatic colorectal cancer are still limited. As apoptosis contributes to the overall sensitivity to radiotherapy or chemotherapy, a better understanding of the apoptotic process in metastatic tumour tissues is necessary. MATERIALS AND METHODS: Precision cut tissue slices (PCTS) of three human liver metastases were used to investigate the effect of activating CD95 antibodies (concentrations: 0.1 MUg/ml, 1 MUg/ml and 1 MUg/ml and 1 MUg/ml actinomycin D) as well as TNFalpha (concentrations 1 ng/ml; 10 ng/ml and 10 ng/ml and 1 MUg/ml actinomycin D) directly in tumour tissue after 6 h, 12 h and 24 h. The apoptotic effect was assessed immunohistochemically. RESULTS: Activating CD95 antibodies combined with actino-mycin D led to a significant increase in apoptosis after 12 h. Using TNFalpha at a high dosage, a significant increase in the apoptosis rate was observed after 6 h and after 12 h in all dosage groups. CONCLUSIONS: PCTS can be used to investigate the effect of different apoptotic signals directly in human tumour tissues. TNFalpha is able to effectively induce apoptosis in liver metastases of colorectal carcinoma. Thus, the extrinsic pathway of apoptosis may be a promising target in the development of new therapeutic approaches. PMID- 20952730 TI - Transplanted mesenchymal stem cells can inhibit the three developmental stages of murine acute graft-versus-host disease. AB - BACKGROUND: Recent data have demonstrated that mesenchymal stem cells (MSCs) have potent immune regulation capacity in vitro, enhancing their therapeutic appeal for their utilisation in the management of acute graft-versus-host disease (aGvHD). However, their immunoregulatory activity in vivo is largely unknown. MATERIALS AND METHODS: Using murine compact bone-derived MSCs in an aGvHD model, the phenotypic status of splenocytes of aGvHD and aGvHD+MSC groups of mice were examined by flow cytometry. RESULTS: MSC infusion decreased the expression of MHC II and CD69 molecules on splenic CD11b+ cells of aGvHD mice, which resulted in decreased maturation of antigen-presenting cells. Moreover, the down-regulated ratio of CD3+CD69+ to CD3+ cells, leading to restrained early activation and effector T-cell formation, resulted in the enhancement of the absolute and relative number of splenic CD3+ cells by MSCs co-transfer. CONCLUSION: This study demonstrated that MSCs can inhibit the three developmental stages of aGvHD. PMID- 20952731 TI - Apoptosis and cell proliferation correlated with tumor grade in patients with lung adenocarcinoma. AB - BACKGROUND: Apoptosis and cell proliferation in patients with adenocarcinoma of the lung have not been well described with relation to fine-needle aspiration biopsies (FNABs). To investigate the contribution of apoptosis to the growth of adenocarcinoma of the lung, both apoptosis and cell proliferation were analysed for correlation with the grade of the tumor. PATIENTS AND METHODS: Fifty tumors from 50 patients with adenocarcinoma of the lung were studied. Twelve tumors were well-differentiated, 22 were moderately differentiated and 16 were poorly differentiated. The detection of DNA fragments in situ using the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) assay was applied to investigate active cell death (apoptosis) and the MIB-1 antigen was used to investigate cell proliferation. RESULTS: The TUNEL indices were 0.55+/-0.09, 0.90+/-0.33 and 3.1+/-0.99 in well-, moderately and poorly differentiated adenocarcinoma of the lung respectively. The MIB-1 antigen labeling indices were 7.1+/-0.12, 14.3+/-3.5 and 28.7+/-6.9, respectively, in the same order of tumor differentiation. The differences in both TUNEL and MIB-1 labeling indices were significant between well-, moderately and poorly differentiated adenocarcinoma of the lung and a positive correlation was found between the TUNEL indices and the MIB-1 indices. CONCLUSION: Apoptosis (cell death) and cell proliferation increases as the grade of differentiation decreases in adenocarcinoma of the lung, suggesting a rapid turn over of the tumor cells in tumors with a lower grade of differentiation. PMID- 20952732 TI - Novel microminipig model of atherosclerosis by high fat and high cholesterol diet, established in Japan. AB - Novel atherosclerotic lesions were induced in the Microminipig (MMP, registered with the Japanese Ministry of Agriculture, Forestry and Fisheries as a novel variety of swine), the smallest pig available for experimental use, by feeding a high fat (12%) and high cholesterol (5%) diet (HFCD) with sodium cholate (SC, 0.7%) (HFCD/SC) for three months. Three MMPs were used: a male fed with normal diet (M-ND), and a male and an ovariectomized female fed with HFCD/SC (M-HFCD/SC and Fx-HFCD/SC). HFCD/SC induced hypercholesterolemia accompanied by an increase in serum total cholesterol (T-Cho), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and cholesterol ester (CE) from the first week. Serum levels of T-Cho, LDL-C and CE reached a maximum in two to three weeks, and HDL-C gradually increased during the experimental period (duration). Serum lipoprotein analysis showed a dominant LDL-C fraction, as seen in humans, in all three MMPs. Body weight gain in the MMPs fed with HFCD/SC was greater than in the animal fed with M-ND. At the end of the experiment, computed tomography scans of conscious animals showed increases in subcutaneous and abdominal fat in those fed with HFCD/SC, suggesting the induction of obesity. Atherosclerotic lesions in systemic arteries (including external and internal iliac arteries, abdominal aorta, coronary artery, cerebral arterial circle), fatty changes, and foamy cell infiltration in the liver and spleen were histopathologically observed in the MMPs fed with HFCD/SC. Atherosclerosis and the pathological findings induced by HFCD/SC in MMPs were similar to the pathological changes associated with human atherosclerosis, suggesting that the MMP has the potential to be a suitable animal model for human atherosclerosis. PMID- 20952733 TI - Scintigraphic assessment of salivary gland function in a rat model. AB - BACKGROUND: Salivary gland dysfunction with xerostomia is a major clinical problem without a causal therapy in most cases. The development of an animal model for scintigraphic assessment of salivary gland function has great clinical relevance for the investigation of promising new diagnostic and therapeutic strategies for chronic salivary gland diseases. This study reports the first experiences with scintigraphic analyses of salivary gland function in a rat model. MATERIALS AND METHODS: Anatomical and scintigraphic studies were performed for topographic differentiation of major salivary glands of Wistar rats. (99m)technetium pertechnetate salivary gland scanning was performed, appropriate regions of interest were determined and the gland-to-background ratio was examined for the evaluation of salivary gland function. RESULTS: The quantitative analysis of salivary gland scintigraphy revealed a reliable comparison of major salivary glands on both sides with the gland-to-background ratio ranging from 1.26 to 1.94 with an average of 1.51. CONCLUSION: This model seems to be appropriate for functional studies in an experimental setting. PMID- 20952734 TI - Certain surfactants show promise in the therapy of pulmonary tuberculosis. AB - BACKGROUND/AIM: The aim of the present study was to develop the basis for the use of surfactants in the treatment of pulmonary tuberculosis (TB). Bacteria are surrounded by a thick lipid coat primarily consisting of trehalose dimycolate (TDM) and, consequently, are well shielded from the immune system's response and antibiotics. This protective barrier was removed by exposing the bacteria to certain surfactants. MATERIALS AND METHODS: Dodecyl maltoside (DDM) and octyl glucoside (OG) were utilized as non-toxic surfactants. RESULTS: Electron microscopy (EM) studies revealed that aggregated bacteria were also covered with excessive TDM which exacerbate the treatment efforts. Light and EM studies demonstrated that DDM and OG disperse the aggregated bacteria and are bactericidal. CONCLUSION: The studies presented here establish that certain surfactants are proficient in removing MTB's shield and, because they are well known as cell permeabilizing agents, they may also enhance the effectiveness of antibiotics and the immune system's response in the treatment of pulmonary TB. PMID- 20952735 TI - Inhibin/activin-betaC subunit in human endometrial adenocarcinomas and HEC-1a adenocarcinoma cell line. AB - INTRODUCTION: Inhibins and activins are important regulators of the female reproductive system. Recently, two novel inhibin subunits, named betaC (betaC) and betaE (betaE), have been identified. However, only limited data on the expression of the betaC subunit in human endometrioid adenocarcinomas exist. MATERIALS AND METHODS: Samples of uterine endometrioid adenocarcinomas were obtained and analysed by immunohistochemistry for the immunolabelling with an inhibin-betaC antibody. Additionally, the endometrial cancer cell line HEC-1a was used to assess the inhibin-betaC expression with the use of immunofluorescence. RESULTS: Expression of the inhibin-betaC subunit was demonstrated at the protein level by means of immunohistochemical evaluation in human endometrioid adenocarcinomas and the HEC-1a cell line. DISCUSSION: This study demonstrated, for the first time, that the novel inhibin/activin-betaC subunit is expressed in human endometrioid adenocarcinomas and in the human endometrial carcinoma cell line HEC-1a. Whether this novel beta-subunit has a substantial role in the pathogenesis and malignant transformation in human endometrium is still under investigation. PMID- 20952736 TI - Diffuse alveolar damage due to inappropriate strategy of mechanical ventilation in an experimental porcine model. AB - BACKGROUND: The aim of the study was to determine how tidal volumes may affect the lung and haemodynamics during mechanical ventilation. MATERIALS AND METHODS: With the approval of the Ethics Committee, the study included a total of 24 healthy piglets, average weight 30 kg (range 28-33 kg). The animals were ventilated for 90 minutes under general anaesthesia with two different tidal volume strategies and allocated into three groups. Group A, animals were healthy controls, Group B, animals comprised 8 piglets with an abdominal aortic aneurysm and ventilated with a low tidal volume strategy (VT(exp) 7 ml/kg). Group C comprised 8 animals seven days after kidney transplantation, ventilated with a high tidal volume strategy (VT(exp) 12 ml/kg). Changes in lung mechanics and hemodynamics were assessed at 30th and 90th minutes. Lung tissue samples were examined histologically. RESULTS: Protective ventilation in Group A and B did not confer any haemodynamic and lung mechanic differences. Significant differences were only found in Group C at 90 minutes for increased preload of both heart ventricles (CVP; t-test 4.07, p<0.01 and PAoP; t-test 8.43, p<0.01), pulmonary vascular resistance (t-test 3.11, p<0.05), and decreased expiratory tidal volume (t-test 6.07, p<0.01), dynamic lung compliance (t-test 3.83, p<0.01) and cardiac output (t-test 2.07, p<0.01). Diffuse alveolar damage was detected histologically. CONCLUSION: Mechanical ventilation at high tidal volumes reaching 12 ml/kg caused functional changes in the lungs, diffuse alveolar damage and reduction of cardiac output within 90 minutes. PMID- 20952737 TI - A simple method to record parietal cells in the fundic mucosa in baboons. AB - BACKGROUND: Gastric parietal cells in a baboon were recently found to be auto fluorescent. AIM: To study gastric sections with a fluorescent microscope in a cohort of baboons. MATERIAL AND METHODS: Gastric sections from 38 baboons were stained with hematoxylin-eosin (H&E) and examined in a fluorescence microscope (FLM). The thickness of the parietal cell population was assessed at x 10 magnification. RESULTS: H&E stained all mucosal cells: fovelar, parietal and chief cells. When the same sections were analyzed with an FLM, only parietal cells were auto-fluorescent, whereas fovelar and chief cells remained non fluorescent. Parietal cells formed a distinct, continuous auto-fluorescent band. The ratio of the auto-fluorescent parietal cell band/total mucosa ranged between 0.20 and 0.30. CONCLUSION: Gastric parietal cells became auto-fluorescent when H&E-stained sections from baboon stomachs were observed with an FLM. Eosin was the stain responsible for this optical phenomenon. PMID- 20952738 TI - Effect of itraconazoles on the production of pro-inflammatory substances in mouse macrophage-like cells. AB - BACKGROUND, MATERIALS AND METHODS: Synthetic triazoles are widely used for the treatment of fungal infection. In order to understand their possible anti inflammatory action, we investigated the effect of itraconazole and its hydroxylated derivative (hydroxyitraconazole) on the production of various pro inflammatory substances by mouse macrophage-like RAW264.7 cells. RESULTS: These compounds did not apparently show any growth inhibitory or stimulatory effects over a wide range of concentrations (0.2-50 MUg/ml). Itraconazoles dose dependently increased the production of prostaglandin E2 (PGE2) and tumor necrosis factor-alpha (TNF-alpha) without affecting the production of interleukin 1beta (IL-1beta) and nitric oxide (NO). LPS treatment significantly enhanced the production of NO, PGE2, TNF-alpha and IL-1beta. The addition of itraconazoles to LPS-stimulated RAW264.7 cells significantly reduced the production of NO, but rather enhanced the production of PGE2, TNF-alpha and IL-1beta. ESR spectroscopy demonstrated that itraconazoles did not significantly scavenge NO and superoxide anion radicals, indicating that the inhibition of NO production by itraconazoles is not due to their radical-scavenging activity. Hydroxyitraconazole was slightly more cytostatic, and more efficiently inhibited NO production, but enhanced the production of other pro-inflammatory substances. CONCLUSION: These data suggest that itraconazoles regulate NO and other pro-inflammatory substances differently in activated macrophages. PMID- 20952739 TI - Isochromosome 5p, a novel recurrent abnormality in breast cancer: is it a common abnormality in cancer? AB - BACKGROUND: The detection of recurring genetic changes in breast cancer can be extremely difficult. The tumors display very complex structural chromosomal rearrangements the origin of which are often very difficult to establish. The identification of recurrent chromosomal changes is a useful strategy for understanding tumorigenesis and specific chromosomal associations. Isochromosome i(5p) is a frequent finding in several types of cancer but it has been rarely described in breast cancer. The aim of the present study was to investigate the presence of i(5p) in primary breast tumors. MATERIALS AND METHODS: Sixteen cases of breast cancer were cytogenetically studied by direct culture of cancerous cells and G-banding technique. We focused on structural aberrations of chromosome 5 in order to identify the presence of i(5p) in breast cancer. RESULTS: All the cases presented complex chromosomal changes with hyperploidization and various unidentified marker chromosomes being the prominent finding. Among 16 cases studied 6 cases presented an i(5p). No other structural abnormalities of chromosome 5 could be identified. CONCLUSION: The presence of i(5p) in breast tumors suggests that this chromosomal abnormality plays an important role in the development of breast cancer. Isochromosome 5p needs to be further molecularly analyzed as a candidate region for the isolation of genes related to carcinogenesis. Moreover, the fact that i(5p) has been described in several different tumor types suggests that there are no fundamental tissue-specific differences in the genetic mechanisms leading to tumorigenesis. PMID- 20952740 TI - Immediate and short-, mid- and long-term effects of in vivo ionizing radiation exposure in BALB/c mice: I. Activation of lymphocytes and subpopulations. AB - BACKGROUND: The main aim of this work was to study the effects of single whole body irradiation (WBI) on the lymphoproliferative response in radiation-sensitive BALB/c mice. MATERIALS AND METHODS: Mice were irradiated (0-5 Gy) and euthanized immediately afterward; other animals were subjected to WBI (4 Gy) and were analyzed after periods of 0-180 days. Splenic cell number, lymphoproliferative response and lymphocyte subpopulations were studied. RESULTS: This study shows that immediately after exposure, an inhibition of the basal mitogen lymphoproliferative response was produced; furthermore, B-cells appear to be more radiosensitive than T-cells. However, up to 90 day's post-irradiation, mice spleens clearly show low cell numbers, and subpopulations and T-cell mitogens did not return to normal, while the basal response and B-cell mitogens peaked on day 15 post-WBI. CONCLUSION: In our model, B-cells regenerate earlier than T-cells, while Th lymphocytes regenerate faster than Tc lymphocytes. PMID- 20952741 TI - Metabolite formation of 17alpha-hydroxyprogesterone as a consequence of e-(aq) emission and progesterone effect regarding cancer. AB - Based on previous investigations on several hormones, 17alpha-hydroxyprogesterone (17alpha-HOPRG) was studied in respect to cancer initiation by its metabolites resulting from electron emission. The emission of electrons (e-(aq)) from its singlet excited state of 17alpha-HOPRG and HPLC-analysis of products were studied. Possible carcinogenicity of metabolites originating from 17alpha-HOPRG and the effect of progesterone (PRG) in this respect were studied in vitro. The results showed that 17alpha-HOPRG is very sensitive towards oxygen. The highest Q(e-(aq)) values were obtained by dissolution and UV-irradiation of substrate in airfree media. 17alpha-HOPRG metabolites showed a strong anticancer activity, which is, however, lower compared to that of PRG-metabolites. Mixture of both hormones, 17alpha-HOPRG and PRG, in respect to carcinogenicity showed a synergistic effect of PRG on 17alpha-HOPRG. Reaction mechanisms are presented. PMID- 20952742 TI - Multiple biological complex of alkaline extract of the leaves of Sasa senanensis Rehder. AB - Previous studies have shown anti-inflammatory potential of alkaline extract of the leaves of Sasa senanensis Rehder (SE). The aim of the present study was to clarity the molecular entity of SE, using various fractionation methods. SE inhibited the production of nitric oxide (NO), but not tumour necrosis factor alpha by lipopolysaccharide (LPS)-stimulated mouse macrophage-like cells. Lignin carbohydrate complex prepared from SE inhibited the NO production to a comparable extent with SE, whereas chlorophyllin was more active. On successive extraction with organic solvents, nearly 90% of SE components, including chlorophyllin, were recovered from the aqueous layer. Anti-HIV activity of SE was comparable with that of lignin-carbohydrate complex, and much higher than that of chlorophyllin and n-butanol extract fractions. The CYP3A inhibitory activity of SE was significantly lower than that of grapefruit juice and chlorophyllin. Oral administration of SE slightly reduced the number of oral bacteria. When SE was applied to HPLC, nearly 70% of SE components were eluted as a single peak. These data suggest that multiple components of SE may be associated with each other in the native state or after extraction with alkaline solution. PMID- 20952743 TI - Successful anatomic repair of fetoscopic access sites in the mid-gestational rabbit model using amnion cell engineering. AB - BACKGROUND/AIM: Our aim was to evaluate the impact of in vitro cultured amnion cells, injected and/or seeded in different scaffolds, on in vivo fetal membrane repair. MATERIALS AND METHODS: Amnion cells, isolated from allogeneic fetal membranes, were cultured on three different scaffolds for 14 to 21 days. In 33 mid-gestational rabbits, fetoscopic access sites were randomly allocated to four closure study groups: conventional collagen plug, as well as collagen plug, collagen foil, and fibrin glue as scaffolds for the cultured amnion cells. All membrane access sites were sealed with fibrin glue, and the myometrium closed with sutures. Fetal survival, amnion membrane integrity, and the presence of amniotic fluid were evaluated one week later. RESULTS: Cultures showed good survival in the collagen scaffolds. The use of collagen plug as a scaffold for the in vitro cultured amnion cells improved the integrity of fetal membranes to 80%, better than that of any other study group. CONCLUSION: Despite the need for additional studies, the present data suggest that amnion cells can be a practical and important source of cells for the engineering of constructs for sealing of the fetal membrane. PMID- 20952744 TI - Non-antibiotics reverse resistance of bacteria to antibiotics. AB - BACKGROUND: Most clinical isolates that exhibit a multi-drug resistant phenotype owe that resistance to over-expressed efflux pumps. Compounds that are efflux pump inhibitors (EPIs) reduce or reverse resistance to antibiotics to which the bacterial strain is initially resistant. We have evaluated non-antibiotics to reduce resistance of commonly encountered bacterial pathogens to antibiotics. MATERIALS AND METHODS: The effect of non-antibiotics on the susceptibility of bacteria to antibiotics was conducted by minimum inhibition concentration determinations of the antibiotic in the absence and presence of the non antibiotic. RESULTS: Non-antibiotics such as chlorpromazine, amitryptiline and trans-chlorprothixene are shown to reduce or reverse resistance of a variety of bacteria to antibiotics. CONCLUSION: The results suggest that non-antibiotics may serve as adjuncts to conventional antibiotics for the therapy of problematic antibiotic infections caused by bacteria that owe their resistance to over expressed efflux pumps. PMID- 20952745 TI - Association of vitamin D receptor Taq I polymorphism and susceptibility to oral squamous cell carcinoma. AB - BACKGROUND: It has been hypothesised that vitamin D receptor (VDR) gene polymorphisms may influence both the risk of cancer occurrence and prognosis. MATERIALS AND METHODS: The distribution of VDR Taq I polymorphism in 64 patients with OSCC was determined by polymerase chain reaction based restriction fragment length polymorphism (RFLP) and compared with that of 87 healthy controls. RESULTS: There was a significant difference in the distribution of VDR Taq I genotypes between OSCC patients and healthy controls. Patients with the VDR Tt genotype were found to be at significantly higher risk for OSCC than those with other genotypes (p=0.036). In particular, female OSCC patients were at higher risk (p<0.001) for oral cancer. CONCLUSION: These results suggest that the VDR Taq I polymorphism may be associated with susceptibility to OSCC. Female predilection of the OSCC risk in association with VDR gene polymorphism should also be investigated. PMID- 20952746 TI - Comorbidity of personality disorders with alcohol abuse. AB - There is high comorbidity of alcohol dependence with mood, anxiety, substance abuse and personality disorders. Personality disorders, in particular, are considered to be an important contributing and/or predisposing factor in the pathogenesis, clinical course and treatment outcome of alcohol dependence. According to clinical and epidemiological studies, the prevalence of personality disorders in alcoholism ranges from as low as 22-40% to as high as 58-78%. The literature has focused primarily on antisocial and borderline personality disorders; however, almost the whole spectrum of personality disorders can be encountered in alcohol dependence, such as the dependent, avoidant, paranoid and others. A number of factors, such as sampling methods, diagnostic criteria used or assessment procedures applied, may explain this wide variation. The quest of a distinct 'alcoholic personality' dates from the first half of the 20th century but failed to reveal consistent and strong substantiation. However, renewed efforts provided evidence for the importance of impulsivity/ disinhibition and neuroticism/negative affectivity in the development of alcohol dependence; the role of other personality traits such as extraversion/sociability is still unclear. These findings led to a number of typologies, some of the most popular and influential being those of Cloninger, Babor, and Lesch. PMID- 20952747 TI - Diagnostics of neuroendocrine tumours. AB - Neuroendocrine tumours (NETs) are rare pathologies which origin from neuroectodermic and endodermic cells and that can produce peptides and amino acids. About 70% of NETs derive from gastroenterohepatic (GEP) system and the other 30% from the different sites through the body. They are distinguished into single and multiple localizations and also into sporadic, familial multiple endocrine-related forms and recurrent forms. Moreover, when they produce hormones they usually are symptomatic; yet, they are characterized by the synthesis and secretion in the blood stream of several tumor-specific markers or can express somatostatin receptors in their cellular surface. The diagnosis and follow-up of NETs rely on laboratory studies, histopathology and the combination of anatomical and functional imaging, with the latter being the main method for monitoring response to therapy. In recent years, nuclear medicine has contributed to the impressive development of the knowledge of NETs in terms of biology (receptor scintigraphy), pharmacology (development of new tracers) and therapy (radiometabolic therapy). Nuclear medicine procedures for diagnosis and treatment of NETs are based on the biological properties of these tumours: the expression of somatostatin receptors. Somatostatin receptor scintigraphy not only has a crucial role in diagnosis and staging of NETs, but also in assessing suitability for treatment with cold and radiolabelled somatostatin analogues, as well as in monitoring response to treatment and detecting recurrent disease. In conventional nuclear medicine, the two most important functional imaging modalities are 111In octrescan and 123I-MIBG. Over the last 5 years, due to the development of new tracers, such as 68Ga labelled-DOTA-peptides PET and 18F-DOPA, PET has also been employed with significant benefits in the diagnosis and management of NETs. PMID- 20952748 TI - Relationship between body mass index, age and hypoxemia in patients with extremely severe obesity undergoing bariatric surgery. AB - BACKGROUND: Morbid obesity is frequently accompanied by serious co-morbidity, enclosed obstructive sleep apnea and hypoventilation syndrome, and thus many morbidly obese patients require surgical interventions. The aim of this study was to evaluate the relationship between arterial oxygen (pO2) and carbon dioxide (pCO2) partial pressure, age, loss of excess weight, and body mass index (BMI) in obese patients scheduled to undergo bariatric surgery. PATIENTS AND METHODS: A group of 11 patients (4 men, 7 women, median age 38 years, range 23-58 years) with extremely severe obesity (BMI>50 kg/m2) underwent laparoscopic Roux-en-Y gastric bypass. Preoperatively, BMI, pO2, and pCO2 were 52.7+/-2.4 kg/m2, and 70.9+/-5.3 and 43.1+/-6.5 mmHg, respectively. Hypoxemia (pO2<75 mmHg) was present in all patients, but no relationship between BMI and age (R=-0.24, p=0.44) or between BMI and pO2 (R=0.09, p=0.77) was found. RESULTS: As expected, there was a significant correlation between age and both pO2 (R=-0.58, p=0.04) and pCO2 (R=0.85, p=0.0004), while no relationship between BMI and age (R=-0.24, p=0.44), nor between BMI and pO2 (R=0.09, p=0.77) was found. Finally, there was a significant correlation between pO2 and loss of excess weight (R=-0.69, p=0.02). No intra- or postoperative complications were observed, and 12 months after surgery BMI decreased to 32.5+/-2.7 kg/m2 (p<0.001) and pCO2 to 37.9+/-5.3 mmHg (p=0.05), while pO2 reached 85.8+/-6.8 (p<0.001) mmHg. CONCLUSIONS: In obese patients, the severity of hypoxemia is mainly related to age. The amount of weight reduction, rather than lower baseline BMI values, may justify the significant postoperative pO2 improvement. PMID- 20952749 TI - Ulnar artery thrombosis and nerve entrapment at Guyon's canal: our diagnostic and therapeutic algorithm. AB - Hypothenar hammer syndrome is a rare condition of ulnar artery aneurysm or thrombosis, which can be associated with a neuropathy of the ulnar nerve. There is no agreement regarding an optimal diagnosis and treatment for this syndrome. Most authors suggest angiography as the gold standard for diagnosis and recommend observation for the thrombotic type, and reconstructive surgery for the aneurysmal type. We report here our diagnostic and therapeutic algorithm, reviewing 9 patients with ulnar artery thrombosis and nerve entrapment at Guyon's canal; and an evaluation of the type of management including: anamnesis, diagnostic tests, and reconstructive surgery. We consider resection of the arterial thrombotic segment as the treatment of choice, due to the fact that ulnar arterial thrombosis can induce severe chronic inflammation into Guyon's canal and ulnar nerve sufferance. Therefore, we propose a planned approach, including 3 steps: clinical evaluation with Tinel and Allen's tests; magnetic resonance and ultrasound images; ulnar nerve decompression and arterial reconstruction. We believe that this practice is important for the early therapy of ulnar arterio-neuropathy in affected patients. PMID- 20952750 TI - Epithelioid angiosarcoma of the scapula. AB - Epithelioid angiosarcoma is a rare variation of an angiosarcoma and its localization in the bone is exceptionally infrequent. This report presents the case of a 48-year-old male with an epithelioid angiosarcoma of the scapula. In CT and MRI scans an inhomogeneous tumour with osseous destructions, lytic areas, central necrosis and marginal hyperperfusion was observed. The bordering skeletal muscles were already infiltrated. The tumour was treated initially with neoadjuvant chemotherapy, followed by dose escalation, peripheral blood stem cell transplantation and resection of the lesion. Despite advanced local tumour stage at initial presentation, the patient is in complete remission. PMID- 20952751 TI - Psychoneuroendocrine modulation of regulatory T lymphocyte system: in vivo and in vitro effects of the pineal immunomodulating hormone melatonin. AB - BACKGROUND: At present, it is known that cancer-related immunosuppression would mainly depend on an immunosuppressive action mediated by a subtype of CD4+ lymphocytes, the so-called regulatory T lymphocytes (T-reg), which are identified as CD4+CD25+ cells. Moreover, it has been shown that anticancer immunity is under psychoneuroendocrine regulation, mainly mediated by the pineal hormone melatonin (MLT). This study was performed to investigate the in vivo and in vitro effects of MLT on T-reg generation. MATERIALS AND METHODS: We evaluated the in vivo effects of MLT (20 mg/daily orally in the evening) in 20 patients with untreatable metastatic solid tumor and the in vitro effects of MLT incubation (at 10 and 100 pg/ml) of pure lymphocyte cultures on T-reg cell count. RESULTS: MLT induced a statistically significant decline in mean T-reg cell numbers in patients who achieved disease control, whereas no effect was seen in those who had progressed. In contrast, no in vitro effect of MLT incubation was apparent. CONCLUSION: This preliminary study would suggest that MLT may exert in vivo an inhibitory action on T-reg cell generation in cancer patients which is associated with a control of the neoplastic progression, whereas no direct effect was seen in vitro on lymphocyte differentiation. This finding would suggest that MLT may counteract T-reg cell generation in vivo by inhibiting macrophage activity which is involved in stimulating T-reg cell production. PMID- 20952752 TI - Metastatic medullary carcinoma of the vulva in a patient with MEN IIb syndrome. AB - BACKGROUND: Multiple endocrine neoplasia (MEN) IIb is a rare genetic syndrome characterized by the occurrence of medullary thyroid carcinoma (MTC), pheochromocytoma and mucosal neuromas. CASE REPORT: A 43-year-old woman with MEN IIb syndrome presented to our department with a painful enlargement of the left side of her vulva, which was initially presumed to be an inflammatory Bartholin's gland process. Upon admission, the patient was on antibiotics with no response and surgery was decided. A wide local excision was performed and histology revealed a metastatic medullary carcinoma of the vulva. CONCLUSION: MEN IIb syndrome is a clinical entity that may present multiple metastatic sites. To our knowledge, this is the first case of vulvar metastasis as part of the syndrome. PMID- 20952753 TI - Smooth-pursuit eye movement--a convenient bedside indicator for evaluating frontal lobe and intellectual function. AB - We hypothesized that smooth-pursuit eye movement is related to higher brain functions and that its impairment (iSPEM) could be useful in diagnosing neurological dysfunctions. We prospectively examined 305 patients and studied the relations between iSPEM and five items that reflect intellectual and/or frontal lobe function (dementia, sucking, snouting, hand grasping, elbow flexion response). We divided these patients into four subgroups: group A, patients with cerebellar ataxia as the presenting manifestation and with main lesions in the cerebellum; group B, patients with main lesions in brain regions other than the cerebellum; group C, patients with main lesions in the spinal cord, peripheral nerves, and muscles; and group D, patients with non-organic functional disorders, such as paroxysmal attacks and physical pain. Consequently, iSPEM was significantly (p<0.01) related to impairment in intellectual and frontal lobe functions in patients with cerebral lesions, and it also can be regarded as being equivalent to primitive reflexes. PMID- 20952754 TI - Reduced side-effects of adjuvant hormone therapy in breast cancer patients by complementary medicine. AB - A clinical investigation (representing evidence-based medicine level III) was performed to evaluate the benefit of complementary medicine in breast cancer patients undergoing adjuvant hormone therapy (HT). PATIENTS AND METHODS: The patients (n=129) were treated according to international guidelines. All patients suffered from arthralgia and mucosal dryness induced by the adjuvant HT. To reduce these side-effects, the patients were complementarily treated with a combination of sodium selenite, proteolytic plant enzymes (bromelaine and papain) and Lens culinaris lectin. On the basis of case report formulas (CRFs), self assessment of defined side-effects of HT (arthralgia and mucosal dryness) were documented before as well as 4 and 8 weeks after complementary treatment. Validation was carried out by scoring from 1 (no side-effects/optimal tolerability) to 6 (extreme side-effects/extremely bad tolerability). RESULTS: The severity of side-effects of HT was reduced by complementary treatment with sodium selenite, plant enzymes (bromelaine and papain) and Lens culinaris lectin. The mean score of symptoms declined from 4.2 (before treatment) to 3.2 (after 4 weeks of treatment) to 2.7 (after 8 weeks of treatment) for arthralgia and from 3.2 (before treatment) to 2.9 (after 4 weeks of treatment) to 2.6 (after 8 weeks of treatment) for mucosal dryness, the primary aims of this investigation. The reduction of side-effects of HT was statistically significant (p<0.001 after 4 weeks and p<0.0001 after 8 weeks). CONCLUSION: This investigation demonstrates benefits of indication-based complementary treatment in breast cancer patients, e.g. reduction of side-effects of adjuvant HT. A randomized controlled trial is planned to integrate the complementary treatment with the combination of sodium selenite, proteolytic enzymes and Lens culinaris lectin into evidence-based medicine. PMID- 20952755 TI - Depression, anxiety and general psychopathology in breast cancer patients: a cross-sectional control study. AB - OBJECTIVE: A significant proportion of breast cancer patients experience psychiatric morbidity. The present study compared the psychopathological profile (depression, anxiety and general psychopathology) of Greek women with breast cancer with a group of healthy controls. MATERIALS AND METHODS: Patients (n=109) were recruited from a specialized oncology breast cancer department and healthy controls (n=71) from a breast outpatient clinic. General psychopathology was assessed by the SCL-90-R. The Montgomery-Asberg Depression Rating Scale (MADRS) and the Spielberger State-Trait Anxiety Inventory (STAI) were used for assessing depression and anxiety. Demographics and clinical characteristics were also recorded. Data were modeled using multiple regression analysis. RESULTS: The mean age was 54.7+/-18.1 years for the control group and 51.2+/-9.5 years for the patient group (p=0.288). Mean scores on SCL-90-R, MADRS and STAI were significantly higher in the cancer group compared to controls (p<0.05). Multiple regression analysis revealed that breast cancer was independently and positively associated with all psychological measures (p<0.05). Regression coefficients ranged from 0.19 (SCL-90-R, psychotism) to 0.33 (MADRS). Lower anger/aggressiveness and anxiety were found in highly educated women; divorced/widowed women scored higher on obsessionality and MADRS compared to married women. Psychiatric treatment was associated with higher scores on somatization, depression, phobic anxiety and general psychopathology. CONCLUSION: Anxiety, depression, and overall psychopathology are more frequent in breast cancer patients compared to controls. Disease makes a larger independent contribution to all psychopathological measures than any other investigated variable. Therefore, breast cancer patients should be closely followed up in order to identify and timely treat any mental health problems that may arise. PMID- 20952756 TI - Accommodating heterogenous rates of evolution in molecular divergence dating methods: an example using intercontinental dispersal of Plestiodon (Eumeces) lizards. AB - Identifying and dating historical biological events is a fundamental goal of evolutionary biology, and recent analytical advances permit the modeling of factors known to affect both the accuracy and the precision of molecular date estimates. As the use of multilocus data sets becomes increasingly routine, it becomes more important to evaluate the potentially confounding effects of rate heterogeneity both within (e.g., codon positions) and among loci when estimating divergence times. Here, using Plestiodon lizards as a test case, we examine the effects of accommodating rate heterogeneity among data partitions on divergence time estimation. Plestiodon inhabits both East Asia and North America, yet both the geographic origin of the genus and timing of dispersal between the continents have been debated. For each of the eight independently evolving loci and a combined data set, we conduct single model and partitioned analyses. We found that extreme saturation has obscured the underlying rate of evolution in the mitochondrial DNA (mtDNA), resulting in severe underestimation of the rate in this locus. As a result, the age of the crown Plestiodon clade was overestimated by 15-17 Myr by the unpartitioned analysis of the combined loci data. However, the application of partition-specific models to the combined data resulted in ages that were fully congruent with those inferred by the individual nuclear loci. Although partitioning improved divergence date estimates of the mtDNA-only analysis, the ages were nonetheless overestimated, thus indicating an inadequacy of our current models to capture the complex nature of mtDNA evolution in over large time scales. Finally, the statistically incongruent age distributions inferred by the partitioned and unpartitioned analyses of the combined data support mutually exclusive hypotheses of the timing of intercontinental dispersal of Plestiodon from Asia to North America. Analyses that best capture the rate of evolution in the combined data set infer that this exchange occurred via Beringia ~18.0-30 Ma. PMID- 20952757 TI - The shape and temporal dynamics of phylogenetic trees arising from geographic speciation. AB - Phylogenetic trees often depart from the expectations of stochastic models, exhibiting imbalance in diversification among lineages and slowdowns in the rate of lineage accumulation through time. Such departures have led to a widespread perception that ecological differences among species or adaptation and subsequent niche filling are required to explain patterns of diversification. However, a key element missing from models of diversification is the geographical context of speciation and extinction. In this study, we develop a spatially explicit model of geographic range evolution and cladogenesis, where speciation arises via vicariance or peripatry, and explore the effects of these processes on patterns of diversification. We compare the results with those observed in 41 reconstructed avian trees. Our model shows that nonconstant rates of speciation and extinction are emergent properties of the apportioning of geographic ranges that accompanies speciation. The dynamics of diversification exhibit wide variation, depending on the mode of speciation, tendency for range expansion, and rate of range evolution. By varying these parameters, the model is able to capture many, but not all, of the features exhibited by birth-death trees and extant bird clades. Under scenarios with relatively stable geographic ranges, strong slowdowns in diversification rates are produced, with faster rates of range dynamics leading to constant or accelerating rates of apparent diversification. A peripatric model of speciation with stable ranges also generates highly unbalanced trees typical of bird phylogenies but fails to produce realistic range size distributions among the extant species. Results most similar to those of a birth-death process are reached under a peripatric speciation scenario with highly volatile range dynamics. Taken together, our results demonstrate that considering the geographical context of speciation and extinction provides a more conservative null model of diversification and offers a very different perspective on the phylogenetic patterns expected in the absence of ecology. PMID- 20952758 TI - ALCAM/CD166: cancer-related issues. AB - Activated leucocyte adhesion molecule (ALCAM) was originally identified as a transmembrane receptor which is involved in T-cell activation and has other still unresolved functions in hematopoiesis, development, inflammation and transendothelial migration of neutrophils. ALCAM is a member of a subfamily of immunoglobulin receptors with five immunoglobulin-like domains (VVC2C2C2) in the extracellular domain and is expressed in many types of tumors. The tumor-type dependent impact of its expression level with respect to prognosis points to a possible context-dependent function. Most functional investigations have focused on malignant melanoma, in which high ALCAM expression at the protein level correlates with a poor prognosis. ALCAM mediates low-affinity homophilic interactions and much stronger interactions with CD6. Modulation of ALCAM function with agents such as transfected dominant negative ALCAM and ligand binding secreted ALCAM both lead to inhibition of matrix metalloproteinase-2 activation, but their impact with respect to invasion in vitro and metastasis in vivo are different. Single-chain Fv fragments directed against ALCAM are efficiently internalized, paving the way for exploration of immunoconjugates as therapeutic agents. Validation experiments of the target with modulatory agents for possible therapeutic application in oncology are discussed. PMID- 20952759 TI - Characterization of soy-based changes in Wnt-frizzled signaling in prostate cancer. AB - BACKGROUND: A soy-based diet has been associated with a decreased risk of prostate cancer through its anti-androgenic effects. Because the Wnt/beta catenin pathway has been associated with aggressive prostate cancer, we have sought to further evaluate this pathway with respect to soy protein and prostate cancer. MATERIALS AND METHODS: Previously we have treated rat and human prostate cancer cell lines with soy protein isolates or purified genistein and used gene expression profiling and cross species analysis to identify genes with similar expression changes. One pathway that was identified included the Wnt/beta cantenin pathway. Here the initial data are evaluated and extended with immunohistochemistry in human prostate cancer, and Western blotting, small interfering ribonucleic acid (siRNA) inhibition and bromodeoxyuridine (BrDU) labeling in prostate cancer cell lines. RESULTS: The Wnt/beta-catenin pathway is modulated by both soy protein isolates and genistein in the genomic results. Immunohistochemistry demonstrated staining of Wnt pathway component molecules, in particular frizzled 3, glycogen synthase kinase 3 (GSK-3), and beta-catenin, in prostate tumors. Western blotting noted increased GSK3 and decreased expression of beta-catenin in soy treated prostate cancer PC3 cells. Supporting this finding, siRNA blocking of GSK3 accelerated growth whereas inhibition of frizzled 3 suppressed growth based on growth curves and BrDU labeling. CONCLUSION: Soy protein appears to regulate prostate cancer via the Wnt/beta-catenin pathway. These data demonstrate that the effect of soy protein effect on prostate cancer may occur through the frizzled 3 receptor with activation of GSK3 leading to increased degradation of beta-catenin and cell growth. PMID- 20952760 TI - Tyrosine kinase-deficient EphB6 receptor-dependent alterations in proteomic profiles of invasive breast carcinoma cells as determined by difference gel electrophoresis. AB - The expression profiles of the erythropoietin producing hepatocellular carcinoma (Eph) receptor family of tyrosine kinases have been previously shown to provide molecular signatures of normal breast cells, breast tumor cells and invasive breast carcinoma cells. In particular, the expression of EphB6 receptor is lost in invasive breast carcinoma cell line MDA-MB-231. The comparative proteomic profiles of native and EphB6-expressing MDA-MB-231 cells using difference gel electrophoresis (DIGE) and liquid chromatography-mass spectrometry of selected proteins are presented in this study. The expression of more than 70 proteins was significantly altered in EphB6-transfected MDA-MB-231 cells. These altered proteins are involved in glycolysis, cell cycle regulation, tumor suppression, cell proliferation, mitochondrial metabolism, mRNA splicing, DNA replication and repair. Although the majority of these proteins have been implicated in tumorigenesis, the impairment of energy homeostasis and altered regulation of signaling pathways appear to be noteworthy targets of EphB6. Based on the identities of altered proteins and the pathways regulated by these proteins, this study suggests that the interactions of EphB6 with a wide variety of proteins lead to altered proteomic profile of EphB6-transfected MDA-MB-231 cells. PMID- 20952761 TI - MicroRNA expression profile of MCF-7 human breast cancer cells and the effect of green tea polyphenon-60. AB - This study reports for the first time the microRNA expression profile of human breast cancer MCF-7 cells and the effect of green tea. Although hundreds of miRNAs have been identified in humans, only a small proportion (25.6%) of miRNAs are expressed in MCF-7 cells. Low concentration treatment with Polyphenon-60 significantly alters the miRNA expression profile in MCF-7 cells. Twenty three miRNAs have been identified with differential expression after a 48 h treatment with 10 MUg/ml Polyphenon-60 (green tea extract). These miRNAs include miR-21 and miR-27 that were found to be down-regulated following treatment with green tea. These two miRNAs have previously been identified as being overexpressed in MCF-7 breast cancer cells, with miR-21 specifically implicated in down-regulating the tumor suppressor gene, tropomyosin-1. This data supports the hypothesis that Polyphenon-60-induced modification of the breast cancer miRNA expression profile contributes to the efficacy of green tea treatment. The resulting decrease in carcinogenesis is further supported by the altered miRNA regulation of potential oncogenes and tumor-suppressor genes. PMID- 20952762 TI - Analysis of protein phosphorylation in cisplatin-treated human cells following annexin V-based separation and multi-antibody screening. AB - Cancer chemotherapy relies heavily on DNA damaging agents such as cisplatin to induce tumour cell death. The response of cells to genotoxic insult, including cell cycle arrest, DNA repair and cell death, is mediated by the DNA damage response (DDR). To address the relationship between the DDR and the outcome of exposure, this study utilised a magnetic-activated cell sorting (MACS(r))-based approach to isolate apoptotic and non-apoptotic cells from a DNA polymerase eta deficient human cell line. The pattern of phosphorylation of the key DNA damage response protein RPA2 on serine 4/8 was altered in apoptotic cells isolated following cisplatin treatment. By combining MACS(r) with multi-antibody screening for phosphorylated proteins, apoptosis-associated changes were characterized in a number of key signalling pathways. Phosphorylation of Erk1 on Thr202/Tyr204, and Erk2 on Thr185/Tyr187 was increased in apoptotic cells. This approach provides novel insights into the relationship between cisplatin-induced protein phosphorylation and the cellular consequences of exposure to this chemotherapeutic agent. PMID- 20952763 TI - Ondansetron does not block paracetamol-induced analgesia in a mouse model of fracture pain. AB - BACKGROUND: The aim of this study was to assess any interaction between ondansetron and paracetamol on a model of post-fracture pain in mice. METHODS: In protocol A, after fracture of the tibia, mice were assigned to four groups: paracetamol 30 mg kg-1, paracetamol 50 mg kg-1, paracetamol 100 mg kg-1, or a saline vehicle i.p. In protocol B, after fracture of the tibia, mice were randomized to receive either paracetamol (100 mg kg-1) plus saline (vehicle), paracetamol (100 mg kg-1) plus ondansetron (1 mg kg-1), paracetamol (100 mg kg-1) plus ondansetron (2 mg kg-1), saline plus ondansetron (2 mg kg-1), or saline plus saline i.p. Three tests were used to assess pain behaviour: von Frey filament application, hot-plate test, and a subjective pain scale. Rescue analgesia with morphine was administered as necessary. RESULTS: In protocol A, paracetamol (100 mg kg-1)-treated animals had less mechanical nociception, thermal nociception, and a lower subjective pain scale rating, when compared with those receiving paracetamol at 30 or 50 mg kg-1 or saline [ED50 paracetamol=46.3 (6.34) mg kg-1]. No difference was found between paracetamol (30 mg kg-1) and saline-treated animals. In protocol B, the mechanical withdrawal threshold, the thermal withdrawal latency, and the subjective pain scale were lower after injection of paracetamol (100 mg kg-1)+saline, paracetamol (100 mg kg-1)+ondansetron (1 mg kg 1), and paracetamol (100 mg kg-1)+ondansetron (2 mg kg-1), whereas in mice receiving saline+ondansetron (2 mg kg-1) or saline+saline, there was no difference. CONCLUSION: We found that paracetamol 100 mg kg-1 blocked the development of hyperalgesia and allodynia after fracture pain and ondansetron did not modify the antinociceptive effect of paracetamol in this model. PMID- 20952765 TI - Array comparative genomic hybridization for the detection of submicroscopic copy number variations of the X chromosome in women with premature ovarian failure. PMID- 20952764 TI - Clinical predictors of outcome from an Australian pharmacological relapse prevention trial. AB - AIMS: To assess which baseline characteristics of patients predict response to treatment with acamprosate (ACAMP) and naltrexone (NTX) in alcohol dependence. METHODS: Outcome data from a 12-week randomized controlled trial of NTX, ACAMP and placebo for alcohol dependence were analysed by multiple logistic regression analyses to determine the predictive effects of gender and the baseline measures of dependence severity, craving, depression, anxiety and readiness to change in addition to NTX and ACAMP treatment. Moderators of the effect of each medication on outcomes were also examined. RESULTS: Relapse was predicted by the interaction terms of ACAMP and alcohol dependence severity, NTX and depression as well as NTX and the readiness to change measure Taking Steps. Abstinence was similarly predicted by the interaction term ACAMP and alcohol dependence severity. CONCLUSION: The efficacy of NTX and ACAMP in reducing relapse or lapse is influenced by different clinical characteristics. PMID- 20952766 TI - Inaccuracy of radiological and ECG criteria for right ventricular outflow tract implantation of pacemaker leads. AB - We present three cases of active fixation pacemaker lead implantation, where the leads were believed to be inserted in the right ventricular outflow tract (RVOT) septal position, using established radiological criteria. However, when the exact location of the leads was documented by three-dimensional echocardiography, true septal RVOT position was achieved in only one patient. In the other two patients, the leads were, in fact, implanted into the RVOT anterior free wall. The electrocardiogram criteria were not able to identify the septal position from the anterior RVOT free wall position. PMID- 20952767 TI - Effects of n-3 polyunsaturated fatty acids and of rosuvastatin on left ventricular function in chronic heart failure: a substudy of GISSI-HF trial. AB - AIMS: The GISSI-HF trial showed that n-3 polyunsaturated fatty acids (PUFA), but not rosuvastatin, reduce morbidity and mortality in patients with symptomatic heart failure (HF) of any cause. The aim of this echocardiographic substudy of GISSI-HF was to investigate the effects of n-3 PUFA and of rosuvastatin on left ventricular (LV) function in such patients. METHODS AND RESULTS: Six hundred and eight chronic HF patients were randomized to n-3 PUFA (n=312) or placebo (n=296); a second randomization was performed to rosuvastatin (n=212) or placebo (n=207). Echocardiographic examinations were recorded at baseline and at 1, 2, and 3 years; offline analysis was performed by a core laboratory to ensure consistent quantitative analysis. Baseline LV ejection fraction (EF) was 30% (95%CI 29-31). Left ventricular ejection fraction increased with n-3 PUFA by 8.1% at 1 year, 11.1% at 2 years, and 11.5% at 3 years vs. 6.3% at 1 year, 8.2% at 2 years, and 9.9% at 3 years in the placebo group (P=0.0050). No other echocardiographic parameter changed significantly. Rosuvastatin effects were not statistically significant. CONCLUSION: n-3 PUFA can provide a small but statistically significant advantage in terms of LV function in patients with symptomatic HF of any aetiology, already treated with recommended therapies. PMID- 20952768 TI - Influence of cardiomegaly on disordered breathing during exercise in chronic heart failure. AB - AIMS: Heart failure (HF) patients breathe with a rapid shallow pattern during exercise. This study examined the relationship between cardiac size and tachypnoeic breathing in HF patients during exercise. METHODS AND RESULTS: Thirty seven HF patients [age = 55 +/- 13 years, ejection fraction (EF) = 27 +/- 10%, New York Heart Association (NYHA) class = 2.3 +/- 1.2] and 42 controls (CTL) (age = 56 +/- 14 years, EF = 63 +/- 8%) were recruited. Participants underwent maximal exercise testing, pulmonary function testing, and chest radiography for calculation of total thoracic cavity volume (TTCV), diaphragm, heart, and lung volumes. Heart failure patients were divided into two groups: Group A = cardiac volume < median (n = 18) and Group B = cardiac volume >= median of the HF patients (n = 19). There was no difference between groups for TTCV (CTL = 8203 +/ 1489 vs. Group A = 8694 +/- 1249 vs. Group B = 8195 +/- 1823 cm(3)). Cardiac volume was different between groups for both absolute (CTL = 630 +/- 181 vs. Group A = 894 +/- 186 vs. Group B = 1401 +/- 382 cm(3), P< 0.001 for all comparisons) and %TTCV (CTL = 8 +/- 2 vs. Group A = 10 +/- 1 vs. Group A = 18 +/- 5%, P< 0.001 for all comparisons). Similarly, total lung volume as a %TTCV was significantly different among the groups (CTL = 70 +/- 4 vs. Group A = 65 +/- 5 vs. Group A = 58 +/- 7%, P< 0.01 for all comparisons). In HF patients, there was a trend (P = 0.10) towards an independent association between cardiac size and tidal volume (V(T)) at 75% of VO(2) peak whereas this relationship was statistically significant at VO(2) peak (P = 0.02) as patients with larger cardiac size had reduced V(T). CONCLUSION: This study demonstrates the close relationship between cardiac size and breathing pattern during exercise in HF patients. These results suggest cardiac size may pose a significant constraint on the lungs during exercise and may contribute to tachypnoeic breathing. PMID- 20952769 TI - Familial dilated cardiomyopathy: another risk factor for anthracycline-induced cardiotoxicity? PMID- 20952771 TI - Irrelevant onsets cause inhibition of return regardless of attentional set. AB - It is disputed whether onsets capture spatial attention either in a purely stimulus-driven fashion or only when they are contingent on one's attentional set. According to the latter assumption, interference from irrelevant onsets may result from nonspatial filtering costs. In the present study, we used inhibition of return (IOR) as a marker for spatial attention. IOR occurs mainly for locations that attention has visited before. Participants searched for a red object among white objects. An attentional set for redness was demonstrated by a spatial validity effect of red cues on response times. However, a stronger validity effect was found for irrelevant white onsets, which slowed responses when the onset contained a distractor, but speeded them when the onset contained a target. Most importantly, this onset benefit for targets turned into a deficit at longer SOAs, indicating IOR. We conclude that onset distractors capture spatial attention regardless of the observer's attentional set. PMID- 20952772 TI - Parallel, independent attentional control settings for colors and shapes. AB - Attentional capture can be contingent on attentional control settings (ACSs), such that peripheral cues influence processing for a subsequent target only when they share a critical feature with the target. Our previous demonstration that two ACSs from within the same feature category can be maintained simultaneously allows us to investigate the processing stage at which such ACSs are implemented. We compared the relative efficacy of ACSs from two different feature categories (shape and color) that are associated with different levels within the visual processing hierarchy. Participants were instructed to respond to one of two colors at one location and one of two shapes at another location, while ignoring the nontarget color and shape. We observed that spatial capture was modulated by whether the cues fit an ACS, with slightly greater contingent capture effects for ACSs defined by color than by shape. Thus, two ACSs from different feature sets (color and shape) can be maintained in parallel, although effectiveness of the control set varied with the type of feature. PMID- 20952774 TI - Object-based attention: shifting or uncertainty? AB - The contribution of object-based attentional guidance to visual processing is widely accepted, and recent models of attentional selection now include both space- and object-based representations. Nevertheless, although the mechanism of space-based attentional selection has been well characterized, the mechanism underlying object-based attentional selection remains poorly understood. Recent attempts at identifying the mechanism giving rise to object-based attentional selection have put forth two conflicting alternatives. The first suggests that object-based effects are driven by attentional uncertainty (i.e., the attentional prioritization hypothesis), whereas the second suggests that objects guide attentional selection only when an attentional shift is necessitated (i.e., the attentional-shifting hypothesis). Here, we directly investigated which of the two suggested accounts drives object-based effects, by pitting attentional certainty against attentional shifting. In a series of four experiments, we manipulated the certainty of target location, shifting of attention, and the stimulus onset asynchrony. It was observed that object-based effects depended solely on certainty of the forthcoming target location. These results suggest that attentional prioritization, and not a mere shift of attention, gives rise to object-based guidance of attentional selection. In addition, these results lend further support to the attentional prioritization account of object-based attention and provide further constraints on the mechanisms of object-based selection. PMID- 20952773 TI - Characteristic sounds make you look at target objects more quickly. AB - When you are looking for an object, does hearing its characteristic sound make you find it more quickly? Our recent results supported this possibility by demonstrating that when a cat target, for example, was presented among other objects, a simultaneously presented "meow" sound (containing no spatial information) reduced the manual response time for visual localization of the target. To extend these results, we determined how rapidly an object-specific auditory signal can facilitate target detection in visual search. On each trial, participants fixated a specified target object as quickly as possible. The target's characteristic sound speeded the saccadic search time within 215-220 msec and also guided the initial saccade toward the target, compared with presentation of a distractor's sound or with no sound. These results suggest that object-based auditory-visual interactions rapidly increase the target object's salience in visual search. PMID- 20952775 TI - Focusing on the bodily self: the influence of endogenous attention on visual body processing. AB - The present study explores whether endogenous attention can modulate body perception. A modified version of the Posner paradigm was used to direct participants' attention toward the appearance of distinct body images, which differed only in detailed idiosyncratic features: one's own and another person's hands. Hand stimuli were preceded by symbolic cues that predicted their identity with high probability, which made it possible to compare the processing of expected (valid) and unexpected (invalid) targets. Results revealed that endogenous attention influenced the processing of participants' own hands by speeding participants' responses to valid in contrast to invalid trials. Crucially, no validity effect was found for the hands of another person. These findings cannot be explained in terms of perceptual familiarity, since an optimization of the processing for both familiar and unfamiliar faces by symbolic cues was observed. In light of these results, it is suggested that participants are able to anticipate particular stimuli within the same perceptual category as long as these stimuli appear to be remarkably distinct to them, which is probably the case for particular faces and their own bodies, in contrast to other people's bodies. PMID- 20952776 TI - Direction information in multiple object tracking is limited by a graded resource. AB - Is multiple object tracking (MOT) limited by a fixed set of structures (slots), a limited but divisible resource, or both? Here, we answer this question by measuring the precision of the direction representation for tracked targets. The signature of a limited resource is a decrease in precision as the square root of the tracking load. The signature of fixed slots is a fixed precision. Hybrid models predict a rapid decrease to asymptotic precision. In two experiments, observers tracked moving disks and reported target motion direction by adjusting a probe arrow. We derived the precision of representation of correctly tracked targets using a mixture distribution analysis. Precision declined with target load according to the square-root law up to six targets. This finding is inconsistent with both pure and hybrid slot models. Instead, directional information in MOT appears to be limited by a continuously divisible resource. PMID- 20952777 TI - Task switching under predictable and unpredictable circumstances. AB - Task switching was examined under predictable and unpredictable circumstances. In the first two experiments (in predictable conditions), the upcoming task was determined by the trial sequence. In unpredictable conditions, this task was signaled by the stimulus. Under speeded conditions, participants had to judge either the parity of a digit or the vowel/consonant nature of a letter. On bivalent trials, a digit and a letter were presented. On univalent trials, a task relevant character occurred alongside a task-irrelevant character (e.g., "&"). Task-switching costs were found, and response times were generally slower on bivalent than on univalent trials. This crosstalk effect was reduced when a task repetition was expected. In the final experiment, trial predictability was defined according to whether a task precue was presented prior to or concurrently with the trial stimulus. Contrasting patterns of crosstalk effects were obtained and are discussed in terms of exogenous and endogenous factors that affect task switching. PMID- 20952778 TI - Parallel response selection in dual-task situations via automatic category-to response translation. AB - In contrast to the response selection bottleneck theory of dual-task performance, recent studies have demonstrated compatibility effects between secondary and primary responses on Task 1, suggesting that response information for two tasks may be generated in parallel. In two experiments, we examined the nature of Task 2 response activation in parallel with Task 1, using a psychological refractory period paradigm. Evidence of Task 2 to Task 1 response priming when each Task 2 stimulus was unique indicated that automatic parallel generation of response information occurred for Task 2 via abstract semantic category-to-response translation processes, independent of any direct stimulus-response influences. These findings are discussed in terms of their implications for the traditional response selection bottleneck theory of dual-task performance. PMID- 20952779 TI - Semantic memory for contextual regularities within and across scene categories: evidence from eye movements. AB - When encountering familiar scenes, observers can use item-specific memory to facilitate the guidance of attention to objects appearing in known locations or configurations. Here, we investigated how memory for relational contingencies that emerge across different scenes can be exploited to guide attention. Participants searched for letter targets embedded in pictures of bedrooms. In a between-subjects manipulation, targets were either always on a bed pillow or randomly positioned. When targets were systematically located within scenes, search for targets became more efficient. Importantly, this learning transferred to bedrooms without pillows, ruling out learning that is based on perceptual contingencies. Learning also transferred to living room scenes, but it did not transfer to kitchen scenes, even though both scene types contained pillows. These results suggest that statistical regularities abstracted across a range of stimuli are governed by semantic expectations regarding the presence of target predicting local landmarks. Moreover, explicit awareness of these contingencies led to a central tendency bias in recall memory for precise target positions that is similar to the spatial category effects observed in landmark memory. These results broaden the scope of conditions under which contextual cuing operates and demonstrate how semantic memory plays a causal and independent role in the learning of associations between objects in real-world scenes. PMID- 20952780 TI - The effectiveness of a gaze cue depends on the facial expression of emotion: evidence from simultaneous competing cues. AB - The gaze of a fearful face should be a particularly effective cue to attention; it allows one to rapidly allocate attention to potential threats. Prior data from investigations of this issue have been mixed. We report a novel method in which the gazes of two faces simultaneously cued different directions. Across trials, the emotion expressed by each face varied between happy, neutral, and fearful. Results showed that attention followed a fearful gaze when it competed with a neutral gaze but did not consistently follow a happy gaze when it competed with a neutral gaze. These results suggest that fear moderates the effectiveness of gaze cuing, and we present a parsimonious account that reconciles previously inconsistent data. We also found that presenting a fearful and a happy face simultaneously eliminates this effect, suggesting that emotional expressions interact in ways that may be important for understanding how emotional stimuli influence attention in more complex environments. PMID- 20952781 TI - The visual system discounts emotional deviants when extracting average expression. AB - There has been a recent surge in the study of ensemble coding, the idea that the visual system represents a set of similar items using summary statistics (Alvarez & Oliva, 2008; Ariely, 2001; Chong & Treisman, 2003; Parkes, Lund, Angelucci, Solomon, & Morgan, 2001). We previously demonstrated that this ability extends to faces and thus requires a high level of object processing (Haberman & Whitney, 2007, 2009). Recent debate has centered on the nature of the summary representation of size (e.g., Myczek & Simons, 2008) and whether the perceived average simply reflects the sampling of a very small subset of the items in a set. In the present study, we explored this further in the context of faces, asking observers to judge the average expressions of sets of faces containing emotional outliers. Our results suggest that the visual system implicitly and unintentionally discounts the emotional outliers, thereby computing a summary representation that encompasses the vast majority of the information present. Additional computational modeling and behavioral results reveal that an intentional cognitive sampling strategy does not accurately capture observer performance. Observers derive precise ensemble information given a 250-msec exposure, suggesting a rapid and flexible system not bound by the limits of serial attention. PMID- 20952782 TI - How might the discrepancy in the effects of perceptual variables on numerosity judgment be reconciled? AB - It has been claimed that a genuinely abstract numerical representation would be capable of representing the numerosity of any set of discrete elements independently of the attributes of the individual elements. In practice, however, perceptual variables, such as element size, density, and others, affect numerosity judgment. In this study, we examined how perceptual variables affect the performance of numerosity judgments under the control of factors such as amount of practice and set size. In Experiment 1, we introduced the numerosity comparison task to less experienced observers in order to examine the effect of element size and array area. In Experiment 2, we examined whether and how practice would influence precision and accuracy in numerosity comparison and demonstrated that the effects of perceptual variables mostly disappeared. In Experiment 3, we examined whether the effect of practice could transfer to the performance in different stimulus conditions. Taking the results together, we demonstrate that differences in practice might be the source of inconsistent results for perceptual variables. PMID- 20952783 TI - Weber-Fechner behavior in symmetry perception? AB - The literature contains several allusions to the idea that detection of (mirror) symmetry in the presence of noise follows the Weber-Fechner law. This law usually applies to first-order structures, such as length, weight, or pitch, and it holds that just-noticeable differences in a signal vary in proportion to the strength of the signal. Symmetry, however, is a higher order structure, and this theoretical note starts from the idea that, in noisy symmetry, the regularity-to noise ratio defines the strength of the signal to be considered. We argue that the detectability of the symmetry follows a psychophysical law that also holds for Glass patterns. This law deviates from the Weber-Fechner law in that it implies that, in the middle range of noise proportions, the sensitivity to variations in the regularity-to-noise ratio is disproportionally higher than in both outer ranges. PMID- 20952784 TI - Limits of generalization between categories and implications for theories of category specificity. AB - Both domain-specific and expertise accounts of category specialization assume that generalization occurs within a domain but not between domains. Yet it is often difficult to define the boundaries and critical features of object domains. Differences in how categories are defined make it difficult to adjudicate between accounts of category specificity and may lead to contradictory results. For example, evidence for whether car experts recruit the fusiform face area is mixed, and this inconsistency may be due to the inclusion of antique cars in one of those previous studies (e.g., Grill-Spector, Knouf, & Kanwisher, 2004). The present study tested the generalization of expertise from modern to antique cars and found that modern-car experts showed expert discrimination and holistic processing of modern cars but not of antique cars. These findings suggest that the neural specialization underlying perceptual expertise is highly specific and may not generalize to distinct subclasses, even when they share some degree of perceptual and conceptual features. PMID- 20952785 TI - Slant perception in near space is categorically biased: evidence for a vertical tendency. AB - The geographical slants of hills are known to appear quite exaggerated. Here, we examine the visual and haptic perception of the geographical slant of surfaces within reach under full-cue conditions and show that the perceived orientation of even these surfaces is biased. An exaggeration with respect to deviations from horizontal is shown to be present cross-modally. Experiment 1 employed numerical estimation to show the effect for visually observed surfaces, while controlling for verbal numerical bias. Experiment 2 demonstrated that the bias is present even when manual measures show good calibration. Experiment 3 controlled for direction of gaze. Experiment 4 measured the same bias for haptic surfaces. Experiment 5 showed that the bias can also be observed using the nonnumeric task of angle bisection. These results constrain theories of geographical slant perception and appear most consistent with functional scale expansion of deviations from horizontal. PMID- 20952786 TI - A balancing act: physical balance, through arousal, influences size perception. AB - Previous research has demonstrated that manipulating vision influences balance. Here, we question whether manipulating balance can influence vision and how it may influence vision--specifically, the perception of width. In Experiment 1, participants estimated the width of beams while balanced and unbalanced. When unbalanced, participants judged the widths to be smaller. One possible explanation is that unbalanced participants did not view the stimulus as long as when balanced because they were focused on remaining balanced. In Experiment 2, we tested this notion by limiting viewing time. Experiment 2 replicated the findings of Experiment 1, but viewing time had no effect on width judgments. In Experiment 3, participants' level of arousal was manipulated, because the balancing task likely produced arousal. While jogging, participants judged the beams to be smaller. In Experiment 4, participants completed another arousing task (counting backward by sevens) that did not involve movement. Again, participants judged the beams to be smaller when aroused. Experiment 5A raised participants' level of arousal before estimating the board widths (to control for potential dual-task effects) and showed that heightened arousal still influenced perceived width of the boards. Collectively, heightened levels of arousal, caused by multiple manipulations (including balance), influenced perceived width. PMID- 20952787 TI - The effects of interference and retention delay on temporal generalization performance. AB - This study investigated the effect of forgetting of the standard duration on temporal discrimination in a generalization task. In two experiments, participants were given a temporal generalization task with or without a retention delay between the learning of the standard duration and the testing of the comparison durations. During this delay, they either performed or did not perform an interference task. Results failed to reveal any effect of 15-min and 24-h retention delays on time judgments (Experiment 1). However, when an interference task was performed during the 15-min delay (Experiment 2), there was a subjective shortening effect, indicating that the standard duration was judged shorter with than without an interference task. These findings suggest that when an interference task occurs immediately after initial temporal encoding, it affects the process of consolidation in reference memory. PMID- 20952788 TI - Nonindependent and nonstationary response times in stopping and stepping saccade tasks. AB - Saccade stop signal and target step tasks are used to investigate the mechanisms of cognitive control. Performance of these tasks can be explained as the outcome of a race between stochastic go and stop processes. The race model analyses assume that response times (RTs) measured throughout an experimental session are independent samples from stationary stochastic processes. This article demonstrates that RTs are neither independent nor stationary for humans and monkeys performing saccade stopping and target-step tasks. We investigate the consequences that this has on analyses of these data. Nonindependent and nonstationary RTs artificially flatten inhibition functions and account for some of the systematic differences in RTs following different types of trials. However, nonindependent and nonstationary RTs do not bias the estimation of the stop signal RT. These results demonstrate the robustness of the race model to some aspects of nonindependence and nonstationarity and point to useful extensions of the model. PMID- 20952789 TI - Cast shadow can modulate the judged final position of a moving target. AB - Observers tend to localize the final position of a suddenly vanished moving target farther along in the direction of the target motion (representational momentum). We report here that such localization errors are mediated by perceived motion rather than by retinal motion. By manipulating the cast shadow of a moving target, we induced illusory motion to a target stimulus while keeping the retinal motion constant. Participants indicated the vanishing point of the target by directing a mouse cursor. The resulting magnitude of localization errors was modulated on the basis of the induced direction of the target. Such systematic localization biases were not obtained in a control condition in which the motion paths of the ball and shadow were switched. Our results suggest that cues to object motion trajectory, such as cast shadows, are used for the localization task, supporting a view that a predictive mechanism is responsible for the production of localization errors. PMID- 20952790 TI - Crossmodal facilitation of masked visual target identification. AB - In the present study, participants identified the location of a visual target presented in a rapidly masked, changing sequence of visual distractors. In Experiment 1, we examined performance when a high tone, embedded in a sequence of low tones, was presented in synchrony with the visual target and observed that the high tone improved visual target identification, relative to a condition in which a low tone was synchronized with the visual target, thus replicating Vroomen and de Gelder's (2000, Experiment 1) findings. In subsequent experiments, we presented a single visual, auditory, vibrotactile, or combined audiotactile cue with the visual target and found similar improvements in participants' performance regardless of cue type. These results suggest that crossmodal perceptual organization may account for only a part of the improvement in participants' visual target identification performance reported in Vroomen and de Gelder's original study. Moreover, in contrast with many previous crossmodal cuing studies, our results also suggest that visual cues can enhance visual target identification performance. Alternative accounts for these results are discussed in terms of enhanced saliency, the presence of a temporal marker, and attentional capture by oddball stimuli as potential explanations for the observed performance benefits. PMID- 20952791 TI - The Venus effect in real life and in photographs. AB - The toilet of Venus is the subject of many paintings. Typically, Venus appears with a small mirror in which her face is visible. Observers tend to say that Venus is admiring herself in a mirror, even when the location of the mirror makes this impossible. We demonstrate that the Venus effect is not specific to paintings by showing that it occurs in real life (Experiment 1) and in photographs (Experiments 1-4). The original description of the effect implied that observers describe Venus as seeing in a mirror what they (the observers) see. We used different photographs to compare the responses when the person in front of the mirror could or could not see him or herself and when the image of his or her face was or was not visible to the observer. Observers tend to state that a person can see his or her own reflection when he or she appears near a mirror, whether or not his or her face is visible in the mirror. A task based on a top-down view of a room confirmed that people lack sensitivity to the role of the viewpoint (Experiment 5). We discuss these findings in relation to other evidence of difficulty in understanding what is visible in a mirror. PMID- 20952792 TI - Visual and auditory accessory stimulus offset and the Simon effect. AB - We investigated the effect on the right and left responses of the disappearance of a task-irrelevant stimulus located on the right or left side. Participants pressed a right or left response key on the basis of the color of a centrally located visual target. Visual (Experiment 1) or auditory (Experiment 2) task irrelevant accessory stimuli appeared or disappeared at locations to the right or left of the central target. In Experiment 1, responses were faster when onset or offset of the visual accessory stimulus was spatially congruent with the response. In Experiment 2, responses were again faster when onset of the auditory accessory stimulus and the response were on the same side. However, responses were slightly slower when offset of the auditory accessory stimulus and the response were on the same side than when they were on opposite sides. These findings indicate that transient change information is crucial for a visual Simon effect, whereas sustained stimulation from an ongoing stimulus also contributes to an auditory Simon effect. PMID- 20952793 TI - The effects of temporal delay and orientation on haptic object recognition. AB - We examined the effects of interstimulus interval (ISI) and orientation changes on the haptic recognition of novel objects, using a sequential shape-matching task. The stimuli consisted of 36 wedge-shaped plastic objects that varied along two shape dimensions (hole/bump and dip/ridge). Two objects were presented at either the same orientation or a different orientation, separated by either a short (3-sec) ISI or a long (15-sec) ISI. In separate conditions, ISI was blocked or randomly intermixed. Participants ignored orientation changes and matched on shape alone. Although performance was better in the mixed condition, there were no other differences between conditions. There was no decline in performance at the long ISI. There were similar, marginally significant benefits to same orientation matching for short and long ISIs. The results suggest that the perceptual object representations activated from haptic inputs are both stable, being maintained for at least 15 sec, and orientation sensitive. PMID- 20952794 TI - An expectations-based approach to explaining the cross-modal influence of color on orthonasal olfactory identification: the influence of the degree of discrepancy. AB - In the present study, we explored the conditions under which color-generated expectations influence participants' identification of flavored drinks. Four experiments were conducted in which the degree of discrepancy between the expected identity of a flavor (derived from the color of a drink) and the actual identity of the flavor (derived from orthonasal olfactory cues) was examined. Using a novel experimental approach that controlled for individual differences in color-flavor associations, we first measured the flavor expectations held by each individual and only then examined whether the same individual's identification responses were influenced by his or her own expectations. Under conditions of low discrepancy, the perceived disparity between the expected and the actual flavor identities was small. When a particular color--identified by participants as one that generated a strong flavor expectation--was added to these drinks (as compared with when no such color was added), a significantly greater proportion of identification responses were consistent with this expectation. This held true even when participants were explicitly told that color would be an uninformative cue and were given as much time as desired to complete the task. By contrast, under conditions of high discrepancy, adding the same colors to the drinks no longer had the same effect on participants' identification responses. Critically, there was a significant difference in the proportion of responses that were consistent with participants' color-based expectations in conditions of low as compared with high discrepancy, indicating that the degree of discrepancy between an individual's actual and expected experience can significantly affect the extent to which color influences judgments of flavor identity. PMID- 20952795 TI - As bitter as a trombone: synesthetic correspondences in nonsynesthetes between tastes/flavors and musical notes. AB - In parallel to studies of various cases of synesthesia, many cross-modal correspondences have also been documented in nonsynesthetes. Among these correspondences, implicit associations between taste and pitch have been reported recently (Crisinel & Spence, 2009, 2010). Here, we replicate and extend these findings through explicit matching of sounds of varying pitch to a range of tastes/flavors. In addition, participants in the experiment reported here also chose the type of musical instrument most appropriate for each taste/flavor. The association of sweet and sour tastes to high-pitched notes was confirmed. By contrast, umami and bitter tastes were preferentially matched to low-pitched notes. Flavors did not display such strong pitch associations. The choice of musical instrument seems to have been driven primarily by a matching of the hedonic value and familiarity of the two types of stimuli. Our results raise important questions about our representation of tastes and flavors and could also lead to applications in the marketing of food products. PMID- 20952796 TI - Adaptive psychophysical procedures, loss functions, and entropy. AB - In this article, we present a new strategy for locating a point on a psychometric function (threshold determination) for yes-no procedures, called EntFirst. Our results show that it performs better than many existing strategies for estimating the 50% threshold that are commonly used in nonlaboratory settings. We also provide a review of existing algorithms for finding thresholds, with an emphasis on identifying the types of problems for which each algorithm is useful. Finally, we address a number of issues that are not adequately covered in the literature, including choosing an appropriate loss function to evaluate the performance of an algorithm for a given problem. PMID- 20952797 TI - Exploring the differences in distributional properties between Stroop and Simon effects using delta plots. AB - Stroop and Simon tasks are logically similar and are often used to investigate cognitive control and inhibition processes. We compare the distributional properties of Stroop and Simon effects with delta plots and find different although stable patterns. Stroop effects across a variety of conditions are smallest for fast responses and increase as responses slow. Simon effects across a variety of conditions, however, are largest for fast responses but decrease, and even reverse, as responses slow. We show in three experiments that these diverging patterns hold within participants and even when the stimulus materials are identical across the tasks. These stable differences in time course serve as bedrock phenomena for building and testing theories of cognitive control and inhibition. The results of two additional experiments suggest that the determinant of time course is not simply whether the distracting information is location. PMID- 20952798 TI - High-temperature gas chromatography-mass spectrometry for skin surface lipids profiling. AB - Skin surface lipids (SSLs) arising from both sebaceous glands and skin removal form a complex lipid mixture composed of free fatty acids and neutral lipids. High-temperature gas chromatography coupled with electron impact or chemical ionization mass spectrometry was used to achieve a simple analytical protocol, without prior separation in classes and without prior cleavage of lipid molecules, in order to obtain simultaneously i) a qualitative characterization of the individual SSLs and ii) a quantitative evaluation of lipid classes. The method was first optimized with SSLs collected from the forehead of a volunteer. More than 200 compounds were identified in the same run. These compounds have been classified in five lipid classes: free fatty acids, hydrocarbons, waxes, sterols, and glycerides. The advantage to this method was it provided structural information on intact compounds, which is new for cholesteryl esters and glycerides, and to obtain detailed fingerprints of the major SSLs. These fingerprints were used to compare the SSL compositions from different body areas. The squalene/cholesterol ratio was used to determine the balance between sebaceous secretion and skin removal. This method could be of general interest in fields where complex lipid mixtures are involved. PMID- 20952799 TI - DNA-based detection of the fungal pathogen Geomyces destructans in soils from bat hibernacula. AB - White-nose syndrome (WNS) is an emerging disease causing unprecedented morbidity and mortality among bats in eastern North America. The disease is characterized by cutaneous infection of hibernating bats by the psychrophilic fungus Geomyces destructans. Detection of G. destructans in environments occupied by bats will be critical for WNS surveillance, management and characterization of the fungal lifecycle. We initiated an rRNA gene region-based molecular survey to characterize the distribution of G. destructans in soil samples collected from bat hibernacula in the eastern United States with an existing PCR test. Although this test did not specifically detect G. destructans in soil samples based on a presence/absence metric, it did favor amplification of DNA from putative Geomyces species. Cloning and sequencing of PCR products amplified from 24 soil samples revealed 74 unique sequence variants representing 12 clades. Clones with exact sequence matches to G. destructans were identified in three of 19 soil samples from hibernacula in states where WNS is known to occur. Geomyces destructans was not identified in an additional five samples collected outside the region where WNS has been documented. This study highlights the diversity of putative Geomyces spp. in soil from bat hibernacula and indicates that further research is needed to better define the taxonomy of this genus and to develop enhanced diagnostic tests for rapid and specific detection of G. destructans in environmental samples. PMID- 20952800 TI - Ambispora granatensis, a new arbuscular mycorrhizal fungus, associated with Asparagus officinalis in Andalucia (Spain). AB - A new dimorphic fungal species in the arbuscular mycorrhiza-forming Glomeromycota, Ambispora granatensis, was isolated from an agricultural site in the province of Granada (Andalucia, Spain) growing in the rhizosphere of Asparagus officinalis. It was propagated in pot cultures with Trifolium pratense and Sorghum vulgare. The fungus also colonized Ri T-DNA transformed Daucus carota roots but did not form spores in these root organ cultures. The spores of the acaulosporoid morph are 90-150 MUm diam and hyaline to white to pale yellow. They have three walls and a papillae-like rough irregular surface on the outer surface of the outer wall. The irregular surface might become difficult to detect within a few hours in lactic acid-based mountings but are clearly visible in water. The structural central wall layer of the outer wall is only 0.8-1.5 MUm thick. The glomoid spores are formed singly or in small, loose spore clusters of 2-10 spores. They are hyaline to pale yellow, (25)40-70 MUm diam and have a bilayered spore wall without ornamentation. Nearly full length sequences of the 18S and the ITS regions of the ribosomal gene place the new fungus in a separate clade next to Ambispora fennica and Ambispora gerdemannii. The acaulosporoid spores of the new fungus can be distinguished easily from all other spores in genus Ambispora by the conspicuous thin outer wall. PMID- 20952801 TI - Common genetic variants are significant risk factors for early menopause: results from the Breakthrough Generations Study. AB - Women become infertile approximately 10 years before menopause, and as more women delay childbirth into their 30s, the number of women who experience infertility is likely to increase. Tests that predict the timing of menopause would allow women to make informed reproductive decisions. Current predictors are only effective just prior to menopause, and there are no long-range indicators. Age at menopause and early menopause (EM) are highly heritable, suggesting a genetic aetiology. Recent genome-wide scans have identified four loci associated with variation in the age of normal menopause (40-60 years). We aimed to determine whether theses loci are also risk factors for EM. We tested the four menopause associated genetic variants in a cohort of approximately 2000 women with menopause<=45 years from the Breakthrough Generations Study (BGS). All four variants significantly increased the odds of having EM. Comparing the 4.5% of individuals with the lowest number of risk alleles (two or three) with the 3.0% with the highest number (eight risk alleles), the odds ratio was 4.1 (95% CI 2.4 7.1, P=4.0*10(-7)). In combination, the four variants discriminated EM cases with a receiver operator characteristic area under the curve of 0.6. Four common genetic variants identified by genome-wide association studies, had a significant impact on the odds of having EM in an independent cohort from the BGS. The discriminative power is still limited, but as more variants are discovered they may be useful for predicting reproductive lifespan. PMID- 20952802 TI - Defective T-cell Proliferation and IL-2 Production in a Subgroup of Patients with Coronary Artery Disease. AB - Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by innate and adaptive immune responses to a variety of microbial and self-antigens. Given the crucial role of adaptive immunity in the pathogenesis of atherosclerosis, this study was performed to investigate the proliferative response of peripheral blood mononuclear cells (PBMC) and interleukin (IL)-2 production in patients with coronary artery disease (CAD). In this study, 25 patients with chronic stable CAD and 25 healthy individuals were investigated. The PBMCs were separated and stimulated with phytohaemagglutinin (PHA). MTT assay was performed to measure cell viability and proliferation. IL-2 concentrations in cell culture supernatants were determined by Enzyme-Linked Immunosorbent Assay. PHA-stimulated cells revealed a significantly increased optical density (OD) in both groups of patients (p=0.004) and controls (p<0.001). However, the patient group showed a significantly lower Stimulation index (SI) (p=0.001). Upon in vitro stimulation with PHA, IL-2 levels were significantly increased in both groups of patients and controls (p<0.001). However, IL-2 concentrations were significantly lower in the patient group (p=0.018). Six patients showed defective IL-2 production, whereas similar finding was not observed in the normal control subjects (p=0.022). PBMCs from patients with coronary artery disease showed defective PHA-induced mitogenesis and IL-2 production. Considering the autoimmune nature of atherosclerosis, decreased IL-2 production may potentially enhance the atherogenic process, leading to spontaneous activation of autoreactive T lymphocytes. PMID- 20952803 TI - Tolerance Induction by CD40 Blocking through Specific Antibody in Dendritic Cells. AB - Blocking antibodies are valuable tools for inhibiting the specific receptor- ligand interactions. The interaction of co-stimulatory molecules on the antigen presenting cells with their ligands on T cells is an essential step for T cell activation. In the present study, the effect of blocking antibody against CD40 on its T cell stimulatory potential is investigated.The DCs (dendritic cells) were collected from the mice spleens and then cultured in vitro. We used purified rat anti-mice CD40 (Clone HM40-3) (BD USA) as a blocking antibody and the appropriate titer of the blocking antibody was determined by flow cytometry. The DCs were then treated by antibody and used in MLR assay. The results of these experiments showed that CD40 blockade were associated with the increase in the of IL-4 secretion, shifting the DCs to stimulate Th2 cytokine production by the allogenic T cells, while the secretion of IL-12 by DCs decreased. Similarly, the DCs with reduced CD40 expression poorly responded to alloantigen stimulation in the MLR. Collectively, these results emphasize the importance of CD40 pathway in tolerogenic DCs generation and also support the idea that downregulation of CD40 is effective in inhibiting the allostimulatory function. PMID- 20952804 TI - The accuracy of serum galactomannan assay in diagnosing invasive pulmonary aspergillosis. AB - Galactomannan (GM) antigen is an aspergillus specific antigen that is released during the growth phase of invasive aspergillosis. We aimed to find the optimum cutoff and accuracy of serum Galactomannan assay in immunocompromised patients. Immunocompromised patients diagnosed with invasive pulmonary aspergillosis (IPA) based on the European Organization for Research and Treatment of Cancer/Invasive Mycosis Study Group (EORTC/MSG) with three levels of certainty proven, probable and possible, referred for GM antigen measurement at Immunology, Asthma and Allergy Research Institute (IAARI) from 2006 to 2009 and if they met the criteria were enrolled in this study. Totally 49 patients with IPA were enrolled in our study. According to EORTC/MSG, patients categorized into three levels of certainty: They were diagnosed as 'proven' invasive pulmonary aspergillosis 16(32.7%), 'probable' 18(36.7%) and 'possible' 15(30.6%). The most common host risk factor was solid tumors 17(34.7%). The accuracy of Galactomannan assay increased from 0.5 to 2 cutoffs. The optimum sensitivity and specificity obtained at the index cutoff of >=1.5 for diagnosis of "proven" IPA; which were respectively, 69.2% and 72.2%. Other cutoffs had high variance between sensitivity and specificity for diagnosis of IPA. The calculated cutoff gained by receiver operating characteristic (ROC) analysis for detecting proven IPA was 1.5. Intermediate accuracy of serum GM test in conjunct with clinical findings would help early IPA detection among immunocompromised patients. PMID- 20952805 TI - The prevalence of celiac autoantibodies in hepatitis patients. AB - Celiac disease has been associated with other autoimmune disorders such as autoimmune hepatitis, moreover it is known that T cell mediated immune response to dietary gluten and released cytokines are important for the entheropathy seen in celiac disease. We investigated celiac autoantibodies in patients with autoimmune hepatitis (AIH), and chronic hepatitis B (CHB).Sera from 84 patients with Autoimmune Hepatitis (AIH) type 1 and 88 patients with Chronic Hepatitis B (CHB) were tested for Immunoglobulin A and G antibodies to Gliadin, Immunoglobulin A antibodies to tissue transglutaminase using enzyme immunoassay, and Immunoglobulin A anti-endomysial antibodies by both indirect immunofluorescence, and enzyme immunoassay. The patients positive for anti endomysial antibodies and/or anti tissue transglutaminase antibodies were considered for deuodenal biopsy. The study was approved by Research Center for Gastroenterology and Liver Disease Ethics Committee and all patients gave their written informed consent to participate.Immunoglobulin A anti-endomysial and Immunoglobulin A anti-gliadin antibodies were positive in two out of 84 patients with AIH. Moreover, Immunoglobulin A anti-gliadin antibodies were positive in another patient who was also positive for anti tissue transglutaminase antibodies. Tissue transglutaminase antibodies were positive in eight (9.1%) of 88 patients with CHB, two of which were also positive for anti-endomysial antibodies. One of the patients with CHB was only positive for anti-endomysial antibodies.Compared with the general population, the prevalence of celiac autoantibodies in CHB and AIH patients is relatively high, and it is noteworthy that most positive patients were asymptomatic for celiac disease. We suggest screening for celiac disease before and during treatment in patients with viral and autoimmune hepatitis. PMID- 20952806 TI - Steroid Phobia among Parents of Asthmatic Children: Myths and Truth. AB - Asthma is one of the most common chronic diseases of childhood. Inhaled corticosteroids (ICS) are the recommended controller drug for asthma treatment. The aim of our study was to determine concerns and fears of parents of children with asthma towards the use of ICS. One hundred parents of asthmatic children were interviewed using structural questionnaire. Airway inflammation was reported by only 6% of interviewed parents, whereas airway narrowing was addressed by 34%. Interesting data, 71% of parents were concerned with the role of steroids in asthma treatment, but more than half (53%) of them addressed fears from side effects. Apparent gaps were found in knowledge of parents of asthmatic children about ICS as controller asthma medication. So, physician and health providers should explain to asthmatic parents that airway inflammation is the core for asthma management. This may remove fears about ICS and thus improve adherence to treatment. PMID- 20952807 TI - Effects of Maternal Nicotine Exposure on Expression of Collagen Type IV and its Roles on Pulmonary Bronchogenesis and Alveolarization in Newborn Mice. AB - Nicotine is one the chemical substance with high level of toxically. It crosses the placenta and accumulates in the developing organs of fetus. Our previous investigations indicated that collagen type IV plays a key role in basement membrane of various embryonic organs. In this study we evaluated the effect of maternal nicotine exposure pre and postnatal period on collagen IV expression during bronchogenesis and alveolarization in the lungs of newborn mice. Female Balb/C mice were mated and Sperm positive in vaginal smear was designated as embryonic day zero. Pregnant mice were divided into 2 experimental and 2 control groups. Experimental group 1, received 3 mg/kg nicotine intrapritoneally from day 5 of gestation to last day of pregnancy. Experimental group 2 received the same amount of nicotine during the same gestational days as well as 2 first week after birth (lactation). The control groups received the same volume of normal saline during the same periods. At the end of exposure times, all of newborns were anesthetized and their lungs were removed for immunohistochemical method. RESULTS: Our finding indicated that collagen reaction in the bronchial basement membrane and extra cellular matrix of lung parenchyma in experimental groups increased significantly compared to control groups. Our results also showed alveolar remodeling and abnormal bronchogenesis were observed in experimental group especially group 2. These data indicate that maternal nicotine exposure may induce abnormal collagen IV expression and cause defects in bronchopulmonary development. PMID- 20952808 TI - International Study of Asthma and Allergy in Childhood Phase III (ISAAC III): The Role of Non-Response in Valencia. AB - A study was done about non-participation during Phase III of the International Study of Asthma and Allergy in Childhood (ISAAC III) in Valencia to determine whether the non-response rate significantly affected the results obtained in Valencia. Of the schools selected to participate in ISAAC III, 13.3% denied not to, the main reason being they were already participated in a similar study. The ISAAC III questionnaire was handed out to participating schools for the parents of 6,358 schoolchildren aged 6-7 years. Of these, 53.4% responded correctly. The remaining 46.6% were given a non-response questionnaire (NRQ), of which 4.1% completed the questionnaire correctly. The main reason why parents who received the NRQ did not participate in ISAAC III was that their children had neither asthma nor other atopic disease, so interest was null. No significant statistical differences were observed between the prevalence of asthma in the schoolchildren who participated in ISAAC III and in the non-participants who answered the NRQ. These results suggest that the ISAAC III results relating to asthma are not biased by non-response. PMID- 20952809 TI - Autoimmune Lymphoproliferative Syndrome (ALPS) in a Boy with Massive Lymphadenopathy. AB - Autoimmune lymphoproliferative syndrome (ALPS) is an uncommon nonmalignant lymphoproliferative disease which is characterized by chronic, persistent or recurrent lymphadenopathy, splenomegaly, hepatomegaly, immune cytopenia , hypergammaglobinemia and increased risk of lymphoma. We report a 2-year old boy with hepatosplenomegaly as first presentation. Petechial and purpuric rashes with massive cervical lymphadenopathies developed 10 months later.In laboratory tests anemia, thrombocytopenia and hypergammaglobinemia were observed. According to flocytometry increased double negative T cells and by apoptosis assay decrease apoptosis of lymphocytes accompanied clinical manifestations, thus diagnosis of ALPS was established. In conclusion; in all patients with massive lymphadenopathy and hepatosplenomegay; especially with cytopenia; ALPS should be considered. PMID- 20952810 TI - Telomere sister chromatid exchange and the process of aging. AB - Telomeres are a hotspot for sister chromatid exchange (T-SCE). Any biological consequence of this form of instability remained obscure until quantitative modeling revealed a link between elevated T-SCE rates and accelerated cellular replicative senescence. This work strongly suggests that progressive telomere erosion is not the only determinant of replicative capacity; instead, T-SCE need to be considered as an independent factor controlling colony growth and senescence. Additionally high T-SCE rates have been observed in cells with deficiencies in WRN and BLM, the genes that are defective in Werner's and Bloom's syndromes, implying a connection to premature aging. In this Research Perspective we will explore some of the implications this recent work has for human health. PMID- 20952812 TI - Probing DNA conformational changes with high temporal resolution by tethered particle motion. AB - The tethered particle motion (TPM) technique informs about conformational changes of DNA molecules, e.g. upon looping or interaction with proteins, by tracking the Brownian motion of a particle probe tethered to a surface by a single DNA molecule and detecting changes of its amplitude of movement. We discuss in this context the time resolution of TPM, which strongly depends on the particle-DNA complex relaxation time, i.e. the characteristic time it takes to explore its configuration space by diffusion. By comparing theory, simulations and experiments, we propose a calibration of TPM at the dynamical level: we analyze how the relaxation time grows with both DNA contour length (from 401 to 2080 base pairs) and particle radius (from 20 to 150 nm). Notably we demonstrate that, for a particle of radius 20 nm or less, the hydrodynamic friction induced by the particle and the surface does not significantly slow down the DNA. This enables us to determine the optimal time resolution of TPM in distinct experimental contexts which can be as short as 20 ms. PMID- 20952813 TI - Error estimation for perfusion parameters obtained using the two-compartment exchange model in dynamic contrast-enhanced MRI: a simulation study. AB - In theory, the application of the two-compartment exchange model (2CXM) to data from a dynamic contrast-enhanced (DCE) MRI exam allows the estimation of the plasma flow, plasma volume, extraction flow and extravascular-extracellular volume. The aim of this paper was to explore whether simulations based on the 2CXM could provide useful information on the trustworthiness of the results. The deviations from the input values of the haemodynamic quantities were estimated for a 'reference tissue' with a clear bi-phasic response and four 'limit tissues' with more challenging 2CXM fitting properties. The impact of the instrumental factors sampling step (T(s)), acquisition window (T(acq)) and contrast-to-noise ratio (CNR) was investigated. Each factor was varied separately, while keeping the other ones at a value above concern. Measurement guidelines to ensure that all deviations fell within a predefined range (+/-20%) could not be derived, but simulations for fixed T(s) and T(acq) were found to provide a practical tool for studying the error behaviour to be expected from a given experimental set-up and for comparing measurement protocols. At the level of an individual DCE exam, a bootstrap version of the simulation approach was shown to lead to a useful estimate of the errors on the fitted parameters. PMID- 20952811 TI - Intracellular protein glycosylation modulates insulin mediated lifespan in C.elegans. AB - O-linked-beta-N-acetylglucosamine (O-GlcNAc) modification is a regulatory, nuclear and cytoplasmic post-translational glycosylation of proteins associated with age-related diseases such as Alzheimer's, Parkinson's, and type II diabetes. Global elevation of O-GlcNAc levels on intracellular proteins can induce insulin resistance, the hallmark of type II diabetes, in mammalian systems. InC. elegans, attenuation of the insulin-like signal transduction pathway increases adult lifespan of the nematode. We demonstrate that the O-GlcNAc cycling enzymes OGT and OGA, which add and remove O-GlcNAc respectively, modulate lifespan in C. elegans. Median adult lifespan is increased in an oga-1 deletion strain while median adult life span is decreased upon ogt-1 deletion. The O-GlcNAc-mediated effect on nematode lifespan is dependent on the FoxO transcription factor DAF-16. DAF-16 is a key factor in the insulin-like signal transduction pathway to regulate reproductive development, lifespan, stress tolerance, and dauer formation in C. elegans. Our data indicates that O-GlcNAc cycling selectively influences only a subset of DAF-16 mediated phenotypes, including lifespan and oxidative stress resistance. We performed an affinity purification of O-GlcNAc modified proteins and observed that a high percentage of these proteins are regulated by insulin signaling and/or impact insulin pathway functional outcomes, suggesting that the O-GlcNAc modification may control downstream effectors to modulate insulin pathway mediated cellular processes. PMID- 20952814 TI - Viscoelasticity-based MR elastography of skeletal muscle. AB - An in vivo multifrequency magnetic resonance elastography (MRE) protocol was developed for studying the viscoelastic properties of human skeletal muscle in different states of contraction. Low-frequency shear vibrations in the range of 25-62.5 Hz were synchronously induced into the femoral muscles of seven volunteers and measured in a cross-sectional view by encoding the fast-transverse shear wave component parallel to the muscle fibers. The so-called springpot model was used for deriving two viscoelastic constants, MU and alpha, from the dispersion functions of the complex shear modulus in relaxed and in loaded muscle. Representing the shear elasticity parallel to the muscle fibers, MU increased in all volunteers upon contraction from 2.68 +/- 0.23 kPa to 3.87 +/- 0.50 kPa. Also alpha varied with load, indicating a change in the geometry of the mechanical network of muscle from relaxation (alpha = 0.253 +/- 0.009) to contraction (alpha = 0.270 +/- 0.009). These results provide a reference for a future assessment of muscular dysfunction using rheological parameters. PMID- 20952815 TI - Thyroid volume measurement in external beam radiotherapy patients using CT imaging: correlation with clinical and anthropometric characteristics. AB - The aim of this study is to define criteria for accurate representation of the thyroid in human models used to represent external beam radiotherapy (EBRT) patients and evaluate the relationship between the volume of this organ and clinical and anthropometric characteristics. From CT images, we segmented the thyroid gland and calculated its volume for a population of 188 EBRT patients of both sexes, with ages ranging from 1 to 89 years. To evaluate uncertainties linked to measured volumes, experimental studies on the Livermore anthropomorphic phantom were performed. For our population of EBRT patients, we observed that in children, thyroid volume increased rapidly with age, from about 3 cm(3) at 2 years to about 16 cm(3) at 20. In adults, the mean thyroid gland volume was 23.5 +/- 9 cm(3) for males and 17.5 +/- 8 cm(3) for females. According to anthropometric parameters, the best fit for children was obtained by modeling the log of thyroid volume as a linear function of body surface area (BSA) (p < 0.0001) and age (p = 0.04) and for adults, as a linear function of BSA (p < 0.0001) and gender (p = 0.01). This work enabled us to demonstrate that BSA was the best indicator of thyroid volume for both males and females. These results should be taken into account when modeling the volume of the thyroid in human models used to represent EBRT patients for dosimetry in retrospective studies of the relationship between the estimated dose to the thyroid and long-term follow up data on EBRT patients. PMID- 20952816 TI - Dosimetry for ion beam radiotherapy. AB - Recently, ion beam radiotherapy (including protons as well as heavier ions) gained considerable interest. Although ion beam radiotherapy requires dose prescription in terms of iso-effective dose (referring to an iso-effective photon dose), absorbed dose is still required as an operative quantity to control beam delivery, to characterize the beam dosimetrically and to verify dose delivery. This paper reviews current methods and standards to determine absorbed dose to water in ion beam radiotherapy, including (i) the detectors used to measure absorbed dose, (ii) dosimetry under reference conditions and (iii) dosimetry under non-reference conditions. Due to the LET dependence of the response of films and solid-state detectors, dosimetric measurements are mostly based on ion chambers. While a primary standard for ion beam radiotherapy still remains to be established, ion chamber dosimetry under reference conditions is based on similar protocols as for photons and electrons although the involved uncertainty is larger than for photon beams. For non-reference conditions, dose measurements in tissue-equivalent materials may also be necessary. Regarding the atomic numbers of the composites of tissue-equivalent phantoms, special requirements have to be fulfilled for ion beams. Methods for calibrating the beam monitor depend on whether passive or active beam delivery techniques are used. QA measurements are comparable to conventional radiotherapy; however, dose verification is usually single field rather than treatment plan based. Dose verification for active beam delivery techniques requires the use of multi-channel dosimetry systems to check the compliance of measured and calculated dose for a representative sample of measurement points. Although methods for ion beam dosimetry have been established, there is still room for developments. This includes improvement of the dosimetric accuracy as well as development of more efficient measurement techniques. PMID- 20952817 TI - Comparison of five directed graph measures for identification of leading interictal epileptic regions. AB - Directed graphs (digraphs) derived from interictal periods of intracerebral EEG (iEEG) recordings can be used to estimate the leading interictal epileptic regions for presurgery evaluations. For this purpose, quantification of the emittance contribution of each node to the rest of digraph is important. However, the usual digraph measures are not very well suited for this quantification. Here, we compare the efficiency of recently introduced local information (LI) measure and a new measure called total global efficiency with classical measures like global efficiency, local efficiency and node degree. For evaluation, the estimated leading interictal epileptic regions based on five measures are compared with seizure onset zones obtained by visual inspection of epileptologists for five patients. The comparison revealed the superior performance of the LI measure. We showed efficiency of different digraph measures for the purpose of source and sink node identification. PMID- 20952818 TI - Impedance measurement to assess epicardial fat prior to RF intraoperative cardiac ablation: a feasibility study using a computer model. AB - Radiofrequency (RF) cardiac ablation is used to treat certain types of arrhythmias. In the epicardial approach, efficacy of RF ablation is uncertain due to the presence of epicardial adipose tissue interposed between the ablation electrode and the atrial wall. We planned a feasibility study based on a theoretical model in order to assess a new technique to estimate the quantity of fat by conducting bioimpedance measurements using a multi-electrode probe. The finite element method was used to solve the electrical problem. The results showed that the measured impedance profile coincided approximately with the epicardial fat profile measured under the probe electrodes and also that the thicker the epicardial fat, the higher the impedance values. When the lateral fat width was less than 4.5 mm, the impedance values altered, suggesting that measurements should always be conducted over a sizeable fat layer. We concluded that impedance measurement could be a practical method of assessing epicardial fat prior to RF intraoperative cardiac ablation, i.e. 'to map' the amount of adipose tissue under the probe. PMID- 20952821 TI - TDP-43 models coverage. PMID- 20952820 TI - Beneficial effect of a CNTF tetrapeptide on adult hippocampal neurogenesis, neuronal plasticity, and spatial memory in mice. AB - A therapeutic strategy against cognitive disorders like Alzheimer's disease is to take advantage of the regenerative ability of the brain and the properties of neurotrophic factors to shift the balance from neurodegeneration to neurogenesis and neuronal plasticity. Although the ciliary neurotrophic factor (CNTF) has some of the required neuroprotective characteristics, its clinical use, due to its side effects, i.e., anorexia, skeletal muscle loss, hyperalgesia, cramps, and muscle pain, has not materialized. In the present study, we report that Peptide 6c (GDDL) that corresponds to CNTF amino acid residues 147-150, enhances the dentate gyrus neurogenesis and neuronal plasticity, and improves cognition without weight loss or any other apparent side effects in mice. Normal adult C57Bl6 mice received subcutaneous implants of extended release depot pellets containing vehicle or Peptide 6c for 30 days of continuous dosing. Dentate gyrus neurogenesis was assessed by stereological analysis of cells expressing neuronal markers, doublecortin and NeuN, and BrdU uptake. We found that Peptide 6c significantly increased early neuronal commitment, differentiation, and survival of newborn progenitor cells. These newborn neurons were functionally integrated into the hippocampal network, since basal expression of c-fos was enhanced and neuronal plasticity was increased, as reflected by higher expression of MAP2a,b and synaptophysin. Consequently, Peptide 6c treatment improved encoding of hippocampal-dependent information in a spatial reference memory task in mice. Overall, these findings demonstrated the therapeutic potential of Peptide 6c for regeneration of the brain and improvement of cognition. PMID- 20952823 TI - Using the International Classification of Functioning, Disability and Health (ICF) to describe the functioning of traumatised refugees. AB - The aim of this project was to use the International Classification of Functioning, Disability and Health (ICF) to develop an interdisciplinary instrument consisting of a Core Set, a number of codes selected from ICF, to describe the overall health condition of traumatised refugees. We intended to test 1) whether this tool could prove suitable for an overall description of the functional abilities of traumatised refugees before, during and after the intervention, and 2) whether the Core Set could be used to trace a significant change in the functional abilities of the traumatised refugees by comparing measurements before and after the intervention. In 2007, eight rehabilitation centres for traumatised refugees in Denmark agreed on a joint project to develop a tool for interdisciplinary documentation and monitoring, including physical, mental and social aspects of the person's health condition. ICF, developed and approved by WHO in 2001, was found suitable because it offers a common and standardised language and a corresponding frame of reference to describe health and associated conditions in terms of functioning rather than symptoms and diagnosis. Traumatised refugees are in most cases severely affected mentally by the traumas they have been subjected to, physically by injuries suffered during torture and war, psycho-somatically with pain, and socially by cultural uprooting, as well as by social difficulties in the exile community. The rehabilitation perspective thus seems to be more meaningful than the traditional treatment perspective because it takes into account the very complex situation of this group. The aim of the project was to find out whether any functional changes could be monitored using the instrument. The aim was neither to study nor to describe the effect of rehabilitation approaches, such as conditions related to traumatised refugees' networks or environments that might affect the refugees' living conditions. It was also not the intention to discuss the cause of the potential changes of the functional abilities. The project selected a Comprehensive Core Set of 106 codes among 1,464 possible codes (1) used by an interdisciplinary group of international and national experts in rehabilitation of traumatised refugees. The Comprehensive Core Set was furthermore reduced to a Brief Core Set of 32 codes by the interdisciplinary team (key persons) at the centres included in the project. From each centre six clients were randomly selected from those who fulfilled the inclusion criteria. All were scored within a four week period after the start, before any intervention was initiated, and up to a month after the first scoring. The results from this project led us to the conclusion that it is possible to develop an instrument based on the ICF classification. The instrument is useful for a general description of the total health condition (physical and mental functional ability as well as the environmental impact) of traumatized refugees. The tool helps describe changes in the functional abilities used in connection with the preparation of the plan of action. It can also be used to describe the refugees included in the study and their general condition. The ICF Core Set for traumatised refugees has not yet been validated, but the results of the project provide a basis for further development. PMID- 20952824 TI - Living in exile when disaster strikes at home. AB - As the number of migrants,- forced or voluntary,- increases, there is a growing need to understand how negative events in the country of origin influence those residing abroad. This issue has been actualized by the recent earthquakes in Haiti and Chile. Persons in exile have frequently been exposed to severe human rights violations and other stressors prior to emigration. The present study explored possible associations between ongoing and former stressors and mental health problems among persons living in exile as the Tsunami disaster of 2004 struck their country of origin. The contribution of former exposure and exilerelated difficulties in explaining current mental health problems was explored together with Tsunami related bereavement and social support. Following the Tsunami disaster of 2004 a questionnaire was administered to individuals of Tamil and Acehnese origin residing in Norway. The results suggest an independent contribution of exilerelated difficulties, former exposure and social support in explaining current mental health problems in this group. The study also disclosed methodological challenges involved both in relation to recruiting participants and in isolating the contribution of a particular stressor in populations with high levels of former exposure as well as ongoing stress. PMID- 20952825 TI - The land of milk and honey: a picture of refugee torture survivors presenting for treatment in a South African trauma centre. AB - Intake data obtained from 55 refugee torture survivors accessing trauma treatment services at a centre in Johannesburg, South Africa, paints a picture of suffering beyond the torture experience. The intake forms part of a more comprehensive monitoring and evaluation system developed for the work done with torture survivors accessing psychosocial services. The diverse sample with different nationalities highlights that torture occurs in many countries on the African continent. It also highlights South Africa's role as a major destination for refugee and asylum seekers. However, "the land of milk and honey" and the process of arriving here, often poses additional challenges for survivors of torture. This is reflected in the high levels of Post Traumatic Stress Disorder (69%), anxiety (91%), and depression (74%) for our sample, all of which were significantly correlated. The loss of employment status from before the torture experience until the time of intake was great for this sample, impacting on their recovery. In addition the presence of medical conditions (44%), disabilities (19%), and pain (74%) raise serious questions regarding interventions that focus mainly on psychosocial needs. No significant gender differences were found. The paper begins to paint a clearer picture of the bio-psycho-social state of torture survivors accessing services in South Africa, as well as highlighting many of the contextual challenges which impact on recovery. PMID- 20952826 TI - Transitory Ischemia as a form of white torture: a case description in Spain. AB - Transitory Ischemia is a form of torture that has been insufficiently described and studied in forensic and psychiatric studies of torture. It is usually left out of medical evaluation reports and not explored in detail under the Istanbul Protocol. Although ischemia, when experienced during brief periods of time, does not produce any detectable sequelae, prolonged periods of ischemia can be detected by either clinical examination or electromyography. The authors describe the use of brief periods of ischemia as a torture technique against a non-violent activist in Seville (Spain). PMID- 20952827 TI - Group therapy model for refugee and torture survivors. AB - The paper discusses the Center for Torture and Trauma Survivors' therapy group model for torture survivors and describes two of its variants: The Bashal group for African and Somali women and the Bhutanese multi-family therapy group. Group therapies in this model extend to community healing. Groups develop their cohesion to graduate to a social community club or initiate a community organization. New graduates from the group join the club and become part of the social advocacy process and of group and individual support and community healing. The BASHAL Somali women's group that developed spontaneously into a socio-political club for African women, and the Bhutanese family group that consciously developed into a Bhutanese community organization are discussed as two variants of this new model of group therapy with torture survivors. PMID- 20952828 TI - Understanding the relevance of sample size calculation. PMID- 20952829 TI - Targeting CYP450 modulation to decrease the risk of induced cataract in the experimental model. AB - BACKGROUND: Diabetes is one of the major causes of cataract. Some drugs prescribed for the treatment of diabetes are the modulators of CYP450, which may alter the risk of cataract. OBJECTIVE: To study the effect of CYP450 modulation in galactosemic cataract. MATERIALS AND METHODS: Male Sprague-Dawley suckling rats were allotted to four groups (n = 6), as follows: Group 1: Normal control, Group 2: Galactose control, Group 3: CYP450 inhibitor pretreated and Group 4: CYP450 inducer pretreated. Cataract was induced in animals of all groups except group 1 by feeding them galactose (50%), 21 days after parturition. From the eighteenth day of life, CYP450 inhibitor (nifedipine; 8.1 mg/kg) and CYP450 inducer (pioglitazone; 3.8 mg/kg) were given orally to groups 3 and 4, respectively. The maturation pattern of the cataract was observed by an operating microscope, every third day. Biochemical changes in the lenses of all groups, for example, CYP450 activity expressed as ?M NADPH oxidized / unit time, alterations in the levels of total proteins, soluble proteins, and reduced glutathione (GSH) following the induction of cataract, were estimated. RESULTS: The microscopic examination of the lenses indicated that CYP450 inhibitor pre-treatment delayed (fourteenth day) the occurrence of cataract, while CYP450 inducer pretreatment demonstrated an early (ninth day) cataract as compared to galactose control rats (twelfth day). A significant decrease and increase in CYP450 activity was observed with the CYP450 inhibitor and inducer pre-treatment, respectively. There was no alteration in the GSH level, but a significant increase in total and soluble protein was found in groups 3 and 4 as compared to group 2. CONCLUSION: CYP450 may have a role in the initiation of cataract without any effect on the maturation pattern, as revealed by the delayed occurrence of cataract with the CYP450 inhibitor and an early onset of cataract with the CYP450 inducer. PMID- 20952830 TI - Stimuli-sensitive hydrogels: a novel ophthalmic drug delivery system. AB - BACKGROUND: Stimuli-sensitive hydrogels are three-dimensional, hydrophilic, polymeric networks capable of imbibing large amounts of water or biological fluids on stimulation, such as pH, temperature and ionic change. AIM: To develop hydrogels that are sensitive to stimuli, i.e. pH, in the cul-de-sac of the eye for providing a prolonged effect and increased bioavailability with reduction in frequency of administration. MATERIALS AND METHODS: Hydrogels were formulated by using timolol maleate as the model drug, polyacrylic acid as the gelling agents, hydroxyl ethyl cellulose as the viscolizer and sodium chloride as the isotonic agent. Stirring of ingredients in pH 4 phosphate buffer at high speed was carried out. The dynamic dialysis technique was used for drug release studies. In vivo study for reduction in intraocular pressure was carried out by using albino rabbits. STATISTICAL ANALYSIS: Drug release studies data were used for statistical analysis in first-order plots, Higuchi plots and Peppas exponential plots. Student t-test was performed for in vivo study. RESULTS: Viscosity of the hydrogel increases from 3.84 cps to 9.54 cps due to change in pH 4 to pH 7.4. The slope value of the Peppas equation was found to be 0.3081, 0.3743 and 0.2964. Up to 80% of drug was released in an 8 h drug release study. Sterile hydrogels with no ocular irritation were obtained. CONCLUSIONS: Hydrogels show increase in viscosity due to change in pH. Hydrogels were therapeutically effacious, stable, non-irritant and showed Fickian diffusion. In vivo results clearly show a prolonged reduction in intraocular pressure, which was helpful for reduction in the frequency of administration. PMID- 20952831 TI - Correlation between ocular parameters and amplitude of accommodation. AB - AIM: To study the relationship between ocular parameters and amplitude of accommodation (AA) in the peri-presbyopic age group (35-50 years). MATERIALS AND METHODS: Three hundred and sixteen right eyes of consecutive patients in the age group 35-50 years, who attended our outpatient clinic, were studied. Emmetropes, hypermetropes and myopes with best-corrected visual acuity of 20/20, J1 in both eyes were included. The AA was calculated by measuring the near point of accommodation. The axial length (AL), central anterior chamber depth (CACD) and lens thickness (LT) were also measured. RESULTS: There was moderate correlation (Pearson's correlation coefficient r = 0.56) between AL and AA as well as between CACD and AA (r = 0.53) in myopes in the age group 35-39 years. In the other age groups and the groups taken as a whole, there was no correlation. In hypermetropes and emmetropes, there was no correlation between AA and the above ocular parameters. No significant correlation existed between LT and AA across different age groups and refractive errors. CONCLUSION: There was no significant correlation between AA and ocular parameters like anterior chamber depth, AL and LT. PMID- 20952832 TI - Comparison of the diagnostic ability of Moorfield's regression analysis and glaucoma probability score using Heidelberg retinal tomograph III in eyes with primary open angle glaucoma. AB - PURPOSE: To compare the diagnostic performance of the Heidelberg retinal tomograph (HRT) glaucoma probability score (GPS) with that of Moorfield's regression analysis (MRA). MATERIALS AND METHODS: The study included 50 eyes of normal subjects and 50 eyes of subjects with early-to-moderate primary open angle glaucoma. Images were obtained by using HRT version 3.0. RESULTS: The agreement coefficient (weighted k) for the overall MRA and GPS classification was 0.216 (95% CI: 0.119 - 0.315). The sensitivity and specificity were evaluated using the most specific (borderline results included as test negatives) and least specific criteria (borderline results included as test positives). The MRA sensitivity and specificity were 30.61 and 98% (most specific) and 57.14 and 98% (least specific). The GPS sensitivity and specificity were 81.63 and 73.47% (most specific) and 95.92 and 34.69% (least specific). The MRA gave a higher positive likelihood ratio (28.57 vs. 3.08) and the GPS gave a higher negative likelihood ratio (0.25 vs. 0.44).The sensitivity increased with increasing disc size for both MRA and GPS. CONCLUSIONS: There was a poor agreement between the overall MRA and GPS classifications. GPS tended to have higher sensitivities, lower specificities, and lower likelihood ratios than the MRA. The disc size should be taken into consideration when interpreting the results of HRT, as both the GPS and MRA showed decreased sensitivity for smaller discs and the GPS showed decreased specificity for larger discs. PMID- 20952833 TI - Incidence of preoperative high blood pressure in cataract surgery among hypertensive and normotensive patients. AB - Incidence of preoperative rise in blood pressure (BP) in cataract surgery among hypertensive and normotensive patients. OBJECTIVE: To study the incidence of preoperative rise in BP in cataract surgery among normotensive individuals and hypertensive patients with historic good BP control in a population without other major chronic diseases. SETTINGS: Ophthalmology Service of a University Hospital. MATERIALS AND METHODS: A prospective study with 822 patients older than 40 years of age, with cataract surgery indication, and without major chronic diseases other than hypertension. The patients were divided in two groups: hypertensive and normotensive. Preoperative data, physical exams and medical adverse events were recorded in an evaluation questionnaire. RESULTS: The sample included 427 normotensive (52%) and 395 hypertensive patients (48%). The two groups had similar proportions of operations that were cancelled and not subsequently rescheduled, 2% (eight patients) in each group. The incidence of preoperative rise in BP was 3.7% in the normotensive group and 10.9% in the hypertensive group (P < 0.001). CONCLUSION: Hypertensive patients with historic good BP control and without other major co-morbidities present a larger incidence of preoperative rise in BP than normotensive individuals in cataract surgery. PMID- 20952834 TI - Etiology and antibacterial susceptibility pattern of community-acquired bacterial ocular infections in a tertiary eye care hospital in south India. AB - AIMS: To identify the etiology, incidence and prevalence of ocular bacterial infections, and to assess the in vitro susceptibility of these ocular bacterial isolates to commonly used antibiotics. MATERIALS AND METHODS: Retrospective analysis of consecutive samples submitted for microbiological evaluation from patients who were clinically diagnosed with ocular infections and were treated at a tertiary eye care referral center in South India between January 2002 and December 2007. RESULTS: A total of 4417 ocular samples was submitted for microbiological evaluation, of which 2599 (58.8%) had bacterial growth, 456 (10.3%) had fungal growth, 15 (0.34%) had acanthamoebic growth, 14 (0.32%) had mixed microbial growth and the remaining 1333 (30.2%) had negative growth. The rate of culture-positivity was found to be 88% (P < 0.001) in eyelids' infection, 70% in conjunctival, 69% in lacrimal apparatus, 67.4% in corneal, 51.6% in intraocular tissues, 42.9% in orbital and 39.2% in scleral infections. The most common bacterial species isolated were Staphylococcus aureus (26.69%) followed by Streptococcus pneumoniae (22.14%). Sta. aureus was more prevalent more in eyelid infections (51.22%; P = 0.001) coagulase-negative staphylococci in endophthalmitis (53.1%; P = 0.001), Str. pneumoniae in lacrimal apparatus and corneal infections (64.19%; P = 0.001), Corynebacterium species in blepharitis and conjunctivitis (71%; P = 0.001), Pseudomonas aeruginosa in keratitis and dacryocystitis (66.5%; P = 0.001), Haemophilus species in dacryocystitis and conjunctivitis (66.7%; P = 0.001), Moraxella lacunata in blepharitis (54.17%; P = 0.001) and Moraxella catarrhalis in dacryocystitis (63.83%; P = 0.001). The largest number of gram-positive isolates was susceptible to moxifloxacin (98.7%) and vancomycin (97.9%), and gram-negative isolates to amikacin (93.5%) and gatifloxacin (92.7%). CONCLUSIONS: Gram-positive cocci were the most frequent bacteria isolated from ocular infections and were sensitive to moxifloxacin and vancomycin, while gram-negative isolates were more sensitive to amikacin and gatifloxacin. PMID- 20952835 TI - Technical aspects of laser treatment for acute retinopathy of prematurity under topical anesthesia. AB - Retinopathy of prematurity (ROP) is a significant cause of childhood blindness. The criteria for laser therapy have been revised from threshold ROP to include the earlier stage of high-risk prethreshold ROP. Laser photocoagulation is an established technique for the treatment of ROP. However, the detailed procedure and techniques for laser photocoagulation have not yet been published. Adequate and appropriate laser photocoagulation for ROP is different from the application of lasers in adult retinal vascular diseases, and many ophthalmologists need to be trained in this technique if the outreach of ROP treatment programs is to improve. Laser under topical anesthesia has been practiced in India as a preferred modality especially due to logistics and risks of general anesthesia in these pre-term babies. We discuss the details of the technique as practiced at tertiary care ophthalmic hospitals in India, so that the nuances in treatment parameters and clinical decision-making can be usefully applied to ophthalmic practice. This will ultimately lead to safe and effective treatment delivery in ROP. PMID- 20952836 TI - Principles of sample size calculation. AB - In most areas in life, it is difficult to work with populations and hence researchers work with samples. The calculation of the sample size needed depends on the data type and distribution. Elements include consideration of the alpha error, beta error, clinically meaningful difference, and the variability or standard deviation. The final number arrived at should be increased to include a safety margin and the dropout rate. Over and above this, sample size calculations must take into account all available data, funding, support facilities, and ethics of subjecting patients to research. PMID- 20952837 TI - A simple nomogram for sample size for estimating sensitivity and specificity of medical tests. AB - Sensitivity and specificity measure inherent validity of a diagnostic test against a gold standard. Researchers develop new diagnostic methods to reduce the cost, risk, invasiveness, and time. Adequate sample size is a must to precisely estimate the validity of a diagnostic test. In practice, researchers generally decide about the sample size arbitrarily either at their convenience, or from the previous literature. We have devised a simple nomogram that yields statistically valid sample size for anticipated sensitivity or anticipated specificity. MS Excel version 2007 was used to derive the values required to plot the nomogram using varying absolute precision, known prevalence of disease, and 95% confidence level using the formula already available in the literature. The nomogram plot was obtained by suitably arranging the lines and distances to conform to this formula. This nomogram could be easily used to determine the sample size for estimating the sensitivity or specificity of a diagnostic test with required precision and 95% confidence level. Sample size at 90% and 99% confidence level, respectively, can also be obtained by just multiplying 0.70 and 1.75 with the number obtained for the 95% confidence level. A nomogram instantly provides the required number of subjects by just moving the ruler and can be repeatedly used without redoing the calculations. This can also be applied for reverse calculations. This nomogram is not applicable for testing of the hypothesis set up and is applicable only when both diagnostic test and gold standard results have a dichotomous category. PMID- 20952838 TI - Spectral domain optical coherence tomography findings of acute branch retinal artery occlusion from calcific embolus. AB - An 82-year-old female presented with sudden painless decrease in vision in the right eye after awakening. She could see the "superior half" of her vision from the right eye only. On examination, best-corrected vision was 20/300 in the right eye and 20/30 in the left eye. The fundus in the right eye revealed recent superotemporal branch retinal artery occlusion (BRAO) with calcified plaque at the disc. Spectral domain optical coherence tomography (OCT) (OTI Ophthalmic Technologies, Inc.), revealed hyperreflectivity and increased thickness of the inner retinal layers of the superior compared to the inferior retina. Imaging at the optic disc revealed the blocked artery containing a highly reflective material. The high reflectivity of the material and underlying optical shadowing could be characterized as calcific emboli. PMID- 20952839 TI - Functional and structural analysis of partial optic nerve avulsion due to blunt trauma: case report. AB - Partial optic nerve avulsion (ONA) secondary to finger gouging is an uncommon but devastating injury. A 21-year-old man who had an acute vision loss after accidentally getting poked by himself in his right eye when he fell down during jogging is reported. The patient was diagnosed with partial ONA. Magnetic resonance imaging revealed intact optic nerve. Optical coherence tomography (OCT) revealed deep cavity at the inferior-temporal half of the optic disc. Retinal nerve fiber layer thickness was also thin at the inferior quadrant with circumpapillary OCT scan. Visual field test and electrophysiological tests showed functional abnormality compatible with optic nerve lesion. Diagnostic tools for anatomical and functional evaluation may reveal the course of this injury. PMID- 20952841 TI - Orbito-sinal foreign body. AB - Perforating injuries of the orbit involving the paranasal sinuses are uncommon. We report a case in which a large wooden foreign body lodged in the posterior orbit and maxillary sinus was surgically removed by a combined approach by ophthalmologists and ear, nose and throat surgeons. PMID- 20952840 TI - A rare case of orbital apex syndrome with herpes zoster ophthalmicus in a human immunodeficiency virus-positive patient. AB - We report a rare instance of favorable outcome in orbital apex syndrome secondary to herpes zoster ophthalmicus (HZO) in a human immunodeficiency virus (HIV) positive patient. The patient complained of pain and decrease in vision in one eye (20/640) for 2 weeks accompanied with swelling, inability to open eye, and rashes around the periocular area and forehead. The presence of complete ophthalmoplegia, ptosis, relative afferent pupillary defect, and anterior uveitis with decreased corneal sensation prompted a diagnosis of HZO with orbital apex syndrome. The enzyme-linked immunosorbent assay test and a low CD4 count confirmed HIV. Highly active antiretroviral therapy (HAART), systemic acyclovir, and systemic steroids were started. Visual acuity and uveitis improved within 10 days. By the end of the fourth week, ocular motility also recovered and the final visual acuity was 20/25. We highlight the role of HAART, used in conjunction with systemic steroid and acyclovir therapy, in improving the outcome. PMID- 20952842 TI - Pyomyositis of extraocular muscle: case series and review of the literature. AB - Pyomyositis is a primary acute bacterial infection usually caused by Staphylococcus aureus. Any skeletal muscle can be involved, but the thigh and trunk muscles are commonly affected. Only three cases of extraocular muscle (EOM) pyomyositis have been reported. We herein present four cases of isolated EOM pyomyositis. Three of our cases presented with acute onset of proptosis, pain, swelling and redness. One patient presented with mass in the inferior orbit for 4 months. One patient had central retinal artery occlusion on presentation. None of them had marked systemic symptoms. Computed tomography scan of all patients showed a typical hypodense rim enhancing lesion of the muscle involved. Three patients were started on intravenous antibiotics immediately on diagnosis and the pus was drained externally. Two patients underwent exploratory orbitotomy. In conclusion, it should be considered in any patient presenting with acute onset of orbital inflammation. Management consists of incision and drainage coupled with antibiotic therapy. PMID- 20952843 TI - DNA chip-assisted diagnosis of a previously unknown etiology of intermediate uveitis- Toxoplasma gondii. AB - We report the use of DNA chip technology in the identification of Toxoplasma gondii as the etiological agent in two patients with recurrent intermediate uveitis (IU). Both patients had recurrent episodes of vitritis (with no focal retinochoroidal lesion) over varying time intervals and were diagnosed to have IU. The tuberculin test was negative in both. Blood counts, erythrocyte sedimentation rate, and serum angiotensin convertase enzyme levels were normal. In both cases, the vitreous fluid tested positive for the T. gondii DNA sequence by using a uveitis DNA chip (XCyton Pvt. Ltd., Bangalore, India). It contained complimentary sequences to "signature genes" of T. gondii, Mycobacterium tuberculosis, M. chelonae, and M. fortuitum. The enzyme-linked immunosorbent assay (ELISA) detected elevated serum antitoxoplasma IgG levels in both. They responded to the antitoxoplasma therapy with oral co-trimoxazole (and additional intravitreal clindamycin in patient 1), with no recurrence during follow-ups of 6 and 8 months, respectively. PMID- 20952844 TI - Cataract surgery under topical anesthesia using 2% lignocaine jelly and intracameral lignocaine: is manual small incision cataract surgery comparable to clear corneal phacoemulsification? AB - A prospective comparative study was undertaken to compare the patients' pain experience, surgical outcome and surgeon's experience in phacoemulsification and manual small incision cataract surgery (MSICS) under topical anesthesia supplemented with intracameral lignocaine (TASIL). In Group 1 (n=88) phacoemulsification was done and in Group 2 (n=92) MSICS was done. Pain scores were marked by the patients on a Visual analog scale (VAS) after the surgery. The surgical experience was noted on a questionnaire by the operating surgeon. Descriptive analysis and one-tailed Mann-Whitney test were used to draw results. The average VAS score in Group 1 was 0.65 (SD 1.31) and in Group 2 it was 0.90 (SD 1.22). This difference in the average was not statistically significant with P=0.09. The study demonstrates that MSICS and phacoemulsification both can be done safely under TASIL with acceptable patient comfort, and the pain experienced by the patients during the procedures is comparable. PMID- 20952845 TI - Risk factors for intraocular penetration of caterpillar hair in Ophthalmia Nodosa: a retrospective analysis. AB - We report risk factors associated with intraocular penetration of caterpillar hair seen at our institute from January 2005 to December 2007. Records of all patients with caterpillar hair induced ophthalmitis (CHIO) were retrospectively reviewed for clinical characteristics, anatomic location of lodgment of the caterpillar hair, treatment methods, and outcomes. Out of a total of 544 cases of CHIO, 19 eyes (seven in the anterior chamber and 12 in the posterior segment) experienced intraocular penetration (3.5%). The presence of deep intracorneal hair (80 cases, 14.7%) was found to be the only risk factor for intraocular penetration ( P < 0.001). The removal of intracorneal hair was possible in only 29 out of 80 eyes (36%) and this was associated with a significantly reduced risk of intraocular penetration ( P = 0.022). Patients with retained intracorneal hairs should be counseled regarding risk of intraocular penetration and closely followed up for at least six months. PMID- 20952846 TI - Presumed sclerotomy site bleeding inflowing into the anterior chamber after the removal of a 23-gauge microcannula in 23-gauge sutureless vitrectomy. AB - We experienced two cases of the influx of the sclerotomy site bleeding into the anterior chamber during 23-gauge sutureless vitrectomy for pseudophakic rhegmatogenous retinal detachment. Soon after the removal of a 23-gauge microcannula at the end of the surgery, presumed sclerotomy site hemorrhage was rapidly fluxed into the anterior chamber. The anterior chamber bleeding might come from the sclerotomies rather than from episcleral vessels. The posterior pressure in the gas-filled pseudophakic eye might have pushed the sclerotomy site bleeding into the anterior chamber. We could not find any vitreous hemorrhages. The hemorrhage within the anterior chamber spontaneously absorbed within 14 days. PMID- 20952847 TI - Chikungunya virus iridocyclitis in Fuchs' heterochromic iridocyclitis. AB - We are reporting a case of bilateral Fuchs' heterochromic iridocyclitis with chikungunya virus infection in the left eye. A 20-year-old female was presented with a past history of fever suggestive of chikungunya with bilateral Fuchs' heterochromic iridocyclitis and complicated cataract. She had a tripod dendritic pattern of keratic precipitates by confocal microscopy in the left eye with a stippled pattern of keratic precipitates in both eyes. The real-time polymerase chain reaction (RT-PCR) assay in the aqueous humor detected 98 copies/ml of chikungunya virus RNA. The patient underwent clear corneal phacoemulsification with in-the-bag intraocular lens implantation in the left eye with a good visual outcome. This is the first report where the presence of chikungunya virus RNA has been associated with a case of bilateral Fuchs' heterochromic iridocyclitis. PMID- 20952848 TI - Sabouraud dextrose agar for the diagnosis of fungal keratitis. PMID- 20952849 TI - Presentation of retinoblastoma in pregnancy. PMID- 20952850 TI - Retinoblastoma in pregnancy. PMID- 20952851 TI - Comment on: Spectral domain optical coherence tomography predates fluorescein angiography in diagnosing central serous chorioretinopathy. PMID- 20952852 TI - Disadvantages of photodynamic therapy for polypoidal choroidal vasculopathy. PMID- 20952853 TI - Evaluation of retinal nerve fiber layer thickness measurements using optical coherence tomography in patients with tobacco-alcohol-induced toxic optic neuropathy. PMID- 20952854 TI - Misinnervation in the third nerve palsy: vertical synergistic divergence or consummate congenital bilateral asymmetrical Brown's syndrome with congenital ptosis? PMID- 20952855 TI - Topiramate-associated bilateral anterior uveitis and angle closure glaucoma. PMID- 20952856 TI - Comments on: masters theses from a university medical college: publication in indexed scientific journals. PMID- 20952857 TI - Corneal lesions in erythema multiforme minor--are systemic steroids indicated? PMID- 20952858 TI - Reducing endophthalmitis in India: an example of the importance of critical appraisal. PMID- 20952859 TI - Incidence of post-cataract endophthalmitis at Aravind Eye Hospital. PMID- 20952860 TI - Presidential address. PMID- 20952861 TI - Effectiveness of cryosurgery in xanthelasma palpebrarum. AB - 100 cases of xanthelasma palpebrarum were subjected to closed probe cryosurgery using nitrous oxide gas as the cryogen. Each freeze thaw cycle was fixed for 15 seconds. The procedure was done in a single session in all the cases. All these cases were followed up for 6 months. At the end of 6 months follow up in 68 cases, treated sites looked absolutely normal, in other 6 cases, treated sites looked almost normal except for pin head sized hypopigmentation in the centre of their treated lesions, while in remaining 26 cases, recurrence was observed in the form of yellowish papules/plaques. No other sequelae in the form of scarring or milia were observed in any case. PMID- 20952862 TI - Methotrexate in Psoriatics over 50 years of age. AB - Retrospective analysis was made of data on the use of methotrexate in elderly psoriatics. Pre-methotrexate assessment of patients induced liver function tests and a liver biopsy in 11 out of 14 patients. Post-methotrexate biopsies were done in 3 patients with total cumulative dose of methotrexate exceeding 1.5 gms. No significant worsening in the liver histology grade was noticed in the elderly patients. No significant side effect of methotrexate was noticed. PMID- 20952863 TI - A study of palmar dermatoglyphics and palmar freckles. AB - A study of palmar dermatoglyphics in genodermatoses was conducted in 219 probands and 100 control subjects by standard ink and roller method, during the period 1977-81 at Government General Hospital, Madras. A study of palmar dermatoglyphics in 20 probands with definite clinical and histopathological evidence of Neurofibromatosis revealed an increased incidence of ulnar loop pattern over the finger tips in both sexes. This digital pattern was not found to be of statistical significance, but a statistically significant reduction in the mean a b ridge count was observed in female cases. An increased incidence of palmar freckles (60%) was observed as a serendipity while taking the palm prints. Some of the palmar freckles with tiny palpable underlying nodules on histopathological study revealed miniature neurofibroma in the dermis. This serendipity has been recorded as an important clinical sign of neurofibromatosis by the author in her thesis submitted for Doctorate degree in 1981. PMID- 20952864 TI - Effect of socio-economic status on the prevalence of dermatophytosis in Madras. AB - A total of 462 patients living in varying socio-economic conditions were screened for tinea infection. 372/462 (70.7%) were found to be culture positive for dermatophytes. Trichophyton rubrum was the most frequently isolated dermatophyte. 35% of the infected cases were from the very low income group (group-I), 34.2% from low income group (group-II), 23.3% from middle income group (group-III) and 1.8% from moderately rich group (group-IV). Recurrent, chronic and extensive dermatophytosis were found to be most common in group-I (20.3%) and group-II (17.8%), whereas localized infections were common in group-IV (66.6%) and group III (65.7%). Recurrence chronicity were more frequent in tinea cruris and tinea corporis. The present study suggests that group-I and group-II may be the likely reservoirs of human ringworm infections in Madras. PMID- 20952865 TI - Metronidazole in management of trophic ulcers in leprosy. AB - Efficacy of metronidazole was assessed in 20 leprosy cases with trophic ulcers with poor response to oral and topical antibiotic. Oral metronidazole 400 mg three times daily for one week and topical metronidazole gel 1% for three weeks were found to be very effective. PMID- 20952866 TI - Paucity of immune complexes in skin lesions of lichen planus. AB - The significance of deposition of immunoglobulin and/or complements at the dermoepidermal junction (DEJ) and civatte bodies in skin lesions of 15 histopathologically confirmed cases of lichen planus (LP) was evaluated. Civatte boides were seen in 6 (40%) patients while in 9 (60%) these were absent. IgM, IgG, IgA and C3 were seen within civatte bodies in 6, 3, 2 and 3 specimens respectively in various combinations. LP lesions of a shorter duration (one year or less) had civatte bodies while these were absent in those with disease of a longer duration (more than 1 year). Immune complex deposition was seen in only 2 patients. It is concluded that civatte bodies are of diagnostic importance in lichen planus lesions of a short duration only and immune complexes do not seem to play a significant role in its pathogenesis. PMID- 20952867 TI - Acneform eruptions and antitubercular drugs. AB - Out of total 774 cases under antitubercular therapy only 11 cases (1.42%) developed acneform eruptions. Individual drugs found to cause these eruptions were Isoniazid (0.53%), Rifampicin (1.48%) and Ethambutol (0.63%). PMID- 20952868 TI - Tumoral calcinosis. AB - Tumoral calcinosis is an unusual clinical disorder in which large masses of calcium are deposited in the periarticular tissues of the body. The characteristic clinical, radiological and histopathological features of this disorder occurring in three middle aged female patients are reported. PMID- 20952870 TI - Ehlers-Danlos syndrome. AB - A case of Ehlers-Danlos Syndrome in a 19 years old male involving cutaneous and skeletal systems is reported. A clinical scoring system to diagnose such cases is highlighted. PMID- 20952869 TI - A study of peripheral T-Lymphocytes in alopecia areata. AB - Estimation of peripheral T-lymphocytes (active and total) was carried out in 100 cases of alopecia areata as per method described by Boyam (1977) and West et al (1978). Clinically patients were divided in two groups, alopecia areata circumscribed (group I) and severe alopecia areata (group II). Thirty healthy subjects served as controls. Decrease in percentage of both active and total E RFC was observed in 70% cases. The decrease was more significant in group II. PMID- 20952871 TI - Verrucous cutaneous lupus erythematosus. AB - An unusual case of cutaneous lupus erythematous with verrucous lesions is reported for its rarity and clinical interest. PMID- 20952872 TI - Recurrent herpes zoster in a child with SLE. AB - A 12-year-old girl had systemic lupus erythematosus (SLE) and type IV lupus nephritis since three-and-a-half years. She was treated with prednisolone and cyclophosphamide. She had first attack of herpes zoster (HZ) involving eighth and ninth thoracic segments on right side at the age of nine years. Second attack occurred on the same segments on same side at the age of twelve years. The second attack of herpes zoster was treated with oral acyclovir 400 mg five times a day for seven days plus analgesics and multi-vitamins. Most probably this is the first case of recurrent herpes zoster (RHZ) in a child in Indian literature. PMID- 20952873 TI - Disseminated cutaneous herpes zoster: A clinical predictor of human immunodeficiency virus infection. AB - A 45-year-old woman presented with thoracic (3,4,5) herpes zoster with cutaneous dissemination. She was found positive for human immunodeficiency virus infection. Mucocutaneous examination revealed presence of oral thrush and oral hairy leukoplakia. The patient possibly acquired the infection through blood transfusion. PMID- 20952874 TI - Langerhans cell histiocytosis. AB - A case of Langerhans Cell Histiocytosis (LCH) is reported in 11/2 years old boy. He had seborrhoeic dermatitis like condition of scalp, papular lesions with purpura typical of Letterer-Siwe disease associated with constitutional symptoms, hepatosplenomegaly, jaundice, anaemia and thrombocytopenia. Peripheral blood film and bone marrow examination showed presence of LCH cells. PMID- 20952875 TI - Cutaneous lymphoma mimicking seborrhoeic dermatitis. AB - A case of non Hodgkins lymphoma presenting with cutaneous lesions mimicking seborrhoeic dermatitis is reported. Clinician should have a high index of suspicion to diagnose lymphoma in its early stage, since it can mimic many benign dermatoses. PMID- 20952876 TI - Porokeratosis plantaris palmaris et disseminata. AB - A 65-year-old man presented with typical lesions of porokeratosis palmaris et disseminata clinically and histopathologically. Although this disease has autosomal dominant mode of inheritance, no family history of similar illness was seen in our case. PMID- 20952877 TI - Bilateral pigmented hairy epidermal naevus. AB - A 15-year-old boy developed bilateral Becker's naevus over scapular region without any associated abnormality. PMID- 20952878 TI - Trichophyton tonsurans infection in a 12 day-old infant. AB - Trichophyton tonsurans infection starting at the age of 12 days is reported. The diagnosis was confirmed by KOH examination and culture. Onset of superficial fungal infections in infancy is unusual. PMID- 20952879 TI - Chromoblastomycosis. AB - This is an account of twenty eight years of sufferings of a young sikh agriculturist, who ultimately succumbed to chromoblastomycosis- a not so uncommon mycotic infection, despite the use of toxic (amphoterecin-B) and newer antimycotic drugs (ketoconazole). Involvement of face, small and large gut, larynx and trachea are the other highlights of this case. PMID- 20952880 TI - Colchicine in the treatment of subcorneal pustular dermatosis. AB - A male patient with subcorneal pustular dermatosis was initially treated with dapsone with excellent response. Since he developed hypersensitivity to dapsone, corticosteroid was given instead of dapsone. But steroid also was withdrawn since he developed hypertension and diabetes. There was relapse of skin lesions which were treated with oral colchicine, which has profound inhibitory effects on neutrophils. There was excellent therapeutic response to colchicine and the drug well-tolerated. PMID- 20952881 TI - Pemphigus vulgaris and pregnancy. PMID- 20952882 TI - Dystrophia mediana canaliformis affecting all ten finger nails. PMID- 20952883 TI - Pulse steroid therapy in pemphigus. PMID- 20952884 TI - Idiopathic familial pigmentation of tongue. PMID- 20952886 TI - Familial koilonychia with superimposed myxoid cyst. PMID- 20952885 TI - Bullosis diabeticorum. PMID- 20952887 TI - Generalized lichen nitidus associated with chronic renal failure. PMID- 20952888 TI - Secondary syphilis with unusual skin manifestations. PMID- 20952889 TI - Letter. PMID- 20952890 TI - Tetracycline therapy for bullous perphigoid. PMID- 20952892 TI - Focal dermal hypoplasia (Goltz syndrome). PMID- 20952891 TI - Subcorneal pustular dermatosis. PMID- 20952893 TI - Tinea capitis in a 50-year-old owman. PMID- 20952894 TI - Hereditary sensory and autonomic neuropathy type II. PMID- 20952895 TI - Probable mechanism of varicella-induced koebnerization in psoriasis. PMID- 20952896 TI - Autologous miniature skin punch grafting in vitiligo. AB - Forty-five sites of stable vitiligo in 32 patients refractory to medical treatment were subjected to autologous miniature skin punch grafting. Main instruments used were skin biopsy punches 1-3 mm in diameter. Donor sites selected were either gluteal region or extensor aspect of the thigh which were not affected by the disease in the past. Most of the grafts changed from brown to black and upper scales desquamated within 10-15 days. Uniform perigraft pigmentation was observed by 1-11/2 months and 90% area was covered within 3-4 months. The cases were followed up for six months. Fair to excellent results were observed in 87.5% of the cases. PMID- 20952897 TI - Study of exfoliative dermatitis. AB - A study of 46 cases of exfoliative dermatitis revealed peak distribution in sixth decade and very high preponderance in males (M:F = 6.67 : 1). The highest single cause was found to be psoriasis (41.30%). Injudicious use of topical medicaments including herbal medicines and haphazard treatment were found to be the precipitating factors in 34% cases of pre-existing dermatoses. Laboratory investigations contributed little towards diagnosis except in lymphoma group; but were helpful in knowing systemic implications of the disease. Skin biopsy was found to be helpful in diagnosing underlying skin disorders in 18 cases (40.91%). Two cases (43.5%) had malignancy as the cause of exfoliative dermatitis. PMID- 20952898 TI - Managing recurrent genital herpes with acyclovir. AB - Seventy five patients of recurrent genital herpes (RGH) treated with oral or topical acyclovir and placebo were compared and followed for periods ranging 4 to 8 years in a prospective study. Oral acyclovir definitely helps RGH patients; it shortens healing time; postpones recurrences and instills confidence in the patients. There is sufficient evidence that RGH dies a natural death with time as seen after 8 years follow up in placebo group patients. Topical use of acyclovir cream is not as useful as believed. PMID- 20952899 TI - Dermatological manifestations of human immunodeficiency virus infected / acquired immunodeficiency syndrome patients in a referral hospital of Central Kerala. AB - A number of skin diseases are described in association with HIV infection/AIDS. In the present study the frequency of various skin manifestations among HIV infected / AIDS patients are noted. Generalised pruritus and dry skin were the common manifestations encountered. There was a significant absence of Kaposi's sarcoma, multi-dermatomal herpes zoster and oral hairy leukoplakia. A prominent hyperpigmented band on finger nails was seen. PMID- 20952900 TI - A comparative study of various therapeutic regimens in urticaria. AB - 127 patients of urticaria were treated with chlorpheniramine maleate alone and in combination with cyproheptadine hydrochloride, ranitidine and doxepin and levamisole. Chlorpheniramine and doxepin combination showed a satisfactory result in 88.46% of patients. Overall study showed that a combination regimen is better than the antihistaminics alone. Drowsiness was the commonest side effect. Levamisole and chlorpheniramine maleate combination was found to be more effective than the antihimstamine alone. PMID- 20952901 TI - Drug-induced pseudolymphoma syndrome. AB - Five cases of pseudolymphoma syndrome (PS) in children aged six to twelve years were observed after anticonvulsant drugs. In two cases PS was observed after ten days and in three after fifteen days of therapy with the offending drug. Three cases of PS were due to carbamazepine and had morbilliform rash and two cases due to phenobarbitone had erythroderma. All had fever, generalised lymphadenopathy and 4/5 had hepatosplenomegaly. Therapy with 15 mg prednisolone daily and withdrawal of the offending durg led to cure in 4/5 cases and one died due to congestive cardiac failure. PMID- 20952902 TI - Pyoderma gangrenosum in childhood. AB - We have treated 4 cases of pyoderma gangrenosum in infancy and childhood in past 2 years. The ages at onset were 6 months, 8 months, 6 months and 11.5 years respectively. Initial lesions were papulopustular in 3 and nodular in 1 patients but later on all of them developed ulcerative lesions with erythematous, violaceous, infiltrated or undermined edges. The lesions were numerous in 3 patients but few in 1 patient. The first patient had very high leucocyte count. In the second patient skin lesions of PG followed measles vaccinations. We could not reveal any association in the other two patients. None of the patient responded to antibiotic therapy. Three patients were treated successfully with dapsone and one with a combination of dapsone and prednisolone. We conclude that pyoderma gangrenosum is not so rare in infancy and it is more likely to occur without associated systemic diseases. PMID- 20952903 TI - Sezary syndrome in a young woman. AB - A young female patient suffered for 4 months from a widespread erythrodermic rash of unknown origin, marked by a peculiar hyperaesthesia. Haematological and biopsy findings were initially non-specific. A rapid deterioration, accompanied by infiltration of the skin, lymphadenopathy and hepatosplenomegaly was suggestive of Sezary syndrome, which was confirmed by finding of 40% of the lymphocytes being atypical (Sezary cells). PMID- 20952904 TI - Chronic lymphocytic leukaemia manifestating as exfoliative dermatitis. AB - A 60-year-old patient reported with a history of redness and peeling of the skin, and sensations of chills and tightness of the skin of three months duration. Clinical examination revealed exfoliative dermatitis, generalised lymphadenopathy and hepatosplenomegely. A peripheral smear showed features of chronic lymphocytic leukaemia. PMID- 20952905 TI - Chronic lymphocytic leukaemia presenting as chronic generalised erythroderma. AB - A 40-year-old lady presented with pyrexia of unknown origin and chronic generalised erythroderma. The blood picture was of leukaemia and the cutaneous histopathology showed leukaemic infiltration of the dermis. PMID- 20952906 TI - Keratosis follicularis spinulosa decalvans. AB - The case findings in a 22-year-old male patient of keratosis follicularis spinulosa decalvans are described. In addition to the characteristic cutaneous, occular and histological features, he had striking angular stomatitis and fissuring of the tongue simulating vitamin B-complex deficiency. This is an unreported feature to our knowledge. The mode of inheritance suggested X-linked trait. PMID- 20952907 TI - Basal cell carcinoma in a long standing case of lupus vulgaris. AB - A case of a 67-year-old male patient with a longstanding lupus vulgaris developing basal cell carcinoma is reported. PMID- 20952908 TI - Trichorhinophalangeal syndrome type 1. PMID- 20952909 TI - Generalised morphoea with lichen sclerosus et atrophicus and unusual bone changes. AB - A 26-year-old male patient presented with multiple plaques on the limbs and trunk suggestive of morphoea. He also exhibited multiple, small, atrophic, hypopigmented macules on the left side of the trunk, the histopathology of which was consistent with lichen sclerosus et atrophicus (LSA). The patient developed large ulcers on the left leg and foot, and contractures with flexion deformity of the left ring and little fingers. This combination of generalised morphoea with LSA and unusual osteolytic bone changes is uncommon. PMID- 20952910 TI - Progressive symmetric erythokeratoderma. AB - Progressive symmetric erythrokeratoderma (PSEK, Gottron's Syndrome) in a 10 year old-boy is reported. The diagnosis was confirmed by histopathology. PMID- 20952911 TI - Tuberculosis verrucosa cutis of the scrotum. AB - A 13-year-old boy had asymptomatic slowly progressive warty growth on the scrotum for 4 years. Examination revealed a 4 cm x 2 cm keratotic, nontender, indurated plaque on the right side of the scrotum. Histopathological examination of the lesion showed epithelioid cell granuloma with giant cells and lymphocytes in the dermis. Mantoux test was 15 mm x 20 mm. A diagnosis of tuberculosis verrucosa cutis of the scrotum was made. Six months of therapy with INH 150 mg and rifampicin 300 mg daily resulted in complete clearance of the lesion. PMID- 20952912 TI - Multiple dermatofibromas with unusual features. AB - A 51-year-old-male with multiple dermatofibromas over both elbows and feet is reported for its rarity and unusual features. PMID- 20952913 TI - Punctuate porokeratosis. AB - An 18 year-old-girl with multiple lesions of punctate porokeratosis on her right palm is described. The diagnosis was confirmed by histopathology. The disease has been reported rarely. Histopathology is important to distinguish it from other similar looking conditions. PMID- 20952914 TI - Clinical profile of stds in HIV infected individuals. PMID- 20952915 TI - Ceftriaxone in the management of chancroid. PMID- 20952917 TI - Co-ordination in leprosy elimination programme. PMID- 20952916 TI - Herpes zoster with ulnar nerve paresis. PMID- 20952918 TI - Anaerobic peptostreptococcal positive case of hidradenitis suppurativa. PMID- 20952920 TI - Klippel - Trenaunay syndrome. PMID- 20952919 TI - Blepharochalasis. PMID- 20952921 TI - Vogt-Koyanagi-Harada syndrome. PMID- 20952922 TI - Haemorrhagic chicken pox with pneumonitis. PMID- 20952923 TI - Tattooing practices in Kumbh Mela. PMID- 20952924 TI - Exfoliative cheilitis. PMID- 20952925 TI - Renal functional status in leprosy. AB - Renal functional impairment is known to occur in lepsory, specially of multibacillary type. Pedal oedema was seen in 30% patients. Urine analysis showed proteinurea in 3.33%. epithelial casts in 13.33% and microscopic haematuria in 6.66%. A raised 24 hours urinary protein excretion was seen in 53.33%, 60% had a low 24 hours creatinine clearance rate. Abnormal serum creatinine was found in 16.66%, raised serum urea values were seen in 6.66% cases. PMID- 20952926 TI - A comparative study of loratadine versus pheniramine maleate in chronic idiopathic urticaria. AB - Fifty cases with chronic idiopathic urticaria of more than 3 months duration were selected and divided into two groups. Group 'A' was given 10 mg loratadine once daily, while group 'B' was given pheniramine maleate 25 mg, twice daily for one month. All patients were followed for one month more. 48% excellent response was observed in group 'A' while 16% excellent response was observed in group 'B'. Good response was observed in 24% of patients in group 'A', while in group 'B' 16% of patients had good response. No side effects were observed in loratadine group, while drowsiness was observed in pheniramine group. PMID- 20952927 TI - Study of formaldehyde-induced fluorescence in cutaneous melanomas and naevi. AB - We have investigated 16 cases of cutaneous malignant melanomas and 34 cases of various types of neavi for formaldehyde-induced fluorescence. All cutaneous malignant melanomas (100%), but only two out of 34 naevi (5.88%) showed FIF positivity. The significance of this finding as a predictor of biological behaviour is discussed. PMID- 20952928 TI - Clinical profile of sexual transmitted diseases in cuttack. AB - Out of total 2330 patients, 516 patients with STD i.e., 22.14%, were analysed during the period 1993 to 1994. Frequency of different STDs observed in order were herpes progenitalis (21.89%), syphilis (16.27%), chancroid (11.82%) and granuloma inguinale (7.55%), gonococcal urethritis and genital warts (3.87% each). L G V was found in 0.58% of cases, HIV infection in 3 cases only (0.56%). Other miscellaneous infections like candidiasis (13.75%), trichomoniasis (2.7%) and molluscum (2.14%) were responsible in 18% as a whole and nonspecific infection in 14%. Most of the patients were married, were from low socio-economic status and there was always a male preponderance with a peak age between 20 to 30 years. PMID- 20952929 TI - Nylon friction dermatitis: A distinct subset of macular amyloidosis. AB - 43 patients were taken up for the study, all of whom were asymptomatic and presented with bluish black pigmentation. 23 patients presented with pigmentation which was proximal and distal to the bony prominences, all of whom gave a history of using nylon scrubbers during bathing. 20 patients gave no history of friction and the pigmentation was present on the extensor forearms, shins and upper back. Histopathological examination confirmed amyloid deposits. PMID- 20952930 TI - Disseminated herpes zoster. AB - Eleven case of disseminated herpes zoster (DHZ) who were hospitalised in the Dermatovenereology ward from January 1992 to April 1995 were selected for this study. All had classical herpes zoster (HZ) but within another 2 to 15 days had developed aberrant vesicles on the trunk, limbs and face. None of them had serious associated immunosuppressive disorder or malignancy. However, 3 cases had diabetes mellitus, 2 were receiving prednisolone 15 mg daily for the last few days, 2 had anaemia and deficiencies and 1 had a urinary tract infection. Only one patient needed oral acyclovir therapy. All were cured without any sequelae. PMID- 20952931 TI - Blue rubber bleb naevus. AB - A 35 year old female had multiple progressive painful, tender, soft, bluish compressible nodules with the feel of rubber nipples. There was no evidence of gastrointestinal haemangiomas or other systemic abnormalities. Histopathologically, cavernous haemangioma with prominent smooth muscle outline proved the clinical diagnosis of blue rubber bleb naevus. Only cutaneous lesions were seen in the patient. PMID- 20952932 TI - Proteus syndrome. AB - Proteus syndrome is a hamartomatous disorder characterised by focal overgrowths that can involve any structure of the body. An eleven-year-old girl with Proteus syndrome has been described with clitoromegaly. PMID- 20952933 TI - Herpes zoster at two different sites in the same individual. AB - Herpes zoster occuring at two different sites in the same individual at the same time, involving more than two segments at each site has rarely been reported. We recently observed two such cases. The first patient was HIV-infected 10 year old haemophiliac who had zoster involving the distribution of the right C4, 5, 6 and left L 2, 3, 4 dermatomes and the second one was a 50 year old renal transplant recipient on immunosuppressive drugs who developed zoster at left C3, 4, 5 and left T 7, 8, 9. PMID- 20952934 TI - Association of alopecia areata, vitiligo and pemphigus vulgaris. AB - A 50-year-old female had vitiligo and alopecia universalis. She developed pemphigus vulgaris with a history of recent increase in the size of the vitiligo patch. Corticosteroid therapy controlled the pemphigus vulgaris, halted the extension of the vitiligo lesion and promoted regrowth of hair. The coexistence of these three diseases in the same patient lends credence to the contention that autoimmunity plays a role in the pathogenesis of these diseases. PMID- 20952935 TI - Follicular mucinosis. AB - A case of follicular mucinosis is being reported. Clinically, the patient had discrete follicular and non-follicular papules on the face, neck and arms. Light microscopy confirmed the follicular outer root sheath, and sebaceous gland epithelial degenerative changes. The infiltrating inflammatory cells were morphologically benign. The response to oral dapsone therapy is highlighted. PMID- 20952936 TI - Eosinophilic cellulitis - A case study and management with griseofulvin. AB - A 47 year old hypertensive and diabetic male patient suffering from eosinophilic cellulitis (Wells syndrome) is being reported. The patient responded very well to oral griseofulvin at the time of first presentation and subsequent three recurrences in a period of three years. PMID- 20952937 TI - Urticaria pigmentosa mimicking xanthoma disseminatum. AB - A case of urticaria pigmentosa mistaken for xanthoma disseminatum is presented. PMID- 20952938 TI - Incontinentia pigmenti. AB - A case of incontinentia pigmenti, a rare genodermatosis, is being presented. PMID- 20952939 TI - Multicentric lupus vulgaris. AB - A 60 year old female patient presented with disseminated tuberculosis. She had multicentric lupus vulgaris and her joints, bones, lymph nodes and lungs were also affected. Haematogenous dissemination was because of her poor health. PMID- 20952940 TI - Phenytoin therapy in recessive dystrophic epidermolysis bullosa. AB - A case of recessive dystrophic epidermolysis bullosa in a 17-year-old boy is described. The diagnosis was based on clinical and histophathological findings. The patient is being treated with 200-300 mg of phenytoin sodium per day maintaining a blood level of 13-15 mg/litre and is under remission for 1 year. PMID- 20952941 TI - Cutaneous vasculitis with peripheral neuropathy. AB - a 40-year-old male patient presented with cutaneous vasculitis affecting both lower legs without any evidence of systemic involvement and a bilateral sensory neuropathy affecting both lateral popliteal nerves. Treatment with oral prednisolone resulted in healing of the cutaneous lesions but the sensory loss persisted. PMID- 20952943 TI - Dermatitis artefacta. PMID- 20952942 TI - Congenital anomaly of the toes, microophthalmos and haemangioma. AB - A two-and-half month-old female infant with cavernous haemangioma, agenesis and syndactyly of toes, microophthalmia and microcornea is reported. PMID- 20952945 TI - Actinophytosis (botryomycosis) due to staphylococcus aureus in a patient with diabetes mellitus. PMID- 20952944 TI - Disseminated herpes zoster vs unusal presentation of chicken pox. PMID- 20952946 TI - Febrile herxheimer reaction. PMID- 20952947 TI - ? Carbamazepine syndrome. PMID- 20952948 TI - Psoriasis and nail involvement. PMID- 20952950 TI - Childhood herpetiform pemphigus responsive to co-trimoxazole. PMID- 20952949 TI - Perilymphatic Iatrogenic depigmentation. PMID- 20952951 TI - Scleredema adultorum : Report of two cases. PMID- 20952952 TI - Immunofluorescence of the immunobullous disorders part one : Methodology. AB - In the past two decades the immunofluorescence techniques have greatly contributed to the diagnosis, treatment and understanding of the immunobullous disorders. The methodology of direct and indirect immunofluorescence as applied to the immunobullous disorders is described in detail. PMID- 20952953 TI - Therapeutic regional dermabrasion in papular lichen amyloidosis of shins. AB - Therapeutic regional dermabrasion of shins is a useful surgical method for planing away the persistent pruritic lichenified hyperkeratotic eruptions of papular lichen amyloidosis. Nine patients (6 females and 3 males) of 35 to 52 years age having papular lichen amyloidosis on shins, refractory to various medical lines of treatment for 5-12 years duration were subjected to regional dermabrasion. Extensor surfaces (shins) of both lower extremities (18 sites) in all 9 cases were treated by multiple sittings of spot dermabrasion. All 18 sites healed with superficial scarring and complete response (100%) with total clearance of lesions was observed in all 18 sites. Pruritus stopped in all the 18 dermabraded sites immediately. No local recurrence has been observed in any sites over a minimum follow up peroid of 11/2 years. Apart from superficial scarring occurring at all 18 sites the other side effect observed was varying degree of hypopigmentation in 10 out of the 18 sites dermabraded. Complication in the form of parchment like deep atrophic scarring with persistant hypopigmentation, erythema and at places depigmentation were obseved at 2 sites which were dermabraded deeply. Similar complications with delayed wound healing were observed at the 3rd site as sequel to secondary bacterial infection following spot dermabrasion. PMID- 20952954 TI - Clinical profile of psoriasis in North India. AB - A prospective study of 530 patients of psoriasis drawn from northern parts of India revealed a male preponderance; 60% patients having onset before the age of 30 years; youngest age at onset being one week and the oldest 72 years. Family history was positive in 14% cases. Only 30% psoriatics showed clear cut worsening in winter months. Skin and scalp were the commonest sites; 54% had nail changes when first seen and in 8 patients involvement of nails was the only manifestation of psoriasis. Joint symptoms were present in 10% of cases but frank arthritis was seen in only 7 cases. The presence of joint affection was invariably associated with nail abnormalities. Psoriatic arthritis among the Indian patients is not only rare but shows a milder course as compared to the western countries. PMID- 20952955 TI - A study of geriatric dermatoses. AB - A total of 200 patients aged 55 years and above were studied for cutaneous changes associated with ageing. The majority of patients (66%) were found to be in the age group of 55 to 64 years, of these 63% were males and 37% females. Pruritus was the commonest complaint in 78.5%. A variety of cutaneous lesions were observed. The commonest were cherry angiomas, seborrhoeic keratosis and naevus cell naevi. Not a single case of cutaneous malignancy was seen. Only 34.5% of the total dermatoses were found to be of infective aetiology. Diabetes was the most commonly associated systemic ailment. A psychosomatic background was observed in nearly 9.5% of the cases. PMID- 20952956 TI - Itraconazole versus griseofulvine in the treatment of tinea corporis and tinea cruris. AB - 126 patients (82 males and 44 females) aged above 12 years, suffering from tinea corporis and/or tinea cruris, were treated with either itraconazole (100 mg once a day for 2 weeks and then plecebo for 2 weeks) (63 patients), or griseofulvin (250 mg twice a day for 4 weeks). 90.47% of the patients treated with itraconzole improved whereas griseofulvin imporved 76.19% of patients, clinically. Mycological response was 72% with itraconazole and 57% with griseofulvin. PMID- 20952957 TI - Ciprofloxacin therapy in chronic folliculitis of legs. AB - The efficacy of ciprofloxacin was evaluated in 25 patients with chronic folliculitis of legs in a double-blind cross over study. Though ciprofloxacin was found to be far more effective than the placebo the average remission time was only 44.5 days. PMID- 20952958 TI - Cervical spine in psoriasis. AB - X-rays of the cervical spines from patients with psoriasis and psoriatic arthritis were compared with similar films from a control population. Apophyseal narrowing, sclerosis, and calcification of anterior ligamants were found more commonly in patients than in controls. PMID- 20952959 TI - Mikulicz's syndrome. AB - A rare case of Mikulicz's syndrome with underlying tuberculosis in a 65-year old male with bilaterally symmetrical, asymptomatic enlargement of parotid, submandibular and lacrimal glands is reported. PMID- 20952960 TI - Angiokeratoma corporis diffusum. AB - A case of angiokeratoma corporis diffusum having some classical features with dilatation of retinal vessels, but without urinary signs of renal involvement, is reported. PMID- 20952961 TI - Herpes associated erythema multiforme annularis concentricum. AB - A young man had large, concentric plaques over the back and extensors of forearms for eight weeks. Past history suggested recurrent herpes labialis. Serum anti HSV 1 IgG titre was raised to 32 micrograms/l and histopathology of an active lesion suggested erythema multiforme. Symptomatic treatment and oral zinc therapy subsided EM lesions but concentric depigmentation developed after healing. PMID- 20952962 TI - Waardenburg's syndrome. AB - Three children in a family of five presented with heterochromia iridis, lateral displacement of inner canthi and varying degrees of sensorineural deafness. All the 3 showed iris atrophy. The father of the children had only heterochromia iridis. A diagnosis of Waardenburg's syndrome Type I was made in the children with the father probably representing a forme fruste of the condition. PMID- 20952963 TI - Speckled lentiginous naevus. AB - 20-year-old male had a spotted discoloured area around the nipple of right breast since early childhood. Histopathologically, it was diagnosed as speckled lentiginous naevus and is reported here for its unusual localisation. PMID- 20952964 TI - Cutaneous loxoscelism. AB - A case of spider bitea presenting as cutaneous loxoscelism is reported. The clinical features and management of spider bite are highlighted and the relevant literature has been reviewed. PMID- 20952965 TI - Pangeria. AB - A case of pangeria, with multiple leg ulcers and premature senility with a history of cataractomy, starting at the age of 6 years, without any history of consanguinity, is reported. PMID- 20952966 TI - Sneddon-wilkinson disease and arthritis. AB - Sneddon-Wilkinson disease (subcorneal pustular dermatosis) is an uncommon disorder. An unusual association with seronegative arthritis is reported with review of literature. PMID- 20952967 TI - Folliculitis decalvans. AB - Two cases of folliculitis decalvans presenting with cicatricial alopecia over the scalp are reported for its rarity and clinical interest. PMID- 20952968 TI - Syndromic approach to a case of balanoposthitis. AB - The newly introduced simplified syndromic approach for the mamagement of sexually transmitted diseases was used in a case of balanoposthitis. Gram staining from the glans penis confirmed the case as bacterial balanoposthitis. Topical zinc sulphadiazine cream was found to be very effective in curing bacterial balanoposthitis within seven days. PMID- 20952969 TI - Lymphangioma circumscriptum masquerading as larva migrans. PMID- 20952971 TI - Peg - 200 with 12% salicylic acid ointment in pityriasis amiantacea. PMID- 20952970 TI - Ciprofloxacin-induced bullous fixed drug eruption. PMID- 20952972 TI - Kyrle's disease. PMID- 20952973 TI - Subacute cutaneous lupus erythematosus. PMID- 20952974 TI - HIV Seropositivity in truck-drivers. PMID- 20952975 TI - Sub-acute cutaneous lupus erythematosus. PMID- 20952976 TI - Connective tissue naevus-naevus elasticus. PMID- 20952977 TI - Naevus lipomatoides cutaneous superficialis. PMID- 20952978 TI - Mycological aspects of dermatomycosis in Yavatmal (Maharashtra). PMID- 20952979 TI - Chromoblastomycosis. PMID- 20952980 TI - Papillon lefevre syndrome. PMID- 20952982 TI - Sexually induced penile oedema. PMID- 20952981 TI - Tinea corporis in neonate due to trichophyton violaceum. PMID- 20952983 TI - Immunofluorescence of the immunobullous disorders Part two: The clinical disorders. AB - The immunofluorescence findings in the immunobullous disorders are reviewed together with a summary of clinical and histopathological findings. PMID- 20952984 TI - Evaluation of H2 receptor antagonists in chronic idiopathic urticaria. AB - H1-antagonist (hydroxyzine hydrochloride) in dosage of 10 mg-25 mg thrice a day failed to elicit satisfactory response in 60 out of 170 patients of chronic idiopathic urticaria. Additional administration of H2-antagonist (cimetidine) in dosage of 200 mg four times a day, in patients not responding earlier to H1 antagonist alones exhibited moderate to good improvement of various parameters of urticaria in approximately 85% patients. PMID- 20952985 TI - Role of colchicine in primary localised cutaneous amyloidosis. AB - Fifteen patients with primary localised cutaneous amyloidosis (PLCA), of which 8 had macular amyloidosis (MA) and 7 lichen amyloidosis (LA), received oral colchicine 1 mg/day in 2 divided doses for a period of 3 months. Pruritus completely disappeared in all MA patients and 30-60% diminution occurred in LA patients within 15 days. Flattening of the papules and diminution in thickness of the skin also started within one month in all LA patients, within 90 days of therapy pigmentation almost disappeared in ail patients of MA and size of papuies decreased by 80-98% in all LA patients. No significant side effect was seen in these patients due to colchicine therapy. PMID- 20952986 TI - A study of immunoglobulins and complements (C3 & C4) in alopecia areata. AB - Estimation of serum Immunoglobulins (IgG, IgM and IgA) and complements (C3 and C4) was carried out in 100 cases of alopecia areata as per method described by Mancini (1965).[1] Clinically patients were divided in two groups, alopecia areata circumscribed (group I) and severe alopecia areata (group II). Significant decrease in levels of one or more Immunoglobulins were observed in most of the patients. However, Serum complements (C3 and C4) were within range of normal control values. PMID- 20952987 TI - Correlation of isolates from pyoderma and carrier sites. AB - 100 cases of pyoderma were studied to find out whether there is any correlation between isolates from pyodermas, normal skin and nasal flora of the individual. From each patient six swabs were taken, two each from the lesion, healthy skin distant from the lesion and anterior nares. One swab from each site was used for direct microscopic examination and the other for culture and antibiotic susceptibility study. Isolates from lesion and normal skin and/or nose were identical in 37% cases of pyodermas. Isolates from lesion and normal skin were identical in 16% of cases; from lesion and nose in 14% cases, from all the three sites i.e., lesion, skin and nose in 7%. Staphylococcus aureus was the causative organism in 35 out of these 37 cases. Only in 2 cases was Staph albus isolated. In addition, antibiotic susceptibility pattern of the isolates were also the same in 12 out of these 37 cases. PMID- 20952988 TI - A clinico-aetiological profile of 375 cases of lichen planus. AB - The study of clinical, histopathological and aetiological pattern, of lichen planus (LP) in 375 patients was done in this part of Western Rajasthan. The incidence of LP was 0.8%. 58.7% cases were male and maximum number of cases (46.93%) were in age group of 20-39 years. In 70.66% of patients only skin was involved while in 10.18% of cases only mucous membrane was involved. In 61.6% patients the lower extremities were involved. Familial LP was seen in 8 families. Association of LP was found with hypertension (2.4%), polymorphic light eruption (2.1%), vitiligo (1.9%) and diabetes mellitus (1.6%). 48.5% of cases showed lymphocytosis with raised ESR. Actinic LP was seen in 14.1% of cases. 13.1% of patients showed combination of typical LP or its variants to which term lichen planus variata was given. PMID- 20952989 TI - Dermatophytoses in a desert district of Western Rajasthan. AB - Clinico-mycological study of 250 cases of dermatophytoses was undertaken in a desert district of Western Rajasthan. Incidence of dermatophytoses in this area was 8.60% with tinea cruris (34.4%) as the major clinical type followed by tinea corporis (24.0%) Incidence of tinea capitis was 16.8% and 90% of those affected were in the age group of 0-10 years. Male preponderance was observed (M:F=2:1). There were 15 cases of tinea faciei (6%), majority belonging to 0-10 years age group. Trichophyton violaceumwas isolated In majority (55.76%) from all clinical types followed by Trichophyton rubrum(42.3%). PMID- 20952990 TI - Sequential clinico-histological studies in psoriasis following methotrexate therapy. AB - Ten cases of psoriasis were studied to see the pattern of histological resolution and to evaluate clinico-histological correlation in psoriasis following weekly methotrexate therapy. Five sequential biopsies were taken in each patient. Scaling was first to regress followed by induration and erythema in 18, 26 and 35 days, respectively. Uniform granular layer appeared in 4 days, stratum corneum became orthokeratotic in 7 days, mitotic activity got restricted to basal layer in 7 days and rete ridges elongation was reduced to half in 11 days. Mild acanthosis, cellular infiltrate and vascular dilatation pesisted even after full clinical regression. Interestingly, 5 out of 10 biopsies revealed increase in cellular infiltrate and oedema after first methotrexate pulse. PMID- 20952991 TI - Solar urticaria. AB - A 35-year-old female and a 41-year-old male presented with clinical features suggestive of solar urticaria. The diagnosis of solar urticaria and the effectiveness of a combination of H1 and H2 blocking antihistamines were confirmed by phototesting with a solar simulator. PMID- 20952992 TI - Sweet's syndrome. AB - A series of 10 cases of Sweet's syndrome observed during a period of 3 years in Eastern parts of Libya is reported. All the patients were females. Fever and peripheral neutrophilia were not found in all these cases. Dapsone was found to be very effective in the cases in which it was tried. PMID- 20952993 TI - Tuberous sclerosis : A three-generation pedigree. AB - This is a report of tuberous sclerosis in members of three generations originating from parents, both suffering from the disease. Out of 12 family members only two were exempted and clinical expression varied from minimum lesion like adenoma sebaceum only to severe mental retardation and epilepsy. PMID- 20952994 TI - Incontinentia pigmenti. AB - Three cases of incontinentia pigmenti are reported. All the patients were female with bizarre pigmentation and verrucous and nodular lesions on the body. In all the cases there was absence of the vesicular stage and systemic involvement. PMID- 20952995 TI - Keratoacanthoma centrifugum marginatum. AB - A case of 38-year-old male with multiple keratoacanthoma centrifugum marginatum is reported. Clinical presentation was in the form of multiple, firm, non-tender skin coloured nodules of variable sizes. Diagnosis was confirmed by the histopathological examination. The case is being reported because it is a rare variant of keratoacanthoma. PMID- 20952996 TI - Papuloerythroderma of ofuji. AB - A 62-year old female had intensely pruritic eruption consisting of widespread coalescing sheets of uniform erythematous papules with characterstic sparing of body folds (deck-chair sign). Papuloerhthroderma of Ofuji is a rare disease of unknown aetiology. PMID- 20952997 TI - Pemphigus herpetiformis. AB - A 70-year old Indian lady with a two year history of a blistering eruption is described. This eruption clinically resembled dermatitis herepetiformis and responded to dapsone, however, histological and immunological investigations showed features of pemphigus herepetiformis. PMID- 20952998 TI - Lip leishmaniasis. AB - A case of leishmaniasis of lip without any involvement of other parts of the body in a 36 year-old-male is described. PMID- 20952999 TI - Vesicular and bullous eruptions in tropical (filarial) eosinophilia. AB - A case of tropical (filarial) eosinophilia (TE) presented with vesicular and bullous eruptions. The patient had skin and mucosal blistering. Histopathological changes were that of bullous pemphigoid. The patient had very high eosinophilia with abnormal vacuoles in the cytoplasm. ELISA test was positive for filarial antibodies. There were no pulmonary signs or symptoms. X-ray chest was normal. The patient responded well to diethylcarbamazine. PMID- 20953000 TI - Vulval elephantiasis : A sequel to tubercular lymphadenitis. AB - Two cases of vulval elephantiasis arising as a sequel to complete destruction of regional lymph nodes of tubercular aetiology are described for its rarity. PMID- 20953001 TI - Cockayne's syndrome. AB - A 10-year old boy, a product of consanguineous marriage was diagnosed clinically as a case of Cockayne's syndrome because of delayed milestones, deaf mutism with spastic paraplegia, dwarfism, salt and pepper fundus, typical facies and a photosensitive rash on the butterfly area of the face. PMID- 20953002 TI - Keratitis, ichthyosis and deafness (KID) syndrome. AB - Keratitis, ichthyosis, deafness (KID) syndrome is a genetically determined disorder. The present case is having marked photophobia, bilateral corneal ulceration with vascularisation, neurosensory deafness and skin changes. PMID- 20953003 TI - Atypical gorlin's syndrome. AB - A 21-year-old woman presented with complaints of skin lesions on her face, palms and soles. On examination, 8 to 10 well-defined, pigmented nodules with raised and pearly borders were seen on the face. Multiple pits were present on the palms and soles. Biopsy of both lesions revealed the presence of basal cell epitheliomas. The patient also gave history of removal of a keratocyst of mandible 10 years back. The case was diagnosed as Gorlin's syndrome. It is atypical due to the low number of basal cell epitheliomas, the occurrence of only a single odontogenic cyst and the absence of other features usually associated with this condition. PMID- 20953004 TI - Cutaneous B-cell lymphoma. AB - Primary cutaneous B-cell lymphoma is associated with poor prognosis. But with low grade pathology it may have a good prognosis. A 32-year-old man presented with hyperpigmented patches over chest which on biopsy showed perivascular infiltrate and was treated as vasculitis. After 8 months he came again with multiple nodules and plaques with ulceration. Biopsy of the plaque showed evidence of B-cell lymphoma. With chemotherapy the patient died after 6 months. Retrospective study of the earliest biopsy showed atypical lymphoid cells. This emphasizes the importance of the dermatopathological interpretation at the earliest stage. PMID- 20953005 TI - Erythropoietic protoporphyria (Report of three cases). AB - Three Libyan patients developing clinical manifestations of erythropoietic protoporphyria (EPP) at 5 years, 7 years and 3 years of age are reported. All of them had variable degree of photosensitivity leading to pitted scarring. Red blood cells in peripheral blood smear revealed positive pink fluorescence in all. First patient responded well with chloroquine therapy and the 3rd patient showed improvement with oral beta-carotene therapy, but the second patient did not show significant response to either. PMID- 20953006 TI - Autohaemotherapy in chronic urticaria. PMID- 20953007 TI - Post-kala-azar dermal leishmaniasis with atypical presentation. PMID- 20953008 TI - Scleredema. PMID- 20953009 TI - Kissing lupus vulgaris. PMID- 20953010 TI - Depression manifesting as urticaria. PMID- 20953011 TI - Occurrence of squamous cell carcinoma and multiple cutaneous horns in porokeratosis. PMID- 20953012 TI - A clinico-mycological study of superficial mycoses in upper Assam. AB - Clinico-mycological study of one hundred clinically diagnosed cases of superficial mycoses was conducted for one year. Overall male predominance was observed and T. rubum was the commonest isolate. PMID- 20953013 TI - Oval cells and cystic structures in multiplication of M leprae. AB - Ten preserved biopsy suspensions from leprosy patients were inoculated in biphasic medium and incubated alternatively in refrigerator and at 37 degrees C. The cultures were observed every week for 3 months. The typical actinomycetoid growth appeared within 3-5 days. Microscopically, two types of cysts (unstained and dark) were seen along with oval cells. Dark cysts showed developement of irregular septae or cracks breaking the mass into irregular quadrangular pieces. Granular acid-fast material could be made out inside the cracks and around the cysts. Oval cells were seen either independently or organised around pink homogeneous material. The oval cells were stained blue or pink. Some of them showed both blue and pink shades. PMID- 20953014 TI - Lichen simplex chronicus - A Psychocutaneous disorder? AB - Lichen simplex chronicus is classified as a skin disorder determined or influenced by emotional factors. This study was conducted to determine the involvement of the psyche in this psychocutaneous disorder. Forty six patients of lichen simplex chronicus were chosen for this study. The severity of pruritus was rated on a 10 point scale. They then underwent a psychiatric interview using the Hamilton anxiety-depression scale to quantitate their mental state. The numerical values of anxiety and depression did not exceed 50% of the measuring scale. This could be due to the 'venting' or exteriorisation of the inner turmoil, in this case by itching. The correlation between anxiety and pruritus and that of depression and pruritus was studied and it was surmised that depression may be related to pruritus compared to anxiety. PMID- 20953015 TI - Oral leucoplakia. AB - Oral leucoplakia was predominantly seen in elderly age group. Addiction to tobacco was observed in majority of patients (80.8%). Clinically commonest site of involvement was buccal mucosa (67.33%), followed by labial mucosa (13.86%). Majority of patients (57.35%) were having homogenous type of leucoplakia, followed by verrucous variety (25%). 26-48% cases were also having oral submucous fibrosis. Histologically various combinations of hyperkeratosis, hyperorthokeratosis and acanthosis were observed in 77.93% of cases. Dysplastic lesions were reported in 17.65% cases. In 80% of dysplastic lesions, band like infiltrate of mononuclear cells in subepithelial zone was seen. Malignant transformation was noticed in 2.94% cases. Excellent therapeutic results were obtained by cryosurgery. In resistant cases good results were observed with high dosage of vitamin A. PMID- 20953016 TI - Clinicomycological study of tinea capitis in desert district of Rajasthan. AB - The clinicomycological study was conducted on 200 cases of Tinea capitis in Jodhpur. Incidence of tinea capitis among superficial mycoses was 4.43 and male to female ratio being 1.8:1. Majority of patients were from urban area (88%) and positive family history of dermatophytoses was present in 29% of cases. Majority of patients attended hospital OPD from July to October (39.%%) and January to April (49%). Persons using mustard oil as hair applicant had single or less lesions as compared to individual using other oil. Endothrix involvement of hair was seen in 78% cases and Trichophyton violaceum was predominant fungus (88.5%) recovered on culture. PMID- 20953018 TI - Unusual clinical and histopathological presentation of facial tuberculosis. AB - Atypical facial lupus vulgaris is described in two cases. The first case resembled sarcoidosis clinically and histologically but responded well to ATT. The second case whose clinical diagnosis of lupus vulgaris was confirmed therapeutically had an atypical histology. PMID- 20953017 TI - Comparison of topical methenamine, glutaraldehyde and tap water Iontophoresis for palmoplantar hyperhidrosis. AB - Sixty patients with palmo-plantar hyperhidrosis were studied to compare the efficacy and safety of topical methenamine in the treatment of palmo-plantar hyperhidrosis with established therapies like glutaraldehyde and tap water iontophoresis. Patients were randomly allocated to 3 treatment groups: topical Methenamine (10%) solution, topical Glutaraldehyde (5% for palms and 10% for soles) and tap water iontophoresis. Hyperhidrosis was graded into 4 grades. The total duration of therapy was 4 weeks for all the 3 groups. Patients were followed up weekly for 4 weeks and 2 weeks after completion of therapy. Response to therapy was evaluated by the change in the grade of hyperhidrosis. Side effects like irritation and pigmentation were looked for at every follow up. Wilcoxon's rank sum test was used for comparison between changes in grading of 2 groups. It showed that methenamine is superior to tap water iontophoresis and acts faster than glutaraldehyde. Fewer side effects were noted with mether amine. PMID- 20953019 TI - Treatment of Reiter's disease. AB - Two classical cases of Reiter's disease, one successfully treated with methotrexate and the other with sulphasalazine are reported. PMID- 20953020 TI - Air-borne contact dermatitis caused exclusively by xanthium strumarium. AB - Most cases having air-borne contact dermatitis (ABCD) in India are considered to be caused by Parthenium hysterophorus. In some cases however, other plants have also been noticed to give positive patch test reactions. We are reporting two cases presenting as ABCD who showed positive patch tests with Xanthium strumarium while the patch tests with Parthenium hysterophorus were negative. It is therefore necessary to realise that every case of ABCD is not caused by Parthenium, and patch testing with Parthenium alone can lead to serious mistakes. PMID- 20953021 TI - Persistent congenital milia with naevus spilus. AB - We are reporting a case of solitary persistent left-sided endoareolar congenital milia in association with no serious malformation or abnormality of any structure except the presence of naevus spilus, on the back of the ipsilateral forearm. PMID- 20953022 TI - Acrokeratosis verruciformis of Hopf. AB - A 24-year-old male presented with numerous progressive warty lesions mainly involving the limbs of 6 years duration. There was absence of family history of the disease. Presence of keratotic lesions and histopathology led to a diagnosis of acrokeratosis verruciformis. PMID- 20953023 TI - Congenital syphilis - stigmata. AB - A 70-year-old male presented with recurrent ulceration on lower leg, extensors of forearms, arms, forehead and elbows with cigrette paper scarring. Palatal and nasal septal perforations, sudden blindness in one eye, hepatosplenomegaly, anterior bowing and thickening of tibia (sabre tibia) were present. VDRL and TPHA were positive. PMID- 20953024 TI - Hereditary onycho-osteo dysplasia syndrome. AB - We report a two and a half year old male child with dystrophy of all the nails, absent patellae and iliac horns. In addition he had dysmorphic facial features, sparing of lunula and bilateral hallux valgus deformity, hitherto not reported earlier. PMID- 20953025 TI - Aids patient presenting with common skin diseases. AB - A male labourer aged 30 years, presenting with multiple lesions characteristic of molluscum contagiosum over face along with warty lesions on upper arem and psoriasiform lesion over extremities and trunk associated with fever, anorexia, malaise, loss of weight, bloody diarrhoea, lymphadenopathy and pneumonitis, was detected to be seropositive for HIV spot test and Elisa test confirmed by Western blot test. PMID- 20953026 TI - Milia en plaque. AB - Milia en plaque is an unusual presentation of milia. The exact pathomechanism and reason for postauricular localization is not yet understood. Faster resolution of lesions after usage of trichloracetic acid alongwith topical tretinoin was encouraging and may be used as adjunct in treatment of milia. PMID- 20953027 TI - Generalized granuloma annulare. AB - A 35-years-old female patient had generalized pruritic papular lesions, distributed like dermatitis herpetiformis for last 4 years. Histopathologic changes were typical of granuloma annulare with negative results of direct immunofluorescence. The patient did not have association of diabetes mellitus or any other systemic disease. She failed to respond to dapsone therapy and 13-cis retinoic acid. PMID- 20953028 TI - Mycosis fungoides : Tumour D'emblee. AB - A 60-years old male patient presented with nodules and noduloulcerative lesions of mycosis fungoides (MF) of 6 months duration without any previous premycotic, patch or plaque stage. PMID- 20953029 TI - Porokeratosis of mibelli in a family. AB - The occurrence of porokeratosis of Mibelli in all members of a family when only one parent (mother) had the disease is reported. The 17 members of the third generation are still under 17 years of age and have not revealed any lesions of porokeratosis. PMID- 20953030 TI - Subungual malignant melanoma clinically resembling granuloma pyogenicum. AB - A 37-year-old labourer developed longitudinally split dystrophic nail with blackish discolouration in the centre 5 months following blunt trauma to the right thumb nail. Six months later, a well defined exudative erythematous to violaceous nodule developed and this recurred inspite of repeated surgical interventions. Patient had large, firm to hard epitrochlear and axillary lymphadenopathy. Histopathological examination confirmed the diagnosis of malignant melanoma. PMID- 20953031 TI - Congenital leopard vitiligo associated with multiple sclerosis. AB - A 31-year old Muslim male presented with congenital leopard vitiligo associated with multiple sclerosis. Five other family members had similar cutaneous lesions since birth. The disease appeared to be transmitted by autosomal dominant pattern with variable penetrance. PMID- 20953032 TI - Ainhum in supernumery fingers. AB - A case of ainhum occuring in supernumery fingers bilateraly in a thirteen year old girl is presented. PMID- 20953033 TI - Macular atrophic lesions in acne vulgaris. AB - Macular atrophic lesions coexisting with comedonal lesions are described in a case of acne vulgaris. PMID- 20953034 TI - Chronic urticaria treated with soft nasal filters. AB - A 22-year-old boy having two attacks of urticaria per day for the last 5 years and intermittent attacks of sneezing and rhinorrhoea, and without any clues to the causative agent in spite of a detailed history and follow up, showed almost complete relief on wearing an ordinary cloth mask for 3 days. He was subsequently trained to use the soft nasal filters and obtained almost 80% relief in urticaria and complete relief in rhinitis during the next 1 year. Wearing the mask for 2 days again led to complete relief and further training in the proper use of the filters was helpful. PMID- 20953035 TI - Kyrle's disease. PMID- 20953036 TI - Sister Mary Joseph's nodule as presenting sign of ovarian carcinoma. PMID- 20953038 TI - Atypical subcorneal pustular dermatosis. PMID- 20953037 TI - Alopecia areata and xerosis in Down's syndrome. PMID- 20953039 TI - Erythema annulare centrifugum responding to dapsone. PMID- 20953041 TI - Jarisch-Herxheimer reaction in early syphilis. PMID- 20953040 TI - Dermatologists' view of WHO MDT regimen. PMID- 20953042 TI - In situ monitoring of photodynamic inactivation of the membrane functions of bacteria using electrochemical sensors. AB - The photodynamic inactivation of the membrane functions of bacteria was analyzed in situ, using K(+) and tetraphenylphosphonium (TPP(+)) electrodes, as well as an oxygen electrode. Tetrakis(4-N-trimethylaminophenyl)porphine (TTMAPP) and rose bengal were used, since both dyes act strongly on bacteria, such as Staphylococcus aureus. After a short time lag, they inhibited the respiration of bacteria and increased the permeability of the cytoplasmic membrane to K(+), while dissipating the membrane potential. This combination of sensors is quite useful for visualizing the actions of photosensitizers on the bacterial membrane. TTMAPP and rose bengal impaired the bacterial function by reducing the membrane potential within minutes of photo-irradiation. PMID- 20953043 TI - Recognition of chemical identity of organic adsorbates on solid surfaces at the nanoscale by molecular STM tips. AB - This paper reviews chemically selective imaging at the single-atom/molecule level by molecular STM tips. The molecular tips enable the recognition of a particular chemical species on the basis of chemical interactions with a sample molecule, including hydrogen-bond, metal-coordination, and charge-transfer interactions. The chemical selectivity can be tailored by designing functional groups of the tip molecules. Moreover, the rational design of the molecular tip allows sophisticated chemical recognition. The discrimination of DNA bases and chiral recognition on a single molecule basis are thereby achieved. The molecular tips also revealed rectified electron transmission within an electron donor-acceptor molecular pair. Self-assembled monolayers, carboxylated carbon nanotube, and conducting polymers can be utilized for the preparation of molecular tips. This technique may be coined "intermolecular tunneling microscopy" as its principle goes, and is of general significance for novel molecular imaging of chemical identities at the membrane and solid surfaces. PMID- 20953044 TI - AFM studies of cellular mechanics during osteogenic differentiation of human amniotic fluid-derived stem cells. AB - Amniotic fluid-derived stem cells (AFSCs) are becoming an important source of cells for regenerative medicine given with apparent advantages of accessibility, renewal capacity and multipotentiality. In this study, the mechanical properties of human amniotic fluid-derived stem cells (hAFSCs), such as the average Young's modulus, were determined by atomic force microscopy (3.97 +/- 0.53 kPa for hAFSCs vs. 1.52 +/- 0.63 kPa for fully differentiated osteoblasts). These differences in cell elasticity result primarily from differential actin cytoskeleton organization in these two cell types. Furthermore, ultrastructures, nanostructural details on the surface of cell, were visualized by atomic force microscopy (AFM). It was clearly shown that surface of osteoblasts were covered by mineralized particles, and the histogram of particles size showed that most of the particles on the surface of osteoblasts distributed from 200 to 400 nm in diameter, while the diameter of hAFSCs particles ranged from 100 to 200 nm. In contrast, there were some dips on the surface of hAFSCs, and particles were smaller than that of osteoblasts. Additionally, as osteogenic differentiation of hAFSCs progressed, more and more stress fibers were replaced by a thinner actin network which is characteristic of mature osteoblasts. These results can improve our understanding of the mechanical properties of hAFSCs during osteogenic differentiation. AFM can be used as a powerful tool for detecting ultrastructures and mechanical properties. PMID- 20953045 TI - Real-time two-dimensional imaging of potassium ion distribution using an ion semiconductor sensor with charged coupled device technology. AB - Two-dimensional real-time observation of potassium ion distributions was achieved using an ion imaging device based on charge-coupled device (CCD) and metal-oxide semiconductor technologies, and an ion selective membrane. The CCD potassium ion image sensor was equipped with an array of 32 * 32 pixels (1024 pixels). It could record five frames per second with an area of 4.16 * 4.16 mm(2). Potassium ion images were produced instantly. The leaching of potassium ion from a 3.3 M KCl Ag/AgCl reference electrode was dynamically monitored in aqueous solution. The potassium ion selective membrane on the semiconductor consisted of plasticized poly(vinyl chloride) (PVC) with bis(benzo-15-crown-5). The addition of a polyhedral oligomeric silsesquioxane to the plasticized PVC membrane greatly improved adhesion of the membrane onto Si(3)N(4) of the semiconductor surface, and the potential response was stabilized. The potential response was linear from 10(-2) to 10(-5) M logarithmic concentration of potassium ion. The selectivity coefficients were K(K(+),Li(+))(pot) = 10(-2.85), K(K(+),Na(+))(pot) = 10(-2.30), K(K(+),Rb(+))(pot) =10(-1.16), and K(K(+),Cs(+))(pot) = 10(-2.05). PMID- 20953047 TI - DNA detection on a power-free microchip with laminar flow-assisted dendritic amplification. AB - In this paper, we describe DNA detection experiments using our two original technologies, power-free microchip and laminar flow-assisted dendritic amplification (LFDA), which were previously applied to immunoassays. A microchip was fabricated by combining a poly(dimethylsiloxane) (PDMS) part having microchannel patterns and a glass plate modified with probe DNA. We carried out two kinds of experiments: the detection of 21-base biotinylated target DNA and the detection of single-nucleotide polymorphism (SNP) in 56-base unlabeled target DNA by sandwich hybridization with biotinylated probe DNA. For both of the experiments, the necessary solutions were injected into microchannels not by an external power source, but by air dissolution into the PDMS part. After a hybridization reaction, the LFDA was started by injecting FITC-labeled streptavidin and biotinylated anti-streptavidin antibody onto the reaction site. With a detection time of 20 min, the limit of detection (LOD) for the biotinylated target was 2.2 pM, and the LOD for the SNP was 10-30 pM, depending on the SNP type. PMID- 20953048 TI - Voltammetric detection of biological molecules using chopped carbon fiber. AB - Voltammetric detection of biological molecules was carried out using chopped carbon fibers produced from carbon fiber reinforced plastics that are biocompatible and inexpensive. Because chopped carbon fibers normally are covered with a sizing agent, they are difficult to use as an electrode. However, when the surface of a chopped carbon fiber was treated with ethanol and hydrochloric acid, it became conductive. To evaluate the functioning of chopped carbon fibers, voltammetric measurements of [Fe(CN)(6)](3-) were carried out. Redoxes of FAD, ascorbic acid and NADH as biomolecules were recorded using cyclic voltammetry. The sizing agents used to bundle the fibers were epoxy, polyamide and polyurethane resins. The peak currents were the greatest when using the chopped carbon fibers that were created with epoxy resins. When the electrode response of the chopped carbon fibers was compared with that of a glassy carbon electrode, the peak currents and the reversibility of the electrode reaction were sufficient. Therefore, the chopped carbon fibers will be useful as disposable electrodes for the sensing of biomolecules. PMID- 20953049 TI - Electrochemical monitoring of the interaction between 4-nonylphenol and DNA by graphite and carbon nanotube modified graphite electrodes. AB - The interaction of 4-nonylphenol (NP) with deoxyribonucleic acid (DNA) was explored electrochemically by using differential pulse voltammetry (DPV) in combination with unmodified and modified pencil graphite electrodes (PGE) with single walled carbon nanotubes (SWCNT). The differentiation of the two oxidation signals coming from NP and DNA base, guanine was studied before and after the interaction process. In addition, the effect of NP concentration was investigated in order to determine the optimum experimental conditions. The detection limit and the reproducibility were determined by using CNT-modified electrodes. PMID- 20953050 TI - Electrochemical behavior and voltammetric determination of 2,4,6 triaminopyrimidine at glassy carbon electrode modified with multi-walled carbon nanotubes/nafion. AB - A multi-wall carbon nanotubes (MWCNTs) composite with Nafion was modified on a glass carbon electrode. The modified electrode was then used as a voltammetric sensor in detecting 2,4,6-triaminopyrimidine (TAP). The surface morphology of the Nafion/MWCNTs composite film was characterized by atomic force microscopy (AFM), and the electrochemical behavior of TAP at this sensor was investigated in detail. The results indicated that the Nafion/MWCNTs modified electrode exhibited efficient electrocatalytic oxidation for TAP with relatively high sensitivity, stability and lifetime. Under the optimized condition using linear sweep voltammetry (LSV), the Nafion/MWCNTs modified electrode exhibited a linear voltammetric response for TAP in the concentration range of 2.0 * 10(-7) to 3.6 * 10(-5) mol L(-1), with a detection limit of 5.0 * 10(-8) mol L(-1). The electrode was applied to detect TAP added to human blood serum, with an average recovery value of 101.3%. PMID- 20953051 TI - A highly selective colorimetric and "off-on-off" fluorescent probe for fluoride ions. AB - In this paper, a highly selective and sensitive probe for fluoride ions (F(-)), containing a phenylpyridylvinylene derivative reporter and a Si-O bond receptor, was designed and characterized. The reaction mechanism is based on the intramolecular charge transfer (ICT) mechanism. Upon addition of F(-), probe 1 showed a remarkable red-shift (183 nm) in the absorption spectra accompanying with the color changes from colorless to purple, so probe 1 could serve as a "naked-eye" probe for F(-). The absorbance of probe 1 at 545 nm increased linearly with the concentration of F(-) from 20 to 150 uM. The detection limit was calculated to be 0.1 uM. Besides, "off-on-off" fluorescence intensity changes were also observed in the fluorescence spectra. The present results may provide a useful approach for the development of highly selective dual-channel probes for F(-). PMID- 20953052 TI - Identification and characterization of new degradation products of cefepime dihydrochloride monohydrate drug substance during stress stability studies. AB - The degradation products of Cefepime dihydrochloride that emerged throughout stress stability studies have been determined, identified and characterized. The two new impurities were detected by gradient reverse-phase high performance liquid chromatography (HPLC), and Impurity-I was formed in the range from 0.2 to 11.0% and Impurity-II range from 0.2 to 3.5%. These impurities have been identified by LC/MS, and were not reported in the literature. These impurities were synthesized, isolated and characterized. Based on the spectral data, the impurities were named (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2 (methoxyimino)acetamido]-3-[(1-methyl-1-pyrrolidinium)methyl]-3-cephem-4 carboxylate-1-oxide (Impurity-I); (2RS)-2[[(Z)-2-(2-amino-4-thiazolyl)-2 (methoxyimino)acetamido]-methyl]-1,2,5,7-tetrahydro-7-oxo-4H-furo[3,4 d][1,3]thiazine (Impurity-II). The structures were established unambiguously by independent synthesis and co-injection in HPLC to confirm the retention times and relative retention times. The structural elucidation of these impurities by spectral data ((1)H NMR, (13)C NMR, 2D-NMR (COSY, HSQC and HMBC), LC/MS, TOF-MS, elemental analysis and IR), synthesis, isolation and the formation of these impurities are discussed in detail. PMID- 20953053 TI - Chiral separation of sertraline with microemulsion electrokinetic chromatography on a polymer/beta-cyclodextrin assembling molecular film modified capillary. AB - A capillary modified by assembling a molecular film was presented for the chiral separation of sertraline by microemulsion electrokinetic chromatography. The assembling molecular film was constructed with poly(diallyldimethylammonium chloride) and beta-cyclodextrin via inclusion complexation. The separation efficiency of cis-trans isomers and enantiomers of sertraline was improved with a running microemulsion that contained the acetonitrile, sodium dodecyl sulfate, n butanol and n-hexane buffered with sodium tetraborate. The baseline separation of four sertraline cis-trans isomers and enantiomers was achieved under the optimum conditions. The detection limit for isomers and enantiomers of sertraline (1S,4S, 1R,4R, 1S,4R, 1R,4S) was 0.15, 0.15, 0.30, 0.30 mg/L, respectively. The mechanism of chiral separation was studied and it could be applied for the determination of commercial Zoloft tablet samples satisfactorily. PMID- 20953054 TI - Determination of Cr(III) and Cr(VI) at sub-ppb levels in water with solid-phase extraction/metal furnace atomic absorption spectrometry. AB - A simple method using solid-phase extraction combined with metal furnace atomic absorption spectrometry was developed for the determination of Cr(III) and Cr(VI) at sub-ppb levels in water. A 500-ml water sample was adjusted to pH 3 with nitric acid and then passed through an iminodiacetate extraction disk placed on a cation-exchange extraction disk at a flow rate of 20-40 ml min(-1) for concentrating Cr(III). The filtrate was adjusted to pH 10 with aqueous ammonia and then passed through an anion-exchange extraction disk at a flow rate of 2 ml min(-1) for concentrating Cr(VI). The Cr(III) and Cr(VI) collected were eluted with 40 ml of 3 mol l(-1) nitric acid for Cr(III) and 40 ml of 1 g l(-1) diphenylcarbazide solution for Cr(VI). Each eluate was diluted to 50 ml with deionized water and injected into a U-type tungsten board on the metal furnace. The calibration curves of Cr(III) and Cr(VI) showed good linearity in the range of 0.1-0.5 ng. The detection limits corresponding to three times the standard deviation (n = 5) of blank values were 8.1 pg for both Cr(III) and Cr(VI). The analytical value of total Cr (Cr(III) + Cr(VI)) in certified reference material of river water (JSAC 0302-3) was in good agreement with the reference value. The recovery test for 0.50 ug (1.00 ug l(-1)) of Cr(III) and Cr(VI) added to 500 ml of the water samples showed sufficient values (98.1-106%), except for river water sampled downstream due to relatively higher COD(Mn) value. The relative standard deviations (n = 5) were less than 5% for both Cr(III) and Cr(VI). PMID- 20953055 TI - Sensitive analysis of blonanserin, a novel antipsychotic agent, in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry. AB - A rapid and sensitive method for analysis of blonanserin in human plasma by ultra performance liquid chromatography-tandem mass spectrometry is presented. After pretreatment of a plasma sample by solid-phase extraction, blonanserin was analyzed by the system with a C(18) column. This method gave satisfactory recovery rates, reproducibility, and good linearity of calibration curve in the range of 0.01-10.0 ng/mL for quality control samples spiked with blonanserin. The detection limit was as low as 1 pg/mL. This method seems very useful in forensic and clinical toxicology and pharmacokinetic studies. PMID- 20953056 TI - In vitro measurements of extracellular L-glutamate level in region CA3 of mouse hippocampal slices under chemical stimulation. AB - The concentration level of extracellular L-glutamate released from region CA3 of mouse hippocampal slices under tetraethylammonium (TEA) chloride and KCl stimulation was measured with independent methods, i.e., a capillary-based enzyme sensor, a patch sensor, and an enzyme-based imaging method. The L-glutamate level was compared with those at regions CA1 and DG. It was found that the enhanced concentration level at CA3 by TEA stimulation is very similar to that at CA1, but it is much lower than that at DG. The order of the regional distribution of L glutamate, i.e., DG > CA1 ~ CA3, was the same as that obtained by K(+) stimulation. However, in the presence of an uptake inhibitor, DL-TBOA, KCl stimulation showed the strongest L-glutamate flux at CA1, while TEA stimulation exhibited the strongest flux at CA3. The usefulness of the present approach for knowing the extracellular L-glutamate level in acute hippocampal slices is discussed. PMID- 20953057 TI - An effective pulse sequence for detecting a ligand binding with a protein receptor using a WET sequence and the repeated Z-filters. AB - WaterLOGSY and STD experiments are widely used as NMR-based screening techniques in drug research. In the present study, an improved STD pulse sequence was developed, and its efficiency and applicability of observing the ligand signals were evaluated compared with the WaterLOGSY experiment. A combination of presaturation, a WET sequence and subsequent repeated Z-filters can provide the most effective water suppression, which is incorporated into the STD pulse sequence. In a sample solution of tryptophan and glucose in the presence of human serum albumin, the improved STD experiment only succeeded in selective detections of the bound ligand signals, even resonating close to water. PMID- 20953058 TI - Simultaneous separation and determination of eleven nucleosides and bases in beer, herring sperm DNA and RNA soft capsule by high-performance liquid chromatography. AB - A simple and rapid high-performance liquid chromatography method was developed for the determination of eleven nucleosides and bases in beer, herring sperm DNA and RNA soft capsules. The separation was carried out on an Agilent extend-C(18) column with a simple gradient elution of acetonitrile and water as the mobile phase. Good linear relationships between the peak areas and the concentrations of the analytes were obtained. The detection limits for eleven analytes were in the range of 0.007-0.037 mg/L by UV detection at 260 nm. The relative standard deviations (RSDs) of the retention times were in the range of 0.78-1.85% for intra-day and 0.87-1.94% for inter-day, respectively. The RSDs of the peak areas were in the range of 2.71-3.22% for intra-day and 3.03-3.39% for inter-day, respectively. This method has been successfully applied to simultaneous determination of eleven nucleosides and bases in beer, herring sperm DNA and RNA soft capsules with the recoveries in the range of 93.7-108.3%. PMID- 20953060 TI - Prevalence and clinical implication of metabolic syndrome in chronic heart failure. AB - BACKGROUND: Metabolic syndrome (MetS) is a pathological condition with a clustering of metabolic components and is a well-known risk and prognostic factor for ischemic heart disease (IHD). However, the prevalence and clinical significance of MetS remain to be fully elucidated in chronic heart failure (CHF), an important clinical syndrome caused by various cardiac abnormalities. METHODS AND RESULTS: The present nationwide, large-scale clinical study enrolled 3,603 patients with stage C/D CHF from 6 institutes in Japan. First, the prevalence of MetS in CHF patients was demonstrated to be 45% in males and 19% in females, which is more than double compared with the general population in Japan. The CHF patients with MetS were characterized by younger age, higher prevalence of current smoking and drinking, IHD, and hypertensive heart disease, whereas the prevalence of HF with preserved ejection fraction and MetS was higher in elderly female patients. Next, the contribution of the metabolic components (waist circumference, hypertension, glucose intolerance/diabetes mellitus and dyslipidemia) was found to be comparable between the ischemic and the non ischemic CHF patients. CONCLUSIONS: The prevalence of MetS in CHF patients is more than double compared with the general population in Japan and suggest that the metabolic components may have a substantial effect on the development of both ischemic and non-ischemic CHF. PMID- 20953061 TI - Tissue characterization of coronary plaques and assessment of thickness of fibrous cap using integrated backscatter intravascular ultrasound. Comparison with histology and optical coherence tomography. AB - BACKGROUND: The purpose of this study was to develop a new online integrated backscatter intravascular ultrasound (IB-IVUS) system and to validate its ability to measure fibrous cap thickness by comparing IB-IVUS images with those from optical coherence tomography (OCT). METHODS AND RESULTS: Images were acquired from 125 segments of 26 coronary arteries obtained at autopsy from 11 cadavers. In the training study (n=30), 242 regions-of-interest on color-coded maps were compared with histology. In the validation study, 95 cross-sections were diagnosed by IB-IVUS and histology. In 24 patients with stable angina, 28 arterial cross-sections were imaged by IB-IVUS and OCT in vivo. In the training study, cutoff values of 39 decibels (dB) and 17dB were the optimal predictors of lipid pool/fibrosis and fibrosis/calcification, respectively, with 38-MHz mode; 42dB and 20dB, respectively, with 43-MHz mode. In the validation study, IB classified the fibrous, lipid-rich and fibrocalcific components with an accuracy of 92%, 91% and 95%, respectively. Agreement between the histological and IB-IVUS diagnoses was excellent (Cohen's kappa=0.83). There was a correlation between the fibrous cap thickness measured by IB-IVUS and OCT (r=0.74, P<0.001). CONCLUSIONS: The IB-IVUS system with improved resolution provides high diagnostic accuracy for the analysis of the tissue characteristics of coronary plaques, and enables estimation of the thickness of the fibrous cap in the clinical setting. PMID- 20953062 TI - Sympathoinhibition by atorvastatin in hypertensive patients. AB - BACKGROUND: Experimental animal data suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) might reduce enhanced sympathetic activity, a hallmark of hypertensive patients. This hypothesis was tested for the first time in patients with primary hypertension. METHODS AND RESULTS: Using a prospective, randomized, placebo-controlled, double-blind, cross over design, a proof-of-principle trial was performed in 13 patients with mild to moderate primary hypertension, who were randomly assigned to a regimen of atorvastatin (80mg/day) for 3 weeks, followed by placebo for 3 weeks or to a regimen of placebo for 3 weeks, followed by atorvastatin (80mg/day) for 3 weeks. Microneurography was used at the end of each treatment period to measure sympathetic nervous system activity (muscle sympathetic nerve activity: MSNA). Heart rate variability (HRV) and plasma norepinephrine concentrations were also measured. Additionally, effects on blood pressure (BP) and heart rate (HR) were assessed by 24-h ambulatory BP measurement. Atorvastatin reduced postganglionic MSNA (atorvastatin 35.0+/-2.0 vs placebo: 39.2+/-1.5 bursts/min, P=0.008) and heart frequency corrected MSNA (atorvastatin: 58.5+/-2.0 vs placebo: 64.7+/-3.0 bursts/100 beats, P=0.02). Atorvastatin had no significant effect on plasma norepinephrine levels, HRV, BP or HR. CONCLUSIONS: In patients with mild to moderate hypertension, atorvastatin reduces postganglionic MSNA, which supports the hypothesis that HMG-CoA reductase plays a role in sympathetic nervous system activity. PMID- 20953063 TI - Influence of dynamic training on hemodynamic, neurohormonal responses to static exercise and on inflammatory markers in patients after coronary artery bypass grafting. AB - BACKGROUND: Little is known about the influence of dynamic training on the hemodynamic and neurohormonal responses to static exercise and on inflammatory markers in optimally treated post-coronary artery bypass grafting (CABG) patients. METHODS AND RESULTS: One hundred and twenty male patients, aged 55+/-6 years, 3 months after receiving CABG, were randomized to either 6 weeks of aerobic training on a cycloergometer, 3 times a week, at a 70-80% of the maximum tolerated heart rate (HR) (training group, n=60) or to a control group (n=60). At baseline and at the end of the study, all patients underwent: (1) a cardiopulmonary test; (2) handgrip at 30% of maximal voluntary contraction for 3min in a sitting position during in which HR, blood pressure (BP), stroke volume (SV, by impedance cardiography), cardiac output (CO) and total peripheral resistance (TPR) were monitored; and (3) plasma level assessment of catecholamines, nitric oxide and inflammatory markers. During the final tests, handgrip-induced increases in HR, BP, and TPR (14% vs 27%, P<0.01) were lower, whereas SV and CO were higher (by 13% and 15%, respectively, P<0.05) in trained patients compared with controls. Moreover, a higher increase in nitric oxide level (46% vs 14%, P<0.01) and a lower increase in noradrenaline (11% vs 20%, P<0.05) were observed in trained patients compared with controls. Accordingly, training caused significant improvement in peak oxygen uptake per kilogram body weight (peak VO(2)) and inflammatory markers. CONCLUSIONS: Short-term dynamic training caused significant improvement of hemodynamic and neurohormonal responses to handgrip, cardiovascular fitness and inflammatory state. PMID- 20953064 TI - Stability control of MTL1 mRNA by the RNA-binding protein Khd1p in yeast. AB - Khd1p (KH-domain protein 1) is a yeast RNA-binding protein highly homologous to mammalian hnRNP K. Khd1p associates with hundreds of potential mRNA targets including a bud-localized ASH1 mRNA and mRNAs encoding membrane-associated proteins such as Mid2p and Mtl1p. While Khd1p negatively regulates gene expression of Ash1p by translational repression, Khd1p positively regulates gene expression of Mtl1p by mRNA stabilization. To investigate how Khd1p regulates the stability of MTL1 mRNA, we searched for cis-acting elements and trans-acting factors controlling MTL1 mRNA stability. Regional analysis revealed that partial deletion of the coding sequences of MTL1 mRNA restored the decreased MTL1 mRNA and protein levels in khd1Delta mutants. This region, encompassing nucleotides 532 to 1032 of the Mtl1p coding sequence, contains CNN repeats that direct Khd1p binding. Insertion of this sequence into other mRNAs conferred mRNA instability in khd1Delta mutants. We further searched for factors involved in the destabilization of MTL1 mRNA. Mutations in CCR4 and CAF1/POP2, encoding major cytoplasmic deadenylases, or of SKI genes, which code for components of a complex involved in 3' to 5' degradation, did not restore the decreased MTL1 mRNA levels caused by khd1Delta mutation. However, mutations in DCP1 and DCP2, encoding a decapping enzyme complex, and XRN1, encoding a 5'-3' exonuclease, restored the decreased MTL1 mRNA levels. Furthermore, Khd1p colocalized with Dcp1p in processing bodies, cytoplasmic sites for mRNA degradation. Our results suggest that MTL1 mRNA bears a cis-acting element involved in destabilization by the decapping enzyme and the 5'-3' exonuclease, and Khd1p stabilizes MTL1 mRNA through binding to this element. PMID- 20953065 TI - Is there an undiscovered neurocircuit for regulating GH secretion? -Pitfalls of GHRP-2 and ITT as GH provocative tests-. AB - GH secretion is mainly regulated at the hypothalamus by a dual interplay between growth hormone releasing hormone (GHRH) and somatostatin, which are modulated by various factors. We examined the regulatory mechanism of GH secretion in an apparently healthy young man without decreased IGF-1 concentration and nocturnal GH secretion, but who showed low responses to insulin tolerance (ITT) and to GHRP 2 tests. The patient also had no GH response to acute aerobic exercise. However, he had normal secretion of pituitary hormone based on hypothalamic releasing hormone tests combined with CRH, GRH as GHRH, LH-RH and TRH. In addition, he had a GH response without paradoxical secretion to TRH stimulation as well as an ACTH response to subcutaneous glucagon stimulation, and AVP secretion responded to 5% hypertonic saline infusion, though it was not adequately stimulated by ITT. MRI showed no structural abnormalities in the hypothalamus-pituitary gland. These findings indicate that this subject may have an undiscovered neurocircuit for regulating GH secretion, as well as other neurohormones, to maintain homeostasis, even though there were low responses of the hormones to ITT and GHRP-2 stimuli, probably via altered secretion of hypothalamic hormones. PMID- 20953066 TI - Recurrent pregnancy-induced diabetes insipidus in a woman with hemochromatosis. AB - Diabetes insipidus is a rare disorder in pregnant women, predating pregnancy or appearing for the first time during gestation. In pregnancy it usually affects women with HELLP syndrome or acute fatty liver of pregnancy and results from the reduced hepatic degradation of placental vasopressinase leading to its increased activity. Although infiltrative diseases have been found to cause diabetes insipidus in non-pregnant population, very few studies showed that these disorders may manifest for the first time during gestation. We describe here the case of transient diabetes insipidus in two subsequent pregnancies of a female with hemochromatosis. The first symptoms of this disease appeared for the first time at the beginning of the third trimester of her second pregnancy, and diagnosis was established on the basis of typical clinical presentation, confirmed by a water deprivation test. Diabetes insipidus resulted from the increased activity of vasopressinase, caused by hemochromatosis-induced liver dysfunction, the presence of which was confirmed between the pregnancies by liver biopsy and identification of the HFE gene mutation. Subsequent desferrioxamine treatment resulted in a less severe clinical course of diabetes insipidus in the last patient's pregnancy. In both pregnancies, the patient was successfully treated with oral desmopressin, which is resistant to degradation by placental vasopressinase. Although unrecognized pituitary disorders may pose a serious health problem to the mother and fetus, hemochromatosis-induced diabetes insipidus, as the case of our patient demonstrates, if effectively diagnosed and treated, cannot be regarded as a contraindication for pregnancy. PMID- 20953067 TI - Serum gamma-glutamyltransferase, triglyceride and total cholesterol are possible prediabetic risk markers in young Japanese men. AB - Serum profiles of lipids and/or liver enzymes are established markers for the estimation of insulin resistance and diabetic risk in the non-diabetic middle aged population. To identify prediabetic markers in young subjects, 110 young male subjects (20-29 years of age) with normal glucose tolerance (NGT) were divided into two groups by median body mass index (BMI), <22.18 (n=55) and >=22.18 (n=55) kg/m(2). Indices of insulin sensitivity including HOMA-IR and ISI composite, indices of beta-cell function including HOMA-beta, insulinogenic index (DeltaI(30)/DeltaG(30)) and DeltaI(30)/DeltaG(30)/ HOMA-IR were calculated. Statistical associations between these parameters and the serum lipid profiles and liver function were evaluated. Alanine aminotransferase (ALT), gamma glutamyltransferase (GGT), total cholesterol (TC) and triglyceride (TG) levels were inversely correlated with the ISI composite among individuals with BMI >=22.18 kg/m(2) but not those with BMI <22.18 kg/m(2). Multivariate regression analysis revealed that, in Group N, the plasma glucose levels at 60 min (PG(60)) were inversely correlated with the ISI composite and the insulinogenic index, and were positively correlated with the GGT, TC and TG levels. On the other hand, in Group L, PG(60) was correlated with the insulinogenic index, TC and TG levels. In conclusion, elevated levels of GGT, TC and TG are good clinical markers to predict diabetic risks, even in young NGT males. Of these, GGT was the most strongly related factor among subjects with relatively high BMI. PMID- 20953068 TI - Foreword to 4th International Conference on Whole-body Vibration Injuries held at Hilton Montreal Bonaventure Hotel, Montreal, Canada 2-4 June 2009. PMID- 20953069 TI - Relative contribution of translational and rotational vibration to discomfort. AB - Understanding how vibration affects discomfort is an important factor for improving work and travelling experience. Methods of evaluating health effects from whole-body vibration are closely linked to those for evaluating discomfort in ISO 2631-1. The standard includes a method to evaluate discomfort using twelve axes of vibration with a similar approach to that for evaluating health effects; thus using all twelve axes gives a possibility to evaluate both health and discomfort. The full 12-axis method has not been widely used in practice or validated in a multi-axis environment. The standard guidance is not explicit, thus different interpretations are possible especially when determining the method of comparing or combining vibration in different axes. Furthermore there are not enough studies conducted in multi-axis environments to suggest the optimal combination of axes. In this study ISO 2631-1 method was tested and optimised using a multi-axis test bench at Loughborough University, UK. Subjects were exposed to stimuli which represented vibration characteristics from field measurements. Each stimulus, lasting 15 s, was judged using a continuous judgement, cross-modal matching method. The seat translational and rotational and the backrest translational axes were used in the analyses. There was no vibration at the floor, in order to constrain the number of independent variables. Results showed that correlation for discomfort improved with more complex analysis procedures. However a good correlation was also achieved using just seat translational axes with optimised multiplying factors. The results showed that frequency weightings and r.m.s. averaging improved correlation between vibration and subjective ratings of discomfort. Multiplying factors specified in ISO 2631-1 degraded the correlation between objective and subjective measures of discomfort, therefore an improved set of factors were determined. The new factors showed improvement by placing more emphasis on seat fore-and-aft and lateral axes. PMID- 20953070 TI - Time domain detection of shocks and impacts in whole-body vibration. AB - A method for detecting shocks and impacts in whole-body vibration time histories has been developed that is suitable for implementation as a computer algorithm. The procedure consists of comparing the magnitudes of a higher-order mean value and the impulsiveness calculated for successive time segments of the acceleration time history. The indicators were the ratio of the 12th-order root mean value to the root mean square RMT/RMS, and the impulsiveness corresponding to a cumulative probability value of 0.97, I(0.97) (i.e., the magnitude of the positive and negative excursions exceeded 3% of the time divided by 2RMS). Both indicators have a value of 2.16 for random vibration with a Gaussian amplitude distribution, and deviate from this value when the motion possesses other characteristics. For seat motion in the Z-direction analyzed using frequency weighting W(b), and time segments of ~20 s, shocks and impacts could be identified when RMT/RMS >= 2.5, and I(0.97) <= 2.6. A subjective visual classification of 160 exposures to vibration recorded in a range of military vehicles operating under different conditions was performed by a jury of two observers. The subjective classification agreed with computer identification of shocks and impacts in 94% of the cases. PMID- 20953071 TI - Frequency weightings for fore-and-aft vibration at the back: effect of contact location, contact area, and body posture. AB - Fore-and-aft vibration of a backrest can influence discomfort and the risk of injury associated with whole-body vibration. Relevant standards (BS 6841:1987 and ISO2631-1:1997) recommend the W(c) frequency weighting for evaluating fore-and aft vibration of backrests, but do not specify the precise location for measuring vibration. This study determined equivalent comfort contours for fore-and-aft vibration of the backs of seated persons from 2 to 80 Hz using the method of magnitude estimation, examining the effect of input location, contact area, and body posture. The equivalent comfort contours indicate decreased sensitivity to vibration acceleration at frequencies greater than 8 Hz. Equivalent comfort contours with a full backrest were similar to those with contact at only the highest location on the back. The derived frequency weightings are broadly consistent with frequency weighting W(c) but suggest somewhat greater sensitivity at frequencies greater than 30 Hz and vary in shape with changes in vibration magnitude. It is concluded that with low and moderate magnitudes of vibration the severity of fore-and-aft vibration of a backrest can be assessed from the frequency-weighted fore-and-aft acceleration measured at the highest point of contact between the backrest and the body if the frequency weighting W(c) is employed in the evaluation. PMID- 20953072 TI - High cycle fatigue behaviour of functional spinal units. AB - Vibrations have been shown to be an important risk factor for spinal pathologies. The underlying mechanisms are poorly understood and in vivo data scarce and difficult to obtain. Consequently numerical models are used to estimate spinal loading; requiring fatigue strength information, which was obtained in this study for spinal specimens from young and old male donors of working age in vitro. Bone mineral density (BMD) and endplate area were determined using CT scans. Three groups were investigated: young specimens in neutral posture, young in flexed posture, and old in neutral posture. The loading consisted of 300,000 sinusoidal compression cycles of 2 kN, inducing a nucleus pressure peek of approximately 1.4 MPa. No failure of the young specimens in neutral posture was observed, but four specimens from older donors with low BMD failed. The product between endplate area and BMD was shown to be useful to predict fatigue strength for old donors and should therefore be considered with regard to whole body vibration injuries. In flexed posture, two specimens from young donors failed. One failure can be attributed to low BMD following the trend for the old specimens; the other failure could not be explained, leaving the influence of flexion yet unclear. PMID- 20953073 TI - Biodynamic response and spinal load estimation of seated body in vibration using finite element modeling. AB - Trunk biomechanical models play an indispensable role in predicting muscle forces and spinal loads under whole-body vibration (WBV) exposures. Earlier measurements on the force-motion biodynamic response (impedance, apparent mass) at the body seat interface and vibration transmissibility (seat to head) have led to the development of different mechanical models. Such models could simulate the overall passive response and serve as an important tool for vehicle seat design. They cannot, however, evaluate physiological parameters of interest under the WBV. On the contrary, anatomical models simulating human's physiological characteristics can predict activities in muscles and their dynamic effects on the spine. In this study, a kinematics-driven nonlinear finite element model of the spine, in which the kinematics data are prescribed, is used to analyse the trunk response in seated WBV. Predictions of the active model (i.e., with varying muscle forces) as compared with the passive model (i.e., with no muscle forces) compared satisfactorily with measurements on vertical apparent mass and seat-to head transmissibility biodynamic responses. Results demonstrated the crucial role of muscle forces in the dynamic response of the trunk. Muscle forces, while maintaining trunk equilibrium, substantially increased the compression and shear forces on the spine and, hence, the risk of tissue injury. PMID- 20953074 TI - Seat-to-head transfer function of seated men--determination with single and three axis excitations at different magnitudes. AB - Most research has investigated the seat-to-head transmissibility during single axis excitations. Associations between head accelerations and discomfort or effects on vision were reported. Possible differences between the seat-to-head transmissibility determined during different vibration magnitudes with a variable number of excitation axes have not been systematically examined. An experimental study was performed with 8 male subjects sitting on a rigid seat with hands on a support. They were exposed to random whole-body vibration (E1=0.45 ms(-2), E2=0.90 ms(-2), and E3=1.80 ms(-2)) to single- and three-axis vibration. All translational and rotational seat-to-head transmissibilities were calculated. The effects of the factors vibration magnitude and number of axes on the peak modulus and frequency of the seat-to-head transmissibilities were tested. In general the head motions follow constant pattern. These pattern of head motions comprise a combination of rotational and translational shares of transmissions, i.e. the curves show a dependence on the factors 'vibration magnitude' and 'number of vibration axes'. Mechanical properties of the soft tissue, relative motions of body parts, and muscle reactions were supposed to cause the nonlinearities of the head. Future research should consider effects of multi-axis vibration, if conclusions shall be drawn for the evaluation of possible health effects and model validations. PMID- 20953075 TI - A longitudinal study of low back pain and daily vibration exposure in professional drivers. AB - The aim of this study was to investigate the relation between low back pain (LBP) outcomes and measures of daily exposure to whole-body vibration (WBV) in professional drivers. In a study population of 202 male drivers, who were not affected with LBP at the initial survey, LBP in terms of duration, intensity, and disability was investigated over a two-year follow-up period. Vibration measurements were made on representative samples of machines and vehicles. The following measures of daily WBV exposure were obtained: (i) 8-h energy-equivalent frequency-weighted acceleration (highest axis), A(8)(max) in ms(-2) r.m.s.; (ii) A(8)(sum) (root-sum-of-squares) in ms(-2) r.m.s.; (iii) Vibration Dose Value (highest axis), VDV(max) in ms(-1.75); (iv) VDV(sum) (root-sum-of-quads) in ms( 1.75). The cumulative incidence of LBP over the follow-up period was 38.6%. The incidence of high pain intensity and severe disability was 16.8 and 14.4%, respectively. After adjustment for several confounders, VDV(max) or VDV(sum) gave better predictions of LBP outcomes over time than A(8)(max) or A(8)(sum), respectively. Poor predictions were obtained with A(8)(max), which is the currently preferred measure of daily WBV exposure in European countries. In multivariate data analysis, physical work load was a significant predictor of LBP outcomes over the follow-up period. Perceived psychosocial work environment was not associated with LBP. PMID- 20953076 TI - An evaluation of the methods for deriving representative frequency response functions of the human whole-body system. AB - The biodynamic response functions of the human whole-body system measured with subjects participating in an experiment are commonly arithmetically averaged and used to represent their mean response functions in many studies. The reported means were further averaged to form the reference means for standardization and various applications. The objectives of this study are to clarify whether this response-based averaging process could significantly misrepresent the characteristics of the original functions, and to explore appropriate methods for deriving representative functions. A set of reported mechanical-equivalent models for 12 subjects was used to derive the vertical and fore-and-aft cross-axis response functions expressed in apparent mass. The response-based average was directly compared with the response derived from a property-based derivation method. This study found that the response-based average could differ from the property-based mean response by more than 30%, especially in the fore-and-aft cross-axis response functions. This study also theoretically demonstrated that the discrepancies result from the non-linear relationship between the apparent mass and the properties of a dynamic system. Therefore, the discrepancies depend on the variability of the subjects' dynamic properties. Practically, the discrepancies in the vertical response could be reduced to an acceptable level (e.g., <10%) if a sufficient number of subjects with similar body weights are selected or grouped in the measurement. However, it is very difficult to reduce the discrepancies in the fore-and-aft cross-axis to such a level. While more demanding than the response-based method, the property-based method is theoretically more reliable for deriving the representative response functions for each axis. PMID- 20953077 TI - Long term WBV measurements on vehicles travelling on urban paths. AB - This paper describes the results of a long-term whole-body-vibration monitoring campaign performed on different cars with different drivers. The weighted and the un-weighted root-mean-square acceleration, the MTVV and the VDV have been monitored on five different cars in regular usage for over one hundred hours of measurements on urban roads and highways. The variability of the above parameters has been statistically analyzed in order to assess the time requested for the convergence of standard indexes to their average values. The aim is to supply a general reliability evaluation so as to minimize the on-field tests and to provide a scientific support to the design of such experiments. A comparison between different vehicles is presented and discussed; the correlation with speed measured by a GPS system is analyzed with probabilistic assessments. Results showed that the minimum time for reliable measurement was approximately 30 min for each driving condition (urban, carriage road, highway). The MTVV/a(w) ratio was usually larger than 1.5 (even on short measurement periods), thus indicating the unsuitability of the basic ISO 2631 criterion. The 8-h based VDV provided indications compatible with the a(v) criterion. PMID- 20953078 TI - Biodynamic responses of the seated human body to single-axis and dual-axis vibration. AB - Occupational exposures to vibration always involve multi-axis vibration. Since human responses to vibration are highly nonlinear and cross-coupled, it is to be expected that excitation in one axis will alter response to vibration in another axis. The purpose of this study was to investigate nonlinearity in the apparent masses of subjects seated without a backrest and exposed to single-axis and dual axis vertical and fore-and-aft excitation. The driving point apparent masses and cross-axis apparent masses in the two translational directions were measured with twelve subjects exposed to random vibration (0.2 to 20 Hz) in all 15 possible combinations of four vibration magnitudes (0, 0.25, 0.5, or 1.0 ms(-2) r.m.s.) in the fore-and-aft and vertical directions. With single-axis excitation (either fore-and-aft or vertical), the median in-line apparent mass exhibited a nonlinear characteristic in which the body softened with increasing magnitude of vibration. With dual-axis excitation, at all magnitudes of vertical excitation the resonance frequency in the vertical apparent mass reduced as the magnitude of fore-and-aft vibration increased, and at all except the greatest magnitude of fore-and-aft excitation the resonance frequency in the fore-and-aft apparent mass reduced as the magnitude of vertical vibration increased. The coherency between the fore-and aft acceleration and the fore-and-aft force was lowered by the addition of vertical excitation, and the coherency between the vertical acceleration and the vertical force was lowered by the addition of fore-and-aft excitation. The nonlinearity evident in both in-line apparent masses was also evident in the cross-axis apparent masses. It is concluded that with dual-axis excitation the fore-and-aft and vertical response of the seated human body is nonlinear, with resonance frequencies decreasing with increasing magnitude of vibration. Consequently, vibration in one axis (either fore-and-aft or vertical) affects the apparent mass of the body measured in the other axis (either vertical or fore-and aft). PMID- 20953079 TI - Assessment and prediction of whole-body vibration exposure in transport truck drivers. AB - The European Directive 2002/44/EC on the minimum Health and Safety prescriptions regarding the exposure of workers to vibrations, was implemented in Italy through the Legislative Decree 187/2005, recently amended by the Legislative Decree 81/2008. The Decrees contain legal obligations and minimum requirements for the evaluation by direct measurement, which is the reference method, although not always appropriate or necessary, and by means of vibration data banks or information provided by equipment manufacturers. The values assessed must be representative of the actual working environment: in order to adapt assessed values to real working conditions it may be useful to adopt some statistical models. Statistically significant relationships were observed by means of a multiple linear regression on a limited set of measures on different models of trucks, in different operating conditions and settings: the relative influence of predictor variables was then assessed. Finally a short digression about the evolution of the suspension fitting has been made in order to briefly describe the historical context of WBV exposure level reduction and the state of the art of industrial vehicle comfort improvement technologies. PMID- 20953080 TI - Assessing combined exposures of whole-body vibration and awkward posture--further results from application of a simultaneous field measurement methodology. AB - The drivers of ten vehicles (tram, helicopter, saloon car, van, forklift, two mobile excavators, wheel loader, tractor, elevating platform truck) were studied with regard to the combined exposures of whole-body vibration and awkward posture during occupational tasks. Seven degrees of freedom (DOFs), or body angles, were recorded as a function of time by means of the CUELA measuring system (Computer assisted registration and long-term analysis of musculoskeletal workloads) for the purpose of posture assessment. The vibrational exposure is expressed as the vector sum of the frequency-weighted accelerations in the three Cartesian coordinates; these were recorded simultaneously with the posture measurement. Based upon the percentage of working time spent under different workloads, a scheme is proposed for classification of the two exposures into three categories. In addition, a risk of adverse health effects classified as low, possible or high can be assigned to the combination of the two exposures. With regard to posture, the most severe exposure was measured for the drivers of the wheel loader and for the tractor driver, whereas the lowest exposure was measured for the helicopter pilots and van drivers. With regard to the combination of whole-body and posture exposures, the tractor driver and the elevating platform truck driver exhibited the highest workloads. PMID- 20953081 TI - A quasi-static discomfort measure in whole-body vibration. AB - A new methodology for objective evaluation of discomfort in whole-body vibration (WBV) is introduced in this work. The proposed objective discomfort characterizes discomfort based on the relative motion between adjacent segments of the human body from neutral positions. It peaks when the joints reach their limits. The objective discomfort has been tested on five subjects in the fore-aft direction using discrete sinusoidal frequencies of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 12, 14, and 16 Hz. Each frequency file runs for 15 s with a 3 s resting period as a reference for discomfort comparison. All files run at a constant acceleration of 0.7 m/s(2). The subjects were tested with back support and without back support, and their subjective discomfort was reported based on the Borg CR-10 scale. The proposed objective discomfort has shown significant correlation with the subjective discomfort. The objective discomfort has also been tested on five subjects under multiple-axis random WBV with three common industrial seating configurations (seat-mounted control, floor-mounted control, and steering wheel), and has shown promising results. PMID- 20953082 TI - A variable parameter single degree-of-freedom model for predicting the effects of sitting posture and vibration magnitude on the vertical apparent mass of the human body. AB - Models of the vertical apparent mass of the human body are mostly restricted to a sitting posture unsupported by a backrest and ignore the variations in apparent mass associated with changes in posture and changes in the magnitude of vibration. Using findings from experimental research, this study fitted a single degree-of-freedom lumped parameter model to the measured vertical apparent mass of the body measured with a range of sitting postures and vibration magnitudes. The resulting model reflects the effects of reclining a rigid backrest or reclining a foam backrest (from 0 to 30 degrees), the effects of moving the hands from the lap to a steering wheel, the effects of moving the horizontal position of the feet, and the effects of vibration magnitude (from 0.125 to 1.6 ms(-2) r.m.s.). The error between the modelled and the measured apparent mass was minimised, for both the apparent masses of individual subjects and the median apparent masses of groups of 12 subjects, for each sitting posture and each vibration magnitude. Trends in model parameters, the damping ratios, and the damped natural frequencies were identified as a function of the model variables and show the effects of posture and vibration magnitude on body dynamics. For example, contact with a rigid backrest increased the derived damped natural frequency of the principal resonance as a result of reduced moving mass and increased stiffness. When the rigid backrest was reclined from 0 to 30o, the damping decreased and the resonance frequency increased as a result of reduced moving mass. It is concluded that, by appropriate variations in model parameters, a single degree-of-freedom model can provide a useful fit to the vertical apparent mass of the human body over a wide range of postures and vibration magnitudes. When measuring or modelling seat transmissibility, it may be difficult to justify an apparent mass model with more than a single degree-of freedom if it does not reflect the large influences of vibration magnitude, body posture, and individual variability. PMID- 20953083 TI - Whole-body vibratory response study using a nonlinear multi-body model of seat occupant system with viscoelastic flexible polyurethane foam. AB - Vehicle occupants are exposed to low frequency vibrations with possible harmful effects such as mild discomfort, lower back pain, and even injury to the spine. Occupational drivers and operators of heavy machinery are exposed to significantly longer duration and higher levels of vibration. Thus, the modeling and prediction of biodynamic response of seated occupants to such vibrations is very important. Since the properties of seating foam affect the response of the occupant, there is need for good models of seat-occupant systems through which the effects of foam properties on the dynamic response can be directly evaluated. A nonlinear planar seat-occupant model which incorporates the nonlinear viscoelastic behavior of seating foam has been developed. This model is used to study response of the occupant to harmonic excitation applied at the seat base, in terms of the frequency response in vertical and fore-and-aft directions, the deflection shapes at resonance, as well as the seat-to-head-transmissibility. In addition, to better understand the role of flexible polyurethane foam in characterizing the system behavior, the response of a single-degree-of-freedom foam-block system is also studied. The effects of different masses riding on the foam block and undergoing vertical vibrations at different acceleration levels are also investigated. PMID- 20953084 TI - Influence of mono-axis random vibration on reading activity. AB - Recent studies on train passengers' activities found that many passengers were engaged in some form of work, e.g., reading and writing, while traveling by train. A majority of the passengers reported that their activities were disturbed by vibrations or motions during traveling. A laboratory study was therefore set up to study how low-frequency random vibrations influence the difficulty to read. The study involved 18 healthy male subjects of 23 to 32 yr of age group. Random vibrations were applied in the frequency range (1-10 Hz) at 0.5, 1.0 and 1.5 m/s(2) rms amplitude along three directions (longitudinal, lateral and vertical). The effect of vibration on reading activity was investigated by giving a word chain in two different font types (Times New Roman and Arial) and three different sizes (10, 12 and 14 points) of font for each type. Subjects performed reading tasks under two sitting positions (with backrest support and leaning over a table). The judgments of perceived difficulty to read were rated using 7-point discomfort judging scale. The result shows that reading difficulty increases with increasing vibration magnitudes and found to be maximum in longitudinal direction, but with leaning over a table position. In comparison with Times New Roman type and sizes of font, subjects perceived less difficulty with Arial type for all font sizes under all vibration magnitude. PMID- 20953085 TI - Influence of support conditions on vertical whole-body vibration of the seated human body. AB - The vibration transmission to the lumbar and thoracic segments of seated human subjects exposed to whole body vibration of a vehicular nature have been mostly characterised without the back and hand supports, which is not representative of general driving conditions. This non-invasive experimental study investigated the transmission of vertical seat vibration to selected vertebrae and the head along the vertical and fore-aft axes of twelve male human subjects seated on a rigid seat and exposed to random vertical excitation in the 0.5-20 Hz range. The measurements were performed under four different sitting postures involving combinations of back support conditions and hands positions, and three difference magnitudes of vertical vibration (0.25, 0.5 and 1.0 m/s(2) rms acceleration). The results showed significant errors induced by sensor misalignment and skin effects, which required appropriate correction methodologies. The averaged corrected responses revealed that the back support attenuates vibration in the vertical axis to all the body locations while increasing the fore-aft transmissibility at the C7 and T5. The hands position generally has a relatively smaller effect, showing some influences on the C7 and L5 vibration. Sitting without a back support resulted in very low magnitude fore-aft vibration at T5, which was substantially higher with a back support, suggestive of a probable change in the body's vibration mode. The effect of back support was observed to be very small on the horizontal vibration of the lower thoracic and lumbar regions. The results suggest that distinctly different target body-segment biodynamic functions need to be defined for different support conditions in order to represent the unique contribution of the specific support condition. These datasets may then be useful for the development of biodynamic models. PMID- 20953086 TI - Apparent mass and seat-to-head transmissibility responses of seated occupants under single and dual axis horizontal vibration. AB - The apparent mass and seat-to-head-transmissibility response functions of the seated human body are investigated under exposures to fore-aft (x), lateral (y), and combined fore-aft and lateral (x and y) axis whole-body vibration. The experiments were performed to study the effects of hands support, back support and vibration magnitude on the body interactions with the seat pan and the backrest, characterised in terms of fore-aft and lateral apparent masses and the vibration transmitted to the head under single and dual-axis horizontal vibration. The data were acquired with 9 subjects exposed to two different magnitudes of vibration applied along the individual x- and y- axis (0.25 and 0.4 m/s(2) rms), and along both the-axis (0.28 and 0.4 m/s(2) rms) in the 0.5 to 20 Hz frequency range, and analyzed to derive the biodynamic responses. A method was further derived to obtain total seated body apparent mass response from those measured at the backrest and the seatpan. The results revealed coupled effects of hands and back support conditions on the responses, while the vibration magnitude effect was relatively small. For a given postural condition, the biodynamic responses to dual-axis vibration could be estimated from the direct- and cross axis responses to single-axis vibration, suggesting weakly nonlinear behaviour. PMID- 20953087 TI - Design and evaluation of a suspension seat to reduce vibration exposure of subway operators: a case study. AB - Subway operators have complained about discomfort caused by whole-body vibration. To address this problem, a suspension seat with extensive ergonomic features has been adapted to the confined space of the subway operator cab. The suspension was modified from an existing suspension in order to reduce the dominant frequency of the subway vertical vibration (2.4 Hz). The suspension seat has been extensively tested on a vertical hydraulic shaker. These tests have shown that the SEAT value was lower for a higher vibration level, for higher subject weight, and for the suspension adjusted at median height. The seat also produces a lower SEAT value when there was a predominance of the 6 Hz vibration component. The horizontal seat adjustments had no influence on the suspension SEAT value. Removing the suspension damper also decreases the SEAT value for all the tested configurations. The final version of the suspension seat prototype was validated during normal subway operation with 19 different operators having weight in the 5th, 50th and 95th percentile of the operator population. Accelerations were measured with triaxial accelerometers at the seat cushion, above the suspension and on the floor. In addition to the vibration measurements, each operator was asked about his perceived discomfort from vibration exposure. Globally, the suspension seat attenuated the vertical vibration (SEAT values from 0.86 to 0.99), but discomfort due to amplification of the 2.4 Hz component occurred when the suspension height was adjusted at the minimum, even when the global weighted acceleration was lower (SEAT value < 1). These results suggest that in order to reduce the discomfort caused by whole-body vibration, the transmissibility of the seat should also be considered, in particular when there is a dominant frequency in the vibration spectra. PMID- 20953088 TI - Examination of the frequency-weighting curve for accelerations measured on the seat and at the surface supporting the feet during horizontal whole-body vibrations in x- and y-directions. AB - In a laboratory experiment, six male subjects were exposed to sinusoidal (0.8, 1.6, 3.15, 6.3 and 12.5 Hz) or random octave band-width white noise (mid frequencies identical to those of the sinusoidal vibrations) whole-body vibration in x- or y-directions, at six levels of magnitude (0.4, 0.8 and 1.6 m/s(2) r.m.s. non- and frequency-weighted) with two repetitions. In order to examine time effects, additional reference stimuli were used. Each subject was exposed to these 304 exposure conditions with a duration of about one minute on four different days (76 exposures per day). The subject's sensations of vibration intensity and vibration comfort were obtained by cross modality matching (length of a line). The subjects sat with an upright posture on a hard seat without backrest, hands on the thighs. The derived equivalent sensation contours suggest an underestimation of the sensation varying in extent from 2 dB to 8 dB at 1.6, 3.15, 6.3 and 12.5 Hz in comparison with the reference frequency 0.8 Hz for both types and directions of signals by the current evaluation methods according to ISO 2631-1 with the most pronounced effects revealed at the frequencies 3.15 and 6.3 Hz and at lower intensities (overall vibration total value a(ov) around 0.48 m/s(2) to 0.8 m/s(2) at the reference frequency 0.8 Hz). PMID- 20953090 TI - Association of cardiomegaly with coronary artery histopathology and its relationship to atheroma. AB - AIMS: Hypertrophied hearts at autopsy often display excessive coronary artery atherosclerosis, but the histopathology of coronary arteries in hearts with and without cardiomegaly has rarely been compared. METHODS: In this study, forensic autopsies provided hearts with unexplained enlargement plus comparison specimens. Right coronary artery was opened longitudinally and flattened for formalin fixation and H&E-stained paraffin sections were cut perpendicular to the endothelial surface. The micro-scopically observed presence or absence of a necrotic atheroma in the specimen was recorded. At multiple sites far removed from any form of atherosclerosis, measurements were taken of intimal thickness, numbers of smooth muscle cells (SMC) and their ratio, the thickness per SMC, averaged over the entire nonatheromatous arterial length. When the mean thickness per SMC exceeded a certain cutoff point, the artery was declared likely to contain a necrotic atheroma. RESULTS: The prevalence of specimens with necrotic atheromas increased stepwise with increasing heart weight, equally with fatal or with incidental cardiomegaly, and equally with hypertension- or obesity-related hypertrophy, rejecting further inclusion of appreciable age, race, or gender effects. The prevalence of specimens with thickness per SMC exceeding the cutoff point was almost always nearly identical to the prevalence of observed necrotic atheroma, showing the two variables to be tightly linked to each other with quantitative consistency across group comparisons of every form. CONCLUSIONS: In summary, cardiomegaly, irrespective of the specific cause, seems to accelerate the risk of atheromas, and to do so by first altering the arterial architecture, especially by increasing intimal thickness per SMC. PMID- 20953091 TI - Validity of self-reported height and weight in a Korean population. AB - BACKGROUND: Accessible public information on self-reported height and weight is not widely used in studies of obesity, mainly because of the questionable validity of body mass index (BMI) values calculated from these data. To assess the utility of self-reported measurement, we compared self-reported and standard measurements of height and weight in a Korean population that is leaner than Western populations. METHODS: A cross-sectional comparison of self-reported and measured height and weight was conducted among a population of participants in a cancer screening program. A total of 557 men and 1010 women aged 30 to 70 years were included in the current analysis. RESULTS: Self-reported height was higher than measured values in both men and women. Self-reported weight was higher than measured weight in women, but was not different in men. BMI calculated from measured values was higher than BMI derived from self-reported height and weight among men. Younger age was a predictor of accuracy in self-reported height, and higher weight and BMI were predictors of under-reporting of weight. The prevalence of obesity based on self-reported values was lower than the true prevalence of obesity. With respect to classifying individuals as obese, the specificity and sensitivity of BMI calculated from self-reported values were very high for both sexes. CONCLUSIONS: Self-reported height and weight were reasonably valid in this study population. PMID- 20953092 TI - Pichia porticicola sp. nov., a novel ascomycetous yeast related to Pichia acaciae isolated from galleries of ambrosia beetles in Japan. AB - Eleven strains of yeasts, isolated from galleries of ambrosia beetles in Japan, formerly identified as Pichia acaciae were found to have different sequences in the D1/D2 domain of the large subunit (LSU) rRNA gene. After detailed taxonomic studies including a DNA-DNA reassociation experiment, 11 strains were found to represent a novel species of the genus Pichia. It is described as Pichia porticicola sp. nov. (type strain NBRC 100302(T) = CBS 11715(T)). The eleven strains were isolated from various samples associated with different kinds of insects and trees which were collected in 11 prefectures, from the north to the south of Japan. This species might be a common species in galleries of ambrosia beetles in Japan. PMID- 20953093 TI - Candida potacharoeniae sp. nov. and Candida spenceri sp. nov., two novel galactose-containing ascomycetous anamorphic yeast species isolated in Thailand. AB - Fifteen strains of anamorphic yeasts isolated from various natural substrates collected in various places in Thailand were found to represent two novel species of anamorphic yeast genus Candida based on the sequence analysis of the D1/D2 domain of the large subunit rRNA genes, chemotaxonomic and conventional properties used for the classification of yeasts. These strains are located in the clade including Candida etchellsii and Candida magnoliae. Fourteen strains represented by ST-490(T) (BCC 15176(T)=NBRC 106439(T)= CBS 11674(T)) are closely related to Candida sorbosivorans in the D1/D2 sequences but 11 nucleotides (2.4%) were substituted. The remaining strain, ST-594(T) (=BCC 15278(T)=NBRC 106446(T)=CBS 11673(T)) showed a close relationship to Candida geochares but 21 nucleotides (4.7%) were substituted. Apparently, these strains represent two novel Candida species of the Starmerella clade. The two species are described as Candida potacharoeniae sp. nov. and Candida spenceri sp. nov. in the present paper. Like the most species of this clade, the two species contain galactose in the cells in addition to glucose and mannose and have high mol% G + C of 54.4 55.9 and 54.9, respectively. PMID- 20953094 TI - Role of bottom-fermenting brewer's yeast KEX2 in high temperature resistance and poor proliferation at low temperatures. AB - Variants of bottom-fermenting brewer's yeast that grew at high temperatures and showed poor proliferation and fermentation at low temperatures were isolated. Similar variants of laboratory yeast were also isolated and found to be incapable of mating. The KEX2 gene was cloned by complementation. It was shown to be responsible for these traits, because a KEX2 disruptant of Saccharomyces cerevisiae (S. cerevisiae) laboratory yeast grew poorly at low temperatures and was resistant to high temperatures. In addition, a Saccharomyces bayanus (S. bayanus)-type KEX2 (Sb-KEX2) disruptant of bottom-fermenting brewer's yeast grew poorly at low temperatures and was resistant to high temperatures. The KEX2 gene product plays an important role in proliferation of yeast at low temperatures, which is an important trait of bottom-fermenting brewer's yeast. These findings advance our understanding of the proliferation of yeast at low temperatures, especially that of bottom-fermenting brewer's yeast. PMID- 20953095 TI - Description of Ectothiorhodospira salini sp. nov. AB - Strain JA430(T) is a Gram-negative, vibrioid to spiral shaped phototrophic purple sulfur bacterium isolated from anoxic sediment of a saltern at Kanyakumari in a mineral salts medium that contained 2% NaCl (w/v). Strain JA430(T) grows optimally at 5-6% NaCl and tolerates up to 12% NaCl. Intracellular photosynthetic membranes were of the lamellar type. Bacteriochlorophyll a and carotenoids of the spirilloxanthin series are present as photosynthetic pigments. Major cellular fatty acids are C(18:1)omega7c, C(16:0), C(19:0)cycloomega8c and C(16:1)omega7c/C(16:1)omega6c. Strain JA430(T) exhibits photoorganoheterotrophy and chemoorganoheterotrophy and requires para-aminobenzoic acid, pantothenate and pyridoxal phosphate for growth. Phylogenetic analysis on the basis of 16S rRNA gene sequence analysis showed that strain JA430(T) forms monophyletic group in the genus Ectothiorhodospira. The highest sequence similarity for strain JA430(T) was found with the type strains of Ectothiorhodospira variabilis DSM 21381(T) (96.1%) and Ectothiorhodospira haloalkaliphila ATCC 51935(T) (96.2%). Morphological and physiological characteristics discriminate strain JA430(T) from other species of the genus Ectothiorhodospira, for which we describe this as a novel species, Ectothiorhodospira salini sp. nov. ( = NBRC 105915(T) = KCTC 5805(T)). PMID- 20953096 TI - Unique profiles of changes in cell membrane fluidity during ethanol-induced yeast to-pseudohyphal transition in Candida tropicalis. AB - A dimorphic transition from the yeast form to filamentous one in Candida tropicalis pK233 is triggered by the addition of ethanol into the glucose semi defined liquid medium and the process of filamentation accompanies temporal depolarization of yeast cells. The transition is completely prevented by further supplementation of myo-inositol at the start of cultivation. The addition of ethanol caused an increase in membrane fluidity during the process of depolarization, and then fluidity was gradually lowered to the level equivalent with that of the stationary-phase yeast cells in accordance with filamentation. The increase in membrane fluidity of ethanol-induced cells appeared parallel with reduction in the content of membrane phosphatidylinositol, which was rich in saturated palmitic acid. Introduction of exogenous myo-inositol or 1 M sorbitol into the ethanol-supplemented culture at the start of cultivation restored yeast growth and the reduction of membrane fluidity occurred, coupled with the recovery of the phosphatidylinositol content. PMID- 20953097 TI - Engineered ACC deaminase-expressing free-living cells of Mesorhizobium loti show increased nodulation efficiency and competitiveness on Lotus spp. AB - Ethylene inhibits the establishment of symbiosis between rhizobia and legumes. Several rhizobia species express the enzyme ACC deaminase, which degrades the ethylene precursor 1-cyclopropane-1-carboxilate (ACC), leading to reductions in the amount of ethylene evolved by the plant. M. loti has a gene encoding ACC deaminase, but this gene is under the activity of the NifA-RpoN-dependent promoter; thus, it is only expressed inside the nodule. The M. loti structural gene ACC deaminase (acdS) was integrated into the M. loti chromosome under a constitutive promoter activity. The resulting strain induced the formation of a higher number of nodules and was more competitive than the wild-type strain on Lotus japonicus and L. tenuis. These results suggest that the introduction of the ACC deaminase activity within M. loti in a constitutive way could be a novel strategy to increase nodulation competitiveness of the bacteria, which could be useful for the forage inoculants industry. PMID- 20953098 TI - Asaia astilbes sp. nov., Asaia platycodi sp. nov., and Asaia prunellae sp. nov., novel acetic acid bacteria isolated from flowers in Japan. PMID- 20953099 TI - Characterization of Staphylococcus aureus derived from bovine mastitis and isolation of two lytic bacteriophages. PMID- 20953100 TI - Discrimination of Saccharomyces cerevisiae and Saccharomyces paradoxus strains by the SUC2 gene sequences. PMID- 20953101 TI - [A fundamental study of non-contrast enhanced MR angiography using ECG gated-3D fast spin echo at 3.0 T]. AB - Contrast-enhanced magnetic resonance angiography (CE-MRA) is frequently performed in body and extremity studies because of its superior ability to detect the vascular stenosis. However, nephrotoxicity of the contrast medium has been emphasized in recent years. Non-contrast MRA using the three-dimensional electrocardiogram-synchronized fast spin echo method (FBI, NATIVE and TRANCE) is recommended as a substitute for CE-MRA. There are a few reports in the literature that evaluate the detectability of vascular stenosis using non-contrast MRA on 3.0 T MRI. The purpose of this study was to evaluate the detectability of vascular stenosis using non-contrast MRA at 3.0 T with an original vascular phantom. The vascular phantom consisted of silicon tubes. 30% and 70% stenosis of luminal diameter were made. Each silicon tube connected a pump producing a pulsatile flow. A flowing material to was used in this study to show the similarity of the intensity to blood on MRI. MRA without a contrast medium (NATIVE sequence) were performed in the vascular phantom by changing the image matrix, static magnetic field strength and flow velocity. In addition, the NATIVE sequence was used with or without flow compensation. Vascular stenosis was quantitatively estimated by measurement of the signal intensities in non-contrast MRA images. MRA with NATIVE sequence demonstrated an accurate estimation of 30% vascular stenosis at slow flow velocity. However, 30% stenosis was overestimated in cases of high flow velocity. Estimation was improved by using a flow compensation sequence. 70% stenosis was overestimated on MRA with NATIVE sequence. Estimation of 70% stenosis was improved by using a flow compensation sequence. Accurate estimation of vascular stenosis in MRA with a NATIVE sequence is improved by using the flow compensation technique. MRA with NATIVE sequence is considered to be a promising method for the evaluation of patients with severe renal dysfunction as a substitute for CT angiography or CE-MRA. PMID- 20953102 TI - [Utility of noise addition image made by using water phantom and image addition and subtraction software]. AB - In optimizing exposures, it is very important to evaluate the impact of image noise on image quality. To realize this, there is a need to evaluate how much image noise will make the subject disease invisible. But generally it is very difficult to shoot images of different quality in a clinical examination. Thus, a method to create a noise addition image by adding the image noise to raw data has been reported. However, this approach requires a special system, so it is difficult to implement in many facilities. We have invented a method to easily create a noise addition image by using the water phantom and image add-subtract software that accompanies the device. To create a noise addition image, first we made a noise image by subtracting the water phantom with different SD. A noise addition image was then created by adding the noise image to the original image. By using this method, a simulation image with intergraded SD can be created from the original. Moreover, the noise frequency component of the created noise addition image is as same as the real image. Thus, the relationship of image quality to SD in the clinical image can be evaluated. Although this method is an easy method of LDSI creation on image data, a noise addition image can be easily created by using image addition and subtraction software and water phantom, and this can be implemented in many facilities. PMID- 20953103 TI - [Use experience and problems in the optimization of intensity modulated radiation therapy (IMRT)--Focus on head & neck]. AB - We present the main points of the optimization in IMRT. The skin surface of the planned target volume was reduced by a few millimeters, in view of the limitations of a calculation grid in accurately estimating the influence of build up or contamination of electrons. Air cavities such as nasal or oral cavities were, in general, filled with water equivalent density in the dose calculation. Planned target volume was contracted by 5 mm when PTV of a higher prescribed dose was delineated adjacent to it. The 5 mm width of ring-shaped ROI was set at 5 mm outside of the entire PTV to eliminate hot spots. Physical quality assurance is extremely important to eradicate unexpected dose inhomogeneity, and meticulous efforts are required. PMID- 20953104 TI - [A system of setting exposure conditions in general X-rays using a calculating formula]. AB - The purpose of this study was to determine the exposure conditions for general X rays by calculation. The concept of the basic equation for the calculation is that the dose after transmitting an object is determined by entering the exposure conditions. For this purpose, we formulated a basic equation by mathematically representing all factors that influence imaging conditions. Using the basic equation, we succeeded in determining the optimal exposure condition for a patient's body thickness by calculation. Even if another equipment, grid, added filter, etc., is used, optimal exposure conditions can be determined by adding correction factors determined by simple added measurements; this confirmed the versatility of the system. The calculation accuracy was verified to be within 15%. By using this system, we succeeded in optimizing exposure conditions for general X-rays. PMID- 20953105 TI - [Visualization of stenosis in vascular access by bubble method under carbon dioxide (CO2) angiographic procedures]. AB - A percutaneous transvascular angioplasty (PTA) is performed to relieve failed vascular access for hemodialysis. Angiography using non-ionic iodinated contrast media is the imaging modality of choice for performing PTA. However, the use of iodinated contrast media is contraindicated for patients with a history of iodine allergy. Since 1920, carbon dioxide (CO(2)) has been used as a safe contrast medium in various studies. In CO(2) shunt angiography for hemodialysis, visualization of the vascular structures was often suboptimal due to shunt specific conditions, such as rapid flow and narrow diameter of the vessels. In the present report, we attempted an improvement of the visualization by injection of CO(2) bubbles in view of the properties of CO(2) (floating and low viscosity). The results indicated that the CO(2) bubbles angiography clearly demonstrated the narrow vessels and stenotic portions that were not visualized by conventional CO(2) angiography. In addition, the required volume of CO(2) could be reduced in comparison with previous studies in the literature. Therefore, the method seemed to be effective in reducing exposure and preventing complication by CO(2). Thus, CO(2) bubbles angiography may be useful for shunt angiography and sequential angioplasty when experiencing shunt problems. PMID- 20953106 TI - [Estimation of exposure dose on MDCT examination--the measurement of organ dose and effective dose by anthropomorphic phantom]. AB - In order to evaluate the exposure dose in CT examinations, we measured the tissue and organ doses by test site in 4-row, 16-row, and 64-row multi detector CT by using an anthropomorphic phantom and fluorescent glass dosimeters. Furthermore, we calculated the effective dose by using the tissue weighting factor recommended by the ICRP in 2007. The effective dose in the head and neck examinations was 1.4 3.1 mSv, whereas the maximum skin dose was 278.9 mGy in head perfusion CT. The effective dose in examinations of the body trunk was 10.1-35.2 mSv. In addition, the organ dose and skin dose in the scanning range was similar to the CTDI(vol) in head and neck examinations, while it was higher than the CTDI(vol) in examinations of the body trunk. The exposure dose of patients undergoing CT is high in comparison to other radiological examinations. As a result, due to consecutive examinations, an absorbed dose of more than 100 mGy is possible. A future problem therefore remains how to lower the overall exposure dose with the introduction of new radiographic diagnostic modalities, such as phase scan or coronary CT angiography. PMID- 20953107 TI - [A survey of medical information education in radiological technology schools]. AB - The purpose of this study was to clarify actual conditions and problems in medical information education and to propose the educational concept to be adopted in medical information. A questionnaire survey was carried out by the anonymous method in June 2008. The survey was intended for 40 radiological technology schools. The questionnaire items were as follows: (1) educational environment in medical information education, (2) content of a lecture in medical information, (3) problems in medical information education. The response rate was 55.0% (22 schools). Half of the responding schools had a laboratory on medical information. Seventeen schools had a medical information education facility, and out of them, approximately 50% had an educational medical information system. The main problems of the medical information education were as follows: (a) motivation of the students is low, (b) the educational coverage and level for medical information are uncertain, (c) there are not an appropriate textbook and educational guidance. In conclusion, these findings suggest that it is necessary to have a vision of medical information education in the education of radiological technologists. PMID- 20953108 TI - [Examination of safety improvement by failure record analysis that uses reliability engineering]. AB - How the maintenance checks of the medical treatment system, including start of work check and the ending check, was effective for preventive maintenance and the safety improvement was verified. In this research, date on the failure of devices in multiple facilities was collected, and the data of the trouble repair record was analyzed by the technique of reliability engineering. An analysis of data on the system (8 general systems, 6 Angio systems, 11 CT systems, 8 MRI systems, 8 RI systems, and the radiation therapy system 9) used in eight hospitals was performed. The data collection period assumed nine months from April to December 2008. Seven items were analyzed. (1) Mean time between failures (MTBF) (2) Mean time to repair (MTTR) (3) Mean down time (MDT) (4) Number found by check in morning (5) Failure generation time according to modality. The classification of the breakdowns per device, the incidence, and the tendency could be understood by introducing reliability engineering. Analysis, evaluation, and feedback on the failure generation history are useful to keep downtime to a minimum and to ensure safety. PMID- 20953109 TI - [Philosophy and guide for achieving successful academic research]. PMID- 20953110 TI - [Security infrastructure for health information]. PMID- 20953111 TI - [Educational lecture: Clinical significance of cerebral circulation]. PMID- 20953112 TI - [Detective quantum efficiency (DQE) and noise-equivalent number of quanta (NEQ)]. PMID- 20953113 TI - [Experiment-research methodology]. PMID- 20953114 TI - [Adjustment of image processing parameters of REGIUS]. PMID- 20953115 TI - [How to use DICOM image communication tool by the personal computer--network communication is analyzed using command prompt and WIRESHARK]. PMID- 20953116 TI - [Quality assurance guideline for medical imaging display systems: Japan Industries Association of Radiological Systems Standards JESRA X-0093*A-2010]. PMID- 20953117 TI - Loss of productivity due to depression among Korean employees. AB - OBJECTIVES: The aim of this study was to investigate the difference in productivity between those who are depressed and those who are not. METHODS: A cross-sectional study of depressive and non-depressive employees at a workplace was performed. Data was collected between April and June 2008 through self reported questionnaires including the Stanford Presenteeism Scale. One thousand employees participated in this study. Inappropriate responses including missing data or non-relevant responses were excluded. Finally, data of 612 subjects was analyzed using the SPSS program. RESULTS: The productivity of employees with depression was lower than that of employees without depression. The difference in productivity loss due to impaired presenteeism was significantly different between the two groups, but the productivity loss due to absenteeism was not. CONCLUSIONS: From the results of this study, we can deduce that depression among employees leads to productivity loss. Therefore, we must consider the management of depression in the workplace and improve the activities of occupational nurses and doctors during the mental health screening of employees. PMID- 20953118 TI - Toxicokinetics and metabolism deteriorated by acute nephrotoxicity after a single intravenous injection of hydrofluoric acid in rats. AB - OBJECTIVES: This study was designed to investigate the early dynamic state of hydrofluoric acid (HFA) in blood and urine as a model of accidental occupational exposure to a subtoxic dose of HFA. It was also aimed at determining the relationship between the kinetics and harmful effects of HFA on the kidney. METHODS: Rats received a single intravenous injection of HFA (3.2, 6.4, or 9.6 (LD(5)) mg/kg) or saline. The volume of each injection was 1 ml and the concentrations of HFA were 0.1, 0.2, and 0.3%, respectively. Ionized fluoride (F) was measured for the biological monitoring of HFA. Serum F concentrations were determined at 0, 5, 10, 30, 60, 120, and 300 min. Pharmacokinetic parameters were calculated with two-compartment modeling. Urine was directly collected from bladder for 300 min to determine the extent of the renal damage. RESULTS: AUC(0 >300) values were significantly higher in the 9.6 mg/kg group than in the 3.2 and 6.4 groups. The total body clearance, V(1), V(2) and V(ss) were significantly lower in the 6.4 and 9.6 mg/kg groups than in the 3.2 mg/kg group. These results indicate that HFA was retained in blood. This could be a result of renal dysfunction. NAG/Cr and glucose excretion amount in urine were increased, and the clearance rate of F, urine volume and excretion amounts of electrolytes were decreased in the 9.6 mg/kg group compared with the saline group. These findings indicate renal tubular damage and a decrease in the amount of excretion of HFA from the kidney. CONCLUSIONS: We consider that acute nephrotoxicity of HFA caused renal injury, and the harmful effects of HFA were subsequently aggravated by its delayed metabolism. PMID- 20953119 TI - MicroRNAs and their therapeutic potential for human diseases: microRNAs, miR-143 and -145, function as anti-oncomirs and the application of chemically modified miR-143 as an anti-cancer drug. AB - We examined the expression levels of microRNAs (miRNAs; miRs) in colorectal tumors (63 cancer specimens and 65 adenoma specimens) compared to adjacent non tumorous tissues. Decreased expression of miR-143 and -145 was frequently observed in the adenoma and cancer samples. As the down-regulation of miR-143 and -145 was observed even in the early phase of adenoma formation, their decreased expression would appear to contribute mainly to the initiation of tumorigenesis. For clinical application, we added aromatic benzene-pyridine (BP-type) analogs to the 3'-overhang region of the RNA-strand and changed the sequences of the passenger strand in the miR-143 duplex (miR-143BPs), leading to greater activity and increased resistance to nuclease. The cell growth inhibitory effect of the chemically modified miR-143BPx in vitro was greater than that of the endogenous miR-143. The modified miR-143BPx showed a significant tumor-suppressive effect on xenografted tumors of human colorectal cancer DLD-1 cells. These findings suggest that miR-143 and -145 are important onco-related genes for the initiation of colorectal tumor development and that chemically modified miR-143BPx may be a candidate for an RNA medicine for the treatment of colorectal tumors. PMID- 20953120 TI - MicroRNAs and their therapeutic potential for human diseases: aberrant microRNA expression in Alzheimer's disease brains. AB - MicroRNAs (miRNAs) are a group of small noncoding RNAs that regulate translational repression of multiple target mRNAs. The miRNAs in a whole cell regulate greater than 30% of all protein-coding genes. The vast majority of presently identified miRNAs are expressed in the brain in a spatially and temporally controlled manner. They play a key role in neuronal development, differentiation, and synaptic plasticity. However, at present, the pathological implications of deregulated miRNA expression in neurodegenerative diseases remain largely unknown. This review will briefly summarize recent studies that focus attention on aberrant miRNA expression in Alzheimer's disease brains. PMID- 20953121 TI - MicroRNAs and their therapeutic potential for human diseases: MiR-133a and bronchial smooth muscle hyperresponsiveness in asthma. AB - MicroRNAs (miRNAs) play important roles in normal and diseased cell functions. The small-GTPase RhoA is one of the key proteins of bronchial smooth muscle (BSM) contraction, and an upregulation of RhoA has been demonstrated in BSMs of experimental asthma. Although the mechanism of RhoA upregulation in the diseased BSMs is not fully understood, recent observations suggest that RhoA translation is controlled by a miRNA, miR-133a, in cardiomyocytes. Similarly, in human BSM cells (hBSMCs), our recent studies revealed that an upregulation of RhoA was induced when the function of endogenous miR-133a was inhibited by its antagomir. Treatment of hBSMCs with interleukin-13 (IL-13) caused an upregulation of RhoA and a downregulation of miR-133a. In a mouse model of allergic bronchial asthma, increased expression of IL-13 and RhoA and the BSM hyperresponsiveness were observed. The level of miR-133a was significantly decreased in BSMs of the diseased animals. These findings suggest that RhoA expression is negatively regulated by miR-133a in BSMs and that the miR-133a downregulation causes an upregulation of RhoA, resulting in an augmentation of the contraction. MiR-133a might be a key regulator of BSM hyperresponsiveness and provide us with new insight into the treatment of airway hyperresponsiveness in asthmatics. PMID- 20953122 TI - MicroRNAs and their therapeutic potential for human diseases: preface. PMID- 20953123 TI - Hydrophobic silicone elastomer chamber for recording trajectories of motile porcine sperms without adsorption. AB - Motile porcine sperms adhere to hydrophilic materials such as glass and plastics. The adsorption of sperms to a hydrophobic poly(dimethylsiloxane) (PDMS) membrane is less compared with that to glass. We investigated the linear velocity (LV) and amplitude of lateral head displacement (ALHD) of motile porcine sperm on glass and PDMS preparations using computer-assisted sperm analysis (CASA). Significant decreases were observed in the 15-min LV (P<0.05) and ALHD (P<0.05) in motile porcine sperm on glass preparations compared with those on PDMS preparations. These differences were due to adsorption of the head and/or neck to hydrophilic substrates. Because of the elasticity of PDMS, we propose that a PDMS membrane should be used for CASA. To investigate the dynamics of motile porcine sperms with microfluidics, we do not recommend plasma treatment to bond PDMS and glass in the microchannel preparation; instead, we suggest that a PDMS molding process without plasma treatment be used for preparation of microfluidic channels. PMID- 20953124 TI - Relationships between uterine blood flow, peripheral sex steroids, expression of endometrial estrogen receptors and nitric oxide synthases during the estrous cycle in mares. AB - The objective of this study was to investigate the relationships between uterine perfusion and estrogen, progesterone and the uterine nitric oxide synthase (NOS) system in five trotter mares during the estrous cycle. Color Doppler sonography for measurement of uterine blood flow and collection of blood for determination of plasma estrogen and progesterone concentrations were performed on days 0 (= ovulation), 1, 5, 11 and 15 and daily during estrus (days -1 to -4) of one estrous cycle; endometrial biopsy collection for mRNA expression analysis of NOS and estrogen receptors was performed on days 0, 1, 5, 11, 15 and -3. Blood flow in each uterine artery was assessed by calculating the mean time-averaged maximum velocity (TAMV) and the pulsatility index (PI). Plasma concentrations of estrogen and progesterone were determined using specific enzyme immunoassays. The mRNA expressions of endothelial NOS (eNOS), inducible NOS (iNOS) as well as estrogen receptors alpha (ERalpha) and beta (ERbeta) were quantified using reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. The TAMV and PI had a biphasic pattern during the estrous cycle (P<0.05), with maximum and minimum, respectively, values on days 5 and -4. Estrogen receptor mRNA concentrations increased significantly during days 15 (ERalpha) and -3 (ERbeta). Transcript expression of eNOS, but not iNOS, had a biphasic pattern during the cycle (P<0.05) with maximum levels on days 5 and -3 and correlated positively with TAMV (r=0.81, P=0.05). We infer that the uterine NOS system, especially eNOS, plays an important role in the regulation of uterine blood flow during the estrous cycle in mares. PMID- 20953125 TI - Usage of analgesic in a murine model infected latently with pseudorabies virus. AB - Butorphanol tartrate (BT) was injected into mice before injection with acetylcholine in a murine model infected latently with pseudorabies virus. The analgesic effect and its influence on virus reactivation were observed. Mice preinjected with BT showed suppression of screaming, moving and excitation and the same level of movement after excitation as mice injected with PBS. In the group injected with BT i.p., one mouse died and another developed diarrhea with increased virus excretion. These results showed that BT has analgesic effects by both injection routes, s.c. and i.p.; however, BT induced death as a side effect, especially with i.p. injection. The injection route for BT should therefore be investigated further. PMID- 20953126 TI - Radiofrequency radiation at 40 kHz induces hepatic injury in Long-Evans Cinnamon (LEC) rats, an animal model for human Wilson disease. AB - In the present study, we examined effects of radiofrequency (RF) radiation at 40 kHz on hepatic injury in Long-Evans Cinnamon (LEC) rats, an animal model for human Wilson disease, which is a heritable disease of copper metabolism in the liver. The activities of ALT and AST in serum of LEC rats exposed to RF radiation for 2 weeks were approximately 3.8-fold and 2-fold higher than those in serum of sham-exposed rats, respectively. Although there were no significant differences in hepatic copper contents between LEC rats exposed to RF radiation for 2 weeks and sham-exposed rats, copper contents in the kidney and serum of exposed LEC rats were approximately 4.2-fold and 12.9-fold higher than those in sham-exposed rats, respectively. Relative O2--scavenging activities in the S-100 fraction of the liver of LEC rats exposed to RF radiation for 2 weeks were 1.6-fold higher than those in sham-exposed rats. No significant differences were observed in activities of AST and ALT in serum and relative O2--scavenging activity in the S 100 fraction of the liver of normal control WKAH rats that were sham-exposed and exposed to RF radiation. No significant differences were observed in copper contents in the liver, kidney and serum of WKAH rats that were sham-exposed and exposed to RF radiation for 2 weeks. The results show that RF radiation at 40 kHz induced hepatic injury in LEC rats. PMID- 20953127 TI - Congenital cutaneous fibropapillomatosis with no evidence of papillomavirus infection in a piglet. AB - Multiple yellowish-white, cauliflower-like mass lesions on the skin of the head and back in a 4-month-old piglet were pathologically examined. These lesions had developed before the weaning period. Histologically, the cutaneous neoplasms were characterized by papillary outgrowth of connective tissue covered by thick epidermis. Hyperplasia of the epidermis was corresponded with proliferation of capillaries, lympho-plasmacytic infiltration, and proliferation of fibroblasts in the dermal stroma. There were no inclusion bodies and significant degeneration in the keratinocytes. Papillomavirus antigen and DNA were not detected in these lesions by immunohistochemistry and polymerase chain reaction, respectively. Accordingly, the fibropapillomatosis of the present case might be hamartomatous rather than infectious. PMID- 20953128 TI - Footpad dermatitis in broiler chickens in Japan. AB - The prevalence of footpad dermatitis (FPD) in broiler chickens in Japan was investigated. In the first examination at slaughterhouses, lesions were commonly observed on the footpads of a total of 8,985 broiler chickens from 45 flocks on 36 farms. In 3 flocks, all the birds examined had lesions. In the other 42 flocks, the incidence of FPD ranged from 31.9% (81/254) to 99.5% (1/222). The footpad lesions were classified into 4 categories according to the severity of dermatitis as follows; score 0, 1,181 birds (13.1%); score 1, 2,992 birds (33.3%); score 2, 3,000 birds (33.4%); and score 3, 1,812 birds (20.2%). The mean scores of the flocks varied widely from 0.31 to 2.69. Males had higher mean scores than females. No significant differences were found between the mean scores of birds reared in windowless houses and those in open-sided houses. On 4 farms, the investigation was carried out in different seasons, and 3 of them showed higher mean scores in winter than in summer. Next, observation of 2,255 birds from 15 flocks on 5 farms during a 4-week rearing period revealed that FPD was already produced at 7 days of age and worsened with age. PMID- 20953129 TI - Contribution of enhanced efflux to reduced susceptibility of Salmonella enterica serovar Choleraesuis to fluoroquinolone and other antimicrobials. AB - We examined antimicrobial susceptibility and efflux systems in laboratory-derived mutants of Salmonella enterica serovar Choleraesuis selected by culture on fluoroquinolone-containing plates. The mutants exhibited decreased susceptibilities to quinolones and several other antimicrobials. Mutations in the gyrA gene were not always found in the mutants. Accumulation assays revealed that intracellular enrofloxacin concentrations were significantly lower in the mutants compared with parent isolates. Increased expression of acrB mRNA can explain the decreased susceptibilities to several antimicrobials but not in the case of carbonyl cyanide m-chlorophenylhydrazone (CCCP). Decreased susceptibility to CCCP may result from the increased expression of emrA mRNA. These results suggest that the enhancement of multiple efflux pumps is responsible for decreased susceptibilities to several antimicrobials in the laboratory-derived mutants. PMID- 20953130 TI - Immunohistochemical study on the secretory host defense system of bactericidal peptides in rat digestive organs. AB - To clarify the fundamental regulation mechanism against indigenous bacterial proliferation in the alimentary tract, we immunohistochemically examined the localization of 4 bactericidal peptides (BP) in the rat digestive exocrine glands. In the upper alimentary tract, lysozyme was detected in the gustatory, extraorbital lacrimal and parotid glands. Secretory phospholipase A2 (sPLA2) was detected in the extraorbital lacrimal glands. beta-defensin1 was detected in the gustatory and extraorbital lacrimal glands. beta-defensin2 was detected in the Harderian glands. In the stomach, beta-defensins were detected in the gastric superficial epithelial cells. In the small and large intestines, only lysozyme and sPLA2 were detected in the Paneth cells. In the cecum, all 4 BP were detected in the middle to apical portions of the crypts, and only sPLA2 was detected in the basal portion. No BP were localized in other exocrine glands associated with the alimentary tract. In addition, all 4 BP were also detected in the columnar epithelial cells of the apical portions of intestinal villi. In the intestinal superficial epithelial cells, lysozyme and beta-defensins were detected in the ascending colon, whereas only beta-defensin1 was detected in the descending colon and rectum. These results suggest that BP are mainly secreted from exocrine tissues in the initial portion of the digestive tract and play a role in host defense against indigenous bacteria throughout the digestive tract. Part of the BP in the chyme might be absorbed by the epithelium at the most inner sites of mucosae in the small and large intestines. PMID- 20953131 TI - Isolation of Staphylococcus aureus from raw fish in relation to culture methods. AB - Five hundred and fifty fish samples from various stages in the course of distribution in Hyogo Prefecture (209 retailed in super markets, 173 obtained from fishery cooperatives at a harbor, 91 caught by trawling and 77 caught by rod fishing) were examined for contamination with Staphylococcus aureus (S. aureus). S. aureus was detected in 41 (19.6%) of the retail fish samples and 46 (26.6%) of the samples from the fishery cooperatives. No S. aureus was isolated from the live fish (91 trawled and 77 fished by rod). With regard to the retail fish, the contamination rate of processed fish (26.0%) was significantly higher than that of unprocessed fish (14.2%). For 88 samples, the efficacy of the selective medium was compared using Baird-Parker agar and mannitol salt agar supplemented with egg yolk (MSEY agar) by the direct plate and enrichment culture methods. Using the direct culture method, the S. aureus positive rate with the Baird-Parker agar (30.7%) was significantly higher (P<0.01) than that with the MSEY agar (6.8%). The enrichment culture method remarkably raised the S. aureus detection rate. Seventy-eight (85.7%) of 91 isolates belonged to the human ecovar. Sixty-two (68.1%) of the 91 isolates had some enterotoxin genes, including 44 (48.4%) with the sea gene. These data showed that the fish were contaminated with S. aureus after landing and that Baird-Parker agar had an advantage in detecting S. aureus with a direct plate culture. PMID- 20953132 TI - Natural occurrence of grape poisoning in two dogs. AB - Clinical grape poisoning in two dogs (a 1.6-year-old male Shih Tzu and a 5-year old female Yorkshire Terrier) was described in the present study. Clinical signs included decreased urine output in the Shih Tzu and ataxia in the Yorkshire Terrier after grape ingestion. The Shih Tzu died 5 days post-grape ingestion, while the Yorkshire Terrier died 3 days post-grape ingestion. Erythematous serosae and mucosae, multifocal red small intestinal foci, and blood and grape seeds were identified in the intestinal lumen. Brownish-yellow crystals were bilaterally identified in the renal pelvis. The primary histological findings were acute tubular necrosis of the proximal convoluted tubules, severe necrosis, and mineralization in the renal cortical tubules. Blood urea nitrogen, creatinine, and alanine aminotransferase were increased in the dogs. Many Korean veterinary clinicians have suspected clinical grape poisoning. However, to our knowledge, grape poisoning has not been identified by pathologic and clinicopathologic basis until this writing in Korea. Education and knowledge about the risks of grape poisoning is necessary for the prevention of accidental exposures. PMID- 20953133 TI - Molecular and phenotypic characteristics of CMY-2 beta-lactamase-producing Salmonella enterica serovar Typhimurium isolated from cattle in Japan. AB - Isolates of extended-spectrum cephalosporin (ESC)-resistant Salmonella enterica serovar Typhimurium obtained from two different farms in Fukushima Prefecture, Japan, in 2007 were characterized in order to determine the genetic basis of resistance. ESC resistance in the two isolates was mediated by an AmpC beta lactamase encoded by the bla(CMY-2) gene, which is located in a large self transmissible plasmid in each isolate. The sizes of the bla(CMY-2)-carrying plasmids were different. The replicon types of the plasmids were I1-Igamma and A/C. The results of macrorestriction analysis and phage typing suggest a close relationship between both isolates. This is the first report of ESC-resistant S. Typhimurium isolated from cattle in Japan. PMID- 20953134 TI - In vivo cell tracking of canine allogenic mesenchymal stem cells administration via renal arterial catheterization and physiopathological effects on the kidney in two healthy dogs. AB - Stem cell therapy is being special premise for various renal diseases. However, there is limited literature on localization and pathologic and functional effects of allogenic mesenchymal stem cells (MSCs) in healthy dogs. Two healthy dogs were included in this study. Canine MSCs (cMSCs) were cultured from canine bone marrow and incubated with superparamagnetic iron oxide (SPIO) for in vivo cell tracking via MR imaging. The dogs were given the MSC (3 * 10(6) cells) into a renal artery via femoral artery catheterization. Follow-up serial renal assessments included ultrasonography and MRI, serum chemistry, urine analysis, and renal clearance tests. The dogs were euthanized at days 8 and 35 respectively for histopathologic evaluation of kidney. Strong hypointensity in MRI was detected in the treated renal cortex the day after cMSCs infusion. However they disappeared from MR image by the 8th day. Of the serum chemistry tests, serum hepatic enzymes (ALT, AST) were significantly elevated for one week after cMSCs treatment. Histopathological findings also revealed infiltration of SPIO-containing cells into the parenchyma of kidney. On 35th day, histopathology, glomerular atrophy, tubular necrosis, and mineralization were found in the subcapsular cortex, with fibrosis of the interstitial tissues. In vivo MRI studies of stem cells were useful in determining the sequential location of stem cells in the renal parenchyma of healthy dogs. Allogenic stem cells administered via renal artery caused inflammation, tubular necrosis, mineralization, and fibrosis without functional complications. PMID- 20953135 TI - Influence of zinc deficiency to the mice infected with Babesia microti. AB - Zinc (Zn) is an essential trace element for DNA synthesis and for cell growth and differentiation. The deficiency induces a wide range of disorders including immunodeficiency. In this study, the influence of Zn deficiency to the mice infected with Babesia microti was examined, and was compared with the influence in the rats infected with B. rodhaini previously reported. Experiments of B. microti infection were conducted using Zn-deficient (ZD; allowed to eat ad libitum on the ZD diet), Zn-adequate (ZA; allowed to eat ad libitum on the ZA diet), and diet-restricted (DR; supplied 2 g/day on the ZA diet) mice. It was suggested that the Zn deficiency exacerbated the infection dynamics of the mice with B. microti by the growth retardation, the reduction of immunity and the decrease in PCV. The results in the mice supported the consequences in the rats previously reported. PMID- 20953136 TI - FAK: dynamic integration of guidance signals at the growth cone. AB - During the formation of neural circuitry, axons are known to be guided to their specific targets by a relatively small arsenal of guidance signals. However, the molecular integration of this guidance information inside the axonal growth cone (GC) is still baffling. Focal adhesion kinase (FAK) is a cytosolic kinase which interacts with a complex molecular network via multiple phosphorylation sites. Paradoxically, FAK activation is required by both attractive and repulsive cues to control respectively axon outgrowth and disassembly of adhesive structures together with cytoskeletal dynamics. It was suggested that FAK might work as a versatile molecular integrator switching to different functions depending on its activation state. Two studies published recently by our group and Woo et al. shed light on this issue: for the first time, these works report a detailed molecular analysis of FAK activation and phosphorylation pattern in primary neuronal cultures in response to the repulsive cues Semaphorin3A and ephrinA1 respectively. Here we comment on the major novelties provided by these papers in the context of previous literature and we speculate on the future avenues of investigation opened by these works. PMID- 20953137 TI - Arsenic trioxide-mediated growth inhibition of myeloma cells is associated with an extrinsic or intrinsic signaling pathway through activation of TRAIL or TRAIL receptor 2. AB - Arsenic trioxide (ATO) is a well-known inhibitor of cell proliferation. Preclinical and clinical studies showed that ATO has anti-myeloma effects. However, the underlying mechanism remains elusive. In this study, the molecular mechanisms of ATO-induced myeloma apoptosis were explored on four myeloma cell lines of wild type or mutant p53 status and also on six primary myeloma cells. ATO induced potent inhibition of myeloma cell growth and myeloma cell apoptosis compared with controls. Further investigation showed that ATO down-regulated c Myc and phosphorylated (p)-Rb while up-regulating p53, p21Cip1, and p27Kip1 proteins, resulting in G0/G1 or G2/M cell cycle arrest. ATO treatment increased mRNA levels of interferon regulatory factor-1 and TRAIL, as well as protein levels of caspase 8 and cleaved caspase 3, indicating the involvement of the extrinsic apoptotic pathway in the mutated p53 myeloma cells. ATO also activated caspases 3 and 9, indicating involvement of the intrinsic apoptotic pathway in the wild type p53 myeloma cells. More importantly, these molecular changes induced by ATO-treated myeloma cells are very similar to the baseline expression pattern of hyperdiploid myeloma, which has a relative good prognosis with high expression of TRAIL and interferon related genes. Together, our data suggest that ATO induces apoptosis in MM through either extrinsic or intrinsic signaling pathway, depending on the p53 genetic background. These observations may be employed as prognostic tools and lead to novel therapies in primary myelomas. PMID- 20953138 TI - Inhibition of ATM kinase activity does not phenocopy ATM protein disruption: implications for the clinical utility of ATM kinase inhibitors. AB - Biallelic mutations in ataxia-telangiectasia mutated (ATM), which encodes for a protein kinase, cause ataxia telangiectasia (A-T). A-T is a pleiotropic disease, with a characteristic hypersensitivity to ionizing radiation (IR). A-T patients typically lack both detectable ATM protein and ATM kinase activity, and small molecule inhibitors of ATM kinase activity have been developed as strategies to improve radiotherapy for the treatment of cancers. As predicted, inhibition of ATM kinase activity is sufficient to radiosensitize cells. However, we recently showed that inhibition of ATM kinase activity disrupts DNA damage-induced sister chromatid exchange (SCE). This result was unanticipated since SCE is normal in A T cells that lack detectable ATM protein. In these studies, we showed, for the first time, that the consequences of inhibition of ATM kinase activity and adaptation to ATM protein disruption are distinct. Here, we discuss the mechanistic implications of this finding for the function of ATM at the replication fork and the clinical utility of ATM kinase inhibitors. PMID- 20953139 TI - Increasing reactive oxygen species as a therapeutic approach to treat hereditary leiomyomatosis and renal cell carcinoma. AB - Hereditary leiomyomatosis renal cell carcinoma (HLRCC)-associated renal tumors are aggressive and tend to metastasize early. There are currently no effective forms of therapy for patients with advanced HLRCC-associated kidney cancer. We have previously shown that HLRCC cells express a high level of reactive oxygen species (ROS). In the present study we investigated the cytotoxic effects of increasing ROS level using bortezomib in combination with cisplatin on HLRCC cells in vitro and in an in vivo xenograft model. The cytotoxic effect of several ROS inducers on FH-deficient cells was assessed by synthetic lethality. ROS inducers had a pronounced impact on the viability of FH-deficient cells. Because of its high potency, the proteasome inhibitor bortezomib was further investigated. Bortezomib induced apoptosis in vitro in HLRCC cells and inhibited HLRCC tumour growth in vivo. Bortezomib-associated cytotoxicity was highly correlated with cellular ROS level: combining bortezomib with other ROS inducers enhanced cytotoxicity, while combining bortezomib with a ROS scavenger inhibited its cytotoxic effect. Finally, HLRCC murine xenografts were treated with bortezomib and cisplatin, another ROS inducer. This regimen induced HLRCC tumour regression in vivo. These findings suggest that increasing ROS level in HLRCC above a certain threshold can induce HLRCC-tumor cell death. Increasing tumor ROS with bortezomib in combination with cisplatin represents a novel targeted therapeutic approach to treat advanced HLRCC-associated renal tumors. PMID- 20953140 TI - Maximizing early detection of esophageal squamous cell carcinoma via SILAC proteomics. PMID- 20953141 TI - Cytoplasmic retention of protein tyrosine kinase 6 promotes growth of prostate tumor cells. AB - Protein tyrosine kinase 6 (PTK6) is an intracellular tyrosine kinase that is nuclear in epithelial cells of the normal prostate, but cytoplasmic in prostate tumors and in the PC3 prostate tumor cell line. The impact of altered PTK6 intracellular localization in prostate tumor cells has not been extensively explored. Knockdown of endogenous cytoplasmic PTK6 resulted in decreased PC3 cell proliferation and colony formation, suggesting that cytoplasmic PTK6 stimulates oncogenic pathways. In contrast, reintroduction of PTK6 into nuclei of PC3 cells had a negative effect on growth. Enhanced tyrosine phosphorylation of the PTK6 substrate Sam68 was detected in cells expressing nuclear-targeted PTK6. We found that mechanisms regulating nuclear localization of PTK6 are intact in PC3 cells. Transiently overexpressed PTK6 readily enters the nucleus. Ectopic expression of ALT-PTK6, a catalytically inactive splice variant of PTK6, did not affect localization of endogenous PTK6 in PC3 cells. Using leptomycin B, we confirmed that cytoplasmic localization of endogenous PTK6 is not due to Crm-1/exportin-1 mediated nuclear export. In addition, overexpression of the PTK6 nuclear substrate Sam68 is not sufficient to bring PTK6 into the nucleus. While exogenous PTK6 was readily detected in the nucleus when transiently expressed at high levels, low-level expression of inducible wild type PTK6 in stable cell lines resulted in its cytoplasmic retention. Our results suggest that retention of PTK6 in the cytoplasm of prostate cancer cells disrupts its ability to regulate nuclear substrates and leads to aberrant growth. In prostate cancer, restoring PTK6 nuclear localization may have therapeutic advantages. PMID- 20953142 TI - MDM-2 antagonists induce p53-dependent cell cycle arrest but not cell death in renal cancer cell lines. AB - Renal cell cancers (RCC) are notoriously resistant to chemotherapy and radiotherapy. While mutations of the p53 tumor suppressor gene frequently contribute to therapy resistance in other epithelial cancers, p53 mutations are relatively rare in RCC. To date, there is conflicting evidence as to whether p53 signaling and function are otherwise proficient or defective in tumors with wild type p53. In this study, we assayed p53 function in a series of RCC cell lines and normal proximal epithelial tubule cells using two different MDM-2 antagonists, Nutlin-3a and MI-219. Most cell lines with wild-type p53 responded to MDM-2 antagonists as evidenced by induction of p53 and its target gene p21. RCC cell lines treated with MDM-2 antagonists consistently accumulated in the G2/M phase of the cell cycle and this event was associated with inhibition of proliferation in RCC cell lines but not in normal proximal epithelial tubule cells. MDM-2 antagonists did not induce significant cell death in RCC cell lines, even with induction of p53-dependent pro-apoptotic genes. In contrast, MDM-2 antagonists caused significant cell death in LNCaP prostate adenocarcinoma cells. RCC cell lines with reduced p53, either by mutation or through ectopic expression of p53 shRNA, demonstrated enhanced sensitivity to cell death following sequential treatment with DNA damage and G2/M checkpoint abrogation. Our results suggest that wild-type p53 RCC cell lines are proficient in p53-dependent cell cycle arrest but defective in p53-dependent cell death. PMID- 20953143 TI - Regulation of calcium channels by RGK proteins. AB - The RGK family of proteins, small GTPases of the Ras superfamily, are known to regulate calcium currents. It is commonly thought that this is due to an interaction with the Cavbeta subunit, however, the mechanism of this inhibition is unclear. There have been conflicting reports of whether RGK proteins can affect channel trafficking or whether they reduce calcium currents by interacting with channels at the membrane. In the last year, several studies have emerged which explore the intricacies of RGK protein interaction with the channel itself and the importance of the Cavbeta subunit for this interaction, in addition to providing some tantalizing suggestions for the mechanism by which RGK proteins reduce or eliminate calcium currents. In this review, we present an overview of these recent advances and suggest a model that may synthesize these latest works. PMID- 20953144 TI - Activation of the epithelial sodium channel by the metalloprotease meprin beta subunit. AB - The Epithelial Na(+) Channel (ENaC) is an apical heteromeric channel that mediates Na(+) entry into epithelial cells from the luminal cell surface. ENaC is activated by proteases that interact with the channel during biosynthesis or at the extracellular surface. Meprins are cell surface and secreted metalloproteinases of the kidney and intestine. We discovered by affinity chromatography that meprins bind gamma-ENaC, a subunit of the ENaC hetero oligomer. The physical interaction involves NH(2)-terminal cytoplasmic residues 37-54 of gamma-ENaC, containing a critical gating domain immediately before the first transmembrane domain, and the cytoplasmic COOH-terminal tail of meprin beta (residues 679-704). This potential association was confirmed by co-expression and co-immunoprecipitation studies. Functional assays revealed that meprins stimulate ENaC expressed exogenously in Xenopus oocytes and endogenously in epithelial cells. Co-expression of ENaC subunits and meprin beta or alpha/beta in Xenopus oocytes increased amiloride-sensitive Na(+) currents approximately two-fold. This increase was blocked by preincubation with an inhibitor of meprin activity, actinonin. The meprin-mediated increase in ENaC currents in oocytes and epithelial cell monolayers required meprin beta, but not the alpha subunit. Meprin beta promoted cleavage of alpha and gamma-ENaC subunits at sites close to the second transmembrane domain in the extracellular domain of each channel subunit. Thus, meprin beta regulates the activity of ENaC in a metalloprotease dependent fashion. PMID- 20953145 TI - Unified modeling of the mammalian and fish proton-dependent oligopeptide transporter PepT1. AB - Electrophysiological and biophysical analyses were used to compare the partial and complete transport cycles of the intestinal oligopeptide transporter PepT1 among three species (seabass, zebrafish and rabbit). On the whole, the presteady state currents of the fish transporters were similar to each other. Rabbit PepT1 differed from the fish transporters by having slower-decaying currents, and the charge vs. potential (Q/V) and time constant vs. potential (tau/V) curves shifted to more positive potentials. All of the isoforms were similarly affected by external pH, showing acidity-induced slowing of the transients and positive shifts in the Q/V and tau/V curves. Analysis of the pH-dependence of the unidirectional rates of the intramembrane charge movement suggested that external protonation of the protein limits the speed of this process in both directions. The complete cycle of the transporter was studied using the neutral dipeptide Gly Gln. Michaelis-Menten analysis confirmed that, in all species, acidity significantly increases the apparent affinity for the substrate but does not strongly impact maximal transport current. Simulations using a kinetic model incorporating the new findings showed good agreement with experimental data for all three species, both with respect to the presteady-state and the transport currents. PMID- 20953146 TI - Activation of Atg1 kinase in autophagy by regulated phosphorylation. AB - Autophagy is a highly regulated trafficking pathway that leads to selective degradation of cellular constituents such as protein aggregates and excessive and damaged organelles. Atg1 is an essential part of the core autophagic machinery, which triggers induction of autophagy and the Cvt pathway. Although changes in Atg1 phosphorylation and complex formation are thought to regulate its function, the mechanism of Atg1 kinase activation remains unclear. Using a quantitative mass spectrometry approach, we identified 29 phosphorylation sites, of which five are either upregulated or downregulated by rapamycin treatment. Two phosphorylation sites, threonine 226 and serine 230, are evolutionarily conserved and located in the activation loop of the amino terminal kinase domain of Atg1. These phosphorylation events are not required for Atg1 localization to the phagosome assembly site (PAS), or the proper assembly of the multisubunit Atg1 kinase complex and binding to its activator Atg13. However, mutation of either one of these sites results in a loss of Atg1 kinase activity and its function in autophagy and the Cvt pathway. Taken together, our data suggest that phosphorylation of Atg1 on multiple sites provides critical mechanisms to regulate Atg1 function in autophagy and the Cvt pathway. PMID- 20953147 TI - Towards the global understanding of the autophagy regulatory network. PMID- 20953148 TI - Endosomal protein sorting and autophagy genes contribute to the regulation of yeast life span. AB - Accumulating evidence from various organisms points to a role for autophagy in the regulation of life span. By performing a genome-wide screen to identify novel life span determinants in Saccharomyces cerevisiae, we have obtained further insights into the autophagy-related and -unrelated degradation processes that may be important for preventing cellular senescence. The generation of multivesicular bodies and their fusion with the vacuole in the endosomal pathway emerged as novel cell functions involved in yeast chronological survival and longevity extension. PMID- 20953149 TI - Autophagy: a target for retinoic acids. AB - Autophagy is an intracellular catabolic process that responds with great sensitivity to nutrient availability, implying that certain macro- or micro nutrients are involved. We found that retinoic acid promotes autophagosome maturation through a pathway independent from the classic nuclear retinoid receptors. Retinoic acid redistributes the cation-independent mannose-6-phosphate receptor from the trans-Golgi region to maturing autophagosomal structures inducing their acidification. Manipulation of the autophagic activity by retinoids could have enormous health implications, since they are essential dietary components and frequently used pharmaceuticals. PMID- 20953150 TI - Specification and behavior of AMPs, muscle-committed transient Drosophila stem cells. AB - During development, transient stem cells play critical roles in the formation of specific tissues. Adult Muscle Precursors (AMPs) are at the origin of all adult Drosophila muscles and as we report here represent a novel population of muscle committed transient stem cells. Similar to vertebrate muscle stem cells, AMPs keep Notch signaling active and express Enhancer of split m6 (E(spl)m6) gene, a read-out of Notch pathway. To get insights into AMP cell specification we performed a gain-of-function screen and found that the rhomboid-triggered Epidermal Growth Factor (EGF) signaling pathway controls both the specification and the subsequent maintenance of AMPs. Our findings are supported by the identification of EGF-secreting cells in the lateral domain and the EGF-dependent regulatory modules that drive expression of the ladybird gene in lateral AMPs. Interestingly, by targeting GFP to the AMP cell membranes we also demonstrated that AMPs send long cellular processes and form a network of interconnected cells. As revealed by laser ablation experiments, the main role of AMP cell connections is to maintain their correct spatial positioning. PMID- 20953151 TI - Sexual conflict and gene expression: exploring sex-specific associations between fitness and transcriptional variation. AB - In recent years, the field of evolutionary biology received a fresh impulse from the increased technical and logistical availability and cost-effectiveness of genomics techniques. In particular, we have for the first time the opportunity to effectively explore and understand the genetic basis of traits variation in laboratory (and ultimately wild) populations. Traits that are most relevant in evolutionary and ecological contexts (e.g. morphological, life-history and behavioural traits) typically show a complex genetic architecture, being affected by many loci with small effect. Such loci often interact with one another over the same trait (epistasis), affect several traits simultaneously (pleiotropy), and/or depend in their effects on the "environmental condition" in which they are expressed (genotype by environment interactions). Modern genomics offers tools, such as microarrays and high-throughput sequencing, to gather an unprecedented amount of data on gene expression and sequence variation, and can be used in the attempt to construct a genotype-phenotype map, linking genes (or gene networks), and the variation in their sequence and expression, with the natural variation of phenotypic characters. PMID- 20953152 TI - Sound production during agonistic behavior of male Drosophila melanogaster. AB - Male Drosophila fruit flies acquire and defend territories in order to attract females for reproduction. Both, male-directed agonistic behavior and female directed courtship consist of series of recurrent stereotypical components. Various studies demonstrated the importance of species-specific sound patterns generated by wing vibration as being critical for male courtship success. In this study we analyzed the patterns and importance of sound signals generated during agonistic interactions of male Drosophila melanogaster. In contrast to acoustic courtship signals that consist of sine and pulse patterns and are generated by one extended wing, agonistic signals lack sine-like components and are generally produced by simultaneous movements of both wings. Though intra-pulse oscillation frequencies (carrier frequency) are identical, inter-pulse intervals are twice as long and more variable in aggression signals than in courtship songs, where their precise temporal pattern serves species recognition. Acoustic signals accompany male agonistic interactions over their entire course but occur particularly often after tapping behavior which is a major way to identify the gender of the interaction partner. Since similar wing movements may either be silent or generate sound and wing movements with sound have a greater impact on the subsequent behavior of a receiver, sound producing wing movements seem to be generated intentionally to serve as a specific signal during fruit fly agonistic encounters. PMID- 20953153 TI - The path to developing a cervical cancer vaccine. AB - The path that led me to where I am today in my career as a vaccinologist was not a straight one: it was riddled with twists and turns, opportunities and obstacles and full of decisions that could have taken me down very different avenues. Working and interacting with many dedicated and brilliant scientists and taking apprenticeships to become a better and more versatile scientist have been rewarding experiences and more than once luck has come into play. PMID- 20953154 TI - Molecular and structural characterization of the L1 virus-like particles that are used as vaccine antigens in CervarixTM, the AS04-adjuvanted HPV-16 and -18 cervical cancer vaccine. AB - CervarixTM is a prophylactic human papillomavirus (HPV)-16/18 vaccine developed for the prevention of cervical cancer. The vaccine antigens are HPV-16 and HPV-18 L1 virus-like particles (VLPs) made from baculovirus expression vector system (BEVS)-produced HPV-16 and HPV-18 L1 proteins, respectively. In this study, we demonstrate that truncation of the nuclear targeting and DNA binding signals at the C-terminus of the HPV-16 and HPV-18 L1 proteins prevented intranuclear formation of the VLPs in the host cells and led to cytoplasmic localization of the L1 proteins as shown by in situ immunogold detection and electron microscopy. Following purification, these L1 proteins were able to form VLPs. The characteristics of these HPV-16 and HPV-18 L1 VLPs were studied using various physicochemical and immunological techniques. Amino acid analysis, SDS-PAGE and western blotting demonstrated the high purity of the L1 proteins and batch-to batch consistency. The structure of the VLPs was shown to be similar to that reported for the native virions, as evaluated by microscopic observations, protein tomography and disc centrifugation experiments. The presence of important conformation-dependent neutralizing epitopes, such as U4, V5 and J4, was confirmed by ELISA and surface plasmon resonance. Structural robustness and consistency among batches was also observed by differential scanning calorimetry and electron microscopy. Moreover, adsorption to aluminum was shown not to impair VLP structure. In conclusion, the BEVS-produced HPV-16 and HPV-18 L1 VLPs display key structural and immunological features, which contribute to the efficacy of CervarixTM vaccination. PMID- 20953156 TI - microRNA access to the target helicases from rice. AB - Major classes of small RNAs include microRNAs (miRNAs) and small interfering RNAs (siRNAs). miRNAs are single-stranded RNA molecules of around 22 nucleotides in length. Most miRNAs show imperfect homology with their targets. The biogenesis mechanisms of miRNAs are different for plant and animals. Silencing of genes by miRNAs may serve as an appropriate tool to speed-up analyses of gene functions in a post-genome era. We have identified in silico a set of miRNAs that control helicase gene expression by regulating its mRNA stability and translation in rice. Our analysis revealed that several rice helicases have distinct miRNA specificities. Such analyses will be a prerequisite to refining our understanding of target selection and regulation of helicase gene expression by miRNAs in rice. Further, we discuss recent findings on miRNA gene family and its gene structure, criteria for miRNA annotation and on miRNA biogenesis that involve transcription, processing and maturation of miRNAs. PMID- 20953155 TI - Free edges in epithelia as cues for motility. AB - One of the primary functions of any epithelium is to act as a barrier. To maintain integrity, epithelia migrate rapidly to cover wounds, and there is intense interest in understanding how wounds are detected. Numerous soluble factors are present in the wound environment and epithelia can sense the presence of adjacent denuded extracellular matrix. However, the presence of such cues is expected to be highly variable, and here we focus on the presence of edges in the epithelial sheets as a stimulus, since they are universally and continuously present in wounds. Using a novel tissue culture model, free edges in the absence of any other identifiable cues were found to trigger activation of the epidermal growth factor receptor and increase cell motility. Edges bordered by inert physical barriers do not activate the receptor, indicating that activation is related to mechanical factors rather than to specific cell cell interactions. PMID- 20953157 TI - Effects of different maturity stages on antioxidant content of Ivorian Gnagnan (Solanum indicum L.) berries. AB - Gnagnan (Solanum indicum L.) is a spontaneous plant widely distributed in Ivory Coast. During ripening stages, Solanum indicum L. presents different colours (green, yellow and red) and is reported to contain several albeit poorly characterized antioxidant compounds. This paper describes in detail the antioxidant profile (ascorbic acid, carotenoids and polyphenols), antioxidant capacity (FRAP test and Folin-Ciocalteau assay) and the colour changes of Gnagnan berries at different ripening levels. Ascorbic acid content was similar in green and yellow berries, but significantly lower in red ones. Red berries showed a higher content of carotenoids compared to green and yellow ones. Regarding polyphenols, several phenolic acids and flavonoids were found in all berries. The content of caffeoylquinic acids, caffeic acid, flavonol glycosides and naringenin was higher in red berries, while the content of p-coumaric acid and feruloylquinic acids was similar among the three colours. The FRAP assay increased with the ripening process, whereas total polyphenols were similar among berries. Significant differences were found for the colorimetric indexes among products of different degrees of ripening. The present results show the important role of the ripening stage in increasing the antioxidant content of Gnagnan berries. PMID- 20953158 TI - Anti-adhesive activities of flavan-3-ols and proanthocyanidins in the interaction of group A-streptococci and human epithelial cells. AB - Bacterial adhesion to epithelial cells is a key step in infections, allowing subsequent colonization, invasion and internalization of pathogens into tissues. Anti-adhesive agents are therefore potential prophylactic tools against bacterial infections. The range of anti-adhesive compounds is largely confined to carbohydrate analogues. Tannins are generously recognized as potent antimicrobials, but little data exist on their anti-adherence potency. Using a model for mucosal pathogenesis with labeled group A-streptococci (GAS) and human laryngeal HEp-2 cells, a series of flavan-3-ols (epicatechin, epigallocatechin, epigallocatechin-3-O-gallate) and highly purified and chemically characterized proanthocyanidin samples including procyanidins based on epicatechin, catechin or 'mixed' constituent flavanyl units, prodelphinidins made up of (epi)gallocatechin monomeric unts as well as oligomers possessing A-type units in their molecules was evaluated for anti-adhesive effects. Reduced microbial adherence was observed exclusively for prodelphinidins, suggesting that pyrogallol-type elements, i.e., (epi)gallocatechin units are important structural features. This is the first report on structure-activity relationships regarding the anti-adhesive potency of proanthocyanidins. In addition, the structures of the first chemically defined proanthocyanidins from Pelargonium sidoides are disclosed. PMID- 20953159 TI - Mechanisms of the gastric antiulcerogenic activity of Anacardium humile St. Hil on ethanol-induced acute gastric mucosal injury in rats. AB - Leaves and bark infusions Anacardium humile St. Hil. (Anacardiaceae), known as in Brazil as "cajuzinho do cerrado", have been used in folk medicine as an alternative treatment for ulcers and gastritis. This study evaluated the gastroprotective activity of an ethyl acetate extract of the leaves of A. humile (AcF) and the mechanism involved in this gastroprotection. Pretreatment concentrations (50, 100, 200 mg x kg-1) were administered by gavage. Following a 60 min. period, all the rats were orally administered 1 mL of absolute ethanol. One hour after the administration of ethanol, all groups were sacrificed, and the gastric ulcer index was calculated. Prostaglandin PGE2 concentration, gastric adherent mucous, and the participation of nitric oxide (NO) and sulfhydryl compounds in the gastroprotection process were also analyzed using the most effective tested dose (50 mg x kg-1). A histological study of the glandular stomach for the evaluation of the epithelial damage and mucus content was also performed. AcF significantly reduced the gastric damage produced by ethanol. This effect was statistically significant for the 50 mg x kg-1 group compared to control. Also, it significantly increased the PGE2 (by 10-fold) and mucous production, while pretreatment with NG-nitro-L-arginine methyl ester (L-NAME) or N-ethylmaleimide (NEM) completely abolished the gastroprotection. AcF has a protective effect against ethanol, and this effect, might be due to the augmentation of the protective mechanisms of mucosa. PMID- 20953160 TI - Role of oxidant scavengers in the prevention of Ca2+ homeostasis disorders. AB - A number of disorders, such as Alzheimer disease and diabetes mellitus, have in common the alteration of the redox balance, resulting in an increase in reactive oxygen species (ROS) generation that might lead to the development of apoptosis and cell death. It has long been known that ROS can significantly alter Ca2+ mobilization, an intracellular signal that is involved in the regulation of a wide variety of cellular functions. Cells have a limited capability to counteract the effects of oxidative stress, but evidence has been provided supporting the beneficial effects of exogenous ROS scavengers. Here, we review the effects of oxidative stress on intracellular Ca2+ homeostasis and the role of antioxidants in the prevention and treatment of disorders associated to abnormal Ca2+ mobilization induced by ROS. PMID- 20953161 TI - tmRNA-SmpB: a journey to the centre of the bacterial ribosome. AB - Ribosomes mediate protein synthesis by decoding the information carried by messenger RNAs (mRNAs) and catalysing peptide bond formation between amino acids. When bacterial ribosomes stall on incomplete messages, the trans-translation quality control mechanism is activated by the transfer-messenger RNA bound to small protein B (tmRNA-SmpB ribonucleoprotein complex). Trans-translation liberates the stalled ribosomes and triggers degradation of the incomplete proteins. Here, we present the cryo-electron microscopy structures of tmRNA-SmpB accommodated or translocated into stalled ribosomes. Two atomic models for each state are proposed. This study reveals how tmRNA-SmpB crosses the ribosome and how, as the problematic mRNA is ejected, the tmRNA resume codon is placed onto the ribosomal decoding site by new contacts between SmpB and the nucleotides upstream of the tag-encoding sequence. This provides a structural basis for the transit of the large tmRNA-SmpB complex through the ribosome and for the means by which the tmRNA internal frame is set for translation to resume. PMID- 20953162 TI - Adhesion shapes T cells for prompt and sustained T-cell receptor signalling. AB - During T-cell migration, cell polarity is orchestrated by chemokine receptors and adhesion molecules and involves the functional redistribution of molecules and organelles towards specific cell compartments. In contrast, it is generally believed that the cell polarity established when T cells meet antigen-presenting cells (APCs) is controlled by the triggered T-cell receptor (TCR). Here, we show that, during activation of human T lymphocytes by APCs, chemokines and LFA-1 establish cell polarity independently of TCR triggering. Chemokine-induced LFA-1 activation results in fast recruitment of MTOC and mitochondria towards the potential APC, a process required to amplify TCR Ca(2+) signalling at the upcoming immunological synapse, to promote nuclear translocation of transcriptional factor NFATc2 and boost CD25 expression. Our data show that the initial adhesive signals delivered by chemokines and LFA-1 shape and prepare T cells for antigen recognition. PMID- 20953163 TI - Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch. AB - Two transcription factors, Pax5 and Blimp-1, form a gene regulatory network (GRN) with a double-negative loop, which defines either B-cell (Pax5 high) or plasma cell (Blimp-1 high) status as a binary switch. However, it is unclear how this B cell GRN registers class switch DNA recombination (CSR), an event that takes place before the terminal differentiation to plasma cells. In the absence of Bach2 encoding a transcription factor required for CSR, mouse splenic B cells more frequently and rapidly expressed Blimp-1 and differentiated to IgM plasma cells as compared with wild-type cells. Genetic loss of Blimp-1 in Bach2(-/-) B cells was sufficient to restore CSR. These data with mathematical modelling of the GRN indicate that Bach2 achieves a time delay in Blimp-1 induction, which inhibits plasma cell differentiation and promotes CSR (Delay-Driven Diversity model for CSR). Reduction in mature B-cell numbers in Bach2(-/-) mice was not rescued by Blimp-1 ablation, indicating that Bach2 regulates B-cell differentiation and function through Blimp-1-dependent and -independent GRNs. PMID- 20953164 TI - Multiple C-terminal tail Ca(2+)/CaMs regulate Ca(V)1.2 function but do not mediate channel dimerization. AB - Interactions between voltage-gated calcium channels (Ca(V)s) and calmodulin (CaM) modulate Ca(V) function. In this study, we report the structure of a Ca(2+)/CaM Ca(V)1.2 C-terminal tail complex that contains two PreIQ helices bridged by two Ca(2+)/CaMs and two Ca(2+)/CaM-IQ domain complexes. Sedimentation equilibrium experiments establish that the complex has a 2:1 Ca(2+)/CaM:C-terminal tail stoichiometry and does not form higher order assemblies. Moreover, subunit counting experiments demonstrate that in live cell membranes Ca(V)1.2s are monomers. Thus, contrary to previous proposals, the crystallographic dimer lacks physiological relevance. Isothermal titration calorimetry and biochemical experiments show that the two Ca(2+)/CaMs in the complex have different properties. Ca(2+)/CaM bound to the PreIQ C-region is labile, whereas Ca(2+)/CaM bound to the IQ domain is not. Furthermore, neither of lobes of apo-CaM interacts strongly with the PreIQ domain. Electrophysiological studies indicate that the PreIQ C-region has a role in calcium-dependent facilitation. Together, the data show that two Ca(2+)/CaMs can bind the Ca(V)1.2 tail simultaneously and indicate a functional role for Ca(2+)/CaM at the C-region site. PMID- 20953165 TI - A phospho/methyl switch at histone H3 regulates TFIID association with mitotic chromosomes. AB - Histone methylation patterns are correlated with eukaryotic gene transcription. High-affinity binding of the plant homeodomain (PHD) of TFIID subunit TAF3 to trimethylated lysine-4 of histone H3 (H3K4me3) is involved in promoter recruitment of this basal transcription factor. Here, we show that for transcription activation the PHD of TAF3 can be replaced by PHDs of other high affinity H3K4me3 binders. Interestingly, H3K4me3 binding of TFIID and the TAF3 PHD is decreased by phosphorylation of the adjacent threonine residue (H3T3), which coincides with mitotic inhibition of transcription. Ectopic expression of the H3T3 kinase haspin repressed TAF3-mediated transcription of endogenous and of reporter genes and decreased TFIID association with chromatin. Conversely, immunofluorescence and live-cell microscopy studies showed an increased association of TFIID with mitotic chromosomes upon haspin knockdown. Based on our observations, we propose that a histone H3 phospho-methyl switch regulates TFIID mediated transcription during mitotic progression of the cell cycle. PMID- 20953166 TI - Estimating age and the likelihood of having attained 18 years of age using mandibular third molars. AB - OBJECTIVE: Age estimation methods using mandibular third molar (M3) root formation were tested. Diagnostic accuracy of M3 to predict age 18 was tested. DESIGN: Methods were tested on a target sample of 300 dental panoramic radiographs (age 11-25). Diagnostic accuracy was assessed on separate reference data (n = 1,663, age 9-25). Root stage was the diagnostic test predicting 18 years of age. METHODS: Root stage of M3 was assessed and age estimated (n = 157) using published methods that use Demirjian or Moorrees root stages. The difference between dental and known ages was assessed. Diagnostic tests and likelihood ratios were calculated for reference data. MAIN OUTCOME MEASURE: Mean difference (bias), standard deviation and absolute mean difference between dental age and known ages. Likelihood ratio of age 18, given M3 root stage. RESULTS: Only six of 37 methods estimated age with bias not significant to zero. Mean absolute difference between dental and known age for these methods ranged from 1.45 to 1.97 years. Standard deviation of bias for all methods was around 2 years and 95% confidence interval of estimated age is +/- 4 years. The best methods using Demirjian and Moorrees stages are detailed. Likelihood ratio of being at least 18 if M3 was mature was 13.61. If M3 was 'A1/2' (apex half closed) or mature, on the balance of probabilities, estimated age was at least 18. CONCLUSION: Most methods using M3 root formation estimate age with significant bias. If M3 is mature, age 18 is more than likely attained. PMID- 20953167 TI - A pilot study of bioaerosol reduction using an air cleaning system during dental procedures. AB - BACKGROUND: Bioaerosols are defined as airborne particles of liquid or volatile compounds that contain living organisms or have been released from living organisms. The creation of bioaerosols is a recognized consequence of certain types of dental treatment and represents a potential mechanism for the spread of infection. OBJECTIVES: The aims of the present study were to assess the bioaerosols generated by certain dental procedures and to evaluate the efficiency of a commercially available Air Cleaning System (ACS) designed to reduce bioaerosol levels. METHODS: Bioaerosol sampling was undertaken in the absence of clinical activity (baseline) and also during treatment procedures (cavity preparation using an air rotor, history and oral examination, ultrasonic scaling and tooth extraction under local anaesthesia). For each treatment, bioaerosols were measured for two patient episodes (with and without ACS operation) and between five and nine bioaerosol samples were collected. For baseline measurements, 15 bioaerosol samples were obtained. For bioaerosol sampling, environmental air was drawn on to blood agar plates using a bioaerosol sampling pump placed in a standard position 20 cm from the dental chair. Plates were incubated aerobically at 37 degrees C for 48 hours and resulting growth quantified as colony forming units (cfu/m3). Distinct colony types were identified using standard methods. Results were analysed statistically using SPSS 12 and Wilcoxon signed rank tests. RESULTS: The ACS resulted in a significant reduction (p = 0.001) in the mean bioaerosols (cfu/m3) of all three clinics compared with baseline measurements. The mean level of bioaerosols recorded during the procedures, with or without the ACS activated respectively, was 23.9 cfu/m3 and 105.1 cfu/m3 (p = 0.02) for cavity preparation, 23.9 cfu/m3 and 62.2 cfu/m3 (p = 0.04) for history and oral examination; 41.9 cfu/m3 and 70.9 cfu/m3 (p = 0.01) for ultrasonic scaling and 9.1 cfu/m3 and 66.1 cfu/m3 (p = 0.01) for extraction. The predominant microorganisms isolated were Staphylococcus species and Micrococcus species. CONCLUSION: These findings indicate potentially hazardous bioaerosols created during dental procedures can be significantly reduced using an air cleaning system. PMID- 20953168 TI - The efficacy of infiltration anaesthesia for adult mandibular incisors: a randomised double-blind cross-over trial comparing articaine and lidocaine buccal and buccal plus lingual infiltrations. AB - AIM: To compare the efficacy of 2% lidocaine and 4% articaine both with 1:100,000 adrenaline in anaesthetising the pulps of mandibular incisors. METHODS: Thirty one healthy adult volunteers received the following local anaesthetic regimens adjacent to a mandibular central incisor: 1) buccal infiltration of 1.8 mL lidocaine plus dummy lingual injection (LB), 2) buccal plus lingual infiltrations of 0.9 mL lidocaine (LBL), 3) buccal infiltration of 1.8 mL articaine plus dummy lingual injection (AB), 4) buccal plus lingual infiltrations of 0.9 mL articaine (ABL). Pulp sensitivities of the central incisor and contralateral lateral incisor were assessed electronically. Anaesthetic efficacy was determined by two methods: 1) Recording the number of episodes with no responses to maximal electronic pulp tester stimulation during the course of the study period, 2) recording the number of volunteers with no response to maximal pulp tester stimulation within 15 min and maintained for 45 min (defined as sustained anaesthesia). Data were analysed by McNemar, chi-square, Mann-Whitney and paired t-tests. RESULTS: For both test teeth, the number of episodes of no sensation on maximal stimulation was significantly greater after articaine than lidocaine for both techniques. The split buccal plus lingual dose was more effective than the buccal injection alone for both solutions (p <0.001). 4% articaine was more effective than 2% lidocaine when comparing sustained anaesthesia in both teeth for each technique (p <0.001), however, there was no difference in sustained anaesthesia between techniques for either tooth or solution. CONCLUSIONS: 4% articaine was more effective than 2% lidocaine (both with 1:100,000 adrenaline) in anaesthetising the pulps of lower incisor teeth after buccal or buccal plus lingual infiltrations. PMID- 20953169 TI - Gastrointestinal pathology of autologous graft-versus-host disease following hematopoietic stem cell transplantation: a clinicopathological study of 17 cases. AB - Graft-versus-host disease is the major complication after allogeneic hematopoietic stem cell transplantation and is attributable to donor T-cell recognition of recipient alloantigens. In patients undergoing autologous hematopoietic stem cell transplantation in which there is no genetic disparity to induce an alloresponse, a syndrome similar to allogeneic graft-versus-host disease has been described. Designated as autologous graft-versus-host disease, it typically involves the skin and has reportedly caused little morbidity in this patient population. Recent data, however, suggest that autologous graft-versus host disease can cause significant disease in the gastrointestinal tract, but its pathological spectrum of abnormalities and disease incidence are not well established. We report the development of autologous graft-versus-host disease following hematopoietic stem cell transplantation in 17 patients (15 with multiple myeloma) based on 388 autologous stem cell transplants carried out at our institution over a 6-year period. This represents a total incidence rate of 4% and among those transplanted for multiple myeloma, 6%. In all, 16 of the 17 patients had colonic biopsies performed for the diagnostic evaluation of persistent diarrhea. Biopsies in all 16 patients showed pathological evidence for graft-versus-host disease and were graded using standard grading criteria established for allogeneic graft-versus-host disease. Grades ranged from mild (grade 1/4) to severe (grade 4/4). Changes secondary to medication or infection were excluded. Responses to steroid and immunosuppressive therapy were variable but improved with continuing institutional experience. Outcomes ranged from a prompt, complete resolution of symptoms to death. Patients treated with autologous hematopoietic stem cell transplantation, particularly those with multiple myeloma, may develop a potentially life-threatening syndrome pathologically identical to allogeneic graft-versus-host disease. This diagnosis must be considered when interpreting biopsies from patients with gastrointestinal symptoms following autologous hematopoietic stem cell transplantation. PMID- 20953170 TI - Maternal mRNA deadenylation and decay by the piRNA pathway in the early Drosophila embryo. AB - Piwi-associated RNAs (piRNAs), a specific class of 24- to 30-nucleotide-long RNAs produced by the Piwi-type of Argonaute proteins, have a specific germline function in repressing transposable elements. This repression is thought to involve heterochromatin formation and transcriptional and post-transcriptional silencing. The piRNA pathway has other essential functions in germline stem cell maintenance and in maintaining germline DNA integrity. Here we uncover an unexpected function of the piRNA pathway in the decay of maternal messenger RNAs and in translational repression in the early embryo. A subset of maternal mRNAs is degraded in the embryo at the maternal-to-zygotic transition. In Drosophila, maternal mRNA degradation depends on the RNA-binding protein Smaug and the deadenylase CCR4, as well as the zygotic expression of a microRNA cluster. Using mRNA encoding the embryonic posterior morphogen Nanos (Nos) as a paradigm to study maternal mRNA decay, we found that CCR4-mediated deadenylation of nos depends on components of the piRNA pathway including piRNAs complementary to a specific region in the nos 3' untranslated region. Reduced deadenylation when piRNA-induced regulation is impaired correlates with nos mRNA stabilization and translational derepression in the embryo, resulting in head development defects. Aubergine, one of the Argonaute proteins in the piRNA pathway, is present in a complex with Smaug, CCR4, nos mRNA and piRNAs that target the nos 3' untranslated region, in the bulk of the embryo. We propose that piRNAs and their associated proteins act together with Smaug to recruit the CCR4 deadenylation complex to specific mRNAs, thus promoting their decay. Because the piRNAs involved in this regulation are produced from transposable elements, this identifies a direct developmental function for transposable elements in the regulation of gene expression. PMID- 20953171 TI - Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. AB - Vitamin K occurs in the natural world in several forms, including a plant form, phylloquinone (PK), and a bacterial form, menaquinones (MKs). In many species, including humans, PK is a minor constituent of hepatic vitamin K content, with most hepatic vitamin K content comprising long-chain MKs. Menaquinone-4 (MK-4) is ubiquitously present in extrahepatic tissues, with particularly high concentrations in the brain, kidney and pancreas of humans and rats. It has consistently been shown that PK is endogenously converted to MK-4 (refs 4-8). This occurs either directly within certain tissues or by interconversion to menadione (K(3)), followed by prenylation to MK-4 (refs 9-12). No previous study has sought to identify the human enzyme responsible for MK-4 biosynthesis. Previously we provided evidence for the conversion of PK and K(3) into MK-4 in mouse cerebra. However, the molecular mechanisms for these conversion reactions are unclear. Here we identify a human MK-4 biosynthetic enzyme. We screened the human genome database for prenylation enzymes and found UbiA prenyltransferase containing 1 (UBIAD1), a human homologue of Escherichia coli prenyltransferase menA. We found that short interfering RNA against the UBIAD1 gene inhibited the conversion of deuterium-labelled vitamin K derivatives into deuterium-labelled-MK 4 (MK-4-d(7)) in human cells. We confirmed that the UBIAD1 gene encodes an MK-4 biosynthetic enzyme through its expression and conversion of deuterium-labelled vitamin K derivatives into MK-4-d(7) in insect cells infected with UBIAD1 baculovirus. Converted MK-4-d(7) was chemically identified by (2)H-NMR analysis. MK-4 biosynthesis by UBIAD1 was not affected by the vitamin K antagonist warfarin. UBIAD1 was localized in endoplasmic reticulum and ubiquitously expressed in several tissues of mice. Our results show that UBIAD1 is a human MK 4 biosynthetic enzyme; this identification will permit more effective decisions to be made about vitamin K intake and bone health. PMID- 20953172 TI - A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity. AB - The derivation of human ES cells (hESCs) from human blastocysts represents one of the milestones in stem cell biology. The full potential of hESCs in research and clinical applications requires a detailed understanding of the genetic network that governs the unique properties of hESCs. Here, we report a genome-wide RNA interference screen to identify genes which regulate self-renewal and pluripotency properties in hESCs. Interestingly, functionally distinct complexes involved in transcriptional regulation and chromatin remodelling are among the factors identified in the screen. To understand the roles of these potential regulators of hESCs, we studied transcription factor PRDM14 to gain new insights into its functional roles in the regulation of pluripotency. We showed that PRDM14 regulates directly the expression of key pluripotency gene POU5F1 through its proximal enhancer. Genome-wide location profiling experiments revealed that PRDM14 colocalized extensively with other key transcription factors such as OCT4, NANOG and SOX2, indicating that PRDM14 is integrated into the core transcriptional regulatory network. More importantly, in a gain-of-function assay, we showed that PRDM14 is able to enhance the efficiency of reprogramming of human fibroblasts in conjunction with OCT4, SOX2 and KLF4. Altogether, our study uncovers a wealth of novel hESC regulators wherein PRDM14 exemplifies a key transcription factor required for the maintenance of hESC identity and the reacquisition of pluripotency in human somatic cells. PMID- 20953173 TI - Magnetic torque tweezers: measuring torsional stiffness in DNA and RecA-DNA filaments. AB - We introduce magnetic torque tweezers, which enable direct single-molecule measurements of torque. Our measurements of the effective torsional stiffness C of dsDNA indicated a substantial force dependence, with C = approximately 40 nm at low forces up to C = approximately 100 nm at high forces. The initial torsional stiffness of RecA filaments was nearly twofold larger than that for dsDNA, yet at moderate torques further build-up of torsional strain was prevented. PMID- 20953174 TI - Clonal tracking of hESCs reveals differential contribution to functional assays. AB - Human embryonic stem cells (hESCs) have unique self-renewal and differentiation properties, which are experimentally measured using functional assays. hESC cultures are known to be heterogeneous, but whether subsets of cells contribute differently to functional assays has yet to be examined. Here, using clonal tracking by retroviral integration, we analyzed in situ the propensity of individual hESCs to contribute to different functional assays. We observed different clonal distributions in teratomas versus in vitro differentiation assays. Some hESC subsets apparently contributed substantially to lineage specific embryoid body differentiation and lacked clonogenic capacity, although they had self-renewal ability. In contrast, other subsets of self-renewing hESCs with clonogenic ability contributed to teratoma formation but were less frequently observed after in vitro differentiation. Our study suggests that assays used to measure pluripotency may detect distinct subsets of hESCs. These findings have direct implications for hESC-based therapies that may be optimized based on such functional assays. PMID- 20953175 TI - Mutation discovery by targeted genomic enrichment of multiplexed barcoded samples. AB - Targeted genomic enrichment followed by next-generation DNA sequencing has dramatically increased efficiency of mutation-discovery efforts. We describe a protocol for genomic enrichment of pooled barcoded samples in a single assay that increases experimental flexibility and efficiency. We screened 770 genes (1.4 megabases) in thirty N-ethyl-N-nitrosourea (ENU)-mutagenized rats and identified known variants at >96% sensitivity as well as new mutations at a false positive rate < 1 in 8 megabases. PMID- 20953176 TI - Efficient CNS gene delivery by intravenous injection. AB - We administered recombinant SV40-derived viral vectors (rSV40s) intravenously to mice with or without prior intraperitoneal injection of mannitol to deliver transgenes to the central nervous system (CNS). We detected transgene-expressing cells (mainly neurons) most prominently in the cortex and spinal cord; prior intraperitoneal mannitol injection increased CNS gene delivery tenfold. Intravenous injection of rSV40s, particularly with mannitol pretreatment, resulted in extensive expression of multiple transgenes throughout the CNS. PMID- 20953177 TI - Dual RMCE for efficient re-engineering of mouse mutant alleles. AB - We have developed dual recombinase-mediated cassette exchange (dRMCE) to efficiently re-engineer the thousands of available conditional alleles in mouse embryonic stem cells. dRMCE takes advantage of the wild-type loxP and FRT sites present in these conditional alleles and in many gene-trap lines. dRMCE is a scalable, flexible tool to introduce tags, reporters and mutant coding regions into an endogenous locus of interest in an easy and highly efficient manner. PMID- 20953178 TI - Exciton-like trap states limit electron mobility in TiO2 nanotubes. AB - Nanoparticle films have become a promising low-cost, high-surface-area electrode material for solar cells and solar fuel production. Compared to sintered nanoparticle films, oriented polycrystalline titania nanotubes offer the advantage of directed electron transport, and are expected to have higher electron mobility. However, macroscopic measurements have revealed their electron mobility to be as low as that of nanoparticle films. Here, we show, through time resolved terahertz spectroscopy, that low mobility in polycrystalline TiO(2) nanotubes is not due to scattering from grain boundaries or disorder-induced localization as in other nanomaterials, but instead results from a single sharp resonance arising from exciton-like trap states. If the number of these states can be lowered, this could lead to improved electron transport in titania nanotubes and significantly better solar cell performance. PMID- 20953180 TI - Binding-induced folding of prokaryotic ubiquitin-like protein on the Mycobacterium proteasomal ATPase targets substrates for degradation. AB - Mycobacterium tuberculosis uses a proteasome system that is analogous to the eukaryotic ubiquitin-proteasome pathway and is required for pathogenesis. However, the bacterial analog of ubiquitin, prokaryotic ubiquitin-like protein (Pup), is an intrinsically disordered protein that bears little sequence or structural resemblance to the highly structured ubiquitin. Thus, it was unknown how pupylated proteins were recruited to the proteasome. Here, we show that the Mycobacterium proteasomal ATPase (Mpa) has three pairs of tentacle-like coiled coils that recognize Pup. Mpa bound unstructured Pup through hydrophobic interactions and a network of hydrogen bonds, leading to the formation of an alpha-helix in Pup. Our work describes a binding-induced folding recognition mechanism in the Pup-proteasome system that differs mechanistically from substrate recognition in the ubiquitin-proteasome system. This key difference between the prokaryotic and eukaryotic systems could be exploited for the development of a small molecule-based treatment for tuberculosis. PMID- 20953179 TI - The program for processing newly synthesized histones H3.1 and H4. AB - The mechanism by which newly synthesized histones are imported into the nucleus and deposited onto replicating chromatin alongside segregating nucleosomal counterparts is poorly understood, yet this program is expected to bear on the putative epigenetic nature of histone post-translational modifications. To define the events by which naive pre-deposition histones are imported into the nucleus, we biochemically purified and characterized the full gamut of histone H3.1 containing complexes from human cytoplasmic fractions and identified their associated histone post-translational modifications. Through reconstitution assays, biophysical analyses and live cell manipulations, we describe in detail this series of events, namely the assembly of H3-H4 dimers, the acetylation of histones by the HAT1 holoenzyme and the transfer of histones between chaperones that culminates with their karyopherin-mediated nuclear import. We further demonstrate the high degree of conservation for this pathway between higher and lower eukaryotes. PMID- 20953181 TI - Structural basis for cooperative RNA binding and export complex assembly by HIV Rev. AB - HIV replication requires nuclear export of unspliced viral RNAs to translate structural proteins and package genomic RNA. Export is mediated by cooperative binding of the Rev protein to the Rev response element (RRE) RNA, to form a highly specific oligomeric ribonucleoprotein (RNP) that binds to the Crm1 host export factor. To understand how protein oligomerization generates cooperativity and specificity for RRE binding, we solved the crystal structure of a Rev dimer at 2.5-A resolution. The dimer arrangement organizes arginine-rich helices at the ends of a V-shaped assembly to bind adjacent RNA sites and structurally couple dimerization and RNA recognition. A second protein-protein interface arranges higher-order Rev oligomers to act as an adaptor to the host export machinery, with viral RNA bound to one face and Crm1 to another, the oligomers thereby using small, interconnected modules to physically arrange the RNP for efficient export. PMID- 20953182 TI - Oxygen reduction in nanoporous metal-ionic liquid composite electrocatalysts. AB - The improvement of catalysts for the four-electron oxygen-reduction reaction (ORR; O(2) + 4H(+) + 4e(-) -> 2H(2)O) remains a critical challenge for fuel cells and other electrochemical-energy technologies. Recent attention in this area has centred on the development of metal alloys with nanostructured compositional gradients (for example, core-shell structure) that exhibit higher activity than supported Pt nanoparticles (Pt-C; refs 1-7). For instance, with a Pt outer surface and Ni-rich second atomic layer, Pt(3)Ni(111) is one of the most active surfaces for the ORR (ref. 8), owing to a shift in the d-band centre of the surface Pt atoms that results in a weakened interaction between Pt and intermediate oxide species, freeing more active sites for O(2) adsorption. However, enhancements due solely to alloy structure and composition may not be sufficient to reduce the mass activity enough to satisfy the requirements for fuel-cell commercialization, especially as the high activity of particular crystal surface facets may not easily translate to polyfaceted particles. Here we show that a tailored geometric and chemical materials architecture can further improve ORR catalysis by demonstrating that a composite nanoporous Ni-Pt alloy impregnated with a hydrophobic, high-oxygen-solubility and protic ionic liquid has extremely high mass activity. The results are consistent with an engineered chemical bias within a catalytically active nanoporous framework that pushes the ORR towards completion. PMID- 20953183 TI - Observation of the fractional quantum Hall effect in an oxide. AB - The quantum Hall effect arises from the cyclotron motion of charge carriers in two-dimensional systems. However, the ground states related to the integer and fractional quantum Hall effect, respectively, are of entirely different origin. The former can be explained within a single-particle picture; the latter arises from electron correlation effects governed by Coulomb interaction. The prerequisite for the observation of these effects is extremely smooth interfaces of the thin film layers to which the charge carriers are confined. So far, experimental observations of such quantum transport phenomena have been limited to a few material systems based on silicon, III-V compounds and graphene. In ionic materials, the correlation between electrons is expected to be more pronounced than in the conventional heterostructures, owing to a large effective mass of charge carriers. Here we report the observation of the fractional quantum Hall effect in MgZnO/ZnO heterostructures grown by molecular-beam epitaxy, in which the electron mobility exceeds 180,000 cm(2) V(-1) s(-1). Fractional states such as nu = 4/3, 5/3 and 8/3 clearly emerge, and the appearance of the nu = 2/5 state is indicated. The present study represents a technological advance in oxide electronics that provides opportunities to explore strongly correlated phenomena in quantum transport of dilute carriers. PMID- 20953184 TI - DNA-controlled assembly of a NaTl lattice structure from gold nanoparticles and protein nanoparticles. AB - The formation of diamond structures from tailorable building blocks is an important goal in colloidal crystallization because the non-compact diamond lattice is an essential component of photonic crystals for the visible-light range. However, designing nanoparticle systems that self-assemble into non compact structures has proved difficult. Although several methods have been proposed, single-component nanoparticle assembly of a diamond structure has not been reported. Binary systems, in which at least one component is arranged in a diamond lattice, provide alternatives, but control of interparticle interactions is critical to this approach. DNA has been used for this purpose in a number of systems. Here we show the creation of a non-compact lattice by DNA-programmed crystallization using surface-modified Qbeta phage capsid particles and gold nanoparticles, engineered to have similar effective radii. When combined with the proper connecting oligonucleotides, these components form NaTl-type colloidal crystalline structures containing interpenetrating organic and inorganic diamond lattices, as determined by small-angle X-ray scattering. DNA control of assembly is therefore shown to be compatible with particles possessing very different properties, as long as they are amenable to surface modification. PMID- 20953185 TI - Waterproof AlInGaP optoelectronics on stretchable substrates with applications in biomedicine and robotics. AB - Inorganic light-emitting diodes and photodetectors represent important, established technologies for solid-state lighting, digital imaging and many other applications. Eliminating mechanical and geometrical design constraints imposed by the supporting semiconductor wafers can enable alternative uses in areas such as biomedicine and robotics. Here we describe systems that consist of arrays of interconnected, ultrathin inorganic light-emitting diodes and photodetectors configured in mechanically optimized layouts on unusual substrates. Light emitting sutures, implantable sheets and illuminated plasmonic crystals that are compatible with complete immersion in biofluids illustrate the suitability of these technologies for use in biomedicine. Waterproof optical-proximity-sensor tapes capable of conformal integration on curved surfaces of gloves and thin, refractive-index monitors wrapped on tubing for intravenous delivery systems demonstrate possibilities in robotics and clinical medicine. These and related systems may create important, unconventional opportunities for optoelectronic devices. PMID- 20953186 TI - Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. AB - Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 * 10-17). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 * 10-3). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 * 10 20, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV. PMID- 20953187 TI - Association analyses identify six new psoriasis susceptibility loci in the Chinese population. AB - We extended our previous genome-wide association study for psoriasis with a multistage replication study including 8,312 individuals with psoriasis (cases) and 12,919 controls from China as well as 3,293 cases and 4,188 controls from Germany and the United States and 254 nuclear families from the United States. We identified six new susceptibility loci associated with psoriasis in the Chinese study containing the candidate genes ERAP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A (combined P < 5 * 10-8) and replicated one locus, 5q33.1 (TNIP1-ANXA6), previously reported (combined P = 3.8 * 10-21) in the European studies. Two of these loci showed evidence for association in the German study at ZNF816A and GJB2 with P = 3.6 * 10-3 and P = 7.9 * 10-3, respectively. ERAP1 and ZNF816A were associated with type 1 (early onset) psoriasis in the Chinese Han population (test for heterogeneity P = 6.5 * 10-3 and P = 1.5 * 10-3, respectively). Comparisons with the results of previous GWAS of psoriasis highlight the heterogeneity of disease susceptibility between the Chinese and European populations. Our study identifies new genetic susceptibility factors and suggests new biological pathways in psoriasis. PMID- 20953188 TI - Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. AB - Psoriasis is a multifactorial skin disease characterized by epidermal hyperproliferation and chronic inflammation, the most common form of which is psoriasis vulgaris (PsV). We present a genome-wide association analysis of 2,339,118 SNPs in 472 PsV cases and 1,146 controls from Germany, with follow-up of the 147 most significant SNPs in 2,746 PsV cases and 4,140 controls from three independent replication panels. We identified an association at TRAF3IP2 on 6q21 and genotyped two SNPs at this locus in two additional replication panels (the combined discovery and replication panels consisted of 6,487 cases and 8,037 controls; combined P = 2.36 * 10-10 for rs13210247 and combined P = 1.24 * 10-16 for rs33980500). About 15% of psoriasis cases develop psoriatic arthritis (PsA). A stratified analysis of our datasets including only PsA cases (1,922 cases compared to 8,037 controls, P = 4.57 * 10-12 for rs33980500) suggested that TRAF3IP2 represents a shared susceptibility for PsV and PsA. TRAF3IP2 encodes a protein involved in IL-17 signaling and which interacts with members of the Rel/NF-kappaB transcription factor family. PMID- 20953189 TI - Genome-wide association analysis identifies three psoriasis susceptibility loci. AB - We carried out a meta-analysis of two recent psoriasis genome-wide association studies with a combined discovery sample of 1,831 affected individuals (cases) and 2,546 controls. One hundred and two loci selected based on P value rankings were followed up in a three-stage replication study including 4,064 cases and 4,685 controls from Michigan, Toronto, Newfoundland and Germany. In the combined meta-analysis, we identified three new susceptibility loci, including one at NOS2 (rs4795067, combined P = 4 * 10-11), one at FBXL19 (rs10782001, combined P = 9 * 10-10) and one near PSMA6-NFKBIA (rs12586317, combined P = 2 * 10-8). All three loci were also associated with psoriatic arthritis (rs4795067, combined P = 1 * 10-5; rs10782001, combined P = 4 * 10-8; and rs12586317, combined P = 6 * 1-5) and purely cutaneous psoriasis (rs4795067, combined P = 1 * 10-8; rs10782001, combined P = 2 * 10-6; and rs12586317, combined P = 1 * 10-6). We also replicated a recently identified association signal near RNF114 (rs495337, combined P = 2 * 10-7). PMID- 20953191 TI - The kinetic parameters and energy cost of the Hsp70 chaperone as a polypeptide unfoldase. AB - Hsp70-Hsp40-NEF and possibly Hsp100 are the only known molecular chaperones that can use the energy of ATP to convert stably pre-aggregated polypeptides into natively refolded proteins. However, the kinetic parameters and ATP costs have remained elusive because refolding reactions have only been successful with a molar excess of chaperones over their polypeptide substrates. Here we describe a stable, misfolded luciferase species that can be efficiently renatured by substoichiometric amounts of bacterial Hsp70-Hsp40-NEF. The reactivation rates increased with substrate concentration and followed saturation kinetics, thus allowing the determination of apparent V(max)' and K(m)' values for a chaperone mediated renaturation reaction for the first time. Under the in vitro conditions used, one Hsp70 molecule consumed five ATPs to effectively unfold a single misfolded protein into an intermediate that, upon chaperone dissociation, spontaneously refolded to the native state, a process with an ATP cost a thousand times lower than expected for protein degradation and resynthesis. PMID- 20953190 TI - A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. AB - To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 * 10-8 and two loci with a combined P < 5 * 10-7). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 * 10-6). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis. PMID- 20953192 TI - Small-molecule inactivation of HIV-1 NCp7 by repetitive intracellular acyl transfer. AB - The zinc fingers of the HIV-1 nucleocapsid protein, NCp7, are prime targets for antiretroviral therapeutics. Here we show that S-acyl-2-mercaptobenzamide thioester (SAMT) chemotypes inhibit HIV by modifying the NCp7 region of Gag in infected cells, thereby blocking Gag processing and reducing infectivity. The thiol produced by SAMT reaction with NCp7 is acetylated by cellular enzymes to regenerate active SAMTs via a recycling mechanism unique among small-molecule inhibitors of HIV. PMID- 20953193 TI - The functional asymmetry of auditory cortex is reflected in the organization of local cortical circuits. AB - The primary auditory cortex (A1) is organized tonotopically, with neurons sensitive to high and low frequencies arranged in a rostro-caudal gradient. We used laser scanning photostimulation in acute slices to study the organization of local excitatory connections onto layers 2 and 3 (L2/3) of the mouse A1. Consistent with the organization of other cortical regions, synaptic inputs along the isofrequency axis (orthogonal to the tonotopic axis) arose predominantly within a column. By contrast, we found that local connections along the tonotopic axis differed from those along the isofrequency axis: some input pathways to L3 (but not L2) arose predominantly out-of-column. In vivo cell-attached recordings revealed differences between the sound-responsiveness of neurons in L2 and L3. Our results are consistent with the hypothesis that auditory cortical microcircuitry is specialized to the one-dimensional representation of frequency in the auditory cortex. PMID- 20953194 TI - Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. AB - Many mutations confer one or more toxic function(s) on copper/zinc superoxide dismutase 1 (SOD1) that impair motor neuron viability and cause familial amyotrophic lateral sclerosis (FALS). Using a conformation-specific antibody that detects misfolded SOD1 (C4F6), we found that oxidized wild-type SOD1 and mutant SOD1 share a conformational epitope that is not present in normal wild-type SOD1. In a subset of human sporadic ALS (SALS) cases, motor neurons in the lumbosacral spinal cord were markedly C4F6 immunoreactive, indicating that an aberrant wild type SOD1 species was present. Recombinant, oxidized wild-type SOD1 and wild-type SOD1 immunopurified from SALS tissues inhibited kinesin-based fast axonal transport in a manner similar to that of FALS-linked mutant SOD1. Our findings suggest that wild-type SOD1 can be pathogenic in SALS and identify an SOD1 dependent pathogenic mechanism common to FALS and SALS. PMID- 20953195 TI - Fezf2 directs the differentiation of corticofugal neurons from striatal progenitors in vivo. AB - In the developing cerebral cortex, cell-extrinsic and cell-intrinsic signals govern the establishment of neuron subtype-specific identity. Here we show that, within the niche of the striatum, the expression of a single transcription factor, Fezf2, is sufficient to generate corticofugal neurons from progenitors fated to become medium spiny neurons. This demonstrates that a specific population of cortical projection neurons can be directed to differentiate outside of the cortex by cell-autonomous signaling. PMID- 20953196 TI - N-type Ca2+ channels carry the largest current: implications for nanodomains and transmitter release. AB - Presynaptic terminals favor intermediate-conductance Ca(V)2.2 (N type) over high conductance Ca(V)1 (L type) channels for single-channel, Ca(2+) nanodomain triggered synaptic vesicle fusion. However, the standard Ca(V)1>Ca(V)2>Ca(V)3 conductance hierarchy is based on recordings using nonphysiological divalent ion concentrations. We found that, with physiological Ca(2+) gradients, the hierarchy was Ca(V)2.2>Ca(V)1>Ca(V)3. Mathematical modeling predicts that the Ca(V)2.2 Ca(2+) nanodomain, which is ~25% more extensive than that generated by Ca(V)1, can activate a calcium-fusion sensor located on the proximal face of the synaptic vesicle. PMID- 20953197 TI - Non-redundant odor coding by sister mitral cells revealed by light addressable glomeruli in the mouse. AB - Sensory inputs frequently converge on the brain in a spatially organized manner, often with overlapping inputs to multiple target neurons. Whether the responses of target neurons with common inputs become decorrelated depends on the contribution of local circuit interactions. We addressed this issue in the olfactory system using newly generated transgenic mice that express channelrhodopsin-2 in all of the olfactory sensory neurons. By selectively stimulating individual glomeruli with light, we identified mitral/tufted cells that receive common input (sister cells). Sister cells had highly correlated responses to odors, as measured by average spike rates, but their spike timing in relation to respiration was differentially altered. In contrast, non-sister cells correlated poorly on both of these measures. We suggest that sister mitral/tufted cells carry two different channels of information: average activity representing shared glomerular input and phase-specific information that refines odor representations and is substantially independent for sister cells. PMID- 20953198 TI - Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. AB - For many antibodies, each antigen-binding site binds to only one antigen molecule during the antibody's lifetime in plasma. To increase the number of cycles of antigen binding and lysosomal degradation, we engineered tocilizumab (Actemra), an antibody against the IL-6 receptor (IL-6R), to rapidly dissociate from IL-6R within the acidic environment of the endosome (pH 6.0) while maintaining its binding affinity to IL-6R in plasma (pH 7.4). Studies using normal mice and mice expressing human IL-6R suggested that this pH-dependent IL-6R dissociation within the acidic environment of the endosome resulted in lysosomal degradation of the previously bound IL-6R while releasing the free antibody back to the plasma to bind another IL-6R molecule. In cynomolgus monkeys, an antibody with pH-dependent antigen binding, but not an affinity-matured variant, significantly improved the pharmacokinetics and duration of C-reactive protein inhibition. Engineering pH dependency into the interactions of therapeutic antibodies with their targets may enable them to be delivered less frequently or at lower doses. PMID- 20953199 TI - The histone H4 Lys 20 methyltransferase PR-Set7 regulates replication origins in mammalian cells. AB - The initiation of DNA synthesis is governed by the licensing of replication origins, which consists of assembling a pre-replication complex (pre-RC) on origins during late M- and G1-phases. In metazoans, functional replication origins do not show defined DNA consensus sequences, thus evoking the involvement of chromatin determinants in the selection of these origins. Here, we show that the onset of licensing in mammalian cells coincides with an increase in histone H4 Lys 20 monomethylation (H4K20me1) at replication origins by the methyltransferase PR-Set7 (also known as Set8 or KMT5A). Indeed, tethering PR Set7 methylase activity to a specific genomic locus promotes the loading of pre RC proteins on chromatin. In addition, we demonstrate that PR-Set7 undergoes a PCNA- and Cul4-Ddb1-driven degradation during S phase that contributes to the disappearance of H4K20me1 at origins and the inhibition of replication licensing. Strikingly, expression of a PR-Set7 mutant insensitive to this degradation causes the maintenance of H4K20me1 and repeated DNA replication at origins. These results elucidate a critical role for PR-Set7 and H4K20me1 in the chromatin events that regulate replication origins. PMID- 20953200 TI - A negative regulator of MAP kinase causes depressive behavior. AB - The lifetime prevalence (~16%) and the economic burden ($100 billion annually) associated with major depressive disorder (MDD) make it one of the most common and debilitating neurobiological illnesses. To date, the exact cellular and molecular mechanisms underlying the pathophysiology of MDD have not been identified. Here we use whole-genome expression profiling of postmortem tissue and show significantly increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1, encoded by DUSP1, but hereafter called MKP-1) in the hippocampal subfields of subjects with MDD compared to matched controls. MKP-1, also known as dual-specificity phosphatase-1 (DUSP1), is a member of a family of proteins that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of the MAPK cascade, a major signaling pathway involved in neuronal plasticity, function and survival. We tested the role of altered MKP-1 expression in rat and mouse models of depression and found that increased hippocampal MKP-1 expression, as a result of stress or viral-mediated gene transfer, causes depressive behaviors. Conversely, chronic antidepressant treatment normalizes stress-induced MKP-1 expression and behavior, and mice lacking MKP-1 are resilient to stress. These postmortem and preclinical studies identify MKP-1 as a key factor in MDD pathophysiology and as a new target for therapeutic interventions. PMID- 20953202 TI - The complexities of identifying a cell of origin for human prostate cancer. PMID- 20953201 TI - IL-35-mediated induction of a potent regulatory T cell population. AB - Regulatory T cells (T(reg) cells) have a critical role in the maintenance of immunological self-tolerance. Here we show that treatment of naive human or mouse T cells with IL-35 induced a regulatory population, which we call 'iT(R)35 cells', that mediated suppression via IL-35 but not via the inhibitory cytokines IL-10 or transforming growth factor-beta (TGF-beta). We found that iT(R)35 cells did not express or require the transcription factor Foxp3, and were strongly suppressive and stable in vivo. T(reg) cells induced the generation of iT(R)35 cells in an IL-35- and IL-10-dependent manner in vitro and induced their generation in vivo under inflammatory conditions in intestines infected with Trichuris muris and within the tumor microenvironment (B16 melanoma and MC38 colorectal adenocarcinoma), where they contributed to the regulatory milieu. Thus, iT(R)35 cells constitute a key mediator of infectious tolerance and contribute to T(reg) cell-mediated tumor progression. Furthermore, iT(R)35 cells generated ex vivo might have therapeutic utility. PMID- 20953203 TI - Non-genetic contributions of the sperm nucleus to embryonic development. AB - Recent data from several laboratories have provided evidence that the newly fertilized oocyte inherits epigenetic signals from the sperm chromatin that are required for proper embryonic development. For the purposes of this review, the term epigenetic is used to describe all types of molecular information that are transmitted from the sperm cell to the embryo. There are at least six different forms of epigenetic information that have already been established as being required for proper embryogenesis in mammals or for which there is evidence that it may do so. These are (i) DNA methylation; (ii) sperm-specific histones, (iii) other chromatin-associated proteins; (iv) the perinuclear theca proteins; (v) sperm-born RNAs and, the focus of this review; and (vi) the DNA loop domain organization by the sperm nuclear matrix. These epigenetic signals should be considered when designing protocols for the manipulation and cryopreservation of spermatozoa for assisted reproductive technology as necessary components for effective fertilization and subsequent embryo development. PMID- 20953204 TI - Rimonabant inhibits TNF-alpha-induced endothelial IL-6 secretion via CB1 receptor and cAMP-dependent protein kinase pathway. AB - AIM: To investigate whether rimonabant, a cannabinoid receptor antagonist, had inhibitory effects on inflammatory reactions in human umbilical vein endothelial cells (HUVEC). METHODS: TNF-alpha-induced IL-6 production was measured by ELISA and effects on related signaling pathways were investigated by immunoblot analysis. Cellular cAMP level was measured using kinase-coupled luciferase reaction. RESULTS: Rimonabant at 1 and 10 MUmol/L significantly inhibited TNF alpha-induced IL-6 production when added 15, 30 and 60 minutes before TNF-alpha treatment. Rimonabant also inhibited TNF-alpha-induced phosphorylation of IkappaB kinase (IKK) alpha/beta and IkappaB-alpha degradation. ACEA, a cannabinoid receptor subtype 1 (CB1) agonist, added before rimonabant abolished the former effects of rimonabant. H-89, an inhibitor of cAMP-dependent protein kinase (PKA), abolished the inhibitory effects of rimonabant on TNF-alpha induced IL-6 production. Rimonabant also increased the phosphorylation of PKA regulatory subunit II (PKA-RII), implying the essential role of PKA activation in the inhibitory effects of rimonabant. Treatment with the phosphatidylinositol 3 kinase (PI3K) inhibitor, wortmannin did not abolish the inhibitory effects of rimonabant on TNF-alpha induced IL-6 production. CONCLUSION: Rimonabant had anti inflammatory effects on endothelial cells and inhibited TNF-alpha-induced IKKalpha/beta phosphorylation, IkappaB-alpha degradation and IL-6 production in HUVEC. This effect was related to CB1 antagonism and PKA activation. PMID- 20953205 TI - The role of Nrf2 signaling in the regulation of antioxidants and detoxifying enzymes after traumatic brain injury in rats and mice. AB - AIM: To determine whether Nrf2 signaling pathway activation could attenuate oxidative stress and neuronal damage following traumatic brain injury (TBI). METHODS: Controlled cortical impact (CCI) injury was performed in Sprague-Dawley rats and Nrf2-knockout or control mice. Sulforaphane (SFN), a potent Nrf2 activator, was used to activate Nrf2. Oxidative stress, lesion volume, neuron degeneration, and neurologic dysfunction were determined using biochemical, histopathological and neuroethologic approaches. Protein and mRNA levels of Nrf2 and the antioxidant enzymes heme oxygenase 1 (HO-1) and NAD(P)H:quinine oxidoreductase 1 (NQO1) were assessed using Western blot analysis and RT-PCR. RESULTS: Activation of Nrf2 by SFN( 5 mg/kg, ip) induced the nuclear translocation and activation of Nrf2, which resulted in an up-regulation of Nrf2 dependent antioxidant enzymes and a reduction of oxidative damage after TBI. In accordance with these biochemical changes, SFN also significantly reduced neuronal death, contusion volume, and neurological dysfunction after TBI. Furthermore, Nrf2-knockout mice showed more severe oxidative stress and neurologic deficits after TBI and did not benefit from the effects of SFN. CONCLUSION: Nrf2 plays a pivotal role in cell defenses against the oxidative stress of TBI. In addition, pharmacological activation of the Nrf2 signaling pathway by small molecule inducers such as SFN attenuated oxidative stress and neuronal damage following TBI. PMID- 20953206 TI - Differentiation of embryonic stem cells into hepatocytes that coexpress coagulation factors VIII and IX. AB - AIM: To establish an efficient culture system to support embryonic stem (ES) cell differentiation into hepatocytes that coexpress F-VIII and F-IX. METHODS: Mouse E14 ES cells were cultured in differentiation medium containing sodium butyrate (SB), basic fibroblast growth factor (bFGF), and/or bone morphogenetic protein 4 (BMP4) to induce the differentiation of endoderm cells and hepatic progenitor cells. Hepatocyte growth factor, oncostatin M, and dexamethasone were then used to induce the maturation of ES cell-derived hepatocytes. The mRNA expression levels of endoderm-specific genes and hepatocyte-specific genes, including the levels of F-VIII and F-IX, were detected by RT-PCR and real-time PCR during various stages of differentiation. Protein expression was examined by immunofluorescence and Western blot. At the final stage of differentiation, flow cytometry was performed to determine the percentage of cells coexpressing F-VIII and F-IX, and ELISA was used to detect the levels of F-VIII and F-IX protein secreted into the culture medium. RESULTS: The expression of endoderm-specific and hepatocyte-specific markers was upregulated to highest level in response to the combination of SB, bFGF, and BMP4. Treatment with the three inducers during hepatic progenitor differentiation significantly enhanced the mRNA and protein levels of F-VIII and F-IX in ES cell-derived hepatocytes. More importantly, F VIII and F-IX were coexpressed with high efficiency at the final stage of differentiation, and they were also secreted into the culture medium. CONCLUSION: We have established a novel in vitro differentiation protocol for ES-derived hepatocytes that coexpress F-VIII and F-IX that may provide a foundation for stem cell replacement therapy for hemophilia. PMID- 20953208 TI - No association between LRP5 gene polymorphisms and bone and obesity phenotypes in Chinese male-offspring nuclear families. AB - AIM: To investigate the effect of low-density lipoprotein receptor-related protein 5 (LRP5) gene polymorphisms on bone and obesity phenotypes in young Chinese men. METHODS: A total of 1244 subjects from 411 Chinese nuclear families were genotyped by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique at the Q89R, N740N, and A1330V sites in the LRP5 gene. Bone mineral density (BMD) in the lumbar spine and the hip, total fat mass and total lean mass were measured using dual-energy X-ray absorptiometry. The association between LRP5 gene polymorphisms and peak BMD, body mass index (BMI), total fat mass, total lean mass and percentage of fat mass was assessed using a quantitative transmission disequilibrium test (QTDT). RESULTS: No significant within-family associations were found between genotypes or haplotypes of the LRP5 gene and peak BMD, BMI, total fat mass, total lean mass and percentage of fat mass. The 1000 permutations that were subsequently simulated were in agreement with these within-family association results. CONCLUSION: Our results suggest that common polymorphic variations of the LRP5 gene do not influence peak bone mass acquisition and obesity phenotypes in young Chinese men. PMID- 20953209 TI - Implantation of bFGF-treated islet progenitor cells ameliorates streptozotocin induced diabetes in rats. AB - AIM: To examine whether implantation of islet preparation-derived proliferating islet cells (PIC) could ameliorate diabetes in rats. METHODS: PIC were expanded from rat islet preparation by supplementation of basic fibroblast growth factor (bFGF) and implanted into rats with streptozotocin (STZ)-induced diabetes through the portal vein. Body weight and blood glucose levels were measured. Serum insulin levels were measured by radioimmunoassay. The presence of insulin positive cells was determined by hematoxylin and immunohistochemical staining. RESULTS: Cultured islet cells (CIC) were demonstrated to dedifferentiate in vitro, and the apoptosis ratios reached more than 50% by the 15th day post isolation. PIC cells treated with bFGF (20 ng/mL) continued growing within 30 days after isolation, and no apoptotic cells were detected. Implantation of PIC into diabetic rats was capable of ameliorating diabetes, in terms of the restoration of euglycemia, weight gain, improved glucose response and elevated serum insulin levels for up to 130 days. Livers derived from PIC-implanted rats were examined for insulin expression and single insulin-positive cells. In addition, most islets of PIC-implanted STZ-induced diabetic rats were intact at 130 days post-transplantation and comparable to those of normal rats. CONCLUSION: Implantation of bFGF-treated proliferating islet cells is a promising cellular therapeutic approach for diabetes. PMID- 20953207 TI - Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets. AB - Hepatocellular carcinoma (HCC) is a major health problem worldwide responsible for 500 000 deaths annually. A number of risk factors are associated with either the induction of the disease or its progression; these include infection with hepatitis B or C virus, alcohol consumption, non-alcoholic steatohepatitis and certain congenital disorders. In around 80% of the cases, HCC is associated with cirrhosis or advanced fibrosis and with inflammation and oxidative stress. In this review we focus firstly on the different risk factors for HCC and summarize the mechanisms by which each is considered to contribute to HCC. In the second part we look at the molecular processes involved in cancer progression. HCC development is recognized as a multistep process that normally develops over many years. Over this period several mutations accumulate in the cell and that stimulate malign transformation, growth, and metastatic behavior. Over the recent years it has become evident that not only the tumor cell itself but also the tumor microenviroment plays a major role in the development of a tumor. There is a direct link between the role of inflammation and cirrhosis with this microenviroment. Both in vitro and in vivo it has been shown that tumor formation and metastatic properties are linked to epithelial-mesenchymal transition (EMT), a process by which facillitates the tumor cell's attempts to migrate to a more favourable microenviroment. Several groups have analyzed the gene expression in HCC and its surrounding tissue by microarray and this has resulted in the molecular classification into a distinct number of classes. Here we also found a role for hypoxia induced gene expression leading to a clinically more aggressive gene expression in HCC. Molecular analysis also helped to identify important cellular pathways and possible therapeutic targets. The first molecule that in this way has shown clinical application for liver cancer is the multikinase inhibitor sorafenib, others are currently in different stages of clinical studies like the mTOR inhibitor everolimus. PMID- 20953210 TI - Hyposmotic challenge modulates function of L-type calcium channel in rat ventricular myocytes through protein kinase C. AB - AIM: To study the effects and mechanisms by which hyposmotic challenge modulate function of L-type calcium current (I(Ca,L)) in rat ventricular myocytes. METHODS: The whole-cell patch-clamp techniques were used to record I(Ca,L) in rat ventricular myocytes. RESULTS: Hyposmotic challenge(~220 mosmol/L) induced biphasic changes of I(Ca,L), a transient increase followed by a sustained decrease. I(Ca,L) increased by 19.1%+/-6.1% after short exposure (within 3 min) to hyposmotic solution. On the contrary, long hyposmotic challenge (10 min) decreased I(Ca,L) to 78.1%+/-11.0% of control, caused the inactivation of I(Ca,L), and shifted the steady-state inactivation curve of I(Ca,L) to the right. The decreased I(Ca,L) induced by hyposmotic swelling was reversed by isoproterenol or protein kinase A (PKA) activator foskolin. Hyposmotic swelling also reduced the stimulated I(Ca,L) by isoproterenol or foskolin. PKA inhibitor H 89 abolished swelling-induced transient increase of I(Ca,L), but did not affect the swelling-induced sustained decrease of I(Ca,L). NO donor SNAP and protein kinase G (PKG) inhibitor Rp-8-Br-PET-cGMPS did not interfere with swelling induced biphasic changes of I(Ca,L). Protein kinase C (PKC) activator PMA decreased I(Ca,L) and hyposmotic solution with PMA reverted the decreased I(Ca,L) by PMA. PKC inhibitor BIM prevented the swelling-induced biphasic changes of I(Ca,L). CONCLUSION: Hyposmotic challenge induced biphasic changes of I(Ca,L), a transient increase followed by a sustained decrease, in rat ventricular myocytes through PKC pathway, but not PKG pathway. PKA system could be responsible for the transient increase of I(Ca,L) during short exposure to hyposmotic solution. PMID- 20953211 TI - Population pharmacokinetics of rhTNFR-Fc in healthy Chinese volunteers and in Chinese patients with Ankylosing spondylitis. AB - AIM: To investigate the population pharmacokinetics of recombinant human tumor necrosis factor receptor-Fc fusion protein (rhTNFR-Fc) administered via subcutaneous (SC) injection in healthy Chinese volunteers and in Chinese patients with ankylosing spondylitis (AS). METHODS: Thirty-two healthy volunteers were randomly assigned to receive a single SC injection of 12.5, 25, 37.5, or 50 mg of rhTNFR-Fc. Twenty male patients with moderate AS were randomly assigned to receive seven consecutive SC injections of rhTNFR-Fc at either 25 mg twice a week (BIW) or 50 mg once a week (QW). Population pharmacokinetic (PK) analysis was applied to obtain PK parameters of rhTNFR-Fc by the NONMEM method. RESULTS: The data were best described by a one-compartment model with lag time. We found that gender had a significant effect on the apparent clearance (CL/F), with the male CL/F ratio being only 0.665 times the female ratio; the absorption coefficient (F) of multiple dosages of rhTNFR-Fc was only 0.674 times that of a single dosage. The outcome parameters were CL/F (female: 0.168 L/h, male: 0.110 L/h), the apparent volume of distribution (Vd/F: 15.5 L), the absorption rate constant (Ka) (single dosage: 0.0605 h-1, multiple dosage: 0.0408 h-1), and the lag time (T(lag): 1.03 h). The inter-individual variability in the CL/F, Vd/F, Ka, and T(lag) were 33.3%, 42.7%, 55.6%, and 81.8%, respectively. CONCLUSION: Chinese females have a higher CL/F than Chinese males, and multiple dosings can significantly decrease the absorption of rhTNFR-Fc (SC). The population PK parameters of rhTNFR-Fc in healthy Chinese volunteers and patients with AS were similar to those reported for subjects in published American studies. PMID- 20953212 TI - Complex traits: Using genetic architecture to improve predictions. PMID- 20953214 TI - Retraction. Bleomycin/interleukin-12 electrochemogene therapy for treating naturally occurring spontaneous neoplasms in dogs. PMID- 20953215 TI - Using economic data to reduce healthcare-acquired infection. PMID- 20953213 TI - Mechanisms of trinucleotide repeat instability during human development. AB - Trinucleotide expansion underlies several human diseases. Expansion occurs during multiple stages of human development in different cell types, and is sensitive to the gender of the parent who transmits the repeats. Repair and replication models for expansions have been described, but we do not know whether the pathway involved is the same under all conditions and for all repeat tract lengths, which differ among diseases. Currently, researchers rely on bacteria, yeast and mice to study expansion, but these models differ substantially from humans. We need now to connect the dots among human genetics, pathway biochemistry and the appropriate model systems to understand the mechanism of expansion as it occurs in human disease. PMID- 20953216 TI - Regional anaesthesia and pain relief after surgery. PMID- 20953217 TI - Front-of-pack nutrition labelling: where to now? PMID- 20953218 TI - The excess cost associated with healthcare-associated bloodstream infections at Auckland City Hospital. AB - AIM: This study was undertaken to determine the cost of healthcare-associated bloodstream infections (HA-BSI) in adult patients admitted to an Auckland City Hospital. METHOD: A matched cohort study was performed with a 1:2 or 1:1 match in which all patients admitted between January and June 2005 who had HA-BSI were included. Controls were selected from patients admitted between July 2004 and December 2006. Patients with haemodialysis central line-related HA-BSI were not matched with controls as the admission was related purely to that episode of infection. RESULTS: There were 106 episodes of HA-BSI in 99 patients. Fifty-five patients were able to be matched 1:1 or 1:2 with controls, group 1. Nineteen BSI episodes were in patients undergoing renal replacement therapy by haemodialysis and the patients were admitted as a consequence of this episode of infection, group 2. An episode of HA-BSI increased the length of the hospital admission by 9.7 days and 7.9 days in group 1 and group 2, respectively. The excess cost associated with an episode of HA- BSI was $20,394 in group 1 and $11,139 in group 2. CONCLUSION: There are substantial costs associated with HA-BSI. A proportion of these infections can be reduced by effective infection control measures. PMID- 20953219 TI - Introduction of continuous regional analgesia via wound catheters in a peripheral hospital. AB - PURPOSE: To review the effectiveness of continuous regional analgesia (CRA) via wound catheters after abdominal surgery in a district general hospital (Wanganui, New Zealand). METHODS: Retrospective review of postoperative analgesia after CRA via wound catheters was introduced (April 2008 to December 2008). Pain scores, HDU stay, opiate use and complications were recorded. RESULTS: Fifty-four patients' notes have been reviewed after elective and emergency laparotomies. Twenty-seven had WC (+/- patient controlled analgesia [PCA]), 15 had PCA only, 12 had epidural (+/- PCA). Resting pain scores were nil or zero in 18/27 (66.7%) wound catheter, 9/15 (60%) PCA and 5/12 (41.7%) epidural patients. Moderate/severe pain on movement was scored in patients 5/27 (18.5%) with wound catheter, 6/15 (40%) with PCA, 5/12 (41.7%) with epidural catheters. A single PCA syringe lasted over 24 hours in 18/27 (66.7%) wound catheter, 6/15 (40%) PCA, and 5/8 (63%) epidural + PCA patients. Eight adverse effects were seen; 4 wound infections (2 wound catheter, 1 PCA, 1 epidural patient) and 4 blockages of epidural catheters in epidural group. No adverse effect was found directly related to the WC. CONCLUSIONS: Continuous regional analgesia via wound catheters provides effective and safe postoperative analgesia for surgical patients in a small district general hospital. Used as part of a multimodal approach it allows easy step-down from HDU to surgical wards. This technique has been readily accepted over the year by theatre, HDU, ward, and anaesthetics colleagues. PMID- 20953220 TI - Ten-year review of intussusception at Starship Hospital: 1998-2007. AB - AIMS: To review the demographics, presenting features, rates of air enema reduction success, prevalence of pathological lead points and surgical intervention rates and outcomes in patients with intussusception at Starship Children's Hospital (Auckland, New Zealand). To use this data to guide management of children at a national level in New Zealand. METHOD: Retrospective case series. Patients discharged from Starship Children's Hospital between 1 January 1998 and 31 December 2007 with a diagnosis of intussusception were obtained from coding data. RESULTS: 189 patients were analysed. 30% presented with the classic triad of pain, rectal bleeding and mass. 150/189 proceeded to air enema reduction which was successful in 118 (78.7%) of cases with 2 perforations. 54/189 (28.6%) proceeded for operative reduction of which 26 patients required surgical resection. Clinical and radiological evidence of bowel obstruction and duration of symptoms were associated with failed enema and surgical resection. CONCLUSION: Intussusception only occasionally presents with the typical triad of abdominal pain, rectal bleeding and abdominal mass. Air enema reduction is successful at this institution with a low level of complication. Maori and Pacific patients had higher rates of failed enema reduction and need for surgery compared to European patients. Further research is needed from peripheral centres to evaluate outcomes of children treated in district hospitals to identify how and where these children are best managed. PMID- 20953221 TI - Christchurch experience of pulmonary embolism with and without thrombolysis. AB - AIMS: Thrombolysis for normotensive patients with large clot burden pulmonary embolism remains debatable. We aim to document our current management of pulmonary embolism, examining determinants of therapy and outcomes. METHOD: A retrospective chart-based review of all patients admitted with pulmonary embolism under Cardiology service in Christchurch Hospital between 2002-2007. All related CT pulmonary angiograms were also reviewed for quantification of clot burden and evidence of right ventricular strain. RESULTS: 120 patients were admitted during the audit period. Hypotensive patients had a significantly higher troponin level and Qanadli scores. RV/LV ratio >1 in CTPA was 80% sensitive and 57% specific in predicting RV strain on echocardiogram. Forty-six patients were thrombolysed, most with large clot burden and right ventricular strain. No treatment related death or intracranial haemorrhages occurred; however six patients required blood transfusion and six patients had persistent pulmonary hypertension at 6 months. There was a higher in-patient event rate in thrombolysed group, due to increased bleeding, compared to non-thrombolysed patients. CONCLUSION: Thrombolysis was successfully performed with relatively low in-patient and 6-month event rate. Long term advantage over routine anticoagulation was not demonstrated. The role of thrombolysis in normotensive patients with large clot burden remains uncertain. CTPA markers of RV strain correlated well with echocardiography. PMID- 20953222 TI - Surgical outcomes following laparoscopic adrenalectomy for treatment of Conn's syndrome (primary hyperaldosteronism) between 1999 and 2006. AB - BACKGROUND: Primary hyperaldosteronism is a recognised cause of secondary hypertension with its aetiology most commonly due to a secreting aldosterone adenoma of the adrenal gland. Laparoscopic resection of the adrenal tumour has now become the accepted form of intervention. The aim of this study was to assess the effectiveness of such procedures performed by one surgeon over a 7-year period. METHOD: An observational study was conducted in respect of 33 patients who underwent adrenalectomies for primary hyperaldosteronism between 1999-2006. Information on blood pressure, electrolytes, medications, histology, patient characteristics and patients' perception of benefit was gathered via clinical notes and a patient questionnaire. RESULTS: 33 patients were reviewed. The mean follow-up was 38.4 months. Blood pressure and number of medications all had statistically significant decreases. Systolic blood pressure decreased from 146 mmHg preoperatively to 130 mmHg at final follow-up (p<0.00005). Diastolic blood pressure decreased from 91.0 mmHg preoperatively to 81.5 mmHg (p<0.00005). There was also a significant decrease in number of blood pressure medications from 2.3 preoperatively to 1.0 on average (p<0.00005). Only one patient required potassium at final review. Overall 36% had clinical cure and 50% had significant improvement in terms of blood pressure and medications requirements. CONCLUSION: The results suggest unilateral laparoscopic adrenalectomy is an effective tool in treatment for benign primary hyperaldosteronism caused by aldosterone secreting adenomas. PMID- 20953223 TI - Task Manager: an innovative approach to improving hospital communication after hours. AB - AIM: To improve communication between doctors and nurses after hours, by developing a tool to display ward tasks, allowing staff to prioritise their work, without constant interruption from pagers (beepers). SETTING: Middlemore Hospital, a large metropolitan 800-bed hospital in Auckland, New Zealand. METHOD: Introduction of computerised system (Task Manager) to identify, allocate and complete after-hours tasks. RESULTS: In the first 6 months 21,000 tasks have been completed in Task Manager. Paging of junior doctors has decreased by over 30% and there is broad acceptance of the tool by both nursing and medical staff. Task Manager has collected real-time data on the type of after hours tasks (nearly 50% are phlebotomy-related tasks), busy times of the day (1600 hours to 2400 hours) and who is performing most of the tasks. CONCLUSION: Task Manager is a simple yet powerful tool for prioritising routine tasks after hours. It allows staff to quickly create tasks, and communicate effectively with other members of the team. It has reduced the frequency of junior doctors paging so that they can continue their work with fewer interruptions. Whilst it was introduced to improve effective communication after hours, it has become apparent that there are multiple 'tasks' that are ordered in a multitude of ways in our hospital and many could be served by Task Manager. PMID- 20953224 TI - Outcome of patients on azathioprine: a need for a better pre-treatment assessment and dosing guideline. AB - BACKGROUND: Azathioprine (AZA) is a commonly used drug for the management of various rheumatologic disorders. Due to individual variation of the metabolism of AZA, related to genetic polymorphism of the thiopurine methyl transferase (TPMT), serious toxic effects can result if inappropriate dose is administered. AZA dosing according to patients TPMT status can reduce drug-induced morbidity and can be cost effective. AIM: To determine the current local practice of AZA dosing, identify AZA-related toxicity and to compare the local practice with the British Society of Rheumatology (BSR) recommendations. METHODS: Retrospective review of patients on AZA for various rheumatologic conditions from inpatient (n=22) and outpatient (n=38) database at Middlemore Hospital, from January 2003 to January 2007. Data were collected on patient's demographics, treatment history including AZA dosing regimen, TPMT testing, drug-related toxicities and their management. RESULTS: The mean age was 53 years; 73% were females. 43% of European ethnicity; mean weight of patient was 75+/-25 kg. 42% had SLE, 22% had rheumatoid arthritis, and 13% had systemic vasculitis. Average initial dose of AZA prescribed was 100+/-37 mg. 45% developed AZA related toxicity. AZA was withdrawn in 35 % of patients due to drug-related side-effects and inefficacy.15% of the patients required dose reduction. TPMT status was tested in 6 (10%) patients; three had low TMPT level, needing dose reduction. BSR recommendation for AZA dosing was followed in 15% cases. CONCLUSION: A significant proportion of the studied cohort of rheumatologic patients on AZA had drug-related toxicity resulting in discontinuation of AZA. Our data suggests that better pre-treatment assessment including TPMT testing and the practice of guideline based dosing regimen would reduce the incidence of undue side-effects and discontinuation of such treatment. PMID- 20953225 TI - Fibrates plus betaine: a winning combination? AB - Because most of the cardiac risk remains despite successful statin therapy there has been renewed interest in fibrate therapy for persisting hyperlipidaemia. Fibrate therapy lowers triglycerides but causes the urinary loss of betaine, which is an essential metabolite that is involved in osmoregulation, in methyl group metabolism, and which also affects lipid partitioning in the body. Loss of betaine is associated with an elevation of homocysteine and may compromise the potential benefits of fibrate therapy. However, betaine deficiency could be easily and inexpensively corrected by concurrent betaine supplementation. Clinical trials of combinations of betaine and fibrate, to complement statin therapy, are needed to determine the value of these agents in reducing the residual cardiovascular disease risk. PMID- 20953226 TI - Persistent arthritis following Chikungunya virus infection. PMID- 20953227 TI - Axillary breast cancer in a Nigerian woman. AB - Ectopic breast cancer is rare and diagnosis is commonly delayed. We report the case of a 34-year-old Nigerian woman with a locally advanced invasive ductal carcinoma in the axillary breast. She underwent an axillary mastectomy and is due to receive adjuvant chemotherapy and radiotherapy. The management of this patient is discussed in relation to existing medical literature on the subject. PMID- 20953228 TI - Pituitary involvement in Langerhans-cell histiocytosis. PMID- 20953229 TI - Medical image. Combination NSAID-codeine preparations and gastrointestinal toxicity. PMID- 20953230 TI - Very cheap drinking in New Zealand: some alcohol is more affordable than bottled water and nearly as cheap as milk. PMID- 20953231 TI - Answer to NZMJ about Ron Jones' research. PMID- 20953232 TI - Hype around high-dose vitamin C is unjustified. PMID- 20953234 TI - The Brain's Cutting-Room Floor: Segmentation of Narrative Cinema. AB - Observers segment ongoing activity into meaningful events. Segmentation is a core component of perception that helps determine memory and guide planning. The current study tested the hypotheses that event segmentation is an automatic component of the perception of extended naturalistic activity, and that the identification of event boundaries in such activities results in part from processing changes in the perceived situation. Observers may identify boundaries between events as a result of processing changes in the observed situation. To test this hypothesis and study this potential mechanism, we measured brain activity while participants viewed an extended narrative film. Large transient responses were observed when the activity was segmented, and these responses were mediated by changes in the observed activity, including characters and their interactions, interactions with objects, spatial location, goals, and causes. These results support accounts that propose event segmentation is automatic and depends on processing meaningful changes in the perceived situation; they are the first to show such effects for extended naturalistic human activity. PMID- 20953235 TI - Age-Related Differences in Functional Nodes of the Brain Cortex - A High Model Order Group ICA Study. AB - Functional MRI measured with blood oxygen dependent (BOLD) contrast in the absence of intermittent tasks reflects spontaneous activity of so-called resting state networks (RSN) of the brain. Group level independent component analysis (ICA) of BOLD data can separate the human brain cortex into 42 independent RSNs. In this study we evaluated age-related effects from primary motor and sensory, and, higher level control RSNs. One hundred sixty-eight healthy subjects were scanned and divided into three groups: 55 adolescents (ADO, 13.2 +/- 2.4 years), 59 young adults (YA, 22.2 +/- 0.6 years), and 54 older adults (OA, 42.7 +/- 0.5 years), all with normal IQ. High model order group probabilistic ICA components (70) were calculated and dual-regression analysis was used to compare 21 RSN's spatial differences between groups. The power spectra were derived from individual ICA mixing matrix time series of the group analyses for frequency domain analysis. We show that primary sensory and motor networks tend to alter more in younger age groups, whereas associative and higher level cognitive networks consolidate and re-arrange until older adulthood. The change has a common trend: both spatial extent and the low frequency power of the RSN's reduce with increasing age. We interpret these result as a sign of normal pruning via focusing of activity to less distributed local hubs. PMID- 20953236 TI - Cannabidiol As a Putative Novel Therapy for Diabetic Retinopathy: A Postulated Mechanism of Action as an Entry Point for Biomarker-Guided Clinical Development. AB - Diabetic retinopathy is a leading cause of blindness in the Western world. However, treatment options for diabetic retinopathy are limited and display poor efficacy with marked patient-to-patient variation in therapeutic outcomes. Discovery of new molecular entities acting on mechanistically novel biological pathways remains as one of the key research priorities in diabetic retinopathy. Moreover, given the variable success of the existing treatment modalities, a targeted and personalized drug development strategy could be more fruitful for rational and successful transition of preclinical discoveries to the clinical realm. This review is focused on cannabidiol, a non-psychoactive native cannabinoid, as an emerging and novel therapeutic modality based on systematic studies in animal models of inflammatory retinal diseases including diabetic retinopathy - one of the retinal diseases associated with vascular neuroinflammation. We present the postulated and preclinically documented novel mechanisms that may underlie cannabidiol mode of action in diabetic retinopathy. We discuss the interindividual variation in pharmacokinetic pathways as well as in the SLC29A1 gene, a molecular target for cannabidiol. We emphasize that the novel mode of action of cannabidiol and the previous failures with nontargeted interventions in diabetic retinopathy collectively demand a more rational and personalized clinical development strategy for compounds that have shown promise at the preclinical stage. Moreover, it is noteworthy that ophthalmology, as a medical specialty, has fewer examples (e.g., compared to oncology) of personalized medicine and biomarker applications thus far. Understanding the biological action of cannabidiol in preclinical studies is therefore a rational first step to proactively map the pertinent biomarker strategies in clinical proof of concept studies in diabetic retinopathy, and to allow advances at the hitherto neglected intersection of personalized medicine and ophthalmology. PMID- 20953237 TI - Subpicosecond Excited-State Proton Transfer Preceding Isomerization During the Photorecovery of Photoactive Yellow Protein. AB - The ultrafast excited-state dynamics underlying the receptor state photorecovery is resolved in the M100A mutant of the photoactive yellow protein (PYP) from Halorhodospira halophila. The M100A PYP mutant, with its distinctly slower photocycle than wt PYP, allows isolation of the pB signaling state for study of the photodynamics of the protonated chromophore cis-p-coumaric acid. Transient absorption signals indicate a subpicosecond excited-state proton-transfer reaction in the pB state that results in chromophore deprotonation prior to the cis-trans isomerization required in the photorecovery dynamics of the pG state. Two terminal photoproducts are observed, a blue-absorbing species presumed to be deprotonated trans-p-coumaric acid and an ultraviolet-absorbing protonated photoproduct. These two photoproducts are hypothesized to originate from an equilibrium of open and closed folded forms of the signaling state, I(2) and I(2)'. PMID- 20953238 TI - Pathophysiological interference with neurovascular coupling - when imaging based on hemoglobin might go blind. AB - Assessing neuronal activity by non-invasive functional brain imaging techniques which are based on the hemodynamic response depends totally on the physiological cascade of metabolism and blood flow. At present, functional brain imaging with near infrared spectroscopy (NIRS) or BOLD-fMRI is widely used in cognitive neuroscience in healthy subjects where neurovascular coupling and cerebrovascular reactivity can be assumed to be intact. Local activation studies as well as studies investigating functional connectivity between brain regions of the resting brain provide a rapidly increasing body of knowledge on brain function in humans and animals. Furthermore, functional NIRS and MRI techniques are increasingly being used in patients with severe brain diseases and this use might gain more and more importance for establishing their use in the clinical routine. However, more and more experimental evidence shows that changes in baseline physiological parameters, pharmacological interventions, or disease-related vascular changes may significantly alter the normal response of blood flow and blood oxygenation and thus may lead to misinterpretation of neuronal activity. In this article we present examples of recent experimental findings on pathophysiological changes of neurovascular coupling parameters in animals and discuss their potential implications for functional imaging based on hemodynamic signals such as fNIRS or BOLD-fMRI. To enable correct interpretation of neuronal activity by vascular signals, future research needs to deepen our understanding of the basic mechanisms of neurovascular coupling and the specific characteristics of disturbed neurovascular coupling in the diseased brain. PMID- 20953239 TI - Leaders of neuronal cultures in a quorum percolation model. AB - We present a theoretical framework using quorum percolation for describing the initiation of activity in a neural culture. The cultures are modeled as random graphs, whose nodes are excitatory neurons with k(in) inputs and k(out) outputs, and whose input degrees k(in) = k obey given distribution functions p(k). We examine the firing activity of the population of neurons according to their input degree (k) classes and calculate for each class its firing probability Phi(k)(t) as a function of t. The probability of a node to fire is found to be determined by its in-degree k, and the first-to-fire neurons are those that have a high k. A small minority of high-k-classes may be called "Leaders," as they form an interconnected sub-network that consistently fires much before the rest of the culture. Once initiated, the activity spreads from the Leaders to the less connected majority of the culture. We then use the distribution of in-degree of the Leaders to study the growth rate of the number of neurons active in a burst, which was experimentally measured to be initially exponential. We find that this kind of growth rate is best described by a population that has an in-degree distribution that is a Gaussian centered around k = 75 with width sigma = 31 for the majority of the neurons, but also has a power law tail with exponent -2 for 10% of the population. Neurons in the tail may have as many as k = 4,700 inputs. We explore and discuss the correspondence between the degree distribution and a dynamic neuronal threshold, showing that from the functional point of view, structure and elementary dynamics are interchangeable. We discuss possible geometric origins of this distribution, and comment on the importance of size, or of having a large number of neurons, in the culture. PMID- 20953240 TI - Human cell-based micro electrode array platform for studying neurotoxicity. AB - At present, most of the neurotoxicological analyses are based on in vitro and in vivo models utilizing animal cells or animal models. In addition, the used in vitro models are mostly based on molecular biological end-point analyses. Thus, for neurotoxicological screening, human cell-based analysis platforms in which the functional neuronal networks responses for various neurotoxicants can be also detected real-time are highly needed. Microelectrode array (MEA) is a method which enables the measurement of functional activity of neuronal cell networks in vitro for long periods of time. Here, we utilize MEA to study the neurotoxicity of methyl mercury chloride (MeHgCl, concentrations 0.5-500 nM) to human embryonic stem cell (hESC)-derived neuronal cell networks exhibiting spontaneous electrical activity. The neuronal cell cultures were matured on MEAs into networks expressing spontaneous spike train-like activity before exposing the cells to MeHgCl for 72 h. MEA measurements were performed acutely and 24, 48, and 72 h after the onset of the exposure. Finally, exposed cells were analyzed with traditional molecular biological methods for cell proliferation, cell survival, and gene and protein expression. Our results show that 500 nM MeHgCl decreases the electrical signaling and alters the pharmacologic response of hESC-derived neuronal networks in delayed manner whereas effects can not be detected with qRT PCR, immunostainings, or proliferation measurements. Thus, we conclude that human cell-based MEA platform is a sensitive online method for neurotoxicological screening. PMID- 20953241 TI - Educational intervention approaches to ameliorate adverse public health and environmental effects from global warming. PMID- 20953242 TI - Recent advances in the understanding of the pathogenesis of serous carcinoma: the concept of low- and high-grade disease and the role of the fallopian tube. AB - In the past 50 years, the concept of serous ovarian cancer has been progressively refined, with the distinction of the borderline serous tumour, identification of a smaller subset of well-differentiated serous malignancies and, recently, closer attention to the pathogenesis of high-grade serous malignancies. High-grade serous carcinoma, traditionally presumed to arise within Mullerian inclusion cysts of the ovarian surface, cortex and peritoneum, has recently been linked to the distal fallopian tube. This review addresses the disparate forms of serous neoplasia, which reflect both different genetic abnormalities and stages of differentiation of Mullerian epithelium. The significance of these different origins is addressed in the context of ovarian cancer prevention. PMID- 20953243 TI - The pathogenesis of prostate cancer: from molecular to metabolic alterations. AB - Prostate cancer (PCa) is a heterogeneous disease with regard to molecular alterations and clinical course. The investigation of genetic alterations associated with PCa pathogenesis is highly challenging. Genome-wide analyses and epidemiological studies have identified only a handful of candidate genes possibly associated with hereditary or sporadic PCa. Cancer cells often rely for survival on common biochemical pathways such as enhanced anaerobic glycolysis and lipogenesis. The lipogenic enzyme fatty acid synthase seems to play a crucial part in PCa by conferring growth and survival advantages to cancer cells. We summarize the current understanding of the molecular events in PCa, and highlight the importance of altered lipid metabolism in the development and progression of prostate malignancy. PMID- 20953244 TI - Locating Patient Expertise in Everyday Life. AB - Coping with a new health issue often requires individuals to acquire knowledge and skills to manage personal health. Many patients turn to one another for experiential expertise outside the formal bounds of the health-care system. Internet-based social software can facilitate expertise sharing among patients, but provides only limited ways for users to locate sources of patient expertise. Although much prior research has investigated expertise location and systems to augment expertise sharing in workplace organizations, the transferability of this knowledge to other contexts, such as personal health, is unclear. Guided by expertise locating frameworks drawn from prior work, we conducted a field study to investigate expertise locating in the informal and everyday context of women diagnosed with breast cancer. Similarities between patients' expertise locating practices and practices of professionals in workplace organizations suggest similar support strategies could apply in both contexts. However, unlike professionals, unsolicited advice often triggered patients to locate expertise. They identified expertise through various forms of gatekeeping. The high-stakes nature of problems patients faced also led them to use triangulation strategies in anticipation of breakdowns in expertise location. Based on these key differences, we explored five design additions to social software that could support patients in their critical need to locate patient expertise. PMID- 20953245 TI - Emergence of Modular Structure in a Large-Scale Brain Network with Interactions between Dynamics and Connectivity. AB - A network of 32 or 64 connected neural masses, each representing a large population of interacting excitatory and inhibitory neurons and generating an electroencephalography/magnetoencephalography like output signal, was used to demonstrate how an interaction between dynamics and connectivity might explain the emergence of complex network features, in particular modularity. Network evolution was modeled by two processes: (i) synchronization dependent plasticity (SDP) and (ii) growth dependent plasticity (GDP). In the case of SDP, connections between neural masses were strengthened when they were strongly synchronized, and were weakened when they were not. GDP was modeled as a homeostatic process with random, distance dependent outgrowth of new connections between neural masses. GDP alone resulted in stable networks with distance dependent connection strengths, typical small-world features, but no degree correlations and only weak modularity. SDP applied to random networks induced clustering, but no clear modules. Stronger modularity evolved only through an interaction of SDP and GDP, with the number and size of the modules depending on the relative strength of both processes, as well as on the size of the network. Lesioning part of the network, after a stable state was achieved, resulted in a temporary disruption of the network structure. The model gives a possible scenario to explain how modularity can arise in developing brain networks, and makes predictions about the time course of network changes during development and following acute lesions. PMID- 20953247 TI - Cystic lesions of the pancreas. AB - In contrast to the relatively uniform pathology and the unyielding dismal outcome associated with infiltrating ductal adenocarcinoma of the pancreas, cystic lesions have a broad spectrum of gross and microscopic pathologies, and a range of clinical outcomes. The common cystic lesions of the pancreas are reviewed with emphasis on practical tips for distinguishing between the main entities. PMID- 20953246 TI - Activation of frontal neocortical areas by vocal production in marmosets. AB - Primates often rely on vocal communication to mediate social interactions. Although much is known about the acoustic structure of primate vocalizations and the social context in which they are usually uttered, our knowledge about the neocortical control of audio-vocal interactions in primates is still incipient, being mostly derived from lesion studies in squirrel monkeys and macaques. To map the neocortical areas related to vocal control in a New World primate species, the common marmoset, we employed a method previously used with success in other vertebrate species: Analysis of the expression of the immediate early gene Egr-1 in freely behaving animals. The neocortical distribution of Egr-1 immunoreactive cells in three marmosets that were exposed to the playback of conspecific vocalizations and vocalized spontaneously (H/V group) was compared to data from three other marmosets that also heard the playback but did not vocalize (H/n group). The anterior cingulate cortex, the dorsomedial prefrontal cortex and the ventrolateral prefrontal cortex presented a higher number of Egr-1 immunoreactive cells in the H/V group than in H/n animals. Our results provide direct evidence that the ventrolateral prefrontal cortex, the region that comprises Broca's area in humans and has been associated with auditory processing of species-specific vocalizations and orofacial control in macaques, is engaged during vocal output in marmosets. Altogether, our results support the notion that the network of neocortical areas related to vocal communication in marmosets is quite similar to that of Old world primates. The vocal production role played by these areas and their importance for the evolution of speech in primates are discussed. PMID- 20953248 TI - Automated assessment of pavlovian conditioned freezing and shock reactivity in mice using the video freeze system. AB - The Pavlovian conditioned freezing paradigm has become a prominent mouse and rat model of learning and memory, as well as of pathological fear. Due to its efficiency, reproducibility and well-defined neurobiology, the paradigm has become widely adopted in large-scale genetic and pharmacological screens. However, one major shortcoming of the use of freezing behavior has been that it has required the use of tedious hand scoring, or a variety of proprietary automated methods that are often poorly validated or difficult to obtain and implement. Here we report an extensive validation of the Video Freeze system in mice, a "turn-key" all-inclusive system for fear conditioning in small animals. Using digital video and near-infrared lighting, the system achieved outstanding performance in scoring both freezing and movement. Given the large-scale adoption of the conditioned freezing paradigm, we encourage similar validation of other automated systems for scoring freezing, or other behaviors. PMID- 20953249 TI - Effect of sampling frequency on the measurement of phase-locked action potentials. AB - Phase-locked spikes in various types of neurons encode temporal information. To quantify the degree of phase-locking, the metric called vector strength (VS) has been most widely used. Since VS is derived from spike timing information, error in measurement of spike occurrence should result in errors in VS calculation. In electrophysiological experiments, the timing of an action potential is detected with finite temporal precision, which is determined by the sampling frequency. In order to evaluate the effects of the sampling frequency on the measurement of VS, we derive theoretical upper and lower bounds of VS from spikes collected with finite sampling rates. We next estimate errors in VS assuming random sampling effects, and show that our theoretical calculation agrees with data from electrophysiological recordings in vivo. Our results provide a practical guide for choosing the appropriate sampling frequency in measuring VS. PMID- 20953250 TI - Differential effects of emotional information on interference task performance across the life span. AB - While functioning in multiple domains declines with age, emotional regulation appears to remain preserved in older adults. The Emotion Inhibition (Emotional Stroop) Test requires participants to name the ink color in which neutrally and emotionally valenced words are printed. It was employed in the current investigation as a measure of affective regulation in the context of an interference task in relation to age. Results demonstrated that while participants ranging from 20 to 50 years of age performed significantly worse on the emotion Stroop Inhibition relative to the neutral Stroop Inhibition condition, subjects over 60 years of age displayed the converse of this pattern, performing better on the emotion than the neutral condition, suggesting that they are less affected by the emotional impact of the positive and negative words used in the former condition. This pattern of age-related change in the ability to manage emotion may be related to blunting of affective signaling in limbic structures or, at the psychological level, focusing on emotional regulation. PMID- 20953252 TI - When to Cry Over Spilled Milk: Young Children's Use of Category Information to Guide Inferences About Ambiguous Behavior. AB - Three studies (N = 171) examined preschool children's tendency to use category information to make inferences about ambiguous behavior. Children heard stories in which category information about story characters was manipulated and behavioral information was held constant. Participants were asked to evaluate, explain, and determine the significance of the behavior in question. Children tended to be harsher judges of the same ambiguous behaviors when performed by (a) humans as compared to animals, (b) boys compared to girls, and (c) older children compared to younger children. Results suggest that young children hold differentiated notions of the mental states and dispositions that underlie behavior and that these notions vary as a function of category membership. These findings support the conclusion that even young children can hold and use multiple folk psychologies. PMID- 20953251 TI - Innate recognition of pheromone and food odors in moths: a common mechanism in the antennal lobe? AB - The survival of an animal often depends on an innate response to a particular sensory stimulus. For an adult male moth, two categories of odors are innately attractive: pheromone released by conspecific females, and the floral scents of certain, often co-evolved, plants. These odors consist of multiple volatiles in characteristic mixtures. Here, we review evidence that both categories of odors are processed as sensory objects, and we suggest a mechanism in the primary olfactory center, the antennal lobe (AL), that encodes the configuration of these mixtures and may underlie recognition of innately attractive odors. In the pheromone system, mixtures of two or three volatiles elicit upwind flight. Peripheral changes are associated with behavioral changes in speciation, and suggest the existence of a pattern recognition mechanism for pheromone mixtures in the AL. Moths are similarly innately attracted to certain floral scents. Though floral scents consist of multiple volatiles that activate a broad array of receptor neurons, only a smaller subset, numerically comparable to pheromone mixtures, is necessary and sufficient to elicit behavior. Both pheromone and floral scent mixtures that produce attraction to the odor source elicit synchronous action potentials in particular populations of output (projection) neurons (PNs) in the AL. We propose a model in which the synchronous output of a population of PNs encodes the configuration of an innately attractive mixture, and thus comprises an innate mechanism for releasing odor-tracking behavior. The particular example of olfaction in moths may inform the general question of how sensory objects trigger innate responses. PMID- 20953253 TI - Shift work and cancer: the evidence and the challenge. AB - BACKGROUND: In 2007, the International Agency for Research on Cancer (IARC) classified shift work with circadian disruption or chronodisruption as a probable human carcinogen. Short-term disturbances of biological 24-hour-rhythms following exposures to light and darkness at unusual times are well-known as "jet-lag" and "shift-lag" symptoms. However, that chronic disturbances or disruptions of timely sequenced circadian rhythms (chronodisruption) should contribute to long-term developments of cancer is a relatively new concept. This review provides background and practical information with regard to the open question "does shift work cause cancer?" METHODS: Overview on the basis of a selective literature search via Medline and ISI Web of Knowledge until 2009 from the viewpoints of occupational medicine, epidemiology, chronobiology, and occupational science. RESULTS: The postulated causal links between shift-work and cancer in humans are biologically plausible in the light of experimental findings, but to date we lack epidemiological studies which could describe or exonerate risks in humans. Monetary compensation has already been paid for such cases in at least one country (Denmark). In Germany, however, according to the applicable law, a new occupational disease can only be recognized when certain conditions for the recognition of "general scientific merit" have been met. We present the current state of knowledge regarding prevention. CONCLUSION: While causal links between shift-work and cancer developments are not established, future shift-work planning should pay more attention to insights from occupational medicine, chronobiology, and occupational science. PMID- 20953254 TI - Perinatal problems in multiple births. AB - BACKGROUND: Multiple pregnancies have become more common in the industrialized world because of rising maternal ages and advances in reproductive medicine. METHODS: Selective literature review. RESULTS: Multiple pregnancy carries a higher risk of prematurity, intrauterine growth restriction, and prenatal death, as well as elevated risks to the mother including preeclampsia, diabetes, and hemorrhage during delivery. Genetic tests and ultrasonography are the most important tests for monitoring during pregnancy. Ultrasound aids in the detection of the feto-fetal transfusion syndrome and in the determination of zygosity. CONCLUSIONS: The care of women with multiple pregnancies requires the collaboration of specialists in prenatal medicine, obstetrics, and neonatology as well as a properly functioning integration of outpatient and inpatient care. PMID- 20953255 TI - Correspondence (letter to the editor): Wholesale accusations? PMID- 20953256 TI - Correspondence (letter to the editor): Opinion leaders. PMID- 20953257 TI - Correspondence (letter to the editor): Trend gives cause for concern. PMID- 20953258 TI - Correspondence (letter to the editor): Notorious weaknesses. PMID- 20953259 TI - Correspondence (letter to the editor): National foundation. PMID- 20953260 TI - Correspondence (letter to the editor): Search bias. PMID- 20953261 TI - Correspondence (letter to the editor): Need for advice. PMID- 20953263 TI - Concentration-enhanced rapid detection of human chorionic gonadotropin (hCG) on a Au surface using a nanofluidic preconcentrator. AB - Here, we report a new method of concentration-enhanced binding kinetics for a rapid immunoassay screening test on a gold surface in a poly(dimethylsiloxane) (PDMS) microfluidic chip format. The use of alkylthiolate self-assembled monolayers on gold surfaces of a PDMS-glass microchip resulted in accelerated binding kinetics of Human chorionic gonadotropin (hCG) at an electrokinetic trapping zone. We used a PBS solution (buffer concentration ~ 150 mM), not a dibasic buffer system (~10 mM), for the dynamic preconcentrating operation and the preconcentration of cy3 labeled streptavidin onto biotinylated Au surface revealed that the binding kinetics of the protein were linearly proportional to the concentration profile of the preconcentration plug. We showed rapid detection of hCG in the clinical range with a shorten assay time of 10 min. Also, we demonstrated that the amount of sample needed were detection was decreased from ~4 mL to ~25 MUL in the standard serum tests. The enhanced binding kinetics between hcG Ag-Ab via preconcentration showed good feasibility for use in a rapid immunoassay screening test. PMID- 20953264 TI - Development and Perceived Utility and Impact of an Internet Intervention for Insomnia. AB - Insomnia is a major health problem, with significant psychological, health, and economic consequences. Studies have demonstrated that cognitive-behavioural therapy can effectively treat insomnia; however, treatment availability is limited by many factors, including a lack of trained clinicians. One potential way to overcome these barriers is to use the Internet to deliver treatment. Toward this aim, we developed a self-guided, interactive, tailored Internet intervention for adults with insomnia (SHUTi: Sleep Healthy Using The Internet). The current paper provides a detailed description of SHUTi and examines users' perceptions of the intervention's usefulness and effectiveness. The study was part of a larger randomised controlled trial (RCT) to test the efficacy of SHUTi, but findings in this paper are based only on the 21 participants who completed the post-assessment after using SHUTi. The overwhelming majority rated SHUTi as convenient, understandable, and useful. Nearly all (95%) indicated that the program had at least somewhat improved their sleep, sleep efficiency, and overall quality of life. Ninety percent perceived the intervention as effective and predicted it would be effective in producing a long-term cure. Although these results were based on a small sample, they provide encouraging evidence of the potential for Internet interventions to be accepted by patients. PMID- 20953265 TI - Local Dynamic Stability Assessment of Motion Impaired Elderly Using Electronic Textile Pants. AB - A clear association has been demonstrated between gait stability and falls in the elderly. Integration of wearable computing and human dynamic stability measures into home automation systems may help differentiate fall-prone individuals in a residential environment. The objective of the current study was to evaluate the capability of a pair of electronic textile (e-textile) pants system to assess local dynamic stability and to differentiate motion-impaired elderly from their healthy counterparts. A pair of e-textile pants comprised of numerous e-TAGs at locations corresponding to lower extremity joints was developed to collect acceleration, angular velocity and piezoelectric data. Four motion-impaired elderly together with nine healthy individuals (both young and old) participated in treadmill walking with a motion capture system simultaneously collecting kinematic data. Local dynamic stability, characterized by maximum Lyapunov exponent, was computed based on vertical acceleration and angular velocity at lower extremity joints for the measurements from both e-textile and motion capture systems. Results indicated that the motion-impaired elderly had significantly higher maximum Lyapunov exponents (computed from vertical acceleration data) than healthy individuals at the right ankle and hip joints. In addition, maximum Lyapunov exponents assessed by the motion capture system were found to be significantly higher than those assessed by the e-textile system. Despite the difference between these measurement techniques, attaching accelerometers at the ankle and hip joints was shown to be an effective sensor configuration. It was concluded that the e-textile pants system, via dynamic stability assessment, has the potential to identify motion-impaired elderly. PMID- 20953266 TI - Calibration of Flow Cytometry for Quantitative Quantum Dot Measurements. AB - Observations of quantum dot (QD) labeled cells in biomedical research are mainly qualitative in nature, which limits the ability of researchers to compare results experiment-to-experiment and lab-to-lab to improve the state-of-the-art. Labeled cells are useful in a range of in vitro and in vivo assays where tracking behavior of administered cells is integral for answering research questions in areas such as tissue engineering and stem cell therapy. Before the full potential of QD based toolsets can be realized in the clinic, uptake of QDs by cells must be quantified and standardized. This unit describes a novel, simple method to assess the number of QDs per cell using flow cytometry and commercially available standards. This quick and easy method can be used by all researchers to calibrate their flow cytometry instruments and settings, and quantify QD uptake by cells for in vitro and in vivo experimentation for comparable results across QD conjugate types, cell types, research groups, lots of commercial QDs, and homemade QDs. PMID- 20953267 TI - Categorical representation of facial expressions in the infant brain. AB - Categorical perception, demonstrated as reduced discrimination of within-category relative to between-category differences in stimuli, has been found in a variety of perceptual domains in adults. To examine the development of categorical perception in the domain of facial expression processing, we used behavioral and event-related potential (ERP) methods to assess discrimination of within-category (happy-happy) and between-category (happy-sad) differences in facial expressions in 7-month-old infants. Data from a visual paired-comparison test and recordings of attention-sensitive ERPs showed no discrimination of facial expressions in the within-category condition whereas reliable discrimination was observed in the between-category condition. The results also showed that face-sensitive ERPs over occipital-temporal scalp (P400) were attenuated in the within-category condition relative to the between-category condition, suggesting a potential neural basis for the reduced within-category sensitivity. Together, these results suggest that the neural systems underlying categorical representation of facial expressions emerge during the early stages of postnatal development, before acquisition of language. PMID- 20953268 TI - AN INTEGRATIVE ANALYSIS OF CANCER GENE EXPRESSION STUDIES USING BAYESIAN LATENT FACTOR MODELING. AB - We present an applied study in cancer genomics for integrating data and inferences from laboratory experiments on cancer cell lines with observational data obtained from human breast cancer studies. The biological focus is on improving understanding of transcriptional responses of tumors to changes in the pH level of the cellular microenvironment. The statistical focus is on connecting experimentally defined biomarkers of such responses to clinical outcome in observational studies of breast cancer patients. Our analysis exemplifies a general strategy for accomplishing this kind of integration across contexts. The statistical methodologies employed here draw heavily on Bayesian sparse factor models for identifying, modularizing and correlating with clinical outcome these signatures of aggregate changes in gene expression. By projecting patterns of biological response linked to specific experimental interventions into observational studies where such responses may be evidenced via variation in gene expression across samples, we are able to define biomarkers of clinically relevant physiological states and outcomes that are rooted in the biology of the original experiment. Through this approach we identify microenvironment-related prognostic factors capable of predicting long term survival in two independent breast cancer datasets. These results suggest possible directions for future laboratory studies, as well as indicate the potential for therapeutic advances though targeted disruption of specific pathway components. PMID- 20953269 TI - PMN-PT single crystal thick films on silicon substrate for high-frequency micromachined ultrasonic transducers. AB - In this work, a novel high-frequency ultrasonic transducer structure is realized by using PMNPT-on-silicon technology and silicon micromachining. To prepare the single crystalline PMNPT-on-silicon wafers, a hybrid processing method involving wafer bonding, mechanical lapping and wet chemical thinning is successfully developed. In the transducer structure, the active element is fixed within the stainless steel needle housing. The measured center frequency and -6 dB bandwidth of the transducer are 35 MHz and 34%, respectively. Owing to the superior electromechanical coupling coefficient (k(t)) and high piezoelectric constant (d(33)) of PMNPT film, the transducer shows a good energy conversion performance with a very low insertion loss down to 8.3 dB at the center frequency. PMID- 20953270 TI - Uvf - Unified Volume Format: A General System for Efficient Handling of Large Volumetric Datasets. AB - With the continual increase in computing power, volumetric datasets with sizes ranging from only a few megabytes to petascale are generated thousands of times per day. Such data may come from an ordinary source such as simple everyday medical imaging procedures, while larger datasets may be generated from cluster based scientific simulations or measurements of large scale experiments. In computer science an incredible amount of work worldwide is put into the efficient visualization of these datasets. As researchers in the field of scientific visualization, we often have to face the task of handling very large data from various sources. This data usually comes in many different data formats. In medical imaging, the DICOM standard is well established, however, most research labs use their own data formats to store and process data. To simplify the task of reading the many different formats used with all of the different visualization programs, we present a system for the efficient handling of many types of large scientific datasets (see Figure 1 for just a few examples). While primarily targeted at structured volumetric data, UVF can store just about any type of structured and unstructured data. The system is composed of a file format specification with a reference implementation of a reader. It is not only a common, easy to implement format but also allows for efficient rendering of most datasets without the need to convert the data in memory. PMID- 20953271 TI - Cell Traction Forces (CTFs) and CTF Microscopy Applications in Musculoskeletal Research. AB - Most connective tissue cells (e.g. tendon and ligament cells) attach to extracellular matrix (ECM) and exert so-called cell traction forces (CTFs) to the ECM. CTFs are essential for many cellular functions such as maintenance of cell shape, cell motility, and cell communication. Therefore, many techniques have been developed over the years to measure CTFs in order to better understand tissue physiology and pathology. This article provides a brief review of CTF in terms of its generation and transmission and also CTF measurement techniques, with a focus on cell traction force microscopy (CTFM). Examples of using CTFM to determine CTFs are given to illustrate various applications of CTFM. Finally, the potential applications of CTFM in musculoskeletal research are suggested. PMID- 20953272 TI - Antibiotic administration alters the community structure of the gastrointestinal micobiota. AB - We recently demonstrated that antibiotic administration has a reproducible effect on the community structure of the indigenous gastrointestinal microbiota of mice. In this addendum we report on additional experimentation using the antibiotic vancomycin. In accord with our previous findings, vancomycin administration results in consistent alteration of the microbiota of the cecal contents and the cecal mucosa. These alterations are largely reversed by a three-week period of recovery without antibiotics. In contrast to our previous results using other antibiotics, the alterations in community structure associated with vancomycin occured without a significant decrease in the overall bacterial biomass. These results indicate that different antibiotics have specific effects on the gut microbiota. This points the way towards targeted, therapeutic alteration of the gut bacterial community as a whole. PMID- 20953273 TI - STUDYING TRAVEL-RELATED INDIVIDUAL ASSESSMENTS AND DESIRES BY COMBINING HIERARCHICALLY STRUCTURED ORDINAL VARIABLES. AB - Ordinal measures are frequently encountered in travel behavior research. This paper presents a new method for combining them when a hierarchical structure of the data can be presumed. This method is applied to study the subjective assessment of the amount of travel by different transportation modes among a group of French clerical workers, along with the desire to increase or decrease the use of such modes. Some advantages of this approach over traditional data reduction technique such as factor analysis when applied to ordinal data are then illustrated. In this study, combining evidence from several variables sheds light on the observed moderately negative relationship between the personal assessment of the amount of travel and the desire to increase or decrease it, thus integrating previous partial (univariate) results. We find a latent demand for travel, thus contributing to clarify the behavioral mechanisms behind the induced traffic phenomenon. Categorizing the above relationship by transportation mode shows a desire for a less environmental-friendly mix of modes (i.e. a greater desire to use heavy motorized modes and a lower desire to use two-wheeled modes), whenever the respondents do not feel to travel extensively. This result, combined with previous theoretical investigations concerning the determinants of the desire to alter trips consumption levels, shows the importance of making people aware of how much they travel. PMID- 20953274 TI - Social coordination in toddler's word learning: interacting systems of perception and action. AB - We measured turn-taking in terms of hand and head movements and asked if the global rhythm of the participants' body activity relates to word learning. Six dyads composed of parents and toddlers (M = 18 months) interacted in a tabletop task wearing motion-tracking sensors on their hands and head. Parents were instructed to teach the labels of 10 novel objects and the child was later tested on a name-comprehension task. Using dynamic time warping, we compared the motion data of all body-part pairs, within and between partners. For every dyad, we also computed an overall measure of the quality of the interaction, that takes into consideration the state of interaction when the parent uttered an object label and the overall smoothness of the turn-taking. The overall interaction quality measure was correlated with the total number of words learned.In particular, head movements were inversely related to other partner's hand movements, and the degree of bodily coupling of parent and toddler predicted the words that children learned during the interaction. The implications of joint body dynamics to understanding joint coordination of activity in a social interaction, its scaffolding effect on the child's learning and its use in the development of artificial systems are discussed. PMID- 20953275 TI - I've Fallen and I Can't Get Up: Can High Ability Students Recover From Early Mistakes in CAT? AB - A difficult result to interpret in Computerized Adaptive Tests (CATs) occurs when an ability estimate initially drops and then ascends continuously until the test ends, suggesting that the true ability may be higher than implied by the final estimate. We explain why this asymmetry occurs and show that early mistakes by high ability students can lead to considerable underestimation, even in tests with 45 items. The opposite response pattern, where low ability students start with lucky guesses, leads to much less bias. We show that using Barton and Lord's (1981) four-parameter model and a less informative prior can lower bias and RMSE for high ability students with a poor start, as the CAT algorithm ascends more quickly after initial underperformance. We also show that the 4PM slightly outperforms a CAT in which less discriminating items are initially used. The practical implications and relevance for psychological measurement more generally are discussed. PMID- 20953276 TI - Association Rule Discovery Has the Ability to Model Complex Genetic Effects. AB - Dramatic advances in genotyping technology have established a need for fast, flexible analysis methods for genetic association studies. Common complex diseases, such as Parkinson's disease or multiple sclerosis, are thought to involve an interplay of multiple genes working either independently or together to influence disease risk. Also, multiple underlying traits, each its own genetic basis may be defined together as a single disease. These effects - trait heterogeneity, locus heterogeneity, and gene-gene interactions (epistasis) - contribute to the complex architecture of common genetic diseases. Association Rule Discovery (ARD) searches for frequent itemsets to identify rule-based patterns in large scale data. In this study, we apply Apriori (an ARD algorithm) to simulated genetic data with varying degrees of complexity. Apriori using information difference to prior as a rule measure shows good power to detect functional effects in simulated cases of simple trait heterogeneity, trait heterogeneity and epistasis, and moderate power in cases of trait heterogeneity and locus heterogeneity. Also, we illustrate that bootstrapping the rule induction process does not considerably improve the power to detect these effects. These results show that ARD is a framework with sufficient flexibility to characterize complex genetic effects. PMID- 20953277 TI - Fast and robust deconvolution-based image reconstruction for photoacoustic tomography in circular geometry: experimental validation. AB - Photoacoustic tomography (PAT) is a fast-developing biomedical imaging technology suitable for in vivo imaging. PAT in spherical or circular geometry gives good image resolution yet is slow or expensive in signal acquisition and image formation. Reducing the number of detection angles can ameliorate such issues usually at the expense of image quality. This paper introduces a deconvolution based algorithm that models the imaging process as a linear and shift-invariant system. As demonstrated by the in vivo experiment, this algorithm not only runs much faster than the back-projection algorithm, but also shows stronger robustness in that it provides better image quality when detection angles are sparse. Therefore, this algorithm promises to enable real-time PAT in circular geometry. PMID- 20953279 TI - Time-preference, Non-cognitive Skills and Well-being across the Life Course: Do Non-cognitive Skills Encourage Healthy Behavior? PMID- 20953280 TI - Determination of Major Lineages of Mycobacterium tuberculosis Complex using Mycobacterial Interspersed Repetitive Units. AB - We present a novel Bayesian network (BN) to classify strains of Mycobacterium tuberculosis Complex (MTBC) into six major genetic lineages using mycobacterial interspersed repetitive units (MIRUs), a high-throughput biomarker. MTBC is the causative agent of tuberculosis (TB), which remains one of the leading causes of disease and morbidity world-wide. DNA fingerprinting methods such as MIRU are key components of modern TB control and tracking. The BN achieves high accuracy on four large MTBC genotype collections consisting of over 4700 distinct 12-loci MIRU genotypes. The BN captures distinct MIRU signatures associated with each lineage, explaining the excellent performance of the BN. The errors in the BN support the need for additional biomarkers such as the expanded 24-loci MIRU used in CDC genotyping labs since May 2009. The conditional independence assumption of each locus given the lineage makes the BN easily extensible to additional MIRU loci and other biomarkers. PMID- 20953278 TI - Prevention of Gastric Cancer: When is Treatment of Helicobacter Pylori Warranted? AB - Chronic gastritis induced by Helicobacter pylori (H. pylori) is the strongest known risk factor for adenocarcinoma of the distal stomach, yet the effects of bacterial eradication on carcinogenesis remain unclear. H. pylori isolates possess substantial genotypic diversity, which engenders differential host inflammatory responses that influence clinical outcome. H. pylori strains that possess the cag pathogenicity island and secrete a functional cytotoxin induce more severe gastric injury and further augment the risk for developing distal gastric cancer. Carcinogenesis is also influenced by host genetic diversity, particularly involving immune response genes such as interleukin-1beta and tumor necrosis factor-alpha. Human trials and anima studies have indicated that eradication of H. pylori prior to the development of atrophic gastritis offers the best chance for prevention of gastric cancer. However, although the timing of intervention influences the magnitude of suppression of premalignant and neoplastic lesions, bacterial eradication, even in longstanding infections, is of clear benefit to the host. It is important to gain insight into the pathogenesis of H. pylori-induced gastritis and adenocarcinoma not only to develop more effective treatments for gastric cancer, but also because it might serve as a paradigm for the role of chronic inflammation in the genesis of other malignancies that arise within the gastrointestinal tract. PMID- 20953281 TI - Nanoscopic mechanical anisotropy in hydrogel surfaces. AB - The bulk mechanical properties of soft materials have been studied widely, but it is unclear to what extent macroscopic behavior is reflected in nanomechanics. Using an atomic force microscopy (AFM) imaging method called force spectroscopy mapping (FSM), it is possible to map the nanoscopic spatial distribution of Young's modulus, i.e. "stiffness," and determine if soft or stiff polymer domains exist to correlate nano- and macro-mechanics. Two model hydrogel systems typically used in cell culture and polymerized by a free radical polymerization process, i.e. poly (vinyl pyrrolidone) (PVP) and poly(acrylamide) (PAam) hydrogels, were found to have significantly different nanomechanical behavior despite relatively similar bulk stiffness and roughness. PVP gels contained a large number of soft and stiff nanodomains, and their size was inversely related to crosslinking density and changes in crosslinking efficiency within the hydrogel. In contrast, PAam gels displayed small nanodomains occuring at low frequency, indicating relatively uniform polymerization. Given the responsiveness of cells to changes in gel stiffness, inhomogeneities found in the PVP network indicate that careful nanomechanical characterization of polymer substrates is necessary to appreciate complex cell behavior. PMID- 20953282 TI - Children's Evaluation of Other People's Self-Descriptions. AB - Children's evaluations of what people communicate about themselves were examined in three studies with a total of 296 participants (aged four to 12). Participants heard scenarios in which characters' motivations to reveal truthful information were systematically manipulated to examine (1) children's understanding that people do not always reveal true information, and (2) children's use of contextual cues to judge the credibility of what individuals say about themselves. Results from Study 1 suggest that elementary school children are quite sophisticated at reasoning with reference to motive information. Study 2 suggests that preschool children can also make use of motive information that is salient and familiar. For example, even preschool children responded that boys are less likely than girls to reveal to peers that they like to play with dolls. Study 3 suggests that children's reasoning about self-presentation is linked to their beliefs about social acceptability norms. PMID- 20953283 TI - Translational benchmark risk analysis. AB - Translational development - in the sense of translating a mature methodology from one area of application to another, evolving area - is discussed for the use of benchmark doses in quantitative risk assessment. Illustrations are presented with traditional applications of the benchmark paradigm in biology and toxicology, and also with risk endpoints that differ from traditional toxicological archetypes. It is seen that the benchmark approach can apply to a diverse spectrum of risk management settings. This suggests a promising future for this important risk analytic tool. Extensions of the method to a wider variety of applications represent a significant opportunity for enhancing environmental, biomedical, industrial, and socio-economic risk assessments. PMID- 20953284 TI - Children in Asian cultures say yes to yes-no questions: Common and cultural differences between Vietnamese and Japanese children. AB - We investigated whether children's response tendency toward yes-no questions concerning objects is a common phenomenon regardless of languages and cultures. Vietnamese and Japanese 2- to 5-year-old (N = 108) were investigated. We also examined whether familiarity with the questioning issue has any effect on Asian children's yes bias. As the result, Asian children showed a yes bias to yes-no questions. The children's response tendency changes dramatically with their age: Vietnamese and Japanese 2- and 3-year-olds showed a yes bias, but 5-year-olds did not. However, Asian 4-year-olds also showed a yes bias only in the familiar condition. Also, Asian children showed a stronger yes bias in the familiar condition than the unfamiliar condition. These two findings in Asian children were different from the previous finding investigated North American children (Fritzley & Lee, 2003). Moreover, there was a within-Asian cross-cultural difference. Japanese children showed different response tendencies, which were rarely observed in Vietnamese children. Japanese 2-year-olds and some 3-year-olds showed a "no answer" response: they tended not to respond to an interviewer's questions. Japanese 4- and 5-year-olds also showed an "I don't know" response when they were asked about unfamiliar objects. Japanese children tended to avoid a binary decision. We discussed the cross-cultural differences. PMID- 20953285 TI - Young children's yes bias: How does it relate to verbal ability, inhibitory control, and theory of mind? AB - The aim of the present study was to investigate how young children reduce a yes bias, the tendency to answer 'yes' to yes-no questions. Specifically, we examined three possible factors: verbal ability, inhibitory control and theory of mind. Results revealed that verbal ability and inhibitory control were strongly associated with a yes bias even after controlling for age. Regression analyses revealed that these two factors significantly predicted a yes bias. Theory of mind was not significantly correlated with a yes bias. The results indicate that young children may have to inhibit a dominant 'yes' response when they are supposed to respond 'no'. The development of verbal skills may reduce young children's yes biases. PMID- 20953286 TI - Are There Limits to Collectivism? Culture and Children's Reasoning About Lying to Conceal a Group Transgression. AB - This study explored the effects of collectivism on lying to conceal a group transgression. Seven-, 9-, and 11-year-old US and Chinese children (N = 374) were asked to evaluate stories in which protagonists either lied or told the truth about their group's transgression and were then asked about either the protagonist's motivations or justification for their own evaluations. Previous research suggests that children in collectivist societies such as China find lying for one's group to be more acceptable than do children from individualistic societies such as the United States. The current study provides evidence that this is not always the case: Chinese children in this study viewed lies told to conceal a group's transgressions less favourably than did US children. An examination of children's reasoning about protagonists' motivations for lying indicated that children in both countries focused on an impact to self when discussing motivations for protagonists to lie for their group. Overall, results suggest that children living in collectivist societies do not always focus on the needs of the group. PMID- 20953287 TI - Mechanisms for Frequency Control in Neuronal Competition Models. AB - We investigate analytically a firing rate model for a two-population network based on mutual inhibition and slow negative feedback in the form of spike frequency adaptation. Both neuronal populations receive external constant input whose strength determines the system's dynamical state-a steady state of identical activity levels or periodic oscillations or a winner-take-all state of bistability. We prove that oscillations appear in the system through supercritical Hopf bifurcations and that they are antiphase. The period of oscillations depends on the input strength in a nonmonotonic fashion, and we show that the increasing branch of the period versus input curve corresponds to a release mechanism and the decreasing branch to an escape mechanism. In the limiting case of infinitely slow feedback we characterize the conditions for release, escape, and occurrence of the winner-take-all behavior. Some extensions of the model are also discussed. PMID- 20953288 TI - An Approach Toward Oxidopyrylium Ylides Using Rh(II)-Catalyzed Cyclization Chemistry. AB - The Rh(II)-catalyzed reaction of the E-isomer of 2-diazo-3,6-dioxo-6-phenyl-hex enoic acid methyl ester was carried out in the presence of various carbonyl compounds and was found to give 1,3-dioxoles in moderate to good yield. In an attempt to prepare the starting -diazo substrate, an unexpected pseudo dimerization reaction was encountered when 5-phenyl-furan-2,3-dione was heated in the presence of sodium methoxide. PMID- 20953290 TI - Pharmacological Preconditioning with GYKI 52466: A Prophylactic Approach to Neuroprotection. AB - Some toxins and drugs can trigger lasting neuroprotective mechanisms that enable neurons to resist a subsequent severe insult. This "pharmacological preconditioning" has far-reaching implications for conditions in which blood flow to the brain is interrupted. We have previously shown that in vitro preconditioning with the AMPA receptor antagonist GYKI 52466 induces tolerance to kainic acid (KA) toxicity in hippocampus. This effect persists well after washout of the drug and may be mediated via inverse agonism of G-protein coupled receptors (GPCRs). Given the amplifying nature of metabotropic modulation, we hypothesized that GYKI 52466 may be effective in reducing seizure severity at doses well below those normally associated with adverse side effects. Here we report that pharmacological preconditioning with low-dose GYKI imparts a significant protection against KA-induced seizures in vivo. GYKI (3 mg/kg, s.c.), 90-180 min prior to high-dose KA, markedly reduced seizure scores, virtually abolished all level 3 and level 4 seizures, and completely suppressed KA-induced hippocampal c-FOS expression. In addition, preconditioned animals exhibited significant reductions in high frequency/high amplitude spiking and ECoG power in the delta, theta, alpha, and beta bands during KA. Adverse behaviors often associated with higher doses of GYKI were not evident during preconditioning. The fact that GYKI is effective at doses well-below, and at pre-administration intervals well-beyond previous studies, suggests that a classical blockade of ionotropic AMPA receptors does not underlie anticonvulsant effects. Low-dose GYKI preconditioning may represent a novel, prophylactic strategy for neuroprotection in a field almost completely devoid of effective pharmaceuticals. PMID- 20953289 TI - What is the Degree of Segregation between Striatonigral and Striatopallidal Projections? AB - In contrast to most other brain regions, in the striatum the output neurons (the medium-sized spiny neurons, MSNs) are GABAergic and act by inhibiting their targets. The standard model of the basal ganglia is built on the segregation of information processing in the direct and indirect pathways, which act in opposing directions to control movement. The MSNs participating in these two pathways can be identified according to their projection sites and the proteins they express. The differential expression of two of the five known dopamine receptor subtypes, D1 and D2, in the two populations of MSNs is of particular importance, since it confers to dopamine the ability to exert opposite functional modulation on the direct and indirect pathways. However, beyond this simple view of the striatal output organization, anatomical studies questioned the segregation of direct and indirect projections to the SNr, while other studies disclosed variable degrees of overlapping expression of dopamine receptor subtypes in striatal MSNs. New ways to address these issues have emerged recently, using mouse models in which specific populations of striatal neurons are genetically tagged. Here, we review classical and recent studies supporting the segregation of striatonigral and striatopallidal neurons. We also consider this issue at a functional level by focusing on the regulation of striatal signaling pathways in the two populations of MSNs, which clearly emphasize their profound differences. We discuss the anatomical and functional evidence challenging some aspects of this segregation and outline questions that are still to be addressed. PMID- 20953291 TI - Reducing barriers to ethics in neuroscience. AB - Ethics is a growing interest for neuroscientists, but rather than signifying a commitment to the protection of human subjects, care of animals, and public understanding to which the professional community is engaged in a fundamental way, interest has been consumed by administrative overhead and the mission creep of institutional ethics reviews. Faculty, trainees, and staff (n = 605) in North America whose work involves brain imaging and brain stimulation completed an online survey about ethics in their research. Using factor analysis and linear regression, we found significant effects for invasiveness of imaging technique, professional position, gender, and local presence of bioethics centers. We propose strategies for improving communication between the neuroscience community and ethics review boards, collaborations between neuroscientists and biomedical ethicists, and ethics training in graduate neuroscience programs to revitalize mutual goals and interests. PMID- 20953293 TI - Space-time Bayesian small area disease risk models: development and evaluation with a focus on cluster detection. AB - This paper extends the spatial local-likelihood model and the spatial mixture model to the space-time (ST) domain. For comparison, a standard random effect space-time (SREST) model is examined to allow evaluation of each model's ability in relation to cluster detection. To pursue this evaluation, we use the ST counterparts of spatial cluster detection diagnostics. The proposed criteria are based on posterior estimates (e.g., misclassification rate) and some are based on post-hoc analysis of posterior samples (e.g., exceedance probability). In addition, we examine more conventional model fit criteria including mean square error (MSE). We illustrate the methodology with a real ST dataset, Georgia throat cancer mortality data for the years 1994-2005, and a simulated dataset where different levels and shapes of clusters are embedded. Overall, it is found that conventional SREST models fair well in ST cluster detection and in goodness-of fit, while for extreme risk detection the local likelihood ST model does best. PMID- 20953292 TI - The Reemergence of Nitrite as a Beneficial Agent in the Treatment of Ischemic Cardiovascular Diseases. AB - Nitrite was a therapeutic agent used in the treatment of angina pectoris and hypertension, but was replaced by nitroglycerin. However, nitrite has recently been rediscovered following observations that this anion possesses novel pharmacologic actions such as producing vasodilation, modulating hypoxic vasodilation, and providing cytoprotection in ischemia-reperfusion injury. Moreover, recent observations in animal and human studies have demonstrated that the reduction of nitrite to vasoactive nitric oxide occurs through both enzymatic and non-enzymatic processes. These findings suggest that nitrite may act as a storage form for nitric oxide and provide support for investigating the use of nitrite in the treatment of ischemic disease states including pulmonary hypertension. PMID- 20953295 TI - GPIHBP1 and the processing of triglyceride-rich lipoproteins. AB - GPIHBP1 is a new addition to a group of proteins required for the lipolysis of triglyceride-rich lipoproteins. GPIHBP1 contains an acidic domain and an Ly6 domain with ten cysteines. GPIHBP1 binds lipoprotein lipase (LPL) avidly and likely tethers LPL to the luminal surface of capillaries.Inactivation of Gpihbp1 in mice is associated with milky plasma and severe chylomicronemia, even on a low fat chow diet. Recently, four missense mutations in GPIHBP1 were identified in humans with severe chylomicronemia (C65Y, C65S, C68G, and Q115P). All four mutations involve highly conserved residues within GPIHBP1's Ly6 domain.This review will provide an update on GPIHBP1's role in the processing of chylomicrons and the pathogenesis of chylomicronemia. PMID- 20953296 TI - Heterospecific Acoustic Interference: Effects on Calling in Oophaga pumilio. AB - Call rate suppression is a common short-term solution for avoiding acoustic interference in animals. It has been widely documented between and within frog species, but the effects of non-anuran calling on frog vocalizations is less well known. Heterospecific acoustic interference on the calling of Oophaga pumilio (Bauer, 1994) (formerly Dendrobates pumilio) males was studied in a lowland, wet tropical forest in SE Nicaragua. Acoustic playback experiments were conducted to characterize the responses of O. pumilio males to interfering calls of cicadas, two species of crickets and a sympatric dendrobatid frog, Phyllobates lugubris. Call rate, call bout duration, percent of time calling, dominant frequency and latency to first-call were analyzed. Significant call rate suppression was observed during all stimulus playbacks, yet no significant differences were found in spontaneous call rates during pre- and post-playback trials. Dominant frequency significantly decreased after P. lugubris playback and first-call latency significantly decreased in response to both cicada and tree cricket playbacks. These results provide robust evidence that O. pumilio males can dynamically modify their calling pattern in unique ways, depending on the source of the heterospecific acoustic interference. PMID- 20953297 TI - Valence Effects in Reasoning About Evaluative Traits. AB - Reasoning about evaluative traits was investigated among a group of 7- and 8-year olds (N = 34), a group of 11- to 13-year olds (N = 25), and a group of adults (N = 23) to determine whether their inferences would be sensitive to the valence of social and academic traits. Four aspects of trait-relevant beliefs were examined: (1) malleability, (2) stability over time, (3) origin in terms of nature versus nurture, and (4) an inference criterion that concerns how readily traits are inferred. Although there was evidence of an age-related decrease in the tendency to emphasize positive information, participants of all ages responded that positive traits are less malleable and more stable over time than negative traits, that the positive influences of biological and environmental factors are likely to override the negative influences, and that competence can be more readily inferred from positive outcomes than from negative outcomes. PMID- 20953294 TI - MRI in the early identification and classification of high-risk atherosclerotic carotid plaques. AB - Stroke is a leading cause of mortality and long-term morbidity. As a means for stroke prevention, an estimated 99,000 carotid endarterectomy procedures were performed in the USA in 2006. Traditionally, the degree of luminal stenosis has been used as a marker of the stage of atherosclerosis and as an indication for surgical intervention. However, prospective clinical trials have shown that the majority of patients with a history of recent transient ischemic attack or stroke have mild-to-moderate carotid stenosis. Using stenosis criteria, many of these symptomatic individuals would be considered to have early-stage carotid atherosclerosis. It is evident that improved criteria are needed for identifying the high-risk carotid plaque across a range of stenoses. Histological studies have led to the hypothesis that plaques with larger lipid-rich necrotic cores, thin fibrous cap rupture, intraplaque hemorrhage, plaque neovasculature and vessel wall inflammation are characteristics of the high-risk, 'vulnerable plaque'. Despite the widespread consensus on the importance of these plaque features, testing the vulnerable plaque hypothesis in prospective clinical studies has been hindered by the lack of reliable imaging tools for in vivo plaque characterization. MRI has been shown to accurately identify key carotid plaque features, including the fibrous cap, lipid-rich necrotic core, intraplaque hemorrhage, neovasculature and vascular wall inflammation. Thus, MRI is a histologically validated technique that will permit prospective testing of the vulnerable plaque hypothesis. This article will provide a summary of the histological validation of carotid MRI, and highlight its application in prospective clinical studies aimed at early identification of the high-risk atherosclerotic carotid plaque. PMID- 20953298 TI - Preschoolers can recognize violations of the Gricean maxims. AB - Grice (Syntax and semantics: Speech acts, 1975, pp. 41-58, Vol. 3) proposed that conversation is guided by a spirit of cooperation that involves adherence to several conversational maxims. Three types of maxims were explored in the current study: 1) Quality, to be truthful; 2) Relation, to say only what is relevant to a conversation; and 3) Quantity, to provide as much information as required. Three- to five-year-olds were tested to determine the age at which an awareness of these Gricean maxims emerges. Children requested the help of one of two puppets in finding a hidden sticker. One puppet always adhered to the maxim being tested, while the other always violated it. Consistently choosing the puppet that adhered to the maxim was considered indicative of an understanding of that maxim. The results indicate that children were initially only successful in the Relation condition. While in general, children performed better at first in the Quantity condition compared with the Quality condition, 3-year-olds never performed above chance in the Quantity condition. The findings of the present study indicate that preschool children are sensitive to the violation of the Relation, Quality, and Quantity maxims at least under some conditions. PMID- 20953299 TI - Combining Statistical and Geometric Features for Colonic Polyp Detection in CTC Based on Multiple Kernel Learning. AB - Colon cancer is the second leading cause of cancer-related deaths in the United States. Computed tomographic colonography (CTC) combined with a computer aided detection system provides a feasible approach for improving colonic polyps detection and increasing the use of CTC for colon cancer screening. To distinguish true polyps from false positives, various features extracted from polyp candidates have been proposed. Most of these traditional features try to capture the shape information of polyp candidates or neighborhood knowledge about the surrounding structures (fold, colon wall, etc.). In this paper, we propose a new set of shape descriptors for polyp candidates based on statistical curvature information. These features called histograms of curvature features are rotation, translation and scale invariant and can be treated as complementing existing feature set. Then in order to make full use of the traditional geometric features (defined as group A) and the new statistical features (group B) which are highly heterogeneous, we employed a multiple kernel learning method based on semi definite programming to learn an optimized classification kernel from the two groups of features. We conducted leave-one-patient-out test on a CTC dataset which contained scans from 66 patients. Experimental results show that a support vector machine (SVM) based on the combined feature set and the semi-definite optimization kernel achieved higher FROC performance compared to SVMs using the two groups of features separately. At a false positive per scan rate of 5, the sensitivity of the SVM using the combined features improved from 0.77 (Group A) and 0.73 (Group B) to 0.83 (p <= 0.01). PMID- 20953300 TI - Multi-pinhole SPECT Imaging with Silicon Strip Detectors. AB - Silicon double-sided strip detectors offer outstanding instrinsic spatial resolution with reasonable detection efficiency for iodine-125 emissions. This spatial resolution allows for multiple-pinhole imaging at low magnification, minimizing the problem of multiplexing. We have conducted imaging studies using a prototype system that utilizes a detector of 300-micrometer thickness and 50 micrometer strip pitch together with a 23-pinhole collimator. These studies include an investigation of the synthetic-collimator imaging approach, which combines multiple-pinhole projections acquired at multiple magnifications to obtain tomographic reconstructions from limited-angle data using the ML-EM algorithm. Sub-millimeter spatial resolution was obtained, demonstrating the basic validity of this approach. PMID- 20953301 TI - Multiplexed magnetic microsphere immunoassays for detection of pathogens in foods. AB - Foodstuffs have traditionally been challenging matrices for conducting immunoassays. Proteins, carbohydrates, and other macromolecules present in food matrices may interfere with both immunoassays and PCR-based tests, and removal of particulate matter may also prove challenging prior to analyses. This has been found true when testing for bacterial contamination of foods using the standard polystyrene microspheres utilized with Luminex flow cytometers. Luminex MagPlex microspheres are encoded with the same dyes as standard xMAP microspheres, but have superparamagnetic properties to aid in preparation of samples in complex matrices. In this work, we present results demonstrating use of MagPlex for sample preparation and identification of bacteria and a toxin spiked into a variety of food samples. Fluorescence-coded MagPlex microsphere sets coated with antibodies for Salmonella, Campylobacter, Escherichia coli, Listeria, and staphylococcal enterotoxin B (SEB) were used to capture these bacteria and toxin from spiked foodstuffs and then evaluated by the Luminex system in a multiplex format; spiked foods included apple juice, green pepper, tomato, ground beef, alfalfa sprouts, milk, lettuce, spinach, and chicken washes. Although MagPlex microspheres facilitated recovery of the microspheres and targets from the complex matrices, assay sensitivity was sometimes inhibited by up to one to three orders of magnitude; for example the detection limits E. coli spiked into apple juice or milk increased 100-fold, from 1000 to 100,000 cfu/mL. Thus, while the magnetic and fluorescent properties of the Luminex MagPlex microspheres allow for rapid, multiplexed testing for bacterial contamination in typically problematic food matrices, our data demonstrate that achieving desired limits of detection is still a challenge. PMID- 20953302 TI - Combining Mixture Components for Clustering. AB - Model-based clustering consists of fitting a mixture model to data and identifying each cluster with one of its components. Multivariate normal distributions are typically used. The number of clusters is usually determined from the data, often using BIC. In practice, however, individual clusters can be poorly fitted by Gaussian distributions, and in that case model-based clustering tends to represent one non-Gaussian cluster by a mixture of two or more Gaussian distributions. If the number of mixture components is interpreted as the number of clusters, this can lead to overestimation of the number of clusters. This is because BIC selects the number of mixture components needed to provide a good approximation to the density, rather than the number of clusters as such. We propose first selecting the total number of Gaussian mixture components, K, using BIC and then combining them hierarchically according to an entropy criterion. This yields a unique soft clustering for each number of clusters less than or equal to K. These clusterings can be compared on substantive grounds, and we also describe an automatic way of selecting the number of clusters via a piecewise linear regression fit to the rescaled entropy plot. We illustrate the method with simulated data and a flow cytometry dataset. Supplemental Materials are available on the journal Web site and described at the end of the paper. PMID- 20953303 TI - STRUCTURE AND FUNCTION OF THE MIDDLE EAR APPARATUS OF THE AQUATIC FROG, XENOPUS LAEVIS. AB - We report the results of anatomical and vibrometric studies of the middle ear of the African clawed frog, Xenopus laevis. The cartilaginous tympanic disk of Xenopus shows pronounced sexual dimorphism, that of male frogs being much larger than that of females, relative to body size. The stapes footplate, however, is not enlarged in males. The cucullaris muscle was found to insert on the stapes in frogs of both sexes. Using laser interferometry to examine the response of middle ear structures to airborne sound, the stapes footplate was found to vibrate close to 180 degrees out-of-phase with the tympanic disk across a range of frequencies, this resembling the relationship between tympanic membrane and footplate movement previously described in ranid frogs. By contrast, whereas there is a pronounced difference in vibration velocity between tympanic membrane and footplate in ranids, the footplate vibration velocity in Xenopus was found to be similar to that of the tympanic disk. This may be interpreted as an adaptation to improve the detection of sound underwater. PMID- 20953304 TI - TGF-beta1-Induced Expression of the Anti-Apoptotic PAI-1 Protein Requires EGFR Signaling. AB - TGF-beta1 and its target gene encoding plasminogen activator inhibitor-1 (PAI-1) are major regulators of capillary outgrowth, vessel maturation and angiogenic network stability. The increasing realization of the complexity of PAI-1 action in the vascular system requires analysis of specific signaling events that impact its expression in a physiologically-relevant cell system. PAI-1 was required for tubular differentiation and maintenance of cellular survival in complex gels since targeted disruption of PAI-1 synthesis or activity with antisense constructs or function-blocking antibodies resulted in network regression. Indeed, serum-deprivation-induced apoptosis of tubulogenic T2 cells was concentration-dependently inhibited by addition of a stable PAI-1 mutant protein consistent with the established pro-survival role of PAI-1 in vascular endothelial cells. PAI-1 induction and ERK pathway activation in response to TGF beta1 was attenuated by EGFR signaling blockade (with AG1478) or preincubation with the MMP/ADAM inhibitor GM6001. The combination of AG1478 + GM6001 completely ablated both responses suggesting that EGFR transactivation is important in PAI-1 gene control and may, at least partially, involve ligand shedding. TGF-beta1 stimulated PAI-1 induction was preceded, in fact, by EGFR phosphorylation on Y845 (a src kinase target residue). EGFR1 knockdown with lentiviral shRNA constructs, moreover, effectively decreased (by >75%) TGF-beta1-stimulated PAI-1 expression whereas infection with control (i.e. GFP) viruses had no effect. TGF-beta1 failed to induce PAI-1 synthesis in EGFR-deficient fibroblasts while introduction of a wild-type EGFR1 construct in EGFR(-/-) cells rescued the PAI-1 response to TGF beta1 confirming, at a genetic level, the targeted knockdown data. The continued clarification of novel cooperative signaling cascades that impact expression of important angiogenic genes (e.g. PAI-1) may provide therapeutically useful targets to manage the pathophysiology of human neoplastic and vascular diseases. PMID- 20953306 TI - Lifetime Suicidal Ideation and Suicide Attempts in Asian Americans. AB - Few studies have examined the role of culturally relevant factors in suicidal behavior among Asian Americans. Using the National Latino and Asian American Study (NLAAS) (Alegria et al., 2004; Heeringa et al., 2004), the current study examined the role of culturally related variables (family conflict, perceived discrimination, and ethnic identity) on suicidal ideation and suicide attempts in a nationally representative sample of 2,095 Asian Americans. Important covariates were sociodemographic characteristics (gender, age, marital status, years of education, household poverty, and nativity status), depressive and anxiety disorders, and number of chronic conditions. Gender related correlates were also explored. The lifetime prevalence of suicidal ideation and attempts was 8.8% and 2.5%, respectively. Female gender, family conflict, perceived discrimination, and the presence of lifetime depressive or anxiety disorders were positively correlated with suicidal ideation and attempts. A high level of identification with one's ethnic group was associated with lower rates of suicide attempts. Among Asian men, but not women, the presence of chronic medical conditions was associated with suicidal ideation. Findings highlight the contributions to suicide risk of cultural factors and gender differences in Asian Americans. PMID- 20953307 TI - PNA-based microbial pathogen identification and resistance marker detection: an accurate, isothermal rapid assay based on genome-specific features. AB - With the rapidly growing availability of the entire genome sequences of microbial pathogens, there is unmet need for increasingly sensitive systems to monitor the gene-specific markers for diagnosis of bacteremia that enables an earlier detection of causative agent and determination of drug resistance. To address these challenges, a novel FISH-type genomic sequence-based molecular technique is proposed that can identify bacteria and simultaneously detect antibiotic resistance markers for rapid and accurate testing of pathogens. The approach is based on a synergistic combination of advanced Peptide Nucleic Acid (PNA)-based technology and signal-enhancing Rolling Circle Amplification (RCA) reaction to achieve a highly specific and sensitive assay. A specific PNA-DNA construct serves as an exceedingly selective and very effective biomarker, while RCA enhances detection sensitivity and provide with a highly multiplexed assay system. Distinct-color fluorescent decorator probes are used to identify about 20 nucleotide-long signature sequences in bacterial genomic DNA and/or key genetic markers of drug resistance in order to identify and characterize various pathogens. The technique's potential and its utility for clinical diagnostics are illustrated by identification of S. aureus with simultaneous discrimination of methicillin-sensitive (MSSA) versus methicillin-resistant (MRSA) strains. Overall these promising results hint to the adoption of PNA-based rapid sensitive detection for diagnosis of other clinically relevant organisms. Thereby, new assay enables significantly earlier administration of appropriate antimicrobial therapy and may, thus have a positive impact on the outcome of the patient. PMID- 20953308 TI - The convergence of bio, nano, and information technology: When Worlds Collide. PMID- 20953309 TI - Preliminary Support for Multidimensional Treatment Foster Care in Reducing Substance Use in Delinquent Boys. AB - Although effective outpatient treatments have been identified for the well documented negative outcomes associated with delinquency and substance use, effective treatments for youths in out-of-home care are rare. In this study, 12- and 18-month substance use outcomes were examined for a sample of 79 boys who were randomly assigned to Multidimensional Treatment Foster Care (experimental condition) or to group care (comparison condition). The boys in the experimental condition had lower levels of self-reported drug use at 12 months and lower levels of tobacco, marijuana, and other drug use at 18 months. Limitations and future directions are discussed. PMID- 20953310 TI - The Impact of Gamma Hydroxybutyrate (GHB) Legal Restrictions on Patterns of Use: Results from an International Survey. AB - AIMS: To conduct an Internet-based survey of GHB use, identifying differences by respondent residence. METHODS: We recruited GHB-knowledgeable persons via "social networking Internet sites." Individuals (n=314) or groups (n=66) were approached based on GHB-use testimonials. DATA COLLECTED: location, use, reason for cessation (if applicable). FINDINGS: We recruited 155 GHB users. U.S. respondents (53 of 70; 76%) compared to non-U.S. respondents (38 of 85; 45%) were older and more highly educated (p<0.05) but manifest a 3-fold greater adjusted odds of GHB cessation (Odds Ratio [OR] 3.1; 95% CI 1.4-6.9; p < 0.05). Of the 80 respondents stating reason for cessation, 36 (45%) cited legal risk, price, or access; 44 (55%) cited health or related concerns. U.S. compared to non-U.S. respondents more frequently invoked legal and related concerns (OR 2.5; 95% CI 0.99-6.3; p=0.05). In a nested analysis, narrowly stated legal (n=4/5 U.S.) versus health (n=6/18 U.S.) reasons differed by location (p=0.048, one-tailed). CONCLUSIONS: In the U.S., where GHB has stricter legal penalties, GHB cessation is more likely, with legal and related reasons more commonly invoked for cessation. These findings support a link between declining U.S. GHB abuse and more stringent restrictions; although other un-assessed factors may also explain this association. The Impact of Gamma Hydroxybutyrate (GHB) Legal Restrictions on Patterns of Use: Results from an International Survey. PMID- 20953311 TI - Sex differences in the electrocommunication signals of the electric fish Apteronotus bonapartii. AB - The South American weakly-electric knifefish (Apteronotidae) produce highly diverse and readily quantifiable electrocommunication signals. The electric organ discharge frequency (EODf), and EOD modulations (chirps and gradual frequency rises (GFRs)), vary dramatically across sexes and species, presenting an ideal opportunity to examine the proximate and ultimate bases of sexually dimorphic behavior. We complemented previous studies on the sexual dimorphism of apteronotid communication signals by investigating electric signal features and their hormonal correlates in Apteronotus bonapartii, a species which exhibits strong sexual dimorphism in snout morphology. Electrocommunication signals were evoked and recorded using a playback paradigm, and were analyzed for signal features including EOD frequency and the structure of EOD modulations. To investigate the androgenic correlates of sexually dimorphic EOD signals, we measured plasma concentrations of testosterone and 11-ketotestosterone. A. bonapartii responded robustly to stimulus playbacks. EODf was sexually monomorphic, and males and females produced chirps with similar durations and amounts of frequency modulation. However, males were more likely than females to produce chirps with multiple frequency peaks. Sexual dimorphism in apteronotid electrocommunication signals appears to be highly evolutionarily labile. Extensive interspecific variation in the magnitude and direction of sex differences in EODf and in different aspects of chirp structure suggest that chirp signals may be an important locus of evolutionary change within the clade. The weakly-electric fish represent a rich source of data for understanding the selective pressures that shape, and the neuroendocrine mechanisms that underlie, diversity in the sexual dimorphism of behavior. PMID- 20953312 TI - Plasmon-controlled fluorescence: A new detection technology. AB - Fluorescence is widely used in biological research. Future advances in biology and medicine often depend on the advances in the capabilities of fluorescence measurements. In this overview paper we describe how a combination of fluorescence, and plasmonics, and nanofabrication can fundamentally change and increase the capabilities of fluorescence technology. This change will be based on the use of surface plasmons which are collective oscillations of free electrons in metallic surfaces and particles. Surface plasmon resonance is now used to measure bioaffinity reactions. However, the uses of surface plasmons in biology are not limited to their optical absorption or extinction. We have shown that fluorophores in the excited state can create plasmons which radiate into the far field; additionally fluorophores in the ground state can interact with and be excited by surface plasmons. These interactions suggest that the novel optical absorption and scattering properties of metallic nanostructures can be used to control the decay rates, location and direction of fluorophore emission. We refer to this technology as plasmon-controlled fluorescence. We predict that plasmon controlled fluorescence (PCF) will result in a new generation of probes and devices. PCF is likely to allow design of structures which enhance emission at specific wavelengths and the creation of new devices which control and transport the energy from excited fluorophores in the form of plasmons, and then convert the plasmons back to light. PMID- 20953313 TI - Mothers' and Children's Concentrations of Oxytocin Following Close, Physical Interactions with Biological and Non-biological Children. AB - The current study examined the concentration of mothers' peripherally produced oxytocin after close physical interactions with their biological and non biological children. Each of 35 mothers and children participated in a computer game that promoted physical contact. In one interaction context, mothers interacted with their own children, and in the other context, mothers interacted with unfamiliar children. After the activity, urine samples were collected from the mothers and were assayed for oxytocin. Data from 26 mothers were available for oxytocin analyses. Oxytocin levels were higher among mothers following interactions with unfamiliar children than following interactions with their own children. Possible explanations for the differences in oxytocin levels across contexts are discussed. PMID- 20953314 TI - Selective TRAIL-triggered apoptosis due to overexpression of TRAIL death receptor 5 (DR5) in P-glycoprotein-bearing multidrug resistant CEM/VBL1000 human leukemia cells. AB - The death-inducing cytokine, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), holds enormous promise as a cancer therapeutic due to its highly selective apoptosis-inducing action on neoplastic versus normal cells. Our results revealed that TRAIL selectively triggered apoptosis in the P-glycoprotein (P-gp, ABCB1) and DR5 overexpressing CEM/VBL1000 multidrug resistant leukemia cell line, but not in the parental CEM cells. Moreover, TRAIL treatment reduced P gp expression in these cells. Mechanistic analysis of TRAIL-induced apoptosis revealed that TRAIL hypersensitivity is due to robust upregulation of the TRAIL receptor DR5 at the protein and mRNA levels during development of MDR in the CEM/VBL1000 variant. DR5 upregulation was independent of the level of expression of endoplasmic reticulum stress regulator C/EBP homologous transcription factor (CH0P/GADD153). TRAIL-triggered apoptosis was associated with increased expression of FADD; activation of caspases-3, -8, -9, and -10; and cytochrome c release from mitochondria. Therefore, both the extrinsic and intrinsic apoptosis pathways are involved in this process. These findings for the first time reveal that TRAIL treatment selectively causes apoptosis in P-gp-overexpressing CEM/VBL1000 cells through strong upregulation of DR5. Moreover, this hypersensitivity to TRAIL and its effect on reducing P-gp expression in these cells hold significant clinical implications for using TRAIL to eradicate MDR malignant cells. PMID- 20953315 TI - Formation of Tethered Supported Bilayers by Vesicle Fusion onto Lipopolymer Monolayers Promoted by Osmotic Stress. PMID- 20953316 TI - Distinguishing symptoms of grief and depression in a cohort of advanced cancer patients. AB - Several studies have shown that the symptoms of grief are different from symptoms of depression among bereaved family members. This study is an attempt to replicate this finding among advanced cancer patients and examine clinical correlates of patient grief and depression. Analyses were conducted on data from interviews with 123 advanced cancer patients. Grief was measured using symptoms from the patient version of the Inventory of Complicated Grief-Revised (ICG-R) and symptoms of depression were assessed using the Structured Clinical Interview for DSM-IV (SCID). A factor analysis revealed that symptoms of patient grief formed a coherent factor that was distinct from a depression factor. Patient grief "caseness" (defined as being in the top 10% of the distribution of grief scores), but not major depressive disorder, was uniquely associated with the wish to die (odds ratio [OR] 10.13 [0.1.08-95.06]). Both depression and grief were significantly associated with mental health service use (OR 16.07 [1.68, 153.77] vs. 4.82; CI = [1.09, 21.41]) and negative religious coping (OR 1.36 [1.06, 1.73] vs. 1.25 [1.05, 1.49]); neither was associated with terminal illness acknowledgement. PMID- 20953317 TI - Co-morbidity of alcohol dependence and select affective and anxiety disorders among individuals of East Indian and African ancestry in Trinidad and Tobago. AB - The present study sought to determine whether an association exists between alcohol dependence and select affective and anxiety disorders in patients presenting at substance abuse centres in Trinidad and Tobago (TT). The participants in this study were 143 alcohol dependents, of either East Indian ancestry (Indo-TT) or African ancestry (Afro-TT) and 109 controls matched by age, gender and ethnicity. A structured interview was used to gather information on demographics, psychiatric diagnoses and personal drinking and drug use. A blood sample was obtained and used to genotype for the presence of ADH and ALDH1 polymorphisms and serum levels of hepatic enzymes. Forty-one per cent of Indo-TT and 37% of Afro-TT with alcohol dependence had co-morbid major depressive disorders independent of alcohol and/or drug use. Thirty-nine per cent of Indo-TT and 37% of Afro-TT with alcohol dependence had co-morbid major depression induced by alcohol or drug use. The severity of depression was significantly associated with severity of alcohol dependence. Neither major depression nor the severity of depressive episodes was associated with values of any liver function test or the presence of ALDH1*2 or ADH1C*2 alleles. However in participants of African descent elevated alanine transaminase ALT was associated (p = 0.038) with not having substance-induced major depression. Co-morbidity of major depressive disorder with alcohol dependence is common in the two major ethnic groups in Trinidad and Tobago and appears to be as likely the consequence of drinking and/or drug use, as the cause. Clinicians should solicit a history of depression from patients with alcohol dependence. PMID- 20953319 TI - Solubility of alpha-Tocopheryl Succinate in Supercritical Carbon Dioxide Using Offline HPLC-MS/MS Analysis. AB - The solubility of the vitamin E-related compound alpha-tocopheryl succinate in supercritical carbon dioxide was measured at pressures ranging from (15.0 to 30.0) MPa and temperatures of (40 and 50) degrees C using a simple microsampling type apparatus with a 100.5 MUL sample loop to remove aliquots and collect them in ethanol for off line analysis. alpha-Tocopheryl succinate concentrations in the collected samples were measured using HPLC-MS/MS analysis. The solubility of alpha-tocopheryl succinate in supercritical carbon dioxide ranged from mole fractions of 0.28 * 10(-5) at 15.0 MPa and 50 degrees C to 2.56 * 10(-5) at 30.0 MPa and 50 degrees C. PMID- 20953318 TI - Zidovudine and Lamivudine for HIV Infection. AB - Zidovudine and lamivudine (ZDV and 3TC) are long-standing nucleoside analog reverse transcriptase inhibitors (NRTIs) with extensive clinical experience in a wide spectrum of patients from in utero through childhood and adult ages. The safety profiles of both drugs are well-known and side effects for ZDV most commonly include nausea/vomiting, fatigue, anemia/neutopenia, and lipoatrophy; while 3TC is well-tolerated. ZDV-3TC is currently a viable alternative NRTI backbone for initial three-drug therapy of HIV infection when tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) cannot be used because of a relative or absolute contraindication. ZDV-3TC continue to be viable alternatives for children, pregnant women and in resource limited settings where other recommended options are not readily available. ZDV-3TC penetrate the Central Nervous System (CNS) well, which makes ZDV-3TC attractive for use in patients with HIV associated neurological deficits. Additional benefits of these drugs may include the use of ZDV in combination with certain NRTIs to exert selective pressure to prevent particular drug resistance mutations from developing, and giving a short course of ZDV-3TC to prevent resistance after prophylactic single dose nevirapine. PMID- 20953320 TI - Rowlinson's concept of an effective hard sphere diameter. AB - Attention is drawn to John Rowlinson's idea that the repulsive portion of the intermolecular interaction may be replaced by a temperature-dependent hard sphere diameter. It is this approximation that made the development of perturbation theory possible for realistic fluids whose intermolecular interactions have a steep, but finite, repulsion at short separations. PMID- 20953321 TI - The Interplay between Sexually Transmitted Infections and HIV: An Evolving Story. PMID- 20953322 TI - Use of the Aerosol Rabbitpox Virus Model for Evaluation of Anti-Poxvirus Agents. AB - Smallpox is an acute disease caused by infection with variola virus that has had historic effects on the human population due to its virulence and infectivity. Because variola remains a threat to humans, the discovery and development of novel pox therapeutics and vaccines has been an area of intense focus. As variola is a uniquely human virus lacking a robust animal model, the development of rational therapeutic or vaccine approaches for variola requires the use of model systems that reflect the clinical aspects of human infection. Many laboratory animal models of poxviral disease have been developed over the years to study host response and to evaluate new therapeutics and vaccines for the treatment or prevention of human smallpox. Rabbitpox (rabbitpox virus infection in rabbits) is a severe and often lethal infection that has been identified as an ideal disease model for the study of poxviruses in a non-rodent species. The aerosol infection model (aerosolized rabbitpox infection) embodies many of the desired aspects of the disease syndrome that involves the respiratory system and thus may serve as an appropriate model for evaluation of antivirals under development for the therapeutic treatment of human smallpox. In this review we summarize the aerosol model of rabbitpox, discuss the development efforts that have thus far used this model for antiviral testing, and comment on the prospects for its use in future evaluations requiring a poxviral model with a focus on respiratory infection. PMID- 20953323 TI - Current Status and Future Prospects of Proton MR Spectroscopy of the Breast with a 1.5T MR Unit. AB - Proton MR spectroscopy of the mammary gland area is used to be considered in the realm of basic research, but as a result of the advances in MR techniques, it is now being performed in ordinary clinical practice. It is particularly noteworthy that useful clinical data are now being accumulated with 1.5T MR units, which are the standard units. We think that, at this point, it is very important to systematically review the techniques, clinical applications, and future prospects of proton MR spectroscopy. We have performed proton MR spectroscopy with a 1.5T MR unit in over 3000 cases at our hospital. In this paper, we will comment on the current status of proton MR spectroscopy of the breast, primarily in regard to differentiation between benign and malignant lesions and prediction of the efficacy of chemotherapy while describing the data obtained at our hospital. PMID- 20953325 TI - A unique case of lemierre syndrome associated with thrombophilia in an adult and the role of anticoagulation. AB - Acute septic thrombophlebitis of the internal jugular vein (IJV), better known as Lemierre syndrome, is a rare entity which poses several challenges in management. Treatment involves prompt use of intravenous antibiotics over a prolonged period of time, typically 6-8 weeks. The use of anticoagulation is controversial, but indicated for some. We describe the first reported case of Lemierre syndrome associated with a hypercoagulable state in an adult. We propose that all patients with Lemierre syndrome should be evaluated for hypercoagulable states and that the indications for anticoagulation in Lemierre syndrome are (1) propagation or nonresolution of IJV thrombus despite antibiotics and (2) identification of a hypercoagulable state, as in our case. PMID- 20953324 TI - Overview of cellular immunotherapy for patients with glioblastoma. AB - High grade gliomas (HGG) including glioblastomas (GBM) are the most common and devastating primary brain tumours. Despite important progresses in GBM treatment that currently includes surgery combined to radio- and chemotherapy, GBM patients' prognosis remains very poor. Immunotherapy is one of the new promising therapeutic approaches that can specifically target tumour cells. Such an approach could also maintain long term antitumour responses without inducing neurologic defects. Since the past 25 years, adoptive and active immunotherapies using lymphokine-activated killer cells, cytotoxic T cells, tumour-infiltrating lymphocytes, autologous tumour cells, and dendritic cells have been tested in phase I/II clinical trials with HGG patients. This paper inventories these cellular immunotherapeutic strategies and discusses their efficacy, limits, and future perspectives for optimizing the treatment to achieve clinical benefits for GBM patients. PMID- 20953326 TI - Social Support: A Mixed Blessing for Women in Substance Abuse Treatment. AB - Using a personal social network framework, this qualitative study sought to understand how women in substance abuse treatment describe their network members' supportive and unsupportive behaviors related to recovery. Eighty-six women were interviewed from residential and outpatient substance abuse treatment programs. Positive and negative aspects of women's social networks were assessed via open ended questions. Analysis was guided by grounded theory techniques using three coders. The findings extend classic social support concepts such as emotional, tangible, and informational support. Practice implications are presented in light of the potential roles network members may play in substance use and recovery. PMID- 20953327 TI - Efficient Controls for Finitely Convergent Sequential Algorithms. AB - Finding a feasible point that satisfies a set of constraints is a common task in scientific computing: examples are the linear feasibility problem and the convex feasibility problem. Finitely convergent sequential algorithms can be used for solving such problems; an example of such an algorithm is ART3, which is defined in such a way that its control is cyclic in the sense that during its execution it repeatedly cycles through the given constraints. Previously we found a variant of ART3 whose control is no longer cyclic, but which is still finitely convergent and in practice it usually converges faster than ART3 does. In this paper we propose a general methodology for automatic transformation of finitely convergent sequential algorithms in such a way that (i) finite convergence is retained and (ii) the speed of convergence is improved. The first of these two properties is proven by mathematical theorems, the second is illustrated by applying the algorithms to a practical problem. PMID- 20953328 TI - 12/15-lipoxygenase is an interleukin-13 and interferon-gamma counterregulated mediator of allergic airway inflammation. AB - Interleukin-13 and interferon-gamma are important effectors of T-helper cells. Interleukin-13 increases expression of the arachidonic acid-metabolizing enzyme, 15-lipoxygenase-1, in a variety of cell types. 15-lipoxygenase-1 is dramatically elevated in the airways of subjects with asthma. Studies in animals indicate that 15-lipoxygenase-1 contributes to the development of allergic airway inflammation but is protective in some other forms of inflammation. We tested the hypothesis that the ability of interleukin-13 and interferon-gamma to counterregulate allergic airway inflammation was potentially mediated by counterregulation of 12/15-lipoxygenase, the mouse ortholog of 15-lipoxygenase-1. The airways of mice were treated with interleukin-13 or interferon-gamma one day prior to each of the four allergen exposures. Interleukin-13 augmented and interferon-gamma inhibited allergic airway inflammation independently of systemic IgE and mucosal IgA responses but in association with counterregulation of 12/15-lipoxygenase. Interleukin-13 and interferon-gamma counterregulate 12/15-lipoxygenase potentially contributing to the effects of these cytokines on allergic airway inflammation. PMID- 20953329 TI - Bidirectional Influences in Mother-Toddler Dyads: An Examination of the Relative Influence of Mothers' and Children's Behaviors. AB - This study examined bidirectional relations between mothers' lax and overreactive discipline and children's misbehavior and negative affect. We examined the moment to-moment stability of mothers' and children's behaviors (actor effects) and mothers' and children's influence on their partners' subsequent behaviors (partner effects). Participants were 71 mothers and their 24-48-month-old children observed during a thirty-minute interaction. Both children and mothers exhibited stability in their own behaviors and influenced the subsequent behaviors of their partners. Additionally, a comparison of partner effects indicated that overreactive discipline more strongly predicted child negative affect than child negative affect predicted overreactive discipline. In contrast, although a child's negative affect predicted lax discipline, lax discipline did not predict subsequent child negative affect. PMID- 20953330 TI - Helping Aging Parents of Adult Children with Serious Mental Illness. AB - This manuscript reports the results of a study that pilot tested a home delivered, multi-dimensional problem-solving intervention aimed at helping aging parental caregivers of adult children with schizophrenia. The results indicate that the participants (N=5) who received the 10-session intervention showed increased life satisfaction and emotional well being, and reduced feelings of burden, compared to those participants in the control group (N=10). If a planned larger scale evaluation of the intervention provides evidence of its effectiveness, practitioners could have a valuable new treatment tool to provide assistance to this caregiver population. PMID- 20953331 TI - Thromboelastometric profiles of horses affected by exercise-induced pulmonary hemorrhages. AB - Exercise-induced pulmonary hemorrhage (EIPH) commonly occurs in race horses. Thromboelastometry (TEM) investigates the whole hemostatic process by evaluating the viscoelastic properties of the blood clot from its formation to fibrinolysis. The aim of this study was to assess whether horses with EIPH have abnormal thromboelastometric profiles. Intrinsic and extrinsic pathways, fibrinogen activity and fibrinolysis were investigated by TEM before and after the race in negative controls and in horses on which EIPH was confirmed by bronchoscopy. Compared with controls, horses with EIPH had an increased coagulability in both pre- and postrace samplings, especially for the intrinsic pathway and for the fibinrolytic activity. These results suggest that coagulation is preactivated in horses prone to develop EIPH, possibly due to recent or recurrent hemorrhage. PMID- 20953333 TI - Fertility Rates of Ewes Treated with Medroxyprogesterone and Injected with Equine Chorionic Gonadotropin plus Human Chorionic Gonadotropin in Anoestrous Season. AB - The aim of the present paper was to investigate the efficiency of the equine chorionic gonadotropin (eCG) plus human chorionic gonadotropin (hCG) associated with medroxyprogesterone acetate (MAP) to estrous ewes synchronization. Ninety Texel ewes were investigated during seasonal anoestrous. The ewes received intravaginal sponges containing MAP (60 mg) for nine days. At the time of sponges' withdrawal, the ewes were divided into three groups (G): (1) receiving 2 mL of saline i.m. (n = 30), (2) receiving eCG 400 IU i.m. (n = 30), and (3) receiving eCG 400 IU plus hCG 200 IU i.m. (n = 30). Twelve h after sponges' removal, teaser rams were used to estrus check and remained with the ewes for 96 h. The artificial insemination was made with fresh semen 10 h after estrus detection. The effect of the treatment was not significant for the estrous rates among the groups: 73%, 90%, and 86%, respectively. The main effect was observed in the pregnancy and lambing rates among the groups: 70%, 86%, 56%, and 80%, 120%, 56%, respectively. Based on these results from our study, the use of the MAP-eCG is the best choice to improve the fertility rate on ewes. PMID- 20953332 TI - Current and future trends in magnetic resonance imaging assessments of the response of breast tumors to neoadjuvant chemotherapy. AB - The current state-of-the-art assessment of treatment response in breast cancer is based on the response evaluation criteria in solid tumors (RECIST). RECIST reports on changes in gross morphology and divides response into one of four categories. In this paper we highlight how dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted MRI (DW-MRI) may be able to offer earlier, and more precise, information on treatment response in the neoadjuvant setting than RECIST. We then describe how longitudinal registration of breast images and the incorporation of intelligent bioinformatics approaches with imaging data have the potential to increase the sensitivity of assessing treatment response. We conclude with a discussion of the potential benefits of breast MRI at the higher field strength of 3T. For each of these areas, we provide a review, illustrative examples from clinical trials, and offer insights into future research directions. PMID- 20953334 TI - Automatic Detection of Stress States in Type 1 Diabetes Subjects in Ambulatory Conditions. AB - Two levels of control are crucial to the robustness of an artificial beta-cell, a medical device that would automatically regulate blood glucose levels in patients with type 1 diabetes. A low-level component would attempt to regulate blood glucose continuously, while a supervisory-level, or monitoring, component would detect underlying changes in the subject's glucose-insulin dynamics and take corrective actions accordingly. These underlying changes, or "faults," can include changes in insulin sensitivity, sensor problems, and insulin delivery problems, to name a few. A multivariate statistical monitoring technique, principal component analysis (PCA), has been applied to both simulated and experimental type 1 diabetes data. The objective of this study was to determine if PCA could be used to distinguish between normal patient data, and data for abnormal conditions that included a variety of "faults." The PCA results showed a high degree of accuracy; for data from nine type 1 diabetes subjects in ambulatory conditions, 33 of 37 total test days (89%), including fault days and normal days, were classified correctly. Thus, the proposed monitoring technique shows considerable promise for incorporation into an artificial beta-cell. PMID- 20953335 TI - Future Directions in the Study of Close Relationships: Conflict is Bad (Except When It's Not). AB - Beneficial and detrimental correlates of interpersonal disagreement have been postulated and documented. The conclusion: Conflict is both bad and good. The evidence for these paradoxical effects is summarized. In this essay, we argue that the consequences of conflict for individuals depends on its frequency, the way in which it is managed, and the quality of the relationship in which it arises. Nonlinear patterns of association are hypothesized such that constructive conflicts, particularly those arising in supportive relationships, should (up to a limit) predict more beneficial and fewer detrimental outcomes. In contrast, coercive conflicts, particularly those arising in unsupportive relationships, should predict more adverse and fewer favorable outcomes. PMID- 20953336 TI - Family Matters: The Role of Mental Health Stigma and Social Support on Depressive Symptoms and Subsequent Help Seeking Among African American Boys. AB - African American adolescent boys underutilize mental health service due to stigma associated with depression. Gaining an increased understanding of how depressed, African American adolescent boys perceive their mental health needs and engage in help-seeking behaviors might play an essential role in efforts to improve their symptoms and access to care. Using a mixed-methods design, this study examined the influence of mental health stigma and social support on depressive symptoms among African American adolescent boys. Findings indicated the protective effects of social support in decreasing depressive symptoms, especially when participants experienced mental health stigma. Results also revealed the pivotal role of family social support over both professional and peer support for participants who struggled with depressive symptoms. The primacy of family support among the sample, combined with the frequent distrust of professionals and peer networks, would indicate that working with families may improve initial identification of depression among African American adolescent boys and decrease their barriers to care. PMID- 20953337 TI - Unprecedented Fe(IV) Species in a Diheme Protein MauG: A Quantum Chemical Investigation on the Unusual Mossbauer Spectroscopic Properties. AB - Ferryl species are important catalytic intermediates in heme enzymes. A recent experimental investigation of a diheme protein MauG reported the first case of using two Fe(IV) species as an alternative to compound I in catalysis. Both Fe(IV) species have unusual Mossbauer properties, which was found to originate from novel structural features based on a quantum chemical investigation. With comparison to the previously reported Fe(IV)=O and Fe(IV)-OH species, results here provide the first evidence of a couple of new mechanisms by which proteins influence the properties of ferryl species by directly providing the O via Tyr, or stabilizing exogenous O via hydrogen bonding interaction. These results expand our ability to identify and evaluate high-valent heme proteins and models. PMID- 20953338 TI - Infant Symbolic Play as an Early Indicator of Fetal Alcohol-Related Deficit. AB - Infant symbolic play was examined in relation to prenatal alcohol exposure and socioenvironmental background and to predict which infants met criteria for fetal alcohol syndrome (FAS) at 5 years. 107 Cape Coloured, South African infants born to heavy drinking mothers and abstainers/light drinkers were recruited prenatally. Complexity of play, socio-demographic and psychological correlates of maternal alcohol use, and quality of parenting were assessed at 13 months, and IQ and FAS diagnosis at 5 years. The effect of drinking on spontaneous play was not significant after control for social environment. By contrast, prenatal alcohol and quality of parenting related independently to elicited play. Elicited play predicted 5-year Digit Span and was poorer in infants subsequently diagnosed with FAS/partial FAS and in nonsyndromal heavily exposed infants, compared with abstainers/light drinkers. Thus, symbolic play may provide an early indicator of risk for alcohol-related deficits. The independent effects of prenatal alcohol and quality of parenting suggest that infants whose symbolic play is adversely affected by alcohol exposure may benefit from stimulation from a responsive caregiver. PMID- 20953339 TI - Sign Languages: Contribution to Neurolinguistics from Cross-Modal Research. AB - Using sign language research as an example, we argue that both the cross linguistic descriptive approach to data, advocated by Evans and Levinson (2009), as well as abstract ('formal') analyses are necessary steps towards the development of "neurolinguistic primitives" for investigating how human languages are instantiated in the brain. PMID- 20953340 TI - Detail in network models of epidemiology: are we there yet? AB - Network models of infectious disease epidemiology can potentially provide insight into how to tailor control strategies for specific regions, but only if the network adequately reflects the structure of the region's contact network. Typically, the network is produced by models that incorporate details about human interactions. Each detail added renders the models more complicated and more difficult to calibrate, but also more faithful to the actual contact network structure. We propose a statistical test to determine when sufficient detail has been added to the models and demonstrate its application to the models used to create a synthetic population and contact network for the USA. PMID- 20953341 TI - C-F Bond Formation for the Synthesis of Aryl Fluorides. AB - A selection of carbon-fluorine bond-forming reactions is presented with particular focus on transition metal-mediated fluorination. A brief summary of conventional fluorination reactions is followed by a discussion of fluorination reactions mediated by palladium and silver. Investigations into the mechanism as well as the conceptual difficulty associated with transition metal-mediated carbon-fluorine bond formation are presented. PMID- 20953342 TI - Coordinate Transcriptomic and Metabolomic Effects of the Insulin Sensitizer Rosiglitazone on Fundamental Metabolic Pathways in Liver, Soleus Muscle, and Adipose Tissue in Diabetic db/db Mice. AB - Rosiglitazone (RSG), developed for the treatment of type 2 diabetes mellitus, is known to have potent effects on carbohydrate and lipid metabolism leading to the improvement of insulin sensitivity in target tissues. To further assess the capacity of RSG to normalize gene expression in insulin-sensitive tissues, we compared groups of 18-day-treated db/db mice with increasing oral doses of RSG (10, 30, and 100 mg/kg/d) with untreated non-diabetic littermates (db/+). For this aim, transcriptional changes were measured in liver, inguinal adipose tissue (IAT) and soleus muscle using microarrays and real-time PCR. In parallel, targeted metabolomic assessment of lipids (triglycerides (TGs) and free fatty acids (FFAs)) in plasma and tissues was performed by UPLC-MS methods. Multivariate analyses revealed a relationship between the differential gene expressions in liver and liver trioleate content and between blood glucose levels and a combination of differentially expressed genes measured in liver, IAT, and muscle. In summary, we have integrated gene expression and targeted metabolomic data to present a comprehensive overview of RSG-induced changes in a diabetes mouse model and improved the molecular understanding of how RSG ameliorates diabetes through its effect on the major insulin-sensitive tissues. PMID- 20953343 TI - Relations between early family risk, children's behavioral regulation, and academic achievement. AB - This study examined relations among early family risk, children's behavioral regulation at 54 months and kindergarten, and academic achievement in first grade using data on 1,298 children from the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and Youth Development. Family risk was indexed by ethnic minority status, low maternal education, low average family income from 1 - 54 months, and high maternal depressive symptoms from 1 - 54 months. Results of structural equation modeling indicated that minority status, low maternal education, and low family income had significant negative effects on reading, math, and vocabulary achievement in first grade. Modest indirect effects were also found from ethnicity, maternal education, and maternal depressive symptoms, through 54-month and kindergarten behavioral regulation to first-grade achievement. Discussion focuses on the importance of behavioral regulation for school success especially for children facing early risk. PMID- 20953345 TI - Demonstration of a micro-fabricated hydrogen storage module for micro-power systems. AB - The objective of this work was to demonstrate a micro-fabricated hydrogen storage module for micro-power systems. Hydrogen storage materials were developed as thin film inks to be compatible with an integrated manufacturing process. Performance and durability of storage modules were evaluated. Further, applications were demonstrated for a nickel-hydrogen battery and a micro-fabricated hydrogen-air PEM fuel cell. The ink making process, in which polymer binders and solvents were added to the palladium-treated alloys, slightly decreased the storage capacities, but had little effect on the activation properties of the treated alloys. After 5000 absorption/desorption cycles under hydrogen, the hydrogen storage capacities of the thin-film inks remained high. Absorption/desorption behavior of the ink was tested in the environment of a new type nickel-hydrogen battery, in which it would in contact with 26wt% KOH solution, and the ink showed no apparent degradation. Storage modules were used as the successfully as hydrogen source for PEM fuel cell. PMID- 20953346 TI - Rapid and Sensitive Colorimetric ELISA using Silver Nanoparticles, Microwaves and Split Ring Resonator Structures. AB - We report a new approach to colorimetric Enzyme-Linked Immunosorbent Assay (ELISA) that reduces the total assay time to < 2 min and the lower-detection limit by 100-fold based on absorbance readout. The new approach combines the use of silver nanoparticles, microwaves and split ring resonators (SRR). The SRR structure is comprised of a square frame of copper thin film (30 um thick, 1 mm wide, overall length of ~9.4 mm on each side) with a single split on one side, which was deposited onto a circuit board (2*2 cm(2)). A single micro-cuvette (10 ul volume capacity) was placed in the split of the SRR structures. Theoretical simulations predict that electric fields are focused in and above the micro cuvette without the accumulation of electrical charge that breaks down the copper film. Subsequently, the walls and the bottom of the micro-cuvette were coated with silver nanoparticles using a modified Tollen's reaction scheme. The silver nanoparticles served as a mediator for the creation of thermal gradient between the bioassay medium and the silver surface, where the bioassay is constructed. Upon exposure to low power microwave heating, the bioassay medium in the micro cuvette was rapidly and uniformly heated by the focused electric fields. In addition, the creation of thermal gradient resulted in the rapid assembly of the proteins on the surface of silver nanoparticles without denaturing the proteins. The proof-of-principle of the new approach to ELISA was demonstrated for the detection of a model protein (biotinylated-bovine serum albumin, b-BSA). In this regard, the detection of b-BSA with bulk concentrations (1 uM to 1 pM) was carried out on commercially available 96-well high throughput screening (HTS) plates and silver nanoparticle-deposited SRR structures at room temperature and with microwave heating, respectively. While the room temperature bioassay (without microwave heating) took 70 min to complete, the identical bioassay took < 2 min to complete using the SRR structures (with microwave heating). A lower detection limit of 0.01 nM for b-BSA (100-fold lower than room temperature ELISA) was observed using the SRR structures. PMID- 20953347 TI - Detection of Social Interaction in Smart Spaces. AB - The pervasive sensing technologies found in smart environments offer unprecedented opportunities for monitoring and assisting the individuals who live and work in these spaces. An aspect of daily life that is important for one's emotional and physical health is social interaction. In this paper we investigate the use of smart environment technologies to detect and analyze interactions in smart spaces. We introduce techniques for collect and analyzing sensor information in smart environments to help in interpreting resident behavior patterns and determining when multiple residents are interacting. The effectiveness of our techniques is evaluated using two physical smart environment testbeds. PMID- 20953348 TI - A Stochastic Model for Nucleation Kinetics Determination in Droplet-Based Microfluidic Systems. AB - The measured induction times in droplet-based microfluidic systems are stochastic and are not described by the deterministic population balances or moment equations commonly used to model the crystallization of amino acids, proteins, and active pharmaceutical ingredients. A stochastic model in the form of a Master equation is formulated for crystal nucleation in droplet-based microfluidic systems for any form of nucleation rate expression under conditions of time varying supersaturation. An analytical solution is provided to describe the (1) time evolution of the probability of crystal nucleation, (2) the average number of crystals that will form at time t for a large number of droplets, (3) the induction time distribution, and (4) the mean, most likely, and median induction times. These expressions are used to develop methods for determining the nucleation kinetics. Nucleation kinetics are determined from induction times measured for paracetamol and lysozyme at high supersaturation in an evaporation based high-throughput crystallization platform, which give low prediction errors when the nucleation kinetics were used to predict induction times for other experimental conditions. The proposed stochastic model is relevant to homogeneous and heterogeneous crystal nucleation in a wide range of droplet-based and microfluidic crystallization platforms. PMID- 20953349 TI - HIV treatment in US prisons. AB - Arguably one of the most marginalized populations in our society, prisoners bear a disproportionate burden of infectious diseases, particularly HIV. In addition, groups known to be at an inordinately higher risk of HIV, including minorities, the addicted, the mentally ill and the impoverished are overrepresented among incarcerated populations. This concentration of HIV among groups that have been historically difficult to reach, with limited intersections with healthcare, provides an opportunity for testing, diagnosis, treatment, linkage to care and prevention. Providing HIV care within correctional facilities poses unique challenges. Barriers to confidentiality, access to medication and prior records, and lack of comprehensive discharge planning can serve as obstacles to providing optimal care. This article discusses the public health implications and importance of providing HIV care to prisoners, and also discusses the practicalities of working within an environment that poses particular barriers to care. PMID- 20953350 TI - Jagged1 expression regulated by Notch3 and Wnt/beta-catenin signaling pathways in ovarian cancer. AB - Ovarian serous carcinoma is a highly aggressive neoplastic disease in women. Our previous studies have demonstrated Notch3 gene amplification and upregulation in many ovarian serous carcinomas and Notch pathway activity contributed to drug resistance. Among different Notch3 ligands, Jagged1 is most dominant in ovarian cancer, and Notch3 pathway activity correlated with Jagged1 expression level in ovarian carcinoma tissues. In this study, we found that Jagged1 expression depended on Notch3 pathway activation. Knockdown of either Notch3 or RBPjk, a Notch-interacting transcription factor critical in Notch signaling, suppressed Jagged1 expression in ovarian cancer cells. Moreover, Jagged1 expression was upregulated in human ovarian surface epithelial cells after ectopic expression of Notch3 intracellular domain and was upregulated in mouse epithelial cells isolated from Notch3-inducible mice after induction. We also found that inhibition of Wnt/beta-catenin signaling reduced Jagged1 expression, and co administration of shRNAs targeting both Notch3 and beta-catenin reduced Jagged1 expression much more than targeting either individual gene. Taken together, our data suggested a positive regulatory loop between Notch3 and its ligand, Jagged1, in ovarian cancer cells. In addition, Wnt/beta-catenin pathway activation also up regulated Jagged1. Both mechanisms may sustain Notch3 signaling in ovarian cancer cells and contribute to the pathogenesis of ovarian carcinoma. PMID- 20953351 TI - Inter-relationships among behavioral markers, genes, brain and treatment in dyslexia and dysgraphia. AB - Cross-country, longitudinal twin studies provide strong evidence for both the biological and environmental basis of dyslexia, and the stability of genetic influences on reading and spelling, even when skills improve in response to instruction. Although DNA studies aimed at identifying gene candidates in dyslexia and related phenotypes (behavioral expression of underlying genotypes); and imaging studies of brain differences between individuals with and without dyslexia and the brain's response to instructional treatment are increasing, this review illustrates, with the findings of one multidisciplinary research center, an emerging trend to investigate the inter-relationships among genetic, brain and instructional treatment findings in the same sample, which are interpreted in reference to a working-memory architecture, for dyslexia (impaired decoding and spelling) and/or dysgraphia (impaired handwriting). General principles for diagnosis and treatment, based on research with children who failed to respond to the regular instructional program, are summarized for children meeting research criteria for having or being at risk for dyslexia or dysgraphia. Research documenting earlier emerging specific oral language impairment during preschool years associated with reading and writing disabilities during school years is also reviewed. Recent seminal advances and projected future trends are discussed for linking brain endophenotypes and gene candidates, identifying transchromosomal interactions, and exploring epigenetics (chemic al modifications of gene expression in response to developmental or environmental changes). Rather than providing final answers, this review highlights past, current and emerging issues in dyslexia research and practice. PMID- 20953352 TI - Reelin Signaling, Hippocampal Neurogenesis, and Efficacy of Aspirin Intake & Stem Cell Transplantation in Aging and Alzheimer's disease. AB - Comprehending the mechanisms underlying the pathophysiology of aging and Alzheimer's disease has immense value for developing strategies that promote successful aging and prevent or cure Alzheimer's disease. The first issue of the new journal, "Aging & Disease" comprises articles that discuss the current knowledge pertaining to changes in reelin signaling in normal & pathological forms of aging, memory and neurogenesis in Aging & Alzheimer's disease, the efficacy of a non-steroidal anti-inflammatory drug aspirin in combination with docosahexaenoic acid for reducing the risk for Alzheimer's disease, and the usefulness of stem cell transplantation for improving memory in aging and Alzheimer's disease. The highlights and the importance of the above issues to Aging and Alzheimer's disease are discussed in this commentary. PMID- 20953354 TI - Pressure and temperature changes in in vitro applications with the laser and their implications for middle ear surgery. AB - Background. The purpose of this study was to evaluate the thermal and pressure effects using a Titan Sapphire chirped-pulse amplifier system configured to deliver ultrashort pulses of 180 femtoseconds (fs) in an inner ear model. Materials and Methods. Temperature increases and heat exchange processes in the fluid (physiological saline) were examined in a calorically and physiologically approximated cochlea model for applying laser parameters effective in the creation of footplate perforations. Results. In the effective energy density range, the highest temperature increases achieved with the Carbon dioxide (CO(2)) laser were about 11 degrees C. The lowest temperature maxima were 6 degrees C with the Er:YAG laser (Yttrium-Aluminum-Oxide doted with Erbium3+-ions) and <5 degrees C with the femtosecond laser. Comparison of the laser-induced pressure with the limit graph published by Pfander indicated that the use of the fs laser is unobjectionable for fluences <1 J/cm(2). Conclusions. Our investigations demonstrated that the application of the fs laser in middle ear surgery presents a new and promising addition to the range of ultrashort wavelength lasers used for this purpose. PMID- 20953353 TI - TNF superfamily: a growing saga of kidney injury modulators. AB - Members of the TNF superfamily participate in kidney disease. Tumor necrosis factor (TNF) and Fas ligand regulate renal cell survival and inflammation, and therapeutic targeting improves the outcome of experimental renal injury. TNF related apoptosis-inducing ligand (TRAIL and its potential decoy receptor osteoprotegerin are the two most upregulated death-related genes in human diabetic nephropathy. TRAIL activates NF-kappaB in tubular cells and promotes apoptosis in tubular cells and podocytes, especially in a high-glucose environment. By contrast, osteoprotegerin plays a protective role against TRAIL induced apoptosis. Another family member, TNF-like weak inducer of apoptosis (TWEAK induces inflammation and tubular cell death or proliferation, depending on the microenvironment. While TNF only activates canonical NF-kappaB signaling, TWEAK promotes both canonical and noncanonical NF-kappaB activation in tubular cells, regulating different inflammatory responses. TWEAK promotes the secretion of MCP-1 and RANTES through NF-kappaB RelA-containing complexes and upregulates CCl21 and CCL19 expression through NF-kappaB inducing kinase (NIK-) dependent RelB/NF-kappaB2 complexes. In vivo TWEAK promotes postnephrectomy compensatory renal cell proliferation in a noninflammatory milieu. However, in the inflammatory milieu of acute kidney injury, TWEAK promotes tubular cell death and inflammation. Therapeutic targeting of TNF superfamily cytokines, including multipronged approaches targeting several cytokines should be further explored. PMID- 20953355 TI - Identification of Aluminum Responsive Genes in Al-Tolerant Soybean Line PI 416937. AB - Soybean is one of the most aluminum (Al) sensitive plants. The complex inheritance of Al tolerance trait has so far undermined breeding efforts to develop Al-tolerant soybeans. Discovering the genetic factors underlying the Al tolerance mechanisms would undoubtedly accelerate the pace of such endeavor. As a first step toward this goal, we analyzed the transcriptome profile in roots of Al tolerant soybean line PI 416937 comparing Al-treated and untreated control plants using DNA microarrays. Many genes involved in transcription activation, stress response, cell metabolism and signaling were differentially expressed. Patterns of gene expression and mechanisms of Al toxicity and tolerance suggest that Cys2His2 and ADR6 transcription activators, cell wall modifying enzymes, and phytosulfokines growth factor play role in soybean Al tolerance. Our data provide insights into the molecular mechanisms of soybean Al tolerance and will have practical value in genetic improvement of Al tolerance trait. PMID- 20953356 TI - Utility of accelerometers to measure physical activity in children attending an obesity treatment intervention. AB - Objectives. To investigate the use of accelerometers to monitor change in physical activity in a childhood obesity treatment intervention. Methods. 28 children aged 7-13 taking part in "Families for Health" were asked to wear an accelerometer (Actigraph) for 7-days, and complete an accompanying activity diary, at baseline, 3-months and 9-months. Interviews with 12 parents asked about research measurements. Results. Over 90% of children provided 4 days of accelerometer data, and around half of children provided 7 days. Adequately completed diaries were collected from 60% of children. Children partake in a wide range of physical activity which uniaxial monitors may undermonitor (cycling, nonmotorised scootering) or overmonitor (trampolining). Two different cutoffs (4 METS or 3200 counts.min(-1)) for minutes spent in moderate and vigorous physical activity (MVPA) yielded very different results, although reached the same conclusion regarding a lack of change in MVPA after the intervention. Some children were unwilling to wear accelerometers at school and during sport because they felt they put them at risk of stigma and bullying. Conclusion. Accelerometers are acceptable to a majority of children, although their use at school is problematic for some, but they may underestimate children's physical activity. PMID- 20953357 TI - Effects of the PPARalpha Agonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism. AB - Gemfibrozil is a widely prescribed hypolipidemic agent in humans and a peroxisome proliferator and liver carcinogen in rats. Three-month feed studies of gemfibrozil were conducted by the National Toxicology Program (NTP) in male Harlan Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters, primarily to examine mechanisms of hepatocarcinogenicity. There was morphologic evidence of peroxisome proliferation in rats and mice. Increased hepatocyte proliferation was observed in rats, primarily at the earliest time point. Increases in peroxisomal enzyme activities were greatest in rats, intermediate in mice, and least in hamsters. These studies demonstrate that rats are most responsive while hamsters are least responsive. These events are causally related to hepatotoxicity and hepatocarcinogenicity of gemfibrozil in rodents via peroxisome proliferator activated receptor-alpha (PPARalpha) activation; however, there is widespread evidence that activation of PPARalpha in humans results in expression of genes involved in lipid metabolism, but not in hepatocellular proliferation. PMID- 20953358 TI - Nitric oxide synthase enzymes in the airways of mice exposed to ovalbumin: NOS2 expression is NOS3 dependent. AB - OBJECTIVES AND DESIGN: The function of the airway nitric oxide synthase (NOS) isoforms and the lung cell types responsible for its production are not fully understood. We hypothesized that NO homeostasis in the airway is important to control inflammation, which requires upregulation, of NOS2 protein expression by an NOS3-dependent mechanism. MATERIALS OR SUBJECTS: Mice from a C57BL/6 wild type, NOS1(-/-), NOS2(-/-), and NOS3(-/-) genotypes were used. All mice strains were systemically sensitized and exposed to filtered air or ovalbumin (OVA) aerosol for two weeks to create a subchronic model of allergen-induced airway inflammation. METHODS: We measured lung function, lung lavage inflammatory and airway epithelial goblet cell count, exhaled NO, nitrate and nitrite concentration, and airway NOS1, NOS2, and NOS3 protein content. RESULTS: Deletion of NOS1 or NOS3 increases NOS2 protein present in the airway epithelium and smooth muscle of air-exposed animals. Exposure to allergen significantly reduced the expression of NOS2 protein in the airway epithelium and smooth muscle of the NOS3(-/-) strain only. This reduction in NOS2 expression was not due to the replacement of epithelial cells with goblet cells as remaining epithelial cells did not express NOS2. NOS1(-/-) animals had significantly reduced goblet cell metaplasia compared to C57Bl/6 wt, NOS2(-/-), and NOS3(-/-) allergen-exposed mice. CONCLUSION: The airway epithelial and smooth muscle cells maintain a stable airway NO concentration under noninflammatory conditions. This "homeostatic" mechanism is unable to distinguish between NOS derived from the different constitutive NOS isoforms. NOS3 is essential for the expression of NOS2 under inflammatory conditions, while NOS1 expression contributes to allergen-induced goblet cell metaplasia. PMID- 20953360 TI - Geomasking sensitive health data and privacy protection: an evaluation using an E911 database. AB - Geomasking is used to provide privacy protection for individual address information while maintaining spatial resolution for mapping purposes. Donut geomasking and other random perturbation geomasking algorithms rely on the assumption of a homogeneously distributed population to calculate displacement distances, leading to possible under-protection of individuals when this condition is not met. Using household data from 2007, we evaluated the performance of donut geomasking in Orange County, North Carolina. We calculated the estimated k-anonymity for every household based on the assumption of uniform household distribution. We then determined the actual k-anonymity by revealing household locations contained in the county E911 database. Census block groups in mixed-use areas with high population distribution heterogeneity were the most likely to have privacy protection below selected criteria. For heterogeneous populations, we suggest tripling the minimum displacement area in the donut to protect privacy with a less than 1% error rate. PMID- 20953361 TI - Multivariate logistic regression with incomplete covariate and auxiliary information. AB - In this article, we propose and explore a multivariate logistic regression model for analyzing multiple binary outcomes with incomplete covariate data where auxiliary information is available. The auxiliary data are extraneous to the regression model of interest but predictive of the covariate with missing data. describe how the auxiliary information can be incorporated into a regression model for a single binary outcome with missing covariates, and hence the efficiency of the regression estimators can be improved. We consider extending the method of Horton and Laird (2001) to the case of a multivariate logistic regression model for multiple correlated outcomes, and with missing covariates and completely observed auxiliary information. We demonstrate that in the case of moderate to strong associations among the multiple outcomes, one can achieve considerable gains in efficiency from estimators in a multivariate model as compared to the marginal estimators of the same parameters. PMID- 20953359 TI - The Misregulation of Cell Adhesion Components during Tumorigenesis: Overview and Commentary. AB - Cell adhesion complexes facilitate attachment between cells or the binding of cells to the extracellular matrix. The regulation of cell adhesion is an important step in embryonic development and contributes to tissue homeostasis allowing processes such as differentiation and cell migration. Many mechanisms of cancer progression are reminiscent of embryonic development, for example, epithelial-mesenchymal transition, and involve the disruption of cell adhesion and expression changes in components of cell adhesion structures. Tight junctions, adherens junctions, desmosomes, and focal adhesion besides their roles in cell-cell or cell-matrix interaction also possess cell signaling function. Perturbations of such signaling pathways can lead to cancer. This article gives an overview of the common structures of cell adhesion and summarizes the impact of their loss on cancer development and progression with articles highlighted from the present issue. PMID- 20953362 TI - Low Voltage Electrowetting-on-Dielectric Platform using Multi-Layer Insulators. AB - A low voltage, two-level-metal, and multi-layer insulator electrowetting-on dielectric (EWD) platform is presented. Dispensing 300pl droplets from 140nl closed on-chip reservoirs was accomplished with as little as 11.4V solely through EWD forces, and the actuation threshold voltage was 7.2V with a 1Hz voltage switching rate between electrodes. EWD devices were fabricated with a multilayer insulator consisting of 135nm sputtered tantalum pentoxide (Ta(2)O(5)) and 180nm parylene C coated with 70nm of CYTOP. Furthermore, the minimum actuation threshold voltage followed a previously published scaling model for the threshold voltage, V(T), which is proportional to (t/epsilon(r))(1/2), where t and epsilon(r) are the insulator thickness and dielectric constant respectively. Device threshold voltages are compared for several insulator thicknesses (200nm, 500nm, and 1um), different dielectric materials (parylene C and tantalum pentoxide), and homogeneous versus heterogeneous compositions. Additionally, we used a two-level-metal fabrication process, which enables the fabrication of smaller and denser electrodes with high interconnect routing flexibility. We also have achieved low dispensing and actuation voltages for scaled devices with 30pl droplets. PMID- 20953363 TI - Bortezomib in kidney transplantation. AB - Although current therapies for pretransplant desensitization and treatment of antibody-mediated rejection (AMR) have had some success, they do not specifically deplete plasma cells that produce antihuman leukocyte antigen (HLA) antibodies. Bortezomib, a proteasome inhibitor approved for the treatment of multiple myeloma (a plasma cell neoplasm), induces plasma cell apoptosis. In this paper we review the current body of literature regarding the use of this biological agent in the field of transplantation. Although limited experience with bortezomib may seem to show promise in the realm of transplant recipients desensitization and treatment of AMR, there is also experience that may suggest otherwise. Bortezomib's role in desensitization protocols and treatment of AMR will be defined better as more clinical data and trials become available. PMID- 20953365 TI - Exercise Training for Heart Failure Patients with and without Systolic Dysfunction: An Evidence-Based Analysis of How Patients Benefit. AB - Significant benefits can be derived by heart failure patients from exercise training. This paper provides an evidence-based assessment of expected clinical benefits of exercise training for heart failure patients. Meta-analyses and randomized, controlled trials of exercise training in heart failure patients were reviewed from a search of PubMed, Cochrane Controlled Trial Registry (CCTR), CINAHL, and EMBASE. Exercise training improves functional capacity, quality of life, hospitalization, and systolic and diastolic function in heart failure patients. Heart failure patients with preserved systolic function (HFnEF) participating in exercise training studies are more likely to be women and are 5 7 years older than their systolic heart failure (CHF) counterparts. All patients exhibit low functional capacities, although in HFnEF patients this may be age related, therefore subtle differences in exercise prescriptions are required. Published works report that exercise training is beneficial for heart failure patients with and without systolic dysfunction. PMID- 20953364 TI - Gene-environment interaction research and transgenic mouse models of Alzheimer's disease. AB - The etiology of the sporadic form of Alzheimer's disease (AD) remains largely unknown. Recent evidence has suggested that gene-environment interactions (GxE) may play a crucial role in its development and progression. Whereas various susceptibility loci have been identified, like the apolipoprotein E4 allele, these cannot fully explain the increasing prevalence of AD observed with aging. In addition to such genetic risk factors, various environmental factors have been proposed to alter the risk of developing AD as well as to affect the rate of cognitive decline in AD patients. Nevertheless, aside from the independent effects of genetic and environmental risk factors, their synergistic participation in increasing the risk of developing AD has been sparsely investigated, even though evidence points towards such a direction. Advances in the genetic manipulation of mice, modeling various aspects of the AD pathology, have provided an excellent tool to dissect the effects of genes, environment, and their interactions. In this paper we present several environmental factors implicated in the etiology of AD that have been tested in transgenic animal models of the disease. The focus lies on the concept of GxE and its importance in a multifactorial disease like AD. Additionally, possible mediating mechanisms and future challenges are discussed. PMID- 20953366 TI - Anti-inflammatory nutrition as a pharmacological approach to treat obesity. AB - Obesity is a multifactorial condition resulting from improper balances of hormones and gene expression induced by the diet. Obesity also has a strong inflammatory component that can be driven by diet-induced increases in arachidonic acid. The purpose of this paper is to discuss the molecular targets that can be addressed by anti-inflammatory nutrition. These molecular targets range from reduction of proinflammatory eicosanoids to the modulation of features of the innate immune system, such as toll-like receptors and gene transcription factors. From knowledge of the impact of these dietary nutrients on these various molecular targets, it becomes possible to develop a general outline of an anti inflammatory diet that can offer a unique synergism with more traditional pharmacological approaches in treating obesity and its associated comorbidities. PMID- 20953367 TI - Sociodemographic variation of caries risk factors in toddlers and caregivers. AB - Objectives. Dental caries is the most common chronic childhood disease, with numerous identified risk factors. Risk factor differences could indicate the need to target caregiver/patient education/preventive care intervention strategies based on population and/or individual characteristics. The purpose of this study was to evaluate caries risk factors differences by race/ethnicity, income, and education. Methods. We enrolled 396 caregiver-toddler pairs and administered a 105-item questionnaire addressing demographics, access to care, oral bacteria transmission, caregiver's/toddler's dental and medical health practices, caregiver's dental beliefs, and caregiver's/toddler's snacking/drinking habits. Logistic regressions and ANOVAs were used to evaluate the associations of questionnaire responses with caregiver's race/ethnicity, income, and education. Results. Caregivers self-identified as Non-Hispanic African-American (44%), Non Hispanic White (36%), Hispanic (19%), and "other" (1%). Differences related to race/ethnicity, income, and education were found in all risk factor categories. Conclusions. Planning of caregiver/patient education/preventive care intervention strategies should be undertaken with these caries risk factor differences kept in mind. PMID- 20953368 TI - NKT cells in sepsis. AB - Sepsis is currently a leading cause of death in hospital intensive care units. Previous studies suggest that the pathophysiology of sepsis involves the hyperactivation of complex proinflammatory cascades that include the activation of various immune cells and the exuberant secretion of proinflammatory cytokines by these cells. Natural killer T-cells (NKTs) are a sublineage of T cells that share characteristics of conventional T cells and NK cells and bridge innate and adaptive immunity. More recently, NKT cells have been implicated in microbial immunity, including the onset of sepsis. Moreover, apolipoprotein E (apoE), a component of triglyceride-rich lipoproteins, has been shown to be protective in endotoxemia and gram-negative infections in addition to its well-known role in lipid metabolism. Here, we will review the role of NKT cells in sepsis and septic shock, the immunoregulatory role of apoE in the host immune response to infection, and propose a mechanism for this immunoregulation. PMID- 20953369 TI - Visual Performance of Tecnis ZM900 Diffractive Multifocal IOL after 2500 Implants: A 3-Year Followup. AB - Purpose. To evaluate visual performance for near, intermediate, and distant vision; complaints of photic phenomena, and patient satisfaction with the new diffractive multifocal IOL used in eyes which underwent phacoemulsification. Methods. Two thousand and five hundred consecutive eyes undergoing Tecnis ZM900 multifocal IOL implantation were included in this retrospective analysis. The minimum followup of 3 months was required after the surgery. Patients were assessed for uncorrected near visual acuity (UNVA) at a fixed distance (33 cm), uncorrected intermediate visual acuity (UIVA) at 60 cm, and uncorrected distance visual acuity (UDVA). Using a subjective questionnaire, patients satisfaction, their independence from using glasses, and the perception of glare and halo phenomena were also evaluated at the last follow-up. Results. Two thousand and five hundred eyes of 1558 patients underwent cataract surgery and Tecnis ZM900 multifocal IOL implantation. Four hundred and eighty seven patients (31.3%) were men, and 1071 (68.7%) were women. The mean age of the patients was 66.17 years. A UDVA of 20/30 or better was achieved by 85% of eyes. A UNVA of J1 was achieved by 93.7% of eyes and that of J2 or better was achieved by 98%. A UIVA of J4 or better was achieved by 65% and J5 or better was achived by more than 82.8% of the eyes in the study. Glare and halos were reported as severe by only 6.1% and 2.12% of patients, respectively. Ninety seven percent reported complete spectacle independence and 88% stated that they are totally satisfied with their quality of vision and would choose to have the same lens implanted again after the first implant. Five percent of the eyes in the study needed a second procedure (enhancement) to achieve a better visual result. No patient underwent lens exchange. Conclusion. Excellent near, intermediate, and distant vision was observed in patients implanted with the Tecnis ZM900 diffractive multifocal IOL. Spectacle independence and a minimum occurrence of photic phenomena make this IOL an excellent option in patients with cataract. PMID- 20953371 TI - Esophageal Crohn's disease treated "topically" with swallowed aerosolized budesonide. AB - Proximal Crohn's disease, involving the esophagus, the stomach, the duodenum, and the proximal jejunum, is uncommon. Treatment for proximal Crohn's disease is based on data derived from case series than from controlled trials. We present a case of Crohn's colitis with concomitant proximal esophagogastroduodenal involvement treated with conventional treatment plus swallowed aerosolized budesonide as a novel adjuvant topical treatment for the esophageal disease, and we review the treatment options for proximal Crohn's disease. PMID- 20953370 TI - Burkitt lymphoma: pathogenesis and immune evasion. AB - B-cell lymphomas arise at distinct stages of cellular development and maturation, potentially influencing antigen (Ag) presentation and T-cell recognition. Burkitt lymphoma (BL) is a highly malignant B-cell tumor associated with Epstein-Barr Virus (EBV) infection. Although BL can be effectively treated in adults and children, leading to high survival rates, its ability to mask itself from the immune system makes BL an intriguing disease to study. In this paper, we will provide an overview of BL and its association with EBV and the c-myc oncogene. The contributions of EBV and c-myc to B-cell transformation, proliferation, or attenuation of cellular network and immune recognition or evasion will be summarized. We will also discuss the various pathways by which BL escapes immune detection by inhibiting both HLA class I- and II-mediated Ag presentation to T cells. Finally, we will provide an overview of recent developments suggesting the existence of BL-associated inhibitory molecules that may block HLA class II mediated Ag presentation to CD4+ T cells, facilitating immune escape of BL. PMID- 20953372 TI - Comparable Renal Function at 6 Months with Tacrolimus Combined with Fixed-Dose Sirolimus or MMF: Results of a Randomized Multicenter Trial in Renal Transplantation. AB - In a multicenter trial, renal transplant recipients were randomized to tacrolimus with fixed-dose sirolimus (Tac/SRL, N = 318) or tacrolimus with MMF (Tac/MMF, N = 316). Targeted tacrolimus trough levels were lower in the Tac/SRL group after day 14. The primary endpoint was renal function at 6 months using creatinine clearance (Cockcroft-Gault) and was comparable at 66.4 mL/min (SE 1.4) with Tac/SRL and at 65.2mL/min (SE 1.3) with Tac/MMF (completers). Biopsy-confirmed acute rejection was 15.1% (Tac/SRL) and 12.3% (Tac/MMF). In both groups, graft survival was 93% and patient survival was 99.0%. Premature withdrawal due to an adverse event was twice as high in the Tac/SRL group, 15.1% versus 6.3%. Hypercholesterolemia incidence was higher with Tac/SRL (P < .05) while CMV, leukopenia, and diarrhea incidences were higher with Tac/MMF (P < .05). The incidence of any antidiabetic treatment for >30 consecutive days in previously nondiabetic patients was 17.8%, Tac/SRL, and 24.8%, Tac/MMF. Evaluation at 6 months showed comparable renal function using tacrolimus/sirolimus and tacrolimus/MMF regimens. PMID- 20953373 TI - Impact of weight loss on physical function with changes in strength, muscle mass, and muscle fat infiltration in overweight to moderately obese older adults: a randomized clinical trial. AB - Purpose. Evaluate the effects of weight loss on muscle mass and area, muscle fat infiltration, strength, and their association with physical function. Methods. Thirty-six overweight to moderately obese, sedentary older adults were randomized into either a physical activity plus weight loss (PA+WL) or physical activity plus successful aging health education (PA+SA) program. Measurements included body composition by dual-energy X-ray absorptiometry, computerized tomography, knee extensor strength, and short physical performance battery (SPPB). Results. At 6 months, PA+WL lost greater thigh fat and muscle area compared to PA+SA. PA+WL lost 12.4% strength; PA+SA lost 1.0%. Muscle fat infiltration decreased significantly in PA+WL and PA+SA. Thigh fat area decreased 6-fold in comparison to lean area in PA+WL. Change in total SPPB score was strongly inversely correlated with change in fat but not with change in lean or strength. Conclusion. Weight loss resulted in additional improvements in function over exercise alone, primarily due to loss of body fat. PMID- 20953375 TI - Subacute ruminal acidosis and evaluation of blood gas analysis in dairy cow. AB - Subacute Ruminal Acidosis (SARA) corresponds to an imbalance between lactate producing bacteria and lactate-using bacteria, which results in a change in ruminal pH associated with a prevalent consumption of rapidly fermentable carbohydrates. In our study, 216 primiparus and multiparus dairy cows were selected from 20 Italian intensive dairy herds and were divided into three groups based on the risk of SARA. All the dairy cows had high average milk production. After blood sampling, a complete blood gas analysis was performed. One-way ANOVA was performed to compare the three groups. O(2) Cont, PCO(2), blood pH, O(2)Hb, urinary pH, and rumen pH were significantly lower in cows with rumen pH < 5.5. These results indicate that blood gas analysis is a valuable tool to diagnose acidosis in dairy cows because it provides good assessment of acidosis while being less invasive than rumen pH analysis. PMID- 20953374 TI - Preclinical research into basic mechanisms of radiation-induced heart disease. AB - Radiation-induced heart disease (RIHD) is a potentially severe side effect of radiotherapy of thoracic and chest wall tumors if all or part of the heart was included in the radiation field. RIHD presents clinically several years after irradiation and manifestations include accelerated atherosclerosis, pericardial and myocardial fibrosis, conduction abnormalities, and injury to cardiac valves. There is no method to prevent or reverse these injuries when the heart is exposed to ionizing radiation. This paper presents an overview of recent studies that address the role of microvascular injury, endothelial dysfunction, mast cells, and the renin angiotensin system in animal models of cardiac radiation injury. These insights into the basic mechanisms of RIHD may lead to the identification of targets for intervention in this late radiotherapy side effect. PMID- 20953376 TI - Effect of feeding status on adjuvant arthritis severity, cachexia, and insulin sensitivity in male Lewis rats. AB - We studied the effect of food restriction, overfeeding, and normofeeding on cachexia, inflammatory and metabolic parameters, and insulin sensitivity in chronic adjuvant arthritis (AA) in rats. Food restriction during AA increased circulating ghrelin, corticosterone, decreased leptin, and ameliorated arthrogram score and systemic inflammation compared to normofeeding. Overfeeding worsened arthrogram score and systemic inflammation, and led to lipid accumulation in the liver, but not to alterations of adipokine and ghrelin plasma levels relative to normofeeding. Independently of feeding status, AA induced cachexia, in which modulation of mRNA expressions for appetite-regulating neuropeptides (NPY, AgRP, POMC, CART) in the arcuate nucleus (ARC) does not play a primary role. The overexpression of IL-1beta mRNA in the ARC suggests its role in the mechanisms of impaired energy balance during AA under all feeding conditions. Normal HOMA index in all arthritic groups does not indicate the development of insulin resistance by feeding interventions in these rats. PMID- 20953377 TI - Clinicopathologic significance of HIF-1alpha, CXCR4, and VEGF expression in colon cancer. AB - We investigated the clinicopathologic significance of HIF-1, CXCR4, and VEGF expression using immumohistochemistry in human colon cancer. HIF-1, CXCR4, and VEGF high expression levels were correlated positively with TNM stage, lymph node involvement, and distant metastasis Furthermore, we found that combined high expression of any two of the three molecules (P = .028 for HIF-1/CXCR4, P = .007 for HIF-1/VEGF, and P = .004 for CXCR4/VEGF) had stronger correlation with lymph node metastasis than did each alone. However, a relationship with distant metastasis is seen only with the combinations CXCR4/VEGF (P = .069 for HIF 1/CXCR4, P = .062 for HIF-1/VEGF, and P = .035 for CXCR4/VEGF) as compared with those of single molecule high expression alone. Combined expression of all three molecules strongly correlates with lymph node metastasis and distant metastasis. The mRNA expression of HIF-1, CXCR4, and VEGF were quantified by real-time PCR in different colon cancer tissue samples, the experiment results shown that fresh colon tissue samples significantly overexpressed CXCR4 and VEGF mRNA compared with negative control. Therefore, the disease-free survival of all patients after curative resection can be considered in association with all three markers expression. PMID- 20953378 TI - Angiogenesis and breast cancer. AB - Angiogenesis is an essential step for breast cancer progression and dissemination. The development of new blood vessels in cancer setting (angiogenesis) is conducted by numerous physiological and pathological stimuli, where the main stimulus is hypoxia. The knowledge of different molecular pathways regulating angiogenesis is constantly growing. An increased and complex scenario of angiogenesis is nowadays available in breast cancer, specifically, and permits not only to understand most of the important phases of neoplastic growth but also offer an exciting perspective for new therapeutic proposals based on blocking new blood vessels sprouting. This review focused on historical and recent understanding of angiogenesis occurrence in breast cancer. PMID- 20953379 TI - Two cases of small cell carcinoma of the gallbladder. AB - Small cell carcinoma of the gallbladder is a rare disease process with approximately 40 cases reported in the literature. It is most often found in elderly female population and is associated with cholelithiasis and cigarette smoking. A multidisciplinary approach to treatment with wide surgical resection and adjuvant chemotherapy is the current standard of care. Notwithstanding prompt medical intervention, it is a disease with a poor prognosis. The pathology is characterized by early metastases and extensive local invasion. Herein, we report two cases of small cell carcinoma addressed at our institution. In both cases, a radical resection was performed with subsequent referral to oncology for additional therapy. PMID- 20953380 TI - Possible Link between Metabolic Syndrome and Chronic Kidney Disease in the Development of Cardiovascular Disease. AB - Metabolic syndrome (MetS) is a clinical syndrome that consists of visceral obesity, dyslipidemia, hypertension, and impaired insulin sensitivity. Although individual components of MetS have been implicated in the development of chronic kidney disease (CKD), few studies have examined the effect of combinations of the components of MetS on the development of CKD and cardiovascular disease (CVD). The prevalence of MetS is increasing worldwide in both developing and developed countries, and early detection and treatment of MetS would be a cost-effective strategy for preventing the development of CKD. Visceral obesity and insulin resistance are two important features of MetS that may be associated with renal damage. Lifestyle modifications, including caloric restriction and exercise, are necessary to treat MetS. Initial antihypertensive therapy should consist of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. An improved understanding of the mechanism responsible for the association between MetS and renal damage should be helpful in determining the treatment regimens directed at cardiovascular and renal protection. PMID- 20953381 TI - The p110alpha and p110beta isoforms of class I phosphatidylinositol 3-kinase are involved in toll-like receptor 5 signaling in epithelial cells. AB - BACKGROUND: Bacterial flagellin triggers inflammation in mammalian cells via Toll like receptor (TLR) 5. Release of the chemokine IL-8 in response to flagellin involves NF-kappaB, p38 MAP kinase, and phosphatidylinositol 3-kinase (PI3K). However, PI3K has been reported to be either pro- or anti-inflammatory in different model systems. We hypothesized that this could be due to different activities of the p110alpha and beta isoforms of PI3K. RESULTS: PI3K and Akt were rapidly activated in Caco-2 colon carcinoma cells by flagellin. Using a plasmid based shRNA delivery system and novel p110 isoform-specific inhibitors, we found that flagellin-induced IL-8 production was dependent on both p110alpha and p110beta. However in the mouse, inhibition of p110beta but not p110alpha reduced the increase of serum IL-6 levels induced by intraperitoneal injection of flagellin. CONCLUSIONS: These data demonstrate that the p110alpha and beta isoforms of class IA PI3K are both required for the proinflammatory response to flagellin. PMID- 20953382 TI - The use of rose bengal plate test to asses cattle exposure to Brucella infection in traditional and smallholder dairy production systems of tanga region of Tanzania. AB - A cross-sectional epidemiological study was conducted to determine the seroprevalence and to identify risk factors for bovine brucellosis seropositivity in traditional and smallholder dairy cattle production systems in the Tanga region of North-eastern Tanzania. The study populations comprised 246 indigenous and 409 crossbred cattle, randomly selected from 105 smallholder dairy and 25 traditional managed herds, respectively. Individual animal and herd-level data were collected using a structured questionnaire. Serum samples were screened for Brucella antibodies using the Rose Bengal Plate Test The overall seroprevalence of Brucella antibodies in the smallholder dairy and traditional managed cattle was 4.1% and 7.3% respectively. The corresponding overall herd prevalence was 10.5% and 20% respectively. Using multivariate logistic regression analysis, closeness to stock route, access to surface drinking water and location were identified as the major risk factors for individual herd seroprevalence. Older animals (>=6 years) were associated with increased risk of sero-positivity compared to animals of age category of <=6 years. The results showed that brucellosis is prevalent and widely distributed locally, underscoring the need for further studies including surveillance and institution of preventive and control measures particularly among female young-stock and the general public who are at high risk of contracting brucellosis. PMID- 20953383 TI - Systematic review of integrative health care research: randomized control trials, clinical controlled trials, and meta-analysis. AB - A systematic review was conducted to assess the level of evidence for integrative health care research. We searched PubMed, Allied and Complementary Medicine (AMED), BIOSIS Previews, EMBASE, the entire Cochrane Library, MANTIS, Social SciSearch, SciSearch Cited Ref Sci, PsychInfo, CINAHL, and NCCAM grantee publications listings, from database inception to May 2009, as well as searches of the "gray literature." Available studies published in English language were included. Three independent reviewers rated each article and assessed the methodological quality of studies using the Scottish Intercollegiate Guidelines Network (SIGN 50). Our search yielded 11,891 total citations but 6 clinical studies, including 4 randomized, met our inclusion criteria. There are no available systematic reviews/meta-analyses published that met our inclusion criteria. The methodological quality of the included studies was assessed independently using quality checklists of the SIGN 50. Only a small number of RCTs and CCTs with a limited number of patients and lack of adequate control groups assessing integrative health care research are available. These studies provide limited evidence of effective integrative health care on some modalities. However, integrative health care regimen appears to be generally safe. PMID- 20953384 TI - Selective Th2 Upregulation by Crocus sativus: A Neutraceutical Spice. AB - The immunomodulatory activity of an Indian neutraceutical spice, saffron (Crocus sativus) was studied on Th(1) and Th(2) limbs of the immune system. Oral administration of alcoholic extract of Crocus sativus (ACS) at graded dose levels from 1.56-50 mg/kg p.o. potentiated the Th(2) response of humoral immunity causing the significant increases in agglutinating antibody titre in mice at a dose of 6.25 mg/kg and an elevation of CD19(+) B cells and IL-4 cytokine, a signature cytokine of Th(2) pathway. Appreciable elevation in levels of IgG-1 and IgM antibodies of the primary and secondary immune response was observed. However, ACS showed no appreciable expression of the Th(1) cytokines IL-2 (growth factor for CD4(+) T cells) and IFN-gamma (signature cytokine of Th(1) response). A significant modulation of immune reactivity was observed in all the animal models used. This paper represents the selective upregulation of the Th(2) response of the test material and suggests its use for subsequent selective Th(2) immunomodulation. PMID- 20953385 TI - Effectiveness of pharmacopuncture for asthma: a systematic review and meta analysis. AB - Pharmacopuncture is a new needle therapy that integrates acupuncture and herbal therapies, and it has the potential to treat many diseases. A systematic review was performed to summarize and critically evaluate clinical trial evidence regarding the effectiveness of pharmacopuncture for asthma. Eight electronic databases and six journals were searched in this study. Randomized clinical trials (RCTs) in which human patients with asthma were treated with pharmacopuncture were included. The selection of studies, data extraction, and validation were performed independently by two reviewers. Four RCTs met our inclusion criteria, and the evidence from all RCTs in this study was positive. The meta-analysis showed statistically significant effects of pharmacopuncture compared to conventional treatment (n = 341, Risk Ratio = 1.13, 95% CI of 1.05 to 1.23, P = .002, heterogeneity: chi(2) = 3.55, P = .31, I(2) = 16%). Two trials showed favorable effects of pharmacopuncture on peak expiratory flow (PEF). However, few rigorous trials have tested the effects of pharmacopuncture on asthma. The results of our systematic review point to the potential benefits of pharmacopuncture for adults with asthma, and we suggest further RCTs and the development of a standard method of pharmacopuncture therapy. PMID- 20953386 TI - Characterization of the Antidiabetic Role of Parkinsonia aculeata (Caesalpineaceae). AB - This paper reports the characterization of the antidiabetic role of a hydroethanolic extract from Parkinsonia aerial parts (HEPA), in normal and alloxan-induced diabetic rats, treated with HEPA (125 and 250 mg/kg; p.o.). Oral glucose tolerance test, acute oral toxicity test and preliminary phytochemical analyses were performed. The diabetic rats treated with HEPA showed a significant reduction in serum and urinary glucose, urinary urea and triglyceride levels, as compared to the diabetic untreated group. However, in the normal treated groups, a significant reduction was found only in serum triglyceride levels. In all treated diabetic groups, an improvement in hepatic glycogen was observed, as well as a decrease in liquid intake and urinary volume, and an enhancement in the weight of skeletal muscles (soleus and extensor digitorum longus), kidneys and epididymal adipose tissue. Nevertheless, body and liver weights were ameliorated only in the diabetic group treated with HEPA (250 mg/kg). Moreover, oral glucose tolerance was higher in animals treated with HEPA, while results also showed that HEPA could be considered toxicologically safe. Phytochemical analysis revealed the presence of tanins, flavonoids and steroids in HEPA. In conclusion, P. aculeata presents an antidiabetic activity and other beneficial effects that ameliorate diabetes and associated complications. PMID- 20953387 TI - KIOM-79 Prevents Lens Epithelial Cell Apoptosis and Lens Opacification in Zucker Diabetic Fatty Rats. AB - Damage of lens epithelial cells (LECs) has been implicated in cataract formation. The aim of this study was to investigate the protective effect of KIOM-79, a combination of four plant extracts, on LECs. We examined the levels of advanced glycation end products (AGEs), nuclear factor-kappaB (NF-kappaB) activation and inducible nitric oxide synthase (iNOS) expression in LECs during cataract development using the Zucker diabetic fatty (ZDF) rat, an animal model of type 2 diabetes. KIOM-79 was orally administered by gavage to ZDF rats once a day for 13 weeks. Apoptosis was detected by TUNEL assay, and NF-kappaB activation and iNOS expression were studied by southwestern histochemistry and immunohistochemistry, respectively. In diabetic cataractous lenses, TUNEL-positive LECs were markedly increased 20-fold, and AGEs were highly accumulated (2.7-fold) in LECs. In addition, both NF-kappaB activation, and iNOS expression were significantly enhanced 3- to 5-fold, respectively, compared to levels found in normal ZL rats. However, the administration of KIOM-79 delayed the development of diabetic cataracts and prevented LEC apoptosis (70%) through the inhibition of AGEs, NF kappaB-activation and iNOS expression. These observations suggest that KIOM-79 is useful in inhibiting diabetic cataractogenesis and acts through an antiapoptotic mechanism to protect LECs from injury. PMID- 20953388 TI - Anti-inflammatory, immunomodulatory, and heme oxygenase-1 inhibitory activities of ravan napas, a formulation of uighur traditional medicine, in a rat model of allergic asthma. AB - Ravan Napas (RN) is a traditional formula used to treat pulmonary symptoms and diseases such as coughing, breathing difficulty, and asthma in traditional Uighur medicine. The purpose of this study was to investigate the anti-inflammatory, and immuno-modulatory activity of RN in a well-characterized animal model of allergic asthma. Rats were sensitized with intraperitoneal (ip) ovalbumin (OVA) and alum, and then challenged with OVA aerosols. The asthma model rats were treated with RN; saline- and dexamethasone- (DXM-) treated rats served as normal and model controls. The bronchoalveolar lavage fluid (BALF) cellular differential and the concentrations of sICAM-1, IL-4, IL-5, TNF-alpha, INF-gamma, and IgE in serum were measured. Lung sections underwent histological analysis. The immunohistochemistry S-P method was used to measure the expression of ICAM-1 and HO-1 in the lung. RN significantly reduced the number of inflammatory cells in BALF and lung tissues, decreased sICAM-1, IL-4, IL-5, TNF-alpha, and IgE in serum, and increased serum INF-gamma. There was a marked suppression of ICAM-1 and HO-1 expression in the lung. Our results suggest that RN may have an anti inflammatory and immuneregulatory effect on allergic bronchial asthma by modulating the balance between Th1/Th2 cytokines. PMID- 20953389 TI - Ocimum gratissimum Aqueous Extract Induces Apoptotic Signalling in Lung Adenocarcinoma Cell A549. AB - Ocimum gratissimum (OG) is widely used as a traditional herb for its antibacterial activity in Taiwan. Recently, antitumor effect of OG on breast cancer cell is also reported; however, the effects of OG on human pulmonary adenocarcinoma cell A549 remain unclear. Therefore, we aimed to investigate whether aqueous OG extract (OGE) affects viability of A549 cells and the signals induced by OGE in A549 cells. Cell viability assays revealed that OGE significantly and dose-dependently decreased the viability of A549 cell but not that of BEAS-2B cell. Morphological examination and DAPI staining indicated that OGE induced cell shrinkage and DNA condensation for A549 cells. Further investigation showed that OGE enhanced activation of caspase-3, caspase-9 and caspase-8 and increased protein level of Apaf-1 and Bak, but diminished the level of Bcl-2. Additionally, OGE inhibited the phosphorylation of extracellular signal regulated kinase (ERK) yet enhanced the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAP kinase (p38). In conclusion, our findings indicate that OGE suppressed the cell viability of A549 cells, which may result from the activation of apoptotic signaling and the inhibition of anti-apoptotic signaling, suggesting that OGE might be beneficial to lung carcinoma treatment. PMID- 20953390 TI - Ethanol extract of chinese propolis facilitates functional recovery of locomotor activity after spinal cord injury. AB - An ethanol extract of Chinese propolis (EECP) was given intraperitoneally to rats suffering from hemitransection of half of their spinal cord (left side) at the level of the 10th thoracic vertebra to examine the effects of the EECP on the functional recovery of locomotor activity and expression of mRNAs of inducible nitric oxide (NO) synthase (iNOS) and neurotrophic factors in the injury site. Daily administration of EECP after the spinal cord injury ameliorated the locomotor function, which effect was accompanied by a reduced lesion size. Furthermore, the EECP suppressed iNOS gene expression, thus reducing NO generation, and also increased the expression level of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the lesion site, suggesting that the EECP reduced the inflammatory and apoptotic circumstances through attenuation of iNOS mRNA expression and facilitation of mRNA expression of neurotrophins in the injured spinal cord. These results suggest that Chinese propolis may become a promising tool for wide use in the nervous system for reducing the secondary neuronal damage following primary physical injury. PMID- 20953391 TI - Anticancer Potential of Aqueous Ethanol Seed Extract of Ziziphus mauritiana against Cancer Cell Lines and Ehrlich Ascites Carcinoma. AB - Ziziphus mauritiana (Lamk.) is a fruit tree that has folkloric implications against many ailments and diseases. In the present study, anticancer potential of seed extract of Ziziphus mauritiana in vitro against different cell lines (HL-60, Molt-4, HeLa, and normal cell line HGF) by MTT assay as well as in vivo against Ehrich ascites carcinoma bearing Swiss albino mice was investigated. The extract was found to markedly inhibit the proliferation of HL-60 cells. Annexin and PI binding of treated HL-60 cells indicated apoptosis induction by extract in a dose dependent manner. The cell cycle analysis revealed a prominent increase in sub Go population at concentration of 20 MUg/ml and above. Agarose gel electrophoresis confirmed DNA fragmentation in HL-60 cells after 3 h incubation with extract. The extract also exhibited potent anticancer potential in vivo. Treatment of Ehrlich ascites carcinoma bearing Swiss albino mice with varied doses (100-800 mg/kg b.wt.) of plant extract significantly reduced tumor volume and viable tumor cell count and improved haemoglobin content, RBC count, mean survival time, tumor inhibition, and percentage life span. The enhanced antioxidant status in extract treated animals was evident from decline in levels of lipid peroxidation and increased levels of glutathione, catalase, and superoxide dismutase. PMID- 20953392 TI - Clinical approach to the standardization of oriental medical diagnostic pattern identification in stroke patients. AB - In Korea, many stroke patients receive oriental medical care, in which pattern identification plays a major role. Pattern-identification is Oriental Medicine's unique diagnostic system. This study attempted to standardize oriental medical pattern-identification for stroke patients. This was a community-based multicenter study that enrolled stroke patients within 30 days after their ictus. We assessed the patients' general characteristics and symptoms related to pattern identification. Each patient's pattern was determined when two doctors had the same opinion. To determine which variables affect the pattern-identification, binary logistic regression analysis was used with the backward method. A total of 806 stroke patients were enrolled. Among 480 patients who were identified as having a certain pattern, 100 patients exhibited the Fire Heat Pattern, 210 patients the Phlegm Dampness Pattern, nine patients the Blood Stasis Pattern, 110 patients the Qi Deficiency Pattern, and 51 patients the Yin Deficiency Pattern. After the regression analysis, the predictive logistic equations for the Fire Heat, Phlegm Dampness, Qi Deficiency, and Yin Deficiency patterns were determined. The Blood Stasis Pattern was omitted because the sample size was too small. Predictive logistic equations were suggested for four of the patterns. These criteria would be useful in determining each stroke patient's pattern in clinics. However, further studies with large samples are necessary to validate and confirm these criteria. PMID- 20953393 TI - Biological Evaluation of Polyherbal Ayurvedic Cardiotonic Preparation "Mahamrutyunjaya rasa". AB - Mahamrutyunjaya rasa (MHR), an Ayurvedic formulation, used as cardiotonic, contains potentially toxic compounds like aconitine, which are detoxified during preparation using traditional methods. Comparative toxicological evaluation of laboratory prepared formulation (F1) and two marketed formulations (F2 and F3) were performed based on their effects on viability of H9c2 cells and after single oral dose administration in mice. Cardioprotective effect of formulations at 25 and 50 mg/kg doses were studied in isoproterenol- (ISO-) induced myocardial infarcted rats. F1 and F2 did not affect the cell viability, while F3 decreased the cell viability in concentration and time-dependent manner. Rats administered with ISO showed significant increase in the serum levels of glutamate oxaloacetate transaminase, alkaline phosphotase, creatinine kinase isoenzymes, lactate dehydrogenase, and uric acid, while F1 and F2 treatment showed significant reduction in the same. F3 showed further increase in the serum levels of enzymes and uric acid in ISO-challenged rats. High pressure liquid chromatographic analysis of formulations showed higher concentration of aconitine in F3. Study shows that F1 and F2 possess cardioprotective property with higher safety, while formulation F3 cannot be used as cardioprotective due to its cytotoxic effects. Thus, proper quality assessment methods are required during preparation of traditional formulations. PMID- 20953394 TI - Hemidesmus indicus and Hibiscus rosa-sinensis Affect Ischemia Reperfusion Injury in Isolated Rat Hearts. AB - Hemidesmus indicus (L.) R. Br. (HI) and Hibiscus rosa-sinensis L. (HRS) are widely used traditional medicine. We investigated cardioprotective effects of these plants applied for 15 min at concentrations of 90, 180, and 360 MUg/mL in Langendorff-perfused rat hearts prior to 25-min global ischemia/120-min reperfusion (I/R). Functional recovery (left ventricular developed pressure-LVDP, and rate of development of pressure), reperfusion arrhythmias, and infarct size (TTC staining) served as the endpoints. A transient increase in LVDP (32%-75%) occurred at all concentrations of HI, while coronary flow (CF) was significantly increased after HI 180 and 360. Only a moderate increase in LVDP (21% and 55%) and a tendency to increase CF was observed at HRS 180 and 360. HI and HRS at 180 and 360 significantly improved postischemic recovery of LVDP. Both the drugs dose dependently reduced the numbers of ectopic beats and duration of ventricular tachycardia. The size of infarction was significantly decreased by HI 360, while HRS significantly reduced the infarct size at all concentrations in a dose dependent manner. Thus, it can be concluded that HI might cause vasodilation, positive inotropic effect, and cardioprotection, while HRS might cause these effects at higher concentrations. However, further study is needed to elucidate the exact mechanism of their actions. PMID- 20953395 TI - Beneficial effect of the traditional chinese drug shu-xue-tong on recovery of spinal cord injury in the rat. AB - Shu-Xue-Tong (SXT) is a traditional Chinese drug widely used to ameliorate stagnation of blood flow, such as brain or myocardial infarction. Whether SXT may have therapeutic value for spinal cord injury (SCI), during which ischemia plays an important role in its pathology, remains to be elucidated. We hypothesized that SXT may promote SCI healing by improving spinal cord blood flow (SCBF), and a study was thus designed to explore this possibility. Twenty-five male Sprague Dawley rats were used. SCI was induced by compression, and SXT was administrated 24 h postinjury for 14 successive days. The effects of SXT were assessed by means of laser-Doppler flowmetry, motor functional analysis (open-field walking and footprint analysis), and histological analysis (hematoxylin-eosin and thionin staining and NeuN immunohistochemistry). SXT significantly promoted SCBF of the contused spinal cord and enhanced the recovery of motor function. Histological analysis indicated that the lesion size was reduced, the pathological changes were ameliorated, and more neurons were preserved. Based on these results we conclude that SXT can effectively improve SCI. PMID- 20953396 TI - Evaluation of the Potential of Brazilian Propolis against UV-Induced Oxidative Stress. AB - This study investigated the potential use of topically and orally administered propolis extracts to prevent UV irradiation-induced oxidative stress in skin. The results illustrated that green propolis extract (GPE) contained greater amounts of polyphenols, coumaric acid, drupanin, baccharin and artepillin C than did brown propolis extract (BPE). GPE showed higher antioxidant activity than BPE when the IC(50) (concentration that caused 50% inhibition) values were compared. Interesting, the oral treatment of hairless mice demonstrated a recovery of 30.0% for GPE and 22.8% for BPE with respect to UV irradiation-induced GSH depletion. The topical pretreatment of animals with both propolis extract solutions recovered around 14.0% of the depleted GSH. However, the employed treatments did not inhibit the increase of cutaneous proteinase secretion/activity caused by irradiation. These findings indicate that despite differences in composition and antioxidant properties, GPE and BPE both successfully prevent UV-induced GSH depletion in vivo and are both promising antioxidant systems against oxidative stress in skin. Based on these findings, complementary studies should be performed to enhance our understanding of the protective effects of propolis extracts in skin. PMID- 20953397 TI - Analgesic and Anti-Inflammatory Properties of Extracts from the Bulbils of Dioscorea bulbifera L. var sativa (Dioscoreaceae) in Mice and Rats. AB - The aqueous and methanol extracts from the dry bulbils of Dioscorea bulbifera L. var sativa (Dioscoreaceae)-evaluated orally at the doses of 300 and 600 mg/kg against pain induced by acetic acid, formalin, pressure and against inflammation induced by carrageenan, histamine, serotonin and formalin in mice and rats, showed a dose dependant inhibition of pain and inflammation with a maximum effect of 56.38%, 73.06% and 42.79% produced by the aqueous extract, respectively on pain induced by acetic acid, formalin and pressure while the methanol extract at the same dose respectively inhibited these models of pain by 62.70%, 84.54% and 47.70%. The oral administration of aqueous and methanol extracts caused significant anti-inflammatory activity on paw oedema induced by histamine, serotonin and formalin. The present results show that the bulbils of Dioscorea bulbifera var sativa possess potent analgesic and anti-inflammatory activities. These activities may results from the inhibition of inflammatory mediators such as histamine, serotonin and prostaglandins. Thus, the analgesic activity of the bulbils of Dioscorea bulbifera may be at least partially linked to its anti inflammatory activity. PMID- 20953398 TI - Berberine Moderates Glucose and Lipid Metabolism through Multipathway Mechanism. AB - Berberine is known to improve glucose and lipid metabolism disorders, but the mechanism is still under investigation. In this paper, we explored the effects of berberine on the weight, glucose levels, lipid metabolism, and serum insulin of KKAy mice and investigated its possible glucose and lipid-regulating mechanism. We randomly divided KKAy mice into two groups: berberine group (treated with 250 mg/kg/d berberine) and control group. Fasting blood glucose (FBG), weight, total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL c), low-density lipoprotein-cholesterol (LDL-c), and fasting serum insulin were measured in both groups. The oral glucose tolerance test (OGTT) was performed. RT(2) PCR array gene expression analysis was performed using skeletal muscle of KKAy mice. Our data demonstrated that berberine significantly decreased FBG, area under the curve (AUC), fasting serum insulin (FINS), homeostasis model assessment insulin resistance (HOMA-IR) index, TC, and TG, compared with those of control group. RT(2) profiler PCR array analysis showed that berberine upregulated the expression of glucose transporter 4 (GLUT4), mitogen-activated protein kinase 14 (MAPK14), MAPK8(c-jun N-terminal kinase, JNK), peroxisome proliferator-activated receptor alpha (PPARalpha), uncoupling protein 2 (UCP2), and hepatic nuclear factor 4alpha(HNF4alpha), whereas it downregulated the expression of PPARgamma, CCAAT/enhancer-binding protein (CEBP), PPARgamma coactivator 1alpha(PGC 1alpha), and resistin. These results suggest that berberine moderates glucose and lipid metabolism through a multipathway mechanism that includes AMP-activated protein kinase-(AMPK-) p38 MAPK-GLUT4, JNK pathway, and PPARalpha pathway. PMID- 20953399 TI - Isolated and combined effects of electroacupuncture and meditation in reducing experimentally induced ischemic pain: a pilot study. AB - Acupuncture and meditation are promising treatment options for clinical pain. However, studies investigating the effects of these methods on experimental pain conditions are equivocal. Here, the effects of electroacupuncture (EA) and meditation on the submaximum effort tourniquet technique (SETT), a well established, opiate-sensitive pain paradigm in experimental placebo research were studied. Ten experienced meditators (6 male subjects) and 13 nonmeditators (6 male subjects) were subjected to SETT (250 mmHG) on one baseline (SETT only) and two treatment days (additional EA contralaterally to the SETT, either at the leg on ST36 and LV3 or at the arm on LI4 and LI10 in randomized order). Numeric Rating Scale (NRS) ratings (scale 0-10) were recorded every 3 min. During baseline, meditation induced significantly greater pain tolerance in meditators when compared with the control group. Both the EA conditions significantly increased pain tolerance and reduced pain ratings in controls. Furthermore, EA diminished the group difference in pain sensitivity, indicating that meditators had no additional benefit from acupuncture. The data suggest that EA as a presumable bottom-up process may be as effective as meditation in controlling experimental SETT pain. However, no combined effect of both the techniques could be observed. PMID- 20953400 TI - Different brain network activations induced by modulation and nonmodulation laser acupuncture. AB - The aim of this study is to compare the distinct cerebral activation with continued wave (CW) and 10 Hz-modulated wave (MW) stimulation during low-level laser acupuncture. Functional magnetic resonance imaging (fMRI) studies were performed to investigate the possible mechanism during laser acupuncture stimulation at the left foot's yongquan (K1) acupoint. There are 12 healthy right handed volunteers for each type of laser stimulation (10-Hz-Modulated wave: 8 males and 4 females; continued wave: 9 males and 3 females). The analysis of multisubjects in this experiment was applied by random-effect (RFX) analysis. In CW groups, significant activations were found within the inferior parietal lobule, the primary somatosensory cortex, and the precuneus of left parietal lobe. Medial and superior frontal gyrus of left frontal lobe were also aroused. In MW groups, significant activations were found within the primary motor cortex and middle temporal gyrus of left hemisphere and bilateral cuneus. Placebo stimulation did not show any activation. Most activation areas were involved in the functions of memory, attention, and self-consciousness. The results showed the cerebral hemodynamic responses of two laser acupuncture stimulation modes and implied that its mechanism was not only based upon afferent sensory information processing, but that it also had the hemodynamic property altered during external stimulation. PMID- 20953401 TI - Growth Inhibition and Induction of Apoptosis in SHG-44 Glioma Cells by Chinese Medicine Formula "Pingliu Keli". AB - The present study was carried out to evaluate the effects of the water extract of Chinese medicine "Pingliu Keli" (PK) on human glioma cell viability and apoptosis and to investigate its mechanisms of action in SHG-44 cells. MTT assay showed that PK had a strong cytotoxic effect on SHG-44 cells. The number of live cells was less than 20% after exposure to 90 MUg/mL PK for 24 h. PK increased cytotoxicity of SHG-44 cells in a dose-dependent manner. PK caused arrest of SHG 44 cells in G1 phase at low concentration and in G2 phase at high concentration. The percentage of apoptotic cells by flow cytometric analysis of the DNA-stained cells increased to 38% and 52% after treatment with 72 and 108 MUg/mL PK, respectively. In addition, PK increased the expression of proapoptotic protein (Bax) and decreased antiapoptotic protein (Bcl-2), with a concomitant increase in the levels of cleaved caspase-3, cleaved caspase-9 and cleaved poly-ADP-ribose polymerase (PARP). These results suggest that PK has a significant apoptosis inducing effect on SHG-44 glioma cells in vitro and caspase-3 may act as a potential mediator in the process. PMID- 20953402 TI - Use of Complementary and Alternative Medicine among People with Type 2 Diabetes in Taiwan: A Cross-Sectional Survey. AB - Research into CAM use by people with diabetes is limited. This study explored CAM use among patients who attend diabetic clinics for followup treatment. Special attention was paid to patients' changing patterns of CAM use before and after diagnosis with Type 2 diabetes, their experience of CAM use, and their management of CAM use with conventional medicines. A retrospective cross-sectional survey (n = 326) was undertaken in three census regions in Taiwan, including metropolitan, urban, and rural areas in 2006-7 (87.4% response rate). Participants reported extensive use of CAM with conventional medicines. The prevalence of CAM use was 22.7% before and 61.0% after diagnosis with Type 2 diabetes with nutritional supplements being the most commonly used CAM before and after diagnosis. However, the disclosure rate of CAM use to healthcare professionals remained low (24.6%), and lack of knowledge about CAM ingredients was common (63.4%). Awareness of the widespread use of CAM by people with Type 2 diabetes is crucial for healthcare professionals. The self-administration of both conventional medicines and CAM without disclosure of CAM use to healthcare professionals may result in ineffective diabetes management and adverse effects. CAM information needs to be incorporated into clinical practice and patient and professional education. PMID- 20953403 TI - Dynamic determinants of longevity and exceptional health. AB - It is well known from epidemiology that values of indices describing physiological state in a given age may influence human morbidity and mortality risks. Studies of connection between aging and life span suggest a possibility that dynamic properties of age trajectories of the physiological indices could also be important contributors to morbidity and mortality risks. In this paper we use data on longitudinal changes in body mass index, diastolic blood pressure, pulse pressure, pulse rate, blood glucose, hematocrit, and serum cholesterol in the Framingham Heart Study participants, to investigate this possibility in depth. We found that some of the variables describing individual dynamics of the age-associated changes in physiological indices influence human longevity and exceptional health more substantially than the variables describing physiological state. These newly identified variables are promising targets for prevention aiming to postpone onsets of common elderly diseases and increase longevity. PMID- 20953405 TI - Easiness of use and validity testing of VS-SENSE device for detection of abnormal vaginal flora and bacterial vaginosis. AB - Accessing vaginal pH is fundamental during gynaecological visit for the detection of abnormal vaginal flora (AVF), but use of pH strips may be time-consuming and difficult to interpret. The aim of this study was to evaluate the VS-SENSE test (Common Sense Ltd, Caesarea, Israel) as a tool for the diagnosis of AVF and its correlation with abnormal pH and bacterial vaginosis (BV). The study population consisted of 45 women with vaginal pH >= 4.5 and 45 women with normal pH. Vaginal samples were evaluated by VS-SENSE test, microscopy and microbiologic cultures. Comparing with pH strips results, VS-SENSE test specificity was 97.8% and sensitivity of 91%. All severe cases of BV and aerobic vaginitis (AV) were detected by the test. Only one case with normal pH had an unclear result. Concluding, VS-SENSE test is easy to perform, and it correlates with increased pH, AVF, and the severe cases of BV and AV. PMID- 20953404 TI - In vivo imaging biomarkers in mouse models of Alzheimer's disease: are we lost in translation or breaking through? AB - Identification of biomarkers of Alzheimer's Disease (AD) is a critical priority to efficiently diagnose the patients, to stage the progression of neurodegeneration in living subjects, and to assess the effects of disease modifier treatments. This paper addresses the development and usefulness of preclinical neuroimaging biomarkers of AD. It is today possible to image in vivo the brain of small rodents at high resolution and to detect the occurrence of macroscopic/microscopic lesions in these species, as well as of functional alterations reminiscent of AD pathology. We will outline three different types of imaging biomarkers that can be used in AD mouse models: biomarkers with clear translational potential, biomarkers that can serve as in vivo readouts (in particular in the context of drug discovery) exclusively for preclinical research, and finally biomarkers that constitute new tools for fundamental research on AD physiopathogeny. PMID- 20953406 TI - The effect of glucagon-like Peptide-2 receptor agonists on colonic anastomotic wound healing. AB - Background. Glucagon-like peptide 2 (GLP-2) is an intestinal specific trophic hormone, with therapeutic potential; the effects on intestinal healing are unknown. We used a rat model of colonic healing, under normoxic, and stress (hypoxic) conditions to examine the effect of GLP-2 on intestinal healing. Methods. Following colonic transection and reanastomosis, animals were randomized to one of six groups (n = 8/group): controls, native GLP-2, long-acting GLP-2 (GLP-2- MIMETIBODY, GLP-2-MMB), animals were housed under normoxic or hypoxic (11% O(2)) conditions. Animals were studied five days post-operation for anastomotic strength and wound characteristics. Results. Anastomotic bursting pressure was unchanged by GLP-2 or GLP-2-MMB in normoxic or hypoxic animals; both treatments increased crypt cell proliferation. Wound IL-1beta increased with GLP 2; IFNgamma with GLP-2 and GLP-2-MMB. IL-10 and TGF-beta were decreased; Type I collagen mRNA expression increased in hypoxic animals while Type III collagen was reduced with both GLP-2 agonists. GLP-2 MMB, but not native GLP-2 increased TIMP 1-3 mRNA levels in hypoxia. Conclusions. The effects on CCP, cytokines and wound healing were similar for both GLP-2 agonists under normoxic and hypoxic conditions; anastomotic strength was not affected. This suggests that GLP-2 (or agonists) could be safely used peri-operatively; direct studies will be required. PMID- 20953407 TI - Mesenchymal Stem Cells and the Origin of Ewing's Sarcoma. AB - The origin of Ewing's sarcoma is a subject of much debate. Once thought to be derived from primitive neuroectodermal cells, many now believe it to arise from a mesenchymal stem cell (MSC). Expression of the EWS-FLI1 fusion gene in MSCs changes cell morphology to resemble Ewing's sarcoma and induces expression of neuroectodermal markers. In murine cells, transformation to sarcomas can occur. In knockdown experiments, Ewing's sarcoma cells develop characteristics of MSCs and the ability to differentiate into mesodermal lineages. However, it cannot be concluded that MSCs are the cell of origin. The concept of an MSC still needs to be rigorously defined, and there may be different subpopulations of mesenchymal pluripotential cells. Furthermore, EWS-FLI1 by itself does not transform human cells, and cooperating mutations appear to be necessary. Therefore, while it is possible that Ewing's sarcoma may originate from a primitive mesenchymal cell, the idea needs to be refined further. PMID- 20953409 TI - Lycopene prevents development of steatohepatitis in experimental nonalcoholic steatohepatitis model induced by high-fat diet. AB - We investigated the preventive effect of lycopene on nonalcoholic steatohepatitis induced by high-fat diet in rats. Forty male Sprague-Dawley rats were divided into 4 groups. They were fed standard diet, high-fat diet (HFD), high-fat diet plus lycopene at a dose of 2 mg/kg body weight and the high-fat diet lycopene at a dose of 4 mg/kg BW for a period of 6 weeks. Inflammation, steatosis, alpha smooth muscle actin (alpha-SMA), and cytochrome P450 2E1 (CYP 2E1) expression increased significantly in the rats fed HFD and decreased in the rats administered by lycopene. Significantly elevated levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor (TNF alpha), and serum and liver malondialdehyde (MDA) were observed in rats fed the high-fat diet as compared to the control rats (P < .01). Supplementation with lycopene lowered serum MDA and tumor necrosis factor (TNF-alpha) levels and elevated liver GSH level (P < .001). Insulin resistance was higher in the rats fed HFD than in rats supplemented with lycopene. The data indicate that supplementation with lycopene can reduce high-fat diet-induced oxidative stress to the cells. PMID- 20953408 TI - Recent advances in application of male germ cell transplantation in farm animals. AB - Transplantation of isolated germ cells from a fertile donor male into the seminiferous tubules of infertile recipients can result in donor-derived sperm production. Therefore, this system represents a major development in the study of spermatogenesis and a unique functional assay to determine the developmental potential and relative abundance of spermatogonial stem cells in a given population of testis cells. The application of this method in farm animals has been the subject of an increasing number of studies, mostly because of its potential as an alternative strategy in producing transgenic livestock with higher efficiency and less time and capital requirement than the current methods. This paper highlights the salient recent research on germ cell transplantation in farm animals. The emphasis is placed on the current status of the technique and examination of ways to increase its efficiency through improved preparation of the recipient animals as well as isolation, purification, preservation, and transgenesis of the donor germ cells. PMID- 20953410 TI - Lipid mediators and human leukemic blasts. AB - Some of the most potent inflammatory mediators share a lipid origin. They regulate a wide spectrum of cellular processes including cell proliferation and apoptosis. However, the precise roles and ways (if any) in which these compounds impact the growth and apoptosis of leukemic blasts remain incompletely resolved. In spite of this, significant advances have been recently made. Here we briefly review the current knowledge about the production of lipid mediators (prostaglandins, leukotrienes, platelet-activating factor) by leukemic blasts, the enzymatic activities (phospholipase A(2), cyclooxygenases, lipoxygenases) involved in their productions and their effects (through specific membrane bound receptors) on the growth, and apoptosis of leukemic blasts. PMID- 20953411 TI - The acute effects of swimming on appetite, food intake, and plasma acylated ghrelin. AB - Swimming may stimulate appetite and food intake but empirical data are lacking. This study examined appetite, food intake, and plasma acylated ghrelin responses to swimming. Fourteen healthy males completed a swimming trial and a control trial in a random order. Sixty min after breakfast participants swam for 60 min and then rested for six hours. Participants rested throughout the control trial. During trials appetite was measured at 30 min intervals and acylated ghrelin was assessed periodically (0, 1, 2, 3, 4, 6, and 7.5 h. N = 10). Appetite was suppressed during exercise before increasing in the hours after. Acylated ghrelin was suppressed during exercise. Swimming did not alter energy or macronutrient intake assessed at buffet meals (total trial energy intake: control 9161 kJ, swimming 9749 kJ). These findings suggest that swimming stimulates appetite but indicate that acylated ghrelin and food intake are resistant to change in the hours afterwards. PMID- 20953413 TI - Growth, thermal stability and structure of ultrathin Zn-layers on Pd(1 1 1). AB - Low-energy ion scattering with monolayer sensitivity was applied to investigate ultrathin films of zinc on Pd(1 1 1). Uptake curves taken at 150 K indicate the simultaneous growth of multilayers with negligible interlayer transport. Annealing experiments for two-monolayer films reveal a rapid decrease in the zinc content on the surface layer at temperatures above 300 K, forming a metastable state with a Pd:Zn surface ratio of approx. 1:1 in the temperature region between 400 and 550 K. This state is most easily explained as a slightly buckled p(2 * 1) PdZn surface alloy, with Zn atoms located approx. 0.25 A above their Pd counterparts. PMID- 20953412 TI - Video-assisted thyroidectomy for papillary thyroid carcinoma. AB - Background. The results of video-assisted thyroidectomy (VAT) were evaluated in a large series of patients with papillary thyroid carcinoma (PTC), especially in terms of completeness of the surgical resection and short-to-medium term recurrence. Methods. The medical records of all patients who underwent video assisted thyroidectomy for PTC between June 1998 and May 2009 were reviewed. Results. Three hundred fifty-nine patients were included. One hundred twenty-six patients underwent concomitant central neck node removal. Final histology showed 285 pT1, 26 pT2, and 48 pT3 PTC. Lymph node metastases were found in 27 cases. Follow-up was completed in 315 patients. Mean postoperative serum thyroglobulin level off levothyroxine was 5.4 ng/mL. Post operative ultrasonography showed no residual thyroid tissue in all the patients. Mean post-operative (131)I uptake was 1.7%. One patient developed lateral neck recurrence. No other recurrence was observed. PMID- 20953414 TI - Structural modifications during heating of bulk nanocrystalline FeAl produced by high-pressure torsion. AB - The deformation-induced nanostructure developed during high-pressure torsion of B2 long-range ordered FeAl is shown to be unstable upon heating. The structural changes were analyzed using transmission electron microscopy, differential scanning calorimetry and microhardness measurements. Heating up to 220 degrees C leads to the recurrence of the chemical long-range order that is destroyed during deformation. It is shown that the transition to the long-range-ordered phase evolves in the form of small ordered domains homogeneously distributed inside the nanosized grains. At temperatures between 220 and 370 degrees C recovery of dislocations and antiphase boundary faults cause a reduction in the grain size from 77 to 35 nm. Grain growth occurs at temperatures above 370 degrees C. The evolution of the strength monitored by microhardness is discussed in the framework of grain-size hardening and hardening by defect recovery. PMID- 20953415 TI - Two- vs. three-dimensional presentation of mental rotation tasks: Sex differences and effects of training on performance and brain activation. AB - The well-documented sex difference in mental rotation favoring males has been shown to emerge only for 2-dimensional presentations of 3-dimensional objects, but not with actual 3-dimensional objects or with virtual reality presentations of 3-dimensional objects. Training studies using computer games with mental rotation-related content have demonstrated training effects on mental rotation performance. Here, we studied the combined effect of a two-week mental rotation (MR) training on 2-dimensional vs. 3-dimensional presentations of a classic Shepard-Metzler task (presented in a pretest-training-posttest design) and their accompanying cortical activation patterns assessed via EEG in a sample of 38 male and 39 female adolescents of about 15 years of age. Analysis of one performance parameter (reaction times) displayed only main effects of dimensionality (with shorter RTs on the 3D vs. 2D version of the MR task) and of training (significant shortening of RTs), but no significant sex difference. Analysis of the other performance parameter (scores) in the MR task revealed a sex difference favoring males that first, appeared only in the 2D version, but not in the 3D version of the MR task and, secondly, diminished after training. Neurophysiologically we observed a complex sex * dimensionality * training * hemisphere interaction showing that the hypothesized decrease of brain activation (increase in neural efficiency) with training emerged for males in both 2D and 3D conditions, whereas for females this decrease was found only in the 3D but not with the 2D version of the MR task. PMID- 20953416 TI - Marine microbial genomics in Europe: current status and perspectives. AB - The oceans are the Earth's largest ecosystem, covering 70% of our planet and providing goods and services for the majority of the world's population. Understanding the complex abiotic and biotic processes on the micro- to macroscale is the key to protect and sustain the marine ecosystem. Marine microorganisms are the 'gatekeepers' of the biotic processes that control the global cycles of energy and organic matter. A multinational, multidisciplinary approach, bringing together research on oceanography, biodiversity and genomics, is now needed to understand and finally predict the complex responses of the marine ecosystem to ongoing global changes. Such an integrative approach will not only bring better understanding of the complex interplay of the organisms with their environment, but will reveal a wealth of new metabolic processes and functions, which have a high potential for biotechnological applications. This potential has already been recognized by the European commission which funded a series of workshops and projects on marine genomics in the sixth and seventh framework programme. Nevertheless, there remain many obstacles to achieving the goal - such as a lack of bioinformatics tailored for the marine field, consistent data acquisition and exchange, as well as continuous monitoring programmes and a lack of relevant marine bacterial models. Marine ecosystems research is complex and challenging, but it also harbours the opportunity to cross the borders between disciplines and countries to finally create a rewarding marine research era that is more than the sum of its parts. PMID- 20953417 TI - Marine genomics: at the interface of marine microbial ecology and biodiscovery. AB - The composition and activities of microbes from diverse habitats have been the focus of intense research during the past decade with this research being spurred on largely by advances in molecular biology and genomic technologies. In recent years environmental microbiology has entered very firmly into the age of the 'omics' - (meta)genomics, proteomics, metabolomics, transcriptomics - with probably others on the rise. Microbes are essential participants in all biogeochemical processes on our planet, and the practical applications of what we are learning from the use of molecular approaches has altered how we view biological systems. In addition, there is considerable potential to use information about uncultured microbes in biodiscovery research as microbes provide a rich source of discovery for novel genes, enzymes and metabolic pathways. This review explores the brief history of genomic and metagenomic approaches to study environmental microbial assemblages and describes some of the future challenges involved in broadening our approaches - leading to new insights for understanding environmental problems and enabling biodiscovery research. PMID- 20953418 TI - Randomized Controlled Trials of Acupuncture (1997-2007): An Assessment of Reporting Quality with a CONSORT- and STRICTA-Based Instrument. AB - The present study describes the development of a comprehensive quality of reporting assessment tool and its application to acupuncture RCTs from 1997-2007. This Oregon CONSORT STRICTA Instrument (OCSI) is based on the revised CONSORT guidelines as modified by the STRICTA recommendations for acupuncture trials. Each of the resulting 27 OCSI items were applied to English language prospective RCTs that compared acupuncture, using manual and/or electro-stimulation, to no treatment, a sham procedure, or usual biomedical care. The 333 RCTs that met inclusion criteria were dispersed among 27 countries and 141 journals. Mean quality of reporting score for all articles was 63.0% (SD 16.5). Mean OCSI scores revealed a 30.9% improvement over the ten-year period (P < .001). Our findings suggest that to enhance quality of reporting, authors should better attend to seven specific OCSI items in three categories: practitioner training, adverse events, and aspects of randomization and blinding (n = 5). The broad diversity in geographical origin, publication site and quality of reporting, viewed in light of the considerable room for improvement in mean OCSI scores, emphasizes the importance of making STRICTA as well as CONSORT more widely known to journals and to the acupuncture research community. PMID- 20953419 TI - What's in a Name? Can Mullein Weed Beat TB Where Modern Drugs Are Failing? AB - Common mullein weed (Verbascum thapsus) has a large number of synonyms and old local "nick names" which connect the plant with mycobacteria. A strong history of medicinal use has been uncovered for the treatment of tuberculosis, tubercular skin disease, leprosy, and mycobacterial disease in animals. Here, we examine problems encountered in treating such diseases today, the historical and scientific links between mullein and pathogenic bacteria, and the possibility that this common weed could harbour the answer to beating one of the world's biggest infectious killers. PMID- 20953420 TI - Suppressive Effect on Lipopolysaccharide-Induced Proinflammatory Mediators by Citrus aurantium L. in Macrophage RAW 264.7 Cells via NF-kappaB Signal Pathway. AB - Citrus fruits have been used as an edible fruit and a traditional medicine since ancient times. In particular, the peels of immature citrus fruits are used widely in traditional herbal medicine in Korea, as they are believed to contain bioactive components exerting anti-inflammatory activity. This study examined whether the crude methanol extract of Citrus aurantium L. (CME) has a suppressive effect on inducible enzymes and proinflammatory cytokines by inhibiting the NF kappaB pathway in LPS-stimulated macrophage RAW 264.7 cells. The cells were pretreated with the indicated concentrations of CME (5, 10, 20, and 50 MUg/mL) and then treated with LPS (1 MUg/mL). The results showed that CME (10, 20, and 50 MUg/mL) inhibited the LPS- (1 MUg/mL) induced mRNA and protein expression of iNOS in macrophage Raw 264.7 cells. In addition, the expression of COX-2 was inhibited at the mRNA and protein levels by CME in a dose-dependent manner. The mRNA expression of proinflammatory cytokines, such as TNF-alpha and IL-6, were markedly reduced by CME (10, 20, and 50 MUg/mL). Moreover, CME clearly suppressed the nuclear translocation of the NF-kappaB p65 subunits, which was correlated with its inhibitory effect on I-kappaB phosphorylation. These results suggest that CME has anti-inflammatory properties by modulating the expression of COX-2, iNOS, and proinflammatory cytokines, such as TNF-alpha and IL-6, in macrophage RAW 264.7 cells via the NF-kappaB pathway. PMID- 20953421 TI - The basic cardiovascular responses to postural changes, exercise, and cold pressor test: do they vary in accordance with the dual constitutional types of ayurveda? AB - According to Ayurveda, the native Indian system of healthcare, three Doshas, namely, Vata, Pitta, and Kapha, are the basic mutually reciprocal mechanisms that are responsible for the maintenance of homeostasis in human beings. Ayurveda classifies entire human population into seven constitutional types (Prakriti), based on the dominance of any single or a combination of two or three Doshas. Considering the fact that, in the recent past there have been several studies that have proposed some important genetic, biochemical and haematological bases for Prakriti, we conducted the present study in 90 randomly selected clinically healthy volunteers belonging to dual constitutional types (Dvandvaja Prakriti) to evaluate the variability of heart rate and arterial blood pressure in response to specific postural changes, exercise, and cold pressor test. The results of this study, in general, suggest that these basic cardiovascular responses do not vary significantly as per the dual constitutional types. However, we noted a significant fall in the diastolic blood pressure immediately after performing the isotonic exercise for five minutes, in Vata-Kapha individuals in comparison to the other two groups, namely, Pitta-Kapha and Vata-Pitta. PMID- 20953422 TI - Electroacupuncture inhibits inflammation reaction by upregulating vasoactive intestinal Peptide in rats with adjuvant-induced arthritis. AB - Acupuncture is emerging as an alternative therapy for rheumatoid arthritis (RA). However, the molecular mechanism underlying this beneficial effect of acupuncture has not been fully understood. Here, we demonstrated that electroacupuncture at acupoints Zusanli (ST36), Xuanzhong (GB39); and Shenshu (BL23) markedly decreased the paw swelling and the histologic scores of inflammation in the synovial tissue, and reduced the body weight loss in an adjuvant-induced arthritis rat model. However, the electrical stimulation at nonacupoint did not produce any beneficial effects against the experimental arthritis. Most interestingly, the electroacupuncture treatment resulted in an enhanced immunostaining for vasoactive intestinal peptide (VIP), a potent anti-inflammatory neuropeptide, in the synovial tissue. Moreover, the VIP-immunostaining intensity was significantly negatively correlated with the scores of inflammation in the synovial tissue (r = -0.483, P = .0026). In conclusion, these findings suggest that electroacupuncture may offer therapeutic benefits for the treatment of RA, at least partially through the induction of VIP expression. PMID- 20953423 TI - In Vivo Effects of Cagaita (Eugenia dysenterica, DC.) Leaf Extracts on Diarrhea Treatment. AB - Eugenia dysenterica is a plant typically found in the Cerrado biome and commonly used in popular medicine due to its pharmacological properties, which include antidiarrheal, skin healing, and antimicrobial activities. The effects of ethanolic extract, aqueous extract and infusion of E. dysenterica leaves on intestinal motility and antidiarrheal activity were evaluated using ricin oil induced diarrhea in rats. At doses of 400 and 800 mg.Kg(-1), the ethanolic extract decreased intestinal motility while the other extracts showed no significant effects. Moreover, serum levels of chloride, magnesium, and phosphorus were also measured in rats. Histopathologic and enzymatic analyses were also performed to investigate any toxic effect. Animals treated with infusion, ethanolic extract, ricin oil, and loperamide presented morphological alterations in the small intestine, such as mucosa lesion, epithelial layer damage, and partial loss and/or morphological change of villi. Furthermore, the liver showed congestion and hydropic degeneration. Serum levels of alanine aminotransferase increased significantly in all treatments, but none rose above reference values. In summary, our results suggest that compounds present in leaves of E. dysenterica may have therapeutic benefits on recovery from diarrhea despite their toxic effects. PMID- 20953424 TI - Toxicity Profile of the Aqueous Ethanol Root Extract of Corrigiola telephiifolia Pourr. (Caryophyllaceae) in Rodents. AB - Corrigiola telephiifolia Pourr. (Caryophyllaceae) is a Moroccan medicinal plant. Despite its popular usage, no study has been published concerning its toxicological profile. The acute toxicity of C. telephiifolia root extract was evaluated by giving it orally to mice at single doses of 5000, 10000, and 14000 mg/kg bodyweight. The extract was also administered at doses of 5, 70, and 2000 mg/kg bodyweight per day to rats for a forty-day toxicity study. No mortality or signs of toxicity were observed in the acute study. In the forty-day study in rats, the extract at 5 mg/kg/day showed no toxicological effects in either sex. At 70 mg/kg/day, the treated group differed from the control only by a significant decrease in serum concentrations of sodium and chloride ions (P < .05). At the dose of 2000 mg/kg/day, the extract significantly increased the serum concentrations of creatinine, alkaline phosphatase, gamma glutamyltransferase and phosphorus (P < .05) all suggestive of functional nephrotoxicity and hepatotoxicity. The relative bodyweight of both sexes decreased at the dose of 2000 mg/kg/day, with a fast recovery for males. Histological examination did not reveal any treatment-related effects. In conclusion, Corrigiola extract appears safe at the doses used ethno-medicinally. Much higher doses pose toxicological risks. PMID- 20953425 TI - Mesotherapy versus Systemic Therapy in the Treatment of Acute Low Back Pain: A Randomized Trial. AB - Pharmacological therapy of back pain with analgesics and anti-inflammatory drugs is frequently associated with adverse effects, particularly in the elderly. Aim of this study was to compare mesotherapic versus conventional systemic administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids in patients with acute low back pain. Eighty-four patients were randomized to receive anti-inflammatory therapy according to the following protocols: (a) mesotherapy group received the 1st and 4th day 2% lidocaine (1 mL) + ketoprofen 160 mg (1 mL) + methylprednisolone 40 mg (1 mL), then on 7th, 10th, and 13th day, 2% lidocaine (1 mL) + ketoprofen 160 mg (1 mL) + methylprednisolone 20 mg (1 mL) (b) conventional therapy group received ketoprofen 80 mg * 2/die and esomeprazole 20 mg/die orally for 12 days, methylprednisolone 40 mg/die intramuscularly for 4 days, followed by methylprednisolone 20 mg/die for 3 days, and thereafter, methylprednisolone 20 mg/die at alternate days. Pain intensity and functional disability were assessed at baseline (T0), at the end of treatment (T1), and 6 months thereafter (T2) by using visual analogic scale (VAS) and Roland-Morris disability questionnaire (RMDQ). In both groups, VAS and RMDQ values were significantly reduced at the end of drug treatment and after 6 months, in comparison with baseline. No significant differences were found between the two groups. This suggests that mesotherapy may be a valid alternative to conventional therapy in the treatment of acute low back pain with corticosteroids and NSAIDs. PMID- 20953426 TI - Evaluation of the Anxiolytic Activity of NR-ANX-C (a Polyherbal Formulation) in Ethanol Withdrawal-Induced Anxiety Behavior in Rats. AB - The present study investigates the anxiolytic activity of NR-ANX-C, a standardized polyherbal formulation containing the extracts of Withania somnifera, Ocimum sanctum, Camellia sinensis, Triphala, and Shilajit in ethanol withdrawal- (EW-) induced anxiety behavior in rats. Ethanol dependence in rats was produced by substitution of drinking water with 7.5% v/v alcohol for 10 days. Then, ethanol withdrawal was induced by replacing alcohol with drinking water, 12 hours prior to experimentation. After confirming induction of withdrawal symptoms in the alcohol deprived animals, the anxiolytic activity of the test compound in graded doses (10, 20, and 40 mg/kg) was compared to the standard drug alprazolam (0.08 mg/kg) in the elevated plus maze and bright and dark arena paradigms. In our study, single and repeated dose administration of NR-ANX-C reduced EW-induced anxiety in a dose-dependent manner. Even though the anxiolytic activity was not significant at lower doses, NR-ANX-C at the highest dose tested (40 mg/kg) produced significant anxiolytic activity that was comparable to the standard drug alprazolam. Based on our findings we believe that NR-ANX-C has the potential to be used as an alternative to benzodiazepines in the treatment of EW-induced anxiety. PMID- 20953427 TI - Inner Correspondence and Peacefulness with Practices among Participants in Eurythmy Therapy and Yoga: A Validation Study. AB - Several mind body medicine interventions require an active participation of the practitioners. We intended to develop a questionnaire to operationalize and measure the "inner correspondence" of individuals practicing Yoga or Eurythmy Therapy. In an anonymous cross-sectional study we enrolled 501 individuals (61% yoga). Exploratory factor analysis (study 1) of the 12-item instrument (Cronbach's alpha = .84) pointed to a 3-factor solution, with one major scale and good internal consistency (alpha = .83) and two minor scales with weak internal consistency. To improve the quality of the main scale, we added 8 new items which were tested in a sample of 135 individuals (study 2: 71% Yoga). Factor analysis confirmed a 12-item single factor (alpha = .95), that is, Inner Correspondence/Peaceful Harmony with Practices (ICPH). The scale correlated strongly with mindfulness (FMI; r > .50), moderately with life and patient satisfaction (BMLSS; r between .32 and .43), and weakly negative with symptom score (VAS; r = -.23). In conclusion, the scale ICPH was confirmed as a relevant tool to measure the inner correspondence and feelings of peacefulness with practices. It can be used in clinical studies to assess the efficacy of mind-body practices involving physical movements. PMID- 20953428 TI - Law's Dilemma: Validating Complementary and Alternative Medicine and the Clash of Evidential Paradigms. AB - This paper examines the (in)compatibility between the diagnostic and therapeutic theories of complementary and alternative medicine (CAM) and a science-based regulatory framework. Specifically, the paper investigates the nexus between statutory legitimacy and scientific validation of health systems, with an examination of its impact on the development of complementary and alternative therapies. The paper evaluates competing theories for validating CAM ranging from the RCT methodology to anthropological perspectives and contends that while the RCT method might be beneficial in the regulation of many CAM therapies, yet dogmatic adherence to this paradigm as the exclusive method for legitimizing CAM will be adverse to the independent development of many CAM therapies whose philosophies and mechanisms of action are not scientifically interpretable. Drawing on history and research evidence to support this argument, the paper sues for a regulatory model that is accommodative of different evidential paradigms in support of a pluralistic healthcare system that balances the imperative of quality assurance with the need to ensure access. PMID- 20953429 TI - Dietary phenethyl isothiocyanate alters gene expression in human breast cancer cells. AB - Phenethyl isothiocyanate (PEITC), a component in cruciferous vegetables, can block chemical carcinogenesis in animal models. Our objective was to determine the effect of treatment with PEITC on gene expression changes in MCF-7 human breast cancer cells in order to evaluate potential mechanisms involved in its chemopreventive effects. MCF-7 cells were treated for 48 hours with either PEITC (3 MUM) or the vehicle. Total RNA was extracted from cell membrane preparations, and labeled cDNA's representing the mRNA pool were reverse-transcribed directly from total RNA isolated for use in the microarray hybridizations. Two specific human GE Array Kits (Superarray Inc.) that both contain 23 marker genes, related to signal transduction pathways or cancer/tumor suppression, plus 2 housekeeping genes (beta-actin and GAPDH), were utilized. Arrays from treated and control cells (n = 4 per group) were evaluated using a Student's t-test. Gene expression was significantly induced for tumor protein p53 (p53), cyclin-dependent kinase inhibitor 1C (p57 Kip2), breast cancer Type 2 early onset (BRCA2), cAMP responsive element binding protein 2 (ATF-2), interleukin 2 (IL-2), heat shock 27 KD protein (hsp27), and CYP19 (aromatase). Induction of p57 Kip2, p53, BRCA2, IL 2, and ATF-2 would be expected to decrease cellular proliferation and increase tumor suppression and/or apoptosis. PEITC treatment produced significant alterations in some genes involved in tumor suppression and cellular proliferation/apoptosis that may be important in explaining the chemopreventive effects of PEITC. PMID- 20953430 TI - Evaluation of traditional Indian antidiabetic medicinal plants for human pancreatic amylase inhibitory effect in vitro. AB - Pancreatic alpha-amylase inhibitors offer an effective strategy to lower the levels of post prandial hyperglycemia via control of starch breakdown. Eleven Ayurvedic Indian medicinal plants with known hypoglycemic properties were subjected to sequential solvent extraction and tested for alpha-amylase inhibition, in order to assess and evaluate their inhibitory potential on pancreatic alpha-amylase. Analysis of 91 extracts, showed that 10 exhibited strong Human Pancreatic Amylase (HPA) inhibitory potential. Of these, 6 extracts showed concentration dependent inhibition with IC(50) values, namely, cold and hot water extracts from Ficus bengalensis bark (4.4 and 125 MUgmL(-1)), Syzygium cumini seeds (42.1 and 4.1 MUgmL(-1)), isopropanol extracts of Cinnamomum verum leaves (1.0 MUgmL(-1)) and Curcuma longa rhizome (0.16 MUgmL(-1)). The other 4 extracts exhibited concentration independent inhibition, namely, methanol extract of Bixa orellana leaves (49 MUgmL(-1)), isopropanol extract from Murraya koenigii leaves (127 MUgmL(-1)), acetone extracts from C. longa rhizome (7.4 MUgmL(-1)) and Tribulus terrestris seeds (511 MUgmL(-1)). Thus, the probable mechanism of action of the above fractions is due to their inhibitory action on HPA, thereby reducing the rate of starch hydrolysis leading to lowered glucose levels. Phytochemical analysis revealed the presence of alkaloids, proteins, tannins, cardiac glycosides, flavonoids, saponins and steroids as probable inhibitory compounds. PMID- 20953431 TI - Anticancer Potentials of Root Extract of Polygala senega and Its PLGA Nanoparticles-Encapsulated Form. AB - Ethanolic extract of Polygala senega (EEPS) had little or no cytotoxic effects on normal lung cells, but caused cell death and apoptosis to lung cancer cell line A549. In the present paper, ethanolic root extract of P. senega (EEPS) was nanoencapsulated (size: 147.7 nm) by deploying a biodegradable poly-(lactic-co glycolic) acid (PLGA). The small size of the NEEPS resulted in an enhanced cellular entry and greater bioavailability. The growth of cancer cells was inhibited better by NEEPS than EEPS. Both EEPS and NEEPS induced apoptosis of A549 cells, which was associated with decreased expression of survivin, PCNA mRNA, and increased expression of caspase-3, p53 mRNAs of A549 cells. The results show that the anticancer potential of the formulation of EEPS-loaded PLGA nanoparticles was more effective than EEPS per se, probably due to more aqueous dispersion after nanoencapsulation. Therefore, nanoencapsulated ethanolic root extract of P. senega may serve as a potential chemopreventive agent against lung cancer. PMID- 20953432 TI - Oral Treatment with Extract of Agaricus blazei Murill Enhanced Th1 Response through Intestinal Epithelial Cells and Suppressed OVA-Sensitized Allergy in Mice. AB - To clarify the mechanism of the antiallergic activity of Agaricus blazei Murill extract (ABME), the present paper used an in vivo allergy model and an in vitro intestinal gut model. During OVA sensitization, the serum IgE levels decreased significantly in ABME group. Interleukin (IL)-4 and -5 produced from OVA restimulated splenocytes was significantly decreased, and anti-CD3epsilon/CD28 antibody treatment also reduced IL-10, -4, and -5 production and increased IFN gamma production in ABME group. These results suggest that oral administration of ABME improves Th1/Th2 balance. Moreover, a coculture system constructed of Caco-2 cells and splenocytes from OT-II mice or RAW 264.7 cells indicated that the significant increases in IFN-gamma production by ABME treatment. Therefore, it was concluded that the antiallergic activity of ABME was due to the activation of macrophages by epithelial cells and the promotion of the differentiation of naive T cells into Th1 cells in the immune. PMID- 20953433 TI - Comparative effects of acupressure at local and distal acupuncture points on pain conditions and autonomic function in females with chronic neck pain. AB - Acupressure on local and distal acupuncture points might result in sedation and relaxation, thereby reducing chronic neck pain. The aim was to investigate the effect of acupressure at local (LP) and distal acupuncture points (DP) in females with chronic neck pain. Thirty-three females were assigned to three groups: the control group did not receive any stimuli, the LP group received acupressure at local acupuncture points, GB 21, SI 14 and SI 15, and the DP group received acupressure at distal acupuncture points, LI 4, LI 10 and LI 11. Verbal rating scale (VRS), Neck Disability Index (NDI), State-Trait Anxiety Inventory (STAI), muscle hardness (MH), salivary alpha-amylase (sAA) activity, heart rate (HR), heart rate variability (HRV) values and satisfaction due to acupressure were assessed. VRS, NDI, STAI and MH values decreased after acupressure in the LP and the DP group. HR decreased and the power of high frequency (HF) component of HRV increased after acupressure in only the LP group. Although acupressure on not only the LP but also the DP significantly improved pain conditions, acupressure on only the LP affected the autonomic nervous system while acupuncture points per se have different physical effects according to location. PMID- 20953434 TI - Black tea and theaflavins assist healing of indomethacin-induced gastric ulceration in mice by antioxidative action. AB - The healing activities of black tea (BT) and the theaflavins (TF) against the indomethacin-induced stomach ulceration were studied in a mouse model. Indomethacin (18 mg/kg, p.o.) administration induced maximum ulceration in the glandular portion of the gastric mucosa on the 3rd day, accompanied by increased lipid peroxidation and protein oxidation, depletion of thiol-defense and mucin, as well as reduced expressions of cyclooxygenases (COX) and prostaglandin (PG) E synthesis in the gastric tissues, and plasma total antioxidant status of mice. Treatment with BT (40 mg/kg), TF (1 mg/kg), and omeprazole (3 mg/kg) produced similar (74%-76%) ulcer healing, as revealed from the histopathological studies. Treatment with all the above samples reversed the adverse oxidative effects of indomethacin significantly. BT and TF also enhanced the PGE synthesis by augmenting the expressions of COX 1 and 2, but did not modulate acid secretion. PMID- 20953435 TI - Investigation of Antidiabetic, Antihyperlipidemic, and In Vivo Antioxidant Properties of Sphaeranthus indicus Linn. in Type 1 Diabetic Rats: An Identification of Possible Biomarkers. AB - The present investigation was aimed to study the antidiabetic, antihyperlipidemic, and in vivo antioxidant properties of the root of Sphaeranthus indicus Linn. in streptozotocin- (STZ-) induced type 1 diabetic rats. Administration of ethanolic extract of Sphaeranthus indicus root (EESIR) 100 and 200 mg/kg to the STZ-induced diabetic rats showed significant (P < .01) reduction in blood glucose and increase in body weight compared to diabetic control rats. Both the doses of EESIR-treated diabetic rats showed significant (P < .01) alteration in elevated lipid profile levels than diabetic control rats. The EESIR treatment in diabetic rats produced significant increase in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and decrease in thiobarbituric acid reactive substances (TBARS) levels than diabetic control rats. Administration of EESIR 200 mg/kg produced significant (P < .01) higher antioxidant activity than EESIR 100 mg/kg. The high performance liquid chromatography (HPLC) analysis of EESIR revealed the presence of biomarkers gallic acid and quercetin. In conclusion, EESIR possess antidiabetic, antihyperlipidemic, and in vivo antioxidant activity in type 1 diabetic rats. Its antioxidant and lipid lowering effect will help to prevent diabetic complications, and these actions are possibly due to presence of above biomarkers. PMID- 20953436 TI - Ocimum gratissimum Aqueous Extract Protects H9c2 Myocardiac Cells from H(2)O(2) Induced Cell Apoptosis through Akt Signalling. AB - Increased cell death of cardiomyocyte by oxidative stress is known to cause dysfunction of the heart. O. gratissimum is one of the more well-known medicinal plants among the Ocimum species and widely used in treatment of inflammatory diseases. In this study, we hypothesized that aqueous extract of O. gratissimum leaf (OGE) may protect myocardiac cell H9c2 from oxidative injury by hydrogen peroxide (H(2)O(2)). Our results revealed that OGE pretreatment dose-dependently protects H9c2 cells from cell death when exposed to H(2)O(2). Additionally, DNA condensation induced by H(2)O(2) was also reduced by OGE pretreatment, suggesting that Ocimum gratissimum extract may attenuate H(2)O(2)-induced chromosome damage. Further investigation showed that OGE pretreatment inhibited H(2)O(2)-induced activation of caspase-3 and caspase-9, as well as H(2)O(2)-induced upregulation of proapoptotic Apaf-1 and the release of cytosolic cytochrome c, but has little effect on the activation of caspase-8. Additionally, OGE pretreatment significantly upregulated Bcl-2 expression and Akt phosphorylation, and slightly affected the phosphorylation of mitogen-activated protein kinases including p38 MAPK and JNK. Taken together, our findings revealed that Ocimum gratissimum extract effectively inhibited the mitochondrial pathway and upregulated Bcl-2 expression, which may be important in protecting H9c2 cells from H(2)O(2)-induced cell death. PMID- 20953438 TI - Thermochemistry of imidazolium-based ionic liquids: experiment and first principles calculations. AB - In this work the molar enthalpy of formation of the ionic liquid 1-ethyl-3 methylimidazolium dicyanoamide in the gaseous phase [C(2)MIM][N(CN)(2)] was measured by means of combustion calorimetry and enthalpy of vaporization using transpiration. Available, but scarce, primary experimental results on enthalpies of formation of imidazolium based ionic liquids with the cation [C(n)MIM] (where n = 2 and 4) and anions [N(CN)(2)], [NO(3)] and [NTf(2)] were collected and checked for consistency using a group additivity procedure. First-principles calculations of the enthalpies of formation in the gaseous phase for the ionic liquids with the common cation [C(n)MIM] (where n = 2 and 4) and with the anions [N(CN)(2)], [NO(3)], [NTf(2)], [Cl], [BF(4)] and [PF(6)] have been performed using the G3MP2 theory. It has been established that the gaseous phase enthalpies of formation of these ionic liquids obey the group additivity rules. PMID- 20953437 TI - Recovery Effects of a 180 mT Static Magnetic Field on Bone Mineral Density of Osteoporotic Lumbar Vertebrae in Ovariectomized Rats. AB - The effects of a moderate-intensity static magnetic field (SMF) on osteoporosis of the lumbar vertebrae were studied in ovariectomized rats. A small disc magnet (maximum magnetic flux density 180 mT) was implanted to the right side of spinous process of the third lumbar vertebra. Female rats in the growth stage (10 weeks old) were randomly divided into 4 groups: (i) ovariectomized and implanted with a disc magnet (SMF); (ii) ovariectomized and implanted with a nonmagnetized disc (sham); (iii) ovariectomized alone (OVX) and (vi) intact, nonoperated cage control (CTL). The blood serum 17-beta-estradiol (E(2)) concentrations were measured by radioimmunoassay, and the bone mineral density (BMD) values of the femurs and the lumbar vertebrae were assessed by dual energy X-ray absorptiometry. The E(2) concentrations were statistically significantly lower for all three operated groups than those of the CTL group at the 6th week. Although there was no statistical significant difference in the E(2) concentrations between the SMF-exposed and sham-exposed groups, the BMD values of the lumbar vertebrae proximal to the SMF-exposed area statistically significantly increased in the SMF-exposed group than in the sham-exposed group. These results suggest that the SMF increased the BMD values of osteoporotic lumbar vertebrae in the ovariectomized rats. PMID- 20953439 TI - Total syntheses of subereamollines A and B. AB - The first total syntheses of (+)- and (-)-subereamollines A and B are reported. The enantiomeric forms of the natural products were obtained by preparative chiral HPLC separation of the corresponding racemates. PMID- 20953440 TI - XCC2--a new coupled cluster model for the second-order polarization propagator. AB - A new coupled cluster model of the polarization propagator, denoted as XCC2, is presented. The XCC2 approach employs time-independent coupled cluster theory of polarization propagators of Moszynski et al. [Collect. Czech. Chem. Commun., 2005, 70, 1109] and excitation operators from the time-dependent (TD) CC2 method. The performance of XCC2 was investigated by calculating static and dynamic dipole polarizabilities for a test set of over 20 molecules and comparing them with TD CCSD results. The quality of XCC2 dispersion coefficients for several noncovalent molecular complexes was also tested against the benchmark values. This numerical study reveals that the average percent error of XCC2 is significantly reduced in comparison to the TD-CC2 method (4-fold reduction for the mean polarizabilities and 2-fold reduction for anisotropic polarizabilities is observed). Since the computational requirements of both XCC2 and TD-CC2 methods are virtually the same, the new XCC2 method can be viewed as a practical alternative for TD-CC2 for property calculations, giving the second-order polarization propagators of near CCSD quality in many cases, but retaining at the same time the lower computational cost of the TD-CC2 model. PMID- 20953473 TI - Synthesis and biological evaluation of conformationally restricted sigma(1) receptor ligands with 7,9-diazabicyclo[4.2.2]decane scaffold. AB - The key step in the synthesis of the 7,9-diazabicyclo[4.2.2]decane system was a modified Dieckmann condensation of piperazinebutyrate 11, which makes use of trapping the first cyclized intermediate with TMS-Cl. Reduction of the bicyclic ketone 14 with LiBH(4) at -90 degrees C provided diastereoselectively (>99 : 1) the syn-configured alcohol 15a, which was converted into the final alcohol and ethers 16a-g. The configuration at the 2-position was established by X-ray structure analysis of methyl and ethyl ethers 15b and 15c. In contrast to bicyclic systems with a three-carbon bridge, inversion of the configuration at the 2-position of the alcohol 15a failed to give the inverted alcohol 19a. However, an unselective reduction of the ketone 24 with L-Selectride led to the diastereomeric alcohols 16a and 25a in the ratio 36 : 64. LiAlH(4) reduction of the tosylate 20 and the alkene 18 yielded the diazabicyclo-decane 26 and -decene 27 without further substituents at the four-carbon bridge. The sigma(1) and sigma(2) receptor affinities were investigated in receptor binding studies with radioligands. All test compounds showed a lower sigma(1) affinity than the corresponding bicyclic derivatives with a three-membered bridge. The reduced sigma(1) receptor affinity is attributed to the larger four-membered bridge. This hypothesis is supported by the alkene 27, which represents the most potent sigma(1) ligand of this series (K(i) = 7.5 nM). In the alkene 27 the size and flexibility of the bridge is considerably reduced by the double bond. The methyl ether 25b and the unsubstituted derivatives 26 and 27 revealed moderate inhibition of the growth of the human tumor cell lines A-427, 5637 and MCF-7. Again, these compounds are less potent than the analogues with a three-membered bridge. The IC(50)-value of the most potent sigma(1) ligand 27 against the small cell lung cancer cell line A-427 (IC(50) = 10 MUM) should be emphasized, since this cell line is particularly sensitive to homologues with a three-carbon bridge. PMID- 20953472 TI - Dispersion dominated halogen-pi interactions: energies and locations of minima. AB - The interactions of halogen atoms with aromatic pi-systems can be crucial for structural stability and ligand binding. However, many aspects of the nature and energetics of these interactions remain elusive. Therefore, we designed model systems mimicking the T-shaped complex of chloro- and bromobenzene with tyrosine as found, e.g., in serine protease-inhibitor complexes. Three dimensional potential energy surfaces (3D-PES) were calculated at a high level of theory, up to CCSD(T). On these 3D-PES the exact location of the minima and, even more important, the shape of favorable interaction regions were determined. We show that the height of the halogen atom above the tyrosine-ring is decisive, while the lateral position is of minor influence. Finally, a truncated harmonic potential is developed to modify the Amber/GAFF force field to shift the locations of the minima to the correct regions. PMID- 20953475 TI - A single source precursor for low temperature processing of nanocrystalline MgAl2O4 spinel: synthesis and characterization of [MgAl2(MU3-O)(MU2 O(i)Pr)4(O(i)Pr)2]4. AB - A novel polynuclear single-source precursor was prepared and characterized by single-crystal X-ray diffraction and multinuclear NMR spectroscopy. Nano crystalline MgAl(2)O(4) spinel was synthesized via sol-gel processing of [MgAl(2)(MU(3)-O)(MU(2)-O(i)Pr)(4)(O(i)Pr)(2)](4). XRD, TGA-DSC and HRTEM confirmed the formation of a spinel phase at 475 degrees C, a temperature lower than any known processing temperature for MgAl(2)O(4). PMID- 20953474 TI - Reconstruction and stability of beta-cristobalite 001, 101, and 111 surfaces during dehydroxylation. AB - We analysed the dehydroxylation of 001, 101, and 111 beta-cristobalite surfaces using the periodic density functional theory method and established the OH density stability diagrams of these surfaces as a function of temperature and water partial pressure. Our calculations suggest that important surface reconstructions, involving SiO(2) unit migrations, are required to reach the experimentally measured values for hydroxyl coverage. Our thermochemical data, i.e., 3.7-5.2 OH nm(-2) in standard conditions and 1.4-2.6 OH nm(-2) at P = 10( 10) atm and T = 800 K, agree with the experimental values for amorphous silica and explain the trends observed, although some topological differences obviously exist between our periodic models and amorphous silica surfaces. PMID- 20953477 TI - Analyses of interfacial resistances in a membrane-electrode assembly for a proton exchange membrane fuel cell using symmetrical impedance spectroscopy. AB - Interfacial resistances between the polymer electrolyte membrane (PEM) and catalyst layer (CL) in membrane-electrode assemblies (MEAs) have yet to be systematically examined in spite of its great importance on the fuel cell performance. In order to investigate ionic transport through the PEM/CL interface, the symmetrical impedance mode (SIM) was employed in which the same type of gas was injected (H(2)/H(2)). In this study, the ionic transport resistance at the interface was controlled by the additionally sprayed outer ionomer on the surface of each CL. Effectiveness of the outer ionomer on ionic transport at the interface was quantitatively explained by the reduced contact, proton hydration, and charge transport resistances in the SIM. To characterize the ionic transport resistance, the concept of total resistance (R(tot)) in the SIM was introduced, representing the overall ohmic loss due to proton transport in an MEA. This concept was successfully supported via an agreement of the interpretation and the linear correlation that was obtained between the admittance (1/R(tot)) and the performance of a fuel cell in the ohmic loss region. This correlation will enable researchers to predict the performance of a fuel cell under the influence of proton transport by examining the R(tot) in the SIM. PMID- 20953478 TI - Synthetic training sets for the development of discriminant functions for the detection of volatile organic compounds from passive infrared remote sensing data. AB - A novel synthetic data generation methodology is described for use in the development of pattern recognition classifiers that are employed for the automated detection of volatile organic compounds (VOCs) during infrared remote sensing measurements. The approach used is passive Fourier transform infrared spectrometry implemented in a downward-looking mode on an aircraft platform. A key issue in developing this methodology in practice is the need for example data that can be used to train the classifiers. To replace the time-consuming and costly collection of training data in the field, this work implements a strategy for taking laboratory analyte spectra and superimposing them on background spectra collected from the air. The resulting synthetic spectra can be used to train the classifiers. This methodology is tested by developing classifiers for ethanol and methanol, two prevalent VOCs in wide industrial use. The classifiers are successfully tested with data collected from the aircraft during controlled releases of ethanol and during a methanol release from an industrial facility. For both ethanol and methanol, missed detections in the aircraft data are in the range of 4 to 5%, with false positive detections ranging from 0.1 to 0.3%. PMID- 20953479 TI - Cleavage specificities of the brother and sister proteases Lys-C and Lys-N. AB - Understanding of protease specificity is essential in proteomics strategies to correctly compare peptide fragmentation spectra with spectra predicted from data extracted from sequence databases. Here we evaluate the specificities of two proteolytic enzymes Lys-C and Lys-N, which cleave peptide-bonds at, respectively, the C- and N-terminal side of a lysine residue. PMID- 20953480 TI - Metal-catalysed cleavage of carbon-carbon bonds. AB - Reactions cleaving carbon-carbon bonds with the assistance of transition metals as the catalyst have provided various molecular transformations that are otherwise difficult to execute, opening a scenic avenue along organic synthesis. Construction of structural motifs like medium-sized carbocycles and chiral quaternary carbon centres have been set within an access of such paradoxical approaches in the past decade. PMID- 20953481 TI - Cationic diiron and diruthenium MU-allenyl complexes: synthesis, X-ray structures and cyclization reactions with ethyldiazoacetate/amine affording unprecedented butenolide- and furaniminium-substituted bridging carbene ligands. AB - The novel cationic diiron MU-allenyl complexes [Fe(2)Cp(2)(CO)(2)(MU-CO){MU eta(1):eta(2)(alpha,beta)-C(alpha)(H)=C(beta)=C(gamma)(R)(2)}](+) (R = Me, 4a; R = Ph, 4b) have been obtained in good yields by a two-step reaction starting from [Fe(2)Cp(2)(CO)(4)]. The solid state structures of [4a][CF(3)SO(3)] and of the diruthenium analogues [Ru(2)Cp(2)(CO)(2)(MU-CO){MU-eta(1):eta(2)(alpha,beta) C(alpha)(H)=C(beta)=C(gamma)(R)(2)}][BPh(4)] (R = Me, [2a][BPh(4)]; R = Ph, [2c][BPh(4)]) have been ascertained by X-ray diffraction studies. The reactions of 2c and 4a with Bronsted bases result in formation of the MU-allenylidene compound [Ru(2)Cp(2)(CO)(2)(MU-CO){MU-eta(1):eta(1) C(alpha)=C(beta)=C(gamma)(Ph)(2)}] (5) and of the dimetallacyclopentenone [Fe(2)Cp(2)(CO)(MU-CO){MU-eta(1):eta(3) C(alpha)(H)=C(beta)(C(gamma)(Me)CH(2))C(=O)}] (6), respectively. The nitrile adducts [Ru(2)Cp(2)(CO)(NCMe)(MU-CO){MU-eta(1):eta(2) C(alpha)(H)=C(beta)=C(gamma)(R)(2)}](+) (R = Me, 7a; R = Ph, 7b), prepared by treatment of 2a,c with MeCN/Me(3)NO, react with N(2)CHCO(2)Et/NEt(3) at room temperature, affording the butenolide-substituted carbene complexes [Ru(2)Cp(2)(CO)(MU-CO){MU-eta(1):eta(3)-C(alpha)(H)[upper bond 1 start]C(beta)C(gamma)(R)(2)OC(=O)C[upper bond 1 end](H)] (R = Me, 10a; R = Ph, 10b). The intermediate cationic compound [Ru(2)Cp(2)(CO)(MU-CO){MU-eta(1):eta(3) C(alpha)(H)[upper bond 1 start]C(beta)C(gamma)(Me)(2)OC(OEt)C[upper bond 1 end](H)](+) (9) has been detected in the course of the reaction leading to 10a. The addition of N(2)CHCO(2)Et/NHEt(2) to 7a gives the 2-furaniminium-carbene [Ru(2)Cp(2)(CO)(MU-CO){MU-eta(1):eta(3)-C(alpha)(H)[upper bond 1 start]C(beta)C(gamma)(Me)(2)OC(OEt)C[upper bond 1 end](H)](+) (11). The X-ray structures of 10a, 10b and [11][BF(4)] have been determined. The reactions of 4a,b with MeCN/Me(3)NO result in prevalent decomposition to mononuclear iron species. PMID- 20953482 TI - Mg(OOCCH(3))(2) as an electrolyte additive for quasi-solid dye-sensitized solar cells: with the purpose of enhancing both the photovoltage and photocurrent by modifying the TiO(2)/dye/electrolyte interfaces. AB - The interface modification effect within quasi-solid dye-sensitized solar cells and the photovoltaic performance were investigated after the introduction of Mg(OOCCH(3))(2) as an additive into a polymer gel electrolyte. Electrochemical impedance spectroscopy showed that the addition of Mg(OOCCH(3))(2) into the polymer gel electrolyte can efficiently retard charge recombination at the TiO(2)/electrolyte interface. Mg(OOCCH(3))(2) in the electrolyte can also contribute to the enhancement of the incident photon-to-electron conversion efficiency by modifying the dye molecules. This results in an improvement in the photovoltage and photocurrent due to a barrier layer at the TiO(2)/electrolyte interface and the promotion of charge injection at the dye/TiO(2) interface, respectively. Photovoltaic measurements reveal that a conversion efficiency enhancement from 4.05% to 4.96% under 100 mW cm(-2) is obtained after the amount of Mg(OOCCH(3))(2) added was optimized. PMID- 20953483 TI - 'Dispersible electrodes': a solution to slow response times of sensitive sensors. AB - Herein, we introduce the concept of utilizing conductive gold-coated magnetic nanoparticles as 'dispersible electrodes', which serve as the active element in the selective capture and direct electro-analytical quantification of analytes. This concept reduces response times and decreases detection limits by bringing the sensor to the analyte rather than the conventional paradigm of the analyte finding the sensor. PMID- 20953484 TI - Mild and efficient CO-mediated eliminative deoxygenation of epoxides catalyzed by supported gold nanoparticles. AB - Supported gold nanoparticles (NPs), which are well-known epoxidation catalysts, were found to be exceptionally active for the selective deoxygenation of epoxides into alkenes using cheap and easily accessible CO and H(2)O as the reductant. PMID- 20953485 TI - Taking multicalixarenes into the nanoworld: first third-generation calixarene dendrimer. AB - We report the first synthesis of a dendritic multicalixarene, featuring twenty one calixarene units, which when adsorbed onto mica, forms regular assemblies which can then further aggregate to form larger clusters. PMID- 20953486 TI - Direct use of allylic alcohols in the allylation of sulfonylimidates. AB - We have developed catalytic allylation reactions of sulfonylimidates using allylic alcohols as allylating reagents. Stoichiometric amounts of neither activators nor bases are required in this reaction. PMID- 20953488 TI - Self-crosslinked alkaline polymer electrolyte exceptionally stable at 90 degrees C. AB - We report a specially designed alkaline polymer electrolyte (APE) with extraordinary stability in both physical and chemical properties, which enables applications of fuel cells and electrolysis at elevated temperatures. PMID- 20953487 TI - Synthesis of coesite nanocrystals from ethane bridged periodic mesoporous organosilica at low temperature and extreme pressure. AB - Coesite nanocrystals have been synthesized from periodic mesoporous organosilica (PMO) with (CH(2))(2) bridges heated at 300 degrees C for 150 min and 12 GPa. The crystals are not sintered, single crystalline, and have diameters of ca. 100 300 nm. Below 300 degrees C, an amorphous non-porous organosilica glass was obtained. Heating above 300 degrees C at 12 GPa results in the rapid crystal growth and micron size coesite crystals were formed. PMID- 20953489 TI - Combinatorial discovery of new methanol-tolerant non-noble metal cathode electrocatalysts for direct methanol fuel cells. AB - Combinatorial synthesis and screening were used to identify methanol-tolerant non platinum cathode electrocatalysts for use in direct methanol fuel cells (DMFCs). Oxygen reduction consumes protons at the surface of DMFC cathode catalysts. In combinatorial screening, this pH change allows one to differentiate active catalysts using fluorescent acid-base indicators. Combinatorial libraries of carbon-supported catalyst compositions containing Ru, Mo, W, Sn, and Se were screened. Ternary and quaternary compositions containing Ru, Sn, Mo, Se were more active than the "standard" Alonso-Vante catalyst, Ru(3)Mo(0.08)Se(2), when tested in liquid-feed DMFCs. Physical characterization of the most active catalysts by powder X-ray diffraction, gas adsorption, and X-ray photoelectron spectroscopy revealed that the predominant crystalline phase was hexagonal close-packed (hcp) ruthenium, and showed a surface mostly covered with oxide. The best new catalyst, Ru(7.0)Sn(1.0)Se(1.0), was significantly more active than Ru(3)Se(2)Mo(0.08), even though the latter contained smaller particles. PMID- 20953490 TI - An arrayed high-content chemotaxis assay for patient diagnosis. AB - Chemotaxis assays are essential tools for the study of gradient sensing and directed cell migration, and have the potential to aid in the diagnosis and characterization of patients with immune disorders. Current methods are limited in their ability to meet the more demanding requirements for clinical applications. Because patient samples have a short lifespan and sometimes a limited volume (e.g. pediatrics), the operational requirements for an efficient chemotaxis assay are increased in the clinical setting. Here we describe a microscale assay platform for gradient generation that overcomes these limitations. Passive fluidic methods are leveraged to provide a reliable microfluidic gradient generation device, operable in only three pipetting steps. In addition, arrayed imaging and advanced cell tracking algorithms enabled a 50 fold increase in throughput over current methods. These methods were employed to aid in the diagnostic evaluation of an infant who presented with severe, recurrent bacterial infections. Analysis of the infant's neutrophils revealed impaired cell polarization and chemotaxis in a gradient of the chemoattractant fMLP. The patient was subsequently diagnosed with an inhibitory mutation in the Rho GTPase, Rac2. The approach also enabled a microenvironmental screen of human primary neutrophil chemotaxis on fibronectin, fibrinogen and laminin with results suggesting that fibronectin, although commonly used, may not be the most appropriate matrix protein for chemotaxis assays. Together, these findings demonstrate the use of arrayed micro-devices to aid in the diagnosis of a primary immunodeficiency disorder, and illustrate the capability for increased throughput microenvironmental studies and screening targeted to specific human diseases. PMID- 20953491 TI - Synthesis of substituted 8-aminoquinolines and phenanthrolines through a Povarov approach. AB - The synthesis of 8-aminoquinolines and 1,10-phenanthrolines with substituents in alpha of the nitrogen has been performed through an inverse-demanding aza-Diels Alder (Povarov reaction) in the fluoroalcohols TFE or HFIP. This path involves simple starting materials: 1,2-phenylenediamines, enol ethers and aldehydes. PMID- 20953492 TI - N-heterocyclic carbene-catalyzed tandem aza-benzoin/Michael reactions: on site reversal of the reactivity of N-Boc imines. AB - A tandem NHC-catalyzed aza-benzoin/Michael reaction has been developed as a method to efficiently produce dihydroindenones and pyrrolidinone-containing tricycles. The novel reaction pattern involves tert-butyl aryl(tosyl)methylcarbamates reacting as both electrophile and nucleophile on the same carbon. PMID- 20953493 TI - Synthesis of a new hydrophilic poly(ethylene glycol)-ionic liquid and its application in peptide synthesis. AB - The synthesis of a new hydrophilic ammonium-based poly(ethylene glycol)-ionic liquid (PEG-IL) is reported; the structure was assigned by NMR ((1)H, (13)C) and MALDI mass spectrometry. The viscosity and thermal stability were also studied, as well as its polarity. Its application as an alternative solvent in the synthesis of dipeptides under microwave irradiation is also described. PMID- 20953494 TI - Commercially activated carbon as the source for producing multicolor photoluminescent carbon dots by chemical oxidation. AB - Using commercially activated carbon, we developed a simple and effective direct chemical oxidation route to prepare good biocompatible multicolor photoluminescent carbon dots. PMID- 20953495 TI - DFT characterization of the reaction pathways for terminal- to MU-hydride isomerisation in synthetic models of the [FeFe]-hydrogenase active site. AB - The mechanism of terminal- to MU-hydride isomerisation in models of synthetic complexes resembling the [FeFe]-hydrogenase active site has been elucidated by DFT calculations, revealing that Ray-Dutt reaction pathways are generally favoured, and providing some clues for the rational design of novel synthetic catalysts to produce H(2). PMID- 20953496 TI - Tetrasubstituted furans by Pd(II)/Cu(I)-cocatalyzed three-component domino reactions of 2-(1-alkynyl)-2-alken-1-ones, nucleophiles and diaryliodonium salts. AB - A novel Pd(OAc)(2)/CuI-cocatalyzed three-component reaction of 2-(1-alkynyl)-2 alken-1-ones, nucleophiles and diaryliodonium salts has been developed. The procedure allows the synthesis of tetrasubstituted furans in good to high yields under mild conditions. PMID- 20953497 TI - Microcrystalline sodium tungsten bronze nanowire bundles as efficient visible light-responsive photocatalysts. AB - Microcrystalline sodium tungsten bronze nanowire bundles were obtained via a facile hydrothermal synthesis, and were applied in water purification as visible light-driven photocatalysts for the first time. PMID- 20953498 TI - Evolution of self-diffusion and local structure in some amines over a wide temperature range at high pressures: a molecular dynamics simulation study. AB - Self-diffusion and structural properties of ammonia, methylamine and trimethylamine have been studied by molecular dynamics simulation in the temperature range between the melting pressure curve and 700 K at pressures up to 400 MPa. The calculation results agree well with the experiment, which suggests that one can use the simulation method as a powerful tool to obtain self diffusion coefficients over wide range of temperatures and pressures, under which it is rather difficult for experiments. The local structures of such fluids are investigated by calculating radial distribution functions (RDFs), the numbers of hydrogen bonds and coordination numbers. The correlation between self-diffusion and structural properties, and the influence of temperature and pressure on them are discussed. The simulation results demonstrate that the temperature effects are more pronounced than the pressure effects on self-diffusion and structural properties, and the effect of hydrogen bonding on the translational dynamics in any of these systems is a minor factor, while it is mainly affected by the close packing of amine molecules. PMID- 20953499 TI - Validity of time-dependent trial states for the Holstein polaron. AB - Validity of three time-dependent trial states of the Holstein Hamiltonian, namely the D(2), Merrifield and D Ansatze has been examined in detail with regards to their deviations from the exact solution to the time-dependent Schrodinger equation. Linear absorption spectra are also calculated as an additional indicator of the Ansatz validity. It is found that the D Ansatz is the most accurate trial state of the three, and all Ansatze fail to provide an adequate description of system dynamics in the weak-coupling regime. PMID- 20953500 TI - Structure-based identification of MHC binding peptides: Benchmarking of prediction accuracy. AB - Identification of MHC binding peptides is essential for understanding the molecular mechanism of immune response. However, most of the prediction methods use motifs/profiles derived from experimental peptide binding data for specific MHC alleles, thus limiting their applicability only to those alleles for which such data is available. In this work we have developed a structure-based method which does not require experimental peptide binding data for training. Our method models MHC-peptide complexes using crystal structures of 170 MHC-peptide complexes and evaluates the binding energies using two well known residue based statistical pair potentials, namely Betancourt-Thirumalai (BT) and Miyazawa Jernigan (MJ) matrices. Extensive benchmarking of prediction accuracy on a data set of 1654 epitopes from class I and class II alleles available in the SYFPEITHI database indicate that BT pair-potential can predict more than 60% of the known binders in case of 14 MHC alleles with AUC values for ROC curves ranging from 0.6 to 0.9. Similar benchmarking on 29,522 class I and class II MHC binding peptides with known IC(50) values in the IEDB database showed AUC values higher than 0.6 for 10 class I alleles and 9 class II alleles in predictions involving classification of a peptide to be binder or non-binder. Comparison with recently available benchmarking studies indicated that, the prediction accuracy of our method for many of the class I and class II MHC alleles was comparable to the sequence based methods, even if it does not use any experimental data for training. It is also encouraging to note that the ranks of true binding peptides could further be improved, when high scoring peptides obtained from pair potential were re-ranked using all atom forcefield and MM/PBSA method. PMID- 20953501 TI - Production of recombinant isotopically labelled peptide by fusion to an insoluble partner protein: generation of integrin alphavbeta6 binding peptides for NMR. AB - The integrin alphavbeta6 is up-regulated in several cancers and has clinical potential for both tumour imaging and therapy. Peptide ligands have been developed which show good binding specificity for alphavbeta6 and provide an opportunity to study the interaction in more detail by NMR. Such studies ideally require (15)N and (13)C labelled peptides, and recombinant expression within E. coli provides a cost effective way of generating isotopically labelled proteins and peptides. In this study we have used an insoluble fusion partner (ketosteroid isomerase) to produce high yields of recombinant peptide. The insoluble nature of the fusion allowed simple product recovery by cell lysis and centrifugation, and thorough washing of the insoluble pellet to remove contaminating proteins avoided the need for nickel-affinity chromatography in denaturing conditions which is the standard procedure. The protocol described here is convenient to scale-up and requires only one chromatography step (reverse-phase HPLC) which is comparable to solid-phase synthesis. PMID- 20953502 TI - Multi-enzyme logic network architectures for assessing injuries: digital processing of biomarkers. AB - A multi-enzyme biocatalytic cascade processing simultaneously five biomarkers characteristic of traumatic brain injury (TBI) and soft tissue injury (STI) was developed. The system operates as a digital biosensor based on concerted function of 8 Boolean AND logic gates, resulting in the decision about the physiological conditions based on the logic analysis of complex patterns of the biomarkers. The system represents the first example of a multi-step/multi-enzyme biosensor with the built-in logic for the analysis of complex combinations of biochemical inputs. The approach is based on recent advances in enzyme-based biocomputing systems and the present paper demonstrates the potential applicability of biocomputing for developing novel digital biosensor networks. PMID- 20953503 TI - Ultrasensitive nucleic acid detection using confocal laser scanning microscope with high crystalline silver dendrites. AB - A new kind of silver micro-dendrites with no surfactants protected has been synthesized for the separation and detection of DNA merely by earth gravity as the density of silver is larger than that of water. Through this approach, the DNA of human T-lymphotropic virus type I (HTLV-I) can be detected down to 10 pM with the detection range from 10 pM to 100 nM. PMID- 20953504 TI - Visible spectrum of titanium dioxide. AB - The electronic spectrum in the region 17 500 cm(-1) to 18 850 cm(-1) of a cold molecular beam of TiO(2) has been investigated using laser induced fluorescence (LIF) and mass-resolved resonance enhanced multi-photoionization (REMPI) spectroscopy. Bands at 18 412 cm(-1), 18 470 cm(-1) and 18 655 cm(-1) were recorded at a resolution of 35 MHz, rotationally analyzed, and assigned as the A(1)B(2) (0,1,2) <-X[combining tilde](1)A(1) (0,0,0), A(1)B(2) (1,0,0) < X[combining tilde](1)A(1) (0,0,0) and A(1)B(2) (1,1,0) <-X[combining tilde](1)A(1) (0,0,0) transitions. The dispersed fluorescence from the A(1)B(2) (0,1,2) and A(1)B(2) (1,0,0) levels were combined with previous results to produce an improved set of vibrational parameters for the X[combining tilde](1)A(1) state. The optical Stark effect in the A(1)B(2) (0,1,2) < X[combining tilde](1)A(1) (0,0,0) and A(1)B(2) (1,0,0) <-X[combining tilde](1)A(1) (0,0,0) bands were recorded and combined with earlier results for A(1)B(2) (1,1,0) <-X[combining tilde](1)A(1) (0,0,0) to determine the permanent electric dipole moment for these states. The origin and harmonic vibrational constants for the A(1)B(2) state are determined to be: T(000) = 17 593(5) cm(-1), omega(1) = 876(3) cm(-1), omega(2) = 184(1) cm(-1), and omega(3) = 316(2) cm(-1). A normal coordinate analysis was performed and Franck-Condon factors calculated. PMID- 20953505 TI - Fluorescence micro(spectro)scopy as a tool to study catalytic materials in action. AB - Following its widespread use in biomedical research, fluorescence microscopy has recently been introduced in the catalysis field to study chemocatalytic processes with a high spatiotemporal resolution, a unique sensitivity down to the single molecule level and this under in situ conditions. This tutorial review is structured around the length scales that are currently accessible in fluorescence microscopy and discusses the different conceptual approaches that have been developed to study molecular concentration and dynamics like diffusion and catalytic conversion at these micron and sub-micron levels. PMID- 20953506 TI - Network based analysis of hepatitis C virus core and NS4B protein interactions. AB - Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide. Here we attempt to further our understanding of the biological context of protein interactions in HCV pathogenesis, by investigating interactions between HCV proteins Core and NS4B and human host proteins. Using the yeast two-hybrid (Y2H) membrane protein system, eleven human host proteins interacting with Core and 45 interacting with NS4B were identified, most of which are novel. These interactions were used to infer overall protein interaction maps linking the viral proteins with components of the host cellular networks. Core and NS4B proteins contribute to highly compact interaction networks that may enable the virus to respond rapidly to host physiological responses to HCV infection. Analysis of the interaction networks highlighted enriched biological pathways likely influenced in HCV infection. Inspection of individual interactions offered further insights into the possible mechanisms that permit HCV to evade the host immune response and appropriate host metabolic machinery. Follow-up cellular assays with cell lines infected with HCV genotype 1b and 2a strains validated Core interacting proteins ENO1 and SLC25A5 and host protein PXN as novel regulators of HCV replication and viral production. ENO1 siRNA knockdown was found to inhibit HCV replication in both the HCV genotypes and viral RNA release in genotype 2a. PXN siRNA inhibition was observed to inhibit replication specifically in genotype 1b but not in genotype 2a, while SLC25A5 siRNA facilitated a minor increase in the viral RNA release in genotype 2a. Thus, our analysis can provide potential targets for more effective anti-HCV therapeutic intervention. PMID- 20953507 TI - High isoelectric point sub-proteome analysis of Acinetobacter radioresistens S13 reveals envelope stress responses induced by aromatic compounds. AB - In the present study, the high isoelectric point sub-proteome of Acinetobacter radioresistens S13 grown on aromatic compounds (benzoate or phenol) was analyzed and compared to the protein pattern, in the same pI range, of acetate-grown bacteria (control condition). Analyses concerned both soluble and membrane enriched proteomes and led to the identification of 25 proteins that were differentially expressed among the growth conditions considered: most of them were up-regulated in cells grown on aromatic compounds. Up to 17 identified proteins can be, more or less directly, related to the so called "envelope stress responses": these signal transduction pathways are activated when bacterial cells are exposed to stressing environments (e.g., heat, pH stress, organic solvents, osmotic stress) causing accumulation of misfolded/unfolded cell wall proteins into the periplasmic space. For, at least, five of these proteins (a DegP-like serine protease, a peptidyl-prolyl cis-trans isomerase, a phosphatidylserine decarboxylase, a pseudouridine synthase, and a TolB-like protein) a direct induction via either the sigma(E) or the Cpx alternative signalling systems mediating envelope stress responses was previously demonstrated in Gram-negative bacteria. The proteins identified in this study include periplasmic proteases, chaperones, enzymes catalyzing peptydoglycan biogenesis, proteins involved in outer membrane integrity, cell surface properties and cellular redox homeostasis. The present study brings additional information to previous works on the acidic proteome of A. radioresistens S13, thus complementing and refining the metabolic picture of this bacterial strain during growth on aromatic compounds. PMID- 20953508 TI - Self-assembled monolayer based impedimetric platform for food borne mycotoxin detection. AB - A self-assembled monolayer (SAM) of 11-amino-1-undecanethiol (AUT) has been fabricated onto a gold (Au) substrate to co-immobilize anti-ochratoxin-A antibodies (AO-IgGs) and bovine serum albumin (BSA) to detect food borne mycotoxin [i.e., ochratoxin-A (OTA)]. AUT/Au electrode, AO-IgGs/AUT/Au immunoelectrode and BSA/IgGs/AUT/Au immunoelectrode have been characterized using scanning electron microscopy (SEM) and electrochemical studies such as cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). Electrochemical studies reveal that the AUT-SAM with NH2 groups provide favorable conditions to immobilize AO-IgGs with better orientation, resulting in enhanced electron transport to obtain improved sensing characteristics. The EIS response studies of the BSA/AO-IgGs/AUT/Au immunoelectrode obtained as a function of OTA concentration reveal that the value of the charge transfer resistance (RCT) increases with increased OTA concentration. The BSA/AO-IgGs/AUT/Au immunoelectrode exhibits linearity over 0.5 6.0 ng/dl, detection limit of 0.08 ng/dl using 3sigmab/m criteria, response time of 30 s and sensitivity of ~36.83 Omega/ng dl(-1) cm(-2) with a regression coefficient of 0.999. Attempts have been made to monitor the change in RCT of BSA/AO-IgGs/AUT/Au immunoelectrode on addition of coffee samples. PMID- 20953509 TI - Tuning the packing density of host molecular self-assemblies at the solid-liquid interface using guest molecule. AB - The use of THB molecules as a guest template tunes the formation of a two dimensional honeycomb network in preference to alternative close packed structures of TECDB self-assembled on HOPG surface at the solid-liquid interface. PMID- 20953510 TI - The origin of the conformational preference of N,N'-diaryl-N,N'-dimethyl ureas. AB - Poly aromatic ureas and poly aromatic amides are important classes of foldamers oligomers with well defined conformations. We have explored the origins of the conformational preference of some N,N'-diaryl-N,N'-dimethyl ureas by a combination of NMR spectroscopy and electronic structure calculations using both a recently developed density functional (M06-2X) and a DFT approach (DFT-D) having empirical corrections for dispersive interactions. We have validated the DFT-D approach for structures of this type using high level wavefunction calculations, (CCSD(T)), of the unsubstituted N,N'-diphenyl-N,N'-dimethyl urea. For the N,N'-diaryl-N,N'-dimethyl ureas we have identified a number of 'endo' conformers (i.e. having an E,E geometrical conformation about the two urea C-N bonds), both pi- and tert-butyl-stacked, as well as 'exo' structures (having a Z geometrical conformation about at least one of the C-N bonds), and have computed the relative energies of these conformers as well as the barriers for their interconversion. We find that the relative energies of the 'endo' structures closely follow the relative values of the dispersive interactions. The calculations have allowed us to associate different conformers with the various peaks in the NMR spectra, which point to relatively small differences in energy between the conformers. Somewhat larger energy differences are predicted by the two computational approaches, with the M06-2X functional performing the better of the two. It is suggested that the continuum model employed may not be sufficiently accurate to reflect the solvation of the various conformers. PMID- 20953511 TI - FTIR microspectroscopy of melanocytic skin lesions: a preliminary study. AB - Fourier transform infrared (FTIR) microspectroscopy has been employed to investigate benign (ordinary dermal and Reed nevi), dysplastic and malignant (invasive melanoma) skin lesions through the analysis of spectral changes of melanocytes as well as in the evaluation of the presence of melanin. Hierarchical cluster analysis and principal component analysis led to a satisfactory separation of malignant from dysplastic and normal melanocytes. Also, on enlarging the clustering with spectra from Reed and dermal nevi, the multivariate analysis segregated well the spectral data into discrete clusters, allowing the obtaining of reliable average spectra for analysis at the molecular level of the main groups or components responsible for the biological and biochemical changes. The most significant spectral characteristics appear to be related to differences in secondary protein structures, in nucleic acid conformation, in intra- and intermolecular bonding. In all cases, supervised and unsupervised spectral analyses resulted in satisfactory agreement with histopathological findings. PMID- 20953512 TI - Vibrational spectroscopy differentiates between multipotent and pluripotent stem cells. AB - Over the last few years, there has been an increased interest in the study of stem cells in biomedicine for therapeutic use and as a source for healing diseased or injured organs/tissues. More recently, vibrational spectroscopy has been applied to study stem cell differentiation. In this study, we have used both synchrotron based FTIR and Raman microspectroscopies to assess possible differences between human pluripotent (embryonic) and multipotent (adult mesenchymal) stem cells, and how O(2) concentration in cell culture could affect the spectral signatures of these cells. Our work shows that infrared spectroscopy of embryonic (pluripotent) and adult mesenchymal (multipotent) stem cells have different spectral signatures based on the amount of lipids in their cytoplasm (confirmed with cytological staining). Furthermore, O(2) concentration in cell culture causes changes in both the FTIR and Raman spectra of embryonic stem cells. These results show that embryonic stem cells might be more sensitive to O(2) concentration when compared to mesenchymal stem cells. While vibrational spectroscopy could therefore be of potential use in identifying different populations of stem cells further work is required to better understand these differences. PMID- 20953513 TI - Noninvasive biochemical monitoring of physiological stress by Fourier transform infrared saliva spectroscopy. AB - Physical stress affects the immune system, activates the sympathetic (SNS) and parasympathetic (PNS) subsystems of autonomic nervous system (ANS), and increases the activity of the hypothalamic-pituitary-adrenal axis (HPA). The specific response of the major regulatory systems depends on the human functional state. Saliva is a unique diagnostic fluid, the composition of which immediately reflects the SNS, PNS, HPA and immune system response to stress. A new method of saliva biomarker determination by Attenuated Total Reflection Fourier-Transform Infrared (ATR FTIR) spectroscopy has been developed to monitor the exercise induced metabolic changes in saliva from male endurance athletes. The method has been tested using a group of professional athletes by analysing saliva samples collected before and after the exercise, and the saliva composition monitoring by ATR FTIR spectroscopy was shown to be suitable for real-time checking of response to stress. PMID- 20953514 TI - Application of the UV-C photo-assisted peroxymonosulfate oxidation for the mineralization of dimethyl phthalate in aqueous solutions. AB - In this study, the degradation of dimethyl phthalate (DMP), taken as model compound for phthalate esters, by the photo-assisted peroxymonosulfate (PMS) process was investigated. The high oxidation potential of hydroxyl and sulfate radicals generated by the activation of PMS under UV-C light irradiation was used to completely oxidize aqueous DMP solutions. Experiments were conducted at varying initial pH values (3.0, 6.0, and 9.0) and PMS concentrations (0-60 mM) to evaluate the effect of different reaction conditions on DMP treatment performance with the PMS/UV-C process. It was observed that lowering the initial reaction pH slightly improved the degradation rate of DMP. On the contrary, TOC abatements were slightly enhanced with increasing initial reaction pH. An adequate (optimum) PMS concentration of 40 mM resulted in the fastest and highest DMP degradation rates and efficiencies, respectively. At an initial concentration of 100 mg L( 1), more than 95% DMP removal was obtained after only 20 min under PMS/UV-C treatment conditions. For the proposed adequate PMS concentration (40 mM) the lowest electrical energy per order (EE/O) value was calculated as 2.9 kW h m(-3) order(-1). PMID- 20953515 TI - Intensification of gas-phase photoxidative dehydrogenation of ethanol to acetaldehyde by using phosphors as light carriers. AB - In this work a significant improvement of VO(x)/TiO(2) photocatalytic activity in the selective partial oxidation of ethanol to acetaldehyde was achieved by the simultaneous irradiation with light emitting phosphorescent particles and UVA LEDs as external light source. Photocatalytic tests were carried out in a gas solid photocatalytic fluidized bed reactor at high illumination efficiency, in which the bed is constituted by VO(x)/TiO(2) photocatalyst at nominal V(2)O(5) content of 5 wt% and suitable selected phosphors, diluted with glass spheres. In this way, phosphors were fluidized together with the catalyst, excited by external UVA-LEDs, emitting their stored energy in close proximity to the catalyst. In the absence of phosphors the ethanol consumption rate initially grows linearly with initial alcohol concentration, then bends towards an asymptotic value for initial ethanol concentration higher than 0.5 vol%. By contrast, when phosphors are present, the ethanol consumption rate increased linearly in the overall range. In all cases acetaldehyde was the main product detected in gas phase with a selectivity of about 97%, ethylene and carbon dioxide the by-products. The results evidenced that the presence of phosphors allowed improved photon transfer, increasing the apparent quantum yield from 2 to 30% together with a high photoreactivity. PMID- 20953516 TI - Label-free molecular imaging of immunological synapses between dendritic and T cells by Raman micro-spectroscopy. AB - Confocal Raman micro-spectroscopy (CRMS) was used to measure spectral images of immunological synapse formation between dendritic and T cells without using molecular labels or other invasive procedures. The purpose-built inverted CRMS instrument integrated an environmental enclosure and a near-infrared laser to allow measurements on live cells maintained under physiological conditions. The integration of the wide-field fluorescence also enabled viability assays and direct comparison between Raman spectral images and gold-standard immuno fluorescence images for specific molecules. Raman spectral images of nucleus and proteins were built by fuzzy c-mean clustering method. The Raman images were found to be in good correspondence with the immuno-fluorescence images of DNA and actin. These results indicate that actin is a main contributor to the Raman spectrum of the cytoplasm of dendritic and T cells. While for control cells the Raman spectral images of proteins indicated a more homogeneous distribution of proteins in the cytoplasm of dendritic cells, they indicated a higher accumulation of proteins at the immunological synapses when dendritic cells were pre-treated with laminin. These conclusions were also supported by confocal immuno-fluorescence imaging after cell fixation and labelling. This study demonstrates the potential of CRMS for label-free non-invasive imaging of junctions between live cells. Therefore, this technique may become a useful tool for studying cellular processes in live cells and where non-invasive molecular specific imaging is desirable, such as cell-cell interactions. PMID- 20953517 TI - Mechanisms in aminocatalysis. AB - The mechanisms of the alpha-, beta- and gamma-functionalisations of aldehydes and alpha,beta-unsaturated aldehydes by secondary amines are presented and discussed. PMID- 20953518 TI - Tetradentate selenium ligand as a building block for homodinuclear complexes of Pd(II) and Ru(II) having seven membered rings or bis-pincer coordination mode: high catalytic activity of Pd-complexes for Heck reaction. AB - 1,2,4,5-Tetrakis(phenyselenomethyl)benzene (L) has been synthesized by reaction of in situ generated PhSe(-) with 1,2,4,5-tetrakis(bromomethyl)benzene in N(2) atmosphere. Its first bimetallic complexes and a bis-pincer complex having compositions [(eta(3)-C(3)H(5))(2)Pd(2)(L)][ClO(4)](2) (1) [Pd(2)(C(5)H(5)N)(2)(L)][BF(4)](2) (2) and [(eta(6) C(6)H(6))(2)Ru(2)(L)Cl(2)][PF(6)](2) (3) have been synthesized by reacting L with [Pd(eta(3)-C(3)H(5))Cl](2), [Pd(CH(3)CN)(4)][BF(4)](2) and [(eta(6) C(6)H(6))(2)RuCl(2)](2) respectively. The structures of ligand L and its all three complexes have been determined by X-ray crystallography. In 1 and 3, ligand L forms with two organometallic species seven membered chelate rings whereas in 2 it ligates in a bis-pincer coordination mode. The geometry around Pd in 1 or 2 is close to square planar whereas in 3, Ru has pseudo-octahedral half sandwich "Piano-Stool" geometry. The Pd-Se bond distances are in the ranges 2.4004(9) 2.4627(14) A and follow the order 1 > 2, whereas Ru-Se bond lengths are between 2.4945(16) and 2.5157(17) A. The 1 and 2 have been found efficient catalysts for Heck reaction of aryl halides with styrene and methyl acrylate. The 2 is superior to 1. The TON and TOF values (per Pd) are up to ~47500 and ~2639 h(-1) respectively. PMID- 20953519 TI - Synthesis, characterization and photovoltaic applications of a low band gap polymer based on s-tetrazine and dithienosilole. AB - A new copolymer of dithienosilole (DTS) and dithienyl-s-tetrazine (TTz), PDTSTTz, has been designed and synthesized. This solution processable polymer shows a low band gap, strong absorption and good thermal stability. Solar cells from the blend of this polymer with PC(71)BM showed power conversion efficiency (PCE) up to 4.2%. PMID- 20953520 TI - A tetranuclear cobalt(II) chain with slow magnetization relaxation. AB - A solvothermally derived tetranuclear cobalt(II) complex, [Co(4)(phen)(4)Cl(8)] (phen = phenanthroline), featuring a zig-zag backbone of {Co(MU(2)-Cl)(2)Co} planes, exhibits ferromagnetic exchange and slow relaxation of the magnetization and represents the first Co SMM with a linear core structure. PMID- 20953522 TI - West is West, East is East. The divide in science. PMID- 20953521 TI - Dalton Discussion 12: Catalytic C-H and C-X bond activation (DD12). PMID- 20953523 TI - An investigation on lung tissue damage and morphological changes in newborns of pregnant rats exposed to methidathion. Protective effects of caffeic acid phenethyl ester. AB - OBJECTIVE: To investigate histopathological changes in the lungs and morphological changes of newborn rats whose mothers are exposed to methidathion (MD) during their pregnancy, and also the effects of caffeic acid phenethyl ester (CAPE) on these changes. METHODS: The study was conducted in the Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey between May and June 2007. Fifty female Wistar albino rats were randomly divided into 5 groups, as follows: Group I (n=10): control group, Group II (n=10): 5mg/kg/day MD treated group in the first 7 days of pregnancy, Group III (n=10): 5 mg/kg/day MD + 10 umol/kg/day CAPE treated group in the first 7 days of pregnancy, Group IV (n=10): 5mg/kg/day MD treated group in the last 7 days of pregnancy, and Group V (n=10): 5 mg/kg/day MD + 10 umol/kg/day CAPE treated group in the last 7 days of pregnancy. The MD was administrated by oral gavage in corn oil, and the CAPE was administrated intraperitoneally. RESULTS: Tremors, agitation, and spasm of extremities were observed in pregnant rats after administration of MD. Histopathological examination of lung tissues revealed peribronchial inflammation, alveolar and bronchoalveolar hemorrhage, intraparenchymal vascular congestion and thrombosis, alveolar destruction, and intraparenchymal infiltration. CONCLUSION: Methidathion causes low weight gain and deaths among pregnant rats, increases intrauterine fetus deaths, causes low birth weights in the newborns, and histopathological changes in the lung tissues of newborn rats. The CAPE has an ameliorating effect on these histopathological alterations. PMID- 20953524 TI - Tumor necrosis factor rs361525 (-238G>A) polymorphism contributes to hepatocellular carcinoma susceptibility. AB - OBJECTIVE: To assess the effect of the common polymorphisms of the tumor necrosis factor (TNF)-238G>A with hepatocellular carcinoma (HCC) risks. METHODS: The study design was cross-sectional, and carried out in Zhongshan Hospital Fudan University, Shanghai, China from December 2009 to May 2010. A comprehensive search was conducted to identify all studies on the association of TNF rs361525 ( 238G>A) polymorphism with HCC risk. The fixed or random effect pooled measure was selected based on homogeneity testing among studies. Heterogeneity among studies was evaluated using Q test and I2. Publication bias was estimated using a modified Egger's linear regression test. RESULTS: This current analysis including 708 HCC and 1,349 controls on TNF rs361525 (-238G>A) showed a significantly increased risk of HCC in different genetic models (heterozygote comparison: odds ratio [OR]=1.70, 95% confidence interval [CI]: 1.21-2.39, P heterogeneity=0.292; dominant model comparison: OR=1.68, 95% CI: 1.20-2.35, P heterogeneity=0.270; complete overdominant model comparison: OR=1.62, 95% CI: 1.16-2.28. P heterogeneity=0.391; and allele comparison: OR=1.62, 95% CI: 1.18-2.23, P heterogeneity=0.253). Neither heterogeneity nor publication bias was detected when analyses were performed on all 4 models. CONCLUSION: This meta-analysis supports TNF rs361525 (-238G>A) polymorphism being associated with HCC in an Asian population. PMID- 20953525 TI - Role of saffron (Crocus sativus L.) and honey syrup on aluminum-induced hepatotoxicity. AB - OBJECTIVE: To study the biochemical and molecular hepatotoxicity induced by aluminium chloride (AlCl3) and the protective role of saffron and honey against such toxicity. METHODS: This study was performed in the Department of Biology, College of Science, King Khalid University, Abha, Kingdom of Saudi Arabia between July and August 2009. Two mice strains, BALB/c and C57BL/6 (20 animals from each strain), were used and randomly divided into 4 groups: control group; AlCl3 group; AlCl3+saffron group; and AlCl3+honey group. Changes in liver biochemical markers such as gamma-glutamyl transpeptidase (GGT), alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin and lipid peroxidation levels were estimated. Induced and suppressed mRNA in the liver homogenate was scanned followed by up- and down- regulated genes were isolated, cloned, and sequenced. RESULTS: There was a significant increase in the cholesterol levels, triglycerides, GGT, ALT, AST, ALP, lipid peroxidation, and presence of hyperglycemia in the AlCl3 group compared to the control. However, treating those animals exposed to AlCl3 by saffron and honey improved the disrupted liver biochemical markers and alleviated the increase of lipid peroxidation. Seven down-regulated genes (3 BALB/c and 4 C57BL/6) and 5 up regulated genes (2 BALB/c and 3 C57BL/6) were observed. Aa2-245 gene was observed as being up-regulated in AlCl3+ saffron and AlCl3+honey groups in the BALB/c strain. CONCLUSION: The use of saffron and honey minimized the toxic effect of AlCl3 in the liver by alleviating its disruptive effect on the biochemical and molecular levels. PMID- 20953526 TI - Antioxidant and hepatoprotective effects of extract of ginkgo biloba in rats of non-alcoholic steatohepatitis. AB - OBJECTIVE: To evaluate the therapeutic effect and mechanism of extract of ginkgo biloba (EGB) in treatment of diet-induced non-alcoholic steatohepatitis (NASH) in rats. METHODS: The experiment was conducted in the Laboratory, Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China from June 2009 to December 2009. In this study, the rat model of NASH was produced by feeding high-fat diet. Sixty rats were randomly divided into 3 groups: Normal group: normal diet, drinking water; Model group: high-fat diet, single-distilled water 10 ml/kg gavage once a day for 12 weeks; and Treated group: high-fat diet, EGB 6 mg/kg gavage once a day for 12 weeks. At the end of 12 weeks, all rats were killed. The serum biochemical, fibrosis markers, superoxide dismutase (SOD), malondialdehyde (MDA), the pathological changes, and the expression levels of nuclear factor KB (NF-κB)p65 protein in the liver were observed. RESULTS: The contents of serum alanine transaminase aspartate aminotransferase, fibrosis markers, and pathological grading of liver fibrosis and the staining intensity of NF-κBp65 protein in the liver of rats in treated group were significantly lower than those in the model group. Activities of superoxide dismutase were elevated, but levels of malondialdehyde were decreased in the treated group as compared with the model group. CONCLUSION: Extract of ginkgo biloba has antioxidant and hepatoprotective effects and can inhibit liver fibrosis in rat of NAHS. PMID- 20953527 TI - Assessment of the relationship of vitamin D with serum antioxidant vitamins E and A and their deficiencies in Iranian pregnant women. AB - OBJECTIVE: To assess the relationship between vitamin D and serum antioxidant vitamins E and A, and their deficiencies in pregnant women. METHODS: This cross sectional study was carried out in the maternity clinic of Naghavi Specialists and Subspecialities Polyclinic, affiliated to Kashan University of Medical Sciences Kashan, Iran between April 2008 and August 2009. One hundred and forty seven pregnant women were recruited. Vitamin D, A, and E status were assessed using serum at 5-9 months of pregnancy. The prevalence of vitamin deficiency was reported using defined cutoff values. Correlations between vitamin D and vitamins A and E were reported. Data were compared using the analysis of variance and coefficient correlation linear Pearson's. The relative difference between the groups were considered statistically significant (p<0.05). RESULTS: Serum concentrations of vitamin D were 7.2 +/- 2.31, 17.72 +/- 5 and 33.05 +/- 0.94 ug/ml, for vitamin E 2.15 +/- 1.3 and 8.07+/- 2.3 ug/ml, and for vitamin A 0.16+/ 0.05 and 0.46+/-0.13. We used the defined cutoff values in determining vitamins D, A, and E deficiency. The prevalence of vitamin D deficiency was 95.8%, vitamin A was 7%, and vitamin E was 58.6%. The correlation coefficient between serum vitamin D and vitamin E shows an inverse relationship (r=0.24, p=0.004). CONCLUSION: Extent vitamins D, A, and E deficiency among pregnant women is a major public health problem in Kashan, Iran. PMID- 20953528 TI - A comparison of sevoflurane induction versus propofol induction for laryngeal mask airway insertion in elderly patients. AB - OBJECTIVE: To compare 8% or 5% sevoflurane and propofol induction according to the ease of laryngeal mask airway (LMA) placement and hemodynamic effects in elderly patients. METHODS: Ninety unpremedicated American Society of Anesthesiologists (ASA) I-III male patients >65 years, undergoing day case urological surgical intervention under general anesthesia at the Numune Education and Research Hospital, Ankara, Turkey between October 2008 to May 2009 were studied. The patients were group into 3 and were administered intravenous (intravenous) 5 ug/kg alfentanil before induction. Patients in group propofol (P) (n=29), anesthesia was induced 1.5 mg/kg propofol intravenous; in Group 8 (n=28) and Group 5 (n=28) anesthesia was induced with 8% and 5% sevoflurane in 60% nitrous oxide, and 40% oxygen with tidal-volume-breath (TVB). RESULTS: Induction times were as follows: in Group P = 54.76 +/- 12.29 sec; Group 8 = 69.93 +/- 18.76 sec, and in Group 5 = 92.14 +/- 27.68 sec (p<0.01). Apnea duration was longer in Group P (6.55 +/- 4.07 min.) than in group 8 (1.73 +/- 2.49 min), and group 5 (1.12 +/- 1.12 min) (p<0.01). The decrease in mean arterial pressure (MAP) before alfentanil (control) and after induction was significantly different between the groups. CONCLUSION: In elderly patients who will be administered day case anesthesia, in the placement of LMA, 5 ug/kg alfentanil followed by 5% sevoflurane induction by TVB method with minimal hemodynamic changes could be an alternative to propofol induction. PMID- 20953529 TI - Biomechanical effects of the Coflex implantation on the lumbar spine. A nonlinear finite element analysis. AB - OBJECTIVE: To evaluate the effect of the stabilization of the Coflex device on the biomechanical behavior of the instrumented and adjacent spinal segments. METHODS: The study was carried out at the Department of Orthopedics, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai, China between September 2009 and May 2010. Upon validation, a finite element model of L3-S1 segment was developed to simulate and analyze the biomechanics of the intact and Coflex implanted states subjected to simulate loading of flexion, extension, lateral bending, and axial rotation. RESULTS: This study predicted that the segmental motion, intradiscal pressure, and facet contact force at the levels adjacent to the Coflex implanted level were not significantly affected by the implantation of Coflex device. There was a significant decrease in range of motion in extension at the instrumented level of the Coflex implanted model relative to the intact model. Furthermore, the level implanted with Coflex device showed a significant decrease in intradiscal pressure in extension and a decrease in facet contact force in extended, lateral bending and axial rotational conditions, compared with the intact model. CONCLUSION: This study suggests that the Coflex device has the potential of effectively unloading the disc in extension and the facet joints in extension, lateral bending, and axial rotation at the Coflex implanted level, without deleterious effects on the adjacent segments under the simulated physiological condition. PMID- 20953530 TI - Tubeless percutaneous nephrolithotomy with double-J stent compared with external ureteral catheter to decrease postoperative complications. AB - OBJECTIVE: To compare the efficacy of tubeless percutaneous nephrolithotomy (PCNL) using double-J stent and tubeless PCNL with external ureteral catheter in decreasing post-PCNL complications. METHODS: This prospective randomized comparative study includes 148 cases with kidney stones. They were operated by either tubeless PCNL with double-J stent (Group 1) or tubeless with ureteric catheter (Group 2). Group 1 consists of 72 cases (54 males and 18 females). Group 2 consists of 76 patients (56 males and 20 females). Both groups were compared from the point of post-PCNL complications without using tissue sealants or tract cauterization. The study was carried out in the Department of Urology, Al-Thawrah Modern General and Ibn-Seena Hospital, Sana'a, Yemen between January 2008 and January 2010. RESULTS: In Group 1, the post-PCNL complications were leakage of urine in 4 (5.6%), hematuria >48 hours in 6 (8.3%), fever in 2 (2.8%), and the length of hospital stay was 36-48 hours. In Group 2, the post-PCNL complications were leakage of urine in 13 (17.1%), hematuria in 9 (11.8%), 5 (6.6%) has fever, colonic injury in one, and fluid collections in 8 (10.5%). There was significant difference in urine leakage (p=0.028). CONCLUSION: Tubeless PCNL with double-J stent was the best method to decrease the complications and length of hospital stay. PMID- 20953531 TI - Phacoemulsification in high myopia. AB - OBJECTIVE: To analyze the visual results of phacoemulsification in highly myopic eyes, to investigate the risk factors for poor postoperative visual acuity and to assess postoperative complications. METHODS: This retrospective study reviewed the records of 209 eyes of 150 patients with high myopia who underwent phacoemulsification and foldable intraocular lens (IOL) implantation between January 1998 and July 2008 at Beyoglu Education and Research Eye Hospital, Istanbul, Turkey. RESULTS: Postoperative best-corrected visual acuity (BCVA) was 0.5 or better in 63.2% of eyes. One hundred forty-seven (70.3%) eyes were within +/-1.0 diopter (D) of the intended target refraction. In multiple regressions, only pre-existing myopic chorioretinal macular degeneration was found to be associated with poor BCVA (p=0.000). Nor patient age nor axial length (AL) had any correlation with postoperative BCVA. Retinal detachment (RD) occurred in one eye (0.5%) during mean follow-up (18.7+/-8.9 months). CONCLUSION: Most of the eyes with high myopia achieved satisfactory improvement in BCVA with few complications. Myopic retinal degenerative changes were the single independent factor limiting visual potential. Our lower incidence of postoperative RD could be attributed partially to our lower neodymium:yttrium-aluminum-garnet (Nd:YAG) laser capsulotomy rates and our surgical modification involving the implementation of primary posterior capsulorhexis in all patients younger than 40. PMID- 20953532 TI - Association between glucose variability and adverse in-hospital outcomes for Chinese patients with acute coronary syndrome. AB - OBJECTIVE: To investigate the association between mean blood glucose (MBG) and glucose variability (GV) during hospitalization, and adverse in-hospital outcomes for patients with acute coronary syndrome (ACS). METHODS: This is a retrospective cohort study and conducted in 2 tertiary hospitals in Beijing, China. All data were collected from the medical records concerning ACS patients admitted to the hospital between January 2003 to December 2006. Hyperglycemia was related to clinical outcomes (including major adverse cardiovascular events [MACEs] and in hospital death) using coefficient of variation of blood glucose (GluCV) or mean blood glucose (MBG). Total cohort was stratified by GluCV or MBG quartiles. Diabetic and non-diabetic subgroups were then separately analyzed. Multivariate logistic regression analysis was performed to evaluate the independent risk factor of in-hospital death. RESULTS: A total of 1756 cases were enrolled in this study. For total cohort or non-diabetic cohort, prevalence of adverse outcomes was higher in patients with higher MBG or GluCV (p for trend <0.001). For diabetic ACS patients, MACEs were found more common in MBG or GluCV quartiles (p for trend <0.001), in-hospital mortality increased across MBG (p for trend <0.001), or GluCV quartiles (p for trend=0.004). Multivariate logistic regression analysis showed that GluCV (odds ratio: 1.29) was a stronger predictor of in hospital death than MBG (odds ratios: 1.20). CONCLUSION: The GluCV is a better discriminator of in-hospital mortality than MBG in ACS patients. PMID- 20953533 TI - Pathogens of spontaneous bacterial peritonitis change in northern China. AB - OBJECTIVE: To determine the identity of microorganisms isolated from patients diagnosed with spontaneous bacterial peritonitis (SBP). METHODS: We reviewed cases diagnosed with SBP over a 14-year period. The medical records of 780 SBP diagnosed patients with decompensated cirrhosis and ascites admitted to Tangdu Hospital, Xian, Shaanxi Province, China were retrospectively reviewed between January 1996 and December 2009. The patients were placed into 2 groups, and the clinical data were compared between the 2 groups. Ascitic fluid was collected from these patients and cultured for bacteria using the MicroScan WalkAway 40 system. RESULTS: There was a significant difference in the ratio of pathogens between group A (48 patients, from January 1996 to December 2002) and group B (50 patients, from January 2003 to December 2009) (chi2=9.630, p=0.002). The SBP patients with gram-positive bacteria needed significantly more antibiotics within 30 days compared to those with gram-negative bacteria (chi2=12.285, p=0.000). CONCLUSION: In recent years, the types of isolated pathogens have significantly changed in northern China. Such changes have also been observed in other countries and have been attributed to long-term antibiotic therapy and invasive procedures. Changes in the epidemiology of pathogens that cause SBP must be monitored for optimal treatment. PMID- 20953534 TI - Flu vaccine among health workers in Qatar. AB - OBJECTIVE: To assessed the coverage rate of influenza vaccination among Health Care Workers at Hamad Medical Corporation in 2006 vaccination campaign and also assessed the reasons for non-vaccination in among physicians and nurses. METHODS: This is an observational study conducted in Hamad Medical Corporation, Doha, Qatar between April 2007 and August 2007. The 2006 vaccination campaign records were analyzed to determine the influenza vaccination coverage rate among all staff in 6 independent facilities. We used a self-administrative questionnaire to assess the reasons for not getting the influenza vaccine among a random sample of non-vaccinated physicians and nurses. RESULTS: Approximately 19.4% of all staff were vaccinated and there were statistically significant differences between the type of health care facilities among physicians and nurses group. Approximately 58% of the random sample of 1261 physicians and nurses returned the questionnaire. The most frequently cited reasons for non-vaccination were lack of time to get immunized (16.5%) and concerns on vaccine side effects (13.6%). CONCLUSION: Influenza vaccination coverage of health care workers is low and variable depending on type of health care setting, therefore, it is essential to identify the reasons for low vaccination rate in different health care facility in which assists the guidance to improve the coverage rates for the following years. PMID- 20953535 TI - Mood problems of mothers with disabled children in Saudi Arabia. A preliminary prospective study. AB - OBJECTIVE: To explore the presence and the degree of mood problems in mothers with disabled children. METHODS: We conducted a prospective study during the period of November 2009 to February 2010, in 75 mothers (study group) with physical, mental or sensory disabled children admitted at Sultan Bin Abdul-Aziz Humanitarian City, Riyadh, Saudi Arabia and 35 mothers (control group) with healthy children. The Hospital Anxiety and Depression Scale was used to measure the mood symptoms of mothers. The demographic data of mothers were also collected. RESULTS: The mean age of the children with disability was 4.8+/-3.3 and healthy children 5.3 +/- 2.3 (range 1-14) years. The mean age of mothers in the study group (n=75) was 32.3+/-7.9 and the control group was 39.9+/-7.9 years. Compared to control, mothers of disabled children scored significantly higher anxiety (4.9+/-1.9, 8.7+/-3.1, p=0.027), depression (5.4+/-2.8, 7.7+/-3.2, p=0.032), and total Hospital Anxiety and Depression Scale (HADS) (9.8+/-3.8, 16.4 +/- 5.5, p=0.022). Compared to mothers of male disabled children anxiety, depression and the HADS scored higher in mothers of female disabled children, however, these differences were not significantly significant. There was no significant differences among mothers of children with physical, sensory or mental disability on total HADS. CONCLUSION: Mothers of disabled children in Saudi Arabia showed higher scores of anxiety, depression, and total HADS. PMID- 20953536 TI - Congenital esophageal stenosis and antral web. A new association and management challenge. AB - Congenital esophageal stenosis is a rare condition that may be associated with other anomalies. Antral web is also a rare congenital condition. Association of both conditions is extremely rare. We present this rare association in preterm baby in whom initially misdiagnosis of esophageal atresia and trachea-esophageal fistula then followed by a dilemma in differentials diagnosis to explain the uneventful postoperative recovery. The aim of this report is to highlight the diagnostic and therapeutic difficulty of this rare condition. PMID- 20953537 TI - Rickets and dysmorphic findings in a child with abetalipoproteinemia. AB - Abetalipoproteinemia (ABL) is characterized by acanthocytosis, hypocholesterolemia, and steatorrhea. Here, we describe a case of ABL associated with rickets and dysmorphic findings and the subsequent therapeutic course in an 18-month-old male referred for evaluation for failure to thrive and chronic fatty diarrhea. Examination revealed a pale child, dysmorphic face, and signs of rickets. Laboratory examination revealed low hemoglobin (3.7 gm/dl), low albumin (28 gm/L), low cholesterol and triglyceride levels. The blood smear showed acanthocytes while the small bowel histology showed the enterocytes were distended with lipid droplets. He was diagnosed with ABL and treated with fat soluble vitamins (ADEK), and hydrolyzed protein formula containing medium chain triglycerides. Three months later, his fatty diarrhea becomes normal stool, his serum fat-soluble vitamins normalized, and his weight increased from 4.1 kg to 5.9 kg. PMID- 20953538 TI - A comparative analysis of length of stay of traumatic and non-traumatic brain injured patients in Saudi Arabia. PMID- 20953539 TI - Pregnancy outcome in women with inflammatory bowel disease. PMID- 20953540 TI - Enchondromas in the small bones of the hand. PMID- 20953541 TI - Hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient male newborns in Al-Ahsa, Saudi Arabia. PMID- 20953542 TI - Inflammatory bowel disease in Western Saudi Arabia. PMID- 20953543 TI - Management of type 2 diabetes. Current practice in Saudi Arabia. PMID- 20953544 TI - Regional disparity in prevalence of malnutrition in Saudi children. PMID- 20953545 TI - The importance of HIV antenatal screening programs for pregnant women. PMID- 20953546 TI - The use of sweat chloride test for screening cystic fibrosis among malnourished children suffering from frequent respiratory infections. PMID- 20953547 TI - Levels of platinum group metals in selected species (Sarotherodon melanotheron, Chonophorus lateristriga, Macrobrachium vollenhovenii and Crassostrea tulipa) in some estuaries and lagoons along the coast of Ghana. AB - The use of some biota as bioindicators of heavy metal pollution has been demonstrated as particularly adequate due to their capacity of bioconcentration. This study evaluated the levels of platinum group metals (PGMs) in some selected species along the coastal belt of Ghana, using the neutron activation analysis (NAA) method. The result was processed to evaluate pollution indices in order to map the distribution of the metals in those species in the lagoons and estuaries along the costal belt of Ghana. The analysis showed significant levels of all PGMs in blackchin tilapia (Sarotherodon melanotheron Cichlidae), brown goby (Chonophorus lateristriga Gobiidae), shrimp (Macrobrachium vollenhovenii Palaemonidae), and mangrove oysters (Crassostrea tulipa Ostreidae) in the lagoons and river Pra estuary. However, the oysters showed an elevated mean concentration of 0.13 MUg/g (dry weight) Pd. From the pollution indices, most of the sampling sites registered mean contamination factor (CF) values between 1.20 and 3.00 for Pt, Pd, and Rh. The pollution load index (PLI) conducted also gave an average pollution index between 0.79 and 2.37, indicating progressive contamination levels. The results revealed that anthropogenic sources, industrial and hospital effluent, etc., together with vehicular emissions, could be the contributing factors to the deposition of PGMs along the Ghanaian coast. PMID- 20953548 TI - Accumulation of soil carbon and phosphorus contents of a rehabilitated forest. AB - The world's tropical rainforests are decreasing at an alarming rate as they are converted to agricultural land, pasture, and plantations. Decreasing tropical forests affect global warming. As a result, afforestation progams have been suggested to mitigate this problem. The objective of this study was to determine the carbon and phosphorus accumulation of a rehabilitated forest of different ages. The size of the study area was 47.5 ha. Soil samples were collected from the 0-, 6-, 12-, and 17-year-old rehabilitated forest. Twenty samples were taken randomly with a soil auger at depths of 0-20 and 20-40 cm. The procedures outlined in the Materials and Methods section were used to analyze the soil samples for pH, total C, organic matter, total P, C/P ratio, yield of humic acid (HA), and cation exchange capacity (CEC). The soil pH decreased significantly with increasing age of forest rehabilitation regardless of depth. Age did not affect CEC of the rehabilitated forest. Soil organic matter (SOM), total C, and total P contents increased with age. However, C/P ratio decreased with time at 0 20 cm. Accumulation of HA with time and soil depth was not consistent. The rehabilitated forest has shown signs of being a C and P sink. PMID- 20953549 TI - Rare cause for sudden right heart failure. AB - Right heart failure occurs daily in clinical settings, but an underlying cardiac malignant tumor is very uncommon. We report a case of a 48-year-old man presenting only with palpitations and decompensated heart failure. Echocardiographic imaging revealed a large tumor of the right ventricle. Shortly after a putatively successful surgical approach, the patient was admitted again with heart failure symptoms. On reassessment, a complete relapse with multiple metastases could be seen. Generally, cardiac malignant tumors are diagnosed at a time-point when therapeutic options are very limited or even postmortem. Broad echocardiographic screening in patients with unspecific symptoms might be helpful to detect cardiac malignant tumors at early stages. PMID- 20953550 TI - High origin of radial arteries: a report of two rare cases. AB - Variations in the arterial supply of the upper limb are relatively common, with reported prevalence rates ranging from 11 to 24.4%. Of these, the most commonly encountered variation in the arm is a high origin of the radial artery. However, after consecutively dissecting and examining 600 Singaporean Chinese cadavers (1,200 upper limbs), we found only two cases of this. In both cases, the brachioradial artery originated from the upper one-third of the brachial artery and continued distally as the radial artery in the forearm. The local prevalence of 0.33% of this variation is significantly lower compared against populations from other geographical regions. Although rare, recognition of the variation is of fundamental importance to clinical practice. PMID- 20953551 TI - Design and generation of MLPA probe sets for combined copy number and small mutation analysis of human genes: EGFR as an example. AB - Multiplex ligation-dependent probe amplification (MLPA) is a multiplex copy number analysis method that is routinely used to identify large mutations in many clinical and research labs. One of the most important drawbacks of the standard MLPA setup is a complicated, and therefore expensive, procedure of generating long MLPA probes. This drawback substantially limits the applicability of MLPA to those genomic regions for which ready-to-use commercial kits are available. Here we present a simple protocol for designing MLPA probe sets that are composed entirely of short oligonucleotide half-probes generated through chemical synthesis. As an example, we present the design and generation of an MLPA assay for parallel copy number and small-mutation analysis of the EGFR gene. PMID- 20953552 TI - A lesson in survival, by Giardia lamblia. AB - In the relationships between host and parasites, there is a cross-talk that involves diverse mechanisms developed by two different genetic systems during years of evolution. On the one hand, immunocompetent hosts have developed effective innate and acquired immune responses that are used to restrict or avoid parasitism. On the other hand, parasites evade the immune response, expressing different antigens on their surface or by using other specific mechanisms, such as nutrient depletion. In this review, we analyze the survival mechanisms used by the protozoan parasite Giardia lamblia during infection. In particular, we examine the multiple roles played by the enzyme arginine deiminase during colonization of the gut, also involving the parasite's mechanism of antigenic variation. Potential drug targets for the treatment of giardiasis are also discussed. PMID- 20953553 TI - Zebrin II expressing Purkinje cell phenotype-related and -unrelated cerebellar abnormalities in Cav2.1 mutant, rolling mouse Nagoya. AB - Rolling mouse Nagoya is an ataxic mutant mouse that carries a mutation in a gene encoding for the alpha 1A subunit of the voltage-gated P/Q-type Ca2+ channel (Cav2.1). This report summarizes our studies and others concerning cerebellar abnormalities in rolling mice based on chemical neuroanatomy. While there are no obvious cerebellar deformations in this mutant mouse, the altered functions of Purkinje cells can be revealed as a reduced expression of type 1 ryanodine receptor (RyR1) in all Purkinje cells uniformly throughout the cerebellum, and as an ectopic expression of tyrosine hydroxylase (TH) in the Purkinje cell subsets with the zebrin II-immunopositive phenotype. As the mutated Cav2.1 channel is expressed at uniform levels in all Purkinje cells, its copresence with RyR1 staining suggests that a Cav2.1 channel dysfunction links with the expression of RyR1 in Purkinje cells of rolling mice. However, an ectopic expression of TH in the Purkinje cells is topologically related to the projection of corticotrophin releasing factor-immunopositive climbing fibers rather than expression of the mutated Cav2.1 channel. On the other hand, increased levels of serotonin (5-HT) in 5-HTergic fibers were revealed immunohistochemically in Purkinje cells of the vermis of rolling cerebellum. Thus, to determine whether or not cerebellar abnormalities are related to Purkinje cell populations revealed by zebrin II expression is essential for enhancing our understanding of the pathogenesis of hereditary cerebellar ataxic mutants such as rolling mice. PMID- 20953554 TI - Multifunctional receptor stabilin-1 in homeostasis and disease. AB - The multifunctional scavenger receptor stabilin-1 (STAB1, FEEL-1, CLEVER-1, KIAA0246) is expressed on tissue macrophages and sinusoidal endothelial cells in healthy organisms, and its expression on both macrophages and different subtypes of endothelial cells is induced during chronic inflammation and tumor progression. Stabilin-1 is a type-1 transmembrane receptor that mediates endocytic and phagocytic clearance of "unwanted-self" components, intracellular sorting of the endogenously synthesized chitinase-like protein SI-CLP, and transcytosis of the growth hormone family member placental lactogen. The central sorting station for stabilin-1 trafficking seems to be the trans-Golgi network (TGN). Transport of stabilin-1 in the TGN requires interaction with GGA adaptors that bind to the classical DDSLL motif and a novel acidic cluster in its cytoplasmic tail. Degradation of stabilin-1 seems to depend on the interaction with sorting nexin 17. However, the mechanisms keeping stabilin-1 on the cell surface remain to be identified. This issue deserves specific attention due to the growing amount of data indicating that function of stabilin-1 in cell adhesion events is essential for inflammation and metastasis. Taking into consideration the complexity of stabilin-1-mediated processes, investigation of stabilin-1 functions in the animal models, as well as mathematic modeling of intracellular trafficking and extracellular contact, would enable prediction of stabilin-1 behavior in complex biological systems and would open perspectives for therapeutic targeting of stabilin-1 pathways in chronic inflammation and carcinogenesis. PMID- 20953555 TI - Cell secretion: current structural and biochemical insights. AB - Essential physiological functions in eukaryotic cells, such as release of hormones and digestive enzymes, neurotransmission, and intercellular signaling, are all achieved by cell secretion. In regulated (calcium-dependent) secretion, membrane-bound secretory vesicles dock and transiently fuse with specialized, permanent, plasma membrane structures, called porosomes or fusion pores. Porosomes are supramolecular, cup-shaped lipoprotein structures at the cell plasma membrane that mediate and control the release of vesicle cargo to the outside of the cell. The sizes of porosomes range from 150 nm in diameter in acinar cells of the exocrine pancreas to 12 nm in neurons. In recent years, significant progress has been made in our understanding of the porosome and the cellular activities required for cell secretion, such as membrane fusion and swelling of secretory vesicles. The discovery of the porosome complex and the molecular mechanism of cell secretion are summarized in this article. PMID- 20953556 TI - New antibody conjugates in cancer therapy. AB - Targeting of radiation, drugs, and protein toxins to cancers selectively with monoclonal antibodies (MAbs) has been a topic of considerable interest and an area of continued development. Radioimmunotherapy (RAIT) of lymphoma using directly labeled MAbs is of current interest after approval of two radiolabeled anti-CD20 MAbs, as illustrated with the near 100% overall response rate obtained in a recent clinical trial using an investigational radiolabeled anti-CD22 MAb, 90Y-epratuzumab. The advantage of pretargeted RAIT over directly labeled MAbs is continuing to be validated in preclinical models of lymphoma and solid tumors. Importantly, the advantages of combining RAIT with radiation sensitizers, with immunotherapy, or a drug conjugate targeting a different antigen are being studied clinically and preclinically. The area of drug-conjugated antibodies is progressing with encouraging data published for the trastuzumab-DM1 conjugate in a phase I clinical trial in HER2-positive breast cancer. The Dock-and-Lock platform technology has contributed to the design and the evaluation of complex antibody-cytokine and antibody-toxin conjugates. This review describes the advances made in these areas, with illustrations taken from advances made in the authors' institutions. PMID- 20953557 TI - miR-126 and miR-126*: new players in cancer. AB - Cancer progression is characterized by autarky in growth signals, insensitivity to growth-restrictive signals, evasion of apoptosis, a limitless potential to replicate, sustained angiogenesis, and tissue invasion, including metastasis. The regulation of these cellular processes relies on a fine-tuned control of molecular signal cascades. In recent years, short noncoding RNAs termed microRNAs (miRNAs) have been described as a novel class of molecular regulators. These affect various signaling cascades during the progression of neoplastic diseases by the regulation of gene expression on the post-transcriptional level. The novel endothelial cell-derived secreted protein epidermal growth factor-like domain 7 (EGFL7) has been suggested to control vascular tubulogenesis. Further, the two biologically active miRNAs miR-126 and its complement miR-126*, which are encoded by intron 7 of the egfl7 gene, have been described to mediate vascular functions. Knock-out studies in zebrafish and mice suggested a major role of miR-126 in angiogenesis and vascular integrity, which was mediated by the repression of inhibitors of VEGF-induced proliferation in endothelial cells. Recent studies revealed the distribution and function of miR-126 and miR-126* in various types of cancer, and assigned a role to both miRNAs as suppressors of tumor formation. Indeed, miR-126 and miR-126* have been reported to impair cancer progression through signaling pathways that control tumor cell proliferation, migration, invasion, and survival. Conversely, miR-126 and miR-126* may have a supportive role in the progression of cancer as well, which might be mediated by the promotion of blood vessel growth and inflammation. In this work, we will summarize the current knowledge on functions of miR-126/miR-126* that are relevant for cancer formation, and we will discuss their potential clinical use as predictive markers of survival and application as novel therapeutic targets for the treatment of neoplastic diseases. PMID- 20953558 TI - A comparative study of surgical morbidity associated with mandibular third-molar surgery in young and aging populations. AB - AIM: Prophylactic surgical extraction of impacted third molars is a common practice throughout the world justified on the presumption that the risk of surgical morbidity increases with increasing age, among other reasons. The aim of this study was to analyze and compare surgical morbidity associated with third molar extractions in young and aging populations. METHODS AND MATERIALS: A review of records for all patients who underwent the surgical extraction of impacted third molars between April 2001 and June 2006 at the Lagos University Teaching Hospital was carried out. RESULTS: A total of 506 patients had surgical extractions of impacted third molars under local anaesthesia during the period of the study. Of these, 470 (92.9 percent) patients were below the age of 40 years (Group A) and 36 (7.1 percent) patients were 40 years of age and older (Group B). No incidences of severe intraoperative complications (excessive bleeding or mandibular fractures) were recorded in either group, but other postoperative complications were reported in 70 (13.8 percent) patients. Of these 70 patients, 65 (92.9 percent) were from Group A and 5 (7.1 percent) were from Group B, and their complications included infected socket, dry socket, paraesthesia, and buccal space abscess. CONCLUSION: No significant difference in post-operative complications following surgical removal of mandibular third molars was found between patients 40 years old and greater and those below age 40. Prophylactic surgical extraction of impacted mandibular third molars, based on the assumption that surgical morbidity increases with age, may not be justifiable. CLINICAL SIGNIFICANCE: Age does not predispose patients who had surgical extraction of mandibular third molars above 40 years of age to any additional surgical complications when compared to patients below the age of 40 years receiving comparable treatment. PMID- 20953559 TI - Management of aphthous ulceration with topical quercetin: a randomized clinical trial. AB - AIM: Recurrent aphthous ulceration is the most commonly known oral mucosal disease. Quercetin is a useful therapeutic agent for the treatment of colitis and gastric ulcer. The objective of this study was to determine the effect of topical application of quercetin in the treatment of minor aphthous ulcers. METHODS AND MATERIALS: Forty male patients with no known pathology of the oral mucosa other than minor aphthous ulcers were enrolled in this study. Patients were randomly divided into two groups, each consisting of 20 patients. Group 1 (control group) patients used a benzydamine hydrochloride mouthwash three times daily. Group 2 patients placed two to three dabs of quercetin three times daily directly on their ulcers. Clinical evaluation of patients included assessment of ulcer size, pain measure, and interviews regarding the topical application of quercetin in terms of consistency, taste, local tolerability, and ease of application. RESULTS: The topical application of quercetin cream to minor mouth ulcers relieved pain and produced complete healing in seven of the Group 2 patients (35 percent) in 2-4 days, 18 patients (90 percent) in 4-7 days, and 20 patients (100 percent) in 7-10 days. When comparing the mean ulcer size after 10 days, lesions in the Group 2 patients were smaller than those in Group 1, and the size difference between the two groups was significantly different (p<0.004). Also, 90 percent of patients responded that they appreciated the ease of application when using the topical quercetin, and they did not object to its consistency or taste. CONCLUSION: Quercetin is a safe, well-tolerated, and highly effective promising new, adjunctive treatment for healing common aphthous ulcers. CLINICAL SIGNIFICANCE: Although aphthous ulcers typically resolve on their own in one to two weeks, the daily topical application of quercetin may be useful in accelerating the healing process of minor aphthous ulcers. PMID- 20953560 TI - Are flowable resin-based composites a reliable material for metal orthodontic bracket bonding? AB - AIM: To compare the tensile bond strength (TBS) and adhesive remnant index (ARI) of three flowable resin-based composites and three orthodontic adhesive systems for metal bracket bonding. METHODS AND MATERIALS: Sixty bovine incisors were randomly divided into six groups. Enamel surfaces were etched with 37 percent phosphoric acid for 30 seconds and stainless steel orthodontic brackets were bonded using either flowable resin-based composites (3M Flow, FL; Tetric Flow, TF; and Wave, WA) or orthodontic bonding systems (Transbond XT, TX; Concise Orthodontic, CO; Fill Magic Ortodontico, FM). All specimens were thermal cycled and stored in distilled water at 37 degrees C for 24 hours, after which they were subsequently tested for TBS using a universal testing machine. ARI scores were determined after the failure of brackets. TBS and ARI data were submitted to ANOVA, Tukey, and Kruskal-Wallis tests (p=0.05), respectively. RESULTS: Rankings of the resin-based composites based on TBS means (MPa) were TX (6.4 +/- 2.1), followed by CO (4.5 +/- 2.7), FM (3.7 +/- 1.2), FL (3.6 +/- 1.2), TF (3.3 +/- 1.2), and WA (2.4 +/- 0.6). CO exhibited the lowest ARI mean score (0.9 +/- 1.2) which was significantly different from the other five materials: TX (2.8 +/- 0.42), FM (2.8 +/- 0.42), FL (2.9 +/- 0.32), TF (2.9 +/- 0.32), and WA (3.0 +/- 0.01). However, there were no statistically significant differences among the other groups with mean scores of 2.8-3.0. A score of 3.0 indicated that all the resin remained bonded to the tooth surface. CONCLUSION: The flowable resin-based composites tested (Fl, TF, and WA) used to bond metal orthodontic brackets to bovine enamel had low mean TBS values but acceptable ARI mean scores. CLINICAL SIGNIFICANCE: Flowable composites may not be appropriate for bracket bonding, unless the teeth to be bonded are not subjected to higher orthodontic stresses, such as those without an antagonist. PMID- 20953561 TI - Oral hygiene status among orthodontic patients. AB - AIM: The aim of this study was to evaluate the oral hygiene status of patients with fixed orthodontic appliances. METHODS AND MATERIALS: The following indices were used to evaluate the oral hygiene status of patients in orthodontic treatment: gingival bleeding index (GBI), plaque index (PI), and ortho-plaque index (OPI). A self-administrated questionnaire was prepared covering oral hygiene practice, oral hygiene cleaning aids, and number of visits to a dental hygienist. RESULTS: Fifty patients (15-30 years old) were selected for the study from among the orthodontic patients treated at the King Saud University College of Dentistry, Riyadh, Saudi Arabia. Results showed that the PI and OPI were high with mean scores of 65.24 (SD 16.43) and 53.56 (SD 8.74) respectively, while the average GBI was a much lower value at 19.14 (SD 7.95). No significant difference was observed between male and female patients for the PI (p=0.925) and for the OPI (p=0.072), but a significant difference was observed for the GBI at the 5 percent significance level (p=0.033). The result of OPI showed that 20 (40 percent) of the patients had fair oral hygiene, whereas 30 (60 percent) had poor oral hygiene. Only 16 (32 percent) of the participants reported visiting the dental hygienist during their orthodontic treatment, while the remaining 34 (68 percent) did not. CONCLUSIONS: The oral home care of the orthodontic patients surveyed was not at an optimal level, which indicated the need to establish an oral hygiene maintenance program. CLINICAL SIGNIFICANCE: Inadequate oral home care among orthodontic patients may make them more prone to develop gingivitis during orthodontic treatment. It is, therefore, essential that oral hygiene instructions and a hygiene maintenance program not be overlooked during orthodontic treatment. PMID- 20953562 TI - Third-molar agenesis among patients from the East Anatolian Region of Turkey. AB - AIM: The aim of this study was to determine the frequency and distribution of third-molar agenesis in orthodontic patients from the East Anatolian Region of Turkey. METHODS AND MATERIALS: Our data were obtained from the panoramic radiographs of the 2,579 patients 12 to 16 years of age in the Department of Orthodontics at the Ataturk University in Erzurum, Turkey. Subjects with congenital deformities, such as a cleft palate, were excluded from the study. Statistical analysis was performed using SPSS software and a chi-squared test. RESULTS: Of the 2,579 subjects, 1,964 (76.2 percent) had all four third-molar teeth, 238 (9.2 percent) had three, 214 (8.3 percent) had two, 66 (2.6 percent) had one third molar, and 97 (3.8 percent) had agenesis of all third-molar teeth. There was no significant difference in agenesis of third-molar teeth between the right and left sides and no gender predilection was noted. However, significantly more third-molar teeth were found to be missing from the maxilla compared to the mandible, with a ratio of approximately 1.5:1. CONCLUSION: According to our results, the absence of one third molar is the most frequently detected pattern in the East Anatolian population. Additionally, the absence of third molars is more frequent in the maxilla than the mandible. CLINICAL SIGNIFICANCE: To date no information about third-molar agenesis in the East Anatolian population from Turkey is documented. This is believed to be the first known study on this subject in this population. PMID- 20953563 TI - Management of crowded class 1 malocclusion with serial extractions: report of a case. AB - AIM: The purpose of this article is to show the value of serial extractions in a young patient with severe crowding. BACKGROUND: Serial extraction is a technique advocated for use by Kjellgren in 1948 due to a shortage of orthodontists at the time. This form of treatment was intended to facilitate the treatment of orthodontic cases by general dentists to minimize the demand upon the orthodontist. CASE DESCRIPTION: An eight-year-old Sudanese female did not like the appearance of her anterior teeth. Clinical examination revealed a Class I molar relationship, severe crowding of the maxillary and mandibular arches, minimum overjet, and minimum overbite. RESULTS: The patient's treatment included serial extractions. The treatment resulted in improved esthetics, good arch alignment, and occlusion while maintaining her Class I molar relationship, overjet, and overbite. SUMMARY: This case demonstrated that despite the criticism some may direct toward this interceptive technique, good clinical results can be achieved in carefully selected cases. CLINICAL SIGNIFICANCE: There are certain clinical situations when treatment planning the use of serial extractions can prove beneficial to young patients. PMID- 20953564 TI - Hereditary opalescent dentin: a report of two cases. AB - AIM: The aim of this case report is to present the clinical and radiographic findings of hereditary opalescent dentin to facilitate an early diagnosis. BACKGROUND: Hereditary opalescent dentin (or dentinogenesis imperfecta) may manifest itself in three variations: i.e., Shields type I, Shields type II, and Shields type III. Dentinogenesis imperfecta occurs as an autosomal dominant trait with variable expressivity, either in presence with osteogenesis imperfecta or as a separate clinical entity in persons who have none of the features of osteogenesis imperfecta. CASE DESCRIPTION: A seven-year old boy and his mother were both diagnosed with hereditary opalescent dentin. A review of the family dental history revealed that this condition affected not only the child's mother but his maternal grandfather and great grandfather. Both the son and the mother exhibited the same clinical and radiologic features as those reported previously with no evidence of osteogenesis imperfecta. SUMMARY: Being an autosomal disease, hereditary opalescent dentin runs in the family and can affect both the deciduous and permanent dentitions as a dominant trait. CLINICAL SIGNIFICANCE: Once a patient is diagnosed with hereditary opalescent dentin, other family members should be evaluated given the condition is hereditary. PMID- 20953565 TI - Direct laminate veneers with resin composites: two case reports with five-year follow-ups. AB - AIM: The aim of this report is to present five-year follow-ups of two different applications for the use of direct laminate resin-based composite veneers to improve esthetics. BACKGROUND: Defects in the maxillary anterior teeth, such as enamel hypoplasia and peg lateral, can present esthetic challenges. Furthermore, a treatment plan that can be completed in a single appointment is highly desirable. This case report presents two different clinical cases involving the use of direct laminate resin-based composite veneers with five-year follow-ups. CASE REPORT: Case 1: A 17-year-old female patient was referred for treatment of her anterior teeth, which were unesthetically altered due to enamel hypoplasia and dental caries. A treatment plan was developed that included restoring the affected teeth with direct resin-based composite laminate veneers to improve the patient's appearance. The six maxillary anterior teeth were prepared for and restored with direct resin-based composite laminate veneers. At the five-year follow-up, the patient was satisfied with the restorations both esthetically and functionally. Case 2: A 15-year-old female patient also was referred for treatment to improve the appearance of her maxillary anterior teeth. A treatment plan was developed with two objectives: (1) to restore the undersized supernumerary crown in the area of the maxillary right lateral incisor and (2) to close the anterior diastemas. The facial surfaces were conservatively prepared and resin-based composite was applied with the aid of transparent crown forms. After completion of the treatment, the patient was recalled at six-month intervals. At the five-year follow-up appointment, the restorations were intact, no adverse effects were noted, and the resultant appearance was highly satisfactory for the patient. SUMMARY: The use of direct resin-based composite laminate veneers and adhesive bonding systems has been shown to provide an esthetic alternative to metal-ceramic or all-ceramic crowns for the rehabilitation of anterior teeth. This treatment option offers another advantage, namely a lower cost compared to an indirect technique. Other more complex and costly treatment options in the future are not ruled out. CLINICAL SIGNIFICANCE: In the present two cases, the initial and five-year follow-up results support the use of direct resin-based composite laminate veneers with minimal altering of healthy tooth structure. Such results should encourage clinicians to seek a cost effective technique such as direct resin restorations to improve a patient's esthetic appearance in a single appointment. PMID- 20953567 TI - AAOMP case challenge: Incidental radiopaque lesions of the jaws. PMID- 20953566 TI - An evaluation of the fit of metal-ceramic restorations made with an autoclaved silicone-based impression material. AB - AIM: To demonstrate the clinical feasibility of autoclaving certain silicone impression materials in order to avoid potential cross-contamination during handling, transport, and subsequent processing. BACKGROUND: Semicritical devices are recommended to be treated at least with high-level disinfectants or actually steam sterilized at 134 degrees C. To date dental impressions have been disinfected rather than sterilized, so the question remains should they be sterilized before being sent to the dental laboratory? CASE DESCRIPTIONS: Two identical impressions per case were made of metal-ceramic crown and fixed partial denture preparations on the same patient using addition type polyvinyl siloxane (PVS) impression materials (AFFINIS,(r) Coltene/Whaledent AG, 9450 Altstatten, Switzerland) in different trays. The first impression (IMPx1) was cleaned and treated with an intermediate-level disinfectant (FD 322--Fast Disinfection Spray, Durr Dental, 74321 Bietigheim-Bissingen, Germany). The second impression (IMPx2) was cleaned, treated with an intermediate-level disinfectant as with IMPx1, subjected to a computer tomography (CT) scan with a dimensional resolution of +/- 10 um, steam sterilized, and then subjected to a second CT scan. The dimensional changes of the second impression after steam sterilization were calculated by comparing the overlay of the two CT scans and expressed by color coding of the impression graphics. After the second scan, the impression was sent to a dental laboratory to fabricate a metal-ceramic crown or metal-ceramic fixed partial denture restoration to the one produced from the first impression (IMPx1) subjected only to disinfection. This process was repeated for four clinical cases. CONCLUSION: Impressions made with AFFINIS(r) silicone impression materials in a rigid reinforced polycarbonate impression tray or in a metal dual-arch tray can be autoclaved. The overall dimensional stability of the impressions and the quality of single crowns and small fixed partial dentures made using IMPx2 was not compromised. The maximum dimensional differences at the preparations of the nonautoclaved and the autoclaved impressions were found to be within acceptable limits of about 50-100 um. CLINICAL SIGNIFICANCE: Steam sterilization of AFFINIS(r) impressions is possible without adversely affecting dimensional change. In addition, clinicians can clearly indicate to the dental practice and laboratory personnel that sterilization of the impressions has been performed, cross-contamination is unlikely, and the impressions present no apparent health hazard during transport and subsequent processing. PMID- 20953568 TI - [Isolated systolic hypertension. An independent disease]. AB - Hypertension can be classified based on certain criteria, such as severity, existence of specific end-organ damage, or the dominant blood pressure subphenotype so that isolated diastolic hypertension (IDH), mixed systolic diastolic hypertension (SDH), and isolated systolic hypertensive (ISH) states can be defined. The FRAMINGHAM study was the first to demonstrate a continuous increase of systolic blood pressure with age and a peak of diastolic pressure between 55 and 65 years of age. This results not only in a high prevalence of hypertension of approximately 50-80% beyond the age of 60 but also in a disproportionately high increase in isolated systolic hypertension. ISH develops either as a new condition mostly from the group of primary high-normal blood pressure or secondly through burnout of existing systolic-diastolic hypertension with highly progressive vascular ageing.The pathophysiological background lies in remodeling processes in the macrovascular and microvascular compartments with stiffening of conduit and peripheral arterial vessels. In clinical practice these processes are easy to measure by determining pulse wave velocity (PWV), the augmentation index, and pulse pressure. These parameters are closely related to cardiovascular and cerebrovascular morbidity and mortality ISH is not only a hypertension subphenotype but often indicates significant organ damage or may even be considered to be a secondary form of hypertension characterized by remodeled and stiffened arterial vessel walls and this condition is difficult to treat. It appears therefore that ISH warrants special therapeutic strategies with a focus on antiproliferative, antistiffening, anti-atherosclerotic, and vasodilating actions. As a result of the available data from the results of treatment studies it appears that renin-angiotensin system (RAS) blockers and calcium channel blockers (CCBs) are the preferred drugs for treatment of this condition. PMID- 20953570 TI - [Allergy to car seat]. AB - This is a case report of a female patient showing a delayed allergic reaction to epoxy resin. The allergic contact dermatitis occurred after sitting in her new car equipped with artificial leather seats. PMID- 20953571 TI - [Linear IgA disease of the oral mucosa with pharyngeal and esophageal involvement]. AB - A 69-year-old man presented with multiple recurrent oral ulcerations for about 20 years. After he began having difficulty in breathing and swallowing, esophagogastroscopy was performed and showed ulcerations, erosions and scars on the mucous membrane of the pharynx as well of the esophagus. Linear IgA disease (LAD) was diagnosed based on histopathological and immunofluorescence examinations. In this patient with LAD, the buccal, pharyngeal and esophageal mucosa was affected without involvement of the skin. PMID- 20953572 TI - [Acrodermatitis enteropathica-like skin lesions due to Crohn's disease-associated zinc deficiency]. AB - We report a case of acrodermatitis enteropathica-like skin eruptions presenting with alopecia, perleche, glossitis, and genital erosions as well as multifocal eczematoid, psoriasiform, and bullous skin lesions due to zinc deficiency in Crohn's disease. PMID- 20953573 TI - [Topical tacrolimus in necrobiosis lipoidica]. AB - Necrobiosis lipoidica (NL) is a chronic inflammatory skin disease that is difficult to treat. The etiology is unknown, but vascular abnormalities and immunologic factors have been implicated. We treated a patient with long-standing NL with multiple vascular risk factors (diabetes mellitus, protein S-deficiency, and antiphospholipid syndrome) with topical tacrolimus, a non-steroidal immunomodulator that causes no skin atrophy. After 12 weeks of topical tacrolimus (0.1%) ointment, our patient already showed a good remission with a significant decrease in inflammatory signs. PMID- 20953574 TI - Small Rab GTPase Rab7b promotes megakaryocytic differentiation by enhancing IL-6 production and STAT3-GATA-1 association. AB - Induction of the differentiation of human leukemia cells is a useful strategy in treatment of human leukemia. However, the molecular mechanisms involved in leukemia cell differentiation have not been fully elucidated. Interleukin 6 (IL 6) is a pleiotropic cytokine acting on a variety of cell types, and plays important roles in hematopoiesis. GATA binding protein 1 (GATA-1) is an important transcription factor involved in either megakaryocytic or erythrocytic differentiation. Herein we report that Rab7b, a late endosome/lysosome-localized myeloid small GTPase, promotes phorbol-12-myristate-13-acetate (PMA)-induced megakaryocytic differentiation by increasing nuclear factor kappaB (NF-kappaB) dependent IL-6 production and subsequently enhancing the association of activated signal transducer and activator of transcription 3 (STAT3) with GATA-1. By using PMA-induced megakaryocytic differentiation of leukemia cells as a model, we investigated the roles of Rab7b in megakaryocytic differentiation. We find that Rab7b can potentiate PMA-induced upregulation of megakaryocytic markers, production of IL-6, and activation of NF-kappaB. Inhibitor of NF-kappaB and neutralizing antibodies for IL-6 or the IL-6 signaling receptor gp130 can block the effects of Rab7b in megakaryocytic differentiation. In Rab7b-silenced cells, PMA-induced activation of NF-kappaB, IL-6 production, and megakaryocytic differentiation are impaired. Furthermore, we demonstrate that IL-6-induced activation of STAT3 and the subsequent association of STAT3 with GATA-1 may contribute to PMA-induced and Rab7b-mediated transcriptional upregulation of megakaryocytic differentiation markers. Therefore, our data suggest that Rab7b may play important roles in megakaryopoiesis by activating NF-kappaB and promoting IL-6 production. Our study also indicates that the IL-6-induced association of STAT3 with GATA-1 may regulate megakaryocytic differentiation. PMID- 20953575 TI - Anti-inflammatory effect of methyl dehydrojasmonate (J2) is mediated by the NF kappaB pathway. AB - Inflammation as a major defense mechanism against pathogens is modulated by diverse microbial products. A variety of plant and microbial products interacting with Toll-like receptors initiate a wide spectrum of responses from phagocytosis to cytokine production, which modulates inflammation. Jasmonates are fatty acid derived cyclopentanones produced by plants and lower eukaryotes that play an important role in the defense against insects. In this study, we are set up to define the molecular targets of J2 action. While the lipopolysaccharide (LPS) stimulation of macrophage cell line RAW264.7 induced TNF-alpha, IL-6, iNOS, and COX-2 that were associated with an increase in miR-155 and miR-146a, the J2 suppressed the induction of these inflammatory cytokines and enzymes as well as miR-155 in a dose-dependent manner. To assess the associations of miR-155 with inflammatory markers, we overexpressed miR-155 and found attenuation of COX-2 suppression with J2 treatment. Furthermore, J2 inhibited NF-kappaB, p65, and IkappaB but had no or only minimal effects on the mitogen-activated protein kinase pathway. In conclusion, the present study demonstrates that J2 suppresses LPS stimulation of RAW264.7 cells by targeting NF-kappaB pathways. PMID- 20953576 TI - Annexin 1 mimetic peptide protects against renal ischemia/reperfusion injury in rats. AB - Inflammation is currently recognized as a key mechanism in the pathogenesis of renal ischemia-reperfusion (I/R) injury. The importance of infiltrating neutrophil, lymphocytes, and macrophage in this kind of injury has been assessed with conflicting results. Annexin 1 is a protein with potent neutrophil anti migratory activity. In order to evaluate the effects of annexin A1 on renal I/R injury, uninephrectomized rats received annexin A1 mimetic peptide Ac2-26 (100 MUg) or vehicle before 30 min of renal artery clamping and were compared to sham surgery animals. Annexin A1 mimetic peptide granted a remarkable protection against I/R injury, preventing glomerular filtration rate and urinary osmolality decreases and acute tubular necrosis development. Annexin A1 infusion aborted neutrophil extravasation and attenuated macrophage infiltration but did not prevent tissue lymphocyte traffic. I/R increased annexin A1 expression (assessed by transmission electron microscopy) in renal epithelial cells, which was attenuated by exogenous annexin A1 infusion. Additionally, annexin A1 reduced I/R injury in isolated proximal tubules suspension. Annexin A1 protein afforded striking functional and structural protection against renal I/R. These results point to an important role of annexin A1 in the epithelial cells defense against I/R injury and indicate that neutrophils are key mediators for the development of tissue injury after renal I/R. If these results were confirmed in clinical studies, annexin A1 might emerge as an important tool to protect against I/R injury in renal transplantation and in vascular surgery. PMID- 20953577 TI - [Non-invasive imaging modalities for preoperative axillary lymph node staging in patients with breast cancer]. AB - In the last decade sentinel lymph node biopsy has become a well-established method for axillary lymph node staging in patients with breast cancer. Using preoperative imaging modalities it can be tested whether patients are suitable for sentinel node biopsy or if they should directly undergo an axillary dissection. The imaging modalities used must be mainly characterized by a high positive predictive value (PPV). For this question B-mode ultrasound is the best evaluated method and provides clear morphological signs for a high PPV (>90%) but the sensitivity barely exceeds 50%. It has not yet been proven whether other modalities such as duplex sonography, magnetic resonance imaging, computed tomography (CT) or scintigraphy might achieve a higher sensitivity while still maintaining a high PPV. There is only some evidence that positron emission tomography (PET) might achieve a higher sensitivity. This should be confirmed by further studies because PET or PET/CT will play an increasing role for an initial whole body staging in patients with breast cancer in the near future. PMID- 20953578 TI - Deficiency in the extracellular signal-regulated kinase 1 (ERK1) protects leptin deficient mice from insulin resistance without affecting obesity. AB - AIMS/HYPOTHESIS: Extracellular signal-regulated kinase (ERK) activity is increased in adipose tissue in obesity and type 2 diabetes mellitus and strong evidences suggests that it is implicated in the downregulation of insulin signalling and action in the insulin-resistant state. To determine the role of ERK1 in obesity-associated insulin resistance in vivo, we inactivated Erk1 (also known as Mapk3) in obese leptin-deficient mice (ob/ob). METHODS: Mice of genotype ob/ob-Erk1-(/)- were obtained by crossing Erk1-(/)- mice with ob/ob mice. Glucose tolerance and insulin sensitivity were studied in 12-week-old mice. Tissue specific insulin sensitivity, insulin signalling, liver steatosis and adipose tissue inflammation were determined. RESULTS: While ob/ob-Erk1-(/)- and ob/ob mice exhibited comparable body weight and adiposity, ob/ob-Erk1-(/)- mice did not develop hyperglycaemia and their glucose tolerance was improved. Hyperinsulinaemic-euglycaemic clamp studies demonstrated an increase in whole body insulin sensitivity in the ob/ob-Erk1-(/)- mice associated with an increase in both insulin-stimulated glucose disposal in skeletal muscles and adipose tissue insulin sensitivity. This occurred in parallel with improved insulin signalling in both tissues. The ob/ob-Erk1-(/)- mice were also partially protected against hepatic steatosis with a strong reduction in acetyl-CoA carboxylase level. These metabolic improvements were associated with reduced expression of mRNA encoding inflammatory cytokine and T lymphocyte markers in the adipose tissue. CONCLUSIONS/INTERPRETATION: Our results demonstrate that the targeting of ERK1 could partially protect obese mice against insulin resistance and liver steatosis by decreasing adipose tissue inflammation and by increasing muscle glucose uptake. Our results indicate that deregulation of the ERK1 pathway could be an important component in obesity-associated metabolic disorders. PMID- 20953579 TI - Associations between physical fitness and HbA1(c) in type 2 diabetes mellitus. AB - AIM/HYPOTHESIS: In people with type 2 diabetes, exercise improves glucose control (as reflected in HbA1(c)) and physical fitness, but it is not clear to what extent these exercise-induced improvements are correlated with one another. We hypothesised that reductions in HbA1(c) would be related: (1) to increases in aerobic fitness and strength respectively in patients performing aerobic training or resistance training; and (2) to changes in strength and aerobic fitness in patients performing aerobic and resistance training. METHODS: We randomly allocated 251 type 2 diabetes patients to aerobic, resistance, or aerobic plus resistance training, or to a sedentary control group. Peak oxygen consumption VO2(peak), workload, treadmill time and ventilatory threshold measurements from maximal treadmill exercise testing were measured at baseline and 6 months. Muscular strength was measured as the maximum weight that could be lifted eight times on the leg press, bench press and seated row exercises. RESULTS: With aerobic training, significant associations were found between changes in both VO2(peak) (p = 0.040) and workload (p = 0.022), and changes in HbA1(c.) With combined training, improvements in VO2(peak) (p = 0.008), workload (p = 0.034) and ventilatory threshold (p = 0.003) were significantly associated with changes in HbA1(c.) Increases in strength on the seated row (p = 0.006) and in mid-thigh muscle cross-sectional area (p = 0.030) were significantly associated with changes in HbA1(c) after resistance exercise, whereas the association between increases in muscle cross-sectional area and HbA1(c) in participants doing aerobic plus resistance exercise (p = 0.059) was of borderline significance. CONCLUSIONS/INTERPRETATION: There appears to be a link between changes in fitness and HbA1(c). The improvements in cardiorespiratory fitness with aerobic training may be a better predictor of changes in HbA1(c) than improvements in strength. PMID- 20953581 TI - Dissociation between fatty liver and insulin resistance: the role of adipose triacylglycerol lipase. AB - Non-alcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance and type 2 diabetes in humans. Ongoing research aims to clarify the mechanisms involved in this relationship. Studying pathways that are involved in the dissociation between fatty liver and insulin resistance may help to achieve this goal. Among several enzymes that regulate the fate of hepatic lipids, adipose triacylglycerol lipase (ATGL) is of interest. This article briefly summarises novel information about the impact of ATGL in this process. PMID- 20953582 TI - The beta and alpha cell-specific Znt8-knockout mouse model: new mechanistic insights? PMID- 20953583 TI - Determinants of arterial and central venous blood pressure variation in ventilated critically ill children. AB - PURPOSE: Ventilation-induced arterial pressure variation predicts volume responsiveness in adults. Several factors are known to influence the interpretability of these variations. We analysed ventilation-induced variations in critically ill children with reference to ventilatory and circulatory parameters. METHODS: We prospectively included 20 paediatric patients. Variation of systolic pressure (SPV), pulse pressure (PPV) and central venous pressure (CVP) were assessed during pressure-controlled ventilation with inspiratory pressures (P(insp)) of 20 and 28 cmH(2)O. Blood gases were analysed and echocardiography was performed. RESULTS: SPV, PPV and CVP variation significantly increased with elevated P(insp) (p < 0.001, p = 0.008 and p = 0.003). Baseline CVP and shortening fraction were significant negative predictors of PPV and SPV. CONCLUSION: This preliminary study identified P(insp) as a determinant of SPV, PPV and CVP variation in children. Further independent determinants of SPV and PPV were baseline CVP and ventricular performance, both of which must be considered when interpreting pressure variations. PMID- 20953584 TI - The role of metabolites and metabolomics in clinically applicable biomarkers of disease. AB - Metabolomics allows the simultaneous and relative quantification of thousands of different metabolites within a given sample using sensitive and specific methodologies such as gas or liquid chromatography coupled to mass spectrometry, typically in discovery phases of studies. Biomarkers are biological characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathological processes or pharmacologic responses to a therapeutic intervention. Biomarkers are widely used in clinical practice for the diagnosis, assessment of severity and response to therapy in a number of clinical disease states. In human studies, metabolomics has been applied to define biomarkers related to prognosis or diagnosis of a disease or drug toxicity/efficacy and in doing so hopes to provide greater pathophysiological understanding of disease or therapeutic toxicity/efficacy. This review discusses the application of metabolomics in the discovery and subsequent application of biomarkers in the diagnosis and management of inborn errors of metabolism, cardiovascular disease and cancer. We critically appraise how novel biomarkers discovered through metabolomic analysis may be utilized in future clinical practice by addressing the following three fundamental questions: (1) Can the clinician measure them? (2) Do they add new information? (3) Do they help the clinician to manage patients? Although a number of novel biomarkers have been discovered through metabolomic studies of human diseases in the last decade, none have currently made the transition to routine use in clinical practice. Metabolites identified from these early studies will need to form the basis of larger, prospective, externally validated studies in clinical cohorts for their future use as biomarkers. At this stage, the absolute quantification of these biomarkers will need to be assessed epidemiologically, as will the ultimate deployment in the clinic via routine biochemistry, dip stick or similar rapid at- or near-patient care technologies. PMID- 20953585 TI - Excretion of 2,3-dihydroxy-propionamide (OH-PA), the hydrolysis product of glycidamide, in human urine after single oral dose of deuterium-labeled acrylamide. AB - A dose of 0.99 mg d(3)-acrylamide (d(3)-AA) (13.2 MUg/kg body weight) was ingested by a healthy male volunteer. Urine samples were collected over a period of 46 h after the intake and analyzed for the hydrolysis product of glycidamide (GA), 2,3-dihydroxy-propionamide (OH-PA), a metabolite of the toxicologically relevant oxidative AA metabolism pathway; 5.4% of the administered d(3)-AA dose was eliminated as OH-PA within 46 h after ingestion. Therefore, OH-PA represents a major metabolite of the oxidative metabolism pathway. Elimination kinetics of OH-PA is similar to the oxidative metabolites N-acetyl-S-(2-carbamoyl-2 hydroxyethyl)-cysteine (GAMA) and N-acetyl-S-(1-carbamoyl-2-hydroxyethyl) cysteine (iso-GAMA). The major excretion of d(3)-OH-PA took place between 8 and 22 h with the highest urinary d(3)-OH-PA concentration (c (max)) of 69.3 MUg/L urine, 18 h (t (max)) postdose. OH-PA (5.4%), together with the other known urinary metabolites of the oxidative pathway GAMA (4.6%) and iso-GAMA (0.8%), represents 10.8% of the total AA dose. The share of the oxidative pathway metabolites is much smaller than the share of the reductive pathway metabolite N acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) that represents 51.7% of the ingested d(3)-AA dose. However, this new quantitative human data on OH-PA together with the previous data on the other oxidative pathway metabolites are of special importance when evaluating the carcinogenic potential of AA and when comparing human data with data from animal studies. PMID- 20953586 TI - PARP-1 expression and activity in primary human lung cells. AB - Activation of poly(ADP-ribose) polymerase-1 (PARP-1) in response to DNA damage is an important mechanism to keep homeostasis or to trigger apoptosis. The expression and function of (PARP-1) was studied in primary cells cultured from human lung. Normal human bronchial epithelial cells (NHBEC) and peripheral lung cells (PLC) from lung cancer patients were grown as explant cultures and were followed over a period of 12 weeks. PARP-1 protein was expressed in all explant cultures from bronchial epithelium. The levels of PARP protein differed between individuals by a factor of 2.3 in the first explant. Three cases were followed for more than 100 days. The expression levels varied intra-individually by a factor of 1.3-1.4 over this time period. PARP-1 activity was determined immunohistochemically after induction of DNA damage with H(2)O(2) (0.05-0.3 mM, 5 min). The fluorescence signal for ADP-ribose polymers attached to chromatin proteins correlated well with the concentration of H(2)O(2). PARP-1 activity differed by a factor of 3.1 in NHBECs obtained from the first generation of explants from 11 cases. PARP-1 activity is present in NHBECs until the 8th and in PLCs until the 12th week and declined to about half of the start level. Primary cultures of NHBECs and PLC are suitable to study the effect of external factors on PARP-1 expression and function. PMID- 20953587 TI - Illumination and mood. PMID- 20953588 TI - Conditioned cues for smoking elicit preparatory responses in healthy smokers. AB - RATIONALE: Smoking cues are theorized to be conditioned stimuli (CSs) formed by repeated pairing with drug. Smoking paraphernalia can elicit subjective and physiological responses in smokers, indicative of positive affect and motivation to consume. Although these responses are probably the result of conditioning, direct evidence from human conditioning studies with physiological measures of motivational valence is rare. OBJECTIVE: The present study investigated the motivational properties of experimentally conditioned cues for smoking. METHODS: Thirty-nine smokers completed a differential conditioning protocol. Abstract pictures were used as CSs and single puffs on a cigarette as unconditioned stimulus (US). Skin conductance responses and facial electromyography of the zygomatic, corrugator, and orbicularis oris muscles were measured during conditioning. RESULTS: The conditioned cue for smoking (CS+) elicited stronger skin conductance responses and more activity of the zygomatic and orbicularis oris muscles than the CS-. CONCLUSIONS: These results support the notion that through pairing with smoking, neutral stimuli acquire the ability to elicit preparatory physiological responses, which are assumed to play an important role in the maintenance of addiction and relapse in the natural environment. PMID- 20953590 TI - Examining the influence of 'noise' on judgements of spatial extent. AB - The line bisection task--commonly used as a clinical measure of unilateral neglect--requires participants to place a mark on a horizontal line to indicate where they think centre is. In general, results suggest that the allocation of attention mediates bisection. In addition, previous research shows that participants rarely explore the endpoints of lines, suggesting that peripheral visual information informs bisection. Here, we examined bisection performance under conditions in which differing levels of 'noise' were introduced to the line to examine the hypothesis that the fidelity and symmetry of peripheral information would inform performance. Contrary to our expectations, results showed that symmetrically introducing noise to the line biased bisection further leftward compared to a 'no-noise' condition. Furthermore, asymmetrical noise increased leftward bisection errors primarily when lines were presented in left space or when the greater amount of noise was on the left half of the line. These results indicate that the fidelity of peripheral visual information mediates bisection behaviour that is already biased leftwards probably due to right hemisphere attentional mechanisms. PMID- 20953591 TI - Central sensitization does not identify patients with carpal tunnel syndrome who are likely to achieve short-term success with physical therapy. AB - The aim of the current study was to identify whether hyperexcitability of the central nervous system is a prognostic factor for individuals with carpal tunnel syndrome (CTS) likely to experience rapid and clinical self-reported improvement following a physical therapy program including soft tissue mobilization and nerve slider neurodynamic interventions. Women presenting with clinical and electrophysiological findings of CTS were involved in a prospective single-arm trial. Participants underwent a standardized examination and then a physical therapy session. The physical therapy sessions included both soft tissue mobilization directed at the anatomical sites of potential median nerve entrapment and a passive nerve slider neurodynamic technique targeted to the median nerve. Pressure pain thresholds (PPT) over the median, radial and ulnar nerves, C5-C6 zygapophyseal joint, carpal tunnel and tibialis anterior muscle were assessed bilaterally. Additionally, thermal detection and pain thresholds were measured over the carpal tunnel and thenar eminence bilaterally to evaluate central nervous system excitability. Subjects were classified as responders (having achieved a successful outcome) or non-responders based on self-perceived recovery. Variables were entered into a stepwise logistic regression model to determine the most accurate variables for determining prognosis. Data from 72 women were included in the analysis, of which 35 experienced a successful outcome (48.6%). Three variables including PPT over the C5-C6 joint affected side <137 kPa, HPT carpal tunnel affected side <39.6o and general health >66 points were identified. If 2 out of 3 variables were present (LR + 14.8), the likelihood of success increased from 48.6 to 93.3%. We identified 3 factors that may be associated with a rapid clinical response to both soft tissue mobilization and nerve slider neurodynamic techniques targeted to the median nerve in women presenting with CTS. Our results support that widespread central sensitization may not be present in women with CTS who are likely to achieve a successful outcome with physical therapy. Future studies are now necessary to validate these findings. PMID- 20953589 TI - Presynaptic control of serotonin on striatal dopamine function. AB - RATIONALE: The influences of the serotonergic system on dopamine (DA) neuron activity have received considerable attention during the last three decades due to the real opportunity to improve disorders related to central DA neuron dysfunctions such as Parkinson's disease, schizophrenia, or drug abuse with serotonergic drugs. Numerous biochemical and behavioral data indicate that serotonin (5-HT) affects dopaminergic terminal function in the striatum. OBJECTIVE: The authors propose a thorough examination of data showing controversial effects induced by striatal 5-HT on dopaminergic activity. RESULTS: Inhibitory and excitatory effects of exogenous 5-HT have been reported on DA release and synthesis, involving various striatal 5-HT receptors. 5-HT also promotes an efflux of DA through reversal of the direction of DA transport. By analogy with the mechanism of action described for amphetamine, the consequences of 5-HT entering DA terminals might explain both the excitatory and inhibitory effects of 5-HT on presynaptic DA terminal activity, but the physiological relevance of this mechanism is far from clear. The recent data suggest that the endogenous 5-HT system affects striatal DA release in a state-dependent manner associated with the conditional involvement of various 5-HT receptors such as 5 HT(2A), 5-HT(2C), 5-HT(3), and 5-HT(4) receptors. CONCLUSION: Methodological and pharmacological issues have prevented a comprehensive overview of the influence of 5-HT on striatal DA activity. The distribution of striatal 5-HT receptors and their restricted influence on DA neuron activity suggest that the endogenous 5-HT system exerts multiple and subtle influences on DA-mediated behaviors. PMID- 20953592 TI - Effects of nicotine administration and nicotine cessation on bone histomorphometry and bone biomarkers in Sprague-Dawley male rats. AB - Nicotine is a major alkaloid of tobacco, which can increase free radical formation, leading to osteoporosis. The effects of nicotine administration and cessation on bone histomorphometry and biomarkers were studied in 28 Sprague Dawley male rats. Rats aged 3 months and weighing 250-300 g were divided into four groups: control (C, normal saline for 4 months), nicotine for 2 months (N2), nicotine for 4 months (N4), and nicotine cessation (NC). The NC group was given nicotine for the first 2 months and then allowed to recover for the following 2 months without nicotine. Histomorphometric analysis was done using an image analyzer. ELISA kits were used to measure serum osteocalcin (bone formation marker) and pyridinoline (PYD, bone resorption marker) levels at month 0, month 2, and month 4. All test groups showed a significant decrease in BV/TV, Ob.S/BS, dLS/BS, MAR, BFR/BS, and osteocalcin levels and an increase in sLS/BS and PYD levels compared to group C. No significant differences were observed in all parameters measured among the test groups, except for MAR and BFR/BS. In conclusion, nicotine administration at a dose of 7 mg/kg for 2 and 4 months has detrimental effects on bone metabolism. Nicotine administration at 7 mg/kg for 2 months is sufficient to produce significant effects on bone histomorphometric parameters and biomarkers. In addition, prolonging the treatment for another 2 months did not show any significant differences. Cessation of nicotine for 2 months did not reverse the effects. PMID- 20953593 TI - Pharmacokinetics of teriparatide (rhPTH[1-34]) and calcium pharmacodynamics in postmenopausal women with osteoporosis. AB - Teriparatide (rhPTH[1-34]) affects calcium metabolism in a pattern consistent with the known actions of endogenous parathyroid hormone (PTH). This report describes the pharmacokinetics and resulting serum calcium response to teriparatide in postmenopausal women with osteoporosis. Pharmacokinetic samples for this analysis were obtained from 360 women who participated in the Fracture Prevention Trial. Postmenopausal women with osteoporosis received daily subcutaneous injections of either teriparatide 20 MUg (4.86 MUmol) or placebo, median 21 months' treatment. Serum teriparatide and calcium concentrations were measured throughout the study. An indirect-response model was developed to describe the pharmacokinetic-pharmacodynamic relationship between teriparatide concentrations and serum calcium response. The pharmacokinetics of teriparatide were characterized by rapid absorption (maximum concentration achieved within 30 min) and rapid elimination (half-life of 1 h), resulting in a total duration of exposure to the peptide of approximately 4 h. Teriparatide transiently increased serum calcium, with the maximum effect observed at approximately 4.25 h (median increase 0.4 mg/dl [0.1 mmol/l]). Calcium concentrations returned to predose levels by 16-24 h after each dose. Persistent hypercalcemia was not observed; one teriparatide 20 MUg-treated patient had a predose serum calcium value above the normal range but <11.0 mg/dl (2.75 mmol/l). Following once-daily subcutaneous administration, teriparatide produces a modest but transient increase in serum calcium, consistent with the known effects of endogenous PTH on mineral metabolism. The excursion in serum calcium is brief, due to the short length of time that teriparatide concentrations are elevated. PMID- 20953594 TI - Lipids extracted from urines and stones of nephrolithiasis patients: clinical significance? PMID- 20953595 TI - Transurethral lithotripsy with holmium-YAG laser of a large exogenous prostatic calculus. AB - Prostatic calculi are classified into two types, endogenous and exogenous calculi, based on their origin. Endogenous calculi are commonly observed in elderly men; however, exogenous prostatic calculi are extremely rare. We report here the case of a 51-year-old man who suffered incontinence and pollakiuria with a giant exogenous prostatic calculus almost completely replacing the prostatic tissue. X-rays and computed tomography demonstrated a large calculus of 65 * 58 mm in the small pelvic cavity. The patient underwent a transurethral lithotripsy with a holmium-YAG laser and a total of 85 g of disintegrated stones was retrieved and chemical stone analysis revealed the presence of magnesium ammonium phosphate. The incontinence improved and the voiding volume increased dramatically, and no stone recurrence in the prostatic fossa occurred at the 2 years follow-up. The etiology of this stone formation seemed to be based on some exogenous pathways combined with urinary stasis and chronic urinary infection due to compression fracture of the lumbar vertebra. PMID- 20953596 TI - Cortical nephrocalcinosis in an infant caused by primary hyperoxaluria type 1. PMID- 20953597 TI - Spectrum of renal findings in pediatric fibromuscular dysplasia and neurofibromatosis type 1. AB - BACKGROUND: Fibromuscular dysplasia (FMD) and neurofibromatosis type 1 (NF1) are the most common causes of pediatric renal artery stenosis (RAS) in western countries, and characterization of their angiographic features could aid in an accurate diagnosis and in treatment. OBJECTIVE: This study characterizes renal angiographic findings in pediatric fibromuscular dysplasia (FMD) and neurofibromatosis type 1(NF1). MATERIALS AND METHODS: We reviewed 68 angiograms performed over 11 years on 43 children with renovascular hypertension (20 male, 23 females; ages 1 month to -19 years; median/average 9.8 years). Ten patients were diagnosed with NF1, and 33 had presumed FMD. The frequency, extent and distribution of lesions were determined and analyzed. RESULTS: Stenosis was found in 91% of patients (n=39/43), with 86% showing stenosis of 1st or 2nd order arteries, and 12% distal to 2nd order. Stenoses in multiple 1st/2nd order arteries were found in 32% of patients, and 36/43 patients had 1-2 stenoses. The most common lesion was a <= 5 mm stenosis in a 1st/2nd order artery, in 42%. Mean percentage of stenosis in a 1st/2nd order vessel was 62%; >= 70% stenosis was found in 53%, and >= 90% stenosis in 29%. Bilateral disease was noted in 30% of patients. Intraparenchymal disease, distal to 2nd order branches, was seen in 30%. Aneurysms were seen in 28%, beading in 19% and collaterals in 51% (associated with >= 70% stenosis). Mid-aortic narrowing was seen in 16%, more often in patients with NF1. CONCLUSION: We provide a descriptive characterization of renal angiographic findings in pediatric FMD and NF1. PMID- 20953598 TI - Bacterial communities involved in soil formation and plant establishment triggered by pyrite bioweathering on arctic moraines. AB - In arctic glacier moraines, bioweathering primed by microbial iron oxidizers creates fertility gradients that accelerate soil development and plant establishment. With the aim of investigating the change of bacterial diversity in a pyrite-weathered gradient, we analyzed the composition of the bacterial communities involved in the process by sequencing 16S rRNA gene libraries from different biological soil crusts (BSC). Bacterial communities in three BSC of different morphology, located within 1 m distance downstream a pyritic conglomerate rock, were significantly diverse. The glacier moraine surrounding the weathered site showed wide phylogenetic diversity and high evenness with 15 represented bacterial classes, dominated by Alphaproteobacteria and pioneer Cyanobacteria colonizers. The bioweathered area showed the lowest diversity indexes and only nine bacterial families, largely dominated by Acidobacteriaceae and Acetobacteraceae typical of acidic environments, in accordance with the low pH of the BSC. In the weathered BSC, iron-oxidizing bacteria were cultivated, with counts decreasing along with the increase of distance from the rock, and nutrient release from the rock was revealed by environmental scanning electron microscopy-energy dispersive X-ray analyses. The vegetated area showed the presence of Actinomycetales, Verrucomicrobiales, Gemmatimonadales, Burkholderiales, and Rhizobiales, denoting a bacterial community typical of developed soils and indicating that the lithoid substrate of the bare moraine was here subjected to an accelerated colonization, driven by iron-oxidizing activity. PMID- 20953599 TI - Ionic liquids for two-phase systems and their application for purification, extraction and biocatalysis. AB - The development of biotechnological processes using novel two-phase systems based on molten salts known as ionic liquids (ILs) got into the focus of interest. Many new approaches for the beneficial application of the interesting solvent have been published over the last years. ILs bring beneficial properties compared to organic solvents like nonflammability and nonvolatility. There are two possible ways to use the ILs: first, the hydrophobic ones as a substitute for organic solvents in pure two-phase systems with water and second, the hydrophilic ones in aqueous two-phase systems (ATPS). To effectively utilise IL-based two-phase systems or IL-based ATPS in biotechnology, extensive experimental work is required to gain the optimal system parameters to ensure selective extraction of the product of interest. This review will focus on the most actual findings dealing with the basic driving forces for the target extraction in IL-based ATPS as well as presenting some selected examples for the beneficial application of ILs as a substitute for organic solvents. Besides the research focusing on IL based two-phase systems, the "green aspect" of ILs, due to their negligible vapour pressure, is widely discussed. We will present the newest results concerning ecotoxicity of ILs to get an overview of the state of the art concerning ILs and their utilisation in novel two-phase systems in biotechnology. PMID- 20953600 TI - Polyoxometalate/laccase-mediated oxidative polymerization of catechol for textile dyeing. AB - The synergistic effect between polyoxometalates (POMs), namely K(5)[SiW(11)V(V)O(40)].11H(2)O and H(5)[PMo(10)V(V) (2)O(40)].13H(2)O and laccase from ascomycete Myceliophthora thermophila has been employed for the first time in oxidative polymerization of catechol. Such a laccase-mediator system allowed the formation of a relatively high molecular weight polycatechol as confirmed by size exclusion chromatography and electrospray ionization mass spectrometry (ESI MS) (3990 Da when using K(5)[SiW(11)V(V)O(40)].11H(2)O and 3600 Da with H(5)[PMo(10)V(V) (2)O(40)].13H(2)O). The synthesized polymers were applied as dyes for the dyeing of flax fabrics. The color intensity of flax fabrics colored with polymer solutions was evaluated by diffuse reflectance spectrophotometry via k/s measurements (+10% of fixation ratio). A new synthetic process allowed a dyeing polymer, provided upon flax coloration, better color fixation and color resistance when compared to that obtained by conventional synthesis with laccase solely or with addition of organic mediator (1-hydroxybenzotriazole). PMID- 20953602 TI - Isolation and characterization of endophytic bacterium LRE07 from cadmium hyperaccumulator Solanum nigrum L. and its potential for remediation. AB - Valuable endophytic strains facilitating plants growth and detoxification of heavy metals are required because the application of plant-endophyte symbiotic system is a promising potential technique to improve efficiency of phytoremediation. In this study, endophytic bacterium LRE07 was isolated from cadmium hyperaccumulator Solanum nigrum L. It was identified as Serratia sp. by 16S rRNA sequence analysis. The endophytic bacterium LRE07 was resistant to the toxic effects of heavy metals, solubilized mineral phosphate, and produced indoleacetic acid and siderophore. The heavy metal detoxification was studied in growing LRE07 cells. The strain bound over 65% of cadmium and 35% of zinc in its growing cells from single metal solutions 72 h after inoculation. Besides the high removal efficiencies in single-ion system, an analogous removal phenomenon was also observed in multi-ions system, indicating that the endophyte possesses specific and remarkable heavy metal remediation abilities. PMID- 20953603 TI - Genetic analysis around aminoalcohol dehydrogenase gene of Rhodococcus erythropolis MAK154: a putative GntR transcription factor in transcriptional regulation. AB - NADP(+)-dependent aminoalcohol dehydrogenase (AADH) of Rhodococcus erythropolis MAK154 catalyzes the reduction of (S)-1-phenyl-1-keto-2-methylaminopropane ((S) MAK) to d-pseudoephedrine, which is used as a pharmaceutical. AADH is suggested to participate in aminoalcohol or aminoketone metabolism in this organism because it is induced by the addition of several aminoalcohols, such as 1-amino-2 propanol. Genetic analysis of around the aadh gene showed that some open reading frames (ORFs) are involved in this metabolic pathway. Four of these ORFs might form a carboxysome-like polyhedral organelle, and others are predicted to encode aminotransferase, aldehyde dehydrogenase, phosphotransferase, and regulator protein. OrfE, a homologous ORF of the FadR subfamily of GntR transcriptional regulators, lies downstream from aadh. To investigate whether or not orfE plays a role in the regulation of aadh expression, the gene disruption mutant of R. erythropolis MAK154 was constructed. The DeltaorfE strain showed higher AADH activity than wild-type strain. In addition, a transformed strain, which harbored multi-orfE, showed no AADH activity even in the induced condition with 1-amino-2 propanol. These results suggest that OrfE is a negative regulator that represses aadh expression in the absence of 1-amino-2-propanol. PMID- 20953604 TI - Antimicrobial polymers: mechanism of action, factors of activity, and applications. AB - Complex epidemiological situation, nosocomial infections, microbial contamination, and infection risks in hospital and dental equipment have led to an ever-growing need for prevention of microbial infection in these various areas. Macromolecular systems, due to their properties, allow one to efficiently use them in various fields, including the creation of polymers with the antimicrobial activity. In the past decade, the intensive development of a large class of antimicrobial macromolecular systems, polymers, and copolymers, either quaternized or functionalized with bioactive groups, has been continued, and they have been successfully used as biocides. Various permanent microbicidal surfaces with non-leaching polymer antimicrobial coatings have been designed. Along with these trends, new moderately hydrophobic polymer structures have been synthesized and studied, which contain protonated primary or secondary/tertiary amine groups that exhibited rather high antimicrobial activity, often unlike their quaternary analogues. This mini-review briefly highlights and summarizes the results of studies during the past decade and especially in recent years, which concern the mechanism of action of different antimicrobial polymers and non-leaching microbicidal surfaces, and factors influencing their activity and toxicity, as well as major applications of antimicrobial polymers. PMID- 20953605 TI - Prevalence of triceps tendon tears on MRI of the elbow and clinical correlation. AB - OBJECTIVE: Triceps tendon injuries are reported to be very rare. To our knowledge, there have been no studies describing its prevalence or injury patterns on MR imaging. The purpose of this retrospective study was to determine the prevalence and patterns of triceps injuries based on a large series of consecutive MR examinations. Clinical correlation was obtained. MATERIALS AND METHODS: From 801 consecutive elbow MR examinations over a 15-year period, 28 patients with 30 triceps tendon injuries were identified and graded as partial tendon tear and complete tendon tear. The patients' medical records were reviewed to determine age, gender, cause of tears, and management. RESULTS: The prevalence of triceps tendon injuries was 3.8%. There were 5 women and 23 men with partial or complete tears (mean age: 46.6 years; range: 2.7 to 75.1 years). The most common injury was partial tear, found in 18 patients. There were 10 patients with 12 complete tears (2 had re-torn following surgical repair). A tear was suspected in 12 out 28 (43%) patients prior to the MRI. The most common presenting symptom was pain. The most common cause was athletic injury (8 patients [29%], including weightlifting [2 patients]). Tendon tear was found to be a complication of infection in 6 patients, and in 3 patients the tears were a complication of steroid use. Thirteen tendon tears were surgically repaired (8 of these were complete tears). CONCLUSIONS: Triceps tendon injury is not as rare as commonly reported and may often be clinically underdiagnosed. PMID- 20953606 TI - Bone marrow MR imaging findings in disuse osteoporosis. AB - OBJECTIVE: To demonstrate MR imaging findings in the cortical and trabecular bone as well as marrow changes in patients with disuse osteoporosis (DO). MATERIALS AND METHODS: Sixteen patients (14 men, 2 women, aged 27-86 years) with clinical and radiographic evidence of DO of a lower limb joint (10 knees, 6 ankles) with MR examination of the same joint performed within a 1-month period were selected, as well as 16 healthy volunteers (7 men, 9 women, aged 25-75 years, 10 knees and 6 ankles). MR imaging findings of the bone marrow were analyzed by 2 musculoskeletal radiologists in consensus regarding: diffuse or focal signal alteration, reinforcement of vertical or longitudinal trabecular lines, and presence of abnormal vascularization. RESULTS: All patients (100%,16/16) with DO presented MR imaging abnormalities of the bone marrow, such as: accentuation of vertical trabecular lines (50%, 8/16), presence of subchondral lobules of fat (37.5%, 6/16), presence of horizontal trabecular lines (31%, 5/16), prominence of bone vessels (25%, 4/16), and presence of dotted areas of high signal intensity on T2-weighted fat-suppressed sequences (12.5%, 2/16). Such MR findings did not appear in the control individuals. CONCLUSION: There are several MR imaging findings in bones with DO that range from accentuation of vertical and horizontal marrow lines, presence of subchondral lobules of fat, prominent bone vascularization and the presence of dotted foci of high signal intensity on T2 weighted fat-suppressed sequences. Recognition of these signs may prove helpful in the identification of DO as well as distinguishing these findings from other entities. PMID- 20953601 TI - Spatial distribution and abundances of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) in mangrove sediments. AB - We investigated the diversity, spatial distribution, and abundances of ammonia oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) in sediment samples of different depths collected from a transect with different distances to mangrove forest in the territories of Hong Kong. Both the archaeal and bacterial amoA genes (encoding ammonia monooxygenase subunit A) from all samples supported distinct phylogenetic groups, indicating the presences of niche-specific AOA and AOB in mangrove sediments. The higher AOB abundances than AOA in mangrove sediments, especially in the vicinity of the mangrove trees, might indicate the more important role of AOB on nitrification. The spatial distribution showed that AOA had higher diversity and abundance in the surface layer sediments near the mangrove trees (0 and 10 m) but lower away from the mangrove trees (1,000 m), and communities of AOA could be clustered into surface and bottom sediment layer groups. In contrast, AOB showed a reverse distributed pattern, and its communities were grouped by the distances between sites and mangrove trees, indicating mangrove trees might have different influences on AOA and AOB community structures. Furthermore, the strong correlations among archaeal and bacterial amoA gene abundances and their ratio with NH (4) (+) , salinity, and pH of sediments indicated that these environmental factors have strong influences on AOA and AOB distributions in mangrove sediments. In addition, AOA diversity and abundances were significantly correlated with hzo gene abundances, which encodes the key enzyme for transformation of hydrazine into N(2) in anaerobic ammonium oxidizing (anammox) bacteria, indicating AOA and anammox bacteria may interact with each other or they are influenced by the same controlling factors, such as NH (4) (+) . The results provide a better understanding on using mangrove wetlands as biological treatment systems for removal of nutrients. PMID- 20953607 TI - Solitary fibrous tumor: an update on the spectrum of extrapleural manifestations. AB - Solitary fibrous tumor (SFT) is a rare tumor initially believed to be a benign localized pleural tumor of mesothelial origin. Over the past few years, the literature on this tumor has grown tremendously. The tumor is now reported in diverse bodily locations, and recognized to have a wider range of clinical and radiological features. The most common extrapleural sites of the tumor are the orbits and the extremities. Tumors are often well-circumscribed masses, and vary in size from 1 cm to over 30 cm. The admixture of histological components in the tumor, namely, fibrous tissue, cellular components, and highly vascularized areas consisting of numerous closely packed small to medium-sized blood vessels, influence the imaging appearances of the tumor. On magnetic resonance imaging (MRI), the diagnosis of solitary fibrous tumor is suggested by a well circumscribed mass that has smooth margins, and focal or diffuse hypointense signal on T2-weighted imaging due to fibrous content in the tumor. SFTs demonstrate strong focal or diffuse contrast enhancement due to the highly vascularized areas in the tumor. PMID- 20953608 TI - Optimal left ventricular lead position assessed with phase analysis on gated myocardial perfusion SPECT. AB - PURPOSE: The aim of the current study was to evaluate the relationship between the site of latest mechanical activation as assessed with gated myocardial perfusion SPECT (GMPS), left ventricular (LV) lead position and response to cardiac resynchronization therapy (CRT). METHODS: The patient population consisted of consecutive patients with advanced heart failure in whom CRT was currently indicated. Before implantation, 2-D echocardiography and GMPS were performed. The echocardiography was performed to assess LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV) and LV ejection fraction (LVEF). The site of latest mechanical activation was assessed by phase analysis of GMPS studies and related to LV lead position on fluoroscopy. Echocardiography was repeated after 6 months of CRT. CRT response was defined as a decrease of >=15% in LVESV. RESULTS: Enrolled in the study were 90 patients (72% men, 67+/-10 years) with advanced heart failure. In 52 patients (58%), the LV lead was positioned at the site of latest mechanical activation (concordant), and in 38 patients (42%) the LV lead was positioned outside the site of latest mechanical activation (discordant). CRT response was significantly more often documented in patients with a concordant LV lead position than in patients with a discordant LV lead position (79% vs. 26%, p<0.01). After 6 months, patients with a concordant LV lead position showed significant improvement in LVEF, LVESV and LVEDV (p<0.05), whereas patients with a discordant LV lead position showed no significant improvement in these variables. CONCLUSION: Patients with a concordant LV lead position showed significant improvement in LV volumes and LV systolic function, whereas patients with a discordant LV lead position showed no significant improvements. PMID- 20953609 TI - Percutaneous transthoracic computed tomography-guided AICD insertion in a patient with extracardiac Fontan conduit. AB - Percutaneous pulmonary venous atrial puncture was performed under computed tomography guidance to successfully place an automated implantable cardiac defibrillator into a 26-year-old patient with extracardiac Fontan conduit who had presented with two out-of-hospital cardiac arrests. The procedure avoided the need for lead placement at thoracotomy. PMID- 20953610 TI - Midterm results of uterine artery embolization using narrow-size calibrated embozene microspheres. AB - PURPOSE: To evaluate safety and efficacy of uterine artery embolization using narrow-size-range polyphosphazene-coated hydrogel microspheres (Embozene, CeloNova Biosciences, Newnan, GA). METHODS: Between May 2006 and September 2008, a total of 121 consecutive patients (mean +/- SD age 42.1 +/- 5.4 years, range 30.5-51.5 years) were enrolled onto this single-center study. The primary study endpoint was safety as assessed by the society of interventional radiology (SIR) classification. The secondary endpoint was efficacy, which was based on a 1-year magnetic resonance imaging study and relief of symptoms documented by the Medical Outcomes Study 36-Item Short-Form Health Survey questionnaire over a 2-year interval. RESULTS: The mean +/- SD diameter of the dominant fibroid was 6.4 +/- 2.6 (range, 2.9-13.9) cm and the mean volume 137.2 +/- 245.1 (range, 5.3-1184) ml. Most patients had multiple fibroids with 11% more than 10. A total of 240 of 242 interventions were completed as planned, a technical success rate of 99.2%. According to the SIR classification, one type A, eight type C, and one type D complication occurred. Total devascularization was noted in 96% (116 of 121) of dominant fibroids. Volume decrease was 4% at 2 weeks, 52% (P < 0.001) at 3 months, 78% (P < 0.001) at 6 months, and 91% at 12 months (P < 0.001). The latter difference was statistically significant (P = 0.007). A total of 92% had improved hypermenorrhea at 1 year and 94% at 2 years. Dysmenorrhea was improved in 96% at 1 year and in 95% at 2 years. The overall health status score was 60.4 +/- 26.2 points at baseline and 96.9 +/- 3.8 after 1 year (P = 0.0019). CONCLUSION: Uterine artery embolization with Embozene microspheres is a safe procedure. Its efficacy is demonstrated by high fibroid devascularization and volume reduction rates and significant improvements of clinical symptoms and quality-of-life scores during follow-up. PMID- 20953611 TI - Impact of cytokine gene polymorphisms on risk and treatment outcomes of aplastic anemia. AB - Autoreactive cytotoxic T cells play a key role in the pathogenesis of aplastic anemia (AA) by myelosuppressive cytokines including interferon-gamma, tumor necrosis factor alpha, and transforming growth factor beta. The purpose of this study is to determine which single nucleotide polymorphisms (SNPs) in cytokine genes were relevant to AA risk and whether the relevant SNPs were associated with response to immunosuppressive therapy (IST). Among 84 screened patients, 80 patients confirmed as having acquired AA, and 84 age- and sex-matched healthy controls were analyzed consecutively. We genotyped ten polymorphisms in three cytokine genes (IFNG, TNF, and TGFB1) and FAS gene. We assessed the association between polymorphisms and AA risk, and the association between polymorphisms and response to IST in three genetic models (dominant, recessive, and additive). The IFNG -2,353 T allele (dominant model, OR = 0.43, p = .012) and TCA haplotype (dominant model, OR = 0.50, p = .038) were significantly associated with the development of AA. In addition, this relevant IFNG -2,353 T allele and TCA haplotype were related to the response of IST (dominant model, OR = 0.076, p = .034). Concerning TGFB1, although its polymorphisms are not related to AA susceptibility, P10L T allele (recessive model, OR = 0.18, p = .038) and CT haplotype (dominant model, OR = 5.68, p = .038) were associated with response to IST. This exploratory study concurred with prior studies indicating that polymorphisms in IFNG are related to AA susceptibility. In addition, it was found that polymorphisms in IFNG and TGFB1 are associated with response to IST. PMID- 20953613 TI - Plaque regression in one artery is not necessarily associated with parallel changes in other vascular beds. AB - It remains unclear whether atherosclerosis in one vascular bed progresses in parallel with that in other vascular beds. We investigated serial changes in vessel wall areas (VWAs) in various vessels over 2 years of follow-up. Vessel wall areas in the thoracic descending aorta (TDA), common carotid artery (CCA), right (RCA), and left main trunk (LMT) of coronary artery were determined in 52 patients with coronary artery disease (CAD) using 64-slice multidetector computed tomography. Plasma levels of high-sensitivity CRP (hs-CRP) and matrix metalloproteinase (MMP)-9, as well as urinary 8-iso-prostaglandin F2alpha (PGF2alpha) were determined at the baseline. After the follow-up period, plaque progression in a specific vessel did not parallel that of other vessels, although changes in TDA-VWAs were weakly correlated with those of LMT-VWAs. Basal levels of hs-CRP, MMP-9, and PGF2alpha did not predict progression or regression of VWAs in any vessels. Multivariate analyses showed that LDL-cholesterol < 100 mg/dl and use of statin emerged as predictors of regressing VWAs in TDA (p < 0.05 and p < 0.05, respectively) and LMT (p < 0.05 and p = 0.13, respectively). Changes in soft plaques over 2 years paralleled those of VWAs in both coronary arteries. In conclusion, the progression or regression of atherosclerotic plaques is inhomogeneous among the vascular beds of patients with CAD. PMID- 20953614 TI - Are pulmonary artery pulsatility indexes able to differentiate chronic pulmonary thromboembolism from pulmonary arterial hypertension? An echocardiographic and catheterization study. AB - The differentiation between chronic pulmonary thromboembolic hypertension (CTEPH) and pulmonary arterial hypertension (PAH) remains a clinical challenge. The aim of our study was to evaluate the usefulness of both echocardiographically and invasively derived pulmonary artery pulsatility indexes in the etiologic differentiation of patients with CTEPH and PAH. We retrospectively analyzed the results of echocardiographic and invasive hemodynamic examinations in 125 patients with either CTEPH (n = 62) or PAH (n = 63). Invasive data were obtained in 52 patients with CTEPH and 43 PAH patients. Using echocardiography, pulmonary artery systolic (PASP), diastolic (PADP) and mean (PAMP) pressures were estimated from velocities of tricuspid regurgitation and pulmonary regurgitation, respectively. Pulse pressure (PP) was calculated as the difference between PASP and PADP. To obtain pulmonary artery pulsatility indexes, we normalized PP by PASP (PP/PASP), by PAMP (PP/PAMP) and by PADP (PP/PADP). Pulsatility indexes assessed by echocardiography did not differ between CTEPH and PAH patients except for PP/PAMP [PP/PAMP (1.82 +/- 0.33 vs. 1.40 +/- 0.3, p < 0.001)]. Invasively derived pulsatility indexes were significantly higher in subjects with CTEPH (0.60 +/- 0.08 vs. 0.53 +/- 0.09 for PP/PASP; 0.98 +/- 0.21 vs. 0.81 +/- 0.21 for PP/PAMP; 1.58 +/- 0.52 vs. 1.21 +/- 0.41 for PP/PADP; all p < 0.001). The areas under the receiver-operating characteristic curves analysis showed that no cutoff value allowed discriminating between CTEPH and PAH by using echocardiographically or invasively derived pulsatility indices. Invasively derived pulmonary artery pulsatility indexes as well as echocardiographically determined PP/PAMP indexes are higher in CTEPH compared to PAH. However, due to the important overlap no optimal threshold values of these parameters can be given to allow satisfactory discrimination of the two diseases in clinical practice. PMID- 20953615 TI - Reduced renal function is associated with combined increases in ventricular systolic stiffness and arterial load in patients undergoing cardiac catheterization for coronary artery disease. AB - Although mildly reduced renal function is associated with increased risk for heart failure in patients with coronary artery disease (CAD), mechanisms underlying the association remain unclear. We tested the hypothesis that abnormal ventricular-arterial interaction may occur in mildly reduced renal function. We examined the relationships of the estimated glomerular filtration rate (eGFR) with various indices reflecting ventricular-arterial coupling [effective arterial elastance (the ratio of left ventricular (LV) end-systolic pressure to stroke volume, E (a)], LV end-systolic elastance (the ratio of LV end-systolic pressure to end-systolic volume, E (es)), and the total arterial compliance (the ratio of stroke volume to aortic pulse pressure)] and those of LV systolic and diastolic function [peak systolic and diastolic mitral annular velocities (S' and E') and the ratio of peak early diastolic mitral inflow to annular velocity (E/E')] in 320 consecutive patients who underwent cardiac catheterization for CAD and had normal (>= 0.50) ejection fractions (EF). As eGFR decreased, E (a) and E (es) increased and total arterial compliance and E' decreased. eGFR did not correlate with E (a)/E (es), S', or E/E'. After adjusting for potential confounders, the findings were generally similar, but the correlation of eGFR with E' did not remain significant. In conclusion, reduced renal function may be associated with combined increases in ventricular-systolic stiffness and arterial load in known or suspected CAD patients with normal EF. PMID- 20953616 TI - Coffee consumption but not green tea consumption is associated with adiponectin levels in Japanese males. AB - PURPOSE: Coffee is among the most widely consumed beverages in the world. Numerous epidemiological studies have reported a significant inverse association between coffee consumption and risk of type 2 diabetes mellitus, but the underlying mechanisms are still not fully understood. Therefore, we conducted an epidemiological study to clarify the relationship between coffee consumption and adiponectin levels in Japanese males. We also evaluated whether green tea consumption affected adiponectin levels. METHODS: We carried out a cross sectional study. The subjects were 665 male employees in Japan. Coffee consumption was assessed, using a self-administered questionnaire, as the number of times per week and cups per day respondents drank, and subjects were grouped into four levels (non, 1-5 times/week, 1-2 cups/day and >=3 cups/day). RESULTS: The means of adiponectin levels were positively associated with coffee consumption. A dose-response relationship was found between coffee consumption and circulating adiponectin levels. The relationship remained significant after adjustment for potential confounding factors (P for trend <0.05). However, green tea consumption was not significantly associated with adiponectin levels (P for trend = 0.90). CONCLUSIONS: We not only revealed that habitual coffee consumption is associated with higher adiponectin levels in Japanese males but also found a dose-dependent association between coffee consumption and adiponectin levels. Therefore, our study suggested that coffee components might play an important role in the elevation of adiponectin level. PMID- 20953618 TI - Individualised treatment in alcohol-dependent patients. AB - Long-term relapse prevention is the biggest challenge in treating alcohol dependent patients. It is equally based on psychotherapy and pharmacotherapy. Psychotherapy includes motivational interviewing, community reinforcement, cognitive behavioural therapy, motivational enhancement, twelve-step facilitation, social network behaviour therapy, cue exposure, etc. For pharmacological treatment, we dispose of disulfiram, acamprosate and naltrexone. Reviews and meta-analyses reveal only modest effect sizes of these approaches probably because they are usually tested in large and heterogeneous samples where "one size does not fit all". However, attempts to form more homogeneous subgroups for which specific psychotherapies should be more effective ("matching") also failed. We suppose that this failure may have to do with the fact that these studies used only psychopathology and behavioural analyses as a basis for subtyping. Things look more promising once biologically defined endophenotypes are used as well in order to form more homogeneous subgroups. For example, naltrexone treatment seems more effective in carriers of a specific variant of the mu-opioid receptor gene. The same could be true for acamprosate if a newly found polymorphism was used to preselect potential responders. Very recently biological differences between patient groups are also being detected using functional imaging. Naltrexone is suggested to work better in a subgroup of patients with higher cue reactivity when shown appetitive alcohol pictures. MR spectroscopy of brain glutamate levels may detect potential acamprosate responders. On such a basis, an individualised approach in the treatment of alcoholism ("personalised medicine") seems to hold promise. PMID- 20953619 TI - Ranibizumab for retinal arterial macroaneurysms. PMID- 20953620 TI - Clinical outcomes of posterior chamber toric phakic intraocular lens implantation for the correction of high myopic astigmatism in eyes with keratoconus: 6-month follow-up. AB - BACKGROUND: To assess the early clinical outcomes of toric implantable collamer lenses (toric ICLTM, STAAR Surgical) for the correction of high myopic astigmatism with keratoconus. METHODS: This study evaluated 27 eyes of 14 patients with spherical equivalents of -10.11 +/- 2.46 D (mean +/- standard deviation) and astigmatism of -3.03 +/- 1.58 D who underwent toric ICL implantation for mild keratoconus. Before, and 1, 3 and 6 months after surgery, we assessed the safety, efficacy, predictability, stability, and adverse events of the surgery. RESULTS: LogMAR uncorrected visual acuity (UCVA) and LogMAR best spectacle-corrected visual acuity (BSCVA) were -0.09 +/- 0.16 and -0.15 +/- 0.09 respectively, 6 months after surgery. The safety and efficacy indices were 1.12 +/- 0.18 and 1.01 +/- 0.25. At 6 months, 85% and 96% of the eyes were within +/ 0.5 and +/-1.0 D respectively of the targeted correction. Manifest refraction changes of 0.00 +/- 0.35 D occurred from 1 week to 6 months. No vision threatening complications occurred during the observation period. CONCLUSIONS: Toric ICL implantation was good in all measures of safety, efficacy, predictability, and stability for the correction of spherical and cylindrical errors in eyes with early keratoconus throughout the 6-month follow-up period, suggesting its viability as a surgical option for the treatment of such eyes. PMID- 20953621 TI - Gender differences in psychophysically determined maximum acceptable weights and forces for industrial workers observed after twenty years. AB - PURPOSE: In the year 1991, manual materials handling guidelines were published by Liberty Mutual Research Institute for Safety. In these guidelines, maximum acceptable weights (MAWs) and forces (MAFs) for lifting, lowering, pushing, pulling, and carrying were derived from studies conducted in a 20 year span before the above publication date. The question is whether the present generation of workers has retained the same gender differences and absolute values in psychophysically determined MAWs and MAFs as those reflected in the guideline. METHODS: Twenty-four female industrial workers performed 20 variations of lifting, lowering, pushing, pulling, and carrying. A psychophysical methodology was used whereby the workers chose a workload they could sustain for 8 h without "straining themselves or without becoming unusually tired, weakened, overheated or out of breath." RESULTS: In females, MAWs of lifting, lowering, and carrying averaged 53% of the present-day male values, similar to the 55% in the guideline. MAFs of pushing and pulling were 83 and 86% of the present-day male values but slightly higher than the 73 and 78% in the guideline, respectively for initial and sustained forces. CONCLUSIONS: The similarity of gender differences between the guideline and the present findings was coupled with dramatic decreases in MAWs of lifting, lowering, and carrying. Such decreases may reflect a new psychophysical set point; however, considerations about adjusting existing guidelines on lifting, lowering, and carrying may not be appropriate until additional data from other sources inside and outside the US confirm the present findings. PMID- 20953622 TI - The importance of job control for workers with decreased work ability to remain productive at work. AB - PURPOSE: Workers with decreased work ability are at greater risk of reduced productivity at work. We hypothesized that work-related characteristics play an important role in supporting workers to remain productive despite decreased work ability. METHODS: The study population consisted of 10,542 workers in 49 different companies in the Netherlands in 2005-2009. Productivity loss at work was defined on a 10-point scale by asking how much work was actually performed during regular hours on the last regular workday when compared with normal. Independent variables in the logistic regression analysis were individual characteristics, work-related factors, and the work ability index. Additive interactions between work-related factors and decreased work ability were evaluated by the relative excess risk due to interaction (RERI). RESULTS: The odds ratios and 95% confidence intervals (CI) for the likelihood of productivity loss at work were 2.03 (1.85-2.22), 3.50 (3.10-3.95), and 5.54 (4.37-7.03) for a good, moderate, and poor work ability, compared with an excellent work ability (reference group). Productivity loss at work was associated with lack of job control, poor skill discretion, and high work demands. There was a significant interaction between decreased work ability and lack of job control (RERI = 0.63 95% CI 0.11-1.16) with productivity loss at work. CONCLUSION: The negative effects on work performance of decreased work ability may be partly counterbalanced by increased job control. This suggests that interventions among workers with (chronic) disease that cause a decreased work ability should include enlargement of possibilities to plan and pace their own activities at work. PMID- 20953623 TI - Workplace stress and prescription of antidepressant medications: a prospective study on a sample of Italian workers. AB - PURPOSE: The main aim of this study was to examine prospectively the relationship between antidepressant prescriptions (ADP), as a proxy of depressive symptoms, and work-related stress, measured according to the demand-control model. METHODS: A cohort of 2,046 union workers who participated in a survey on working conditions and health in 1999-2000 was followed up to 2005, through the Regional Drug Prescription Register, for an ADP. The relative risks associated with demand, control and job strain were estimated using Poisson regression, adjusting for age, sex and other workplace factors (shift work, overtime, loud noise and psychological violence). RESULTS: In final multivariable models, high demand significantly increased the risk of depressive symptoms among blue collars (RR = 1.82), whereas among white collars, it was significantly protective (RR = 0.38). No significant relationship was found for job control or strain in either occupational class. CONCLUSIONS: The direct association observed elsewhere among blue collars between depressive symptoms and demand was confirmed, but not for job control or job strain. It cannot be ruled out that the association with demand was at least in part determined by reverse causation, due to exposure over reporting among subjects with subclinical depressive symptoms at baseline. The protective effect of demand among white collars is not consistent with the literature and may be attributable to the particular characteristics of this sample, which included mainly workers employed in public administrative positions. PMID- 20953624 TI - In airways ATP refills sarcoplasmic reticulum via P2X smooth muscle receptors and induces contraction through P2Y epithelial receptors. AB - In airway smooth muscle (ASM), ATP induces a contraction associated with the increase of [Ca(2+)](i). Cytosolic Ca(2+) is extruded to the extracellular space by the Na(+)/Ca(2+) exchanger (NCX) in its normal mode. Some agonists activate the reverse mode of the NCX (NCX(REV)), inducing Ca(2+) entry. We investigated whether ATP, via P2X receptors, activates the NCX(REV) and whether the increment in [Ca(2+)](i) is used for contraction or for the sarcoplasmic reticulum (SR) refilling in guinea pig ASM. ATP contracted the ASM and this effect was blocked by indomethacin. Suramin and RB2 diminished the contraction induced by ATP; PPADS did not modify this response. In myocytes, ATP produces an increase in [Ca(2+)](i) not modified by indomethacin. In tracheal strips, using simultaneous measurements, ATP induced a biphasic change in [Ca(2+)](i), (a Ca(2+) peak followed by a plateau) accompanied by a contraction. Indomethacin or epithelium removal abolished this contraction, but not the Ca(2+) peak, whereas the plateau was decreased by indomethacin. In myocytes, the ATP-induced [Ca(2+)](i) increment was inhibited by suramin (~96%), PPADS (~40%), and RB2 (~57%). ATP augmented the NCX(REV) and this effect was abolished by SKF 96365 and TNP-ATP (P2X(1) and P2X(3) receptors antagonist). P2X(1) and P2X(3) receptors were corroborated by immunoblotting of ASM. NCX(REV) activation and ATP in the presence of RB2 favor the SR Ca(2+) refilling. In tracheal rings, successive ATP stimulations were reduced with KB-R7943. Therefore, ATP: (1) indirectly promotes muscle contraction via epithelial P2Y receptors and prostaglandins release; (2) increases the [Ca(2+)](i) through a prostaglandin-independent manner by activating P2X and P2Y receptors in smooth muscle; and (3) activates P2X(1) and P2X(3) receptors and the NCX(REV) which refills the SR. PMID- 20953625 TI - Estradiol reduces dendritic spine density in the ventral striatum of female Syrian hamsters. AB - Estradiol affects a variety of brain regions by modulating physiological and cellular functions as well as neuronal morphology. Within the striatum, estradiol is known to induce physiological and molecular changes, yet estradiol's effects on striatal dendritic morphology have not yet been evaluated. Using ballistic delivery of the lipophilic dye DiI to tissue sections, we were able to evaluate estradiol's effects on striatal morphology in female Syrian hamsters. We found that estradiol significantly decreased spine density within the nucleus accumbens core, with no effect in the nucleus accumbens shell or caudate. Interestingly, estradiol treatment caused a significant deconstruction of spines from more to less mature spine subtypes in both the nucleus accumbens core and shell regardless of changes in spine density. These results are significant in that they offer a novel mechanism for estradiol actions on a wide variety of nucleus accumbens functions such as motivation or reward as well as their pathological consequences (e.g. drug addiction). PMID- 20953626 TI - Prominent periventricular fiber system related to ganglionic eminence and striatum in the human fetal cerebrum. AB - Periventricular pathway (PVP) system of the developing human cerebrum is situated medial to the intermediate zone in the close proximity to proliferative cell compartments. In order to elucidate chemical properties and developing trajectories of the PVP we used DTI in combination with acetylcholinesterase histochemistry, SNAP-25 immunocytochemistry and axonal cytoskeletal markers (SMI312, MAP1b) immunocytochemistry on postmortem paraformaldehyde-fixed brains of 30 human fetuses ranging in age from 10 to 38 postconceptional weeks (PCW), 2 infants (age 1-3 months) and 1 adult brain. The PVP appears in the early fetal period (10-13 PCW) as two defined fibre bundles: the corpus callosum (CC) and the fetal fronto-occipital fascicle (FOF). In the midfetal period (15-18 PCW), all four components of the PVP can be identified: (1) the CC, which at rostral levels forms a voluminous callosal plate; (2) the FOF, with SNAP-25-positive fibers; (3) the fronto-pontine pathway (FPP) which for a short distance runs within the PVP; and (4) the subcallosal fascicle of Muratoff (SFM) which contains cortico-caudate projections. The PVPs are situated medial to the internal capsule at the level of the cortico-striatal junction; they remain prominent during the late fetal and early preterm period (19-28 PCW) and represent a portion of the wider periventricular crossroad of growing associative, callosal and projection pathways. In the perinatal period, the PVPs change their topographical relationships, decrease in size and the FOF looses its SNAP-25-reactivity. In conclusion, the hitherto undescribed PVP of the human fetal cerebrum contains forerunners of adult associative and projection pathways. Its transient chemical properties and relative exuberance suggest that the PVP may exert influence on the development of cortical connectivity (intermediate targeting) and other neurogenetic events such as neuronal proliferation. The PVP's topographical position also indicates that it is a major site of vulnerability in hypoxic ischaemic perinatal brain injury. PMID- 20953627 TI - Current knowledge on PB1-F2 of influenza A viruses. AB - Almost 10 years ago, an eleventh protein of influenza A viruses was discovered in a search for CD8+ T-cell epitopes. This protein was named PB1-F2 since it is encoded in the +1 reading frame of the PB1 gene segment. Various studies have shown that PB1-F2 has a pleiotropic effect: (1) The protein can induce apoptosis in a cell type-dependent manner, (2) PB1-F2 is able to promote inflammation, and (3) finally it up-regulates viral polymerase activity by its interaction with the PB1 subunit. These properties could contribute to an enhanced pathogenicity. However, the underlying mechanism is not fully understood yet. New data suggest that some effects of PB1-F2 are strain-specific and host-specific. PMID- 20953628 TI - Kinetics of circulating antigen 14-3-3 in sera of rabbits firstly infected with Schistosoma japonicum and treated with/without praziquantel. AB - A sandwich ELISA was developed for the detection of circulating antigen 14-3-3 in the sera of rabbits. Rabbits that were infected with 500 cercariae of Schistosoma japonicum were grouped and the kinetics of 14-3-3 was observed. For the treated group, the 14-3-3 protein could be detected as early as 2-4 weeks postinfection and then its levels rose rapidly and reached a peak at around 6 weeks. The 14-3-3 levels in the sera significantly decreased after the infected rabbits were treated with praziquantel at 6 weeks postinfection and declined to the initial level about 8 weeks posttreatment. While in the untreated group, 14-3-3 levels reached a peak in 8 weeks postinfection and then remained at plateau level for about 6 weeks. Our findings showed that detection of S. japonicum 14-3-3 has an important value for diagnosis of acute infection of S. japonicum and evaluation of chemotherapy. PMID- 20953629 TI - Ticks (Acari: Ixodidae) infesting wild birds in the Atlantic Forest in northeastern Brazil, with notes on rickettsial infection in ticks. AB - A total of 232 individuals representing 46 species of birds were mist-netted and screened for ticks in a region of the Atlantic Forest, State of Bahia, Brazil. Thirty-eight (16.4%) of these birds representing 17 species were found infested by immature stages of Amblyomma ticks, namely, Amblyomma longirostre (Koch, 1844) (15 larvae and seven nymphs), Amblyomma nodosum (Neumann, 1899) (nine nymphs), Amblyomma calcaratum (Neumann, 1899) (five nymphs), Amblyomma cajennense (Fabricius, 1787) (seven larvae), and Amblyomma parkeri (Fonseca and Aragao, 1952) (four larvae). Overall, 21 larvae and five nymphs collected from birds could not be identified to species and were morphologically identified as Amblyomma spp. Among 13 A. longirostre larvae and two A. parkeri larvae, two individuals of A. longirostre (15.4%) were found infected by Rickettsia amblyommii. This study provides some bird species found infested by A. longirostre, A. parkeri, A. calcaratum, A. nodosum, or A. cajennense for the first time and expands the distribution of R. amblyommii-infected A. longirostre ticks. PMID- 20953630 TI - Proteomic survey of the cestode Mesocestoides corti during the first 24 hours of strobilar development. AB - Despite the fact that cestodes represent major etiological agents of both human and domestic animal diseases, little is known about the molecular aspects of cestode development. In this work, Mesocestoides corti, a model cestode species, was studied from the early development of its larval form (tetrathyridium) into adult worms (strobilation) using different proteomic approaches. The protein profiles of M. corti tetrathyridia induced or not induced to undergo strobilation were compared. Proteomic mapping by two-dimensional gel electrophoresis showed the resolution of 248 and 154 spots from tetrathyridia that were subjected or not subjected to strobilation induction, respectively, allowing for the detection of at least nine spots exclusive to each group. Spot analysis by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) or MALDI-TOF MS/MS identified four reference proteins (six spots). LC-MS/MS analyses of protein extracts identified 66 proteins, eight of which were found exclusively in non-induced tetrathyridia, while 13 were found exclusively in strobilation induced tetrathyridia. Among the proteins exclusively identified in strobilation induced worms, there was a predominance of proteins with functions relating to chaperone activity and protein synthesis and turnover. Quantitative differential expression analysis between M. corti tetrathyridia prior to and after strobilation induction revealed six proteins upregulated in strobilation-induced worms; these proteins were involved in metabolic pathways, cell proliferation, and cytoskeletal rearrangement. Overall, despite the absence of a sequenced M. corti genome, using sequences from other platyhelminthes, we were able to establish comprehensive protein profiles for tetrathyridia prior to and after strobilation induction and identify several proteins potentially involved in the early events leading to strobilation. PMID- 20953631 TI - Hypothermia translocates nitric oxide synthase from cytosol to membrane in snail neurons. AB - Neuronal nitric oxide (NO) levels are modulated through the control of catalytic activity of NO synthase (NOS). Although signals limiting excess NO synthesis are being extensively studied in the vertebrate nervous system, our knowledge is rather limited on the control of NOS in neurons of invertebrates. We have previously reported a transient inactivation of NOS in hibernating snails. In the present study, we aimed to understand the mechanism leading to blocked NO production during hypothermic periods of Helix pomatia. We have found that hypothermic challenge translocated NOS from the cytosol to the perinuclear endoplasmic reticulum, and that this cytosol to membrane trafficking was essential for inhibition of NO synthesis. Cold stress also downregulated NOS mRNA levels in snail neurons, although the amount of NOS protein remained unaffected in response to hypothermia. Our studies with cultured neurons and glia cells revealed that glia-neuron signaling may inhibit membrane binding and inactivation of NOS. We provide evidence that hypothermia keeps NO synthesis "hibernated" through subcellular redistribution of NOS. PMID- 20953632 TI - Therapeutic targeting of the innate immune system in domestic animals. AB - Since first being described in the fruit fly Drosophila melanogaster, the knowledge regarding Toll-like receptors (TLRs) has transformed our understanding of immunology. TLRs are a family of conserved pattern recognition receptors (PRR) that recognise specific microbial-associated molecular patterns and allow the cell to distinguish between self and non-self materials. The very property of the TLRs, to link innate and adaptive immunity, offers a novel opportunity to develop vaccines that engage TLR signalling. The presence of TLR ligands as adjuvants in conjunction with a vaccine is shown to increase the efficacy and response to the immunisation with a particular antigen. Here, we focus on the findings pertaining to TLR ligands as adjuvants and discuss the importance of these studies in the development of an optimal vaccine in farm and companion animals. PMID- 20953634 TI - Ibandronate affects bone growth and mineralization in rats with normal and reduced renal function. AB - Bisphosphonates have been shown to attenuate ectopic calcification in experimental uremia. While they are known to reduce bone turnover, the effects on endochondral bone formation have not yet been addressed. To address this issue, we administered male Sprague-Dawley rats weekly subcutaneous injections of either vehicle or ibandronate (1.25 MUg/kg body weight) for a total of 10 weeks. The rats were randomly allocated into one of four groups: (1) vehicle-treated, sham operated rats; (2) ibandronate-treated, sham-operated rats; (3) vehicle-treated, 5/6 nephrectomized rats; (4) ibandronate-treated, 5/6 nephrectomized rats. Bones were double labeled with tetracycline and demeclocycline in vivo, and tibiae were removed for analysis. Weight gain was similar in all groups. Ibandronate reduced body length gain and tibial growth rate in the sham-operated animals but not in the rats showing chronic renal failure (CRF). The height of the proliferative zone of the epiphyseal growth plate was reduced in the ibandronate-treated controls and tended to be reduced in CRF rats. A significant correlation between tibial growth rate and height of the proliferative zone was observed. Mineral apposition rates were significantly reduced in ibandronate-treated, sham-operated rats and tended to be reduced in CRF rats. In conclusion, ibandronate interferes with tibial growth and bone mineralization in young rats with normal and reduced renal function. PMID- 20953633 TI - beta-Adrenergic receptor subtype expression in myocyte and non-myocyte cells in human female bladder. AB - beta(3)-Adrenergic receptor agonists are currently under clinical development for the treatment of overactive bladder, a condition that is prevalent in postmenopausal women. These agents purportedly relax bladder smooth muscle through a direct action at the myocyte beta(3)-receptor. The aim of this study was to examine the expression of the individual beta-adrenergic receptors in full thickness sections from ageing human female bladder. We obtained a series of rabbit polyclonal antibodies generated against each of the three beta-adrenergic receptors, and validated their receptor specificity in CHOK1 cells expressing each of the individual receptors. Immunostaining for beta(1), beta(2), and beta(3) were each more prominent in the urothelium than in the detrusor, with all receptors expressed in the same cell types, indicating co-expression of all three receptors throughout the urothelium in addition to the detrusor. Staining of all receptors was also observed in suburothelial myofibroblast-like cells, intramural ganglion cells, and in Schwann cells of intramural nerves. The beta(3)-receptor in the human urothelium appears to be functional, as two different selective beta(3)-receptor agonists, TAK677 and BRL37344, stimulate cAMP formation in URO tsa cells. Densitometry analysis indicates a persistent expression of all receptors throughout the bladder with increasing age, with the exception of the beta(2)-receptor in the urothelium of the trigone, which appears to decrease slightly in older women. These data indicate that beta(3)-receptor expression is maintained with age, but may function in concert with other beta-receptors. Activation of the myocyte receptor may be influenced by action on non-myocyte structures including the intramural ganglion cells and myofibroblasts. PMID- 20953635 TI - The relationship between arginine vasopressin levels and hyponatremia following a percutaneous renal biopsy in children receiving hypotonic or isotonic intravenous fluids. AB - Post-operative hyponatremia is a common complication in children which results from hypotonic fluid administration in the presence of arginine vasopressin (AVP) excess. We evaluated the relationship between the change in serum sodium and AVP levels following percutaneous renal biopsy in children receiving either hypotonic or isotonic fluids. This study was prompted after we encountered a patient who developed near-fatal hyponatremic encephalopathy following a renal biopsy while receiving hypotonic fluids. The relationship between the change in serum sodium and AVP levels was evaluated prior to (T0) and at 5 h (T5) following a percutaneous renal biopsy in 60 children receiving either hypotonic (0.6% NaCl, 90 mEq/L) or isotonic fluids (0.9% NaCl, 154 mEq/L). The proportion of patients with elevated AVP levels post-procedure was similar between those receiving 0.6 or 0.9% NaCl (30 vs. 26%). Patients receiving 0.6% NaCl with elevated AVP levels experienced a fall in serum sodium of 1.9 +/- 1.5 mEq/L, whereas those receiving 0.9% NaCl had a rise in serum sodium of 0.85 +/- 0.34 mEq/L with no patients developing hyponatremia. There were no significant changes in serum sodium levels in patients with normal AVP concentrations post-procedure in either group. In conclusion, elevated AVP levels were common among our patients following a percutaneous renal biopsy. Isotonic fluids prevented a fall in serum sodium and hyponatremia, while hypotonic fluids did not. PMID- 20953636 TI - Pollen counts and their relationship to meteorological factors in Ankara, Turkey during 2005-2008. AB - Pollen plays an important role in the development and exacerbation of allergic diseases. We aimed to investigate the days with highest counts of the most allergenic pollens and to identify the meteorological factors affecting pollen counts in the atmosphere of Ankara, Turkey. Airborne pollen measurements were carried out from 2005 to 2008 with a Burkard volumetric 7-day spore trap. Microscope counts were converted into atmospheric concentrations and expressed as pollen grains/m(3). Meteorological parameters were obtained from the State Meteorological Service. All statistical analyses were done with pollen counts obtained from March to October for each year. The percentages of tree, grass and weed pollens were 72.1% (n = 24,923), 12.8% (n = 4,433) and 15.1% (n = 5,219), respectively. The Pinaceae family from tree taxa (39% to 57%) and the Chenopodiaceae/Amaranthaceae family from weed taxa, contributed the highest percentage of pollen (25% to 43%), while from the grass taxa, only the Poaceae family was detected from 2005 to 2008. Poaceae and Chenopodiaceae/Amaranthaceae families, which are the most allergenic pollens, were found in high numbers from May to August in Ankara. In multiple logistic regression analysis, wind speed (OR = 1.18, CI95% = 1.02-1.36, P = 0.023) for tree pollen, daily mean temperature (OR = 1.10, CI95% = 1.04-1.17, P = 0.001) and sunshine hours (OR = 1.15, CI95% = 1.01 1.30, P = 0.033) for grass pollen, and sunshine hours (OR = 3.79, CI95% = 1.03 13.92, P = 0.044) for weed pollen were found as significant risk factors for high pollen count. The pollen calendar and its association with meteorological factors depend mainly on daily temperature, sunshine hours and wind speed, which may help draw the attention of physicians and allergic patients to days with high pollen counts. PMID- 20953637 TI - Single-nucleotide polymorphism in the hyaluronan and proteoglycan link protein 1 (HAPLN1) gene is associated with spinal osteophyte formation and disc degeneration in Japanese women. AB - Spinal osteoarthritis including disc degeneration is a very common condition in the axial skeletons of aged people. Recently, spinal osteoarthritis has been shown to be influenced by specific genetic risk factors. Vertebral osteophytes, endplate sclerosis, and intervertebral disc narrowing are recognized as radiographic features of spinal disc degeneration. HAPLN1 is a key component of the cartilage extracellular matrix; thus, variations in this gene may affect the pathogenesis of cartilage-related diseases such as spinal degeneration. Here, we examine the association between an HAPLN1 gene polymorphism and the radiographic features of spinal degeneration. We evaluated the degree of endplate sclerosis, osteophyte formation, and disc space narrowing in 622 Japanese postmenopausal women. Four SNPs in the HAPLN1 gene-in the 5' flanking region, intron 1, intron 2, and intron 4-were analyzed using the TaqMan polymerase chain reaction method. We found that compared to subjects with the CC or CT genotype, those with the TT genotype for an SNP at intron 2 (rs179851) were significantly overrepresented among the subjects with higher scores for osteophyte formation (P = 0.0001; odds ratio 2.12; 95% confidence interval 1.45-3.11, as determined by logistic regression analysis) and disc space narrowing (P = 0.0057; odds ratio 1.83; 95% confidence interval 1.19-2.83). Consistent with the involvement of the HAPLN1 gene in cartilage metabolism, a variation in a specific HAPLN1 gene locus may be associated with spinal degeneration. PMID- 20953638 TI - Clinical outcomes of microscopic decompression for degenerative lumbar foraminal stenosis: a comparison between patients with and without degenerative lumbar scoliosis. AB - We performed microscopic lumbar foraminotomy in all the patients diagnosed with degenerative lumbar foraminal stenosis (DLFS) and retrospectively reviewed the clinical outcomes and the factors influencing them. The preoperative Japanese Orthopaedic Association (JOA) score of 13.8 significantly improved to 21.9 postoperatively. Although leg pain reduced in 44 patients (95.7%) immediately after surgery, it recurred in 9 patients (19.6%). The recurrence frequency was significantly higher and the JOA score improvement ratios significantly lower in patients with degenerative lumbar scoliosis (DLS) than in those without DLS. Even among patients with DLS, those with <3 degrees Cobb angle difference between the supine and standing positions showed satisfactory results, with no recurrence. In conclusion, microscopic lumbar foraminotomy for DLFS produced satisfactory clinical outcomes even in patients with DLS. However, the outcomes were poor in patients with unstable DLS. PMID- 20953639 TI - Relationships between maximal oxygen uptake and endothelial function in healthy male adults: a preliminary study. AB - Aerobic capacity, as indicated by maximal oxygen uptake (VO2 max) has an important role in contrasting the traditional cardiovascular risk factors and preventing cardiovascular morbidity and mortality. It is known that endothelial function, measured as flow-mediated dilation (FMD) of the brachial artery, is strictly linked to atherogenesis and cardiovascular risk. However, the relationship between VO2 max and FMD has not been fully investigated especially in healthy non-obese subjects. This preliminary study cross-sectionally investigated the relationship between VO2 max and FMD in 22 non-obese, healthy sedentary male subjects. Dividing the cohort in two subgroups of 11 subjects each according to the median value of VO2 max, the FMD was significantly lower in the subgroup with lower VO2 max (mean +/- sem: 7.1 +/- 0.7 vs. 9.5 +/- 0.8 %; P = 0.035). Absolute VO2 max (mL min(-1)) was significantly and independently correlated with body fat mass (r = -0.50; P = 0.018) and with FMD (r = 0.44; P = 0.039). This preliminary study suggests that maximal oxygen uptake is independently correlated with endothelial function in healthy non-obese adults. These results are also in agreement with the possibility that improving maximal oxygen uptake may have a favorable effect on endothelial function and vice versa. PMID- 20953640 TI - The prevalence and characteristics of latent autoimmune diabetes in adults (LADA) and its relation with chronic complications in a clinical department of a university hospital in Korea. AB - Few studies were performed to evaluate the prevalence of latent autoimmune diabetes in adults (LADA) and the difference of chronic complications between LADA, T1DM, and T2DM in Korean. The aim of this study is to establish the prevalence of LADA in a diabetic clinic of Soonchunhyang University hospital and to compare the phenotypic characteristics according to DM classification based on positivity of glutamic acid decarboxylase antibodies (GADA). Also, another important point concerns the occurrence of diabetes chronic microvascular complications in LADA. 323 patients who were checked GADA among diabetic patients admitted at Soonchunhyang University hospital were recruited. Twenty-eight patients (8.7%) were identified as positive for GADA. 11.5% (n = 37) were diagnosed with T1DM and 5.3% (n = 17) were diagnosed with LADA. GADA titer showed significant negative correlation with age of onset, total cholesterol (TC), triglyceride (TG), fasting C-peptide, stimulated C-peptide, BMI, and positive correlation with HbA1C and HDL-C. Compared with those that tested negative for GADA, patients with GADA positive had lower values of onset age, BMI, TC, TG, LDL C, fasting, and stimulated C-peptide levels and higher values of HbA1C. A significant gradual increase of values was observed for the onset age, BMI, SBP, DBP, fasting, and stimulated C-peptide across the T1DM, LADA, and T2DM subgroups. Concerning the chronic complications there was no difference in prevalence of retinopathy, neuropathy and nephropathy between three groups. Of LADA patients, 12 patients were receiving insulin treatment and mean time to insulin initiation was about 37 months. In conclusion, because our study suggests LADA subgroups in Korea appear to have a faster decline in C-peptide levels, it is worth detecting the patients with LADA early and effort to preserve beta cell function. Furthermore, our results showed that the prevalence of microvascular complication was comparable between the subgroups. PMID- 20953642 TI - Plasma homovanillic acid correlates inversely with history of childhood trauma in personality disordered and healthy control adults. AB - Studies of the cerebrospinal fluid (CSF) level of the dopamine metabolite, homovanillic acid (HVA), suggest a relationship between CSF HVA concentration and history of childhood trauma. In this study, the authors test the hypothesis that this relationship is also present using peripheral levels of HVA in healthy volunteers and in personality disordered subjects. 68 personality disordered (PD) and healthy control (HC) subjects were chosen, in whom morning basal plasma HVA (pHVA) concentrations and an assessment of childhood trauma were obtained. History of childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). A significant inverse correlation was found between CTQ Total scores and pHVA concentration across all subjects. In addition, pHVA was lower, and CTQ scores were higher, in PD as compared with HC subjects. Correlations with other personality and behavioral measures were not statistically significant. The data suggest that pHVA concentrations are inversely correlated with history of childhood trauma and that variability in this index of dopamine function may be affected by the history of childhood trauma in healthy and personality disordered subjects. PMID- 20953641 TI - Treadmill training restores spatial cognitive deficits and neurochemical alterations in the hippocampus of rats submitted to an intracerebroventricular administration of streptozotocin. AB - The intracerebroventricular infusion of streptozotocin (icv-STZ) has been largely used in research to mimic the main characteristics of Alzheimer's disease (AD), including cognitive decline, impairment of cholinergic transmission, oxidative stress and astrogliosis. Moderate physical exercise has a number of beneficial effects on the central nervous system, as demonstrated both in animals and in human studies. This study aimed to evaluate the effect of 5-week treadmill training, in the icv-SZT model of sporadic AD, on cognitive function, oxidative stress (particularly mediated by NO) and on the astrocyte marker proteins, glial fibrillary acidic protein (GFAP) and S100B. Results confirm the spatial cognitive deficit and oxidative stress in this model, as well as astroglial alterations, particularly a decrease in CSF S100B. Physical exercise prevented these alterations, as well as increasing the hippocampal content of glutathione and GFAP per se in the CA1 region. These findings reinforce the potential neuroprotective role of moderate physical exercise. Astroglial changes observed in this dementia model contribute to understanding AD and other diseases that are accompanied by cognitive deficit. PMID- 20953643 TI - Subclinical myasthenia gravis causing increased sensitivity to botulinum toxin therapy. AB - In rare patients receiving botulinum toxin (BT) therapy the potency of the BT drug may be increased by pre-existent impairment of neuromuscular transmission (INT). Appropriate dose adjustment may correct for this. Subclinical INT has previously been described by us for the first time in a patient with Lambert Eaton myasthenic syndrome. We are now describing subclinical INT for the first time in a patient with ocular myasthenia gravis. Due to its unpredictability subclinical INT may pose a risk to patients receiving BT therapy. PMID- 20953645 TI - Glycation products in infant formulas: chemical, analytical and physiological aspects. AB - Infant formulas are milk-based products, which are adapted to the composition of human milk. To ensure microbiological safety and long shelf life, infant formulas usually undergo rigid heat treatment. As a consequence of the special composition and the heat regimen, infant formulas are more prone to thermally induced degradation reactions than regular milk products. Degradation reactions observed during milk processing comprise lactosylation yielding the Amadori product lactulosyllysine, the formation of advanced glycation end products (AGEs), and protein-free sugar degradation products, as well as protein or lipid oxidation. Several methods have been developed to estimate the heat impact applied during the manufacturing of infant formulas, including indirect methods such as fluorescence analysis as well as the analysis of defined reaction products. Most studies confirm a higher degree of damage in infant formulas compared to regular milk products. Differences between various types of infant formulas, such as liquid, powdered or hypoallergenic formulas depend on the analyzed markers and brands. A considerable portion of protein degradation products in infant formulas can be avoided when process parameters and the quality of the ingredients are carefully controlled. The nutritional consequences of thermal degradation products in infant formulas are largely unknown. PMID- 20953644 TI - A proposal to change existing virus species names to non-Latinized binomials. AB - A proposal has been posted on the ICTV website (2011.001aG.N.v1.binomial_sp_names) to replace virus species names by non Latinized binomial names consisting of the current italicized species name with the terminal word "virus" replaced by the italicized and non-capitalized genus name to which the species belongs. If implemented, the current italicized species name Measles virus, for instance, would become Measles morbillivirus while the current virus name measles virus and its abbreviation MeV would remain unchanged. The rationale for the proposed change is presented. PMID- 20953646 TI - Optimization of matrix metalloproteinase fluorogenic probes for osteoarthritis imaging. AB - Among the classical collagenases, matrix metalloproteinase-13 (called MMP-13, collagenase-3) is one of the most important components for cartilage destruction of osteoarthritis (OA) developments. Despite many efforts, the detection methods of MMP-13 activity have been met with limited success in vivo, in part, due to the low sensitivity and low selectivity by homology of MMP family. Previously, we demonstrated the use of strongly dark-quenched fluorogenic probe allowed for the visual detection of MMP-13 in vitro and in OA-induced rat models. In this study, we described the optimization of MMP-13 fluorogenic probe for OA detection in vivo. Three candidate probes demonstrated recovered fluorescent intensity proportional with MMP-13 concentrations, respectively; however, Probe 2 exhibited both high signal amplification and selective recognition for MMP-13, not MMP-2 and MMP-9 in vitro. When Probe 2 was applied to OA-induced rat models, clear visualization of MMP-13 activity in OA-induced cartilage was obtained. Optimized MMP-13 fluorogenic probe can be applied to detect and image OA and have potential for evaluating the in vivo efficacy of MMP-13 inhibitors which are being tested for therapeutic treatment of OA. PMID- 20953647 TI - In vitro degradation and antitumor activity of oxime bond-linked daunorubicin GnRH-III bioconjugates and DNA-binding properties of daunorubicin-amino acid metabolites. AB - Bioconjugates with receptor-mediated tumor-targeting functions and carrying cytotoxic agents should enable the specific delivery of chemotherapeutics to malignant tissues, thus increasing their local efficacy while limiting the peripheral toxicity. In the present study, gonadotropin-releasing hormone III (GnRH-III; Glp-His-Trp-Ser-His-Asp-Trp-Lys-Pro-Gly-NH(2)) was employed as a targeting moiety to which daunorubicin was attached via oxime bond, either directly or by insertion of a GFLG or YRRL tetrapeptide spacer. The in vitro antitumor activity of the bioconjugates was determined on MCF-7 human breast and HT-29 human colon cancer cells by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Their degradation/stability (1) in human serum, (2) in the presence of cathepsin B and (3) in rat liver lysosomal homogenate was analyzed by liquid chromatography in combination with mass spectrometry. The results show that (1) all synthesized bioconjugates have in vitro antitumor effect, (2) they are stable in human serum at least for 24 h, except for the compound containing an YRRL spacer and (3) they are hydrolyzed by cathepsin B and in the lysosomal homogenate. To investigate the relationship between the in vitro antitumor activity and the structure of the bioconjugates, the smallest metabolites produced in the lysosomal homogenate were synthesized and their binding to DNA was assessed by fluorescence spectroscopy. Our data indicate that the incorporation of a peptide spacer in the structure of oxime bond-linked daunorubicin-GnRH-III bioconjugates is not required for their antitumor activity. Moreover, the antitumor activity is influenced by the structure of the metabolites (daunorubicin-amino acid derivatives) and their DNA binding properties. PMID- 20953648 TI - Anti-tubercular drug designing by structure based screening of combinatorial libraries. AB - In the current study, the applicability and scope of descriptor based QSAR models to complement virtual screening using molecular docking approach have been applied to identify potential virtual screening hits targeting DNA gyrase A from Mycobacterium tuberculosis, an effective and validated anti-mycobacterial target. Initially QSAR models were developed against M. fortuitum and M. smegmatis using a series of structurally related fluoroquinolone derivatives as DNA gyrase inhibitors. Both the QSAR models yielded significant cross validated Q2 values of 0.6715 and 0.6944 and R2 values of 0.7250 and 0.7420, respectively. The statistically significant models were validated by a test set of 22 compounds with predictive R2 value of 0.7562 and 0.7087 for M. fortuitum and M. smegmatis respectively. To aid the creation of novel antituberculosis compounds, combinatorial library was developed on fluoroquinolone template to derive a data set of 5280 compounds whose activity values have been measured by the above models. Highly active compounds predicted from the models were subjected to molecular docking study to investigate the mechanism of drug binding with the DNA gyrase A protein of M. tuberculosis and the compounds showing similar type of binding patterns with that of the existing drug molecules, like sparfloxacin, were finally reported. It is seen that hydrophobic characteristics of molecular structure together with few hydrogen bond interactions are playing an essential role in antimicrobial activity for the fluoroquinolone derivatives. A representative set of seven compounds with high predicted MIC values were sorted out in the present study. PMID- 20953650 TI - Laparoscopic versus open groin hernia repair: are we getting closer to specific clinical recommendations? PMID- 20953649 TI - Quantum chemical modeling of perovskite: An investigation of piezoelectricity in ferrite of yttrium. AB - In a previous article, we used Hartree-Fock (HF) theory to study the piezoelectricity in BaTiO3. In this paper, we applied the Douglas-Kroll-Hess second order scalar relativistic method to investigate the possible piezoelectric properties in the perovskite YFeO3 structure, which has not yet been studied experimentally. The 30s20p13d and 31s21p17d Gaussian basis sets for the Fe (5D) and Y (2D) atoms, respectively, were built with the Generator Coordinate HF method. After contraction to [13s7p5d] and [13s8p7d], in combination with the 20s14p/6s4p basis set for the O (3P) atom from literature, they had their quality evaluated using calculations of the total and the orbital energies for the 2FeO+1 and 1YO+1 fragments. The dipole moment, the total energy, and the total atomic charges in YFeO3 in C(s) space group were calculated. The results and the analysis lead us to believe that the perovskite YFeO3 does not present piezoelectric properties. PMID- 20953651 TI - Letter. Re: Orenstein et al. (2010) Activation of human mononuclear cells by porcine biologic meshes in vitro. Hernia 14(4):401-407. PMID- 20953652 TI - Correlation between antimicrobial consumption and resistance among Staphylococcus aureus and enterococci causing healthcare-associated infections at a university hospital in Taiwan from 2000 to 2009. AB - This study investigated the correlation between antibiotic consumption and resistance among Staphylococcus aureus and enterococci causing healthcare associated infections at a university hospital in Taiwan from 2000 to 2009. Overall, the trend of total consumption (defined daily dose [DDD] per 1,000 patient-days) of glycopeptides, including vancomycin and teicoplanin, significantly increased during 2000 to 2003 and remained stable during 2004-2009. Vancomycin consumption significantly increased during 2003 and decreased after 2004. A significant decrease in the resistance rate with time was found for oxacillin- and gentamicin-resistant S. aureus. In contrast, the rates of vancomycin- and teicoplanin-resistant enterocci increased significantly. A significant correlation was found between the increased use of extended-spectrum cephalosporins, beta-lactam-beta-lactamase inhibitor combinations, carbapenems and the decreased prevalence of methicillin-resistant S. aureus (MRSA). In contrast, the increased use of teicoplanin, extended-spectrum cephalosporins, beta-lactam-beta-lactamase inhibitor combinations, and carbapenems was correlated with the increased prevalence of vancomycin-resistant enterococci (VRE). In conclusion, this 10-year study in a single institution identified different correlations between the prescription of antibiotics and the resistance rates of MRSA and VRE. Strict implementation of infection control policy based on these correlates would be helpful in decreasing the presence of these multidrug resistant pathogens in hospitals. PMID- 20953653 TI - Antimicrobial susceptibility of intra-abdominal gram-negative bacilli from Europe: SMART Europe 2008. AB - As part of the worldwide Study for Monitoring Antimicrobial Resistance Trends (SMART), a total of 3,030 clinical isolates of gram-negative bacilli from intra abdominal infections were collected from 43 hospital centres from 13 European countries during 2008. Of 51 species, the most commonly isolated species were Escherichia coli (49.3%), followed by Klebsiella pneumoniae (10.5%) and Pseudomonas aeruginosa (8.6%). Respectively, 17.9%, 11.6%, 5.5% and 4.5% of K. pneumoniae, E. coli, Proteus mirabilis and K. oxytoca were extended-spectrum beta lactamase (ESBL)-positive. All isolates were tested using a panel of 12 antimicrobial agents, and susceptibilities were determined using European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints. The most active agents against the study isolates (including those producing ESBLs) were amikacin, ertapenem and imipenem. Overall, with the exception of the carbapenems, most agents exhibited dramatically reduced susceptibilities against ESBL-positive and multi-drug-resistant isolates. PMID- 20953654 TI - Genetic and physical mapping of sex-linked AFLP markers in Nile tilapia (Oreochromis niloticus). AB - Identification of the sex-determining genes of the Nile tilapia (Oreochromis niloticus) has important implications for commercial aquaculture. We previously identified an XX/XY sex-determining locus in this species within a 10-cM interval between markers GM201 and UNH995 on linkage group one (LG1). In order to refine this region, we developed new AFLP markers using bulked segregant analysis of the mapping families. We identified three AFLP markers that showed a sex-specific pattern of segregation. All three mapped near, but just outside, the previously identified sex-determining region on LG1. Hybridization of BAC clones containing these markers to chromosome spreads confirmed that the XX/XY sex-determining locus is on one of the small chromosomes in O. niloticus. PMID- 20953655 TI - Cytoskeleton-mediated templating of complex cellulose-scaffolded extracellular structure and its association with oikosins in the urochordate Oikopleura. AB - Oriented cellulose deposition is critical to plant patterning and models suggest microtubules constrain cellulose synthase movements through the plasma membrane. Though widespread in plants, urochordates are the only animals that synthesize cellulose. We characterized the distinctive cellulose microfibril scaffold of the larvacean house and its interaction with house structural proteins (oikosins). Targeted disruption of cytoskeletal elements, secretory pathways, and plasma membrane organization, suggested a working model for templating extracellular cellulose microfibrils from animal cells that shows both convergence and differences to plant models. Specialized cortical F-actin arrays template microfibril orientation and glycosylphosphatidylinositol-anchored proteins in lipid rafts may act as scaffolding proteins in microfibril elongation. Microtubules deliver and maintain cellulose synthase complexes to specific cell membrane sites rather than orienting their movement through the membrane. Oikosins are incorporated into house compartments directly above their corresponding cellular field of expression and interact with the cellulose scaffold to a variable extent. PMID- 20953656 TI - Global molecular dysfunctions in gastric cancer revealed by an integrated analysis of the phosphoproteome and transcriptome. AB - We integrated LC-MS/MS-based and protein antibody array-based proteomics with genomics approaches to investigate the phosphoproteome and transcriptome of gastric cancer cell lines and endoscopic gastric biopsies from normal subjects and patients with benign gastritis or gastric cancer. More than 3,000 non redundant phosphorylation sites in over 1,200 proteins were identified in gastric cancer cells. We correlated phosphoproteome data with transcriptome data sets and reported the expression of 41 protein kinases, 5 phosphatases and 65 phosphorylated mitochondrial proteins in gastric cancer cells. Transcriptional expression levels of 190 phosphorylated proteins were >2-fold higher in gastric cancer cells compared to normal stomach tissue. Pathway analysis demonstrated over-presentation of DNA damage response pathway and underscored critical roles of phosphorylated p53 in gastric cancer. This is the first study to comprehensively report the gastric cancer phosphoproteome. Integrative analysis of the phosphoproteome and transcriptome provided an expansive view of molecular signaling pathways in gastric cancer. PMID- 20953657 TI - Heat-shock protein 60 translocates to the surface of apoptotic cells and differentiated megakaryocytes and stimulates phagocytosis. AB - Heat-shock protein 60 (Hsp60) is a highly conserved stress protein which has chaperone functions in prokaryotes and mammalian cells. Hsp60 is associated with the mitochondria and the plasma membrane through phosphorylation by protein kinase A, and is incorporated into lipid membranes as a protein-folding chaperone. Its diverse intracellular chaperone functions include the secretion of proteins where it maintains the conformation of precursors and facilitates their translocation through the plasma membrane. We report here that Hsp60 is concentrated in apoptotic membrane blebs and translocates to the surface of cells undergoing apoptosis. Hsp60 is also enriched in platelets derived from terminally differentiated megakaryocytes and expressed at the surface of senescent platelets. Furthermore, the exposure of monocytic U937 cells to Hsp60 enhanced their phagocytic activity. Our results suggests that externalized Hsp60 in apoptotic cells and senescent platelets influences events subsequent to apoptosis, such as the clearance of apoptotic cells by phagocytes. PMID- 20953659 TI - Healthy baboon with no upper jaw or nose: an extreme case of adaptability in the Kibale National Park, Uganda. AB - We describe and document with digital images an adult female baboon (Papio anubis) from the Kibale National Park, Uganda, who was missing all but the basal part of her upper jaw and nose, i.e., no premaxilla and very little of the maxilla and nasal bones. She appeared otherwise healthy, well integrated into a social group, and apparently reproducing, based on the fact that she was grooming a juvenile who suckled from her and that she appeared to be pregnant. Her extreme deformity raises numerous questions and demonstrates the highly adaptable capabilities of wild baboons. PMID- 20953658 TI - Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. AB - In recent years the etiopathology of a number of debilitating diseases such as type 2 diabetes, arthritis, atherosclerosis, psoriasis, asthma, cystic fibrosis, sepsis, and ulcerative colitis has increasingly been linked to runaway cytokine mediated inflammation. Cytokine-based therapeutic agents play a major role in the treatment of these diseases. However, the temporospatial changes in various cytokines are still poorly understood and attempts to date have focused on the inhibition of specific cytokines such as TNF-alpha. As an alternative approach, a number of preclinical studies have confirmed the therapeutic potential of targeting alpha7 nicotinic acetylcholine receptor-mediated anti-inflammatory effects through modulation of proinflammatory cytokines. This "cholinergic anti inflammatory pathway" modulates the immune system through cholinergic mechanisms that act on alpha7 receptors expressed on macrophages and immune cells. If the preclinical findings translate into human efficacy this approach could potentially provide new therapies for treating a broad array of intractable diseases and conditions with inflammatory components. PMID- 20953660 TI - Medulloblastoma with melanotic differentiation: case report and review of the literature. AB - Medulloblastoma with melanotic differentiation, a rare variant of medulloblastoma, often carries a poor prognosis. We present such a case of a 4 year male with this rare, aggressive tumor. Additionally, we have reviewed the literature and report on the features important in the pathologic and radiologic diagnosis in this type of tumor, as well as review clinical outcomes. This subtype of medulloblastoma occurs more frequently in males, at a younger median age than the other subtypes of medulloblastoma. The prognosis is generally very poor. However, it is important to note, that a subset of patients with M0 disease who can achieve a gross total resection followed by radiation and platinum based chemotherapy can become long term survivors of this aggressive subtype of medulloblastoma. PMID- 20953661 TI - Expression of Gli1 and PARP1 in medulloblastoma: an immunohistochemical study of 65 cases. AB - Activation of the sonic hedgehog (SHH) signalling pathway, which is involved in the formation of a significant proportion of medulloblastomas, is characterised by up-regulation and nuclear localisation of downstream transcription factor Gli1. Our aim was to analyse Gli1 expression by immunohistochemistry in a large group of medulloblastomas, to assess possible correlations with WNT (wingless) pathway activation and poly(ADP-ribose) polymerase-1 (PARP1) expression, previously shown to be associated with SHH pathway activation in a mouse model of medulloblastoma. We analysed expression and localisation of Gli1, beta-catenin and PARP1 by immunohistochemistry in a series of 65 consecutive medulloblastomas. Gli1 was positive in 40 (61.5%) medulloblastomas, as revealed by either strong (21 cases) or mild (19 cases) nuclear reaction in more than 50% of tumour cells. Nuclear positivity for PARP1 was noted in all 65 cases, ranging from 46% to 100% (mean 80%) but was not correlated with Gli1 positivity. Gli1 was positive in 9 of 11 cases with nuclear localisation of beta-catenin, signifying concurrent activation of SHH and WNT pathways. Overall survival of patients with strong nuclear reaction to Gli1 was better compared with patients with Gli1-negative medulloblastomas. Immunohistochemical detection of Gli1 could be useful in identifying medulloblastomas with SHH pathway activation. As revealed by nuclear reaction to Gli1, the SHH pathway is activated in approximately 60% of medulloblastomas. In some medulloblastomas, both SHH and WNT appear to be activated. PARP1 is highly expressed in medulloblastomas. It might be useful as a target to increase the effectiveness of current treatment modalities. PMID- 20953662 TI - Glioblastoma multiforme of the elderly: the prognostic effect of resection on survival. AB - According to recent developments the best treatment options for glioblastoma (GBM) consist in maximum safe resection and additional adjuvant treatment with radiotherapy (RT) and alkylating chemotherapy (CHX). These options have been evaluated for populations with a median age of approximately 58 years. We therefore addressed the issue of whether elderly patients (>65 years) could also benefit from cytoreductive surgery (CS) and adjuvant treatment using alkylating chemotherapy. One-hundred and three patients suffering from newly diagnosed, primary supratentorial glioblastoma multiforme >65 years (median 70.8 years) were identified in our single-center glioma database (2002-2007) and retrospectively divided into group A (n = 31) treated with surgery alone (biopsy, BY, n = 21, CS n = 10), group B (n = 37) surgery plus radiation (BY n = 18, CS n = 19), and group C (n = 35) surgery, RT and CHX (BY n = 4, CS n = 31). Progression-free survival (PFS) and overall survival (OAS) were determined in each group and correlated to age, Karnofsky performance score (KPS), and extent of resection (biopsy (BY), partial (PR), and complete resection (CR)). Progression was defined according the Macdonald criteria. For all patients PFS and OAS were 3.2 months and 5.1 months (m) respectively. PFS and OAS for groups A/B/C were 1.8/3.2/6.4 m (P = 0.000) and 2.2/4.4/15.0 m (P = 0.000), respectively. Median age for groups A/B/C was 74.4/70.6/68.5 years and median KPS was 60/70/80. Age (<75, >=75) was inversely correlated with OAS (5.8/2.5 m, P = 0.01). KPS (<70, >=70) was correlated with OAS 2.4/6.5 m (P = 0.000). Extent of resection (BY, PR, or CR) correlated with PFS (2.1/3.4/6.4 m, P = 0,000) and OS (2.2/7.0/13.9 m, P = 0,000), respectively. Our study shows that elderly GBM patients can benefit from maximum treatment procedures with cytoreductive microsurgery, radiation therapy, and chemotherapy. Treatment options are obviously affected by KPS and age. The most impressive outcome predictor in this population was the extent of microsurgical resection for patients treated with adjuvant radiotherapy and chemotherapy. To conclude, elderly GBM patients should not be per se excluded from intensive treatment procedures. PMID- 20953663 TI - Chitosan films are NOT antimicrobial. AB - Chitosan is a promising biomaterial for biomedical applications and is currently applied as wound dressings. While chitosan solutions demonstrate strong bactericidal activity against a range of medically important bacteria, the study here reports a loss of this beneficial property in thin films cast from the same solutions. Chitosan films (20 microm) showed no inhibitory effects against Escherichia coli, Staphylococcus aureus or S. epidermidis species. In contrast, solutions used to prepare the films showed almost complete inhibition (approximately 98 +/- 2%) when tested on bacterial lawns and in liquid cultures. Increased acidity of the chitosan solutions (pH 5) was shown to promote the bactericidal effects of this biopolymer. The concept that devices fabricated from chitosan have an inherent antimicrobial activity is suggested as an important misconception. PMID- 20953664 TI - Cloning, expression, and PCR application of DNA polymerase from the hyperthermophilic archaeon, Thermococcus celer. AB - The family B DNA polymerase gene was amplified from Thermococcus celer genomic DNA by using the degenerate primers and DNA walking PCR. The Tce DNA polymerase gene was cloned and sequenced. The gene contains an ORF of 2,325 bp encoding 774 amino acid residues with a calculated molecular weight of 89,788.9 kDa. The Tce DNA polymerase was purified by heat treatment and heparin column chromatography. The optimal conditions for PCR were determined. Long-range PCR and time-saving PCR were performed using various specific ratios of Taq and Tce DNA polymerases (Tce plus DNA polymerase). Tce plus DNA polymerase surpassed the PCR performance of Tce, Taq and Pfu DNA polymerases in terms of yield and efficiency. PMID- 20953665 TI - Improvement of acetic acid tolerance and fermentation performance of Saccharomyces cerevisiae by disruption of the FPS1 aquaglyceroporin gene. AB - The FPS1 gene coding for the Fps1p aquaglyceroporin protein of an industrial strain of Saccharomyces cerevisiae was disrupted by inserting CUP1 gene. Wild type strain, CE25, could only grow on YPD medium containing less than 0.45% (v/v) acetic acid, while recombinant strain T12 with FPS1 disruption could grow on YPD medium with 0.6% (v/v) acetic acid. Under 0.4% (v/v) acetic acid stress (pH 4.26), ethanol production and cell growth rates of T12 were 1.7 +/- 0.1 and 0.061 +/- 0.003 g/l h, while those of CE25 were 1.2 +/- 0.1 and 0.048 +/- 0.003 g/l h, respectively. FPS1 gene disruption in an industrial ethanologenic yeast thus increases cell growth and ethanol yield under acetic acid stress, which suggests the potential utility of FPS1 gene disruption for bioethanol production from renewable resources such as lignocelluloses. PMID- 20953666 TI - Cloning and expression of three fatty acid desaturase genes from cold-sensitive lima bean (Phaseolus lunatus L.). AB - The critical chilling temperature of cold-sensitive lima bean (Phaseolus lunatus L.) seedlings was determined to be approx. 8 degrees C. The full-length cDNAs of PlSAD, PlFAD2, and PlFAD3 encoding three fatty acid desaturases were isolated from lima bean leaves. The PlSAD open reading frame (ORF) had 1,317 bp and a single intron of 601 bp, encoding a polypeptide of 438 amino acids that showing 86% homology with the plastidial stearoyl-acyl carrier protein desaturase in soybean. The PlFAD2 ORF contained 1,059 bp and was uninterrupted, encoding a polypeptide of 352 amino acids having 85% identity with the microsomal omega-6 desaturase GmFAD2-3 in soybean. PlFAD3 ORF had 1,116 bp and seven introns, encoding a polypeptide of 371 amino acids showing 91% homology with the microsomal omega-3 desaturase FAD3 in cowpea. PlSAD and PlFAD2 were expressed highly in leaves but poorly in roots and stems, while PlFAD3 was expressed in three tissues. All three genes were significantly induced in leaves by drought. PlSAD and PlFAD3 in leaves were down-regulated by high temperature and salinity, whereas PlFAD2 was up-regulated by the two stresses. The expression patterns of the three genes in lima bean leaves under suboptimal temperature, 18 degrees C, were different from those under 8 degrees C. The down-regulation of PlSAD transcript at chilling temperature might be an important factor contributing to chilling susceptibility for lima bean plants. PMID- 20953667 TI - Bidirectionalization of a methyl jasmonate-inducible plant promoter. AB - A unidirectional promoter can be transformed into a bidirectional module by artificial methods. Here we report the bidirectionalization of the methyl jasmonate (MeJA)-inducible PtDrl02 promoter derived from poplar [(Populus tomentosa * P. bolleana) * P. tomentosa] in planta. Construction of the bidirectional PtDrl02 promoter (designated as mPtDrl02) was rapidly achieved by introducing a minimal 35S promoter in the opposite orientation to the 5' end of PtDrl02. beta-Glucuronidase (GUS) and green fluorescent protein (GFP) reporter genes were also interchangeably linked to the 3'-and 5'-ends of mPtDrl02 to produce GFP/mPtDrl02/GUS and GUS/mPtDrl02/GFP vectors, respectively. Using the Agrobacterium-mediated transient expression approach, we demonstrated that the mPtDrl02 module was able to drive gene (GUS and GFP) expression in both orientations simultaneously. Furthermore, the cooperative and concurrent activity from both directions of the mPtDrl02 module was demonstrated following MeJA induction. To our knowledge, this is the first report of an artificial MeJA responsive bidirectional promoter in perennial plants. PMID- 20953668 TI - New method to enhance ajmalicine production in Catharanthus roseus cell cultures based on the use of cyclodextrins. AB - The joint use of cyclodextrins and methyljasmonate, when accompanied by a short exposure to UV, enhanced extracellular ajmalicine accumulation to 1040 +/- 26.6 mg/l in suspension cultured cells of Catharanthus roseus. The success of this strategy is due to the use of cyclodextrins, which not only induce ajmalicine biosynthesis but also promote adduct formation. This removes ajmalicine from the medium, reduces feedback inhibition and ajmalicine degradation, and allows its accumulation in the culture medium at elevated concentrations. PMID- 20953669 TI - Utilization of dry distiller's grain and solubles as nutrient supplement in the simultaneous saccharification and ethanol fermentation at high solids loading of corn stover. AB - Dry distiller's grain and solubles (DDGS) is a major by-product of corn-based ethanol production and is usually used as animal feed. Here, it was added to the simultaneous saccharification and ethanol fermentation (SSF) carried out at high solids loading of steam explosion pretreated corn stover using a mutant strain Saccharomyces cerevisiae DQ1. The performance of SSF process with DDGS was comparable to those using the expensive yeast extract supplementation. With 30% (w/w) solids plus the addition of cellulase and 1g DDGS l(-1), the final ethanol reached 55 g l(-1) (7% v/v). The results indicated that the expensive supplement of yeast extract could be replaced by DDGS. PMID- 20953670 TI - Making priors a priority. AB - When we build a predictive model of a drug property we rigorously assess its predictive accuracy, but we are rarely able to address the most important question, "How useful will the model be in making a decision in a practical context?" To answer this requires an understanding of the prior probability distribution ("the prior") and hence prevalence of negative outcomes due to the property being assessed. In this perspective, we illustrate the importance of the prior to assess the utility of a model in different contexts: to select or eliminate compounds, to prioritise compounds for further investigation using more expensive screens, or to combine models for different properties to select compounds with a balance of properties. In all three contexts, a better understanding of the prior probabilities of adverse events due to key factors will improve our ability to make good decisions in drug discovery, finding higher quality molecules more efficiently. PMID- 20953671 TI - Adult height and the risk of cardiovascular disease among middle aged men and women in Japan. AB - An inverse association between height and risk of cardiovascular disease has been reported, but the evidence is limited for stroke subtypes, in particular in Asian populations. Further, few studies have examined how socioeconomic status in adulthood influence the relationship between height and risk of cardiovascular disease. This study examined the association between height and risks of stroke and coronary heart disease, and whether education level, an indicator of adult socioeconomic status, modify the effect of height on those risks, within a cohort of the Japan Public Health Center-based Prospective Study (JPHC Study). The hazard ratios for the incidence of cardiovascular disease associated with height were calculated by a 16-year follow-up of 15,564 Japanese men and women, aged 40 59. The hazard ratios were adjusted for age, gender, area, education, occupation and cardiovascular risk factors. Height was inversely associated with risks of total stroke, either hemorrhagic or ischemic stroke but not with coronary heart disease. The adjusted hazard ratios (95% confidence interval (CI)) of total stroke, hemorrhagic stroke, and ischemic stroke for a 1 SD height increments were 0.82 (95% CI: 0.74, 0.90), 0.80 (95% CI: 0.70, 0.92), and 0.83 (95% CI: 0.73, 0.95), respectively. No multiplicative interaction was observed between height and education level on stroke risk. Short stature was associated with increased risk of total stroke, either hemorrhagic or ischemic stroke, independent of adult socioeconomic status and cardiovascular risk factors, but not with risk of coronary heart disease in Japanese men and women. PMID- 20953672 TI - The fourth branch of the superior rectal artery and its significance in transanal haemorrhoidal dearterialisation. AB - INTRODUCTION: Transanal haemorrhoidal dearterialisation is a non-excisional surgical method for the treatment of haemorrhoidal disease. It uses a Doppler ultrasound probe to accurately identify the site to suture-ligate the piles, resulting in a decrease in the arterial inflow to the piles and their subsequent regression. METHODS: A total of 140 consecutive patients who underwent transanal haemorrhoidal dearterialisation were studied. The number and locations of the haemorrhoidal arteries were documented. The presenting symptoms and their subsequent resolution were noted. RESULTS: The median number of haemorrhoidal arteries ligated was four. Seventy-five patients (53.6%) had four haemorrhoidal arteries ligated. A total of 82 patients (58.6%) had a 'fourth' haemorrhoidal artery in the left anterior one o'clock position. Symptoms of bleeding, prolapse, pain and itching resolved in 92, 65, 68 and 60% of patients who presented with the respective symptoms preoperatively. CONCLUSION: There is a fourth haemorrhoidal artery consistently found in the left anterior one o'clock position. Adequate treatment of this artery minimises the recurrence of haemorrhoidal symptoms. PMID- 20953673 TI - Recent progress in understanding the interaction between avermectins and ligand gated ion channels: putting the pests to sleep. AB - Avermectins and milbemycins are an important family of anthelmintics, insecticides and acaricides. Their mode of action is as positive allosteric modulators of ligand-gated chloride channels, and at higher concentrations, they gate some channels directly. Though it has long been known that the avermectins do not compete for the ligand binding site, the actual site at which they interact with their receptors has been unclear. Recent data demonstrate the importance to drug binding of amino acid residues predicted to line a water filled pocket in the channel domain. This pocket acts as the binding site for anaesthetics and other modulators of mammalian GABA(A) and glycine receptors, suggesting similarities in the mode of action between these drugs and the avermectins/milbemycins. PMID- 20953674 TI - Indirect rapid prototyping of biphasic calcium phosphate scaffolds as bone substitutes: influence of phase composition, macroporosity and pore geometry on mechanical properties. AB - While various materials have been developed for bone substitute and bone tissue engineering applications over the last decades, processing techniques meeting the high demands of scaffold shaping are still under development. Individually adapted and mechanically optimised scaffolds can be derived from calcium phosphate (CaP-) ceramics via rapid prototyping (RP). In this study, porous ceramic scaffolds with a periodic pattern of interconnecting pores were prepared from hydroxyapatite, beta-tricalcium phosphate and biphasic calcium phosphates using a negative-mould RP technique. Moulds predetermining various pore patterns (round and square cross section, perpendicular and 60 degrees inclined orientation) were manufactured via a wax printer and subsequently impregnated with CaP-ceramic slurries. Different pore patterns resulted in macroporosity values ranging from about 26.0-71.9 vol% with pore diameters of approximately 340 MUm. Compressive strength of the specimens (1.3-27.6 MPa) was found to be mainly influenced by the phase composition as well as the macroporosity, both exceeding the influence of the pore geometry. A maximum was found for scaffolds with 60 wt% hydroxyapatite and 26.0 vol% open porosity. It has been shown that wax ink-jet printing allows to process CaP-ceramic into scaffolds with highly defined geometry, exhibiting strength values that can be adjusted by phase composition and pore geometry. This strength level is within and above the range of human cancellous bone. Therefore, this technique is well suited to manufacture scaffolds for bone tissue engineering. PMID- 20953675 TI - Establishing new acceptance limits for dissolution performance verification of USPC apparatus 1 and 2 using USPC prednisone tablets reference standard. AB - PURPOSE: On 1 March 2010, the US Pharmacopeial Convention released into commerce Lot P1I300 of its Prednisone Tablets Reference Standard for use in periodic performance verification testing (PVT) of dissolution Apparatus 1 and 2. This report presents the collaborative study data, development of the acceptance limits, and results from supporting work for this Lot. METHODS: The collaborative study involved 25 collaborators who provided data for Apparatus 1 and 31 who provided data for Apparatus 2. These limits are for the geometric mean and percent coefficient of variation (%CV) instead of per-individual results as for prior lots. Stability of results and sensitivity to test performance parameters were also studied. RESULTS: To determine new PVT acceptance limits, the authors calculated geometric mean and variance components as percent coefficient of variation. The move to the geometric mean and %CV criteria brings the acceptance criteria in line with current accepted statistics and provides a more realistic assessment of the system's performance. Results for Apparatus 1 are stable over time, but for Apparatus 2, the mean decreases over time. Acceptance criteria are adjusted for this trend. Lot P1 demonstrates sensitivity to test performance parameters (vessels and degassing). CONCLUSIONS: Apparatus 1 results are stable over time. Those in Apparatus 2 show a decrease over time in the geometric mean but show no trend in variability. The current tablets are shown to remain sensitive to two operational parameters, degassing and vessel dimensions, not covered by mechanical calibration. The new acceptance limits for Lot P1 are based on geometric mean and %CV for Prednisone Tablets Reference Standard Lot P1I300. The limits better control variability than the prior per-individual-result limits. PMID- 20953676 TI - Human NPC1L1 expression is positively regulated by PPARalpha. AB - PURPOSE: Niemann-Pick C1-like 1 (NPC1L1), a pharmacological target of ezetimibe, is responsible for cholesterol absorption in enterocytes and hepatocytes. In the present study, the involvement of peroxisome proliferator-activated receptor alpha (PPARalpha) and its cofactor, PPARgamma coactivator 1alpha (PGC1alpha) in the transcriptional regulation of human NPC1L1 was analyzed. METHODS: Reporter gene assays and electrophoretic mobility shift assays (EMSAs) were performed with the 5'-flanking region of the human NPC1L1 gene and the effect of siPPARalpha was examined. RESULTS: PPARalpha-mediated transactivation was observed with human NPC1L1 promoter constructs. Detailed analyses using deletion- and mutated promoter constructs revealed the presence of a functional PPARalpha-response element (PPRE) upstream of the human NPC1L1 gene (-846/-834), a direct binding of PPARalpha and RXRalpha to which was confirmed by EMSAs. Moreover, PPARalpha specific knockdown resulted in a significant decrease in the endogenous expression of NPC1L1 mRNA and protein in human-derived HepG2 cells. Furthermore, cotransfection of PGC1alpha stimulated the SREBP2/HNF4alpha- and PPARalpha/RXRalpha-mediated activation of the human NPC1L1 promoter. CONCLUSIONS: We found that PPARalpha positively regulates human NPC1L1 transcription via direct binding to a PPRE. Additionally, PGC1alpha stimulates the SREBP2/HNF4alpha and PPARalpha/RXRalpha-mediated transactivation of human NPC1L1. These findings may provide new insights into the close relationship of glucose, fatty acids and cholesterol homeostasis. PMID- 20953677 TI - (6R, 10R)-6,10,14-trimethylpentadecan-2-one, a dominant and behaviorally active component in male orchid bee fragrances. AB - 6,10,14-Trimethylpentadecan-2-one (Hexahydrofarnesyl acetone; HHA) previously has been found to be a major component in tibial fragrances of male orchid bees, Euglossa spp. HHA is a chiral molecule with four possible stereoisomers, (6R, 10R)-, (6R, 10S)-, (6S, 10R)-, and (6S, 10S)-6,10,14-trimethylpentadecan-2-one. In the present study, we characterized HHA extracted from Euglossa as the pure enantiomer (6R, 10R)-6,10,14-trimethylpentadecan-2-one. During bioassays in Mexico and Panama, the synthetic RR-isomer attracted males of six species of orchid bees, including three that were known to contain HHA in their tibial fragrances. Possible sources of HHA for wild bees are flowers of euglossophilous orchids and aroids. With a molecular weight of 268, HHA is the largest natural molecule known to attract male orchid bees in pure form. Its attractiveness to males suggests that low-volatility compounds have a function in male signals, e.g., serve as a "base note" in complex odor bouquets. PMID- 20953678 TI - Tri-trophic level impact of host plant linamarin and lotaustralin on Tetranychus urticae and its predator Phytoseiulus persimilis. AB - The impact of linamarin and lotaustralin content in the leaves of lima beans, Phaseolus lunatus L., on the second and third trophic levels was studied in the two-spotted spider mite, Tetranychus urticae (Koch), and its predator Phytoseiulus persimilis Athias-Henriot. The content of linamarin was higher in terminal trifoliate leaves (435.5 ppm) than in primary leaves (142.1 ppm) of Henderson bush lima beans. However, linamarin concentrations were reversed at the second trophic level showing higher concentrations in spider mites feeding on primary leaves (429.8 ppm) than those feeding on terminal trifoliate leaves (298.2 ppm). Concentrations of linamarin in the predatory mites were 18.4 and 71.9 ppm when feeding on spider mites grown on primary and terminal leaves, respectively. The concentration of lotaustralin in primary lima bean leaves was 103.12 ppm, and in spider mites feeding on these leaves was 175.0 ppm. Lotaustralin was absent in lima bean terminal trifoliate leaves and in mites feeding on these leaves. Fecundity of spider mites feeding on lima bean leaves (primary or trifoliate) was not significantly different from mites feeding on red bean, Phaseolus vulgaris L., primary leaves. However, the progeny sex ratio (in females per male) of spider mites feeding on lima bean leaves was significantly lower than progeny of spider mites feeding on red bean leaves (control). Fecundity and progeny sex ratio of P. persimilis were both significantly affected by the concentration of linamarin present in the prey. Changes in concentration of linamarin in living tissue across the three trophic levels are discussed. PMID- 20953679 TI - Effectiveness of implementation of a new drug storage label and error-reducing process on the accuracy of drug dispensing. AB - This study evaluated the effectiveness of implementation of an improved storage label and an error-reducing process on the incidence of drug-dispensing errors. A total of 27 pharmacists (11 male and 16 female) were included. Questionnaires were distributed to pharmacists to measure their degree of satisfaction with the format and content of the labels. The questionnaires were completed before and one month after implementation of new label. Pharmacists were also requested to follow a new error-reducing dispensing process by circling the following items on the new storage label: drug name, appearance, packaging, dose, and formulation. The pharmacists' degrees of satisfaction increased significantly after implementation of the new label with respect to these questionnaire items: all label format items, edition appropriateness, use of capital fonts to distinguish similar drug names, reminder images to help with drug differentiation, and complete label information. The outpatient monthly drug-dispensing error rate was significantly decreased. PMID- 20953680 TI - Wireless Body Area Network (WBAN) design techniques and performance evaluation. AB - In recent years interest in the application of Wireless Body Area Network (WBAN) for patient monitoring applications has grown significantly. A WBAN can be used to develop patient monitoring systems which offer flexibility to medical staff and mobility to patients. Patients monitoring could involve a range of activities including data collection from various body sensors for storage and diagnosis, transmitting data to remote medical databases, and controlling medical appliances, etc. Also, WBANs could operate in an interconnected mode to enable remote patient monitoring using telehealth/e-health applications. A WBAN can also be used to monitor athletes' performance and assist them in training activities. For such applications it is very important that a WBAN collects and transmits data reliably, and in a timely manner to a monitoring entity. In order to address these issues, this paper presents WBAN design techniques for medical applications. We examine the WBAN design issues with particular emphasis on the design of MAC protocols and power consumption profiles of WBAN. Some simulation results are presented to further illustrate the performances of various WBAN design techniques. PMID- 20953681 TI - Association between internet gambling and problematic internet use among adolescents. AB - The study objectives were to evaluate the correlates and psychosocial implications of internet gambling among adolescents, as well as the association between internet gambling and problematic internet use. A cross-sectional study design was applied among a random sample (N = 484) of adolescents (71.2% boys; 28.8% girls; mean age +/- standard deviation, SD = 14.88 +/- 0.55 years). Self completed questionnaires, including internet gambling practices, internet use characteristics, Young Internet Addiction Test, and Strengths and Difficulties Questionnaire were utilized. The prevalence of internet gambling was 15.1%. Internet gambling was associated with psychosocial maladjustment, including Abnormal Conduct Problems (gender adjusted odds ratio, AOR = 3.83; 95% confidence interval, 95% CI: 1.86-7.92) and Borderline Peer Problems (AOR = 2.04; 95% CI: 1.09-3.85). The likelihood of concomitant problematic internet use was significantly higher among internet gamblers (AOR = 1.81; 95% CI: 1.03-3.19). Multivariate regression analyses indicated that among all characteristics of internet use assessed, utilizing the internet for the purposes of gambling practices was independently associated with problematic internet use among adolescents (AOR = 3.43; 95% CI: 1.40-8.39). Thus, the study findings suggest that adolescents who participate in internet gambling practices are more likely to concomitantly present with problematic internet use. PMID- 20953682 TI - A farewell. PMID- 20953683 TI - Probative value of absolute and relative judgments in eyewitness identification. AB - It is well-accepted that eyewitness identification decisions based on relative judgments are less accurate than identification decisions based on absolute judgments. However, the theoretical foundation for this view has not been established. In this study relative and absolute judgments were compared through simulations of the WITNESS model (Clark, Appl Cogn Psychol 17:629-654, 2003) to address the question: Do suspect identifications based on absolute judgments have higher probative value than suspect identifications based on relative judgments? Simulations of the WITNESS model showed a consistent advantage for absolute judgments over relative judgments for suspect-matched lineups. However, simulations of same-foils lineups showed a complex interaction based on the accuracy of memory and the similarity relationships among lineup members. PMID- 20953684 TI - Efficacy and safety of rosuvastatin 5 mg in combination with fenofibric acid 135 mg in patients with mixed dyslipidemia - a phase 3 study. AB - BACKGROUND: Patients with mixed dyslipidemia characterized by elevated low density lipoprotein cholesterol (LDL-C), elevated triglycerides (TG), and reduced high-density lipoprotein cholesterol (HDL-C) often require combination therapy to improve multiple lipid and nonlipid parameters. This phase 3, multicenter, randomized, double-blind study evaluated the efficacy and safety of rosuvastatin 5 mg coadministered with fenofibric acid 135 mg in patients with mixed dyslipidemia. METHODS: A total of 760 patients with TG >= 150 mg/dL, HDL-C <40 mg/dL (<50 mg/dL for women), and LDL-C >= 130 mg/dL were randomized for a 12-week treatment period to rosuvastatin 5 mg, fenofibric acid 135 mg, or rosuvastatin 5 mg + fenofibric acid 135 mg. The primary efficacy comparisons were mean percentage changes in HDL-C and TG (rosuvastatin + fenofibric acid vs. rosuvastatin monotherapy), and LDL-C (rosuvastatin + fenofibric acid vs. fenofibric acid monotherapy). RESULTS: Treatment with rosuvastatin + fenofibric acid resulted in statistically significant greater improvements in HDL-C (23.0% vs. 12.4%; P < 0.001) and TG (-40.3% vs. -17.5%; P < 0.001), compared with rosuvastatin monotherapy; and LDL-C (-28.7% vs. -4.1%; P < 0.001), compared with fenofibric acid monotherapy. All secondary efficacy variables improved with combination therapy. Combination therapy was generally well tolerated with a safety profile consistent with individual monotherapies. No unexpected muscle, hepatic, or renal safety signals were identified with combination therapy versus individual monotherapies. CONCLUSION: In conclusion, rosuvastatin 5 mg + fenofibric acid 135 mg resulted in comprehensive improvements in the lipid profile of patients with mixed dyslipidemia without unanticipated adverse events. PMID- 20953685 TI - Erythropoietin (EPO) affords more potent cardioprotection by activation of distinct signaling to mitochondrial kinases compared with carbamylated EPO. AB - PURPOSE: Erythropoietin (EPO) and its non-erythrogenic derivative, carbarmylated EPO (CEPO), have been reported to activate different receptors (homomeric EPO receptor vs. heteromeric receptor consisting of EPO receptor monomer and common beta-subunit). The aim of this study was to examine differences between EPO and CEPO in efficacy of cardioprotection against infarction and in activation of pro survival kinases. METHODS: In isolated rat hearts, infarction was induced by global ischemia followed by reperfusion. Infarct size was determined 2 h after reperfusion, and ventricular tissues for immunoblotting were sampled at 5 min after reperfusion. RESULTS: Pretreatment with EPO (10 units/ml) before ischemia reduced infarct size (% of risk area; %IS/AR) from 47.0 +/- 2.1% of the control after 20-min ischemia to 24.7 +/- 4.3% and from 62.0 +/- 3.0% after 25-min ischemia to 45.5 +/- 4.1%. Desialylated EPO (asialoEPO, 100 ng/ml) mimicked the protection by EPO. However, CEPO (100 ng/ml) failed to reduce infarct size after 20-min ischemia (%IS/AR = 47.5 +/- 5.9%) and that after 25-min ischemia (%IS/AR = 56.1 +/- 4.2%). The infarct size-limiting effect of CEPO was not shown either by increasing CEPO dose to 500 ng/ml or by shortening ischemia to 15 min. Both EPO and CEPO enhanced phosphorylation of cytosolic GSK-3beta upon reperfusion. In contrast, phosphorylation of GSK-3beta, Akt, and PKC-epsilon in mitochondria upon reperfusion was significantly enhanced by EPO but not by CEPO. CONCLUSION: EPO affords more potent protection against infarction than does CEPO by distinct activation of signaling leading to phosphorylation of pro-survival protein kinases in mitochondria upon reperfusion. PMID- 20953687 TI - Emergence of amantadine-resistant avian influenza H5N1 virus in India. AB - This study reports the genetic characterization of highly pathogenic avian influenza (HPAI) virus (subtype H5N1) isolated from poultry in West Bengal, India. We analyzed all the eight genome segments of two viruses isolated from chickens in January 2010 to understand their genetic relationship with other Indian H5N1 isolates and possible connection between different outbreaks. The hemagglutinin (HA) gene of the viruses showed multiple basic amino acids at the cleavage site, a marker for high virulence in chickens. Of greatest concern was that the viruses displayed amino acid substitution from serine-to-asparagine at position 31 of M2 ion channel protein suggesting emergence of amantadine resistant mutants not previously reported in HPAI H5N1 outbreaks in India. Amino acid lysine at position 627 of the PB2 protein highlights the risk the viruses possess to mammals. In the phylogenetic trees, the viruses clustered within the lineage of avian isolates from India (2008-2009) and avian and human isolates from Bangladesh (2007-2009) in all the genes. Both these viruses were most closely related to the viruses from 2008 in West Bengal within the subclade 2.2.3 of H5N1 viruses. PMID- 20953686 TI - Compositionality of arm movements can be realized by propagating synchrony. AB - We present a biologically plausible spiking neuronal network model of free monkey scribbling that reproduces experimental findings on cortical activity and the properties of the scribbling trajectory. The model is based on the idea that synfire chains can encode movement primitives. Here, we map the propagation of activity in a chain to a linearly evolving preferred velocity, which results in parabolic segments that fulfill the two-thirds power law. Connections between chains that match the final velocity of one encoded primitive to the initial velocity of the next allow the composition of random sequences of primitives with smooth transitions. The model provides an explanation for the segmentation of the trajectory and the experimentally observed deviations of the trajectory from the parabolic shape at primitive transition sites. Furthermore, the model predicts low frequency oscillations (<10 Hz) of the motor cortex local field potential during ongoing movements and increasing firing rates of non-specific motor cortex neurons before movement onset. PMID- 20953688 TI - Food neophobia in young adults: genetic architecture and relation to personality, pleasantness and use frequency of foods, and body mass index--a twin study. AB - Food neophobia has been studied extensively in children, but its causal origins and relationship to eating behavior in adults are not well understood. We studied genetic and environmental effects on variation in food neophobia, measured using the Food Neophobia Scale, and explored associations between food neophobia and personality, pleasantness and use frequency of food groups, and body mass index in young adult twins (N = 1175, aged 20-25 years, 54.7% women). In women, additive genetic effects (heritability) accounted for 61% of variation in food neophobia, whereas in men, shared environmental effects explained 45% of the variation. Food neophobia negatively correlated with the personality trait Openness, corrected for the structural overlap (r = -0.23), and in women, these two traits had a genetic correlation (r (g) = -0.39). In addition, food neophobia negatively correlated with pleasantness and use frequency of fruits and vegetables and of fish and with mean pleasantness of foods. Once evolutionarily important, food neophobia should at present be considered in nutrition counseling as a possible barrier to a balanced diet. PMID- 20953689 TI - Mr. Right and Mr. Right Now: romantic and casual partner-seeking online among young men who have sex with men. AB - Dating is a normative behavior for youth, yet few studies have examined the relationship between romantic partner-seeking and sexual behavior among young men who have sex with men (YMSM). This omission is most notable across studies examining YMSM's partner-seeking behaviors online. In this study, we examined the relationship between sexual behaviors and online partner-seeking behaviors for casual and romantic partners in a sample of YMSM (N = 431; M = 21.49 years old, SD = 1.94) who reported using the Internet to meet other men. Using analysis of covariance (ANCOVA), we found YMSM in the High Romantic/High Casual group had more unprotected partners than YMSM in other categories. YMSM in the High Romantic/Low Casual group had fewer unprotected partners than the High Romantic/High Casual group. We discuss the implications of our findings and conclude that there is a need to further examine romantic partner-seeking among YMSM. PMID- 20953691 TI - Effect of a community popular opinion leader HIV/STI intervention on stigma in urban, coastal Peru. AB - Evaluating interventions that reduce HIV stigma may help to craft effective stigma-reduction programs. This study evaluates the effects of a community popular opinion leader HIV/STI intervention on stigma in urban, coastal Peru. Mixed effects modeling was used to analyze data on 3,049 participants from the Peru site of the NIHM collaborative trial. Analyses looked at differences between the comparison and intervention groups on a stigma index from baseline to 12- and 24-month follow-up. Sub-analyses were conducted on heterosexual-identified men (esquineros), homosexual-identified men (homosexuales), and socially marginalized women (movidas). Compared to participants in the comparison group, intervention participants reported lower levels of stigma at 12- and 24-month follow-up. Similar results were found within esquineros and homosexuales. No significant differences were found within movidas. Findings suggest that interventions designed to normalize HIV prevention behaviors and HIV communication can reduce HIV-related stigma and change community norms. PMID- 20953692 TI - Standard measures are inadequate to monitor pediatric adherence in a resource limited setting. AB - This study aims to compare the use and cost of objective and subjective measures of adherence to pediatric antiretroviral treatment in a primary care facility in South Africa. In a 1-month longitudinal study of 53 caregiver-child dyads, pharmacy refill (PR), measurement of returned syrups (RS), caregiver self-report (3DR) and Visual Analogue Scale (VAS) were compared to Medication Event Monitoring System (MEMS). Adherence was 100% for both VAS and 3DR; by PR and RS 100% and 103%, respectively. MEMS showed that 92% of prescribed doses were administered, but only 66% of these within the correct 12-hourly interval. None of the four measures correlated significantly with MEMS. MEMS data suggest that timing of doses is often more deviant from prescribed than expected and should be better addressed when monitoring adherence. Of all, MEMS was by far the most expensive measure. Alternative, cheaper electronic devices need to be more accessible in resource-limited settings. PMID- 20953693 TI - Prediction of nucleosome DNA formation potential and nucleosome positioning using increment of diversity combined with quadratic discriminant analysis. AB - In this work, a novel method was developed to distinguish nucleosome DNA and linker DNA based on increment of diversity combined with quadratic discriminant analysis (IDQD), using k-mer frequency of nucleotides in genome. When used to predict DNA potential for forming nucleosomes, the model achieved a high accuracy of 94.94%, 77.60%, and 86.81%, respectively, for Saccharomyces cerevisiae, Homo sapiens, and Drosophila melanogaster. The area under the receiver operator characteristics curve of our classifier was 0.982 for S. cerevisiae. Our results indicate that DNA sequence preference is critical for nucleosome formation potential and is likely conserved across eukaryotes. The model successfully identified nucleosome-enriched or nucleosome-depleted regions in S. cerevisiae genome, suggesting nucleosome positioning depends on DNA sequence preference. Thus, IDQD classifier is useful for predicting nucleosome positioning. PMID- 20953694 TI - Chromosome elimination by wide hybridization between Triticeae or oat plant and pearl millet: pearl millet chromosome dynamics in hybrid embryo cells. AB - Wide crossing is one of a number of practical methods that can be used to expand genetic variation in common wheat (Triticum aestivum). However, in crosses between wheat and distantly related species such as maize (Zea mays) and pearl millet (Pennisetum glaucum), non-wheat chromosomes are often eliminated from the hybrid during embryogenesis. In this study, we used pearl millet pollen to pollinate the pistils of a range of plants in the tribe Triticeae, as well as oat. Seven days after pollination, the dynamics of the pearl millet chromosomes in the embryos were observed using in situ hybridization, probing both the pearl millet genomic DNA and its centromere-specific repeats. In embryos from the crosses with oat, all seven of the pearl millet chromosomes were retained. However, in hybrids with the Triticeae species, chromosome elimination occurred during embryogenesis. Pearl millet chromosome showed chromosome rearrangements and non-disjunction together with micronuclei. These rearranged chromosomes and micronuclei derived from the breakage of bridges and retention of acentric fragments in anaphase, respectively. The cause of the chromosome elimination of wheat-pearl millet hybrid is not malfunction of the kinetochores binding to the spindles but the malfunction of the sister chromatids segregation at anaphase especially of chromosome arm. PMID- 20953695 TI - Placental growth factor neutralising antibodies give limited anti-angiogenic effects in an in vitro organotypic angiogenesis model. AB - Vascular Endothelial Growth Factor Receptor (VEGFR) mediated signalling drives angiogenesis. This is predominantly attributed to the activity of VEGFR-2 following binding of VEGF-A. Whether other members of the VEGFR and ligand families such as VEGFR-1 and its ligand Placental Growth Factor (PlGF) can also contribute to developmental and pathological angiogenesis is less clear. We explored the function of PlGF in VEGF-A dependent angiogenesis using an in vitro co-culture assay in which endothelial cells are cultured on a fibroblast feeder layer. In the presence of 2% FS MCDB media (containing limited growth factors) in vitro endothelial tube formation is driven by endogenous angiogenic stimuli which are produced by the fibroblast and endothelial cells. Under these conditions independent sequestration of either free VEGF-A or PlGF with polyclonal and monoclonal antibodies inhibited tube formation suggesting that both ligands are required to drive an angiogenic response. Endothelial tube formation could only be driven within this assay by the addition of exogenous VEGF-A, VEGF-E or VEGF A/PlGF heterodimer, but not by PlGF alone, implying that activation of either VEGFR-2/VEGFR-1 heterodimers or VEGFR-2 homodimers were responsible for eliciting an angiogenic response directly, but not VEGFR-1 homodimers. In contrast to results obtained with an endogenous angiogenic drive, sequestration of PlGF did not affect endothelial tube formation when the assay was driven by 1 ng/ml exogenous VEGF-A. These data suggest that although neutralising PlGF can be shown to reduce endothelial tube formation in vitro, this effect is only observed under restricted culture conditions and is influenced by VEGF-A. Such data questions whether neutralising PlGF would have a therapeutic benefit in vivo in the presence of pathological concentrations of VEGF-A. PMID- 20953696 TI - Distribution of polychlorinated biphenyls and organochlorine pesticides in wild mussels from two different sites in central Croatian Adriatic coast. AB - Levels of 24 organochlorine compounds were investigated in wild mussels collected at two locations (Krka estuary and Kastela Bay) on the Croatian Adriatic coast in 2003, 2005, 2006, 2007, and 2008. PCB and OCP ranges found at the two locations overlapped and followed similar profiles despite the differences between the two locations indicating that they share a common pollutants source. Among organochlorine pesticides, the dominant compound was DDT. Among indicator PCBs, the dominant compound was PCB-153, while PCB-118 was dominant among the remaining 11 congeners. Generally, the sum of six indicator PCBs was constantly greater than the sum of 11 congeners at both locations. alpha-HCH/gamma-HCH and DDE/DDT ratios were below 1, indicating recent input of gamma-HCH and DDT into the marine environment. In the investigated period, almost all organochlorine compounds reached the highest values in 2006. The levels of PCBs and OCPs in this study were considerably below the Croatian maximum permissible levels, confirming that they do not pose any threat for human health. PMID- 20953697 TI - Characterizing wetland change at landscape scale in Jiangsu Province, China. AB - Human activities produced great impacts on wetlands worldwide. Taking Jiangsu Province, China, as a representative wetland region subject to extensive human activities, the aim of this study is to understand the conversion trajectory and spatial differentiation in wetland change from a multi-scale perspective. Based on multi-temporal Landsat images, it was found that the natural wetlands decreased by 11.2% from 1990 to 2006 in Jiangsu Province. Transition matrices showed that the conversion of natural wetlands to human-made wetlands (mostly aquaculture ponds) was the major form of natural wetland reduction, accounting for over 60% of the reduction. Percentage reduction and area reduc tion of natural wetlands were respectively quantified within different wetland cover zones using a moving window analysis. Average percentage reduction showed a decreasing tendency with increasing wetland cover. The high-cover and mid-cover zone presented the largest area reduction at the scales of 1-2 km and 4-8 km, respectively. Local hotspots of natural wetland reduction were mapped using the equal-interval and quantile classification schemes. The hotspots were mostly concentrated in the Lixiahe marshes and the coastal wetland areas. For the area reduction hotspots, the quantile classification presented larger area and more patches than the equal-interval classification; while an opposite result was shown for the percentage reduction hotspots. With respect to the discontinuous distribution of the natural wetlands, area reduction could be more appropriate to represent reduction hotspots than percentage reduction in the study area. These findings could have useful implications to wetland conservation. PMID- 20953698 TI - Baseline of the spatial and temporal metal contamination in Dilek National Park, Turkey. AB - Dilek National Park in Western Turkey is a protected habitat for several endangered and threatened species. In an attempt to protect the endangered species, the park was classified as a World Heritage Preserve. Even with this change, the animal and flora variety are still at risk from previous metal contamination. Water samples were collected 10 cm below the water surface and sediment from 0-30 and 30-60 cm depth. Inorganic elements were found in all sediment samples. Sodium had the highest aqueous concentration (10,312 mg/L), while Cu, Fe, Mn, and Zn were present at levels significantly lower than the chronic exposure criteria. Zn was the least prevalent (0.4 mg/kg) compound found in the sediment. The highest toxic contaminant concentration was Mg at an average of 1,100 mg/kg. The main contamination source of that seems to be Great Meandrous River. More studies are needed to develop a protection and remediation strategy for Dilek National Park. PMID- 20953699 TI - The effect of epigenetic regulation of fucosylation on TRAIL-induced apoptosis. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many cancer cells but not in normal ones. Recombinant TRAIL and agonistic antibodies to its cognate receptors are currently being studied as promising anticancer drugs. However, preclinical and clinical studies have shown that many types of human cancers are resistant to TRAIL agonists. We previously reported that a deficiency of fucosylation, which is one of the most common oligosaccharide modifications, leads to resistance to TRAIL-induced apoptosis. In contrast, DNA methylation is associated with silencing of various tumor suppressor genes and resistance of cancer cells to anticancer drugs. The aim of this study is to clarify the involvement of DNA methylation in the regulation of cellular fucosylation and the susceptibility to TRAIL-induced apoptosis. When nineteen cancer cell lines with relatively low fucosylation levels were treated with a novel methyltransferase inhibitor, zebularine, an increase in the fucosylation level was observed in many cancer cell lines. The expression of fucosylation-related genes, such as the FX, GDP-fucose transporter, and Fut4 genes, was significantly increased after the treatment with zebularine. Moreover, a synergistic effect of zebularine on TRAIL-induced apoptosis was observed in several cancer cell lines, in which fucosylation was increased by treatment with zebularine. This synergistic effect was independent of the expression of TRAIL receptors and caspase-8. These results indicate that cellular fucosylation is regulated through DNA methylation in many cancer cells. Moreover, zebularine might be useful as a combination drug with TRAIL-based therapies in patients with TRAIL-resistant cancer. PMID- 20953700 TI - Aspartate release and signalling in the hippocampus. AB - The Ca(2+)-dependent release of aspartate from hippocampal preparations was first reported 35 years ago, but the functional significance of this process remains uncertain. Aspartate satisfies all the criteria normally required for identification of a CNS transmitter. It is synthesized in nerve terminals, is accumulated and stored in synaptic vesicles, is released by exocytosis upon nerve terminal depolarization, and activates postsynaptic NMDA receptors. Aspartate may be employed as a neuropeptide-like co-transmitter by pathways that release either glutamate or GABA as their principal transmitter. Aspartate mechanisms include vesicular transport by sialin, vesicular content sensitive to glucose concentration, release mainly outside the presynaptic active zones, and selective activation of extrasynaptic NR1-NR2B NMDA receptors. Possible neurobiological functions of aspartate in immature neurons include activation of cAMP-dependent gene transcription and in mature neurons inhibition of CREB function, reduced BDNF expression, and induction of excitotoxic neuronal death. Recent findings suggest new experimental approaches toward resolving the functional significance of aspartate release. PMID- 20953701 TI - Negative feedback regulation of Raf/MEK/ERK cascade after sublethal cerebral ischemia in the rat hippocampus. AB - Sublethal preconditioning ischemia protects neurons from lethal ischemia, and activation of ERK is associated with this protection. However, sublethal ischemia and reperfusion also results in rapid inactivation of ERK, which contributes to the dual-phase activation profile of ERK. In the present study, we observed sublethal ischemia-induced rapid inactivation of ERK was accompanied by phosphorylation of Raf-1 at Ser289/296/301 sites. Inhibition of calcium signaling by ketamine resulted in down-regulation of the Raf-1/ERK cascade and decreased phosphorylation of Raf-1 at Ser289/296/301. The MEK inhibitor U0126 suppressed ERK activity and phosphorylation of Raf-1 at Ser289/296/301 but not Raf-1 activation elicited by its dephosphorylation at S259 following ischemia. The PP2A inhibitor cantharidin but not Pin1 inhibitor juglone blocked Raf-1 dephosphorylation at Ser289/296/301 and ERK dephosphorylation and led to ERK sustained activation, which is associated with transcriptional up-regulation of genes related to differentiation. Furthermore, dual-phase activation of ERK did not alter the mRNA levels of genes related to proliferation or differentiation. These results indicate the initial robust activation of ERK phosphorylates Raf-1 at Ser289/296/301, resulting in Raf-1inhibition and then prompt inactivation of ERK following sublethal preconditioning ischemia. Dual-phase activation of ERK may exert its neuroprotection against lethal ischemia through blocking cell proliferation and differentiation. PMID- 20953702 TI - L-364,718 potentiates electroacupuncture analgesia through cck-a receptor of pain related neurons in the nucleus parafascicularis. AB - Electroacupuncture (EA) has been successfully used to alleviate pain produced by various noxious stimulus. Cholecystokinin-8 (CCK-8) is a neuropeptide involved in the mediation of pain. We have previously shown that CCK-8 could antagonize the analgesic effects of EA on pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the nucleus parafascicularis (nPf). However, its mechanism of action is not clear. In the present study, we applied behavioral and neuroelectrophysiological methods to determine whether the mechanisms of CCK-8 antagonism to EA analgesia are mediated through the CCK-A receptors of PENs and PINs in the nPf of rats. We found that focusing radiant heat on the tail of rats caused a simultaneous increase in the evoked discharge of PENs or a decrease in the evoked discharge of PINs in the nPf and the tail-flick reflex. This showed that radiant heat could induce pain. EA stimulation at the bilateral ST 36 acupoints in rats for 15 min resulted in an inhibition of the electrical activity of PEN, potentiation of the electrical activity of PIN, and prolongation in tail flick latency (TFL), i.e. EA stimulation produced an analgesic effect. The analgesic effect of EA was antagonized when CCK-8 was injected into the intracerebral ventricle of rats. The antagonistic effect of CCK-8 on EA analgesia was reversed by an injection of CCK-A receptor antagonist L-364,718 (100 ng/MUl) into the nPf of rats. Our results suggest that the pain-related neurons in the nPf have an important role in mediating EA analgesia. L-364,718 potentiates EA analgesia through the CCK-A receptor of PENs and PINs in the nPf. PMID- 20953703 TI - Comparing BRIN-BD11 culture producing insulin using different type of microcarriers. AB - This research was conducted to examine the growth profile, growth kinetics, and insulin-secretory responsiveness of BRIN-BD11 cells grown in optimized medium on different types of microcarriers (MCs). Comparisons were made on modified polystyrene (Hillex((r)) II) and crosslinked polystyrene Plastic Plus (PP) from Solohill Engineering. The cell line producing insulin was cultured in a 25 cm(2) T-flask as control while MCs based culture was implemented in a stirred tank bioreactor with 1 L working volume. For each culture type, the viable cell number, glucose, lactate, glutamate, and insulin concentrations were measured and compared. Maximum viable cell number was obtained at 1.47 * 10(5) cell/mL for PP microcarrier (PPMCs) culture, 1.35 * 10(5) cell/mL Hillex((r)) II (HIIMCs) culture and 0.95 * 10(5) cell/mL for T-flask culture, respectively. The highest insulin concentration has been produced in PPMCs culture (5.31 mg/L) compared to HIIMCs culture (2.01 mg/L) and T-flask culture (1.99 mg/L). Therefore overall observation suggested that PPMCs was likely preferred to be used for BRIN-BD11 cell culture as compared with Hillex((r)) II MCs. PMID- 20953704 TI - Fanconi syndrome following honeybee stings. AB - A 32-year-old gentleman was attacked by honey bees about 8 months and immediately afterwards his eyelids, cheeks and pinnae became swollen, red, and tender. However, the patient did not develop any renal or serum sickness symptoms and his physical examination and laboratory investigations were normal. He recovered completely. A week later, while working on his farm, he experienced a sudden loss of muscular tone in all four limbs without losing his consciousness. The medical examination subsequently revealed flaccid quadriparesis associated with a serum potassium of 2.1 mEq/L. He was also found to have hyperchloremic metabolic acidosis with normal anion gap and preserved ability to acidify urine to a pH of 5.5. These findings were suggestive of proximal renal tubular acidosis (Fanconi syndrome). Other abnormalities like hypophosphataemia, hypouricemia, renal glucosuria and high urinary excretion of calcium, phosphorus and uric acid further supported the diagnosis of proximal tubular dysfunction. The renal biopsy revealed dense lymphocytic interstitial infiltrate, a feature often seen in Sjogren's syndrome, in which at least 50% of patients fail to acidify urine. In our patient, thorough search for other causes of proximal renal tubular acidosis was negative. PMID- 20953705 TI - Two icodextrin exchanges per day in peritoneal dialysis patients with ultrafiltration failure: one center's experience and review of the literature. AB - BACKGROUND: At present, only one exchange of an icodextrin-based solution is recommended to increase peritoneal ultrafiltration (UF) during long-dwell exchanges in peritoneal dialysis (PD) patients with impaired UF. AIM: To review our experience with two icodextrin exchanges per day on net UF and body weight in PD patients with poor UF. METHODS: Data were analyzed on nine patients with poor UF on chronic PD who were given two icodextrin exchanges per day for 6 months and had various clinical and biochemical parameters assessed monthly. RESULTS: Administration of icodextrin twice daily reduced the body weight in six of nine patients by an average of 2.9 +/- 1.2 kg, a reduction that was maintained throughout the study; two patients gained 0.5 kg; and, in one patient, the measurements were inadequate. Mean blood pressure was reduced. Mean serum creatinine increased slightly. Serum sodium levels decreased from a mean baseline level of 134 +/- 3 to 132 +/- 4 mmol/L at three and six months. Among the diabetics in this group, average daily insulin requirements were 44 +/- 35 units/day at baseline and 40 +/- 23 units/day after 6 months. Hb1Ac levels remained stable throughout the study period. CONCLUSION: The use of two icodextrin exchanges per day reduced body weight in six of the nine patients and appeared to be safe. Long-term prospective studies are needed to assess the contribution of twice-daily icodextrin to the management of peritoneal dialysis patients with ultrafiltration failure and its long-term safety. PMID- 20953706 TI - Incidence and risk factors for lymphoma in a single-center inflammatory bowel disease population. AB - AIMS: Previous studies on the risk of lymphoma in inflammatory bowel disease (IBD) have yielded conflicting results. We aim to determine the incidence and risk factors for lymphoma in a large IBD population. METHODS: Patients with lymphoma were identified from a single-center IBD database. The standardized incidence ratio (SIR) of lymphoma was estimated using data from the Surveillance, Epidemiology and End Results (SEER) registry. Risk factors for lymphoma were determined by comparing cases with a matched IBD control group. RESULTS: Eleven lymphomas were identified among 3,585 IBD patients during an average of 8.4 years of observation. Three patients were excluded. In the remaining eight, median age at diagnosis was 47 years and mean IBD duration was 20 years (range 7.5-45 years). The SIR for lymphoma was 1.6 [95% confidence interval (CI) 0.6-3.0], and for non-Hodgkin lymphoma (NHL), 1.5 (0.3-2.8). Three lymphoma patients (38%) received prior immunomodulators and two (25%) received biologics, versus 57% and 39% in the control group, respectively (P = 0.4). No correlation was seen with tobacco exposure, disease duration, use, or dose or duration of immunosuppressive therapy. CONCLUSIONS: In this IBD cohort, risk of lymphoma was not increased compared with the general population. Risk of lymphoma was not associated with any demographic or therapy-related factors. PMID- 20953708 TI - Optimal timing in screening patients with congestive heart failure and healthy subjects during circadian observation. AB - Congestive heart failure (CHF) is a major medical challenge in developed countries. In order to screen patients with CHF and healthy subjects during circadian observation, accurate judgment and fast response are imperative. In this study, optimal timing during circadian observation via the heart rate variability (HRV) was sought. We tested 29 CHF patients and 54 healthy subjects in the control group from the interbeat interval databases of PhysioBank. By invoking the alpha1 parameter in detrended fluctuation analysis of HRV, we found that it could be used as an indicator to screen the patients with CHF and subjects in normal sinus rhythm (NSR) under Kruskal-Wallis test. By invoking Fano factor, the optimal timing to screen CHF patients and healthy subjects was found to be from 7 PM to 9 PM during the circadian observation. In addition, this result is robust in a sense that the same result can be achieved by using different ECG recording lengths of 2, 5, 10, ... , and 120 min, respectively. Furthermore, a support vector machine was employed to classify CHF and NSR with alpha1 parameter of a moving half-hour ECG recordings via leave-one-out cross validation. The results showed that the superlative screening performance was obtained in the 7 pm-9 pm period during circadian observation. It is believed that this result of optimal timing will be helpful in the non-invasive monitoring and screening of CHF patients and healthy subjects in the clinical practice. PMID- 20953707 TI - Assessment of psychiatric outcomes in Japan based on diagnostic procedure combination information. AB - We evaluated psychiatric care in terms of relationships between patient characteristics and a comprehensive measurement of psychiatric outcomes among inpatients with lengths of stay (LOSs) of 90 days or fewer in a psychiatric hospital in Japan. The sample consisted of inpatients discharged from an acute care psychiatric hospital between September 1 and December 31, 2007. Multivariate analyses were performed to identify patient characteristics related to the outcome of acute psychiatric care. The type of admission was related to difference in Global Assessment of Functioning (GAF) scores (P < 0.001), health care cost (P < 0.001), length of time spent in seclusion (P < 0.001), and length of time spent in restraints (P < 0.01). Diagnosis showed a minimal or non existent relationship to the outcome variables. The GAF scores of involuntary patients with initially low scores on this axis were greatly improved at discharge. Patients who were admitted involuntarily received more coercive interventions and treatments, such as seclusion and restraints, than did patients with who were admitted voluntarily. Diagnostic groups did not differ in terms of GAF scores. Further studies utilizing diagnostic procedure combination (DPC) data from multiple medical institutions are necessary to verify the present findings. PMID- 20953709 TI - Self-concept clarity and religious orientations: prediction of purpose in life and self-esteem. AB - The present study concerns the relationship between self-concept clarity, religiosity, and well-being, as well as the mediating influence of religiosity on the relationship between self-concept clarity and sense of meaning in life and self-esteem. Self-concept clarity was found to be a significant predictor of sense of meaning in life and self-esteem; intrinsic religious orientation was found to be a predictor of sense of meaning in life, while the quest religious orientation was a predictor for self-esteem. The cross-products of self-concept clarity and intrinsic religious orientation were found to be related to the sense of purpose in life, which would point to religiosity being a mediator of the relationship between self-concept clarity and sense of purpose in life. The cross products of self-concept clarity and quest religious orientation were found to be a predictor of self-esteem, which indicates a mediating effect of this religious orientation in the relationship of self-concept clarity and self-esteem. PMID- 20953710 TI - Using pictures to evoke spiritual feelings in breast cancer patients: development of a new paradigm for neuroimaging studies. AB - This study was designed to develop and validate a method for enhancing spiritual feelings, particularly in women who have received a diagnosis of breast cancer. The protocol specifically was developed to be used in functional magnetic resonance imaging (fMRI) studies. Eighteen breast cancer survivors rated pictures for their ability to enhance feelings of spirituality, happiness, and sadness. Results indicate that presenting carefully selected pictures with spiritual content (e.g., nature scenes, people engaged in contemplative behaviors) can effectively enhance spiritual feelings among breast cancer survivors. Future fMRI studies will explore the use of the protocol developed in this study for investigating neural activity during spiritual feelings and states. PMID- 20953711 TI - Anasakti, the Hindu ideal, and its relationship to well-being and orientations to happiness. AB - Anasakti, a Sanskrit term for traits like non-attachment, equipoise, selfless duty orientation, and effort in the absence of concern for the outcome, can be regarded as a Hindu-ideal cluster of personality traits. The relationship of Anasakti with well-being and the three distinct happiness orientations was explored through a study of 676 college students and a sample of 65 yogic practitioners in India. The findings revealed that the yogic practitioners were markedly higher in Anasakti than the secular population. For the yogic population, there was a large correlation between Anasakti and the Orientation to Meaningful Life, and it accounted for more than 20% of the variance in the regression of Anasakti against all the measures of well-being. The yogic population's scores also correlated with several other measures of well-being. The scores of the secular population were less strongly related to the well-being scores; though, several correlation coefficients were statistically significant. PMID- 20953712 TI - I'm a Jesus girl: coping stories of Black American women diagnosed with breast cancer. AB - Breast cancer continues to be the most diagnosed cancer for all women, excluding non-melanoma skin cancer, in the United States. Incidence rates are 1 in 8 for an American woman being diagnosed. Moreover, statistics indicate that every 13 min an American woman dies from complications related to breast cancer. Despite all the gains made in the area of cancer research, Black American women continue to have a 67% higher mortality rate than their White counterparts. There is no preparation for a diagnosis of breast cancer. Upon hearing the words: you have breast cancer, a woman's life is forever altered. The woman's initial reactions of denial and/or anger yield to strategic responses. These responses may strengthen the woman's resiliency both during and following treatments. Research indicates that Black Americans, specifically Black American women, exhibit greater religiosity/spirituality than do other racial/ethnic groups. In addition, the use of religiosity/spirituality by Black Americans increases during a crisis. This qualitative study examines how religiosity/spirituality was utilized as a coping mechanism by a group of Black American women following their diagnoses of breast cancer. PMID- 20953713 TI - Psychometric evaluation of the Fatigue Severity Scale in patients with major depression. AB - PURPOSE: This study aimed to investigate the psychometric properties of the Fatigue Severity Scale (FSS), a widely used unidimensional fatigue measure, in patients with major depression. METHODS: Subjects included were 72 patients with major depressive disorder, diagnosed with the DSM-IV based M.I.N.I. 5.0.0., without comorbid fatigue-associated conditions and Hamilton Depression Rating Scale (HDRS) scores >= 17 as well as 40 sex- and age-matched healthy controls. The FSS was administered to patients on two time points separated by a 1-week interval and to controls. The vitality subscale of the 36-item Short Form Health Survey (SF-36vit) and a visual analogue fatigue scale (VASF) were also administered. RESULTS: A total of 79.2% of patients vs. 15% of controls were fatigue cases according to the M.I.N.I. fatigue/energy loss item. The distribution of FSS scores was negatively skewed in the patient group, demonstrating a ceiling effect. The FSS presented satisfactory test-retest reliability (intraclass correlation coefficient 0.993), internal consistency (Cronbach's alpha coefficient 0.947), concurrent validity (correlations with SF 36vit, VASF and HDRS were -0.52, 0.73 and 0.32, respectively) and discriminative validity between patients and controls. Factor analysis demonstrated a unidimensional structure. The optimal FSS cutoff score for clinically significant fatigue was 5.4 against the presence of fatigue/energy loss according to the M.I.N.I. as a 'gold standard'. CONCLUSION: When administered to patients with major depression, the FSS was shown to have satisfactory psychometric properties with the exception of a ceiling effect, which may pose limitations to its use in this population. PMID- 20953714 TI - Living with chronic pain. PMID- 20953715 TI - Translation of the Social Difficulties Inventory (SDI-21) into three South Asian languages and preliminary evaluation of SDI-21(Urdu). AB - PURPOSE: In the United Kingdom, cross-cultural adaptation of questionnaires would allow for inclusivity in assessment in cancer clinics for non-English speakers. The aim was to translate the Social Difficulties Inventory (SDI-21) into Urdu, Punjabi and Hindi and undertake preliminary evaluation of translated versions. METHODS: The study comprised three stages: (1) translation/back translation and evaluation of cultural equivalence of the SDI-21, (2) south Asian (SA) patient evaluation of SDI-21 translations and (3) evaluation using Rasch analysis comparing English and Urdu SDI-21 from data pooled from this and three other studies. RESULTS: Forward/backward translation resulted in minor amendments particularly in forward translation of SDI-21(Hindi). The majority of the 55 patients interviewed found the SDI-21 acceptable and clear, resulting in no amendments (all versions). Rasch analysis demonstrated good fit. Differential item functioning (DIF) was found for one item, in the comparison of white English (WE)- and SA Urdu-speaking groups. Detailed DIF analysis comparing self completion and read-aloud administration by language group demonstrated this DIF only held for the comparison between SA English speakers (self-completion) and SA Urdu (read out). CONCLUSIONS: Translated versions are culturally and linguistically acceptable. The SDI-21 (Urdu) performs similarly to the English version when self-completed. PMID- 20953716 TI - Coding and traceability in Iran. AB - Transplantation has a long history in Iran. Cornea was the first tissue transplantation in 1935. The Central Eye Bank of Iran was established in 1991 and the Iranian Tissue Bank (ITB) in 1994. Now, there are also some private cell and tissue banks in the country, that produce different tissue grafts such as homograft heart valves, musculoskeletal tissues, soft tissues, cartilages, pericardium, amniotic membrane and some cell based products. There is not a separate legislation for tissue transplantation but the legal framework for tissue donation is based on the "Deceased or Brain dead patient organ transplantation" act (passed on April 6, 2000). For tissue banking there is no regulatory oversight by the national health authority. To increase the level of safety and considering the importance of effective traceability, each tissue bank has its own policy and terminology for coding and documentation without any correlation to others. In some cases tissue banks have implemented ISO based standards (i.e., ISO 9001) as a basic quality management system. PMID- 20953717 TI - Are you too burnt out to read this? I expect not. PMID- 20953718 TI - Burnout and career satisfaction among surgical oncologists compared with other surgical specialties. AB - INTRODUCTION: Little is known regarding the rate of burnout, career satisfaction, and quality of life (QOL) among surgical oncologists compared with other surgical subspecialties. METHODS: The American College of Surgeons conducted a survey in 2008 involving 7,905 respondents, of whom 407 were surgical oncologists. Demographic variables, practice characteristics, career satisfaction, burnout, and quality of life (QOL) of surgical oncologists were compared with other surgical subspecialties using validated instruments. RESULTS: Surgical oncologists were younger (mean age 49.9 years), more likely to be female (26%), and had younger children than other surgical subspecialties. With respect to practice characteristics, surgical oncologists had been in practice fewer years and had fewer nights on call per week than other surgical disciplines but worked more hours (mean 62.6/week), were more likely to be in an academic practice (59.5%), were more likely to be paid on a salaried basis (68%), and had more time devoted to non-patient activities (e.g., research). Compared with surgeons from all other specialties, surgical oncologists had similar incidence of burnout (36%), suicide ideation (4.9%), and QOL, but lower incidence of depression (24%), and better indices of career satisfaction. CONCLUSIONS: These data provide a frame of reference for valid comparisons of burnout, QOL, and career satisfaction indices for the surgical oncology community relative to all other surgical specialties. Surgical oncologists have higher career satisfaction and lower risk of depression than surgeons in other surgical disciplines but still experience high rates of burnout. PMID- 20953720 TI - Impact of surgical experience on in-hospital complication rates in patients undergoing minimally invasive prostatectomy: a population-based study. AB - BACKGROUND: The relationship between provider volume and complication and transfusion rates in patients undergoing minimally invasive prostatectomy (MIRP) for prostate cancer has not been assessed. Temporal trends in MIRP annual surgical caseload (AC), impact of MIRP surgical experience (SE), and in-hospital complication and transfusion rates were evaluated. METHODS: Between 2002 and 2008, 2,666 patients in Florida underwent MIRP. Surgical experience was defined as the number of procedures performed from the beginning of the study until each individual MIRP. Multivariable logistic regression models using generalized estimating equations assessed the relationship between SE and in-hospital complication and transfusion rates. RESULTS: Overall AC and SE ranged from 1-171 and 1-500, respectively. Between 2002 and 2005, 94-100% of surgeons were considered as low AC tertile (<=15 MIRP) vs. 76-82% between 2006 and 2008. For the same time periods, low AC tertile surgeons performed 46-100 and 27-32% of all MIRPs respectively. Multivariable logistic regression models revealed 51 and 68% lower complication rates in patients operated on by surgeons of intermediate (17 76 MIRPs) and high SE (>=77 MIRPs) relative to surgeons of low SE (<=16 MIRPs). Similarly, transfusion rates were 80 and 83% lower for the same groups. CONCLUSIONS: Our study is the first to indicate that high SE reduces MIRP complication and transfusion rates. Despite this observation, even in the most contemporary study year, most MIRP surgeons (82%) were in the low AC tertile and contributed to as many as 32% of all MIRPs. These findings should be considered at informed consent. PMID- 20953721 TI - The BRAF mutation is predictive of aggressive clinicopathological characteristics in papillary thyroid microcarcinoma. AB - BACKGROUND: This study analyzed the utility of BRAF mutation screening of ultrasonography-guided fine-needle aspiration biopsy (FNAB) specimens for predicting aggressive clinicopathological characteristics of papillary thyroid microcarcinoma (PTMC). METHODS: We assessed the T1799A BRAF mutation status in FNAB specimens obtained from 61 PTMC patients before undergoing operations for PTMC. We examined whether the BRAF mutation was associated with clinicopathologic characteristics in PTMC. Additionally, we reviewed the BRAF mutation status, and clinical, ultrasound (US), hematological, and pathology records of the patients and analyzed the associations between these characteristics and lateral lymph node metastasis (LNM). RESULTS: Analysis of the preoperative FNABs accurately reflected the BRAF status of the resected tissues in 19 of the 20 paired samples (95% concordance). We observed that the BRAF mutation was statistically significantly associated with multifocality, extrathyroidal invasion, lateral LNM, and advanced tumor stages III and IV. The BRAF mutation, pathologic features (central LNM), and US features (upper pole location) were independent predictive factors for lateral LNM in a multivariate analysis with odds ratios of 18.144 (95% confidence interval [95% CI], 1.999-164.664; P = 0.01), 8.582 (95% CI, 1.014 76.662; P = 0.049) and 9.576 (95% CI, 1.374-66.728; P = 0.023), respectively. CONCLUSIONS: BRAF mutation-positive PTMCs were more likely to manifest aggressive characteristics (extrathyroidal extension and LNM). The BRAF mutation screening of FNAB specimens can be used to predict aggressive clinicopathological characteristics of PTMC. Lateral neck nodes should be meticulously analyzed for cases of PTMC demonstrating the following three characteristics: BRAF mutation, central LNM, and US features in the upper pole location. PMID- 20953722 TI - Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity. AB - Increased susceptibility to infections, particularly respiratory viral infections, is a hallmark of advancing age. The underlying mechanisms are not well understood, and there is a scarcity of information regarding the contribution of the innate immune system, which is the first line of defense against infections. In the present study, we have investigated the effect of advancing age on plasmacytoid dendritic cell (PDC) function because they are critical in generating a robust antiviral response via the secretion of interferons (IFN). Our results indicate that PDCs from the aged are impaired in their capacity to secrete IFN-I in response to influenza virus and CPG stimulation. Additionally, we observed a severe reduction in the production of IFN-III, which plays an important role in defense against viral infections at respiratory mucosal surfaces. This reduction in IFN-I and IFN-III were a result of age-associated impaired phosphorylation of transcription factor, IRF-7. Furthermore, aged PDCs were observed to be impaired in their capacity to induce perforin and granzyme in CD8 T cells. Comparison of the antigen-presenting capacity of aged PDC with young PDC revealed that PDCs from aged subjects display reduced capacity to induce proliferation and IFN-gamma secretion in CD4 and CD8 T cells as compared with PDCs from young subjects. In summary, our study demonstrates that advancing age has a profound effect on PDC function at multiple levels and may therefore, be responsible for the increased susceptibility to infections in the elderly. PMID- 20953724 TI - New terpenoids, olibanumols D-G, from traditional Egyptian medicine olibanum, the gum-resin of Boswellia carterii. AB - A new prenylaromadendrane-type diterpene, olibanumol D (1), and three new oleanane- and lupane-type triterpenes, olibanumols E (2), F (3), and G (4), were isolated from the traditional Egyptian medicine olibanum, the exuded gum-resin from Boswellia carterii Birdw. Their structures were established mainly on the basis of 1D and 2D NMR spectral data. Compounds 1 and 2 exhibited nitric oxide production inhibitory activity in lipopolysaccharide-activated mouse peritoneal macrophages. PMID- 20953723 TI - Antinociceptive activity of Hypericum grandifolium Choisy in mice. AB - The present study investigated the antinociceptive activity of different extracts prepared from the aerial parts of blossom of Hypericum grandifolium Choisy-a species native to the Macaronesian Region-using the acetic acid-induced writhing, formalin and tail flick test in mice. Oral administration of methanol extract (500 and 1,000 mg/kg p.o.), the aqueous, butanol and chloroform fractions (500 mg/kg p.o.) as well as subfractions F2 and F3 (45 mg/kg p.o.) from the chloroform fraction significantly inhibited acetic acid-induced writhing, with values ranging from 28 to 50% of inhibition. The methanol extract (1,000 mg/kg p.o.) and chloroform fraction (500 mg/kg p.o.) significantly reduced both phases of formalin-induced pain (with inhibition values ranging from 18 to 53%), whereas subfraction F2 (45 mg/kg p.o.) significantly inhibited the late phase (30%). In the tail flick assay, only the chloroform fraction (500 mg/kg p.o.) significantly prolonged the tail flick response. Different constituents, such as flavonoids and benzophenone derivatives, could account for the effects observed. Taking together, the results indicate that Hypericum grandifolium Choisy possesses both peripheral and central antinociceptive activities in mice, suggesting an interesting therapeutic potential for this species in pain diseases. PMID- 20953725 TI - Restricted diffusion in cellular media: (1+1)-dimensional model. AB - We consider the diffusion of molecules in a one-dimensional medium consisting of a large number of cells separated from the extra-cellular space by permeable membranes. The extra-cellular space is completely connected and allows unrestricted diffusion of the molecules. Furthermore, the molecules can diffuse within a given cell, i.e., the intra-cellular space; however, direct diffusion from one cell to another cell cannot occur. There is a movement of molecules across the permeable membranes between the intra- and extra-cellular spaces. Molecules from one cell can cross the permeable membrane into the extra-cellular space, then diffuse through the extra-cellular space, and eventually enter the intra-cellular space of a second cell. Here, we develop a simple set of model equations to describe this phenomenon and obtain the solutions using an eigenfunction expansion. We show that the solutions obtained using this method are particularly convenient for interpreting data from experiments that use techniques from nuclear magnetic resonance imaging. PMID- 20953726 TI - Travelling waves in hyperbolic chemotaxis equations. AB - Mathematical models of bacterial populations are often written as systems of partial differential equations for the densities of bacteria and concentrations of extracellular (signal) chemicals. This approach has been employed since the seminal work of Keller and Segel in the 1970s (Keller and Segel, J. Theor. Biol. 30:235-248, 1971). The system has been shown to permit travelling wave solutions which correspond to travelling band formation in bacterial colonies, yet only under specific criteria, such as a singularity in the chemotactic sensitivity function as the signal approaches zero. Such a singularity generates infinite macroscopic velocities which are biologically unrealistic. In this paper, we formulate a model that takes into consideration relevant details of the intracellular processes while avoiding the singularity in the chemotactic sensitivity. We prove the global existence of solutions and then show the existence of travelling wave solutions both numerically and analytically. PMID- 20953727 TI - Concurrent Sweet's syndrome and erythema nodosum. PMID- 20953728 TI - Does cultural competency training of health professionals improve patient outcomes? A systematic review and proposed algorithm for future research. AB - BACKGROUND: Cultural competency training has been proposed as a way to improve patient outcomes. There is a need for evidence showing that these interventions reduce health disparities. OBJECTIVE: The objective was to conduct a systematic review addressing the effects of cultural competency training on patient-centered outcomes; assess quality of studies and strength of effect; and propose a framework for future research. DESIGN: The authors performed electronic searches in the MEDLINE/PubMed, ERIC, PsycINFO, CINAHL and Web of Science databases for original articles published in English between 1990 and 2010, and a bibliographic hand search. Studies that reported cultural competence educational interventions for health professionals and measured impact on patients and/or health care utilization as primary or secondary outcomes were included. MEASUREMENTS: Four authors independently rated studies for quality using validated criteria and assessed the training effect on patient outcomes. Due to study heterogeneity, data were not pooled; instead, qualitative synthesis and analysis were conducted. RESULTS: Seven studies met inclusion criteria. Three involved physicians, two involved mental health professionals and two involved multiple health professionals and students. Two were quasi-randomized, two were cluster randomized, and three were pre/post field studies. Study quality was low to moderate with none of high quality; most studies did not adequately control for potentially confounding variables. Effect size ranged from no effect to moderately beneficial (unable to assess in two studies). Three studies reported positive (beneficial) effects; none demonstrated a negative (harmful) effect. CONCLUSION: There is limited research showing a positive relationship between cultural competency training and improved patient outcomes, but there remains a paucity of high quality research. Future work should address challenges limiting quality. We propose an algorithm to guide educators in designing and evaluating curricula, to rigorously demonstrate the impact on patient outcomes and health disparities. PMID- 20953729 TI - Interventions encouraging the use of systematic reviews in clinical decision making: a systematic review. AB - BACKGROUND: Systematic reviews have the potential to inform clinical decisions, yet little is known about the impact of interventions on increasing the use of systematic reviews in clinical decision-making. PURPOSE: To systematically review the evidence on the impact of interventions for seeking, appraising, and applying evidence from systematic reviews in decision-making by clinicians. DATA SOURCES: Medline, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, and LISA were searched from the earliest date available until July 2009. STUDY SELECTION AND DATA EXTRACTION: Two independent reviewers selected studies for inclusion if the intervention intended to increase seeking, appraising, or applying evidence from systematic reviews by a clinician. Information about the study population, features of each intervention, methods used to measure the use of systematic reviews and those used to measure professional performance or health care outcomes, existence and use of statistical tests, study outcomes, and comparative data were extracted. DATA SYNTHESIS: A total of 8,104 titles and abstracts were reviewed, leading to retrieval of 189 full-text articles for assessment; five of these studies met all inclusion criteria. All five studies reported on professional performance behavior; none reported on patient health outcomes. One study reported positive outcomes in improving preventive care. Three studies focused on obstetrical care, with two reporting no impact on professional practice change, and one study reporting increases in the use of prophylactic oxytocin and episiotomy. One study found no improvement in the sealant rate of newly erupted molars among dentists in Scotland. LIMITATIONS: The small number of studies available for examination indicates the difficulty in summarizing and identifying key aspects in successful strategies that encourage clinicians to use systematic reviews in decision-making. Other concerns lay in selective reporting and lack of blinding during data collection. CONCLUSIONS: The limited empirical data render the strength of evidence weak for the effectiveness and types of interventions that encourage clinicians to use systematic reviews in clinical decision making. PMID- 20953730 TI - Prevalence of endocrine diseases in morbidly obese patients scheduled for bariatric surgery: beyond diabetes. AB - BACKGROUND: Bariatric surgery allows stable body weight reduction in morbidly obese patients. In presurgical evaluation, obesity-related co-morbidities must be considered, and a multidisciplinary approach is recommended. Precise guidelines concerning the endocrinological evaluation to be performed before surgery are not available. The aim of this study was to evaluate the prevalence of common endocrine diseases in a series of obese patients scheduled for bariatric surgery. METHODS: We examined 783 consecutive obese subjects (174 males and 609 females) aged 18-65 years, who turned to the obesity centre of our department from January 2004 to December 2007 for evaluation before bariatric surgery. Thyroid, parathyroid, adrenal and pituitary function was evaluated by measurement of serum hormones. Specific imaging or supplementary diagnostic tests were performed when indicated. RESULTS: The overall prevalence of endocrine diseases, not including type 2 diabetes mellitus, was 47.4%. The prevalence of primary hypothyroidism was 18.1%; pituitary disease was observed in 1.9%, Cushing syndrome in 0.8%, while other diseases were found in less than 1% of subjects. Remarkably, the prevalence of newly diagnosed endocrine disorders was 16.3%. CONCLUSIONS: A careful endocrinological evaluation of obese subjects scheduled for bariatric surgery may reveal undiagnosed dysfunctions that require specific therapy and/or contraindicate the surgical treatment in a substantial proportion of patients. These results may help to define the extent of the endocrinological screening to be performed in obese patients undergoing bariatric surgery. PMID- 20953731 TI - Employment is associated with the health-related quality of life of morbidly obese persons. AB - BACKGROUND: We aimed to investigate whether employment status was associated with health-related quality of life (HRQoL) in a population of morbidly obese subjects. METHODS: A total of 143 treatment-seeking morbidly obese patients completed the Medical Outcome Study 36-Item Short-Form Health Survey (SF-36) and the Obesity and Weight-Loss Quality of Life (OWLQOL) questionnaires. The former (SF-36) is a generic measure of physical and mental health status and the latter (OWLQOL) an obesity-specific measure of emotional status. Multiple linear regression analyses included various measures of the HRQoL as dependent variables and employment status, education, marital status, gender, age, body mass index (BMI), type 2 diabetes, hypertension, obstructive sleep apnea, and treatment choice as independent variables. RESULTS: The patients (74% women, 56% employed) had a mean (SD, range) age of 44 (11, 19-66) years and a mean BMI of 44.3 (5.4) kg/m(2). The employed patients reported significantly higher HRQoL scores within all eight subscales of SF-36, while the OWLQOL scores were comparable between the two groups. Multiple linear regression confirmed that employment was a strong independent predictor of HRQoL according to the SF-36. Based on part correlation coefficients, employment explained 16% of the variation in the physical and 9% in the mental component summaries of SF-36, while gender explained 22% of the variation in the OWLQOL scores. CONCLUSION: Employment is associated with the physical and mental HRQoL of morbidly obese subjects, but is not associated with the emotional aspects of quality of life. PMID- 20953732 TI - Increased in vitro lysosomal function in oxidative stress-induced cell lines. AB - Exposure of mammalian cells to oxidative stress alters lysosomal enzymes. Through cytochemical analysis of lysosomes with LysoTracker, we demonstrated that the number and fluorescent intensity of lysosome-like organelles in HeLa cells increased with exposure to hydrogen peroxide (H2O2), 6-hydroxydopamine (6-OHDA), and UVB irradiation. The lysosomes isolated from HeLa cells exposed to three oxidative stressors showed the enhanced antimicrobial activity against Escherichia coli. Further, when lysosomes that were isolated from HeLa cells exposed by oxidative stress were treated to normal HeLa cells, the viability of the HeLa cells was drastically reduced, suggesting increased in vitro lysosomal function (i.e., antimicrobial activity, apoptotic cell death). In addition, we also found that cathepsin B and D were implicated in increased in vitro lysosomal function when isolated from HeLa cells exposed by oxidative stress. Decrease in cathepsin B activity and increase in cathepsin D activity were observed in lysosomes isolated from HeLa cells after treatment with H2O2, 6-ODHA, or UVB, but cathepsin B and D were not the sole factors to induce cell death by in vitro lysosomal function. Therefore, these studies suggest a new approach to use lysosomes as antimicrobial agents and as new materials for treating cancer cell lines. PMID- 20953733 TI - A novel magneto-fluorescent nano-bioprobe for cancer cell targeting, imaging and collection. AB - Silica-coated magnetic polystyrene nanospheres (MPN) containing CdTe/CdS quantum dots (QDs) and Fe3O4 nanoparticles were prepared, and novel anti-EGFR antibodies were conjugated onto these magneto-fluorescent nanocomposites (MPN-QDs-SiO2) for cancer cell targeting, imaging and collection. Transmission electron microscopy (TEM), scanning electron microscopy (SEM) images and energy-dispersive x-ray spectrometry (EDS) data showed that the MPN had been successfully coated with QDs and a silica shell, and the nanocomposites obtained with negative charged surfaces were well dispersed. The bioconjugates could be used for specifically labeling and separating cancer cells (MDA-MB-435S, SMMC-7721), but did not recognize and separate the K562 cells because the human epidermal growth factor receptor (EGFR) was not expressed on the surface. Because the anti-EGFR antibody, which we have developed, could specifically recognize certain cancer cells that highly expressed EGFR on their surface, these nanoscale bioconjugates, synchronously exhibiting fluorescence and magnetism, may be used in novel bioprobes for labeling and collecting rare cancer cells, which may be beneficial for early cancer diagnosis. PMID- 20953734 TI - Complex catabolic effects of central alpha-MSH infusion in rats of altered nutritional states: differences from leptin. AB - The hypothalamic melanocortin (MC) system is a major catabolic regulator of energy balance: it suppresses food intake (FI), elevates metabolic rate, and reduces body weight (BW). The primary activator of the MC system [mainly via the alpha-melanocyte stimulating hormone (alpha-MSH)] is the adipocyte-derived leptin. With increasing BW, resistance develops to leptin-induced anorexia, but independent of this, in genetically modified animals, some alpha-MSH actions were maintained. We investigated the responsiveness of the MC system in its complexity (FI vs. metabolic correlates) in genetically intact male Wistar rats of different nutritional states (and different leptin sensitivities), i.e., in rats aged 2 months [normally fed (NF2)] or 6 months [calorie-restricted (CR6), fed ad libitum (NF6), and high-fat diet-induced obese (HF6) groups]. A 7-day-long, 1-MUg/MUl/h intracerebroventricular infusion of alpha-MSH reduced BW in all groups, particularly in NF6 and NF2 animals, and even CR6 rats lost BW upon alpha-MSH infusion (in contrast to leptin administration). Anorexia developed in NF2-NF6 and less in CR6 groups, and some FI fall was also seen in HF6 rats. The hypermetabolic effects (temperature/heart rate elevations) were most pronounced in CR6 and next in HF6 rats. These data suggest that alpha-MSH responsiveness is maintained in various forms (depending on nutritional state), despite obesity induced leptin resistance. PMID- 20953735 TI - Neuroprotection induced in vitro by ischemic preconditioning and postconditioning: modulation of apoptosis and PI3K-Akt pathways. AB - Preconditioning and postconditioning are mild ischemic exposures before or after severe injurious ischemia, respectively, that elicit endogenous neuroprotective responses. Molecular mechanisms of neuroprotection through preconditioning and postconditioning are not completely understood. Here we optimized the in vitro oxygen and glucose deprivation (OGD) models of preconditioning and postconditioning in primary cortical neuron cultures that allow the studies of the corresponding molecular mechanisms of neuroprotection. We found that the cortical cells preconditioned with a single 45-min OGD treatment administered 24 h prior to injurious 2 h OGD were robustly protected after both 3 h and 16 h of reperfusion. For the postconditioning treatment, we found that three cycles of 15 min OGD followed by 15 min reperfusion, applied immediately after injurious 2 h OGD and prior to complete reperfusion, resulted in effective neuroprotection at both 3 h and 16 h of reperfusion. Using real-time RT-PCR arrays focused on genes of the apoptosis and PI3K-Akt pathways, we found that injurious OGD mainly induced apoptosis-related and repressed PI3K-Akt pathway-related genes after either 3 h or 16 h of reperfusion. Preconditioning treatment resulted in the activation of both pro-survival and anti-apoptotic pathways after 3 h of reperfusion and mainly anti-apoptotic pathway after 16 h of reperfusion. In contrast, the activation of PI3K-Akt pathway mainly contributed to the neuroprotective effect by the postconditioning treatment after 3 h of reperfusion, but differential gene expression likely contributed minimally, if at all, to the neuroprotection observed after 16 h of reperfusion. Among the novel markers of neuroprotection, Nol3 gene upregulation was observed after 3 h of reperfusion following either preconditioning or postconditioning treatments and after 16 h of reperfusion following preconditioning treatment. PMID- 20953736 TI - Relationship between striatal dopamine transporter availability and sleep quality in healthy adults. AB - PURPOSE: Our previous study using (123)I-iodo-benzamide single photon emission computed tomography (SPECT) showed a positive relationship in healthy adults between striatal postsynaptic D(2)/D(3) receptor availability and sleep duration in good sleepers. To further investigate the role of dopamine (DA) in the sleep wake cycle, we explored the correlation between presynaptic dopamine transporter (DAT) availability and sleep quality in healthy volunteers. METHODS: A total of 83 healthy volunteers (33 males, 50 females; mean age, 34.62 years), including 39 good sleepers and 44 poor sleepers, were recruited. The sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Striatal DAT availability was determined by (99m)Tc-TRODAT-1 SPECT, and the DAT availability in the good and poor sleepers was compared. Furthermore, the correlation between PSQI and DAT availability was analyzed. RESULTS: There was no significant difference in DAT availability between the good and poor sleepers. No significant relationship was found between the global score or individual-component PSQI scores and DAT availability in the good sleepers. However, the sleep duration component score in the poor sleepers negatively correlated with DAT availability in the caudate (rho = -0.31, P = 0.049). CONCLUSIONS: The study demonstrates that healthy poor sleepers, with a lower DAT availability in the caudate, sleep for a shorter length of time. This suggests that a decrease in DA reuptake due to reduced DAT availability causes a shorter sleep duration in poor sleepers. PMID- 20953737 TI - Achieving high research reporting quality through the use of computational ontologies. AB - Systematic reviews and meta-analyses constitute one of the central pillars of evidence-based medicine. However, clinical trials are poorly reported which delays meta-analyses and consequently the translation of clinical research findings to clinical practice. We propose a Center of Excellence in Research Reporting in Neurosurgery (CERR-N) and the creation of a clinically significant computational ontology to encode Randomized Controlled Trials (RCT) studies in neurosurgery. A 128 element strong computational ontology was derived from the Trial Bank ontology by omitting classes which were not required to perform meta analysis. Three researchers from our team tagged five randomly selected RCT's each, published in the last 5 years (2004-2008), in the Journal of Neurosurgery (JoN), Neurosurgery Journal (NJ) and Journal of Neurotrauma (JoNT). We evaluated inter and intra observer reliability for the ontology using percent agreement and kappa coefficient. The inter-observer agreement was 76.4%, 75.97% and 74.9% and intra-observer agreement was 89.8%, 80.8% and 86.56% for JoN, NJ and JoNT respectively. The inter-observer kappa coefficient was 0.60, 0.54 and 0.53 and the intra-observer kappa coefficient was 0.79, 0.82 and 0.79 for JoN, NJ and JoNT journals respectively. The high degree of inter and intra-observer agreement confirms tagging consistency in sections of a given scientific manuscript. Standardizing reporting for neurosurgery articles can be reliably achieved through the integration of a computational ontology within the context of a CERR N. This approach holds potential for the overall improvement in the quality of reporting of RCTs in neurosurgery, ultimately streamlining the translation of clinical research findings to improvement in patient care. PMID- 20953738 TI - Taxane-based chemotherapy enhances response to neoadjuvant treatment for stage II and III breast cancer. AB - Reducing primary tumor volume is the main role of neoadjuvant chemotherapy for breast cancer. We evaluated the benefit of adding docetaxel to anthracyclin as neoadjuvant therapy. This study is a retrospective cohort analysis comparing the efficacy of neoadjuvant chemotherapy in patients subjected to docetaxel and epirubicin or 5-fluoruracil, epirubicin and cyclophosphamide combinations (DE and FEC group, respectively). The mean number of chemotherapy delivered was similar in both groups (P = 0.8). A total of 316 patients were treated (151 in FEC group and 165 in DE group). Primary endpoint was the clinical and pathological response to therapy. Breast conserving surgery rate was compared. In T1/2 staged patients, the complete clinical response rate was 7.5% in FEC group and 32% in DE group (P = 0.002), and the breast conserving surgery rate was 72 and 73% in FEC and DE groups, respectively (P = 0.9). In the subset of patients staged as T3 and T4a-c, objective response was higher in DE group (P < 0.0001 and P = 0.008, respectively). Breast conserving surgery rate was 38 and 63% in FEC and DE groups, respectively, in T3 staged patients and, 20.5 and 37% in T4a-c staged patients (P = 0.003 and 0.08). Despite the similar number of chemotherapy cycles delivered in both groups, the presence of microscopic axillary lymph node involvement after chemotherapy was less frequent in DE group. Neoadjuvant chemotherapy with DE combination is more effective in terms of clinical and pathological response propitiating higher breast conserving surgery rate than FEC combination in stage II and III breast cancer. PMID- 20953739 TI - Clinical significance of microsatellite instability for stage II or III colorectal cancer following adjuvant therapy with doxifluridine. AB - Microsatellite instability (MSI) is a molecular marker that can provide valuable prognostic information for colorectal cancer (CRC). However, the predictive role of the MSI status remains less clear than its role in prognostication due to mixed results from previous studies. Therefore, this study investigated the usefulness of the MSI status as a predictive factor for stage II or III CRC patients who received adjuvant doxifluridine therapy. Among 3030 patients with CRC who underwent surgical resection between 1997 and 2006, 564 patients were diagnosed with stage II or III, and adjuvant doxifluridine therapy was administered to 394 patients (70.0%). The MSI status was assessed using the markers BAT25 and BAT26, and samples with instability at both markers were scored as exhibiting high-frequency MSI (MSI-H). Among the 564 patients, 290 patients (51.4%) had stage II, and MSI-H was found in 41 patients (7.3%). With a median follow-up duration of 35.1 months (range, 0.5-135.2), the 5-year overall survival (OS) rate and relapse-free survival (RFS) rate were 87.5 and 76.2%, respectively. MSI-H showed a favorable survival trend for OS (P = 0.098) and significant survival benefit for RFS (P = 0.037) in all patients. In a univariate analysis, the doxifluridine-treated patients with MSI-H showed improved RFS compared to those with low or stable MSI (MSI-L/S) (P = 0.036), while the MSI status was not significantly associated with OS (P = 0.107). In a multivariate analysis, MSI-H was not significantly associated with RFS (Hazard ratio = 2.467, P = 0.125). In conclusion, this study confirmed the positive prognostic role of MSI-H. However, MSI-H patients with stage II or III CRC did not seem to benefit from doxifluridine adjuvant therapy. PMID- 20953740 TI - Stroke prevention in the high-risk atrial fibrillation patient: Medical management. AB - Medical management of patients with atrial fibrillation (AF) at high risk for stroke is limited by problems of imperfect tools for assessment of thromboembolism and bleeding risks. Improved instruments, such as the CHA2DS2VASc and HAS-BLED risk stratification scores, have been incorporated into European practice guidelines. Until recently, the most effective therapy for stroke prevention has been anticoagulation with a vitamin K antagonist, but new oral anticoagulants in development, antiarrhythmic drugs that reduce adverse cardiovascular events in patients with AF, and interventional techniques for occlusion of the left atrial appendage represent promising options for stroke prevention. These new strategies will need focused evaluation in the most challenging AF patients-those with a high risk of bleeding, prior thromboembolism, or thrombosis-prone surfaces such as mechanical heart valve prostheses or drug-eluting coronary stents, for whom the limitations of currently available treatment options and a paucity of data are particularly acute. PMID- 20953741 TI - Patient-derived determinants for participation in placebo-controlled clinical trials for fibromyalgia. AB - Perspectives of patients with fibromyalgia influence their likelihood of participating in randomized placebo-controlled trials and potentially clash with current, well-established methodology of randomized controlled trial design. Mandates to use only acetaminophen for breakthrough pain and that require discontinuation of concomitant medications, especially in studies lacking an active comparator arm, could bias a trial cohort to thereby reduce the generalizability of study findings and conclusions. This study evaluates factors affecting willingness to participate in such clinical trials, including the impact of altruism, payment, study duration, forced discontinuation of specific medications, and subject demographics for patients seen by rheumatologists proficient and avidly interested in treating fibromyalgia. PMID- 20953742 TI - Nuclear neuroimaging in acute and subacute ischemic stroke. AB - Neuroimaging in ischemic stroke continues to be one of the most developing fields in nuclear medicine. Many studies have established the efficacy of blood flow and metabolism measurements in acute ischemic stroke. Although the release of recombinant tissue plasminogen activator in clinical practice has minimized the use of SPECT or PET in the first few hours of ischemic stroke onset, implementing these techniques into a set of initial examinations is still beneficial to exclude risky patients for reperfusion therapy beyond several hours after onset. Rescuing of viable tissue suffering ischemic penumbra is an important target of early therapeutic strategy. Ischemic penumbra can be visualized by means of perfusion imaging, central type benzodiazepine receptor imaging, and hypoxy imaging. In the later phase of subacute ischemic stroke, inflammation and apoptosis can be visualized by means of peripheral-type benzodiazepine receptor imaging and annexin V imaging, respectively. Imaging of the penumbra and cellular responses will help evaluate the effects of drugs and interventions for ischemic stroke, suggesting its potential as a marker of the efficacy of future therapeutic regimens. PMID- 20953743 TI - Peripheral calcifying odontogenic cyst: a case report and review of the literature. AB - The peripheral calcifying odontogenic cyst (PCOC) accounts for less than 25% of the cases of calcifying odontogenic cysts and most commonly appears as a nodule on the gingiva. This paper aims to present both a case report of a PCOC located in the left vestibular maxilla as well as a review of the English-language literature. An 11-year-old female patient presented a swelling in the vestibular region of teeth 12 and 13. Periapical and panoramic radiographs demonstrated irregular calcification. Surgical excision was performed. Microscopic examination showed an odontogenic cystic lesion lined by ameloblastoma-like epithelium, containing numerous ghost cells. Areas of calcification associated with ghost cells could also be observed. The patient was diagnosed with PCOC. The patient has been disease-free for 36 months. The review of the cases of PCOC showed 44 well-defined cases. The mean age was of 49.4 years at the time of diagnosis. The reported cases appeared as a painless swelling, with a slight predilection for females, and were more frequently located in the anterior region of the maxilla or mandible. Surgical excision is the treatment of choice, and recurrence is rare. PMID- 20953745 TI - AA amyloidosis associated with macroglobulinemia. PMID- 20953744 TI - Trabecular and psammomatoid juvenile ossifying fibroma of the skull base mimicking psammomatoid meningioma. AB - Ossifying fibroma (OF) is a fibro-osseous tumor that usually occurs in young people and arises in the craniofacial bones. We report a case of a 15-year-old boy who developed progressive proptosis and hypertelorism and was found to have a mid-face and skull base tumor, initially diagnosed as psammomatoid meningioma. The tumor recurred and the resected specimen revealed a unique OF having trabecular and psammomatoid features. The clinical, radiographic, histopathologic findings and differential diagnoses of the case are presented. PMID- 20953746 TI - Hyaluronic acid improves "pleasantness" and tolerability of nebulized hypertonic saline in a cohort of patients with cystic fibrosis. AB - INTRODUCTION: Inhaled hypertonic saline improves lung function and decreases pulmonary exacerbations in people with cystic fibrosis. However, side effects such as cough, narrowing of airways and saltiness cause intolerance of the therapy in 8% of patients. The aim of our study was to compare the effect of an inhaled solution of hyaluronic acid and hypertonic saline with hypertonic solution alone on safety and tolerability. METHODS: A total of 20 patients with cystic fibrosis aged 6 years and over received a single treatment regimen of 7% hypertonic saline solution or hypertonic solution with 0.1% hyaluronate for 2 days nonconsecutively after a washout period in an open crossover study. Cough, throat irritation, and salty taste were evaluated by a modified ordinal score for assessing tolerability; "pleasantness" was evaluated by a five-level, Likert-type scale. Forced expiratory volume in 1 second was registered before and after the end of the saline inhalations. RESULTS: All 20 patients (nine males, 11 females, mean age 13 years, range 8.9-17.7) completed the study. The inhaled solution of 0.1% hyaluronic acid and hypertonic saline significantly improved tolerability and pleasantness compared to hypertonic saline alone. No major adverse effects were observed. No difference was documented in pulmonary function tests between the two treatments. CONCLUSION: Hyaluronic acid combined with hypertonic saline solution may contribute to improved adherence to hypertonic saline therapy. Further clinical trials are needed to confirm our findings. Considering the extraordinary versatility of hyaluronic acid in biological reactions, perspective studies could define its applicability to halting progression of lung disease in cystic fibrosis. PMID- 20953747 TI - Characterization of particles in protein solutions: reaching the limits of current technologies. AB - Recent publications have emphasized the lack of characterization methods available for protein particles in a size range comprised between 0.1 and 10 MUm and the potential risk of immunogenicity associated with such particles. In the present paper, we have investigated the performance of light obscuration, flow microscopy, and Coulter counter instruments for particle counting and sizing in protein formulations. We focused on particles 2-10 MUm in diameter and studied the effect of silicon oil droplets originating from the barrel of pre-filled syringes, as well as the effect of high protein concentrations (up to 150 mg/ml) on the accuracy of particle characterization. Silicon oil was demonstrated to contribute significantly to the particle counts observed in pre-filled syringes. Inconsistent results were observed between different protein concentrations in the range 7.5-150 mg/ml for particles <10 MUm studied by optical techniques (light obscuration and flow microscopy). However, the Coulter counter measurements were consistent across the same studied concentration range but required sufficient solution conductivity from the formulation buffer or excipients. Our results show that currently available technologies, while allowing comparisons between samples of a given protein at a fixed concentration, may be unable to measure particle numbers accurately in a variety of protein formulations, e.g., at high concentration in sugar-based formulations. PMID- 20953748 TI - Identification of peptide mimotopes of gp96 using single-chain antibody library. AB - Heat shock proteins such as gp96 are immunogenic and are widely used as vaccines in immunotherapy of cancers. The present study focuses on the use of peptide mimotopes as immunotherapeutic vaccines for prostate cancer. To this end, we developed a 15-mer gp96 peptide mimotope specifically reactive to MAT-LyLu gp96 peptide complex using combinatorial single-chain antibody and peptide phage display library. The immunogenicity of the synthesized gp96 mimotope was analyzed initially in normal BALB/c mice in combination with various adjuvants such as complete Freund's adjuvant (CFA), aluminum salts (ALUM), granulocyte-macrophage colony-stimulating factor (GM-CSF), and liposome, of which CFA served as a positive control. The antibody response was determined and found that the gp96 mimotope with ALUM showed a significant increase in antibody titer, followed by GM-CSF and liposomes. Further, the T cell (CD4(+) and CD8(+)) populations from splenocytes, as well as IgG isotypes, interleukin-4, and interleukin-5 of gp96 mimotope with ALUM-immunized animals, were analyzed. The results suggest that the gp96 mimotope may elicit a potent and effective antitumor antibody response. Further, the study identifies ALUM and GM-CSF as adjuvant options to drive an appropriate protective immune response as these adjuvants have prior use in humans. PMID- 20953750 TI - Clinical profile of insulinoma: analysis from a tertiary care referral center in India. AB - OBJECTIVE: To describe the clinical presentation, localization techniques, surgical procedures and outcome in patients with insulinoma. METHODS: Retrospective analysis of case records of patients diagnosed with insulinoma between January 1993 and June 2009 at a tertiary-care hospital was done. Seventeen patients underwent diagnostic 72-h fast. The sensitivity of computed tomography (CT) of pancreas was judged using intraoperative findings as the gold standard. RESULTS: Twenty-six patients (19 women) with mean age 42.2 years (median age 39.5 years) with biochemical/imaging evidence of insulinoma were included. All patients who underwent 72-h fast developed symptomatic hypoglycemia within 48 h. The sensitivity and positive predictive value (PPV) of CT of pancreas was 68.4% and 92.8%, respectively. Twenty patients underwent surgery, of whom four were operated on without preoperative localization. Four patients had recurrence of symptoms. Of the six patients who were not operated upon, the lesion was localized in four. CONCLUSION: This audit shows that all patients with insulinoma develop hypoglycemia within 48 h of fasting. CT of pancreas localizes the lesion in two thirds of cases and would be a useful initial investigation in patients with suspected insulinoma. PMID- 20953751 TI - Prognostic significance of HE4 expression in pulmonary adenocarcinoma. AB - We investigated the possibility of human epididymis 4(HE4) to predict survival for patients with pulmonary adenocarcinoma. One hundred and thirty-seven patients with pulmonary adenocarcinoma underwent surgery in our institute from 2000 to 2008. We used immunohistochemical analysis to determine the expression of HE4 and compared with the clinicopathological factors and survival. Serum levels of HE4 in lung adenocarcinoma were investigated by enzyme immunometric assay. Fifty seven of 137 cases (41.6%) were HE4 positive. It was found that there was no correlation between HE4 expression by immunohistochemistry and clinicopathological factors, however, adenocarcinoma subtype was significantly associated with HE4 expression. Sera in lung adenocarcinoma were significantly higher than in healthy control. Five-year disease-free survival in the HE4 positive group (44.6%) was significantly different from that in the negative group (82.3%, p = 0.001) by immunohistochemistry. The five-year overall survival rate was 60.1% in the HE4-positive group, as compared with 90.8% in the HE4 negative group (p = 0.001). In multivariate Cox regression analysis, positive HE4 protein expression was a worse prognosis factor of disease-free and overall survival (HR = 3.7, 95%CI = [1.7-8.4], p = 0.001; HR = 5.5, 95%CI = [1.8-17.2], p = 0.003, respectively), in addition to nodal status as a powerful value. When HE4 expression in adenocarcinoma cases except the BAC were analyzed, nodal status and HE4 expression were independent prognostic factors in disease-free and overall survivals. These data showed that HE4 expression is associated with a worse prognosis and is a possible prognostic factor of lung adenocarcinoma. PMID- 20953752 TI - [Rene Schubert on his 100th birthday]. PMID- 20953749 TI - Influence of physical exercise on neuroimmunological functioning and health: aging and stress. AB - Chronic and acute stress, with associated pathophysiology, are implicated in a variety of disease states, with neuroimmunological dysregulation and inflammation as major hazards to health and functional sufficiency. Psychosocial stress and negative affect are linked to elevations in several inflammatory biomarkers. Immunosenescence, the deterioration of immune competence observed in the aged aspect of the life span, linked to a dramatic rise in morbidity and susceptibility to diseases with fatal outcomes, alters neuroimmunological function and is particularly marked in the neurodegenerative disorders, e.g., Parkinson's disease and diabetes. Physical exercise diminishes inflammation and elevates agents and factors involved in immunomodulatory function. Both the alleviatory effects of life-long physical activity upon multiple cancer forms and the palliative effects of physical activity for individuals afflicted by cancer offer advantages in health intervention. Chronic conditions of stress and affective dysregulation are associated with neuroimmunological insufficiency and inflammation, contributing to health risk and mortality. Physical exercise regimes have induced manifest anti-inflammatory benefits, mediated possibly by brain-derived neurotrophic factor. The epidemic proportions of metabolic disorders, obesity, and diabetes demand attention; several variants of exercise regimes have been found repeatedly to induce both prevention and improvement under both laboratory and clinical conditions. Physical exercise offers a unique non-pharmacologic intervention incorporating multiple activity regimes, e.g., endurance versus resistance exercise that may be adapted to conform to the particular demands of diagnosis, intervention and prognosis inherent to the staging of autoimmune disorders and related conditions. PMID- 20953756 TI - [Psychiatric symptoms in German short-term and long-term prisoners]. AB - Previous studies have indicated high prevalence rates of mental disorders among prisoners. Based on a sample of 98 male German long-term prisoners and 94 male German short-term prisoners, psychiatric symptoms were comparatively assessed by means of the brief symptom inventory (BSI). The study showed a considerable increased in psychological stress, especially with regard to long-term prisoners. In this context a significant difference (p<0.01) was found between short-term and long-term prisoners where 65% of long-term prisoners and 40% of short-term prisoners showed a noticeable increase in the amount of psychological stress. Furthermore, high prevalence rates of a history of attempted suicide (29.7%) and self-injurious behavior (43.2%) were found. The following clinical implications are deduced from this study: there is a general need for treatment during imprisonment, especially with respect to long-term prisoners. In addition, the high rates of attempted suicide and self-injurious behavior require a focus on a more elaborated crisis management as well as psychotherapeutic treatment for this population. PMID- 20953757 TI - [Psychiatry during National Socialism: historical knowledge, implications for present day ethical debates]. AB - This contribution is a synthesis of the results of historical research on psychiatry during the Nazi period and some implications for present day debates in medical ethics. The focus is on three issues: the relationship between physicians and the state, the impact of eugenically and economically motivated health and social policies for psychiatry (e.g. forced sterilization, patient killing/euthanasia) and psychiatric research. Three myths are deconstructed: 1) that medical atrocities were imposed from above by Nazi politicians on apolitical physicians, 2) that mass sterilization and patient killing had nothing to do with contemporary state of the art of medical reasoning and practice and 3) that ethically unacceptable research on psychiatric patients had nothing to do with the contemporary state of the art of biomedical sciences. It is argued that the findings on these issues of Nazi medicine are not specific to Germany and the period between 1933 and 1945 but they were the extreme manifestations of some potential problems implicit in modern medicine in general. PMID- 20953759 TI - Platelet concentrate vs. saline in a rat patellar tendon healing model. AB - PURPOSE: To evaluate single centrifuge platelet concentrate as additive for improved tendon healing. Platelet-rich plasma has been reported to improve tendon healing. Single centrifuge platelet concentration may increase platelet concentration enough to positively affect tendon healing. A single centrifuge process will lead to a blood product with increased platelet concentrations which, when added to a surgically created tendon injury, will improve tendon healing when compared with a saline control. METHODS: Lewis rats had a surgical transection of the patellar tendon that was subsequently stabilized with a cerclage suture. Prior to skin closure, the tendon was saturated with either a concentrated platelet solution or saline. At 14 days, all animals were killed, and the extensor mechanism was isolated for testing. Biomechanical testing outputs included ultimate tensile load, stiffness, and energy absorbed. RESULTS: Comparisons between the control group and the concentrated platelet group revealed no differences. A subgroup of the concentrated platelet group consisting of specimens in whom the concentration process was most successful showed significantly higher ultimate tensile load (P < 0.05) and energy absorbed to failure (P < 0.05) when compared to the control group. CONCLUSION: When successful, single centrifuge platelet concentration yields a solution that improves tendon healing when compared with a saline control. Single-spin platelet concentration may yield a biologically active additive that may improve tendon healing, but more studies must be undertaken to ensure that adequate platelet concentration is possible. PMID- 20953760 TI - Women with patellofemoral pain syndrome have quadriceps femoris volume and strength deficiency. AB - PURPOSE: the aim of this study was to assess muscle torque, total volume, and cross-sectional area, and lower limb function of the quadriceps muscle in women with unilateral patellofemoral pain syndrome (PFPS). METHODS: twenty-four women with unilateral patellofemoral pain participated in the study, with each subject acting as their own internal control by using the unaffected limb. quadriceps muscle torque was measured with the Isomed 2000. The total volume and cross sectional area (CSA) of the quadriceps muscle were measured by using magnetic resonance imaging. Lower limb function was assessed by hop and step-down tests. RESULTS: there was a significant difference in the total volume (P < 0.05) and in the cross-sectional area (P < 0.05) of the quadriceps muscle between affected and unaffected sides. There was a significant difference in the peak torque of the quadriceps muscle at 60 degrees /s between affected and unaffected sides (P < 0.05). There were significant correlations between quadriceps largest CSA and volume on the affected side (P < 0.05) and on the unaffected side (P < 0.05). There were significant negative correlations between the smallest CSA and the peak torque at 180 degrees /s (P < 0.05) and at 60 degrees /s (P < 0.05) on the affected side. CONCLUSIONS: decreased torque, total volume, and CSA of the quadriceps muscle are presented in unilateral with PFPS although cause or effect cannot be established. Large prospective longitudinal studies are needed to detect the changes in the muscle structure and to establish whether these features are a cause of PFPS. PMID- 20953761 TI - A mechanized and standardized pivot shifter: technical description and first evaluation. AB - PURPOSE: The pivot shift test (PST) is a complex, multiplanar maneuver used to assess rotatory instability of the knee. The grading is subjective due to the broad range of examination techniques and lack of tibiofemoral motion quantification. The goal of this study was to develop and evaluate a mechanized device for quantitative assessment of the PST. METHODS: We constructed a mechanized pivot shifter (MPS). In five cadaveric hip-to-toes specimens, the anterior cruciate ligament was resected. We used a surgical navigation system for acquisition of the tibiofemoral motion path during the PST. Two sets of measurements were obtained for the MPS and for two examiners performing the manual technique. RESULTS: Mean lateral compartment translation magnitudes for each MPS measurement were 13.5 mm (sigma = 6.7) and 13.6 mm (sigma = 6.7). For examiner 1, 14.9 mm (sigma = 6.5) and 15.7 mm (sigma = 6.3). For examiner 2, 16.9 mm (sigma = 6.3) and 16.1 mm (sigma = 5.2). Differences were not significant (n.s.). The MPS had narrower limits of agreement than both examiner 1 and examiner 2. CONCLUSION: The MPS demonstrated no significant differences in the tibiofemoral translation magnitudes compared to the manual technique. It resulted in better test-retest reliability and more consistent measurements of tibiofemoral translation when compared to manual PST. The high repeatability factor conferred by the MPS is a clinical advantage. PMID- 20953762 TI - Long-term outcome after meniscal repair. AB - PURPOSE: the purpose of this study was to analyse the clinical and radiological results of meniscal repairs and identify factors that correlate with the success of this procedure. METHODS: a retrospective review of 119 meniscal repairs was completed. The average follow-up was 70 months. Successful meniscal repairs were observed critically in terms of radiographic changes and clinical outcomes and compared with failed meniscal repairs. RESULTS: the overall success rate of meniscal repairs was 74%. Meniscal repairs that were performed within 6 weeks of injury had better results (83%) than late repairs (52%). The best results were obtained with the inside-out technique using #0 PDS suture (80%) compared to all inside Biofix arrows (70%) and combined repairs (63%). Patients with associated ACL injury had a better chance of a successful outcome, but this was only significant when the ACL was reconstructed at the time of repair (P < 0.05). Those patients who had failed meniscal repair had increased radiographic osteoarthritic changes (81%) on long-term follow-up compared to patients with successful repair (14%). CONCLUSION: this retrospective study shows the clinical and radiological importance of meniscal repair. Successful results in this study were associated with younger age and earlier repair using inside-out technique. Furthermore, increased success was seen in meniscal repairs performed in association with ACL reconstruction. PMID- 20953763 TI - Multidetector CT for thorn (wooden) foreign bodies of the knee. AB - PURPOSE: Thorn (wooden) foreign bodies of the knee present a challenge in their diagnosis. Partly because of inaccurate history and sometimes a long duration of symptoms, radiographs are negative and MRI may show synovitis without a specific pathology. METHODS: We report a case of a 16-year-old male patient with a date palm thorn foreign body, which caused septic arthritis. He underwent two open surgeries. Both failed to detect the loose body. An MRI of the knee showed a high signal in the posterolateral compartment; however, the pathology could not be confirmed except by 64 Multidetector CT (MDCT) that clearly identified the thorn and its location. RESULTS: Arthroscopic removal and synovectomy were done by a 4 portal technique. The patient went on to complete recovery. CONCLUSION: Multidetector CT has proven very useful in identifying wooden foreign bodies, their size and location. PMID- 20953764 TI - Does autograft choice determine intermediate-term outcome of ACL reconstruction? AB - PURPOSE: Many clinical studies and systematic reviews have compared the short term (2 years) outcomes of ACL reconstruction with hamstring and patellar tendon autograft. Few differences have been observed, with the exception of increased kneeling pain with patellar tendon grafts. The goal of this systematic review is to determine whether there are differences in clinical, patient-reported, or radiographic outcomes based on graft choice at a minimum of 5 years after ACL reconstruction. METHODS: A systematic review was performed to identify all prospective outcome studies comparing patellar tendon and hamstring autograft ACL reconstruction with minimum follow-up of at least 5 years. Seven studies were identified and meta-analysis of select data determined to be sufficiently homogenous was performed (failure and laxity). RESULTS: Five randomized controlled trials and two prospective cohorts comparing hamstring and patellar tendon autografts were identified. Clinical assessment [failure rate, International Knee Documentation Committee (IKDC) class, Lachman, pivot shift, and KT 1000 testing] showed no difference between grafts. Patient-reported outcomes (Lysholm, Cincinnati, and IKDC) showed no difference. Both anterior knee pain (3/3 studies) and kneeling pain (4/4 studies) were more frequent in the patellar tendon group. However, the patient-reported outcomes in these studies were not different. Radiographic evidence of osteoarthritis was inconsistent between autograft choices. CONCLUSION: This level II systematic review demonstrates no difference in major clinical results between graft types with the exception of increased anterior knee and kneeling pain. There exists a potential for increased incidence of osteoarthritis in the patellar tendon group but increased sample size is required. These longer-term outcomes are similar to results of prior systematic reviews with two-year follow-up. PMID- 20953765 TI - Particle size characterization of titanium dioxide in sunscreen products using sedimentation field-flow fractionation-inductively coupled plasma-mass spectrometry. AB - Sedimentation field-flow fractionation-inductively coupled plasma-mass spectrometry (SdFFF-ICP-MS) was successfully applied to investigate particle size distribution of titanium dioxide (TiO(2)) in sunscreen samples after hexane extraction to remove organic components from the samples. Three brands of sunscreen products of various sun protection factor (SPF) value were used as samples. Different particle size distribution profiles were observed for sunscreen samples of various brands and SPF values; however, the particle size distributions of titanium dioxide in most sunscreen samples investigated in this work were larger than 100 nm. The titanium dioxide concentrations were higher for the products of higher SPF values. By comparing the results obtained from online SdFFF-ICP-MS and those from the off-line ICP-MS determination of titanium after acid digestion, ICP-MS was found to effectively atomize and ionize the titanium dioxide particle without the need for acid digestion of the samples. Therefore, the online coupling between SdFFF and ICP-MS could be effectively used to provide quantitative information of titanium dioxide concentrations across particle size distribution profiles. PMID- 20953766 TI - Tracing the biological origin of animal glues used in paintings through mitochondrial DNA analysis. AB - We report the development of a suitable protocol for the identification of the biological origin of binding media on tiny samples from ancient paintings, by exploitation of the high specificity and high sensitivity offered by the state-of the art DNA analysis. In particular, our aim was to molecularly characterize mitochondrial regions of the animal species traditionally employed for obtaining glues. The model has been developed using aged painting models and then tested to analyze the organic components in samples from the polychrome terracotta Madonna of Citerna by Donatello (1415-1420), where, by GC-MS and FTIR spectroscopy, animal glues and siccative oils were identified. The results obtained are good in terms of both sensibility and specificity of the method. First of all, it was possible to confirm that Donatello used animal glue for the preparation of the painted layers of the Madonna of Citerna and, specifically, glue derived from Bos taurus. Data obtained from sequencing confirm that each sample contains animal glue, revealing that it was mostly prepared from two common European taurine lineages called T2 and T3. There is one remarkable exception represented by one sample which falls into a surviving lineage of the now extinct European aurochs. PMID- 20953767 TI - Simultaneous determination of NOGE-related and BADGE-related compounds in canned food by ultra-performance liquid chromatography-tandem mass spectrometry. AB - An improved analytical method enabling rapid and accurate determination and identification of bisphenol F diglycidyl ether (novolac glycidyl ether 2-ring), novolac glycidyl ether 3-ring, novolac glycidyl ether 4-ring, novolac glycidyl ether 5-ring, novolac glycidyl ether 6-ring, bisphenol A diglycidyl ether, bisphenol A (2,3-dihydroxypropyl) glycidyl ether, bisphenol A (3-chloro-2 hydroxypropyl) glycidyl ether, bisphenol A bis(3-chloro-2-hydroxypropyl) ether, and bisphenol A (3-chloro-2-hydroxypropyl) (2,3-dihydroxypropyl) ether in canned food and their contact packaging materials has been developed by using, for the first time, ultra-performance liquid chromatography coupled with tandem mass spectrometry. After comparison of electrospray ionization and atmospheric pressure chemical ionization in positive and negative-ion modes, tandem mass spectrometry with positive electrospray ionization was chosen to carry out selective multiple reaction monitoring analysis of novolac glycidyl ethers, bisphenol A diglycidyl ether, and its derivatives. The analysis time is only 5.5 min per run. Limits of detection varied from 0.01 to 0.20 ng g(-1) for the different target compounds on the basis of a signal-to-noise ratio (S/N) = 3; limits of quantitation were from 0.03 to 0.66 ng g(-1). The relative standard deviation for repeatability was <8.01%. Analytical recovery ranged from 87.60 to 108.93%. This method was successfully applied to twenty samples of canned food and their contact packaging materials for determination of migration of NOGE, BADGE, and their derivatives from can coatings into food. PMID- 20953768 TI - Elemental 2D imaging of paintings with a mobile EDXRF system. AB - Imaging techniques are now used commonly and intensively in cultural heritage object analysis. Nowadays, many different techniques in nature as well as many applications exist, where they can be applied. X-ray radiography and infrared reflectography as well as UV photography are some of the most applied techniques. The study of works of art usually requires these techniques to be non-invasive. Furthermore, they are frequently required to perform in situ analysis. A few years ago, our laboratory developed a mobile energy-dispersive X-ray fluorescence and UV-vis-NIR coupled spectrometer, especially designed for fieldwork studies, where all three techniques can be applied strictly at the same site of analysis. Recent developments on a new positioning system have now allowed us to perform 2D elemental mappings with our equipment, which is especially well adapted to painting analysis. The system control is carried out entirely through a laptop computer running a dedicated homemade software. The positioning is achieved by means of a CCD camera embedded in the system and controlled via a Wi-Fi connection through the computer. The data acquisition system, which is made through a homemade multichannel pulse height analyzer, being also managed via the software mentioned above, goes through an Ethernet connection. We will present here the new developments of the system and an example of in situ 2D elemental mapping applied on an anonymous oil painting on wood panel. The discovery of a hidden painting under this oil painting makes it a good choice for a first example of 2D large scan with a mobile instrument. PMID- 20953769 TI - Elemental analysis of a single-wall carbon nanotube candidate reference material. AB - A material containing single-wall carbon nanotubes (SWCNTs) with other carbon species, catalyst residues, and trace element contaminants has been prepared by the National Institute of Standards and Technology for characterization and distribution as Standard Reference Material SRM 2483 Carbon Nanotube Soot. Neutron activation analysis (NAA) and inductively coupled plasma mass spectrometry (ICP-MS) were selected to characterize the elemental composition. Catalyst residues at percentage mass fraction level were determined with independent NAA procedures and a number of trace elements, including selected rare earth elements, were determined with NAA and ICP-MS procedures. The results of the investigated materials agreed well among the NAA and ICP-MS procedures and good agreement of measured values with certified values was found in selected SRMs included in the analyses. Based on this work mass fraction values for catalyst and trace elements were assigned to the candidate SRM. PMID- 20953770 TI - Comparison of the duplex-destabilizing effects of nucleobase-caged oligonucleotides. AB - Nucleobase-caged oligonucleotide residues have photolabile "caging groups" that prevent the formation of Watson-Crick base pairs until the unmodified nucleobase is restored in a photolysis event. This principle can be used to put a growing variety of powerful nucleic acid-based applications under the precise spatiotemporal control using light as an addressing mechanism. Examples for applications include light control of transcription, RNAi, nucleic acid folding, primer extension, and restriction endonuclease as well as DNAzyme, aptamer, and antisense activity. However, a comparison of the duplex-destabilization properties of the various caged residues that have been used up to date and rules for achieving a maximal duplex destabilization with a minimum amount of modified residues are still missing. We present both a comparison of the duplex destabilizing capabilities of various nucleobase-caged residues and address the question of influence on neighboring base pairs. PMID- 20953771 TI - The use of circular dichroism as a simple heparin-screening strategy. AB - Heparin, a heterogeneous polysaccharide, is used extensively as an anticoagulant. Recently, however, tainted heparin was associated with acute reactions that lead to numerous deaths. Extensive investigations ultimately showed oversulfated chondroitin sulfate, a semi-synthetic polysaccharide, to be present in the contaminated samples. These events highlighted the need for new, convenient heparin-screening methods capable of rapidly determining sample purity. In this work, we report the use of circular dichroism spectroscopy to analyze heparin samples for the presence of heparin-like adulterants (e.g., chondroitin sulfate A, dermatan sulfate, and oversulfated chondroitin sulfate) in a simple and straightforward manner. This strategy exploits the subtle differences in the optical properties of each polymer; these differences result from structural dissimilarities. To the best of our knowledge, the findings presented here are the first report of heparin purity screening using traditional spectropolarimetry techniques. PMID- 20953772 TI - Determination of galactosamine impurities in heparin samples by multivariate regression analysis of their (1)H NMR spectra. AB - Heparin, a widely used anticoagulant primarily extracted from animal sources, contains varying amounts of galactosamine impurities. Currently, the United States Pharmacopeia (USP) monograph for heparin purity specifies that the weight percent of galactosamine (%Gal) may not exceed 1%. In the present study, multivariate regression (MVR) analysis of (1)H NMR spectral data obtained from heparin samples was employed to build quantitative models for the prediction of %Gal. MVR analysis was conducted using four separate methods: multiple linear regression, ridge regression, partial least squares regression, and support vector regression (SVR). Genetic algorithms and stepwise selection methods were applied for variable selection. In each case, two separate prediction models were constructed: a global model based on dataset A which contained the full range (0 10%) of galactosamine in the samples and a local model based on the subset dataset B for which the galactosamine level (0-2%) spanned the 1% USP limit. All four regression methods performed equally well for dataset A with low prediction errors under optimal conditions, whereas SVR was clearly superior among the four methods for dataset B. The results from this study show that (1)H NMR spectroscopy, already a USP requirement for the screening of contaminants in heparin, may offer utility as a rapid method for quantitative determination of %Gal in heparin samples when used in conjunction with MVR approaches. PMID- 20953773 TI - Biocatalytic nylon nanofibrous membranes. AB - Nylon-6 nanofibrous membranes (NFM) have been prepared, characterized and used to build-up electrochemical biosensing devices. The assembly and the functioning of biocatalytic NFM are described in connection with the physical and the covalent immobilization of glucose oxidase for the detection of glucose. Effects of the enzyme loading, the mediator, the pH, the surface acidity and the kinetic of the catalysis have been thoroughly investigated. The results show that NFM allow the binding of proteins without the need for the hydrolysis step, in contrast to the nylon film. Furthermore, the high surface-to-volume ratio of the NFM allow superior loading of the enzyme with respect to thin film technology. The immobilization step does not affect the permeability of the coating to the mediator used. These results give evidence that NFM are a promising and inexpensive coating for a novel electrochemical transducer. PMID- 20953774 TI - Electron energy loss spectroscopy elucidates the elusive darkening of zinc potassium chromate in Georges Seurat's A Sunday on La Grande Jatte--1884. AB - The color darkening of selected brushstrokes of Georges Seurat's A Sunday on La Grande Jatte--1884 was noted as early as 1892. Artificial aging of model systems containing zinc yellow (K(2)O.4ZnCrO(4).3H(2)O) mixed with linseed oil successfully replicated the phenomena observed on La Grande Jatte. Electron energy loss spectroscopy measurements performed on the uppermost few microns of thin sections of the paint layers (obtained with focused ion beam milling) determined that samples which turned olive green (aged at 90% RH, with SO(2) and light) contain mostly the altered species Cr(III) and that the ochre-yellow coloration of specimens aged at 50% RH with SO(2) and light is due to the presence of dichromate ions (Cr (VI)). The altered species are only present in the first few microns of paint and are likely poorly crystalline, so that they eluded other types of bulk and surface measurements, but they create a substantial color alteration at the surface of the paint films. A similar phenomenon was confirmed on a sample from La Grande Jatte, where Cr(III) and Cr(VI) dichromate ions were detected in the ochre-colored, altered brushstrokes of zinc yellow. Laboratory simulations demonstrated that the equilibrium between chromate and dichromate ions is reversible within the paint film and that the orange dichromate ions can be transformed back into bright yellow chromates by exposure to highly alkaline gases. PMID- 20953775 TI - Evaluating the effects of immunotoxicants using carbon fiber microelectrode amperometry. AB - Carbon fiber microelectrode amperometry (CFMA) is explored as a technique for studying the effects of immunotoxicants on single-cell in vitro exocytosis function in a mouse peritoneal mast cell (MPMC)/fibroblast co-culture model. MPMCs were acutely exposed to between 10 and 100 MUM of the immunotoxicants mono 2-ethylhexyl phthalate (MEHP) and bisphenol A (BPA), and release of serotonin was evaluated by CFMA. A significant decrease in the quantal content of serotonin was measured for all levels of exposure to both MEHP and BPA. The overall efficiency of the exocytotic function of MPMCs was found to be impaired by all exposure concentrations of BPA, but this efficiency was only impaired at the lowest exposure concentration of MEHP. This study illustrates the potential of CFMA as a technique for determining quantitative and biophysical chemical information in in vitro immunotoxicological studies. PMID- 20953776 TI - Automatic optosensing device based on photo-induced fluorescence for determination of piceid in cocoa-containing products. AB - Piceid (3,4',5-trihydroxystilbene-3-beta-D: -glucoside) is a stilbene which occurs naturally in various families of plants and has been shown to protect lipoproteins from oxidative damage and to have cancer chemopreventive activity. This paper deals with the determination of piceid in cocoa-containing products by using photo-induced fluorescence and the aid of a multicommutated continuous-flow assembly which was provided with an on-line photoreactor. A strongly fluorescent photoproduct is generated from piceid when it is irradiated under UV light for 30 s, which is retained on Sephadex QAE A-25 and directly monitored on this active solid support at 257/382 nm (lambda (exc)/lambda (em), respectively). The pre concentration of the photoproduct of piceid on the solid support greatly improves both sensitivity and selectivity. The influence of different experimental parameters, both chemical (pH, ionic strength) and hydrodynamic (irradiation time, flow rate, photoreactor length, sampling time), was tested. The sample pre treatment included delipidation with toluene and cyclohexane, stilbene extraction with ethanol/water (80:20, v/v) and clean-up by solid-phase extraction on C(18) cartridges and methanol/water (40:20, v/v) as eluting solution. This procedure allowed the elimination of the aglycon of piceid, resveratrol and other potential interfering species and a recovery of about a 90% piceid. The method was applied to the analysis of piceid in cocoa powder, dark chocolate and milk chocolate. The quantification limits were 1.4, 1.1 and 0.09 mg kg(-1), respectively. Relative standard deviations ranged from 1.8% to 3.1%. This is the first reported non chromatographic method for determination of piceid in these foods. PMID- 20953777 TI - Multivariate statistical differentiation of renal cell carcinomas based on lipidomic analysis by ambient ionization imaging mass spectrometry. AB - Desorption electrospray ionization (DESI) mass spectrometry (MS) was used in an imaging mode to interrogate the lipid profiles of thin tissue sections of 11 sample pairs of human papillary renal cell carcinoma (RCC) and adjacent normal tissue and nine sample pairs of clear cell RCC and adjacent normal tissue. DESI MS images showing the spatial distributions of particular glycerophospholipids (GPs) and free fatty acids in the negative ion mode were compared to serial tissue sections stained with hematoxylin and eosin (H&E). Increased absolute intensities as well as changes in relative abundance were seen for particular compounds in the tumor regions of the samples. Multivariate statistical analysis using orthogonal projection to latent structures treated partial least square discriminate analysis (PLS-DA) was used for visualization and classification of the tissue pairs using the full mass spectra as predictors. PLS-DA successfully distinguished tumor from normal tissue for both papillary and clear cell RCC with misclassification rates obtained from the validation set of 14.3% and 7.8%, respectively. It was also used to distinguish papillary and clear cell RCC from each other and from the combined normal tissues with a reasonable misclassification rate of 23%, as determined from the validation set. Overall DESI-MS imaging combined with multivariate statistical analysis shows promise as a molecular pathology technique for diagnosing cancerous and normal tissue on the basis of GP profiles. PMID- 20953778 TI - Development of sample preparation method for auxin analysis in plants by vacuum microwave-assisted extraction combined with molecularly imprinted clean-up procedure. AB - A novel sample preparation method for auxin analysis in plant samples was developed by vacuum microwave-assisted extraction (VMAE) followed by molecularly imprinted clean-up procedure. The method was based on two steps. In the first one, conventional solvent extraction was replaced by VMAE for extraction of auxins from plant tissues. This step provided efficient extraction of 3-indole acetic acid (IAA) from plant with dramatically decreased extraction time, furthermore prevented auxins from degradation by creating a reduced oxygen environment under vacuum condition. In the second step, the raw extract of VMAE was further subjected to a clean-up procedure by magnetic molecularly imprinted polymer (MIP) beads. Owing to the high molecular recognition ability of the magnetic MIP beads for IAA and 3-indole-butyric acid (IBA), the two target auxins in plants can be selectively enriched and the interfering substance can be eliminated by dealing with a magnetic separation procedure. Both the VMAE and the molecularly imprinted clean-up conditions were investigated. The proposed sample preparation method was coupled with high-performance liquid chromatogram and fluorescence detection for determination of IAA and IBA in peas and rice. The detection limits obtained for IAA and IBA were 0.47 and 1.6 ng/mL and the relative standard deviation were 2.3% and 2.1%, respectively. The IAA contents in pea seeds, pea embryo, pea roots and rice seeds were determined. The recoveries were ranged from 70.0% to 85.6%. The proposed method was also applied to investigate the developmental profiles of IAA concentration in pea seeds and rice seeds during seed germination. PMID- 20953779 TI - Combination of a two-step fluorescence assay and a two-step anti-Factor Xa assay for detection of heparin falsifications and protein in heparins. AB - There are several methods for sensitive detection of oversulfated chondroitin sulfate (OSCS) in heparin. Although contamination with OSCS is unlikely to be repeated, use of other compounds to counterfeit heparin must be considered. We have previously developed a two-step fluorescence microplate assay (two-step FI assay) for detection of OSCS. First, the heparin sample is incubated with heparinase I, then its increasing effect on the fluorescence intensity (FI) of the sensor molecule Polymer-H is measured (PolyH assay). The high sensitivity of the assay is shown to be based on heparinase I inhibition by OSCS. The objective of this study was to evaluate another assay option - indirect quantification of OSCS after heparinase I incubation by means of the anti-Factor Xa (aXa) activity of the remaining undegraded heparin (two-step aXa assay). We also examined, whether other heparin mimetics (HepM), direct Factor Xa inhibitors (DXI), and protein impurities are detectable by use of these assays. Heparin was spiked with different amounts of HepM including OSCS, pentosan polysulfate, dextran sulfate, curdlan sulfate, the natural contaminant dermatan sulfate, the DXI rivaroxaban, and BSA as a protein. These samples were compared with pure heparin in the two step FI assay, the two-step aXa assay, and in the PolyH assay and the aXa assay without heparinase I incubation. Both two-step assays sensitively measured contamination with all the HepM (LOD <= 0.5%, LOQ <= 0.7%). The two-step aXa assay also detected rivaroxaban (LOD 0.3%, LOQ 0.4%), whereas the two-step FI assay was shown to be suited to determination of protein impurities (LOD 0.11%, LOQ 0.13%). Use of two different heparinase I inactivation procedures enabled clear differentiation between protein, HepM, and both contaminants. Finally, with the aXa assay the heparin potency can be determined in the same assay run, whereas the FI increase in the PolyH assay was shown to be useful for identification. In conclusion, both the two-step FI assay and the two-step aXa assay are sensitive, rapid, and simple tests for the detection of counterfeit heparin. Comprehensive information about heparin quality can be obtained by their combined use and the parallel measurement of non-incubated heparin samples. PMID- 20953781 TI - Surveying selenium speciation from soil to cell--forms and transformations. AB - The aim of this review is to present and evaluate the present knowledge of which selenium species are available to the general population in the form of food and common supplements and how these species are metabolized in mammals. The overview of the selenium sources takes a horizontal approach, which encompasses identification of new metabolites in yeast and food of plant and animal origin, whereas the survey of the mammalian metabolism takes a horizontal as well as a vertical approach. The vertical approach encompasses studies on dynamic conversions of selenium compounds within cells, tissues or whole organisms. New and improved sample preparation, separation and detection methods are evaluated from an analytical chemical perspective to cover the progress in horizontal speciation, whereas the analytical methods for the vertical speciation and the interpretations of the results are evaluated from a biological angle as well. PMID- 20953780 TI - Targeted analysis of glycomics liquid chromatography/mass spectrometry data. AB - Hydrophilic interaction chromatography (HILIC) liquid chromatography/mass spectrometry (LC/MS) is appropriate for all native and reductively aminated glycan classes. HILIC carries the advantage that retention times vary predictably according to oligosaccharide composition. Chromatographic conditions are compatible with sensitive and reproducible glycomics analysis of large numbers of samples. The data are extremely useful for quantitative profiling of glycans expressed in biological tissues. With these analytical developments, the rate limiting factor for widespread use of HILIC LC/MS in glycomics is the analysis of the data. In order to eliminate this problem, a Java-based open source software tool, Manatee, was developed for targeted analysis of HILIC LC/MS glycan datasets. This tool uses user-defined lists of compositions that specify the glycan chemical space in a given biological context. The program accepts high resolution LC/MS data using the public mzXML format and is capable of processing a large data file in a few minutes on a standard desktop computer. The program allows mining of HILIC LC/MS data with an output compatible with multivariate statistical analysis. It is envisaged that the Manatee tool will complement more computationally intensive LC/MS processing tools based on deconvolution and deisotoping of LC/MS data. The capabilities of the tool were demonstrated using a set of HILIC LC/MS data on organ-specific heparan sulfates. PMID- 20953782 TI - Levels, seasonal patterns, and potential sources of organochlorine pesticides in the urban atmosphere of Beijing, China. AB - Air samples collected monthly on the roof of a building in Beijing were analyzed for the levels, seasonal patterns, and potential sources of organochlorine pesticides (OCPs). A high-volume air sampler with polyurethane foam and quartz fiber filters was used to collect monthly samples from November 2005 to April 2009. Hexachlorobenzene (HCB) and DDT isomers were the most abundant organochlorinated pesticides in the Beijing atmosphere. Higher OCP concentrations were generally found in summer, except for HCB. Coal combustion, waste incineration, and fuel combustion were assumed to be the potential HCB emission sources. Significant input of either of these OCPs during our study period was considered very unlikely. PMID- 20953783 TI - Development of fluorophore dynamics imaging as a probe for lipid domains in model vesicles and cell membranes. AB - The ability to detect raft structures in membranes continues to present a problem, especially in the membranes of live cells. Rafts, generally considered to be small (< 200 nm) sphingolipid-rich regions, are commonly modelled using lipid vesicle systems where the ability of fluorophore-labelled lipids to preferentially locate into domains (basically large rafts) is investigated. Instead, in this study the motional properties of different fluorophores were determined using two-photon excitation and time-correlated single-photon counting coupled with diffraction-limited imaging with polarizing optics in scanning mode to obtain nanosecond rotational correlation time images. To develop the method, well-characterized domain-containing models consisting of giant unilamellar vesicles comprising mixtures of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, sphingomyelin and cholesterol were used with the fluorophores diphenylhexatriene, 1-palmitoyl-2-{6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl}-sn-glycero-3 phosphocholine and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(7-nitro-2-1,3 benzoxadiazol-4-yl). Accordingly, images of rotational correlation times of the probes revealed domain structures for all three probes consistent with other studies using different approaches. Rotational correlation time images of living cell membranes were also observed. The method has the advantage that not only does it enable domains to be visualised or imaged in a unique manner but that it can also potentially provide useful information on the lipid dynamics within the structures. PMID- 20953785 TI - Incorporating ecosystem function concept in environmental planning and decision making by means of multi-criteria evaluation: the case-study of Kalloni, Lesbos, Greece. AB - Nature provides life-support services which do not merely constitute the basis for ecosystem integrity but also benefit human societies. The importance of such multiple outputs is often ignored or underestimated in environmental planning and decision making. The economic valuation of ecosystem functions or services has been widely used to make these benefits economically visible and thus address this deficiency. Alternatively, the relative importance of the components of ecosystem value can be identified and compared by means of multi-criteria evaluation. Hereupon, this article proposes a conceptual framework that couples ecosystem function analysis, multi criteria evaluation and social research methodologies for introducing an ecosystem function-based planning and management approach. The framework consists of five steps providing the structure of a participative decision making process which is then tested and ratified, by applying the discrete multi-criteria method NAIADE, in the Kalloni Natura 2000 site, on Lesbos, Greece. Three scenarios were developed and evaluated with regard to their impacts on the different types of ecosystem functions and the social actors' value judgements. A conflict analysis permitted the better elaboration of the different views, outlining the coalitions formed in the local community and shaping the way towards reaching a consensus. PMID- 20953784 TI - Pulsed lavage improves fixation strength of cemented tibial components. AB - Pulsatile lavage is purported to improve radiographic survival in cemented total knee arthroplasty (TKA). Similarly, a potential improvement of fixation strength of the tibial tray has been assumed based on the increased cement penetration. In this study, the influence of pulsed lavage on fixation strength of the tibial component and bone cement penetration was evaluated in six pairs of cadaveric specimens. Following surgical preparation, the tibial surface was irrigated using pulsatile lavage on one side of a pair, while on the other side syringe lavage was applied. All tibial components were implanted using the same cementing technique. Cement penetration and bone mineral density was assessed based on computed tomography data. Fixation strength of the tibial trays was determined by a pull-out test with a material testing machine. Median pull-out forces and cement penetration were significantly (p = 0.031) improved in the pulsed lavage group as compared to the syringe lavage group. Enhanced fixation strength is suggested as being a key to improved survival of the implant. Consequently, pulsatile lavage should be considered as a mandatory preparation step when cementing tibial components in TKA. PMID- 20953786 TI - Differential sensitivity of Arabidopsis siRNA biogenesis mutants to genotoxic stress. AB - Plant response to stress has been linked to different RNA-silencing processes and epigenetic mechanisms. Our recent results showed that Arabidopsis thaliana Dicer like (DCL) mutants were impaired in transgenerational changes, recombination frequency and stress tolerance. We also found that transgenerational changes were dependent on changes in DNA methylation. Here, we hypothesized that plants deficient in the production of small RNAs would show an impaired abiotic stress response. To test this, we exposed A. thaliana dcl2, dcl3, dcl4, dcl2 dcl3 (d2d3), dcl2 dcl4 (d2d4), dcl2 dcl3 dcl4 (d2d3d4), nrpd1a, rdr2 and rdr6 mutants to methyl methane sulfonate (MMS). We found dcl4 and rdr6 to be more sensitive and dcl2, dcl3, d2d3 and rdr2 plants more resistant to MMS, as shown by fresh weight, root length and survival rate. The in vitro repair assay showed the lower ability of dcl2 and dcl3 to repair UV-damaged DNA. To summarize, we found that whereas mutants impaired in transactivating siRNA biogenesis were more sensitive to MMS, mutants impaired in natural antisense siRNA and heterochromatic siRNA biogeneses were more tolerant. Our data suggest that plant response to MMS is in part regulated through biogenesis of various siRNAs. PMID- 20953787 TI - The naked truth: Sphynx and Devon Rex cat breed mutations in KRT71. AB - Hair is a unique structure, characteristic of mammals, controlling body homeostasis, as well as cell and tissue integration. Previous studies in dog, mouse, and rat have identified polymorphisms in Keratin 71 (KRT71) as responsible for the curly/wavy phenotypes. The coding sequence and the 3' UTR of KRT71 were directly sequenced in randomly bred and pedigreed domestic cats with different pelage mutations, including hairless varieties. A SNP altering a splice site was identified in the Sphynx breed and suggested to be the hairless (hr) allele, and a complex sequence alteration, also causing a splice variation, was identified in the Devon Rex breed and suggested to be the curly (re) allele. The polymorphisms were genotyped in approximately 200 cats. All the Devon Rex were homozygous for the complex alterations and most of the Sphynx were either homozygous for the hr allele or compound heterozygotes with the Devon-associated re allele, suggesting that the phenotypes are a result of the identified SNPs. Two Sphynx carrying the proposed hr mutation did not carry the Devon-associated alteration. No other causative mutations for eight different rexoid and hairless cat phenotypes were identified. The allelic series KRT71( + ) > KRT71( hr ) > KRT71( re ) is suggested. PMID- 20953788 TI - Cushing's syndrome cured by resection of an appendiceal carcinoid tumor. PMID- 20953789 TI - Balancing zinc deficiency leads to an improved healing of colon anastomosis in rats. AB - BACKGROUND: In colorectal surgery, anastomotic leakage is a relevant complication. The aim of this study was to investigate whether intraperitoneally (i.p.) administered zinc improves the healing of colon anastomosis in rats. MATERIALS AND METHODS: Male Wistar rats (66) received zinc-deficient diet for 21 days. To determine the effective dose of zinc which is necessary to compensate this deficiency, preliminary analysis in 30 rats were performed. In these rats, analysis by atom-absorption spectrophotometry revealed a dose of 1.0 mg zinc aspartate/kg body weight to be the compensatory dosage. In the remaining zinc deficient rats (n= 36), a transverse colonic anastomosis was performed. Eighteen rats received either a zinc supplementation i.p. or 0.9% NaCl i.p. (n = 18; control group). On postoperative days 3, 5, and 14, the surface of the mucosal villi, expression of MMP 2, MMP 8, MMP 13, TIMP 1, as well as the collagen types I/III ratio were analyzed. RESULTS: Protein expression of MMP 2 and MMP 8 was significantly higher in the anastomosis of the zinc group on day 3 and on day 5. The collagen types I/III ratio was significantly increased in the zinc group on days 5 and 14. CONCLUSION: Balancing zinc deficiency benefits wound healing of colonic anastomosis qualitatively due to an increased collagen type I/III ratio. Surprisingly, these zinc supplements, however, increased the expression of MMP 2 and MMP 8 that are supposed to impair wound healing in case of an over expression. Thus, further investigations are needed to elucidate the influence of zinc supplementation on regulation of MMPs. PMID- 20953790 TI - Magnetic resonance imaging, risk factors and co-morbidities in children with cerebral palsy. AB - Cerebral palsy (CP) continues to be a major problem in India. The present study provides an insight into the various clinical and neuroradiological correlates of CP. The study included 102 children with CP and was subjected to magnetic resonance imaging (MRI) of the brain. Forty-seven (46%) patients belonged to the 1-3 years age group and 84 (82%) were born at term. Of 102 children, 39 (38%) were delivered at home. Based on their tone and topographic pattern of weakness, it was found that 47 (46%) had spastic diplegia and 35 (34%) spastic quadriplegia. Hemiplegic, dystonic, and atonic CP accounted for the remaining 20%. The occurrence of severe birth asphyxia, which is rarely seen in developed countries, continues to be a major problem in developing countries, and accounted 64 (62%) of the patients. Cognitive delay (82%) was the most common co-morbidity, followed by seizure disorder (52%), feeding difficulties (22%) and visual abnormalities (29%). Ninety-one (89%) children had an abnormal MRI. Periventricular white matter injury (PWMI) was observed in 48 (47.1%), followed by diffuse encephalopathy (29%). Focal lesions (6%) and malformations (3%) were less common. In children with spastic diplegia, PWMI was the most common MRI abnormality, whereas in spastic quadriplegia, diffuse encephalopathy was most common. MRI scans help in revealing the pathologic basis of CP and had strong correlations with clinical findings. PMID- 20953791 TI - Tolerability and safety of novel half milliliter formulation of glatiramer acetate for subcutaneous injection: an open-label, multicenter, randomized comparative study. AB - Daily glatiramer acetate (GA) 20 mg/1.0 mL is a first-line treatment for relapsing-remitting multiple sclerosis (RRMS). To reduce the occurrence of injection pain and local injection site reactions (LISRs), a reduced volume formulation of GA was developed. This study compared pain and LISRs after injecting the marketed and the novel formulations. RRMS patients currently injecting GA participated in this multicenter, randomized, crossover comparative study. All patients administered once-daily subcutaneous injections of GA 20 mg/1.0 mL (marketed formulation) or GA 20 mg/0.5 mL (reduced volume formulation) for 14 days. Patients were crossed-over to the alternate treatment for an additional 14 days. Using a Visual Analog Scale (VAS), patients recorded in daily diaries the severity of injection pain immediately and 5 min post-injection, and the presence and severity of LISRs (swelling, redness, itching, lump) within 5 min and 24 h post-injection. VAS pain scores were ranked significantly lower immediately and 5 min after GA 20 mg/0.5 mL injections (p < 0.0001). Although LISRs were rare for both preparations, the severity of reactions ranked significantly lower and fewer symptoms occurred within 5 min and 24 h of using the reduced volume formulation (p < 0.0001). GA injected subcutaneously in a reduced volume formulation is a more tolerable option. PMID- 20953792 TI - Spontaneous arm movement activity assessed by accelerometry is a marker for early recovery after stroke. AB - The factors determining recovery from hemiparetic stroke are manifold. We studied spontaneous arm movement activity in the acute phase after stroke as a predictor of recovery. Included in this prospective study were 25 patients (63 +/- 10 years; 9 women, 16 men) with acute middle cerebral artery stroke and 7 control patients without neurological disease (61 +/- 14 years; 3 women, 4 men). Movement activity was measured continuously for 4 days in both arms using Actiwatches and analysed off-line. Movement activity of the nonaffected arm ranged from <10 to >16 h per day in the stroke patients. Nine stroke patients with an initial decline in arm movement activity showed no increase in movement activity in either arm over 4 days after stroke, and the other 16 patients improved steadily after admission (p < 0.003). C-reactive protein was elevated in the non recovering patients (4.4 +/- 4.9 mg/dl) related to a low number of waking hours (r = -0.512, p < 0.01). Stroke severity, location and treatment, as well as arterial blood pressure (162 +/- 21 mmHg) and body temperature (36.9 +/- 06 degrees C) were not different among the groups. The impairment was still different among the two groups 3 months after stroke. Our results support the notion that in the acute stage after middle cerebral artery stroke there are patients with a secondary decline in general motor activity related to an enhanced sleep demand as assessed with accelerometry. This impairment was related to elevated C-reactive protein. PMID- 20953793 TI - Heterogeneous patterns of tissue injury in NARP syndrome. AB - Point mutations at m.8993T>C and m.8993T>G of the mtDNA ATPase 6 gene cause the neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome, a mitochondrial disorder characterized by retinal, central and peripheral neurodegeneration. We performed detailed neurological, neuropsychological and ophthalmological phenotyping of a mother and four daughters with NARP syndrome from the mtDNA m.8993T>C ATPase 6 mutation, including 3-T brain MRI, spectral domain optical coherence tomography (SD-OCT), adaptive optics scanning laser ophthalmoscopy (AOSLO), electromyography and nerve conduction studies (EMG-NCS) and formal neuropsychological testing. The degree of mutant heteroplasmy for the m.8993T>C mutation was evaluated by real-time allele refractory mutation system quantitative PCR of mtDNA from hair bulbs (ectoderm) and blood leukocytes (mesoderm). There were marked phenotypic differences between family members, even between individuals with the greatest degrees of ectodermal and mesodermal heteroplasmy. 3-T MRI revealed cerebellar atrophy and cystic and cavitary T2 hyperintensities in the basal ganglia. SD-OCT demonstrated similarly heterogeneous areas of neuronal and axonal loss in inner and outer retinal layers. AOSLO showed increased cone spacing due to photoreceptor loss. EMG-NCS revealed varying degrees of length-dependent sensorimotor axonal polyneuropathy. On formal neuropsychological testing, there were varying deficits in processing speed, visual-spatial functioning and verbal fluency and high rates of severe depression. Many of these cognitive deficits likely localize to cerebellar and/or basal ganglia dysfunction. High-resolution retinal and brain imaging in NARP syndrome revealed analogous patterns of tissue injury characterized by heterogeneous areas of neuronal loss. PMID- 20953794 TI - The relationship between oxygenation and myoelectric activity in the forearm and shoulder muscles of males and females. AB - The aim was to investigate the relationship between oxygen saturation (StO(2)%) measured with near-infrared spectroscopy (NIRS) and myoelectric activity (root mean square, RMS) for the extensor carpi radialis (ECR) and trapezius muscles. In addition, gender differences were examined for submaximal (10-70% MVC) and sustained (10% MVC for 5 min) isometric contractions. Thirteen males and 15 females participated. Changes in StO(2)% (?StO(2)%) and RMS, expressed as percentages of maximum, were calculated for each submaximal contraction. A good correlation between ?StO(2)% and RMS was seen for the ECR (r = -0.53) and a moderate correlation seen for the trapezius muscle (r = -0.44). The ANOVA showed a significant decrease in ECR-?StO(2)% over force with females demonstrating a tendency for larger changes than males. ECR-RMS increased over force with no impact of gender. For the trapezius, ?StO(2)% decreased over force but was not gender dependent. Trapezius-RMS increased over force with females demonstrating a tendency for greater change than males. For the sustained contraction, ECR StO(2)% changed over time but was not gender dependent. ECR-RMS increased over time with females showing a greater response than males. Trapezius-StO(2)% changed over time and differed between genders, i.e., males increased while females decreased. RMS increased over time similarly for both genders. In conclusion, our data show that the ECR and trapezius aerobic demands during isometric contractions are negatively correlated to electromyography (EMG) RMS. The present study also suggests some gender specificity for forearm and shoulder myoelectric activity and oxygenation for submaximal and sustained contractions. PMID- 20953795 TI - Identifying a long standing error in single-bolus determination of the hepatic extraction ratio for indocyanine green. AB - For approximately 50 years, hepatic clearance of indocyanine green (ICG) has been used to assess liver function. Steady-state infusion of ICG with simultaneous measurement of arterial and hepatic venous ICG concentrations provides unambiguous measures of the extraction ratio for ICG and the hepatic blood flow rate, but also requires cannulation of a hepatic vein. Transient clearance following injection of a single bolus of ICG, which typically involves only measurement of arterial ICG concentration, is a more commonly used procedure. Since drawing blood from a hepatic vein is often impossible, and, in any event can be difficult, there has been considerable interest in the claim by Grainger et al. (Clin Sci 64:207-212, 1983) that a single-bolus, two-compartment model "enabled the hepatic extraction ratio (ER(ss)) of dye to be determined solely from the plasma disappearance curve". The principal purpose of this paper is to show that the claim by Grainger et al. is not valid because it ignores the fact that a finite fraction of ICG entering the liver passes directly into hepatic veins without being sequestered in the liver. A valid relationship between ER(ss) and parameters determined from single-bolus clearance data is derived in this paper. For individuals with normally functioning livers, the single-bolus method of Grainger et al. yields an extraction ratio approximately 20% too large, but in cirrhotic patients with extensive intrahepatic shunting, the extraction ratio evaluated using the single-bolus method of Grainger et al. may be too large by a factor of two. PMID- 20953796 TI - Urticaria due to Urtica dioica in a neonate. AB - Urticaria is one of the most common dermatoses during the childhood, but it is very rare in the neonates. A 17-day-old infant with a generalized urticaria was admitted to our pediatric emergency unit. The mother of the infant reported having applied water boiled with stinging nettle (Urtica dioica) onto her nipples twice a day (before and after each breastfeeding) for 2 days in order to heal her nipple cracks. Serum total immunoglobulin E (IgE) and specific IgE levels for stinging nettle were high in the infant and the mother. The rashes began to regress within the first day of the hospitalization and disappeared completely on the second day without treatment. The skin prick test with the water boiled with stinging nettle was positive for the infant with significant induration, but not for the mother. Conclusion Reporting the first urticaria case in newborns due to stinging nettle, the authors suggest that breastfeeding mothers should always consult a physician before using skincare products. PMID- 20953797 TI - Association between toll-like receptor 10 (TLR10) gene polymorphisms and childhood IgA nephropathy. AB - Toll-like receptors (TLRs) play an important role in the induction and regulation of the innate immune system and adaptive immune responses. TLR10 gene polymorphisms have been reported to be associated with a range of immune-related diseases. In this study, we investigated the association of TLR10 gene polymorphisms with immunoglobulin A nephropathy (IgAN) in Korean children. To examine the association, we genotyped one promoter single nucleotide polymorphisms (SNP) [rs10004195 (-113T/A)] and three missense SNPs [rs11096957 (Asn241His), rs11096955 (Ile369Leu), and rs4129009 (Ile775Val)] using direct sequencing in 199 IgAN patients and 289 control subjects. Our case-control analysis showed that rs10004195 was associated with IgAN (codominant model, p = 0.016 in TT vs. TA; p = 0.044 in TT vs. AA; dominant model, p = 0.0068). In addition, when comparing the proteinuria level of IgAN patients according to the genotypes of each SNP, we found that in dominant model of rs1004195, the level of proteinuria of patients with TA or AA genotypes (median, 4.01 mg/m(2)/h) was higher than that of patients with TT genotype (2.00 mg/m2/h, p = 0.033). In conclusion, these results suggest that TLR10 gene may be associated with susceptibility to IgAN in Korean children. PMID- 20953798 TI - Prey-mediated avoidance of an intraguild predator by its intraguild prey. AB - Intraguild (IG) predation is an important factor influencing community structure, yet factors allowing coexistence of IG predator and IG prey are not well understood. The existence of spatial refuges for IG prey has recently been noted for their importance in allowing coexistence. However, reduction in basal prey availability might lead IG prey to leave spatial refuges for greater access to prey, leading to increased IG predation and fewer opportunities for coexistence. We determined how the availability of prey affected space-use patterns of bobcats (Lynx rufus, IG prey) in relation to coyote space-use patterns (Canis latrans, IG predators). We located animals from fall 2007 to spring 2009 and estimated bobcat home ranges and core areas seasonally. For each bobcat relocation, we determined intensity of coyote use, distance to water, small mammal biomass, and mean small mammal biomass of the home range during the season the location was collected. We built generalized linear mixed models and used Akaike Information Criteria to determine which factors best predicted bobcat space use. Coyote intensity was a primary determinant of bobcat core area location. In bobcat home ranges with abundant prey, core areas occurred where coyote use was low, but shifted to areas intensively used by coyotes when prey declined. High spatial variability in basal prey abundance allowed some bobcats to avoid coyotes while at the same time others were forced into more risky areas. Our results suggest that multiple behavioral strategies associated with spatial variation in basal prey abundance likely allow IG prey and IG predators to coexist. PMID- 20953799 TI - Three different patterns of how low-intensity waves can affect the energy budget of littoral fish: a mesocosm study. AB - In a mesocosm study, somatic and otolith growth of six types of juvenile cyprinids differing in body size and body shape were studied in a low-intensity wave treatment and a no-wave control. Depending on fish type, somatic growth was either reduced by up to 60% or increased by up to 50% following exposure to the wave treatment. Somatic growth and otolith daily increment width (ODIW), the latter being used as a proxy for the fish energy turnover, were compared to reveal the effects of waves on the energy budget of the fish. Three different reaction types to waves, which correlated to the body morphology of the six fish groups, could be distinguished. Small and fusiform fish benefitted from low intensity waves and showed higher somatic growth rates and greater ODIW in the wave treatment. In small, deep-bodied fish, growth and ODIW were reduced by waves. Finally, in larger fish with either a fusiform or deep-bodied shape, ODIW was decoupled from somatic growth, with larger ODIW in waves, but reduced somatic growth. These results show that low-intensity hydrodynamic stress is a much more important and complex habitat factor than previously assumed. It is concluded that hydrodynamic stress by waves should be accounted for in bioenergetic models and studies on habitat choice in littoral fish species. PMID- 20953800 TI - Advantages of the hand-assisted versus the open approach to elective colectomies. AB - BACKGROUND: Hand-assisted laparoscopic colectomy has been introduced as an alternative to standard laparoscopy. However, to date, it has not been established whether intraabdominal placement of a hand abrogates the benefits of minimally invasive techniques. The authors hypothesized that the hand-assisted approach confers advantages of minimal access surgery over traditional open colectomy. METHODS: Consecutive patients undergoing elective open (OC) and hand assisted (HALC) colon resections were retrospectively reviewed. Open colectomies performed by the laparoscopic surgeons were excluded. Outcome measures included patient demographics, operative time, perioperative complications, operative and total hospital charges, and length of hospital stay. Statistical analysis was performed with a p value less than 0.05 considered significant. RESULTS: The study identified and reviewed 323 consecutive elective OCs and 66 consecutive elective HALCs. Of these, 228 OCs (70.6%) and 52 HALCs (78.8%) were left-sided. The two groups were similar in age, sex, and body mass index (BMI). The mean operative time was longer in the HALC group (202 vs 160 min; p<0.05). No major intraoperative complications occurred in either group, and no conversions from HALC to OC were performed. Postoperatively, 14 OC patients (3.8%) required blood transfusion versus no HALC patients. The rate of wound infections also was higher in the OC group (3.4%, n=11) than in the HALC group (1.5%, n=1) (p=0.04). All seven mortalities (2.3%) occurred in the OC group. The median hospital stay was significantly shorter in the HALC group (5.3 vs 8.4 days; p<0.001). The total hospital charges were significantly lower in the HALC group ($24,132 vs $33,150; p<0.001). CONCLUSION: Hand-assisted laparoscopic colectomy is a safe alternative to traditional open colonic resection. In this series, it was associated with decreased postoperative morbidity and mortality. Despite longer operative times, the use of the hand-assisted techniques significantly reduced the hospital stay and decreased the total hospital charges. Overall, in the elective setting, hand assisted laparoscopic colectomy appears to be advantageous over the traditional open colectomy. PMID- 20953801 TI - Predictors of hemoglobin decline in non-metastatic prostate cancer patients on androgen deprivation therapy: a matched cohort study. AB - PURPOSE: The extent and severity of hemoglobin decline after the initiation of androgen deprivation therapy (ADT) is unclear, and predictors of hemoglobin decline in older men with prostate cancer (PC) are not well-characterized. METHODS: Three cohorts were recruited in this prospective study to evaluate the impact of ADT and other factors on hemoglobin decline. Cohorts included ADT users initiating continuous ADT, PC controls, and healthy controls, matched on age and education. All patients with PC had non-metastatic disease. Univariate and multivariable associations between changes in hemoglobin over 12 months and baseline characteristics were evaluated using linear regression models. RESULTS: We included 250 men (mean age 69 years). The baseline mean hemoglobin was 141 g/L in ADT users, 144 g/L in PC controls, and 149 g/L in healthy controls (p < 0.001). Over 12 months, the mean hemoglobin level declined in ADT users by 8.9 g/L, compared to 0.56 and 2.03 g/L among PC controls and healthy controls, respectively (p < 0.001). Statistically significant predictors of greater hemoglobin decline included ADT use (p < 0.001), lower activities of daily living score (p < 0.001), higher Charlson comorbidity score (p = 0.02), higher baseline hemoglobin level (p < 0.001), and non-White race (p = 0.04) but not age (p = 0.50). CONCLUSIONS: In men with non-metastatic prostate cancer, ADT was independently associated with a decline in hemoglobin level over 12 months. Other predictors of declining hemoglobin included comorbidity, functional status, baseline hemoglobin level, and race. These findings may help clinicians identify patients starting ADT who would benefit from closer hemoglobin monitoring. PMID- 20953802 TI - Comorbid mental disorders and psychosocial distress in patients with brain tumours and their spouses in the early treatment phase. AB - PURPOSE: The aim of this study was to examine the prevalence of comorbid mental disorders as well as the extent of psychosocial distress in patients with intracranial tumours and their partners during the early treatment phase. Moreover, we aimed to identify which events are experienced as most distressing in the context of the early diagnosis of brain cancer by patients and spouses. METHODS: Structured clinical interviews for DSM-IV (SCID-IV) were conducted with 26 patients and their partners after the first neurosurgical treatment within the first 3 months after the detection of a brain tumour. Screening measures (NCCN distress thermometer, HADS, IES-R) were used to assess the extent of psychosocial distress as well as anxiety, depression and traumatic stress responses. Distressing experiences were assessed via a structured questionnaire and interview. RESULTS: Thirty-eight per cent of the patients and 47% of the partners suffered from a psychiatric disorder. Most frequent diagnoses were adjustment disorder and acute stress disorder. The majority of the participants suffered from elevated psychosocial distress. Partners were equally or even more affected than the patients. For the patients, the experience most frequently described as distressing was the first detection of the tumour. The majority of the partners reported to be distressed by the fear of surgery outcomes. CONCLUSIONS: This study revealed that during this very first treatment phase, both brain tumour patients and their spouses show a high prevalence of comorbid mental disorders and psychosocial distress. The findings suggest that research and clinical efforts are needed to address the psychosocial concerns of these populations. PMID- 20953803 TI - Comparison of pegfilgrastim on day 2 vs. day 4 as primary prophylaxis of intense dose-dense chemotherapy in patients with node-positive primary breast cancer within the prospective, multi-center GAIN study: (GBG 33). AB - BACKGROUND: Preliminary data suggest that pegfilgrastim given on day 4 (P4) might be superior to pegfilgrastim on day 2 (P2) in reducing grade 4 leucopenia. METHODS: Patients with node-positive primary breast cancer receiving epirubicin paclitaxel-cyclophosphamide chemotherapy were randomized to receive P2 versus P4. Primary endpoint was leucopenia grade 4, assuming a risk reduction of 50% with P4 from 50% in P2 to 25% with P4. RESULTS: Three-hundred fifty-one patients were randomized to P2 (n = 174) versus P4 (n = 177). The rate of leucopenia (grade 4) was 47.1% with P2 and 42.0% with P4 (p = 0.387), neutropenia (grade 3 + 4) was 47.9% versus 40.8% (p = 0.337), FN was 4.7% versus 8.0% (p = 0.271), and infections was 29.9% versus 25.4% (p = 0.404), respectively. CONCLUSION: This study failed to demonstrate that pegfilgrastim on day 4 was more efficacious than on day 2 with respect to grade 4 leucopenia (the primary endpoint), febrile neutropenia, or infections. PMID- 20953804 TI - Treatment modalities and outcomes for asymptomatic meningiomas. AB - OBJECTIVES: The aim of this study is to investigate the outcomes of asymptomatic meningiomas (MNGs) after a variety of treatment modalities, including observation, microsurgery (MS), and gamma knife radiosurgery (GKRS). METHODS: From 1996 to 2008, 154 patients with asymptomatic MNGs were treated, and their medical records and imaging data were retrospectively analyzed. There were 121 females and 33 males with a mean age of 59.2 years (range 27-87). Treatment modalities were essentially chosen by patient preference from observation, MS, and GKRS. The mean follow-up duration was 61.2 months (range 24-157) from diagnosis. RESULTS: Of our patient sample, 77 patients initially opted for observation. Tumor volume increased in 24 (31.2%) of these patients. MS or GKRS was required in nine of these patients, and the mean duration until intervention was 48.8 months (range 13-134). MS was performed as an initial treatment in eight patients without resulting in permanent neurologic deficit. No tumor recurrence occurred after surgery (mean follow-up 59.6 months; range 24-108). GKRS was performed in 69 patients. After GKRS, tumor size was stable in 57 and decreased in 12 patients, while no patient showed an increase in tumor size (mean follow-up 63.0 months; range 24-110). Transient complications developed in 27 patients (39.1%), though permanent neurologic deficit did not develop in any patient. The progression-free survival (PFS) rates at 4 and 5 years with observation were 77.2 +/- 5.5% and 61.8% +/- 7.7%. The difference in PFS between GKRS and observation was statistically significant (p = 0.001). CONCLUSIONS: There is a substantial probability of growth of asymptomatic MNGs. GKRS can lower this possibility, but the risk of transient complications due to irradiation exists. There are no significant differences in final outcome according to initial treatment. Considering the clinical course and final outcome, both observation with regular follow-up and GKRS may be reasonable choices for asymptomatic MNGs according to preference of the patients. PMID- 20953805 TI - Surgical treatment of trigeminal neuralgia. Results from the use of glycerol injection, microvascular decompression, and rhizotomia. AB - PURPOSE: The study aims to assess the efficacy and safety of surgical treatment of trigeminal neuralgia (TN) in our department and to identify prognostic factors. METHODS: Seventy patients receiving surgical treatment for TN during the period 2003-2004 were included in this retrospective study. The surgical procedures used were glycerol injection (GI), microvascular decompression (MVD), or rhizotomia (RIZ). All patients were divided into spontaneous onset TN type1 (brief lancinating pain) or TN type 2 (continuous pain component). Two patients had bilateral TN; each side was regarded as a separate case. These 70 patients had a total of 160 interventions (110 GI, 40 MVD, and ten RIZ) performed in the period 1998-2007. Data were obtained by chart review and telephone interview. Patients provided information about pre- and postoperative pain characteristics including subtype, duration, intensity, and the use of antiepileptic drugs. Outcome was evaluated using a pain vector diagram. RESULTS: To quantify self reported pain, we developed a new vector-based pain diagram. The subtype of TN was shown to be a very important prognostic factor. One year after MVD, 90% of patients with type 1 TN still had positive effect, whereas this was only true in 73% of patients with type 2 TN. After RIZ, the results were 71% and 33% for types 1 and 2, respectively. For comparison, GI had a significant lower effect but if the treatment led to hypoesthesia, 41% continued to have a positive effect 1 year after surgery, compared to only 24% if postoperative sensation was normal. Type 2 TN was found to be dominated by women with left-sided TN outside the V2 dermatome and with a lower probability of a neurovascular conflict. As expected, 1/5 of the cases developed postoperative hypoesthesia in the face following a nerve destructive procedure (RIZ and GI). Using MVD, the risk of serious side effects was about 4%. Complementary and alternative treatment had no general or permanent effect in the investigated population-quite the contrary. CONCLUSIONS: Regarding prognosis and outcome, we find that it is very important to classify TN in subgroups (types 1 and 2). Dealing with medically treatment-resistant type 1 TN, MVD and RIZ are reasonably safe and effective interventions. The surgical results dealing with type 2 TN are still very poor. All patients with medically treatment resistant TN should be offered referral to a neurosurgical unit with experience in treating this painful disease. We recommend using a vector-based pain diagram when evaluating the outcome of multiple interventions. PMID- 20953806 TI - Microneurovascular decompression in patients with hemifacial spasm caused by vascular compression of facial nerve at cisternal portion. AB - BACKGROUND: Hemifacial spasm is commonly caused by arterial compression of the facial nerve. Although vascular compression usually occurs at the facial nerve exit zone, in some cases, the facial nerve is compressed more distally. We analyzed the clinical outcome of microneurovascular decompression in patients with hemifacial spasm caused by either distal or proximal compression. METHOD: From September 1978 to March 2009, 2,137 patients underwent microneurovascular decompression for hemifacial spasm due to vascular compression of the facial nerve, including 2,022 patients (94.6%) with proximal compression, 101 patients (4.7%) with both proximal and distal (mixed) compression, and 14 patients (0.7%) with only distal compression. FINDINGS: Complete remission of facial spasm occurred in 10 of 14 patients (71.4%) with compression of the cisternal portion, compared with 1,773 of 2,022 patients (87.7%) with proximal compression (P = 0.08) and 87 of 101 patients (86.1%) with mixed compression (P = 0.23). Permanent facial weakness occurred in one patient (7.1%) with compression of the cisternal portion, 18 patients (0.9%) with proximal compression, and one patient (1.0%) with mixed compression. Permanent hearing loss occurred in no patients with compression of the cisternal portion, 29 patients (1.4%) with proximal compression, and three patients (3.0%) with mixed compression. CONCLUSIONS: Outcomes after microneurovascular decompression for hemifacial spasm with compression of the cisternal portion were not statistically different than with proximal compression of the facial nerve. When the clinical diagnosis of hemifacial spasm is confirmed and vascular compression is seen only in the cisternal portion of the facial nerve, microneurovascular decompression for these patients provides outcomes similar to those with proximal compression of the facial nerve. PMID- 20953807 TI - Test-retest reliability of MRI-based disk position diagnosis of the temporomandibular joint. AB - This study evaluated the test-retest reliability for determining the temporomandibular joint (TMJ) disk position, diagnosed using magnetic resonance imaging (MRI). These assessments were done as a base-line measurement for a prospective cohort study, which examines the risk factors for precipitation and progression of temporomandibular disorders. Fifteen subjects (mean age, 24.2 +/- 0.94 years; male/female = 8/7) were recruited from the students of Okayama University Dental School. Sagittal MR TMJ images were taken with a 1.5-T MR scanner (Magneton Vision, Siemens) in close and maximal open positions twice at about 1-week (6-11 days) interval. The images were displayed using 200% magnification on a computer screen with a commercially available image software package (OSIRIS, UIN/HCUG). Three calibrated examiners diagnosed the disk positions using the standardized criteria. The disk position of each joint was classified as normal, anterior disk displacement with or without reduction, and others. The first and second disk position diagnoses were compared, and the test retest reliability level was calculated using the kappa index. The second disk position diagnosis was consistent with the first in 27 out of 30 joints. The calculated kappa value representing the test-retest reliability level between the first and second disk position diagnosis was 0.812. These results indicated that the test-retest reliability of MRI-based diagnosis of TMJ disk positions at about 1-week interval was substantially high, even though they were not completely consistent. PMID- 20953808 TI - How to repair fillings made by silorane-based composites. AB - In 2007, the low shrinkage silorane-based composites with a completely new resin chemistry were introduced. As for the case of composite repair, the question of whether this new material class can be repaired with the same methods like dimethacrylate-based composites arises. The ability of a silorane-based composite (SBC) to be repaired was therefore examined in a shear-bond test. Specimens of SBC were polymerised, water-stored at 37 degrees C for 1 week and then repaired with fresh dimethacrylate-based composite (MBC) or SBC material by using several intermediate agents (IMA). The shear-bond strength was then measured after an additional water storage of 1 week. As IMA, we tested an experimental silorane flowable composite, two dimethacrylate-based flowable composites, a filled silorane system adhesive bond and a conventional unfilled adhesive, a silane in addition to an adhesive as well as a repair kit. Additionally, repairs of MBC with dimethacrylate-based flowable composite were prepared. Specimens of MBC and SBC bonded to dentine with the corresponding adhesives were used as a reference. The repairs of MBC with the flowable composite resin Tetric Evo Flow exhibited the highest mean repair bond strength value (42.2 MPa). For repair of SBC, the highest shear-bond strengths were measured for repairs using a silane additionally to a dimethacrylate-based adhesive resin, followed by repairs with the experimental silorane-based flowable composite resin Hermes Flow as IMA. SBC can be repaired in combination with a MBC; then a silane coupling agent plus a dimethacrylate-based IMA should be used. A silorane flowable as IMA is the best choice when SBC is to be repaired with SBC. PMID- 20953809 TI - Palmar fasciitis with polyarthritis syndrome in a patient with breast cancer. AB - Palmar fasciitis and polyarthritis syndrome (PFPAS) is a rare paraneoplastic syndrome often associated with ovarian and pancreatic cancers, and rarely lung and breast cancers. A 39-year-old patient with breast cancer underwent neoadjuvant chemotherapy, radical mastectomy, and radiation therapy. Subsequently, the patient developed PFPAS coinciding with progression of the breast cancer. The rheumatological symptoms were severe causing significant distress and handicap. The patient had a partial response to treatment with corticosteroids. A literature review of PFPAS and its relation to breast cancer is discussed. PMID- 20953810 TI - Dementia and cognitive impairment in amyotrophic lateral sclerosis: a review. AB - Amyotrophic lateral sclerosis (ALS) is generally considered to be a paradigm of pure motor neuron disorder; nevertheless, the possible occurrence of cognitive impairment up to a frank dementia in patients affected by ALS is recognized. The appraisal of the cognitive impairment in ALS patients is crucial not only to the therapeutic trials of this incurable disease, but also to the planning of care, compliance to interventions, the end-of-life decisions. The cognitive/behavioral changes of ALS patients are consistent with frontotemporal dysfunctions; the overlap of neuropathological features of ALS and frontotemporal lobe degeneration (FTLD) supports, in addition, the putative spectrum of ALS and FTD. In the present review, the pertinent clinical, genetic, neuropathological, neuropsychological and neuroimaging data of the literature are comprehensively and critically discussed. The distinct and overlapping features of ALS and FTD are pointed out, as well as the undisclosed questions deserving additional studies. PMID- 20953811 TI - Treatment options of cognitive impairment in multiple sclerosis. AB - Multiple sclerosis (MS) is a progressive disease of the CNS, characterized by the production of widespread lesions in the brain and spinal cord. Inflammatory demyelination has traditionally been seen as the main disease process in MS; however, axonal damage or loss is increasingly being documented to occur early in the disease. Cognitive deficits can occur independently of physical disability, which complicates their identification and recognition. More recently, cortical demyelination has been identified among possible causes of cognitive impairment in MS. Neuropsychological studies have consistently demonstrated that 40-65% of patients with MS experience cognitive dysfunction, particularly in recent memory, information processing speed, and sustained attention. Early detection of cognitive impairment is essential to enable therapeutic intervention to alleviate symptoms or prevent further cognitive decline, although how best to manage MS related cognitive impairment is currently unclear. Treatment strategies for cognitive impairment in MS are still in their infancy. This article will summarize several pharmacological attempts to enhance cognitive performances in people with MS. PMID- 20953812 TI - Guillain-Barre syndrome in children. AB - Guillain-Barre syndrome (GBS) is one of the reasons of acute polyneuropathy causing severe morbidity and mortality. Forty-six patients with GBS were included in our study. Clinical, laboratory, electrophysiological and prognostic features of the patients were evaluated retrospectively. Patients were divided into two groups. Group A consisted of children who attained a full recovery within 2 months from onset of the disease; group B consisted of children who experienced complete or partial recovery beyond 2 months from onset of the disease. Acute inflammatory demyelinating polyradiculoneuropathy was found in 56.5% of patients and axonal form in 43.5% patients. Antecedent events were found in 28 (60.9%) patients. Five patients (10.8%) needed mechanical ventilation and one patient (2.1%) died. Poor outcome was related with clinic stage and electrophysiological subtypes (axonal form). In our study, poor prognostic factors were related with clinic stage and electrophysiological subtypes (axonal form). PMID- 20953813 TI - BDNF Val66Met polymorphism and brain volumes in multiple sclerosis. AB - Brain derived neurotrophic factor (BDNF) regulates several CNS physiological and pathological processes. To investigate in multiple sclerosis (MS) patients, the relationship between the Val66Met polymorphism of BDNF and clinical markers of disease activity and MRI markers of focal and diffuse brain pathologies. 45 MS patients and 34 healthy controls (HCs) were genotyped and subjected to clinical MRI examination. Global white matter fraction (gWM-f), gray matter-f (GM-f), cerebrospinal fluid-f (CSF-f), and abnormal WM-f were measured. We studied 26 Val/Val and 19 Val/Met patients and 23 Val/Val and 11 Val/Met HCs. We found that Val/Val patients had lower GM-f and higher CSF-f than Val/Val HCs; such differences were not statistically significant comparing Val/Met patients to HCs. The regression analysis showed that both Val/Met genotype and relapse number were associated with lower CSF-f. Our data suggest that Met allele might be a protective factor against MS as it is associated to a lower brain atrophy. PMID- 20953814 TI - Potential relevance of low-intensity microembolic signals by TCD monitoring. AB - The significance of low-intensity microembolic signals (MES), as well as their relationship with high-intensity MES, has not yet been studied. We monitored MES by TCD in 256 arteries of 229 patients with carotid stenosis. All microemboli were detected automatically without a preliminary set threshold. For those 110 patients who evidenced any emboli, the correlation between the number of high- and low-intensity MES was r = 0.50, p < 0.0001. A statistically significant relationship between both types of MES was found, with a degree of association of 0.42, as assessed by Cohen's kappa. Later occurrence of high-intensity MES based on early low-intensity MES was statistically significant, with a chi-square p = 0.0006 and a degree of association of 0.24, as assessed by Cohen's kappa. There is a significant relationship between low- and high-intensity MES, thereby indicating that many MES routinely rejected because of their low intensity are real. PMID- 20953815 TI - Efficacy and tolerability of tocilizumab in rheumatoid arthritis patients seen in daily clinical practice in Japan: results from a retrospective study (REACTION study). AB - Tocilizumab, a humanized monoclonal antibody to the interleukin 6 (IL-6) receptor, was approved for use as rheumatoid arthritis (RA) therapy in Japan in 2008, but its efficacy and tolerability in daily practice has not yet been reported. We report the results of a multicenter retrospective study on the efficacy and safety of tocilizumab involving all patients (n = 229) who were started on tocilizumab therapy at three rheumatology institutes in Japan from April 2008 through to March 2009. Tocilizumab was infused every 4 weeks at a dose of 8 mg/kg according to the drug labeling. Among the 229 patients, 55% concomitantly received methotrexate (MTX) and 63% had previously received anti tumor necrosis factor (TNF) therapy. Average disease activity score (DAS) 28 of all 229 patients significantly decreased from 5.70 to 3.25 after 24 weeks of therapy. A European League Against Rheumatism (EULAR) good response and DAS28 remission was achieved in 57.4 and 40.7% of the patients, respectively, at 24 weeks. White blood cell counts significantly decreased and liver enzymes and total cholesterol slightly but significantly increased; however, liver enzyme levels did not increase in patients without MTX. Tocilizumab was discontinued in 47 cases (20.5%) due to lack of efficacy (5.2%), adverse events (11.4%), and other reasons (3.9%). The overall retention rate at 24 weeks was 79.5%. Based on these results, we conclude that tocilizumab therapy in daily rheumatology practice appears to be highly efficacious and well tolerated among active RA patients, including the anti-TNF therapy-refractory population. Tocilizumab infusion is therefore applicable not only as an alternative approach for anti-TNF therapy-resistant patients, but also as primary biologic therapy for active RA patients. PMID- 20953816 TI - Anti-leukemic activity of dasatinib in both p53(wild-type) and p53(mutated) B malignant cells. AB - The multi-kinase inhibitor dasatinib induced a variable but significant decrease of viability in both p53(wild-type) (EHEB, JVM-2, JVM-3) and p53(mutated) (MEC-1, MEC-2, BJAB) prolymphocytic B leukemic cells, due to a combination of cell cycle block in G1 and apoptosis. Antibody phospho-kinase array analysis revealed that dasatinib inhibited the phosphorylation of various kinases, including ERK1/2 and p38/MAPK as well as of STAT3 transcription factors, in both p53(wild-type) and p53(mutated) cells. Therefore, dasatinib might offer a novel therapeutic strategy not only for p53(wild-type), but also for p53(mutated) B malignancies that have the worst prognosis and urgently need innovative therapeutic approaches. PMID- 20953817 TI - Predictive value of C-reactive protein on 30-day and 1-year mortality in acute coronary syndromes: an analysis from the ACUITY trial. AB - We sought to evaluate the association between C-reactive protein (CRP) sampled on admission and short- and long-term mortality in patients with acute coronary syndromes (ACS) undergoing early invasive treatment. Baseline levels of CRP were determined in 2,974 patients with moderate and high-risk ACS undergoing an early invasive treatment strategy in the large-scale randomized ACUITY trial. The relationship of CRP to 30-day and 1-year clinical outcomes were assessed according to quartiles of CRP values. Patients with CRP levels in the fourth quartile compared to the first quartile had significantly higher 30-day mortality (2.3 vs. 0.3%, P = 0.0004) and 1-year mortality (5.5 vs. 2.8%, P = 0.0003). CRP level as a continuous variable was associated with 30-day mortality (OR [95% CI] for one unit increase in logarithmically transformed CRP level = 1.42 [1.08 1.89], P = 0.01) and 1-year mortality (OR [95% CI] = 1.24, [1.04-1.47], P = 0.02). By multivariable analysis, higher baseline CRP levels independently predicted 30-day and 1-year mortality, a relationship that was particularly strong for patients with the highest quartile of CRP (OR [95% CI] = 5.19 [1.14 23.68], P = 0.009). In troponin-positive patients, increasing quartiles of CRP were associated with a trend for 30-day mortality (P (trend) = 0.08) and a significant increase in 1-year mortality (P (trend) = 0.02); this relationship was not present in troponin-negative patients. Baseline CRP level is a powerful independent predictor of both early and late mortality in patients with ACS being treated with an early invasive strategy, especially in troponin positive patients. PMID- 20953818 TI - Interleukin-10 -1082 promoter polymorphism and gastric cancer risk in a Chinese Han population. AB - Studies investigating the association between interleukin-10 (IL-10) -1082 promoter polymorphism and gastric cancer risk report conflicting results. Our recent meta-analysis suggests that the IL-10 -1082 promoter polymorphism may be associated with gastric cancer among Asians. The objective of this study was to investigate the association between IL-10 -1082 promoter polymorphism and gastric cancer risk in Chinese Han patients. We extracted the peripheral blood samples in 150 patients with gastric cancer and 150 controls. PCR-RFLP analysis was performed to detect IL-10 -1082 promoter polymorphism in these patients. Patients with gastric cancer had a significantly lower frequency of AA (OR = 0.45, 95% CI = 0.27, 0.76; P = 0.003) than controls. Patients with cardia gastric cancer had a significantly higher frequency of GG (OR = 2.17, 95% CI = 1.08, 4.38; P = 0.03) than those with noncardia gastric cancer. Patients with advanced gastric cancer had a significantly higher frequency of AA (OR = 5.21, 95% CI = 1.71, 15.87; P = 0.004) than those with early gastric cancer. When stratified by the Lauren's classification, histological differentiation of gastric cancer, no statistically significant results were observed. This study suggests that the IL-10 -1082 promoter polymorphism may be associated with gastric cancer in Chinese Han patients, and that difference in genotype distribution may be associated with the location and stage of gastric cancer. PMID- 20953819 TI - GnRH analogue attenuated apoptosis of rat hippocampal neuron after ischemia reperfusion injury. AB - The expression and new functions of reproductive hormones in organs beyond hypothalamus-pituitary-gonad axis have been reported. So far, there is no report about the protective effects of GnRH analogue to hippocampal neurons suffering from ischemia-reperfusion injury. Middle cerebral artery occlusion model together with TUNEL staining were made in vivo and oxygen-glucose deprivation model together with double staining of Annexin V/PI with flow cytometer were made in vitro to observe the anti-apoptotic effects of GnRH analogue to hippocampal neurons after ischemia-reperfusion injury. The results found that the number of TUNEL positive pyramidal neurons in CA1 region in GnRH analogue experiment group was less than that in control group in vivo; the percentage of apoptotic neurons in GnRH analogue experiment group was less than that in control group in vitro. These findings suggested that pretreatment with certain concentration of GnRH analogue could attenuate apoptosis of hippocampal neurons. GnRH analogue has the protective effects to neurons. PMID- 20953820 TI - Studies on curcumin and curcuminoids. XXXIX. Photophysical properties of bisdemethoxycurcumin. AB - The steady-state absorption and fluorescence, as well as the time-resolved fluorescence properties of bisdemethoxycurcumin dissolved in several solvents differing in polarity and H-bonding capability were measured. The photodegradation quantum yield of the compound in acetonitrile and methanol was determined. The bisdemethoxycurcumin decay mechanisms from the S(1) state were discussed and compared with those of curcumin. The differences in S(1) dynamics observed between bisdemethoxy-curcumin and curcumin could be ascribed to a difference in H-bond acceptor/donor properties of the phenolic OH and a difference in strength of the intramolecular H-bond in the keto-enol moiety within the two molecules. PMID- 20953821 TI - Kinetics of surfactant-induced aggregation of lysozyme studied by fluorescence spectroscopy. AB - The study of protein conformational changes in the presence of surfactants and lipids is important in the context of protein folding and misfolding. In the present study, we have investigated the mechanism of the protein conformational change coupled with aggregation leading to size growth of Hen Egg White Lysozyme (HEWL) in the presence of an anionic detergent such as sodium dodecyl sulphate (SDS) in alkaline pH. We have utilized intrinsic protein fluorescence (tryptophan) and extrinsic fluorescent reporters such as 8-anilinonaphthalene-1 sulfonic acid (ANS), dansyl and fluorescein to follow the protein conformational change in real-time. By analyzing the kinetics of fluorescence intensity and anisotropy of multiple fluorescent reporters, we have been able to delineate the mechanism of surfactant-induced aggregation of lysozyme. The kinetic parameters reveal that aggregation proceeds with an initial fast-phase (conformational change) followed by a slow-phase (self-assembly). Our results indicate that SDS, below critical micelle concentration, induces conformational expansion that triggers the aggregation process at a micromolar protein concentration range. PMID- 20953822 TI - An easy and efficient fluorescent method for detecting aldehydes and its application in biotransformation. AB - Water-soluble aldehydes (acetaldehyde, propionaldehyde) and non-water-soluble aldehydes (butyraldehyde and phenylacetaldehyde) were easily detected by an efficient fluorescent method with 5-aminofluorescein as probe. Under optimal detection conditions, 5-aminofluorescein could selectively respond to aldehydes with high sensitivity in comparison with other carbonyl compounds like ketones and acids. Thus, the proposed method was used to monitor microbial oxidation and succeeded in trapping transiently-produced aldehydes during biotransformation of primary alcohols by Gluconobacter oxydans. PMID- 20953823 TI - Efficient encapsulation of chloroform with cryptophane-M and the formation of exciplex studied by fluorescence spectroscopy. AB - Efficient encapsulation of small molecules with supermolecules is one of significantly important subjects due to strong application potentials. This article presents the interaction between cryptophane-M and chloroform by fluorescence spectroscopy. The sonicated cryptophane-M solution exhibits light green color in chloroform, and the solid obtained from the evaporation of chloroform also has different color from that of cryptophane-M. In contrast, the sonicated cryptophane-M solutions in other solvents are colorless, and the solid obtained from the evaporation of these solvents has the same color as that of cryptophane-M. Furthermore, the freshly prepared cryptophane-M solution in different solvents is almost colorless, and the solid obtained from the evaporation of these solvents displays the same color as that of cryptophane-M. Although the sonicated cryptophane-M solutions in different solvents have very similar absorption spectra, they exhibit quite different emission spectra in chloroform. In contrast, the freshly-prepared cryptophane-M solutions show similar absorption and emission spectroscopy in various solvents. The variation of the fluorescence spectroscopy in binary solvents with the increasing chloroform ratio suggests that cryptophane-M and chloroform form a 1:1 exciplex, and the binding constant is estimated to be 292.95 M(-1). Although all solvents are able to enter into the cavity of cryptophane-M, only chloroform can stay in the cavity of cryptophane-M for a while, which is mostly due to the strong intermolecular interaction between cryptophane-M and chloroform, and this results in the formation of the exciplex between them. PMID- 20953824 TI - Iridium(III) complexes with orthometalated phenylimidazole ligands subtle turning of emission to the saturated green colour. AB - A series of novel six iridium complexes (1-6) bearing two substituted phenylimidazole and an additional acetylacetone as the third co-auxilary ligand are reported. The lowest absorption band for all iridium complexes consist of a mixture of heavy atom Ir(III) enhanced (3)MLCT and (3) pi-pi* transitions and the phosphorescent peak wavelength can be fine-tuned to cover the spectral range 455 518 nm with high quantum efficiencies. The peak wavelength of the dopants can be finely tuned depending upon the electronic properties of the substituents. On the basis of onset potentials of the oxidation and reduction, the HOMO-LUMO energies were calculated and the reported iridium complexes emit green light with exceeding higher efficiency. PMID- 20953825 TI - A series of carbazole cationic compounds with large two-photon absorption cross sections for imaging mitochondria in living cells with two-photon fluorescence microscopy. AB - A series of carbazole cationic compounds based on donor- Pi-acceptor (D-Pi-A) structure were synthesized and characterized. They exhibit large two-photon absorption cross sections when excited by a 810 nm a laser beam, and their photophysical properties show that the intramolecular charge transfer (ICT) character is predominant. Moreover these compounds can easily pass though the intact cell membrane of living cells, amongst, 3-(1-hydroxyethyl-4-vinylpyridium iodine)-N-butyl carbazole (9B-HVC) has been proven to be capable of accumulating within the mitochondria possessing large membrane potential and imaging this organelle in living cells by means of two-photon fluorescence microscopy. At the same time usable fluorescent photos can be obtained at lower incident excitation power (5 mW) and low-micromolar concentrations (2 MUM), which does not result in significant reduction in cell viability over a period of at least 24 h. PMID- 20953826 TI - Study on the interaction of an anthracycline disaccharide with DNA by spectroscopic techniques and molecular modeling. AB - This study was designed to examine the interaction of 4'-O-(a-L-Cladinosyl) daunorubicin (DNR-D5), a disaccharide anthracycline with calf thymus deoxyribonucleic acid (ctDNA) by UV/Vis in combination with fluorescence spectroscopy and molecular modeling techniques under physiological conditions (Britton-Robinson buffer solutions, pH = 7.4). By the analysis of UV/Vis spectrum, it was observed that upon binding to ctDNA the anthraquinone chromophore of DNR-D5 could slide into the base pairs. Moreover, the large binding constant indicated DNR-D5 had a high affinity with ctDNA. At the same time, fluorescence spectra suggested that the quenching mechanism of the interaction of DNR-D5 to ctDNA was a static quenching type. The binding constants between DNR-D5 and ctDNA were calculated based on fluorescence quenching data at different temperatures. The negative ?G implied that the binding process was spontaneous, and negative ?H and negative DeltaS suggested that hydrogen bonding force most likely played a major role in the binding of DNR-D5 to ctDNA. Moreover, the results obtained from molecular docking corroborate the experimental results obtained from spectroscopic investigations. PMID- 20953827 TI - Biomarkers of human oocyte developmental competence expressed in cumulus cells before ICSI: a preliminary study. AB - PURPOSE: To identify reliable genomic biomarkers expressed in cumulus cells that accurately and non-invasively predict the oocyte developmental competence and reinforce the already used morphological criteria. METHODS: Eight consenting patients were selected for ovarian stimulation and ICSI procedures. Cumulus oocyte complexes were transvaginally punctured and individually selected based on both good morphological criteria and high zona pellucida birefringence. Following ICSI, two 3-day embryos per patient were transferred. Pregnancy outcome was recorded and proven implantation was thereafter confirmed. Differential gene expression was assessed using two microarray platforms. Further real-time PCR validation, Ingenuity pathways analysis and intra-patient analysis were performed on 17 selected candidates. RESULTS: Seven genes were differentially (p <= 0.05) associated to successful pregnancy and implantation. These biomarkers could be used to predict the oocyte developmental competence. CONCLUSIONS: These genomic markers are a powerful reinforcement of morphological approaches of oocyte selection. Their large-scale validation could increase pregnancy outcome and single embryo transfer efficiency. PMID- 20953828 TI - Emotional dysregulation and interpersonal difficulties as risk factors for nonsuicidal self-injury in adolescent girls. AB - The purpose of this study was to examine a model of factors that place psychiatrically hospitalized girls at risk for non-suicidal self-injury (NSSI). The role of familial and peer interpersonal difficulties, as well as emotional dysregulation, were examined in relationship to NSSI behaviors. Participants were 99 adolescent girls (83.2% Caucasian; M age = 16.08) admitted to a psychiatric hospital. Structural equation modeling indicated the primacy of emotional dysregulation as an underlying process placing adolescents at risk for NSSI and mediating the influence of interpersonal problems through the family and peer domains. When family and peer relationships were characterized by conflict and lack of support for managing emotions, adolescents reported more dysregulated emotion processes. Family relational problems were directly and indirectly related to NSSI through emotional dysregulation. The indirect processes of peer relational problems, through emotional dysregulation, were significantly associated with NSSI frequency and severity. The findings suggest that the process by which interpersonal difficulties contribute to NSSI is complex, and is at least partially dependent on the nature of the interpersonal problems and emotion processes. PMID- 20953829 TI - Adolescents' commitment to continuing psychotropic medication: a preliminary investigation of considerations, contradictions, and correlates. AB - This mixed-method study examines (1) the extent to which fifty adolescents receiving wraparound treatment and prescribed psychotropic medication for various psychiatric disorders report that they would continue taking medication if the decision was entirely their own (termed "medication commitment"); (2) their general subjective experiences with medication; and (3) which medication experiences and clinical, social, and demographic factors are associated with greater medication commitment. We found that most adolescents (62%) would discontinue treatment; these "less committed" youth were more likely to report various negative medication perceptions and experiences in open-ended questions, relative to "committed" youth. Multivariate analysis indicated that significant correlates of commitment to medication were: taking antipsychotic medication, greater perceived family support, and lack of perceived coercion to take the medication; clinical or demographic factors were not significantly related to medication commitment. The results reinforce the importance of addressing youths' concerns about medication and maximizing their participation in treatment decision-making. PMID- 20953830 TI - Suicidal ideation, parent-child relationships, and adverse childhood experiences: a cross-validation study using a Graphical Markov Model. AB - Suicide is one of the leading causes of death in many Western countries. An exploration of factors associated with suicidality may help to understand the mechanisms that lead to suicide. Two samples in Germany (n = 500 and n = 477) were examined via Internet regarding suicidality, depression, alcohol abuse, adverse childhood experiences, and parent-child relationships. A Graphical Markov Model was constructed from the first subsample, testing for main, quadratic and interaction effects. All effects in the model were cross-validated using the second subsample. Depression was found to be a strong predictor of suicidality; alcohol abuse was not a predictor. Both maternal and paternal love also predicted suicidality; the former had an indirect effect via depression and the latter a direct effect. Early experiences with violence showed both a direct and indirect association with suicidality. In addition to depression being a predictor for suicidality, various pathways connect suicidality with early childhood experiences. PMID- 20953831 TI - Time to move forward from "first-generation" prognostic gene signatures in early breast cancer. PMID- 20953832 TI - Primary systemic therapy for operable breast cancer patients: the need for the new generation of trial design. PMID- 20953833 TI - Crosstalk between nicotine and estrogen-induced estrogen receptor activation induces alpha9-nicotinic acetylcholine receptor expression in human breast cancer cells. AB - The primary aim of this study was to elucidate the role of the estrogen receptor (ER), a transcription factor involved in the nicotine- and 17beta-estradiol (E2) mediated up-regulation of alpha9-nAChR gene expression. A real-time polymerase chain reaction (PCR) assay was used to quantify the alpha9-nAChR mRNA expression levels of surgically isolated (n=339) and laser-capture microdissected tissues (ER+ versus ER-, n= 6 per group). Chromatin immunoprecipitation (ChIP) and luciferase-promoter activity assays were used to investigate the ER-mediated transcriptional regulation of alpha9-nAChR gene expression. We observed that breast tumors with higher alpha9-nAChR mRNA expression levels (i.e., a mean fold ratio in the tumor/normal-paired samples of greater than tenfold) were associated with the lowest 5-year disease-specific survival rate (50%, dead/alive= 4/4, total = 8 patients, P= 0.006), in contrast to breast tumors with low levels (i.e., a mean fold ratio of less than onefold) of alpha9-nAChR expression (88%, dead/alive= 3/22, total= 25 patients). Furthermore, higher alpha9-nAChR mRNA expression levels were preferentially detected in ER+ tumor tissues in comparison to ER- tumor tissues (ER+ versus ER- patients: n=160 vs. 72; mean fold ratios of alpha9-nAChR expression = 11 +/- 3 vs. 6.7 +/- 2.3 fold, respectively). In vitro promoter-binding assays demonstrated that the ER is a major transcription factor that mediates nicotine- and E2-induced up-regulation of alpha9-nAChR gene expression in MCF-7 cells. In conclusion, our data indicate that the ER plays a central role in mediating alpha9-nAChR gene up-regulation in response to either nicotine or E2 stimulation. PMID- 20953834 TI - Are we missing the mTOR target in breast cancer? PMID- 20953835 TI - Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer. AB - The mammalian target of rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation, and metabolism through translational control. RPS6KB1 (S6K1) and RPS6KB2 (S6K2) are situated in the commonly amplified 17q21-23 and 11q13 regions. S6K1 amplification and protein overexpression have earlier been associated with a worse outcome in breast cancer, but information regarding S6K2 is scarce. The aim of this study was to evaluate the prognostic and treatment predictive relevance of S6K1/S6K2 gene amplification, as well as S6K2 protein expression in breast cancer. S6K1/S6K2 gene copy number was determined by real-time PCR in 207 stage II breast tumors and S6K2 protein expression was investigated by immunohistochemistry in 792 node-negative breast cancers. S6K1 amplification/gain was detected in 10.7%/21.4% and S6K2 amplification/gain in 4.3%/21.3% of the tumors. S6K2 protein was detected in the nucleus (38%) and cytoplasm (76%) of the tumor cells. S6K1 amplification was significantly associated with HER2 gene amplification and protein expression. S6K2 amplification correlated significantly with high S6K2 mRNA levels, ER+ status and CCND1 amplification. S6K1 and S6K2 gene amplification was associated with a worse prognosis independent of HER2 and CCND1. S6K2 gain and nuclear S6K2 expression was related to an improved benefit from tamoxifen among patients with ER+, respectively ER+/PgR+ tumors. In the ER+/PgR- subgroup, nuclear S6K2 rather indicated decreased tamoxifen responsiveness. S6K1 amplification predicted reduced benefit from radiotherapy. This is the first study showing that S6K2 amplification and overexpression, like S6K1 amplification, have prognostic and treatment predictive significance in breast cancer. PMID- 20953836 TI - Validity evidence for the measurement of the strength of motivation for medical school. AB - The Strength of Motivation for Medical School (SMMS) questionnaire is designed to determine the strength of motivation of students particularly for medical study. This research was performed to establish the validity evidence for measuring strength of motivation for medical school. Internal structure and relations to other variables were used as the sources of validity evidence. The SMMS questionnaire was filled out by 1,494 medical students in different years of medical curriculum. The validity evidence for the internal structure was analyzed by principal components analysis with promax rotation. Validity evidence for relations to other variables was tested by comparing the SMMS scores with scores on the Academic Motivation Scale (AMS) and the exhaustion scale of Maslach Burnout Inventory-Student Survey (MBI-SS) for measuring study stress. Evidence for internal consistency was determined through the Cronbach's alpha for reliability. The analysis showed that the SMMS had a 3-factor structure. The validity in relations to other variables was established as both, the subscales and full scale scores significantly correlated positively with the intrinsic motivation scores and with the more autonomous forms of extrinsic motivation, the correlation decreasing and finally becoming negative towards the extrinsic motivation end of the spectrum. They also had significant negative correlations with amotivation scale of the AMS and exhaustion scale of MBI-SS. The Cronbach's alpha for reliability of the three subscales and full SMMS scores was 0.70, 0.67, 0.55 and 0.79. The strength of motivation for medical school has a three factor structure and acceptable validity evidence was found in our study. PMID- 20953837 TI - Prevalence of porcine reproductive and respiratory syndrome virus (PRRSV) antigen positive uterine tissues in gilts culled due to reproductive disturbance in Thailand. AB - The objective of the present study was to determine the prevalence of porcine reproductive and respiratory syndrome virus (PRRSV) antigen-positive uterine tissue in gilts culled due to reproductive disturbance in relation to age at culling, reasons for culling, herds, and PRRSV vaccination. Uterine tissues of 100 gilts from six swine herds in Thailand were collected. The immunohistochemistry was performed to detect the PRRSV antigen using a polymer based non-avidin-biotin technique. PRRSV was detected in the cytoplasm of the macrophages in the subepithelial connective tissue layers of the endometrium in 33.0% of the culled gilts. The detection of PRRSV antigen varied among the herds from 14.3% to 80.0% (P = 0.018). The detection of PRRSV in the uterine tissues at different ages was not statistically different (29.6%, 39.4%, and 40.9% in gilts culled at 6-8, 9-10, and 11-16 months of age, respectively, P = 0.698), similar to the reasons for culling (P = 0.929). PRRSV antigen was found in 24.5% of the gilts vaccinated against the EU-strain-modified-live PRRSV vaccine and in 23.1% of the gilts vaccinated against the US-strain-modified-live PRRSV (P = 0.941). The level of antibody titers against PRRSV had no impact on PRRSV antigen detection in the uterine tissues. Similarly, the detection of PRRSV antigen did not differ between the virgin gilts (35.4%) and the gilts mated before culling (30.8%) (P = 0.622). It can be concluded that PRRSV remains in the uterine tissue of the infected gilts for several months even though vaccinations and acclimatization have been carried out. PMID- 20953838 TI - Seroepidemiology of leptospirosis in livestock in Trinidad. AB - A study was conducted to determine the seroprevalence of leptospirosis and infecting serovars across livestock (cattle, sheep, goats, and pigs) in Trinidad using the microscopic agglutination test with an international panel of 23 serovars. Of a total of 590 cattle tested, 21.5% were seropositive with agglutinations to 13 of the 23 antigens used in the panel. Icterohaemorrhagiae (9.3%), Sejroe (4.1%), Ballum (4.1%), and Autumnalis (1.9%) were the predominant serogroups detected in the cattle sampled (n = 590). Of 222 sheep tested, 5.0% were seropositive with agglutinations to five serovars belonging to two serogroups. These serogroups were Autumnalis at 2.7%, and Icterohaemorrhagiae at 2.3% of all sheep tested (n = 222). Of a total of 180 goats tested, 3.3% were seropositive, all agglutinating to the Icterohaemorrhagiae serogroup, 1.7% to serovar Copenhageni, 1.1% to serovar Mankarso, and 0.6% to serovar Icterohaemorrhagiae. Among pigs (n = 200), 5.0% were seropositive for five serovars belonging to three serogroups. These serogroups were Icterohaemorrhagiae at 2.5%, Australis at 2%, and Ballum at 0.5%. Overall, age and sex of animals were not significantly associated with leptospirosis with the exception of cattle where age was a significant factor for seropositivity. It was concluded that for livestock, leptospirosis may be an important zoonotic and economic disease, particularly in the case of cattle. It is imperative that the impact of leptospirosis on abortion, stillbirths, and decreased milk production in livestock in the country be assessed. PMID- 20953839 TI - Farmers' perceptions of the causes of low reproductive performance in cows kept under low-input communal production systems in South Africa. AB - The objective of the study was to determine farmers' perceptions of the causes of low reproductive performance in Nguni cows raised on communal rangelands in the Eastern Cape Province of South Africa. Data were collected using participatory rural appraisals and structured questionnaires that were administered to 551 randomly selected farmers from ten communities in the Eastern Cape. Cattle herd sizes ranged from 3 to 11 and were mainly composed of cows. Cattle sales were ranked as the most important use of cattle in all the villages. Tick-borne diseases and poor animal condition were reported as chief constraints of cattle production in most communities. More than 60% of the interviewees reported that the age at puberty and age at first calving for their cows varied between 18 and 36, and 24 and 48 months, respectively. About 95% of the respondents reported long calving intervals and low bull numbers as major causes of low reproductive performance in cows in the communal areas. It was concluded that farmers perceived delayed age at puberty and at first calving, long calving intervals and low bull numbers as the major causes of low reproductive performance in Nguni cows raised on communal rangelands in South Africa. PMID- 20953840 TI - Lessons for primary prevention of asthma: foreign-born children have less association of SES and pests with asthma diagnosis. AB - There are no proven interventions for primary prevention of asthma. As asthma prevalence varies globally, comparing asthma in native and foreign-born children might provide insights. We pooled data from five cross sectional asthma surveys (N = 962). Place of birth was associated with asthma (OR = 3.4, P < 0.001). In children not born in the US, lower socio-economic status had no significant effect on asthma (OR = 0.71, P = 0.53), while for children born in the US, the effect was significant (OR = 2.1, P = 0.001). The odds ratio for exposure to household pests was significant (OR = 1.6, P < 0.008) for children born in the US but was non-significant for children born outside the US (OR = 0.29, P = 0.11). Our findings are consistent with foreign-born children experiencing protective factors or US born children experiencing detrimental environmental exposures. PMID- 20953841 TI - Relationship between obstructive coronary artery disease and abnormal stress testing in patients with paroxysmal or persistent atrial fibrillation. AB - Atrial fibrillation (AF) has been linked to the presence of underlying coronary artery disease (CAD). However, whether the higher burden of CAD observed in AF patients translates into higher burden of myocardial ischemia is unknown. In 87 patients (71% male, mean age 61 +/- 10 years) with paroxysmal or persistent AF and without history of CAD, MSCT coronary angiography and stress testing (exercise ECG test or myocardial perfusion imaging) were performed. CAD was classified as obstructive (>=50% luminal narrowing) or not. Stress tests were classified as normal or abnormal. A population of 122 patients without history of AF, similar to the AF group as to age, gender, symptomatic status and pre-test likelihood, served as a control group. Based on MSCT, 17% of AF patients were classified as having no CAD, whereas 43% showed non-obstructive CAD and the remaining 40% had obstructive CAD. A positive stress test was observed in 49% of AF patients with obstructive CAD. Among non-AF patients, 34% were classified as having no CAD, while 41% showed non-obstructive CAD and 25% had obstructive CAD (P = 0.013 compared to AF patients). A positive stress test was observed in 48% of non-AF patients with obstructive CAD. In conclusion, the higher burden of CAD observed in AF patients is not associated to higher burden of myocardial ischemia. PMID- 20953842 TI - Gender and ethnic differences in prevalence of self-reported insomnia among patients with obstructive sleep apnea. AB - BACKGROUND: Insomnia and obstructive sleep apnea (OSA) are the two most common sleep disorders. Studies have shown that complaints of insomnia are prevalent among sleep clinic patients evaluated for OSA. Less is known about the gender and ethnic variations in this association. OBJECTIVES: This paper aims to study the influence of gender and ethnicity in the prevalence of insomnia in patients with OSA and explore the association between these two disorders with an emphasis on psychophysiologic insomnia. METHODS AND MEASUREMENTS: We reviewed case files, including self-reported questionnaires and polysomnography studies of 300 OSA patients [apnea-hypopnea index (AHI) of >10] from three ethnic groups--Caucasian, Hispanic, and African American, 50 patients each, male and female, seen at a tertiary care county hospital adult sleep center. Self-reported insomnia was classified as sleep onset insomnia, sleep maintenance insomnia, or insomnia with early morning awakening. Psychophysiologic insomnia was documented if the patient reported two of the following five symptoms: racing thoughts when trying to sleep, increased muscle tension when trying to sleep, fear of being unable to sleep, fear of being unable to fall back to sleep after waking up, and lying in bed worrying. Fischer exact tests for each contingency table were run using SPSS. RESULTS: Among OSA patients, women were older, had higher body mass index, and lower AHI at the time of diagnosis, compared to men. Insomnia was more prevalent among patients with OSA (84%) than the reported 30% among general adult population. Sleep onset insomnia was reported more frequently by women (62%) than men (53%) (p = 0.03). Similarly self-reported psychophysiologic insomnia also showed a female preponderance (53% vs. 45%, p = 0.03). Caucasian women had the highest rate of self-reported sleep maintenance insomnia (80%). Hispanic women are more likely to complain of symptoms suggestive of psychophysiologic insomnia (58%). CONCLUSIONS: There is a higher prevalence of insomnia in OSA patients. Ethnicity and gender possibly exhibit a complex and significant influence on the reported subtype of insomnia. Further larger studies may help confirm, as well as clarify, mechanisms that underlie the ethnic and gender differences that we have noted. PMID- 20953843 TI - Mathematical modeling of stem cell proliferation. AB - The mathematical models prevalently used to represent stem cell proliferation do not have the level of accuracy that might be desired. The hyperbolastic growth models promise a greater degree of precision in representing data of stem cell proliferation. The hyperbolastic growth model H3 is applied to experimental data in both embryonic stem cells and adult mesenchymal stem cells. In the embryonic stem cells the results are compared with other popular models, including the Deasy model, which is used prevalently for stem cell growth. In the case of modelling adult mesenchymal stem cells, H3 is also successfully applied to describe the proliferative index. We demonstrated that H3 can accurately represent the dynamics of stem cell proliferation for both embryonic and adult mesenchymal stem cells. We also recognize the importance of additional factors, such as cytokines, in determining the rate of growth. We propose the question of how to extend H3 to a multivariable model that can include the influence of growth factors. PMID- 20953844 TI - Calcium supplements: an additional source of lead contamination. AB - The risk posed by the quantity of heavy metal lead present in Ca supplements is of grave concern. Some lead levels have been measured up to the extent of regulatory limit set by the United States. Calcium supplements inevitably get contaminated with lead as both are naturally occurring elements having the same charge density. Therefore, it is imperative to indicate the level of this toxic metal in these supplements in order to create awareness among consumers. The calcium in the supplements is derived from natural as well as synthetic/refined sources (chelated or non-chelated). In this study, a sophisticated analytical technique, atomic absorption spectrometer (both with FAAS and GFAAS modes of atomization), was used for the purpose of analyzing Pb contents in 27 commonly used Ca supplements manufactured by different national and multinational companies. The daily intake of lead through these supplements was calculated. Only 10% of the calcium supplements analyzed met the criteria of acceptable Pb levels (1.5 MUg/daily dose) in supplements/consumer products set by the United States. It was also found that Pb intake was highest in chelated calcium supplements whereas lowest through calcium supplements with vitamin D formulation. The Pb concentration in calcium supplements was significantly increased (p < 0.001) according to their composition. In order to validate our results from the study conducted, IAEA-certified reference material (animal bone, H-5) was analyzed for Pb levels. The limit of detection of the method used was 0.05 MUg/g and a 95% lead recovery of IAEA-certified reference material (animal bone, H-5). PMID- 20953845 TI - Effects of zinc supplementation and deficiency on bone metabolism and related gene expression in rat. AB - One hundred male rats were randomly divided into four groups (n = 25) and fed a Zn-adequate diet (ZA, 46.39 mg/kg), Zn-deficient diet (ZD, 3.20 mg/kg), Zn overdose diet (ZO, 234.39 mg/kg), or were pair-fed a Zn-adequate diet (PF) for 5 weeks, respectively. The body weight, femur weight, and activity of alkaline phosphatase (ALP) were reduced in the ZD group but were increased in the ZO group. Zn concentrations in both liver and femur were elevated in the ZO group, whereas femur Zn was decreased in the ZD group. The concentrations of calcium and phosphorus were lower in the ZD than those in other groups. Serum calcium concentration was decreased in the ZD. The relative expression level of ALP was decreased in both ZD and PF, and no significant differences were observed between ZO and ZA. Insulin-like growth factor-I (IGF-I) mRNA level was reduced in the ZD but unchanged in the ZO and PF group. Zn deficiency also decreased ALP mRNA level as compared with that of PF group. Carbonic anhydrase II mRNA level was not affected by Zn. Nevertheless, dietary Zn influenced the growth, bone metabolism, and expression of IGF-I and ALP in male growing rats. PMID- 20953846 TI - Lumbar catheter for monitoring of intracranial pressure in patients with post hemorrhagic communicating hydrocephalus. AB - BACKGROUND: We investigated the feasibility and accuracy of intracranial pressure (ICP)-measurement by lumbar drainage (LD) catheter in patients with post hemorrhagic communicating hydrocephalus (PHCH). METHODS: Patients with subarachnoid hemorrhage (SAH, n = 21) or spontaneous ganglionic hemorrhage (ICH, n = 22) with ventricular involvement and the need for external ventricular drainage (EVD) due to acute hydrocephalus were included. When EVD weaning was not feasible due to persistent hydrocephalus, an additional LD was placed, after which EVD was clamped off. During this overlap period, patients underwent simultaneous pressure recording via EVD ("EVD-ICP") and LD ("LD-ICP"). Testing included manual compression of the jugular veins and body-posture changes from supine to 30 degrees position. After EVD removal, we evaluated sensitivity and specificity of ICP-rise >20 mmHg during continuous monitoring via LD for the detection of persistent PHCH using additional evaluation with computed tomography (CT). RESULTS: A total of 1,806 measurements were performed in 43 patients. "LD ICP" was strongly correlated to "EVD-ICP", with determination coefficients R(2) for the baseline measurements and each of the maneuvers ranging from 0.95-0.99, and slopes ranging 0.96-1.01. Sensitivity of "LD-ICP" >20 mmHg for detection of persistent PHCH as compared to CT was 81% and specificity was 100%. Two patients with severe SAH developed reversible signs of herniation after gradually increasing differences between "LD-ICP" and "EVD-ICP" indicated a cranio-spinal pressure gradient, likely due to cerebrospinal fluid overdrainage via LD. CONCLUSION: ICP measured via LD highly and reliably correlated to ICP measured via EVD in patients with PHCH. PMID- 20953847 TI - Advances in prevention of mother-to-child HIV transmission: the international perspectives. AB - We have sufficient knowledge and unprecedented access to global resources to dramatically reduce the transmission of HIV-1 from mother to children worldwide. Most transmission occurs during delivery and after birth through breastfeeding. For this reason, efforts to interrupt transmission have focused on peripartum period and safe infant feeding. This includes the use of antiretroviral therapy, elective cesarean section, avoidance of breastfeeding, and exclusive breastfeeding. This review summarizes recent studies and new international development on the prevention of mother-to-child HIV transmission. Prevention of mother-to-child transmission of HIV should now be integrated as part of basic maternal and child health services. PMID- 20953848 TI - Successful management of congenital chylous ascites in a premature infant using somatostatin analogue. AB - Congenital chylous ascites (CCA) is a rare disease defined as the accumulation of chylomicron-rich lymphatic fluid within the peritoneal cavity, resulting from maldevelopment of the intra-abdominal lymphatic system. Cases unresponsive to conservative treatment usually require surgical intervention. We report a case of CCA in a premature neonate, who was treated successfully with intravenous infusion of octreotide, a synthetic somatostatin analogue after failure to response to traditional supportive therapies. PMID- 20953849 TI - Congenital and perinatal infections: throwing new light with an old TORCH. AB - Infections acquired in utero or in the immediate post-natal period play a prominent role in perinatal and childhood morbidity. The TORCH constellation continues to be popular among perinatologists and paediatricians, although its limitations are increasingly known. A host of new organisms are now considered to be perpetrators of congenital and perinatal infections, and a diverse range of diagnostic tests are now available for confirming infection in the infant. In general, the collective TORCH serological panel has low diagnostic yield; instead individual tests ordered according to clinical presentation can contribute better towards appropriate diagnosis. This review captures the essence of established congenital infections such as cytomegalovirus, rubella, toxoplasmosis, syphilis and herpes simplex virus, as well as more recent entrants such as HIV and hepatitis B infection, varicella and tuberculosis. Selective screening of the mother and newborn, encouraging good personal hygiene and universal immunization are some measures that can contribute towards decreasing the incidence and morbidity of congenital and perinatal infections. PMID- 20953850 TI - Fevers and the rheumatologist. AB - Fevers in children are mainly due to infection, malignancy or inflammatory conditions. Rheumatologists have an important role in the care of inflammatory conditions, many of which are associated with fevers. Seven conditions, the hereditary recurrent fever syndromes, have been defined with the presenting symptom of recurring fever, and for which mutation of a single gene has been defined: Chronic infantile neurological articular syndrome (CINCA), Familial cold autoinflammatory syndrome (FACS), Familial Mediterranean fever (FMF), hyperimmunoglobulinemia D (HIDS), Muckle-Wells syndrome (MWS), Pyogenic sterile arthritis and Pyoderma gangrenosum (PAPA) and Tumour necrosis factor receptor associated periodic syndrome (TRAPS) . These conditions will be discussed in detail in regard to how they fit into the wider picture of pediatric rheumatological conditions, how the diagnoses may be established and the current recommended treatments for each condition. PMID- 20953851 TI - Developmental and neurophysiologic deficits in iron deficiency in children. AB - INTRODUCTION: Several studies in animals and humans have clearly demonstrated the effect of ID on development, cognition, behavior and neurophysiology. The effect of ID have been shown: on brain metabolism, neurotransmitter function, and myelination. Changes in brain iron content caused by early ID in animals are not reversible by iron therapy, inspite of correction of anemia and other tissue deficits and result in changes in behavior which continue into adulthood. ID has repercussions in the perinatal period, infancy and childhood. Some effects are irreversible while other defects may be corrected: timing of ID in a child may be critical. DEVELOPMENTAL DEFICITS: Children (6-23 months) with moderate to severe anemia (ID) or chronic anemia (>3 months) had lower mental and psychomotor development scores than the nonanemic, and except for some continued to have lower scores in spite of iron therapy for 3 months although anemia was corrected. The deficits persisted on re-evaluation at 5, 11-14, and at 19 years. SCHOLASTIC ACHIEVEMENT: Scholastic achievement is lower and ID children are twice more likely to have problems with mathematics. Ten year follow-up indicated special educational assistance was required for initially anemic children. ID affects WICS items of information, comprehension and verbal performance and full scale IQ. EEG power spectrum had a slower activity suggesting developmental lag compared to iron sufficient children. Treatment with iron improved IQ scores significantly; other studies found differential effects: improvement in cognition and mental scores in older but not in younger children. IQ levels are affected by ID: IQ at 4 years may be predicted by hemoglobin at 5 and 36 months. NEUROPHYSIOLOGICAL DEFICITS: Abnormal Evoked Response Potentials (ERPs):ABRs and VEPs are seen in ID, which persist in children who were anemic in infancy on retesting at 4 years. Differences have been consistently found in ID infants and in older children. Iron supplementation may significantly reduce latencies of some ERPs. ID affects newborn temperament, ERPs and recognition memory. Iron supplementation in infants (<1,301 g) improved neurocognitive and psychomotor development by 5.3 years (median age). Preventive iron supplementation in well nourished infants also show a positive effect on motor development. The changes are usually subtle, however, with prevalence of anemia of 79.2% in children 6-35 months and 57.9% in pregnant women (NFHS-3, 2005-06), the adverse effects of cognitive, development and behavioral defects should not be underestimated. PMID- 20953852 TI - Sleep apnea in congestive heart failure. AB - Obstructive sleep apnea (OSA) is a form of sleep disordered breathing in which pharyngeal muscle relaxation leads to recurrent nighttime apneas and hypopneas that, through increased afterload, intermittent hypoxia, and excess sympathetic activity, weaken the already failing heart. This review presents the current evidence regarding the complex relationship between OSA and heart failure (HF), including support for OSA as both a cause and consequence of HF. The impact of OSA on other cardiovascular diseases, such as hypertension, ischemic heart disease and arrhythmias, as they relate to HF development or exacerbation, also are reviewed. PMID- 20953853 TI - Hard-on-hard total hip impingement causes extreme contact stress concentrations. AB - BACKGROUND: Impingement events, in addition to their role immediately proximate to frank dislocation, hold the potential to damage new-generation hard-on-hard bearings as a result of the relatively unforgiving nature of the materials and designs. Because of the higher stiffness and tighter design tolerances of metal on-metal and ceramic implants, surgical positioning plausibly has become even more important. QUESTIONS/PURPOSES: We asked (1) whether, and under what cup orientation conditions, hard-on-hard impingements might challenge implant material failure strength; and (2) whether particle generation propensity at impingement and egress sites would show similar dependence on cup orientation. METHODS: Realistic computational simulations were enabled by multistage finite element analyses, addressing both global construct motion and loading, and focal stress concentrations at neck impingement and rim egress sites. The global model, validated by a cadaveric simulation in a servohydraulic hip simulator, included both hardware components and advanced anisotropic capsule characterization. Parametric computational runs explored the effect of cup orientation for both ceramic-on-ceramic and metal-on-metal bearing couples for two distinct motion sequences associated with dislocation. RESULTS: Stress concentrations from impingement increased nearly linearly with increased cup tilt and with cup anteversion. In some situations, peak values of stress approached or exceeded 1 GPa, levels challenging the yield strength of cobalt-chromium implants, and potentially the fracture strength of ceramics. The tendency for impingement events to generate debris, indexed in terms of a new scraping severity metric, showed orientation dependences similar to that for bulk material failure. CONCLUSIONS: Damage propensity arising from impingement events in hard total hip bearings is highly orientation-dependent. PMID- 20953854 TI - Validity of the alpha angle measurement on plain radiographs in the evaluation of cam-type femoroacetabular impingement. AB - BACKGROUND: Cam-type femoroacetabular impingement is secondary to lack of concavity at the anterosuperior femoral head-neck junction, resulting in reduced femoral head-neck offset and femoral head asphericity. This morphologic deformity can be detected by MRI and plain radiographs and quantified using the alpha angle. QUESTIONS/PURPOSES: We evaluated the accuracy and reproducibility of plain radiography in the diagnosis of cam-type deformity. METHODS: Sixty-eight patients (37 females, 31 males) with a mean age of 38 years (range, 17-60 years) were treated for intraarticular hip pathology with 43 hips having cam-type femoroacetabular impingement and 25 having isolated labral tears. All patients had alpha angle measurements made on plain radiographs (AP pelvis, crosstable lateral, Dunn view) and multiplanar MRI using an alpha angle of more than 50.5 degrees as the gold standard. RESULTS: The Dunn view had a sensitivity of 91%, specificity of 88%, positive predictive value of 93%, negative predictive value of 84%, and accuracy of 90% for diagnosing the cam deformity associated with femoroacetabular impingement. The Pearson correlation coefficients between the MRI and plain radiography values were 0.702, 0.552, and 0.349 for the Dunn, crosstable lateral, and AP views, respectively. CONCLUSIONS: Our observations validate the clinical use of the Dunn view in the evaluation of the femoral head neck contour in cam-type femoroacetabular impingement. LEVEL OF EVIDENCE: Level I, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20953857 TI - Equipment limitations of a multichannel infusion pump. PMID- 20953855 TI - Do large heads enhance stability and restore native anatomy in primary total hip arthroplasty? AB - BACKGROUND: Dislocation remains a serious complication in hip arthroplasty. Resurfacing proponents tout anatomic femoral head restoration as an advantage over total hip arthroplasty. However, advances in bearings have expanded prosthetic head options from traditional sizes of 22, 26, 28, and 32 mm to diameters as large as 60 mm. Large heads reportedly enhance stability owing to increased range of motion before impingement and increased jump distance to subluxation. Available larger diameter material combinations include metal- or ceramic-on-highly crosslinked polyethylene and metal-on-metal, each with distinct advantages and disadvantages. QUESTIONS/PURPOSES: We sought to determine (1) if using larger diameter heads has lowered our dislocation rate; and (2) how closely an anatomic metal-on-metal bearing with diameters to 60 mm replicates native femoral head size. METHODS: We retrospectively reviewed 2020 primary arthroplasties performed with large heads (>= 36 mm) in 1748 patients and noted dislocation incidence. In a prospective subset of 89 cases using anatomic heads, native femoral head diameter was measured intraoperatively with calipers by an independent observer and later compared with implanted size. RESULTS: One dislocation has occurred in 2020 hips for an incidence of 0.05%. The prosthetic head averaged 0.7 mm larger than the native head with 68 of 89 (76%) reconstructed to within +/- 2 mm of native size. CONCLUSIONS: Larger diameter heads have contributed to lower dislocation rates and large-diameter metal-on metal articulation can provide close anatomic restoration in primary THA. PMID- 20953858 TI - The art and science of cancer education and evaluation: toward facilitating improved patient outcomes. AB - Cancer education is a constantly evolving field, as science continues to advance both our understanding of cancer and its effects on patients, families, and communities. Moving discoveries to practice expeditiously is paramount to impacting cancer outcomes. The continuing education of cancer care professionals throughout their practice life is vital to facilitating the adoption of therapeutic innovations. Meanwhile, more general educational programs serve to keep cancer patients, their families, and the public informed of the latest findings in cancer research. The National Cancer Institute conducted an assessment of the current knowledge base for cancer education which involved two literature reviews, one of the general literature of the evaluation of medical and health education efforts, and the other of the preceding 5 years of the Journal of Cancer Education (JCE). These reviews explored a wide range of educational models and methodologies. In general, those that were most effective used multiple methodologies, interactive techniques, and multiple exposures over time. Less than one third of the articles in the JCE reported on a cancer education or communication product, and of these, only 70% had been evaluated for effectiveness. Recommendations to improve the evaluation of cancer education and the educational focus of the JCE are provided. PMID- 20953859 TI - Resistance to platinum-based chemotherapy in lung cancer cell lines. AB - PURPOSE: A series of six lung cancer cell lines of different cell origin (including small cell and mesothelioma) were characterized immunohistochemically and the role of a series of protein candidates previously implicated in drug resistance were investigated. METHODS: These include colony-forming and cell growth assays, immunohistochemistry, siRNA knockouts, real-time PCR and western blots. RESULTS: No correlation was found with AKT, HO-1, HO-2, GRP78, 14-3-3zeta and ERCC1 levels and cisplatin nor oxaliplatin cytotoxicity, but an association was observed with levels of the enzyme, dihydrodiol dehydrogenase (DDH); an enzyme previously implicated in the development of platinum resistance. The relationship appeared to hold true for those cell lines derived from lung epithelial primary tumors but not for the neuroendocrine/small-cell and mesothelioma cell lines. siRNA knockouts to DDH-1 and DDH-2 were prepared with the cell line exhibiting the greatest resistance to cisplatin (A549) resulting in marked decreases in the DDH isoforms as assessed by real-time PCR, western blot and enzymatic activity. The DDH-1 knockout was far more sensitive to cisplatin than the DDH-2 knockout. CONCLUSION: Thus, sensitivity to cisplatin appeared to be associated with DDH levels in epithelial lung cancer cell lines with the DDH-1 isoform producing the greatest effect. Results in keeping with transfection experiments with ovarian and other cell lines. PMID- 20953860 TI - A phase I clinical trial of FOLFIRI in combination with the pan-cyclin-dependent kinase (CDK) inhibitor flavopiridol. AB - BACKGROUND: The cyclin-dependent kinase inhibitor flavopiridol increases irinotecan- and fluorouracil-induced apoptosis. We conducted a phase I trial of FOLFIRI + flavopiridol in patients with advanced solid tumors. DESIGN: FOLFIRI + flavopiridol were administered every 2 weeks. Based on sequence-dependent inhibition, flavopiridol was given 3 h after irinotecan but before 5-FU. Two maximum tolerated doses were determined, one with flavopiridol administered over 1 h, and one with flavopiridol split as a 30-min bolus followed by a 4-h infusion. RESULTS: A total of 74 patients were enrolled and 63 were evaluable. The MTD with FOLFIRI was flavopiridol 80 mg/m(2) over 1 h or 35 mg/m(2) bolus + 35 mg/m(2) over 4 h. Dose-limiting toxicities were diarrhea, fatigue, neutropenia, and neuropathy. Clinical activity included 2 partial responses in small bowel cancer and bladder cancer and 1 complete response in mucosal melanoma. Stable disease was seen in 22 patients. Pharmacokinetic studies showed increasing C(max) with increasing flavopiridol dose. Clinical benefit was correlated with the presence of wild-type p53. Of 25 patients with colorectal cancer, 11 had as best response SD for >3 m (median 6 m, range 4.2-15.4 m), despite failing >=1 irinotecan-containing regimen. CONCLUSIONS: Treatment with flavopiridol and FOLFIRI is a safe and effective regimen. Concentrations of flavopiridol that enhance the effects of FOLFIRI can be achieved. Clinical activity is encouraging and includes prolonged stable disease in patients with irinotecan-refractory colorectal cancer. PMID- 20953861 TI - Targeting energy expenditure via fuel switching and beyond. AB - Since over-nutrition accelerates the development of obesity, progression to type 2 diabetes, and the associated co-morbidity and mortality, there has been a keen interest in therapeutic interventions targeting mechanisms that may curb appetite, increase energy expenditure or at least attenuate insulin resistance. Over the past decade, numerous peri-mitochondrial targets in the de novo lipid synthesis pathway have been linked to an increase in energy expenditure and the drug development industry has pursued the gene products involved as candidates to develop drugs against. The basis of this link, and specifically the premise that lowering tissue and cellular malonyl-CoA can increase energy expenditure, is scrutinised here. The argument presented is that fuel switching as effected by changes in cellular malonyl-CoA concentrations will not trigger the mitochondria to increase energy expenditure because: (1) an increase in beta-oxidation by lowering respiratory exchange ratio (indicative of the metabolic fuel consumed) does not equal an increase in energy expenditure (how rapidly fuel is consumed); (2) the ATP:oxygen ratios (i.e. ATP energy made:oxygen required for the reaction) are similar when metabolising lipids (2.8) vs glucose (3.0); (3) substrate availability (NEFA) does not drive energy expenditure in vivo; and (4) the availability of ADP in the mitochondrial matrix determines the rate of energy expenditure, not the availability of fuel to enter the mitochondrial matrix. To increase mitochondrial energy expenditure, work must be done (exercise) and/or the mitochondrial proton leak must be enhanced, both of which increase availability of ADP. In fact, despite the historic taboo of chemical uncoupling, this mechanism validated in humans is closest on task to increasing whole-body energy expenditure. Chemical uncoupling mimics the naturally occurring phenomenon of proton leak, accelerating the metabolism of glucose and lipids. However, it is completely non-genomic (i.e. the target is a location, not a gene product) and is not associated with addiction or mood alterations common to satiety agents. A significant hurdle for drug development is to discover a safe mitochondrial uncoupler and to formulate it potentially as a pro-drug and/or oral pump, to avoid the issue of overdosing experienced in the 1930s. The potential therapeutic impact of such a compound for an over-nutritioned patient population could be profound. If effective, the mitochondrial uncoupler mechanism could resolve many of the associated diseases such as type 2 diabetes, hypertension, obesity, depression, sleep apnoea, non-alcoholic steatohepatitis, insulin resistance and hyperlipidaemia, therefore becoming a 'disease-modifying therapy'. PMID- 20953862 TI - Association of exposure to diabetes in utero with adiposity and fat distribution in a multiethnic population of youth: the Exploring Perinatal Outcomes among Children (EPOCH) Study. AB - AIMS/HYPOTHESIS: To evaluate whether exposure to maternal gestational diabetes (GDM) is associated with adiposity and fat distribution in a multiethnic population of children. METHODS: Retrospective cohort study of 82 children exposed to maternal GDM and 379 unexposed youths 6-13 years of age with measured BMI, waist circumference, skinfold thickness, and visceral and subcutaneous abdominal fat. RESULTS: Exposure to maternal GDM was associated with higher BMI (p = 0.02), larger waist circumference (p = 0.004), more subcutaneous abdominal fat (p = 0.01) and increased subscapular to triceps skinfold thickness ratio (p = 0.01) in models adjusted for age, sex, race/ethnicity and Tanner stage. Adjustment for socioeconomic factors, birthweight and gestational age, maternal smoking during pregnancy and current diet and physical activity did not influence associations; however, adjustment for maternal pre-pregnancy BMI attenuated all associations. CONCLUSIONS/INTERPRETATION: Exposure to maternal GDM is associated with increased overall and abdominal adiposity, and a more central fat distribution pattern in 6- to 13-year-old youths from a multi-ethnic population, providing further support for the fetal overnutrition hypothesis. PMID- 20953863 TI - Posterior shoulder instability: current concepts review. AB - PURPOSE: Posterior shoulder instability has been difficult to diagnose and even more challenging to manage. However, it is being diagnosed and treated more frequently, particularly after sports injuries. The purpose of this article is to review literature concerning the management of these pathologies. METHODS: A literature review was carried out in the main medical databases to evaluate the several studies concerning the open and arthroscopic treatment of posterior shoulder instability. RESULTS: Because of better awareness of the pathology, better technical investigations, and a better understanding of shoulder biomechanics, more and more mechanical factors that can cause posterior instability have been described. Structural abnormalities can be divided into bony abnormalities and soft-tissue abnormalities. Each group can also be divided into abnormalities caused by trauma (macro- or microtrauma) or congenital. These abnormalities can be treated with non-anatomic and anatomic stability procedures. During the last decades, the latter have been described more frequently, most of them arthroscopically. CONCLUSION: For surgical treatment to be successful, the instability must be attributable to mechanical factors that can be modified by surgery. Because of better knowledge of the pathology, a more specific surgery can be performed. This lesion-specific surgery has improved clinical results compared to non-anatomic stability procedures, particularly when that surgery has been performed arthroscopically. PMID- 20953865 TI - Shotgun lipidomics for candidate biomarkers of urinary phospholipids in prostate cancer. AB - Qualitative and quantitative profiling of six different categories of urinary phospholipids (PLs) from patients with prostate cancer was performed to develop an analytical method for the discovery of candidate biomarkers by shotgun lipidomics method. Using nanoflow liquid chromatography-electrospray ionization tandem mass spectrometry, we identified the molecular structures of a total of 70 PL molecules (21 phosphatidylcholines (PCs), 11 phosphatidylethanolamines (PEs), 17 phosphatidylserines (PSs), 11 phosphatidylinositols (PIs), seven phosphatidic acids, and three phosphatidylglycerols) from urine samples of healthy controls and prostate cancer patients by data-dependent collision-induced dissociation. Identified molecules were quantitatively examined by comparing the MS peak areas. From statistical analyses, one PC, one PE, six PSs, and two PIs among the PL species showed significant differences between controls and cancer patients (p < 0.05, Student's t test), with concentration changes of more than threefold. Cluster analysis of both control and patient groups showed that 18:0/18:1-PS and 16:0/22:6-PS were 99% similar in upregulation and that the two PSs (18:1/18:0, 18:0/20:5) with two PIs (18:0/18:1 and 16:1/20:2) showed similar (>95%) downregulation. The total amount of each PL group was compared among prostate cancer patients according to the Gleason scale as larger or smaller than 6. It proposes that the current study can be utilized to sort out possible diagnostic biomarkers of prostate cancer. PMID- 20953864 TI - Early functional outcome after subvastus or parapatellar approach in knee arthroplasty is comparable. AB - PURPOSE: In total knee arthroplasty, tissue-sparing techniques are considered more important, as functional gain could become more advantageous when early mobilization is commenced. The parapatellar approach is most often used, whereas the subvastus approach is a suitable alternative. Presently, it is unknown, according to true objective measurements, which of the two is most advantageous. METHODS: In this prospective randomized double-blind, short-term trial measurements (KSS, WOMAC, PDI, VAS, ability to perform) were obtained at day 1, day 3, 1 week, 6 weeks, and 3 months. RESULTS: The subvastus group (n=20) showed only significantly less extension lag direct postoperative (P=0.04) compared with the parapatellar group (n=20). Other scores were not significantly different. The Dynaport(r)knee test, an objective performance-based tool, could not demonstrate significant differences. A blunt anatomical dissection was carried out in both observational and histological to support findings. A dense innervation of the distal vastus medialis was found. This is at risk employing the subvastus approach. Both approaches harm the suprapatellar bursa. The vastus medialis sheath must be detached distally to open the knee joint. No true separate vastus medialis obliquus could be identified. CONCLUSION: Comparable to literature, only mild advantage employing the subvastus approach was found, but only early postoperative and not objectively. As this approach is also not suitable in every case, we will continue to use the parapatellar approach. PMID- 20953866 TI - Innovative methodology to transfer conventional GC-MS heroin profiling to UHPLC MS/MS. AB - Nowadays, in forensic laboratories, heroin profiling is frequently carried out by gas chromatography coupled with mass spectrometry (GC-MS). This analytical technique is well established, provides good sensitivity and reproducibility, and allows the use of large databases. Despite those benefits, recently introduced analytical techniques, such as ultra-high-pressure liquid chromatography (UHPLC), could offer better chromatographic performance, which needs to be considered to increase the analysis throughput for heroin profiling. With the latter, chromatographic conditions were optimized through commercial modeling software and two atmospheric pressure ionization sources were evaluated. Data obtained from UHPLC-MS/MS were thus transferred, thanks to mathematical models to mimic GC MS data. A calibration and a validation set of representative heroin samples were selected among the database to establish a transfer methodology and assess the models' abilities to transfer using principal component analysis and hierarchical classification analysis. These abilities were evaluated by computing the frequency of successful classification of UHPLC-MS/MS data among GC-MS database. Seven mathematical models were tested to adjust UHPLC-MS/MS data to GC-MS data. A simplified mathematical model was finally selected and offered a frequency of successful transfer equal to 95%. PMID- 20953867 TI - Nano-HPLC-MS analysis of phospholipids in cerebrospinal fluid of Alzheimer's disease patients--a pilot study. AB - There is emerging evidence that lipids play an important role in many neurodegenerative processes, for example in Alzheimer's disease (AD). Although different lipid alterations in the AD brain have been reported, there have only been very few investigations of lipid changes in the cerebrospinal fluid (CSF). Recent developments in mass spectrometry (MS) have enabled fast and sensitive detection of lipid species in different biological matrixes. In this study we developed an on-line HPLC-MS method for phospholipid profiling in the CSF based on nano-HPLC separation using an Amide column and detection with electrospray (ESI) quadrupole-time of flight (QTOF) MS. We achieved good separation, reproducibility, and sensitivity in monitoring of the major phospholipid classes, phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylinositol (PI), and sphingomyelin (SM) in CSF. To emphasize the applicability of the method, a pilot study was performed on a group of CSF samples (N = 16) from individuals with probable AD and non-demented controls. We observed a statistically significant increase of SM levels (24.3 +/- 2.4%) in CSF from probable AD individuals vs. controls. Our findings indicate that SM levels in the CSF could potentially provide a new lead in AD biomarker research, and show the potential of the method for disease-associated CSF phospholipid screening. PMID- 20953869 TI - RNAi as a potential tool for biotechnological applications in fungi. AB - RNA interference (RNAi) is a post-transcriptional gene-silencing (PTGS) phenomenon in which double-stranded RNA (dsRNA) triggers the degradation of homologous mRNA species, thereby reducing gene expression. In fungi, the use of RNAi as a tool for reverse genetics, aimed at modification of gene expression, is constantly growing, with more than 40 species already proven to be responsive. This technology has the ability to co-down-regulate the expression of several genes; however, this trait also makes it susceptible to non-target effects, which can be addressed using both available and developing bioinformatic tools. Moreover, the functionality of absorbed exogenous RNAi molecules, and the various classes of small RNAs found in fungi, offer great versatility and flexibility in acquiring the desired effects on gene expression, even without the necessity to genetically modify the targeted strain. There is an emerging role for RNAi as a potential tool for biotechnological applications. This is evident from current investigations in fungi, demonstrating the contribution of RNAi to progress research and applications in biomaterials production, bioconversion, plant fungal interactions and virulence factors of human pathogens. Possible problems and prospects for the use of RNAi in fungal biotechnology are discussed. PMID- 20953868 TI - Quantification of the effect of glycocalyx condition on membrane receptor interactions using an acoustic wave sensor. AB - The effect of the cell glycocalyx on the binding of a membrane receptor, class I major histocompatibility complex (MHC) human leukocyte antigen (HLA)-A2, to an immobilized anti-HLA antibody was investigated using an acoustic sensor based on a Love wave geometry. The enzyme neuraminidase was used to remove sialic acid residues from the cell glycocalyx. Real-time measurements of the amplitude of the acoustic wave showed that treatment with neuraminidase facilitates HLA/anti-HLA mediated cell attachment via a 3.6-fold increase of the two-dimensional (2D) binding constant of the interaction. This could be attributed to better approach of binding partners due to favorable condition of the desialylated glycocalyx. The results underline the importance of microtopological factors in membrane receptor binding and reveal the potential of the Love wave sensor and 2D binding parameters for studying cell-substrate binding events. PMID- 20953870 TI - Semi-automated volumetric analysis of lymph node metastases during follow-up- initial results. AB - OBJECTIVE: Quantification of tumour burden in oncology requires accurate and reproducible evaluation. The current standard is RECIST measurement with its inherent disadvantages. Volumetric analysis is an alternative for therapy monitoring. The aim of this study was to evaluate the feasibility of volumetric analysis of lymph node metastases using a software prototype in a follow-up setting. METHODS: MSCT was performed in 50 patients covering the chest, abdomen and pelvis. A total of 174 suspicious lymph nodes were evaluated by two radiologists regarding short axis diameters and volumetric analysis using semi automated software. Quality of segmentation, time, maximum diameter and volume were documented. Variability of the derived change rates was computed as the standard deviation of the difference of the obtained respective change rates. RESULTS: The software performance provides robust volumetric analysis. Quality of segmentation was rated acceptable to excellent in 76-79% by each reader. Mean time spent per lesion was 38 s. The variability of change in effective diameters was 10.6%; for change rates of RECIST maximum diameter variability was 27.5%. CONCLUSION: Semi-automated volumetric analysis allows fast and convenient segmentation of most lymph node metastases. Compared with RECIST the inter observer-variability in baseline and follow-up is reduced. This should principally allow subtle changes to be subclassified within the RECIST stable range as minor response [-15% to +10%]. PMID- 20953871 TI - Antibiotic-impregnated ventriculoperitoneal shunts--a multi-centre British paediatric neurosurgery group (BPNG) study using historical controls. AB - BACKGROUND: Ventriculoperitoneal shunt infection remains a significant problem. The introduction of antibiotic-impregnated shunt (AIS) systems in the prevention of shunt infection may represent a potential advance; however, there are no randomized controlled trials to establish a robust evidence-based practice. Previously published single-institution cohort studies have provided varying results on the efficacy of AIS systems in the prevention of shunt infection. In this study, we evaluate combined outcomes from three paediatric neurosurgical units in the use of AIS systems for paediatric patients with hydrocephalus. METHODS: The three units established independent databases with data collected from varying time frames. All procedures, where a complete AIS system or part was implanted into patients from 0-16 years in age, were included. The primary outcome measure was shunt infection rate. Shunt procedures were classified as de novo (DNS) and clean revision (CRS). An infant (<1 year) de novo insertion subgroup was also analyzed. AIS shunts were compared to a historical control of non-AIS shunts and results were analysed by centre using an odds ratio with a 95% confidence interval and combined across centres by meta-analysis. RESULTS: A total of 581 AIS implantation procedures were performed in all three units. The comparative non-AIS historical cohort comprised of 1,963 procedures. The pooled effect estimate indicated a clinical advantage for AIS shunts compared to non-AIS shunts, odds ratio (OR), 0.60 (95% CI 0.38, 0.93). The de novo infant group comprised 153 AIS systems, and 465 de novo shunts in the historical non-AIS cohort. Again the pooled effect estimate indicated a clinical advantage for AIS shunts compared to non-AIS shunts, OR 0.38 (95% CI, 0.17; 0.85); however, there was a large overlap of confidence intervals in the results from the different sites indicating the uncertainty in the treatment effect estimates. Over 80% of organisms were gram positive in the infected AIS cohort with a median time to infection of 19 days. Two rifampicin-resistant organisms and three MRSA organisms were detected. CONCLUSION: Data from this exclusively paediatric multi-centre historical control study suggest that AIS may significantly reduce infection rates in de novo and clean revision shunt implants. Although the possibility of bias cannot be excluded due to study design, this is the largest study on an exclusively paediatric cohort comparing standard shunts to AIS implants. Future double-blinded RCTs are needed to confirm AIS efficacy. PMID- 20953872 TI - Problems of randomization to open or laparoscopic sigmoidectomy for diverticular disease. AB - PURPOSE: Although complicated sigmoid diverticulitis is the most common reason for laparoscopic sigmoidectomy, the level of evidence for preference of the laparoscopic approach is low. METHODS: A multicenter, randomized clinical trial comparing laparoscopic and open sigmoidectomy for diverticulitis was conducted to evaluate the short- and mid-term outcome after both techniques. Data were assessed from randomized patients and from patients who refused randomization. Results of the here presented interim analysis describe the difficulties in randomization leading to abortion of recruitment. RESULTS: 149 patients were enrolled in the randomized trial within 36 months until the interim analysis. A further 294 nonrandomized patients who preferred one of both surgical approaches were assessed. Several differences between these groups were apparent including simple epidemiological characteristics such as age (65 vs. 60 years, p < 0.001), gender (65% vs. 55% female, p = 0.05), BMI (27 vs. 26 kg/m(2), p = 0.01), and ASA class < III (72% vs. 87%, p < 0.001). CONCLUSION: The majority of eligible patients refused a random allocation. A widespread presumption of the advantages of laparoscopic surgery was probably the main reason for refusal. Patients participating in randomization did not reflect the general population in recruiting hospitals. Future trials comparing minimal invasive procedures should be conducted before presumptions concerning the outcome are widespread in the general population. PMID- 20953873 TI - Porcine dermal collagen matrix injection may enhance flap repair surgery for complex anal fistula. AB - INTRODUCTION: The use of biomaterials to treat anal fistula has drawn great interest. More recently, a porcine dermal matrix injection has been proposed as infill biomaterial to treat fistulas. METHODS: We propose a novel approach consisting in non-cutting seton positioning followed by flap repair associated with dermal matrix injection into the fistula tracts after several weeks. RESULTS: We report our experience with this two-staged procedure on 11 consecutive patients with recurrent high trans-sphincteric fistulas with a minimum follow-up of 6 months. CONCLUSIONS: In our experience, this two-stage approach seems to be safe and effective. PMID- 20953874 TI - Differences in muscle trauma quantifiable in the laboratory between the minimally invasive anterolateral and transgluteal approach. AB - INTRODUCTION: In Europe the minimized transgluteal (TG) and anterolateral (AL) approaches are increasingly preferred in hip arthroplasty (THA). METHOD: The present investigation determined which of these approaches causes the least muscle trauma. Forty patients who received a THA were enrolled in this prospective randomized study. Muscle trauma was quantified by perioperatively measuring the serum concentration of skeletal troponin I (sTnI). The Harris hip score (HHS) was determined before and 12 months after surgery. RESULTS: It increased significantly in all patients without being different between the groups (AL, 48.2->83.6; TG, 50.8->85.9). Patients in the TG group had a higher sTnI than those in the AL group 24 h postoperatively (21.6 vs. 10.9 nmol/ml, p = 0.022). The AL approach results in a reduced muscle traumatization compared with the TG approach, without this being revealed by the HHS. PMID- 20953875 TI - Single tooth tells us the date of birth. AB - The atmospheric carbon-14 ((14)C) concentration remained relatively stable until 1955, but then rapidly increased after 1955 by nuclear bomb tests, peaked in 1963, and decreased thereafter. Recently, Spalding et al. proposed epoch-making method for determining date of birth (DOB) using the tooth enamel (14)C incorporated during enamel formation. However, because the (14)C level analyzed in one tooth gives two possible age ranges (up-slope or down-slope of the bomb curve), a variety of teeth that formed in different periods are required for estimating DOB in this method. Enamel formation in a tooth moves from the incisal (occlusal) side to the cervical side. Taking advantage of this characteristic, we have first succeeded in specifying the age range from only single tooth by measuring (14)C in the incisal (occlusal) and cervical regions of the enamel separately. To date, no method of determining DOB or age estimation from single tooth enamel has been made. Furthermore, this method of dividing tooth into smaller parts could be useful for producing a more accurate DOB. Our new method is a powerful tool for identification when we can use only extremely few specimens in forensic casework. PMID- 20953876 TI - The effect of doxycycline temperature-sensitive hydrogel on inhibiting the corneal neovascularization induced by BFGF in rats. AB - BACKGROUND: To study the effect of doxycycline temperature-sensitive hydrogel (DTSH) on inhibiting the corneal neovascularization (NV) induced by the basic fibroblast growth factor (bFGF). METHODS: Corneal NV was induced by slow-release polymer pellets containing bFGF, using a rat corneal pocket model. After being implanted with bFGF pellets, the female Sprague-Dawley rats were randomly divided into seven groups (12 rats/group). The grouped rats were given topically normal saline solution and neutralized DTSH at a concentration of 0%, 0.01%, 0.05%, 0.1%, 0.5%, and 1% respectively, and treated for 6 consecutive days. After 6 days of treatment, the cornea was perfused with India ink. The length and area of the corneal vessel were measured and analyzed by Image Pro-Plus 5.1. RESULTS: Compared to the control group given saline solution, the study groups given DTSH at a concentration of 0.05%, 0.1%, 0.5%, and 1% showed significant reduction in the vessel length (respectively, 58%, 60%, 52%, and 37%) and the vessel area (respectively, 61%, 62%, 49%, and 39%) (p < 0.001). However, no such significant reduction was observed in the study group given 0.01% DTSH (p = 0.133 and 0.166 for vessel length and area respectively). Study groups given 0.05% and 0.1% DTSH showed better effects than groups given 0.01% and 1% DTSH with regard to reducing the vessel length and the vessel area (p < 0.05). CONCLUSION: The study results showed that topical DTSH effectively inhibited corneal NV at the ideal concentration of 0.05% and 0.1%. Therefore, topical DTSH could be considered as an alternative treatment for the clinical management of corneal NV. PMID- 20953877 TI - Hemodilution therapy using automated erythrocytapheresis in central retinal vein occlusion: results of a multicenter randomized controlled study. AB - BACKGROUND: Central retinal vein occlusion (CRVO) leads to poor visual outcome in most eyes. Abnormal hemorheology was suspected to play a major role in its pathogenesis. CRVO treatment is still a matter of debate but several studies have pointed out the efficacy of isovolumic hemodilution. The aim of this study was to assess the feasibility and efficacy of hemodilution using automated erythrocytapheresis in recent-onset CRVO. METHODS: In this prospective randomized controlled multicenter study, 61 consecutive CRVO patients were enrolled when they met the following criteria: CRVO lasting for 3 weeks or less, visual acuity ranging from 20/200 to 20/32, age between 18 and 85 years, no diabetes, no uncontrolled systemic hypertension, no antiplatelet or anticoagulant therapy, hematocrit higher than 38%, and signed informed consent. Patients were randomly assigned to the hemodilution group (n = 31) or to the control group (n = 30). Hemodilution therapy consisted of one session of erythrocytapheresis on outpatient basis, followed by additional session(s) for 6 weeks if needed. Target hematocrit was 35%. Follow-up was 12 months. RESULTS: No statistical differences in age, associated risk factors, or CRVO characteristics were observed at baseline between both groups. Mean visual acuity was equivalent to 20/80 in the hemodilution group and to 20/63 in the control group (non-significant difference). In the treated group, mean number of hemodilution sessions was 3.3 (range, 1 to 6), and no major side-effects occurred. At the 12-month follow-up visit, 64.5% of the hemodilution group had visual acuity of 20/40 or better compared to 40% of the control group (p = .048). Visual change was a gain of 1.7 ETDRS line in the hemodilution group versus a loss of 2.3 lines in the control group (p = .007). There was less conversion into an ischemic form in the hemodilution group (11%) than in the control group (50%, p = .004). Mean final retinal thickness was 289 MUm in the hemodilution group versus 401 MUm in the control group (p = .068). CONCLUSIONS: This multicenter controlled randomized study demonstrated that automated erythrocytapheresis is a safe and effective tool for performing hemodilution and confirmed that hemodilution therapy can improve the final prognosis of CRVO when applied in the early phase of the disease. PMID- 20953878 TI - A comparison of energy expenditure estimates from the Actiheart and Actical physical activity monitors during low intensity activities, walking, and jogging. AB - Combining accelerometry with heart rate monitoring has been suggested to improve energy estimates, however, it remains unclear whether the single, currently existing commercially available device combining these data streams (Actiheart) provides improved energy estimates compared to simpler and less expensive accelerometry-only devices. The purpose of this study was to compare the validity of the heart rate (HR), accelerometry (ACC), and combined ACC/HR estimates of the Actiheart to the ACC estimates of the Actical during low and moderate intensity activities. Twenty-seven participants (mean age 26.3 +/- 7.3) wore an Actical, Actiheart and indirect calorimeter (K4b(2)) while performing card playing, sweeping, lifting weights, walking and jogging activities. All estimates tended to underestimate energy, sometimes by substantial amounts. Viewed across all activities studied, there was no significant difference in the ability of the waist-mounted Actical and torso-mounted Actiheart (ACC, HR, ACC/HR) estimates to predict energy expenditure. However, the Actiheart provided significantly better estimates than the Actical for the activities in which acceleration of the pelvis is not closely related to energy expenditure (card playing, sweeping, lifting weights) and the Actical provided significantly better estimates for level walking and level jogging. Similar to a previous study, the ACC component of the Actiheart was found to be the weakest predictor of energy suggesting it may be responsible for the failure of the combined ACC/HR estimate to equal or better the estimates derived solely from a waist mounted ACC device. PMID- 20953879 TI - Mesenchymal stem cells improve the healing of ischemic colonic anastomoses (experimental study). AB - OBJECTIVE: The goal of this study is to examine if allogenic mesenchymal stem cell (MSC) transplantation is a useful therapy for left ischemic colon anastomosis in rats. Problems with anastomosis healing may lead to serious postoperative complications. Bone marrow-derived mesenchymal stem cells (BM MSCs), which are also referred to as stromal progenitor cells, are self-renewing and expandable stem cells. Recent studies have suggested that BM-MSCs play a crucial role in the processes of intestinal repair and accelerate angiogenesis. METHODS: MSCs were isolated from rats before analysis by light and scanning electron microscopy. Forty male Wistar albino rats weighing 250-280 g were divided into four equal groups (n = 10) as follows: group 1: control, ischemic left colonic anastomoses (fourth day); group 2: control, ischemic left colonic anastomoses (seventh day); group 3: ischemic left colonic anastomoses + locally transplanted BM-MSCs (fourth day); group 4: ischemic left colonic anastomoses + locally transplanted BM-MSCs (seventh day). Histopathological features and anastomotic strength were evaluated. RESULTS: BM-MSCs therapy significantly accelerated all of the healing parameters for ischemic colonic anastomosis except for inflammation on the fourth day. On the seventh day, BM-MSCs augmented the levels of the hydroxyproline and bursting pressure. Histological parameters, especially angiogenesis, were also found to be important for healing of ischemic colonic anastomoses. CONCLUSIONS: This is the first study to use locally transplanted cell therapy for the healing of ischemic colonic anastomosis. BM MSCs therapy significantly accelerated all of the healing parameters for ischemic colonic anastomosis. PMID- 20953880 TI - Learning curve for standardized laparoscopic surgery for colorectal cancer under supervision: a single-center experience. AB - BACKGROUND: Laparoscopic resection for colorectal cancer is increasingly being performed worldwide. Although learning standardized procedures under the supervision of an experienced surgeon may be effective, there is currently no information on the learning curve under such circumstances. This single-center study aimed to evaluate the learning curve for laparoscopic resection for colorectal cancer of one surgical fellow with no previous experience with laparoscopic colectomy. METHODS: Data were analyzed for 108 consecutive patients who underwent laparoscopic resection for colorectal cancer between July 2007 and October 2009. Surgery was performed by a single fellow with no prior experience with laparoscopic colorectal resection. The learning effect was evaluated by dividing the patients into two groups: group 1 consisted of the first 50 patients and group 2 included the last 58 patients. Short-term outcomes were compared between groups. RESULTS: More complex procedures were performed more frequently in group 2 than in group 1 (p=0.0086). A significantly greater percentage of cases was completed by the trainee in group 2 than in group 1 (91% vs. 68%; p=0.0030) and were performed independent of the supervisor (81% vs. 38%; p<0.0001). All procedures after the 65th case were completed by the trainee. Mean number of lymph nodes harvested (15 vs. 16), conversion to open surgery (0% vs. 2%), and postoperative complications (4% vs. 12%) did not differ significantly between groups. There were no intraoperative complications or mortality. Operating time for sigmoidectomy/high anterior resection reached a steady state after 35 cases. CONCLUSIONS: The present study shows that training in laparoscopic surgery for colorectal cancer under the supervision of an experienced surgeon can be performed safely without jeopardizing the short-term outcomes. More complex procedures were performed successfully by the trainee during the later period, even though he was more independent of the supervisor. PMID- 20953881 TI - Feasibility of the transtracheal approach for the thoracic cavity in a large animal model. AB - BACKGROUND: The aim of this study was to evaluate the performance of a novel transtracheal endoscopic technique for thoracic evaluation and intervention in a large animal model. METHODS: In 12 animals (6 pigs and 6 dogs) under general anesthesia, a tracheal incision was made on the right lateral wall of the lower trachea and used as an entrance for thoracic evaluation and intervention. Postoperative follow-up included endoscopy at 1 and 2 weeks after surgery and necropsy at 2 weeks after surgery. RESULTS: Transtracheal opening and thoracic exploration were achieved in all animals. Four animals (3 pigs and 1 dog) died as a result of complications from the procedure. At the follow-up endoscopy, healing at the tracheal opening region was noted in seven animals. CONCLUSIONS: The transtracheal approach to the thoracic cavity is technically feasible in both porcine and canine models (4/12 animals died). The canine model is perhaps more suitable than the porcine model for the study of the transtracheal approach to the thoracic cavity. PMID- 20953882 TI - Guidelines for institutions granting bariatric privileges for the use of laparoscopic techniques. PMID- 20953883 TI - Nutritional effect of oral supplement enriched in beta-hydroxy-beta methylbutyrate, glutamine and arginine on resting metabolic rate after laparoscopic gastric bypass. AB - BACKGROUND: Weight regain that begins 12-18 months after laparoscopic gastric bypass has been attributed to changes in resting metabolic rate (RMR), which is largely determined by lean body mass (LBM). An oral supplement containing beta hydroxy-beta-methylbutyrate, glutamine, and arginine (HMB/Glu/Arg) has helped to restore LBM in cachexia due to cancer and in critically ill trauma patients. The objective of this study was to evaluate the effect of oral HMB/Glu/Arg on LBM and RMR following laparoscopic gastric bypass (LGB). METHODS: Patients who underwent LGB were randomized to receive 24 g of HMB/Glu/Arg dissolved in water twice daily for 8 weeks or to receive no supplement. Weight loss, LBM, and RMR were assessed preoperatively, 2 and 8 weeks postoperatively. LBM was determined by dual emission x-ray absorptiometry (DXA) and RMR was measured by indirect calorimetry. RESULTS: Thirty patients were enrolled: 80% white; 20% African American; 96.7% women; mean age 46.9+/-8.4 years; mean weight 113.4+/-11.6 kg; and mean body mass index (BMI) 43.3+/-4.1 kg/m2. The experimental and control groups included 14 and 16 patients, respectively, and there was no difference in baseline demographics and characteristics between the two groups. At 8 weeks, weight, BMI, LBM, and RMR significantly decreased by 15.7+/-2.5 kg, 6.0+/-1.0 kg/m2, 7.8+/-4.0 kg, and 290.6+/-234.9 kcal/day, respectively (P<0.0001 for each variable). However, when comparing these changes between the two groups, no statistical significance was observed. CONCLUSIONS: There is a significant decrease in weight, BMI, LBM, and RMR in all subjects after LGB, and these changes were not affected by the use of HMB/Glu/Arg. Potential preservation of LBM as a result of HMB/Glu/Arg requires further investigation. However, its consumption (78 calories per serving) did not adversely affect weight loss in the experimental group. PMID- 20953884 TI - Application of the transorally inserted anvil (OrVil) after laparoscopy-assisted total gastrectomy. AB - BACKGROUND: Laparoscopy-assisted total gastrectomy (LATG) is not a commonly performed procedure due to the surgical difficulty associated with reconstruction. Although various reconstruction methods have been reported, a standard technique has not yet been established. In this study, we compared the short-term outcomes of LATG reconstructed by mini-laparotomy and by the newly developed transorally inserted anvil (OrVil). METHODS: From April 2006, a series of 45 patients underwent LATG. Of these, 15 were reconstructed by mini-laparotomy and 30 by OrVil. Short-term outcomes were compared between the two groups. RESULTS: Operation time was significantly shortened and intraoperative blood loss significantly reduced by the use of OrVil. The postoperative course, including morbidity, did not differ between the two groups. CONCLUSIONS: LATG using OrVil for the treatment of early gastric cancer is a technically feasible surgical procedure with sufficient lymph node dissection, satisfactory early recovery, and acceptable morbidity. It will be necessary to perform this novel technique in a large number of patients to confirm its feasibility. PMID- 20953885 TI - On the road to single-site laparoscopic adjustable gastric banding: lessons learned from 60 cases. AB - BACKGROUND: Single-site laparoscopic surgery is a promising emerging technique with potential to decrease postoperative pain, reduce port-site complications, and improve cosmetic results. Laparoscopic adjustable gastric banding (LapGB) is a procedure that lends itself well to single-site laparoscopic surgery because the surgery is confined to a single region of the body, the need for a larger incision for port implantation and the fact that bariartric patients are more likely to be body image conscious. The procedure is, however, technically challenging and potentially more time consuming and hazardous. To simplify learning, a hybrid technique that used multiple conventional trocars and laparoscopic equipment through a single periumbilical incision while retaining the use of the Nathanson retractor via a separate epigastric incision was developed. The authors' experience and results with this technique are described. METHODS: This retrospective review describes the prospectively collected data for the first 60 consecutive cases completed using the minimally invasive technique described. RESULTS: The 60 cases in this study comprised 12 men and 48 women with an average age of 39 years (range 20-59 years). Their average body mass index (BMI) was 39.1 kg/m(2) (range 32-52 kg/m(2)). Four patients (6.7%) needed an additional port either for hemostasis or for access difficulties. Concomitant hiatal hernia repair was performed for 13 patients. Five patients (8.3%) had superficial wound infection requiring oral antibiotic therapy and dressings. No other complications were observed. Overall, the average operating time was 55 min (range 30-160 min). For both surgeons, the learning curve was six cases, with a significant difference in the operating times between the first six cases and the remaining cases (p < 0.0001, Mann-Whitney U test). CONCLUSIONS: The authors' early experience with the minimally invasive LapGB technique shows that it is feasible and safe. It can be used either as a bridging technique to single-site LapGB or on its own as a minimally invasive technique. PMID- 20953886 TI - An experimental 392-year documentary-based multi-proxy (vine and grain) reconstruction of May-July temperatures for Koszeg, West-Hungary. AB - In this paper, we present a 392-year-long preliminary temperature reconstruction for western Hungary. The reconstructed series is based on five vine- and grain related historical phenological series from the town of Koszeg. We apply dendrochronological methods for both signal assessment of the phenological series and the resultant temperature reconstruction. As a proof of concept, the present reconstruction explains 57% of the temperature variance of May-July Budapest mean temperatures and is well verified with coefficient of efficiency values in excess of 0.45. The developed temperature reconstruction portrays warm conditions during the late seventeenth and early eighteenth centuries with a period of cooling until the coldest reconstructed period centred around 1815, which was followed by a period of warming until the 1860s. The phenological evidence analysed here represent an important data source from which non-biased estimates of past climate can be derived that may provide information at all possible time-scales. PMID- 20953887 TI - Open sutureless lumbar hernia repair using a 'memory ring' patch. AB - Various techniques have been used to repair lumbar hernias. We describe here a sutureless repair with a flat 'memory ring' patch performed as a day case. PMID- 20953888 TI - Nerve degeneration in inguinal hernia specimens. AB - BACKGROUND: The histological study of the herniated inguinal area is rare in the literature. This report is focused on the detection of structural changes of the nerves within tissues bordering the inguinal hernia of cadavers. Their physiopathological consequences are hypothesized. MATERIALS AND METHODS: Primary inguinal hernia was diagnosed in 30 fresh cadavers. Tissue specimens from the inguinal region close to and around the hernia opening were excised for histological examination. A control of the data was achieved through tissue samples excised from equivalent sites of the inguinal region in 15 cadavers without hernia. RESULTS: The detected nerves in the inguinal area demonstrated pathological changes such as fibrotic degeneration, atrophy, and fatty dystrophy of the axons. The thickening of the perineural sheath was constantly seen. These findings were consistently present, independent of the hernia type. CONCLUSIONS: The detected nerve alterations lead us to imagine a worsening, or even the cessation, of the nervous impulse to the muscles, leading to atrophy and weakening of the abdominal wall. This could represent one of the multifactorial causes of hernia genesis. PMID- 20953889 TI - Antimicrobial effect of medical textiles containing bioactive fibres. AB - Over the last few years, the textile industry has developed different methods for obtaining fabrics and fibres with an antimicrobial action for use in hospital environments and for other purposes. This study evaluates the antimicrobial action of Bioactive((r))-treated fabric (BTF), a commercially available textile containing silver for use in healthcare environments. Unlike other biocides used in hospital fabrics, the prolonged use of silver has not been related to the appearance of resistant bacteria or cross-resistance to antibiotics, in spite of being extensively used in some treatments. Thirty-three hospital strains of bacteria were tested. This study showed the capacity of BTF for significantly reducing the number of microorganisms present, compared with the reduction observed in control fabrics (CF). The antimicrobial action of BTF was expressed as log(10) reduction (LR) from an initial inoculum of about 10(5) colony-forming units (cfu). According to the bacterial species, an LR of between 2.6 and 5.0, and 4.1 and 5.0 (5.0 indicating total inhibition of bacterial growth) were observed, respectively, after 24 and 48 h for BTF. Acinetobacter strains were the most resistant to CF after 72 h (0.8 LR). All of the microorganisms, except two strains of Enterococcus faecalis, were totally inhibited after 72 h on BTF. PMID- 20953890 TI - Glycosylation of mucins present in gastric juice: the effect of helicobacter pylori eradication treatment. AB - It is suggested that gastric mucins, and in particular some specific glycan structures that can act as carbohydrate receptors, are involved in the interactions with Helicobacter pylori adhesins. The main aim of our study was to evaluate glycosylation pattern of glycoproteins of gastric juice before and at the end of eradication therapy. Gastric juices were taken from 13 clinical patients and subjected to analysis. Pooled fractions of the void volume obtained after gel filtration were subjected to ELISA tests. To assess the relative amounts of carbohydrate structures, lectins and monoclonal antibodies were used. Changes in the level of MUC 1 and MUC 5AC mucins and of carbohydrate structures, which are suggested to be receptors for Helicobacter pylori adhesins, were observed by the end of the eradication treatment. Our results support the idea about the involvement of MUC 5AC and MUC 1 with some specific sugar structures in the mechanism of Helicobacter pylori infection. PMID- 20953891 TI - Tubulin pools in human erythrocytes: altered distribution in hypertensive patients affects Na+, K+-ATPase activity. AB - The presence of tubulin in human erythrocytes was demonstrated using five different antibodies. Tubulin was distributed among three operationally distinguishable pools: membrane, sedimentable structure and soluble fraction. It is known that in erythrocytes from hypertensive subjects (HS), the Na(+), K(+) ATPase (NKA) activity is partially inhibited as compared with erythrocytes from normal subjects (NS). In erythrocytes from HS the membrane tubulin pool is increased by ~150%. NKA was found to be forming a complex with acetylated tubulin that results in inhibition of enzymes. This complex was also increased in erythrocytes from HS. Treatment of erythrocytes from HS with nocodazol caused a decrease of acetylated tubulin in the membrane and stimulation of NKA activity, whereas taxol treatment on erythrocytes from NS had the opposite effect. These results suggest that, in erythrocytes from HS, tubulin was translocated to the membrane, where it associated with NKA with the consequent enzyme inhibition. PMID- 20953892 TI - Characterization of a regulatory unit that controls melanization and affects longevity of mosquitoes. AB - Melanization is an innate immune response in arthropods that encapsulates and kills invading pathogens. One of its rate-limiting steps is the activation of prophenoloxidase (PPO), which is controlled by an extracellular proteinase cascade and serpin inhibitors. The molecular composition of this system is largely unknown in mosquitoes with the exception of serpin-2 (SRPN2), which was previously identified as a key negative regulator of melanization. Using reverse genetic and biochemical techniques, we identified the Anopheles gambiae clip serine proteinase CLIPB9 as a PPO-activating proteinase, which is inhibited by SRPN2. Double knockdown of SRPN2 and CLIPB9 reversed the pleiotrophic phenotype induced by SRPN2 silencing. This study identifies the first inhibitory serpin serine proteinase pair in mosquitoes and defines a regulatory unit of melanization. Additionally, the interaction of CLIPB9 and SRPN2 affects the life span of adult female mosquitoes and therefore constitutes a well-defined potential molecular target for novel late-life acting insecticides. PMID- 20953893 TI - Transforming growth factor-beta-inducible early response gene 1 is a novel substrate for atypical protein kinase Cs. AB - The protein kinase C (PKC) family of serine/threonine kinases consists of ten different isoforms grouped into three subfamilies, denoted classical, novel and atypical PKCs (aPKCs). The aPKCs, PKCiota/lambda and PKCzeta serve important roles during development and in processes subverted in cancer such as cell and tissue polarity, cell proliferation, differentiation and apoptosis. In an effort to identify novel interaction partners for aPKCs, we performed a yeast two-hybrid screen with the regulatory domain of PKCiota/lambda as bait and identified the Kruppel-like factors family protein TIEG1 as a putative interaction partner for PKCiota/lambda. We confirmed the interaction of both aPKCs with TIEG1 in vitro and in cells, and found that both aPKCs phosphorylate the DNA-binding domain of TIEG1 on two critical residues. Interestingly, the aPKC-mediated phosphorylation of TIEG1 affected its DNA-binding activity, subnuclear localization and transactivation potential. PMID- 20953895 TI - Influence of induction conditions on the expression of carbazole dioxygenase components (CarAa, CarAc, and CarAd) from Pseudomonas stutzeri in recombinant Escherichia coli using experimental design. AB - Carbazole 1,9a-dioxygenase (CarA), the first enzyme in the carbazole degradation pathway used by Pseudomonas sp., was expressed in E. coli under different conditions defined by experimental design. This enzyme depends on the coexistence of three components containing [2Fe-2S] clusters: CarAa, CarAc, and CarAd. The catalytic site is present in CarAa. The genes corresponding to components of carbazole 1,9a-dioxygenase from P. stutzeri were cloned and expressed by salt induction in E. coli BL21-SI (a host that allows the enhancement of overexpressed proteins in the soluble fraction), using the vector pDESTTM14. The expression of these proteins was performed under different induction conditions (cell concentration, temperature, and time), with the help of two-level factorial design. Cell concentration at induction (measured by absorbance at 600 nm) was tested at 0.5 and 0.8. After salt induction, expression was performed at 30 and 37 degrees C, for 4 h and 24 h. Protein expression was evaluated by densitometry analysis. Expression of CarAa was enhanced by induction at a lower cell concentration and temperature and over a longer time, according to the analysis of the experimental design results. The results were validated at Abs (ind) = 0.3, 25 degrees C, and 24 h, at which CarAa expression was three times higher than under the standard condition. The behavior of CarAc and CarAd was the inverse, with the best co-expression condition tested being the standard one (Abs (ind) = 0.5, T = 37 degrees C, and t = 4 h). The functionality of the proteins expressed in E. coli was confirmed by the degradation of 20 ppm carbazole. PMID- 20953894 TI - Characterization of commercial cellulases and their use in the saccharification of a sugarcane bagasse sample pretreated with dilute sulfuric acid. AB - This study aimed to correlate the efficiency of enzymatic hydrolysis of the cellulose contained in a sugarcane bagasse sample pretreated with dilute H(2)SO(4) with the levels of independent variables such as initial content of solids and loadings of enzymes and surfactant (Tween 20), for two cellulolytic commercial preparations. The preparations, designated cellulase I and cellulase II, were characterized regarding the activities of total cellulases, endoglucanase, cellobiohydrolase, cellobiase, beta-glucosidase, xylanase, and phenoloxidases (laccase, manganese and lignin peroxidases), as well as protein contents. Both extracts showed complete cellulolytic complexes and considerable activities of xylanases, without activities of phenoloxidases. For the enzymatic hydrolyses, two 2(3) central composite full factorial designs were employed to evaluate the effects caused by the initial content of solids (1.19-4.81%, w/w) and loadings of enzymes (1.9-38.1 FPU/g bagasse) and Tween 20 (0.0-0.1 g/g bagasse) on the cellulose digestibility. Within 24 h of enzymatic hydrolysis, all three independent variables influenced the conversion of cellulose by cellulase I. Using cellulase II, only enzyme and surfactant loadings showed significant effects on cellulose conversion. An additional experiment demonstrated the possibility of increasing the initial content of solids to values much higher than 4.81% (w/w) without compromising the efficiency of cellulose conversion, consequently improving the glucose concentration in the hydrolysate. PMID- 20953896 TI - Neurologic complications after intrathecal liposomal cytarabine in combination with systemic polychemotherapy in primary CNS lymphoma. AB - Intrathecal application of liposomal cytarabine (Ara-C) (DepoCyte((r))) has been associated with neurotoxicity when applied as part of a polychemotherapy regimen. Patients with primary central nervous system lymphoma treated with high-dose systemic methotrexate (MTX)- and Ara-C-based polychemotherapy including six cycles of liposomal Ara-C (50 mg intrathecally every 3 weeks) were prospectively monitored for neurotoxic side-effects. Between November 2005 and February 2009, 149 intrathecal applications of liposomal cytarabine (DepoCyte((r))) were carried out in 33 patients, 7 (21%) of whom developed an incomplete conus medullaris/cauda equina syndrome with incontinence for bladder (6) and bowel function (3) or lumbosacral polyradicular paresis (1), resolving only incompletely over a follow-up period of 9-30 months. In six of these seven patients, lumbosacral magnetic resonance imaging (MRI) was negative for leptomeningeal infiltration or arachnoiditis. Cerebrospinal fluid (CSF) analysis performed in six of these seven patients showed normal cell count in all and increased total protein in four of them. One patient among these seven suffered a seizure without other identifiable causes. Conus/cauda syndrome has to be considered as a serious potential neurotoxic side-effect in patients receiving liposomal Ara-C as part of a multimodal regimen including high-dose systemic MTX and Ara-C. PMID- 20953897 TI - Neurologic complications of intrathecal liposomal cytarabine administered prophylactically to patients with non-Hodgkin lymphoma. AB - Central nervous system (CNS) prophylaxis is required during initial treatment of non-Hodgkin lymphoma (NHL) subtypes that carry a high risk of CNS involvement. Intrathecal (IT) liposomal cytarabine, a formulation with prolonged half-life, has been shown to be safe and effective in the treatment of meningeal disease in patients with high-grade lymphoma. We retrospectively reviewed all adult patients with high-grade NHL that received prophylactic therapy with IT liposomal cytarabine and developed neurologic complications in our institution between April 2007 and May 2009. We recorded information on hospital admission, chemotherapy regimens, clinical features, neuroimaging, cerebrospinal fluid, neurophysiology data, and outcome. Neurotoxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Four of fourteen patients (28%) developed moderate or severe neurotoxicity (grades 2 and 3 of the NCI-CTC), manifested as conus medullaris/cauda equine syndrome or pseudotumour cerebri-like syndrome, after a median of 3.5 IT courses of liposomal cytarabine. All patients had received corticosteroids to prevent arachnoiditis. Liposomal cytarabine given via the IT route, even with concomitant corticosteroid administration, can result in significant neurotoxicity in some patients. We discuss the potential pathogenesis of these effects and suggest hypothetical therapeutic measures to prevent these complications. Specialists should be aware of these possible complications when administering prophylactic IT liposomal cytarabine in high-grade NHL patients, and additional prospective studies should be conducted to more clearly delineate the frequency and characteristics of these complications. PMID- 20953898 TI - Abnormalities in periodontal and salivary tissues in conditional presenilin 1 and presenilin 2 double knockout mice. AB - We used forebrain-specific conditional presenilin 1 (PS1) and presenilin 2 (PS2) double knockout mice (dKO mice), which exhibit neurodegenerative disease-like symptoms, including inflammation of the brain and periphery, to investigate whether periodontal and salivary tissues display alterations. Mandibles were dissected for alveolar bone height analysis. Maxillae were fixed and decalcified for histological observation and osteoclast detection. Submandibular glands were fixed for histological observation. The submandibular gland and the gingiva of the mandibular incisor teeth were used to assay inflammatory mediators. At 9 months, the number of osteoclasts had significantly increased in the periodontal ligament and the periodontal tissues exhibited obvious histomorphological abnormalities in the dKO mice compared to the control mice at the same age. Alveolar bone loss in dKO mice increased with age. The salivary tissues in dKO mice exhibited obvious age-dependent histomorphological abnormalities. The levels of the inflammatory mediators IL-1beta, TNF-alpha, and GM-CSF in the submandibular gland and gingiva also increased in an age-dependent manner. These findings suggest that inflammation in the dKO brain could expand to the periphery, including the oral tissue, which could ultimately induce abnormalities in the periodontal and salivary tissues. PMID- 20953899 TI - Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis. AB - The incidence of brain metastasis is increasing, however, little is known about molecular mechanism responsible for lung cancer-derived brain metastasis and their development in the brain. In the present study, brain pathology was examined in an experimental model system of brain metastasis as well as in human brain with lung cancer metastasis. In an experimental model, after 3-6 weeks of intracardiac inoculation of human lung cancer-derived (HARA-B) cells in nude mice, wide range of brain metastases were observed. The brain sections showed significant increase in glial fibrillary acidic protein (GFAP)-positive astrocytes around metastatic lesions. To elucidate the role of astrocytes in lung cancer proliferation, the interaction between primary cultured mouse astrocytes and HARA-B cells was analyzed in vitro. Co-cultures and insert-cultures demonstrated that astrocytes were activated by tumor cell-oriented factors; macrophage migration inhibitory factor (MIF), interleukin-8 (IL-8) and plasminogen activator inhibitor-1 (PAI-1). Activated astrocytes produced interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta), which in turn promoted tumor cell proliferation. Semi quantitative immunocytochemistry showed that increased expression of receptors for IL-6 and its subunits gp130 on HARA-B cells. Receptors for TNF-alpha and IL 1beta were also detected on HARA-B cells but down-regulated after co-culture with astrocytes. Insert-culture with astrocytes also stimulated the proliferation of other lung cancer-derived cell lines (PC-9, QG56, and EBC-1). These results suggest that tumor cells and astrocytes stimulate each other and these mutual relationships may be important to understand how lung cancer cells metastasize and develop in the brain. PMID- 20953901 TI - Sexual well-being: a comparison of U.S. black and white women in heterosexual relationships. AB - In the United States, considerable attention has been directed to sexual behaviors of black and white adolescents, particularly age at first sexual experience and the prevalence of teenage pregnancies. More limited attention has been paid to comparing established sexual relationships in these two racial groups. In this study, we used a national probability sample to compare black (n = 251) and white (n = 544) American women, aged 20-65 years, who were in an established heterosexual relationship of at least 6 months duration. We focused on two aspects of their sexual well-being; how a woman evaluated (1) her sexual relationship and (2) her own sexuality. A range of possible determinants of sexual well-being, including demographic factors, physical and mental health, and aspects of the women's recent sexual experiences, were also assessed using Telephone-Audio-Computer-Assisted Self-Interviewing (T-ACASI). We found no significant difference between black and white women in their evaluation of their sexual relationships nor in the independent variables that were correlated with this evaluation. Black women, however, evaluated their own sexuality more positively than white women. In examining the correlates of this evaluation, a woman's rating of her own sexual attractiveness proved to be the strongest predictor, with black women rating themselves significantly more sexually attractive than did the white women. Overall, these findings were consistent with previous findings that, compared to white women, black women in the United States have higher self-esteem and tend towards more independence and individualism. PMID- 20953900 TI - Spectrofluorimetric method for determination and validation of cefixime in pharmaceutical preparations through derivatization with 2-cyanoacetamide. AB - A simple, sensitive and accurate method has been developed for spectrofluorimetric determination of cefixime in pure form and pharmaceutical preparations. The method is based on the reaction of cefixime with 2 cyanoacetamide in the presence of 21% ammonia at 100 degrees C. The fluorescent reaction product showed maximum fluorescence intensity at lambda 378 nm after excitation at lambda 330 nm. The factors affecting the derivatization reaction were carefully studied and optimized. The fluorescence intensity versus concentration plot was rectilinear over the range of 0.02 to 4 MUg mL(-1) with correlation coefficient of 0.99036. The limit of detection (LOD) and limit of quantification (LOQ) was found to be 2.95 ng mL(-1) and 9.84 ng mL(-1), respectively. The proposed method was validated statistically and through recovery studies. The method was successfully applied for the determination of cefixime in pure and dosage form with percent recoveries from 98.117% to 100.38%. The results obtained from the proposed method have been compared with the official HPLC method and good agreement was found between them. PMID- 20953902 TI - Incorporating emotions specific to the sexual response into theories of emotion using the Indiana Sexual and Affective Word Set. AB - The sexual response includes an emotional component, but it is not clear whether this component is specific to sex and whether it is best explained by dimensional or discrete emotion theories. To determine whether the emotional component of the sexual response is distinct from other emotions, participants (n = 1099) rated 1450 sexual and non-sexual words according to dimensional theories of emotion (using scales of valence, arousal, and dominance) and according to theories of basic emotion (using scales of happiness, anger, sadness, fear, and disgust). In addition, ratings were provided for newly developed scales of sexual valence, arousal, and energy. A factor analysis produced four factors, together accounting for 91.5% of the variance in participant ratings. Using logistic regression analysis, we found that one word category or factor, labeled "sexual," was predicted only by the new sexual arousal and energy scales. The remaining three factors, labeled "disgusting," "happy," and "basic aversive" were best predicted by basic (or discrete) emotion ratings. Dimensional ratings of valence, sexual valence, and arousal were not predictive of any of the four categories. These results suggest that the addition of sexually specific emotions to basic emotion theories is justified and needed to account fully for emotional responses to sexual stimuli. In addition, the findings provide initial validation for the Indiana Sexual and Affective Words Set (ISAWS), supporting its use in future studies. PMID- 20953903 TI - Religious congregations' involvement in HIV: a case study approach. AB - Comparative case studies were used to explore religious congregations' HIV involvement, including types and extent of activities, interaction with external organizations or individuals, and how activities were initiated and have changed over time. The cases included 14 congregations in Los Angeles County representing diverse faith traditions and races-ethnicities. Activities fell into three broad categories: (1) prevention and education; (2) care and support; and (3) awareness and advocacy. Congregations that engaged early in the epidemic focused on care and support while those that became involved later focused on prevention and education. Most congregations interacted with external organizations or individuals to conduct their HIV activities, but promoting abstinence and teaching about condoms were conducted without external involvement. Opportunities exist for congregations to help address a variety of HIV-related needs. However, activities that are mission-congruent, such as providing pastoral care for people with HIV, raising HIV awareness, and promoting HIV testing, appear easier for congregations to undertake than activities aimed at harm reduction. PMID- 20953904 TI - Polycystic ovary syndrome increases the risk of endometrial cancer in women aged less than 50 years: an Australian case-control study. AB - OBJECTIVE: Although polycystic ovary syndrome (PCOS) is commonly cited as a risk factor for endometrial cancer, supporting epidemiological evidence is currently very limited. Our aim was to assess the associations between PCOS, PCOS symptoms, and risk of endometrial cancer in women aged less than 50 years. METHODS: Data came from a national population-based case-control study in Australia. Cases with newly diagnosed histologically confirmed endometrial cancer were identified through treatment clinics and cancer registries Australia wide. Controls were randomly selected from the national electoral roll. Women were interviewed about their reproductive and medical history, including self-reported PCOS, and lifestyle. Current analyses were restricted to women aged under 50 (156 cases, 398 controls). We estimated odds ratios (OR) using logistic regression to adjust for confounding factors. RESULTS: Women with PCOS had a fourfold increased risk of endometrial cancer compared to women without PCOS (OR 4.0, 95% CI 1.7-9.3). This association was attenuated when additionally adjusted for body mass index (OR 2.2, 95% CI 0.9-5.7). Risk was slightly greater when restricted to Type I cancers. PCOS symptoms including hirsutism and very irregular periods were significantly associated with endometrial cancer risk. CONCLUSIONS: These data extend existing findings, including adjustment for confounders, suggesting PCOS is a risk factor for endometrial cancer. PMID- 20953905 TI - LFA-1 gene polymorphisms are associated with the sporadic infiltrative duct breast carcinoma in Chinese Han women of Heilongjiang Province. AB - The infiltrative duct carcinoma (IDC) is the most common malignant breast cancer in females and genetic factors appear to play a significant role in the susceptibility of IDC. The LFA-1 is a crucial co-stimulatory molecule in immune system and may affect the development of breast IDC. In order to clarify the association of LFA-1 polymorphisms with IDC, a case-control study was conducted in women from Heilongjiang Province, Northeast of China. We scrutinized four genetic polymorphisms in LFA-1 gene, which may influence the activity and function of LFA-1. Our research subjects consist of 537 cases with IDC and 577 age-matched healthy controls. Genotypes were determined by PCR-RFLP. Data were analyzed using the chi(2) test by SPSS 13.0 and Haploview 4.1 softwares. The association between LFA-1 polymorphisms and the clinical features of IDC was analyzed. In rs2230433, the frequency of GG genotype and G allele was lower in cases than in controls (P = 0.0316 and 0.0480). And rs2230433, CG genotype was higher in cases (P = 0.0397). In rs8058823, the frequency of AA genotype and A allele was lower in cases than in controls (P = 0.00000418 and 0.00000267). And rs8058823, AG genotype was higher in cases (P = 0.00000747). The frequency of haplotype CCGA was lower in patients. Significant association was shown between the four SNPs of LFA-1 gene and estrogen receptor (ER), progesterone receptor (PR), C-erbB-2, and P53 statuses. In addition, no association was found between LFA-1 gene polymorphisms and tumor size, and neither was it between LFA-1 gene polymorphisms and lymph node metastasis. Our results primarily suggested that LFA 1 gene polymorphisms may predict the sporadic breast IDC risk and prognosis factors in Chinese Han women in Heilongjiang Province. PMID- 20953906 TI - Differential roles of phosphorylated AMPA receptor GluR1 subunits at Serine-831 and Serine-845 sites in spinal cord dorsal horn in a rat model of post-operative pain. AB - Previous studies have demonstrated that the enhanced levels of phosphorylated alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor GluR1 subunits at Serine-831 (pGluR1-Ser-831) and Serine-845 (pGluR1-Ser-845) in the spinal cord dorsal horn are involved in central sensitization of inflammatory pain. However, whether the phosphorylatory regulation of AMPA receptor GluR1 subunits is implicated in the development and maintenance of post-operative pain remains unclear. The current study aims to examine the functional regulation of AMPA receptor GluR1 subunit through its phosphorylation mechanism during the period of post-operative painful events in rats. Our data indicated that the expression of pGluR1-Ser-831 in ipsilateral spinal cord dorsal horn increased significantly at 3 h after incision, then decreased gradually, and returned to the normal level 3 day post-incision. Meanwhile, the expression of pGluR1-Ser-845 and GluR1 in ipsilateral spinal cord dorsal horn remained unchanged. The cumulative pain scores increased at 3 h after incision, gradually decreased afterwards and returned to the baseline values at 4 day after incision and the trend was almost parallel to the expression changes of pGluR1-Ser-831 in spinal dorsal horn. Intrathecal injection of a calcium-dependent protein kinase (PKC) inhibitor, Go6983 (10 MUM), significantly reversed the incision-mediated over expression of pGluR1-Ser-831 in spinal dorsal horn at 3 h after incision and decreased the cumulative pain scores as well. These results indicate that the phosphorylation of GluR1 subunits at Serine-831 and Serine-845 sites might be differentially regulated following surgical procedures and support a neurobiological mechanism of post-operative pain involved in phosphorylation of AMPA subunits GluR1-Ser-831, but not pGluR1-Ser-845. Our study suggests that the therapeutic targeting the phosphorylation regulation of AMPA receptor GluR1 subunit at Serine-831 site would be potentially significant for treating postoperative pain. PMID- 20953907 TI - Comparison of the quality of life between patients with non-small-cell lung cancer and healthy controls. AB - PURPOSE: We explored covariates of the quality of life (QOL) in non-small-cell lung cancer (NSCLC) patients and made a comparison with healthy controls. METHODS: We assessed the QOL of 220 consecutive NSCLC patients at a university hospital. The QOL data were measured by the brief version of the World Health Organization's Quality of Life and by utility using the standard gamble method. We selected demographically matched healthy controls from the 2001 National Health Interview Survey for comparison. Multiple linear regression models were constructed to explore significant factors of QOL after controlling for covariates. RESULTS: Patients with more advanced stages of NSCLC had poorer scores than did the healthy controls in the physical and psychological domains. Patients with disease duration of longer than 1 year tended to report higher physical and environment QOL than did those with NSCLC diagnosed for less than 1 year. Insight into one's own illness was associated with a higher utility, better social support, and improved financial resources. CONCLUSIONS: QOL was significantly associated with staging and duration of NSCLC. Disease insight appears to be a positive factor for operable NSCLC patients of the Taiwanese culture, which implies that clinicians should respect patient autonomy in diagnosis disclosure. PMID- 20953910 TI - Prospective evaluation of laparoscopic celiac plexus block in patients with unresectable pancreatic adenocarcinoma. AB - INTRODUCTION: The efficacy of laparoscopic celiac plexus block (CPB) in patients with unresectable pancreatic cancer has not been reported. METHODS: Patients with elevated pain scores scheduled for laparoscopy for diagnosis/staging of unresectable pancreatic adenocarcinoma were eligible. The study was designed to evaluate 20 consecutive patients with validated quality of life (EORTC QLQ-C30, QLQ-PAN26) and validated pain assessment tools [Brief Pain Inventory (BPI)]. Questionnaires were obtained preoperatively, and postoperatively at 1, 4, and 8 weeks. Laparoscopic CPB was performed by bilateral injection of 20 cc 50% alcohol utilizing a recently described laparoscopic technique. Functional and symptom scoring was performed by EORTC scoring manual. RESULTS: Median age was 61 years (range 42-80 years), and mean preoperative pain score [worst in 24 h on 0-10 visual analogue scale (VAS)] was 7.8 [standard deviation (SD) 1.6]. Median total operative time (laparoscopy + biopsy + CBP) was 57 min (range 29-92 min), and all patients except one were discharged on day of surgery. No major complications occurred. EORTC functional scales did not change significantly during the postoperative period. EORTC symptomatic pain scores decreased significantly. These findings were also observed in the BPI, with significant decreases in visual analogue score for reported mean (preoperative versus week 4, mean: 5.7 versus 2.7; p < 0.01) and worst (preoperative versus week 4, mean: 7.8 versus 5.1; p < 0.01) pain during a 24-h period. CONCLUSIONS: This study documents the efficacy of laparoscopic CPB. The procedure was associated with minimal morbidity, brief operative times, outpatient management, and reduction in pain scores similar to that reported with other approaches to celiac neurolysis. PMID- 20953911 TI - An effective automatic procedure for testing parameter identifiability of HIV/AIDS models. AB - Realistic HIV models tend to be rather complex and many recent models proposed in the literature could not yet be analyzed by traditional identifiability testing techniques. In this paper, we check a priori global identifiability of some of these nonlinear HIV models taken from the recent literature, by using a differential algebra algorithm based on previous work of the author. The algorithm is implemented in a software tool, called DAISY (Differential Algebra for Identifiability of SYstems), which has been recently released (DAISY is freely available on the web site http://www.dei.unipd.it/~pia/ ). The software can be used to automatically check global identifiability of (linear and) nonlinear models described by polynomial or rational differential equations, thus providing a general and reliable tool to test global identifiability of several HIV models proposed in the literature. It can be used by researchers with a minimum of mathematical background. PMID- 20953912 TI - Gastrointestinal stromal tumor of the rectum with bone and liver metastasis: a case study. AB - Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract and may arise from any part of the gastrointestinal system. However, it is most frequently observed in the stomach (60%) and small intestines (30%). GIST is observed at a rate of 4% in the rectum. Distant metastases of GIST are rare, and the liver is the most common site of metastasis. This case is presented because of the rare incidence of bone metastasis to the femur head. PMID- 20953908 TI - I'm so tired: biological and genetic mechanisms of cancer-related fatigue. AB - OBJECTIVE: The goal of this paper is to discuss cancer-related fatigue (CRF) and address issues related to the investigation into potential biological and genetic causal mechanisms. The objectives are to: (1) describe CRF as a component of quality of life (QOL); (2) address measurement issues that have slowed progress toward an understanding of mechanisms underlying this symptom; (3) review biological pathways and genetic approaches that have promise for the exploration of causal mechanisms of CRF; and (4) offer directions for future research. METHODS: Review, synthesis, and interpretation of the literature. RESULTS: Until recently, CRF and QOL have been understood primarily as subjective patient reported experiences. With increased understanding of human genetics, theories and research are being expanded to incorporate biological and genetic understandings of these subjective experiences. Proposed biological and genetic mechanisms of CRF that have been examined include cytokine dysregulation, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, five hydroxy tryptophan (5 HT) neurotransmitter dysregulation, circadian rhythm disruption, alterations in adenosine triphosphate (ATP) and muscle metabolism, and vagal afferent activation. Approaches to the study of genetic mechanisms have also been addressed including candidate genes, genome-wide scanning, and gene expression. Based on the review and synthesis of the literature, directions for future research are proposed. CONCLUSIONS: Understanding the biological and genetic basis of CRF has the potential to contribute to a more complete understanding of the genetic determinants of QOL. PMID- 20953913 TI - Aetiology and antimicrobial resistance of neonatal sepsis at a tertiary care centre in eastern India: a 3 year study. AB - OBJECTIVE: To review aetiological agents of neonatal sepsis and their antibiotic resistance pattern over the past 3 years, at a 20 bedded Level III neonatal intensive care unit (NICU) in eastern India. METHODS: Blood culture reports of culture positive sepsis were reviewed for the period 2007-2009. Demographic data of the babies was collected. RESULTS: Blood culture was done for 997 neonates with suspected clinical sepsis. The incidence of culture proven neonatal sepsis among inborn babies was 14.8/1,000 live births. The proportion of culture positive sepsis for outborn babies admitted in neonatal intensive care unit was 8.3%. Gram negative aetiology was predominant (71.6%), with Klebsiella pneumoniae being the most common isolate. Non fermenting Gram negative bacilli like Acinetobacter sp emerged as an important cause of infection. The aetiology of early onset and late onset sepsis was similar. The proportion of resistance to common first and second line antibiotics like ampicillin (98.5%), gentamicin (84.4%), amikacin (65.6%) and cefotaxime (81.3%) was high. CONCLUSIONS: The present study is the first in recent years from eastern India on aetiology and antimicrobial resistance in neonatal sepsis. Two areas of concern were the emergence of non fermenting Gram negative bacilli as causative organisms and the alarming degree of antibiotic resistance observed for commonly used antibiotics. PMID- 20953914 TI - PHACE/S syndrome: a syndromic infantile segmental hemangioma. AB - PHACES syndrome is a neurocutaneous disorder characterized by posterior fossa brain malformations, hemangiomas, cardiac anomalies and coarctation of aorta, eye anomalies +/- sternal clefts. All reported cases are sporadic and notably common in females. The underlying cause is unknown. Here is described, one of the twin baby with characteristic features of PHACE syndrome. The presence of large segmental hemangioma, especially on face should prompt the primary care provider to act early, to prevent complications related to facial hemangiomas and other associated anomalies. PMID- 20953915 TI - Efficacy of pretreatment of allografts with methoxypolyethylene glycol succinimidyl-propionic acid ester in combination with an anti-OX40L monoclonal antibody in relieving graft-versus-host disease in mice. AB - We designed to determine whether pretreatment of allografts with methoxypolyethylene glycol-succinimidyl-propionic acid ester (mPEG-SPA) and an anti-OX40L monoclonal antibody (McAb) can relieve acute graft-versus-host disease in allogeneic bone marrow transplantation recipients. Responder splenocytes from C57BL/6 donor mice were incubated with stimulator splenocytes from BALB/c recipient mice for 7 days in the presence or absence of anti-OX40L McAb followed by mPEG-SPA modification. Donor BM cells plus mixed culture T cells were then transplanted into myeloablatively irradiated BALB/c mice. The signs of GVHD were less evident in mice of groups B (mPEG-SPA modification group), C (anti-OX40L McAb pretreated group) and D (dual-treated group), with average survival durations all longer than those in group A (non-treated BMT group) (P < 0.05). The survival rates on day 60 post-BMT in groups B, C and D were 50, 41.7 and 66.7%, respectively. After BMT, serum IL-4 and IL-10 levels elevated in groups B, C (P < 0.05) and even more significantly increased in group D (P < 0.01), while serum IFN-gamma levels decreased in these three groups (P < 0.01). In conclusion, the combination of mPEG-SPA and anti-OX40L McAb can block T cell-activated antigens, co-stimulatory pathways and induce the immune shift of Th cells toward Th2 cells; their effects in ameliorating GVHD are synergistic. PMID- 20953916 TI - The relevance of fatalism in the study of Latinas' cancer screening behavior: a systematic review of the literature. AB - BACKGROUND: Fatalism has been identified as a dominant belief among Latinos and is believed to act as a barrier to cancer prevention. However, controversy exists over the utility of the construct in explaining health disparities experienced by disadvantaged populations above the influence of structural barriers such as low socioeconomic status (SES) and limited access to health care. PURPOSE: This paper reviews the empirical research on fatalism and Latinas' participation in cancer screening in an attempt to determine whether fatalism predicts participation in cancer screening after accounting for structural barriers. METHOD: Google Scholar, ERIC, CINAHL, Medline, PsychINFO, ProQuest, PubMed, and PsychARTICLES were searched for empirical studies published prior to February 25, 2010. RESULTS: A total of 43 articles were obtained and 11 met the inclusion criteria. The majority of studies (64%) reported a statistically significant association between fatalism and utilization of cancer screening services after accounting for structural barriers. However, mixed findings and limitations in measurement and design across studies preclude clear conclusions about the nature of the relationship. CONCLUSION: Preliminary evidence for an inverse association between fatalism and Latinas' utilization of cancer screening services after accounting for structural barriers was identified. However, additional research that addresses methodological limitations is warranted to advance our understanding of the utility of fatalism in explaining inequities in cancer burden experienced by this at-risk group. PMID- 20953919 TI - Changes to the manuscript review system and page format. PMID- 20953917 TI - Methamphetamine causes persistent immune dysregulation: a cross-species, translational report. AB - Methamphetamine (MA) dependence causes serious cognitive impairments that can persist during abstinence and negatively affect recovery outcomes. Evidence suggests that immune factors, such as cytokines, chemokines, and cellular adhesion molecules, contribute to MA-induced immune dysfunction, neuronal injury, and persistent cognitive impairments, yet the role of MA-induced brain inflammation remains unclear. To address this question, we used a cross-species, translational approach. Thirty-two male C57BL/6J mice were administered MA (1 mg/kg) or saline subcutaneously for seven consecutive days. Mice were euthanized at 72 h or 3 weeks after the last drug dose, and blood and brain samples were collected. In addition, 20 adults in remission from MA dependence and 20 non dependent controls completed neuropsychological assessments and a blood draw. Multiplex assays were used to measure cytokine, chemokine, and intercellular adhesion molecule (ICAM-1) expression in mouse and human samples. A number of significant MA-induced changes in neuroimmune factors were observed. Of particular interest were the chemokine monocyte chemoattractant protein 1 (MCP-1) and the cellular adhesion molecule ICAM-1, which were similarly increased in the plasma of MA exposed mice as well as humans. In human participants, MA-induced changes in the cytokine and chemokine milieu were accompanied by increased cognitive impairments. Mice showing MA-induced changes in peripheral immune molecule expression also had significant brain-region specific changes in pro inflammatory cytokines, chemokines, and ICAM-1. This cross-species, translational study suggests that chronic CNS immune dysregulation may in part contribute to the longlasting neuropsychiatric consequences of MA dependence. PMID- 20953920 TI - Orthopedic research in the final year of the Bone and Joint Decade. PMID- 20953921 TI - Results of terrible triads in the elbow: the advantage of primary restoration of medial structure. AB - BACKGROUND: The purpose of this study was to report the clinical and radiological outcomes and surgical strategy for terrible triad injury of the elbow. We hypothesized that the outcomes of this type of injury would be satisfactory if the medial structure was routinely restored at the same time as the repair of the lateral structure. METHODS: We retrospectively reviewed the results of this treatment performed in 13 elbows with terrible triads. Our surgical protocol included fixation or replacement of the radial head and repair of the ruptured lateral ulnar collateral ligament through the lateral traumatic window. In all cases, simultaneous fixation of the coronoid and repair of the common flexor muscle were performed through the medial traumatic window. In eight patients with medial collateral ligament injury, the ligament was always repaired. The follow up period ranged from 18 to 41 months (mean, 25 months). RESULTS: The flexion extension arc of the elbow averaged 128 degrees and forearm rotation averaged 134.6 degrees . The mean Mayo elbow performance score was 95 points (range, 85 to 100), which corresponded to ten excellent results, and three good results. Concentric stability was restored to all cases. As postoperative complications, one patient had ulnar nerve neuropathy. CONCLUSIONS: The present operative procedures restoring all damaged lateral and medial structures through the lateral and the medial windows provided satisfactory clinical and radiological outcomes and are recommended for patients with terrible triad injury. PMID- 20953922 TI - Joint space wider than 2 mm is essential for an eccentric rotational acetabular osteotomy for adult hip dysplasia. AB - BACKGROUND: Satisfactory intermediate-term results after an eccentric rotational acetabular osteotomy (ERAO) for the treatment of early osteoarthritis secondary to developmental dysplasia of the hip (DDH) have been reported. The purpose of this study was to investigate whether a minimum joint space width (JSW) in patients with advanced osteoarthritis secondary to DDH influences intermediate term clinical and radiographic outcomes after performing an ERAO. METHODS: A total of 113 patients (116 hips) with a JSW of <=3 mm were consecutively treated by ERAO for advanced osteoarthritis of the hip and then were followed for more than 5 years. Based on the preoperative JSW, the patients were divided into three groups: minimum JSW of <=1 mm (JS1 group); JSW >1 mm but <=2 mm (JS2 group); JSW > 2 mm but <=3 mm (JS3 group). The average ages of the JS1, JS2, and JS3 patients were 40, 44, and 43 years, respectively. The average follow-up period was 10.6 years. RESULTS: Overall conversion to total hip arthroplasty (THA) was performed in 14 joints. According to a Kaplan-Meier survivorship analysis at 15 years after the index operation, 96% of the patients with a JSW of >2 mm (JS3 group) did not require conversion to THA. CONCLUSIONS: A JSW of >2 mm before surgery is considered essential to obtain an excellent intermediate-term result following performance of an ERAO. PMID- 20953923 TI - Multiinstitutional epidemiological study regarding osteoarthritis of the hip in Japan. PMID- 20953924 TI - Effect of periacetabular osteotomy for acetabular dysplasia clarified by three dimensional finite element analysis. AB - BACKGROUND: Finite element analysis (FEA) has been applied for the biomechanical analysis of acetabular dysplasia, but not for biomechanical studies of periacetabular osteotomy (PAO) or those performing analysis taking into consideration the severity of acetabular dysplasia. This study aimed to perform biomechanical evaluation of changes in stress distribution following PAO and to determine the effect of the severity of developmental dysplasia of the hip (DDH) using three-dimensional FEA. METHODS: A normal model was designed with a 25 degrees center-edge (CE) angle and a 25 degrees vertical-center-anterior margin (VCA) angle. DDH models were designed with CE and VCA angles each of 10, 0, or 10 degrees . Post-PAO models were created by separating each DDH model and rotating the acetabular bone fragment in the anterolateral direction so that the femoral head was covered by the acetabular bone fragment, with CE and VCA angles each at 25 degrees . RESULTS: Compared to the normal hip joint model, the DDH models showed stress concentration in the acetabular edge and contacting femoral head, and higher stress values; stress increased with decreasing CE and VCA angles. Compared to the DDH models, the post-PAO models showed near-normal patterns of stress distribution in the acetabulum and femoral head, with stress concentration areas shifted from the lateral to medial sides. Stress dispersion was especially apparent in the severe acetabular dysplasia models. PAO provided greater decreases in the maximum values of von Mises stress in the load-bearing area of the acetabulum and femoral head when applied to the DDH models of higher degrees of severity, although the values increased with increasing severity of DDH. CONCLUSIONS: PAO is expected to provide biomechanical improvement of the hip joint and to be particularly effective in patients with severe preoperative DDH, although the results also suggested a limitation in the applicability of PAO for these patients. PMID- 20953925 TI - A longitudinal study of the relationship between the status of bone marrow abnormalities and progression of knee osteoarthritis. AB - BACKGROUND: Bone marrow abnormalities (BMAs) detected on magnetic resonance imaging (MRI) are suggested to be involved in the pathogenesis of osteoarthritis (OA), and the size of the BMAs is associated with the progression of OA. However, it still remains unclear as to whether the associations of BMA size and OA severity are observed equally or whether they differ from early to advanced stages of OA. In the present study we examined whether BMA enlargement and OA progression differed according to the severity of OA. METHODS: One hundred and eighty patients with knee OA were enrolled in the present study, and 122 of these patients completed this study. Radiography and knee MRI were done two times in all patients, at the baseline and 6 months or later at the time of patient follow up. The severity of OA was evaluated by radiography using the Kellgren-Lawrence (K-L) grade. The patients who showed a deterioration in the K-L grade during the follow-up examination (59/122) were defined as the deterioration group. T2 weighted fat-suppressed MR images were used to score the size of the BMAs according to the whole-organ magnetic resonance imaging score (WORMS). A new scoring system, the spacial BMA score (s-score) was defined to assess the size of the BMAs three-dimensionally. RESULTS: In patients with K-L grade 2, the s-score changes during the follow-up period in the deterioration group were significantly increased in comparison to those in the no-change group (P = 0.04), and no significant s-score changes were observed in patients with either K-L grade 1 or 3 (P = 0.07 and 0.57) between the deterioration group and the no-change group during the follow-up examination. In patients with K-L grade 3, the s-score at the baseline in the deterioration group was higher than that in the no-change group (P = 0.05). CONCLUSIONS: The relationship between the size and enlargement of BMAs and the progression of OA changed depending upon the severity of OA. PMID- 20953926 TI - Preoperative botulinum toxin test injections before muscle lengthening in cerebral palsy. AB - BACKGROUND: Muscle weakening is a well-known side effect of muscle-tendon lengthening. Botulinum toxin A (BTX-A) weakens the muscle temporarily by blocking the neuromuscular junction. Hence application of the drug is a logical step to test whether weakness deteriorates function prior to an operation. In the present study, BTX-A application is used to test preoperatively whether the gait pattern depends on the strength of the tested muscle. Since 1999, instrumented gait analysis, including kinematic, kinetic, and dynamic electromyographic data, is routinely used to define the individual surgical program. METHODS: In our series of 110 consecutive patients with cerebral palsy (CP) considered for surgical muscle lengthening from 1999 to 2008, BTX-A was applied to identify patients at risk for functional deterioration. Gait analysis was repeated 6 weeks (maximum effect of BTX-A) and 12 weeks (follow-up) after the test injection to check for loss of joint control (excessive ankle dorsiflexion, knee flexion, increased anterior pelvic tilt). RESULTS: In all, 20.9% (n = 23) showed deterioration in gait after preoperative BTX-A test injections (n = 112, two patients had two test trials) in all muscles considered for lengthening. As a consequence, their lengthening surgery was canceled. A total of 68 patients underwent surgery as planned, and in none of them did gait function deteriorate. These clinical data were compared to those of a historical group (n = 105) before this test, where 18% showed functional deterioration after surgery. The similar percentage of patients filtered out by the test suggests that there could be a context to the number of poor results in the historical group. CONCLUSIONS: We conclude that preoperative BTX-A test injection is a reliable tool for filtering out patients with risk of deterioration after muscle lengthening surgery in patients with CP and can be helpful to avoid poor outcomes. PMID- 20953927 TI - Multicenter phase II trial assessing effectiveness of imatinib mesylate on relapsed or refractory KIT-positive or PDGFR-positive sarcoma. AB - BACKGROUND: Imatinib myselate is a molecularly targeted drug that inhibits Abl tyrosine kinase, as well as type III tyrosine kinase receptors such as platelet derived growth factor receptor (PDGFR), KIT, colony-stimulating factor 1 receptor (CSF-1R), and discoidin domain receptor (DDR). Ph1 chromosome-positive chronic myeloid leukemias (CMLs), KIT-positive gastrointestinal stromal tumors (GISTs), and PDGFR-positive dermatofibrosarcoma protuberans (DFSP) have been reported to be responsive to imatinib treatment. We conducted a multicenter Phase II trial of imatinib in patients with relapsed or refractory KIT-positive (excluding GISTs) or PDGFR-positive sarcomas. METHODS: Patient ages ranged from 12 and 75 years. Eligibility criteria included (1) metastatic sarcomas with a definitive diagnosis based on histopathology or that were completely unresectable and locally advanced; (2) relapsed or refractory cases that had completed standard treatment; and (3) a tumor confirmed by immunohistochemical staining to be KIT- or PDGFR positive. A 600-mg dose of imatinib was administered to patients once a day, with each patient receiving six courses of the drug and each course lasting 4 weeks. In cases categorized as stable or progressive, the imatinib dose was increased to 800 mg/day administered twice daily. RESULTS: A total of 25 patients who met the eligibility criteria were enrolled in the trial; 22 were evaluated for response. The response rate with a 600 mg/day dose of imatinib was 4.5% (0 complete response, 1 partial response). There were no other objective responses after increasing imatinib to 800 mg/day (0/10). We estimated 50% progression-free survival to be 61.0 days for an imatinib dose of 600 mg/day based on the Kaplan Meier method. Side effects of imatinib were generally similar to those observed in previous clinical trials. CONCLUSIONS: Our results did not indicate effectiveness of imatinib monotherapy at a dose of 600 or 800 mg/day in patients with relapsed or refractory KIT-positive (excluding GISTs) or PDGFR-positive sarcomas. Our findings suggest the need to evaluate the synergistic effect of combination therapy with other anticancer drugs. PMID- 20953928 TI - Noninvasive up-regulation of angiopoietin-2 and fibroblast growth factor-2 in bone marrow by pulsed electromagnetic field therapy. AB - BACKGROUND: Pulsed electromagnetic field (PEMF) therapy has been widely used in clinical practice for bone fracture healing. However, the mechanism of its action remains to be elucidated. Our object was to investigate the mechanism by which PEMF accelerates bone fracture healing. METHODS: We used 20 mice in this study. Ten mice received PEMF for 10 h/day for 1 week via the coils of a PEMF stimulation device (PEMF group), while the remaining 10 mice did not (control group). The femurs were harvested immediately after euthanasia to examine the proteins included in the bone marrow. The proteins examined by Western blotting were growth factors with angiogenetic activities, including tunica interna endothelial cell kinase-2, angiopoietin-1, angiopoietin-2, fibroblast growth factor-2, and vascular endothelial growth factor. The expression levels of angiogenesis-related proteins extracted from the bone marrow of each mouse were compared. RESULTS: The expression levels of angiopoietin-2 and fibroblast growth factor-2 were significantly higher in the PEMF group than in the control group. This difference suggests that PEMF may induce an angiogenesis-prone environment in the bone marrow. Such angiogenesis acceleration represents one possible mechanism for the acceleration of bone fracture healing by PEMF. There were no significant differences between the two groups for the expression levels of tunica interna endothelial cell kinase-2, angiopoietin-1, and vascular endothelial growth factor. The lack of increase in tunica interna endothelial cell kinase-2 expression may indicate that PEMF does not unnecessarily increase blood vessels in normal bone marrow. The lack of an increase in the expression level of vascular endothelial growth factor suggests that PEMF does not have invasive effects including the induction of hypoxic conditions and inflammation on the bone marrow. CONCLUSION: The angiogenesis-promoting function of PEMF may contribute to its mechanism to noninvasively accelerate bone fracture healing. PMID- 20953929 TI - Distribution and role of tenascin-C in human osteoarthritic cartilage. AB - BACKGROUND: Tenascin-C (TN-C) is expressed in the cartilage of osteoarthritis (OA). We examined whether TN-C was involved in cartilage repair of the diseased joints. Human articular cartilage samples were obtained from patients with OA and those with normal joints. METHODS: Immunohistochemistry testing of TN-C, chondroitin sulfate (CS), and proliferating cell nuclear antigen (PCNA) was performed. Chondrocytes were isolated from human cartilage and cultured. After treatment with TN-C, chondrocyte proliferation s was analyzed by bromodeoxyuridine (BrdU) incorporation assay using an enzyme-linked immunosorbent assay kit. Glycosaminoglycan content was determined by dimethylmethylene blue (DMMB) assay. The mRNA expression of aggrecan was also analyzed, by quantitative real-time polymerase chain reaction (PCR). RESULTS: In osteoarthritic cartilage, increased TN-C staining was observed with the degeneration of articular cartilage in comparison with normal cartilage. TN-C staining was shown in the cartilage surface overlying CS-positive areas. In addition, the expression of PCNA in the positive areas for TN-C was significantly higher than that in the negative areas. Treatment of human articular chondrocytes with 10 MUg/ml TN-C accelerated chondrocyte proliferation, increased the proteoglycan amount in culture, and increased the expression of aggrecan mRNA. CONCLUSIONS: Our findings indicate that the distribution of TN-C is related to CS production and chondrocyte proliferation in osteoarthritic cartilage and that TN-C has effects on DNA synthesis, proteoglycan content, and aggrecan mRNA expression in vitro. TN-C may be responsible for repair in human osteoarthritic cartilage. PMID- 20953930 TI - Prevention of steroid-induced osteonecrosis by intravenous administration of vitamin E in a rabbit model. AB - BACKGROUND: We focused on vitamins with marked antioxidant potency to see whether their use might prevent the development of steroid-induced osteonecrosis. METHODS: Fifteen Japanese white rabbits weighing about 3.5 kg were injected once into the right gluteal muscle with methylpred-nisolone (MPSL) 40 mg/kg (S group). In addition, 10 other rabbits received consecutive daily intravenous injections of vitamin E 50 mg/kg, starting from the day of MPSL administration (E group). All animals were killed 2 weeks after MPSL administration, and femurs were extracted and stained with H&E. Blood levels of reduced glutathione (GSH) were also measured. RESULTS: In the S group the osteonecrosis development rate was 93%, in contrast to 0% in the E group (P < 0.01). Also, GSH levels in the S group abruptly decreased from the first day after MPSL administration, whereas in the E group, the decline in GSH levels was significantly suppressed on days 1 and 3 after MPSL administration (P< 0.05). CONCLUSIONS: Vitamin E administration significantly inhibited steroid-induced oxidative stress. The results of this study suggest that the administration of vitamin E may be a novel and simple method to prevent the development of steroid-induced osteonecrosis. PMID- 20953931 TI - Insufficiency fractures of bilateral distal tibias associated with chronic liver disease. PMID- 20953932 TI - Voiding dysfunction caused by an intrapelvic synovial cyst that resulted from a screw misplaced when fixing the metal cup during total hip arthroplasty. PMID- 20953933 TI - Osteochondral flap fracture of the olecranon with subluxation of the elbow in a child. PMID- 20953934 TI - Allogeneic and autologous stem cell transplantation in advanced small round cell sarcomas. PMID- 20953935 TI - Technique to secure loose anchors during rotator cuff repair. PMID- 20953936 TI - Temporary hemiepiphysiodesis with the eight-Plate for angular deformities: mid term results. AB - BACKGROUND: Angular deformities can be treated with corrective osteotomies and application of internal or external fixation. In children, this major intervention can be avoided with temporary hemiepiphysiodesis (i.e., guided growth). Recently, a new device called the eight-Plate Guided Growth System, consisting of a two-hole plate and two screws, was presented as an alternative to the widely used Blount staple to perform temporary hemiepiphysiodesis in children. METHODS: Forty-three patients (54 physes, 51 limbs) underwent treatment between August 2004 and December 2005 with average follow-up after plate insertion of 2 years 2 months (range, 1 year 6 months to 2 years 6 months). Rate of correction and reversibility of this intervention were calculated. RESULTS: Average age at eight-Plate implantation was 9 years 7 months (age range, 4 years 0 months to 14 years 3 months). eight-Plates were inserted for an average 14.2 months (range, 5.0-27.4 months). No growth disturbance was observed. Mechanical lateral distal femoral angle changed an average 10.00 degrees (range, 1-18 degrees) or 0.65 degrees/month (range, 0.05-1.22 degrees/month). Medial proximal tibial angle changed an average 7.78 degrees (range, 0-14 degrees) or 0.58 degrees/month (range, 0.13-1.67 degrees/month). In the two distal tibial cases, lateral distal tibial angle improved 6 degrees and 10 degrees (average change, 0.44 degrees/month). Mechanical axis deviation improved an average 25.4 mm (range, 0-74 mm) or 1.73 mm/month (range, 0-6.4 mm/month). Ten patients (13 limbs) had more than 10 months of radiographic follow-up after plate removal; ten limbs showed average rebound of 15.7 mm or 1.0 mm/month, indicating the reversibility of this procedure. Four cases failed to achieve correction. CONCLUSIONS: The eight-Plate effectively treats angular deformities in growing children and is less likely to extrude spontaneously than the Blount staple. We have not observed growth disturbance or other complications related to this device. PMID- 20953937 TI - Ascomycota has a faster evolutionary rate and higher species diversity than Basidiomycota. AB - Differences in rates of nucleotide or amino acid substitutions among major groups of organisms are repeatedly found and well documented. A growing body of evidence suggests a link between the rate of neutral molecular change within populations and the evolution of species diversity. More than 98% of terrestrial fungi belong to the phyla Ascomycota or Basidiomycota. The former is considerably richer in number of species than the latter. We obtained DNA sequences of 21 protein-coding genes from the lichenized fungus Rhizoplaca chrysoleuca and used them together with sequences from GenBank for subsequent analyses. Three datasets were used to test rate discrepancies between Ascomycota and Basidiomycota and that within Ascomycota: (i) 13 taxa including 105 protein-coding genes, (ii) nine taxa including 21 protein-coding genes, and (iii) nuclear LSU rDNA of 299 fungal species. Based on analyses of the 105 protein-coding genes and nuclear LSU rDNA datasets, we found that the evolutionary rate was higher in Ascomycota than in Basidiomycota. The differences in substitution rates between Ascomycota and Basidiomycota were significant. Within Ascomycota, the species-rich Sordariomycetes has the fastest evolutionary rate, while Leotiomycetes has the slowest. Our results indicate that the main contribution to the higher substitution rates in Ascomycota does not come from mutualism, ecological conditions, sterility, metabolic rate or shorter generation time, but is possibly caused by the founder effect. This is another example of the correlation between species number and evolutionary rates, which is consistent with the hypothesis that the founder effect is responsible for accelerated substitution rates in diverse clades. PMID- 20953938 TI - New functional sites in MutS affect DNA mismatch repair. AB - The MutS protein plays an important role in the DNA mismatch repair system. Mutations in the mutS gene can lead to genome instability and ultimately cell malfunction. Here we have established a method for identifying functional defective mutants of MutS by random mutation and rifampicin screening. Some novel functional sites in MutS were identified. The MutS mutant strains were analyzed using surface plasmon resonance, gel filtration and far-western methods to determine the molecular mechanisms behind the DNA mismatch repair function of MutS. PMID- 20953939 TI - Marek's disease virus-encoded microRNAs: genomics, expression and function. AB - MicroRNAs (miRNAs) are the recently discovered small non-coding RNA molecules that have post-transcriptional regulatory functions in many important biological processes. A large number of miRNAs have been found to be encoded by viral genomes, especially in herpesviruses. Previous research regarding miRNAs encoded by herpesviruses, including Marek's disease virus (MDV), has demonstrated their involvement in lytic replication, latent infection, T-lymphocyte transformation and tumorigenesis. MDV is an oncogenic alphaherpesvirus, with the ability to induce tumors in natural hosts; however, formation of these tumors can be prevented by immunization with attenuated or nonpathogenic forms of the virus. Marek's disease is considered to be a good biomedical model for investigating the biology, genetics, and immunology of tumorigenesis. In this paper, we review the discovery and identification of MDV-encoded miRNAs, along with their genomics, expression profiles, and currently known functions. We also discuss the prospects and techniques possibly applicable to the further investigation of the biological roles of MDV-encoded miRNAs. PMID- 20953940 TI - Structural characteristics of the hydrophobic patch of azurin and its interaction with p53: a site-directed spin labeling study. AB - Site-directed spin labeling (SDSL) is a powerful tool for monitoring protein structure, dynamics and conformational changes. In this study, the domain specific properties of azurin and its interaction with p53 were studied using this technique. Mutations of six residues, that are located in the hydrophobic patch of azurin, were prepared and spin labeled. Spectra of the six azurin mutants in solution showed that spin labeled residues 45 and 63 are in a very restricted environment, residues 59 and 65 are in a spacious environment and have free movement, and residues 49 and 51 are located in a relatively closed pocket. Polarity experiments confirmed these results. The changes observed in the spectra of spin labeled azurin upon interaction with p53 indicate that the hydrophobic patch is involved in this interaction. Our results provide valuable insight into the topographic structure of the hydrophobic domain of azurin, as well as direct evidence of its interaction with p53 in solution via the hydrophobic patch. Cytotoxicity studies of azurin mutants showed that residues along the hydrophobic patch are important for its cytotoxicity. PMID- 20953941 TI - Detecting CD20-rituximab specific interactions on lymphoma cells using atomic force microscopy. AB - Elucidating the underlying mechanisms of cell physiology is currently an important research topic in life sciences. Atomic force microscopy methods can be used to investigate these molecular mechanisms. In this study, single-molecule force spectroscopy was used to explore the specific recognition between the CD20 antigen and anti-CD20 antibody Rituximab on B lymphoma cells under near physiological conditions. The CD20-Rituximab specific binding force was measured through tip functionalization. Distribution of CD20 on the B lymphoma cells was visualized three-dimensionally. In addition, the relationship between the intramolecular force and the molecular extension of the CD20-Rituximab complex was analyzed under an external force. These results facilitate further investigation of the mechanism of Rituximab's anti-cancer effect. PMID- 20953942 TI - Cell-death-mode switch from necrosis to apoptosis in hydrogen peroxide treated macrophages. AB - Cell death is typically defined either as apoptosis or necrosis. Because the consequences of apoptosis and necrosis are quite different for an entire organism, the investigation of the cell-death-mode switch has considerable clinical significance. The existence of a necrosis-to-apoptosis switch induced by hydrogen peroxide in macrophage cell line RAW 264.7 cells was confirmed by using flow cytometry and fluorescence microscopy. With the help of computational simulations, this study predicted that negative feedbacks between NF-kappaB and MAPKs are implicated in converting necrosis into apoptosis in macrophages exposed to hydrogen peroxide, which has significant implications. PMID- 20953943 TI - Complex positive selection pressures drive the evolution of HIV-1 with different co-receptor tropisms. AB - HIV-1 co-receptor tropism is central for understanding the transmission and pathogenesis of HIV-1 infection. We performed a genome-wide comparison between the adaptive evolution of R5 and X4 variants from HIV-1 subtypes B and C. The results showed that R5 and X4 variants experienced differential evolutionary patterns and different HIV-1 genes encountered various positive selection pressures, suggesting that complex selection pressures are driving HIV-1 evolution. Compared with other hypervariable regions of Gp120, significantly more positively selected sites were detected in the V3 region of subtype B X4 variants, V2 region of subtype B R5 variants, and V1 and V4 regions of subtype C X4 variants, indicating an association of positive selection with co-receptor recognition/binding. Intriguingly, a significantly higher proportion (33.3% and 55.6%, P<0.05) of positively selected sites were identified in the C3 region than other conserved regions of Gp120 in all the analyzed HIV-1 variants, indicating that the C3 region might be more important to HIV-1 adaptation than previously thought. Approximately half of the positively selected sites identified in the env gene were identical between R5 and X4 variants. There were three common positively selected sites (96, 113 and 281) identified in Gp41 of all X4 and R5 variants from subtypes B and C. These sites might not only suggest a functional importance in viral survival and adaptation, but also imply a potential cross immunogenicity between HIV-1 R5 and X4 variants, which has important implications for AIDS vaccine development. PMID- 20953944 TI - Retrovirus-mediated delivery of an IL-4 receptor antagonist inhibits allergic responses in a murine model of asthma. AB - This work reports the investigation of the effect of airway IL-4RA gene transfer by a recombinant retroviral vector on airway inflammation and airway responsiveness in asthmatic mice. The retrovirus-mediated delivery of IL-4RA to the airways of mice inhibited elevations of airway responsiveness and the development of allergic inflammation in asthmatic mice, and regulated the Th1/Th2 balance in OVA-sensitized and -challenged mouse models. This suggests that gene therapy is a therapeutic option for treating and controlling chronic airway inflammation and asthma symptoms. PMID- 20953945 TI - Overexpression of the Rap2.4f transcriptional factor in Arabidopsis promotes leaf senescence. AB - Senescence is a complex and highly regulated process. Leaf senescence is influenced by endogenous developmental and external environmental signals. In this work, we found that expression of an Ap2/DREB-type transcription factor gene, Arabidopsis Rap2.4f (At4g28140), was upregulated by salt, mannitol, and dark treatments. Constitutively overexpressing Rap2.4f under the control of the CaMV 35S promoter led to an increased chlorophyll degradation rate and upregulation of many senescence-associated genes in the transgenic Arabidopsis lines. Our results show that Rap2.4f is a positive regulator of senescence, promoting both developmental and dark-induced leaf senescence. PMID- 20953946 TI - Natural refuge crops, buildup of resistance, and zero-refuge strategy for Bt cotton in China. AB - In the context of genetically modified crops expressing the Bacillus thuringiensis (Bt) toxin, a 'refuge' refers to a crop of the same or a related species that is planted nearby to enable growth and reproduction of the target pest without the selection pressure imposed by the Bt toxin. The goal of this study is to discuss the role of natural refuge crops in slowing down the buildup of resistance of cotton bollworm (CBW), and to evaluate China's no-refuge policy for Bt cotton. We describe in detail the different factors that China should consider in relation to the refuge policy. Drawing on a review of scientific data, economic analyses of other cases, and a simulation exercise using a bio economic model, we show that in the case of Bt cotton in China, the no-refuge policy is defensible. PMID- 20953947 TI - Phylogenetic status of Pneumocystis from corticosteroid-treated gerbils. AB - Pneumocystis spp. infect the lungs of multiple mammalian species and cause disease in immunosuppressed individuals. The Pneumocystis isolates that have been studied to date fall into two major clades, those from primates and those from rodents. Within each of these clades, different species have been described on the basis of host specificity and differences in sequence and morphology. Here, we demonstrate that dexamethasone immunosuppression consistently results in histologically apparent lung infection in gerbils (28/35 animals). Sequence analysis of the 18S, 5.8S and internal transcribed spacer regions of the rDNA and a portion of the mitochondrial large subunit rDNA demonstrated that this gerbil Pneumocystis is grouped with other rodent Pneumocystis spp., but is distinct from them. Our results suggest that gerbil Pneumocystis differs sufficiently from Pneumocystis species found in other rodents to be considered a separate species. PMID- 20953948 TI - Identification of Pseudomonas aeruginosa genes associated with antibiotic susceptibility. AB - Pseudomonas aeruginosa causes acute and chronic infections in humans and these infections are difficult to treat due to the bacteria's high-level of intrinsic and acquired resistance to antibiotics. To address this problem, it is crucial to investigate the molecular mechanisms of antibiotic resistance in this organism. In this study, a P. aeruginosa transposon insertion library of 17000 clones was constructed and screened for altered susceptibility to seven antibiotics. Colonies grown on agar plates containing antibiotics at minimum inhibitory concentrations (MICs) and those unable to grow at 1/2 MIC were collected. The transposon-disrupted genes in 43 confirmed mutants that showed at least a three fold increase or a two-fold decrease in susceptibility to at least one antibiotic were determined by semi-random PCR and subsequent sequencing analysis. In addition to nine genes known to be associated with antibiotic resistance, including mexI, mexB and mexR, 24 new antibiotic resistance-associated genes were identified, including a fimbrial biogenesis gene pilY1 whose disruption resulted in a 128-fold increase in the MIC of carbenicillin. Twelve of the 43 genes identified were of unknown function. These genes could serve as targets to control or reverse antibiotic resistance in this important human pathogen. PMID- 20953949 TI - Phenotype prediction of nonsynonymous single nucleotide polymorphisms in human phase II drug/xenobiotic metabolizing enzymes: perspectives on molecular evolution. AB - Nonsynonymous single nucleotide polymorphisms (nsSNPs) in coding regions can lead to amino acid changes that might alter the protein's function and account for susceptibility to disease and altered drug/xenobiotic response. Many nsSNPs have been found in genes encoding human phase II metabolizing enzymes; however, there is little known about the relationship between the genotype and phenotype of nsSNPs in these enzymes. We have identified 923 validated nsSNPs in 104 human phase II enzyme genes from the Ensembl genome database and the NCBI SNP database. Using PolyPhen, Panther, and SNAP algorithms, 44%-59% of nsSNPs in phase II enzyme genes were predicted to have functional impacts on protein function. Predictions largely agree with the available experimental annotations. 68% of deleterious nsSNPs were correctly predicted as damaging. This study also identified many amino acids that are likely to be functionally critical, but have not yet been studied experimentally. There was significant concordance between the predicted results of Panther and PolyPhen, and between SNAP non-neutral predictions and PolyPhen scores. Evolutionarily non-neutral (destabilizing) amino acid substitutions are thought to be the pathogenetic basis for the alteration of phase II enzyme activity and to be associated with disease susceptibility and drug/xenobiotic toxicity. Furthermore, the molecular evolutionary patterns of phase II enzymes were characterized with regards to the predicted deleterious nsSNPs. PMID- 20953950 TI - Bioavailability of hydrophobic organic contaminants in sediment with different particle-size distributions. AB - Few studies have been conducted examining the distribution of different-sized particles in sediment and its potential impact on bioavailability of sediment associated contaminants. In the current study, three sediments composed of different particle sizes, i.e., fine (0-180 MUm), combined (0-500 MUm), and coarse (180-500 MUm), were used to evaluate the bioaccumulation potential and toxicokinetic rates of four hydrophobic organic contaminants (HOCs) including two polychlorinated biphenyls (PCB-101 and PCB-118), a metabolite of an organochlorine insecticide (p,p'-DDE), and a polybrominated diphenyl ether (BDE 47) to the benthic oligochaete Lumbriculus variegatus. Two chemical approaches, Tenax extraction and matrix-solid phase microextraction (SPME), were also used to measure bioavailability of the sediment-associated HOCs. The uptake and elimination rates of HOCs by L. variegatus from coarse sediment were greater than those from fine sediment, although the biota-sediment accumulation factors (BSAFs) were not significantly different among sediments with different particle sizes. The freely dissolved HOC concentrations measured by matrix-SPME were greater in coarse sediment, however, no difference was found in uptake and desorption rates for the matrix-SPME and Tenax extraction measurements. Although BSAFs in L. variegatus were the same among sediments, kinetic rates of HOCs for organisms and freely dissolved HOC concentrations were lower in fine sediment, suggesting that sediment ingestion may also play a role in organism uptake, especially for HOCs in fine sediment. PMID- 20953952 TI - Seroma as a late complication after breast augmentation. AB - This report with late seromas occurring in the periprosthetic cavity. This complication is a rare development after breast augmentation. From 1996 to 2009, the authors performed 568 initial breast augmentation procedures. During this period, they observed late seromas in six cases. In five of the six cases, the initial operations were performed by the authors (0.88% of all breast augmentation operations performed at the authors' center during the respective period). In one case, the operation had been performed in another clinic. Late seromas occurred at various intervals 2 to 10 years after the initial breast augmentation. In five of the six reported cases, revision surgery was required. In one case, conservative treatment was applied. An implant rupture was observed in only one case. In the remaining five cases, the implants were intact. In the authors' opinion, seromas may occur when any sliding surfaces are present and as a result of micromotion of implants in cavities. The inner surface of a capsule with a synovial metaplasia becomes a target for chronic infections. PMID- 20953951 TI - Hypoxylon sp., an endophyte of Persea indica, producing 1,8-cineole and other bioactive volatiles with fuel potential. AB - An endophytic fungus of Persea indica was identified, on the basis of its anamorphic stage, as Nodulosporium sp. by SEM. Partial sequence analysis of ITS rDNA revealed the identity of the teleomorphic stage of the fungus as Hypoxylon sp. It produces an impressive spectrum of volatile organic compounds (VOCs), most notably 1,8-cineole, 1-methyl-1,4-cyclohexadiene, and tentatively identified (+) .alpha.-methylene-.alpha.-fenchocamphorone, among many others, most of which are unidentified. Six-day-old cultures of Hypoxylon sp. displayed maximal VOC antimicrobial activity against Botrytis cinerea, Phytophthora cinnamomi, Cercospora beticola, and Sclerotinia sclerotiorum suggesting that the VOCs may play some role in the biology of the fungus and its survival in its host plant. Media containing starch- or sugar-related substrates best supported VOC production by the fungus. Direct on-line quantification of VOCs was measured by proton transfer mass spectrometry covering a continuous range with optimum VOC production occurred at 6 days at 145 ppmv with a rate of production of 7.65 ppmv/h. This report unequivocally demonstrates that 1,8-cineole (a monoterpene) is produced by a microorganism, which represents a novel and important source of this compound. This monoterpene is an octane derivative and has potential use as a fuel additive as do the other VOCs of this organism. Thus, fungal sourcing of this compound and other VOCs as produced by Hypoxylon sp. greatly expands their potential applications in medicine, industry, and energy production. PMID- 20953953 TI - Attractive composite faces of different races. PMID- 20953955 TI - Is hyaluronic acid gel a good option for breast augmentation? PMID- 20953956 TI - Successful use of squeezed-fat grafts to correct a breast affected by Poland syndrome. AB - This study attempted to reconstruct deformities of a Poland syndrome patient using autologous fat tissues. All injected fat tissues were condensed by squeezing centrifugation. Operations were performed four times with intervals over 6 months. The total injection volume was 972 ml, and the maintained volume of 628 ml was measured by means of a magnetic resonance image (MRI). The entire follow-up period was 4.5 years. After surgery, several small cysts and minimal calcifications were present but no significant complications. The cosmetic outcomes and volume maintenance rates were excellent despite the overlapped large volume injections. In conclusion, higher condensation of fat tissues through squeezing centrifugation would help to achieve better results in volume maintenance and reduce complications. It is necessary, however, to perform more comparative studies with many clinical cases for a more scientific analysis. The study experiments with squeezed fat simply suggest a hypothesis that squeezing centrifugation could select healthier cells through pressure disruption of relatively thinner membranes of larger, more vulnerable and more mature fat cells. PMID- 20953957 TI - Monoblock thoracobrachioplasty in males: a proposed technique mimicking the pectoral fold. AB - A growing number of men with massive weight loss are seeking improvement of arm deformity extending through the axilla and on to the chest. Although contouring techniques addressing the male arm and anterior chest deformities as separate entities have been described, when a combination of those techniques is performed, the surgical outcomes may lead to improper placement of the resultant scars. The authors propose an upper body-contouring treatment by monoblock thoracobrachioplasty aimed at correcting chest, axilla, and arm deformities in men through a single continuous incision, resulting in a thoracic scar placed right on the pectoral fold. The described surgical approach provides excellent chest contour and simultaneously addresses the upper extremity and axillary contour deformities in men after massive weight loss. The final position of the scar on the thorax corresponds to the inferior pectoral groove, resembling the division of two aesthetic units in the thorax and resulting in anatomically favorable scar positioning. A limitation of this proposed technique is the potential retraction of the axillary part of the continuous scar that may need revision. Careful preoperative evaluation and markings followed by intraoperative skillful handling are needed to prevent complications. The procedure appears relatively simple and easy to perform but requires a learning curve for previewing the ideal positioning of the resultant scar to obtain aesthetically favorable results. Monoblock thoracobrachioplasty mimicking the pectoral fold is a treatment option to be added to the armamentarium of techniques for postbariatric male patients. PMID- 20953958 TI - Radiotransparency of polyvinylpyrrolidone-hydrogel and hydrogel breast implants: a quantitative analysis with mastectomy specimens. AB - Breast cancer is the most common cancer in women. Past evidence suggested that women with silicone implants who had cancer presented with more advanced disease and had the worst prognosis due to difficulty visualizing early lesions on mammography. Hence, new filling materials have been developed. In this study, 10 mastectomy specimens were used. Mammograms of specimens alone and specimens covering polyvinylpyrrolidone-hydrogel and hydrogel implants were performed. The variables studied were number of mammograms necessary to examine each specimen, kilovolts and milliamperes of each mammogram, number of isolated microcalcifications, microcalcification clusters and macroscopic calcifications, and rarefaction areas. No significant differences were found in number of mammograms (p = 0.439), isolated microcalcifications (p = 0.178), macrocalcifications (p = 1.0), and presence of rarefaction areas (p = 0.368). The difference in number of microcalcification clusters was significant (p = 0.0498). Significant differences (p < 0.001) also were observed in the kilovolts and milliamperes of the mammograms performed for specimens alone versus those with implants. Polyvinylpyrrolidone-hydrogel and hydrogel breast implants allow adequate visualization of mammary glands at the expense of greater radiation doses, although it must be considered that the experimental situation does not fully match the real clinical setting. PMID- 20953959 TI - Effects of intracoronary injection of autologous bone marrow-derived stem cells on natriuretic peptides and inflammatory markers in patients with acute ST elevation myocardial infarction. AB - BACKGROUND: Intracoronary administration of autologous bone marrow stem cells (BMC) has been shown to result in a subtle improvement of global left ventricular ejection fraction after ST-elevation myocardial infarction (STEMI), but the overall benefits of BMC therapy are still unclear. We studied the influence of intracoronary injections of BMC on levels of natriuretic peptides and inflammatory mediators, which are well established prognostic biomarkers, in patients with STEMI. METHODS: In this randomized, double-blind study, consecutive patients with an acute STEMI treated with thrombolysis followed by PCI 2-6 days after STEMI, were randomly assigned to receive either intracoronary BMC or placebo medium into the infarct-related artery. Blood samples were drawn for biochemical determinations. RESULTS: From baseline to 6 months, there was a significant decrease in the levels of N-terminal probrain natriuretic peptide (NT proBNP), interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) in the whole patient population (P < 0.001 for all). However, no difference was observed between the BMC group (n = 39) and the placebo group (n = 39) in the change of the levels of NT-proANP (median -54 vs. +112 pmol/L), NT-proBNP (-88 vs. -115 pmol/L) or inflammatory markers IL-6 (-3.86 vs. -5.61 pg/mL), hsCRP ( 20.29 vs. -22.36 mg/L) and tumor necrosis factor alpha (-0.12 vs. -0.80 pg/mL) between baseline and 6 months. CONCLUSION: Intracoronary BMC therapy does not appear to exert any significant effects on the secretion of natriuretic peptides or inflammatory biomarkers in STEMI patients. PMID- 20953960 TI - Prognostic implications of aquaporin-4 antibody status in neuromyelitis optica patients. AB - Neuromyelitis optica (NMO) is an inflammatory/demyelinating disorder predominantly affecting the optic nerves and spinal cord. Recent findings showed an underlying humoral abnormality in NMO, characterized by a serum antibody against aquaporin-4 (Aqp-4-Ab). In this study, we evaluated the Aqp-4-Ab status among Turkish patients with NMO to determine the clinical and prognostic relevance. Serum samples from 35 consecutive patients with NMO followed at a single center and diagnosed according to the 2006 revised criteria, were evaluated for Aqp-4-Ab. All samples were obtained during a relapse prior to any immunosuppressive treatment. Aqp-4-Ab was positive in 21/35 (60%) patients. Among these cases, 11 had an EDSS of 6.0 or more, whereas only two patients in the seronegative group had such severe disability (p < 0.05). Overall, seropositive cases had a mean EDSS score of 5.1 +/- 2.2 compared with 3.5 +/- 1.7 in seronegative cases (p < 0.01). There were trends towards female predominance in seropositive cases and a monophasic course predominance in seronegative cases. Disease duration, age at onset, number of attacks and time to definite NMO did not differ between groups. Our findings in this single-center cohort suggest that the presence of Aqp-4-Ab might have a prognostic significance indicating a more severe disease course. PMID- 20953961 TI - Does it pay to delay? Flesh flies show adaptive plasticity in reproductive timing. AB - Life-history plasticity is widespread among organisms. However, an important question is whether it is adaptive. Most models for plasticity in life-history timing predict that animals, once they have reached the minimal nutritional threshold under poor conditions, will accelerate development or time to reproduction. Adaptive delays in reproduction are not common, especially in short lived species. Examples of adaptive reproductive delays exist in mammalian populations experiencing strong interspecific (e.g., predation) and intraspecific (e.g., infanticide) competition. But are there other environmental factors that may trigger an adaptive delay in reproductive timing? We show that the short lived flesh fly Sarcophaga crassipalpis will delay reproduction under nutrient poor conditions, even though it has already met the minimal nutritional threshold for reproduction. We test whether this delay strategy is an adaptive response allowing the scavenger time to locate more resources by experimentally providing supplemental protein pulses (early, mid and late) throughout the reproductive delay period. Flies receiving additional protein produced more and larger eggs, demonstrating a benefit of the delay. In addition, by tracking the allocation of carbon from the pulses using stable isotopes, we show that flies receiving earlier pulses incorporated more carbon into eggs and somatic tissue than those given a later pulse. These results indicate that the reproductive delay in S. crassipalpis is consistent with adaptive post-threshold plasticity, a nutritionally linked reproductive strategy that has not been reported previously in an invertebrate species. PMID- 20953962 TI - Asymmetric life-history decision-making in butterfly larvae. AB - In temperate environments, insects appearing in several generations in the growth season typically have to decide during the larval period whether to develop into adulthood, or to postpone adult emergence until next season by entering a species specific diapause stage. This decision is typically guided by environmental cues experienced during development. An early decision makes it possible to adjust growth rate, which would allow the growing larva to respond to time stress involved in direct development, whereas a last-minute decision would instead allow the larva to use up-to-date information about which developmental pathway is the most favourable under the current circumstances. We study the timing of the larval pathway decision-making between entering pupal winter diapause and direct development in three distantly related butterflies (Pieris napi, Araschnia levana and Pararge aegeria). We pinpoint the timing of the larval diapause decision by transferring larvae from first to last instars from long daylength (inducing direct development) to short daylength conditions (inducing diapause), and vice versa. Results show that the pathway decision is typically made in the late instars in all three species, and that the ability to switch developmental pathway late in juvenile life is conditional; larvae more freely switched from diapause to direct development than in the opposite direction. We contend that this asymmetry is influenced by the additional physiological preparations needed to survive the long and cold winter period, and that the reluctance to make a late decision to enter diapause has the potential to be a general trait among temperate insects. PMID- 20953963 TI - Coping with uncertainty: breeding adjustments to an unpredictable environment in an opportunistic raptor. AB - No environment is truly constant in time. As a result, animals have evolved multiple adjustments to cope with such fluctuations. However, the allocation of effort to costly activities that imply long-term commitments, such as breeding, may be extremely challenging when future resources change constantly and unpredictably, a context that has received little investigation. To fill this gap, we studied the breeding response by a wetland-dependent raptor, the black kite Milvus migrans, to within and between-years fluctuations in resource availability (inundation levels). The breeding performance of the population was decomposed into reproductive components expressed in a sequence of successive tasks along the breeding cycle (e.g. timing of laying, clutch size, hatching success, brood reduction). Variation in each component was related to resource levels observed at different key dates of the season in order to test whether and when population-level reproduction was adjusted to available resources. Along a 22-year time-series, inundation levels fluctuated unpredictably within and among years, and mostly affected the later components of kites' reproduction, such as hatching success and the incidence of brood reduction, which were the main determinants of the population yearly breeding output. Results were consistent with multiple adjustments to cope with uncertainty. As the season progressed and resources became easier to assess, a bet-hedging waiting strategy based on a conservatively small, invariant and asynchronous clutch gave way to real-time resource-tracking mechanisms mediated by progressive adjustments to current prey availability, so that population-level breeding rates were determined and tuned to resources rather late in the season. Such adjustments were the likely outcome of the interaction between parental tactics and environmental constraints. Behavioural flexibility, such as dietary opportunism, probably promoted further resistance to resource oscillations. Given that all ecosystems show some degree of unpredictability, resource-tracking adjustments, such as the ones depicted here, are likely to be commonplace in most communities. PMID- 20953965 TI - The cellular mechanisms underlying the inhibitory effects of isoflurane and sevoflurane on arginine vasopressin-induced vasoconstriction. AB - PURPOSE: Arginine vasopressin (AVP) is a potent vasoconstrictor that is sometimes used for the treatment of refractory vasodilatory shock. AVP constricts vascular smooth muscle by increasing both intracellular calcium concentration ([Ca(2+)](i)) and myofilament Ca(2+) sensitivity. However, the modulation of AVP mediated vasoconstriction by volatile anesthetics remains to be determined. This study investigates the effects of isoflurane and sevoflurane on AVP-induced vasoconstriction and elucidates the underlying mechanisms, with an emphasis on the Ca(2+)-mediated pathways and Ca(2+) sensitization pathways of rat aortic smooth muscle. METHODS: The effects of isoflurane and sevoflurane on AVP-induced vasoconstriction and on the AVP-induced increase in [Ca(2+)](i) and Rho activity in rat aorta were investigated by isometric force recording, by measuring [Ca(2+)](i) using fluorescence dye, and by Western blotting techniques. RESULTS: Arginine vasopressin (10-7M) elicited a transient contractile response that was inhibited by isoflurane and sevoflurane in a concentration-dependent manner. AVP (10-7 M) induced a transient increase in intracellular Ca(2+) concentration ([Ca(2+)](i)). Isoflurane and sevoflurane also inhibited an AVP-induced increase in [Ca(2+)](i) in a concentration-dependent manner. AVP (10-7 M) increased the Rho activity that was attenuated by 2 minimum alveolar concentration of sevoflurane (P < 0.01), but not by an equipotent concentration of isoflurane. CONCLUSION: Arginine vasopressin-induced vasoconstriction is mediated by an increase in [Ca(2+)](i) and by the activation of the Rho-Rho kinase pathway in rat aortic smooth muscle. Although both isoflurane and sevoflurane, at clinically relevant concentrations, attenuate AVP-induced contraction, the cellular mechanisms of their inhibitory effects appear to differ. PMID- 20953964 TI - Colloid solutions: a clinical update. AB - Albumin, dextran, gelatin, and hydroxyethyl starch (HES) solutions are colloids that efficiently expand the circulating blood volume. The administration of colloids restores the intravascular volume with minimal risk of tissue edema in comparison with crystalloid solutions alone. However, colloids are always given for surgical and critically ill patients. The type of the colloid, volumes applied, aggressiveness of fluid resuscitation, and the volume status at the initial phase of administration determine their clinical responses. The outcome after fluid resuscitation with various colloids in critically ill patients seems to be comparable according to systematic reviews. A randomized, adequately powered clinical trial comparing modern nonprotein colloid to albumin is still lacking. Rapidly degradable HES solutions have good hemodynamic effects, and the risk of adverse renal and coagulation effects, as well as allergic reactions, is minimal. The current investigation has also shown the beneficial effect of HES solution (especially HES 130/0.4) on inflammatory response, postoperative nausea and vomiting, and postoperative outcome. The indication of colloids with an assessment of the degree of hypovolemia and safety profiles should thus be taken into consideration before colloid administration. PMID- 20953966 TI - Survivorship analysis of 150 consecutive patients with DIAMTM implantation for surgery of lumbar spinal stenosis and disc herniation. AB - Recently, the Device for Intervertebral Assisted Motion (DIAMTM) has been introduced for surgery of degenerative lumbar disc diseases. The authors performed the current study to determine the survivorship of DIAMTM implantation for degenerative lumbar disc diseases and risk factors for reoperation. One hundred and fifty consecutive patients underwent laminectomy or discectomy with DIAMTM implantation for primary lumbar spinal stenosis or disc herniation. The characteristics of the 150 patients included the following: 84 males and 66 females; mean age at the time of surgery, 46.5 years; median value of follow-up, 23 months (range 1-48 months); 96 spinal stenosis and 54 disc herniations; and 146 one-level (115, L4-5; 31, L5-6) and 4 two-level (L4-5 and L5-6). In the current study, due to lumbosacral transitional vertebra (LSTV) L6 meant lumbarization of S1 and this had a prominent spinous process so that the DIAMTM was implanted at L5-6. Reoperations due to any reasons of the DIAMTM implantation level or adjacent levels were defined as a failure and used as the end point for determining survivorship. The cumulative reoperation rate and survival time were determined via Kaplan-Meier analysis. The log-rank test and Cox regression model were used to evaluate the effect of age, gender, diagnosis, location, and level of DIAMTM implantation on the reoperation rate. During a 4-year follow-up, seven patients (two males and five female) underwent reoperation at the DIAMTM implantation level, giving a reoperation rate of 4.7%. However, no patients underwent reoperation for adjacent level complications. The causes of reoperation were recurrent spinal stenosis (n = 3), recurrent disc herniation (n = 2), post laminectomy spondylolisthesis (n = 1), and delayed deep wound infection (n = 1). The mean time between primary operation and reoperation was 13.4 months (range 2 29 months). Kaplan-Meier analysis predicted an 8% cumulative reoperation rate 4 years post-operatively. Survival time was predicted to be 45.6 +/- 0.9 months (mean +/- standard deviation). Based on the log-rank test, the reoperation rate was higher at L5-6 (p = 0.002) and two-level (p = 0.01) DIAMTM implantation compared with L4-5 and one-level DIAMTM implantation. However, gender (p = 0.16), age (p = 0.41), and diagnosis (p = 0.67) did not significantly affect the reoperation rate of DIAMTM implantation. Based on a Cox regression model, L5-6 [hazard ratio (HR), 10.3; 95% CI, 1.7-63.0; p = 0.01] and two-level (HR, 10.4; 95% CI, 1.2-90.2; p = 0.04) DIAMTM implantation were also significant variables associated with a higher reoperation rate. Survival time was significantly lower in L5-6 (47 vs. 22 months, p = 0.002) and two-level DIAMTM implantation (46 vs. 18 months, p = 0.01) compared with L4-5 and one-level DIAMTM implantation. The current results suggest that 8% of the patients who have a DIAMTM implantation for primary lumbar spinal stenosis or disc herniation are expected to undergo reoperation at the same level within 4 years after surgery. Based on the limited data set, DIAMTM implantation at L5-6 and two-level in patients with LSTV are significant risk factors for reoperation. PMID- 20953967 TI - Proinflammatory cytokines in the cerebrospinal fluid of patients with lumbar radiculopathy. AB - In pathologic radicular pain of lumbar spinal stenosis, cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukins (ILs) play a crucial role in the pathogenesis of nerve degeneration and pain. We investigated TNF-alpha and IL 6 levels in the cerebrospinal fluid (CSF) of patients with radicular pain caused by lumbar spinal stenosis (LSS). A total of 30 LSS patients and 10 age-matched controls were examined. CSF samples were obtained adjacent to the level of stenosis in 30 LSS patients, and at the L4-L5 level in the 10 control patients. TNF-alpha and IL-6 levels in the samples were analyzed using enzyme-linked immunosorbent assays (ELISA). We compared the amounts of TNF-alpha and IL-6 with severity of pain (low back and leg pain), walking ability, and severity of stenosis (cross-sectional area of dural space). The concentration of IL-6 was significantly higher in LSS patients than in controls, but TNF-alpha levels were beneath the limit of detection. There was no correlation between IL-6 levels and severity of pain or walking ability (p > 0.05). However, there was a significant correlation between IL-6 levels and severity of stenosis (p < 0.05). The current study showed that the increased CSF IL-6 levels in LSS patients with radicular pain were not correlated with pain severity; although not proven in this study, the increase in CSF IL-6 concentration could indicate pathological nerve damage or degeneration of lumbar radiculopathy represented by the severity of stenosis. PMID- 20953969 TI - Stimulation of TLR7 prior to polymicrobial sepsis improves the immune control of the inflammatory response in adult mice. AB - OBJECTIVE: The role of Toll-like receptor 7 (TLR7), so far regarded as a receptor for viral RNA, was evaluated in a murine sepsis model. MATERIAL: We used the colon ascendens stent peritonitis model (CASP) in female C57B/6 mice. R-848 (1.5 MUg/g body weight) was injected intravenously prior to sepsis induction. METHODS: We determined levels of cytokines by CBA detection kit. Different cell populations were isolated from the spleen by magnetic cell separation and the expression of TLR7 was visualized by immunofluorescence staining. Bacterial load of organs was quantified by incubating suspensions on agar in colony forming units. RESULTS: R-848 application per se led to elevated cytokine levels in serum, spleen and peritoneal cavity. Expression of TLR7 on splenocytes was upregulated following CASP. Bacterial clearance in polymicrobial sepsis was significantly increased in spleen and peritoneum of mice pre-treated with the TLR7-agonist. Cytokine release was regulated in the peritoneum and spleen. Furthermore, apoptosis in thymus and spleen during polymicrobial sepsis was significantly decreased following TLR7 agonist application. CONCLUSIONS: TLR7 seems to be essential for pathogen defence not only in viral but also in bacterial infections. Pharmacological stimulation of this receptor prior to induction of sepsis improves the host's capacity to cope with pathogens. PMID- 20953970 TI - Exogenous procalcitonin evokes a pro-inflammatory cytokine response. AB - OBJECTIVE AND DESIGN: Procalcitonin (ProCT) is increased in serum of septic patients and those with systemic inflammation. Endogenous levels of ProCT might influence the response of polymorphonuclear leukocytes (PMNs), independently of endotoxin, in clinical disease. SUBJECTS: Healthy human volunteers. TREATMENT: Recombinant human ProCT (rhProCT). METHODS: Whole blood and PMNs were exposed in vitro to exogenous rhProCT. Interleukin (IL)-6, IL-8, IL-10, IL-13, tumor necrosis factor-alpha (TNFalpha), IL-1beta, and macrophage inflammatory protein (MIP)-1beta (pg/ml) were measured by multiplex suspension bead-array immunoassay, and migration and phagocytosis were measured in PMNs. RESULTS: In a whole-blood model, a dose-dependent increase in IL-6, TNFalpha, and IL-1beta of the cell-free supernatant was noted. Pre-incubation with ProCT, at doses consistent with clinical sepsis, resulted in a decrease in PMN migration without alteration in phagocytosis of Staphylococcus aureus or indirect measurements of bacterial killing. CONCLUSION: Clinically relevant levels of ProCT influence immunologic responses that may contribute to systemic inflammatory response and septic shock. PMID- 20953972 TI - Elaborating on the construct validity of the Levenson self-report psychopathy scale in incarcerated and non-incarcerated samples. AB - The Levenson Self-Report Psychopathy Scale (LSRP) is a promising, efficient measure of the psychopathic personality. Previous examinations of its latent structure have yielded inconsistent results; therefore, the goal of the current study was to evaluate previously reported two- and three-factor models in three separate groups of male correctional inmates (n = 573), male college students (n = 202), and female college students (n = 200). Confirmatory factor analyses revealed that the best-fitting model across all the three groups was the three factor model proposed by Brinkley et al. (Assessment 15:464-482, 2008). The convergent and discriminant validity of this three-factor structure as well as a revised 19-item total score were elaborated on in terms of predicting scores on conceptually relevant external criteria. The LSRP total and factor scales evidenced good convergent and discriminant validity with a few notable exceptions. Implications for theory and future research are discussed. PMID- 20953971 TI - Pol II-directed short RNAs suppress the nuclear export of mRNA. AB - The synthesis and subsequent nuclear export of non-coding RNA (ncRNA) directed by RNA polymerase (Pol) II is very sensitive to abiotic and biotic external stimuli including pathogen challenges. To assess whether stress-induced ncRNAs may suppress the nuclear export of mRNA, we exploited the ability of Agrobacterium tumefaciens to co-deliver Pol I, II and III promoter-based vectors for the transcription of short (s) ncRNAs, GFP mRNA or genomic RNA of plant viruses (Tobacco mosaic virus, TMV; or Potato virus X, PVX) into the nucleus of Nicotiana benthamiana cells. We showed that, in contrast to Pol I- and Pol III-derived sncRNAs, all tested Pol II-derived sncRNAs (U6 RNA, tRNA or artificial RNAs) resulted in decreased expression of GFP and host mRNA. The level of this inhibitory effect depended on the non-coding transcript length and promoter strength. Short coding RNA (scRNA) can also compete with mRNA for nuclear export. We showed that scRNA, an artificial 117-nt short sequence encoding Elastin-Like peptide element tandems with FLAG sequence (ELF) and the 318-nt N. benthamiana antimicrobial peptide thionin (defensin) gene efficiently decreased GFP expression. The stress-induced export of Pol II-derived sncRNA and scRNA into the cytoplasm via the mRNA export pathway may block nucleocytoplasmic traffic including the export of mRNA responsible for antivirus protection. Consistent with this model, we observed that Pol II-derived sncRNAs as well as scRNA, thionin and ELF strongly enhanced the cytoplasmic reproduction of TMV and PVX RNA. PMID- 20953973 TI - Decrements in Miranda abilities: an investigation of situational effects via a mock-crime paradigm. AB - Programmatic research has made important advances during the last decade in understanding how cognitive and psychological variables affect Miranda comprehension and reasoning. However, the effects of situational stressors are largely overlooked in determining the validity of Miranda waivers. As the first systematic investigation, this study uses a 2 * 2 * 2 factorial design on 123 undergraduate participants to examine the effects of being apprehended via a mock crime (i.e., stealing a watch from a Plexiglas case) paradigm on Miranda comprehension and reasoning. Besides the mock-crime condition, the mode of advisement (oral or written) and the length of the warning (124 vs. 228 words) were also investigated. When compared to controls, the mock-crime scenario produced moderate to large effects (ds from .58 to .75) on both Miranda recall and subsequent reasoning. In addition, oral advisements resulted in non significant trend for decrements in Miranda recall. No main effects were observed for length and no significant interactions were found. Interestingly, specific components (e.g., right to counsel and free legal services) were generally more affected than the more familiar first two components (i.e., right to silence and evidence against you). Within the crime-scenario condition, participants with substantially increased state anxiety predictably performed more poorly than those participants whose state anxiety remained relatively stable. Directions for future research and the implications of these findings on our understanding of Miranda abilities are discussed. PMID- 20953974 TI - Design elements in implementation research: a structured review of child welfare and child mental health studies. AB - Implementation science is an emerging field of research with considerable penetration in physical medicine and less in the fields of mental health and social services. There remains a lack of consensus on methodological approaches to the study of implementation processes and tests of implementation strategies. This paper addresses the need for methods development through a structured review that describes design elements in nine studies testing implementation strategies for evidence-based interventions addressing mental health problems of children in child welfare and child mental health settings. Randomized trial designs were dominant with considerable use of mixed method designs in the nine studies published since 2005. The findings are discussed in reference to the limitations of randomized designs in implementation science and the potential for use of alternative designs. PMID- 20953975 TI - Cotton plants expressing CYP6AE14 double-stranded RNA show enhanced resistance to bollworms. AB - RNA interference (RNAi) plays an important role in regulating gene expression in eukaryotes. Previously, we generated Arabidopsis and tobacco plants expressing double-stranded RNA (dsRNA) targeting a cotton bollworm (Helicoverpa armigera) P450 gene, CYP6AE14. Bollworms fed on transgenic dsCYP6AE14 plants showed suppressed CYP6AE14 expression and reduced growth on gossypol-containing diet (Mao et al., in Nat Biotechnol 25: 1307-1313, 2007). Here we report generation and analysis of dsRNA-expressing cotton (Gossypium hirsutum) plants. Bollworm larvae reared on T2 plants of the ds6-3 line exhibited drastically retarded growth, and the transgenic plants were less damaged by bollworms than the control. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) showed that the CYP6AE14 expression level was reduced in the larvae as early as 4 h after feeding on the transgenic plants; accordingly, the CYP6AE14 protein level dropped. These results demonstrated that transgenic cotton plants expressing dsCYP6AE14 acquired enhanced resistance to cotton bollworms, and that RNAi technology can be used for engineering insect-proof cotton cultivar. PMID- 20953976 TI - Brodie's abscess presenting in a young soccer player following ankle injury. PMID- 20953977 TI - Palliative endoscopic trans-anal resection of advanced rectosigmoid carcinoma. AB - There is no consensus on optimal treatment of patients with rectosigmoid cancer and unresectable metastatic disease. This is a retrospective review of all patients who underwent palliative endoscopic trans-anal resection (ETAR) of rectosigmoid cancer over a 10-year period. Fourteen patients (11 male) with a mean age 69.7 years (range 51-86) underwent ETAR; 11 for rectal tumours and 3 for rectosigmoid tumours. Indications included tenesmus (5), troublesome bleeding (6), mucous discharge (1) and obstructed defaecation (8). The number of treatment episodes varied from 1 to 4 (median 1). The symptom-free interval was mean 6.25 months (range 2-15). Eight patients had lifelong relief of symptoms and four patients are currently symptom free. There were two short-term failures treated with stenting (1) and abdominoperineal resection (1). There were no immediate post-treatment complications. One patient developed increasing incontinence and another pelvic pain after ETAR attributable to local tumour infiltration. ETAR provides a convenient and safe method of palliation for patients with local symptoms of advanced rectosigmoid carcinoma. PMID- 20953978 TI - Severe systemic sepsis due to pyogenic liver abscess. PMID- 20953979 TI - Malignant priapism: a case report. AB - BACKGROUND: Metastatic involvement of the penis is most commonly from a primary malignant genitourinary tumour. It is a rare phenomenon usually reflecting disseminated malignancy associated with a poor prognosis. Metastasis to the penis mimicking priapism is extremely rare, particularly in the absence of disseminated disease. MATERIALS AND METHODS: We describe a case of painful priapism caused by a high-grade urothelial malignancy without disseminated disease. CONCLUSION: Life expectancy is estimated at less than 1 year in these patients. Our patient remains in clinical and radiologic remission over 36 months from his original radical surgery. PMID- 20953980 TI - Have developments in palliative care services impacted on place of death of colorectal cancer patients in Ireland? A population-based study. AB - BACKGROUND: Whether developments in palliative care have impacted on where cancer patients die is unknown. We investigated time trends in place of death for colorectal cancer. METHODS: Details were abstracted on 10,175 colorectal cancer deaths during 1994-2004. Time trends were analysed by joinpoint regression. RESULTS: Nearly half (49%) of deaths occurred in acute hospitals, 29% at home, 13% in hospices and 7% in nursing homes. Hospital deaths were unchanged over time. Hospice deaths rose from 6% in 1994 to 17% in 2003. Home deaths decreased significantly, but only in health boards with hospices [estimated annual percentage change (EAPC) = -3.6%, 95%CI -4.19 to -2.97%, p < 0.001]. Nursing home deaths rose significantly in areas without hospices (EAPC = 8.0%, 95%CI 2.27 to 13.94%, p = 0.011). CONCLUSIONS: Most colorectal cancer deaths occur in hospital. Availability of hospice facilities is a key determinant of where the burden of death falls. The results suggest unmet demand for hospice care in Ireland. PMID- 20953981 TI - A comparative study of faecal occult blood kits in a colorectal cancer screening program in a cohort of healthy construction workers. AB - BACKGROUND: The incidence of colorectal cancer (CRC) has been increasing. We evaluated uptake rates and outcomes of faecal immunochemical test (FIT) and Guaiac test (gFOBT) kits as part of a two-step CRC screening. METHODS: A 3-year CRC screening program for a defined population of construction workers was conducted. Those satisfying the inclusion criteria were provided with gFOBT or FIT kits. Individuals testing positive were invited for a colonoscopy. RESULTS: A total of 909 faecal testing kits were distributed. Age range was 53-60 years. Compliance rate was higher for FIT (58.3%) as compared to gFOBT (46.7%) (p = 0.0006). FIT detected adenomatous polyps and CRC in 37.5 and 25%, respectively, whereas; gFOBT detected 23.5 and 18%. Colonoscopies were normal in 53 and 25% tested positive by gFOBT and FIT, respectively (p = 0.016). CONCLUSION: The FIT was more cost-effective when compared with gFOBT with higher return rate, sensitivity and specificity. A comparative study of faecal occult blood kits in a CRC screening program in a healthy cohort of construction workers. PMID- 20953982 TI - Practices for predicting and preventing preterm birth in Ireland: a national survey. AB - BACKGROUND: Preterm birth can result in adverse outcomes for the neonate and/or his/her family. The accurate prediction and prevention of preterm birth is paramount. This study describes and critically analyses practices for predicting and preventing preterm birth in Ireland. METHODS: A questionnaire seeking information on practices for predicting and preventing preterm birth was mailed to all consultant obstetricians practising in Ireland in February 2006. RESULTS: For predicting preterm birth, 97% of respondents did not use foetal fibronectin testing, 71% carried out routine second and third trimester cervical assessments and 75% routinely screened for genital tract infection. For preventing preterm birth, 62% prescribed bed rest, 24% prescribed antibiotics, 14% routinely inserted a cervical cerclage in women with a history of mid-trimester miscarriage and 61% routinely used tocolytics. CONCLUSION: The findings of this survey, for the most part, reflect the empirical evidence base, international practices and best practice recommendations. PMID- 20953983 TI - Postoperative pseudomeningocele in a 40-year-old man. PMID- 20953984 TI - 17beta-Estradiol attenuates diet-induced insulin resistance and glucose intolerance through up-regulation of caveolin-3. AB - BACKGROUND: Although estrogen contributes to glucose homeostasis, its mechanisms remain unclear. AIMS: To investigate the role of caveolin-3 in estrogen's effects on glucose metabolism. METHODS: Ovariectomized (OVX) and sham-operated rats, fed with normal chow diet (NCD) or high-calorie diet (HCD), received 17beta-estradiol (E(2)) or placebo. Fasting plasma glucose (FPG) was detected and HOMA-IR was calculated. Primary cultured skeletal muscle cells were treated with E(2), in the presence or absence of beta-methyl-cyclodextrin and tamoxifen. Glucose consumption and transportation and expression of caveolin-3 were examined. RESULTS: In NCD-fed rats, OVX or E(2) had no effects on FPG or HOMA-IR. In HCD fed rats, OVX led to the increase of FPG and HOMA-IR, which was attenuated by E(2). In cultured cells, E(2) improved glucose consumption and transportation and enhanced caveolin-3 expression, which were blocked by beta-methyl-cyclodextrin and tamoxifen. CONCLUSION: Caveolin-3 plays an important role in the mechanism by which E(2) attenuates diet-induced glucose intolerance. PMID- 20953985 TI - Analysis of various malignant neoplasms detected by FDG-PET cancer screening program: based on a Japanese Nationwide Survey. AB - OBJECTIVE: The most distinctive feature of FDG-PET cancer screening program is the ability to find various kinds of malignant neoplasms in a single test. The aim of this survey is to clarify the range and frequency of various malignant neoplasms detected by FDG-PET cancer screening performed in Japan. METHODS: "FDG PET cancer screening" was defined as FDG-PET or positron emission tomography and computed tomography (PET/CT) scan with or without other tests performed for cancer screening of healthy subjects. This survey was based on a questionnaire regarding FDG-PET cancer screening. We analyzed the situation of 9 less frequently found malignant neoplasms including malignant lymphoma, malignancy of head and neck, esophagus, hepatobiliary and gallbladder, pancreas, kidney, cervical and uterine, ovary, and bladder. RESULTS: The detailed information of subjects with the suspected 9 kinds of malignant neoplasms mentioned above in the FDG-PET cancer screening program was studied in a total of 1,219 cases from 212 facilities. A statistical significance between PET/CT and PET was found in relative sensitivity and PPV for renal cell cancer. Malignant lymphoma was frequently of indolent type, suspected head and neck cancers had many false positive results, and pancreatic cancer detected in this program was often in the advanced stage even in asymptomatic subjects. The recommendation of combined screening modality to PET or PET/CT was as follows: gastric endoscopy for assessing early esophageal cancer; abdominal ultrasound for screening hepatobiliary and gallbladder cancer; pelvic magnetic resonance imaging for assessing gynecological and pelvic cancers; and the CA125 blood test for screening ovarian cancer. Delayed image was helpful depending on the type of suspected malignant neoplasm. CONCLUSION: We analyzed various types of malignant neoplasms detected by the FDG-PET cancer screening program and presented recommended combination of examinations to cover FDG-PET and PET/CT. PMID- 20953986 TI - Evaluation of micro-CT for emphysema assessment in mice: comparison with non radiological techniques. AB - OBJECTIVES: To define the potential, limitations and synergies of micro-CT and other non-radiological techniques for the quantification of emphysema and related processes in mice, by performing a complete characterization of the elastase induced emphysema model. MATERIALS AND METHODS: Ninety A/J mice (45 treated and 45 controls) were studied at different time points using breath-hold gated micro CT, functional test parameters, RT-PCR for RNA cytokine expression, Luminex technology for cytokine plasma concentration and histomorphometry. RESULTS: Both histomorphometry and micro-CT imaging reflect rapid initial emphysema progression followed by steady-state development at decreasing rates. Cytokine measurements reveal an acute inflammatory response within the first 24 h that disappears after the first week. Limited systemic effect was observed based on plasma cytokine concentration. Lung compliance decreases during the acute inflammation phase and increases afterwards. CONCLUSION: Histomorphometry is the most sensitive technique since it detects airspace enlargement before the other methods (1 h after treatment). Micro-CT correlates well with histology (r2 = 0.63) proving appropriate for longitudinal studies. Functional test parameters do not necessarily correlate with the extent of emphysema, as they can be influenced by acute inflammation. Finally, cytokine measurements correlate with the presence of inflammation in histology but not with emphysema. PMID- 20953987 TI - High glucose condition upregulated Txnip expression level in rat mesangial cells through ROS/MEK/MAPK pathway. AB - Thioredoxin interacting protein (Txnip) is one of the most abundantly up regulated genes in response to hyperglycemia. The increased renal expression of Txnip was associated with type IV collagen accumulation in streptozotocin-induced diabetic mice. As the mechanism of action of high glucose is unknown, we undertook the investigation of the signaling pathway on the upregulation of Txnip expression induced by high glucose in rat mesangial cells. Rat mesangial cells were exposed to normal (5.5 mM) or high (25 mM) glucose at different time points. Txnip expression was determined using real-time RT-PCR and western-blotting at transcription and translation level, respectively. Intracellular reactive oxygen species (ROS) was detected by FACS Calibur flow cytometer using fluorescent probe (DCFH-DA).The treatment with high glucose resulted in an increase of Txnip mRNA from 4 h to 12 h and Txnip protein from 12 to 24 h in comparison with normal glucose condition. In addition, N-acetyl-cysteine (NAC) was found to decrease Txnip protein expression under high glucose condition. Furthermore, p38MAPK inhibitor SB203580 suppressed Txnip expression at transcription and protein level significantly to high glucose exposure. These results suggest that high glucose exposure improves Txnip mRNA and protein expression level by ROS/MEK/MAPK signaling pathway. PMID- 20953988 TI - Effect of DEM mesh size on AnnAGNPS simulation and slope correction. AB - The objective of this paper is to study the impact of the mesh size of the digital elevation model (DEM) on terrain attributes within an Annualized AGricultural NonPoint Source pollution (AnnAGNPS) Model simulation at watershed scale and provide a correction of slope gradient for low resolution DEMs. The effect of different grid sizes of DEMs on terrain attributes was examined by comparing eight DEMs (30, 40, 50, 60, 70, 80, 90, and 100 m). The accuracy of the AnnAGNPS stimulation on runoff, sediments, and nutrient loads is evaluated. The results are as follows: (1) Rnoff does not vary much with decrease of DEM resolution whereas soil erosion and total nitrogen (TN) load change prominently. There is little effect on runoff simulation of AnnAGNPS modeling by the amended slope using an adjusted 50 m DEM. (2) A decrease of sediment yield and TN load is observed with an increase of DEM mesh size from 30 to 60 m; a slight decrease of sediment and TN load with the DEM mesh size bigger than 60 m. There is similar trend for total phosphorus (TP) variation, but with less range of variation, the simulation of sediment, TN, and TP increase, in which sediment increase up to 1.75 times compared to the model using unadjusted 50 m DEM. In all, the amended simulation still has a large difference relative to the results using 30 m DEM. AnnAGNPS is less reliable for sediment loading prediction in a small hilly watershed. (3) Resolution of DEM has significant impact on slope gradient. The average, minimum, maximum of slope from the various DEMs reduced obviously with the decrease of DEM precision. For the grade of 0~15 degrees , the slopes at lower resolution DEM are generally bigger than those at higher resolution DEM. But for the grade bigger than 15 degrees , the slopes at lower resolution DEM are generally smaller than those at higher resolution DEM. So it is necessary to adjust the slope with a fitting equation. A cubic model is used for correction of slope gradient from lower resolution to that from higher resolution. Results for Dage watershed showed that fine meshes are desired to avoid large underestimates of sediment and total nitrogen loads and moderate underestimates of total phosphorus loads even with the slopes for the 50 m DEM adjusted to be more similar to the slopes from the 30 m DEM. Decreasing the mesh size beyond this threshold does not substantially affect the computed runoff flux but generated prediction errors for nitrogen and sediment yields. So the appropriate DEM will control error and make simulation at acceptable level. PMID- 20953989 TI - Development of brain structures, connections, and functions. PMID- 20954006 TI - Characterization and use of human brain microvascular endothelial cells to examine beta-amyloid exchange in the blood-brain barrier. AB - Alzheimer's disease (AD) is characterized by excessive cerebrovascular deposition of the beta-amyloid peptide (Abeta). The investigation of Abeta transport across the blood-brain barrier (BBB) has been hindered by inherent limitations in the cellular systems currently used to model the BBB, such as insufficient barrier properties and poor reproducibility. In addition, many of the existing models are not of human or brain origin and are often arduous to establish and maintain. Thus, we characterized an in vitro model of the BBB employing human brain microvascular endothelial cells (HBMEC) and evaluated its utility to investigate Abeta exchange at the blood-brain interface. Our HBMEC model offers an ease of culture compared with primary isolated or coculture BBB models and is more representative of the human brain endothelium than many of the cell lines currently used to study the BBB. In our studies, the HBMEC model exhibited barrier properties comparable to existing BBB models as evidenced by the restricted permeability of a known paracellular marker. In addition, using a simple and rapid fluormetric assay, we showed that antagonism of key Abeta transport proteins significantly altered the bi-directional transcytosis of fluorescein-Abeta (1-42) across the HBMEC model. Moreover, the magnitude of these effects was consistent with reports in the literature using the same ligands in existing in vitro models of the BBB. These studies establish the HBMEC as a representative in vitro model of the BBB and offer a rapid fluorometric method of assessing Abeta exchange between the periphery and the brain. PMID- 20954007 TI - Advances in avian immunology--prospects for disease control: a review. AB - In order to develop novel solutions to avian disease problems, including novel vaccines and/or vaccine adjuvants, and the identification of disease resistance genes which can feed into conventional breeding programmes, it is necessary to gain a more thorough understanding of the avian immune response and how pathogens can subvert that response. Birds occupy the same habitats as mammals, have similar ranges of longevity and body mass, and face similar pathogen challenges, yet birds have a different repertoire of organs, cells, molecules and genes of the immune system compared to mammals. This review summarises the current state of knowledge of the chicken's immune response, highlighting differences in the bird compared to mammals, and discusses how the availability of the chicken genome sequence and the associated postgenomics technologies are contributing to theses studies and also to the development of novel intervention strategies againts avian and zoonotic disease. PMID- 20954008 TI - Aspergillus infections in birds: a review. AB - Aspergillosis is an infectious, non-contagious fungal disease caused by species in the ubiquitous opportunistic saprophytic genus Aspergillus, in particular Aspergillus fumigatus. This mycosis was described many years ago, but continues to be a major cause of mortality in captive birds and, less frequently, in free living birds. Although aspergillosis is predominantly a disease of the respiratory tract, all organs can be involved, leading to a variety of manifestations ranging from acute to chronic infections. It is believed that impaired immunity and the inhalation of a considerable amount of spores are important causative factors. The pathogenesis, early diagnostic methods and antifungal treatment schedules need to be further studied in order to control this disease. The aim of the present review is to present the current knowledge on aspergillosis with the main emphasis on A. fumigatus infections in captive and free-living birds rather than domestic poultry. The review covers aetiology, epidemiology, pathogenesis, clinical signs and lesions, diagnosis, treatment and prevention. PMID- 20953990 TI - Adolescent brain development and the risk for alcohol and other drug problems. AB - Dynamic changes in neurochemistry, fiber architecture, and tissue composition occur in the adolescent brain. The course of these maturational processes is being charted with greater specificity, owing to advances in neuroimaging and indicate grey matter volume reductions and protracted development of white matter in regions known to support complex cognition and behavior. Though fronto subcortical circuitry development is notable during adolescence, asynchronous maturation of prefrontal and limbic systems may render youth more vulnerable to risky behaviors such as substance use. Indeed, binge-pattern alcohol consumption and comorbid marijuana use are common among adolescents, and are associated with neural consequences. This review summarizes the unique characteristics of adolescent brain development, particularly aspects that predispose individuals to reward seeking and risky choices during this phase of life, and discusses the influence of substance use on neuromaturation. Together, findings in this arena underscore the importance of refined research and programming efforts in adolescent health and interventional needs. PMID- 20954009 TI - Prevalence and molecular characterization of chloramphenicol resistance in Riemerella anatipestifer isolated from ducks and geese in Taiwan. AB - Riemerella anatipestifer is a Gram-negative bacterium that can cause disease in a wide range of wild and domesticated birds, especially waterfowl. The presence of an antibiotic-resistance gene in R. anatipestifer has not yet been reported, indicating the need for investigation. In the present study, 40.5% of R. anatipestifer isolates were found to exhibit resistance to chloramphenicol, while 45.9% showed intermediate resistance and 13.5% were susceptible to chloramphenicol, an antibiotic that has been prohibited for use in food animals in Taiwan since 2003. The resistance gene was identified as the cat gene and cloned by library sequencing. The prevalence of the cat gene in Taiwanese R. anatipestifer isolates was 78.4%. The position of the cat gene was then determined within the novel plasmid, designated pRA0511. pRA0511 was sequenced and shown to be 11,435 bp in size with 10 open reading frames (ORFs). Proteins putatively encoded by these 10 ORFs included four drug-resistance-associated proteins. Two proteins designed as chloramphenicol acetyltransferases (CATs) were encoded by two non-adjacent ORFs, and the other two were TetX2 and a multi-drug ABC transporter permease/ATPase. The putative CAT protein had 62.9 to 79.5% homology to a known type B CAT. The pRA0511 plasmid is the first identified drug resistance plasmid in R. anatipestifer, more specifically associated with chloramphenicol resistance. PMID- 20954011 TI - Compromised T-cell immunity in turkeys may lead to an unpredictable avian metapneumovirus vaccine response and variable protection against challenge. AB - Avian metapneumovirus (aMPV) is an important respiratory pathogen of turkeys with considerable economic impact on poultry production. Although vaccination is widely used for the control of the disease, questions regarding vaccine safety and efficacy remain to be elucidated. This report describes the problems associated with reproducibility of the aMPV-vaccine response, comparing T lymphocyte-compromised and T-cell-intact turkeys. In three consecutive experiments, turkeys partially depleted of T-lymphocytes by treatment with cyclosporin A as well as untreated turkeys were vaccinated with a commercial live aMPV subtype A (aMPV-A) vaccine at 2 weeks of age. Two weeks later they were challenged with a virulent aMPV-A strain. Despite similar genetic background of the turkeys, comparable housing conditions under isolation and the application of the same aMPV-A vaccine, considerable variation was observed among the experiments regarding replication of the vaccine virus, vaccine-induced clinical signs and protection against challenge infection. The results indicate that differences in the outcome of aMPV-A vaccination may be associated with T lymphocyte suppression and additionally with an interfering aMPV-B vaccine exposure at the hatchery in two of the experiments. Our study provides possible explanations for the variable protection provided by aMPV vaccines under field conditions. PMID- 20954010 TI - Antibody fragments, expressed by a fowl adenovirus vector, are able to neutralize infectious bursal disease virus. AB - Single-chain variable fragments (scFv) contain the heavy and light chain variable domains of immunoglobulin, joined by a short peptide linker. Previously, our laboratory has produced neutralizing scFv to epitopes of infectious bursal disease virus (IBDV). The in vitro delivery and expression of one of these scFv with and without the C(H)2-C(H)4 Fc domain of chicken IgY attached (scFv-Fc) by a serotype 8 fowl adenovirus (FAdV-8) vector was investigated in the present study. A panel of FAdV-8 vectors was constructed, each containing a different transgene (scFv or scFv-Fc), a different promoter to drive scFv and scFv-Fc transcription (CMVie or the fowl adenovirus major late promoter), and a different sized, right hand end genomic deletion (52 bp or 2.3 kb). This panel was used to establish what effect these variables had on protein production, viral replication and scFv transcription, as measured by enzyme-linked imunosorbent assay and real-time polymerase chain reaction. Our results showed that, using a FAdV-8 vector containing the optimal CMVie promoter/2.3 kb deletion combination, we successfully expressed a secreted form of both scFv and scFv-Fc that were able to neutralize IBDV both in vitro and in ovo. These studies indicate that the FAdV-8 vector may be a promising candidate to deliver and express therapeutic molecules such as scFv and scFv-Fc in vivo in poultry. PMID- 20954012 TI - Surface IgM on DT40 cells may be a component of the putative receptor complex responsible for the binding of infectious bursal disease virus. AB - To investigate the host-pathogen interactions between infectious bursal disease virus (IBDV) and target B-lymphocytic cells, a cDNA T7 phage display library from the chicken bursa of Fabricius was constructed and screened for virus binding. Surface immunoglobulin M (sIgM) was isolated as a putative candidate binding site and its interactions with IBDV were further investigated using a chicken bursal lymphoma-derived cell line DT40. The results showed that the lambda light chain of sIgM specifically interacted with IBDV in a virulence-independent manner in vitro, and most of the binding of IBDV to DT40 cells was inhibited by sIgM specific monoclonal antibodies. Further, the infectivity of IBDV in vitro was reduced by sIgM-specific monoclonal antibodies. Our data provided evidence that sIgM may participate as one of the putative membrane binding sites responsible for IBDV infection. PMID- 20954013 TI - Expression profiling of genes associated with regulatory functions of T-cell subsets in Marek's disease virus-infected chickens. AB - The environment of tumours caused by Marek's disease virus (MDV) in chickens has been shown to have an immunoregulatory phenotype. The objective of the present study was to examine the expression of key T-regulatory markers during various stages of MDV pathogenesis. Specific-pathogen free (SPF) as well as major histocompatibility complex-defined chickens were infected with the RB1B and JM-16 strains of MDV, respectively. CD4(+) and CD8(+) T cells from the spleens of infected as well as age-matched controls were sorted by flow cytometry at 4, 10, and 21 days post infection (d.p.i.). The expression of molecules such as CTLA-4, IL-2aR (CD25), PD-1 and PDL-1 was quantified by real-time, quantitative, reverse transcription polymerase chain reaction. There was an up-regulation of CTLA-4 in CD4(+) T cells at 4 d.p.i. The expression of PD-1 was also up-regulated in the CD4(+) T-cell subset of SPF birds at 21 d.p.i. Furthermore, the expression of PD 1 was enhanced in CD4(+) and CD8(+) T cells of genetically susceptible chickens, linking this molecule to susceptibility to disease. The expression of CD25 was down-regulated in both SPF and genetically defined birds after infection. This may be a mechanism through which the virus exerts its immunosuppressive effects. In conclusion, the results of the present study provide more insight into immunomodulatory processes that occur in the lymphoid tissues of MDV-infected chickens. PMID- 20954014 TI - A proof-of-principle study to identify suitable vaccine seed candidates to combat introductions of Eurasian lineage H5 and H7 subtype avian influenza viruses. AB - Vaccination against avian influenza (AI) is now included amongst the prevention and control measures recommended by international animal health organizations to combat the disease in poultry. For optimal control of human influenza infections, the antigenic variability within subtypes requires the annual update of seed strains for inclusion in vaccines. The decisions taken are based on serological cross-reactivity of viral strains measured by haemagglutination inhibition (HI) tests. The reason for this is to ensure that the vaccine contains strains that are related antigenically to the current circulating field strain as field viruses evolve or are substituted by variants of distinct antigenicity. Such an annual approach is not viable economically for the poultry industry. In the current study, we have applied a similar HI-based approach to demonstrate, as proof of principle, that cross-reactive strains can be identified. Applying the same approach used by the World Health Organization to investigate antigenic differences among human influenza viruses, we assessed the serological cross reactivity of a selection of natural H5 and H7 subtype viruses. Analysing HI data, we have identified strains that are cross-reactive and may have the potential to act as seed viruses for future vaccine development. This study should be considered a starting point for a more informed approach to the selection of seed strains for the development of avian influenza vaccines against field infections caused by viruses of H5 and H7 subtypes. PMID- 20954015 TI - Characterization of reticuloendotheliosis virus isolates obtained from broiler breeders, turkeys, and prairie chickens located in various geographical regions in the United States. AB - Nine reticuloendotheliosis virus (REV) isolates obtained from broiler breeders, turkeys, and prairie chickens located in three different geographical regions in the USA, and three isolates obtained from known contaminated live-virus vaccines were characterized using polymerase chain reaction (PCR) and indirect immunofluorescence (IFA) assays. All isolates were propagated in chicken embryo fibroblasts obtained from a specific pathogen free breeder flock. PCR analysis of all 12 isolates resulted in the amplification of the 291-bp REV long-terminal repeat region (LTR); none of the isolates exhibited a different pattern or shift from the expected PCR product of REV LTR. The subtype of the REV isolates was determined by IFA using REV-specific monoclonal antibodies, 11B118.22, 11C237.8, and 11D182. Results from sub-typing indicated that all nine isolates from broiler breeders, turkeys, and prairie chickens belonged to subtype 3, and are antigenically related to the chick syncytial virus (CSV) strain of REV, the prototype of subtype 3 REV. In contrast, the three isolates from contaminated vaccines were classified as subtype 2, and were antigenically related to spleen necrosis virus (SNV) strain of REV, the prototype of subtype 2 REV. Three isolates representing REV isolated from broiler breeders, turkeys, and prairie chickens were cloned and further evaluated by DNA sequence analysis of the envelope gene. Results from DNA sequence analysis confirmed those from sub-typing and indicated that the three REV isolates representing those from broiler breeders, turkeys, and prairie chickens are closely related to CSV of REV, with an amino acid homology of 98% or greater as compared with SNV with an amino acid homology of 95% or less. Data from this study clearly indicate that subtype 3 is the most common subtype of REV circulating in three different avian species, namely broiler breeders, turkeys and prairie chickens, located in three different geographical regions in the United States. PMID- 20954016 TI - Pyrosequencing analysis for a rapid classification of fowl adenovirus species. AB - A rapid fowl adenovirus (FAdV) classification method based on a 30-bp sequence of the hexon loop (L1) was developed using the pyrosequencing technique. FAdV identification is relevant for epidemiological studies and for the adoption of a correct strategy where vaccination is to be used for the control of the disease. FAdV typing is usually performed using polymerase chain reaction coupled with either conventional DNA sequencing or restriction enzyme analysis; however, both methods can be time consuming and/or very expensive to be used as a routine tool. In the present study, polymerase chain reaction and subsequent pyrosequence analysis of the variable hexon L1 region were assessed in order to rapidly differentiate FAdV species. Forty-nine FAdV samples (22 reference strains and 27 field isolates) were tested and the results were compared with those obtained by conventional DNA sequencing. The results clearly demonstrated that pyrosequence analysis provides a new approach for a rapid differentiation and classification of the FAdV species that is faster, more cost-effective and easier to interpret than other techniques commonly used. PMID- 20954017 TI - Oral vaccination of 1-day-old turkeys with in vitro attenuated Histomonas meleagridis protects against histomonosis and has no negative effect on performance. AB - One-day-old turkey poults were vaccinated against histomonosis (syn. histomoniasis) via the oral route by application of in vitro attenuated Histomonas meleagridis. Subsequently, two different groups composed of 14 birds each were challenged cloacally with highly virulent histomonads after 2 or 4 weeks. Two additional groups of non-vaccinated birds were infected with the challenge inoculum at the same time points. In addition, a group of 19 birds, of which 14 were vaccinated but not challenged, were kept for clinical and serological examinations. Non-vaccinated and non-challenged birds (n=10) represented the negative control group. All non-vaccinated but infected birds and 10 out of 14 vaccinated turkeys challenged 2 weeks post vaccination (w.p.v.) contracted severe histomonosis. Turkeys challenged 4 w.p.v. and all remaining birds used in this experiment did not show any pathognomonic clinical signs. In addition, no adverse effect regarding the weight gain could be observed in birds that were vaccinated but not challenged. The excretion of attenuated and virulent live histomonads was observed very infrequently by re-isolation, but transmission to in-contact birds was very efficient. Presence of antibodies was first noticed 3 w.p.v. and antibody levels remained above the cut-off value until termination of the experiment at 16 w.p.v. The present experiment demonstrates for the first time the potential efficacy of in vitro attenuated histomonads used as an orally applied vaccine to 1-day-old turkeys for protection against fatal histomonosis without affecting performance. PMID- 20954018 TI - Early warning indicators for hock burn in broiler flocks. AB - Hock burn is a common disease of broiler chickens affecting flock welfare and farmer income. Here we use hierarchical logistic regression (HLR) models to identify risk factors for hock burn using data from 5895 flocks, collected over 3.5 years by a large UK broiler company. The results suggest that at 2 weeks of age, weight and weight density may be useful predictors of flocks at risk of a high incidence of hock burn. In contrast, stocking density at placement is not. The use of these and other variables in disease prevention add value to routinely collected management data and can assist in improving broiler welfare and farm income. PMID- 20954019 TI - Shedding and serologic responses following primary and secondary inoculation of house sparrows (Passer domesticus) and European starlings (Sturnus vulgaris) with low-pathogenicity avian influenza virus. AB - Waterfowl and shorebirds are well-recognized natural reservoirs of low pathogenicity avian influenza viruses (LPAIV); however, little is known about the role of passerines in avian influenza virus ecology. Passerines are abundant, widespread, and commonly come into contact with free-ranging birds as well as captive game birds and poultry. We inoculated and subsequently challenged house sparrows (Passer domesticus) and European starlings (Sturnus vulgaris) with wild bird origin LPAIV H3N8 to evaluate their potential role in transmission. Oropharyngeal shedding was short lived, and was detected in more starlings (97.2%) than sparrows (47.2%; n=36 of each). Cloacal shedding was rare in both species (8.3%; n=36 of each) and no cage-mate transmission occurred. Infectious LPAIV was cultured from oropharyngeal and cloacal swabs and gastrointestinal and respiratory tissues from both species. Seroconversion was detected as early as 3 days post inoculation (d.p.i.) (16.7% of sparrows and 0% of starlings; n=6 each); 50% of these individuals seroconverted by 5 d.p.i., and nearly all birds (97%; n=35) seroconverted by 28 d.p.i. In general, pre-existing homologous immunity led to reduced shedding and increased antibody levels within 7 days of challenge. Limited shedding and lack of cage-mate transmission suggest that passerines are not significant reservoirs of LPAIV, although species differences apparently exist. Passerines readily and consistently seroconverted to LPAIV, and therefore inclusion of passerines in epidemiological studies of influenza outbreaks in wildlife and domestic animals may provide further insight into the potential involvement of passerines in avian influenza virus transmission ecology. PMID- 20954022 TI - Biofilms isolated from washing machines from three continents and their tolerance to a standard detergent. AB - The goal of this comparative study was to investigate biofilm forming microorganisms living in washing machines (WMs). Biofilms were sampled from 11 washing machines from four countries and three continents. Among the 94 isolated strains, 30% were potential human pathogens. Representative strains were selected and biofilm formation was evaluated with the crystal violet (CV) assay. The majority of the WM isolates formed more biofilm than their reference strains. Biofilms of P. putida WM (the largest biofilm producer) were exposed to different concentrations (0.0007-7 g l(-1)) of the standard detergent IEC-A* at 30 degrees C for 30 min and observed with confocal laser scanning microscopy. Using quantitative CVA, P. putida WM biofilm removal required higher detergent concentrations than the type strain. However, for both strains the recommended detergent concentration (7 g l(-1)) was insufficient to completely clean surfaces from cell debris and exopolymeric substances. PMID- 20954025 TI - Aquaculture and fisheries pose unique occupational hazards. PMID- 20954026 TI - Despite advances made in this area, it remains among the most dangerous of trades. Preface. PMID- 20954027 TI - A persistent high human cost of protein: commercial fishing and aquaculture. PMID- 20954028 TI - An interview with Vietnamese fishermen of Louisiana in the wake of the oil spill. PMID- 20954029 TI - Occupational fatalities in the United States commercial fishing industry, 2000 2009. AB - The occupational fatality rate among commercial fishermen decreased in the United States during 1992-2008; however, commercial fishing continues to be one of the most dangerous occupations in the United States, with an average annual fatality rate of 129 deaths per 100,000 fishermen in 2008. By contrast, the average annual occupational fatality rate among all US workers during the same period was four deaths per 100,000 workers. During the 1990s, numerous safety interventions were developed for Alaska fisheries that resulted in a significant decline in the state's commercial fishing fatality rate. In 2007, the National Institute for Occupational Safety and Health (NIOSH) expanded surveillance of commercial fishing fatalities to the rest of the United States. The purpose of this report is to identify the hazards and risk factors for all causes of occupational mortality in the US commercial fishing industry, and to explore how those hazards and risk factors differ among fisheries and locations. During 2000-2009, 504 commercial fishing fatalities occurred in the United States. Most (261, 52%) occurred following a vessel disaster (defined as a sinking, capsizing, or other event in which the crew was forced to abandon ship) or a fall overboard (155, 31%). Fatalities occurred in Alaska (133, 26%), Northeast (124, 25%), Gulf of Mexico (116, 23%), West Coast (83, 16%), and the Mid- and South Atlantic (41, 8%) regions. Fatalities occurred most commonly while fishing for shellfish (226, 47%), groundfish (144, 30%) and pelagic fish (97, 20%). Average annual fatality rates were calculated for selected fisheries. The Northeast multispecies groundfish fleet had the highest average annual fatality rate (600 deaths per 100,000 full-time equivalent [FTE] fishermen) followed by the Atlantic scallop fleet (425 deaths per 100,000 FTE fishermen) and the West Coast Dungeness crab fleet (310 deaths per 100,000 FTE fishermen). To reduce fatalities among fishermen at greatest risk, additional prevention measures tailored to specific high-risk fisheries should be considered. PMID- 20954030 TI - The development and efficacy of safety training for commercial fishermen. AB - Commercial fishing is still the most dangerous occupation in the United States. Efforts to have more stringent safety regulations in this industry beginning in the 1960s, culminated in the Commercial Fishing Vessel Safety Act of 1988. The purpose of this paper is to provide a short history of the development of safety training in the United States and the current training infrastructure. This paper will also review studies available regarding the effectiveness of safety training in reducing fatalities among fishermen. The lack of familiarity and practice with marine survival equipment such as life rafts, immersion suits, and emergency locating beacons has been noted in National Transportation Safety Board and US Coast Guard casualty reports as a contributing factor in fatalities. These reports have demonstrated the importance of not just having survival equipment onboard, but training in how to use it effectively in an emergency. There is evidence that safety training has made a measurable impact in surviving an emergency at sea and that recent training (within 5 years) is most effective in saving lives. More recently, studies have been completed to understand how skills may diminish over time since initial training. PMID- 20954031 TI - Utilizing United States Coast Guard data to calculate incidence rates and identify risk factors for occupational fishing injuries in New Jersey. AB - Commercial fishing has high rates of work-related injury and death and needs preventive strategies. Work-related fatal and nonfatal injury rates for New Jersey (NJ) commercial fishermen who suffered unintentional traumatic injuries from 2001 to 2007 are calculated using data from the United States Coast Guard (USCG) Marine Safety and Pollution Database and estimated denominator data. Fatalities were compared to those ascertained by the NJ Fatality Assessment Control and Evaluation (FACE) surveillance system. For the study years, 225 nonfatal injuries and 31 fatal injuries were reported. Among nonfatal injuries, the causes by frequency were fall onto surface, crushed between objects, struck by moving object, line handling/caught in lines, collision with fixed objects, fall into water, and other noncontact injuries. The distribution of fatal injuries differed, with the most frequent cause as crushed between objects. Falls into water and several noncontact injuries accounted for most of the other fatalities. The large majority (96%) of nonfatal injuries were contact injuries, whereas only 68% of fatalities were classified as contact. The overall incidence rate of nonfatal injuries was 1188 per 100,000 full-time equivalents (FTEs) per year. The rate varied considerably by year, from a low of 286 per 100,000 FTEs in 2001 and 2007 to 3806 per 100,000 FTEs in 2003. The overall occupational fatality rate over the period 2001-2007 was 164 per 100,000 FTEs per year. These results can aid in targeting the commercial fishing industry for injury prevention strategies and interventions, especially for falls, crushing injuries, and drownings. PMID- 20954032 TI - Factors influencing safety among a group of commercial fishermen along the Texas Gulf Coast. AB - The commercial fishing trades are among the most dangerous jobs in the world. Little published information exists regarding some populations of commercial fishermen such as along the United States Gulf Coast. Studying these unique and often vulnerable groups is important to characterize potential influences on or barriers to safety in anticipation of designing interventions that can change safety behaviors. Working closely with the United States Coast Guard (USCG), a cross-sectional convenience sample of Gulf Coast shrimp fishermen in and near the Port of Galveston, Texas, was surveyed. The survey included demographic factors and broadly covered areas such as type of work and fishing activities, general or global perceptions and beliefs related to safety and accidents, self-report of ability to use safety equipment or apply procedures aboard vessel, and training considerations. Surveys were obtained following informed consent (n = 133). Of the participants, 96.7% were male with 60.9% >=40 years old. A majority were of Asian descent (57.1% of all fishermen, 82.1% of shrimp fishermen). Over half claimed to speak little or no English and nearly 60% considered the job to be very safe to neutral. A third to half of respondents expressed doubt about their knowledge of using essential safety equipment in the event of emergency. A large portion of the participants preferred hands-on safety training (40.6%). Important findings about this group of commercial fishermen will help with future development of effective prevention practices through the delivery of culturally appropriate safety awareness training. One element that must be addressed in training programs is to increase the awareness among fishermen about the severe occupational risks inherent in this type of work. Community trust and collaborative partnerships are essential to the success of such initiatives. PMID- 20954034 TI - Risk factors for musculoskeletal symptoms among crawfish farmers in Louisiana--a pilot study. AB - The prevalence of musculoskeletal symptoms (MSS) among crawfish farmers is unknown. The purpose of this study was to assess the prevalence of MSS in nine body regions among crawfish farmers, and to examine associations between MSS and crawfish farm work activities. Questionnaires were mailed to randomly selected crawfish farmers in the State of Louisiana, USA. Site-specific MSS, demographics, and crawfish farm work information was obtained from the previous six months. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with logistic regression adjusting for potential confounders. Among the participants (N = 184), shoulder MSS were reported most frequently (62%). Wrist/hand and low back MSS were significantly associated with tractor use (OR(adj) = 2.89; 95% CI = 1.28 6.56) and (OR(adj) = 2.41; 95% CI = 1.03-5.67), respectively. Also, upper back MSS were associated with the number of years working on a crawfish farm (OR(adj) = 3.07; 95% CI = 1.17-8.04). Shoulder and low back MSS were common. Tractor use may increase the risk of wrist/hand and low back MSS. Future studies need accurately assess exposures to physical risk factors for MSS so ergonomic interventions can be developed. PMID- 20954033 TI - Cultural influences on safety and health education among Vietnamese fishermen. AB - Every ethnic group has its own cultural background and history that influences how it views health behaviors. By virtue of their work history, many Vietnamese have pursued the fishing industry when migrating to the United States. Even though the fishing trades are among the most dangerous jobs in the world, there has been little attention in the literature to the significant role that culture plays in the expression and experience of occupational health practices among Vietnamese shrimp fishermen. Three focus group sessions were conducted to identify factors that hinder or facilitate receptivity to available training and to guide culturally appropriate content. Participants were recruited using purposive sampling among various Vietnamese shrimp fishermen communities in Texas. Utilizing a series of open-ended questions, sessions were conducted in their native language among owners/captains/deckhands; support infrastructure- adult family members and religious/community leaders; and industry management and insurance representatives. Translations of transcribed documents were compared with simultaneous translations to ensure thematic consistency. Conducting hands on training among Vietnamese by experienced fishermen, specifically targeting captains, was considered key to safety culture on the vessels. Findings of the study support that training should occur in a variety of formats (hands-on), but should be periodic, current, practical, convenient, taught in the primary language of the audience by an experienced individual, culminate in a certificate of completion, and target captains first. These findings illustrate the importance of considering cultural factors in the design of workplace interventions that focus on changes in safety and occupational health behaviors. PMID- 20954035 TI - Assessment of physical risk factors for the shoulder using the Posture, Activity, Tools, and Handling (PATH) method in small-scale commercial crab pot fishing. AB - An observational work-sampling technique--Posture, Activity, Tools, and Handling (PATH)--was used to describe the prevalence of awkward postures and other physical risk factors for shoulder symptoms among a purposive sample of 11 small scale commercial crab pot fishing crews. Fishing activities with awkward shoulder postures included hooking the buoy, feeding the rope into the hydraulic puller, and handling the crab pots. Increasing the size of the crew decreased the frequency of awkward shoulder postures for the captain but not for the mate. Awkward shoulder postures varied by technique, task distribution, equipment, and boat characteristics and setup, indicating these factors may be important determinants of exposure. Care should be taken in assuming personal techniques drives ergonomic exposure variability among these small-scale commercial fishermen. PMID- 20954036 TI - Risk analysis of tractor overturns on catfish farms. AB - Fatal and nonfatal injuries occur on catfish farms as a result of tractor overturns, but these injuries can be greatly mitigated when a tractor is equipped with a rollover protective structure (ROPS) and seatbelt. This study analyzed the proportion of tractors on catfish farms in Mississippi not equipped with ROPS and the cost of retrofitting those tractors with a ROPS and seatbelt as compared to the expected benefits gained from adding the protection. To determine if farmers have the financial incentive to retrofit older tractors, a net present value framework was used because the expected benefits occur over a number of years. The ROPS retrofit is a one-time cost that occurs immediately, and thus the present value does not need to be calculated, i.e., time period 0. According to this study adding ROPS will provide a net benefit of $22,877 in the event of an overturn. When dealing with small farms (<125 acres) where an average tractor is used for approximately twice as many hours compared to an average tractor on large farms, the extra hours worked by a single tractor resulted in total benefits of retrofitting ROPS of $9.45 per year, whereas for large farms the net benefit is $4.70 (=125 acres). Given that the least expensive retrofit is $147, it would take 15.5 years of tractor use on the small farms for the expected benefits to outweigh the cost. Given the large range of costs that could occur due to an overturn, there could be a significant premium for not having ROPS protection. In other words, there likely is a smaller range of costs from an overturn with ROPS than without ROPS because ROPS reduces the more serious incidents. PMID- 20954037 TI - Review of occupational hazards associated with aquaculture. AB - Aquaculture is an emerging sector that is associated with most of the same hazards that are present in agriculture generally, but many fish farming tasks entail added danger, including working around water and working at night. Comprehensive studies of these hazards have not been conducted, and substantial uncertainty exists as to the extent of these hazards. The question addressed in this investigation was, "What is known about potential hazardous occupational exposures to aquatic plant and animal farmers?" In this review, causes of death included drowning, electrocution, crushing-related injury, hydrogen sulfide poisoning, and fatal head injury. Nonfatal injuries were associated with slips, trips, and falls; machines; strains and sprains; chemicals; and fires. Risk factors included cranes (tip over and power line contact), tractors and sprayer equipped all-terrain vehicles (overturn), heavy loads (lifting), high-pressure sprayers, slippery surfaces, rotting waste (hydrogen sulfide production), eroding levees (overturn hazard), storm-related rushing water, diving conditions (bends and drowning), nighttime conditions, working alone, lack of training, lack of or failure to use personal flotation devices, and all-terrain vehicle speeding. Other hazards included punctures or cuts from fish teeth or spines, needlesticks, exposure to low temperatures, and bacterial and parasitic infections . PMID- 20954038 TI - Workers need training to avoid heat illness and recognize the symptoms in themselves and coworkers. PMID- 20954041 TI - Impact of a secondary treated bleached Kraft pulp mill effluent in both sexes of goldfish (Carassius auratus L.). AB - The aim of the present study was to assess the toxic effects of a secondary treated effluent from a modern pulp mill processing Eucalyptus globulus on both sexes of goldfish. The effects in the exposed fish were investigated by measuring biomarkers which have been used to assess the effects of BKME on aquatic biota, with particular emphasis in fish. However, few studies have been focused on effluents from pulp mill plants processing eucalyptus. The relative proportion of cytochrome P450 (CYP1A) and vitellogenin (VTG) induction were analyzed in the livers of males and females goldfish, exposed to different concentrations of a bleached Kraft pulp mill (BKPM) effluent. Somatic indices such as HSI (hepatosomatic index) and GSI (gonadosomatic index) were calculated and a significant reduction was found in males GSI. A significant increase of HSI was recorded for both sexes exposed to 50% BKPM effluent. Exposure to BKPM effluent induced CYP1A synthesis in both sexes and decreased VTG synthesis in females according to the different effluent concentrations suggesting that the secondary treated effluent contained compounds that affect fish negatively. The results suggest that BKPM effluent can cause sex-related biochemical changes in xenobiotic metabolism. PMID- 20954040 TI - Biodegradation of polyether algal toxins--isolation of potential marine bacteria. AB - Marine algal toxins such as brevetoxins, okadaic acid, yessotoxin, and ciguatoxin are polyether compounds. The fate of polyether toxins in the aqueous phase, particularly bacterial biotransformation of the toxins, is poorly understood. An inexpensive and easily available polyether structural analog salinomycin was used for enrichment and isolation of potential polyether toxin degrading aquatic marine bacteria from Florida bay area, and from red tide endemic sites in the South Florida Gulf coast. Bacterial growth on salinomycin was observed in most of the enrichment cultures from both regions with colony forming units ranging from 0 to 6*10(7) per mL. The salinomycin biodegradation efficiency of bacterial isolates determined using LC-MS ranged from 22% to 94%. Selected bacterial isolates were grown in media with brevetoxin as the sole carbon source to screen for brevetoxin biodegradation capability using ELISA. Out of the two efficient salinomycin biodegrading isolates MB-2 and MB-4, maximum brevetoxin biodegradation efficiency of 45% was observed with MB-4, while MB-2 was unable to biodegrade brevetoxin. Based on 16S rRNA sequence similarity MB-4 was found have a match with Chromohalobacter sp. PMID- 20954042 TI - Emission of organic compounds from mould and core binders used for casting iron, aluminium and bronze in sand moulds. AB - Emissions from mould and core sand binders commonly used in the foundry industry have been investigated. Degradation of three different types of binders was investigated: Furfuryl alcohol (FA), phenolic urethane (PU) and resol-CO2 (RC). In each group of binders, at least two different binder compositions were tested. A test method that provides uniform test conditions is described. The method can be used as a general test method to analyse off gases from binders. Moulds, containing a standard size casting, were produced and the amount and type of organic compounds, resulting from thermal degradation of binders, was monitored when cast iron, bronze and aluminium was poured in the moulds. Binder degradation was measured by collecting off gases in a specially designed ventilation hood at a constant flow rate. Samples were taken from the ventilation system and analysed for hydrocarbons and CO content. It is shown how off-gases vary with time after pouring and shake out. Also the composition of off-gases is analysed and shown. It is further shown how the composition of off-gasses varies between different types of binders and with varying composition of the binders as well as function of the thermal load on the moulding sand. PMID- 20954043 TI - Removal of a potent cyanobacterial hepatotoxin by peat. AB - Microcystins (cyclic heptapeptides), produced by a number of freshwater cyanobacteria, are of health concern in potable water supplies. In this article, the adsorptive removal of microcystin-RR (MCRR) from the aqueous solution by a low-cost adsorbent, peat, was investigated. The BET surface area of peat was found to be 12.134 m2/g. The adsorption process was pH dependent, with maximum adsorption occurring at pH 3. Kinetic studies revealed that the adsorption of MCRR onto peat was a rapid process. The adsorption capacity (Qmax) as revealed by the Langmuir model was found to be 286 MUg/g at pH 3. Among various desorption media studied, strong alkali solutions (2 N NaOH) showed the highest desorption (97%). Thus, peat has potential to be used as an adsorbent for the removal of the cyanotoxin, MCRR, from drinking water. PMID- 20954044 TI - Enantioselectivity of racemic metolachlor and S-metolachlor in maize seedlings. AB - Chiral herbicides may have enantioselective effects on plants. In this study, we assessed and compared the enantioselectivity of the chiral herbicides rac metolachlor and S-metolachlor to maize seedlings. The superoxide dismutase activity (SOD) activity of roots and stem leaves treated by rac-metolachlor was 1.38 and 1.99 times that of roots and stem leaves treated by S-metolachlor. The peroxidase activity (POD) activity of roots and stem leaves was 1.48 and 2.79 times that of roots and stem leaves treated by S-metolachlor, respectively, while the catalase activity (CAT) activity was 4.77 and 8.37 times greater, respectively. The Hill reaction activity of leaves treated by rac-metolachlor were 1.45, 1.33, and 1.14 times those treated by S-metolachlor with treatments of 18.6, 37.2, and 74.4 MUM. The differences observed between treatments of rac- and S-metolachlor were significant. Significant differences in maize seedling morphology were also observed between rac- and S-metolachlor treatments. The degradation rate of S-metolachlor in roots was greater than that of rac metolachlor. The half-lives of rac- and S-metolachlor were 80.6 and 60.3 h at 18.6 MUM; 119.5 and 90 h at 37.2 MUM; and 169 and 164.8 h at 74.4 MUM, respectively. Using the liquid chromatography-mass spectrometry method, hydroxymetolachlor, deschlorometolachlor and deschlorometolachlor propanol were considered to be possible metabolites. We determined the enantioselective toxicity of rac- and S-metolachlor to maize and speculated on the proposed metabolic pathway of metolachlor in maize roots. These results will help to develop an understanding of the proper application of rac- and S-metolachlor in crops, and give some information for environmental safety evaluation of rac- and S-metolachlor. PMID- 20954045 TI - Determination of the insecticide diflubenzuron in mushrooms by kinetic method and high-performance liquid chromatographic method. AB - In the present study, a new sensitive and simple kinetic-spectrophotometric method for the determination of the insecticide diflubenzuron [1-(4-chlorophenyl) 3-(2,6-diflubenzoil)urea] is proposed. The method is based on the inhibited effect of diflubenzuron on the oxidation of sulphanilic acid (SA) by hydrogen peroxide in phosphate buffer in presence Cu(II) ion. Diflubenzuron was determined with linear calibration graph in the interval from 0.31 to 3.1 MUg mL-1 and from 3.1 to 31.0 MUg mL-1. The optimized conditions yielded a theoretical detection limit of 0.18 MUg mL-1 corresponding to 0.036 mg kg(-1)mushroom sample based on the 3S(b) criterion. The RSD is 5.03-1.83 % and 2.81-0.71 % for the concentration interval of diflubenzuron 0.31-3.1 MUg mL-1 and 3.1-31.0 MUg mL-1, respectively. The reaction was followed spectrophotometrically at 370 nm. The kinetic parameters of the reaction are reported, and the rate equations are suggested. The developed procedure was successfully applied to the rapid determination of diflubenzuron in spiked mushroom samples of different mushroom species. The HPLC method was used like a comparative method to verify results. PMID- 20954046 TI - Cross-reactivity of anti-Salmonella egg-yolk antibodies to Salmonella serovars. AB - The cross-reactivity of egg yolk antibodies specific to antigens of Salmonella Enteritidis and Salmonella Typhimurium to killed bacterial cells of common Salmonella serovars were tested using an indirect Enzyme Linked Immunosorbent Assay (ELISA). Egg yolk antibodies were produced against purified fimbriae, flagella and lipopolysaccharide (LPS) of S. Enteritidis strain ATCC13076 and flagella, LPS and outer membrane proteins (OMP) of S. Typhimurium strain ATCC13311. For immunological specificity of egg yolk antibodies against killed bacterial cells, we found that the titers of the anti-S. Enteritidis egg yolk antibodies were higher than those of the anti-S. Typhimurium antibodies. In the evaluation of cross-reactivity of these egg yolk antibodies to various Salmonella serovars, we observed that the anti-S. Enteritidis antibodies exhibited more specific affinity than those of the anti-S. Typhimurium antibodies. All S. Enteritidis strains reacted specifically with the anti-S. Enteritidis fimbrial and flagellar egg yolk antibody whereas anti-S. Enteritidis LPS and anti-S. Typhimurium LPS, OMP and flagellar antibodies displayed non-specific reactivity to all Salmonella serovars used in this study. This finding suggests that it may be possible to design a anti-fimbrial egg yolk antibody of S. Enteritidis as a diagnostic tool and a cocktail of OMP and LPS antigens of S. Enteritidis and S. Typhimurium could be used for administering broad spectrum passive immunity to protect against the colonization of pathogenic Salmonella strains in food animals. PMID- 20954047 TI - Transfer of pesticides to the brew during mate drinking process and their relationship with physicochemical properties. AB - In order to evaluate the extraction of pesticide residues that are transferred to the brew during mate drinking process of P.U.1 yerba mate leaves (Ilex paraguariensis), a special device to simulate the way in which mate is drunk in Uruguay was developed. The transfer to the brew of 12 organophosphates, 5 synthethic pyrethroids and one organochlorine pesticide from spiked samples was studied. The relationship between the transfer data thus obtained and physicochemical properties like water solubility (Ws), octanol-water coefficient (Kow) and Henry's constant (H) was evaluated. The extractability of the pesticide residues from yerba mate can be correlated with log Ws and log Kow. These transfer values allowed the calculation of ARLs (acceptable residue level) for the pesticides following Food and Agriculture Organization (FAO), World Health Organizaion (WHO) guidelines. These results can help the future establishment of maximum residue levels (MRLs). PMID- 20954048 TI - Introduction to the special series on integrating personality, psychopathology, and psychotherapy using interpersonal assessment. AB - The interpersonal paradigm in personality assessment employs multiple models, measures, and methods to examine the interpenetration of personality, psychopathology, and psychotherapy. Its organizing framework is the nomological net of agency and communion, which are fundamental metaconstructs that can be conceptualized and measured at multiple levels ranging from broad interpersonal motives to stable interpersonal dispositions to specific interpersonal behaviors. This Special Series presents diverse research and clinical applications of interpersonal theory and assessment to (a) enhance diagnosis, case conceptualization, and treatment planning; (b) identify developmental catalysts of and current influences on psychopathological symptoms; and (c) articulate different ways in which personality, psychopathology, and psychotherapy are interrelated. Each article demonstrates the integrative nature of interpersonal assessment while concurrently exemplifying the unique assumptions and methods of contemporary interpersonal diagnosis. PMID- 20954049 TI - An interpersonal perspective on the personality assessment process. AB - Many aspects of therapeutic approaches to the personality assessment process derived from or are consistent with Sullivan's interpersonal approach to clinical practice, but the link between such approaches and contemporary interpersonal theory remains underdeveloped. In this article, I argue that contemporary interpersonal theory provides a valuable framework within which to conceptualize the personality assessment process. Specifically, I argue that interpersonal models can parsimoniously represent client behavior and can facilitate discussions of assessment data with assessees. Further, I show that hypotheses on the therapeutic mechanisms of personality assessment can be reframed in contemporary interpersonal metatheory so that they can be compared and tested directly. PMID- 20954050 TI - Assessment of repeated relational patterns for individual cases using the SASB based Intrex questionnaire. AB - Repeated interpersonal patterns are central to case conceptualization and treatment planning in interpersonal and attachment-based approaches to therapy. In this study, raters (133 college students, 165 inpatients) provided data on the Intrex questionnaire (Benjamin, 2000) about self-treatment, relationship with a significant other, and remembered interactions with parents in childhood. Within subject profiles were inspected for precise behavioral matches conforming to 3 "copy process" (CP) patterns: identification (behaving like an important other), recapitulation (behaving as if the other person is still present and in charge), and introjection (treating the self the way another did). We observed CP evidence in most individual ratings. Consistent with expectation, nonclinical raters tended to copy a securely attached pattern of affiliation, low hostility, and moderate degrees of enmeshment and differentiation. Only patients copied maladaptive behavior at greater than base rate expectation. We discuss implications and provide recommendations for use of Intrex in individual assessment of CP. PMID- 20954051 TI - Affect dysregulation in individuals with borderline personality disorder: persistence and interpersonal triggers. AB - We hypothesized that affect dysregulation among individuals with borderline personality disorder (BPD) would involve greater persistence of negative affect between interpersonal events and heightened reactivity to stimuli indicating risk of rejection or disapproval, specifically perceptions of others' communal (agreeable-quarrelsome) behaviors. A total of 38 participants with BPD and 31 controls collected information about affect and perceptions of the interaction partner's behavior during interpersonal events for a 20-day period. Negative and positive affect persisted more across interpersonal events for individuals with BPD than for controls. In addition, individuals with BPD reported a greater increase in negative affect when they perceived less communal behavior and a smaller increase in positive affect when they perceived more communal behavior in others. Findings indicate the importance of interpersonal perceptions in the affect dysregulation of individuals with BPD. PMID- 20954053 TI - Interpersonal subtypes in social phobia: diagnostic and treatment implications. AB - Interpersonal assessment may provide a clinically useful way to identify subtypes of social phobia. In this study, we examined evidence for interpersonal subtypes in a sample of 77 socially phobic outpatients. A cluster analysis based on the dimensions of dominance and love on the Inventory of Interpersonal Problems Circumplex Scales (Alden, Wiggins, & Pincus, 1990) found 2 interpersonal subtypes of socially phobic patients. These subtypes did not differ on pretreatment global symptom severity as measured by the Brief Symptom Inventory (Derogatis, 1993) or diagnostic comorbidity but did exhibit differential responses to outpatient psychotherapy. Overall, friendly-submissive social phobia patients had significantly lower scores on measures of social anxiety and significantly higher scores on measures of well-being and satisfaction at posttreatment than cold submissive social phobia patients. We discuss the results in terms of interpersonal theory and the clinical relevance of assessment of interpersonal functioning prior to beginning psychotherapy with socially phobic patients. PMID- 20954052 TI - Modeling stability and change in borderline personality disorder symptoms using the revised Interpersonal Adjective Scales-Big Five (IASR-B5). AB - Personality disorders have been defined as "stable over time." However, research now supports marked change in the symptoms of these disorders and significant individual variability in the trajectories across time. Using the Longitudinal Study of Personality Disorders (Lenzenweger, 2006), we explore the ability of the Revised Interpersonal Adjective Scales--Big Five (IASR-B5; Trapnell & Wiggins, 1990) to predict individual variation in initial value and rate of change in borderline personality disorder symptoms. The dimensions of the IASR-B5 predict variability in initial symptoms and rates of change. Interaction effects emerged between Dominance and Conscientiousness, Love and Neuroticism, and Conscientiousness and Neuroticism in predicting initial symptoms; and between Dominance and Love and Love and Neuroticism in predicting rates of change, suggesting that the effects of broad domains of personality are not merely additive but conditional on each other. PMID- 20954054 TI - Personality, interpersonal circumplex, and DSM-5: A commentary on five studies. AB - Much of personality is interpersonal, and what is interpersonal can be elegantly organized through the crossing of 2 fundamental dimensions of personality: agency and communion. The interpersonal circumplex has enriched substantially what is known about personality and in particular personality disorder, emphasizing to clinicians the importance of considering maladaptive interpersonal functioning when conducting clinical assessments. The purpose of this article is to provide a commentary on 5 articles concerning the interpersonal perspective on personality assessment. The contributions of these 5 studies are also understood relative to the proposed revisions to the American Psychiatric Association's personality disorder nomenclature, as the proposed revisions will be cutting out half of the interpersonal circumplex from further recognition. PMID- 20954055 TI - "I fired my last doctor for not taking me seriously": collaborating with a difficult medical patient in a multidisciplinary primary care facility. AB - We present the case of a multidisciplinary primary care assessment of a 32-year old woman with multiple medical and psychological complaints. Following the collaborative care model, this assessment was conducted by a team consisting of a clinical health psychologist, Dr. J. L. Skillings, and a family physician, Dr. W. J. Murdoch. We describe the primary care environment in which this referral was made including the methods that were utilized to insure a successful professional collaboration. We report the results and recommendations from a comprehensive biopsychosocial assessment; we place emphasis on the psychological diagnosis and pain symptoms. We also describe the feedback session in which the assessment results were provided to the patient and her spouse by both physician and psychologist. Multiperspective commentary about the assessment is offered by the patient and her husband as well as the physician and psychologist assessors. PMID- 20954056 TI - Bifactor models and rotations: exploring the extent to which multidimensional data yield univocal scale scores. AB - The application of psychological measures often results in item response data that arguably are consistent with both unidimensional (a single common factor) and multidimensional latent structures (typically caused by parcels of items that tap similar content domains). As such, structural ambiguity leads to seemingly endless "confirmatory" factor analytic studies in which the research question is whether scale scores can be interpreted as reflecting variation on a single trait. An alternative to the more commonly observed unidimensional, correlated traits, or second-order representations of a measure's latent structure is a bifactor model. Bifactor structures, however, are not well understood in the personality assessment community and thus rarely are applied. To address this, herein we (a) describe issues that arise in conceptualizing and modeling multidimensionality, (b) describe exploratory (including Schmid-Leiman [Schmid & Leiman, 1957] and target bifactor rotations) and confirmatory bifactor modeling, (c) differentiate between bifactor and second-order models, and (d) suggest contexts where bifactor analysis is particularly valuable (e.g., for evaluating the plausibility of subscales, determining the extent to which scores reflect a single variable even when the data are multidimensional, and evaluating the feasibility of applying a unidimensional item response theory (IRT) measurement model). We emphasize that the determination of dimensionality is a related but distinct question from either determining the extent to which scores reflect a single individual difference variable or determining the effect of multidimensionality on IRT item parameter estimates. Indeed, we suggest that in many contexts, multidimensional data can yield interpretable scale scores and be appropriately fitted to unidimensional IRT models. PMID- 20954057 TI - The state-trait anxiety inventory, trait version: does it really measure anxiety? AB - To clarify what is actually measured by the trait version of the State-Trait Anxiety Inventory (STAI; Spielberger, Gorsuch, & Lushene, 1970), we conducted a confirmatory factor analysis of various models and evaluated convergent and discriminant validity. The best fit was obtained with both a bifactor model, comprising 2 specific factors plus a general factor, and a 1-construct, 2-method model. The total score and the 2 method subscales of the STAI trait version were more strongly correlated with depression than with anxiety. In the bifactor model with 2 specific factors, the depression subscale showed stronger correlations with measures of depression than with measures of anxiety. The correlation of the hypothetical anxiety subscale with measures of depression was equivalent to or higher than its correlation with measures of anxiety. These results suggest that the questionnaire does not strictly evaluate anxiety but, rather, negative affect. PMID- 20954058 TI - Revision, criterion validity, and multigroup assessment of the reactions to homosexuality scale. AB - Internalized homonegativity encompasses negative attitudes toward one's own sexual orientation and is associated with negative mental and physical health outcomes. The Reactions to Homosexuality Scale (Ross & Rosser, 1996), an instrument used to measure internalized homonegativity, has been criticized for including content irrelevant to the construct of internalized homonegativity. We revised the scale using exploratory and confirmatory factor analyses and identified a 7-item, 3-factor reduced version that demonstrated measurement invariance across racial/ethnic categorizations and between English and Spanish versions. We also investigated criterion validity by estimating correlations with hypothesized outcomes associated with outness, relationship status, sexual orientation, and gay community affiliation. The evidence of measurement invariance suggests that this scale is appropriate for pluralistic treatment or study groups. PMID- 20954059 TI - The assessment of self-oriented and socially prescribed perfectionism: subscales make a difference. AB - Campbell and Di Paula (2002) suggested differentiating Perfectionistic Striving and Importance of Being Perfect subscales when measuring self-oriented perfectionism and Others' High Standards and Conditional Acceptance subscales when measuring socially prescribed perfectionism. In this study, we investigated the utility of this differentiation by analyzing data from 1,041 students and examining correlations with positive striving and maladaptive evaluation concerns aspects of perfectionism and with positive and negative indicators of well-being and psychological adjustment. As expected, (a) Perfectionistic Striving scores showed higher correlations with positive striving aspects of perfectionism and with positive indicators of well-being and adjustment than Importance of Being Perfect scores, and (b) Conditional Acceptance scores showed higher correlations with maladaptive evaluation concerns aspects of perfectionism and with negative indicators of well-being and adjustment than Others' High Standards scores. The findings indicate that Campbell and Di Paula's differentiation provides for a more detailed and informative assessment of multidimensional perfectionism and its different aspects. Moreover, it provides for new insights into self-oriented and socially prescribed perfectionism and their relationships and associations. PMID- 20954060 TI - Maternal personality influences the relationship between maternal reports and laboratory measures of child temperament. AB - Previous research has indicated that agreement between maternal reports of child temperament and laboratory measures is modest; however, it is unclear whether maternal characteristics influence convergence between methods. We examined whether mothers' personality influenced agreement between maternal reports and observational measures of child traits. A total of 64 mothers and children participated in this study. Maternal negative emotionality (NE) moderated the relationship between maternal reports and laboratory measures of child temperament: Greater convergence was found between maternal ratings of children's negative emotional traits and laboratory measures for mothers with higher NE than mothers with lower NE. Findings are consistent with the possibility that mothers' own traits influence the extent to which they successfully encode and/or report on analogous child behaviors. PMID- 20954061 TI - A principal components analysis of Rorschach aggression and hostility variables. AB - We examined the structure of 9 Rorschach variables related to hostility and aggression (Aggressive Movement, Morbid, Primary Process Aggression, Secondary Process Aggression, Aggressive Content, Aggressive Past, Strong Hostility, Lesser Hostility) in a sample of medical students (N= 225) from the Johns Hopkins Precursors Study (The Johns Hopkins University, 1999). Principal components analysis revealed 2 dimensions accounting for 58% of the total variance. These dimensions extended previous findings for a 2-component model of Rorschach aggressive imagery that had been identified using just 5 or 6 marker variables (Baity & Hilsenroth, 1999; Liebman, Porcerelli, & Abell, 2005). In light of this evidence, we draw an empirical link between the historical research literature and current studies of Rorschach aggression and hostility that helps organize their findings. We also offer suggestions for condensing the array of aggression related measures to simplify Rorschach aggression scoring. PMID- 20954062 TI - The relationship between personality organization as assessed by theory-driven profiles of the Dutch Short Form of the MMPI and self-reported features of personality organization. AB - In this study, we investigated the relationships between features of personality organization (PO) as assessed by theory driven profiles of the Dutch Short Form of the MMPI (DSFM; Luteijn & Kok, 1985) and 2 self-report measures of personality pathology, that is, the Dutch Inventory of Personality Organization (Berghuis, Kamphuis, Boedijn, & Verheul, 2009) and the Dutch Schizotypy Personality Questionnaire-Revised (Vollema & Hoijtink, 2000), in a sample of 190 outpatient psychiatric patients. Results showed that the single scales of all 3 measures segregated into 2 theoretically expected and meaningful dimensions, that is, a dimension assessing severity of personality pathology and an introversion/extraversion dimension. Theory-driven combinations of single DSFM subscales as a measure of level of PO distinguished characteristics of patients at various levels of PO in theoretically predicted ways. Results also suggest that structural personality pathology may not be fully captured by self-report measures. PMID- 20954063 TI - The devil is in the details: A comment on "What might this be? Rediscovering the Rorschach as a tool for personnel selection in organizations" (Del Giudice, 2010). PMID- 20954067 TI - eDiary and Female Sexual Distress Scale((c)) in evaluating distress in hypoactive sexual desire disorder (HSDD). AB - Sex-related distress is integral to the diagnosis of hypoactive sexual desire disorder (HSDD). This article describes the results of three prospective, non treatment validation studies (two North American and one European), each testing over 200 participants with HSDD, other types of female sexual dysfunction (FSD), or no FSD in which the 12-item Female Sexual Distress Scale((c)) (FSDS((c))), the 13-item FSDS-Revised((c))(FSDS-R((c))), and a single question asked using a daily electronic diary (the eDiary For HSDD Trials((c)); eDiary) were used to measure sex-related distress. FSDS results with 30- and seven-day recall were equivalent. The results observed with FSDS-R Item 13 (a single question assessing concern due to low sexual desire) were comparable to the FSDS. Mean eDiary monthly distress scores were closer to the minimum possible score (equivalent to "a little bit" of distress) and were about twice as variable as FSDS or FSDS-R Item 13 scores in participants with HSDD. All three measures confirmed that there is more distress in women with HSDD compared to women with no sexual dysfunction at all time points, demonstrating discriminant validity. PMID- 20954068 TI - Comparative nephrotoxicitiy induced by melamine, cyanuric acid, or a mixture of both chemicals in either Sprague-Dawley rats or renal cell lines. AB - Acute nephrotoxicities of melamine (MEL), cyanuric acid (CA), and a mixture of both melamine and cyanuric acid (MC) were comparatively investigated in male Sprague-Dawley rats at 5 doses each with 10-fold dose interval as follows: MEL at 0.0315, 0.315, 3.15, 31.5, and 315 mg/kg; CA at 0.025, 0.25, 2.5, 25, and 250 mg/kg, and MC: [1*: (0.0315 + 0.025), 10*: (0.315 + 0.25), 100*: (3.15 + 2.5), 1000*: (31.5 + 25), and (315 + 250) mg/kg]. No marked adverse effects in renal function were observed in animals treated with MEL alone or CA alone, but evidence related to nephrotoxicity was noted in rats administered MC. Renal calculi and increased kidney weights were found in rats 7 d after daily oral administration of MC. Blood urea nitrogen (BUN) and creatinine were significantly elevated in the high dose MC groups at 100* or 1000*. In addition, elevated numbers of white blood cells (WBC), neutrophils, and lymphocytes in vivo and increased levels of prostaglandin E(2) (PGE(2)) in vitro were found in the MC group. Based on these data, the NOAEL (no-observed-adverse-effect level) for nephrotoxicity for MC was estimated to be 3.15 mg/kg body weight (bw)/d (MEL) plus 2.5 mg/kg bw/d (CA). If a safety factor of 1000 or more were applied to NOAEL, tolerable daily intake (TDI) would be 0.00315 and 0.0025 mg/kg/d or less for MEL and CA, respectively, which is far below the TDI of 0.2 mg/kg/d set by World Health Organization (WHO). In addition, in vitro cytotoxicity assays showed that the ACHN human renal adenocarcinoma cell line was more sensitive to MEL, CA, and MC than the MDCK canine kidney epithelial cell line. The 24-h half maximal inhibitory concentration (IC(50)) values for MEL (4792, 2792 MUg/ml) were less than those of CA (9890, 6725 MUg/ml, respectively) in MDCK and ACHN cell lines, suggesting that MEL may be more cytotoxic than CA. Furthermore, the 24-h IC(50) value for MC was found to be 208 MUg/ml in ACHN cells. Data suggest that NOAELs based upon acute nephrotoxic parameters for MC were low, which might require further reassessment of the current TDI. PMID- 20954069 TI - Toxicometabolomics of urinary biomarkers for human gastric cancer in a mouse model. AB - Toxicometabolomics of urinary biomarkers for human gastric cancer in a mouse model was investigated using (1)H-nuclear magnetic resonance (NMR) spectroscopy. A human gastric adenocarcinoma cell line (1 * 10(7) cells/ml) was grafted onto the skin of the back of intact male BALB/c-nu/nu mice. After the xenografted tumors developed, urine was collected and analyzed for endogenous metabolites. Global profiling combined with principal components analysis (PCA), partial least squares-discriminant analysis (PLS-DA), and orthogonal projections to latent squares-discriminant analysis (OPLS-DA) showed distinct separation of clusters between control and tumor-bearing mice. Targeted profiling revealed significant changes in trimethylamine oxide (TMAO), 3-indoxylsulfate, hippurate, and citrate levels in mice carrying human gastric cancer cells compared to normal mice. The levels of TMAO (0.41-fold) and hippurate (0.26-fold) in tumor-bearing mice were significantly decreased, whereas the levels of 3-indoxylsulfate (3.39-fold), 2 oxoglutarate (2.32-fold), and citrate (1.9-fold) were significantly increased in urine samples of tumor-bearing mice. Data suggest that TMAO, hippurate, 3 indoxylsulfate, 2-oxoglutarate, and citrate may serve as useful urinary biomarkers for gastric tumorigenesis in a mouse model. PMID- 20954070 TI - Role of metabolism in 1-bromopropane-induced hepatotoxicity in mice. AB - A possible role of metabolism in 1-bromopropane (1-BP)-induced hepatotoxicity was investigated in male ICR mice. The depletion of glutathione (GSH) by formation of GSH conjugates was associated with increased hepatotoxicity in 1-BP-treated mice. The formation of S-propyl and 2-hydroxypropyl GSH conjugates were identified in the liver following 1-BP treatment. In addition, the formation of reactive metabolites of 1-BP by certain cytochrome P-450 (CYP) may be involved in 1-BP induced hepatotoxicity. The decreased content of hepatic GSH produced by 1-BP was associated not only with increased activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but also with elevated levels of hepatic thiobarbituric acid-reactive substance (TBARS) in mice where metabolic enzymes were induced by pretreatment with phenobarbital. In addition, the hepatotoxicity induced by 1-BP was prevented by pretreatment with SKF-525A. Taken together, the formation of reactive metabolites by CYP and depletion of GSH may play important roles in hepatotoxicity induced by 1-BP. PMID- 20954071 TI - Effects of gut microflora on pharmacokinetics of hesperidin: a study on non antibiotic and pseudo-germ-free rats. AB - Hesperidin is a biologically active flavanone glycoside occurring abundantly in citrus fruits. In the present study, effects of intestinal microflora on pharmacokinetics of hesperidin were investigated using a pseudo-germ-free rat model treated with antibiotics. After administration of hesperidin to rats, hesperetin, hesperetin glucuronides, and metabolites postulated to be eriodictyol, hemoeriodictyol, and their glucuronides were detected in urine while hesperetin glucuronide was predominantly found in plasma. The plasma concentration-time profile of hesperetin was compared between non-antibiotic exposed and pseudo-germ-free rats administered this compound. The maximal concentration (C(max)) values of hesperetin in non-antibiotic-exposed and pseudo germ-free rats were 0.58 and 0.20 MUg/ml, respectively, and area under the curve (AUC) values were 6.3 and 2.8 MUg-h/ml, respectively. Thus, systemic exposure as evidenced by AUC and C(max) was significantly higher in normal compared to pseudo germ-free rats. Fecal beta-glucosidase activities of non-antibiotic-exposed and pseudo-germ-free rats were 0.21 and 0.11 nmol/min/mg, while fecal alpha rhamnosidase activities were 0.37 and 0.12 nmol/min/mg, respectively. The rate of hesperidin transformation to hesperetin was 6.9 and 2.9 nmol/min/g in fecal samples in non-antibiotic-exposed and pseudo-germ-free rats, respectively. Taken together, these results showed that pharmacokinetic differences between non antibiotic-exposed and pseudo-germ-free rats may be attributed to differing hesperidin uptake, as well as alterations in metabolic activities of intestinal flora. PMID- 20954072 TI - Upregulation of cyclooxygenase-2 by 4-nonylphenol is mediated through the cyclic amp response element activation pathway. AB - The organic compound nonylphenol (NP) belongs to the family of alkylphenols and is a product of industrial synthesis formed during phenol alkylation. Nonylphenol is considered to be an endocrine disruptor due to weak ability to mimic estrogen and subsequently to disrupt the natural balance of hormones in a given organism. Since the endocrine and immune systems share portions of common signaling pathways, it is conceivable that NP may also affect immune system functions. However, the influence of NP on inflammation and macrophages responsiveness to NP is unclear. Thus, the effects of NP were investigated on cyclooxygenase (COX)-2 expression in cultured macrophages. NP induced COX-2 protein and gene expression in murine macrophage RAW264.7 cells and enhanced COX-2 promoter activity and prostaglandin E(2) production. Transfection of RAW264.7 cells with hCOX-2 or various deletion and mutation promoter constructs revealed that the cyclic AMP response element (CRE) was the predominant mediator responsive to NP-induced effects. Moreover, transfection with pCRE-Luc plasmid followed by immunoblotting demonstrated that NP activated CRE sites and CRE binding protein (CREB) phosphorylation. NP also increased nuclear CREB accumulation and CREB binding to the COX-2 promoter. Phosphatidylinositol 3 (PI3)-kinase, Akt, and the mitogen activated protein kinases (MAP kinases) p38 and JNK were also significantly activated by NP. Our data demonstrate that NP induces COX-2 expression through the PI3-kinase/Akt/MAP kinases/CRE pathway. These findings provide insight into the signal transduction pathways involved in the inflammatory responses induced by NP in macrophages. PMID- 20954073 TI - Ceramide produces apoptosis through induction of p27(kip1) by protein phosphatase 2A-dependent Akt dephosphorylation in PC-3 prostate cancer cells. AB - Ceramide induces cell cycle arrest and apoptotic cell death associated with increased levels of p27(kip1). The aim of this study was to examine the effects of ceramide on p27(kip1) protein levels as a measure of cell cycle arrest and apoptosis. Results showed that ceramide increased p27(kip1) protein levels through activation of protein phosphatase 2A (PP2A) in PC-3 prostate cancer cells. Treatment of cells with the PP2A inhibitor okadaic acid or with PP2A Calpha siRNA inhibited ceramide-induced enhanced p27(kip1) protein expression and Akt dephosphorylation, and prevented Skp2 downregulation. Overexpression of constitutively active Akt attenuated ceramide-induced Skp2 downregulation and p27(kip1) upregulation. In addition, ceramide stimulated binding of the PP2A catalytic subunit PP2A-Calphabeta to Akt as assessed by immunoprecipitation experiments, indicating that PP2A is involved in the induction of p27(kip1) via inhibition of Akt pathway. Finally, whether PP2A can regulate p27(kip1) expression independently of Akt pathway was determined. Knockdown of PP2A-Calpha with siRNA reduced p27(kip1) levels in the presence of Akt inhibitor. These data reveal that PP2A is a regulator of ceramide-induced p27(kip1) expression via Akt dependent and Akt-independent pathways. PMID- 20954074 TI - Cytoprotective effects of triphlorethol-A against formaldehyde-induced oxidative damage and apoptosis: role of mitochondria-mediated caspase-dependent pathway. AB - The toxicity of formaldehyde (HCHO) has been attributed to its ability to form adducts with DNA and proteins. Triphlorethol-A, derived from Ecklonia cava, was reported to exert a cytoprotective effect against oxidative stress damage via an antioxidant mechanism. The aim of this study was to examine the mechanisms underlying the triphlorethol-A ability to protect Chinese hamster lung fibroblast (V79-4) cells against HCHO-induced damage. Triphlorethol-A significantly decreased the HCHO-induced intracellular reactive oxygen species (ROS) production. Triphlorethol-A prevented increased cell damage induced by HCHO via inhibition of mitochondria-mediated caspase-dependent apoptosis pathway. Triphlorethol-A diminished HCHO-induced mitochondrial dysfunction, including loss of mitochondrial membrane action potential (Deltapsi) and adenosine triphosphate (ATP) depletion. Furthermore, the anti-apoptotic effect of triphlorethol-A was exerted through inhibition of c-Jun NH(2)-terminal kinase (JNK), which was enhanced by HCHO. Our data indicate that triphlorethol-A exerts a cytoprotective effect in V79-4 cells against HCHO-induced oxidative stress by inhibiting the mitochondria-mediated caspase-dependent apoptotic pathway. PMID- 20954075 TI - Capsaicin impairs proliferation of neural progenitor cells and hippocampal neurogenesis in young mice. AB - Capsaicin (N-vanillyl-8-methyl-1-nonenamide) is a major pungent ingredient in hot peppers and induces apoptosis in malignant carcinoma cell lines. However, the adverse effects of capsaicin on neuronal development have not been fully explored. The aim of this study was to determine whether capsaicin affected murine-derived cerebellar multi-potent neural progenitor cells (NPC) or adult hippocampal neurogenesis in vivo. Capsaicin dose-dependently suppressed NPC proliferation, and higher concentrations were cytotoxic. Capsaicin decreased the activation of extracellular signal-regulated kinases (ERK) without markedly affecting p38 kinases. Capsaicin reduced the number of newly generated cells in the dentate gyrus of the hippocampus but did not significantly alter learning and memory performance in young adult mice. Interestingly, capsaicin decreased ERK activation in the hippocampus, suggesting that reduced ERK signaling may be involved in the capsaicin-mediated regulation of hippocampal neurogenesis. PMID- 20954076 TI - Rapid and direct detection of apolipoprotein E genotypes using whole blood from humans. AB - Polymerase chain reaction (PCR) is a powerful molecular biological tool in the field of toxicity testing and diagnostics. The use of PCR for large-scale genetic testing requires an effective method of sample processing. Unfortunately, isolation of PCR-quality DNA is time-consuming. PCR performed directly on whole blood is preferred because of time efficiency, cost of the procedure, and possible automation for large-scale toxicity evaluation and diagnosis. The apolipoprotein E (APOE) gene contains two single-nucleotide polymorphisms (SNP) located at codons 112 and 158, producing three APOE protein isoforms known to be associated with the risks of developing cardiovascular disease and susceptibility to Alzheimer's disease. In the present study, an attempt was made to use the AnyDirect solution for APOE genotyping by PCR using whole blood directly without DNA purification. Results for two PCR methods, (1) conventional PCR using purified DNA and conventional buffer and (2) direct PCR using whole blood and AnyDirect solution, were compared in four different PCR-based APOE genotyping methods including PCR restriction-fragment-length polymorphism (PCR-RFLP), allele specific PCR, SNaPshot mini-sequencing, and multiplex tetra-primer amplification refractory mutation system (T-ARMS) PCR. There was complete concordance in the APOE genotypes between conventional PCR and direct PCR, in all four different PCR based APOE genotyping methods. Data demonstrated that the four different PCR based APOE genotyping methods are able to determine the APOE genotypes successfully using whole blood directly with the use of AnyDirect solution. The direct multiplex T-ARMS PCR using whole blood may be the most rapid, simple, and inexpensive method for detecting APOE genotypes among four different APOE genotyping methods. PMID- 20954077 TI - Antidiabetic effects and gene expression profiling in obese mice treated with Isaria sinclairii over a 6-month period. AB - The molecular mechanisms underlying the glucose-lowering effects of Isaria sinclairii (Cicada Dongchunghacho), a fungus cultured on silkworm, are not fully elucidated. Thus the glucose-lowering effects of I. sinclairii as potential an antidiabetic agent were investigated in C57BL/6 obese (ob/ob) mice over a 6-mo period. For a period of 26 wk, ob mice were administered either 5 or 10% (w/w) I. sinclairii powder (IS), 10% dry mulberry leaf powder (ML), or 10% silkworm (SW) powder in the standard diet while a control group received only standard diet. The ML and SW preparations served as positive controls. Isaria sinclairii at 10% in the diet was more effective in reducing body weight compared to 10% ML, 10% SW, or 5% I. sinclairii. The fall in blood glucose levels in the groups treated for 26 wk was greater in both IS groups at 1 mo compared to ML or SW but equal in all groups at 6 mo. Microarray analyses were performed with a mouse 7.4K cDNA clone set array to identify the gene-expression profiles for the IS-, ML-, and SW exposed ob mouse liver. The 10% IS group, compared to control, showed that 15 genes including glucokinase (Gk-rs1) and LDL receptor relating protein 1 were upregulated and 12 genes including cell translocation gene2 (antiproliferative) and hydroxyprostaglandin dehydrogenase (Hpgd 15) were downregulated. Upregulation of Gk-rs 1 and downregulation of Hpgd 15 were previously shown to occur in drug induced suppression of diabetes. With ML, Lepr (leptin receptor), Pik3cb (phosphatidylinositol 3-kinase), and Prodh (proline dehydrogenase), related to suppression of diabetes, were upregulated. In the case of SW, the enzymes (G2an, alpha glucosidase 2) and Mmp9 (matrix metalloproteinase 9) involved in elevation of blood glucose levels were both downregulated. Data suggest that I. sinclarii is effective in lowering blood glucose due to the upregulation of glucokinase (Gk rs1) and downregulation of hydroxyprostaglandin dehydrogenase (Hpgd 15), both associated with suppression of diabetes, indicating that microarray analysis is a useful tool to assess pharmacological potency of therapeutic compounds. PMID- 20954078 TI - Determination of cytotoxicity attributed to multiwall carbon nanotubes (MWCNT) in normal human embryonic lung cell (WI-38) line. AB - Carbon nanotubes (CNT) possess beneficial physicochemical and mechanical properties; however, despite these advantages there are concerns regarding the adverse effects of CNT on lung and development of diseases, such as lung cancer and mesothelioma. According to fiber characteristics of length and diameter (aspect ratio), fibers with high aspect ratio (10-15 nm diameter and containing two different length distributions of 545 +/- 230 and 10451 +/- 8422 nm length) are more toxic to lung than low-aspect-ratio fibers (10-15 nm diameter and length of 192 nm). It was thus of interest to investigate the effects of multiwall carbon nanotubes (MWCNT) on the viability of normal human embryonic lung cells (WI-38) using trypan blue dye exclusion, the tetrazolium salt WST-1 (4-[3-(4 iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate) assay, and lactate dehydrogenase (LDH) activity assay. MWCNT produced cell growth inhibition and death at 12.5-200 MUg/ml after 24-72 h of incubation. In addition, high-aspect-ratio MWCNT were found to produce higher incidence of cytotoxicity than low-aspect-ratio fibers at 50-200 MUg/ml concentration. In the presence of less than 10% trace element content such as iron in MWCNT, the trace element exerted no marked effect on cellular viability. Data indicate that MWCNT inhibited cell proliferation and triggered cell death, and it would appear that the MWCNT fiber characteristics rather than impurities play a predominant role in the observed the cytotoxicity attributed to MWCNT. PMID- 20954079 TI - Toxicity and clearance of intratracheally administered multiwalled carbon nanotubes from murine lung. AB - Carbon nanotubes (CNT) are known to have widespread industrial applications; however, several reports indicated that these compounds may be associated with adverse effects in humans. In this study, multiwalled carbon nanotubes were administered to murine lungs intratracheally to determine whether acute and chronic pulmonary toxicity occurred. In particular, pristine multiwalled carbon nanotubes (PMWCNT) and acid-treated multiwalled carbon nanotubes (TMWCNT) were used in this study. In broncheoalveolar lavage fluid (BALF) cell analysis, PMWCNT induced more severe acute inflammatory cell recruitment than TMWCNT. Histopathologically, both PMWCNT and TMWCNT induced multifocal inflammatory granulomas in a dose-dependent manner. The observed granulomas were reversible, with TMWCNT-induced granulomas diminishing faster than PMWCNT-induced granulomas. Although the area of granuloma reduced with time, hyperplasia and dysplastic characteristics such as mitotic figures, anisokaryosis, and anisocytosis were still observed. These findings demonstrate that MWCNT induces granulomatous inflammation, and the duration and pattern of inflammation seem to vary depending upon the types of MWCNT to which mice are exposed. Therefore, toxicity studies on various types of CNT are needed as the responsiveness to these compounds differs. PMID- 20954080 TI - Effects of in utero exposure to DI(n-Butyl) phthalate on development of male reproductive tracts in Sprague-Dawley rats. AB - The purpose of this study was to determine the effects of di(n-butyl) phthalate (DBP) administration on male reproductive organ development in F1 Sprague-Dawley rats following in utero exposure. During gestation days (GD) 10-19, pregnant rats were administered daily, orally, DBP at 250, 500, or 700 mg/kg or flutamide (1, 12.5, or 25 mg/kg/d) as a positive control. The male offspring were sacrificed at 31 d of age. DBP and flutamide dose-dependently significantly increased the incidence of hypospadias and cryptorchidism in F1 male offspring. The weights of testes and accessory sex organs (epididymides, seminal vesicles, ventral prostate, levator ani plus bulbocavernosus muscles (LABC), and Cowper's glands) were significantly reduced in DBP-treated animals. Furthermore, cauda agenesis of epididymides and ventral prostate atrophy were observed in high-dose 700-mg/kg DBP males. Anogenital distance (AGD) and levels of dihydrotestosterone (DHT) and testosterone were significantly decreased in the DBP (700 mg/kg/d)-treated groups. In particular, the expression of androgen receptor (AR) and 5alpha reductase type 2 in the proximal penis was markedly depressed following administration of DBP (700 mg/kg/d) or flutamide (25 mg/kg/d). The expression of sonic hedgehog (Shh) in the urethral epithelium of the proximal penis was significantly less in the DBP (700 mg/kg/d)- or flutamide (25 mg/kg/d)-treated groups. In addition, DBP dose-dependently significantly increased the expression of estrogen receptor (ER alpha) in the undescended testis. Data demonstrated that in utero exposure to DBP produced several abnormal responses in male reproductive organs, and these effects may be due to disruption of the stage-specific expression of genes related to androgen-dependent organs development. PMID- 20954081 TI - Functional role of phospholipase D (PLD) in di(2-ethylhexyl) phthalate-induced hepatotoxicity in Sprague-Dawley rats. AB - Phospholipase D (PLD) is an enzyme that catalyzes the hydrolysis of phosphatidyl choline (PC) to generate phosphatidic acid (PA) and choline. PLD is believed to play an important role in cell proliferation, survival signaling, cell transformation, and tumor progression. However, it remains to be determined whether enhanced expression of PLD in liver is sufficient to induce hepatotoxicity. The aim of this study was to investigate the possible role of PLD in di(2-ethylhexyl) phthalate (DEHP)-induced hepatotoxicity in Sprague-Dawley rats. The phthalate, DEHP (500 mg/kg/d), was administered orally, daily to prepubertal rats (4 wk of age, weighing approximately 70-90 g) for 1, 7, or 28 d. In this study, protein expression levels of PLD1/2, peroxisome proliferator activated receptor (PPAR), and cytochrome P-450 (CYP) were determined by Western blot analysis using specific antibodies. Liver weight was significantly increased in the DEHP treatment groups. Immunohistochemical analysis demonstrated that DEHP produced strong staining of proliferating cell nuclear antigen (PCNA) at 28 d of exposure, suggestive of hepatocyte proliferation. A significant rise in PLD1/2 expression was observed in liver of DEHP-exposed rats after 7 d. Further, PPARalpha, constitutive androstane receptor (CAR), pregnane X receptor (PXR), and CYP2B1 protein expression levels were markedly elevated in DEHP-treated groups. Our results suggest that DEHP significantly enhanced the expression of PLD, which may be correlated with PPARalpha-induced hepatotoxicity through a complex interaction with nuclear receptors including CAR and PXR. PMID- 20954082 TI - Proteomic analysis of proteins secreted by HepG2 cells treated with butyl benzyl phthalate. AB - Proteomic changes in proteins secreted by human hepatocellular carcinomas (HepG2) cells exposed to butyl benzyl phthalate (BBP) were evaluated. HepG2 cells were treated with three different concentrations of BBP (0, 10, or 25 MUM) for 24 or 48 h. Following incubation, the cells were subjected to proteomic analysis using two different pI ranges (4-7 and 6-9) and large-size two-dimensional gel electrophoresis. Results showed resolution of a total of 2776 protein spots. Of these, 29, including 19 upregulated and 10 downregulated proteins, were identified by electrospray ionization-mass spectrometry-mass spectrometry (ESI MS/MS). Among these, the identities of cystatin C, Rho guanine nucleotide dissociation inhibitor, gelsolin, DEK protein, Raf kinase inhibitory protein, triose phosphate isomerase, heptaglobin-related protein, inter-alpha-trypsin inhibitor heavy chain H2, and electron transfer flavoprotein subunit beta were confirmed by Western blot analysis. These proteins were found to be involved in apoptosis, signaling, tumor progression, energy metabolism, and cell structure and motility. Therefore, these proteins have potential to be employed as biomarkers of BBP exposure and may be useful in understanding mechanisms underlying the adverse effects of BBP. PMID- 20954083 TI - Assessment of bisphenol A exposure in Korean pregnant women by physiologically based pharmacokinetic modeling. AB - The objective of this study was to predict the exposure to bisphenol A (BPA) after oral intake in human blood and tissues using physiologically based pharmacokinetic (PBPK) modeling. A refined PBPK model was developed taking into account of glucuronidation, biliary excretion, and slow absorption of BPA in order to describe the second peak of BPA observed following oral intake. This developed model adequately described the second peak and BPA concentrations in blood and various tissues in rats after oral administration. A prospective validation study in rats additionally supported the proposed model. For extrapolation to humans, a daily oral BPA dose of 0.237 mg/70 kg/d or 0.0034 mg/kg/d was predicted to achieve an average steady-state blood concentration of 0.0055 ng/ml (median blood BPA concentration in Korean pregnant women). This dose was lower than the reference dose (RfD, 0.016 mg/kg/d) and the tolerable daily intake established by the European Commission (10 MUg/kg/d). Data indicate that enterohepatic recirculation may be toxicologically important as this pathway may increase exposure and terminal half-life of BPA in humans. PMID- 20954084 TI - Effects of cooking variables on formation of heterocyclic amines (HCA) in roasted pork and mackerel. AB - The aim of this study was to evaluate the effects of cooking temperature, time, and water content on the formation of heterocyclic amines (HCA) in roasted pork and mackerel using a kinetic model. The levels of 2-amino-6-methyldipiryd[1,2 a:3',2'-d]imidazole (Glu-p-1), 1-methyl-9H-pyrido[4,3-b]-indol (harman), 9H pyrido[4,3-b]-indol (norharman), and 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) in pork and mackerel rose with increasing cooking temperature and time. The concentration of PhIP ranged from 6 to 54 ng/g in roasted pork and was the HCA most sensitive to cooking temperature and time. In the roasted mackerel, levels of harman and norharman increased markedly at 230 degrees C. The kinetics of HCA generation followed first-order reaction (A = A(0) * e(-kt)). In roasted pork, activation enthalpies (DeltaH) ranged from 10.3 to 41.6 kJ/mol, whereas in roasted mackerel, DeltaH ranged from 12.3 to 49.3 kJ/mol. The activation entropies (DeltaS) were less than zero for all HCA, ranging from -159 to -309 kJ/mol-K. The data of the kinetic parameters may be used to predict the formation and temperature sensitivity of HCA in roasted pork and mackerel. PMID- 20954085 TI - A new labdanic norditerpene from Pinus sylvestris. AB - A new labdanic norditerpene and six known labdanic diterpenes were isolated from the petroleum ether extract of the needles of Pinus sylvestris. By spectroscopic methods, the isolated compounds were determined as 15-norpinifolic acid (1), pinifolic acid (2), 4-eplimbricataloic acid (3), monomethyl pinifolate (4), 18alpha-acetoxylabd-8(17)-en-15-oic acid (5), 2-pentenoic acid (6) and 3beta hydroxy-8(17),E-13-labdadien-15-oic acid (7), respectively. Compound 1 showed significant anti-tumour activity. PMID- 20954086 TI - A new hexenol glycoside from leaves of Smallanthus sonchifolius. AB - A new hexenol glycoside with two known compounds was isolated from the leaves of Smallanthus sonchifolius. The structure of the new compound was elucidated as Z hex-3-en-1-ol O-alpha-L-arabinopyransyl (1''-2')-beta-D-glucopyranoside (1) on the basis of spectroscopic analysis and chemical evidence. The two known compounds were identified as ent-15beta-hydroxy-kaur-16-en-19-oic acid (2) and ent-18-hydroxy-kaur-16-en-19-oic acid (3) by comparison of their spectral data with the reported data. Compounds 2 and 3 were isolated for the first time from the title plant. PMID- 20954087 TI - Essential oil analysis and phytotoxic activity of two ecotypes of Zataria multiflora Boiss. growing in Iran. AB - This study was conducted to assess the allelopathic effect of essential oils (EOs) obtained from the aerial parts of two different ecotypes (ECTPs A and B) of Zataria multiflora Boiss. with the aim of evaluating their in vitro germination and growth inhibition potential. Gas chromatography (GC) and GC-mass spectrometry (GC-MS) analysis of the oils revealed that carvacrol and linalool (77.4% and 90.6%) were the two major oil components in ECTPs A and B, respectively, which were regarded as two different chemotypes. Other important volatile compounds found in ECTP A were alpha-pinene (2.7%), p-cymene (7.9%) and gamma-terpinene (3.5%). However, in ECTP B these compounds were in lesser amounts and gamma terpinene was not detected. The inhibitory effects of both EOs of ECTPs at concentrations of 0, 80, 160, 320 and 640 uL L-1 on the seed germination and seedling growth of four noxious weeds were evaluated. A significant reduction (p <= 0.05) in germination rate, seedling length, root and stem fresh and dry weights were observed by ECTPs; the highest suppressing effect was observed at 320 and 640 uL L-1. The results reported in this study suggest that herbicidal properties of the two ECTP oils could be attributed to their major components. PMID- 20954088 TI - Crocetin from the tubular calyx of Nyctanthes arbor-tristis. AB - A carotenoid aglycone Ag-NY1 was isolated from the orange coloured tubular calyx of flowers of Nyctanthes arbor-tristis. The elucidation of the structure through a detailed spectroscopic study revealed that the carotenoid molecule is crocetin, which is the major aglycone present in the stigma of Crocus sativus. The compound exhibited a good membrane stabilising activity as compared to the corresponding glycoside crocin. PMID- 20954089 TI - Quality control for Coptidis rhizoma through the determination of five alkaloids by HPLC-ELSD coupled with chemometrics. AB - A simple, sensitive and reliable high-performance liquid chromatography (HPLC) method with evaporative light scattering detection (ELSD) has been developed for simultaneous determination of five major alkaloids in Coptidis rhizoma. Simultaneous separation of five alkaloids was achieved on a Kromasil C18 analytical column (250 mm x 4.6 mm, 5 um) with the isocratic elution of acetonitrile : water (30:70, v/v, the pH was adjusted to 6.0 with 0.2 moL L-1 trichloroacetic acid). The drift tube temperature of the ELSD system was set at 115 degrees C and the nitrogen flow rate was 2.8 L min-1. All the five calibration curves showed a good linear relationship (r2 > 0.9991) within the test ranges. The limit of detections and quantifications for the five alkaloids in ELSD were less than 0.88 and 2.73 ng, respectively. The established method was successfully applied to quantify the five ingredients in different C. rhizoma samples and evaluate the internal quality of C. rhizoma samples from various sources by analysing the chemical fingerprints using similarity analysis (SA), hierarchical clustering analysis (HCA) and principal component analysis (PCA), which provided a useful basis of overall evaluation of the quality of C. rhizoma. PMID- 20954090 TI - Isolation of chemical constituents from Enicosanthum cupulare (King) Airy-Shaw. AB - Six chemical constituents were isolated from Enicosanthum cupulare (King) Airy Shaw. The structures of the isolated compounds were determined using 1D, 2D-NMR and were found to be identical to those previously reported for these compounds. Three aporphine alkaloids, O-methylmoschatoline, liriodenine and oxostephanine were isolated from this plant for the first time. In addition, we examined the effects of these compounds on melanogenesis in murine B16 melanoma cells; O methylmoschatoline increased melanin content in these cells. PMID- 20954091 TI - Carbon sources of natural cyanamide in Vicia villosa subsp. varia. AB - The 13C labels of [13C]carbon dioxide and D-[13C6]glucose were incorporated into cyanamide (NH2CN) when they were administered to Vicia villosa subsp. varia shoots. In contrast, the administration of sodium [2,3-13C2]pyruvate did not affect the relative area of the [M + 1]+ ion of cyanamide in the gas chromatography-mass spectrometry analysis. [2,3-13C2]pyruvate was incorporated into organic acids that are part of the citric acid cycle, such as succinate and fumarate, confirming that the shoots absorbed and metabolised it. These observations demonstrated that the carbon atom of cyanamide is derived from any of the carbohydrates that are present upstream of pyruvate in the metabolic pathway. PMID- 20954092 TI - Novel 4-(2-methylphenyl)-flavan, rhusjavanins A and B, from the roots of Rhus semialata. AB - In this study, two novel flavan derivatives, namely, rhusjavanins A and B, along with two known flavans 2,3-trans-3,4-trans-3,4,7,4'-tetrahydroxyflavan and 2,3 trans-3,4-cis-3,4,7,4'-tetrahydroxyflavan, have been isolated from the roots of Rhus javanica. The structures were elucidated on the basis of spectroscopic data. PMID- 20954093 TI - A new prenylated xanthone from Garcinia xipshuanbannaensis Y.H. Li. AB - A new prenylated xanthone, named bannaxanthone I, has been isolated from the leaves of Garcinia xipshuanbannaensis, along with five other known compounds, bannaxanthone E, mangostinone, tovophyllin A, garcinone E, and gamma-mangostin. The structure of the new compound was elucidated on the basis of high-resolution fast atom bombardment mass spectra (HRFABMS), 1D-and 2D-NMR experiments, including heteronuclear multiple bond connectivity (HMBC), heteronuclear single quantum coherence (HSQC) and 1H-1H-COSY (correlated spectroscopy, COSY). PMID- 20954094 TI - Solvent-free microwave extraction and hydrodistillation of essential oils from endemic Origanum husnucanbaseri H. Duman, Aytac & A. Duran: comparison of antibacterial activity and contents. AB - The essential oils (EOs) obtained by solvent-free microwave extraction (SFME) and hydrodistillation (HD) from endemic Origanum husnucanbaseri H. Duman, Aytac & A. Duran were investigated using the gas chromatography-mass spectrometry system. The main constituents of both oils obtained from SFME and HD from O. husnucanbaseri are borneol (15.2-12.8%), alpha-terpineol (12.3-10.8%) and trans sabinene hydrate (11.8-9.92%). The EO obtained from SFME contained substantially higher amounts of oxygenated compounds and lower amounts of monoterpenes than that from HD. The antibacterial activities of the EOs from SFME and HD were evaluated by the disc diffusion method against six bacterial strains. The EO extracted by SFME was more effective than the EO extracted by HD against the tested bacteria, except for Klebsiella pneumoniae American type culture collection (ATCC) 13883. Streptococcus pyogenes ATCC 19615 and Staphylococcus aureus ATCC 25923 in particular were more sensitive against the EO extracted by SFME. PMID- 20954095 TI - A new antioxidant xanthone from the pericarp of Garcinia mangostana Linn. AB - The air-dried fruit hulls of Garcinia mangostana Linn. were extracted with 85% ethanol. Furthermore, a new xanthone, 1,3,6-trihydroxy-2,5-bis(3-methylbut-2 enyl)-6',6'-dimethyl-4',5'-dihydropyrano[2',3':7,8]xanthone, along with five known xanthones related to their antioxidant activity was purified by silica gel column chromatography and then identified using spectroscopic methods (1D and 2D NMR, MS). The antioxidant activities were evaluated using 1,1-diphenyl-2 picrylhydrazyl (DPPH) radical-scavenging capability. An activity-guided isolation and purification process were used to identify the components, showing the strong DPPH radical-scavenging activity of G. mangostana. PMID- 20954097 TI - Increasingly heterogeneous ages at first birth by education in Southern European and Anglo-American family-policy regimes: A seven-country comparison by birth cohort. AB - According to the 'reproductive polarization' hypothesis, family-policy regimes unfavourable to the combination of employment with motherhood generate greater socio-economic differentials in fertility than other regimes. This hypothesis has been tested mainly for 'liberal' Anglo-American regimes. To investigate the effects elsewhere, we compared education differentials in age at first birth among native-born women of 1950s and 1960s birth cohorts in seven countries representing three regime types. Women with low educational attainment have continued to have first births early, not only in Britain and the USA but also in Greece, Italy, and Spain. Women at all other levels of education have experienced a shift towards later first births, a shift that has been largest in Southern Europe. Unlike the educationally heterogeneous changes in age pattern at first birth seen under the Southern European and Anglo-American family-policy regimes, the changes across birth cohorts in the study's two 'universalistic' countries, Norway and France, have been educationally homogeneous. PMID- 20954098 TI - Prenatal development in rural South Africa: relationship between birth weight and access to fathers and grandparents. AB - Birth weight is an indicator of prenatal development associated with health in infancy and childhood, and may be affected by the family environment experienced by the mother during pregnancy. Using data from KwaZulu-Natal, South Africa, we explore the importance of the mother's access to the father and grandparents of the child during pregnancy. Controlling for household socio-economic indicators and maternal characteristics, the survival and residence of the biological father with the mother are positively associated with birth weight. The type of relationship seems to matter: married women have the heaviest newborns, but co residence with a non-marital partner is also associated with higher birth weight. Access to the maternal grandmother may also be important: women whose mothers are alive have heavier newborns, but no additional benefit is observed from residing together. Co-residence with any grandparent is not associated with birth weight after controlling for the mother's partnership. PMID- 20954100 TI - Current issues and new directions in Psychology and Health: the potential contribution of health psychology to developing effective interventions to reduce tobacco smoking. PMID- 20954101 TI - Assessment of the RBANS Visual and Verbal Indices in a sample of neurologically impaired elderly participants. AB - With increases in the older adult population, brief assessments sensitive to dementia are essential. This study assessed the effectiveness of the verbal memory and visual processing indices proposed by Duff et al. (2009) to differentiate participants with neurological disorders. Participants included individuals diagnosed with mild cognitive impairment (MCI; n = 38), Alzheimer's disease (AD; n = 100), or Parkinson's disease (PD; n = 35), with ages ranging from 65-93 years. In addition, normal control participants (n = 100) within the same age range were used for comparison. ANOVA and posthoc analyses revealed that the normal control and AD groups were significantly different from all groups for Verbal and Visual Indices. However, the MCI and PD groups did not differ from each other. Predictive discriminant analysis (PDA) assessed classification rates of the groups, and the normal participants were classified best (63% to 92%). The AD group followed with percentages ranging from 64% to 76%. Specifically, when classifying the normal and AD groups using both Verbal and Visual Indices of the RBANS together, sensitivity was 92.0% (n = 92) and specificity was 79.0% (n = 79). Overall classification rates for this analysis were 85.5%. Overall, the RBANS Verbal and Visual Indices may provide additional information when working with neurologically impaired older adults, with overall classification rates ranging from 61.5% to 85.5%. PMID- 20954102 TI - Neural temporal dynamics of contingency judgement. AB - The present study captures the dynamics of neural processing across positively contingent, negatively contingent, and noncontingent relations. In the setting of a hypothetical chat room conversation, participants rated the contingency of emotional response between two individuals. Event-related potentials (ERPs) were time-locked to the onset of each emotional event. Although each event alone was ambiguous regarding contingency, its neural response was characteristic of the overall contingent relation and the subsequent contingency rating. Very early displays of contingency modified the ERP anterior N1 (AN1) component amplitude. In contrast, the ERP selection negativity (SN) component amplitude seemed to be more sensitive to display properties than contingency. Our results point to the recruitment of early attentional processes for contingency judgement and highlight the efficiency of statistical information processing. PMID- 20954103 TI - Success of Malone's antegrade continence enema (MACE) from the patients' perspective. AB - PURPOSE: Fecal incontinence (FI) is a devastating problem for children. The failure of optimal medical treatment may require further interventions such as appendicocutaneostomy. We report on a patients' perspective of the success of a Malone procedure for FI. PATIENTS AND METHODS: The records of 32 patients who had undergone ACE procedure in the past 9 years were reviewed. Patients and families were contacted, and telephone inquiries were conducted to assess the overall success of the operation. The questionnaire covered the concerns of patients/families about the stoma, functional results and changes in the patients' quality of life (QOL). RESULTS: The indications for ACE stomas were meningomyelocele in 17 patients, anorectal malformation in 8, Hirschsprung/NID in 3, spinal tumor in 3 and traumatic spinal injury in one. 7 laparoscopic and 25 conventional operations were performed. The vermiform appendix was used in 27 of the patients and a cecal flap was used in 5. The most frequent complication was stenosis of the stoma orifice observed in 14 patients. 8 patients responded to dilatations while 6 patients required minor surgical revision. There were 2 perforations during catheterization, and they required surgical repair of the conduit. 5 patients had mild leakage from the stoma; all 5 were open ACE procedures, and required revision. 25 patients could be reached by phone. 5 of these children stopped using the stoma due to previous perforation in 2 patients and stricture in 1. The remaining 2 stopped using their stomas because "they did not like the idea of it". 16 patients are completely clean. 3 patients have occasional soiling. Only one patient was not satisfied with using the ACE stoma and stated that it did not sufficiently improve her condition. 8 patients complained about the duration of the enema (longer than 1 h); however, 5 of them refuse to use the stoma every day. All patients but one perceived a significant improvement in their QOL. Mean QOL scores before and after the procedure were 5.8 (2-9) and 11.5 (5-14), respectively. CONCLUSIONS: ACE stomas provide a satisfactory improvement in patients' quality of life. Stoma-related complications are not uncommon. The most common problems are strictures, followed by stoma leakage. PMID- 20954104 TI - Morbidity after ganglioneuroma excision: is surgery necessary? AB - INTRODUCTION: Ganglioneuroma (GN), the benign form of peripheral neuroblastic tumour, is often asymptomatic and the diagnosis can be incidental. Our aim was to evaluate the incidence of complications after surgical treatment following diagnosis of this tumour. MATERIAL AND METHODS: 24 consecutive children were diagnosed with GN in our centre between January 1989 and December 2009. All patients had negative urinary catecholamines and/or biopsy confirming the diagnosis of GN. Data are reported as mean +/- SD. RESULTS: Age at diagnosis was 73 +/- 43 months. The most common presentation was respiratory symptoms and/or abdominal pain; 9 (38%) patients were asymptomatic. Tumour location was in the chest (n=14), abdomen (n=7), or pelvis (n=3). 23 children (9 asymptomatic) were operated on; 1 child with a thoracic mass did not undergo surgery because of severe neurological impairments from birth unrelated to GN. 13 children (4 asymptomatic) had a thoracotomy, 8 children (4 asymptomatic) had laparotomy, and 2 (1 asymptomatic) underwent perineal resection. A macroscopically complete surgical excision was performed in 17 cases (74%) and a macroscopically near complete excision in 6 (26%). At histological examination, resection margins contained tumour in 10 patients (43%) and were free of tumour in the remaining 13 (57%). 7 children (30%) had complications after surgery including 3 patients with Horner's syndrome (which persisted in 2), 1 with chylothorax, 1 with pneumothorax, 1 with pain in the arm, and 1 who developed adhesive intestinal obstruction. 2 children received adjuvant chemotherapy. We re-evaluated the histology specimens according to the International Neuroblastoma Pathology Classification and found that the diagnosis of GN was confirmed in 20 cases (83%), while intermixed ganglioneuroblastoma (iGNB) was diagnosed in 4 patients (17%). At 33.5 +/- 40 months (range 1-137) follow-up, all 24 patients, including the child not operated on and the children with incomplete resection or iGNB, are alive with no tumour progression or recurrence. CONCLUSIONS: GN excision is associated with postoperative complications which can be persistent and may affect the quality of life of survivors. In our series we did not observe tumour progression in spite of incomplete excision. The rationale for GN excision should be revisited. PMID- 20954105 TI - Pneumovesicoscopic correction of primary vesicoureteral reflux (VUR) in children. Our experience. AB - AIM: We report our experience with pneumovesicoscopic cross-trigonal ureteral reimplantation to correct primary vesicoureteral reflux (VUR) in children. MATERIAL AND METHODS: 14 children (10 girls, 4 boys, aged 4 to 12 years) with persistent VUR >= grade III (5 bilateral, 19 refluxing ureters) underwent pneumovesicoscopic Cohen's cross-trigonal reimplantation. Under cystoscopic control, a first midline 5-mm trocar was introduced for a 0 degrees ?30 degrees telescope at the dome of the bladder, and 2 left and right 3- or 5-mm trocars were inserted through the anterolateral wall. The ureter was freed by creating a sharp plane between the detrusor muscle and the ureteral wall. If necessary, the ureter was tailored outside the bladder. Submucosal tunnel(s) were prepared with the help of scissors and graspers. The detrusor at the site of the ureter mobilization was repaired and ureteroneocystomy was performed using 4-5 interrupted absorbable sutures. A 12-Ch Foley catheter was introduced at the site of the dome port. The urethral and suprapubic catheters were removed 2-3 days after the procedure and the patients were discharged on day 3. RESULTS: One boy developed mild suprapubic emphysema postoperatively. Mean operating time was 136 min (range 80-230 min). No patient required conversion to the open technique. Renal US, VCUG, and MAG3 radionuclide scans were obtained in all patients between 3-6 months postoperatively, and provided evidence of reflux resolution in 13 out of 14 patients. CONCLUSION: Our experience seems to confirm that pneumovesicoscopic cross-trigonal ureteral reimplantation can be performed safely and effectively. PMID- 20954106 TI - Outcome of congenital diaphragmatic hernia repair depending on patch type. AB - INTRODUCTION: Patch repair of a congenital diaphragmatic hernia is associated with a much higher rate of recurrence than when primary repair is feasible. The biosynthetic options for the repair materials continue to expand. We therefore reviewed our experience to benchmark complication rates as we progress with the use of new materials. METHODS: A retrospective review was conducted of all patients who underwent repair of congenital diaphragmatic hernia from January 1994 to May 2009. RESULTS: Of the 155 patients included in the study, 101 patients had primary closure and 54 received a diaphragmatic patch. The rates of recurrence, Small Bowel Obstruction (SBO), and subsequent abdominal operation were all significantly higher in the group of patients requiring patch repair. There were 3 types of patch repairs: 37 patients received a SIS patch, 12 had a nonabsorbable patch, and 5 received an AlloDerm patch. The incidence of SBO in patients with a nonabsorbable mesh was 17% and was associated with a 50% recurrence rate and 67% re-recurrence rate. SIS was associated with 19% incidence of SBO, a recurrence rate of 22% and a 50% re-recurrence rate, whereas AlloDerm had a 40% incidence of SBO, 40% recurrence rate, and 100% re-recurrence rate. DISCUSSION: As we move towards the next generation of materials, these data do not justify the continued comparison with nonabsorbable patches. We do not have enough comparative data to define a superior biosynthetic material, but we plan to use our data on SIS to benchmark our experience with future generation materials. PMID- 20954107 TI - Does pre-biopsy contrast enema delay the diagnosis of long segment Hirschsprung's disease? AB - INTRODUCTION: The diagnosis of long segment Hirschsprung's disease (LSHD) is frequently delayed. Our purpose was to: 1) summarize contrast enema (CE) findings in patients with LSHD, and 2) evaluate the utility of CE by comparing LSHD patients managed with/without pre-biopsy CE. METHODS: All LSHD cases (transition zone [TZ] proximal to the splenic flexure) treated between 1984 and 2009 were stratified according to whether a pre-biopsy CE was done (Group 1) or not (Group 2). CE were reviewed by a single pediatric radiologist, and the original reports were categorized as "helpful", "inconclusive" or "misleading". Group comparisons included elapsed days from admission to diagnostic rectal biopsy/first operation and initial hospitalization length of stay (LOS). RESULTS: 29 patients (16 in Group 1; 13 in Group 2) were identified. CE review revealed TZ in 7/16 (44%); and of these, 6 (86%) underestimated the actual aganglionic segment length. 6/16 (38%) original CE reports were "misleading". Overall, Group 1 patients experienced a significant delay in time to biopsy (p=0.047), first operation (p=0.005), and showed a trend towards prolonged LOS. CONCLUSIONS: Pre-biopsy CE offers little to the diagnosis of LSHD and may contribute to diagnosis/treatment delays. Even if a TZ is recognized in biopsy proven HD, the predicted aganglionic segment length should not guide the operative planning. PMID- 20954108 TI - What is the incidence of Barrett's and gastric metaplasia in esophageal atresia/tracheoesophageal fistula (EA/TEF) patients? AB - OBJECTIVE: Aim of the study was to document the incidence of gastric and intestinal metaplasia (Barrett's esophagus) in a closely followed group with EA/TEF, determine the efficacy of pH probe studies in diagnosing reflux and, moreover, to determine the lag period between the development of gastroesophageal reflux disease (GERD) and metaplasia. MATERIALS AND METHODS: Patients who underwent EA/TEF correction were followed up over an 18-year period (1990-2009) with regular pH probe and endoscopy investigations. Biopsies were performed at 3 year intervals to evaluate for metaplastic changes in the esophageal epithelium. The interval between esophageal atresia correction and the development of erosive esophagitis, gastric metaplasia and Barrett's esophagus was determined. The development of complicated GERD was statistically correlated to age at detection. RESULTS: 51 patients (28 male) underwent EA/TEF correction during the study period. The ages of the children followed up ranged from 7 months to 19 years. There were 5 Type A, 44 Type C and 2 Type D fistulas. 37 patients (5 Type A, 31 Type C, 1 Type D) had documented reflux and 14 did not. 17 (46%) of the patients with reflux underwent an anti-reflux operation. 4 of the 17 underwent 2 or more anti-reflux procedures. 21 patients had pH probe studies positive for reflux, 3 had negative pH probe studies after an anti-reflux operation. 18 of the 37 patients with reflux (about 50%) needed esophageal dilatation for either anastamotic or non-anastamotic strictures. Only 4/14 (28.5%) patients without reflux underwent dilatations and only in their first year of life (p=NS). 15 patients had mucosal abnormalities in endoscopic biopsies. 8 patients had gastric metaplasia and 1 patient had Barrett's esophagus. The mean age in the group with metaplasia (gastric and intestinal) was 13 years, which was significantly different from the mean age of the group (5.2 years) without mucosal changes (p<0.001). 2 patients with normal pH probe studies had metaplasia on biopsies. CONCLUSION: Metaplasia arises in about 15% of patients with EA/TEF. The lag time to developing metaplasia from the time of initial surgical correction is about 10 years. Endoscopy and biopsies are the best way of detecting mucosal changes. PMID- 20954111 TI - Hiatus hernia after laparoscopically assisted gastric pull-up for esophageal replacement. PMID- 20954109 TI - Portal venous gas detected by ultrasound differentiates surgical NEC from other acquired neonatal intestinal diseases. AB - BACKGROUND: The definite clinical diagnosis of acquired neonatal intestinal diseases (ANID) is a challenge, usually met by applying Bell's or, more recently, Gordon's classification. Both classifications incorporate radiological pneumatosis intestinalis (PI) as a cornerstone of the NEC diagnosis. However, PI may be absent or difficult to identify by abdominal X-ray. Portal venous gas detected by ultrasound (PVG-US) has been proposed as another characteristic of NEC, but its incidence in other entities of ANID remains unknown. OBJECTIVE: To determine whether PVG-US and Gordon's classification can help to differentiate between NEC and other ANID, especially SIP. METHODS: Retrospective analysis of the data of 83 infants, who underwent laparotomy for a clinical diagnosis of ANID was performed. The results of PVG-US and other markers of ANID were compared with the operative result, defined as the gold standard for diagnosis. RESULTS: The NEC diagnosis was confirmed in 28/83 infants and PVG-US was present in 23 (82%) of those patients prior to operation. PVG-US was detected in 2 patients without NEC (one volvulus, one SIP), resulting in an 82% sensitivity and a 96% specificity. The sensitivity and specificity of radiological PI for patients with NEC was lower (75 and 91%), but the combination of PVG-US and radiological PI increased the sensitivity for NEC detection to 89%. Gordon's classification had a sensitivity of 93% and a specificity of 92% for NEC diagnosis. CONCLUSION: Screening for PVG-US and Gordon's classification are valid tools to differentiate between NEC and other ANID including SIP. Although an effect of these proposed diagnostic tools on treatment regimen and operative management has yet to be verified, the improvement in diagnosing ANID is certainly valuable. PMID- 20954112 TI - TGFbeta/activin signaling pathway activation in intimal hyperplasia and atherosclerosis. AB - PURPOSE: Intimal hyperplasia and atherosclerosis are the Achilles' heels of vascular interventions. Many cytokines and growth factors have been shown to mediate these pathological processes. There are conflicting data concerning the expression of transforming growth factor-beta1 (TGFbeta1) antigen in human intimal hyperplasia and atherosclerotic lesions and conflicting views about whether TGFbeta1 is pro- or anti-atherogenic. The presence of TGFbeta1 is not sufficient to infer activation of its signaling pathway because TGFbeta1 may be present in inactive complexes. MATERIALS AND METHODS: A sensitive immuno fluorescence assay (cyanine-3 tyramide signal amplification system) was used on human coronary artery and aorta sections with early or advanced stage lesions to detect TGFbeta1, activin, Smad2-P, a marker of the activated TGFbeta1/activin pathway and components of latent TGFbeta complexes. RESULTS: All antigens were readily detected in the media and neointima of early stage lesions. The levels were either reduced or undetectable in the media of advanced lesions but were increased in the neointima in areas of high cell density. In marked contrast to activin, TGFbeta1 and LAP1 expression levels were closely correlated with Smad2-P throughout the artery wall. CONCLUSION: Discrepancies in previous data for TGFbeta1 expression are probably due to assay sensitivity. TGFbeta1, but not activin, expression is consistently correlated with Smad pathway activation in the artery wall. The pattern of Smad2 activation supports a model in which TGFbeta/activin signaling is anti-atherogenic in the media of normal artery walls but is equally compatible with an anti-atherogenic or pro-atherogenic response to TGFbeta/activin in the neointima of lesions. PMID- 20954113 TI - [Malaria: an evaluation of 40 cases]. AB - In this study, the epidemiological, clinical, laboratory and therapeutic features of forty adult malaria patients referred our clinic between February 1996 September 2009, were assessed retrospectively. Diagnosis was established by Giemsa-stained thick and/or thin blood smears in all cases. Thirty-four patients were male and 6 patients were female and mean age was 31.1 years. All patients had a history of travel to endemic areas (24 cases to Africa, Afghanistan, Azerbaijan, Arabian Peninsula, 16 cases to Southestern Anatolia Region), and none of them had chemoprophylaxis. Plasmodium vivax was detected in 20 patients, and P.falciparum in 18 and mixed (P. vivax and P. falciparum) in two. Parasitemia ranged from 0.5%- 25%. Fever (100%), periodic fever (62.5%), splenomegaly (72.5%), hepatomegaly (45.0%), anemia (67.5%), leukopenia (32.5%), thrombocytopenia (75.0%), a rise in erytrocyte sedimentation rate (65.0%), abnormalities in hepatic enzymes (62.5%), hyponatremia (32.5%), hypoglisemia (25%) and an elevated serum creatinine level (27.5%) were determined in the patients. Two patients with P. falciparum developed acute renal failure and cerebral involvement died soon after admission. Acute renal failure, acute respiratory distress syndrome, cerebral involvement and dissemine intravasculer coagulation were observed in one patient with falciparum malaria who recovered completely. In conclusion, every febril patients with a history of travel to the endemic regions should raise the suspicion of malaria. Effective pre-exposure chemoprophylaxis and personal protection measures should be provided to travellers visiting endemic regions. PMID- 20954114 TI - [The protoskolicidal effect of 1% polyvinylpyrrolidone-iodine (PVP-1) and 2% taurolidine on abdominal hydatidosis]. AB - The aim of this study is to determine the efficacy of 1% polyvinylprolidone iodine (Betadine, PVP-I) and 2% Taurolidine as scolicidal agents for the prevention of abdominal hydatidosis defined as the rupture of the echinococcal cyst spontaneously or traumatically. The study was carried out in fifty mice randomly assigned into 5 treatment groups as following: group with no expose to any scolicidal agent, groups with 1% PVP-I for 2 and 5 minutes; groups with 2 % Taurolidine for 2 minutes, and 5 minutes. PVP-I has found to be effective according to results of staining with the eosin dye in vitro and abdominal hydatidosis in vivo, while Taurolidine was ineffective as a scolicidal agent. PMID- 20954115 TI - [Serum levels of macrophage migration inhibitory factor and leptin in patients with acute trichinellosis]. AB - The aim of this study was to examine the serum levels of MIF and leptin in patients infected with Trichinella britovi. Thirtysix patients with acute trichinellosis and 20 healthy control subjects were included in the study. Serum high sensitive C-reactive protein (hs-CRP), MIF and leptin levels were studied. Assessments were performed in the patients group during acute infection and after the treatment periods and we also compared these values with healthy controls. In the patients, hs-CRP, leukocyte and eosinophil counts, and the levels of muscle enzymes in the acute infectious period were found to be significantly higher than those in the post treatment period (p < 0.05). Both leptin and MIF were higher in acute trichinellosis patients when compared to controls. However, this was only significant for leptin. This study indicates that leptin and MIF levels are increased in the sera of patients with acute trichinellosis. PMID- 20954116 TI - [Distribution of intestinal parasites detected in the Tokat public health laboratory during the period from January 2007 - December 2009]. AB - In this study, the results of 1868 stool samples and 215 cellophane tapes examined in the Tokat Public Health Laboratory between January 2007-December 2009 and the distribution of these parasites were evaluated retrospectively. A total of 1868 stool specimens from 1146 (61.3%) males and 722 (38.7%) females were examined for intestinal parasites using direct examination and the formol-ethyl acetate concentration methods. Intestinal parasites were found in 40 (2.1%) females and 85 (4.6%) males. A total of 215 cellophane tape specimens from 86 (40%) females and 129 (60%) males were examined. Parasites were detected in 6 (2.8%) female and 11 (5.1%) male patients. The distribution of intestinal parasites detected in stool specimens was as follows: 52 (2.8%) Giardia intestinalis, 15 (0.8%) Entamoeba histolytica/dispar, 46 (2.5%) Entamoeba coli, 2 (0.1%) Hymenolepis nana, 16 (0.9%) Taenia saginata, 3 (0.2%) Ascaris lumbricoides, and 1 (0.05%) Trichuris trichiura. Parasites detected in cellophane tape specimens included 17 (7.9%) Enterobius vermicularis and 3 (1.4%) Taenia saginata. Despite being labor-intensive, parasitological examination of stool samples with necessary staining methods by experienced staff will surely help to determine both the diagnosis and exact prevalence of intestinal parasitic infections in Turkey. PMID- 20954117 TI - [A retrospective evaluation of the prevalence of intestinal parasites in Istanbul, Turkey]. AB - The aim of this study is to estimate the prevalence of intestinal parasites, in comparison to previous studies in Istanbul and different geographic regions of Turkey. Between January 1999-December 2009, a total of 27664 stool samples from patients with suspicious intestinal parasitic infections who were admitted to Istanbul University Cerrahpasa Medical School Hospital were examined for intestinal parasites by using native lugol and formalin-ethyl acetate concentration technique, in adition to the scotch cellophane tape that was adapted to 1423 children to investigate the Enterobius vermicularis infection. Intestinal parasites were found in 1114 (4%) out of 27664 stool samples examined. The prevalence of intestinal parasites is as follows: Blastocystis hominis in 2.1%, Giardia intestinalis in 1.4%, Taenia saginata in 0.2%, Entamoeba histolytica/dispar in 0.05% and Ascaris lumbricoides in 0.03%. Hymenolepis nana (6), Trichuris trichiura (3), Strongyloides stercoralis (2), Fasciola hepatica (1), Dicrocoelium dendriticum (1) and Isospora belli (1) were found in small numbers. Furthermore Entamoeba coli (119), Iodamoeba butschlii (5), Trichomonas hominis (2), Chilomastix mesnili (1), parasites which exist as commensals in the intestines were also determined. Enterobius vermicularis was detected in 129 (9%) out of 1423 cellophane tape samples. This study showed that the intestinal parasites are still an important public health problem in Istanbul. PMID- 20954118 TI - [Investigation of intestinal parasites in students of Mustafa Cengiz primary school in Van]. AB - Intestinal parasites still maintain as a major public health problem in our country. In this study, we aimed to investigate the distribution of intestinal parasites in 1st and 2nd grade students of Mustafa Cengiz Primary School, aged between 7-9 and to contribute to the parasitological data of our province. For this purpose, stool examinations of a total of 195 students, including 82 boys and 113 girls, were performed. The results of the microscopic analysis of stool samples revealed one or more parasites in a total of 117 (60%) samples including 45 male students (54.8%) and 72 female students (63.7%). The diagnosed parasites and their ratios in children were; Giardia intestinalis 36.4%, Entamoeba coli 17.9%, Blastocystis hominis 14.4%, Hymenolepis nana 10.8%, Chilomastix mesnili 3.6%, Ascaris lumbricoides 2.6%, Entamoeba hartmanni 1.5%, Trichuris trichiura 1%, Iodamoeba butschlii 0.5%, Retortamonas intestinalis 0.5% ve Endolimax nana 0.5%, respectively. From 117 positive samples for parasites, only one parasite was found in 71 (60.7%), and more than one parasites were found in 46 (39.3%). As a result, parasitic infectious diseases still maintain its importance in our region. We conclude that incidence of parasitic infectious diseases will be reduced with education about personal hygiene and improvement of physical conditions. PMID- 20954119 TI - [The investigation of intestinal parasites in foreign high school students]. AB - Intestinal parasites are important health problem especially in undeveloped or underdeveloped countries with low socio-economic status,. In this study, stool and cellophane tape samples were analyzed for intestinal parasites in 192 foreign students who were came from 28 different countries and attending a high school with the age of 15 to 21 (age mean: 17.92 +/- 1.30) in Kayseri. At least one or more intestinal parasite species were found in 73 (38 %) of them. The distribution of parasites which were detected in stool samples as follow; Blastocystis hominis; 63 (32.8%); Giardia intestinalis, 13 (6.7 %); Endolimax nana, 8 (4.1%); Entamoeba coli, 7 (3.6%); Iodamoeba butschlii, 1 (0.52%). There was no any parasite in cellophane tape samples. PMID- 20954120 TI - [The clinical, serological and morphological analysis of 91 patients with cystic echinococcosis following surgery]. AB - Cystic echinococcocis (CE) is a zoonotic infection caused by metacestod form of Echinococcus granulosus. In this study, 91 patients with CE were revealed according to their gender, age, symptoms, cyst localization and size, and also to their preoperative serologic analysis results. These patients were recruited in Pathology Department of Inonu University, School of Medicine, Turgut Ozal Medical Center between January 2002 and December 2005. They had already undergone surgery following the preliminary diagnosis of CE and were diagnosed definitively after histopathological analysis. Thirty-seven of them were female (41%) and the rest were male (n=54, 59%). Mean age was 36.24 +/- 20.35 (range: 4-80 years). Lung and liver were the most common localizations for CE cysts (n=67, 73.63%). Fifty patients' preoperative serological analysis (IHA) were already available (55%) and 46 of them (92%) were positive. Since histopathological definitive diagnosis was CE, false negative result rate was assessed as 8%. Intraabdominal CE cyst localization was found related with bigger cyst size and multiple organ involvement. Symptom duration was correlated with cyst size (p < 0.05; r < sup > 2 < /sup > =0.09). IHA results were failed to be found related with clinical features of the cysts. PMID- 20954121 TI - [Case report: primary splenic hydatidosis]. AB - Hydatidosis, caused by Echinococcus granulosus is still an important problem in endemic areas as Middle and Eastern Europe including Turkey, South America, Avustralia, New Zealand and South Africa. Hydatid disease affects more common liver and lung. Isolated splenic hydatidoses are quite rare in the medical literature. Here we report a case of isolated primary splenic hydatid cyst which is treated by splenectomy. PMID- 20954122 TI - [Case report: Budd-Chiari syndrome and esophageal variceal bleeding due to alveolar echinococcosis]. AB - Alveolar echinococcosis of the liver is a rare larval cestode disease which is due to the intrahepatic growth of the tapeworm Echinococcus multilocularis. This cestode naturally evolves as a larval stage within cysts in the body of carnivores. Humans are accidental intermediate hosts and become infected, either by eating food contaminated with carnivore-originated eggs or by touching foxes. It behaves as malignant liver tumour and rarely causes Budd-Chiari syndrome and variceal bleeding. Budd-Chiari syndrome is a hepatic venous outflow tract obstruction and may be present abdominal pain, hepatomegaly and ascites. Parasitic cysts may cause compression and thrombosis of the hepatic venous outflow tract. It may present as portal hypertension and variceal upper gastrointestinal bleeding. We here in report a 47-year-old woman without a prior history of liver disease presented with Budd-Chiari syndrome and variceal bleeding due to Alveolar echinococcosis. The course of this rare disease is demonstrated by means of the most important laboratory, serologic and radiologic parameters. PMID- 20954123 TI - [A view of mites infestation on cheese and stored foods in terms of public health]. AB - Mites are small live organism that may result in a large number of allergenic diseases such as atopic dermatitis, allergic rhinitis and asthma that may cause individuals' physical, social and mental health, adversely affects quality of life. Mites that can be found everywhere where people live are found in various foodstuffs. The purpose of this review is to examine the types of mites and possible illness result from mites can be found in stored foods especially cheese in terms of public health assessment. Finding mite in the stored foods except for some local cheeses is not desirable because of it's health risks. However, especially in cheese which is maturing in the open always to be the case of mite enfestation. In particular, this risk is much higher in some enterprises where have not taken measures enough in terms of food safety. Besides the lack of standarts related to cheese, fighting against mite in quality assurance systems have generally not been taken into consideration. Whereas mites in cheese consumed by individuals at any age, there is always a possibility of the potential cause of the allergic reactions seen in the consumer. Prevention of possible infestations in cheese, potential presence of storage mite and cheese mite in various stored foods and local cheese of Turkey should be investigated more comprehensive and protective measures should be developed in order to protect public health against mites. PMID- 20954124 TI - [The molecular diagnosis of Dirofilaria immitis in vector mosquitoes in Felahiye district of Kayseri]. AB - This study was designed to determine the potential vectors of Dirofilaria immitis by molecular techniques in Felahiye district of Kayseri. Mosquitoes were sampled from 11 points between June-August 2008 and collected live samples were brought to laboratory. In order to allow the larval development, mosquitoes were incubated in in vitro conditions for seven days. After this mosquitoes were killed and species identifications were done. Among the totally collected 301 mosquitoes, 96 (31.9%) were belonging to Aedes vexans and 205 (68.1%) to Culex pipiens. Head-thorax and abdomens of each sample were dissected to determine the infective and infected mosquitoes and totally 54 pools (2-17 sample/pool) were constituted according to species and collected region. Genomic DNA was extracted from pools and analyzed by PCR using species specific primers. Dirofilaria immitis DNA was found in 2/54 of the pools formed with one head-thorax and one abdomen pool of Ae. vexans. The minimum infection rate (MIRs) was calculated as 0.33 % in the study area. MIRs of 20 pools consisted from Ae. vexans was determined as 1.04 %. No filarial DNA was detected in 34 pools consisted from Cx. pipiens. Consequently, Ae. vexans was the active potential vector of D. immitis in the study area. PMID- 20954125 TI - [The occurence of the hindgut ciliate Hemiprorodon gymnoposthium (Ciliophora: Buetschliidae) from domestic horses in Cyprus]. AB - Hemiprorodon gymnoposthium was investigated in the intestine of horses, found in Cyprus. It was found in four of fifth horses examined and thus had a frequency of appearence of 80%. This study reports for the first time the presence of Hemiprorodon gymnoposthium in the intestine of Equids in Cyprus. In addition, it is the second report from the world. Specimens were found to be similar to the original description on the basis of morphological characters and biometric data. PMID- 20954126 TI - [The struggle against malaria in the Ottoman Empire during World War I and the legal regulations made to this end]. AB - One of the most important disadvantages of war environmental is infectious diseases. The Ottoman Empire combated infectious diseases in addition to the war because of Balkan wars and afterwards first world war. Because of increasing migrations to Anatolia after Balkan wars spread some epidemic diseases, such as cholera, typhoid fever, plaque, dysentery, syphilis. With the start of the First World War, malaria began to spread within civilian population as well as the military. The population fell from power because of illness and therefore could not process the land tax failed to pay taxes. Founded in 1914 with the fight against epidemic diseases was initiated by the Sihhiye ministry. Quinine was formed as tablets which was imported from Germany by legal regulation and was distributed to the public by Ziraat Bank. However, malaria epidemic could not be prevented because of long war years, lack of population, insufficiency of the preventive methods and lack of quinine, and about three quarters of the population caught malaria and in four years 412.000 soldiers had malaria and 20.000 of them died despite of measures. PMID- 20954127 TI - [Forensic entomology]. AB - Odour of the animal or human corpses immediately after death is very attractive for insects and other invertebrates. Blue and green bottle flies from the Calliphoridae family are the first colonizers of cadaver and immediately later necrophagous Diptera from the Sarcophagidae family settle on the same corpse. It is essential to determine the time past after death for elucidating the event in case of the homicide or suspicious death, and it is directly proportional to the post mortem interval expected time, which is based upon the speed of the larval growth. In this article, we purposed to stress the special interest of forensic entomology for the scientists who will apply this science in their forensic researches and case studies, and also to provide information to our judges, prosecutors and law enforcement agents in order to consider the entomological samples to be reliable and applicable evidences as biological stains and hairs. We are of the opinion that if any forensic entomologist is called to the crime scene or if the evidences are collected and then delivered to an entomologist, the forensic cases will be elucidated faster and more accurately. PMID- 20954128 TI - Disc degeneration: current surgical options. AB - Chronic low back pain attributed to lumbar disc degeneration poses a serious challenge to physicians. Surgery may be indicated in selected cases following failure of appropriate conservative treatment. For decades, the only surgical option has been spinal fusion, but its results have been inconsistent. Some prospective trials show superiority over usual conservative measures while others fail to demonstrate its advantages. In an effort to improve results of fusion and to decrease the incidence of adjacent segment degeneration, total disc replacement techniques have been introduced and studied extensively. Short-term results have shown superiority over some fusion techniques. Mid-term results however tend to show that this approach yields results equivalent to those of spinal fusion. Nucleus replacement has gained some popularity initially, but evidence on its efficacy is scarce. Dynamic stabilisation, a technique involving less rigid implants than in spinal fusion and performed without the need for bone grafting, represents another surgical option. Evidence again is lacking on its superiority over other surgical strategies and conservative measures. Insertion of interspinous devices posteriorly, aiming at redistributing loads and relieving pain, has been used as an adjunct to disc removal surgery for disc herniation. To date however, there is no clear evidence on their efficacy. Minimally invasive intradiscal thermocoagulation techniques have also been tried, but evidence of their effectiveness is questioned. Surgery using novel biological solutions may be the future of discogenic pain treatment. Collaboration between clinicians and basic scientists in this multidisciplinary field will undoubtedly shape the future of treating symptomatic disc degeneration. PMID- 20954129 TI - Endovascular intervention for central venous cannulation in patients with vascular occlusion after previous catheterization. AB - OBJECTIVES: This study was designed to assess endovascular intervention for central venous cannulation in patients with vascular occlusion after previous catheterization. METHODS: Patients referred for endovascular management of central venous occlusion during a 42-month period were identified from a regional endovascular database, providing prospective information on techniques and clinical outcome. Corresponding patient records, angiograms, and radiographic reports were analyzed retrospectively. RESULTS: Sixteen patients aged 48 years (range 0.5-76), including 11 females, were included. All patients but 1 had had multiple central venous catheters with a median total indwelling time of 37 months. Eleven patients cannulated for hemodialysis had had significantly fewer individual catheters inserted compared with 5 patients cannulated for nutritional support (mean 3.6 vs. 10.2, p<0.001) before endovascular intervention. Preoperative imaging by magnetic resonance tomography (MRT) in 8 patients, computed tomography (CT) venography in 3, conventional angiography in 6, and/or ultrasonography in 8, verified 15 brachiocephalic, 13 internal jugular, 3 superior caval, and/or 3 subclavian venous occlusions. Patients were subjected to recanalization (n=2), recanalization and percutaneous transluminal angioplasty (n=5), or stenting for vena cava superior syndrome (n=1) prior to catheter insertion. The remaining 8 patients were cannulated by avoiding the occluded route. CONCLUSIONS: Central venous occlusion occurs particularly in patients under hemodialysis and with a history of multiple central venous catheterizations with large-diameter catheters and/or long total indwelling time periods. Patients with central venous occlusion verified by CT or MRT venography and need for central venous access should be referred for endovascular intervention. PMID- 20954130 TI - Endoprosthesis placement for treatment of a left common carotid artery pseudoaneurysm after attempted central venous access. PMID- 20954131 TI - Double-lumen central venous port catheters: simultaneous application for chemotherapy and parenteral nutrition in cancer patients. AB - PURPOSE: This study was designed to evaluate the clinical benefit of low-profile double-lumen port catheters in patients receiving simultaneous chemotherapy and parenteral nutrition (PN). Potential advantages, complications, and the durations of simultaneous and single use of the catheter were assessed. METHODS: At a university teaching hospital, 10 patients received a double-lumen port catheter (5 men, 5 women; mean age 61.5 +/- 12 years). All port implantations were performed under ultrasonographic and fluoroscopic guidance in the radiologic interventional suite. Procedure-related immediate, early, and late complications were recorded until removal of the device, patient's death, or completion of follow-up period. Application times and durations for chemotherapy or PN were determined. RESULTS: No immediate complications were observed. First use of the port system for chemotherapy was within 12 days (+/- 25 days, range 0-84 days) and within 17 hours (+/- 22 hours, range 0-72 hours) for PN on average. During the application of PN, no delay or interruption of chemotherapy was observed. The port catheter was used for the simultaneous application of chemotherapy and PN for a total of 1,216 hours. One port catheter was removed after 30 days due to suspected port infection. CONCLUSION: Central venous double-lumen port systems as a therapeutic option in patients requiring chemotherapy and PN can increase safety during those simultaneous applications, while offering improved patient comfort. PMID- 20954132 TI - Sirolimus damages podocytes in rats with protein overload nephropathy. AB - BACKGROUND: Conversion from calcineurin inhibitors (CNIs) to sirolimus could significantly improve long-term graft survival after kidney transplantation. Proteinuria was found in some recipients after the switch, which could be alleviated by an angiotensin II receptor blocker (ARB). But the mechanisms for this have remained unclear. In this study, we utilized a rat model with protein overload nephropathy to explore the mechanisms of sirolimus-related proteinuria. METHODS: A rat model with protein overload nephropathy was induced by repeated injections of bovine serum albumin. Model rats also received sirolimus (rapamycin) treatment or ARB agent (losartan) pretreatment. Urinary protein excretion from 24-hour urine specimens was calculated, and the morphological changes of renal tissues were analyzed by hematoxylin and eosin staining and electron microscopy. The expression of desmin, a sensitive marker of podocyte injury, was detected by immunohistochemical staining. RESULTS: Rapamycin increased urinary protein excretion and intratubular protein cast formation in rats with protein overload nephropathy. The foot process effacement of podocytes was found by electron microscopy after rapamycin treatment. The expression of desmin was up-regulated after rapamycin treatment. However, losartan pretreatment could attenuate proteinuria in spite of rapamycin treatment. CONCLUSION: Sirolimus aggravates proteinuria in rats with protein overload nephropathy by damaging podocytes, a barrier of glomerular filtration. Furthermore, angiotensin II receptor blocker can counteract the effect of sirolimus, not only through hemodynamic changes but also partly by repairing the injury of podocytes. This study might be useful for understanding the mechanism of sirolimus-related proteinuria and guiding clinical treatments. PMID- 20954133 TI - Mitochondrial DNA copy number correlates with oxidative stress and predicts mortality in nondiabetic hemodialysis patients. AB - BACKGROUND: Oxidative stress is highly prevalent in hemodialysis patients and may contribute to atherosclerosis and mortality. The copy number of mitochondrial DNA (mtDNA) is affected by oxidative stress in blood circulation. This study aimed to test whether mtDNA copy number correlates with oxidative stress and predicts all cause mortality in nondiabetic hemodialysis patients. METHODS: Ninety-five nondiabetic hemodialysis patients and 95 healthy subjects were enrolled. Plasma thiobarbituric acid-reactive substances (TBARS) and plasma free thiol were used as indicators of oxidative stress and antioxidant defense, respectively. Mitochondrial DNA copy number in peripheral blood leukocytes was measured by determining relative amounts of mtDNA to nuclear DNA by quantitative real-time PCR. All-cause mortality of hemodialysis patient was recorded during a follow-up of 3 years. RESULTS: Nondiabetic hemodialysis patients showed higher TBARS levels, lower free thiol levels and higher mtDNA copy numbers compared with normal control subjects. The plasma TBARS level was a significant factor correlating positively to the mtDNA copy number (p=0.024). Patients with a mtDNA copy number higher than the median had a higher all-cause mortality than patients with a lower mtDNA copy number (17.0% vs. 4.2%; log-rank test: p=0.038). A 1-log increase in mtDNA copy number was independently related to an increase in the risk for mortality (hazard ratio 21.360; 95% confidence interval, 1.298-351.572). CONCLUSIONS: Nondiabetic hemodialysis patients had higher oxidative stress and mtDNA copy numbers than healthy subjects. The mtDNA copy number correlates with oxidative stress and predicts mortality in nondiabetic hemodialysis patients. PMID- 20954134 TI - Non-adherence in patients on chronic hemodialysis: an international comparison study. AB - BACKGROUND: Adherence to diet and fluid restrictions by adults on hemodialysis treatment is challenging. This study compared non-adherence (NA) to diet and fluid restrictions between adult US and German hemodialysis patients, and assessed potential predictors for NA. METHODS: A cross-sectional multicenter comparative study of 456 adult hemodialysis patients was conducted in 12 outpatient-based hemodialysis centers in the United States and Germany. NA was based on self-report using the Dialysis Diet and Fluid Non-adherence Questionnaire (DDFQ). Laboratory marker, interdialytic weight gain (IDWG) and dialysis adequacy (Kt/V) information were obtained from medical records. Mean time on dialysis was 50 months (range 3-336); mean age was 62 years (range 19 91), with the majority of patients (89.7%) being white. RESULTS: Self-reported frequency of NA to diet was 80.4% and to fluid 75.3% in the total sample. The degree of NA to diet and fluid differed significantly, with the US patients (68.1% vs. 61.1%) reporting less NA when compared with German (81.6% vs. 79.0%) patients (p<0.0001). Phosphorus, albumin, IDWG and Kt/V levels were higher in the US compared with the German subsample (all p<0.0001; IDWG p<0.003). Generalized regression models revealed that education (p<0.01) and smoking (p<0.01) predicted NA to diet, whereas single marital status (p<0.008) and male sex (p<0.04) were independent predictors for NA to fluid. CONCLUSIONS: NA persists as one of the most challenging tasks in health care of patients with chronic conditions, including hemodialysis patients. Our findings suggest that patient, condition related, socioeconomic and health care system-related factors may contribute to NA to diet and fluid restrictions. PMID- 20954135 TI - Nephrology fellows show consistent use of, and improved knowledge from, a nephrologist-programmed teaching instrument. AB - INTRODUCTION: Teaching nephrology through a traditional classroom-based approach has significant time and place limitations. In the 21st century, these limitations are more prevalent and harder to resolve. Fortunately, online teaching instruments can overcome these restrictions. On this basis, we hypothesized that a nephrology-focused online teaching instrument, programmed and maintained by nephrology educators, would result in sustained use by, and improved test scores for, nephrology fellows. METHODS: To test this hypothesis, we programmed and managed a 3-tiered Web-based teaching instrument based on the Blackboard platform. Nephrology fellows from Emory University, from the Classes of 2008-2010, were the primary subjects asked to use this instrument. We tracked their use of every teaching resource for 20 months. In addition we tested their knowledge of nephrolithiasis before and after using our interactive teaching module. RESULTS: Both the e-Library and Discussion forums showed increases in total use from years 1 to 2 (31% and 91% increases, respectively). When stratified by category or year in training, the changes in average monthly use of all online teaching resources were nonsignificant. Eight of 10 renal fellows showed increases in postmodule test scores (42.3% increase for the Class of 2009; 10.7% increase for the Class of 2010). CONCLUSIONS: Our results demonstrate sustained use in all 3 tiers of the online instrument. There was a significant improvement in knowledge after using the online module. The results indicate that nephrology educators can program sustainable online teaching tools that improve fellows' knowledge of nephrology. PMID- 20954136 TI - Peripheral artery calcifications evaluated by histology correlate to those detected by CT: relationships with fetuin-A and FGF-23. AB - BACKGROUND: Calcification of arteries is a frequent occurrence in hemodialysis (HD) patients and is linked to mortality. This study was conducted to evaluate the correspondence between coronary calcification scores and calcifications observed histologically in peripheral arteries in HD patients. In addition the association of humoral parameters including fetuin-A and fibroblast growth factor 23 (FGF-23) with arterial calcifications was studied. PATIENTS AND METHODS: HD patients (n=44) were studied with multislice computed tomography (CT) and histological quantification of arterial calcifications in the lower epigastric artery sampled at the time of renal transplant. In addition, humoral assays were performed including fetuin-A and FGF-23. RESULTS: There was a significant correlation between medial calcification of the artery and Agatston scores. Natural logarithm (Ln) FGF-23 significantly correlated to Ln Agatston score but not to Ln medial calcification. A significant negative correlation between fetuin A and Ln FGF-23 was observed, changing to borderline significance after correction for age and Ln HD age. Ln Agatston score in a multiregression analysis was predicted by Ln FGF-23 and age. CONCLUSIONS: The association found between histologically evaluated calcification of the media of a peripheral artery in HD and the multislice CT Agatston scores is in favor of a generalized arterial calcification, either intimal or of tunica media, when calcium deposits are found in the coronary arteries. The association of FGF-23 with coronary calcification score, already reported, and less so with histological medial calcification is in favor of a link between the protein and intimal more than the medial calcification. FGF-23 may be considered a potential biomarker of arterial calcification in HD patients. The negative association between fetuin-A and FGF 23 may suggest a linkage between these humoral substances, vascular calcifications and mortality. The nature of this linkage requires further studies. PMID- 20954137 TI - WITHDRAWN: Kidney injury molecule-1: a novel kidney-specific injury molecule playing potential double-edged functions in kidney injury. AB - Ahead of Print article withdrawn by Publisher. Kidney injury molecule-1 (KIM-1), a recently discovered transmembrane protein, is expressed in dedifferentiated renal proximal tubular epithelial cells in damaged regions. Many studies have confirmed that KIM-1 is a specific marker of renal proximal tubular damage. Recently, more attention has been paid to its potential pathophysiological functions in renal injury or repair. A number of studies have illustrated the different functions of KIM-1 in various renal diseases, including its protective functions in acute kidney injury and damaging functions in chronic kidney disease. Although the exact functions of KIM-1 still remain unclear, some scientists speculate that KIM-1 may be a therapeutic target for kidney injury. In this review, some of the known features and functions of KIM-1 are highlighted. PMID- 20954138 TI - Life-threatening hypercalcemia in patients with rhabdomyolysis-induced oliguric acute renal failure. AB - BACKGROUND: In a third of patients presenting with rhabdomyolysis-induced acute renal failure (ARF), a biphasic plasma calcium profile may occur. METHODS: We report a case of rhabdomyolysis-induced ARF presenting hypocalcemia during oliguria, followed by a severe hypercalcemia in the polyuric phase. A hypocalcemia-induced acute increase of plasma parathyroid hormone in the early stage of ARF was followed by a down-regulation of parathyroid hormone, 1,25(OH)2 vitamin D and 25(OH) vitamin D during the renal function recovery, associated with an acute hypercalcemia. The plasma calcium increase induced in our patient severe neurological disturbances, life-threatening short QT interval and Brugada like syndrome at risk of malignant arrhythmias. This complication was treated by hemodialysis and pamidronic acid infusion. RESULTS: This case confirms that the pathogenesis of the biphasic calcium profile may be related to the massive calcium uptake in the ischemic muscle cells during oliguria, followed by a muscle calcium release later in the polyuric stage of ARF. Therefore, the behavior of calciotropic hormones may be the consequence rather than the cause of plasma calcium changes. CONCLUSIONS: We would like to emphasize the danger of sudden death that may occur in the recovery phase of rhabdomyolysis-induced ARF when the physician might be wrongly convinced that the major risks have disappeared. PMID- 20954139 TI - High-sodium diet promotes a profibrogenic reaction in normal rat kidneys: effects of Tempol administration. AB - BACKGROUND: Studies carried out in vitro have recently shown that salt loading induces an increasing mechanical stretch and a flow-induced superoxide production in the thick ascending limb of Henle's loop. In this regard, we hypothesized that the oxidative stress induced by salt overload could stimulate inflammatory and fibrogenic signaling pathways in normal rats. METHODS: Sprague Dawley rats were fed with an 8% NaCl high- (HS) or 0.4% NaCl normal-salt (NS) diet for 3 weeks, with or without Tempol (T) administration (1 mM, administered in drinking water). Mean arterial pressure (MAP), glomerular filtration rate (GFR) and urinary sodium excretion (UVNa) were measured. NAD(P)H oxidase p47phox, angiotensin II (Ang II), transforming growth factor beta1 (TGF-beta1), a-smooth muscle actin (a-SMA) and nuclear factor-kappa B (NF-kB) expression were evaluated in renal tissues by immunohistochemistry. RESULTS: A high NaCl diet produced a slight but significant increase in MAP and enhanced UVNa and oxidative stress. Administration of a high NaCl diet induced the overexpression of TGF-beta1, a-SMA and NF-?B in cortex and medulla, while Ang II increased in proximal convoluted tubules, and decreased in cortical collecting ducts. Tempol administration prevented these changes and simultaneously normalized MAP accompanied by an enhancement in GFR and UVNa. CONCLUSION: The results showed that a high NaCl diet is able to produce a renal profibrotic response also in normal rats, which could be associated with oxidative stress rather than intrarenal Ang II expression. PMID- 20954140 TI - Cyclosporine A causes maturation failure in embryonic-type glomeruli persisting after birth. AB - INTRODUCTION: We analyzed renal histologic and immunohistologic findings in children with nephrotic syndrome (NS) who did (n=5) or did not (n=17) develop cyclosporine A (CyA) nephropathy despite appropriately low serum CyA concentrations being maintained over 2 years. METHODS: To discriminate embryonic type from mature glomeruli, we performed staining for type IV collagen a1, laminin beta1 and laminin beta2. Staining patterns were used to semiquantitatively assess glomerular immaturity (glomerular immaturity index, or GII). RESULTS: In follow-up biopsy specimens, residual embryonic-type, collapsed embryonic-type and sclerotic glomeruli that had failed to differentiate were observed. Patients with early-onset CyA nephropathy had a high GII. In patients with a high GII, arteriopathy developed early in CyA treatment. Arteriopathy was observed mostly near embryonic-type glomeruli. Taken together, these glomeruli (surviving embryonic-type, collapsing embryonic-type, and sclerotic glomeruli) essentially equaled the total number of embryonic-type glomeruli in specimens obtained before CyA treatment. CONCLUSION: Our findings indicate a need for caution in CyA therapy for patients with NS, even for a relatively short course of administration, because some patients may have embryonic-type glomeruli or immature arterioles that predispose them to CyA nephropathy. PMID- 20954143 TI - Trisomy 1q42-qter associated with monosomy 6q27-qter: a case report. AB - PURPOSE: Partial trisomy 1q42-qter is a rare chromosomal aberration. Most cases arise from de novo unbalanced translocations or from unbalanced inheritance of parental balanced rearrangements. METHODS: Descriptive case report. RESULTS: A 4 year-old boy had shown an increased neck translucency at the fetal ultrasound examination performed at the 11th week of gestation. Amniocentesis, performed at the 18th week of gestation, did not demonstrate any genetic abnormality. A second fetal ultrasound examination, carried out at the 35th week of gestation, showed congenital clubfeet and hydrocephalus. At birth, clinical examination revealed congenital bilateral ventriculomegaly, bilateral congenital equinovarus clubfeet, low-set ears, plagiocephaly, micrognathia, hypertelorism, prominent forehead, broad nasal bridge, hypertonic syndrome, and inguinal hernia. Ophthalmologic consultation showed the presence of optic pit in his left eye. Genetic counseling was performed. Chromosome analysis demonstrated a partial trisomy 1q42.2-qter associated with a partial monosomy 6q27-qter. Moreover, deletions of the distal region on the long arm of chromosome 6 are frequently associated with both ocular abnormalities and several solid tumor types. Moderate mental and psychomotor retardation has occurred. CONCLUSIONS: This case emphasizes the importance of scheduling a screening test for eye diseases and tumor in these patients. PMID- 20954144 TI - Vitrectomy for vitreous opacities and macular pucker in Gaucher disease. AB - PURPOSE: To report significant surgical results in an uncommon ophthalmologic complication of a rare disease. METHODS: Interventional case report. RESULTS: A 16-year-old girl with type III Gaucher disease experienced visual loss in both eyes. Ophthalmologic examination revealed dense whitish vitreous opacities and macular pucker OU. Visual acuity (VA) OD was 20/63 and OS was 20/25. She underwent 25-gauge vitrectomy with removal of the vitreous core, posterior vitreous cortex, and indocyanine green?stained internal limiting membrane OD. Visual acuity improved, reaching 20/25 1 year after surgery despite the appearance of small preretinal flecks. Visual acuity OS decreased some time later and vitrectomy was performed when VA OS was 20/100. Three years after surgery, BCVA was 20/25 OD and 20/20 OS 1 year after surgery. CONCLUSIONS: We describe a young patient with Gaucher disease with severe bilateral vitreous opacities and macular pucker. After surgery, vitreous opacities partially and progressively recurred, but the overall favorable outcome strongly supports a surgical approach in cases of this kind. PMID- 20954145 TI - Surgical reposition of a dislocated Ex-PRESS miniature device. AB - PURPOSE: To present a technique of surgical reposition of the Ex-PRESS miniature glaucoma device when dislocated in corneal limbus. METHODS: A 54-year-old woman diagnosed with glaucoma, with a 3-month history of Ex-PRESS miniature implant, was referred to our department because of progressive intraocular pressure (IOP) rise. Slit-lamp biomicroscopy showed the posterior flange of the implant located in the corneal limbus; IOP was 34 mmHg. Surgical technique consisted of reopening of the conjunctiva and the scleral flap, excision of the corneal tissue covering the flange, and stitching the implant to the sclera with polyprolene suture. RESULTS: Postoperatively, IOP rapidly reduced to 5 mmHg and was balanced to 10 mmHg in the follow-up. CONCLUSIONS: Corneal dislocation of the Ex-PRESS implant, when associated with ocular hypertension, needs surgical treatment. Before considering a trabeculectomy, it could be valuable to attempt an implant reposition. PMID- 20954146 TI - Analysis of the diurnal intraocular pressure profile pre and post trabeculectomy using 24-hour monitoring of intraocular pressure. AB - PURPOSE: To compare the diurnal intraocular pressure (IOP) profile pre and post trabeculectomy with a control group of medically controlled patients. We compared the change in mean, peak, and diurnal IOP fluctuation. METHODS: This was an observational study of patients at the Bristol Eye Hospital, United Kingdom. All patients underwent initial and subsequent phasing, with surgery between for cases. The unpaired Student t test compared the changes (initial-subsequent) in mean, peak, and fluctuation between cases and controls. RESULTS: Fifteen eyes underwent trabeculectomy surgery while the control group contained 17 eyes controlled on topical medical treatment. There was a statistically significant reduction in both mean IOP of 3.7 mmHg (p=0.002) and peak IOP of 4.4 mmHg (p=0.025) in the surgical group compared to the medical group. There was no statistically significant change in the IOP fluctuation between the 2 study groups (p=0.296). CONCLUSIONS: There is a significant reduction in mean IOP and peak IOP following trabeculectomy. We showed no statistically significant change in the diurnal fluctuation of IOP following trabeculectomy. PMID- 20954147 TI - Intravitreal bevacizumab in a patient with a macular star in malignant hypertension. AB - PURPOSE: To report a case of retinopathy secondary to malignant hypertension showing a macular star, which responded favorably to a single intravitreal injection of bevacizumab (IVB). METHODS: A 46-year-old man with malignant hypertension showing incomplete macular star in his right eye with best-corrected visual acuity (BCVA) of 20/32 underwent IVB. RESULTS: Subsequent examinations revealed a progressive resolution of the macular star with functional recovery over the follow-up. In particular, at the 9-month examination BCVA was 20/20, fundus biomicroscopy disclosed resolution of the macular star, and the retinal sensitivity improved remarkably. CONCLUSIONS: Intravitreal injection of bevacizumab can be a useful approach to treat the exudative manifestations of malignant hypertension. PMID- 20954148 TI - Sequential anterior ischemic optic neuropathy and central retinal artery and vein occlusion after ranibizumab for diabetic macular edema. AB - PURPOSE: To describe a rare adverse event characterized by anterior ischemic optic neuropathy (AION) associated with central retinal artery occlusion (CRAO) followed by central retinal vein occlusion (CRVO) secondary to treatment with intravitreal injection of ranibizumab for diabetic macular edema (DME). METHODS: A patient with DME refractory to focal grid laser photocoagulation in the left eye was prospectively followed and treated with intravitreal injection of ranibizumab. Over a 12-month period and after 4 injections, best-corrected visual acuity (BCVA) improved from 20/63 to 20/50 (Snellen equivalent) and central retinal thickness (CRT) reduced from 551 to 279 um. In July 2009, BCVA dropped to 20/100 with CRT of 421 um due to the recurrence of DME and a further injection was administered. RESULT: One month later, the left eye showed a sudden visual acuity loss. Best-corrected visual acuity was 20/400 and the fundus examination revealed a hyperemic and swollen optic disc, with several retinal hemorrhages. Retina at the posterior pole was pale, with attenuation and sheathing of arterial vessels. Fluorescein angiography showed a delayed optic disc and arterial filling with retinal ischemia involving both posterior pole and periphery and confirmed the diagnosis of AION associated with CRAO. One month later, the BCVA decreased to 20/800, and fundus examination evidenced a CRVO with diffuse retinal hemorrhages in the 4 quadrants, congestion, and tortuosity of the retinal veins. CONCLUSIONS: Although severe ocular adverse events are generally rare, patients receiving intraocular anti-vascular endothelial growth factor injection should be monitored carefully for the development of vascular complications. PMID- 20954149 TI - Toxic anterior segment syndrome after uncomplicated cataract surgery. PMID- 20954150 TI - Potential diagnostic value of fluorescein angiography and color Doppler imaging in primary open-angle glaucoma. PMID- 20954151 TI - Stippling: a first trimester marker for thanatophoric dysplasia type I. PMID- 20954152 TI - Measurement of thioredoxin and thioredoxin reductase. AB - The thioredoxin system is ubiquitous, providing reducing equivalents to essential biosynthetic enzymes like ribonucleotide reductase. It is essential for cellular redox regulation, control of oxidative stress, and protection against oxidative damage. This unit includes protocols for measuring thioredoxin or thioredoxin reductase in biological preparations or as purified enzymes. PMID- 20954153 TI - Measurement of MnSOD and CuZnSOD activity in mammalian tissue homogenates. AB - Three basic forms of mammalian SODs exist and they are distinguished by their sizes and locations. SOD enzyme activity is not easily monitored by direct measurement because the substrate disappearance is very rapid at physiological pH. Activity can be measured as described in this unit by a number of indirect competitive inhibition assays based on the principle that the superoxide anion radical will reduce an inhibitory substrate [such as nitroblue tetrazolium (NBT) or cytochrome c] and SOD activity will reduce the rate of reduction in a competitive fashion. The SOD-mediated inhibition of the indicator substrate reduction can then be quantitated and plotted as a function of the quantity of protein added to the reaction to construct an inhibition curve. PMID- 20954154 TI - The heme biosynthesis pathway and clinical manifestations of abnormal function. AB - Biosynthesis of heme is important for both prokaryotes and eukaryotes. The enzymes for this multistep process are distributed between the cytosol and mitochondria in eukaryotes. In humans there are inherited and acquired disorders characterized by over synthesis of one or more enzymes or absence of an enzyme. This overview discusses each enzyme in the heme biosynthesis pathway. PMID- 20954155 TI - Measurement of ALA synthase activity. AB - In most cells, delta-aminolevulinate (ALA) synthase is the rate-limiting enzyme in heme synthesis. It is inducible by drugs and toxins and is feedback regulated by heme. This unit describes a radiometric assay using [14C]succinate as a substrate and a colorimetric assay based on the conversion of ALA to a pyrrole. PMID- 20954156 TI - Measurement of heme concentration. AB - Heme (iron protoporphyrin IX) is a prosthetic group for a number of hemoproteins in different tissues (e.g., hemoglobin, myoglobin, cytochrome P-450s, mitochondrial cytochromes, catalases, and peroxidases). Mutations in the biosynthetic pathway can affect the synthesis and/or degradation of heme. Several assays are provided in this unit for quantifying heme: a spectrophotometric assay based on the characteristic absorption spectrum of oxidized and reduced form of the hemochrome formed by replacing the nitrogen ligands with pyridine; a fluorescence assay based on removal of the iron by a heated, strong oxalic acid solution to produce fluorescent protoporphyrin; a reversed-phase HPLC assay to measure heme and intermediates in the synthetic pathway; and a radiometric assay to measure newly synthesized heme in tissue culture cells. PMID- 20954157 TI - Measurement of uroporphyrinogen decarboxylase activity. AB - Uroporphyrinogen decarboxylase (UROD) catalyzes decarboxylation of the four acetate side chains of urophyrinogen to form coproporphyrinogen. Activity of UROD can be measured using an enzymatically prepared substrate or a chemically prepared one. For the former, bacterial porphobilinogen deaminase is prepared and used to prepare the porphyrinogen substrate for the enzymatic assay. Erythrocyte lysates can be used to measure hemoglobin content as an indicator of UROD activity. PMID- 20954158 TI - Measurement of protoporphyrinogen oxidase activity. AB - Protoporphyrinogen oxidase catalyzes the oxidation of protoporphyrinogen to protophyrin. It is a membrane-bound mitochondrial enzyme and it is the target of photobleaching herbicides. The basic assay presented in this unit for measuring oxidase activity is based on oxidation of the colorless, nonfluorescent substrate, protoporphyrinogen, to the colored, fluorescent protophyrin. Alternate protocols are provided for the measuring the accumulation of protoporphyrinogen resulting from a decrease in oxidase activity due to treatment with diphenyl ether herbicides or oxidase inhibitor. PMID- 20954159 TI - Measurement of ascorbic acid and dehydroascorbic acid in biological samples. AB - Ascorbic acid and dehydroascorbic acid are commonly used biomarkers of oxidative stress in a variety of experimental models. However, the accurate measurement of these labile compounds remains a challenge both in terms of sample collection and analysis. Determination of dehydroascorbic acid most commonly involves indirect measurement. The concentration is calculated by subtraction of the measured ascorbic acid concentration from that of total ascorbic acid analyzed after reduction of the dehydroascorbic acid present; a method referred to as the subtraction method. Consequently, successful determination of dehydroascorbic acid is dependent upon proper sample handling, quantitative reduction of the compound, and accurate quantification of both ascorbic acid and total ascorbic acid. The unit presents a detailed introduction to ascorbate analysis in biological samples and discusses common problems and pitfalls. The analytical method described is based on reversed-phase HPLC with coloumetric detection. This method includes co-analysis of isoascorbic acid and uric acid. Where applicable, uric acid can conveniently be used as an endogenous intrasample standard that significantly improves the accuracy of the subsequent dehydroascorbic acid calculation. PMID- 20954160 TI - Catalase activity assays. AB - Catalase (hydrogen peroxide/hydrogen peroxide oxidoreductase) is an important cellular antioxidant enzyme that defends against oxidative stress. It is found in the peroxisomes of most aerobic cells. It serves to protect the cell from toxic effects of high concentrations of hydrogen peroxide (H(2)O(2)) by catalyzing its decomposition into molecular oxygen and water, without the production of free radicals. It is important to measure catalase levels because oxidative stress is inherent in pathological conditions such as cancer, diabetes, cataracts, atherosclerosis, neurodegenerative disease, aging, and nutritional deficiencies. This unit provides methods for catalase activity measurements. PMID- 20954161 TI - Measurement of the vitamin E metabolites, carboxyethyl hydroxychromans (CEHCs), in biological samples. AB - Metabolites of alpha- and gamma-tocopherol, 2,5,7,8-tetramethyl-2-(2' carboxyethyl)-6-hydroxychroman (alpha-CEHC) and 2,7,8-trimethyl-2-(beta carboxyethyl)-6-hydroxychroman (gamma-CEHC), respectively, are produced in the liver and have been measured in biological fluids and tissue. Compared to alpha tocopherol concentrations, metabolite concentrations are as much as a factor of a thousand lower, requiring extremely sensitive methodology to attain accurate measurements. This unit presents a protocol for CEHC extraction from biological samples, and describes very specific and sensitive HPLC/MS analysis. PMID- 20954162 TI - Mineral profile in globe artichoke as affected by genotype, head part and environment. AB - BACKGROUND: The globe artichoke is an important vegetable, widely consumed in the Mediterranean Basin, and is spreading also to other parts of the world. The mineral profile of globe artichoke has been very little investigated. The purpose of this work was to evaluate the content of some essential macrominerals (Na, K, Ca, Mg) and microminerals (Fe, Cu, Mn, Zn) in nine genotypes of globe artichoke in relation to different head parts (bracts and receptacle), locations and seasons. RESULTS: The mineral profile was significantly affected by genotype, head fraction, location and season. Great variation was found among studied genotypes. 'Blanc Hyerois', Harmony F1', 'Madrigal F1' and 'Violetto di Provenza' showed high levels of both macro- and micromineral content. In particular, these, as well as other genotypes, had a higher content in the receptacle (edible part) than in the bracts. The globe artichoke had a high level of K and mainly, compared to some vegetables, low Na/K ratio, which is important in preventing hypertension and cardiovascular diseases. CONCLUSIONS: The results obtained partially improve the lack of data in the literature and this knowledge could be used to develop different crop managements and/or breeding programmes to improve the mineral composition, and thereby enhance human nutrition and health. PMID- 20954163 TI - Three-dimensional image-guided placement of percutaneous pedicle screws without the use of biplanar fluoroscopy or Kirschner wires: technical note. AB - BACKGROUND: Percutaneous pedicle screws are commonly used in minimally invasive spinal procedures. Traditional techniques of percutaneous pedicle screw placement have employed the use of multiplanar fluoroscopy and Kirschner wires (K-wires). The use of multiplanar fluoroscopy for the placement of percutaneous pedicle screws likely increases radiation exposure to the surgeon when compared to open techniques. K-wires can break or become bent during the procedure, making it difficult to insert and remove instrumentation over them. Additionally, there is also a risk of visceral or vascular injury with the use of K-wires. The authors present a novel method of percutaneous pedicle screw placement utilizing three dimensional (3D) fluoroscopy-based image guidance in which K-wires are not used and there is minimal to no radiation exposure to the surgeon and operating room staff. METHODS: Thirty-six screws were placed in 15 patients using this technique. An independent radiologist graded screw placement using computed tomographic (CT) scans and the breach rate of the percutaneous pedicle screws was compared to the breach rate of 33 pedicle screws placed contralaterally using the mini-open technique. RESULTS: No bony breach was noted by any screw in either group and no complications occurred in this study as a result of screw placement. CONCLUSIONS: Percutaneous pedicle screws can be placed accurately and safely using 3D image guidance without the use of K-wires. Little to no radiation exposure to the surgeon or OR staff occurs with this technique. No complications occurred in this study as a result of screw placement or image guidance. PMID- 20954164 TI - MRI of renal oxygenation and function after normothermic ischemia-reperfusion injury. AB - The in vivo assessment of renal damage after ischemia-reperfusion injury, such as in sepsis, hypovolemic shock or after transplantation, is a major challenge. This injury often results in temporary or permanent nonfunction. In order to improve the clinical outcome of the kidneys, novel therapies are currently being developed that limit renal ischemia-reperfusion injury. However, to fully address their therapeutic potential, noninvasive imaging methods are required which allow the in vivo visualization of different renal compartments and the evaluation of kidney function. In this study, MRI was applied to study kidney oxygenation and function in a murine model of renal ischemia-reperfusion injury at 7 T. During ischemia, there was a strongly decreased oxygenation, as measured using blood oxygen level-dependent MRI, compared with the contralateral control, which persisted after reperfusion. Moreover, it was possible to visualize differences in oxygenation between the different functional regions of the injured kidney. Dynamic contrast-enhanced MRI revealed a significantly reduced renal function, comprising perfusion and filtration, at 24 h after reperfusion. In conclusion, MRI is suitable for the noninvasive evaluation of renal oxygenation and function. Blood oxygen level-dependent or dynamic contrast-enhanced MRI may allow the early detection of renal pathology in patients with ischemia-reperfusion injury, such as in sepsis, hypovolemic shock or after transplantation, and consequently may lead to an earlier intervention or change of therapy to minimize kidney damage. PMID- 20954165 TI - The impact of ageing and changing utilization patterns on future cardiovascular drug expenditure: a pharmacoepidemiological projection approach. AB - PURPOSE: To develop a method for projecting the impact of ageing and changing drug utilization patterns on future drug expenditure. METHODS: Applying nationwide registries, prescriptions of three categories of cardiovascular drugs were followed for all Danish residents from 1 January 1996 until 2006. The official Danish population forecast 2006-2015 was applied for projecting the population composition. A previously developed pharmacoepidemiological semi Markov model was extended to apply for projection of future drug utilization. We either assumed that past trends in model parameters (incidence, discontinuation and drug user mortality) would continue during 2006-2015, or that all model parameters would remain unchanged at their values in 2005. Yearly drug expenditure per user of a particular drug was assumed to remain unchanged. Scenarios of future treatment prevalence with different drug categories were modelled by extrapolating future age- and gender-specific parameter values (treatment incidence, discontinuation and drug user mortality) from historic point estimates and their historic trend. RESULTS: Provided a continuance of past trends, increasing utilization of ACE inhibitors, angiotensin II antagonists and statins translates into a rise in annual expenditure of 176%, mainly explained by increases in treatment incidence. Due to pharmacoepidemiological disequilibrium, unchanged model parameters would imply an increase of 64%, ageing alone 14%. CONCLUSION: Increasing cardiovascular drug utilization may pose a substantial burden on future health care resources. However, prescribing behaviour is likely to depend on changing clinical guidelines. Despite the limited impact as cost driver, population ageing remains a challenge for future health care services. PMID- 20954166 TI - Diagnostic accuracy of transvaginal ultrasound for non-invasive diagnosis of bowel endometriosis: systematic review and meta-analysis. AB - OBJECTIVE: To critically analyze the diagnostic value of transvaginal sonography (TVS) for non-invasive, presurgical detection of bowel endometriosis. METHODS: MEDLINE (1966-2010) and EMBASE (1980-2010) databases were searched for relevant studies investigating the diagnostic accuracy of TVS for diagnosing deep infiltrating endometriosis involving the bowel. Diagnosis was established by laparoscopy and/or histopathological analysis. Likelihood ratios (LRs) were recalculated in addition to traditional measures of effectiveness. RESULTS: Out of 188 papers, a total of 10 studies fulfilled predefined inclusion criteria involving 1106 patients with suspected endometriosis. The prevalence of bowel endometriosis varied from 24 to 73.3%. LR+ ranged from 4.8 to 48.56 and LR- ranged from 0.02 to 0.36, with wide confidence intervals. Pooled estimates of sensitivities and specificities were 91 and 98%; LR+ and LR- were 30.36 and 0.09; and positive and negative predictive values were 98 and 95%, respectively. Three of the studies used bowel preparations to enhance the visibility of the rectal wall; one study directly compared the use of water contrast vs. no prior bowel enema, for which the LR- was 0.04 and 0.47, respectively. CONCLUSIONS: TVS with or without the use of prior bowel preparation is an accurate test for non invasive, presurgical detection of deep infiltrating endometriosis of the rectosigmoid. PMID- 20954167 TI - Knowledge of prenatal screening and psychological management of test decisions. AB - OBJECTIVES: To study associations between pregnant women's knowledge of prenatal screening and decisional conflict in deciding whether to participate in first trimester screening for Down syndrome in a setting of required informed consent, and to study associations between knowledge and personal wellbeing, and worries in pregnancy. METHODS: A population-based cross-sectional study with 6427 pregnant women consecutively included before the time of a nuchal translucency scan. Participants were recruited from three Danish obstetric departments offering prenatal screening free of charge. The results presented are based on 4111 pregnant women (64%). Knowledge was measured using 15 questions. The primary outcomes were measured using pre-existing validated scales, i.e. The Decisional Conflict Scale, the WHO Well-Being Index and the Cambridge Worry Scale. Associations were analyzed by multivariate logistic and linear regression analyses. RESULTS: A higher level of knowledge was associated with less decisional conflict when deciding whether to participate in first-trimester Down syndrome screening (adjusted odds ratio 1.31 (95% CI, 1.26-1.37)). An increased level of knowledge was also associated with higher levels of wellbeing (adjusted linear coefficient 0.51 (95% CI, 0.26-0.75), P < 0.001). Knowledge was not associated with worries, either in general or specifically about something being wrong with the baby. CONCLUSION: The results of this study indicate the importance of ensuring a high level of knowledge for pregnant women making choices about participation in prenatal screening for Down syndrome in order to improve the psychological management of test decisions. PMID- 20954168 TI - How to identify the thymus in the fetus: the thy-box. PMID- 20954169 TI - Responses of Rhynchophorus ferrugineus adults to selected synthetic palm esters: electroantennographic studies and trap catches in an urban environment. AB - BACKGROUND: The red palm weevil (RPW), Rhynchophorus ferrugineus Olivier, accidentally introduced into the European countries facing the Mediterranean basin, is becoming the most serious pest for ornamental palms in the urban environment. In the present work, tests were conducted on the electroantennogram (EAG) and behavioural responses of RPW adults to five selected synthetic palm esters, ethyl propionate, ethyl butyrate, ethyl isobutyrate, ethyl lactate and ethyl acetate, to assess the application of a mass trapping technique in an urban environment. RESULTS: In the laboratory, EAG bioassays on RPW adults with the synthetic palm esters showed: (1) positive dose-dependent responses; (2) differences among the treatments; (3) a greater response to ethyl propionate; (4) a higher sensitivity of female antennae compared with male antennae. In the urban environment, RPW behavioural responses, evaluated over six biweekly observations on pheromone- and molasses- baited traps, showed that more adults were caught by traps supplemented with ethyl propionate and ethyl acetate than by traps supplemented with only ethyl propionate. Similar catches were recorded in the traps supplemented with ethyl propionate or ethyl acetate. CONCLUSION: This study supports the application of the mass trapping implemented with synthetic palm esters as a potential tool for the management of RPW populations to protect ornamental palms in urban environments. PMID- 20954170 TI - Exposure risk assessment and evaluation of the best management practice for controlling pesticide runoff from paddy fields. Part 2: model simulation for the herbicide pretilachlor. AB - BACKGROUND: Monitoring studies revealed high concentrations of pesticides in the drainage canal of paddy fields. It is important to have a way to predict these concentrations in different management scenarios as an assessment tool. A simulation model for predicting the pesticide concentration in a paddy block (PCPF-B) was evaluated and then used to assess the effect of water management practices for controlling pesticide runoff from paddy fields. RESULTS: The PCPF-B model achieved an acceptable performance. The model was applied to a constrained probabilistic approach using the Monte Carlo technique to evaluate the best management practices for reducing runoff of pretilachlor into the canal. The probabilistic model predictions using actual data of pesticide use and hydrological data in the canal showed that the water holding period (WHP) and the excess water storage depth (EWSD) effectively reduced the loss and concentration of pretilachlor from paddy fields to the drainage canal. The WHP also reduced the timespan of pesticide exposure in the drainage canal. CONCLUSIONS: It is recommended that: (1) the WHP be applied for as long as possible, but for at least 7 days, depending on the pesticide and field conditions; (2) an EWSD greater than 2 cm be maintained to store substantial rainfall in order to prevent paddy runoff, especially during the WHP. PMID- 20954171 TI - Noncellulosomal cohesin from the hyperthermophilic archaeon Archaeoglobus fulgidus. AB - The increasing numbers of published genomes has enabled extensive survey of protein sequences in nature. During the course of our studies on cellulolytic bacteria that produce multienzyme cellulosome complexes designed for efficient degradation of cellulosic substrates, we have investigated the intermodular cohesin-dockerin interaction, which provides the molecular basis for cellulosome assembly. An early search of the genome databases yielded the surprising existence of a dockerin-like sequence and two cohesin-like sequences in the hyperthermophilic noncellulolytic archaeon, Archaeoglobus fulgidus, which clearly contradicts the cellulosome paradigm. Here, we report a biochemical and biophysical analysis, which revealed particularly strong- and specific-binding interactions between these two cohesins and the single dockerin. The crystal structure of one of the recombinant cohesin modules was determined and found to resemble closely the type-I cohesin structure from the cellulosome of Clostridium thermocellum, with certain distinctive features: two of the loops in the archaeal cohesin structure are shorter than those of the C. thermocellum structure, and a large insertion of 27-amino acid residues, unique to the archaeal cohesin, appears to be largely disordered. Interestingly, the cohesin module undergoes reversible dimer and tetramer formation in solution, a property, which has not been observed previously for other cohesins. This is the first description of cohesin and dockerin interactions in a noncellulolytic archaeon and the first structure of an archaeal cohesin. This finding supports the notion that interactions based on the cohesin-dockerin paradigm are of more general occurrence and are not unique to the cellulosome system. PMID- 20954175 TI - Adsorption of plasmid DNA on ceramic hydroxyapatite chromatographic materials. AB - The adsorption of plasmid DNA onto two different types of ceramic hydroxyapatite beads with a particle diameter of 20 MUm, namely Ceramic Hydroxyapatite Type II and the Type III, which is not commercially available, were investigated. Type II and the Type III have a pore diameter of 80 and 240 nm, respectively. Equilibrium and dynamic binding capacity for a 4.9 kbp model plasmid on Ceramic Hydroxyapatite Type II and Type III were enhanced by addition of NaCl to the adsorption buffer. This result indicates that the adsorption mechanism cannot be solely explained by electrostatic interaction. The affinities of plasmid DNA for Ceramic Hydroxyapatite Type II (with a K(D) of ~0.005 mg/mL) and to Hydroxyapatite Type III (with a K(D) of ~0.045 mg/mL) were not affected by NaCl, whereas the binding capacity was. This observation corroborates the assumption that a change of the shape of the plasmid molecule is affected and could be the reason for increased binding capacity with salt. The maximal binding capacity shows that at least a part of the CHT II bead must be accessible for the plasmid, whereas CHT III can be saturated with the plasmid. In both cases, an extremely hindered transport takes place. PMID- 20954176 TI - Gas-diffusion microextraction. AB - Gas-diffusion microextraction (GDME) is an innovative technique that combines the advantages of membrane-aided gas-diffusion with microextraction concepts. GDME makes uses of a novel portable and low-cost device that comprises a small, commercially available, semi-permeable membrane. Furthermore, if derivatization is integrated into the GDME concept, considerable enrichment factors can be obtained. It may become a powerful tool for any analyst who intends to quantify volatile and semi-volatile analytes in various kinds of matrices. The analysis of vicinal diketones in beer was used as a case study to show GDME applicability and capabilities. Vicinal diketones were derivatized with o-phenylenediamine and then determined by HPLC-UV. Obtained results showed good repeatability and precision with extraction periods at the minute time span. PMID- 20954178 TI - A systemic view of biodiversity and its conservation: processes, interrelationships, and human culture: presentation of a systemic view of biodiversity and its conservation that emphasizes complex interrelationships among subsystems and includes human culture. AB - Historically, views and measurements of biodiversity have had a narrow focus, for instance, characterizing the attributes of observable patterns but affording less attention to processes. Here, we explore the question: how does a systems thinking view - one where the world is seen as elements and processes that connect and interact in dynamic ways to form a whole - affect the way we understand biodiversity and practice conservation? We answer this question by illustrating the systemic properties of biodiversity at multiple levels, and show that biodiversity is a collection of dynamic systems linking seemingly disparate biological and cultural components and requiring an understanding of the system as a whole. We conclude that systems thinking calls traditional views of species, ecosystem function, and human relationships with the rest of biodiversity into question. Finally, we suggest some of the ways in which this view can impact the science and practice of conservation, particularly through affecting our conservation targets and strategies. PMID- 20954179 TI - An immune paradox: how can the same chemokine axis regulate both immune tolerance and activation?: CCR6/CCL20: a chemokine axis balancing immunological tolerance and inflammation in autoimmune disease. AB - Chemokines (chemotactic cytokines) drive and direct leukocyte traffic. New evidence suggests that the unusual CCR6/CCL20 chemokine receptor/ligand axis provides key homing signals for recently identified cells of the adaptive immune system, recruiting both pro-inflammatory and suppressive T cell subsets. Thus CCR6 and CCL20 have been recently implicated in various human pathologies, particularly in autoimmune disease. These studies have revealed that targeting CCR6/CCL20 can enhance or inhibit autoimmune disease depending on the cellular basis of pathogenesis and the cell subtype most affected through different CCR6/CCL20 manipulations. Here, we discuss the significance of this chemokine receptor/ligand axis in immune and inflammatory functions, consider the potential for targeting CCR6/CCL20 in human autoimmunity and propose that the shared evolutionary origins of pro-inflammatory and regulatory T cells may contribute to the reason why both immune activation and regulation might be controlled through the same chemokine pathway. PMID- 20954180 TI - SMN and Gemins: 'we are family' ... or are we?: insights into the partnership between Gemins and the spinal muscular atrophy disease protein SMN. AB - Gemins 2-8 and Unr-interacting protein (UNRIP) are intimate partners of the survival motor neuron (SMN) protein, which is the determining factor for the neuromuscular disorder spinal muscular atrophy (SMA). The most documented role of SMN, Gemins and UNRIP occurs within the large macromolecular SMN complex and involves the cytoplasmic assembly of spliceosomal uridine-rich small nuclear ribonucleoproteins (UsnRNPs), a housekeeping process critical in all cells. Several reports detailing alternative functions for SMN in either motor neurons or skeletal muscles may, however, hold the answer to the extreme neuromuscular tissue specificity observed in SMA. Recent discoveries indicate that collaboration between SMN and Gemins also extends to these non-canonical functions, hence raising the possibility that mutations in Gemin genes may be the cause of unlinked neuromuscular hereditary syndromes. This review evaluates the functions of Gemins and UNRIP inside the SMN complex and discusses whether these less notorious SMN complex members are capable of acting independently of SMN. PMID- 20954177 TI - Systems genetics analysis of mouse chondrocyte differentiation. AB - One of the goals of systems genetics is the reconstruction of gene networks that underlie key processes in development and disease. To identify cartilage gene networks that play an important role in bone development, we used a systems genetics approach that integrated microarray gene expression profiles from cartilage and bone phenotypic data from two sets of recombinant inbred strains. Microarray profiles generated from isolated chondrocytes were used to generate weighted gene coexpression networks. This analysis resulted in the identification of subnetworks (modules) of coexpressed genes that then were examined for relationships with bone geometry and density. One module exhibited significant correlation with femur length (r = 0.416), anteroposterior diameter (r = 0.418), mediolateral diameter (r = 0.576), and bone mineral density (r = 0.475). Highly connected genes (n = 28) from this and other modules were tested in vitro using prechondrocyte ATDC5 cells and RNA interference. Five of the 28 genes were found to play a role in chondrocyte differentiation. Two of these, Hspd1 and Cdkn1a, were known previously to function in chondrocyte development, whereas the other three, Bhlhb9, Cugbp1, and Spcs3, are novel genes. Our integrative analysis provided a systems-level view of cartilage development and identified genes that may be involved in bone development. PMID- 20954181 TI - The battle for creativity: frontiers in science and science education. PMID- 20954182 TI - Structure-based prediction of protein-peptide specificity in Rosetta. AB - Protein-peptide interactions mediate many of the connections in intracellular signaling networks. A generalized computational framework for atomically precise modeling of protein-peptide specificity may allow for predicting molecular interactions, anticipating the effects of drugs and genetic mutations, and redesigning molecules for new interactions. We have developed an extensible, general algorithm for structure-based prediction of protein-peptide specificity as part of the Rosetta molecular modeling package. The algorithm is not restricted to any one peptide-binding domain family and, at minimum, does not require an experimentally characterized structure of the target protein nor any information about sequence specificity; although known structural data can be incorporated when available to improve performance. We demonstrate substantial success in specificity prediction across a diverse set of peptide-binding proteins, and show how performance is affected when incorporating varying degrees of input structural data. We also illustrate how structure-based approaches can provide atomic-level insight into mechanisms of peptide recognition and can predict the effects of point mutations on peptide specificity. Shortcomings and artifacts of our benchmark predictions are explained and limits on the generality of the method are explored. This work provides a promising foundation upon which further development of completely generalized, de novo prediction of peptide specificity may progress. PMID- 20954183 TI - The antinuclear antibody test: last or lasting gasp? PMID- 20954184 TI - Clinical images: Baker's cyst in rheumatoid arthritis. PMID- 20954185 TI - Interferon-alpha accelerates murine systemic lupus erythematosus in a T cell dependent manner. AB - OBJECTIVE: To investigate the mechanism by which interferon-alpha (IFNalpha) accelerates systemic lupus erythematosus (SLE) in (NZB*NZW)F1 (NZB/NZW) mice. METHODS: NZB/NZW mice were treated with an adenovirus expressing IFNalpha. In some mice, T cells were depleted with an anti-CD4 antibody. The production of anti-double-stranded DNA (anti-dsDNA) antibodies was measured by enzyme-linked immunosorbent assay and enzyme-linked immunospot assay. Germinal centers and antibody-secreting cells (ASCs) in spleens and IgG deposition and leukocyte infiltrates in kidneys were visualized by immunofluorescence staining. The phenotype of splenic cells was determined by flow cytometry. Finally, somatic hypermutation and gene usage in VH regions of IgG2a and IgG3 were studied by single-cell polymerase chain reaction. RESULTS: IFNalpha-accelerated lupus in NZB/NZW mice was associated with elevated serum levels of IgG2 and IgG3 anti dsDNA antibodies and accumulation of many IgG ASCs in the spleen, which did not develop into long-lived plasma cells. Furthermore, IgG2a and IgG3 antibodies in the mice were highly somatically mutated and used distinct repertoires of VH genes. The induction of SLE in the mice was associated with an increase in B cell Toll-like receptor 7 expression, increased serum levels of BAFF, interleukin-6 (IL-6), and tumor necrosis factor alpha, and induction of T cells expressing IL 21. Although IFNalpha drove a T cell-independent increase in serum levels of IgG, autoantibody induction and the development of nephritis were both completely dependent on CD4+ T cell help. CONCLUSION: These findings demonstrate that, although IFNalpha activates both innate and adaptive immune responses in NZB/NZW mice, CD4+ T cells are necessary for IFNalpha-driven induction of anti-dsDNA antibodies and clinical SLE. PMID- 20954186 TI - Osteoarthritic chondrocyte-secreted morphogens induce chondrogenic differentiation of human mesenchymal stem cells. AB - OBJECTIVE: The potential of stem cells to repair compromised cartilage tissue, such as in osteoarthritis (OA), depends strongly on how transplanted cells respond to factors secreted from the residing OA chondrocytes. This study was undertaken to determine the effect of morphogenetic signals from OA chondrocytes on chondrogenic differentiation of human mesenchymal stem cells (MSCs). METHODS: The effect of OA chondrocyte-secreted morphogens on chondrogenic differentiation of human MSCs was evaluated using a coculture system involving both primary and passaged OA chondrocytes. The findings were compared against findings for human MSCs cultured in OA chondrocyte-conditioned medium. Gene expression analysis, biochemical assays, and immunofluorescence staining were used to characterize the chondrogenic differentiation of human MSCs. Mass spectrometry analysis was used to identify the soluble factors. Numerical analysis was carried out to model the concentration profile of soluble factors within the human MSC-laden hydrogels. RESULTS: The human MSCs cocultured with primary OA chondrocytes underwent chondrogenic differentiation even in the absence of growth factors; however, the same effect could not be mimicked using OA chondrocyte-conditioned medium or expanded cells. Additionally, the cocultured environment down-regulated hypertrophic differentiation of human MSCs. Mass spectrometry analysis demonstrated cell-cell communication and chondrocyte phenotype-dependent effects on cell-secreted morphogens. CONCLUSION: The experimental findings, along with the results of the numerical analysis, suggest a crucial role of soluble morphogens and their local concentrations in the differentiation pattern of human MSCs in a 3-dimensional environment. The concept of using a small number of chondrocytes to promote chondrogenic differentiation of human MSCs while preventing their hypertrophic differentiation could be of great importance in formulating effective stem cell-based cartilage repair. PMID- 20954187 TI - Suppression of autoimmunity and organ pathology in lupus-prone mice upon inhibition of calcium/calmodulin-dependent protein kinase type IV. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic inflammatory disease associated with aberrant immune cell function. Treatment involves the use of indiscriminate immunosuppression, which results in significant side effects. SLE T cells express high levels of calcium/calmodulin-dependent protein kinase type IV (CaMKIV), which translocates to the nucleus upon engagement of the T cell receptor-CD3 complex and accounts for abnormal T cell function. The purpose of this study was to determine whether inhibition of CaMKIV would improve disease pathology. METHODS: We treated MRL/lpr mice with KN-93, a CaMKIV inhibitor, starting at week 8 or week 12 of age and continuing through week 16 and evaluated skin lesions, proteinuria, kidney histopathology, proinflammatory cytokine production, and costimulatory molecule expression. We also determined the effect of silencing of CAMK4 on interferon-gamma (IFNgamma) expression by human SLE T cells. RESULTS: CaMKIV inhibition in MRL/lpr mice resulted in significant suppression of nephritis and skin disease, decreased expression of the costimulatory molecules CD86 and CD80 on B cells, and suppression of IFNgamma and tumor necrosis factor alpha production. In human SLE T cells, silencing of CAMK4 resulted in suppression of IFNgamma production. CONCLUSION: We conclude that suppression of CaMKIV mitigates disease development in lupus-prone mice by suppressing cytokine production and costimulatory molecule expression. Specific silencing of CAMK4 in human T cells results in similar suppression of IFNgamma production. Our data justify the development of small-molecule CaMKIV inhibitors for the treatment of patients with SLE. PMID- 20954188 TI - In vivo fluorescence imaging of E-selectin: quantitative detection of endothelial activation in a mouse model of arthritis. AB - OBJECTIVE: In vivo optical imaging can delineate at the macroscopic level processes that are occurring at the cellular and molecular levels. E-selectin, a leukocyte adhesion molecule expressed on endothelium, is induced by tumor necrosis factor alpha (TNFalpha) and other cytokines involved in the pathogenesis of rheumatoid arthritis (RA). Collagen-induced arthritis (CIA) in mice is widely used to study the disease mechanisms and identify new treatments for RA. The purpose of this study was to demonstrate E-selectin-targeted fluorescence imaging in vivo in a mouse model of paw edema generated by local injection of TNFalpha as well as in mice with CIA. METHODS: Animals with either CIA or TNFalpha-induced paw edema were injected with anti-E-selectin or control antibodies labeled with a DyLight 750-nm near-infrared (NIR) probe. In vivo imaging studies were undertaken using an NIR optical imaging system, and images were coregistered with plain radiographic images. RESULTS: The mean fluorescence intensity measured over the time-course of TNFalpha-induced edema demonstrated a 1.97-fold increase (P<0.001) in signal in inflamed paws at 8 hours following injection of anti-E-selectin antibody, as compared to that in the isotype control. In the CIA model, a 2.34 fold increase in E-selectin-targeted signal was demonstrated (P<0.01). Furthermore, significant E-selectin-targeted signal was observed in the paws of animals immunized with collagen that did not display overt signs of arthritis. CONCLUSION: E-selectin-targeted fluorescence in vivo imaging is a quantifiable method of detecting endothelial activation in arthritis and can potentially be applied to the quantification of disease and the investigation of the effects of new therapies. Importantly, this approach may also be useful for the detection of subclinical disease in RA. PMID- 20954189 TI - Pattern on the antinuclear antibody-HEp-2 test is a critical parameter for discriminating antinuclear antibody-positive healthy individuals and patients with autoimmune rheumatic diseases. AB - OBJECTIVE: To identify features of antinuclear antibody (ANA)-HEp-2 test results that discriminate ANA-positive healthy individuals and patients with autoimmune rheumatic diseases (ARDs). METHODS: We sequentially retrieved data on 918 healthy individuals and 153 patients with ARDs after clinical assessment. ANA-positive healthy individuals for whom data were available were reevaluated after 3.6-5.0 years. An ANA-HEp-2 test result was considered positive when a clear ANA pattern was observed at 1:80 dilution in 2 distinct commercial HEp-2 slides by 2 blinded independent observers. RESULTS: ANAs were present in 118 healthy individuals (12.9%) and 138 patients with ARDs (90.2%). The ANA titer was higher in patients with ARDs than in healthy individuals (P<0.001). The ANA pattern profile was distinct in the 2 groups. Nuclear homogeneous, nuclear coarse speckled, and nuclear centromeric patterns appeared exclusively in patients with ARDs. The nuclear dense fine speckled pattern occurred only in healthy individuals. The most frequent ANA pattern in both groups was the nuclear fine speckled pattern, which occurred at lower titer in healthy individuals than in patients with ARDs (P<0.001). Anti-extractable nuclear antigen was present in 1 healthy individual (anti-SSA/Ro) and in 52 patients with ARDs (37.7%). None of the 40 reevaluated healthy individuals developed ARDs, and 29 (72.5%) remained ANA positive. All healthy individuals who became ANA negative had an ANA titer of 1:80 at baseline. CONCLUSION: Our findings suggest that the titer, and especially the pattern, on the ANA-HEp-2 test strongly enhances our ability to discriminate ANA-positive healthy individuals and patients with ARDs. PMID- 20954190 TI - Systemic lupus erythematosus monocytes are less responsive to interleukin-10 in the presence of immune complexes. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a systemic inflammatory disease characterized by autoantibody production and immune complex deposition. The level of interleukin-10 (IL-10), predominantly an antiinflammatory cytokine, is paradoxically elevated in patients with SLE. The aim of this study was to examine the hypothesis that the antiinflammatory function of IL-10 is impaired in monocytes from patients with SLE with long-term exposure to immune complexes. METHODS: CD14+ monocytes were isolated from healthy donors and patients with SLE. Cultured CD14+ cells were treated with heat-aggregated human IgG (325 MUg/ml) in the presence or absence of IL-10 (20 ng/ml). To study gene expression, RNA was extracted 3 hours after treatment. To study cytokine production, supernatants were harvested after 8 hours. To study IL-10 signaling, cell lysates were obtained from CD14+ cells treated with human IgG (325 MUg/ml) for 1 hour followed by IL-10 (20 ng/ml) treatment for 10 minutes. Western blot analysis was used to assess STAT-3 phosphorylation. All experiments were performed in pairs. RESULTS: When stimulated with human IgG, SLE monocytes produced more tumor necrosis factor alpha (TNFalpha) and IL-6 than did control cells. The suppressive effect of IL-10 on human IgG-induced TNFalpha and IL-6 production was lower in SLE monocytes compared with control monocytes, although IL-10 receptor expression was similar in SLE and control monocytes. Human IgG suppressed IL-10 receptor expression and altered IL-10 signaling in control monocytes. Like SLE monocytes, interferon alpha (IFNalpha)-primed control monocytes stimulated with human IgG were also less responsive to IL-10. CONCLUSION: Human IgG and IFNalpha modulate IL-10 function. In SLE monocytes, which are considered to be IFNalpha primed and persistently exposed to immune complexes, responses to IL-10 are abnormal, limiting the antiinflammatory effect of this cytokine. PMID- 20954192 TI - The effect of genotype on methotrexate polyglutamate variability in juvenile idiopathic arthritis and association with drug response. AB - OBJECTIVE: The response to and toxicity of methotrexate (MTX) are unpredictable in patients with juvenile idiopathic arthritis (JIA). Intracellular polyglutamation of MTX, assessed by measuring concentrations of MTX polyglutamates (MTXGlu), has been demonstrated to be a promising predictor of drug response. Therefore, this study was aimed at investigating the genetic predictors of MTXGlu variability and associations between MTXGlu and drug response in JIA. METHODS: The study was designed as a single-center cross sectional analysis of patients with JIA who were receiving stable doses of MTX at a tertiary care children's hospital. After informed consent was obtained from the 104 patients with JIA, blood was withdrawn during routine MTX-screening laboratory testing. Clinical data were collected by chart review. Genotyping for 34 single-nucleotide polymorphisms (SNPs) in 18 genes within the MTX metabolic pathway was performed. An ion-pair chromatographic procedure with mass spectrometric detection was used to measure MTXGlu1-7. RESULTS: Analysis and genotyping of MTXGlu was completed in the 104 patients. K-means clustering resulted in 3 distinct patterns of MTX polyglutamation. Cluster 1 had low red blood cell (RBC) MTXGlu concentrations, cluster 2 had moderately high RBC MTXGlu1+2 concentrations, and cluster 3 had high concentrations of MTXGlu, specifically MTXGlu3-5. SNPs in the purine and pyrimidine synthesis pathways, as well as the adenosine pathway, were significantly associated with cluster subtype. The cluster with high concentrations of MTXGlu3-5 was associated with elevated liver enzyme levels on liver function tests (LFTs), and there were higher concentrations of MTXGlu3-5 in children who reported gastrointestinal side effects and had abnormal findings on LFTs. No association was noted between MTXGlu and active arthritis. CONCLUSION: MTXGlu remains a potentially useful tool for determining outcomes in patients with JIA being treated with MTX. The genetic predictors of MTXGlu variability may also contribute to a better understanding of the intracellular biotransformation of MTX in these patients. PMID- 20954191 TI - Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcgamma receptor. AB - OBJECTIVE: Rheumatoid arthritis (RA) is associated with the presence of anti citrullinated protein antibodies (ACPAs). Nearly two-thirds of patients with ACPA positive RA have immune complexes that contain citrullinated fibrinogen, and these citrullinated fibrinogen-containing immune complexes (cFb-IC) can exacerbate disease in murine models of RA; however, the exact role of such ACPA ICs in RA pathogenesis has remained elusive. We undertook the present study to investigate a novel mechanism by which ACPAs specifically targeting citrullinated fibrinogen may directly stimulate macrophage tumor necrosis factor (TNF) production. METHODS: Murine or human macrophages were stimulated with native fibrinogen (nFb), cFb, or in vitro-generated nFb-IC or cFb-IC, and TNF production was measured by enzyme-linked immunosorbent assay. ICs were generated with either polyclonal anti-Fb antibodies or pooled IgG from patients with ACPA-positive RA. To evaluate the role of the Toll-like receptor 4 (TLR-4)/myeloid differentiation protein (MyD88) pathway and the Fcgamma receptor (FcgammaR) pathway in the induction of TNF by Fb and Fb-IC, parallel experiments were performed using 1) TLR-4-deficient or MyD88-deficient macrophages, and 2) inhibitors of TLR-4 or FcgammaR. RESULTS: Citrullinated Fb stimulated macrophage TNF production more potently than did native Fb. Incorporation of cFb into ICs augmented its ability to stimulate TNF production by macrophages. Stimulation of TNF by cFb was dependent on TLR-4 and MyD88, while stimulation by cFb-IC was dependent on both TLR-4/MyD88 and FcgammaR. CONCLUSION: We demonstrated that cFb-IC can costimulate macrophages via dual engagement of TLR-4 and FcgammaR, resulting in the synergistic induction of TNF production. Our findings suggest a potential role of citrullination in increasing the potency of an endogenous innate immune ligand and provide insight into the mechanism by which anticitrulline autoimmunity may contribute to the onset and propagation of inflammation in RA. PMID- 20954193 TI - Clinical Images: Systemic sclerosis-related telangiectases. PMID- 20954194 TI - Recent progress in chiral photonic band-gap liquid crystals for laser applications. AB - This article describes a brief review of recent research advances in chiral liquid crystals (CLCs) for laser applications. The CLC molecules have an intrinsic capability to spontaneously organize supramolecular helical assemblages consisting of liquid crystalline layers through their helical twisting power. Such CLC supramolecular helical structures can be regarded as one-dimensional photonic crystals (PhCs). Owing to their supramolecular helical structures, the CLCs show negative birefringence along the helical axis. Selective reflection of circularly polarized light is the most unique and important optical property in order to generate internal distributed feedback effect for optically-excited laser emission. When a fluorescent dye is embedded in the CLC medium, optical excitation gives rise to stimulated laser emission peak(s) at the band edge(s) and/or within the CLC selective reflection. Furthermore, the optically-excited laser emission peaks can be controlled by external stimuli through the self organization of CLC molecules. This review introduces the research background of CLCs carried out on the PhC realm, and highlights intriguing precedents of various CLC materials for laser applications. It would be greatly advantageous to fabricate active CLC laser devices by controlling the supramolecular helical structures. Taking account of the peculiar features, we can envisage that a wide variety of supramolecular helical structures of CLC materials will play leading roles in next-generation optoelectronic molecular devices. PMID- 20954195 TI - Critical analysis of simultaneous blockage of histone deacetylase and multiple receptor tyrosine kinase in the treatment of prostate cancer. AB - BACKGROUND: The concept of molecular tumor targeting might be an innovative option to treat advanced prostate cancer. We analyzed the effect of combining the multiple receptor tyrosine kinase inhibitor AEE788 and the histone deacetylase (HDAC) inhibitor valproic acid (VPA) on adhesion and growth properties of prostate cancer cell lines. METHODS: PC-3, DU-145, and LNCaP cells were treated with AEE788, VPA or with an AEE788-VPA combination, and cell cycle progression investigated. Furthermore, tumor cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins was evaluated, and integrin alpha and beta subtypes were analyzed. Finally, effects of drug treatment on cell signaling pathways were determined. RESULTS: AEE788 moderately and VPA strongly reduced tumor cell adhesion and growth. VPA impaired cell cycle progression and altered the expression level of the cell cycle regulating proteins cdk1, cdk2, cdk4, cyclin B, D1, cyclin E, p21, and p27. VPA also acted on the membranous, cytoplasmic, and gene expression pattern of various integrin alpha and beta subtypes. AEE788 acted likewise, but more moderately. Combining AEE788 and VPA did not result in an additive anti-tumor effect. Signaling analysis revealed that the EGFr downstream target Akt was similarly modified in the presence of VPA or the VPA-AEE788 combination, but not influenced by AEE788 alone. CONCLUSIONS: The AEE788-VPA combination has no advantage over VPA monotreatment in vitro. The non responsiveness of Akt PMID- 20954196 TI - Fabrication of FeF3 Nanoflowers on CNT branches and their application to high power lithium rechargeable batteries. PMID- 20954197 TI - Validation of limited lymphadenectomy for lower-third gastric cancer based on depth of tumour invasion. AB - BACKGROUND: This study aimed to determine the appropriate extent of lymph node (LN) dissection in gastric cancer by analysing LN metastasis patterns from prospectively collected topographical data on nodal status at Seoul National University Hospital, Korea. METHODS: The metastasis rate for each LN station was analysed according to the depth of tumour invasion in patients with primary lower third gastric cancer who underwent curative gastrectomy. The Maruyama Index of unresected disease (MI) was calculated using the WinEstimate((r)) program with simulation of various extents of LN dissection. RESULTS: LN metastasis in mucosal cancer was rare; 2.6 per cent of patients had a MI of more than 5 with simulation of D1 plus station 7 dissection, whereas 0.9 per cent had a MI above 5 with D1 plus stations 7 and 8a. In submucosal cancer, 3.3 per cent of tumours metastasized to level 2 LN stations outside the range of D1 plus stations 7, 8a and 9. The proportion of patients with a MI above 5 was 9.0 per cent with D1 plus stations 7, 8a and 9 dissection. The nodal metastasis rate was higher at level 1 and 2 for muscularis propria or deeper cancers. CONCLUSION: D1 dissection plus stations 7 and 8a for mucosal cancer, and D2 dissection for cancers of the muscularis propria or deeper seems appropriate. For submucosal cancer, an expanded dissection to the D2 level should be considered to ensure complete removal of metastatic LNs. PMID- 20954198 TI - A comparison between simulated and experimental basis sets for assessing short-TE in vivo 1H MRS data at 1.5 T. AB - A number of algorithms designed to determine metabolite concentrations from in vivo (1)H MRS require a collection of single metabolite spectra, known as a basis set, which can be obtained experimentally or by simulation. It has been assumed that basis sets can be used interchangeably, but no systematic study has investigated the effects of small variations in basis functions on the metabolite values obtained. The aim of this study was to compare the results of simulated with experimental basis sets when used to fit short-TE (1)H MRS data of variable quality at 1.5 T. Two hundred and twelve paediatric brain tumour spectra were included in the analysis, and each was analysed twice with LCModelTM using a simulated and experimental basis set. To determine the influence of data quality on quantification, each spectrum was assessed and 152 were classified as being of 'good' quality. Bland-Altman statistics were used to measure the agreement between the two basis sets for all available spectra and only 'good'-quality spectra. Monte-Carlo simulations were performed to investigate the influence of minor shifts in metabolite frequencies on metabolite concentration estimates. All metabolites showed good agreement between the two basis sets, and the average metabolite limits of agreement were approximately +/-3.84 mM for all available data and +/-0.99 mM for good-quality data. Errors obtained from the Monte-Carlo analysis were found to be more accurate than the Cramer-Rao lower bounds (CRLB) for 12 of 15 metabolites when metabolite frequency shifting was considered. For the majority of purposes, a level of agreement of +/-0.99 mM between simulated and experimental basis sets is sufficiently small for them to be used interchangeably. Multiple analyses using slightly modified basis sets may be useful in estimating fitting errors, which are not predicted by CRLBs. PMID- 20954199 TI - Enhanced differentiation of embryonic and neural stem cells to neuronal fates on laminin peptides doped polypyrrole. AB - PPy is a conducting polymer material that has been widely investigated for biomedical applications. hESCs and adult rNSCs were grown on four PPy surfaces doped with PSS or peptide from laminin (p20, p31, and a mixture of p20 and p31) respectively. After 7 d, both PPy/p20 and PPy/p31 promoted neuroectoderm formation from hESCs. After 14 d of culture, surfaces containing p20 showed the highest percentage of neuronal differentiation from hESC, while the PPy/p31 surface showed better cell attachment and spreading. In rNSCs cultures, a higher percentage of neurons were found on the PPy/p20 surface than other surfaces at 7 and 14 d. For differentiated neurons, p20 promoted both the primary and total neurite outgrowth. Longer primary neurites were found on p20-containing surfaces and a longer total neurite length was found on PPy/p20 surface. These results demonstrated that, by doping PPy with different bioactive peptides, differentiation of stem cells seeded at different stages of development is affected. PMID- 20954200 TI - Enzymatic synthesis of poly(alpha-ethyl beta-aspartate) by poly(ethylene glycol) modified poly(aspartate) hydrolase-1. AB - We recently discovered that poly(aspartate) (PAA) hydrolase-1 from Pedobacter sp. KP-2 has a unique property of specifically cleaving the amide bond between beta aspartate units in thermally synthesized PAA (tPAA). In the present study, the enzymatic synthesis of poly(alpha-ethyl beta-aspartate) (beta-PAA) was performed by taking advantage of the substrate specificity of PAA hydrolase-1. No polymerization of diethyl L-aspartate by native PAA hydrolase-1 occurred because of the low dispersibility of the enzyme in organic solvent. Poly(ethylene glycol) (PEG) modification of the enzyme improved its dispersibility and enabled it to polymerize the monomer substrate. MALDI-TOF MS analysis showed that the synthesized polymer was observed in the range of m/z = 750-2 500. This analysis also revealed that the polymer was composed of ethyl aspartate units, containing either an ethyl ester or a free carboxyl end group at its carboxyl terminus. (1) H NMR analysis demonstrated that the synthesized polymer consisted of only beta amide linkages. Thus, the present results indicate that PAA hydrolase-1 modified with PEG is useful for the synthesis of beta-PAA due to its unique substrate specificity and good dispersibility in organic solvent. PMID- 20954201 TI - The synthesis of a multiblock osteotropic polyrotaxane by copper(I)-catalyzed huisgen 1,3-dipolar cycloaddition. AB - The design and synthesis of a novel bone-targeting polyrotaxane delivery system that utilizes alendronate (ALN) as targeting moiety is presented in this manuscript. For the introduction of ALN, it is first conjugated to alpha cyclodextrin (alpha-CD) and subsequently threaded onto a short poly(ethylene glycol) (PEG) chain, forming a pseudopolyrotaxane. Using click chemistry, this assembly is copolymerized with bulky monomers that bear imaging and/or therapeutic agent(s) to prevent ALN-functionalized alpha-CD from dethreading. Overall bone affinity of this novel polymer conjugate can be easily controlled by changing the number of ALN-alpha-CD incorporated. The osteotropicity of the delivery system was also confirmed in vivo. PMID- 20954202 TI - Inhibitory effect of hydrophilic polymer brushes on surface-induced platelet activation and adhesion. AB - Poly(N,N-dimethylacrylamide) (PDMA) brushes are successfully grown from unplasticized poly(vinyl chloride) (uPVC) by well-controlled surface-initiated atom transfer radical polymerization (SI-ATRP). Molecular weights of the grafted PDMA brushes vary from ~ 35,000 to 2,170000 Da, while the graft density ranges from 0.08 to 1.13 chains . nm(-2). The polydispersity of the grafted PDMA brushes is controlled within 1.20 to 1.80. Platelet activation (expression of CD62) and adhesion studies reveal that the graft densities of the PDMA brushes play an important role in controlling interfacial properties. PDMA brushes with graft densities between 0.35 and 0.50 chains . nm(-2) induce a significantly reduced platelet activation compared to unmodified uPVC. Moreover, the surface adhesion of platelets on uPVC is significantly reduced by the densely grafted PDMA brushes. PDMA brushes that have high molecular weights lead to a relatively lower platelet activation compared to low-molecular-weight brushes. However, the graft density of the brush is more important than molecular weight in controlling platelet interactions with PVC. PDMA brushes do not produce any significant platelet consumption in platelet rich plasma. Up to a seven-fold decrease in the number of platelets adhered on high graft density brushes is observed compared to the bare PVC surface. Unlike the bare PVC, platelets do not form pseudopodes or change morphology on PDMA brush-coated surfaces. PMID- 20954203 TI - Differences in cytotoxicity of beta-sheet peptides originated from silk and amyloid beta. AB - The relationships between amino acid sequence, nano-assemblies, and cytotoxicity to neuron cytotoxicity were investigated using beta-sheet-forming peptides from Araneus ventricosus spider silk, and amyloid forming peptides Abeta(12-28) (beta1), Abeta(28-42) (beta2), and full-length Abeta(1-42). Although silk derived peptides formed nano-assemblies, nanofilaments, and nanofibrils with beta-sheet contents raging from 24 to 40%, they showed no significant cytotoxicity to neurons. In contrast, nano-assemblies and nanofibrils formed from Abeta peptides with high beta-sheet content demonstrated cytotoxicity to the neurons. These differences in cell response between the silk beta-sheets and Abeta peptides indicate that the general propensity to form beta sheets and form nanostructures is not sufficient to predict cytotoxicity, while surface charges of the assemblies are significant factors that impact cytotoxicity. PMID- 20954204 TI - Comparison of pulsed photothermal radiometry, optical coherence tomography and ultrasound for melanoma thickness measurement in PDMS tissue phantoms. AB - Melanoma accounts for 75% of all skin cancer deaths. Pulsed photothermal radiometry (PPTR), optical coherence tomography (OCT) and ultrasound (US) are non invasive imaging techniques that may be used to measure melanoma thickness, thus, determining surgical margins. We constructed a series of PDMS tissue phantoms simulating melanomas of different thicknesses. PPTR, OCT and US measurements were recorded from PDMS tissue phantoms and results were compared in terms of axial imaging range, axial resolution and imaging time. A Monte Carlo simulation and three-dimensional heat transfer model was constructed to simulate PPTR measurement. Experimental results show that PPTR and US can provide a wide axial imaging range (75 MUm-1.7 mm and 120-910 MUm respectively) but poor axial resolution (75 and 120 MUm respectively) in PDMS tissue phantoms, while OCT has the most superficial axial imaging range (14-450 MUm) but highest axial resolution (14 MUm). The Monte Carlo simulation and three-dimensional heat transfer model give good agreement with PPTR measurement. PPTR and US are suited to measure thicker melanoma lesions (>400 MUm), while OCT is better to measure thin melanoma lesions (<400 MUm). PMID- 20954205 TI - High-performance liquid chromatographic enantioseparation of (R,S)-fluoxetine using Marfey's reagent and (S)-N-(4-nitrophenoxycarbonyl) phenylalanine methoxyethyl ester as chiral derivatizing reagents along with direct thin-layer chromatographic resolution and isolation of enantiomers using L-tartaric acid as mobile phase additive. AB - Chiral assay of enantiomers of fluoxetine was achieved in pharmaceutical formulations using direct and indirect methods. L-tartaric acid was used as a mobile phase additive in thin-layer chromatography; the enantiomers were separated and isolated and were used to determine the elution order in HPLC. (R,S)-flouxetine was derivatized with (S)-N-(4-nitrophenoxycarbonyl)phenylalanine methoxyethyl ester [(S)-NIFE], Marfey's reagent and 1-fluoro-2,4-dinitrophenyl-L methionine amide (FDNP-L-Met-NH2. The diastereomers were separated using RP-HPLC. The effect of flow rate and TFA concentration on resolution was studied. The diastereomers obtained by derivatization with FDNP-L-Met-NH2 were also separated by RP-TLC. PMID- 20954206 TI - Liquid chromatography tandem mass spectrometry method for the quantification of sarpogrelate, a selective 5-HT(2A) receptor antagonist, in plasma: application to a pre-clinical pharmacokinetic study. AB - A simple LC-MS/MS method was developed and validated for the estimation of sarpogrelate in 50 uL of rat plasma. The analyte and internal standard (IS) were extracted from rat plasma by acetonitrile precipitation and they were separated on a reversed-phase C8 column with gradient program. The MS acquisition was performed with multiple reaction monitoring mode using m/z 430.2 to m/z 135.0 for analyte and m/z 448.2 to m/z 285.3 for IS. The calibration curves were linear over the range of 1-1000 ng/mL with the correlation coefficient greater than 0.999. With dilution integrity up to 20-fold, the upper limit of quantification was extendable up to 15,000 ng/mL. The method was successfully applied to the analysis of rat plasma samples after single dose oral administration of sarpogrelate at 5 mg/kg to rats for the determination of its pharmacokinetics. Following oral administration the maximum mean concentration in plasma (C(max), 11514 ng/mL) was achieved at 0.25 h (T(max)) and the area under curve (AUC0-24) was 11051 +/- 3315 ng h/mL. The half-life (t(1/2)) and clearance (Cl) were 2.9 +/ 1.1 h and 490 +/- 171 mL/h/kg, respectively. We believe that development of a method in rodent plasma would facilitate the ease of adaptability of sarpogrelate in human plasma. PMID- 20954207 TI - Rational design for variability minimization in bioanalytical method validation: illustration with LC-MS/MS assay method for terbinafine estimation in human plasma. AB - Terbinafine, a widely used antifungal drug, is a challenging molecule for quantitative bioanalysis due to certain factors contributing assay variability. Despite previous attempts at human plasma determination of terbinafine, exhaustive stability of the drug or an internal standard was lacking. Internal standard stability with negligible variation throughout the analysis is an indicator of a reliable bioanalytical method as the majority of LC-MS/MS assays are based on analyte/IS response ratios for quantitation. A newly developed high throughput simple LC-MS/MS method is described for human plasma determination of terbinafine using naftifine internal standard and eluting all compounds within 2 min. A solid-phase extraction of terbinafine achieving mean recovery of 84.3% (CV < 4%) without compromising sensitivity (limit of quantitation 5.11 ng/mL) or linearity (5.11-3014.19 ng/mL) is delineated in this paper. A heated nebulizer in positive multiple reaction monitoring mode was employed with transitions m/z 292.2 ->141.1 and 288.2 ->117.0 for terbinafine and naftifine, respectively, resulting in excellent chromatographic separation on a Hypurity Advance (50 x 4.6 mm, 5 um) column. The developed method was successfully applied to clinical samples and for the first time demonstrated marked improved extraction efficiency and reliable long-term plasma stability results without any internal standard response variation during the entire course of study. PMID- 20954208 TI - Evaluation of 60Co-gamma radiosterilization on Chinese medicines with HPLC/FTIR. AB - The aim of this study was to evaluate the effect of radiosterilization on 30 Chinese medicines using gamma-rays from the isotope 60Co. Two groups of Chinese medicines, non-treated and dry samples, were treated using a 60Co irradiation source at the doses 0, 3, 6 and 9 kGy. After storage for 3 months, characterizations of chemical compounds and functional groups were performed by high-performance liquid chromatography (HPLC) and Fourier transform infrared spectroscopy. The results of radiosterlization showed that nearly all of the medicines were decontaminated under the dose of 9 kGy. In most samples, chemical compounds and functional groups were not altered by the irradiation treatment. However, minor changes were found in the molecular structures of 14 medicines under the reported 'safety dose' (10 kGy). The drying process before irradiation could decrease the chemical changes caused by gamma-rays to 50%. The HPLC analysis of nine medicines revealed minor changes at a dose of 3 kGy. The findings in this study provide important information that may suggest the need for a re-evaluation of the reported safety dose. Therefore, further investigation may be warranted to insure the safety of gamma-radiosterlization of Chinese medicines. PMID- 20954209 TI - Analysis of amino acid neurotransmitters in hypothalamus of rats during cerebral ischemia-reperfusion by microdialysis and capillary electrophoresis. AB - In this work, focal cerebral ischemia and reperfusion were induced by the model of middle cerebral artery occlusion. The dialysate of extracellular fluid in the hypothalamus of rats were obtained by using brain microdialysis technique. An efficient and sensitive MEKC method for the simultaneous determination of multiple amino acid neurotransmitters in microdialysate was developed by capillary electrophoresis with laser-induced fluorescence detection and 5-(4, 6 dichloro-s-triazin-2-ylamino) fluorescein derivatization. Different parameters that influenced derivatization reaction and CE separation were studied and optimized. This method was used to investigate the dynamic change of fourteen amino acid neurotransmitters in microdialysates during cerebral ischemia/reperfusion period. Our results reveal that MCAO and reperfusion elicited significant increases in the extracellular levels of Arg, Lys, Trp, Phe, Gln, GABA, Asn, Pro, Ser, Ala, Tau, Gly, Glu and Asp. The excitatory/inhibitory neurotransmitter balance was disturbed during ischemia/reperfusion. The dynamic changes and functional status of releasable neurotransmitters during ischemia/reperfusion were discussed. PMID- 20954210 TI - Liquid chromatography tandem mass spectrometry pharmacokinetic study of DL praeruptorin A in rat plasma. AB - DL-praeruptorin A is a novel drug with valuable apoptosis and inflammation inhibitory effects in cardiac muscle. Previous pharmacokinetic studies of DL praeruptorin A have had limited success due to its very low plasma concentrations. In this study, we developed and validated a new rapid, sensitive and specific high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC/ESI-MS/MS) method for quantitative analysis of dl praeruptorin A in rat plasma. DL-Praeruptorin A and diazepam (internal standard) extracted from rat plasma samples with chloroform and analyzed on an XTerraTM RP18 column (150 mm x 4.6 mm i.d., 5 um) were chromatographically separated within 5.5 min using methanol-water (75:25, v/v; flow rate 1 mL/min) as the mobile phase. DL-praeruptorin A was detected in positive ion mode using multiple reaction monitoring. The method was validated and the specificity, linearity, lower limit of quantitation (LLOQ, 2.5 ng/mL), precision (intra- and inter-day <11.0%), accuracy (90.2-96.3%), recovery (>79.2%) and stability were determined. The correlation coefficient (r2) for the linear range of 2.5-2500.0 ng/mL was >0.999. No matrix effects were observed. The validated method was successfully applied to pharmacokinetic studies of dl-praeruptorin A after intravenous administration to rats. The LLOQ obtained with this method was lower than in previous studies and could be valuable for determination of dl-praeruptorin A in therapeutic drug monitoring and preclinical studies to establish appropriate dose and frequency. PMID- 20954211 TI - Purification and characterization of a superoxide dismutase from Panax ginseng. AB - A superoxide dismutase (SOD) with the molecular weight of 31,079 has been purified as a homodimer from Panax ginseng by employing neutral pH buffer extraction, ammonium sulfate precipitation, isoelectric point precipitation and ion exchange methods. The enzyme's specific activity determined by an improved Marklund method was 9480.43 U/mg. Metal analysis showed that the SOD contained iron with the stoichiometry of 0.9 +/- 0.3 Fe/subunit and exhibited high thermal stability (70 degrees C) over the pH range from 4.0 to 9.0. Its maximum absorption wavelength was 278 nm and it was sensitive to hydrogen peroxide, trichloromethane-ethanol and urea. These results indicate that the enzyme is an iron SOD. PMID- 20954212 TI - Determination of sialic acids in infant formula by liquid chromatography tandem mass spectrometry. AB - A liquid chromatographic/tandem mass spectrometric method using pneumatically assisted electrospray ionization (LC-ESI-MS/MS) was developed for determination of N-acetylneuramic acid and N-glycolylneuramic acid in infant formula. Reconstituted samples were hydrolysed in dilute sulfuric acid and deproteinized with acetonitrile. The extract was analysed directly without further clean-up by hydrophilic interaction chromatography. The substances were detected in negative ion mode and matrix matched standards were used for calibration. The relative intra-laboratory reproducibility standard deviation was better than 6% for both substances. An R2 of 0.985 was obtained by comparison with a classical colorimetric assay based on reaction with resorcinol. The developed method is expected to be applied for accurate routine analysis of infant formulas. PMID- 20954213 TI - Enantioseparation of dansyl amino acids by HPLC on a monolithic column dynamically coated with a vancomycin derivative. AB - In this work a chiral stationary phase was prepared by dynamically coating a monolithic reversed-phase HPLC column with a vancomycin-derivative as chiral selector. A hydrophobic alkyl-chain was attached to the vancomycin molecule, providing the immobilization of the chiral selector on the reversed-phase material. Dansyl amino acids were chosen as model analytes for testing the separation power of the dynamically coated phase. All investigated compounds were separated into their enantiomers. Compared with a conventionally packed vancomycin-CSP, a reversal of the enantiomer elution order was obtained. PMID- 20954214 TI - Development and validation of a rapid and sensitive LC-ESI-MS/MS method for ondansetron quantification in human plasma and its application in comparative bioavailability study. AB - The validation of a high throughput and specific method using a high-performance liquid chromatography coupled to electrospray (ES+) ionization tandem triple quadrupole mass spectrometric (LC-ESI-MS/MS) method for ondansetron quantification in human plasma is described. Human plasma samples were extracted by liquid-liquid extraction (LLE) using methyl tert-butyl ether and analyzed by LC-ESI-MS/MS. The limit of quantification was 0.2 ng/mL and the method was linear in the range 0.2-60 ng/mL. The intra-assay precisions ranged from 1.6 to 7.7%, while inter-assay precisions ranged from 2.1 to 5.1%. The intra-assay accuracies ranged from 97.5 to 108.2%, and the inter-assay accuracies ranged from 97.3 to 107.0%. The analytical method was applied to evaluate the relative bioavailability of two pharmaceutical formulations containing 8 mg of ondansetron each in 25 healthy volunteers using a randomized, two-period crossover design. The geometric mean and respective 90% confidence interval (CI) of ondansetron test/reference percent ratios were 90.15% (81.74-99.44%) for C(max) and 93.11% (83.01-104.43%) for AUC(0-t). Based on the 90% confidence interval of the individual ratios (test formulation/reference formulation) for C(max) and AUC(0 inf), it was concluded that the test formulation is bioequivalent to the reference one with respect to the rate and extent of absorption of ondansetron. PMID- 20954215 TI - Development of a validated LC method for enantiomeric separation and determination of adrafinil and its related substances on a Chiralcel OJ-H column connected to PDA and polarimetric detectors in series. AB - A rapid and reliable high-performance liquid chromatographic method for resolution of enantiomers of adrafinil [(+/-)-ADL], a novel vigilance promoting agent, and its synthetic intermediates was developed. The separation was carried out on a Chiralcel OJ-H using n-hexane-ethanol (62:38 v/v) as a mobile phase. The detection was carried out at 225 nm using a photodiode array (PDA) detector. The optical rotation and order of elution of enantiomers were assigned. The method is suitable not only for process development of ADL but also for quality assurance of bulk drugs and pharmaceuticals. PMID- 20954216 TI - Bioanalytical method development and validation of novel antithrombotic agent S002-333 by LC-MS/MS and its application to pharmacokinetic studies. AB - A rapid, sensitive and simple liquid chromatography-tandem mass spectrometry (LC MS/MS) method using an electrospray ionization (ECI) source for the quantification of novel anti-thrombotic agent S002-333 [2-(4-methoxy benzenesulfonyl)-2,3,4,9-tetrahydro-1H-beta-carboxylic acid amide] in rabbit plasma was developed and validated. The extraction from plasma was carried out by simple protein precipitation extraction method. The chromatographic separation was performed on an Ultramex Cyno, (150 x 4.6 mm, 5 um) with a guard column, using acetonitrile-water (75:25,v/v) with flow rate of 0.6 mL/min as the mobile phase. The tandem mass spectrometer was tuned in the multiple reaction monitoring mode to monitor the m/z transitions 386.4/215.4 for S002-333 and m/z 393.4/171 for the internal standard dexamethasone, using positive ion mode. The MS/MS response was linear over the concentration range from 1.56 to 200 ng/mL, with a lower limit of detection of 0.78 ng/mL. The accuracy and precision of the method were within the acceptable limit of +/-20% at the lower limit of quantitation and +/-15% at other concentrations and showed no significant matrix effect. The validated method can be used in most or all stages of the screening and optimizing process for future method validation of pharmacokinetic studies. PMID- 20954217 TI - Mixed-mode solid-phase extraction for sample cleanup in hair analysis for methadone and its main metabolite. AB - A simple and rapid method for the determination of methadone and its main metabolite EDDP in hair has been developed and validated. The analytes were completely extracted from the matrix after a short alkaline incubation, and the extracts were further cleaned up by solid-phase extraction using mixed-mode cartridges. Linearity was obtained from 0.1 (lower limit of quantitation, LLOQ) to 30 ng/mg for both compounds, with correlation coefficients higher than 0.99. Intra- and interday precision and accuracy were in conformity with internationally accepted guidelines for bioanalytical method validation, and the cleanup procedure presented mean extraction efficiencies higher than 90% for both analytes. This high efficiency greatly contributed to the low limits of quantitation achieved, and therefore this method can be successfully applied in the determination of methadone and EDDP in hair samples in clinical and forensic scenarios where these compounds are involved. PMID- 20954218 TI - Development and validation of amitriptyline and its metabolite in human plasma by ultra performance liquid chromatography-tandem mass spectrometry and its application to a bioequivalence study. AB - A method based on ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) in combination with solid-phase extraction for sample pretreatment has been developed for the simultaneous analysis of amitriptyline and its main metabolite in human plasma. The extraction of the analytes from plasma samples was carried out by means of a selective SPE procedure using hydrophilic-lipophilic balance cartridges. The assay involves a simple solid phase extraction (SPE) procedure of 0.2 mL of human plasma and analysis was performed on a triple-quadrupole tandem mass spectrometer by multiple reactions monitoring (MRM) mode via electrospray ionization (ESI). The standard calibration curve was linear over the ranges 0.370-95.539 ng/mL for amitriptyline and 0.365 94.374 ng/mL for nortriptyline, expressed by the linear correlation coefficient r2, which was better than 0.995 for both. The intra- and inter-day precision and accuracy of the quality control samples were within 10.0%. The recovery was 85.3, 88.4 and 80.7% for amitriptyline, nortriptyline and doxepin respectively. Total run time was 1.2 min only for each sample, which makes it possible to analyze more than 400 samples per day. The method was highly reproducible and gave peaks with excellent chromatography properties. PMID- 20954219 TI - A rapid and reliable UPLC-MS/MS method for the identification and quantification of fourteen synthetic anti-diabetic drugs in adulterated Chinese proprietary medicines and dietary supplements. AB - An ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for simultaneous qualitative and quantitative analysis of 14 synthetic anti-diabetic drugs in adulterated Chinese proprietary medicines (CPMs) and dietary supplements. The samples were prepared by ultrasonic extraction with methanol and separated on a C18 column with mobile phase consisting of acetonitrile and water (both containing 0.10% formic acid). Gradient elution was applied with a flow rate of 0.20 mL/min. Two transitions from protonated molecules were monitored for each synthetic anti-diabetic drug in positive mode of electrospray ionization (ESI). The two transitions, the peak area ratio of the two transitions and the retention time were used for identification. The more intensive transition was used for quantification. The analysis time was 6 min per sample. Satisfactory linear relationships were estimated between the peak area and the concentration with correlation coefficients higher than 0.995. The limit of detection ranged from 0.03 to 5.45 ng/mL. The relative standard deviation of intra-day precision was below 7.6%, the RSD of inter-day precision was below 15% and the relative error of accuracy was between -10 and 7.8%. The proposed method is rapid, selective, reliable and was successfully applied to the analysis of 30 real samples of 22 CPMs and eight dietary supplements from the local market in China. PMID- 20954220 TI - Regarding the paper 'Sample size calculations for evaluating a diagnostic test when the gold standard is missing at random'. PMID- 20954221 TI - The "occlusis" model of cell fate restriction. AB - A simple model, termed "occlusis", is presented here to account for both cell fate restriction during somatic development and reestablishment of pluripotency during reproduction. The model makes three assertions: (1) A gene's transcriptional potential can assume one of two states: the "competent" state, wherein the gene is responsive to, and can be activated by, trans-acting factors in the cellular milieu, and the "occluded" state, wherein the gene is blocked by cis-acting, chromatin-based mechanisms from responding to trans-acting factors such that it remains silent irrespective of whether transcriptional activators are present in the milieu. (2) As differentiation proceeds in somatic lineages, lineage-inappropriate genes shift progressively and irreversibly from competent to occluded state, thereby leading to the restriction of cell fate. (3) During reproduction, global deocclusion takes place in the germline and/or early zygotic cells to reset the genome to the competent state in order to facilitate a new round of organismal development. PMID- 20954222 TI - Recyclable catalysts for palladium-catalyzed C-O coupling reactions, Buchwald Hartwig aminations, and Sonogashira reactions. PMID- 20954223 TI - Unusual silicon connectivities in the binary compounds GdSi5, CeSi5, and Ce2Si7. PMID- 20954224 TI - Reaction-driven mixing and dispersion. PMID- 20954225 TI - Urothermal synthesis of crystalline porous materials. PMID- 20954226 TI - Acid/base- and anion-controllable organogels formed from a urea-based molecular switch. PMID- 20954227 TI - Ordering, interaction, and reactivity of the low-lying npi* and pipi* excited triplet states of acetophenone derivatives. PMID- 20954228 TI - ortho-Metalation of iron(0) tribenzylphosphine complexes: homogeneous catalysts for the generation of hydrogen from formic acid. PMID- 20954229 TI - A modular, efficient, and stereoselective synthesis of substituted piperidin-4 ols. PMID- 20954230 TI - A potential antitumor drug (arginine deiminase) reengineered for efficient operation under physiological conditions. AB - Arginine deiminase (ADI, EC 3.5.3.6) is a potential antitumor drug for the treatment of arginine-auxotrophic tumors such as hepatocellular carcinomas (HCCs) and melanomas, and studies on human lymphatic leukemia cell lines have confirmed that ADI has antiangiogenic activity. Recent studies showed that a combination of taxane and ADI-PEG20, which induces caspase-independent apoptosis, is more effective than taxane monotherapy for prostate cancer. The main limitation of ADI from Pseudomonas plecoglossicida (PpADI) and of many other ADI enzymes lies in their pH-dependent activity profile. PpADI has a pH optimum at 6.5 and a pH shift from 6.5 to 7.5 results in an ~80 % activity drop (the pH of human plasma is 7.35 to 7.45). In 2010, we reported a proof of concept for ADI engineering by directed evolution that resulted in variant M2 (K5T/D44E/H404R). M2 has a pH optimum of pH 7.0, a fourfold higher k(cat) value than the wild-type PpADI (pH 7.4, 0.5 M phosphate buffer), and an increased K(m) value for substrate arginine. In our latest work, variants M5 (K5T/D38H/D44E/A128T/H404R) and M6 (K5T/D38H/D44E/A128T/E296K/H404R) were generated by directed evolution by employing PBS buffer (pH 7.4), which mimics physiological conditions. The S(0.5) value of parent M3 (K5T/D44E/A128T/H404R) decreased from 2.01 to 1.48 mM (M5) and 0.81 mM (M6). The S(0.5) value of M6 (0.81 mM) is lower than that of wild-type PpADI (1.30 mM); the k(cat) values improved from 0.18 s(-1) (wild-type PpADI) to 17.56 s(-1) (M5, 97.6-fold) and 11.64 s(-1) (M6, 64.7-fold). PMID- 20954231 TI - Light-driven transport of a molecular walker in either direction along a molecular track. PMID- 20954232 TI - Surface chemical properties of eutectic and frozen NaCl solutions probed by XPS and NEXAFS. AB - We study the surface of sodium chloride-water mixtures above, at, and below the eutectic temperature using X-ray photoelectron spectroscopy (XPS) and electron yield near-edge X-ray absorption fine structure (NEXAFS) spectroscopy. The NaCl frozen solutions are mimicking sea-salt deposits in ice or snow. Sea-salt particles emitted from the oceans are a major contributor to the global aerosol burden and can act as a catalyst for heterogeneous chemistry or as cloud condensation nuclei. The nature of halogen ions at ice surfaces and their influence on surface melting of ice are of significant current interest. We found that the surface of the frozen solution, depending on the temperature, consists of ice and different NaCl phases, that is, NaCl, NaCl.2H(2)O, and surface adsorbed water. PMID- 20954233 TI - Developmental triclosan exposure decreases maternal and neonatal thyroxine in rats. AB - Disruption of maternal thyroid hormones during fetal developmental may result in irreversible neurological consequences in offspring. The present study tested the hypothesis that perinatal triclosan exposure of dams decreases thyroxine in dams and offspring prior to weaning. Pregnant Long-Evans rats received triclosan by oral gavage (0-300 mg/kg/d) in corn oil from gestational day (GD)6 through postnatal day (PND)21. Serum was obtained from pups on PND4, 14, and 21, and from dams on PND22. Serum thyroxine (T4) was reduced 31% in dams on PND22. In pups, a unique pattern of hypothyroxinemia was observed; serum T4 decreased 27% in PND4 pups with no significant reduction observed on PND14 or PND21. Comparable reductions of approximately 30% in serum T4 at 300 mg/kg/d for dams and PND4 neonates and a lack of effect at PND14 and PND21 suggest that toxicokinetic or toxicodynamic factors may have contributed to a reduced exposure or a reduced toxicological response during the lactation period. PMID- 20954234 TI - The art of writing science. PMID- 20954235 TI - Recognition of Smac-mimetic compounds by the BIR domain of cIAP1. AB - Inhibitor of apoptosis proteins (IAPs) are negative regulators of apoptosis. As IAPs are overexpressed in many tumors, where they confer chemoresistance, small molecules inactivating IAPs have been proposed as anticancer agents. Accordingly, a number of IAP-binding pro-apoptotic compounds that mimic the sequence corresponding to the N-terminal tetrapeptide of Smac/DIABLO, the natural endogenous IAPs inhibitor, have been developed. Here, we report the crystal structures of the BIR3 domain of cIAP1 in complex with Smac037, a Smac-mimetic known to bind potently to the XIAP-BIR3 domain and to induce degradation of cIAP1, and in complex with the novel Smac-mimetic compound Smac066. Thermal stability and fluorescence polarization assays show the stabilizing effect and the high affinity of both Smac037 and Smac066 for cIAP1- and cIAP2-BIR3 domains. PMID- 20954236 TI - Enzyme-ligand interactions that drive active site rearrangements in the Helicobacter pylori 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase. AB - The bacterial enzyme 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) plays a central role in three essential metabolic pathways in bacteria: methionine salvage, purine salvage, and polyamine biosynthesis. Recently, its role in the pathway that leads to the production of autoinducer II, an important component in quorum-sensing, has garnered much interest. Because of this variety of roles, MTAN is an attractive target for developing new classes of inhibitors that influence bacterial virulence and biofilm formation. To gain insight toward the development of new classes of MTAN inhibitors, the interactions between the Helicobacter pylori-encoded MTAN and its substrates and substrate analogs were probed using X-ray crystallography. The structures of MTAN, an MTAN-Formycin A complex, and an adenine bound form were solved by molecular replacement and refined to 1.7, 1.8, and 1.6 A, respectively. The ribose-binding site in the MTAN and MTAN-adenine cocrystal structures contain a tris[hydroxymethyl]aminomethane molecule that stabilizes the closed form of the enzyme and displaces a nucleophilic water molecule necessary for catalysis. This research gives insight to the interactions between MTAN and bound ligands that promote closing of the enzyme active site and highlights the potential for designing new classes of MTAN inhibitors using a link/grow or ligand assembly development strategy based on the described H. pylori MTAN crystal structures. PMID- 20954237 TI - Probing the active site of the sugar isomerase domain from E. coli arabinose-5 phosphate isomerase via X-ray crystallography. AB - Lipopolysaccharide (LPS) biosynthesis represents an underexploited target pathway for novel antimicrobial development to combat the emergence of multidrug resistant bacteria. A key player in LPS synthesis is the enzyme D-arabinose-5 phosphate isomerase (API), which catalyzes the reversible isomerization of D ribulose-5-phosphate to D-arabinose-5-phosphate, a precursor of 3-deoxy-D-manno octulosonate that is an essential residue of the LPS inner core. API is composed of two main domains: an N-terminal sugar isomerase domain (SIS) and a pair of cystathionine-beta-synthase domains of unknown function. As the three-dimensional structure of an enzyme is a prerequisite for the rational development of novel inhibitors, we present here the crystal structure of the SIS domain of a catalytic mutant (K59A) of E. coli D-arabinose-5-phosphate isomerase at 2.6-A resolution. Our structural analyses and comparisons made with other SIS domains highlight several potentially important active site residues. In particular, the crystal structure allowed us to identify a previously unpredicted His residue (H88) located at the mouth of the active site cavity as a possible catalytic residue. On the basis of such structural data, subsequently supported by biochemical and mutational experiments, we confirm the catalytic role of H88, which appears to be a generally conserved residue among two-domain isomerases. PMID- 20954238 TI - Genotype-phenotype correlation of two prevalent GJB2 mutations in Chinese newborn infants ascertained from the Universal Newborn Hearing Screening Program. PMID- 20954239 TI - MACS syndrome: A combined collagen and elastin disorder due to abnormal Golgi trafficking. PMID- 20954240 TI - Homology modeling and deletion mutants of human nicotinamide mononucleotide adenylyltransferase isozyme 2: new insights on structure and function relationship. AB - Nicotinamide mononucleotide adenylyltransferase (NMNAT) catalyzes the formation of NAD by means of nucleophilic attack by 5'-phosphoryl of NMN on the alpha phosphoryl group of ATP. Humans possess three NMNAT isozymes (NMNAT1, NMNAT2, and NMNAT3) that differ in size and sequence, gene expression pattern, subcellular localization, oligomeric state and catalytic properties. Of these, NMNAT2, the least abundant isozyme, is the only one whose much-needed crystal structure has not been solved as yet. To fill this gap, we used the crystal structures of human NMNAT1 and NMNAT3 as templates for homology-based structural modeling of NMNAT2, and the resulting raw structure was then refined by molecular dynamics simulations in a water box to obtain a model of the final folded structure. We investigated the importance of NMNAT2's central domain, which we postulated to be dispensable for catalytic activity, instead representing an isozyme-specific control domain within the overall architecture of NMNAT2. Indeed, we experimentally confirmed that removal of different-length fragments from this central domain did not compromise the enzyme's catalytic activity or the overall tridimensional structure of the active site. PMID- 20954241 TI - Protein folding pathways and state transitions described by classical equations of motion of an elastic network model. AB - Protein topology defined by the matrix of residue contacts has proved to be a fruitful basis for the study of protein dynamics. The widely implemented coarse grained elastic network model of backbone fluctuations has been used to describe crystallographic temperature factors, allosteric couplings, and some aspects of the folding pathway. In the present study, we develop a model of protein dynamics based on the classical equations of motion of a damped network model (DNM) that describes the folding path from a completely unfolded state to the native conformation through a single-well potential derived purely from the native conformation. The kinetic energy gained through the collapse of the protein chain is dissipated through a friction term in the equations of motion that models the water bath. This approach is completely general and sufficiently fast that it can be applied to large proteins. Folding pathways for various proteins of different classes are described and shown to correlate with experimental observations and molecular dynamics and Monte Carlo simulations. Allosteric transitions between alternative protein structures are also modeled within the DNM through an asymmetric double-well potential. PMID- 20954242 TI - Methionyl-tRNA synthetase from Caenorhabditis elegans: a specific multidomain organization for convergent functional evolution. AB - Methionyl-tRNA synthetase (MetRS) is a multidomain protein that specifically binds tRNAMet and catalyzes the synthesis of methionyl-tRNAMet. The minimal, core enzyme found in Aquifex aeolicus is made of a catalytic domain, which catalyzes the aminoacylation reaction, and an anticodon-binding domain, which promotes tRNA protein association. In eukaryotes, additional domains are appended in cis or in trans to the core enzyme and increase the stability of the tRNA-protein complexes. Eventually, as observed for MetRS from Homo sapiens, the C-terminal appended domain causes a slow release of aminoacyl-tRNA and establishes a limiting step in the global aminoacylation reaction. Here, we report that MetRS from the nematode Caenorhabditis elegans displays a new type of structural organization. Its very C-terminal appended domain is related to the oligonucleotide binding-fold-based tRNA-binding domain (tRBD) recovered at the C terminus of MetRS from plant, but, in the nematode enzyme, this domain is separated from the core enzyme by an insertion domain. Gel retardation and tRNA aminoacylation experiments show that MetRS from nematode is functionally related to human MetRS despite the fact that their appended tRBDs have distinct structural folds, and are not orthologs. Thus, functional convergence of human and nematode MetRS is the result of parallel and convergent evolution that might have been triggered by the selective pressure to invent processivity of tRNA handling in translation in higher eukaryotes. PMID- 20954243 TI - Mitochondrial DNA integrity is essential for mitochondrial maturation during differentiation of neural stem cells. AB - Differentiation of neural stem cells (NSCs) involves the activation of aerobic metabolism, which is dependent on mitochondrial function. Here, we show that the differentiation of NSCs involves robust increases in mitochondrial mass, mitochondrial DNA (mtDNA) copy number, and respiration capacity. The increased respiration activity renders mtDNA vulnerable to oxidative damage, and NSCs defective for the mitochondrial 8-oxoguanine DNA glycosylase (OGG1) function accumulate mtDNA damage during the differentiation. The accumulated mtDNA damages in ogg1(-/-) cells inhibit the normal maturation of mitochondria that is manifested by reduced cellular levels of mitochondrial encoded complex proteins (complex I [cI], cIII, and cIV) with normal levels of the nuclear encoded cII present. The specific cI activity and inner membrane organization of respiratory complexes are similar in wt and ogg1(-/-) cells, inferring that mtDNA damage manifests itself as diminished mitochondrial biogenesis rather than the generation of dysfunctional mitochondria. Aerobic metabolism increases during differentiation in wild-type cells and to a lesser extent in ogg1(-/-) cells, whereas anaerobic rates of metabolism are constant and similar in both cell types. Our results demonstrate that mtDNA integrity is essential for effective mitochondrial maturation during NSC differentiation. PMID- 20954244 TI - Exploring the trigger sequence of the GCN4 coiled-coil: biased molecular dynamics resolves apparent inconsistencies in NMR measurements. AB - Trigger sequences are indispensable elements for coiled-coil formation. The monomeric helical trigger sequence of the yeast transcriptional activator GCN4 has been investigated recently using several solution NMR observables including nuclear Overhauser enhancement (NOE) intensities and 3J(HN, HCalpha)-coupling constants, and a set of 20 model structures was proposed. Constrained to satisfy the NOE-derived distance bounds, the NMR model structures do not appear to reproduce all the measured 3J(HN-HCalpha)-coupling constant values, indicating that the alpha-helical propensity is not uniform along the GCN4 trigger sequence. A recent methodological study of unrestrained and restrained molecular dynamics (MD) simulations of the GCN4 trigger sequence in solution showed that only MD simulations incorporating time-averaged NOE distance restraints and instantaneous or local-elevation 3J-coupling restraints could satisfy the entire set of the experimental data. In this report, we assess by means of cluster analyses the model structures characteristic of the two simulations that are compatible with the measured data and compare them with the proposed 20 NMR model structures. Striking characteristics of the MD model structures are the variability of the simulated configurations and the indication of entropic stability mediated by the aromatic N-terminal residues 17Tyr and 18His, which are absent in the set of NMR model structures. PMID- 20954245 TI - Phenotypic variability of a deletion and duplication 6q16.1 -> q21 due to a paternal balanced ins(7;6)(p15;q16.1q21). AB - Constitutional insertional translocations are rare findings in clinical cytogenetics. Here, we report on the unbalanced segregation of a balanced paternal insertional translocation ins(7;6)(p15;q16.1q21) to three children. Investigations by conventional karyotyping, FISH with locus-specific probes, microsatellite marker analysis, and SNP-array based copy number analysis revealed a direct orientation of the inserted segment, a size of 11.3 Mb, and breakpoints between rs4370337 and rs12660854 and rs12110990 and rs4946730 on 6q16.1 and 6q21, respectively, as well as within BAC clone RP11-182J2 on 7p15. A 17-year-old daughter inherited the der(6) chromosome and was affected by severe mental retardation, obesity, and minor anomalies. Two further children inherited the der(7) chromosome. A daughter shows an almost unremarkable phenotype and only minor features in neuropsychological testing at 19 years of age. Her 14-year-old half-brother demonstrates a mild delay in cognitive development most likely jointly caused by the chromosomal rearrangement and asphyxia during delivery. The patient with the deletion confirms the previously reported phenotype of severe mental retardation and obesity in patients with del(6)(q16.2), while both patients with partial trisomy for the same segment of chromosome 6 are further examples for a generally less severe phenotype associated with duplications than with deletions, and even for the recent insight that chromosomal aneusomies of several megabases may go without major clinical consequences. PMID- 20954246 TI - Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations. AB - Reports on Noonan syndrome (NS) have documented multiple types of coagulation defects and bleeding diathesis, and a wide range of clinical presentations. Early studies suggested that a large proportion of NS patients have coagulation defects, whereas more recent reports indicate low rates of coagulopathy. The aim of this study was to evaluate phenotypic characteristics, PTPN11 gene mutations, and hematological and coagulation parameters in 30 clinically diagnosed cases of NS. One of the NS patients had a history of easy bruising; however, his hematological and coagulation tests were normal. None of the other patients had clinical coagulation problems. In the NS group, values for platelet count, activity of factors XI, XII, and protein C were significantly lower than the corresponding means for the control group. However, the results of coagulation tests in the NS group were diagnostically inconclusive and only one patient had clinical signs of coagulopathy. Interestingly, two NS patients had low protein C activity. One of these children had an A1517C mutation and transient myelodysplasia. The other patient had a C1528G mutation in exon 13 that has not been reported previously. Neither of these individuals experienced a thrombotic event or any complication during approximately 3 years of follow-up. For all patients clinically diagnosed with NS, a thorough history of coagulation issues should be taken and first-line coagulation testing should be done to evaluate for bleeding diathesis. However, if these assessments reveal nothing abnormal, complications related to coagulation are unlikely and extensive testing is unnecessary. PMID- 20954247 TI - A comparative study of crested gibbons (Nomascus). AB - Crested gibbons (Nomascus) are in the rarest genus of the family Hylobatidae, with the Hainan gibbon (Nomascus hainanus) being the rarest primate in the world. In the past, the number of species in this genus has been at the center of much controversy, in part, because their color changes during immaturity as well as other factors, such as physical similarities in genitalia, creating difficulties in accurately determining the sex of individuals. Furthermore, owing to their rarity, illusiveness, and the rough terrain that comprises their native habitat, Nomascus is one of the least studied Hylobatidae. This article represents the most comprehensive dissemination of visual characteristics of the genus Nomascus to assist in the accurate identification of captive and wild crested gibbons. Through differences in pelage color, skeletal anatomy, dentition, vocalizations, behavior, distribution, and genetic studies, we are able to determine more accurately whether or not a subspecies should be elevated to species level. From the current data, there are six species and one subspecies in the genus Nomascus. However, reports of a recently identified light-cheeked gibbon (Nomascus sp.) in northeast Cambodia, Central Vietnam, and South Lao PDR, will add additional taxa to this genus. PMID- 20954248 TI - Calculating pKa values in the cAMP-dependent protein kinase: the effect of conformational change and ligand binding. AB - The conformational change observed upon ligand binding and phosphorylation for the cAMP-dependent protein kinase (protein kinase A-PKA) is of high importance for the regulation of its activity. We calculate pKa values and net charges for 18 3D structures of PKA in various conformations and liganded states to examine the role of electrostatics in ligand binding and activation. We find that the conformational change of PKA takes place without any significant net proton uptake/release at all pH values, thus indicating that PKA has evolved to reduce any pH-dependent barriers to the conformational motion. We furthermore find that the binding of ligands induces large changes in the net charge of PKA at most pH values, but significantly, we find that the net charge difference at physiological pH is close to zero, thus indicating that the active-site pKa values have been preorganized for substrate binding. We are unable to unequivocally resolve the identity of the groups responsible for determining the pH-activity profile of PKA but speculate that the titration of Lys 168 or the titration of ATP itself could be responsible for the loss of activity at high pH values. Finally, we examine the effect of point mutations on the pKa values of the PKA catalytic residues and find these to be relatively insensitive to both noncharge-altering and charge-altering mutations. PMID- 20954249 TI - Lemurs in a complex landscape: mapping species density in subtropical dry forests of southwestern Madagascar using data at multiple levels. AB - The study of southern dry forest lemurs has been largely restricted to small reserves; yet, the majority of the region's lemur populations reside outside protected areas. Lemur catta and Propithecus verreauxi occupy the same forests but have different dietary preferences. This study assessed L. catta and P. verreauxi population densities across a 3-km dry forest gradient (1,539 ha) in southern Madagascar. The study was designed to allow lemur densities to be related to particular forest types. A particular aim of this study was to collect lemur data in both protected and unprotected areas. Density estimates were calculated using point transect distance sampling in a study area that contained the Beza Mahafaly Special Reserve and the adjacent disturbed forests. The highest densities recorded for each species were in the protected area where the two species were most segregated in their distribution, with L. catta density highest in gallery forest type and P. verreauxi density highest in dry deciduous. Densities of both species varied widely outside the protected area, but P. verreauxi density was more uniform than was L. catta. Results of this study indicate that patterns of lemur density in protected areas are not representative of patterns in disturbed forests; this also suggests that we cannot fully understand the ecological constraints facing primate species by studying them only in protected areas. This research highlights the value of pairing the study of landscape-level patterns of species distribution with both local ground-level ecological interpretations and broad-scale satellite data; information from only one level may give an incomplete view of the community. PMID- 20954250 TI - Population-level right-handedness for a coordinated bimanual task in naturalistic housed chimpanzees: replication and extension in 114 animals from Zambia and Spain. AB - Recently, many studies have been conducted on manual laterality in chimpanzees. Nevertheless, whether nonhuman primates exhibit population-level handedness remains a topic of considerable debate. One of the behaviors studied has been bimanual coordinated actions. Although recent studies have highlighted that captive chimpanzees show handedness at population level for these tasks, some authors have questioned the validity and consistency of these results. The first reason has been the humanization of the samples. The second one has been that the results refer to animals in American biomedical centers and the studies were conducted by the same team [WD Hopkins et al.]. This article aims to assess the laterality in bimanual coordination (tube task) activities in animals housed in an intermediate environment (Chimfunshi, Zambia). This has been conducted by replicating previous studies on similar samples (Mona Foundation, Spain), and then by extending the results to chimpanzees housed in intermediate settings. Individuals were evaluated through four experimental sessions (tests). Results indicated that 86% of the Chimfunshi sample was lateralized (48% RH, 38% LH). Furthermore, the sample showed population-level right-handedness in the mean handedness index, in Test 1, Test 2, and the first half of the study (Test 112). Rearing experience did not have an influence on handpreference. Taken together, the two sample (intermediate settings: Chimfunshi and Mona) results indicate a clear right-handedness. In conclusion, this replication and extension shows that (1) the Mona and Chimfunshi chimpanzees are right-handed in certain conditions, (2) the results are consistent with those obtained by Hopkins in captive settings, (3) the humanization of the samples does not affect manual laterality, (4) females are right-handed at population-level, but not males, and (5) these results reinforce the fact that the complexity of the task plays a dominant role in the expression of hand laterality among chimpanzees. PMID- 20954251 TI - Bonding, biophilia, biosynergy, and the future of primates in the wild. AB - Human and nonhuman primates bond with one another in countless ways, and the results are varied and vital to the individuals and species involved. The manifesto that is the basis for the collection of essays in which this commentary is included proposes that the "human/nonhuman bonds that arise in primatological research and practice deserve and demand study and research." An essential corollary of this proposal is that the primatologists themselves must be studied. The aim of this essay is to explore the influence of human/nonhuman primate bonding on conservation practice and on the future of primates in the wild. This commentary applies the author's professional experience as a conservation psychologist and his research on the impact of profound interspecies bonds on human worldviews, attitudes, and behavior. It examines two general categories of bonds: those driven by Biophilia (human fascination with life) and those influenced by Biosynergy (mutual enrichment of life). It is the author's premise that biosynergy promotes complex collaborative interspecies bonds that broaden the conservationist's desire to enhance synergy among all organisms in an ecosystem. Conversely, biophilia induces relatively simple unidirectional bonds between humans and other animals that deepen the conservationist's desire to understand and protect certain species. This contrast raises some crucial questions. Do biophilia-driven bonds between conservationists and their favorite primates blind them to the synergistic needs of all species and impair their ability to work for sustained preservation of threatened habitat? Does biosynergy based human/nature bonding enhance focus on conservation as an ecological science and thus ignore species-specific factors crucial to assure survival of endangered primates? How can both types of bonds be optimally applied to the conservation of wildlife and wilderness? PMID- 20954252 TI - Influence of diet transition on serum calcium and phosphorus and fatty acids in zoo giraffe (Giraffa camelopardalis). AB - In response to new recommendations for feeding giraffe in zoos, giraffe (n = 6) were transitioned from a typical hoofstock diet to diets containing reduced starch, protein, Ca and P and added n3 fatty acids. This diet was fed as a 50:50 mix with alfalfa and grass hay. Over the next 4 years, serum Ca, P, and fatty acids were measured every 6 months (summer and winter). Serum Ca was not affected by season (P = 0.67) or by diet (P = 0.12). Serum P was not affected season (P = 0.14), but was reduced by diet (P<0.01), and serum Ca:P was also increased by diet (P<0.01). The ratio of serum Ca:P tended to be affected by season (P = 0.07), in which animals tended to have greater Ca:P during the summer vs. the winter. The diet transition resulted in reduced serum saturated fatty acids (including lauric, myristic, palmitic, arachidic, and behenic acids), and increases in n6 fatty acids (including linolenic and arachidonic acids) and n3 fatty acids (docosahexaenoic acid) (P<0.05 for each). Overall, this diet transition resulted in blood nutrient profiles that more closely match that of values found in free-ranging giraffe. PMID- 20954253 TI - The use of technology to enhance zoological parks. AB - Technology can be used in a zoological setting to improve visitor experience, increase research opportunities, and enhance animal welfare. Evaluating the quality of these technological innovations and their use by nonhuman and human counterparts is a critical part of extending the uses of technology to enhance animal welfare and visitor experience at zoological parks. Survey data from a small sample of institutions housing primates suggest that computers, television, radio, and sprinklers are the most prevalent types of technological enrichment currently used. Survey respondents were positive about the technology implemented, stating a desire to increase its use. PMID- 20954254 TI - Syrian hamster males below an age threshold do not elicit aggression from unfamiliar adult males. AB - In many species, young males are the dispersers, leaving their natal area after weaning to establish a breeding area of their own. As young males disperse, however, they are bound to encounter unfamiliar adult males with established territories. Such interactions between an adult male and a young male may always be agonistic. Alternatively, there may be an age threshold below which aggression is not elicited and above which the adult male is aggressive toward the juvenile male. To test these two alternative hypotheses, we paired 47 young Syrian hamster (Mesocricetus auratus) males ranging from 24 to 65 days of age with 47 adult male hamsters and measured aggressive and investigatory behavior for 5 min. We observed no aggression by the adult toward young males between 24 and 47 days of age or toward the single male that was 49 days of age. Young males that were 50 days of age or older, however, elicited significant levels of aggression from the adults. These results indicate that in Syrian hamsters, young males are less vulnerable to adult aggression up to an age threshold and are more vulnerable to adult aggression beyond that threshold. This pattern may facilitate the establishment of territories by dispersing young males below that age threshold. PMID- 20954257 TI - Hereditary hemochromatosis is characterized by a clinically definable arthropathy that correlates with iron load. AB - OBJECTIVE: To determine the frequency and character of arthropathy in hereditary hemochromatosis (HH) and to investigate the relationship between this arthropathy, nodal interphalangeal osteoarthritis, and iron load. METHODS: Participants were recruited from the community by newspaper advertisement and assigned to diagnostic confidence categories for HH (definite/probable or possible/unlikely). Arthropathy was determined by use of a predetermined clinical protocol, radiographs of the hands of all participants, and radiographs of other joints in which clinical criteria were met. RESULTS: An arthropathy considered typical for HH, involving metacarpophalangeal joints 2-5 and bilateral specified large joints, was observed in 10 of 41 patients with definite or probable HH (24%), all of whom were homozygous for the C282Y mutation in the HFE gene, while only 2 of 62 patients with possible/unlikely HH had such an arthropathy (P=0.0024). Arthropathy in definite/probable HH was more common with increasing age and was associated with ferritin concentrations>1,000 MUg/liter at the time of diagnosis (odds ratio 14.0 [95% confidence interval 1.30-150.89], P=0.03). A trend toward more episodes requiring phlebotomy was also observed among those with arthropathy, but this was not statistically significant (odds ratio 1.03 [95% confidence interval 0.99-1.06], P=0.097). There was no significant association between arthropathy in definite/probable HH and a history of intensive physical labor (P=0.12). CONCLUSION: An arthropathy consistent with that commonly attributed to HH was found to occur in 24% of patients with definite/probable HH. The association observed between this arthropathy, homozygosity for C282Y, and serum ferritin concentrations at the time of diagnosis suggests that iron load is likely to be a major determinant of arthropathy in HH and to be more important than occupational factors. PMID- 20954258 TI - Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. AB - OBJECTIVE: Both Th1 cells and Th17 cells have been recognized in rheumatoid arthritis (RA); however, it remains unclear whether Th1 cells and/or Th17 cells are involved in driving disease chronicity and destructiveness. The aim of this study was to identify and characterize the functional role of Th17 cells in early RA. METHODS: Flow cytometry analysis was performed on peripheral blood mononuclear cells (PBMCs) from treatment-naive patients with early RA and age matched healthy volunteers. PBMCs from these patients, naive T cells, and primary CCR6- Th1 cells and CCR6+ Th17 cells were sorted and cultured in the absence or presence of synovial fibroblasts from patients with early RA (RASFs), and cytokine expression and gene transcription were analyzed. In addition, tumor necrosis factor alpha (TNFalpha)- and interleukin-17A (IL-17A)-blocking experiments were performed. RESULTS: In the PBMCs of treatment-naive patients with early RA, an increased fraction of IL-17A-and TNFalpha-producing CCR6+ Th17 cells was observed. When cocultured with RASFs, these primary Th17 cells were potent inducers of IL-6 and IL-8 and the tissue-destructive enzymes matrix metalloproteinase 1 (MMP-1) and MMP-3, whereas primary Th1 cells or naive T cells were not. Importantly, specific up-regulation of IL-17A but not TNFalpha or interferon-gamma was observed in RASF/Th17 cell cocultures. In addition to TNFalpha blocking, IL-17A neutralization was required to further down-regulate Th17 activity in RASF/Th17 cell cocultures. CONCLUSION: Th17 cells, but not Th1 cells, cooperated with RASFs in a proinflammatory feedback loop, revealing a potential mechanism by which human Th17 cells drive chronic destructive disease in patients with RA. Furthermore, the neutralization of IL-17A activity is essential in current anti-TNF therapies to suppress Th17 cell activity in patients with early RA and potentially other Th17 cell-mediated disorders. PMID- 20954259 TI - When is a joint injection accurate? Comment on the article by Cunnington et al. PMID- 20954260 TI - Premature arthritis is a distinct type II collagen phenotype: comment on the article by Kannu et al. PMID- 20954261 TI - Bone marrow necrosis and sickle cell crisis associated with double heterozygosity for HbS and HbOARAB. PMID- 20954262 TI - Prolonged 18FDG-PET negative complete remission in a heavily pretreated, elderly patient with diffuse large B cell lymphoma treated with lenalidomide, low dose dexamethasone, and colony stimulating factor (Rd-G). AB - Diffuse large B-cell lymphoma (DLBCL) is a common lymphoid malignancy among adults in the developed world and accounts for about a third of all patients newly diagnosed with non-Hodgkin lymphoma each year. The prognosis of patients with DLBCL has improved over the past 10 years since the advent of chemoimmunotherapy regimens such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). However, a significant number of patients still experience disease relapse or progression after first or second line therapy, and ~40% of patients will die within 5 years. In particular, elderly patients and those ineligible for high-dose chemotherapy due to comorbidities require effective salvage treatment options with favorable toxicity profile. Several novel therapeutic approaches have been proposed for these patients including monoclonal antibodies, radioimmunotherapy, proteasome inhibitors, mTOR inhibitors, and the immunomodulatory drugs such as thalidomide and lenalidomide. PMID- 20954263 TI - No postnatal maternal effect on male aggressiveness in wild-derived strains of house mice. AB - Male aggressiveness is a complex behavior influenced by a number of genetic and non-genetic factors. Traditionally, the contribution of each of these factors has been established from experiments using artificially selected strains for high/low aggressive phenotypes. However, little is known about the factors underlying aggressive behavior in natural populations. In this study, we assess the influence of genetic background vs. postnatal maternal environment using a set of cross-fostering experiments between two wild-derived inbred strains, displaying high (STRA, derived from Mus musculus domesticus) and low (BUSNA, derived from Mus musculus musculus) levels of aggressiveness. The role of maternal environment was tested in males with the same genetic background (i.e. strain origin) reared under three different conditions: unfostered (weaned by mother), infostered (weaned by an unfamiliar dam from the same strain), and cross fostered (weaned by a dam from a different strain). All males were tested against non-aggressive opponents from the A/J inbred strain. Resource-holding potential was assessed through body weight gains and territory ownership. The STRA males were shown to be aggressive in both neutral cage and resident-intruder tests. On the contrary, the BUSNA males were less aggressive in all tests. We did not find a significant effect of postnatal maternal environment; however, we detected significant maternal effect on body weight with differences between the strains, fostering type and interactions between these factors. We conclude that the aggressiveness preserved in the two strains has significant genetic component whose genetic basis can be dissected by quantitative trait loci analysis. PMID- 20954264 TI - Structure determination of a protein assembly by amino acid selective cross saturation. AB - Amino acid selective cross-saturation (ASCS) method not only provides information about the interface of a protein assembly by the spin relaxation experiment, but also identifies the amino acid residues in the acceptor protein, which are located close to the selectively labeled amino acid residues in the donor protein. Here, a new method was developed to build a precise structural model of a protein assembly, which satisfies the experimental ASCS values, using simulated annealing computation. This method was applied to the ubiquitin-yeast ubiquitin hydrolase 1 (Ub-YUH1) complex to build a precise complex structure compatible with that determined by X-ray crystallography. PMID- 20954265 TI - Probing structures of nanomaterials using advanced electron microscopy methods, including aberration-corrected electron microscopy at the Angstrom scale. AB - Structural and compositional studies of nanomaterials of technological importance have been carried out using advanced electron microscopy methods, including aberration-corrected transmission electron microscopy (AC-TEM), AC-high angle annular dark field scanning TEM (AC-HAADF-STEM), AC-energy filtered TEM, electron stimulated energy dispersive spectroscopy in the AC-(S)TEM and high-resolution TEM (HRTEM) with scanning tunneling microscopy (STM) holder. The AC-EM data reveal improvements in resolution and minimization in image delocalization. A JEOL 2200FS double-AC field emission gun TEM/STEM operating at 200 kV in the Nanocentre at the University of York has been used to image single metal atoms on crystalline supports in catalysts, grain boundaries in nanotwinned metals, and nanostructures of tetrapods. Joule heating studies using HRTEM integrated with an STM holder reveal in situ crystallization and edge reconstruction in graphene. Real-time in situ AC-HAADF-STEM studies at elevated temperatures are described. Dynamic in-column energy filtering in an AC environment provides an integral new approach to perform dynamic in situ studies with aberration correction. The new results presented here open up striking new opportunities for atomic scale studies of nanomaterials and indicate future development directions. PMID- 20954266 TI - Evaluation of a lecture recording system in a medical curriculum. AB - Recently, the Medical University of South Carolina adopted a lecture recording system (LRS). A retrospective study of LRS was implemented to document the students' perceptions, pattern of usage, and impact on the students' grades in three basic sciences courses (Cell Biology/Histology, Physiology, and Neurosciences). The number of accesses and length of viewings of the recordings were recorded per week for each student and correlated with the grades in each of the three courses. Attendance records were not available. The results showed considerable variability in the use of the LRS by both faculty and students during the entire semester and across all three courses, including week to week variations. Data indicated that 30% of the students did not use the LRS at all with 41% of the students using it very little (less than 10 times for a total of 131 recordings). Specific patterns of usage were identified for each of the three courses throughout the semester, with an increase in access prior or during examination weeks. However, the statistical analysis showed that there was no correlation between the final grades and the usage of LRS. Finally, a survey of the students' perception showed that 74% agreed/strongly agreed that the recordings were useful with 6% disagreeing/strongly disagreeing and 11% undecided. This study showed that the use of LRS might be a viable alternative for students unable to attend lecture due to circumstances such as illness but that more research is needed to truly understand the best pedagogical use of LRS. PMID- 20954267 TI - Enrichment of circulating tumor cells from a large blood volume using leukapheresis and elutriation: proof of concept. AB - BACKGROUND: The aim of this study was to determine the applicability of a sequential process using leukapheresis, elutriation, and fluorescence-activated cell sorting (FACS) to enrich and isolate circulating tumor cells from a large blood volume to allow further molecular analysis. METHODS: Mononuclear cells were collected from 10 L of blood by leukapheresis, to which carboxyfluorescein succinimidyl ester prelabeled CaOV-3 tumor cells were spiked at a ratio of 26 to 106 leukocytes. Elutriation separated the spiked leukapheresates primarily by cell size into distinct fractions, and leukocytes and tumor cells, characterized as carboxyfluorescein succinimidyl ester positive, EpCAM positive and CD45 negative events, were quantified by flow cytometry. Tumor cells were isolated from the last fraction using FACS or anti-EpCAM coupled immunomagnetic beads, and their recovery and purity determined by fluorescent microscopy and real-time PCR. RESULTS: Leukapheresis collected 13.5 x 109 mononuclear cells with 87% efficiency. In total, 53 to 78% of spiked tumor cells were pre-enriched in the last elutriation fraction among 1.6 x 109 monocytes. Flow cytometry predicted a circulating tumor cell purity of ~90% giving an enrichment of 100,000-fold following leukapheresis, elutriation, and FACS, where CaOV-3 cells were identified as EpCAM positive and CD45 negative events. FACS confirmed this purity. Alternatively, immunomagnetic bead adsorption recovered 10% of tumor cells with a median purity of 3.5%. CONCLUSIONS: This proof of concept study demonstrated that elutriation and FACS following leukapheresis are able to enrich and isolate tumor cells from a large blood volume for molecular characterization. PMID- 20954268 TI - Organic electronics - from materials to applications. PMID- 20954269 TI - Charge transport physics of conjugated polymer field-effect transistors. PMID- 20954270 TI - Follicular lesions of the thyroid: a retrospective study of 1,348 fine needle aspiration biopsies. AB - Fine needle aspiration (FNA) has proven to be an effective tool in management of patients with thyroid nodules. However, the diagnosis of follicular patterned lesions can be challenging. The surgical and cytopathology computer database at a large referral medical center was searched for cases that had both cytologic and histologic thyroid accessions from January 2004 to November 2008. A total of 1,255 histologic thyroid specimens and 2,776 thyroid FNA biopsies were retrieved for review. Histologically, 272 overt malignancies were identified; 20 (7.4%) were follicular carcinomas. Cytologically, 1,348 cases were follicular-patterned lesions, comprising 1,044 cases of "benign follicular nodules" (BFN), 137 cases of "follicular lesions of undetermined significance" (FLUS), and 167 cases of "suspicious for follicular neoplasm" (SFN). Seventy-nine (7.5%) of BFN, 23 (16.8%) of FLUS, and 65 (38.9%) of SFN cases had histologic follow-up. Overt malignancy, a cystic papillary carcinoma, was identified histologically in only one case of BFN, for a negative predictive value of 98.7%. Overt malignancy was identified histologically in two cases of FLUS, both follicular variant of papillary carcinoma, for a positive predictive value of 8.7%. Overt malignancy was identified histologically in 14 cases of SFN, for a positive predictive value of 21.5%. Five follicular carcinomas were identified histologically in the SFN category, all minimally invasive. Incidental ("occult") papillary microcarcinoma were identified histologically in all three categories. In this study, the risk of overt malignancy increases from 1.3%, to 8.7%, to 21.5% for BFN, FLUS, and SFN, respectively. All follicular carcinomas identified histologically occurred in the SFN category and all were minimally invasive. Papillary microcarcinomas can occur in any of the three diagnostic categories. PMID- 20954271 TI - Acute myeloid leukemia with myelodysplasia-related changes with erythroid differentiation involving pleural fluid: a case report and brief cytopathologic review. AB - The vast majority of malignant pleural effusions are caused by metastatic adenocarcinoma, most frequently from breast or lung primaries. However, a minority of cases show evidence of involvement by a hematopoietic neoplasm such as lymphoma or leukemia. We report a rare case of a 54-year-old male with a prior diagnosis of acute myeloid leukemia with myelodysplastic-related changes (AML MDS) with erythroid differentiation having new onset pleural effusions containing leukemic blasts. The pleural specimen was comprised of blast forms having large round nuclei with finely dispersed chromatin and prominent nucleoli, with scattered binucleate forms. The blasts expressed CD45 and CD34 and were negative for epithelial and mesothelial markers. Previous bone marrow biopsies had shown that the blasts exhibited strong staining for hemoglobin and lacked expression of Factor VIII and myeloperoxidase, consistent with erythroid differentiation. Although rare, this case indicates the need for consideration of unusual disease states presenting within a pleural fluid and highlights the differential diagnosis and immunohistochemical profile of AMLs with erythroid differentiation. PMID- 20954272 TI - Fine needle aspiration cytology of myositis ossificans. AB - In this case report, we described the fine needle aspiration cytology (FNAC) of myositis ossificans (MO) in a young boy. The patient presented with a painful hard mass in the upper right thigh and restricted range of motion around hip joint since 2 weeks. He had history of trauma. Computerized tomographic (CT) scan showed a heterogeneous mass in the upper part of quadriceps with peripheral areas of calcification and central hyperlucency. The FNAC smear of MO shows fibroblasts, osteoblasts, multinucleated giant cells, degenerated muscle cells and osteoid. Clinical presentation along with cytology and radiologic findings are helpful to diagnose this entity. PMID- 20954273 TI - Neoadjuvant treatment for resectable pancreatic cancer: time for phase III testing? AB - This paper discusses the rationale for phase III testing of neoadjuvant therapy in patients affected by resectable pancreatic adenocarcinoma. The therapeutic management of patients affected by resectable pancreatic cancer is particularly troublesome due to the aggressiveness of the disease and to the limited efficacy and sometimes unfavourable risk-benefit ratio of the available therapeutic tools. Conflicting data on the role of adjuvant chemoradiation have been reported, while adjuvant single-agent chemotherapy significantly improved overall survival (OS) when compared to surgery alone. However, the OS figures for adjuvant chemotherapy remain disappointing. In effect, pancreatic cancer exhibits a prominent tendency to recur after a brief median time interval from surgery and extra-pancreatic dissemination represents the predominant pattern of disease failure. Neoadjuvant treatment has a strong rationale in this disease but limited information on the efficacy of this approach is available from single arm trials with low levels of evidence. Thus, in spite of two decades of investigation there is currently no evidence to support the routine use of pre-surgical therapy in clinical practice. To foster knowledge on the optimal management of this disease, and to produce evidence-based treatment guidelines, there is no alternative to well designed randomized trials. Systemic chemotherapy is a candidate for testing because it is supported by a more robust rationale than chemoradiation. Combination chemotherapy regimens with elevated activity in advanced disease warrant investigation. Caution would suggest the running of an exploratory phase II randomized trial before embarking on a large phase III study. PMID- 20954274 TI - Role of endoscopic ultrasound during hospitalization for acute pancreatitis. AB - Endoscopic ultrasound (EUS) is often used to detect the cause of acute pancreatitis (AP) after the acute attack has subsided. The limited data on its role during hospitalization for AP are reviewed here. The ability of EUS to visualize the pancreas and bile duct, the sonographic appearance of the pancreas, correlation of such appearance to clinical outcomes and the impact on AP management are analyzed from studies. The most important indication for EUS appears to be for detection of suspected common bile duct and/or gall bladder stones and microlithiasis. Such an approach might avoid diagnostic endoscopic retrograde cholangio-pancreatography with its known complications. The use of EUS during hospitalization for AP still appears to be infrequent but may become more frequent in future. PMID- 20954275 TI - Clostridium difficile infection and inflammatory bowel disease: understanding the evolving relationship. AB - Clostridium difficile (C. difficile) infection (CDI) is the leading identifiable cause of antibiotic-associated diarrhea. While there is an alarming trend of increasing incidence and severity of CDI in the United States and Europe, superimposed CDI in patients with inflammatory bowel disease (IBD) has drawn considerable attention in the gastrointestinal community. The majority of IBD patients appear to contract CDI as outpatients. C. difficile affects disease course of IBD in several ways, including triggering disease flares, sustaining activity, and in some cases, acting as an "innocent" bystander. Despite its wide spectrum of presentations, CDI has been reported to be associated with a longer duration of hospitalization and a higher mortality in IBD patients. IBD patients with restorative proctocolectomy or with diverting ileostomy are not immune to CDI of the small bowel or ileal pouch. Whether immunomodulator or corticosteroid therapy for IBD should be continued in patients with superimposed CDI is controversial. It appears that more adverse outcomes was observed among patients treated by a combination of immunomodulators and antibiotics than those treated by antibiotics alone. The use of biologic agents does not appear to increase the risk of acquisition of CDI. For CDI in the setting of underlying IBD, vancomycin appears to be more efficacious than metronidazole. Randomized controlled trials are required to clearly define the appropriate management for CDI in patients with IBD. PMID- 20954276 TI - Alcoholic hepatitis 2010: a clinician's guide to diagnosis and therapy. AB - Alcoholic hepatitis (AH) remains a common and life threatening cause of liver failure, especially when it is severe. Although the adjective "acute" is frequently used to describe this form of liver injury, it is usually subacute and has been developing for weeks to months before it becomes clinically apparent. Patients with this form of alcoholic liver disease usually have a history of drinking heavily for many years. While certain aspects of therapy, mainly nutritional support and abstinence are well established, significant debate has surrounded the pharmacologic treatment of AH, and many institutions practice widely varying treatment protocols. In recent years a significant amount of literature has helped focus on the details of treatment, and more data have accumulated regarding risks and benefits of pharmacologic treatment. In particular, the efficacy of pentoxifylline has become increasingly apparent, and when compared with the risks associated with prednisolone, has brought this drug to the forefront of therapy for severe AH. This review will focus on the clinical and laboratory diagnosis and pharmacologic therapies that should be applied during hospitalization and continued into outpatient management. We conclude that the routine use of glucocorticoids for severe AH poses significant risk with equivocal benefit, and that pentoxifylline is a better, safer and cheaper alternative. While the full details of nutritional support lie beyond the scope of this article, nutrition is a cornerstone of therapy and must be addressed in every patient diagnosed with AH. Finally, while traditional psychosocial techniques play a major role in post-hospitalization care of alcoholics, we hope to make the medical clinician realize his or her role in reducing recidivism rates with early and frequent outpatient visits and with the use of baclofen to reduce alcohol craving. PMID- 20954277 TI - Diagnosis and management of angioedema with abdominal involvement: a gastroenterology perspective. AB - Abdominal involvement in angioedema is often a challenge to diagnose. Acute onset abdominal pain is its most common presenting symptom, and misdiagnosis may lead to unnecessary surgical intervention. Familiarity with the types and presentations of angioedema can be invaluable to clinicians as they consider the differential diagnoses of a patient presenting with abdominal pain. Detailed personal and family histories, careful physical examination of the patient, combined with knowledge of angioedema types, can help clinicians perform their diagnostic evaluation. An accurate diagnosis is essential in order to provide appropriate treatment to patients with angioedema. Depending upon the diagnosis, treatment may be the avoidance of provoking factors (such as allergens or medications), inhibiting histamine-provoked reactions, or treating C1 esterase inhibitor deficiency. PMID- 20954278 TI - Anti-inflammatory effects of Mangifera indica L. extract in a model of colitis. AB - AIM: To investigate the effect of aqueous extract from Mangifera indica L. (MIE) on dextran sulfate sodium (DSS)-induced colitis in rats. METHODS: MIE (150 mg/kg) was administered in two different protocols: (1) rectally, over 7 d at the same time as DSS administration; and (2) once daily over 14 d (by oral gavage, 7 d before starting DSS, and rectally for 7 d during DSS administration). General observations of clinical signs were performed. Anti-inflammatory activity of MIE was assessed by myeloperoxidase (MPO) activity. Colonic lipid peroxidation was determined by measuring the levels of thiobarbituric acid reactive substances (TBARS). Reduced glutathione (GSH) levels, expression of inflammatory related mediators [inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, respectively] and cytokines [tumor necrosis factor (TNF)-alpha and TNF receptors 1 and 2] in colonic tissue were also assessed. Interleukin (IL)-6 and TNF-alpha serum levels were also measured. RESULTS: The results demonstrated that MIE has anti-inflammatory properties by improvement of clinical signs, reduction of ulceration and reduced MPO activity when administered before DSS. In addition, administration of MIE for 14 d resulted in an increase in GSH and reduction of TBARS levels and iNOS, COX-2, TNF-alpha and TNF R-2 expression in colonic tissue, and a decrease in IL-6 and TNF-alpha serum levels. CONCLUSION: MIE has anti inflammatory activity in a DSS-induced rat colitis model and preventive administration (prior to DSS) seems to be a more effective protocol. PMID- 20954279 TI - HBx-induced reactive oxygen species activates hepatocellular carcinogenesis via dysregulation of PTEN/Akt pathway. AB - AIM: To investigate the role of hepatitis B virus X-protein (HBx)-induced reactive oxygen species (ROS) on liver carcinogenesis in HBx transgenic mice and HepG2-HBx cells. METHODS: Cell growth rate was analyzed, and through western blotting, mitogenic signaling was observed. Endogenous ROS from wild and HBx transgenic mice and HepG2-Mock and HBx cells were assayed by FACScalibur. Identification of oxidized and reduced phosphatase and tensin homolog (PTEN) was analyzed through N-ethylmaleimide alkylation, nonreducing electrophoresis. RESULTS: We observed that the cell-proliferation-related phosphoinositide 3 kinase/Akt pathway is activated by HBx in vivo and in vitro. Increased ROS were detected by HBx. Tumor suppressor PTEN, via dephosphorylation of Akt, was oxidized and inactivated by increased ROS. Increased oxidized PTEN activated the mitogenic pathway through over-activated Akt. However, treatment with ROS scavenger N-acetyl cysteine can reverse PTEN to a reduced form. Endogenously produced ROS also stimulated HBx expression. CONCLUSION: HBx induced ROS promoted Akt pathways via oxidized inactive PTEN. HBx and ROS maintained a positive regulatory loop, which aggravated carcinogenesis. PMID- 20954280 TI - Peri-nuclear antibodies correlate with survival in Greek primary biliary cirrhosis patients. AB - AIM: To investigate possible associations of anti-nuclear envelope antibody (ANEA) with disease severity and survival in Greek primary biliary cirrhosis (PBC) patients. METHODS: Serum samples were collected at diagnosis from 147 PBC patients (85% female), who were followed-up for a median 89.5 mo (range 1-240). ANEA were detected with indirect immunofluorescence on 1% formaldehyde fixed Hep2 cells, and anti-gp210 antibodies were detected using an enzyme linked immunosorbent assay. Findings were correlated with clinical data, histology, and survival. RESULTS: ANEA were detected in 69/147 (46.9%) patients and 31/147 (21%) were also anti-gp210 positive. The ANEA positive patients were at a more advanced histological stage (I-II/III-IV 56.5%/43.5% vs 74.4%/25.6%, P = 0.005) compared to the ANEA negative ones. They had a higher antimitochondrial antibodies (AMA) titer (<= 1:160/> 1:160 50.7%/49.3% vs 71.8%/28.2%, P = 0.001) and a lower survival time (91.7 +/- 50.7 mo vs 101.8 +/- 55 mo, P = 0.043). Moreover, they had more advanced fibrosis, portal inflammation, interface hepatitis, and proliferation of bile ductules (P = 0.008, P = 0.008, P = 0.019, and P = 0.027, respectively). They also died more frequently of hepatic failure and/or hepatocellular carcinoma (P = 0.016). ANEA positive, anti-gp210 positive patients had a difference in stage (I-II/III-IV 54.8%/45.2% vs 74.4%/25.6%, P = 0.006), AMA titer (<= 1:160/> 1:160 51.6%/48.4% vs 71.8%/28.2%, P = 0.009), survival (91.1 +/- 52.9 mo vs 101.8 +/- 55 mo, P = 0.009), and Mayo risk score (5.5 +/- 1.9 vs 5.04 +/- 1.3, P = 0.04) compared to the ANEA negative patients. ANEA positive, anti-gp210 negative patients had a difference in AMA titer (<= 1:160/> 1:160 50%/50% vs 71.8%/28.2%, P = 0.002), stage (I-II/III-IV 57.9%/42.1% vs 74.4%/25.6%, P = 0.033), fibrosis (P = 0.009), portal inflammation (P = 0.018), interface hepatitis (P = 0.032), and proliferation of bile ductules (P = 0.031). Anti-gp210 positive patients had a worse Mayo risk score (5.5 +/- 1.9 vs 4.9 +/- 1.7, P = 0.038) than the anti-gp210 negative ones. CONCLUSION: The presence of ANEA and anti-gp210 identifies a subgroup of PBC patients with advanced disease severity and poor prognosis. PMID- 20954281 TI - Pancreatic function, quality of life and costs at long-term follow-up after acute pancreatitis. AB - AIM: To evaluate long-term endocrine and exocrine pancreatic function, quality of life and health care costs after mild acute pancreatitis and severe acute pancreatitis (SAP). METHODS: Patients prospectively included in 2001-2005 were followed-up after 42 (36-53) mo. Pancreatic function was evaluated with laboratory tests, the oral glucose tolerance test (OGTT), fecal elastase-1 and a questionnaire. Short Form (SF)-36, was completed. RESULTS: Fourteen patients with a history of SAP and 26 with mild acute pancreatitis were included. Plasma glucose after OGTT was higher after SAP (9.2 mmol/L vs 7.0 mmol/L, P = 0.044). Diabetes mellitus or impaired glucose tolerance in fasting plasma glucose and/or 120 min plasma glucose were more common in SAP patients (11/14 vs 11/25, P = 0.037). Sick leave, time until the patients could take up recreational activities and time until they had recovered were all longer after SAP (P < 0.001). No significant differences in SF-36 were seen between the groups, or when comparing with age and gender matched reference groups. Total hospital costs, including primary care, follow-up and treatment of complications, were higher after SAP (median ?16 572 vs ?5000, P < 0.001). CONCLUSION: Endocrine pancreatic function was affected, especially after severe disease. SAP requires greater resource use with long recovery, but most patients regained a good quality of life. PMID- 20954282 TI - Pulmonary involvement in inflammatory bowel disease. AB - AIM: To determine the relationship of pulmonary abnormalities and bowel disease activity in inflammatory bowel disease (IBD). METHODS: Thirty ulcerative colitis (UC) and nine Crohn's disease patients, and 20 control subjects were enrolled in this prospective study. Detailed clinical information was obtained. Extent and activity of the bowel disease were established endoscopically. Each patient underwent pulmonary function tests and high-resolution computed tomography (HRCT). Blood samples for measurement of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), angiotensin converting enzyme and total IgE were delivered by the patients. RESULTS: Ten (25.6%) patients had respiratory symptoms. A pulmonary function abnormality was present in 22 of 39 patients. Among all patients, the most prevalent abnormalities in lung functions were a decrease in forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC), forced expiratory flow (FEF) 25%-75%, transfer coefficient for carbon monoxide (DLCO), DLCO/alveolar volume. Increased respiratory symptoms score was associated with high endoscopic activity index in UC patients. Endoscopic and clinical activities in UC patients were correlated with FEV1, FEV1/FVC, and FEF 25%-75%. Smoking status, duration of disease and medication were not correlated with pulmonary physiological test results, HRCT abnormalities, clinical/endoscopic disease activity, CRP, ESR or total IgE level or body mass index. CONCLUSION: It is important that respiratory manifestations are recognized and treated early in IBD. Otherwise, they can lead to destructive and irreversible changes in the airway wall. PMID- 20954283 TI - Association of p53/p21 expression with cigarette smoking and prognosis in esophageal squamous cell carcinoma patients. AB - AIM: To investigate the expression of p53 and p21 and associations with possible risk factors, such as cigarette smoking, in esophageal squamous cell carcinoma (ESCC) in northeastern Iran, a region with a high incidence of ESCC. METHODS: The expression of p53 and p21 proteins was investigated immunohistochemically in tumor tissue from 80 ESCC patients and in 60 available paraffin-embedded blocks of adjacent normal specimens from the cases, along with normal esophageal tissue from 80 healthy subjects. RESULTS: Positive expression of p53 protein was detected in 56.2% (45/80) of ESCC cases, and in none of the normal esophageal tissue of the control group (P < 0.001). Furthermore, 73.8% (59/80) of ESCC cases and 43.8% (35/80) of controls had positive expression of p21 protein (P < 0.001). Cigarette smoking was significantly associated with p53 over-expression in ESCC cases (P = 0.010, OR = 3.64; 95% CI: 1.32-10.02). p21 over-expression was associated with poorer clinical outcome among the ESCC patients (P = 0.009). CONCLUSION: Over-expression of p53 in association with cigarette smoking may play a critical role in ESCC carcinogenesis among this high-risk population of northeastern Iran. Furthermore, p21 over-expression was found to be associated with poor prognosis, specifically in the operable ESCC patients. PMID- 20954284 TI - Etiology and long-term outcome of extrahepatic portal vein obstruction in children. AB - AIM: To study the management and outcome of children with extrahepatic portal vein obstruction (EHPVO) in a whole country population. METHODS: A nationwide multicenter retrospective case series of children with EHPVO was conducted. Data on demographics, radiographic studies, laboratory workup, endoscopic and surgical procedures, growth and development, were extracted from the patients' charts. Characteristics of clinical presentation, etiology of EHPVO, management and outcome were analyzed. RESULTS: Thirty patients, 13 males and 17 females, 19 (63.3%) Israeli and 11 (36.7%) Palestinians, were included in the analysis. Age at presentation was 4.8 +/- 4.6 years, and mean follow-up was 4.9 +/- 4.3 years. Associated anomalies were found in 4 patients. The incidence of EHPVO in Israeli children aged 0-14 years was 0.72/million. Risk factors for EHPVO were detected in 13 (43.3%) patients, including 9 patients (30%) with perinatal risk factors, and 4 patients (13.3%) with prothrombotic states: two had low levels of protein S and C, one had lupus anticoagulant, and one was homozygous for methyltetrahydrofolate reductase mutations. In 56.6% of patients, no predisposing factors were found. The most common presenting symptoms were an incidental finding of splenomegaly (43.3%), and upper gastrointestinal bleeding (40%). No differences were found between Israeli and Palestinian children with regard to age at presentation, etiology and clinical symptoms. Bleeding occurred in 18 patients (60%), at a median age of 3 years. Sclerotherapy or esophageal banding was performed in 20 patients. No sclerotherapy complications were reported. Portosystemic shunts were performed in 11 patients (36.6%), at a median age of 11 (range 3-17) years: splenorenal in 9, mesocaval in 1, and a meso-Rex shunt in 1 patient. One patient underwent splenectomy due to severe pancytopenia. Patients were followed up for a median of 3 (range 0.5-15) years. One patient died aged 3 years due to mucopolysaccharidase deficiency type III. None of the patients died due to gastrointestinal bleeding. CONCLUSION: EHPVO is a rare disorder. The etiological factors are still mostly unknown, and the endoscopic and surgical treatment options ensure a good long-term prognosis. PMID- 20954285 TI - Glycemic index, glycemic load and insulinemic index of Chinese starchy foods. AB - AIM: To determine the glycemic index (GI), glycemic load (GL) and insulinemic index (II) of five starchy foods that are commonly used in Chinese diets. METHODS: Ten healthy subjects aged between 20-30 years were recruited. Each subject was asked to consume 50 g of available carbohydrate portions of test foods and reference food. Finger capillary blood samples were collected at the start of eating and 15, 30, 45, 60, 90 and 120 min after consumption. The GI and II of foods were calculated from the ratio of incremental area under the glucose/insulin response curves of test and reference foods. The GL for each test food was determined from its GI value and carbohydrate content. RESULTS: The results showed that brown rice elicited the highest postprandial glucose and insulin responses, followed by taro, adlay, yam and mung bean noodles, which produced the lowest. Among the five starchy foods, brown rice evoked the highest GI and GL at 82 +/- 0.2 and 18 +/- 0.2, followed by taro (69 +/- 0.4, 12 +/- 0.2), adlay (55 +/- 0.4, 10 +/- 0.2), yam (52 +/- 0.3, 9 +/- 0.0) and mung bean noodles (28 +/- 0.5, 7 +/- 0.2), respectively. The II values of the test foods corresponded with GI values. Similarly, brown rice gave the highest II at 81 +/- 0.1, followed by taro (73 +/- 0.3), adlay (67 +/- 0.3), yam (64 +/- 0.5) and mung bean noodles (38 +/- 0.3). All five starchy foods had lower GI, GL and II than reference bread (P < 0.05). CONCLUSION: The GI, GL and II values of starchy foods provide important information for the public to manage their diet and could be useful for the prevention of lifestyle-related diseases such as diabetes mellitus. PMID- 20954286 TI - CABYR RNAi plasmid construction and NF-kappaB signal transduction pathway. AB - AIM: To construct the CABYR RNAi plasmid and study its relation with the nuclear factor (NF)-kappaB signal transduction pathway. METHODS: Human CABYR mRNA sequence was obtained from GenBank. The structure of cDNA sequence for the short hairpin RNA was BbsI + sense + loop + antisense + transcription terminator + KpnI + BamHI. A CABYR silencing plasmid was constructed and transfected into the human embryo cell line 293T. Quantitative real-time polymerase chain reaction was used to analyze CABYR and NF-kappaB gene expression. RESULTS: The CABYR and NF-kappaB expressions were detected in 293T cells. The oligonucleotide (5' GCTCAGATGTTAGGTAAAG-3') efficiently silenced the expression of CABYR. The expression of NF-kappaB was not significantly affected by silencing CABYR (P = 0.743). CONCLUSION: CABYR can be found in the human embryo cell line 293T. Cabyrmid 2 can efficiently silence its target, CABYR, indicating that CABYR is not related with the NF-kappaB signal transduction pathway. PMID- 20954288 TI - Five-year long-term outcomes of laparoscopic surgery for colon cancer. AB - AIM: To perform a meta-analysis to answer whether long-term recurrence rates after laparoscopic-assisted surgery are comparable to those reported after open surgery. METHODS: A comprehensive literature search of the MEDLINE database, EMBASE database, and the Cochrane Central Register of Controlled Trials for the years 1991-2010 was performed. Prospective randomized clinical trials (RCTs) were eligible if they included patients with colon cancer treated by laparoscopic surgery vs open surgery and followed for more than five years. RESULTS: Three studies involving 2147 patients reported long-term outcomes based on five-year data and were included in the analysis. The overall mortality was similar in the two groups (24.9%, 268/1075 in the laparoscopic group and 26.4%, 283/1072 in open group). No significant differences between laparoscopic and open surgery were found in overall mortality during the follow-up period of these studies [OR (fixed) 0.92, 95% confidence intervals (95% CI): 0.76-1.12, P = 0.41]. No significant difference in the development of overall recurrence was found in colon cancer patients, when comparing laparoscopic and open surgery [2147 pts, 19.3% vs 20.0%; OR (fixed) 0.96, 95% CI: 0.78-1.19, P = 0.71]. CONCLUSION: This meta-analysis suggests that laparoscopic surgery was as efficacious and safe as open surgery for colon cancer, based on the five-year data of these included RCTs. PMID- 20954287 TI - Up-regulation of PIK3CA promotes metastasis in gastric carcinoma. AB - AIM: To explore expressions of PIK3CA in the progression of gastric cancer from primary to metastasis and its effects on activation of phosphatidylinositol 3 kinase (PI3K)/Akt pathway. METHODS: mRNA and protein levels of PIK3CA were assessed, respectively, by real-time quantitative polymerase chain reaction and immunohistochemistry in specimens of normal gastric mucosa, primary foci and lymph node and distant metastasis of gastric cancer. Akt and phosphorylated Akt protein were also examined by Western blotting in these tissues, in order to analyze the effect of PIK3CA expression level changes on the activation of PI3K/Akt signaling pathway. RESULTS: PIK3CA mRNA in lymph node metastasis were approximately 5 and 2 folds higher, respectively, than that in the corresponding normal gastric mucosa and primary gastric cancer tissues (P < 0.05), while no statistical significance was found compared with distant metastasis. Immunohistochemically, PIK3CA protein expression was discovered in 7 (35%) specimens of 20 primary foci vs 10 (67%) of 15 of lymph node metastasis or 11 (61%) of 18 of distant metastasis (35% vs 67%, P = 0.015; 35% vs 61%, P = 0.044). With the increased level of PIK3CA expression, the total Akt protein expression remained almost unchanged, but p-Akt protein was upregulated markedly. CONCLUSION: Increased expression of PIK3CA is expected to be a promising indicator of metastasis in gastric cancer. Up-regulation of PIK3CA may promote the metastasis of gastric cancer through aberrant activation of PI3K/Akt signaling. PMID- 20954289 TI - Diagnosis of bile duct hepatocellular carcinoma thrombus without obvious intrahepatic mass. AB - AIM: To study the diagnosis of hepatocellular carcinoma (HCC) presenting as bile duct tumor thrombus with no detectable intrahepatic mass. METHODS: Six patients with pathologically proven bile duct HCC thrombi but no intrahepatic mass demonstrated on the preoperative imaging or palpated intrahepatic mass during operative exploration, were collected. Their clinical and imaging data were retrospectively analyzed. The major findings or signs on comprehensive imaging were correlated with the surgical and pathologic findings. RESULTS: Jaundice was the major clinical symptom of the patients. The elevated serum total bilirubin, direct bilirubin and alanine aminotransferase levels were in concordance with obstructive jaundice and the underlying liver disease. Of the 6 patients showing evidence of viral hepatitis, 5 were positive for serum alpha fetoprotein and carbohydrate antigen 19-9, and 1 was positive for serum carcinoembryonic antigen. No patient was correctly diagnosed by ultrasound. The main features of patients on comprehensive imaging were filling defects with cup-shaped ends of the bile duct, with large filling defects presenting as casting moulds in the expanded bile duct, hypervascular intraluminal nodules, debris or blood clots in the bile duct. No obvious circular thickening of the bile duct walls was observed. CONCLUSION: Even with no detectable intrahepatic tumor, bile duct HCC thrombus should be considered in patients predisposed to HCC, and some imaging signs are indicative of its diagnosis. PMID- 20954290 TI - Laparoscopic wedge resection of synchronous gastric intraepithelial neoplasia and stromal tumor: a case report. AB - Synchronous occurrence of epithelial neoplasia and gastrointestinal stromal tumor (GIST) in the stomach is uncommon. Only rare cases have been reported in the literature. We present here a 60-year-old female case of synchronous occurrence of gastric high-level intraepithelial neoplasia and GIST with the features of 22 similar cases and detailed information reported in the English-language literature summarized. In the present patient, epithelial neoplasia and GIST were removed en bloc by laparoscopic wedge resection. To the best of our knowledge, this is the first reported case treated by laparoscopic wedge resection. PMID- 20954291 TI - Haemodynamic and renal effects of tadalafil in patients with cirrhosis. AB - A recent report introduced the phosphodiesterase-5 inhibition by vardenafil as a novel treatment of portal hypertension in patients with cirrhosis. In the herein presented "letter to the editor", the administration of tadalafil did not influence portal haemodynamics but impaired systemic haemodynamics in patients with cirrhosis. Our observations concur with the results of a report in a previous issue of World Journal of Gastroenterology (October 2008). Moreover, tadalafil adversely affected renal function in patients with decompensated liver disease. PMID- 20954292 TI - Closed-system devices: when seatbelts are not enough. PMID- 20954293 TI - Correlation between the European System for Cardiac Operative Risk Evaluation and sexual function after coronary artery bypass graft surgery. AB - INTRODUCTION: The published studies discussing the prognostic factors for expected sexual function after coronary artery bypass graft (CABG) are still limited. AIM: Examining the correlation between the European System for Cardiac Operative Risk Evaluation (EuroSCORE) and the abridged form of International Index of Erectile Function questionnaire (IIEF-5), as a quick and inexpensive tool for the cardiologist to predict the sexual function after CABG. MAIN OUTCOME MEASURES: Validated standardized questionnaire commonly used by cardiologists in identifying appropriate weight to various risk factors related to adult cardiac operations. METHODS: Preoperatively patients were evaluated as regards to the sexual function by (IIEF-5) and pharmaco-penile duplex ultrasound. Moreover all patients were evaluated bu EuroSCORE. Six months after surgery, the erectile function of all patients was revaluated according to the same preoperative procedures. The patients were categorized with EuroSCORE as follows: The low-risk group (EuroSCORE 0-2), the medium-risk group (EuroSCORE 3-5), and the high-risk group (EuroSCORE 6 plus). RESULTS: The EuroSCORE was negatively correlated with the IIEF-5 score (r = -0.224, P = 0.025 or rs = -0.259, P = 0.009). Moreover, low risk patients had significantly higher IIEF-5 scores compared with medium-risk patients (mean standard deviation = 15.27 6.03 vs. 12.18 6.07, P < 0.05). CONCLUSIONS: There is an inverse correlation between the components of EuroSCORE and the IIEF-5 score. Patients with higher EuroSCORE had lower IIEF-5 scores and vice versa. The EuroSCORE is a useful, quick, and inexpensive tool that allows prediction of ED in those patients with coronary artery disease patients who are undergoing CABG. PMID- 20954294 TI - Vive la difference: Letter from the guest editor. PMID- 20954295 TI - CFTR's proteolysis protection. The cystic fibrosis transmembrane conductance regulator impedes proteolytic stimulation of the epithelial Na+ channel. PMID- 20954296 TI - Mercury detoxification and natural product synthesis: the work of Christopher T. Walsh. PMID- 20954297 TI - Retraction. Mutual regulation of protein-tyrosine phosphatase 20 and protein tyrosine kinase Tec activities by tyrosine phosphorylation and dephosphorylation. PMID- 20954298 TI - Subjective versus objective debate. PMID- 20954299 TI - Clinical Trials Registry-India: raising the veil. PMID- 20954300 TI - Protecting the sacred aspect of birth. PMID- 20954301 TI - A new birthday custom. PMID- 20954302 TI - Influence of interdomain interfaces. Regulation of response regulator autophosphorylation through interdomain contacts. PMID- 20954303 TI - Retraction. The novel protein-tyrosine phosphatase PTP20 is a positive regulator of PC12 cell neuronal differentiation. PMID- 20954304 TI - [The clinical picture of rheumatoid arthritis--the complex of three independent mechanisms]. AB - The assumption of inflamation as the only cause of the complex clinical picture of rheumatoid atrhritis does not correspond to facts. We have found and proven the existence of three seemingly unconnected mechanisms, and only their combination can account for the general clinical picture of rheumatoid arthritis. They are: 1. immunologic synovitis, responsible for pain, swelling and stiffnes; 2. oncological process ("tumorlike proliferation"), responsible for the destruction of joints; 3. Primary necrotizing process, responsible for the (sometimes lethal) destructions in the heart and blood vessels. PMID- 20954305 TI - [The diversity of extended gene haplotypes HLA-B*27 in Croatia]. AB - In the present study the extended haplotypes of HLA-B*27 gene were analysed in the sample of 42 Croatian families. Peripheral blood (2 ml) was collected from all the individuals and genomic DNA was extracted using a commercial kit. The HLA alleles were determined using the method PCR sequence specific primers (PCR-SSP) while the microsatellite alleles were amplified using the method PCR-STR. Analysis of HLA-A-B*27-D6S2927-STR MICA-TNFalpha-DRB1 extended haplotypes demonstrated the strongest linkage disequilibrium between HLA-B*27 alleles and microsatellite alleles D6S2927-1 and STR_MICA-A4. Analysis indicated that the rare allele B*2730 is always present in the extended haplotype HLA-A3-B*2730 D6S2927-1-STR MICA-A4-TNFalpha-9-DRB1*16. The results of the present study will be applied in future studies of association between microsatellite alleles and spondyloarthropathies and contribute to a better understanding of peptide binding to HLA class I molecules, as well as other aspects of immune response. PMID- 20954306 TI - [Renal involvement in patients with rheumatoid arthritis]. AB - In rheumatoid arthritis (RA) kidney is commonly affected organ with clinical presentation characterised by proteinuria (often nephrotic range) and microhematuria followed by chronic renal failure. This condition is well recognized as a rheumatoid nephropathy (rheumatoid glomerulonephritis), which is mediated by an immunological inflammation and by nephrotoxic effects of numerous drugs usually used in rheumatoid arthiritis treatment, such as NSAID, DMARD. In the patohistological examination various kinds of associated renal lesions could be seen. The most often are amyloidosis, glomerulonephritis, interstitial nephritis. In this study, we presented 15 patients, 10 women and 5 men, mean age of 60.2 with average rheumatoid arthritis duration of 19.4 years and signs of rheumatoid nephropathy. In all patients renal biopsy was performed with frequency of histopathological findings as follows: amyloidosis in 5 patients, IgA nephropathy in 3 patients, FSGS in 3 patients, mesangial proliferative glomerulonephritis in 3 patients, minimal change disease, pauci-immune glomerulonephritis and thin membrane disease in 1 patient. In all patients (except patient with thin membrane nephropathy) we started immunossuppresive therapy with glucocorticoids in combination with cyclophosphamide or cyclosporin or azatioprine. In conclusion, in all patients with rheumatoid arthritis, parameters of renal function should be monitored and in the case of patologic results, renal biopsy should be be performed. In the treatment of RA patients with related renal disorder, suspected causal drug should be removed from the treatment and specific immunosuppressive therapy initiated. PMID- 20954307 TI - [Arthritis in paraneoplastic syndrome--a way to early cancer diagnosis? A case report]. AB - Paraneoplastic syndrome is defined by clinical, radiological, and biological features associated with malignant disease without direct tumor invasion. The aim of our study was to present clinical and laboratory features of six cases ofparaneoplastic arthritis, witch can help to establish early cancer diagnosis, and help to distinguish paraneoplastic arthritis from other rheumatic diseases. According to our case analysis, pareneoplastic arthritis has occurred in both sex equally, all patients were older than 45 years, in most of cases it occurred within 14 months before cancer diagnosis, usually in early stage of cancer. Clinical features of paraneoplastic arthritis were: symmetric poliarthritis, usually were affected small hand joints and knees, predominant acute onset, and rheumatic nodes weren't present. Laboratory tests showed: high inflammatory markers (C-reactive protein, and erythrocyte sedimentation level), negative rheumatoid factor, and negative anti-citrullinated protein antibody. X-ray scan did not show signs of joint destruction. Long term remission ofparaneoplastic arthritis was achieved by treatment of cancer. PMID- 20954308 TI - [Capillaroscopy--an insufficiently known and underused method in rheumatology]. AB - Capillaroscopy is a noninvasive and harmless morphological method for examination of the nailfold capillaries in both suspected and already diagnosed patients with systemic connective disease. The most useful aspect is in discrimination between the patients with primary and secondary Raynaud's phenomenon. Many of the mentioned features should make capillaroscopy a part of the diagnostic algorithm and follow-up in everyday rheumatologic practice. PMID- 20954309 TI - [Richard von Volkmann, one career of orthopaedic surgeon and poet]. AB - Richard von Volkman was one of the most famous and important surgeons in the 19th century. He pioneered antiseptic procedures and was especially known for his achivements in orthopedic surgery. Von Volkmann was born in Leipzig, Germany and attended medical schools in Giessen, Halle, and Berlin. Starting in 1867, he worked as a professor of surgery at the University of Halle, also leading its surgical clinic. He was active as a surgeon during Seven Weeks' War with Austria in 1866 and the Franco-Prussian war 1870/1871, in the latter as consulting Generalarzt. He was important in the introduction of antiseptic wound treatment in Germany, and through it to the United States of America. Two observations in orthopaedic surgery bear his name to these days: Volkmans contracture and Heuter Volkmans low. Volkmann also wrote poetry under the name Richard Leander and his book entitled "Dreams by French Firesides" which still has a place in literature. He died of paralysis due to a chronic spinal disease, following a prolonged illness, in the Binswanger institution in Jena in 1889, at the top of his careere. PMID- 20954310 TI - [Pathology and pathobiology of the oesophageal carcinoma]. AB - Carcinoma of the oesophagus including carcinoma of gastro-oesophageal junction are rapidly increasing in incidence. During recent years there have been changes in the knowledge surrounding biology of the disease progression. Identification of dysplasia in mucosal biopsies is the most reliable pathologic indicator of an increased risk of development of squamous cell carcinoma and passes through the sequence of chronic esophagitis, low-grade and high-grade dysplasia and invasive carcinoma. Although Barrett's esophagus is a precursor to esophageal adenocarcinoma and have a well described sequence of carcinogenesis: the Barrett's metaplasia-dysplasia-adenocarcinoma sequence, not all patients with this disorder require intensive surveillance. The natural history of dysplasia is poorly understood, particularly in low-risk regions, and prospective follow-up studies are needed. Adjunctive methods to improve reproducibility, such as immunostaining for alpha-methylacyl-coenzyme A racemase (AMACR), show promise, but require confirmation in larger studies. In addition, several controversial methods such as detection of p16, p53, and DNA content abnormalities may help identify patients at particularly high risk for progression to cancer, but these techniques are not yet widely available for routine clinical application. More studies are needed to define other early nonmorphologic biomarkers for risk of squamous cell carcinoma. Recent evidence regarding the importance of several histopathologically derived prognostic factors, such as circumferential resection margin status and lymph node metastases are evaluated, including lymph node micrometastases and the sentinel node concept. With the rising use of multimodal treatments for oesophageal cancer it is important that the response of the tumour to this therapy can be carefully documented by histopathology. PMID- 20954311 TI - [Incidence of surgical site infection after open heart surgery]. AB - INTRODUCTION: Despite modem surgical techniques, preoperative preventive use of antibiotics and optimal treatment of operative site, surgical site infections (SSI) are significant medical problem in the countries worldwide. OBJECTIVE: The aim of this paper was to estimate the frequency of SSI after open heart surgery and to identify the most frequent causes of these infections. MATERIAL AND METHODS: A prospective cohort study was performed during the period from January 2008 to December 2009 at the Clinic of Cardiovascular Surgery of the Institute of Cardiovascular Diseases, Vojvodina. The surveillance was consistent throughout the study period. During hospitalization, patients were evaluated daily by the infection control nurse. Isolation, identification and sensitivity tests of causative agents to antimicrobial drugs, obtained from patients' material, were carried out by standard microbiological methods. The descriptive epidemio-logical method was used. The incidence rates of hospital infections were calculated. RESULTS: During the study period, among 23 patients, 24 SSIs were registered. The average incidence rate of patients with SSI was 0.98% and SSI rate was 1.02% (ranged from 0% to 3.7%). There was no difference in the incidence rates according to gender (p = 0.65).The mean age of patients with SSI was 64.7 years. Except one, all patients had the ASA score higher than 2. The patients with SSIs were hospitalized approximately 3.8 times longer than the patient without SSI (p = 0.03). The most common causes of SSI were: Staphylococcus aureus (30%), coagulasa-negative Staphylococcus spp, Acinetobacter spp (8%), Enterococcus spp and Klebsiella pneumoniae. CONCLUSION: Although the incidence rate of hospital infections is low, it is necessary to maintain continuous surveillance of surgical site infections and to implement the preventive measures. PMID- 20954312 TI - [Stricture recanalisation of the distal urether with various endoprothesis]. AB - INTRODUCTION: Application of the metallic stents in the interventional uroradioligy is the result of continous development of the new generation methods percutaneous nephrostomy (PCN), ballon catheter dilatation (BCD), methal and covered stent application. Application of metal stents in the renal canal system was attempted in order to eliminate BCD and PCN--related limitations as well as poor therapeutic results of these methods in a number of etiopathogenic groups of urinary stasis. Years--long application of interventional uroradiology methods, until the development of metallic stengts had shown the following therapeutics facts: PCN is incapable to resolve the caus of urinary obstruction. Permanent good therapeutic BCD results mostly depend on pathohistological aspect of the stricture, metallic stents are most frequently the last choice in therapeutics approch to urinary tract obstructions and their application is directly dependent on previous therapeutics results accomplished by PCN and BCD. In therapeutical sequences new generation of covered stents have important place as method of selection in patients of irreversibile uroopstruction of distal ureter. OBJECTIVE: The main goal of this study was to analize therapeutics results, advanteges and shortages of insercion plastics and opened metallic endoprothesis, and to analize results of covered methal applications on the contrary of using older interventional uroradiology methods. METHOD: Sixthytwo patients with distal urether strictures threated in the Deparment of interventional uroradiology Institute od Radiology Clinical centre of Serbia in Belgrade, participated in the study. Results were analized with Person's 2-test, Fisher test and Student T test. RESULTS: In our study we had highly significant differences in comparison with number of patients and type of stents during the time after recanalization was reached. Also it was highly significant differences acorrding the type od used interventional uroradiology method that treated proliferation and the success of recanalization. CONCLUSION: Application of covered temporary uretheral stents have number advanteges against using generation older permanent methal endoprothesis. PMID- 20954313 TI - [Penetrant injuries of colon--our experience]. AB - In attemption to determine the place of primary repair in management of colon injuries, an open, non randomized clinical study was performed. Retrospective (RS) group of 62 patients according to exclusion criteria by Stone (S/F) and Flint (F1) was managed by one or two stage surgical procedure. Prospective (PR) group of 34 patients was managed using one stage repair non-selectively: two stage procedures were performed in 3 cases of advanced peritonitis and multi segmental lacerations with impaired circulation of colon. In RS group 36 patients were managed by primary repair and in PR group, 31 were managed by primary repair. Both groups were of similar age/sex. Indexes of trauma severity were similar (TS, ISS, PATI). The latent time was shorter in PR group. Associated injuries to other body regions and abdominal organs were similar in both groups. S/F criteria and Flint grading in both (RS vs. PR) groups were similar. Comparison of attempted and successful primary repairs justifies the more liberal use of primary repair in early management of colon injuries. PMID- 20954314 TI - [Anesthesiologic care of children with neurologic trauma]. AB - Neurotrauma is a leading cause of childhood mortality. Physicians are in a continuous search for means to decrease mortality and morbidity caused by head injury. Treatment of these patients requires familiarity with both cerebral pathophysiology and actions of anaesthetic agents on brain. Early treatment of hypotension and hypoventilation would cut mortality rate by at least one third. Prevention of increased intracranial pressure is the best treatment for head injury. Anaesthetist, neurosurgeon and radiologist should all be members of a team which can secure timely diagnosis and treatment of an injured child. Paying attention to every detail is of huge significance. Treatment of the child in a pediatric trauma center or an accident and emergencies center for adults with both personnel and equipment capable for handling paediatric patients offers greater probability of survival. PMID- 20954315 TI - [Influence of lymphocitic thyroiditis on prognostic outcome differentiated thyroid carcinoma]. AB - BACKGROUND/AIM: Thyroid carcinoma is rare malignant tumors. They are typically presented with slow progression and clinical course. Lymphocytic infiltration, including fagocytosis of neoplastic cells by macrophage plays an important role in preventing development of distant metastases. This paper sets the following objectives: Establish whether presence or absence of Hashimoto thyroiditis in differentiated thyroid carcinoma (DTC) is a favourable prognostic factor. METHODS: The group under examination here are all newly diagnosed patients with differentiated thyroid carcinoma surgically treated at the Surgery Clinic in Podgorica from 2003. to 2010. A total of 125 patients, aged 11 to 79, were included in this research. The patients were divided in two groups, those with and those without lymphocytic infiltration. Both groups were mutually compared for their prognostic factors. For the identification of T and B lymphocytes, anti CD 3 and anti-CD 20 antibodies were used. Student t-test was used for comparison of clinical and pathological parameters among groups, Hi square test for comparison of frequency, and Coxs regression model for time dependant variables as frequency of recurrence among groups with various stages of disease. Survival curve (Kaplan-Meier) is used for comparison of time dependant variables (survival, recurrence, death). The follow-up time ranges from 10 to 70 months in both groups of patients. RESULTS ARE AS FOLLOWS: presence of lymphocytic infiltration in thyroid tissue in patients with differentiated thyroid carcinoma is significant prognostic factor (P < 0.0001). But, absence of lymphocytic infiltration is a poor prognostic factor in patients with invasive extra thyroid tumours (P < 0.0001). Also, absence of lymphocytic infiltration is a poor prognostic factor for development of lymphogenic and hematogenic metastases. The presence of T or B lymphocytes and varying degree of their presence is not a significant prognostic factor (P < 0.0046). Patients without lymphocytic infiltration are significantly more numerous in the fourth stage of disease (P < 0.0001). There is no statistically significant difference in terms of the presence of T or B lymphocytes in the tissue. Chronic lymphocytic thyroidis hahshimoto is a favourable prognostic factor in our examined group (P < 0.0001). Local invasiveness and extrathyroid expansion is significantly smaller in the group of patients with the presence of lymphocytic infiltration (P < 0.0001). By means of univariate analysis, we found that factors with a significant impact on survival rate include age (P < 0.0001), size of tumour (P < 0.018), extrathyroid invasiveness (P < 0.0001), hematogenic metastases (P < 0.049). Lymphocytic infiltration is present in 81% of patients in their thyroid gland, and in 19% patients there are no lymphocytes in tissue. Limphocitic infiltration has a favourable influence on tumor variables. CONCLUSION. This research has shown that lymphocytes in tissue as part of Hashimoto thzroiditis have an effect on certain prognostic factors of differentiated thyroid carcinoma as size, smaller invasiveness and extrathyroid tumour growth and incidence of hematogenic metastases. PMID- 20954316 TI - [Cystic mesenchimal hamartoma of the liver in two-year-old patient--case report]. AB - Mesenchymal hamartoma is an uncommon benign hepatic tumor arising from the mesenchyme of the portal triad. This lesion is relatively uncommon, representing 5% of all primary hepatic pediatric tumors. This form of hamartoma usually presents before the age of 2 years, typically with abdominal swelling as the initial symptom. The classic management of these lesions has been excision either by hepatic lobectomy or wedge resection. We present a case of 2-year-old girl with a right hepatic lobe tumor, 66 x 57 x 71 in diameter that was completely removed by right hepatic lobectomy. PMID- 20954317 TI - [Therapeutic targets and molecular mechanisms]. PMID- 20954318 TI - [Molecular target therapy in cancer]. AB - Many molecular target drugs have been developed based on the progress in the study of molecular biology. Majority of treatment for common malignancy include molecular target drugs. Patients selection has become possible by pharmacogenomical tests in some molecular target therapy. Development of active molecular target therapy will enable the increment of curative populations even in advanced malignancies. Intensive proof of principle study will open doors for the identification of new molecular targets. PMID- 20954319 TI - [Historical aspect of molecular-targeted therapy for cancer]. AB - Recently, discovery and identification of critical molecules responsible for cancer progression lead to development of specific target-directed therapies, including monoclonal antibodies and small molecular compounds. For the past 15 years, the advent of target-specific therapeutics has remarkably improved the clinical outcomes of certain patients with various malignancies, and it was followed by the understanding of mechanism of the drug resistance. Moreover, useful biomarkers were developed to further increase the power of patient selection for molecular-targeted therapy. From the historical point of view, we review the progress in developing new molecular-targeted drugs for personalized medicine. PMID- 20954320 TI - [Drug discovery sciences in Japan with focus on molecular-targeted drugs]. AB - Since the beginning of 2000, molecular-targeted therapy was introduced mainly in the clinical oncology fields. Based on the results of molecular biological analyses on cancer evolution and progression, various drugs targeting key molecules involved in cancer cell proliferation, invasion and metastasis have been developed and examined. As expected, they showed very sharp effects in the suppression of tumor growth. Simultaneously, they sometimes showed mechanism based adverse effects in particular tissues. In Japan, there have been many promising trials to develop novel molecular-targeted therapy. Application of results of glycobiology for these trials also seems promising. "On-target" side effects and prediction of drug-sensitivity are now urgent issues to be discreetly solved. PMID- 20954321 TI - [Receptor-type tyrosine kinase inhibitors for the treatment of many human diseases]. AB - Since the discovery of several oncogenes encoding growth factor and its specific receptor in the early 1980s, small molecule inhibitors as well as monoclonal antibodies for receptor-type tyrosine kinases have been successfully developed for cancer therapy. Such growth factor signaling is perturbed not only in cancer but also in many human diseases. This article reviews the perspective of tyrosine kinase inhibitors on the clinical use for cancer as well as non-malignant diseases, such as vascular disorders, fibrosis and viral infections involving platelet-derived growth factor(PDGF) signaling. PMID- 20954322 TI - [Cytoplasmic kinase inhibitors]. AB - Protein kinases play essential roles in the regulation of cell proliferation. Point mutations or/and fusions of protein kinases are frequently identified in human cancers, and targeting such activated kinases provides us with a chance to eradicate tumor cells. This was first proved by imatinib mesylate that inhibits ABL tyrosine kinase and, thereby, efficiently kills malignant cells in chronic myeloid leukemia. In addition, other clinical trials are ongoing for kinase inhibitors against EML4--ALK in lung cancer, JAK2 in myeloproliferative disorders and BRAF in malignant melanoma. Early reports indeed reveal that such targeting compounds are promising drugs for human cancers with activated kinases. PMID- 20954323 TI - [Proteasome inhibitors]. AB - The 26S proteasome is a multicatalytic enzyme responsible for degradation of a large fraction of intracellular proteins. Targeting the proteasome activity is a rational and novel strategy for cancer therapy that can lead to cell death for transformed cells. Today, bortezomib, a first-in-class proteasome inhibitor, has established clinical efficacy and an approved clinical indication for the treatment of relapsed and refractory multiple myeloma. Since bortezomib has also shown to induce chemosensitization, the drug is utilized for combination with a variety of chemotherapeutics. In this review, we provide an overview of the current state of the use of bortezomib and second generation proteasome inhibitors. PMID- 20954324 TI - [Anti-angiogenic drugs]. AB - Angiogenesis or neovascularization, the formation of neo-vessels, is a physiological phenomenon endued in vasculature, but is involved in various pathological conditions including cancers and ocular diseases. Angiogenesis is required for tumor growth and metastasis, whereas angiogenesis is the major cause of blindness in the adult. Bevacizumab, a neutralizing anti-VEGF monoclonal antibody, is developed as the first anti-angiogenic drug in 2004. Thereafter, various drugs targeting VEGF-mediated signals have been developed to control tumor angiogenesis. Thus, anti-angiogenic drugs are now recognized in the clinic as a major step forward for the treatment of cancers and ocular diseases. This review focuses on the current status of anti-angiogenesis treatment. PMID- 20954325 TI - [Synthetic ligands for nuclear receptors]. AB - Fat-soluble ligands like steroid hormones serve to activate nuclear receptors. Nuclear receptors are ligand-dependent transcription factors to transcriptionally activate sets of target genes, and such ligand-dependent transcription mediates a number of transcriptional coregulators. Since nuclear receptors form a gene superfamily, their protein structures are divided into several functional domains. The C-terminal ligand binding domain is structurally altered upon ligand binding, and switches interaction of co-transcriptional regulators; from co repressors to co-activators. Likewise, owing to ligand-dependent structure alteration of the entire receptor proteins, the N-terminal domains of receptors become accessible to co-activators. Synthetic agonists/antagonists are potent to induce structural alteration in ligand-type dependent manner, resulting in pharmacological association with transcriptional co-regulators. PMID- 20954326 TI - [Development of anti-inflammatory drugs targeted against prostaglandin-related molecules]. AB - Prostaglandin E2 (PGE2) is a proinflammatory mediator that is synthesized by cyclooxygenases (COX-1 and COX-2) and prostaglandin E synthases (cPGES-1 and mPGES-1); PGE2 exerts its biological effects by binding to specific receptors. Although non-steroidal anti-inflammatory drugs(NSAIDs), which are non-selective COX inhibitors, have been very often used as painkillers, their side effects such as gastrointestinal hemorrhage remain a serious problem. Therefore, the selective COX-2 inhibitors were developed; the use of these inhibitors exerted anti inflammatory effects without the increased risk of gastrointestinal events. Unfortunately, however, several clinical studies demonstrated that the inhibition of COX-2 was associated with the increased risk of cardiovascular events. Consequently, mPGES-1 and PGE2 receptors are currently expected to be attractive targets for anti-inflammatory drug development in order to reduce the side effects. PMID- 20954327 TI - [Targeted therapy by monoclonal antibodies]. AB - Human monoclonal antibodies are virtually indispensable for immunotherapy of cancer, infectious diseases, autoimmune diseases, or organ transplantation. The hybridoma technique, developed by Georges Kohler and Cesar Milstein in 1975, has been shown to be most and highly producible method for generating murine monoclonal antibodies. However, poor results were obtained when it was administered in human bodies. With development of biotechnology, human monoclonal antibodies have been manufactured with higher efficiency. A major hindrance of producing therapeutic human monoclonal antibodies is the lack of an appropriate strategy for determining and selecting the antibodies that would be effective in vivo. In this review, we give an overview of the present techniques on therapeutic monoclonal antibodies. PMID- 20954328 TI - [Molecular targeted therapy in lung cancer]. AB - Lung cancer continues to be the leading cause of cancer death worldwide, and nonsmall cell lung cancer(NSCLC) is the most common type of lung cancer. Despite many clinical trials of platinum-based chemotherapy in combination with various drugs, the median survival time of NSCLC patients remains poor. The overall 5 year survival rate is approximately 15%, and has improved only marginally over the last few decades despite the introduction of new therapeutic agents. A recent milestone in this field has been the development of molecular-targeting drugs, among which gefitinib and erlotinib targeting the epidermal growth factor receptor (EGFR) have improved the efficacy of therapy for NSCLC. Anti angiogenetic drug, such as bevacizumab, had become clinical use in the treatment for NSCLC. Moreover, discovery of EML4-ALK made the marvelous progress in cancer research in NSCLC. In this review, we discuss about the development of molecular targeting drugs, such as EGFR-TKI, anti-angiogenetic drug, and EMLA-ALK inhibitors. PMID- 20954329 TI - [Molecular targeted therapy for breast cancer treatment, challenge to cure]. AB - Clinical outcome of breast cancer patients has been improved by development of molecular target agents such as trastuzumab and lapatinib. However, it is still difficult to "cure" all the patients. In order to improve the results, understanding the mechanisms of action and resistance is crucial. Detection of accurate predictive markers of response to these therapies are also required. Various new drugs and their combinations are being challenged in the (pre)clinical trial along this strategy. In this review, we summarize the current findings in target therapy for breast cancer patients. PMID- 20954330 TI - [Hepatocellular carcinoma]. AB - One of the advances in recent years about the treatment of hepatocellular carcinoma is clinical evidence of the molecular target drug, sorafenib. Although sorafenib shows little anti-tumor effect indicated by tumor shrinkage, it has inhibitory effect of tumor development to be the first drug shown to extend survival in hepatocellular carcinoma. Because its side effects are different than the traditional cytotoxic drugs, to better understand the side effects and its treatment is necessary for sorafenib treatment. More appropriate use of sorafenib is recommended because of serious adverse events or deaths in Japan. Position of sorafenib in the treatment of hepatocellular carcinoma among hepatic arterial infusion chemotherapy and transcatheter arterial embolization is not yet clear. Many clinical trials of molecular target drugs against hepatocellular carcinoma are underway. PMID- 20954331 TI - [Current status and perspectives of biologics in the treatment of metastatic colorectal cancer]. AB - Since the mid 1990s, colorectal cancer treatment has undergone substantial changes and improvements. Combination chemotherapy in first-line treatment of metastatic colorectal disease is the standard of care. Regimens based on either irinotecan or oxaliplatin given with 5-fluorouracil are prevailing. Recently, bevacizumab has become the routine standard addition to FOLFOX in first-line regimens in Japan. This preference is based on the data from NO16966 study, which resulted in a far less substantial improvement in progression free survival and no benefit in response rate. Other clinical trials indicated that the addition of the anti-EGFR monoclonal antibody confers modest benefit to FOLFOX or FOLFIRI. At present, how to combine the available agents and what the ideal combinations should be remain unclear. PMID- 20954332 TI - [Molecular targeted therapy for renal cell carcinoma and other urological cancers]. AB - In Japan, therapeutic strategy for metastatic renal cell carcinoma(RCC) has been markedly changed since the recent introduction of multiple tyrosine kinase inhibitors, including sorafenib and sunitinib, into the clinical practice. In addition to these agents, inhibitors of mTOR(mammalian target of rapamycin) are scheduled to be available in patients with metastatic RCC near future. In this review, we would like to summarize the current status of these molecular targeted agents for the treatment of RCC, and subsequently describe the important issues associated with the administration of these agents, such as the effects on quality of life and the possible use as neoadjuvant setting. Finally, the prospects for the use of molecular targeted agents against urological cancers other than RCC are mentioned. PMID- 20954333 TI - [Molecular targeted therapeutics for leukemia]. AB - Recent molecular biological analyses of leukemia cells have revealed that deregulation of various cellular signaling pathways and deregulation of epigenetic regulation are involved in the development of leukemia. Based on these findings, many kinds of small molecular compounds have been developed to inhibit the function of proteins that are involved in signaling pathways or to modify the epigenetic regulation. These reagents include tyrosine kinase inhibitors, histone deacetylase inhibitors and DNA metyltransferase inhibitors. Furthermore, a monoclonal antibody against CD33 conjugated to an anti-cancer agent is currently being used for AML treatment. Effects of combinations of these reagents have also been examined in detail. These molecular targeted therapies are expected to improve the effectiveness of leukemia therapy. PMID- 20954334 TI - [Molecular target drugs for malignant lymphoma]. AB - According to revised WHO classification for lymphoid malignancies, biological differences among pathological subtypes of lymphomas could be key points for molecular target therapies. For B cell lymphomas, CD20, CD22, CD19 can be molecules for target therapies, whereas there are not so many molecular targets in T cell lymphomas yet. However, novel molecular target drugs are developing from home and abroad. Especially, inhibitors for mTOR, IKK/JAK, HDAC, proteasome, HSP90, and proapoptotic molecules are developing in clinical trials for B cell- and T cell-lymphomas, and their anti-lymphoma activities will be considerably promising. Moreover, immunomodulatory drugs such as lenalidomide are also tried to investigate the effect on lymphomas. Here, some novel molecular drugs currently under development will be reviewed about their anti-lymphoma effects. PMID- 20954335 TI - [Structure-guided molecular-targeting approach for development of AIDS therapeutics]. AB - The development of AIDS therapeutics from the first three dideoxynucleoside reverse transcriptase inhibitors to the most recently approved HIV integrase inhibitor and CCR5 inhibitor employed a structure-guided molecular-targeting approach, which made its swift progress and evolution possible. Indeed, the recent efforts to develop new classes of antiretroviral agents more extensively involve predictive modeling based on crystallography, which has certainly maximized our chances of success. Although we have now faced multiple major problems, which represent the challenges different than those we faced in the development of the first drugs, it is likely that further improved approaches to explore new treatment modalities will enable us to control HIV diseases more efficiently and more PMID- 20954336 TI - [Rheumatoid arthritis]. AB - Etiology of rheumatoid arthritis(RA) has not been clarified, however many candidate molecules for the target of RA treatment have been identified. Among those, regulation of TNF or IL-6 using antibodies or receptor molecules has brought a paradigm shift in the therapeutic strategy of RA and has become a standard therapy in daily practice. Many targeted therapy are now in the development for the treatment of RA, however, those target molecules are deeply involved in the immune function, and inhibition of these molecules may increase the susceptibility for infections. Also, using these expensive drugs for this chronic disease raises a pharmacoeconomical issue. There are many issues remaining to be solved. PMID- 20954337 TI - [Incretin related drugs]. AB - Incretin, GIP and GLP-1, are blood glucose lowering hormones secreted from K cells and L cells, and are rapidly degenerated by DPP-4 within a few minutes. Recently incretin related drugs, GLP-1 analogs and DPP-4 inhibitors are developed. GLP-1 analogs have amino acid substitutions, which make the GLP-1 peptide resistant to degeneration by DPP-4, while DPP-4 inhibitors prevent endogenous GLP-1 to be degenerated by DPP-4. Since they exert blood glucose lowering effect only when blood glucose levels are high, hypoglycemia rarely occurs when administrated without other anti-diabetic drugs. Incretin related drugs are expected to be a new strategy for treating type 2 diabetes. PMID- 20954338 TI - [Molecular targeted therapy in Alzheimer disease]. AB - Alzheimer disease(AD) is the most common cause of dementia in the elderly. However, the availability of effective disease-modifying drugs for AD is currently limited. Thus, with the aging of the population, the mechanism-based therapeutics for AD is desperately needed. This article will discuss the recent advances of the development of drugs based on "amyloid hypothesis", and the results of clinical trials. The inhibitors or modulators targeting beta- and gamma-secretases that are responsible enzymes for the generation of amyloid-beta peptide(Abeta) deposited in the Abeta brain, or Abeta immunotherapy using anti Abeta antibodies, are promising candidates. Finally potential mechanism-based adverse effects of these treatments and the strategies to tackle these problems will be discussed. PMID- 20954339 TI - [Molecular target drug for hypertension and cardiovascular disease]. AB - Cardiovascular disease or hypertension is caused by genetic abnormalities and/or environment factors. Molecular biological and biochemical analyses have demonstrated the cardiovascular disease or hypertension is related to increased gene products such as vasoactive peptide, activated signal transduction pathways, and cell surface antigen, etc. Molecular target drugs have been designed to suppress these molecules via receptor, signal transduction pathways, or mRNA. Differing from conventional drug, molecular target drugs show higher specificity for pathophysiology in cardiovascular disease or hypertension. Although term of 'molecular target drug' is not used frequently in the field of cardiovascular or hypertension, I describe in this review, angiotensin receptor blocker, endothelin receptor blocker and statin, because these three drugs are indispensable to treat these diseases in the present clinical setting. PMID- 20954340 TI - [Personalized medicine and molecular targets of drugs]. AB - Progress in genomics has increased the understanding of molecular basis underlying many diseases, which has led to development of molecular targeted drugs and personalized medicine. The incorporation of several targeted drugs and the response biomarker into practice has remarkably improved patient outcomes in several diseases, and FDA has validated possible biomarkers and is using corresponding FDA-approved drug labels with 3 recommendation levels of testing, "required", "recommended", and "information only". The day of practical pharmacogenomics for the bedside has probably arrived. Even so, the results of drug development and its individualization have been rather disappointing on the whole. The contribution of genomic marker research and molecular targeted therapies to practical medicine and the problems of the day were reviewed. PMID- 20954341 TI - [Pharmacoeconomics of molecular target drugs in Japan]. AB - Various molecular target drugs are developed in recent era in Japan, especially for treatment of cancer, rheumatoid arthritis and other diseases. Although they are much more effective compared to previous drugs, their costs are much more expensive. Thus, pharmacoeconomic analysis in which we evaluate their efficiency, would be highly needed. When we take pharmacoeconomic analyses, we need to assess both costs and health outcomes. In addition, we must compare cost-effectiveness of new interventions and control. To estimate costs of each intervention, not only direct medical costs, but direct non-medical costs (e.g. transportation costs, caregiving costs, house--modification costs) and indirect costs, or productivity losses should be separately calculated and presented. To evaluate efficiencies of anti-rheumatoid biologic agent in Japan, we started to collaborate with large-scale cohort of patient with rheumatoid arthritis in Japan, IORRA cohort in Tokyo Women's Medical University. With this data, we are taking various pharmacoeconomic analysis. PMID- 20954342 TI - [Unique adverse effects of molecular targeted drugs]. AB - Molecular targeted drugs have been developed to act principally on specific molecules expressed on either cancer cells or normal surrounding cells in cancerous tissues. Ideally, expressions of these targeted molecules are markedly increased in cancerous tissues as compared with normal tissue. This class of drugs has been expected to have superior antitumor effects without any toxicities. Over the last decade, however, the introduction of molecular targeted drugs into clinical setting revealed unexpected, occasionally lethal, "off targeted" adverse effects which were different from the toxic profiles of cytotoxic drugs. In this review, the adverse effects of molecular targeted drugs, the managements of these toxicities and the molecular mechanism underlying of these toxicities are reviewed. PMID- 20954343 TI - [Possible relation between clinical guidelines and legal standard of medicine]. AB - Legal standard of medicine is not equal across the all kinds of medical institutions. Each medical institution is required its respective standard of medicine in which its doctors are expected to have studied medical informations, which have been spread among medical institutions with similar characteristics. Therefore, in principle, clinical guidelines for the treatment of a disease formed by public committees do not directly become the medical standards of respective disease treatment. However, doctors would be legally required to practice medicine with reference to the clinical guidelines because medical informations, mediated by internet or many kinds of media, have been spread very fast to all medical institutions these days. Moreover, doctors would be required to inform their patients of non-standardized new treatments, even if such treatments are not listed in clinical guidelines in case patients have special concern about new treat- PMID- 20954344 TI - [Screening for prostate cancer]. AB - The exposure rate of screening for prostate cancer in Japan is still very low and many clinically significant cancer cases may be missed until developing clinically advanced disease. The most recent paper from the European Randomized Study of Screening for Prostate Cancer (ERSPC) confirmed that introduction of population-based screening for prostate cancer could lead decrease in the mortality rate of prostate cancer. Establishing an optimal screening system, which minimizes underdetection, undertreatment, overdetection, overtreatment, loss of QOL due to treatment would make PSA screening be more useful. It is very important to provide PSA-based screening in Japan using the fact sheets provided by the Japanese Urological Association. PMID- 20954345 TI - [Surgical treatment for recurrent pulmonary carcinoma including same and different cell types]. AB - There are many problems regarding diagnosis of the next lung cancer as local recurrence, metastasis or 2nd primary and there is a limit to only morphologic findings. It may be necessary to examine oncogene abnormalities for example p53 mutation. From the above-mentioned facts, this study distinguished the recurrent resected lung tumors between same (As: n = 19) and different (Ah: n = 8) cell types from the 1st lung cancer. These 2 groups were compared each other and with group B, which was treated to recurrent lung cancer only with chemotherapy and/or radiation, and group C, which was not treated. On 5-year survival after the 1st operation, group As was 78.9%, group Ah was 75.0%, group B was 15.0%, group C was 0%. On 5-year survival after the 2nd operation, group As was 21.1%, group Ah was 42.9%. There were long intervals between the 1st and the 2nd operations (overall mean 56.1+/- 45.6 month, max 190 month), therefore we must follow up on patients undergone resection of lung cancer at the long-term periods. Recent amelioration of chemotherapy and radiotherapy can keep patients with recurrent lung cancer survive by over 5 years. It is important not only to perform an aggressive 2nd operation for recurrent lung cancer but also to estimate post-2nd-operative lung function for selection of operative procedure and to prefer multidisciplinary treatment. PMID- 20954346 TI - [Surgical treatment and outcome for postoperative recurrent or second primary lung cancer]. AB - From 2000 to 2009, we retrospectively reviewed 62 patients who underwent surgical treatment for postoperative recurrent or 2nd primary lung cancer. Of the 62 patients, 43 were men and 19 were women with an average age of 67.6 years old. The histology of the initial primary lung cancer was adenocarcinoma in 42 patients, squamous cell carcinoma in 18, large cell carcinoma in 1 and small cell carcinoma in 1. The surgical procedures for 1st operation were lobectomy with mediastinal lymph node dissection in 52, bilobectomy with mediastinal lymph node dissection in 4, sleeve lobectomy with mediastinal lymph node dissection in 3, and lobectomy + segmentectomy or wedge resection with mediastinal lymph node dissection in 3. p-stage of the 1st primary lung cancer was IA in 22, IB in 16, II A in 7, IIB in 6, IIIA in 6, IIIB in 4, and IV in 1. On the 2nd operation, 56 patients underwent limited surgery. Five patients underwent a lobectomy twice metachronous bilateral lesions and 1 patient underwent completion pneumonectomy (CP) at the 2nd operation. The average age at 2nd operation was 71.8 years old. Of these, 42 patients were diagnosed 2nd primary lung cancer, 20 patients were recurrent disease histologically. The 5-year survival rate of the patients with metachronous and recurrent disease from the 2nd operation was 54.1%, and 43.1%, respectively. Although lobectomy or CP should be considered the surgical procedure of choice for patients with metachronous lung cancer, with this result, we consider that postoperative good survival can be expected by even the limited operation for cases of postoperative recurrent or 2nd primary lung cancer because of possible early detection. We conclude that limited surgery may be a treatment of choice for recurrent or 2nd primary lung cancer after initial operation. PMID- 20954347 TI - [Surgical results for second primary lung cancer]. AB - Of 897 patients who underwent operation for lung cancer between April 1996 and March 2010, 57 patients underwent pulmonary resection for 2nd primary lung cancer. There were 44 men and 13 women. The average age at the 2nd operation was 71. The initial pulmonary resection was lobectomy in 49 patients, segmentectomy in 4 and wedge resection in 4. The 2nd pulmonary resection was lobectomy in 10 patients, segmentectomy in 12 and wedge resection in 35. Preoperative stage of the 2nd primary lung cancer was IA in 43, IB in 13 and IIB in 1. Postoperative stage was IA in 38, IB in 10, IIA in 1, IIB in 3, IIIA in 2 and IIIB in 3. Surgical complications occurred in 4, but there were no perioperative deaths. The 5-year survival rate for 2nd primary lung cancers was 59.9%. The 5-year survival rate for patients treated with wedge resection was 71.1%. The 5-year survival rate of the patients with p-stage IA was 72.7%, and that for patients with p stage IB or more advanced diseases was 32.9%. We conclude that an aggressive surgical approach for a 2nd primary lung cancer is effective and is linked with good outcome if the tumor is detected at stage IA, when the possible cure by performing wedge resection is promissing. PMID- 20954348 TI - [Surgical treatment for recurrent and second primary lung cancer]. AB - We analyzed 39 patients who underwent a 2nd resection for recurrent (solitary pulmonary metastasis) or 2nd primary lung cancer. Based on the pathological findings, 18 patients were diagnosed as recurrent lung cancer, and 21 patients were diagnosed as 2nd primary lung cancer. Overall 5-year survival was 69.4%. There are no difference between recurrent group and 2nd primary group. It is difficult to distinguish preoperatively between recurrent lung cancer and 2nd primary lung cancer, so we must be consider the 2nd resection as a curative resection for "2nd primary lung cancer". PMID- 20954349 TI - [Surgical treatment for metachronous lung cancer]. AB - We performed a retrospective review of 45 consecutive patients with metachronous multiple primary lung cancer who underwent resection between 1990 and 2009. Surgical treatment of the 1st tumor consisted of 39 lobectomies and 3 segmentectomies, and 3 wedge resections. The 2nd tumor was removed by means of a lobectomy in 9 patients, a segmentectomy in 17 patients, a wedge resection in 19 patients. No postoperative mortality was observed. Histologic classification was similar in 86.4% of patients and different in 13.6%. Postoperative stage of the 2nd tumor was IA in 31 patients, IB in 7, IIA in 1, IIIA in 3, IIIB in 3. Median follow-up was 48.4 months after 2nd operation. The 5-year survival rate was 90.8% after 1st operation and 85.6% after 2nd operation. The 5-year survival rate in patients with p-stage IA was 96.4%. Patients with metachronous lung cancer could have a favorable outcome. Thus we need careful follow-up of the patients after treatment on the 1st lung cancer, and moreover an aggressive surgical treatment is recommended as long as their performance state or residual pulmonary function allows. PMID- 20954350 TI - [Therapeutic strategy for secondary lung cancer]. AB - Among 659 resected lung cancer cases from 1994 to 2009, 57 secondary lung cancers (8.6%) were evaluated. The secondary tumors were synchronous, located in the same lobe in 10, the ipsilateral different lobe in 17, and the contralateral lobe in 13, or metachronous, located in the contralateral lobe in 15, and the ipsilateral different lobe in 5. Both the tumors were removed in 49 cases. Chemotherapy, stereotactic radiotherapy (SRT), photo dynamic therapy (PDT), or best supportive care (BSC) was selected after a lobectomy or segmentectomy of the 1st tumor in 8 cases considering the patient's condition. Lobectomy or segmentectomy should be indicated for the 1st tumor considering curability. Bilobectomy is adopted for multiple cancers involving middle lobe. According to the operability or pulmonary function, the same strategy is adopted for secondary cancer. Considering the patient's condition, possibility of metastases and the tumor location and histologic type, partial resection, SRT, PDT, or BSC could be selected. PMID- 20954351 TI - [Iterative surgical resections for second primary and local recurrent lung cancer; comparison of lobectomy and limited resection]. AB - During a 24-year period (1986-2009), 74 patients (3.5%) underwent iterative surgical resections for 2nd primary and recurrent lung cancer. Patients are classified to 5 groups: 20 2nd primary lung cancer patients undergoing lobectomy (A), 24 2nd primary lung cancer patients undergoing limited resection (B), 11 2nd primary bronchioloalveolar carcinoma (BAC) patients undergoing limited resection (C), 8 recurrent lung cancer patients undergoing lobectomy (D), and 11 recurrent lung cancer patients undergoing limited resection (E). There were 13 (65%) patients with pathological stage IA in group A, 20 (83%) in B, 11 (100%) in C, 2 (25%) in D, and 8 (73%) in E. There were 18 (90%) patients with adenocarcinoma in group A, 15 (63%) in B, 11 (100%) in C, 5 (63%) in D, and 9 (82%) in E. Overall hospital mortality was 5%, including 3 deaths in A and 1 death in D. Five-year and 10-year survival after the 2nd surgery was 55% and 55% in A, 63% and 50% in B, 100% and 100% in C, 57% and 37% in D, and 70% and 53% in E. These data showed that limited resections had low surgical risk and good long-term results. Limited resection appears to achieve better outcomes for 2nd primary and recurrent lung cancer and should be chosen whenever possible. PMID- 20954352 TI - [Video-assisted thoracic surgery for metachronous lung cancer]. AB - Of 1,391 patients who underwent operation for primary lung cancer between 2000 and 2009, 50 patients (3.6%) had a past history of pulmonary resection for lung cancer. Three patients underwent completion pneumonectomy by thoracotomy and in the other 47 patients video-assisted thoracic surgery (VATS) was performed. We considered 42 cases (3 of completion pneumonectomy and 39 of VATS) to be metachronous lung cancer and 8 cases of VATS to be recurrence by detailed histologic assessment. We examined 39 cases of metachronous lung cancer resected by VATS. The patients were aged 68 +/- 8 years and 4 patients were aged 80-years or more. The surgical procedures performed were lobectomy in 4 patients, segmentectomy in 3, and wedge resection in 40. The operation time was 121 +/- 66 minutes and the blood loss was 67 +/- 140 ml. There were no major complications. We registered 6 deaths during follow-up; 3 were due to disease progression and 3 were due to other causes. The survival rate of the 42 patients including 3 patients who underwent completion pneumonectomy was 74.9% at 5 years. Early detection of metachronous lung cancer and surgical resection offers a favorable prognosis. PMID- 20954353 TI - [Thoracoscopic subsegmental and segmental resection for postoperative local recurrence of lung cancer based on the three-dimensional structure after lung resection]. AB - After lung cancer surgery, because chest computed tomography (CT) examinations are conducted frequently, recurrent cancer is often discovered at an early stage. In postoperative cases, because the lung volume has already decreased, radical limited surgery is therefore required. Before performing lung resection, we create a three-dimensional image of the lung, using CTTRY, on a personal computer and conduct a simulation of the resection range before moving on to surgery and accurately and smoothly performing thoracoscopic segmental and subsegmental resection. In the past 2 years, we have treated 5 cases of ipsilateral cancer and surgery for recurrence using this surgical technique. This case was a 66-year-old female. Right lower lobectomy was performed to treat primary squamous cell carcinoma of the lung. Recurrence was observed in CT examinations during the follow-up, and right S2 segmentectomy was performed. For performing radical limited surgery for recurrent lung cancer, avoiding completion pneumonectomy, it is therefore very useful to review the surgical procedures using CTTRY. PMID- 20954354 TI - [Use of cyber library and digital tools are crucial for academic surgeons]. AB - In addition to busy clinical work, an academic surgeon has to spend a lot of time and efforts in writing and submitting articles to scientific journals, teaching young surgical trainees to write an article, organizing and updating his/her academic performances in the curriculum vitae, and writing research grant applications. The use of cyber library and commercially available computer software is useful in saving time and effort. PMID- 20954355 TI - [Clinical experience with intravenous administration of nifekalant hydrochloride for ventricular tachycardia in a hemodialysis patient after open heart surgery]. AB - A 78-year-old man with chronic renal failure (CRF) on hemodialysis (HD) was diagnosed as having severe aortic regurgitation with left ventricular dysfunction. Aortic valve replacement with a 21 mm ATS mechanical bileaflet prosthesis was performed without intraoperative complications. Sustained ventricular tachycardia suddenly occurred 1 day after surgery, then intravenous administration of nifekalant hydrochloride (NIF) was started at a dose of 0.40 mg/kg/hr. Life-threating ventricular arrhythmia was controlled, hemodynamic compromise was improved dramatically. NIF was regulated with a low-dose of 0.24 mg/kg/hr to prevent malignant side effect such as torsa de pointes. Since QTc was elongated to 0.57 seconds 11 hours after administration, NIF was stopped. Low dose intravenous administration of NIF in patients with CRF on HD could be useful to prevent ventricular tachyarrhythmias without any adverse effect after cardiac surgery. PMID- 20954356 TI - [Evaluation of a new method of pericardial drainage after cardiac surgery]. AB - Recently pericardial drainage after cardiac surgery has been done using silicon tubes of small diameter. For more effective drainage, we set one of the drainage tubes circularly, coursing behind the left ventricle, through the transverse sinus, and ending at the right side of the atrium (circular pericardial drainage). As compared to conventional drainage using 28 Fr chloroethilene tubes, drainage time was shorter and no late tamponade had occurred. Circular pericardial drainage may be useful. PMID- 20954357 TI - [Surgical treatment with the rifampicin-soaked vascular prosthesis for mycotic pseudoaneurysm after aortic root replacement]. AB - A 59-year-old man had undergone aortic root replacement for annuloaortic ectasia (AAE) and aortic regurgitation (AR) 18 years before. The computed tomography (CT) showed a pseudoaneurysm of ascending aorta 4 years after the 1st operation. Re aortic root replacement was done 15 years after the 1st operation because of the pseudoaneurysm. However, 3 years after the 2nd operation, the patient suffered from fever and another pseudoaneurysm was revealed by CT. Echocardiography showed a vegetation attached to the aortic valve. The 3rd operation was successfully performed using rifampicin-soaked vascular prosthesis. The postoperative course was uneventful. Thus, graft infection was effectively treated with a rifampicin soaked vascular prosthesis. PMID- 20954358 TI - [Surgical treatment of carcinoid heart disease]. AB - A 70-year-old female with severe tricuspid regurgitation and stenosis was admitted to our institution because of watery diarrhea and peripheral edema. The urinary 5-hydroxyindoleacetic acid (5-HIAA) level was 292.9 mg/l (normal, 0.5-5.0 mg/l). Abdominal computed tomography showed enhanced multiple nodules in the liver. The liver biopsy revealed metastatic carcinoid disease, which was thought as an etiology in severe tricuspid regurgitation and stenosis. We administered long acting somatostatin analog, octreotide to control carcinoid symptoms. After improvement of general condition, she successfully underwent bioprosthetic valve replacement with concomitant octreotide administration. Postoperative course was uneventful. She had been followed up with administration of octreotide at outpatient clinic. Cardiac surgery for carcinoid heart disease is complicated by hemodynamic instability secondary to carcinoid crises which can be provoked pharmacologically by administration of vasoactive medications. Octreotide is an effective tool to manage manifestation of carcinoid activity. We could performed surgical treatment of carcinoid heart disease safely in the perioperative presence of octreotide. PMID- 20954359 TI - [Simultaneous endovascular aortic aneurysm repair and coronary artery bypass grafting in a patient with abdominal aortic aneurysm and left main trunk lesion]. AB - To patients with severe coronary artery disease (CAD) and expanding large abdominal aortic aneurysm (AAA), simultaneous coronary artery bypass grafting (CABG) and AAA repair has been recommended. A 68-year-old woman had a CAD and an AAA 71 mm in diameter which was enlarging. Coronary angiography showed severe stenoses in the left main trunk (LMT), the left anterior descending artery and the circumflex artery. On-pump beating CABG and AAA repair with endovascular aneurysm repair (EVAR) were performed simultaneously, because intraaortic balloon pumping (IABP) might be needed due to severe stenoses of LMT. Just after EAVR, on pump beating CABG was performed. The patient was discharged 15 days after the operation. It was suggested that a simultaneous operation of CABG and EVAR might be safe and effective for high risk patients with CAD and AAA. PMID- 20954360 TI - [Infected left atrial myxoma; report of a case]. AB - We report a rare case of infected left atrial myxoma. A 69-year-old male was admitted to our hospital due to cerebral infarction accompanied by lower limb ischemia. Transesophageal echocardiography showed a mobile left atrial tumor. On the 16th hospital day, he sufferd from high fever and Klebsiella pneumoniae was positive by blood culture. We excised the left atrial tumor, preventing systemic embolism and progression of sepsis. Histological examination showed a typical myxoma and organized thrombus with Gram-positive bacterial colonies, which disagreed with those in blood culture. After he recovered from sepsis, the 3rd toe of the right foot was amputated and then right femoro-popliteal bypass was done because of failure of wound healing. He was discharged from the hospital on the 74th postoperative day in good condition. PMID- 20954361 TI - [Somatic symptoms in those hospitalized for dizziness or vertigo]. AB - Anxiety and depression greatly affect the prognosis of and burden on subjects seen for dizziness or vertigo, who usually report multiple somatic symptoms. We studied the prevalence of these symptoms in 145 subjects hospitalized for dizziness or vertigo and taking part in 4-day group vestibular rehabilitation. Questionnaires given to determine the prevalence of somatic symptoms assessed headache, insomnia, diarrhea, constipation, stomachache, chest pain, palpitations, dyspnea, general fatigue, and stress. Quantitation used aerical rating scale (NRS). Anxiety and depression were assessed using the hospital anxiety and depression scale (HADS). Disability due to dizziness was assessed using the dizziness handicap inventory (DHI). We conducted correlational analysis between dizziness and somatic symptoms. The top four average NRS scores for somatic symptoms were dizziness at 3.5 +/- 2.8, general fatigue at 2.8 +/- 2.6, insomnia at 2.4 +/- 2.6, and headache at 1.8 +/- 2.3. These symptoms resembled those reported for subjects with anxiety and depression. The correlation between headache and dizziness NRS scores was R = 0.48 (P < 0.0001). The total HADS score was 13.9 +/- 8.1 points (anxiety 7.2 +/- 4.3, depression 6.7 +/- 4.3). The average DHI score was 36.3 +/- 24.1 points. These results indicate that those with dizziness reported several somatic symptoms related to anxiety and depression attributable to dizziness. This underscores the need to treat these somatic symptoms when treating subjects seen chiefly dizziness or vertigo. PMID- 20954362 TI - [Clinical usefulness of smell identification test card: Open Essence]. AB - Since the Odor Stick Identification Test for Japanese (OSIT-J) has proved clinically useful in Japan, the Open Essence (OE) smell identification test card has been developed to amend OSIT-J deficits. To determine its clinical effectiveness, we administered the OE to 93 Japanese subjects reporting olfactory dysfunction. They scored their olfactory dysfunction on levels one to five, i.e., normal to anosmic, using the Japan Rhinologic Society Self-Administered Odor Questionnaire (SAOQ) and the visual analog scale (VAS). They also took the Japanese standard olfactory test (T & T olfactometry) and intravenous olfactometry (Alinamin test). Opinions on the OE and OSIT-J were recorded from those previously administered the OSIT-J and testers familiar with OSIT-J administration. The OE took 5.1+/- 1.6 minutes to administer. Scores correlated significantly for the OE, self-reported olfactory function, SAOQ, VAS, T & T olfactometry recognition threshold, and Alinamin latency and duration time. Subjects and testers reported the OE to be easier, shorter, more interesting, and more convenient, indicating its utility in clinical olfactory dysfunction evaluation and its convenience for both subjects and testers. PMID- 20954363 TI - [Primary syphilis with initial lower-lip sclerosis--a case report]. AB - We report a case of primary syphilis with initial lower-lip sclerosis. 54-year old man seen for a left lower-lip lesion was found in serological testing to have elevated syphilis-rapid plasma regain (STS-RPR) and treponema pallidum lipid antigen (TPLA), diagnosed as primary syphilis. Following four weeks of 1500 mg/day amoxicillin administration, the lesion had almost disappeared. Serological data had improved to within the negative range six months after antibiotic treatment started. This case underscores the need to recognize syphilis of the lip even in the outpatient setting. PMID- 20954364 TI - [Relationship between chronic obstructive pulmonary disease and gastroesophageal reflux disease defined by the Frequency Scale for the Symptoms of gastroesophageal reflux disease]. AB - Little is known about gastroesophageal reflux disease (GERD) in chronic obstructive pulmonary disease (COPD) patients. The aim of this study was to investigate the prevalence, clinical characteristics and risk factors for GERD in COPD patients, based on the Frequency Scale for the Symptoms of GERD (FSSG). In 228 COPD patients, the prevalence of GERD was 26.7%, independent of COPD stage. Logistic regression multivariate analysis revealed significant risk factors for accompanying GERD were age (p = 0.009; odds ratio (OR), 0.933; 95% confidence interval (CI) 0.885 to 0.983) and number of COPD exacerbation within one year (p = 0.043; OR, 1.675; 95% CI, 1.075 to 2.764). The risk factors of COPD exacerbation were total FSSG score (p = 0.031; OR, 1.079; 95% CI, 1.007 to 1.156) and inhaled corticosteroid use (p = 0.003; OR, 3.238; 95% CI, 1.482 to 7.076). Moreover, the Spearman rank correlation test showed that FSSG score was weakly but significantly correlated with the number of COPD exacerbations (rs = 0.317, p < 0.001). In conclusion, the incidence of GERD in COPD patients is high, and the incidence of GERD is closely related to COPD exacerbation. PMID- 20954365 TI - [Experimental inhalation therapy with nebulized tiotropium in COPD patients unable to use the Handihaler]. AB - BACKGROUND: We report the efficacy and safety of experimentally nebulized tiotropium use. We identified 19 elderly very severe COPD (GOLD stage IV) inpatients unable to use tiotropium in the Handihaler by themselves from January 2008 through May 2009. The contents of an 18 microg capsule of tiotropium were dissolved in 5 ml saline and nebulized via a nebulizer. RESULTS: Nebulized tiotropium improved the symptoms of all COPD patients, and the ADL scores of 12 COPD patients. All COPD patients tolerated nebulized tiotropium well, although mild dry mouth was reported by a single COPD patient. CONCLUSION: Tiotropium therapy for COPD patients is recommended in all GOLD stages. Our report showed that COPD patients (GOLD stage IV) who had difficulties using a tiotropium Handihaler benefitted from nebulized tiotropium. This helped them to continue their COPD therapy and was demonstrated to be an effective and well tolerated treatment option. PMID- 20954366 TI - [Usefulness of serum procalcitonin measurement in the diagnosis of respiratory infectious diseases]. AB - The serum concentration of procalcitonin (PCT) is specifically elevated in severe bacterial infections. In Japan, PCT has been used as a serum marker for bacterial sepsis since February, 2006. However, the evidence of it in respiratory infectious diseases is limited. In the present study, we analyzed 57 episodes of systemic inflammatory response syndrome in 53 inpatients to investigate the usefulness of serum PCT measurement in respiratory infectious diseases. Although the sensitivity and a negative predictive value in common bacterial infections were low, the specificity and positive predictive value were 95% and 93%, respectively. This suggests that the significance of serum PCT measurement relies on confirming the diagnosis of common bacterial infections. Analysis using a receiver operating characteristic (ROC) curve demonstrated that serum PCT was a more reliable measure of bacterial sepsis than leukocyte counts in the peripheral blood or serum C-reactive protein. In cases of community-acquired pneumonia, except atypical pneumonia, the hospital mortality rate was significantly higher in PCT-positive patients than in PCT-negative patients (38% vs. 0%), indicating that serum PCT could be a factor predicting in-hospital death. PMID- 20954367 TI - [Analysis of blood cultures in patients presenting with community-acquired pneumonia at the emergency room]. AB - We retrospectively analyzed the clinical and laboratory features of 111 patients with community-acquired pneumonia (CAP) who required hospitalization. Blood culture was positive in 22, and negative in 89 subjects. We compared positive and negative groups in terms of background, physical exam findings, laboratory data, radiographic data, severity, and clinical outcome. Univariate analysis showed significant differences in heart rate, changes in consciousness, (PaO2/FiO2), C reactive protein (CRP), and infiltration on chest x-ray films. The clinical outcome was poorer in the positive group. Multivariate analysis identified CRP and infiltration as predictors of bacteremia. According to the receiver operating characteristic (ROC) curve, CRP had moderate accuracy (AUC = 0.83 [95% confidence interval (CI) 0.60-0.88]), and diagnostic accuracy was optimal when the CRP cut off point was 16.3 mg/dl. Fifty-seven patients, who showed mild to moderate severity according to A-DROP system and had CRP levels less than 16.3 mg/dl, were less likely to have positive blood cultures. In addition, initial administration of antibiotics was effective in each of the 57 bacteremic patients. Therefore, blood culture need not be performed in such cases. PMID- 20954368 TI - [A case of squamous cell lung carcinoma with gastric metastasis diagnosed by gastroendoscopic biopsy]. AB - A 59-year-old man was referred to our hospital due to of a right pulmonary hilar mass shadow found on a chest X-ray film in October 2008. Bronchoscopy and transbronchial biopsy at that time revealed squamous cell carcinoma. The clinical stage was IIIB (T4N2M0). He was readmitted 2 months later because of appetite loss and severe anemia. An abdominal CT scan showed thickening of the stomach wall. Gastroendoscopy showed a submucosal tumor with central depression in the middle body of the stomach. We histologically confirmed that the gastric lesion was metastasis from the squamous cell lung carcinoma. Here we report a rare case of squamous cell lung carcinoma with gastric metastasis diagnosed by gastroendoscopic biopsy while the patient was alive. PMID- 20954369 TI - [A case of diffuse alveolar hemorrhage occurring during the course of rheumatoid arthritis]. AB - A 70-year-old woman, who underwent treatment with prednisolone and methotrexate for rheumatoid arthritis, was admitted to our hospital due to rapidly progressive dyspnea. A chest CT scan showed diffuse ground-glass opacities and reticulonodular shadows in both lungs. Intubation was performed due to severe hypoxia. The color of the bronchoalveolar lavage, using three sequential aliquots, became progressively more reddish, suggesting alveolar hemorrhage. Based on this, we made a diagnosis of diffuse alveolar hemorrhage. To the best of our knowledge, few studies have reported cases of diffuse alveolar hemorrhage associated with rheumatoid arthritis as an underlying disease. We consider that diffuse alveolar hemorrhage may occur as a complication of rheumatoid arthritis. PMID- 20954370 TI - [Spontaneous regression of mucosa-associated lymphoid tissue lymphoma of the lung]. AB - We report a case of mucosa-associated lymphoid tissue (MALT) lymphoma of the lung that regressed spontaneously. An 82-year-old man was referred to our hospital because of an abnormal chest shadow. Chest CT scans showed soft tissue components along the periphery of the left main bronchus. Bronchoscopy showed an edematous and protruding lesion. Pathological findings showed diffuse invasion of small lymphoid cells of B-cell origin in the submucosal layers. These cells formed lymphoepithelial lesions. Southern blot hybridization demonstrated monoclonality and immunoglobulin heavy-chain gene rearrangement. We diagnosed MALT lymphoma of the lung. Spontaneous regression was found clinically 16 days after the first tumor biopsy for diagnosis by bronchoscopy. Autofluorescence imaging (AFI) 8 months after the first biopsy showed a decrease in magenta color. Immunohistochemical staining showed marked decrease in CD20 + B cells and an increase in the proportion of T cells, the majority of which were CD4 + T cells. No relapse of these lesions was detected 20 months after the first visit. It may be possible to closely follow up pulmonary MALT lymphoma without immediate treatment. PMID- 20954371 TI - [A case of disseminated actinomycosis which extended from the thoracic cavity]. AB - A 74-year-old man was referred to our hospital with a high grade fever, a left abdominal tumor and bloody sputum since the beginning of April 2006. We made an incision of the abdominal tumor, and the Gram-stain smear demonstrated Gram positive rods. Actinomycosis was diagnosed because tissue culture demonstrated Actinomyces israelii. Penicillin was administered, and his clinical features improved. It is difficult to distinguish actinomycosis from malignancy or tuberculosis, therefore actinomycosis should be considered in the differential diagnosis of a mass shadow, and it can be cured with penicillin. PMID- 20954372 TI - [Two patients with novel influenza A virus (H1N1) pneumonia treated with steroid therapy after an incorrect diagnosis of rapid progressive interstitial pneumonia due to the negative results of a rapid-antigen test]. AB - We encountered 2 patients with novel influenza A (H1N1) pneumonia initially treated with steroid therapy after an incorrect diagnosis of cryptogenic organizing pneumonia and acute interstitial pneumonia, made because of atypical radiological findings and negative rapid antigen test results. After the patients were discharged, we performed reverse-transcriptase polymerase chain reaction tests for the presence of novel influenza A (H1N1); the results were positive, and we established the correct diagnosis of infection by novel influenza A (H1N1) virus pneumonia. Diagnostic clues included radiological findings similar to those of previously reported cases of novel influenza A (H1N1) virus pneumonia and an increase in similar cases due to the novel influenza A (H1N1) pandemic, suggesting that these 2 patients were also suffering from it. Similar cases of inappropriate treatment resulting from an initially incorrect diagnosis of cryptogenic organizing pneumonia or acute interstitial pneumonia may occur, and greater attention should be paid to accurate diagnosis. PMID- 20954373 TI - [A case of pulmonary Mycobacterium abscessus disease complicated with esophago pulmonary fistula causing repeated exacerbation]. AB - We report a case of fatal pulmonary infection caused by Mycobacterium abscessus in a middle-aged patient with acquired esophago-pulmonary fistula which contributed to repeated exacerbation. Acquired benign esophago-pulmonary fistula is uncommon. After a 55-year-old woman was diagnosed with pulmonary Mycobacterium avium disease in 1989 and improved with multidrug chemotherapy, she developed pulmonary M. abscessus in 2001. Despite multi-drug treatment, she suffered repeated exacerbation and her condition gradually deteriorated. Chest computed tomography (CT) showed esophago-pulmonary fistula which was comfermed by esophagoscopy. An M. abscess infection may give rise to adhesions between the tracheobronchial lymph nodes and the neighboring esophagus, with subsequent development of a traction diverticulum which may extend to the tracheobronchial tree. In the present case, aspiration of liquids through the fistula induced a cough reflex, and M. abscessus spread through the airway. It might be possible that esophago-pulmonary fistula is not only a complication of pulmonary M. abscessus infection but also an exacerbation factor. PMID- 20954374 TI - [A case of tuberculous lateral great adductor muscle abscess during treatment of miliary tuberculosis]. AB - We report a rare case of a thigh abscess which appeared during treatment of miliary tuberculosis. A 72-year-old woman with a history of diabetes mellitus was being treated for systemic sclerosis with prednisolone. She was then admitted to our hospital with fever, and chest computed tomography showed an abnormal shadow. She was given a diagnosis of miliary tuberculosis, and antituberculous therapy was initiated with isoniazid, rifampicin, ethambutol and pyrazinamide. Although this combination of antituberculous drugs was effective, 3 months after the initiation of treatment, a collection of fluid appeared in her left thigh. Further examination revealed the fluid to be positive for Mycobacterium tuberculosis on PCR and negative on mycobacterial culture. We thus diagnosed this phenomenon to be a paradoxical reaction. PMID- 20954375 TI - [A case of scrub typhus with lung involvement]. AB - A 65-year-old-woman complained of lumbago from the end of March 2008. Three weeks later, she visited a local clinic because of high fever, and she was given a diagnosis of urinary tract infection. Although levofloxacin was given, her condition did not improve and she was referred to the urology department of our hospital. Two days after hospitalization, she rapidly developed respiratory failure. Chest CT revealed bilateral pleural effusion, interlobular septal thickening, diffuse ground-glass opacities and mediastinal lymphadenopathy. We suspected scrub typhus because we noticed a localized necrotic skin lesion on her left lower leg. When minocycline was administered, both her clinical condition and radiographic imaging promptly improved. Because lung involvement with scrub typhus is very rare in Japan, we report this case of scrub typhus with various lung findings. PMID- 20954376 TI - [Three cases of lung cancer detected after smoking cessation]. AB - COPD is an independent risk factor for lung cancer. There is emerging evidence that chronic inflammation may play a significant role in the pathogenesis of lung cancer as a tumor promoter. Cigarette smoke exponentially up-regulates the production of cytokines. After stopping smoking, the risk of lung cancer remains increased in patients with COPD. We report 3 patients with COPD in whom lung cancer was detected within 16 months after smoking cessation. All were outpatients of our hospital, and participated in a program for smoking cessation according to their doctor's advice. Two successfully stopped smoking, and the other was in the program for smoking cessation. It was difficult to detect lung cancers on chest X-ray films 8-11 months previously. Periodic medical examination chest X-ray films revealed lung cancers 2-16 months after smoking cessation. Heavy smokers, especially COPD patients, have a high risk of developing lung cancer at the start of smoking cessation, and therefore have a high risk of contracting lung cancer even after halting smoking. Generally, most patients do not visit hospitals for the purpose of only smoking cessation after successfully halting smoking. Nevertheless, it is necessary for previously heavy smokers, especially COPD patients, to undergo repeated careful medical examination to detect lung cancer. PMID- 20954377 TI - [A case of pulmonary sarcoidosis with rapid progression of multiple cystic lesions]. AB - A 51-year-old woman presented with cough, fever, and increased serum ACE activity. Computed tomography (CT) revealed a bilateral diffuse pattern of ground glass opacities with enlarged bilateral hilar/mediastinal lymph nodes. Sarcoidosis was diagnosed by transbronchial lung biopsy in August 2005. After treatment with 30 mg/day prednisolone, her symptoms and chest CT findings improved markedly, and her serum ACE activity also decreased. Although her symptoms had been stable, and ACE activity had been at a normal level on treatment with 10 mg/day prednisolone, multiple cystic lesions, which were not observed in May 2007, appeared in bilateral peripheral lung lesions on CT in January 2008, and progressed rapidly. We present an interesting case of pulmonary sarcoidosis, with rapid progression of multiple cystic lesions without enlargement of hilar/mediastinal lymph nodes and increased serum ACE activity on treatment with prednisolone. PMID- 20954378 TI - [Perioperative outcome of laparoscopic radical cystectomy: comparison to open radical cystectomy]. AB - OBJECTIVES: This study is to elucidate the advantage of laparoscopic radical cystectomy (LRC) over open radical cystectomy (ORC) in an early perioperative period. MATERIALS AND METHODS: We investigated the perioperative outcome of the consecutive patients who underwent radical cystectomy at Yokohama City University Hospital. The data of 11 patients who underwent LRC from February 2008 to May 2009 was compared with that of 11 patients who had ORC from October 2006 to April 2009. RESULTS: The operative time was significantly longer in LRC (p = 0.00794); the mean operative time for LRC and ORC was 521 and 428 minutes respectively. The blood loss was significantly smaller in LRC (p = 0.0014); the mean volume of bleeding by LRC and ORC was 801 and 2,156 ml respectively. The date of the diet resumption after the operation comes significantly earlier in the case of LRC (p = 0.0142); the mean number of days to the resumption after LRC and ORC were 4.6 and 9.3 respectively. The top C-reactive protein (CRP) figure was significantly lower in LRC (p = 0.0124); the mean of peak CRP after LRC and ORC was 10.8 and 16.6 mg/dl respectively. As for postoperative complications, there were no significant differences between two groups (p = 0.375); the rate of complications occurred after LRC and ORC was 27 and 45% respectively. Also no significant differences were observed as to the number of dissected lymph nodes among these two groups (p = 0.262); the mean number in LRC and ORC was 10.9 and 13.7 respectively. CONCLUSIONS: From our investigations it is appropriate to conclude that in an early perioperative period LRC has advantages over ORC: a smaller amount of blooding, an earlier date of the diet resumption, and a lower peak of CRP. LRC is less invasive than ORC, though the former takes longer time for an operation than the latter. PMID- 20954379 TI - [Scleroderma-like skin sclerosis induced by docetaxel chemotherapy for hormone refractory prostate cancer: a case report]. AB - We report the first case of scleroderma-like skin sclerosis induced by docetaxel chemotherapy for prostate cancer in Japan. A 67-year-old man underwent radical prostatectomy for cT3aN0M0 prostate cancer in 2003. Thereafter PSA recurrence developed and antiandrogen deprivation therapy was used. However, we diagnosed this case as hormone refractory prostate cancer and began docetaxel chemotherapy in October 2008. There were no nonhematological adverse events through two courses of treatment. He presented to dermatology due to pain and swelling of both upper arms on the second day of the third course. However, when treated with a cooling method, swelling of the upper arms became worse and CPK rose to 1,921 IU/I on the eighth day. We administered a steroid ointment and an antibiotic due to suspicion of thrombophlebitis. Nevertheless, CPK rose to 2,791 IU/I and a skin biopsy was done. In consequence, scleroderma-like skin sclerosis induced by docetaxel chemotherapy was diagnosed. Swelling appeared in both lower limbs and the pain got worse on the 17th day. Therefore docetaxel chemotherapy was discontinued and prednisolone was increased to 30 mg/day, in addition to beginning codeine use for the pain. Thereafter, the painful sclerosis was ameliorated. PMID- 20954380 TI - [Successful renal contraction therapy in polycystic kidney patient with renal transcatheter arterial embolization prior to ABO incompatible kidney transplantation]. AB - 28-year-old female received dialysis treatment due to chronic renal failure caused by polycystic kidney disease. Later, she underwent a laparoscopic splenectomy and ABO incompatible living kidney transplantation successfully following bilateral renal contraction therapy with renal transcatheter arterial embolization (renal TAE). A unilateral or bilateral native nephrectomy of a massively enlarged kidney performed at the time of renal transplantation is a common treatment in polycystic kidney patients scheduled for transplantation. On the other hand, when treated with renal TAE, such patients can avoid a laparotomy, which provides several advantages when undergoing peritoneal dialysis in the future or a laparoscopic splenectomy prior to ABO incompatible kidney transplantation. Furthermore, we consider that bilateral renal TAE is necessary for polycystic kidney patients prior to renal transplantation for a variety of reasons, including problems associated with contrast nephropathy if renal TAE for left kidney is remained after renal transplantation. PMID- 20954381 TI - [Case of primary amelanotic malignant melanoma of the female urethra]. AB - We report a rare case of primary amelanotic malignant melanoma of the female urethra. A 58-year-old female with complaint of nodule on the external urethral meatus was referred to our hospital. Pathological diagnosis of the biopsy specimen from the nodule was malignant melanoma. Computed tomography of the chest and abdomen as well as bone scan showed no evidence of metastasis. Sentinel biopsy from the inguinal lymph nodes revealed no metastasis. Thereafter, the patient underwent radical urethrectomy, whose limits of resection were the bulbocavernosal muscles bilaterally, the arch of the pubic symphysis anteriorly, the anterior vaginal wall posteriorly, and the urethra up to the level of the bladder neck superiorly. The histopathological diagnosis was amelanotic malignant melanoma of the urethra. The patient had received six cycles of DAV-Feron (dacarbazine, nimustine, vincristine, and interferon-beta) in an adjuvant setting, and there is no sign of recurrence 25 months after operation. PMID- 20954382 TI - [Polyorchidim: a case report and review of the literature]. AB - A 28-year-old male presented with a small painless lump in his left hemiscrotum. A physical examination revealed a non-tender mass that was palpable on the tail of left epididymis, and the testis and spermatic cord were normal. Ultrasonography showed an isoechoic round shaped tumor, 16 mm in diameter. An exploration of the scrotum was performed, based on a preoperative diagnosis of a left epididymal tumor. The tumor was located below the tail of epididymis, and had a whitish capsule, which looked similar to tunica albuginea testis. A frozen section revealed testicular tissue without any malignant change, and therefore polyorchidism was diagnosed. The accessory testis was resected because there was no connection with the epididymis and vas deferens. Polyorchidism is a rare congenital anomaly with 24 cases reported in the Japanese literature. The indications for the resection of an accessory testis are controversial. Patients with intrascrotal polyorchidism might be recommended to undergo a resection of the accessory testes if there are signs of dysplasia during an intraoperative biopsy. Patients must be followed up with regular clinical and ultrasonic examinations when accessory testes are preserved. However, extrascrotal supernumerary testes should be managed by an orchiectomy because of the increased risk of malignancy. PMID- 20954383 TI - [Preface for special issue on biofuels and bioenergy]. AB - Biofuels and bioenergy not only benefit independence of energy supply, but also mitigate CO2 emissions. This special issue includes review reports and research articles involving various biofuels and bioenergy products and systems such as fuel ethanol, biodiesel, biogas, biohydrogen, microbial fuel cells and microbial electrolysis cells. Both fundamental research and technology development are highlighted. And in the meantime, challenges for large scale production and application of biofuels and bioenergy are discussed. Taking advantages of modern biotechnology advances, solutions to address these challenges are envisioned. PMID- 20954384 TI - [China's crop residues resources evaluation]. AB - The availability of crop residues in China is reviewed in this article. The definition of crop residues is clarified as the total byproducts of field production and processing industry thereafter, and methodology for evaluating crop residues is discussed. Based on literature, the progress on the crop residue assessment is addressed. The annual field crops residues in China from 1991 to 1999 were estimated between 6.0-6.8 hundred million tons, while the data for the process residues were not available. From 2000 to 2007, the annual crop residues were estimated between 5.9-7.3 hundred million tons, while the processing residues at the range of 0.9-1.1 hundred million tons. The reasons for the significant variations are due to the disagreement on crop residue definition, different, even inaccurate residue to grain ratio data used in the estimations, and the lacking of clear understanding on the statistical analysis and grain outputs related to the crop residue evaluation. With the complete statistic analysis method, the author's group evaluated the residues in 2006 and 2007 to be 7.4 hundred million tones in total, including 6.5 hundred million tons for field crop residues and 0.9 hundred million tons for process residues. Moreover, the geographic distribution of the field crop residues was analyzed based on the harvest indices (HI) tested within the near five years. PMID- 20954385 TI - [Progress on cellulase and enzymatic hydrolysis of lignocellulosic biomass]. AB - Biofuels and bio-based chemicals from lignocellulosic biomass are sustainable, making them alternatives to petroleum-derived fuels and chemicals to address the challenges of the shortage of crude oil supply and climate change resulted from the overconsumption of petroleum-based products, particularly in China. However, high cost in liberating sugars from lignocellulosic biomass is still the bottleneck of the commercialization of biofuels and bio-based chemicals. In this article, the major components of cellulases and their synergistic role in the hydrolysis of pre-treated biomass is reviewed, followed by how to evaluate the enzymatic hydrolysis. With the elucidation of the underlying mechanism of the conformations of the enzyme molecules and their effectiveness in attacking cellulose substrate, more efficient enzymes are expected to be developed. Using the high production strain Penicillium decumbens, the on-site production of cellulases for cellulose ethanol production is discussed. PMID- 20954386 TI - [Progress and strategies on bioethanol production from lignocellulose by consolidated bioprocessing (CBP) using Saccharomyces cerevisiae]. AB - Ethanol production from lignocelluloses of consolidated bioprocessing (CBP) is a system in which cellulase and hemicellulase production, substrate hydrolysis, and fermentation are combined or partially combined by ethanologen microorganisms that express cellulolytic or hemicellulolytic enzymes or engineering cellulolytic microorganisms with ethanol production properties. Due to its potential for significant cost reduction, CBP is receiving more and more attention. In this review article, we discuss the factors that influence the expression level of cellulases in Saccharomyces cerevisiae and updated progress in bioethanol production from lignocellulose by the CBP strategy using the yeast species. PMID- 20954387 TI - [Application of systems biology and synthetic biology in strain improvement for biofuel production]. AB - Biofuels are renewable and environmentally friendly, but high production cost makes them economically not competitive, and the development of robust strains is thus one of the prerequisites. In this article, strain improvement studies based on the information from systems biology studies are reviewed, with a focus on their applications on stress tolerance improvement. Furthermore, the contribution of systems biology, synthetic biology and metabolic engineering in strain development for biofuel production is discussed, with an expectation for developing more robust strains for biofuel production. PMID- 20954388 TI - [Fuel ethanol production from cassava feedstock]. AB - The regions suitable for growing cassava include five provinces in Southern China, with Guangxi alone accounting for over 65% of the total cassava production in the country. In this article, the state-of-the-art development of fuel ethanol production from cassava in China is illustrated by the construction of the cassava fuel ethanol plant with its annual production capacity of 200 000 metric tons. And in the meantime, problems and challenges encountered in the development of China's cassava fuel ethanol are highlighted and the strategies to address them are proposed. PMID- 20954389 TI - [Advances in biodiesel research]. AB - Biodiesel is renewable and environmentally friendly; however, there are still many challenges for its commercial production as an alternative of petroleum based transportation fuels, particularly in China with very limited resources for its biofuels development. In this article, the update progress of biodiesel R & D and production is reviewed, with a focus on its feedstock supply, manufacturing processes, quality control and byproduct utilization. It is concluded that the strategy of biorefinery to ultimately explore feedstock potentials will make biodiesel production more economically competitive. PMID- 20954390 TI - [Progress on biodiesel production with enzymatic catalysis in China]. AB - This paper reports the progress of biodiesel production with enzymatic catalysis in Beijing University of Chemical Technology, one of the leaders in biodiesel R & D in China, which includes screening of high-yield lipase production strains, optimization and scale-up of the lipase fermentation process, lipase immobilization, bioreactor development and scale-up, biodiesel separation and purification and the by-product glycerol utilization. Firstly, lipase fermentation was carried out at industrial scale with the 5 m3 stirred tank bioreactor, and the enzyme activity as high as 8 000 IU/mL was achieved by the species Candida sp. 99-125. Then, the lipase was purified and immobilized on textile membranes. Furthermore, biodiesel production was performed in the 5 m3 stirred tank bioreactor with an enzyme dosage as low as 0.42%, and biodiesel that met the German biodiesel standard was produced. And in the meantime, the byproduct glycerol was used for the production of 1,3-propanediol to partly offset the production cost of biodiesel, and 76.1 g/L 1,3-propanediol was obtained in 30 L fermentor with the species Klebsiella pneumoniae. PMID- 20954391 TI - [Strategies for research and development and commercial production of microalgae bioenergy]. AB - With the dwindling of fossil fuels supply and the urgent need for the development of low-carbon economy, microalgae bioenergy, both renewable and environmentally friendly, has become one of the worldwide focuses. Given its benefit to the security of national energy supply, microalgae energy is particularly significant for China, with more than 50% crude oil imported and limited arable land for grain and edible oil production. In this article, both the advantages of microalgae bioenergy and the challenges of its development are addressed, which involves fundamental research and technology development as well as commercial production. Furthermore, strategies are proposed for China's microalgae bioenergy development, and its prospects are projected. PMID- 20954393 TI - [Progress on biogas technology and engineering]. AB - Dwindling supplies of conventional energy sources and the demand to increase the share of renewable energy for sustainability have increased the significance of biogas, the product of synergistic fermentation of biodegrable organic wastes from municipal, agricultural and industrial activities by microbial populations under anaerobic conditions. With extensive research and engineering practice, many technologies and modes have been developed for biogas production and application. Currently, the most widely used mode is the complete-mixing mesophilic fermentation. Europe, especially Germany, is leading the world in the combined heat and power production (CHP) from biogas. In this paper, updated progress in biogas technologies is reviewed, with focuses on anaerobic microorganisms, bioreactor configurations and process development, biogas production and applications, in which perspectives of biogas as a clean and renewable energy are projected. PMID- 20954392 TI - [Current status and prospects of biobutanol manufacturing technology]. AB - Butanol is not only an important chemical feedstock but also expected to become a new generation biofuel. Thus, biological butanol production using renewable feedstocks has attracted renewed attention due to the worries of global oil supply and its impact on social and economic development. However, compared with petrochemical-derived butanol, biological butanol production is still not economically competition, because of its major drawbacks: high cost of the feedstocks, low butanol concentration in the fermentation broth and the co production of low-value byproducts acetone and ethanol. Recently, Shanghai cooperative bio-butanol group (SCBG) developed a simple-to-complex technical route to improve bio-butanol production with a focus on: increasing butanol ratio in the solvent through metabolic engineering of Clostridia spp.; introducing and optimizing the butanol synthetic pathway in the species with high butanol tolerance; overcoming the glucose repression effect to utilize low-cost non-grain based feedstocks. SCBG believes that, through extensive domestic and international industry-university-research cooperation, a sustainable and economically viable process for biological butanol production can be established in the near future. PMID- 20954394 TI - [Progress and technology development on hydrogen production through bioconversion of lignocellulosic biomass]. AB - Hydrogen production from lignocellulosic biomass is both sustainable and environmentally friendly, which is garnering more and more attention across the world, with an expectation to challenge the shortage of fossil fuels supply and climate change as well. In this article, the update research progress and technology development of biohydrogen production are reviewed, with a focus on biomass pretreatment, hydrogen-producing microorganisms and process engineering strategies. And in the meantime, a roadmap for more efficient and economic biohydrogen production is envisioned. PMID- 20954395 TI - [Biomass energy utilization in microbial fuel cells: potentials and challenges]. AB - Microbial fuel cells (MFCs) that can harvest biomass energy from organic wastes through microbial catalysis have garnered more and more attention within the past decade due to its potential benefits to ecological environment. In this article, the updated progress in MFCs is reviewed, with a focus on frontier technologies such as chamber configurations, feedstock varieties and the integration of MFCs with microbial electrolysis cells for hydrogen production. And on the other hand, the challenges like development of cost-effective electrode materials, improvement of biomass energy recovery and power output, design and optimization of commercial MFC devices are presented. PMID- 20954396 TI - [Process strategy for ethanol production from lignocellulose feedstock under extremely low water usage and high solids loading conditions]. AB - The massive water and steam are consumed in the production of cellulose ethanol, which correspondingly results in the significant increase of energy cost, waster water discharge and production cost as well. In this study, the process strategy under extremely low water usage and high solids loading of corn stover was investigated experimentally and computationally. The novel pretreatment technology with zero waste water discharge was developed; in which a unique biodetoxification method using a kerosene fungus strain Amorphotheca resinae ZN1 to degrade the lignocellulose derived inhibitors was applied. With high solids loading of pretreated corn stover, high ethanol titer was achieved in the simultaneous saccharification and fermentation process, and the scale-up principles were studied. Furthermore, the flowsheet simulation of the whole process was carried out with the Aspen plus based physical database, and the integrated process developed was tested in the biorefinery mini-plant. Finally, the core technologies were applied in the cellulose ethanol demonstration plant, which paved a way for the establishment of an energy saving and environment friendly technology of lignocellulose biotransformation with industry application potential. PMID- 20954397 TI - [Cellulose hydrolysis and ethanol production by a facultative anaerobe bacteria consortium H and its identification]. AB - The recalcitrance of lignocellulosic biomass makes its hydrolysis by cellulases less effective, and the consolidated bioprocessing (CBP) strategy that combines enzyme production, cellulose hydrolysis and fermentation, particularly the synergetic role of different microbes in attacking cellulose component could be a solution. In this article, a facultative anaerobe microbial consortium named H was isolated, which exhibited high stability even after 30 subcultures, with pH ranging from 6 to 9. Within three days, 0.5 g filter paper immerged in 100 mL PCS buffer was completely degraded, and 1.54 g/L ethanol was produced, correspondingly. Further analysis on the component of the microbe consortium was carried out though 16S rDNA and DGGE, and Clostridium thermosuccinogene, Clostridium straminisolvens and Clostridium isatidis that can directly convert cellulose to ethanol were identified, indicating that Clostridium spp. played important role in cellulose degradation through the synergistic coordination of different species, and the characterization of the consortium will benefit the analysis of the underlying mechanisms as well as the optimization of the CBP process for more efficient cellulose degradation and ethanol production. PMID- 20954398 TI - [Ethanol production from sweet sorghum stalks by advanced solid state fermentation (ASSF) technology]. AB - A robust strain of the species Saccharomyces cerevisiae CGMCC1949 was screened and identified, and advanced solid state fermentation (ASSF) technology for fuel ethanol production from sweet sorghum stalks was thus developed. The fermentation time was shortened to less than 30 h, and ethanol yield was 92% of its theoretical maximum. And in the meantime, the cost-effective storage was established for sweet sorghum stalks, with less than 5% sugar loss after 200 days of storage, making the plant operation could extend up to 200 days without feedstock shortage. With the fermentation kinetics and heat-mass transfer models, modeling of the ASSF process was investigated, and the rotating drum bioreactor was designed. Furthermore, the ASSF technology was successfully applied in the pilot plant in which the rotating drum bioreactor was scaled up to 127 m3, and ethanol yield of 91% was achieved. At the end, techno-economic analysis (TEA) conducted by ASPEN indicated that ethanol production from sweet sorghum stalks by the ASSF is economically competitive. PMID- 20954399 TI - [Feasibility of planting sweet sorghum in sugarcane region to prolong milling duration for bioethanol production]. AB - In order to explore the feasibility of planting sweet sorghum in sugarcane growing area to prolong milling duration for bioethanol production, 15 varieties were sown monthly from March to September in Liuzhou of Central Guangxi Zhuang Autonomous Region. Yields of fresh stem, grain and leave were documented. The results showed that all varieties grew well when sown from March to August, but could not get mature when sown after late September. The high fresh stem yields were observed for the varieties Sart and PT3-S, 79.28 t/hm2 and 78.58 t/hm2 for single growing season, and 157.95 t/hm2 and 155.25 t/hm2 for two growing seasons. Ripening began from the end of June to late December, making the feed stock available for ethanol production from July to the end of December, even January next year. PMID- 20954400 TI - [Simultaneous saccharification and fermentation of Jerusalem artichoke tubers to ethanol with an inulinase-hyperproducing yeast Kluyveromyces cicerisporus]. AB - Jerusalem artichoke tubers with inulin as major component are potential feedstock for fuel ethanol production, and Kluyveromyces cicerisporus Y179 expressing high level of inulinase is suitable for ethanol production with this feedstock by simultaneous saccharification and fermentation approach. In this article, the impact of inoculum, aeration and temperature on ethanol production by the yeast was studied. The experimental results illustrated that inoculum with different levels and seed collected at different cultivation times had negligible effect, while anaerobic conditions enhanced ethanol production, and more ethanol was produced by the yeast at 30 degrees C than at 37 degrees C or 42 degrees C. The medium using Jerusalem artichoke tuber meal as sole component with 22% (W/V) total sugars was inoculated with 36 h-precultured seed at 10% (V/V), and the batch fermentation was conducted in a 5 L fermentor at 30 degrees C with a stirring speed of 300 r/min under anaerobic conditions. After 144 h, 12.3% (V/V) ethanol was produced and the yield of ethanol from sugars was 86.9% of its theoretical one, with 93.6% sugars consumed. These results indicate that K. cicerisporus Y179 is a promising candidate for industrial ethanol production using Jerusalem artichoke tuber feedstock. PMID- 20954401 TI - [Butanol production from hydrolysate of Jerusalem artichoke juice by Clostridium acetobutylicum L7]. AB - Butanol production from acid hydrolysate of Jerusalem artichoke juice by Clostridium acetobutylicum L7 was investigated, and it was found that natural components of the hydrolysate were suitable for solvent production with the species. With batch fermentation using the medium containing 48.36 g/L total sugars, 8.67 g/L butanol was produced at 60 h, and the ratio of butanol to acetone to ethanol was 0.58:0.36:0.06, which were similar to the fermentation with fructose as carbon source, but both of these two fermentations were slower than that with glucose as carbon source, indicating the fructose transport of the species might not be effective as that for glucose. When the total sugars of the medium were increased to 62.87 g/L, the residual sugars increased slightly from 3.09 g/L to 3.26 g/L, but butanol production of the fermentation system was improved significantly, with 11.21 g/L butanol produced and the ratio of butanol to acetone to ethanol at 0.64:0.29:0.05, which illustrated that an excess in sugars enhanced the butanol biosynthesis of the species by compromising its acetone production. When the sugar concentration of the medium was further increased, much more sugars were remained unconsumed, making the process economically unfavourable. PMID- 20954402 TI - [Microbial lipid production by Rhodosporidium toruloides in a two-stage culture mode]. AB - To shorten the cultivation time and reduce the consumption of raw materials for microbial lipid production, oleaginous yeast Rhodosporidium toruloides AS 2.1389 was cultivated using a two-stage culture mode, in which the cell propagation and lipid accumulation were separated. The yeast cells recovered from the propagation culture were re-suspended in glucose solution for lipid accumulation, through which lipid content over 55% of the dry cell weight was achieved, the longer the propagation stage was, the higher the lipid content. Analysis of the lipid indicated that the long-chain fatty acids with 16 and 18 carbon atoms were major components, suggesting that the lipid can be an alternative feedstock for biodiesel production. PMID- 20954403 TI - [Stability of the hydrogenase from Tetraselmis subcordiformis and its preliminary purification]. AB - Tetraselmis subcordiformis, a marine green alga, can produce hydrogen by photobiologically hydrolyzing seawater with hydrogenase. In this study, the preliminary purification of the enzyme was explored by ammonium sulfate precipitation, and the impact of sodium dithionite, beta-mercaptoethanol and glycerol on the enzyme stability during the process was investigated. The experimental results illustrated that sodium dithionite provided significant protection on the hydrogenase by depleting oxygen, while glycerol, a protectant against the structure instability of the enzyme, also presented protection. Crude enzyme with specific activity of 0.557 U/mg protein was extracted using 60%-70% saturated ammonium sulfate solution supplemented with 200 mmol/L sodium dithionite and 5% glycerol, and the hydrogenase recovery yield was about 30%. PMID- 20954404 TI - [Isolation and identification of a methanogen from the high temperature oil reservoir water]. AB - To explore new microbial resources in deep subsurface oil reservoirs, strain DL-7 was isolated with Hungate technology from oil reservoir water sampled from Dagang oilfield, China. Physiological and biochemical examinations showed that H2/CO2 is the unique substrate of the strain, which cannot metabolize formate, methanol, trimethylamine, acetate and other secondary alcohols. The optimum growth conditions were further identified to be 60 degrees C, pH 7.0-7.5 and 0.25% NaCl. Moreover, the strain cannot grow without yeast extract. Analysis of its 16S rRNA sequence indicated that a similarity of 99.7% presents between the strain and the model species M. marburgensis DSM2133T (X15364). PMID- 20954405 TI - [Cloning of the promoter region of the trehalose-6-phosphate synthase gene TPS1 of the self-flocculating yeast and exploration of the promoter activity on ethanol stress]. AB - Improving stress tolerance of the microbial producers is of great importance for the process economy and efficiency of bioenergy production. Key genes influencing ethanol tolerance of brewing yeast can be revealed by studies on the molecular mechanisms which can lead to the further metabolic engineering manipulations for the improvement of ethanol tolerance and ethanol productivity. Trahalose shows protective effect on the cell viability of yeast against multiple environmental stress factors, however, further research is needed for the exploration of the underlying molecular mechanisms. In this study, the promoter region of the trehalose-6-phosphate synthase gene TPS1 was cloned from the self-flocculating yeast Saccharomyces cerevisiae flo, and a reporter plasmid based on the expression vector pYES2.0 on which the green fluorescence protein EGFP was directed by the TPS1 promoter was constructed and transformed to industrial yeast strain Saccharomyces cerevisiae ATCC4126. Analysis of the EGFP expression of the yeast transformants in presence of 7% and 10% ethanol revealed that the P(TPS1) activity was strongly induced by 7% ethanol, showing specific response to ethanol stress. The results of this study indicate that trehalose biosynthesis in self flocculating yeast is a protective response against ethanol stress. PMID- 20954406 TI - [Impact of distillage recycling on the glycolysis key enzymes, stress response metabolites and intracelluler components of the self-flocculating yeast]. AB - This research aimed to study the effect of distillage recycling on ethanol fermentation, the key glycolytic enzymes and cell composition of the self flocculating yeast. With the self-flocculating yeast SPSC01 and medium composed of 220 g/L glucose, 8 g/L yeast extract and 6 g/L peptone, continuous ethanol fermentation was carried out at the dilution rate of 0.04 h(-1) with a 1.5 L tank bioreactor. Fermentation broth was collected every 3 days, and ethanol and other volatile byproducts were removed by distillation, but the stillage with high boiling byproducts was recycled to prepare the medium instead of fresh water. The system was run for 20 days, during which ethanol and biomass concentrations in the effluent decreased continuously, indicating the significant inhibition of the high boiling byproducts accumulated within the system. Thus, the activities of the key enzymes of the glycolytic pathway: hexokinase, 6-phosphofructose kinase, and pyruvate kinase were analyzed, and it was observed that all of them were inhibited. Furthermore, the biosynthesis of the stress response metabolites glycerol and trehalose was investigated, and it was found that glycerol production that can protect yeast cells against osmotic pressure stress was enhanced, but trehalose biosynthesis that can protect yeast cells against ethanol inhibition was not improved, correspondingly. And in the meantime, the biosynthesis of the major intracellular components proteins and hydrocarbons was adjusted, correspondingly. PMID- 20954407 TI - [Black spots on a white coat]. PMID- 20954408 TI - [Burnout and the quality of life of workers in food industry--a pilot study in Serbia]. AB - BACKGROUND/AIM: Burnout syndrome as a consequence of a long stress at workplace can seriously disturb health and quality of life in exposed workers. It is necessary to have adequate burnout prevention and its detection. Worldwide much attention is paid to protect burnout and methods for its determination constantly improve. In Serbia there has not been a study of that kind yet. The aim of the study was to investigate burnout syndrome impact on the quality of life of workers in food industry in Nis, and to call attention of researchers in Serbia on this phenomenon, as well as to test probability of applying the original, standardized questionnaires (CBI, ComQolA5) to working population in Serbia. METHODS: This study was performed in Nis within a period from 2008 to 2009 in the Institute for Workers Health Protection. A total of 489 workers were included in this study by the use of the standard questionnaire for burnout (CBI) and quality of life (ComQoL-A5). Scale confidence for measuring burnout and quality of life was determined by Cronbach alpha coefficient. ANOVA analysis was used for rating influence of burnout on the quality of life. RESULTS: The values of Cronbach alpha coefficient showed a high confidence of the scale for measurement personal burnout (0.87), work-related burnout (0.86) and subjective quality of life (0.83). We detected increased scores as a result of personal burnout (60.0), as well as of work-related burnout (67.9). The workers suggested relationship with the family and friends as a very important part for their quality of life (10.8), health (9.8) and safety (8.0). Productivity (6.8), emotional well-being (6.6) and material property (4.5) had smaller influence on their quality of life. An increase in score of work-related burnout by 1 was statistically significantly related to decreasing inter scores for subjective quality of life in health (B = 0.097), relationship with family and friends (B = -0.048), safety (B = -0.061) and place in community (B = -0.105). A statistically significant relation between work-related burnout and subjective quality of life in productivity, material and emotional well-being was not determined. CONCLUSION: There is a high score of both personal and work related burnout among manufacturing workers in food industry. A negative correlation between burnout and subjective quality of life was also proved impacting health and well-being of workers, but also their productivity. The questionnaires we used (CBI, ComQolA5) could be considered as reliable and valid instruments for testing burnout and quality of life in Serbia. PMID- 20954409 TI - [Quantitative analysis of dendritic branching pattern of large neurons in human cerebellum]. AB - BACKGROUND/AIM: Dentate nucleus (nucleus dentatus) is the most distant of the cerebellar nuclei and the major system for information transfer in the cerebellum. So far, dendritic branches of four different kinds of large neurons of dentate nucleus, have been considered mainly qualitatively with no quantification of their morphological features. The aim of the study was to test the qualitative hypothesis that the human dentate nucleus is composed of various types of the large neurons by quantitative analysis of their dendritic branching patterns. METHODS: Series of horizontal sections of the dentate nuclei were taken from 15 adult human brains, free of diagnosed neurological disorders. The 189 Golgi-impregnated images of large neurons were recorded by a digital camera connected to a light microscope. Dendritic branching patterns of digitized neuronal images were analyzed by modified Sholl and fractal analyses. RESULTS: The number of intersections (N(m)), critical radius (r(c)) and fractal dimension (D) of dendritic branching pattern for four types of the large neurons were calculated, statistically evaluated and analyzed. The results show that there is a significant difference between four neuronal types in one morphometric parameter at least. CONCLUSION: The present study is the first attempt to analyze quantitatively the dendritic branching pattern of neurons from the dentate nucleus in the human. The hypothesis that the four types of the large neurons exist in this part of human cerebellum is successfully supported. PMID- 20954410 TI - [Rapid simultaneous determination of organophosphorus pesticides in human serum and urine by liquid chromatography-mass spectrometry]. AB - BACKGROUND/AIM: Analysis of organophosphosphorus compounds and their metabolites in a biological material includes the use of numerous methods, covering both preparation of samples for analysis and their identification that is considered to be very complex. Low concentrations monitoring requires implementation of highly sensitive analytical techniques. The aim of this study was to develop and validate an original and sensitive method for the detection and quantitation of organophosphorus pesticides (dimethoate, diazinon, malathion and malaoxon) in human biological matrices (serum, urine). METHODS: This method was based on a solid-phase extraction procedure, a chromatographic separation using an ACQUITY UPLC HSST3 column and mass spectrometric detection in the positive ion mode. Mobile phase: was consited of Solvent A (5 mM ammonium formate pH 3.0) and Solvent B (0.1% acetic formate in methanol), in a linear gradient (constant flow rate 0.3 mL/min). RESULTS: The standard curve was linear in the range of 0.05 5.00 mg/L for malathion and malaoxon, 0.10-5.00 mg/L for dimethoate and 0.05-2.50 mg/L for diazinon. The correlation coefficient was r > or = 0.99. Extraction recoveries were satisfactory and ranged between 90-99%. The limits of detection (LOD) was between 0.007-0.07 mg/L and the limits of quantitation (LOQ) ranged between 0.022-0.085 mg/L. Intra- and interassay precision and accuracy were satisfactory for all of the pesticides analyzed. CONCLUSION: The method of liquid chromatography-mass spectrometry is simple, accurate, and useful for the determination of organophosphorus pesticides in both clinical and forensic toxicology. PMID- 20954411 TI - [Significance of serum tumor markers monitoring metastases in carcinomas of unknown primary site]. AB - BACKGROUND/AIM: Unknown primary tumors represent a heterogeneous group of malignancies that are indicative of ominous prognosis. Cancer of unknown primary site (CUP) is defined as the lack of any detectable primary site after full evaluation, and accounts for approximately 3-5% of all newly diagnosed patients with malignancies. The aim of this report was to present the prognostic and predictive value of 8 serum tumor markers in this group of patients. METHODS: The study involved 63 patients. On histological examination, all the patients were presented with metastatic tumors whose primary site (origin) could not be detected with noninvasive diagnostic techniques. Following the routine light microscopy, all histological findings were classified into one of the following three groups: plano-cellular carcinoma--8 patients; adenocarcinoma--33 patients; unclassifiable (undifferentiated) carcinoma--22 patients. In all the cases we evaluated 8 serum tumor markers: alpha-fetoproteins (AFP), chronic gonadotrophin beta submit, human (beta-HCG), neuron specific enolase (NSE), marker of malignant ovarian tumors (CA 125), prostate-specific antigene (PSA), marker of malignant brest tumor (CA 15-3), marker of malignant pancreas tumor and gastrointestinal tumor (Ca 19-9), carcinoembryonic antigen (CEA) at the time of diagnosis. The patients on chemotherapy had the markers determined after the third and sixth chemocycle, i.e. at the time of illness progression observation, if present. The patients responding to chemotherapy with complete response (CR), partial response (PR) or stable disease (SD) had the markers determined after three-month periods until the time of relapse or progression. Chemotherapy was applied in 32 patients (20 females and 12 males), aged 29-70 years, who met the inclusion criteria. The following chemotherapy regimen was used: doxorubicin 50 mg/m2 (day 1), cisplatin 60 mg/m2 (day 1), and etoposide 120 mg/m2 (days 1-3). The period between two chemotherapy cycles was three weeks, and maximum five weeks in the case of prolonged hematological toxicity. RESULTS: Most commonly elevated were NSE values (82.54%), while AFP values were least commonly elevated (11.11%). Average survival time was 17.89 months (95% CI 12.96; 22.83). The probability of 24 months' survival was 0.228. The group of 32 patients treated with chemotherapy had 12 (37.5%) fatal outcomes in the observed period (72 months). Average survival time was 26.6 months (95% CI 19.5; 33.7). Average tumor marker values before and after the chemotherapy were significantly lower for NSE and CA 125. Survival was significantly better in cases of NSE and CA 125 decrease of more than 20%. CONCLUSION: Increased values of serum tumor markers are very often in CUP. The tumors show nonspecific overexpression of tumor markers. The NSE and CA 125 levels show good correlation with response to the given chemotherapy. However, a routine evaluation of commonly used serum tumor markers has not been proven of any prognostic and predictive assistance. PMID- 20954412 TI - [Urgent percutaneous coronary intervention leads to a decrease in serum concentrations of soluble CD40 ligand]. AB - BACKGROUND/AIM: Inflammation as a consequence of vascular injury after percutaneous coronary intervention (PCI) is a pathological substrate of restenosis and of its complications. The aim of the study was to examine perprocedural inflammatory response expressed by soluble CD40 ligand (sCD40L) and C-reactive protein (CRP) in patients treated with PCI and dual antiplatelet therapy. METHODS: The experimental group included 52 patients (80.8% men, age 60 +/- 9 years) with angina pectoris treated by PCI (22 urgent PCI) with stent implantation, and dual antiplatelet therapy (tienopiridins and aspirin), according to the current recommendations for the execution of the intervention. The control group consisted of 8 patients (70.5% men, age 59 +/- 7 years) with angina pectoris, who had undergone coronarography taking aspirin 3 days prior to it. In all the patients 24 hours before and after the PCI concentrations of CRP and sCD40L in the blood were determined. RESULTS: In the experimental group, the concentration of sCD40L was lower as compared to the control (p < 0.02). In 34 (65%) patients postprocedural decrease in sCD40L was recorded, in 18 (34.6%) of them increase, while in 50 (96%) patients there was a rise in CRP. The patients with postprocedural fall in sCD40L hod greater preprocedural concentration of sCD40L (p < 0.001), and less postprocedural concentration of sCD40L (p < 0.001), compared to the group with an increase in sCD40L after the PCI, while CRP levels between these groups were not statistically different. Patients treated with emergency PCI compared to elective patients had a postprocedural decrease in sCD40L (p = 0.02). Increase in the level of CRP was higher in the group with emergency PCI in relation to elective PCI (p < 0.01). CONCLUSION: Emergency PCI procedures in the treatment of patients with unstable angina pectoris lead to a postprocedural fall in the serum concentration of sCD40L. Dual antiplate therapy with tienopiridins and aspirin inhibits the release of sCD40L. Regardless a clinical presentation of coronary disease PCI leads to an postprocedural increase in concentrations of CRP in the serum. PMID- 20954413 TI - [Professional stress in general practitioners and psychiatrists--the level of psycologic distress and burnout risk]. AB - BACKGROUND/AIM: So far, studies of stress have shown that physicians are at a high risk of sickness from psychic and somatic disorders related to professional stress, that can lead to important disturbance of personal, familiar and professional functionating. The aim of this study was to investigate the doctors exposition level to professional stress, to compare stress level in general practitioners (GP) group with that in the group of psychiatrists and risk level for the apperance of burnout syndrome. METHODS: This cross-section study included subjects recruited by a random sample method. Thirty General Practice doctors and 30 psychiatrists (totally 60 doctors) filled the set of 3 questionnaires: Sociodemographics features, General Health Questionnaire (GHQ; Goldberg D, 1991), and Maslach Burnout Inventory (MBI; Maslach C, 1996). Appropriate statistical procedures (Pearson test, t-test, variance analysis) in interpretation of the results were used. RESULTS: A total level of psychic distress measured with the GHQ test in both groups of physicians was very low implying their good mental health. A difference in Burnout risk based on MBI test between the groups was statistically significant (chi2 = 4,286; p < 0.05) only at subscale Personal Accomplishment (MBI-PA); it was a consequence of a higher number of GPs with medium burnout risk (13.3 : 0.0%). However, even 35 physicians from the sample were affected with a high burnout risk measured with subscales Emotional Ehausation (MBI-EE) and MBI-DP, showing that both groups of physicians had risk for the appearance of burnout syndrome. CONCLUSION: The obtained results showed a high burnout risk level in both, GPs and psychiatrists, groups. In both groups there was no presence of psychic disorders (anxiety, depression, insomnia), while there was a high level of emotional ehausation and overtension by job, and also a lower total personal accomplishment. Level of exposition to professional stress is higher in GPs than in psychiatrists, but the difference was not statistically significant. PMID- 20954414 TI - [Evaluation of low level laser and interferential current in the therapy of complex regional pain syndrome by infrared thermographic camera]. AB - BACKGROUND/AIM; Complex regional pain syndrom type I (CRPS I) is characterised by continuous regional pain, disproportional according to duration and intensity and to the sort of trauma or other lesion it was caused by. The aim of the study was to evaluate and compare, by using thermovison, the effects of low level laser therapy and therapy with interferential current in treatment of CRPS I. METHODS: The prospective randomized controlled clinical study included 45 patients with unilateral CRPS 1, after a fracture of the distal end of the radius, of the tibia and/or the fibula, treated in the Clinical Centre in Nis from 2004 to 2007. The group A consisted of 20 patients treated by low level laser therapy and kinesy therapy, while the patients in the group B (n = 25) were treated by interferential current and kinesy-therapy. The regions of interest were filmed by a thermovision camera on both sides, before and after the 20 therapeutic procedures had been applied. Afterwards, the quantitative analysis and the comparing of thermograms taken before and after the applied therapy were performed. RESULTS: There was statistically significant decrease of the mean maximum temperature difference between the injured and the contralateral extremity after the therapy in comparison to the status before the therapy, with the patients of the group A (p < 0.001) as well as those of the group B (p < 0.001). The decrease was statistically significantly higher in the group A than in the group B (p < 0.05). CONCLUSIONS: By the use of the infrared thermovision we showed that in the treatment of CRPS I both physical medicine methods were effective, but the effectiveness of laser therapy was statistically significantly higher compared to that of the interferential current therapy. PMID- 20954415 TI - [Candida albicans infection in patients with oral squamous cell carcinoma]. AB - BACKGROUND/AIM: Systemic candidiasis in intensive care units remains an improtant problem due to antifungal resistance. Patients undergoing radiotherapy for head and neck cancer are at increased risk of developing oral candidiasis and they more frequent have prior fungi colonization. Due to identification of specific risk factors predisposing to fungal infection in order to threat such patients the aim of this study was to determine the presence of Candida species in patients with oral squamous cell carcinoma and compare it to the control subjects (patients with benign oral mucosal lesions). METHODS: A total number of 30 consecutive oral cancer examined patients were included in this prospective study (24 men and 6 women with a mean age of 61.47 years, range 41-81 years). The control group consisted of 30 consecutive patients with histologically proven benign oral mucosal lesions (16 men and 14 women with a mean age of 54.53 years, range 16-83 years). The samples for mycological examination were obtained by using sterile cotton swabs from the cancer lesion surface and in the patients of the control group from the benign mucosal lesion surface. Samples were inoculated in Sabouraud dextrose agar. For identification purposes, Mackenzie germ tube test was performend on all isolates. RESULTS: The prevalence of Candida was significantly higher in oral cancer patients than in control subjects (chi2 = 5.455, p = 0.020). Candida was found on nine of the 30 cancer surfaces; 5 (16.7%) were identified as non-albicans Candida and 4 (13.3%) as Candida albicans. In the control group, only Candida albicans was isolated from 2 (6.7%) patients. In this study, no statistically significant differences in the presence of Candida species was found with respect to gender, age, smoking, alcohol consumption, wearing of dental protheses and the site of cancer lesion. CONCLUSION: The increased prevalence of yeasts on the surfaces of oral carcinoma indicates a need for their suppression before any cancer treatment. There was no evidence for an association between gender, age, smoking, alcohol consumption, wearing of dental protheses, the site of cancer lesion and the yeast presence. PMID- 20954416 TI - [Human rights and medicine]. PMID- 20954417 TI - [Forensic interpretation of the maxillary tuberosity fracture caused by tooth extraction]. AB - BACKGROUND: Maxillary tuberosity during teeth extraction can occur in dental practice. The aim of this paper was to present a case of the maxillary tuberosity fracture occurred during tooth extraction, which was the subject of the forensic expertise. CASE REPORT: The maxillary tuberosity fracture created during the extraction of the upper molar was neither timely nor adequately managed by the doctor who started extraction. After the treatment at the specialist institution, the patient sued the doctor for the criminal offense of negligent treatment. The task of the expert was to give a professional answer to the question whether the doctor, who caused a maxillary tuberosity fracture during the tooth extraction, acted negligently and applied inadequate treatment. CONCLUSION: The maxillary tuberosity fracture during molar extraction may be its complication. If it is diagnosed promptly, immediately and adequately managed, there is no possibility for negligence action. PMID- 20954418 TI - [Diagnosis and the treatment of primary amyloidosis]. AB - BACKGROUND: Primary amyloidosis belongs to a group of monoclonal plasma cell disorders, characterized by extracellular deposition of immunoglobulin light chain fibrils in various tissues and subsequent multiorgan dysfunction. CASE REPORT: We present a 51-year-old female with 2-years history of fatigue on exertion, oedema of face, abdomen and legs, bone pain and obstipation. After diagnostic procedures such as electrophoresis and immunoelectrophoresis of serum and urine proteins, immunohistohemical staining of bone marrow biopsy specimens and Congo red staining of rectal biopsy specimens, the patient received misdiagnosis of multiple myeloma and was referred to our hospital for further treatment. We reevaluated and complemented diagnostic procedures (ehocardiosonography and biopsy of subcutaneaus tissue with Congo red staining), and established diagnosis of primary amyloidosis. The therapy had started with intravenous (i.v.) melphalan and dexamethasone (totally eight cycles) and continued with peroral melphalan and i.v. dexamethasone. Stabilization of the disease was achieved after 35 months of the treatment. CONCLUSION: The case of this rare and often fatal disease emphasizes significance of early diagnosis and, consequently, initiation of specific therapies which are indispensable to improve the disease prognosis. PMID- 20954419 TI - [A bad luck of a physician: II class Army Medical Corps Captain Perisa Sljivic (1851-1877)]. PMID- 20954420 TI - PCR mutation detection protocols. Preface. PMID- 20954422 TI - Clinically justified application of obstetric ultrasound. PMID- 20954421 TI - Interview with a Quality Leader: Dr. Ashish Jha. Kevin C. Park, interviewer. AB - Dr. Jha is an Associate Professor of Medicine at Harvard Medical School. The major themes of his research are: 1. Quality of care provided by healthcare systems, with a focus on healthcare disparities as a marker of poor care. 2. Information technology among other tools as potential solutions for reducing medical errors and disparities while improving overall quality. 3.Organizations that provide care for minorities and underserved populations and the role clinical information systems can play in improving their care. PMID- 20954423 TI - [Opinions, beliefs and awareness about the value of mammography screening]. PMID- 20954424 TI - Schizophrenia. PMID- 20954425 TI - The diagnostic concept of schizophrenia: its history, evolution, and future prospects. AB - More than a century since the delineation of dementia praecox by Kraepelin, the etiology, neuropathology, and pathophysiology of schizophrenia remain elusive. Despite the availability of criteria allowing reliable diagnostic identification, schizophrenia essentially remains a broad clinical syndrome defined by reported subjective experiences (symptoms), loss of function (behavioral impairments), and variable patterns of course. Research has identified a number of putative biological markers associated with the disorder, including neurocognitive dysfunction, brain dysmorphology, and neurochemical abnormalities. Yet none of these variables has to date been definitively proven to possess the sensitivity and specificity expected of a diagnostic test. Genetic linkage and association studies have targeted multiple candidate loci and genes, but failed to demonstrate that any specific gene variant, or a combination of genes, is either necessary or sufficient to cause schizophrenia. Thus, the existence of a specific brain disease underlying schizophrenia remains a hypothesis. Against a background of an ever-increasing volume of research data, the inconclusiveness of the search for causes of the disorder fuels doubts about the validity of the schizophrenia construct as presently defined. Given the protean nature of the symptoms of schizophrenia and the poor coherence of the clinical and biological findings, such doubts are not without reason. However, simply dismantling the concept is unlikely to result in an alternative model that would account for the host of clinical phenomena and research data consistent with a disease hypothesis of schizophrenia. For the time being, the clinical concept of schizophrenia is supported by empirical evidence that its multiple facets form a broad syndrome with non-negligible internal cohesion and a characteristic evolution over time. The dissection of the syndrome with the aid of endophenotypes is beginning to be perceived as a promising approach in schizophrenia genetics. PMID- 20954426 TI - Genetics in schizophrenia: where are we and what next? AB - Understanding the genetic basis of schizophrenia continues to be major challenge. The research done during the last two decades has provided several candidate genes which unfortunately have not been consistently replicated across or within a population. The recent genome-wide association studies (GWAS) and copy number variation (CNV) studies have provided important evidence suggesting a role of both common and rare large CNVs in schizophrenia genesis. The burden of rare copy number variations appears to be increased in schizophrenia patients. A consistent observation among the GWAS studies is the association with schizophrenia of genetic markers in the major histocompatibility complex (6p22.1)-containing genes including NOTCH4 and histone protein loci. Molecular genetic studies are also demonstrating that there is more overlap between the susceptibility genes for schizophrenia and bipolar disorder than previously suspected. In this review we summarize the major findings of the past decade and suggest areas of future research. PMID- 20954428 TI - Structural neuroimaging in schizophrenia: from methods to insights to treatments. AB - Historically, Kraepelin speculated that dementia praecox resulted from damage to the cerebral cortex, most notably the frontal and temporal cortices. It is only recently, however, that tools have been available to test this hypothesis. Now, more than a century later, we know that schizophrenia is a brain disorder. This knowledge comes from critical advances in imaging technology--including computerized axial tomography, magnetic resonance imaging, and diffusion imaging- all of which provide an unprecedented view of neuroanatomical structures, in vivo. Here, we review evidence for structural neuroimaging abnormalities, beginning with evidence for focal brain abnormalities, primarily in gray matter, and proceeding to the quest to identify abnormalities in brain systems and circuits by focusing on damage to white matter connections in the brain. We then review future prospects that need to be explored and pursued in order to translate our current knowledge into an understanding of the neurobiology of schizophrenia, which can then be translated into novel treatments. PMID- 20954427 TI - The epidemiology of schizophrenia: replacing dogma with knowledge. AB - Major advances have been made in our understanding of the epidemiology of schizophrenia. We now know that the disorder is more common and severe in young men, and that the incidence varies geographically and temporally. Risk factors have been elucidated; biological risks include a family history of the disorder, advanced paternal age, obstetric complications, and abuse of drugs such as stimulants and cannabis. In addition, recent research has also identified social risk factors such as being born and brought up in a city, migration, and certain types of childhood adversity such as physical abuse and bullying, as well as social isolation and adverse events in adult life. Current research is focussing on the significance of minor psychotic symptoms in the general population, gene environmental interaction, and how risk factors impact on pathogenesis; perhaps all risk factors ultimately impact on striatal dopamine as the final common pathway. PMID- 20954429 TI - Functional magnetic resonance imaging in schizophrenia. AB - The integration of functional magnetic resonance imaging (fMRI) with cognitive and affective neuroscience paradigms enables examination of the brain systems underlying the behavioral deficits manifested in schizophrenia; there have been a remarkable increase in the number of studies that apply fMRI in neurobiological studies of this disease. This article summarizes features of fMRI methodology and highlights its application in neurobehavioral studies in schizophrenia. Such work has helped elucidate potential neural substrates of deficits in cognition and affect by providing measures of activation to neurobehavioral probes and connectivity among brain regions. Studies have demonstrated abnormalities at early stages of sensory processing that may influence downstream abnormalities in more complex evaluative processing. The methodology can help bridge integration with neuropharmacologic and genomic investigations. PMID- 20954430 TI - Pharmacologic treatment of schizophrenia. AB - Despite pharmacologic advances, the treatment of schizophrenia remains a challenge, and suboptimal outcomes are still all too frequent. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good "effectiveness" measure mapping onto functional outcomes is still lacking. Moreover, the field has to advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate whether, and which, first- or second-generation antipsychotics should be used. However an individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Moreover acute and long-term goals and effects of medication treatment need to be balanced. While the acute response to appropriately dosed first-generation antipsychotics may not differ much from second-generation antipsychotics, advantages of lower rates of extrapyramidal side effects, tardive dyskinesia, and, possibly, relapse may favor second generation antipsychotics. However when considering individual adverse effect profiles, the differentiation into first- and second-generation antipsychotics as unified classes can not be upheld, and a more differentiated view and treatment selection is required. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To improve the treatment outcomes in schizophrenia, research efforts are needed that elucidate biomarkers of the illness and of treatment response (both therapeutic and adverse effects). Moreover, new treatment options are needed that affect nondopaminergic targets with relevance for symptom reduction, relapse prevention, enhanced efficacy for nonresponders, and reduced key adverse effects. PMID- 20954432 TI - The assessment of neuropsychological functioning in schizophrenia. AB - Overwhelming evidence suggests that compromised neuropsychological function is frequently observed in schizophrenia. The neuropsychological profile is typically characterized by prominent specific deficits in memory and learning, working memory, executive functions, attention, and processing speed, which are evident on a background of a generalized cognitive deficit. This paper provides a review of studies of neuropsychological functioning in schizophrenia. The main cognitive ability areas affected in schizophrenia are described, and the degree of impairment in each ability area as found in studies of schizophrenia patients is summarized, based on meta-analytic findings. Recent studies that have compared neuropsychological functioning across psychotic disorders are presented, and finally, neuropsychological assessment batteries specifically developed for schizophrenia are introduced. PMID- 20954431 TI - Beyond the dopamine receptor: novel therapeutic targets for treating schizophrenia. AB - All current drugs approved to treat schizophrenia appear to exert their antipsychotic effects through blocking the dopamine D2 receptor. Recent meta analyses and comparative efficacy studies indicate marginal differences in efficacy of newer atypical antipsychotics and the older drugs, and little effects on negative and cognitive symptoms. This review integrates findings from postmortem, imaging, and drug-challenge studies to elucidate a corticolimbic "pathologic circuit" in schizophrenia that may be particularly relevant to the negative symptoms and cognitive impairments of schizophrenia. Potential sites for pharmacologic intervention targeting glutatatergic, GABAergic, and cholinergic neurotransmission to treat these symptoms of schizophrenia are discussed. PMID- 20954433 TI - Remission in schizophrenia: validity, frequency, predictors, and patients' perspective 5 years later. AB - In March 2005, the Remission in Schizophrenia Working Group (RSWG) proposed a consensus definition of symptomatic remission in schizophrenia and developed specific operational criteria for its assessment. They pointed out, however, that the validity and the relationship to other outcome dimensions required further examination. This article reviews studies on the validity, frequency, and predictors of symptomatic remission in schizophrenia and studies on patients' perspectives. These studies have demonstrated that the RSWG remission criteria appear achievable and sustainable for a significant proportion of patients, and are related to a better overall symptomatic status and functional outcome and, to a less clear extent, to a better quality of life and cognitive performance. However, achieving symptomatic remission is not automatically concurrent with an adequate status in other outcome dimensions. The results of the present review suggest that the RSWG remission criteria are valid and useful. As such, they should be consistently applied in clinical trials. However the lack of consensus definitions of functional remission and adequate quality of life hampers research on their predictive validity on these outcome dimensions. Future research should therefore search for criteria of these dimensions and test whether the RSWG remission criteria consistently predict a "good" outcome with respect to functioning and quality of life. PMID- 20954434 TI - The lifetime trajectory of schizophrenia and the concept of neurodevelopment. AB - Defining the lifetime trajectory of schizophrenia and the mechanisms that drive it is one of the major challenges of schizophrenia research. Kraepelin assumed that the mechanisms were neurodegenerative ("dementia praecox"), and the early imaging work using computerized tomography seemed to support this model. Prominent ventricular enlargement and increased cerebrospinal fluid on the brain surface suggested that the brain had atrophied. In the 1980s, however, both neuropathological findings and evidence from magnetic resonance imaging (MRI) provided evidence suggesting that neurodevelopmental mechanisms might be a better explanation. This model is supported by both clinical and MRI evidence, particularly the fact that brain abnormalities are already present in first episode patients. However, longitudinal studies of these patients have found evidence that brain tissue is also lost during the years after onset. The most parsimonious explanation of these findings is that neurodevelopment is a process that is ongoing throughout life, and that schizophrenia occurs as a consequence of aberrations in neurodevelopmental processes that could occur at various stages of life. PMID- 20954435 TI - Cognitive training in schizophrenia: a neuroscience-based approach. AB - Meta-analytic data from over a decade of research in cognitive remediation, when combined with recent findings from basic and clinical neuroscience, have resulted in a new understanding of the critical elements that can contribute to successful cognitive training approaches for schizophrenia. Some of these elements include: the use of computerized repetitive practice methods, high dosing schedules, a focus on sensory processing, and carefully constrained and individually adapted learning trials. In a preliminary randomized controlled trial of cognitive training exercises based on these principles, we demonstrated significant improvements in working memory, verbal learning and memory, and global cognition in patients with schizophrenia. These cognitive improvements were accompanied by neurobiological findings suggestive of learning-induced cortical plasticity. Future directions for research and essential remaining questions are discussed. PMID- 20954436 TI - Anaerobic bacteria infection in cystic fibrosis airway disease. AB - Depletion of the periciliary liquid in "Cystic Fibrosis" airway disease results in reduced mucociliary transport, persistent mucus hypersecretion and consequently increased height of the luminal mucus layer, so hypoxic gradients in the mucus plugs are developed. Because of anaerobic lung zones, it is highly probable that anaerobic bacteria not detected by routine bacteriologic culture methods also reside within the mucus. Notwithstanding this evidence, microbiology laboratories working in the cystic fibrosis field do not generally use strict anaerobic bacteriologic cultures to determine the presence of anaerobic bacteria in the Cystic Fibrosis lung. The aim of this review is to focus on the published data regarding the finding of anaerobic bacteria in cystic fibrosis airway disease. Therefore, microbiology, diagnosis, antimicrobial susceptibility and possible impact on clinical management of anaerobic bacteria lung infection in cystic fibrosis are described. PMID- 20954438 TI - Characterisation of AIDS presenters and their response to antiretroviral therapy at legnano general hospital (Italy) during the period 2000-2008. AB - The aim of this study was to characterise the AIDS presenters diagnosed between 2000 and 2008 in Legnano (Italy), and describe their initial response to highly active antiretroviral therapy (HAART) and trends over time. Seventy-six (48.7%) of 156 patients diagnosed as having AIDS in the period 2000-2008 were AIDS presenters. The proportion of AIDS presenters increased from 23.8% in 2000 to 70.6% in 2008 (p = 0.009). The major risk factors were heterosexual transmission and a foreign place of birth, and did not significantly change over time. The median CD4+ cell count at diagnosis was 30 cells/microl and the median level of HIV RNA was 5.38 log copies/ml, with no differences between the transmission risk groups. Fifteen AIDS presenters died of AIDS-defining diseases; the others started HAART (72% with 2 NRTIs + boosted PI), and 40% after a drug resistance test. The median duration of the initial HAART was 107 days. After three months, 34% of the patients had undetectable HIV-RNA levels and the median CD4+ cell count was 140 cells/microl; the corresponding figures after 12, 24 and 48 months were respectively 84%, 82.3% and 94.1%, and 310, 370 and 380 cells/microl. In conclusion, the AIDS presenters were mainly heterosexual men and immigrants. Their proportion increased significantly over time, and a substantial proportion maintained an immunovirological response to HAART. PMID- 20954437 TI - Performance of genotypic tropism testing in clinical practice using the enhanced sensitivity version of Trofile as reference assay: results from the OSCAR Study Group. AB - OBJECTIVE: The goal of the OSCAR programme is to evaluate the performances of genotypic HIV-1 tropism testing in clinical practice using the enhanced sensitivity version of Trofile (ESTA) as reference-assay. METHODS: HIV-1 coreceptor-usage was assessed using plasma samples from 406 HIV-1 infected patients by ESTA and by gp120 V3 population-sequencing followed by Geno2pheno (set at a False Positive Rate [FPR] of 10% and 5%). RESULTS: ESTA was successful in 365 (89.9%) samples indicating R5 in 254 (69.6%), and DM/X4 in 111 (30.4% of samples (104 [28.5%] DM and 7 [1.9%] X4). Genotypic-testing successfully assessed viral tropism for all 406 samples, including the 41 with undetermined result by ESTA. Genotypic-tropism testing at a FPR of 5% and 10% was 81.1% and 78.4% concordant with ESTA, respectively. Despite a sensitivity of 48.7% and 55.9% at a FPR of 5% and 10%, respectively, a high concordance (specificity: 95.3% for FPR of 5% and 88.2% for FPR of 10%) between genotypic-tropism testing and ESTA was reached in the detection of R5-tropic viruses. CONCLUSION: Our results are in line with other European studies, and support the routine use of genotypic tropism testing in clinical-settings for monitoring of HIV-1 infected patients candidate to or failing CCR5-antagonists. PMID- 20954439 TI - A strategy to increase the specificity of Syber Green I qRT-PCR in hepatitis A detection. AB - Various methods for the recovery and detection of HAV have been suggested, and molecular tests have recently provided an effective replacement for the traditional methods. Real-time RT-PCR technology offers many advantages over conventional RT-PCR in terms of rapidity and specificity. Most procedures are based on the TaqMan chemistry, but some researchers have used the SYBR Green I approach, which is less expensive and simpler to carry out. However the formation of primer-dimers needs to be distinguished from specific products through a melting curve analysis. This study focused on a strategy to increase the specificity of Syber Green I chemistry, thus nullifying the primer-dimers interference. To this end, forward and reverse primers were specially designed for hairpin loop formation, a strategy widely used to improve the specificity and the efficiency of PCR. Two different concentrations of primers were assayed (200 nM and 400 nM) in a one-step, real-time RT-PCR procedure, evaluating the specificity of the amplicons and the optimization of the real-time protocol. We demonstrated that this approach can increase the specificity of the Syber Green I qRT-PCR performance with a good reproducibility of the method. Because of the simplicity of the assay and the lower costs involved, this procedure could be a valid alternative to HAV monitoring from environmental matrices. PMID- 20954440 TI - Staphylococcus aureus nosocomial infections: the role of a rapid and low-cost characterization for the establishment of a surveillance system. AB - Continuous surveillance on resistance patterns and characterization of Staphylococcus aureus represent simple and low-cost techniques to understand and evaluate the effectiveness of infection control and antimicrobial prescribing measures. In this study we analyzed the antibiotic susceptibility and trends for S. aureus strains collected from bacteraemia cases in a five year period. Between 2004 and 2008 we noted a progressive decrease in the number of S. aureus isolates compared to all pathogens from clinical specimens and S. aureus bloodstream infections (BSI) reflected a similar trend. In particular we analyzed 185 isolates from blood cultures: 89 isolates were MSSA and 96 isolates were MRSA. Molecular SCCmec typing of these strains showed an absolute prevalence of types I and II, whereas five spa types from 96 isolates were obtained. Resistance pattern analysis allowed us to place MRSA strains into 12 antibiotypes and the major antibiotype was resistant to penicillin, gentamicin, erythromycin, clindamycin and ciprofloxacin. The predominant antibiotype among the MSSA isolates was resistant only to penicillin. In addition, 19.1% of MSSA are susceptible to all antibiotics tested. We also found a close association between antibiotyping 1 and genotyping t002/SCCmecI of MRSA strains, suggesting a nosocomial scenario dominated by a few particular clones. PMID- 20954441 TI - Aneurysm and Helicobacter pylori relationship: the seropositivity of CagA, VacA and other antigens of Helicobacter pylori in abdominal and ascending aortic aneurysms. AB - Helicobacter pylori is thought to be related to atherosclerosis and aneurysm development. We aimed to detect virulance factors of H. pylori and examine the potential etiopathogenetic relationship between aortic aneurysm and H. pylori, 58 abdominal aortic aneurysm (AAA) and 38 ascending aortic aneurysm (AsAA) cases and 57 Healty control group (HCG) were included. We investigated H. pylori IgG by ELISA and virulance factors by Western-Blot (WB) method. No difference was found between AAA (67.24%), AsAA (73.68%) and HCG (57.89%) for H. pylori IgG (p > 0.05). A significant difference was found between AsAA (78.95%) and HCG (57.89%) for H.pylori IgG (p < 0.05) by ELISA and a significant difference was found only between AsAA (100%) and HCG (37.5%) for H. pylori IgG in the 45-55 age group by WB. A statistically significant difference was found between AAA and AsAA for VacA and CagA + VacA and CagA + VacA + UreA antigens and also a significant difference was found between AsAA and HCG for CagA + UreA antigens (p < 0.05). Finally, we suggest that H. pylori VacA has a more important role than CagA in the development of two aneurysms especially in ruptured AAA. New extended studies detecting H. pylori DNA are needed to detect the aetiopathogenesis between aneurysm types and H. pylori. PMID- 20954442 TI - Identification and genetic characterization of metallo-beta-lactamase-producing strains of Pseudomonas aeruginosa in Tehran, Iran. AB - Metallo-beta-lactamases (MBLs) are being reported with increasing frequency worldwide. The aim of this study was to investigate the prevalence of blalMP-1, blaVIM-1,2 and blaSPM-1 genes encoding metallo-beta-lactamases (MBLs) among a collection of Pseudomonas aeruginosa strains isolated from patients at different hospitals in Tehran and to trace the disseminated clones at these hospitals by pulsed field gel electrophoresis (PFGE). Susceptibility of 610 P aeruginosa to 14 different antibiotics was determined using disc diffusion method. Isolates showing resistance to imipenem and ceftazidime were subjected to micro broth dilution assay to determine their MIC values. The blaIMP-1, blaVIM-1, blaVIM-2, and blaSPM-1, genes were amplified by PCR. Isolates containing blaVIM-1 were analyzed by PFGE. Sixty-eight isolates were resistant to imipenem (MIC > or = 4 microg/ml) of which 16 isolates carried blaVIM-1 gene using PCR assay. No other MBL genes were detected in this study. Three different unrelated patterns were found for isolates containing blaVIM-1 gene by PFGE of which pattern A was predominant. All isolates were susceptible to colistin and polymixin B. blaVIM-1 was the main gene encoding MBL among the isolates of P aeruginosa in our study. Clonal spread of isolates containing blaVIM-1 had occurred at Tehran hospitals. However, heterogeneous clones also were involved in the outbreaks. PMID- 20954443 TI - Occurrence of Listeria monocytogenes in ready-to-eat foods from supermarkets in Southern Italy. AB - The study provides data on the prevalence of Listeria monocytogenes in ready-to eat (RTE) foods from supermarkets in Southern Italy. The pathogen was detected in 105/1045 (10%) RTE food samples. In particular, it was highlighted in 4/392 (1%) pastries, 23/112 (20.5%) vacuum-packaged sliced salami samples, 2/108 (1.9%) cream cheese samples, 31/115 (27%) mayonnaise based deli salads and 45/132 (34.1%) smoked salmon samples. The mozzarella samples were L. monocytogenes negative. Given the considerable public health implications, the study confirms that surveillance of listeriosis in Europe should be improved and coordinated between European Union Member States in order to better estimate the burden of disease and to prevent foodborne outbreaks, assessing the human health risk arising from RTE foods. PMID- 20954444 TI - Human cytomegalovirus load in fresh and glycerolized skin grafts. AB - This study evaluated the detection of Human Cytomegalovirus (HCMV)-DNA in donors' skin samples. HCMV-DNA was quantified in 100 skin specimens, including 50 fresh samples and as many corresponding glycerol-preserved specimens by a home-made Real Time PCR. HCMV-DNA was detected in 19/50 (38%) fresh specimens and 23/50 (46%) glycerol-preserved (p = n.s.). Nevertheless, the mere detection of HCMV-DNA does not imply the presence of infectious virions and therefore does not imply a risk of HCMV transmission, as treatment with glycerol is particularly efficacious in inactivating viral particles. Therefore, HCMV serology confirms its pivotal role in the setting of skin grafting. PMID- 20954445 TI - Development of a multiplex PCR for the simultaneous amplification and genotyping of glycoprotein N among human cytomegalovirus strains. AB - Genomic variation among human cytomegalovirus (HCMV) strains is probably involved in HCMV-induced pathogenesis. The envelope glycoprotein N (gN) showed extensive genetic polymorphism as HCMV isolates have been clustered into four distinct gN variants (gN-1, gN-2, gN-3, gN-4) whose distribution has been analyzed worldwide using different methodological approaches (PCR-RFLP, PCR-Cloning, PCR Sequencing). This paper describes a new method for concurrent detection of gN genotypes among HCMV strains using a multiplex gN-variants specific PCR plus visualization on agarose gel, avoiding subsequent steps such as cloning, restriction or sequencing. This novel approach will reduce costs and shorten the detection time of gN polymorphisms among HCMV clinical isolates. PMID- 20954446 TI - Enfuvirtide administration in HIV-positive transgender patient with soft tissue augmentation: US evaluation. AB - Enfuvirtide is a large protein that should be injected subcutaneously to ensure an appropriate absorption. Here we report the case of a transgender HIV-positive patient receiving enfuvirtide with an individualized background regimen of antiretroviral drugs, who had previously undergone liquid silicone oil injections. We performed US scan to detect silicone-free areas for following enfuvirtide injections. US can be useful in the correct management of those patients with liquid silicone oil soft tissue augmentation who require subcutaneously injected drugs. PMID- 20954447 TI - Acute varicella-zoster virus necrotizing meningoencephalomyelitis with sudden visual loss and paraparesis in an HIV-infected patient. AB - We describe a case of acute varicella-zoster virus (VZV) hemorrhagic meningoencephalomyelitis in an HIV-infected patient. On admission the patient's CSF was mild haemorrhagic and xanthochromic after centrifugation and he had thoracic skin blisters. VZV DNA was isolated from both the thoracic blisters and CSF. Treatment consisted of aggressive antiviral, steroid and immunoglobulin therapy, which was able to stop disease progression. The patient survived but was left blind and paretic. In conclusion, a diagnosis of CNS infection caused by VZV, based upon CSF analysis and examination of the skin for typical blisters, requires aggressive empiric antiviral therapy in order to maximise patient survival. PMID- 20954448 TI - Varicella zoster virus encephalitis during treatment with anti-tumor necrosis factor-alpha agent in a psoriatic arthritis patient. AB - The introduction of targeted immunotherapies has greatly improved the therapeutic options of several inflammatory diseases such as psoriatic arthritis. However treatment-related opportunistic infections and viral reactivations may still occur. We describe a case of varicella zoster virus (VZV) encephalitis due to the reactivation of latent VZV infection during a long therapy with the anti-tumor necrosis factor-alpha (TNF-alpha) drug Adalimumab. The low incidence of VZV encephalitis in patients treated with biological agents does not justify VZV serological screening in these subjects, but careful monitoring of the patients is recommended to recognize early signs and symptoms of herpes zoster to start prompt antiviral therapy to prevent associated complications. PMID- 20954449 TI - Rapidly progressive and fatal EBV-related encephalitis in a patient with advanced HIV-1 infection at presentation: a case report and review of the literature. AB - Epstein-Barr virus (EBV) has been associated with primary central nervous system lymphoma and other EBV-related malignancies in HIV infected patients, and detection of EBV DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) has been demonstrated to be a good marker of PCNSL. Conversely, EBV has been rarely associated with encephalitis in HIV patients. Here we describe for the first time the case of an HIV-infected, late presenter Caucasian man, diagnosed with a rapidly progressive diffuse encephalitis at presentation. A very high viral load for EBV was detected in CSF by PCR. The patient died 12 days after the onset of encephalitis in spite of supportive, antiviral and antiretroviral therapy. Our experience would suggest that in profoundly immunosuppressed HIV patients EBV may cause severe encephalitis in the absence of lymphoproliferative disorders. PMID- 20954450 TI - A carbapenem-resistant Klebsiella pneumoniae isolate harboring KPC-1 from Italy. AB - Carbapenem-resistant gram-negative pathogens represent an emerging threat to the management of hospital-acquired infections. Although the isolation of carbapenem resistant enterobacteriaceae remains unusual, the frequency of carbapenemases producing Klebsiella pneumoniae is increasing in different geographic regions: the majority of isolates has been collected in the USA, but recently KPC producing K. pneumoniae were reported from China, Israel, Greece, France, Norway and Sweden. We report a KPC 1-producing K. pneumoniae isolate from Italy. This datum enlarges the geographical area where the KPC-producing K. pneumoniae strains are diffuse. PMID- 20954451 TI - Anthropometric and body composition characteristics in pre- and postmenopausal Asian Indian women: Santiniketan women study. AB - The present cross-sectional study was aimed to investigate anthropometric and body composition characteristics in pre- and postmenopausal Asian Indian women. A total of 245 healthy women aged 25 to 65 years took part in the study. A random sampling procedure using a local voters' registration list was followed to select the participants. All participants belonged to the Bengalee population and were inhabitants of the Bolpur-Santiniketan area (lying in between 23 degrees 40' north latitude and 87degrees 43' east longitude) West Bengal, India. Before the actual commencement of the study, written information was communicated to select individuals, and an appointment was requested at their respective houses. Anthropometric measures, namely height, weight etc., were collected using standard techniques. Percentages of body fat (%BF) and body mass index (BMI) were measured using an Omron body fat analyser. All subjects were categorized into two groups: premenopausal (Group I; n = 145, mean age = 32.66 +/- 5.75 years) and postmenopausal (Group II; n = 100, mean age = 52.72 +/- 5.62 years). It was observed that 80.00% women were cohabited and 80.82% were housewife with 44.08% of them having an education up to secondary level. Furthermore, 62.45% subjects had monthly family expenditure of > or = 5000 Indian Rupees. One way ANOVA revealed that there was significant group difference for age, age at menarche, MWC, WHR, FM, FFM and %BF across the groups. Intercorrelation matrix (Pearson's correlation) showed that age had significantly positive association with MWC (p < 0.01), MHC (p < 0.05), WHR (p < 0.01), FM (p < 0.01), and %BF (p < 0.01), whereas FFM has had negative association with age. Most interestingly, it was observed that there was significant difference [chi2 (1) = 9.73] for central obesity status across the groups. It seems reasonable to argue that onset of menopause does play a vital role to alter body composition and in turn CVD risk factors. PMID- 20954452 TI - Digital 2D-photogrammetry and direct anthropometry--a comparing study on test accomplishment and measurement data. AB - The aim of this methodological anthropometric study was to compare direct anthropometry and digital two-dimensional photogrammetry in 18 male and 27 female subjects, aged 24 to 65 years, from Potsdam, Germany. In view of the rising interest in reliable biometric kephalofacial data, we focussed on head and face measurements. Out of 34 classic facial anatomical landmarks, 27 landmarks were investigated both by direct anthropometry and 2D-photogrammetry; 7 landmarks could not be localized by 2D-photogrammetry. Twenty-six kephalofacial distances were analysed both by direct anthropometry and digital 2D-photogrammetry. Kephalofacial distances are on average 7.6% shorter when obtained by direct anthropometry. The difference between the two techniques is particularly evident in total head height (vertex-gnathion) due to the fact that vertex is usually covered by hair and escapes from photogrammetry. Also the distances photographic sellion-gnathion (1.3 cm, i. e. 11.6%) and nasal-gnathion (1.2 cm, i. e. 9.4%) differ by more than one centimetre. Differences below 0.5 cm between the two techniques were found when measuring mucosa-lip-height (2.2%), gonia (3.0%), glabella-stomion (3.9%), and nose height (glabella-subnasal) (4.0%). Only the estimates of forehead width were significantly narrower when obtained by 2D photogrammetry (-1.4 cm, -13.1%). The methodological differences increased with increasing magnitude of the kephalometric distance. Apart from these limitations, both techniques are similarly valid and may replace each other. PMID- 20954453 TI - Estimation of sex from the dimensions of foot, footprints, and shoe. AB - This study intends to determine if the sex of an individual can be identified by foot lengths, shoe lengths, and/or footprints. For this purpose, foot length, foot breadth, and foot heel breadth of 506 subjects, comprising 253 females and 253 males ranging from 17.56 to 82.92 years of age, were taken. In addition, the footprints (length, breadth, and heel breadth) and footwear (length and breadth) of the same subjects were measured. Finally, the shoe size of the subjects was recorded. Univariate and multivariate discriminant function models were developed for sex allocations. Statistical analyses indicated that univariate models correctly assign approximately 67-94% of individuals to their correct sex groups. Among univariate models the most reliable measurement was shoe length. The results of multivariate models were better than those of univariate ones, with an approximately 82-96% correct assignment. The best multivariate model was comprised of four variables: foot length, shoe length, shoe breadth and shoe size. It could be suggested that these discriminant functions can provide useful clues to establish personal identity whenever complete or partial feet, footprints, or footwear are recovered. PMID- 20954454 TI - Relationship between adult stature, BMI and WHR in Backa and Banat. AB - BACKGROUND: Adult height can be a marker of living conditions in early life. The aim of this study was to assess relationship between adult stature, overweight and central obesity in Backa and Banat--Vojvodina (Serbia). 4,504 adults, average age 40.62 +/- 10.74, were tested. METHODOLOGY: The analysis of differences in morphological variables, BMI, WHR in stature, age and educational groups was carried out using t-test and chi-square test. Models of logistic regression were used to estimate the risk (OR; 95% CI) of obesity in different stature groups. RESULTS: This study showed that education was a significant factor that influences stature. Most short stature subjects had primary education. The highest percentage of those with university-level education was in the tall stature group. Among men, short stature did not correlate with overweight/obesity while a smaller correlation was observed in relation to central adiposity. It, however, had a more marked influence among women. Short stature women were more susceptible to overweight in 20-49 y age groups, and to abdominal obesity in 50 59 y age group. CONCLUSION: Short stature can potentially be an independent risk factor for developing overweight/obesity in women and to a lesser extent for central obesity of both men and women. PMID- 20954455 TI - Association between BMI and age at menarche in girls from different socio economic groups. AB - OBJECTIVE: The study examines whether the differences in both average BMI values and the prevalence of the underweight, overweight and obesity between girls with early, average and late age at menarche depend on the socio-economic status. SUBJECTS AND METHODS: The data were obtained from 2694 female students aged 15-18 years. Height and weight were measured and used to calculate BMI. The girls were divided into three groups in terms of their socio-economic status. Each girl was also classified as early, on time or late maturing based on the age at menarche. RESULTS: The inverse correlation between BMI values and age at menarche was observed. In groups of the same socio-economic status the highest BMI value was always observed in girls with early age at menarche and the lowest in those with late age at menarche. The maturation rate had also statistically significant effect on the prevalence of underweight, overweight and obesity. The early maturing girls presented a lower prevalence of underweight and higher prevalence of overweight and obesity than average and late maturing girls. This relationship was evident for both the entire sample material and in socio-economic groups. CONCLUSION: The relationship between BMI and age at menarche occurs regardless of socio-economic status. PMID- 20954456 TI - Parental education and living environmental influence on physical development, nutritional habits as well as level of physical activity in Polish children and adolescents. AB - The aim of this work was to evaluate the physical development and nutritional status, the nutrition habits as well as level of physical activity of boys and girls in relation to the socio-economic status of their families. The study was conducted on a group of 529 boys and 535 girls aged 7-16 years from Swietokrzyskie Province in Poland. Boys and girls from high SES families had the greatest body height, BMI, upper arm muscle area, as well as upper arm fat tissue area, while the lowest values of these features occurred among those studied coming from families of a low SES. The higher the family SES, the higher habitual frequency of consuming vegetables and fruit as well as fish. The diet of children coming from higher SES families was also linked with a higher total protein content as well as animal protein, all analysed minerals and some vitamins, but there were no significant differences of energetic value in daily food rations as well as fat content. The longer time spent on some sedentary activities was connected with a higher family SES. The girls coming from a high status families also declared a higher level of physical activity, whereas such relationship was not observed among boys. A more rational set of nutritional habits observed among children from a higher SES families can be the basic reason for their higher advancement in development. A shorter time devoted to sedentary activities is assumed to be the main cause of a smaller relative body mass and less obesity among girls and boys from low SES families. PMID- 20954458 TI - The variation in age at menarche: an indicator of historic developmental tempo. AB - Ample literature describes the history of the association between the advances in the health and wealth of people, and mortality rates, life expectancy and adult height. Twenty-nine German studies with n > 200 subjects published since 1848 on menarcheal age, were reanalyzed, and 101 studies from various other European and non-European countries. On average, mean age at menarche declined since the mid 19th century. Historic urban samples tended to decline earlier than rural groups, upper class women earlier than working class women. In Germany, minimum values for the age at menarche were seen already between the two World Wars (Leipzig 12.6 years in 1934, Halle 13.3 years in 1939). Values for mean age and SD for age at menarche were strongly associated. With improving historic circumstances, the two parameters declined in parallel. The standard deviation for menarcheal age dropped from over 2.5 years in mid-19" century France to little more or even less than 1 year in most modern countries. In the German studies the correlation between menarcheal age and SD was almost complete with r = 0.96 (y = 0.35x - 3.53). Similar associations between mean age at menarche and SD for age were found in other European countries. The obvious and immediate effects of historic events on menarcheal age, and particularly on the age distribution, indicate that menarche is a sensitive indicator of public health and wealth, and may be an appropriate estimator for the socio-economic background of historic populations. PMID- 20954457 TI - Reconstruction of dietary habits on the basis of dental microwear and trace elements analysis of individuals from Gan cemetery (district Galanta, Slovakia). AB - The aim of the study was to determine the diet of a historical human population. Dental microwear and trace elements were analyzed. Although 38 individuals had been buried in the cemetery, only 13 of them were suitable for the analysis of trace elements and 17 skeletal remains for microwear analysis. Buccal microwear has been studied in a sample of 17 teeth from Gan cemetery. Teeth molds of the buccal surface were obtained and observed at 120x magnification with a scanning electron microscope (SEM). Length and orientation of each striation have been determined with a SigmaScan Pro 5.0 image analysis program. The results of the analysis from Gan were compared with the previous study in a sample of 153 molar teeth from different modern hunter-gatherer, pastorals, and agriculturalist groups, with different diets (Inuit, Fueguians, Bushmen, Australian aborigines, Andaman's, Indians from Vancouver, Veddahs, Tasmanians, Lapps, and Hindus), preserved at museum collections. Buccal dental microwear density and length by orientation showed almost an inclination to hunter-gatherers from tropic and arid climates. The sample for the trace elements analysis consisted of 10 permanent molars and 3 permanent premolars. All analyzed teeth were intact, with fully developed roots, without dental caries, calculus and abrasion. Samples were analyzed using the method of optical emission spectrometry with inductively coupled plasma. Three elements: Ca, Sr, and Zn were chosen as basic diet determinants. Concentrations of these elements and their ratios were used for description of a relative proportion of plant and animal protein in a diet. The values of the Sr and Zn concentrations indicate that a diet of investigated population was rich in plant food. Higher Sr values in women can indicate lower proportion of animal protein in a diet, but significant differences have not been found. Differences between non-adult and adult individuals and between individuals with and without grave furnishings have also not been significant. PMID- 20954459 TI - Recruitment of underage test persons: motivators and barriers in an anthropological EU-survey on a sensitive topic. AB - Recruiting test persons is crucial in many scientific fields. The recognition of motivators or barriers to survey participation may support the design and recruitment strategy of future studies. The recruitment of under age test persons is very complex and sensitive. This paperpresents and analyses the experiences in recruitment of female juveniles (10-18 years old) in Germany, Italy and Lithuania within the context of an EU funded project concerning the extremely sensitive topic of "child pornography". The purpose of the project was to develop a method for age estimation of juveniles on photographs and videos. The faces of the test persons were photographed and anthropologically measured after an informed consent was signed by their parents and themselves. The analysis of the recruitment strategies and response rates revealed that culturally influenced factors played a significant role in the individual decision for or against a participation in the study. In all countries, the sensitive topic of child pornography had a great influence on the decision process. Many German parents agreed especially in light of this topic while in Italy and Lithuania the word "child pornography" triggered a very negative response. In Germany, the anthropological investigation of the faces provoked negative associations with the anthropometric surveys in the Third Reich. Social and political climate were further relevant factors for decision-making especially in Lithuania. The "top down" principle of recruitment proved to be very effective for this kind of study. The authorities of headmasters, scientists and institutions positively influenced the decisions of the parents. PMID- 20954460 TI - Diagnosis and treatment of hypertensive disorders during pregnancy. AB - Pregnancy is a cardiovascular and metabolic challenge to the human female body. This review summarizes current knowledge on the regulation of blood pressure and plasma volume in normal and hypertensive pregnant women. During pregnancy, systemic vascular resistance and blood pressure decrease, whereas cardiac output and blood volume increase to safeguard an adequate circulation in the utero placental arterial bed. Hypertension affects 10% of all pregnancies and is accompanied by an increase in foetal and maternal morbidity and mortality. Hypertension in pregnancy includes a wide spectrum of conditions, including pre eclampsia and eclampsia, pre-eclampsia superimposed on chronic hypertension, chronic hypertension, and gestational hypertension. Endothelial dysfunction, oxidative stress and an exaggerated inflammatory response are features related to hypertensive disorders. Microangiopathic disorders can easily mimic hypertensive disorders during pregnancy. Although they have some symptoms in common, they require another type of management. To reduce the risk of maternal and foetal complications due to haemodynamic maladaptations, the current management includes rest at home or in the hospital, close monitoring of maternal and foetal signs and symptoms, early start of antihypertensive therapy, and timely delivery regarding maternal and foetal survival chances. Thresholds to initiate blood pressure lowering treatment during pregnancy are 160 mmHg systole or 110 mmHg diastole. Below these thresholds, treatment must be individualized because current evidence does not support aggressive medical interventions. Alpha methyldopa and dihydropyridinic calcium channel blockers are among the recommended antihypertensives. PMID- 20954461 TI - Aetiology and physiopathology of preeclampsia and related forms. AB - Preeclampsia, a pregnancy-specific syndrome characterized by hypertension, proteinuria and oedema, resolves on placental delivery. Its pathogenesis is thought to be associated to a hypoxic placenta. Placental hypoxia is responsible for the maternal vascular dysfunction via the increased placental release of anti angiogenic factors such as soluble flt1 and endoglin. These soluble receptors bind VEGF, PLGF and TGFbeta1 and 3 in the maternal circulation, causing endothelial dysfunction in many maternal tissues. Despite these recent and important new molecular findings, it is important to consider that normal pregnancy is also characterized by systemic inflammation, oxidative stress and alterations in levels of angiogenic factors and vascular reactivity. Both the placenta and maternal vasculatures are major sources of reactive oxygen and nitrogen species which can produce powerful pro-oxidants that covalently modify proteins and alter vascular function in preeclampsia. Finally, the recent demonstration of activating auto-antibodies to the Angiotensin 1 receptor that experimentally play a major pathogenic role in preeclampsia further indicates the pleiotropism of aetiologies of this condition. PMID- 20954462 TI - Genotypic evaluation of etravirine sensitivity of clinical human immunodeficiency virus type 1 (HIV-1) isolates carrying resistance mutations to nevirapine and efavirenz. AB - BACKGROUND: Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with a pattern of resistance mutations quite distinct from the current NNRTIs. METHODS: We collected all routine samples of HIV-1 patients followed in the AIDS reference laboratory of UCLouvain (in 2006 and 2007) carrying resistance-associated mutations to nevirapine (NVP) or efavirenz (EFV). The sensitivity to Etravirine was estimated using three different drug resistance algorithms: ANRS (July 2008), IAS (December 2008) and Stanford (November 2008). We also verified whether the mutations described as resistance mutations are not due to virus polymorphisms by the study of 58 genotypes of NNRTI-naive patients. RESULTS: Sixty one samples harboured resistance to NVP and EFV: 41/61 had at least one resistance mutation to Etravirine according to ANRS-IAS algorithms; 42/61 samples had at least one resistance mutation to Etravirine according to the Stanford algorithm. 48 and 53 cases were fully sensitive to Etravirine according to ANRS-IAS and Stanford algorithms, respectively. Three cases harboured more than three mutations and presented a pattern of high-degree resistance to Etravirine according to ANRS-IAS algorithm, while one case harboured more than three mutations and presented high degree resistance to Etravirine according to the Stanford algorithm. The V1061 and V179D mutations were more frequent in the ARV-naive group than in the NNRTI experienced one. CONCLUSIONS: According to the currently available algorithms, Etravirine can still be used in the majority of patients with virus showing resistance to NVP and/or EFV, if a combination of other active drugs is included. PMID- 20954463 TI - Evaluation of the use of a combined HCV antigen/antibody assay in routine laboratory practice. AB - BACKGROUND: Combined hepatitis C virus (HCV) antigen/antibody (Ag/Ab) assays offer the advantage of a shorter window phase compared to traditional anti-HCV antibody assays. These assays have been extensively evaluated for the screening of healthy blood donors, but not in routine laboratory practice. METHODS: We evaluated the performance of the combined HCV Ag/Ab assay Monolisa Ultra and compared it to Monolisa anti-HCV Plus (which only detects anti-HCV antibodies) in 61 HCV RNA-positive patients (genotypes 1 to 5) and in 276 consecutive AxSYM HCV reactive patients. Discordant sera were tested with immunoblot and PCR. RESULTS: All 61 PCR-positive sera were positive with AxSYM, Monolisa Ultra, and Monolisa Plus. Of the 276 consecutive AxSYM-reactive patients, 177 were confirmed as HCV positive, 78 were HCV-negative and 21 were HCV-indeterminate. There were 4 false positive results with Monolisa Ultra compared to 1 false-positive result with Monolisa PLus. The signal/cut-off ratio in immunoblot-negative sera was significantly higher with HCV Ultra compared to HCV Plus (p < 0.01). Sensitivity and specificity in AxSYM-reactive sera were 99.4% and 94.9% for Monolisa Ultra and 99.4% and 98.7% for Monolisa Plus. CONCLUSION: When used as a secondary test, the sensitivity of the combined HCV Ag/Ab assay Monolisa Ultra was excellent, but specificity was reduced in AxSYM-reactive sera compared to Monolisa Plus. PMID- 20954464 TI - Evaluation of the Sysmex pocH-1001 haematology analyser in an outdoor oncology service. AB - Since rapid blood count analysis as near patient testing is expanding, we evaluated the use of a Sysmex pocH-100i compact haematology analyser in an outdoor oncology setting according to the recently published International Council for Standardization in Haematology (ICSH) guidelines. In total, 838 blood samples from oncology patients were analysed by pocH-100i and re-analysed by a high-throughput haematology analyser for comparison (Abbott CD-4000 or Sysmex XE 2100) to evaluate in use imprecision, comparability and vote-outs. Imprecision was less than 5%, except for platelet enumeration in the low range (within-run imprecision 7%). Good comparability was found even for platelet enumeration in the low range (r2 = 0.82). Vote-outs were found in 10.6% of examined samples. In conclusion, the Sysmex pocH-100i demonstrates good imprecision conform with former publications, produces reliable results in normal and in lower ranges comparable to the results of high throughput haematology analysers. In a well controlled management plan the Sysmex pocH-100i is suitable for near patient testing in oncology. PMID- 20954465 TI - The Belgian 2010 consensus recommendations for the treatment of multiple myeloma. AB - Since the introduction of novel therapeutic agents including thalidomide, lenalidomide and bortezomib, the prognosis of multiple myeloma (MM) has significantly improved. These agents have been incorporated into numerous treatment schedules for newly diagnosed as well as more advanced MM patients. Hence, the therapeutic options for MM have become more complex and subject to rapid changes. The multiple myeloma study group (MMSG) of the Belgian Hematological Society has established recommendations for the treatment of MM as based on an extensive review of the literature which is also summarized in this paper. The recommendations are the result of a consensus opinion between haematologists with experience in the field and representing most haematology centres in Belgium. Where applicable, reimbursement criteria are also taken into account. The consensus recommendations should be a reference for use by clinical haematologists in daily practice. PMID- 20954466 TI - A man with recurrent skin ulcerations. AB - Pyoderma gangrenosum is a rare, chronic, non infectious ulcerative skin disease. It is an inflammatory neutrophilic dermatosis. It is associated in 50% with a systemic disorder. Unfortunately, there are no randomized controlled studies concerning PG treatment. Immunosuppression is the mainstay of treatment and includes local and systemic measures, with high risk of potential side effects. Multidisciplinary care to patients with PG is essential for best management. We present a patient with pyoderma gangrenosum which was admitted in our Infectious Diseases Unit and first treated based on an infectious assumption. Collaboration between internists and dermatologists led to quick correct diagnosis, PG management, exclusion of an associated systemic disorder and management of further complications. PMID- 20954467 TI - Repeated, severe headache in a lung transplant patient: a case report. AB - We report a patient in whom a double lung transplantation has been performed for end-stage bronchiectasis due to IgG2 deficiency, under treatment with monthly intravenous immunoglobulins (IVIG) and Later switched to subcutaneous (SC) IG on her request. After the transplantation procedure which was uneventful, she continued to receive weekly SCIG. She developed repeated episodes of aseptic meningitis, which was finally resolved by switching again to monthly IVIG (slower infusion rate) in combination with low dose sodium valproate. This is to our knowledge the first case of aseptic meningitis due to SC IG treatment after lung transplantation. PMID- 20954468 TI - Invasive infection with Rhodococcus equi--two case reports and review of literature. AB - Rhodococcus equi infection is rare in humans, but has increasingly been reported in the last three decades, particularly in immunocompromised patients. The infection is mainly pulmonary but can also assume an extra-pulmonary form. R. equi infection is difficult to diagnose at an early stage both from a clinical and microbiologic view. Only correct and timely diagnosis and treatment can help reduce significant morbidity and mortality. Optimal treatment probably consists of prolonged, preferably triple combination therapy, including vancomycin, with optimization of pharmacokinetic parameters and screening for drug interactions, when indicated. Two clinical cases of invasive R. equi infection are reported in this manuscript: a pulmonary form and an extra-pulmonary form with brain abscesses, both in immunocompromised patients, with detailed description of symptoms, analysis, treatment, and outcome. PMID- 20954469 TI - Recurrent haemophagocytic syndrome in an HIV-infected patient. AB - We describe a case of recurrent haemophagocytic syndrome (HS) in an HIV-infected patient.The first episode was associated with active human herpesvirus 8 infection and progressive Kaposi's sarcoma which was successfully treated with splenectomy, foscarnet and chemotherapy. The second episode was triggered by a Clostridium difficile colitis and resolved completely after treatment with metronidazole only. Recurrent HS has rarely been described in adult patients out of the setting of relapsing malignancy or autoimmune disease.The chronic immune dysregulation and suppression due to HIV-infection may predispose our patient to development of associated HS. Prognosis of HS remains poor, especially in HIV infected patients. Rapidly unmasking the causative factor and timely instauration of adequate treatment are critical and may improve outcome. PMID- 20954470 TI - Posterior reversible encephalopathy syndrome: a rare neurological manifestation in Von Hippel-Lindau disease. AB - We report on a 34-year-old woman, who was recently diagnosed with Von Hippel Lindau disease (VHL), genetically confirmed. At this moment, she presented with an acute history of arterial hypertension, headache, cortical blindness and epilepsy. On the basis of clinical and magnetic resonance imaging (MRI) criteria the diagnosis of a posterior reversible encephalopathy syndrome (PRES) was made. A iodine 123-Labeled metaiodobenzylguanidine (MIBG) scan revealed the presence of bilateral adrenal pheochromocytomas. PMID- 20954471 TI - Nephrocalcinosis in a patient with complete distal renal tubular acidosis. PMID- 20954473 TI - Important news in health and nursing and midwifery. PMID- 20954472 TI - Broncho-oesophageal fistula after brachytherapy. PMID- 20954474 TI - Influenza vaccination update. PMID- 20954475 TI - Passion for university nursing wins the day. PMID- 20954476 TI - Nursing provided valuable lessons for top union role. PMID- 20954477 TI - Mandatory reporting--a panacea for poor practice? PMID- 20954478 TI - Rural nurse specialist leads NZ's primary care reform push. PMID- 20954479 TI - Development of HIV resource for aged care facilities. PMID- 20954480 TI - Nursing migration: issues of equity and balance. PMID- 20954481 TI - Nurse-led interventions to reduce cardiac risk factors in adults. PMID- 20954482 TI - Seeking a change in mental health. PMID- 20954483 TI - The changing face of private mental health nursing. PMID- 20954484 TI - Mental health: every nurses' business. PMID- 20954485 TI - The arts and mental wellbeing: opportunities and challenges. PMID- 20954486 TI - Reducing reliance on seclusion in acute psychiatry. PMID- 20954487 TI - Reflections on practice. PMID- 20954488 TI - An opportunity to build the future. Interview by Val J. Halamandaris. PMID- 20954489 TI - Caring for your loved ones by preparing for death. PMID- 20954490 TI - Honoring caregivers who reflect Mother Teresa's values. PMID- 20954491 TI - Make 'meaningful use' of health information technology meaningful. PMID- 20954492 TI - Telehomecare's potential to reduce hospitalizations and medical costs. PMID- 20954493 TI - In memory of Dr. Robert N. Butler adversary of ageism. PMID- 20954494 TI - Remote monitoring and the Center for Medicare and Medicaid Innovation. PMID- 20954495 TI - Taking the onus off providers: South Carolina's in-home worker--authentication and tracking system. PMID- 20954496 TI - Are you chopping wood--or building a fire? PMID- 20954497 TI - Tools for transforming tomorrow in home care & hospice. PMID- 20954498 TI - Using video in the Web boosts your Google 'juice'. PMID- 20954499 TI - My moonbeam dream. PMID- 20954500 TI - A community of shared values: empowered by technology. PMID- 20954501 TI - Health promotion in Asian-Americans. AB - Healthy People 2010 was developed to meet the nation's goals for better health by the end of the present decade. Its purpose focuses on eliminating health disparities in the U.S. (Ghosh, 2003). Six areas for concentration of efforts were selected specifically because of their direct impact on the health of minorities: infant mortality, immunizations, diabetes, cardiovascular diseases, HIV/AIDS, and cancer. This paper reviews the six key areas to discover the most significant points of focus for health promotion of the Asian-American population to be lack of immunizations, which results in high incidence of hepatitis B infections and liver disease. PMID- 20954502 TI - Hepatitis B. General information. PMID- 20954503 TI - The digestive system. PMID- 20954505 TI - Colon polyp. PMID- 20954504 TI - Constipation in children. PMID- 20954506 TI - Crohn's disease. PMID- 20954507 TI - The only constant in the NHS is change. PMID- 20954508 TI - Liberating the NHS. PMID- 20954509 TI - Is it time to integrate non-technical skills and other human factors into perioperative training programmes? PMID- 20954510 TI - Surgical care practitioners...our experience. AB - Julie Quick and Sarah Williams--surgical care practitioners and Sarah Addison- consultant surgeon, present their own experiences of the surgical care practitioner (SCP) role and answer the question posed by Kim Sayers (pseudonym): 'Surgical care practitioners...why?' (JPP March 2010). PMID- 20954511 TI - Advanced trauma life support radiographic trauma series: part 1--The cervical spine radiograph. AB - Plain cervical spine radiographs are the first line investigation in trauma patients to exclude cervical spine fractures and dislocations. Adequate views are essential to reduce the risk of missing diagnoses. Injuries may however not be visible on plain cervical spine radiographs despite adequate views. Additional imaging such as computer tomography scanning is indicated in the event of a normal plain radiograph if there is any clinical suspicion of injury. PMID- 20954512 TI - Electrosurgery in perioperative practice. PMID- 20954513 TI - The differences of anaesthetic care in paediatrics compared to adults. AB - In the study of holistic perspectives in perioperative care the following article focuses on the care required for paediatric patients through the perioperative period. This incorporates an understanding of the anatomical, physiological and pharmacological differences from adult practice, acknowledging the most important principles of patient safety. The planning, implementation, equipment adaptations and psychological challenges associated with this group will be discussed in relation to improving the overall perioperative experience. PMID- 20954514 TI - Is there adequate information on operation notes? The application of the Royal College of Surgeons of England guidelines. AB - An audit was performed to review the compliance and applicability of the Royal College of Surgeons of England (RCSEng) guidelines for operation notes in a regional plastic surgery department. 137 operation notes were initially audited revealing a variable quality when compared to the guidelines. An aide-memoire (Figure 1) was used to detail each of the ten guidelines and allowed the surgeon to record if any of the guidelines were not applicable. 151 operation notes were subsequently reviewed, and showed an improvement in the recording of the operative note and the varied applicability of the guidelines to this particular speciality. It is concluded that the RCSEng guidelines are not universally applicable to plastic surgery. The difference between 'not applicable' and 'failure to record' is potentially important if these guidelines are used by non clinical audit staff in a target driven environment. PMID- 20954515 TI - The early days of antibiotics. AB - Today most of us take antibiotics used in our everyday practice very much for granted. Few of us, indeed, have escaped being dosed with them at one time or another. Yet professionals of my generation, as nurses, medical students or doctors in the 1940's, will well remember our amazement at the seemingly miraculous recoveries we saw of desperately ill septic patients when Penicillin, dispensed in little ampoules of brown powder, first became generally available in civilian hospitals. PMID- 20954516 TI - Nurses followed Dr.'s DNR order on patient. Wheelock v. Doers, E2009-01968-COA-R3 TNCIV (9/14/2010)-TN. PMID- 20954517 TI - You have duty to intervene when treatment is contraindicated. Case on point: Wulbrecht v. Jehle, 2010-20229 NYMISC (6/14/2010)-NY. PMID- 20954518 TI - NC: Judgment for defendants reversed: court erred in excluding RN & MD testimony. Grantham ex rel. Trust Co. of Sterne, Agee & Leach, Inc. v. Crawford, 693 S.E.2d 245, A (5/18/2010)-NC. PMID- 20954519 TI - Must nurse expert have recent hands-on experience? Case on point: Baptist Medical Center of Beaches, Inc. v. Rhodin, 1D10-859 (7/16/2010)-FL. PMID- 20954520 TI - Have your say on the main issues. PMID- 20954521 TI - Neonatal staff shortages hamper the care of vulnerable babies and families in Wales. PMID- 20954522 TI - Cardiac surgery poised for revamp as NHS group prepares to release recommendations. PMID- 20954523 TI - Sure Start funds face cuts as health policies are targeted for review. PMID- 20954524 TI - Diaries as a method of data collection in research. AB - Diary records in healthcare research are becoming more common. This article describes the use of a diary as a method in which mothers' experiences of caring for children were explored in a hermeneutic phenomenological study or similar. Data for the original study were collected using three interviews and a diary recorded on three separate occasions. The challenges and issues that can arise when using diaries are discussed here. PMID- 20954525 TI - Going it alone: the beginning of a nurse-led retrieval service. AB - Training for experienced paediatric intensive care nurses to work as retrieval nurse practitioners is being offered by the South Thames Retrieval Service. To date, nine such practitioners have been assessed as competent to practise independently and in their first three and a half years of practice have transferred 366 critically ill children. Potential obstacles included: limitations to prescribing, resistance to nurses performing a traditional medical role and adaptation in the paediatric intensive care unit environment. Continuing evaluation is essential to ensure a high standard of care. PMID- 20954526 TI - An evaluation of observed structural clinical examinations. AB - This article describes a mixed methods study of the experience of pre- and post registration child health nursing students taking observed structured clinical examinations (OSCEs). Effectiveness of OSCEs as learning, teaching and assessment strategies in preparing for practice was assessed by questionnaire. The results were positive among both groups. However, it was less clear among the post registration students whether OSCEs suited their acquired learning styles or increased students' confidence in their clinical skills. PMID- 20954527 TI - Managing the emotional aspects of end of life care for children and young people. AB - Caring for a child at the end of life stage is one of the greatest challenges a nurse can encounter in practice. The way professionals help support, maintain and give comfort to the child and his or her family helps shape the experience the young patient is about to face. Whatever the stage of your nursing career it is likely you will provide end of life care to a child or young person and their family. This article is designed to help enable professionals to cope emotionally and provide the best quality of care in an emotionally charged situation. The information contained may be used as a guidance tool through is challenging and difficult time. PMID- 20954528 TI - Changes ahead require new, increased competencies. Leadership skills for health care reform. PMID- 20954530 TI - Trust & confidence. Does your board have these in you? PMID- 20954529 TI - Say hello to modern governance. Opening the door to board enhancement. PMID- 20954531 TI - Mergers acquisitions: a CEO roundtable. PMID- 20954532 TI - Work survival. The 85 percent solution. PMID- 20954533 TI - Time management. Jump start productivity. PMID- 20954534 TI - Communication. Building your collaboration skills. PMID- 20954535 TI - Addressing racial and ethnic disparities in healthcare. Senior management has an ethical responsibility to take a leadership role. PMID- 20954536 TI - Dealing with B team members. Holding up a mirror can have a positive effect on them and the organization. PMID- 20954537 TI - Leadership needed to improve organ donation system. An executive call to action to save lives. PMID- 20954538 TI - Healthcare reform's independent payment advisory board. New group to control Medicare expenditures. PMID- 20954539 TI - Essential skills for a new communications era. The basics are still key to your career success. PMID- 20954540 TI - Board member healthcare evaluation incorporates core competencies. Practice has a positive influence on both trustee and organizational performance. PMID- 20954541 TI - Rounding to influence. Leadership method helps executives answer the "hows" in patient safety initiatives. PMID- 20954542 TI - A new view of IT in healthcare. Supporting physicians in IT development can lead to productive relationships. PMID- 20954543 TI - Hospital board and CEO recruitment. PMID- 20954544 TI - Decisions near the end of life. PMID- 20954546 TI - Healthcare executives' role in emergency preparedness. PMID- 20954545 TI - Organ/tissue/blood/blood stem cells donation process. PMID- 20954547 TI - Healthcare executives' responsibility to their communities. PMID- 20954548 TI - Singapore Declaration on equitable access to health information in the Western Pacific Region. PMID- 20954549 TI - Melioidosis in Malaysia. AB - Melioidosis is an important cause of sepsis in the tropics, is caused by an environmental saprophyte--B. pseudomallei. It affects mainly adults with underlying predisposing condition such as diabetes. The range of symptoms varies from benign and localized abscesses, to severe community-acquired pneumonia to acute fulminating septicaemia with multiple abscesses often leading to death. B. pseudomallei is an intracellular pathogen and some of the virulence mechanisms that govern the complex interaction between the organism and the host have been elucidated. Isolation of B. pseudomallei from bodily fluids of patients remains the "gold standard" in diagnosis but a sensitive and specific serological test can lend support to the diagnosis of melioidosis. Ceftazidime is the treatment of choice for severe melioidosis, but the response is slow. Maintenance or eradication therapy for a prolonged period is necessary to prevent relapse and recurrence. Monitoring IgG antibody levels may be useful as a guideline to determine the duration of eradication therapy. PMID- 20954550 TI - Predicted equations for ventilatory function among Kuching (Sarawak, Malaysia) population. AB - Spirometry data of 869 individuals (males and females) between the ages of 10 to 60 years were analyzed. The analysis yielded the following conclusions: 1. The pattern of Forced Vital Capacity (FVC) and Forced Expiratory Volume in One Second (FEV1) for the selected subgroups seems to be gender dependant: in males, the highest values were seen in the Chinese, followed by the Malay, and then the Dayak; in females, the highest values were seen in the Chinese, followed by the Dayak, and then the Malay. 2. Smoking that did not produce respiratory symptom was not associated with a decline in lung function, in fact we noted higher values in smokers as compared to nonsmokers. 3. Prediction formulae (54 in total) are worked out for FVC & FEV1 for the respective gender and each of the selected subgroups. PMID- 20954551 TI - Severe traumatic brain injury: outcome in patients with diffuse axonal injury managed conservatively in Hospital Sultanah Aminah, Johor Bahru--an observational study. AB - Patients with isolated severe head injury with diffuse axonal injury and without any surgical lesion may be treated safely without cerebral resuscitation and intracranial pressure (ICP) monitoring. Seventy two patients were divided into three groups of patients receiving treatment based on ICP-CPP-targeted, or conservative methods either with or without ventilation support. The characteristics of these three groups were compared based on age, gender, Glasgow Coma Scale (GCS), pupillary reaction to light, computerized tomography scanning according to the Marshall classification, duration of intensive care unit (ICU) stays, Glasgow Outcome Score (GOS) and possible complications. There were higher risk of mortality (p < 0.001), worse GCS improvement upon discharge (p < 0.001) and longer ICU stays (p = 0.016) in ICP group compared to Intubation group. There were no significant statistical differences of GOS at 3rd and 6th months between all three groups. PMID- 20954552 TI - Profile of low vision children in the special education schools in Malaysia. AB - This study looked at the causes of vision loss, levels of distance, near vision and the use of low vision devices (LVDs) in children studying at special schools in Malaysia. A total of 139 children from two special education schools took part. Visual acuity was measured with and without LVDs. Those who required further assessment were referred to Low Vision Clinic. Near visual acuity in 71 children ranged from N4 to N64. Sixty eight children could not read the N64 chart or they were totally blind. Only eight students were using LVDs before intervention. Seventy one children were referred for low vision assessment and 48 were found to benefit from the LVDs prescribed. The major cause of visual impairment was cataract (17%). Hand held magnifier was the most preferred LVD. Majority of the children attending the blind schools had residual vision but did not have LVDs. LVDs are able to significantly improve near visual acuity and hence there is a need to prescribe and train the children to use the LVDs. PMID- 20954553 TI - Surgical management of large acoustic neuromas: a review. AB - Acoutic neuromas operated at UMMC from 2001 to 2006 were retrospectively reviewed. There were a total of 27 cases. All tumors were large, measuring more than 2 cm. Hearing loss was the most common presenting symptom (63%), followed by headache (52%), dysequilibrium (30%), facial numbness (30%), tinnitus (26%) and gait disturbances (15%). Eleven (41%) of patients had hydrocephalus at the time of presentation, for which a shunt procedure was required. The translabrynthine (TL) approach was used for 12 patients and the retrosigmoid (RS) with or without presigmoid clearance for the remaining 15. Major complications included one mortality and three cerebrovascular accidents (CVA's). The one-year facial nerve outcome was good to acceptable in 62% (House-Brackmann Grade I - IV) of patients. A literature review of current management of acoustic neuromas is presented. PMID- 20954554 TI - Placenta accreta: clinical risk factors, accuracy of antenatal diagnosis and effect on pregnancy outcome. AB - The aim of this study is to evaluate the clinical risk factors, accuracy of antenatal ultrasound for diagnosis, and the effect of these on pregnancy outcome. It is a retrospective study looking at cases which had hysterectomy following vaginal or caesarean section deliveries from 1993 to 2005. Data regarding the maternal demographic characteristics, number of previous CS, number of previous termination/curettage, antenatal scan findings (state features) and the gestation at which accreta was first suspected/diagnosed, MRI scan findings, pregnancy outcome (need for hysterectomy, amount of blood loss, amount of transfusion, length of ICU and hospital stay, other maternal complications, and neonatal outcome) were collected and evaluated. There were a total of 40 cases diagnosed to have abnormal placental attachment and majority of these were actually diagnosed antenatally by sonography. Visualisation of an absence or thinning of hypoechoic myometrial zone had the highest sensitivity to detect placenta accreta followed by intraplacental lacunae, focal mass tissue elevation and disruption of uterine serosal bladder wall. PMID- 20954555 TI - Preterm birth: mode of delivery and neonatal outcome. AB - To evaluate the perinatal outcome of premature babies according to the mode of delivery. A total of 113 pregnant women and 124 neonates who delivered from 30 to 35 weeks of gestation were enrolled and outcomes of 70 neonates born vaginally were compared to 54 neonates born by caesarean. Neonatal mortality rate was 20 percent for infants in caesarean group as compared to 10 percent for vaginal group. There was no significant difference in the neonatal morbidity among both the groups. Caesarean delivery cannot be routinely recommended, unless there are obstetric indications. PMID- 20954556 TI - Retrospective review of surgical management of foreign body ingestion. AB - Endoscopic examination and removal of foreign body under general anaesthesia are recommended for persistent symptomatic patient with or without significant findings on radiological examination. This report evaluates the management outcome of surgical removal of foreign body ingestion in upper gastrointestinal tract. A total of 70 cases with full documentation were reviewed retrospectively from June 1998 until December 2007. There were 32 male and 38 female with age range from 6 months to 87 years old (mean: 36.9 years). Sixty five patients (93%) were adults and 15 (7%) were below 13 years. Fish bones were the most common foreign body found (44.3%). Radiologically, foreign bodies were highly suspicious in 51 cases (76.1%). Intraoperatively, thirty six cases (70.6%) were positive. From 16 cases (23.9%) with normal radiograph, 10 cases (62.5%) were found to have foreign bodies. Therefore the plain radiograph is helpful, but clinical presentation is more reliable to determine surgical removal under general anaesthesia. PMID- 20954557 TI - The prevalence and characteristics associated with mother-infant bed-sharing in Klang district, Malaysia. AB - This was a cross-sectional study to determine the prevalence and characteristics of mother-infant bed-sharing practice in Klang district, Malaysia. Data was collected by face-to-face interview using a structured questionnaire for a four month period in 2006. A total of 682 mother-infant pairs attending government health clinics were included in the study. Data regarding socio-demographic characteristics of the mothers, information on the infants, bed-sharing and breastfeeding practices were collected. The mean maternal age was 28.4 +/- 5.1 years while the mean infant gestational age was 38.8 +/- 1.8 weeks. The study showed the prevalence of bed-sharing was 73.5% (95% CI: 70.0, 76.7). In multivariate analysis; area of interview, maternal occupation, family income, breastfeeding and infant birth weight were associated with bed-sharing after adjusted for maternal ethnicity, age, marital status, educational level, parity, infant gender and infant gestational age. In conclusion, bed-sharing is a common practice in Klang district, Malaysia, not specific to ethnicity, but strongly associated with low family income and breastfeeding. PMID- 20954558 TI - Risk factors associated with development of dengue haemorrhagic fever or dengue shock syndrome in adults in Hospital Tengku Ampuan Afzan Kuantan. AB - A retrospective study was conducted to investigate 183 serologically-confirmed cases of dengue fever (DF) admitted from October 2004 to March 2005 in a large hospital in Pahang. Clinical and laboratory features, progress and outcome of these patients were analysed in order to identify risk factors associated with development of dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). Individually, we found that older patients, secondary dengue infection, high baseline haematocrit levels, low platelet levels and prolonged activated partial thromboplastin time (APTT) ratio were significant associations with bleeding tendencies. Of these risk factors, haematocrit and APTT ratio were two independent significant risk factors on multivariate analysis. Older patients with primary infection and younger patients with secondary infection had significant bleeding tendencies. We also verified the validity of the haematocrit levels suggested as cut-off levels for plasma leakage for the Malaysian population by Malaysian Clinical Practice Guidelines for Dengue Infection in Adults (2003). PMID- 20954559 TI - A rare case of alpha-thalassaemia intermedia in a Malay patient double heterozygous for alpha(+)-thalassaemia and a mutation in alpha1 globin gene CD59 (GGC --> GAC). AB - A rare case of thalassaemia-intermedia involving a non-deletion alpha thalassemia point mutation in the alpha1-globin gene CD59 (GGC --> GAC) and a deletion alpha+ (-alpha(3.7)) thalassaemia in which use of high performance liquid chromatography (HPLC) C-gram Hb subtype profile and DNA molecular analysis helped establish the diagnosis. PMID- 20954560 TI - Central retinal artery occlusion and ophthalmoplegia following spinal surgery in the prone position. AB - A 14 year old boy underwent a 7 hour long spinal surgery for scoliosis in the prone position. In the immediate postoperative period, he developed right proptosis, periorbital swelling, chemosis and total ophthalmoplegia. The vision in his right eye was only counting fingers and the intraocular pressure was 68 mmHg. Fundus examination revealed occlusion of the right central retinal artery. A rare manifestation of both vein and artery occlusion was possible in this patient as a result of external ocular compression due to a prolonged period in the prone position. This report highlights the importance of being aware of the possible complications of external ocular compression in non-ocular surgery. PMID- 20954561 TI - Mild autosomal recessive osteopetrosis: successful treatment with bone marrow transplant. AB - We describe a 5 1/2 year old boy who was diagnosed with mild autosomal recessive osteopetrosis based on the presence of bony sclerosis, extramedullary haematopoeisis, leukoerythroblastosis and visual impairment who had an allogeneic bone marrow transplant from a matched sibling donor. Conditioning regime was busulphan 16 mg/kg and cyclophosphamide 200 mg/kg. Apart from transient hypercalcaemia, there were no major post transplant complications. Four years post transplant, the extramedullary haematopoeisis has resolved completely with normal blood counts. Apart from a fracture after a trivial fall two months after transplant, he has not suffered any fracture related limb deformities. PMID- 20954562 TI - A rare X-linked inherited mucocutaneous syndrome in two siblings. AB - We report on an 11 year-old boy with dyskeratosis congenita who presented with dystrophic nails, dysphagia, hyperpigmentation and oral leukoplakia. He had a brother who died 14 years earlier with similar presenting symptoms and aplastic anaemia. Genetic studies of our patient demonstrated the presence of a DKC1 mutation and confirmed our diagnosis. Further genetic screening revealed that his mother and one of his four sisters are heterozygous for the same mutation. PMID- 20954563 TI - Subclavian artery stent fracture. AB - We report a case of a 52 year-old dentist who had stent implantation for a left subclavian artery stenosis. However, this was later complicated by a stent fracture within one week of stent placement. A chest radiograph showed two pieces of the fractured stent, which was confirmed by computed tomographic angiogram (CTA) of the affected artery. We then discuss the occurrence of stent fractures, which are not uncommon but serious complications of endovascular therapy. PMID- 20954564 TI - Fundamentals of the management of non-Hodgkin lymphoma. AB - The incidence of Non-Hodgkin's lymphomas (NHL) is rising worldwide and if not adequately treated carries a high mortality rate. The pattern and frequency of NHL vary in different populations and geographical regions. It has considerable biologic and clinical heterogeneity and a definitive diagnosis can be made only after histopathogical examination. The histology and the extent of the lymphoma are the major determinants of optimal therapeutic regimen and treatment outcome. Additionally, the overall treatment strategies should be tailored according to medical status and preference of the patient. A holistic approach provided by a multi-disciplinary team of health care professionals is the cornerstone of ensuring successful treatment outcome. Importantly, therapy should be expedited and where possible performed in experienced centers. Patients achieving remission would require long-term monitoring for disease recurrence and late effects of cytotoxic chemotherapy and radiotherapy. Hence, clinicians should have a fundamental understanding in the biology and the principles of treatment of NHL. This review provides an evidence-based and systematic approach in designing therapeutic strategies for individual patients with newly diagnosed and relapsed NHL focusing on the common types of NHL with particular reference to the current practice within the local settings. The role of standard and novel therapeutic modalities in treatment will be summarized. PMID- 20954565 TI - Shifting workplace behavior to inspire learning: a journey to building a learning culture. AB - This article discusses the process of building a learning culture. It began with establishing acceptance and connection with the nurse unit manager and the ward team. In the early phases of developing rapport, bullying became apparent. Because bullying undermines sharing and trust, the hallmarks of learning environments, the early intervention work assisted staff to recognize and counteract bullying behaviors. When predominantly positive relationships were restored, interactions that facilitated open communication, including asking questions and providing feedback-behaviors commensurate with learning in the workplace-were developed during regular in-service sessions. Staff participated in role-play and role modeling desired behaviors. Once staff became knowledgeable about positive learning interactions, reward and recognition strategies began to reinforce attitudes and behaviors that align with learning. Through rewards, all nurses had the opportunity to be recognized for their contribution. Nurses who excelled were invited to become champions to continue engaging the key stakeholders to further build the learning environment. PMID- 20954566 TI - A model for international nursing collaboration. AB - This article describes arguments for the development of a model for exchange of experiences among nurses, nurse managers, and nurse educators from two countries based on theories of reflection and practice and Freire's theory of dialogical action and its characteristics. The collaboration focused on exchange of experiences within nursing practice, leadership and management, and nursing education. The model consists of several activities: careful selection of participants in the exchange program; participants' observations and studies of caring in nursing practice in the other culture; keeping a diary about one's own reflections, thoughts, and questions; and participation in reflective dialogue and meetings with colleagues. The model included selection and implementation of a subject and written assignments for planned change in nursing practice within participants' own clinical nursing setting. After an implementation period of 6 months to 1 year, the outcome of the implemented change was reported in seminars and workshops. PMID- 20954567 TI - A community health service-learning roundtable: nursing education partnership for community health improvement. AB - This article describes the formation of a campus-community partnership that focused its efforts on a single vulnerable community within an urban setting. Challenges that were faced and how those challenges were engaged to maintain a viable serving and learning presence within the community are discussed. Previous insights from similar articles are reinforced, and new insights for future work are highlighted. This article and similar articles are creating a body of knowledge about the practical aspects of creating and maintaining partnerships, which can provide guidance for those who wish to duplicate partnerships in other situations and also contribute to data sets of experiences from which theories on this kind of human relating can be formed, challenged, or validated. PMID- 20954568 TI - The Bucket List: a service-learning approach to community engagement to enhance community health nursing clinical learning. AB - Community health nursing education at the undergraduate level is experiencing new and distinct challenges. Reduction in funding for public health services creates fewer resources and learning opportunities for students. To effectively deal with this problem, it is necessary to reconsider how clinical experiences are implemented. Using a service-learning theoretical framework to engage students in a mutually beneficial relationship with underserved and vulnerable populations could address the issue. The "Bucket List" of service-learning and community engagement activities was developed with the goals of improving quality and comprehension of community health didactic, addressing the need to restructure community health clinical experiences, and meeting projected demands for community health nursing services in partnership with communities. PMID- 20954569 TI - Clinical teachers' conceptions of nursing. AB - Lack of knowledge exists about clinical teachers' understanding of nursing. A likely relationship between teachers' conceptions of nursing and what they focus on when teaching nursing students in the clinical setting means that the identification of different conceptions of nursing is important. This study investigated clinical teachers' experiences of nursing and clinical teaching of undergraduate nursing students. This article reports on clinical teachers' conceptions of nursing. Semistructured interviews of 20 nurses employed as clinical teachers in Australian universities were conducted. Data were analyzed using a phenomenographic approach. The findings suggest that nursing is conceived as performing tasks; providing appropriate care; providing individualized patient care aimed at achieving patient outcomes; or collaborating with health care team members to provide appropriate, individualized patient care aimed at achieving patient outcomes. Insights will assist with future preparation and support of clinical teachers, the education of nursing students, and improved curriculum design. PMID- 20954570 TI - Using a wellness program in public housing for community nursing clinical experiences. AB - A group of senior baccalaureate nursing students have been working with elderly and disabled residents in public housing as part of a Wellness Program for more than 5 years. This placement is an alternative to traditional Visiting Nurse Association placements, and encourages students to expand outreach and develop interventions for vulnerable populations while fulfilling nursing educational objectives. PMID- 20954571 TI - The role of the Medical Reserve Corps in nursing education. AB - Graduates of baccalaureate nursing programs are expected to demonstrate basic competency in responding to emergencies, including those related to emergency preparedness and disaster response. Faculty find it challenging to provide learning experiences that enable students to use appropriate assessment, clinical judgment, and decision making skills during disaster, mass casualty, and other emergency situations. This article describes a partnership between a school of nursing and a university health service to form a Medical Reserve Corps. The partnership resulted in unique and diverse learning experiences for nursing students in collaboration with volunteers from other professional disciplines and laypeople. The Medical Reserve Corps provides opportunities for students to experience emergency preparedness and disaster responses firsthand and to develop competencies required for generalist nursing practice. PMID- 20954572 TI - Preparing underemployed Latino U.S. nurses through the Mexico NCLEX-RN Success Program. AB - The critical nursing shortage in U.S. communities along the United States-Mexico border is compounded by the need for nurses who are linguistically and culturally concordant with the growing number of Latinos in these communities. The innovative 16-week Mexico NCLEX-RN Success Program responds to this need by helping underemployed Latino nurses, who were educated in Mexico and live in the United States, adapt linguistically and culturally to multiple-choice testing. Ten of the program students have taken the NCLEX-RN with a 50% pass rate, which is twice as high as the internationally educated candidate passing average. This demonstrates potential for the program to build the human capacity of U.S. communities along the United States-Mexico border by infusing linguistically and culturally concordant nurses into the workforce and materializing the dream of underemployed Latino nurses to implement their hard-earned and urgently needed nursing skills. Lessons learned from the program are discussed. PMID- 20954574 TI - Empathic anger in junior nursing students. AB - The ideal clinical experience fosters development of psychomotor, cognitive, and affective skills while affording initial socialization into the profession. It is expected that during these experiences, nursing students will encounter illustrative exemplars of caring and professional values. The primary stressors during initial clinical experiences arise from issues related to performance and socialization. Nursing students view a good relationship with the RNs at the clinical site as the most crucial influence on their professional growth and development. Even more distressing to students than being treated poorly themselves is watching patients receive uncaring treatment. Students' sadness and anger provoked by perceived uncaring treatment blends to form empathic distress. A content analysis of an assigned narrative from junior nursing students explores empathic anger experienced by the students during their initial clinical rotations. PMID- 20954573 TI - Health care for the homeless: a partnership between a city and a school of nursing. AB - Although there is extant research on the homeless, less is available suggesting an innovative community partnership such as Project HOPE. This partnership provided baccalaureate nursing students with greater understanding of underserved populations and health care delivery systems, and encouraged their future work with marginalized populations upon graduation. Students collected descriptive information on the homeless population. Correlations were found among site placement: age, clothing and supplies given, wound care, referrals given, assessments, and season of the year. Student evaluations revealed paradigm shifts in attitudes and inspired advocacy toward this population. Through the descriptive information and qualitative comments, we gained insight on demographics, conditions observed, and interventions offered, which provided direction for quality improvement in curriculum design for the Community Health Nursing course, direction for future student groups working in shelters and with street outreach workers, and information useful to strengthening partnerships with local organizations working with the homeless population. PMID- 20954575 TI - The obesity epidemic. AB - Obesity is common, serious, and costly. This epidemic has affected all of the United States. The related health care costs are staggering. However, many occupational health nurses have not yet implemented weight management programs at their companies or taken steps to improve their own health. This article explores the obstacles to weight loss and suggests reasons and resources to implement on site weight loss programs. PMID- 20954576 TI - Social media. AB - Various social media sites, including Facebook, have become part of everyday life. They are used by individuals of all ages and are even favored by companies and organizations as a promotional mechanism. Professional organizations, including the American Association of Occupational Health Nurses, Inc., would be remiss to overlook the potential of social media. PMID- 20954577 TI - Tailored e-mails in the workplace. AB - Employee wellness programs can potentially contribute to a stronger and healthier work force, with increased dexterity and positive mental health. Programs that keep the work force physically active can reduce heart disease, type 2 diabetes, hypertension, hyperlipidemia, cerebrovascular accident, and workplace injury. The occupational health nurse provides information to motivate employees to take the first step toward an active lifestyle. The purpose of this article is to present the qualitative evaluation results of an intervention study that tested the effectiveness of tailored e-mail communications designed to increase intentional physical activity in a group of manufacturing workers. The increase in overall physical activity demonstrates the effectiveness of the workplace interventions. Research will now strengthen theoretical concepts, refine messages, and increase both the dose and the power of the interventions. PMID- 20954578 TI - The aging nurse. AB - With the aging of the current nursing work force, nursing leaders must develop strategies to maintain current employment levels and improve availability of nurses to care for patients. One way to maintain current levels is to retain older nurses at the bedside by adapting the current working environment to meet the needs and the limitations associated with aging. This article includes a review of literature on the effects of aging on the human body, cognitively, physically, and psychosocially; current trends in the aging population; the advantages and disadvantages of employing aging nurses; retention strategies to keep aging nurses at the bedside; methods to adapt the work environment to aging nurses' needs; policies that address the needs of aging nurses; and implications for occupational health nursing practice. This article is limited to aging as it relates to nurses employed in hospitals. PMID- 20954580 TI - Dengue disease. AB - Dengue is currently the world's most rapidly spreading mosquito-borne illness. PMID- 20954581 TI - Epithelial thickness profile as a method to evaluate the effectiveness of collagen cross-linking treatment after corneal ectasia. AB - PURPOSE: To illustrate the hypothesis that epithelial thickness profile maps could be a useful adjunct to topography in monitoring patients after corneal collagen cross-linking (CXL) treatment. METHODS: Epithelial thickness profile in vivo was measured by Artemis very high-frequency (VHF) digital ultrasound scanning (ArcScan Inc) across the central 10-mm corneal diameter of a patient before collagen CXL for corneal ectasia after LASIK and at intervals up to 2 years later. Manifest refraction, corneal topography, and corneal front-surface aberrations were also monitored. Epithelial thickness changes were cross correlated with corneal topography changes and corneal front-surface aberration changes. RESULTS: Corneal collagen CXL appeared effective in halting the progression of corneal ectasia. Manifest refraction showed a reduction in spherical equivalent over time after CXL in both eyes. Corneal topography demonstrated stable central keratometry in both eyes. Corneal wavefront aberrations demonstrated a reduction of higher order root-mean-square coma and spherical aberration in both eyes. The epithelial thickness profile was altered, with a slight reduction of the area of epithelial thinning and decreased peripheral thickening. This resulted in minimizing the difference between the thinnest and thickest epithelium and might indicate an improvement of the condition. There were no significant changes in minimum stromal and minimum corneal thicknesses. CONCLUSIONS: Epithelial thickness maps provide useful information for monitoring the progression of corneal ectasia after corneal collagen CXL, showing in this case, at least no further progression of the ectasia. PMID- 20954582 TI - Bringing adjunctive treatments into the mainstream. PMID- 20954585 TI - Clip & Save Drug Chart: FDA-approved drugs to treat sleep disorders. PMID- 20954587 TI - Concentric ring scanning laser ophthalmoscope artifacts and dysphotopsia in diffractive multifocal pseudophakia. AB - A 67-year-old woman had decreased visual acuity in her left eye and disturbing concentric ring dysphotopsias after bilateral implantation of ReSTOR (SN60D3; Alcon Laboratories, Inc., Fort Worth, TX) diffractive multifocal intraocular lenses (IOLs). Monochromatic (820-nm infrared and 488-nm red-free) scanning laser ophthalmoscopy (SLO) documented central retinal concentric ring patterns resembling the patient's drawings of her dysphotopsia, prompting investigation of the relationship of these phenomena. Similar SLO findings were present in four eyes of three additional ReSTOR pseudophakes without dysphotopsia, but absent in monofocal pseudophakes or phakic individuals. Optical analysis shows that concentric ring SLO imaging artifacts can be caused by coherent reflection of monochromatic laser radiation off the diffractive optical element on the IOL's anterior surface, whereas concentric ring dysphotopsias are due to diffraction or projection of broad spectrum light sources in ordinary environments. Thus, the IOL's diffractive optics is the origin of both concentric ring dysphotopsia and SLO artifacts, but diffraction or projection causes the visual phenomenon, whereas coherent reflection produces the imaging anomaly. PMID- 20954588 TI - Ocular findings in a patient with Castleman's disease before and after treatment with immunosuppression and plasmapheresis. AB - A 12-year-old girl with a 3-month history of epistaxis and Castleman's disease presented with blurred vision in both eyes for 2 weeks. Indirect ophthalmoscopy revealed a blurred optic disc margin, venous engorgement and tortuosity, intraretinal hemorrhages and cotton wool spots, and serous detachment of the neurosensory retina in the posterior pole of each eye. Fluorescein angiography and laboratory tests revealed abnormalities consistent with the clinical examination. Six months following institution of immunosuppressive treatment, cryoglobulin levels decreased and visual acuity and funduscopic abnormalities were markedly improved. However, a few microaneurysms, retinal hemorrhages, and venous engorgement and tortuosity persisted. One month after the cessation of immunosuppressive treatment, symptoms related to the hyperviscosity syndrome recurred and the patient was treated with one session of plasmapheresis. One month after the plasmapheresis, the patient's symptoms resolved, laboratory values were normal, visual acuity was 20/15 in both eyes, and the funduscopic examination of each eye was unremarkable. PMID- 20954589 TI - Desperate times call for desperate measures: where are we in addressing academic dishonesty? PMID- 20954590 TI - Reflective journaling 2.0: using blogs to enhance experiential learning. PMID- 20954591 TI - Limbal relaxing incisions using a reference point and corneal topography for intraoperative identification of the steepest meridian. AB - PURPOSE: To examine the efficacy and safety of topography-based limbal relaxing incision (LRI) surgery. METHODS: Forty-four eyes of 36 consecutive patients who underwent cataract surgery more than 1 month previously, had refractive against the-rule astigmatism of >=2.00 diopters (D), and were scheduled to undergo LRI surgery were enrolled in the study. Patients were randomized into two groups-a topography-based LRI group (19 eyes of 14 patients) and a conventional LRI group (25 eyes of 22 patients). The topography-based LRI procedure comprised 3 steps: placing a mark on the cornea and conjunctiva, identifying this mark in the topographic image, and performing LRI based on the location of the mark. In the conventional LRI group, the horizontal meridian was marked under a slit lamp and LRIs were made based on the position of the horizontal mark. RESULTS: Corneal astigmatism in the topography-based LRI group before and 1 month after surgery was 2.03+/-0.92 D and 1.33+/-0.69 D, respectively (P=.014). Corneal astigmatism in the conventional LRI group before and 1 month after surgery was 2.36+/-0.77 D and 0.93+/-0.70 D, respectively (P<.0001). Fourier harmonic analysis of the topography data demonstrated that regular astigmatism was significantly decreased in the two groups. The mean regular astigmatism was not significantly different before and after LRI between groups, whereas the variances (mean of the deviation squared from its mean) of regular astigmatism were significantly different between groups 1 month after LRI. CONCLUSIONS: Compared with conventional LRI surgery, a topography-based procedure may reduce the deviation of the effect of LRIs. PMID- 20954592 TI - New axis-marking method for a toric intraocular lens: mapping method. AB - PURPOSE: A new axis-marking method, the mapping method, for toric intraocular lens (IOL) implantation is described, and its accuracy is compared with that of conventional methods. METHODS: For toric IOL implantation, the steepest corneal axis was determined by IOLMaster optical biometer measurement (Carl Zeiss Meditec). Three marking methods for accurate alignment of the IOL astigmatism axis to the steepest corneal axis were evaluated and compared. For method 1, the patient was seated at the surgical table and instructed to gaze at a distant target. Using a toric reference marker, the corneal limbus was marked at the 3-, 6-, and 9-o'clock positions. The goal axis was also marked using a toric axis marker. Method 2 used a horizontal slit beam for reference marking points at 3 and 9 o'clock. Method 3 was the new mapping method, in which an anterior segment photograph was used to identify several reference vessel points and axis marking points and to calculate actual lengths from the reference vessel points to the axis marking points. During surgery, the axis marking points were marked on the limbus of the eye using calipers. The accuracy of the three axis-marking methods was evaluated using anterior segment photographs. RESULTS: With method 1, the average axis-marking error was 3.69+/-1.49 degrees . With method 2, the average axis-marking error was 3.14+/-1.64 degrees . With method 3, the new mapping method, the average axis-marking error was 2.29+/-1.06 degrees . The new mapping method was more accurate than methods 1 and 2 (P<.01 and P=.016, respectively, paired t test). Axis-marking errors of the two conventional methods were not significantly different (P=.061). CONCLUSIONS: The new axis-marking method, which uses distinct conjunctival vessels as a reference point, showed less axis-marking error compared to the conventional methods examined in this study. PMID- 20954593 TI - Correlation among ocular spherical aberration, corneal spherical aberration, and corneal asphericity before and after LASIK for myopic astigmatism with the SCHWIND AMARIS platform. AB - PURPOSE: To determine the spherical wave aberration of the human eye based on corneal topography. METHODS: Based on the pre- and postoperative status of 146 consecutive eyes (median patient age 36 years), the correlations between spherical aberration and asphericity and between corneal and ocular spherical aberrations were determined using simple linear regression methods. The asphericity (Q) values for which spherical aberration equals zero as well as the reference Q values for which corneal spherical aberration equals ocular spherical aberration have been determined. Patients underwent LASIK using the AMARIS excimer laser platform (SCHWIND eye-tech-solutions). All ablations were based on aspheric aberration-neutral profiles. RESULTS: Corneal and ocular spherical aberrations correlate well with Q value and the value p . R(-3) in patients before and after LASIK for myopic astigmatism. A Q value of -0.19 to -0.27 can provide zero ocular spherical aberration in patients before and after LASIK for myopic astigmatism. Ocular spherical aberration is induced at a rate of half the induced corneal spherical aberration. A reference Q value of -0.12 to +0.01 can provide corneal spherical aberration equal to ocular spherical aberration in patients before and after LASIK for myopic astigmatism. CONCLUSIONS: Ocular and corneal wave aberrations are two different concepts that are not interchangeable. As for spherical aberration, a simple static model with a reference cornea deviating from a Cartesian oval can provide a 2:1 correspondence between corneal and ocular spherical aberration. PMID- 20954594 TI - Finding a professional home. PMID- 20954595 TI - Poster presentations. AB - Poster presentations are often part of major conferences. This column offers suggestions for working with presenters and information about facilitating the poster session process in continuing nursing education. PMID- 20954596 TI - Uncivil student behaviors in clinical settings: strategies for clinical nurse educators. AB - Clinical educators may have difficulty determining how best to respond to uncivil behaviors from students in clinical settings. This column describes communication, ground rules, and policy enabling clinical educators to teach effectively and minimize inappropriate student responses. PMID- 20954598 TI - Anemia of chronic disease, older adults, and medicare. PMID- 20954599 TI - MDS 3.0 Section O: an update for certified therapeutic recreation practice with medicare patients. PMID- 20954603 TI - Skin emergencies. PMID- 20954604 TI - This issue: skin emergencies. PMID- 20954606 TI - A 20-year-old male with back pain. Neuroblastoma. PMID- 20954605 TI - A 15-year-old boy with vomiting, abdominal distention. PMID- 20954607 TI - A 7-year-old girl with ongoing weight loss. Hypophosphatemic rickets. PMID- 20954608 TI - Cutaneous drug reactions in children. PMID- 20954609 TI - MRSA, staphylococcal scalded skin syndrome, and other cutaneous bacterial emergencies. PMID- 20954610 TI - Blisters and pustules in the newborn. PMID- 20954611 TI - Bruising in infancy: when is it an emergency? PMID- 20954612 TI - Eczema herpeticum and eczema vaccinatum in children. PMID- 20954613 TI - Stevens-Johnson syndrome and toxic epidermal necrolysis. PMID- 20954614 TI - Radiologic case study. Peroneus longus rupture. PMID- 20954615 TI - Understanding the molecular basis of polydactyly. PMID- 20954616 TI - The dilemma of the wedding band. PMID- 20954617 TI - Additional thoughts on orthopedic residency and fellowships. PMID- 20954618 TI - The no-touch approach for operative treatment of pilon fractures to minimize soft tissue complications. PMID- 20954619 TI - Limb preservation in patients with bone and soft tissue tumors. PMID- 20954620 TI - Introduction of new devices and technologies into a spine surgery practice: a review of processes and regulations. PMID- 20954621 TI - Vitamin D supplementation to reduce the risk of falls and fractures: the dosing dilemma. PMID- 20954622 TI - The influence of fracture fixation biomechanics on fracture healing. PMID- 20954623 TI - Should age be a determining factor in total hip arthroplasty? PMID- 20954624 TI - Acute achilles tendon ruptures. PMID- 20954627 TI - Evidence for what purpose? PMID- 20954628 TI - Use of image-free navigation in determination of acetabular cup orientation: analysis of factors affecting precision. AB - We have been using an image-free total hip arthroplasty (THA) navigation system (OrthoPilot; Aesculap, Tuttlingen, Germany) to ensure accurate and reproducible acetabular cup orientation. In this study, the accuracy of this system in the assessment of acetabular cup orientation was evaluated by comparing the intraoperative inclination and anteversion angles presented by the navigation system and the corresponding postoperative values obtained by computed tomography measurement. In the intraoperative accuracy analysis, we additionally examined the influence of factors such as body mass index and soft tissue thickness on assessment error. Intraoperative and postoperative results obtained from 115 consecutive navigated THAs were compared and analyzed. In both inclination and anteversion angles, good agreement was observed; a discrepancy of more than 5 degrees was observed in 1 and 3 cases, respectively. In the analysis of factors potentially affecting the accuracy of the intraoperative assessment, no correlation between each parameter and the intraoperative and postoperative discrepancy was demonstrated. PMID- 20954629 TI - Acetabular center axis: is it the future of hip navigation? AB - There are 2 distinct methods of cup navigation in total hip arthroplasty. One predicts orientation of the acetabulum through bony landmarks outside the acetabulum (eg, the anterior pelvic plane); its unreliability is well published. The other identifies acetabular center axis (ACA) and is patient-specific method that is independent of pelvic tilt, making it more reliable. Data from readily palpable acetabular registration points were compared with postoperative pelvic computed tomography images in 137 cases. Findings show that ACA software is accurate in determining acetabular/cup version and inclination. Cup center axis should coincide within 4 mm of ACA to minimize impingement and maximize stability without altering preoperative femoral version. PMID- 20954630 TI - 3D CT analysis of combined cup and stem anteversion in cases of cup navigation in hip arthroplasty. AB - Navigation of the cup in total hip arthroplasty is well analyzed and shows accurate results, reducing cup outliers of Lewinnek's "safe zone." With regard to the combined anteversion of cup and stem, however, a "new" safe zone with a range of 25 degrees to 50 degrees has been published. The aim of this study was to analyze total anteversion (cup and stem) by postoperative 3D computed tomography in isolated cup navigation cases. In 46 patients, the mean combined anteversion was 34.4 degrees (range, 16.3 degrees -57.3 degrees , SD +/- 9.3 degrees ) with 10 outliers. The mean cup anteversion was 19.5 degrees (range, 11 degrees -27 degrees , SD +/- 3.7 degrees ). Regarding Lewinnek's "safe zone" (cup only), we observed 5 outliers. An improvement of technique of stem implantation or navigation may reduce outliers of combined anteversion. PMID- 20954631 TI - Computer-assisted revision of failed unicompartmental knee arthroplasty. AB - The authors performed a matched-paired study comparing 22 computer-assisted surgery (CAS)-unicompartmental knee replacement (UKR) revisions with a similar group of knee replacement revisions performed conventionally. The aim of the study was to assess differences in implants used in the revision, surgical time, limb alignment, joint line restoration, and procedure costs. In the conventional group, there was a higher percentage of posterior stabilized (PS) and condylar constrained knee (CCK) implants, as well as a higher percentage of augmentations/stems/offsets. There were no statistically significant differences in postoperative mechanical axis, surgical time, or hospital stay. There were fewer outliers and better joint line restoration in the CAS group. More blood transfusions were performed in the conventional group, and costs were higher in this group as well. PMID- 20954632 TI - Navigated revision TKR: a comparative study with conventional instruments. AB - We selected 86 cases for the study: 50 navigated revision total knee replacements (TKRs) and 36 conventional revision TKRs. We hypothesized that the rate of satisfactory implantation would be higher for navigated revision TKR than for conventional revision TKR. The primary criterion was the rate of optimally implanted prostheses on postoperative anteroposterior and lateral long leg radiographs. Thirty-one navigated cases (62%) and 14 conventional cases (39%) had an optimal global implantation (P<.05). The use of a standard navigation software for revision TKR allows a significant improvement of the accuracy of implantation. However, development of dedicated software will allow addressing more precisely the specific features of a revision TKR, such as stem extension navigation, defects filling, and joint line reconstruction. PMID- 20954633 TI - Novel approach to reducing discrepancies in radiographic and navigational limb alignments in computer-assisted TKA. AB - This study was conducted (1) to document discrepancies between preoperative and postoperative radiographic measurements and postregistration and postimplantation intraoperative navigational measurements of coronal limb alignments, and (2) to identify predictors of discrepancies between radiographic and navigational measures. In addition, we propose the use of a novel radiographic measuring method, and we demonstrate that this method reduces discrepancies. For 107 total knee arthroplasties performed using a navigation system, coronal alignment were assessed using preoperative and postoperative whole limb radiographs using the standard and novel radiographic methods. During surgery, coronal limb alignment was measured using the navigation system postregistration and postprosthesis implantation. Strengths of correlations and discrepancies between radiographic and navigational assessments were compared between the standard and novel methods. Multivariate regression was performed to identify predictors of discrepancies. Differences between radiographic and navigational measurements were observed for both preoperative and postoperative assessments, but discrepancies were greater for preoperative assessments, despite their stronger correlations. Extent of preoperative varus deformity was identified as the strongest predictor of discrepancy in preoperative radiographic and navigational measurements, and varus malalignment was identified as the strongest predictor of discrepancy in postoperative measurements. Strengths of correlations between radiographic and navigational measurements were similar for the standard and novel radiographic methods, but discrepancies between the 2 were significantly smaller for the novel method for both preoperative and postoperative assessments. The authors propose the use of the described novel radiographic method that reduces discrepancies between radiographic and navigational measurements. PMID- 20954634 TI - Primary resection of the posterior cruciate ligament does not produce a gap mismatch in the navigated gap technique. AB - Treatment of the posterior cruciate ligament (PCL) is a matter of continued controversy in total knee arthroplasty. By using so-called cruciate ligament substituting implant designs, retention and resection of the PCL produce equivalent clinical results. However, it remains unclear whether primary resection of the PCL leads to relevant instabilities of the flexion gap. Especially when the increasingly popular navigated gap technique is used, this would result in a nonanatomic size selection and positioning of the femoral component and thus compromise the clinical outcome. The objective of this retrospective study was therefore to determine whether the navigated gap technique leads to a mismatch of the flexion and extension gap in primary routine resection of the PCL. In 92 patients consecutively enrolled in this study (92 knees), the flexion and extension gap were determined and documented after tibial resection, using the navigated gap technique navigation system (OrthoPilot 4.0; B. Braun Aesculap, Tuttlingen, Germany). The flexion gap was 10.4 +/- 2.6 (2.5 19.5) mm; the extension gap was 10.4 +/- 2.4 (5.5-17.5) mm. The individual difference was normally distributed around 0.0 +/- 2.9 (-7 to 7) mm. In the navigated gap technique, primary routine resection of the PCL does not lead to a mismatch of the flexion and extension gap, so that a systematic nonanatomic resection of the femur can be ruled out. PMID- 20954635 TI - Computer modeling to predict effects of implant malpositioning during TKA. AB - Computer-assisted surgery has focused on alignment of implants and soft tissue balancing but the end results during surgery as they pertain to long-term function of the implants are not yet realized. One parameter that continues to be variable despite the use of computer navigation is the placement of the implants in the transverse plane. The objective of this study was to determine whether implant and anatomic registrations could be used in a computer model (LifeMOD/KneeSIM, LifeModeler, Inc., San Clemente, California) to show differences in the resulting contact patterns of the medial and lateral condyles of the polyethylene insert. The simulations included tibiofemoral and patellofemoral contact, passive soft tissue (medial and lateral collateral, and posterior cruciate ligaments, as well as the capsular tissues), and active muscle elements (quadriceps and hamstrings). Components of a fixed-bearing cruciate retaining total knee (Columbus knee system; B. Braun Aesculap, Tuttlingen, Germany) were imported into the model. The systems were subjected to one 60 second cycle of a lunge. Both the femoral and the tibial components were positioned in 5 degrees of internal or external rotation in varying combinations and the resulting kinematics analyzed. The resulting kinematics showed variations in anteroposterior translation of the lateral and medial femoral condyles that resembled several of those reported in the literature for individual patients with a cruciate-retaining knee implant system. PMID- 20954636 TI - Clinical and radiologic outcomes of contemporary 3 techniques of TKA. AB - This report compares the radiologic and early clinical results of total knee arthroplasty (TKA) performed by the same surgeon using 3 techniques. In this prospective study, 75 knees were randomized to conventional technique (25 knees), image-free navigation system (25 knees), or minimally invasive surgery (MIS) (25 knees). Age range of the 43 women (65 knees) and 5 men (10 knees) was 58 to 81 years. Posterior stabilized knee prosthesis was used in all patients. Data was collected according to Knee Society System for radiologic evaluation of x-rays. Knee Society clinical (KS-C) and functional knee scores were measured preoperatively and at 6 weeks, 3 months, 6 months, 1 year, and 2 years. The postoperative KS-C was not statistically better in the MIS group (mean, 88 +/- 11.5; range, 70-100) than the conventional (mean, 85.9 +/- 7.8; range, 74-94) (P=.68) or navigation group (mean, 85 +/- 11; range, 63-100) (P=.59). Mean postoperative delta (mechanical axis) angle was significantly different (P=.014): 2.38 degrees in the conventional group (SD=2.88 degrees ; 95% CI, 1.19 degrees 3.57 degrees ; range, -1.59 degrees to 6.86 degrees ), 0.61 degrees in the navigation group (SD=2.07 degrees ; 95% CI, -0.24 degrees to 1.46 degrees ; range, -2.07 degrees to 4.25 degrees ), and 4.25 degrees in the MIS group (SD=6.52 degrees ; 95% CI, 1.56 degrees -6.94 degrees ; range, -6.72 degrees to 15.60 degrees ). Significant difference could be elicited between navigation assisted and MIS groups, with navigation-assisted surgery providing more accurate alignment of the mechanical axis (P=.014). Of the three techniques, navigation assisted surgery gives superior prosthesis alignment and promising longevity of TKA. PMID- 20954637 TI - Computer-assisted high tibial osteotomy: preliminary results. AB - Open-wedge high tibial osteotomy (HTO) is an established technique for the treatment of symptomatic varus malaligned knees. In this study, we prospectively followed up 13 patients (14 knees) who underwent navigation system-supported HTO for varus knee deformity. Preoperatively all patients underwent a physical examination, and anteroposterior and laterolateral lower limb weight-bearing digital radiographs were obtained. The following parameters were examined: (1) Insall-Salvati index; (2) posterior tibial slope angle; (3) mechanical femorotibial angle; (4) inferior limb length. At a mean follow-up of 12.6 months, clinical examination showed satisfactory results in all patients. The mean Modified Cincinnati Rating System Questionnaire rating increased significantly from 46.5 +/- 7.2 to 84.6 +/- 8, while the mean Knee Society Score increased significantly from 51.4 +/- 9.9 to 85.1 +/- 7.3. The mean Insall-Salvati index changed from 1.11 preoperatively to 1.10 postoperatively (P=.742). According to the navigation system data, the femorotibial mechanical axis was corrected from a varus of 6.3 degrees +/- 1.9 degrees to a valgus of 2.1 degrees +/- 1.6 degrees . These data matched postoperative radiographic lower limb weight-bearing data. In the group of patients in whom we evaluated the posterior tibial slope with the navigation system, we detected an increase of 0.3 degrees +/- 0.4 degrees compared with the preoperative radiographic examination evaluations; the comparison between the postoperative and the preoperative radiograhic examination results showed an increase of 0.5 degrees +/- 0.7 degrees (P=.87). The results of our study seem to show greater accuracy of mechanical axis correction and smaller increase in tibial slope when a navigation system is used in open-wedge HTO. PMID- 20954638 TI - Navigated knee kinematics after tear of the ACL and its secondary restraints: preliminary results. AB - In this study we evaluated the role of the anterior cruciate ligament (ACL) and its secondary restraint in controlling knee stability using a navigation system. The purpose of this study was to evaluate the kinematics of the knee in different conditions of instability: ACL intact, after transection of the posterolateral (PL) bundle, after transection of the anteromedial (AM) bundle, and after lesion of the anterolateral femorotibial ligament (ALFTL). Anterior tibial translation and rotation were measured with a computer navigation system in 6 knees in whole fresh-frozen human cadavers by use of a manual maximum load. Anterior translation was evaluated at 30 degrees , 60 degrees , and 90 degrees of flexion; rotation at 0 degrees , 15 degrees , 30 degrees , 45 degrees , 60 degrees , and 90 degrees of flexion. Cutting the PL bundle does not increase anterior translation and rotation of the knee. Cutting the AM bundle significantly increased the anteroposterior (AP) translation at 30 degrees and 60 degrees of flexion (P=.01), but does not increase rotation of the knee. Cutting the ALFTL increased anterior translation at 60 degrees of flexion (P=.04) and rotation at 30 degrees , 45 degrees , and 60 degrees of flexion (P=.03). The PL bundle does not affect anterior translation and rotation of the knee. The AM bundle is the primary restraint of the anterior translation but does not affect rotation of the knee. The lateral compartment becomes the primary restraint of rotation after ACL cut. The primary kinematic effect of an ACL injury is an increase in anterior tibial translation, but there is no significant change in maximum internal or external rotation. The lesion of the ALFTL increases tibial rotation and could be correlated to the pivot shift phenomenon. PMID- 20954639 TI - Comparison of intraoperative stability in ACL reconstruction based on femoral tunnel positions. AB - This study evaluated and compared the intraoperative stabilities using the low and high femoral tunnel techniques in ACL reconstruction. Seventy patients who underwent ACL reconstruction were equally allocated to low or high femoral tunnel groups (35 in the low femoral tunnel group and 35 in the high femoral tunnel group) for this study. The authors compared intraoperative anterior, internal rotational, and external rotational stabilities at 0 degrees , 30 degrees , 60 degrees , and 90 degrees of knee flexion using a navigation system after reconstruction. The low femoral tunnel group showed significantly better intraoperative internal rotational stability at 0 degrees and 30 degrees of flexion than the high tunnel group; however, no significant intergroup differences were found for anterior and external rotational stabilities at any flexion angle. These findings suggested that the low femoral tunnel group showed better internal rotational stability at time zero condition during ACL reconstruction than the high femoral tunnel group, but anterior and external rotational stabilities were similar. However, to determine whether these results may affect clinical results, further studies based on more accurate measurement of rotational stability in clinical settings are needed. PMID- 20954640 TI - Conversion to deep anterior lamellar keratoplasty (DALK): learning curve with big bubble technique. AB - BACKGROUND AND OBJECTIVE: To report the perioperative complications and clinical outcomes of 50 deep anterior lamellar keratoplasty (DALK) cases. PATIENTS AND METHODS: Fifty eyes of 50 patients with pathologies involving the corneal stroma and sparing the Descemet's membrane and endothelium were included consecutively in this prospective, noncomparative interventional case series study. DALK was performed using the big-bubble technique. RESULTS: The most frequent indication for DALK surgery was keratoconus (26 eyes), followed by corneal dystrophy (10 eyes) and superficial corneal scar (14 eyes). The average follow-up period was 12.0 +/- 3.9 months. DALK was completed in 41 cases (82%). A big bubble was achieved successfully in 37 cases (74%). Descemet's membrane perforations occurred in 14 (28%) eyes, 8 of which were macroperforation and necessitated conversion to penetrating keratoplasty. Complications tended to decrease throughout the study. Postoperative best-corrected visual acuity of 0.5 or better was present in 30 of 41 (73.2%) eyes that underwent DALK. There was no episode of graft rejection. CONCLUSION: DALK big-bubble technique may be a valuable procedure during transition from penetrating keratoplasty to anterior lamellar keratoplasty. It provided acceptable visual and refractive outcome even during the learning period in a variety of corneal lesions. PMID- 20954642 TI - Optical coherence tomography/scanning laser ophthalmoscopy imaging of optic nerve head drusen. AB - BACKGROUND AND OBJECTIVE: To evaluate optical coherence tomography/scanning laser ophthalmoscopy (OCT/SLO) imaging for optic nerve head drusen (ONHD). PATIENTS AND METHODS: Nine consecutive eyes with ONHD were imaged. Each underwent visual field testing, 20-MHz B-scan ultrasonography, photography, and OCT/SLO imaging of the nerve head. Similar evaluation was performed on 12 matched, disease-free control eyes for comparison. RESULTS: OCT/SLO imaging of ONHD demonstrated lucencies (100%), variable amounts of displacement, and thickening of the overlying nerve fiber layer, as well as disorganization of the adjacent retinal pigment epithelium (44%). Optic nerve head topography was measured (using horizontal and vertical electronic calipers). Mean disc diameter was 1.81 mm (range: 1.49 to 2.12 mm). All ONHD demonstrated anterior displacement of the base of the optic nerve cup (shallowing) compared to controls. The cup base was a mean +0.32 mm anterior to the retinal pigment epithelium for ONHD versus -0.23 mm for normal controls. CONCLUSION: OCT/SLO revealed unique and clinically helpful views of ONHD. PMID- 20954641 TI - Stanford University network for diagnosis of retinopathy of prematurity (SUNDROP): 36-month experience with telemedicine screening. AB - BACKGROUND AND OBJECTIVE: to report the 36-month experience of the Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) telemedicine initiative. PATIENTS AND METHODS: retrospective analysis of the SUNDROP archival data between December 1, 2005, and November 30, 2008, to evaluate this diagnostic technology for retinopathy of prematurity (ROP) screening. A total of 230 consecutively enrolled infants meeting ROP examination criteria were screened with the Ret-Cam II (Clarity Medical Systems, Pleasanton, CA) and evaluated by the SUNDROP reading center at Stanford University. Outcomes included referral-warranted ROP, treatment-warranted ROP, and anatomic outcomes. RESULTS: in the initial 36-month period, the SUNDROP telemedicine initiative did not miss any treatment-warranted ROP. A total of 230 infants (460 eyes) were imaged, resulting in 1,059 examinations and 10,921 unique images. Ten infants were identified with referral-warranted ROP: nine underwent laser photocoagulation and one regressed spontaneously. The sensitivity was 100% with a specificity of 99.5%. No patient progressed to retinal detachment or other adverse outcomes. CONCLUSION: the SUNDROP telemedicine screening initiative for ROP has demonstrated high reliability for identification of treatment-warranted disease. All cases of treatment-warranted disease were captured. There were no adverse outcomes. PMID- 20954643 TI - Narrow- and open-angle measurements with anterior-segment optical coherence tomography and PentacamTM. AB - BACKGROUND AND OBJECTIVE: To assess the agreement of the Pentacam (Oculus, Wetzlar, Germany) and anterior-segment optical coherence tomography (AS-OCT) in measuring open and narrow angles. PATIENTS AND METHODS: Prospective observational case series in which 39 healthy normal subjects (39 eyes) and 25 patients with narrow angles (37 eyes) were enrolled between May and September 2008. The anterior chamber measurements were performed by AS-OCT and the Pentacam. RESULTS: There was no significant difference in the open-angle measurements between the Pentacam and AS-OCT (P > .05). However, in patients with narrow angles, the average values of nasal and temporal anterior chamber angles taken by the Pentacam were larger than those of AS-OCT (25.5 degrees +/- 5.66 degrees and 25.77 degrees +/- 5.15 degrees vs 13.40 degrees +/- 6.81 degrees and 12.13 degrees +/- 6.47 degrees ; P < .001). CONCLUSION: Both AS-OCT and the Pentacam can reliably measure anterior chamber angles in healthy normal subjects. The difference in measuring narrow angles by the two instruments was due to inability to view the angle recess or the scleral spur with the Pentacam. PMID- 20954644 TI - A machine vision method for automated alignment of fundus imaging systems. AB - BACKGROUND AND OBJECTIVE: To report a method to track the pupil in three axes simultaneously prior to imaging the fundus. PATIENTS AND METHODS: The system is based on parallax optical alignment to detect the center of the pupil. The system consists of two cameras acquiring pupil images from two distinct directions and an operator-supervised algorithm to derive the coordinates of the pupil center and output of commands to drive a three-axes computer-controlled stage. The system was tested in a cohort of 45 individuals 61 +/- 15 years of age, 26 with and 19 without glaucoma. The tracking was performed without pharmacologic pupil dilation. RESULTS: The variability of the pupil center determination (assessed by the standard deviation) was +/- 0.19 and +/- 0.33 mm for the vertical and horizontal directions, respectively. The processing time of the algorithm was 0.75 msec. The tracking converged to within a preset tolerance of +/- 0.5 mm in 45 of the 45 eyes. CONCLUSION: Image acquisition and processing of pupil images can be used to align fundus imaging systems rapidly, accurately, and with minimal operator intervention. PMID- 20954645 TI - Reduction of Nd:YAG capsulotomy rates after implantation of a single-piece acrylic hydrophilic intraocular lens with 360 degrees squared optic edge: 24 month results. AB - BACKGROUND AND OBJECTIVE: Posterior capsule opacification remains a significant problem following cataract surgery. The aim of the study was to evaluate the incidence of symptomatic posterior capsule opacification requiring Nd:YAG capsulotomy in patients who underwent cataract extraction and implantation of the Rayner C-flex 570C intraocular lens (IOL) (Rayner Intraocular Lens, Ltd., Sussex, UK). PATIENTS AND METHODS: A retrospective study of 3,461 eyes that underwent cataract extraction and insertion of the Rayner C-flex IOL from January 2004 to December 2005. The cases that received Nd: YAG capsulotomies were evaluated. RESULTS: Over a 24-month period, 3,461 Rayner C-flex IOLs were implanted. Nd:YAG capsulotomy was performed in 58 of these cases. The rate of Nd:YAG capsulotomy was 0.6% at 12 months and 1.7% at 24 months. The mean time to Nd:YAG capsulotomy was 9.3 months (range: 1.3 to 22.7 months). The follow-up period was 5.3 to 29.0 months. CONCLUSION: The incidence of symptomatic posterior capsule opacification with the Rayner C-flex IOL is low. PMID- 20954646 TI - Sleeve technique to maintain a large mucosal ostium during endoscopic dacryocystorhinostomy. AB - Currently, many surgeons use bicanalicular silicone tubes as a stent to keep the intranasal mucosal ostium patent when they perform endoscopic dacryocystorhinostomy. The authors describe the sleeve technique using bicanalicular silicone tubes. After inserting the bicanalicular silicone tube, a sleeve is passed over it. The sleeve prevents the nasal mucosa from obstructing the intranasal mucosal ostium and enlarges the mucosal ostium. In primary acquired nasolacrimal duct obstruction, the sleeve technique was applied to 61 cases (group 1); the other 75 cases (group 2) were intubated by bicanalicular silicone tube only. The overall success rate was 95.1% in group 1 and 90.7% in group 2 (P = .51), and the average mucosal ostium at 6 months postoperatively was 3.2 +/- 1.1 and 1.9 +/- 1.0 mm (P = .04), respectively. The authors believe that the sleeve technique has the advantage of maintaining a larger intranasal mucosal ostium. PMID- 20954647 TI - Imaging modalities for localization of an iStent((r)). AB - The iStent (Glaukos Corporation, Laguna Hills, CA) is a 1-mm, titanium trabecular bypass stent implanted across the inner wall of Schlemm's canal under direct gonioscopy. This study was designed to determine the best modality to identify iStent placement when gonioscopic visualization is not possible. In this in vitro study on a human cadaver eye, ultrasound biomicroscopy (UBM), anterior segment optical coherence tomography (AS-OCT), and B-scan ultrasonography were done to visualize and precisely locate two intentionally misplaced iStents. UBM could localize both intentionally misplaced stents, whereas AS-OCT could not visualize the iStent that was lodged in the sulcus. B-scan ultrasonography was unable to detect either of the stents. UBM may be a useful imaging modality to identify iStent in the anterior or posterior chamber, whereas AS-OCT is limited to detection of stents in the anterior chamber alone. B-scan ultrasonography is unable to identify iStent in either the anterior or posterior chamber. PMID- 20954648 TI - Development of subretinal fibrosis after anti-VEGF treatment in neovascular age related macular degeneration. AB - BACKGROUND AND OBJECTIVE: to describe the development or progression of subfoveal fibrosis after anti-vascular endothelial growth factor (VEGF) therapy in the absence of significant subfoveal hemorrhage in neovascular age-related macular degeneration. PATIENTS AND METHODS: retrospective case series. RESULTS: seven eyes of seven patients with neovascular age-related macular degeneration developed subfoveal fibrosis after anti-VEGF therapy in the absence of significant subfoveal hemorrhage. Five of seven patients experienced vision loss of 0.3 logarithm of the minimum angle of resolution units or greater. CONCLUSION: subfoveal fibrosis may develop or progress in neovascular age-related macular degeneration despite the absence of significant subfoveal hemorrhage and treatment with anti-VEGF. Development of anti-fibrotic therapeutics may be beneficial in reducing the incidence of subretinal fibrosis. PMID- 20954649 TI - Anatomical reconstruction of the knee extensor apparatus for prepatellar myxofibrosarcoma. AB - A novel reconstruction of the knee extensor apparatus was attempted in a 69-year old patient with prepatellar myxoid fibrosarcoma. The skin (35*25 cm), subcutaneous tumor, quadriceps tendon, patella, anterior capsule, and patella tendon were widely resected en-bloc. Following wide resection, the excised quadriceps tendon, patella, and patella tendon were anatomically reimplanted into the original site after being devitalized in liquid nitrogen. These complexes were covered by a free vascularized latissimus dorsi myocutaneous flap. At 18 month follow-up, the strength of active knee extension was 4+ of 5 in the muscle manual test. The active range of motion was 110 degrees in flexion and -10 degrees in extension. The tumor showed no evidence of disease. The patella and femur joint showed no osteoarthritis on plain radiographs. This procedure is the only way to achieve anatomical reconstruction. Reattachment of patella tendon to the tibial tuberosity was possible. The use of liquid nitrogen to devitalize is straightforward and the operation time can be shortened. To our knowledge, this type of reconstructive procedure has never been reported in the English literature. PMID- 20954650 TI - Bilateral simultaneous femoral diaphyseal fractures in a patient with long-term ibandronate use. AB - Bisphosphonates are the most common medication used to treat patients with documented osteoporosis. Recently, reports have associated long-term bisphosphonate use with low-energy femur fractures. While no definitive mechanism has been associated, bisphosphonate use has been strongly implicated. This article presents the case of a 65-year-old woman with a 2-year history of ibandronate use presenting with simultaneous low-energy femoral shaft fractures. The patient reported prodromal bilateral thigh pain and was seen by a spine surgeon. A review of the literature implicates long-term ibandronate use in low energy femur fractures. With most of the basic science studies demonstrating suppressed bone turnover after 5 years of treatment with alendronate, the significance of the present case also lies in the relatively short duration of time the patient was on ibandronate before suffering the bilateral femoral shaft fractures. Possible pathophysiology for the fractures includes suppressed bone turnover that may allow microcracks to propagate in cortical bone, which can weaken the bone and possibly predispose it to fractures. Patients who have been on bisphosphonates long term should be questioned about thigh pain and have radiographs of their femurs obtained if pain exists. Furthermore, if a patient presents with a single subtrochanteric or diaphyseal low-energy femur fracture after long-term bisphosphonate use, a radiograph of the contralateral femur should be obtained to assess for a cortical stress reaction. PMID- 20954651 TI - Extracorporeal shock wave therapy for calcific tendinitis at unusual sites around the hip. AB - Extracorporeal shock wave therapy has been considered to be an effective treatment for various pathogenic orthopedic conditions. However, it is not generally recognized in treatment for calcific tendinitis around the hip region. This article presents 2 cases of calcific tendinitis at the hip, located in the pectineus muscle and the rectus femoris muscle, where successful treatment was achieved using extracorporeal shock wave therapy. In 1 case, a 60-year-old woman presented with pain in her right thigh of 1 month's duration that had become severe in intensity for 1 week. Physical examination revealed marked localized tenderness over the posterolateral aspect of the right thigh when positioned in flexion, abduction, and external rotation. Anteroposterior and frog-leg lateral radiographs revealed nodular-shaped calcium deposits at the posterolateral aspect of the proximal thigh. T1- and T2-weighted magnetic resonance imaging of the hip joint revealed a 2.7*1.3-cm, low-signal density area near the femoral insertion of pectineus and gluteus maximus muscle with inflammatory infiltration in the surrounding soft tissue. Treatment was started in the form of extracorporeal shock wave therapy, doses of which were administered in 3 sessions with an interval of 7 days. Radiographs of the affected thigh taken 4 weeks after therapy showed disintegration of the calcium deposits. PMID- 20954652 TI - Bilateral femoral neck stress fractures in a fire academy student. AB - Unilateral femoral neck stress fractures are well documented in active patients; however, the risk of a subsequent contralateral stress fracture remains unknown in patients who continue to be active. This article describes a 24-year-old male fire academy student who sustained a left femoral neck stress fracture, followed approximately 11 months later by a right femoral neck stress fracture, both of which went on to completely displace. A review of the index radiographs of each hip from outside institutions revealed femoral neck stress fractures that went undiagnosed until they displaced. The patient was referred to our institution and underwent closed reduction and internal fixation using cannulated screws in both cases. A full endocrine evaluation was performed in the following weeks and proved unremarkable. Although it is difficult to extrapolate the results from 1 patient beyond the case studied, there is cause for concern in patients who remain active following femoral neck stress fractures. Our case highlights the significance of obtaining a complete and thorough medical history on physical examination and appropriately counseling patients regarding activity level. Until further research explores this possible relationship, physicians evaluating patients with a history of a stress fracture are encouraged to be vigilant of subsequent contralateral fractures and educate patients of this potentially avoidable injury. PMID- 20954653 TI - Septic knee-induced deep venous thrombosis in a young adult. AB - This article describes a case of a 26-year-old man presenting with left knee pain of 1 week's duration, fever, and acute onset of shortness of breath the day of admission. An arthrocentesis of the knee joint was grossly positive for methicillin-resistant Staphylococcus aureus. A left lower extremity venous duplex showed thrombosis of the superficial femoral, popliteal, posterior tibial, peroneal, and gastrocnemius veins. Pulmonary computed tomography-angiography was positive for acute pulmonary emboli. Initial management consisted of anticoagulation, intravenous antibiotics, and 2 arthroscopic irrigation and debridement procedures. After a normal transesophageal echocardiogram, a diagnosis of septic knee-induced deep venous thrombosis (DVT) of the left lower leg with subsequent septic pulmonary emboli was established. The patient was discharged to a long-term care facility for a 6-week monitored course of intravenous antibiotics. His DVT and pulmonary emboli were managed successfully with oral warfarin. Two months after his initial presentation, the patient returned with acute worsening knee pain. A knee arthrocentesis was unremarkable; however, radiographic imaging revealed fulminant osteomyelitis of the distal femur. He has since undergone open arthrotomy with excisional irrigation and debridement and is on a chronic oral antibiotic regimen. Sparse pediatric literature has shown an association between musculoskeletal sepsis and thrombosis. Only 1 case of septic knee-induced DVT exists in the adult literature, and it was not associated with pulmonary emboli. Our case provides evidence that DVT must be considered by the treating physician as a possible and devastating complication of septic arthritis. PMID- 20954654 TI - Severe musculoskeletal infection variant in Lemierre's syndrome. AB - Lemierre's syndrome is a severe complication of Fusobacterium necrophorum oropharyngeal infection associated with metastatic foci of infection, internal jugular vein thrombosis, and septicemia. Musculoskeletal manifestations include isolated or multifocal septic arthritis, soft tissue abscesses, pyomyositis, and osteomyelitis. This article describes a case of a variant of Lemierre's syndrome in a 17-year-old girl, demonstrating a relentless case of limb infection refractory to multiple surgical debridements and broad-spectrum and targeted antibiotics. The patient had F. necrophorum within a peritonsillar abscess and multiple foci within her right lower extremity. Overall, she required 12 surgical procedures and 14 weeks of antibiotic therapy to resolve the infection. Further unique findings in this case include the presence of a recent lateral meniscus tear with associated hemarthrosis treated with a short course of oral steroids prior to the diagnosis of septic arthritis. Knee arthroscopy with lysis of adhesions and manipulation at 6 months postinfection demonstrated significant chondral damage. Outcome at >2-year follow-up revealed pain-free activities of daily living and the ability to return to competitive, club-level collegiate softball. Clinically relevant findings illustrated in this case include potential development of antibiotic resistance within Fusobacterium genus with little to no response to several surgical debridements and broad-spectrum and targeted antibiotics, and development of multifocal, ipsilateral septic arthritis and soft tissue abscesses and pyomyositis in the context of steroid use and recent intra articular knee injury. PMID- 20954655 TI - Infantile kyphosis secondary to lumbar hypoplasia: six cases with excessive upright sleeping as a possible cause. AB - Abnormal thoracolumbar kyphosis in infants may be due to lumbar hypoplasia that resolves with development of upright posture. The cause of this deformity has not been previously identified. The goal of this study was to find whether excessive time in an upright posture while sleeping and sitting may play a role in the etiology of infantile thoracolumbar kyphosis. We retrospectively reviewed infants with the diagnosis of kyphosis from 2001 to 2005. Inclusion criteria were patients diagnosed prior to age 3 years without syndromic, neuromuscular, or congenital kyphosis and minimum 2-year follow-up. Serial radiographic evaluation was used to assess change in kyphotic deformity. Six infants with an average age of 7 months at the time of diagnosis were identified. All had marked thoracolumbar kyphosis with vertebral wedging and scalloping. Some had pseudosubluxation at the T12-L1 level. The initial average Cobb angle was 30 degrees (normal, 0 degrees -5 degrees ). Careful history revealed that all patients slept in an upright posture in addition to sitting while awake. All of the patients were observed following parental instruction in proper sleeping and sitting habits. At last follow-up, all patients had normal sagittal alignment with an average Cobb angle of 1.3 degrees . Proper sleeping and sitting habits with good spine support is recommended for infantile thoracolumbar kyphosis with lumbar hypoplasia. Allowing "tummy time" during waking hours may help the paraspinal muscles gain strength to provide support to the spine. Radiographic evidence of vertebral body height restoration may be delayed for several years. PMID- 20954656 TI - Recurrent hemarthrosis in a hemophilic patient after revision total knee arthroplasty. AB - Recurrent hemarthrosis following a revision total knee arthroplasty is a rare complication. The likelihood of encountering bleeding complications in patients with hemophilia C following major surgery is unpredictable. Although the use of postoperative chemotherapeutic agents to prevent deep venous thrombosis (DVT) is considered the standard of care for most patients, its use in the hemophiliac population is unknown. This case describes a woman with Hemophilia C who presented with recurrent hemarthrosis 9 days after her revision total knee arthroplasty. Initial treatment efforts were directed towards treating the patient's underlying coagulopathy. Repeated transfusions of fresh frozen plasma and desmopressin were given in an attempt to achieve hemostasis. However the hemarthrosis did not resolve and 36 days postoperatively, a pseudoaneurysm of the left superior geniculate artery was found by angiography and percutaneously embolized. This article presents the first case, to our knowledge, of recurrent hemarthrosis in a hemophiliac patient after revision total knee arthroplasty. It further highlights the importance of considering all possible causes of postoperative bleeding to make a timely diagnosis in the face of a confounding clinical picture. PMID- 20954657 TI - Acute limb ischemia following closed reduction of a hip arthroplasty dislocation. AB - Hip dislocation is a well-described complication of total hip arthroplasty (THA) and dislocation rates are substantially higher following revision hip arthroplasty. Vascular complications following closed reduction of hip dislocations are exceedingly rare, but a high index of suspicion is essential for patients with underlying vascular abnormalities. Popliteal artery aneurysms are the most common peripheral arterial aneurysms with a prevalence of 1% and they should be suspected in patients with prominent popliteal pulses. This article presents a case of an 84-year-old man with a revision total THA who sustained a posterior hip dislocation. The hip was reduced under conscious sedation using the Bigelow technique. The leg was distally neurovascularly intact based on the clinical exam immediately before and after the reduction. Over the next few hours, the foot became progressively ischemic and an urgent computed tomography angiogram revealed bilateral popliteal artery aneurysms with acute thrombosis of the aneurysm on the affected limb. The patient underwent emergent femoral popliteal bypass using a Dacron supported interpositional graft. The majority of the foot was salvaged but the toes eventually became necrotic. Direct compression of the aneurysm during reduction of the hip dislocation in conjunction with transiently decreased blood pressure from conscious sedation likely resulted in a low flow state within the artery leading to thrombosis of the aneurysm. To our knowledge, this is the first reported case of such an event. This case emphasizes the need for a high index of suspicion for vascular injuries following manipulation of limbs with underlying arterial aneurysms. Reduction maneuvers for hip dislocations should be modified to minimize compression of the popliteal fossa in limbs with vascular abnormalities. Serial postreduction neurovascular exams are essential for identification and prompt management of vascular complications. PMID- 20954658 TI - Spontaneous totally thrombosed pseudoaneurysm mimicking a tendon tear of the wrist. AB - Wrist pseudoaneurysm is commonly caused by iatrogenic procedures such as blood gas puncture, arterial-venous shunting for hemodialysis, or noniatrogenic causes such as blunt trauma. The mechanism of pseudoaneurysm formation is arterial wall damage with subsequent blood leakage that collects in surrounding tissue. This article presents a case of a 32-year-old woman who had sudden onset left wrist pain with a snap sound and a mass 1 cm in diameter after pulling a heavy object while working. A wrist flexor tendon tear was diagnosed after evaluation. Musculoskeletal ultrasound revealed a partially thrombosed pseudoaneurysm. The wrist pseudoaneurysm was totally thrombosed and symptoms subsided after 3 weeks of follow-up. This case study reminds us that pseudoaneurysm could be easily confused with other wrist diseases. We discuss the differential diagnosis and management of wrist pseudoaneurysm as a reference for clinical practice. PMID- 20954659 TI - The triple PCL sign: bucket handle tears of both medial and lateral menisci in a chronically ACL-deficient knee. AB - Bucket handle tears of both menisci in the setting of acute or chronic anterior cruciate ligament (ACL) tears of the same knee have rarely been reported in the literature. This article presents a case of a bucket handle tear affecting both the medial and lateral menisci in a patient with chronic ACL rupture. Both bucket handle tears were displaced and locked in the intercondylar notch. A new magnetic resonance image (MRI) sign suggested on sagittal view is called the triple PCL sign, comprising the intact posterior cruciate ligament (PCL) and the 2 displaced fragments in the intercondylar notch from the two bucket handle tears. The precise diagnosis of this condition is of obvious importance for optimal operative planning. While finding the displaced fragment from the medial meniscus is expected to cause the double PCL sign, the torn ACL may have made it easier to visualize the bucket handle tear of the lateral meniscus in the same sagittal plane as the PCL. Only 5 other reports mention bimeniscal bucket handle tears of both the medial and lateral menisci in association with an ACL tear. None have shown the suggested triple PCL sign because of lack of overlap between the 2 bucket handle tears in the coronal plane while lying in the intercondylar notch causing them not to fall in the same sagittal plane. Our patient showed some overlap between the 2 meniscal fragments while lying in the notch to create the triple PCL sign on sagittal MRI. PMID- 20954660 TI - Treatment strategies for intramedullary nailing of femoral shaft fractures. AB - Intramedullary nailing has become the gold standard to treat femoral shaft fractures. It is unknown which nailing technique orthopedic surgeons prefer. The goal of this study was to determine current techniques and perioperative complications of intramedullary nailing of diaphyseal femoral fractures. Fifty one institutions in 26 countries participated in an international survey to assess detailed descriptions of preferred operative strategies and perioperative complications. Altogether, 517 cases of diaphyseal femoral fractures were collected. The Internet-based survey incorporated information about fracture classification, time to operation, Injury Severity Score, type of nail, and operative technique, as well as perioperative complications such as infection, femoral neck fracture, and hardware failure. The preferred position for implantation was supine (91.1%). Most surgeons used a traction table (57.1%) and an antegrade implantation technique (84.5%). Intraoperative fractures of the femoral neck occurred in 1.2% of cases when a traction table was used and in 0.2% if no traction table was used, but without statistical significance (P>.16). In 59.2% of the cases, an isolated femur fracture was present, while the rest sustained multiple injuries. In polytrauma patients and patients with severe thorax injuries, most surgeons chose a delayed treatment with intramedullary femoral nails. Interestingly, 38.0% of the patients with severe thorax injuries were treated on the first day with intramedullary femoral nails. The total rate of complications for intramedullary femoral nailing was low (4.9%), but a high rate of intraoperative femoral neck fractures was observed (1.4%). PMID- 20954661 TI - Surgeon variability in the treatment of pelvic ring injuries. AB - Pelvic ring injuries are associated with the potential for long-term disability and high mortality rates. No well-established, definitive treatment algorithms have been presented in the literature. We evaluated agreement among surgeons in selecting treatment of pelvic ring injuries and investigated the relationship between type of injury and treatment plan. We conducted a prospective agreement analysis of pelvic ring injury images at a level I regional trauma center. Eighty nine isolated pelvic ring disruptions were selected; they were the only injuries present on the images and were thought to comprise a variety of pelvic fracture types from a database of 1600 pelvic fractures. Sets of injury images were randomly ordered and distributed to 5 orthopedic trauma surgeons blinded to patient name, attending surgeon, date of injury, and eventual treatment. Surgeons reviewed images, independently selected preferred treatments, and classified injuries with the Young-Burgess and Tile systems. Eight weeks later, images were again randomly ordered and distributed to the same 5 orthopedic surgeons, who again independently selected preferred treatments and classified injuries. Kappa analyses of agreement among surgeons and within each surgeon over time were conducted. Analysis among surgeons' treatment plans based on radiographic assessment alone revealed a mean kappa value of 0.47, indicating moderate level of agreement. Analysis of data collected 8 weeks later yielded a mean kappa value of 0.56, representing moderate agreement within each surgeon over time. Young Burgess and Tile classifications yielded consistent treatment plans for certain fracture types and varied plans for other types. Our results question the usefulness of the 2 classification systems for predicting treatment decisions. PMID- 20954662 TI - Analysis of synovial fluid in culture-negative samples of suspicious periprosthetic infections. AB - Synovial fluid analysis can help to rule out a periprosthetic infection. The goal of this study was to evaluate the prognostic significance of synovial fluid suspicious for a periprosthetic infection given the synovial leukocyte count and percent of neutrophils. From August 2006 to November 2008, patients who had synovial fluid aspirated for painful knees and elevated C-reactive protein levels after total knee arthroplasty but revealed no growth of any microorganism were retrospectively evaluated by medical record review. Mean follow-up period was 827.7+/-250.6 days from the date of joint aspiration results. The optimal cut-off values for synovial leukocyte counts and percent neutrophils were determined using receiver operating characteristic curves. From a total of 56 patients, 14 were classified as having poor results. The remaining 42 patients had an uneventful clinical course with a stable prosthesis on radiographs without specific therapy during the follow-up period. The receiver operating characteristic curve showed that a synovial leukocyte count of 3600/uL had an 86% sensitivity and 79% specificity; with 89% synovial neutrophils, the sensitivity was 72% and specificity 62%. The synovial fluid leukocyte count and percent neutrophils were significant predictors of outcome in patients with cultures that were negative but suspicious for periprosthetic infections. PMID- 20954663 TI - An anatomical update on the morphologic variations of S1 and S2. AB - Although percutaneous fixation with iliosacral screws has been shown to be a safe and reproducible method for sacroiliac dislocation and sacral fractures, it is a technically demanding technique, and one of its contraindications is sacral anatomical variations and dysmorphism. The incidence and pattern of S1 and S2 anatomical variations were evaluated in 61 patients (35 women and 26 men) using magnetic resonance imaging of the sacrum in an attempt to explore the possible existence of groups of individuals in whom percutaneous sacroiliac fixation is difficult due to local anatomy. S1 and S2 dimensions in both the transverse and coronal planes were recorded and evaluated. In each individual, S1 and S2 dimensions both in the coronal and transverse planes were proportional, with S2 dimensions being 80% of those of S1 on average. Patients were separated into 4 groups based on the S1 and S2 body size and the asymmetry of dimensions in the transverse and coronal planes. In 48 patients (78.6%), dimensions in both planes were symmetrical despite the varying size of the S1 and S2 body. In 2 patients (3.3%) there was a combination of large transverse plane and small coronal plane dimensions, with large S1 and S2 body size. In 9 patients (14.8%), coronal plane dimensions were disproportionately smaller compared to those of the transverse plane, with a varying size of S1 and S2 body making effective sacroiliac screw insertion a difficult task. Thus, a preoperative imaging study, preferably computed tomography scan, of S1 and S2 body size and coronal plane dimensions and an intraoperative fluoroscopic control of S1 and S2 dimensions on the coronal plane are suggested for safe sacroiliac screw fixation. PMID- 20954664 TI - Intra-articular injection of hyaluronic acid following arthroscopic partial meniscectomy of the knee. AB - The short-term recovery period post-arthroscopic meniscectomy is characterized by pain and impaired function most likely related to the irrigation of synovial fluid from the knee intraoperatively. Consequently, along with removal of harmful debris, the irrigation fluid dilutes the hyaluronic acid layer covering the joint tissues. Hyaluronic acid contributes to the homeostasis of the joint environment and is an important component of synovial fluid and cartilage matrix. Hence, the instillation of hyaluronic acid after the procedure may relieve symptoms. This prospective, single-blind, randomized, controlled study evaluated clinical outcome after hyaluronic acid injection to patients who underwent arthroscopic meniscectomy of the knee. Patients with ligamentous injuries or severe chondral damage were excluded. Fifty-six patients with a mean age of 34 years (range, 17 44 years) were injected with Viscoseal (TRB Chemedica International S.A., Geneva, Switzerland) or normal saline immediately post-arthroscopy and divided into the Viscoseal group or control group, respectively. Patients were evaluated for pain, swelling, and function at 1, 4, and 12 weeks postoperatively. Patients in the control group reported more pain at week 1, with a mean visual analog score (VAS) of 43, than did patients in the Viscoseal group, with a mean VAS of 28 (P=.006). At 4 weeks postoperatively, none of the Viscoseal patients had consumed analgesics, where 9 (of 28) in the control group reported acetaminophen intake (P=.039). No significant difference in knee function was found between groups. Intra-articular injection of Viscoseal after arthroscopic meniscectomy reduced pain in the short-term recovery period. PMID- 20954665 TI - Modified extension-block K-wire fixation technique for the treatment of bony mallet finger. AB - This article describes the treatment of a bony mallet finger deformity using 2 extension-block Kirschner wires (K-wires) with a transarticular K-wire fixation technique for precise alignment of the terminal extensor tendon-bone relationship and effective immobilization of the distal interphalangeal joint. Twenty-nine patients (33 fingers) with a bony mallet finger deformity and fracture fragment involving more than one-third of the articular surface were treated surgically. The fracture fragment was fixed and the mallet finger deformity was corrected in all patients using modified extension-block K-wires (2 dorsal extension-block pins) with a transarticular K-wire (volar side pin) fixation technique. Active motion of the proximal interphalangeal and metacarpophalangeal joints was not restricted. The wires are removed in the clinic 6 weeks postoperatively when the bridging trabeculae were observed in the radiographs, and immobilization in a stock splint was continued for an additional 2 weeks. According to Crawford's evaluation criteria, there were 24 (73%) excellent, 7 (21%) good, and 2 (6%) fair results. Three patients showed radiological signs of mild degenerative changes, which did not limit their daily activities. Nail ridging occurred in 3 cases (9%), which disappeared after an average of 6 months with normal growth, and mild scarring at the dorsal pin site occurred in 2 cases (6%). Modified extension block K-wires with a transarticular K-wire fixation technique is an acceptable alternative treatment modality for the management of bony mallet finger deformities with or without subluxation of the distal phalanx. PMID- 20954666 TI - Better functional outcome of salvage THA than bipolar hemiarthroplasty for failed intertrochanteric femur fracture fixation. AB - Failure of intertrochanteric fracture fixation often occurs in patients who have poor bone quality, severe osteoporosis, or unstable fracture patterns. The purpose of this study is to compare the results of total hip arthroplasty (THA) with bipolar hemiarthroplasty as the salvage procedures for failed fixation of intertrochanteric fractures of the femur. Eighteen consecutive patients who were treated for failed intertrochanteric fracture fixation were reviewed retrospectively. The patients were divided into 2 groups of salvage procedures: THA (9 patients) and bipolar hemiarthroplasty (9 patients). In the THA group, mean Harris Hip Score (HHS), visual analog scale (VAS) score, and Salvati and Wilson score were 82.1, 0.9, and 31.3, retrospectively. In the bipolar hemiarthroplasty group, mean HHS, VAS score, and Salvati and Wilson score were 68.6, 3.1 and 25.1, retrospectively. Total hip arthroplasty was better than bipolar hemiarthroplasty treatment in HHS (P=.040), VAS score (P=.001), and Salvati and Wilson score (P=.033). There were no significant differences in hospital stay, operating time, and transfusion volume between the 2 groups. Total hip arthroplasty seems to be more reliable salvage procedure for failed intertrochanteric fracture fixation in functional outcome and pain relief. PMID- 20954667 TI - Mechanical evaluation of cross pins used for femoral fixation of hamstring grafts in ACL reconstructions. AB - The goal of this study was to test the mechanical strength of 4 different cross pins currently available for femoral fixation by loading each cross pin to failure as received and determine the effect of 1 million cycles of fatigue loading. Additionally, the strength of resorbable pins was tested after prolonged exposure to biologic conditions. Six implants each of the Arthrotek LactoSorb (Biomet, Warsaw, Indiana), Mitek RigidFix (DePuy Mitek Inc, Raynham, Massachusetts), Arthrotek Bone Mulch Screw (Biomet), cortical allograft, and control were tested for 3-point failure without prior loading and after cyclic loading between 50 to 200 N at 10 Hz for 1 million cycles. The bioabsorbable pins were placed in sterile water at 37 degrees C and tested after 2, 4, and 6 months for 3-point failure strength. All implants tested without antecedent loading demonstrated adequate strength for initial fixation for hamstring grafts. During fatigue testing, RigidFix implants (n=6) failed at 18,893+/-8365 cycles (with a central deformation of 0.48+/-0.11 mm prior to fracture). All of the other implants tested endured 1 million cycles of loading (50-200 N) without fracture or 1.5 mm central deformation. Neither of the bioabsorbable pins demonstrated a significant change in yield strength after prolonged exposure to water. All implants tested demonstrated adequate strength for initial fixation of hamstring grafts. The metal and bone implants far exceed the strength required to sustain mechanical fixation until biological fixation occurs; both polymeric implants demonstrated that they maintained enough mechanical strength to achieve this goal. PMID- 20954668 TI - Open reduction internal fixation of displaced sacral fractures: technique and results. AB - Pelvic ring disruption with an associated sacral fracture is typically a result of high-energy injury. Due to significant local soft tissue trauma and the complex neurovascular anatomy in the region, exposure and reduction of sacral fractures has proven to be difficult, hazardous, and fraught with complications. We describe a modified reduction technique to address displacement in sacral fractures to show that it can be safe and effective through evaluation of radiographic, clinical, and functional outcomes. We retrospectively reviewed the radiographic and clinical results of consecutive patients treated at a single institution by the senior surgeon (K.F.D.) with open reduction for displaced sacral fractures. Radiographic follow-up was available on all patients. Complete clinical follow-up was available on 19 of 20 patients. The average duration of follow-up was 3.7 years. All fractures united with no additional surgery. There were no infections or additional neurologic deficits or vascular injuries. There was 1 asymptomatic hardware failure 2 years postoperatively with no further displacement. Average preoperative displacement on the anteroposterior (AP) radiograph was 14.72 mm with a long-term follow-up displacement of 3.25 mm. Iowa Pelvic Score questionnaires demonstrated an average score of 92.2. Eighty-nine percent of patients returned to full time work or their previous activity level. The technique of open reduction and fixation of displaced sacral fractures described in this review is safe and effective with a low complication rate and clinical results comparable to or exceeding that of previously published series. PMID- 20954669 TI - Inhibition of TGF-beta-induced collagen production in rabbit flexor tendon with mannose-6-phosphate in vitro. AB - The flexor tendon affects postoperative range of motion in the hand. Transforming growth factor-beta (TGF-beta) is a key cytokine in the adhesion formation between the flexor tendon and its surrounding fibro-osseous sheath. The purpose of this study was to examine the inhibition of TGF-beta-induced collagen-I production in rabbit flexor tendons with mannose-6-phosphate in vitro. Sheath fibroblasts, epitenon tenocytes, and endotenon tenocytes from rabbit flexor tendons were isolated and each was supplemented with TGF-beta along with increasing doses of mannose-6-phosphate. The enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR) measured collagen-I production. The luciferase assay measured TGF-beta bioactivity. Results were compared with TGF-beta alone and unsupplemented controls. TGF-beta-induced collagen-I production was downregulated significantly with the addition of mannose-6 phosphate in a dose-dependent manner in all 3 cells cultures. The mannose-6 phosphate also reduced TGF-beta bioactivity. The study shows that mannose-6 phosphate was effective in TGF-beta inhibition in cultured flexor tendon cells. The findings presented here encourage further experiments that use the agents to modulate TGF-beta levels and reduce adhesion formation after flexor tendon repair. PMID- 20954670 TI - The study of epidurography and multispiral CT scanning examinations in the diagnosis of lumbar nerve root canal stenosis. AB - Both computed tomography (CT) and magnetic resonance imaging (MRI) scans are used for the diagnosis of lumbar nerve root canal stenosis by imaging measurement, but the findings have considerable variability and the specificity of these examinations is difficult to estimate. A prospective study was conducted to determine the association between epidurography and multispiral CT scanning and the diagnosis of lumbar nerve root canal stenosis. Twenty-nine patients underwent multispiral computed tomography epidurographies from December 2007 to October 2008, and among them 26 patients underwent all 3 examinations of CT, MRI, and multispiral computed tomography epidurography. Twenty-three patients underwent surgical treatment. The imaging features were investigated, and the sensitivity, specificity and total consistency rates were analyzed. Multispiral computed tomography epidurographies show the extent of soft-tissue as well as bone. The sensitivity of CTs, MRIs, and multispiral computed tomography epidurographies is 76.5%, 88.2% and 94.1%, specificity 60.0%, 60.0%, and 80.0%, and total consistent rate 72.7%, 81.0%, and 90.9%, respectively, for diagnosis of lumbar nerve root canal stenosis. Multispiral computed tomography epidurography could obtain the image findings giving consideration to both bone and soft-tissue by contrast medium and 3-dimensional reconstruction. Multispiral computed tomography epidurography was used because of its contrast medium distribution rather than its imaging measurement because it could avoid the variability between image findings and clinical pathological process. Multispiral computed tomography epidurography had better imaging characteristics for the diagnosis of lumbar nerve root canal stenosis than CT or MRI scans. PMID- 20954672 TI - Mortality following revision joint arthroplasty: is age a factor? AB - With the demand for total joint arthroplasty and overall life expectancy increasing, there will be an increase in the need for revision arthroplasty surgeries. Given that revision joint surgeries are more demanding for both surgeon and patient with longer operative times, increased blood loss, and multiple patient comorbidities, the current mindset is that older patients who undergo a total hip revision or total knee revision have higher mortality rates than younger patients. We identified 1737 revision total joint patients who were at least 2 years postoperative for inclusion in the study. The overall perioperative mortality rate (defined as deaths occurring between 0 and 3 months following revision joint surgery) was calculated and then stratified by revision knee surgery, revision hip surgery, and age. In addition, mortality rates were compared for patients younger than 70 years, between 70 and 80 years and older than 80 years. The overall perioperative mortality rate after revision total hip or knee surgery was 0.7%. After stratifying by age, the perioperative mortality rate was 0.2% in patients younger than 70 years, 0.8% in patients 70 to 79 years, and 2.63% in patients older than 80 years. Of the 1737 patients, 541 died >1 year following their revision surgery at an average time to death of 6.9 years. The observed perioperative mortality rates following revision total joint surgery at a single center were extremely low among all age groups. Therefore, the age of patients undergoing revision surgery should not be the sole determinant of perioperative survival. Additionally, it appears that the mean postoperative survival noted here seems to justify the additional resources used in revision surgery regardless of age. As limited resources exert pressure on an already overburdened healthcare system, rationing of care for certain procedures may ensue using age as a specific criteria. This study should add clarity to this issue. PMID- 20954671 TI - Comparison of the mini-midvastus with the mini-medial parapatellar approach in primary TKA. AB - A prospective randomized study was performed to compare the clinical and radiological results of primary total knee arthroplasties (TKAs) using a mini midvastus approach or a mini-medial parapatellar approach in 134 patients. The mini-midvastus approach was used on 68 patients (group A) and the mini-medial parapatellar approach on 66 patients (group B). All knees were implanted with the same posterior-stabilized prosthesis by the same surgeon (T.-S.T.) with the same set of downsized instruments. Mean follow-up in both groups was 30.5 months (range, 24-48 months). Patients in group A achieved an active straight-leg raise and 90 degrees of flexion significantly earlier (P=.017 and P=.025, respectively). However, no significant difference was detected between the groups with respect to range of movement and Knee Society scores at all the postoperative visits and at final follow-up (all, P>.05). In contrast, the tourniquet time was significantly longer in group A (P=.015), with a higher incidence of medialized tibial component (P=.031). We believe that the early clinical results are similar between the mini-midvastus and mini-medial parapatellar approach. The mini-medial parapatellar approach is easier to initially apply and provides better visualization for TKA. PMID- 20954673 TI - Toe-touch weight bearing: myth or reality? AB - Toe-touch weight bearing and partial weight bearing are commonly prescribed orders. The purpose of this study is to evaluate the validity of toe-touch weight bearing and partial weight bearing regimens. Twenty-five orthopedic surgeons participated in the study. They were asked to answer a questionnaire regarding toe-touch weight bearing and partial weight bearing definitions, and were asked to bear weight partially according to the accepted definitions of each order. Weight bearing on the affected limb was measured by the SmartStep System (Andante Medical Devices, Ltd, Omer, Israel). There was a 40% success rate for toe-touch weight bearing as measured by kilograms and 58% as measured by percentage of body weight. There was a 22% success rate for partial weight bearing as measured by kilograms and 50% success rate as measured by percentage of body weight. For toe touch weight bearing as measured by kilograms, 52% exerted a mean 15.9 kg more than the maximum. For partial weight bearing as measured by kilograms, 64% exerted too much weight with an average of 14.2 kg more than the maximum. There was a significantly higher success rate for the percentage of body weight order than the kilogram order. The partial weight bearing order with the percent body weight order had a lower mean deviation from desired performance. This study and others demonstrate the need for standardization of weight bearing orders. PMID- 20954674 TI - Introduction to customized ablation: eighth year in review. PMID- 20954675 TI - Transitioning to optimized correction with the WaveLight ALLEGRETTO WAVE: case distribution, visual outcomes, and wavefront aberrations. AB - PURPOSE: To describe the outcomes of the first 285 eyes receiving LASIK or photorefractive keratectomy (PRK) using an optimized ablation profile at a refractive surgery practice experienced with customized ablation. METHODS: A retrospective chart review was performed on all patients who underwent refractive treatments using the ALLEGRETTO WAVE Eye-Q platform (Alcon Laboratories Inc) between September 2008 and July 2009. Patients were divided into LASIK and PRK treatments, then further subdivided based on pre- and targeted postoperative refraction. Pre- and postoperative measures of uncorrected distance visual acuity (UDVA), corrected distance visual acuity, manifest refraction, keratometry, and wavefront values were taken and compared, and the average changes in keratometry and higher order aberrations were calculated. RESULTS: At 3 months postoperative, 92% of myopes and 63% of hyperopes undergoing LASIK with a target of emmetropia achieved UDVA of 20/20. Of PRK eyes targeted for emmetropia, 80% of myopic eyes achieved UDVA of 20/20 (the hyperopic subgroup was too small to analyze). In both LASIK and PRK subgroups, total wavefront aberrations decreased, as did some higher order aberrations. CONCLUSIONS: This group of patients, who all achieved excellent postoperative UDVA, represents our initial surgical experience with the ALLEGRETTO WAVE, using only a standard (global surgeon) nomogram. These results may serve as an estimate of what a practice could expect in terms of initial outcomes with this system. PMID- 20954676 TI - LASIK for -6.00 to -12.00 D of myopia with up to 3.00 D of cylinder using the ALLEGRETTO WAVE: 3- and 6-month results with the 200- and 400-Hz platforms. AB - PURPOSE: To report the refractive results after LASIK for high myopia and cylinder at one center with one surgeon comparing two laser platforms. METHODS: A total of 206 eyes of 121 patients were treated for -6.00 to -12.00 diopters (D) of spherical equivalent refractive error with up to 3.00 D of cylinder. All eyes underwent LASIK with the ALLEGRETTO WAVE 200-Hz (n=141) or 400-Hz (n=65) laser (Alcon Laboratories Inc) between 2003 and 2009. Corneal flaps were created with the IntraLase femtosecond laser (Abbott Medical Optics) at an intended thickness of 100 or 110 MUm in all cases. RESULTS: At 3- and 6-month follow-up in the 200 Hz group, 77% (109/141) and 86% (121/141) of eyes, respectively, were within +/ 0.50 D of intended correction. In the 400-Hz group, 98.5% (64/65) and 100% (65/65) of eyes were within +/-0.50 D of intended correction at 3 and 6 months postoperatively. At 3- and 6-month follow-up, 84% (119/141) and 77% (109/141) of eyes, respectively, in the 200-Hz group and 80% (52/65) and 92% (60/65) of eyes, respectively, in the 400-Hz group had 20/20 or better uncorrected distance visual acuity. At 6-month follow-up, refractive predictability and visual acuity were statistically superior in eyes in the 400-Hz group (chi square, P<.01). No eyes underwent retreatment as a secondary procedure during the time of analysis. CONCLUSIONS: LASIK with the ALLEGRETTO WAVE 200- and 400-Hz laser is effective and predictable for the treatment of high myopia with astigmatism in appropriately selected patients. The acuity and predictability of refractive results may be slightly better when using the 400-Hz platform. PMID- 20954677 TI - LASIK for mixed astigmatism using the ALLEGRETTO WAVE: 3- and 6-month results with the 200- and 400-Hz platforms. AB - PURPOSE: To report the refractive results after LASIK for mixed astigmatism at one center with one surgeon comparing two laser platforms. METHODS: A total of 137 eyes of 69 patients were treated with LASIK for mixed astigmatism up to 3.33 diopters (D) using either the ALLEGRETTO WAVE 200- or 400-Hz laser (Alcon Laboratories Inc) between April 2006 and December 2009. The degree of astigmatism was higher in the 400-Hz group. Corneal flaps were created with the IntraLase femtosecond laser (Abbott Medical Optics) in all cases. RESULTS: The refractive outcomes with both laser systems were statistically similar. At 6 months, 78% of eyes had 20/20 or better uncorrected distance visual acuity (UDVA) with all but one eye achieving 20/30 or better UDVA. At 6 months, 10% of eyes treated with the 200-Hz system lost one line of corrected distance visual acuity (CDVA) whereas no eyes treated with the 400-Hz system lost any lines of CDVA. Residual astigmatism was <0.50 D for all eyes treated with both platforms. CONCLUSIONS: Both laser platforms provided predictable and effective treatment of mixed astigmatism in the patient populations treated, with over 90% of eyes achieving UDVA of 20/25 or better 6 months after surgery. PMID- 20954678 TI - Presbyopia corrections with the WaveLight ALLEGRETTO: 3-month results. AB - PURPOSE: Progressive multifocal LASIK (PML) is a corneal surgical technique that is based on the principles of LASIK to create a multifocal or aspheric corneal surface. This retrospective study was conducted to evaluate the efficacy and safety of this procedure. METHODS: One hundred seventy-eight patients underwent PML with the WaveLight ALLEGRETTO platform (Alcon Laboratories Inc), of which 102 patients had at least 3-month follow-up. RESULTS: After surgery, 81% of patients had 20/20 or better binocular uncorrected distance visual acuity (UDVA), and 98% had 20/25 or better binocular UDVA. Additionally, 44% of patients had Jaeger (J) 1 binocular near visual acuity, 60% had J2, and 96% had J3. CONCLUSIONS: This study suggests that PML performed with the WaveLight ALLEGRETTO platform is a safe and effective treatment for this patient population. PMID- 20954679 TI - Stability of simultaneous topography-guided photorefractive keratectomy and riboflavin/UVA cross-linking for progressive keratoconus: case reports. AB - PURPOSE: To follow the stability of a simultaneously delivered therapy that corrects aberrations and stiffens the corneal collagen of eyes with progressive keratoconus. METHODS: Two patients with progressive keratoconus underwent partial treatment (70% cylinder and sphere up to 50-MUm central depth) with topographic customized photorefractive keratectomy (PRK) using the T-CAT module of the ALLEGRETTO WAVE Eye-Q excimer laser (Alcon Laboratories Inc), and then immediate corneal collagen cross-linking (CXL) with riboflavin 0.1% drops every 2 minutes while exposed to mean 365-nm ultraviolet A (UVA) light at 3.0 mW/cm2 for 30 minutes (the Athens Protocol). Pre- and postoperative evaluations included manifest and cycloplegic refraction, Scheimpflug corneal tomography and pachymetry, and slit-lamp examination of corneal clarity with a minimum follow-up of 30 months. RESULTS: Both treated eyes experienced rapid healing of the epithelial surface within 5 days and progressive improvement of vision. In the first case, partial treatment reduced the astigmatism and aberrations, allowing for successful soft contact lens wear at 3 months. Follow-up at 13, 19, 30, and 36 months showed progressive reduction of refractive myopia and keratometric power. In the second case, laser treatment led to a near emmetropic refraction with an uncorrected visual acuity of 20/20 at 3 months, which remained unchanged at 21 and 30 months postoperative. CONCLUSIONS: Partial topography-guided PRK followed by riboflavin/UVA CXL is a safe and effective therapy that halts the progression of keratoectasia and reduces the spherocylindrical refraction and aberrations to improve the visual function of patients with progressive keratoconus. Stability and progressive improvement over time is observed, although limitations may exist for steeper and thinner corneas. PMID- 20954680 TI - Technical aspects of the WaveLight FS200 femtosecond laser. AB - PURPOSE: To demonstrate the feasibility and technical features of the WaveLight FS200 femtosecond laser (WaveLight GmbH) in refractive and corneal laser surgery. METHODS: The reproducibility of femtosecond laser-created flap dimensions and channels used for corneal ring segment implantation were measured by means of an optical coherence tomography system in porcine corneas. The increase in the intraocular pressure (IOP) during applanation with the corneal interface was measured by means of an IOP sensor. The possibility of creating a channel for gas diffusion within the stroma was investigated to minimize opaque bubble layer formation. RESULTS: The technical features, such as optical design, pulse energy, and scanning algorithms at a high repetition rate, allow reproducibility for tissue cutting with a standard deviation of <10 MUm in depth and 0.1 mm laterally. Intraocular pressure increases up to 150 mmHg during applanation. The use of a gas channel minimizes the creation of an opaque bubble layer during the femtosecond laser procedure. CONCLUSIONS: The WaveLight FS200 femtosecond laser provides a high reproducibility for cutting three-dimensional tissue structures. The IOP increase is comparable to other microkeratomes and femtosecond lasers. The minimized opaque bubble layers allow the surgeon to perform an excimer laser treatment immediately after FS200 flap creation. PMID- 20954681 TI - An Editor's exit. Editor's-in-Chief of 21 years reflections. PMID- 20954682 TI - From the AAO. PMID- 20954683 TI - The 25th anniversary of excimer lasers in refractive surgery: historical review. PMID- 20954685 TI - Effects of accommodation training on accommodation and depth of focus in an eye implanted with a crystalens intraocular lens. AB - PURPOSE: To investigate objective measures of the effects of accommodative training of a pseudophakic eye implanted with a Crystalens AT-52SE (eyeonics Inc) intraocular lens (IOL) on reading performance, accommodation, and depth of focus. METHODS: Objective dynamic measures of accommodation, pupil size, and depth of focus were quantified from wavefront measures before and after 1 week of accommodative training that began 29 months after implantation of an accommodating IOL in one patient. Depth of focus was estimated from 50% cut-off of peak performance levels for defocus curves that were computed from the image quality metric VSOTF based on ocular wavefront aberrations. RESULTS: The patient reported improved near vision reading performance after completing the training procedure. After training, there was a shift in conjugate focus in the hyperopic direction, yet the depth of focus increased significantly for near objects. Simulated retinal images and the calculated modulation transfer function of the eye both demonstrated improved quality for near vision after training. CONCLUSIONS: The subjective report of improved near vision after training was correlated with improvement of objective measures. Depth of focus increased for near objects with attempts to accommodate after training. This change was linked to increases in aberrations and pupil size and occurred despite the conjugate focus shifting in the hyperopic direction. These results demonstrate that accommodative training may be useful in improving near vision in patients with accommodating IOLs. PMID- 20954686 TI - A new coordinate system convention in schematic eye modeling. AB - PURPOSE: To discuss standardizing methods for presenting results from schematic eye calculations where light is entering the eye and forming an image on the retina. METHODS: Published methods, measurement equipment, and software were evaluated. RESULTS: The methods already used by ray tracing software are proposed, where everything is viewed from behind the eye and a conventional (x,y) coordinate system is used for images and plots. For meaningful evaluation in comparison to the image, any representations of the cornea, pupil, imaging wavefront, point spread function (PSF), and spot diagram are rotated by 180 degrees about the optical axis for display to match the image orientation of a standard text chart. If a Zernike sag surface is used for a corneal surface of a schematic eye, this is also defined from the rear; however, care must be taken to ensure that the ordering of the Zernike terms is correct. CONCLUSIONS: Simulated images can be viewed from behind the eye and oriented so that text has a normal appearance. This requires a rotation of the imaging wavefront and PSF by 180 degrees about the optical axis. PMID- 20954687 TI - Effect of incident light wavelength and corneal edema on light scattering and penetration: laboratory study of human corneas. AB - PURPOSE: The outcome of ultrashort pulse laser surgery of the cornea is strongly influenced by the light scattering properties of the tissue, for which little data are available. The purpose of the present study is to provide quantitative values for light scattering and its relation to the degree of edema. METHODS: An experimental optical measuring setup based on confocal geometry was used to measure the unscattered and scattered fractions of light transmitted by eye bank corneas presenting various degrees of edema. From these measurements, the effective light penetration depth in the cornea was calculated as a function of wavelength. RESULTS: Corneal transparency depends on the pathological state of the cornea and on wavelength. It may be predicted as a function of corneal thickness, ie, the degree of edema. In healthy and edematous cornea, the percentage of scattered light decreases with increasing wavelength. The total penetration depths at the wavelengths of ~1050 nm (which is used in typical clinical systems) and 1650 nm (which is recommended for future devices) are comparable; however, the former is limited by scattering, which degrades the laser beam quality, whereas the latter is only limited by optical absorption, which may be compensated for. CONCLUSIONS: The use of longer wavelengths should help improve the surgical outcome in ultrashort pulse laser surgery of the cornea when working on pathological tissue. A wavelength of approximately 1650 nm appears to be a good compromise, as it allows for reduced light scattering while keeping optical absorption reasonably low. PMID- 20954688 TI - Noise in wavefront error measurement from pupil center location uncertainty. AB - PURPOSE: To examine the impact of pupil center location uncertainty in wavefront sensing on the variance in repeated measures of higher order root-mean-square (RMS) wavefront error (WFE). METHODS: Dilated WFE for one normal eye and one eye with keratoconus of two patients were measured using a custom Shack-Hartmann wavefront sensor (lenslet spacing 400 MUm). Twelve measurements for each patient were averaged to form the best estimate of each eye's WFE and standard deviation. The percentage of the standard deviation of the actual measurements attributable to the uncertainty in pupil center location was modeled by inducing random offsets in the pupil center up to 50, 100, 150, and 200 MUm. RESULTS: The percentage of standard deviation of the actual measurements accounted for by pupil location uncertainty form a complex interaction between magnitude and distribution of the higher order WFE with the magnitude of pupil centering error. The larger the WFE and pupil center uncertainty, the greater the effect. CONCLUSIONS: As pupil center uncertainty increases, so does the WFE variation in repeated measurements. The larger the underlying WFE, the greater the impact on measurement variation. Increasing measurement variation decreases the ability to detect changes in WFE (eg, as a function of aging or clinical intervention) and decreases the accuracy with which wavefront-guided corrections can be made. PMID- 20954689 TI - Structures of 2-acetylaminofluorene modified DNA revisited: insight into conformational heterogeneity. AB - Despite the extensive data on dG-AAF, the major DNA adduct derived from the model carcinogen 2-acetylaminofluorene, little is known with respect to its solution structures. Here, we provide NMR/CD evidence for three conformers of dG-AAF in duplex DNA: major groove B-type (B), base-displaced stacked (S), and minor groove wedge (W). The S/B/W-conformational heterogeneities were found to be sensitive to the nature of the flanking DNA sequence contexts and pH. PMID- 20954690 TI - Base-catalyzed feedback in the urea-urease reaction. AB - The bell-shaped rate-pH curve coupled to production of base in the urea-urease reaction was utilized to give feedback-driven behavior: an acid-to-base pH clock (a kinetic switch), bistability and hysteresis between an acid/base state when the initial pH was adjusted by a strong acid, and aperiodic pH oscillations when the initial pH was adjusted by a weak acid in an open reactor. A simple model of the reaction reproduced most of the experimental results and provided insight into the role of self-buffering in the dynamics. This reaction suggests new possibilities in the development of biocompatible feedback to couple to pH sensitive processes for bioinspired applications in medicine, engineering, or materials science. PMID- 20954691 TI - One-pot conversions of olefins to cyclic carbonates and secondary allylic and homoallylic amines to cyclic carbamates. AB - Sequential treatment of a 1,2-disubstituted olefin with m-CPBA, Br3CCO2H, and DBU results in the one-pot, stereospecific conversion of the olefin to the corresponding disubstituted cyclic carbonate (1,3-dioxolan-2-one). The reaction proceeds via an initial epoxidation followed by S(N)2-type epoxide ring opening by Br3CCO2H and subsequent base-promoted carbonate formation upon elimination of bromoform. When a solution of a secondary allylic or homoallylic amine and Br3CCO2H is sequentially treated with m-CPBA then DBU, the product of the reaction is a cyclic carbamate (1,3-oxazolidin-2-one or 1,3-oxazinan-2-one). PMID- 20954692 TI - Synthesis of cytotoxic aza analogues of jaspine B. AB - A straightforward access to pyrrolidine-based analogues of jaspine B was developed. Five stereoisomers were prepared including the all-cis derivatives presenting the configuration of the natural anhydrophytosphingosine. The synthesis of the latter relied on an original Staudinger-type cyclization process. The compounds were evaluated regarding their ability to alter tumor cells' viability and to interfere with the metabolism of sphingolipids. PMID- 20954693 TI - Unexpected cleavage of 2-azido-2-(hydroxymethyl)oxetanes: conformation determines reaction pathway? AB - An unanticipated cleavage of 2-azido-2-(hydroxymethyl)oxetanes is reported. In attempts to oxidize the title oxetanyl alcohols to the corresponding carboxylic acids with RuO4, cleaved nitriles were formed as the sole isolable products, while a closely related tetrahydrofuran gave solely the expected carboxylic acid. Quantum chemical calculations suggest that the divergent outcomes are governed by conformational differences in the azidoalcohols. PMID- 20954694 TI - Asymmetric synthesis of telcagepant, a CGRP receptor antagonist for the treatment of migraine. AB - A highly efficient, asymmetric synthesis of telcagepant (1), a CGRP receptor antagonist for the treatment of migraine, is described. This synthesis features the first application of iminium organocatalysis on an industrial scale. The key to the success of this organocatalytic transformation was the identification of a dual acid cocatalyst system, which allowed striking a balance of the reaction efficiency and product stability effectively. As such, via an iminium species, the necessnary C-6 stereogenicity was practically established in one operation in >95% ee. Furthermore, we enlisted an unprecedented Doebner-Knoevenagel coupling, which was also via an iminium species, to efficiently construct the C3-C4 bond with desired functionality. In order to prepare telcagepant (1) in high quality, a practical new protocol was discovered to suppress the formation of desfluoro impurities formed under hydrogenation conditions to <0.2%. An efficient lactamization facilitated by t-BuCOCl followed by a dynamic epimerization crystallization resulted in the isolation of caprolactam acetamide with the desired C3 (R) and C6 (S) configuration cleanly. Isolating only three intermediates, the overall yield of this cost-effective synthesis was up to 27%. This environmentally responsible synthesis contains all of the elements required for a manufacturing process and prepares telcagepant (1) with the high quality required for pharmaceutical use. PMID- 20954695 TI - Bipartite design of a self-fibrillating protein copolymer with nanopatterned peptide display capabilities. AB - The development of biomatrices for technological and biomedical applications employs self-assembled scaffolds built from short peptidic motifs. However, biopolymers composed of protein domains would offer more varied molecular frames to introduce finer and more complex functionalities in bioreactive scaffolds using bottom-up approaches. Yet, the rules governing the three-dimensional organization of protein architectures in nature are complex and poorly understood. As a result, the synthetic fabrication of ordered protein association into polymers poses major challenges to bioengineering. We have now fabricated a self-assembling protein nanofiber with predictable morphologies and amenable to bottom-up customization, where features supporting function and assembly are spatially segregated. The design was inspired by the cross-linking of titin filaments by telethonin in the muscle sarcomere. The resulting fiber is a two protein system that has nanopatterned peptide display capabilities as shown by the recruitment of functionalized gold nanoparticles at regular intervals of ~ 5 nm, yielding a semiregular linear array over micrometers. This polymer promises the uncomplicated display of biologically active motifs to selectively bind and organize matter in the fine nanoscale. Further, its conceptual design has high potential for controlled plurifunctionalization. PMID- 20954696 TI - Temperature dependence of regioselectivity in nucleophilic photosubstitution of 4 nitroanisole. The activation energy criterion for regioselectivity. AB - Photosubstitution of the nitro group vs the methoxy group of triplet 4 nitroanisole by hydroxide ion in water leads to product yields of about 80% 4 methoxyphenol and 20% 4-nitrophenol. The ratio depends slightly on temperature from 3 to 73 degrees C. The slight temperature variation in the yield ratio is reproduced almost perfectly with a simple Arrhenius model for a mechanism involving bonding of hydroxide ion with the triplet state of 4-nitroanisole. The competing transition states have activation energies of 2.2 and 2.6 kcal/mol, respectively. Correct prediction of regioselectivity can be done for this case by quantum chemical calculation of the competing triplet transition-state energies, or those of the corresponding triplet sigma-complexes. Other models for aromatic photosubstitution regioselectivity in mechanisms of the S(N)2Ar* type, such as those based on calculated electron densities, HOMO/LUMO coefficients, or energy gap sizes, are discussed and shown to be inferior to the relative activation energies model. The photoreaction in alcohol solvents, claimed by others to generate the same products as in water and to have an exceedingly large variation of the product ratio with temperature, may reflect chemical changes other than those reported. PMID- 20954697 TI - Stable electron field emission from PMMA-CNT matrices. AB - We have created PMMA-CNT matrices by embedding opened-tip vertically aligned multiwalled carbon nanotubes (VA-MWCNTs) with poly(methyl methacrylate) (PMMA). These PMMA-CNT matrices are excellent electron field emitters with an emission threshold field of 1.675 V/MUm, more than 2-fold lower that that of the as-grown sample. In addition, the emission site density from these matrices is high, merely filling up the entire sample surface. Emission stability test at ~1.35 mA/cm(2) was performed continuously for 40 h with no significant degradation. On the basis of our theoretical simulation and hypothetical modeling, we attribute these performances to the reduced screening effect and fewer Joule heatings due to the shorter effective transport distance of the electrons in MWCNTs. PMID- 20954699 TI - Nanocomposites of vertically aligned single-walled carbon nanotubes by magnetic alignment and polymerization of a lyotropic precursor. AB - We demonstrate a novel path for the fabrication of thin-film polymer nanocomposites containing vertically aligned single-walled carbon nanotubes (SWNTs). Liquid crystal mesophases of hexagonally packed cylindrical micelles orient with their long axes parallel to an applied magnetic field and template the alignment of SWNTs sequestered in the micellar cores. The mesophase is a stable single-phase material containing monomers that can be polymerized after nanotube alignment to form the nanocomposite polymer. The space-pervasive nature of magnetic fields and the tunable physicochemical properties of multicomponent mesophases make this an attractive approach that can be leveraged for application in diverse nanocomposite systems. PMID- 20954698 TI - Dual-channel single-molecule fluorescence resonance energy transfer to establish distance parameters for RNA nanoparticles. AB - The increasing interest in RNA nanotechnology and the demonstrated feasibility of using RNA nanoparticles as therapeutics have prompted the need for imaging systems with nanometer-scale resolution for RNA studies. Phi29 dimeric pRNAs can serve as building blocks in assembly into the hexameric ring of the nanomotors, as modules of RNA nanoparciles, and as vehicles for specific delivery of therapeutics to cancers or viral infected cells. The understanding of the 3D structure of this novel RNA dimeric particle is fundamentally and practically important. Although a 3D model of pRNA dimer has been proposed based on biochemical analysis, no distance measurements or X-ray diffraction data have been reported. Here we evaluated the application of our customized single molecule dual-viewing system for distance measurement within pRNA dimers using single-molecule Fluorescence Resonance Energy Transfer (smFRET). Ten pRNA monomers labeled with single donor or acceptor fluorophores at various locations were constructed and eight dimers were assembled. smFRET signals were detected for six dimers. The tethered arm sizes of the fluorophores were estimated empirically from dual-labeled RNA/DNA standards. The distances between donor and acceptor were calculated and used as distance parameters to assess and refine the previously reported 3D model of the pRNA dimer. Distances between nucleotides in pRNA dimers were found to be different from those of the dimers bound to procapsid, suggesting a conformational change of the pRNA dimer upon binding to the procapsid. PMID- 20954700 TI - A bioinspired synthetic approach for building metal-organic frameworks with accessible metal centers. AB - We demonstrate how a bioinspired synthetic approach can help organic linkers distinguish between different types of metal centers in metal-organic frameworks (MOFs). Modification of an organic building unit with methyl groups enables the unit to selectively coordinate to one of the two metal sites present in the MOFs. We report four new porphyrin-based, pillared-paddlewheel frameworks: PPF-11 Zn/Zn, -Co/Co, -Mn/Zn, and -Fe/Zn, where the first and second metals indicate the metal center for the porphyrin core and paddlewheel cluster, respectively. These compounds exhibit 3D MOFs in which 2D layers are pillared by a sterically controlled bipyridine, leaving the metal centers inside the porphyrin structurally unconnected. PMID- 20954701 TI - Identification of a novel type of CA19-9 carrier in human bile and sera of cancer patients: an implication of the involvement in nonsecretory exocytosis. AB - Carbohydrate antigen 19-9 (CA19-9) is a well-known tumor marker for pancreatic cancer. Although the CA19-9 level is measured using anti-sialyl Lewis A antibodies, it remains unknown which molecules carry CA19-9 other than mucins. Here we report the identification and characterization of a novel type of CA19-9 carrier, BGM (bile globular membrane), which is thought to exist in normal bile and to be secreted into sera of patients with pancreatic cancer. We purified the BGM from bile juice using a beta-casein column because surface plasmon resonance analysis could detect such carrier vesicles binding to beta-casein in sera of patients with pancreatic cancer. We identified characteristic molecules for BGM such as AHNAK (desmoykoin) and a novel golgin family member, CABIN (CAsein Binding domain integral protein with golgIN motif) by mass spectrometry analysis. BGM was detected in the sera of patients with pancreatic cancer as well as athymic mice with transplanted pancreatic cancer cells. Down regulation of CABIN inhibited the secretion of CA19-9 on BGM in pancreatic cancer cell lines. We measured and visualized BGM in sera of patients with cancer. Thus, BGM might be another CA19-9 carrier (glyco-lipids on membrane vesicles) other than mucins and could be applied to the diagnosis of pancreatic cancer. PMID- 20954702 TI - Spatial segmentation of imaging mass spectrometry data with edge-preserving image denoising and clustering. AB - In recent years, matrix-assisted laser desorption/ionization (MALDI)-imaging mass spectrometry has become a mature technology, allowing for reproducible high resolution measurements to localize proteins and smaller molecules. However, despite this impressive technological advance, only a few papers have been published concerned with computational methods for MALDI-imaging data. We address this issue proposing a new procedure for spatial segmentation of MALDI-imaging data sets. This procedure clusters all spectra into different groups based on their similarity. This partition is represented by a segmentation map, which helps to understand the spatial structure of the sample. The core of our segmentation procedure is the edge-preserving denoising of images corresponding to specific masses that reduces pixel-to-pixel variability and improves the segmentation map significantly. Moreover, before applying denoising, we reduce the data set selecting peaks appearing in at least 1% of spectra. High dimensional discriminant clustering completes the procedure. We analyzed two data sets using the proposed pipeline. First, for a rat brain coronal section the calculated segmentation maps highlight the anatomical and functional structure of the brain. Second, a section of a neuroendocrine tumor invading the small intestine was interpreted where the tumor area was discriminated and functionally similar regions were indicated. PMID- 20954703 TI - Metabolomics approach for investigation of effects of dengue virus infection using the EA.hy926 cell line. AB - This paper describes a multiplatform analytical approach combining proton nuclear magnetic resonance ((1)H NMR) spectroscopy and mass spectrometry (MS), together with pattern recognition tools in a metabolomic study used to investigate the effects of dengue virus infection. The four serotypes of dengue, DEN-1, DEN-2, DEN-3, and DEN-4, were inoculated into the EA.hy926 cell line, which was then incubated for various time intervals. Principal component analysis (PCA) of the (1)H NMR and MS data revealed metabolic profile patterns or fingerprint patterns that can be attributed to specific virus serotypes. Distinct effects of infection by each serotype were demonstrated, and these differences were attributed to changes in levels of metabolites (including amino acids, dicarboxylic acids, fatty acids, and organic acids related to the tricarboxylic acid (TCA) cycle). The study demonstrated application of metabolomics to improve understanding of the effect of dengue infection on endothelial cells' metabolome. PMID- 20954705 TI - Structure of solvent-free nanoparticle-organic hybrid materials. AB - We derive the radial distribution function and the static structure factor for the particles in model nanoparticle-organic hybrid materials composed of nanoparticles and attached oligomeric chains in the absence of an intervening solvent. The assumption that the oligomers form an incompressible fluid of bead chains attached to the particles that is at equilibrium for a given particle configuration allows us to apply a density functional theory for determining the equilibrium configuration of oligomers as well as the distribution function of the particles. A quasi-analytic solution is facilitated by a regular perturbation analysis valid when the oligomer radius of gyration R(g) is much greater than the particle radius a. The results show that the constraint that each particle carries its own share of the fluid attached to itself yields a static structure factor that approaches zero as the wavenumber approaches zero. This result indicates that each particle excludes exactly one other particle from its neighborhood. PMID- 20954704 TI - Hydrogen bonding between solutes in solvents octan-1-ol and water. AB - The 1:1 equilibrium constants, K, for the association of hydrogen bond bases and hydrogen bond acids have been determined by using octan-1-ol solvent at 298 K for 30 acid-base combinations. The values of K are much smaller than those found for aprotic, rather nonpolar solvents. It is shown that the log K values can satisfactorily be correlated against alpha(H)2.beta(H)2, where alpha(H)2 and beta(H)2 are the 1:1 hydrogen bond acidities and basicities of solutes. The slope of the plot, 2.938, is much smaller than those for log K values in the nonpolar organic solvents previously studied. An analysis of literature data on 1:1 hydrogen bonding in water yields a negative slope for a plot of log K against alpha(H)2.beta(H)2, thus showing how the use of very strong hydrogen bond acids and bases does not lead to larger values of log K for 1:1 hydrogen bonding in water. It is suggested that for simple 1:1 association between monofunctional solutes in water, log K cannot be larger than about -0.1 log units. Descriptors have been obtained for the complex between 2,2,2-trifluoroethanol and propanone, and used to analyze solvent effects on the two reactants, the complex, and the complexation constant. PMID- 20954706 TI - Photochemical production and consumption mechanisms of nitric oxide in seawater. AB - Nitric oxide (NO*) is an active odd-nitrogen species that plays a critical role in determining the levels of ozone (O3) and other nitrogen species in the troposphere. Here, we provide experimental evidence for photochemical formation of NO* in seawater. Photoproduction rates and overall scavenging rate constants were measured by irradiation of surface seawater samples collected from the Seto Inland Sea, Japan. Photoproduction rates of NO* ranged from 8.7 * 10-12 M s-1 to 38.8 * 10-12 M s-1 and scavenging rate constants were 0.05-0.33 s-1. The steady state concentrations of NO* in seawater, which were calculated from the photoproduction rates and scavenging rate constants were in the range 2.4-32 * 10 11 M. Estimation from the scavenging rate constant showed that the NO* lifetime in seawater was a few seconds. Our results indicate that nitrite photolysis plays a crucial role in the formation of NO*, even though we cannot exclude minor contributions from other sources. Analysis of filtered and unfiltered seawater samples showed no significant difference in NO* photoformation rates, which suggests a negligible contribution of NO* produced by photobiological processes. Using an estimated value of the Henry's law constant (kH ~ 0.0019 M atm-1), a supersaturation of surface seawater of 2 to 3 orders of magnitude was estimated. On the basis of the average values of the surface seawater concentration and the atmospheric NO* concentration, a sea-to-air NO* flux was estimated. PMID- 20954707 TI - Human muscarinic acetylcholine receptors are a target of the marine toxin 13 desmethyl C spirolide. AB - Spirolides are a group of cyclic imine marine toxins recently described. Although no human intoxication has been related to their presence in shellfish yet, the possible toxicological consequences to human health are actually unknown. The elucidation of the spirolide mechanism/s of action would help to estimate the threat to human consumers. Previous toxicological studies in mice suggested the involvement of acetylcholine receptors. In this work, the effects of the 13 desmethyl C spirolide on the activity and the expression of muscarinic acetylcholine receptors (mAChR) were analyzed using a human neuroblastoma cell model. The 13-desmethyl C spirolide inhibited the acetylcholine-induced calcium signal with a reduction of the maximum response to acetylcholine in the presence of the toxin. The 13-desmethyl C spirolide also reduced binding of the mAChR specific antagonist [(3)H]QNB to neuroblastoma cells. The effect of the 13 desmethyl C spirolide persisted after toxin removal and was inhibited by protection of the primary binding site with high concentrations of atropine suggesting an interaction of the spirolide with the orthologous binding site of mAChR. Moreover, the toxin induced a change in the characteristics of the membrane-associated M3 mAChRs, although it did not alter the total levels of M3 mAChR protein. The 13-desmethyl C spirolide targets mAChRs causing a reduction of function, a decrease of specific antagonist binding to mAChRs, and alteration of membrane-bound receptors that might have important toxicological implications. PMID- 20954708 TI - Hydraulic/partitioning tracer tomography for DNAPL source zone characterization: small-scale sandbox experiments. AB - Dense nonaqueous phase liquids (DNAPL) are prevalent at a large number of sites throughout the world. The variable release history, unstable flow, and geologic heterogeneity make the spatial distribution of DNAPLs complex. This causes difficulties in site remediation contributing to long-term groundwater contamination for decades to centuries. We present laboratory experiments to demonstrate the efficacy of Sequential Successive Linear Estimator (SSLE) algorithm that images DNAPL source zones. The algorithm relies on the fusion of hydraulic and partitioning tracer tomography (HPTT) to derive the best estimate of the K heterogeneity, DNAPL saturation (S(N)) distribution, and their uncertainty. The approach is nondestructive and can be applied repeatedly. Results from our laboratory experiments show that S(N) distributions compare favorably with DNAPL distributions observed in the sandbox but not so with local saturation estimates from core samples. We also found that the delineation of K heterogeneity can have a large impact on computed S(N) distributions emphasizing the importance of accurate delineation of hydraulic heterogeneity. PMID- 20954709 TI - Isolation and characterization of lignins from Eucalyptus tereticornis (12ABL). AB - A three-step sequential extraction-precipitation method was used to isolate lignin from Eucalyptus tereticornis. The ball-milled eucalyptus was extracted with 96% dioxane, 50% dioxane, and 80% dioxane containing 1% NaOH at boiling temperature, consecutively resulting in solubilization of lignin and hemicelluloses. By precipitating such solutions into 70% aqueous ethanol, the hemicelluloses were removed substantially although there were still some carbohydrates left over, especially for lignin fraction extracted by 50% dioxane. Lignins dissolved in the 70% ethanol solutions were recovered via concentration and precipitation into acidified water. About 37% of the original lignin was released following such procedure whereas only 13.5% can be isolated by traditional milled wood lignin (MWL) method. The obtained lignin fractions were analyzed by high performance anion exchange chromatography (HPAEC) following acid hydrolysis for sugar composition of the contaminating carbohydrates and characterized by quantitative (31)P NMR as well as two-dimensional heteronuclear single-quantum coherence ((13)C-(1)H) NMR. The results showed that 96% aqueous dioxane extraction of ball-milled wood under conditions used in this study resulted in lignin preparation with very similar structures and sugar composition as traditional MWL. Therefore extracting ball-milled wood with 96% aqueous dioxane produced lignin in 33.6% yield, which makes it very attractive as an alternative to the traditional MWL method. However further extraction with 50% aqueous dioxane or 80% aqueous dioxane containing 1% NaOH gave just a little more lignins with different carbohydrate compositions from those in MWL. The eucalyptus lignins obtained were syringyl and guaiacyl type units. Lignin fraction obtained from 96% dioxane extraction was found to have more phenolic hydroxyl and less aliphatic hydroxyl than the other two preparations. PMID- 20954710 TI - Transition metal catalyzed enantioselective alpha-heterofunctionalization of carbonyl compounds. PMID- 20954711 TI - Triggered polycatenated DNA scaffolds for DNA sensors and aptasensors by a combination of rolling circle amplification and DNAzyme amplification. AB - The concept of triggered polycatenated DNA scaffolds has been elegantly introduced into ultrasensitive biosensing applications by a combination of rolling circle amplification (RCA) and DNAzyme amplification. As compared to traditional methods in which one target could only initiate the formation of one circular template for RCA reaction, in the present study two species of linear single-stranded DNA (ssDNA) monomers are self-assembled into mechanically interlocked polycatenated nanostructures on capture probe-tagged magnetic nanoparticles (MNPs) only upon the introduction of one base mutant DNA sequence as initiator for single-nucleotide polymorphisms (SNPs) analysis. The resultant topologically polycatenated DNA ladder is further available for RCA process by using the serially ligated circular DNA as template for the synthesis of hemin/G quadruplex HRP-mimicking DNAzyme chains, which act as biocatalytic labels for the luminol-H(2)O(2) chemiluminescence (CL) system. Notably, the problem of high background induced by excess hemin itself is circumvented by immobilizing the biotinylated RCA products on streptavidin-modified MNPs via biotin-streptavidin interaction. Similarly, a universal strategy is contrived by substitutedly employing aptamer as initiator for the construction of polycatenated DNA scaffolds to accomplish ultrasensitive detection of proteins based on structure switching of aptamer upon target binding, which is demonstrated by using thrombin as a model analyte in this study. Overall, with two successive amplification steps and one magnetic separation procedure, this flexible biosensing system exhibits not only high sensitivity and specificity with the detection limits of SNPs and thrombin as low as 71 aM and 6.6 pM, respectively, but also excellent performance in real human serum assay with no PCR preamplification for SNPs assay. Given the unique and attractive characteristics, this study illustrates the potential of DNA nanotechnology in bioanalytical applications for both fundamental and practical research. PMID- 20954712 TI - Arsenite induces endothelial cell permeability increase through a reactive oxygen species-vascular endothelial growth factor pathway. AB - As a potent environmental oxidative stressor, arsenic exposure has been reported to exacerbate cardiovascular diseases and increase vascular endothelial cell monolayer permeability. However, the underlying mechanism of this effect is not well understood. In this paper, we test our hypothesis that reactive oxygen species (ROS)-induced vascular endothelial growth factor (VEGF) expression may play an important role in an arsenic-caused increase of endothelial cell monolayer permeability. The mouse brain vascular endothelial cell bEnd3 monolayer was exposed to arsenite for 1, 3, and 6 days. The monolayer permeability, VEGF protein release, and ROS generation were determined. In addition, VE-cadherin and zonula occludens-1 (ZO-1), two membrane structure proteins, were immunostained to elucidate the effects of arsenite on the cell-cell junction. The roles of ROS and VEGF in arsenite-induced permeability was determined by inhibiting ROS with antioxidants and immuno-depleting VEGF with a VEGF antibody. We observed that arsenite increased bEnd3 monolayer permeability, elevated the production of cellular ROS, and increased VEGF release. VE-cadherin and ZO-1 disruptions were also found in cells treated with arsenite. Furthermore, both antioxidant (N acetyl cysteine and tempol) and the VEGF antibody treatments significantly lowered the arsenite-induced permeability of the bEnd3 monolayer as well as VEGF expression. VE-cadherin and ZO-1 disruptions were also diminished by N-acetyl cysteine and the VEGF antibody. Our data suggest that the increase in VEGF expression caused by ROS may play an important role in the arsenite-induced increase in endothelial cell permeability. PMID- 20954714 TI - Free energy density functional for adsorption of fluids in nanopores. AB - A classical free energy density functional, which is isomorphic to a usual effective hard sphere model + mean field approximation for tail contribution, is proposed for treatment of real fluids in inhomogeneous states. In the framework of the classical density functional theory (DFT), the present functional is applied to two representative model fluids, namely, a Lennard-Jones fluid and a hard core attractive Yukawa fluid, subject to influence of various external fields. A comprehensive comparison with simulation results and a detailed analysis show that the present functional holds simultaneously all of the desirable properties inherent in an excellent functional, such as high accuracy, computational simplicity, consistency with a hard wall sum rule, nonrecourse to use of adjustable parameter(s) and weighted densities, reproduction of bulk second-order direct correlation function (DCF) in bulk limit, and applicability to subcritical fluid phenomena. PMID- 20954715 TI - Synthesis and RCM reactions using a recyclable Grubbs-Hoveyda metathesis catalyst activated by a light fluorous tag. AB - A recyclable Grubbs-Hoveyda second-generation catalyst activated by a light fluorous tag was prepared. The modified light fluorous catalyst exhibited higher catalytic activity than the parent or the previously reported light fluorous variant for RCM reactions and could be routinely recovered. The light fluorous tag incorporated in the catalyst served as both an activator as well as a handle for separation and recovery with fluorous solid-phase extraction. PMID- 20954713 TI - Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2: implications for the mechanism of enzyme inhibition. AB - Molinate is a thiocarbamate herbicide used as a pre-emergent in rice patty fields. It has two predominant sulfoxidation metabolites, molinate sulfoxide and molinate sulfone. Previous work demonstrated an in vivo decrease in liver aldehyde dehydrogenase (ALDH) activity in rats treated with molinate and motor function deficits in dogs dosed chronically with this compound. ALDH is an enzyme important in the catabolism of many neurotransmitters, such as dopamine. Inhibition of this enzyme may lead to the accumulation of endogenous neurotoxic metabolites such as 3,4-dihydroxyphenylacetaldehyde, a dopamine metabolite, which may account for the observed neurotoxicity. In this study, the relative reactivity of molinate and both of its sulfoxidation metabolites toward ALDH was investigated, as well as the mechanism of inhibition. The ALDH activity was monitored in two different model systems, human recombinant ALDH (hALDH2) and mouse striatal synaptosomes. Molinate sulfone was found to be the most potent ALDH inhibitor, as compared to molinate and molinate sulfoxide. The reactivity of these three compounds was also assessed, using N-acetyl Cys, model peptides, and hALDH2. It was determined that molinate sulfone is capable of covalently modifying Cys residues, including catalytic Cys302 of ALDH, accounting for the observed enzyme inhibition. PMID- 20954716 TI - Electron transfer of site-specifically cross-linked complexes between ferredoxin and ferredoxin-NADP(+) reductase. AB - Ferredoxin (Fd) and Fd-NADP(+) reductase (FNR) are redox partners responsible for the conversion between NADP(+) and NADPH in the plastids of photosynthetic organisms. Introduction of specific disulfide bonds between Fd and FNR by engineering cysteines into the two proteins resulted in 13 different Fd-FNR cross linked complexes displaying a broad range of activity to catalyze the NADPH dependent cytochrome c reduction. This variability in activity was thought to be mainly due to different levels of intramolecular electron transfer activity between the FNR and Fd domains. Stopped-flow analysis revealed such differences in the rate of electron transfer from the FNR to Fd domains in some of the cross linked complexes. A group of the cross-linked complexes with high cytochrome c reduction activity comparable to dissociable wild-type Fd/FNR was shown to assume a similar Fd-FNR interaction mode as in the native Fd:FNR complex by analyses of NMR chemical shift perturbation and absorption spectroscopy. However, the intermolecular electron transfer of these cross-linked complexes with two Fd binding proteins, nitrite reductase and photosystem I, was largely inhibited, most probably due to steric hindrance by the FNR moiety linked near the redox center of the Fd domain. In contrast, another group of the cross-linked complexes with low cytochrome c reduction activity tends to mediate higher intermolecular electron transfer activity. Therefore, reciprocal relationship of intramolecular and intermolecular electron transfer abilities was conferred by the linkage of Fd and FNR, which may explain the physiological significance of the separate forms of Fd and FNR in chloroplasts. PMID- 20954717 TI - Determination of cyclic volatile methylsiloxanes in biota with a purge and trap method. AB - The three cyclic volatile methylsiloxanes (cVMS), octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclohexasiloxane (D6), are recently identified environmental contaminants. Methods for the trace analysis of these chemicals in environmental matrices are required. A purge and trap method to prepare highly purified sample extracts with a low risk of sample contamination is presented. Without prior homogenization, the sample is heated in water, and the cVMS are purged from the slurry and trapped on an Isolute ENV+ cartridge. They are subsequently eluted with n-hexane and analyzed with GC/MS. The method was tested for eight different matrices including ragworms, muscle tissue from lean and lipid-rich fish, cod liver, and seal blubber. Analyte recoveries were consistent within and between matrices, averaging 79%, 68%, and 56% for D4, D5, and D6, respectively. Good control of blank levels resulted in limits of quantification of 1.5, 0.6, and 0.6 ng/g wet weight. The repeatability was 12% (D5) and 15% (D6) at concentrations 9 and 2 times above the LOQ. The method was applied to analyze cVMS in fish from Swedish lakes, demonstrating that contamination in fish as a result of long-range atmospheric transport is low as compared to contamination from local sources. PMID- 20954718 TI - Temporal resolution of solid-phase microextraction: measurement of real-time concentrations within a dynamic system. AB - To address the challenge of measuring real-time analyte concentrations within dynamic systems, the temporal resolution of the solid-phase microextraction (SPME) approach has been investigated. A mass-uptake model for SPME within a dynamic system was developed and validated, with experimental factors affecting the temporal resolution (sampling time, agitation, SPME fiber dimensions, sample concentration and change rate, and instrument sensitivity) characterized. Calibration methods for time-resolved sampling in a dynamic system were compared. To demonstrate the efficacy of time-resolved SPME, this approach was successfully applied to investigate the binding kinetics between plasma proteins and pharmaceuticals, which verified a decrease in free pharmaceutical concentrations over time in the presence of bovine serum albumin. The current study provides the theoretical and logistical framework for applying SPME to the real-time measurement of dynamic systems, facilitating future SPME applications such as in vivo metabolomic studies. PMID- 20954719 TI - Lectin-based biosensor strategy for electrochemical assay of glycan expression on living cancer cells. AB - In this article, we report a novel lectin-based biosensor for electrochemical assay of cancer-associated glycosylation by comparative study of mannose and sialic acid expression on normal and cancer cells derived from human lung, liver, and prostate. Using a sandwich format, high sensitivity and selectivity were achieved by combining the lectin-based biosensor with the {lectin-Au-Th} bioconjugates featuring lectin and thionine (Th) labels linked to gold nanoparticles (AuNPs) for signal amplification. The proposed strategy demonstrated that mannose exhibited high expression levels in both normal and cancer cells, while sialic acid was more abundant in cancer cells as compared to normal ones. The results were in good agreement with those from fluorescent microscopy studies. The differences in the two glycan expression indicated that sialic acid could serve as a potential biomarker for early cancer detection. The lectin-based biosensor was also successfully used to quantify cancer cells and evaluate the average amount of sialic acid on single cell surface, which could supply significant information on glycan functions in cancer progression. Overall, the lectin-based electrochemical biosensor provides an effective pathway to analyze glycan expression on living cells and may greatly facilitate the medical diagnosis and treatment in early process of cancer. PMID- 20954720 TI - Colorimetric sensor array for determination and identification of toxic industrial chemicals. AB - A low-cost yet highly sensitive colorimetric sensor array for the detection and identification of toxic industrial chemicals (TICs) has been developed. The sensor consists of a disposable array of cross-responsive nanoporous pigments whose colors are changed by diverse chemical interactions with analytes. Clear differentiation among 20 different TICs has been easily achieved at both their IDLH (immediately dangerous to life or health) concentration within 2 min of exposure and PEL (permissible exposure limit) concentration within 5 min of exposure with no errors or misclassifications. Detection limits are generally well below the PEL (in most cases below 5% of PEL) and are typically in the low ppb range. The colorimetric sensor array is not responsive to changes in humidity or temperature over a substantial range. The printed arrays show excellent batch to batch reproducibility and long shelf life (greater than 3 months). PMID- 20954721 TI - Triterpenoidal alkaloids from Buxus natalensis and their acetylcholinesterase inhibitory activity. AB - Acetylcholinesterase (AChE) inhibition-directed phytochemical studies on the methanolic extract of Buxus natalensis, collected in South Africa, resulted in the isolation of 12 compounds: O(2)-natafuranamine (1), O(10)-natafuranamine (2), cyclonataminol (3), 31-demethylbuxaminol A (4), buxaminol A (5), buxafuranamide (6), buxalongifolamidine (7), buxamine A (8), cyclobuxophylline K (9), buxaminol C (10), methyl syringate (11), and p-coumaroylputrescine (12). Compounds 1-4 were new alkaloids, and compound 5 was isolated for the first time as a natural product. Their structures were elucidated with the aid of extensive NMR and mass spectroscopic studies. Compounds 1 and 2 are members of a rarely occurring class of Buxus alkaloids, having a tetrahydrofuran ring incorporated in their structures. Compounds 1-12 exhibited strong to moderate AChE inhibitory activity. PMID- 20954722 TI - Caffeic acid esters and lignans from Piper sanguineispicum. AB - Three new caffeic acid esters (1-3), four new lignans (4-7), and the known compounds (7'S)-parabenzlactone (8), dihydrocubebin (9), and justiflorinol (10) have been isolated from leaves of Piper sanguineispicum. Their structures were determined by spectroscopic methods, including 1D and 2D NMR, HRCIMS, CD experiments, and chemical methods. Compounds 1-10 were assessed for their antileishmanial potential against axenic amastigote forms of Leishmania amazonensis. Caffeic acid esters 1 and 3 exhibited the best antileishmanial activity (IC(50) 2.0 and 1.8 MUM, respectively) with moderate cytotoxicity on murine macrophages. PMID- 20954723 TI - Enantioselective total synthesis of (-)- and (+)-petrosin. AB - The enantioselective total synthesis of (-)- and (+)-petrosin is described. The union of two key segments was executed by Suzuki-Miyaura coupling. The quinolizidine rings were stereoselectively constructed via a diastereoselective Mannich reaction and an aza-Michael reaction. The 16-membered ring was constructed by ring-closing metathesis with the second-generation Grubbs catalyst. PMID- 20954724 TI - Enantioselective Michael reaction of alpha-alkyl-beta-keto esters and enones under multifunctional catalysis. AB - An efficient approach for the enantioselective Michael additions of beta-alkyl beta-keto esters to beta-substituted alpha,beta-unsaturated ketones has been developed. The Michael products could be obtained in good to excellent yields (75 98%) with excellent diastereoselectivities (up to >99:1 dr) and enantioselectivities (up to 96% ee) and could easily be transformed into a synthetically useful hexahydrophenanthrene structure under mild conditions in good yield. PMID- 20954725 TI - Cinchona alkaloid-catalyzed asymmetric trifluoromethylation of alkynyl ketones with trimethylsilyl trifluoromethane. AB - The first catalytic enantioselective trifluoromethylation of alkynyl ketones 1 with (trifluoromethyl)trimethylsilane is disclosed by an operationally simple procedure, based on the combination of ammonium bromide of bis-cinchona alkaloids with Me(4)NF to afford trifluoromethyl-substituted tertiary propargyl alcohols (up to 96% ee), which are the important chiral building blocks for pharmaceuticals. Biologically attractive aryl heteroaryl trifluoromethyl carbinols were also synthesized. PMID- 20954726 TI - Degradable nitric oxide-releasing biomaterials via post-polymerization functionalization of cross-linked polyesters. AB - The synthesis of diverse nitric oxide (NO)-releasing network polyesters is described. The melt phase condensation of polyols with a calculated excess of diacid followed by thermal curing generates cross-linked polyesters containing acid end groups. Varying the composition and curing temperatures of the polyesters resulted in materials with tunable thermal and degradation properties. Glass transition temperatures for the synthesized materials range from -25.5 to 3.2 degrees C, while complete degradation of these polyesters occurs within a minimum of nine weeks under physiological conditions (pH 7.4, 37 degrees C). Post-polymerization coupling of aminothiols to terminal carboxylic acids generate thiol-containing polyesters, with thermal and degradation characteristics similar to those of the parent polyesters. After nitrosation, these materials are capable of releasing up to 0.81 MUmol NO cm(-2) for up to 6 d. The utility of the polyesters as antibacterial biomaterials was indicated by an 80% reduction of Pseudomonas aeruginosa adhesion compared to unmodified controls. PMID- 20954727 TI - Surface characterization of carbohydrate microarrays. AB - Carbohydrate microarrays are essential tools to determine the biological function of glycans. Here, we analyze a glycan array by time-of-flight secondary ion mass spectrometry (ToF-SIMS) to gain a better understanding of the physicochemical properties of the individual spots and to improve carbohydrate microarray quality. The carbohydrate microarray is prepared by piezo printing of thiol terminated sugars onto a maleimide functionalized glass slide. The hyperspectral ToF-SIMS imaging data are analyzed by multivariate curve resolution (MCR) to discern secondary ions from regions of the array containing saccharide, linker, salts from the printing buffer, and the background linker chemistry. Analysis of secondary ions from the linker common to all of the sugar molecules employed reveals a relatively uniform distribution of the sugars within the spots formed from solutions with saccharide concentration of 0.4 mM and less, whereas a doughnut shape is often formed at higher-concentration solutions. A detailed analysis of individual spots reveals that in the larger spots the phosphate buffered saline (PBS) salts are heterogeneously distributed, apparently resulting in saccharide concentrated at the rim of the spots. A model of spot formation from the evaporating sessile drop is proposed to explain these observations. Saccharide spot diameters increase with saccharide concentration due to a reduction in surface tension of the saccharide solution compared to PBS. The multivariate analytical partial least squares (PLS) technique identifies ions from the sugars that in the complex ToF-SIMS spectra correlate with the binding of galectin proteins. PMID- 20954728 TI - Ultrasensitive sensing of Hg(2+) and CH(3)Hg(+) based on the fluorescence quenching of lysozyme type VI-stabilized gold nanoclusters. AB - This study presents a one-step approach to prepare lysozyme type VI-stabilized gold nanoclusters (Lys VI-AuNCs) for the ultrasensitive detection of Hg(2+) and CH(3)Hg(+) based on fluorescence quenching. The optical properties and size of Lys VI-AuNCs are highly dependent on the concentration of Lys VI, which acts as both a reducing and a stabilizing agent. With an increase in the concentration of Lys VI, we observed a systematic blue shift in the fluorescence maxima, an increase in the quantum yields, and a reduction in the particle size. When using 25 mg/mL Lys VI as a reducing agent, the formed Lys VI-AuNCs (denoted as Au-631) were found to be highly stable in a high-concentration glutathione or NaCl. Additionally, the Au-631 were capable of sensing Hg(2+) and CH(3)Hg(+) through the interaction between Hg(2+)/CH(3)Hg(+) and Au(+) on the Au surface; the limits of detection (LODs) for Hg(2+) and CH(3)Hg(+) were 3 pM and 4 nM, respectively. The selectivity of this probe is more than 500-fold for Hg(2+) over any metal ions. As compared to bovine serum albumin-stabilized AuNCs, Au-631 provided an approximately 330-fold improvement in the detection of Hg(2+). To the best of our knowledge, Au-631 not only provide the first example for detecting CH(3)Hg(+) but also have the lowest LOD value for Hg(2+) when compared to other AuNC-based Hg(2+) sensors. Importantly, this probe was successfully applied to the determination of Hg(2+) and CH(3)Hg(+) in seawater. PMID- 20954729 TI - Diastereoselective access to trans-2-substituted cyclopentylamines. AB - A highly diastereoselective synthesis of trans-2-substituted cyclopentylamines via a tandem hydrozirconation/Lewis acid-mediated cyclization sequence applied to butenyl oxazolidines is described. The method allows an easy preparation of diversely substituted cyclopentylamines which appear to be useful synthetic intermediates. This was further illustrated by the syntheses of (+/-)-Rodocaine, (+/-)-trans-pentacin, and enantiomerically enriched trans-cyclopentane-1,2 diamine. PMID- 20954730 TI - Engineering sticky superomniphobic surfaces on transparent and flexible PDMS substrate. AB - Following the achievement of superhydrophobicity which prevents water adhesion on a surface, superomniphobicity extends this high repellency property to a wide range of liquids, including oils, solvents, and other low surface energy liquids. Recent theoretical approaches have yield to specific microstructures design criterion to achieve such surfaces, leading to superomniphobic structured silicon substrate. To transfer this technology on a flexible substrate, we use a polydimethylsiloxane (PDMS) molding process followed by surface chemical modification. It results in so-called sticky superomniphobic surfaces, exhibiting large apparent contact angles (>150 degrees ) along with large contact angle hysteresis (>10 degrees ). We then focus on the modified Cassie equation, considering the 1D aspect of wetting, to explain the behavior of droplets on these surfaces and compare experimental data to previous works to confirm the validity of this model. PMID- 20954731 TI - Properties and synthesis of 2-{2-fluoro (or bromo)-4-[(2 oxocyclopentyl)methyl]phenyl}propanoic acid: nonsteroidal anti-inflammatory drugs with low membrane permeabilizing and gastric lesion-producing activities. AB - We previously proposed that membrane permeabilization activity of NSAIDs is involved in NSAID-induced gastric lesions. We here synthesized derivatives of loxoprofen that have lower membrane permeabilization activity than other NSAIDs. Compared to loxoprofen, the derivatives 10a and 10b have lower membrane permeabilization activity and their oral administration produced fewer gastric lesions but showed an equivalent anti-inflammatory effect. These results suggest that 10a and 10b are likely to be therapeutically beneficial as safer NSAIDs. PMID- 20954733 TI - Hydrophobic self-assembly of a perylenediimide-linked DNA dumbbell into supramolecular polymers. AB - The self-assembly of DNA dumbbell conjugates possessing hydrophobic perylenediimide (PDI) linkers separated by an eight-base pair A-tract has been investigated. Cryo-TEM images obtained from dilute solutions of the dumbbell in aqueous buffer containing 100 mM NaCl show the presence of structures corresponding to linear end-to-end assemblies of 10-30 dumbbell monomers. The formation of assemblies of this size is consistent with analysis of the UV-vis and fluorescence spectra of these solutions for the content of PDI monomer and dimer chromophores. Assembly size is dependent upon the concentration of dumbbell and salt as well as the temperature. Kinetic analysis of the assembly process by means of salt-jump stopped-flow measurements shows that it occurs by a salt triggered isodesmic mechanism in which the rate constants for association and dissociation in 100 mM NaCl are 3.2 * 10(7) M(-1)s(-1) and 1.0 s(-1), respectively, faster than the typical rate constants for DNA hybridization. TEM and AFM images of samples deposited from solutions having higher concentrations of dumbbell and NaCl display branched assemblies with linear regions >1 MUm in length and diameters indicative of the formation of small bundles of dumbbell end to-end assemblies. These observations provide the first example of the use of hydrophobic association for the assembly of small DNA duplex conjugates into supramolecular polymers and larger branched aggregates. PMID- 20954735 TI - Effect of chemical substituents on the energetical landscape of a molecular photoswitch: an ab initio study. AB - The effect of chemical substitutions on the energetical landscape of an optical molecular switch (Phys. Chem. Chem. Phys. 2008, 10, 1243) was studied with the aid of ab initio electronic structure methods. Series of different chemical moieties were substituted into the molecular frame of 7-hydroxyquinoline as well as into the "molecular crane" at position 8 of the frame. It was shown that the pi-electron-donating/withdrawing properties of substituents substantially modify the energetical landscape of the system in the ground as well as in the lowest excited pipi* and npi* singlet states. PMID- 20954734 TI - Exploring cellular contact guidance using gradient nanogratings. AB - Nanoscale surface features that mimic extracellular matrix are critical environmental cues for cell contact guidance and are vital in advanced medical devices in order to manipulate cell behaviors. Among them, nanogratings (line-and space gratings) are common platforms to study geometric effects on cell contact guidance, especially cell alignment, but generally are one pattern height per platform. In this study, we developed a strategy to fabricate controlled substrates with a wide range of pattern shapes and surface chemistries and to separate surface chemistry and topography effects. As a demonstration of this strategy, six nanograting platforms on three materials were fabricated and applied to examine and differentiate the effects of surface topography and surface chemistry on cell contact guidance of murine preosteoblasts. All of the six platforms contained the same gradient in pattern height (0 to ~350 nm). They were prepared using nanoimprint lithography and annealing for thermoplastic materials (low molecular weight polystyrene (PS) and polymethylmethacrylate (PMMA)) and photoimprint for a thermoset material (a cross-linked dimethacrylate (DMA)). Each material contains two platforms that are only different in line-and space pitch (420 or 800 nm). The DMA nanogratings had a reverse line-and-space profile to those of the PS and PMMA nanogratings. Using these platforms, a full range of cell alignment, from randomly orientated to completely parallel to the grating direction was achieved. Results from focal adhesion assays and scanning electronic microscopy indicated a change in cell-substrate contact from a noncomposite state (full contact) to a composite state (partial contact between cell and substrate) as pattern height increased. These gradient platforms allowed for the separation of surface chemistry and surface topography to provide insight into the mechanisms responsible for cell contact guidance on nanopatterned surfaces. PMID- 20954736 TI - Synthesis of functional polymer brushes containing carbohydrate residues in the pyranose form and their specific and nonspecific interactions with proteins. AB - Three novel N-substituted acrylamide monomers containing different carbohydrate residues, 2'-acrylamidoethyl-alpha-d-mannopyranoside, 2'-acrylamidoethyl-beta-d glucopyranoside, and 2'-acrylamidoethyl-beta-d-galactopyranoside, in the pyranose form were synthesized. The corresponding glycopolymer brushes were prepared on silicon substrates by surface-initiated atom transfer radical polymerization (SI ATRP) using unprotected glycomonomers. The formation of glycopolymer brushes was well-characterized using ellipsometry, ATR-FTIR, water contact angle analysis, atomic force microscopy analysis, and X-ray photoelectron spectroscopy. The effects of halogen, ligand, and solvent on the polymerization were thoroughly investigated. It was shown that CuCl/CuCl2/tris(2-dimethylaminoethyl)amine (Me6TREN) catalytic system with an optimized ratio of Cu(I)/Cu(II) produced glycopolymer with high molecular weight (Mn = 44-140 kDa) and relatively narrow molecular weight distribution (PDI = 1.4). The dry thickness of resulting glycopolymer brushes (10-36 nm) showed a proportional relationship with the molecular weight of free polymer generated in the solution. The grafting densities of obtained glycopolymer brushes were between 0.12 and 0.17 chains/nm(2). The grafting of glycopolymer resulted in highly hydrophilic surface layer with very low water contact angles (<10 degrees ). The glycopolymer brushes showed ultralow protein adsorption from bovine serum albumin (BSA) and fibrinogen (Fb) solutions. Glycopolymer brushes containing glucose units showed relatively better protection against BSA and Fb adsorption than those brushes containing mannose and galactose units. Synthesized glycopolymer brushes retained specific protein interactions, as evident from the interaction with Concanavalin A (Con A). The interaction of surface-grafted glycopolymer brushes with Con A depended on both the stereochemistry of carbohydrate units and the chemical structures present. In addition, the newly synthesized glycopolymer brushes performed significantly better in comparison with currently available structures in terms of specific protein interactions. PMID- 20954737 TI - Blue shift of the isolated CD stretching band of CH2DOH in water induced by changes in the hydrogen-bonding pattern. AB - The wavenumber shift in the CD stretching (nu(CD)) band of the monodeuterated methanol (CH(2)DOH) has been monitored in water-methanol mixtures. For the pure liquid, two dominant bands are observed at 2148 and 2176 cm(-1) in the nu(CD) region. The matrix isolation technique and spectral simulation based on quantum chemical calculations have revealed that these two bands are categorized into the C(1) mode and originate from methanol molecules participating in different hydrogen(H)-bonding patterns. The simulation results for methanol clusters have suggested that the 2148 cm(-1) band is concerned with the end-donor species in the H-bonding network. The relative intensity of the band near 2148 cm(-1) decreases with increasing water concentration, indicating that the population of the end-donor species decreases by the addition of water. This spectral change causes the blue shift in the mean center of the nu(CD) band of CH(2)DOH in water. PMID- 20954738 TI - Theory and validation of solid-phase microextraction and needle trap devices for aerosol sample. AB - Previous aerosol studies utilizing solid-phase microextraction (SPME) predominantly focused on volatile and semivolatile compounds in the gaseous phase. Difficulties were associated with quantitative analysis of these compounds when they were associated with atmospheric particles. The present study combines SPME technology with that of carboxen packed needles (needle trap, NT) for analysis of gaseous and particle-bound compounds in atmospheric samples. The NT device is constructed as a micro trap by placing some small sorbents in a needle. Aerosol samples are collected by drawing air through the NT device with a pump. The trapped components contain both gaseous chemical compounds as well as particulate matter present in the sample. The total concentration of analytes in an aerosol sample can be obtained on the basis of the exhaustive sampling mode of the NT device. Direct SPME is simultaneously used to determine gaseous compound in the aerosol sample. As a result, the SPME and NT devices, when used together, can provide a complete solution to highly efficient and accurate aerosol studies. The theoretical considerations of SPME and NT devices for aerosol sampling are validated by sampling seasalt aerosol, barbecue, and cigarette smoke. The concentrations of PAHs in the different phases of the samples are few ng/L. Result analysis shows that SPME and the NT device demonstrate several important advantages such as simplicity, convenience, and low costs under laboratory and on site field sampling conditions. PMID- 20954739 TI - Electrochemical properties and myocyte interaction of carbon nanotube microelectrodes. AB - Arrays of carbon nanotube (CNT) microelectrodes (nominal geometric surface areas 20-200 MUm(2)) were fabricated by photolithography with chemical vapor deposition of randomly oriented CNTs. Raman spectroscopy showed strong peak intensities in both G and D bands (G/D = 0.86), indicative of significant disorder in the graphitic layers of the randomly oriented CNTs. The impedance spectra of gold and CNT microelectrodes were compared using equivalent circuit models. Compared to planar gold surfaces, pristine nanotubes lowered the overall electrode impedance at 1 kHz by 75%, while nanotubes treated in O(2) plasma reduced the impedance by 95%. Cyclic voltammetry in potassium ferricyanide showed potential peak separations of 133 and 198 mV for gold and carbon nanotube electrodes, respectively. The interaction of cultured cardiac myocytes with randomly oriented and vertically aligned CNTs was investigated by the sectioning of myocytes using focused-ion-beam milling. Vertically aligned nanotubes deposited by plasma enhanced chemical vapor deposition (PECVD) were observed to penetrate the membrane of neonatal-rat ventricular myocytes, while randomly oriented CNTs remained external to the cells. These results demonstrated that CNT electrodes can be leveraged to reduce impedance and enhance biological interfaces for microelectrodes of subcellular size. PMID- 20954740 TI - Piriform spider silk sequences reveal unique repetitive elements. AB - Orb-weaving spider silk fibers are assembled from very large, highly repetitive proteins. The repeated segments contain, in turn, short, simple, and repetitive amino acid motifs that account for the physical and mechanical properties of the assembled fiber. Of the six orb-weaver silk fibroins, the piriform silk that makes the attachment discs, which lashes the joints of the web and attaches dragline silk to surfaces, has not been previously characterized. Piriform silk protein cDNAs were isolated from phage libraries of three species: A. trifasciata , N. clavipes , and N. cruentata . The deduced amino acid sequences from these genes revealed two new repetitive motifs: an alternating proline motif, where every other amino acid is proline, and a glutamine-rich motif of 6-8 amino acids. Similar to other spider silk proteins, the repeated segments are large (>200 amino acids) and highly homogenized within a species. There is also substantial sequence similarity across the genes from the three species, with particular conservation of the repetitive motifs. Northern blot analysis revealed that the mRNA is larger than 11 kb and is expressed exclusively in the piriform glands of the spider. Phylogenetic analysis of the C-terminal regions of the new proteins with published spidroins robustly shows that the piriform sequences form an ortholog group. PMID- 20954741 TI - Nanoscale chemical imaging using top-illumination tip-enhanced Raman spectroscopy. AB - We present a new top-illumination scheme for tip-enhanced Raman spectroscopy (TERS) in a gap-mode configuration with illumination and detection in a straightforward fashion perpendicular to the sample surface. This illumination focuses the light tightly around the tip end, which effectively diminishes far field background contributions during TERS measurements. The setup maintains the entire functionality range of both the scanning probe microscopy and the confocal optical microscopy of the setup. For the first time, we show large (64 * 64 up to 200 * 200 pixels), high-resolution TERS imaging with full spectral information at every pixel, which is necessary for the chemical identification of sample constituents. With a scanning tunneling microscope tip and feedback, these TERS maps can be recorded with a resolution better than 15 nm (most likely even less, as discussed with Figure 6). An excellent enhancement (~10(7)*, sufficient for detection of few molecules) allows short acquisition times (<<1 s/pixel) and reasonably low laser power (in the microwatt regime) yielding spectroscopic images with high pixel numbers in reasonable time (128 * 128 pixels in <25 min). To the best of our knowledge, no Raman maps with similar pixel numbers and full spectral information have ever been published. PMID- 20954742 TI - Electrospun ultralong hierarchical vanadium oxide nanowires with high performance for lithium ion batteries. AB - Ultralong hierarchical vanadium oxide nanowires with diameter of 100-200 nm and length up to several millimeters were synthesized using the low-cost starting materials by electrospinning combined with annealing. The hierarchical nanowires were constructed from attached vanadium oxide nanorods of diameter around 50 nm and length of 100 nm. The initial and 50th discharge capacities of the ultralong hierarchical vanadium oxide nanowire cathodes are up to 390 and 201 mAh/g when the lithium ion battery cycled between 1.75 and 4.0 V. When the battery was cycled between 2.0 and 4.0 V, the initial and 50th discharge capacities of the nanowire cathodes are 275 and 187 mAh/g. Compared with self-aggregated short nanorods synthesized by hydrothermal method, the ultralong hierarchical vanadium oxide nanowires exhibit much higher capacity. This is due to the fact that self aggregation of the unique nanorod-in-nanowire structures have been greatly reduced because of the attachment of nanorods in the ultralong nanowires, which can keep the effective contact areas of active materials, conductive additives, and electrolyte large and fully realize the advantage of nanomaterial-based cathodes. This demonstrates that ultralong hierarchical vanadium oxide nanowire is one of the most favorable nanostructures as cathodes for improving cycling performance of lithium ion batteries. PMID- 20954743 TI - Octupole-like supramolecular aggregates of conical iron fullerene complexes into a three-dimensional liquid crystalline lattice. AB - The installation of three structural features into a fullerene molecule, a conical shape, a polar iron-ferrocene complex, and long alkyl chains, allowed dipolar molecules 1 and 2 to undergo microphase separation and to form a three dimensional lattice in a crystalline and a thermotropic liquid crystalline phase. The key feature is a tetrameric octupole-like aggregate, in which four dipoles are arranged supramolecularly to cancel the molecular polarity, forming a sphere. In addition to this lattice formation mechanism, the molecules incorporate noteworthy features, such as redox active C(60)/ferrocene and luminescent cyclophenacene. PMID- 20954745 TI - Sensitive fluorometric nanoparticle assays for cell counting and viability. AB - We have developed easy-to-use homogeneous methods utilizing time-resolved fluorescence resonance energy transfer (TR-FRET) and fluorescence quenching for quantification of eukaryotic cells. The methods rely on a competitive adsorption of cells and fluorescently labeled protein onto citrate-stabilized colloidal gold nanoparticles or carboxylate-modified polystyrene nanoparticles doped with an Eu(III) chelate. In the gold nanoparticle sensor, the adsorption of the labeled protein to the gold nanoparticles leads to quenching of the fluorochrome. Eukaryotic cells reduce the adsorption of labeled protein to the gold particles increasing the fluorescence signal. In the Eu(III) nanoparticle sensor, the time resolved fluorescence resonance energy transfer between the nanoparticles and an acceptor-labeled protein is detected; a decrease in the magnitude of the time resolved energy transfer signal (sensitized time-resolved fluorescence) is proportional to the cell-nanoparticle interaction and subsequent reduced adsorption of the labeled protein. Less than five cells were detected and quantified with the nanoparticle sensors in the homogeneous microtiter assay format with a coefficient of variation of 6% for the gold and 12% for the Eu(III) nanoparticle sensor. The Eu(III) nanoparticle sensor was also combined with a cell impermeable nucleic acid dye assay to measure cell viability in a single tube test with cell counts below 1000 cells/tube. This sensitive and easy-to-use nanoparticle sensor combined with a viability test for a low concentration of cells could potentially replace existing microscopic methods in biochemical laboratories. PMID- 20954744 TI - A conserved helical capping hydrogen bond in PAS domains controls signaling kinetics in the superfamily prototype photoactive yellow protein. AB - PAS domains form a divergent protein superfamily with more than 20 000 members that perform a wide array of sensing and regulatory functions in all three domains of life. Only nine residues are well-conserved in PAS domains, with an Asn residue at the start of alpha-helix 3 showing the strongest conservation. The molecular functions of these nine conserved residues are unknown. We use static and time-resolved visible and FTIR spectroscopy to investigate receptor activation in the photosensor photoactive yellow protein (PYP), a PAS domain prototype. The N43A and N43S mutants allow an investigation of the role of side chain hydrogen bonding at this conserved position. The mutants exhibit a blue shifted visible absorbance maximum and up-shifted chromophore pK(a). Disruption of the hydrogen bonds in N43A PYP causes both a reduction in protein stability and a 3400-fold increase in the lifetime of the signaling state of this photoreceptor. A significant part of this increase in lifetime can be attributed to the helical capping interaction of Asn43. This extends the known importance of helical capping for protein structure to regulating functional protein kinetics. A model for PYP activation has been proposed in which side-chain hydrogen bonding of Asn43 is critical for relaying light-induced conformational changes. However, FTIR spectroscopy shows that both Asn43 mutants retain full allosteric transmission of structural changes. Analysis of 30 available high-resolution structures of PAS domains reveals that the side-chain hydrogen bonding of residue 43 but not residue identity is highly conserved and suggests that its helical cap affects signaling kinetics in other PAS domains. PMID- 20954746 TI - Direct cellular lysis/protein extraction protocol for soil metaproteomics. AB - We present a novel direct protocol for deep proteome characterization of microorganisms in soil. The method employs thermally assisted detergent-based cellular lysis (SDS) of soil samples, followed by TCA precipitation for proteome extraction/cleanup prior to liquid chromatography-mass spectrometric characterization. This approach was developed and optimized using different soils inoculated with genome-sequenced bacteria (Gram-negative Pseudomonas putida or Gram-positive Arthrobacter chlorophenolicus). Direct soil protein extraction was compared to protein extraction from cells isolated from the soil matrix prior to lysis (indirect method). Each approach resulted in identification of greater than 500 unique proteins, with a wide range in molecular mass and functional categories. To our knowledge, this SDS-TCA approach enables the deepest proteome characterizations of microbes in soil to date, without significant biases in protein size, localization, or functional category compared to pure cultures. This protocol should provide a powerful tool for ecological studies of soil microbial communities. PMID- 20954749 TI - 1,4-Dilithio-1,3-dienes: reaction and synthetic applications. AB - The development of organometallic reagents remains one of the most important frontiers in synthetic chemistry. Commonly used organometallic reagents (such as RLi and RMgBr) are typically monometallic compounds, although they aggregate in many cases. When two carbon-metal bonds are in the same molecule in close proximity, however, these two carbon-metal moieties may exhibit novel reactivity. In this Account, we outline our work on new reactions and synthetic applications of the organo-dilithio reagents 1,4-dilithio-1,3-butadienes. The 1,4-dilithio-1,3 butadienes can be accessed readily in high efficiency with a wide variety of substitution patterns on the butadienyl skeleton. The configuration has been predicted and demonstrated to favor a double dilithium bridging structure in both solution and solid states. The two Li atoms are bridged by a butadiene moiety and are in close proximity. By taking advantage of this unique configuration, we have developed useful and interesting synthetic methodologies. Three types of reactions of 1,4-dilithio-1,3-butadienes, termed dilithio reagents here, have been developed and are discussed. An intramolecular reaction is introduced in the first section. The reaction is a result of the intracooperative effect among the two C-Li moieties, the butadienyl bridge, and the substituents. A useful transformation from silylated 1,4-dilithio-1,3-butadienes to alpha-lithio siloles is described. Second, we discuss an intermolecular reaction that results from the intercooperative effect of the two C-Li moieties toward substrates. As an example of the formation of functionalized cyclic dianions from the linear dianions of the dilithio reagents and organic substrates, we describe the isolation and structural characterization of a novel type of cyclic dianion; that is, fully substituted oxy-cyclopentadienyl dilithium formed via the reaction of dilithio reagents with CO. We also describe diverse reactions of dilithio reagents with nitriles to form substituted pyridines, tricyclic 1-bipyrrolines, and siloles, demonstrating the remarkable effect of substituents on the butadienyl skeleton. Third, we discuss transmetalation of dilithio reagents to generate other organo dimetallic compounds. This section focuses on organo-dicopper compounds and their reactivity toward the synthesis of strained ring systems, such as semibullvalenes and twisted four-membered rings, with the metal-mediated C-C bond-forming approach. In addition to these three representative reactions, other useful applications are also briefly introduced. The dimetallic 1,4-dilithio-1,3 butadienes and their transmetalated derivatives provide unique synthetic organometallic reagents that are very different from monometallic reagents, both in terms of reactivity and synthetic application. These organo-dimetallic reagents provide access to interesting and useful compounds that are not available by other means. Moreover, given the possibilities afforded, the study of organo-dimetallic and organo-polymetallic compounds should yield further synthetic applications in the near future. PMID- 20954748 TI - Glycosaminoglycans of the porcine central nervous system. AB - Glycosaminoglycans (GAGs) are known to participate in central nervous system processes such as development, cell migration, and neurite outgrowth. In this paper, we report an initial glycomics study of GAGs from the porcine central nervous system. GAGs of the porcine central nervous system, brain and spinal cord were isolated and purified by defatting, proteolysis, anion-exchange chromatography, and methanol precipitation. The isolated GAG content in brain was 5 times higher than in spinal cord (0.35 mg/g of dry sample, compared to 0.07 mg/g of dry sample). In both tissues, chondroitin sulfate (CS) and heparan sulfate (HS) were the major and the minor GAG, respectively. The average molecular masses of CS from brain and spinal cord were 35.5 and 47.1 kDa, respectively, and those for HS from brain and spinal cord were 56.9 and 34 kDa, respectively. The disaccharide analysis showed that the compositions of CS from brain and spinal cords are similar, with uronic acid (1->3) 4-O-sulfo-N acetylgalactosamine residue corresponding to the major disaccharide unit (CS type A) along with five minor disaccharide units. The major disaccharides of both brain and spinal cord HS were uronic acid (1->4) N-acetylglucosamine and uronic acid (1->4) 6-O-sulfo-N-sulfoglucosamine, but their composition of minor disaccharides differed. Analysis by (1)H and two-dimensional NMR spectroscopy confirmed these disaccharide analyses and provided the glucuronic/iduronic acid ratio. Finally, both purified CS and HS were biotinylated and immobilized on BIAcore SA biochips. Interactions between these GAGs and fibroblast growth factors (FGF1 and FGF2) and sonic hedgehog (Shh) were investigated by surface plasmon resonance. PMID- 20954750 TI - Reactions of aromatic N-heterocycles with d0fn-metal alkyl complexes supported by chelating diamide ligands. AB - Aromatic heterocycles are a prominent feature within natural products and pharmaceuticals and considerable efforts are directed toward their synthesis and functionalization. These molecules also appear as unwanted impurities in carbon based fuels, and processes that fragment them are of increasing interest. Early transition metal-carbon bonds show diverse reactivity toward aromatic heterocycles: researchers have reported both functionalization, relevant to synthetic efforts, and ring opening, relevant to their removal from fuels. In particular, chelating ferrocene-diamides possess unique electronic characteristics as ancillary ligands that enable a wide range of reactivity behaviors for the resulting metal complexes. In this Account, we describe our efforts to understand the reactivity of group 3 metal and uranium alkyl complexes supported by these organometallic ligands toward aromatic N-heterocycles. Two geometrically related ancillary ligands were investigated: 1,1'-ferrocenylene diamides and pincer-type pyridine-diamides. A substrate-dependent behavior was observed. For example, all the benzyl metal complexes cleaved 1-methylimidazole. In the case of pyridines, differences in reactivity were identified: C-H activation and C-C coupling occurred with substituted pyridines, while alkyl transfer predominated with isoquinoline and chelating pyridines. The products of the C-C coupling or the alkyl-transfer reactions underwent subsequent hydrogen transfer: within the same ring for the substituted pyridines and between two different heterocycles for isoquinoline and chelating pyridines. The comparison between yttrium and lutetium benzyl complexes supported by ferrocene- or pyridine diamide ligands indicated that similar reactions occurred for specific substrates (1-methylimidazole, 2-picoline, and isoquinoline). A broader range of reaction types and a larger substrate scope were identified, however, for the ferrocene than for the pyridine-type complexes. Based on the reactions discussed in this Account and on isolated examples drawn from the literature, we conclude that the ferrocene-diamides represent a versatile ligand framework. We propose that iron's ability to accommodate changes in the electronic density at the metal center more readily than classical supporting ligands leads to the privileged status of these organometallic ancillary ligands. PMID- 20954747 TI - Functional proteomic analysis for regulatory T cell surveillance of the HIV-1 infected macrophage. AB - Regulatory T cells (Treg) induce robust neuroprotection in murine models of neuroAIDS, in part, through eliciting anti-inflammatory responses for HIV-1 infected brain mononuclear phagocytes (MP; macrophage and microglia). Herein, using both murine and human primary cell cultures in proteomic and cell biologic tests, we report that Treg promotes such neuroprotection by an even broader range of mechanisms than previously seen including inhibition of virus release, killing infected MP, and inducing phenotypic cell switches. Changes in individual Treg induced macrophage proteins were quantified by iTRAQ labeling followed by mass spectrometry identifications. Reduction in virus release paralleled the upregulation of interferon-stimulated gene 15, an ubiquitin-like protein involved in interferon-mediated antiviral immunity. Treg killed virus-infected macrophages through caspase-3 and granzyme and perforin pathways. Independently, Treg transformed virus-infected macrophages from an M1 to an M2 phenotype by down- and up- regulation of inducible nitric oxide synthase and arginase 1, respectively. Taken together, Treg affects a range of virus-infected MP functions. The observations made serve to challenge the dogma of solitary Treg immune suppressor functions and provides novel insights into how Treg affects adaptive immunosurveillance for control of end organ diseases, notably neurocognitive disorders associated with advanced viral infection. PMID- 20954751 TI - Recent experimental advances on excited-state intramolecular proton coupled electron transfer reaction. AB - Proton-coupled electron transfer reactions form the basis of many important chemical processes including much of the energy conversion that occurs within living cells. However, much of the physical chemistry that underlies these reaction mechanisms remains poorly understood. In this Account, we report on recent progress in the understanding of excited-state intramolecular proton coupled electron transfer (PCET) reactions. The strategic design and synthesis of various types of PCET molecules, along with steady-state and femtosecond time resolved spectroscopy, have uncovered the mechanisms of several excited-state PCET reactions in solution. These experimental advancements correlate well with current theoretical models, in which the proton has quantum motion with a high probability of tunneling. In addition, the rate of proton transfer is commonly incorporated within the rate of rearrangement of solvent molecules. As a result, the reaction activation free energy is essentially governed by the solvent reorganization because the charge redistribution is considered based on a solvent polarity-induced barrier instead of the height of the proton migration barrier. In accord with this theoretical basis, we can rationalize the observation that the proton transfer for many excited-state PCET systems occurs during the solvent relaxation time scale of 1-10 ps: the highly exergonic reaction takes place before the system reaches its equilibrium polarization. Also, we have used various derivatives of proton transfer molecules, especially those of 3 hydroxyflavone to clearly demonstrate how researchers can tune the dynamics of excited-state PCET through changes in the magnitude or direction of the dipole vector within the reaction. Subsequently, using 2-(2'-hydroxyphenyl)benzoxazole as the parent model, we then report on methods for the development of an ideal system for probing PCET reaction. Because future biomedical applications of such systems will likely occur in aqueous environments, we discuss various 7-azaindole analogues, for which proton transfer requires the assistance of protic solvent molecules. These results provide a unique contrast to the ubiquitous studies on the dynamic solvent effects of PCET molecules that undergo intrinsic intramolecular proton motion. PMID- 20954752 TI - Mechanisms of single-walled carbon nanotube nucleation, growth, and healing determined using QM/MD methods. AB - Since their discovery in the early 1990s, single-walled carbon nanotubes (SWNTs) have spawned previously unimaginable commercial and industrial technologies. Their versatility stems from their unique electronic, physical/chemical, and mechanical properties, which set them apart from traditional materials. Many researchers have investigated SWNT growth mechanisms in the years since their discovery. The most prevalent of these is the vapor-liquid-solid (VLS) mechanism, which is based on experimental observations. Within the VLS mechanism, researchers assume that the formation of a SWNT starts with co-condensation of carbon and metal atoms from vapor to form liquid metal carbide. Once the liquid reaches supersaturation, the solid phase nanotubes begin to grow. The growth process is partitioned into three distinct stages: nucleation of a carbon "cap precursor," "cap-to-tube" transformation, and continued SWNT growth. In recent years, molecular dynamics (MD) simulations have come to the fore with respect to SWNT growth. MD simulations lead to spatial and temporal resolutions of these processes that are superior to those possible using current experimental techniques, and so provide valuable information regarding the growth process that researchers cannot obtain experimentally. In this Account, we review our own recent efforts to simulate SWNT nucleation, growth, and healing phenomena on transition-metal catalysts using quantum mechanical molecular dynamics (QM/MD) methods. In particular, we have validated each stage of the SWNT condensation mechanism using a self-consistent-charge density-functional tight-binding (SCC DFTB) methodology. With respect to the nucleation of a SWNT cap-precursor (stage 1), we have shown that the presence of a transition-metal carbide particle is not a necessary prerequisite for SWNT nucleation, contrary to conventional experimental presumptions. The formation and coalescence of polyyne chains on the metal surface occur first, followed by the formation of the SWNT cap-precursor, "ring condensation", and the creation of an sp(2)-hybridized carbon structure. In our simulations, the nucleation process takes approximately 400 ps. This first step occurs over a much longer time scale than the second stage of SWNT condensation (approximately 50 ps). We therefore observe SWNT nucleation to be akin to the rate-limiting step of the SWNT formation process. In addition to the QM/MD simulation of various stages of SWNT nucleation, growth, and healing processes, we have determined the effects of temperature, catalyst composition, and catalyst size on the kinetics and mechanism of SWNT growth. With respect to temperature dependence, we observe a "sweet-spot" with respect to the efficiency of SWNT growth. In addition, Ni-catalyzed SWNT growth is observed to be 70-100% faster compared to Fe-catalyzed SWNT growth, depending on the catalyst particle size. We also observe a noticeable increase in SWNT growth rates using smaller catalyst particles. Finally, we review our recent QM/MD investigation of SWNT healing. In particular, we recount mechanisms by which adatom defects, monovacancy defects, and a "5-7 defect" are removed from a nascent SWNT. The effectiveness of these healing mechanisms depends on the rate at which carbon moieties are incorporated into the growing SWNT. Explicitly, we observe that healing is promoted using a slower carbon supply rate. From this rudimentary control of SWNT healing, we propose a route towards chirality-controlled SWNT growth. PMID- 20954753 TI - Solvolysis of substituted benzoyl chlorides in nonionic and mixed micellar solutions. AB - The solvolysis of substituted benzoyl chlorides is sensitive both to substituent electronic effects and to medium effects. The solvolysis reactions of substituted benzoyl chlorides have been analyzed in the presence of nonionic micelles. The reaction is inhibited or catalyzed depending on the reaction mechanism, dissociative or associative, respectively. The micellar effects observed can be related to the low water content and low polarity of the interface as well as an increase of the nucleophilic character of the interfacial water. Moreover, the effect of the micellar surface charge on the solvolysis mechanism with high associative character was systematically studied. Mixed micelles of nonionic ionic surfactants with a variable ionic content were prepared and characterized regarding charge and polarity. A correlation between the net charge of the micelles and the rate constants at the micellar interface was observed. The results suggest that the transient state for this mechanism is highly stabilized in a positively charged environment while the negative surface given by anionic micelles strongly inhibit the solvolysis reaction. PMID- 20954754 TI - Ion mobility and collision-induced dissociation analysis of carbonic anhydrase 2. AB - Folding analysis of the zinc protein, carbonic anhydrase 2 (CA2), was performed using electrospray ionization ion mobility spectrometry coupled with collision induced dissociation (ESI IMS/CID). Multiply protonated ions with a bimodal charge state distribution were observed indicating the presence of at least two folding states for gas-phase CA2 ions as was described in a previous study (Nabuchi, Y.; Murao, N.; Asoh, Y.; Takayama, M. Anal. Chem. 2007, 79, 8342-8349). In the IMS driftgram, several ions with different mobility were observed for each multiply charged ion, and this suggests that CA2 ions consist of several components with different folding states. IMS/CID spectra were acquired against precursor ions separated by mobility. The CID spectra gave several characteristic product ions including those from the N- and C-terminal region of CA2. A shift to larger charge number for the most abundant of the several product ions was observed for ions having a larger drift time. This charge number shift indicates that the folding state of the ion is more unfolded. Furthermore, differences in the production of an ion corresponding to the N-terminal side fragment gave information about the unfolding process of CA2. PMID- 20954755 TI - Automated broadband phase correction of Fourier transform ion cyclotron resonance mass spectra. AB - It has been known for 35 years that phase correction of FTICR data can in principle produce an absorption-mode spectrum with mass resolving power as much as a factor of 2 higher than conventional magnitude-mode display, an improvement otherwise requiring a (much more expensive) increase in magnetic field strength. However, temporally dispersed excitation followed by time-delayed detection results in steep quadratic variation of signal phase with frequency. Here, we present a robust, rapid, automated method to enable accurate broadband phase correction for all peaks in the mass spectrum. Low-pass digital filtering effectively eliminates the accompanying baseline roll. Experimental FTICR absorption-mode mass spectra exhibit at least 40% higher resolving power (and thus an increased number of resolved peaks) as well as higher mass accuracy relative to magnitude mode spectra, for more complete and more reliable elemental composition assignments for mixtures as complex as petroleum. PMID- 20954756 TI - Creative self-efficacy development and creative performance over time. AB - Building from an established framework of self-efficacy development, this study provides a longitudinal examination of the development of creative self-efficacy in an ongoing work context. Results show that increases in employee creative role identity and perceived creative expectation from supervisors over a 6-month time period were associated with enhanced sense of employee capacity for creative work. Contrary to what was expected, employees who experienced increased requirements for creativity in their jobs actually reported a decreased sense of efficaciousness for creative work. Results show that increases in creative self efficacy corresponded with increases in creative performance as well. PMID- 20954757 TI - Internship: a recruitment and selection perspective. AB - In this study, we examined internship as a recruitment and selection process. On the basis of impression management theory, we hypothesized that both organizations and interns make efforts to impress the other party during the internship if they intend to hire or be hired. Using longitudinal data collected at 3 points from 122 intern-supervisor dyads in the United States, we found that 60% of internships turned into job offers from the host organizations. Interns wishing to be hired were more likely to use self-promotion and ingratiation, which increased the likelihood of job offers. Organizations wishing to hire appeared to be more open to interns' creativity, which increased interns' application intentions. For interns who indicated prior to their internship that they were not interested in working in their host organizations after graduation, supervisory mentoring did not influence their subsequent intentions to apply for full-time employment. PMID- 20954758 TI - Longitudinal risk factors for intimate partner violence among men in treatment for alcohol use disorders. AB - OBJECTIVE: This study examined static and time-varying risk factors for perpetration of intimate partner violence (IPV) among men in treatment for alcohol use disorders. METHOD: Participants were 178 men diagnosed with alcohol abuse or dependence and their partners. Most (85%) of the men were European American; their average age was 41.0 years. Participants completed measures assessing initial alcohol problem severity, baseline beliefs related to alcohol use, antisocial personality characteristics, alcohol and drug use, relationship adjustment, and IPV. RESULTS: According to couples' reconciled reports, 42% of participants perpetrated IPV at baseline. Among this group, the IPV recurrence rate was 43% at 6-month follow-up and 36% at 12-month follow-up. For participants without IPV perpetration at baseline, new incidence of IPV was 15% and 7% at the 6-month and 12-month follow-up points, respectively. Fixed marker predictors of IPV rates included baseline alcohol problem severity variables, baseline beliefs related to alcohol use, and antisocial personality characteristics. Variable risk factor predictors included alcohol and drug use variables, relationship adjustment factors, and anger. Alcohol use variables and anger were associated with new incidents of IPV among those without reported IPV at baseline only. CONCLUSIONS: Findings suggest that assessing and monitoring IPV occurrence by both partners is important for men in treatment for alcohol use disorders. Results indicate vulnerability factors that may identify individuals at risk for IPV and provide targets for IPV prevention among those with alcohol use disorders. These findings can aid in the development of more comprehensive models that more precisely predict IPV. PMID- 20954759 TI - Catastrophic misinterpretations as a predictor of symptom change during treatment for panic disorder. AB - OBJECTIVE: Cognitive models of panic disorder suggest that change in catastrophic misinterpretations of bodily sensations will predict symptom reduction. To examine change processes, we used a repeated measures design to evaluate whether the trajectory of change in misinterpretations over the course of 12-week cognitive behavior therapy is related to the trajectory of change in a variety of panic-relevant outcomes. METHOD: Participants had a primary diagnosis of panic disorder (N = 43; 70% female; mean age = 40.14 years). Race or ethnicity was reported as 91% Caucasian, 5% African American, 2.3% biracial, and 2.3% "other." Change in catastrophic misinterpretations (assessed with the Brief Body Sensations Interpretation Questionnaire; Clark et al., 1997) was used to predict a variety of treatment outcomes, including overall panic symptom severity (assessed with the Panic Disorder Severity Scale [PDSS]; Shear et al., 1997), panic attack frequency (assessed with the relevant PDSS item), panic-related distress/apprehension (assessed by a latent factor, including peak anxiety in response to a panic-relevant stressor-a straw breathing task), and avoidance (assessed by a latent factor, which included the Fear Questionnaire-Agoraphobic Avoidance subscale; Marks & Mathews, 1979). RESULTS: Bivariate latent difference score modeling indicated that, as expected, change in catastrophic misinterpretations predicted subsequent reductions in overall symptom severity, panic attack frequency, distress/apprehension, and avoidance behavior. However, change in the various symptom domains was not typically a significant predictor of later interpretation change (except for the distress/apprehension factor). CONCLUSIONS: These results provide considerable support for the cognitive model of panic and speak to the temporal sequence of change processes during therapy. PMID- 20954760 TI - Relations as rules: the role of attention in the Dimensional Change Card Sort task. AB - Preschoolers are typically unable to switch sorting rules during the Dimensional Change Card Sort task. One explanation for this phenomenon is attentional inflexibility (Kirkham, Cruess, & Diamond, 2003). In 4 experiments with 3- to 4 year-olds, we tested this hypothesis by examining the influence of dimensional salience on switching performance. Results from these experiments demonstrated that it was more difficult for children to redirect attention from attribute based rule sets, such as color and shape, than from spatial relational rule sets. Overall, these findings point to a role for attention in performance on the Dimensional Change Card Sort task. PMID- 20954761 TI - Differential susceptibility to parenting among African American youths: testing the DRD4 hypothesis. AB - To test the differential susceptibility to parenting hypothesis, a 4-wave, randomized prevention design was used to examine the impact of the Strong African American Families program on past-month substance use across 29 months as a function of DRD4 genotype. Youths (N = 337; M age = 11.65 years) were assigned randomly to treatment condition. Those carrying a 7-repeat allele showed greater differential response to intervention vs. control than those with two 4-repeat alleles. Control youths but not treatment youths with a 7-repeat allele reported increases in past-month substance use across the 29-month study period, but this pattern did not emerge for those with the 4-repeat allele. Supporting the differential susceptibility to parenting hypothesis, the results suggest a greater preventive effect for youths carrying a 7-repeat allele, a role for DRD4 in the escalation of substance use during adolescence, and potential for an enhanced understanding of early-onset substance use. PMID- 20954762 TI - Parenting self-efficacy and parenting practices over time in Mexican American families. AB - Drawing on social cognitive theory, this study used a longitudinal cross-lagged panel design and a structural equation modeling approach to evaluate parenting self-efficacy's reciprocal and causal associations with parents' positive control practices over time to predict adolescents' conduct problems. Data were obtained from teachers, mothers, and adolescents in 189 Mexican American families living in the southwest United States. After accounting for contemporaneous reciprocal relationships between parenting self-efficacy (PSE) and positive control, results indicated that parenting self-efficacy predicted future positive control practices rather than the reverse. PSE also showed direct effects on decreased adolescent conduct problems. PSE functioned in an antecedent causal role in relation to parents' positive control practices and adolescents' conduct problems in this sample. These results support the cross-cultural applicability of social cognitive theory to parenting in Mexican American families. An implication is that parenting interventions aimed at preventing adolescent conduct problems need to focus on elevating the PSE of Mexican American parents with low levels of PSE. In addition, future research should seek to specify the most effective strategies for enhancing PSE. PMID- 20954763 TI - Effects of family foundations on parents and children: 3.5 years after baseline. AB - This study investigated the ability of a psychosocial prevention program implemented through childbirth education programs to enhance the coparental and couple relationship, parental mental health, the parent-child relationship, and child outcomes. A sample of 169 heterosexual, adult couples expecting their first child was randomized to intervention and control conditions. The intervention families participated in Family Foundations, a series of eight classes delivered before and after birth, which was designed as a universal prevention program (i.e., applicable to all couples, not just those at high risk). Intent-to-treat analyses utilizing data collected from child age 6 months through 3 years indicated significant program effects on parental stress and self-efficacy, coparenting, harsh parenting, and children's emotional adjustment among all families, and maternal depression among cohabiting couples. Among families of boys, program effects were found for child behavior problems and couple relationship quality. These results indicate that a universal prevention approach at the transition to parenthood focused on enhancing family relationships can have a significant and substantial positive impact on parent and child well being. PMID- 20954764 TI - Should I stay or should I go? Predicting dating relationship stability from four aspects of commitment. AB - Many have argued that it is important to examine different aspects of commitment in romantic relationships, but few studies have done so. Using a large, national sample of unmarried adults in relationships (N = 1184), this study examined four aspects of relationship commitment and their associations with relationship adjustment and stability. We examined dedication (i.e., interpersonal commitment) as well as three types of constraint commitment: perceived constraints (e.g., social pressure to stay together or difficulty of termination procedures, measured using Stanley and Markman's [1992] Commitment Inventory), material constraints (e.g., signing a lease, owning a pet), and felt constraint (i.e., feeling trapped). Cross-sectionally, these four facets of commitment were associated in expected directions with relationship adjustment, as well as perceived likelihood of relationship termination and of marriage. Longitudinally, each facet uniquely predicted relationship stability. More dedication, more material and perceived constraints and less felt constraint were uniquely associated with a higher likelihood of staying together over an 8-month period. PMID- 20954765 TI - Romantic partners' individual coping strategies and dyadic coping: implications for relationship functioning. AB - Individual coping strategies and dyadic coping independently predict partner well being and relationship functioning; however, it is unclear whether the coping processes are inter-related and whether they uniquely contribute to romantic relationship functioning. One hundred heterosexual dating couples rated the individual coping strategy of negative mood regulation as well as positive and negative dyadic coping. Relationship functioning was assessed via partners' reports of relationship satisfaction and observers' ratings of negative interaction in conflict. Actor-Partner Interdependence Models (APIMs; Cook & Kenny, 2005; Kashy & Kenny, 2000) revealed associations between individual coping and dyadic coping in the predicted directions. APIMs also indicated the unique contributions of positive and negative dyadic coping to relationship functioning, above and beyond contributions of individual coping strategies. Implications of dyadic coping as a target of efforts to prevent or treat partner and/or relational distress are discussed. PMID- 20954766 TI - Relationship adjustment, PTSD symptoms, and treatment utilization among coupled National Guard soldiers deployed to Iraq. AB - Although combat-related posttraumatic stress disorder (PTSD) is associated with considerable impairment in relationship adjustment, research has yet to investigate how PTSD symptoms and relationship distress uniquely and jointly predict utilization of a range of mental health services. The present study sought to examine these issues utilizing a longitudinal sample of National Guard soldiers surveyed 2-3 months following return from deployment to Iraq and again 12 months later (N = 223). Results indicated that PTSD symptom severity, but not relationship adjustment, uniquely predicted greater odds of utilizing individual oriented mental health services. A significant interaction was found indicating associations between PTSD symptoms and the odds of using services were increased when soldiers reported greater relationship adjustment. For utilization of family oriented care, greater relationship distress was significantly correlated with greater odds of using services, but associations with PTSD symptoms were nonsignificant. The association between relationship distress and utilization of family-oriented services did not vary significantly with severity of PTSD symptoms. Results suggest supportive intimate relationships facilitate mental health treatment utilization for soldiers with PTSD symptoms. PMID- 20954767 TI - Provider role attitudes, marital satisfaction, role overload, and housework: a dyadic approach. AB - Treating the marital dyad as the unit of analysis, this study examined the within couple patterning of 272 dual-earner spouses' provider role attitudes and their longitudinal associations with marital satisfaction, role overload, and the division of housework. Based on the congruence of husbands' and wives' provider role attitudes, couples were classified into one of four types: (a) main secondary, (b) coprovider, (c) ambivalent coprovider, and (d) mismatched couples. Nearly half of all spouses differed in their attitudes about breadwinning. A series of mixed model ANCOVAs revealed significant between- and within-couple differences in human capital characteristics, spouses' perceptions of marital satisfaction and role overload, and the division of housework across 3 years of measurement. Coprovider couples reported higher levels of marital satisfaction and a more equitable division of housework than the other couple groups. Wives in the ambivalent coprovider couples' group reported higher levels of role overload than their husbands to a greater extent than was found in the other couple groups. As the first study to adopt a dyadic approach that considers the meanings that both spouses in dual-earner couples ascribe to paid employment, these findings advance understanding of how dual-earner spouses' provider role attitudes serve as contexts for marital quality, behavior, and role-related stress. PMID- 20954768 TI - Support behavior and relationship satisfaction in couples dealing with diabetes: main and moderating effects. AB - This study examined associations between support behavior, i.e. active engagement and protective buffering, and relationship satisfaction in both patients with diabetes and their partners. Active engagement refers to supportive behavior characterized by involving one's partner in discussions, asking how the other feels, and problem solving strategies. Protective buffering refers to less supportive behavior characterized by denying fears and worries, and by pretending everything is fine. Furthermore, we examined whether there were interactive effects of these two support behaviors on patients' and partners' relationship satisfaction. At baseline (T1), 205 couples rated to which degree they received active engagement and protective buffering from their partners, and completed a measure of relationship satisfaction. At three follow-up assessments, couples were asked to fill out the same measures. Using dyadic data analytic approaches, we found relationship satisfaction to be positively associated with active engagement, and negatively with protective buffering, in both patients and partners. Moreover, we found a moderating effect, in that the negative association between protective buffering and relationship satisfaction was only present when levels of active engagement were relatively low. Again, these results were found for patients as well as their partners. We were able to replicate the T1 results at the other three assessment points. Our findings illustrate the need to consider adequate and less adequate support behaviors simultaneously, and to study the effects on both patients and partners. PMID- 20954769 TI - Developmental trajectories of marital happiness in continuously married individuals: a group-based modeling approach. AB - Most contemporary studies of change in marital quality over time have used growth curve modeling to describe continuously declining mean curves. However, there is some evidence that different trajectories of marital quality exist for different subpopulations. Group-based trajectory modeling provides the opportunity to conduct an empirical investigation of the variance in marital quality trajectories. We applied this method to analyze data from continuously married individuals from the Marital Instability over the Life Course Study (N = 706). Instead of a single continuously declining trajectory of marital happiness, we found 5 distinct trajectories. Nearly two thirds of participants reported high and stable levels of happiness over time, and the other one third showed either a pattern of continuous low happiness, low happiness that subsequently declined, or a curvilinear pattern of high happiness, decline, and recovery. Marital problems, time spent in shared activities, and (to a lesser degree) economic hardship were able to distinguish trajectory group membership. Our results suggest that marital happiness may have multiple distinct trajectories across reasonably diverse populations. Implications for theory, research, and practice are discussed. PMID- 20954770 TI - Family functioning and interactive patterns in the context of infant psychopathology. AB - Family functioning and mother-infant relational patterns were examined in 38 clinic-referred infants and 34 matched non-referred infants. Referred infants were diagnosed with the Diagnostic Classification for Zero to Three. On the family level, referred families showed significantly lower family functioning in all domains of emotional and instrumental communication, regardless of the specific infant's diagnoses. On the dyadic level, referred mothers were more intrusive and their infants were more withdrawn during dyadic interactions. Clinic-referred mothers reported higher levels of phobia and depression. Global family functioning was predicted by the infant's clinical status, maternal intrusiveness, and maternal psychopathology. Infant mental health clinicians need to address both family level and dyadic level of functioning, regardless of the reason for the infant's referral. PMID- 20954771 TI - Power and conflict resolution in sibling, parent-child, and spousal negotiations. AB - This study used a within-family observational design to examine conflict strategies (planning, opposition) and resolutions (standoff, win-loss, compromise) across family subsystems, with an emphasis on power differences between parents and children during relatively symmetrical within-generation (spousal, sibling) and relatively asymmetrical between-generation (parent-child) dyadic interactions. Up to six dyads in 67 families (children's ages ranging from 3 to 12 years) discussed an unresolved conflict. Results revealed that within generation discussions ended more in standoff, whereas between-generation discussions ended with more win-loss resolutions. Multilevel analyses indicated that parents engaged in more planning and opposition than children; however, they opposed more and planned less with their spouses than their children. In general, more planning and less opposition were associated with achieving resolutions rather than failing to resolve differences. Some effects were qualified by within family differences between mothers versus fathers and older versus younger siblings, as well as between-family differences in younger siblings' age. Implications for theories of power and family relationship dynamics are discussed. PMID- 20954772 TI - Familism, mother-daughter mutuality, and suicide attempts of adolescent Latinas. AB - National surveys in the U.S. reveal that Latina adolescents have higher rates of suicide attempts than females of other ethnic and racial groups. Past reports indicate that the suicide attempts among Latinas are lodged within family contexts in which sociocultural and individual experiences influence parental and adolescent behaviors. To better understand the parent-adolescent relations that explain the Latina suicidal phenomenon, we examined how the high value on family unity and support, as reflected by familism, and its effects on mother-daughter mutuality (i.e., reciprocal empathy and engagement) were evident in a group of adolescent Latinas with suicide attempts and a group of adolescent Latinas without suicide attempts. Drawing from data on 169 mother-daughter dyads recruited from Latino communities in a Northeastern metropolis and who self identified as being of Latino origin or heritage, we considered how differences in familism between mothers and daughters influenced their sense of mutuality, the adolescents' internalizing and externalizing behaviors, and suicide attempts. Results show that gaps in familism (mothers scoring higher than their daughters on the scale) predicted less mother-daughter mutuality and more externalizing behaviors in the adolescents. Also, mother-daughter mutuality was negatively related to internalizing and externalizing behaviors which, in turn, predicted suicide attempts. Findings point to further research on family interactions that raise the risk for suicidality in Latino youth, particularly to including fathers and siblings in study designs. Clinical implications point to enhancing family and dyadic communication skills focusing mutuality while observing the cultural value of familism. PMID- 20954773 TI - Maternal mood, video-mediated cognitions, and daily stress during home-based, family interactions. AB - This article presents an in vivo investigation of maternal negative mood, maternal video-mediated cognitions, and daily stressors in families with young children. Specifically, it was hypothesized that greater levels of maternal depressed, anxious, and hostile mood states immediately prior to a daily, reportedly routine, stressful parent-child interaction would be significantly associated with higher percentages of dysfunctional and lower percentages of functional cognitions. Forty-five mothers of 2- to 5-year-old children participated in this study by rating their mood before being videotaped in a daily routine with their child they reported as recurrent and stressful (e.g., mealtime). Using video-mediated recall (VMR) methodology, mothers were instructed to recall their cognitions upon immediate video review. Results indicated that greater levels of negative mood were associated with a greater percentage of dysfunctional cognitions and a smaller percentage of functional cognitions. Levels of maternal depressed mood were significantly and independently associated with greater rates of dysfunctional and lower rates of functional cognitions. Negative mood states were not consistently associated with the amount of maternal self-reported general irrationality, pointing to the utility of the VMR to elicit maternal cognitions specific to the observed interaction, which may have more implications for clinical intervention than more general irrationality measures. Evaluating maternal mood and using video-mediated maternal cognitions regarding daily family stressors can precipitate clinical interventions meant to reduce family-related stress and potentially improve maternal and child mental health outcomes. PMID- 20954774 TI - Grandmother involvement as a protective factor for early childhood social adjustment. AB - Despite high rates of grandmother involvement with young grandchildren, very little research has examined the associations between nonresidential grandmother involvement and grandchild social adjustment. The present study involved 127 families enrolled in the Family Transitions Project to consider the degree to which mother-reported maternal grandmother involvement buffered 3- and 4-year-old grandchildren from economic, parenting, and child temperamental risks for reduced social competence and elevated externalizing behaviors. Findings indicate that higher levels of mother-reported grandmother involvement reduced the negative association between observed grandchild negative emotional reactivity and social competence. Furthermore, higher levels of mother-reported grandmother involvement protected grandchildren from the positive association between observed mother harsh parenting and grandchild externalizing behaviors. These findings underscore the relevance of moving beyond the nuclear family to understand factors linked to social adjustment during early childhood. PMID- 20954775 TI - The work-family interface in the United States and Singapore: conflict across cultures. AB - This article examines the work-family interface in a cross-cultural comparison between two nationally representative samples from the United States (n = 1,860) and Singapore (n = 1,035) with emphasis on work-family conflict. Family-to-work conflict was negatively related to marital satisfaction in both Singapore and the United States, although the effect was stronger in the United States. Similarly, family-to-work conflict was positively related to job satisfaction in the United States but was negatively related in Singapore. As expected, schedule flexibility was negatively related to depression in the United States, but in Singapore the relationship was positive. These findings suggest that theoretical relationships in the work-family interface developed in the more culturally individualistic West may need to be adapted when studying populations in the more collectivist East. PMID- 20954776 TI - Cost-benefit analysis of multisystemic therapy with serious and violent juvenile offenders. AB - This study investigated the economics of multisystemic therapy (MST) versus individual therapy (IT) using rearrest data from a 13.7-year follow-up (Schaeffer & Borduin, 2005) of a randomized clinical trial with serious juvenile offenders (Borduin et al., 1995). Two types of benefits of MST were evaluated: The value to taxpayers was derived from measures of criminal justice system expenses (e.g., police and sheriff's offices, court processing, jails, community supervision), and the value to crime victims was derived in terms of both tangible (e.g., property damage and loss, health care, police and fire services, lost productivity) and intangible (e.g., pain, suffering, reduced quality of life) losses. Results indicated that the reductions in criminality in the MST versus IT conditions were associated with substantial reductions in expenses to taxpayers and intangible losses to crime victims, with cumulative benefits ranging from $75,110 to $199,374 per MST participant. Stated differently, it was estimated that every dollar spent on MST provides $9.51 to $23.59 in savings to taxpayers and crime victims in the years ahead. The economic benefits of MST, as well as its clinical effectiveness, should be considered by policymakers and the public at large in the selection of interventions for serious juvenile offenders. PMID- 20954777 TI - Socioeconomic and psychosocial predictors of interleukin-6 in the MIDUS national sample. AB - OBJECTIVE: To investigate whether psychosocial factors (i.e., depression, anxiety, and well-being) moderated educational gradients in interleukin-6 (IL-6) levels using data from the Survey of Midlife Development in the U.S. (MIDUS). The influences of educational attainment and psychosocial factors on IL-6 in middle aged and older adults were also examined. DESIGN: Telephone interviews and mail surveys were utilized to collect educational attainment and psychosocial information from respondents (N = 1028). Respondents also participated in an overnight clinic visit, during which health information and a fasting blood sample were obtained. MAIN OUTCOME MEASURES: Serum levels of IL-6. RESULTS: Greater educational attainment predicted lower levels of IL-6 independent of age and gender, although this effect was attenuated after taking health behaviors, body mass index, waist-to-hip ratio, and chronic illnesses into account. Psychological well-being interacted with education to predict IL-6, such that for those with less education, higher well-being was associated with lower levels of IL-6. CONCLUSION: The findings indicate a strong association between education and inflammation, which can be further moderated by psychosocial factors. The health benefits associated with psychological well-being were particularly evident for individuals with low educational attainment. PMID- 20954778 TI - Maintenance of physical activity and dietary change following a telephone delivered intervention. AB - OBJECTIVE: To examine the maintenance of behavioral changes 6 months following a telephone-delivered physical activity and diet intervention. DESIGN: Patients (n = 434) with Type 2 diabetes or hypertension were recruited from 10 primary care practices in a disadvantaged community; practices were randomized to a telephone counseling intervention (TC; 5 practices, n = 228) or usual care (UC; 5 practices, n = 206). MAIN OUTCOME MEASURES: Validated, self-report measures of physical activity and diet were taken at baseline, 12 months (end-of intervention), and 18 months (6 months postintervention completion). RESULTS: For physical activity, the significant (p < .001) within-groups improvements from baseline observed at 12 months remained at 18 months, in both the TC (62.2 +/- 14.2 minutes/week; 2.2 +/- 0.3 sessions/week) and UC (74.7 +/- 14.9 minutes/week; 2.1 +/- 0.4 sessions/week) groups. For all dietary outcomes, significant (p < .05) between-groups maintenance effects, similar to end-of-intervention outcomes, remained [TC-UC changes from baseline to 18 months (95% CI)]: total fat [-1.33 ( 2.16, -0.50)% energy/day], saturated fat [-1.06 (-1.70, -0.43)% energy/day], fiber intake [1.90 (0.72, 3.15) grams/day], and fruit [0.22 (0.05, 0.40) servings/day]), except vegetables [0.59 (-0.01, 1.17) servings/day; p = .05]. Intervention effects across all health behavior outcomes were stronger for the subgroup (n = 145) adhering to the study protocol. CONCLUSION: Telephone delivered interventions can promote maintenance of health behavior change. Studies with longer-term follow-up are needed, particularly to determine how intervention duration and intensity might further enhance maintenance. PMID- 20954779 TI - Motivating blood donors to recruit new donors: experimental evaluation of an evidence-based behavior change intervention. AB - OBJECTIVE: A sustainable, evidence-based intervention to motivate current blood donors to recruit new donors was evaluated using a quasi-experimental, in-service trial at three donation centers. DESIGN: Participating blood donors in three conditions (N = 734), received (1) an evidence-based leaflet designed to enhance recruitment motivation and five postcards facilitating recruitment and donor registration, (2) five postcards alone, or (3) no materials. MAIN OUTCOME MEASURES: Self-reported donor recruitment by donors was measured at 1-week and 6 week follow-up. RESULTS: At 1-week and at 6-week follow-up, donors in both intervention conditions reported talking to more people about donation and asking more people to donate than control participants. Intervention participants also reported persuading more people to register as a donor than control participants. Results indicated that postcards plus leaflet was somewhat more effective than the postcards alone. Donors' intentions to recruit at 1-week follow-up mediated the behavioral effects at 6-week follow-up. CONCLUSION: Motivating and facilitating recruitment of new blood donors through existing donors has the potential to continually replenish the donor population. PMID- 20954780 TI - A general approach to causal mediation analysis. AB - Traditionally in the social sciences, causal mediation analysis has been formulated, understood, and implemented within the framework of linear structural equation models. We argue and demonstrate that this is problematic for 3 reasons: the lack of a general definition of causal mediation effects independent of a particular statistical model, the inability to specify the key identification assumption, and the difficulty of extending the framework to nonlinear models. In this article, we propose an alternative approach that overcomes these limitations. Our approach is general because it offers the definition, identification, estimation, and sensitivity analysis of causal mediation effects without reference to any specific statistical model. Further, our approach explicitly links these 4 elements closely together within a single framework. As a result, the proposed framework can accommodate linear and nonlinear relationships, parametric and nonparametric models, continuous and discrete mediators, and various types of outcome variables. The general definition and identification result also allow us to develop sensitivity analysis in the context of commonly used models, which enables applied researchers to formally assess the robustness of their empirical conclusions to violations of the key assumption. We illustrate our approach by applying it to the Job Search Intervention Study. We also offer easy-to-use software that implements all our proposed methods. PMID- 20954781 TI - Verbal memory in drug-naive, newly diagnosed Parkinson's disease. The retrieval deficit hypothesis revisited. AB - OBJECTIVE: The retrieval deficit hypothesis on memory impairment in patients with Parkinson's disease (PD) implies a selective impairment in recall of learned material with normal encoding, retention, and recognition. This hypothesis has been challenged by new data. We have therefore investigated verbal memory and learning in a large sample of newly diagnosed, drug naive, non-demented patients with PD. METHOD: From a sample of patients with PD from the Norwegian ParkWest study, 133 PD patients and 133 controls matched on sex, age, and education were included. The California Verbal Learning Test-2 (CVLT-2) was used to assess verbal memory. RESULTS: Patients performed significantly worse than controls on free and cued recall as well as on recognition memory. Patients used the semantic clustering learning strategy significantly less extensively than the controls and the learning slope of the PD patients was significantly less steep. There was no difference in retention when controlling for encoding. Patients did not perform better on the recognition measure or on cued recall (d-prime), as compared to free recall. Executive functions explained a substantial part of the memory deficits. CONCLUSIONS: This study suggests that memory impairment in drug naive early PD to a large degree is a deficit of learning/ encoding and not of retention or retrieval. An implication is that the retrieval deficit hypothesis should be moderated in its general form. Executive deficits and less extensive use of the efficient semantic clustering learning strategy had a strong impact on learning and memory. PMID- 20954782 TI - Cultural conditioning: understanding interpersonal accommodation in India and the United States in terms of the modal characteristics of interpersonal influence situations. AB - We argue that differences between the landscapes of influence situations in Indian and American societies induce Indians to accommodate to others more often than Americans. To investigate cultural differences in situation-scapes, we sampled interpersonal influence situations occurring in India and the United States from both the influencee's (Study 1) and the influencer's (Study 2) perspectives. We found that Indian influence situations were dramatically more likely than U.S. situations to feature other-serving motives and to result in positive consequences for the relationship. Yet Study 3 found that targets of influence felt no less free to decide whether to accommodate in India than the United States, but felt more concerned about the influencer. To investigate the effects of situation-scapes on people's expectations and decisions, we exposed Indian and American participants to descriptions of situations from both societies (with their origins obscured). Study 4 found that both groups of participants expected more positive consequences from accommodation in Indian situations than in American situations. Finally, Study 5 found that both groups decided to accommodate more often in Indian situations than in American situations. At the same time, Indian participants were more likely than Americans to accommodate across all situations, but both groups converged over 100 trials as they were exposed to more and more situations drawn from each other's cultures. We interpret these effects in terms of the default decisions or biases conditioned by people's recently encountered situations. PMID- 20954783 TI - Matters of the variable heart: respiratory sinus arrhythmia response to marital interaction and associations with marital quality. AB - Maintenance of relationship quality requires self-regulation of emotion and social behavior, and women often display greater effort in this regard than do men. Furthermore, such efforts can deplete the limited capacity for self regulation. In recent models of self-regulation, resting level of respiratory sinus arrhythmia, quantified as high-frequency heart rate variability (HF-HRV), is an indicator of self-regulatory capacity, whereas transient increases in HF HRV reflect self-regulatory effort. To test these hypotheses in marriage, 114 young couples completed measures of marital quality and a positive, neutral, or negative initial marital task, preceded and followed by resting baseline assessments of HF-HRV. Couples then discussed a current marital disagreement. Resting HF-HRV was correlated with marital quality, suggesting that capacity for self-regulation is associated with adaptive functioning in close relationships. For women but not men, the negative initial task produced a decrease in resting HF-HRV. This effect was mediated by the husbands' negative affect response to the task and their ratings of wives as controlling and directive. When the subsequent disagreement discussion followed the negative initial task, women displayed increased HF-HRV during the discussion but a decrease when it followed the neutral or positive task. The valence of the initial task had no effect on men's HF-HRV during disagreement. Negative marital interactions can reduce women's resting HF-HRV, with potentially adverse health consequences. Women's reduced health benefit from marriage might reflect the depleting effects on self regulatory capacity of their greater efforts to manage relationship quality. PMID- 20954784 TI - For God (or) country: the hydraulic relation between government instability and belief in religious sources of control. AB - It has been recently proposed that people can flexibly rely on sources of control that are both internal and external to the self to satisfy the need to believe that their world is under control (i.e., that events do not unfold randomly or haphazardly). Consistent with this, past research demonstrates that, when personal control is threatened, people defend external systems of control, such as God and government. This theoretical perspective also suggests that belief in God and support for governmental systems, although seemingly disparate, will exhibit a hydraulic relationship with one another. Using both experimental and longitudinal designs in Eastern and Western cultures, the authors demonstrate that experimental manipulations or naturally occurring events (e.g., electoral instability) that lower faith in one of these external systems (e.g., the government) lead to subsequent increases in faith in the other (e.g., God). In addition, mediation and moderation analyses suggest that specific concerns with order and structure underlie these hydraulic effects. Implications for the psychological, sociocultural, and sociopolitical underpinnings of religious faith, as well as system justification theory, are discussed. PMID- 20954785 TI - Deconstructing the better-than-average effect. AB - The tendency for people to evaluate themselves more favorably than an average peer--the better-than-average effect (BTAE)--is among the most well-documented effects in the social-psychological literature. The BTAE has been demonstrated in many populations with various methodologies, and several explanations have been advanced for it. Two essential questions remain conspicuously unanswered in the BTAE literature. The first concerns the extent to which the BTAE can be represented as a social-comparative phenomenon, and the second concerns the role that strategic motivational processes play in self versus average-peer judgments. With regard to the first question, Study 1 provides direct experimental evidence that self versus average-peer judgments are made relationally rather than independently and, further, that self-ratings anchor these relational judgments. Moreover, Study 1 demonstrates that the consequence of this comparison is for judgments of average to be assimilated toward, not contrasted from, self-ratings. Studies 2-4 provide evidence that self-enhancement motives play a moderating role in the outcome of self versus average-peer judgments. We show that for dimensions on which the self is positively evaluated, enhancement motives restrict the extent to which average-peer assimilation occurs (Study 2). But for dimensions on which the self is negatively evaluated, enhancement motives amplify average-peer assimilation (Studies 3 and 4). Discussion focuses on the function of such differential assimilation, the relation of the current findings to extant perspectives, and directions for future research. PMID- 20954786 TI - I fear your envy, I rejoice in your coveting: on the ambivalent experience of being envied by others. AB - We present 2 studies on being envied. Study 1 used an emotional narrative methodology. We asked 44 Spanish (23 women, 21 men) and 48 European American (36 women, 12 men) participants to tell us about a recent experience in which others envied them. We classified the antecedents, relationship context, markers of envy, coping strategies, and positive and negative implications of being envied. In Study 2, 174 Spanish (88 women, 86 men) and 205 European American (106 women, 99 men) participants responded to a situation in which they had something someone else wanted. We manipulated the object of desire (academic achievement or having "a better life"). We measured individual differences in orientation to achievement (i.e., vertical individualism), cooperation and interpersonal harmony (i.e., horizontal collectivism), a zero-sum view of success, beliefs that success begets hostile coveting, fear of success, and dispositional envy. We also measured participants' appraisals, positive and negative emotions, and coping strategies. The findings from both studies indicate that being envied has both positive (e.g., increased self-confidence) and negative consequences (e.g., fear of ill will from others). Being envied had more positive and more negative psychological and relational consequences among those participants who were achievement oriented (European Americans) than among participants who were oriented to cooperation and interpersonal harmony (Spanish). PMID- 20954787 TI - Do you two know each other? Transitivity, homophily, and the need for (network) closure. AB - The authors investigate whether need for closure affects how people seek order in judging social relations. In Study 1, the authors find that people who have a high need for closure (NFC) were more likely to assume their social contacts were connected to each other (i.e., transitivity) when this was not the case. In Studies 2 and 3, the authors examine another form of order in network relations- racial homophily--and find that high-NFC participants were more inclined to believe that 2 individuals from the same racial category (e.g., African American) were friends than two racially dissimilar individuals. Furthermore, high-NFC individuals were more likely to make errors when judging a racially mixed group of people; specifically, they recalled more racial homophily (racially similar people sitting closer together) than had actually appeared. PMID- 20954788 TI - How people see others is different from how people see themselves: a replicable pattern across cultures. AB - Consensus studies from 4 cultures--in Belgium, the Czech Republic, Estonia, and Germany--as well as secondary analyses of self- and observer-reported Revised NEO Personality Inventory (NEO PI-R) data from 29 cultures suggest that there is a cross-culturally replicable pattern of difference between internal and external perspectives for the Big Five personality traits. People see themselves as more neurotic and open to experience compared to how they are seen by other people. External observers generally hold a higher opinion of an individual's conscientiousness than he or she does about him- or herself. As a rule, people think that they have more positive emotions and excitement seeking but much less assertiveness than it seems from the vantage point of an external observer. This cross-culturally replicable disparity between internal and external perspectives was not consistent with predictions based on the actor-observer hypothesis because the size of the disparity was unrelated to the visibility of personality traits. A relatively strong negative correlation (r = -.53) between the average self-minus-observer profile and social desirability ratings suggests that people in most studied cultures view themselves less favorably than they are perceived by others. PMID- 20954789 TI - Isolated inferior wall ST segment depression as an early sign of acute anterior wall myocardial infarction. AB - BACKGROUND: Reciprocal changes may accompany ST segment elevation in the ischemic territory during acute myocardial infarction (AMI). We examined the hypothesis that isolated inferior ST segment depression on admission is an early sign of anterior wall infarction. METHODS: 49 patients admitted to the coronary care unit between January 1996 and June 2008 who presented with inferior ST segment depression in the absence of ST segment elevation. Electrocardiograms (ECGs) obtained on admission and at 24-48 h were reviewed. Culprit artery was determined based on angiographic and echocardiographic data. RESULTS: All patients had ST segment depression in the inferior leads on admission. A subgroup (55%) presented with concomitant ST segment depression in V5-V6. Follow-up ECG showed that 35% developed ST segment elevations and/or T wave inversions in anterior wall leads over 24-48 h. The left anterior descending (LAD) artery or one of its branches was the culprit in 60% of the patients. Sum of ST segment depression, V5-V6 involvement or presence of 'hyperacute' T waves did not predict LAD involvement. CONCLUSION: Isolated ST segment depression in the inferior wall leads during ACS is usually an early sign of anterior wall AMI, in which the LAD or one of its branches is the culprit artery. PMID- 20954790 TI - Spiro azepane-oxazolidinones as Kv1.3 potassium channel blockers: WO2010066840. AB - This article evaluates a patent application from Solvay Pharmaceuticals, which claims spiro azepane-oxazolidinones as novel blockers of the voltage-gated potassium channel Kv1.3 for the treatment of diabetes, psoriasis, obesity, transplant rejection and T-cell mediated autoimmune diseases such as rheumatoid arthritis and MS. The patent describes a new chemotype of Kv1.3 blockers and thus illustrates the growing interest of the pharmaceutical industry in Kv1.3 as a target of immunosuppression and metabolic disorders. This article briefly summarizes the chemistry and biological data provided in the patent and then compares the new compounds to Kv1.3 blockers previously disclosed by both academia and pharmaceutical companies. PMID- 20954791 TI - Diagnosis of myocardial infarction using the new universal definition: is it enough for risk stratification and guiding decision for revascularization? AB - Abstract Objectives: Evaluate the new ESC/ACCF/AHA/WHF universal definition of myocardial infarction (MI) in relation to its prognostic implications and the role for guiding decision for revascularization. It was also compared with the multivariable based GRACE Risk Score (GRS). METHODS: Single centre registry of 389 consecutive patients admitted with non-ST-segment elevation (NSTE) ACS. We calculated the adjusted HR & 95%CI for death/MI at 30-days and one-year follow up, between the presence or absence of MI using: (1) universal definition: > 99th URL for cTnI (> 0.06 ng/ml) or MBm (> 3.2 ng/ml); (2) MBm > 2 * URL (> 12.2 ng/ml); 3) old WHO: MBact > 2 * URL (> 32U/l). Logistic analysis was performed to test the interaction between tertiles of biomarkers or GRS and the effect of revascularization on the outcome. RESULTS: The universal definition increased the incidence of MI in 3.5-fold for cTnI, but was not an independent predictor of outcome. The GRS was the only independent predictor of prognosis at 30-days and one-year. The interaction with the prognostic impact of revascularization was only present for the GRS categorized by tertiles. CONCLUSIONS: In a contemporary unselected population with NSTE-ACS, the universal definition of MI alone was not adequate for risk assessment and revascularization decision making. These purposes were fully addressed with the GRS. PMID- 20954792 TI - Nanoscaffold based stem cell regeneration therapy: recent advancement and future potential. AB - IMPORTANCE OF THE FIELD: Over the past years, extensive research has been directed towards tissue engineering using conventional scaffolds. In-depth studies in this field have led to the realization that in vivo cells interact with the extracellular matrix, composed of nanofibers at sub-micron scale, which not only provides the mechanical support to the cells but also plays a key role in regulation of cellular behavior. This has led to the development of nanofibrous scaffold (NFS) technology which in combination with stem cells is emerging as an important tool in the development of tissue engineering and regenerative medicine. AREAS COVERED IN THIS REVIEW: This review summarizes the three methods of nanofibrous scaffold preparation and provides a state-of-the-art update on the recent advancement in the use of nanoscaffolds in stem cell regeneration therapy. WHAT THE READER WILL GAIN: The review gives the reader an insight on nanoscaffold based therapy methods, such as how these scaffolds can potentially be designed and used in successful development of stem cell based therapies. TAKE HOME MESSAGE: NFS technology when coupled with stem cells and exploited in the right way has a strong potential of being used in stem cell based regenerative medicine. PMID- 20954793 TI - Ocular acid burn due to 20% concentrated salicylic acid. AB - This is a case report of severe conjunctival and corneal epithelial defects resulting from accidental exposure to salicylic acid that was mistakenly used instead of artificial tears (eye drops). The patient was treated with tobramycin 0.3%-dexamethasone 1% 3 times a day, cyclopentolate 1% twice a day, and artificial tears 6 times a day and underwent daily examinations until the corneal and conjunctival epithelial defects resolved. The corneal and conjunctival epithelial defects slowly resolved over 14 days. Visual acuity improved to its preinjury level of 20/40 in the affected eye. No residual corneal scarring was evident. Slowly resolving corneal and conjunctival epithelial defects can occur from direct contact with salicylic acid; therefore, this medication should be packaged and labeled differently from eye drops. PMID- 20954794 TI - The alpha1-adrenergic receptors: diversity of signaling networks and regulation. AB - The alpha(1)-adrenergic receptor (AR) subtypes (alpha(1a), alpha(1b), and alpha(1d)) mediate several physiological effects of epinephrine and norepinephrine. Despite several studies in recombinant systems and insight from genetically modified mice, our understanding of the physiological relevance and specificity of the alpha(1)-AR subtypes is still limited. Constitutive activity and receptor oligomerization have emerged as potential features regulating receptor function. Another recent paradigm is that beta arrestins and G protein coupled receptors themselves can act as scaffolds binding a variety of proteins and this can result in growing complexity of the receptor-mediated cellular effects. The aim of this review is to summarize our current knowledge on some recently identified functional paradigms and signaling networks that might help to elucidate the functional diversity of the alpha(1)-AR subtypes in various organs. PMID- 20954795 TI - Preparation and in vitro/in vivo evaluation of dextran matrix tablets of budesonide in experimental ulcerative colitis in rats. AB - Budesonide is an anti-inflammatory drug of choice for treatment of ulcerative colitis which affects the rectum and a part of or the entire colon. Delivery of budesonide specifically to the colon would increase the efficacy of the drug and reduce the side-effects. The aim of this study was to develop an oral matrix system formulation for budesonide to deliver the major part of the drug to the colon for treatment of ulcerative colitis that has not been reported before. Directly compressed matrix tablets were prepared using different molecular weights of dextran and three ratios of drug-to-polymer. The physical properties of the tablets including weight variation, hardness, content uniformity, and release profile in HCl 0.1 N, phosphate buffer pH 7.4 and 6.8 containing 4% rat caecal and colonic contents were studied. The efficacy of the desired formulation was also evaluated against acetic acid-induced colitis in rats. Physical properties of the tablets were in the ranges recommended by official references. More than 10% of the drug was released in HCl 0.1 N and pH 7.4, while a very drastic increase was observed after exposure to pH 6.8 containing rat caecal contents. The efficacy of the selected formulation against rat-induced colitis was also increased in comparison to the non-targeted formulation of budesonide. In conclusion, matrix tablets with a 1:10 drug-to-dextran ratio with high molecular weight could deliver the drug specifically to the colon and are promising for treatment of ulcerative colitis. PMID- 20954796 TI - Are developmentally exposed C57BL/6 mice insensitive to suppression of TDAR by PFOA? AB - Perfluorooctanoic acid (PFOA) is an environmentally persistent fluorinated compound that is present in biological samples worldwide and associated with multisystem toxicity in laboratory animal models. Several studies have reported suppression of T-cell-dependent antibody responses (TDAR) in adult rodent models after 15 or 28 days of exposure. A related compound, perfluorooctane sulfonate (PFOS), was reported to suppress TDAR in developmentally exposed mice. The developmental effects of PFOA exposure on TDAR have not been explored; therefore, the objective of our study was to determine if TDAR suppression would occur in developmentally exposed mice. Pregnant C57BL/6 mice were given 0, 0.5, or 1 mg PFOA/kg body weight (BW) in drinking water from gestation day (GD) 6 to GD17. At postnatal day (PND) 2, litters/dam were reduced to three males and three females. On PND21, female offspring were weaned and separated and on PND43, they were intravenously immunized with sheep red blood cells. Serum for evaluation of IgM titers and PFOA concentrations was collected 5 days later. Booster immunizations were given 14 days later; serum for evaluation of IgG titers and PFOA concentrations was collected 5 days later. Litter weights were statistically decreased by 10% in the 1 mg/kg group relative to controls, but liver weights, lymphoid organ weights, and TDAR did not differ in female offspring by dose. Mean PFOA serum concentrations were 122 ng/mL (0.5 mg/kg) and 183 ng/mL (1 mg/kg) and <1 ng/mL for controls. PFOA serum concentrations in offspring were 400-fold lower than serum concentrations reported to suppress TDAR in adults; however, mice exposed during development did not survive doses higher than 1 mg/kg. Therefore, although TDAR in adult mice is sensitive to PFOA exposure, the doses and exposure scenario of this study did not induce developmental immunotoxicity (DIT). C57BL/6 mice are likely more sensitive to the overt developmental toxicity of PFOA than to potential DIT. PMID- 20954797 TI - Triptolide induces adverse effect on reproductive parameters of female Sprague Dawley rats. AB - The aim of this study was to investigate the adverse effects of triptolide, a diterpenoid triepoxid and a major active component isolated from Triptergium wilfordii Hook.f (TWHF), on various reproductive parameters of female Sprague Dawley (SD) rats. Female SD rats were treated with triptolide by oral administration (gastric infusion; 0, 100, 200, and 400 MUg/kg) once-daily for 90 days. During the experimental period, vaginal smears were taken to monitor the estrous phase for the last 30 days. Relative ovary and uterus weights to body and histopathologically changes were determined on the last day. Serum levels of estradiol (E(2)), progesterone (P), follicle-stimulating hormone (FSH), and luteotropic hormone (LH) were assessed by enzyme immunoassay. ERalpha expression in the uterus and ovaries were analyzed from using immunohistochemical detection. The results showed that treatment with 200 and 400 ug/kg of triptolide significantly reduced serum levels of E(2) and P and increased levels of FSH and LH. At these dose levels, relative weights of ovary and uterus were significantly reduced. Qualitative histological analysis of the ovaries revealed a reduction in developing follicles and increase in atretic follicles in treated animals. Further, estrous cycles were prolonged significantly. The expression of ERalpha in ovaries and the uterus decreased in treated animals. These data suggest that triptolide had a direct effect on the ovaries, and the decrease in steroids elicited feedback on FSH and LH. Thus, reduced levels of E(2) and P may affect follicular development, estrous cycle, and expression of ERalpha. PMID- 20954798 TI - Inhibitory effect of ebselen on lactate dehydrogenase activity from mammals: a comparative study with diphenyl diselenide and diphenyl ditelluride. AB - Ebselen is a seleno compound whose antioxidant properties have been attributed to its thiol-peroxidase and thioredoxin-like activity. However, the excessive oxidation of thiols can be potentially toxic. Thus, this work investigated whether lactate dehydrogenase (LDH) can be a possible in vitro target to the toxicity of ebselen, in comparison with diphenyl diselenide [(PhSe)(2)] and diphenyl ditelluride [(PhTe)(2)]. Ebselen was the most potent inhibitor of LDH. A maximal inhibitory effect was obtained at 2 MUM to LDH purified and at 20 MUM to LDH from heart and liver homogenates. Moreover, (PhSe)(2), followed by (PhTe)(2), also presented a significant inhibitory effect on LDH activity. DL-dithiothreitol (DTT) was able to revert the inhibition of LDH induced by all compounds tested, confirming the involvement of essential thiol groups on LDH inhibition by organochalcogens. In conclusion, our results show that liver and heart LDH may be a possible target for the toxicity of organochalcogens at relative low concentrations. Our results also indicate that the use of LDH, as a marker of cell viability, may be biased by a direct inhibitory effect of ebselen or other chalcogenides on LDH, resulting in false protection in an in vitro system. PMID- 20954799 TI - Oxidative pathways as a drug target for the treatment of autism. AB - IMPORTANCE OF THE FIELD: Autism is a severe, pervasive developmental disorder, the aetiology of which is poorly understood. Current pharmacological treatment options for autism are often focused on addressing comorbid behavioural problems, rather than core features of the disorder. Investigation of a new treatment approach is needed. AREAS COVERED IN THIS REVIEW: Recent research has indicated a possible role of abnormalities in oxidative homeostasis in the pathophysiology of autism, based on reports that a range of oxidative biomarkers are significantly altered in people with autism. This article reviews the current findings on oxidative stress in autism, including genetic links to oxidative pathways, changes in antioxidant levels and other oxidative stress markers. We conducted a search of the literature up to June 2010, using Medline, Pubmed, PsycINFO, CINAHL PLUS and BIOSIS Previews. WHAT THE READER WILL GAIN: This review provides an overview of the current understanding of the role of oxidative stress in autism. This will assist in highlighting areas of future therapeutic targets and potential underlying pathophysiology of this disorder. TAKE HOME MESSAGE: Abnormalities in oxidative homeostasis may play a role in the pathophysiology of autism. Antioxidant treatment may form a potential therapeutic pathway for this complex disorder. PMID- 20954801 TI - Gallic acid-induced human pulmonary fibroblast cell death is accompanied by increases in ROS level and GSH depletion. AB - Gallic acid (GA), as a polyhydroxylphenolic compound, has various biological properties, including an anticancer effect. However, little is known about the toxicological effect of GA in primary normal cells. In the present study, we investigated the molecular mechanisms of GA on human pulmonary fibroblast (HPF) cell death in relation to apoptosis. HPF cell growth was dose dependently diminished with an IC(50) of approximately 400 MUM of GA at 24 hours. GA-induced HPF cell death was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). All the tested caspase inhibitors (e.g., pan-caspase, caspase 3, -8, or -9 inhibitor) did not rescue HPF cells from GA-induced cell death. GA increased reactive oxygen species (ROS) levels and glutathione (GSH)-depleted cell numbers. Caspase inhibitors partially altered ROS levels, but did not reduce GSH-depleted cell number, in GA-treated HPF cells. In conclusion, we demonstrated that GA induced the growth inhibition and death of HPF cells, which was accompanied by ROS increase and GSH depletion. PMID- 20954800 TI - Involvement of the p38 pathway in the differential induction of heme oxygenase-1 by statins in Neuro-2A cells exposed to lipopolysaccharide. AB - Heme oxygenase-1 (HO-1) expression, in response to various stimuli, has been generally reported to protect against cellular stress. However, we previously demonstrated simvastatin-induced HO-1-exaggerated nuclear factor kappa beta (NF kappabeta) activation and superoxide production on exposure to lipopolysaccharide (LPS). The addition of the iron chelator, desferrioxamine, to reduce the accumulation of ferric iron from heme by HO-1 resulted in a blockade of aggravated superoxide production. In this study, we demonstrated that, unlike simvastatin, neither atorvastatin- nor rosuvastatin-induced HO-1 upregulation resulted in increased NF-kappabeta activation and superoxide production of Neuro 2A cells against LPS. Moreover, increased superoxide formation by either atorvastatin or rosuvastatin, in the presence or absence of LPS, could not be reduced by the addition of desferrioxamine, unlike simvastatin. In contrast to our previous experiment, in which simvastatin activated ERK and p38, but not JNK or Akt, both atorvastatin and rosuvastatin phosphorylated ERK, but not p38. Inhibition of p38 activation by 5 MUM of SB203580 effectively reduced exaggerated HO-1 upregulation in cells pretreated with simvastatin, but not atorvastatin or rosuvastatin, plus exposure to LPS. The addition of an ERK inhibitor (50 MUM of PD98059) did not decrease HO-1 upregulation in cells following any statin pretreatment. Further, the effect of simvastatin on primary cultures of cortical neurons was also different from that on Neuro-2A cells, as HO-1 upregulation did not result in exaggerated NF-kappabeta activation and superoxide production. This study demonstrated the involvement of p38 in the differential induction of HO-1 by different statins and showed the different physiological relevance of experiments on different cell types. PMID- 20954802 TI - A new fibrinolytic enzyme (55 kDa) from Allium tuberosum: purification, characterization, and comparison. AB - Chives have been used both as food and as medicine. Previously, two fibrinolytic enzymes, ATFE-I (90 kDa) and ATFE-II (55 kDa), were identified in chives (Allium tuberosum), a perennial herb. In the present work, ATFE-II was purified by ion exchange chromatography followed by gel filtration. In addition, the enzyme properties of ATFE-I and ATFE-II were compared. The molecular mass and isoelectric point (pI value) of ATFE-II were 55 kDa and pI 4.0, respectively, as revealed using one- or two-dimensional fibrin zymography. ATFE-II was optimally active at pH 7.0 and 45 degrees C. ATFE-II degraded the Aalpha-chain of human fibrinogen but did not hydrolyze the Bbeta-chain or the gamma-chain, indicating that the enzyme is an alpha-fibrinogenase. The proteolytic activity of ATFE-II was completely inhibited by 1 mM leupeptin, indicating that the enzyme belongs to the cysteine protease class. ATFE-II was also inhibited by 1 mM Fe2(+). ATFE-II exhibited high specificity for MeO-Suc-Arg-Pro-Tyr-p-nitroaniline (S-2586), a synthetic chromogenic substrate of chymotrypsin. Thus proteolytic enzymes from A. tuberosum may be useful as thrombolytic agents. PMID- 20954803 TI - Toxic effects of celastrol on embryonic development of zebrafish (Danio rerio). AB - Celastrol is a terpenoid purified from Tripterygium wilfordii Hook F. As a natural product with pharmacological activities, this compound is a promising candidate for drug development. To provide more information about its toxicity for clinical trials, toxicity assessment of celastrol was conducted with zebrafish model in vivo. 1hour post-fertilization (hpf) embryos were treated with various concentrations of celastrol for 120h. Developmental phenotypes were observed and survival rates were recorded. The results showed that the hatching rates of embryos treated with 1.0MUM or higher celastrol were significantly lower. Embryos exposed to 1.0MUM celastrol had no blood flow in trunk vessels at 48hpf with a median effect concentration (EC(50)) of 0.94MUM. At 72hpf serious edema in pericardial sac was observed in the surviving larvae (hatched from embryos treated with 1.5MUM celastrol). Bent tails or hook-like tails were seen as 0.5MUM celastrol and the EC(50) for tail malformation was 0.66 MUM at 72hpf. The lethal effect of celastrol on zebrafish embryos was dose-dependent and the LC(50) values of celastrol on 1hpf embryos were approximately 1.40MUM. These results indicate that celastrol affects the normal development of zebrafish embryo in MUM concentrations. PMID- 20954804 TI - An alternative antidote therapy in amitriptyline-induced rat toxicity model: theophylline. AB - We planned this study in order to investigate the effects of theophylline on cardiovascular parameters in an anaesthetized rat model of amitriptyline toxicity. In the preliminary study, we tested theophylline as 1 mg/kg of bolus, followed by a 0.5-mg/kg infusion. Toxicity was induced by the infusion of 0.94 mg/kg/min of amitriptyline up to the point of a 40-45% inhibition of mean arterial pressure (MAP). The rats were randomized to two groups: a group of 5% dextrose bolus followed by 5% dextrose infusion, and another group with theophylline bolus followed by infusion. Amitriptyline caused a significant decrease in MAP and prolongation in QRS; however, it did not alter heart rate (HR). When compared to the dextrose group, theophylline administration increased MAP, shortened prolonged QRS duration, and increased HR (P < 0.05, respectively). There was no statistically significant difference in the results of arterial blood-gas analyses among the groups (P > 0.05). Bolus doses followed by a continuous infusion of theophylline were found to be effective in reversing the hypotension and QRS prolongation seen in amitriptyline toxicity. One of the possible explanations of this beneficial effect is nonselective adenosine antagonism of theophylline. Further studies are needed to reveal the exact mechanism of the observed effect. PMID- 20954805 TI - Thirteen compounds promoting oligodendrocyte progenitor cell differentiation and remyelination for treating multiple sclerosis: WO2010054307. AB - BACKGROUND: The application is in the field of cellular therapy and neural repair. OBJECTIVE: It aims at identifying and characterizing compounds and molecules that promote the differentiation of oligodendrocyte progenitor cells and remyelination of the nervous system. METHODS: Library of compounds and molecules were screened on a series of assays specifically designed and developed to assess the activity and potency of compounds and molecules on the differentiation of oligodendrocyte progenitor cells and on remyelination of nerve cells in in vitro and in vivo models, such as cultures of neural progenitor and stem cells, cerebellar organotypic cultures, the zebrafish and the cuprizone mediated demyelination mouse models. RESULTS: In all, 13 compounds were identified and characterized, after a secondary screening, for inducing the differentiation of oligodendrocyte progenitor cells and for promoting myelination and remyelination in vitro and in vivo. CONCLUSION: The 13 compounds, promoting the differentiation of oligodendrocyte progenitor cells and myelination of nerve cells, may be used for the treatment of multiple sclerosis (MS) and other myelin related disorders. The application claims the use of the compounds to promote the differentiation of oligodendrocyte progenitor cells and endogenous remyelination for the treatment of demyelinating diseases alone or in combination with other agents and drugs, such as immunomodulatory, immunosuppressive, neuroprotective and neuroregenerative agents. PMID- 20954806 TI - Fermentation metabolites from Lactobacillus gasseri and Propionibacterium freudenreichii exert bacteriocidal effects in mice. AB - Lactobacillus gasseri OLL 2716 promotes the elimination of Helicobacter pylori and is utilized in yogurts that are specifically labeled as health foods. On the other hand, milk whey fermented by Propionibacterium freudenreichii ET-3, which increases the numbers of Bifidobacterium, is effective for intestinal disorders. We previously demonstrated that oral administration of L. gasseri and P. freudenreichii fermentation metabolites (LP-FM) improved calf intestinal microflora and reduced the incidence of diarrhea. However, the detailed immunological mechanisms responsible for these effects remain to be fully understood. In this study, we investigated whether LP-FM stimulates the innate immune response and promotes the elimination of Listeria monocytogenes in mice. The C57BL/6 female mice that were treated with LP-FM or L. gasseri fermentation metabolites alone for 4 weeks had more peripheral white blood cells than the untreated control mice. In particular, LP-FM-treated mice had higher CD4- and CD8 positive T-cell counts. The levels of reactive oxygen and nitrogen species produced by peritoneal macrophages were also higher in LP-FM-treated mice. Furthermore, LP-FM-treated mice that were infected with L. monocytogenes exhibited significant enhancement of the elimination of Listeria from the spleen and the liver in comparison with untreated control mice infected with Listeria. The activation of innate immunity by LP-FM was increased by the combination of fermentation metabolites from P. freudenreichii. These results suggest that LP FM, which contains metabolites from L. gasseri and P. freudenreichii, stimulates the function of the innate immune system, thereby significantly promoting the elimination of L. monocytogenes in mice. PMID- 20954807 TI - Soybean supplementation helps reverse age- and scopolamine-induced memory deficits in mice. AB - Phytoestrogens are nonsteroidal plant compounds that are able to exert estrogenic effects. Soybean is a rich source of phytoestrogens, especially isoflavones. Soy isoflavones are utilized for estrogen replacement therapy. Estrogen is reported to influence several areas of brain that are involved in cognition and behavior. Therefore, the present study was undertaken to examine whether dietary supplementation with soybean improves the cognitive function of mice. Soybean was administered in three different concentrations (2%, 5% and 10% [wt/wt]) in the normal diet to young and mature mice for 60 successive days. The passive avoidance paradigm and the elevated plus maze served as the exteroceptive behavioral models, whereas scopolamine (1.4 mg/kg, i.p.) served as the interoceptive behavioral model. The brain acetylcholinesterase activity (AChE) activity, brain thiobarbituric acid-reactive substances (TBARS), reduced glutathione (GSH), and total blood cholesterol levels were also measured in the present study. The administration of soybean for 60 consecutive days protected (P < .05) the animals from developing memory impairment. Soybean administration also resulted in diminished brain AChE activity, decrease in brain TBARS, and increase in GSH levels, thereby indicating facilitated cholinergic transmission, reduced free radical generation, and enhanced scavenging of free radicals. Thus, soybean appears to be a useful remedy for improving memory and for the management of cognitive deficits owing to its pro-estrogenic, antioxidant, procholinergic, and/or neuroprotective properties. PMID- 20954808 TI - In vivo, in vitro evaluation of linseed mucilage based buccal mucoadhesive microspheres of venlafaxine. AB - The purpose of the present research work was to extract linseed mucilage, use it as a mucoadhesive agent and to develop mucoadhesive microspheres for buccal delivery with an intention to avoid hepatic first-pass metabolism, by enhancing residence time in the buccal cavity. Linseed mucilage was extracted and used to prepare microspheres with varying concentrations of mucilage from formulation F1 F4 (1-2.5%) by spray-drying technique. The microspheres were evaluated for the yield, particle size, incorporation efficiency, swelling property, in vitro mucoadhesion, in vitro drug release, histological study, and stability. Microspheres were characterized by differential scanning colorimetry, scanning electron microscopy, and X-ray diffraction study. Further, the bioavailability study using the New Zealand rabbits was carried out. Formulation F4 showed the maximum mucoadhesion 89.37 +/- 1.35%, 92.10 +/- 1.37% incorporation efficiency, highest swelling index 0.770 +/- 1.23. F4 showed a marked increase in the bioavailability after buccal administration (51.86 +/- 3.95) as compared to oral route (39.60 +/- 6.16). Also it took less time to reach maximum plasma concentration of 21.38 +/- 1.05 ng/ml as compared to oral solution where it required 180 min to reach maximum plasma concentration of 17.98 +/- 1.14. It is concluded from the results that linseed mucilage can be used in the production of the mucoadhesive microspheres. PMID- 20954810 TI - Diagnostic value and cost considerations of routine fine-needle aspirations in the follow-up of thyroid nodules with benign readings. AB - BACKGROUND: Fine-needle aspiration (FNA) is the most accurate tool to identify malignancy in solitary thyroid nodules. Although some recommend routinely repeating FNA for nodules that are initially read as benign, there is no consensus. We evaluated clinical relevancy and considered costs of routine follow up FNA in nodules initially read as benign. METHODS: We reviewed the records of all 739 patients who underwent FNA of solitary thyroid nodules at our institution from 1988 to 2004. A total of 815 aspirations were required to obtain satisfactory specimens. According to their physicians practice, some patients had a "follow-up biopsy" after an initially benign FNA reading as a matter of routine (Group I approach) or if their clinical status changed (Group II approach). The outcome information for at least 4 years after the initial FNA in these two groups was compared. In addition, hypothetical costs relating to both methods for deciding whether to do a follow-up FNA were considered. RESULTS: The initial FNA was benign in 576 (78%), suspicious for follicular neoplasms in 106 (14.4%), and malignant in 57 patients (7.7%). Follow-up FNA was performed in 292 patients with initially benign lesions, 235 in Group I approach and 57 in Group II approach. The FNA diagnosis according to Group I approach remained benign on follow-up biopsy in 96.2% (226/235), was altered to follicular neoplasm in 3% (7/235), and was suspicious for malignancy in 0.8% (2/235). When following Group II approach, the follow-up FNA was benign in 93% (53/57), undetermined in 1.7% (1/57), and showed follicular neoplasm in 5.3% (3/57). Combining Groups I and II methods, 5 of 292 patients had a malignant nodule on histological examination, a false negative rate of 1.7% for the initial FNA, but without a difference in prevalence of thyroid malignancy between the groups. Cost-consequence analysis showed no benefit in routine follow-up FNA after initially benign FNA readings. CONCLUSIONS: Routine follow-up FNA in patients whose initial FNA is benign has a low diagnostic upgrading value and is relatively costly. In patients whose initial FNA is benign, we recommend the FNA be repeated only if clinically suspicious signs or complaints develop. PMID- 20954809 TI - Genistein induces estrogen-like effects in ovariectomized rats but fails to increase cardiac GLUT4 and oxidative stress. AB - This study aimed to determine whether a 2-week genistein treatment induced estrogen-like effects in ovariectomized (OVX) Sprague-Dawley rats, after 2 weeks of subcutaneous genistein injections (250 mg/kg of body weight/day). Uterine weight, uterine-to-body weight ratio, femur weight, and femur-to-body weight ratio were all significantly increased with genistein in OVX rats. Body weight was significantly decreased with genistein in OVX rats. Genistein had no effect on the weights of heart, heart-to-body ratio, and fat pad but significantly decreased heart rate and pulse pressure. Genistein had no effect on cardiac GLUT4 protein, oxidative stress, plasma glucose, nonesterified fatty acids, or low density lipoprotein levels; however, plasma insulin levels were significantly increased. Our results show that a 2-week genistein treatment produced favorable estrogen-like effects on some physical and physiological characteristics in OVX rats. However, based on our experimental conditions, the effects of genistein were not associated with changes in cardiac GLUT4 or oxidative stress. PMID- 20954811 TI - Repeated-dose (28 days) oral toxicity study in rats of an antiacne formula (BC AF) derived from plants. AB - To evaluate the safety of a formula (BC-AF) consisting of the extracts of danshen (Salvia miltiorrhiza), loquat leaf (Glycyrrhiza uralensis), and licorice (Eriobotrya japonica), a preliminary 28-day, repeated-dose oral toxicity study was performed in Sprague-Dawley rats. Eighty animals were divided into four groups, with each group comprising 10 male and 10 female rats. BC-AF was administered once-daily by oral gavage at doses of 0 (control), 2.5 (low), 5 (middle), and 10 (high) g/kg body weight successively for each group for 28 days, respectively. Rats in all groups were sacrificed on day 29, except half of the males and females in the high-dose group that were kept for an additional 2 weeks to observe any possible toxicity after drug withdrawal. In 4 weeks, there were no toxicity reactions or abnormal deaths in any animal groups. There was no significant difference, in comparison to the control group, in clinical signs, organ weights, hematological and serological parameters, or histopathologic findings. In conclusion, the 28-day repeated-dose oral toxicity study demonstrates that BC-AF produced no effects in either male or female rats following oral administration of up to 10 g/kg. PMID- 20954812 TI - Presentation of clinically solitary thyroid nodules in surgical patients. AB - BACKGROUND: Thyroid nodules occupy a unique position in relation to clinical diagnosis since most patients with a thyroid nodule do not present with overt symptoms. There are, however, no good published data demonstrating the way in which clinically solitary thyroid nodules come to medical attention, with most of the literature being anecdotal. This study aims to evaluate the mode of presentation of solitary thyroid nodules, and to assess whether the presence of a malignancy influences that presentation. METHODS: In this retrospective cohort study, data were obtained from the University of Sydney Endocrine Surgery Database and through a review of the patient records. The study cohort comprised 419 consecutive patients who presented with a clinically solitary thyroid nodule and who subsequently underwent surgery. Patient files lacking data on mode of presentation and patients in whom thyroid nodules were incidentally discovered during parathyroid surgery were excluded, leaving a total of 299 patients. Data were analyzed using a computer-based statistical software package. Continuous variables were compared using Student's t-test. Categorical variables were analyzed using Fishers exact test. Statistical significance was set at p < 0.05. RESULTS: Solitary thyroid nodules are most commonly detected by the patients themselves (40%), followed by the incidental discovery of nodules on imaging studies performed for unrelated reasons (30%), and lastly due to third-party diagnosis by family, friends, acquaintances, or medical practitioners (30%). Nodules detected by medical practitioners were statistically more likely to be malignant (p = 0.02). No other differences between the clinical presentation of benign and malignant nodules were found. CONCLUSIONS: Patients themselves are the ones who most commonly first become aware of the thyroid nodules that are eventually seen by thyroid surgeons. Incidental discovery on image studies is also important. Thyroid nodules detected by medical practitioners should be dealt with most urgently because they are most likely to be malignant. PMID- 20954813 TI - Serological markers of Hepatitis B and C among juvenile immigrants from Albania settled in Greece. AB - BACKGROUND: Greece is a place of settlement for a large number of immigrants, particularly from Albania, which constitute special community groups for public health policies. OBJECTIVES: This study was designed to assess the seroprevalence of serological markers for Hepatitis B and C among juvenile immigrants from Albania settled in Greece. METHODS: The study population included 504 subjects, 418 males and 86 females, aged 10-23 years old who have emigrated from Albania to Pogoniani-Greece and participated voluntarily in vaccination programmes against Hepatitis B. The serum samples were examined with enzyme immune assays for the immunological markers HBsAg, anti-HBc, anti-HBs and anti-HCV. HBsAg positive samples were further tested for IgM anti-HBc, HBeAg and anti-HBe. RESULTS: Among the examined subjects, 40.5% were found positive for anti-HBc, indicating an HBV contamination. Specifically, 11.7% were carriers of HBsAg, whereas 28.8% were negative for HBsAg but positive for anti-HBc. Only 6.5% was positive exclusively for anti-HBs. The rest (53.0%) presented no positive serological markers. Among the HBsAg positive patients, 8.5% were found positive for HBeAg, while 5.1% was positive for IgM anti-HBc. Finally, only 0.6% of the sample presented antibodies against HCV. CONCLUSION: The examined migratory population is described by a high prevalence of Hepatitis B. Therefore, specific public health measures are necessary. However, no data was found that indicate potential public health dangers regarding hepatitis C. PMID- 20954814 TI - Blood aging, safety, and transfusion: capturing the "radical" menace. AB - Throughout their life span, circulating red blood cells (RBCs) transport oxygen (O(2)) primarily from the lungs to tissues and return with carbon dioxide (CO(2)) from respiring tissues for final elimination by lungs. This simplistic view of RBCs as O(2) transporter has changed in recent years as other gases, for example, nitric oxide (NO), and small molecules, such as adenosine triphosphate (ATP), have been shown to either be produced and/or carried by RBCs to perform other signaling and O(2) sensing functions. In spite of the numerous biochemical and metabolic changes occurring within RBCs during storage, prior to, and after transfusion, perturbations of RBC membrane are likely to affect blood flow in the microcirculation. Subsequent hemolysis due to storage conditions and/or hemolytic disorders may have some pathophysiological consequences as a result of the release of Hb. In this review, we show that evolution has provided a multitude of protection and intervention strategies against free Hb from "cradle" to "death"; from early biosynthesis to its final degradation and a lot more in between. Furthermore, some of the same naturally occurring protective mechanisms can potentially be employed to oxidatively inactivate this redox active protein and control its damaging side reactions when released outside of the RBC. PMID- 20954815 TI - Clinical characteristics and outcome of familial nonmedullary thyroid cancer: a retrospective controlled study. AB - BACKGROUND: Familial nonmedullary thyroid cancer (FNMTC) is a disease defined by clustering of thyroid cancers of follicular cell origin, and it is estimated to account for 5% of all thyroid cancers. Several studies found FNMTC to be more aggressive than sporadic disease, whereas others found them to have a similar course and outcome. The purpose of this study was to determine whether FNMTC is more aggressive than sporadic thyroid cancer. METHODS: A retrospective controlled study of FNMTC versus sporadic nonmedullary thyroid cancers was conducted using a registry of patients with thyroid cancer. Data on disease severity at presentation, treatment modalities, and outcome were collected. RESULTS: Sixty seven patients with FNMTC and 375 controls with sporadic disease were included. Follow-up period was 8.6 +/- 10 years for patients with FNMTC and 8.4 +/- 9.1 years for sporadic cases. Patients with FNMTC had comparable disease severity at diagnosis as sporadic patients, underwent similar surgical and radioiodine treatments, and had similar long-term disease-free survival. Long-term outcome in families with three or more affected relatives was similar to families with only two affected relatives. CONCLUSIONS: Our results suggest that FNMTC is not more aggressive than sporadic thyroid cancer within our studied population. After a similar therapeutic strategy, FNMTC and sporadic cases had comparable prognosis, including in families with three or more affected members. PMID- 20954816 TI - Assessment of early cartilage degeneration after slipped capital femoral epiphysis using T2 and T2* mapping. AB - BACKGROUND: T2 and T2* mapping are novel tools to assess cartilage quality. PURPOSE: To evaluate hip cartilage quality in the long-term follow-up of patients with slipped capital femoral epiphysis (SCFE) with T2 and T2* mapping. MATERIAL AND METHODS: Thirty-three patients (19 men, 14 women, mean age 24 +/- 6.0 years, range 18-51 years) with a history of SCFE in 41 hips and 10 healthy controls (seven men, mean age 22 +/- 4 years) were included. Follow-up period was 12 +/- 6 (range 4-39 years) years. Coronal T2 and T2* mapping were performed on a 1.5 T scanner. T2 and T2* values of the hip articular cartilage were determined in the medial, central, and lateral portion of the hip within the weight bearing zone. Clinical symptoms including pain were assessed with the Harris hip score. Statistical analysis was performed using Mann-Whitney U test and Spearman rank sum test. RESULTS: In hips after SCFE T2 (central portion: 25.71 ms +/- 4.84 ms vs. 29.71 ms +/- 7.04 ms, p<0.05) and T2* (central portion: 20.76 ms +/- 3.17 ms vs. 23.06 ms +/- 2.68 ms, P<0.01) of cartilage were significantly lower, compared to controls. The differences were most apparent in the lateral portion of the hip articular cartilage. Abnormal cartilage T2 and T2* were not associated with hip pain or impaired hip function. SCFE was unilateral in 23 cases (70%). In the patients' unaffected hips without SCFE, areas of significantly reduced T2 (central portion: 26.07 ms +/- 4.27 ms, P<0.05) and T2* (lateral portion: 23.23 ms +/- 2.45 vs. 25.11 ms +/- 3.01 ms, P<0.05) were noted. CONCLUSION: T2 and T2* mapping of the hip in patients after SCFE are significantly different from healthy controls and may offer additional information about cartilage quality. PMID- 20954817 TI - Sorafenib: rays of hope in thyroid cancer. AB - BACKGROUND: Sorafenib (BAY 43-9006) is an inhibitor of multiple-receptor tyrosine kinases involved in tumor growth and angiogenesis, which can be advantageously administered orally. Initially used as monotherapy in advanced renal cell carcinoma, sorafenib was proven to increase progression-free survival while enhancing disease control. Clinical trials on sorafenib are at present ongoing for the treatment of various malignancies, including thyroid cancer (TC). SUMMARY: Specifically, in two phase II studies recently conducted on papillary TC, although the respective results were not entirely compatible as regard partial response rate and progression-free survival, sorafenib demonstrated a relatively favorable benefit/risk profile. In another more recent phase II study, whose primary endpoint was the reinduction of radioactive iodine uptake at 26 weeks, although no reinduction of radioactive iodine uptake was observed, 59% had a beneficial response and 34% had stable disease. Sorafenib hence appears to be a valid alternative to conventional treatment of metastatic papillary TC refractory to radioiodine therapy. CONCLUSIONS: Further prospective investigations are required to define the characteristics of tumor response to the drug and the factors inducing resistance to treatment. A major issue demanding immediate attention involves optimization of sorafenib treatment: this concerns multidrug combination with different tyrosine kinase inhibitors or immunomodulating agents with the aim of reducing doses and thereby improving drug tolerability and antineoplastic capability. PMID- 20954818 TI - White fibrous papulosis of the neck. AB - A 56-year-old white man with multiple, discrete nonfollicular papules on the neck is presented. Clinical and histopathologic features were compatible with the entity of white fibrous papulosis of the neck (WFPN). Pseudoxanthoma elasticum like papillary dermal elastolysis (PXE-PDE) and WFPN are further clinicopathologic patterns of intrinsic aging. Clinically, WFPN is characterized by isolated, whitish papules, whereas those of PXE-PDE are yellowish and often coalesce to form "cobblestone" plaques. Our case showed clearly marginated whitish papules. The major histopathologic feature of WFPN is superficial dermal fibrosis with scant elastolysis; in PXE-PDE, there is papillary dermal elastolysis but no sign of fibrosis. No recurrence was performed in the 3 years' follow-up in our case. Surgical treatment may be considered in such cases with well-circumscribed lesions. PMID- 20954819 TI - Thyrotropin receptor-stimulating Graves' disease immunoglobulins induce hyaluronan synthesis by differentiated orbital fibroblasts from patients with Graves' ophthalmopathy not only via cyclic adenosine monophosphate signaling pathways. AB - BACKGROUND: Both expression of the thyrotropin receptor (TSHR) and the production of hyaluronan (HA) by orbital fibroblasts (OF) have been proposed to be implicated in the pathogenesis of Graves' ophthalmopathy (GO). HA is synthesized by three types of HA synthase. We hypothesized that TSHR activation by recombinant human TSH (rhTSH) and TSHR-stimulating Graves' disease immunoglobulins (GD-IgGs) via induced cyclic adenosine monophosphate (cAMP) signaling increases HA synthesis in differentiated OF from GO patients. METHODS: Cultured human OF, obtained during decompression surgery from 17 patients with severe GO, were stimulated in vitro to differentiate into adipocytes. Differentiation was evaluated by phase-contrast microscopy. The differentiated OF were stimulated by rhTSH or by TSHR-stimulating GD-IgG. We measured cAMP using a biochemical assay, HA synthase mRNA expression by quantitative polymerase chain reaction, and HA in the supernatant by enzyme-linked immunosorbent assay. RESULTS: All differentiated OF cultures expressed higher levels of TSHR mRNA than nondifferentiated OF cultures. Stimulation by rhTSH induced a marked cAMP response in 11 of 12 differentiated OF cultures, but no measurable HA response in all but one differentiated OF cultures. By contrast, stimulation by GD-IgG induced a moderate cAMP response in a number of differentiated OF cultures, but a marked HA response in the majority of differentiated OF cultures. CONCLUSION: Stimulation of differentiated OF by GD-IgG, but not by rhTSH, induces HA synthesis in the majority of patients, suggesting that in most patients TSHR mediated cAMP signaling does not play a pivotal role in GD-IgG-induced HA synthesis in differentiated OF cultures. PMID- 20954820 TI - Value of postoperative thyroglobulin and ultrasonography for the indication of ablation and 131I activity in patients with thyroid cancer and low risk of recurrence. AB - BACKGROUND: This study investigated the value of postoperative stimulated thyroglobulin (Tg) combined with neck ultrasonography for the prediction of the posttherapy whole-body scanning (RxWBS) and the efficacy of ablation with 30 mCi 131I in patients with thyroid cancer and low risk of recurrence to identify those who do not require ablation or only need a low 131I activity. METHODS: A total of 237 consecutive patients with well-differentiated thyroid cancer and low risk of recurrence who were initially treated by total thyroidectomy followed by remnant ablation with 1.1 or 3.7 GBq (30 or 100 mCi) 131I were studied. Neck ultrasonography, Tg after levothyroxine withdrawal, and anti-Tg antibodies (TgAb) were obtained before, and RxWBS was performed 7 days after 131I administration. Patients with TgAb were excluded. RESULTS: Postoperative ultrasonography revealed lymph node metastases in 5/237 (2%) patients. RxWBS showed ectopic uptake in 3/232 (1.3%) patients with negative ultrasonography. The negative predictive value of postoperative stimulated Tg <1 ng/mL (n = 132) or <10 ng/mL (n = 213) combined with negative ultrasonography was 100%. Among patients with detectable postoperative stimulated Tg <10 ng/mL and negative ultrasonography, 50 received 1.1 GBq 131I and 31 received 3.7 GBq. In the control assessment, stimulated Tg <1 ng/mL and neck ultrasonography without anomalies were achieved in 47/50 (94%) and in 29/31 patients (93.5%). All patients with stimulated Tg <=1 ng/mL, negative TgAb, and normal ultrasonography before ablation continued to show the same results 8-12 months after initial therapy as expected, irrespective of the administration of 1.1 GBq (n = 82) or 3.7 GBq 131I (n = 50). CONCLUSIONS: Measurement of stimulated Tg combined with neck ultrasonography after total thyroidectomy may exclude the need for ablation in 56% of low-risk patients without TgAb (Tg <1 ng/mL) and permit the administration of an activity of 1.1 GBq 131I in another 34% with low Tg levels. PMID- 20954821 TI - Nasal rhinosporidiosis in humans: new interpretations and a review of the literature of this enigmatic disease. AB - Rhinosporidiosis is a disease caused by Rhinosporidium seeberi which primarily affects the mucosa of the nose, conjunctiva and urethra. While it is endemic in some Asian regions, isolated cases are reported in other parts of the world as a result of the socio-cultural phenomenon of the migration. Its manifestation is a polypoid mass growing inside the affected cavity and the only treatment is surgical excision. Rhinosporidiosis is a condition which both clinicians and microbiologists should keep in mind when managing patients with nasal masses even those from non endemic areas. It is critical in such cases to follow the clinical course to ensure against recurrence of the disease. This study describes the clinical features, diagnosis, and treatment of rhinosporidiosis of the nose and nasopharynx in a series of three cases in East Delhi, India. PMID- 20954822 TI - Intra- and postoperative parathyroid hormone-kinetics do not advocate for autotransplantation of discolored parathyroid glands during thyroidectomy. AB - BACKGROUND: Thyroidectomy continues to pose the risk of typical complications, including postoperative hypocalcemia and permanent hypoparathyroidism. The strategic decision on how to preserve parathyroid hormone (PTH) secretion relies on assessing the viability of the parathyroid glands (PGs). The aim of this study was to assess parathyroid discoloration as an indicator for loss of parathyroid function. METHODS: The prospective study included 29 patients (24 women, 5 men; age 53.2 +/- 13.0 years) who underwent near-total or total thyroidectomy. An intra- and postoperative PTH and calcium monitoring was performed. The intraoperative situs of the PGs was documented by a study protocol. The patients were grouped in three categories: group A, 12 patients with four visualized and normally colored PGs; group B, 13 patients with four visualized and three or four discolored PGs; group C, 4 patients who had undergone autotransplantation of two PGs. RESULTS: Compared to group A, groups B and C showed sharper intraoperative PTH declines. PTH values recovered more quickly in group B than in group C. However, no significant differences in PTH kinetics were found in the general linear model for repeated measures (p = 0.132). However, a significantly higher incidence of protracted hypocalcemia-related symptoms for more than 14 postoperative days was found for group C (50.0%) than for groups A (0%) and B (0%; p = 0.011). None of the patients developed permanent hypoparathyroidism. CONCLUSIONS: The function of discolored PGs is only transiently impaired and recovers within a short time after surgery. Our observations do not support autotransplantation as a generally applicable first-line intervention for discolored PGs in the absence of other criteria for autotransplantation. PMID- 20954823 TI - Cyclophosphamide-induced leakage of gastrointestinal ammonia into the common bloodstream in rats. AB - The kinetics of ammonia of gastrointestinal origin has been studied in rats in hematopoietic or neurovascular forms of acute lethal cyclophosphamide intoxication. Portal and caval blood ammonia, glutamine and urea, and blood markers of cytolysis were determined, and transperitoneal ammonia and glutamine fluxes were estimated after the single high-dose cyclophosphamide intraperitoneal (i.p.) administration. Within 3 hours after the administration of cyclophosphamide (200, 600, or 1,000 mg/kg), the portal ammonia level increased 1.4, 1.8, and 2.5 times, respectively; the ammonia level in v. cava caud. caudally of vv. renales inflow increased 1.5, 2.1, and 3.3 times, and cranially of vv. hepaticae, 1.8, 2.7, and 4.2 times, respectively; glutamine:ammonia and urea:ammonia ratios decreased. The rate of ammonia and glutamine accumulation in saline solution injected i.p. exceeded that in control rats dose dependently. At 18 hours after the administration of cyclophosphamide, the increased blood ammonia, glutamine and urea, and glutamine:ammonia ratio persisted. Therefore, in the rat, the high-dose i.p. administration of cyclophosphamide induces the early hyperammonemia, resulting from the enhanced transperitoneal diffusion of gastrointestinal ammonia into the blood, combined with the restriction of glutamine and urea synthesis. These alterations may contribute to neurological complications of myelosuppressive therapeutic regimens of cyclophosphamide administration. PMID- 20954824 TI - Age modifies the response to recombinant human thyrotropin. AB - BACKGROUND: A standardized protocol is used to administer recombinant human thyrotropin (rhTSH) in preparation for diagnostic studies and treatment in patients with thyroid cancer. The expectation is that serum TSH concentrations will peak on the day after the second injection and will be sufficiently elevated to stimulate uptake of radioiodine. We wished to test the hypothesis that TSH concentrations achieved after rhTSH injection are influenced by age. METHODS: Patients with thyroid cancer undergoing diagnostic radioiodine scanning were identified by chart review. Serum TSH concentrations were documented 24 and 72 hours after two rhTSH injections (days 3 and 5, respectively). Responses were subdivided into four ascending patient age groups: <35, 35-49, 50-64, and >64 years. TSH concentrations after rhTSH administration were documented according to patient age. RESULTS: There was a significant correlation between the serum TSH concentrations at both days 3 and 5 and patient age (p < 0.0001). None of the other factors examined (gender, menopausal status, weight, body mass index, baseline TSH, serum creatinine, and estimated glomerular filtration rate) were significant in multivariate analyses. The mean TSH concentration on day 3 increased significantly when patients were divided into the aforementioned groups of ascending age (96, 107, 142, and 196 mIU/L, p < 0.0001). Day 5 concentrations increased in a similar manner. CONCLUSIONS: Both days 3 and 5 TSH concentrations were higher in older individuals after rhTSH administration. This finding did not appear to be related to body weight, body mass index, or glomerular filtration rate in a simple manner. The TSH concentration achieved may be a result of complex interactions between distribution within fat and muscle body compartments, hepatic function, and renal function. Prospective studies could examine whether the magnitude of the TSH elevation after rhTSH administration affects diagnostic or therapeutic efficacy. PMID- 20954826 TI - Regional variations in palliative care: do cardiologists follow guidelines? AB - OBJECTIVES: Regional variation in health care use in the last 6 months of life is well documented. Our objective was to examine whether an association exists between cardiologists' tendencies to discuss palliative care for patients with advanced heart failure and the regional use of health care in the last 6 months of life. METHODS: We performed a national mail survey of a random sample of 994 eligible Cardiologists from the American Medical Association Masterfile. Hypothetical patient scenarios were used to explore physician management of patient scenarios. RESULTS: We received 614 responses (response rate: 62%). In a 75-year-old with symptomatic chronic heart failure and asymptomatic nonsustained ventricular tachycardia, cardiologists in regions with high use in the last 6 months of life were less likely to have discussions about palliative care (23% versus 32% for comparisons between the highest and lowest quintiles, p = 0.04). Similarly, in an 85 year-old with symptomatic chronic heart failure and an acute exacerbation, cardiologists in high use regions were less likely to have discussions about palliative care (35% versus 47%, p = 0.0008). CONCLUSIONS: Despite professional guidelines suggesting that cardiologists discuss palliative care with patients with late stage heart failure, less than half of cardiologists would discuss palliative care in two elderly patients with late-stage heart failure and this guideline discordance was worse in the regions with more health care use in the last 6 months of life. PMID- 20954827 TI - Effects of erdosteine on cyclosporine-A-induced hepatotoxicity in rats. AB - Cyclosporine A (CsA) is a potent immunosuppressive agent used for organ transplantations and various autoimmune disorders. However, hepatotoxicity due to CsA remains one of the major side effects. The use of antioxidants reduces the adverse effects of CsA. The aim of this study was to determine the protective effects of erdosteine on CsA-induced liver injury through tissue oxidant/antioxidant parameters and to evaluate light microscopic alterations in rat-liver tissues. Rats were randomly divided into four experimental groups: The control group received sunflower oil (2 mL/kg/day, per orally; p.o.), while the other groups were treated with CsA (25 mg/kg/day, p.o.) or erdosteine (10 mg/kg/day, p.o.) or CsA+erdosteine, respectively. Serum aspartate aminotransferase and alanine aminotransferase levels, tissue malondialdehyde and nitric oxide levels, and superoxide dismutase, glutathione peroxidase and catalase enzyme activities were measured. Histological examination was performed. CsA caused a significant deterioration in the hepatic function tests, morphology, and gave rise to severe oxidative stress in the liver. Erdostein significantly improved the functional and histological parameters and attenuated the oxidative stresss induced by CsA. Erdostein protects liver tissue against oxygen free radicals and prevents hepatic dysfunction and morphological abnormalities associated with chronic CsA administration. PMID- 20954828 TI - Prevalence and predictors of parental grief and depression after the death of a child from cancer. AB - PURPOSE: To investigate patterns of grief and depression in a sample of parents whose child had died of cancer, and to examine factors related to burden of illness and end-of-life care as potential predictors of parental grief and depression outcomes. METHODS: Fifty-eight parents completed standardized self report questionnaires measuring prolonged grief disorder (Inventory of Complicated Grief-Revised [ICG-R]) and depression (Beck Depression Inventory Second Edition [BDI-II]) and participated in structured interviews designed to elicit their perceptions of their child's end-of-life care and burden of illness. The majority of participants were mothers (84%) and the mean length of time since child death was 4.5 (standard deviation [SD] = 2.4) years (range, 1.0-9.8 years). RESULTS: Rates of prolonged grief disorder (PGD) were similar to those reported in other bereaved populations (10.3%); however, 41% of parents met diagnostic criteria for grief-related separation distress. Twenty-two percent of parents reported clinically significant depressive symptoms. Time since death and parental perception of the oncologist's care predicted parental grief symptoms but not depressive symptoms. Perceptions of the child's quality of life during the last month, preparedness for the child's death, and economic hardship also predicted grief and depression outcomes. CONCLUSIONS: A minority of parents met criteria for PGD and depression, however, almost half the sample was experiencing significant separation distress associated with persistent longing and yearning for their child. Time since death is a significant predictor of parental psychological distress. This study also highlights the importance of end-of-life factors in parents' long-term adjustment and the need for optimal palliative care to ensure the best possible outcomes for parents. PMID- 20954829 TI - Cell-based vascularization strategies for skin tissue engineering. AB - Providing a blood-vascular network to promote survival and integration of cells in thick dermal substitutes for application in full-thickness wounds is essential for the successful outcome of skin tissue engineering. Nevertheless, promoting vascularization also represents a critical bottleneck in today's skin tissue engineering practice. Several cell types have been considered and tested, mostly in preclinical studies, to increase vascularization. When the clinical situation allows delayed reconstruction of the defect, an autologous approach is preferable, whereas in acute cases allogeneic therapy is needed. In both cases, the cells should be harvested with minimal donor-site morbidity and should be available in large amounts and safe in terms of tumor formation and transmission of animal diseases. Here, we outline the different mechanisms of cell-based vascularization and subsequently elaborate in more detail on the candidate cell types and their pros and cons in terms of clinical application and regulation of the wound healing process. PMID- 20954830 TI - MG132, a proteasome inhibitor-induced calf pulmonary arterial endothelial cell growth and death, are changed by MAPK inhibitors. AB - MG132, as a proteasome inhibitor, has been shown to induce apoptotic cell death through the formation of reactive oxygen species (ROS). In this study, we investigated the effects of MAPK inhibitors on MG132-treated calf pulmonary artery endothelial cells (CPAECs) in relation to cell death, ROS, and glutathione (GSH). MG132 inhibited the growth of CPAEC and also induced apoptosis, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). MG132 increased ROS levels and GSH-depleted cell numbers in CPAEC. Treatment with MAPK (MEK, JNK, and p38) inhibitors showed a slight enhancement of cell-growth inhibition by MG132. All the MAPK inhibitors decreased cell death by MG132. Especially, the JNK inhibitor showed a strong effect. They all did not affect ROS levels and GSH depletion in MG132-treated CPAEC, but increased ROS and GSH levels in MG132-untreated CPAEC. In conclusion, MG132 induced apoptosis in CPAEC, which was accompanied by ROS increase and GSH depletion. The changes of MG132-induced CPAEC growth inhibition and death by MAPK inhibitors were not tightly correlated to ROS and GSH levels. PMID- 20954831 TI - Short communication: Transmitted drug resistance and molecular epidemiology in antiretroviral naive HIV type 1-infected patients in Rhode Island. AB - Transmission of HIV-1 drug resistance has important clinical and epidemiological consequences including earlier treatment failure and forward transmission of resistance strains in high-risk groups. To evaluate the prevalence and molecular epidemiology of transmitted drug resistance in Rhode Island, we collected genotypic, demographic, clinical, and laboratory data from treatment-naive individuals presenting to the largest outpatient HIV clinic in the state from January 2007 to November 2007. Sequences from 35 treatment-naive individuals were available, 83% of whom were men who had sex with men (MSM). All sequences were HIV-1 subtype B. Drug resistance mutations were identified in 7/35 [20%; 95% confidence interval (CI), 0.08-0.37] patients, six of whom had K103N. Two phylogenetic transmission clusters were found, involving 17% (6/35) of individuals, three in each cluster. We did not find an association between belonging to a cluster and age, gender, AIDS-defining illness, CD4 cell count, or viral load. Drug resistance mutations were more commonly observed in transmission clusters (p = 0.08). Individuals in one cluster all had K103N and were MSM who had attended local bathhouses. Individuals forming clusters were significantly more likely to have visited a bathhouse compared to nonclusters (p = 0.02). The prevalence of transmitted drug resistance in Rhode Island is high, further justifying genotypic testing on presentation to care and prior to treatment initiation. Molecular epidemiological analysis and association of resistance with phylogenetic networks using data obtained for clinical purposes may serve as useful tools for the prevention of drug resistance transmission and for contact tracing. PMID- 20954832 TI - Evaluation of thiol-based antioxidant therapeutics in cystic fibrosis sputum: Focus on myeloperoxidase. AB - Neutrophil-dependent reactions catalysed by myeloperoxidase (MPO) are thought to play important roles in the pulmonary pathobiology of cystic fibrosis (CF). Aerosolized thiol antioxidants such as glutathione (GSH) and N-acetylcysteine (NAC) are currently being utilized as therapeutics to modify CF respiratory tract oxidative processes. This study hypothesized that MPO in CF airway lining fluids may be a target of such therapeutics. MPO activity in sputum from 21 adult CF patients was found to be inversely associated with lung function (FEV(1)). In contrast, systemic inflammation (assessed by plasma C-reactive protein) was not correlated with lung function. Ex vivo studies revealed that GSH and NAC effectively scavenged N-chloramines in sputum and inhibited sputum MPO activity with potency exquisitely dependent upon MPO activity levels. Detailed kinetic analyses revealed that NAC and GSH inhibit MPO by distinct mechanisms. Activation of the key pro-inflammatory transcription factor NF-kappaB in cultured HBE1 cells was inhibited by GSH. The findings reveal that MPO activity and its reactive products represent useful predictors of the doses of inhaled thiol antioxidants required to ameliorate airway oxidative stress and inflammation in CF patients and provide mechanistic insight into the antioxidative/anti-inflammatory mechanisms of action of GSH and NAC when administered into the CF lung. PMID- 20954833 TI - Effect of Apocynin, an inhibitor of NADPH oxidase, in the inflammatory process induced by an experimental model of spinal cord injury. AB - NADPH-oxidase is an enzyme responsible for reactive oxygen species production, and inhibition of this enzyme represents an attractive therapeutic target for the treatment of many diseases. The aim of this study was to investigate the effects of Apocynin, NADPH-oxidase inhibitor, in the modulation of secondary injury in the spinal cord. The injury was induced by application of vascular clips to the dura via a four-level T5-T8 laminectomy in mice. Treatment with Apocynin 1 and 6 h after the trauma significantly decreased (1) the degree of spinal cord inflammation and tissue injury, (2) neutrophil infiltration, (3) adhesion molecule expression, (4) nuclear transcription factor-kappaB expression, (5) nitrotyrosine and poly-ADP-ribose formation, (6) pro-inflammatory cytokines production, (7) apoptosis and (8) mitogen-activated protein kinase activation. Moreover, Apocynin significantly ameliorated the loss of limb function (evaluated by motor recovery score). Thus, it is proposed that Apocynin may be useful in the treatment of inflammation associated with spinal cord trauma. PMID- 20954834 TI - Determination of mean recency period for estimation of HIV type 1 Incidence with the BED-capture EIA in persons infected with diverse subtypes. AB - The IgG capture BED enzyme immunoassay (BED-CEIA) was developed to detect recent HIV-1 infection for the estimation of HIV-1 incidence from cross-sectional specimens. The mean time interval between seroconversion and reaching a specified assay cutoff value [referred to here as the mean recency period (omega)], an important parameter for incidence estimation, is determined for some HIV-1 subtypes, but testing in more cohorts and new statistical methods suggest the need for a revised estimation of omega in different subtypes. A total of 2927 longitudinal specimens from 756 persons with incident HIV infections who had been enrolled in 17 cohort studies was tested by the BED-CEIA. The omega was determined using two statistical approaches: (1) linear mixed effects regression (omega(1)) and (2) a nonparametric survival method (omega(2)). Recency periods varied among individuals and by population. At an OD-n cutoff of 0.8, omega(1) was 176 days (95% CL 164-188 days) whereas omega(2) was 162 days (95% CL 152-172 days) when using a comparable subset of specimens (13 cohorts). When method 2 was applied to all available data (17 cohorts), omega(2) ranged from 127 days (Thai AE) to 236 days (subtypes AG, AD) with an overall omega(2) of 197 days (95% CL 173-220). About 70% of individuals reached a threshold OD-n of 0.8 by 197 days (mean omega) and 95% of people reached 0.8 OD-n by 480 days. The determination of omega with more data and new methodology suggests that omega of the BED-CEIA varies between different subtypes and/or populations. These estimates for omega may affect incidence estimates in various studies. PMID- 20954835 TI - Induction of in situ DNA double-strand breaks and apoptosis by 200 MeV protons and 10 MV X-rays in human tumour cell lines. AB - PURPOSE: To clarify the properties of clinical high-energy protons by comparing with clinical high-energy X-rays. MATERIALS AND METHODS: Human tumor cell lines, ONS76 and MOLT4, were irradiated with 200 MeV protons or 10 MV X-rays. In situ DNA double-strand breaks (DDSB) induction was evaluated by immunocytochemical staining of phosphorylated histone H2AX (gamma-H2AX). Apoptosis was measured by flow-cytometry after staining with Annexin V. The relative biological effectiveness (RBE) was obtained by clonogenic survival assay. RESULTS: DDSB induction was significantly higher for protons than X-rays with average ratios of 1.28 (ONS76) and 1.59 (MOLT4) at 30 min after irradiation. However the differences became insignificant at 6 h. Also, apoptosis induction in MOLT4 cells was significantly higher for protons than X-rays with an average ratio of 2.13 at 12 h. However, the difference became insignificant at 20 h. RBE values of protons to X-rays at 10% survival were 1.06 +/- 0.04 and 1.02 +/- 0.15 for ONS76 and MOLT4, respectively. CONCLUSIONS: Cell inactivation may differ according to different timings and/or endpoints. Proton beams demonstrated higher cell inactivation than X-rays in the early phases. These data may facilitate the understanding of the biological properties of clinical proton beams. PMID- 20954836 TI - Albumin level and stroke. Potential association between lower albumin level and cardioembolic aetiology. AB - BACKGROUND: Lower level of albumin was related to worse prognosis of stroke and clinical trials showed that albumin therapy reduced mortality. However, stroke is heterogeneous and differences in the baseline concentration of albumin among subtypes of stroke were not assessed. The aim was to assess albumin level in patients with ischemic stroke classified by mechanism. METHODS: Prospective controlled clinical study, including 200 patients with ischemic stroke and 50 controls. Patients were classified following Trial of ORG 10172 in Acute Stroke Treatment criteria. Plasma levels of albumin, fibrinogen, D-dimer, and C-reactive protein were assessed during 48 hr after admission. The National Institutes of Health Stroke Scale (NIHSS) on admission, in-hospital mortality, and Rankin score on discharge were recorded. Dependence was defined as mRS > 2. RESULTS: Patients with cardioembolic stroke showed significantly higher D-dimer and lower albumin. Mortality was related to higher NIHSS, higher D-dimer, lower albumin, and cardioembolic aetiology. Dependence was strongly related to lower albumin and higher NIHSS. LOGISTIC REGRESSION: The cardioembolic aetiology (OR 0.101, 95% CI 0.010-1.007, p = .051) and the higher NIHSS score (OR 0.871, 95% CI 0.758-1.002, p = .053) were related to mortality; NIHSS (OR 1.560, 95% CI 1.323-1.838, p < .0001) and older age (OR 1.052, 95% CI 1.012-1.093, p = .010) were independently related to dependence. DISCUSSION: Patients with cardioembolic stroke showed lower albumin and higher risk of mortality than non-cardioembolic ones. Lower mean level of albumin was related to mortality and dependence in all patients. Reduced albumin may be a marker of chronic systemic inflammation, which may be the mechanism for cardiopathy and bad outcome of stroke. In addition, direct effects on ischemic tissue were suggested in experimental models. PMID- 20954837 TI - Low avidity and level of serum anti-Abeta antibodies in patients with cerebral amyloid angiopathy-related cerebral hemorrhage. AB - Cerebral amyloid angiopathy (CAA) is characterized by the deposition of the beta amyloid protein (Abeta) in small cerebral vessels, which is considered a common cause of intracerebral hemorrhage (CAAH) in elderly people. Little is known about the properties of serum naturally occurring anti-Abeta antibodies in patients with CAAH. We investigated the avidity and levels of anti-Abeta antibodies in 20 patients and 20 age-matched healthy controls by an enzyme-linked immunosorbent assay with thiocyanate elution. Our study revealed that both the levels and the avidity of these endogenous anti-Abeta antibodies were lower in patients with CAAH than in controls, which may be a new mechanism for the impaired clearance of cerebral Abeta and have important implications for the development of immune based therapeutic strategies for CAA. PMID- 20954838 TI - Low calcitonin receptor like receptor expression in endometrial vessels from women with unexplained infertility. AB - Adrenomedullin (AM) and its receptor subunit, calcitonin receptor-like receptor (CLR) are known to be important for endothelial function. The genotypes and phenotypes of AM and CLR in the endometrium were studied in relation to unexplained infertility. Endometrial biopsies from 12 fertile and 11 infertile women and blood samples from 156 fertile and 106 infertile women were collected. Protein and mRNA expression of AM and CLR was determined using immunohistochemistry and real time PCR. Allele and genotype frequencies in the AM (rs4399321 and rs7944706) and CLR genes (rs696574, rs1528233 and rs3771073) were performed using Taqman genotyping assays. Unexplained infertility was characterised by lower number of vessels stained with CLR in endometrium compared to fertile controls. There was no difference in AM expression. This could not be explained by SNP analysis in the AM or CLR genes. Imbalance in the AM/CLR system might alter endothelial function in women with unexplained infertility. PMID- 20954839 TI - Prevalence of genotypic resistance to antiretroviral drugs in treatment-naive youths infected with diverse HIV type 1 subtypes and recombinant forms in Dar es Salaam, Tanzania. AB - As human immunodeficiency virus (HIV) diversity may have an impact on both vaccine efficacy and drug resistance, it is important to have knowledge of circulating genetic variants. With widespread use of antiretroviral (ARV) drugs in Africa, one of the major potential challenges is the risk of emergence of ARV drug-resistant HIV strains. This study aimed to determine the circulating HIV subtypes and recombinant forms, as well as the prevalence of ARV drug resistance mutations, among 75 treatment-naive HIV-infected youths in Dar es Salaam, Tanzania. Gag (n = 48), partial pol (n = 44), and partial env (n = 35) sequencing was performed; all three regions were sequenced in 26 samples. Evidence of infection with recombinant viruses was found in 12 (46%) participants; AC recombinants were the most commonly detected and they were identified in six (23%) participants. Of individuals infected with nonrecombinant strains, subtype A was most commonly detected in seven (27%) participants, followed by subtype C detected in six (23%) participants and subtype D detected in one (4%) participant. Among the pol sequences from 44 individuals, three (7%) had resistance to nucleoside reverse transcriptase (RT) inhibitors and four (9%) had nonnucleoside RT inhibitor resistance mutations. Of these, three (7%) individuals were infected with viruses with cross-resistance mutations to both classes of RT inhibitors. These resistant mutations were all associated with drugs currently used in first-line therapy and in the prevention of vertical transmission. This high prevalence of resistance mutations is of considerable concern in apparently drug-naive populations as it may result in treatment failure and the spread of ARV-resistant strains. PMID- 20954841 TI - Combination of intra-bone marrow-bone marrow transplantation and subcutaneous donor splenocyte injection diminishes risk of graft-versus-host disease and enhances survival rate. AB - The combination of allogeneic bone marrow transplantation (allo-BMT) and donor lymphocyte infusion (DLI) is a useful method for establishing donor chimerism and preventing a relapse of leukemia/lymphoma. However, there is a risk of inducing uncontrollable fatal graft-versus-host disease (GVHD). In fact, allo-BMT plus intravenous (IV)-DLI using donor splenocytes induces fatal GVHD in recipient mice. In this study, we examined the effects of the combination of intra-bone marrow (IBM)-BMT and the subcutaneous injection of donor splenocytes (SC-DLI) on the allo-BMT system. Recipient BALB/c mice were conditioned by sublethal irradiation (5 Gy), followed by IBM-BMT plus IV-DLI or SC-DLI in C57BL/6 mice. The IV-DLI group showed better engraftment of donor hemopoietic cells than the control group (without DLI) but showed fatal GVHD. The SC-DLI group, however, showed good reconstitution and mild GVHD. These results suggest that the combination of SC-DLI and IBM-BMT promotes the reconstitution of hemopoiesis and helps reduce the risk of GVHD. PMID- 20954843 TI - Immunocompromise as major risk factor for necrotising infections of orbital and ocular adnexa caused by Pseudomonas aeruginosa. PMID- 20954840 TI - Comparison of methods to detect HIV dual infection. AB - Current methods to detect intraclade HIV dual infection are poorly suited for determining its prevalence in large cohorts. To investigate the potential of ultra-deep sequencing to screen for dual infection, we compared it to bulk sequence-based synonymous mixture index and the current standard of single genome sequencing. The synonymous mixture index identified samples likely to harbor dual infection, while ultra-deep sequencing captured more intra-host viral diversity than single genome sequencing at approximately 40% of the cost and 20% of the laboratory and analysis time. The synonymous mixture index and ultra-deep sequencing are promising methods for rapid and cost-effective systematic identification of HIV dual infection. PMID- 20954844 TI - Radiological signs of periorbital trauma - the Singapore experience. AB - PURPOSE: To describe the radiological signs and demographic characteristics of patients who suffered facial trauma in South-East Asia. MATERIALS AND METHODS: This is a retrospective cross-sectional study of a 399 patients who presented with facial trauma over a 2-year period in a tertiary referral centre in South East Asia. Patients with available CT scan films were included. Demographics, bony and soft tissue radiology characteristics were analyzed. RESULTS: Male to female ratio was 320 (80%):79 (20%). Most of the facial trauma was due to Road Traffic Accident. Of 399 patients, 273 (68%) showed radiological signs of bone or soft tissue trauma. Of these 273 patients, left to right side involvement was 114 (41.7%) / 82 (30.03%), and 77 (28.2%) had bilateral involvement. Floor was the most involved wall (229[83.8%]) and the most involved rim was the inferior rim (164[60.07%]). There were 39 (14.2%) patients with blowout fracture. Bony nasolacrimal duct was broken in 56 (20.5%) patients. Optic canal fracture was found in 7 (2.5%) patients and it was associated with roof and superior rim fracture (P-values were 0.016, 0.046, respectively). Thirty-three (12.08%) patients had radiological signs of extraocular muscle involvement. Traumatic intracranial signs were associated with roof and superior rim fractures (P < 0.001 for both). CONCLUSION: Floor and inferior rim were the most affected orbital structures in facial trauma. We described radiological risk factors association with optic canal, NLD fracture and intracranial involvement. We described extraocular muscle morphological signs, which could alert to the possibility of orbital floor fracture in equivocal cases. PMID- 20954845 TI - Our experience with the masquerade procedure for total eyelid loss. AB - PURPOSE: To describe our experience of the Masquerade Procedure, a historical procedure that is poorly described in the modern literature. METHODS: We performed a masquerade procedure in two complex surgical cases where traditional methods of eyelid reconstruction or closure were not possible. The first case suffered a partial de-gloving injury with a right sided anterior exenteration and loss of the upper and lower eyelids. On the left side, he lost the lower forehead and brow as well as the entire left upper eyelid leaving superior bulbar conjunctiva only. The cornea of the left eye was completely exposed and required urgent coverage. The second case was involved in a light aircraft crash and suffered extensive facial burns with periocular involvement bilaterally. On the left side, there was complete loss of the upper and lower eyelids and fornices extending to the bulbar conjunctiva. The cornea was keratinized and vascularised due to chronic exposure. RESULTS: In the first patient, poor eyelid closure led to corneal ulceration and scarring. A repeat procedure involved the use of a cheek rotation flap, and ultimately the fashioning of a small port-hole aperture inferiorly to avoid corneal exposure. The patient maintains navigational vision. The second patient had two attempts at a masquerade procedure, however the poor blood supply led to complete and partial failure of the first and second procedures respectively. CONCLUSION: The masquerade procedure may be considered in extreme circumstances, however in our experience, multiple interventions and further reconstructive surgery may subsequently be required. PMID- 20954846 TI - A lentiviral strategy for highly efficient retrograde gene transfer by pseudotyping with fusion envelope glycoprotein. AB - The lentiviral vector system based on human immunodeficiency virus type 1 (HIV-1) is used extensively in gene therapy trials of neurological and neurodegenerative diseases. Retrograde axonal transport of viral vectors offers a great advantage to the delivery of genes into neuronal cell bodies that are situated in regions distant from the injection site. Pseudotyping of HIV-1-based vectors with selective variants of rabies virus glycoprotein (RV-G) increases gene transfer via retrograde transport into the central nervous system. Because large-scale application for gene therapy trials requires high titer stocks of the vector, pseudotyping of a lentiviral vector that produces more efficient retrograde transport is needed. In the present study, we developed a novel vector system for highly efficient retrograde gene transfer by pseudotyping an HIV-1 vector with a fusion envelope glycoprotein (termed FuG-B) in which the cytoplasmic domain of RV G was substituted by the corresponding part of vesicular stomatitis virus glycoprotein. The FuG-B pseudotype shifted the transducing property of the lentiviral vector and enhanced the retrograde transport-mediated gene transfer into different brain regions innervating the striatum with greater efficiency than that of the RV-G pseudotype in mice. In addition, injection of the FuG-B pseudotyped vector into monkey striatum (caudate and putamen) allowed for highly efficient gene delivery into the nigrostriatal dopamine system, which is a major target for gene therapy of Parkinson's disease. Our strategy provides a powerful tool for the treatment of certain neurological and neurodegenerative diseases by promoting retrograde gene delivery via a lentiviral vector. PMID- 20954847 TI - p38 mitogen activated protein kinase controls two successive-steps during the early mesodermal commitment of embryonic stem cells. AB - Embryonic stem (ES) cells differentiate in vitro into all cell lineages. We previously found that the p38 mitogen activated kinase (p38MAPK) pathway controls the commitment of ES cells toward either cardiomyogenesis (p38 on) or neurogenesis (p38 off ). In this study, we show that p38alpha knock-out ES cells do not differentiate into cardiac, endothelial, smooth muscle, and skeletal muscle lineages. Reexpression of p38MAPK in these cells partially rescues their mesodermal differentiation defects and corrects the high level of spontaneous neurogenesis of knock-out cells. Wild-type ES cells were treated with a p38MAPK specific inhibitor during the differentiation process. These experiments allowed us to identify 2 early independent successive p38MAPK functions in the formation of mesodermal lineages. Further, the first one correlates with the regulation of the expression of Brachyury, an essential mesodermal-specific transcription factor, by p38MAPK. In conclusion, by genetic and biochemical approaches, we demonstrate that p38MAPK activity is essential for the commitment of ES cell into cardiac, endothelial, smooth muscle, and skeletal muscle mesodermal lineages. PMID- 20954848 TI - Association of CD1A +622 T/C, +737 G/C and CD1E +6129 A/G genes polymorphisms with multiple sclerosis. AB - Antibodies and specific T cells to glycolipids have been found in MS patients. CD1 molecules are involved in presentation of lipid antigens to T-cells. Therefore, functional polymorphisms in two CD1 genes (+622 T/C and +737 G/C in CD1A along with +6129 A/G in CD1E) might be associated with susceptibility to MS. First, 351 MS patients and 342 controls were enrolled in this study. Allele specific oligonucleotide polymerase chain reaction and PCR-RFLP methods were used for genotyping. The frequency of CD1A genotypes was not different between cases and controls. However, investigating females, the frequency of CD1A*01 allele was significantly higher in patients with PP-MS compared to controls (p = 0.028) as well as to RR-MS and SP-MS (p = 0.042 and 0.021, respectively). The distribution of CD1E +6129 A allele (CD1E*01) and CD1E*01/01 genotype is more frequent in normal controls in comparison with MS patients (p = 0.001 and p = 0.0003, respectively). In addition, after categorization of study groups according to disease types, differences between alleles and genotypes of CD1E gene polymorphism remained significant for RR-MS patients compared to those of normal controls (p = 0.0001 and p = 0.0003, respectively). CD1E and CD1A genes may be involved in networks which determine susceptibility to RR-MS and PP-MS, respectively. PMID- 20954849 TI - Effect of ibuprofen on bilirubin-albumin binding affinity in premature infants. AB - AIM: To evaluate the effect of ibuprofen on bilirubin-albumin binding affinity and unbound bilirubin in premature infants. STUDY DESIGN: A prospective study with subjects serving as their own controls was performed on <30 weeks' gestational age infants with unconjugated hyperbilirubinemia and who received ibuprofen for patent ductus arteriosus. Infants with congenital malformation, TORCH infections, and conjugated hyperbilirubinemia were excluded. Total serum bilirubin (TSB) and unbound bilirubin (modified peroxidase test) were measured prior to (baseline) and after (follow-up) initiation of ibuprofen. The bilirubin/albumin equilibrium association binding constant was calculated using albumin, TSB, and unbound bilirubin. RESULTS: Ten infants were studied. The mean TSB between baseline (5.9+/-1.7 mg/dL) was higher than that at follow-up [4.9+/ 1.7 mg/dL]. Mean unbound bilirubin at baseline (0.75+/-0.65 MUg/dL) was similar to that at follow-up (0.63+/-0.46 MUg/dL). No difference existed between mean baseline binding constant (49+/-50 L/MUmol) and that at follow-up (44+/-36 L/MUmol). The ratio of unbound bilirubin with and without ibuprofen, index of displacing effect, was 0.88 (95% CI 0.63-1.14). CONCLUSIONS: Ibuprofen may not be associated with bilirubin displacing effect in relatively stable premature infants with mild to moderate unconjugated hyperbilirubinemia. PMID- 20954850 TI - Do uterotrophic drugs increase the risk of fatal hemorrhagic brain stroke? AB - OBJECTIVE: To evaluate whether uterotrophic agents increase the risk of fatal hemorrhagic brain stroke. METHODS: Between 1991 and 1992, there were 230 maternal deaths among 2,420,000 pregnant women in Japan and the causes of these deaths was investigated in 1994. Using information provided in this report, we identified 35 women who died from or were assumed to die from hemorrhagic brain stroke. We assumed that 93% of women would have tried vaginal delivery. The risk of fatal hemorrhagic brain stroke after uterotrophic agent use was calculated according to the assumption that 5.0-40% of women received uterotrophic agents. RESULTS: Use of uterotrophic agents for induction/augmentation of labor was confirmed in five (14.3%) of the 35 women who died from hemorrhagic brain stroke. The incidence of fatal brain stroke after the use of uterotrophic agents was only significantly higher than that for spontaneous hemorrhagic brain stroke if these agents were administered in <= 6.0% of women. CONCLUSIONS: Because more than 6.0% of women received uterotrophic agents, these agents are unlikely to increase the risk of fatal hemorrhagic brain stroke. PMID- 20954851 TI - Twins are a risk factor for developing severe hypertensive disorders in the puerperium following a normotensive pregnancy. PMID- 20954852 TI - Parental factors affecting the weights of the placenta and the offspring. AB - AIM: To determine parental, especially paternal factors associated with the weight of the placenta and offspring. METHODS: This population-based birth-cohort study includes 2947 singleton children born from April 2006 to 2007 and living in Drenthe, The Netherlands. Placental weight and birth weight were measured and questionnaires were filled out for this cohort. Associations between parental factors, and the weight of the placenta and the offspring were evaluated using univariate and multivariate linear regression models. RESULTS: Univariate regression revealed that the paternal birth weight and body mass index (BMI) of the father were predictors for placental and birth weight of the offspring. However, they were not independent predictors. Independent predictors for placental weight were the maternal factors of pre-pregnancy BMI, birth weight, and diabetes. The maternal factors of weight gain during pregnancy, birth weight, smoking during pregnancy, and diabetes were independent predictors for birth weight of the offspring. CONCLUSION: Paternal as well as maternal factors influence the weight of the placenta and the offspring. PMID- 20954853 TI - NCI classification of thrombocytopenia in extremely preterm neonates and its association with mortality and morbidity. AB - BACKGROUND: Thrombocytopenia (TP) is a common finding among preterm neonates and has been associated with mortality and morbidities. Yet, there is no consistent classification for neonatal TP. TP in adults has recently been graded by the National Cancer Institute (NCI) Common Toxicity Criteria and has been shown to predict clinical outcomes. OBJECTIVE: To use the NCI classification for TP in preterm neonates and elucidate its association with clinical outcomes. METHODS: Retrospective chart review was done on neonates born at gestational age (GA) <=28 weeks and survived for >=7 days. TP was classified as per NCI guidelines at 7 days and 28 days of age and their association with mortality, major morbidities and hospital length of stay (LOS) were investigated. RESULTS: A total of 286 patients were included in the study with a mean GA of 26.3+/-1.5 weeks and birth weight of 899+/-215 g. NCI TP grades at 7 days were significantly (P<0.001) associated with mortality, LOS, intraventricular hemorrhage and Gram negative infections. In addition to these outcomes, necrotizing enterocolitis, Gram positive and fungal infections were also significantly associated with NCI TP grades at 28 days. CONCLUSIONS: Classification of TP using the NCI criteria in extreme preterm neonates is clinically applicable. This grading system of platelet counts is significantly associated with mortality, morbidity and LOS in preterm neonates. PMID- 20954854 TI - Abdominal circumference ratio for the diagnosis of intertwin birth weight discordance. AB - OBJECTIVES: We assessed the accuracy of predicting severe twin birth weight discordance (>25%) using the estimated fetal weights (EFW) and abdominal circumference (AC) ratio. METHOD: A cohort of twin gestations underwent ultrasound examinations within two weeks from birth. We focused on the accuracy of EFW and on the diagnosis of severe birth weight discordance by the difference in EFWs and the AC ratio. RESULTS: The 661 eligible twin pairs included 51 (7.7%) severely discordant pairs. The accuracy of an EFW to predict the actual birth weight was quite poor, with an acceptable specificity (96.4%), but low sensitivity (28.6-40.5%), to detect severely discordant pairs, whereas an AC ratio of 1.3 detected these discordant pairs with sensitivity and specificity of 97.3-100% and 99.6-99.7%, respectively. CONCLUSION: By comparing EFWs, 59.5-71.4% of discordant pairs >25% are missed, whereas an AC ratio >1.3 would identify almost all cases. PMID- 20954855 TI - Expression of soluble Fas in the cerebrospinal fluid of preterm infants with posthemorrhagic hydrocephalus and cystic white matter damage. AB - Perinatal brain damage may result in impaired neurological development in extremely preterm infants. The underlying pathophysiological mechanisms are complex, and biomarkers of prognostic value are not available. The aim of this study was to analyze soluble Fas (sFas) concentrations in the cerebrospinal fluid (CSF) representative for involvement of apoptotic processes in preterm infants developing posthemorrhagic hydrocephalus (PHHC) and to link them to white matter damage (WMD) diagnosed by cranial ultrasound. A total of 29 preterm infants with PHHC were included in the study; 17 of them had signs of cystic WMD (cWMD) on ultrasound examinations. CSF samples were obtained at first ventriculostomy, and results were compared to those of a reference group of 24 preterm and term infants without neurologic diseases. sFas concentrations were elevated in CSF samples of PHHC patients compared to the reference group. In patients with cWMD, sFas concentrations were significantly higher than in patients without cWMD. These results indicate that apoptosis via the Fas pathway is involved in the pathogenesis of cWMD in the context of PHHC, and that sFas in the CSF may serve as a marker of cWMD development. PMID- 20954856 TI - Development and evaluation of nifedipine controlled release tablets prepared using mucoadhesive swellable polymer. AB - Nifedipine is embedded in Gelcarin GP-379 to develop a prolonged release matrix. The effect of polymers levels (15, 20, 30 and 50% w/w), diluent type (lactose Fast Flo, DiTab, and Avicel PH-101), and drug levels (13, 20 and 30% w/w) on in vitro release rate of the drug were investigated. The formulation containing 13% nifedipine, 20% Gelcarin GP-379, and lactose Fast Flo controlled the dissolution rate of nifedipine and released approximately 51% drug at 8 h of testing dissolution. The use of different types of diluents, different drug levels, and different rotational speeds during dissolution testing did affect the drug release rate from the swellable matrices. The dissolution data were analyzed according to Higuchi model, zero order, first order, and Peppas kinetic model. Drug release was found to follow the anomalous diffusion model for swellable matrix. PMID- 20954857 TI - Primary prevention using statins: to be or not to be? PMID- 20954858 TI - A comparison of chromosome repair kinetics in G(0) and G(1) reveals that enhanced repair fidelity under noncycling conditions accounts for increased potentially lethal damage repair. AB - Potentially lethal damage (PLD) and its repair were studied in confluent human fibroblasts by analyzing the kinetics of chromosome break rejoining and misrejoining in irradiated cells that were either held in noncycling G(0) phase or allowed to enter G(1) phase of the cell cycle immediately after 6 Gy irradiation. Virally mediated premature chromosome condensation (PCC) methods were combined with fluorescence in situ hybridization (FISH) to study chromosomal aberrations in interphase. Flow cytometry revealed that the vast majority of cells had not yet entered S phase 15 h after release from G(0). By this time some 95% of initially produced prematurely condensed chromosome breaks had rejoined, indicating that most repair processes occurred during G(1). The rejoining kinetics of prematurely condensed chromosome breaks was similar for each culture condition. However, under noncycling conditions misrepair peaked at 0.55 exchanges per cell, while under cycling conditions (G(1)) it peaked at 1.1 exchanges per cell. At 12 h postirradiation, complex-type exchanges were sevenfold more abundant for cycling cells (G(1)) than for noncycling cells (G(0)). Since most repair in G(0)/G(1) occurs via the non-homologous end-joining (NHEJ) process, increased PLD repair may result from improved cell cycle-specific rejoining fidelity of the NHEJ pathway. PMID- 20954859 TI - Ribonucleotide reductase inhibition enhances chemoradiosensitivity of human cervical cancers. AB - For repair of damaged DNA, cells increase de novo synthesis of deoxyribonucleotide triphosphates through the rate-limiting, p53-regulated ribonucleotide reductase (RNR) enzyme. In this study we investigated whether pharmacological inhibition of RNR by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) enhanced chemoradiation sensitivity through a mechanism involving sustained DNA damage. RNR inactivation by 3-AP and resulting chemoradiosensitization were evaluated in human cervical (CaSki, C33-a) cancer cells through study of DNA damage (gamma-H2AX signal) by flow cytometry, RNR subunit p53R2 and p21 protein steady-state levels by Western blot analysis and laser scanning imaging cytometry, and cell survival by colony formation assays. 3-AP treatment led to sustained radiation- and cisplatin-induced DNA damage (i.e. increased gamma-H2AX signal) in both cell lines through a mechanism of inhibited RNR activity. Radiation, cisplatin and 3-AP exposure resulted in significantly elevated numbers and persistence of gamma-H2AX foci that were associated with reduced clonogenic survival. DNA damage was associated with a rise in p53R2 but not p21 protein levels 6 h after treatment with radiation and/or cisplatin plus 3-AP. We conclude that blockage of RNR activity by 3-AP impairs DNA damage responses that rely on deoxyribonucleotide production and thereby may substantially increase chemoradiosensitivity of human cervical cancers. PMID- 20954860 TI - Bystander cell death and stress response is inhibited by the radical scavenger alpha(1)-microglobulin in irradiated cell cultures. AB - Alpha-particle irradiation of cells damages not only the irradiated cells but also nontargeted bystander cells. It has been proposed that the bystander effect is caused by oxidants and free radicals generated by the radiation. Recent studies have shown that alpha(1)-microglobulin protects against cell damage caused by oxidants and free radicals. Using a novel experimental system that allows irradiation of 0.02% of a human hepatoma monolayer, leaving 99.98% as bystander cells, we investigated the influence of oxidative stress and the cell protective effects of alpha(1)-microglobulin during alpha-particle irradiation. The results showed an increase in cell death in both irradiated cells and bystander cells. A significant increase in apoptosis, oxidation markers and expression of the stress response genes heme oxygenase 1, superoxide dismutase, catalase, glutathione peroxidase 1, p21 and p53 were observed. Addition of alpha(1)-microglobulin reduced the amount of dead cells and inhibited apoptosis, formation of oxidation markers, and up-regulation of stress response genes. The results emphasize the role of oxidative stress in promoting bystander effects. Furthermore, the results suggest that alpha(1)-microglobulin protects nonirradiated cells by eliminating oxidants and free radicals generated by radiation and imply that alpha(1)-microglobulin can be used in radiation therapy of tumors to minimize damage to surrounding tissues. PMID- 20954861 TI - Gene expression profiles in mouse liver after long-term low-dose-rate irradiation with gamma rays. AB - Changes in gene expression profiles in mouse liver induced by long-term low-dose rate gamma irradiation were examined by microarray analysis. Three groups of male C57BL/6J mice were exposed to whole-body radiation at dose rates of 17-20 mGy/day, 0.86-1.0 mGy/day or 0.042-0.050 mGy/day for 401-485 days with cumulative doses of approximately 8 Gy, 0.4 Gy or 0.02 Gy, respectively. The gene expression levels in the livers of six animals from each exposure group were compared individually with that of pooled sham-irradiated animals. Some genes revealed a large variation in expression levels among individuals within each group, and the number of genes showing common changes in individuals from each group was limited: 20 and 11 genes showed more than 1.5-fold modulation with 17-20 mGy/day and 0.86-1.0 mGy/day, respectively. Three genes showed more than 1.5-fold modulation even at the lowest dose-rate of 0.04-0.05 mGy/day. Most of these genes were down-regulated. RT-PCR analysis confirmed the expression profiles of the majority of these genes. The results indicate that a few genes are modulated in response to very low-dose-rate irradiation. The functional analysis suggests that these genes may influence many processes, including obesity and tumorigenesis. PMID- 20954862 TI - Cancer incidence and mortality in populations living near uranium milling and mining operations in grants, New Mexico, 1950-2004. AB - In a previous cohort study of workers engaged in uranium milling and mining activities near Grants, Cibola County, New Mexico, we found lung cancer mortality to be significantly increased among underground miners. Uranium mining took place from early in the 1950s to 1990, and the Grants Uranium Mill operated from 1958 1990. The present study evaluates cancer mortality during 1950-2004 and cancer incidence during 1982-2004 among county residents. Standardized mortality (SMR) and incidence (SIR) ratios and 95% confidence intervals (CI) were computed, with observed numbers of cancer deaths and cases compared to expected values based on New Mexico cancer rates. The total numbers of cancer deaths and incident cancers were close to that expected (SMR 1.04, 95% CI 1.01-1.07; SIR 0.97, 95% CI 0.92 1.02). Lung cancer mortality and incidence were significantly increased among men (SMR 1.11, 95% CI 1.02-1.21; SIR 1.40, 95% CI 1.18-1.64) but not women (SMR 0.97, 95% CI 0.85-1.10; SIR 1.01, 95% CI 0.78-1.29). Similarly, among the population of the three census tracts near the Grants Uranium Mill, lung cancer mortality was significantly elevated among men (SMR 1.57; 95% CI 1.21-1.99) but not women (SMR 1.12; 95% CI 0.75-1.61). Except for an elevation in mortality for stomach cancer among women (SMR 1.30; 95% CI 1.03-1.63), which declined over the 55-year observation period, no significant increases in SMRs or SIRs for 22 other cancers were found. Although etiological inferences cannot be drawn from these ecological data, the excesses of lung cancer among men seem likely to be due to previously reported risks among underground miners from exposure to radon gas and its decay products. Smoking, socioeconomic factors or ethnicity may also have contributed to the lung cancer excesses observed in our study. The stomach cancer increase was highest before the uranium mill began operation and then decreased to normal levels. With the exception of male lung cancer, this study provides no clear or consistent evidence that the operation of uranium mills and mines adversely affected cancer incidence or mortality of county residents. PMID- 20954863 TI - Factors affecting the yields of C1' and C5' oxidation products in radiation damaged DNA: the indirect effect. AB - This study reports the effects of denaturation and deoxygenation on radiation induced formation of 2-deoxyribonolactone (2-dL) and 5'-aldehyde (5'-Ald) lesions in highly polymerized DNA. The radiation-chemical yields of 2-dL were determined through quantification of its dephosphorylation product 5-methylenefuranone (5MF). The formation of 5'-Ald was monitored qualitatively through the release of furfural (Fur) under the same conditions. The yields of 2-dL were found to be 7.3 +/- 0.3 nmol J(-1), or about 18% of the yield of free base release measured in the same samples. Denaturation increased the efficiency of 2-dL formation approximately twofold while deoxygenation resulted in a fourfold decrease. The release of Fur is about twofold lower than that of 5MF in aerated native DNA samples and is further reduced by denaturation of the DNA. Unlike 5MF, the formation of Fur requires the presence of molecular oxygen, which is consistent with peroxyl radical-mediated oxidation of C5' radicals into 5'-Ald. In contrast, the existence of an oxygen-independent pathway of 2-dL formation suggests that C1' sugar radicals can also be oxidized by radiation-produced oxidizing intermediates such as electron-loss centers on guanines. PMID- 20954864 TI - Effect of low doses of 14 MeV neutrons on polymers. AB - The structural modifications of polymers irradiated with 14 MeV neutrons were studied. Two elastomers, a polypropylene-type polymer and poly(ethylene oxide) were exposed to low doses of fast neutrons in the range of 0.3-14 Gy. The radiation damages were observed at the molecular scale by infrared spectroscopy. The morphological changes were investigated by steric exclusion chromatography, insoluble fraction measurements, differential scanning calorimetry and X-ray diffraction. It was found that neutrons provoked oxidation processes accompanied by modifications in the polymer architecture, including chain scissions, crosslinking reactions and changes in the crystallinity. Moreover, the conventional antioxidants were shown to be inefficient in inhibiting the aging of the polymers. These results also suggest that the radiation damages could be used successfully for dosimetry applications using an easily implementable protocol. PMID- 20954865 TI - The relative abundance of deer mice with antibody to Sin Nombre virus corresponds to the occurrence of hantavirus pulmonary syndrome in nearby humans. AB - Sin Nombre virus (SNV) is the principal cause of hantavirus pulmonary syndrome (HPS) in the United States and deer mice (Peromyscus maniculatus) are its principal rodent host, and thus the natural cycle of the virus is related to the occurrence of HPS. Prevalence of rodent infection appears to be associated with fluctuations in deer mouse populations and, indirectly, with timing and amount of precipitation, a complex of biologic events. Given that rodent population abundances fluctuate, often acutely, it is not unreasonable to assume a direct correlation between the numbers of infected rodents and the number of human infections, unless confounding factors are involved. During a 13-year longitudinal study at a site in southwestern Colorado, we accumulated data regarding deer mice and antibody to SNV and therefore had the opportunity to compare dynamics of deer mouse populations, seroprevalence of antibody to SNV in the rodents, and numbers of HPS cases in Durango and in the State of Colorado as a whole. If abundances of deer mouse populations are directly correlated with occurrence of HPS, it is reasonable to assume that low densities of deer mice and low prevalences of antibody to SNV would lead to fewer human cases than would high densities and high prevalences. Our results substantiate such an assumption and suggest that the risk of acquisition of HPS is likely related to both high numbers of infected deer mice and human activities, rather than being strictly related to prevalence of SNV in the host rodent. PMID- 20954866 TI - Apparent disappearance of Vesicular Stomatitis New Jersey Virus from Ossabaw Island, Georgia. AB - Ossabaw Island, Georgia, is the only reported endemic focus of Vesicular Stomatitis New Jersey Virus (VSNJV) in the United States. Based on recent negative serologic results of white-tailed deer and feral swine and the failure to isolate VSNJV from Lutzomyia shannoni, it appears that VSNJV is no longer present at this site. This apparent disappearance does not appear to be related to a change in L. shannoni habitat, specifically to the density of tree holes in the maritime and mixed hardwood forests. We believe that the disappearance of VSNJV from Ossabaw Island is directly related to a reduction in the feral swine population and a subsequent increase in the utilization of white-tailed deer by the known vector, L. shannoni. PMID- 20954867 TI - Natural infections of man-biting sand flies by Leishmania and Trypanosoma species in the northern Peruvian Andes. AB - The natural infection of sand flies by Leishmania species was studied in the Andean areas of Peru where cutaneous leishmaniasis caused by Leishmania (Viannia) peruviana is endemic. Sand flies were captured by human bait and Center for Disease Control (CDC) light trap catches at Nambuque and Padregual, Department of La Libertad, Peru, and morphologically identified. Among 377 female sand flies dissected, the two dominant man-biting species were Lutzomyia (Helcocyrtomyia) peruensis (211 flies) and Lutzomyia (Helcocyrtomyia) caballeroi (151 flies). Another sand fly species captured by light trap was Warileya phlebotomanica (15 flies). The natural infection of sand flies by flagellates was detected in 1.4% of Lu. (H.) peruensis and 2.6% of Lu. (H.) caballeroi, and the parasite species were identified as Le. (V.) peruviana and Trypanosoma avium, respectively, by molecular biological methods. The results indicated that the vector species responsible for the transmission of leishmaniasis in the study areas is Lu. (H.) peruensis. In addition, the presence of Trypanosoma in man-biting sand fly species means that more careful consideration is necessary for vector research in areas of Andean Peru where leishmaniasis is endemic. PMID- 20954868 TI - Smart dressings for the prevention of infection in pediatric burns patients. PMID- 20954870 TI - The risks of acquiring hospital-acquired infections from wet breathing systems. PMID- 20954869 TI - Interspecies bacterial communication as a target for therapy in otitis media. PMID- 20954872 TI - Tenofovir disoproxil fumarate in the treatment of chronic hepatitis B. AB - Tenofovir is a nucleotide analog reverse transcriptase inhibitor approved recently by the US FDA for the treatment of chronic hepatitis B (CHB) in adult patients based on the results of two double-blind randomized trials demonstrating superiority of tenofovir compared with adefovir. Tenofovir is available orally as tenofovir disoproxil fumarate (ester pro-drug of tenofovir) and inhibits replication of both hepatitis B virus and HIV-1. Owing to its potent antiviral activity, favorable safety profile, and higher barrier to the development of resistance, tenofovir has replaced adefovir as a first-line oral monotherapy option in the treatment of CHB in the 2009 update of the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines. Additionally, tenofovir monotherapy or in combination with nucleoside analogs are options for patients who have developed resistance to other CHB therapies including lamivudine and adefovir. PMID- 20954873 TI - New drugs for HIV-1: challenges and novel candidates. AB - The XVIII International Conference of the International AIDS Society held in Vienna on the 18-23 July 2010 brought together scientists, clinicians, policymakers, people living with HIV/AIDS and journalists from across the globe. Keynote speakers relevant to the theme of this report included Sharon Lewin (Alfred Hospital, Melbourne, Australia) and Tae-Wook Chun (National Institute of Allergy and Infectious Diseases, MA, USA), among others. A total of 19,100 delegates from across 193 countries attended the conference, which comprised 248 sessions, accompanied by 6238 abstracts and posters. The remit was broad, covering scientific, social and political aspects of the HIV/AIDS epidemic. This article focuses on the issue of eliminating latent reservoirs of HIV-1 infection, highlighting selected potential novel therapeutic interventions in overcoming challenges in HIV-1 suppression. PMID- 20954874 TI - The wonder world of microbial viruses. AB - The first congress on Viruses of Microbes took place at the Institut Pasteur in Paris, France, on 21-25 June 2010. The advances in genomics and metagenomics reported at this meeting reveal striking and unexpected complexity of the virus world. Viruses, in particular viruses that infect prokaryotes and unicellular eukaryotes, are emerging as the most abundant class of biological entities on earth and a major evolutionary and geochemical force. PMID- 20954875 TI - When to start antiretroviral therapy in children with TB? AB - The initiation of antiretroviral therapy (ART) after starting TB treatment is complex, involving many variables including treatment tolerance, drug co toxicities, pharmacokinetic drug interactions and polypharmacy impacts on adherence. Delayed ART potentially allows better determination of a specific cause for a drug side effect, decreasing the severity of paradoxical reactions and adherence difficulties. However, of overriding importance is mortality associated with delayed ART initiation versus mortality associated with immune restoration disease with early ART. While results of adult randomized trials addressing this question are becoming available, there are little data to inform the 'when to start' question for children. PMID- 20954876 TI - Do IFN-gamma-release assays predict the risk of TB? New evidence from a study on patients with silicosis. AB - IFN-gamma-release assays (IGRAs) are new tools for the diagnosis of latent TB infection which, until recently, relied only on the use of the tuberculin skin test (TST). However, while the positive predictive value of a positive TST for active TB is well established, little evidence on this issue is available for IGRAs. In a study conducted on silicosis patients in Hong Kong, China, Leung et al. found that a positive response to an IGRA, the T-SPOT.TB, was associated with a larger than fourfold increase in the risk of developing TB compared with those who tested negative, while a smaller than twofold increase was observed for TST positives compared with negatives. This study provides further support to the guidelines from public health agencies recommending the use of IGRAs in place of or in addition to TST. Several issues regarding their optimal use, however, remain open to debate. PMID- 20954877 TI - Immunomodulatory cell therapy in sepsis: have we learnt lessons from the past? AB - Sepsis still constitutes a public health challenge worldwide since its incidence constantly increases over time but its related mortality remains more or less constant. There is thus an unquestionable and urgent need to develop innovative and efficacious therapies for the treatment of this deadly disease. In this study, the authors propose that injection of mesenchymal stem cells rescues mice from death after septic shock owing to their potent immunosuppressive and anti inflammatory properties. The authors conclude that immunomodulatory cell therapy may represent an effective treatment for sepsis. While the potential therapeutic value of these cells is not to be challenged, considering the present lack of convincing data about mesenchymal stem cell use in sepsis, we do not believe that they constitute the next topical clinical trial in the field. Rather, recent evidence indicates that most septic patients actually present with profound immune alterations suggesting that anti-inflammatory approaches could deleteriously amplify this state. Therefore, in this article, we propose hypotheses explaining why the future of clinical trials in sepsis immunology will likely rely on stimulating immune functions for rebalancing immune homeostasis. PMID- 20954878 TI - Clostridium difficile infection in cancer patients and hematopoietic stem cell transplant recipients. AB - Clostridium difficile has become the most common bacterial cause of nosocomial diarrhea. High rates of C. difficile infection (CDI) coupled with increasing morbidity and mortality attributed to CDI have sparked a renewed interest in this disease. Emergence of hypervirulent strains, rising rates of severe and recurrent infection and associated infection control challenges, and diagnostic and therapeutic dilemmas are major issues in the non-oncology population. Scant data on CDI exist in the cancer/transplant population. The purpose of this article is to describe the epidemiology, pathogenesis and management of CDI in patients receiving cancer chemotherapeutic agents, and in hematopoietic stem cell transplant recipients. PMID- 20954879 TI - Cracking the Toll-like receptor code in fungal infections. AB - Innate control of fungal infection requires the specific recognition of invariant fungal molecular structures by a variety of innate immune receptors, including Toll-like receptors. In addition to the role in inducing protective immune responses, Toll-like receptor engagement may paradoxically favor fungal infections, by inducing inflammatory pathology and impairing antifungal immunity. Although the dissection of complex genetic traits modulating susceptibility to fungal infections is complex, the contribution of host genetics may hold the key to elucidating new risk factors for these severe, often fatal diseases. Understanding host-pathogen interactions at the innate immune interface will eventually lead to the development of new therapeutics and genetic markers in fungal infections. PMID- 20954880 TI - Commercially available assays for multiplex detection of alpha human papillomaviruses. AB - Five main groups of commercial assays for the multiplex detection of alpha human papillomaviruses (HPVs) are currently available. DNA-based screening assays, which test for the presence of 13-14 HPVs without determination of HPV type, have been the standard for HPV detection in the last decade. Assays that combine testing for 14 HPVs and HPV-16 and HPV-18 genotyping are a potential future standard for HPV detection. The clinical value of HPV genotyping assays has still not been finally determined. Recently, one of the mRNA-based assays showed equal clinical sensitivity but higher clinical specificity for CIN2+/CIN3+ in comparison with the validated DNA-based assay. In situ hybridization assays are too laborious and have insufficient clinical sensitivity to be used in routine screening. Automation, price reduction and improvement of clinical specificity are the main goals for the future development of HPV assays. PMID- 20954881 TI - Prevention of vertical transmission of HIV-1 in resource-limited settings. AB - One of the most exciting areas of HIV research is that of prevention of vertical transmission from mother to child, since it accounts for 90% of childhood HIV infections, and therefore prevention in this context has an enormous potential impact on the spread of HIV among children. Focused research has yielded highly successful strategies for reducing infant infection rates, particularly in the developed world, and much work is underway to implement appropriate strategies in resource-limited settings, although this is not without challenges. Although transmission rates in some settings have been reduced to approximately 1%, scale up and widespread implementation and application of strategic interventions for prevention of mother-to-child transmission of HIV during pregnancy, delivery and breastfeeding are needed in the developing world. PMID- 20954882 TI - Antiretroviral-based HIV prevention strategies for women. AB - Almost three decades have elapsed since researchers identified HIV as the cause of AIDS, with current estimates from UNAIDS that 33.4 million adults were living with HIV/AIDS in 2008. Two-thirds of this burden of disease is in Sub-Saharan Africa, and 60% of those infected are women. The disease still remains incurable and current prevention strategies including abstinence, male/female condom use and male circumcision are only partially effective. New strategies to curb the epidemic are urgently needed. Scientists are diligently exploring HIV prevention methods that are safe, effective and affordable. These new biological interventions include oral pre-exposure prophylaxis using oral antiretroviral (ARV) drugs, ARV treatment in HIV-infected persons to reduce transmission and topical ARV-based microbicide formulations. PMID- 20954883 TI - Camelpox: epidemiology, diagnosis and control measures. AB - Camelpox is an economically important contagious skin disease of camelids caused by camelpox virus (CMLV) and is characterized by mild local skin infection and less common severe systemic infections. The disease is confined to camel-rearing belts particularly in developing countries and causes economic impact due to considerable loss in terms of morbidity, mortality, loss of weight and reduction in milk yield. The virus has gained attention from researchers due to its recent emergence with close genetic relatedness to variola virus, the causative agent of smallpox, and carrying genes responsible for host immune evasion mechanisms. CMLV was earlier thought to be a zoonotic agent but so far little evidence has been documented from Somalia. Although the disease can be diagnosed based on clinical signs, the similar confounding skin lesions necessitate identification of infection by molecular biology based diagnostic techniques, namely restriction enzyme analysis of the virus genome and specific genes, genus- and species specific diagnostic PCRs including real-time quantitative PCR, and sequence and phylogenetic analysis for diagnosis and differentiation of CMLV. The entire genome sequence of CMLV is known and it contains more than 211 putative genes, which code for different proteins with host range, immunomodulation, virulence and other functions. Both inactivated and live-attenuated vaccines are available in some countries. However, live vaccines are preferred as they provide long lasting immunity. Considering the virus spreads through contaminated environments, an improved diagnostic and control method would be of immense value to curtail the infection in the field. Alternative therapeutics such as antiviral agents is an area that needs to be explored. This article discusses the epidemiology and biology of the disease, novel diagnostic approaches and control measures. PMID- 20954886 TI - On the origins of physicians: Darwinian or Lamarckian evolution? AB - Achieving acceptance to a North American and some European medical schools is one of the most difficult academic tasks faced by undergraduate students. The limited number of spots allows for only a fraction of the most highly promising applicants to be accepted each year. Perhaps one of the difficulties that many students face when applying to medical school is that due to the current restriction on enrollment, the application process poses selective pressures, independent of the applicants' suitability for the medical profession. Here I discuss, based on personal experiences, how I believe the process could become more just to all applicants. Allowing public needs and student interest to better dictate the number of graduating physicians could help relieve some of the current admission pressures, including the rather arbitrary selection of a small fraction of applicants from a large group of sufficiently proficient students. I believe that this proposal, if implemented, will likely not only remove some biases of our admission system, but also sufficiently change the landscape of those accepted, to include students with a genuine professional interest in the underserviced field of family practice. PMID- 20954887 TI - Anemia in the setting of traumatic brain injury: the arguments for and against liberal transfusion. AB - Anemia is recognized as a possible cause of secondary injury following traumatic brain injury (TBI). Cogent arguments can be made for both liberal and restrictive blood transfusion practices in this setting. In this narrative review, we summarize available knowledge regarding the risks of anemia and transfusion in patients with TBI. Laboratory studies using animal models and healthy human subjects suggest that anemia below a hemoglobin (Hb) concentration of 7 g/dL results in impaired brain function and below 10 g/dL may be detrimental to recovery from TBI. Clinical studies that have evaluated the association of anemia with clinical outcomes have not consistently demonstrated harm, but they generally have important methodological weaknesses. Alternatively, studies that have analyzed transfusion as a predictor of worse outcome have consistently identified such an association, but these studies may involve residual confounding. What little information exists from randomized trials that have included patients with TBI and evaluated liberal versus restrictive transfusion strategies is inconclusive. Since anemia in the setting of TBI is relatively common and there is considerable variation in transfusion preferences, greater study of this topic - preferably with one or more rigorous, adequately powered, non-inferiority randomized trials - is desirable. PMID- 20954888 TI - Antinociceptive effect of riluzole in rats with neuropathic spinal cord injury pain. AB - Symptoms of neuropathic spinal cord injury (SCI) pain include cutaneous hypersensitivity and spontaneous pain below the level of the injury. Riluzole, an FDA-approved drug for the treatment of amyotrophic lateral sclerosis, has been demonstrated to attenuate neural excitotoxicity by blocking the effects of the excitatory amino acid glutamate on glutamate receptors and by inhibiting voltage gated Na(+) and Ca(2+) channels. Neuropathic pain in rat models of SCI is thought to be mediated by dysfunctional ion channels and glutamate receptors expressed on CNS neurons. Thus riluzole's mechanism of action could be relevant in treating neuropathic SCI pain. The current study evaluated the antinociceptive potential of riluzole in rats following a SCI. Four weeks after a brief compressive injury to the mid-thoracic spinal cord, rats displayed significantly decreased hind paw withdrawal thresholds, suggestive of below-level cutaneous hypersensitivity. A single systemic dose of riluzole (8 mg/kg) injected intraperitoneally (i.p.) reversed cutaneous hypersensitivity in SCI rats. To identify riluzole's CNS site of action, riluzole was injected intrathecally (i.t.) and intracerebroventricularly (i.c.v.) in SCI rats. Significant antinociceptive effects were obtained following i.c.v., but not i.t., injection. Systemic riluzole was also antinociceptive in uninjured rats, increasing the latency to respond to an acute noxious thermal stimulus in the tail flick test. Unlike in SCI rats, however, riluzole was not effective when administered directly into the CNS, indicating a peripherally mediated antinociceptive mechanism. Although riluzole appears to have a general antinociceptive effect, the site of action may be model dependent. In total, these data indicate that riluzole may be an effective clinical analgesic for the treatment of below-level neuropathic SCI pain. Although the exact mechanism of action is not clear, there is a predominant supraspinal component of riluzole-induced antinociception in SCI rats. PMID- 20954889 TI - Competition drives specialization in pollination systems through costs to male fitness. AB - Specialization in pollination systems played a central role in angiosperm diversification, yet the evolution of specialization remains poorly understood. Competition through interspecific pollen transfer may select for specialization through costs to male fitness (pollen lost to heterospecific flowers) or female fitness (heterospecific pollen deposited on stigmas). Previous theoretical treatments of pollination focused solely on seed set, thus overlooking male fitness. Here we use individual-based models that explicitly track pollen fates to explore how competition affects the evolution of specialization. Results show that plants specialize on different pollinators when visit rates are high enough to remove most pollen from anthers; this increases male fitness by minimizing pollen loss to foreign flowers. At low visitation, plants generalize, which minimizes pollen left undispersed in anthers. A model variant in which plants can also evolve differences in sex allocation (pollen/ovule production) produces similar patterns of specialization. At low visitation, plants generalize and allocate more to female function. At high visitation, plants specialize and allocate equally to both sexes (in line with sex-allocation theory). This study demonstrates that floral specialization can be driven by selection through male function alone and more generally highlights the importance of community context in the ecology and evolution of pollination systems. PMID- 20954890 TI - Predator functional response changed by induced defenses in prey. AB - Functional responses play a central role in the nature and stability of predator prey population dynamics. Here we investigate how induced defenses affect predator functional responses. In experimental communities, prey (Paramecium) expressed two previously undocumented inducible defenses--a speed reduction and a width increase--in response to nonlethal exposure to predatory Stenostomum. Nonlethal exposure also changed the shape of the predator's functional response from Type II to Type III, consistent with changes in the density dependence of attack rates. Handling times were also affected by prey defenses, increasing at least sixfold. These changes show that induced changes in prey have a real defensive function. At low prey densities, induction led to lower attack success; at high prey densities, attack rates were actually higher for induced prey. However, induction increased handling times sufficiently that consumption rates of defended prey were lower than those of undefended prey. Modification of attack rate and handling time has important potential consequences for population dynamics; Type III functional responses can increase the stability of population dynamics and persistence because predation on small populations is low, allowing a relict population to survive. Simulations of a predator-prey population dynamic model revealed the stabilizing potential of the Type III response. PMID- 20954891 TI - Some recent events in biological monitoring. PMID- 20954901 TI - CYP3A5-mediated metabolism of midazolam in recombinant systems is highly sensitive to NADPH-cytochrome P450 reductase activity. AB - Data from in vitro drug metabolism studies with recombinant enzyme systems are frequently used to predict human drug metabolism in vivo. However, for the CYP3A probe substrate midazolam (MDZ), considerable variability in enzyme kinetic parameters has been observed in different in vitro studies. The aim of this study was to explore the effect of varying activities of the electron donor NADPH cytochrome P450 reductase (CPR) on CYP3A5-mediated metabolism of MDZ. Microsomes with similar levels of CYP3A5 but 12-fold difference in CPR activity showed a 30 fold difference in intrinsic clearance for the formation of 1'-OH-MDZ. Significantly higher K(m) and lower V(max) for the formation of 1'-OH-MDZ were found in microsomes with low CPR activity compared with microsomes with higher CPR activity (P = 0.024 and 0.001). In the microsomes with lowest CPR activity, the formation of 1'-OH-MDZ displayed Michaelis-Menten kinetics, whereas substrate inhibition was observed in the two preparations with higher CPR activity. The present study shows that the CPR activity in different recombinant enzyme preparations is crucial for in vitro CYP3A5-mediated clearance of MDZ. This suggests that the CPR activity of enzyme preparations could be an important factor for the ability of in vitro data to predict human drug metabolism in vivo. PMID- 20954892 TI - The head-fixed behaving rat--procedures and pitfalls. AB - This paper describes experimental techniques with head-fixed, operantly conditioned rodents that allow the control of stimulus presentation and tracking of motor output at hitherto unprecedented levels of spatio-temporal precision. Experimental procedures for the surgery and behavioral training are presented. We place particular emphasis on potential pitfalls using these procedures in order to assist investigators who intend to engage in this type of experiment. We argue that head-fixed rodent models, by allowing the combination of methodologies from molecular manipulations, intracellular electrophysiology, and imaging to behavioral measurements, will be instrumental in combining insights into the functional neuronal organization at different levels of observation. Provided viable behavioral methods are implemented, model systems based on rodents will be complementary to current primate models--the latter providing highest comparability with the human brain, while the former offer hugely advanced methodologies on the lower levels of organization, for example, genetic alterations, intracellular electrophysiology, and imaging. PMID- 20954903 TI - The monitoring of DNA adducts as an approach to carcinogen detection. PMID- 20954909 TI - High HIV type 1 group M pol diversity and low rate of antiretroviral resistance mutations among the uniformed services in Kinshasa, Democratic Republic of the Congo. AB - For the first time the genetic diversity among the uniformed personnel in Kinshasa, the capital city of the Democratic Republic of Congo (DRC), a country that has experienced military conflicts since 1998 and in which the global HIV 1/M pandemic started, has now been documented. A total of 94 HIV-1-positive samples, collected in 2007 in Kinshasa garrison settings from informed consenting volunteers, were genetically characterized in the pol region (protease and RT). An extensive diversity was observed, with 51% of the strains corresponding to six pure subtypes (A 23%, C 13.8%, D, G, H, J, and untypable), 15% corresponding to nine different CRFs (01, 02, 11, 13, 25, 26, 37, 43, and 45), and 34% being unique recombinants with one-third being complex mosaic viruses involving three or more different subtypes/CRFs. Only one strain harbored a single mutation, I54V, associated with drug resistance to protease inhibitors. Due to their high mobility and potential risk behavior, HIV infections in military personnel can lead to an even more complex epidemic in the DRC and to a possible increase of subtype C. PMID- 20954934 TI - Selective cortical mapping of biological motion processing in young infants. AB - How specialized is the infant brain for perceiving the facial and manual movements displayed by others? Although there is evidence for a network of regions that process biological motion in adults--including individuated responses to the perception of differing facial and manual movements--how this cortical specialization develops remains unknown. We used functional near infrared spectroscopy [Lloyd-Fox, S., Blasi, A., & Elwell, C. Illuminating the developing brain: The past, present and future of functional near-infrared spectroscopy. Neuroscience and Biobehavioral Reviews, 34, 269-284, 2010] to investigate the ability of 5-month-old infants to process differing biological movements. Infants watched videos of adult actors moving their hands, their mouth, or their eyes, all in contrast to nonbiological mechanical movements, while hemodynamic responses were recorded over the their frontal and temporal cortices. We observed different regions of the frontal and temporal cortex that responded to these biological movements and different patterns of cortical activation according to the type of movement watched. From an early age, our brains selectively respond to biologically relevant movements, and further, selective patterns of regional specification to different cues occur within what may correspond to a developing "social brain" network. These findings illuminate hitherto undocumented maps of selective cortical activation to biological motion processing in the early postnatal development of the human brain. PMID- 20954935 TI - Learning increases the survival of newborn neurons provided that learning is difficult to achieve and successful. AB - Learning increases neurogenesis by increasing the survival of new cells generated in the adult hippocampal formation [Shors, T. J. Saving new brain cells. Scientific American, 300, 46-52, 2009]. However, only some types of learning are effective. Recent studies demonstrate that animals that learn the conditioned response (CR) but require more trials to do so retain more new neurons than animals that quickly acquire the CR or that fail to acquire the CR. In these studies, task parameters were altered to modify the number of trials required to learn a CR. Here, we asked whether pharmacological manipulations that prevent or facilitate learning would decrease or increase, respectively, the number of cells that remain in the hippocampus after training. To answer this question, we first prevented learning with the competitive N-methyl-D-aspartate (NMDA) receptor antagonist (RS)-3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid. As a consequence, training did not increase cell survival. Second, we facilitated learning with the cognitive enhancer D-cycloserine, which increases NMDA receptor activity via its actions at the glycine binding site. Administration of D cycloserine each day before training increased the number of learned responses and the number of cells that survived. All animals that learned the CR retained more of the new cells, but those that learned very quickly retained fewer than those that required more training trials to learn. Together, these results demonstrate that NMDA receptor activation modifies learning and as a consequence alters the number of surviving cells in the adult hippocampus. PMID- 20954937 TI - Intention processing in communication: a common brain network for language and gestures. AB - Human communicative competence is based on the ability to process a specific class of mental states, namely, communicative intention. The present fMRI study aims to analyze whether intention processing in communication is affected by the expressive means through which a communicative intention is conveyed, that is, the linguistic or extralinguistic gestural means. Combined factorial and conjunction analyses were used to test two sets of predictions: first, that a common brain network is recruited for the comprehension of communicative intentions independently of the modality through which they are conveyed; second, that additional brain areas are specifically recruited depending on the communicative modality used, reflecting distinct sensorimotor gateways. Our results clearly showed that a common neural network is engaged in communicative intention processing independently of the modality used. This network includes the precuneus, the left and right posterior STS and TPJ, and the medial pFC. Additional brain areas outside those involved in intention processing are specifically engaged by the particular communicative modality, that is, a peri sylvian language network for the linguistic modality and a sensorimotor network for the extralinguistic modality. Thus, common representation of communicative intention may be accessed by modality-specific gateways, which are distinct for linguistic versus extralinguistic expressive means. Taken together, our results indicate that the information acquired by different communicative modalities is equivalent from a mental processing standpoint, in particular, at the point at which the actor's communicative intention has to be reconstructed. PMID- 20954936 TI - Differential callosal contributions to bimanual control in young and older adults. AB - Our recent work has shown that older adults are disproportionately impaired at bimanual tasks when the two hands are moving out of phase with each other [Bangert, A. S., Reuter-Lorenz, P. A., Walsh, C. M., Schachter, A. B., & Seidler, R. D. Bimanual coordination and aging: Neurobehavioral implications. Neuropsychologia, 48, 1165-1170, 2010]. Interhemispheric interactions play a key role during such bimanual movements to prevent interference from the opposite hemisphere. Declines in corpus callosum (CC) size and microstructure with advancing age have been well documented, but their contributions to age deficits in bimanual function have not been identified. In the current study, we used structural magnetic resonance and diffusion tensor imaging to investigate age related changes in the relationships between callosal macrostructure, microstructure, and motor performance on tapping tasks requiring differing degrees of interhemispheric interaction. We found that older adults demonstrated disproportionately poorer performance on out-of-phase bimanual control, replicating our previous results. In addition, older adults had smaller anterior CC size and poorer white matter integrity in the callosal midbody than their younger counterparts. Surprisingly, larger CC size and better integrity of callosal microstructure in regions connecting sensorimotor cortices were associated with poorer motor performance on tasks requiring high levels of interhemispheric interaction in young adults. Conversely, in older adults, better performance on these tasks was associated with larger size and better CC microstructure integrity within the same callosal regions. These findings implicate age-related declines in callosal size and integrity as a key contributor to bimanual control deficits. Further, the differential age-related involvement of transcallosal pathways reported here raises new questions about the role of the CC in bimanual control. PMID- 20954938 TI - Interactions between auditory and visual semantic stimulus classes: evidence for common processing networks for speech and body actions. AB - Incongruencies between auditory and visual signals negatively affect human performance and cause selective activation in neuroimaging studies; therefore, they are increasingly used to probe audiovisual integration mechanisms. An open question is whether the increased BOLD response reflects computational demands in integrating mismatching low-level signals or reflects simultaneous unimodal conceptual representations of the competing signals. To address this question, we explore the effect of semantic congruency within and across three signal categories (speech, body actions, and unfamiliar patterns) for signals with matched low-level statistics. In a localizer experiment, unimodal (auditory and visual) and bimodal stimuli were used to identify ROIs. All three semantic categories cause overlapping activation patterns. We find no evidence for areas that show greater BOLD response to bimodal stimuli than predicted by the sum of the two unimodal responses. Conjunction analysis of the unimodal responses in each category identifies a network including posterior temporal, inferior frontal, and premotor areas. Semantic congruency effects are measured in the main experiment. We find that incongruent combinations of two meaningful stimuli (speech and body actions) but not combinations of meaningful with meaningless stimuli lead to increased BOLD response in the posterior STS (pSTS) bilaterally, the left SMA, the inferior frontal gyrus, the inferior parietal lobule, and the anterior insula. These interactions are not seen in premotor areas. Our findings are consistent with the hypothesis that pSTS and frontal areas form a recognition network that combines sensory categorical representations (in pSTS) with action hypothesis generation in inferior frontal gyrus/premotor areas. We argue that the same neural networks process speech and body actions. PMID- 20954958 TI - Mindfulness effects on caregiver stress: should we expect more? PMID- 20954957 TI - Revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA): extending the CONSORT statement. AB - The Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) were published in five journals in 2001 and 2002. These guidelines, in the form of a checklist and explanations for use by authors and journal editors, were designed to improve reporting of acupuncture trials, particularly the interventions, thereby facilitating their interpretation and replication. Subsequent reviews of the application and impact of STRICTA have highlighted the value of STRICTA as well as scope for improvements and revision. To manage the revision process a collaboration between the STRICTA Group, the CONSORT Group, and the Chinese Cochrane Centre was developed in 2008. An expert panel with 47 participants was convened that provided electronic feedback on a revised draft of the checklist. At a subsequent face-to-face meeting in Freiburg, a group of 21 participants further revised the STRICTA checklist and planned dissemination. The new STRICTA checklist, which is an official extension of CONSORT, includes six items and 17 sub-items. These set out reporting guidelines for the acupuncture rationale, the details of needling, the treatment regimen, other components of treatment, the practitioner background, and the control or comparator interventions. In addition, and as part of this revision process, the explanations for each item have been elaborated, and examples of good reporting for each item are provided. In addition, the word "controlled" in STRICTA is replaced by "clinical," to indicate that STRICTA is applicable to a broad range of clinical evaluation designs, including uncontrolled outcome studies and case reports. It is intended that the revised STRICTA, in conjunction with both the main CONSORT Statement and extension for nonpharmacologic treatment, will raise the quality of reporting of clinical trials of acupuncture. PMID- 20954959 TI - Efficacy of Ankaferd Blood Stopper in postpolypectomy bleeding. PMID- 20954960 TI - Effect of slow abdominal breathing combined with biofeedback on blood pressure and heart rate variability in prehypertension. AB - OBJECTIVE: Prehypertension is a new category designated by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) in 2003. Managing prehypertension with nonpharmacological intervention is possibly beneficial to the prevention of hypertension. In this study, we observed the effect of slow abdominal breathing combined with electromyographic (EMG) biofeedback training on blood pressure (BP) in prehypertensives and assessed the changes of heart rate variability (HRV) in order to find an optional intervention to prevent hypertension and acquire some experimental data to clarify the underlying neural mechanism. METHODS: Twenty-two (22) postmenopausal women with prehypertension were randomly assigned to either the experiment group or the control group. The experiment group performed 10 sessions of slow abdominal breathing (six cycles/min) combined with frontal electromyographic (EMG) biofeedback training and daily home practice, while the control group only performed slow abdominal breathing and daily home practice. BP and HRV (including R-R interval and standard deviation of the normal-normal intervals [SDNN]) were measured. RESULTS: Participants with prehypertension could lower their systolic blood pressure (SBP) 8.4 mm Hg (p < 0.001) and diastolic blood pressure (DBP) 3.9 mm Hg (p < 0.05) using slow abdominal breathing combined with EMG biofeedback. The slow abdominal breathing also significantly decreased the SBP 4.3 mm Hg (p < 0.05), while it had no effect on the DBP (p > 0.05). Repeated-measures analyses showed that the biofeedback group + abdominal respiratory group (AB+BF) training was more effective in lowering the BP than the slow breathing (p < 0.05). Compared with the control group, the R-R interval increased significantly during the training in the AB+BF group (p < 0.05). The SDNN increased remarkably in both groups during the training (p < 0.05). CONCLUSIONS: Slow abdominal breathing combined with EMG biofeedback is an effective intervention to manage prehypertension. The possible mechanism is that slow abdominal breathing combined with EMG biofeedback could reduce sympathetic activity and meanwhile could enhance vagal activity. PMID- 20954961 TI - Using traditional acupuncture for breast cancer-related hot flashes and night sweats. AB - OBJECTIVES: Women taking tamoxifen experience hot flashes and night sweats (HF&NS); acupuncture may offer a nonpharmaceutical method of management. This study explored whether traditional acupuncture (TA) could reduce HF&NS frequency, improve physical and emotional well-being, and improve perceptions of HF&NS. DESIGN/SETTINGS/LOCATION: This was a single-arm observational study using before and after measurements, located in a National Health Service cancer treatment center in southern England. SUBJECTS: Fifty (50) participants with early breast cancer completed eight TA treatments. Eligible women were >= 35 years old, >= 6 months post active cancer treatment, taking tamoxifen >= 6 months, and self reporting >= 4 HF&NS incidents/24 hours for >= 3 months. INTERVENTIONS: Participants received weekly individualized TA treatment using a core standardized protocol for treating HF&NS in natural menopause. OUTCOME MEASURES: Hot Flash Diaries recorded HF&NS frequency over 14-day periods; the Women's Health Questionnaire (WHQ) assessed physical and emotional well-being; the Hot Flashes and Night Sweats Questionnaire (HFNSQ) assessed HF&NS as a problem. Measurements taken at five points over 30 weeks included baseline, midtreatment, end of treatment (EOT), and 4 and 18 weeks after EOT. Results for the primary outcome: Mean frequency reduced by 49.8% (95% confidence interval 40.5-56.5, p < 0.0001, n = 48) at EOT over baseline. Trends indicated longer-term effects at 4 and 18 weeks after EOT. At EOT, seven WHQ domains showed significant statistical and clinical improvements, including Anxiety/Fears, Memory/Concentration, Menstrual Problems, Sexual Behavior, Sleep Problems, Somatic Symptoms, and Vasomotor Symptoms. Perceptions of HF&NS as a problem reduced by 2.2 points (standard deviation = 2.15, n = 48, t = 7.16, p < 0.0001). CONCLUSIONS: These results compare favorably with other studies using acupuncture to manage HF&NS, as well as research on nonhormonal pharmaceutical treatments. In addition to reduced HF&NS frequency, women enjoyed improved physical and emotional well being, and few side-effects were reported. Further research is warranted into this approach, which offers breast cancer survivors choice in managing a chronic condition. PMID- 20954962 TI - Effects of two natural medicine formulations on irritable bowel syndrome symptoms: a pilot study. AB - OBJECTIVE: The study objective was to assess the effects and tolerability of two novel natural medicine formulations in improving bowel habit and abdominal symptoms in patients with irritable bowel syndrome (IBS). The DA-IBS formula was designed to treat diarrhea-predominant and alternating bowel habit IBS, and the C IBS formula was designed to treat constipation-predominant IBS. DESIGN: This was a two arm, open-label, uncontrolled pilot study. SETTINGS/LOCATION: Subjects were recruited from the greater Lismore area (NSW, Australia) in 2001. SUBJECTS: The study included 31 patients who fulfilled the Rome II criteria for IBS. Twenty-one (21) patients were classified as suffering from diarrhea-predominant or alternating bowel habit IBS and 10 patients were classified with constipation predominant IBS. INTERVENTIONS: The DA-IBS formula consisted of a mixture of dried, powdered bilberry fruit, slippery elm bark, agrimony aerial parts, and cinnamon quills. The C-IBS formula consisted of a mixture of dried powdered slippery elm bark, lactulose, oat bran, and licorice root. The aim of each formula was to normalize stool frequency and stool consistency. RESULTS: Ingestion of the DA-IBS formula was associated with a small, but significant increase in bowel movement frequency (p = 0.027). Subjects in the DA-IBS group also experienced reductions in straining (p = 0.004), abdominal pain (p = 0.006), bloating (p < 0.0001), flatulence (p = 0.0001), and global IBS symptoms (p = 0.002) during the treatment phase of the trial. Subjects in the C-IBS group experienced a 20% increase in bowel movement frequency (p = 0.016) and significant reductions in straining (p < 0.0001), abdominal pain (p = 0.032), bloating (p = 0.034), and global IBS symptom severity (p = 0.0005), as well as improvements in stool consistency (p < 0.0001). Both formulas were well tolerated. CONCLUSIONS: The DA-IBS formula was not effective in improving bowel habit in individuals with diarrhea-predominant or alternating bowel habit IBS, although it did significantly improve a number of IBS symptoms. The C-IBS formula significantly improved both bowel habit and IBS symptoms in patients with constipation-predominant IBS. Further research is warranted on C-IBS, as a potentially useful therapeutic formula. PMID- 20954963 TI - Auriculotherapy for pain management: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVES: Side-effects of standard pain medications can limit their use. Therefore, nonpharmacologic pain relief techniques such as auriculotherapy may play an important role in pain management. Our aim was to conduct a systematic review and meta-analysis of studies evaluating auriculotherapy for pain management. DESIGN: MEDLINE,((r)) ISI Web of Science, CINAHL, AMED, and Cochrane Library were searched through December 2008. Randomized trials comparing auriculotherapy to sham, placebo, or standard-of-care control were included that measured outcomes of pain or medication use and were published in English. Two (2) reviewers independently assessed trial eligibility, quality, and abstracted data to a standardized form. Standardized mean differences (SMD) were calculated for studies using a pain score or analgesic requirement as a primary outcome. RESULTS: Seventeen (17) studies met inclusion criteria (8 perioperative, 4 acute, and 5 chronic pain). Auriculotherapy was superior to controls for studies evaluating pain intensity (SMD, 1.56 [95% confidence interval (CI): 0.85, 2.26]; 8 studies). For perioperative pain, auriculotherapy reduced analgesic use (SMD, 0.54 [95% CI: 0.30, 0.77]; 5 studies). For acute pain and chronic pain, auriculotherapy reduced pain intensity (SMD for acute pain, 1.35 [95% CI: 0.08, 2.64], 2 studies; SMD for chronic pain, 1.84 [95% CI: 0.60, 3.07], 5 studies). Removal of poor quality studies did not alter the conclusions. Significant heterogeneity existed among studies of acute and chronic pain, but not perioperative pain. CONCLUSIONS: Auriculotherapy may be effective for the treatment of a variety of types of pain, especially postoperative pain. However, a more accurate estimate of the effect will require further large, well-designed trials. PMID- 20954964 TI - Tumor therapy with Amanita phalloides (death cap): stabilization of B-cell chronic lymphatic leukemia. AB - BACKGROUND: Molecular events that cause tumor formation upregulate a number of HOX genes, called switch genes, coding for RNA polymerase II transcription factors. Thus, in tumor cells, RNA polymerase II is more active than in other somatic cells. Amanita phalloides contains amanitin, inhibiting RNA polymerase II. Partial inhibition with amanitin influences tumor cell--but not normal cell- activity. OBJECTIVES: To widen the treatment spectrum, homeopathic dilutions of Amanita phalloides, containing amanitin, were given to a patient with leukemia. Monitoring the leukemic cell count, different doses of amanitin were given. RESULTS: The former duplication time of leukemic cells was 21 months. Within a period of 21 months, the cell count is stabilized to around 10(5)/MUL. No leukemia-associated symptoms, liver damage, or continuous erythrocyte deprivation occur. CONCLUSIONS: This new principle of tumor therapy shows high potential to provide a gentle medical treatment. PMID- 20954966 TI - Conducting literature searches on Ayurveda in PubMed, Indian, and other databases. AB - BACKGROUND: Literature searches for articles on Ayurveda provide special challenges, since many of the Indian journals in which such articles appear are not indexed by current medical databases such as PubMed and Cochrane Central Register of Controlled Trials. AIM: The aim of this study was to develop a comprehensive search strategy on Ayurveda topics and to map the existing databases containing Ayurveda journal publications. METHODS: We have developed a literature search procedure that can recover the great majority of articles on any given topic associated with Ayurveda. RESULTS: Our system is formulated in an easily reproducible fashion that all researchers can use. Using the keywords related to Ayurveda and vitiligo, we searched 41 databases that may contain complementary and alternative medicine publications. Only 11 databases yielded results; PubMed contained 9 articles. Each of 14 other databases named in our search procedure averaged 23 articles. International Bibliographic Information of Dietary Supplements, for example, gave 22, of which 1 satisfied our eligibility criteria. "Annotated Bibliography of Indian Medicine" gave 47, of which 7 satisfied eligibility criteria. CONCLUSIONS: This article proposes guidelines enabling comprehensive searches to locate all types of Ayurvedic articles, not necessarily only randomized controlled trials. PMID- 20954965 TI - Review of hepatitis B therapeutics. AB - Currently, there are 7 approved therapies for chronic hepatitis B virus (HBV) infection, an increase from just 3 agents 5 years ago. This review will focus on the pharmacology, potency, and adverse events associated with immunomodulatory agents and nucleos(t)ide analogues, with an emphasis on targets of therapy within the HBV life cycle. We will also offer guidelines for the use of available anti HBV agents and review the emerging challenges in hepatitis B management, including HBV drug resistance, its management, and the potential role of combination therapy. PMID- 20954967 TI - Plasticity of marrow mesenchymal stem cells from human first-trimester fetus: from single-cell clone to neuronal differentiation. AB - Recent results have shown that bone marrow mesenchymal stem cells (BMSCs) from human first-trimester abortus (hfBMSCs) are closer to embryonic stem cells and perform greater telomerase activity and faster propagation than mid- and late prophase fetal and adult BMSCs. However, no research has been done on the plasticity of hfBMSCs into neuronal cells using single-cell cloned strains without cell contamination. In this study, we isolated five single cells from hfBMSCs and obtained five single-cell cloned strains, and investigated their biological property and neuronal differentiation potential. We found that four of the five strains showed similar expression profile of surface antigen markers to hfBMSCs, and most of them differentiated into neuron-like cells expressing Nestin, Pax6, Sox1, beta-III Tubulin, NF-L, and NSE under induction. One strain showed different expression profile of surface antigen markers from the four strains and hfBMSCs, and did not differentiate toward neuronal cells. We demonstrated for the first time that some of single-cell cloned strains from hfBMSCs can differentiate into nerve tissue-like cell clusters under induction in vitro, and that the plasticity of each single-cell cloned strain into neuronal cells is different. PMID- 20954968 TI - Multicenter, open-label, randomized phase II controlled trial of an investigational recombinant Meningococcal serogroup B vaccine with and without outer membrane vesicles, administered in infancy. AB - BACKGROUND: In the absence of an efficacious broadly protective vaccine, serogroup B Neisseria meningitidis (MenB) is the leading cause of bacterial meningitis and septicemia in many industrialized countries. An investigational recombinant vaccine that contains 3 central proteins; Neisserial adhesin A (NadA), factor H binding protein (fHBP) and Neisserial heparin binding antigen (NHBA) has been developed. These antigens have been formulated with and without outer membrane vesicles (rMenB+OMV and rMenB, respectively) from the New Zealand epidemic strain (B:4:P1.7-2,4). In this trial, we assessed the immunogenicity of these formulations in infants, who are at greatest risk of contracting MenB disease. METHODS: A total of 147 infants from the United Kingdom were enrolled and randomly assigned to receive rMenB or rMenB+OMV at 2, 4, 6, and 12 months of age or a single dose at 12 months of age. Serum samples taken before and after vaccination were assayed in a standardized serum bactericidal antibody assay against 7 MenB strains. Local and systemic reactogenicity were recorded for 7 days after each vaccination. Analysis was according to protocol. RESULTS: After 3 doses, both vaccines were immunogenic against strains expressing homologous or related NadA and fHBP. rMenB+OMV demonstrated greater immunogenicity than did rMenB and was immunogenic against strains expressing homologous PorA. Both vaccines elicited anamnestic responses after the fourth dose. For both vaccines, responses were lower against strains expressing heterologous fHBP variants and after a single dose at 12 months. CONCLUSIONS: The rMenB+OMV vaccine has the potential to protect infants from MenB disease, although the breadth of protection afforded to heterologous antigens requires additional investigation. PMID- 20954971 TI - A case of unrecognized prehospital anaphylactic shock. AB - Abstract A case of prehospital anaphylactic shock that presented atypically, without a known exposure, is discussed. Anaphylaxis is a potentially life threatening allergic reaction that requires prompt recognition and aggressive treatment. While there is little diagnostic dilemma (specifically used in the conclusion section of this paper) in the recognition and management of "classic" presentations of anaphylaxis there is likely a need for further education of prehospital providers, as well as emergency physicians, on how to recognize atypical cases of anaphylaxis. These cases can be equally severe, with potentially fatal consequences if missed. The diagnosis and management of anaphylaxis are reviewed, as well as barriers that providers encounter in diagnosing uncommon presentations. PMID- 20954972 TI - Coffee, nutritional status, and renal artery resistive index. AB - BACKGROUND: The relationship between nutrition and atherosclerosis is known, even dissociated from protein malnutrition. Cardiovascular impact of several nutrients is known; among them the action of coffee is still debated and cardiovascular effect of caffeine has been investigated without definite results. OBJECTIVE: The aim of this study is to investigate whether coffee habits, and/or quantity of coffee consumption, have any relationship with renal resistive index (RRI), a hallmark of arterial stiffness (AS). The relationship of AS with nutritional status assessed by body composition and serum albumin, insulin resistance (assessed by HOMA), and renal function assessed by glomerular filtration rate (GFR) is concurrently investigated. METHODS: This study was done with 221 consecutive patients, without diabetes, cancer, liver, renal, and heart disease, referred for clinical noninvasive assessment and nutritional counseling: 124 essential hypertensive and 97 nonhypertensive patients were eligible. Personalized Mediterranean diet, physical activity increase, and smoking withdrawal counseling were provided. RESULTS: By multiple linear regression, fat free mass (FFM), HOMA (positive relationship), and number of cups of coffee/day (negative relationship) account for 17.2% of the variance to RRI. By odds ratios lower risk to increased RRI is associated with higher serum albumin, higher hemoglobin, and FFM; greater risk is associated with hypertension, insulin resistance (HOMA >= 3.0), and renal insufficiency (GFR <= 90); coffee, assessed by number of cups/day, reduces risk. CONCLUSION: Coffee use is inversely associated with RRI. Habitual coffee users have risk protection to higher RRI; lower serum albumin, insulin resistance, and renal insufficiency are associated with greater RRI. PMID- 20954973 TI - Pulmonary hypertension in hemodialysis patients without arteriovenous fistula: the effect of dialyzer composition. AB - Pulmonary hypertension (PHT) increases mortality rate in hemodialysis (HD) patients. Numerous clinical, hemodynamic, and metabolic abnormalities have been suggested to be associated with the development of PHT in HD patients. We aimed to investigate the acute effects of two different dialyzer membranes on pulmonary arterial pressure (PAP) throughout a HD session in maintenance HD patients. Seventy-four HD patients dialyzed through permanent tunneled jugular central venous catheter were enrolled. A first-use cellulose acetate and high-flux polysulfone dialysis membrane were tested using a crossover design. For each membrane, pre- and post-dialysis pulmonary artery pressures were measured echocardiographically. Elevated pulmonary artery pressure was observed in 68.8% of patients (n = 51), whereas mild PHT was observed in 28.3% of patients (n = 21) and moderate PHT in 40.5% (n = 30). Decrease in pulmonary artery pressure following HD procedure performed using high-flux polysulfone membrane was significantly higher than the decrease observed following HD procedure performed using cellulose acetate membrane (p < 0.05). Significant decrease in pulmonary artery pressures was observed only after HD procedures performed using high-flux polysulfone membrane (p < 0.05). Ultrafiltered volume was only significantly correlated with the decrease in pulmonary artery pressure observed after HD procedure performed through high-flux polysulfone membrane (beta = 0.411, p < 0.05). PHT seems to be prevalent among HD patients even in the absence of AV fistula and abnormal cardiac functions. Membrane composition seems to be important, which may overwhelm the improving effects of ultrafiltration. PMID- 20954974 TI - Proteomic profiling of uremia in serum using magnetic bead-based sample fractionation and MALDI-TOF MS. AB - BACKGROUNDS: Uremia is a term used to loosely describe the illness accompanying renal failure, in particular the nitrogenous waste products associated with the failure of this organ. At present, the diagnosis of uremia could be implemented by clinical symptoms, laboratory examinations, or image analysis. To develop alternative methods and potential new biomarkers for diagnosis, we employed a novel platform called ClinProt to investigate serum peptidome of uremia. METHODS: The first-morning serum samples from 30 patients, including 10 non-dialysis (ND), 10 peritoneal dialysis (PD), and 10 hemodialysis (HD) patients, were collected and screened to describe their variability of the serum peptidome. The results in uremia were compared to the findings in 13 normal controls. Specimens were purified with magnetic beads-based weak cation exchange chromatography and analyzed in a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS: Compared to normal controls, we screened 7, 7, and 9 significantly expressed polypeptides in ND, PD, and HD groups, respectively. Group comparisons were done by means of t-tests, the statistical significance was set at p < 0.05. A genetic algorithm was used to set up the classification models between uremia groups and normal controls. Cross-validation of normal controls from ND, PD, and HD was 99.30%, 95.12%, and 98.61%, respectively. The recognition capabilities were 100%. CONCLUSIONS: We were able to identify serum protein fingerprints in small sample sizes of recipients with uremia and establish the models for diagnosis of uremia. This preliminary study demonstrated that proteomics is an emerging tool for early diagnosis of uremia and helps us to better understand the pathogenesis of the disease process. PMID- 20954975 TI - Perfusion defects on real-time myocardial contrast echocardiography predict higher mortality in patients with end-stage renal disease - a 3-year follow-up. AB - AIM: The aim of this study was to assess the prognostic significance of myocardial contrast echocardiography (MCE) in patients with end-stage renal disease (ESRD) on a 3-year follow-up and to compare the value of MCE with demographic, clinical, and laboratory parameters. METHODS: Fifty-eight ESRD patients on regular dialysis were prospectively screened for coronary artery disease (CAD) using perfusion assessment on real-time MCE. We analyzed the following end points during the 3-year follow-up: death, cardiovascular complications, and combined end point, which consisted of adverse cardiac events mentioned above. All features were compared between the two groups with and without perfusion disturbances on MCE. RESULTS: No adverse events related to MCE administration have been observed. Twenty-seven (47%) patients with ESRD demonstrated perfusion defects on MCE. The patients with perfusion defects on MCE comparison with those without perfusion disturbances were older (p = 0.008) and had lower ejection fraction (EF) (p = 0.0001) and higher wall motion index (WMSI) (p = 0.0001). After the 3-year follow-up, the incidence of death (p = 0.00018), cardiovascular end points, revascularizations [both percutaneous coronary intervention (PCI) and coronary artery bypass grafts (CABG) p = 0.0016 and p = 0.004, respectively], and composite end point (p = 0.0015) was significantly higher in patients with perfusion defect on MCE. CONCLUSIONS: In patients with ESRD, MCE appears to be a safe and useful tool for risk stratification. MCE facilitates decision for coronary angiography. PMID- 20954976 TI - Ischemic nephropathy: proteinuria and renal resistance index could suggest if revascularization is recommended. AB - BACKGROUND: The aim of endovascular therapy in renal artery stenosis (RAS) is to preserve renal function and have a better hypertension control. The purpose of our study was to determine which biochemical and instrumental parameters could predict a better renal outcome in patients with RAS treated with percutaneous transluminal angioplasty and stenting (RPTAS). METHODS: We performed an observational study based on 40 patients with RAS who met the following criteria before revascularization: urinary protein excretion of over 250 mg/24 h, normal renal function, and/or mild-moderate renal insufficiency (I, II, and III levels of classification of chronic kidney disease, K-DOQI). RESULTS: Assessment at 12 months after RPTAS showed in 20 patients (Group A) that proteinuria serum creatinine (Scr) and creatinine clearance (CrCl) significantly worsened from the baseline; whereas in 20 patients (Group B) proteinuria remained unchanged and the renal function improved after the procedure. CONCLUSIONS: In our study, the decline of renal function after RPTAS is associated with an elevated renal resistance index (RI) in both kidneys (0.83 +/- 0.2) and preexisting proteinuria. PMID- 20954977 TI - Effect of IL-6 C-572G polymorphism on idiopathic membranous nephropathy risk in a Han Chinese population. AB - Membranous glomerulonephritis (MGN) is viewed as an immune-mediated glomerular disease, with immunologic expression occurring in genetically susceptible persons. The cytokine interleukin-6 (IL-6) gene polymorphism is known to impair intracellular signaling pathways following adaptive immune response. Our study gauged the effects of IL-6 C-572G (rs1800796) single nucleotide polymorphism (SNP) on MGN among Taiwan's Han Chinese population, as analyzed in 265 controls and 106 MGN patients. Genotyping for IL-6 C-572G SNP was performed by restriction fragment length polymorphism assay. Data showed stark differences in genotype and allele frequency distributions at IL-6 C-572G SNP between MGN patients and controls (p = 1.6E-04 and 1.7E-04, respectively). People with C allele or with CC genotype at IL-6 C-572G SNP showed higher risk of MGN (odds ratio = 2.42 and 2.71, respectively; 95% confidence interval = 1.51-3.87 and 1.60-4.60, respectively). These point to IL-6 C-572G polymorphism as the underlying cause of MGN; polymorphism merits further investigation. PMID- 20954978 TI - Definite and probable septic pericarditis in hemodialysis. AB - INTRODUCTION: Although the incidence of septic pericarditis in hemodialysis populations is less frequent in the modern antibiotic era, it is still a cause of death partly because diagnosis is sometimes difficult and uncertain. METHODS: From 2002 to 2006, 12 out of a total of 12,213 maintenance hemodialysis patients were referred for management of septic pericarditis. Patients were diagnosed as either definite or probable septic pericarditis. A definite diagnosis of septic pericarditis is based on the discovery of pathogenic bacteria in pericardial effusion, whereas a probable diagnosis is based on the proof of bacterial infection elsewhere in a patient with otherwise unexplained pericarditis, or appropriate response to a trial of systemic antibiotics. RESULTS: Four (33.3%) patients were diagnosed as definite pericarditis, whereas eight (66.7%) patients as probable pericarditis. It was found that although oxacillin-resistant Staphylococcus aureus (ORSA) (4/12 or 33.3%) and tuberculous (4/12 or 33.3%) pericarditis were common, salmonella pericarditis (2/12 or 16.7%) was also not uncommon. Pericardiocentesis, or pericardial window with pericardiectomy, was performed in three (25%) and two (16%) of patients with cardiac tamponade, respectively. Two patients died because of severe ORSA (1/12 or 8%) and salmonella (1/12 or 8%) sepsis. Finally, there were four (33%) patients who developed constrictive pericarditis after follow-up. CONCLUSIONS: These data are important because the spectrum of septic pericarditis was clearly different between Taiwan and other developed countries. Furthermore, it is the only report in which patients were diagnosed as either definite or probable septic pericarditis, therefore improving the sensitivity of diagnosis as in the case of tuberculous pericarditis. PMID- 20954979 TI - Catheter access for hemodialysis defines higher mortality in late-presenting dialysis patients. AB - BACKGROUND: This study explores the relationship between mortality and late presentation for dialysis, focusing on the role of catheter access for hemodialysis (HD). METHODS: We analyzed data from a cohort of 286 patients commencing dialysis in 2000-2001. Survival and factors associated with death were analyzed by univariate and multivariate analysis. Dialysis access was considered in three groups: HD-AVF, HD-Catheter, and peritoneal dialysis (PD). Late referral (LR) was defined as first review by a nephrologist less than 90 days before dialysis. RESULTS: One-year mortality was low at 10.1%. HD-Catheter patients were older (p < 0.001), more hypoalbuminemic (p < 0.001), more anemic (p = 0.005), and more likely to be LR (p < 0.001). HD-Catheter patients did not have significantly higher comorbidity (p = 0.128). HD-Catheter was strongly associated with late presentation (75% LR vs. 28% early referral, p < 0.001). Factors associated with death by univariate analysis included age (p < 0.0001), comorbidity (p < 0.0001), HD-Catheter (p < 0.0001), LR (p = 0.0001), hypoalbuminemia (p = 0.0011), and diabetes (p = 0.02). When corrected for these factors, HD-Catheter was associated with death (HR 2.226, 95% CI 1.314-3.772, p = 0.003) but LR was not (p = 0.38). CONCLUSIONS: A predominant feature of LR that predicts mortality is the use of catheter access for HD. This may be modifiable in those LR patients who do not present as uremic emergencies. PMID- 20954980 TI - Association of glutathione S-transferase M1 and T1 gene polymorphism with oxidative stress in diabetic and nondiabetic chronic kidney disease. AB - BACKGROUND AND OBJECTIVE: Glutathione S-transferases (GSTs) belong to a family of ubiquitous and multifunctional enzymes that work as one of the endogenous antioxidants in our body. This study was designed to look into the association of GST polymorphism with oxidative stress in both diabetic and nondiabetic chronic kidney disease (CKD). DESIGN AND METHODS: Three groups of patients (50 in each): diabetics without CKD (DM), diabetic CKD (DM-CKD), and nondiabetic CKD (NDM-CKD) and 50 age- and sex-matched healthy controls were recruited. Genotyping was done for GSTM1 and GSTT1 genes using a multiplex polymerase chain reaction. Serum GST and malondialdehyde (MDA) as a marker of oxidative stress were measured spectrophotometrically. RESULTS: Based on genotyping, subjects were categorized as GSTM1+/GSTT1+, GSTM1-/GSTT1+, GSTM1+/GSTT1-, and GSTM1-/GSTT1-. Serum GST levels were lower among subjects with deletion in one/both GST genes, whereas MDA levels were found to be correspondingly raised. A negative correlation for MDA versus GST levels was observed among genotypes with one/both gene deletions. Presence of GSTM1+/GSTT1- and GSTM1-/GSTT1- was significantly higher among patients with CKD in both diabetics and nondiabetics. INTERPRETATIONS AND CONCLUSIONS: GSTM1 and GSTT1 deletions singly or together were associated with lower GST levels and higher oxidative stress in both diabetic and nondiabetic CKD. Interestingly, GSTT1 deletion appears to be associated with both diabetic and nondiabetic CKD irrespective of the GSTM1 status. PMID- 20954981 TI - Important determinants of quality of life in a peritoneal dialysis population in Turkey. AB - BACKGROUND: Patients' health-related quality of life (HRQoL) is an important indicator for predicting the effectiveness of treatment, morbidity, and mortality. The aim of this study was to determine the level of HRQoL and the most important factors affecting HRQoL in patients receiving peritoneal dialysis (PD). METHODS: This cross-sectional study was performed with 156 patients, 30 of whom (19.2%) had automated PD (APD), were over 18 years of age, and were followed up at the Erciyes University Continuous Ambulatory Peritoneal Dialysis (CAPD) Unit during the previous year. HRQoL, depression, and fatigue were measured by means of the Short Form-36 (SF-36), Beck Depression Inventory (BDI), and Fatigue Severity Scale (FSS), respectively. RESULTS: The mean mental component summary (MCS) score was 42.1 +/- 11.9 and physical component summary (PCS) score was 39.1 +/- 11.2, which was lower than MCS. Depression was the strongest predictor for both diminished mental (beta = -24.4, p < 0.001) and physical (beta = -16.5, p < 0.001) HRQoL. Fatigue was the next strongest predictor for diminished physical HRQoL only (beta = -7.74, p < 0.001). Depression and fatigue accounted for 37% of physical HRQoL impairment. Depression as a sole factor was responsible for 31% of mental HRQoL impairment. Age, hospitalization, total cholesterol, serum albumin levels, and Kt/V urea had affected the SF-36 in some domains score but not in all. CONCLUSION: HRQoL in our PD patients can be evaluated at a slightly poor level compared to the results of previous studies. Impaired HRQoL is more closely associated with depression and fatigue. Depression was the strongest predictor of both mental and physical HRQoL. Fatigue was the next strongest predictor for physical HRQoL only. PMID- 20954982 TI - Study of urinary proteomes in Anderson-Fabry disease. AB - BACKGROUND: Anderson-Fabry disease (AFD) is an X-linked genetic disorder with deficient alpha-galactosidase A activity. The main aim of this work was to investigate possible differences in urine proteins between healthy controls and AFD patients and to identify abnormal proteins as potential biomarkers of disease. MATERIAL AND METHODS: We studied 2D electrophoresis images of urine samples collected from AFD patients and healthy subjects. The proteins were separated using isoelectric focusing method followed by SDS-PAGE. The proteins were then visualized by silver staining and characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). RESULTS: We found out that the urinary spectra of all the Fabry disease samples included identical proteins with molecular weight around 20-40 kDa. The concentration of some proteins was more than three times higher in the AFD samples, compared to the controls. The abundant proteins were identified by MALDI TOF MS and included the following: alpha-1-antitrypsin, alpha-1-microglobulin, prostaglandin H2 d-isomerase, complement-c1q tumor necrosis factor-related protein, and Ig kappa chain V-III. Possible glycosylation at Asn51 and Asn78 sites of the prostaglandin H2 d-isomerase was detected. CONCLUSIONS: AFD urinary proteomics revealed increased secretion of several proteins. We postulate that the observed difference in the amount of prostaglandin H2 d-isomerase and its position on two-dimensional gels might be related to different glycosylation in AFD subjects. PMID- 20954983 TI - Amelioration of gentamicin nephrotoxicity by green tea extract in uninephrectomized rats as a model of progressive renal failure. AB - RATIONALE: Gentamicin (GM) is an effective antibiotic against severe infection but has limitations related to nephrotoxicity. This study investigates whether green tea extract (GTE), an antioxidant, could ameliorate the nephrotoxic effect of GM in uninephrectomized rats. OBJECTIVES: The right kidneys of 40 rats were surgically removed and 1 week later the animals were divided into four groups (n = 10). Group 1 served as control, Group 2 as GTE group, Group 3 as GM group, and Group 4 as GM+GTE group. Kidney function, inflammatory cytokine TNF-alpha, oxidant and antioxidant parameters of renal tissue, as well as histopathological studies were assessed. MAIN FINDINGS: Injecting uninephrectomized rats with GM induced renal dysfunction as shown by significant elevations in serum creatinine and urea. Serum TNF-alpha and oxidative stress parameters (superoxide anion and lipid peroxides) were also significantly increased. On the contrary, antioxidative parameters [superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH)] were significantly decreased. Histopathological examination of renal tissue illustrated features of degeneration, marked cellular infiltration, tubular dilatation, and varying degrees of necrosis. GTE given to GM rats reduced these nephrotoxicity parameters. Serum creatinine, urea, and TNF-alpha were almost normalized in the GM+GTE group. The oxidative stress parameters were significantly decreased and the antioxidative parameters were significantly increased. CONCLUSION: GTE ameliorates GM-induced nephrotoxicity and oxidative damage by improving antioxidant defense and tissue integrity. Further human studies are necessary to demonstrate the antioxidant effects of GTE on renal diseases. Nevertheless, green tea (GT) may offer an inexpensive, nontoxic, and effective intervention strategy in subjects with a risk for GM-induced nephrotoxicity. PMID- 20954984 TI - The mechanism of myocardium and pancreas injury in rabbits with acute renal failure might be related to myeloperoxidase and membrane pump activities. AB - There is increasing evidence indicating that the distant organ injury is a major contributor of high mortality in patients subjected to acute renal failure (ARF). However, sources and mechanisms that ARF causes distant organ injury remain to be determined. The aim of this study is to explore the mechanism from polymorphonuclear neutrophil (PMN) sequestration and membrane pump suppression. To achieve this, we examined myeloperoxidase (MPO), a marker of PMN accumulation in tissues, and membrane pump activities of heart, pancreas, and kidney in two ARF rabbit models. Rabbits are randomly assigned to control, HgCl(2)-treated, and glycerin-treated groups. ARF animal models are established by hypodermic injection of 1% HgCl(2) with 1.3 mL/kg bodyweight (bw) in HgCl(2)-treated group or intramuscular injection of 50% glycerin with 10 mL/kg bw in glycerin-treated group, respectively, and all animals in each group are further divided into 12 h, 24 h, and 48 h subgroups with each consisting of six rabbits. Six healthy rabbits serve as control group. Results have shown that MPO activities of kidney, myocardium, and pancreas in two model groups were significantly increased than control group at diverse time points. Membrane pump activities of kidney in two model groups are significantly lower than the control group at multiple time points. Moreover, Na(+)-K(+)-, Ca(2+)-, Mg(2+)-, and Ca(2+)-Mg(2+)-ATPase activities of myocardium and pancreas in two model groups are gradually declined with the development of ARF. These findings suggest that PMN sequestration and membrane pump suppression plays an important role in the pathogenesis of ARF and also a major mechanism of myocardium and pancreas injury during the process of ARF. PMID- 20954985 TI - Glomerular deposition of immune complexes as a first manifestation of malignant melanoma - a case report. AB - INTRODUCTION: Immune complex (IC) deposition in renal tissue is considered as a possible tumor marker. This raised the hypothesis that some tumor markers might be related to the patient prognosis, with emphasis in the possibility to detect them in tissue sample, not only in blood. We report a patient with membranous glomerulonephritis (MGN) and tumoral IC deposition that were detected previous to the diagnosis of melanoma. CASE REPORT: A 55-year-old male was admitted to our department with symptoms of renal disease; a kidney biopsy was performed and the diagnosis was phase II MGN. A few months later he returned to the hospital with ascites, dyspnea, anorexia, and macular erythematous skin lesions in the body. A new urinalysis showed proteinuria, hematuria, and leukocyturia; the chest X-ray showed a lung nodule; and a brain CT scan revealed a frontal nodular lesion, suggesting metastasis. The brain biopsy suggested the diagnosis of metastatic melanoma and a posterior kidney immunohistochemistry study with S-100 and HMB-45 antibodies showed glomerular and tubular positivity for these markers. CONCLUSIONS: MGN and deposition of tumoral IC as a first manifestation of melanoma has not been previously reported. This case reinforces the importance of a clinical evolution focused on the diagnosis of a hidden cancer in patients with MGN. Oncologists should also be aware of the potential occurrence of glomerular lesion in their patients and that could be important during tumor therapy. PMID- 20954986 TI - Non-dilated obstructive uropathy - an unrecognized cause of acute renal failure in hospitalized US patients: three case reports seen over 6 months in a northwestern Wisconsin nephrology practice. AB - The syndrome of non-dilated obstructive uropathy (NDOU) and acute renal failure (ARF) is well reported. However, the literature suggests that this syndrome is rare, accounting for less than 5% of cases of urinary obstruction. Our recent experience with three cases of NDOU seen within a space of months implies otherwise. Between March 2009 and October 2009, in a small Midwestern American town Nephrology practice, we successfully managed three cases of NDOU. They all presented with newly symptomatic ARF. Renal imaging revealed no dilatation in both kidneys in one, only unilateral dilatation in the second, and dilatation was absent in a single functioning kidney in the third. They comprised of two males and one female, mean age 61 years (peak creatinine: 320-880 MUmol/L). Despite the absence of dilatation on renal imaging, strong suspicion for NDOU led to decompression procedures with prompt recovery of kidney function in all three patients - two required percutaneous nephrostomy tube placements and/or ureteric stents and one responded to simple Foley catheter drainage. One required temporary hemodialysis. We submit that NDOU may be more common than previously speculated. A high index of suspicion is warranted as significant renal salvage can often be achieved by timely decompression procedures. PMID- 20954987 TI - AA type renal amyloidosis secondary to FMF: a long-term follow-up in two patients. AB - Renal amyloidosis, which leads to renal failure, is the most important long-term complication of familial Mediterranean fever (FMF). Resolution of nephrotic syndrome secondary to amyloidosis in FMF following colchicine treatment has rarely been reported. We describe two patients with FMF and nephrotic syndrome. These patients were treated with colchicine 1.5 mg/day and had a complete remission of nephrotic syndrome with a stable clinical course over 30 years. To our knowledge, our patients have the longest follow-up time without proteinuria. PMID- 20954988 TI - Rapamycin therapy for renal, brain, and skin lesions in a tuberous sclerosis patient. AB - Tuberous sclerosis complex (TSC) is an inherited multisystem disorder; it may involve kidney, brain, skin, lungs, and liver. We report a 37-year-old female TSC patient presenting with skin lesions (angiofibromas, molluscum pendulum). Radiologic examination revealed additional brain and renal lesions consisting of tumors, cysts, and angiomyolipomas. Treatment with rapamycin disclosed improvement in skin lesions. The number and volume of angiofibromas and molluscum pendulum reduced progressively in 6 months. During the ninth month of treatment, magnetic resonance imaging was repeated for renal and brain lesions. Imaging results showed reduction in tumor and angiomyolipoma volumes. Oral rapamycin therapy can improve renal, brain, and skin lesions in TSC disease. Therefore, it may be an alternative therapy for TSC patients. PMID- 20954989 TI - Role of stem cells in kidney repair. AB - End-stage renal disease and acute renal failure are the most important issues of practical and clinical nephrology, bearing in mind their high mortality rate, solely symptomatic treatment, and overall economic impact on society. The advances in stem cell biology opened the door for the new era in treatment of many disorders, including renal, offering new therapeutical solutions. Findings suggesting that the adult kidney contains stem cells and that stem cells from bone marrow have potential to differentiate into renal cells focused research on the possible application of these cells in therapy of kidney disorders. The other promising candidates for stem cell therapy for the kidney are embryonic stem cells and amniotic fluid-derived stem cells. This article focuses on the characteristics and possible application of these types of stem cells. PMID- 20954990 TI - Toward the optimal clinical use of the fraction excretion of solutes in oliguric azotemia. AB - While the fractional excretion of solutes have long been considered excellent research tools to investigate tubular physiology, their clinical use has become common over the last 40 years in the diagnoses of many disorders; however, none have reached the clinical utility of the fractional excretion of sodium in the ability to distinguish pre-renal azotemia from acute tubular necrosis. Nevertheless, there are many drugs and medical conditions that interfere with that utility and recently other solutes, including urea, uric acid and lithium, have been recently investigated to improve the diagnostic ability in clinical situations where the fractional excretion of sodium is known to be unreliable. We review the tubular physiology of these solutes and show how the differences in tubular physiology might be exploited to develop a strategy for their optimal clinical use. PMID- 20954991 TI - Hepatitis B virus infection and related factors in hemodialysis patients in China - systematic review and meta-analysis. AB - AIMS: To provide a comprehensive and reliable tabulation of available data on the epidemiological characteristics and risk factors for hepatitis B virus (HBV) infection in maintenance hemodialysis (HD) patients in China and help to inform prevention programs and guide future research. METHODS: A systematic review was constructed based on the computerized literature database. Confidence intervals (95% CI) of infection rates were calculated using the approximate normal distribution model. Odds ratios (OR) and 95% CI were calculated by fixed or random effects models. Hepatitis B surface antigen positivity (HBsAg (+)) was set as the sign of HBV infection. RESULTS: Fifty studies met our inclusion criteria. The pooled prevalence of HBV infection among HD patients in China was 11.9%. Blood transfusion was correlated with an increase in HBV infection (p = 0.05). HD patients with a long-term history were more likely to be infected than those with a short-term history. The levels of alanine aminotransferase were higher in the HBsAg (+) patients (p < 0.001). Large doses of HBV vaccine (80 MUg/dose) increased the seroconversion rate. The response rate of intradermal injection of HBV vaccine was higher than that of intramuscular injection. CONCLUSION: Hepatitis B is still one of the main complications in HD patients in China, and the frequency of blood transfusion and duration of HD were the risk factors. Large doses and intradermal injection of HBV vaccine were recommended to prevent HBV infection in HD patients. The findings of this meta-analysis have implications for optimal prevention and treatment of Hepatitis B in HD patients. PMID- 20955007 TI - Adaptive changes of the yeast mitochondrial proteome in response to salt stress. AB - Mitochondria are dynamic organelles with the capacity to adapt to environmental stimuli and stress. Here we use yeast (Saccharomyces cerevisiae) in combination with proteomic approaches to quantify the changes in the protein composition of mitochondria in the presence of salt stress provoked by NaCl. We identified 15 proteins that were more than twofold overrepresented in salt adapted mitochondria. These proteins are mainly involved in the oxidative stress defense, the biosynthesis of amino acids and ubiquinone or in the metabolism of pyruvate and acetate. Loss of function of most of the upregulated proteins did not result in a significant growth phenotype under high salt conditions. However, all identified proteins were necessary to sustain efficient growth under oxidative stress caused by hydrogen peroxide. Additionally, a subset of outer mitochondrial membrane proteins was shown to be upregulated upon salt stress. We furthermore identified nine proteins that were more than threefold underrepresented in salt adapted mitochondria. These proteins were mainly glycolytic enzymes or proteins with a predominant localization at the endoplasmatic reticulum. Our results underline the complex nature of the stress adaptation of mitochondria and identify functional groups of proteins whose specific role in salt resistance should be revealed in the future. PMID- 20955008 TI - Metabolome analysis of differential responses of diploid and haploid yeast to ethanol stress. AB - Metabolomic analysis was carried out to investigate the metabolic differences of diploid (alpha/a) and homogenous haploid (alpha,a) yeasts, and further assess their response to ethanol stress. The dynamic metabolic variations of diploid and haploid caused by 3 and 7% (v/v) ethanol stress were evaluated by gas chromatography coupled to time-of-flight mass spectrometry combined with statistical analysis. Metabolite profiles originating from three strains in presence/absence of ethanol stress were distinctive and could be distinguished by principal components analysis. Results showed that the divergence among the strains with ethanol stress was smaller than without it. Furthermore, the levels of most glycolytic intermediates and amino acids in haploid were lower than these in diploid with/without ethanol stress, which was considered as species-specific behaviors. The increases of protective metabolites including polyols, amino acids, precursors of phospholipids, and unsaturated fatty acids under ethanol stress in three strains revealed the ethanol stress-specific responses. Higher fold change in most of these protectants in haploid indicated that haploid was more susceptible to ethanol stress than diploid. These findings provided underlying basis for better understanding diploid and haploid yeasts, and further breeding tolerant strains for efficient ethanol fermentation. PMID- 20955006 TI - Adaptive response and tolerance to weak acids in Saccharomyces cerevisiae: a genome-wide view. AB - Weak acids are widely used as food preservatives (e.g., acetic, propionic, benzoic, and sorbic acids), herbicides (e.g., 2,4-dichlorophenoxyacetic acid), and as antimalarial (e.g., artesunic and artemisinic acids), anticancer (e.g., artesunic acid), and immunosuppressive (e.g., mycophenolic acid) drugs, among other possible applications. The understanding of the mechanisms underlying the adaptive response and resistance to these weak acids is a prerequisite to develop more effective strategies to control spoilage yeasts, and the emergence of resistant weeds, drug resistant parasites or cancer cells. Furthermore, the identification of toxicity mechanisms and resistance determinants to weak acid based pharmaceuticals increases current knowledge on their cytotoxic effects and may lead to the identification of new drug targets. This review integrates current knowledge on the mechanisms of toxicity and tolerance to weak acid stress obtained in the model eukaryote Saccharomyces cerevisiae using genome-wide approaches and more detailed gene-by-gene analysis. The major features of the yeast response to weak acids in general, and the more specific responses and resistance mechanisms towards a specific weak acid or a group of weak acids, depending on the chemical nature of the side chain R group (R-COOH), are highlighted. The involvement of several transcriptional regulatory networks in the genomic response to different weak acids is discussed, focusing on the regulatory pathways controlled by the transcription factors Msn2p/Msn4p, War1p, Haa1p, Rim101p, and Pdr1p/Pdr3p, which are known to orchestrate weak acid stress response in yeast. The extrapolation of the knowledge gathered in yeast to other eukaryotes is also attempted. PMID- 20955009 TI - Dynamic lipidomic insights into the adaptive responses of Saccharomyces cerevisiae to the repeated vacuum fermentation. AB - Vacuum fermentation is utilized in a wide range of life science industries and biomedical R&D. Little is known, however, on the effects of the vacuum on the yeast, and in particular, on the yeast lipidome that plays a central role in maintaining cell membrane and other vital (yeast) cell functions. The present study evaluated the adaptive responses of Saccharomyces cerevisiae to repeated vacuum fermentation by lipidomic analysis. We employed gas chromatography coupled to time-of-flight mass spectrometry (GC-TOF-MS) and liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI/MS(n)) to quantify a total of 13 intermediate sterols and 139 phospholipid species of yeast cells. Principal components analysis found that the PI (phosphatidylinositol) 26:0, PI 28:0, PE (phosphatidylethanolamine) 32:1, and PE 34:1 were potential biomarkers to distinguish the vacuum fermentation process. Quantitative analysis showed that vacuum fermentation increased the synthesis of PI and the PC (phosphatidylcholine) species with short saturated acyl chains. The synthesis of PC via CDP-choline and turnover of PC were enhanced, instead of formation via methylation of PE. Additionally, increased PI at the expense of PE and PG (phosphatidylglycerol) was associated with enhancement of ethanol productivity. Vacuum fermentation caused eburicol accumulation, suggesting that vacuum can activate the branch of the ergosterol biosynthesis pathway. Eburicol decrease and PI increase contributed to recovery of cellular activities with oxygenating treatment. Ethanol productivity was increased by sixfold in vacuum-treated cells. These observations may allow the development of future mechanistic approaches to optimization of yeast fermentation under vacuum for bioindustry and life science applications. In particular, our findings on changes in lipid molecular species and the ergosterol biosynthesis pathway elucidate the defense responses of yeast cell membranes during the repeated vacuum fermentation, which by extension, provided an important lead insight on how best to protect the cell membranes from the extreme long-term stress conditions. PMID- 20955011 TI - Evolution in response to direct and indirect ecological effects in pitcher plant inquiline communities. AB - Ecologists have long recognized the importance of indirect ecological effects on species abundances, coexistence, and diversity. However, the evolutionary consequences of indirect interactions are rarely considered. Here I conduct selection experiments and examine the evolutionary response of Colpoda sp., a ciliated protozoan, to other members of the inquiline community of purple pitcher plants (Sarracenia purpurea). I measured the evolution of six traits in response to (1) predation by mosquito larvae, (2) competition from other ciliated protozoans, and (3) simultaneous predation and competition. The latter treatment incorporated both direct effects and indirect effects due to interactions between predators and competitors. Population growth rate and cell size evolved in response to direct effects of predators and competitors. However, trait values in the multispecies treatment were similar to those in the monoculture treatment, indicating that direct effects were offset by strong indirect effects on the evolution of traits. For most of the traits measured, indirect effects were opposed to, and often stronger than, direct effects. These indirect effects occurred as a result of behavioral changes of the predator in the presence of competitors and as a result of reduced densities of competitors in the presence of predators. Incorporating indirect effects provides a more realistic description of how species evolve in complex natural communities. PMID- 20955010 TI - Genomic expression program involving the Haa1p-regulon in Saccharomyces cerevisiae response to acetic acid. AB - The alterations occurring in yeast genomic expression during early response to acetic acid and the involvement of the transcription factor Haa1p in this transcriptional reprogramming are described in this study. Haa1p was found to regulate, directly or indirectly, the transcription of approximately 80% of the acetic acid-activated genes, suggesting that Haa1p is the main player in the control of yeast response to this weak acid. The genes identified in this work as being activated in response to acetic acid in a Haa1p-dependent manner include protein kinases, multidrug resistance transporters, proteins involved in lipid metabolism, in nucleic acid processing, and proteins of unknown function. Among these genes, the expression of SAP30 and HRK1 provided the strongest protective effect toward acetic acid. SAP30 encode a subunit of a histone deacetylase complex and HRK1 encode a protein kinase belonging to a family of protein kinases dedicated to the regulation of plasma membrane transporters activity. The deletion of the HRK1 gene was found to lead to the increase of the accumulation of labeled acetic acid into acid-stressed yeast cells, suggesting that the role of both HAA1 and HRK1 in providing protection against acetic acid is, at least partially, related with their involvement in the reduction of intracellular acetate concentration. PMID- 20955012 TI - Predictive adaptive responses: Condition-dependent impact of adult nutrition and flight in the tropical butterfly Bicyclus anynana. AB - The experience of environmental stress during development can substantially affect an organism's life history. These effects are often mainly negative, but a growing number of studies suggest that under certain environmental conditions early experience of such stress may yield individuals that are less sensitive to environmental stress later on in life. We used the butterfly Bicyclus anynana to study the effects of limited larval and adult food and forced flight on individual performance measured as reproduction and adult life span. Larvae exposed to food stress showed longer development and produced smaller adults. Thus, they were not able to fully compensate for the food deprivation during development. Females that experienced food stress during development did not increase tolerance for adult food limitation. However, females exposed to food stress during development coped better with forced flight compared with the control group. The apparent absence of costs of flight in poor-quality females may be a by-product of an altered body allocation, as females experiencing both food stress treatments had increased thorax ratios, compared with controls, and increased flight performances. The results reveal an important plasticity component to variation in flight performance and suggest that the cost of flight depends on an individual's internal condition. PMID- 20955077 TI - Mesenchymal stem cell-conditioned medium triggers neuroinflammation and reactive species generation in organotypic cultures of rat hippocampus. AB - Cell therapy using bone marrow-derived mesenchymal stem cells (MSCs) seems to be a new alternative for the treatment of neurodegenerative diseases. Despite several promising results with their use, possible side effects are still unknown. In a previous work, we have shown that MSC-conditioned medium is toxic to hippocampal slice cultures and aggravates cell death induced by oxygen and glucose deprivation. In this work, we investigated whether the inflammatory response and/or reactive species formation could be involved in that toxicity. Rat organotypic hippocampal cultures were exposed for 24 h to conditioned medium from MSCs isolated from rat bone marrow. A marked glial activation was observed after exposure of cultures to MSC-conditioned medium, as evidenced by glial fibrillary acid protein (GFAP) and isolectin B(4) increase. Tumor necrosis factor alpha and interleukin-6 levels were increased in the culture medium, and 2,7 dihydrodichlorofluorescein diacetate oxidation (indicating reactive species generation) and inducible nitric oxide synthase (iNOS) immunocontent were also higher after exposure of cultures to MSC-conditioned medium. Antioxidants (ascorbic acid and TROLOX((r))), N(omega)-nitro-l-arginine methyl ester hydrochloride, and anti-inflammatory drugs (indomethacin and dexamethasone) reduced cell death in hippocampal organotypic cultures after their exposure to MSC-conditioned medium. The results obtained here suggest that MSC-secreted factors trigger reactive species generation and neuroinflammation in organotypic cultures of hippocampus, introducing a note of caution in the use of these cells for neurological application. PMID- 20955078 TI - Callose deposition: a multifaceted plant defense response. AB - Callose deposition in Arabidopsis has emerged as a popular model system to quantify activity of plant immunity. However, there has been a noticeable rise in contradicting reports about the regulation of pathogen-induced callose. To address this controversy, we have examined the robustness of callose deposition under different growth conditions and in response to two different pathogen associated molecular patterns, the flagellin epitope Flg22 and the polysaccharide chitosan. Based on a commonly used hydroponic culture system, we found that variations in growth conditions have a major impact on the plant's overall capacity to deposit callose. This environmental variability correlated with levels of hydrogen peroxide (H2O2) production. Depending on the growth conditions, pretreatment with abscissic acid stimulated or repressed callose deposition. Despite a similar effect of growth conditions on Flg22- and chitosan induced callose, both responses showed differences in timing, tissue responsiveness, and colocalization with H2O2. Furthermore, mutant analysis revealed that Flg22- and chitosan-induced callose differ in the requirement for the NADPH oxidase RBOHD, the glucosinolate regulatory enzymes VTC1 and PEN2, and the callose synthase PMR4. Our study demonstrates that callose is a multifaceted defense response that is controlled by distinct signaling pathways, depending on the environmental conditions and the challenging pathogen-associated molecular pattern. PMID- 20955079 TI - Genomic and evolutionary features of the SPI-1 type III secretion system that is present in Xanthomonas albilineans but is not essential for xylem colonization and symptom development of sugarcane leaf scald. AB - Xanthomonas albilineans is the causal agent of sugarcane leaf scald. Interestingly, this bacterium, which is not known to be insect or animal associated, possesses a type III secretion system (T3SS) belonging to the injectisome family Salmonella pathogenicity island 1 (SPI-1). The T3SS SPI-1 of X. albilineans shares only low similarity with other available T3SS SPI-1 sequences. Screening of a collection of 128 plant-pathogenic bacteria revealed that this T3SS SPI-1 is present in only two species of Xanthomonas: X. albilineans and X. axonopodis pv. phaseoli. Inoculation of sugarcane with knockout mutants showed that this system is not required by X. albilineans to spread within xylem vessels and to cause disease symptoms. This result was confirmed by the absence of this T3SS SPI-1 in an X. albilineans strain isolated from diseased sugarcane. To investigate the importance of the T3SS SPI-1 during the life cycle of X. albilineans, we analyzed T3SS SPI-1 sequences from 11 strains spanning the genetic diversity of this species. No nonsense mutations or frameshifting indels were observed in any of these strains, suggesting that the T3SS SPI-1 system is maintained within the species X. albilineans. Evolutionary features of T3SS SPI-1 based on phylogenetic, recombination, and selection analyses are discussed in the context of the possible functional importance of T3SS SPI-1 in the ecology of X. albilineans. PMID- 20955080 TI - Interaction between Diplodia pinea and D. scrobiculata in red and jack pine seedlings. AB - Sphaeropsis sapinea sensu lato is a conifer fungal pathogen that causes shoot blight and stem cankers. Recently, the former S. sapinea has been divided into two species, Diplodia pinea and D. scrobiculata. The aims of the study were to determine the contribution of each species in disease development on red and jack pines by means of co-inoculations and molecular identifications, and to evaluate how the presence of each species affects the development and aggressiveness of the other. Symptom severity (distance below the inoculation site at which necrotic needles were observed) and identification length (the maximum distance from inoculation site from which either D. pinea or D. scrobiculata was identified using molecular methods) were recorded 4 weeks after inoculating wounded seedlings with agar plugs colonized by these pathogens. The results suggested that D. pinea was much more aggressive on both hosts than D. scrobiculata. When a seedling was co-inoculated with these pathogens, the symptom development appeared to be mainly due to D. pinea. The presence of D. pinea also interfered with the establishment of D. scrobiculata in the plant tissue. However, D. scrobiculata showed antagonism toward D. pinea. When both pathogens co-occurred in a single seedling, symptom severity caused by D. pinea was less than when D. pinea alone was present. PMID- 20955081 TI - Genetic and morphological evidence that Phoma sclerotioides, causal agent of brown root rot of alfalfa, is composed of a species complex. AB - Phoma sclerotioides, causal agent of brown root rot of alfalfa, causes severe root and crown lesions on alfalfa and other perennial forage legumes in regions with harsh winters. Isolates of P. sclerotioides exhibit diverse cultural morphologies on potato dextrose agar (PDA), suggesting that they may exhibit a high degree of genetic diversity. To investigate the genetic relatedness of P. sclerotioides isolates, 154 isolates from North America were sequenced at 10 loci. Maximum parsimony and maximum likelihood analyses of the complete 10-locus data set placed isolates into multiple strongly supported clades, and analyses of gene-jackknife and single-gene partitions of the data set indicated robust support for six major clades and three subclades. Genetic differences corresponded closely to differences in conidial size and septation, pycnidial neck length, mycelial pigmentation, and growth rate in axenic culture at 18 and 25 degrees C. Isolates exhibited morphologies broadly consistent with the species description of P. sclerotioides, and new species were not designated. On the basis of genetic and morphological differences, we propose establishing seven infraspecific varieties within P. sclerotioides: P. sclerotioides var. sclerotioides, champlainii, viridis, obscurus, steubenii, macrospora, and saskatchewanii. All varieties of P. sclerotioides caused brown root rot of alfalfa and grew well at low temperatures. PMID- 20955082 TI - Meloidogyne virulence locus molecular marker for characterization of selected mi virulent populations of Meloidogyne spp. is correlated with several genera of betaproteobacteria. AB - Resistance to root-knot nematodes in tomato is conferred by the Mi resistance gene to the three most important species of Meloidogyne: M. arenaria, M. incognita, and M. javanica. Nevertheless, the Mi gene is unable to inhibit the reproduction of selected and naturally Mi-virulent populations of root-knot nematodes. As pathogenicity assays are time consuming, molecular markers were developed for the easy identification of Mi-virulent populations of Meloidogyne. The sequence characterized amplified region-Meloidogyne virulence locus (MVC) molecular marker is reported to differentiate Mi-avirulent and naturally Mi virulent from selected Mi-virulent populations. This marker was used to compare acquired virulence in populations of M. javanica from Spain. The original populations used to develop the MVC marker were included as control for reference. Results showed that this marker did not amplify genomic DNA extracted from single juveniles or females of any of the populations tested either from Spain or Japan. In silico analyses performed with the recently published complete genome of M. incognita, indicated that the MVC marker is not correlated to a MVC or to any eukaryotic organism but to several betaproteobacteria genus from the family Comamonadaceae. PMID- 20955083 TI - In the eye of the beholder: the effect of rater variability and different rating scales on QTL mapping. AB - The agronomic importance of developing durably resistant cultivars has led to substantial research in the field of quantitative disease resistance (QDR) and, in particular, mapping quantitative trait loci (QTL) for disease resistance. The assessment of QDR is typically conducted by visual estimation of disease severity, which raises concern over the accuracy and precision of visual estimates. Although previous studies have examined the factors affecting the accuracy and precision of visual disease assessment in relation to the true value of disease severity, the impact of this variability on the identification of disease resistance QTL has not been assessed. In this study, the effects of rater variability and rating scales on mapping QTL for northern leaf blight resistance in maize were evaluated in a recombinant inbred line population grown under field conditions. The population of 191 lines was evaluated by 22 different raters using a direct percentage estimate, a 0-to-9 ordinal rating scale, or both. It was found that more experienced raters had higher precision and that using a direct percentage estimation of diseased leaf area produced higher precision than using an ordinal scale. QTL mapping was then conducted using the disease estimates from each rater using stepwise general linear model selection (GLM) and inclusive composite interval mapping (ICIM). For GLM, the same QTL were largely found across raters, though some QTL were only identified by a subset of raters. The magnitudes of estimated allele effects at identified QTL varied drastically, sometimes by as much as threefold. ICIM produced highly consistent results across raters and for the different rating scales in identifying the location of QTL. We conclude that, despite variability between raters, the identification of QTL was largely consistent among raters, particularly when using ICIM. However, care should be taken in estimating QTL allele effects, because this was highly variable and rater dependent. PMID- 20955084 TI - A novel member of the genus Nepovirus isolated from Cucumis melo in Japan. AB - An unusual virus was isolated from a Japanese Cucumis melo cv. Prince melon plant showing mild mottling of the leaves. The virus had a broad experimental host range including at least 19 plant species in five families, with most infected plants showing no symptoms on inoculated and uninoculated systemically infected leaves. The virus particles were spherical, approximately 28 nm in diameter, and the coat protein (CP) had an apparent molecular mass of about 55 kDa. The virus possessed a bi-partite genome with two RNA species, of approximately 8,000 and 4,000 nucleotides. Both genome components for the new virus were sequenced. Amino acid sequence identities in CP between the new virus and previously characterized nepoviruses were found to be low (less than 27%); however, in phylogenetic reconstructions the closest relationship was revealed between the new virus and subgroup A nepoviruses. These results suggest that the new virus represents a novel member of the genus Nepovirus. A new name, Melon mild mottle virus, has been proposed for this new virus. PMID- 20955085 TI - High prevalence of asymptomatic bocavirus in daycare: is otitis media a confounder? PMID- 20955087 TI - Small-area variations in sales of TNF inhibitors in Sweden between 2000 and 2009. AB - OBJECTIVE: To measure small-area variations in sales per capita of tumour necrosis factor (TNF) inhibitors. METHODS: For 2000-2009, sales data on etanercept, infliximab, and adalimumab were retrieved from the Swedish National Corporation of Pharmacies, which keeps data on drugs dispensed in ambulatory care and hospitals. As points of reference, data were retrieved on all drugs, non biologic treatments for chronic inflammatory disorders (sulfasalazine, methotrexate, azathioprine), and for a biologic used in a different therapeutic area (trastuzumab). As a corollary measure to sales per capita, penetration of biologics in the rheumatoid arthritis (RA) population was calculated using nationwide registers. Small areas were defined as the 21 counties of Sweden. RESULTS: From 2000 to 2009, annual TNF inhibitor sales increased 9-fold from 195 to 1779 million SEK (0.7-5.0% of total drug expenditure). The county variation in sales per capita, initially 6.2-fold (coefficient of variation 42%), decreased to 2.3-fold in 2009 (24%). During the same period, total drug expenditure per capita remained at a 1.2-fold county variation (4-6%). Sales per capita variations of non-biologic treatments against chronic inflammatory diseases ranged from 1.5 to 1.8 (12-16%). For trastuzumab, a 3.2-fold variation (30%) was observed in 2009. At the patient level, there was a 2-fold county variation (from 10% to 21%) in biologic penetration in RA. County-specific sales per capita were associated with mean RA duration (r = -0.52, p = 0.015) and C-reactive protein at treatment initiation (r = -0.49, p = 0.025), while pain was borderline significant (r = 0.43, p = 0.055). CONCLUSIONS: Despite universal access to treatment, substantial but decreasing small-area variations were observed. Although geographic variations are anticipated initially, their persistence calls for investigation of patient equity and treatment appropriateness as counties seem to have different initiation thresholds. PMID- 20955088 TI - Epidemiology of symptom-defined gastroesophageal reflux disease and reflux esophagitis: the systematic investigation of gastrointestinal diseases in China (SILC). AB - OBJECTIVE: Gastroesophageal reflux disease (GERD) is thought to be less prevalent in China than in Western countries. However, essential population-based endoscopy data are lacking for this country. MATERIAL AND METHODS: As part of a wider study, 3600 individuals selected randomly from the Shanghai region were asked to undergo endoscopy. Participants completed a general information questionnaire and a Chinese version of the Reflux Disease Questionnaire. When sufficient numbers were available, associations were assessed using multiple logistic regression or the Wilcoxon rank-sum test. RESULTS: Of 3153 (87.6%) individuals who completed the survey, 1030 (32.7%) agreed to endoscopy and 1029 endoscopies were suitable for analysis. Symptom-defined GERD was more prevalent in the endoscopy group (4.7%) than in the non-endoscopy group (1.7%). Prevalence estimates were 6.4% for reflux esophagitis, 1.8% for endoscopically suspected esophageal metaplasia and 0.7% for hiatus hernia. Reflux esophagitis was more prevalent in patients with symptom-defined GERD than in those without (12.5% [6/48] vs. 6.1% [60/981]), and was significantly associated with reflux symptoms of any frequency or severity (OR = 2.10, 95% CI 1.13-3.89) and with negative Helicobacter pylori infection (OR = 0.44, 95% CI 0.25-0.80). Only 28.8% of participants with reflux esophagitis had heartburn and/or regurgitation symptoms. Epigastric burning was significantly more severe and frequent in participants with reflux esophagitis than in those without (p = 0.05). CONCLUSIONS: Reflux esophagitis is less prevalent in China than reported in Western countries. Further work is needed to establish why reflux esophagitis appears less symptomatic in China than in Western countries. PMID- 20955089 TI - The role of endoscopic retrograde cholangiography for biliary stricture after adult living donor liver transplantation: technical aspect and outcome. AB - OBJECTIVE: Biliary strictures, occurring after living donor liver transplantation (LDLT) with duct-to-duct biliary reconstruction, are usually treated by endoscopic retrograde cholangiography (ERC); nevertheless, its therapeutic value is still under evaluation. The aim of this study was to describe technical aspects of ERC in treating biliary strictures and evaluate their outcomes. MATERIAL AND METHODS: A total of 147 patients who underwent ERC for biliary strictures distal to left and right main hepatic ducts occurring after LDLT performed between January 2004 and March 2007 were retrospectively analyzed. Biliary strictures were treated by both balloon dilation and stenting in consecutive ERC sessions. Then, we evaluated immediate and final endoscopic success rates. RESULTS: Immediate endoscopic success was achieved in 82/147 (55.8%) patients and final endoscopic success in 52/141 (36.9%). An average of 6.3 endoscopic sessions and 12.7 months were required to achieve final endoscopic success. ERC-related complications including death in one patient occurred in about 7.2%. Mean recurrence-free period after final endoscopic success was 21.5 months, with six (11.5%) patients having a relapse of biliary strictures. Final endoscopic success group compared with failure group showed significantly later occurrence of biliary strictures after LDLT. CONCLUSIONS: Achieving final endoscopic success using ERC alone for treating post-LDLT biliary strictures distal to left and right main hepatic ducts is rather difficult, although outcomes are improving with time. Strategies are thought to be needed to improve outcomes such as technical/instrumental improvement. PMID- 20955090 TI - Accelerated progression of hepatocellular carcinoma with cytokeratin 19 expression during treatment with lamivudine for hepatitis B virus-related liver cirrhosis. PMID- 20955091 TI - Calcium channel blockers and biliary pancreatitis. PMID- 20955093 TI - Adenomyosis to uterine transplantation. PMID- 20955094 TI - Surgical treatment of vulvar vestibulitis: a review. AB - Vulvar vestibulitis syndrome, a subset of vulvodynia, is a complex pain syndrome. It causes severe dyspareunia and affects mainly young women. The etiology is unknown and no uniformly effective treatment exists. Surgery has been considered as 'the last resort' in the management of patients not responding to conservative treatment modalities. For this review, all studies of surgical treatment of vulvar vestibulitis were evaluated. We describe the evolution of vestibulectomy techniques through the years. Our aim was also to find out whether any surgical technique is better than others providing better patient satisfaction and lower complication rates. We conclude that surgical technique as such plays a relatively small role. Surgery seems to be effective. However, lack of randomized trials and insufficient data on complication rates must be emphasized. PMID- 20955095 TI - Comparison of first and second trimester ultrasound screening for fetal anomalies in the southeast region of Sweden. AB - OBJECTIVE: To assess and compare the sensitivity for detecting fetal anomalies and chromosomal aberrations by routine ultrasound examination performed in the second trimester with results from an examination performed at 11-14 weeks gestation. DESIGN: Observational study. SETTING: Five centers in the southeast region of Sweden. POPULATION: A total of 21,189 unselected pregnant women. METHODS: The scan was performed at one center in the first trimester and at the remaining four centers in the second trimester. Outcome measures resulting from first trimester scanning were compared with those from the second trimester scanning. MAIN OUTCOME MEASURES: Detection rates of fetal structural anomalies and chromosomal aberrations. Results. At the first trimester scan 13% of all anomalies were detected, and at the second trimester scan 29% were detected. Lethal anomalies were detected at a high level at both times: 88% in the first, 92% in the second. The percentage of chromosomal aberrations discovered at the early scan was 71%, in the later 42%. The percentage of heart malformations detected was surprisingly low. CONCLUSION: The results showed the advantages of the later scan in discovering anomalies of the heart, urinary tract and CNS, and of the early scan in discovering chromosomal aberrations. Lethal malformations were detected at a high level in both groups, but detection of heart malformations needs improvement. PMID- 20955096 TI - Decreased 1,25-dihydroxy vitamin D levels in women with intrahepatic cholestasis of pregnancy. AB - OBJECTIVE: The pathogenesis of intrahepatic cholestasis of pregnancy (ICP) involves impaired bile acid and estrogen/progesterone metabolism and excretion based on genetic and environmental factors. The role of vitamin D is undefined. DESIGN: Observational study. SETTING: Department of Obstetrics and Gynecology, Danderyd Hospital, Stockholm, Sweden. POPULATION: Swedish. METHOD: We measured serum 1,25-dihydroxy vitamin D3 (1,25-D3) and parathormone in 22 women with ICP at presentation, in comparison with 11 healthy women at delivery. RESULTS: ICP women had significantly (p = 0.0041) lower levels of 1,25-D3 in serum (76.4 +/- 23.1 vs. 112.0 +/- 40 ng/L, mean +/- SD), unrelated to serum bile acids. 1,25-D3 levels were inversely correlated (p < 0.05) to meconium staining of amniotic fluid. Parathormone levels did not differ between ICP and healthy women. CONCLUSION: Lower 1,25-D3 levels in ICP are inversely correlated by meconium staining, a major indicator of fetal distress. Our finding may have pathogenetic and clinical implications since vitamin D regulates steroid metabolism and 1,25 D3 deficiency may impair fetal outcome. PMID- 20955097 TI - Obstetric hospitalizations among Italian women, regular and irregular immigrants in North-Eastern Italy. AB - OBJECTIVE: Italy has become an important host country for economic immigrants. The study is aimed at providing a descriptive analysis of obstetric hospitalizations among Italian and immigrant women in North-Eastern Italy. DESIGN: Population-based registry descriptive study. SETTING: Veneto Region, Italy. METHODS: All obstetric hospitalizations in 2006-2007 were extracted from the regional archive of hospital discharge records (n = 144,698). Discharges for vaginal delivery, cesarean section, threatened abortion and other antepartum diagnoses, miscarriages, and induced abortions were identified among residents with Italian or foreign citizenship, and irregular immigrants. Hospitalization rates for the above diagnostic categories were computed for Italian and foreign Veneto residents. MAIN OUTCOME MEASURES: Delivery rates, proportion of cesarean sections, hospitalization rates for antepartum hospitalizations, miscarriage, induced abortion, and hospitalization rate ratios of immigrants versus Italian women. RESULTS: Among Italian women, regular and irregular immigrants, the percentages of teenage deliveries were 0.7, 2.9, and 8.4%; the ratios of miscarriages to deliveries were 0.16, 0.15 and 0.35; the ratios of induced abortions to deliveries were 0.13, 0.24 and 0.81, respectively. Regular immigrants accounted for 10% of population aged 15-49 and for 20% of deliveries. The age-related increase in miscarriage risk was steeper among regular immigrants. The induced abortions to deliveries ratio peaked among Italians aged <25 and regular immigrants aged >=35 years. 40% of Italians and 30% of regular immigrants sought care outside nearest hospitals. CONCLUSIONS: Wide differences in reproductive behavior, health status, and patterns in the access to health services exist between Italians, regular and irregular immigrants even though they represent three connected populations. PMID- 20955098 TI - Down-regulated progesterone receptor A and B coinciding with successful treatment of endometrial hyperplasia by the levonorgestrel impregnated intrauterine system. AB - OBJECTIVE: To investigate whether regression of endometrial hyperplasia observed after 3 months of treatment with levonorgestrel impregnated intrauterine system device (LNG-IUS) was sustained after 6 months and whether these effects were still occurring synchronously with extinguished expression of progesterone receptors and increased apoptosis. DESIGN: Retrospective population-based observational study. SETTING: Six local hospitals and one university hospital in northern Norway. POPULATION: Patients (n = 41) with low and medium risk endometrial hyperplasia. METHODS: Histopathological treatment response comparing LNG-IUS (n = 25) and standard per oral medroxyprogesterone (n = 16). Expression of progesterone receptor A (PR-A), progesterone receptor B (PR-B), ER-alpha, ER beta, Bcl-2, BAX, Caspase-3 and metallothionein (MT) were investigated by immunohistochemistry; results were evaluated by a semi-quantitative H-score. MAIN OUTCOME MEASURES: Response to progestin treatment. RESULTS: All the LNG-IUS treated patients had therapy response after 6 months. PR-A and PR-B in glands were almost extinguished for IUD users compared to the oral group. Estrogen receptors were also reduced. Co-existent changes in apoptosis were differently modulated in glands and stroma in the two treatment groups. Bcl-2 was different in glands and stroma in responders and non-responders to oral therapy. CONCLUSION: The study confirms that LNG-IUS can be safely used for 6 months as treatment for endometrial hyperplasia. The clinical effect is accompanied by almost extinguished PR-receptors in glands coinciding with modulation of apoptosis. The results strongly indicate that progestins activate non-classical initiated signaling pathways. PMID- 20955099 TI - Sexual behavior and contraception among young Polish women. AB - OBJECTIVE: To analyze sexual behavior and the use of contraception among young women in Poland. DESIGN: Cross-sectional study. POPULATION: 1,478 young women in higher (78.9%) and secondary (21.1%) education. SETTING: Gdansk region in Poland. METHODS: The data were gathered between September and December 2008 by the use of a questionnaire prepared for the purpose of this study, completed anonymously and in person by the young women. RESULTS: Sexual activity had been initiated by 67.2% of the women studied at a mean age of 18.7 years (+/-1.97). Assessment was made of changes in their contraceptive practice between the time of sexual initiation and later sexual activity. Since their first experience of intercourse 67.0% did not change their contraceptive methods. As many as 40.1% continued using either low effective methods or no contraception. Early sexual initiation was linked to a significantly lower likelihood of highly effective contraception, more frequent unprotected sexual intercourse and more sexual partners (p < 0.05). Over half of women assigned to a 'high-risk' group with regard to the chance of unintended pregnancy and sexually transmitted infection, declared that their behavior did not carry any risk, similar (p > 0.05) to those who did not have a history of hazardous behavior. CONCLUSION: Sexual behavior differentiates Polish women from the women in Western Europe. Despite the welcome tendency toward choosing reliable contraceptives, use of appropriate contraception is still insufficient. PMID- 20955100 TI - Severe acute maternal morbidity and mode of delivery in the Netherlands. AB - OBJECTIVE: To evaluate the risk of severe acute maternal morbidity (SAMM) related to mode of delivery. DESIGN: Prospectively nationwide population based cohort study. Setting. All 98 maternity units in the Netherlands. POPULATION: All pregnant women in the Netherlands. METHODS: Cases were collected during a 2-year period. Incidence was assessed for all cases and for a subgroup of cases in which a direct relation between SAMM and mode of delivery was possible. In the latter group, all cases not clearly related to mode of delivery were excluded. Incidence of cesarean section (CS) compared to (attempted) vaginal delivery was calculated, and risk of SAMM after previous CS was assessed. MAIN OUTCOME MEASURES: Incidence of SAMM by mode of delivery; odds ratios (OR). RESULTS: The incidence of SAMM possibly related to mode of delivery was 6.4/1,000 during elective CS compared to 3.9/1,000 during attempted vaginal delivery (OR 1.7: 95% CI 1.4-2.0). Women with a previous CS were at increased risk for SAMM in their present pregnancy (OR 3.0: 95% CI 2.7-3.3). CONCLUSION: CS in a previous as well as present pregnancy increased the risk of SAMM. The risk remained increased after excluding those cases where SAMM was not clearly related to mode of delivery. PMID- 20955101 TI - Short- and long-term results of secondary anterior sphincteroplasty in 33 patients with obstetric injury. AB - OBJECTIVE: To study short- and long-term improvement in obstetric anal incontinence after secondary overlapping sphincteroplasty and repeat repairs. DESIGN: A prospective analysis based on incontinence scores and patient satisfaction. SETTING: Department of Gastroenterological Surgery, Oslo University Hospital, a tertiary unit also dealing with sphincter repair. POPULATION: Of 40 obstetric patients operated consecutively from February 1996 to April 2004, 33 (83%) patients with median age of 36 years were eligible for evaluation. METHODS: Wexner's and St. Mark's incontinence score, clinical examination, anal ultrasonography and manometry, and neurophysiological examination when indicated. Patient satisfaction to treatment was recorded. The patients had anterior overlapping sphincteroplasty. Five had repeat operations, four sphincteroplasty and two post-anal repair. MAIN OUTCOME MEASURES: Anal incontinence, patient satisfaction. RESULTS: The 33 patients were examined after median 7 (range 2-62) months and 103 (62-162) months. Median incontinence scores preoperatively and after short- and long-term follow-up were 12 (5-20), 7 (5-20) (p < 0.01) and 9 (0 18) (p < 0.05), respectively. Three patients (9%) had normalized anal incontinence (score <=1) after short- and long-term follow-up. Corresponding numbers for improved anal incontinence were 22 (67%) and 16 (49%), respectively. Improvement in incontinence scores and patients' satisfaction were concordant. Symptom duration (n = 7), pudendal neuropathy (n = 6), repeat repair (n = 5) and instrument delivery (n = 3) were associated with adverse outcome. CONCLUSIONS: Improvement in anal incontinence at short-term follow-up is attenuated at long term follow-up. Stoma formation, sacral nerve stimulation and neo-sphincter formation must be considered in compliant patients. PMID- 20955102 TI - Anthropometry and cardiovascular risk factors in women and offspring after pregnancies complicated by preeclampsia or diabetes mellitus. AB - OBJECTIVE: To explore whether there are any differences in cardiovascular risk factors, including anthropometrics, blood pressure and serum glucose between women and offspring after pregnancies complicated by preeclampsia or diabetes mellitus, compared to uncomplicated pregnancies. DESIGN: Longitudinal follow-up of mother and child previously recruited to a pregnancy biobank in Norway. SETTING: University hospital. POPULATION: Women with a history of preeclampsia (n = 23), gestational diabetes mellitus (n = 12), diabetes mellitus type 1 (n = 11), or controls (n = 17), and their respective child were recruited 5-8 years after the index pregnancy. METHODS: Anthropometrics and blood pressures were measured in mother and child. All non-diabetic women underwent an oral glucose challenge test. MAIN OUTCOME MEASURES: Body mass index, waist circumference, waist to hip ratio, serum glucose, systolic and diastolic blood pressure. RESULTS: Women in the preeclampsia and diabetes mellitus groups had a slightly higher median systolic blood pressure (p < 0.05), and were more often abdominally obese (waist circumference >=88 cm) compared with controls (p < 0.05). A waist to hip ratio >=0.85 was more common in the diabetes group compared to the controls (p < 0.01). Fasting serum glucose was higher in the gestational diabetes mellitus group (p < 0.05) compared to controls. A higher proportion of children of mothers with diabetes mellitus and preeclampsia were overweight or obese compared to controls, but the difference was not statistically significant. CONCLUSIONS: This clinical study has identified several modifiable risk factors for cardiovascular disease in women and children 5-8 years after pregnancies complicated by preeclampsia or diabetes mellitus. Potential intervention strategies could focus on life style alterations after delivery, with emphasis on weight management. PMID- 20955103 TI - Dietary intake and physical activity in women and offspring after pregnancies complicated by preeclampsia or diabetes mellitus. AB - Women with a history of diabetes mellitus (DM) or preeclampsia (PE) in pregnancy run an increased risk of future cardiovascular associated diseases. Offspring of such pregnancies may possibly also have an altered risk in health status. Descriptive studies of dietary intake and physical activity in mother and children several years after pregnancies complicated by PE or DM are lacking. By the use of a simple questionnaire survey, we aimed at exploring whether there are any differences in these lifestyle factors between women and between offspring 5 8 years after PE (23 women-child pairs) or DM (23 women-child pairs) in pregnancy, compared to uncomplicated pregnancies (controls, 17 women-child pairs). Our data showed that women in the DM- and PE-group were less physically active compared to controls (p < 0.01 and p < 0.05, respectively), and more children in the control-group followed the Norwegian fruit recommendations compared to children in the DM-group (p < 0.01). PMID- 20955106 TI - Social and behavioral characteristics of HIV-positive MSM who trade sex for methamphetamine. AB - BACKGROUND: Previous research among drug-using men who have sex with men (MSM) indicates that trading sex for methamphetamine may be common. OBJECTIVES: This study identified background characteristics, substance use variables, contextual factors, and sexual risk behaviors associated with trading sex for methamphetamine in a sample of HIV-positive MSM. Baseline data were gathered from 155 participants who were enrolled in a sexual risk-reduction intervention. Logistic regression was used to compare MSM who traded sex for methamphetamine with men who did not. RESULTS: Forty-three percent of the sample reported trading sex for methamphetamine in the past 2 months. Trading sex for methamphetamine was associated with being a binge user, homelessness, having an income of less than $20,000 per year, being less assertive at turning down drugs, engaging in more anal sex without a condom, and seeking out risky sex partners when high on methamphetamine. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: These data suggest that the trading of sex for methamphetamine may be a primary source of new HIV infections within and outside of the MSM community, necessitating targeted interventions with this vulnerable subgroup. PMID- 20955107 TI - Heroin anticraving medications: a systematic review. AB - BACKGROUND: Heroin craving is a trigger for relapse and dropping out of treatment. Methadone has been the standard medication for the management of heroin craving. OBJECTIVES: We explored the medication options other than methadone which may have heroin anticraving properties. METHODS: To be selected for the review, articles had to include outcome measures of the effect of the studied medication on subjective and/or objective opiate craving and be of the following two types: (1) randomized, controlled, and/or double-blind clinical trials (RCTs) examining the relationship between the studied medication and heroin craving; (2) nonrandomized and observational studies (NRSs) examining the relationship between the studied medication and heroin craving. Thirty-three articles were initially included in the review. Twenty-one were excluded because they did not meet the inclusion criteria. We present the results of 12 articles that met all the inclusion criteria. RESULTS: Some new medications have been under investigation and seem promising for the treatment of opiate craving. Buprenorphine is the second most studied medication after methadone for its effect on opiate craving. At doses above 8 mg daily, it seems very promising and practical for managing opiate craving in patients receiving long-term opioid maintenance treatment. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: In doses higher than 8 mg daily, buprenorphine is an appropriate treatment for opiate craving. More research with rigorous methodology is needed to study the effect of buprenorphine on heroin craving. Also more studies are needed to directly compare buprenorphine and methadone with regard to their effects on heroin craving. PMID- 20955108 TI - Evaluation of models for predicting drug-drug interactions due to induction. AB - IMPORTANCE OF THE FIELD: Drug-drug interactions caused by induction of metabolizing enzymes, particularly CYP3A, can impact the efficacy and safety of co-administered drugs. It is, therefore, important to understand a new compound's potential for enzyme induction and to understand how to use the induction data generated in vitro to predict potential for drug-drug interactions in vivo. AREAS COVERED IN THIS REVIEW: Recent advances in methods for using in vitro data to predict potential for CYP3A induction in vivo are reviewed. WHAT THE READER WILL GAIN: The reader will gain a comprehensive understanding of the advantages and disadvantages of various prediction methods for induction and be able to directly compare different methods using a common in vitro data set. TAKE HOME MESSAGE: The various methods for predicting clinical CYP3A induction from in vitro induction data all have demonstrated utility; it is the authors' opinion that the correlation-based approaches offer as good or better predictivity and have simpler input requirements than more complex approaches. Of the different correlation approaches, the relatively simple unbound C(max)/EC(50) or AUC/EC(50) approaches are the simplest and yet show the best correlation to the observed clinical data. While the approaches discussed herein represent an improvement in our understanding of the predictive value of in vitro induction data, it is important to recognize that there is still room for improvement in quantitative prediction of magnitude of drug interactions due to induction. PMID- 20955109 TI - Pharmacokinetic evaluation of idebenone. AB - IMPORTANCE OF THE FIELD: Idebenone is a synthetic short chain benzoquinone that acts as an electron carrier in the mitochondrial electron transport chain, thereby, facilitating the production of ATP. In addition, idebenone is an antioxidant and can inhibit lipid peroxidation and may protect cell membranes and mitochondria from oxidative damage. High dose idebenone (Catena((r))) is approved in Canada for the symptomatic treatment of Friedreich's ataxia and is currently under clinical investigation for use in a number of mitochondrial and neuromuscular diseases. AREAS COVERED IN THIS REVIEW: This review summarizes the pharmacology, pharmacokinetic and clinical efficacy/safety data of idebenone and its metabolites and provides an update of the clinical trials completed and in progress. WHAT THE READER WILL GAIN: Following oral administration, idebenone is rapidly metabolized via oxidative shortening by a number CYP isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) to yield QS10, QS8, QS6 and QS4. Idebenone and these metabolites concomitantly undergo conjugation via glucuronidation and sulfatation to yield conjugated moieties represented as idebenone-C, QS10-C, QS8 C, QS6-C and QS4-C. Previous reports in the literature were only able to quantify plasma concentrations of idebenone measured together with its conjugates. More recently, highly sensitive and specific liquid chromatography method with tandem mass spectrometric methods have been developed, allowing the quantification of the parent molecule idebenone and its main metabolite QS10, separately. TAKE HOME MESSAGE: After absorption, idebenone is rapidly metabolized by first pass metabolism and shows dose-proportional pharmacokinetics in healthy subjects in daily doses up to 2250 mg. The recent development of advanced analytical techniques allows the detection of idebenone and unconjugated metabolites in plasma and consequently opens the possibility for evaluation of pharmacokinetic/pharmacodynamic relationships which will be helpful to further understand the metabolism and therapeutic potential of idebenone. In clinical studies, idebenone was safe and well tolerated at doses up to 2250 mg/day. PMID- 20955110 TI - Bevacizumab for metastatic renal cell carcinoma: a monoclonal antibody in a sea of small molecules. AB - Several years ago, the oncologist was limited to a narrow scope of immunotherapeutic agents for the treatment of metastatic renal cell carcinoma (mRCC). Within the past 5 years, however, a total of 6 targeted agents have been approved for the treatment of this disease. The abundance of novel therapies has introduced a new dilemma for the oncologist--namely, how can one make evidence based choices amongst available agents? Recently, two Phase III studies (AVOREN and Cancer and Leukemia Group B [CALGB] 90206) assessed the activity of 1st-line therapy with bevacizumab in combination with interferon-alfa (IFN-alfa) as compared to IFN-alfa alone. Both trials demonstrated a significant benefit in progression-free survival (PFS) with bevacizumab, with no benefit in overall survival (OS). Herein, the implications of these data are assessed in the context of data reported from other recent pivotal trials in mRCC. Methods to resolve areas of clinical equipoise in the treatment of mRCC (i.e., comparative trial designs and biomarker analyses) are also proposed. PMID- 20955111 TI - Genetically modified dendritic cells in cancer immunotherapy: a better tomorrow? AB - IMPORTANCE OF THE FIELD: Dendritic cells (DC) are powerful antigen-presenting cells that induce and maintain primary cytotoxic T lymphocyte (CTL) responses directed against tumor antigens. Consequently, there has been much interest in their application as antitumor vaccines. AREAS COVERED IN THIS REVIEW: A large number of DC-based vaccine trials targeting a variety of cancers have been conducted; however, the rate of reported clinically significant responses remains low. Modification of DC to express tumor antigens or immunostimulatory molecules through the transfer of genes or mRNA transfection offers a logical alternative with potential advantages over peptide- or protein antigen-loaded DC. In this article, we review the current results and future prospects for genetically modified DC vaccines for the treatment of cancer. WHAT THE READER WILL GAIN: Genetically-modified dendritic cell-based vaccines represent a powerful tool for cancer therapy. Numerous preclinical and clinical studies have demonstrated the potential of dendritic cell vaccines alone or in combination with other therapeutic modalities. TAKE HOME MESSAGE: Genetically modified DC-based anti cancer vaccination holds promise, perhaps being best employed in the adjuvant setting with minimal residual disease after primary therapy, or in combination with other antitumor or immune-enhancing therapies. PMID- 20955112 TI - T regulatory cells in cancer: recent advances and therapeutic potential. AB - IMPORTANCE OF THE FIELD: The active suppression of immune responses against tumor is a major barrier to the likely success of cancer immunotherapy. There is now compelling evidence implicating T regulatory cells (Tregs) as being key players driving immune suppression. Elevated frequencies of Tregs within the peripheral circulation and tumor microenvironment of cancer patients correlate with poor prognosis and reduced survival. Understanding the mechanism of Treg elevation is critical for the development of new approaches aiming to modulate the frequency and function of Tregs to enhance the efficacy of cancer immune-based therapies. AREAS COVERED IN THIS REVIEW: This review focuses on current knowledge concerning Tregs in cancer and discusses putative mechanisms which underlie the expansion of Tregs in cancer patients. Additionally, we review current strategies to deplete/suppress Treg activity, the limitations of these strategies and future perspective for improving their efficacy. WHAT THE READER WILL GAIN: An insight of the current aspects concerning Treg subsets in cancer and an overview of recent advances in the identification of Treg-specific markers, in addition to the potential strategies to target Tregs for enhancing antitumor immunity. TAKE HOME MESSAGE: Mechanisms by which Treg functions modulate the immune response to tumors are becoming further understood. However, specific markers to tumor specific/induced Tregs are yet to be clearly identified, which is a major limitation in optimizing strategies to specifically target Tregs in cancer. Despite this, strategies aimed at modulating Tregs in patients are providing some early encouraging results supporting the overall concept and indicating that further studies are clearly warranted. PMID- 20955113 TI - Stem cell-derived neurotrophic support for the neuromuscular junction in spinal muscular atrophy. AB - IMPORTANCE OF THE FIELD: Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by specific degeneration of alpha-motor neurons in the spinal cord. The use of cell transplantation to restore lost function through cell replacement or prevent further degeneration of motor neurons and synapses through neurotrophic support heralds tremendous hope in the SMA field. AREAS COVERED IN THIS REVIEW: Much research has been carried out in the last decade on the use of embryonic stem cells in cell replacement strategies for various neurodegenerative diseases. Cell replacement is contingent on the ability of transplanted cells to integrate and form new functional connections with host cells. In the case of SMA, cell replacement is a tall order in that axons of transplanted cells would be required to grow over long distances from the spinal cord through growth-averse terrain to synapse with muscles in the periphery. The efficacy of neurotrophic support is contingent on the ability of transplanted cells to secrete neurotrophins appropriate for degenerating motor neurons in the spinal cord or development/stability of the neuromuscular junction (NMJ) in the periphery. WHAT THE READER WILL GAIN: The reader will gain an understanding of the potential of neurotrophins to promote development of the NMJ in a diseased or injured environment. TAKE HOME MESSAGE: Neurotrophins play a major role in NMJ development and thus may be a key factor in the pathogenesis of NMJs in SMA. Further research into the signaling mechanisms involved in NMJ maturation may identify additional mechanisms by which transplanted cells may be of therapeutic benefit. PMID- 20955114 TI - Omalizumab for pediatric asthma. AB - IMPORTANCE TO THE FIELD: Omalizumab is of proven efficacy in the treatment of severe allergic bronchial asthma and works through inhibiting the activity of IgE and the allergic immune mechanism IgE mediates. It has been demonstrated to be efficacious in children with asthma but is not approved by the FDA for use in children below 12 years of age. AREAS COVERED IN THIS REVIEW: Omalizumab is a 95% humanized monoclonal antibody that binds to circulating IgE at the same site on the Fc domain as the high-affinity IgE receptor, FcepsilonRI. This blocks the interaction between IgE and mast cells and basophils, thereby preventing the release of inflammatory mediators that cause allergic signs and symptoms. WHAT THE READER WILL GAIN: From the review of the literatures and statements from the FDA, Genentec and Novartis, the reader will gain a better appreciation of the value of omalizumab in treatment of severe asthma and the current status of its reported side effects. TAKE HOME MESSAGE: Omalizumab is of proven efficacy in adults and children with severe asthma and allows a markedly reduced dependence on oral and inhaled corticosteroids and decreased hospitalizations. A potential mechanism of omalizumab's effect on thrombus formation and cardiovascular effect is postulated. PMID- 20955115 TI - Canakinumab for treatment of cryopyrin-associated periodic syndrome. AB - IMPORTANCE OF THE FIELD: Autoinflammatory syndromes such as cryopyrin-associated periodic syndromes (CAPS) place a heavy burden on affected individuals as well as on their families due to significant morbidity and increased mortality. The inflammatory response in CAPS is caused by an overwhelming activation of the pro inflammatory cytokine IL-1, which was identified as a promising treatment target. AREAS COVERED IN THIS REVIEW: This article focuses on the pathogenic background and different clinical manifestations in CAPS. Furthermore, the development program and characteristics of canakinumab, a recently approved fully human anti IL-1beta mAb for the treatment of CAPS, are described and compared to other available IL-1 blocking agents. WHAT THE READER WILL GAIN: Canakinumab targets selectively human IL-1beta with high affinity and prevents the cytokine from interaction to its receptor and, thus, effectively blocks the inflammatory response in CAPS. In all studies performed, canakinumab showed a rapid improvement of symptoms of CAPS and a complete clinical response was achieved in most patients. Inflammatory markers such as C-reactive protein and serum amyloid A protein were reduced to normal levels within few days. In comparison to other IL-1 blockers, canakinumab provides a longer plasma half-life and less injection site reactions. TAKE HOME MESSAGE: Canakinumab offers the possibility of permanent disease control, almost symptom-free life, and hopefully less long-term morbidity and mortality in patients with CAPS. PMID- 20955116 TI - Invasive community-associated MRSA infections: epidemiology and antimicrobial management. AB - IMPORTANCE OF THE FIELD: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is now a predominant cause of infections in the community and is adding to the overwhelming MRSA burden in the hospital setting. CA-MRSA is most commonly noted as a prominent pathogen in skin and soft tissue infections (SSTI) but has been increasingly described in more invasive disease. New developments in the epidemiology and treatment of CA-MRSA have emerged to improve the understanding of this disease. AREAS COVERED IN THIS REVIEW: We present the latest epidemiologic and clinical treatment studies of CA-MRSA in a variety of infection types. The methods used involve a comprehensive literature search of the previous 10 years, including a detailed focus on new literature in the last 5 years. The search terms used were 'CA-MRSA epidemiology', 'S. aureus resistance', 'CA-MRSA treatment', and 'S. aureus virulence'. WHAT THE READER WILL GAIN: An in-depth understanding of the changing epidemiology of CA-MRSA and management of SSTI and more invasive infections with this pathogen. Adjunctive and alternative therapies are also reviewed. TAKE HOME MESSAGE: The epidemiology of CA-MRSA is rapidly evolving. Increasing multi-drug resistance along with virulence factors associated with this serious disease complicate its treatment. Additional clinical trials are needed to select optimal regimens in the treatment of invasive CA-MRSA infections. PMID- 20955117 TI - Thrombolysis for stroke. PMID- 20955118 TI - Stenting for carotid artery stenosis: festina lente . . . hasten slowly. PMID- 20955119 TI - Thrombolysis for acute stroke in Australia: outcomes from the Safe Implementation of Thrombolysis in Stroke registry (2002-2008). AB - OBJECTIVE: To report Australian outcomes from the Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Register (SITS-ISTR). DESIGN: Observational study using data collected prospectively from December 2002 to December 2008. SETTING: Centres administering thrombolysis for acute stroke in Australia and worldwide. PATIENTS: All patients treated with recombinant tissue plasminogen activator for acute stroke in participating centres, regardless of stroke severity, time of treatment and other clinical factors. INTERVENTION: Thrombolysis for acute stroke, administered according to local protocol. MAIN OUTCOME MEASURES: Functional outcome as 3-month modified Rankin score (mRS), and frequency of symptomatic intracerebral haemorrhage (ICH). RESULTS: During the study period, a total of 32 countries participated, and confirmed baseline data were available for 581 Australian patients and 20 953 patients in the rest of the world. Australian patients were older (median age, 73 v 69 years; P < 0.001), were less independent before stroke (premorbid mRS of 0-1, 87.5% v 91.2%; P < 0.005), and had more comorbidities and more severe strokes. Comparing the Australian cohort with the rest of the world, the odds ratio of 3-month mRS of 0 2 was 0.98 (95% CI, 0.88-1.08; P = 0.63), the odds ratio of symptomatic ICH was 0.98 (95% CI, 0.83-1.16; P = 0.85 [by the definition used by the National Institute of Neurological Disorders]) and the odds ratio of death was 1.04 (95% CI, 0.91-1.19; P = 0.54). Good outcome in the Australian cohort was predicted by younger age, presence of hyperlipidaemia, lower premorbid mRS, absence of infarct on early brain imaging, less severe stroke, and lower baseline blood glucose level. CONCLUSION: Clinical outcomes after thrombolysis in Australia were similar to those worldwide. PMID- 20955120 TI - Lost in transition? Access to and uptake of adult health services and outcomes for young people with type 1 diabetes in regional New South Wales. AB - OBJECTIVE: To document diabetes health services use and indices of glycaemic management of young people with type 1 diabetes from the time of their first contact with adult services, for those living in regional areas compared with those using city and state capital services, and compared with clinical guideline targets. DESIGN, SETTING AND SUBJECTS: Case note audit of 239 young adults aged 18-28 years with type 1 diabetes accessing five adult diabetes services before 30 June 2008 in three geographical regions of New South Wales: the capital (86), a city (79) and a regional area (74). MAIN OUTCOME MEASURES: Planned (routine monitoring) and unplanned (hospital admissions and emergency department attendance for hypoglycaemia or hyperglycaemia) service contacts; recorded measures of glycated haemoglobin (HbA(1c)), body mass index (BMI), and blood pressure (BP). RESULTS: Routine preventive service uptake during the first year of contact with adult services was significantly higher in the capital and city. Fewer regional area patients had records of complications assessment and measurements of HbA(1c), BMI and BP across all audited years of contact (HbA(1c): 73% v 94% city, 97% capital; P < 0.001). Across all years, regional area patients had the highest proportion of HbA(1c) values > 8.0% (79% v 62% city, 56% capital) and lowest proportion < 7% (4% v 7%, 22%) (both P < 0.001). Fewer young people made unplanned use of acute services for diabetes crisis management in the capital (24% v 49% city, 50% regional area; P < 0.001). In the regional area, routine review did not occur reliably even annually, with marked attrition of patients from adult services after the first year of contact. CONCLUSION: Inadequate routine specialist care, poor diabetes self-management and frequent use of acute services for crisis management, particularly in regional areas, suggest service redesign is needed to encourage young people's engagement. PMID- 20955121 TI - Doctors' knowledge of patient radiation exposure from diagnostic imaging requested in the emergency department. AB - OBJECTIVE: To assess emergency department (ED) doctors' knowledge of radiation doses associated with diagnostic imaging and to describe their practice with regard to informing patients of risk. DESIGN, PARTICIPANTS AND SETTING: Prospective, questionnaire-based observational study in May 2009 among all 110 doctors in the EDs of a 570-bed teaching hospital and a 200-bed district hospital. MAIN OUTCOME MEASURES: Percentage knowledge score; and frequency of discussing radiation risk with patients, based on responses to three scenarios rated on a visual analogue scale (VAS), where a score of 100 indicates doctors would always discuss it. RESULTS: 96 doctors (87%) completed the questionnaire. The overall mean knowledge score was 40% (95% CI, 38%-43%). Senior doctors scored somewhat higher than junior doctors, but not significantly (42% v 39%; P = 0.75). Over three-quarters of doctors (78%) underestimated the lifetime risk of fatal cancer attributable to a single computed tomography scan of the abdomen. Most doctors (76%) reported never having had any formal training on risks to patients from radiation exposure. The frequency at which doctors would inform patients of the risk of radiation varied greatly depending on the clinical scenario (mean VAS scores, between 38 and 90). CONCLUSION: Emergency doctors in our sample had a varied knowledge of the risks from radiation exposure, but overall knowledge was poor. Staff should receive education, and the diagnostic imaging request process may need to include information on radiation doses and risks. PMID- 20955122 TI - Influenza A testing and detection in patients admitted through emergency departments in Sydney during winter 2009: implications for rational testing. AB - AIM: To examine factors associated with testing and detection of influenza A in patients admitted to hospital for acute care during the winter 2009 pandemic influenza outbreak. DESIGN, SETTING AND PARTICIPANTS: Retrospective observational study of patients who were tested for influenza A after being admitted to hospital through emergency departments of the Sydney South West Area Health Service from 15 June to 30 August 2009. MAIN OUTCOME MEASURES: The association of factors such as age, diagnosis at admission, hospital and week of admission with rates of testing and detection of influenza A. RESULTS: 17,681 patients were admitted through nine emergency departments; 1344 (7.6%) were tested for influenza A, of whom 356 (26.5%) tested positive for pandemic influenza. Testing rates were highest in 0-4-year-old children, in the peak period of the outbreak, and in patients presenting with a febrile or respiratory illness. Positive influenza test results were common across a range of diagnoses, but occurred most frequently in children aged 10-14 years (64.3%) and in patients with a diagnosis at admission of influenza-like illness (59.1%). Using multivariate logistic regression, patients with a diagnosis at admission of fever or a respiratory illness at admission were most likely to be tested (odds ratios [ORs], 15 [95% CI, 11-21] and 17 [95% CI, 15-19], respectively). These diagnoses were stronger predictors of influenza testing than the peak testing week (Week 4; OR, 7.0 [95% CI, 3.8-13]) or any age group. However, diagnosis at admission and age were significant but weak predictors of a positive test result, and the strongest predictor of a positive test result was the peak epidemic week (Week 3; OR, 120 [95% CI, 27-490]). CONCLUSION: The strongest predictor of a clinician's decision to test for influenza was the diagnosis at admission, but the strongest predictor of a positive test was the week of admission. A rational approach to influenza testing for patients who are admitted to hospital for acute care could include active tracking of influenza testing and detection rates, testing patients with a strong indication for antiviral treatment, and admitting only those who test negative to "clean" wards during the peak of an outbreak. PMID- 20955123 TI - Management of pancreatic exocrine insufficiency: Australasian Pancreatic Club recommendations. AB - Pancreatic exocrine insufficiency (PEI) occurs when the amounts of enzymes secreted into the duodenum in response to a meal are insufficient to maintain normal digestive processes. The main clinical consequence of PEI is fat maldigestion and malabsorption, resulting in steatorrhoea. Pancreatic exocrine function is commonly assessed by conducting a 3-day faecal fat test and by measuring levels of faecal elastase-1 and serum trypsinogen. Pancreatic enzyme replacement therapy is the mainstay of treatment for PEI. In adults, the initial recommended dose of pancreatic enzymes is 25,000 units of lipase per meal, titrating up to a maximum of 80,000 units of lipase per meal. In infants and children, the initial recommended dose of pancreatic enzymes is 500 units of lipase per gram of dietary fat; the maximum daily dose should not exceed 10,000 units of lipase per kilogram of bodyweight. Oral pancreatic enzymes should be taken with meals to ensure adequate mixing with the chyme. Adjunct therapy with acid-suppressing agents may be useful in patients who continue to experience symptoms of PEI despite high-dose enzyme therapy. A dietitian experienced in treating PEI should be involved in patient management. Dietary fat restriction is not recommended for patients with PEI. Patients with PEI should be encouraged to consume small, frequent meals and to abstain from alcohol. Medium-chain triglycerides do not provide any clear nutritional advantage over long-chain triglycerides, but can be trialled in patients who fail to gain or to maintain adequate bodyweight in order to increase energy intake. PMID- 20955124 TI - A stroke of luck ... or just the ideal model of care? PMID- 20955125 TI - Insulin-dependent diabetes and aeromedical certification - the Australian perspective. AB - Whether pilots with insulin-dependent diabetes should be allowed to fly has long been a controversial issue. Hypoglycaemia remains a significant threat to flight safety, and a barrier for pilots with insulin-dependent diabetes to overcome. Some countries allow recreational pilots to fly while treated with insulin under strict conditions. Recent changes in aeromedical certification in Australia will give pilots with diabetes more freedom to exercise the privileges of their licence, while adopting mechanisms to ensure the safety of air navigation. PMID- 20955126 TI - Taxing junk food: applying the logic of the Henry tax review to food. AB - The recent review of taxation in Australia - the Henry tax review - has recommended that the federal government increase the taxes already levied on tobacco and alcohol. Tobacco and alcohol taxes are put forward as the best way of reducing the social harms caused by the use and misuse of these substances. Junk foods have the same pattern of misuse and the same social costs as tobacco and alcohol. The Henry tax review rejects the idea of taxing fatty foods, and to date the government has not implemented a tax on junk food. We propose that a tax on junk food be implemented as a tool to reduce consumption and address the obesity epidemic. PMID- 20955127 TI - People at the centre of complex adaptive health systems reform. AB - Health systems are increasingly recognised to be complex adaptive systems (CASs), functionally characterised by their continuing and dynamic adaptation in response to core system drivers, or attractors. The core driver for our health system (and for the health reform strategies intended to achieve it) should clearly be the improvement of people's health - the personal experience of health, regardless of organic abnormalities; we contend that a patient-centred health system requires flexible localised decision making and resource use. The prevailing trend is to use disease protocols, financial management strategies and centralised control of siloed programs to manage our health system. This strategy is suggested to be fatally flawed, as: people's health and health experience as core system drivers are inevitably pre-empted by centralised and standardised strategies; the context specificity of personal experience and the capacity of local systems are overlooked; and in line with CAS patterns and characteristics, these strategies will lead to "unintended" consequences on all parts of the system. In Australia, there is still the time and opportunity for health system redesign that truly places people and their health at the core of the system. PMID- 20955128 TI - Bradycardia in a patient taking black cohosh. AB - Cimicifuga racemosa, better known as black cohosh, has been widely used in Western cultures as a herbal treatment for relieving symptoms of menopause. It has previously been linked to cases of liver toxicity. We report a case of reversible complete heart block in a woman who had recently begun taking a herbal supplement containing black cohosh. We review the known side effect profile of black cohosh and its relationship to our case. PMID- 20955129 TI - Evidence of increasing frequency of herpes zoster management in Australian general practice since the introduction of a varicella vaccine. PMID- 20955130 TI - Complexity of risk for transfusion malaria and differentiated response to risk management. PMID- 20955131 TI - Lost opportunities with Australia's health workforce? PMID- 20955132 TI - Caregivers' intentions regarding pandemic (H1N1) 2009 influenza vaccination for their children. PMID- 20955133 TI - The WHO Surgical Safety Checklist. PMID- 20955134 TI - Patient safety: time for a transformational change in medical education. PMID- 20955136 TI - Using the quality improvement cycle on clinical indicators--improve or remove? AB - The variable life-adjusted display is a graphical, statistical methodology used in Queensland to monitor patient outcomes of clinical indicators. The quality improvement cycle is a systematic approach employed by patient safety and quality programs worldwide to improve patient care. The quality improvement cycle is beneficial to the review and refinement of indicator definitions. Indicators with definitional issues that are not subject to the quality improvement cycle may initially prompt quality improvement opportunities, but are more likely to potentially lead to unnecessary chart and clinical reviews, which will disengage coders and clinicians. Queensland recently used the quality improvement cycle to refine the laparoscopic cholecystectomy complications of surgery indicator definition and several maternity definitions. PMID- 20955135 TI - Routine use of administrative data for safety and quality purposes--hospital mortality. AB - Worldwide, current practice is to report hospital mortality using the hospital standardised mortality ratio (HSMR). An HSMR is generated by comparing an indirectly standardised expected mortality rate against a hospital's observed mortality rate. A hospital's HSMR can be compared with the overall outcomes for all hospitals in a population, or with peer hospitals. HSMRs should be used as screening tools that alert institutions to the need for further investigation, rather than as definitive measures of the quality of care provided by individual hospitals. HSMRs are computed from existing hospital administrative data sources, which are fit for such a purpose. The addition of clinical or physiological data does not, at present, add to the discriminative powers of the risk adjustment models used to adjust HSMR values for differences in hospitals' casemixes. There has been concern that HSMRs may be too variable over time for individual values to be interpretable. A study of HSMR outcomes in Australian hospitals confirmed earlier reports of the stability of the measure. Considerable progress has been made with developing Australian HSMRs for use as routine measures to improve the safety and quality of Australian hospital care. PMID- 20955137 TI - Measuring safety and quality to improve clinical outcomes--current activities and future directions for the Australian Cardiac Procedures Registry. AB - Routine monitoring of performance in the provision of cardiac services aids quality assurance and enables comparisons of performance to national and international standards. The Australasian Society of Cardiac and Thoracic Surgeons conducts a surgical registry that has grown from six hospitals participating in 2001 to 21 contributing in 2010. Variation in performance is monitored on a quarterly basis through the use of control chart methodology, and a peer-review mechanism and governance process for reporting have been established. Proposed future developments of the registry include its expansion to include interventional cardiology procedures, such as implantation of stents and cardiac devices, and a modular format, with the patient rather than the procedure being the key element of the system. An Australian Cardiac Procedures Registry will provide information to stakeholders, including consumers, clinicians, health funders and policymakers, on performance standards and quality of care of medical services affecting an ever-increasing number of Australians. PMID- 20955138 TI - Investigating apparent variation in quality of care: the critical role of clinician engagement. AB - This article reports the experience of the Victorian Department of Health in seeking clinician engagement in the testing of 11 quality-of-care indicators in 20 health services in Victoria. The Department previously developed a suite of 18 core indicators and seven subindicators known as the AusPSI set. We used routinely collected administrative data from the Victorian Admitted Episodes Dataset to produce variable life-adjusted display (VLAD) control charts for 11 selected indicators. The Department recognises that clinicians are responsible for the safety and quality of the care they provide, and therefore the necessity of engaging clinicians in the process of investigating apparent variation in patient care. Although using readily available and inexpensive routinely collected administrative data to measure clinical performance has a certain appeal, the use of administrative data and VLADs to identify apparent variations has posed significant challenges due to concerns about the quality of the data and resource requirements. When clinicians at a major Melbourne hospital were engaged, it resulted in an improvement in clinical practice. Investigating apparent variation in patient care provides an ideal opportunity for emerging clinical leaders to take local ownership and develop expertise in investigating apparent variation in processes of care and implementing change as required. PMID- 20955139 TI - Safer use of antimicrobials in hospitals: the value of antimicrobial usage data. AB - The National Antimicrobial Utilisation Surveillance Program (NAUSP) collects aggregate data from hospitals in all Australian states and provides reports of monthly hospital inpatient antimicrobial usage to contributing hospitals. These data provide an Australian peer-group benchmark; hospitals can compare their usage with similar hospitals and identify areas of antimicrobial use that require more in-depth analysis. Overall high usage has been used by hospitals and area health services as a stimulus for initiation or expansion of antimicrobial stewardship programs. High use of particular classes of antimicrobials has triggered individual drug audits and been used to tailor interventions. Longitudinal antimicrobial usage data have been used by hospitals to measure the effects of antimicrobial stewardship strategies and provide feedback to prescribers. PMID- 20955140 TI - Using what we gather--harnessing information for improved care. AB - Currently available data can be used to focus clinical quality, patient centredness and safety of care in hospitals. PMID- 20955141 TI - Measuring hospital performance--2008 forum summary. AB - A Clinical Excellence Commission seminar explored how clinical practice variation can be monitored, and identified directions and opportunities in this field. PMID- 20955142 TI - Clinical practice variation. AB - Although difficult to quantify, there is known widespread variation in the way that best available evidence is applied in clinical practice. The reasons for gaps between evidence and practice are complex, and efforts to improve uptake are unlikely to be successful if they are one-dimensional or focus on individual health professionals. This article provides contextual reference for articles in this Supplement in addressing how and why clinical variation exists, the importance of reducing it and strategies to drive a more streamlined approach to evidence-based care in Australian health care systems. PMID- 20955143 TI - Effect of polyethylene glycols on the trans-ungual delivery of terbinafine. AB - Topical nail drug delivery could be improved by identifying potent chemical penetration enhancers. The purpose of this study was to assess the effect of polyethylene glycols (PEGs) on the trans-ungual delivery of terbinafine. In vitro permeation studies were carried out by passive and iontophoresis (0.5 mA/cm2) processes for a period of 1 h using gel formulations containing different molecular weight PEGs (30%w/w). The release of drug from the loaded nail plates and the possible mechanisms for the enhanced delivery was studied. Passive delivery using formulation with low molecular weight PEGs (200 and 400 MW) indicated moderate enhancement in the permeation and drug load in the nail plate, compared to the control formulation. However, the effect of low molecular weight PEGs was predominant during iontophoresis process with greater amount of terbinafine being permeated (~35 ug/cm2) and loaded into the nail plate (~2.7 ug/mg). However, little or no effect on drug delivery was observed with high molecular weight PEGs (1000- 3350 MW) in passive and iontophoresis processes. Release of drug from the nail plates loaded by iontophoresis using low molecular weight PEG (400 MW) exhibited sustain effect which continued over a period of 72 days. The enhancement in drug permeation by low molecular weight PEGs is likely due to their ability to lead to greater water uptake and swelling of nail. This study concluded that the low molecular weight PEGs are indeed a promising trans ungual permeation enhancer. PMID- 20955144 TI - Auraptene: a natural biologically active compound with multiple targets. AB - Auraptene is the most abundant prenyloxycoumarin that occurs in nature. It has been isolated from plants belonging to many genus of the Rutaceae family, comprising several edible fruits and vegetables. Although known for a long time, only in the last decade auraptene was seen to exert valuable pharmacological properties as orally active cancer chemopreventive, anti-bacterial, anti protozoal, anti-fungal, anti-inflammatory, and anti-oxidant agent. The aim of this review is to examine in detail the in so far reported effects and what is known about the mechanism of action underlying the observed pharmacological activities of this secondary metabolite by means of a survey of the current literature in which auraptene has been reported as an inhibitor of key biological targets like metalloproteinases, glycoprotein P, PPARs, and several others. PMID- 20955145 TI - Anthraquinones: analytical techniques as a novel tool to investigate on the triggering of biological targets. AB - Approximately, 63% of marketed drugs derive from natural products or their semi synthetic derivatives. Compounds from living organisms often exert a biological activity, triggering several targets, which may be useful for the improvement of novel pharmaceuticals. These natural products can be extracted from plants, marine organisms, or microorganism fermentation broths. In the vast array of bioactive secondary metabolites known up to now, anthraquinones are among the most investigated natural products, in particular for what concerns their mechanism of action. This review focuses on the analytical aspects of anthraquinones, from their separation to recent and new high-throughputs techniques for the simultaneous determination of these analytes in biological matrices that can greatly contribute to sharply depict the targets of these secondary metabolites as well as on an updated survey of their biological activities. PMID- 20955146 TI - Therapeutic and diagnostic applications of nanoparticles. AB - Nanoparticles are sphere-like biocompatible materials made of inert silica, metal or crystals of a few nanometers in size. They are emerging as a novel class of therapeutics for cancer treatment. Being more selective and specific toward their targets, nanoparticles have the ability to enhance the anticancer effects and to simultaneously reduce systemic toxicity compared with conventional therapeutics. Furthermore, they offer the potential to overcome drug resistance leading to higher intracellular drug accumulation. Nowadays, nanotechnologies are applied to molecular diagnostics and incorporated in cutting-edge molecular diagnostic methods, such as DNA and protein microarray biochips. Nanotechnologies enable diagnosis at the single-cell and single-molecule levels. Recent progress in cancer nanotechnology raises exciting opportunities for specific drug delivery. The purpose of this review is to give an overview about different types of nanoparticles and to summarize the latest results regarding their diagnostic and therapeutic applications in the clinic with more focus on cancer treatment. Furthermore, we discuss opportunities, limitations, and challenges faced by therapeutic nanoparticles. PMID- 20955147 TI - Activation of latent HIV-1 expression by protein kinase C agonists. A novel therapeutic approach to eradicate HIV-1 reservoirs. AB - The persistence of latent HIV-infected cellular reservoirs represents the major hurdle to virus eradication in patients treated with highly active antiretroviral therapy. The molecular mechanisms by which integrated HIV-1 is repressed during latency have been partially identified in different models of HIV-1 latency, and the involvement of multiple processes has been demonstrated. Therefore, several molecular targets amenable to pharmacological manipulation have emerged to antagonize HIV-1 latency in the viral reservoirs. In this context, it has been suggested that successful depletion of such latent reservoirs will require a combination of therapeutic agents that can specifically and efficiently act on cells harbouring latent HIV-1 provirus. HIV-1 reactivation therapy is a potential therapeutic option to purge the viral reservoirs. The goal of this therapy is to enhance the transcriptional activity of the latent HIV-1 without inducing the polyclonal activation of non-infected cells. In this sense natural or semisynthetic protein kinase C agonists lacking tumour-promoter activities clearly fulfil this criterion, thereby opening new research avenues to purge HIV 1 reservoirs. In this review article, we have succinctly summarized the known effects of "natural products", focusing on phorboids like prostratin and ingenols, macrolides like bryostatin 1, and macrocyclic polyesters like ingols and jatrophanes. A comprehensive view on the molecular mechanisms underlying the principle of HIV-1 reactivation from latency is provided, discussing the combination of "natural products" with other experimental or conventional therapeutics. PMID- 20955149 TI - Proteases of Porphyromonas gingivalis as important virulence factors in periodontal disease and potential targets for plant-derived compounds: a review article. AB - Periodontitis is a common chronic inflammatory disorder of bacterial origin, which affects the tooth-supporting tissues. A wide range of evidences suggests that Porphyromonas gingivalis plays a key role in the initiation and progression of chronic periodontitis. This Gram-negative anaerobic bacterium produces several types of proteolytic enzymes, including gingipains, collagenases, and a dipeptidyl aminopeptidase IV. Although these enzymes have physiological functions for P. gingivalis, they have been suggested to play multiple roles in the pathogenic process of periodontitis. Indeed, P. gingivalis proteases hydrolyze a variety of serum and tissue proteins thus contributing to neutralize the immune defense system and to cause tissue destruction. Considering the key roles that P. gingivalis proteases may play in the pathogenesis of periodontitis, inhibitors of these enzymes are considered potentially new therapeutics agents. In recent years, several groups have identified natural plant-derived inhibitors effective on P. gingivalis proteases. More specifically, polyphenols isolated from cranberry and green tea were found to inhibit several proteases produced by P. gingivalis. This paper will discuss the pathological roles of P. gingivalis proteases and review the scientific literature for bioactive plant-derived compounds endowed with a capacity to inhibit these enzymes. PMID- 20955150 TI - Triterpene derivatives as inhibitors of protein involved in the inflammatory process: molecules interfering with phospholipase A2, cycloxygenase, and lipoxygenase. AB - Over the past years, there was an explosion in the knowledge of the protein target and molecular mechanism associated with various disease types and in the new research of drugs of natural origin. The key idea is to evaluate bioactive natural products interacting with protein domains of different genetic origin but structurally preserved to develop libraries of compounds biologically validated and selected from an evolutionistic point of view. Compared with synthetic compounds, natural products have a major number of unused scaffolds and not comparable to the libraries of synthetic compounds, and could represent a promising starting points for the discovery of new bioactive compounds. Many natural products are reported to interact with proteins involved in serious diseases, such as inflammation and cancer. Recently various chemical classes of plant secondary metabolites have emerged as potential therapeutic compounds in several inflammatory diseases. Owing to the findings that triterpenoids, a common class of plant secondary metabolites, have anti-inflammatory and anti-cancer effects on humans, the interest in their potential application in human health and disease is increasing. The present review describes anti-inflammatory triterpenes derivatives from plant and fungi reported during the last two decades in order to provide an account of this field of investigation, sorting compounds according to their targets, phospholipase A(2) (PLA(2)), cycloxygenase (COX), and lipoxygenase (LOX). The attempt is also being made to enumerate the possible leads for further synthetic and drug discovery program development. PMID- 20955151 TI - Natural products triggering biological targets--a review of the anti-inflammatory phytochemicals targeting the arachidonic acid pathway in allergy asthma and rheumatoid arthritis. AB - Inflammation is a natural response of living organisms to the presence of internal and external substances which are recognized by the host as being "non self" or "foreign invader". It is also a cascade leading to the healing of damaged tissue. Uncontrolled inflammation often results in chronic diseases such as arthritis, autoimmune disorder, cancer, dementia, diabetic, neurodegeneration and vascular disease. The list keeps growing due to the increasing numbers of identified molecular markers that are associated with inflammatory genes or transcription factors. Among various transcription factors, nuclear factor kappa B (NF-kB) is the master switch for proinflammatory genes and transactivates arachidonic acid pathway enzymes when activated. Through evolution, plants have developed vast classes of compounds to fight inflammation. Most of them belong to the chemical group of alkaloids, coumarins, flavonoids, polyphenols and terpenoids. This review article presents and discusses results obtained from literature search on recent findings in plant-derived compounds, which exhibit anti-inflammatory activity in rheumatoid arthritis, allergy and asthma via the suppression of the arachidonic acid pathway. IC(50)s of the compounds obtained from the literature are thus tabulated into six groups of inhibitors based on the enzyme target of phospholipase A2, cyclooxygenase 1 and 2, 5-, 12- and 15 lipoxygenase. Modulation of Th1/Th2 cytokines and histamine/mucus release by some of these enzyme inhibitors are also briefly discussed. PMID- 20955152 TI - Natural products triggering biological targets. PMID- 20955148 TI - The targets of curcumin. AB - Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal preparation or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-kB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer's disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacological aspects of curcumin as well as the underlying action mechanisms. The recently identified molecular targets and signaling pathways modulated by curcumin are also discussed here. PMID- 20955153 TI - Mesenchymal stem cells for multiple sclerosis: does neural differentiation really matter? AB - The lack of therapies fostering remyelination and regeneration of the neural network deranged by the autoimmune attack occurring in multiple sclerosis (MS), is raising great expectations about stem cells therapies for tissue repair. Mesenchymal stem cells (MSCs) have been proposed as a possible treatment for MS due to the reported capacity of transdifferentiation into neural cells and their ability at modulating immune responses. However, recent studies have demonstrated that many other functional properties are likely to play a role in the therapeutic plasticity of MSCs, including anti-apoptotic, trophic and anti oxidant effects. These features are mostly based on the paracrine release of soluble molecules, often dictated by local environmental cues. Based on the modest evidence of long-term engraftment and the striking clinical effects that are observed immediately after MSCs administration in the experimental model of MS, we do not favor a major role for transdifferentiation as an important mechanism involved in the therapeutic effect of MSCs. PMID- 20955154 TI - Bone marrow mesenchymal stem cells: agents of immunomodulation and neuroprotection. AB - Mesenchymal stromal cells (MSC) are part of the bone marrow stem cells repertoire which also includes the main stem cells population of the bone marrow, the hematopoietic stem cells. The main role of MSCs is to support hematopoiesis but they can also give rise to cells of the mesodermal layers. Recently, significant interactions between MSCs and cells from the immune system have been demonstrated: MSCs were found to downregulate T and B lymphocytes, natural killer cells (NK) and antigen presenting cells through various mechanisms, including cell-to cell interaction and soluble factor production. Besides the immunomodulatory effects, MSCs were shown to possess additional stem cells features, such as the self-renewal potential and multipotency. Their debatable transdifferentiation potential to cells of the endo- and exo-dermal layer, including cells of the CNS, may explain in part their reported neuroprotective effects. Studies in vitro and in vivo (in cells cultures and in animal models) have indicated neuroprotective effects. MSCs are believed to promote functional recovery following CNS injury or inflammation, by producing trophic factors that may facilitate the mobilization of endogenous neural stem cells and promote the regeneration or the survival of the affected neurons. These immunomodulatory and neuroprotective features could make MSCs potential candidates for future therapeutic modalities in immune-mediated and neurodegenerative diseases. PMID- 20955155 TI - The prospect of stem cells as multi-faceted purveyors of immune modulation, repair and regeneration in multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is characterised by an autoimmune attack on components of the myelin sheath and axons leading to neurological disability. Although long-approved current treatments for MS have so far only targeted immune components of the disease in a non-specific manner, the efficacy of these immunomodulatory treatments are limited given that they are only immunosuppressive and/ or immunoregulatory and do not prevent long-term disease progression. As such, there is a clear need for more effective therapies that are capable of targeting other aspects of the disease including neurodegeneration, demyelination and the underlying causes of the autoimmune state. Emerging data suggest that hematopoietic, mesenchymal and neural stem cells have the promise to restore self tolerance, to provide in situ immunomodulation and neuroprotection as well as to promote regeneration. This review will summarise burgeoning experimental and clinical evidence supporting the application of these stem cell populations for the treatment of MS. PMID- 20955156 TI - Transplantation of genetically modified haematopoietic stem cells to induce antigen-specific tolerance as a cure for autoimmune diseases. AB - Autoimmune diseases are incurable and are managed using therapeutic agents. Bone marrow transplantation is being trialled as a treatment for these diseases. While allogeneic bone marrow transplantation shows impressive benefit, its application is hindered by GVHD and high mortality. On the other hand, autologous bone marrow transplantation has lower mortality rate and no GVHD but is associated with higher relapse rates. Given that autoimmune diseases are a result of a failure of immune tolerance and that bone marrow-derived dendritic cells play an important role in establishing immune tolerance, the transplantation of genetically modified haematopoietic stem cells to generate molecular chimerism to induce antigen-specific tolerance offers the potential for developing a cure for autoimmune diseases. In this review, we will discuss key findings from clinical data and animal studies to provide evidence to support the above concept. PMID- 20955157 TI - Gene therapy for immunologic tolerance: using bone marrow-derived cells to treat autoimmunity and hemophilia. AB - Bone marrow derived cells, especially B lymphocytes, have been shown to function as tolerogenic antigen-presenting cells (APC's) both in vivo and in vitro. In addition, it is well established that immunoglobulins can function as potent tolerogenic carriers for associated epitopes. We have taken advantage of these properties to develop a gene therapy approach to induce unresponsiveness in a number of animal models for clinical diseases. In our system, we engineered target peptide-IgG constructs into retroviral vectors and transduced hematopoietic cells to create tolerogenic antigen-presenting cells. In this review, we discuss the strategies and mechanism of our gene therapy approach mediated by B cells, as well as by bone marrow cells, for tolerance acquisition in various mouse models for autoimmune disease and hemophilia A. Our results show that MHC class II and co-stimulatory molecules must be expressed on the tolerogenic antigen presenting cells for efficacy. This therapy requires regulatory T cells for both the induction and maintenance of tolerance. The putative role of epitopes provided by the IgG carrier in this process. Studies in non-human primates and with human T cell clones in vitro are in progress to transition this approach to the clinic. The use of stem cells and B cell delivered gene therapy in human clinical diseases may soon become a reality. PMID- 20955158 TI - Hematopoietic stem cell transplantation for the treatment of autoimmunity in type 1 diabetes. AB - Type 1 diabetes (T1D) is an autoimmune disease that leads to the destruction of the insulin-producing pancreatic b cells. While there is no current cure, recent work in the field of allogeneic hematopoietic stem cell transplantation (HSCT) and the induction of mixed chimerism, a state in which multilineage hematopoietic populations of both recipient and donor co-exist, has demonstrated that it is possible to provide protection from disease onset, as well as reverse the autoimmune state in spontaneously diabetic mice. Furthermore, the establishment of mixed chimerism induces donor-specific tolerance, providing the potential to normalize glucose regulation via pancreatic islet transplantation without the requirement of life-long immunosuppression. Current studies are aimed at understanding the mechanisms involved in both the reversal of autoimmunity and the induction of tolerance, with the aim of moving this promising approach to curing T1D into the clinic. PMID- 20955159 TI - Autologous hematopoietic stem cell transplantation for systemic sclerosis. AB - Systemic sclerosis is a rare disorder manifesting as skin and internal organ fibrosis, a diffuse vasculopathy, inflammation, and features of autoimmunity. Patients with diffuse cutaneous disease or internal organ involvement have a poor prognosis with high mortality. To date no therapy has been shown to reverse the natural course of the disease. Immune suppressive drugs are commonly utilized to treat patients, but randomized trials have generally failed to demonstrate any long-term benefit. In phase I/II trials, autologous hematopoietic stem cell transplantation (HSCT) has demonstrated impressive reversal of skin fibrosis, improved functionality and quality of life, and stabilization of internal organ function, but initial studies were complicated by significant treatment-related mortality. Treatment-related mortality was reduced by better pre-transplant evaluation to exclude patients with compromised cardiac function and by treating patients earlier in disease, allowing selected patients the option of autologous HSCT treatment. There are currently three ongoing randomized trials of autologous HSCT for systemic sclerosis: ASSIST (American Systemic Sclerosis Immune Suppression versus Transplant), SCOT (scleroderma cyclophosphamide versus Transplant), and ASTIS (Autologous Stem cell Transplantation International Scleroderma). The results from these trials should clarify the role of autologous HSCT in the currently limited therapeutic arsenal of severe systemic sclerosis. PMID- 20955160 TI - Stem cell-based therapies and immunomodulatory approaches in newly diagnosed type 1 diabetes. AB - Type 1 diabetes mellitus is an autoimmune disease against pancreatic beta cells. The autoimmune response begins months or years before the clinical presentation. At the time of hyperglycemic symptoms a small amount of beta cell mass still remains. The main therapeutic option to type 1 diabetes mellitus is daily insulin injections which is shown to promote tighter glucose control and to reduce much of diabetic chronic complications. Subgroup analysis of the Diabetes Control and Complication Trial (DCCT) showed another important aspect related to long term complications of diabetes, ie, patients with initially larger residual beta cell mass suffered less microvascular complications and less hypoglycemic events than those patients with small amounts of beta cells at diagnosis. In face of this, beta cell preservation has become another important target in the management of type 1 diabetes and its related complications. In this review, we summarize various immunomodulatory regimens ever used in humans, including stem cell-based strategies, aiming at blocking autoimmunity against pancreatic beta cells and at promoting beta cell preservation and/or possible beta cell regeneration in recent onset type 1 diabetes. PMID- 20955161 TI - Restoration of the immune balance by autologous bone marrow transplantation in juvenile idiopathic arthritis. AB - Juvenile idiopathic arthritis (JIA) is one of the most frequent autoimmune diseases in childhood and is characterized by chronic inflammation of the synovial fluid in joints. Several drugs are available for the treatment of JIA, including various biological agents that interfere with critical cytokine pathways. Though very effective in suppressing disease activity, none of these drugs can cure the disease and induce a lasting medication free remission. A small proportion of JIA patients will become or are unresponsive to any form of medical treatment. For these severely ill patients autologous bone marrow transplantation (aBMT) is a last resort treatment. aBMT is remarkably effective in suppressing disease activity, with beneficial outcome reported in around 70% of these previously refractory patients. Moreover aBMT is the only treatment that can induce a lasting medication-free-disease remission in these patients. In the very long term (after 7 years of remission) however, some disease relapses are observed, with the disease returning in a less severe form compared to prior aBMT. The exact mechanism of how aBMT is inducing this lasting disease remission is still largely unknown, but data from both animal models and humans suggest a prominent role for regulatory T cells. In this review we reviewed the current views of the cellular mechanisms that lay beneath disease induction of JIA and the disease remission caused by aBMT therapy. PMID- 20955162 TI - Stem cell based therapy for autoimmunity. PMID- 20955163 TI - Bladder cancer stem cells. AB - Stem cells are undifferentiated cells that renew themselves while simultaneously producing differentiated tissue- or organspecific cells through asymmetric cell division. The appreciation of the importance of stem cells in normal tissue biology has prompted the idea that cancers may also develop from a progenitor pool (the "cancer stem cell (CSC) hypothesis"), and this idea is gaining increasing acceptance among scientists. CSCs are sub-populations of cancer cells responsible for tumor initiation, differentiation, recurrence, metastasis, and drug resistance. First identified in the hematopoietic system, CSCs have also been discovered in solid tumors of the breast, colon, pancreas, and brain. Recently, the tissue-specific stem cells of the normal urothelium have been proposed to reside in the basal layer, and investigators have isolated phenotypically similar populations of cells from urothelial cancer cell lines and primary tumors. Herein, we review the CSC hypothesis and apply it to explain the development of the two different types of bladder cancer: noninvasive ("superficial") carcinoma and invasive carcinoma. We also examine potential approaches to identify CSCs in bladder cancer as well as therapeutic applications of these findings. While exciting, the verification of the existence of CSCs in bladder cancer raises several new questions. Herein, we identify and answer some of these questions to help readers better understand bladder cancer development and identify reasonable therapeutic strategy for targeting stem cells. PMID- 20955165 TI - Intracellular protozoan parasites of humans: the role of molecular chaperones in development and pathogenesis. AB - Certain kinetoplastid (Leishmania spp. and Tryapnosoma cruzi) and apicomplexan parasites (Plasmodium falciparum and Toxoplasma gondii) are capable of invading human cells as part of their pathology. These parasites appear to have evolved a relatively expanded or diverse complement of genes encoding molecular chaperones. The gene families encoding heat shock protein 90 (Hsp90) and heat shock protein 70 (Hsp70) chaperones show significant expansion and diversity (especially for Leishmania spp. and T. cruzi), and in particular the Hsp40 family appears to be an extreme example of phylogenetic radiation. In general, Hsp40 proteins act as co-chaperones of Hsp70 chaperones, forming protein folding pathways that integrate with Hsp90 to ensure proteostasis in the cell. It is tempting to speculate that the diverse environmental insults that these parasites endure have resulted in the evolutionary selection of a diverse and expanded chaperone network. Hsp90 is involved in development and growth of all of these intracellular parasites, and so far represents the strongest candidate as a target for chemotherapeutic interventions. While there have been some excellent studies on the molecular and cell biology of Hsp70 proteins, relatively little is known about the biological function of Hsp70-Hsp40 interactions in these intracellular parasites. This review focuses on intracellular protozoan parasites of humans, and provides a critique of the role of heat shock proteins in development and pathogenesis, especially the molecular chaperones Hsp90, Hsp70 and Hsp40. PMID- 20955166 TI - Structural modeling studies of aldehyde dehydrogenase X: insights into key interactions in the tetrameric assembly of the isoenzyme. AB - Human mitochondrial aldehyde dehydrogenase is a member of superfamily of multisubunit enzymes, catalyzing the conversion of a broad range of aldehydes to corresponding acids via the NAD (P) (+)-dependent irreversible reaction. They play an important role in the detoxification of acetaldehyde, in the development of alcohol sensitivity and human alcohol-related disorders. The study aimed to understand the role of conserved residues by comparing similarities and differences between the two isoenzymes. A 3D model of the human ALDHX is constructed by molecular modeling based on the crystal structure of human ALDH2 by using MODELLER (8V1) program. Assessment of reliability of the 3D model is carried out by the programs PROCHECK and PROSAII. The ALDHX fold is similar to the previously described ALDH structures. Sequence and structural analyses have highlighted a close structural and functional relationship between the two isoenzymes of human origin. The interfacial residues that are involved in crucial interactions across the interface stabilize the dimer-tetramer interface in the enzyme. Stability factors like salt bonds and hydrogen bonds aid and maintain the tetrameric assembly of the enzyme. PMID- 20955164 TI - Function of cytosolic chaperones in Tom70-mediated mitochondrial import. AB - The great majority of mitochondrial proteins are synthesized by cytosolic ribosomes and then imported into the organelle post-translationally. The translocase of the outer membrane (TOM) is a proteinaceous machinery that contains surface receptors for preprotein recognition and also serves as the main entry gateway into mitochondria. Mitochondrial targeting requires various cytosolic factors, in particular the molecular chaperones Hsc70/Hsp70 and Hsp90. The chaperone activity of Hsc70/Hsp70 and Hsp90 occurs in coordinated cycles of ATP hydrolysis and substrate binding, and is regulated by a number of co chaperone proteins. The import receptor Tom70 is a member of the tetratricopeptide repeat (TPR) co-chaperone family and contains a conserved TPR clamp domain for interaction with Hsc70 and Hsp90. Such interaction is essential for the initiation of the import process. This review will discuss the roles of Hsc70 and Hsp90 in mitochondrial import and summarize recent progress in understanding these pathways. PMID- 20955167 TI - Effects of vector fusion peptides on the conformation and immune reactivity of epitope-shuffled, recombinant multi-epitope antigens. AB - The use of multi-epitopes has been considered as a promising strategy to overcome the obstacle of antigenic variation in malarial vaccine development. Previously, we constructed a multi-epitope artificial antigen, Malaria Random Constructed Antigen-1(M.RCAg-1), to optimize expression of the antigen, and we subcloned the gene into three prokaryotic expression vectors that contain different fusion tags at the N-terminus. Three recombinant proteins expressed by these vectors, named M.RCAg-1/Exp.V-1, V-2, and V-3, were purified after the cleavage of the fusion tag. All three recombinant proteins were able to induce similar levels of antigenicity in BALB/c murine models. However, the antibody responses against the individual epitope peptides of the recombinant products were dramatically different. Additionally, the different epitopes elicited various CD4(+) T-cell responses, as shown by the resulting lymphocyte proliferation and varied IFN gamma and IL-4 levels determined by EILSPOT; however, each could be distinctly recognized by sera derived from malaria patients. Additionally, the rabbit antibody induced by these proteins showed diverse efficacy in malaria parasite growth inhibition assays in vitro. Furthermore, analysis via circular dichroism spectroscopy confirmed that the secondary structure was different among these recombinant proteins. These results suggest that the expressed multi-epitope artificial antigens originating from the different vector fusion peptides indeed affect the protein folding and, subsequently, the epitope exposure. Thus, these proteins are able to induce both distinct humoral and cellular immune responses in animal models, and they affect the efficacy of immune inhibition against the parasite. This work should lead to a further understanding of the impact of vector fusion peptides on the conformation and immune reactivity of recombinant proteins and could provide a useful reference for the development of artificial multi-epitope vaccines. PMID- 20955168 TI - Identify Golgi protein types with modified Mahalanobis discriminant algorithm and pseudo amino acid composition. AB - The Golgi apparatus is an important eukaryotic organelle. Successful prediction of Golgi protein types can provide valuable information for elucidating protein functions involved in various biological processes. In this work, a method is proposed by combining a special mode of pseudo amino acid composition (increment of diversity) with the modified Mahalanobis discriminant for predicting Golgi protein types. The benchmark dataset used to train the predictor thus formed contains 95 Golgi proteins in which none of proteins included has >=40% pairwise sequence identity to any other. The accuracy obtained by the jackknife test was 74.7%, with the ROC curve of 0.772 in identifying cis-Golgi proteins and trans Golgi proteins. Subsequently, the method was extended to discriminate cis-Golgi network proteins from cis-Golgi network membrane proteins and trans-Golgi network proteins from trans-Golgi network membrane proteins, respectively. The accuracies thus obtained were 76.1% and 83.7%, respectively. These results indicate that our method may become a useful tool in the relevant areas. As a user-friendly web server, the predictor is freely accessible at http://immunet.cn/SubGolgi/. PMID- 20955169 TI - Isolation of a new trypsin inhibitor from the Faba bean (Vicia faba cv. Giza 843) with potential medicinal applications. AB - A new 15-kDa Bowman-Birk type trypsin inhibitor (termed VFTI-G1) was isolated from the seeds of Faba bean (Vicia faba cv. Giza 843) using cation exchange chromatography on an SP-Sepharose column, anion exchange chromatography on Q Sepharose and Mono Q columns, and finally size exclusion chromatography on a Superdex 75 column. VFTI-G1 manifested significant antiproteolytic activity against trypsin (5761 BAEE units/mg, K(i) 20.4 * 10(-9) M), but only a slight chymotrypsin inhibitory activity (< 10 BTEE units/mg). The suitable environment to sustain its trypsin inhibitory activity was at temperatures below 60 degrees C and at pH 7. Its trypsin inhibitory activity was inhibited by the reducing agent dithiothreitol in a dose-dependent manner, indicating the significance of intact disulfide bonds to the trypsin inhibitory activity. It inhibited HIV-1 reverse transcriptase (RT) activity with an IC(50) of about 0.76 uM. Furthermore, VFTI-G1 showed specific antiproliferative activity toward HepG2 hepatoma cells by inducing chromatin condensation and cell apoptosis. The HIV-1 RT inhibitory activity of VFTI-G1 and its specific antiproliferative activity toward Hep G2 cells may find medical applications. PMID- 20955170 TI - Biochemical characterization of a new maize (Zea mays L.) peptide growth factor. AB - Coordination of cell growth and cell division is very important for living organisms in order for these to develop harmonically. The present research is concerned with the purification and characterization of a new peptide hormone, namely ZmIGF (Zea mays insulin-like growth factor), which regulates growth and cell division in maize tissues. ZmIGF is a peptide of 5.7 kDa, as determined by mass spectroscopy. It was isolated either from maize embryonic axes of 48-h germinated seeds or from embryogenic callus and purified through several chromatographic procedures to obtain a single peak as shown by Reverse Phase High Performance Liquid Chromatography (RP-HPLC). This peptide exhibits a well defined alpha-helix structure by circular dichroism analysis, similar to that reported for Insulin or for Insulin-like growth factor (IGF-1). Further, ZmIGF seems to perform, in maize, a similar function to that reported for insulin or peptides from the IGF family in animals. Indeed, maize tissues stimulated either by ZmIGF or insulin showed to induce selective synthesis of ribosomal proteins as well as of DNA. Taken together, the previously mentioned data strongly suggest that plants contain a peptide hormone of the IGF family, highly conserved through evolution that regulates growth and development. PMID- 20955171 TI - Bacteriostatic activity of the proregion of human hepcidin. AB - Hepcidin was first identified as an antimicrobial peptide expressed in the liver. It was later demonstrated that hepcidin is in fact the long sought hormone that regulates iron homeostasis in mammals. Hepcidin is encoded as an 84 amino acid prepropeptide that is successively cleaved to yield prohepcidin and the mature 25 amino acid hepcidin. Both the bioactive 25-aa hepcidin and the 35-aa proregion are secreted by liver hepatocytes. The aim of the present study was to assess the antibacterial activity of the proregion peptide from human hepcidin. Using a chemically synthesized peptide corresponding to the proregion, we show that it is bactericidal against Bacillus megaterium (25uM), and inhibits Bacillus subtilis growth at high concentration (200uM). No synergistic interaction of proregion and Hepc25 against Bacillus megaterium was seen. In a further step, the mode of action of proregion on Bacillus megaterium was studied. It caused a slow accumulation of the vital stain SYTOX in the bacteria, indicating that it did not destroy the microbial membranes through a detergent-like mechanism, even at concentrations (80uM) higher than those required to kill the bacteria. This result suggests that the target of proregion might be an intracellular component. Finally, gel retardation assay showed that the DNA binding ability of the hepcidin proregion was equivalent to that observed for magainin 2, an antimicrobial peptide which exerts its antimicrobial effect by interfering with intracellular nucleic acids. In conclusion, we speculate that the proregion of hepcidin may have bacteriostatic effects, and as such may contribute to the innate immune response. PMID- 20955172 TI - PredCSF: an integrated feature-based approach for predicting conotoxin superfamily. AB - Conotoxins are small disulfide-rich peptides that are invaluable channel-targeted peptides and target neuronal receptors. They show prospects for being potent pharmaceuticals in the treatment of Alzheimer's disease, Parkinson's disease, and epilepsy. Accurate and fast prediction of conotoxin superfamily is very helpful towards the understanding of its biological and pharmacological functions especially in the post-genomic era. In the present study, we have developed a novel approach called PredCSF for predicting the conotoxin superfamily from the amino acid sequence directly based on fusing different kinds of sequential features by using modified one-versus-rest SVMs. The input features to the PredCSF classifiers are composed of physicochemical properties, evolutionary information, predicted second structure and amino acid composition, where the most important features are further screened by random forest feature selection to improve the prediction performance. The prediction results show that PredCSF can obtain an overall accuracy of 90.65% based on a benchmark dataset constructed from the most recent database, which consists of 4 main conotoxin superfamilies and 1 class of non-conotoxin class. Systematic experiments also show that combing different features is helpful for enhancing the prediction power when dealing with complex biological problems. PredCSF is expected to be a powerful tool for in silico identification of novel conotonxins and is freely available for academic use at http://www.csbio.sjtu.edu.cn/bioinf/PredCSF. PMID- 20955173 TI - Structural stability of soybean (Glycine max) alpha-amylase: properties of the unfolding transition studied with fluorescence and CD spectroscopy. AB - Stability and unfolding of mammalian and microbial alpha-amylases have been intensively investigated. However, there is only limited information available on the structural stability of plant alpha-amylases, namely of the two isoenzymes from barley AMY1 and AMY2, of the alpha-amylase from mung bean (Vigna radiata), and of the alpha-amylase from malted sorghum (Sorghum bicolor). We report here the stability of soyabean alpha-amylase (GMA), against elevated temperatures and chemical denaturants (GndHCl) by employing circular dichroism and fluorescence spectroscopy. Since it is well-known that calcium ions play a crucial role for enzymatic activity and stability of a-amylases, we performed our studies with calcium bound and calcium free GMA. The thermal unfolding transition temperature decreased from 72 degrees C for calcium saturated samples to 57 degrees C for the case of calcium depleted GMA. Similarly, the GndHCl transition concentration was lowered from 0.70 M for calcium bound GMA to 0.41 M in the absence of calcium. Thermal unfolding of GMA irreversible due to aggregation of the unfolded state. GMA unfolded in 6 M GndHCl shows high degree of reversibility after diluting the unfolded enzyme in native buffer containing 7 M glycerol. Furthermore, the refolded enzyme showed 93% of activity. PMID- 20955174 TI - Identification of a tyrosine phosphatase involved in the response to mechanical injury in leaves of Ricinus communis. AB - Plants defend themselves against biotic or abiotic stress by triggering intracellular signaling pathways that regulate gene expression and responses to the offending agent. Phosphorylation and dephosphorylation represent major mechanisms for the regulation of plant defense pathways. Therefore, MAP kinases and phosphatases have been the focus of many studies in this area. This study identified three phosphatase activities, namely RcPPase I, II and III. Wounding increased the activity levels of RcPPase III, while the activities of RcPPase I and II remained constant compared to the control. N-terminal partial amino acid sequence, biochemical characterization with use of specific substrates and inhibitors indicated that the RcPPase III belong to the family of tyrosine phosphatases (PTPs). PMID- 20955175 TI - An improved profile-level domain linker propensity index for protein domain boundary prediction. AB - Protein domain boundary prediction is critical for understanding protein structure and function. In this study, we present a novel method, an order profile domain linker propensity index (OPI), which uses the evolutionary information extracted from the protein sequence frequency profiles calculated from the multiple sequence alignments. A protein sequence is first converted into smooth and normalized numeric order profiles by OPI, from which the domain linkers can be predicted. By discriminating the different frequencies of the amino acids in the protein sequence frequency profiles, OPI clearly shows better performance than our previous method, a binary profile domain linker propensity index (PDLI). We tested our new method on two different datasets, SCOP-1 dataset and SCOP-2 dataset, and we were able to achieve a precision of 0.82 and 0.91 respectively. OPI also outperforms other residue-level, profile-level indexes as well as other state-of-the-art methods. PMID- 20955176 TI - Expression of the cannabinoid system in muscle: effects of a high-fat diet and CB1 receptor blockade. AB - The ECS (endocannabinoid system) plays an important role in the onset of obesity and metabolic disorders, implicating central and peripheral mechanisms predominantly via CB1 (cannabinoid type 1) receptors. CB1 receptor antagonist/inverse agonist treatment improves cardiometabolic risk factors and insulin resistance. However, the relative contribution of peripheral organs to the net beneficial metabolic effects remains unclear. In the present study, we have identified the presence of the endocannabinoid signalling machinery in skeletal muscle and also investigated the impact of an HFD (high-fat diet) on lipid-metabolism-related genes and endocannabinoid-related proteins. Finally, we tested whether administration of the CB1 inverse agonist AM251 restored the alterations induced by the HFD. Rats were fed on either an STD (standard/low-fat diet) or an HFD for 10 weeks and then treated with AM251 (3 mg/kg of body weight per day) for 14 days. The accumulated caloric intake was progressively higher in rats fed on the HFD than the STD, resulting in a divergence in body weight gain. AM251 treatment reduced accumulated food/caloric intake and body weight gain, being more marked in rats fed on the HFD. CB2 (cannabinoid type 2) receptor and PPARalpha (peroxisome-proliferator-activated receptor alpha) gene expression was decreased in HFD-fed rats, whereas MAGL (monoglyceride lipase) gene expression was up-regulated. These data suggest an altered endocannabinoid signalling as a result of the HFD. AM251 treatment reduced CB2 receptor, PPARgamma and AdipoR1 (adiponectin receptor 1) gene expression in STD-fed rats, but only partially normalized the CB2 receptor in HFD-fed rats. Protein levels corroborated gene expression results, but also showed a decrease in DAGL (diacylglycerol) beta and DAGLalpha after AM251 treatment in STD- and HFD-fed rats respectively. In conclusion, the results of the present study indicate a diet-sensitive ECS in skeletal muscle, suggesting that blockade of CB1 receptors could work towards restoration of the metabolic adaption imposed by diet. PMID- 20955177 TI - Procyanidin B3, an inhibitor of histone acetyltransferase, enhances the action of antagonist for prostate cancer cells via inhibition of p300-dependent acetylation of androgen receptor. AB - Increasing evidence suggests that AR (androgen receptor) acetylation is critical for prostate cancer cell growth. In the present study, we identified Pro-B3 (procyanidin B3) as a specific HAT (histone acetyltransferase) inhibitor. Pro-B3 selectively inhibited the activity of HATs, but not other epigenetic enzymes. Pro B3 substantially inhibited the p300-mediated AR acetylation, both in vitro and in vivo. Pro-B3 inhibited both p300-dependent and agonist-induced AR transcription. We demonstrate that the p300-mediated AR acetylation is critical for the hormone responsiveness of AR. Interestingly, B3 treatment efficiently enhanced the antagonist activity of flutamide through suppression of p300 HAT activity, demonstrating that relative p300 activity is critical for the antagonist action. Finally, Pro-B3 treatment inhibited acetylation-dependent prostate cell proliferation and expression of cell-cycle control genes, subsequently increasing cell death, indicating the functional importance of AR acetylation for prostate cancer cell growth. PMID- 20955179 TI - Reversible male sterility in eggplant (Solanum melongena L.) by artificial microRNA-mediated silencing of general transcription factor genes. AB - Since decades, plant male sterility is considered a powerful tool for biological containment to minimize unwanted self-pollination for hybrid seed production. Furthermore, prevention of pollen dispersal also answers to concerns regarding transgene flow via pollen from Genetically Modified (GM) crops to traditional crop fields or wild relatives. We induced male sterility by suppressing endogenous general transcription factor genes, TAFs, using anther-specific promoters combined with artificial microRNA (amiRNA) technology (Schwab et al., 2006). The system was made reversible by the ethanol inducible expression of an amiRNA-insensitive form of the target gene. We provide proof of concept in eggplant, a cultivated crop belonging to the Solanaceae family that includes many important food crops. The transgenic eggplants that we generated are completely male sterile and fertility can be fully restored by short treatments with ethanol, confirming the efficiency but also the reliability of the system in view of open field cultivation. By combining this system with induced parthenocarpy (Rotino et al., 1997), we provide a novel example of complete transgene containment in eggplant, which enables biological mitigation measures for the benefit of coexistence or biosafety purposes for GM crop cultivation. PMID- 20955178 TI - Regulation of unfolded protein response modulator XBP1s by acetylation and deacetylation. AB - XBP1 (X-box-binding protein 1) is a key modulator of the UPR (unfolded protein response), which is involved in a wide range of pathological and physiological processes. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR. However, the post-translational modulation of XBP1s remains largely unknown. In the present study, we demonstrate that XBP1s is a target of acetylation and deacetylation mediated by p300 and SIRT1 (sirtuin 1) respectively. p300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity. Deficiency of SIRT1 enhances XBP1s-mediated luciferase reporter activity in HEK (human embryonic kidney)-293 cells and the up-regulation of XBP1s target gene expression under ER (endoplasmic reticulum) stress in MEFs (mouse embryonic fibroblasts). Consistent with XBP1s favouring cell survival under ER stress, Sirt1-/- MEFs display a greater resistance to ER-stress-induced apoptotic cell death compared with Sirt1+/+ MEFs. Taken together, these results suggest that acetylation/deacetylation constitutes an important post-translational mechanism in controlling protein levels, as well as the transcriptional activity, of XBP1s. The present study provides a novel insight into the molecular mechanisms by which SIRT1 regulates UPR signalling. PMID- 20955180 TI - Screening for resistance against Pseudomonas syringae in rice-FOX Arabidopsis lines identified a putative receptor-like cytoplasmic kinase gene that confers resistance to major bacterial and fungal pathogens in Arabidopsis and rice. AB - Approximately 20,000 of the rice-FOX Arabidopsis transgenic lines, which overexpress 13,000 rice full-length cDNAs at random in Arabidopsis, were screened for bacterial disease resistance by dip inoculation with Pseudomonas syringae pv. tomato DC3000 (Pst DC3000). The identities of the overexpressed genes were determined in 72 lines that showed consistent resistance after three independent screens. Pst DC3000 resistance was verified for 19 genes by characterizing other independent Arabidopsis lines for the same genes in the original rice-FOX hunting population or obtained by reintroducing the genes into ecotype Columbia by floral dip transformation. Thirteen lines of these 72 selections were also resistant to the fungal pathogen Colletotrichum higginsianum. Eight genes that conferred resistance to Pst DC3000 in Arabidopsis have been introduced into rice for overexpression, and transformants were evaluated for resistance to the rice bacterial pathogen, Xanthomonas oryzae pv. oryzae. One of the transgenic rice lines was highly resistant to Xanthomonas oryzae pv. oryzae. Interestingly, this line also showed remarkably high resistance to Magnaporthe grisea, the fungal pathogen causing rice blast, which is the most devastating rice disease in many countries. The causal rice gene, encoding a putative receptor-like cytoplasmic kinase, was therefore designated as BROAD-SPECTRUM RESISTANCE 1. Our results demonstrate the utility of the rice-FOX Arabidopsis lines as a tool for the identification of genes involved in plant defence and suggest the presence of a defence mechanism common between monocots and dicots. PMID- 20955181 TI - OsCD1 encodes a putative member of the cellulose synthase-like D sub-family and is essential for rice plant architecture and growth. AB - The cell wall plays important roles in plant architecture and morphogenesis. The cellulose synthase-like super-families were reported to contain glycosyltransferases motif and are required for the biosynthesis of cell wall polysaccharides. Here, we describe a curled leaf and dwarf mutant, cd1, in rice, which exhibits multiple phenotypic traits such as the reduction of plant height and leaf width, curled leaf morphology and a decrease in the number of grains and in the panicle length. Map-based cloning indicates that a member of the cellulose synthase-like D (CSLD) group is a candidate for OsCD1. RNAi transgenic plants with the candidate CSLD gene display a similar phenotype to the cd1 mutant, suggesting that OsCD1 is a member of the CSLD sub-family. Furthermore, sequence analysis indicates that OsCD1 contains the common D,D,D,QXXRW motif, which is a feature of the cellulose synthase-like super-family. Analysis of OsCD1 promoter with GUS fusion expression shows that OsCD1 exhibits higher expression in young meristem tissues such as fresh roots, young panicle and stem apical meristem. Cell wall composition analysis reveals that cellulose content and the level of xylose are significantly reduced in mature culm owing to loss of OsCD1 function. Take together, the work presented here is useful for expanding the understanding of cell wall biosynthesis. PMID- 20955182 TI - Overexpression of two cambium-abundant Chinese fir (Cunninghamia lanceolata) alpha-expansin genes ClEXPA1 and ClEXPA2 affect growth and development in transgenic tobacco and increase the amount of cellulose in stem cell walls. AB - Expansins are unique plant cell wall proteins that possess the ability to induce immediately cell wall extension in vitro and cell expansion in vivo. To investigate the biological functions of expansins that are abundant in wood forming tissues, we cloned two expansin genes from the differentiating xylem of Chinese fir (Cunninghamia lanceolata (Lamb.) Hook). Phylogenetic reconstruction indicated that they belong to alpha-expansin (EXPA), named ClEXPA1 and ClEXPA2. Expression pattern analysis demonstrated that they are preferentially expressed in the cambium region. Overexpression of ClEXPA1 and ClEXPA2 in tobacco plants yielded pleiotropic phenotypes of plant height, stem diameter, leaf number and seed pod. The height and diameter growth of the 35S(pro) :ClEXPA1 and 35S(pro) :ClEXPA2 transgenic plants were increased drastically, exhibiting an enlargement of pith parenchyma cell size. Isolated cell walls of ClEXPA1 and ClEXPA2 overexpressors contained 30%-50% higher cellulose contents than the wild type, accompanied by a thickening of the cell walls in the xylem region. Both ClEXPA1 and ClEXPA2 are involved in plant growth and development, with a partially functional overlap. Expansins are not only able to induce cell expansion in different tissues/organs in vivo, but they also can act as a potential activator during secondary wall formation by directly or indirectly affecting cellulose metabolism, probably in a cell type-dependent manner. PMID- 20955183 TI - Waiting for a kidney transplant: patients' experiences of haemodialysis therapy. AB - AIM: This paper is a report of an exploration of the experiences of patients with end-stage kidney disease who were having haemodialysis. BACKGROUND: The losses and lifestyle disruptions caused by end-stage kidney disease are a fundamental source of suffering for people. The hope of a transplant is an important factor in people's ability to cope with end-stage kidney disease and dialysis. METHOD: A Heideggerian phenomenological methodology was used. A purposive sample was selected of 16 patients with end-stage kidney disease having hospital-based haemodialysis therapy in the Republic of Ireland. Qualitative interviews were conducted in 2006-2007. Data were analysed using qualitative interpretive analysis. FINDINGS: The overarching pattern identified was 'Waiting for a kidney transplant'. This pattern consisted of three themes: living in hope, uncertainty and being on hold. Participants described their experiences of living in hope while they waited for a kidney transplant. However, as the waiting time continued indefinitely, participants became uncertain, and this meant that they were unable to contemplate opportunities in the future. Moreover, the restrictions of haemodialysis therapy prevented them from performing many of the activities they had taken for granted in the past. Consequently, they described their experiences of being on hold while they waited for a kidney transplant. CONCLUSION: Nurses should engage in open and honest discussions with patients in relation to kidney transplantation so that they are able to recognize and address their concerns about kidney transplantation. PMID- 20955184 TI - Improving insight into delusions: a pilot study of metacognitive training for patients with schizophrenia. AB - AIM: The paper is a report of a study conducted to test the implementation of the French version of the metacognitive training programme and its effects on psychotic symptoms and awareness of the disorder. BACKGROUND: Understanding of the mechanisms underlying the psychotic experience has considerably improved in recent years. Psychotic symptoms are associated with cognitive biases that trigger, worsen or maintain them. Metacognitive training aims to make patients aware of their cognitive biases, train them to see these distortions in a critical way, and help them complete or change their problem-solving repertoire. METHOD: A small, uncontrolled pilot study was carried out. Patients suffering from schizophrenia or schizoaffective disorder with persistent psychotic symptoms were recruited in an outpatient rehabilitation unit. They were assessed at pre- and post-test with the Psychotic Symptom Rating Scales, Positive and Negative Syndrome Scale and Scale to Assess Unawareness of Mental Disorder. The metacognitive training was administered every week in group sessions during an 8 months period in 2008. FINDINGS: Twenty-five patients consented to participate. Eighteen patients completed 8 to 16 one-hour weekly sessions of metacognitive training. Participants reduced substantially the severity of their delusions and improved their awareness of delusions, attribution of the delusions to the disease and awareness of the disorder. The improvements were accompanied by a reduction in depression. CONCLUSION: Metacognitive training appears to be a promising new technology which requires further research. It can be easily used by nurses to help patients with delusions to take into account their cognitive biases. PMID- 20955185 TI - Satellite dialysis nursing: technology, caring and power. AB - AIM: This paper is a report of an exploration of nurses' perceptions of the quality of satellite dialysis care and how aspects of power that influenced quality nursing care. BACKGROUND: In Australia, the majority of people living with established kidney failure undertake haemodialysis in nurse-run satellite dialysis units. Haemodialysis nurses provide the majority of care, and their perceptions of what constitutes quality nursing care may influence their care of the person receiving haemodialysis. METHOD: A critical ethnographic study was conducted where data were collected from one metropolitan satellite dialysis unit in Australia over a 12-month period throughout 2005. The methods included non participant observation, interviews, document analysis, reflective field notes and participant feedback. FINDINGS: Three theoretical constructs were identified: 'What is quality?', 'What is not quality?' and What influences quality?' Nurses considered technical knowledge, technical skills and personal respect as characteristics of quality. Long-term blood pressure management and arranging transport for people receiving dialysis treatment were not seen to be priorities for quality care. The person receiving dialysis treatment, management, nurse and environment were considered major factors determining quality dialysis nursing care. CONCLUSION: Aspects of power and oppression operated for nurses and people receiving dialysis treatment within the satellite dialysis context, and this environment was perceived by the nurses as very different from hospital dialysis units. PMID- 20955186 TI - Impact of communication skills training on parents perceptions of care: intervention study. AB - AIM: This paper is a report of a study of the effects of communication-skills training for healthcare professionals on parents' perceptions of information, care and continuity. BACKGROUND: As training in communication skills has been more and more integrated into clinical practice it has been subject to an increasing number of studies. However, the majority of studies have been conducted in outpatient clinics, have only targeted physicians, and have not been evaluated from the perspective of patients. METHOD: This intervention study, conducted from 2005 to 2007, was performed to investigate the effect of a 3-day communication course offered to all healthcare professionals in a department of paediatrics. In a pre-/post-test design, the effect of the intervention was evaluated by the parents using electronic questionnaires filled in on touch screen computers located centrally in the wards. RESULTS: A total of 895 parents answered the questionnaires before the course (80%) and 1937 answered after the course (72%). For the questions on care and continuity, the proportion of satisfied parents increased statistically significantly for 4 out of 13 questions, e.g. Did you feel that the staff understood you situation? and Did you find that the information given by the different nurses was consistent? For the information questions, no statistically significant differences were found. CONCLUSION: It is possible to incorporate key communication skills into clinical practice by targeting all healthcare professionals. Communication skills training using interactive methods such as role-play and feedback on video recordings is recommended. PMID- 20955187 TI - A multimodal approach to emotion recognition ability in autism spectrum disorders. AB - BACKGROUND: Autism spectrum disorders (ASD) are characterised by social and communication difficulties in day-to-day life, including problems in recognising emotions. However, experimental investigations of emotion recognition ability in ASD have been equivocal, hampered by small sample sizes, narrow IQ range and over focus on the visual modality. METHODS: We tested 99 adolescents (mean age 15;6 years, mean IQ 85) with an ASD and 57 adolescents without an ASD (mean age 15;6 years, mean IQ 88) on a facial emotion recognition task and two vocal emotion recognition tasks (one verbal; one non-verbal). Recognition of happiness, sadness, fear, anger, surprise and disgust were tested. Using structural equation modelling, we conceptualised emotion recognition ability as a multimodal construct, measured by the three tasks. We examined how the mean levels of recognition of the six emotions differed by group (ASD vs. non-ASD) and IQ (>= 80 vs. < 80). RESULTS: We found no evidence of a fundamental emotion recognition deficit in the ASD group and analysis of error patterns suggested that the ASD group were vulnerable to the same pattern of confusions between emotions as the non-ASD group. However, recognition ability was significantly impaired in the ASD group for surprise. IQ had a strong and significant effect on performance for the recognition of all six emotions, with higher IQ adolescents outperforming lower IQ adolescents. CONCLUSIONS: The findings do not suggest a fundamental difficulty with the recognition of basic emotions in adolescents with ASD. PMID- 20955188 TI - Confirming the etiology of adolescent acting-out behaviors: an examination of observer-ratings in a sample of adoptive and biological siblings. AB - BACKGROUND: A recent meta-analysis revealed moderate shared environmental influences (C) on most forms of child and adolescent psychopathology (Burt, 2009), including antisocial behavior. Critically, however, the research analyzed in this meta-analysis relied largely on specific informant-reports (and particularly parent and child reports), each of which is subject to various sources of rater bias. Observer-ratings of children's behaviors avoid many of these biases, and are thus well suited to verify the presence of C. Given this, we sought to buttress the evidence supporting C in two key ways. First, we sought to confirm that C contributes to observer-ratings in a sample of adoptive siblings, as similarity between adoptive siblings constitutes a 'direct' estimate of C. Second, we sought to confirm that these shared environmental influences persist across informants (i.e., the effects are not specific to the rater or the context in question). METHODS: The current study examined the etiology of observer-ratings of acting-out behaviors, as well as sources of etiological overlap across observer-ratings, adolescent self-report and maternal-report in sample of over 600 biological and adoptive sibling pairs from the Sibling Interaction and Behavior Study (SIBS). RESULTS: Results revealed moderate and significant shared environmental influences on observer-ratings (31%), as well as on the other informant-reports (20-23%). Moreover, a portion of these effects overlapped across measures (C correlations ranged from .32 to .34). CONCLUSIONS: Such findings argue against passive gene-environment correlations (rGE) and rater bias as primary explanations for earlier findings of C on antisocial behavior, and in this way, offer a critical extension of prior work indicating that the role of shared environmental influences on child and adolescent antisocial behavior was dismissed too soon. PMID- 20955189 TI - Parent ratings of executive functioning in children adopted from psychosocially depriving institutions. AB - BACKGROUND: Previous studies have found that post-institutionalized (PI) children are particularly susceptible to attention problems and perform poorly on executive functioning (EF) lab tasks. METHODS: Parent ratings of EF were examined in 288 school-age and 130 preschool-age children adopted from psychosocially depriving Russian institutions that provided adequate physical resources but not one-on-one interactions with a consistent set of responsive caregivers. RESULTS: Results revealed a step-like association between age at adoption and EF deficits; school-age children adopted after 18 months of age had greater EF difficulties than younger-adopted children and the never-institutionalized normative sample. The onset of adolescence was associated with a greater increase in EF deficits for children adopted after 18 months than for younger-adopted children. Preschool age children were not found to have greater EF difficulties than the normative sample. CONCLUSIONS: These findings suggest that prolonged early psychosocial deprivation may increase children's risk of EF deficits and that the developmental stresses of adolescence may be particularly challenging for older adopted PI children. PMID- 20955190 TI - Activities of muscadine grape skin and quercetin against Helicobacter pylori infection in mice. AB - AIMS: To explore the preventative potential of muscadine grape skin (MGS) and the single flavonoid, quercetin, as an alternative means for ameliorating Helicobacter pylori infection and/or the H. pylori-induced inflammatory response in mice. METHODS AND RESULTS: The antimicrobial and anti-inflammatory properties of MGS and quercetin, a major phenolic constituent, were evaluated against H. pylori in vitro and in vivo. The antimicrobial activity of quercetin was evaluated against 11 H. pylori strains in vitro with inhibition of all strains at 128-64 MUg ml(-1) . In vivo studies showed a moderate reduction in H. pylori counts following treatment with 5 and 10% MGS or quercetin (25 mg kg(-1) body weight) in addition to significantly reduced inflammatory cytokines (TNF-alpha, IL-1beta and IFN-gamma) when compared with untreated mice. CONCLUSIONS: MGS and quercetin did not significantly reduce H. pylori growth in a mouse model. However, these products were effective in regulating the inflammatory response to H. pylori infection. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results suggest that H. pylori infection may be reduced or prevented via the consumption of fruits rich in certain phenolic compounds (e.g. quercetin) such as muscadine grapes. PMID- 20955191 TI - Identification of novel halotolerant bacillopeptidase F-like proteinases from a moderately halophilic bacterium, Virgibacillus sp. SK37. AB - AIMS: Virgibacillus sp. SK37 isolated from Thai fish sauce produced numerous NaCl activated subtilisin-like proteinases. Our objectives were to purify, characterize and identify these extracellular proteinases. METHODS AND RESULTS: Three major subtilisin-like enzymes including 19, 34 and 44 kDa were partially purified and showed maximum activity at pH 8, 55-60 degrees C, 25-30% NaCl and 70 100 mmol l(-1) CaCl(2) . Enzymes showed stability at 0-30% NaCl and <20 mmol l( 1) CaCl(2) and were completely inhibited by phenylmethanesulphonyl fluoride but not by ethylenediaminetetraacetic acid. The isoelectric points of 19-, 34- and 44 kDa proteinases were at 3.6, 5.2 and 3.8, respectively, based on 2D electrophoresis. Peptide mass fingerprint and de novo peptide homology analysis of tryptic peptides using MALDI-TOF and LC-MS/MS, respectively, suggested that all three enzymes were novel and homologous to bacillopeptidase F. CONCLUSIONS: The three major proteinases are a member of bacillopeptidase F-like enzymes exhibiting thermophilic and halotolerant characteristics with high stability at 30% NaCl. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report on bacillopeptidase F-like proteinases in genus Virgibacillus with a distinct halotolerant feature. They showed potential to be a processing aid for food and biotechnological applications, particularly in high salt condition. PMID- 20955192 TI - Isolation and characterization of new potential probiotic bacteria based on quorum-sensing system. AB - AIMS: This work was aimed at identifying strains which can degrade quorum-sensing (QS) molecules from fish gut, with properties suitable for use as probiotic in aquaculture. METHODS AND RESULTS: A total of 200 strains were obtained from the intestine gut of Carassius auratus gibelio after enrichment in KG medium contained 500 MUg l(-1) of C6-HSL as the sole source of carbon and nitrogen; one strain named QS inhibitor (QSI)-1 was identified as the genus Bacillus spp. by morphological phenotypes, and the strain also possessed an aiiA homologue gene using PCR amplification. In vitro, QSI-1 strongly interfered with violacein production by Chromobacterium violaceum. Coculture of QSI-1 with fish pathogen effectively reduced the amount of acyl-homoserine lactones (AHLs) and the extracellular proteases activity of Aeromonas hydrophila YJ-1. The oral LD50 of QSI-1 to fish was more than 10(11) CFU shown that it was avirulent to fish. Fish fed diet supplemented with QSI-1 had good survival, suggesting that QSI-1 showed protection against Aer. hydrophila infection. CONCLUSIONS: The results indicate that the isolate QSI-1 might have the potential possibility to be used as a probiotic in aquaculture. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report to describe a bacterium isolated from the intestine gut of C. auratus gibelio which can degrade AHLs and has the probiotic characteristics for its use in aquaculture. PMID- 20955193 TI - Potential pathogenic bacteria in metalworking fluids and aerosols from a machining facility. AB - The metalworking and machining industry utilizes recirculating metalworking fluids for integral aspects of the fabrication process. Despite the use of biocides, these fluids sustain substantial biological growth. Subsequently, the high-shear forces incurred during metalworking processing aerosolize bacterial cells and may cause dermatologic and respiratory effects in exposed workers. We quantified and identified the bacterial load for metalworking fluid and aerosol samples of a machining facility in the US Midwest during two seasons. To investigate the presence of potentially pathogenic bacteria in fluid and air, we performed 16S rRNA gene surveys. The concentration of total bacterial cells (including culturable and nonculturable cells) was relatively constant throughout the study, averaging 5.1 * 108 cells mL-1 in the fluids and 4.8 * 105 cells m-3 in the aerosols. We observed bacteria of potential epidemiologic significance from several different bacterial phyla in both fluids and aerosols. Most notably, Alcaligenes faecalis was identified through both direct sequencing and culturing in every sample collected. Elucidating the bacterial community with gene surveys showed that metalworking fluids were the source of the aerosolized bacteria in this facility. PMID- 20955194 TI - Effect of temperature and starvation upon survival strategies of Pseudomonas fluorescens CHA0: comparison with Escherichia coli. AB - Microorganisms in aquatic systems are exposed to continuous modifications in their environmental conditions. In these systems, both autochthonous and allochthonous bacteria respond to adverse conditions by expressing viable but nonculturable phenotype. On the basis of this common response, the behaviour of a few species is extrapolated to others. We compared the survival strategies of Escherichia coli (allochthonous, mesophile bacterium) and Pseudomonas fluorescens CHA0 (ubiquitous, psychrotrophic bacteria) under nonoptimal temperature and nutrient deprivation. In the absence of nutrients, the effect of temperature on the loss of culturability did not show a common pattern. Whereas the survival of E. coli had an inverse relationship with temperature, whereas for P. fluorescens a direct relationship between temperature and T90 values was only established in the range 5-15 degrees C, with an inverse relationship at higher temperatures. When the subproteome of the outer membrane of P. fluorescens was comparatively analysed, starvation was not the main source of change. The most relevant modifications were due to variations in temperature. OprF, the major surface protein of the genus Pseudomonas, showed a high expression in nonculturable as well as culturable populations under all the adverse situations analysed. We therefore propose OprF as a suitable marker for Pseudomonas detection in the environment. PMID- 20955195 TI - Divergence of Eurosta solidaginis in response to host plant variation and natural enemies. AB - We tested the hypothesis that forest and prairie populations of the gall-inducing fly, Eurosta solidaginis, have diverged in response to variation in selection by its host plant Solidago altissima, and its natural enemies. A reciprocal cross infection design experiment demonstrated that fly populations from the prairie and forest biomes had higher survival on local biome plants compared to foreign biome host plants. Flies from each biome also had an oviposition preference for their local plants. Each fly population induced galls of the size and shape found in their local biome on host plants from both biomes indicating a genetic basis to the differences in gall morphology. Solidago altissima from the prairie and forest biomes retained significant morphological differences in the common garden indicating that they are genetically differentiated, possibly at the subspecies level. The populations are partially reproductively isolated as a result of a combination of prezygotic isolation due to host-associated assortative mating, and postzygotic isolation due to low hybrid survival. We conclude that E. solidaginis is undergoing diversifying selection to adapt to differences between prairie and forest habitats. PMID- 20955196 TI - Mercury methylation in Sphagnum moss mats and its association with sulfate reducing bacteria in an acidic Adirondack forest lake wetland. AB - Processes leading to the bioaccumulation of methylmercury (MeHg) in northern wetlands are largely unknown. We have studied various ecological niches within a remote, acidic forested lake ecosystem in the southwestern Adirondacks, NY, to discover that mats comprised of Sphagnum moss were a hot spot for mercury (Hg) and MeHg accumulation (190.5 and 18.6 ng g-1 dw, respectively). Furthermore, significantly higher potential methylation rates were measured in Sphagnum mats as compared with other sites within Sunday Lake's ecosystem. Although MPN estimates showed a low biomass of sulfate-reducing bacteria (SRB), 2.8 * 104 cells mL-1 in mat samples, evidence consisting of (1) a twofold stimulation of potential methylation by the addition of sulfate, (2) a significant decrease in Hg methylation in the presence of the sulfate reduction inhibitor molybdate, and (3) presence of dsrAB-like genes in mat DNA extracts, suggested that SRB were involved in Hg methylation. Sequencing of dsrB genes indicated that novel SRB, incomplete oxidizers including Desulfobulbus spp. and Desulfovibrio spp., and syntrophs dominated the sulfate-reducing guild in the Sphagnum moss mat. Sphagnum, a bryophyte dominating boreal peatlands, and its associated microbial communities appear to play an important role in the production and accumulation of MeHg in high-latitude ecosystems. PMID- 20955197 TI - Complex evolutionary transitions and the significance of c(3)-c(4) intermediate forms of photosynthesis in Molluginaceae. AB - C(4) photosynthesis is a series of biochemical and structural modifications to C(3) photosynthesis that has evolved numerous times in flowering plants, despite requiring modification of up to hundreds of genes. To study the origin of C(4) photosynthesis, we reconstructed and dated the phylogeny of Molluginaceae, and identified C(4) taxa in the family. Two C(4) species, and three clades with traits intermediate between C(3) and C(4) plants were observed in Molluginaceae. C(3)-C(4) intermediacy evolved at least twice, and in at least one lineage was maintained for several million years. Analyses of the genes for phosphoenolpyruvate carboxylase, a key C(4) enzyme, indicate two independent origins of fully developed C(4) photosynthesis in the past 10 million years, both within what was previously classified as a single species, Mollugo cerviana. The propensity of Molluginaceae to evolve C(3)-C(4) and C(4) photosynthesis is likely due to several traits that acted as developmental enablers. Enlarged bundle sheath cells predisposed some lineages for the evolution of C(3)-C(4) intermediacy and the C(4) biochemistry emerged via co-option of photorespiratory recycling in C(3)-C(4) intermediates. These evolutionarily stable transitional stages likely increased the evolvability of C(4) photosynthesis under selection environments brought on by climate and atmospheric change in recent geological time. PMID- 20955198 TI - Development and evaluation of loop-mediated isothermal amplification for rapid detection of Haemophilus parasuis. AB - Loop-mediated isothermal amplification (LAMP) is a novel nucleic acid amplification method performed under isothermal conditions and has a high specificity and efficiency. We developed a LAMP assay targeting the 16S rRNA gene for rapid detection of Haemophilus parasuis. The results obtained from testing 31 H. parasuis strains and 28 other bacterial species strains showed that LAMP was as specific as, and more sensitive than, nested PCR. Fifty-five lung samples were collected from 55 healthy pigs. All the samples were negative for H. parasuis by bacterial isolation, nested PCR and LAMP, respectively. In addition, 122 lung samples were collected from 122 pigs with apparent respiratory problems. Sixty five were positive by bacterial isolation. All the samples that were positive by bacterial isolation were also positive by nested PCR and LAMP. The LAMP assay demonstrated higher sensitivity than nested PCR, picking up 16 additional cases. The LAMP assay also gave a same result compared with the nested PCR when the two assays were used, respectively, to detect H. parasuis from samples obtained from experimentally infected pigs. We concluded that LAMP is a highly sensitive and reliable method for detection of H. parasuis infection. PMID- 20955199 TI - Translational errors: from yeast to new therapeutic targets. AB - Errors occur randomly and at low frequency during the translation of mRNA. However, such errors may also be programmed by the sequence and structure of the mRNA. These programmed events are called 'recoding' and are found mostly in viruses, in which they are usually essential for viral replication. Translational errors at a stop codon may also be induced by drugs, raising the possibility of developing new treatment protocols for genetic diseases on the basis of nonsense mutations. Many studies have been carried out, but the molecular mechanisms governing these events remain largely unknown. Studies on the yeast Saccharomyces cerevisiae have contributed to characterization of the HIV-1 frameshifting site and have demonstrated that frameshifting is conserved from yeast to humans. Yeast has also proved a particularly useful model organism for deciphering the mechanisms of translation termination in eukaryotes and identifying the factors required to obtain a high level of natural suppression. These findings open up new possibilities for large-scale screening in yeast to identify new drugs for blocking HIV replication by inhibiting frameshifting or restoring production of the full-length protein from a gene inactivated by a premature termination codon. We explore these two aspects of the contribution of yeast studies to human medicine in this review. PMID- 20955200 TI - Endogenous MU-opioid peptides modulate immune response towards malignant melanoma. AB - Opioids exert major effects not only in the central nervous system but also in immune responses. We investigated the effects of MU-opioid peptides, secreted by tumor cells, on anti-tumor immune responses. For this purpose, tumor growth was studied in wild-type and MU-opioid receptor-deficient (MOR-/-) mice injected with B16 melanoma cells. The ability of these cells to produce opioids was studied by Western blots in vitro. Finally, biopsy material from human melanomas was investigated by immunohistochemistry for beta endorphin expression. Injection of B16 melanoma cells, producing endogenous beta endorphin, in the flank of MOR-/- mice revealed a profound reduction in tumor growth, paralleled by a significantly higher infiltration of immune cells into the tumors, when compared to tumor growth after injection of B16 melanoma cells into wild-type mice. Opioids present in B16 cell supernatant significantly reduced the proliferation of normal but not MOR-/- leucocytes. Immunohistochemical analyses of biopsies from human melanoma tissues showed a positive correlation between expression of beta endorphin and tumor progression. Our data provide evidence that MU-opioid peptides may play a major role in cancer progression by modulating immune response. This finding may have implications for the future optimization of immunointerventions for cancer. PMID- 20955201 TI - Tight junctions in the stratum corneum explain spatial differences in corneodesmosome degradation. AB - To maintain stratum corneum integrity while simultaneously desquamating at a steady rate, degradation of corneodesmosomes must proceed in a controlled manner. It is unknown why corneodesmosomes are present only at the cell periphery in the upper stratum corneum. To explore this, we studied distributions of three major corneodesmosomal components, corneodesmosin, desmoglein 1 and desmocollin 1 in normal adult human epidermis. Immunofluorescent microscopy studies of skin surface corneocytes detected all three components only at the cell edges. Immunoelectron microscopy revealed selective loss of these components at the central areas starting from the deep cornified layers. We hypothesized that tight junctions (TJs) formed in the superficial granular layer may prevent protease access by functioning as a barrier between the peripheral and the central intercellular spaces in the stratum corneum. Ultrastructural examination demonstrated TJs up to the junctions between the seventh and the eighth deepest cornified layers. Immunoelectron microscopy also detected clusters of occludin and claudin-1 immunolabels at the cell periphery, and kallikrein 7 immunolabels outside of TJs in the lower cornified layers. With colloidal lanthanum nitrate perfusion assay of stripped stratum corneum, the tracer was excluded from TJ domains. Taken together, we propose that TJs inhibit access of proteases to the peripheral corneodesmosomes forming the structural basis for the basket-weave like appearance of the stratum corneum. PMID- 20955202 TI - IL-1 signalling is dispensable for protective immunity in Leishmania-resistant mice. AB - Leishmaniasis is a parasitic disease affecting ~12 million people. Control of infection (e.g. in C57BL/6 mice) results from IL-12-dependent production of IFNgamma by Th1/Tc1 cells. In contrast, BALB/c mice succumb to infection because of preferential Th2-type cytokine induction. Infected dendritic cells (DC) represent important sources of IL-12. Genetically determined differences in DC IL 1alpha/beta production contribute to disease outcome. Whereas the course of disease was not dramatically altered in IL-1RI(-/-) mice, local administration of IL-1alpha to infected C57BL/6 mice improved disease outcome. To definitively elucidate the involvement of IL-1 in immunity against leishmaniasis, we now utilized IL-1alpha/beta-double-deficient C57BL/6 mice. C57BL/6 mice are believed to be a good surrogate model for human, self limited cutaneous leishmaniasis (CL). Leishmania major-infected IL-1alpha/beta(-/-) mice were resistant to experimental CL comparable to controls. In addition, DC-based vaccination against leishmaniasis in C57BL/6 mice was independent of IL-1. Thus, in Leishmania resistant C57BL/6 mice, IL-1 signalling is dispensable for protection. PMID- 20955204 TI - Platelet lysate modulates MMP-2 and MMP-9 expression, matrix deposition and cell to-matrix adhesion in keratinocytes and fibroblasts. AB - Cell-matrix interactions are an essential element of wound healing, while platelet derivatives are used in clinical settings for the treatment of chronic wounds. We used a platelet lysate (PL), which had been previously shown to accelerate in vitro the wounding of HaCaT keratinocytes and fibroblasts (J Cell Mol Med, 13, 2009, 2030; Br J Dermatol, 159, 2008, 537), to study the modulation of MMP-2 and MMP-9 collagenase expression, collagen type I and III production and syndecan-4 expression and rearrangement in these cells. Zymography and Western blot analyses showed that exposure to 20% (v/v) PL for 24 h induced an apparently ERK1/2- and p38-dependent, NF-kappaB-independent, translational upregulation of MMP-9 in HaCaT, while HaCaT MMP-2 and fibroblast collagenases were almost unaffected. The use of in-cell ELISA showed that PL induced an increase in the collagen III production of fibroblasts. In-cell ELISA and immunofluorescence microscopy revealed an increase in the expression of syndecan-4 and its rearrangement to form focal adhesions in both cell types after PL exposure. Taken together, data indicate that PL promotes keratinocyte epithelialization and regulates fibroblast matrix deposition, thus providing a molecular basis for the ability of this platelet derivative to heal severe and problematic wounds without leading to heavy scarring and keloid formation. PMID- 20955203 TI - TNF receptor I on human keratinocytes is a binding partner for staphylococcal protein A resulting in the activation of NF kappa B, AP-1, and downstream gene transcription. AB - Primary human keratinocytes and immortalized HaCaT cells were analysed for their capacity to bind purified staphylococcal protein A (SpA). Co-incubation with FITC labelled SpA led to a dose-depending attachment. Pull-down experiments with cellular extracts revealed the TNFalpha receptor I (TNF RI) as binding partner on keratinocytes. Thus, we next looked for expression of this receptor in human epidermis and cultured keratinocytes. TNF RI is strongly expressed on all keratinocytes analysed, both at the mRNA and protein level and activation by SpA at optimal doses of 50-100 MUg/ml resulted in the phosphorylation of the TNF RI downstream kinases MEK1/2, JNK1/2, and p38 subsequently leading to translocation of the p65 NF kappa B subunit and AP-1 into the nucleus. This translocation was then followed by increased expression of IL-8 and COX-2, two known NF kappa B induced pro-inflammatory genes. To further test the relevance of our findings, we analysed in vitro production of over 100 strains isolated from atopic eczema showing that more than 85% of the tested strains produced extracellular SpA in substantial amounts. Thus, besides superantigens, haemolysins, and other cell wall components, Staphylococcus aureus exerts pro-inflammatory stimuli on human keratinocytes through the production of SpA signalling through TNF RI. PMID- 20955205 TI - A founder effect of c.1938delC in ITGB4 underlies junctional epidermolysis bullosa and its application for prenatal testing. AB - Junctional epidermolysis bullosa associated with pyloric atresia (JEB-PA) is one of the most severe inherited skin diseases, characterized by generalized blister formation and occlusion of the pylorus at birth. Most JEB-PA patients have mutations in the gene encoding beta4 integrin (ITGB4). No recurrent mutations in ITGB4 have been described as having founder effects. We collected three JEB-PA families with c.1938delC in ITGB4. Haplotype analysis using single nucleotide polymorphism markers throughout ITGB4 suggested one rare haplotype (2.8% of the Han Chinese and ethnic Japanese populations) in all alleles with c.1938delC. The parents of one of the three families sought prenatal diagnosis for a subsequent pregnancy. We succeeded in performing prenatal exclusion of JEB-PA using the foetal genomic DNA. Our study clearly demonstrated that recurrent c.1938delC in ITGB4 is a founder mutation in JEB-PA patients, and that genotyping of the mutation can be utilized for prenatal diagnosis of JEB-PA. PMID- 20955206 TI - Familial aplasia of the trapezius muscle: clinical and MRI findings. AB - A 5-year-old boy was referred to our neurology clinic for suspected myopathy. His parents reported normal upper extremity strength and no limitation in daily activities; however, he was unable to raise his arms above his head. On examination, both shoulders were down-slanting and anteriorly displaced, leading to a webbed neck appearance. Muscle MRI demonstrated isolated bilateral aplasia of the trapezius muscles. His father was found to have a unilateral partial trapezius hypoplasia with no functional consequences. CONCLUSION: Congenital aplasia of the trapezius muscle is a rare condition; bilateral aplasia of the muscle, having been reported in only five cases, is most often associated with aplasia of the pectoralis major. This is the first report to our knowledge to demonstrate bilateral isolated trapezius aplasia by MRI. PMID- 20955207 TI - Post-adoption contact, adoption communicative openness, and satisfaction with contact as predictors of externalizing behavior in adolescence and emerging adulthood. AB - BACKGROUND: This study examined the relation between three variables related to adoptive family relationships (post-adoption contact between adoptive and birth family members, adoption communicative openness, and satisfaction with contact) and adoptee externalizing behavior in adolescence and emerging adulthood. METHOD: The study included 190 families of infant-placed, domestic adoptees during childhood, adolescence, and emerging adulthood. Structural equation modeling (SEM) was used to analyze predictors of externalizing behavior from contact (adoptive parents and adolescent reports), adoption communicative openness (adoptive mothers), and satisfaction with contact (adoptive parents and adolescent). RESULTS: Externalizing behavior showed moderate stability across childhood, adolescence, and emerging adulthood. Contact and adoption communicative openness were related to each other, but not to externalizing behaviors in adolescence or emerging adulthood. Controlling for the effect of Childhood Externalizing, adoptive families most satisfied with contact reported relative declines in adoptee externalizing behavior during adolescence compared to those in less satisfied families. Satisfaction was also indirectly associated with Emerging Adult Externalizing, through its effect on Adolescent Externalizing. CONCLUSIONS: Although contact and adoption communicative openness were highly correlated with each other, neither was related to adoptees' externalizing behavior in adolescence or emerging adulthood. Family-level satisfaction with contact was more predictive of externalizing outcomes. PMID- 20955208 TI - Assessment of serum sodium to urinary sodium divided by (serum potassium)2 to urinary potassium as a screening tool for primary aldosteronism. AB - BACKGROUND: The SUSPPUP ratio [(serum sodium/urinary sodium)/(serum potassium2/urinary potassium)] has been proposed as a marker to screen for primary aldosteronism (PA). The original study found an area under the receiver operating characteristic (ROC) curve of 0.90 to detect PA; the sensitivity was 89% and specificity 86% for a ratio over 5.3 L mmol-1. MATERIALS AND METHODS: Patients attending a hypertension unit between 2001 and 2006 and for who renin and aldosterone measurements and concomitant serum and urinary biochemistry data were available were included if diagnosed with PA (n = 449) or essential hypertension (n = 2209). We compared the diagnostic value of the SUSPPUP ratio and of serum potassium in the whole population, in patients without interfering drugs and in patients with lateralized PA. RESULTS: The area under the ROC curve was significantly worse for the SUSPPUP ratio than for serum potassium in all groups: 0.72 vs. 0.76 in the whole population; 0.73 vs. 0.78 without interfering drugs; 0.76 vs. 0.82 for patients with lateralized PA. In the whole population, sensitivity was 71% for a SUSPPUP ratio >= 5.3 L mmol-1 and serum potassium < 3.7 mmol L-1, but specificity of the SUSPPUP ratio was significantly worse (61% vs. 69%). Using low serum potassium and/or high SUSPPUP ratio increased the sensitivity to 87% but decreased the specificity to 47%. CONCLUSIONS: The SUSPPUP ratio was outperformed by serum potassium as a screening tool for PA in this large validation sample. Its value as an adjunct to serum potassium is questionable because of the low specificity of their combination. PMID- 20955209 TI - The value of copper and zinc levels in hernia formation. AB - BACKGROUND: A defect in collagen metabolism is suspected to be one of the factors responsible for hernia formation. Lysyl oxidase is a copper-dependent enzyme in the process that provides for the structural integrity of collagen molecules, while zinc is essential for tissue maintenance. MATERIALS AND METHODS: In a prospective fashion, copper and zinc levels were measured in plasma and tissue specimens obtained from indirect (n=23), direct (n=20) and incisional hernia patients (n=19) and from healthy controls (laparoscopic cholecystectomy patients, n=15) by enzymatic colorimetric analysis. RESULTS: Groups were similar in age, comorbid diseases and body mass index. Whereas plasma levels of Cu and Zn in hernia and control patients were similar, and tissue levels were significantly lower in all hernia groups (especially the incisional hernia group) compared to controls (P<0.001). The incisional hernia group had significantly lower tissue copper levels than direct hernia patients and lower zinc levels than indirect hernia patients. CONCLUSIONS: Patients with all types of hernia, especially those with incisional hernias, have significantly lower tissue copper and zinc levels than control patients, despite having similar plasma levels. This finding might reflect excessive consumption or dysfunction of lysyl oxidase as playing a role in the aetiology of hernias. PMID- 20955210 TI - Fenoldopam in critically ill patients with early renal dysfunction. A crossover study. AB - BACKGROUND: Acute kidney injury is a frequent problem among many critically ill patients, commonly in the context of multiple organ failure and decreased renal perfusion. Its presence conveys a poor prognosis. Currently, effective therapeutic interventions are limited and dopaminergic agonists have been suggested as an option to prevent further damage. METHODS: We performed a randomized, double-blinded, prospective crossover study in 17 patients admitted to our trauma intensive care unit (ICU) with evidence of impaired renal function. Patients were randomized to a 24-h intravenous infusion of low-dose fenoldopam or placebo. When the infusion of fenoldopam or placebo was completed, patients underwent a 24-h "washout" period in which no study intervention was performed. This sequence was repeated in each patient with the opposite agent, so each patient served as his own control. Four-hour creatinine collections were taken during the last 4 h of each infusion and washout periods to determine creatinine clearance changes during and after the administration of the study drug. RESULTS: The creatinine clearance was higher with fenoldopam infusion than with placebo infusion (P = 0.045). The FENa was not significantly different. CONCLUSIONS: Our study showed that low-dose Fenoldopam increases creatinine clearance in the critically ill with renal insufficiency. Fenoldopam may be a useful drug in ICU patients with early renal dysfunction. PMID- 20955211 TI - Cigarette smoke elicits relaxation of renal arteries. AB - BACKGROUND: Epidemiological studies suggest that cigarette smoking - probably by eliciting hyperperfusion - increases glomerular filtration rate; thus, we hypothesized that cigarette smoke affects the vasomotor tone of renal arteries. MATERIALS AND METHODS: Acute changes in the resistance index of a segmental renal artery were measured in healthy individuals during smoking. In addition, the effects of water-soluble components of cigarette smoke on the isometric tension of isolated rat renal arteries were investigated in various conditions. RESULTS: In humans, cigarette smoking transiently reduced the resistance index of the renal artery segments (83.25 +/- 5.67% of the baseline, P < 0.05). In the experimental model, water-soluble components of cigarette smoke (wCS) - either nicotinic or nicotine-free - elicited dose-dependent relaxations of rat isolated renal arteries (1% solution of nicotinic wCS: 41.18 +/- 14.86% relaxation, 5% nicotinic wCS: 79.28 +/- 8.91% relaxation, 10% nicotinic wCS 90.3 +/- 6.1% relaxation, P < 0.05), which were not affected by removal of the endothelium, or by the soluble guanylate cyclase inhibitor oxadiazolo-quinoxalin-1, or the non specific potassium channel blocker tetraethylammonium, or the K(ATP) channel blocker glibenclamide. However, relaxations were reduced by catalase (1000 U mL-1 catalase + 5% nicotinic wCS: 49.71 +/- 18.4%, P < 0.05) and enhanced by superoxide dismutase (200 U mL-1 SOD + 5% nicotinic wCS: 95.7 +/- 2.3%, P < 0.05). CONCLUSIONS: On the basis of these findings, we propose that cigarette smoking could contribute to the increased glomerular filtration rate observed in healthy smokers. In addition, cigarette smoke via hydrogen peroxide mediation reduces vasomotor tone of renal arteries, which could lead to hyperperfusion of kidneys. PMID- 20955212 TI - Long-term efficacy of danazol treatment in hereditary angioedema. AB - BACKGROUND: No systematic study has been published yet on the long-term efficacy of attenuated androgens in hereditary angioedema (HAE). Our aim was to conduct a follow-up study in two (German and Hungarian) cohorts of HAE patients (45 and 39 patients, respectively) undergoing uninterrupted treatment for 6 years with similar (starting dose 128 +/- 78 mg per day and 136 +/- 70 mg per day, respectively) and constant doses of danazol. DESIGN: The frequencies of subcutaneous, abdominal and laryngeal attacks were recorded each year. RESULTS: The annual frequency of all the three types of attacks was significantly lower during the first year of danazol treatment, compared to the last year before baseline. During subsequent years in Hungarian patients, the frequency of both subcutaneous and abdominal attacks - but not that of laryngeal attacks - increased significantly. In the case of abdominal attacks, a significant increase in the attack frequency was observed only in female patients. In the German cohort, by contrast, no change in the frequency of either type of attack was found during the 6-year study period. CONCLUSIONS: The differences observed between these cohorts cannot be related to drug dose, the age or gender distribution of subjects or the age at the onset of symptoms or the length of diagnostic delay in the patients. There were, however, marked differences in the baseline pattern of attacks: significantly - 3 times - more abdominal attacks were recorded in German patients. Further studies are necessary to clarify the mechanism of these findings. PMID- 20955213 TI - Treatment for prolactinomas and hyperprolactinaemia: a lifetime approach. AB - BACKGROUND: Prolactinomas are the most common hormone-secreting pituitary tumours and are amenable to medical therapy with dopamine agonists. Indication for treatment will most commonly result from hypogonadism, infertility or symptoms related to tumour size. Thus, both diagnosis and treatment will essentially depend on the patients' stage of life, namely prepubertal, reproductive or postreproductive stage. This review will focus on a lifespan-dependent diagnosis and treatment for prolactinoma and hyperprolactinaemia. METHODS: PubMed, the Cochrane Library, the Web of Science and EMBASE were searched electronically. No restriction was made with respect to language. Relevant current articles will be included in this review. RESULTS: Prevalence of prolactinomas and clinical symptoms are age group-specific, and treatment of first choice is dopamine agonists over the whole lifespan. Open questions in the treatment for hyperprolactinaemia include optimal choice and duration of pharmacological treatment. In addition, concerns have been raised on the safety of dopamine agonists since a reported association of valvular heart disease with dopaminergic treatment in patients with Parkinson's disease. CONCLUSIONS: Clinical presentation and consequences of hyperprolactinaemia and prolactinoma will differ in the specific stages of reproductive life and require an adequate lifetime dependent diagnostic and therapeutic approach. PMID- 20955214 TI - Addiction research centres and the nurturing of creativity. The Centre for Alcohol and Drug Research: social science alcohol and drug research in Denmark. AB - AIMS: The purpose of this paper is to introduce the social science alcohol and drug research undertaken by the Centre for Alcohol and Drug Research (CRF) and at the same time offer an insight into the development in Danish alcohol and drug research throughout the past 15-20 years. METHOD: A review of articles, books and reports published by researcher from CRF from the mid-1990s until today and an analysis of the policy-making in the Danish substance use and misuse area. RESULTS: CRF is a result of the discussions surrounding social, health and allocation policy questions since the mid-1980s. Among other things, these discussions led to the formal establishment of the Centre in 1991 under the Aarhus University, the Faculty of Social Science. Since 2001 the Centre has received a permanent basic allocation, which has made it possible to appoint tenured senior researchers; to work under a more long-term research strategy; to function as a milieu for educating PhD students; and to diversify from commissioned research tasks to initiating projects involving more fundamental research. Research at the Centre is today pivoted around four core areas: consumption, policy, prevention and treatment. CONCLUSION: The emergence, continuation, financing and character of the research taking place at CRF can be linked closely to the specific Danish drug and alcohol discourse and to the division of the responsibility for alcohol and drug research into separate Ministries. PMID- 20955215 TI - The road to smoke-free legislation in Ireland. AB - AIM: To describe the process through which Ireland changed its policies towards smoking in work-places and distil lessons for others implementing or extending smoke-free laws. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: This analysis is informed by a review of secondary sources including a commissioned media analysis, documentary analysis and key informant interviews with policy actors who provide insight into the process of smoke-free policy development. The policy analysis techniques used include the development of a time-line for policy reform, stakeholder analysis, policy mapping techniques, impact analysis through use of secondary data and a review process. The policy analysis triangle, which highlights the importance of examining policy content, context, actors and processes, will be used as an analytical framework. FINDINGS: The importance of the political, economic, social and cultural context emerged clearly. The interaction of the context with the policy process both in identification of need for policy and its formulation demonstrated the opportunity for advocates to exert influence at all points of the process. The campaign to support the legislation had the following characteristics: a sustained consistent simple health message, sustained political leadership/commitment, a strong coalition between the Health Alliance, the Office of Tobacco Control and the Department of Health and Children, with cross-party political support and trade union support. The public and the media support clearly defined the benefit of deliberate and consistent planning and organization of a communication strategy. CONCLUSIONS: The Irish smoke-free legislation was a success as a policy initiative because of timing, dedication, planning, implementation and the existence of strong leadership and a powerful convinced credible political champion. PMID- 20955216 TI - Decreased bone density in men on methadone maintenance therapy. AB - AIMS: Opioid use may impact adversely upon skeletal health. Participants in methadone maintenance programmes commonly have prolonged exposure to opioids. We sought to determine whether participants in a methadone maintenance programme have evidence of altered bone mineral density (BMD) and bone turnover. DESIGN: Cross-sectional study of people taking methadone maintenance therapy (MMT). SETTING: Clinical research centre. PARTICIPANTS: Eighty-three people (48 men, 35 women) who had taken MMT for a median (interquartile range) of 11 (6-16) years. Comparison data were from both a normative database and control subjects recruited and assessed at the same location as the participants taking MMT. MEASUREMENTS: BMD at lumbar spine, total hip and total body; biochemical markers of bone turnover. FINDINGS: In men taking MMT, BMD was lower than normal at each skeletal site [mean, 95% confidence interval Z-score -1.1 (-1.6 to -0.7) at the lumbar spine, -1.0 (-1.3 to -0.7) at the total hip, and -1.1 (-1.4 to -0.8) at the total body, P < 0.001 at each site]. BMD in the women taking MMT was not different from control values. Bone turnover was within the normal range in both genders. Serum testosterone was lower in the men taking MMT than in controls. CONCLUSIONS: BMD is lower than normal throughout the skeleton in men, but not women, taking MMT. Assessment of skeletal health, including estimation of absolute fracture risk, should be undertaken in men participating in methadone maintenance programmes. PMID- 20955217 TI - Behavioral interventions to promote smoking cessation and prevent weight gain: a reply. PMID- 20955218 TI - Metabolomic analysis of human plasma from haemodialysis patients. AB - BACKGROUND: Urea and creatinine are widely used as biomarkers for disease. However, these parameters have been criticized as markers for several reasons. Thus, we conducted this study to identify novel biomarkers that can be used as alternatives to urea and creatinine to estimate the adequate dialysis dose by metabolomic analyses of plasma samples from patients undergoing haemodialysis. MATERIAL AND METHODS: Liquid chromatography-electrospray ionization (ESI)-time-of flight mass spectrometry (MS) was used to analyse low molecular weight molecules present in the plasma samples of 10 patients with end-stage renal disease (ESRD) who were being treated with haemodialysis, and in 16 healthy subjects. RESULTS: In plasma samples obtained after haemodialysis, the relative quantities of 54 peaks were significantly (P < 0.05) decreased when compared with those in the plasma before haemodialysis. The candidate biomarkers were allocated to three groups. Molecules in Group A improved completely with a large variance, molecules in Group B improved partially but with a large variance, and molecules in Group C improved partially with low variance after haemodialysis. Small cohort validation study consisting of the patients with ESRD undergoing haemodialysis indicates that three candidate biomarkers in Group C would be a very useful marker to estimate adequate haemodialysis dose. CONCLUSIONS: 1-Methylinosine and two unknown molecules whose m/z at ESI-positive mode are 257.1033 and 413.1359 were found as effective candidate biomarkers to estimate adequate haemodialysis dose, which has to be confirmed in prospective studies. PMID- 20955219 TI - Vitamin D deficiency prevalence and cardiovascular risk in Israel. AB - BACKGROUND: Accumulated data in the past years suggest that vitamin D deficiency has an adverse effect on cardiovascular (CVD) health and that its prevalence is significantly higher among patients with CVD risk factors, contributing to the pathogenesis of CVD. MATERIALS AND METHODS: This is a cross-sectional analysis of a relatively large database derived from a health care maintenance organization. The population consisted of individuals 18 years and older who had undergone blood tests for vitamin D levels for any reason during 2001-2008. RESULTS: The study population consisted of 34,874 individuals: 26,699 (76.6%) were women at a mean +/- SD age of 55 +/- 15 and 8175 men (23.4%) aged 55 +/- 17. The mean +/- SD vitamin D level was 23.2 +/- 10.1 and 22.7 +/- 9.9 for men and women, respectively. The prevalence of vitamin D deficiency or insufficiency (vitamin D levels < 30 ng mL(-1)) for the entire study population was surprisingly high for men and women (79.2% and 77.5%, respectively). This remained consistent with only little variation when stratified by age. The group with vitamin D < 15 ng mL(-1) vs. the group with vitamin D levels >= 30 ng mL(-1) demonstrated a significant (P < 0.031) age-adjusted odds ratios for the presence of hypertension, diabetes mellitus, dyslipidemia, obesity and peripheral vascular disease for women (OR = 1.19; 1.65; 1.13; 2.28; 1.85, respectively), and the presence of all the above except hypertension in men (OR = 1.51; 1.28; 2.06; 1.73, respectively). CONCLUSIONS: Vitamin D deficiency is associated with CVD and other risk factors in this Israeli study population. The prevalence of the deficiency in Israel is similar to the prevalence found in less sunny regions. PMID- 20955220 TI - Minimising cold ischaemic injury in an experimental model of kidney transplantation. AB - BACKGROUND: Cold ischaemic (CI) injury is associated with reduced renal graft function and survival. However, there is little evidence on the benefits of reducing CI injury within a 24 h period in donation after cardiac death (DCD) kidney transplantation. METHODS: Porcine kidneys subjected to 10-min warm ischaemia were retrieved and flushed with hyperosmolar citrate (HOC) preservation solution at 4 degrees C. They were stored on ice for periods of 2, 6, 18 or 24 h (n = 6). Renal function and injury were assessed during 3 h of ex-vivo reperfusion with oxygenated autologous blood. RESULTS: Area under the curve (AUC) serum creatinine (Cr) levels were significantly higher in the 18- and 24-h groups and creatinine clearance (CrCl) lower compared to the 2-h group (P = 0.001, 0.003). Urinary biomarkers of ischaemic damage (Endothelin-1, Total nitric oxide) and renal and tubular cell function significantly correlated with the duration of CI time (r = 0.726, 0.642; P <= 0.001). CONCLUSIONS: This study demonstrated the progressive effects of CI injury in DCD porcine kidneys over a 24 h hypothermic storage period. This highlights the need to minimise the cold storage period to improve graft function in DCD kidney transplantation. PMID- 20955221 TI - Comparison of seasonal variations in water-use efficiency calculated from the carbon isotope composition of tree rings and flux data in a temperate forest. AB - Tree-ring delta(13) C is often interpreted in terms of intrinsic water-use efficiency (WUE) using a carbon isotope discrimination model established at the leaf level. We examined whether intra-ring delta(13) C could be used to assess variations in intrinsic WUE (W(g), the ratio of carbon assimilation and stomatal conductance to water) and variations in ecosystem WUE (W(t) , the ratio of C assimilation and transpiration) at a seasonal scale. Intra-ring delta(13) C was measured in 30- to 60-um-thick slices in eight oak trees (Quercus petraea). Canopy W(g) was simulated using a physiologically process-based model. High between-tree variability was observed in the seasonal variations of intra-ring delta(13) C. Six trees showed significant positive correlations between W(g) calculated from intra-ring delta(13) C and canopy W(g) averaged over several days during latewood formation. These results suggest that latewood is a seasonal recorder of W(g) trends, with a temporal lag corresponding to the mixing time of sugars in the phloem. These six trees also showed significant negative correlations between photosynthetic discrimination Delta calculated from intra ring delta(13) C, and ecosystem W(t), during latewood formation. Despite the observed between-tree variability, these results indicate that intra-ring delta(13) C can be used to access seasonal variations in past W(t). PMID- 20955222 TI - Physiological and morphological adaptations in relation to water use efficiency in Mediterranean accessions of Solanum lycopersicum. AB - The physiological traits underlying the apparent drought resistance of 'Tomatiga de Ramellet' (TR) cultivars, a population of Mediterranean tomato cultivars with delayed fruit deterioration (DFD) phenotype and typically grown under non irrigation conditions, are evaluated. Eight different tomato accessions were selected and included six TR accessions, one Mediterranean non-TR accession (NTR(M)) and a processing cultivar (NTR(O)). Among the TR accessions two leaf morphology types, normal divided leaves and potato-leaf, were selected. Plants were field grown under well-watered (WW) and water-stressed (WS) treatments, with 30 and 10% of soil water capacity, respectively. Accessions were clustered according to the leaf type and TR phenotype under WW and WS, respectively. Correlation among parameters under the different water treatments suggested that potential improvements in the intrinsic water-use efficiency (A(N)/g(s)) are possible without negative impacts on yield. Under WS TR accessions displayed higher A(N)/g(s), which was not due to differences in Rubisco-related parameters, but correlated with the ratio between the leaf mesophyll and stomatal conductances (g(m)/g(s)). The results confirm the existence of differential traits in the response to drought stress in Mediterranean accessions of tomato, and demonstrate that increases in the g(m)/g(s) ratio would allow improvements in A(N)/g(s) in horticultural crops. PMID- 20955223 TI - A new filter that accurately mimics the solar UV-B spectrum using standard UV lamps: the photochemical properties, stabilization and use of the urate anion liquid filter. AB - The physiological effects unique to solar ultraviolet (UV)-B exposure (280-315 nm) are difficult to accurately replicate in the laboratory. This study evaluates the effectiveness of the sodium urate anion in a liquid filter that yields a spectrum nearly indistinguishable from the solar UV-B spectrum while filtering the emissions of widely used UV-B lamps. The photochemical properties and stability of this filter are examined and weighed against a typical spectrum of ground-level solar UV-B radiation. To test the effectiveness of this filter, light-saturated photosynthetic oxygen evolution rates were measured following exposure to UV-B filtered either by this urate filter or the widely used cellulose acetate (CA) filter. The ubiquitous marine Chlorophyte alga Dunaliella tertiolecta was tested under identical UV-B flux densities coupled with ecologically realistic fluxes of UV-A and visible radiation for 6 and 12 h exposures. These results indicate that the urate-filtered UV-B radiation yields minor photosynthetic inhibition when compared with exposures lacking in UV-B. This is in agreement with published experiments using solar radiation. In sharp contrast, radiation filtered by CA filters produced large inhibition of photosynthesis. PMID- 20955224 TI - The 13C/12C isotopic signal of day-respired CO2 in variegated leaves of Pelargonium * hortorum. AB - In leaves, although it is accepted that CO(2) evolved by dark respiration after illumination is naturally (13) C-enriched compared to organic matter or substrate sucrose, much uncertainty remains on whether day respiration produces (13) C depleted or (13) C-enriched CO(2). Here, we applied equations described previously for mesocosm CO(2) exchange to investigate the carbon isotope composition of CO(2) respired by autotrophic and heterotrophic tissues of Pelargonium * hortorum leaves, taking advantage of leaf variegation. Day-respired CO(2) was slightly (13) C-depleted compared to organic matter both under 21% O(2) and 2% O(2). Furthermore, most, if not all CO(2) molecules evolved in the light came from carbon atoms that had been fixed previously before the experiments, in both variegated and green leaves. We conclude that the usual definition of day respiratory fractionation, that assumes carbon fixed by current net photosynthesis is the respiratory substrate, is not valid in Pelargonium leaves under our conditions. In variegated leaves, total organic matter was slightly (13) C-depleted in white areas and so were most primary metabolites. This small isotopic difference between white and green areas probably came from the small contribution of photosynthetic CO(2) refixation and the specific nitrogen metabolism in white leaf areas. PMID- 20955225 TI - Auxin depletion in barley plants under high-temperature conditions represses DNA proliferation in organelles and nuclei via transcriptional alterations. AB - Many plant species are susceptible to high-temperature (HT) injury during reproductive development. We recently demonstrated that HT represses the expression of YUCCA auxin biosynthesis genes and reduces endogenous auxin in the developing anthers of barley and Arabidopsis. Here, we show that DNA proliferation in mitochondria, chloroplasts and nuclei of developing panicles is inhibited with increasing temperatures in barley. Following DNA proliferation suppression, terminal abnormalities were observed in the organelles of anther wall cells, including mitochondrial swelling and overdevelopment of chloroplasts. Comprehensive transcriptome analyses using both reproductive organs and vegetative tissues showed high and positive pairwise correlations between the expression profiles of auxin-induced genes, DNA replication-related genes and mitochondrial-related genes. In contrast, the expression profiles of auxin repressed protein genes and photosynthesis-/chloroplast-related genes were negatively correlated with those of the previously mentioned genes. Under HT conditions, the former was repressed and the latter was up-regulated in the developing panicles. Furthermore, application of exogenous auxin promoted the expression of DNA replication-related genes under HT conditions, inducing anther cell proliferation. These suggest that compromised auxin biosynthesis/IAA level under HT condition results in nuclear and organellar DNA proliferation arrest due to co-transcriptional alterations. PMID- 20955226 TI - Separating parental environment from seed size effects on next generation growth and development in Arabidopsis. AB - Plant growth and development is profoundly influenced by environmental conditions that laboratory experimentation typically attempts to control. However, growth conditions are not uniform between or even within laboratories and the extent to which these differences influence plant growth and development is unknown. Experiments with wild-type Arabidopsis thaliana were designed to quantify the influences of parental environment and seed size on growth and development in the next generation. A single lot of seed was planted in six environmental chambers and grown to maturity. The seed produced was mechanically sieved into small and large size classes then grown in a common environment and subjected to a set of assays spanning the life cycle. Analysis of variance demonstrated that seed size effects were particularly significant early in development, affecting primary root growth and gravitropism, but also flowering time. Parental environment affected progeny germination time, flowering and weight of seed the progeny produced. In some cases, the parental environment affected the magnitude of (interacted with) the observed seed size effects. These data indicate that life history circumstances of the parental generation can affect growth and development throughout the life cycle of the next generation to an extent that should be considered when performing genetic studies. PMID- 20955228 TI - 'Fumes from the spleen' on preparing a scientific poster. PMID- 20955227 TI - Minimum hydraulic safety leads to maximum water-use efficiency in a forage grass. AB - Understanding how water-use regulation relates to biomass accumulation is imperative for improving crop production in water-limited environments. Here, we examine how the vulnerability of xylem to water stress-induced cavitation and the coordination between water transport capacity and assimilation (A) influences diurnal water-use efficiency (WUE) and dry-matter production in Lolium perenne L. - a commercial forage grass. Plants were exposed to a range of water stresses, causing up to 90% leaf death, by withholding water and then rewatering to observe the recovery process. Leaf hydraulic conductance (K(leaf) ) declined to 50% of maximum at a leaf water potential (psi(leaf) ) of -1 MPa, whereas complete stomatal closure occurred well after this point, at -2.35 MPa, providing no protection against hydraulic dysfunction. Instantaneous A remained maximal until >70% of hydraulic conductivity had been lost. Post-stress rewatering showed that 95% loss of K(leaf) could be incurred before the recovery of gas exchange exceeded 1 d, with a rapid transition to leaf death after this point. Plants exposed to sustained soil water deficits through restricted nightly watering regimes did not suffer cumulative losses in K(leaf) ; instead, psi(leaf) and gas exchange recovered diurnally. The effect was improved WUE during the day and optimal psi(leaf) during the night for the maintenance of growth. PMID- 20955229 TI - Prenatal and childhood environmental tobacco smoke exposure and age at menarche. AB - Previous studies have reported mixed results regarding the association between age at menarche and environmental tobacco smoke exposure, both prenatally and during early childhood; however, few studies have had data available during both time periods. The present study examined whether exposure to prenatal tobacco smoke (PTS) via maternal smoking during pregnancy or childhood environmental tobacco smoke (ETS) was associated with age at menarche in a multi-ethnic birth cohort. With the uniquely available prospectively collected data on body size and growth at birth and in early life, we further examined whether the association between PTS and ETS exposure and age at menarche was mediated by these variables. From 2001 to 2006, we recruited 262 women born between 1959 and 1963 who were enrolled previously in a New York City site of the National Collaborative Perinatal Project. Mothers who smoked during pregnancy vs. those who did not were more likely to be White, younger, have more education and have lower birthweight babies. Daughters with heavy PTS exposure (>= 20 cigarettes per day) had a later age at menarche (>12 years vs. <= 12 years), odds ratio (OR) =2.1 [95% confidence interval (CI) 0.9, 5.0] compared with daughters with no PTS. Daughters exposed to only childhood ETS had a later age at menarche, OR=2.1 [95% CI 1.0, 4.3], and those exposed to PTS and ETS combined had a statistically significant later age at menarche, OR=2.2 [95% CI 1.1, 4.6] compared with daughters with no PTS and no ETS. These results did not change after further adjustment for birthweight and postnatal growth suggesting that exposure to PTS and ETS is associated with later age at menarche even after considering possible relationships with growth. PMID- 20955230 TI - Prenatal environmental tobacco smoke exposure and early childhood body mass index. AB - Maternal smoking during pregnancy is associated with increased risk of childhood overweight body mass index (BMI). Less is known about the association between prenatal secondhand tobacco smoke (SHS) exposure and childhood BMI. We followed 292 mother-child dyads from early pregnancy to 3 years of age. Prenatal tobacco smoke exposure during pregnancy was quantified using self-report and serum cotinine biomarkers. We used linear mixed models to estimate the association between tobacco smoke exposure and BMI at birth, 4 weeks, and 1, 2 and 3 years. During pregnancy, 15% of women reported SHS exposure and 12% reported active smoking, but 51% of women had cotinine levels consistent with SHS exposure and 10% had cotinine concentrations indicative of active smoking. After adjustment for confounders, children born to active smokers (self-report or serum cotinine) had higher BMI at 2 and 3 years of age, compared with unexposed children. Children born to women with prenatal serum cotinine concentrations indicative of SHS exposure had higher BMI at 2 (mean difference [MD] 0.3 [95% confidence interval -0.1, 0.7]) and 3 (MD 0.4 [0, 0.8]) years compared with unexposed children. Using self-reported prenatal exposure resulted in non-differential exposure misclassification of SHS exposures that attenuated the association between SHS exposure and BMI compared with serum cotinine concentrations. These findings suggest active and secondhand prenatal tobacco smoke exposure may be related to an important public health problem in childhood and later life. In addition, accurate quantification of prenatal secondhand tobacco smoke exposures is essential to obtaining valid estimates. PMID- 20955231 TI - Adverse perinatal and neonatal outcomes and their determinants in rural Vietnam 1999-2005. AB - Population-based estimations of perinatal and neonatal outcomes are sparse in Vietnam. There are no previously published data on small for gestational age (SGA) infants. A rural population in northern Vietnam was investigated from 1999 to 2005 (n=5521). Based on the birthweight distributions within the population under study, reference curves for intrauterine growth for Vietnamese infants were constructed and the prevalence and distribution of SGA was calculated for each sex. Neonatal mortality was estimated as 11.6 per 1000 live births and the perinatal mortality as 25.0 per 1000 births during the study period. The mean birthweight was 3112 g and the prevalence of low birthweight was 5.0%. The overall prevalence of SGA was 6.4%. SGA increased with gestational age and was 2.2%, 4.5% and 27.1% for preterm, term and post-term infants, respectively. Risk factors for SGA were post-term birth: adjusted odds ratio (AOR) 7.75 [95% CI 6.02, 9.98], mothers in farming occupations AOR 1.72 [95% CI 1.21, 2.45] and female infant AOR 1.61 [95% CI 1.27, 2.03]. There was a pronounced decrease in neonatal mortality after 33 weeks of gestation. Suggested interventions are improved prenatal identification of SGA infants by ultrasound investigation for fetal growth among infants who do not follow their expected clinical growth curve at the antenatal clinic. Other suggestions include allocating a higher proportion of preterm deliveries to health facilities with surgical capacity and neonatal care. PMID- 20955232 TI - Effects of social and psychosocial factors on risk of preterm birth in black women. AB - Our objective was to examine how social and psychosocial factors may influence the risk of preterm birth. The design of the study was a hybrid retrospective and prospective cohort. African-American women residing in Baltimore, Maryland, were enrolled prenatally if they received care at one of three Johns Hopkins Medical Institution prenatal clinics (n=384) or enrolled post-partum if they delivered at Johns Hopkins Medical Institution with late, none or intermittent prenatal care (N=459). Preterm birth was defined as less than 37 weeks completed gestation. Interview data were collected on 832 enrolled women delivering singletons between March 2001 and July 2004. The preterm birth rate was 16.4%. In both unadjusted and adjusted models, exposure to racism over a woman's lifetime had no effect on risk of preterm birth in our sample. However, we found evidence of a three-way interaction between reported lifetime experiences of racism, depressive symptoms during pregnancy and stress during pregnancy on preterm birth risk. Racism scores above the median (more racism) were associated with an increased risk of preterm birth in three subgroups with the effect moderated by depressive symptoms and stress. Social and psychosocial factors may operate in a complex manner related to risk of preterm birth. PMID- 20955233 TI - Parental occupation and preterm births: a nationwide epidemiological study in Sweden. AB - The hypothesis was that some occupations could lead to preterm birth (PTB) because of potential exposures to various agents. The objective in this nationwide follow-up study was to analyse the association between PTB and parental occupational groups, controlling for potential confounders. Data from the Swedish Medical Birth Register, in which all children born in Sweden from 1990 onward are registered with their parents, were linked to census data. Inclusion criteria for the study population were employment (both women and men) and age >20 years (women). There were 816,743 first singleton live births from 1990 to 2004, of whom 43,956 were PTBs. A total of 7659 of the 43,956 PTBs were very PTBs. Odds ratios (ORs) with 95% confidence intervals were calculated separately for mothers and fathers to estimate the odds of PTB and very PTB in 51 occupational groups (reference groups: mothers or fathers who were 'Technical, science research-related workers and physicians') and by family income level. Women and men with low family incomes had increased ORs of PTB and very PTB. Significantly increased ORs of PTB (including very PTB) were found in four maternal and nine paternal occupational groups after accounting for family income, geographic region of residence, civil status, smoking habits, maternal age at infant's birth and period of birth. Further studies should examine specific agents in those parental occupations that were associated with increased odds of PTB and very PTB. PMID- 20955235 TI - Prevalence, pattern and risk factors for undernutrition in early infancy using the WHO Multicentre Growth Reference: a community-based study. AB - This cross-sectional study set out to determine the prevalence, pattern and risk factors for undernutrition during early infancy in a setting with substantial non hospital births against the backdrop of limited evidence on nutritional status in the first three months of life based on an exclusively breast-fed reference population. Undernutrition based on z-scores below -2 for weight-for-age, height/length-for-age and body-mass-index-for-age among infants (0-3 months) attending clinics for routine Bacille de Calmette-Guerin (BCG) immunisation in Lagos, Nigeria from July 2005 to March 2008 was determined using current World Health Organisation's Multicentre Growth Reference (WHO-MGR). Maternal and infant factors associated with undernutrition were explored with multivariable logistic regression analyses. Of the 5888 full-term infants enrolled 51% were born outside hospital and 99.4% were exclusively breast-fed. 811 (13.8%) were underweight (weight-for-age), 1802 (30.8%) were stunted (height/length-for-age) and 579 (10.0%) were wasted (body-mass-index-for-age). Altogether, 3635 (61.6%) infants were not undernourished while 192 (3.3%) were undernourished by all three nutritional measures. Intrauterine growth restriction was a significant contributor to undernutrition. Maternal age, multiple pregnancies and gender were associated with all nutritional indices. Additionally, maternal education, ownership/type of residence, parity, antenatal care, place of delivery and hyperbilirubinaemia were predictive of underweight, stunting and wasting. We conclude that undernutrition is prevalent in the first three months of life in this population and can be detected early at routine immunisation clinics shortly after birth. Maternal/perinatal history offers valuable predictors in resource poor communities where the majority of births occur outside hospital. PMID- 20955234 TI - Pre-pregnancy stress reactivity and pregnancy outcome. AB - Stress has been proposed as a cause of preterm birth (PTB) and small-for gestational age (SGA), but stress does not have the same effects on all women. It may be that a woman's reaction to stress relates to her pregnancy health, and previous studies indicate that higher reactivity is associated with reduced birthweight and gestational age. The objective of this study was to examine the relationship between pre-pregnancy cardiovascular reactivity to stress and pregnancy outcome. The sample included 917 women in the Coronary Artery Risk Development in Young Adults Study who had cardiovascular reactivity measured in 1987-88 and at least one subsequent singleton livebirth within an 18-year period. Cardiovascular reactivity was measured using a video game, star tracing and cold pressor test. Gestational age and birthweight were based on the women's self report, with PTB defined as birth <37 weeks' gestation and SGA as weight <10th percentile for gestational age. Linear and Poisson regression and generalised estimating equations were used to model the relationship between reactivity to stress and birth outcomes with control for confounders. Few associations were seen between reactivity and pregnancy outcomes. Higher pre-pregnancy diastolic blood pressure (adjusted relative risk 1.14; 95% confidence interval [CI] 0.98, 1.34) and mean arterial pressure reactivity (1.15; 0.98, 1.36) were associated with risk of PTB at first pregnancy, while SGA was associated with lower systolic blood pressure reactivity (0.76; 0.60, 0.95). No associations were seen with other measures of reactivity. Contrary to hypothesis, the association between heart rate reactivity and PTB in first pregnancy was stronger in whites (adjusted relative risk 1.39; 1.03, 1.88) than in blacks (1.00; 0.83, 1.20; P for interaction = 0.08). Similar results were found for mean arterial pressure. No strong associations were found between higher pre-pregnancy stress reactivity and SGA or PTB, and stress reactivity did not have a stronger association with birth outcomes in blacks than whites. PMID- 20955236 TI - Why are they having infant colic? A nested case-control study. AB - We aimed to analyse infant (birth characteristics, feeding type, faecal enzyme activities) and environmental (maternal smoking, nutrition and psychological status, mother-child bonding, family structure, support for the mother, familial atopy) risk factors for infant colic and to follow infants with respect to physical growth, sleeping status up to 8 months of age in a nested case-control study. 660 mothers who delivered at Dr Zekai Tahir Burak Maternity Hospital, were enrolled within 3-72 h post delivery. Each infant with inconsolable persistent crying and four matched infants with no crying episodes were invited by phone to Hacettepe University Ihsan Dogramaci Children's Hospital at 30-45 days post partum. At 40-55 days, we examined the infants and gave mothers a questionnaire, including crying characteristics of the infants; 47 infants were diagnosed with colic and 142 as non-colic. When the infants were 7-8 months old, another interview was done. The colic group had higher proportions of less-educated (<= 8 years) and smoking mothers, extended family and families with domestic violence than the non-colic group. The colic group of mothers had significantly higher rates of 'impaired bonding' in the Postpartum Bonding Questionnaire, higher scores on the Edinburgh Postnatal Depression Scale, higher scores for hostility subscales of the Brief Symptom Inventory and a more irregular sleep pattern than the non-colic group. No differences were revealed for faecal enzyme activities. At 7-8 months, the colic group was shorter than the non-colic group. Colic was associated with various perinatal factors (maternal education, smoking habits, cheese consumption, hostility scores and domestic violence) and having colic in infancy negatively affected the sleeping pattern and the height of the infant. PMID- 20955237 TI - Attention deficit/hyperactivity disorder in primary school children of Tabriz, North-West Iran. AB - This study aimed to estimate the prevalence of attention deficit/hyperactivity disorder (ADHD), as well as its subtypes, in elementary school children and their demographic characteristics. A random clustered sample of elementary students was selected from schools of Tabriz, North-West Iran. The clinical diagnosis of ADHD was based on DSM-IV-TR criteria using an interview with children who were selected as scoring high on the Conner's teacher rating scale. A total of 30 schools and 1658 students were evaluated. The prevalence rate of clinical ADHD in the elementary students of Tabriz was 9.7%. Only two had been diagnosed previously. The mean age (standard deviation) was 9.39 (1.27) years. ADHD was more common among boys, students of the third level and children with an un educated mother or father. It was not related to the type of school, age or birth order. Students with ADHD had lower school performance and orderliness reported by the school. Inattentiveness was more common among schoolgirls while the most common subtype was the combined one. Inattentive students had a significantly lower school performance. ADHD is common in elementary schools of this region and is correlated with poor performance. Greater awareness of parents and teachers concerning children at risk is necessary for an early diagnosis. PMID- 20955238 TI - How long do preconception risk prediction models hold? Influence of selective fertility on model performance. AB - Risk estimates derived from preconception prediction models can be used to counsel women with regard to any future pregnancies. Women with a high predicted risk of an adverse pregnancy outcome may decide more frequently not to try for another pregnancy than women with a low predicted risk. This prediction-guided selective fertility can cause a change in the composition of the pregnant population with respect to those parameters that are included in the prediction model. The question is whether such a change in composition could influence the performance parameters of the prediction model, such as sensitivity, specificity, positive and negative predictive values as well as the discriminative ability, when evaluating risks in the new population and whether it could compromise the longevity of the model. Using a hypothetical example, we show that the original sensitivity and specificity estimates of a preconception prediction model for an adverse pregnancy outcome no longer hold when the model is applied to a population affected by model-based selective fertility: sensitivity decreases, while specificity increases. However, individual patient risk estimates remain unbiased and discriminative ability, expressed as the area under the receiver operating characteristic curve, remains unaffected. PMID- 20955239 TI - Modulation of lipid droplets by Mycobacterium leprae in Schwann cells: a putative mechanism for host lipid acquisition and bacterial survival in phagosomes. AB - The predilection of Mycobacterium leprae (ML) for Schwann cells (SCs) leads to peripheral neuropathy, a major concern in leprosy. Highly infected SCs in lepromatous leprosy nerves show a foamy, lipid-laden appearance; but the origin and nature of these lipids, as well as their role in leprosy, have remained unclear. The data presented show that ML has a pronounced effect on host-cell lipid homeostasis through regulation of lipid droplet (lipid bodies, LD) biogenesis and intracellular distribution. Electron microscopy and immunohistochemical analysis of lepromatous leprosy nerves for adipose differentiation-related protein expression, a classical LD marker, revealed accumulating LDs in close association to ML in infected SCs. The capacity of ML to induce LD formation was confirmed in in vitro studies with human SCs. Moreover, via confocal and live-cell analysis, it was found that LDs are promptly recruited to bacterial phagosomes and that this process depends on cytoskeletal reorganization and PI3K signalling. ML-induced LD biogenesis and recruitment were found to be independent of TLR2 bacterial sensing. Notably, LD recruitment impairment by cytoskeleton drugs decreased intracellular bacterial survival. Altogether, our data revealed SC lipid accumulation in ML-containing phagosomes, which may represent a fundamental aspect of bacterial pathogenesis in the nerve. PMID- 20955240 TI - Pseudomonas aeruginosa pilin activates the inflammasome. AB - IL-1beta is produced from inactive pro-IL-1beta by activation of caspase-1 brought about by a multi-subunit protein platform called the inflammasome. Many bacteria can trigger inflammasome activity through flagellin activation of the host protein NLRC4. However, strains of the common human pathogen Pseudomonas aeruginosa lacking flagellin can still activate the inflammasome. We set out to identify what non-flagellin components could produce this activation. Using mass spectroscopy, we identified an inflammasome-activating factor from P. aeruginosa as pilin, the major component of the type IV bacterial pilus. Purified pilin introduced into mouse macrophages by liposomal delivery activated caspase-1 and led to secretion of mature IL-1beta, as did recombinant pilin purified from Escherichia coli. This was dependent on caspase-1 but not on the host inflammasome proteins NLRC4, NLRP3 or ASC. Mutants of P. aeruginosa strain PA103 lacking pilin did not activate the inflammasome following infection of macrophages with live bacteria. Type III secretion remained intact in the absence of pili, showing this was not due to a lack of effector delivery. Our observations show pilin is a novel activator of the inflammasome in addition to flagellin and the recently described PrgJ protein family, the basal body rod component of the type III apparatus. PMID- 20955241 TI - The first vitellogenin receptor from a Lepidopteran insect: molecular characterization, expression patterns and RNA interference analysis. AB - The vitellogenin receptor (VgR) belongs to the low-density lipoprotein receptor (LDLR) superfamily, and is an important carrier for the uptake of vitellogenin (Vg) into developing oocytes of all oviparous species. The first full-length message for a VgR from a Lepidopteran insect was cloned and sequenced from the ovary of Spodoptera litura Fabricius (GenBank accession no. GU983858). The coding region consisted of 5370 bp flanked by a 49 bp 5'-untranslated region (UTR) and a 177 bp 3'-UTR, which encoded a 1798-residue protein with a predicted molecular weight (MW) of 201.69 kDa. S. litura VgR (SlVgR)comprised two ligand binding sites with four LDLR class A repeats in the first domain and seven in the second domain, an epidermal growth factor-like domain containing an LDLR class B repeat and a YWXD motif, a transmembrane domain and a cytoplasmic domain. A phylogenetic relationship placed SlVgR as a separate group from the other insects. SlVgR messenger RNA (mRNA) was specifically expressed in the ovarian tissues. The developmental expression patterns showed that VgR mRNA was first transcribed in 6(th) day female pupae and the maximum level of VgR mRNA appeared in 36-h-old adults. Immunoblot analysis detected an ovary-specific VgR protein with a MW of ~200 kDa, whose development profiles were consistent with VgR mRNA expression patterns. RNA inteference (RNAi) specifically disrupted the VgR gene by injection of 3 or 5 ug VgR double-stranded RNA per insect in 4(th) or 6(th) day pupae. RNAi of SlVgR led to a phenotype characterized by high Vg accumulation in the haemolymph, low Vg deposition in the ovary and the failure of insect spawning. These results mean that VgR is critical for binding Vg and transporting it into the oocytes of the insect ovary, thus playing an important role in insect reproduction. PMID- 20955243 TI - The p53/p21Cip1/ Waf1 pathway mediates the effects of SPARC on melanoma cell cycle progression. AB - Secreted protein acidic and rich in cysteine (SPARC), or osteonectin, belongs to the family of matricellular proteins that modulate cell-matrix interactions and cellular functions. SPARC is highly expressed in melanoma, and we reported that SPARC promotes epithelial/mesenchymal-like changes and cell migration. Here, we used siRNA and conditional shRNA to investigate the contribution of tumor-derived SPARC to melanoma cell growth in vitro and in vivo. We found that depletion of SPARC induces G2/M cell cycle arrest and tumor growth inhibition with activation of p53 and induction of p21(Cip1/Waf1) acting as a checkpoint, preventing efficient mitotic progression. In addition, we demonstrate that reduced mesenchymal features and the invasive potential of SPARC-silenced cells are independent of p21(Cip1/Waf1) induction and cell cycle arrest. Importantly, overexpression of SPARC reduces p53 protein levels and leads to an increase in cell number during exponential growth. Our findings indicate that in addition to its well-known function as a mediator of melanoma cell migration and tumor-host interactions, SPARC regulates, in a cell-autonomous manner, cell cycle progression and proliferation through the p53/p21(Cip1/Waf1) pathway. PMID- 20955244 TI - Penultimate interpretation. AB - Interpretation is at the center of psychoanalytic activity. However, interpretation is always challenged by that which is beyond our grasp, the 'dark matter' of our mind, what Bion describes as ' O'. O is one of the most central and difficult concepts in Bion's thought. In this paper, I explain the enigmatic nature of O as a high-dimensional mental space and point to the price one should pay for substituting the pre-symbolic lexicon of the emotion-laden and high dimensional unconscious for a low-dimensional symbolic representation. This price is reification--objectifying lived experience and draining it of vitality and complexity. In order to address the difficulty of approaching O through symbolization, I introduce the term 'Penultimate Interpretation'--a form of interpretation that seeks 'loopholes' through which the analyst and the analysand may reciprocally save themselves from the curse of reification. Three guidelines for 'Penultimate Interpretation' are proposed and illustrated through an imaginary dialogue. PMID- 20955242 TI - Different types of DNA damage play different roles in the etiology of sunlight induced melanoma. PMID- 20955245 TI - The life instinct. AB - In psychoanalytic writing an oversimplified interpretation of Freud's concept of the life and death instincts sometimes colours the presentation. Roughly, there is an implication that the life instinct is 'good' and the death instinct 'bad'. Freud however is clear that: "Neither of these instincts is any less essential than the other; the phenomena of life arise from the concurrent or mutually opposing action of both"(1933b, p. 209). In this paper I look in detail at the characteristics of the life instinct as conceptualized by Freud, and draw on Bion's work 'on linking' to elaborate Freud's view that binding is the life instinct's key characteristic. I suggest that there are pathological forms of both the life and death instinct if defused (separated off) from the other, and I explore a pathological variation of the life instinct in which binding is without the negation, rest, limit or end provided by the 'opposing action' of the death instinct. I consider an instance of the kind that any analyst might meet clinically, in which an inhibited patient experiences severe anxiety that life giving connections threaten to proliferate indiscriminately and to an overwhelming intensity and size. PMID- 20955246 TI - The dual aspect of fantasy: flight from reality or imaginative realm? Considerations and hypotheses from clinical psychoanalysis. AB - This paper discusses the view that fantasizing, understood as a flight into fantasy, belongs to a type of mental functioning distinct from imaginative fantasy. From this the idea emerges, proposed by Winnicott, that withdrawal into fantasy assumes a dissociative quality, which is formed early on as a defensive solution following the loss of hope in object relations. Such a defence becomes the foundation for a dangerous enclave in which the individual ends up enclosing himself, experiencing an illusory self-sufficiency. In this perspective, the author maintains that the flight into fantasy must be understood as a risk factor for the draining of the self or for a crystallization into psychopathological structures, becoming an automatic activity of 'non-thought' that substitutes for the working-through processes necessary for the development of the mind. The paper investigates this psychopathological dynamic, which was already present in Breuer and Freud's writings, examining subsequent contributions of various authors. Clinical material (of both children and adults) illustrates how the flight into fantasy may take the form of an anti-relational realm of the mind, compromising the operations necessary to the integration of psychic life. There is also a discussion of which therapeutic tools may help the patient to gradually abandon the withdrawal in favour of an authentically nourishing relational nature. PMID- 20955247 TI - Reflection in psychoanalysis: on symbols and metaphors. AB - Psychoanalysis is an art of reflection, i.e. it tries to facilitate the subject's retrieval of his own self. The 'material' to be reflected upon consists of the products of human symbolization. But there are two views of reflection. In one, the self is searched in a temporal, structural and procedural 'anterior' (the model of archaeology). In the other the self is to be found in a still evolving meaning process, i.e. it resides in a 'future' (the model of teleology). Both these pictures are common in psychoanalysis. The aim of this paper is to study the figures of symbolization through the archaeology/teleology reflection model. The author tries to show that 'symbol' leans on archaeology while 'metaphor' comprises a teleological conception. In order to show the relevance of this finding, the author draws the outlines of both an archaeological and a teleological model in psychoanalysis. It is stated that the former builds on an inherent symbol model while the figure for the latter is metaphor. PMID- 20955248 TI - Self-criticism and unconscious grandiosity: transference-countertransference dimensions. AB - The problems posed in understanding and working through the patient's layers of self-criticism are challenging for both patient and analyst. In particular, this paper explores some countertransference phenomena related to underlying grandiosity embedded in self-criticism. For patients who are self-critical, analyzing grandiose elements may create further grounds for self-reproach or open up new modes of self-experience and freedom. The paper tries to focus on how the analyst's experience of the patient's self-criticism often shifts over the course of analytic work. It is important for the analyst to not be crippled by a fear of considering the relevance of underlying grandiosity in relation to self-reproach. Understanding this dimension of self-reproach can help elucidate why it is so durable and refractory to interpretation. The patient has a stake in holding on to this self-punishment because it perpetuates self-regulatory fantasies. These fantasies sometimes relate to the feeling that the patient will be more successful or better loved by holding on to aspects of self-reproach. Sometimes these fantasies are based in competitive or dominant strategies related to winning out or retaliating over parents or siblings. PMID- 20955249 TI - Freud and the Hammerschlag family: a formative relationship. AB - From his obituary of Samuel Hammerschlag, we know of Freud's great veneration for his teacher of Jewish religion. However, not only Hammerschlag himself but his whole family had a formative influence on young Freud, who was deeply impressed by their humanity. This paper describes Freud's relationships with all the family members. In particular, it shows how warmly he felt towards the only daughter, Anna Hammerschlag, who was his patient for a while and whom he chose as a godmother for his youngest daughter Anna. By virtue of the crucial role she played in Freud's 'specimen dream' of July 1895 ('Irma's injection'), she also became as it were the godmother of Freud's magnum opus, The Interpretation of Dreams. All the known extant letters from Freud to members of the Hammerschlag family are published here for the first time in English translation. PMID- 20955250 TI - The expulsion of evil and its return: an unconscious fantasy associated with a case of mass hysteria in adolescents. AB - The formal study of hysteria started with psychoanalysis, which opened paths to studying the unconscious. However, we have found no psychoanalytic or psychiatric studies in the literature reporting epidemics of hysteria in hundreds of adolescent girls affected for several months like the one we describe. This epidemic occurred in a religious boarding-school in a rural area of Mexico. Our study aimed to determine psychoanalytic and sociocultural elements contributing to explain a behavioural epidemic outbreak during which young girls were unable to walk normally and which led to a temporary cessation of routine activities at the boarding-school. Key informers were interviewed, including the first cases of affected adolescent girls and the nuns. Interviews included questions concerning informers' life history and their life at the boarding-school before and during the epidemic. We found that this boarding-school functioned as a large family affected by a psychotic episode which resulted from modes of communication of its members. This article describes the phenomenon and emphasizes perceived communication among members of the boarding-school and visitors at the time of the outbreak. PMID- 20955251 TI - The French model at work: indication and the Jean Favreau Centre for Consultation and Treatment. AB - The goal of this paper is to present the way in which an analyst trained in the French Model at the Paris Psychoanalytical Society and working at its policlinic, the Jean Favreau Centre for Consultation and Treatment (CCTP), approaches the question of indication. After a brief examination of Freud 's 1905 text on indication I will discuss certain concepts, such as representation and tertiary processes, which form the basis of our listening to today's patients. After presenting certain elements of the French Model I will then discuss a period which was a turning point in French psychoanalysis. Psychodrama, a psychoanalytically inspired treatment modality developed in France, which is useful when the capacity to represent is limited will be introduced. Two clinical illustrations of consultations at the CCTP will then follow. PMID- 20955252 TI - Current analytical practice and the analyst's position. PMID- 20955253 TI - Sandor Ferenczi's Clinical Diary in our current psychoanalytic practice. PMID- 20955254 TI - Corrective emotional experience revisited. PMID- 20955255 TI - On: Responding to Rachel Blass' article 'Affirming "That's not psycho-analysis!" On the value of the politically incorrect act of attempting to define the limits of our field'. PMID- 20955256 TI - On: Response to Rachel B. Blass' paper about the value of attempting to define the limits of psychoanalysis. PMID- 20955257 TI - On 'Affirming "That's not psycho-analysis!"'. PMID- 20955258 TI - On: 'Affirming: "That's not psychoanalysis!"' by R. Blass. PMID- 20955261 TI - Histopathological and molecular features of late relapses in non-seminomas. AB - OBJECTIVE: * To describe the histopathological types of late relapses of germ cell tumours and to search for molecular markers associated with chemotherapy resistance. PATIENTS AND METHODS: * Samples from 14 patients with late relapse from a non-seminoma were analysed. * Archival tumour tissue was gathered at intial diagnosis (n= 9) and at relapse (n= 9), mostly after previous treatment with chemotherapy. * In addition to routine histopathology, tumours were analysed for microsatellite instability and screened for mutations in the KRAS and BRAF genes. RESULTS: * Relapse occurred after 76.5 months (median, range: 24-209 months). * The histology in relapse was pure yolk sac tumour in four of the nine patients analysed. * Three had a non-germ cell malignancy, one was a mixed non seminoma and one was a pure mature teratoma. * One sample with non-germ cell malignancy originated from a yolk sac tumour without any evidence of teratoma. * In four of 12 evaluable patients, high-level microsatellite instability was observed. * All patients were KRAS wild-type but four showed a BRAF mutation at V600E. CONCLUSIONS: * Many late relapses of germ cell tumours show pure yolk sac histology. * Non-germ cell malignancies do not necessarily develop from teratoma but can also arise from yolk sac histology. * The biology underlying chemotherapy resistance in late relapse could be related to a high incidence of microsatellite instability and BRAF mutation V600E, which were found in half of the patients. PMID- 20955262 TI - Association of the T-786C, G894T and 4a/4b polymorphisms of the endothelial nitric oxide synthase gene with vasculogenic erectile dysfunction in Iranian subjects. AB - OBJECTIVE: * To investigate the association of the T-786C, G894T and variable number of tandem repeats (VNTRs) in intron 4 (a/b) polymorphisms of the eNOS gene in Iranian subjects with vasculogenic erectile dysfunction (ED). PATIENTS AND METHODS: * A total of 322 consecutive patients with vasculogenic ED were recruited. Patients with concomitant risk factors for ED were excluded. * Patients with ED were identified based on history-taking, detailed physical examination, serum biochemistry, sex hormone measurements, application of the International Index of Erectile Function (IIEF) questionnaire, and penile duplex Doppler ultrasonography after intracavernosal injection of 20 ug prostaglandin E(1) . The control group comprised 318 age-matched healthy male volunteers. * Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and the T-786C, G894T and VNTR intron 4 polymorphisms of the eNOS gene were determined. RESULTS: * After multivariate regression analysis, significant differences were seen in the frequencies of genotypes and alleles of the two T-786C and G894T polymorphisms when patients with ED and normal controls were compared. * In a multiple logistic regression analysis, the odds ratio (OR) of increased ED was strongly associated with the -786C allele [adjusted OR = 3.12, 95% confidence interval (CI) = 2.28-4.25; P= 0.001] and the 894T allele (adjusted OR = 3.87, 95% CI = 2.53-4.87; P= 0.001). * The data showed a higher prevalence of the T-786C CC genotype (adjusted OR = 2.72, 95% CI = 1.88-3.65; P= 0.006), and the G894T GT (adjusted OR = 1.72, 95% CI 1.24-2.83; P= 0.037) and G894T TT genotypes (adjusted OR = 3.42, 95% CI 2.42-4.26; P= 0.001) in patients with ED than in the controls. CONCLUSIONS: * The findings of the present study suggest that the eNOS T-786C and G894T polymorphisms are strong predictors of the predisposition to ED in addition to traditional risk factors, signifying a genetic influence for this multifactorial disease. * Further studies in different ethnic populations are needed to better elucidate the role of eNOS gene polymorphism in the pathogenesis of ED. PMID- 20955263 TI - Intra-individual short-term variability of prostate-specific antigen and other kallikrein markers in a serial collection of blood from men under evaluation for prostate cancer. AB - STUDY TYPE: Diagnostic (exploratory cohort). LEVEL OF EVIDENCE: 2b. OBJECTIVE: To assess variation of total prostate-specific antigen (tPSA), free PSA (fPSA), percent fPSA, human glandular kallikrein 2 (hK2) and intact PSA measured three times within 2 weeks. Knowledge of the variation in an individual's PSA level is important for clinical decision-making. PATIENTS AND METHODS: Study participants were 149 patients referred for prostate biopsy, of which 97 had benign disease and 52 had prostate cancer. Three blood samples were drawn with a median of 4 h between first and second samples and 12 days between first and third samples. Variability was described by absolute differences, ratios and intra-individual coefficients of variation. Total PSA, fPSA, hK2 and intact PSA were measured in anticoagulated blood plasma. RESULTS: At baseline, the median tPSA was 6.8 (interquartile range, 4.5-9.6) ng/mL. The intra-individual variation was low for all biomarkers, and lowest for tPSA. For 80% of participants, the ratio between first and second time points for tPSA was in the range 0.91-1.09 and the ratio for percent fPSA was in the range 0.89-1.15. Total coefficients of variation between time 1 and 2 for tPSA, fPSA, percent fPSA, hK2 and intact PSA were 4.0%, 6.6%, 6.0%, 9.2% and 9.5%, respectively. The measurements taken several days apart varied more than those taken on the same day, although the variation between both time points was not large. CONCLUSIONS: The intra-individual variation for all the kallikrein-like markers studied was relatively small, especially for samples drawn the same day. Few cases are reclassified between the time points. This indicates the high short-term biological and technical reproducibility of the tests in clinical use. PMID- 20955264 TI - Preliminary study with bicalutamide in heterosexual and homosexual patients with prostate cancer: a possible implication of androgens in male homosexual arousal. AB - OBJECTIVE: * Not only has a precise characterization of libido and sexual arousal in men as a central neural process been lacking, but the interactive role of gonadal hormones and sexual orientation in such processes has never been investigated. We investigate the relationships among sexual hormones, sexual arousal, and sexual orientation in men by comparing the self-reported sexual response of heterosexual and homosexual men with locally advanced prostate neoplasm, receiving the non-steroidal anti-androgen bicalutamide as monotherapy. PATIENTS AND METHODS: * 29 Romanian men participated in this study: 17 heterosexual and 12 homosexual. Patients were undergoing treatment for prostate cancer consisting of a standard daily dose of 50 mg bicalutamide, a fast acting non-steroidal anti-androgen with action comparable to other anti-androgen drugs but with reportedly fewer sexual side effects. * Patients retrospectively provided information regarding their sexual functioning measured by the IIEF prior to commencing bicalutamide treatment. * Then, about five weeks later, patients were asked to prospectively provide information regarding their current sexual functioning while undergoing bicalutamide treatment. RESULTS: * Overall IIEF scores as well as the Erectile Function, Orgasmic Function, Sexual Desire, and Overall Satisfaction subscales showed group, treatment, and group by treatment effects. * The Intercourse Satisfaction subscale showed group and group by treatment effects. * On most subscales, homosexual men showed lower functioning than heterosexual men, primarily in response to treatment with bicalutamide. CONCLUSIONS: * Treatment with an anti-androgen in a clinical population of men undergoing therapy for prostate cancer affected homosexual men more than heterosexual men, although not all heterosexual men were unaffected. * These results are discussed in the context of dual sexual natures, a concept recently developed in the sexual literature. * Furthermore, these findings reiterate the importance of incorporating such variables as sexual orientation into studies investigating medical treatments on sexual response. PMID- 20955265 TI - Mid-term evaluation of the transobturator male sling for post-prostatectomy incontinence: focus on prognostic factors. AB - OBJECTIVE: * To assess clinical outcomes at mid-term follow-up and determine preoperative factors associated with the failure of the Advance(TM) male sling for post-prostatectomy incontinence (PPI). PATIENTS AND METHODS: * A prospective evaluation was conducted of 136 consecutive patients implanted with the Advance(TM) male sling for mild to moderate stress urinary incontinence after prostatectomy. * Patients were preoperatively evaluated using medical history, ASA score, urodynamics, 24-h pad test and pad usage. * The clinical outcome was evaluated according to pad use and the Patient Global Impression of Improvement scale and by assessment of side effects. 'Cure' was defined as no pad usage and 'improvement' as a decrease in pad use by >50%. * Factors related to functional outcome were studied by univariate and multivariate analysis. RESULTS: * After a mean +/- SD (range) follow-up of 21 +/- 6 (12-36) months, 62% of patients were cured, 16% improved and 22% not improved. * Failure (no cure or improvement) was associated with previous urethral stricture surgery (P= 0.013) and a 24-h pad test >200 g/day (P= 0.026), and there was a trend for an association with previous radiation therapy (P= 0.053). * Age, learning curve and type of prostatectomy did not affect the results. * Immediate postoperative complications were limited to two cases of dysuria, one case of perineal haematoma and two cases of perineal paresthesia. During follow-up, 10% of patients had perineal pain and 14% of patients had mild dysuria. None required surgical management. CONCLUSION: * The results of the present study, with a follow-up of up to 3 years, confirm that the Advance(TM) male sling is an efficient treatment for PPI. However, particular attention should be given to the preoperative data associated with failure. PMID- 20955266 TI - Low serum testosterone levels are poor predictors of sexual dysfunction. AB - OBJECTIVE: * To identify predictors of sexual dysfunction using baseline data from the reduction by dutasteride of prostate cancer events (REDUCE) study. PATIENTS AND METHODS: * REDUCE was a 4-year randomized, double-blind, placebo controlled study evaluating the efficacy and safety of once-daily dutasteride 0.5 mg in over 8000 men aged 50-75 years with a prostate-specific antigen (PSA) level of 2.5-10 ng/mL (50-60 years) or 3.0-10 ng/mL (>60 years) and a negative prostate biopsy within 6 months of enrolment. * Baseline values (mean serum testosterone, age, International Prostate Symptom Score [IPSS], total prostate volume [TPV], body mass index [BMI], and presence of diabetes/glucose intolerance) were compared in subjects with and without sexual dysfunction (sexual inactivity, impotence, decreased libido or a Problem Assessment Scale of the Sexual Function Index [PAS-SFI] score <9). RESULTS: * Multivariate logistic regression showed that baseline age and IPSS were significant predictors of all four sexual function criteria examined (P < 0.0001). * BMI was a significant predictor of decreased libido, impotence and a PAS-SFI score <9, while diabetes/glucose intolerance was a significant predictor of sexual inactivity, impotence and a PAS SFI score <9. * Testosterone and TPV were not significant predictors of any sexual function criterion examined. CONCLUSIONS: * Age, IPSS, BMI and diabetes/glucose intolerance, but not serum testosterone or TPV, were significant independent predictors of sexual dysfunction in the REDUCE study population. * The lack of association between sexual dysfunction and serum testosterone questions the value of modestly reduced or low normal testosterone levels as criteria for choosing testosterone replacement in older men with sexual dysfunction. PMID- 20955267 TI - LESSons in minimally invasive urology. AB - Since the introduction of laparoscopic surgery, the promise of lower postoperative morbidity and improved cosmesis has been achieved. LaparoEndoscopic Single Site (LESS) surgery potentially takes this further. Following the first human urological LESS report in 2007, numerous case series have emerged, as well as comparative studies comparing LESS with standard laparoscopy. Technological developments in instrumentation, access and optics devices are overcoming some of the challenges that are raised when operating through a single site. Further advances in the technique have included the incorporation of robotics (R-LESS), which exploit the ergonomic benefits of ex vivo robotic platforms in an attempt to further improve the implementation of LESS procedures. In the future, urologists may be able to benefit from in vivo micro-robots that will allow the manipulation of tissue from internal repositionable platforms. The use of magnetic anchoring and guidance systems (MAGS) might allow the external manoeuvring of intra-corporeal instruments to reduce clashing and facilitate triangulation. However, the final promise in minimally invasive surgery is natural orifice transluminal endoscopic surgery (NOTES), with its scarless technique. It remains to be seen whether NOTES, LESS, or any of these future developments will prove their clinical utility over standard laparoscopic methods. PMID- 20955268 TI - America's initial application of the Kolff artificial kidney. PMID- 20955269 TI - Fluid overload and acute kidney injury. AB - Acute kidney injury is commonly encountered in critically ill patients, and is associated with worse outcomes. Fluid therapy is a key component in the management of these patients, often leading to fluid overload, especially in the setting of septic acute kidney injury. Emerging data overwhelmingly suggest that fluid overload in these patients may be associated with adverse outcomes. Management of such patients should include a strategy of early guided resuscitation, followed by careful assessment of fluid status, and early initiation of renal replacement therapy as soon as it is deemed safe, aiming for a neutral or negative fluid balance. This review will focus on the pathophysiological link between fluid overload and acute kidney injury, mechanisms of organ dysfunction in fluid overload, and strategies for management. PMID- 20955270 TI - Role of plasmapheresis in the management of myeloma kidney: a systematic review. AB - Multiple myeloma complicated by acute renal failure is a diagnosis often encountered by the practicing nephrologist. The role of plasmapheresis in such patients has been of interest for decades. Three randomized controlled trials (RCTs) and multiple observational trials have evaluated the potential role of plasmapheresis in the management of this condition. This systematic review presents the results of these trials regarding survival benefits, recovery from dialysis, and improvement in renal function. A comprehensive search revealed 56 articles. Of these, only 8 articles met our inclusion criteria (3 RCTs, 1 correction of results, and 4 observational trials). Two of the 3 RCTs showed no difference in survival benefit. Two of the 3 RCTs showed a greater percentage of patients stopping dialysis in the intervention group; however, these results were not reproduced in the largest trial. All the studies showed an improvement in renal function for patients receiving plasmapheresis; however, only 2 RCTs and 1 retrospective study showed a statistically significant improvement in renal function among patients who received plasmapheresis in comparison with a control group. Our systematic review does not suggest a benefit of plasmapheresis independent of chemotherapy for multiple myeloma patients with acute renal failure in terms of overall survival, recovery from dialysis, or improvement in renal function. PMID- 20955271 TI - Sudden unexpected death in patients with epilepsy receiving renal replacement therapy with dialysis: a 17-year experience at a single institution. AB - Epilepsy is the most common acquired chronic neurological disorder; each year about 1 in a 1000 patients with chronic epilepsy die suddenly, unexpectedly, and without explanation, even with postmortem examination (SUDEP). Seizure incidence is approximately 10% in patients with chronic renal failure and hemodialysis associated seizure has been considered to be a common complication of people on hemodialysis treatment. Considering this, we evaluated the incidence of seizures in 189 patients under dialytic treatment. PMID- 20955272 TI - Renal replacement therapy in Nepal. AB - Renal replacement therapy in Nepal fulfills only a small part of the current needs, with 97 hemodialysis machines available for the general population of 29 million. Transportation difficulties to dialysis centers preclude many of the patients from end-stage renal disease care, due to the rural nature of the population. Peritoneal dialysis (PD) organized into rural sub segments, considering the Mexican model of PD and government funding appear to offer some solution to provision of care for this mountainous rural country. We review the current statistics of dialysis patients, hemodialysis numbers, and renal transplantations within Nepal and offer suggestions regarding possibilities for increasing renal care within the country. PMID- 20955273 TI - Biocompatibility of heparin-grafted hemodialysis membranes: impact on monocyte chemoattractant protein-1 circulating level and oxidative status. AB - This prospective observational study aimed at evaluating efficacy and biocompatibility performances of the new heparin-coated Evodial dialyzers with/without systemic heparin reduction. After a 4-week wash-out period with reference polysulfone F70S dialyzers, 6 hemodialysis patients were sequentially dialyzed with Evodial, F70S, and Evodial dialyzers using 30% heparin reduction, each period of treatment was 4 weeks. Removal rates (RR) (urea, creatinine, and beta2-microglobulin), dialysis dose, and instantaneous clearances (urea and creatinine) were measured as well as inflammatory (C-reactive protein, fibrinogen, interleukin 6, tumor necrosis factor alpha, and monocyte chemoattractant protein-1) and oxidative stress (OS) (superoxide anion, homocysteine, and isoprostanes) parameters at the end of each study period. Patients treated with Evodial or F70S dialyzers for 4 weeks presented comparable dialysis efficacy parameters including urea and creatinine RR, dialysis dose and instantaneous clearances. By contrast, a significantly lower but reasonably good beta2-microglobulin RR was achieved with Evodial dialyzers. Regarding biocompatibility, no significant difference was observed with inflammation and OS except for postdialysis monocyte chemoattractant protein-1 which significantly decreased with Evodial dialyzers. Thirty percent heparinization reduction with Evodial dialyzers did not induce any change in inflammation but led to an improvement in OS as demonstrated by a decrease in postdialysis superoxide production and predialysis homocysteine and isoprostane. This bioactive dialyzer together with heparin dose reduction represents a good trade-off between efficacy and biocompatibility performance (improvement in OS with a weak decrease in efficacy) and its use is encouraging for hemodialysis patients not only in reducing OS but also in improving patient comorbid conditions due to lesser heparin side effects. PMID- 20955274 TI - Effect of a single hemodialysis session on inflammatory markers. AB - Inflammation is a common feature of end-stage renal disease. Although there is evidence for hemodialysis (HD)-induced inflammatory process, the effect of a dialysis session on changes in inflammatory markers is still unclear. Seventeen patients of end-stage renal disease on maintenance HD along with 20 age-matched and sex-matched healthy controls were recruited after informed consent. C reactive protein (CRP) and lipoprotein-associated phospholipase A2 (LpPLA2) activity were measured in the study and control groups. Intradialytic in CRP and LpPLA2 were studied. Comparison of pre-HD vs. the control group and predialytic and postdialytic values was performed using the Mann-Whitney U test and Wilcoxon's test, respectively. Statistical evaluation of intradialytic changes in inflammatory markers was performed using Friedman's test. Hemodialysis patients had higher CRP levels compared with controls (P=0.001). Post-HD LpPLA2 activity (n=17) was higher (P=0.039) compared with the pre-HD activity. Intradialytic changes in inflammatory markers showed a significant increase (P=0.012) in LpPLA2 activity (n=7), while no change (P=0.133) was observed in CRP levels (n=17). Evidence on the pro-inflammatory state being initiated by dialysis is provided by increased LpPLA2 activity. This may add to the atherogenic mileu and cause endothelial dysfunction in this high-risk group. Drugs that inhibit the LpPLA2 pathway have been developed and may be effective in these patients. PMID- 20955275 TI - Plasma fibroblast growth factor-23 levels are independently associated with carotid artery atherosclerosis in maintenance hemodialysis patients. AB - Fibroblast growth factor-23 (FGF-23) has been suggested to play a role in vascular calcification in chronic kidney disease. Common carotid artery intima media thickness (CIMT) assessment and common carotid artery (CCA) plaque identification using ultrasound are well-recognized tools for identification and monitoring of atherosclerosis. The aim of this study was to test that elevated FGF-23 levels might be associated with carotid artery atherosclerosis in maintenance hemodialysis (HD) patients. In this cross-sectional study, plasma FGF 23 concentrations were measured using a C-terminal human enzyme-linked immunosorbent assay kit. Carotid artery intima-media thickness was measured and CCA plaques were identified by B-Mode Doppler ultrasound. One hundred twenty eight maintenance HD patients (65 women and 63 men, mean age: 55.5 +/- 13 years, mean HD vintage: 52 +/- 10 months, all patients are on HD thrice a week) were involved. The mean CIMT were higher with increasing tertiles of plasma FGF-23 levels (0.66 +/- 0.14 vs. 0.75 +/- 0.05 vs. 0.86 +/- 0.20 mm, P<0.0001). Log plasma FGF-23 were higher in patients with plaques in CCA than patients free of plaques (3.0 +/- 0.17 vs. 2.7 +/- 0.23, P<0.0001). Significant correlation was recorded between log plasma FGF-23 and CIMT (r=0,497, P=0.0001). In multiple regression analysis, a high log FGF-23 concentration was a significant independent risk factor of an increased CIMT. Further studies are needed to clarify whether an increased plasma FGF-23 level is a marker or a potential mechanism for atherosclerosis in patients with end-stage renal disease. PMID- 20955276 TI - Whole-blood viscosity increases significantly in small arteries and capillaries in hemodiafiltration. Does acute hemorheological change trigger cardiovascular risk events in hemodialysis patient? AB - Whole-blood viscosity is increasingly being recognized as a factor implicated in the vascular disease progression in high-risk chronic kidney disease patients. Intermittent hemodialysis and hemodiafiltration sessions, characterized by rapid volume changes and anemia correction by erythropoietin stimulating agents, are favorable conditions for enhancing whole-blood viscosity changes and consequently triggering cardiovascular events. To evaluate whole-blood viscosity changes induced by hemodiafiltration, a cross-sectional study has been performed in a group of 28 stable patients. In order to assess the impact of vessel size on whole-blood viscosity changes, we performed a dynamic whole viscosity analysis on a wide spectrum of shear rates reproducing vasculature hemorheologic conditions. Blood viscosity changes are dependent on patient characteristics, hemoglobin, and total plasma protein concentrations. Whole blood viscosity increases significantly during hemodiafiltration over the complete spectrum of shear rates. Dynamic whole-blood viscosity (WBV) increases up to 60%, predominantly at low shear rates in small arterioles and capillary beds. This observation underlines the potential pathogenic contribution of WBV increase in capillaries triggering cardiovascular events in the postdialysis period. Eight patients died from cardiovascular events. Higher WBV increase was noted in this group but did not reach statistical significance due to the insufficient power of the study. Hemorheological changes associated with WBV increase in capillary beds may contribute to aggravate silent tissue hypoxemia and precipitate cardiovascular events in chronic kidney disease patients. Prospective studies specifically designed and powered to evaluate the impact of WBV changes on cardiovascular events in dialysis patients are required. PMID- 20955277 TI - Reproducibility of regional pulse-wave velocity in uremic subjects. AB - Despite the clinical importance of pulse-wave velocity (PWV), there are no standards for accurate carotid-radial pulse-wave measurement in uremic patients with respect to carotid-femoral measurement. We assessed the reproducibility of PWV values using the carotid-radial PWV measurement. We have measured the carotid femoral PWV and carotid-radial PWV with an automated system (Pulse Pen, DiaTecne) using 2 different blind operators in 105 hemodialysis (HD) patients. The carotid femoral waveforms were acquired by the first blind operator simultaneously with 2 pressure-sensitive transducers and the transit time of the pulse was calculated using the system software. Similarly, the second blind operator acquired the carotid-radial waveforms. The two operators performed 2 consecutive measurements from the same subject, in a random order. In fact, after the first operator had completed 2 consecutive measurements from 1 subject, all of the sensors were detached, and the second operator attached sensors again to the same subject. The measurements were performed during interval of a midweek dialysis-free day. To evaluate the reproducibility of the system, both within-observer and between observer analyses were performed. We studied 105 dialysis patients (HD) and 20 controls. All HD patients had three dialysis sessions lasting at least 4 h/wk. A total of 28 patients (26.7%) had diabetic nephropathy. The mean age of HD was 64.6 +/- 16.1 years, the body weight was 71.1 +/- 15.1 kg, and the height was 164.6 +/- 6.1 cm. All population studied is referral at a tertiary care from at least 6 months (mean 11.1 +/- 2.1 months). A total of 45% of patients are smokers or ex-smokers. The PWV of carotid-femoral is 8.58 +/- 3.99 and the PWV of carotid radial is 8.70 +/- 4.01 m/sec, respectively, by the first and the second operator; the difference of PWV (femoral-radial measure) is -0.037 +/- 0.99 m/sec. The linear correlation of carotid-femoral vs. carotid-radial PWV measurements is the highest (R(2) =0.90). The results regarding reproducibility, including mean differences and standard deviations, standard errors, and correlation coefficients were analyzed for each regional PWV value for the between-observer and within-observer studies. All of the measurements showed significant correlation coefficients, ranging from 0.94 to 0.98. The reproducibility of regional PWV values for 2 consecutive measurements from the same subject was also analyzed using Bland-Altman plots, with the reproducibility expressed as the mean difference and 2 standard deviations between the measurements obtained by the 2 operators during carotid-femoral and carotid radial measurements. Carotid-radial PWV measurement provides an accurate analysis with a high reproducibility with respect to carotid-femoral PWV measurement, and it can be used for arterial stiffness analysis in hemodialysis patients. PMID- 20955278 TI - Myocardial stunning in hemodialysis: what is the overall message? AB - Heart failure and cardiovascular events are common in chronic renal failure. Hemodialysis (HD) causes significant hemodynamic changes and hypotension. New evidence based on intradialytic echocardiography demonstrates transient cardiac dysfunction or stunning in majority of chronic HD patients. Over time, this group may progress to chronic heart failure and appears to predict higher cardiovascular events and mortality. Although the exact etiology is unclear, alterations in HD technique and cardiac medications may reduce this complication. We review the current understanding of acute cardiac stunning during HD and present a systematic management algorithm to optimizing overall outcomes in this high-risk population. PMID- 20955279 TI - The impact of extended-hours home hemodialysis and buttonhole cannulation technique on hospitalization rates for septic events related to dialysis access. AB - Few studies adequately document adverse events in patients receiving long, slow, and overnight hemodialysis (NHD). Concerns about high rates of dialysis access complications have been raised. This is an observational cohort study comparing hospital admission rates for vascular access complications between alternate nightly NHD (n=63) and conventional hemodialysis (n=172) patients established on chronic hemodialysis for at least 3 months. Overall, hospital admission rates and hospital admission rates for cardiac and all infective events are also reported. The NHD cohort was younger and less likely to be female, diabetic, or have ischemic heart disease than the conventional hemodialysis cohort. When NHD and buttonhole cannulation technique were used simultaneously, there was a demonstrated increased risk of septic dialysis access events: incidence rate ratio 3.0 (95% confidence interval 1.04-8.66) (P=0.04). The majority of blood culture isolates in NHD patients were gram-positive organisms, particularly Staphylococcus aureus. Alternate nightly NHD did not significantly change total hospital admissions or hospital admissions for indications other than dialysis access complications, compared with conventional hemodialysis. Our data suggest that buttonhole cannulation technique should be used with caution in patients performing extended-hours hemodialysis as this combination appears to increase the risk of septic access complications. Randomized-controlled trials are needed to confirm these findings. PMID- 20955280 TI - Patient perceptions of remote monitoring for nocturnal home hemodialysis. AB - Adoption of nocturnal home hemodialysis (NHHD) has been slow, due in part to patient-perceived barriers, such as anxiety and lack of self-efficacy. This study investigates patient perception of remote monitoring in addressing these barriers. Perceptions of remote patient monitoring (RPM) were studied through a quantitative survey and qualitative interviews. The NHHD and conventional hemodialysis (CHD) were included in the survey (209 in total). Twenty semistructured interviews were conducted as well as a focus group that included NHHD patients and family caregivers. The CHD patients had greater interest in adopting NHHD with RPM than without (1.90+/-1.37 vs. 1.71+/-1.28, P<0.002), with the negative intensity ratio declining from 10.50 to 5.56. Interest in RPM was correlated with interest in NHHD (r=0.768, P<0.001). Other significant factors correlated with interest in NHHD include the belief that remote monitoring will ease the performing of NHHD (r=0.452, P=0.001) and the belief that RPM should be mandatory (r=0.541, P=0.000). Qualitative findings supported three themes: (1) There is an expectation for the use of RPM, (2) RPM should be used at a minimum transitionally, and (3) RPM acts as a surrogate support of family-caregivers. The RPM may lower perceived barriers to the adoption of NHHD, in part through its surrogate support of family caregivers. However, RPM alone is likely insufficient to alter patients' attitudes to undergo NHHD. RPM is a common expectation of CHD patients considering the therapy, at a minimum during the transitional phase. PMID- 20955281 TI - Updated comorbidity assessments and outcomes in prevalent hemodialysis patients. AB - When evaluating clinical characteristics and outcomes in patients on hemodialysis, the prevalence and severity of comorbidity may change over time. Knowing whether updated assessments of comorbidity enhance predictive power will assist the design of future studies. We conducted a secondary data analysis of 1846 prevalent hemodialysis patients from 15 US clinical centers enrolled in the HEMO study. Our primary explanatory variable was the Index of Coexistent Diseases score, which aggregates comorbidities, as a time-constant and time-varying covariate. Our outcomes of interest were all-cause mortality, time to first hospitalization, and total hospitalizations. We used Cox proportional hazards regression. Accounting for an updated comorbidity assessment over time yielded a more robust association with mortality than accounting for baseline comorbidity alone. The variation explained by time-varying comorbidity assessments on time to death was greater than age, baseline serum albumin, diabetes, or any other covariates. There was a less pronounced advantage of updated comorbidity assessments on determining time to hospitalization. Updated assessments of comorbidity significantly strengthen the ability to predict death in patients on hemodialysis. Future studies in dialysis should invest the necessary resources to include repeated assessments of comorbidity. PMID- 20955282 TI - Prevention of secondary hyperparathyroidism in hemodialysis patients: the key role of native vitamin D supplementation. AB - Secondary hyperparathyroidism (SHPT) is a frequent complication in chronic kidney disease, especially in hemodialysis (HD) patients. Treatments for SHPT include calcitriol analogues (CA), phosphate binders, cinacalcet (CC), and surgical parathyroidectomy (PTX). This study aimed to assess the incidence and prevalence of SHPT in a single center during the period when native vitamin D (N-VitD) supplementation and CC treatment became available. All incident and prevalent HD patients were prospectively recorded and compared using 3 periods from 2004 to 2005 (period 1), 2006 to 2007 (period 2), and 2008 to 2009 (period 3). SHPT was diagnosed with serum parathyroid hormone (PTH) levels >300 pg/mL or the need for CA, CC, or PTX. Between periods 1 and 3, in incident patients (n=120 and 101), N VitD prescription increased from 11% to 68% (P<0.0001), CA prescription remained stable (40%), and patients with PTH>300 pg/mL decreased from 40% to 12% (P<0.0001). In prevalent HD patients (n=235), N-VitD treatment increased from 55% to 91% (P<0.0001), whereas treatment with CA decreased from 67% to 17% (P<0.0001). Patients with serum PTH>300 pg/mL decreased from 38% to 13% (P<0.001), whereas patients with PTH<150 pg/mL remained stable (<30%). New CC prescriptions decreased from 45 to 3 (P<0.0001). Since 2004, SHPT has decreased drastically in incident and prevalent HD patients. The preventive role of N-VitD supplementation appears to be obvious and represents one more argument for its general recommendation in CKD patients. PMID- 20955283 TI - Is there an association between intradialytic hypotension and serum magnesium changes? AB - Intradialytic hypotension (IDH) is the most common complication of hemodialysis (HD). The aim of this study was to investigate the significance of intradialytic changes of serum magnesium (sMg) and its relation to IDH. We considered 58 patients undergoing HD. Serum magnesium was measured at start, after 2 hours, and at the end of the HD sessions. Total sMg concentration corrected for albumin was according to Krolles proposed formula. Blood pressure was measured every 30 min. Data were analyzed by SPSS.15. A P value of less than 0.05 was considered as significant. Occurrence of IDH among HD patients was 27.6% (16/58). Serum magnesium decreased significantly during HD session (P<0.05). Comparing corrected sMg in IDH group with non-IDH group showed that: corrected sMg was 0.66 +/- 0.14 mmol/L vs. 0.84 +/- 0.26 mmol/L at the start of dialysis (P=0.43), 0.62 +/- 0.17 mmol/L vs. 0.74 +/- 0.23 mmol/L (P=0.04) at 2 hours, and 0.61 +/- 0.12 mmol/L vs. 0.72 +/- 0.22 mmol/L (P=0.03) at the end of dialysis. Intradialytic hypotension episodes were significantly related to a decrease in sMg during dialysis (P=0.02). There was a significant decrease in sMg levels during dialysis. Intradialytic hypotension was significantly related to lowered sMg levels during dialysis. PMID- 20955284 TI - Tuberculosis in patients on hemodialysis in an endemic region. AB - Clinical presentation of tuberculosis is different in hemodialysis patients than in the general population. This study aimed to analyze hemodialysis patients with tuberculosis in Istanbul. Patients who were on a chronic hemodialysis program in Istanbul for more than 3 months and diagnosed to have tuberculosis at least 3 months after the start of hemodialysis were included. To discard the effect of immigration from other cities, we included only patients who had started their dialysis program in Istanbul. Their demographic and clinical data were analyzed using Statistical Package for Social Sciences for Windows ver. 13.0. Of the 925 patients screened from 7 different centers, 31 (3.35%) were found to have tuberculosis. The mean age was 52.3+/-13.5 years. The male/female ratio was 18/13. The mean duration of dialysis therapy and the duration of dialysis till the diagnosis of tuberculosis were 62.6+/-54.3 and 21.7+/-25.7 months, respectively. Extrapulmonary tuberculosis constituted 48.39%. Treatment ended with a cure in 18 (58.05%); was still ongoing in 12 (38.70%) patients; and 1 (3.25%) died of pulmonary tuberculosis. The lower incidence of tuberculosis compared with previous reports may be related to the differences in the diagnostic criteria and the decrease in the rate of tuberculosis during recent years. The demographic and clinical parameters of the patients were quite similar to the average dialysis population in Turkey. Hence, we cannot address a subpopulation with additional risk. It is important to prevent tuberculosis in hemodialysis patients due to difficulties in the diagnosis and treatment. Thus we recommend routine screening of hemodialysis patients and effective isolation and treatment of infected patients. PMID- 20955285 TI - Intima-media thickness of carotid arteries and erectile dysfunction in hemodialysis patients. AB - The prevalence of erectile dysfunction (ED) in hemodialysis (HD) is extremely high. The objective of this study was to evaluate the association between the intima-media thickness of carotid arteries and ED in HD patients. The survey was organized as a cross-sectional study in men aged up to 65 years, in the HD. All respondents voluntarily completed the questionnaire of the International Index of Erectile Function-5, adjusted for the Serbian language, verified routine laboratory analysis, calculated body mass index, demographic structure, duration of dialysis, the presence of hepatotropic viruses and erythropoietin therapy, smoking and drinking alcohol, determined the quality of HD, verified significantly comorbidities and measured the intima-media thickness of carotid artery using the Doppler method. The prevalence of ED in our study was 82.2%. Erectile dysfunction significantly more prevalent in older (P = 0.001) and obese patients (P = 0.047). It is significantly represented in patients with cardiovascular disease (P = 0.006), in those who consume alcohol (P = 0.04) and patients with higher values of intima-media thickness of carotid arteries (P = 0.007). Spearman's coefficient of linear correlation (rho=-0.34, P=0.006) and linear regression (b=-2.02, P<0.001) indicated a negative association between intima-media thickness and the International Index of Erectile Function score. The prevalence of ED in our patients was 82.2%, more common in older and obese patients, a significant determinant of alcohol consumption and cardiovascular disease. Increased thickness of the intima media of the carotid arteries was associated with a higher incidence of ED. PMID- 20955286 TI - Comparison of effects of automated peritoneal dialysis and continuous ambulatory peritoneal dialysis on health-related quality of life, sleep quality, and depression. AB - Few studies investigating the effects of automated peritoneal dialysis (APD) and continuous ambulatory peritoneal dialysis (CAPD) on health-related quality of life (HRQoL), depression, and sleep quality exist in the literature. We aimed to determine differences between APD and CAPD modalities with respect to these parameters. Twenty APD and 48 CAPD patients were included in this cross-sectional study. Biochemical values were measured at outpatient evaluation. A modified postsleep inventory was used to evaluate sleep quality. Health-related quality of life and depression were evaluated by the Short Form of Medical Outcomes Study and Beck Depression Inventory, respectively. Automated peritoneal dialysis and CAPD patients were compared in terms of sleep quality, HRQoL, and depression. Our results showed that there were no significant differences between APD and CAPD in any of the studied parameters. Moderate or severe sleep problems were found in 60% and 69% of the APD and CAPD patients, respectively. Mean HRQoL scores for any of the 8 Short Form of Medical Outcomes Study-36 domains were similar in the 2 groups. The mean physical component score was 51.1 +/- 21.2 and 48.9 +/- 18.2 in APD and CAPD patients, respectively (P=0.672). The mean mental component score was 47.5 +/- 20.1 in APD patients, whereas it was 42.4 +/- 19.5 in CAPD patients (P=0.291). Depression was detected in 70% of APD and 62.5% of the CAPD patients. The mean Beck Depression Inventory scores were also similar in the 2 groups. This study showed that HRQoL, sleep quality, and depression were similar in APD and CAPD patients. PMID- 20955287 TI - Status epilepticus induced by putrid salted gray mullet fish intoxication in patients with chronic kidney disease. AB - Neurological and psychiatric symptoms are common presentations, but are often ignored in fresh salted gray Mullet fish intoxication. We report 2 patients with chronic renal failure at a predialyzed stage who developed refractory status epilepticus after ingestion of putrid salted gray Mullet. We warn consultant neurologists that fresh salted gray Mullet fish intoxication must be considered when patients with chronic kidney disease present with seizures or other unexplained neurological or psychiatric symptoms. PMID- 20955288 TI - Psoas abscess caused by acupuncture? PMID- 20955290 TI - Regulation of xenogeneic porcine pancreatic islets. AB - The use of xenogeneic porcine pancreatic islets has been shown to be a potentially promising alternative to using human allogeneic islets to treat insulin-dependent type 1 diabetes (T1D). This article provides an overview of the existing FDA regulatory framework that would be applied to the regulation of clinical trials utilizing xenogeneic porcine pancreatic islets to treat T1D. PMID- 20955291 TI - The immunology of corneal xenotransplantation: a review of the literature. AB - As the worldwide demand for human donor corneas far exceeds supply, there is a need for a new source of corneas for clinical transplantation. Genetically engineered pigs may prove to be that new source, particularly as current evidence indicates that the anatomical and biomechanical properties of human and pig corneas are similar. Experience with clinical and experimental corneal xenotransplantation has been comprehensively reviewed and is summarized. Studies in small and large animal models have documented that both humoral and cellular immune responses play roles in xenograft rejection. Recent progress in the genetic manipulation of pigs has led to the prospect that clinical corneal xenotransplantation, in the absence of exogenous immunosuppressive therapy, may become successful in the foreseeable future. PMID- 20955292 TI - The fate of human platelets perfused through the pig liver: implications for xenotransplantation. AB - BACKGROUND: Pig liver xenotransplantation could offset the shortage of livers available for orthotopic liver transplantation. Studies in pig and baboon liver xenografts revealed the main obstacle to be a lethal thrombocytopenia that occurred within minutes to hours of transplantation. METHODS: We have created a model of xenotransplantation-induced thrombocytopenia using ex vivo pig liver perfusion with human platelets. Thrombocytopenia was examined using fluorescently labeled platelets during the ex vivo perfusion and coculture with primary liver sinusoidal endothelial cells (LSEC). RESULTS: Ex vivo liver perfusion revealed that 93% of human platelets were removed from circulation after 15 min. Endothelial cells and platelets were not activated based on tissue factor release into the perfusate. Biopsies from the ex vivo perfusion at 15 and 30 min and in vitro analysis indicated that human platelets are phagocytosed by pig LSEC and degraded in phagosomes. Sixty to 120 min after the addition of platelets to the ex vivo perfusion system, we observed platelet fragments and degraded platelets in hepatocytes. Platelet phagocytosis was not mediated by opsonization as Fc blocking had no effect on platelet phagocytosis. In vitro uptake of human platelets by primary LSEC cultures peaked at 15 min followed by a greater than 55% decrease in platelet fluorescence after 3 h. Primary pig LSEC phagosomes containing human platelets were colocalized with lysosomes positive for lysosome associated membrane protein-1 (LAMP1), indicating the formation of mature phagosomes within pig LSEC. CONCLUSIONS: Our observation of pig LSEC phagocytosis of human platelets describes a novel mechanism of large-particle uptake in the liver. The creation of a model system to study xenotransplantation-induced thrombocytopenia makes possible the investigation into mechanisms that mediate platelet loss. PMID- 20955293 TI - An in vitro model of pig liver xenotransplantation--pig complement is associated with reduced lysis of wild-type and genetically modified pig cells. AB - BACKGROUND: After pig liver transplantation in humans, the graft will produce pig complement (C). We investigated in vitro the lysis of wild-type (WT), alpha1,3 galactosyltransferase gene-knockout (GTKO), and CD46 transgenic (CD46) pig peripheral blood mononuclear cells (PBMC) caused by human anti-pig antibodies (Abs) + pig C. METHODS: Human serum IgM/IgG binding to WT and GTKO PBMC was determined by flow cytometry, and lysis of pig PBMC by a C-dependent cytotoxicity assay using (i) human serum (human Abs + C), (ii) GTKO pig serum (anti-Gal Abs + pig C), (iii) heat-inactivated human serum (human Abs) + rabbit C, or (iv) human Abs + pig C (serum). RESULTS: Binding of human IgM and IgG to GTKO PBMC was less than to WT PBMC (P < 0.05). In the presence of human Abs, lysis of WT and GTKO PBMC by rabbit C was 87 and 13%, respectively (WT vs. GTKO, P < 0.01), but was only 37 and 0.4% in the presence of pig C (WT vs. GTKO, P < 0.05). Human/rabbit C induced lysis was greater than pig C-induced lysis for both WT and GTKO PBMC. CD46 pig PBMC reduced rabbit/human C- and pig C-mediated lysis (P < 0.05). CONCLUSIONS: Pig livers, particularly from GTKO and CD46 pigs, are likely to have an immunologic advantage over other organs after transplantation into humans. In the absence of pig antibodies directed to human tissues, pig complement is unlikely to cause problems after liver xenotransplantation, especially if GTKO/CD46 pigs are used as the source of the livers. PMID- 20955294 TI - Creation of a prevascularized site for cell transplantation in rats. AB - INTRODUCTION: Transplanted cells, especially islet cells, are likely to become apoptotic due to local hypoxia leading to graft dysfunction. Isolated pancreatic islet cells depend on the diffusion of oxygen from the surrounding tissue; therefore, access to sufficient oxygen supply is beneficial, particularly when microcapsules are used for immunoisolation in xenotransplantation. The aim of this study was to create a prevascularized site for cell transplantation in rats and test its effectiveness with microencapsulated HEK293 cells. METHODS: The combination of implantation of a foam dressing, vacuum-assisted wound closure (foam+VAC) and hyperbaric oxygenation (HBO) was used in 40 Sprague-Dawley rats. Blood flow and vascular endothelial growth factor (VEGF) levels were determined. Sodium cellulose sulphate (SCS)-microencapsulated HEK293 cells were xenotransplanted into the foam dressing in rats pre-treated with HBO, and angiogenesis and apoptosis were assessed. RESULTS: Vessel ingrowth and VEGF levels increased depending on the duration of HBO treatment. The area containing the foam was perfused significantly better in the experimental groups when compared to controls. Only a small amount of apoptosis occurs in SCS microencapsulated HEK293 cells after xenotransplantation. CONCLUSION: As ischemia damaged cells are likely to undergo cell death or loose functionality due to hypoxia, therefore leading to graft dysfunction, the combination foam+VAC and HBO might be a promising method to create a prevascularized site to achieve better results in xenogeneic cell transplantation. PMID- 20955295 TI - Korean attitudes to Xenotransplantation: a survey conducted in 2009. AB - BACKGROUND: Xenotransplantation research has been being actively conducted in Korea. However, there are numbers of socio-ethical issues involved in this research, and it is necessary to know public attitudes toward the research, inducing "public consensus" for the sound development of the technology. MATERIALS AND METHODS: A telephone survey consisting of 10 questionnaire items was conducted to investigate the attitudes of Koreans on social and ethical issues related to xenotransplantation. Participants were randomly selected in proportion to the 2009 Korean population census. The response rate was 22.3%. Finally, 500 sets of data were collected and analyzed with SPSS(r) 12. A statistical analysis was performed using the chi-square test. RESULTS: In the first phase of the study, 69.8% of the respondents were positive about xenotransplantation while 29.0% were negative. However, after being informed of the specific benefit and risk, 58.4% of the respondents stated that xenotransplantation research should be continued, while 38.6% of them indicated that these studies should be prohibited; 63.0% of the respondents agreed with lifelong surveillance after xenotransplantation, while 34.0% disagreed. To avoid triggering immune response in the transplantees, 63.0% of the respondents also approved of the necessity of genetic modification of pigs. If xenotransplantation proves to be safe, 56.8% of the respondents said that they would accept it if necessary; 69.8% of the respondents would recommend it for their family members and friends as a therapeutic option if they are in need. Men were more positive than women about the necessity of animal experimentation for xenotransplantation research, the necessity of lifelong surveillance, and the necessity of genetic modification of pigs. There was no significant difference between the religious and non-religious group except about the issue of lifelong surveillance. CONCLUSION: Korean people have relatively positive attitudes toward xenotransplantation research and animal experiments regarding xenotransplantation. PMID- 20955296 TI - Effect of antivenin dose on outcome from crotalid envenomation. PMID- 20955297 TI - Comparative stability of canine and feline hemostatic proteins in freeze-thaw cycled fresh frozen plasma. AB - OBJECTIVE: To evaluate the stability of canine and feline hemostatic proteins in freeze-thaw-cycled (FTC) fresh frozen plasma (FFP). DESIGN: Prospective study. SETTING: Veterinary Teaching Hospital. ANIMALS: Nine blood donor dogs and 10 blood donor cats. INTERVENTIONS: Whole blood was collected and separated into packed RBC and plasma units according to standard methods. Each unit of plasma was divided into 2 equal aliquots and frozen (-41 degrees C). One aliquot from each donor (FTC) was then thawed and then refrozen (-41 degrees C) until time of analysis. The second aliquot (nonfreeze-thaw-cycled; NFTC) remained frozen until time of analysis. The hemostatic proteins assessed included coagulation factors, anticoagulant factors (antithrombin and Protein C), and adhesive proteins (fibrinogen and von Willebrand Factor). The coagulant activities of factors II, VII, VIII, IX, X, XI, and XII were measured in modified one-stage activated partial thromboplastin time or prothrombin time assays. Antithrombin and Protein C activities were measured in chromogenic substrate assays. Clottable fibrinogen was measured via the Clauss method, and von Willebrand Factor concentration (vWF:Ag) was measured in an ELISA. A paired t-test was utilized to identify differences in factor activity or concentration between FTC FFP and NFTC FFP. MEASUREMENTS AND MAIN RESULTS: No clinically or statistically significant differences (all P>0.05) were identified between FTC FFP and NFTC FFP. CONCLUSIONS: Refreezing FFP within 1 hour of initial thawing appeared to have no deleterious effects on the hemostatic protein activity or content of that unit. Transfusion of FTC FFP is expected to provide the recipient with comparable replacement of hemostatic proteins as FFP that has remained frozen. PMID- 20955298 TI - The prevalence of albuminuria in dogs and cats in an ICU or recovering from anesthesia. AB - OBJECTIVE: To evaluate the prevalence of albuminuria in dogs and cats admitted to the ICU or recovering from an anesthetic event. DESIGN: Prospective clinical study over a 10-week period in 2003. SETTING: Veterinary teaching hospital. ANIMALS: One hundred and five dogs and 22 cats. INTERVENTIONS: Urine was collected from dogs and cats admitted to the ICU or recovering from an anesthetic event. When possible, a second urine sample was collected approximately 48 hours later from those animals that had albuminuria during the initial screening. MEASUREMENTS AND MAIN RESULTS: All dog samples and most cat samples were screened for albumin using a commercial point-of-care immunoassay. Aliquots of samples that tested positive were stored at -20 degrees C until subsequent albumin quantification via antigen capture ELISA. Albuminuria was detected in 63 of 105 (60.0%) dogs and in 14 of 22 (63.6%) cats; the prevalence was higher in animals admitted to ICU than in those recovering from anesthesia. In subsequent samples from 26 dogs, urine albumin decreased in 20 (76.9%) when compared with the first sample; urine albumin was undetectable in 5 (19.2%). In subsequent samples from 6 cats, 4 (66.7%) had decreases in urine albumin when compared with the first sample; 1 (16.7%) was negative for urine albumin. Eleven of 12 dogs (91.7%) and 3 of 4 cats (75%) that died within 3 days of admission to the ICU had abnormal urine albumin; whereas 52 of 93 (55.9%) and 11 of 18 (61.1%) dogs and cats, respectively, who survived more than 3 days had abnormal urine albumin. Dogs with albuminuria were at increased risk of death. CONCLUSIONS: The prevalence of albuminuria in animals admitted to the ICU or recovering from anesthesia is higher than reported previously and transient in some patients. The presence of albuminuria may be a negative prognostic indicator in this population. PMID- 20955299 TI - Thromboelastography in healthy horses and horses with inflammatory gastrointestinal disorders and suspected coagulopathies. AB - OBJECTIVES: To evaluate the use of citrated recalcified (nonactivated) thromboelastography (TEG) in healthy horses and horses with colitis and suspected coagulopathies. DESIGN: Prospective, observational study conducted between October 2007 and June 2009. SETTING: Veterinary Teaching Hospital. ANIMALS: Forty five healthy adult horses and 12 sick adult horses with colitis and prolonged prothrombin time (PT) or activated partial thromboplastin time (aPTT). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Whole blood was collected on admission. Coagulation profile (PT, aPTT, platelet count, and fibrinogen concentration) and citrated recalcified whole blood TEG analysis (R-time [R], K time [K], angle [alpha], maximum amplitude [MA], G value [G], lysis at 60 min [LY60]) were evaluated. Mean values (SD) for TEG parameters in healthy horses were: R=10.4 (3.1) minutes; K=3.5 (1.2) minutes; alpha=46.3 (11.0) degrees ; MA=55.6 (5.1) mm; G=6,429 (1,341) dyn/cm2, and LY60=5.1 (2.4)%. Mean coefficients of variation for intra-assay/interindividual variability in healthy horses were: R=4.7%/30.7%, K=4.8%/35.3%, alpha=4.4%/23.8%, MA=1.4%/9.3%, G=3.4%/20.8%, and LY60=13.1%/47.7%, respectively. Horses with colitis and prolonged PT and/or aPTT had longer mean values for R (P<0.001) and K (P<0.001), narrower mean alpha (P<0.001), decreased mean MA (P=0.001), and smaller mean G (P=0.02); changes consistent with hypocoagulability. CONCLUSIONS: Citrated recalcified (nonactivated) TEG demonstrated changes consistent with hypocoagulability in horses with colitis that had preidentified coagulation abnormalities. This technique has high interindividual variability and low intra-assay variability. TEG may be useful for detecting hypocoagulable states in horses with colitis and suspected coagulopathies. PMID- 20955300 TI - Age-associated changes to pathogen-associated molecular pattern-induced inflammatory mediator production in dogs. AB - OBJECTIVE: To determine whether older dogs will have a more pronounced pro inflammatory response and blunted anti-inflammatory response to pathogen associated molecular patterns (PAMPs) compared with younger dogs. DESIGN: Prospective. SETTING: University teaching hospital. ANIMALS: Thirty-eight privately owned sexually altered dogs of various ages. INTERVENTIONS: Blood was collected for HCT, WBC count, plasma biochemical analysis, and whole blood culture. Whole blood was stimulated with lipopolysaccharide (LPS) or, lipoteichoic acid or, peptidoglycan or, addition of phosphate-buffered saline. Tumor necrosis factor (TNF), interleukin (IL)-6, and IL-10 production from whole blood were compared among young, middle aged, and geriatric dogs. MEASUREMENTS AND MAIN RESULTS: LPS, lipoteichoic acid, and peptidoglycan stimulated significant TNF, IL-6, and IL-10 production from canine whole blood compared with phosphate-buffered saline. Whole blood from geriatric dogs had a blunted IL-10 response to LPS stimulation and middle-aged dogs had increased LPS-induced TNF production compared with the other groups. CONCLUSION: PAMPs from gram-positive and gram-negative bacteria stimulate TNF, IL-6, and IL-10 production from canine whole blood. The inflammatory mediator response to PAMPs from gram-negative bacteria alters with age and may be one factor contributing to mortality in geriatric dogs with sepsis. PMID- 20955301 TI - Continuous positive airway pressure administered via face mask in tranquilized dogs. AB - OBJECTIVE: To evaluate the tolerance of a continuous positive airway pressure (CPAP) mask in tranquilized dogs and compare PaO2 in arterial blood in dogs receiving oxygen with a regular face mask or CPAP mask set to maintain a pressure of 2.5 or 5 cm H2O. DESIGN: Prospective, randomized clinical study. SETTING: University teaching hospital. ANIMALS: Sixteen client-owned dogs without evidence of cardiopulmonary disease were studied. INTERVENTIONS: Eight animals were randomly assigned to each of 2 treatment groups: group A received 2.5 cm H2O CPAP and group B received 5 cm H2O CPAP after first receiving oxygen (5 L/min) by a regular face mask. Animals were tranquilized with acepromazine 0.05 mg/kg, i.v. and morphine 0.2 mg/kg, i.m.. An arterial catheter was then placed to facilitate blood sampling for pHa, PaO2, and PaCO2 determinations before and after treatments. Direct mean arterial pressure, heart rate, respiratory rate, and temperature were also recorded after each treatment. MEASUREMENTS AND MAIN RESULTS: CPAP administration was well tolerated by all animals. The mean arterial pressure, heart rate, respiratory rate, temperature, PaCO2, and pHa, did not differ at any time point between groups. Differences were seen in oxygenation; in group A, PaO2 significantly increased from a mean of 288.3 +/- 47.5 mm Hg with a standard mask to a mean of 390.3 +/- 65.5 mm Hg with the CPAP mask and in group B, PaO2 increased similarly from 325.0 +/- 70.5 to 425.2 +/- 63.4 mm Hg (P<0.05); no differences were detected between the 2 CPAP treatments. CONCLUSIONS: In healthy tranquilized dogs noninvasive CPAP is well tolerated and increases PaO2 above values obtained when using a regular face mask. PMID- 20955302 TI - Comparison of regular insulin infusion doses in critically ill diabetic cats: 29 cases (1999-2007). AB - OBJECTIVE: To compare biochemical parameters, neurologic changes, length of hospital stay, and clinical improvement in 3 groups of cats with diabetic ketosis/diabetic ketoacidosis (DK/DKA) prescribed varied doses of regular insulin as a continuous rate of infusion (CRI). DESIGN: Retrospective study. SETTING: University teaching hospital. ANIMALS: Twenty-nine client-owned cats with DK/DKA prescribed a regular insulin CRI. INTERVENTIONS: Cats were grouped as follows: 7 cats each in Group 1 and 2, (prescribed 1.1 and 2.2 U/kg/d, respectively), and 15 cats in Group 3 (prescribed increasing doses as needed). MEASUREMENTS AND MAIN RESULTS: None of the groups received the total prescribed dose of insulin. The mean actual dose administered/kg/d ranged from 0.30 (0.21) to 0.87 (0.32) U/kg/d in Groups 1, 2, and 3. There was no difference in mean minimum blood glucose (BG) per 4 hours or change in BG from baseline per 4 hours between Groups 1 and 2 (P=0.63, 0.50). There was no difference between groups regarding the time required to reach a BG <= 13.9 mmol/L (250 mg/dL), serum phosphorus or potassium concentrations relative to baseline values (P=0.53, 0.90), length of time until urine or serum ketones were no longer detected (P=0.73), the animal commenced eating (P=0.24), or length of hospital stay (P=0.63). Four of the cats had declining mentation during hospitalization; there were no relationships between osmolality at presentation, either prescribed or administered insulin dose, and mentation changes. Three of the 4 cats with declining mentation survived. Twenty seven of the 29 cats (93%) survived to discharge. CONCLUSIONS: In this study, prescribing the published canine dose (2.2 U/kg/d) of regular insulin to cats with DK/DKA does not appear to increase the frequency of adverse neurologic or biochemical sequelae compared with cats that are prescribed the published cat dose (1.1 U/kg/d). The use of a sliding scale for determination of infusion rates significantly reduces the amount of insulin cats receive in this setting. Determination of whether adverse sequelae would occur more frequently if cats with DK/DKA received the full insulin prescribed doses of 1.1, 2.2, or >2.2 U/kg/d is warranted. Further controlled studies are necessary to determine if higher doses of insulin are associated with beneficial effects on morbidity or mortality. PMID- 20955303 TI - Treatment and diagnosis of a dog with fulminant neurological deterioration due to anatoxin--a intoxication. AB - OBJECTIVE: To describe the clinical features, treatment, diagnostic work-up, and outcome of a dog with acute neurologic signs subsequent to algal toxin exposure. CASE SUMMARY: A Golden Retriever was presented for evaluation of acute onset of paraparesis after swimming in a man-made pond in early June and ingesting algae from a nearby bucket. The dog was anxious, had mild ptyalism, and when excited, developed generalized self-limiting tremors that progressed to generalized fasciculations and lateral recumbency. The dog was treated with activated charcoal and crystalloid fluids. Two hours after the presentation, the dog acutely decompensated and was ultimately euthanized. Gastric contents, bucket contents, pond water, bile, and urine were positive for anatoxin-a. NEW OR UNIQUE INFORMATION PROVIDED: Anatoxin-a intoxication is rarely confirmed in dogs but should be considered as a differential diagnosis in any dog with acute neurologic signs. We report the first successful detection of anatoxin-a in urine and bile of a dog exposed to blue green algae. This new test provides an enhanced diagnostic tool in suspect cases and has possible therapeutic implications in dogs. PMID- 20955304 TI - Evaluation of CALC-I gene (CALCA) expression in tissues of dogs with signs of the systemic inflammatory response syndrome. AB - OBJECTIVE: To perform a qualitative evaluation of procalcitonin gene (CALCA) expression in a tissue-specific manner in dogs with signs of the systemic inflammatory response syndrome (SIRS). DESIGN: Observational study. SETTING: University Veterinary Teaching Hospital. ANIMALS: Nine clinical cases and 5 research dogs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fresh tissue samples (thyroid, lung, liver, spleen) from 9 dogs that died with a diagnosis of parvoviral infection or SIRS were collected and immediately stored at -80 degrees C. Diagnosis of parvoviral infection was based on clinical signs, positive fecal antigen test, and confirmed by polymerase chain reaction (PCR). Clinical diagnosis of SIRS was based on the clinical criteria reported in veterinary literature. Necropsy was performed on all subjects in the study. Furthermore, thyroid, lung, liver, spleen were collected from 5 normal research dogs immediately postmortem for testing. The 9 dogs with a clinical diagnosis of SIRS died from either parvovirus (n=5), bacterial sepsis (n=3), or neoplasia (n=1). CALCA was amplified by PCR in the following samples: thyroid (9/9), spleen (6/9), lung (4/9), liver (3/9). Only thyroid expressed CALCA in the 5 normal dogs. CONCLUSIONS: In SIRS, extrathyroidal transcription of CALCA was documented. Quantitative analysis (real-time polymerase chain reaction) in a wider population of SIRS and normal dogs will provide essential information about the extent and source of extrathyroidal expression of canine CALCA induced by septic and nonseptic systemic inflammation. PMID- 20955305 TI - European outbreak of atypical myopathy in the autumn 2009. AB - BACKGROUND: Atypical myopathy is an acute, severe rhabdomyolysis occurring in grazing horses. In the beginning of October 2009, a new outbreak occurred in several European countries. Geographic, demographic and clinical data of the reported cases in the month October 2009 are described. KEY FINDINGS: The survival rate in this outbreak was 25%. The most frequently observed clinical signs were congested mucous membranes, dyspnea, tachycardia, depression, weakness, stiffness, recumbency, trembling, sweating, and myoglobinuria. Nonsurvivors were significantly more likely to be recumbent than survivors. Prognostic factors, symptomatic treatment, and preventive measures are discussed. SIGNIFICANCE: Differences were encountered during the described outbreak of atypical myopathy in October 2009 compared with previous outbreaks reported. Equine practitioners should be aware that previous epidemiological studies have shown that after a high prevalence in the autumn, new cases are likely to occur in the following spring. PMID- 20955306 TI - Canine pedal injury resulting from metal landscape edging. AB - BACKGROUND: This study was performed to document the frequency and severity of limb injuries that occur when dogs come in contact with metal landscape edging. A retrospective study from 1997 to 2007 was performed at Colorado State University veterinary teaching hospital. Sixty dogs were admitted to hospital for traumatic limb injuries resulting from metal landscape edging identified by a computerized medical records search. KEY FINDINGS: Most dogs were young, large breed dogs. All 60 dogs suffered traumatic pedal lacerations when contacting metal landscape edging, the majority of which occurred on the forelimbs. Eighty-five percent required surgical repair. All 60 dogs were discharged from the hospital and 30 were available for long-term follow-up. While most dogs healed with a perfect cosmetic outcome, 3 dogs with tendon involvement developed residual digital deformities. SIGNIFICANCE: Dogs are at risk of injury when exposed to metal landscape edging. Severity of pedal injury determines treatment protocol and prognosis for recovery. PMID- 20955307 TI - Transition: bridge over troubled water? PMID- 20955308 TI - Increased use of oral contraceptives in Spain: related factors and time trend, 2003-2006. AB - AIMS: We aimed to determine the prevalence of consumption of oral contraceptives (OCs) among women living in Spain and to identify the factors associated with this consumption. METHODS: Descriptive cross-sectional epidemiologic study on consumption of OCs by women aged 16-50 years resident in Spain. As the dependent variable, we took the answer to the question, "In the last two weeks, have you taken the contraceptives pill?" Independent variables were sociodemographic, comorbidity, and healthcare resources. Using logistic multivariate regression models, we have analyzed the temporal evolution of OCs consumption between 2003 and 2006. MAIN OUTCOME MEASURES: We used secondary individualized data drawn from the 2003 (n=5,807) and 2006 (n=9,103) Spanish National Health Surveys. RESULTS: In 2003, the 4.99% of women reported having taken the contraceptive pill; this proportion increased to 9.44% in 2006 (P<0.05). Multivariate analysis highlighted the association between OCs use gynecologist visits (odds ratio [OR]=5.67, 95% confidence interval [CI]=2.52-12.79 in 2003, and OR=5.09, 95% CI=2.87-9.02 in 2006); cervical smear test (OR=2.98 95% CI=1.83-4.85 in 2003 and OR=1.79 95% CI=1.28-2.50 in 2006); and risk variables such alcohol consumption or hypertension in the year 2006 (OR=1.53, 95% CI=1.05-2.22). CONCLUSIONS: We can conclude that there was a significant increase in OC use among women living in Spain from 2003 to 2006. The OC consumers in our study were young women who visited the gynecologist and took preventive measures such as smear testing, although they did have risk variables associated with OC, such as alcohol use and arterial hypertension. PMID- 20955309 TI - Risk factors of Peyronie's disease. What does our clinical experience show? AB - INTRODUCTION: Peyronie's disease (PD) is a localized fibrosis that affects the tunica albuginea of the penis. Its origin can be associated with coital penile trauma in men with autoimmune hypersensitivity and a presumed genetic predisposition. AIM: To identify clinical and traumatic risk factors in a patient population with PD, when compared to a control group. METHODS: From November 2007 to March 2010, 317 patients sought medical attention for PD. As control group, 147 consecutive patients, who came for a prostate exam, were studied. Clinical, traumatic, and sexual history of these patients was gathered. Risks factors were considered only if they had been present before the onset of PD symptoms. MAIN OUTCOME MEASURE: The International Index of Erectile Function and the International Prostate Symptoms Score. A univariate logistic regression model (chi-square) (odds ratios [ORs] and 95% confidence intervals [CI]) was used to estimate the association of risk factors with PD; and the Student's t-test was implemented for age. RESULTS: The mean age of patients with PD and control group was 56.7 and 58.8, respectively (P<0.923). The mean evolution time of the disease was 17.7 months (2-48). Erectile dysfunction (ED) and coital trauma constituted the only two independent risk factors for PD compared to the control group (P<0.05 and 0.002, respectively) with an OR of 1.5 (95% CI 1.0-2.3) and 2.69 (95% CI 1.41-5.21), respectively. Patients with ED and diabetes mellitus and with a mild-to-moderate ED also presented a higher predisposition (P=0.008 and 0.00001), with an OR of 3.64 (95% CI 1.33-10.79) and 5.58 (95% CI 3.03-10.42), respectively. CONCLUSION: Erectile dysfunction and coital trauma have proven to be independent risk factors for the development of PD. PMID- 20955310 TI - Clitoral and vulvar vestibular sensation in women taking 20 mcg ethinyl estradiol combined oral contraceptives: a preliminary study. AB - INTRODUCTION: Many women taking low-dose (20 mcg) oral contraceptive pills (OCPs) complain of decreased libido and arousal and some develop vulvar vestibular pain and dyspareunia. Free testosterone concentrations are decreased by the OCP. Genital sensation has not been objectively measured in women taking OCPs. AIM: We assessed whether the 20 mcg ethinyl estradiol combined OCP and associated decrease in free testosterone levels affected genital sensation in a pilot study of a group of asymptomatic OCP users and controls. METHODS: Clitoral thermal, vibratory, and vestibular pain thresholds, sexual functioning, and free testosterone levels were measured in 24 women taking 20 mcg ethinyl estradiol combined OCPs and 28 comparison women not using hormonal contraception. MAIN OUTCOME MEASURES: Female Sexual Functioning Index (FSFI), free testosterone, and clitoral heat, cold, and vibratory thresholds for sensation and vestibular pain thresholds. RESULTS: Free testosterone levels were lower in OCP users. There were no differences in FSFI scores, clitoral thermal or vibratory thresholds, or vestibular pain thresholds between groups. CONCLUSIONS: Low-dose (20 mcg) oral contraceptives decrease free testosterone but are not associated with alterations in clitoral or vestibular sensation. Further studies of genital sensation in women with OCP-related sexual dysfunction are warranted. PMID- 20955311 TI - The high risk of obstructive sleep apnea--an independent risk factor of erectile dysfunction in ST-segment elevation myocardial infarction patients. AB - INTRODUCTION: Sleep-related breathing disorders are highly prevalent in patients with established cardiovascular disease. Obstructive sleep apnea (OSA) is associated with several cardiovascular conditions such as hypertension, ischemic heart disease, arrhythmias, and erectile dysfunction (ED). AIM: The aim of this prospective study was to investigate the prevalence of ED in ST-segment elevation myocardial infarction (STEMI) patients at high risk of OSA, and to evaluate the leading factors that increase the risk of ED. METHODS: We prospectively studied 90 consecutive male STEMI patients. MAIN OUTCOME MEASURES: A risk of OSA was assessed using the Berlin questionnaire (BQ) and Epworth Sleepiness Scale (ESS). Erectile function was assessed using the International Index of Erectile Function (IIEF). RESULTS: Thirty-two (35.6%) patients were at high risk of OSA. Patients were at high risk of OSA who on admission had significantly higher mean ESS score, and abnormal BQ, higher incidence of hypertension, and higher body mass index. They were also found to have significantly higher mean C-reactive protein level and higher incidence of ED. The mean IIEF score was significantly lower in patients at high risk of OSA (16.2 +/- 5.4 vs. 20.5 +/- 6.4; P = 0.004). In the multiple logistic regression analysis, high risk of OSA was strong and an independent risk factor of ED in STEMI patients (odds ratio 55.71, 95% confidence interval 3.36-923.81; P = 0.005). Conclusion. ED was highly prevalent in STEMI patients at high risk of OSA. High risk of OSA was strong, independent risk factor for developing ED. PMID- 20955312 TI - Increased risk for cancer following erectile dysfunction: a nationwide population based follow-up study. AB - INTRODUCTION: Previous studies have suggested that erectile dysfunction (ED) is associated with chronic inflammation, which is also a principle mechanism of carcinogensis. However, very few studies have attempted to examine the association between ED and subsequent cancer. AIM: Using a nationwide population based data set, the aim of this study is to investigate the risk for cancer during a 5-year follow-up period after a diagnosis of ED, compared to patients without ED during the same period, while adjusting for socio-demographic characteristics. MAIN OUTCOME MEASURE: Stratified Cox proportional hazard regression was performed to compare the 5-year cancer-free survival rate for the two cohorts. METHODS: This study used data sourced from the Taiwan "Longitudinal Health Insurance Database." The study cohort comprised 1,882 patients with ED and 9,410 randomly selected subjects as the comparison cohort. Each patient was then individually tracked for 5 years from their index ambulatory care visit to identify those who had diagnosed episodes of cancer. RESULTS: Of the sampled patients, 183 (1.6%) had cancer within the 5-year follow-up period, that is, 43 individuals (2.3% of the patients with ED) from the study cohort and 140 individuals (1.6% of patients in the comparison cohort) from the comparison cohort. After adjusting for the patients' monthly income, the geographic location and urbanization level of the community in which the patient resided, hypertension, diabetes, coronary heart disease, and hyperlipidemia, regression analysis reveals that the hazard of having cancer during the 5-year follow-up period was 1.42 (95% CI = 1.03-2.09, P = 0.039) times greater for patients with ED than comparison patients. However, data on smoking, which is an important factor in ED and cancer, is not available and remains a potential confounder. CONCLUSIONS: We conclude that the incidence of cancer in the 5 years after an ED diagnosis is significantly higher than in the general population. PMID- 20955313 TI - Farnesoid X receptor activation improves erectile function in animal models of metabolic syndrome and diabetes. AB - INTRODUCTION: The farnesoid X receptor (FXR) is critically involved in the regulation of the hepato-biliary system. Recent data suggest a role for FXR in modulating other metabolic pathways and vascular function. AIM: To investigate whether long-term administration of the selective FXR agonist INT-747 ameliorates erectile function, we tested it in two animal models of metabolic derangements: a rabbit model of high-fat diet (HFD)-induced metabolic syndrome (MetS) and a rat model of streptozotocin (STZ)-induced type 1 diabetes. METHODS: HFD rabbit or STZ rats with or without chronic INT-747 dosing (10 mg/kg/day for 12 weeks). INT-747 addition to rabbit penile smooth muscle cells (rpSMCs). MAIN OUTCOME MEASURE: Effects of INT-747 on metabolic features and erectile function in animal models and clarification of mechanism of action in isolated cells. RESULTS: INT-747 dosing normalized visceral adiposity and glucose intolerance in HFD rabbits. INT 747 increased penile FXR expression and partially restored endothelial nitric oxide synthase and dimethylarginine dimethylaminohydrolase 1 expression as well as impaired nitric oxide (NO)-dependent relaxation (improved responsiveness to acetylcholine and electrical field stimulation). INT-747 was also effective in regulating NO downstream events, as shown by increased sodium nitroprusside induced relaxation. Because phosphodiesterase type 5 and protein kinase G (PKG) were unaltered by INT-747, we analyzed the calcium-sensitizing RhoA/ROCK pathway. HFD increased, and INT-747 normalized, RhoA membrane translocation/activation. RhoA/ROCK signaling inhibition by INT-747 was confirmed in rpSMCs by confocal microscopy, MYPT1-phosphorylation, cytoskeleton remodeling, cell migration, and smooth muscle-related genes expression. In STZ rats, FXR penile expression was not altered but was significantly upregulated by INT-747 dosing. In this model, INT-747 improved penile erection induced by electrical stimulation of cavernous nerve and hypersensitivity to intracavernous injection of a ROCK-inhibitor, Y 27632, without improving hyperglycemia. CONCLUSION: In HFD rabbits, INT-747 dosing improved glucose sensitivity and MetS-associated erectile dysfunction, via upregulation of NO transmission and inhibition of RhoA/ROCK pathway. In STZ rats, INT-747 restored in vivo penile erection and sensitivity to ROCK inhibition, independently of effects on glycemia. PMID- 20955314 TI - The treatment of vulvar lichen sclerosus and female sexual dysfunction. AB - INTRODUCTION: Women with lichen sclerosus (LS) are more likely to have dyspareunia, decreased orgasm, and decreased coital frequency as compared to unaffected women. It is unknown whether standard medical therapy to treat LS results in improved sexual functioning. AIMS: To describe sexual function in women with LS and to assess if LS-associated sexual dysfunction decreases after appropriate medical therapy. METHODS: Women enrolled in a double-blind trial 12 week trial comparing clobetasol vs. pimecrolimus for the treatment of LS were administered the Female Sexual Distress Scale (FSDS) upon enrollment and at the end of the trial. The difference in the total score on the FSDS between the two groups before and after treatment was assessed with a paired t-test. MAIN OUTCOME MEASURES: The change in mean FSDS score from baseline to 12 weeks. RESULTS: A total of 31 out of 36 enrolled women had adequate treatment of LS as determined by a dermatopathologist's evaluation of pre and post-treatment biopsy specimens. The mean baseline FSDS score for the clobetasol group was 29 and, post-treatment, it was 15 (P=0.001). In the pimecrolimus group, the mean baseline FSDS score was 27 and, post-treatment, it was 21 (P=0.001). CONCLUSIONS: Despite adequate treatment, women with LS continue to have significant sexual dysfunction as assessed by the FSDS. PMID- 20955315 TI - Trans-corporal incision of Peyronie's plaques. AB - INTRODUCTION: Patients presenting with Peyronie's disease (PD) curvature and erectile dysfunction (ED) can achieve straightening and rigidity through penile prosthesis implantation and manual modeling and, if necessary, a relaxing tunical incision with or without grafting. Unfortunately, this maneuver will not correct PD-induced shortening. In addition, incision and grafting after the prosthesis has already been implanted adds to operative time and risk, and may indicate mobilization of the neurovascular bundle and, possibly, a secondary skin incision. AIM: This work describes trans-corporal incision (TCI), a minimally invasive endoscopic approach for plaque incision from within the corpora cavernosa, restoring straightness and length to the penis, before calibration of the corpora cavernosa, allowing implantation of a longer prosthesis in a straight penis, with neither mobilizing the neurovascular bundle nor a secondary incision. METHODS: Sixteen patients with PD deformity and refractory ED were operated upon. Intra-operative artificial erection demonstrated the deformity. Through a penoscrotal incision, the corpora were dilated. TCI was performed to incise Peyronie's plaques at the point of maximum deformity. Artificial erection was re induced and correction of curvature evaluated. Length was measured before and after TCI. Implantation proceeded as usual. MAIN OUTCOME MEASURES: Penile straightness and length. RESULTS: Following implantation, the penis was straight in all cases. Pre-TCI length of the corpora was unequal on either side. Post-TCI, both corpora were of equal length with an average increase of 2.5 cm (11.9%) on the right side and 1.9 (9.1%) on the left. CONCLUSION: TCI; corporoscopic incision of Peyronie's plaques upon implantation of penile prosthesis is a minimally invasive approach that restores both straightness and length to patients with PD and ED, with neither mobilization of the neurovascular bundle nor plaque incision and grafting. PMID- 20955316 TI - Stronger evidence for small fiber sensory neuropathy in restless genital syndrome: two case reports in males. AB - INTRODUCTION: Restless genital syndrome (ReGS) is characterized by unwanted, unpleasant genital sensations, restless legs, and/or overactive bladder, as well as neuropathy of the dorsal nerve of the clitoris. So far, ReGS has only been reported in females. AIM: To report the occurrence of ReGS in two males. METHODS: Two males with unwanted genital sensations presented in our clinic. In-depth interview, routine and hormonal investigations, electro-encephalography, magnetic resonance imaging of brain and pelvis, manual examination of the pubic bone, and sensory testing of genital dermatomes were performed. In both males, conventional transcutaneous electrical nerve stimulation was applied bilaterally at the pudendal dermatome. MAIN OUTCOME MEASURES: Oral report, questionnaire on frequency and intensity of restless genital feelings, restless legs, overactive bladder, and satisfaction with the transcutaneous electrical nerve stimulation (TENS) treatment. RESULTS: ReGS in a 74-year-old male manifested as unpleasant genital sensations of being on the edge of an orgasm with overactive bladder, in the absence of erection and ejaculation. Genital sensory testing elicited bilateral points of static mechanical hyperesthesia in the pudendal dermatome. Manual examination of the dorsal nerve of the penis (DNP) elicited the genital sensations. TENS application resulted in a 90% reduction of genital sensations and complaints of overactive bladder syndrome (OAB). ReGS in a 38-year-old male manifested as unwanted and unpleasant spontaneous ejaculations and complaints of OAB. Genital sensory testing elicited bilateral points of static mechanical hyperesthesia in the pudendal dermatome. Manual examination of the DNP elicited the genital sensations. TENS application had no effect on genital complaints and complaints of OAB. CONCLUSIONS: ReGS is not a typical female disorder as it also affects males. This notion and the finding of typical sensory abnormalities of the genital end branches of the pudendal nerve in males and females--as previously reported--provides strong evidence for Small Fiber Sensory Neuropathy as a common cause of ReGS. PMID- 20955317 TI - Vaginismus and dyspareunia: relationship with general and sex-related moral standards. AB - INTRODUCTION: Relatively strong adherence to conservative values and/or relatively strict sex-related moral standards logically restricts the sexual repertoire and will lower the threshold for experiencing negative emotions in a sexual context. In turn, this may generate withdrawal and avoidance behavior, which is at the nucleus of vaginismus. AIM: To examine whether indeed strong adherence to conservative morals and/or strict sexual standards may be involved in vaginismus. MAIN OUTCOME MEASURES: The Schwartz Value Survey (SVS) to investigate the individual's value pattern and the Sexual Disgust Questionnaire (SDQ) to index the willingness to perform certain sexual activities as an indirect measure of sex-related moral standards. METHODS: The SVS and SDQ were completed by three groups: women diagnosed with vaginismus (N=24), a group of women diagnosed with dyspareunia (N=24), and a healthy control group of women without sexual complaints (N=32). RESULTS: Specifically, the vaginismus group showed relatively low scores on liberal values together with comparatively high scores on conservative values. Additionally, the vaginismus group was more restricted in their readiness to perform particular sex-related behaviors than the control group. The dyspareunia group, on both the SVS and the SDQ, placed between the vaginismus and the control group, but not significantly different than either of the groups. CONCLUSIONS: The findings are consistent with the view that low liberal and high conservative values, along with restricted sexual standards, are involved in the development/maintenance of vaginismus. PMID- 20955318 TI - Effect of corticosterone and paroxetine on masculine mating behavior: possible involvement of neurogenesis. AB - INTRODUCTION: Corticosterone inhibits male rodent sexual behavior while the mechanism remains obscured. Recent studies have disclosed that neurogenesis in the subventricular zone (SVZ) can be increased by pheromone exposure from the opposite sex, and neurogenesis is essential for normal mating behavior of female mice. Together with the neurogenesis-inhibiting effect of corticosterone, we hypothesize that cell proliferation in the olfactory system is essential for male rodent sexual functioning. AIM: The current study explored the relationship between cell proliferation in the olfactory system and male sexual behavior. MAIN OUTCOME MEASURES: Sexual behavior performance, proliferative cell counts, and c fos-expressing cell counts. METHODS: Adult male rats were treated with corticosterone and/or paroxetine, an antidepressant, for 2 weeks. These two drugs were shown to suppress and enhance hippocampus and SVZ cell proliferation, respectively. Mating behavior was assessed after the treatment, and proliferation of new cells and c-fos-expressing cells, activated neurons in the mating-related regions in the brain, were analyzed. To further confirm the necessity of cell proliferation in mating, inhibition of cell proliferation was performed by intracerebroventricular infusion of cytostatic cytosine arabinose (Ara-c). RESULTS: Corticosterone treatment, which inhibited cell proliferation in both the SVZ and olfactory epithelium, led to inhibited male sexual performance. In contrast, paroxetine increased cell proliferation and improved the performance in corticosterone-treated animals. When cell proliferation in the brain was inhibited by Ara-c, a suppressed sexual performance was found. However, cell proliferation in olfactory epithelium was not inhibited by Ara-c and thus the sexual inhibition is unlikely to be linked to this region. Furthermore, a decrease in c-fos expression in the mating-related regions upon female pheromone stimulation was found. CONCLUSIONS: These results suggest that cell proliferation in the SVZ and hippocampus may be involved in the reproduction of the male rodents, and pharmacological treatments may affect sexual functioning through alteration of neurogenesis. PMID- 20955319 TI - Psychiatric and neurologic aspects of war: an overview and perspective. AB - The growing number of soldiers returning home with psychiatric and neurologic disorders, notably posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI), underscores the need for an interdisciplinary framework for understanding the emergent consequences of combat. Among the challenges facing the scientific community is the development of effective treatment strategies for TBI from blast and other injuries, given the confounding effects of comorbid psychological symptoms on accurate diagnoses. At the individual level, emerging technologies-including virtual reality, the use of genetic biomarkers to inform treatment response, and new brain imaging methodology-are playing an important role in the development of differential therapeutics to best address a soldier's particular clinical needs. At the macro level, new approaches toward understanding the political, cultural, and ideological contexts of mass conflict, the decision to join in violence, and ways of preventing genocide are discussed. PMID- 20955320 TI - Recent advances in preventing mass violence. AB - Since his presidency of the Carnegie Corporation of New York and co-chairmanship of the Carnegie Commission on Preventing Deadly Conflict, David Hamburg has been actively engaged in projects related to the prevention of genocide and other mass violence. In these remarks to the Association for Research in Nervous and Mental Disease, he describes the significance of preventing mass violence in the 21st century. In particular, he discusses the danger of nuclear and other highly lethal weapons, emphasizing examples of prevention drawn from the Cold War and subsequent period. He delineates practical steps that can be taken to prevent war and genocide, including restraints on weaponry, preventive diplomacy, fostering indigenous democracy, fostering equitable socioeconomic development, education for human survival, and international justice in relation to human rights. Training and support in preventive diplomacy are highlighted as crucially important, particularly in the context of the United Nations, using the novel Mediation Support Unit based out of the Department of Political Affairs as a key example. He concludes that the creation of international centers for the prevention of mass atrocities could provide a crucial resource in preventing mass violence. PMID- 20955321 TI - "When hatred is bred in the bone:" the social psychology of terrorism. AB - Terrorists are not crazed fanatics. Indeed, terrorist groups screen out emotionally unstable individuals--they would be a security risk. Rather it is group, organizational, and social psychology, with particular emphasis on collective identity that motivates terrorist behavior. There is a diverse spectrum of terrorist psychologies and motivations. In terms of generational provenance, nationalist-separatist terrorists are carrying on the mission of their parents-they are loyal to families who have been damaged by the regime. In contrast, social-revolutionary terrorists are disloyal to families who are loyal to the regime. Religious fundamentalist terrorists are "killing in the name of God." Suicide, proscribed by the Koran, has been reframed as martyrdom, which is highly valued. The new media, especially the Internet, have played an increasingly prominent role in radicalizing individuals, creating a virtual community of hatred. Understanding terrorist psychology is crucial to formulating effective counter-terrorist strategy. Key elements include inhibiting potential terrorists from joining the group, creating tension within the group, facilitating exit from the group, reducing support for the group, and delegitimating its leader. PMID- 20955322 TI - A trauma-like model of political extremism: psycho-political fault lines in Israel. AB - This study examines a trauma-like model of potentially violent political extremism among Jewish Israelis. We study the psychosocial characteristics of political extremists that may lie at the root of sociopolitical instability and assess personal (gender, stressful life events, Holocaust family background, and political activism) and psychological parameters (self- and political transcendence, perceived political threats, in/out-group identification ratio) that may predict readiness to engage in destructive political behavior. We examine the ideological zeal of various political groups, the relationship between the latter and perceived political threats, and the predictors of extreme political activism. Results showed that the extreme political poles displayed high level of ideological and morbid transcendence. Right extremists displayed higher perceived threats to physical existence and national identity. Left extremists scored highest on perceived moral integrity threat. Higher perceived threats to national identity and moral integrity, risk, and self-transcendence statistically explain morbid transcendence. When fear conjures up extremely skewed sociopolitical identifications across political boundaries, morbid transcendence may manifest itself in destructive political activity. PMID- 20955323 TI - From an unlicensed philosopher: reflections on brain, mind, society, culture- each other's environments with equal "ontologic standing". AB - Philosophic conclusions drawn from work with psychologically and morally injured combat veterans include that brain, mind, society, and culture "co-evolved." The four encompass the complete human phenomenon, but not all are reducible to the physical brain. None of the four are "ontologically prior" to the others, when viewed over the entire lifecycle. All four are what I call "each other's environments," with obligatory cross-boundary flows--each with each in both directions. Rigorous, but nonreductionist interdisciplinary research, in the vein of "evo-devo" in embryology, is called for in the study of the human phenomena. On the basis of these conclusions, I offer a few practical comments on clinical work with psychologically and morally injured combat veterans. PMID- 20955324 TI - Military traumatic brain injury: an examination of important differences. AB - Traumatic brain injury, especially mild traumatic brain injury, is a common consequence of modern warfare. In the current conflicts in Iraq and Afghanistan, much attention has been devoted to blast as a "new" mechanism of brain injury. While the evidence for primary blast effects upon the central nervous system is limited and controversial, there are a number of aspects of blast-induced brain injury that may be different. These include high rates of sensory impairment, pain issues, and polytrauma. In addition, the emotional context in which the injury occurred must also be considered in understanding the clinical presentation of these patients. Successful treatment of these individuals must use a multidisciplinary approach focused on the varied conditions that occur in those injured. PMID- 20955325 TI - Effects of psychological and biomechanical trauma on brain and behavior. AB - The current conflicts in Iraq and Afghanistan have resulted in a large cohort of military personnel exposed to combat-related psychological trauma as well as biomechanical trauma, including proximity to blast events. Historically, the long term effects of both types of trauma have been viewed as having different neural substrates, with some controversy over the proper attribution of such symptoms evident after each of the major conflicts of the last century. Recently, great effort has been directed toward distinguishing which neuropsychiatric sequelae are due to which type of trauma. Of interest, however, is that the chronic effects of exposure to either process are associated with a significant overlap in clinical symptoms. Furthermore, similar brain regions are vulnerable to the effects of either psychological or biomechanical trauma, raising the possibility that shared mechanisms may underlie the clinically observed overlap in symptom profile. This paper reviews the literature on the neural substrate of biomechanical and psychological injury and discusses the implications for evaluation and treatment of the neuropsychiatric sequelae of these processes. PMID- 20955327 TI - Posttraumatic stress disorder: a history and a critique. AB - Although posttraumatic stress disorder (PTSD) is sometimes considered to be a relatively new diagnosis, as the name first appeared in 1980, the concept of the disorder has a very long history. That history has often been linked to the history of war, but the disorder has also been frequently described in civilian settings involving natural disasters, mass catastrophes, and serious accidental injuries. The diagnosis first appeared in the official nomenclature when Diagnostic and Statistical Manual of Mental Disorders (DSM)-I was published in 1952 under the name gross stress reaction. It was omitted, however, in the next edition in 1968, after a long period of relative peace. When DSM-III was developed in the mid-1980s the recent occurrence of the Vietnam War provoked a more thorough examination of the disorder. PTSD was defined as a stress disorder that is a final common pathway occurring as a consequence of many different types of stressors, including both combat and civilian stress. The definition of PTSD has filled an important niche in clinical psychiatry. Its definition continues to raise important questions about the relationship between a stressor, the individual experiencing it, and the characteristic symptoms. PMID- 20955326 TI - A unified science of concussion. AB - The etiology, imaging, and behavioral assessment of mild traumatic brain injury (mTBI) are daunting fields, given the lack of a cohesive neurobiological explanation for the observed cognitive deficits seen following mTBI. Although subjective patient self-report is the leading method of diagnosing mTBI, current scientific evidence suggests that quantitative measures of predictive timing, such as visual tracking, could be a useful adjunct to guide the assessment of attention and to screen for advanced brain imaging. Magnetic resonance diffusion tensor imaging (DTI) has demonstrated that mTBI is associated with widespread microstructural changes that include those in the frontal white matter tracts. Deficits observed during predictive visual tracking correlate with DTI findings that show lesions localized in neural pathways subserving the cognitive functions often disrupted in mTBI. Unifying the anatomical and behavioral approaches, the emerging evidence supports an explanation for mTBI that the observed cognitive impairments are a result of predictive timing deficits caused by shearing injuries in the frontal white matter tracts. PMID- 20955328 TI - Posttraumatic stress disorder and traumatic stress: from bench to bedside, from war to disaster. AB - War is a tragic event and its mental health consequences can be profound. Recent studies indicate substantial rates of posttraumatic stress disorder and other behavioral alterations because of war exposure. Understanding the psychological, behavioral, and neurobiological mechanism of mental health and behavioral changes related to war exposure is critical to helping those in need of care. Substantial work to encourage bench to bedside to community knowledge and communication is a core component of addressing this world health need. PMID- 20955329 TI - Evidence-based treatments for PTSD, new directions, and special challenges. AB - This paper provides a current review of existing evidence-based treatments for posttraumatic stress disorder (PTSD), with a description of psychopharmacologic options, prolonged exposure therapy, cognitive processing therapy, and eye movement desensitization and reprocessing, especially as they pertain to military populations. It further offers a brief summary of promising treatments with a developing evidence base, encompassing both psychotherapy and pharmacotherapy. Finally, challenges to the treatment of PTSD are summarized and future directions suggested. PMID- 20955330 TI - Buddy-to-Buddy, a citizen soldier peer support program to counteract stigma, PTSD, depression, and suicide. AB - Citizen soldiers (National Guard and Reserves) represent approximately 40% of the two million armed forces deployed to Afghanistan and Iraq. Twenty-five to forty percent of them develop PTSD, clinical depression, sleep disturbances, or suicidal thoughts. Upon returning home, many encounter additional stresses and hurdles to obtaining care: specifically, many civilian communities lack military medical/psychiatric facilities; financial, job, home, and relationship stresses have evolved or have been exacerbated during deployment; uncertainty has increased related to future deployment; there is loss of contact with military peers; and there is reluctance to recognize and acknowledge mental health needs that interfere with treatment entry and adherence. Approximately half of those needing help are not receiving it. To address this constellation of issues, a private-public partnership was formed under the auspices of the Welcome Back Veterans Initiative. In Michigan, the Army National Guard teamed with the University of Michigan and Michigan State University to develop innovative peer to-peer programs for soldiers (Buddy-to-Buddy) and augmented programs for military families. Goals are to improve treatment entry, adherence, clinical outcomes, and to reduce suicides. This manuscript describes training approaches, preliminary results, and explores future national dissemination. PMID- 20955331 TI - Suicide risk and prevention in veteran populations. AB - Rates of suicide among veterans of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) rose significantly from 2005 to 2007, adding to existing concerns about veteran suicide risk by the Department of Veterans Affairs. This paper summarizes the available data about risk and rates of suicide in veterans, including the choice of appropriate comparison groups and the identification of risk factors. The data suggest that taking into account the selection bias of who enters the military (known as the healthy soldier effect), rates of suicide in veterans are higher than expected, especially among activity duty OEF/OIF veterans and even more so among those who experienced injuries and trauma. Thus, the experiences of war and the downstream sequelae, in particular the individuals' psychological reactions and societal responses, lead to suicide risk. This paper describes the VA's response to these data in developing and implementing suicide prevention interventions. PMID- 20955332 TI - Monitoring mental health treatment acceptance and initial treatment adherence in veterans: veterans of Operations Enduring Freedom and Iraqi Freedom versus other veterans of other eras. AB - Identifying factors that influence mental health outcomes in veterans can aid in the redesign of programs to maximize the likelihood of early resolution of problems. To that end, we examined demographic and clinical process data from 2,684 veterans who scored positive on a mental health screen. We investigated this data set for patterns and possible predictors of mental health referral acceptance and attendance. The majority of patients had not received mental health treatment within the last two years (76%). Veterans of Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) were more likely to accept a mental health referral for depression but were equally likely to attend a mental health visit as other era veterans. Decreased acceptance was associated with provider type and contact method, clinic location, depression only, and specific age ranges (65 74). Among those who accepted a referral, decreased attendance was associated with clinic location, depression only, and retirement. No variables predicted OEF/OIF acceptance/attendance. In conclusion, our findings illustrate the importance of close, continual monitoring of clinical process data to help reveal targets for improving mental health care for veterans. PMID- 20955333 TI - Development and early evaluation of the Virtual Iraq/Afghanistan exposure therapy system for combat-related PTSD. AB - Numerous reports indicate that the growing incidence of posttraumatic stress disorder (PTSD) in returning Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) military personnel is creating a significant health care and economic challenge. These findings have served to motivate research on how to better develop and disseminate evidence-based treatments for PTSD. Virtual reality-delivered exposure therapy for PTSD has been previously used with reports of positive outcomes. The current paper will detail the development and early results from use of the Virtual Iraq/Afghanistan exposure therapy system. The system consists of a series of customizable virtual scenarios designed to represent relevant Middle Eastern contexts for exposure therapy, including a city and desert road convoy environment. The process for gathering user-centered design feedback from returning OEF/OIF military personnel and from a system deployed in Iraq (as was needed to iteratively evolve the system) will be discussed, along with a brief summary of results from an open clinical trial using Virtual Iraq with 20 treatment completers, which indicated that 16 no longer met PTSD checklist-military criteria for PTSD after treatment. PMID- 20955334 TI - Virtual reality exposure therapy for combat-related posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) is a chronic, debilitating, psychological condition that occurs in a subset of individuals who experience or witness life threatening traumatic events. PTSD is highly prevalent in those who served in the military. In this paper, we present the underlying theoretical foundations and existing research on virtual reality exposure therapy, a recently emerging treatment for PTSD. Three virtual reality scenarios used to treat PTSD in active duty military and combat veterans and survivors of terrorism are presented: Virtual Vietnam, Virtual Iraq, and Virtual World Trade Center. Preliminary results of ongoing trials are presented. PMID- 20955335 TI - House calls revisited: leveraging technology to overcome obstacles to veteran psychiatric care and improve treatment outcomes. AB - Despite an increasing number of military service members in need of mental health treatment following deployment to Iraq and Afghanistan, numerous psychological and practical barriers limit access to care. Perceived stigma about admitting psychological difficulties as well as frequent long distances to treatment facilities reduce many veterans' willingness and ability to receive care. Telemedicine and virtual human technologies offer a unique potential to expand services to those in greatest need. Telemedicine-based treatment has been used to address multiple psychiatric disorders, including posttraumatic stress disorder, depression, and substance use, as well as to provide suicide risk assessment and intervention. Clinician education and training has also been enhanced and expanded through the use of distance technologies, with trainees practicing clinical skills with virtual patients and supervisors connecting with clinicians via videoconferencing. The use of these innovative and creative vehicles offers a significant and as yet unfulfilled promise to expand delivery of high-quality psychological therapies, regardless of clinician and patient location. PMID- 20955336 TI - Improvement in cerebral function with treatment of posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are signature illnesses of the Iraq and Afghanistan wars, but current diagnostic and therapeutic measures for these conditions are suboptimal. In our study, functional magnetic resonance imaging (fMRI) is used to try to differentiate military service members with: PTSD and mTBI, PTSD alone, mTBI alone, and neither PTSD nor mTBI. Those with PTSD are then randomized to virtual reality exposure therapy or imaginal exposure. fMRI is repeated after treatment and along with the Clinician-Administered PTSD Scale (CAPS) and Clinical Global Impression (CGI) scores to compare with baseline. Twenty subjects have completed baseline fMRI scans, including four controls and one mTBI only; of 15 treated for PTSD, eight completed posttreatment scans. Most subjects have been male (93%) and Caucasian (83%), with a mean age of 34. Significant improvements are evident on fMRI scans, and corroborated by CGI scores, but CAPS scores improvements are modest. In conclusion, CGI scores and fMRI scans indicate significant improvement in PTSD in both treatment arms, though CAPS score improvements are less robust. PMID- 20955338 TI - Using biological markers to inform a clinically meaningful treatment response. AB - Combat veterans with posttraumatic stress disorder (PTSD) demonstrate less robust improvement following treatments than do civilians with PTSD. This paper discusses a theoretical model for evaluating treatment response based on the extent of change in biological markers of symptom severity or resilience between treatment initiation and termination. Such analysis permits a determination of biological change associated with the liberal criteria commonly used to determine treatment response in combat PTSD, and a comparison of this to the biological change associated with clinical response determined according to the conservative definition more appropriate to civilian PTSD. Interim data supporting the utility of this approach is presented based on preliminary analyses from our work in progress. We propose that future studies consider the unique consequences of combat trauma and develop treatments that incorporate the complex nature of the exposure and response characteristic of a veteran population. PMID- 20955337 TI - Variant brain-derived neurotrophic factor Val66Met endophenotypes: implications for posttraumatic stress disorder. AB - Recently, a common single nucleotide polymorphism (SNP) has been identified in the gene encoding brain-derived neurotrophic factor (BDNF). The variant BDNF(Met) has been shown to have decreased activity-dependent BDNF secretion from neurons and to lead to impairments in specific forms of learning and altered susceptibility to stress. A mouse model containing BDNF(Met) has also been linked to increased anxiety-like behavior. In a translational study, mice and human carriers of the BDNF(Met) allele were compared in their ability to extinguish a learned fear memory. Both showed slower suppression of the learned fear response. In humans, the neural correlates of this behavior were validated using fMRI. As anxiety and fear extinction lie at the core of symptoms and therapeutic approaches to posttraumatic stress disorder (PTSD), we propose that BDNF genotype and neuroimaging may be useful as biomarkers to provide guidance for more customized therapeutic directions. The aim of this paper is to review the available knowledge on the BDNF Val66Met SNP, with emphasis on anxiety- and fear related endophenotypes and its potential implications for PTSD. PMID- 20955339 TI - Psychiatric and neurologic aspects of war: concluding comments on the ARNMD conference. AB - These concluding remarks address some of the main disorders that were described during the 89th Annual Conference of the Association for Research in Nervous and Mental Disease entitled "Psychiatric and Neurologic Aspects of War," held December 16, 2009 at The Rockefeller University, New York, New York. Brief remarks are also made on the roles of clinical scientists to consider some of the diagnostic, therapeutic, and societal elements that were discussed at the conference. PMID- 20955340 TI - Isoproterenol facilitation of slow pathway ablation in incessant dual atrioventricular nodal nonreentrant tachycardia. AB - Catheter ablation of the slow atrioventricular (AV) nodal pathway is the treatment of choice for dual AV nodal nonreentrant tachycardia. Rapid ventricular rates during incessant tachycardia may compromise catheter stability and increase the risk of AV block. Conduction via the slow AV nodal pathway may mimic junctional beats with retrograde block, which is an indicator to cease ablation. We report a case of incessant dual AV nodal nonreentrant tachycardia where intravenous isoproterenol was instrumental in facilitating catheter ablation by eliminating these two factors. PMID- 20955341 TI - Limitations of the db/db mouse in translational wound healing research: Is the NONcNZO10 polygenic mouse model superior? AB - Murine models have provided valuable insights into the pathogenesis of both diabetes and chronic wounds. However, only a few published reports to date have investigated wound healing differences among the differing diabetic mouse models. The goal of the present study was to further define the wound healing deficiency phenotypes of streptozotocin-induced (STZ-induced), Akita, and db/db diabetic mice in comparison with a promising new polygenic strain of Type 2 diabetes (NONcNZO10) by using three specific wound models that targeted different critical processes in the pathogenesis of chronic wounds. Incisional, excisional, and ischemia/reperfusion wound models were established on mice of each strain. Wound healing parameters including tensile strength, epithelial gap, and wound necrosis were evaluated. In contrast to the other diabetic mice, the NONcNZO10 strain was found to have significant wound healing impairments in all wound healing models. Not only do the NONcNZO10 mice appear to better model human Type 2 diabetes, these provocative findings suggest that the mice may show more clinically relevant wound healing deficiencies than previous diabetic mouse models. PMID- 20955342 TI - Incidental dual atrioventricular nodal physiology in children and adolescents: clinical follow-up and implications. AB - BACKGROUND: Dual atrioventricular (AV) nodal physiology is a substrate for the development of AV nodal reentrant tachycardia (AVNRT). However, the risk of developing AVNRT in patients with dual AV nodal physiology is not known. The purpose of this study is to identify the risk of developing AVNRT in children and adolescents with incidental findings of dual AV nodal physiology after accessory pathway ablation. METHODS: This is a single center retrospective study of patients who underwent intracardiac electrophysiology study at The Children's Hospital, Denver, from March 1993 to August 2008, with findings of dual AV nodal physiology after successful ablation of an accessory pathway. Follow-up was obtained by chart review with the primary outcome of recurrent supraventricular tachycardia. Extended clinical follow-up was also achieved through phone contact with patients or parents of patients. RESULTS: Mean age at initial electrophysiology study was 12.8 years (+/-3.7 years). Follow-up was obtained on all 66 patients for a mean duration of 3.1 years (+/-2.8 years). Mean age at follow-up was 15.8 years (+/-4.6 years). Recurrent supraventricular tachycardia occurred in nine of the 66 patients (13.6%). AVNRT was induced in two of the 66 patients (3.0%). CONCLUSION: This study supports the hypothesis that incidental dual AV nodal physiology does not predict AVNRT in children and adolescents with after successful accessory pathway ablation. PMID- 20955343 TI - Local expression of indoleamine 2,3-dioxygenase suppresses T-cell-mediated rejection of an engineered bilayer skin substitute. AB - Engineered skin substitutes (ESSs) comprising both keratinocytes and fibroblasts can afford many advantages over the use of autologous keratinocyte grafts for the treatment of full-thickness and partial-thickness burns. In this study, we investigated the efficacy of a novel ESS containing both genetically altered fibroblasts that express the immunosuppressive factor indoleamine 2,3-dioxygenase (IDO) and primary keratinocytes from a nonautologous source to confer immune protection of xenogeneic cells cultured in a bilayer ESS. The results show that engraftment of IDO expressing skin substitutes on the back of rats significantly improves healing progression over 7 days compared with both nontreated and non IDO-expressing skin substitutes (p<0.001). Immuno-staining of CD3 and CD31 suggests that IDO-expressing skin substitutes significantly suppress T cell infiltration (p<0.001) and improve neovascularization by four-fold (12.6+/-1.2 vs. 3.0+/-1.0 vessel-like structure/high power field), respectively. In conclusion, we found that IDO expression can improve the efficacy of nonautologous ESS for the purpose of wound healing by mitigating T-cell infiltration as well as promoting vascularization of the graft. PMID- 20955344 TI - Mesenchymal stem cells' interaction with skin: wound-healing effect on fibroblast cells and skin tissue. AB - Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the ability to secrete growth factors. Because wound healing is associated with fibroblast cells and extracellular matrix (ECM) in the dermis and epidermis, we used fibroblast cells to resolve the question of whether or not MSCs regulate wound healing in vitro via a regenerative function. Using a cell proliferation assay, we demonstrated that conditioned media (CM) obtained from MSCs significantly enhanced the cell survival ability of fibroblast cells. Moreover, by measurement of mRNA and protein, we observed that CM also promoted the production or secretion of collagen, elastin, and fibronectin. To better understand the effects of ECM-related wound healing, we measured the level of collagen-degradative enzyme (matrix metalloprotease-1), and observed that CM suppressed matrix metalloprotease-1 expression. For the determination of oxidative stress, which has an influence on wound healing, we performed the superoxide dismutase and glutathione peroxidase assays; our results suggested that CM inhibited the oxidative stress of fibroblast cells. In order to widely investigate the wound healing effects of MSCs, we performed in vivo experiments, and observed that MSCs stimulated wound healing. In summary, the results of this study suggest that MSCs inhibit the loss of fibroblast cells and ECM, and accumulation of oxidative stress. We found that MSCs stimulate wound healing in vitro and in vivo, suggesting that MSCs have the potential to enhance wound healing. PMID- 20955345 TI - Dynamics of plateau bursting depending on the location of its equilibrium. AB - We present a mathematical analysis of the dynamics that underlies plateau bursting in models of endocrine cells under variation of the location of the (unstable) equilibrium around which these bursting patterns are organised. We focus primarily on the less well-studied case of pseudo-plateau bursting, but also consider the square-wave case. The behaviour of such models is explained using the theory for systems with multiple time scales and it is well known that the underlying so-called fast subsystem organises their dynamics. However, such results are valid only in a sufficiently small neighbourhood of the singular limit that defines the fast subsystem. Hence, the slow variable (intracellular calcium concentration) must be very slow, which is actually not the case for pseudo-plateau bursting. Furthermore, the theoretical predictions are also only valid for parameter values such that the equilibrium is close to a homoclinic bifurcation occuring in the fast subsystem. In the present study, we use numerical explorations to discuss what happens outside this theoretically known neighbourhood of parameter space. In particular, we consider what happens as the equilibrium moves outside a small neighbourhood of the homoclinic bifurcation that occurs in the fast subsystem, and relatively fast speeds are allowed for the slow variable which is controlled by a relatively large value of a parameter epsilon. The results obtained complement our earlier work [Tsaneva-Atanasova et al. (2010) J Theor Biol264, 1133-1146], which focussed on how the bursting patterns vary with the rate of change epsilon of the slow variable: we fix epsilon and move the equilibrium over the full range of the bursting regime. Our findings show that the transitions between different bursting patterns are rather similar for square-wave and pseudo-plateau bursting, provided that the value of epsilon for the pseudo-plateau-bursting model is chosen so that it is much larger than for the square-wave bursting model. Furthermore, the two families of tonic spiking and plateau bursting, which are generally viewed as two separately generated families, are actually connected into a single family in the two parameter plane through branches of unstable periodic orbits. PMID- 20955347 TI - Regional differences in wound oxygenation during normal healing in an equine model of cutaneous fibroproliferative disorder. AB - Wound repair in horse limbs is often complicated by the development of exuberant granulation tissue (EGT) and excessive scarring while body wounds tend to repair uneventfully. EGT resembles the human keloid. While the events leading to keloid formation are not fully elucidated, tissue hypoxia has been proposed as a major contributing factor. The objective of this study was to investigate tissue oxygen saturation in healing full-thickness wounds created on the horse limb and body, using near-infrared spectroscopy. Spectroscopic reflectance data were collected from both anatomic sites at specific times following wounding. The oxygen saturation values of limb wounds were significantly inferior to those of body wounds during the early period of healing, indicating a temporary, relative state of hypoxia in the former during the inflammatory phase of repair. Horses present a weak, persistent inflammatory response to wounding, especially at the limb level. The relative hypoxia present acutely in limb wounds of horses may promote a feeble yet prolonged inflammatory response, which could interfere with and retard the subsequent phases of healing. Ongoing low-grade inflammation in horse wounds is accompanied by up-regulation of various inflammatory and profibrotic mediators, which might ultimately promote the development of fibroproliferative disorders such as EGT. PMID- 20955346 TI - Improved diabetic wound healing through topical silencing of p53 is associated with augmented vasculogenic mediators. AB - Diabetes is characterized by several poorly understood phenomena including dysfunctional wound healing and impaired vasculogenesis. p53, a master cell cycle regulator, is upregulated in diabetic wounds and has recently been shown to play a regulatory roles in vasculogenic pathways. We have previously described a novel method to topically silence target genes in a wound bed with small interfering (si)RNA. We hypothesized that silencing p53 results in improved diabetic wound healing and augmentation of vasculogenic mediators. Paired 4-mm stented wounds were created on diabetic db/db mice. Topically applied p53 siRNA, evenly distributed in an agarose matrix, was applied to wounds at postwound day 1 and 7 (matrix alone and nonsense siRNA served as controls). Animals were sacrificed at postwound days 10 and 24. Wound time to closure was photometrically assessed, and wounds were harvested for histology, immunohistochemistry, and immunofluorescence. Vasculogenic cytokine expression was evaluated via Western blot, reverse transcription-polymerase chain reaction, and enzyme-linked immunosorbent assay. The ANOVA/t-test was used to determine significance (p<= 0.05). Local p53 silencing resulted in faster wound healing with wound closure at 18+/-1.3 d in the treated group vs. 28+/-1.0 d in controls. The treated group demonstrated improved wound architecture at each time point while demonstrating near-complete local p53 knockdown. Moreover, treated wounds showed a 1.92-fold increase in CD31 endothelial cell staining over controls. Western blot analysis confirmed near-complete p53 knockdown in treated wounds. At day 10, VEGF secretion (enzyme-linked immunosorbent assay) was significantly increased in treated wounds (109.3+/-13.9 pg/mL) vs. controls (33.0+/-3.8 pg/mL) while reverse transcription-polymerase chain reaction demonstrated a 1.86-fold increase in SDF 1 expression in treated wounds vs. controls. This profile was reversed after the treated wounds healed and before closure of controls (day 24). Augmented vasculogenic cytokine profile and endothelial cell markers are associated with improved diabetic wound healing in topical gene therapy with p53 siRNA. PMID- 20955348 TI - Unsuspected pulmonary emboli adversely impact survival in patients with cancer undergoing routine staging multi-row detector computed tomography scanning. AB - BACKGROUND: While symptomatic venous thromboembolism adversely impacts survival among cancer patients, the outcome of cancer patients with unsuspected pulmonary embolism (UPE) found on routine cancer staging multi-row detector computed tomography (MDCT) scans is unknown. OBJECTIVE: To determine whether UPE detected on routine staging MDCT scans impacts overall survival among cancer patients. PATIENTS AND METHODS: We performed a matched cohort study of cancer patients diagnosed with UPE on routine staging scans between May 2003 and August 2006. Two controls (n = 137) were individually matched by age (+/- 5 years), cancer type and stage for each UPE patient (n = 70). We used Cox's proportional hazard models to compare the mortality between UPE patients and their matched controls. RESULTS: The hazard ratio (HR) for death among UPE patients was 1.51 (95% CI 1.01 2.27, P = 0.048). Compared with their matched controls, patients with UPE more proximal than the subsegmental arterial branches had a HR for death at 6 months of 2.28 (95% CI 1.20-4.33, P = 0.011) and an overall HR of 1.70 (95% CI 1.06 2.74, P = 0.027). Survival among UPE patients with isolated subsegmental PE (ISSPE) was not significantly different than that of matched controls (HR 1.04 95% CI 0.44-2.39, P = 0.92). CONCLUSIONS: UPE identified more proximal than the subsegmental arterial branches has a significant negative impact on survival among cancer patients. PMID- 20955349 TI - Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease. AB - BACKGROUND: Previous studies have demonstrated considerable variation in the antiplatelet effect of aspirin. OBJECTIVES: To investigate the impact of platelet turnover on the antiplatelet effect of aspirin in patients with stable coronary artery disease (CAD) and to identify determinants of platelet turnover. METHODS: Platelet turnover was evaluated by measurements of immature platelets and thrombopoietin in 177 stable CAD patients on aspirin monotherapy, including 85 type 2 diabetics and 92 non-diabetics. Whole blood platelet aggregation was determined using the VerifyNow((r)) Aspirin test and multiple electrode aggregometry (MEA, Multiplate((r)) ) induced by arachidonic acid (AA) (1.0 mm), adenosine diphosphate (ADP) (10 MUm) and collagen (1.0 MUg mL(-1) ). RESULTS: Immature platelet levels significantly correlated with MEA (r = 0.31-0.36, P values < 0.0001) and the platelet activation marker sP-selectin (r = 0.19, P = 0.014). Contrary to the VerifyNow((r)) test, MEA significantly correlated with variations in platelet count (r = 0.45-0.68, P-values < 0.0001). Among patients with residual platelet reactivity according to AA, there were significantly more diabetics (61% vs. 41%, P = 0.027) and higher levels of sP-selectin (77.7 +/- 29 vs. 70.2 +/- 25 ng mL(-1) , P = 0.070) and serum thromboxane B(2) (0.81 [0.46; 1.70] vs. 0.56 [0.31; 1.12] ng mL(-1) , P = 0.034). In a multivariate regression analysis, immature platelet levels were determined by thrombopoietin levels (P < 0.001), smoking (P = 0.020) and type 2 diabetes (P = 0.042). CONCLUSIONS: The antiplatelet effect of aspirin was reduced in CAD patients with an increased platelet turnover. Once-daily dosing of aspirin might not suffice to adequately inhibit platelet aggregation in patients with an increased platelet turnover. PMID- 20955351 TI - Becoming baby-friendly in Spain: a quality-improvement process. AB - AIM: To describe the implementation process and effect of a quality-improvement intervention aimed at achieving compliance with the Baby-friendly Hospital Initiative (BFHI). METHODS: We conducted a prospective study of the development and evaluation of a quality-improvement intervention at the Yecla Hospital, Spain. A random sample of 1273 infants born in the hospital was followed up in primary care centres between 1997 and 2005. The study interventions were process oriented training, audit and feedback, quality-improvement cycles and provision of breastfeeding support resources. The main outcome measures were changes in compliance with the Global Criteria for the BFHI and breastfeeding rates before, during and after the intervention. RESULTS: Compliance with the Global Criteria increased progressively, and in 2004 all criteria were met. The median duration of breastfeeding went up gradually from the start of the intervention. The likelihood of being breastfed at different ages among infants born in 2005 was between 45% [odds ratio (OR) 0.55; 95% confidence interval (CI) 0.38-0.79] and 86% (OR 0.14; 95% CI 0.09-0.20) higher than among infants born in 1997. CONCLUSION: Quality-improvement interventions based on participation, training, audit and feedback of information, and provision of resources are useful for the implementation of the BFHI, which is associated with a significant increase in breastfeeding rates. PMID- 20955350 TI - Loss of Klotho during melanoma progression leads to increased filamin cleavage, increased Wnt5A expression, and enhanced melanoma cell motility. AB - We have previously shown that Wnt5A-mediated signaling can promote melanoma metastasis. It has been shown that Wnt signaling is antagonized by the protein Klotho, which has been implicated in aging. We show here that in melanoma cells, expressions of Wnt5A and Klotho are inversely correlated. In the presence of recombinant Klotho (rKlotho), we show that Wnt5A internalization and signaling is decreased in high Wnt5A-expressing cells. Moreover, in the presence of rKlotho, we observe an increase in Wnt5A remaining in the medium, coincident with an increase in sialidase activity, and decrease in syndecan expression. These effects can be inhibited using a sialidase inhibitor. In addition to its effects on Wnt5A internalization, we also demonstrate that Klotho decreases melanoma cell invasive potential by a second mechanism that involves the inhibition of calpain and a resultant decrease in filamin cleavage, which we demonstrate is critical for melanoma cell motility. PMID- 20955353 TI - Diagnostic difficulties in the classification of transient neurological attacks. AB - BACKGROUND: It is frequently difficult to distinguish transient ischaemic attacks (TIA) from other transient (<24 h) neurological attacks (TNA). We aimed to classify patients with TNA and identify the most frequent problems in establishing a diagnosis. METHODS: Analysis of a consecutive cohort of patients referred to a TIA Clinic during 5 years. TNA were classified as TIA, mimic and difficult to classify/possible TIA. Reasons limiting classification were listed and grouped. RESULTS: Four hundred and fifty-eight patients were included. Diagnoses were as follows: TIA-259 (56.6%), mimic-90 (19.7%) and difficult to classify/possible TIA-109 (23.8%). Amongst the 109 patients, main difficulties in the differential diagnosis were between TIA and seizure, psychiatric disturbance, peripheral vertigo, pre-syncope and metabolic condition. The reasons contributing for classification difficulties were as follows: atypical symptoms (49 patients), paucity of details in symptoms description (24 patients), presence of focal symptoms accompanying psychiatric symptoms (anxiety or panic) (12 patients), restraints formulated by current criteria of TIA and migraine (16 patients), previous neurological deficit (eight patients). CONCLUSION: This systematic study identified distinct groups of reasons limiting the diagnosis of TNA. Different clinical approaches should be applied according to specific reasons for classification difficulty. These strategies may help to clarify the aetiology of transient neurological symptoms and improve TIA diagnosis. PMID- 20955352 TI - Oxygen tension modulates the cytokine response of oral epithelium to periodontal bacteria. AB - BACKGROUND: There is an inverse relationship between pocket depth and pocket oxygen tension with deep pockets being associated with anaerobic bacteria. However, little is known about how the host tissues respond to bacteria under differing oxygen tensions within the periodontal pocket. AIM: To investigate the effect of different oxygen tensions upon nuclear factor-kappa B (NF-kappaB) activation and the inflammatory cytokine response of oral epithelial cells when exposed to nine species of oral bacteria. MATERIALS AND METHODS: H400 oral epithelial cells were equilibrated at 2%, 10% or 21% oxygen. Cells were stimulated with heat-killed oral bacteria at multiplicity of infection 10:1, Escherichia coli lipopolysaccharide (15 MUg/ml) or vehicle control. Interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha) levels were measured by enzyme-linked immunosorbent assay and NF-kappaB activation was measured by reporter vector or by immunohistochemical analysis. RESULTS: Tannerella forsythensis, Porphyromonas gingivalis and Prevotella intermedia elicited the greatest epithelial NF-kappaB activation and cytokine responses. An oxygen tension-dependent trend in cytokine production was observed with the highest IL-8 and TNF-alpha production observed at 2% oxygen and lowest at 21% oxygen. CONCLUSIONS: These data demonstrate a greater pro-inflammatory host response and cell signalling response to bacteria present in more anaerobic conditions, and hypersensitivity of epithelial cells to pro-inflammatory stimuli at 2% oxygen, which may have implications for disease pathogenesis and/or therapy. PMID- 20955354 TI - Outcome of different post-orchiectomy management for stage I seminoma: Japanese multi-institutional study including 425 patients. AB - OBJECTIVES: To clarify the contemporary clinical outcome of stage I seminoma and to provide information on treatment options to patients. METHODS: A retrospective analysis of 425 patients who underwent orchiectomy for stage I seminoma between 1985 and 2006 at 25 hospitals in Japan. Relapse-free survival rates were calculated using the Kaplan-Meier method and clinicopathological factors associated with relapse were examined by univariate and multivariate analyses using the Cox proportional hazards model. RESULTS: A total of 30 out of 425 patients had relapsed. Relapse-free survival rates at 10 years were 79, 94 and 94% in the surveillance, chemotherapy and radiotherapy groups, respectively. Post orchiectomy management and rete testis invasion were identified as independent predictive factors associated with relapse. Rete testis invasion remained to be an independent predictive factor, even if the cases with relapses in the contralateral testis were censored. Only one patient, who relapsed after adjuvant radiotherapy, died of the disease. Overall survival at 10 years was 100, 100 and 99% in the surveillance, chemotherapy and radiotherapy groups, respectively. More than half of the patients were lost to follow up within 5 years. CONCLUSIONS: The outcome of Japanese patients with stage I seminoma is similar to previously published Western reports. Surveillance policy is becoming a popular option in Japan, although the relapse rate in patients opting for surveillance policy is higher than those opting for adjuvant chemotherapy or radiotherapy. Rete testis invasion is an independent predictive factor associated with relapse regardless of the post-orchiectomy management. Long-term follow up is mandatory for detection of late relapse. PMID- 20955355 TI - Cohort profile: the German ClinSurv HIV project--a multicentre open clinical cohort study supplementing national HIV surveillance. AB - BACKGROUND: New forms of HIV/AIDS therapy require new surveillance instruments to meet shifting public health demands. The Clinical Surveillance of HIV Disease (ClinSurv HIV) project was established in 1999 as a collaboration between major HIV treatment centres in Germany and the Robert Koch Institute (RKI). The project contributes to national HIV surveillance and focuses on the changing epidemiology of HIV/AIDS after the introduction of new therapies in 1995. METHODS: ClinSurv HIV is designed as an open multicentre observational cohort study of HIV-infected patients. Anonymized data on diagnoses, treatment and laboratory parameters are collected in a standardized format. Data are currently sampled biannually via 11 centres specializing in HIV diagnosis and care within the legal framework of the German Protection against Infection Act [Infektionsschutzgesetz (IfSG)]. RESULTS: A total of 14874 patients were enrolled in the study by 30 June 2009. Of these, 10221 patients (68.7%) were enrolled after 1 January 1999 and 6006 patients (40.4%) were known to have been diagnosed as positive for HIV before 1999. Evaluation indicators, such as the number of newly enrolled patients per half year period, loss to follow-up, completeness of data per case, availability of data per possible clinical contact, and internal quality control parameters, show a very stable evolution in the cohort, which although open, can be observed. Comparison with the national HIV surveillance data suggests a high degree of representativeness according to major demographic variables. CONCLUSION: Bearing in mind the obvious strengths and weaknesses discussed, the German ClinSurv HIV cohort provides a broad range of research opportunities in the field of HIV/AIDS both within Germany and in international collaborative research. PMID- 20955356 TI - Trends over time of virological and immunological characteristics in the Swiss HIV Cohort Study. AB - BACKGROUND: The long-term outcome of antiretroviral therapy (ART) is not assessed in controlled trials. We aimed to analyse trends in the population effectiveness of ART in the Swiss HIV Cohort Study over the last decade. METHODS: We analysed the odds of stably suppressed viral load (ssVL: three consecutive values <50 HIV 1 RNA copies/mL) and of CD4 cell count exceeding 500 cells/MUL for each year between 2000 and 2008 in three scenarios: an open cohort; a closed cohort ignoring the influx of new participants after 2000; and a worst-case closed cohort retaining lost or dead patients as virological failures in subsequent years. We used generalized estimating equations with sex, age, risk, non-White ethnicity and era of starting combination ART (cART) as fixed co-factors. Time updated co-factors included type of ART regimen, number of new drugs and adherence to therapy. RESULTS: The open cohort included 9802 individuals (median age 38 years; 31% female). From 2000 to 2008, the proportion of participants with ssVL increased from 37 to 64% [adjusted odds ratio (OR) per year 1.16 (95% CI 1.15-1.17)] and the proportion with CD4 count >500 cells/MUL increased from 40 to >50% [OR 1.07 (95% CI 1.06-1.07)]. Similar trends were seen in the two closed cohorts. Adjustment did not substantially affect time trends. CONCLUSIONS: There was no relevant dilution effect through new participants entering the open clinical cohort, and the increase in virological/immunological success over time was not an artefact of the study design of open cohorts. This can partly be explained by new treatment options and other improvements in medical care. PMID- 20955357 TI - Efficacy, tolerability and risk factors for virological failure of darunavir based therapy for treatment-experienced HIV-infected patients: the Swiss HIV Cohort Study. AB - OBJECTIVES: Darunavir was designed for activity against HIV resistant to other protease inhibitors (PIs). We assessed the efficacy, tolerability and risk factors for virological failure of darunavir for treatment-experienced patients seen in clinical practice. METHODS: We included all patients in the Swiss HIV Cohort Study starting darunavir after recording a viral load above 1000 HIV-1 RNA copies/mL given prior exposure to both PIs and nonnucleoside reverse transcriptase inhibitors. We followed these patients for up to 72 weeks, assessed virological failure using different loss of virological response algorithms and evaluated risk factors for virological failure using a Bayesian method to fit discrete Cox proportional hazard models. RESULTS: Among 130 treatment-experienced patients starting darunavir, the median age was 47 years, the median duration of HIV infection was 16 years, and 82% received mono or dual antiretroviral therapy before starting highly active antiretroviral therapy. During a median patient follow-up period of 45 weeks, 17% of patients stopped taking darunavir after a median exposure of 20 weeks. In patients followed beyond 48 weeks, the rate of virological failure at 48 weeks was at most 20%. Virological failure was more likely where patients had previously failed on both amprenavir and saquinavir and as the number of previously failed PI regimens increased. CONCLUSIONS: As a component of therapy for treatment-experienced patients, darunavir can achieve a similar efficacy and tolerability in clinical practice to that seen in clinical trials. Clinicians should consider whether a patient has failed on both amprenavir and saquinavir and the number of failed PI regimens before prescribing darunavir. PMID- 20955358 TI - Anti-inflammatory and monocyte-suppressing effects of simvastatin in patients with impaired fasting glucose. AB - The aim of our study was to compare the effect of simvastatin on systemic inflammation and monocyte secretory function between individuals with impaired fasting glucose (IFG) and patients with isolated hypercholesterolaemia. The study included 25 patients with IFG and 23 patients with hypercholesterolaemia. The lipid profile, fasting and 2-hr post-glucose load plasma glucose levels, homeostatic model assessment (HOMA) ratio, glycated haemoglobin, plasma high sensitivity C-reactive protein (hsCRP) levels and monocyte release of TNF-alpha, interleukin-1beta, interleukin-6 and MCP-1 were assessed at baseline, and after 30 and 90 days of simvastatin treatment (20 mg/daily). Compared to monocytes of the control patients (22 age-, sex- and weight-matched patients without lipid and glucose metabolism abnormalities), monocytes of the patients with hypercholesterolaemia and patients with IFG released greater amounts of all studied cytokines and exhibited higher plasma levels of hsCRP, with no difference between the two groups of patients. Although in both the patients with hypercholesterolaemia and the patients with IFG simvastatin treatment improved lipid profile, it exhibited no effect on glucose metabolism markers. The drug markedly reduced plasma hsCRP and monocyte secretion of TNF-alpha, interleukin 1beta, interleukin-6 and MCP-1 in a lipid- and glucose-independent manner. Our results indicate that low-grade systemic inflammation and monocyte secretory function are disturbed to a similar degree in the patients with isolated hypercholesterolaemia and in the patients with IFG. They also show that simvastatin is an effective anti-inflammatory drug in patients with isolated early glucose metabolism abnormalities. PMID- 20955359 TI - In vitro approaches to evaluate placental drug transport by using differentiating JEG-3 human choriocarcinoma cells. AB - Human choriocarcinoma cells have been used as models for studying transcellular drug transport through placental trophoblasts. However, these models allow the transport of low-molecular-weight drugs through intercellular gap junctions. This study aimed at investigating the differentiation patterns of JEG-3 choriocarcinoma cells under different culture conditions and establishing the appropriate model of in vitro syncytiotrophoblast drug transport. Paracellular permeability was estimated by measuring the transepithelial electrical resistance (TEER) across JEG-3 cell layers. The mRNA expression levels of non-expressed in choriocarcinoma clone 1 (NECC1) and breast cancer resistance protein (BCRP), and those of E-cadherin (ECAD) and cadherin-11 (CDH11), which are adherens junction associated proteins related to fusogenic ability of syncytiotrophoblasts differentiated from cytotrophoblasts, protein expression levels were considered as the differentiation signals. The highest TEER values were obtained in the JEG 3 cells cultured in the Dulbecco's modified Eagle's medium (DMEM)/Ham's F-12 (1:1) mixed medium (CS-C((r)) ; Dainippon Sumitomo Pharma Co. Ltd., Osaka, Japan). By comparing the TEER values and the differentiation signals, the authors identified at least five JEG-3 cell-differentiation patterns. The differentiation pattern of JEG-3 cultured in CS-C resembled the syncytiotrophoblast-like differentiation signal characterizations in vivo. In conclusion, the syncytiotrophoblast-like models of differentiating JEG-3 cells cultured in CS-C might be appropriate for evaluating drug transport across the placental trophoblast. PMID- 20955360 TI - Zerumbone-induced antinociception: involvement of the L-arginine-nitric oxide cGMP -PKC-K+ ATP channel pathways. AB - This study investigated the antinociceptive effects of zerumbone in chemical behavioural models of nociception in mice. Zerumbone given through intraperitoneal route (i.p.) produced dose-related antinociception when assessed on acetic acid-induced abdominal writhing test in mice. In addition, the i.p. administration of zerumbone exhibited significant inhibition of the neurogenic pain induced by intraplantar (i.pl.) injection of capsaicin and bradykinin. Likewise, zerumbone given by i.p. route reduced the nociception produced by i.pl. injection of glutamate and phorbol myristate acetate (PMA). The antinociception caused by zerumbone in the acetic acid test was significantly attenuated by i.p. pre-treatment of mice with l-arginine (nitric oxide precursor) and glibenclamide (ATP-sensitive K(+) channel inhibitor). However, the antinociception of zerumbone was enhanced by methylene blue (non-specific gyanylyl cyclase inhibitor). Together, these results indicate that zerumbone produces pronounced antinociception against chemical models of nociception in mice. It also strongly suggests that the l-arginine-nitric oxide-cGMP-PKC-K(+) ATP channel pathways, the TRPV1 and kinin B2 receptors play an important role in the zerumbone-induced antinociception. PMID- 20955361 TI - Barriers to adaptive reasoning in community ecology. AB - Recent high-profile calls for a more trait-focused approach to community ecology have the potential to open up novel research areas, generate new insights and to transform community ecology into a more predictive science. However, a renewed emphasis on function and phenotype also requires a fundamental shift in approach and research philosophy within community ecology to more fully embrace evolutionary reasoning. Such a subject-wise transformation will be difficult due to at least four factors: (1) the historical development of the academic discipline of ecology and its roots as a descriptive science; (2) the dominating role of the ecosystem concept in the driving of contemporary ecological thought; (3) the practical difficulties associated with defining and identifying (phenotypic) adaptations, and; (4) scaling effects in ecology; the difficulty of teasing apart the overlapping and shifting hierarchical processes that generate the observed environment-trait correlations in nature. We argue that the ability to predict future ecological conditions through a sufficient understanding of ecological processes will not be achieved without the placement of the concept of adaptation at the centre of ecology, with influence radiating outwards through all the related (and rapidly specializing) sub-disciplines. PMID- 20955362 TI - Anti-inflammatory effects of the anticonvulsant drug levetiracetam on electrophysiological properties of astroglia are mediated via TGFbeta1 regulation. AB - BACKGROUND AND PURPOSE: The involvement of astrocytes as immune-competent players in inflammation and the pathogenesis of epilepsy and seizure-induced brain damage has recently been recognized. In clinical trials and practice, levetiracetam (LEV) has proven to be an effective antiepileptic drug (AED) in various forms of epileptic seizures, when applied as mono- or added therapy. Little is known about the mechanism(s) of action of LEV. Evidence so far suggests a mode of action different from that of classical AEDs. We have shown that LEV restored functional gap junction coupling and basic membrane properties in an astrocytic inflammatory model in vitro. EXPERIMENTAL APPROACH: Here, we used neonatal rat astrocytes co cultured with high proportions (30%) of activated microglia or treated with the pro-inflammatory cytokine interleukin-1beta to provoke inflammatory responses. Effects of LEV (50 ug.mL-1) on electrophysiological properties of astrocytes (by whole cell patch clamp) and on secretion of TGFbeta1 (by (ELISA)) were studied in these co-cultures. KEY RESULTS: LEV restored impaired astrocyte membrane resting potentials via modification of inward and outward rectifier currents, and promoted TGFbeta1 expression in inflammatory and control co-cultures. Furthermore, LEV and TGFbeta1 exhibited similar facilitating effects on the generation of astrocyte voltage-gated currents in inflammatory co-cultures and the effects of LEV were prevented by antibody to TGFbeta1. CONCLUSIONS AND IMPLICATIONS: Our data suggest that LEV is likely to reduce the harmful spread of excitation elicited by seizure events within the astro-glial functional syncytium, with stabilizing consequences for neuronal-glial interactions. PMID- 20955363 TI - Interaction of prostanoid EP3 and TP receptors in guinea-pig isolated aorta: contractile self-synergism of 11-deoxy-16,16-dimethyl PGE2. AB - BACKGROUND AND PURPOSE: Surprisingly high contractile activity was reported for 11-deoxy-16,16-dimethyl prostaglandin E2 (DX-DM PGE2) on pig cerebral artery when used as a selective EP3 receptor agonist. This study investigated the selectivity profile of DX-DM PGE2, focusing on the interaction between its EP3 and TP (thromboxane A2-like) agonist activities. EXPERIMENTAL APPROACH: Contraction of guinea-pig trachea (EP1 system) and aorta (EP3 and TP systems) was measured in conventional organ baths. KEY RESULTS: Strong contraction of guinea-pig aorta to sulprostone and 17-phenyl PGE2 (EP3 agonists) was only seen under priming with a second contractile agent such as phenylephrine, histamine or U-46619 (TP agonist). In contrast, DX-DM PGE2 induced strong contraction, which on the basis of treatment with (DG)-3ap (EP3 antagonist) and/or BMS-180291 (TP antagonist) was attributed to self-synergism arising from co-activation of EP3 and TP receptors. EP3/TP self-synergism also accounted for contraction induced by PGF(2alpha) and its analogues (+)-cloprostenol and latanoprost-FA. DX-DM PGE2 also showed significant EP1 agonism on guinea-pig trachea as defined by the EP1 antagonists SC-51322, (ONO)-5-methyl-1 and AH-6809, although AH-6809 exhibited poor specificity at concentrations >=3 uM. CONCLUSIONS AND IMPLICATIONS: EP3/TP self synergism, as seen with PGE/PGF analogues in this study, may confound EP3 agonist potency comparisons and the characterization of prostanoid receptor systems. The competitive profile of a TP antagonist may be distorted by variation in the silent/overt contraction profile of the EP3 system in different studies. The relevance of self-synergism to in vivo actions of natural prostanoid receptor agonists is discussed. PMID- 20955364 TI - Comparative bioactivation of the novel anti-tuberculosis agent PA-824 in Mycobacteria and a subcellular fraction of human liver. AB - BACKGROUND AND PURPOSE: PA-824 is a 2-nitroimidazooxazine prodrug currently in Phase II clinical trial for tuberculosis therapy. It is bioactivated by a deazaflavin (F(420) )-dependent nitroreductase (Ddn) isolated from Mycobacterium tuberculosis to form a des-nitro metabolite. This releases toxic reactive nitrogen species which may be responsible for its anti-mycobacterial activity. There are no published reports of mammalian enzymes bioactivating this prodrug. We have investigated the metabolism of PA-824 following incubation with a subcellular fraction of human liver, in comparison with purified Ddn, M. tuberculosis and Mycobacterium smegmatis. EXPERIMENTAL APPROACH: PA-824 (250 uM) was incubated with the 9000 * g supernatant (S9) of human liver homogenates, purified Ddn, M. tuberculosis and M. smegmatis for metabolite identification by liquid chromatography mass spectrometry analysis. KEY RESULTS: PA-824 was metabolized to seven products by Ddn and M. tuberculosis, with the major metabolite being the des-nitro product. Six of these products, but not the des nitro metabolite, were also detected in M. smegmatis. In contrast, only four of these metabolites were observed in human liver S9; M3, a reduction product previously proposed as an intermediate in the Ddn-catalyzed des-nitrification and radiolytic reduction of PA-824; two unidentified metabolites, M1 and M4, which were products of M3; and a haem-catalyzed product of imidazole ring hydration (M2). CONCLUSIONS AND IMPLICATIONS: PA-824 was metabolized by des-nitrification in Ddn and M. tuberculosis, but this does not occur in human liver S9 and M. smegmatis. Thus, PA-824 was selectively bioactivated in M. tuberculosis and there was no evidence for 'cross-activation' by human enzymes. PMID- 20955365 TI - Critical role of the JNK-p53-GADD45alpha apoptotic cascade in mediating oxidative cytotoxicity in hippocampal neurons. AB - BACKGROUND AND PURPOSE: Glutamate-induced oxidative stress plays a critical role in the induction of neuronal cell death in a number of disease states. We sought to determine the role of the c-Jun NH(2) -terminal kinase (JNK)-p53-growth arrest and DNA damage-inducible gene (GADD) 45alpha apoptotic cascade in mediating glutamate-induced oxidative cytotoxicity in hippocampal neuronal cells. EXPERIMENTAL APPROACH: HT22 cells, a mouse hippocampal neuronal cell line, were treated with glutamate to induce oxidative stress in vitro. Kainic acid-induced oxidative damage to the hippocampus in rats was used as an in vivo model. The signalling molecules along the JNK-p53-GADD45alpha cascade were probed with various means to determine their contributions to oxidative neurotoxicity. KEY RESULTS: Treatment of HT22 cells with glutamate increased the mRNA and protein levels of GADD45alpha, and these increases were suppressed by p53 knock-down. Knock-down of either p53 or GADD45alpha also prevented glutamate-induced cell death. Glutamate-induced p53 activation was preceded by accumulation of reactive oxygen species, and co-treatment with N-acetyl-cysteine prevented glutamate induced p53 activation and GADD45alpha expression. Knock-down of MKK4 or JNK, or the presence of SP600125 (a JNK inhibitor), each inhibited glutamate-induced p53 activation and GADD45alpha expression. In addition, we also confirmed the involvement of GADD45alpha in mediating kainic acid-induced hippocampal oxidative neurotoxicity in vivo. CONCLUSIONS: AND IMPLICATIONS Activation of the JNK-p53 GADD45alpha cascade played a critical role in mediating oxidative cytotoxicity in hippocampal neurons. Pharmacological inhibition of this signalling cascade may provide an effective strategy for neuroprotection. PMID- 20955366 TI - Down-regulation of some miRNAs by degrading their precursors contributes to anti cancer effect of mistletoe lectin-I. AB - BACKGROUND AND PURPOSE: Mistletoe lectin-I (ML-I), the main anti-cancer component of mistletoe extracts, was originally thought to act exclusively on 28S rRNA. Here, we investigate the down-regulating effect and mechanism of CM-1, an ML-I isolated from Chinese mistletoe, on some miRNAs. EXPERIMENTAL APPROACH: The anti cancer effects of CM-1 were assessed in vitro and in vivo in colorectal cancer cells. The miRNAs down-regulated by CM-1 were identified by miRNA microarray assay and validated by qRT-PCR analysis. The suppression of host gene transcription or by degradation of precursors was determined by qRT-PCR and enzyme activity assays respectively. The qRT-PCR, Western blot and immunohistochemistry were used to examine the expression of their target gene and related downstream effector. Cell proliferation was assayed in stably transfected HEK-293 cells with different levels of these miRNAs. KEY RESULTS: CM-1 showed prominent anti-neoplastic activity towards CLY and HT-29 cells both in vitro and in vivo. The miR-135a&b were the miRNAs most down-regulated by CM-1. Their host gene transcription was largely up-regulated, while their precursors were degraded directly by CM-1. The expression of their target gene adenomatous polyposis coli and the phosphorylation of related effector beta-catenin were both significantly up-regulated. The IC(50) values of CM-1 on derivative HEK-293 cells with high miR 135a&b levels were 2-4 times lower than that of control cells. CONCLUSIONS AND IMPLICATIONS: CM-1 down-regulated some miRNAs by degrading their precursors, which contributes to its prominent anti-cancer activity. PMID- 20955367 TI - Myocardial oxidative stress contributes to transgenic beta2-adrenoceptor activation-induced cardiomyopathy and heart failure. AB - BACKGROUND AND PURPOSE: While maintaining cardiac performance, chronic beta adrenoceptor activation eventually exacerbates the progression of cardiac remodelling and failure. We examined the adverse signalling pathways mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS) after chronic beta2-adrenoceptor activation. EXPERIMENTAL APPROACH: Mice with transgenic beta2-adrenoceptor overexpression (beta2-TG) and non transgenic littermates were either untreated or treated with an antioxidant (N acetylcysteine, NAC) or NADPH oxidase inhibitors (apocynin, diphenyliodonium). Levels of ROS, phosphorylated p38 mitogen-activated protein kinase (MAPK), pro inflammatory cytokines and collagen content in the left ventricle (LV) and LV function were measured and compared. KEY RESULTS: beta2-TG mice showed increased ROS production, phosphorylation of p38 MAPK and heat shock protein 27 (HSP27), expression of pro-inflammatory cytokines and collagen, and progressive ventricular dysfunction. beta2-adrenoceptor stimulation similarly increased ROS production and phosphorylation of p38 MAPK and HSP27 in cultured cardiomyocytes. Treatment with apocynin, diphenyliodonium or NAC reduced phosphorylation of p38 MAPK and HSP27 in both cultured cardiomyocytes and the LV of beta2-TG mice. NAC treatment (500 mg.kg-1 .day-1) for 2 weeks eliminated the up-regulated expression of pro-inflammatory cytokines and collagen in the LV of beta2-TG mice. Chronic NAC treatment to beta2-TG mice from 7 to 10 months of age largely prevented progression of ventricular dilatation, preserved contractile function (fractional shortening 37 +/- 5% vs. 25 +/- 3%, ejection fraction 52 +/- 5% vs. 32 +/- 4%, both P < 0.05), reduced cardiac fibrosis and suppressed matrix metalloproteinase activity. CONCLUSION AND IMPLICATIONS: beta2-adrenoceptor stimulation provoked NADPH oxidase-derived ROS production in the heart. Elevated ROS activated p38 MAPK and contributed significantly to cardiac inflammation, remodelling and failure. PMID- 20955369 TI - Aetiology of community-acquired pneumonia in hospitalized adult patients in New Caledonia. AB - OBJECTIVE: To describe the aetiology of community-acquired pneumonia (CAP) in hospitalized adult patients in New Caledonia, a French archipelago in the South Pacific. METHODS: Confirmed CAP patients (n=137) were enrolled prospectively. Pathogens were detected by culture, molecular methods, serology on paired sera, immunofluorescence on nasopharyngeal swabs and antigen detection in urine. RESULTS: The aetiology of CAP was determined in 82 of 137 cases (59.8%), of which 31 exhibited two or more pathogens (37.8%). Hundred and seventeen pathogens were detected: Streptococcus pneumoniae was the most common one (41.0%), followed by influenza virus A (22.1%) and Haemophilus influenzae (10.2%). The frequency of atypical bacteria was low (6.0%). The most frequent and significant coinfection was S. pneumoniae with influenza A virus (P=0.004). Influenza virus was detected from nasopharyngeal swabs in four patients (15.4% of patients tested for influenza) and by PCR from pulmonary specimens in 15 patients (57.7%). CONCLUSIONS : Pneumoniae is the leading cause of CAP in New Caledonian adults. Viral-bacterial co-infections involving S. pneumoniae and influenza virus are very common during the winter. Such adult patients hospitalized with CAP are a clear sentinel group for surveillance of influenza. Vaccination against influenza and S. pneumoniae should be strengthened when risk factors are identified. PMID- 20955368 TI - The SK3/K(Ca)2.3 potassium channel is a new cellular target for edelfosine. AB - BACKGROUND AND PURPOSE: The 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (edelfosine) is an ether-linked phospholipid with promising anti-cancer properties but some side effects that preclude its full clinical therapeutic exploitation. We hypothesized that this lipid could interact with plasma membrane ion channels and modulate their function. EXPERIMENTAL APPROACH: Using cell migration-proliferation assays, patch clamp, spectrofluorimetry and 125I-Apamin binding experiments, we studied the effects of edelfosine on the migration of breast cancer MDA-MB-435s cells, mediated by the small conductance Ca2(+) activated K(+) channel, SK3/K(Ca)2.3. KEY RESULTS: Edelfosine (1 uM) caused plasma membrane depolarization by substantially inhibiting activity of SK3/K(Ca)2.3 channels, which we had previously demonstrated to play an important role in cancer cell migration. Edelfosine did not inhibit 125I-Apamin binding to this SK(Ca) channel; rather, it reduced the calcium sensitivity of SK3/K(Ca)2.3 channel and dramatically decreased intracellular Ca2(+) concentration, probably by insertion in the plasma membrane, as suggested by proteinase K experiments. Edelfosine reduced cell migration to the same extent as known SK(Ca) channel blockers. In contrast, K+ channel openers prevented edelfosine-induced anti migratory effects. SK3 protein knockdown decreased cell migration and totally abolished the effect of edelfosine on MDA-MB-435s cell migration. In contrast, transient expression of SK3/K(Ca)2.3 protein in a SK3/K(Ca)2.3-deficient cell line increased cell migration and made these cells responsive to edelfosine. CONCLUSIONS AND IMPLICATIONS: Our data clearly establish edelfosine as an inhibitor of cancer cell migration by acting on SK3/K(Ca)2.3 channels and provide insights into the future development of a new class of migration-targeted, anti cancer agents. PMID- 20955370 TI - Human immunodeficiency virus, hepatitis B and hepatitis C in an Indonesian prison: prevalence, risk factors and implications of HIV screening. AB - OBJECTIVE: To determine the prevalence and behavioural correlates of HIV, HBV and HCV infections among Indonesian prisoners and to examine the impact of voluntary counselling and testing for all incoming prisoners on access to antiretroviral treatment (ART). METHODS: In a non-anonymous survey in an Indonesian prison for drug-related offences, all incoming prisoners and symptomatic resident prisoners were counselled and offered testing for HIV, hepatitis B and C. RESULTS: Screening was performed in 679 incoming prisoners, of whom 639 (94.1%) agreed to be tested, revealing a seroprevalence of 7.2% (95% CI 5.2-9.2) for HIV, 5.8% (95% CI 3.9-7.6) for HBsAg and 18.6% (95% CI 15.5-21.6) for HCV. Of 57 resident prisoners tested, 29.8% were HIV-positive. HIV infection was strongly associated with injecting drug use (IDU; P < 0.001), but not with a history of unsafe sex. Screening of incoming prisoners was responsible for diagnosing and treating HIV in 73.0%, respectively, and 68.0% of HIV-positive individuals. CONCLUSIONS: HIV and HCV are highly prevalent among incoming Indonesian prisoners and almost entirely explained by IDU. Our study is the first to show that voluntary HIV counselling and testing during the intake process in prison may greatly improve access to ART in a developing country. PMID- 20955371 TI - Subtype prevalence, plasmid profiles and growing fluoroquinolone resistance in Shigella from Kolkata, India (2001-2007): a hospital-based study. AB - OBJECTIVES: Shigellosis is a major public health problem, and increasing antimicrobial resistance has complicated its treatment. We report isolation frequency, plasmid profiles and antimicrobial resistance of Shigella subtypes in Kolkata, India, from a prospective hospital-based study. METHODS: Fresh stool or rectal swabs were collected from children (<5 years) attending the Diarrhea Treatment Unit of a governmental paediatric referral hospital in Kolkata. Samples were processed following standard methods over a 7-year period from January 2001 to December 2007. RESULTS: Of 4478 samples collected, 516 (11.5%) were positive for Shigella spp. S. flexneri (312; 6.9%) was the most frequently isolated serogroup, ranking before S. sonnei (123, 2.7%), S. dysenteriae (48, 1.1%) and S. boydii (33, 0.7%). Although 10 subtypes of S. flexneri were identified, the common ones circulating locally were S. flexneri 2a (179), S. flexneri 6 (38) and S. flexneri 3a (36). Knowledge of Shigella subtypes is important for vaccine development. The majority of Shigella isolates (81.0%) were multidrug (two or more antimicrobial classes) resistant and showed high minimum inhibitory concentration (MIC) with commonly used drugs like ampicillin, tetracycline, co trimoxazole and nalidixic acid. Emergence of fluoroquinolone (FQ)-resistant S. dysenteriae type 1 (100.0%) in 2002-2003 was followed by frequent isolation (>25.0%) of FQ-resistant S. flexneri 2a, and S. flexneri 3a in 2004, which restricted use of fluoroquinolones for treatment. A number of smaller plasmids (<20 kb) with distinct patterns have been observed for several years in predominant subtypes. CONCLUSION: Long-term surveillance of Shigellae and their antimicrobial resistance are mandatory in endemic areas to formulate treatment policy until any suitable candidate vaccine is available to control the disease. PMID- 20955372 TI - Evaluation of Plasmodium vivax ELISA for the blood screen. AB - Plasmodium vivax malaria is the indigenous strain in the Republic of Korea (ROK). Plasmodium vivax can be transmitted through the transfusions of various blood components, which became a severe problem with the safety of blood transfusions and blood-related products in ROK. We evaluated a P. vivax-specific enzyme-linked immunosorbent assay (Genedia Malaria Ab ELISA 2.0, Green Cross, ROK) with blood samples from four groups: 251 samples from P. vivax-infected patients, 39 samples from post-treatment patients upon follow-up, 200 samples from healthy volunteers and 421 samples from domestic travellers to and from high endemic areas of ROK. The positive cases from the ELISA test were confirmed by both Giemsa microscopic and polymerase chain reaction methods. The clinical sensitivity and specificity of detecting P. vivax with ELISA test were 94.4% and 99.0%, respectively. Thirteen of 421 domestic travellers (3.0%) to endemic areas tested positive. The results indicate the effectiveness of detecting antibodies against P. vivax in blood with Genedia Malaria Ab ELISA 2.0 test in a large blood screen setting. PMID- 20955373 TI - Linking research and development to strengthen health systems in Africa. PMID- 20955374 TI - Nurses as patient navigators in cancer diagnosis: review, consultation and model design. AB - The diagnostic phase of cancer care is an anxious time for patients. Patient navigation is a way of assisting and supporting individuals during this time. The aim of this review is to explore patient navigation and its role in the diagnostic phase of cancer care. We reviewed the literature for definitions and models of navigation, preparation for the role and impact on patient outcomes, specifically addressing the role of the nurse in patient navigation. Interviews and focus groups with healthcare providers and managers provided further insight from these stakeholder groups. Common to most definitions of navigation is the navigator's multifaceted role in facilitating processes of care, assisting patients to overcome barriers and providing information and support. Navigation may be provided by laypersons, clerical staff and/or healthcare professionals. In the diagnostic phase it has the potential to affect efficiency of diagnostic testing, patients' experience during this time and preparation for decision making around treatment options. Patient care during the diagnostic phase requires various levels of navigation, according to individual informational, physical and psychosocial needs. Identifying those individuals who require more support--whether physical or psychosocial--during the diagnostic phase is of critical importance. PMID- 20955375 TI - Mitochondrial activity and morphology in developing porcine oocytes and pre implantation non-cultured and cultured embryos. AB - Mitochondria are important determinants of developmental competence for oocytes and embryos owing to their central role in cellular metabolism, yet mitochondrial activity and morphometry during early porcine development have not been quantified. In this study, we examined the membrane potential Deltapsi(m) and the surface density Sv(in,m) of the inner mitochondrial membrane in pig oocytes and pre-implantation embryos using fluorescent probes and confocal microscopy. Mitochondria and their cristae were also examined by transmission electron microscope. Deltapsi(m) was consistently low from immature oocytes up to morulae and increased significantly in the early blastocyst before decreasing at the expanded blastocyst stage. This stage-dependent pattern of Deltapsi(m) changes differs from that reported for other mammals. We also determined that Deltapsi(m) is lower in cultured when compared to non-cultured porcine early blastocysts. Sv(in,m) was higher in immature oocytes than mature oocytes and remained constant up to the 4- to 8-cell embryo stage. It increased significantly at morula and early blastocyst stages. No differences in Sv(in,m) were found between developmentally matched non-cultured and cultured embryos. These results indicate that the inner mitochondrial membrane potential and surface density change significantly during pre-implantation porcine development in relation to metabolic alterations of the embryo. It is possible that modification of Deltapsi(m) by manipulating culture conditions may improve the performance of embryos that develop in vitro. PMID- 20955376 TI - Comparison of cytology and histology results in English cervical screening laboratories before and after liquid-based cytology conversion: do the data provide evidence for a single category of high-grade dyskaryosis? AB - OBJECTIVE: To determine whether the difference between the positive predictive value (PPV) for cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+) of referral from moderate dyskaryosis and from severe dyskaryosis was reduced after laboratories converted from conventional to liquid-based cytology (LBC). Furthermore, to explore the cytology/histology agreement after LBC conversion, and to determine post-LBC whether there was increased support for the use of one single category of high-grade dyskaryosis (equivalent to high-grade squamous intraepithelial lesion). METHODS: The association between cytology and histology has been examined using annual Korner return data (KC61 returns) collected by laboratories from the English National Health Service cervical screening programme. The study compares return data before and after LBC conversion. RESULTS: The study examined data from 102 laboratories that converted from conventional cytology to LBC. Before conversion the PPV for CIN2+ of severe dyskaryosis was 88% and after increased to 90% (P = 0.003). For moderate dyskaryosis the PPV for CIN2+ increased from 70% to 72% (P = 0.06). The absolute difference of 18% between severe and moderate dyskaryosis was therefore the same pre- and post-LBC conversion. The PPV of mild dyskaryosis for CIN2+ before and after conversion reduced from 23% to 19% (P < 0.001). The agreement between cytology and histology measured using a weighted Kappa statistic increased from 0.52 to 0.60 after conversion to LBC because of small increases in the proportions of severe dyskaryosis or worse with CIN3+ outcomes and mild dyskaryosis with CIN1 or less outcomes. CONCLUSIONS: Following LBC conversion there was evidence of a modest increase in the agreement between cytology and histology but no evidence of a change in the absolute difference in PPV for CIN2+ between moderate and severe dyskaryosis. The data support the conclusion that women referred with moderate dyskaryosis will on average have a lower risk of progression to invasive cancer than women referred with severe dyskaryosis. If the data were considered to support the categories of high-grade dyskaryosis (moderate) and high-grade dyskaryosis (severe) before LBC conversion then it can be strongly argued that they also support these categories after conversion. PMID- 20955377 TI - Cannibalism: a social behavior in sporulating Bacillus subtilis. AB - A social behavior named cannibalism has been described during the early stages of sporulation of the Gram-positive Bacillus subtilis. This phenomenon is based on the heterogeneity of sporulating populations, constituted by at least two cell types: (1) sporulating cells, in which the master regulator of sporulation Spo0A is active, and (2) nonsporulating cells, in which Spo0A is inactive. Sporulating cells produce two toxins that act cooperatively to kill the nonsporulating sister cells. The nutrients released by the dead cells into the starved medium are used for growth by the sporulating cells that are not yet fully committed to sporulate, and as a result, sporulation is arrested. This review outlines the molecular mechanisms of the killing and immunity to the toxins, the regulation of their production and other examples of killing of siblings in microorganisms. The biological significance of this behavior is discussed. PMID- 20955378 TI - Immunohistochemical expression of p16(INK4A) protein as a helpful marker of a subset of potentially malignant oral epithelial lesions: study on a series with long-term follow-up. AB - AIM: To examine a group of lesions that progressed to oral squamous cell carcinoma (OSCC) to determine whether p16(INK4A) expression is an early finding during malignant transformation, and whether immunohistochemical evaluation of p16(INK4A) is an appropriate prognostic marker. METHODS AND RESULTS: Twenty cases of OSCC were investigated. All cases had had a biopsy on the same site as OSCC performed at least 1year before OSCC (range 1-11years; mean 3.15+/ 3.1years). Twenty specimens from normal oral mucosa served as controls. p16(INK4A) expression was evaluated by immunohistochemical analysis and cases showing >5% of stained cells were defined as 'positive'. All 20 control cases were negative for p16(INK4A) . Oral lesions were p16(INK4A) -positive in nine cases and negative in 11. No significant relationship was found between p16(INK4A) positivity and the presence/absence of dysplasia. Among OSCC, nine tumours showed p16(INK4A) positivity and 11 showed negativity. A significant relationship (chi(2)=7.1; P<0.01) was found between the presence/absence of p16(INK4A) staining in OSCC and the presence/absence of p16(INK4A) staining in lesions preceding OSCC. CONCLUSIONS: p16(INK4A) immunohistochemistry has a potential role in detecting a subset of p16(INK4A) -positive lesions with malignant potential. PMID- 20955379 TI - Neoangiogenesis in laryngeal carcinoma: angiogenin and CD105 expression is related to carcinoma recurrence rate and disease-free survival. AB - AIMS: Angiogenin regulates angiogenesis supporting primary and metastatic tumour growth. CD105 is a proliferation-associated protein expressed in angiogenic endothelial cells. The aim of this study was to investigate for the first time angiogenin expression in laryngeal squamous cell carcinoma (LSCC) and to evaluate the relationship between angiogenin and CD105 expression, clinicopathological and prognostic parameters. METHODS AND RESULTS: A total of 108 consecutive operable LSCCs were studied. Angiogenin expression was determined immunohistochemically in both carcinoma cells and intratumoral vessels. CD105 expression was evaluated in endothelial cells of LSCC and calculated by a computer-based image analysis system. The percentage of the fields occupied by CD105-assessed microvessels was determined. Angiogenin expression in carcinoma cells was higher in LSCC patients who experienced loco-regional recurrence of disease (P=0.032). Disease-free survival (DFS) was shorter in cases with carcinoma cells showing angiogenin expression >21.0% (P=0.035). Angiogenin expression in carcinoma cells was correlated strongly with the angiogenin score in endothelial cells of intratumoral vessels (P=0.0000). Higher loco-regional carcinoma recurrence rate and shorter DFS in patients with high CD105 expression were found (P=0.0004, P=0.0001). CONCLUSIONS: Angiogenin expression in laryngeal carcinoma cells and CD105 expression can be considered as potentially useful to detect LSCC patients with higher risk of disease recurrence who might benefit from more aggressive therapy. PMID- 20955380 TI - Lack of RUNX3 inactivation in columnar cell lesions of breast. AB - AIMS: Ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) exhibit frequent RUNX3 inactivation by promoter hypermethylation and protein mislocalization. The aim of this study was to analyse columnar cell lesions (CCLs) to further characterize RUNX3 involvement in breast carcinogenesis. METHODS AND RESULTS: RUNX3 expression and methylation was analysed by immunohistochemistry and methylation-specific polymerase chain reaction (PCR), respectively, in 75 CCLs. Our previously reported DCIS and IDC data were also included. Consistent with terminal duct lobular units (TDLUs) (73 of 75, 97%), active nuclear RUNX3 protein was observed in 73 of 75 (97%) CCLs [columnar cell change, 46 of 48 (96%); columnar cell hyperplasia, 12 of 12 (100%) and flat epithelial atypia, 15 of 15 (100%). In contrast to matched TDLUs from cancer specimens [four of 40 (10%)] and CCLs, significantly inactivated RUNX3 expression was detected in DCIS [17 of 20 (85%)] and IDC [18 of 20 (90%)] (all P < 0.001). RUNX3 methylation was more frequent in DCIS [15 of 20 (75%)] and IDC [16 of 20 (80%)] than CCLs [(none of 20 (0%)] and matched TDLUs [one of 10 (10%)] from cancer patients (all P < 0.001). CONCLUSIONS: RUNX3 inactivation occurs specifically in DCIS and IDC cells. In addition, RUNX3 inactivation may not be a common association between CCLs and breast carcinomas. PMID- 20955381 TI - HER2 molecular subtype is a dominant subtype of mammary Paget's cells. An immunohistochemical study. AB - AIMS: To test the hypothesis that the similarity of the molecular subtypes of Paget's cells to the molecular subtypes of the underlying breast carcinomas favours the epidermotrophic theory of the origin of Paget's cells. METHODS AND RESULTS: The immunohistochemical expression of markers that define particular molecular subtypes of breast carcinomas were analysed. The whole analysis was performed by means of tissue microarrays in mammary Paget's disease and in the underlying breast carcinoma(s). Human epidermal growth factor receptor type 2 (HER2)-overexpression subtype [oestrogen receptor (ER(-) ); HER2(+) ] was a dominant molecular subtype of Paget's cells (37 of 43 analysed cases; 86%). Luminal B (ER(+) ; HER2(+) ) and luminal A (ER(+) ; HER(-) ) subtypes were identified in 12% and 2% of cases, respectively. None of the analysed tumours presented a basal-like phenotype. A similar distribution of molecular subtypes was identified in the underlying in situ breast carcinomas (HER2 subtype, 82%; luminal A, 6%; luminal B, 6%; basal-like, 6% of cases) and in the invasive component (HER2 subtype, 84%; luminal A, 8%; luminal B, 8%; basal-like, 0% of cases). CONCLUSIONS: HER2 molecular subtype is the dominant, but not the sole subtype seen in Paget's cells of the nipple. A similar distribution of molecular subtypes in both Paget's cells and in the underlying carcinomas strongly suggests their common origin. PMID- 20955382 TI - Expression of prostate stem cell antigen in high-grade prostatic intraepithelial neoplasia and prostate cancer. AB - AIMS: To investigate prostate stem cell antigen (PSCA) and Ki-67 expression in normal-looking epithelium (NEp), atrophy, high-grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma (PCa). METHODS AND RESULTS: PSCA and Ki-67 were evaluated immunohistochemically in NEp, atrophy, HGPIN and PCa in 20 radical prostatectomies (RPs) and 20 cystoprostatectomies (CyPs). The proportions of PSCA positive cells and of cases with PSCA expression increased from NEp through atrophy and HGPIN to PCa. The differences between NEp and HGPIN and PCa and between atrophy and HGPIN and PCa were statistically significant for the away and adjacent locations, in both the RP and CyP groups. The differences between HGPIN and PCa were statistically significant in the RP group when it was away from PCa and in the CyP group when it was adjacent to and away from PCa. The values in the RPs were slightly greater than in the CyPs, the differences being not statistically significant. The proportions of Ki-67 positive nuclei increased from atrophy and NEp to HGPIN and PCa. The correlation between the proportion of Ki-67 positive nuclei and that of PSCA-positive cells was statistically significant. CONCLUSIONS: PSCA expression, deregulated in atrophy and HGPIN, is a marker associated with neoplastic transformation of prostate cells, both in RPs and CyPs. PMID- 20955383 TI - Comparative evaluation of nm23 and p16 expression as biomarkers of high-risk human papillomavirus infection and cervical intraepithelial neoplasia 2(+) lesions of the uterine cervix. AB - AIMS: To investigate the clinical role of nm23 expression in identifying both high-risk human papillomavirus (HR-HPV) and high-grade cervical lesions or carcinomas [cervical intraepithelial neoplasia 2(+) (CIN2(+) )], and to compare it with p16 overexpression, as this latter biomarker has already been reported widely in HR-HPV infected cervical lesions. METHODS AND RESULTS: Immunohistochemical evaluation of nm23 and p16 in 143 cervical biopsy specimens including negative, low- and high-grade lesions and squamous carcinomas (SC). HR HPV testing by Digene hybrid capture 2 (HC2) and polymerase chain reaction (PCR) on the cervico-vaginal samples of the same patients. In detecting CIN2(+) , p16 was significantly more sensitive and specific than nm23 (96.3% versus 81.8% and 66% versus 36.4%, respectively, both P < 0.0001). Concerning HR-HPV detection by HC2, p16 showed a significantly higher specificity than nm23 (82% versus 47%, P <0.0001), although the sensitivities were comparable (71% versus 76%). We found a significantly direct correlation between nm23 and HC2 findings. However, nm23 expression did not correlate with HPV16/18 infection. In contrast, we observed a significant association between p16 overexpression and HPV16/18 genotypes. CONCLUSIONS: We confirm the diagnostic value of p16 overexpression. Moreover, despite in vitro data regarding the interaction with the HPV-E7 protein, nm23 does not appear to be a more useful biomarker than p16 in identifying CIN2(+) or HR-HPV infection. PMID- 20955384 TI - Endocervical-like (Mullerian) mucinous borderline tumours of the ovary are frequently associated with the KRAS mutation. AB - AIMS: Clinicopathological aspects of the endocervical-like mucinous borderline tumour of the ovary (EMBT), including higher frequencies of bilaterality, endometriosis and hormone receptor reactivity, and often admixtures of various Mullerian-type epithelia, closely resembles endometrioid tumour more than mucinous borderline tumour of the intestinal type (IMBT). Thus, the aims of this study were to determine whether EMBT is really a subtype of mucinous borderline tumours, as shown in the current classification system, and to determine the best classification for EMBT. METHODS AND RESULTS: The clinicopathological and immunohistochemical features of 17 EMBTs were analysed, including oestrogen receptor (ER), progesterone receptor (PR), PTEN, cytokeratins (CK) 7 and 20, and beta-catenin. Additionally, mutational analyses of the KRAS (exon 1) and PTEN genes (all nine exons) were performed in all cases, and the results were compared with literature findings for IMBT and endometrioid tumours. Twelve patients (71%) were confirmed histologically to have endometriosis in one or both ovaries. In seven cases, gradual transitions from endometriotic foci to the EMBT were identified. Immunohistochemically, all cases were reactive for ER and PR, with no nuclear expression of beta-catenin. CK7 positivity was strong in all patients, whereas there was no reactivity for CK20. PTEN reactivity was diffuse in the nuclei of epithelial and underlying stromal cells. Sixty-nine per cent showed KRAS mutations in exon 1 and codon 12, but no PTEN mutation was identified in any of the nine exons. CONCLUSION: Our study suggests that EMBT has features of both mucinous and endometrioid tumours and is an additional tumour type arising in endometriosis. While clinicopathological features of EMBTs are closer to endometrioid tumours, they still have molecular characteristics closer to IMBTs. PMID- 20955385 TI - Expression of aberrantly glycosylated Mucin-1 in ovarian cancer. AB - AIMS: Mucin 1 (MUC1) is an important tumour-associated antigen (TAA), both overexpressed and aberrantly glycosylated in adenocarcinomas. The aim of this study was to examine the MUC1-glycosylation status of primary ovarian adenocarcinomas and metastatic lesions. METHODS AND RESULTS: Paraffin-embedded tissue sections of 37 primary ovarian adenocarcinomas representing all histotypes (22 serous, five mucinous, two clear-cell, eight endometrioid), four serous borderline tumours with intraepithelial carcinoma, seven sections of ovarian endometriosis and 13 metastatic lesions were analysed by immunohistochemistry. Non-neoplastic ovarian surface epithelium and serous cystadenomas were used as controls. All epithelia expressed MUC1 protein. Of primary tumours, 76% expressed the differentiation-dependent glycoform and 84% the cancer-associated glycoform (Tn/Sialyl-Tn-epitopes). In metastatic lesions this was 77% and 85%, respectively. Notably, in 57% of ovarian endometriosis and 75% of intraepithelial lesions, the cancer-associated MUC1 epitopes were expressed, whereas normal ovarian surface epithelium and serous cystadenomas did not express these epitopes. CONCLUSIONS: The underglycosylated MUC1 epitopes are expressed by all histotypes of primary ovarian adenocarcinomas, by the vast majority of metastatic lesions and by possible ovarian cancer precursor lesions, but not by normal ovarian tissue. These results indicate that MUC1-associated Tn/STn-epitopes are important targets for immunotherapy and diagnostic imaging in ovarian cancer patients. PMID- 20955386 TI - Histological changes in patients with chronic upper gastrointestinal ischaemia. AB - AIMS: Diagnosing chronic upper gastrointestinal ischaemia (CUGI) remains a challenge in clinical practice. Histological examination of biopsy material currently plays no role in the diagnosis of transient CUGI, as little is known about gastrointestinal histology in these patients. The aim of this study was to investigate upper gastrointestinal histology in patients with well-defined CUGI. METHODS AND RESULTS: Consecutive patients suspected of CUGI were included prospectively and underwent a diagnostic work-up existing of upper endoscopy, gastrointestinal tonometry and computed tomography (CT) or magnetic resonance (MR) angiography. Results were discussed in a multidisciplinary team and a consensus diagnosis was made. Endoscopic biopsy samples were taken from the descending duodenum, gastric antrum and corpus, and scored using the Sydney, Vienna, Chiu, Marsh and Operative Link for Gastritis Assessment (OLGA) classifications. Gastropathy was scored present or absent. Seventy-nine patients were analysed in 8months. CUGI was diagnosed in 41 patients (52%): 36 males, mean age 60 (17-86) years. Prevalence of gastropathy was significantly higher in patients with ischaemia (P=0.025). No other differences were found between patients with and without ischaemia. CONCLUSIONS: Histological examination of biopsy samples plays no definitive role in diagnosing CUGI, but the presence of histological signs of reactive gastropathy can be used to support the clinical diagnosis of ischaemia. PMID- 20955387 TI - LMO2 promotes angiogenesis probably by up-regulation of bFGF in endothelial cells: an implication of its pathophysiological role in infantile haemangioma. AB - AIMS: Infantile haemangiomas (IHs) are common benign vascular tumours distinctive for their perinatal presentation, rapid growth during the first year of life and subsequent slow involution. Recent research has indicated that endothelial cells of haemangiomas express LIM-only protein 2 (LMO2). The aim of this study was to investigate the role of LMO2 in the pathogenesis of IHs was investigated. METHODS AND RESULTS: Immunoreactivity of LMO2 was assessed in specimens of 19 IH. Stable transfection of LMO2 into human endothelial cell lines (EAhy926) was performed to evaluate the role of LMO2 in terms of the change in cell proliferation, cell cycle and cell migration as well as the expression level of angiogenic factors. Immunoreactivity for LMO2 was detected in all IH specimens, specifically in the nucleus of the endothelial cells. The intensity of LMO2 immunostaining decreased significantly from proliferative to involuting stages. Furthermore, the overexpression of LMO2 enhanced the proliferation and migration of the endothelial cells and promoted G0/G1-S-phase transition in vitro, together with an up-regulation of bFGF expression. CONCLUSIONS: LMO2 probably promotes angiogenesis by up-regulation of bFGF expression and thereby consequently influences progression of IH. PMID- 20955388 TI - TMPRSS2-ERG fusion as a marker of prostatic lineage in small-cell carcinoma. PMID- 20955390 TI - Array comparative genomic hybridization analysis indicates that serous carcinomas of the ovary, fallopian tube and endometrium are distinct entities. PMID- 20955391 TI - Stathmin is superior to AKT and phospho-AKT staining for the detection of phosphoinositide 3-kinase activation and aggressive endometrial cancer. PMID- 20955392 TI - Comparison of endometrial intraepithelial neoplasia with WHO endometrial hyperplasia classification system. A comparative study of 150 cases. PMID- 20955393 TI - Intravascular large B cell lymphoma with hepatic portal vein, splenic vein and mesenteric vein tumour embolism. PMID- 20955394 TI - Characteristics of non-carious cervical lesions--an ex vivo study using micro computed tomography. AB - The aetiology of non-carious cervical lesions (NCCLs) is not well understood and still controversial. The aim of this ex-vivo study was to examine the morphological characteristics of NCCLs for clinical evidence of enamel loss above the cemento-enamel junction (CEJ) as suggested by the abfraction theory. Fifty extracted human teeth with various types of NCCLs were collected and scanned by micro computed tomography. The reconstructed three-dimensional models were evaluated from multiple aspects, including longitudinal cross-section series. The location of internal line angle and proximal exits of the lesions were evaluated in relation to the level of CEJ. The coronal margins of the lesions were inspected for evidence of enamel loss above the CEJ using the bucco-lingual longitudinal sectional images. Coronal margins of the lesions were located along and/or under the CEJ for all of the 50 samples. In most of the lesions, regardless of lesion type, the proximal exits and internal line angles were located below the CEJ. This study did not detect clinical evidence of enamel loss above the occlusal margin of NCCLs as would have been expected according to the general abfraction mechanism. PMID- 20955396 TI - Molecular analysis of intravascular large B-cell lymphoma with neoangiogenesis. PMID- 20955397 TI - Different clinical severity of first episodes and recurrences of thrombotic thrombocytopenic purpura. AB - The clinical course of thrombotic thrombocytopenic purpura (TTP) is characterized by recurrent disease episodes in up to 50% of cases. The clinical presentation and severity of different TTP episodes have not been systematically compared. Laboratory and clinical information from 51 patients with recurrent disease, derived from 136 patients with TTP included in the Milan TTP registry (URL: http://www.ttpdatabase.org), were used to compare mortality, symptoms and disease related laboratory measurements in different disease episodes. The prevalence of severe neurological symptoms (coma, seizures, and focal neurological defects) was significantly lower in recurrences than in the first episode. Platelet counts and haemoglobin levels at presentation were higher in recurrences than in the first disease episode, and lactate dehydrogenase levels were lower. Also, mortality tended to be lower in the second and third disease episodes than in the first. Recurrences of TTP are generally milder than first episodes. These differences in severity should be taken into account in clinical research on TTP and in patient management. PMID- 20955399 TI - Genetic typing of CBL, ASXL1, RUNX1, TET2 and JAK2 in juvenile myelomonocytic leukaemia reveals a genetic profile distinct from chronic myelomonocytic leukaemia. AB - JMML and CMML are rare myelodysplastic/myeloproliferative neoplasms occurring at both ends of life. To investigate relationships between JMML and CMML, genes recently involved in CMML were studied in 68 JMML patients. Mutations in TET2, RUNX1 and JAK2(V617F) are involved in myelodysplastic and/or myeloproliferative syndromes, and more specifically in CMML but were not found in JMML. Pangenomic analysis by SNP-array showed no abnormality at these loci. Three frameshift mutations of ASXL1 leading to a truncated protein were found in three patients (4%) with late onset JMML displaying also RAS activating mutations. Homozygous mutations of CBL with 11q loss of heterozygosity were found in five (7%) JMML. CBL substitutions were different from those reported in CMML, exclusive from other RAS activating mutations, and were germline in all patients. Overall, the pattern of genetic lesions observed in JMML differed from that of CMML. Although signalling deregulation is involved in CMML, transcriptional deregulation seems to play a pivotal role, with mutation of RUNX1, ASXL1 or TET2. Conversely, none of these genes involved in transcription or chromatin remodelling was found to be significantly altered in JMML, while CBL mutations confirm the central role of RAS and growth factor signalling deregulation in JMML. PMID- 20955398 TI - Early and treatment-related deaths in childhood acute myeloid leukaemia in the Nordic countries: 1984-2003. AB - Despite major improvements in the cure rate of childhood acute myeloid leukaemia (AML), 5-15% of patients still die from treatment-related complications. In a historical prospective cohort study, we analysed the frequency, clinical features and risk factors for early deaths (ED) and treatment-related deaths (TRD) in 525 children included in the Nordic Society of Paediatric Haematology and Oncology (NOPHO)-AML-84, -88 and -93 trials. Seventy patients (13%) died before starting treatment or from treatment-related complications. The death rate rose from 11% in NOPHO-AML-84 to 29% in -88, but then fell to 8% in -93. Sixteen patients (3%) died within the first 2 weeks, mainly from bleeding or leucostasis. Hyperleucocytosis, age <2 or >=10 years were risk factors. After day 15, 10% of patients died from treatment-related complications with infection as the main cause of death. Risk factors were age <2 or >=10 years and treatment according to the NOPHO-AML-88 protocol. The number of EDs and TRDs in AML is high. Therefore optimal antifungal prophylaxis is essential, and studies on the benefit of antibacterial prophylaxis and individual risk factors for ED and TRD are needed. PMID- 20955395 TI - Noninvasive biophotonic imaging for studies of infectious disease. AB - According to World Health Organization estimates, infectious organisms are responsible for approximately one in four deaths worldwide. Animal models play an essential role in the development of vaccines and therapeutic agents but large numbers of animals are required to obtain quantitative microbiological data by tissue sampling. Biophotonic imaging (BPI) is a highly sensitive, nontoxic technique based on the detection of visible light, produced by luciferase catalysed reactions (bioluminescence) or by excitation of fluorescent molecules, using sensitive photon detectors. The development of bioluminescent/fluorescent microorganisms therefore allows the real-time noninvasive detection of microorganisms within intact living animals. Multiple imaging of the same animal throughout an experiment allows disease progression to be followed with extreme accuracy, reducing the number of animals required to yield statistically meaningful data. In the study of infectious disease, the use of BPI is becoming widespread due to the novel insights it can provide into established models, as well as the impact of the technique on two of the guiding principles of using animals in research, namely reduction and refinement. Here, we review the technology of BPI, from the instrumentation through to the generation of a photonic signal, and illustrate how the technique is shedding light on infection dynamics in vivo. PMID- 20955400 TI - Improvement in verbal memory after withdrawal of carbamazepine and valproate in patients with well-controlled epilepsy: a randomized, double-blind study. AB - BACKGROUND: For most major antiepileptic drugs, neuropsychological side effects have been reported. Healthy volunteer studies have found that both carbamazepine and valproate impair aspects of verbal memory. OBJECTIVE: The aim of this study was to assess the effects of carbamazepine and valproate on verbal memory, in a well-controlled epilepsy population. METHODS: This was carried out with a randomized, double-blind and placebo-controlled study of anticonvulsant withdrawal in patients receiving monotherapy. RESULTS: In the carbamazepine group (n=92), withdrawal significantly improved recall after 30 min (P=0.03). In the valproate group (n=32), withdrawal significantly improved performance of immediate word span (P=0.04). CONCLUSIONS: Withdrawal was randomized to placebo, but the choice of medication was not randomized to placebo. This means that the shown differences in neuropsychological outcome cannot with full certainty be attributed to either antiepileptic drug. The improvement of memory, after both carbamazepine and valproate withdrawal, was slight, and the impact on daily life function is uncertain. PMID- 20955401 TI - Molecular characterization of paediatric idiopathic hypereosinophilia. AB - The hypereosinophilic syndromes (HES) include a group of heterogeneous diseases characterized by the persistent increase of the number of eosinophils in blood and bone marrow. Few cases of paediatric hypereosinophilia (pHES) have been described in the literature. Early identification of pHES that may evolve towards a lymphomyeloproliferative disease is relevant in light of prognostic and therapeutic implications. Molecular features of 10 pHES patients were analysed at presentation and during their clinical course, including analysis of BCR-ABL1 and FIP1L1/PDGFRA fusion genes, quantitation of WT1 gene copy number and clonality of T-cell receptor (TCR) and immunoglobulin heavy chain (IGH). All patients had normal karyotype and germline TCR configuration. Five children showed IGH clonality at presentation: of these, two developed a B non-Hodgkin lymphoma and a B-lineage acute lymphocytic leukaemia at six and 12 months respectively, two spontaneously reverted to a polyclonal IGH profile during the follow-up, and the last one persisted with pHES without B-clonal evolution after 19 months. One patient had a PDGFRA/FIP1L1 fusion and achieved hematologic and molecular remission after imatinib therapy. IGH rearrangement was observed to be a frequent molecular feature of pHES and may precede B-cell clonal expansion and evolution into B-cell malignancies in children. PMID- 20955402 TI - A randomized phase II trial of Arginine Butyrate with standard local therapy in refractory sickle cell leg ulcers. AB - Sickle cell leg ulcers are often debilitating, refractory to healing, and prone to recurrence. Healing of leg ulcers was incidentally observed during dose ranging trials of Arginine Butyrate in beta haemoglobinopathies. Here, a controlled Phase II trial was performed in sickle cell patients who had lower extremity ulcers refractory to standard care for at least 6 months. Patients were randomized to receive standard local care alone (Control Arm) or standard care with Arginine Butyrate administered 5 d/week (Treatment Arm), for 12 weeks. Ulcers were photographed weekly, traced, and ulcer areas were calculated by computerized planimetry and compared between the two study arms. Twenty-seven study courses were evaluated. Control Arm subjects had 25 ulcers with a mean area of 25.7 cm(2) initially and 23.2 cm(2) after 12 weeks; 2/25 (8%) healed completely. Treatment Arm subjects had 37 ulcers with a mean area of 50.6 cm(2) initially and 28.3 cm(2) at 12 weeks; 11/37 of these (30%) healed completely. After 3 months, proportions of ulcers which healed were 6/25 (24%) and 29/37 (78%), in the Control and Treatment Arms respectively (P < 0.001). These findings strongly suggest that Arginine Butyrate merits further evaluation for the treatment of refractory sickle cell leg ulcers in larger trials. PMID- 20955403 TI - Desensitization to hydroxycarbamide following long-term treatment of thalassaemia intermedia as observed in vivo and in primary erythroid cultures from treated patients. AB - Hydroxycarbamide (HC) is a pharmacological agent capable of stimulating fetal haemoglobin (HbF) production during adult life. High levels of HbF may ameliorate the clinical course of beta-thalassaemia and sickle cell disease. The efficacy of HC for the treatment of thalassaemia major and thalassaemia intermedia is variable. Although an increase of HbF has been observed in most patients, only some patients experience significant improvement in total haemoglobin levels. This study aimed to determine the effectiveness and safety of short- (1 year) and long-term (mean follow-up 68 months) HC treatment in 24 thalassaemia intermedia patients. Additionally, we evaluated if primary erythroid progenitor cells cultured from treated patients responded to HC treatment in a manner similar to that observed in vivo. Our results confirm a good response to HC after a short term follow-up in 70% of thalassaemia intermedia patients and a reduction of clinical response in patients with a long follow-up. Erythroid cultures obtained from patients during treatment reproduced the observed in vivo response. Interestingly, haematopoietic stem cells from long-term treated patients showed reduced ability to develop into primary erythroid cultures some months before the reduction of the 'in vivo' response. The mechanism of this loss of response to HC remains to be determined. PMID- 20955404 TI - Thrombocytopenia in early malaria is associated with GP1b shedding in absence of systemic platelet activation and consumptive coagulopathy. AB - Thrombocytopenia develops early in malaria, but the underlying mechanisms remain incompletely understood. We studied the aetiology of malaria-associated thrombocytopenia in volunteers experimentally infected with Plasmodium falciparum malaria, in Indonesian malaria patients and in ex vivo studies. In experimental human malaria, the decrease in platelet counts was associated with a concurrent rise in young platelets (immature platelet fraction) and thrombopoietin. D-dimer concentrations were moderately elevated without a prolongation in the activated partial thromboplastin time or decrease in fibrinogen. There was no increase in expression of the platelet surface markers CD62P, PAC-1 and CD63 and in plasma concentrations of the platelet factors P-selectin, CXCR4, CXCL7, RANTES and CD40L. In contrast, concentrations of soluble glycoprotein-1b (sGP1b), the external domain of the platelet receptor for von Willebrand factor (VWF), increased early. Indonesian malaria patients also had elevated concentrations of sGP1b, which correlated with VWF concentrations. Finally, incubation of platelets with parasitized erythrocytes in vitro failed to induce platelet aggregation or activation. We concluded that neither compromised platelet production nor platelet activation or consumptive coagulopathy were responsible for the early thrombocytopenia in malaria. We hypothesize that the increase in sGP1b concentrations results from VWF-mediated GP1b shedding; a process that may prevent excessive adhesion of platelets and parasitized erythrocytes. PMID- 20955405 TI - First application of MLPA method in severe von Willebrand disease. Confirmation of a new large VWF gene deletion and identification of heterozygous carriers. PMID- 20955406 TI - HDAC inhibitors induce cell cycle arrest, activate the apoptotic extrinsic pathway and synergize with a novel PIM inhibitor in Hodgkin lymphoma-derived cell lines. PMID- 20955407 TI - Mild to fatal course of pandemic influenza H1N1 in children with acute leukaemia. PMID- 20955408 TI - Alteration in serum B cell-activating factor levels inpatients with idiopathic thrombocytopenic purpura after Helicobacter pylori eradication therapy. PMID- 20955409 TI - Risk stratification of normotensive patients with acute symptomatic pulmonary embolism. AB - Treatment guidelines recommend strong consideration of thrombolysis in patients with acute symptomatic pulmonary embolism (PE) that present with arterial hypotension or shock because of the high risk of death in this setting. For haemodynamically stable patients with PE, the categorization of risk for subgroups may assist with decision-making regarding PE therapy. Clinical models [e.g. Pulmonary Embolism Severity Index (PESI)] may accurately identify those at low risk of overall death in the first 3 months after the diagnosis of PE, and such patients might benefit from an abbreviated hospital stay or outpatient therapy. Though some evidence suggests that a subset of high-risk normotensive patients with PE may have a reasonable risk to benefit ratio for thrombolytic therapy, single markers of right ventricular dysfunction (e.g. echocardiography, spiral computed tomography, or brain natriuretic peptide testing) and myocardial injury (e.g. cardiac troponin T or I testing) have an insufficient positive predictive value for PE-specific mortality to drive decision-making toward such therapy. Recommendations for outpatient treatment or thrombolytic therapy for patients with PE necessitate further development of prognostic models and conduct of clinical trials that assess various treatment strategies. PMID- 20955410 TI - CHIC cells: a novel ALK+ cell line derived from a relapsed anaplastic large cell lymphoma. PMID- 20955411 TI - Risk of venous thromboembolism in patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. PMID- 20955412 TI - One hundred years of sickle cell disease. AB - The first formal report of sickle cell disease occurred 100 years ago. This review traces the early historical reports, the evolution of understanding of the genetics, the molecular and chemical basis of sickle haemoglobin, and the advances made over the last 30-40 years in improving the management. Newborn screening and close follow-up, especially early in life, has significantly improved survival but these advances require resources and sophisticated infrastructure. In sub-Saharan Africa over 250 000 births annually suggest that these advances are unlikely to be implemented within the foreseeable future. Prevention of the disease where possible, could reduce the numbers of new patients allowing better facilities for the care of others. As the disease results from the inheritance of abnormal haemoglobin genes from both parents, it is eminently preventable. The unanswered question, whether genotype detection and counselling will influence reproductive decisions, is currently being addressed by a project in central Jamaica. PMID- 20955413 TI - Rapid identification of IDH1 and IDH2 mutations in acute myeloid leukaemia using high resolution melting curve analysis. PMID- 20955414 TI - Flower power. PMID- 20955415 TI - EgMYB1, an R2R3 MYB transcription factor from eucalyptus negatively regulates secondary cell wall formation in Arabidopsis and poplar. AB - * The eucalyptus R2R3 transcription factor, EgMYB1 contains an active repressor motif in the regulatory domain of the predicted protein. It is preferentially expressed in differentiating xylem and is capable of repressing the transcription of two key lignin genes in vivo. * In order to investigate in planta the role of this putative transcriptional repressor of the lignin biosynthetic pathway, we overexpressed the EgMYB1 gene in Arabidopsis and poplar. * Expression of EgMYB1 produced similar phenotypes in both species, with stronger effects in transgenic Arabidopsis plants than in poplar. Vascular development was altered in overexpressors showing fewer lignified fibres (in phloem and interfascicular zones in poplar and Arabidopsis, respectively) and reduced secondary wall thickening. Klason lignin content was moderately but significantly reduced in both species. Decreased transcript accumulation was observed for genes involved in the biosynthesis of lignins, cellulose and xylan, the three main polymers of secondary cell walls. Transcriptomic profiles of transgenic poplars were reminiscent of those reported when lignin biosynthetic genes are disrupted. * Together, these results strongly suggest that EgMYB1 is a repressor of secondary wall formation and provide new opportunities to dissect the transcriptional regulation of secondary wall biosynthesis. PMID- 20955416 TI - Transcriptome profiles of hybrid poplar (Populus trichocarpa * deltoides) reveal rapid changes in undamaged, systemic sink leaves after simulated feeding by forest tent caterpillar (Malacosoma disstria). AB - * Poplar has been established as a model tree system for genomic research of the response to biotic stresses. This study describes a series of induced transcriptome changes and the associated physiological characterization of local and systemic responses in hybrid poplar (Populus trichocarpa * deltoides) after simulated herbivory. * Responses were measured in local source (LSo), systemic source (SSo), and systemic sink (SSi) leaves following application of forest tent caterpillar (Malacosoma disstria) oral secretions to mechanically wounded leaves. * Transcriptome analyses identified spatially and temporally dynamic, distinct patterns of local and systemic gene expression in LSo, SSo and SSi leaves. Galactinol synthase was strongly and rapidly upregulated in SSi leaves. Genome analyses and full-length cDNA cloning established an inventory of poplar galactinol synthases. Induced changes of galactinol and raffinose oligosaccharides were detected by anion-exchange high-pressure liquid chromatography. * The LSo leaves showed a rapid and strong transcriptome response compared with a weaker and slower response in adjacent SSo leaves. Surprisingly, the transcriptome response in distant, juvenile SSi leaves was faster and stronger than that observed in SSo leaves. Systemic transcriptome changes of SSi leaves have signatures of rapid change of metabolism and signaling, followed by later induction of defense genes. PMID- 20955417 TI - Do the costs and benefits of fungal endophyte symbiosis vary with light availability? AB - * Here, we examined whether fungal endophytes modulated host plant responses to light availability. First, we conducted a literature review to evaluate whether natural frequencies of endophyte symbiosis in grasses from shaded habitats were higher than frequencies in grasses occupying more diverse light environments. Then, in a glasshouse experiment, we assessed how four levels of light and the presence of endophyte symbioses affected the growth of six grass species. * In our literature survey, endophytes were more commonly present in grasses restricted to shaded habitats than in grasses from diverse light environments. * In the glasshouse, endophyte symbioses did not mediate plant growth in response to light availability. However, in the host grass, Agrostis perennans, symbiotic plants produced 53% more inflorescences than nonsymbiotic plants at the highest level of shade. In addition, under high shade, symbiotic Poa autumnalis invested more in specific leaf area than symbiont-free plants. Finally, shade increased the density of the endophyte in leaf tissues across all six grass species. * Our results highlight the potential for symbiosis to alter the plasticity of host physiological traits, demonstrate a novel benefit of endophyte symbiosis under shade stress for one host species, and show a positive association between shade restricted grass species and fungal endophytes. PMID- 20955418 TI - How inflammation modulates central nervous system vessel activation and provides targets for intervention--a personal perspective. AB - I here describe a line of research that grew out of studies of spinal cord damaging decompression sickness, focused on the blood-endothelial interface, that was influenced by the local Shwartzman phenomenon, addressed innate immune and inflammatory mechanisms, and ultimately arrived at mucosal tolerance approaches to prevent stroke. Intranasal instillation of E-selectin is under development as a novel means of targeting immunomodulation to activating blood vessels within the vascular tree supplying the brain. The goal of this form of focused immunomodulation is to prevent recurrent strokes in patients that have previously suffered transient ischemic attacks or strokes. PMID- 20955419 TI - Innate inflammation as the common pathway of risk factors leading to TIAs and stroke. AB - In the early moments of ischemic stroke, the processes of thrombosis, ischemia, and inflammation are intimately interrelated, setting in motion an injury that leads to infarction and permanent damage. Of these, the potential roles that innate inflammation can play in the evolution of brain tissue damage in response to the ischemic injury are not well understood. Observations in the settings of atherosclerotic cardiovascular disease and cerebral ischemia have much to teach each other. The following provides an introductory overview of the conference "Innate Inflammation as the Common Pathway of Risk Factors Leading to Transient Ischemic Attacks and Stroke: Pathophysiology and Potential Interventions," which took place May 9-10, 2010 at the New York Academy of Sciences. This meeting was convened to explore aspects of the cellular and tissue responses to innate inflammation. A faculty of leading experts was assembled to discuss the role of inflammation in laboratory models of stroke and myocardial infarction, define possible novel means from laboratory evidence to alleviate or prevent inflammation underlying stroke and cardiovascular disease, and present information on current examples of clinical translation of these understandings in relation to human stroke and myocardial infarction. PMID- 20955421 TI - The challenge of mixed cerebrovascular disease. AB - Stroke in general, and ischemic stroke in particular, are routinely defined using clinical criteria. Incorporating brain imaging and neuropathological findings into an expanded conceptual definition of stroke will result in a vastly increased prevalence of the disease. The resultant category of mixed cerebrovascular disease thus may include subclinical infarct, cerebral white matter disease, and cerebral microbleeds. Subclinical brain infarcts occur five times more frequently than does clinical ischemic stroke. Abnormalities of cerebral white matter are present in more than 95% of the population over the age of 65 years, and magnetic resonance imaging evidence of cerebral microbleeds is found in at least 18% of the population, beginning at the age of 60 years. Pathologic evidence supports at least a partial microvascular origin for cerebral white matter disease and cerebral microbleeds. Emphasizing mixed cerebrovascular disease as a conceptual framework allows for a focus on common underlying mechanisms and new therapeutic strategies. PMID- 20955420 TI - Platelet-leukocyte interactions link inflammatory and thromboembolic events in ischemic stroke. AB - Stroke is a common and often fatal event, and, in survivors, it is accompanied by a high risk of recurrence. Ischemic stroke is associated with abnormal platelet activity and thrombus formation. In addition to their roles in the development of acute thrombi, platelets serve as a bridge for leukocytes within the vasculature. Myeloid leukocytes are critical mediators of atherosclerosis and atherothrombosis. Interactions between platelets and leukocytes foster an inflammatory and thrombotic milieu that influences lesion progression, facilitates plaque rupture, and triggers thrombus formation and embolization. Accordingly, antiplatelet agents, including aspirin, dipyridamole, and clopidogrel, are recommended therapies for most patients with a history of stroke. In addition to mitigating thrombosis, antiplatelet drugs have direct and indirect effects on inflammation, which may translate to enhanced clinical efficacy. PMID- 20955422 TI - Pharmacological modulation of vascular inflammation in atherothrombosis. AB - Vascular inflammation, especially at the level of endothelial cells, has been shown to play a pivotal role in the inception, progression, and clinical complications of atherosclerosis. The common denominators for the activation of inflammatory genes appear to be a small subset of transcription factors--among which include nuclear factor-kappaB, activator protein-1 (AP-1), and GATA--that function as the central hub of vascular inflammation. Strategies directed to inhibit both the secondary mediators and the primary triggers (atherosclerosis risk factors) appear viable to inhibit atherosclerosis. However, attempts have now been made to address the central hub of vascular inflammation. "Old" drugs, such as dipyridamole, can also now be revisited for properties related to inhibition of vascular inflammation, probably by acting on the common hub of inflammation. PMID- 20955423 TI - NF-kappaB and innate immunity in ischemic stroke. AB - Acute cerebral ischemia elicits an innate immune response that leads to a cascade of events that culminates in necrotic death of neurons and injury to their supportive structures in the neurovascular unit. Indeed, clinical studies have shown a close relationship between elevated levels of inflammatory markers and the risk for ischemic stroke. However, the signaling pathways that link these events are not well understood. A central regulator of inflammatory response is the transcription factor, nuclear factor-kappa B (NF-kappaB). The activation of NF-kappaB is required for the transcriptional induction of many proinflammatory mediators involved in innate immunity, such as cellular adhesion molecules, cytokines, and growth factors. Therefore, factors that modulate the activity of NF-kappaB could potentially regulate inflammatory processes in ischemic stroke. Here, we review the relationship between NF-kappaB and ischemic stroke, its role in the neurovascular unit, and discuss some animal models that suggest that this relationship is causal. PMID- 20955424 TI - The role of the blood transcriptome in innate inflammation and stroke. AB - Cerebrovascular disease is a major cause of death and disability, with a poorer outcome in patients having select risk factors including diabetes and hypertension. Risk factors and the state of cerebral ischemia-reperfusion associated with cerebrovascular occlusion are known to cause inflammatory changes. These events and the inflammatory state are reflected by transcript changes in various components of the blood and can be specifically measured. By defining these changes, new insight into cerebrovascular disease and its therapeutics is being achieved. PMID- 20955425 TI - The neurovascular unit, matrix proteases, and innate inflammation. AB - In the central nervous system, microvessel-neuron interactions appear highly coordinated. The rapid simultaneous responses of the microvasculature, neurons, and glia to focal ischemia in experimental ischemic stroke suggest that these responses could be viewed in a unitary fashion, rather than as individual components. The "neurovascular unit" consists of microvessels (endothelial cells basal lamina matrix-astrocyte end-feet [and pericytes]), astrocytes, neurons and their axons, and other supporting cells that are likely to modulate the function of the "unit." Each cell component generates an inflammatory response to ischemia. Matrix metalloproteinase (MMP)-9 was first associated with hemorrhagic transformation following focal ischemia in an experimental model. A series of studies of ischemic stroke patients also suggests a relationship between MMP-9 levels and several consequences of ischemic injury, including hemorrhagic transformation. Recent experimental work suggests specific cell sources for MMP-9 generation and for matrix proteases from four distinct families that could impact neurovascular unit integrity. PMID- 20955426 TI - Biphasic actions of HMGB1 signaling in inflammation and recovery after stroke. AB - Stroke induces a complex web of pathophysiology that may evolve over hours to days and weeks after onset. It is now recognized that inflammation is an important phenomenon that can dramatically influence outcomes after stroke. In this minireview, we explore the hypothesis that inflammatory signals after stroke are biphasic in nature. The high-mobility group box 1 (HMGB1) protein is discussed as an example of this idea. HMGB1 is normally present in the nucleus. Under ischemic conditions, it is released extracellularly from many types of cells. During the acute phase poststroke, HMGB1 promotes necrosis and influx of damaging inflammatory cells. However, during the delayed phase poststroke, HMGB1 can mediate beneficial plasticity and recovery in many cells of the neurovascular unit. These emerging findings support the hypothesis that inflammation after stroke can be both detrimental and beneficial, depending on the cellular situations involved. PMID- 20955428 TI - Effect of dipyridamole during acute stroke: exploring antithrombosis and neuroprotective benefits. AB - Currently, many stroke-prone individuals take antithrombotic drugs, which have known antiplatelet properties, to decrease stroke incidence. There is now evidence that this regimen could also reduce stroke severity through neuroprotective, nonplatelet mechanisms that include anti-inflammatory processes. Inflammation was found to play an important role in atherosclerosis/thrombosis development and acute stroke progression. In light of these findings, prevention strategies that target inflammatory mediators are under investigation. A common secondary stroke prevention therapeutic, dipyridamole, has shown promise for reducing stroke recurrence without increasing bleeding. In addition to its antiplatelet ability, dipyridamole has positive effects on vascular endothelium and inflammation. This review explores the effect of dipyridamole during acute stroke, revealing its potential use for improving poststroke clinical outcome. PMID- 20955427 TI - Aging and cerebrovascular dysfunction: contribution of hypertension, cerebral amyloid angiopathy, and immunotherapy. AB - Age-related cerebrovascular dysfunction contributes to ischemic stroke, intracerebral hemorrhages (ICHs), microbleeds, cerebral amyloid angiopathy (CAA), and cognitive decline. Importantly, there is increasing recognition that this dysfunction plays a critical secondary role in many neurodegenerative diseases, including Alzheimer's disease (AD). Atherosclerosis, hypertension, and CAA are the most common causes of blood-brain barrier (BBB) lesions. The accumulation of amyloid beta (Abeta) in the cerebrovascular system is a significant risk factor for ICH and has been linked to endothelial transport failure and blockage of perivascular drainage. Moreover, recent anti-Abeta immunotherapy clinical trials demonstrated efficient clearance of parenchymal amyloid deposits but have been plagued by CAA-associated adverse events. Although management of hypertension and atherosclerosis can reduce the incidence of ICH, there are currently no approved therapies for attenuating CAA. Thus, there is a critical need for new strategies that improve BBB function and limit the development of beta-amyloidosis in the cerebral vasculature. PMID- 20955429 TI - Protecting against ischemia-reperfusion injury: antiplatelet drugs, statins, and their potential interactions. AB - Statins and antiplatelet agents are currently used as therapeutic agents for patients with acute myocardial infarction. Statins limit myocardial infarct size by activating phosphatidylinositol-3-kinase (PI3K), ecto-5'-nucleotidase, Akt/endothelial nitric oxide synthase (eNOS), and the downstream effectors inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Inhibition of PI3K, adenosine receptors, eNOS, iNOS, or COX-2 abrogates the protective effects of statins. At >5 mg/kg, aspirin attenuates the myocardial infarct-size limiting effect of statins. In contrast, the combination of low-dose atoravastatin with either the phosphodiesterase-III inhibitor cilostazol or the adenosine reuptake inhibitor dipyridamole synergistically limits infarct size. Low-dose aspirin with dipyridamole started during ischemia augmented the infarct size-limiting effects of simvastatin. In contrast, high-dose aspirin blocked the protective effect of simvastatin. The combination of dipyridamole with low-dose aspirin and simvastatin resulted in the smallest infarct size. According to the most current data available, we believe that antiplatelet regimens may require modification for patients who are receiving statins. PMID- 20955430 TI - Reperfusion of chronic tissue ischemia: nitrite and dipyridamole regulation of innate immune responses. AB - Chronic and intermittent ischemic vascular disorders represent a burgeoning clinical challenge. Previous studies have focused on the idea that therapeutic angiogenesis strategies could alleviate tissue ischemia; however, it is now appreciated that vascular disease is not simply limited to vascular wall cells but also influenced by simultaneously occurring inflammatory responses. Our laboratory has discovered that pharmacological treatment of permanent tissue ischemia with dipyridamole significantly augments ischemic tissue reperfusion, angiogenesis, and arteriogenesis over time. We have found that the beneficial effects of dipyridamole therapy are due to its ability to increase tissue nitric oxide bioavailability that corrects tissue redox imbalance. Importantly, we have also discovered that dipyridamole treatment invoking nitric oxide (NO) production significantly downregulates various innate immune response genes during chronic ischemic tissue injury. These findings demonstrate that dipyridamole-induced production of nitrite/NO significantly decreases inflammatory responses while increasing vascular growth in ischemic tissues. PMID- 20955431 TI - Effect of intravenous administration of dipyridamole in a rat model of chronic cerebral ischemia. AB - Pharmacological therapy able to improve the cognitive performances of patients with chronic vascular pathologies currently remains unavailable. Many studies of chronic cerebral hypotension in rodents have revealed alterations in reference memory and learning. Dipyridamole was introduced into clinical medicine in the early 1960s as a coronary vasodilator. It is a potent inhibitor of platelet activation and reduces formation of thrombi in vivo. In addition, it is an antithrombotic agent used for secondary stroke prevention in combination with aspirin. Recent evidence indicates that dipyridamole has anti-inflammatory properties. Bilateral common carotid artery occlusion (2VO) in the rat is recognized as a valid model of chronic cerebral hypotension, also defined as the "vascular cognitive impairment rat model." Here, we report that dipyridamole reverses the impairment of spatial working memory 90 days after 2VO. This protective effect might be in relation to dipyridamole's anti-inflammatory properties. PMID- 20955432 TI - Impact of innate inflammation in population studies. AB - Innate inflammation plays an important role in the pathogenesis and progression of atherosclerosis, plaque rupture, thrombosis, and stroke. Inflammatory biomarkers related to innate inflammation, including acute phase proteins, may predict first stroke. The utility of high-sensitivity C-reactive protein and other related markers may diminish among populations with established vascular risk. Other biomarkers, including lipoprotein-associated phospholipase A2, may provide complementary information about prognosis after stroke or subclinical vascular disease. The innate immune system originally evolved to provide protection against bacterial infections. Moreover, infections may also contribute to stroke risk. Summary measures representing multiple chronic infections have been associated with risk of stroke and atherosclerosis. Acute infections, particularly respiratory infections, have also been found to serve as precipitants of stroke in recent epidemiological studies. These findings could have clinical implications. Further studies are needed to determine the role of innate inflammation and infection in stroke pathogenesis and prevention. PMID- 20955433 TI - Innate inflammation in myocardial perfusion and its implication for heart failure. AB - Heart failure is characterized by a chronic inflammatory status, with high circulating levels of inflammatory cytokines significantly correlated with deterioration of functional capacity, cardiac performance, and coronary flow reserve--the latter occurring even with normal systemic endothelial function. Impaired coronary flow reserve in heart failure is poorly related to systemic inflammation levels and somewhat matched by a reduction in myocardial contractile reserve. Both coronary flow and myocardial functional reserve can be imaged noninvasively and can be useful clinically for disease severity titration, diagnostic anticipation, and prognostic stratification. Coronary microcirculatory dysfunction can be a trigger of disease and a potential target for therapeutic intervention in heart failure patients. Clinical observational studies showed a striking beneficial effect of endogenous adenosine accumulation on symptoms, exercise capacity, and left ventricular function in chronic heart failure, but this needs to be confirmed in prospective randomized large-scale trials. PMID- 20955434 TI - Linking infection and inflammation in acute ischemic stroke. AB - Infections after ischemic stroke are known to complicate the clinical course and worsen the outcome. Neuroinflammation is one of the predominant mechanisms of secondary progression of brain injury and infection and is far from being well understood. Experimental data demonstrate that ischemic stroke patients are at a higher risk for systemic infections if they show a pronounced anti-inflammatory response after the event, which is considered an indication of a stress-mediated reduction of immune competence. Only a small number of studies describe the time course of inflammation mediators after ischemic stroke in patients with early poststroke infections. Levels of inflammation mediators after the event of stroke differ, depending on clinical severity and concomitant infectious diseases. Thus, sequential dynamics of early inflammation must be considered in the development of both mechanism-targeting anti-inflammatory and anti-infectious treatment strategies in ischemic brain damage. PMID- 20955435 TI - Metalloproteinase and stroke infarct size: role for anti-inflammatory treatment? AB - Deregulation of matrix metalloproteinases (MMPs), the largest class of human proteases, has been implicated in brain damage in both animal and human studies. Some MMPs are elevated after stroke (both in plasma and in brain tissue), and their expression is enhanced by t-PA during thrombolysis related to hemorrhagic transformation events. Although the exact cellular source of MMPs remains unknown, brain endothelium, astrocytes, neurons, and inflammatory-activated cells, such as neutrophils, may release MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, and/or MMP-13. Neurovascular perturbations occurring after stroke lead to blood brain barrier leakage, edema, hemorrhage, leukocyte infiltration, and progressive inflammatory reactions to brain injury over hours or even days after the initial stroke. Synthesized MMP inhibitors and several compounds used for stroke secondary prevention, such as anti-inflammatory drugs, might decrease MMPs and improve the acute treatment of human brain ischemia without compromising the beneficial effects of matrix plasticity during stroke recovery. PMID- 20955436 TI - Role of drug absorption in the pharmacokinetics of therapeutic interventions for stroke. AB - Absorption is a critical component of the pharmacokinetics for solid dosage forms administered orally. Many barriers must be overcome in order for a drug molecule to reach its effect site. To effectively address each of these barriers, drug specific properties, formulation issues, and (patho)physiological changes in the gastrointestinal tract must be considered. First-pass metabolism in the gut and/or liver can dictate the extent to which a drug reaches the systemic circulation. Drug-metabolizing enzymes in the gut and liver are very susceptible to inhibition by other drugs, increasing the risk of drug interactions. In this paper, we will discuss absorption-related issues for solid dosage forms used in the management of stroke patients. PMID- 20955437 TI - Acute anti-inflammatory approaches to ischemic stroke. AB - In preparation for designing and undertaking trials of strategies that can modulate "innate inflammation" to improve outcomes of ischemic injury, consideration of approaches that have managed cellular inflammation in ischemic stroke are instructive. Robust experimental work has demonstrated the efficacy (and apparent safety) of targeting PMN leukocyte-endothelial cell interactions in the early moments following focal ischemia onset in model systems. Four clinical trial programs were undertaken to assess the safety and efficacy of inhibitors to PMN leukocyte interactions with the endothelial cell during ischemic stroke. Experiences in those clinical trial programs indicate specific limitations that halted progress in this line of investigation before an adequate hypothesis test could be achieved. Although innate inflammation is a central part of injury evolution following focal ischemia, great care in the translation from experimental studies to Phase I/II clinical safety assessments and to the design and conduct of Phase III trials is needed. PMID- 20955438 TI - Combating innate inflammation: a new paradigm for acute treatment of stroke? AB - Interference with early steps of platelet adhesion/activation by inhibition of the von Willebrand factor (vWF) receptor glycoprotein (GP)Ib, its ligand vWF, or the collagen receptor GPVI, profoundly limits infarction in the mouse stroke model of transient middle cerebral artery occlusion (tMCAO). A similar pathogenic role was revealed for coagulation factor XII (FXII). Although these findings strongly suggest that microvascular thrombus formation is the leading pathophysiological event in acute stroke, recent studies have shown that these molecules have the additional capacity to guide inflammatory processes, thereby providing an intriguing alternative mechanistic explanation for these observations. Surprisingly, mice lacking T cells are also protected from acute stroke, and these T cell effects are antigen independent. Thus, acute ischemic stroke can be redefined as a thrombo-inflammatory disorder, and multifunctional molecules such as GPIb, GPVI, and FXII may provide new therapeutic targets linking inflammation and thrombus formation. PMID- 20955439 TI - Role of inflammation in cognitive impairment: results of observational epidemiological studies and clinical trials. AB - Inflammation may be an important mechanism underlying dementia and cognitive decline in the elderly. Inflammation has been implicated in the neuropathological cascade leading to the development of Alzheimer's disease and other common forms of dementia in later life. These observations have led to observational epidemiological study to define the association of systemic and brain inflammatory markers on cognitive impairment and dementia. Furthermore, clinical trials have been carried out to better elucidate the possible role of nonsteroidal anti-inflammatory drugs (NSAIDs) in the prevention or slowing of progression of Alzheimer's disease. In this review, we discuss the observational epidemiological and clinical trial evidence of the role of inflammation on the occurrence and prevention of dementia or cognitive decline. NSAIDs hold promise to prevent dementia if given in an appropriate time window during the induction phase of dementia and to subjects with apolipoprotein E (APOE) e4 alleles. Also, immunotherapy may prove beneficial. PMID- 20955440 TI - Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis. AB - BACKGROUND: Non-alcoholic fatty liver disease generally has a benign course; however, patients with non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma. Currently, there is a lack of consensus about optimal NASH treatment. AIM: To assess the efficacy of insulin-sensitizing agents on histological and biochemical outcomes in randomized control trials of biopsy-proven NASH. METHODS: Multiple online databases and conference abstracts were searched. Random effects meta-analyses were performed, with assessment for heterogeneity and publication bias. RESULTS: Nine trials were included; five trials using thiazolidinediones (glitazones), three using metformin and one trial using both drugs. There was no publication bias. Compared with controls, glitazones resulted in improved steatosis (WMD = 0.57, 95% CI 0.36-0.77, P = <0.001), hepatocyte ballooning (WMD = 0.36, 95% CI 0.24-0.49, P < 0.001) and ALT (WMD = 16.4, 95% CI 7.7-25.0, P < 0.001), but not inflammation (P = 0.09) or fibrosis (P = 0.11). In patients without diabetes, glitazones significantly improved all histological and biochemical outcomes, most importantly including fibrosis (WMD = 0.29, 95% CI 0.078-0.51, P = 0.008). Metformin failed to improve any pooled outcome. CONCLUSIONS: Treatment of NASH with glitazones, but not metformin, demonstrates a significant histological and biochemical benefit, especially in patients without diabetes. Additional studies are needed to investigate long-term outcomes of glitazone therapy in patients without diabetes. PMID- 20955441 TI - Meta-analysis: the association of oesophageal adenocarcinoma with symptoms of gastro-oesophageal reflux. AB - BACKGROUND: Endoscopic screening has been proposed for patients with symptoms of gastro-oesophageal reflux disease (GERD) in the hope of reducing mortality from oesophageal adenocarcinoma. Assessing the net benefits of such a strategy requires a precise understanding of the cancer risk in the screened population. AIM: To estimate precisely the association between symptoms of GERD and oesophageal adenocarcinoma. METHODS: Systematic review and meta-analysis of population-based studies with strict ascertainment of exposure and outcomes. RESULTS: Five eligible studies were identified. At least weekly symptoms of GERD increased the odds of oesophageal adenocarcinoma fivefold (odds ratio = 4.92; 95% confidence interval = 3.90, 6.22), and daily symptoms increased the odds sevenfold (random effects summary odds ratio = 7.40, 95% confidence interval = 4.94, 11.1), each compared with individuals without symptoms or less frequent symptoms. Duration of symptoms was also associated with oesophageal adenocarcinoma, but with very heterogeneous results, and unclear thresholds. CONCLUSIONS: Frequent GERD symptoms are strongly associated with oesophageal adenocarcinoma. These results should be useful in developing epidemiological models of the development of oesophageal adenocarcinoma, and in models of interventions aimed at reducing mortality from this cancer. PMID- 20955442 TI - The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn's disease who failed prior infliximab therapy. AB - BACKGROUND: Adalimumab induces and maintains remission in adults with Crohn's disease. AIM: To evaluate safety, fistula healing, quality of life and work productivity in adalimumab-treated patients who failed infliximab, including primary nonresponders. METHODS: After a >=8-week infliximab washout, patients with moderate-to-severe Crohn's disease received open-label adalimumab as induction (160/80 mg at weeks 0/2) and maintenance (40 mg every other week) therapies. At/after 8 weeks, patients with flare/nonresponse could receive weekly therapy. Minimum study duration was 8 weeks, continuing until the commercial availability of adalimumab for Crohn's disease. RESULTS: Of 673 patients enrolled, 17% were infliximab primary nonresponders and 83% were initial responders. Three percent of patients had serious infections (mainly abscesses). Complete fistula healing was achieved by 34/88 (39%) patients with baseline fistulas. Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients, as well as the subgroup of primary nonresponders. CONCLUSIONS: Blinded clinical trials have shown adalimumab to be both an effective first-line therapy for anti-TNF-naive patients and an important treatment option for infliximab-refractory or -intolerant patients. This trial presents open-label experience to support further the safety and effectiveness of adalimumab in patients who failed infliximab therapy, including primary nonresponders (NCT00338650). PMID- 20955443 TI - Risk factors for NSAID-associated upper GI clinical events in a long-term prospective study of 34 701 arthritis patients. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAID)-related GI effects vary based on patient characteristics. AIMS: To assess risk factors for NSAID associated upper GI clinical events and dyspepsia. METHODS: Patients >=50 years with osteoarthritis or rheumatoid arthritis were randomized to etoricoxib or diclofenac in a prespecified intent-to-treat analysis of three double-blind randomized trials. Potential risk factors for upper GI clinical events (bleeding, perforation, obstruction, or ulcer), complicated events (perforation, obstruction, bleeding) and discontinuations due to dyspepsia were assessed with Cox proportional hazard models. RESULTS: Significant predictors of clinical events and complicated events included age >=65 years [hazards ratios (HRs) = 2.25 (1.84-2.76), 4.09 (2.82-5.92)], prior event [HRs = 2.57 (1.94-3.39), 3.23 (2.09-5.00)], low-dose aspirin [HRs = 2.34 (1.87-2.92), 3.41 (2.33-5.00)] and corticosteroid [HRs = 1.85 (1.41-2.43), 2.09 (1.29-3.38)]. Predictors of discontinuation due to dyspepsia included prior dyspepsia [HR = 1.78 (1.44 2.00)], prior event [HR = 1.78 (1.40-2.27)] and age >=65 years [HR = 1.35 (1.16 1.57)]. CONCLUSIONS: Assessment for age >=65 years, prior upper GI clinical events and low-dose aspirin use are key in identifying patients who should either avoid NSAIDs or employ management strategies to reduce NSAID-associated upper GI events. Prior dyspepsia or upper GI clinical events and age >=65 years also predict an increased risk of developing dyspepsia severe enough to necessitate discontinuation of NSAIDs. PMID- 20955444 TI - The effects of dose and timing of esomeprazole administration on 24-h, daytime and night-time acid inhibition in healthy volunteers. AB - BACKGROUND: Symptoms of gastro-oesophageal reflux disease (GERD) may persist despite daily treatment with a proton pump inhibitor (PPI). AIM: To compare the pharmacodynamic effect of various esomeprazole dosage and timing regimens in healthy volunteers. METHODS: The effect of different esomeprazole dosage regimens [20 mg once daily (od) before breakfast or dinner; 20 mg twice daily (b.d.); 40 mg od before breakfast, dinner or at bedtime; and 40 mg b.d.] on 24-h, daytime and night-time acid inhibition was evaluated in a randomized, seven-way crossover study in healthy volunteers. Each regimen was taken for 5 days. RESULTS: Over the 24-h period (day 5), esomeprazole 20 mg b.d. was associated with superior acid inhibition vs. all 20 mg and 40 mg od regimens (P < 0.05), but was less effective than esomeprazole 40 mg b.d. (P < 0.05). Dosing with esomeprazole 20 mg or 40 mg od before breakfast gave improved 24-h and daytime acid inhibition vs. the corresponding administration before dinner or at bedtime (all P < 0.05). Night time acid inhibition was improved when esomeprazole 40 mg od was administered before dinner or at bedtime vs. before-breakfast dosing (P < 0.05). CONCLUSION: Varying the dose and timing of esomeprazole administration may provide acid inhibition appropriate for the symptom pattern of individual patients with GERD. PMID- 20955445 TI - 24-h pH monitoring patterns and clinical response after achalasia treatment with pneumatic dilation or laparoscopic Heller myotomy. AB - BACKGROUND: The most effective treatment for achalasia is pneumatic dilation or myotomy. The best option is still controversial and incidence of complications could help choosing. Gastro-oesophageal reflux (GER) is the most frequent complication after treatment for achalasia. The 24-h pH monitoring (24-h pH) is the best method to evaluate true GER. AIM: To analyse the 24-h pH patterns after treatment, correlating with therapeutic success. METHODS: Untreated patients with achalasia were randomized to pneumatic dilation or laparoscopic Heller myotomy with fundoplication (LHM+Fp) and evaluated with clinical/manometric results and 24-h pH. RESULTS: Ninety-four patients were analysed pre-treatment and 85 post treatment. Clinical success was 73.8% in pneumatic dilation group and 88.3% in LHM+Fp group (P = 0.08). The incidence of GER was 31% in pneumatic dilation, and 4.7% in LHM+Fp (P = 0.001). The occurrence of hypotensive lower oesophageal sphincter (LES) was 53.3% in patients who developed GER and 28.6% in patients with 24-h pH suggesting fermentation (P = 0.019). The rates of dysphagia resolution in patients with 24-h pH of GER and fermentation were respectively 86.7% and 85.7% (P = 0.89). CONCLUSIONS: True GER 24-h pH is more frequent after pneumatic dilation for achalasia, and it is associated with a hypotensive LES. A 24-h pH suggestive of fermentation or true GER is not associated with worse clinical/manometric results. PMID- 20955446 TI - The impact of pre-endoscopy proton pump inhibitor use on the classification of non-erosive reflux disease and erosive oesophagitis. AB - BACKGROUND: Factors associated with non-erosive reflux disease (NERD) and erosive oesophagitis (EO) are incompletely understood and the overlap between the two entities is debated. AIM: To compare clinical, demographic, and endoscopic findings in a large cohort of NERD and EO patients. METHODS: After they completed a validated GERD questionnaire, patients who presented for index endoscopy were enrolled and categorized as NERD or EO. Analysis was performed using Chi-square, Mann-Whitney U-test and multivariate logistic regression. RESULTS: A total of 696 GERD patients [455 (65.4%) NERD; 241 (34.6%) EO]; mean age 57 years; 92% men and 82% Caucasian were prospectively enrolled. Using logistic regression, patients on PPI were more likely to be classified as NERD (OR: 3.2; P < 0.001). NERD patients were older (OR: 1.50; P = 0.05), less likely to have nocturnal symptoms (OR: 0.63; P = 0.04) and hiatal hernia (OR: 0.32; P < 0.001). Compared with PPI-naive NERD patients, those on PPI were more likely to have nocturnal symptoms (69% vs. 29%, P = 0.048) and less likely to have mild-moderate symptoms (63% vs. 79%, P < 0.001) - similar to the EO group. CONCLUSIONS: Pre-endoscopy PPI usage contributes significantly to the classification of GERD patients into the NERD phenotype. NERD patients on PPI therapy demonstrate some features that are significantly different from PPI-naive patients, but similar to EO patients. This observation supports the notion that some PPI NERD patients are actually healed EO patients, and that an overlap does exist between the GERD phenotypes. PMID- 20955447 TI - Measuring symptoms in the irritable bowel syndrome: development of a framework for clinical trials. AB - BACKGROUND: There is uncertainty about how to measure patient-reported outcomes (PROs) in IBS. The Food and Drug Administration (FDA) emphasizes that PROs must be couched in a conceptual framework, yet existing IBS PROs were not based on such a framework. AIM: To perform qualitative analyses to inform a new conceptual framework for IBS symptoms. METHODS: Following FDA guidance, we searched the literature for extant IBS questionnaires. We then performed interviews in IBS patients to learn about the illness experience in their own words. We cultivated vocabulary to inform a conceptual framework depicted with domains, sub-domains, and item categories, per FDA guidance. RESULTS: We identified 13 questionnaires with items encompassing 18 symptoms. We recruited 123 IBS patients for cognitive interviews. Major themes included: pain and discomfort are different - asking about discomfort is nonspecific and should be avoided in future PROs; bowel urgency is multifaceted - PROs should measure bowel immediacy, controllability, and predictability; and PROs should divide bloating into how it feels vs. how it looks. Symptom experience may be determined by 35-item categories within five domains: (i) pain; (ii) gas/bloat; (iii) diarrhoea; (iv) constipation; and (v) extraintestinal symptoms. CONCLUSIONS: We applied FDA guidance to develop a framework that can serve as the foundation for developing a PRO for IBS clinical trials. PMID- 20955448 TI - Antioxidants for liver disease. PMID- 20955450 TI - Infliximab rescue therapy in ulcerative colitis, and the effect on subsequent colectomy rates. PMID- 20955451 TI - Maternal general health and children's cognitive development and behaviour in the early years: findings from the Millennium Cohort Study. AB - BACKGROUND: Mothers often experience physical and psychological difficulties during the post-natal period and these may continue through the early years of raising children and have negative effects on engagement and caregiving. Pathways between maternal depression, parental engagement and caregiving and children's subsequent development have been described in longitudinal studies; yet, less is known about how other aspects of maternal health may influence children's development. METHODS: A longitudinal analysis within the Millennium Cohort Study was conducted including 7906 families from England. Maternal general health and psychological well-being were assessed when their children were 9 months and 3 years old, socio-demographic characteristics were assessed at 9 months, and engagement and caregiving were assessed at 3 years. These were examined as predictors of children's learning and development and behaviour at age 5. RESULTS: There are clear associations between maternal general health and children's development with regard to both learning and development and behaviour. These effects are reduced if psychological distress is taken into account; yet, maternal general health maintains importance as a predictor for children's subsequent development. There is evidence of an association via engagement and caregiving which links maternal health to children's development and evidence of the influence of underlying socio-demographic disadvantage. CONCLUSION: General maternal health as well as psychological well-being during the early years of raising children may be influential for children's development. This study suggests the need for a broader recognition of maternal health as well as psychological well-being as a foundation for family well-being, and speaks to support for mothers in maintaining engagement and caregiving for their children during periods of ill health. PMID- 20955452 TI - In vivo biofilm formation on a soft denture liner in elderly patients with controlled diabetes. AB - OBJECTIVES: This in vivo study evaluated the influence of controlled diabetes on biofilm formation on a soft denture liner in elderly patients. BACKGROUND: Soft denture lining materials are more susceptible to microbial colonisation than denture base acrylic resins. Especially in the elderly, several predisposing factors may accumulate leading to an increased probability of biofilm development that may result in candidiasis, a significant clinical oral disease. MATERIALS AND METHODS: Volunteers wearing complete dentures were divided into two groups (n = 20): diabetic patients with controlled glycaemia, and healthy patients. In both groups, a silicone-based soft liner was placed in a recess created at the base of the maxillary dentures. Subjects cleaned the prosthesis three times a day. Biofilm formed on the liner was quantified at various time points (baseline, two, four and six weeks). Data were analysed by two-way repeated measures ANOVA and Tukey's test (alpha = 0.05). RESULTS: There was no statistical difference in biofilm formation for any of the time points between controlled diabetes patients and healthy patients. CONCLUSION: The results suggest that the control of diabetes in elderly patients provides the same levels of biofilm formation when compared to healthy individuals. PMID- 20955453 TI - Improved detection methods for infected hip joint prostheses. AB - Awareness of the role of bacterial biofilm in the pathogenesis of low-grade or chronic infections diagnosed in hip arthroplasty has been on the rise in recent years. The importance of bacterial biofilm for the development of prosthesis failure is probably underestimated, and terms like aseptic loosening, sterile pus and aseptic necrosis are up for revision. The diagnosis of biofilm has been, and still is, difficult, but new molecular biological techniques, alone or in combination with older established ones, have further helped us to uncover lesions, where biofilm is part of the pathology. This article based on a literature search and own observations is primarily focused on newer methods that help us identify the pathology behind infection-based prosthesis failure. We suggest that the fluorescence in situ hybridization technique on carefully selected biopsy material is used in the future to identify live as well as dead bacteria within their environment. The method is quick and sensitive and provides a reliable result with optimal detection rate. PMID- 20955454 TI - Somatic frameshift mutations of bone morphogenic protein receptor 2 gene in gastric and colorectal cancers with microsatellite instability. AB - Mounting evidence exists that perturbation of bone morphogenic protein (BMP) signaling is involved in cancer development, especially in gastrointestinal cancers. However, somatic mutations of the genes encoding BMP and BMP receptors have not yet been discovered in human cancer tissues. By analyzing a public database, we found that BMP receptor 2 (BMPR2) and BMP1 genes had mononucleotide repeats in their coding sequences that could be mutation targets in cancers with microsatellite instability (MSI). In this study, we analyzed the mutation of BMPR2 and BMP1 genes in gastric (GC) and colorectal cancers (CRC) with MSI [31 GC with high MSI (MSI-H), 13 GC with low MSI (MSI-L), 38 CRC with MSI-H and 15 CRC with MSI-L] by single-strand conformation polymorphism analysis and DNA sequencing. Overall, we found seven frameshift mutations in the BMPR2 gene, but not in the BMP1 gene. The mutations were an identical deletion mutation of one base in the repeats (c.1748delA) that would result in premature stops of the amino acid synthesis (p.Asn583ThrfsX44). The BMPR2 mutations were detected in 6.5% of GC and 13.2% of CRC with MSI-H. All the cancers with the BMPR2 mutation showed loss of BMPR2 expression. Our data indicate that frameshift mutation of BMPR2 gene occurs in GC and CRC with MSI-H, and suggest that the BMPR2 mutation might contribute to cancer pathogenesis by inactivating BMPR2-mediated BMP signaling. PMID- 20955455 TI - Modulation of exogenous antibiotic activity by host cathelicidin LL-37. AB - The increasing number of infections caused by drug-resistant bacteria has spurred efforts to develop new therapeutic strategies. When applied locally, exogenous antibiotics work in an environment rich in endogenous antibacterial molecules such as the cathelicidin peptide LL-37, which has increased expression at infection sites because of the stimulatory effects of bacterial wall products on neutrophils and other cell types. To test for possible additive effects of exogenous and endogenous antibacterial agents, we evaluated the minimal inhibitory concentration (MIC) to assess the antibacterial activity of amoxicillin with clavulanic acid (AMC), tetracycline (T), erythromycin (E) and amikacin (AN) against different clinical isolates of Staphyloccocus aureus in combination with synthetic LL-37. These studies revealed that the antibacterial activity of AMC was strongly potentiated when added in combination with LL-37. However, in the presence of LL-37, we did not observe any decrease in the MIC values of T and E, particularly against methicillin-resistant S. aureus and macrolide-lincosamide-streptogramin B (MLS(B))(+)/beta-lactamase (+) strains, indicating a lack of synergistic action between these molecules. Interaction between exogenous antibiotics and host antibacterial molecules should be considered to provide optimal treatment, especially in cases of topical infections accompanied by increasing expression of host antibacterial molecules. PMID- 20955456 TI - T-cell expression of CD91 - a marker of unresponsiveness to anti-TNF therapy in rheumatoid arthritis. AB - The aim of this study was to investigate the expression of thrombospondin-1 (TSP 1) and its receptors, lipoprotein receptor-related protein/cluster of differentiation (CD)91, calreticulin (CRT), and CD47, on T cells and monocytes from patients with rheumatoid arthritis (RA) treated with anti-tumor necrosis factor (TNF) therapy. The surface expression of CD91 and associated components on CD3- and CD14-positive cells was examined using flow cytometry in 12 patients with established RA before and after beginning therapy and compared with that of 9 healthy controls and 12 patients with early RA treated with conventional therapies. CD3-positive cells from anti-TNF non-responders showed significantly greater expression of CD91 expression than those from responders (p<0.05) after 6 weeks and when all measurements were pooled (p<0.001). CD91 expression on CD3 positive cells from non-responders to other therapies was at the same level as in healthy controls. In contrast, CD14-positive cells showed no differences in CD91 expression between patients and controls or between responders and non-responders to anti-TNF therapy. The expression of TSP-1, CRT, and CD47 showed no differences between responders and non-responders. The results suggest T-lymphocyte expression of CD91 to be a biomarker that signifies unresponsiveness to anti-TNF therapy in patients with RA and may be used to identify potential responders and non-responders. PMID- 20955457 TI - Follicular thyroid neoplasm: clinicopathologic features suggesting malignancy. AB - Thyroid follicular neoplasms are the most common tumors of the thyroid. The criterion for their malignancy is evidence of capsular or vascular invasion, which makes preoperative diagnosis difficult. The poorly differentiated thyroid carcinoma entity was introduced by World Health Organization in its 2004 classification with an incidence still poorly known. We found 356 follicular neoplasms treated between 1990 and 2006. Among these tumor patients, adenomas were more common in women than in men (3.6:1), but carcinomas differed little with respect to gender (1.2:1). All follicular carcinomas (n=39), atypical adenomas (n=6), and oxyphilic adenomas (n=15) were included in the study, as well as 30 consecutive conventional follicular adenomas. Five tumors were reclassified as poorly differentiated follicular thyroid carcinomas, representing 13% of carcinomas in this unselected material. Predictors of malignancy were high proliferation index (PI) by MIB-1 (p<0.001), large tumor size (p<0.001), and old age (p=0.006). High PI was also a marker of worse prognosis in malignant tumors. Oxyphilic tumor cells were more frequent in carcinomas than in adenomas; however, among carcinomas, they were non-prognostic. Probability for malignancy is thus greater in a male patient with a large oxyphilic follicular neoplasm. The PI requires evaluation in all follicular thyroid carcinomas to identify poorly differentiated tumors with worse prognosis. PMID- 20955458 TI - Expression of SATB1 and heparanase in gastric cancer and its relationship to clinicopathologic features. AB - The purpose of this study was to investigate the expression of special AT-rich binding protein 1 (SATB1) and heparanase in human gastric cancer as well as its relationship to the clinicopathologic factors. Specimens from 102 patients who underwent radical gastrectomy between 2000 and 2002 were studied by immunohistochemistry for SATB1 and heparanase expression. SATB1 and heparanase were positively expressed in 48.0% and 51.0% of gastric cancer cases, respectively. The expression of SATB1 and heparanase was significantly correlated with the depth of invasion, tumor-node-metastatsis (TNM) stage, lymph node metastasis, whereas SATB1 expression was also significantly correlated with distant metastasis. Patients with SATB1-negative expression and heparanase negative expression had higher survival rates than those with SATB1-positive or heparanase-positive expression. Moreover, a positive correlation was found between SATB1 and heparanase. In multivariable analysis, SATB1 expression was also identified as an independent prognostic indicator for gastric cancer. Our results suggest that combined analysis of SATB1 and heparanase expression may have significant value in determining invasion and metastasis of gastric cancer and assessing prognosis in patients with gastric cancer. PMID- 20955459 TI - Immunological, antioxidative, and morphological response in combined treatment of ofloxacin and Lactobacillus fermentum ME-3 probiotic in Salmonella Typhimurium murine model. AB - We aimed to elucidate the immunological (cytokines), biochemical (antioxidative), and patho-morphological responses in the gut and liver evoked by the addition of Lactobacillus fermentum ME-3 to ofloxacin (OFX) treatment in an experimental infection model of Salmonella enterica serovar Typhimurium. After challenge with S. Typhimurium and treatment according to different schemes, either with OFX and/or addition of L. fermentum ME-3, the mice were killed. Blood, liver, spleen, and small intestine samples were plated to detect S. Typhimurium and lactobacilli. Histological slides were prepared from the liver and ileum. The cytokines (IL-10, IFN-gamma, and TNF-alpha), the glutathione peroxidase and reductase, the glutathione ratio, and the lipid peroxides (LPO) in mucosa of the small intestine and liver were estimated. The addition of L. fermentum ME-3 to OFX increased the eradication of S. Typhimurium from tested sites because of antagonistic and antioxidative properties, reduced the presence of typhoid nodules in the liver, and decreased the values of LPO. The immunological response included the reduction of pro-inflammatory cytokines interferon-gamma and tumour necrosis factor-alpha and the increase in anti-inflammatory cytokine interleukin 10 in the livers of mice without typhoid nodules. PMID- 20955460 TI - Application of a feasible method for determination of biofilm antimicrobial susceptibility in staphylococci. AB - The aim of this study was to use a practical method to determine the minimal biofilm eradication concentration (MBEC) of vancomycin and to compare the MBEC with minimal inhibitory concentration (MIC) for biofilm-producing and non-biofilm producing isolates of staphylococci. Forty Staphylococcus spp. isolates from central venous catheter, from distinct patients, were selected for this study. The vast majority (28/30) of isolates which were biofilm-producing, presented high MBEC values (>=8 MUg/mL) and could be considered as non-susceptible to vancomycin. All non-biofilm-producing isolates presented low MBEC (<=2 MUg/mL) and were susceptible to vancomycin, according to CLSI breakpoints. While the MBEC and MIC values for biofilm-producing isolates differ significantly, the MBEC and MIC values for non-biofilm producers were the same. The method we have used proved to be a feasible and rapid technique to measure MBEC of Staphylococcus spp. biofilms. The method presented herein might be an alternative tool to evaluate the antibiotic susceptibility in the biofilm mode of growth; the MBEC may be a more appropriate approach to correlate the susceptibility in vitro with clinical outcome resulting from the treatment of Staphylococcus spp. infection. PMID- 20955461 TI - Do we need a booster of Hib vaccine after primary vaccination? A study on anti Hib seroprevalence in Sweden 5 and 15 years after the introduction of universal Hib vaccination related to notifications of invasive disease. AB - The prevalence of IgG ELISA antibodies against Haemophilus influenzae polyribosyl ribitol phosphate (anti-Hib) was studied in two Swedish seroepidemiologic materials. One study was performed in 1997 5 years after the introduction of universal Hib vaccination (N=3320). Ten years later, a similar study was carried out to analyze the effect of vaccination on anti-Hib prevalence (N=2383). The median values of anti-Hib concentrations (EU/mL) were almost identical in the two materials. The antigenic pressure including vaccination, natural infections and possible cross-immunizations was thus assumed to be constant. The joint median was 0.50 EU/mL (95% confidence interval: 0.46, 0.56). However, there were also indications of reduced exposure to 'Hib-antigens' over a 10-year period. The proportion above the cut-off point for protection, 0.15 EU/mL, decreased significantly for children aged 2-19 years from 78% in 1997 to 74% in 2007 (p=0.034), and there was a significant increase in values below the minimal level of detection for adults from 17% in 1997 to 20% in 2007 (p=0.009). In the 2007 material no specific age group could be identified with a lower immune profile than other age groups older than 3 years and there was a significant downward trend of invasive infections caused by Hib according to notification data for the period 1997-2008. Therefore, the conclusion is that presently there is no need for a booster dose of Hib vaccine in Sweden after primary vaccination but the situation should be carefully monitored. PMID- 20955462 TI - Intragraft immunological events associated with EBV DNAemia in liver transplant patients. AB - Epstein-Barr virus (EBV) may cause post-transplant lymphoproliferative disorder, but most EBV infections after liver transplantation (Ltx) are clinically silent reactivations. In this study, we investigated the intragraft immunological events associated with EBV DNAemia. Altogether, 105 adult Ltx patients were monitored for EBV DNAemia. Fourteen (13%) patients developed EBV DNAemia during the first year after transplantation. Liver biopsies obtained associated with EBV DNAemia, without evidence of other herpes or hepatitis viruses or rejection, were available from five patients. The numbers of lymphocytes positive for B-cell marker (CD20), T-cell markers (CD3, CD4 and CD8) and IL-2R, adhesion molecules (ICAM-1, VCAM-1 and ELAM-1) and their ligands [lymphocyte function-associated antigen-1 (LFA-1), very late antigen (VLA-4) and Sialyl Lewis X (sLeX)] were demonstrated in liver biopsies by immunohistochemistry, and zero-biopsies from donor livers were used as controls. EBV DNAemia was associated with increased number of CD20-positive (22+/-30, p=0.09) and significantly increased numbers of CD3 (80+/-16, p=0.001)-, CD4 (23+/-8, p=0.009)- and CD8 (38+/-8, p=0.001) positive lymphocytes in the graft. ICAM-1, but not VCAM-1 or ELAM-1, was strongly expressed and the number of LFA-1-positive cells was significantly increased (48+/-10, p=0.0002). Low-level EBV DNAemia was associated with B- and especially T-cell infiltration of the graft, as well as an increase in ICAM-1 and the number of LFA-1-positive cells. However, EBV DNAemia or these immunological events did not have any effect on the liver transplant. PMID- 20955463 TI - Distribution of viral RNA, sialic acid receptor, and pathology in H5N1 avian influenza patients. AB - Avian influenza virus H5N1 infects and causes severe disease in humans. Despite the increasing number of fatal cases in 15 countries and the threat of influenza pandemic, detailed pathologic and virologic findings in humans are limited. In this study, we describe histopathologic findings, distributions of viral RNA and the Neu5Acalpha2-3Galbeta1-4 sialic acid receptor in human tissues from three fatal avian influenza cases. Many of our findings are in agreement with previously published autopsy studies, that is, viral RNA and receptor were detected in type II pneumocytes, tracheal epithelium, intestinal epithelium, spleen, lymph nodes, and Kupffer's cells. In addition, we detected the viral RNA in glomeruli and renal tubules. There was a good correlation between viral RNA distribution and the presence of the sialic acid receptor. Despite the wide distribution of viral RNA, tissue damage and inflammation were mainly limited to pulmonary tissue. PMID- 20955464 TI - The prevalence of BV in the population on the Aland Islands during a 15-year period. AB - The aim of the study was to describe the prevalence and age distribution of bacterial vaginosis (BV) during an observation period of 15 years in a population study with cross-sectional samples of adult women living on the Aland Islands. The Aland Islands form an archipelago in the Baltic Sea and are a province of Finland. Every fifth year, specific age groups in the adult female population are invited to participate in a screening program for early diagnosis of cervical cancer using a papanicolaou (PAP)-stained vaginal smear. Women in the age groups of 20, 25, 30, 35, 40, 45, 50, 55, and 60 years are called each year. BV diagnosis of the PAP-stained smears uses the classification according to Nugent. The PAP-stained smears from the screening program of cervical cancer 1993, 1998, 2003, and 2008 were used in this study. A total of 3456 slides were investigated and 271 women could be followed for the 15-year observation period. The prevalence of BV declined from 15.6% in 1993 to 8.6% in 2008. The highest prevalence occurred among the age groups of 35 and 50 years. Among the 271 women who could be followed for the 15-year observation period, two-third showed normal/intermediate flora and one-third were infected with BV at least once. As this is a cross-sectional population study spanning 15 years, the prevalence of BV in the female adult population of the Aland Islands can be estimated. The prevalence has declined between 1993 and 2008 from 15.6% to 8.6%. PMID- 20955465 TI - Lactobacillus strains differentially modulate cytokine production by hPBMC from pollen-allergic patients. AB - The objective of this study was to assess the potential immunomodulatory effect of six Lactobacillus strains on human peripheral blood mononuclear cells (hPBMC) isolated from allergic patients. hPBMC from patients allergic to birch pollen or grass pollen were cultured in vitro in the presence or absence of selective bacterial strains. Cultures were left unstimulated or stimulated with alphaCD3/alphaCD28 or Bet v 1. After 1, 4 and 8 days, cells and culture supernatants were harvested and the effect on cellular proliferation and the supernatant levels of several cytokines was assessed. All strains had the ability to repress IL-13 production but did show a differential effect on IFN-gamma induction. Both strains B223 and B1697 showed a lower IFN-gamma, IL-12 and TNF alpha induction as compared with the other tested strains. Strain B633 showed the best proliferation-suppressive properties in alphaCD3/alphaCD28-stimulated cells. Suppression of the T-helper type 2 (Th2) cytokine induction and induction of the Th1 cytokine production by specific strains might be beneficial for allergic patients having a disturbed Th1/Th2 immune balance. Furthermore, hPBMC of patients with seasonal allergy outside the pollen season can be used to determine the immunomodulatory activities of probiotic bacteria. PMID- 20955466 TI - oprM as a new target for reversion of multidrug resistance in Pseudomonas aeruginosa by antisense phosphorothioate oligodeoxynucleotides. AB - Multidrug-resistant Pseudomonas aeruginosa (MDR-PA) is one of the leading Gram negative organisms associated with nosocomial infections. The increasing frequency of MDR-PA has represented a huge challenge in conventional antibacterial therapy. The loss of effectiveness of commonly used antibiotics calls for the immediate need to develop an alternative strategy for combating MDR PA infections. The multiantibiotic resistance of MDR-PA is largely attributable to the production of multidrug efflux pumps, MexAB-OprM. OprM forms the antibiotic-ejecting duct and plays a crucial role in exporting incoming chemotherapeutic agents across the membranes. Disruption of the OprM expression may inhibit the function of multidrug efflux pumps and lead to restoration of MDR PA susceptibility to antibiotics. In this study, we developed a novel anion liposome for encapsulating and delivering specific anti-oprM phosphorothioate oligodeoxynucleotide (PS-ODN617) and polycation polyethylenimine (PEI) complexes. The additions of the encapsulated anti-oprM PS-ODN617/PEI to MDR-PA isolates caused a significant reduction of oprM expression and inhibition of MDR-PA growth in the presence of piperacillin in a concentration-dependent manner. The encapsulated PS-ODN617 treatment also reduced minimal inhibitory concentrations of five most commonly used antibiotics to the sensitive margin values on MDR-PA clinical isolates, respectively. The results of present study firstly indicate that PS-ODN targeted to oprM can significantly restore the susceptibility of MDR PA to existing antibiotics, which appears to be a novel strategy for treating MDR PA infections. PMID- 20955467 TI - Response of Gardnerella vaginalis biofilm to 5 days of moxifloxacin treatment. AB - Polymicrobial communities are often recalcitrant to antibiotics. We tested whether the polymicrobial Gardnerella vaginalis biofilm can be eradicated with moxifloxacin. Twenty women with bacterial vaginosis were treated with 400 mg moxifloxacin for 5 days. The changes in the occurrence and proportions of Gardnerella, Atopobium and Lactobacillus spp. were assessed using FISH. The bacterial biofilm was investigated using desquamated epithelial cells of spontaneously voided urine and sections of vaginal biopsies. Fifteen of 20 women showed a significant and sustained clinical response to moxifloxacin according to Amsel and Nugent criteria. The concentrations of adherent bacteria decreased significantly. The incidence and proportion of Atopobium declined sustainably. The proportions of Lactobacillus in the biofilm mass increased following therapy. Initially, Gardnerella was the main component of the polymicrobial biofilm. Following treatment, Gardnerella was not accessible to FISH in the urine and vaginal samples of 75% of all women. Ten to 12 weeks after the end of therapy, Gardnerella biofilm was cumulatively present in 40%. This was not due to newly acquired disease, but due to reactivation of the persisting, but biochemically inactive biofilm. Despite clear clinical efficacy, and initially definite suppression of the biofilm, moxifloxacin was, similar to metronidazole, not able to eradicate the Gardnerella vaginalis biofilm in all patients. PMID- 20955468 TI - Could Helicobacter organisms cause inflammatory bowel disease? AB - The discovery of Helicobacter pylori sparked a revolution in the understanding and management of peptic ulcer disease and gastric cancer. Other Helicobacter species are recognized as important pathogenic agents in colitic diseases of rodents and primates, in particular Helicobacter bilis, Helicobacter fennelliae, Helicobacter hepaticus and Helicobacter trogontum. Helicobacter bilis and H. hepaticus are now routinely used to initiate rodent models of inflammatory bowel disease (IBD), particularly in immunocompromised hosts. Molecular evidence exists linking various non-pylori Helicobacter spp. with human IBD; however, attempts to culture organisms in this disease cohort have proved unsuccessful to date. Attributing causation has therefore proved elusive. Seven enterohepatic, non pylori Helicobacter organisms have been successfully cultured from humans, namely Helicobacter canadensis, Helicobacter canis, Helicobacter cinaedi, H. fennelliae, Helicobacter pullorum, Helicobacter winghamensis and Helicobacter sp. flexispira taxon 8 (now classified as H. bilis). Of these, H. cinaedi and H. fennelliae are the closest to fulfilling Koch's postulates as causative agents in homosexual proctitis. The possibility that novel Helicobacter organisms have a role in the initiation of human IBD warrants further consideration and targeted investigations. PMID- 20955469 TI - Toxoplasma gondii primary infection in renal transplant recipients. Two case reports and literature review. AB - Toxoplasmosis after solid organ transplantation is a complication associated with high morbidity and mortality. Universal prophylaxis with trimethoprim sulfamethoxazole (TMP-SMX) is effective to prevent post-transplant toxoplasmosis. We report two cases of renal transplant recipients with negative antibodies against Toxoplasma gondii pretransplant who developed toxoplasmosis after TMP-SMX discontinuation. We have also performed a review of published cases of primary toxoplasmosis after renal transplantation. Of 20 cases reviewed, 11 were male and the mean age was 37.8 years (SD = 13.8). Donor serology for T. gondii was determined in 15 donors, two of them (13%) with negative immunoglobulin (Ig)G and four (27%) with positive IgG and IgM antibodies. Fever was present in 85% of primary toxoplasmosis and hematologic abnormalities were observed in 69% of the cases. Ten patients died (50%). All patients with fatal outcomes had clinical evidence of toxoplasmosis during the early post-transplant period (first 90 days), while no patient with late toxoplasmosis died (P = 0.003). Primary toxoplasmosis is associated with high mortality rates and TMP-SMX prophylaxis can delay the onset of symptoms resulting in an improvement of prognosis. PMID- 20955470 TI - Metaplasticity of the human trigeminal blink reflex. AB - Although synaptic plasticity in the human cerebral cortex is governed by metaplasticity, whether a similar mechanism operates at brainstem level is unknown. In this study in healthy humans we examined the effects and interactions induced by pairing supraorbital nerve high-frequency electrical stimulation (HFS) protocols on the R2 component of the trigeminal blink reflex [Mao, J.B. & Evinger, C (2001) J Neurosci., 21:RC151(1-4)]. Changes in the R2 component were tested by pairing three different priming stimulation protocols inducing long term potentiation (LTP)-like or long-term depression (LTD)-like effects (LTP-HFS and LTD-HFS), or no change (CONTROL-HFS) with a subsequent test LTP-HFS. Additionally, to examine changes in the R2 component induced by nonspecific factors, two CONTROL-HFS sessions were paired. Priming LTP-, LTD- or CONTROL-HFS potentiated, inhibited or left unchanged the area of the R2 component. Regardless of the type of priming LTP-, LTD- or CONTROL-HFS, the test LTP-HFS induced negligible differences in the R2 component. When two CONTROL-HFS sessions were paired, the test CONTROL-HFS increased the latency and markedly reduced the duration and area of the R2 component. The analysis of the normalized data across the first three experimental sessions, corrected for the inhibitory effects found in the fourth experiment, showed that the test LTP-HFS potentiated the R2 component area of the trigeminal blink reflex only when preceded by a priming LTD HFS. We propose that homosynaptic metaplasticity might operate in the brainstem circuitry of the blink reflex. PMID- 20955471 TI - Stereo correspondence is optimized for large viewing distances. AB - Stereo '3D' vision depends on correctly matching up the differing images of objects seen by our two eyes. But vertical disparity between the retinal images changes with binocular eye posture, reflecting for example the different convergence angles required for different viewing distances. Thus, stereo correspondence must either dynamically adapt to take account of changes in viewing distance, or be hard-wired to perform best at one particular viewing distance. Here, using psychophysical experiments, we show for the first time that human stereo correspondence does not adapt to changes in physical viewing distance. We examine performance on a stereo correspondence task at a short viewing distance (30 cm) and show that performance is improved when we simulate the disparity pattern for viewing infinity, even though these disparities are impossible at the physical viewing distance. We estimate the vertical extent of the retinally fixed 'search zones' as < 0.6 degrees at 14 degrees eccentricity, suggesting that most V1 neurons must be tuned to near-zero vertical disparity. We also show that performance on our stereo task at 14 degrees eccentricity is affected by the pattern of vertical disparity beyond 20 degrees eccentricity, even though this is irrelevant to the task. Performance is best when vertical disparities within and beyond 20 degrees eccentricity both indicate the same convergence angle (even if not the physical angle), than when the pattern of vertical disparity across the visual field is globally inconsistent with any single convergence angle. This novel effect of the periphery may indicate cooperative interactions between disparity-selective neurons activated by the same eye postures. PMID- 20955472 TI - Dopamine attenuates evoked inhibitory synaptic currents in central amygdala neurons. AB - The central nucleus of the amygdala (CeA) plays a critical role in regulating the behavioral, autonomic and endocrine response to stress. Dopamine (DA) participates in mediating the stress response and DA release is enhanced in the CeA during stressful events. However, the electrophysiological effects of DA on CeA neurons have not yet been characterized. Therefore, the purpose of this study was to identify and characterize the effect of DA application on electrophysiological responses of CeA neurons in coronal brain sections of male Sprague-Dawley rats. We used whole-cell patch-clamp electrophysiological techniques to record evoked synaptic responses and to determine basic membrane properties of CeA neurons both before and after DA superfusion. DA (20-250 MUM) did not significantly alter membrane conductance over the voltage range tested. However, DA significantly reduced the peak amplitude of evoked inhibitory synaptic currents in CeA neurons. Pretreatment with the D(2) receptor antagonist eticlopride failed to significantly block the inhibitory effects of DA. In contrast, pretreatment with the D(1) receptor antagonist SCH-23390 significantly reduced the effects of DA on evoked inhibitory neurotransmission in these neurons. Moreover, bath superfusion of the specific D(1) receptor agonist SKF 39393, but not the D(2) receptor agonist quinpirole, significantly reduced peak amplitude of evoked inhibitory synaptic events. DA reduced the frequency of miniature IPSCs without altering the amplitude, while having no effect on the amplitude of IPSCs elicited by pressure application of GABA. These results suggest that DA may modulate inhibitory synaptic transmission in CeA through D(1) receptor activation primarily by a presynaptic mechanism. PMID- 20955473 TI - Neurotrophin receptors TrkB.T1 and p75NTR cooperate in modulating both functional and structural plasticity in mature hippocampal neurons. AB - Tropomyosin-related kinase (Trk) receptors modulate neuronal structure and function both during development and in the mature nervous system. Interestingly, TrkB and TrkC are expressed as full-length and as truncated splice variants. The cellular function of the kinase-lacking isoforms remains so far unclear. We investigated the role of the truncated receptor TrkB.T1 in the hippocampus of transgenic mice overexpressing this splice variant by analyzing both neuronal structure and function. We observed an impairment in activity-dependent synaptic plasticity as indicated by deficits in long-term potentiation and long-term depression in acute hippocampal slices of transgenic TrkB.T1 mice. In addition, dendritic complexity and spine density were significantly altered in TrkB.T1 overexpressing CA1 neurons. We found that the effect of TrkB.T1 overexpression differs between subgroups of CA1 neurons. Remarkably, overexpression of p75(NTR) and its activation by chemical induction of long-term depression in slice cultures rescued the TrkB.T1-dependent morphological alterations specifically in one of the two subgroups observed. These findings suggest that the TrkB.T1 and p75(NTR) receptor signaling systems might be cross-linked. Our findings demonstrate that TrkB.T1 regulates the function and the structure of mature pyramidal neurons. In addition, we showed that the ratio of expression levels of p75(NTR) and TrkB.T1 plays an important role in modulating dendritic architecture and synaptic plasticity in the adult rodent hippocampus, and, indeed, that the endogenous expression patterns of both receptors change reciprocally over time. We therefore propose a new function of TrkB.T1 as being dominant-negative to p75(NTR). PMID- 20955474 TI - Ryanodine receptors selectively contribute to the formation of taste-evoked calcium signals in mouse taste cells. AB - The peripheral taste system uses multiple signaling pathways to transduce a stimulus into an output signal that activates afferent neurons. All of these signaling pathways depend on transient increases in intracellular calcium, but current understanding of these calcium signals is not well developed. Using molecular and physiological techniques, this study establishes that ryanodine receptors (RyRs), specifically isoform 1, are expressed in taste cells and that their physiological function differs among cell types employing different signaling pathways. RyR1 contributes to some taste-evoked signals that rely on calcium release from internal stores but can also supplement the calcium signal that is initiated by opening voltage-gated calcium channels. In taste cells expressing both signaling pathways, RyR1 contributes to the depolarization induced calcium signal but not to the calcium signal that depends on calcium release from stores. These data suggest that RyR1 is an important regulator of calcium signaling and that its physiological role in taste cells is dictated by the nature of the calcium signaling mechanisms expressed. PMID- 20955476 TI - An integrated review of the literature on challenges confronting the acute care staff nurse in discharge planning. AB - AIMS AND OBJECTIVES: This integrative review presents and synthesises previous research investigating practices, perceptions and experiences of bedside staff nurses relative to hospital discharge planning. BACKGROUND: Preparation for hospital discharge should begin at or prior to admission. Forces in the acute care environment, however, often impede comprehensive discharge planning. Evidence-based redesign of discharge planning processes is a priority for nurses and health care leaders. DESIGN: An integrative review. METHOD: The review was undertaken using eleven search terms to electronically scan CINAHL, Medline, PsycINFO and Dissertations and Theses databases for the period 1990-2009. Hand searching of reference lists and author searches was also conducted. Sixty English language articles were reviewed; 38 of these 60 publications met the study inclusion criteria. RESULTS: Seven themes were identified across the studies. These themes were intra- and interdisciplinary communication; systems and structures; time; role confusion; care continuity; knowledge; and the invisibility of the staff nurse role in discharge planning. CONCLUSIONS: Acute care bedside nurses frequently encounter significant barriers while providing discharge-related care. Although these barriers have been identified consistently in numerous studies spanning nearly two decades, few published reports address interventions designed to overcome identified obstacles and inefficiencies. Additional discharge planning redesign initiatives, which include rigorous evaluation of patient outcomes, are needed. RELEVANCE TO CLINICAL PRACTICE: As the direct caregivers with the most consistent presence and knowledge of patients' postdischarge needs, acute care bedside staff nurses play a critical role in preparing patients and families for the transition from hospital to home. Nurses are uniquely positioned to identify barriers and opportunities in discharge planning processes and contribute significantly to evidence-based reform initiatives. Effective and efficient patient-centred discharge planning processes can facilitate the transition from hospital to home and begin to address the adverse events experienced by some patients in the immediate postdischarge period. PMID- 20955477 TI - Comparison of prenatal education delivered by nurses in Ankara (Turkey) and New Orleans (USA). AB - AIM: This research was planned to compare prenatal education delivered by nurses in Ankara (Turkey) and New Orleans (USA). BACKGROUND: Prenatal education can increase awareness and improve the knowledge about risks factors and complications of pregnant women. Therefore, prenatal education is an important determinant of improved health outcomes of infants and of reduced maternal mortality. DESIGN: A descriptive survey. METHODS: This descriptive study was performed in various obstetrics clinics and antenatal outpatient clinics between April 2002-April 2003. The sample included all graduate nurses in prenatal units who gave their informed consent to participate. A demographic data form to collect data and a prenatal education checklist were prepared by the investigator. RESULTS: There was a significant difference in the educational levels of the nurses both in nursing education and in special courses as preparation to present prenatal education. The topics addressed during the prenatal education also differ significantly. The nurses in the USA mostly had a master's degree, while the nurses in Turkey mostly had two years of education after college. There was a significant difference between the two countries related to the qualification for giving prenatal education and having a certificate. CONCLUSION: There was a significant difference between the educational preparation of presenting nurses as well as the content of prenatal education in Ankara, Turkey and New Orleans, USA. Turkish nurses may benefit from an educational programme to prepare them to present prenatal education that may improve the knowledge of pregnant women and eventually lead to reduced maternal and infant mortality. RELEVANCE TO CLINICAL PRACTICE: The quality of the care provided by the nurses and midwives working in the prenatal area will increase following specific standardised training for becoming proficient. PMID- 20955478 TI - Emergency nurse practitioners: the views of patients and hospital staff at a major acute trust in the UK. AB - AIM: The study reported in this paper aimed at exploring the views of staff and patients of a potential emergency nurse practitioner service in an acute trust in the UK. BACKGROUND: The role of the nurse in emergency care has changed considerably in recent years, and the evolution of the emergency nurse practitioner role has changed emergency service provision dramatically. The emergency nurse practitioner role is not uniformly defined across emergency care in the UK, and the resulting blurring of the role of emergency nurse practitioners with that of emergency department medical staff is not helpful to hospital staff or patients. DESIGN: A quantitative and qualitative mixed method design was used that enabled exploration of an individual's viewpoint within their own practice or natural surroundings. METHOD: Self-completed questionnaires were used to determine health professionals' opinions, and semi-structured interviews were employed to explore patients' views. RESULTS: A total of 144 health professionals responded to the questionnaire survey giving a response rate of 28.5%, and 10 patients participated in qualitative interviews. Health professionals and patients alike were generally supportive of an emergency nurse practitioner service, but there were some concerns in relation to the role and functions of the emergency nurse practitioner and associated accountability issues. CONCLUSIONS: This paper contributes further data that demonstrate the inter-professional and patient support of the advanced role of the emergency nurse practitioner and highlights potential conflictual issues and barriers to implementation that can and must be resolved successfully through proper consultation prior to the service being introduced. RELEVANCE TO CLINICAL PRACTICE: This paper provides important information to health professionals and service providers that should help to facilitate the introduction and maintenance of a successful and effective emergency nurse practitioner service in any trust. PMID- 20955479 TI - A survey of registered nurses' perceptions of the code of professional conduct in Hong Kong. AB - AIM: To examine the perceptions of the code of professional conduct among practising registered nurses in Hong Kong. BACKGROUND: A code of professional conduct is intended to guide nurses in their practice and to ensure congruence with nursing goals and objectives. Such a code for nurses in Hong Kong has been in effect for two decades but, to date, no study has examined the perceptions of it among practising nurses. DESIGN: A survey of 320 practising registered nurses working in a hospital cluster in Hong Kong (mean postregistration experience=11.8 years). METHODS: A questionnaire developed to assess nurses' perceptions of the Code of Professional Conduct devised by the Nursing Council of Hong Kong. RESULTS: Providing safe and competent care, practising in accordance with the law and maintaining agreed standards were ranked in order as the three most important aspects. Safeguarding informed decision-making for patients who were mentally incapacitated or unable to speak for themselves, participating in continuing nursing education and raising objections to practices that compromise safe and appropriate care were considered the most challenging aspects to achieve in professional nursing practice. CONCLUSIONS: To educate nurses to become more assertive in safeguarding patients' rights and to encourage and support lifelong learning remains a major challenge in professional nursing practice. The profession and statutory bodies need to consider how best to enable practising nurses to address these issues. RELEVANCE TO CLINICAL PRACTICE: Examining the perceptions of practising nurses about the professional code is necessary to ensure that the profession is prepared to meet the ever-changing demands and expectations of the public whom it claims to serve. PMID- 20955480 TI - Communication in nursing care for patients requesting euthanasia: a qualitative study. AB - AIM: To describe the communication during the euthanasia care process for mentally competent, terminally ill patients in general hospitals in Flanders, as seen from the perspective of the nurse. BACKGROUND: International literature shows that nurses are involved in the care process surrounding euthanasia, regardless of the legal status of euthanasia in the country being studied. In particular, research shows that communication is an important part of good euthanasia care. However, the actual way nurses' communication contributes to the quality of the euthanasia care process remains unclear. DESIGN: A Grounded Theory Design was used. METHODOLOGY: Analysis of 18 in-depth, semi-structured interviews with nurses from nine different hospitals in Flanders (Belgium). The interviews took place during a 20-month period in 2005-2006. RESULTS: The euthanasia care process for mentally competent, terminally ill patients in general hospitals in Flanders is a complex and dynamic process, the connecting thread of which is nurses' communication. During this process, nurses perceive that they communicate often and a lot, with various people, in different contexts, in different ways and with various purposes. This communicative process is intensified by the moral and psychological weight of the theme, and its impact on everyone involved, as well as by the relatively short period of time, during which it all takes place. CONCLUSION: This article adds to the growing body of literature on nursing care for patients requesting euthanasia. The findings suggest that for nurses, communication is a key instrument for realising good-quality euthanasia care. RELEVANCE TO CLINICAL PRACTICE: Being the essence of nursing care for patients requesting euthanasia, nurses' communication requires support and guidance on the level of nursing education, professional guidelines and hospital context. PMID- 20955481 TI - Nurses' practice of blood transfusion in the United Arab Emirates: an observational study. AB - AIMS: The aim of this study was to document nurses' practice of red blood cells transfusion. BACKGROUND: In the United Arab Emirates hospitals, nurses are responsible for the administration of blood transfusions. The safety and effectiveness of the transfusion process is dependent, among others, on the knowledge and skills of nurses who perform the procedure. Poor practice may result in avoidable complications that may threaten patients' safety. Published work indicated that nurses' practice varied across contexts and highlighted that patients received suboptimal care and incorrect transfusion that culminated in death or morbidity. In the United Arab Emirates, publications related to nurses' practice of blood transfusion are lacking. DESIGN: Descriptive. METHODS: Data were collected by means of non-participant structured observation. Data collection was undertaken in two general public hospitals in the Emirate of Abu Dhabi, United Arab Emirates. A random sample of 50 nurses from both hospitals was selected. Each nurse was observed once, from 10 minutes prior to blood collection until 15 minutes after initiating a transfusion. RESULTS: Forty-nine nurses (98%) were observed. The maximum obtained score was 13 points of a possible score of 21, and 75% of nurses scored below the 50% level. Practice deficiencies included improper patient identification, suboptimal vital signs documentation and invalid methods of blood warming. CONCLUSIONS: Patients in both hospitals were at risk of receiving incorrect blood, suffering unobserved transfusion reaction and acquiring bacterial infection. RELEVANCE TO CLINICAL PRACTICE: This study revealed inadequate practices that nurses and hospitals should strive to change to provide a safer and more effective care that would, hopefully, minimise the risks and maximise the benefits of blood transfusion. These findings also have implications for clinical supervision and nurse education. PMID- 20955482 TI - Urinary incontinence in pregnant women and their quality of life. AB - AIMS AND OBJECTIVES: The aim was to investigate the prevalence of urinary incontinence during pregnancy and the related risk factors as well as to assess its influence on the quality of life. BACKGROUND: Although urinary incontinence is common during pregnancy and can have a substantial impact on quality of life, women rarely seek help for this symptom. DESIGN: This study was designed as a cross-sectional and descriptive survey. METHODS: A total of 393 pregnant women participated in the study between March and June 2007. The data was collected using the International Consultation on Incontinence Questionnaire Short Form and Wagner's quality of life scale. Potential risk factors were investigated through logistic regression analysis. RESULTS: The prevalence of urinary incontinence was 27% (106/393). Factors significantly associated with urinary incontinence included age group, parity, previous urinary incontinence, constipation, urinary incontinence in mother and sister, previous urinary incontinence during pregnancy and postpartum. CONCLUSION: According to the results of our study, urinary incontinence is common in women during pregnancy. The quality of life of pregnant women was found to be either unaffected or affected very little by urinary incontinence. RELEVANCE TO CLINICAL PRACTICE: This study reveals that the prevalence of urinary incontinence during pregnancy is very high. The findings will help increase the awareness of health care workers involved in the care of pregnant women about urinary incontinence and aid the design of more intensive education programmes directed towards the prevention of urinary incontinence during pregnancy. PMID- 20955483 TI - Promoting oral health during pregnancy: current evidence and implications for Australian midwives. AB - AIMS AND OBJECTIVES: The aim of this paper is to examine current evidence supporting the promotion of oral health during pregnancy and proffer aspects of a potential role for Australian midwives. BACKGROUND: Research continues to show that poor oral health during pregnancy can have an impact on the health outcomes of the mother and baby. Poor maternal oral health increases the chances of infants developing early caries and is strongly associated with adverse pregnancy outcomes such as preterm and low birth-weight babies. Unfortunately in Australia, no preventive strategies exist to maintain the oral health of pregnant women. DESIGN: Systematic review. METHOD: This review examines all literature on oral health during pregnancy published to date in the English language and focuses on whether preventive oral health strategies during the prenatal period are warranted in Australia and if so, how they could be provided. RESULTS: Maintaining oral health is important during pregnancy and many developed countries have implemented preventive strategies to address this issue using non dental professionals such as prenatal care providers. However, despite the positive international evidence, limited importance is being given to the oral health of pregnant women in Australia. It is also evident that the unique potential of prenatal care providers such as midwives to assess and improve maternal oral heath is not being thoroughly utilised. Compounding the issue in Australia, especially for pregnant women from socioeconomically disadvantaged backgrounds, is the limited access to public dental services and the high cost of private dental treatment. CONCLUSION: Promoting and maintaining oral health during pregnancy is crucial, and preventive prenatal oral health services are needed in Australia to achieve this. RELEVANCE TO CLINICAL PRACTICE: Midwives have an excellent opportunity to offer preventive oral health services by providing oral health assessments, education and referrals for pregnant women attending antenatal clinics. PMID- 20955484 TI - Safe early discharge for patients undergoing high dose chemotherapy with or without stem cell transplantation: a prospective analysis of clinical variables predictive for complications after treatment. AB - AIM: To identify which patient groups can be safely discharged early after high dose chemotherapy. BACKGROUND: Until recently, the standard of care for patients with haematological malignancies who have been treated with high dose chemotherapy has been to hospitalise them until neutrophil recovery and clinical improvement. Over the past years, a more liberal approach has resulted in a tendency to discharge patients earlier. However, currently it is unclear which clinical variables are important and which patient groups are most suitable to be discharged early. DESIGN: Prospective cohort study. METHODS: The study group of 55 patients underwent 82 admission periods for a total of 2269 patient days, which could be classified into four categories: induction treatment, consolidation treatment and autologous or allogeneic stem cell transplantation. Different clinical variables potentially interfering with early discharge were subsequently analysed for their association with each treatment group. RESULTS: The median duration of admission was 27 days. The incidence of fever (82.9%) and use of intravenous antibiotics (79.3%) was high in all treatment groups. The only statistically significant differences between groups were found for performance status and mucositis. In the patient group undergoing consolidation chemotherapy for acute myeloid leukaemia, the performance status was better and mucositis was less severe. The decline in performance status and the severity of mucositis were as expected most obvious 10-14 days after the start of chemotherapy. CONCLUSION: Patients undergoing consolidation chemotherapy appear to be the most suitable candidates for early discharge, especially in the first-week postchemotherapy treatment. Early discharge can also be considered in patients with a good performance status in the autologous stem cell transplantation group, directly after transplantation. RELEVANCE TO CLINICAL PRACTICE: An important factor in developing an early discharge programme is a good infrastructure, both at home and in the hospital. PMID- 20955485 TI - Is the Hospital Anxiety and Depression Scale (HADS) an appropriate screening tool for use in an alcohol-dependent population? AB - AIMS: To examine the psychometric properties of the Hospital Anxiety and Depression Scale in selected research to determine the suitability of this instrument for use in an alcohol-dependent population. BACKGROUND: Anxiety and depression represent a significant comorbid problem encountered with alcohol dependency. Effective screening for clinically relevant anxiety and depression is crucial for tailoring effective treatment intervention. However, no guidance exists to suggest the most appropriate screening measure in this clinical group. DESIGN: Narrative review. METHODS: Three criteria were used: factor analysis, test-retest reliability and internal consistency reliability. RESULTS: Factor analysis studies highlighted a mostly bi-dimensional model or a tripartite model, with only a couple of exceptions. Test-retest reliability came from only five studies, and while they all showed significantly positive correlated scores, only one study fulfilled criteria for a good or efficient reliability measure. The last evaluation, internal consistency reliability, faired much better in terms of recommended scores for reliability. Nearly all the studies showed a high level of internal consistency reliability. CONCLUSION: It is concluded that the Hospital Anxiety and Depression Scale is likely to be a suitable screening tool for use in an alcohol-dependent population. RELEVANCE TO CLINICAL PRACTICE: Effective screening for anxiety and depression can significantly enhance treatment efficacy when working with those patients presenting with alcohol dependency. This review suggests that the Hospital Anxiety and Depression Scale may be an appropriate instrument to use in this group based on observation of the tools measurement characteristics. PMID- 20955486 TI - Hepatitis C virus among non-injecting cocaine users (NICUs) in South America: can injectors be a bridge? AB - AIM: To investigate the factors associated with hepatitis C virus (HCV) infection among non-injecting cocaine users (NICUs) and to compare practices associated with HCV and HIV infection. DESIGN: An intercountry cross-sectional study. Setting Buenos Aires and Montevideo metropolitan areas. PARTICIPANTS: A total of 871 NICUs. MEASUREMENTS: NICUs were interviewed and their blood was drawn and used for HCV, HIV, HBV surface antigen (HbsAg), HB-anticore and Venereal Disease Research Laboratory (VRDL) antibody assays. Bivariate and multivariate logistic regression analyses included comparisons of HCV and HIV mono-infected participants with HCV-HIV seronegatives. FINDINGS: Prevalence rates were 8.8 [95% confidence interval (CI): 6.9-10.8) for HCV and 7.9 (95% CI: 6.1-9.7) for HIV. HCV-infected NICUs were twice as likely as HCV-HIV seronegatives to have shared straws for cocaine snorting or sniffing, even when adjusted for other variables. HCV prevalence rates ranged from 3.6% among NICUs who denied sharing straws and having had an injection drug user (IDU) or an HIV-positive sexual partner to 12.6% among participants who reported ever having shared straws or having had either an IDU- or HIV-positive sexual partner (chi(2) (trend) = 6.56, P = 0.01). CONCLUSIONS: Non-injecting cocaine users from South America are vulnerable to multiple infections and HCV infection appears to occur through the sharing of straws. HCV infection is associated with intimate relationships with IDUs or HIV seropositive partners, supporting the hypothesis that HCV risk may be due primarily to risk-taking behaviour associated with drugs in this population. PMID- 20955487 TI - Common and drug-specific genetic influences on subjective effects to alcohol, tobacco and marijuana use. AB - AIM: To examine variation in positive and negative subjective effects to alcohol, tobacco and marijuana and covariation between these three drugs and each effect. DESIGN: Retrospective self-reports of subjective effects were collected to estimate the genetic and environmental influences and the extent of their specificity across three drugs. PARTICIPANTS: Data were drawn from 1299 adolescent and young adult same- and opposite sex twin- and sibling-pairs participating in the Colorado Center for Antisocial Drug Dependence (CADD). SETTING: A large, collaborative, longitudinal study of substance use and antisocial behavior in community and clinical adolescents. MEASUREMENT: Subjective effects were assessed using a 13-item questionnaire that included positive and negative responses to alcohol, tobacco and marijuana. FINDINGS: Heritable influences contributed moderately (additive genetic effects 16-56%) to positive and negative subjective effects to all three drugs and did not differ for males and females. Genetic and environmental contributions to positive and negative subjective effects are largely non-overlapping for tobacco and marijuana. Multivariate genetic modeling indicated that subjective effects to alcohol, tobacco and marijuana share a common, heritable etiology and that drug specific genetic influences were an important contributor to individual differences in drug response. CONCLUSIONS: Results from our genetic analyses suggest that subjective effects to these commonly used and misused drugs are heritable and that the genetic and environmental influences on effects to one drug also influence subjective effects to other drugs. PMID- 20955489 TI - A meta-analysis of alcohol toxicology study findings among homicide victims. AB - AIM: To synthesize the results of alcohol toxicology reports for homicide victims and examine variations in these results across person and setting characteristics. METHODS: We meta-analyzed 61 independent studies from 57 published manuscripts which met the study inclusion criteria and reported alcohol toxicology test results for homicide victims. A total of 71, 031 toxicology test results, derived from 78, 265 homicide victims across 13 countries (most from the United States), were examined. RESULTS: On average, 48% of homicide victims tested positive for alcohol and 33% (using the 0.08 threshold) or 35% (using the 0.10 threshold) were determined to be intoxicated. The proportion of homicide victims testing positive for alcohol appeared to be decreasing over time. Further, the proportion testing positive increased with age is higher for female than for male victims, and differs by race. Finally, the overall estimates were relatively stable across study sites. CONCLUSION: Alcohol toxicology test results remain an important method for measuring the success of efforts to manage the consequences of alcohol. However, future toxicology studies should focus upon collecting information on evidence processing time, establishing measurement standards for reporting data and ensuring that subgroup estimates are included for purposes of cross-site comparisons. PMID- 20955488 TI - Dizziness and the genetic influences on subjective experiences to initial cigarette use. AB - AIM: To examine individual differences in positive and negative subjective experiences to initial cigarette use. DESIGN: Retrospective self-reports of initial subjective experiences were examined to estimate the genetic and environmental influences and the extent of their covariation across different effects. PARTICIPANTS: Data was drawn from 2482 young adult same-and opposite sex twins- and siblings participating in the National Longitudinal Study of Adolescent Health. MEASUREMENT: Subjective experiences were retrospectively collected using the Early Smoking Experience (ESE) questionnaire. FINDINGS: Positive experiences evidenced moderate heritable contributions (40%, 95% CI: 0.22 to 0.56), as did an overall hedonic measure (34%, 95% CI: 0.22 to 0.46) and dizziness (34%, 95% CI: 0.15 to 0.52). Negative experiences evidenced small heritable contributions (13%, 95% CI: 0.00 to 0.36). Individual specific environmental influences were strong and accounted for the remaining proportion of observed variation in these experiences. Multivariate genetic modeling identified a moderately heritable underlying factor (37%, 95% CI: 0.22 to 0.52) that influenced the covariation of diverse subjective experiences and loaded most heavily on dizziness. Positive experiences also evidence residual genetic influences that were uncorrelated with other subjective experiences. CONCLUSIONS: How a person experiences their initial few cigarettes is due to both heritable contributions and environmental experiences unique to the person. The covariation of diverse subjective experiences appears to be due to a heritable latent sensitivity to the chemicals contained in an average cigarette and is best indexed by dizziness. PMID- 20955490 TI - Addiction and its sciences-philosophy. AB - Philosophers have been writing about addiction continually since the 1990s, and a number of much older, broader philosophical theories are of direct relevance to the study of addiction. Yet the developments in the philosophical study of addiction have seldom been incorporated into the science of addiction. In this paper I focus upon two issues in the scientific literature: the disease classification of addiction and the claim that addictive behaviour is compulsive. While each of these views is open to debate on empirical grounds, there is a long history of philosophical work which must be engaged if these claims are to be justified in a philosophical sense. I begin by showing how the conceptual work of philosophers such as Boorse and Nordenfelt can be used to critique the claim that addiction is a disease. Following this, I demonstrate how deep philosophical concepts of freedom and willpower are embedded into scientists' claims about compulsion in drug addiction. These concepts are paradoxical and difficult, and they have consumed numerous contemporary philosophers of mind, such as Audi, Arpaly, Frankfurt, Mele, Wallace and Watson, among many others. I show how problems can arise when scientists sidestep the work of these philosophers, and I explain where scientists should seek to include, and sometimes exclude, philosophical concepts. CONCLUSIONS: Many philosophical concepts and theories can be of use to addiction science. The philosophical work must be understood and acknowledged if the science is to progress. PMID- 20955491 TI - The relationship between addiction and reward bundling: an experiment comparing smokers and non-smokers. AB - AIMS: Previous studies indicate that addicts show reduced preference for more delayed versus more immediate rewards compared to non-addicts. This may reflect a lower propensity to view such decisions in terms of the larger sequences to which they typically belong (e.g. smoking is a frequently repeated act). Therefore, this study aims to test whether, in a sequence of decisions involving smaller, sooner (SS) versus larger, later (LL) rewards, suggesting or forcing people with a propensity to addiction to make the decision for the series as a whole would increase LL preference. It is hypothesized that people without a propensity to addiction should benefit less from being encouraged to think of reward sequences because they already tend to take that view. DESIGN: Thirty regular smokers (as exemplars of addicted individuals) and 30 non-smokers chose between small short term and larger long-term monetary rewards over a sequence of four decisions spaced 2 weeks apart. Subjects were divided into three groups: one who made each decision independently with no suggestion that they be considered as a series ('free'), a group to whom it was suggested from the start that they consider each decision as part of the series ('suggested') and a group who were told that their very first choice in the series would be used for the remaining decisions ('forced'). All subjects were paid the amounts they had chosen. SETTING: A laboratory room at the University of Cape Town (UCT). PARTICIPANTS: UCT undergraduate volunteers. ANALYSES: The proportion of LL choices in each subgroup was evaluated by chi(2) tests and a probit model. FINDINGS: Smokers increased their preference for LL rewards when 'bundling' of individual decisions into a sequence was either suggested or forced. This preference increased with repeated experience. Non-smokers showed neither pattern. CONCLUSIONS: The propensity of smokers to prefer small short-term rewards over larger delayed rewards may be mitigated, over a sequence of decisions of this kind, by encouraging or forcing them to think of the sequence as a whole. If replicated, this finding may form the basis of an intervention that could attenuate the choice patterns characteristic of addiction. PMID- 20955492 TI - Cessation of groin injecting behaviour among patients on oral opioid substitution treatment. AB - AIMS: To identify factors that might influence cessation of groin injecting (GI) among patients receiving oral opioid substitution treatment (OST). DESIGN: A cross-sectional survey. SETTING: Drug treatment centres in South East England. PARTICIPANTS: Groin injectors (GIs) attending an ultrasound 'health-check' clinic. MEASUREMENTS: Clinical data and ultrasound images; comparing 65 patients who had injected drugs in the femoral vein (fv) in the previous month (current GIs) with 49 former groin injectors (former GIs). FINDINGS: Most of the 114 clinic attendees were men (69.3%) and white European (95.6%). Mean age, duration of GI and time in treatment were 36.4 years, 54.8 months and 20.5 months, respectively. Former GIs were significantly older (P < 0.001) and had been injecting (P < 0.05) and in treatment (P < 0.05) for longer than current GIs. History of deep vein thrombosis (DVT, P < 0.05) and septicaemia (P < 0.05); moderate/severe chronic venous disease (CVD, P < 0.01); and 'very severe' fv damage on ultrasonography (P < 0.05) were more common among former GIs. A logistic regression model correcting for the effects of covariants revealed age (B 0.08; Wald 7.1; P < 0.01) and severity of venous disease (B 1.1; Wald 4.1; P < 0.05) as the strongest predictors of behaviour change. CONCLUSIONS: GI cessation is associated with longer time in treatment, increasing age and the presence of CVD and severely damaged fv. GI appears to be an intractable behaviour that often persists despite OST and severe health complications. Persistent GI should prompt a review of whether OST is optimized and whether other interventions are needed to promote behaviour change prior to the development of serious harm. PMID- 20955493 TI - Correlation between mutations in the core and NS5A genes of hepatitis C virus genotypes 1a, 1b, 3a, 3b, 6f and the response to pegylated interferon and ribavirin combination therapy. AB - Several studies have reported correlation between mutations in core and NS5A proteins of hepatitis C virus (HCV) and response to interferon (IFN) therapy. In particular, mutations in NS5A protein have been shown to correlate with responsiveness to IFN treatment of HCV-1b in Japanese patients. This study investigated whether amino acid (aa) mutations in the core and NS5A proteins of HCV-1a, 1b, 3a, 3b and 6f correlated with the response to pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy in Thai patients. The entire sequences of core and NS5A of HCV from 76 HCV-infected patients were analysed in comparison with corresponding reference sequences. The data revealed that the number of aa mutations in full-length NS5A, its C-terminus, IFN sensitivity-determining region, variable region 3 (V3) and V3 plus flanking region of HCV-1b NS5A protein were significantly higher in responders than in the treatment failure group (P = 0.010, 0.031, 0.046, 0.020 and 0.006, respectively). Similar results were found in a putative protein kinase R binding domain region in HCV-6f NS5A protein (P = 0.022). Moreover, specific aa substitutions in NS5A that appeared to be associated with responders or the treatment failure group were observed at positions 78 and 305 for HCV-1b (P = 0.028), 64 and 52 for HCV-1a (P = 0.033) and 6f (P = 0.045). Nevertheless, analysis of aa sequences of core protein revealed highly conserved sequences among HCV genotypes and no significant differences between the viruses from responders and the treatment failure group. Our findings indicate that mutations in aa residues of NS5A of HCV-1a, 1b and 6f correlated well with responsiveness to Peg-IFN and RBV combination therapy. PMID- 20955495 TI - Implications of the global increase of diabetes for tuberculosis control and patient care. AB - OBJECTIVES: To review the current knowledge about tuberculosis (TB) and diabetes, assessing the implication of the global increase of diabetes for TB control and patient care. METHODS: Systematic literature review. RESULTS: Using public databases, it can be estimated that 12.6% (95% CI 9.2-17.3%) of new TB cases in the 10 countries with the highest TB burden will be attributable to TB in 2030, a relative increase of 25.5% compared to 2010. Diabetes is associated with a higher age and body weight among patients with TB, but probably not with a specific clinical presentation of TB. Rifampicin hampers glycemic control by increasing the metabolism of most oral antidiabetic drugs, while diabetes patients may have lower concentrations of anti-TB drugs. This might be one factor contributing to higher TB treatment failure rates. CONCLUSIONS: The global epidemic of diabetes has implications for control and treatment of TB. Prospective studies are needed to improve prevention, early detection and treatment of concomitant diabetes and TB, especially in developing countries. PMID- 20955496 TI - Migration and immunization: determinants of childhood immunization uptake among socioeconomically disadvantaged migrants in Delhi, India. AB - OBJECTIVE: To determine the coverage of childhood immunization appropriate for age among socioeconomically disadvantaged rural-urban migrants living in Delhi and to identify the determinants of full immunization uptake among these migrant children. METHODS: This is a cross-sectional survey of 746 rural-urban migrant mothers with a child aged up to 2 years, who were interviewed with a pretested questionnaire. Data pertaining to the reception of various vaccines, migration history and some other social, demographic and income details were collected. Multiple logistic regression analyses were performed to identify the determinants of full immunization status. RESULTS: Immunization coverage rates were lower among migrants than the general population of Delhi and even lower among recent migrants. The likelihood of a child receiving full immunization rose with age of the mother, her educational attainment and the frequency of her use of health care. The head of household having a secured salaried job also significantly increased the likelihood of full immunization, as did post-natal visits by a health worker. CONCLUSION: Migrant status favours low immunization uptake particularly in the vulnerability context of alienation and livelihood insecurity. Services must be delivered with a focus on recent migrants; investments are needed in education, socio-economic development and secure livelihoods to improve and sustain equitable health care services. PMID- 20955497 TI - Investigation of an epidemic of Hepatitis E in Nellore in south India. AB - OBJECTIVE: To determine the incidence of acute hepatitis because of hepatitis E virus (HEV) and the source of the epidemic in Nellore in south India in 2008. METHODS: Anti-HEV IgM ELISA and RT-PCR for HEV-RNA were carried out on blood and stool samples from patients with acute hepatitis presenting to different hospitals in the city. The city was divided into 33 clusters, and 20 families from each cluster were systematically interviewed to determine the incidence of hepatitis E in the city. The survey was conducted on 2685 residents of 673 households from 24th November to 4th December 2008. RESULTS: The overall incidence of hepatitis was 5.7% (152/2685), i.e. an estimated 23,915 persons in the city were affected. There were two deaths because of acute hepatitis in the population surveyed translating to an estimated 315 deaths. Men had higher attack rates than women (7.8%vs. 3.5%) and young adults compared to children under 5 years (6.9%vs. 2.9%). Families drinking water from the pumping station at Bujjamarevu had the highest attack rate of 54.5% (39.8-69.2%). HEV IgM antibodies were present in 80/100 plasma samples tested. HEV-RNA was detected in 43/100 individuals tested, and isolates were characterized as genotype 1 by sequencing. CONCLUSION: Sewage draining into the river close to the pumping stations and broken pipelines crossing sewage drains may have triggered this large outbreak. PMID- 20955498 TI - Barriers to starting ART and how they can be overcome: individual and operational factors associated with early and late start of treatment. AB - OBJECTIVE: Despite expanding access to antiretroviral therapy (ART) in Sub Saharan Africa, there are few data on patients' perceptions about starting ART to explore issues affecting decisions to start ART in eligible individuals during the ART roll out. METHODS: We studied patterns of ART uptake for 957 participants in a trial of cryptococcal disease prevention and performed a qualitative cross sectional study about issues affecting decisions to start ART in this cohort. In depth interviews (IDIs) were conducted with 48 participants who started ART after variable time on the trial. RESULTS: Time to starting ART from trial enrolment decreased during the ART roll out (Median 83 days to 68 days). Multiple factors causing delay to ART were reported; awaiting home visit by service provider (P=0.025), domestic issues (P=0.028), moving from area (P<=0.001) and fear of side effects (P=0.013) were statistically significant. In the IDIs, fear of side effects was the strongest factor for delay and observation of health improvement in others on ART was the strongest inducement to start. Information from patients already taking ART was the most valued source of information. CONCLUSIONS: This study provided novel information about factors encouraging people to start ART early; positive beliefs about ART were the most important. Whilst side effects of ART must not be downplayed, programmes should provide information in a balanced way to prevent unnecessary fear of starting ART. Those already receiving ART were found to be good advocates and should be utilised by ART programmes to educate others. PMID- 20955499 TI - Growth of infants born to HIV-infected women in South Africa according to maternal and infant characteristics. AB - OBJECTIVE: To evaluate growth parameters assessed by weight and length in HIV infected and HIV-uninfected infants born to HIV-infected mothers in South Africa from birth to 6 months of age. METHODS: We calculated z-scores for weight-for-age (WAZ), length-for-age (LAZ) and weight-for-length (WLZ) among a cohort of 840 mother-infant dyads. Multivariable Cox proportional hazards models with time varying covariates were used to estimate the risk of falling <-2 z-scores for WAZ, LAZ, and WLZ as a function of infant and maternal characteristics. RESULTS: By 6 months after birth, a fifth of infants had WAZ <-2, 19% had an LAZ <-2, and 29% had a WLZ <-2. WLZ and WAZ were significantly lower in HIV-infected infants than in uninfected infants by 3 months of age and LAZ by 6 months of age (P<0.001). The risk of WAZ falling <-2 was associated with decreasing maternal CD4 cell count (adj. HR for CD4 cell count <200 cells/MUl: 1.64; 95% CI: 1.10 2.43), premature birth (adj. HR: 2.82; 95% CI: 2.06-3.86) and formula feeding (adj. HR: 3.35; 95% CI: 1.64-6.85). The risk of LAZ falling <-2 was associated with increasingly lower maternal age (adj. HR for<20 years: 0.54; 95% CI: 0.31 0.96), lower maternal CD4 cell count (adj. HR for CD4 cell count <200 cells/MUl: 1.72; 95% CI: 1.14-2.59), premature birth (adj. HR: 2.37; 95% CI: 1.70-3.30) and formula feeding (adj. HR: 4.22; 95% CI: 1.85-9.62). The risk of WLZ falling <-2 was significantly associated with infant HIV infection (adj. HR: 1.64; 95% CI: 1.16-2.32) and formula feeding (adj. HR: 1.78; 95% CI: 1.11-2.83). The risk of WAZ and LAZ falling <-2 was more than two times greater for HIV-infected infants than for uninfected infants with gastrointestinal infections. CONCLUSIONS: HIV infected infants were more likely to be stunted and wasted than uninfected infants, which often occurred within 3 months after birth. Infants who were born to mothers with advanced HIV disease, formula-fed and co-infected with HIV and gastrointestinal infections were at greater risk for growth disturbances. Further interventions are needed to promptly initiate both HIV-infected mothers and infants on appropriate antiretroviral therapy and nutritional supplementation. PMID- 20955500 TI - Testing clinical surveillance of acute flaccid paralysis in Egypt post eradication of poliomyelitis. AB - OBJECTIVE: To assess the knowledge of polio detection and notification by front line clinicians in Egypt. METHODS: This study examines clinicians' knowledge and awareness of polio detection and notification using a multiple-choice questionnaire (maximum score=43) in three large health care centres in central Cairo (n=52). RESULTS: The results reveal a significant variation of knowledge amongst doctors, with junior and senior house officers scoring an average of 30.6 (95% CI: 29.5-31.7), specialist registrars and consultant paediatricians 30.3 (CI 28.9-31.7), and public health doctors 35.4 (CI 32.9-36.8). Mean total scores of public health doctors were significantly higher than those of other clinicians. Senior paediatricians performed no better than newly qualified doctors. CONCLUSIONS: The results suggest that there is a need for more clinical teaching and training amongst junior doctors as well as senior clinicians and consultants. Appropriate knowledge of diagnosing AFP and of the correct protocol amongst clinicians is essential to maintain the high quality of the WHO programme in Egypt. PMID- 20955501 TI - Challenges in HIV and visceral leishmania co-infection: future research directions. PMID- 20955502 TI - Reticulon short hairpin transmembrane domains are used to shape ER tubules. AB - Reticulons are integral membrane proteins that partition into and shape the tubular endoplasmic reticulum (ER). We propose that reticulons use a membrane insertion mechanism to generate regions of high membrane curvature in the ER. A reticulon contains two short hairpin transmembrane domains (TMDs), which could generate membrane curvature by increasing the area of the cytoplasmic leaflet. Here, we test whether the short length of these hairpin TMDs is required for reticulon membrane-shaping functions in mammalian cells. We lengthened the TMDs of reticulon 4 to resemble a typical bi-pass TMD that spans both leaflets. We find that TMD mutants oligomerize like wild type (wt), however, they are not immobilized, do not partition into tubules, do not constrict tubules and no longer suppress peripheral ER cisternae. Therefore, short hairpin TMD length is required for reticulon protein partitioning and membrane-shaping functions. Another membrane protein with a short hairpin TMD is caveolin. We show that an ER retained caveolin construct also partitions within the ER in a manner that is dependent on it containing a short hairpin TMD. These data suggest that a short hairpin TMD may be a general feature used by membrane-shaping proteins to partition into and shape regions of high membrane curvature. PMID- 20955503 TI - Rosai-Dorfman disease manifesting as an epibulbar ocular tumour. AB - The authors report a rare case of extranodal Rosai-Dorfman disease without systemic involvement. A 14-year-old girl presented with a slowly progressive, non tender, well-circumscribed, perilimbal nodule in the right eye. Excisional biopsy was performed and histopathologic and immunohistochemical analysis established the diagnosis. Systemic evaluation revealed no other masses. After complete excision of the epibulbar lesion, the patient is asymptomatic and remains on regular follow up with no signs of recurrence. Rosai-Dorfman disease is an infrequent, benign histiocytic disorder that can rarely manifest as an exclusive extranodal mass. We report a case of solitary epibulbar Rosai-Dorfman disease, successfully treated with complete surgical excision of the lesion. PMID- 20955504 TI - High sensitivity troponins and better patient care. PMID- 20955505 TI - Not a high-sensitivity troponin T assay. PMID- 20955506 TI - Mutualisms in a changing world: an evolutionary perspective. AB - Ecology Letters (2010) 13: 1459-1474 ABSTRACT: There is growing concern that rapid environmental degradation threatens mutualistic interactions. Because mutualisms can bind species to a common fate, mutualism breakdown has the potential to expand and accelerate effects of global change on biodiversity loss and ecosystem disruption. The current focus on the ecological dynamics of mutualism under global change has skirted fundamental evolutionary issues. Here, we develop an evolutionary perspective on mutualism breakdown to complement the ecological perspective, by focusing on three processes: (1) shifts from mutualism to antagonism, (2) switches to novel partners and (3) mutualism abandonment. We then identify the evolutionary factors that may make particular classes of mutualisms especially susceptible or resistant to breakdown and discuss how communities harbouring mutualisms may be affected by these evolutionary responses. We propose a template for evolutionary research on mutualism resilience and identify conservation approaches that may help conserve targeted mutualisms in the face of environmental change. PMID- 20955507 TI - Mimicry between unequally defended prey can be parasitic: evidence for quasi Batesian mimicry. AB - The nature of signal mimicry between defended prey (known as Mullerian mimicry) is controversial. Some authors assert that it is always mutualistic and beneficial, whilst others speculate that less well defended prey may be parasitic and degrade the protection of their better defended co-mimics (quasi-Batesian mimicry). Using great tits (Parus major) as predators of artificial prey, we show that mimicry between unequally defended co-mimics is not mutualistic, and can be parasitic and quasi-Batesian. We presented a fixed abundance of a highly defended model and a moderately defended dimorphic (mimic and distinct non-mimetic) species, and varied the relative frequency of the two forms of the moderately defended prey. As the mimic form increased in abundance, per capita predation on the model-mimic pair increased. Furthermore, when mimics were rare they gained protection from predation but imposed no co-evolutionary pressure on models. We found that the feeding decisions of the birds were affected by their individual toxic burdens, consistent with the idea that predators make foraging decisions which trade-off toxicity and nutrition. This result suggests that many prey species that are currently assumed to be in a simple mutualistic mimetic relationship with their co-mimic species may actually be engaged in an antagonistic co-evolutionary process. PMID- 20955508 TI - Laparoscopic restorative proctocolectomy: a 10-year experience of an evolving technique. AB - AIM: Restorative proctocolectomy is the definitive procedure for ulcerative colitis. The potential benefits of a minimal invasive approach make it appropriate to consider this approach provided that there are no adverse effects. The aim of the present study was to report our experience of laparoscopic assisted and 'total' laparoscopic restorative proctocolectomy (LRPC) and to highlight the difficulties encountered and the functional results obtained. METHOD: Electronic data were prospectively collected from all patients who underwent laparoscopic restorative proctocolectomy (LRPC) from October 1999 to April 2010. RESULTS: Seventy-two (40 male) patients [median body mass index 24 (19-48) kg/m(2) ] underwent LRPC over 10 years. Three had cancer. Forty-two had undergone a previous colectomy (laparoscopic in 38). There were 40 W- and 32 J pouch reconstructions; seven were single-port procedures. The median operation time was 210 (75-330) min. There were five (7%) conversions, one of which resulted in immediate pouch failure. The median time to full diet was 36 (4-168) h, with a median hospital stay of 7 (2-64) days. There were seven (10%) readmissions. Complications were immediate (3%), early (22%) and long term (11%). The incidence of failure (excision or indefinite diversion) was 2.7%. The stoma has been closed in 67 patients. Median frequency of defaecation was 4/24 h, with normal continence in 90% and the ability to defer during the day in 98%. There was no new case of impotence or dyspareunia. CONCLUSION: Laparoscopic restorative proctocolectomy is safe and gives good results when performed by an experienced laparoscopic surgeon. PMID- 20955509 TI - Use of topical negative pressure in assisted abdominal closure does not lead to high incidence of enteric fistulae. PMID- 20955510 TI - Scoring the obstructed defaecation syndrome: need for clarity. PMID- 20955511 TI - The nursing and financial implications of laparoscopic colorectal surgery: data from a randomized controlled trial. AB - AIM: The issue of cost effectiveness of laparoscopic surgery remains uncertain and its impact on the ward nursing staff is unaddressed. This study investigated these issues using patients from a single centre admitted to a randomized controlled trial. METHOD: All patients recruited into the Australasian Laparoscopic Colon Cancer Study (ALCCaS) from The Queen Elizabeth Hospital between January 1999 and March 2005 were included in this study. Data relating to hospital cost were collated from the Hospital Patient Costing System. Nursing interventions were calculated in minutes per patient, using the excelcare Software database. RESULTS: Data from 97 patients were analysed (laparoscopy, 53; open surgery, 44). The median number of hours of nursing input per patient was 80 (27.5-907) h in the open surgery group and 58.5 (15-684.5) h in the laparoscopy group. This difference was further increased after exclusion of patients converted from laparoscopy to open surgery. The median total cost of the procedure was AUS $9698/L 5631 (AUS $3862-90,397) in the open surgery group and AUS $10,951/L 6219 (AUS$2337-66,237) in the laparoscopy group. CONCLUSION: These data suggest that laparoscopic colorectal surgery is equivalent in price to open surgery and there may be added benefits in reduced nursing intensity. PMID- 20955512 TI - Sacral neuromodulation: long-term outcome and quality of life in patients with faecal incontinence. AB - AIM: Since 1994 sacral neuromodulation (SNM) has increasingly been used for the treatment of faecal incontinence, but no long-term data in a large group of patients have so far been published. We report long-term outcome and quality of life in the first 50 patients treated by permanent SNM for faecal incontinence. METHOD: We began to use SNM in 2000. Data from the first 50 patients with faecal incontinence who underwent permanent SNM are presented. Efficacy was assessed using a bowel diary and the Quality of Life score was assessed by the Faecal Incontinence Quality of Life questionnaire (FIQOL) and the standard short form health survey questionnaire (SF-36). RESULTS: Over a median follow up of 7.1 (5.6 8.7) years, forty-two (84%) patients had an improvement in continence of over 50%. Median incontinent episodes and days of incontinence per week decreased significantly during follow up (P<0.002). Improvement was seen in all four categories of the FIQOL scale and in some domains of the SF-36 QOL questionnaire. There were no statistically significant changes in the median resting and squeeze anal canal pressures. CONCLUSION: Initial improvement in continence with SNM was sustained in the majority of patients, with an overall success rate of 80% after a permanent implant at 7 years. PMID- 20955513 TI - Single incision laparoscopic total colectomy and proctocolectomy for benign disease: initial experience. AB - AIM: This paper presents our initial experience of single incision laparoscopic total colectomy and proctocolectomy. METHOD: Four female patients (mean age 35.5 years; mean body mass index 24.7 kg/m(2) ) underwent total colectomy with end ileostomy (n = 2) and proctocolectomy with stapled ileum pouch-anal (n = 1) and rectal (n = 1) anastomosis with loop ileostomy, for benign disease, using a single-incision laparoscopic approach. The single port was placed at the umbilicus or the ileostomy site. Specimen extraction was through the port site. RESULTS: Operative procedures were performed with a mean operative time of 212 min, mean blood loss of 30 ml and no intraoperative complication. No additional abdominal ports were required. A postoperative ileus (n = 1) on day three resolved spontaneously and the. mean hospital stay was 4.5 days. CONCLUSION: Single-incision laparoscopic total colectomy or proctocolectomy is feasible for benign disease in selected patients. PMID- 20955514 TI - Diagnostic performance of chromoendoscopy and narrow band imaging for colonic neoplasms: a meta-analysis. AB - AIM: We conducted a meta-analysis to compare the diagnostic test performance of chromoendoscopy and narrow band imaging (NBI) for colonic neoplasms. METHOD: MEDLINE, EMBASE and the Cochrane Library were searched (1966 to March 2009). Articles were included if: (i) chromoendoscopy or NBI was used, (ii) sensitivity and specificity were reported; (iii) absolute numbers of true-positive, false positive, true-negative and false-negative results were provided or could be calculated; and (iv) pathology was used as the reference standard. Sensitivity and specificity were pooled using random effects model. Secondary analyses were conducted by limiting the studies in which magnifying endoscopy was used alone as a diagnostic modality, and polyp size and macroscopic appearance of lesions were not considered. RESULTS: Of 1342 screened articles, 27 met the inclusion criteria. Pooled sensitivity for chromoendoscopy and NBI was 0.94 (95% CI, 0.92 0.95) and 0.94 (0.91-0.97), and specificity was 0.82 (0.77-0.88) and 0.86 (0.83 0.89), respectively. There were no differences in sensitivity (P = 0.99) or specificity (P = 0.54) between the two methods. In the secondary analysis, pooled sensitivity for choromoendoscopy and NBI was 0.93 (95% CI, 0.90-0.97) and 0.96 (0.93-0.99) and specificity was 0.80 (0.73-0.87) and 0.85 (0.78-0.92). respectively. Overall, the pooled false-negative rate was 0.057 (95% CI, 0.040 0.73) for chromoendoscopy and 0.057 (95% CI, 0.028-0.085) for NBI. CONCLUSION: Chromoendoscopy and NBI had similar diagnostic test characteristics in the assessment of colonic neoplasms; however, the false-negative rate for both methods of 5.7% is an unacceptably high rate and currently therefore, neither method is ready for general use. PMID- 20955515 TI - Characterization of beta-adrenoceptor-mediated relaxation signals in isolated pulmonary artery of Dahl salt-sensitive hypertensive and normotensive rats. AB - 1 Relaxant responses to isoprenaline (ISO) were studied in the pulmonary arteries of normotensive and hypertensive Dahl salt-sensitive rats. Rats were fed either a high-salt (4.0%) or low-salt (0.14%) diet for 5 weeks. Animals fed a high-salt diet (167/123+/-2/2 mmHg) had a significantly higher blood pressure compared to those fed a low-salt diet (127/87 +/- 2/2 mmHg). 2 Isoprenaline-elicited relaxations were not significantly different in tissues from hypertensive compared to normotensive animals. Responses to ISO were significantly attenuated in denuded tissues and substantially more so in hypertensive compared to normotensive animals. While relaxant responses to ISO were resistant to inhibition by Nomega-nitro-L-arginine methyl ester, indomethacin, glibenclamide or a combination of barium chloride and ouabain, they were inhibited by Rp-cAMP, anandamide and acidic buffer. The inhibitory impact of anandamide and acidic buffer was significantly greater in tissues from hypertensive vs. normotensive rats. 3 The resting membrane potential (Em) of smooth muscle cells was -67.0+/ 0.7 mV (n=43 cells) and -66.6+/-0.8 mV (n=55 cells) in pulmonary arteries from hypertensive and normotensive rats, respectively. Isoprenaline produced hyperpolarization of E(m) which was significant in the blood vessels of hypertensive (-71.6+/-0.8 mV; n=29 cells) but not normotensive (-68.1+/-0.7 mV; n=49 cells) rats. 4 The endothelium plays a critical role in beta-adrenoceptor mediated relaxation but nitric oxide is not the mediator for the response. It is possible that the greater hyperpolarization caused by ISO in blood vessels from hypertensive compared to normotensive rats is mediated by activation of TASK-1 channels. PMID- 20955516 TI - Production of the UVB-absorbing compound mycosporine-glutaminol-glucoside by Xanthophyllomyces dendrorhous (Phaffia rhodozyma). AB - The ability of the basidiomycetous yeast Xanthophyllomyces dendrorhous (Phaffia rhodozyma) to accumulate astaxanthin is responsible for the industrial use of this yeast as a microbial source of pigments for aquaculture. It is also hypothesized that astaxanthin accounts for its ability to thrive in highly oxidative and UV-exposed habitats. Here, we assessed the ability of this species to synthesize UV-absorbing compounds generally known as mycosporines, evaluated the effect of culture media in the production of these compounds and compared its UV growth resistance and tolerance with other yeasts. The 48 wild and collection strains screened were positive for mycosporines and a unique compound identified as mycosporine-glutaminol-glucoside (MGG) was detected. Thus, the ability of X. dendrorhous to produce MGG, as described here for the first time, is so far unique among the Cystofilobasidiales. The compound was synthesized constitutively, although growth under visible light and, to a greater extent, UVA radiation stimulated its production. Strains from UV-exposed habitats produced larger quantities and oligotrophic complex media seemed to favor MGG accumulation. UV tolerance and survival of X. dendrorhous was high and comparable to that of the polyextremophilic Rhodotorula mucilaginosa. The taxonomical and ecological implications of the production of MGG by X. dendrorhous are discussed. PMID- 20955517 TI - Serotonin transporter deficient mice are vulnerable to escape deficits following inescapable shocks. AB - Modulation of serotonin transporter (5-HTT) function causes changes in affective behavior, both in humans and rodents. Stressful life events likewise affect emotional behavior. In humans, a low-expressing genetic 5-htt variant, the s allele of the 5-htt linked promoter region, has been associated with increased risk for depression only where there was a history of stressful life events. To investigate this gene by environment interaction in mice, we compared the effects of inescapable shocks on the behavior of wild-type (5-htt+/+), heterozygote (5 htt+/-) and serotonin transporter deficient (5-htt-/-) mice. Inescapable shocks induce behavioral changes including a shock escape deficit, in a subsequent test when escape is possible. Confirming a gene by environment interaction, we found that stress increases escape latencies in a gene-dose dependent manner (5-htt-/ >5-htt+/->5-htt +/+), where as there were no differences among the genotypes in the unstressed condition. The vulnerability to increased escape latency could not be accounted for by enhanced fear learning, as 5-htt-/- mice did not show heightened fear conditioning. The interaction of 5-htt genotype and stress appeared to produce a selective behavioral vulnerability, because no interaction of 5-htt genotype and stress was observed in other measures of anxiety and depression-linked behavior, including the open field, novelty suppressed feeding, and forced swim tests. We replicated prior findings that the 5-htt-/- displays heightened anxiety and depression-like behavior at baseline (unstressed condition). In conclusion, our data offer the possibility for future investigation of the neural basis underlying 5-htt genotype-by-stress interaction shown here. PMID- 20955518 TI - BchJ and BchM interact in a 1 : 1 ratio with the magnesium chelatase BchH subunit of Rhodobacter capsulatus. AB - Substrate channeling between the enzymatic steps in the (bacterio)chlorophyll biosynthetic pathway catalyzed by magnesium chelatase (BchI/ChlI, BchD/ChlD and BchH/ChlH subunits) and S-adenosyl-L-methionine:magnesium-protoporphyrin IX O methyltransferase (BchM/ChlM) has been suggested. This involves delivery of magnesium-protoporphyrin IX from the BchH/ChlH subunit of magnesium chelatase to BchM/ChlM. Stimulation of BchM/ChlM activity by BchH/ChlH has previously been shown, and physical interaction of the two proteins has been demonstrated. In plants and cyanobacteria, there is an added layer of complexity, as Gun4 serves as a porphyrin (protoporphyrin IX and magnesium-protoporphyrin IX) carrier, but this protein does not exist in anoxygenic photosynthetic bacteria. BchJ may play a similar role to Gun4 in Rhodobacter, as it has no currently assigned function in the established pathway. Purified recombinant Rhodobacter capsulatus BchJ and BchM were found to cause a shift in the equilibrium amount of Mg-protoporphyrin IX formed in a magnesium chelatase assay. Analysis of this shift revealed that it was always in a 1 : 1 ratio with either of these proteins and the BchH subunit of the magnesium chelatase. The establishment of the new equilibrium was faster with BchM than with BchJ in a coupled magnesium chelatase assay. BchJ bound magnesium protoporphyrin IX or formed a ternary complex with BchH and magnesium protoporphyrin IX. These results suggest that BchJ may play a role as a general magnesium porphyrin carrier, similar to one of the roles of GUN4 in oxygenic organisms. PMID- 20955519 TI - Chinese hamster apurinic/apyrimidinic endonuclease (chAPE1) expressed in sf9 cells reveals that its endonuclease activity is regulated by phosphorylation. AB - Apurinic/apyrimidinic endonuclease (APE), an essential DNA repair enzyme, initiates the base excision repair pathway by creating a nick 5' to an abasic site in double-stranded DNA. Although the Chinese hamster ovary cells remain an important model for DNA repair studies, the Chinese hamster APE (chAPE1) has not been studied in vitro in respect to its kinetic characteristics. Here we report the results of a kinetic study performed on cloned and overexpressed enzyme in sf9 cells. The kinetic parameters were fully compatible with the broad range of kinetic parameters reported for the human enzyme. However, the activity measures depended on the time point of the culture. We applied inductivity coupled plasma spectrometry to measure the phosphorylation level of chAPE1. Our data showed that a higher phosphorylation of chAPE1 in the expression host was correlated to a lower endonuclease activity. The phosphorylation of a higher activity batch of chAPE1 by casein kinase II decreased the endonuclease activity, and the dephosphorylation of chAPE1 by lambda phosphatase increased the endonuclease activity. The exonuclease activity of chAPE1 was not observed in our kinetic analysis. The results suggest that noticeable divergence in reported activity levels for the human APE1 endonuclease might be caused by unaccounted phosphorylation. Our data also demonstrate that only selected kinases and phosphatases exert regulatory effects on chAPE1 endonuclease activity, suggesting further that this regulatory mechanism may function in vivo to turn on and off the function of this important enzyme in different organisms. PMID- 20955520 TI - Functional importance of a conserved sequence motif in FhaC, a prototypic member of the TpsB/Omp85 superfamily. AB - In Gram-negative bacteria, the two-partner secretion pathway mediates the secretion of TpsA proteins with various functions. TpsB transporters specifically recognize their TpsA partners in the periplasm and mediate their transport through a hydrophilic channel. The filamentous haemagglutinin adhesin (FHA)/FhaC pair represents a model two-partner secretion system, with the structure of the TpsB transporter FhaC providing the bases to decipher the mechanism of action of these proteins. FhaC is composed of a beta-barrel preceded by two periplasmic polypeptide-transport-associated (POTRA) domains in tandem. The barrel is occluded by an N-terminal helix and an extracellular loop, L6, folded back into the FhaC channel. In this article, we describe a functionally important motif of FhaC. The VRGY tetrad is highly conserved in the TpsB family and, in FhaC, it is located at the tip of L6 reaching the periplasm. Replacement by Ala of the invariant Arg dramatically affects the secretion efficiency, although the structure of FhaC and its channel properties remain unaffected. This substitution affects the secretion mechanism at a step beyond the initial TpsA-TpsB interaction. Replacement of the conserved Tyr affects the channel properties, but not the secretion activity, suggesting that this residue stabilizes the loop in the resting conformation of FhaC. Thus, the conserved motif at the tip of L6 represents an important piece of two-partner secretion machinery. This motif is conserved in a predicted loop between two beta-barrel strands in more distant relatives of FhaC involved in protein transport across or assembly into the outer membranes of bacteria and organelles, suggesting a conserved function in the molecular mechanism of transport. PMID- 20955521 TI - Excellence. PMID- 20955522 TI - Teaching pregnant teens. PMID- 20955523 TI - Perinatal palliative care. PMID- 20955525 TI - Vitamin D and breast cancer prevention: practical guidelines for clinicians. PMID- 20955526 TI - Can an OB nurse assist in a disaster? Reflections on the Haiti earthquake of 2010. PMID- 20955527 TI - Retinopathy of prematurity: improving outcomes through evidence-based practice. PMID- 20955528 TI - An update on Clostridium difficile infection and its management. PMID- 20955529 TI - Women's self-diagnostic skills: developing the science. PMID- 20955530 TI - Small size, big risk: preventing neonatal and pediatric medication errors. PMID- 20955531 TI - Pink ribbons and beyond: ways to help in the fight against breast cancer. PMID- 20955532 TI - Lifelong learning: how to make continuing education a part of your career path. PMID- 20955535 TI - Advanced cardiac life support in obstetric settings. PMID- 20955536 TI - Breast cancer screening. PMID- 20955537 TI - Smoking and women's health. PMID- 20955538 TI - Silent healing. PMID- 20955539 TI - Seasonal variation in the month of birth in teenagers and young adults with melanoma suggests the involvement of early-life UV exposure. PMID- 20955540 TI - Cell-based therapy for chronic ischemic heart disease--a clinical perspective. AB - In patients with ischemic heart disease, the goal of cell therapy is to improve perfusion and function of the damaged heart muscle. For this review, we selected articles that reported the findings from the major clinical studies of cardiovascular stem cell therapy in patients with chronic ischemic heart disease. Because of the current status of development of clinical investigation in this field, all relevant studies were included. Initial clinical trials have shown that adult cell-based therapy is safe and may improve the quality of life and the functional status of patients with chronic myocardial ischemia. Adult bone marrow mononuclear cells have been most frequently used in cardiac cell therapy trials to date, but new cell types are now being assessed in both preclinical and clinical studies. Although not well defined, mechanisms underlying the benefits associated with cell therapy are most likely multiple and include a paracrine effect. Cell therapy in patients with chronic ischemic heart disease has been shown to be safe and feasible. Initial data have shown that cell therapy with autologous bone marrow cells is associated with modest functional improvements. This finding needs to be confirmed in subsequent phase 2 and 3 trials. PMID- 20955542 TI - Workshop on advances in Bio Text Mining, Ghent, Belgium. 10-11 May 2010. Abstracts. PMID- 20955541 TI - Statins alter intracellular calcium homeostasis in malignant hyperthermia susceptible individuals. AB - AIMS: Statines, HMG-CoA reductase inhibitors, are widely used to treat hypercholesterinemia. These substances are well tolerated, but myotoxic effects have been reported. The exact mechanisms of the induced myotoxicity are unknown but an involvement of intracellular calcium handling is suspected. Individuals susceptible to malignant hyperthermia (MH) have an impaired calcium homeostasis. An in vitro test measuring contracture responses of isolated muscle bundles is used to investigate cellular processes of MH. Aim of this study was to investigate if statins modify the contracture response of isolated muscle bundles from MH susceptible (MHS) and nonsusceptible (MHN) pigs. METHODOLOGY: With approval of the local ethics committee muscle biopsies of 18 MH susceptible and 12 nonsusceptible pigs were performed. Muscle bundles were mounted on an isometric force transducer, preloaded, and electrically stimulated. After establishment of a stable baseline, muscle bundles were exposed to simvastatin, atorvastatin, gemfibrocil, and the pure solvent. Baseline tension was measured and analyzed for changes with P < 0.05 considered to be significant. RESULTS: There were no differences in weight, length, and predrug baseline tension between the groups. Both simvastatin and atorvastatin induced significant contractures in muscle bundles from MHS pigs. Gemfibrocil and the solvent methanol showed no effect. In MHN muscle bundles, none of the tested substances induced a contracture. Statines induce contractures only in MHS muscle bundles. CONCLUSION: We therefore conclude that the underlying mechanism may be a pathologic influence on intracellular calcium handling that is absent in MHN. A preexisting impairment of the calcium homeostasis seems to be necessary for this behavior because muscle bundles of MHN pigs showed no pathologic reaction. A higher muscle cell vulnerability toward statins is assumed in MHS patients. Statins ought to be used with caution in these individuals. Analogous a diagnostic workup for MH should be considered for patients with statin-induced rhabdomyolyis. PMID- 20955543 TI - Deciphering the intracellular metabolism of Listeria monocytogenes by mutant screening and modelling. AB - BACKGROUND: The human pathogen Listeria monocytogenes resides and proliferates within the cytoplasm of epithelial cells. While the virulence factors essentially contributing to this step of the infection cycle are well characterized, the set of listerial genes contributing to intracellular replication remains to be defined on a genome-wide level. RESULTS: A comprehensive library of L. monocytogenes strain EGD knockout mutants was constructed upon insertion duplication mutagenesis, and 1491 mutants were tested for their phenotypes in rich medium and in a Caco-2 cell culture assay. Following sequencing of the plasmid insertion site, 141 different genes required for invasion of and replication in Caco-2 cells were identified. Ten in-frame deletion mutants were constructed that confirmed the data. The genes with known functions are mainly involved in cellular processes including transport, in the intermediary metabolism of sugars, nucleotides and lipids, and in information pathways such as regulatory functions. No function could be ascribed to 18 genes, and a counterpart of eight genes is missing in the apathogenic species L. innocua. Mice infection studies revealed the in vivo requirement of IspE (Lmo0190) involved in mevalonate synthesis, and of the novel ABC transporter Lmo0135-0137 associated with cysteine transport. Based on the data of this genome-scale screening, an extreme pathway and elementary mode analysis was applied that demonstrates the critical role of glycerol and purine metabolism, of fucose utilization, and of the synthesis of glutathione, aspartate semialdehyde, serine and branched chain amino acids during intracellular replication of L. monocytogenes. CONCLUSION: The combination of a genetic screening and a modelling approach revealed that a series of transporters help L. monocytogenes to overcome a putative lack of nutrients within cells, and that a high metabolic flexibility contributes to the intracellular replication of this pathogen. PMID- 20955544 TI - Heading down the wrong pathway: on the influence of correlation within gene sets. AB - BACKGROUND: Analysis of microarray experiments often involves testing for the overrepresentation of pre-defined sets of genes among lists of genes deemed individually significant. Most popular gene set testing methods assume the independence of genes within each set, an assumption that is seriously violated, as extensive correlation between genes is a well-documented phenomenon. RESULTS: We conducted a meta-analysis of over 200 datasets from the Gene Expression Omnibus in order to demonstrate the practical impact of strong gene correlation patterns that are highly consistent across experiments. We show that a common independence assumption-based gene set testing procedure produces very high false positive rates when applied to data sets for which treatment groups have been randomized, and that gene sets with high internal correlation are more likely to be declared significant. A reanalysis of the same datasets using an array resampling approach properly controls false positive rates, leading to more parsimonious and high-confidence gene set findings, which should facilitate pathway-based interpretation of the microarray data. CONCLUSIONS: These findings call into question many of the gene set testing results in the literature and argue strongly for the adoption of resampling based gene set testing criteria in the peer reviewed biomedical literature. PMID- 20955545 TI - Successful management of refractory pleural effusion due to systemic immunoglobulin light chain amyloidosis by vincristine adriamycin dexamethasone chemotherapy: a case report. AB - INTRODUCTION: Refractory pleural effusion in systemic immunoglobulin light chain amyloidosis without cardiac decompensation is rarely reported and has a poor prognosis in general (a median survival of 1.6 months). Moreover, the optimum treatment for this condition is still undecided. This is the first report on the successful use of vincristine, adriamycin and dexamethasone chemotherapy for refractory pleural effusion due to systemic immunoglobulin light chain amyloidosis without cardiac decompensation. CASE PRESENTATION: We report the case of a 68-year old Japanese male with systemic immunoglobulin light chain amyloidosis presenting with bilateral pleural effusion (more severe on the right side) in the absence of cardiac decompensation that was refractory to diuretic therapy. The patient was admitted for fatigue, exertional dyspnea, and bilateral lower extremity edema. He had been receiving intermittent melphalan and prednisone chemotherapy for seven years. One month before admission, his dyspnea had got worse, and his chest radiograph showed bilateral pleural effusion; the pleural effusion was ascertained to be a transudate. The conventionally used therapeutic measures, including diuretics and thoracocentesis, failed to control pleural effusion. Administration of vincristine, adriamycin, and dexamethasone chemotherapy led to successful resolution of the effusion. CONCLUSION: Treatment with vincristine, adriamycin, and dexamethasone chemotherapy was effective for the refractory pleural effusion in systemic immunoglobulin light chain amyloidosis without cardiac decompensation and appears to be associated with improvement in our patient's prognosis. PMID- 20955546 TI - Lifestyle factors and lumbar disc disease: results of a German multi-center case control study (EPILIFT). AB - INTRODUCTION: In the large-scale case-control study EPILIFT, we investigated the dose-response relationship between lifestyle factors (weight, smoking amount, cumulative duration of different sports activities) and lumbar disc disease. METHODS: In four German study regions (Frankfurt am Main, Freiburg, Halle/Saale, Regensburg), 564 male and female patients with lumbar disc herniation and 351 patients with lumbar disc narrowing (chondrosis) aged 25 to 70 years were prospectively recruited. From the regional population registers, 901 population control subjects were randomly selected. In a structured personal interview, we enquired as to body weight at different ages, body height, cumulative smoking amount and cumulative duration of different sports activities. Confounders were selected according to biological plausibility and to the change-in-estimate criterion. Adjusted, gender-stratified odds ratios with 95% confidence intervals were calculated using unconditional logistic regression analysis. RESULTS: The results of this case-control study reveal a positive association between weight and lumbar disc herniation as well as lumbar disc narrowing among men and women. A medium amount of pack-years was associated with lumbar disc herniation and narrowing in men and women. A non-significantly lowered risk of lumbar disc disease was found in men with high levels of cumulative body building and strength training. CONCLUSIONS: According to our multi-center case-control study, body weight might be related to lumbar disc herniation as well as to lumbar disc narrowing. Further research should clarify the potential protective role of body building or strength training on lumbar disc disease. PMID- 20955547 TI - Successful application of technetium-99m-labeled octreotide acetate scintigraphy in the detection of ectopic adrenocorticotropin-producing bronchial carcinoid lung tumor: a case report. AB - INTRODUCTION: The diagnostic efficacy of somatostatin receptor scintigraphy labeling with 111 indium in the localization of tumors has been assessed in a limited number of patients with contradictory outcomes. Here, we describe the case of a patient with an ectopic adrenocorticotropic hormone-producing bronchial carcinoid tumor diagnosed preoperatively using technetium-99m-labeled octreotide acetate scintigraphy. CASE PRESENTATION: A 29-year-old Asian man presented to our hospital with the typical clinical features of Cushing's syndrome, which he had had for a duration of 18 months. The results of a biochemical evaluation revealed he had adrenocorticotropic hormone-dependent Cushing's syndrome. The results of a spiral abdominal computed tomography scan showed he had bilateral adrenal hypertrophy. A magnetic resonance image of the patient's brain showed he had a normal hypophysis. Whole body technetium-99m-labeled octreotide acetate scintigraphy was performed to check for the presence of an ectopic adrenocorticotropic hormone-producing tumor. The scan results showed a small focal increase in uptake in the lower lobe of our patient's right lung, just above his diaphragm. A spiral chest computed tomography scan also revealed a small non-specific lesion in the same region. A transthoracic biopsy was then performed. Pathological evaluation confirmed the diagnosis of a carcinoid tumor, of the adrenocorticotropic hormone-producing type. After surgical removal, the patient's symptoms resolved and significant clinical improvement was achieved. CONCLUSIONS: This case report shows that technetium-99m-labeled octreotide acetate scintigraphy can effectively detect an ectopic adrenocorticotropic hormone-producing bronchial carcinoid. PMID- 20955548 TI - Distribution of physical activity facilities in Scotland by small area measures of deprivation and urbanicity. AB - BACKGROUND: The aim of this study was to examine the distribution of physical activity facilities by area-level deprivation in Scotland, adjusting for differences in urbanicity, and exploring differences between and within the four largest Scottish cities. METHODS: We obtained a list of all recreational physical activity facilities in Scotland. These were mapped and assigned to datazones. Poisson and negative binomial regression models were used to investigate associations between the number of physical activity facilities relative to population size and quintile of area-level deprivation. RESULTS: The results showed that prior to adjustment for urbanicity, the density of all facilities lessened with increasing deprivation from quintiles 2 to 5. After adjustment for urbanicity and local authority, the effect of deprivation remained significant but the pattern altered, with datazones in quintile 3 having the highest estimated mean density of facilities. Within-city associations were identified between the number of physical activity facilities and area-level deprivation in Aberdeen and Dundee, but not in Edinburgh or Glasgow. CONCLUSIONS: In conclusion, area-level deprivation appears to have a significant association with the density of physical activity facilities and although overall no clear pattern was observed, affluent areas had fewer publicly owned facilities than more deprived areas but a greater number of privately owned facilities. PMID- 20955549 TI - Giant sigmoid diverticulum with coexisting metastatic rectal carcinoma: a case report. AB - INTRODUCTION: Giant diverticulum of the colon is a rare but clinically significant condition, usually regarded as a complication of an already existing colonic diverticular disease. This is the first report of a giant diverticulum of the colon with a co-existing rectal carcinoma. CASE PRESENTATION: We report a case of a 66-year-old Caucasian woman who presented with lower abdominal pain, chronic constipation and abdominal swelling. Preoperative abdominal computed tomography revealed a giant diverticulum of the colon with a coexisting rectal carcinoma and pulmonary metastasis revealed on a further thoracic computed tomography. An en bloc anterior resection of the rectum along with sigmoid colectomy, partial hysterectomy and right salpingoophorectomy was subsequently performed due to extensive adhesions. CONCLUSION: This report shows that the presence of a co-existing distal colorectal cancer can potentially lead to progressive development of a colonic diverticulum to become a giant diverticulum by increasing colonic intra-luminal pressure and through the ball-valve mechanism. This may be of interest to practising surgeons and surgical trainees. PMID- 20955550 TI - Gender differences in the association between pre-adolescent smoking initiation and emotional or behavioural problems. AB - BACKGROUND: Emotional and behavioural problems are a risk factor for the initiation of smoking. In this study, we aimed to assess this relationship beyond clinical cut-off values of problem behaviour. METHODS: Cross-sectional national survey among 9-13 year old children with data on smoking and Childhood Behaviour Checklist (CBCL) (N = 960). Relationships between smoking and tertiles of CBCL scores were assessed. RESULTS: Smoking was reported by 5.9% of the children (7.1% boys and 5.0% girls, P > 0.100). Relationships between smoking and problem behaviour were present in girls, but ot in boys. Among girls, smoking was associated with attention problems, thought problems, and delinquent behaviour. For attention problems and delinquent behaviour the associations were limited to the CBCL-scores in the uppermost 16% which agrees with the subclinical cut-off value. CONCLUSION: Pre-adolescent girls more frequently smoke if having attention problems, delinquent behaviour, or thought problems. PMID- 20955551 TI - Granulomatous pyoderma preceding chronic recurrent multifocal osteomyelitis triggered by vaccinations in a two-year-old boy: a case report. AB - INTRODUCTION: Chronic recurrent multifocal osteomyelitis is a rare, systemic, aseptic, inflammatory disorder that involves different sites. Pathogenesis of chronic recurrent multifocal osteomyelitis is currently unknown. CASE PRESENTATION: A two-year-old Caucasian boy, diagnosed with chronic recurrent multifocal osteomyelitis with granulomatous pyoderma following routine vaccinations is presented for the first time in the literature. CONCLUSION: We conclude that antigen exposures might have provoked this inflammatory condition for our case. Skin and/or bone lesions following vaccinations should raise suspicion of an inflammatory response such as chronic recurrent multifocal osteomyelitis only after thorough evaluation for chronic infection, autoimmune, immunodeficiency or vasculitic diseases. PMID- 20955552 TI - Hypoxia-dependent sequestration of an oxygen sensor by a widespread structural motif can shape the hypoxic response--a predictive kinetic model. AB - BACKGROUND: The activity of the heterodimeric transcription factor hypoxia inducible factor (HIF) is regulated by the post-translational, oxygen-dependent hydroxylation of its alpha-subunit by members of the prolyl hydroxylase domain (PHD or EGLN)-family and by factor inhibiting HIF (FIH). PHD-dependent hydroxylation targets HIFalpha for rapid proteasomal degradation; FIH-catalysed asparaginyl-hydroxylation of the C-terminal transactivation domain (CAD) of HIFalpha suppresses the CAD-dependent subset of the extensive transcriptional responses induced by HIF. FIH can also hydroxylate ankyrin-repeat domain (ARD) proteins, a large group of proteins which are functionally unrelated but share common structural features. Competition by ARD proteins for FIH is hypothesised to affect FIH activity towards HIFalpha; however the extent of this competition and its effect on the HIF-dependent hypoxic response are unknown. RESULTS: To analyse if and in which way the FIH/ARD protein interaction affects HIF-activity, we created a rate equation model. Our model predicts that an oxygen-regulated sequestration of FIH by ARD proteins significantly shapes the input/output characteristics of the HIF system. The FIH/ARD protein interaction is predicted to create an oxygen threshold for HIFalpha CAD-hydroxylation and to significantly sharpen the signal/response curves, which not only focuses HIFalpha CAD hydroxylation into a defined range of oxygen tensions, but also makes the response ultrasensitive to varying oxygen tensions. Our model further suggests that the hydroxylation status of the ARD protein pool can encode the strength and the duration of a hypoxic episode, which may allow cells to memorise these features for a certain time period after reoxygenation. CONCLUSIONS: The FIH/ARD protein interaction has the potential to contribute to oxygen-range finding, can sensitise the response to changes in oxygen levels, and can provide a memory of the strength and the duration of a hypoxic episode. These emergent properties are predicted to significantly shape the characteristics of HIF activity in animal cells. We argue that the FIH/ARD interaction should be taken into account in studies of the effect of pharmacological inhibition of the HIF-hydroxylases and propose that the interaction of a signalling sensor with a large group of proteins might be a general mechanism for the regulation of signalling pathways. PMID- 20955553 TI - A structural constraint for functional interaction between N-terminal and C terminal domains in simian immunodeficiency virus capsid proteins. AB - BACKGROUND: The Gag capsid (CA) is one of the most conserved proteins in highly diversified human and simian immunodeficiency viruses (HIV and SIV). Understanding the limitations imposed on amino acid sequences in CA could provide valuable information for vaccine immunogen design or anti-HIV drug development. Here, by comparing two pathogenic SIV strains, SIVmac239 and SIVsmE543-3, we found critical amino acid residues for functional interaction between the N terminal and the C-terminal domains in CA. RESULTS: We first examined the impact of Gag residue 205, aspartate (Gag205D) in SIVmac239 and glutamate (Gag205E) in SIVsmE543-3, on viral replication; due to this difference, Gag206-216 (IINEEAADWDL) epitope-specific cytotoxic T lymphocytes (CTLs) were previously shown to respond to SIVmac239 but not SIVsmE543-3 infection. A mutant SIVmac239, SIVmac239Gag205E, whose Gag205D is replaced with Gag205E showed lower replicative ability. Interestingly, however, SIVmac239Gag205E passaged in macaque T cell culture often resulted in selection of an additional mutation at Gag residue 340, a change from SIVmac239 valine (Gag340V) to SIVsmE543-3 methionine (Gag340M), with recovery of viral fitness. Structural modeling analysis suggested possible intermolecular interaction between the Gag205 residue in the N-terminal domain and Gag340 in the C-terminal in CA hexamers. The Gag205D-to-Gag205E substitution in SIVmac239 resulted in loss of in vitro core stability, which was recovered by additional Gag340V-to-Gag340M substitution. Finally, selection of Gag205E plus Gag340M mutations, but not Gag205E alone was observed in a chronically SIVmac239 infected rhesus macaque eliciting Gag206-216-specific CTL responses. CONCLUSIONS: These results present in vitro and in vivo evidence implicating the interaction between Gag residues 205 in CA NTD and 340 in CA CTD in SIV replication. Thus, this study indicates a structural constraint for functional interaction between SIV CA NTD and CTD, providing insight into immunogen design to limit viral escape options. PMID- 20955554 TI - Analysis of proteome response to the mobile phone radiation in two types of human primary endothelial cells. AB - BACKGROUND: Use of mobile phones has widely increased over the past decade. However, in spite of the extensive research, the question of potential health effects of the mobile phone radiation remains unanswered. We have earlier proposed, and applied, proteomics as a tool to study biological effects of the mobile phone radiation, using as a model human endothelial cell line EA.hy926. Exposure of EA.hy926 cells to 900 MHz GSM radiation has caused statistically significant changes in expression of numerous proteins. However, exposure of EA.hy926 cells to 1800 MHz GSM signal had only very small effect on cell proteome, as compared with 900 MHz GSM exposure. In the present study, using as model human primary endothelial cells, we have examined whether exposure to 1800 MHz GSM mobile phone radiation can affect cell proteome. RESULTS: Primary human umbilical vein endothelial cells and primary human brain microvascular endothelial cells were exposed for 1 hour to 1800 MHz GSM mobile phone radiation at an average specific absorption rate of 2.0 W/kg. The cells were harvested immediately after the exposure and the protein expression patterns of the sham exposed and radiation-exposed cells were examined using two dimensional difference gel electrophoresis-based proteomics (2DE-DIGE). There were observed numerous differences between the proteomes of human umbilical vein endothelial cells and human brain microvascular endothelial cells (both sham-exposed). These differences are most likely representing physiological differences between endothelia in different vascular beds. However, the exposure of both types of primary endothelial cells to mobile phone radiation did not cause any statistically significant changes in protein expression. CONCLUSIONS: Exposure of primary human endothelial cells to the mobile phone radiation, 1800 MHz GSM signal for 1 hour at an average specific absorption rate of 2.0 W/kg, does not affect protein expression, when the proteomes were examined immediately after the end of the exposure and when the false discovery rate correction was applied to analysis. This observation agrees with our earlier study showing that the 1800 MHz GSM radiation exposure had only very limited effect on the proteome of human endothelial cell line EA.hy926, as compared with the effect of 900 MHz GSM radiation. PMID- 20955555 TI - Tobacco use amongst out of school adolescents in a Local Government Area in Nigeria. AB - INTRODUCTION: Out-of-school adolescents are often neglected when planning for tobacco prevention programmes whereas they are more vulnerable. Few studies exist in Nigeria about their pattern of tobacco use to serve as the basis for effective policy formulation. METHOD: A sub sample of 215 out of school adolescents was analyzed from a descriptive cross sectional study on psychoactive substance use amongst youths in two communities in a Local Government Area in Nigeria which used a multi-stage sampling technique. RESULTS: Males were 53% and females 47%. Only 20.5% had ever used tobacco while 11.6% were current users. Males accounted for 60% of current users compared to 40% amongst females. Of current users, 84% believed that tobacco is not harmful to health. In addition, the two important sources of introduction to tobacco use were friends 72% and relatives 20%. Use of tobacco amongst significant others were: friends 27%, fathers 8.0%, relatives 4.2% and mothers 0.5%. The most common sources of supply were motor parks 52% and friends 16%. CONCLUSION: The study showed that peer influence is an important source of introduction to tobacco use while selling of tobacco to adolescents in youth aggregation areas is common. We advocate for a theory based approach to designing an appropriate health education intervention targeted at assisting adolescents in appreciating the harmful nature of tobacco use in this locality. A point-of-sale restriction to prevent adolescent access to tobacco in youth aggregation areas within the context of a comprehensive tobacco control policy is also suggested. However, more research would be needed for an in-depth understanding of the tobacco use vulnerability of this group of adolescents. PMID- 20955556 TI - The role of sigma factor RpoH1 in the pH stress response of Sinorhizobium meliloti. AB - BACKGROUND: Environmental pH stress constitutes a limiting factor for S. meliloti survival and development. The response to acidic pH stress in S. meliloti is versatile and characterized by the differential expression of genes associated with various cellular functions. The purpose of this study was to gain detailed insight into the participation of sigma factors in the complex stress response system of S. meliloti 1021 using pH stress as an effector. RESULTS: In vitro assessment of S meliloti wild type and sigma factor mutants provided first evidence that the sigma factor RpoH1 plays a major role in the pH stress response. Differential expression of genes related to rhizobactin biosynthesis was observed in microarray analyses performed with the rpoH1 mutant at pH 7.0. The involvement of the sigma factor RpoH1 in the regulation of S. meliloti genes upon pH stress was analyzed by comparing time-course experiments of the wild type and the rpoH1 mutant. Three classes of S. meliloti genes could be identified, which were transcriptionally regulated in an RpoH1-independent, an RpoH1 dependent or in a complex manner. The first class of S. meliloti genes, regulated in an RpoH1-independent manner, comprises the group of the exopolysaccharide I biosynthesis genes and also the group of genes involved in motility and flagellar biosynthesis. The second class of S. meliloti genes, regulated in an RpoH1 dependent manner, is composed of genes known from heat shock studies, like ibpA, grpE and groEL5, as well as genes involved in translation like tufA and rplC. Finally, the third class of S. meliloti genes was regulated in a complex manner, which indicates that besides sigma factor RpoH1, further regulation takes place. This was found to be the case for the genes dctA, ndvA and smc01505. CONCLUSIONS: Clustering of time-course microarray data of S. meliloti wild type and sigma factor rpoH1 mutant allowed for the identification of gene clusters, each with a unique time-dependent expression pattern, as well as for the classification of genes according to their dependence on RpoH1 expression and regulation. This study provided clear evidence that the sigma factor RpoH1 plays a major role in pH stress response. PMID- 20955557 TI - A protein-centric approach for the identification of folate enzymes from the malarial parasite, Plasmodium falciparum, using OFFGELTM solution-based isoelectric focussing and mass spectrometry. AB - BACKGROUND: Plasmodium species are difficult to study using proteomic technology because they contain large amounts of haemoglobin-derived products (HDP), generated by parasite breakdown of host haemoglobin. HDP are known to interfere with isoelectric focussing, a cornerstone of fractionation strategies for the identification of proteins by mass spectrometry. In addition to the challenge presented by this material, as in most proteomes, there exists in this parasite a considerable dynamic range between proteins of high and low abundance. The enzymes of the folate pathway, a proven and widely used drug target, are included in the latter class. METHODS: This report describes a work-flow utilizing a parasite-specific extraction protocol that minimizes release of HDP into the lysate, followed by in-solution based OFFGELTM electrophoresis at the protein level, trypsin digestion and mass spectrometric analysis. RESULTS: It is demonstrated that, by removing HDP from parasite lysates, OFFGELTM-mediated protein separation is able to deliver reduced complexity protein fractions. Importantly, proteins with similar and predictable physical properties are sharply focussed within such fractions. CONCLUSIONS: By following this novel workflow, data have been obtained which allow the unequivocal experimental identification by mass spectrometry of four of the six proteins involved in folate biosynthesis and recycling. PMID- 20955558 TI - Protective effects and potential mechanisms of Pien Tze Huang on cerebral chronic ischemia and hypertensive stroke. AB - BACKGROUND: Stroke caused by brain ischemia is the third leading cause of adult disability. Active prevention and early treatment of stroke targeting the causes and risk factors may decrease its incidence, mortality and subsequent disability. Pien Tze Huang (PZH), a Chinese medicine formula, was found to have anti-edema, anti-inflammatory and anti-thrombotic effects that can prevent brain damage. This study aims to investigate the potential mechanisms of the preventive effects of Pien Tze Huang on brain damage caused by chronic ischemia and hypertensive stroke in rats. METHODS: The effects of Pien Tze Huang on brain protein expression in spontaneously hypertensive rat (SHR) and stroke prone SHR (SHRsp) were studied with 2-D gel electrophoresis and mass spectrometric analysis with a matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF)/TOF tandem mass spectrometer and on brain cell death with enzyme link immunosorbent assay (ELISA) and immunostaining. RESULTS: Pien Tze Huang decreased cell death in hippocampus and cerebellum caused by chronic ischemia and hypertensive stroke. Immunostaining of caspase-3 results indicated that Pien Tze Huang prevents brain cells from apoptosis caused by ischemia. Brain protein expression results suggested that Pien Tze Huang downregulated QCR2 in the electron transfer chain of mitochondria preventing reactive oxygen species (ROS) damage and possibly subsequent cell death (caspase 3 assay) as caused by chronic ischemia or hypertensive stroke to hippocampus and cerebellum. CONCLUSION: Pien Tze Huang showed preventive effects on limiting the damage or injury caused by chronic ischemia and hypertensive stroke in rats. The effect of Pien Tze Huang was possibly related to prevention of cell death from apoptosis or ROS/oxidative damage in mitochondria. PMID- 20955560 TI - Autoantibodies to BRAF, a new family of autoantibodies associated with rheumatoid arthritis. AB - INTRODUCTION: BRAF (v raf murine sarcoma viral oncogene homologue B1) is a serine threonine kinase involved in the mitogen-activated protein kinase (MAPK) signalling pathway, known to be implicated in the production of pro-inflammatory cytokines.We have observed that sera from rheumatoid arthritis (RA) patients recognize the BRAF's catalytic domain, which encompasses amino acids 416 to 766. Here, we identify peptide targets of anti-BRAF autoantibodies and test whether anti-BRAF autoantibodies may interfere with BRAF kinase activity. METHODS: Anti BRAF autoantibodies were detected by ELISA (enzyme-linked immunosorbent assay) in the serum of RA patients and controls, using 40 overlapping 20mer peptides encompassing the catalytic domain of BRAF as immunosorbents. To test whether autoantibodies to BRAF influence BRAF kinase activity, we developed an in vitro phosphorylation assay of MEK1 (mitogen extracellular regulated kinase), a major BRAF substrate. MEK1 phosphorylation by BRAF was tested in the presence of purified anti-BRAF autoantibodies from RA patients or control antibody. RESULTS: We found that one BRAF peptide, P25 (656 to 675), is specifically recognized by autoantibodies from RA patients. Of interest, anti-P25 autoantibodies are detected in 21% of anti-CCP (cyclic citrullinated peptides) negative RA patients. Anti-BRAF autoantibodies activate the in vitro phosphorylation of MEK1 mediated by BRAF. CONCLUSIONS: Anti-BRAF autoantibodies from RA patients preferentially recognize one BRAF peptide: P25. Autoantibody responses to P25 are detected in 21% of anti-CCP negative RA patients. Most anti-BRAF autoantibodies activate BRAF kinase activity. PMID- 20955559 TI - Quantum dot loaded immunomicelles for tumor imaging. AB - BACKGROUND: Optical imaging is a promising method for the detection of tumors in animals, with speed and minimal invasiveness. We have previously developed a lipid coated quantum dot system that doubles the fluorescence of PEG-grafted quantum dots at half the dose. Here, we describe a tumor-targeted near infrared imaging agent composed of cancer-specific monoclonal anti-nucleosome antibody 2C5, coupled to quantum dot (QD)-containing polymeric micelles, prepared from a polyethylene glycol/phosphatidylethanolamine (PEG-PE) conjugate. Its production is simple and involves no special equipment. Its imaging potential is great since the fluorescence intensity in the tumor is twofold that of non-targeted QD-loaded PEG-PE micelles at one hour after injection. METHODS: Para-nitrophenol-containing (5%) PEG-PE quantum dot micelles were produced by the thin layer method. Following hydration, 2C5 antibody was attached to the PEG-PE micelles and the QD micelles were purified using dialysis. 4T1 breast tumors were inoculated subcutaneously in the flank of the animals. A lung pseudometastatic B16F10 melanoma model was developed using tail vein injection. The contrast agents were injected via the tail vein and mice were depilated, anesthetized and imaged on a Kodak Image Station. Images were taken at one, two, and four hours and analyzed using a methodology that produces normalized signal-to-noise data. This allowed for the comparison between different subjects and time points. For the pseudometastatic model, lungs were removed and imaged ex vivo at one and twenty four hours. RESULTS: The contrast agent signal intensity at the tumor was double that of the passively targeted QD-micelles with equally fast and sharply contrasted images. With the side views of the animals only tumor is visible, while in the dorsal view internal organs including liver and kidney are visible. Ex vivo results demonstrated that the agent detects melanoma nodes in a lung pseudometastatic model after a 24 hours wash-out period, while at one hour, only a uniform signal is detected. CONCLUSIONS: The targeted agent produces ultrabright tumor images and double the fluorescence intensity, as rapidly and at the same low dose as the passively targeted agents. It represents a development that may potentially serve to enhance early detection for metastases. PMID- 20955561 TI - Saphenofemoral arteriovenous fistula as hemodialysis access. AB - BACKGROUND: An upper limb arteriovenous (AV) fistula is the access of choice for haemodialysis (HD). There have been few reports of saphenofemoral AV fistulas (SFAVF) over the last 10-20 years because of previous suggestions of poor patencies and needling difficulties. Here, we describe our clinical experience with SFAVF. METHODS: SFAVFs were evaluated using the following variables: immediate results, early and late complications, intraoperative and postoperative complications (up to day 30), efficiency of the fistula after the onset of needling and complications associated to its use. RESULTS: Fifty-six SFAVF fistulas were created in 48 patients. Eight patients had two fistulas: 8 patent (16%), 10 transplanted (20%), 12 deaths (24%), 1 low flow (2%) and 20 thrombosis (39%) (first two months of preparation). One patient had severe hypotension during surgery, which caused thrombosis of the fistula, which was successfully thrombectomised, four thrombosed fistulae were successfully thrombectomised and revised on the first postoperative day. After 59 months of follow-up, primary patency was 44%. CONCLUSION: SFAVF is an adequate alternative for patients without the possibility for other access in the upper limbs, allowing efficient dialysis with good long-term patency with a low complication rate. PMID- 20955562 TI - Pomegranate extract inhibits the interleukin-1beta-induced activation of MKK-3, p38alpha-MAPK and transcription factor RUNX-2 in human osteoarthritis chondrocytes. AB - INTRODUCTION: Pomegranate has been revered throughout history for its medicinal properties. p38-MAPK is a major signal-transducing pathway in osteoarthritis (OA) and its activation by interleukin-1beta (IL-1beta) plays a critical role in the expression and production of several mediators of cartilage catabolism in OA. In this study we determined the effect of a standardized pomegranate extract (PE) on the IL-1beta-induced activation of MKK3/6, p38-MAPK isoforms and the activation of transcription factor RUNX-2 in primary human OA chondrocytes. METHODS: Human chondrocytes were derived from OA cartilage by enzymatic digestion, treated with PE and then stimulated with IL-1beta. Gene expression of p38-MAPK isoforms was measured by RT-PCR. Western immunoblotting was used to analyze the activation of MAPKs. Immunoprecipitation was used to determine the activation of p38-MAPK isoforms. DNA binding activity of RUNX-2 was determined using a highly sensitive and specific ELISA. Pharmacological studies to elucidate the involved pathways were executed using transfection with siRNAs. RESULTS: Human OA chondrocytes expressed p38-MAPK isoforms p38alpha, -gamma and -delta, but not p38beta. IL 1beta enhances the phosphorylation of the p38alpha-MAPK and p38gamma-MAPK isoforms but not of p38delta-MAPK isoform in human OA chondrocytes. Activation of p38-MAPK in human OA chondrocytes was preferentially mediated via activation of MKK3. In addition, we also demonstrate that polyphenol rich PE inhibited the IL 1beta-induced activation of MKK3, p38alpha-MAPK isoform and DNA binding activity of the transcription factor RUNX-2. CONCLUSIONS: Our results provide an important insight into the molecular basis of the reported cartilage protective and arthritis inhibitory effects of pomegranate extract. These novel pharmacological actions of PE on IL-1beta stimulated human OA chondrocytes impart a new suggestion that PE or PE-derived compounds may be developed as MKK and p38-MAPK inhibitors for the treatment of OA and other degenerative/inflammatory diseases. PMID- 20955563 TI - Antecedents of hospital admission for deliberate self-harm from a 14-year follow up study using data-linkage. AB - BACKGROUND: A prior episode of deliberate self-harm (DSH) is one of the strongest predictors of future completed suicide. Identifying antecedents of DSH may inform strategies designed to reduce suicide rates. This study aimed to determine whether individual and socio-ecological factors collected in childhood and adolescence were associated with later hospitalisation for DSH. METHODS: Longitudinal follow-up of a Western Australian population-wide random sample of 2,736 children aged 4-16 years, and their carers, from 1993 until 2007 using administrative record linkage. Children were aged between 18 and 31 years at end of follow-up. Proportional hazards regression was used to examine the relationship between child, parent, family, school and community factors measured in 1993, and subsequent hospitalisation for DSH. RESULTS: There were six factors measured in 1993 that increased a child's risk of future hospitalisation with DSH: female sex; primary carer being a smoker; being in a step/blended family; having more emotional or behavioural problems than other children; living in a family with inconsistent parenting style; and having a teenage mother. Factors found to be not significant included birth weight, combined carer income, carer's lifetime treatment for a mental health problem, and carer education. CONCLUSIONS: The persistence of carer smoking as an independent risk factor for later DSH, after adjusting for child, carer, family, school and community level socio ecological factors, adds to the known risk domains for DSH, and invites further investigation into the underlying mechanisms of this relationship. This study has also confirmed the association of five previously known risk factors for DSH. PMID- 20955564 TI - Interaction of functional NPC1 gene polymorphism with smoking on coronary heart disease. AB - BACKGROUND: The protein of Niemann-pick type C1 gene (NPC1) is known to facilitate the egress of cholesterol and other lipids from late endosomes and lysosomes to other cellular compartments. This study aims to investigate whether the genetic variation in NPC1 is associated with risk of coronary heart disease (CHD) and to detect whether NPC1 might interact with smoking on the risk of CHD. METHODS: We performed a case-control study, including 873 patients with coronary heart disease (CHD) and 864 subjects without CHD as control. Polymorphisms of NPC1 gene were genotyped by polymerase chain reaction (PCR) -restriction fragment length polymorphism (RFLP). RESULTS: A tag-SNP rs1805081 (+644A > G) in NPC1 was identified. The G allele of the +644 locus showed reduced risk of CHD than wild type genotype in Chinese population (recessive model GG vs. AG+AA: odds ratio [OR] 0.647, 95% CI 0.428 to 0.980, P = 0.039; additive model GG vs. AG vs. AA: OR 0.847, 95% CI 0.718 to 0.998, P = 0.0471). Moreover in smokers, the G-allele carriers had reduced risk of CHD compared with A-allele carries (OR 0.552, 95% CI 0.311 to 0.979, P = 0.0421). CONCLUSIONS: The results of the present study suggest that NPC1 variants seem to be contributors to coronary heart disease occurrence in Chinese population. Moreover, in smokers, NPC1 variants seem to confer protection to coronary heart disease. PMID- 20955565 TI - Fine specificity of anti-MSP119 antibodies and multiplicity of Plasmodium falciparum merozoite surface protein 1 types in individuals in Nigeria with sub microscopic infection. AB - BACKGROUND: The absence of antibodies specific for the 19 kDa C-terminal domain of merozoite surface protein 1 (MSP119) has been associated with high-density malaria parasitaemia in African populations. The hypothesis that a high prevalence and/or level of anti-MSP119 antibodies that may inhibit erythrocyte invasion would be present in apparently healthy individuals who harbour a sub microscopic malaria infection was tested in this study. METHODS: Plasma samples were collected from residents in a region in Nigeria hyperendemic for malaria, who had no detectable parasitaemia by microscopy. Using a competition-based enzyme-linked-immunosorbent assay with two invasion-inhibitory monoclonal antibodies (mAbs) 12.10 and 12.8, the levels and prevalence of specific antibodies were measured. The minimum multiplicity of infection was determined using PCR. The prevalence of anaemia was also measured. RESULTS: Plasma samples from 85% of individuals contained antibodies that bound to MSP119. The inhibition of mAb 12.10 binding was strongly correlated with the prevalence (Spearman correlation test, p < 0.0001) and mean titre of anti-MSP119 antibodies (Spearman correlation test, p < 0.001) in the samples. Comparing samples from individuals with multiple infection (group M) and single infection (Group S), group M contained a higher (p = 0.04) prevalence of anti-MSP119 antibodies that competed with mAb 12.10. Using a logistic regression model, it was found that the presence of antibodies competitive with mAb 12.10 was affected negatively by anaemia (p = 0.0016) and positively by the carriage of multiple parasite genotypes (p = 0.04). CONCLUSIONS: In the search for correlates of protection against malaria, which will be essential to evaluate clinical trials of malaria vaccines based on MSP1, this study examines some potential assays and the factors that need to taken into account during their evaluation, using samples from individuals naturally exposed to malaria infection. PMID- 20955566 TI - Evaluation of upper extremity robot-assistances in subacute and chronic stroke subjects. AB - BACKGROUND: Robotic systems are becoming increasingly common in upper extremity stroke rehabilitation. Recent studies have already shown that the use of rehabilitation robots can improve recovery. This paper evaluates the effect of different modes of robot-assistances in a complex virtual environment on the subjects' ability to complete the task as well as on various haptic parameters arising from the human-robot interaction. METHODS: The MIMICS multimodal system that includes the haptic robot HapticMaster and a dynamic virtual environment is used. The goal of the task is to catch a ball that rolls down a sloped table and place it in a basket above the table. Our study examines the influence of catching assistance, pick-and-place movement assistance and grasping assistance on the catching efficiency, placing efficiency and on movement-dependent parameters: mean reaching forces, deviation error, mechanical work and correlation between the grasping force and the load force. RESULTS: The results with groups of subjects (23 subacute hemiparetic subjects, 10 chronic hemiparetic subjects and 23 control subjects) showed that the assistance raises the catching efficiency and pick-and-place efficiency. The pick-and-place movement assistance greatly limits the movements of the subject and results in decreased work toward the basket. The correlation between the load force and the grasping force exists in a certain phase of the movement. The results also showed that the stroke subjects without assistance and the control subjects performed similarly. CONCLUSIONS: The robot-assistances used in the study were found to be a possible way to raise the catching efficiency and efficiency of the pick-and-place movements in subacute and chronic subjects. The observed movement parameters showed that robot-assistances we used for our virtual task should be improved to maximize physical activity. PMID- 20955567 TI - Effect of slice thickness on brain magnetic resonance image texture analysis. AB - BACKGROUND: The accuracy of texture analysis in clinical evaluation of magnetic resonance images depends considerably on imaging arrangements and various image quality parameters. In this paper, we study the effect of slice thickness on brain tissue texture analysis using a statistical approach and classification of T1-weighted images of clinically confirmed multiple sclerosis patients. METHODS: We averaged the intensities of three consecutive 1-mm slices to simulate 3-mm slices. Two hundred sixty-four texture parameters were calculated for both the original and the averaged slices. Wilcoxon's signed ranks test was used to find differences between the regions of interest representing white matter and multiple sclerosis plaques. Linear and nonlinear discriminant analyses were applied with several separate training and test sets to determine the actual classification accuracy. RESULTS: Only moderate differences in distributions of the texture parameter value for 1-mm and simulated 3-mm-thick slices were found. Our study also showed that white matter areas are well separable from multiple sclerosis plaques even if the slice thickness differs between training and test sets. CONCLUSIONS: Three-millimeter-thick magnetic resonance image slices acquired with a 1.5 T clinical magnetic resonance scanner seem to be sufficient for texture analysis of multiple sclerosis plaques and white matter tissue. PMID- 20955568 TI - Admixture mapping of end stage kidney disease genetic susceptibility using estimated mutual information ancestry informative markers. AB - BACKGROUND: The question of a genetic contribution to the higher prevalence and incidence of end stage kidney disease (ESKD) among African Americans (AA) remained unresolved, until recent findings using admixture mapping pointed to the association of a genomic locus on chromosome 22 with this disease phenotype. In the current study we utilize this example to demonstrate the utility of applying a multi-step admixture mapping approach. METHODS: A multi-step case only admixture mapping study, consisted of the following steps was designed: 1) Assembly of the sample dataset (ESKD AA); 2) Design of the estimated mutual information ancestry informative markers (n = 2016) screening panel 3); Genotyping the sample set whose size was determined by a power analysis (n = 576) appropriate for the initial screening panel; 4) Inference of local ancestry for each individual and identification of regions with increased AA ancestry using two different ancestry inference statistical approaches; 5) Enrichment of the initial screening panel; 6) Power analysis of the enriched panel 7) Genotyping of additional samples. 8) Re-analysis of the genotyping results to identify a genetic risk locus. RESULTS: The initial screening phase yielded a significant peak using the ADMIXMAP ancestry inference program applying case only statistics. Subgroup analysis of 299 ESKD patients with no history of diabetes yielded peaks using both the ANCESTRYMAP and ADMIXMAP ancestry inference programs. The significant peak was found on chromosome 22. Genotyping of additional ancestry informative markers on chromosome 22 that took into account linkage disequilibrium in the ancestral populations, and the addition of samples increased the statistical significance of the finding. CONCLUSIONS: A multi-step admixture mapping analysis of AA ESKD patients replicated the finding of a candidate risk locus on chromosome 22, contributing to the heightened susceptibility of African Americans to develop non-diabetic ESKD, and underscores the importance of using mutual information and multiple ancestry inference approaches to achieve a robust analysis, using relatively small datasets of "affected" only individuals. The current study suggests solutions to some limitations of existing admixture mapping methodologies, such as considerations regarding the distribution of ancestry information along the genome and its effects on power calculations and sample size. PMID- 20955569 TI - Effects of aversive odour presentation on inhibitory control in the Stroop colour word interference task. AB - BACKGROUND: Due to the unique neural projections of the olfactory system, odours have the ability to directly influence affective processes. Furthermore, it has been shown that emotional states can influence various non-emotional cognitive tasks, such as memory and planning. However, the link between emotional and cognitive processes is still not fully understood. The present study used the olfactory pathway to induce a negative emotional state in humans to investigate its effect on inhibitory control performance in a standard, single-trial manual Stroop colour-word interference task. An unpleasant (H2S) and an emotionally neutral (Eugenol) odorant were presented in two separate experimental runs, both in blocks alternating with ambient air, to 25 healthy volunteers, while they performed the cognitive task. RESULTS: Presentation of the unpleasant odorant reduced Stroop interference by reducing the reaction times for incongruent stimuli, while the presentation of the neutral odorant had no effect on task performance. CONCLUSIONS: The odour-induced negative emotional state appears to facilitate cognitive processing in the task used in the present study, possibly by increasing the amount of cognitive control that is being exerted. This stands in contrast to other findings that showed impaired cognitive performance under odour-induced negative emotional states, but is consistent with models of mood congruent processing. PMID- 20955570 TI - "...they should be offering it": a qualitative study to investigate young peoples' attitudes towards chlamydia screening in GP surgeries. AB - BACKGROUND: Despite the known health and healthcare costs of untreated chlamydia infection and the efforts of the National Chlamydia Screening Programme (NCSP) to control chlamydia through early detection and treatment of asymptomatic infection, the rates of screening are well below the 2010-2011 target rate of 35%. General Practitioner (GP) surgeries are a key venue within the NCSP however; previous studies indicate that GP surgery staff are concerned that they may offend their patients by offering a screen. This study aimed to identify the attitudes to, and preferences for, chlamydia screening in 15-24 year old men and women attending GP surgeries (the target group). METHODS: We undertook 36 interviews in six surgeries of differing screening rates. Our participants were 15-24 year olds attending a consultation with a staff member. Data were analysed thematically. RESULTS: GP surgeries are acceptable to young people as a venue for opportunistic chlamydia screening and furthermore they think it is the duty of GP surgery staff to offer it. They felt strongly that it is important for surgery staff to have a non-judgmental attitude and they did not want to be singled out as 'needing' a chlamydia screen. Furthermore, our sample reported a strong preference for being offered a screen by staff and providing the sample immediately at the surgery rather than taking home a testing kit. The positive attitude and subjective norms demonstrated by interviewees suggest that young peoples' behaviour would be to accept a screen if it was offered to them. CONCLUSION: Young people attending GP surgeries have a positive attitude towards chlamydia screening and given the right environment are likely to take up the offer in this setting. The right environment involves normalising screening by offering a chlamydia screen to all 15-24 year olds at every interaction with staff, offering screening with a non-judgmental attitude and minimising barriers to screening such as embarrassment. The GP surgery is the ideal place to screen young people for chlamydia as it is not a threatening place for them and our study has shown that they think it is the normal place to go to discuss health matters. PMID- 20955571 TI - The ladies trial: laparoscopic peritoneal lavage or resection for purulent peritonitis and Hartmann's procedure or resection with primary anastomosis for purulent or faecal peritonitis in perforated diverticulitis (NTR2037). AB - BACKGROUND: Recently, excellent results are reported on laparoscopic lavage in patients with purulent perforated diverticulitis as an alternative for sigmoidectomy and ostomy.The objective of this study is to determine whether LaparOscopic LAvage and drainage is a safe and effective treatment for patients with purulent peritonitis (LOLA-arm) and to determine the optimal resectional strategy in patients with a purulent or faecal peritonitis (DIVA-arm: perforated DIVerticulitis: sigmoidresection with or without Anastomosis). METHODS/DESIGN: In this multicentre randomised trial all patients with perforated diverticulitis are included. Upon laparoscopy, patients with purulent peritonitis are treated with laparoscopic lavage and drainage, Hartmann's procedure or sigmoidectomy with primary anastomosis in a ratio of 2:1:1 (LOLA-arm). Patients with faecal peritonitis will be randomised 1:1 between Hartmann's procedure and resection with primary anastomosis (DIVA-arm). The primary combined endpoint of the LOLA arm is major morbidity and mortality. A sample size of 132:66:66 patients will be able to detect a difference in the primary endpoint from 25% in resectional groups compared to 10% in the laparoscopic lavage group (two sided alpha = 5%, power = 90%). Endpoint of the DIVA-arm is stoma free survival one year after initial surgery. In this arm 212 patients are needed to significantly demonstrate a difference of 30% (log rank test two sided alpha = 5% and power = 90%) in favour of the patients with resection with primary anastomosis. Secondary endpoints for both arms are the number of days alive and outside the hospital, health related quality of life, health care utilisation and associated costs. DISCUSSION: The Ladies trial is a nationwide multicentre randomised trial on perforated diverticulitis that will provide evidence on the merits of laparoscopic lavage and drainage for purulent generalised peritonitis and on the optimal resectional strategy for both purulent and faecal generalised peritonitis. TRIAL REGISTRATION: Nederlands Trial Register NTR2037. PMID- 20955572 TI - Steppingstones to the implementation of an inhospital fracture and dislocation registry using the AO/OTA classification: compliance, completeness and commitment. AB - BACKGROUND: Musculoskeletal trauma represents a considerable global health burden, however reliable population-based incidence data are scarce. A fracture and dislocation registry was established within a well-defined population. An audit of the establishment process, feasibility of the registry work and report of the collected data is given. METHODS: Demographic data, fracture type and location, mode of treatment, and the reasons for the secondary procedures were collected and scored using recognized systems, such as the AO/OTA classification and the Gustilo-Anderson classification for open fractures. The reporting was done in the operation planning program by the involved orthopaedic surgeon. Both inpatient and day-case procedures were collected. Data were collected prospectively from 2006 until 2010. Compliance among the surgeons and completeness and accuracy of the data was continuously assured by an orthopaedic surgeon. RESULTS: During the study period, 39 orthopaedic surgeons were involved in the recording of a total of 8,188 procedures, consisting of primary treatment of 4,986 long bone fractures, 467 non long bone fractures, 123 dislocations and 2,612 secondary treatments. In the study period 532 fractures or dislocations were treated at least once for one or more serious complications. For the index year of 2009, a total of 5710 fractures or dislocations were treated in the emergency department or hospitalized, of which the 1594 (28%) were treated at the inpatient or day-case operation rooms, thus registered in the FDR. Quality assurance, educational incentives and continuous feedback between coders and controller in the integrated electronic system are available and used through the features of the electronic database. CONCLUSIONS: Implementing an integrated registry of fractures and dislocations with the electronic hospital system has been possible despite several users involved. The electronic system and the data controller provide for completeness and validity. The FDR has become an indispensable tool for the department for planning and education and will serve as a prerequisite for the conduct and execution of future prospective trials within the department. Further, other departments with similar electronic patient files may fairly easily adopt this system for implementation. PMID- 20955573 TI - GDNF stimulates the proliferation of cultured mouse immature Sertoli cells via its receptor subunit NCAM and ERK1/2 signaling pathway. AB - BACKGROUND: The proliferation and final density of Sertoli cells in the testis are regulated by hormones and local factors. Glial cell line-derived neurotrophic factor (GDNF), a distantly related member of the transforming growth factor-beta superfamily, and its receptor subunits GDNF family receptor alpha 1 (GFRalpha1), RET tyrosine kinase, and neural cell adhesion molecule (NCAM) have been reported to be expressed in the testis and involved in the regulation of proliferation of immature Sertoli cells (ISCs). However, the expression patterns of these receptor subunits and the downstream signaling pathways have not been addressed in ISCs. RESULTS: In the present study, we have reported that the proliferation of cultured ISCs was significantly enhanced by GDNF. The receptor subunits GFRalpha1 and NCAM but not RET were expressed in ISCs, and the stimulatory effect of GDNF on the proliferation of ISCs was significantly reduced by anti-NCAM antibody blocking or siRNA that specifically targets NCAM mRNA. Additionally, the ERK1/2 inhibitor, PD98059, completely abolished the mitogenic effect of GDNF on ISCs. CONCLUSIONS: GDNF stimulates the proliferation of ISCs via its receptor subunit NCAM and the consequent activation of the ERK1/2 signaling pathway. PMID- 20955575 TI - A longitudinal study of tobacco use among American Indian and Alaska Native tribal college students. AB - BACKGROUND: American Indians (AI) have the highest smoking rates of any ethnic group in the US (40.8%), followed most closely by African Americans (24.3%) and European Americans (23.6%). AI smokers also have more difficulty quitting smoking compared to other ethnic groups, evidenced by their significantly lower quit ratios, and are among the least successful in maintaining long term abstinence. While health disparities like these have existed for years among AI, the epidemiology of smoking and nicotine dependence has not been optimally described among this underserved population. Our overarching hypothesis is that the susceptibility of AI to cigarette smoking and nicotine dependence and its consequences has both an underlying nicotine metabolism component as well as psychosocial, cultural, and environment causes. We are well-positioned to explore this issue for the first time in this population. Our objective is to establish a cohort of AI tribal college/university students to determine the predictors of smoking initiation (non-use to experimentation), progression (experimentation to established use), and cessation (established use to cessation). Much of what is known about the process of smoking initiation and progression comes from quantitative studies with non-Native populations. Information related to smoking use among AI tribal college/university (TCU) students is entirely unknown and critically needs further investigation. This study will be the first of its kind among AI college students who are at the highest risk among all ethnic groups for tobacco dependence. METHODS/DESIGN: First year students at Haskell Indian Nations University in Kansas will be recruited over four consecutive years and will be surveyed annually and repeatedly through year 5 of the study. We will use both longitudinal quantitative surveys and qualitative focus group methods to examine key measures and determinants of initiation and use among this high risk group. PMID- 20955574 TI - Evolutionary divergence of chloroplast FAD synthetase proteins. AB - BACKGROUND: Flavin adenine dinucleotide synthetases (FADSs) - a group of bifunctional enzymes that carry out the dual functions of riboflavin phosphorylation to produce flavin mononucleotide (FMN) and its subsequent adenylation to generate FAD in most prokaryotes - were studied in plants in terms of sequence, structure and evolutionary history. RESULTS: Using a variety of bioinformatics methods we have found that FADS enzymes localized to the chloroplasts, which we term as plant-like FADS proteins, are distributed across a variety of green plant lineages and constitute a divergent protein family clearly of cyanobacterial origin. The C-terminal module of these enzymes does not contain the typical riboflavin kinase active site sequence, while the N-terminal module is broadly conserved. These results agree with a previous work reported by Sandoval et al. in 2008. Furthermore, our observations and preliminary experimental results indicate that the C-terminus of plant-like FADS proteins may contain a catalytic activity, but different to that of their prokaryotic counterparts. In fact, homology models predict that plant-specific conserved residues constitute a distinct active site in the C-terminus. CONCLUSIONS: A structure-based sequence alignment and an in-depth evolutionary survey of FADS proteins, thought to be crucial in plant metabolism, are reported, which will be essential for the correct annotation of plant genomes and further structural and functional studies. This work is a contribution to our understanding of the evolutionary history of plant-like FADS enzymes, which constitute a new family of FADS proteins whose C-terminal module might be involved in a distinct catalytic activity. PMID- 20955576 TI - Bisphenol a exposure in Mexico City and risk of prematurity: a pilot nested case control study. AB - BACKGROUND: Presence of Bisphenol A (BPA) has been documented worldwide in a variety of human biological samples. There is growing evidence that low level BPA exposure may impact placental tissue development and thyroid function in humans. The aim of this present pilot study was to determine urinary concentrations of BPA during the last trimester of pregnancy among a small subset of women in Mexico City, Mexico and relate these concentrations to risk of delivering prematurely. METHODS: A nested case-control subset of 60 participants in the Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) study in Mexico City, Mexico were selected based on delivering less than or equal to 37 weeks of gestation and greater than 37 weeks of gestation. Third trimester archived spot urine samples were analyzed by online solid phase extraction coupled with high performance liquid chromatography isotope dilution tandem mass spectrometry. RESULTS: BPA was detected in 80.0% (N = 48) of the urine samples; total concentrations ranged from < 0.4 MUg/L to 6.7 MUg/L; uncorrected geometric mean was 1.52 MUg/L. The adjusted odds ratio of delivering less than or equal to 37 weeks in relation to specific gravity adjusted third trimester BPA concentration was 1.91 (95%CI 0.93, 3.91, p-value = 0.08). When cases were further restricted to births occurring prior to the 37th week (n = 12), the odds ratio for specific-gravity adjusted BPA was larger and statistically significant (p < 0.05). CONCLUSIONS: This is the first study to document measurable levels of BPA in the urine of a population of Mexican women. This study also provides preliminary evidence, based on a single spot urine sample collected during the third trimester, that pregnant women who delivered less than or equal to 37 weeks of gestation and prematurely (< 37 weeks) had higher urinary concentrations of BPA compared to women delivering after 37 weeks. PMID- 20955577 TI - Fragile X astrocytes induce developmental delays in dendrite maturation and synaptic protein expression. AB - BACKGROUND: Fragile X syndrome is the most common inherited form of mental impairment characterized by cognitive impairment, attention deficit and autistic behaviours. The mouse model of Fragile X is used to study the underlying neurobiology associated with behavioral deficiencies. The effect of Fragile X glial cells on the development of neurons has not been studied. We used a co culture technique in combination with morphometrics on immunostained neurons to investigate the role of astrocytes in the development delays associated with hippocampal neuron development. RESULTS: We found that hippocampal neurons grown on Fragile X astrocytes exhibited a significant difference from the neurons grown with normal astrocytes after 7 days in vitro for many parameters including increases in dendritic branching and in area of the cell body. However, after 21 days in culture, the neurons grown on Fragile X astrocytes exhibited morphological characteristics that did not differ significantly from the neurons grown on normal astrocytes. With antibodies to the pre-synaptic protein, synapsin, and to the excitatory post-synaptic protein, PSD-95, we quantified the number of developing excitatory synapses on the dendrites. In addition to the delays in dendritic patterning, the development of excitatory synapses was also delayed in the hippocampal neurons. CONCLUSIONS: These experiments are the first to establish a role for astrocytes in the delayed growth characteristics and abnormal morphological features in dendrites and synapses that characterize the Fragile X syndrome. PMID- 20955578 TI - Internet addiction: a 21st century epidemic? AB - Internet addiction, while not yet officially codified within a psychopathological framework, is growing both in prevalence and within the public consciousness as a potentially problematic condition with many parallels to existing recognized disorders. The rapid and unfettered increase in the number of people accessing a relatively unrestricted internet substantially increases the possibility that those suffering with an underlying psychological comorbidity may be at serious risk of developing an addiction to the internet, lending further credence to this hitherto understudied condition. In this commentary, I outline my recommendations for improved diagnosis, study and prevention of internet addiction. PMID- 20955579 TI - Which medical error to disclose to patients and by whom? Public preference and perceptions of norm and current practice. AB - BACKGROUND: Disclosure of near miss medical error (ME) and who should disclose ME to patients continue to be controversial. Further, available recommendations on disclosure of ME have emerged largely in Western culture; their suitability to Islamic/Arabic culture is not known. METHODS: We surveyed 902 individuals attending the outpatient's clinics of a tertiary care hospital in Saudi Arabia. Personal preference and perceptions of norm and current practice regarding which ME to be disclosed (5 options: don't disclose; disclose if associated with major, moderate, or minor harm; disclose near miss) and by whom (6 options: any employee, any physician, at-fault-physician, manager of at-fault-physician, medical director, or chief executive director) were explored. RESULTS: Mean (SD) age of respondents was 33.9 (10) year, 47% were males, 90% Saudis, 37% patients, 49% employed, and 61% with college or higher education. The percentage (95% confidence interval) of respondents who preferred to be informed of harmful ME, of near miss ME, or by at-fault physician were 60.0% (56.8 to 63.2), 35.5% (32.4 to 38.6), and 59.7% (56.5 to 63.0), respectively. Respectively, 68.2% (65.2 to 71.2) and 17.3% (14.7 to 19.8) believed that as currently practiced, harmful ME and near miss ME are disclosed, and 34.0% (30.7 to 37.4) that ME are disclosed by at-fault-physician. Distributions of perception of norm and preference were similar but significantly different from the distribution of perception of current practice (P < 0.001). In a forward stepwise regression analysis, older age, female gender, and being healthy predicted preference of disclosure of near miss ME, while younger age and male gender predicted preference of no-disclosure of ME. Female gender also predicted preferring disclosure by the at-fault physician. CONCLUSIONS: We conclude that: 1) there is a considerable diversity in preferences and perceptions of norm and current practice among respondents regarding which ME to be disclosed and by whom, 2) Distributions of preference and perception of norm were similar but significantly different from the distribution of perception of current practice, 3) most respondents preferred to be informed of ME and by at-fault physician, and 4) one third of respondents preferred to be informed of near-miss ME, with a higher percentage among females, older, and healthy individuals. PMID- 20955580 TI - Saudi views on consenting for research on medical records and leftover tissue samples. AB - BACKGROUND: Consenting for retrospective medical records-based research (MR) and leftover tissue-based research (TR) continues to be controversial. Our objective was to survey Saudis attending outpatient clinics at a tertiary care hospital on their personal preference and perceptions of norm and current practice in relation to consenting for MR and TR. METHODS: We surveyed 528 Saudis attending clinics at a tertiary care hospital in Saudi Arabia to explore their preferences and perceptions of norm and current practice. The respondents selected one of 7 options from each of 6 questionnaires. RESULTS: Respondents' mean (SD) age was 33 (11) years, 42% were males, 56% were patients, 84% had >= secondary school education, and 10% had previously volunteered for research. Respectively, 40% and 49% perceived that the norm is to conduct MR and TR without consent and 38% and 37% with general or proposal-specific consent; the rest objected to such research. There was significant difference in the distribution of choices according to health status (patients vs. companions) for MR (adjusted Kruskal Wallis test P = 0.03) but not to age group, gender, education level, or previous participation in research (unadjusted P = 0.02 - 0.59). The distributions of perceptions of current practice and norm were similar (unadjusted Marginal Homogeneity test P = 0.44 for MR and P = 0.89 for TR), whereas the distributions of preferences and perceptions of norm were different (adjusted P = 0.09 for MR and P = 0.02 for TR). The distributions of perceptions of norm, preferences, and perceptions of current practice for MR were significantly different from those of TR (adjusted P < 0.009 for all). CONCLUSIONS: We conclude that: 1) there is a considerable diversity among Saudi views regarding consenting for retrospective research which may be related to health status, 2) the distribution of perceptions of norm was similar to the distribution of perceptions of current practice but different from that of preferences, and 3) MR and TR are perceived differently in regard to consenting. PMID- 20955581 TI - Statistical analysis and molecular dynamics simulations of ambivalent alpha helices. AB - BACKGROUND: Analysis of known protein structures reveals that identical sequence fragments in proteins can adopt different secondary structure conformations. The extent of this conformational diversity is influenced by various factors like the intrinsic sequence propensity, sequence context and other environmental factors such as pH, site directed mutations or alteration of the binding ligands. Understanding the mechanism by which the environment affects the structural ambivalence of these peptides has potential implications for protein design and reliable local structure prediction algorithms. Identification of the structurally ambivalent sequence fragments and determining the rules which dictate their conformational preferences play an important role in understanding the conformational changes observed in misfolding diseases. However, a systematic classification of their intrinsic sequence patterns or a statistical analysis of their properties and sequence context in relation to the origin of their structural diversity have largely remained unexplored. RESULTS: In this work, the conformational variability of alpha-helices is studied by mapping sequences from the non-redundant database to identical sequences across all classes of the SCOP (Structural Classification of Proteins) database. Some helices retain their conformations when mapped in the SCOP database while others exhibit a complete/partial switch to non-helical conformations. The results clearly depict the differences in the propensities of amino acids for the variable and conserved helices. Sequences flanking these ambivalent sequence fragments have anisotropic propensities at the N- and C-termini. This structural variability is depicted by molecular dynamics simulations in explicit solvent, which show that the short conserved helices retain their conformations while their longer counterparts fray into two or more shorter helices. Variable helices in the non-redundant database exhibit a trend of retaining helical conformations while their corresponding non helical conformations in SCOP database show large deviations from their respective initial structures by adopting partial or full helical conformations. Partially ambivalent helices are also found to retain their respective conformations. CONCLUSIONS: All sequence fragments which show structural diversity in different proteins of the non-redundant database are investigated. The final conformation of these ambivalent sequences are dictated by a fine tuning of their intrinsic sequence propensity and the anisotropic amino acid propensity of the flanking sequences. This analysis may unravel the connection between diverse secondary structures, which conserve the overall structural fold of the protein thus determining its function. PMID- 20955582 TI - Effectiveness and cost-effectiveness of early assisted discharge for chronic obstructive pulmonary disease exacerbations: the design of a randomised controlled trial. AB - BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) are the main cause for hospitalisation. These hospitalisations result in a high pressure on hospital beds and high health care costs. Because of the increasing prevalence of COPD this will only become worse. Hospital at home is one of the alternatives that has been proved to be a safe alternative for hospitalisation in COPD. Most schemes are early assisted discharge schemes with specialised respiratory nurses providing care at home. Whether this type of service is cost-effective depends on the setting in which it is delivered and the way in which it is organised. METHODS/DESIGN: GO AHEAD (Assessment Of Going Home under Early Assisted Discharge) is a 3-months, randomised controlled, multi-centre clinical trial. Patients admitted to hospital for a COPD exacerbation are either discharged on the fourth day of admission and further treated at home, or receive usual inpatient hospital care. Home treatment is supervised by general nurses. Primary outcome is the effectiveness and cost effectiveness of an early assisted discharge intervention in comparison with usual inpatient hospital care for patients hospitalised with a COPD exacerbation. Secondary outcomes include effects on quality of life, primary informal caregiver burden and patient and primary caregiver satisfaction. Additionally, a discrete choice experiment is performed to provide insight in patient and informal caregiver preferences for different treatment characteristics. Measurements are performed on the first day of admission and 3 days, 7 days, 1 month and 3 months thereafter. Ethical approval has been obtained and the study has been registered. DISCUSSION: This article describes the study protocol of the GO AHEAD study. Early assisted discharge could be an effective and cost-effective method to reduce length of hospital stay in the Netherlands which is beneficial for patients and society. If effectiveness and cost-effectiveness can be proven, implementation in the Dutch health care system should be considered. TRIAL REGISTRATION: Netherlands Trial Register NTR1129. PMID- 20955583 TI - PPARgamma activation attenuates T-lymphocyte-dependent inflammation of adipose tissue and development of insulin resistance in obese mice. AB - BACKGROUND: Inflammation of adipose tissue (AT) has been recently accepted as a first step towards obesity-mediated insulin resistance. We could previously show that mice fed with high fat diet (HFD) develop systemic insulin resistance (IR) and glucose intolerance (GI) associated with CD4-positive T-lymphocyte infiltration into visceral AT. These T-lymphocytes, when enriched in AT, participate in the development of fat tissue inflammation and subsequent recruitment of proinflammatory macrophages. The aim of this work was to elucidate the action of the insulin sensitizing PPARgamma on T-lymphocyte infiltration during development of IR, and comparison of the PPARgamma-mediated anti inflammatory effects of rosiglitazone and telmisartan in diet-induced obesity model (DIO-model) in mice. METHODS: In order to investigate the molecular mechanisms underlying early development of systemic insulin resistance and glucose intolerance male C57BL/6J mice were fed with high fat diet (HFD) for 10 weeks in parallel to the pharmacological intervention with rosiglitazone, telmisartan, or vehicle. RESULTS: Both rosiglitazone and telmisartan were able to reduce T-lymphocyte infiltration into AT analyzed by quantitative analysis of the T-cell marker CD3gamma and the chemokine SDF1alpha. Subsequently, both PPARgamma agonists were able to attenuate macrophage infiltration into AT, measured by the reduction of MCP1 and F4/80 expression. In parallel to the reduction of AT inflammation, ligand-activated PPARgamma improved diet-induced IR and GI. CONCLUSION: Together the present study demonstrates a close connection between PPARgamma-mediated anti-inflammation in AT and systemic improvement of glucose metabolism identifying T-lymphocytes as one cellular mediator of PPARgamma's action. PMID- 20955584 TI - Socio-demographic, lifestyle and health characteristics among snus users and dual tobacco users in Stockholm County, Sweden. AB - BACKGROUND: Socio-demographic and lifestyle characteristics of snus users have not been systematically described. Such knowledge is pivotal for tobacco control efforts and for the assessment of health effects of snus use. METHODS: A cross sectional study was conducted, based on the Stockholm Public Health Survey, including a population-based sample of 34,707 men and women aged 18-84 years. We examined how socio-demographic, lifestyle and health-related characteristics were associated with the prevalence of current daily snus use, smoking and dual tobacco use. Logistic regression was used to calculate odds ratios of prevalence (ORs) and 95% confidence intervals (CIs). RESULTS: Low educational level (OR = 1.60, CI = 1.41-1.81 and OR = 1.49, CI = 1.17-1.89, for men and women respectively), as well as occupational class and low income were associated with snus use. Some unfavourable lifestyle characteristics, including risky alcohol consumption (males: OR = 1.81, CI = 1.63-2.02; females: OR = 1.79, CI = 1.45 2.20), binge drinking and low consumption of fruit and vegetables were also associated with snus use. In contrast, physical inactivity and overweight/obesity were not, nor was perceived health. The prevalence of smoking followed steeper gradients for social as well as lifestyle characteristics. Overweight and obese men were however less often smokers. Perceived poor general health and psychological distress were highly related to smoking. Social disadvantage, as well as unhealthy lifestyle and self-reported poor health were strongly associated with dual use. There were limited differences between men and women. CONCLUSIONS: The social, lifestyle and health profiles of exclusive snus users in Stockholm County are less favourable than those of non-users of tobacco, but more advantageous than those of exclusive smokers. This knowledge should guide tobacco control measures as well as the interpretation of health risks linked to snus use. PMID- 20955585 TI - An Sp185/333 gene cluster from the purple sea urchin and putative microsatellite mediated gene diversification. AB - BACKGROUND: The immune system of the purple sea urchin, Strongylocentrotus purpuratus, is complex and sophisticated. An important component of sea urchin immunity is the Sp185/333 gene family, which is significantly upregulated in immunologically challenged animals. The Sp185/333 genes are less than 2 kb with two exons and are members of a large diverse family composed of greater than 40 genes. The S. purpuratus genome assembly, however, contains only six Sp185/333 genes. This underrepresentation could be due to the difficulties that large gene families present in shotgun assembly, where multiple similar genes can be collapsed into a single consensus gene. RESULTS: To understand the genomic organization of the Sp185/333 gene family, a BAC insert containing Sp185/333 genes was assembled, with careful attention to avoiding artifacts resulting from collapse or artificial duplication/expansion of very similar genes. Twelve candidate BAC assemblies were generated with varying parameters and the optimal assembly was identified by PCR, restriction digests, and subclone sequencing. The validated assembly contained six Sp185/333 genes that were clustered in a 34 kb region at one end of the BAC with five of the six genes tightly clustered within 20 kb. The Sp185/333 genes in this cluster were no more similar to each other than to previously sequenced Sp185/333 genes isolated from three different animals. This was unexpected given their proximity and putative effects of gene homogenization in closely linked, similar genes. All six genes displayed significant similarity including both 5' and 3' flanking regions, which were bounded by microsatellites. Three of the Sp185/333 genes and their flanking regions were tandemly duplicated such that each repeated segment consisted of a gene plus 0.7 kb 5' and 2.4 kb 3' of the gene (4.5 kb total). Both edges of the segmental duplications were bounded by different microsatellites. CONCLUSIONS: The high sequence similarity of the Sp185/333 genes and flanking regions, suggests that the microsatellites may promote genomic instability and are involved with gene duplication and/or gene conversion and the extraordinary sequence diversity of this family. PMID- 20955586 TI - Genome wide analysis of DNA copy number neutral loss of heterozygosity (CNNLOH) and its relation to gene expression in esophageal squamous cell carcinoma. AB - BACKGROUND: Genomic instability plays an important role in human cancers. We previously characterized genomic instability in esophageal squamous cell carcinomas (ESCC) in terms of loss of heterozygosity (LOH) and copy number (CN) changes in tumors using the Affymetrix GeneChip Human Mapping 500K array in 30 cases from a high-risk region of China. In the current study we focused on copy number neutral (CN = 2) LOH (CNNLOH) and its relation to gene expression in ESCC. RESULTS: Overall we found that 70% of all LOH observed was CNNLOH. Ninety percent of ESCCs showed CNNLOH (median frequency in cases = 60%) and this was the most common type of LOH in two-thirds of cases. CNNLOH occurred on all 39 autosomal chromosome arms, with highest frequencies on 19p (100%), 5p (96%), 2p (95%), and 20q (95%). In contrast, LOH with CN loss represented 19% of all LOH, occurred in just half of ESCCs (median frequency in cases = 0%), and was most frequent on 3p (56%), 5q (47%), and 21q (41%). LOH with CN gain was 11% of all LOH, occurred in 93% of ESCCs (median frequency in cases = 13%), and was most common on 20p (82%), 8q (74%), and 3q (42%). To examine the effect of genomic instability on gene expression, we evaluated RNA profiles from 17 pairs of matched normal and tumor samples (a subset of the 30 ESCCs) using Affymetrix U133A 2.0 arrays. In CN neutral regions, expression of 168 genes (containing 1976 SNPs) differed significantly in tumors with LOH versus tumors without LOH, including 101 genes that were up-regulated and 67 that were down-regulated. CONCLUSION: Our results indicate that CNNLOH has a profound impact on gene expression in ESCC, which in turn may affect tumor development. PMID- 20955587 TI - Cronkhite-Canada syndrome associated with rib fractures: a case report. AB - BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare multiple gastrointestinal polyposis. Up till now, many complications of CCS have been reported in the literature, but rib fracture is not included. CASE PRESENTATION: We report a case of a 58-year-old man who was admitted to our hospital with a 6-month history of frequent diarrhea, intermittent hematochezia and a weight loss of 13 kg. On admission, physical examination revealed alopecia of the scalp, hyperpigmentation of the hands and soles, and dystrophy of the fingernails. Laboratory data revealed hypocalcaemia and hypoproteinemia. Esophagogastroduodenoscopy, video capsule endoscopy and colonoscopy revealed various sizes of generalized gastrointestinal polyps. Histological examination of the biopsy specimens obtained from the stomach and the colon showed adenomatous polyp and inflammatory polyp respectively. Thus, a diagnosis of CCS was made. After treatment with corticosteroids for 24 days and nutritional support for two months, his clinical condition improved. Two months later, he was admitted to our hospital for the second time with frequent diarrhea and weight loss. The chest radiography revealed fractures of the left sixth and seventh ribs. Examinations, including emission computed tomography, bone densitometry test, and other serum parameters, were performed, but could not identify the definite etiology of the rib fractures. One month later, the patient suffered from aggravating multiple rib fractures due to the ineffective treatment, persistent hypocalcaemia and malnutrition. CONCLUSIONS: This is the first case of a CCS patient with multiple rib fractures. Although the association between CCS and multiple rib fractures in this case remains uncertain, we presume that persistent hypocalcaemia and malnutrition contribute to this situation, or at least aggravate this rare complication. Besides, since prolonged corticosteroid therapy will result in an increased risk of osteoporotic fracture, CCS patients who accept corticosteroid therapy could be potential victims of rib fracture. PMID- 20955588 TI - Allelotyping identification of genomic alterations in rectal chromosomally unstable tumors without preoperative treatment. AB - BACKGROUND: Numerous studies reported genomic alterations in colorectal human tumors but few focused on rectal tumors with the specification of preoperative treated or untreated tumors. The goals of this study were to list chromosome allelic imbalances and correlate their frequency with tumor progression and to identify potential molecular markers of progression in rectal chromosomally unstable tumors without preoperative treatment. METHODS: Genomic alterations of 57 rectal tumors assessed by allelotyping targeting 33 chromosomal loci, were clusterised and compared to those of 151 left colon tumors. RESULTS: Clustering separated the rectal tumors without preoperative treatment into three subtypes according to the allelic imbalance frequency and genomic alteration associations. The tumors without preoperative treatment displayed a significantly higher allelic imbalance frequency (54%) than the tumors with preoperative treatment (33%), suggesting that treatment could target highly altered tumor clones. Interestingly, the survival analysis identified three potential prognostic molecular survival markers, D1S197, D5S430, and D14S65, for tumors without preoperative treatment. CONCLUSION: Based on the genomic status of 33 chromosomal loci, we observed that rectal tumors without preoperative treatment segregate according to the global allelic imbalance frequency but without correlation to the tumor progression. Moreover, the detailed associations of alterations in rectal tumors are different from those described in colon tumors suggesting that rectal and left tumors should be considered as separate entities. Finally, potential prognostic genomic molecular markers for survival are proposed which status could specify the clinical course of the tumors. PMID- 20955589 TI - Prevalence of and risk factors for perioperative arrhythmias in neonates and children after cardiopulmonary bypass: continuous holter monitoring before and for three days after surgery. AB - BACKGROUND: A comprehensive evaluation of postoperative arrhythmias following surgery for congenital heart disease by continuous Holter monitoring has not been carried out. We aimed, firstly, to establish the time course of pre- and early postoperative arrhythmias by beat-to-beat analysis following cardiopulmonary bypass and, secondly, to examine which surgical procedures present risk factors for specific arrhythmias. METHODS: 494 consecutive patients, including 96 neonates, were studied with serial 24-hour Holter electrocardiograms before as well as uninterruptedly during the first 72 hours after surgery and prior to discharge. RESULTS: Within 24 hours of surgery 59% of the neonates and 79% of the older children developed arrhythmias. Junctional ectopic tachycardia occurred in 9% of neonates and 5% of non-neonates and ventricular tachycardia in 3% and 15%, respectively.For neonates, male sex and longer cross-clamping time independently increased the risk for arrhythmias (odds ratios 2.83 and 1.96/minute, respectively). Ventricular septal defect repair was a strong risk factor for junctional ectopic tachycardia in neonates and in older children (odds ratios 18.8 and 3.69, respectively). For infants and children, older age (odds ratio 1.01/month) and closure of atrial septal defects (odds ratio 2.68) predisposed to arrhythmias of any type. CONCLUSIONS: We present the largest cohort of neonates, infants and children that has been prospectively studied for the occurrence of arrhythmias after cardiac surgery. Postoperative arrhythmias are a frequent and transient phenomenon after cardiopulmonary bypass, provoked both by mechanical irritation of the conduction system and by humoral factors. PMID- 20955591 TI - Endogenous expression of ASLV viral proteins in specific pathogen free chicken embryos: relevance for the developmental biology research field. AB - BACKGROUND: The use of Specific Pathogen Free (SPF) eggs in combination with RCAS retrovirus, a member of the Avian Sarcoma-Leukosis Virus (ASLV) family, is of standard practice to study gene function and development. SPF eggs are certified free of infection by specific pathogen viruses of either exogenous or endogenous origin, including those belonging to the ASLV family. Based on this, SPF embryos are considered to be free of ASLV viral protein expression, and consequently in developmental research studies RCAS infected cells are routinely identified by immunohistochemistry against the ASLV viral proteins p19 and p27. Contrary to this generally accepted notion, observations in our laboratory suggested that certified SPF chicken embryos may endogenously express ASLV viral proteins p19 and p27. Since these observations may have significant implications for the developmental research field we further investigated this possibility. RESULTS: We demonstrate that certified SPF chicken embryos have transcriptionally active endogenous ASLV loci (ev loci) capable of expressing ASLV viral proteins, such as p19 and p27, even when those loci are not capable of producing viral particles. We also show that the extent of viral protein expression in embryonic tissues varies not only among flocks but also between embryos of the same flock. In addition, our genetic screening revealed significant heterogeneity in ev loci composition even among embryos of the same flock. CONCLUSIONS: These observations have critical implications for the developmental biology research field, since they strongly suggest that the current standard methodology used in experimental studies using the chick embryo and RCAS vectors may lead to inaccurate interpretation of results. Retrospectively, our observations suggest that studies in which infected cells have been identified simply by pan-ASLV viral protein expression may need to be considered with caution. For future studies, they point to a need for careful selection and screening of the chick SPF lines to be used in combination with RCAS constructs, as well as the methodology utilized for qualitative analysis of experimental results. A series of practical guidelines to ensure research quality animals and accuracy of the interpretation of results is recommended and discussed. PMID- 20955590 TI - Dasatinib reduces FAK phosphorylation increasing the effects of RPI-1 inhibition in a RET/PTC1-expressing cell line. AB - BACKGROUND: TPC-1 is a papillary thyroid carcinoma (PTC)-derived cell line that spontaneously expresses the oncogene RET/PTC1. TPC-1 treated with the RET/PTC1 inhibitor RPI-1 displayed a cytostatic and reversible inhibition of cell proliferation and a strong activation of focal adhesion kinase (FAK). As dasatinib inhibition of Src results in reduction of FAK activation, we evaluated the effects of TPC-1 treatment with dasatinib in combination with RPI-1. RESULTS: Dasatinib (100 nM) strongly reduced TPC-1 proliferation and induced marked changes in TPC-1 morphology. Cells appeared smaller and more contracted, with decreased cell spreading, due to the inhibition of phosphorylation of important cytoskeletal proteins (p130CAS, Crk, and paxillin) by dasatinib. The combination of RPI-1 with dasatinib demonstrated enhanced effects on cell proliferation (more than 80% reduction) and on the phosphotyrosine protein profile. In particular, RPI-1 reduced the phosphorylation of RET, MET, DCDB2, CTND1, and PLCgamma, while dasatinib acted on the phosphorylation of EGFR, EPHA2, and DOK1. Moreover, dasatinib completely abrogated the phosphorylation of FAK at all tyrosine sites (Y576, Y577, Y861, Y925) with the exception of the autoactivation site (Y397). Notably, the pharmacological treatments induced an overexpression of integrin beta1 (ITB1) that was correlated with a mild enhancement in phosphorylation of ERK1/2 and STAT3, known for their roles in prevention of apoptosis and in increase of proliferation and survival. A reduction in Akt, p38 and JNK1/2 activation was observed. CONCLUSIONS: All data demonstrate that the combination of the two drugs effectively reduced cell proliferation (by more than 80%), significantly decreased Tyr phosphorylation of almost all phosphorylable proteins, and altered the morphology of the cells, supporting high cytostatic effects. Following the combined treatment, cell survival pathways appeared to be mediated by STAT3 and ERK activities resulting from integrin clustering and FAK autophosphorylation. EphA2 may also contribute, at least in part, to integrin and FAK activation. In conclusion, these data implicate ITB1 and EphA2 as promising therapeutic targets in PTC. PMID- 20955592 TI - Electronic versus paper diaries: a pilot study of concordance and adherence in head and neck cancer patients receiving radiation therapy. AB - BACKGROUND: Interactive Voice Response Systems (IVRS) and other electronic data collection methods have begun to replace conventional paper diaries as a way to capture daily patient reports. However, these methods have not been compared in head and neck (H&N) cancer patients receiving radiation therapy. METHODS: 15 subjects with H&N cancer were asked to complete daily IVRS calls and daily paper diaries during radiation therapy. We compared response consistency and comparative adherence across the two methods. RESULTS: 86.1% (1920/2231) of participants' responses were consistent between IVRS and paper diaries. 79.5% of the expected number of paper diaries were completed, compared to 66.2% of IVRS phone calls. CONCLUSIONS: In this pilot study of H&N cancer patients undergoing radiation therapy, concordance was high between responses recorded by paper diaries and IVRS. Although adherence appeared to be higher for the paper diaries, it is possible that they may not have been completed at the proper time. PMID- 20955593 TI - Role of endometrial blood flow assessment with color Doppler energy in predicting pregnancy outcome of IVF-ET cycles. AB - This is a prospective study of 182 women (38 yrs or younger) undergoing IVF-ET. Endometrial thickness, echo pattern and blood flow on transvaginal ultrasonography were recorded eight hours prior to hCG administration. The patients were divided into three groups: A (n = 10) with undetectable endometrial blood flow; B (n = 82) with sub-endometrial blood flow; C (n = 90) with both endometrial and sub-endometrial blood flow. According to IVF-ET outcomes, all patients were re-divided into three groups: 1 non-pregnancy (n = 92); 2 intrauterine pregnancy with live fetus (n = 70); 3 others (n = 20 including biochemical pregnancy, embryonic diapause, ectopic pregnancy and miscarriage). Intrauterine pregnancy with live fetus in Group C (62.2%) was much higher than that in Group A and B (0% and 17.1%, p less than or equal to 0.001). The implantation rate (33.2%) was much higher than that in Group A and B (0% and 19.90%, p less than or equal to 0.001). The pulsatility index, resistance index, and S/D of endometrial spiral arteries were 0.1 +/- 0.2, 0.6 +/- 0.1 and 2.5 +/- 0.4 in Group 2, which were much lower than those in Group 1 and Group 3 (p1-2 less than 0.001, p2-3 less than 0.05). The patients with detectable endometrial blood flow had higher clinical pregnancy rates and implantation rates. PMID- 20955594 TI - Development and formative evaluation of the e-Health Implementation Toolkit (e HIT). AB - BACKGROUND: The use of Information and Communication Technology (ICT) or e-Health is seen as essential for a modern, cost-effective health service. However, there are well documented problems with implementation of e-Health initiatives, despite the existence of a great deal of research into how best to implement e-Health (an example of the gap between research and practice). This paper reports on the development and formative evaluation of an e-Health Implementation Toolkit (e HIT) which aims to summarise and synthesise new and existing research on implementation of e-Health initiatives, and present it to senior managers in a user-friendly format. RESULTS: The content of the e-HIT was derived by combining data from a systematic review of reviews of barriers and facilitators to implementation of e-Health initiatives with qualitative data derived from interviews of "implementers", that is people who had been charged with implementing an e-Health initiative. These data were summarised, synthesised and combined with the constructs from the Normalisation Process Model. The software for the toolkit was developed by a commercial company (RocketScience). Formative evaluation was undertaken by obtaining user feedback. There are three components to the toolkit--a section on background and instructions for use aimed at novice users; the toolkit itself; and the report generated by completing the toolkit. It is available to download from http://www.ucl.ac.uk/pcph/research/ehealth/documents/e-HIT.xls. CONCLUSIONS: The e-HIT shows potential as a tool for enhancing future e-Health implementations. Further work is needed to make it fully web-enabled, and to determine its predictive potential for future implementations. PMID- 20955595 TI - Base of coracoid process fracture with acromioclavicular dislocation in a child. AB - Fracture of the coracoid process is a rare injury. It can be easily missed when associated with other injuries to the shoulder girdle, for instance, acromioclavicular joint (ACJ) dislocation. Clinical attention is easily drawn to the more obvious ACJ dislocation, hence, the need for further radiological evaluation. We report an unusual case of fracture of the base of coracoid process associated with a true acromioclavicular joint dislocation in a 12 year old boy, with no separation of the epiphyseal plate, as one might expect. Treatment also remains controversial. Our patient underwent open reduction internal fixation of the acromioclavicular joint and coracoid process. He subsequently made an uneventful progress with pain free full range of shoulder movement at 5 months, and was discharged at 9 months. PMID- 20955596 TI - Successful C1 inhibitor short-term prophylaxis during redo mitral valve replacement in a patient with hereditary angioedema. AB - Hereditary angioedema is characterized by sudden episodes of nonpitting edema that cause discomfort and pain. Typically the extremities, genitalia, trunk, gastrointestinal tract, face, and larynx are affected by attacks of swelling. Laryngeal swelling carries significant risk for asphyxiation. The disease results from mutations in the C1 esterase inhibitor gene that cause C1 esterase inhibitor deficiency. Attacks of hereditary angioedema result from contact, complement, and fibrinolytic plasma cascade activation, where C1 esterase inhibitor irreversibly binds substrates. Patients with hereditary angioedema cannot replenish C1 esterase inhibitor levels on pace with its binding. When C1 esterase inhibitor is depleted in these patients, vasoactive plasma cascade products cause swelling attacks. Trauma is a known trigger for hereditary angioedema attacks, and patients have been denied surgical procedures because of this risk. However, uncomplicated surgeries have been reported. Appropriate prophylaxis can reduce peri-operative morbidity in these patients, despite proteolytic cascade and complement activation during surgical trauma. We report a case of successful short-term prophylaxis with C1 esterase inhibitor in a 51-year-old man with hereditary angioedema who underwent redo mitral valve reconstructive surgery. PMID- 20955597 TI - Ras-association domain family 1C protein promotes breast cancer cell migration and attenuates apoptosis. AB - BACKGROUND: The Ras association domain family 1 (RASSF1) gene is a Ras effector encoding two major mRNA forms, RASSF1A and RASSF1C, derived by alternative promoter selection and alternative mRNA splicing. RASSF1A is a tumor suppressor gene. However, very little is known about the function of RASSF1C both in normal and transformed cells. METHODS: Gene silencing and over-expression techniques were used to modulate RASSF1C expression in human breast cancer cells. Affymetrix microarray analysis was performed using T47D cells over-expressing RASSF1C to identify RASSF1C target genes. RT-PCR and western blot techniques were used to validate target gene expression. Cell invasion and apoptosis assays were also performed. RESULTS: In this article, we report the effects of altering RASSF1C expression in human breast cancer cells. We found that silencing RASSF1C mRNA in breast cancer cell lines (MDA-MB231 and T47D) caused a small but significant decrease in cell proliferation. Conversely, inducible over-expression of RASSF1C in breast cancer cells (MDA-MB231 and T47D) resulted in a small increase in cell proliferation. We also report on the identification of novel RASSF1C target genes. RASSF1C down-regulates several pro-apoptotic and tumor suppressor genes and up-regulates several growth promoting genes in breast cancer cells. We further show that down-regulation of caspase 3 via overexpression of RASSF1C reduces breast cancer cells' sensitivity to the apoptosis inducing agent, etoposide. Furthermore, we found that RASSF1C over-expression enhances T47D cell invasion/migration in vitro. CONCLUSION: Together, our findings suggest that RASSF1C, unlike RASSF1A, is not a tumor suppressor, but instead may play a role in stimulating metastasis and survival in breast cancer cells. PMID- 20955598 TI - Effects of population outcrossing on rotifer fitness. AB - BACKGROUND: Outcrossing between populations can exert either positive or negative effects on offspring fitness. Cyclically parthenogenetic rotifers, like other continental zooplankters, show high genetic differentiation despite their high potential for passive dispersal. Within this context, the effects of outcrossing may be relevant in modulating gene flow between populations through selection for or against interpopulation hybrids. Nevertheless, these effects remain practically unexplored in rotifers. Here, the consequences of outcrossing on the rotifer Brachionus plicatilis were investigated. Cross-mating experiments were performed between a reference population and three alternative populations that differed in their genetic distance with regard to the former. Two offspring generations were obtained: F1 and BC ('backcross'). Fitness of the outcrossed offspring was compared with fitness of the offspring of the reference population for both generations and for three different between-population combinations. Four fitness components were measured throughout the rotifer life cycle: the diapausing egg-hatching proportion, clone viability (for the clones originating from diapausing eggs), initial net growth rate R for each viable clone, and the proportion of male-producing clones. Additionally, both the parental fertilisation proportion and a compound fitness measure, integrating the complete life cycle, were estimated. RESULTS: In the F1 generation, hybrid vigour was detected for the diapausing egg-hatching proportion, while R was lower in the outcrossed offspring than in the offspring of the reference population. Despite these contrasting results, hybrid vigour was globally observed for the compound measure of fitness. Moreover, there was evidence that this vigour could increase with the genetic differentiation of the outcrossed populations. In the BC generation, the hybrid vigour detected for the egg-hatching proportion in the F1 generation reverted to outbreeding depression. By contrast, signs of hybrid vigour were observed for clone viability and R. The opposing trends observed for different life-cycle stages yielded a global pattern of hybrid vigour in the BC generation for two out of the three between-population comparisons. CONCLUSIONS: Results suggest that outbreeding depression does not constitute a barrier to gene flow. In newly-founded populations, where the population size is still small, dilution of immigrants should be low. Thus, a lack of outbreeding depression would allow gene flow to have an impact on the genetic composition of these populations. PMID- 20955599 TI - The INSIG2 rs7566605 polymorphism is not associated with body mass index and breast cancer risk. AB - BACKGROUND: The single nucleotide polymorphism rs7566605, located in the promoter of the INSIG2 gene, has been the subject of a strong scientific effort aimed to elucidate its possible association with body mass index (BMI). The first report showing that rs7566605 could be associated with body fatness was a genome-wide association study (GWAS) which used BMI as the primary phenotype. Many follow-up studies sought to validate the association of rs7566605 with various markers of obesity, with several publications reporting inconsistent findings. BMI is considered to be one of the measures of choice to evaluate body fatness and there is evidence that body fatness is related with an increased risk of breast cancer (BC). METHODS: we tested in a large-scale association study (3,973 women, including 1,269 invasive BC cases and 2,194 controls), nested within the EPIC cohort, the involvement of rs7566605 as predictor of BMI and BC risk. RESULTS AND CONCLUSIONS: In this study we were not able to find any statistically significant association between this SNP and BMI, nor did we find any significant association between the SNP and an increased risk of breast cancer overall and by subgroups of age, or menopausal status. PMID- 20955600 TI - Obstetric hemorrhage and shock management: using the low technology Non-pneumatic Anti-Shock Garment in Nigerian and Egyptian tertiary care facilities. AB - BACKGROUND: Obstetric hemorrhage is the leading cause of maternal mortality globally. The Non-pneumatic Anti-Shock Garment (NASG) is a low-technology, first aid compression device which, when added to standard hypovolemic shock protocols, may improve outcomes for women with hypovolemic shock secondary to obstetric hemorrhage in tertiary facilities in low-resource settings. METHODS: This study employed a pre-intervention/intervention design in four facilities in Nigeria and two in Egypt. Primary outcomes were measured mean and median blood loss, severe end-organ failure morbidity (renal failure, pulmonary failure, cardiac failure, or CNS dysfunctions), mortality, and emergency hysterectomy for 1442 women with >=750 mL blood loss and at least one sign of hemodynamic instability. Comparisons of outcomes by study phase were assessed with rank sum tests, relative risks (RR), number needed to treat for benefit (NNTb), and multiple logistic regression. RESULTS: Women in the NASG phase (n = 835) were in worse condition on study entry, 38.5% with mean arterial pressure <60 mmHg vs. 29.9% in the pre intervention phase (p = 0.001). Despite this, negative outcomes were significantly reduced in the NASG phase: mean measured blood loss decreased from 444 mL to 240 mL (p < 0.001), maternal mortality decreased from 6.3% to 3.5% (RR 0.56, 95% CI 0.35-0.89), severe morbidities from 3.7% to 0.7% (RR 0.20, 95% CI 0.08-0.50), and emergency hysterectomy from 8.9% to 4.0% (RR 0.44, 0.23-0.86). In multiple logistic regression, there was a 55% reduced odds of mortality during the NASG phase (aOR 0.45, 0.27-0.77). The NNTb to prevent either mortality or severe morbidity was 18 (12-36). CONCLUSION: Adding the NASG to standard shock and hemorrhage management may significantly improve maternal outcomes from hypovolemic shock secondary to obstetric hemorrhage at tertiary care facilities in low-resource settings. PMID- 20955601 TI - Effect of oat bran on time to exhaustion, glycogen content and serum cytokine profile following exhaustive exercise. AB - The aim of this study was to evaluate the effect of oat bran supplementation on time to exhaustion, glycogen stores and cytokines in rats submitted to training. The animals were divided into 3 groups: sedentary control group (C), an exercise group that received a control chow (EX) and an exercise group that received a chow supplemented with oat bran (EX-O). Exercised groups were submitted to an eight weeks swimming training protocol. In the last training session, the animals performed exercise to exhaustion, (e.g. incapable to continue the exercise). After the euthanasia of the animals, blood, muscle and hepatic tissue were collected. Plasma cytokines and corticosterone were evaluated. Glycogen concentrations was measured in the soleus and gastrocnemius muscles, and liver. Glycogen synthetase-alpha gene expression was evaluated in the soleus muscle. Statistical analysis was performed using a factorial ANOVA. Time to exhaustion of the EX-O group was 20% higher (515 +/- 3 minutes) when compared with EX group (425 +/- 3 minutes) (p = 0.034). For hepatic glycogen, the EX-O group had a 67% higher concentrations when compared with EX (p = 0.022). In the soleus muscle, EX O group presented a 59.4% higher glycogen concentrations when compared with EX group (p = 0.021). TNF-alpha was decreased, IL-6, IL-10 and corticosterone increased after exercise, and EX-O presented lower levels of IL-6, IL-10 and corticosterone levels in comparison with EX group. It was concluded that the chow rich in oat bran increase muscle and hepatic glycogen concentrations. The higher glycogen storage may improve endurance performance during training and competitions, and a lower post-exercise inflammatory response can accelerate recovery. PMID- 20955602 TI - Origin and evolutionary plasticity of the gastric caecum in sea urchins (Echinodermata: Echinoidea). AB - BACKGROUND: The digestive tract of many metazoan invertebrates is characterized by the presence of caeca or diverticula that serve secretory and/or absorptive functions. With the development of various feeding habits, distinctive digestive organs may be present in certain taxa. This also holds true for sea urchins (Echinodermata: Echinoidea), in which a highly specialized gastric caecum can be found in members of a derived subgroup, the Irregularia (cake urchins, sea biscuits, sand dollars, heart urchins, and related forms). As such a specialized caecum has not been reported from "regular" sea urchin taxa, the aim of this study was to elucidate its evolutionary origin. RESULTS: Using morphological data derived from dissection, magnetic resonance imaging, and extensive literature studies, we compare the digestive tract of 168 echinoid species belonging to 51 extant families. Based on a number of characters such as topography, general morphology, mesenterial suspension, and integration into the haemal system, we homologize the gastric caecum with the more or less pronounced dilation of the anterior stomach that is observed in most "regular" sea urchin taxa. In the Irregularia, a gastric caecum can be found in all taxa except in the Laganina and Scutellina. It is also undeveloped in certain spatangoid species. CONCLUSIONS: According to our findings, the sea urchin gastric caecum most likely constitutes a synapomorphy of the Euechinoidea. Its occurrence in "regular" euechinoids is linked to the presence of an additional festoon of the anterior stomach in ambulacrum III. Both structures, the additional festoon and the gastric caecum, are absent in the sister taxon to the Euechinoidea, the Cidaroida. Since the degree of specialization of the gastric caecum is most pronounced in the predominantly sediment-burrowing irregular taxa, we hypothesize that its evolution is closely linked to the development of more elaborate infaunal lifestyles. We provide a comprehensive study of the origin and evolutionary plasticity of a conspicuous digestive tract structure, the gastric caecum, in a major taxon of the extant invertebrate macrozoobenthos. PMID- 20955603 TI - Body composition in older acute stroke patients after treatment with individualized, nutritional supplementation while in hospital. AB - BACKGROUND: Individualized, nutritional support reduced undernutrition among older stroke patients and improved quality of life in our recent randomized, controlled trial. Weight control thus seems to be important after stroke, and methods for monitoring nutritional status need to be simple and non-invasive. Here we aimed to assess if the nutritional intervention altered body composition in men and women in this study cohort, and also to examine the correlation between the methods for assessing body-, fat- and fat-free mass. METHODS: Acute stroke patients > 65 years at nutritional risk were randomized to either individualized, nutritional treatment with energy- and protein rich supplementation (intervention, n = 58) or routine, nutritional care (control, n = 66) while in hospital. Body composition was assessed with anthropometry and bioelectrical impedance. The follow-up period was three months. RESULTS: During the first week while in hospital, weight loss was smaller in the intervention group compared with the controls (P = 0.013). After three months weight- and fat loss were significant in both men and women. Whereas no significant differences were found in changes in body composition between the male study groups, in the women both weight loss (P = 0.022) and fat loss (P = 0.005) was smaller in the intervention group compared with the controls. A high correlation (r = 0.87) between mid upper arm circumference (MUAC) and body mass index (BMI) was found. CONCLUSIONS: Individualized nutritional support to older stroke patients in hospital was beneficial for maintaining an adequate body mass and body composition the first week and seemed to have a preventive effect on fat loss among women, but not among men after three months. Measurement of MUAC may be used in the assessment of nutritional status when BMI cannot be obtained. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, number NCT00163007. PMID- 20955604 TI - Gadofluorine M-enhanced MRI shows involvement of circumventricular organs in neuroinflammation. AB - BACKGROUND: Circumventricular organs (CVO) are cerebral areas with incomplete endothelial blood-brain barrier (BBB) and therefore regarded as "gates to the brain". During inflammation, they may exert an active role in determining immune cell recruitment into the brain. METHODS: In a longitudinal study we investigated in vivo alterations of CVO during neuroinflammation, applying Gadofluorine M- (Gf) enhanced magnetic resonance imaging (MRI) in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. SJL/J mice were monitored by Gadopentate dimeglumine- (Gd-DTPA) and Gf-enhanced MRI after adoptive transfer of proteolipid-protein-specific T cells. Mean Gf intensity ratios were calculated individually for different CVO and correlated to the clinical disease course. Subsequently, the tissue distribution of fluorescence labeled Gf as well as the extent of cellular inflammation was assessed in corresponding histological slices. RESULTS: We could show that the Gf signal intensity of the choroid plexus, the subfornicular organ and the area postrema increased significantly during experimental autoimmune encephalomyelitis, correlating with (1) disease severity and (2) the delay of disease onset after immunization. For the choroid plexus, the extent of Gf enhancement served as a diagnostic criterion to distinguish between diseased and healthy control mice with a sensitivity of 89% and a specificity of 80%. Furthermore, Gf improved the detection of lesions, being particularly sensitive to optic neuritis. In correlated histological slices, Gf initially accumulated in the extracellular matrix surrounding inflammatory foci and was subsequently incorporated by macrophages/microglia. CONCLUSION: Gf-enhanced MRI provides a novel highly sensitive technique to study cerebral BBB alterations. We demonstrate for the first time in vivo the involvement of CVO during the development of neuroinflammation. PMID- 20955605 TI - Study protocol: a randomised controlled trial investigating the effect of exercise training on peripheral blood gene expression in patients with stable angina. AB - BACKGROUND: Exercise training has been shown to reduce angina and promote collateral vessel development in patients with coronary artery disease. However, the mechanism whereby exercise exerts these beneficial effects is unclear. There has been increasing interest in the use of whole genome peripheral blood gene expression in a wide range of conditions to attempt to identify both novel mechanisms of disease and transcriptional biomarkers. This protocol describes a study in which we will assess the effect of a structured exercise programme on peripheral blood gene expression in patients with stable angina, and correlate this with changes in angina level, anxiety, depression, and exercise capacity. METHODS/DESIGN: Sixty patients with stable angina will be recruited and randomised 1:1 to exercise training or conventional care. Patients randomised to exercise training will attend an exercise physiology laboratory up to three times weekly for supervised aerobic interval training sessions of one hour in total duration. Patients will undergo assessments of angina, anxiety, depression, and peripheral blood gene expression at baseline, after six and twelve weeks of training, and twelve weeks after formal exercise training ceases. DISCUSSION: This study will provide comprehensive data on the effect of exercise training on peripheral blood gene expression in patients with angina. By correlating this with improvement in angina status we will identify candidate peripheral blood transcriptional markers predictive of improvements in angina level in response to exercise training. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01147952. PMID- 20955606 TI - Quantitative trait loci mapping reveals candidate pathways regulating cell cycle duration in Plasmodium falciparum. AB - BACKGROUND: Elevated parasite biomass in the human red blood cells can lead to increased malaria morbidity. The genes and mechanisms regulating growth and development of Plasmodium falciparum through its erythrocytic cycle are not well understood. We previously showed that strains HB3 and Dd2 diverge in their proliferation rates, and here use quantitative trait loci mapping in 34 progeny from a cross between these parent clones along with integrative bioinformatics to identify genetic loci and candidate genes that control divergences in cell cycle duration. RESULTS: Genetic mapping of cell cycle duration revealed a four-locus genetic model, including a major genetic effect on chromosome 12, which accounts for 75% of the inherited phenotype variation. These QTL span 165 genes, the majority of which have no predicted function based on homology. We present a method to systematically prioritize candidate genes using the extensive sequence and transcriptional information available for the parent lines. Putative functions were assigned to the prioritized genes based on protein interaction networks and expression eQTL from our earlier study. DNA metabolism or antigenic variation functional categories were enriched among our prioritized candidate genes. Genes were then analyzed to determine if they interact with cyclins or other proteins known to be involved in the regulation of cell cycle. CONCLUSIONS: We show that the divergent proliferation rate between a drug resistant and drug sensitive parent clone is under genetic regulation and is segregating as a complex trait in 34 progeny. We map a major locus along with additional secondary effects, and use the wealth of genome data to identify key candidate genes. Of particular interest are a nucleosome assembly protein (PFL0185c), a Zinc finger transcription factor (PFL0465c) both on chromosome 12 and a ribosomal protein L7Ae-related on chromosome 4 (PFD0960c). PMID- 20955607 TI - Organization of GC/MS and LC/MS metabolomics data into chemical libraries. AB - BACKGROUND: Metabolomics experiments involve generating and comparing small molecule (metabolite) profiles from complex mixture samples to identify those metabolites that are modulated in altered states (e.g., disease, drug treatment, toxin exposure). One non-targeted metabolomics approach attempts to identify and interrogate all small molecules in a sample using GC or LC separation followed by MS or MSn detection. Analysis of the resulting large, multifaceted data sets to rapidly and accurately identify the metabolites is a challenging task that relies on the availability of chemical libraries of metabolite spectral signatures. A method for analyzing spectrometry data to identify and Quantify Individual Components in a Sample, (QUICS), enables generation of chemical library entries from known standards and, importantly, from unknown metabolites present in experimental samples but without a corresponding library entry. This method accounts for all ions in a sample spectrum, performs library matches, and allows review of the data to quality check library entries. The QUICS method identifies ions related to any given metabolite by correlating ion data across the complete set of experimental samples, thus revealing subtle spectral trends that may not be evident when viewing individual samples and are likely to be indicative of the presence of one or more otherwise obscured metabolites. RESULTS: LC-MS/MS or GC MS data from 33 liver samples were analyzed simultaneously which exploited the inherent biological diversity of the samples and the largely non-covariant chemical nature of the metabolites when viewed over multiple samples. Ions were partitioned by both retention time (RT) and covariance which grouped ions from a single common underlying metabolite. This approach benefitted from using mass, time and intensity data in aggregate over the entire sample set to reject outliers and noise thereby producing higher quality chemical identities. The aggregated data was matched to reference chemical libraries to aid in identifying the ion set as a known metabolite or as a new unknown biochemical to be added to the library. CONCLUSION: The QUICS methodology enabled rapid, in-depth evaluation of all possible metabolites (known and unknown) within a set of samples to identify the metabolites and, for those that did not have an entry in the reference library, to create a library entry to identify that metabolite in future studies. PMID- 20955609 TI - Use of complementary and alternative medicine by those with a chronic disease and the general population--results of a national population based survey. AB - BACKGROUND: The use of complementary and alternative medicine (CAM) is becoming more common, but population-based descriptions of its patterns of use are lacking. This study aimed to determine the prevalence of CAM use in the general population and for those with asthma, diabetes, epilepsy and migraine. METHODS: Data from cycles 1.1, 2.1 and 3.1 of the Canadian Community Health Survey (CCHS) were used for the study. The CCHS is a national cross-sectional survey administered to 400,055 Canadians aged >=12 between 2001-2005. Self-reported information about professionally diagnosed health conditions was elicited. CCHS surveys use a multistage stratified cluster design to randomly select a representative sample of Canadian household residents. Descriptive data on the utilization of CAM services was calculated and logistic regression was used to determine what sociodemographic factors predict CAM use. RESULTS: Weighted estimates show that 12.4% (95% Confidence Interval (CI): 12.2-12.5) of Canadians visited a CAM practitioner in the year they were surveyed; this rate was significantly higher for those with asthma 15.1% (95% CI: 14.5-15.7) and migraine 19.0% (95% CI: 18.4-19.6), and significantly lower for those with diabetes 8.0% (95% CI: 7.4-8.6) while the rate in those with epilepsy (10.3%, 95% CI: 8.4-12.2) was not significantly different from the general population. CONCLUSION: A large proportion of Canadians use CAM services. Physicians should be aware that their patients may be accessing other services and should be prepared to ask and answer questions about the risks and benefits of CAM services in conjunction with standard medical care. PMID- 20955608 TI - JAB1/CSN5: a new player in cell cycle control and cancer. AB - c-Jun activation domain-binding protein-1 (Jab1) acts as a modulator of intracellular signaling and affects cellular proliferation and apoptosis, through its existence as a monomer or as the fifth component of the constitutive photomorphogenic-9 signalosome (CSN5). Jab1/CSN5 is involved in transcription factor specificity, deneddylation of NEDD8, and nuclear-to-cytoplasmic shuttling of key molecules. Jab1/CSN5 activities positively and negatively affect a number of pathways, including integrin signaling, cell cycle control, and apoptosis. Also, more recent studies have demonstrated the intriguing roles of Jab1/CSN5 in regulating genomic instability and DNA repair. The effects of Jab1/CSN5's multiple protein interactions are generally oncogenic in nature, and overexpression of Jab1/CSN5 in cancer provides evidence that it is involved in the tumorigenic process. In this review, we highlight our current knowledge of Jab1/CSN5 function and the recent discoveries in dissecting the Jab1 signaling pathway. Further, we also discuss the regulation of Jab1/CSN5 in cancers and its potential as a therapeutic target. PMID- 20955610 TI - Splenic infarction during Plasmodium ovale acute malaria: first case reported. AB - The splenic complications of acute malaria include two different prognostic and treatment entities: splenic infarction and splenic rupture. This is the first case of splenic infarction during an acute malaria due to Plasmodium ovale in a 34-year-old man. As in the majority other described cases of splenic infarction, the course was spontaneously favourable, suggesting that this complication was relatively benign compared to splenic rupture, which is life-threatening and usually necessitating surgery. PMID- 20955611 TI - Genome-wide inference of regulatory networks in Streptomyces coelicolor. AB - BACKGROUND: The onset of antibiotics production in Streptomyces species is co ordinated with differentiation events. An understanding of the genetic circuits that regulate these coupled biological phenomena is essential to discover and engineer the pharmacologically important natural products made by these species. The availability of genomic tools and access to a large warehouse of transcriptome data for the model organism, Streptomyces coelicolor, provides incentive to decipher the intricacies of the regulatory cascades and develop biologically meaningful hypotheses. RESULTS: In this study, more than 500 samples of genome-wide temporal transcriptome data, comprising wild-type and more than 25 regulatory gene mutants of Streptomyces coelicolor probed across multiple stress and medium conditions, were investigated. Information based on transcript and functional similarity was used to update a previously-predicted whole-genome operon map and further applied to predict transcriptional networks constituting modules enriched in diverse functions such as secondary metabolism, and sigma factor. The predicted network displays a scale-free architecture with a small world property observed in many biological networks. The networks were further investigated to identify functionally-relevant modules that exhibit functional coherence and a consensus motif in the promoter elements indicative of DNA binding elements. CONCLUSIONS: Despite the enormous experimental as well as computational challenges, a systems approach for integrating diverse genome-scale datasets to elucidate complex regulatory networks is beginning to emerge. We present an integrated analysis of transcriptome data and genomic features to refine a whole-genome operon map and to construct regulatory networks at the cistron level in Streptomyces coelicolor. The functionally-relevant modules identified in this study pose as potential targets for further studies and verification. PMID- 20955612 TI - Systemic vascular function, measured with forearm flow mediated dilatation, in acute and stable cerebrovascular disease: a case-control study. AB - BACKGROUND: Acute ischaemic stroke is associated with alteration in systemic markers of vascular function. We measured forearm vascular function (using forearm flow mediated dilatation) to clarify whether recent acute ischaemic stroke/TIA is associated with impaired systemic vascular function. METHODS: Prospective case control study enrolling 17 patients with recent acute ischaemic stroke/TIA and 17 sex matched controls with stroke more than two years previously. Forearm vascular function was measured using flow medicated dilatation (FMD). RESULTS: Flow mediated dilatation was 6.0 +/- 1.1% in acute stroke/TIA patients and 4.7 +/- 1.0% among control subjects (p = 0.18). The mean paired difference in FMD between subjects with recent acute stroke and controls was 1.25% (95% CI -0.65, 3.14; p = 0.18). Endothelium independent dilatation was measured in six pairs of participants and was similar in acute stroke/TIA patients (22.6 +/- 4.3%) and control subjects (19.1 +/- 2.6%; p = 0.43). CONCLUSIONS: Despite the small size of this study, these data indicate that recent acute stroke is not necessarily associated with a clinically important reduction in FMD. PMID- 20955613 TI - Protective effect of extract of Cordyceps sinensis in middle cerebral artery occlusion-induced focal cerebral ischemia in rats. AB - BACKGROUND: Ischemic hypoxic brain injury often causes irreversible brain damage. The lack of effective and widely applicable pharmacological treatments for ischemic stroke patients may explain a growing interest in traditional medicines. From the point of view of "self-medication" or "preventive medicine," Cordyceps sinensis was used in the prevention of cerebral ischemia in this paper. METHODS: The right middle cerebral artery occlusion model was used in the study. The effects of Cordyceps sinensis (Caterpillar fungus) extract on mortality rate, neurobehavior, grip strength, lactate dehydrogenase, glutathione content, Lipid Peroxidation, glutathione peroxidase activity, glutathione reductase activity, catalase activity, Na+K+ATPase activity and glutathione S transferase activity in a rat model were studied respectively. RESULTS: Cordyceps sinensis extract significantly improved the outcome in rats after cerebral ischemia and reperfusion in terms of neurobehavioral function. At the same time, supplementation of Cordyceps sinensis extract significantly boosted the defense mechanism against cerebral ischemia by increasing antioxidants activity related to lesion pathogenesis. Restoration of the antioxidant homeostasis in the brain after reperfusion may have helped the brain recover from ischemic injury. CONCLUSIONS: These experimental results suggest that complement Cordyceps sinensis extract is protective after cerebral ischemia in specific way. The administration of Cordyceps sinensis extract significantly reduced focal cerebral ischemic/reperfusion injury. The defense mechanism against cerebral ischemia was by increasing antioxidants activity related to lesion pathogenesis. PMID- 20955614 TI - Association between perceived chewing ability and oral health-related quality of life in partially dentate patients. AB - BACKGROUND: One of the most immediate and important functional consequences of many oral disorders is a reduction in chewing ability. The ability to chew is not only an important dimension of oral health, but is increasingly recognized as being associated with general health status. Whether perceived chewing ability and oral health-related quality of life (OHRQoL) are correlated to a similar degree in patient populations has been less investigated. The aim of this study was to examine whether perceived chewing ability was related to OHRQoL in partially dentate patients. METHODS: Consecutive partially dentate patients (N = 489) without signs or symptoms of acute oral disease at Tokyo Medical and Dental University's Prosthodontic Clinic participated in the study (mean age 63.0 +/- 11.5, 71.2% female). A 20-item chewing function questionnaire (score range 0 to 20) was used to assess perceived chewing ability, with higher scores indicating better chewing ability. The 14-item Oral Health Impact Profile-Japanese version (OHIP-J14, score range 0 to 56) was used to measure OHRQoL, with higher scores indicating poorer OHRQoL. A Pearson correlation coefficient was calculated to assess the correlation between the two questionnaire summary scores. A linear regression analysis was used to describe how perceived chewing ability scores were related to OHRQoL scores. RESULTS: The mean chewing function score was 12.1 +/- 4.8 units. The mean OHIP-J14 summary score was 13.0 +/- 9.1 units. Perceived chewing ability and OHRQoL were significantly correlated (Pearson correlation coefficient: -0.46, 95% confidence interval [CI]: -0.52 to -0.38), indicating that higher chewing ability was correlated with lower OHIP-J14 summary scores (p < 0.001), which indicate better OHRQoL. A 1.0-unit increase in chewing function scores was related to a decrease of 0.87 OHIP-J14 units (95% CI: -1.0 to -0.72, p < 0.001). The correlation between perceived chewing ability and OHRQoL was not substantially influenced by age and number of teeth, but by gender, years of schooling, treatment demand and denture status. CONCLUSION: Patients' perception of their chewing ability was substantially related to their OHRQoL. PMID- 20955615 TI - Transcriptome analysis of parallel-evolved Escherichia coli strains under ethanol stress. AB - BACKGROUND: Understanding ethanol tolerance in microorganisms is important for the improvement of bioethanol production. Hence, we performed parallel-evolution experiments using Escherichia coli cells under ethanol stress to determine the phenotypic changes necessary for ethanol tolerance. RESULTS: After cultivation of 1,000 generations under 5% ethanol stress, we obtained 6 ethanol-tolerant strains that showed an approximately 2-fold increase in their specific growth rate in comparison with their ancestor. Expression analysis using microarrays revealed that common expression changes occurred during the adaptive evolution to the ethanol stress environment. Biosynthetic pathways of amino acids, including tryptophan, histidine, and branched-chain amino acids, were commonly up-regulated in the tolerant strains, suggesting that activating these pathways is involved in the development of ethanol tolerance. In support of this hypothesis, supplementation of isoleucine, tryptophan, and histidine to the culture medium increased the specific growth rate under ethanol stress. Furthermore, genes related to iron ion metabolism were commonly up-regulated in the tolerant strains, which suggests the change in intracellular redox state during adaptive evolution. CONCLUSIONS: The common phenotypic changes in the ethanol-tolerant strains we identified could provide a fundamental basis for designing ethanol tolerant strains for industrial purposes. PMID- 20955616 TI - Convergent validity of K-SADS-PL by comparison with CBCL in a Portuguese speaking outpatient population. AB - BACKGROUND: Different diagnostic interviews in child and adolescent psychiatry have been developed in English but valid translations of instruments to other languages are still scarce especially in developing countries, limiting the comparison of child mental health data across different cultures. The present study aims to examine the convergent validity of the Brazilian version of the Schedule for Affective Disorders and Schizophrenia for School-Age Children/Present and Lifetime Version (K-SADS-PL) by comparison with the Child Behavior Checklist (CBCL), a parental screening measure for child/adolescent emotional/behavior problems. METHODS: An experienced child psychiatrist blind to CBCL results applied the K-SADS-PL to a consecutive sample of 78 children (6-14 years) referred to a public child mental health outpatient clinic (response rate = 75%). Three K-SADS-PL parameters were considered regarding current disorders: parent screen interview rates, clinician summary screen interview rates, and final DSM-IV diagnoses. Subjects were classified according to the presence/absence of any affective/anxiety disorder, any disruptive disorder, and any psychiatric disorder based on K-SADS-PL results. All subjects obtained T scores on CBCL scales (internalizing, externalizing, total problems). RESULTS: Significant differences in CBCL mean T-scores were observed between disordered and non-disordered children. Compared to children who screened negative, children positive for any affective/anxiety disorder, any disruptive disorder, and any psychiatric disorder had a higher internalizing, externalizing and total problem T-score mean, respectively. Highly significant differences in T-score means were also found when examining final diagnoses, except for any affective/anxiety disorder. CONCLUSIONS: Evidence of convergent validity was found when comparing K SADS-PL results with CBCL data. PMID- 20955617 TI - Comparison of thymidine phosphorylase expression and prognostic factors in gallbladder and bile duct cancer. AB - BACKGROUND: Biliary tract cancers have limitations in information about different location-related pathogenesis and clinico-pathological characteristics. The goal of this study was to investigate anatomical site-related similarities and differences in biliary tract cancers and to assess the expression and clinical significance of functional proteins such as p53, cyclin D1, survivin, thymidine phosphorylase, and ERCC1. METHODS: One hundred and sixty-one patients with biliary tract adenocarcinomas, who underwent curative or palliative surgery in a single institution between October 1994 and December 2003 were evaluated, retrospectively. The level of protein expression of p53, cyclin D1, survivin, thymidine phosphorylase, and ERCC1 was assessed by immunohistochemistry. RESULTS: With respect to clinico-pathological characteristics, gallbladder cancer was more frequent in women, and bile duct cancer was more common in men. Perineural invasion was more common in bile duct cancer. Recurrence as a distant metastasis was more common in gallbladder cancer. Immunohistochemical analysis revealed that thymidine phosphorylase expression was significantly higher in gallbladder cancer than in bile duct cancer. Positive thymidine phosphorylase and p53 staining were associated with an advanced stage. Differentiation, vascular invasion, perineural invasion, lymphatic invasion, lymph node metastasis, and TNM stage independently predicted poor prognosis in biliary tract cancer. These correlations were seen more clearly in gallbladder cancer. The immunohistochemical staining patterns of p53, cyclin D1, survivin, thymidine phosphorylase, and ERCC1 showed no prognostic significance in biliary tract cancers. CONCLUSIONS: We concluded that gallbladder and bile duct cancers are considered to be separate diseases with different clinico-pathological characteristics and prognostic factors. In addition, we hypothesize that high expression of thymidine phosphorylase by gallbladder cancer results in a higher response rate to capecitabine by gallbladder cancer than bile duct cancer. PMID- 20955618 TI - ProFITS of maize: a database of protein families involved in the transduction of signalling in the maize genome. AB - BACKGROUND: Maize (Zea mays ssp. mays L.) is an important model for plant basic and applied research. In 2009, the B73 maize genome sequencing made a great step forward, using clone by clone strategy; however, functional annotation and gene classification of the maize genome are still limited. Thus, a well-annotated datasets and informative database will be important for further research discoveries. Signal transduction is a fundamental biological process in living cells, and many protein families participate in this process in sensing, amplifying and responding to various extracellular or internal stimuli. Therefore, it is a good starting point to integrate information on the maize functional genes involved in signal transduction. RESULTS: Here we introduce a comprehensive database 'ProFITS' (Protein Families Involved in the Transduction of Signalling), which endeavours to identify and classify protein kinases/phosphatases, transcription factors and ubiquitin-proteasome-system related genes in the B73 maize genome. Users can explore gene models, corresponding transcripts and FLcDNAs using the three abovementioned protein hierarchical categories, and visualize them using an AJAX-based genome browser (JBrowse) or Generic Genome Browser (GBrowse). Functional annotations such as GO annotation, protein signatures, protein best-hits in the Arabidopsis and rice genome are provided. In addition, pre-calculated transcription factor binding sites of each gene are generated and mutant information is incorporated into ProFITS. In short, ProFITS provides a user-friendly web interface for studies in signal transduction process in maize. CONCLUSION: ProFITS, which utilizes both the B73 maize genome and full length cDNA (FLcDNA) datasets, provides users a comprehensive platform of maize annotation with specific focus on the categorization of families involved in the signal transduction process. ProFITS is designed as a user-friendly web interface and it is valuable for experimental researchers. It is freely available now to all users at http://bioinfo.cau.edu.cn/ProFITS. PMID- 20955619 TI - Dose escalation study of an anti-thrombocytopenic agent in patients with chemotherapy induced thrombocytopenia. AB - BACKGROUND: Preclinical studies demonstrated that small chain RNA fragments accelerate the recovery of platelets numbers in animals exposed to high doses of chemotherapeutic drugs. There is anecdotal data supporting the same application in humans. The Phase I clinical trial described here was designed to investigate the relationship between the administration of small chain RNA fragments and the recovery in platelets following Chemotherapy-Induced Thrombocytopenia (CIT). METHODS: Cancer patients with solid tumors that experienced post chemotherapy thrombocytopenia with a nadir of < = 80,000 platelets/ml were eligible for this clinical trial. There were no exclusions based on ECOG status, tumor type, tumor burden or chemotherapeutic agents. Patients received a unique preparation of RNA derived from either E. coli or yeast. Ten patients per group received 20, 40, or 60 mg as a starting dose. Subjects self-administered RNA fragments sublingually on an every other day schedule while undergoing chemotherapy. The dose was escalated in 20 mg increments to a maximum dose of 80 mg if the nadir was < 80,000 platelets/ml at the start of the next cycle. Subjects were treated for three cycles of chemotherapy with the maximum effective dose of RNA fragments. Subjects continued on planned chemotherapy as indicated by tumor burden without RNA fragment support after the third cycle. Subjects kept a diary indicating RNA fragment and magnesium administration, and any experienced side effects. RESULTS: Patients receiving E. coli RNA fragments demonstrated a more rapid recovery in platelet count and higher nadir platelet count. None of the patients receiving the E. coli RNA fragments required a chemotherapy dose reduction due to thrombocytopenia. The optimal dose for minimizing CIT was 80 mg. Conversely, subjects receiving yeast RNA fragments with dose escalation to 80 mg required a chemotherapy dose reduction per American Society of Clinical Oncology guidelines for grade 3 and 4 thrombocytopenia. CONCLUSIONS: Patients receiving myelosuppressive chemotherapy experienced an improvement in the platelet nadir and shorter recovery time when receiving concurrent E coli RNA fragments, when compared to patients who received yeast RNA fragments. These data indicate that 60 and 80 mg doses of E. coli RNA accelerated platelet recovery. Further clinical investigations are planned to quantify the clinical benefits of the E. coli RNA at the 80 mg dose in patients with chemotherapy induced thrombocytopenia. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT01163110. PMID- 20955620 TI - Comparative study of discretization methods of microarray data for inferring transcriptional regulatory networks. AB - BACKGROUND: Microarray data discretization is a basic preprocess for many algorithms of gene regulatory network inference. Some common discretization methods in informatics are used to discretize microarray data. Selection of the discretization method is often arbitrary and no systematic comparison of different discretization has been conducted, in the context of gene regulatory network inference from time series gene expression data. RESULTS: In this study, we propose a new discretization method "bikmeans", and compare its performance with four other widely-used discretization methods using different datasets, modeling algorithms and number of intervals. Sensitivities, specificities and total accuracies were calculated and statistical analysis was carried out. Bikmeans method always gave high total accuracies. CONCLUSIONS: Our results indicate that proper discretization methods can consistently improve gene regulatory network inference independent of network modeling algorithms and datasets. Our new method, bikmeans, resulted in significant better total accuracies than other methods. PMID- 20955621 TI - A simple, rapid method to isolate salt glands for three-dimensional visualization, fluorescence imaging and cytological studies. AB - BACKGROUND: Some plants inhabiting saline environment remove salts via the salt glands embedded in the epidermal tissues. Cytological studies of salt glands will provide valuable information to our understanding of the secretory process. Previous studies on salt gland histology relied mainly on two-dimensional microscopic observations of microtome sections. Optical sectioning properties of confocal laser scanning microscope offer alternative approach for obtaining three dimensional structural information of salt glands. Difficulty in light penetration through intact leaves and interference from neighbouring leaf cells, however, impede the acquiring of good optical salt gland sections and limit its applications in salt gland imaging. Freeing the glands from adjacent leaf tissues will allow better manipulations for three-dimensional imaging through confocal laser scanning microscopy. RESULTS: Here, we present a simple and fast method for the isolation of individual salt glands released from the interference of neighbouring cells. About 100-200 salt glands could be isolated from just one cm2 of Avicennia officinalis leaf within hours and microscopic visualization of isolated salt glands was made possible within a day. Using these isolated glands, confocal laser scanning microscopic techniques could be applied and better resolution salt gland images could be achieved. By making use of their intrinsic fluorescent properties, optical sections of the gland cells could be acquired without the use of fluorescent probes and the corresponding three-dimensional images constructed. Useful cytological information of the salt gland cells could also be obtained through the applications of fluorescent dyes (e.g., LysoTracker(r) Red, FM(r)4-64, Texas Red(r)). CONCLUSIONS: The study of salt glands directly at the glandular level are made possible with the successful isolation of these specialized structures. Preparation of materials for subsequent microscopic observations of salt glands could be achieved within a day. Potential applications of confocal fluorescence microscopic techniques could also be performed using these isolated glands. Experiments designed and targeted directly at the salt glands were explored and cytological information obtained herein could be further incorporated towards the understanding of the mechanism underlying secretion in plant salt glands. PMID- 20955622 TI - Porcine circovirus type 2 (PCV2): genetic variation and newly emerging genotypes in China. AB - BACKGROUND: Porcine circovirus type 2 (PCV2), the causative agent of postweaning multisystemic wasting syndrome (PMWS), is a serious economic problem for the swine industry in China. In this study, we investigated the genetic variation of PCV2 in China using strains isolated from 2004-2008. Viruses were isolated from samples collected from pigs with multi-systemic lesions and clinical signs of PMWS from different regions of China, and the genomes of these viruses were sequenced. The assembled sequences were used to define the genotypes of these strains; PCR-RFLP methodology was used to distinguish isolates and capture ELISA was used to demonstrate the antigenic changes resulted from ORF2 gene mutation of the isolates. RESULTS: We identified 19 PCV2 isolates, including four newly emerging PCV2 mutant strains. The 19 isolates were designated into three genotypes (PCV2a, PCV2b and PCV2d). PCV2d represented a novel genotype and a shift from PCV2a to PCV2b as the predominant genotype in China was identified. This is the first report of 1766 nt PCV2 harboring a base deletion at other new different positions. Amino acid sequence analysis identified two novel ORF2 mutations (resulting in ORF2 sequences 705 and 708 nt in length) in three deletion strains (1766 nt) and one strain with a genome 1767 nt in length. Finding of two amino acids elongation of the ORF2-encoded Cap protein is firstly observed among PCV2 strains all over the world. The isolates were distinguished into different genotypes by PCR-RFLP methodology and antigenic changes were present in Cap protein of mutation isolates by capture ELISA. CONCLUSIONS: The results of this study provide evidence that PCV2 is undergoing constant genetic variation and that the predominant strain in China as well as the antigenic situation has changed in recent years. Furthermore, the PCR-RFLP method presented here may be useful for the differential identification of PCV2 strains in future studies. PMID- 20955623 TI - The limitations of employment as a tool for social inclusion. AB - BACKGROUND: One important component of social inclusion is the improvement of well-being through encouraging participation in employment and work life. However, the ways that employment contributes to wellbeing are complex. This study investigates how poor health status might act as a barrier to gaining good quality work, and how good quality work is an important pre-requisite for positive health outcomes. METHODS: This study uses data from the PATH Through Life Project, analysing baseline and follow-up data on employment status, psychosocial job quality, and mental and physical health status from 4261 people in the Canberra and Queanbeyan region of south-eastern Australia. Longitudinal analyses conducted across the two time points investigated patterns of change in employment circumstances and associated changes in physical and mental health status. RESULTS: Those who were unemployed and those in poor quality jobs (characterised by insecurity, low marketability and job strain) were more likely to remain in these circumstances than to move to better working conditions. Poor quality jobs were associated with poorer physical and mental health status than better quality work, with the health of those in the poorest quality jobs comparable to that of the unemployed. For those who were unemployed at baseline, pre-existing health status predicted employment transition. Those respondents who moved from unemployment into poor quality work experienced an increase in depressive symptoms compared to those who moved into good quality work. CONCLUSIONS: This evidence underlines the difficulty of moving from unemployment into good quality work and highlights the need for social inclusion policies to consider people's pre-existing health conditions and promote job quality. PMID- 20955624 TI - Urine alkalization facilitates uric acid excretion. AB - BACKGROUND: Increase in the incidence of hyperuricemia associated with gout as well as hypertension, renal diseases and cardiovascular diseases has been a public health concern. We examined the possibility of facilitated excretion of uric acid by change in urine pH by managing food materials. METHODS: Within the framework of the Japanese government's health promotion program, we made recipes which consist of protein-rich and less vegetable-fruit food materials for H+-load (acid diet) and others composed of less protein but vegetable-fruit rich food materials (alkali diet). Healthy female students were enrolled in this consecutive 5-day study for each test. From whole-day collected urine, total volume, pH, organic acid, creatinine, uric acid and all cations (Na+,K+,Ca(2+),Mg(2+),NH4+) and anions (Cl-,SO4(2-),PO4-) necessary for the estimation of acid-base balance were measured. RESULTS: Urine pH reached a steady state 3 days after switching from ordinary daily diets to specified regimens. The amount of acid generated ([SO4(2-)] +organic acid-gut alkai) were linearly related with those of the excretion of acid (titratable acidity+ [NH4+] - [HCO3 ]), indicating that H+ in urine is generated by the metabolic degradation of food materials. Uric acid and excreted urine pH retained a linear relationship, where uric acid excretion increased from 302 mg/day at pH 5.9 to 413 mg/day at pH 6.5, despite the fact that the alkali diet contained a smaller purine load than the acid diet. CONCLUSION: We conclude that alkalization of urine by eating nutritionally well-designed food is effective for removing uric acid from the body. PMID- 20955625 TI - Habitual snoring in school-aged children: environmental and biological predictors. AB - BACKGROUND: Habitual snoring, a prominent symptom of sleep-disordered breathing, is an important indicator for a number of health problems in children. Compared to adults, large epidemiological studies on childhood habitual snoring and associated predisposing factors are extremely scarce. The present study aimed to assess the prevalence and associated factors of habitual snoring among Chinese school-aged children. METHODS: A random sample of 20,152 children aged 5.08 to 11.99 years old participated in a cross-sectional survey, which was conducted in eight cities of China. Parent-administrated questionnaires were used to collect information on children's snoring frequency and the possible correlates. RESULTS: The prevalence of habitual snoring was 12.0% (14.5% for boys vs. 9.5% for girls) in our sampled children. Following factors were associated with an increased risk for habitual snoring: lower family income (adjusted odds ratio [OR] = 1.46), lower father's education (OR = 1.38 and 1.14 for middle school or under and high school of educational level, respectively), breastfeeding duration < 6 months (OR = 1.17), pregnancy maternal smoking (OR = 1.51), obesity (OR = 1.50), overweight (OR = 1.35), several respiratory problems associated with atopy and infection, such as chronic/allergic rhinitis (OR = 1.94), asthma (OR = 1.43), adenotonsillar hypertrophy (OR = 2.17), and chronic otitis media (OR = 1.31), and family history of habitual snoring (OR = 1.70). CONCLUSION: The prevalence of habitual snoring in Chinese children was similar to that observed in other countries. The potential predisposing factors covered socioeconomic characteristics, environmental exposures, chronic health problems, and family susceptibility. Compared to socioeconomic status and family susceptibility, environmental exposures and chronic health problems had greater impact, indicating childhood habitual snoring could be partly prevented by health promotion and environmental intervention. PMID- 20955626 TI - A novel method to derive amniotic fluid stem cells for therapeutic purposes. AB - BACKGROUND: Human amniotic fluid stem (hAFS) cells have become an attractive stem cell source for medical therapy due to both their ability to propagate as stem cells and the lack of ethical debate that comes with the use of embryonic stem cells. Although techniques to derive stem cells from amniotic fluid are available, the techniques have limitations for clinical uses, including a requirement of long periods of time for stem cell production, population heterogeneity and xeno-contamination from using animal antibody-coated magnetic beads. Herein we describe a novel isolation method that fits for hAFS derivation for cell-based therapy. METHODS AND RESULTS: With our method, single hAFS cells generate colonies in a primary culture of amniotic fluid cells. Individual hAFS colonies are then expanded by subculturing in order to make a clonal hAFS cell line. This method allows derivation of a substantial amount of a pure stem cell population within a short period of time. Indeed, 108 cells from a clonal hAFS line can be derived in two weeks using our method, while previous techniques require two months. The resultant hAFS cells show a 2-5 times greater proliferative ability than with previous techniques and a population doubling time of 0.8 days. The hAFS cells exhibit typical hAFS cell characteristics including the ability to differentiate into adipogenic-, osteogenic- and neurogenic lineages, expression of specific stem cell markers including Oct4, SSEA4, CD29, CD44, CD73, CD90, CD105 and CD133, and maintenance of a normal karyotype over long culture periods. CONCLUSIONS: We have created a novel hAFS cell derivation method that can produce a vast amount of high quality stem cells within a short period of time. Our technique makes possibility for providing autogenic fetal stem cells and allogeneic cells for future cell-based therapy. PMID- 20955627 TI - Coping strategies for financial burdens in families with childhood pneumonia in Bangladesh. AB - BACKGROUND: This study aimed to determine the out-of pocket expenditure and coping strategies adopted by families of children admitted in a hospital in Bangladesh with pneumonia. METHODS: Trained interviewers surveyed parents of 90 children and conducted in-depth interviews with six families below the age of 5 years who were admitted to the largest pediatric hospital in Bangladesh with a diagnosis of pneumonia. We estimated the total cost of illness associated with hospitalization and explored the coping strategies of the families. RESULTS: The mean expenditure of the families for the illness episode was US$ 94 (+/-SD 52.5) with 75% having spent more than half of their total monthly expenditure on this hospitalization. Three fourths (68/90, 76%) of the families managed the expenditure by borrowing, mortgaging or selling assets; 64% had to borrow the full cost of hospitalization and 10% borrowed from the formal sector with a monthly interest rate of 5 to 30%. The burden was highest for the people from poor income strata. Families earning <=US$ 59 per month were 10 times more likely than families earning >=US$ 59 per month to borrow money (OR = 10.0, 95% CI: 2.8 38.8). To repay their debts, 22% of families reported that they would work extra hours and 50% planned to reduce spending on food and education for their children. CONCLUSIONS: Coping strategies adopted by the families to manage the out-of-pocket expenditure for children requiring hospitalization were catastrophic for the majority of the families. Efforts to prevent childhood pneumonia for example, by vaccination against the most common pathogens, by improving air quality and by improving childhood nutrition can provide a double advantage. They can prevent both disease and poverty. PMID- 20955629 TI - Change in condom and other barrier method use during and after an HIV prevention trial in Zimbabwe. AB - BACKGROUND: We examined the use of male condoms and the diaphragm following completion of a clinical trial of the diaphragm's HIV prevention effectiveness. In the trial, called Methods for Improving Reproductive Health in Africa (MIRA), women were randomized to a diaphragm group (diaphragm, gel and condoms) or a condom-only control group. At trial exit, all women were offered the diaphragm and condoms. METHODS: Our sample consisted of 801 Zimbabwean MIRA participants who completed one post-trial visit (median lapse: nine months; range two to 20 months). We assessed condom, diaphragm and any barrier method use at last sex act at enrolment, final MIRA and post-trial visits. We used multivariable random effects logistic regression to examine changes in method use between these three time points. RESULTS AND DISCUSSION: In the condom group, condom use decreased from 86% at the final trial visit to 67% post trial (AOR = 0.20; 95% CI: 0.12 to 0.33). In the diaphragm group, condom use was 61% at the final trial visit, and did not decrease significantly post trial (AOR = 0.77; 95% CI: 0.55 to 1.09), while diaphragm use decreased from 79% to 50% post trial (AOR = 0.18; 95% CI: 0.12 to 0.28). Condom use significantly decreased between the enrolment and post trial visits in both groups. Use of any barrier method was similar in both groups: it significantly decreased between the final trial and the post-trial visits, but did not change between enrolment and the post-trial visits. CONCLUSIONS: High condom use levels achieved during the trial were not sustained post trial in the condom group. Post-trial diaphragm use remained relatively high in the diaphragm group (given its unknown effectiveness), but was very low in the condom group. Introducing "new" methods for HIV prevention may require time and user skills before they get adopted. Our findings underscore the potential benefit of providing a mix of methods to women as it may encourage more protected acts. PMID- 20955630 TI - Spontaneous rectus sheath hematoma pregnancy: case report and review of the literature. AB - Rectus sheath hematoma (RSH) is a rare, but important potential cause of acute upper abdominal pain in pregnancy. We report a patient with history of hemolysis, elevated liver enzymes, low platelets syndrome who presented with upper abdominal pain, hypotension, elevated hepatic transaminase levels, and a visibly enlarging right costal margin mass at 33 weeks' gestation. She underwent emergent cesarean delivery and upper abdominal exploration with findings of a large hematoma involving the entire right rectus sheath. The current case illustrates that the diagnosis of an RSH in pregnancy can be difficult as its presentation can mimic many common causes of abdominal pain seen outside of pregnancy, as well as many specific to pregnancy. Review of the published cases from the past 20 years shows that correct diagnosis remains difficult in pregnancy despite advances in diagnostic imaging. Although management of an RSH outside of pregnancy is frequently conservative, it is very often treated surgically in pregnant patients and often leads to preterm delivery. PMID- 20955628 TI - Microbiological pattern of arterial catheters in the intensive care unit. AB - BACKGROUND: Intravascular catheter related infection (CRI) is one of the most serious nosocomial infections. Diagnostic criteria include a positive culture from the catheter tip along with blood, yet in many patients with signs of infection, current culture techniques fail to identify pathogens on catheter segments. We hypothesised that a molecular examination of the bacterial community on short term arterial catheters (ACs) would improve our understanding of the variety of organisms that are present in this niche environment and would help develop new methods for the diagnosis of CRI. RESULTS: The whole bacterial community presenting on all ACs was evaluated by molecular methods, i.e., a strategy of whole community DNA extraction, PCR amplification followed by cloning and 16S rDNA sequence analysis. Ten ACs were removed from patients suspected of CRI and 430 clones from 5 "colonised" and 5 "uncolonised" (semi-quantitative method) AC libraries were selected for sequencing and subsequent analysis. A total of 79 operational taxonomic units (OTUs) were identified at the level of 97% similarity belonging to six bacterial divisions. An average of 20 OTUs were present in each AC, irrespective of colonisation status. Conventional culture failed to reveal the majority of these bacteria. CONCLUSIONS: There was no significant difference in the bacterial diversity between the 'uncolonised' and 'colonised' ACs. This suggests that vascular devices cultured conventionally and reported as non infective may at times potentially be a significant source of sepsis in critically ill patients. Alternative methods may be required for the accurate diagnosis of CRI in critically ill patients. PMID- 20955631 TI - The FMR1 gene as regulator of ovarian recruitment and ovarian reserve. AB - The fragile X mental retardation 1 (FMR1) gene is primarily associated with neuro/psychiatric risks. Recent evidence suggests that the gene also exerts controlling functions on follicle recruitment and ovarian reserve (OR). We performed unrestricted Medline and PubMed searches of the medical literature independently under search terms, FMR1 gene, fragile X gene, and in association with premature ovarian aging, primary ovarian insufficiency, occult primary insufficiency, premature ovarian failure, premature menopause, ovarian reserve (OR), diminished ovarian reserve, follicle recruitment and ovarian aging. We also used web-based resources in regards to the FMR1 gene and reviewed additional citations from reviewed publications. Recently published data strongly suggest an independent function of the FMR1 gene on ovaries. This function appears distinct from the gene's neuro/psychiatric effects, associated with a different, and specific, triple nucleotide (CGG) repeat range and characterized by specific genotypes. Ovarian function in all races/ethnicities appears defined by a normal range of 26 to 34 CGG repeats (mean 30), including the reported distribution peak of 29 to 30 repeats in humans and maximal gene translation, reported at 30 repeats. Genotypes, defined by 2 normal count alleles (normal) demonstrate different OR aging patterns from women with 1 (heterozygous) or both alleles outside of range (homozygous). Heterozygous and homozygous genotypes recruit fewer follicles at younger ages, thus preserving OR into advanced age. These observations suggest a direct FMR1 effect on follicular recruitment and OR and, therefore, on women's fecundity. PMID- 20955632 TI - Options of fertility preservation in female cancer patients. AB - Modern combination chemotherapy and radiotherapy regimens have a substantial negative impact on reproduction. Premature ovarian failure and other poor reproductive outcomes subsequent to cancer therapies are being recognized. Furthermore, beside malignancies, treatment of certain precancerous and benign conditions such as myelodysplasia, aplastic anemia, and systemic lupus erythematosus may necessitate administration of high-dose chemotherapeutics with and without stem cell transplantation. Therefore, preservation of gonadal function and fertility has become one of the major quality of life issues for cancer survivors at reproductive ages. In this review, premature ovarian failure and other adverse reproductive outcomes in female patients who receive chemotherapy and radiation will be discussed and the options to preserve their fertility will be delineated. After completion of the educational activity, the reader will be better able to distinguish the experimental approaches to minimizing gonadotoxic therapy, and use the most effective treatment options. PMID- 20955633 TI - EPA inhibits the inhibitor of kappaBalpha (IkappaBalpha)/NF-kappaB/muscle RING finger 1 pathway in C2C12 myotubes in a PPARgamma-dependent manner. AB - The present study was conducted to evaluate the mechanism by which n-3 PUFA regulates the inhibitor of kappaBalpha (IkappaBalpha)/NF-kappaB/muscle RING finger 1 (MuRF1) pathway in C2C12 myotubes. After treatment with 150, 300 or 600 MUm-alpha-linolenic acid (ALA) or -EPA for 24 h in C2C12 myotubes, the levels of phosphorylated IkappaBalpha (p-IkappaBalpha) and total IkappaBalpha were measured by Western blot. Compared with the bovine serum albumin (BSA) control, 150 and 300 MUm-ALA and -EPA, respectively, did not affect the total IkappaBalpha protein level (P>0.05). However, 600 MUm-EPA, but not 600 MUm-ALA, prevented IkappaBalpha phosphorylation and increased the total IkappaBalpha levels (P < 0.01). Furthermore, total nuclear protein was isolated and analysed by the electrophoretic mobility shift assay for NF-kappaB DNA-binding activity after treatment with 600 MUm-ALA or -EPA for 24 h. EPA (600 MUm), but not ALA (600 MUm), decreased the NF-kappaB DNA-binding activity when compared with BSA (P < 0.01). It was further observed that 600 MUm-EPA caused a 3.38-fold reduction in the levels of MuRF1 mRNA expression compared with BSA (P < 0.01). Additionally, 600 MUm-EPA resulted in a 2.3-fold induction of PPARgamma mRNA expression (P < 0.01). In C2C12 myotubes, PPARgamma knockdown by RNA interference significantly decreased PPARgamma mRNA and protein expression to approximately 50 and 60% (P < 0.01), respectively. Interestingly, in C2C12 myotubes with PPARgamma knockdown, 600 MUm-ALA and -EPA did not affect the levels of p-IkappaBalpha and total IkappaBalpha, NF-kappaB DNA-binding activity or MuRF1 mRNA expression when compared with BSA (P>0.05). These results revealed that EPA, but not ALA, inhibited the IkappaBalpha/NF-kappaB/MuRF1 pathway in C2C12 myotubes in a PPARgamma-dependent manner. PMID- 20955634 TI - Comparison of vestibular evoked myogenic potentials elicited by click and short duration tone burst stimuli. AB - INTRODUCTION: Vestibular evoked myogenic potentials are short latency electrical impulses that are produced in response to higher level acoustic stimuli. They are used clinically to diagnose sacculocollic pathway dysfunction. AIM: This study aimed to compare the vestibular evoked myogenic potential responses elicited by click stimuli and short duration tone burst stimuli, in normal hearing individuals. METHOD: Seventeen subjects participated. In all subjects, we assessed vestibular evoked myogenic potentials elicited by click and short duration tone burst stimuli. RESULTS AND CONCLUSION: The latency of the vestibular evoked myogenic potential responses (i.e. the p13 and n23 peaks) was longer for tone burst stimuli compared with click stimuli. The amplitude of the p13-n23 waveform was greater for tone burst stimuli than click stimuli. Thus, the click stimulus may be preferable for clinical assessment and identification of abnormalities as this stimulus has less variability, while a low frequency tone burst stimulus may be preferable when assessing the presence or absence of vestibular evoked myogenic potential responses. PMID- 20955635 TI - Cochlear Implantation in Brown-Vialetto-Van-Laere syndrome. AB - OBJECTIVE: To report outcomes for the first known cochlear implantation procedures in two patients with Brown-Vialetto-Van-Laere syndrome. PATIENTS: Two adult patients (a brother and sister) with post-lingual sensorineural deafness associated with Brown-Vialetto-Van-Laere syndrome. The female patient presented with a milder form of the syndrome. INTERVENTION: Cochlear implantation. MAIN OUTCOME MEASURE: Post-implantation speech discrimination scores. RESULTS: Auditory evoked potential testing suggested pathological changes in both patients' cochleae, auditory nerves, brainstem and (probably) central auditory pathways. In the male patient, despite implantation of the better ear, the Bamford-Kowal-Bench sentence score was zero at 21 months post-implantation. In the female patient, Bamford-Kowal-Bench sentence scores at six months post implantation were 25 per cent in quiet and 3 per cent in noise. CONCLUSION: These poor clinical outcomes appear to be related to retrocochlear and probable central auditory pathway degeneration. PMID- 20955636 TI - Serum matrix metalloproteinases and tympanosclerosis. AB - AIM: To investigate levels of matrix metalloproteinases 2 and 9, and of their tissue inhibitor (i.e. tissue inhibitor matrix metalloproteinase 1), in the serum of patients with tympanosclerosis. MATERIALS AND METHOD: We included 40 patients (age range 13-63 years) who had undergone surgery in the ENT department of Izmir Ataturk Training and Research Hospital between 2002 and 2007. Twenty had uncomplicated chronic otitis media and 20 had tympanosclerosis. We also included as the control group 20 individuals with no history of previous otic complaints or systemic or infectious disease. Serum levels of serum matrix metalloproteinases 2 and 9 and of tissue inhibitor matrix metalloproteinase 1 were measured in all subjects and compared. RESULT: Significantly higher levels of serum matrix metalloproteinases 2 and 9 were found in the tympanosclerosis group, compared with the chronic otitis media and control groups. There was no statistically significant difference in tissue inhibitor matrix metalloproteinase 1 level between the three groups. CONCLUSION: Tympanosclerosis surgery has poor success rates, since the pathological process is still active. We suggest that high levels of matrix metalloproteinases may play a role in the continuation of the disease process. PMID- 20955637 TI - Role of mitomycin C in reducing keloid recurrence: patient series and literature review. AB - OBJECTIVE: To study the role of mitomycin C in reducing keloid recurrence. STUDY DESIGN: Prospective, randomised, controlled trial. SETTING: Tertiary care referral centre. PATIENTS: Case series of 20 patients presenting with 26 pinna swellings, mostly following ear piercing. INTERVENTIONS: We used the technique of surgical shave excision combined with topical application of mitomycin C and secondary wound healing, in all 26 pinnae. RESULTS: Patients were followed up six to 24 months post-operatively. No recurrences were noted during this period. CONCLUSION: Keloids are fibrotic lesions resulting from abnormal wound healing. The uncontrolled proliferation of normal tissue healing processes results in scarring that enlarges well beyond the original wound margins. Successful treatment of keloids remains a challenge because this disease process has a high propensity for recurrence. Various therapies have previously been reported, and success rates are highly variable. We believe that shave excision followed by topical mitomycin C application is a promising treatment option for the management of pinna keloids. PMID- 20955638 TI - Nasal tuberculosis--an update of current clinical and laboratory investigation. AB - OBJECTIVE: To report a case of primary nasal tuberculosis, and to discuss the diagnostic difficulties encountered. SETTING: A teaching hospital in Norwich, UK. METHOD: Case report and review of the English language literature concerning tuberculosis affecting the head and neck region. RESULT: The diagnosis of nasal tuberculosis is based on: histological identification of granulomatous inflammation; positive testing for acid-alcohol resistant bacilli; and positive culture. Newer diagnostic tests have the advantage of speed and improved accuracy, but are not as yet completely evaluated for the diagnosis of extra pulmonary tuberculosis. CONCLUSION: It is important to consider nasal tuberculosis in the initial differential diagnosis. The quest to exclude a malignancy may lead to unacceptable delays in treatment. PMID- 20955639 TI - The needle has been blunt for 20 years. PMID- 20955640 TI - Propofol as a bridge to extubation for high-risk children with congenital cardiac disease. AB - BACKGROUND: Children with congenital cardiac defects may have associated chromosomal anomalies, airway compromise, and/or pulmonary hypertension, which can pose challenges to adequate sedation, weaning from mechanical ventilation, and successful extubation. Propofol, with its unique properties, may be used as a bridge to extubation in certain cardiac populations. MATERIALS AND METHODS: We retrospectively reviewed 0-17-year-old patients admitted to the Cardiac Intensive Care Unit between January, 2007 and September, 2008, who required mechanical ventilation and received a continuous infusion of propofol as a bridge to extubation. Medical charts were reviewed for demographics, associated comorbidities, as well as additional sedation medications and haemodynamic trends including vital signs and vasopressor support during the peri-infusion period. Successful extubation was defined as no re-intubation required for respiratory failure within 48 hours. Outcomes measured were successful extubation, evidence for propofol infusion syndrome, haemodynamic stability, and fluid and inotropic requirements. RESULTS: We included 11 patients for a total of 12 episodes. Propofol dose ranged from 0.4 to 5.6 milligram per kilogram per hour with an average infusion duration of 7 hours. All patients were successfully extubated, and none demonstrated worsening metabolic acidosis suggestive of the propofol infusion syndrome. All patients remained haemodynamically stable during the infusion with average heart rates and blood pressures remaining within age appropriate ranges. One patient received additional fluid but no increase in vasopressors was needed. CONCLUSIONS: This study suggests that propofol infusions may allow for successful extubation in a certain population of children with congenital cardiac disease. Further studies are required to confirm whether propofol is an efficient and safe alternative in this setting. PMID- 20955641 TI - Metabolic syndrome in the elderly living in marginal peri-urban communities in Quito, Ecuador. AB - OBJECTIVE: The proportion of the Latin American population aged >60 years is expected to double during the next few decades. Metabolic syndrome (MetS) is associated with high morbidity and mortality worldwide. However, little is known about MetS in Latin America in general, and in Ecuador in particular. The present study aimed to examine the prevalence of MetS and its association with blood micronutrient, homocysteine (Hcy) and C-reactive protein (CRP) concentrations in the elderly living in a low-income urban area. DESIGN: We performed a cross sectional study. MetS, using the International Diabetes Federation definition, dietary intake and plasma micronutrient, CRP and Hcy concentrations were assessed. SUBJECTS: A total of 352 elderly (>=65 years) Ecuadorians. SETTING: Quito, Ecuador. RESULTS: MetS was prevalent (40%)--considerably more so among women (81%) than men (19%; chi2 = 32.6, P < 0.0001). Further, 53 % of those without MetS exhibited two or more of its components. Micronutrient deficiencies were prevalent, including those of vitamin C, zinc, vitamin B12 and folate. Vitamin C and E concentrations were inversely (OR = 0.78, 95% CI 0.71, 0.86; OR = 0.16, 95% CI 0.03, 0.81, respectively) and CRP (OR = 1.79, 95 % CI 1.04, 3.06) was positively associated with MetS. CONCLUSIONS: The coexistence of MetS with micronutrient deficiencies suggests that elderly Ecuadorians suffer from the double burden of diseases that are increasingly being observed in less developed countries. More research is needed to determine the causal factors, but results presented suggest that these older adults would benefit from interventions to reduce the risk factors for MetS, in particular higher consumption of micronutrient-rich foods. PMID- 20955643 TI - Soft drinks consumption, diet quality and BMI in a Mediterranean population. AB - OBJECTIVES: Evidence of the effects of soft drinks consumption on BMI and lifestyle in adult populations is mixed and quite limited. The aim of the present study was to determine the association of soft drinks consumption with BMI and lifestyle in a representative Mediterranean population. DESIGN: Two independent, population-based, cross-sectional (2000 and 2005) studies. Dietary intake was assessed using a validated FFQ. Weight and height were measured. SETTING: Girona, Spain. SUBJECTS: Random sample of the 35- to 74-year-old population (3910 men and 4285 women). RESULTS: Less than half (41.7%) of the population consumed soft drinks; the mean consumption was 36.2 ml/d. The prevalence of sedentary lifestyle increased with the frequency of soft drinks consumption (P = 0.025). Daily soft drinks consumption significantly increased the risk of low adherence to the Mediterranean diet (OR = 0.57, 95% CI 0.44, 0.74 v. top tertile of Mediterranean diet score). Multiple linear regression analyses, controlled for potential confounders, revealed that an increment in soft drinks consumption of 100 ml was associated with a 0.21 kg/m2 increase in BMI (P = 0.001). Only implausibly low reports of energy consumption showed a null association between soft drinks consumption and BMI. CONCLUSIONS: Soft drinks consumption was not embedded in a healthy diet context and was positively associated with BMI and sedentary lifestyle in this Mediterranean population. PMID- 20955642 TI - Dietary patterns and their associations with health behaviours in Korea. AB - OBJECTIVE: Dietary habits, including dietary patterns, have been associated with the risk of chronic diseases, including cancer. The objective of the present study was to evaluate Korean dietary patterns as assessed by using an FFQ and associations of dietary patterns with lifestyle risk factors. DESIGN: Dietary patterns were analysed by factor analysis using a sixteen-group FFQ. The associations between dietary patterns and lifestyle risk factors were investigated by logistic regression analysis. SETTING: The National Cancer Center in South Korea. SUBJECTS: The study population included 11 440 participants aged >= 30 years who were recruited between 2002 and 2007. RESULTS: Compared with the lowest quartile intake of each dietary pattern, current smoking was positively associated with the Western pattern (OR = 1.55 for the highest quartile, 95 % CI 1.27, 1.88; P < 0.001) and the traditional pattern (OR = 1.34, 95 % CI 1.11, 1.62; P = 0.002) in men, but was inversely associated with the healthy pattern in both genders (P < 0.001) and the traditional pattern (OR = 0.52, 95 % CI 0.36, 0.75; P = 0.001) in women. Alcohol consumption was positively associated with all patterns in both genders, while no association was observed with the healthy pattern in women. Physical activity and dietary supplement use were positively associated with all patterns in both genders, with the exception of physical activity in women, which showed an inverse association with the traditional pattern. CONCLUSIONS: Dietary patterns are strongly associated with health behaviours. The possible confounding effect of other risk behaviours should be appropriately considered when conducting nutritional epidemiological studies. PMID- 20955644 TI - Recruitment of volunteers for a home-delivered meals programme serving homebound older adults: a theoretically derived programme among faith communities. AB - OBJECTIVE: Home-delivered nutrition programmes that are federally subsidized by the US Administration on Aging seek to ensure that socially isolated older adults who are unable to purchase and prepare their own food have nutritious meals delivered to them regularly by both employed and volunteer staff. Unfortunately, there are long waiting lists in some neighbourhoods that are often due to a shortage of volunteers. The present paper describes a theoretically driven community-based project designed to increase volunteer participation in serving Meals on Wheels (MOW) clients. DESIGN: A Support Team model was applied in the project wherein existing social capital among religious faith communities, and social networks within those organizations, was joined with a local MOW programme to create a sustainable meal delivery route to vulnerable homebound older adults. SETTING: The programme participants were in one underserved neighbourhood in Birmingham, Alabama, an urban city in the south-eastern USA. SUBJECTS: The subjects under consideration are both MOW clients and volunteers. MOW clients are those individuals aged 60 years and above who qualify for the service; the volunteers are from community churches. RESULTS: One volunteer route, comprising six congregations that delivered meals to sixteen homebound older adults, was created. The route served more than 2000 meals in 2006 (the year the programme began) and continues to serve clients today. CONCLUSIONS: The programme's successful implementation provides evidence that reliance on theory is critical in planning and developing effective community-based programme interventions. PMID- 20955646 TI - Postprandial metabolic events and fruit-derived phenolics: a review of the science. AB - There is increasing evidence that the postprandial state is an important contributing factor to chronic disease. The role of fruit phenolic compounds to protect health and lower disease risk through their actions in mitigating fed state metabolic and oxidative stressors is of interest and the topic of the present paper. Two main questions are posed: first, what is the role of plant foods, specifically fruits rich in complex and simple phenolic compounds in postprandial metabolic management; and second, does the evidence support consuming these fruits with meals as a practical strategy to preserve health and lower risk for disease? This review provides an overview of the postprandial literature, specifically on the effect of fruits and their inherent phenolic compounds in human subjects on postprandial lipaemia, glycaemia/insulinaemia and associated events, such as oxidative stress and inflammation. Among the identified well-controlled human trials using a postprandial paradigm, >50 % of the trials used wine or wine components and the remaining used various berries. Notwithstanding the need for more research, the collected data suggest that consuming phenolic-rich fruits increases the antioxidant capacity of the blood, and when they are consumed with high fat and carbohydrate 'pro-oxidant and pro inflammatory' meals, they may counterbalance their negative effects. Given the content and availability of fat and carbohydrate in the Western diet, regular consumption of phenolic-rich foods, particularly in conjunction with meals, appears to be a prudent strategy to maintain oxidative balance and health. PMID- 20955647 TI - Fruit polyphenols, immunity and inflammation. AB - Flavonoids are a large class of naturally occurring compounds widely present in fruits, vegetables and beverages derived from plants. These molecules have been reported to possess a wide range of activities in the prevention of common diseases, including CHD, cancer, neurodegenerative diseases, gastrointestinal disorders and others. The effects appear to be related to the various biological/pharmacological activities of flavonoids. A large number of publications suggest immunomodulatory and anti-inflammatory properties of these compounds. However, almost all studies are in vitro studies with limited research on animal models and scarce data from human studies. The majority of in vitro research has been carried out with single flavonoids, generally aglycones, at rather supraphysiological concentrations. Few studies have investigated the anti inflammatory effects of physiologically attainable flavonoid concentrations in healthy subjects, and more epidemiological studies and prospective randomised trials are still required. This review summarises evidence for the effects of fruit and tea flavonoids and their metabolites in inflammation and immunity. Mechanisms of effect are discussed, including those on enzyme function and regulation of gene and protein expression. Animal work is included, and evidence from epidemiological studies and human intervention trials is reviewed. Biological relevance and functional benefits of the reported effects, such as resistance to infection or exercise performance, are also discussed. PMID- 20955648 TI - Fruit polyphenols and CVD risk: a review of human intervention studies. AB - Epidemiological evidence suggests that polyphenols may, in part, explain the cardioprotective properties of fruits. This review aims to summarise the evidence for the effects of fruit polyphenols on four risk factors of CVD: platelet function, blood pressure, vascular function and blood lipids. This review includes human dietary intervention studies investigating fruits and their polyphenols. There was some evidence to suggest that fruits containing relatively high concentrations of flavonols, anthocyanins and procyanindins, such as pomegranate, purple grapes and berries, were effective at reducing CVD risk factors, particularly with respect to anti-hypertensive effects, inhibition of platelet aggregation and increasing endothelial-dependent vasodilation than other fruits investigated. Flavanone-rich fruits, such as oranges and grapefruits, were reported to have hypocholesterolaemic effects, with little impact on other risk factors being examined. However, the evidence was limited, inconsistent and often inconclusive. This is in part due to the heterogeneity in the design of studies, the lack of controls, the relatively short intervention periods and low power in several studies. Details of the polyphenol content of the fruits investigated were also omitted in some studies, negating comparison of data. It is recommended that large, well-powered, long-term human dietary intervention studies investigating a wider range of fruits are required to confirm these observations. Investigations into the potential synergistic effects of polyphenols on a combination of CVD risk markers, dose-response relationships and standardisation in methodology would facilitate the comparison of studies and also provide valuable information on the types of fruits which could confer protection against CVD. PMID- 20955649 TI - The impact of fruit flavonoids on memory and cognition. AB - There is intense interest in the studies related to the potential of phytochemical-rich foods to prevent age-related neurodegeneration and cognitive decline. Recent evidence has indicated that a group of plant-derived compounds known as flavonoids may exert particularly powerful actions on mammalian cognition and may reverse age-related declines in memory and learning. In particular, evidence suggests that foods rich in three specific flavonoid sub groups, the flavanols, anthocyanins and/or flavanones, possess the greatest potential to act on the cognitive processes. This review will highlight the evidence for the actions of such flavonoids, found most commonly in fruits, such as apples, berries and citrus, on cognitive behaviour and the underlying cellular architecture. Although the precise mechanisms by which these flavonoids act within the brain remain unresolved, the present review focuses on their ability to protect vulnerable neurons and enhance the function of existing neuronal structures, two processes known to be influenced by flavonoids and also known to underpin neuro-cognitive function. Most notably, we discuss their selective interactions with protein kinase and lipid kinase signalling cascades (i.e. phosphoinositide-3 kinase/Akt and mitogen-activated protein kinase pathways), which regulate transcription factors and gene expression involved in both synaptic plasticity and cerebrovascular blood flow. Overall, the review attempts to provide an initial insight into the potential impact of regular flavonoid-rich fruit consumption on normal or abnormal deteriorations in cognitive performance. PMID- 20955650 TI - Colonic metabolites of berry polyphenols: the missing link to biological activity? AB - The absorption of dietary phenols, polyphenols and tannins (PPT) is an essential step for biological activity and effects on health. Although a proportion of these dietary bioactive compounds are absorbed intact, depending on their chemical structure and the nature of any attached moiety (e.g. sugar, organic acid), substantial amounts of lower molecular weight catabolites are absorbed after biotransformation by the colon microflora. The main products in the colon are (a) benzoic acids (C6-C1), especially benzoic acid and protocatechuic acid; (b) phenylacetic acids (C6-C2), especially phenylacetic acid per se; (c) phenylpropionic acids (C6-C3), where the latter are almost entirely in the dihydro form, notably dihydrocaffeic acid, dihydroferulic acid, phenylpropionic acid and 3-(3'-hydroxyphenyl)-propionic acid. As a result of this biotransformation, some of these compounds can each reach mm concentrations in faecal water. Many of these catabolites are efficiently absorbed in the colon, appear in the blood and are ultimately excreted in the urine. In the case of certain polyphenols, such as anthocyanins, these catabolites are major products in vivo; protocatechuic acid is reported to represent a substantial amount of the ingested dose of cyanidin-3-O-glucoside. The major catabolites of berries, and especially blackcurrants, are predicted based on compositional data for polyphenols from berries and other sources. Since microbial catabolites may be present at many sites of the body in higher concentration than the parent compound, it is proposed that at least a part of the biological activities ascribed to berry polyphenols and other PPT are due to their colonic catabolites. PMID- 20955651 TI - Berry flavonoids and phenolics: bioavailability and evidence of protective effects. AB - Berries contain vitamin C and are also a rich source of phytochemicals, especially anthocyanins which occur along with other classes of phenolic compounds, including ellagitannins, flavan-3-ols, procyanidins, flavonols and hydroxybenzoate derivatives. This review examines studies with both human subjects and animals on the absorption of these compounds, and their glucuronide, sulphate and methylated metabolites, into the circulatory system from the gastrointestinal tract and the evidence for their localisation within the body in organs such as the brain and eyes. The involvement of the colonic microflora in catabolising dietary flavonoids that pass from the small to the large intestine is discussed along with the potential fate and role of the resultant phenolic acids that can be produced in substantial quantities. The in vitro and in vivo bioactivities of these polyphenol metabolites and catabolites are assessed, and the current evidence for their involvement in the protective effects of dietary polyphenols, within the gastrointestinal tract and other parts of the body to which they are transported by the circulatory system, is reviewed. PMID- 20955652 TI - The future of flavonoid research. AB - There are insufficient data to provide conclusive evidence on the health effects of most flavonoid subclasses. Future research of polyphenol bioactivity requires a more complete understanding of their intake, bioavailability and metabolism. The following summarises the limitations of polyphenol research as described across various reviews throughout the literature and presents the key requirements for future research. These include establishing the effects of processing, bioavailability and metabolism, developing physiologically appropriate in vitro models, standard methods of analysis and appropriate clinical biomarkers. The future of flavonoid research will undoubtedly depend upon the resolve of these issues, and although the field has shown continuous progress for many years, progress will likely slow if these challenges are not met. PMID- 20955654 TI - The correlation between ultrasonography and histology in the search for gallstones. AB - INTRODUCTION: The majority of published data on the sensitivity and specificity of ultrasound in the diagnosis of gallbladder pathology was conducted over 30 years ago and, since the 1990s, ultrasound imaging has been the accepted gold standard. The quality and resolution of ultrasonography has improved significantly since then and we have, therefore, set out to assess whether the progression in technology has translated into improved diagnostic accuracy. PATIENTS AND METHODS: In the period December 2005 to December 2008, a total of 2100 patients underwent laparoscopic cholecystectomy for symptoms related to gallbladder disease. All patients underwent ultrasound examination prior to their surgery and histopathological analysis of their gallbladder postoperatively. We undertook a retrospective analysis of these patients comparing their pre operative ultrasound scan and their histopathology report for the presence or absence of gallstones. Ultrasound scans were performed by a combination of radiologists and ultrasonographers. RESULTS: The study identified a sensitivity of 0.85 and a specificity of 1 for ultrasound in the identification of gallstones. We found a sensitivity of 0.84 and 0.83 for the radiologists and ultrasonographers, respectively. CONCLUSIONS: This study suggests that, despite an evolution in the resolution of ultrasound imaging, there has not been a corresponding improvement in sensitivity. There is a false positive rate of 16% which remains unchanged since the early 1990s. PMID- 20955655 TI - 'Verto-sign': an indicator of increased operative complexity in pelvic trauma surgery. AB - We demonstrate an important, newly defined, radiographic sign present in three acetabular trauma cases, named the 'Verto-sign' which, if present, indicates a particularly complex both column fracture pattern. The 'Verto-sign' is visible on the anteroposterior pelvic radiograph in a rare subtype of both column fractures and is created by the greater sciatic notch fracture fragment rotating internally or externally. The 'Verto-sign' appears, as its name suggests, like a V-shape present above the acetabulum. PMID- 20955656 TI - Use of an endovascular stent graft and percutaneous thrombin injection to treat an iatrogenic hepatic artery pseudoaneurysm. AB - In this report, we present the case and successful radiological treatment of a patient who developed a right hepatic arterypseudoaneurysm following laparoscopic cholecystectomy. Initially, an endovascular stent graft was placed to exclude thepseudoaneurysm; subsequently, a small residual pseudoaneurysm was treated by percutaneous injection of thrombin. Thisreport is the first to describe this combination of radiological treatments for a hepatic artery pseudoaneurysm. PMID- 20955657 TI - Comparison of modified Celsior solution and M-kyoto solution for pancreas preservation in human islet isolation. AB - Since the successful demonstration of the Edmonton protocol, islet transplantation has advanced significantly on several fronts, including improved pancreas preservation systems. In this study, we evaluated two different types of organ preservation solutions for human islet isolation. Modified Celsior (Celsior solution with hydroxyethyl starch and nafamostat mesilate; HNC) solution and modified Kyoto (MK) solution were compared for pancreas preservation prior to islet isolation. Islet yield after purification was significantly higher in the MK group than in the HNC group (MK = 6186 +/- 985 IE/g; HNC = 3091 +/- 344 IE/g). The HNC group had a longer phase I period (digestion time), a higher volume of undigested tissue, and a higher percentage of embedded islets, suggesting that the solution may inhibit collagenase. However, there was no significant difference in ATP content in the pancreata or in the attainability of posttransplant normoglycemia in diabetic nude mice between the two groups, suggesting that the quality of islets was similar among the two groups. In conclusion, MK solution is better for pancreas preservation before islet isolation than HNC solution due to the higher percentage of islets that can be isolated from the donor pancreas. MK solution should be the solution of choice among the commercially available solutions for pancreatic islet isolation leading to transplantation. PMID- 20955658 TI - Comparative analysis of endoderm formation efficiency between mouse ES cells and iPS cells. AB - Definitive endoderm (DE) derived from stem cells holds potential to differentiate into hepatocytes. Stem cell therapy using those cells has potential for a treatment of liver disease. To date, various ways of inducing hepatocytes from embryonic stem (ES) cells have been reported by researchers. However, it has not been proved enough that induced pluripotent stem (iPS) cells behave in the same manner as ES cells in endoderm differentiation. The purpose of this study was to establish an efficient method to induce DE from iPS cells, through comparatively analyzing the efficacy of endoderm formation from mouse ES cells. Furthermore, the efficiency of a serum-free medium in the differentiation into DE was investigated. Mouse ES cells and iPS cells were floated in culture medium for 2 or 5 days and embryoid bodies (EB) were formed. Subsequently, DE was induced with 100 ng/ml activin A and 100 ng/ml basic fibroblast growth factor (bFGF). RT-PCR and real-time PCR analyses were carried out at each step to determine the gene expression of EB markers. The difference in cellular proliferation between serum containing and serum-free media was examined by an MTS assay in EB and DE induction. iPS cells showed the paralleled mRNA expression to ES cells in each step of differentiation into EB, but the levels of expression of Sox17 and Foxa2 were relatively higher in ES cell-derived DE, whereas Cxcr4 expression was higher in iPS cell-derived DE. The utilization of serum-free medium for iPS cells showed significantly favorable cellular proliferation during EB formation and subsequent DE induction. Forming EB for 5 days and subsequently DE induction with activin A and bFGF with serum-free medium was an appropriate protocol in iPS cells. This may represent an important step for generating hepatocytes from iPS cells for the development of cell therapy. PMID- 20955659 TI - Hepatic differentiation of mouse iPS cells in vitro. AB - Induced pluripotent stem (iPS) cells are pluripotent and are able to unlimitedly proliferate in vitro. This technical breakthrough in creating iPS cells from somatic cells has noteworthy implications for overcoming the immunological rejection and the ethical issues associated with the derivation of embryonic stem cells from embryos. In the current work, we present an efficient hepatic differentiation of mouse iPS cells in vitro. iPS cells were cultured free floating to induce the formation of embryoid bodies (EB) for 5 days. EB were transferred to a gelatin-coated plate and treated with 100 ng/ml activin A and 100 ng/ml basic fibroblast growth factor (bFGF) for 3 days to induce definitive endoderm. Cells were further cultured for 8 days with 100 ng/ml hepatocyte growth factor (HGF) to generate hepatocytes. Characterization was performed by RT-PCR assay. Functional analysis for albumin secretion and ammonia removal was also carried out. iPS cell-derived hepatocyte-like cells (iPS-Heps) were obtained at the end of the differentiation program. Expression levels of a gestational hepatocyte gene and lineage-specific hepatic genes intensified in iPS-Heps. The production of albumin increased in a time-dependent manner. iPS-Heps were capable of metabolizing ammonia. We present here instant hepatic differentiation of mouse iPS cells using combined 3-day treatments of activin A and bFGF with subsequent 8 day HGF. Our study will be an important step to generate hepatocytes from human iPS cells as a new source for liver-targeted cell therapies. PMID- 20955660 TI - Establishment of an immortalized porcine liver cell line JSNK-1 with retroviral transduction of SV40T. AB - Maintenance of freshly isolated porcine liver cells in vitro is limited for a short period of time. Therefore, establishment of easy handling cell lines is extremely important for in vitro study for liver cells and their possible utilization for cell differentiation and growth of stem cells. Porcine liver cells were transduced with a retroviral vector SSR#69 expressing SV40T, one of SSR#69-immortalized porcine liver cell lines, JSNK-1, was established and characterized. Morphology of JSNK-1 cells was spindle shaped. When the cells became confluent, JSNK-1 cells revealed hills-and-valleys pattern. In the presence of vitamin A, JSNK-1 cells showed big droplets inside the cytoplasm, which were positive with PAS staining. JSNK-1 cells showed the gene expression of collagen type 1alpha1, collagen type 1alpha2, FLT-1, beta-actin, and SV40T. Immunostaining study revealed that JSNK-1 cells produced collagen, vimentin, and alpha-smooth muscle actin. JSNK-1 cells possessed the characteristics of the liver stellate cells. JSNK-1 cells produced hepatocyte growth factor (HGF) in a time-dependent manner. When cocultured with iPS cells towards the hepatic differentiation, JSNK-1 cells facilitated their hepatic differentiation in terms of albumin production. In conclusion, JSNK-1 cells would be valuable in the study of liver stellate cell pathophysiology and contribute to the optimization of hepatic differentiation of iPS cells. PMID- 20955661 TI - Prospective audit of cross-sectional imaging and radiation exposure in general surgical patients. AB - INTRODUCTION: Most patients admitted with an acute surgical problem undergo some imaging during their in-patient stay. As computed tomography (CT) scanning becomes more readily available, it is becoming the mainstay of assessment. Recent studies have commented on the potential adverse effects of early cross-sectional imaging. This audit aimed to determine the use of early cross-sectional imaging and associated radiation dose in an acute surgical cohort. PATIENTS AND METHODS: Data from 500 acute surgical patients were prospectively collected over a 3-month period. CT scans were undertaken, the effect on subsequent diagnostic and management decisions and the potential associated risks were evaluated. RESULTS: Almost 40% of subjects underwent CT scanning. Of these, 20% did not alter management and could be deemed unnecessary. The radiation exposure equated to an age- and gender-specific risk of fatal cancer induction between 1 in 1675 and 1 in 7130. CONCLUSIONS: Early-cross sectional imaging provides a valuable diagnostic adjunct. Decisions to expose patients to potentially hazardous radiation need to acknowledge the anticipated benefits versus risks. PMID- 20955662 TI - Episiotomy endometrioma masquerading as peri-anal sepsis: surgeons beware! AB - A 34-year-old woman with peri-anal pain and swelling was operated in the emergency setting assuming a diagnosis of a perianal abscess. No pus was revealed. Later magnetic resonance imaging (MRI) suggested induration and a mass effect in the peri-anal region. Examination under anaesthesia was repeated which revealed a mobile but firm mass. Histology from trucut biopsies diagnosed it as a peri-anal endometrioma arising from an episiotomy scar. Peri-anal endometrioma can rarely developin episiotomy scars and can be easily mistaken as an abscess by junior surgeons. PMID- 20955663 TI - Gastric polyp prolapsed into the duodenum as a rare cause of acute pancreatitis. AB - Mechanical gastric polyp complications are very rare occurrences most commonly related to hyperplastic polyps. We report here the case of a young woman with a 12-cm adenomatous polyp on the great curvature of the stomach diagnosed incidentally during tests for anaemia. Later, the patient was referred to hospital for recurrent emergency due to acute pancreatitis caused by the polyp prolapsing into the duodenum. A two-step treatment was undertaken: the first procedure consisted of a surgical polypectomy followed by a second-step total gastrectomy for cancer necessitated by the presence of an invasive adenocarcinoma on the polyp. This case proves malignant adenomatous polyps to be exceptionally responsible for mechanical complications such as acute pancreatitis due to polyp prolapsing into the duodenum. In such a complicated case, we recommend deferredemergency resection of the polyp followed subsequently by gastrectomy for cancer when histologically indicated. PMID- 20955664 TI - Impact of organisational changes on fracture neck of femur management. AB - INTRODUCTION: In 2005, University Hospitals of Leicester formed a Fracture Neck of Femur (#NOF) project group to improve care of this group of patients. SUBJECTS AND METHODS: The salient changes effected by the group were the appointment of designated orthogeriatricians, trauma co-ordinators, clinical aides, and discharge nurses. RESULTS: As a result of these measures, the number of patients going to theatre within 48 h of admission rose from 38.5% in 2005/6 to 90% in 2007/8. In-hospital mortality decreased from 16.5% in 2005/6 to 10.9% in 2007/8. The 30-day mortality dropped from 13% in 2005/6 to 10.9% in 2007/8. Hospital stay reduced from 29 days in 2005/06 to 17 days in 2007/8. CONCLUSIONS: Re organisation of available resources has a positive impact on reducing mortality and in-hospital stay of fracture neck of femur patients. PMID- 20955666 TI - Welsh Surgical Society Spring Meeting, 6-7 May 2010. AB - The 55th meeting of the Welsh Surgical Society was held at the Education Centre, Nevill Hall Hospital, Abergavenny. The prize medals were announced and presented to Simon Weaver (Registrar prize and his second Welsh Surgical Society prize) and Rachel Pollock (Junior prize) by Mr P Braithwaite, former President of the Society. Six of the best were chosen from 34 abstracts selected for presentation at the meeting. PMID- 20955665 TI - Minimising the risk of extensor pollicis longus rupture following volar plate fixation of distal radius fractures: a cadaveric study. AB - INTRODUCTION: Rupture of extensor pollicis longus (EPL) tendon is a recognised complication following volar plate fixation of distal radius fractures, usually from attrition caused by prominent screws. We sought to identify the screw holes in some of the most commonly used plates which may precipitate tendon injury. SUBJECTS AND METHODS: Three fixed-angle volar locking plates were sequentially positioned into 18 cadaveric arms. A wire was passed through each of the holes in the plates using a locking guide and the dorsal relationships noted. RESULTS: Each plate had specific 'high-risk' holes which directed the wire towards the EPL groove. The central screw holes appeared mostly implicated in EPL injury. CONCLUSIONS: Awareness of 'high-risk' holes and appropriate minor alterations in surgical technique may consequently decrease the incidence of EPL irritation and rupture. PMID- 20955667 TI - Delayed distal radio-ulnar joint instability after Galeazzi type fracture fixation in a child. AB - We report a rare case of delayed distal radio-ulnar joint instability with malunion of a Galeazzi-type radius fracture in a 10- year-old boy. He underwent operative intervention with flexible intramedullary nailing of the radius. He had careful clinical and intra-operative evaluation under image intensifier, and regular clinical and radiological assessments subsequently in clinic, and his distal radio-ulnar joint (DRUJ) was stable. He nonetheless developed DRUJ instability with malunion of radial midshaft fracture at 4 months. Corrective osteotomy for forearm fracture malunion is an uncommon procedure in children. He underwent a corrective radial osteotomy at the site of malunion, held with a Pennig external fixator, with reconstruction of the DRUJ subluxation. He made a good recovery with full restoration of wrist and forearm function, which was maintained at 17 months. PMID- 20955668 TI - [A study on transcript a bnormalities of FHIT gene in human non-small cell lung cancer]. AB - BACKGROUND: To explore the role of abnormalities in RNA transcript of FHIT gene in human non-small cell lung cancer(NSCLC). METHODS: Transcript abnormalities of FHIT gene were detected in 35 cancer samples and their corresponding paracancer tissues and normal tissues, four lung cancer cell lines, and 10 lung tissues of benign pulmonary lesions as control by nested RT-PCR. RESULTS: Fourteen of 35 cancer tissues (40%) had abnormalities in RNA transcripts of FHIT. There were 5 paracancer tissues with transcript abnormalities of FHIT gene out of the 14 lung cancers with transcript abnormalities of FHIT gene, with an abnormality rate of 35.71%. All of 4 lung cancer cell lines had transcript abnormalities of FHIT gene. The aberrant rate of FHIT gene in squamous cell carcinoma tissues (58.82%) was significantly higher than that in adenocarcinoma tissues (22.22%) (P<0.05). No relationship was found among the transcript abnormality of the FHIT gene and differentiated degree of the tumor cell, stages of the cancer, size of the primary tumor, location of cancer, and age of the patients (P>0.05). CONCLUSIONS: The results show that there are transcript abnormalities of FHIT gene in NSCLC. FHIT transcript abnormality preferentially occur in squamous cell carcinomas, and it might be the early molecular phenomenon of lung cancer. PMID- 20955669 TI - [Tracheal carina reconstruction and bronchoplasty in the treatment of 94 central type bronchogenic carcinomas]. AB - BACKGROUND: To analyze the short-term effects and long term survival of patients with lung cancer underwent tracheal carina reconstruction and bronchoplasty. METHODS: From April 1985 to May 1999, 94 patients with lung cancer underwent tracheal carina reconstruction and bronchoplasty, 14 for carinal resection and reconstruction and 80 for bronchial sleeves. RESULTS: Postoperative complications were atelectasis ( 19 cases) , arrthymia ( 2 cases) and anastomotic leakage ( 1 case) . There was no operative death in this series. The 1-, 3- and 5-year survival rates were 83. 1%( 74/ 89) , 58. 3%( 35/ 56) and 34. 0%( 18/ 53) respectively for the entire group. The 5-year survival rate was 66. 7%( 6/ 9) in stage N B disease, 40%( 6/ 15) in O B disease and 21. 1%( 4/ 19) in O A disease. The indication of these procedures and the methods of lymph node dissection, bronchoplasty and pulmonary artery reconstruction, and superior vena cava reconstruction have been discussed. CONCLUSIONS: Bronchoplasty for lung cancer is a safe and effective therapy. The long term survival depends on the stage of lung cancer , proper selection of surgical indication, clearance of lymph nodes in operation and multiple modality therpay after operation. PMID- 20955670 TI - [Pre- and post-operative sequential changes of serum p53 antibodies and clinical significance in patients with lung cancer]. AB - BACKGROUND: To explore the relationship between serum p53 antibodies and clinicopathological characteristics in patients with lung cancer and to investigate sequential changing regularity of serump53 antibodies after surgical resection. METHODS: The serum p53 antibody level was detected in 120 patients with lung cancer , and in 30 patients with benign pulmonary lesion and 120 healthy adults as control by enzyme linked immunosorbent assay ( ELISA) . The blood samples were collected on the day before operation and on the 7th , 30th and 90th days postoperatively. RESULTS: The level and positive rate of serum p53 antibodies in patients with lung cancer were significantly higher than those in patients with benign pulmonary disease and normal individuals ( P < 0. 05) , but there was no significant difference between patients with benign pulmonary disease and normal individuals ( P > 0. 05) . The level and positive rate of pre operative serum p53 antibodies in patients with lung cancer were closely related to cell differentiation and stage of lung cancer ( P < 0. 01 or P < 0. 05) . The level of serum p53 antibodies decreased gradually in patients with lung cancer underwent radical removal of the cancer , and completely returned to the normal level around the 30th day after operation , but the level of serum p53 antibodies in patients with lung cancer underwent palliative operation didn't reduce to the normal level on the 30th day after operation. It would increase again when tumor metastasis or recurrence developed. CONCLUSIONS: Detection of serum p53 antibodies is helpful to defferentiate benign from malignant pulmonary diseases. Monitoring of sequential change of pre- and post-operative serum p53 antibodies in patients with lung cancer is helpful to evaluate response to treatment , to judge prognosis and to guide the comprehensive treatment of patients with lung cancer after operation. PMID- 20955671 TI - [Effects of IL-4 and taxol on cellular proliferation of Lewis lung cancer]. AB - BACKGROUND: To investigate the effects of IL-4 and taxol on cellular proliferation of Lewis lung cancer (LLC) . METHODS: LLC cells (1. 25 *10(6)/ mouse) were inoculated subcutaneously to 40 mice , which were randomized into 4 groups and given responsive treatment consecutively in 5 days after inoculation. For group I natrii chloride was injected , for group II IL-4 at 50 ng/ d for 7 days , for group III taxol at 10 mg/ (kg*d) for 10 days , and for group IV IL-4 and taxol were injected altogether at 50 ng/ d for 7 days and 5mg/ (kg*d) for 10 days respectively. On the 18th day , all the mice were killed. Nuclear morphometry , DNA contents and AgNORs were detected by image analysis. RESULTS: Nuclear area , perimeter , mean diameter , DNA contents , and AgNORs counting in group II were 24. 202 +/-5. 012mum(2) , 18. 626 +/-4. 180mum , 2. 642 +/-0. 291mum , 3. 412 +/-0. 910 , and 5. 313 +/-0. 820 respectively , which were significantly less than those in group I ( P < 0. 05) ; the parameters in group III were 18. 373 +/-4. 833mum(2) , 16. 522 +/-2. 518mum , 2. 401 +/-0. 288mum , 3. 096 +/-0. 771 , and 2. 670 +/-0. 401 respectively , which were much less than those in group I ( P < 0. 01) ; the parameters in group IV were 16. 664 +/-4. 761mum(2) , 15. 901 +/-2. 700mum , 2. 283 +/-0. 308mum , 2. 707 +/-0. 807 , and 1. 552 +/-0. 316 respectively , which were remarkably less than those in group I ( P < 0. 01) . Significant differences of the parameters were observed among group II and III and IV ( P < 0. 05) . CONCLUSIONS: Both IL-4 and taxol can remarkably inhibit the proliferation of LLC. The effect of combined treatment is most significant , and the effect of taxol is higher than that of IL-4. PMID- 20955672 TI - [Expression of E-cadherin and its clinical significance in non-small cell lung cancer]. AB - BACKGROUND: To investigate the expression and clinical significance of E-cadherin (E-Cad) in non-small cell lung cancer (NSCLC) and its metastatic lymph nodes. METHODS: E-Cad expression was detected in 30 normal lung tissues , 61 cancerous tissues and 41 metastatic lymph nodes by immunohistochemical method. RESULTS: In all of the normal epithelial cells , expression of E-Cad was clearly evident on cell-cell boundaries. Abnormal expression rate of E-Cad in primary NSCLC and metastatic lymph nodes were 52. 46 % and 63. 41 % respectively , and no significant difference was found between the two groups ( P > 0. 05) . The abnormal E-Cad expression in lung cancer was closely related to the P-TNM stages , pathological grades and lymph node involvement ( P < 0. 001-0. 05) , but not to the histological classification of the cancer ( P > 0. 05) . CONCLUSIONS: E-Cad might be a valuable marker in assessing biological behavior and metastatic potential of NSCLC. PMID- 20955673 TI - [The relationship between Epstein-Barr-virus infection and expression of p53, Bcl 2 and C-myc gene in lung cancer]. AB - BACKGROUND: To investigate the infection rate of EBV and the expression of p53, Bcl-2 and C-myc gene in lung cancer, to explore the relation between EBV and oncogenesis of lung cancer , and the relation between EBV and expression of p53, Bcl-2 and C-myc. METHODS: Forty-eight cases of excised specimen of lung cancer, 2 of lungmetastatic leiomyosar coma, 1 of tuberculoma, 18 of paraneoplastic bronchial mucosa tissue, and 14 of normal lung tissue were analyzed. EBV DNA of the fresh tissue was detected with PCR, and indirect in situ PCR was used to observe the reaction site of EBV DNA, and immunohistochemistry (SABC) was used to detect the expression of p53, Bcl-2, and C-myc gene. RESULTS: Twenty-five cases of the 48 lung cancer had positive staining of EBV DNA and 75% of squamous cell carcinoma showed positive staining of EBV DNA. The positive staining of EBV DNA was closely related to histological classfication of lung cancer ( P < 0. 01) . The positive rate of EBV DNA in paraneoplastic bronchial mucosa tissues and normal pulmonary tissues was 61. 11%( 11/ 18) and 28. 5%( 4/ 14) respectively ( P < 0. 01) . The positive rate of p53, Bcl-2 and C-myc expression in lung cancer tissues was 54. 17%, 37. 5% and 75% respectively. The expression of p53 and Bcl-2 was closely related to histological classification ( P < 0. 05) . The positive rate of p53, Bcl-2 and C-myc expression in patients with positive EBV DNA was significantly higher than that in patients with negative EBV DNA (P < 0. 05) . CONCLUSIONS: Lung cancer has high EBV infection. EBV infection may play an important role in the oncogenesis of lung cancer, which might bring about through activating some oncogenes. PMID- 20955674 TI - [Preliminary study on the expression of aromatase P450 mRNA in human lung cancer tissues]. AB - BACKGROUND: To evaluate the expression , location and distribution of aromatase P450 mRNA in human lung cancer. METHODS: Using aromatase P450 cRNA as probe , the expression of aromatase mRNA were tested in 23 patients with primary lung cancer and 7 patients with pulmonary benign diseases by in situ hybridization. RESULTS: Positive expression of aromatase mRNA was found in 11 cases with squamous cell carcinoma , 6 cases with adenocarcinoma and 2 cases with adenosquamous carcinoma. 3 cases with small cell lung cancer and 1 case with bronchioloalveolar carcinoma were all weak positive. Positive signals were mainly found in cytoplasm and nuclei of tumor cells , and a small quantity of positive expression of aromatase mRNA was found in stromal cells and vascular endothelium cells of the tumor. But no expression of aromatase mRNA was found in the noncancerous tissues and tissues of benign pulmonary lesions. CONCLUSIONS: The results suggest that the expression of aromatase mRNA are general in lung cancer tissues , and it might play an important role in the oncogenesis and development of lung cancer. PMID- 20955675 TI - [The effect of vinblastine on the viscoelastic properties of lung cancer cells]. AB - BACKGROUND: To explore the effect of vinblastine on the viscoelastic properties of highmetastatic human giant cell carcinoma cells ( PC) and low metastatic adenocarcinoma cells (PAa) of the lung and its biomechanical mechanisms. METHODS: The viscoelastic properties of PG and PAa cells and their changes after treated with vinblastine (VCR, 0. 10-2. 00Lg/ml) were detected by micropipette aspiration technique. Viscoelasticity was analyzed by the special three-element standard linear solid model. RESULTS: Before treated with VCR, the elastic coefficients K1 and K2 as well as viscous coefficient L of PAa were significantly higher than those of PG cells. The values of K1, K2 and L of PAa cells decreased along with the increase of VCR concentration. However, the viscoelastic coefficient values in PG cells decreased when the VCR concentration was lower than 1. 00Lg/ml and then turned to increase as concentration of VCR went on increasing. The microtubules and microfilaments were sparse random in the PAa cells and diminished in PG cells. After treated with VCR, they were cut down seriously in PAa cells, and manifestations of mitotic arrest of cell cycle increased unusually in PG cells. CONCLUSIONS: The cytoskeleton structure component changes are related to the viscoelasticity of the tumor cells. The anti-neoplasm actions of cytoskeleton interferents such as VCR might be realized by mainly regulating the message of tumor cells growth and differentiation. PMID- 20955676 TI - [Expression and clinical significance of p53 protein , estrogen and progesterone receptors in non-small cell lung cancer]. AB - BACKGROUND: To investigate the relationships between expression of tumor suppressor gene p53 protein , estrogen receptor (ER) , progesterone receptor (PR) and clinicopathology and prognosis in human non-small cell lung cancer (NSCLC) . METHODS: Expression of p53 protein , ER and PR in 147 NSCLC specimen was detected by SP immunohistochemistry method. RESULTS: Overall , 61. 2 %(90/ 147) tumor tissues had positive p53 staining. The positive rate of p53 expression in squamous cell carcinoma , adenocarcinoma , adenosquamous carcinoma and large cell carcinoma was 63. 5 %(40/ 63) , 57. 6 %(38/ 66) , 66. 7 %(10/ 14) , and 50 %(2/ 4) respectively. The overexpression of p53 protein was associated with the prognosis of patients with adenocarcinoma , the positive rate of p53 expression of patients who survived for less than 3 years was 75 % , which was significantly higher than 44. 7 % of patients who survived for more than 3 years ( P < 0. 025) . For ER and PR , the overall positive rate was 49. 7 %(73/ 147) and 76. 9 %(113/ 147) respectively. The positive rate of squamous cell carcinoma and adenocarcinoma was significantly higher than that of squamous cell carcinoma ( P < 0. 005) . Besides , expression area of ER and PR was often in the nucleus for squamous cell carcinoma and in the cytoplasma for adenocarcinoma ( P < 0. 005) . The 3-year survival rate in patients with cytoplasma-staining for PR was significantly higher than that with nucleus-staining ( P < 0. 025) . CONCLUSIONS: The results suggest that overexpression of p53 in adenocarcinoma could be used as a prognostic factor for the patients. Detection of ER and PR may have a definite value in differentiating squamous cell carcinoma from adenocarcinoma. The prognosis is poor for PCR-positive patients with nucleus-staining. PMID- 20955677 TI - [Evaluation of improved Saccomanno method in management of sputum samples of lung cancer patients]. AB - BACKGROUND: To compare the improved Saccomanno method with conventional method not only on concentrating and detecting cytological sputum but also on preserving sputum samples for further molecular biological and flow cytometry (FCM) investigation in lung cancer patients. METHODS: A total of 125 cases were identified as lung cancer by histological or cellular pathology, and sputum samples from these patients were collected by conventional method and improved Saccomannomethod respectively for sputum smear. Then, some sputum samples collected by improved Saccomanno method were studied by FCM and/ or PCR-SSCP silver stain. RESULTS: The positive smear rates were 55. 2%( 69/ 125) by improved Saccomannomethod and 28%( 35/ 125) by conventionalmethod respectively ( P < 0. 01) . Of the 125 cases, 58 by improved Saccomannomethod and 26 by conventional method were confirmed for histological types of lung cancer respecitvely, and a highly significant difference was observed between the two groups ( P < 0. 01) . The positive smear rate by improved Saccomannomethod had significant correlation with the clinical characteristics such as histology, TNM stage, and type of lung cancer . Moreover, of the samples collected by improved Saccomanno method, 41 cases were selected to detect p53 point mutation by PCR-SSCP-silver stain and 30 cases were selected to quantitate p53 and p21 protein by FCM technique successfully, the positive rates were 53. 7% ( 22/ 41) , 40%( 12/ 30) and 53. 3% ( 16/ 30) respectively. CONCLUSIONS: The results indicate that improved Saccomannomethod has a higher value than conventionalmethod not only on concentrating and detecting cytological sputum but also on preserving sputum sample for further molecular biological study. PMID- 20955678 TI - [Detection of micro-vascular density(MVD) and its clinical significance in lung cancer]. AB - BACKGROUND: To study the relationship between MVD of lung cancer tissues and the pathophysiological characteristics and prognosis in patients with lung cancer. METHODS: The MVD was detected in 114 lung cancer tissues, 30 benign pulmonary tissues by immunohistochemical staining (LSAB method). RESULTS: MVD in lung cancer tissues (30.47+/-10.56) was significantly higher than that in benign pulmonary tissues (10.23+/-6.92)(P<0.01); The MVD was closely related to the size of primary cancer, lymph node status, P-TNM stages, grade of cell differentiation of lung cancer (P<0.01), but not to the histological classification and site of the cancer, and age, sex and smoking or not in the patients with lung cancer (P<0.05); The 5-year survival rate in patients (17.27%) with high MVD (>=30) was significantly lower than that in patients (52.74%) with low MVD (<30)(P<0.01); The survival time of patients with lung cancer was negatively related to MVD (r= 0.521,P<0.01); The results of multivariable COX model showed that the P-TNM and MVD were the most significant variables for predicting prognosis among the all related factors in lung cancer. CONCLUSIONS: Increase of MVD may play an important role in the oncogenesis, development, metastasis of lung cancer and might be served as a tumor marker to evaluate the biological behavior of lung cancer. Detection of MVD might be helpful to predict prognosis and guide the postoperative multi-modality therapy in patients with lung cancer. PMID- 20955679 TI - [A clinicopathological study of mediastinal lymph node metastasis of lung cancer]. AB - BACKGROUND: To investigate the characteristics of mediastinal lymph node metastasis of lung cancer from a view of pathology. METHODS: Radical pulmonectomy or lobectomy combined with extensive dissection of mediastinal lymph node was carrived out in 398 patients with lung cancr. N2 disease was diagnozed in 160 cases, and total 352 groups of mediastinal lymph node invaded were analyzed. RESULTS: N2 disease appeared as single group, multi-groups and jumping-form groups, comprising 41.2%,58.8% and 29.3% respectively. The highest metastatic site of lymph node was group 7 mediastinal lymph node, the followings were group 4, 3 and 5 lymph nodes, comprising 45.6%, 31.3% and 25.6% respectively. The N2 metastasis was highly correlated with the site, size, histological classification and cell differentiation of the cancer. An another characteristic of N2 metastasis was that the metastatic lymph node could invaded into the bronchial wall, especially in adenocarcinoma. CONCLUSIONS: It is necessary to dissect the lymph nodes of the hilar and upper and lower mediastinum at the homolateral thoracic cavity extensively and completely. Attention should be paid to the bronchial wall invasion by the metastatic lymph nodes, too. PMID- 20955680 TI - Presence of intradomicile colonies of the triatomine bug Panstrongylus rufotuberculatus in Munecas, La Paz, Bolivia. AB - Chagas disease is a tropical parasitic disease endemic to Latin America which affects more than 10 million people, and kills more than 15,000 people each year. This condition, caused by the protozoan parasite Trypanosoma cruzi, is principally transmitted by kissing bugs (Triatominae). In Bolivia, recent reports by the Departmental Health Service showed the presence of Panstrongylus rufotuberculatus in dwellings located in the Charazani Valley (La Paz). A study was then carried out in the area to evaluate the degree of domiciliation of this species, and its possible role in the transmission of Chagas disease. In seven communities, 108 dwellings were visited to actively search for the bugs and 217 people participated in a serological study to determine the prevalence of Chagas disease in the population. Nymphs and adults belonging to two species: Panstrongylus geniculatus (5 insects, 1.5%) and P. rufotuberculatus (344 insects, 98.5%) were collected. One P. rufotuberculatus was captured in a bed, while all the other specimens of this species were found in kitchens in which guinea pigs were being reared. A large bug colony has been encountered in a kitchen environment, with more than 300 specimens of all stages. None of the 201 analyzed bugs was positive for T. cruzi. The seroprevalence of Chagas disease in the human population was low (1.3%); no evidence of a local vectorial transmission was found. In conclusion, for the time being there is no evidence of vectorial transmission of Chagas disease in the region. The possible association between reared guinea pigs and the bugs is discussed. The presence of infected people, the migratory movement of the human population and the relatively high colonization process demonstrate that the region needs to be regularly controlled to prevent the area from becoming a local source of Chagas transmission. PMID- 20955681 TI - Electron paramagnetic resonance study of the electron transfer reactions in photosystem II membrane preparations from Arabidopsis thaliana. AB - Arabidopsis thaliana is widely used as a model organism in plant biology as its genome has been sequenced and transformation is known to be efficient. A large number of mutant lines and genomic resources are available for Arabidopsis. All this makes Arabidopsis a useful tool for studies of photosynthetic reactions in higher plants. In this study, photosystem II (PSII) enriched membranes were successfully isolated from thylakoids of Arabidopsis plants and for the first time the electron transfer cofactors in PSII were systematically studied using electron paramagnetic resonance (EPR) spectroscopy. EPR signals from both of the donor and acceptor sides of PSII, as well as from auxiliary electron donors were recorded. From the acceptor side of PSII, EPR signals from Q(A)- Fe2(+) and Phe- Q(A)- Fe2(+) as well as from the free Phe- radical were observed. The multiline EPR signals from the S0- and S2-states of CaMn4O(x)-cluster in the water oxidation complex were characterized. Moreover, split EPR signals, the interaction signals from Y(Z) and CaMn4O(x)-cluster in the S0-, S1-, S2-, and the S3-state were induced by illumination of the PSII membranes at 5K and characterized. In addition, EPR signals from auxiliary donors Y(D), Chl(+) and cytochrome b559 were observed. In total, we were able to detect about 20 different EPR signals covering all electron transfer components in PSII. Use of this spectroscopic platform opens a possibility to study PSII reactions in the library of mutants available in Arabidopsis. PMID- 20955682 TI - Photosystems and global effects of oxygenic photosynthesis. AB - Because life on earth is governed by the second law of thermodynamics, it is subject to increasing entropy. Oxygenic photosynthesis, the earth's major producer of both oxygen and organic matter, is a principal player in the development and maintenance of life, and thus results in increased order. The primary steps of oxygenic photosynthesis are driven by four multi-subunit membrane protein complexes: photosystem I, photosystem II, cytochrome b(6)f complex, and F-ATPase. Photosystem II generates the most positive redox potential found in nature and thus capable of extracting electrons from water. Photosystem I generates the most negative redox potential found in nature; thus, it largely determines the global amount of enthalpy in living systems. The recent structural determination of PSII and PSI complexes from cyanobacteria and plants sheds light on the evolutionary forces that shaped oxygenic photosynthesis. This newly available structural information complements knowledge gained from genomic and proteomic data, allowing for a more precise description of the scenario in which the evolution of life systems took place. This article is part of a Special Issue entitled: Regulation of Electron Transport in Chloroplasts. PMID- 20955683 TI - Choosing between glycolysis and oxidative phosphorylation: a tumor's dilemma? AB - A considerable amount of knowledge has been produced during the last five years on the bioenergetics of cancer cells, leading to a better understanding of the regulation of energy metabolism during oncogenesis, or in adverse conditions of energy substrate intermittent deprivation. The general enhancement of the glycolytic machinery in various cancer cell lines is well described and recent analyses give a better view of the changes in mitochondrial oxidative phosphorylation during oncogenesis. While some studies demonstrate a reduction of oxidative phosphorylation (OXPHOS) capacity in different types of cancer cells, other investigations revealed contradictory modifications with the upregulation of OXPHOS components and a larger dependency of cancer cells on oxidative energy substrates for anabolism and energy production. This apparent conflictual picture is explained by differences in tumor size, hypoxia, and the sequence of oncogenes activated. The role of p53, C-MYC, Oct and RAS on the control of mitochondrial respiration and glutamine utilization has been explained recently on artificial models of tumorigenesis. Likewise, the generation of induced pluripotent stem cells from oncogene activation also showed the role of C-MYC and Oct in the regulation of mitochondrial biogenesis and ROS generation. In this review article we put emphasis on the description of various bioenergetic types of tumors, from exclusively glycolytic to mainly OXPHOS, and the modulation of both the metabolic apparatus and the modalities of energy substrate utilization according to tumor stage, serial oncogene activation and associated or not fluctuating microenvironmental substrate conditions. We conclude on the importance of a dynamic view of tumor bioenergetics. PMID- 20955684 TI - Ethanol effects on binary and ternary supported lipid bilayers with gel/fluid domains and lipid rafts. AB - Ethanol-lipid bilayer interactions have been a recurrent theme in membrane biophysics, due to their contribution to the understanding of membrane structure and dynamics. The main purpose of this study was to assess the interplay between membrane lateral heterogeneity and ethanol effects. This was achieved by in situ atomic force microscopy, following the changes induced by sequential ethanol additions on supported lipid bilayers formed in the absence of alcohol. Binary phospholipid mixtures with a single gel phase, dipalmitoylphosphatidylcholine (DPPC)/cholesterol, gel/fluid phase coexistence DPPC/dioleoylphosphatidylcholine (DOPC), and ternary lipid mixtures containing cholesterol, mimicking lipid rafts (DOPC/DPPC/cholesterol and DOPC/sphingomyelin/cholesterol), i.e., with liquid ordered/liquid disordered (ld/lo) phase separation, were investigated. For all compositions studied, and in two different solid supports, mica and silicon, domain formation or rearrangement accompanied by lipid bilayer thinning and expansion was observed. In the case of gel/fluid coexistence, low ethanol concentrations lead to a marked thinning of the fluid but not of the gel domains. In the case of ld/lo all the bilayer thins simultaneously by a similar extent. In both cases, only the more disordered phase expanded significantly, indicating that ethanol increases the proportion of disordered domains. Water/bilayer interfacial tension variation and freezing point depression, inducing acyl chain disordering (including opening and looping), tilting, and interdigitation, are probably the main cause for the observed changes. The results presented herein demonstrate that ethanol influences the bilayer properties according to membrane lateral organization. PMID- 20955685 TI - Comparative study of the membrane-permeabilizing activities of mastoparans and related histamine-releasing agents in bacteria, erythrocytes, and mast cells. AB - The membrane-permeabilizing activities of mastoparans and related histamine releasing agents were compared through measurements of K(+) efflux from bacteria, erythrocytes, and mast cells. Changes in bacterial cell viability, hemolysis, and histamine release, as well as in the shape of erythrocytes were also investigated. The compounds tested were mastoparans (HR1, a mastoparan from Polistes jadwagae, and a mastoparan from Vespula lewisii), granuliberin R, mast cell-degranulating peptide, and compound 48/80, as well as antimicrobial peptides, such as magainin I, magainin II, gramicidin S, and melittin. We used a K(+)-selective electrode to determine changes in the permeability to K(+) of the cytoplasmic membranes of cells. Consistent with the surface of mast cells becoming negatively charged during histamine release, due to the translocation of phosphatidylserine to the outer leaflet of the cytoplasmic membrane, histamine releasing agents induced K(+) efflux from mast cells, dependent on their ability to increase the permeability of bacterial cytoplasmic membranes rich in negatively charged phospholipids. The present results demonstrated that amphiphilic peptides, possessing both histamine-releasing and antimicrobial capabilities, induced the permeabilization of the cytoplasmic membranes of not only bacteria but mast cells. Mastoparans increased the permeability of membranes in human erythrocytes at higher concentrations, and changed the normal discoid shape to a crenated form. The structural requirement for making the crenated form was determined using compound 48/80 and its constituents (monomer, dimer, and trimer), changing systematically the number of cationic charges of the molecules. PMID- 20955686 TI - The inhibitor profiling of the caspase family of proteases using substrate derived peptide glyoxals. AB - A series of substrate-based alpha-keto-beta-aldehyde (glyoxal) sequences have been synthesised and evaluated as inhibitors of the caspase family of cysteine proteases. A number of potent inhibitor sequences have been identified. For example, a palmitic acid containing sequence pal-Tyr-Val-Ala-Asp-glyoxal was demonstrated to be an extremely effective inhibitor of caspase-1, inhibiting not only the action of the protease against synthetic fluorogenic substrates (K(i)=0.3 nM) but also blocking its processing of pro-interleukin-1beta (pro-IL 1beta). In addition, the peptide Ac-Asp-Glu-Val-Asp-glyoxal, which is based on the consensus cleavage sequence for caspase-3, is a potent inhibitor of this protease (K(i)=0.26 nM) yet only functions as a comparatively modest inhibitor of caspase-1 (K(i)=451 nM). Potent inhibitor sequences were also identified for caspases-6 and -8. However, the degree of discrimination between the family members is limited. The ability of Ac-Asp-Glu-Val-Asp-glyoxal to block caspase-3 like activity in whole cells and to delay the development of apoptosis was assessed. When tested against caspase-3 like activity in cell lysates, Ac-Asp-Glu Val-Asp-glyoxal displayed effective inhibition similar to that observed against recombinant caspase-3. Treatment of whole cells with this potent caspase-3 inhibitor was however, not sufficient to significantly stall the development of apoptosis in-vitro. PMID- 20955687 TI - Tracking of fast moving neuronal vesicles with ageladine A. AB - Ageladine A is a marine natural product that can be used to fluorescently stain living tissues and cells. Its fluorescence is highly pH dependent with the highest intensities under acidic conditions. We have used ageladine A to stain acidic vesicles in cells and found the compound especially useful for tracking transport vesicles in cultured nerve cells. Inward as well as outward ionic currents appear not to be influenced by ageladine A at concentrations of 10 MUM or less. Higher concentrations than 30 MUM reduce whole cell voltage dependent outward currents whereas inward currents remain unchanged up to 100 MUM ageladine A (PC12 cells). Incubation with ageladine A (10 MUM) in cultured hippocampal neurons does not alter miniature excitatory postsynaptic currents (mEPCS) amplitudes, frequency, rise or decay times. Fast moving vesicles are stained the brightest, suggesting they are the most acidic and likely to be Golgi derived and endocytotic vesicles for the fast anterograde and retrograde transport of proteins and other compounds needing an acidic environment. PMID- 20955688 TI - Segmental copy-number gain within the region of isopentenyl diphosphate isomerase genes in sporadic amyotrophic lateral sclerosis. AB - AIMS: Sporadic amyotrophic lateral sclerosis (SALS) seems to be a multifactorial disease, the pathogenesis of which may involve both genetic and environmental factors. The present study aims at identifying a possible genetic change that confers risk for SALS. METHODS: We performed whole-genome screening of a copy number variation (CNV) using a CNV beadchip, followed by real-time quantitative polymerase chain reaction (qPCR) and region-targeted high-density oligonucleotide tiling microarray. RESULTS: Within the 40-kb region on 10p15.3 subtelomere, which harbours two genes encoding isopentenyl diphosphate isomerase 1 (IDI1) and IDI2, we found a segmental copy-number gain in a large proportion of SALS patients. qPCR analysis demonstrated the copy-number gain in 46 out of 83 SALS patients, as compared with 10 out of 99 controls (p=4.86*10(-11), Odds Ratio 10.8); subsequent tiling microarray validated qPCR results and elucidated the fine structure of segmental gains. CONCLUSIONS: A segmental copy-number gain in the IDI1/IDI2 gene region may play a significant role in the pathogenesis of SALS. PMID- 20955689 TI - Anti-angiogenic effects of dietary isothiocyanates: mechanisms of action and implications for human health. AB - Isothiocyanates (ITCs) are electrophilic compounds derived from plants and are thought to play a major role in the potential chemopreventive effects associated with high intake of cruciferous vegetables. ITCs are also being evaluated for chemotherapeutic activity in early phase clinical trials. In addition to their effects on carcinogen metabolism and cancer cell survival and proliferation, ITCs have been shown to effectively interfere with angiogenesis in vitro and in vivo. Angiogenesis is the development of a new blood supply from existing vasculature and is required for tumours to develop beyond a small size limit determined by the diffusion limit for oxygen. Inhibition of angiogenesis may play a key role in the potential chemopreventive/chemotherapeutic activity of ITCs. In this review we highlight recent data demonstrating that ITCs have anti-angiogenic activity and identify potential molecular targets for these effects, including hypoxia inducible factor (HIF), nuclear factor kappaB (NF-kappaB), activator protein 1 (AP1) and tubulin. We also discuss these findings in light of the potential chemopreventive/chemotherapeutic effects of ITCs. PMID- 20955690 TI - Acetaminophen-induced stimulation of MDR1 expression and activity in rat intestine and in LS 174T human intestinal cell line. AB - The well-known analgesic and antipyretic drug N-acetyl-p-aminophenol (acetaminophen; APAP) has been previously reported to affect MDR1 expression in rat liver. In this study, we have investigated the effect of subtoxic doses of APAP on MDR1 expression and activity in rat intestine and human intestinal cells. Administration of APAP at increasing doses of 0.2, 0.3, and 0.6g/kg b.w., i.p. over three consecutive days, induced MDR1 expression in rat duodenum (+240%) and ileum (+160%) as detected by western blotting. This was accompanied by preserved localization of the protein at the surface of the villus, as detected by confocal immunofluorescence microscopy. MDR1 activity was increased by 50% in APAP treated rats, as evaluated by serosal to mucosal secretion of rhodamine 123 in everted intestinal sacs. Treatment with APAP also decreased by 65% the portal vein concentrations of digoxin found in anesthetized rats after intraduodenal administration of this drug, which is consistent with an APAP-induced increased efficacy of intestinal barrier for digoxin net absorption. Exposure of LS 174T human colon adenocarcinoma cells to subtoxic APAP concentration (5mM) induced an increase in MDR1 mRNA expression (+46%), which was accompanied with an enhanced ability (+78%) to reduce intracellular content of rhodamine 123. Taken together these data suggest the existence of APAP-induced stimulation of MDR1 transcription in the intestinal epithelium. These findings are of clinical relevance, as co-administration of APAP with other MDR1 substrates could indirectly inhibit the net intestinal absorption of these drugs, leading to changes in their pharmacokinetics and therapeutic efficacy. PMID- 20955691 TI - High polyphenol, low probiotic diet for weight loss because of intestinal microbiota interaction. AB - The relative proportion of Bacteroidetes to Firmicutes is decreased in obese people. This imbalance in gut microbiota generates signals controlling the expression of genes by the epithelial intestinal cells. Both dairy and non-dairy probiotics increase body weight, reportedly through Lactobacillus species growth in the gut. On the other hand, daily intake of some fruits and drinks such as three apples or three pears or grapefruit, or green tea, which all are rich in polyphenols, can significantly reduce body weight in obese people. Metabolism of polyphenols by microbiota involves the cleavage of glycosidic linkages. Glycans, which are the product of glycosidic cleavage, are necessary for survival of the intestinal microbiota as a nutrient foundation. There are two pivotal points: (i) Firmicutes possess a disproportionately smaller number of glycan-degrading enzymes than Bacteroidetes, (ii) Firmicutes are more repressed than the Bacteroidetes by phenolic compounds' antimicrobial properties. The Bacteroidetes community prevails following dietary polyphenol intake and its fermentation to phenolic compounds, due to having more glycan-degrading enzymes, so this may thus be a mechanism by which dietary polyphenols exert their weight lowering effect. I suggest that future studies utilize clone libraries and fingerprinting techniques enabling identification of the composition and community structure of the microbiota, and dot blot hybridization or fluorescent in situ hybridization to analyze abundance of particular taxa in obese and individuals. A supplementation with polyphenols with high bioavailability in obese individuals with higher Firmicutes/Bacteroides community ratio phenotype, when associated to a probiotic restricted diet, is proposed for weight loss; this hypothesis could have relevant implication in planning a successful dietary regimen and/or neutraceutical/pharmaceutical preparations for achieving and maintaining a normal body weight in obese individuals, especially including much more use of polyphenol-rich foodstuffs and/or polyphenol-rich syrups, and including low amounts of probiotic-rich foodstuffs like yogurt, soy yogurt, or as probiotic supplements. PMID- 20955692 TI - Oncoproteomics. AB - Researchers have long acknowledged that changes in genes or gene activity lead to cancer. However, it was difficult to understand the function of such specific genes and their interaction in communication networks and the roles played by their protein products in molecular pathways. Protein molecules have direct influences on the development of cancer as it fundamentally arises due to aberrant signaling pathways. Identifying and understanding these changes is the primary theme of cancer proteomics, also termed as oncoproteomics. The ultimate objective of oncoproteomics is to acclimatize proteomic technologies for regular use in clinical laboratories for the purpose of diagnostic and prognostic categorization of disease condition, as well as in assessing drug toxicity and efficiency. Information gained from such technologies may soon exert a spectacular change in cancer research and impact dramatically on the care of cancer patients. Investigations of tumor-specific proteomic profiles may also allow better understanding of tumor development and the identification of novel targets for cancer therapy. In this review, we have tried to offer a wide perspective on recent progresses in proteomic research strategies, their applications in the discovery of novel tumor markers and drug targets and their role in illustrating action mechanisms of biomarkers and anticancer drugs including drug resistance. PMID- 20955693 TI - Melting point equations for the ternary system water/sodium chloride/ethylene glycol revisited. AB - Partial phase diagrams are of considerable utility in the development of optimized cryobiological procedures. Recent theoretical predictions of the melting points of ternary solutions of interest to cryobiology have caused us to re-examine measurements that our group made for the ethylene-glycol-sodium chloride-water phase diagram. Here we revisit our previous experiments by measuring melting points at five ethylene-glycol to sodium chloride ratios (R values; R=5, 10, 15, 30, and 45) and five levels of concentration for each ratio. Melting points were averaged from three measurements and plotted as a function of total solute concentration for each R value studied. The new measurements differed from our original experimental values and agreed with predicted values from both theoretical models. Additionally, the data were fit to the polynomial described in our previous report and the resulting equation was obtained: T(m) = (38.3-2.145 x 10-1 R)w + (81.19 - 2.909*10-1 R)w2, where w is the total solute mass fraction. This new equation provided good fits to the experimental data as well as published values and relates the determined polynomial constants to the R value of the corresponding isopleths of the three dimensional phase diagram, allowing the liquids curve for any R value to be obtained. PMID- 20955694 TI - Pharmacological activation and genetic manipulation of cystathionine beta synthase alter circulating levels of homocysteine and hydrogen sulfide in mice. AB - Hydrogen sulfide (H(2)S) is a recently discovered gasotransmitter found in mammalian tissues and blood. Treatment with H(2)S donor molecules has shown promising results in preclinical models of inflammatory and cardiovascular diseases. Augmentation of H(2)S levels thus holds promise as a novel therapeutic approach for treatment of disease in man. Cystathionine beta-synthase (CBS) has been shown to catalyze H(2)S production in vitro. CBS enzyme activity is allosterically regulated by the endogenous activator S-adenosyl methionine. This mode of regulation suggests the possibility for designing a small molecule activator of CBS to enhance H(2)S production. This hypothesis, however, has not been directly tested in vivo. We show here that CBS contributes significantly to endogenous H(2)S production in mice: adenovirus mediated over expression of CBS in the liver significantly increased circulating levels of H(2)S, whereas CBS deficiency resulted in reduced levels. We demonstrate that CBS enzyme from endogenous sources can be activated by S-adenosyl methionine to a greater extent compared to recombinant enzyme, suggesting greater potential for activation than previously anticipated. Importantly, we show that circulating H(2)S levels are increased by pharmacological activation of CBS in vivo; i.e. in the presence of the endogenous activator. Together, our data demonstrate that CBS activity partially regulates endogenous H(2)S in mice, and suggest that pharmacological activation of CBS is a promising approach for enhancing endogenous production of H(2)S for the treatment of cardiovascular and other diseases. PMID- 20955695 TI - Activin A induces a non-fibrotic phenotype in smooth muscle cells in contrast to TGF-beta. AB - AIMS: Activin A and transforming growth factor-beta1 (TGF-beta1) belong to the same family of growth and differentiation factors that modulate vascular lesion formation in distinct ways, which we wish to understand mechanistically. METHODS AND RESULTS: We investigated the expression of cell-surface receptors and activation of Smads in human vascular smooth muscle cells (SMCs) and demonstrated that activin receptor-like kinase-1 (ALK-1), ALK-4, ALK-5 and endoglin are expressed in human SMCs. As expected, TGF-beta1 activates Smad1 and Smad2 in these cells. Interestingly, activin A also induces phosphorylation of both Smads, which has not been reported for Smad1 before. Transcriptome analyses of activin A and TGF-beta1 treated SMCs with subsequent Gene-Set Enrichment Analyses revealed that many downstream gene networks are induced by both factors. However, the effect of activin A on expression kinetics of individual genes is less pronounced than for TGF-beta1, which is explained by a more rapid dephosphorylation of Smads and p38-MAPK in response to activin A. Substantial differences in expression of fibronectin, alpha-V integrin and total extracellular collagen synthesis were observed. CONCLUSIONS: Genome-wide mRNA expression analyses clarify the distinct modulation of vascular lesion formation by activin A and TGF-beta1, most significantly because activin A is non-fibrotic. PMID- 20955696 TI - Intermediate monomer-dimer equilibrium structure of native ICAM-1: implication for enhanced cell adhesion. AB - Dimeric intercellular adhesion molecule-1 (ICAM-1) has been known to more efficiently mediate cell adhesion than monomeric ICAM-1. Here, we found that truncation of the intracellular domain of ICAM-1 significantly enhances surface dimerization based on the two criteria: 1) the binding degree of monomer-specific antibody CA-7 and 2) the ratio of dimer/monomer when a mutation (L42->C42) was introduced in the interface of domain 1. Mutation analysis revealed that the positively charged amino acids, including very membrane-proximal 505R, are essential for maintaining the structural transition between the monomer and dimer. Despite a strong dimer presentation, the ICAM-1 mutants lacking an intracellular domain (IC1DeltaCTD) or containing R to A substitution in position 505 (505R/A) supported a lower degree of cell adhesion than did wild-type ICAM-1. Collectively, these results demonstrate that the native structure of surface ICAM 1 is not a dimer, but is an intermediate monomer-dimer equilibrium structure by which the effectiveness of ICAM-1 can be fully achieved. PMID- 20955697 TI - The inhibitory effect of dexamethasone on platelet-derived growth factor-induced vascular smooth muscle cell migration through up-regulating PGC-1alpha expression. AB - Dexamethasone has been shown to inhibit vascular smooth muscle cell (VSMC) migration, which is required for preventing restenosis. However, the mechanism underlying effect of dexamethasone remains unknown. We have previously demonstrated that peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 alpha (PGC-1alpha) can inhibit VSMC migration and proliferation. Here, we investigated the role of PGC-1alpha in dexamethasone-reduced VSMC migration and explored the possible mechanism. We first examined PGC-1alpha expression in cultured rat aortic VSMCs. The results revealed that incubation of VSMCs with dexamethasone could significantly elevate PGC-1alpha mRNA expression. In contrast, platelet-derived growth factor (PDGF) decreased PGC-1alpha expression while stimulating VSMC migration. Mechanistic study showed that suppression of PGC-1alpha by small interfering RNA strongly abrogated the inhibitory effect of dexamethasone on VSMC migration, whereas overexpression of PGC-1alpha had the opposite effect. Furthermore, an analysis of MAPK signal pathways showed that dexamethasone inhibited ERK and p38 MAPK phosphorylation in VSMCs. Overexpression of PGC-1alpha decreased both basal and PDGF-induced p38 MAPK phosphorylation, but it had no effect on ERK phosphorylation. Finally, inhibition of PPARgamma activation by a PPARgamma antagonist GW9662 abolished the suppressive effects of PGC-1alpha on p38 MAPK phosphorylation and VSMC migration. These effects of PGC-1alpha were enhanced by a PPARgamma agonist troglitazone. Collectively, our data indicated for the first time that one of the anti-migrated mechanisms of dexamethasone is due to the induction of PGC-1alpha expression. PGC 1alpha suppresses PDGF-induced VSMC migration through PPARgamma coactivation and, consequently, p38 MAPK inhibition. PMID- 20955698 TI - Human mitochondrial transcription factor A is required for the segregation of mitochondrial DNA in cultured cells. AB - The segregation and transmission of the mitochondrial genome in humans are complicated processes but are particularly important for understanding the inheritance and clinical abnormalities of mitochondrial disorders. However, the molecular mechanism of the segregation of mitochondrial DNA (mtDNA) is largely unclear. In this study, we demonstrated that human mitochondrial transcription factor A (TFAM) is required for the segregation of mtDNA in cultured cells. RNAi mediated knockdown of TFAM in HeLa cells resulted in the enlarged mtDNA, as indicated by the assembly of fluorescent signals stained with PicoGreen. Fluorescent in situ hybridization confirmed the enlarged mtDNA and further showed the existence of increased numbers of mitochondria lacking mtDNA signals in TFAM knockdown cells. By complementation analysis, the C-terminal tail of TFAM, which enhances its affinity with DNA, was found to be required for the appropriate distribution of mtDNA. Furthermore, we found that TFAM knockdown induced asymmetric segregation of mtDNA between dividing daughter cells. These results suggest an essential role for human TFAM in symmetric segregation of mtDNA. PMID- 20955700 TI - Retinal ganglion cell numbers and delayed retinal ganglion cell death in the P23H rat retina. AB - The P23H-1 rat strain carries a rhodopsin mutation frequently found in retinitis pigmentosa patients. We investigated the progressive degeneration of the inner retina in this strain, focussing on retinal ganglion cells (RGCs) fate. Our data show that photoreceptor death commences in the ventral retina, spreading to the whole retina as the rat ages. Quantification of the total number of RGCs identified by Fluorogold tracing and Brn3a expression, disclosed that the population of RGCs in young P23H rats is significantly smaller than in its homologous SD strain. In the mutant strain, there is also RGC loss with age: RGCs show their first symptoms of degeneration at P180, as revealed by an abnormal expression of cytoskeletal proteins which, at P365, translates into a significant loss of RGCs, that may ultimately be caused by displaced inner retinal vessels that drag and strangulate their axons. RGC axonal compression begins also in the ventral retina and spreads from there causing RGC loss through the whole retinal surface. These decaying processes are common to several models of photoreceptor loss, but show some differences between inherited and light-induced photoreceptor degeneration and should therefore be studied to a better understanding of photoreceptor degeneration and when developing therapies for these diseases. PMID- 20955699 TI - Induction of murine embryonic stem cell differentiation by medicinal plant extracts. AB - Epidemiological evidence indicates that diets high in fruits and vegetables provide a measure of cancer chemoprevention due to phytochemical constituents. Natural products are a rich source of cancer chemotherapy drugs, and primarily target rapidly cycling tumor cells. Increasing evidence indicates that many cancers contain small populations of resistant, stem-like cells that have the capacity to regenerate tumors following chemotherapy and radiation, and have been linked to the initiation of metastases. Our goal is to discover natural product based clinical or dietary interventions that selectively target cancer stem cells, inducing differentiation. We adapted an alkaline phosphatase (AP) stain to assay plant extracts for the capacity to induce differentiation in embryonic stem (ES) cells. AP is a characteristic marker of undifferentiated ES cells, and this represents a novel approach to screening medicinal plant extracts. Following a survey of approximately 100 fractions obtained from 12 species of ethnomedically utilized plants, we found fractions from 3 species that induced differentiation, decreasing AP and transcript levels of pluripotency markers (Nanog, Oct-4, Rex 1). These fractions affected proliferation of murine ES, and human embryonal, prostate, and breast carcinoma cells in a dose-dependent manner. Several phytochemical constituents were isolated; the antioxidant phytochemicals ellagic acid and gallic acid were shown to affect viability of cultured breast carcinoma cells. PMID- 20955701 TI - Bone marrow stromal cell transplants prevent experimental enterocolitis and require host CD11b+ splenocytes. AB - BACKGROUND & AIMS: Bone marrow stromal cells (MSCs) are being evaluated as a cellular therapeutic for immune-mediated diseases. We investigated the effects of MSCs in mice with chemically induced colitis and determined the effects of CD11b(+) cells based on the hypothesis that MSCs increase numbers of regulatory T cells. METHODS: Colitis was induced in mice using trinitrobenzene sulfonic acid; symptoms were monitored as a function of MSC delivery. An immunomodulatory response was determined by measuring numbers of regulatory T cells in mesenteric lymph nodes. In vitro cocultures were used to assess the interaction of MSCs with regulatory T cells and CD11b(+) cells; findings were supported using near infrared tracking of MSCs in vivo. We chemically and surgically depleted splenic CD11b(+) cells before colitis was induced with trinitrobenzene sulfonic acid to monitor the effects of MSCs. We adoptively transferred CD11b(+) cells that were cocultured with MSCs into mice with colitis. RESULTS: Intravenous grafts of MSCs prevented colitis and increased survival times of mice. Numbers of Foxp3(+) regulatory T cells increased in mesenteric lymph nodes in mice given MSCs. MSCs increased the numbers of Foxp3(+) splenocytes in a CD11b(+) cell-dependent manner. Transplanted MSCs colocalized near splenic CD11b(+) cells in vivo. Loss of CD11b(+) cells eliminated the therapeutic effect of MSCs. MSCs increased the anticolitis effects of CD11b(+) cells in mice. CONCLUSIONS: MSC transplants, delivered by specific parameters, reduce colitis in mice. Interactions between MSC and CD11b(+) regulatory T cells might be used to develop potency assays for MSCs, to identify nonresponders to MSC therapy, and to create new cell grafts that are composed of CD11b(+) cells preconditioned by MSCs. PMID- 20955702 TI - Antireflux action of Nissen fundoplication and stretch-sensitive mechanism of lower esophageal sphincter relaxation. AB - BACKGROUND & AIMS: Surgical fundoplication is an effective treatment for gastroesophageal reflux disease. One of the proposed mechanisms for its antireflux action is that it reduces lower esophageal sphincter (LES) relaxation. We investigated whether fundoplication works through a stretch-sensitive mechanism of LES relaxation. METHODS: Studies were performed in rats. Intravenous and arterial lines were placed and tracheal intubation was performed. A midline laprotomy was performed to place sutures through the esophagus to exert axial stretch on the LES, and the vagus nerve was isolated in the neck for electrical stimulation. The LES pressure was monitored with a 2F solid-state pressure transducer placed through a gastrostomy. Cranial displacement of the LES was recorded using piezoelectric crystals. Data were recorded before and after 360 degree Nissen fundoplication. RESULTS: Axial stretch and vagus nerve stimulation induced cranial displacement of the LES as well as LES relaxation in a dose dependent manner. LES relaxation and axial stretch were each significantly reduced after fundoplication (P < .01). Nitric-oxide-induced LES relaxation was not affected by fundoplication. Removal of fundoplication restored axial stretch- and vagus nerve-stimulated LES relaxation as well as LES cranial displacement. CONCLUSIONS: Fundoplication reduces LES relaxation by interfering with axial stretch on the LES. Based on this mechanism of the antireflux actions of fundoplication, it might be possible to design new surgical strategies to treat reflux disease and reduce complications of fundoplication surgery. PMID- 20955703 TI - The G-protein-coupled receptor GPR40 directly mediates long-chain fatty acid induced secretion of cholecystokinin. AB - BACKGROUND & AIMS: Long-chain fatty acid receptors G-protein-coupled receptor 40 (GPR40) (FFAR1) and GPR120 have been implicated in the chemosensation of dietary fats. I cells in the intestine secrete cholecystokinin (CCK), a peptide hormone that stimulates digestion of fat and protein, but these cells are rare and hard to identify. We sought to determine whether dietary fat-induced secretion of CCK is directly mediated by GPR40 expressed on I cells. METHODS: We used fluorescence activated cell sorting to isolate a pure population of I cells from duodenal mucosa in transgenic mice that expressed green fluorescent protein under the control of the CCK promoter (CCK-enhanced green fluorescent protein [eGFP] bacterial artificial chromosome mice). CCK-eGFP cells were evaluated for GPR40 expression by quantitative reverse transcription polymerase chain reaction and immunostaining. GPR40(-/-) mice were bred with CCK-eGFP mice to evaluate functional relevance of GPR40 on long-chain fatty acid-stimulated increases in [Ca(2+)]i and CCK secretion in isolated CCK-eGFP cells. Plasma levels of CCK after olive oil gavage were compared between GPR40(+/+) and GPR40(-/-) mice. RESULTS: Cells that expressed eGFP also expressed GPR40; expression of GPR40 was 100-fold greater than that of cells that did not express eGFP. In vitro, linoleic, oleic, and linolenic acids increased [Ca(2+)]i; linolenic acid increased CCK secretion by 53% in isolated GPR40(+/+) cells that expressed eGFP. In contrast, in GPR40(-/-) that expressed eGFP, [Ca(2+)]i response to linoleic acid was reduced by 50% and there was no significant CCK secretion in response to linolenic acid. In mice, olive oil gavage significantly increased plasma levels of CCK compared with pregavage levels: 5.7-fold in GPR40(+/+) mice and 3.1-fold in GPR40(-/-) mice. CONCLUSIONS: Long-chain fatty acid receptor GPR40 induces secretion of CCK by I cells in response to dietary fat. PMID- 20955704 TI - Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. AB - BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF), a nucleotide analogue and potent inhibitor of hepatitis B virus (HBV) polymerase, showed superior efficacy to adefovir dipivoxil in treatment of chronic hepatitis B through 48 weeks. We evaluated long-term efficacy and safety of TDF monotherapy in patients with chronic hepatitis B who were positive or negative for hepatitis B e antigen (HBeAg(+) or HBeAg(-)). METHODS: After 48 weeks of double-blind comparison of TDF to adefovir dipivoxil, patients who underwent liver biopsy were eligible to continue the study on open-label TDF for 7 additional years; data presented were collected up to 3 years (week 144) from 85% of participants. Primary efficacy end points at week 144 included levels of HBV DNA and alanine aminotransferase, development of resistance mutations, and presence of HBeAg or hepatitis B surface antigen (HBsAg). RESULTS: At week 144, 87% of HBeAg(-) and 72% of HBeAg(+) patients treated with TDF had levels of HBV DNA <400 copies/mL. Among patients who had previously received adefovir dipivoxil and then received TDF, 88% of the HBeAg(-) and 71% of the HBeAg(+) patients had levels of HBV DNA <400 copies/mL; overall, 81% and 74%, respectively, maintained normalized levels of alanine aminotransferase and 34% had lost HBeAg. Amino acid substitutions in HBV DNA polymerase that are associated with resistance to tenofovir were not detected in any patient. Cumulatively, 8% of HBeAg(+) patients lost HBsAg. TDF maintained a favorable safety profile for up to 3 years. CONCLUSIONS: TDF was safe and effective in the long-term management of HBeAg(+) and HBeAg(-) patients with chronic hepatitis B. PMID- 20955705 TI - Assessment of tumor development and wound healing using endoscopic techniques in mice. AB - Mouse models of intestinal inflammation and colon cancer are valuable tools to gain insights into the pathogenesis of the corresponding human diseases. Recently, in vivo mouse endoscopy has been developed, allowing not only the high resolution monitoring and scoring of experimental disease development, but also enables the investigator to perform manipulations, including local injection of reagents or the taking of biopsies for molecular and histopathologic analyses. Chromoendoscopic staining with methylene blue enables visualization of the crypt structure and allows discrimination between inflammatory and neoplastic changes. The development of endoscopic techniques in live mice opened new options for the investigation of disease mechanisms in the gut and for the preclinical testing of potential therapeutic effects of drug candidates. Finally, mouse endoscopy can help to reduce animal numbers needed to gain significant experimental data. PMID- 20955706 TI - Anti-tumor necrosis factor-alpha antibodies induce regulatory macrophages in an Fc region-dependent manner. AB - BACKGROUND & AIMS: Anti-tumor necrosis factor (TNF)alpha antibodies are effective in treating patients with Crohn's disease whereas soluble TNFalpha receptors have not shown clinical efficacy; the mechanism that underlies these different effects is not clear. We examined the immunosuppressive effects of different anti TNFalpha reagents on activated T cells. METHODS: We studied the effects of anti TNFalpha antibodies infliximab and adalimumab, the soluble TNFalpha receptor etanercept, the pegylated F(ab') fragment certolizumab, and certolizumab immunoglobulin (Ig)G on primary activated T cells. T cells were grown in isolation or in a mixed lymphocyte reaction (MLR). Proliferation was measured by (3)H thymidine incorporation and apoptosis was examined using Annexin V labeling and a colorimetric assay for activated caspase-3. Macrophage phenotypes were assayed by flow cytometry and cytokine secretion. RESULTS: Infliximab and adalimumab reduced T-cell proliferation in an MLR whereas etanercept and certolizumab did not; this effect was lost after Fc receptors were blocked. The infliximab F(ab')2 fragment did not inhibit proliferation whereas certolizumab IgG did inhibit proliferation. In the MLR, the antibodies against TNF induced formation of a new population of macrophages in an Fc region-dependent manner; these macrophages had an immunosuppressive phenotype because they inhibit proliferation of activated T cells, produce anti-inflammatory cytokines, and express the regulatory macrophage marker CD206. CONCLUSIONS: Regulatory macrophages have immunosuppressive properties and an important role in wound healing. Antibodies against TNF induce regulatory macrophages in an Fc region dependent manner. These functions of anti-TNFs might contribute to the resolution of inflammation. PMID- 20955707 TI - Bone disease in patients with primary sclerosing cholangitis. AB - BACKGROUND & AIMS: Osteopenic bone disease occurs frequently among patients with chronic liver disease but has not been well studied in those with primary sclerosing cholangitis (PSC). We investigated the prevalence, rate of progression, and independent predictors of bone disease in a large number of patients with all stages of PSC. METHODS: Bone mineral density of the lumbar spine, hip, and total body was measured yearly for 10 years in 237 patients with PSC. RESULTS: Osteoporosis (T-score less than -2.5) was found in 15% of patients and occurred 23.8-fold (95% confidence interval [CI], 4.6-122.8) more frequently in those with PSC than expected from a matched population. By multivariate analysis, age 54 years or older (odds ratio [OR], 7.8; 95% CI, 3.3-18.3), body mass index <= 24 kg/m(2) (OR, 4.9; 95% CI, 1.9-12.6), and inflammatory bowel disease for >= 19 years (OR, 3.6; 95% CI, 1.5-8.4) correlated with the presence of osteoporosis. Osteoporosis was present in 75% of patients with all 3 risk factors but in only 3.1% of those without all of them. Patients with PSC lost 1% of bone mass per year; this rate of bone loss was significantly associated with duration of inflammatory bowel disease. CONCLUSIONS: Osteoporosis occurs frequently among patients with PSC. Old age, low body mass index, and long duration of inflammatory bowel disease can be used to identify patients with PSC who might derive the most benefit from measurements of bone density and treatments for bone diseases. PMID- 20955708 TI - CXCL17 and ICAM2 are associated with a potential anti-tumor immune response in early intraepithelial stages of human pancreatic carcinogenesis. AB - BACKGROUND & AIMS: Anti-tumor immunity changes over the course of tumor progression; it is not clear how or when the developing tumor overcomes immune surveillance. Intraductal papillary mucinous neoplasm (IPMN) is an intraepithelial precursor lesion of pancreatic cancer that progresses from adenoma to carcinoma. We investigated when and how the human anti-tumor immune reaction changes during pancreatic tumor development. METHODS: Using immunohistochemical analysis of cells isolated from patients with IPMN, the numbers of tumor-infiltrating lymphocytes and dendritic cells and the maturation state of dendritic cells in the regional lymph nodes were investigated during tumor progression. Gene expression profiles were compared among epithelial neoplastic cells at each stage of tumor development. Biological functions of the selected gene products were analyzed using syngeneic mouse models. RESULTS: The anti-tumor immune reaction changed from an immune response to immune tolerance between the stages of intraductal papillary mucinous adenoma (IPMA) and intraductal papillary mucinous carcinoma (IPMC). Chemokine (C-X-C motif) ligand 17 (CXCL17) and intercellular adhesion molecule 2 (ICAM2) were involved in immune surveillance during tumor development-their expression levels were up-regulated exclusively in IPMA and disappeared from IPMC. CXCL17 and ICAM2 induced infiltration and accumulation of the tumor epithelial layer by immature myeloid dendritic cells. This was followed by a cellular immune reaction and ICAM2 simultaneously promoted the susceptibility of the tumor cells to cytotoxic T-cell mediated cytolysis. These processes had a synergistic effect to increase the anti tumor immune response. CONCLUSIONS: Immune surveillance occurs during the early intraepithelial stages of human pancreatic carcinogenesis and is mediated by expression of CXCL17 and ICAM2. PMID- 20955710 TI - Sexual dimorphism in the brain aromatase expression and activity, and in the central expression of other steroidogenic enzymes during the period of sex differentiation in monosex rainbow trout populations. AB - Using genetic monosex male and female rainbow trout populations, the potential sex differences in the central expression of estrogen receptors (esr1, esr2a, esr2b), brain aromatase (cyp19a1b) and some other steroidogenic enzymes was studied over the period of sex differentiation (from 35 to 63 dpf: days post fertilization) using quantitative polymerase chain reaction (q-PCR). In addition, aromatase activity was evaluated during this period. The results indicated that brain aromatase (cyp19a1b) expression and activity showed a clear and significant sexually dimorphic pattern with higher levels in male brain between 35 and 53 dpf before the time of gonad morphological differentiation. At that time the expression of a key enzyme involved in the conversion of cholesterol into steroids, the cyp11a1 (p450scc), as well as the estrogen receptors were also sexually dimorphic. The dimorphism was lost from 56 dpf onwards. Transcription factors such as nr5a1b (sf1) and nr0b1 (dax1), but not foxl2a were also higher in males than in females. These results demonstrate that, before or during the early period of morphological gonad differentiation, the brain exhibits a clear sexual dimorphism with respect to the expression and activity of aromatase as well as of certain enzymes and factors involved in steroid synthesis as p450scc and sf1. The results suggest a higher potentiality to produce estrogens by male brains during sex differentiation time. PMID- 20955709 TI - Intraovarian expression of GnRH-1 and gonadotropin mRNA and protein levels in Siberian hamsters during the estrus cycle and photoperiod induced regression/recrudescence. AB - The hypothalamic-pituitary-gonadal (HPG) axis is the key reproductive regulator in vertebrates. While gonadotropin releasing hormone (GnRH), follicle stimulating (FSH), and luteinizing (LH) hormones are primarily produced in the hypothalamus and pituitary, they can be synthesized in the gonads, suggesting an intraovarian GnRH-gonadotropin axis. Because these hormones are critical for follicle maturation and steroidogenesis, we hypothesized that this intraovarian axis may be important in photoperiod-induced ovarian regression/recrudescence in seasonal breeders. Thus, we investigated GnRH-1 and gonadotropin mRNA and protein expression in Siberian hamster ovaries during (1) the estrous cycle; where ovaries from cycling long day hamsters (LD;16L:8D) were collected at proestrus, estrus, diestrus I, and diestrus II and (2) during photoperiod induced regression/recrudescence; where ovaries were collected from hamsters exposed to 14 weeks of LD, short days (SD;8L:16D), or 8 weeks post-transfer to LD after 14 weeks SD (PT). GnRH-1, LHbeta, FSHbeta, and common alpha subunit mRNA expression was observed in cycling ovaries. GnRH-1 expression peaked at diestrus I compared to other stages (p < 0.05). FSHbeta and LHbeta mRNA levels peaked at proestrus and diestrus I (p < 0.05), with no change in the alpha subunit across the cycle (p > 0.05). SD exposure decreased ovarian mass and plasma estradiol concentrations (p<0.05) and increased GnRH-1, LHbeta, FSHbeta, and alpha subunit mRNA expression as compared to LD and, except for LH, compared to PT (p < 0.05). GnRH and gonadotropin protein was also dynamically expressed across the estrous cycle and photoperiod exposure. The presence of cycling intraovarian GnRH-1 and gonadotropin mRNA suggests that these hormones may be locally involved in ovarian maintenance during SD regression and/or could potentially serve to prime ovaries for rapid recrudescence. PMID- 20955711 TI - Cloning and sequence analysis of a vasa homolog in the European sea bass (Dicentrarchus labrax): tissue distribution and mRNA expression levels during early development and sex differentiation. AB - Vasa is a protein expressed mainly in germ cells and conserved across taxa. However, sex-related differences and environmental influences on vasa expression have not been documented. This study characterized the cDNA of a vasa homolog in the European sea bass, Dicentrarchuslabrax (sb-vasa), a gonochoristic fish with temperature influences on gonadogenesis. The 1911 bp open reading frame predicted a 637-amino acid protein with the eight conserved domains typical of Vasa proteins. Comparisons of the deduced amino acid sequence with those of other vertebrates and invertebrates revealed the highest homology (68-85%) with those of other teleosts. An updated tree with the full-length sequences for Vasa proteins in 66 species belonging to six different phyla was constructed, establishing the evolutionary relationships of Vasa amino acid sequences. European sea bass vasa was highly expressed in gonads with little or no expression in other tissues. Real time RT-PCR quantification of the temporal expression of sb-vasa from early development throughout sex differentiation showed that mRNA levels were high in unfertilized eggs, decreased during larval development and increased again during the period of germ cell proliferation. Rearing of fish at high temperature resulted in further increased sb-vasa levels, most likely reflecting temperature effects on both somatic and gonadal growth. Differences in expression were also found well before sex differentiation and persisted until the end of the first year, with higher levels present in females. These differences in expression demonstrate the implication of vasa during the initial stages of fish sex differentiation and gametogenesis and suggest that, through its helicase activity, it might be implicated in the translational regulation of mRNAs involved in the specification and differentiation of gonadal specific cell types. PMID- 20955712 TI - Epigenetic methodologies for behavioral scientists. AB - Hormones are essential regulators of many behaviors. Steroids bind either to nuclear or membrane receptors while peptides primarily act via membrane receptors. After a ligand binds, the conformational change in the receptor initiates changes in cell signaling cascades (membrane receptors) or direct alternations in DNA transcription (steroid receptors). Changes in gene transcription that result are responsible for protein production and ultimately behavioral modifications. A significant part of how hormones affect DNA transcription is via epigenetic modifications of DNA and/or the chromatin in which it is entwined. These alterations lead to transcriptional changes that ultimately define the phenotype and function of a given cell. Importantly we now know that environmental stimuli influence epigenetic marks, which in the context of neuroendocrinology can lead to behavioral changes. Importantly tracking epigenetic states and profiling the epigenome within cells require the use of epigenetic methodologies and subsequent data analysis. Here we describe the techniques of particular importance in the mapping of DNA methylation, histone modifications and occupancy of chromatin bound effector proteins that regulate gene expression. For researchers wanting to move into these levels of analysis we discuss the application of modern sequencing technologies applied in assays such as chromatin immunoprecipitation and the bioinformatics analysis involved in the rich datasets generated. PMID- 20955713 TI - Application of recombinant thioredoxin1 for treatment of heart disease. AB - Thioredoxin 1 (Trx1) is a small molecule with reactive cysteines that reduces proteins with disulfide bonds through a thiol disulfide exchange reaction. Accumulating lines of evidence suggest that Trx1 protects the heart from ischemia/reperfusion injury, pathological hypertrophy, and inflammation; induces preconditioning effects and angiogenesis; and upregulates mitochondrial genes. Exogenously given recombinant Trx1 (r-Trx1) may protect the heart through its actions in both extracellular and intracellular spaces. In this brief review, the potential of Trx1 therapy for heart disease is discussed. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure." PMID- 20955714 TI - Multiple global suppressors of protein stability defects facilitate the evolution of extended-spectrum TEM beta-lactamases. AB - The introduction of extended-spectrum cephalosporins and beta-lactamase inhibitors has driven the evolution of extended-spectrum beta-lactamases (ESBLs) that possess the ability to hydrolyze these drugs. The evolved TEM ESBLs from clinical isolates of bacteria often contain substitutions that occur in the active site and alter the catalytic properties of the enzyme to provide an increased hydrolysis of extended-spectrum cephalosporins or an increased resistance to inhibitors. These active-site substitutions often result in a cost in the form of reduced enzyme stability. The evolution of TEM ESBLs is facilitated by mutations that act as global suppressors of protein stability defects in that they allow the enzyme to absorb multiple amino acid changes despite incremental losses in stability associated with the substitutions. The best-studied example is the M182T substitution, which corrects protein stability defects and is commonly found in TEM ESBLs or inhibitor-resistant variants from clinical isolates. In this study, a genetic selection for second-site mutations that could partially restore function to a severely destabilized primary mutant enabled the identification of A184V, T265M, R275Q, and N276D, which are known to occur in TEM ESBLs from clinical isolates, as suppressors of TEM-1 protein stability defects. Further characterization demonstrated that these substitutions increased the thermal stability of TEM-1 and were able to correct the stability defects of two different sets of destabilizing mutations. The acquisition of compensatory global suppressors of stability costs associated with active-site mutations may be a common mechanism for the evolution of novel protein function. PMID- 20955715 TI - Model for comparative analysis of antigen receptor repertoires. AB - In modern molecular biology one of the standard ways of analyzing a vertebrate immune system is to sequence and compare the counts of specific antigen receptor clones (either immunoglobulins or T-cell receptors) derived from various tissues under different experimental or clinical conditions. The resulting statistical challenges are difficult and do not fit readily into the standard statistical framework of contingency tables primarily due to the serious under-sampling of the receptor populations. This under-sampling is caused, on one hand, by the extreme diversity of antigen receptor repertoires maintained by the immune system and, on the other, by the high cost and labor intensity of the receptor data collection process. In most of the recent immunological literature the differences across antigen receptor populations are examined via non-parametric statistical measures of the species overlap and diversity borrowed from ecological studies. While this approach is robust in a wide range of situations, it seems to provide little insight into the underlying clonal size distribution and the overall mechanism differentiating the receptor populations. As a possible alternative, the current paper presents a parametric method that adjusts for the data under-sampling as well as provides a unifying approach to a simultaneous comparison of multiple receptor groups by means of the modern statistical tools of unsupervised learning. The parametric model is based on a flexible multivariate Poisson-lognormal distribution and is seen to be a natural generalization of the univariate Poisson-lognormal models used in the ecological studies of biodiversity patterns. The procedure for evaluating a model's fit is described along with the public domain software developed to perform the necessary diagnostics. The model-driven analysis is seen to compare favorably vis a vis traditional methods when applied to the data from T-cell receptors in transgenic mice populations. PMID- 20955716 TI - Stability of the genetic code and optimal parameters of amino acids. AB - The standard genetic code is known to be much more efficient in minimizing adverse effects of misreading errors and one-point mutations in comparison with a random code having the same structure, i.e. the same number of codons coding for each particular amino acid. We study the inverse problem, how the code structure affects the optimal physico-chemical parameters of amino acids ensuring the highest stability of the genetic code. It is shown that the choice of two or more amino acids with given properties determines unambiguously all the others. In this sense the code structure determines strictly the optimal parameters of amino acids or the corresponding scales may be derived directly from the genetic code. In the code with the structure of the standard genetic code the resulting values for hydrophobicity obtained in the scheme "leave one out" and in the scheme with fixed maximum and minimum parameters correlate significantly with the natural scale. The comparison of the optimal and natural parameters allows assessing relative impact of physico-chemical and error-minimization factors during evolution of the genetic code. As the resulting optimal scale depends on the choice of amino acids with given parameters, the technique can also be applied to testing various scenarios of the code evolution with increasing number of codified amino acids. Our results indicate the co-evolution of the genetic code and physico-chemical properties of recruited amino acids. PMID- 20955717 TI - Comparison of active transport in neuronal axons and dendrites. AB - This paper presents a theoretical study, based on modified Smith-Simmons equations, that compares transport of intracellular organelles in two different neurite outgrowths, dendrites and axons. It is demonstrated that the difference in microtubule polarity orientations in dendrites and axons has significant implications on motor-assisted transport in these neurite outgrowths. The developed approach presents a qualitative theoretical basis for understanding important questions such as why axons exhibit almost an unlimited grows potential in vitro while dendrites remain relatively short. It is shown that the difference in a microtubule polarity arrangement between axons and dendrites may be a regulatory mechanism for limiting dendritic growth. Other biological implications of the developed theory as well as other possible reasons for the difference in microtubule structure between axons and dendrites are discussed. PMID- 20955718 TI - Electrical stimulation of the lateral habenula produces an inhibitory effect on sucrose self-administration. AB - The lateral habenula (LHb) plays a role in prediction of negative reinforcement, punishment and aversive responses. In the current study, we examined the role that the LHb plays in regulation of negative reward responses and aversion. First, we tested the effect of intervention in LHb activity on sucrose reinforcing behavior. An electrode was implanted into the LHb and rats were trained to self-administer sucrose (20%; 16 days) until at least three days of stable performance were achieved (as represented by the number of active lever presses in self-administration cages). Rats subsequently received deep brain stimulation (DBS) of the LHb, which significantly reduced sucrose self administration levels. In contrast, lesion of the LHb increased sucrose-seeking behavior, as demonstrated by a delayed extinction response to substitution of sucrose with water. Furthermore, in a modified non-rewarding conditioned-place preference paradigm, DBS of the LHb led to aversion to the context associated with stimulation of this brain region. We postulate that electrical stimulation of the LHb attenuates positive reward-associated reinforcement by natural substances. PMID- 20955719 TI - The 4-aminopyridine in vitro epilepsy model analyzed with a perforated multi electrode array. AB - Epileptiform discharges recorded in the 4-aminopyridine (4-AP) in vitro epilepsy model are mediated by glutamatergic and GABAergic signaling. Using a 60-channel perforated multi-electrode array (pMEA) on corticohippocampal slices from 2 to 3 week old mice we recorded interictal- and ictal-like events. When glutamatergic transmission was blocked, interictal-like events no longer initiated in the hilus or CA3/CA1 pyramidal layers but originated from the dentate gyrus granule and molecular layers. Furthermore, frequencies of interictal-like events were reduced and durations were increased in these regions while cortical discharges were completely blocked. Following GABA(A) receptor blockade interictal-like events no longer propagated to the dentate gyrus while their frequency in CA3 increased; in addition, ictal-like cortical events became shorter while increasing in frequency. Lastly, drugs that affect tonic and synaptic GABAergic conductance modulated the frequency, duration, initiation and propagation of interictal-like events. These findings confirm and expand on previous studies indicating that multiple synaptic mechanisms contribute to synchronize neuronal network activity in forebrain structures. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 20955720 TI - Quantification of the Mg2+-induced potency shift of amantadine and memantine voltage-dependent block in human recombinant GluN1/GluN2A NMDARs. AB - Clinically, amantadine and memantine are drugs whose therapeutic utility is linked to their ability to block N-methyl-D-aspartate receptors (NMDARs) in a voltage-dependent manner. Nevertheless many studies that have characterized the pharmacological actions of amantadine and memantine have done so in the absence of physiological levels of Mg(2+) ions. This study quantifies the extent to which Mg(2+) alters the potency of the block produced by both amantadine and memantine at human recombinant GluN1/GluN2A NMDARs. Human recombinant GluN1/GluN2A NMDARs were expressed in Xenopus laevis oocytes and two-electrode voltage-clamp recordings were made at -80, -60 and -40 mV to quantify amantadine and memantine block in the absence and presence of Mg(2+). Amantadine and memantine blocked human GluN1/GluN2A NMDARs in a voltage-dependent manner with IC(50) values (at 80 mV) of 49 +/- 6 MUM (n = 7) and 1.0 +/- 0.3 MUM (n = 7), respectively. In the presence of Mg(2+) (1mM) the equivalent IC(50) values were 165 +/- 10 MUM (n=6) and 6.6 +/- 0.3 MUM (n = 5). Similarly in the presence of amantadine or memantine the potency of Mg(2+) in blocking GluN1/GluN2A NMDARs was reduced. The decrease in the potencies of both amantadine and memantine in the presence of physiological concentrations of Mg(2+) indicates that other targets (e.g. alpha7 nicotinic acetylcholine receptors and 5-HT(3) receptors) in addition to NMDARs may well be sites of the therapeutic action of these channel blockers. PMID- 20955721 TI - Patients with schizophrenia are biased toward low spatial frequency to decode facial expression at a glance. AB - Whereas patients with schizophrenia exhibit early visual processing impairments, their capacity at integrating visual information at various spatial scales, from low to high spatial frequencies, remains untested. This question is particularly acute given that, in ecological conditions of viewing, spatial frequency bands are naturally integrated to form a coherent percept. Here, 19 patients with schizophrenia and 16 healthy controls performed a rapid emotion recognition task with hybrid faces. Because these stimuli displayed in a single image two different facial expressions, in low (LSF) and high (HSF) spatial frequencies, the selected emotion probes which spatial scale is preferentially perceived. In a control experiment participants performed the same task with either low or high spatial frequency filtered faces. Results show that patients have a strong bias towards LSF with hybrid faces compared to healthy controls. However, both patients and healthy controls performed better with HSF filtered faces than with LSF filtered faces in the control experiment, demonstrating that the bias found with hybrid stimuli in patients was not due to an inability to process HSF. Whereas previous works found a LSF contrast deficit in schizophrenia, our results suggest a deficit in the normal time course of concurrently perceiving LSF and HSF. This early visual processing impairment is likely to contribute to the difficulties of patients with schizophrenia with facial processing and therefore social interaction. PMID- 20955722 TI - Identification of characteristic molecular signature for volatile organic compounds in peripheral blood of rat. AB - In a previous report we demonstrated that the transcriptomic response of liver tissue was specific to toxicants, and a characteristic molecular signature could be used as an early prognostic biomarker in rats. It is necessary to determine the transcriptomic response to toxicants in peripheral blood for application to the human system. Volatile organic compounds (VOCs) comprise a major group of pollutants which significantly affect the chemistry of the atmosphere and human health. In this study we identified and validated the specific molecular signatures of toxicants in rat whole blood as early predictors of environmental toxicants. VOCs (dichloromethane, ethylbenzene, and trichloroethylene) were administered to 11-week-old SD male rats after 48h of exposure, peripheral whole blood was subjected to expression profiling analysis. Unsupervised gene expression analysis resulted in a characteristic molecular signature for each toxicant, and supervised analysis identified 1,217 outlier genes as distinct molecular signatures discerning VOC exposure from healthy controls. Further analysis of multi-classification suggested 337 genes as early detective molecular markers for three VOCs with 100% accuracy. A large-scale gene expression analysis of a different VOC exposure animal model suggested that characteristic expression profiles exist in blood cells and multi-classification of this VOC-specific molecular signature can discriminate each toxicant at an early exposure time. This blood expression signature can thus be used as discernable surrogate marker for detection of biological responses to VOC exposure in an environment. PMID- 20955723 TI - EU framework 6 project: predictive toxicology (PredTox)--overview and outcome. AB - In this publication, we report the outcome of the integrated EU Framework 6 PROJECT: Predictive Toxicology (PredTox), including methodological aspects and overall conclusions. Specific details including data analysis and interpretation are reported in separate articles in this issue. The project, partly funded by the EU, was carried out by a consortium of 15 pharmaceutical companies, 2 SMEs, and 3 universities. The effects of 16 test compounds were characterized using conventional toxicological parameters and "omics" technologies. The three major observed toxicities, liver hypertrophy, bile duct necrosis and/or cholestasis, and kidney proximal tubular damage were analyzed in detail. The combined approach of "omics" and conventional toxicology proved a useful tool for mechanistic investigations and the identification of putative biomarkers. In our hands and in combination with histopathological assessment, target organ transcriptomics was the most prolific approach for the generation of mechanistic hypotheses. Proteomics approaches were relatively time-consuming and required careful standardization. NMR-based metabolomics detected metabolite changes accompanying histopathological findings, providing limited additional mechanistic information. Conversely, targeted metabolite profiling with LC/GC-MS was very useful for the investigation of bile duct necrosis/cholestasis. In general, both proteomics and metabolomics were supportive of other findings. Thus, the outcome of this program indicates that "omics" technologies can help toxicologists to make better informed decisions during exploratory toxicological studies. The data support that hypothesis on mode of action and discovery of putative biomarkers are tangible outcomes of integrated "omics" analysis. Qualification of biomarkers remains challenging, in particular in terms of identification, mechanistic anchoring, appropriate specificity, and sensitivity. PMID- 20955724 TI - Phytotoxicity of fusaric acid and analogs to cotton. AB - We developed a cotton cotyledonary leaf bioassay to test the phytotoxicity of fusaric acid (5-butylpicolinic acid), picolinic acid and related analogs. The compounds were dissolved in aqueous Tween 80, and 20 MUL of the test solution was placed at three positions on the leaf, and a needle was used to puncture the leaf through each drop; the results were evaluated after 48 h. In contrast to previous studies, we found the carboxylic acid group is essential for phytotoxicity. Nicotinic acid was considerably less phytotoxic than picolinic acid and conversion of picolinic acid to the amide or N-oxide decreased phytotoxicity. Increasing the alkyl chain length at the 5-position on picolinic acid from two up to five carbons atoms increased phytotoxicity. Fusaric acid methyl ester, the most phytotoxic compound tested, is a naturally occurring compound; as such it has potential as a herbicide in organic farming. PMID- 20955726 TI - General and abdominal obesity in South Korea, 1998-2007: gender and socioeconomic differences. AB - OBJECTIVE: To examine national trends in prevalence and socioeconomic inequalities in both general (measured by body mass index) and abdominal obesity (measured by waist circumference) by gender and socioeconomic position (SEP) indicators. METHODS: Data were from four rounds of nationally representative cross-sectional surveys for Korean men and women aged 25-64 (6,286 in 1998, 4,839 in 2001, 4,181 in 2005, and 2,006 in 2007). We calculated age-adjusted prevalence rates of overweight and abdominal obesity by gender and SEP indicators (education, occupational class, employment status and income) and examined trends of prevalence and its inequalities. RESULTS: Overweight and abdominal obesity has significantly increased in Korean men (P for linear trend <0.01), not in women. For men, high SEP was associated with overweight and abdominal obesity, but the magnitude of socioeconomic differences in obesity measures generally remained unchanged during the study period. Among women, low SEP was associated with overweight. Interestingly, increasing inequalities in abdominal obesity according to education and income were found in women. CONCLUSIONS: Clear gender differences were noted in (1) time trends of overweight and abdominal obesity, (2) relationships between the obesity measures and various SEP indicators, and (3) linear time trends of socioeconomic differentials in obesity. PMID- 20955727 TI - Does self-selection influence the relationship between park availability and physical activity? AB - OBJECTIVE: Increased proximity to parkland is associated with physical activity (PA). This study explored the extent to which self-selection--the idea that active persons simply seek out neighborhoods more endowed with active resources- influences the relationship between park availability and PA. METHOD: In August 2007, measures of parkland availability within 1 km, importance placed on living near parks, and park-based PA participation were assessed for 585 adults in Waterloo, Ontario. RESULTS: Logistic regression revealed that (i) participants who placed greater importance on neighborhood open space were not more likely to live near more parkland; (ii) both park importance and park space availability were associated with increased, and relatively equal, odds of engaging in at least some park-based PA; and (iii) participants who placed a low importance on living near parks but had a higher amount of park space nearby were significantly more likely to engage in park-based PA than participants who also placed a low importance on parks but had less nearby park space. CONCLUSION: The issue of self selection does not solely account for the relationship frequently observed between park space availability and PA. Future prospective and intervention studies are needed to draw more definitive conclusions about causality. PMID- 20955728 TI - Synthesis and in vitro evaluation of carboxymethyl starch-chitosan nanoparticles as drug delivery system to the colon. AB - The purpose of this study was to examine chitosan (CS)-carboxymethyl starch (CMS) nanoparticles as drug delivery system to the colon. The 5-aminosalicylic acid (5 ASA) was chosen as model drug molecule. CS-CMS nanoparticles were formulated by a complex coacervation process under mild conditions. The influence of process variables, including the two ionic polymers, on particle size, and nanoparticles entrapment of 5-ASA was studied. In vitro release of 5-ASA was also evaluated, and the integrity of 5-ASA in the release fraction was assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The release of 5-ASA from nanoparticle was based on the ion-exchange mechanism. The CS-CMS nanoparticles developed based on the modulation of ratio show promise as a system for controlled delivery of drug to the colon. PMID- 20955729 TI - Preparation and chemical and biological characterization of a pectin/chitosan polyelectrolyte complex scaffold for possible bone tissue engineering applications. AB - In this work, porous scaffolds obtained from the freeze-drying of pectin/chitosan polyelectrolyte complexes were prepared and characterized by FTIR, SEM and weight loss studies. Additionally, the cytotoxicity of the prepared scaffolds was evaluated in vitro, using human osteoblast cells. The results obtained showed that cells adhered to scaffolds and proliferated. The study also confirmed that the degradation by-products of pectin/chitosan scaffold are noncytotoxic. PMID- 20955730 TI - Molecular cloning and characterization of novel cathelicidin-derived myeloid antimicrobial peptide from Phasianus colchicus. AB - Cathelicidins were initially characterized as a family of antimicrobial peptides. Now it is clear that they fulfill several immune functions in addition to their antimicrobial activity. In the current work, three cDNA sequences encoding pheasant cathelicidins were cloned from a constructed bone marrow cDNA library of Phasianus colchicus, using a nested-PCR-based cloning strategy. The three deduced mature antimicrobial peptides, Pc-CATH1, 2 and 3 are composed of 26, 32, and 29 amino acid residues, respectively. Unlike the mammalian cathelicidins that are highly divergent even within the same genus, Pc-CATHs are remarkably conserved with chicken fowlicidins with only a few of residues mutated according to the phylogenetic analysis result. Synthetic Pc-CATH1 exerted strong antimicrobial activity against most of bacteria and fungi tested, including the clinically isolated (IS) drug-resistant strains. Most MIC values against Gram-positive bacteria were in the range of 0.09-2.95 MUM in the presence of 100mM NaCl. Pc CATH1 displayed a negligible hemolytic activity against human erythrocytes, lysing 3.6% of erythrocytes at 3.15 MUM (10 MUg/ml), significantly higher than the corresponding MIC. Pc-CATH1 was stable in the human serum for up to 72 h, revealing its extraordinary serum stability. These specific features of Pc-CATH1 may make its applications much wider given the potency and breadth of the peptide's bacteriocidal capacity and its resistance towards serum and high-salt environments. PMID- 20955731 TI - The transcriptomic response to viral infection of two strains of shrimp (Litopenaeus vannamei). AB - The extent to which data-intensive studies of the transcriptome can provide insight into biological responses is not well defined, especially in the case of species (such as shrimp) where much physiological and biochemical knowledge is missing. In this study we took a transcriptomic approach to gain insight into the response to viral infection of two strains of the Pacific whiteleg shrimp (Litopenaeus vannamei) that differ in their resistance to Taura Syndrome Virus (TSV). Changes in gene expression in the hepatopancreas following infection with TSV and Yellow Head Virus (YHV) were assessed using a cDNA microarray containing 2469 putative unigenes. The null hypothesis tested was that significant differences between the transcriptomic responses to viral infection of resistant and sensitive strains would not be detected. This hypothesis was broadly rejected, with the most surprising observation being that the baseline (control, unchallenged) sensitive and resistant strains expressed distinguishable transcriptomic signatures. The resistant line was pre-disposed to lower expression of genes encoding viral (and host) proteins. Many of the genes differentiating resistant and sensitive lines are involved in protein metabolism, cellular trafficking, immune defense and stress response, although it was not possible to clearly identify candidate genes responsible for TSV resistance. In contrast to TSV challenge, YSV either failed to perturb the host transcriptome or created a "confused" response that was difficult to interpret. PMID- 20955732 TI - Null results in TMS: from absence of evidence to evidence of absence. AB - It is always difficult to interpret null results. But as a research method, transcranial magnetic stimulation (TMS) has so many degrees of freedom that null results are often dismissed as meaningless. We feel that this may be unnecessary, if not counterproductive. Null results seem to inherently fulfill an important role in brain mapping. In fact, without null results, neuroimaging as an enterprise would not make sense. We argue that null results are similarly important in TMS research. By itself, neuroimaging research leaves room for doubt concerning whether or not an activated region is actually necessary for intact task performance. Interference methods such as TMS can therefore complement brain research by testing the functional relevance of that region. However, if then only positive TMS results are taken seriously, the brain interference paradigm seems less informative than promised. But how can null results inform us if they only constitute absence of evidence? We suggest that three main arguments contravene interpretation of null results in TMS. These we call the localization argument, the neural efficacy argument, and the power argument. We proceed to discuss in turn how, and under which conditions, each of these arguments may be nuanced. These considerations lead us to value null results along a gradient of meaningfulness, rather than a dichotomy. This perspective may open up a new range of TMS applications, where research questions about the lack of functional relevance of a particular brain region become valid. In this context we make specific recommendations on experimentation and interpretation. We propose that it is often not only meaningful to interpret null results, but also useful to make such findings available to the community, especially now that improved methods and an expanded knowledge base make null results more interpretable than they have been in the past. PMID- 20955733 TI - Hypothalamic interaction with the mesolimbic DA system in the control of the maternal and sexual behaviors in rats. AB - The medial preoptic area (MPOA) of the hypothalamus regulates maternal behavior, male sexual behavior, and female sexual behavior. Functional neuroanatomical evidence indicates that the appetitive aspects of maternal behavior are regulated through MPOA interactions with the mesolimbic dopamine (DA) system; a major focus of this review is to explore whether or not the MPOA participates in the appetitive aspects of sexual behavior via its interaction with the mesolimbic DA system. A second focus of this review is to examine the extent to which estradiol interactions with DA within this circuit regulate all three reproductive behaviors. One mechanism through which estradiol activates male sexual behavior is through the potentiation of DA activity in the MPOA. In the hypothalamus, estradiol has also been found to act in concert with DA, through the activation of similar intracellular signaling pathways, in order to stimulate female sexual behavior. Finally, recent evidence suggests that some effects of estradiol are mediated by direct action of estradiol on the mesolimbic DA system. PMID- 20955735 TI - Essential roles of SIRPalpha in homeostatic regulation of skin dendritic cells. AB - Signal regulatory protein alpha (SIRPalpha) is an immunoglobulin superfamily protein that is predominantly expressed in dendritic cells (DCs). Its cytoplasmic region binds SHP-1 or SHP-2 protein tyrosine phosphatases, while its extracellular region interacts with CD47, another immunoglobulin superfamily protein, constituting cell-cell signaling. SIRPalpha was previously shown to be important for development of contact hypersensitivity, likely as a result of its positive regulation of the priming by DCs of CD4(+) T cells. However, the mechanism by which SIRPalpha regulates DC functions remains unknown. Here we found that the number of I-A(+) cells, which represent migratory DCs such as Langerhans cells (LCs) or dermal DCs from the skin, in the peripheral lymph nodes (LNs) was markedly decreased in mice expressing a mutant form of SIRPalpha that lacks the cytoplasmic region compared with that of wild-type (WT) mice. In addition, an increase of fluorescein isothiocyanate (FITC)-bearing I-A(+) cells in the draining lymph nodes (LNs) after skin-painting with FITC was markedly blunted in SIRPalpha mutant mice. However, migratory ability, as well as expression of CCR7, of bone marrow-derived DCs prepared from SIRPalpha mutant mice were not impaired. By contrast, the number of I-A(+) LCs in the epidermis of SIRPalpha mutant mice was markedly decreased compared with that of WT mice. In addition, the mRNA expression of transforming growth factor-beta receptor II in LCs of SIRPalpha mutant mice was markedly decreased compared with that of WT mice. These results suggest that SIRPalpha is important for homeostasis of LCs in the skin, as well as of migratory DCs in the LNs, but unlikely for migration of these cells from the skin to draining LNs. PMID- 20955734 TI - Parental precaution: neurobiological means and adaptive ends. AB - Humans invest precious reproductive resources in just a few offspring, who remain vulnerable for an extended period of their lifetimes relative to other primates. Therefore, it is likely that humans evolved a rich precautionary psychology that assists in the formidable task of protecting offspring. In this review, we integrate precautionary behaviors during pregnancy and postpartum with the adaptive functions they may serve and what is known of their biological mediators, particularly brain systems motivating security and attachment. We highlight the role of reproductive hormones in (i) priming parental affiliation with young to incentivize offspring protection, (ii) focusing parental attention on cues of potential threat, and (iii) facilitating maternal defense against potentially dangerous conspecifics and predators. Throughout, we center discussion on adaptive responses to threats of disease, accident and assault as common causes of child mortality in the ancestral past. PMID- 20955736 TI - Antipoliovirus activity and mechanism of action of 3-methylthio-5-phenyl-4 isothiazolecarbonitrile. AB - Our previous studies described the synthesis and the antiviral activity of 3,4,5 trisubstituted isothiazole derivatives that were found to be particularly effective against enteroviruses. Compound 3-methylthio-5-phenyl-4 isothiazolecarbonitrile (IS-2) exhibited an interesting anti-poliovirus activity with a high selectivity index. In the present study we investigated the mechanism of action of this compound. Studies on the time of IS-2 addition to poliovirus type 1 infected cells suggested that the compound may inhibit some early process of viral replication. In order to determine its mechanism of action, we evaluated the rate of attachment and internalization of purified [3H]uridine-labeled poliovirus to HEp-2 cells in the presence or absence of IS-2. No effect on poliovirus adsorption and internalization to host cells was detected. We also investigated the influence of the compound on virus uncoating using labeled poliovirus and measuring the radioactivity of oligoribonucleotides formed from viral RNA susceptible to ribonuclease. These experiments demonstrated that poliovirus uncoating is influenced by IS-2 action. PMID- 20955737 TI - Development of molecular tools for the detection of freshwater diatoms. AB - This study was undertaken to develop a reliable and reproducible procedure for the detection and quantitative determination of diatoms in environmental samples. A comparative study of seven different DNA extraction kits was carried out to establish conditions for analysis of diatom containing samples. The best performers were identified using both standard and real-time PCR. We show that the yield of diatom DNA is generally quite low when using commercially available extraction kits; in addition, a new protocol was devised to obtain samples suitable for DNA amplification without the need to perform all the steps required for DNA extraction. This method was tested on environmental samples spiked, in a wide range of total cell mass, with the rarely occurring diatom Neidium affine together with a highly species-specific oligonucleotide designed on the small subunit (SSU) rRNA gene. Thus, we propose a fast and effective procedure that, combined with the use of species-specific oligonucleotide probes can detect minute amounts of a spiked diatom within a complex diatom community. This study provides experimental conditions for a fast and accurate detection of diatoms, and demonstrates the feasibility of the use of molecular tools in the evaluation of water quality. PMID- 20955738 TI - Brain function with complex decision making using electroencephalography. AB - A computer-administered assessment for decision making relevant to daily-living decisions, using the technique of complex decision making (CDM), has been previously developed and tested in our laboratory. The present study sought to identify unique patterns of brain activity in the alpha band associated with CDM. We recorded electroencephalogram (EEG) from 30 scalp sites, during a series of baseline, eyes open fixation tasks, and CDM tasks, in different contexts, in a group of 9 male and 7 female young healthy adults, aged 18 to 34. The decision making contexts, designed to simulate real-world, daily-living decisions, were about taking a bus, choosing a friend, job, medication, and participating in research. Electroencephalograms (EEGs) were divided into the frequency bands, alpha, beta, delta, theta, and gamma, though the primary focus of this paper is the alpha band. Analysis of mean EEG power spectra across the alpha bands - alpha1 (8-10 Hz), alpha2 (10-12 Hz), and alpha 3 (12-14 Hz) - showed significant decreases from baseline to the CDM task. In addition, we observed significant increases in delta, theta, beta, and gamma. There were also significant bivariate correlations between EEG spectra, mostly in low and mid alpha bands, behavioral performance on the CDM task, and scores on standardized measures of executive functioning, including the Trail-making Test and the Wisconsin Card Sorting Task. These results demonstrate how brain activity in complex decision making is distributed across alpha frequency bands and electrode regions and this activity relates to executive functioning. PMID- 20955739 TI - "Interneurons" in the olfactory bulb revisited. AB - The main olfactory bulbs (MOBs) are now one of the most interesting parts of the brain in at least two points; the first station of the olfaction as an excellent model for understanding the neural mechanisms of sensory information processing and one of the most prominent sites whose interneurons are generated continuously in the postnatal and adult periods. Here we point out some new aspects of the MOB organization focusing on the following 4 issues: (1) there might be both axon bearing and anaxonic periglomerular cells (PG cells), (2) most parvalbumin positive medium-sized neurons in the external plexiform layer as well as a few nitric oxide synthase positive PG cells and calretinin positive granule cells are anaxonic but display dendritic hot spots with characteristics of axon initial segments, (3) some of so-called "short-axon cells" project to the higher olfactory related regions and thus should be regarded as "nonprincipal projection neurons" and (4) tyrosine hydroxylase positive GABAergic (DA-GABAergic) juxtaglomerular neurons (JG neurons) are a particular type of JG neurons as a main source of the interglomerular connection, forming an intrabulbar association system. PMID- 20955741 TI - Nuclear localization and antisense effect of PNA internalized by ASGP-R-mediated endocytosis with protein/DNA conjugates. AB - In order for peptide nucleic acids (PNAs) to be effective as therapeutic agents, methods for cellular delivery must be developed. Here we demonstrate spontaneous nuclear localization and antisense effects of peptide nucleic acids (PNAs) delivered to hepatic cells through asialoglycoprotein receptor-mediated endocytosis. Asialofetuin conjugates with DNA oligonucleotides (AF/DNA) complementary to the PNA of interest were designed as cell-specific delivery vectors. PNAs hybridized to the asialofetuin-oligonucleotide conjugates were internalized into murine primary hepatocytes and human HepG2 hepatocarcinoma cells effectively through receptor-mediated endocytosis in vitro. After a 4-h incubation, PNAs were largely localized in the nuclei of the cells; the mechanisms involved are still unclear. More than 70% inhibition of telomerase activity was observed when PNAs complementary to the RNA template of human telomerase were delivered to HepG2 cells using AF/DNA. The PNAs were stably associated with the AF/DNA conjugates in 50% serum at 37 degrees C for at least 3h. The PNAs were spontaneously released from the conjugate through a strand exchange mechanism when complementary nucleic acid was added. The complexation of PNAs with the AF/DNA conjugates resulted in delivery of PNAs to liver after intravenous injection into mice. The present study indicates that conjugation to a natural proteinous ligand can be used as a non-toxic vector for cellular delivery of oligonucleotide analogs. PMID- 20955740 TI - A novel balanced chromosomal translocation found in subjects with schizophrenia and schizotypal personality disorder: altered l-serine level associated with disruption of PSAT1 gene expression. AB - l-Serine is required for the synthesis of glycine and d-serine, both of which are NMDA receptor co-agonists. Although roles for d-serine and glycine have been suggested in schizophrenia, little is known about the role of the l-serine synthesizing cascade in schizophrenia or related psychiatric conditions. Here we report a patient with schizophrenia carrying a balanced chromosomal translocation with the breakpoints localized to 3q13.12 and 9q21.2. We examined this proband and her son with schizotypal personality disorder for chromosomal abnormalities, molecular expression profiles, and serum amino acids. Marked decrease of l-serine and glutamate was observed in the sera of the patient and her son, compared with those in normal controls. Interestingly, expression of PSAT1 gene, which is located next to the breakpoint and encodes one of the enzymes in the l-serine synthesizing cascade, was reduced in both patient and her son. Direct effect of impaired PSAT1 gene expression on decreased serum l-serine level was strongly implicated by rat astrocyte experiments. In summary, we propose an idea that PSAT1 may be implicated in altered serine metabolism and schizophrenia spectrum conditions. PMID- 20955742 TI - Stem cell gene manipulation and delivery as systemic therapeutics. PMID- 20955743 TI - Drug targeting to the kidney. PMID- 20955744 TI - Effect of weight loss intervention on the association between eating behaviour measured by TFEQ-18 and dietary intake in adults. AB - Associations between eating behaviour (cognitive restraint, emotional eating and uncontrolled eating) and dietary intake (energy, energy nutrients and fibre) were assessed in overweight or obese adults (body mass index >27 kg/m(2), n=49) before and after weight loss intervention in a randomized follow-up study lasting 18 months. Counselling was either intensive or short-term. Eating behaviour was assessed using the three-factor eating questionnaire-18 and dietary intake with 5 day food records at 0 and 18 months. The only difference in dietary intake between the groups was higher protein intake (% of energy, E%) in the short-term group at 18 months (18.7 +/- 3.1 E% vs. 17.1 +/- 1.7 E%). Cognitive restraint was associated with lower energy intake at 0 and 18 months (r=-0.34, r=-0.36, respectively) and higher intakes of carbohydrates (r=0.39), sucrose (r=0.33) and fibre (r=0.44) and a lower intake of fat (r=-0.43) at 18 months. Those with the highest cognitive restraint at 18 months had the lowest energy and fat intake, the highest carbohydrate and fibre intake and the greatest weight loss. The results suggest that enhancing cognitive restraint could be a target for improving weight loss counselling, although further evaluation of the causal relationship would be needed in order to find the best practices for enhancing cognitive restraint. PMID- 20955745 TI - Identification of a Passiflora alata Curtis dimeric peptide showing identity with 2S albumins. AB - Antifungal proteins and peptides, essential compounds for plant defense, have been isolated from several tissues of various plants. These proteins could be used as a natural alternative to control phytopathogenic fungi. In this report a heterodimeric antifungal protein named Pa-AFP1, showing higher identity with the 2S albumin family, was purified by using 70-100% ammonium sulfate saturation and further purification steps such as anionic exchange Q-Sepharose chromatography associated with HPLC reversed-phase C4 chromatography. Analysis by Tricine-SDS PAGE revealed two peptidic molecular masses of approximately 4500 Da and 7000 Da, in the presence of beta-mercaptoethanol, while by removing the reducing agent a single protein with molecular mass of about 11,500 Da was obtained. Moreover, dimer mass was confirmed by MALDI-TOF analyses (11,569.76 Da). The antifungal protein, named Pa-AFP1, efficiently inhibited the growth of filamentous fungi Colletotrichum gloeosporioides, and was added to a short list of 2S albumins with antimicrobial properties. Otherwise, this same peptide showed no activity toward bacteria and yeasts. In summary, this compound could be used in the future to develop biotechnological products for the control of phytopathogenic fungi. PMID- 20955746 TI - Involvement of the AT1 receptor in the venoconstriction induced by angiotensin II in both the inferior vena cava and femoral vein. AB - Although angiotensin II-induced venoconstriction has been demonstrated in the rat vena cava and femoral vein, the angiotensin II receptor subtypes (AT(1) or AT(2)) that mediate this phenomenon have not been precisely characterized. Therefore, the present study aimed to characterize the pharmacological receptors involved in the angiotensin II-induced constriction of rat venae cavae and femoral veins, as well as the opposing effects exerted by locally produced prostanoids and NO upon induction of these vasomotor responses. The obtained results suggest that both AT(1) and AT(2) angiotensin II receptors are expressed in both veins. Angiotensin II concentration-response curves were shifted toward the right by losartan but not by PD 123319 in both the vena cava and femoral vein. Moreover, it was observed that both 10(-5)M indomethacin and 10(-4)M L-NAME improve the angiotensin II responses in the vena cava and femoral vein. In conclusion, in the rat vena cava and femoral vein, angiotensin II stimulates AT(1) but not AT(2) to induce venoconstriction, which is blunted by vasodilator prostanoids and NO. PMID- 20955747 TI - Evidence for convergent evolution in the antimicrobial peptide system in anuran amphibians. AB - Amphibians are characterized in part by their highly specialized and glandular skin that enables key physiological functions such as cutaneous respiration and defense against a variety of micro- and macroscopic predators via toxic components (e.g., alkaloids and bufodienolids), biogenic amines, neuropeptides and antimicrobial peptides (AMPs). To date, DNA sequence information regarding AMP genes in anurans is restricted to only a few anuran families and largely to "higher frogs" (Neobatrachia). Here, we analyze the DNA information for the signal sequences of the AMP precursors in anuran amphibians available to the end of 2009 in an explicit phylogenetic framework to characterize the evolution of this large, diverse gene family. Comparison of cDNA sequences suggests that there are at least three different motifs within the signal peptide sequence of the AMP precursor corresponding to the evolutionary lineages Neobatrachia, Bombinatoridae (Bombina spp.) and Pipidae (Xenopus laevis). The signal sequences are strongly conserved within each lineage (as previously noted for Neobatrachia), but highly divergent between them. Together with the lack of a linear relationship between the degree of sequence divergence and evolutionary time, we hypothesize that the anuran AMP system has evolved convergently on at least three occasions. However, additional sampling, especially among the largely poorly sampled non neobatrachian lineages, is required to confirm this hypothesis and could reveal the existence of additional signal sequence motifs. PMID- 20955748 TI - Gonadotropin-releasing hormone II (GnRH II) mediates the anorexigenic actions of alpha-melanocyte-stimulating hormone (alpha-MSH) and corticotropin-releasing hormone (CRH) in goldfish. AB - Intracerebroventricular (ICV) administration of gonadotropin-releasing hormone II (GnRH II), which plays a crucial role in the regulation of reproduction in vertebrates, markedly reduces food intake in goldfish. However, the neurochemical pathways involved in the anorexigenic action of GnRH II and its interaction with other neuropeptides have not yet been identified. Alpha-melanocyte-stimulating hormone (alpha-MSH), corticotropin-releasing hormone (CRH) and CRH-related peptides play a major role in feeding control as potent anorexigenic neuropeptides in goldfish. However, our previous study has indicated that the GnRH II-induced anorexigenic action is not blocked by treatment with melanocortin 4 receptor (MC4R) and CRH receptor antagonists. Therefore, in the present study, we further examined whether the anorexigenic effects of alpha-MSH and CRH in goldfish could be mediated through the GnRH receptor neuronal pathway. ICV injection of the MC4R agonist, melanotan II (80 pmol/g body weight; BW), significantly reduced food intake, and its anorexigenic effect was suppressed by ICV pre-administration of the GnRH type I receptor antagonist, antide (100 pmol/gBW). The CRH-induced (50 pmol/gBW) anorexigenic action was also blocked by treatment with antide. ICV injection of CRH (50 pmol/gBW) induced a significant increase of the GnRH II mRNA level in the hypothalamus, while ICV injection of melanotan II (80 pmol/gBW) had no effect on the level of GnRH II mRNA. These results indicate that, in goldfish, the anorexigenic actions of alpha-MSH and CRH are mediated through the GnRH type I receptor-signaling pathway, and that the GnRH II system regulates feeding behavior. PMID- 20955749 TI - Evaluation of oxidative stress and anti-oxidant status in rat serum following exposure of carbon nanotubes. AB - The aim of the present study was to evaluate the oxidative stress and anti oxidant status in rat serum following intra-tracheal instillation of multi wall carbon nanotubes (MWCNT). The lungs of rats were intra-tracheally instilled with (single dose of) Phosphate-buffered saline (PBS)+1% of Tween 80 (Solvent Control) or MWCNT or carbonyl Iron (negative control) or quartz particles (positive control) at a dose of 0.2, 1 and 5 mg/kg body weight. Following exposure, the blood samples were collected at 1, 7, 30 and 90 days of post instillation of nanoparticles and different parameters were estimated to assess the oxidative stress induced by the instillation of MWCNT. Exposure of MWCNT to rats produced a significant (p<0.05) dose dependent reduction of blood total anti-oxidant capacity, glutathione, superoxide dismutase, catalase activity and increased lipid peroxidation product, (Malondialdehyde) levels than PBS+1% Tween 80 control group. This reduction in the total anti-oxidant capacity in nanotubes exposed rats indicates the reduction in anti-oxidant deference mechanisms due to the instillation of MWCNT. These results indicate that, exposure of multi wall carbon nanotubes induces oxidative stress by reducing the total anti-oxidant capacity in rats. The findings suggest possible occupational health hazard in chronic exposures. PMID- 20955750 TI - Cross-species behavioural genetics: A starting point for unravelling the neurobiology of human psychiatric disorders. AB - Identifying the genetic and neurobiological mechanisms underlying certain behavioural traits is an important strategy to understand the aetiology of various psychiatric disorders and to find potential new treatment possibilities. It has proven a great challenge to develop paradigms that allow translational research for behavioural phenotypes that are relevant for disorders across the psychiatric spectrum. Recently, there has been increasing attention for studies that implement rodent behavioural paradigms in the home cage to assess the association between genetic backgrounds and behavioural traits. The application of interspecies genetics to unravel these traits has revealed novel insights in the genetic mechanisms that are encoding phenotypes relevant to biological processes underlying psychiatric disorders. By means of two examples, namely the stress-induced hyperthermia paradigm and the home cage environment, this review aims to show that by using individual genetic variations with phenotypes obtained from mice and across categories of neuropsychiatric disorders, novel insights in the neurobiological trajectory of psychiatric disorders can be obtained. PMID- 20955751 TI - Hydroxytyrosol rich extract from olive leaves modulates cell cycle progression in MCF-7 human breast cancer cells. AB - Throughout the history, olive (Olea europea L.) leaves have been heavily exploited for the prevention or the treatment of hypertension, carcinogenesis, diabetes, atherosclerosis and so many other traditional therapeutic uses. These activities are thought to be the output of olive micronutrients especially polyphenols. Hydroxytyrosol and oleuropein are considered as major polyphenolic compounds in olive leaf. In this work, a hydroxytyrosol rich olive leaves extract was investigated for potential anti-tumoral activities. In vitro cytotoxic effects against MCF-7 breast cancer cells were examined using MTT and neutral red tests. The anti-tumor activities were further investigated by flow cytometry and western blotting. Cytotoxicity assays resulted in a dose dependent growth inhibition of MCF-7 cells. This inhibition was due to the cell cycle arrest in the G0/G1 phase. The understanding of the molecular mechanism by which olive leaves extract arrested cell growth showed a down-expression of the peptidyl prolyl cis-trans isomerase Pin1 which in turn decreased the level of a G1 key protein; Cyclin D1. Additionally, olive leaves extract treatment up-regulated the AP1 transcription factor member, c-jun. Therefore, olive leaves extract will necessitate further deep investigation for a probable use as a cancer preventive food additive. PMID- 20955752 TI - Methylated chrysin, a dimethoxy flavone, partially suppresses the development of liver preneoplastic lesions induced by N-nitrosodiethylamine in rats. AB - The modifying effect of chemically modified chrysin on formation of preneoplastic foci induced by N-nitrosodiethylamine (DEN) was investigated in male rats. Male Wistar rats were administered three intraperitoneal injections of DEN (200 mg/kg bodyweight) interspersed by 2 weeks with or without an oral dose of dimethoxy flavone (DMF 100 mg/kg bodyweight), 2 weeks after DEN initiation. The number of GST-Pi positive foci and proliferating cell nuclear antigen (PCNA)-positive cells were significantly suppressed by the administration of DMF. Real-time RT-PCR analysis revealed that DMF treatment increased mRNA expression levels of apoptotic proteins p53 and fas, cell cycle regulatory proteins chek 2, cdkn1a, rad 50, anti-inflammatory protein pparg whereas the mRNA expression levels of bcl 2 and prdx-2 were decreased compared to mRNA levels in DEN-treated group. Therefore, we propose that DMF partially suppresses the formation of preneoplastic lesions in rats following DEN exposure by regulating anti inflammatory and apoptosis-promoting events and restoring the cellular redox balance altered by DEN. PMID- 20955753 TI - In vitro biotransformation and investigation of metabolic enzymes possibly responsible for the metabolism of bisdesoxyolaquindox in the liver fractions of rats, chicken, and pigs. AB - Bisdesoxyolaquindox is a reduced metabolite of olaquindox which is used as a medicinal feed additive in veterinary medicine. The relevant metabolism studies of bisdesoxyolaquindox have been carried out for the first time in rat, chicken, and pig liver subcellular fractions in order to understand the metabolic enzymes that are possibly responsible for the metabolism of olaquindox. The metabolites were characterized by high-performance liquid chromatography combined with hybrid ion trap/time-of-flight mass spectrometry. The major metabolic pathways of bisdesoxyolaquindox in the three species were the oxidation of hydroxyl to bisdesoxyolaquindox-2'-carboxyl acid (O10) and the N-dealkylation of the side chain to 3-methylquinoxaline 2-carboxamide (O12). Other metabolic pathways were also proposed which involved the direct methyl oxidation and N-oxide on the quinoxaline ring in the three species as well as N-hydroxylation only in rat. The intrinsic clearance values in the liver microsomes for O10 and O12 were ranked in the order of chicken>pig?rat and rat>pig?chicken, respectively. Inhibition studies indicated that 8-methoxypsoralen, 4-methylpyrazole and alpha naphthoflavone could inhibit the formations of O10 and O12 in all species. Quinidine, troleandomycin, diethyldithiocarbamate, and disulfiram showed an interspecies difference in the inhibition of the formation of two metabolites. In rat and pig liver cytosol, 4-methylpyrazole, menadione and chlorpromazine strongly inhibited the formation of O10. Both diethyldithiocarbamate and disulfiram were found to inhibit O10 formation in rat cytosol but not in pig cytosol. These results indicated the following: In rat liver microsomes, CYP2A might be involved in the formation of O10, and CYP1A, CYP2A and CYP2E would be involved in the O12 formation. In pig liver microsomes, CYP1A and CYP2E might catalyze the formations of O10 and O12. In rat cytosol, alcohol dehydrogenase, aldehyde oxidase and aldehyde dehydrogenase should catalyze the O10 formation. In pig cytosol, alcohol dehydrogenase and aldehyde oxidase might be involved in the formation of O10. In chicken, it was found that various CYP isoenzymes were capable of catalyzing the two reactions; none of the inhibitors of cytosol enzymes inhibited O10 formation in chicken cytosol. PMID- 20955754 TI - High volume individual fibre post versus low volume fibre post: the fracture load of the restored tooth. AB - OBJECTIVES: The purpose of this study was to evaluate the fracture loads of post and-core systems with two different individually formed fibre post designs and polymerization conditions. METHODS: Totally seventy-two (n=8/group) bovine teeth were cut and made up the root length of 15.0mm. They were divided into 3 main groups (Group A, B, C). A: one glass fibre post was light-cured before cementation, B: fibres were bundled to fill the entire root canal opening and light-cured before cementation, C: one unpolymerized glass fibre post was inserted into cement-filled root canal and light-cured with luting cement (ParaCem). Moreover specimens of each group were divided into 3 subgroups according to the post length: subgroup 1: 10mm; subgroup 2: 7.5mm; subgroup 3: 5.0mm. After cementation, the core was built up, and then made the composite resin crown (Filtek Z250). Fabricated specimen was loaded from 45 degrees of palatal side at a crosshead speed of 1.0mm/min. The first load drop and maximum fracture loads were statistically analyzed by ANOVA and Tukey's test. RESULTS: Maximum fracture load of Group B (433 N) and C (418 N) are significantly higher than Group A (284 N) (p<0.01). Short post (5mm) provided higher fracture loads in all main groups, especially in Group C. CONCLUSIONS: Using short and thick fibre post system (the same diameter as the root canal) showed higher strength than one fibre post only. In addition, by curing the cement and the fibre material simultaneously, the strength of the restored tooth was increased. PMID- 20955755 TI - Effects of cinnamaldehyde on the glucose transport activity of GLUT1. AB - There is accumulating evidence that cinnamon extracts contain components that enhance insulin action. However, little is know about the effects of cinnamon on non-insulin stimulated glucose uptake. Therefore, the effects of cinnamaldehyde on the glucose transport activity of GLUT1 in L929 fibroblast cells were examined under both basal conditions and conditions where glucose uptake is activated by glucose deprivation. The data reveal that cinnamaldehyde has a dual action on the glucose transport activity of GLUT1. Under basal conditions it stimulates glucose uptake and reaches a 3.5 fold maximum stimulation at 2.0mM. However, cinnamaldehyde also inhibits the activation of glucose uptake by glucose deprivation in a dose dependent manner. Experiments with cinnamaldehyde analogs reveal that these activities are dependent on the alpha,beta-unsaturated aldehyde structural motif in cinnamaldehyde. The inhibitory, but not the stimulatory activity of cinnamaldehyde was maintained after a wash-recovery period. Pretreatment of cinnamaldehyde with thiol-containing compounds, such as beta mercaptoethanol or cysteine, blocked the inhibitory activity of cinnamaldehyde. These results suggest that cinnamaldehyde inhibits the activation of GLUT1 by forming a covalent link to target cysteine residue/s. This dual activity of cinnamaldehyde on the transport activity of GLUT1 suggests that cinnamaldehyde is not a major contributor to the anti-diabetic properties of cinnamon. PMID- 20955756 TI - Disintegrin-like/cysteine-rich domains of the reprolysin HF3: Site-directed mutagenesis reveals essential role of specific residues. AB - Little is known about the biochemical properties of the non-catalytic domains of snake venom metalloproteinases (SVMPs). The ECD sequence of the disintegrin-like domain (D-domain) has been assigned as the disintegrin motif and, recently, the hyper-variable region (HVR) of the cysteine-rich domain (C-domain) was suggested to constitute a potential protein-protein adhesive interface. Here we show that the recombinant C-domain of HF3, a hemorrhagic SVMP from Bothrops jararaca, as well as three peptides resembling its HVR, inhibit collagen-induced platelet aggregation, which indicates a role for the C-domain and its HVR in targeting HF3 to platelets. Site-directed mutagenesis was used for the first time to identify charged residues essential for the functionality of the disintegrin-like/cysteine rich domains (DC-domains). Residues of the disintegrin loop (E467 and D469), and of the HVR (K568, K569 and K575) of HF3 were individually mutated to Ala. Interestingly, only the mutant D469A was obtained in soluble form in Escherichia coli and this single mutation caused loss of two functional activities of the DC domains: inhibition of platelet aggregation and increase of leukocyte rolling in the microcirculation. In summary we demonstrate that the C-domain and its HVR are critical for HF3 to affect platelets and leukocytes, however, the disintegrin loop may be important for the functionality of the D-domain in the context of the C-domain. PMID- 20955758 TI - Motor programming of finger sequences of different complexity. AB - In a response precuing task, we used behavioral and electrophysiological measures - Contingent Negative Variation (CNV) and the readiness potential (RP) - to investigate the programming of three-element response sequences of different complexity. Precuing effects on foreperiod CNV and RT indicated the use of advance information about response hand and response sequence. Crucially, with advance information about both hand and sequence, heterogeneous response sequences (e.g., 1->2->2) elicited larger foreperiod CNV activity over medial motor areas than homogeneous response sequences (e.g., 1->2->3), whereas CNV activity over lateral motor areas was not influenced by sequence complexity. It was only before response execution that lateral but not medial RP activity was stronger for heterogeneous than homogeneous response sequences. Both behavioral and electrophysiological measures indicated finger-order dependent influences on the duration of on-line response programming during response execution. PMID- 20955760 TI - The end of sleep: 'sleep debt' versus biological adaptation of human sleep to waking needs. AB - It is argued that the latter part of usual human sleep is phenotypically adaptable (without 'sleep debt') to habitual shortening or lengthening, according to environmental influences of light, safety, food availability and socio economic factors, but without increasing daytime sleepiness. Pluripotent brain mechanisms linking sleep, hunger, foraging, locomotion and alertness, facilitate this time management, with REM acting as a 'buffer' between wakefulness and nonREM ('true') sleep. The adaptive sleep range is approximately 6-9h, although, a timely short (<20 min) nap can equate to 1h 'extra' nighttime sleep. Appraisal of recent epidemiological findings linking habitual sleep duration to mortality and morbidity points to nominal causal effects of sleep within this range. Statistical significance, here, may not equate to real clinical significance. Sleep durations outside 6-9h are usually surrogates of common underlying causes, with sleep associations taking years to develop. Manipulation of sleep, alone, is unlikely to overcome these health effects, and there are effective, rapid, non sleep, behavioural countermeasures. Sleep can be taken for pleasure, with minimal sleepiness; such 'sleepability' is 'unmasked' by sleep-conducive situations. Sleep is not the only anodyne to sleepiness, but so is wakefulness, inasmuch that some sleepiness disappears when wakefulness becomes more challenging and eventful. A more ecological approach to sleep and sleepiness is advocated. PMID- 20955759 TI - The feasibility of ambulatory biosensor measurement of salivary alpha amylase: Relationships with self-reported and naturalistic psychological stress. AB - Recent developments in biosensor technology allow point-of-use reporting of salivary alpha amylase (sAA) levels while approaching the precision and accuracy of conventional laboratory-based testing. We deployed a portable prototype sAA biosensor in 54 healthy, male dental students during a low stress baseline and during final exams. At baseline, participants completed the Brief Symptom Inventory (BSI). At baseline and the exam week, participants provided saliva samples at 10 AM, 1 PM, and 5 PM, and rated concurrent subjective distress. Although subjective distress was higher during exams compared to baseline, sAA levels did not differ between baseline and exams. Higher sAA levels were related to higher concurrent subjective distress, and higher depressive and social isolation symptoms on the BSI were related to lower sAA during exams. Results from this study, in combination with previous validation data, suggest that the sAA biosensor is a promising tool for point-of-use measures of exposure to stress. PMID- 20955762 TI - An analysis of network reciprocity in Prisoner's Dilemma games using Full Factorial Designs of Experiment. AB - Despite hundreds of studies on the Prisoner's Dilemma (PD) game, understanding about network reciprocity remains a unsolved puzzle. Thus, we performed a series of Full Factorial Design of Experiments (FFDOE) to evaluate what dominates emerging cooperation in the PD game on various networks. The results qualitatively reveal the influence of each factor and show that some combinations of factors have complicated interactions. Remarkably, the choice of strategy update rule or update dynamics is much more important than the type of network imposed or, at least, the factorial effect of the average degree of the network reported by Nowak (Science 314, 5805, 1560-1563, 2006) and Ohtsuki et al. (Nature 441, 502-505, 2006). Furthermore, the decision of which PD game type to investigate (whether all PD games, PD-Chicken boundary games or Donor & Recipient games) is important for discussing network reciprocity. PMID- 20955761 TI - Impaired memory consolidation during sleep in patients with functional memory disorder. AB - Functional memory disorder (FMD) is characterized by mnestic and attentional deficits without symptoms of mild cognitive impairment or dementia. FMD usually develops in subjects with high psychosocial stress level and is classified to the somatoform disorders. We assessed memory performance (procedural mirror tracing task, declarative visual and verbal memory task) and other cognitive functions before and after one night of sleep in 12 FMD patients (mean age: 51.7 yrs, 7 females) and 12 healthy subjects matched for age, gender and IQ. Memory performance and other neurocognitive tasks did not differ between the groups at baseline. After one night of sleep, FMD patients showed an impairment of declarative memory consolidation compared to healthy subjects (visual task: p=0.004; verbal task: p=0.039). Spectral analysis of sleep-EEG indicated an increased cortical excitation in FMD. We hypothesize that a hyperarousal state in FMD might contribute to sleep disturbance implicating negative effects on declarative memory consolidation. PMID- 20955757 TI - The environment and susceptibility to schizophrenia. AB - In the present article the putative role of environmental factors in schizophrenia is reviewed and synthesized. Accumulating evidence from recent studies suggests that environmental exposures may play a more significant role in the etiopathogenesis of this disorder than previously thought. This expanding knowledge base is largely a consequence of refinements in the methodology of epidemiologic studies, including birth cohort investigations, and in preclinical research that has been inspired by the evolving literature on animal models of environmental exposures. This paper is divided into four sections. In the first, the descriptive epidemiology of schizophrenia is reviewed. This includes general studies on incidence, prevalence, and differences in these measures by urban rural, neighborhood, migrant, and season of birth status, as well as time trends. In the second section, we discuss the contribution of environmental risk factors acting during fetal and perinatal life; these include infections [e.g. rubella, influenza, Toxoplasma gondii (T. gondii), herpes simplex virus type 2 (HSV-2)], nutritional deficiencies (e.g., famine, folic acid, iron, vitamin D), paternal age, fetal/neonatal hypoxic and other obstetric insults and complications, maternal stress and other exposures [e.g. lead, rhesus (Rh) incompatibility, maternal stress]. Other putative neurodevelopmental determinants, including cannabis, socioeconomic status, trauma, and infections during childhood and adolescence are also covered. In the third section, these findings are synthesized and their implications for prevention and uncovering biological mechanisms, including oxidative stress, apoptosis, and inflammation, are discussed. Animal models, including maternal immune activation, have yielded evidence suggesting that these exposures cause brain and behavioral phenotypes that are analogous to findings observed in patients with schizophrenia. In the final section, future studies including new, larger, and more rigorous epidemiologic investigations, and research on translational and clinical neuroscience, gene-environment interactions, epigenetics, developmental trajectories and windows of vulnerability, are elaborated upon. These studies are aimed at confirming observed risk factors, identifying new environmental exposures, elucidating developmental mechanisms, and shedding further light on genes and exposures that may not be identified in the absence of these integrated approaches. The study of environmental factors in schizophrenia may have important implications for the identification of causes and prevention of this disorder, and offers the potential to complement, and refine, existing efforts on explanatory neurodevelopmental models. PMID- 20955763 TI - Effects of hyperthermic seizures on the developing primary visual cortex of the rat. AB - Febrile seizures occurring during childhood have been shown to interfere with the development of cognitive functions. However, an alteration of the developing sensory systems might also result from febrile seizures. In order to test this hypothesis, seizures were induced by hyperthermia in Long Evans rats on postnatal day 10. Extracellular single neuron recordings were carried out from postnatal days 15 to 30 and at adulthood. The response of neurons in the primary visual cortex to drifting sinusoidal gratings was recorded in anaesthetized rats. As soon as postnatal day 15, the neurons of rats having experienced a hyperthermic seizure showed significantly lower optimal spatial frequencies (SF), broader directional and temporal bandwidths, as well as higher contrast thresholds than did neurons recorded in normal rats. At adulthood, significantly broader spatial bandwidths and lower optimal temporal frequencies (TF) were obtained from neurons of rats subjected to hyperthermia. These results suggest that febrile seizures during infancy could affect the development of spatio-temporal receptive field properties of neurons in primary visual cortex. Such alterations of a sensory system might contribute to the cognitive deficits associated with early-onset febrile seizures. PMID- 20955764 TI - Role for voltage gated calcium channels in calcitonin gene-related peptide release in the rat trigeminovascular system. AB - Clinical and genetic studies have suggested a role for voltage gated calcium channels (VGCCs) in the pathogenesis of migraine. Release of calcitonin gene related peptide (CGRP) from trigeminal neurons has also been implicated in migraine. The VGCCs are located presynaptically on neurons and are involved in the release of these peptides to different stimuli. We have examined the presence and importance of VGCCs in controlling the CGRP release from rat dura mater, freshly isolated trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC). Each of the four VGCCs, P/Q-, N-, and L- and T-type are abundantly found in TG and TNC relative to the dura mater and each mediates a significant fraction of high potassium concentration induced CGRP release. In dura mater, blockade of P/Q , N- and L-type VGCCs by omega-agatoxin TK, omega-conotoxin GVIA and nimodipine at 1 MUM respectively, significantly decreased the potassium induced CGRP release. In the absence of calcium ions (Ca2+) and in the presence of a cocktail of blockers, the stimulated CGRP release from dura mater was reduced almost to the same level as basal CGRP release. In the TG omega-conotoxin GVIA inhibited the potassium induced CGRP release significantly. In the absence of Ca2+ and in the presence of a cocktail of blockers the stimulated CGRP release was significantly reduced. In the TNC only the cocktail of blockers and the absence of Ca2+ could reduce the potassium induced release significantly. These results suggest that depolarization by high potassium releases CGRP, and the release is regulated by Ca2+ ions and voltage-gated calcium channels. PMID- 20955765 TI - Pik3c3 deletion in pyramidal neurons results in loss of synapses, extensive gliosis and progressive neurodegeneration. AB - The lipid kinase PIK3C3 (also known as VPS34) regulates multiple aspects of endo membrane trafficking processes. PIK3C3 is widely expressed by neurons in the CNS, and its catalytic product PI3P is enriched in dendritic spines. Here we generated a line of conditional mutant mouse in which Pik3c3 is specifically deleted in hippocampal and in small subsets of cortical pyramidal neurons using the CaMKII Cre transgene. We found that Pik3c3-deficiency initially causes loss of dendritic spines accompanied with reactive gliosis, which is followed by progressive neuronal degeneration over a period of several months. Layers III and IV cortical neurons are more susceptible to Pik3c3-deletion than hippocampal neurons. Furthermore, in aged conditional Pik3c3 mutant animals, there are extensive gliosis and severe secondary loss of wild type neurons. Our analyses show that Pik3c3 is essential for CNS neuronal homeostasis and Pik3c3flox/flox; CaMKII-Cre mouse is a useful model for studying pathological changes in progressive forebrain neurodegeneration. PMID- 20955766 TI - Amygdalar roles during exposure to a live predator and to a predator-associated context. AB - The amygdala plays a critical role in determining the emotional significance of sensory stimuli and the production of fear-related responses. Large amygdalar lesions have been shown to practically abolish innate defensiveness to a predator; however, it is not clear how the different amygdalar systems participate in the defensive response to a live predator. Our first aim was to provide a comprehensive analysis of the amygdalar activation pattern during exposure to a live cat and to a predator-associated context. Accordingly, exposure to a live predator up-regulated Fos expression in the medial amygdalar nucleus (MEA) and in the lateral and posterior basomedial nuclei, the former responding to predator-related pheromonal information and the latter two nuclei likely to integrate a wider array of predatory sensory information, ranging from olfactory to non-olfactory ones, such as visual and auditory sensory inputs. Next, we tested how the amygdalar nuclei most responsive to predator exposure (i.e. the medial, posterior basomedial and lateral amygdalar nuclei) and the central amygdalar nucleus (CEA) influence both unconditioned and contextual conditioned anti-predatory defensive behavior. Medial amygdalar nucleus lesions practically abolished defensive responses during cat exposure, whereas lesions of the posterior basomedial or lateral amygdalar nuclei reduced freezing and increased risk assessment displays (i.e. crouch sniff and stretch postures), a pattern of responses compatible with decreased defensiveness to predator stimuli. Moreover, the present findings suggest a role for the posterior basomedial and lateral amygdalar nuclei in the conditioning responses to a predator-related context. We have further shown that the CEA does not seem to be involved in either unconditioned or contextual conditioned anti-predatory responses. Overall, the present results help to clarify the amygdalar systems involved in processing predator-related sensory stimuli and how they influence the expression of unconditioned and contextual conditioned anti-predatory responses. PMID- 20955767 TI - Enhanced nociceptive responding in two rat models of depression is associated with alterations in monoamine levels in discrete brain regions. AB - Altered pain responding in depression is a widely recognized but poorly understood phenomenon. The present study investigated nociceptive responding to acute (thermal and mechanical) and persistent (inflammatory) noxious stimuli in two animal models of depression, the olfactory bulbectomized (OB) and the Wistar Kyoto (WKY) rat. In addition, this study examined if altered nociceptive behaviour was associated with changes in monoamine levels in discrete brain regions. OB rats exhibited mechanical allodynia (von Frey test) but not thermal hyperalgesia (hot plate and tail-flick tests) when compared to sham-operated counterparts. Formalin-induced nociceptive behaviour was both heightened and prolonged in OB versus sham-operated controls. An inverse correlation was observed between 5-hydroxyindoleacetic acid (5-HIAA) concentration in the hippocampus and amygdaloid cortex and nociceptive behaviour in the formalin test. In comparison, WKY rats exhibited thermal hyperalgesia in the hot plate test, while behaviour in the tail-flick and von Frey tests did not differ between WKY and Sprague-Dawley rats. Furthermore, WKY rats exhibited enhanced formalin-evoked nociceptive responding up to 40 min post administration, an effect inversely correlated with serotonin and 5-HIAA levels in the hypothalamus. In conclusion, these findings demonstrate that altered pain responding observed in clinically depressed patients can be modelled pre-clinically, providing a means of investigating the neurochemical basis of, and possible treatments for, this phenomenon. PMID- 20955768 TI - beta-pompilidotoxin modulates spontaneous activity and persistent sodium currents in spinal networks. AB - The origin of rhythm generation in mammalian spinal cord networks is still poorly understood. In a previous study, we showed that spontaneous activity in spinal networks takes its origin in the properties of certain intrinsically spiking interneurons based on the persistent sodium current (INaP). We also showed that depolarization block caused by a fast inactivation of the transient sodium current (INaT) contributes to the generation of oscillatory activity in spinal cord cultures. Recently, a toxin called beta-pompilidotoxin (beta-PMTX) that slows the inactivation process of tetrodotoxin (TTX)-sensitive sodium channels has been extracted from the solitary wasp venom. In the present study, we therefore investigated the effect of beta-PMTX on rhythm generation and on sodium currents in spinal networks. Using intracellular recordings and multielectrode array (MEA) recordings in dissociated spinal cord cultures from embryonic (E14) rats, we found that beta-PMTX reduces the number of population bursts and increases the background asynchronous activity. We then uncoupled the network by blocking all synaptic transmission (APV, CNQX, bicuculline and strychnine) and observed that beta-PMTX increases both the intrinsic activity at individual channels and the number of intrinsically activated channels. At the cellular level, we found that beta-PMTX has two effects: it switches 58% of the silent interneurons into spontaneously active interneurons and increases the firing rate of intrinsically spiking cells. Finally, we investigated the effect of beta-PMTX on sodium currents. We found that this toxin not only affects the inactivation of INaT but also increases the peak amplitude of the persistent sodium current (INaP). Altogether, theses findings suggest that beta-PMTX acting on INaP and INaT enhances intrinsic activity leading to a profound modulation of spontaneous rhythmic activity in spinal networks. PMID- 20955769 TI - Strain differences in neurogenesis and activation of new neurons in the dentate gyrus in response to spatial learning. AB - Adult neurogenesis continues throughout life in the mammalian hippocampus and evidence suggests that adult neurogenesis is involved in hippocampus-dependent learning and memory. Numerous studies have demonstrated that spatial learning enhances neurogenesis in the hippocampus but few studies have examined whether enhanced neurogenesis is related to enhanced activation of new neurons in response to spatial learning. Furthermore, the majority of these studies have utilized Sprague-Dawley (SD) rats. However, Long-Evans and Sprague-Dawley rats have been reported to have different learning abilities. In order to determine whether these strains exhibit a similar enhancement of neurogenesis and new neuronal activation in response to spatial learning we tested both strains in a hippocampus-dependent or hippocampus-independent version of the Morris water task (MWT) and then compared levels of neurogenesis and activation of these new cells in the hippocampus. Here we show that despite equivalent performance in the MWT, spatial learning produced a different effect on neurogenesis in each strain. Spatial learning increased cell survival and the number of immature neurons in SD rats compared to cage control and cue-trained rats. In Long-Evans (LE) rats however, spatial learning increased cell survival (BrdU-labeling) but did not increase the number of immature neurons (doublecortin-labeling). Furthermore, we report here an intriguing difference in the activation of new neurons (using the immediate early gene product zif268) in SD versus LE rats. In SD rats we show that spatial learning increases the percentage of doublecortin-labeled cells that are activated during a probe trial. Conversely, in LE rats spatial learning increased the activation of BrdU-labeled but not doublecortin-labeled cells. This interesting difference suggests that different ages or maturational stages of cells are recruited by spatial learning in the two strains. These findings may lead to a better understanding of how and why neurogenesis is regulated by spatial learning. PMID- 20955771 TI - Randomized and double-blinded pilot clinical study of the safety and anti diabetic efficacy of the Rauvolfia-Citrus tea, as used in Nigerian traditional medicine. AB - AIM OF THE STUDY: The aim of this randomized and double blinded pilot clinical trial was to investigate the anti-diabetic efficacy of the Rauvolfia-Citrus (RC) tea in humans. We have earlier shown that a combination of calorie-restriction and chronic administration of the RC tea to the genetic diabetic (BKS-db) mice resulted in the normalization of blood sugar, reduction in lipid accumulated in the mice eyes and prevention of the degeneration of the otherwise brittle BKS-db pancreas. The tea is made by boiling foliage of Rauvolfia vomitoria and fruits of Citrus aurantium and is used to treat diabetes in Nigerian folk medicine. MATERIALS AND METHODS: The RC tea was produced using the Nigerian traditional recipe and tested in the traditional dosage on 23 Danish type 2 diabetes (T2D) patients. The participants were divided into two equivalent groups after stratification by sex, age and BMI, in a 4-month double-blinded, placebo controlled and randomized clinical trial. Most of the study subjects (19/23) were using oral anti-diabetic agents (OADs). Mean disease duration was 6+/-4.6 years, mean age was 64+/-7 years and mean BMI was 28.7+/-3.8 kg/m(2). Prior to starting the treatment, the participants received individual dietician consultations. RESULTS: At the end of the 4-month treatment period, the treated group showed an 11% decrease in 2-h postprandial plasma glucose relative to the 3% increase in the placebo group (p=0.004). The improvement in blood glucose clearance with RC tea treatment was reflected in a 6% reduction in HbA(1c) (p=0.02) and in a 10% reduction in fasting plasma glucose (p=0.02), when comparing the post 4-month treatment to pre-treatment baseline values. Though the basal levels of phosphorylated acetyl CoA carboxylase enzyme in skeletal muscle were significantly reduced in the treated group (p=0.04), as compared to the placebo, only the pattern of reductions in the tissue fatty acids (FAs) differed in the two groups. While all types of FAs were reduced in placebo, only saturated (SFA) and monounsaturated (MUFA) FAs were reduced with treatment. Interestingly, a modest increase in the polyunsaturated FAs fraction was observed in the RC treated group. In addition, the reduction in SFA and MUFA with RC tea treatment came solely from the triglyceride fractions, as there was an increase in the skeletal muscle phospholipids. CONCLUSIONS: Chronic administration of the RC tea to overweight T2D on OADs caused significant improvements in markers of glycaemic control and modifications to the fatty acid profile of skeletal muscle, without adverse effects or hypoglycaemia. Further exploration of the anti-diabetic effects of the RC tea is warranted. PMID- 20955770 TI - Tumor necrosis factor-like weak inducer of apoptosis and fibroblast growth factor inducible 14 mediate cerebral ischemia-induced poly(ADP-ribose) polymerase-1 activation and neuronal death. AB - Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Fn14) are expressed in neurons. Here we demonstrate that TWEAK induces a dose-dependent increase in neuronal death and that this effect is independent of tumor necrosis factor alpha (TNF-alpha) and mediated by nuclear factor-kappa B (NF-kappaB) pathway activation. Incubation with TWEAK induces apoptotic cell death in wild-type (Wt) but not in Fn14 deficient (Fn14(-/-)) neurons. Intracerebral injection of TWEAK induces accumulation of poly(ADP-ribose) polymers (PAR) in Wt but not in Fn14(-/-) mice. Exposure to oxygen-glucose deprivation (OGD) conditions increases TWEAK and Fn14 mRNA expression in Wt neurons, and decreases cell survival in Wt but not in Fn14( /-) or TWEAK deficient (TWEAK(-/-)) neurons. Experimental middle cerebral artery occlusion (MCAO) increases the expression of TWEAK and Fn14 mRNA and active caspase-3, and the cleavage of poly(ADP-ribose) polymerase-1 (PARP-1) with accumulation of PAR in the ischemic area in Wt but not Fn14(-/-) mice. Together, these results suggest a model where in response to hypoxia/ischemia the interaction between TWEAK and Fn14 in neurons induces PARP-1 activation with accumulation of PAR polymers and cell death via NF-kappaB pathway activation. This is a novel pathway for hypoxia/ischemia-induced TWEAK-mediated cell death and a potential therapeutic target for ischemic stroke. PMID- 20955772 TI - Anti-inflammatory and antinociceptive effects of Garcinia brasiliensis. AB - AIM OF THE STUDY: In Brazilian folk medicine, the leaves of Garcinia brasiliensis are used to treat tumors, inflammation of the urinary tract and arthritis as well as to relieve pain. Nevertheless, scientific information regarding Garcinia brasiliensis is limited; there are no reports related to its possible anti inflammatory and antinociceptive effects. This study employed in vivo inflammatory and nociceptive models to evaluate the scientific basis for the traditional use of Garcinia brasiliensis. MATERIALS AND METHODS: Carrageenan induced paw edema, peritonitis and fibrovascular tissue growth induced by s.c. cotton pellet implantation were used to investigate the anti-inflammatory activity of Garcinia brasiliensis ethanolic extract (GbEE) in rats. Formalin and acetic acid-induced writhing tests were used to investigate the antinociceptive activity in mice. RESULTS: GbEE at test doses of 30-300 mg/kg p.o. clearly demonstrated anti-inflammatory effects by reduced paw edema induced by carrageenan, inhibited leukocyte recruitment into the peritoneal cavity, and in the model of chronic inflammation using the cotton pellet-induced fibrovascular tissue growth in rats, the GbEE significantly inhibited the formation of granulomatous tissue. The extracts at test doses of 30-300 mg/kg, p.o., clearly demonstrated antinociceptive activity, except for the first phase of the formalin test. CONCLUSION: GbEE markedly demonstrated anti-inflammatory action in rats and antinociceptive activity in mice, which supports previous claims of the traditional use of species of the Garcinia genus for inflammation and pain. PMID- 20955773 TI - Insulin sensitization by voluntary exercise in aging rats is mediated through hepatic insulin sensitizing substance (HISS). AB - BACKGROUND: Food in the upper gastrointestinal tract potentiates the glucose uptake response to insulin. Meal-induced insulin sensitization (MIS) occurs as a result of insulin-mediated release of hepatic insulin sensitizing substance (HISS) that increases glucose uptake in peripheral tissues. HISS release decreases with age, and exercise causes metabolic improvements in aging, therefore it is important to analyze the effect of exercise on age-associated decline in HISS-action. OBJECTIVES: The aim of this study is to test the hypothesis that improved insulin sensitivity, by voluntary running-wheel exercise in aging rats, is attained by preserving the HISS response. We also investigate the possible association of exercise-mediated beneficial changes in metabolic conditions and body composition with improved HISS-action. METHODS: We measured insulin- and HISS-sensitivity in 9, 14 and 21-week old rats with/without exercise. Metabolic markers were also determined in age-matched control and exercised rats. RESULTS: Exercise significantly improved HISS-dependent glucose uptake in all age groups. The direct action of insulin was minimally altered by age or exercise. Body composition and metabolic conditions were beneficially changed with exercise-induced improvements in the HISS response. CONCLUSION: The therapeutic efficacy of voluntary exercise against insulin resistance in aging rats is achieved mainly through restoration of HISS-action. PMID- 20955774 TI - Developmental and metabolic brain alterations in rats exposed to bisphenol A during gestation and lactation. AB - In recent years, considerable research has focused on the biological effect of endocrine-disrupting chemicals. Bisphenol A (BPA) has been implicated as an endocrine-disrupting chemical (EDC) due to its ability to mimic the action of endogenous estrogenic hormones. The aim of this study was to assess the effect of perinatal exposure to BPA on cerebral structural development and metabolism after birth. BPA (1mg/l) was administered in the drinking water of pregnant dams from day 6 of gestation until pup weaning. At postnatal day 20, in vivo metabolite concentrations in the rat pup hippocampus were measured using high field proton magnetic resonance spectroscopy. Further, brain was assessed histologically for growth, gross morphology, glial and neuronal development and extent of myelination. Localized proton magnetic resonance spectroscopy ((1)H MRS) showed in the BPA-exposed rat a significant increase in glutamate concentration in the hippocampus as well as in the Glu/Asp ratio. Interestingly these two metabolites are metabolically linked together in the malate-aspartate metabolic shuttle. Quantitative histological analysis revealed that the density of NeuN-positive neurons in the hippocampus was decreased in the BPA-treated offspring when compared to controls. Conversely, the density of GFAP-positive astrocytes in the cingulum was increased in BPA-treated offspring. In conclusion, exposure to low dose BPA during gestation and lactation leads to significant changes in the Glu/Asp ratio in the hippocampus, which may reflect impaired mitochondrial function and also result in neuronal and glial developmental alterations. PMID- 20955776 TI - Citalopram reduces endotoxin-induced fatigue. AB - Increased levels of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6) may play a role in depression. Mild depressive-like symptoms can be induced in humans through activation of the innate immune system with endotoxin. Whether preventive treatment with antidepressants can reduce endotoxin-induced symptoms has never been tested. In a double-blind, randomized, placebo-controlled, cross-over study, we administered intravenous low-dose endotoxin (0.8 ng/kg) or placebo to 11 healthy subjects who had received oral pre treatment with citalopram (10 mg twice a day) or placebo for 5 days. The Montgomery-Asberg Depression Rating Scale, the State and Trait Anxiety Inventory, and a visual analog scale were used to measure depressive and anxiety symptoms and social anhedonia. Serum levels of TNF and IL-6 were measured with immunoassays. Compared to placebo, endotoxin administration increased serum levels of TNF and IL-6, and caused mild depressive-like symptoms, in particular lassitude and social anhedonia. While citalopram pre-treatment had no effect on the innate immune response to endotoxin, it reduced the endotoxin-induced MADRS total score by 50%, with a moderate effect size (Cohen's d=0.5). Most of the MADRS total score was due to the lassitude item, and citalopram pre-treatment specifically reduced endotoxin-induced lassitude with a large effect size (Cohen's d=0.9). These results suggest that subchronic pre-treatment with the serotonin-reuptake inhibitor citalopram blunts mood symptoms induced by acute immune system activation with endotoxin without inhibiting the peripheral immune response. PMID- 20955775 TI - Childhood onset schizophrenia: support for a progressive neurodevelopmental disorder. AB - Structural brain abnormalities have become an established feature of schizophrenia and increasing evidence points towards the progressive nature of these abnormalities. The brain abnormalities are most profound in early onset cases, which have a severe, treatment refractory phenotype and more salient genetic features. Unique insights could thus be gained in schizophrenia pathology from studying the earliest manifestations of the illness. This paper reviews and updates the findings on anatomic brain development in patients with very early onset schizophrenia while showing preliminary data from ongoing studies. Collectively, our studies demonstrate that childhood-onset schizophrenia (COS) subjects show progressive loss of gray matter, delayed/disrupted white matter (WM) growth, and a progressive decline in cerebellar volume, some of which are shared by their healthy siblings. The developmental patterns or the 'trajectories' of brain development are often more striking than anatomic brain differences at any one point in time; highlighting the importance of longitudinal studies. The sibling findings of partially shared gray matter (GM) deficits which appear to normalize with age, along with other genetic analyses, provide evidence that the brain developmental 'patterns/trajectories' for several regions at particular ages could be useful endophenotypes (trait markers). PMID- 20955777 TI - Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. AB - Noradrenergic pathways have been implicated in growth and progression of ovarian cancer. Intratumoral norepinephrine (NE) has been shown to increase with stress in an animal cancer model, but little is known regarding how tumor NE varies with disease stage and with biobehavioral factors in ovarian cancer patients. This study examined relationships between pre-surgical measures of social support, depressed mood, perceived stress, anxiety, tumor histology and tumor catecholamine (NE and epinephrine [E]) levels among 68 ovarian cancer patients. We also examined whether associations observed between biobehavioral measures and tumor catecholamines extended to other compartments. Higher NE levels were found in advanced stage (p=0.006) and higher grade (p=0.001) tumors. Adjusting for stage, grade, and peri-surgical beta blockers, patients with a perceived lack of social support had significantly higher tumor NE (beta=-0.29, p=0.012). A similar trend was seen for social support and ascites NE (adjusting for stage, peri surgical beta blockers and caffeine: beta=-0.50, p=0.075), but not for plasma NE. Other biobehavioral factors were not related to tumor, ascites, or plasma NE (p values >0.21). Tumor E was undetectable in the majority of tumors and thus E was not further analyzed. In summary, these results suggest that tumor NE provides distinct information from circulating plasma concentrations. Tumor NE levels were elevated in relationship to tumor grade and stage. Low subjective social support was associated with elevated intratumoral NE. As beta-adrenergic signaling is related to key biological pathways involved in tumor growth, these findings may have implications for patient outcomes in ovarian cancer. PMID- 20955779 TI - A pilot study of immune network remodeling under challenge in Gulf War Illness. AB - Gulf War Illness (GWI) is a complex disorder affecting nervous, endocrine and immune regulation. Accordingly, we propose that GWI presents with a distinct pattern of immune signaling. To explore this we compared interaction patterns linking immune markers and their evolution during exercise. Blood was collected from 9 GWI and 11 control subjects prior to a Graded eXercise Test (GXT) (t0), at peak effort (t1) and 4 h post-exercise (t2). Salivary cortisol and plasma, serum or culture supernatants were analyzed for concentrations of neuropeptide Y (NPY), IL-1alpha, IL-5, IL-6, IL-10, TNF-alpha, IFN-gamma and soluble CD26 (sCD26). Immune cell populations were surface stained for CD19, CD2, CD3, CD4, CD8, CD26, CD56, CD16, and CD11a. Mutual information (MI) networks linking these immune markers were generated in each group at each time point. Graph theory was used to describe the evolution of each network's structure and identify potential nucleating points. Distinct in topology, GWI networks had more abundant connections but were less organized. NPY, IL-1alpha, TNF-alpha and CD2+/CD26+ nodes were better integrated in the GWI network at rest. Under effort (t1) these differences were replaced by significant restructuring around nodes for CD19+ B cell population, IL-5, IL-6 and soluble CD26 concentrations. This pattern subsided post-exercise. Further analysis indicated that IL-1alpha and CD2+/CD26+ nodes strongly influenced this characteristic modulation of B and T cell network motifs. This potentially heightened lymphocyte and HPA axis responsiveness to IL 1 stimulation in the context of a mixed Th1:Th2 immune signature supports an autoimmune component in GWI etiology. PMID- 20955778 TI - Immune suppression and immune activation in depression. AB - Depression has been characterized as a disorder of both immune suppression and immune activation. Markers of impaired cellular immunity (decreased natural killer cell cytotoxicity) and inflammation (elevated IL-6, TNFalpha, and CRP) have been associated with depression. These immunological markers have been associated with other medical illnesses, suggesting that immune dysregulation may be a central feature common to both depression and to its frequent medical comorbidities. Yet the significant associations of findings of both immune suppression and immune activation with depression raise questions concerning the relationship between these two classes of immunological observations. Depressed populations are heterogeneous groups, and there may be differences in the immune profiles of populations that are more narrowly defined in terms of symptom profile and/or demographic features. There have been few reports concurrently investigating markers of immune suppression and immune activation in the same depressed individuals. An emerging pre-clinical literature suggests that chronic inflammation may directly contribute to the pathophysiology of immune suppression in the context of illnesses such as cancer and rheumatoid arthritis. This literature provides us with specific immunoregulatory mechanisms mediating these relationships that could also explain differences in immune disturbances between subsets of depressed individuals We propose a research agenda emphasizing the assessment of these immunoregulatory mechanisms in large samples of depressed subjects as a means to define the relationships among immune findings (suppression and/or activation) within the same depressed individuals and to characterize subsets of depressed subjects based on shared immune profiles. Such a program of research, building on and integrating our knowledge of the psychoneuroimmunology of depression, could lead to innovation in the assessment and treatment of depression and its medical comorbidities. PMID- 20955780 TI - Effects of non-occupational environmental exposure to pyrethroids on semen quality and sperm DNA integrity in Chinese men. AB - Observations in several western and Asiatic countries point toward a decline in semen quality which may be associated with environmental exposures. To investigate the effect of environmental exposure to pyrethroids on sperm DNA integrity and semen quality, 240 men were recruited from an infertility clinic through the clinic following strict eligibility screening. Urinary 3 phenoxybenzoic acid (3-PBA) concentration, semen quality, and sperm DNA integrity were evaluated. After adjustment for potential confounders, a significant inverse correlation was observed between the urinary 3-PBA level and the sperm concentration (beta=-0.27, 95%CI: -0.41 to -0.12, P<0.001). Moreover, we also found a significant positive correlation between urinary 3-PBA level and sperm DNA fragmentation (beta=0.27, 95%CI: 0.15-0.39, P<0.001). Our results suggest that non-occupational environmental pyrethroids exposure may have a negative impact on sperm DNA integrity and semen quality in Chinese males. PMID- 20955781 TI - TGFbeta-1 and Wnt-3a interact to induce unique gene expression profiles in murine embryonic palate mesenchymal cells. AB - Development of the secondary palate in mammals is a complex process under the control of numerous growth and differentiation factors that regulate key processes such as cell proliferation, synthesis of extracellular matrix molecules, and epithelial-mesenchymal transdifferentiation. Alterations in any one of these processes either through genetic mutation or environmental insult have the potential to lead to clefts of the secondary palate. Members of the TGFbeta family of cytokines are crucial mediators of these processes and emerging evidence supports a pivotal role for members of the Wnt family of secreted growth and differentiation factors. Previous work in this laboratory demonstrated cross talk between the Wnt and TGFbeta signaling pathways in cultured mouse embryonic palate mesenchymal cells. In the current study we tested the hypothesis that unique gene expression profiles are induced in murine embryonic palate mesenchymal cells as a result of this cross-talk between the TGFbeta and Wnt signal transduction pathways. PMID- 20955783 TI - Copulatory efficiency and fertility in male rats exposed perinatally to flutamide. AB - This study investigated the effects of perinatal treatment with flutamide on male sexual behavior, semen parameters, and fertility in adult male rats. Pregnant rats received 15 mg/kg of flutamide or peanut oil, s.c., at days 19 and 22 of pregnancy and for the first five postnatal days. Treated male offspring showed increases in latency to copulatory behavior, number of mounts without penis intromission, number of intromissions until ejaculation, latency to ejaculation, and reduced number of ejaculations. Flutamide treated rats presented reductions in weight of testes and prostate, percentage of normal spermatozoa, spermatozoa concentration, testicular sperm production, and testosterone level. Normal females mated with treated males presented more pre-implantation losses, reduced implantation rates, and consequently reduced offspring size. The results indicated that perinatal flutamide treatment damaged organizational processes of sexual differentiation, which led to inefficiency in copulatory behavior and reductions in sperm quality and count, resulting in low capacity for producing descendants. PMID- 20955782 TI - Circulating levels of genistein in the neonate, apart from dose and route, predict future adverse female reproductive outcomes. AB - Developmental exposure to estrogenic compounds can disrupt sexual differentiation and adult reproductive function in many animals including humans. Phytoestrogens (plant estrogens) in the diet comprise a significant source of estrogenic exposure to humans, particularly in infants who are fed soy-based infant formula. Animal models have been developed to test the effects of phytoestrogen exposure on the developing fetus and neonate. Here we review studies quantifying the amount of phytoestrogen exposure in human adults and infants and discuss the few available epidemiological studies that have addressed long-term consequences of developmental phytoestrogen exposure. We then describe in detail rodent models of developmental exposure to the most prevalent phytoestrogen in soy products, genistein, and the effects of this exposure on female reproductive function. These models have used various dosing strategies to mimic the phytoestrogen levels in human populations. Serum circulating levels of genistein following each of the models and their correlation to reproductive outcomes are also discussed. Taken together, the studies clearly demonstrate that environmentally relevant doses of genistein have significant negative impacts on ovarian differentiation, estrous cyclicity, and fertility in the rodent model. Additional studies of reproductive function in human populations exposed to high levels of phytoestrogens during development are warranted. PMID- 20955784 TI - Developmental exposure to TCDD reduces fertility and negatively affects pregnancy outcomes across multiple generations. AB - TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is a ubiquitous environmental contaminant and known endocrine disruptor. Since humans and animals are most sensitive to toxicant exposure during development, we previously developed a mouse model of in utero TCDD exposure in order to examine the impact of this toxicant on adult reproductive function. Our initial in utero toxicant-exposure study revealed a dose-dependent reduction in uterine sensitivity to progesterone; however, we did not previously explore establishment or maintenance of pregnancy. Thus, in the current study, we examined pregnancy outcomes in adult C57BL/6 mice with a history of developmental TCDD exposure. Herein we demonstrate reduced fertility and an increased incidence of premature birth (PTB) in F1 mice exposed in utero to TCDD as well as in three subsequent generations. Finally, our studies revealed that mice with a history of developmental TCDD exposure exhibit an increased sensitivity to inflammation which further negatively impacted gestation length in all generations examined. PMID- 20955785 TI - Species- and strain-dependent teratogenicity of methanol in rabbits and mice. AB - Estimates of human risk for developmental toxicity of methanol (MeOH) are based on studies in rodents, which unlike humans use catalase to metabolize MeOH. Rabbits, like humans, may largely use alcohol dehydrogenase (ADH), and more accurately than rodents reflect primate MeOH and formic acid (FA) pharmacokinetic profiles. Here we show that New Zealand white rabbits and one strain of mouse (C3H) are resistant to MeOH teratogenicity, whereas C57BL/6J mice are susceptible. Neither rabbits nor mice were susceptible to the acute MeOH toxicity observed in humans. The strain-dependent teratological susceptibility in mice could not be explained by differences in MeOH or FA disposition, nor could the resistance of rabbits, which exhibited more prolonged FA accumulation, suggesting that different mechanisms underlie MeOH teratogenesis and the FA-mediated acute toxicity in humans. It is not clear if the human risk for MeOH developmental toxicity can be accurately estimated using sensitive rodent strains. PMID- 20955786 TI - Transplacental genotoxicity of antiepileptic drugs: animal model and pilot study on mother/newborn cohort. AB - Antiepileptic drugs (AED) as transplacental agents are known to have adverse effects on fetal development. Genotoxicity of AEDs is still not fully understood. The aim of present study was to investigate the transplacental genotoxicity of valproate on animal model and in 21 mothers and their newborns receiving AED. In both studies, in vivo micronucleus (MN) assay was used. Pregnant dams were exposed to Na-valproate (100mg/kg) on gestational days 12-14. Dams and pups receiving Na-valproate showed a significantly increased MN frequency (5.17 +/- 1.17/1000; 5.20 +/- 1.48/1000) compared to the control (1.0 +/- 0.58/1000; 1.67 +/- 1.03/1000). In mother/newborn study a significant increase of MN frequency was detected in newborns of mothers taking AEDs (3.09 +/- 0.49/10,000) compared to the referent newborns (1.56 +/- 0.22/10,000). The results of this study suggest that AEDs may act as transplacental genotoxins. Launching the mother/newborn cohorts for genotoxicological monitoring may give a significant new insight in health effects of AEDs. PMID- 20955787 TI - Cigarette smoke inhibits recruitment of bone-marrow-derived stem cells to the uterus. AB - Cigarette smoking leads to female infertility and a decreased incidence of endometriosis. Bone marrow derived stem cells are recruited to uterine endometrium and endometriosis. The effect of cigarette smoking on stem cell recruitment to any organ is uncharacterized. We hypothesized that bone marrow derived mesenchymal stem cell recruitment to the uterus and differentiation would be diminished by cigarette smoke. We used human mesenchymal stem cells (hMSC) in vitro and a mouse model of cigarette smoke exposure. After myeloablation female C57BL/6J received bone marrow cells from males. Mice were exposed to room air or smoke from unfiltered cigarettes. Immunofluorescence and Y-FISH was performed on uterine sections. In vitro hMSCs were treated with 8-Br-cAMP to induce endometrial cell differentiation with or without cigarette smoke extract (CSE) and decidualization assessed morphologically and by prolactin expression. After 4 weeks the total number of Y-chromosome cells in the uterus was reduced by 68% in the smoke exposed mice. Both leukocytes and bone marrow derived endometrial cells were reduced by 60% and 73%, respectively. Differentiation of bone marrow derived cell to endometrial epithelial cells was reduced by 84%. hMSC treated with CSE failed to show cytological characteristics of decidualization. mRNA levels of the decidualization marker prolactin were decreased by 90% in CSE treated cells. Smoking inhibits both recruitment of bone marrow derived stem cells to uterus and stem cell differentiation. Inhibition of stem cells recruitment may be a general mechanism by which smoking leads to long term organ damage through inability to repair or regenerate multiple tissues. PMID- 20955788 TI - Isotope-reinforced polyunsaturated fatty acids protect yeast cells from oxidative stress. AB - The facile abstraction of bis-allylic hydrogens from polyunsaturated fatty acids (PUFAs) is the hallmark chemistry responsible for initiation and propagation of autoxidation reactions. The products of these autoxidation reactions can form cross-links to other membrane components and damage proteins and nucleic acids. We report that PUFAs deuterated at bis-allylic sites are much more resistant to autoxidation reactions, because of the isotope effect. This is shown using coenzyme Q-deficient Saccharomyces cerevisiae coq mutants with defects in the biosynthesis of coenzyme Q (Q). Q functions in respiratory energy metabolism and also functions as a lipid-soluble antioxidant. Yeast coq mutants incubated in the presence of the PUFA alpha-linolenic or linoleic acid exhibit 99% loss of colony formation after 4h, demonstrating a profound loss of viability. In contrast, coq mutants treated with monounsaturated oleic acid or with one of the deuterated PUFAs, 11,11-D(2)-linoleic or 11,11,14,14-D(4)-alpha-linolenic acid, retain viability similar to wild-type yeast. Deuterated PUFAs also confer protection to wild-type yeast subjected to heat stress. These results indicate that isotope reinforced PUFAs are stabilized compared to standard PUFAs, and they protect coq mutants and wild-type yeast cells against the toxic effects of lipid autoxidation products. These findings suggest new approaches to controlling ROS-inflicted cellular damage and oxidative stress. PMID- 20955790 TI - Role of nitric oxide produced by iNOS through NF-kappaB pathway in migration of cerebellar granule neurons induced by Lipopolysaccharide. AB - Inflammatory stimulus during development increases the risk for adverse neurologic outcome. One possible mechanism is disrupting neuronal migration. Using lipopolysaccharide (LPS)-treatment to assess inflammatory stimulus on neuronal migration of cerebellar granule neurons, we previously found that LPS activation increased the neuronal migration. The precise mechanisms behind these effects have not been investigated. Independently, it was shown that nitric oxide (NO(*-)) regulates neuronal migration during development, that NO(*-) is produced by inducible nitric oxide synthase (iNOS) in response to LPS through the activation of nuclear factor (NF)-kappaB, and that LPS induce the expression of genes under the transcriptional control of NF-kappaB in primary cultures from developing mouse cerebellum. To investigate the relationship between these events, we used this culture model to study the role of NO(*-) produced by iNOS through NF-kappaB signaling pathway, in the effect of LPS on neuron migration. LPS increased NO(*-) production, iNOS protein levels and NF-kappaB nuclear levels; concomitantly with NO(*-) production, LPS increased the neuronal migration as compared to non stimulated cultures. The necessary roles of the NO(* ) and iNOS were demonstrated by chelating of NO(*-) with hemoglobin and the inhibition of iNOS by 1400W. Each of these treatments reduced neuronal migration induced by LPS. The role of NF-kappaB was showed by using the inhibitor JSH-23, which decreased NO(*-) production and neuronal migration in LPS activated cultures. These results suggest that neuronal migration during development is susceptible to be modified by pro-inflammatory stimulus such as LPS through intracellular pathways associated with their receptors. PMID- 20955789 TI - Thioredoxin 1 as a subcellular biomarker of redox imbalance in human prostate cancer progression. AB - We determined protein levels and subcellular distribution of thioredoxin 1 (Trx1) in human prostate tissues using tissue microarrays and analyzed redox changes in Trx1 in the nucleus and cytoplasm in cell culture models with a redox Western blot technique. We demonstrated increased nuclear Trx1 levels in high- versus low grade human prostate cancers. Despite increased protein levels, the oxidized forms of nuclear Trx1 were higher in prostate cancer cell lines compared to their benign counterparts, suggesting that nuclear redox imbalance occurred selectively in cancer cells. A growth-stimulating dose of androgen caused transient oxidation of Trx1 in androgen-responsive prostate cancer cells only, suggesting a loss of both androgen- and redox-signaling mechanisms during cancer progression. Androgen independent PC3 cells showed a significant increase in nuclear and cytoplasmic Trx1 protein levels, but a significant decrease in total Trx activity. Trx1 redox state and activity correlated with the sensitivity of prostate cancer cells to pro-oxidant agents, and downregulation of Trx1 sensitized cancer cells to these agents. Our findings suggest that loss of Trx function because of oxidation and corresponding redox imbalance may play important roles in prostate cancer progression and response to therapies; and Trx1 may serve as a biomarker of subcellular redox imbalance in prostate cancer. PMID- 20955791 TI - Transport of 5,5-diphenylbarbituric acid and its precursors and their effect on P gp, MRP2 and CYP3A4 in Caco-2 and LS180 cells. AB - AIM: To examine the transport of 5,5-diphenylbarbituric acid sodium (T2007) and its mono- (MMMDPB) and di- (T2000) methoxymethylated precursors and their inducibility potential in Caco-2 and LS180 cells. METHODS: Transport studies of T2000, MMMDPB and T2007 in Caco-2 cells were performed in Transwells. P-gp and CYP3A4 activities were assayed by [(3)H]digoxin and rhodamine 123 cellular retention and testosterone 6beta-hydroxylation, respectively. Expressions of PXR, VDR and CAR mRNA and CYP3A4, MDR1/P-gp and MRP2 mRNA and protein were determined by qPCR and Western blotting, respectively. PXR siRNA was used to assess the involvement of PXR. RESULTS: The P(app(A->B))s and P(app(B->A))s of T2000, MMMDPB and T2007 were similar (30-35*10(-6)cm/s) in Caco-2 cells. Treatment for 3 days with T2000 (15MUM), MMMDPB (70MUM) and T2007 (300MUM) generally furnished a greater induction in LS180 cells over the Caco-2 cells due to the higher, natural abundance of PXR. Changes in expression were confined mostly to MDR1 and CYP3A4: in LS180 cells, treatment for 3 days increased MDR1 and CYP3A4 but not MRP2 mRNA, and elevated P-gp and CYP3A4 protein expression that led to decreased cellular accumulation of [(3)H]digoxin and rhodamine 123, and enhanced testosterone 6beta hydroxylase activity towards T2007, respectively. The silencing of PXR by PXR siRNA in LS180 cells significantly attenuated the induction of MDR1 and CYP3A4. CONCLUSIONS: T2000, MMMDPB, and T2007 exhibited high permeabilities but are not P gp substrates. T2007 and its analogs upregulated CYP3A4 and MDR1 modestly via the PXR. PMID- 20955792 TI - Dimerization of human lysyl hydroxylase 3 (LH3) is mediated by the amino acids 541-547. AB - Lysyl hydroxylases (LH), which catalyze the post-translational modifications of lysines in collagen and collagen-like proteins, function as dimers. However, the amino acids responsible for dimerization and the role of dimer formation in the enzymatic activities of LH have not yet been identified. We have localized the region responsible for the dimerization of lysyl hydroxylase 3 (LH3), a multifunctional enzyme of collagen biosynthesis, to a sequence of amino acids between the glycosyltransferase activity and the lysyl hydroxylase activity domains. This area is covered by amino acids 541-547 in human LH3, but contains no cysteine residues. The region is highly conserved among LH isoforms, and is also involved in the dimerization of LH1 subunits. Dimerization is required for the LH activity of LH3, whereas it is not obligatory for the glycosyltransferase activities. In order to determine whether complex formation can occur between LH molecules originating from different species, and between different LH isoforms, double expressions were generated in a baculovirus system. Heterocomplex formation between mouse and human LH3, between human LH1 and LH3 and between human LH2 and LH3 was detected by western blot analyses. However, due to the low amount of complexes formed, the in vivo function of heterocomplexes remains unclear. PMID- 20955793 TI - Steroid catabolism in marine and freshwater fish. AB - Steroids play important roles in regulating many physiological functions in marine and freshwater fish. Levels of active steroid in blood and tissues are determined by the balance between synthetic and catabolic processes. This review examines what is known about pathways of catabolism of steroids, primarily sex steroids, in marine and freshwater fish. Cytochrome P450 (P450) isoforms present in hepatic microsomes catalyze steroid hydroxylation to metabolites with lower or no activity at estrogen or androgen receptors. Important pathways of steroid catabolism to readily excreted metabolites are glucuronidation and sulfonation of hydroxyl groups. Estradiol, testosterone, DHEA and hydroxylated metabolites of these and other steroids readily form glucuronide and sulfate conjugates in those fish species where these pathways have been examined. Little is known, however, of the structure and function of the UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes involved in steroid conjugation in fish. Glucuronide and sulfate conjugates of steroids may be transported into and out of cells by organic anion transporter proteins and multi-drug resistance proteins, and there is growing evidence that these proteins play important roles in steroid conjugate transport and elimination. Induction or inhibition of any of these pathways by environmental chemicals can result in alteration of the natural balance of steroid hormones and could lead to disruption of the endocrine system. Recent studies in this area are presented, with particular focus on phase II (conjugative) pathways. PMID- 20955794 TI - Nuclear vitamin D receptor expression is associated with improved survival in non small cell lung cancer. AB - Vitamin D has been shown to have anti-proliferative effects in a wide variety of cancers including lung cancer. The anticancer effects of vitamin D are mediated primarily by its active metabolite, 1,25-dihydroxyvitamin D (calcitriol), through vitamin D receptor (VDR) signaling. However, thus far there have been no studies evaluating the association between VDR expression and survival outcome in lung cancer. Using immunohistochemical analysis, we evaluated VDR expression, separately in the nucleus and cytoplasm, in lung cancer samples from 73 non-small cell lung carcinoma (NSCLC) patients with no prior therapy, and investigated the association between VDR expression and overall survival (OS). Cox proportional hazard models were used for our primary analyses. There were 44 deaths during a median follow-up of 51 months (range 13-93 months). High nuclear VDR expression was associated with improved OS after adjusting for age, gender, stage, smoking status, and histology (adjusted hazard ratio, 0.36; 95% confidence interval, 0.17 0.79). There was no association between cytoplasmic VDR expression and OS. Our results suggest that nuclear VDR status may be a prognostic marker in NSCLC. Future large studies to replicate our findings and to assess the impact of VDR gene polymorphisms on VDR expression are required as therapies targeting the vitamin D signaling pathway may be influenced by VDR status in the target lung cancer tissue. PMID- 20955795 TI - Transplant long-surviving induced by CD40-CD40 ligand costimulation blockade is dependent on IFN-gamma through its effect on CD4(+)CD25(+) regulatory T cells. AB - BACKGROUND: IFN-gamma was documented to be commonly associated with acute rejection. In the present study, we investigated the role of IFN-gamma in the transplant long-surviving induced by blocking CD40-CD40 ligand (CD40-CD40L) costimulation and its mechanisms. METHODS: IFN-gamma expression in cardiac allografts and spleens from syngeneic and allogeneic recipients with or without anti-CD40L monoclonal antibody (MR-1) treatment was examined by real-time RT-PCR. The grafts survival time in Wild type (IFN-gamma(+/+)) and IFN-gamma deficient (IFN-gamma(-/-)) recipients was investigated. Mixed lymphocyte reaction (MLR) of CD4(+) T cells and cytotoxic T lymphocyte (CTL) assay of CD8(+) T cells were also studied. FoxP3 expression in allografts and spleens from IFN-gamma(+/+) or IFN gamma(-/-) recipients with MR-1 treatment was examined. Furthermore, FoxP3, IL-10 and CTLA-4 expressions and the suppressive capability of CD4(+)CD25(+) regulatory T cells were examined. RESULTS: Rejected allografts showed significantly higher IFN-gamma expression than long-surviving allografts. Allograft survival was not prolonged in nonimmunosuppressed IFN-gamma(-/-) mice. Administration of MR-1 induced long-term survival in 90.1% of IFN-gamma(+/+) recipients (98+/-6.6 days) but failed to do so in IFN-gamma(-/-) group (16.2+/-4.0 days). IFN-gamma(-/-) recipients facilitated the proliferation and CTL generation of T cells. The allografts and spleens from IFN-gamma(+/+) recipients contained higher FoxP3 expression than IFN-gamma(-/-) recipients. Moreover, CD4(+)CD25(+) T cells from IFN-gamma(+/+) recipients displayed a higher FoxP3 and IL-10 expression and suppressive capability. CONCLUSION: IFN-gamma plays an important role in the long surviving induced by blocking CD40-CD40L through inhibiting the function of activated T cells and increasing suppressive capability of CD4(+)CD25(+) regulatory T cells. PMID- 20955796 TI - Human fetal neural precursor cells can up-regulate MHC class I and class II expression and elicit CD4 and CD8 T cell proliferation. AB - The use of allogeneic fetal neural precursor cells (NPCs) as a cell replacement therapy in neurodegenerative disorders holds great promise. However, previous studies concerning the possibility of alloimmune rejection of the transplanted cells have been inconclusive. Here, we used flow cytometry to quantify the expression of major histocompatibility complex (MHC) molecules by human NPCs, obtained from the cortex or ventral mesencephalon of fetuses with gestational ages between 7 and 11 weeks. MHC class I was undetectable on the surface of freshly isolated primary fetal tissue from either location, but increased over time in proliferating NPC cultures; after 7days in vitro, MHC class I was detectable on most cells. Following differentiation, MHC class I expression persisted on non-neuronal cells. MHC class II levels remained low at all time points but were inducible by pro-inflammatory cytokines, whereas the co stimulatory molecules, CD80 and CD86, remained undetectable. Nonetheless, CD4+ and CD8+ T cells proliferated when peripheral blood mononuclear cells (PBMCs) were cultured with allogeneic NPCs. Weaker responses were obtained when NPCs were co-cultured with purified allogeneic responder T cells, suggesting that indirect allorecognition contributed significantly to PBMC responses. In conclusion, differentiating human NPCs are immunogenic in vitro, suggesting that they may trigger immune rejection unless transplant recipients are immunosuppressed. PMID- 20955797 TI - Intrastriatal botulinum toxin abolishes pathologic rotational behaviour and induces axonal varicosities in the 6-OHDA rat model of Parkinson's disease. AB - Central pathophysiological pathways of basal ganglia dysfunction imply a disturbed interaction of dopaminergic and cholinergic circuits. In Parkinson's disease (PD) imbalanced cholinergic hyperactivity prevails in the striatum. Interruption of acetylcholine (ACh) release in the striatum by locally injected botulinum neurotoxin A (BoNT-A) has been studied in the rat 6-hydroxydopamine (6 OHDA) model of PD (hemi-PD). The hemi-PD was induced by injection of 6-OHDA into the right medial forebrain bundle. Motor dysfunction provoked by apomorphine induced contralateral rotation was completely reversed for more than 3 months by ipsilateral intrastriatal application of 1-2 ng BoNT-A. Interestingly, BoNT-A injected alone into the right striatum of naive rats caused a slight transient ipsilateral apomorphine-induced rotation, which lasted only for about one month. Immunohistochemically, large axonal swellings appeared within the striatum injected with BoNT-A, which we tentatively named BoNT-A-induced varicosities. They contained either choline acetyltransferase or tyrosine hydroxylase. These findings suggest a selective inhibition of evoked release of ACh by locally applied BoNT-A. Intrastriatal application of BoNT-A may antagonize localized relative functional disinhibited hypercholinergic activity in neurodegenerative diseases such as PD avoiding side effects of systemic anti-cholinergic treatment. PMID- 20955799 TI - Dietary administration of nucleotides to enhance growth, humoral immune responses, and disease resistance of the rainbow trout (Oncorhynchus mykiss) fingerlings. AB - A feeding study was conducted to determine the effect of dietary nucleotides (NT) on growth performance, immune responses and resistance of rainbow trout fingerlings to Streptococcus iniae. A basal diet supplemented with 0 (control), 0.5, 1, 1.5 and 2 g NT kg(-1) to formulate five experimental diets. Each diet was randomly allocated to triplicate groups of fish with initial average weight of approximately 23 g. After 8 weeks of feeding trial, fish fed diets with 1.5-2 g NT kg(-1) had the highest final weight and SGR, followed by groups fed the diets with 0.5-1 g NT kg(-1), and lowest in fish fed the NT-free control diet. The feed conversion ratio (FCR) was better when the fish were fed diet with 2 g NT kg(-1). The ACH(50) level and lysozyme activity in serum were found to be significantly (P < 0.05) greater in fish fed nucleotides at 1.5-2 g kg(-1). The fish fed with 2 g NT kg(-1) had higher IgM level. The challenge experiment showed that relative percent survival (RPS) increased significantly (P < 0.05) with increasing levels of nucleotides from 0.5 to 2 g kg(-1) and was lowest in the control group. We therefore recommend dietary nucleotide administration at 1.5-2 g kg(-1) to promote growth and enhance immunity and resistance against S. iniae. PMID- 20955798 TI - Variant base excision repair proteins: contributors to genomic instability. AB - Cells sustain endogenous DNA damage at rates greater than 20,000 DNA lesions per cell per day. These damages occur largely as a result of the inherently unstable nature of DNA and the presence of reactive oxygen species within cells. The base excision repair system removes the majority of DNA lesions resulting from endogenous DNA damage. There are several enzymes that function during base excision repair. Importantly, there are over 100 germline single nucleotide polymorphisms in genes that function in base excision repair and that result in non-synonymous amino acid substitutions in the proteins they encode. Somatic variants of these enzymes are also found in human tumors. Variant repair enzymes catalyze aberrant base excision repair. Aberrant base excision repair combined with continuous endogenous DNA damage over time has the potential to lead to a mutator phenotype. Mutations that arise in key growth control genes, imbalances in chromosome number, chromosomal translocations, and loss of heterozygosity can result in the initiation of human cancer or its progression. PMID- 20955800 TI - Molecular characterization of two isoforms of piscidin 4 from the hybrid striped bass (Morone chrysops * Morone saxatilis). PMID- 20955801 TI - Monitoring in language perception: electrophysiological and hemodynamic responses to spelling violations. AB - The monitoring theory of language perception proposes that competing representations that are caused by strong expectancy violations can trigger a conflict which elicits reprocessing of the input to check for possible processing errors. This monitoring process is thought to be reflected by the P600 component in the EEG. The present study further investigated this monitoring process by comparing syntactic and spelling violations in an EEG and an fMRI experiment. To assess the effect of conflict strength, misspellings were embedded in sentences that were weakly or strongly predictive of a critical word. In support of the monitoring theory, syntactic and spelling violations elicited similarly distributed P600 effects. Furthermore, the P600 effect was larger to misspellings in the strongly compared to the weakly predictive sentences. The fMRI results showed that both syntactic and spelling violations increased activation in the left inferior frontal gyrus (lIFG), while only the misspellings activated additional areas. Conflict strength did not affect the hemodynamic response to spelling violations. These results extend the idea that the lIFG is involved in implementing cognitive control in the presence of representational conflicts in general to the processing of errors in language perception. PMID- 20955802 TI - Impact of transient emotions on functional connectivity during subsequent resting state: a wavelet correlation approach. AB - The functional properties of resting brain activity are poorly understood, but have generally been related to self-monitoring and introspective processes. Here we investigated how emotionally positive and negative information differentially influenced subsequent brain activity at rest. We acquired fMRI data in 15 participants during rest periods following fearful, joyful, and neutral movies. Several brain regions were more active during resting than during movie-watching, including posterior/anterior cingulate cortices (PCC, ACC), bilateral insula and inferior parietal lobules (IPL). Functional connectivity at different frequency bands was also assessed using a wavelet correlation approach and small-world network analysis. Resting activity in ACC and insula as well as their coupling were strongly enhanced by preceding emotions, while coupling between ventral medial prefrontal cortex and amygdala was selectively reduced. These effects were more pronounced after fearful than joyful movies for higher frequency bands. Moreover, the initial suppression of resting activity in ACC and insula after emotional stimuli was followed by a gradual restoration over time. Emotions did not affect IPL average activity but increased its connectivity with other regions. These findings reveal specific neural circuits recruited during the recovery from emotional arousal and highlight the complex functional dynamics of default mode networks in emotionally salient contexts. PMID- 20955803 TI - Adjusting the effect of nonstationarity in cluster-based and TFCE inference. AB - In nonstationary images, cluster inference depends on the local image smoothness, as clusters tend to be larger in smoother regions by chance alone. In order to correct the inference for such nonstationary, cluster sizes can be adjusted according to a local smoothness estimate. In this study, adjusted cluster sizes are used in a permutation-testing framework for both cluster-based and threshold free cluster enhancement (TFCE) inference and tested on both simulated and real data. We find that TFCE inference is already fairly robust to nonstationarity in the data, while cluster-based inference requires an adjustment to ensure homogeneity. A group of possible multi-level adjustments are introduced and their results on simulated and real data are assessed using a new performance index. We also find that adjusting for local smoothness via a separate resampling procedure is more effective at removing nonstationarity than an adjustment via a random field theory based smoothness estimator. PMID- 20955804 TI - Comparison of phylogeographic structure and population history of two Phrynocephalus species in the Tarim Basin and adjacent areas. AB - An aridification of the Tarim Basin and adjacent areas since middle Pleistocene has produced significant genetic structuring of the local fauna. We examined the phylogeographic patterns, population structure and history of Phrynocephalus axillaris and Phrynocephalus forsythii using a mitochondrial fragment ND4 tRNA(LEU). Phylogenetic hypotheses were constructed using maximum parsimony and Bayesian inference, and the divergence times of major lineages were estimated by BEAST. Population structure and history were inferred by nested clade analysis, neutrality tests, mismatch distribution, and isolation by distance analysis. The two species might have experienced different evolutionary history throughout their current distribution. For P. forsythii, a vicariant event, as a consequence of geological isolation and desert expansion, might have produced the significant divergence between the Tarim and the Yanqi populations. For P. axillaris, populations of the Yanqi, Turpan and Hami Basins might have been established through dispersal during demographic expansion. Climatic fluctuations caused alternate expansion and shrinkage of rivers and oases several times, which likely led to habitat fragmentation for both species. Interaction between vicariance, dispersal and habitat fragmentation produced the current distribution and genetic diversity. The observed difference between the two species may be due partially to their different reproductive modes (ovoviviparous vs. oviparous). PMID- 20955805 TI - A polarized light microscopy method for accurate and reliable grading of collagen organization in cartilage repair. AB - OBJECTIVES: Collagen organization, a feature that is critical for cartilage load bearing and durability, is not adequately assessed in cartilage repair tissue by present histological scoring systems. Our objectives were to develop a new polarized light microscopy (PLM) score for collagen organization and to test its reliability. DESIGN: This PLM score uses an ordinal scale of 0-5 to rate the extent that collagen network organization resembles that of young adult hyaline articular cartilage (score of 5) vs a totally disorganized tissue (score of 0). Inter-reader reliability was assessed using Intraclass Correlation Coefficients (ICC) for Agreement, calculated from scores of three trained readers who independently evaluated blinded sections obtained from normal (n=4), degraded (n=2) and repair (n=22) human cartilage biopsies. RESULTS: The PLM score succeeded in distinguishing normal, degraded and repair cartilages, where the latter displayed greater complexity in collagen structure. Excellent inter-reader reproducibility was found with ICCs for Agreement of 0.90 [ICC(2,1)] (lower boundary of the 95% confidence interval is 0.83) and 0.96 [ICC(2,3)] (lower boundary of the 95% confidence interval is 0.94), indicating the reliability of a single reader's scores and the mean of all three readers' scores, respectively. CONCLUSION: This PLM method offers a novel means for systematically evaluating collagen organization in repair cartilage. We propose that it be used to supplement current gold standard histological scoring systems for a more complete assessment of repair tissue quality. PMID- 20955806 TI - Effects of TGF-beta1 on alternative splicing of Superficial Zone Protein in articular cartilage cultures. AB - OBJECTIVE: Superficial Zone Protein (SZP) is expressed by the superficial zone chondrocytes and is involved in boundary lubrication of the articular cartilage surface. SZP protein expression is dependent on anatomical location and is regulated by the transforming growth factor-beta (TGF-beta) pathway. The hypothesis of this study was that between load-bearing, and non-load-bearing locations, of the femoral medial condyle alternative splice isoforms of SZP are different, and regulated by TGF-beta1. METHODS: Using reverse transcription polymerase chain reaction (RT-PCR) we identified differentially expressed SZP alternative splicing. Using recombinant proteins of the N-terminal region produced from these isoforms, we identified differences in binding to heparin and the extracellular matrix. RESULTS: We identified a novel splice form of SZP (isoform E), lacking exons 2-5. Differences in alternative splicing were observed between anterior load-bearing locations of the femoral medial condyle (M1) compared to the posterior non-load-bearing location (M4). TGF-beta1 increased splicing out of exons 4 and 5 encoding a heparin binding domain. The minimal induction time for changes in splicing by TGF-beta1 at the M1 location was 1h, although this did change total SZP mRNA levels. Inhibition of Smad3 phosphorylation inhibited TGF-beta1 induced splicing, and SZP protein expression. Recombinant proteins corresponding to isoforms upregulated by TGF-beta1 had reduced binding. The SZP dimerization domain is located within exon 3. CONCLUSIONS: In conclusion, alternative splicing of SZP is regulated by TGF-beta1 signaling and may regulate SZP interaction with heparin/heparan sulfate or other components in the extracellular matrix of articular cartilage by splicing out of the heparin binding domain. PMID- 20955807 TI - Forecasting the burden of advanced knee osteoarthritis over a 10-year period in a cohort of 60-64 year-old US adults. AB - OBJECTIVE: To forecast the burden of symptomatic knee osteoarthritis (OA) in the elderly US population over a 10-year horizon. DESIGN: Using a computer simulation model of the natural history and management of knee OA combined with population based data from the 2008 US Census we projected the 10-year burden of knee OA among persons 60-64 years of age. Knee OA incidence and progression rates were derived from national cohorts and calibrated to published literature. RESULTS: Using national data we estimated that 13% of 14,338,292 adults 60-64 years old have prevalent symptomatic, radiographic knee OA. Among persons surviving the next decade, 20% will have symptomatic advanced (Kellgren-Lawrence [K-L] grade 3) or end-stage (K-L 4) knee OA. Prevalence of advanced knee OA will range from 10% among non-obese to 35% among obese persons. Our estimates show that a more sensitive imaging tool, such as magnetic resonance imaging (MRI), may increase the number of OA cases diagnosed by up to 94% assuming that 50% of all 'pre radiographic knee OA' (K-L 1) has some evidence of cartilage degeneration seen on MRI. CONCLUSIONS: Projecting new and advanced cases of knee OA among persons aged 60-64 years over the next decade creates a benchmark that can be used to evaluate population-based benefits of future disease-modifying OA drugs that are currently undergoing testing at various stages. PMID- 20955808 TI - Conditioned fear is modulated by D2 receptor pathway connecting the ventral tegmental area and basolateral amygdala. AB - Excitation of the mesocorticolimbic pathway, originating from dopaminergic neurons in the ventral tegmental area (VTA), may be important for the development of exaggerated fear responding. Among the forebrain regions innervated by this pathway, the amygdala is an essential component of the neural circuitry of conditioned fear. The functional role of the dopaminergic pathway connecting the VTA to the basolateral amygdala (BLA) in fear and anxiety has received little attention. In vivo microdialysis was performed to measure dopamine levels in the BLA of Wistar rats that received the dopamine D(2) agonist quinpirole (1 MUg/0.2 MUl) into the VTA and were subjected to a fear conditioning test using a light as the conditioned stimulus (CS). The effects of intra-BLA injections of the D(1) antagonist SCH 23390 (1 and 2 MUg/0.2 MUl) and D(2) antagonist sulpiride (1 and 2 MUg/0.2 MUl) on fear-potentiated startle (FPS) to a light-CS were also assessed. Locomotor performance was evaluated by use of open-field and rotarod tests. Freezing and increased dopamine levels in the BLA in response to the CS were both inhibited by intra-VTA quinpirole. Whereas intra-BLA SCH 23390 did not affect FPS, intra-BLA sulpiride (2 MUg) inhibited FPS. Sulpiride's ability to decrease FPS cannot be attributed to nonspecific effects because this drug did not affect motor performance. These findings indicate that the dopamine D(2) receptor pathway connecting the ventral tegmental area and the basolateral amygdala modulates fear and anxiety and may be a novel pharmacological target for the treatment of anxiety. PMID- 20955809 TI - Involvement of the insular cortex in retention of conditioned taste aversion is not time dependent. AB - In fear-associated learning paradigms, hippocampal lesions induce memory deficits of recent but not remote memories, while amygdala lesions produce retention deficits irrespective of the age of the memory. In conditioned taste aversion (CTA), non-hippocampal mediated learning paradigm, the insular vortex (IC) has shown to have a crucial role in consolidation and storage of CTA memory. Due to the functional and anatomical similarities to the hippocampus, a time dependent role of the IC in CTA retention cannot be ruled out. To test whether the IC shows a time dependent role in CTA memory retention, male Wistar rats were CTA trained on saccharin 0.1% (LiCl 0.15M, 2% b/w, 40 min after drinking) and lesioned with ibotenic acid (200-300 nL, 5mg/mL) unilaterally into the IC 1 week or bilaterally 1 or 6 weeks after CTA. CTA memory was completely disrupted in both bilateral lesion groups but unaffected in the unilateral lesioned group. The resulting preference was comparable to that of the bilaterally IC lesioned animals exposed to the taste for the first time, proving that in these animals a complete amnesic state was achieved. Bilaterally IC lesioned rats showed normal discrimination between preferred (sucrose 5%) and non-preferred (quinone) tastes. Our data indicates that the involvement of the IC in CTA is not time dependent and that CTA memories are stored in each hemisphere separately. PMID- 20955810 TI - Novel mutations reveal two important regions in Aspergillus nidulans transcriptional activator MetR. AB - Expression of the sulfur assimilation pathway in Aspergillus nidulans is under control of sulfur metabolite repression, which is composed of scon genes encoding subunits of ubiquitin ligase and the metR gene coding for a transcriptional activator. In this paper we report three dominant suppressors of methionine requirement isolated from a metB3 diploid strain. All three mutations lead to the substitution of phenylalanine 48 by serine or leucine in the conserved N-terminal region of the MetR protein. Strains carrying the dominant suppressor mutations exhibit increased activities of homocysteine synthase and sulfur assimilation enzymes as well as elevated levels of the corresponding transcripts. These changes are observed even under conditions of methionine repression, which suggests that the mutated MetR protein may be resistant to inactivation or degradation mediated by sulfur metabolite repression. We also found that a mutant impaired in sulfite reductase activity, known until now as sG8, has a frameshift which changes 41 C-terminal amino acids. Therefore, it is now designated metR18. This mutant has elevated levels of MetR-regulated transcripts and of activities of sulfur assimilation enzymes (except sulfite reductase), which can be repressed to the wild type level by exogenous methionine. Thus, metR18 and the three dominant suppressors represent new types of mutations affecting different parts of the A. nidulans MetR protein. PMID- 20955811 TI - New insights into the infection process of Rhynchosporium secalis in barley using GFP. AB - Through the use of a Rhynchosporium secalis isolate transformed with the green fluorescent protein gene and LASER scanning confocal microscopy (LSCM), fungal development during the R. secalis/barley interaction was analysed. Each infection stage was investigated from 0.5h to 14 days post-inoculation (p.i.) with extensive sampling within the first 48 h p.i. Early germination events were observed that had not been previously described. A specific time of germination was noted, with germ tube formation appearing as early as 1h p.i. Conidia were observed within anticlinal grooves of epidermal cells and the formation of bubbles within these pectin-rich regions was observed within 24h p.i. The study reports R. secalis pectinase production and suggests degradation of these pectin rich regions. Reactive oxygen species were present during early penetration, 3h p.i. and co-localised with fungal development. LSCM allowed the visualisation of fungal growth deep within tissues at the later stage of the infection. PMID- 20955812 TI - Paralogous cyp51 genes in Fusarium graminearum mediate differential sensitivity to sterol demethylation inhibitors. AB - Analysis of the genome sequence of Fusarium graminearum revealed three paralogous cyp51 genes (designated cyp51A, -B, and -C) encoding 14-alpha demethylases in this fungus. Targeted gene disruption showed that the cyp51A, -B or -C disruption mutants were morphologically indistinguishable from the parent isolate on potato dextrose agar medium, which indicates that none of these genes is essential for mycelial growth. The sensitivity of cyp51A deletion mutants to seven sterol demethylation inhibitor (DMI) fungicides increased significantly compared to the parent strain, while sensitivity of cyp51C deletion mutants increased to some but not all DMIs. No change in DMI sensitivity was observed for cyp51B deletion mutants. The parental phenotypes of cyp51A and cyp51C deletion mutants were completely restored by genetic complementation with the wild-type cyp51A and cyp51C genes, respectively. The sensitivity of F. graminearum isolates increased significantly when subjected in vitro to a mixture of DMI fungicides triadimefon and tebuconazole as compared to the individual components. These results indicate that different DMI fungicides target different CYP51 proteins in F. graminearum and that a mixture of DMI fungicides can result in synergistic effects. Our findings have directly implications on chemical management strategies of plant diseases caused by Fusarium species. PMID- 20955813 TI - Comparative sequence analysis of wheat and barley powdery mildew fungi reveals gene colinearity, dates divergence and indicates host-pathogen co-evolution. AB - The two fungal pathogens Blumeria graminis f. sp. tritici (B.g. tritici) and hordei (B.g. hordei) cause powdery mildew specifically in wheat or barley. They have the same life cycle, but their growth is restricted to the respective host. Here, we compared the sequences of two loci in both cereal mildews to determine their divergence time and their relationship with the evolution of their hosts. We sequenced a total of 273.3kb derived from B.g. tritici BAC sequences and compared them with the orthologous regions in the B.g. hordei genome. Protein coding genes were colinear and well conserved. In contrast, the intergenic regions showed very low conservation mostly due to different integration patterns of transposable elements. To estimate the divergence time of B.g. tritici and B.g. hordei, we used conserved intergenic sequences including orthologous transposable elements. This revealed that B.g. tritici and B.g. hordei have diverged about 10 million years ago (MYA), two million years after wheat and barley (12 MYA). These data suggest that B.g. tritici and B.g. hordei have co evolved with their hosts during most of their evolutionary history after host divergence, possibly after a short phase of host expansion when the same pathogen could still grow on the two diverged hosts. PMID- 20955814 TI - Molecular cloning and oxidative stress response of a sigma-class glutathione S transferase of the bumblebee Bombus ignitus. AB - Glutathione S-transferases (EC 2.5.1.18; GSTs) are multifunctional enzymes that are mainly involved in xenobiotic metabolism and protection against oxidative damage. Most studies of GSTs in insects have been focused on their role in detoxifying exogenous compounds in particular insecticides. Here, we show the expression profiles of GSTs of the bumblebee Bombus ignitus in response to oxidative stress. We identified a sigma-class GST from B. ignitus (BiGSTS). The BiGSTS gene consists of 4 exons that encode 201 amino acids. Comparative analysis indicates that the predicted amino acid sequence of BiGSTS shares a high identity with the sigma-class GSTs of hymenopteran insects such as Apis mellifera (70% protein sequence identity) and Solenopsis invicta (59% protein sequence identity). Tissue distribution analyses showed the presence of BiGSTS in all tissues examined, including the fat body, midgut, muscle and epidermis. The oxidative stress responses analyzed by quantitative real-time PCR showed that under H(2)O(2) overload, BiGSTS and BiGSTD (identified in our previous study) were upregulated in all tissues examined, including the fat body and midgut of B. ignitus worker bees. Under uniform conditions of H(2)O(2) overload, the expression profile of GSTs and other antioxidant enzyme genes, such as phospholipid-hydroperoxide glutathione peroxidase (Bi-PHGPx) and peroxiredoxins (BiPrx1 and BiTPx1), showed that other antioxidant enzyme genes are acutely induced at 3h after H(2)O(2) exposure, whereas BiGSTS and BiGSTD are highly induced at 9h after H(2)O(2) exposure in the fat body of B. ignitus worker bees. These findings indicate that GSTs and other antioxidant enzyme genes in B. ignitus are differentially expressed in response to oxidative stress. Taken together, our findings indicate that BiGSTS and BiGSTD are oxidative stress inducible antioxidant enzymes that may play a role in oxidative stress response. PMID- 20955815 TI - Improved capacity of a monkey-tropic HIV-1 derivative to replicate in cynomolgus monkeys with minimal modifications. AB - Human immunodeficiency virus type 1 (HIV-1) hardly replicates in Old World monkeys. Recently, a mutant HIV-1 clone, NL-DT5R, in which a small part of gag and the entire vif gene are replaced with SIVmac239-derived ones, was shown to be able to replicate in pigtail monkeys but not in rhesus monkeys (RM). In the present study, we found that a modified monkey-tropic HIV-1 (HIV-1mt), MN4-5S, acquired the ability to replicate efficiently in cynomolgus monkeys as compared with the NL-DT5R, while neither NL-DT5R nor MN4-5S replicated in RM cells. These results suggest that multiple determinants may be involved in the restriction of HIV-1 replication in macaques, depending on the species of macaques. The new HIV 1mt clone will be useful for studying molecular mechanisms by which anti-viral host factors regulate HIV-1 replication in macaques. PMID- 20955816 TI - In vitro and in vivo genotoxicity of radiofrequency fields. AB - There has been growing concern about the possibility of adverse health effects resulting from exposure to radiofrequency radiations (RFR), such as those emitted by wireless communication devices. Since the introduction of mobile phones many studies have been conducted regarding alleged health effects but there is still some uncertainty and no definitive conclusions have been reached so far. Although thermal effects are well understood they are not of great concern as they are unlikely to result from the typical low-level RFR exposures. Concern rests essentially with the possibility that RFR-exposure may induce non-thermal and/or long-term health effects such as an increased cancer risk. Consequently, possible genetic effects have often been studied but with mixed results. In this paper we review the data on alleged RFR-induced genetic effects from in vitro and in vivo investigations as well as from human cytogenetic biomonitoring surveys. Attention is also paid to combined exposures of RFR with chemical or physical agents. Again, however, no entirely consistent picture emerges. Many of the positive studies may well be due to thermal exposures, but a few studies suggest that biological effects can be seen at low levels of exposure. Overall, however, the evidence for low-level genotoxic effects is very weak. PMID- 20955817 TI - The Biomedical Resource Ontology (BRO) to enable resource discovery in clinical and translational research. AB - The biomedical research community relies on a diverse set of resources, both within their own institutions and at other research centers. In addition, an increasing number of shared electronic resources have been developed. Without effective means to locate and query these resources, it is challenging, if not impossible, for investigators to be aware of the myriad resources available, or to effectively perform resource discovery when the need arises. In this paper, we describe the development and use of the Biomedical Resource Ontology (BRO) to enable semantic annotation and discovery of biomedical resources. We also describe the Resource Discovery System (RDS) which is a federated, inter institutional pilot project that uses the BRO to facilitate resource discovery on the Internet. Through the RDS framework and its associated Biositemaps infrastructure, the BRO facilitates semantic search and discovery of biomedical resources, breaking down barriers and streamlining scientific research that will improve human health. PMID- 20955818 TI - Patients with polyps larger than 5 mm in computed tomography colonoscopy screening have high risk for advanced colonic neoplasia in Asia. AB - BACKGROUND & AIMS: Computed tomography colonography (CTC) is a recommended screening modality for colorectal cancer (CRC). It is not known whether polyps 6 9 mm based on CRC are likely to have advanced histologic features in Asian patients. We estimated the risk of advanced colonic neoplasia (ACN) from polyps <10 mm and the risk of ACN detection failure if patients with polyps <10 mm are not referred for colonoscopy. METHODS: The study included 1457 subjects from the Asia-Pacific Working Group on CRC screening and the Hong Kong CRC screening program. Polyps and ACN found during colonoscopy examinations were classified by size and histology. RESULTS: Of the subjects, 38.2% had polyps; 16.7% of these were ACN, 5.4% of ACN were <=5 mm, and 24.7% of the ACN were 6-9 mm. Adopting the policy of reporting polyps found by CTC of <5 mm as normal and repeating CTC in patients with polyps of 6-9 mm, 5.4% of subjects with ACN, 4.5% of male subjects, and 11.5% of subjects with family history of CRC would be classified as normal. In referring patients with polyps of 6-9 mm for CTC surveillance, 20.4% of those with ACN, 22.4% of those that are male, and 23.1% of those with family histories of CRC would have polypectomies delayed by at least 3 years. CONCLUSIONS: A substantial proportion of polyps <10 mm have advanced histologic features in Asia, so patients with a polyp of 6 mm or more at CTC should be offered colonoscopies with polypectomies, rather than CTC surveillance of polyps. PMID- 20955819 TI - Takotsubo cardiomyopathy: a role for magnesium? PMID- 20955820 TI - Classifying fractionated electrograms in human atrial fibrillation using monophasic action potentials and activation mapping: evidence for localized drivers, rate acceleration, and nonlocal signal etiologies. AB - BACKGROUND: Complex fractionated electrograms (CFAEs) detected during substrate mapping for atrial fibrillation (AF) reflect etiologies that are difficult to separate. Without knowledge of local refractoriness and activation sequence, CFAEs may represent rapid localized activity, disorganized wave collisions, or far-field electrograms. OBJECTIVE: The purpose of this study was to separate CFAE types in human AF, using monophasic action potentials (MAPs) to map local refractoriness in AF and multipolar catheters to map activation sequence. METHODS: MAP and adjacent activation sequences at 124 biatrial sites were studied in 18 patients prior to AF ablation (age 57 +/- 13 years, left atrial diameter 45 +/- 8 mm). AF cycle length, bipolar voltage, and spectral dominant frequency were measured to characterize types of CFAE. RESULTS: CFAE were observed at 91 sites, most of which showed discrete MAPs and (1) pansystolic local activity (8%); (2) CFAE after AF acceleration, often with MAP alternans (8%); or (3) nonlocal (far field) signals (67%). A fourth CFAE pattern lacked discrete MAPs (17%), consistent with spatial disorganization. CFAE with discrete MAPs and pansystolic activation (consistent with rapid localized AF sites) had shorter cycle length (P <.05) and lower voltage (P <.05) and trended to have higher dominant frequency than other CFAE sites. Many CFAEs, particularly at the septa and coronary sinus, represented far-field signals. CONCLUSION: CFAEs in human AF represent distinct functional types that may be separated using MAPs and activation sequence. In a minority of cases, CFAEs indicate localized rapid AF sites. The majority of CFAEs reflect far-field signals, AF acceleration, or disorganization. These results may help to interpret CFAE during AF substrate mapping. PMID- 20955821 TI - Maintaining exercise and healthful eating in older adults: the SENIOR project II: study design and methodology. AB - The Study of Exercise and Nutrition in Older Rhode Islanders (SENIOR) Project II is an intervention study to promote the maintenance of both exercise and healthful eating in older adults. It is the second phase of an earlier study, SENIOR Project I, that originally recruited 1277 community-dwelling older adults to participate in behavior-specific interventions designed to increase exercise and/or fruit and vegetable consumption. The general theoretical framework for this research is the Transtheoretical Model (TTM) of Health Behavior Change. The current intervention occurs over a 48-month period, using a manual, newsletters, and phone coaching calls. Annual assessments collect standardized data on behavioral outcomes (exercise and diet), TTM variables (stage of change and self efficacy), psychosocial variables (social support, depression, resilience, and life satisfaction), physical activity and functioning (SF-36, Up and Go, Senior Fitness Test, and disability assessment), cognitive functioning (Trail Making Test and Forward and Backward Digit Span), physical measures (height, weight, and waist circumference), and demographics. The SENIOR Project II is designed to answer the following question as its primary objective: (1) Does an individualized active-maintenance intervention with older adults maintain greater levels of healthful exercise and dietary behaviors for 4years, compared to a control condition? In addition, there are two secondary objectives: (2) What are the psychosocial factors associated with the maintenance of health-promoting behaviors in the very old? (3) What are the effects of the maintenance of health promoting behaviors on reported health outcomes, psychosocial measures, anthropometrics, and cognitive status? PMID- 20955822 TI - Solid cancer, antiphospholipid antibodies, and venous thromboembolism. AB - The pathogenic role of antiphospholipid antibodies (aPL) in the development of venous thromboembolism (VTE) in patients with malignancies has not been established. From May 2006 to April 2008, 258 consecutive patients with solid organ malignancies who developed VTE (VTE+) were recruited. A group of 142 patients matched for age, sex and tumor type cancer patients without VTE (VTE-) and an age-and-sex matched group of 258 healthy subjects were also included. A second blood sample was taken in positive aPL patients at least 12 weeks later. Twenty-one (8.1%) VTE+ patients, 2 (1.4%) VTE- patients (p=0.006) and 2 (0.8%) healthy subjects (p<0.001) were positive for aPL. Persistent aPL positivity was observed in only 4 out of 15 available VTE+ patients. No differences in demographic characteristics, clinical pattern and outcome were observed in VTE+ patients according to aPL status. The low prevalence and transience of aPL positivity in patients with solid-organ malignancies with VTE argues against a pathogenic role in the development of thrombosis in this setting. The published evidence of the relationship between cancer, aPL, and thrombosis is reviewed. PMID- 20955823 TI - A case for the graft-versus-host disease as a model for B cell-mediated autoimmunity. AB - Following allogenic hematopoietic stem cell transplantation (HSCT), patients with autoimmune disease or hematopoietic malignancy may develop acute or chronic graft versus-host (GvH) disease. B lymphocytes, from the recipient as well as from the donor, have recently been implicated in the pathogenesis of such disturbances. Their deleterious effects are accounted for by other tasks B lymphocytes accomplish than the antibody production. We highlight herein some recent observations in the context of B cells in the GvH disease. PMID- 20955824 TI - Ventilation-limited exercise capacity in a 59-year-old athlete. AB - Aerobic exercise performance may be limited by the respiratory system in fit elderly adults whose lungs undergo the normal ageing process or who develop lung diseases but can maintain high pulmonary blood flows and ventilatory requirements. Here we describe a 59-year-old athlete demonstrating high aerobic exercise performance limited by his relatively low ventilatory capacity. The male hobby cyclist (59 years, 176 cm, 83 kg), undergoing cardiopulmonary exercise testing, reported no complaints except a history of dyspnoea and exercise intolerance at high altitude (> 2000 m). Lung function testing indicated mild airway obstruction (FEVC: 4.22 l, FEV1: 2.91 l, FEV1/FEVC: 69%) which was not reversed post-bronchodilator. However, FEV1/FEVC was slightly above the 5th percentile and thus not confirming the diagnosis of COPD. The athlete completed 300 W (3.6 W/kg) and his maximal oxygen uptake was 45 ml/min/kg (156% predicted!). Above 250 W he was unable further increasing minute ventilation, and oxygen pulse and oxygen uptake even decreased. The related changes of the respiratory pattern (increase of breathing frequency, decreases of inspiratory capacity and tidal volume) indicated dynamic lung hyperinflation resulting in cardiac output constraint, arterial oxygen desaturation, severe dyspnoea and exercise limitation. This case report delineates the pathophysiological situation of ventilation-limited exercise capacity in a well-trained middle-aged subject. However, beneficial adaptations to regular exercise may have helped maintain high aerobic performance without any adverse symptoms during submaximal exercise. PMID- 20955825 TI - Bisphosphonate effects on bone turnover, microdamage, and mechanical properties: what we think we know and what we know that we don't know. AB - The bisphosphonates (BPs) have been useful tools in our understanding of the role that bone remodeling plays in skeletal health. The purpose of this paper is to outline what we know, and what is still unknown, about the role that BPs play in modulating bone turnover, how this affects microdamage accumulation, and ultimately what the effects of these changes elicited by BPs are to the structural and the material biomechanical properties of the skeleton. We know that BPs suppress remodeling site-specifically, probably do not have a direct effect on formation, and that the individual BPs vary with respect to speed of onset, duration of effect and magnitude of suppression. However, we do not know if these differences are meaningful in a clinical sense, how much remodeling is sufficient, the optimal duration of treatment, or how long it takes to restore remodeling to pre-treatment levels following withdrawal. We also know that suppression is intimately tied to microdamage accumulation, which is also site specific, that BPs impair targeted repair of damage, and that they can reduce the energy absorption capacity of bone at the tissue level. However, the BPs are clearly effective at preventing fracture, and generally increase bone mineral density and whole bone strength, so we do not know whether these changes in damage accumulation and repair, or the mechanical effects at the tissue level, are clinically meaningful. The mechanical effects of BPs on the fatigue life of bone, or BP effects on bone subject to an impact, are entirely unknown. This paper reviews the literature on these topics, and identifies gaps in knowledge that can be addressed with further research. PMID- 20955826 TI - Germline variation in the MTHFR and MTRR genes determines the nadir of bone density in pediatric acute lymphoblastic leukemia: a prospective study. AB - BACKGROUND: This study aims to identify folate-metabolism-related genetic risk factors for low bone mineral density (BMD) during/after pediatric acute lymphoblastic leukemia (ALL) treatment. PATIENTS AND METHODS: We investigated the influence of methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C) and methionine synthase reductase (MTRR 66A > G) single nucleotide polymorphisms (SNPs) on total body BMD (BMD(TB)) and lumbar spine BMD (BMD(LS)) in 83 patients. Homocysteine, folate and vitamin B12 were determined. BMD was measured repeatedly using dual-energy X-ray absorptiometry in patients >= 4 years (n = 68). RESULTS: Carriers of the MTHFR 677 T-allele showed a lower baseline BMD(TB) than non carriers (-0.38 SDS vs. +0.55 SDS, p = 0.01) and BMD(TB) remained lower during/after treatment. MTHFR 677C>T did not influence treatment-related loss of BMD(TB) (p = 0.39). The MTRR 66 G-allele carriers showed a trend towards a lower BMD(TB) compared with non-carriers. Combining these two SNPs, patients carrying >= 2 risk alleles had a significantly lower BMD(TB) (-1.40 SDS) than patients with one (-0.80 SDS) or no risk alleles (-0.31 SDS). Although carriers of the MTHFR 1298A > C had higher homocysteine levels, this SNP was not related to BMD(TB). BMD(LS) of carriers was similar to non-carriers of the investigated SNPs. CONCLUSIONS: The MTHFR 677C>T SNP and the MTRR 66A >G SNP were identified as determinants of impaired BMD(TB) in childhood ALL patients. PMID- 20955827 TI - Antibody dynamics after tick-borne encephalitis and measles-mumps-rubella vaccination in children post early thymectomy. AB - Thymectomized patients (TP) showed a delayed humoral immune response to tick borne-encephalitis-virus (TBEV) vaccination, which served as a neo-antigen. From the previously published cohort, the TBEV-specific IgG concentrations and avidities were analyzed in 17 TP compared to 30 non-thymectomized healthy controls (HC) 220 weeks after the first TBE vaccination to identify patients with waning antibodies. Only in HC, increase of avidity was significant between 8 and 220 weeks (p<0.001), whereas TP showed a lower avidity maturation at week 48 (p<0.05). Cytomegalovirus (CMV) seropositivity at vaccination did not influence the humoral immune response. The ability of TP to maintain measles, mumps and rubella (MMR)-specific antibodies at least 8 years post (MMR) vaccination was evaluated in the serum samples of TP, retrospectively. Although all TP had MMR vaccination at least 6 months after thymectomy, TP showed no significant difference regarding MMR-specific IgG concentrations or avidities compared to HC. Regarding TBE vaccination, the data confirmed the previous observation of a delayed primary immune response in TP to TBE vaccine and also revealed an altered memory priming by paucity of high-avidity antibodies. PMID- 20955828 TI - Hepatitis A and travel amongst Nova Scotia postsecondary students: evidence for a targeted vs. universal immunization strategy. AB - BACKGROUND: Canadian guidelines recommend hepatitis A virus (HAV) vaccination for high-risk persons, such as travelers to HAV-endemic areas. The US CDC advocates universal immunization. OBJECTIVES: To explore whether a universal strategy for HAV immunization rather than the Canadian targeted approach for travelers is justified by measuring compliance of postsecondary students with Canadian guidelines. METHODS: A cross-sectional study using an electronic survey method elicited HAV risk factors, immunization history, disease status, and factors affecting immunization status from postsecondary students. Seropositivity was determined by measuring HAV antibodies in saliva from a convenience sample of survey participants within each study group. Statistical analysis used Fisher's exact test and logistic regression. RESULTS: We received 2279 completed surveys (10.6% response) and 235 saliva samples (58.7% response). A total of 1380 (60.6%) participants had traveled to HAV-endemic regions and 1851 (81.2%) were planning to do so within the next 5 years. Less than half who traveled to HAV-endemic areas reported a history of HAV vaccination (48.0%). HAV seropositivity rates were higher amongst those who traveled to (63.6%) or were planning to travel to (55.0%) HAV-endemic areas than those who had never traveled or had no plans to travel to such areas (17.4%). Only 8.9% of unvaccinated students were seropositive (5.3% of Canadian-born students). Amongst unvaccinated, seropositive students, there was a nonsignificant trend for higher seropositivity in those who had previously traveled to HAV-endemic areas (14.7%) than those who had not traveled abroad (4.4%), suggesting an exposure to HAV during travel. Nearly all (96.5%) unvaccinated students, who were willing to be vaccinated based on current knowledge or if their doctor recommended it, indicated a willingness to receive vaccine if it were provided free of charge. CONCLUSIONS: Current Canadian guidelines for HAV vaccination are not being followed within the postsecondary student population. Given high rates of travel to HAV-endemic areas in this population, a universal approach to HAV vaccination may be warranted. PMID- 20955829 TI - Shoulder injury related to vaccine administration (SIRVA). AB - Shoulder pain is a common transient side-effect of vaccination. Infrequently, patients can develop prolonged shoulder pain and dysfunction following vaccination. A series of 13 cases are described in which persistent shoulder dysfunction and pain developed following immunization. Common clinical characteristics include absence of a history of prior shoulder dysfunction, previous exposure to vaccine administered, rapid onset of pain, and limited range of motion. The proposed mechanism of injury is the unintentional injection of antigenic material into synovial tissues resulting in an immune-mediated inflammatory reaction. Careful consideration should be given to appropriate injection technique when administering intramuscular vaccinations to reduce the risk of shoulder injury. PMID- 20955830 TI - Divergence, not diversity of an attenuated equine lentivirus vaccine strain correlates with protection from disease. AB - We recently reported an attenuated EIAV vaccine study that directly examined the effect of lentiviral envelope sequence variation on vaccine efficacy. The study [1] demonstrated for the first time the failure of an ancestral vaccine to protect and revealed a significant, inverse, linear relationship between envelope divergence and protection from disease. In the current study we examine in detail the evolution of the attenuated vaccine strain utilized in this previous study. We demonstrate here that the attenuated strain progressively evolved during the six-month pre-challenge period and that the observed protection from disease was significantly associated with divergence from the original vaccine strain. PMID- 20955831 TI - Fingolimod (FTY720), sphingosine 1-phosphate receptor modulator, shows superior efficacy as compared with interferon-beta in mouse experimental autoimmune encephalomyelitis. AB - Fingolimod (FTY720), a sphingosine 1-phosphate (S1P) receptor modulator, inhibits S1P-dependent lymphocyte egress from secondary lymphoid organs and is highly effective in experimental autoimmune encephalomyelitis (EAE) in mice. In this study, we directly compared the therapeutic effects of FTY720 and recombinant mouse interferon (rm-IFN)-beta on relapse and progression of EAE in mice. When FTY720 at oral dose of 0.03 to 1 mg/kg was administered daily after establishment of EAE induced by myelin proteolipid protein (PLP) in SJL/J mice, relapse of EAE was significantly inhibited during administration period. Subcutaneous injection of rm-IFN-beta (10,000 IU/mouse) also inhibited the relapse of EAE at early period; however EAE was relapsed in all the mice within administration period. Therapeutic administration of FTY720 (0.03 to 1 mg/kg) significantly improved the symptoms of chronic EAE induced by myelin oligodendrocyte glycoprotein in C57BL/6 mice whereas rm-IFN-beta (10,000 IU/mouse) showed no clear effect. These results indicate that FTY720 is more efficacious in mouse EAE as compared with rm-IFN beta. FTY720 markedly reduced the frequency of PLP-specific Th17 and Th1 cells in the spinal cord of EAE mice. On the contrary, FTY720 increased the frequency of PLP-specific Th17 and Th1 cells in the inguinal lymph nodes, suggesting inhibition of egress of myelin antigen-specific Th cells from draining lymph nodes. From these results, the ameliorating effects of FTY720 on EAE are likely due to reduction of infiltration of myelin antigen-specific Th17 and Th1 cells into the central nervous system. PMID- 20955832 TI - Innate immunity and cancer therapy. AB - Classical cancer immunotherapy utilizes the immune response against microbial components, and a sequence of immune responses produce antitumor effects. The identification of mammalian Toll-like receptors (TLRs), receptors for microbial components, has shed light on antigen recognition by the innate immune system and provided a molecular basis for our understanding of the relationship between innate immunity and antitumor activity. However, accumulating evidence has revealed another important role of TLRs in maintaining tissue homeostasis and has also shown that tumor cells utilize this function to create favorable conditions for growth and survival, suggesting that TLR signaling acts as a double-edged sword in cancer therapy. In this review, innate immunity-based cancer therapy will be discussed with special reference to TLR-targeting drugs. PMID- 20955833 TI - Chicken type II collagen induced immune tolerance of mesenteric lymph node lymphocytes by enhancing beta2-adrenergic receptor desensitization in rats with collagen-induced arthritis. AB - Chicken type II collagen (CCII) is a protein extracted from the cartilage of chicken breast and exhibits intriguing possibilities for the treatment of autoimmune diseases by inducing oral tolerance. In this study, we investigated the effects of CCII on inflammatory and immune responses to the mesenteric lymph node lymphocytes (MLNLs) and the mechanisms by which CCII regulates beta2 adrenergic receptor (beta2-AR) signal transduction in collagen-induced arthritis (CIA) rats. The onset of secondary arthritis in rats appeared around day 14 after injection of CCII emulsion. Remarkable secondary inflammatory response and lymphocytes proliferation were observed in CIA rats. The administration of CCII (10, 20, 40MUgkg(-1)day(-1), days 15-22) could significantly reduce synovial hyperplasia, lymphatic follicle hyperplasia, inflammatory cells infiltration of MLNLs in CIA rats. CCII (10, 20, 40MUgkg(-1)day(-1), days 15-22) restored the previously decreased level of cAMP of MLNLs of CIA rats. Meanwhile, CCII increased total protein expressions of beta2-AR, GRK2 and decreased that of beta arrestin1, 2 of MLNLs in CIA rats but had an slight effect on GRK3. CCII further increased plasmatic protein expressions of GRK2, G(alpha)s and decreased that of beta-arrestin1, 2, beta2-AR, and increased membrane protein expressions of beta2 AR, GRK2, G(alpha)s and decreased that of beta-arrestin1, 2 of MLNLs in CIA rats. These results demonstrate that the mechanisms of CCII on beta2-AR desensitization and beta2-AR-AC-cAMP transmembrane signal transduction of MLNLs play crucial roles in pathogenesis of this disease. PMID- 20955834 TI - Carotenoids. Guest editors' introduction. PMID- 20955843 TI - Issues and solutions in accurately measuring clinical full-time equivalents. PMID- 20955835 TI - Language sample measures and language ability in Spanish-English bilingual kindergarteners. AB - Measures of productivity and sentence organization are useful metrics for quantifying language development and language impairments in monolingual and bilingual children. It is not yet known what measures within and across languages are most informative when evaluating the language skills of bilingual children. The purpose of this study was to evaluate how measures of language productivity and organization in two languages converge with children's measured language abilities on the Bilingual English Spanish Assessment (BESA), a standardized measure of language ability. 170 kindergarten age children who produced narrative language samples in Spanish and in English based on a wordless picture book were included in the analysis. Samples were analyzed for number of utterances, number of different words, mean length of utterance, and percentage of grammatical utterances. The best predictors of language ability as measured by the BESA scores were English MLU, English grammaticality, and Spanish grammaticality. Results are discussed in relationship to the nature of the measures in each of the languages and in regard to their potential utility for identifying low language ability in bilingual. LEARNING OUTCOMES: The reader will be able to identify (1) why narratives are useful for evaluating bilingual language ability, (2) which measures of productivity and sentence organization in narratives best capture language ability and development in bilingual children, (3) how a bilingual or composite language ability across two languages can be determined, and (4) what relationship exists between measures of productivity and sentence organization in each language with a bilingual language ability score. PMID- 20955846 TI - Impact of fetal growth restriction on mortality and morbidity in a very preterm birth cohort. AB - OBJECTIVE: To assess the impact of being small for gestational age (SGA) on very preterm mortality and morbidity rates by using different birthweight percentile thresholds and whether these effects differ by the cause of the preterm birth. STUDY DESIGN: The study included singletons and twins alive at onset of labor between 24 and 31 weeks of gestation without congenital anomalies from the Models of Organising Access to Intensive Care for very preterm births very preterm cohort in 10 European regions in 2003 (n = 4525). Outcomes were mortality, intraventricular hemorrhage grade III and IV, cystic periventricular leukomalacia, and bronchopulmonary dysplasia (BPD). Birthweight percentiles in 6 classes were analyzed by pregnancy complication. RESULTS: The mortality rate was higher for infants with birthweights <25th percentile when compared with the 50th to 74th percentile (adjusted odds ratio, 3.98 [95% CI, 2.79-5.67] for <10th; adjusted odds ratio, 2.15 [95% CI, 1.54-3.00] for 10th-24th). BPD declined continuously with increasing birthweight. There was no association for periventricular leukomalacia or intraventricular hemorrhage. Seventy-five percent of infants with birthweights <10th percentile were from pregnancies complicated by hypertension or indicated deliveries associated with growth restriction. However, stratifying for pregnancy complications yielded similar risk patterns. CONCLUSIONS: A 25th percentile cutoff point was a means of identifying infants at higher risk of death and a continuous measure better described risks of BPD. Lower birthweights were associated with poor outcomes regardless of pregnancy complications. PMID- 20955848 TI - Regional oxygen saturation of the brain and peripheral tissue during birth transition of term infants. AB - OBJECTIVE: To evaluate regional tissue oxygenation of the brain and preductal and postductal peripheral (muscle) tissue during immediate transition after birth, and to correlate with peripheral preductal and postductal arterial oxygen saturation. STUDY DESIGN: We conducted a prospective observational study. With near-infrared spectroscopy (NIRS), changes in regional oxygen saturation of the brain (rSO2brain), peripheral preductal tissue (rSO2pre), and peripheral postductal tissue (rSO2post) were measured during the first 10 minutes of life in 59 healthy term infants after elective caesarean delivery. Fractional tissue oxygen extraction was calculated for all 3 regions. RESULTS: Mean rSO2brain increased rapidly from 44% (3 minutes) to 76% (7 minutes); thereafter no significant change occurred. Mean rSO2pre and rSO2post increased constantly from minute 3 to minute 10, from 36%(pre)/27%(post) to 66%(pre)/58%(post). Fractional tissue oxygen extraction decreased in all 3 regions during the first minutes of life. Fractional tissue oxygen extraction of the brain did not change significantly after 5 minutes, and preductal and postductal fractional tissue oxygen extraction did not change significantly after 8 minutes. CONCLUSIONS: During transition, the brain had the highest saturation levels, indicating a preference of oxygen delivery to the brain. Fractional tissue oxygen extraction of the brain reached a plateau earlier compared with peripheral tissue. PMID- 20955849 TI - Inter-alpha inhibitor protein level in neonates predicts necrotizing enterocolitis. AB - OBJECTIVES: To compare inter-alpha inhibitor protein (IaIp) levels in neonates with proven necrotizing enterocolitis (NEC) and neonates with other, nonspecific abdominal disorders. STUDY DESIGN: This was a prospective observational study of neonates in the neonatal intensive care unit. NEC was diagnosed according to Bell's staging criteria. The nNeonates in the control group had a nonspecific abdominal disorder, but no radiographic evidence of NEC and no disease progression. All neonates with radiographically confirmed NEC were included. Plasma IaIp levels were quantitated by enzyme-linked immunosorbent assay. RESULTS: Seventeen neonates had confirmed NEC, and 34 neonates had nonspecific abdominal disorders that improved rapidly. Gestational age, postnatal age, weight, sex, maternal obstetric variables, rupture of membranes, and mode of delivery did not differ between the two groups. Mean IaIp level was significantly lower in the NEC group compared with the control group (137 +/- 38 mg/L; 95% confidence interval [CI], 118-157 mg/L vs 258 +/- 53 mg/L; 95% CI, 238-277 mg/L; P <.0001). CONCLUSIONS: The finding of significantly lower IaIp levels in neonates with NEC suggests that IaIp might be a useful, sensitive biomarker, allowing initiation of appropriate therapy and reducing antibiotic overuse in neonates with suspected but unproven NEC. Administration of IaIp may significantly reduce the severity of systemic inflammation and associated tissue injury. PMID- 20955850 TI - Transcutaneous bilirubin levels in late preterm neonates. AB - OBJECTIVE: To examine transcutaneous bilirubin (TcB) levels in late preterm neonates. STUDY DESIGN: Between July 2006 and December 2009, we performed 4387 TcB measurements with a BiliCheck bilirubinometer in 793 healthy late preterm neonates at designated times up to 120 postnatal hours. TcB percentiles are presented on an hour-specific nomogram. Mean increment TcB rates and the rates of increase for different percentiles are calculated as well. RESULTS: We present a percentile-based nomogram that reflects the natural history of TcB in late preterm neonates up to the fifth day of life. TcB levels demonstrated a different pattern of increase in neonates who developed significant hyperbilirubinemia compared with those who did not. However, the rates of TcB increase were quite similar up to age 48 hours, with a substantial overlap of TcB values between the two groups. CONCLUSIONS: We developed of a TcB nomogram designated for hour specific evaluation of hyperbilirubinemia in neonates born between 35(0/7) and 37(6/7) weeks' gestation. PMID- 20955852 TI - Consumption of vegetables, cooked meals, and eating dinner is negatively associated with overweight status in children. AB - OBJECTIVE: To evaluate potential associations between diet- and physical activity related lifestyle patterns and obesity indices in a cohort of children. STUDY DESIGN: Dietary and physical activity information and anthropometric indices were collected from 1138 children (53% girls; age, 11.2 +/- 0.7 years). Dietary intake was evaluated with two 24-hour recalls, which were analyzed for nutrient and food intake, eating frequency, and meal quality. Principal component analysis was used to extract salient lifestyle patterns. RESULTS: Five lifestyle behavioral patterns were identified. The "dinner, cooked meals and vegetables pattern," a multidimensional lifestyle pattern including the consumption of vegetables, cooked meals, and eating dinner, was negatively associated with all obesity indices, even after adjustment for potential confounders and exclusion of low energy reporters. A "high fiber pattern," representing high consumption of whole grain cereals, legumes, and low intake of sugar-sweetened beverages was negatively correlated with obesity indices; when the analysis included only acceptable energy reporters, these associations became non-significant, except for triceps skinfolds. CONCLUSIONS: Our findings are supportive of the synergistic or conditional effects of distinct lifestyle-related behaviors on obesity. Although these results are hypothesis-generating and need replication, they suggest potential preventive approaches, interventional approaches, or both to combat childhood obesity. PMID- 20955853 TI - Abusive head trauma in children presenting with an apparent life-threatening event. AB - OBJECTIVE: To identify rates of abusive head trauma and associated clinical risk factors in patients with an apparent life-threatening event (ALTE). STUDY DESIGN: Retrospective study of infants, 0 to 12 months, admitted for an apparent life threatening event (ALTE; 1999-2003). Patients with abusive head trauma were identified at presentation or on follow-up; statistical analysis identified characteristics associated with abusive head trauma. RESULTS: Of 627 patients with ALTE, 48% were male. Nine (1.4%) were diagnosed with abusive head trauma, of whom 5 were diagnosed in the emergency department. All cases detected in the emergency department had physical examination findings indicative of abusive head trauma. Patient age, male sex, or ethnicity were not significantly different between those with and without abusive head trauma. More children with abusive head trauma had a documented 911 call (56% vs 22%, P = .029), vomiting (56% vs 19%, P = .018), or irritability (22% vs 3%, P = .033). Multivariate analysis revealed odds ratio for abusive head trauma were 4.9 with a 911 call (P = .037), 5.3 with vomiting (P = .024), and 11.9 with irritability (P = .0197). CONCLUSIONS: Abusive head trauma is in the differential for infants with an ALTE, although almost half of the cases are missed by current emergency department management. Vomiting, irritability, or a call to 911 are significantly associated with heightened risk for abusive head trauma. PMID- 20955854 TI - Population trends toward increasing cardiovascular risk factors in Canadian adolescents. AB - OBJECTIVE: To determine prevalence and cross-sectional trends over time for cardiovascular risk factors in Canadian adolescents. STUDY DESIGN: Cross sectional trends in cardiovascular risk and lifestyle factors were gathered annually in 14- to 15-year-old students in the Niagara region, Ontario, Canada. RESULTS: A total of 20 719 adolescents were screened between 2002 and 2008. The proportion of obese adolescents (>95th percentile for body mass index [BMI]) increased significantly, by +0.34%/year (P = .002). The proportions of adolescents with borderline high cholesterol (4.4-5.1 mmol/L) (+0.57%/year; P <.001) and with high cholesterol (>=5.2 mmol/L) (+0.43%/year; P <.001) both increased significantly over time. The proportion of adolescents with prehypertension decreased by -0.23%/year (P = .02), whereas the proportion of those with stage I hypertension (5%-6%) or stage II hypertension (2%-4%) remained constant. The proportion of adolescents classified as being at high cardiovascular risk increased by +0.67%/year (P <.001). Family history, low levels of physical activity, sedentary behaviors, poor nutrition, and lower socioeconomic status were all independently and negatively associated with all aspects of cardiovascular risk. CONCLUSIONS: A significant proportion of 14- to 15-year-old Canadian adolescents have at least one cardiovascular risk factor, and the cross-sectional trends worsened during the period 2002-2008. PMID- 20955855 TI - Variability of the pediatric subspecialty workforce in Canada. AB - OBJECTIVE: To assess the regional variability of the pediatric subspecialty workforce in the academic health science centers in Canada, because effective and efficient delivery of specialized pediatric health care depends on the pediatrician workforce. STUDY DESIGN: This was an analysis of the pediatric subspecialty workforce database of the Pediatric Chairs of Canada for the surveys obtained between 2003/04 and 2005/06. RESULTS: In 2003/2004, 960 pediatrician specialists who spent a majority of their time supporting clinical, educational, research, and administrative activities within the 16 Canadian medical schools were reported. In 2004/05, this figure was 1044, and in 2005/06, it was 1140. The growth was due predominantly to increases in physician workforce in the fields of emergency medicine, respiratory medicine, and neonatology. The average academic pediatric workforce, excluding general pediatricians, increased from 12.86/100 000 child population in 2003/04 to 13.99 in 2004/05 and 15.27 in 2005/06. Substantial regional variability exists, with 4-fold differences in academic pediatrician workforce among the low-supply provinces (Saskatchewan, British Columbia, and Ontario) and high-supply provinces for both total workforce and subspecialists. CONCLUSIONS: The substantial variability in the supply of pediatric subspecialists across Canada requires additional analysis to determine any relationship to child health outcomes. PMID- 20955857 TI - Resistant organisms more likely in children with urinary tract infection who have had recent antimicrobial treatment. PMID- 20955858 TI - Children at risk for food-related anaphylaxis should carry two doses of epinephrine. PMID- 20955859 TI - Diagnostic model appears to be more effective than clinical judgment in detecting serious bacterial infection in young febrile children. PMID- 20955860 TI - The Bayley-III scale underestimates developmental delay in extremely premature and extremely low birth weight infants. PMID- 20955861 TI - Evidence increasing that probiotics reduce incidence of necrotizing enterocolitis in very low birth weight infants. PMID- 20955862 TI - Social determinants of self-reported sleep problems in South Korea and Taiwan. AB - OBJECTIVE: To clarify the social determinants of insomnia in South Korea and Taiwan. METHODS: Cross-sectional surveys were conducted in South Korea (n=1007) and Taiwan (n=785) in 2003. Nationwide samples of people completed a structured questionnaire, based on face-to-face interviews. Outcome measures were self reported sleep problems, defined by at least one of three sleep symptoms on a nightly basis for more than 2 weeks: difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), and early morning waking (EMW). Explanatory variables investigated were demographic characteristics (gender, age), socioeconomic factors (income, education), and social capital, including norms of reciprocity, interpersonal trust, civic association, and social support (i.e., the availability of persons to consult regarding personal problems and important matters). RESULTS: The prevalence of sleep problems was 8.2% in South Korea and 9.3% in Taiwan. Stepwise logistic regression showed that, in South Korea, sleep problems were significantly associated with increasing age (P<.05), low income (P<.01), and having few persons with whom to consult compared to having a spouse/partner (P<.05); in Taiwan, sleep problems were significantly associated with being female (P<.05), increasing age (P<.001), and having family members vs. a spouse/partner to consult (P<.05). CONCLUSION: Self-reported sleep problems in two northeast Asian countries were associated with certain demographic characteristics and socioeconomic factors, which is consistent with previous results in Western countries. In addition, the results of this study suggested that sleep problems may also be associated with social support. PMID- 20955863 TI - Sleep quality in treatment-seeking veterans of Operations Enduring Freedom and Iraqi Freedom: the role of cognitive coping strategies and unit cohesion. AB - OBJECTIVE: Sleep difficulties are common in individuals exposed to stress or trauma, and maladaptive cognitive coping strategies, such as worry and fear of losing vigilance, as well as low social support, may further impair sleep quality. This study examined the severity and correlates of sleep difficulties in a sample of treatment-seeking veterans of Operations Enduring Freedom and Iraqi Freedom (OEF-OIF). METHOD: A total of 167 OEF-OIF veterans seeking behavioral or primary care services completed a questionnaire containing measures of sleep quality, combat exposure, psychopathology, fear of loss of vigilance, cognitive coping strategies, and unit and postdeployment social support within 1 year of returning from deployment. RESULTS: Mean Pittsburgh Sleep Quality Inventory scores in the full sample were indicative of severely impaired sleep. Posttraumatic stress disorder (PTSD) was associated with increased sleep difficulties, most notably sleep disturbances, daytime dysfunction, and sleep quality. Hierarchical regression analysis in the full sample revealed that PTSD symptoms and scores on measures of worry and fear of loss of vigilance were positively associated with sleep difficulties and that scores on a measure of unit member support were negatively associated with sleep difficulties. Among veterans with PTSD, fear of loss of vigilance was positively associated with sleep difficulties and cognitive distraction and unit member support were negatively associated with sleep difficulties. CONCLUSIONS: Treatment-seeking OEF OIF veterans report severe sleep difficulties, with more pronounced impairment in veterans with PTSD. The results of this study suggest that interventions to mitigate worry and fear of loss of vigilance and to enhance perceived unit member support may be helpful in reducing sleep difficulties following return from deployment in this population. PMID- 20955864 TI - The relationship of chronic pain with and without comorbid psychiatric disorder to sleep disturbance and health care utilization: results from the Israel National Health Survey. AB - OBJECTIVE: Chronic pain is associated with health problems including sleep difficulties and increased medical utilization. Because chronic pain is frequently comorbid with psychiatric disorders, it is unclear to what degree chronic pain itself is associated with these problems. In a large population sample, we examined the relationship between chronic pain, both alone and comorbid with psychiatric disorders, with sleep disturbance and increased medical utilization. METHODS: We analyzed data from the Israel National Health Survey (INHS) conducted in 2003-2004 on a representative sample (N=4859) of the adult Israeli population. Data were collected in face-to-face interviews using the Composite International Diagnostic Interview. Statistical analyses were performed using multinomial logistic regression models. RESULTS: Past year chronic pain was reported by 29.9% of all study participants (n=1453). Psychiatric disorders were more common among participants with chronic pain; adjusted odds ratios were 2.23 (95% CI 1.49-3.36) for depressive disorders and 2.94 (95% CI 2.08-4.17) for anxiety disorders. Associations of chronic pain and psychiatric disorders were stronger in men. Chronic pain was associated with both sleep problems and increased health care utilization even for individuals with no psychiatric comorbidity. Sleep difficulties but not health care utilization rates were more pronounced in the comorbid group compared to the chronic pain only group. CONCLUSION: Chronic pain was associated with sleep problems and increased health care utilization in this sample, independent of psychiatric comorbidity. Sleep problems were significantly greater in the comorbid vs. non-comorbid group. In contrast, associations of pain with health care utilization were largely independent of psychiatric comorbidity. PMID- 20955865 TI - Does social support differentially affect sleep in older adults with versus without insomnia? AB - OBJECTIVE: Insomnia is a significant public health problem, particularly among older adults. We examined social support as a potential protective factor for sleep among older adults (60 years and older) with insomnia (n=79) and age- and sex-matched controls without insomnia (n=40). METHODS: Perceived social support, sleep quality, daytime sleepiness, and napping behavior were assessed via questionnaires or daily diaries. In addition, wrist actigraphy provided a behavioral measure of sleep continuity parameters, including sleep latency (SL), wakefulness after sleep onset (WASO), and total sleep time (TST). Analysis of covariance for continuous outcomes or ordinal logistic regression for categorical outcomes were used to examine the relationship between social support and sleep wake characteristics and the degree to which observed relationships differed among older adults with insomnia versus non-insomnia controls. Covariates included demographic characteristics, depressive symptoms, and the number of medical comorbidities. RESULTS: The insomnia group had poorer subjective sleep quality, longer diary-assessed SL and shorter TST as compared to the control group. Higher social support was associated with lesser actigraphy-assessed WASO in both individuals with insomnia and controls. There was a significant patient group by social support interaction for diary-assessed SL, such that higher levels of social support were most associated with shorter sleep latencies in those with insomnia. There were no significant main effects of social support or social support by patient group interactions for subjective sleep quality, daytime sleepiness, napping behavior, or TST (diary or actigraphy assessed). CONCLUSION: These findings extend the literature documenting the health benefits of social support, and suggest that social support may similarly influence sleep in individuals with insomnia as well as non-insomnia controls. PMID- 20955866 TI - Maternal postpartum sleepiness and fatigue: associations with objectively measured sleep variables. AB - OBJECTIVE: To explore whether standardized survey instruments and objective performance measures differentiate traditional constructs of sleepiness and fatigue among a sample of postpartum mothers. Additionally, we wanted to explore the independent associations among these measures with actigraphically measured nocturnal sleep variables. METHOD: Seventy-nine postpartum mothers' subjective sleepiness, fatigue, and performance measures [Stanford Sleepiness Scale (SSS), Epworth Sleepiness Scale (ESS), Visual Analogue of Fatigue Scale (VAS), Profile of Mood States (POMS) subscale items, and the Psychomotor Vigilance Test (PVT)] and objective actigraphically measured sleep were collected during postpartum week 11. A principal components analysis was calculated, then regressions were calculated among resulting factors and among individual measures with total sleep time and sleep efficiency. RESULTS: Three factors accounted for 83.84% of model variance. Factor 1 (41.41%) included the SSS, ESS, and the VAS. Factor 2 (28.13%) included only PVT variables. Factor 3 (14.30%) included the two POMS subscale items. Factor 1 was associated with nocturnal sleep time and Factor 2 was associated with sleep efficiency. The ESS was independently associated with nocturnal sleep time, whereas, POMS-Vigor subscale and median reaction time, together, were associated with sleep efficiency. CONCLUSION: Among postpartum mothers, standard instruments used to measure sleepiness, fatigue, and performance were distributed among three distinct factors that did not clearly identify traditional sleepiness and fatigue constructs. Objectively measured sleep time and sleep efficiency were associated with specific factors, as well as specific measures, that correspond to sleepiness and fatigue states. PMID- 20955867 TI - Relations between sleep, fatigue, and health-related quality of life in individuals with insomnia. AB - OBJECTIVE: This study explored the relations between sleep, fatigue, and health related quality of life in a sample of individuals with chronic insomnia. METHODS: A total of 160 adults meeting the diagnostic criteria for chronic insomnia underwent three nights of polysomnography (PSG) and completed sleep diaries and questionnaires assessing daytime functioning including fatigue and health-related quality of life. RESULTS: A cluster analysis was conducted based on PSG-defined sleep disturbances and fatigue severity. A four-cluster solution (R(2)=0.68) was found, classifying individuals as having either (a) both severe sleep disturbance and severe fatigue (n=15); (b) severe sleep disturbance but milder fatigue (n=15); (c) milder sleep disturbance but severe fatigue (n=68); or (d) both milder sleep disturbance and milder fatigue (n=61). Health-related quality of life was lower in both clusters with severe fatigue compared to those with milder fatigue and was further decreased when severe sleep disturbances were present. Relations between several indicators of fatigue and health-related quality of life were then examined using factor analysis in order to identify different domains of impairment. A three-factor structure was selected, suggesting that daytime symptoms can be classified as relating to fatigue, physical health, or mental health. These different subtypes of daytime impairment were predicted by distinct sets of variables. CONCLUSION: More severe fatigue is not necessarily related to poorer PSG-defined sleep but appears associated with greater impairment in health-related quality of life. Fatigue and health-related quality of life appear to be distinct but interrelated constructs. PMID- 20955868 TI - A randomized controlled trial of quetiapine versus placebo in the treatment of delirium. AB - BACKGROUND: Delirium is a commonly occurring complex neuropsychiatric disorder. Evidence for its treatment based on randomized controlled trials (RCTs) is poor. AIMS: To determine the efficacy and acceptability of quetiapine in the treatment of delirium. METHOD: A double-blind, RCT was conducted. A total of 42 patients were randomized to quetiapine or a placebo group. The primary outcome measure was the Delirium Rating Scale Revised 98. Other scales used were the Brief Psychiatric Rating Scale, Mini-Mental State Examination and Clinical Global Improvement. In order to account for missing data, a nonlinear mixed-effects model was used to estimate the difference between the two groups. RESULTS: The quetiapine group improved more rapidly than the placebo group. Specifically, the quetiapine group recovered 82.7% faster (S.E. 37.1%, P=.026) than the placebo group in terms of DRS-R-98 severity score. In terms of the DRS-R-98 noncognitive subscale, the quetiapine group improved 57.7% faster (S.E. 29.2%, P=.048) than the placebo group. CONCLUSIONS: Quetiapine has the potential to more quickly reduce the severity of noncognitive aspects of delirium. This study was underpowered for treatment comparisons at specific points in time but nonetheless detected significant differences when analyzing the whole study period. While it is not possible to draw definitive conclusions, further larger studies exploring the use of quetiapine in other delirium populations seem justified. Larger increments in the dose of quetiapine may yield even stronger results. PMID- 20955869 TI - A cognitive model of menopausal hot flushes and night sweats. AB - Hot flushes and night sweats (HF/NS) are commonly experienced by mid-aged women during the menopause transition. They affect approximately 70% of women but are regarded as problematic for 15-20% largely due to physical discomfort, distress, social embarrassment, and sleep disturbance. There is a need for effective and acceptable nonmedical treatments for menopausal symptoms due to the declining use of hormone therapy (HT) following publication of the Women's Health Initiative and other prospective studies which associated HT use with increased risk of stroke and breast cancer. HF/NS are an example of a physiological process embedded within, and moderated by, psychological processes, as evidenced by discrepancies between subjective experiences and physiologically measured symptoms. We describe a cognitive model of menopausal hot flushes that can explain symptom perception, cognitive appraisal, and behavioral reactions to symptoms. Theoretically, the model draws on symptom perception theory, self regulation theory, and cognitive behavioral theories. The model can be used to identify the variables to target in psychological interventions for HF/NS and to aid understanding of possible mediating factors. As part of Phase II intervention development, we describe a cognitive behavioral treatment which links the bio psycho-social processes specified in the model to components of the intervention. PMID- 20955870 TI - Pregnancy complications in women with childhood sexual abuse experiences. AB - OBJECTIVE: Childhood sexual abuse (CSA) has an estimated prevalence of 20% and has a constantly growing list of known long-term consequences on physical as well as psychological health which may also influence obstetrical care attributed to it. However, scientific data on the association of CSA and pregnancy are sparse. Therefore, the study investigated pregnancy complications in women exposed to CSA. METHODS: The study was designed as a cohort study comparing 85 women exposed to CSA with 170 matched unexposed women. CSA was identified by interview using modified questions from Wyatt [Child Abuse Negl 9 (1985) 507-519]. Data on pregnancy complications were collected by questionnaire and based on entries in a booklet (Mutterpass) in which all relevant data on pregnancy are documented at each prenatal consultation for any women attending prenatal care in Germany. Statistical analysis was performed with chi square, Fisher's Exact Test, and multiple logistic regression analysis to control the association between CSA and pregnancy complications for confounders significant in univariate analysis, i.e., physical abuse, other adverse experiences during childhood, abuse during pregnancy, substance abuse, and occupation. RESULTS: Women exposed to CSA were significantly more often hospitalized during pregnancy (41.2%/19.4%; OR 2.91, CI 1.64-5.17). They presented more often complications such as premature contractions (38.8%/20%; OR 2.54 CI 1.43-4.51), cervical insufficiency (25.9%/9.4%; OR 3.36, CI 1.65-6.82), and premature birth (18.8%/8.2%; OR 2.58, CI 1.19-5.59). CONCLUSION: Therefore, health care providers should adapt prenatal care to the specific needs of women exposed to CSA. PMID- 20955871 TI - Social support concepts and measures. AB - Distinctions among concepts and approaches to assessing social support are made, and published generic and specialized measures of social support are reviewed. Depending on study aims, investigators may be interested in assessing perceived or received support from the perspective of the provider, the recipient, or both. Whereas some measures inquire about the availability or mobilization of several kinds of supportive resources, others seek supplemental information about the membership and structural properties of the social network as well. Observational and self-reported measures of support are presented, along with brief and extensive measures. A final set of three support measures is highlighted, including their psychometric properties. PMID- 20955872 TI - [Effectiveness of the correct use of inhalation devices in patients with COPD: randomized clinical trial]. AB - BACKGROUND AND OBJECTIVE: We aimed yo assess whether an educational intervention on the use of inhalational devices improve the functional status of patients with COPD. PATIENTS AND METHOD: Randomized controlled trial with parallel design and simple blind trial performed in a clinic with 94 patients diagnosed with COPD and who used inhaled devices. Participants were randomized into 2 groups: the intervention group held a training session on the use of inhalers at baseline and one month and strengthening the control group with routine monitoring. The main outcome measure was the change in the synthetic index BODE (Body-Mass Index, Airflow Obstruction, Dyspnea and Exercise Capacity). RESULTS: Patients in the intervention group (n=48) experienced an improvement in the sensation of breathlessness decreasing by 0.85 points (95% CI -1.14 to -0.56) on the MMRC dyspnea scale, while the control group (n=46) did not show any significant change p<0.0001. On the walking test the intervention group walked 6.19 meters (95% CI 4.02 to 16.40) while the control group walked 20.55 meters lower (95% CI -37.80 to -3.28), significant differences with p=0.009. The BODE index decreased (improved) -0.82 points in the intervention group (95% CI -1.16 to -0.46) and increased (worsened) 0.20 in control group (95% CI -0.16 to 0.56) p<0.0001. CONCLUSIONS: Patients with COPD who receive specific training on inhaler use as compared with those with regular monitoring experience improvement in their functional state. PMID- 20955873 TI - Foreword: tracheobronchial, pulmonary, and mediastinal problems in general thoracic surgery. PMID- 20955874 TI - Preface: tracheobronchial, pulmonary and mediastinal problems in general thoracic surgery. PMID- 20955875 TI - Management of pleural space: effusions and empyema. AB - Pleural effusions are commonly encountered in clinical medicine. They can represent both a diagnostic and a therapeutic challenge. This article discusses the diagnostic modalities used to evaluate the patient with a pleural effusion. Also discussed are the therapeutic options for the 2 most common causes of pleural effusions encountered by the surgeon: pleural sepsis and malignant pleural effusions. PMID- 20955876 TI - Pneumothorax, bullous disease, and emphysema. AB - This article addresses several distinct but related pulmonary conditions that are commonly referred to general thoracic surgeons for decision making and management. The management of various types of pneumothorax is reviewed, with particular attention to the selection of the appropriate level of surgical intervention. The related entities of bullous lung disease and diffuse emphysema are discussed, with a focus on the identification of appropriate circumstances for surgical intervention. The summarized work and the treatment recommendations are supported with an extensive bibliography of important work in this area. PMID- 20955877 TI - The diaphragm. AB - This article discusses the diaphragm from a surgical perspective. Although it is a relatively simple organ compared with other structures, the diaphragm serves important anatomic and functional roles necessary for proper respiratory function. It is an organ of little irregularity or disease, and easily manipulated in the operating room by those who have a basic understanding of its anatomic details. PMID- 20955878 TI - Pulmonary assessment for general thoracic surgery. AB - Preoperative pulmonary assessment is an essential step in the selection and the management of patients who are candidates for thoracic procedures. Despite advances in anesthesia, including the use of epidural analgesics, and advances in surgical techniques and perioperative care, postoperative pulmonary complications remain the leading cause of morbidity and mortality in thoracic surgery. No single parameter is predictive of postoperative complications or mortality in patients who undergo a thoracic procedure. Therefore, patients should not be denied for surgical resection based on any single abnormal test or parameter. A comprehensive assessment of the functional status, exercise tolerance, and pulmonary function should be performed before surgery to select the patients appropriately, predict the risk of postoperative complications, and achieve better outcomes. PMID- 20955879 TI - Hemoptysis and thoracic fungal infections. AB - Hemoptysis and thoracic fungal infections are infrequent but challenging problems, especially when encountered in the emergency setting. The evaluation and management of massive and nonmassive hemoptysis is described with special attention to radiologic, bronchcoscopic, and surgical interventions. The important principles of airway control, stabilization, and definitive management are emphasized. Endemic and opportunistic fungal infections are more common than they seem. The role of the surgeon is to assist in diagnosis, evaluate and treat pulmonary nodules, and consider resectional therapy for mycetoma and invasive fungal infections in selected candidates. PMID- 20955880 TI - The solitary pulmonary nodule: approach for a general surgeon. AB - The solitary pulmonary nodule is a common finding on radiographic studies performed for other reasons. It is important that the probability of malignancy be assessed when these nodules are found. This chapter outlines a diagnostic approach for these nodules to optimize non-invasive and invasive testing, and describes the value of the various modalities used to evaluate these abnormalities. PMID- 20955881 TI - Tumors of the mediastinum and chest wall. AB - Primary tumors of the mediastinum and chest wall comprise a diverse group of conditions with a wide range of presentations. A thorough knowledge of thoracic anatomy is essential for appropriate diagnosis and treatment. Given their proximity to critical structures, treatment of these tumors is often challenging. Although surgery is the mainstay of therapy for most mediastinal and chest wall tumors, a multidisciplinary approach is valuable in many cases. PMID- 20955882 TI - Surgical and nonresectional therapies for pulmonary metastasis. AB - Resection of pulmonary metastases is reasonable and is commonly performed for patients whose primary disease is controlled and for whom the metastatic burden in the chest is such that all disease can be resected safely. The use of video- assisted thoracic surgery rather than an open approach in metastasectomy, however, is still being debated. In addition, nonresectional therapies such as radiofrequency ablation and stereotactic body radiation therapy are being used in centers for patients with oligometastases to the lungs. This article reviews the indications and approaches for surgical resection, as well as these other nonresectional therapies. At present, it is difficult to directly compare these approaches because of the heterogeneous nature of metastasectomy series. Moreover, the stereotactic body radiation therapy and radiofrequency ablation studies have involved smaller numbers of patients and shorter follow-up than the surgical studies. The preliminary data for these nonresectional therapies, however, are encouraging and certainly should be considered in the decision tree when treating patients with pulmonary metastases. PMID- 20955883 TI - Endoscopic evaluation of the tracheobronchial tree and mediastinal lymph nodes. AB - Assessment of the airways and surrounding structures, including the mediastinum and pulmonary parenchyma, has been greatly facilitated by advancements in bronchoscopic techniques, both rigid and flexible. Recent years have seen an explosion in technologies that have revolutionized the ability to visualize, biopsy, or otherwise assess regions of potential pathology within the upper aerodigestive tract and adjacent structures. This article concisely and comprehensively reviews the endoscopic evaluation of the tracheobronchial tree and mediastinum with a focus on emerging technologies and their role in treatment of thoracic disease. PMID- 20955884 TI - The compromised airway: tumors, strictures, and tracheomalacia. AB - Airway obstruction caused by intrinsic laryngeal and tracheal disorders requires a systematic diagnostic approach, including a careful bronchoscopic examination. Tumors of the upper airway are most often malignant; except for the larynx, metastatic lesions predominate. Among the inflammatory strictures, intubation injuries remain common in developed countries. Tracheomalacia related to chronic obstructive lung disease causes high-grade, chronic, long-segment airway obstruction. The surgical treatment for each group of these disorders is described. PMID- 20955885 TI - Pediatric thoracic problems: patent ductus arteriosus, vascular rings, congenital tracheal stenosis, and pectus deformities. AB - In this article the authors examine 4 diseases specific to thoracic surgery in children: patent ductus arteriosus, vascular rings, congenital tracheal stenosis, and pectus deformities. The pathophysiology, clinical presentation, and results of contemporary surgical management are discussed for each diagnosis. Surgical techniques are described and illustrated in detail. PMID- 20955886 TI - Preface. PMID- 20955887 TI - An introduction to the biology of Northern krill (Meganyctiphanes norvegica Sars). AB - This chapter provides a background to research on Northern krill biology, starting with a description of its morphology and identifying features, and the historical path to its eventual position as a single-species genus. There is a lack of any euphausiid fossil material, so phylogenetic analysis has relied on comparative morphology and ontogeny and, more recently, genetic methods. Although details differ, the consensus of these approaches is that Meganyctiphanes is most closely related to the genus Thysanoessa. The light organs (or photophores) are well developed in Northern krill and the control of luminescence in these organs is described. A consideration of the distribution of the species shows that it principally occupies shelf and slope waters of both the western and eastern coasts of the North Atlantic, with a southern limit at the boundary with sub tropical waters (plus parts of the Mediterranean) and a northern limit at the boundary with Arctic water masses. Recent evidence of a northward expansion of these distributional limits is considered further. There have been a variety of techniques used to sample and survey Northern krill populations for a variety of purposes, which this chapter collates and assesses in terms of their effectiveness. Northern krill play an important ecological role, both as a contributor to the carbon pump through the transport of faecal material to the deeper layers, and as a key prey item for groundfish, squid, baleen whales, and seabirds. The commercial exploitation of Northern krill has been slow to emerge since its potential was considered by Mauchline [Mauchline, J (1980). The biology of mysids and euphausiids. Adv. Mar. Biol. 18, 1-681]. However, new uses for products derived from krill are currently being found, which may lead to a new wave of exploitation. PMID- 20955888 TI - Genetics of Northern krill (Meganyctiphanes norvegica Sars). AB - Understanding the origin and maintenance of genetic diversity in the oceanic realm is difficult because barriers to gene flow are far less obvious in marine compared to terrestrial species. This is particularly so for planktonic species such as euphausiids, with no fossil record and high rates of dispersal, and in which paleobiology and evolutionary history remains largely obscure. Population genetics may play an important role in this respect, elucidating population connectivity and shedding light on the historical demography of the investigated species. In turn, the relevant factors that can promote speciation over both at short and long evolutionary timescales can be identified. In this chapter, we outline the available approaches for gathering population genetics information on marine organisms, with a particular focus on the recent achievements in the study of Meganyctiphanes norvegica. For population structure, we review the data available for mitochondrial DNA (mtDNA) markers that show the presence of four temporally stable and genetically distinct gene pools, one in the Mediterranean samples and three others in the North Atlantic Ocean, potentially associated with the basin-scale pattern of circulation. Unpublished data on some nuclear microsatellite markers adds support to this conclusion. In addition, we apply a newly introduced Bayesian coalescent approach, and demonstrate that previously reported mitochondrial sequence diversity is indicative of a recent expansion at the Northern edge of the species' distribution. This does not hold for the Southern and Mediterranean populations that appear to be stable over time. We also review the literature reporting new advances on the analysis of M. norvegica genes and genes' products involved in metabolic pathways that may underline differences at the population level, possibly linked to environmental variation and local adaptations. PMID- 20955889 TI - Population dynamics of Northern krill (Meganyctiphanes norvegica Sars). AB - This chapter reviews the short- and long-term changes in the size and age composition of Northern krill (Meganyctiphanes norvegica) populations and the environmental processes influencing those changes. It examines how populations of this species are affected by rates of reproductive output and mortality, and the effects of development, immigration and dispersion on population structure. This review also takes account of the many behavioural features that directly or indirectly influence M. norvegica population dynamics, such as swarming behaviour, diel vertical migration and diverse feeding strategies. What becomes evident is that M. norvegica shows a wide variability in population size structure over the species extensive distributional range. Nevertheless, there are limits to this variability, as a result of the common life-cycle pattern. PMID- 20955890 TI - Physiology and metabolism of Northern krill (Meganyctiphanes norvegica Sars). AB - Advances in our understanding of the physiology and metabolism of Northern krill, Meganyctiphanes norvegica have been sporadic but significant. Despite problems with keeping M. norvegica in good condition in the laboratory, those who have tried, and succeeded, have contributed to a better knowledge of krill biology and challenged our understanding of some basic biological processes. Most recent work has been concentrated in the fields of digestive physiology, lipid biochemistry, respiration and anaerobiosis, metabolic properties, and pollutants. M. norvegica is capable of digesting an opportunistic, omnivorous diet, showing some digestive enzyme polymorphism and high levels of enzyme activity, the latter varying with season. It also seems capable of digesting cellulose and hemicelluloses, for example, laminarin. The biochemical composition of krill is relatively well known with some recent extensive work focusing on the previously little studied lipid and fatty acid composition, particularly with reference to reproduction, overwintering energy storage and as a nutrition marker. A high aerobic metabolism (but poor anaerobic capacity) is characteristic of M. norvegica, and how this is affected by temperature, low O(2), and season has attracted some attention, particularly in the context of diel vertical migration (DVM) across pronounced pycnoclines. Despite determining high metabolic turnover rates and a high physiological plasticity for this species, we know little of the regulative potential of metabolites, particularly their modulative effect on enzyme activity. Certainly a modest ability to maintain aerobic metabolism when encountering hypoxia, and little or no ability to osmoregulate in hyposaline conditions, does not prevent DVM in adults of this species. The ability to maintain aerobic metabolism develops early in ontogeny at about furcilia III (i.e. concurrent with first DVM behaviour). The respiratory pigment of M. norvegica, haemocyanin, has a low O(2) affinity and high temperature sensitivity (although temperature has the opposite effect on O(2) binding than found for nearly every other haemocyanin). Also surprising is the apparent use of haemocyanin as an energy source/store. While recent work has focused on physiological effects, the ecophysiological effects of transuric elements and trace metals, the effects of pollution generally are widely understudied. PMID- 20955891 TI - Food and feeding in Northern krill (Meganyctiphanes norvegica Sars). AB - Early feeding studies on Meganyctiphanes norvegica described the morphology of the feeding appendages and the actual process of food uptake and digestion. Insights into diurnal, seasonal and ontogenetic pattern in feeding activity and diet were derived from field studies on the Clyde Sea population. Since then, technical advances have confirmed some of the early assumptions and rejected others. Submersible, remotely operated vehicles and echosounders, for instance, proved that M. norvegica stay often close to the seabed and feed on particles in the epibenthic layer and sediment-water interface. Scanning electron microscopy showed that mandibles of the so-called carnivorous M. norvegica have an elaborated grinding region, which allows efficient feeding on diatoms. Three dimensional silhouette video imaging revealed mechanoreception, not vision, as the main sensory modality involved in proximity prey detection by M. norvegica. Fatty acid analysis and stomach content microscopy have now been conducted on M. norvegica across a range of environments including the Gulf of Maine, Greenland Sea, Barents Sea, Scandinavian fjords, the Kattegat and Mediterranean Sea. Regional and seasonal differences in the trophic environment are reflected in their daily ration and in the relative importance of copepods versus phytoplankton in their diet. Overall, phytoplankton is an important food source for M. norvegica during the spring bloom and part of the summer, but copepods are dominant in autumn and winter. Depending on their vertical co-occurrence, M. norvegica can feed on a range of copepods from early stages of Oithona spp. up to adult Calanus spp. There are clear ontogenetic differences in diet, with adults feeding more on copepods and benthic food items than early post-larvae. Future studies should link diet to simultaneously measured growth and reproduction and emphasise comparison across the spectrum of environments inhabited by this versatile species. PMID- 20955892 TI - Growth and moulting in Northern krill (Meganyctiphanes norvegica Sars). AB - Moulting and growth as a key aspect of the life-history of crustaceans has been reviewed here for Meganyctiphanes norvegica. Moulting is a cyclical process with relatively constrained, uniform phases that have been well documented. The crustacean moult cycle has a large influence on growth-rates, reproduction and metabolism. Moult and growth are under hormonal control with further environmental influences. A pre-requisite for intensive studies is a detailed moult staging system. Here, a further refinement and temporal phasing is presented for M. norvegica. On such a basis, the dynamics of cuticle synthesis and degradation are shown. Moult and reproductive cycles are interlinked and krill is able to combine growth and reproduction in a way that allows females to achieve similar net growth rates to males. A synchronisation of physiological processes and behaviour related to growth and reproduction enhances environmental success. Moult staging can also be used to assess growth rates in the field. Some further technical approaches are reviewed. Laboratory maintenance and field data are combined to determine growth rates under various environmental conditions. These are related to life-growth assessments from population studies comparing krill along a latitudinal gradient. Life-cycle and physiological data indicate that Northern krill are able to cope with both warm and cold environments and have highly adaptable phenotypes. The species may serve as useful indicator of environmental change. Its potential proliferation in new environments may also have implications to regional food webs, given the krill's high level of growth and productivity and their pivotal trophic role. PMID- 20955893 TI - Reproduction in Northern krill (Meganyctiphanes norvegica Sars). AB - This review presents the current state of knowledge with regard to the reproductive biology of Northern krill (Meganyctiphanes norvegica). Reproduction is limited to a distinct period of the year. First development of the ovary occurs at the onset of the season, when the stock of primary oocytes issued from the germinal zone starts to accumulate glycoproteic yolk. Previtellogenesis continues throughout the entire reproductive season, but oosorption (the retrieval by the ovary of the yolk constituents from the growing oocytes) may occur in unfavourable conditions and represents an important metabolic process for sustaining females during such periods. Oosorption also occurs at the onset of the resting season. It has been established that individual females may perform several cycles of reproduction each year. Each reproductive cycle spans two moult cycles, one in which lipid yolk is accumulated (vitellogenesis) and another when spawning occurs. The time of spawning does not coincide with the moult (ecdysis), but with the onset of moult preparation (C-D0 moult stages). The complete egg-batch is spawned well before the moult. Storage lipids are accumulated preferentially in the ovary with distinctly high levels of omega-3 polyunsaturated fatty acids in the polar lipid fraction as well as phosphatidylcholine, a key component in the development of the embryo. There is no difference concerning lipid storage between resting females, males and juvenile krill. Beside the ovary, the fat body is an important organ involved in the metabolism and storage of the glycoproteins and lipids that will be transformed into the lipoglycoproteins of the yolk platelets in the ovary. M. norvegica produce large egg batches with the number of mature oocytes in one batch being proportional to the size of the female, with a mean number of 1000 1200 eggs per batch. The number of reproductive cycles per year is a function of the trophic conditions, with the first reproductive cycle being triggered by the first phytoplankton bloom. Other reproductive features reflect specific adaptations of krill to a pelagic life, like swarming and vertical migration behaviour. M. norvegica segregate at night for moulting and mating or spawning, while swimming constantly during their diel vertical migration (DVM). Key questions concerning krill reproduction remain, particularly in identifying the cues that switch krill in and out reproductive development, or between egg building and oosorption. New molecular tools are now available to tackle such questions. PMID- 20955894 TI - Laboratory-based observations of behaviour in Northern krill (Meganyctiphanes norvegica Sars). AB - The behaviour of planktonic animals remains poorly understood due to the difficulty of observing them in situ without influencing their behaviour. Here we review experiments on the behavioural responses of Northern krill, Meganyctiphanes norvegica (and related organisms), in isolation in laboratory based aquaria. The value of this approach lies in the close observation that is possible; the downside is the uncertainty as to how well the observed behaviour relates to the natural behaviour of the subject animal. We discuss studies of swimming and swarming, and the responses of krill to light. We consider techniques involving automatic recordings that avoid, to some extent, making subjective decisions on behaviour. The effects of isolation of such a gregarious animal and of exposure to unnaturally high light levels are also considered. We conclude that such experiments can be of great value as long as these limiting factors are addressed. PMID- 20955895 TI - Diel vertical migration behaviour of the Northern krill (Meganyctiphanes norvegica Sars). AB - The prototype of Meganyctiphanes norvegica diel vertical migration (DVM) behaviour comprises ascent around dusk, feeding near the surface at night, and descent at dawn, explained as a trade-off between feeding and predator avoidance in an environment where both food and risk of predation is highest near surface. Light is the proximate cue, and daytime distribution is deeper in clear waters and sunny weather and nocturnal distributions deeper in moonlight. However, both internal state and external factors further affect and modify the diel migration pattern. While Meganyctiphanes migrates in synchrony to the surface at sunset, part of the population may descend soon after the ascent with individuals re entering upper layers throughout the night. This has been explained with hungry individuals being prone to take larger risks and hence stay shallower, while satiated individuals seek shelter at depth. Females migrate closer to the surface than males of equivalent size, possibly due to their greater demand for energy to fuel egg production. Freshly moulted M. norvegica remain at depth throughout the diel cycle. This has been related to the fact that that krill do not feed during moulting, to reduced swimming capacity, and as a mechanism to avoid cannibalism whilst in a vulnerable condition. In some locations large parts of the population remain at depth at night. Such behaviour may incur access to demersal food sources, provide avoidance of predators, or can be a means to avoid horizontal transport to adjacent, unfavourable areas. Environmental gradients can arrest migrations of M. norvegica, yet the effect of physics is not always distinguished from associated biological properties, like subsurface maxima of phytoplankton located at pycnocline boundaries. Deeper nocturnal distribution when predators were abundant has been reported, and krill may adjust their distribution upwards when exposed to deep-living predators. Instantaneous escape to approaching predators is a common component of the anti-predator repertoire of Meganyctiphanes. Occasionally reported schooling behaviour that overrides normal DVM behaviour may serve anti-predation purposes, as well as being related to reproduction. M. norvegica can remain within confined areas, often defined by the bottom topography, even when exposed to strong currents. Behaviourally mediated retention may be accomplished by vertical migration in depth-stratified flows, but evidence for active use of DVM for the purpose of retention is so far circumstantial among M. norvegica. In several instances, large aggregations of krill that repeatedly occur in the same location appear to be accidental consequences of krill vertical migration behaviour interacting with the mean circulation and bottom topography, rather than representing active retention behaviour. PMID- 20955896 TI - Predation on Northern krill (Meganyctiphanes norvegica Sars). AB - We consider predation as a function of prey concentration with a focus on how this interaction is influenced by biological-physical interactions, and wider oceanographic processes. In particular, we examine how the anti-predation behaviour of Northern krill interacts with ocean-circulation process to influence its vulnerability to predation. We describe how three-dimensional (3D) circulation interacts with in situ light levels to modulate predator-prey interactions from small to large scales, and illustrate how the stability of the predator-prey system is sometimes perturbed as a consequence. Northern krill predators include a wide range of species from the pelagic and benthic strata, as well as birds. Many exhibit adaptations in their feeding strategy to take advantage of the dynamic physical-biological processes that determine the distribution, concentration and vulnerability of Northern krill. Among them, baleen whales appear to have developed particularly efficient predation strategies. A literature search indicates that Northern krill are a major contributor to ecosystem function throughout its distributional range, and a key species with respect to the flow of energy to upper trophic levels. A list of future research needed to fill gaps in our understanding of Northern krill predator-prey interaction is provided. PMID- 20955897 TI - The origins of vocal learning: New sounds, new circuits, new cells. AB - We do not know how vocal learning came to be, but it is such a salient trait in human evolution that many have tried to imagine it. In primates this is difficult because we are the only species known to possess this skill. Songbirds provide a richer and independent set of data. I use comparative data and ask broad questions: How does vocal learning emerge during ontogeny? In what contexts? What are its benefits? How did it evolve from unlearned vocal signals? How was brain anatomy altered to enable vocal learning? What is the relation of vocal learning to adult neurogenesis? No one has described yet a circuit or set of circuits that can master vocal learning, but this knowledge may soon be within reach. Moreover, as we uncover how birds encode their learned song, we may also come closer to understanding how we encode our thoughts. PMID- 20955898 TI - From central pattern generator to sensory template in the evolution of birdsong. AB - Central nervous networks, be they a part of the human brain or a group of neurons in a snail, may be designed to produce distinct patterns of movement. Central pattern generators can account for the development and production of normal vocal signals without auditory feedback in non-songbirds. Songbirds need auditory feedback to develop and maintain the normal song of their species. The prerequisite for the use of auditory feedback for the control of song is a set of acoustic criteria or a template to which voice must match. The template method perhaps evolved to free birds from fixed central pattern generators, resulting in the evolution of diverse and complex songs among oscine songbirds. The evolution of human speech may have followed a similar course. PMID- 20955899 TI - Treating the adult neurogenic bladder. Preface. PMID- 20955900 TI - Basic bladder neurophysiology. AB - Maintenance of normal lower urinary tract function is a complex process that requires coordination between the central nervous system and the autonomic and somatic components of the peripheral nervous system. This article provides an overview of the basic principles that are recognized to regulate normal urine storage and micturition, including bladder biomechanics, relevant neuroanatomy, neural control of lower urinary tract function, and the pharmacologic processes that translate the neural signals into functional results. Finally, the emerging role of the urothelium as a sensory structure is discussed. PMID- 20955901 TI - Pharmacologic therapy for the neurogenic bladder. AB - This article is a review of the current and past literature on medical management of the neurogenic bladder, with a particular focus on spinal cord injury and multiple sclerosis. The use of antimuscarinics, alphaalpha-blocker, and tricyclic antidepressants and their combined use are discussed along with new therapies in human and animal trials. PMID- 20955902 TI - Urodynamics of the neurogenic bladder. AB - Many patients with neurogenic bladders require careful monitoring in order to decrease the risk of infectious and renal complications. Urodynamic testing, with particular attention paid to detrusor pressures, is helpful for risk stratification in these patients and provides key information when assessing effectiveness of treatments. This article reviews the history, indications, and contemporary parameters for urodynamic testing in the neurogenic population. PMID- 20955903 TI - Review of neurologic diseases for the urologist. AB - This article reviews the neurologic conditions associated with a high prevalence of bladder dysfunction and about which significant advances in understanding have occurred in recent years. The importance of the frontal lobes for bladder control has been confirmed through functional brain imaging, and recent findings in the elderly with incontinence suggest the problem may result from disconnection of important frontal areas caused by white matter disease. The very different urologic profile of the two sometimes-confused conditions, multiple system atrophy and Parkinson's disease, is clarified. The advances in treatments for multiple sclerosis in recent years have been remarkable and are briefly described. PMID- 20955904 TI - Management goals for the spina bifida neurogenic bladder: a review from infancy to adulthood. AB - Patients with spina bifida require longitudinal urological care as they transition from childhood to adolescence and then to adulthood. Issues important to urological health, such as protection of the upper tracts and prevention of incontinence, need vigilant follow-up throughout the patient's life. As the child ages, additional issues such as sexual functioning also become increasingly important for social integration. Despite this need for regular assessment, many adult patients with spina bifida lose coordinated urological care after leaving specialized pediatric spina bifida clinics. Consequently, urologists frequently encounter an adult patient with spina bifida in practice and they need to understand the basic urological treatment goals and potential complications for this population. PMID- 20955905 TI - Spinal cord/brain injury and the neurogenic bladder. AB - This article reviews neurogenic bladder related to traumatic injury as well as vascular lesion of brain/spinal cord. Because urological manifestations of traumatic or vascular brain/spinal cord injury are highly diversified and complex, the approaches to achieve accurate diagnosis and administer proper treatment can be complicated. The goal of primary treatment is preservation of renal function and attainment of social continence. Maintaining low intravesical pressure and adequate bladder emptying are central to the treatment strategy. Diagnosis and appropriate urological management of these disease entities should depend on urodynamic studies because of poor correlation between clinical symptoms or somatic neurologic signs and urodynamic findings. PMID- 20955907 TI - Neuromodulation and the neurogenic bladder. AB - Neurogenic bladder resulting from spinal cord injury and spina bifida has a profound impact on voiding function. This article reviews the current literature with regards to electrical stimulation for neurogenic bladder and the clinical outcomes associated with sacral neuromodulation, pudendal neuromodulation, posterior tibial nerve stimulation, and the Finetech-Brindley posterior/anterior stimulator. In addition, the world literature reviewing hemilaminectomy and ventral root micro anastomosis is discussed. The article also examines the safety of magnetic resonance imaging in patients with implanted neurostimulators and discusses common complications. Neuromodulation, both electrical and physical, play an important role in the management of neurogenic bladder. PMID- 20955906 TI - Contemporary management of the neurogenic bladder for multiple sclerosis patients. AB - Urinary symptoms related to multiple sclerosis (MS) present a complex challenge for the treating physician. However, several treatment options are available for the symptomatic patient once the physician understands basic MS disease epidemiology and pathophysiology. Depending of disease status and symptoms, MS urinary symptoms may respond to directed behavioral, pharmacologic, intravesical, neuromodulation, or surgical therapies. PMID- 20955908 TI - Botulinum toxin therapy for neurogenic detrusor overactivity. AB - Detrusor injection of botulinum toxin (BTX) has shown great promise in the treatment of neurogenic detrusor overactivity (NDO) refractory to conservative therapy. Despite a paucity of prospective evidence, there exists a growing consensus that BTX injection therapy is a well-tolerated, low-risk therapy. Injections result in substantial subjective improvement in continence and quality of life. Moreover, assessment of urodynamic parameters demonstrates objective changes: (1) an increase in maximum cystometric capacity; (2) when applicable, a reduction in maximal detrusor voiding pressures; and (3) an increase in bladder compliance in cases where baseline bladder compliance measures were abnormal. While BTX bladder injection offers both objective and subjective measures of incontinence control, treatment duration is limited by the gradual reinnervation of injected tissue over an approximately 6- to 9-month interval. However, repeat injection cycles do appear to achieve similar levels of efficacy. The objective of this review is to provide a focused summary of the current body of literature, investigating the safety and efficacy of bladder BTX injection in patients with NDO. PMID- 20955909 TI - The neurogenic bladder and incontinent urinary diversion. AB - Management of the neurogenic bladder with an incontinent stoma is necessary in situations in which intermittent catheterization via the urethra or a continent stoma is not feasible. Cutaneous ureterostomy, vesicostomy, ileal conduit, and ileovesicostomy have all been used for this purpose. Vesicostomy is most commonly used as a temporizing measure in the pediatric neurogenic population. Both ileal conduit, with or without cystectomy, and ileovesicostomy have contemporary roles in the management of the neurogenic bladder. PMID- 20955910 TI - Bladder tissue engineering. AB - The bladder can lose the ability to store and empty effectively as a result of numerous conditions. When conservative methods to maximize patient safety and quality of life fail, surgical reconstruction of the bladder is usually considered. Augmentation cystoplasty can be performed with the use of the small bowel, large bowel, or less often, stomach. An alternative approach, tissue engineering, identifies the body's own potential for regeneration and supports this propensity with appropriate raw materials and growth factors so that the body's original structure and function may be restored. Tissue engineering can involve the use of a scaffold or matrix alone or of cell-seeded matrices. Harvesting cells and culturing them has become an important tool in tissue engineering. Multiple possibilities for sources of cells have been investigated, including stem cells and differentiated cells from organs other than the bladder; however, to date, autologous bladder cells remain the gold standard for culture and seeding. PMID- 20955911 TI - Urologic complications of the neurogenic bladder. AB - Patients with a neurogenic bladder are at risk for several urologic complications including hydronephrosis, vesicoureteral reflux, renal failure, urinary tract infections, calculus disease, bladder cancer, sexual dysfunction including infertility, and the destroyed bladder and urethra. The management of filling bladder pressures and regular, complete emptying, ideally with clean intermittent catheterization, can prevent or delay many of these complications. Even with optimum management, complications may still develop over time, necessitating regular urologic follow-up to recognize, treat, and prevent further complications. The ultimate goal of the urologist in treating the patient with a neurogenic bladder is to allow for preservation of renal function and continence with minimum complications. PMID- 20955912 TI - Selection and viral load kinetics of an oseltamivir-resistant pandemic influenza A (H1N1) virus in an immunocompromised patient during treatment with neuraminidase inhibitors. AB - Prolonged viral excretion in immunocompromised hosts leads to long oseltamivir treatment and to the subsequent development of oseltamivir-resistant pandemic influenza virus selection. We report the selection and nasopharyngeal shedding kinetics of an oseltamivir-resistant strain in a hospitalized immunocompromised patient with prolonged influenza illness. Viral load quantification and genotyping methods were performed from 7 serial nasopharyngeal samples. Before initial oseltamivir treatment, the viral load was 5.78 log(10) copies/mL of sample and only wild-type virus population was detected. The nasopharyngeal viral load remained above the detection limit although there was a second course of oseltamivir treatment. Twelve days after the onset of symptoms, an oseltamivir resistant strain was selected. After 12 days of inhaled zanamivir treatment, the patient was discharged asymptomatic. The study emphasizes the importance of viral load quantification and surveillance of emergence of resistant strains prospectively because the information provided has important implications in the clinical management of the patient. PMID- 20955913 TI - The limitations of polymerase chain reaction in the setting of possible recurrent tuberculosis: 2 instructional cases. AB - The interpretation of a positive result for Mycobacterium tuberculosis by nucleic acid amplification such as polymerase chain reaction (PCR) can be challenging. We present 2 cases that illustrate the limitations of tuberculosis PCR on respiratory secretions in previously treated patients, even years after the previous disease episode. PMID- 20955914 TI - Travel-associated Legionnaires disease: clinical features of 17 cases and a review of the literature. AB - We retrospectively investigated patients with Legionnaires disease (LD) who had been admitted to the Baskent University Alanya Teaching and Research Hospital, Ankara, Turkey, from January 2002 to September 2009. Twenty definitive cases were followed as LD, 17 (85%) of which were travel associated. The mean age was 61.5 +/- 9.5 years (range, 39-77 years). Diabetes mellitus was found in 7 (41.2%) of those patients. Gastrointestinal or neurologic abnormalities were found approximately in two-thirds and relative bradycardia in 9 (52.9%). LD was severe in 11 (64.7%) patients, which required intensive care unit follow-up. Although appropriate antibiotic therapy was initiated in all patients on admission day, 4 (23.5%) deaths occurred. In conclusion, clinicians should remain vigilant about the diagnosis of LD in patients with community-acquired pneumonia, especially in the presence of extrapulmonary involvement, risk factors for LD, and a history of recent travel. As in our cases, mortality is still high in sporadic cases despite early appropriate treatment. PMID- 20955915 TI - Molecular analysis of 2 cases of methicillin-resistant Staphylococcus aureus cholecystitis and a review of the literature. AB - We present 2 cases of methicillin-resistant Staphylococcus aureus (MRSA) acalculous cholecystitis and review the literature. We performed pulsed field gel electrophoresis, typing of the staphylococcal cassette chromosome mec element, and Panton-Valentine leukocidin testing on the isolates. One each was closely related to USA100 and USA300, indicating that both healthcare- and community associated strains may cause MRSA cholecystitis. PMID- 20955916 TI - Comprehensive assessment of tigecycline activity tested against a worldwide collection of Acinetobacter spp. (2005-2009). AB - A total of 5127 Acinetobacter spp. were collected from 140 hospitals in 32 countries in North America (17.1%), Europe (22.9%), Latin America (25.2%), and the Asia-Pacific (APAC) region (34.8%). Tigecycline MIC distributions were bimodal against isolates from North America and APAC region, while a unimodal pattern was noted for strains from Latin America. A variable MIC distribution was noted in Europe. Only tigecycline (MIC(50/90), 0.5/2 MUg/mL) and polymyxin B (MIC(50/90), 0.5/1 MUg/mL; 98.6% susceptible) exhibited high activity against Acinetobacter spp. Overall, tigecycline inhibited at least 90.0% of Acinetobacter spp. isolates from all countries evaluated at <=2 MUg/mL, as well as 95.0% of those displaying multidrug resistance. Other tested agents showed limited activity and a significant (P < 0.001) trend toward decreased susceptibility during the study period. PMID- 20955917 TI - Correlation between vancomycin and daptomycin MIC values for methicillin susceptible and methicillin-resistant Staphylococcus aureus by 3 testing methodologies. AB - We examined the potential correlation between vancomycin and daptomycin MIC for 298 Staphylococcus aureus by broth microdilution (BMD), Etest, and MicroScan((r)). Etest and BMD identified a significant, albeit poor, correlation between MICs (rho = 0.29, P < .01, and rho = 0.15, P = .01, respectively), but no correlation (rho = 0.08, P = .18) was observed with MicroScan. PMID- 20955918 TI - Cytologic evaluation can predict microbial culture results for infectious causes of pulmonary nodules in patients undergoing fine needle aspiration biopsy. AB - We retrospectively compared cytopathology and microbial culture results for pulmonary fine needle aspiration biopsy specimens over a 10-year period. Eighty samples were submitted for culture, yielding 24 positive cultures with 17 pathogenic organisms. Cytology predicted positive cultures in all cases where organisms were visualized, and it was associated with negative cultures in 24 of 25 cases where inflammatory changes and necrosis were absent. PMID- 20955919 TI - Declining antimicrobial susceptibility of Streptococcus pneumoniae in the United States: report from the SENTRY Antimicrobial Surveillance Program (1998-2009). PMID- 20955920 TI - It's all in the genes. PMID- 20955921 TI - Neurogenetics: advancing the "next-generation" of brain research. AB - There can be little doubt that genetics has transformed our understanding of mechanisms mediating brain disorders. The last two decades have brought tremendous progress in terms of accurate molecular diagnoses and knowledge of the genes and pathways that are involved in a large number of neurological and psychiatric disorders. Likewise, new methods and analytical approaches, including genome array studies and "next-generation" sequencing technologies, are bringing us deeper insights into the subtle complexities of the genetic architecture that determines our risks for these disorders. As we now seek to translate these discoveries back to clinical applications, a major challenge for the field will be in bridging the gap between genes and biology. In this Overview of Neuron's special review issue on neurogenetics, we reflect on progress made over the last two decades and highlight the challenges as well as the exciting opportunities for the future. PMID- 20955922 TI - Tangles of neurogenetics, neuroethics, and culture. AB - Neurogenetics promises rich insights into how the mind works. Researchers investigating the range of topics from normal brain functioning to pathological states are increasingly looking to genetics for clues on human variability and disease etiology. Is it fair to assume this interest in neurogenetics is universal? How should researchers and clinicians approach ideas of consent to research or prediction of disease when a subject or patient understands the mind with concepts or language incompatible with neurogenetics? In this paper we consider how non-Western philosophies bring complexity to ideas of individual and community consent and confidentiality in the context of neurogenetics. PMID- 20955923 TI - Healing genes in the nervous system. AB - The evolution of gene therapy has led to the development of promising new therapeutic approaches. This NeuroView will introduce the variety of delivery vehicles currently available for gene therapy, a range of preclinical strategies for tackling major diseases of the nervous system, the clinical limitations, and ethical considerations. PMID- 20955924 TI - The psychiatric GWAS consortium: big science comes to psychiatry. AB - The Psychiatric GWAS Consortium was founded with the aim of conducting statistically rigorous and comprehensive GWAS meta-analyses for five major psychiatric disorders: ADHD, autism, bipolar disorder, major depressive disorder, and schizophrenia. In the era of GWAS and high-throughput genomics, a major trend has been the emergence of collaborative, consortia approaches. Taking advantage of the scale that collaborative consortia approaches can bring to a problem, the PGC has been a major driver in psychiatric genetics and provides a model for how similar approaches may be applied to other disease communities. PMID- 20955926 TI - The Simons Simplex Collection: a resource for identification of autism genetic risk factors. AB - In an effort to identify de novo genetic variants that contribute to the overall risk of autism, the Simons Foundation Autism Research Initiative (SFARI) has gathered a unique sample called the Simons Simplex Collection (SSC). More than 2000 families have been evaluated to date. On average, probands in the current sample exhibit moderate to severe autistic symptoms with relatively little intellectual disability. An interactive database has been created to facilitate correlations between clinical, genetic, and neurobiological data. PMID- 20955925 TI - Changing the landscape of autism research: the autism genetic resource exchange. AB - Autism Speaks' Autism Genetic Resource Exchange (AGRE) represents the largest private collection of genetic and phenotype data for families with ASD that is made available to qualified researchers worldwide. The availability of large and comprehensive registries that include detailed phenotype and genetic information for individuals affected with an ASD and family members is crucial for the discovery of autism susceptibility genes and the development and application of biologically based approaches to diagnosis and treatment. The model that AGRE has developed can be applied broadly to other disorders with complex etiologies. PMID- 20955927 TI - Nature versus nurture: death of a dogma, and the road ahead. AB - Interaction between the genome and the environment has been widely discussed in the literature, but has the importance ascribed to understanding these interactions been overstated? In this opinion piece, we critically discuss gene environment interactions and attempt to answer three key questions. First, is it likely that gene-environment interactions actually exist? Second, what is the realistic value of trying to unravel these interactions, both in terms of understanding disease pathogenesis and as a means of ameliorating disease? Finally, and most importantly, do the technologies and methodologies exist to facilitate an unbiased search for gene-environment interactions? Addressing these questions highlights key areas of feasibility that must be considered in this area of research. PMID- 20955928 TI - Genetic analysis of pathways to Parkinson disease. AB - In this review I outline the arguments as to whether we should consider Parkinson disease one or more than one entity and discuss genetic findings from Mendelian and whole-genome association analysis in that context. I discuss what the demonstration of disease spread implies for our analysis of the genetic and epidemiologic risk factors for disease and outline the surprising fact that we now have genetically identified on the order of half our risk for developing the disease. PMID- 20955929 TI - From single genes to gene networks: high-throughput-high-content screening for neurological disease. AB - Neuronal development, function, and the subsequent degeneration of the brain are still an enigma in both the normal and pathologic states, and there is an urgent need to find better targets for developing therapeutic intervention. Current techniques to deconstruct the architecture of brain and disease-related pathways are best suited for following up on single genes but would take an impractical amount of time for the leads from the current wave of genetic and genomic data. New technical developments have made combined high-throughput-high-content (HT HC) cellular screens possible, which have the potential to contextualize the information, gathered from a combination of genetic and genomic approaches, into networks and functional biology and can be utilized for the identification of therapeutic targets. Herein we discuss the potential impact of HT-HC cellular screens on medical neuroscience. PMID- 20955930 TI - Neurocognitive phenotypes and genetic dissection of disorders of brain and behavior. AB - Elucidating the molecular mechanisms underlying quantitative neurocognitive phenotypes will further our understanding of the brain's structural and functional architecture and advance the diagnosis and treatment of the psychiatric disorders that these traits underlie. Although many neurocognitive traits are highly heritable, little progress has been made in identifying genetic variants unequivocally associated with these phenotypes. A major obstacle to such progress is the difficulty in identifying heritable neurocognitive measures that are precisely defined and systematically assessed and represent unambiguous mental constructs, yet are also amenable to the high-throughput phenotyping necessary to obtain adequate power for genetic association studies. In this perspective we compare the current status of genetic investigations of neurocognitive phenotypes to that of other categories of biomedically relevant traits and suggest strategies for genetically dissecting traits that may underlie disorders of brain and behavior. PMID- 20955932 TI - Allelic diversity in human developmental neurogenetics: insights into biology and disease. AB - One of the biggest challenges in neuroscience is illuminating the architecture of developmental brain disorders, which include structural malformations of the brain and nerves, intellectual disability, epilepsy, and some psychiatric conditions like autism and potentially schizophrenia. Ongoing gene identification reveals a great diversity of genetic causes underlying abnormal brain development, illuminating new biochemical pathways often not suspected based on genetic studies in other organisms. Our greater understanding of genetic disease also shows the complexity of allelic diversity, in which distinct mutations in a given gene can cause a wide range of distinct diseases or other phenotypes. These diverse alleles not only provide a platform for discovery of critical protein protein interactions in a genetic fashion, but also illuminate the likely genetic architecture of as yet poorly characterized neurological disorders. PMID- 20955931 TI - Human brain evolution: harnessing the genomics (r)evolution to link genes, cognition, and behavior. AB - The evolution of the human brain has resulted in numerous specialized features including higher cognitive processes such as language. Knowledge of whole-genome sequence and structural variation via high-throughput sequencing technology provides an unprecedented opportunity to view human evolution at high resolution. However, phenotype discovery is a critical component of these endeavors and the use of nontraditional model organisms will also be critical for piecing together a complete picture. Ultimately, the union of developmental studies of the brain with studies of unique phenotypes in a myriad of species will result in a more thorough model of the groundwork the human brain was built upon. Furthermore, these integrative approaches should provide important insights into human diseases. PMID- 20955934 TI - The genetics of Alzheimer disease: back to the future. AB - Three decades of genetic research in Alzheimer disease (AD) have substantially broadened our understanding of the pathogenetic mechanisms leading to neurodegeneration and dementia. Positional cloning led to the identification of rare, disease-causing mutations in APP, PSEN1, and PSEN2 causing early-onset familial AD, followed by the discovery of APOE as the single most important risk factor for late-onset AD. Recent genome-wide association approaches have delivered several additional AD susceptibility loci that are common in the general population, but exert only very small risk effects. As a result, a large proportion of the heritability of AD continues to remain unexplained by the currently known disease genes. It seems likely that much of this "missing heritability" may be accounted for by rare sequence variants, which, owing to recent advances in high-throughput sequencing technologies, can now be assessed in unprecedented detail. PMID- 20955935 TI - Episodic neurological channelopathies. AB - Inherited episodic neurological disorders are often due to mutations in ion channels or their interacting proteins, termed channelopathies. There are a wide variety of such disorders, from those causing paralysis, to extreme pain, to ataxia. A common theme in these is alteration of action potential properties or synaptic transmission and a resulting increased propensity of the resulting tissue to enter into or stay in an altered excitability state. Manifestations of these disorders are triggered by an array of precipitants, all of which stress the particular affected tissue in some way and aid in propelling its activity into an aberrant state. Study of these disorders has aided in the understanding of disease risk factors and elucidated the cause of clinically related sporadic disorders. The findings from study of these disorders will aid in the diagnosis and efficient targeted treatment of affected patients. PMID- 20955933 TI - The genetics of child psychiatric disorders: focus on autism and Tourette syndrome. AB - Investigations into the genetics of child psychiatric disorders have finally begun to shed light on molecular and cellular mechanisms of psychopathology. The first strains of success in this notoriously difficult area of inquiry are the result of an increasingly sophisticated appreciation of the allelic architecture of common neuropsychiatric and neurodevelopmental disorders, the consolidation of large patient cohorts now beginning to reach sufficient size to power reliable studies, the emergence of genomic tools enabling comprehensive investigations of rare as well as common genetic variation, and advances in developmental neuroscience that are fueling the rapid translation of genetic findings. PMID- 20955936 TI - Hearing impairment: a panoply of genes and functions. AB - Research in the genetics of hearing and deafness has evolved rapidly over the past years, providing the molecular foundation for different aspects of the mechanism of hearing. Considered to be the most common sensory disorder, hearing impairment is genetically heterogeneous. The multitude of genes affected encode proteins associated with many different functions, encompassing overarching areas of research. These include, but are not limited to, developmental biology, cell biology, physiology, and neurobiology. In this review, we discuss the broad categories of genes involved in hearing and deafness. Particular attention is paid to a subgroup of genes associated with inner ear gene regulation, fluid homeostasis, junctional complex and tight junctions, synaptic transmission, and auditory pathways. Overall, studies in genetics have provided research scientists and clinicians with insight regarding practical implications for the hearing impaired, while heralding hope for future development of therapeutics. PMID- 20955938 TI - Aortic root surgery: from valve sparing to 'spare and plasty'. PMID- 20955939 TI - Legislative update. PMID- 20955937 TI - Genetic advances in the study of speech and language disorders. AB - Developmental speech and language disorders cover a wide range of childhood conditions with overlapping but heterogeneous phenotypes and underlying etiologies. This characteristic heterogeneity hinders accurate diagnosis, can complicate treatment strategies, and causes difficulties in the identification of causal factors. Nonetheless, over the last decade, genetic variants have been identified that may predispose certain individuals to different aspects of speech and language difficulties. In this review, we summarize advances in the genetic investigation of stuttering, speech-sound disorder (SSD), specific language impairment (SLI), and developmental verbal dyspraxia (DVD). We discuss how the identification and study of specific genes and pathways, including FOXP2, CNTNAP2, ATP2C2, CMIP, and lysosomal enzymes, may advance our understanding of the etiology of speech and language disorders and enable us to better understand the relationships between the different forms of impairment across the spectrum. PMID- 20955940 TI - Use of the dynamic volume spline method to predict facial soft tissue changes associated with orthognathic surgery. AB - OBJECTIVE: The shape of the face can be estimated before the surgery by using 3 dimensional computer programs that provide tools to guide skill modifications. The aim of this study was to present the dynamic volume spline method to predict facial soft tissue changes after the modification of the skull associated with orthognathic surgery. STUDY DESIGN: Soft tissue volume is modeled by a dynamic volume spline that includes the elastic behavior of the actual tissue. The model is a hybrid of spring-mass model and finite element model, and combines their advantageous properties. It provides fast and realistic soft tissue simulations. Postsurgical shape of the patient's face is estimated by reshaping the skull and letting the soft tissue model relax over the new boundary conditions formed by the new skull shape. Postsurgical estimations were compared with the conventional method's estimations, where the soft tissue is not modeled biomechanically. Also, postsurgical estimations were compared with the actual postsurgical data for 6 orthognathic surgery patients. RESULTS: The mean of the error between the estimated shapes and the actual postsurgical shapes was ~1.8 mm when the whole face was considered. CONCLUSION: When the facial soft tissue is modeled by the dynamic volume spline, the postsurgical shape is estimated better than by the conventional method and previous methods in the literature. PMID- 20955941 TI - Esthetic alveolar ridge preservation with calcium phosphate and collagen membrane: preliminary report. AB - OBJECTIVE: The objective of this study was to evaluate clinically, histologically and radiographically a ridge preservation technique used on extraction sockets grafted with biphasic calcium phosphate (BCP) and a resorbable collagen membrane. MATERIAL AND METHODS: Patients having a labial socket wall defect more than one third in mesio-distal socket width after maxillary central incisor tooth extraction were included. The labial defect was sealed with resorbable collagen membrane and the defect filled with BCP. The grafted socket was covered with a resorbable collagen wound dressing material. The treated sockets were evaluated after a 4-month healing period when implants were placed and followed for up to 12 months. RESULTS: There were 8 subjects enrolled in this study. A statistical difference was found only in ridge width reduction at 3 mm below the cement enamel junction of the adjacent teeth (P < .05) with 1 mm widening at 8 mm. The amount of new bone formation was extensively varied with diminutive graft remnants. Most cells in the connective tissue were osteopontin positive indicating they were osteoblast-like cells. A declination in the radiodensity of the grafted socket was observed during the analyzed period. CONCLUSION: Ridge preservation with BCP with collagen membrane can be used as an alternative treatment for maintaining ridge dimension before implant placement. PMID- 20955942 TI - Keratocyst of the buccal mucosa: is it odontogenic? AB - Odontogenic keratocyst (OKC) of the buccal mucosa, the diagnosis of which is based on subjective histologic evaluation, is a controversial entity of questionable existence. This report describes 2 rare cases of parakeratinized cyst arising from the buccal mucosa. Case 1 was a 60-year-old man with a 3-cm cyst and case 2 was a 16-year-old boy with a microcyst incidentally discovered on histology. Both lesions were essentially identical in histologic appearance and immunophenotype to intraosseous and gingival OKC, but they were clearly different from orthokeratinized odontogenic cysts and buccal mucosal epidermoid cysts. Step sections failed to reveal any kind of odontogenic tissue or skin adnexa in the cyst wall. These microscopic characteristics reflexively lead to the diagnosis of OKC, if the extragingival occurrence in the buccal mucosa cannot be considered. An alternative nonodontogenic origin includes a keratocyst of the skin, ie, an unusual mucosal presentation of cutaneous keratocyst. Because its true nature, either odontogenic or epidermal, cannot be conclusively proven at this time, we propose a more descriptive and noncommittal term, "mucosal keratocyst," for a particular cyst in a buccal location that is morphologically indistinguishable from OKC. PMID- 20955943 TI - Oral myoepithelioma of soft tissue origin: report of a new case and literature review. AB - Oral myoepithelioma of soft tissue origin, an entity distinct from myoepithelioma of salivary glands, constitutes an extremely rare benign neoplasm, with only 1 previously published case, affecting the tongue of a 22-year-old woman. Ectomesenchymal chondromyxoid tumour (ECT) also is a very rare benign neoplasm of the oral cavity that has a strong predilection for the anterior dorsum of the tongue. The great similarities in the histologic and immunohistochemical characteristics of soft tissue myoepithelioma (STM) and ECT probably indicate that they refer to the same or closely related pathologic entities. The aim of this paper is to report a new case of STM affecting the dorsal tongue of a 45 year-old man. A review of the relevant literature is made and the relationship between oral STM and ECT discussed. PMID- 20955944 TI - The relationship between three-dimensional principal rotations and mandibular deviation. AB - OBJECTIVE: To investigate the rotational variations of three-dimensional (3D) trajectories at anatomic landmarks by different mandibular kinematics, we applied principal axes of inertia to the 3D trajectories. The principal rotations were determined directly from the anatomy-based trajectories produced by a patient specific temporomandibular joint simulation. As a preliminary study, the principal rotations for a pilot group of patients with mandibular deviation were correlated with the deviation. STUDY DESIGN: Three-dimensional mandibular movements from the patients with mandibular deviation were tracked based on a patient-specific splint and an optical tracking system. The dental occlusion recorded on the splint provided synchronization for initial movement in the tracking and the simulation phases. The translation and rotation recorded during tracking were applied sequentially to the mandibular model in relation to a fixed maxilla model. The sequential positions of the points of interest based on the reference coordinate system could also be simulated and traced by the same method. The landmarks selected for analysis were the points of the bilateral condyles and of the mandibular incisor. The moment of inertia tensor was calculated with respect to the 3D trajectory points. Using the unit vectors along the principal axes derived from the tensor matrix, alpha, beta, and gamma rotations (horizontal, sagittal, and frontal planes) around the z-, y-, and x axes, respectively, were determined to represent the principal directions as principal rotations. RESULTS: The measured rotations were correlated with the deviation in 3 orthogonal planes. Under the influence of the mandibular asymmetry, the orientations of the principal axis at the condyles increase counterclockwise in the horizontal plane and clockwise in the frontal plane. At the incisor point, the horizontal and frontal angles increase counterclockwise, but the sagittal angles increase clockwise. The interrelations between different rotations and between landmarks, defined as a correlation coefficient between principal rotations, decrease as the deviation increases. CONCLUSIONS: Three dimensional trajectories at selected landmarks based on the reference coordinate system were evaluated using principal axes of inertia to investigate the functional characteristics of the mandible with a deviation. The movement asymmetry between the condyles increases as the deviation increases in all directions. The principal rotations at the condyles can be explained by those at the incisor with varying degrees despite the deviation. PMID- 20955945 TI - Standing on our standards: time for reflection. PMID- 20955947 TI - Diffuse pigmentation of the oral mucosa. PMID- 20955948 TI - Management of bisphosphonate-associated osteonecrosis: pentoxifylline and tocopherol in addition to antimicrobial therapy. An initial case series. AB - BACKGROUND: Studies of the use of pentoxifylline and alpha-tocopherol in osteoradionecrosis of the jaw have suggested their efficacy in this condition. We report an initial case series of pentoxifylline and alpha-tocopherol for patients with bisphosphonate-associated osteonecrosis (BON). METHODS: Six cases referred for management of BON were provided pentoxifylline and alpha-tocopherol in addition to antimicrobial therapy, and followed for a mean of 10 months. RESULTS: A 74% decrease in area of bony exposure and symptom control was achieved in these cases. DISCUSSION: Pentoxifylline with alpha-tocopherol may represent a strategy for management of BON. Controlled trials in cases of BON appear warranted. PMID- 20955949 TI - Inflammatory cytokines in saliva: early signs of metabolic disorders in chronic kidney disease. A controlled cross-sectional study. AB - OBJECTIVE: The aim of this study was to evaluate correlations between levels of cytokines in secreted stimulated saliva in patients with chronic kidney disease (CKD) and hyposalivation. STUDY DESIGN: Seventy patients with clearance <20 mL/min/1.73 m(2) were evaluated; 40 were predialysis, 21 hemodialysis, and 9 peritoneal dialysis, and they were matched with 70 control subjects. Salivary flow rate was measured and submandibular/sublingual saliva collected. Analyses were performed for whole protein content using a protein assay, and levels of tumor necrosis factor (TNF) alpha, interleukin (IL) 1beta, gamma-interferon (gamma-INF), IL-6, IL-8, IL-10, monocyte chemotactic protein (MCP) 1, and soluble intercellular adhesion molecule (sICAM) 1, by using Luminex technology. RESULTS: Patients with CKD had lower (P = .03) stimulated salivary secretion rate and higher salivary whole protein concentration (P = .002) than control subjects. Concentrations of IL-8 (P = .03) and MCP-1 (P = .002) were decreased and TNF alpha/IL-10 (P = .05) and IL-8/IL10 (P = .03) ratios were decreased in CKD patients. CKD patients with low secretion levels of stimulated saliva expressed decreased levels of TNF-alpha (P = .04), IL-1beta (P = .02), gamma-INF (P = .03), IL-6 (P = .003), IL-8 (P = .005), MCP-1 (P = .006), and sICAM-1 (P = .02). CONCLUSIONS: Salivary cytokines and secretion rates are significantly decreased in CKD patients. Further research is necessary to understand operating mechanisms and clinical implications of the down-regulation of inflammatory markers in saliva. PMID- 20955950 TI - Patients with positional versus nonpositional obstructive sleep apnea: a retrospective study of risk factors associated with apnea-hypopnea severity. AB - OBJECTIVE: The aim of this study was to investigate the differences in and risk factors for positional and nonpositional obstructive sleep apnea (OSA). STUDY DESIGN: One hundred twenty-three nonpositional (supine apnea-hypopnea index [AHI] < 2 times the lateral AHI), 218 positional (supine AHI >= 2 times the lateral AHI), and 109 age-, gender-, and BMI-matched patients with positional OSA performed 2 nights of sleep study. Gender, age, BMI, and percentage of time in supine position, and percentage of time snoring louder than 40 dB were evaluated as risk factors. RESULTS: Both unmatched positional and matched positional patients had less severe overall AHI values, higher mean SpO(2), lower percentage time SpO(2) less than 90%, and lower percentage of time snoring when compared with the nonpositional group. Overall AHI scores were associated with increasing age and percentage of time snoring for positional and nonpositional groups. However, BMIs were associated with the overall AHI only in the nonpositional group. CONCLUSION: The influence of position on OSA severity may contribute to the choice and prognosis of treatment and may represent 2 distinct groups with probable anatomic differences. PMID- 20955951 TI - Markers of bone remodeling in neoplastic and bone-related lesions. AB - OBJECTIVE: The aim of this study was to investigate the expression of bone resorption (RANK/RANKL), bone resorption inhibitor (osteoprotererin [OPG]), and bone formation marker (osteocalcin [OC]) in neoplastic and bone-related lesions (BRL). STUDY DESIGN: Using immunohistochemistry, their expression was evaluated in ossifying fibroma (OF), fibrous dysplasia (FD), simple bone cysts (SBC), central giant cell lesions (CGCL), and osteosarcoma (OS). RESULTS: Quantitative analyses of the expression of bone markers between all lesions, considering fibroblast-like cells and bone matrix, showed that RANK-RANKL presented higher expression in OF and CGCL, whereas OPG and OC presented higher expression in FD and SBC. There was higher expression of all proteins investigated when OS was the BRL. Moreover, the RANKL expression was greater than OPG in this neoplasm. CONCLUSION: Our data indicate that the bone resorption markers are more highly expressed in OF, CGCL, and OS than in FD and SBC, indicating a significant association between these proteins and the clinical behavior of these lesions. PMID- 20955952 TI - Correlation between 3-dimensional facial morphology and mandibular movement during maximum mouth opening and closing. AB - PURPOSE: The purpose of this study was to analyze the relationship between mandibular movement and facial morphology parameters measured using 3-dimensional CT data. MATERIALS AND METHODS: We have developed a mandibular movement tracking and simulation system. The mandibular movement data were acquired from 22 subjects (6 males and 16 females), 3 who had no clinical facial deformities and 19 who had orthofacial deformities. The subjects voluntarily performed maximum mouth opening and closing movements. Three-dimensional maximum linear movements of selected points (bilateral condylions, infradentale, and pogonion) were calculated to represent mandibular movement. Facial morphology values were measured 3-dimensionally from CT data and bilateral morphological values were divided into 2 groups according to the mandibular deviation, the deviated side, and counter-deviated side groups. Correlation coefficients were calculated to evaluate the relationship between mandibular movements and facial morphology. RESULTS: Maximum linear movements of all selected points on the mandible were positively correlated with sella-nasion-point A (SNA) and sella-nasion-point B (SNB). Movements of the infradentale and pogonion were significantly correlated with ramus inclination, lateral mandibular body angle, ramus length, and mandibular body length. Condylar movement was positively correlated with lateral mandibular body angle and mandibular body length. Multiple stepwise linear regression analysis was performed to evaluate the model predicting the effect of morphological values on mandibular movement. Condylar movement was associated with the SNA (R(2) value = 0.32 for the deviated side, R(2) value = 0.26 for the counter-deviated side), and movement of the infradentale was associated with both SNA and ramus length (R(2) value = 0.57). Movement of the pogonion could be predicted by SNA, mandibular length, and condylar head length (R(2) value = 0.65). CONCLUSION: The 3D facial morphology values were associated with variations in mandibular movement, and morphological parameters contributed to predicting the movement of the mandible with different degrees. PMID- 20955953 TI - Effects of citric acid on cultured human osteoblastic cells. AB - We investigated the effects of citric acid (CA) on cultured human osteoblastic (HOB) cells by evaluating cell adhesion, proliferation, and cytotoxicity. (3)H Thymidine-labeled HOB cells were incubated in culture medium supplemented or not with 4%, 6%, 8%, or 10% CA for 1 minute. After incubation, cell morphology was evaluated by Nomarski interferential light microscopy, cell proliferation was accessed by measurements of (3)H-thymidine associated to the cells, and cell lysis was monitored by measuring the amount of (3)H-thymidine released by cells. We observed that most of the CA-treated cells presented numerous atypical vacuoles, and such cells were also highly polymorphic, exhibiting round-shaped cells. Nonetheless, CA at all concentrations assayed did not yield cytotoxicity as measured by (3)H-containing DNA release, although significant decrease in cell proliferation was observed (P > .05). Furthermore, cells which were treated with CA at the lowest concentration assayed (4%) restored normal proliferation rates 3 days after treatment. PMID- 20955954 TI - Real-time polymerase chain reaction of "red complex" (Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola) in periradicular abscesses. AB - OBJECTIVE: The red complex bacteria (Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola) have been implicated, either singly or in combination, in the development of various forms of periodontal diseases. The aim of this study was to investigate the presence of "red complex" in acute periradicular abscesses by real-time polymerase chain reaction (PCR) method. STUDY DESIGN: Microbial samples were collected by aspiration from 32 cases diagnosed as acute periradicular abscess. DNA was extracted from the samples by using a QIAamp DNA mini-kit and analyzed with real-time PCR. RESULTS: At least 1 member of the red complex was found in 84% of the cases. In general T. denticola, P. gingivalis, and T. forsythia were detected in 65.6%, 43.7%, and 40.6% of the cases, respectively. Red complex was detected in 15.6% of samples taken from acute periradicular abscesses. CONCLUSIONS: Our findings suggest that "red complex" can participate in the pathogenesis of acute periradicular abscesses. PMID- 20955955 TI - Comparison of GPX with or without solvent and hand files in removing filling materials from root canals--an ex vivo study. AB - OBJECTIVE: The aim of this study was to compare GPX instruments and hand files for gutta-percha removal. STUDY DESIGN: Fifty maxillary central incisors with a single straight canal were instrumented and filled. The teeth were divided into 5 groups of 10 specimens each, according to the gutta-percha removal techniques: group 1: GPX (21-mm-long teeth); group 2: GPX and xylol as solvent (21-mm-long teeth); group 3: GPX (25-mm-long teeth); group 4: GPX and xylol as solvent (25-mm long teeth); and group 5: hand files and xylol as solvent. The amount of time for gutta-percha removal and the number of fractured instruments were evaluated. Radiographs were taken, and the teeth were grooved longitudinally and split. The area of residual debris was measured using Sigma Scan software. RESULTS: The time for filling material removal was significantly shorter when GPX was used (P < .05). Overall, hand files and solvent produced fewer remnants of filling materials (P < .05). In the GPX 25 mm-long teeth group, the filling material was not removed in the apical third. CONCLUSIONS: Under the experimental conditions, the GPX instruments proved to be faster than hand instruments in removing root filling materials; however, hand instruments left a smaller amount of residual filling materials on the canal walls. The GPX instruments did not pull the gutta percha beyond its tip. PMID- 20955956 TI - Hereditary liver diseases. Preface. PMID- 20955957 TI - Wilson disease. AB - Wilson disease is an inherited autosomal recessive disorder of copper balance leading to hepatic damage and neurological disturbance of variable degree. The defective gene, ATP7B, encodes a hepatic copper-transporting protein, which plays a key role in human copper metabolism. Our knowledge of the genetic basis of Wilson disease has increased dramatically; however, understanding of genotype phenotype correlation and multifarious effects of copper toxicity as basis for targeted and individualised therapy strategies is still insufficient. Clinical manifestations are related to copper accumulation predominantly in the liver and brain and include hepatic disease ranging from mild hepatitis to acute liver failure or cirrhosis and/or neurological symptoms such as dystonia, tremor, dysarthria, psychiatric disturbances. Mixed presentations occur frequently. Early recognition by means of clinical, biochemical or genetic examination and initiation of therapy with copper chelators, zinc salts or even liver transplantation in cases of acute and chronic liver failure are essential for favourable outcome. PMID- 20955958 TI - Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy. AB - Progressive familial intrahepatic cholestasis (PFIC) type 1, 2 and 3 are due to mutations in ATP8B1, ABCB11 and ABCB4, respectively. Each of these genes encodes a hepatocanalicular transporter, which is essential for the proper formation of bile. Mutations in ABCB4 can result in progressive cholestatic disease, while mutations in ATP8B1 and ABCB11 can result both in episodic cholestasis, referred to as benign recurrent intrahepatic cholestasis (BRIC) type 1 and 2, as well as in progressive cholestatic disease. This suggests a clinical continuum and these diseases are therefore preferably referred to as ATP8B1 deficiency and ABCB11 deficiency. Similarly PFIC type 3 is designated as ABCB4 deficiency. Heterozygous mutations in each of these transporters can also be associated with intrahepatic cholestasis of pregnancy. This review summarizes the pathophysiology, clinical features and current as well as future therapeutic options for progressive familial- and benign recurrent intrahepatic cholestasis as well as intrahepatic cholestasis of pregnancy. PMID- 20955959 TI - Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin Johnson, and Rotor syndrome). AB - Hyperbilirubinemia is an important clinical sign that often indicates severe hepatobiliary disease of different etiologies. Inherited non haemolytichyperbilirubinemic conditions include Dubin-Johnson, Rotor, and Gilbert Meulengracht syndromes, which are important differential diagnoses indicating benign disease that require no immediate treatment. Dubin-Johnson and Rotor syndromes are rare, exhibit mixed direct and indirect hyperbilirubinemia as well as typical profiles or urinary coproporphyrin excretion. Gilbert-Meulengracht disease leads to unconjugated hyperbilirubinemia because of impaired glucuronidation activity, and is part of a spectrum of genetic variants also encompassing fatal Crigler-Najjar syndrome. Gilbert-Meulengracht syndrome can be diagnosed by clinical presentation, biochemistry and genotyping, and carries significance regarding the disposition towards drug-associated toxicity. In addition, the precise diagnosis of these inherited hyperbilirubinemic syndromes avoids unnecessary invasive procedures for suspected more severe hepatobiliary disease. PMID- 20955960 TI - Congenital fibrocystic liver diseases. AB - Fibrocystic diseases affecting the liver and often also other organs like the kidneys are a clinically and genetically heterogeneous group of disorders that may present in utero or remain clinically silent into late adulthood. During recent years, substantial progress has been made in unravelling the aetiology with primary cilia playing a central pathogenic role in many if not all of these diseases. The fibrocystogenic process shares some common features including proliferation and dilatation of epithelial bile ducts with concomitant abnormal apoptosis, fluid secretion and extracellular matrix deposition. In this review, we summarise clinical and diagnostic aspects, mechanisms of hepatic cystogenesis, and recent knowledge on potential therapies for these conditions. PMID- 20955961 TI - Cystic fibrosis-associated liver disease. AB - Liver disease is increasingly common in cystic fibrosis (CF). As new therapeutic options emerge, life expectancy increases and common hepatobiliary manifestations impact on quality of life and survival of CF patients. Hepatobiliary abnormalities in CF vary in nature and range from defects attributable to the underlying CFTR gene defect to those related to systemic disease and malnutrition. Today complications of liver disease represent the third most frequent cause of disease-related death in patients with CF. Here we review molecular and clinical genetics of CF, including genetic modifiers of CF associated liver disease, and provide practical recommendations for genetic testing, diagnosis and treatment of hepatobiliary manifestations in CF. PMID- 20955962 TI - The acute hepatic porphyrias: current status and future challenges. AB - The porphyrias are predominantly inherited metabolic disorders, which result from a specific deficiency of one of the eight enzymes along the pathway of haem biosynthesis. Historically, they have been classified into hepatic and erythropoietic forms, based on the primary site of expression of the prevailing dysfunctional enzyme. From a clinical point of view, however, it is more convenient to subdivide them into acute and non-acute porphyrias, thereby primarily considering the potential occurrence of life-threatening acute neurovisceral attacks. Unrecognised or untreated, such an acute porphyric attack is associated with a significant mortality of up to 10%. The acute hepatic porphyrias comprise acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and delta-aminolevulinic acid dehydratase deficiency porphyria. Making a precise diagnosis may be difficult because the different types of porphyrias may show overlapping clinical and biochemical characteristics. To date, the therapeutic possibilities are limited and mainly symptomatic. In this overview we report on what is currently known about pathogenesis, clinic, diagnostics, and therapy of the acute hepatic porphyrias. We further point out actual and future challenges in the management of these diseases. PMID- 20955963 TI - Inborn errors of carbohydrate metabolism. AB - Glycogen storage diseases (GSD) and inborn errors of galactose and fructose metabolism are the most common representatives of inborn errors of carbohydrate metabolism. In this review the focus is set on the current knowledge about clinical symptoms, diagnosis and treatment. Hepatomegaly and hypoglycaemia are the main findings in liver-affecting GSD like type I, III and IX. Diagnosis is usually made by non invasive investigations, e.g. mutation analysis. In GSD I, a carbohydrate balanced diet with frequent meals and nocturnal continuous tube feeding or addition of uncooked corn starch are the mainstays of treatment to prevent hypoglycaemia. Liver transplantation has been performed in different types of GSD. It should only be considered in high risk patients e.g. with substantial cirrhosis. Many countries have included classical galactosaemia in their newborn screening programs. A lactose-free infant formula can be life saving in affected neonates whereas a strict fructose-restricted diet is indicated in hereditary fructose intolerance. PMID- 20955964 TI - Lysosomal storage diseases as differential diagnosis of hepatosplenomegaly. AB - In adults, elevated transaminases and hepatomegaly, often mild, with moderate to massive idiopathic splenomegaly might hint to a lysosomal storage disease (LSD). In most of these cases, hepatosplenomegaly does not eventually lead to cirrhosis, hepatocellular carcinoma or cholestasis. Nevertheless, the hepatic clinical findings might be the incentive for the patient to present at the physician's office. Many of the currently known >50 lysosomal storage diseases might manifest in liver: out of these, the most important ones in adults are: Gaucher disease, cholesterol ester storage disease (CESD) and the Niemann-Pick diseases. An increase of plasma chitotriosidase should alert the physician for the presence of an LSD. For Gaucher's disease, enzyme supplementation and substrate deprivation constitute effective therapeutic options. Fabry's disease, the most prevalent lysosomal storage disease, does usually not affect the liver, but causes painful episodes of hands' or feet pain (acroparesthesias), left ventricular hypertrophy, renal failure, early stroke and decreased life expectancy. The emerging advent of effective therapeutic options and the cumulative prevalence of lysosomal storage diseases urge the hepatologist to add these diagnostic pathways to the clinical repertoire. PMID- 20955965 TI - Alpha-1-antitrypsin deficiency. AB - Alpha-1-antitrypsin deficiency (AATD) is a rare genetic disorder associated with the development of liver and lung disease. AAT is a 52-kD glycoprotein, produced mainly by hepatocytes and secreted into the blood. Agglomeration of the AAT protein in hepatocytes can result in liver disease. Exposure to smoke is the major risk factor for the development of lung disease characterised as early chronic obstructive lung disease (COPD). Diagnosis is based on the analysis of the AAT genotype and phenotype. The measurement of the AAT serum level is useful as screening test. Liver biopsy is not necessary to establish the diagnosis. Therapy for AAT-related liver disease is supportive, a specific therapy is not available. AATD is a rare condition (1:5000-10000) and, as a consequence, data and information on diagnosis and treatment are not easily accessible. This chapter provides a comprehensive overview on AATD, covering basic biology, diagnostic and therapeutic approaches. PMID- 20955966 TI - Liver fibrosis: from animal models to mapping of human risk variants. AB - Liver fibrosis is the sequel of chronic liver diseases and the main reason for increased mortality in affected patients. The extent of liver fibrosis displays great interindividual variation, even after controlling for exogenous factors. Thus, host genetic factors are considered to play an important role in the process of liver scarring. From a genetic perspective, liver fibrosis is a complex trait with many genes contributing to the expression of the phenotype. In genetically manipulated and inbred animals several risk loci for liver fibrosis have been identified. Some of these loci have been replicated in case-control studies of patients with hepatitis C infection. In humans, genetic risk loci were identified by single marker studies, haplotype studies or the combination of single markers. Recently, the first genome-wide association studies have also been performed in patients with liver diseases. Some of the identified gene variants have been functionally characterized in vitro, thereby opening the potential for novel therapeutic approaches and risk stratification. PMID- 20955967 TI - Primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is an idiopathic chronic autoimmune liver disease that primarily affects women. It is believed that the aetiology for PBC is a combination between environmental triggers in genetically vulnerable persons. The diagnosis for PBC is made when two of the three criteria are fulfilled and they are: (1) biochemical evidence of cholestatic liver disease for at least 6 month's duration; (2) anti-mitochondrial antibody (AMA) positivity; and (3) histologic features of PBC on liver biopsy. Ursodeoxycholic acid (UDCA) is the only FDA approved medical treatment for PBC and should be administered at a recommended dose of 13-15 mg/kg/day. Unfortunately despite adequate dosing of UDCA, approximately one-third of patients does not respond adequately and may require liver transplantation. Future studies are necessary to elucidate the role of environmental exposures and overall genetic impact not only in the development of PBC, but on disease progression and variable clinical response to therapy. PMID- 20955968 TI - Primary sclerosing cholangitis. AB - Primary sclerosing cholangitis (PSC) is a chronic bile duct disease leading to fibrotic biliary strictures and liver cirrhosis. The patient population is heterogeneous with regard to disease progression and the presence of co morbidities, complicating the practical handling of patients as well as studies of pathogenetic mechanisms. The aetiology of PSC is unknown, but the recent findings of several robust susceptibility genes emphasise the importance of genetic risk factors. There is no effective medical treatment available to delay the disease progression, but endoscopic therapy of biliary stenoses may be indicated. Follow-up of patients includes management of the inflammatory bowel disease that is found in the majority of cases along with investigations aimed at the early detection of cholangiocarcinoma and colorectal cancer, which also occur at increased frequencies. In the present review, we aim to summarise the present knowledge of PSC with a particular emphasis on the possible basis of disease variability. PMID- 20955969 TI - Autoimmune hepatitis. AB - Autoimmune hepatitis is a chronic inflammatory disease of the liver with a dismal prognosis when left untreated. Key for the improvement of prognosis is a timely diagnosis before cirrhosis has developed. This is reached by the exclusion of other causes of hepatitis, elevated immunoglobulin G, autoantibody profile and histological assessment. Treatment achieves remission rates in 80% of individuals and consists of immunosuppression with corticosteroids and azathioprine. A recent randomised controlled multicenter trial has added budesonide to the effective treatment options in non-cirrhotic patients and leads to a reduction of unwanted steroid side effects. Autoimmune hepatitis is an autoimmune disease of unknown aetiology. Association studies of major histocompatibility complex and other genes demonstrate an influence of immunogenetics. However, apart from the autoimmune polyglandular syndrome type 1, in which 10% of patients suffer from an autoantibody-positive autoimmune hepatitis linked to mutations of the autoimmune regulator gene, there is no clear evidence for a hereditary aetiology of this disease. PMID- 20955970 TI - Alcoholic steatohepatitis. AB - Severe alcoholic steatohepatitis has a poor prognosis and is characterized by jaundice and signs of liver failure. Its incidence is unknown, but prevalence is around 20% in cohorts of alcoholics undergoing liver biopsy. Diagnosis is established with elevated liver transaminases, neutrophil counts, serum bilirubin, and impaired coagulation and a history of excessive alcohol consumption, and exclusion of other etiologies. Histology is helpful but not mandatory. Prognostic scores include the Maddrey's discriminant function, the model of end-stage liver disease, and the Glasgow Alcoholic Hepatitis Score. Pathophysiology involves hepatic fat storage, increased hepatic uptake of gut derived endotoxins triggering Kupffer cell activation and release of proinflammatory triggers, induction of cytochrome P4502E1 producing toxic acetaldehyde and reactive oxygen species, and ethanol-mediated hyperhomocysteinemia causing endoplasmic reticulum stress. Treatment includes abstinence, enteral nutrition, corticosteroids, and possibly pentoxifylline. A debate is ongoing whether certain patients with severe alcoholic steatohepatitis could be eligible for liver transplantation. PMID- 20955971 TI - Nonalcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD), the most common liver disorder in the Western world, is a clinico-histopathological entity in which excessive triglyceride accumulation in the liver occurs. Non-alcoholic steatohepatitis (NASH) represents the necroinflammatory form, which can lead to advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of NAFLD/NASH is complex but increased visceral adiposity plus insulin resistance with increased free fatty acids release play an initial key role for the onset and perpetuation of liver steatosis. Further events in the liver include oxidative stress and lipid peroxidation, decreased antioxidant defences, early mitochondrial dysfunction, iron accumulation, unbalance of adipose-derived adipokines with a chronic proinflammatory status, and gut-derived microbial adducts. New gene polymorphisms increasing the risk of fatty liver, namely APOC3 and PNPLA3, have been lately identified allowing further insights into the pathogenesis of this condition. In our review pathophysiological, genetic, and essential diagnostic and therapeutic aspects of NAFLD are examined with future trends in this field highlighted. PMID- 20955972 TI - Viral hepatitis: human genes that limit infection. AB - Treatment response and susceptibility to chronic viral hepatitis C and B may be modified by host genetic factors. The majority of genetic variants that confer a significant risk have been localized in genes involved in immune response. However, many findings could not be replicated and almost none of the identified risk factors had a noticeable impact on clinical decisions. In contrast, recent findings in independent large genome wide association studies confirmed genetic variants in the interferon gamma gene locus as strong predictors of outcome with outstanding clinical relevance. This review gives an overview on significant genetic susceptibility factors for susceptibility and treatment outcome in chronic viral hepatitis C and B that have been identified by the classical candidate gene approach and genome wide studies and also highlights some recent findings on genetic factors for common adverse drug reactions. PMID- 20955973 TI - Inherited hepatocellular carcinoma. AB - Inherited liver disorders that cause chronic inflammation, fibrosis, and cirrhosis can lead to the development of liver cancer. Because of the rarity and diversity of some of these syndromes, the relative risk of developing HCC in these patients and the age at which tumours typically arise cannot be accurately estimated. Among patients with hereditary hemachromatosis (HH), the annual incidence of HCC is 4% once cirrhosis has been established. Fibrosis and portal hypertension associated with HH can be partially reversed with therapeutic phlebotomy, but it is unclear whether this treatment alters the incidence of HCC in these patients. Importantly, it seems likely that coincidence of these genetic disorders with known HCC risk factors such as alcoholism and viral hepatitis would amplify their oncogenic potential. For this reason, patients with known genetic disorders of the liver should be repeatedly counselled to avoid environmental and toxic injury to the liver. Treatment of HCC in patients with inherited liver disease mirrors that of HCC associated with other etiologies. Unfortunately, there are case series which suggest these patients with inherited liver disease and HCC tend to present at more advanced stages and are therefore not eligible for curative therapies, causing overall decreased survival relative to patients with HCC of viral or other etiologies. PMID- 20955974 TI - Porphyria cutanea tarda--when skin meets liver. AB - Porphyria cutanea tarda (PCT) is the most frequent type of porphyria worldwide and results from a catalytic deficiency of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in heme biosynthesis. At least two different types of PCT are currently distinguished: an acquired variant, also referred to as sporadic or type I PCT, in which the enzymatic deficiency is limited to the liver; and an autosomal dominantly inherited form, also known as familial or type II PCT, in which there is a decrease of enzymatic activity in all tissues. The cutaneous findings include increased photosensitivity, skin fragility, blistering, erosions, crusts, and miliae on the sun-exposed areas of the body. Additionally, hyperpigmentation, hypertrichosis, sclerodermoid plaques, and scarring alopecia might be observed. In patients with type I PCT, there is a significant association with liver disease that can be triggered by genetic and environmental factors, such as alcohol abuse, iron overload, haemochromatosis, polychlorinated hydrocarbons, and hepatitis C virus infection. The diagnosis of PCT can be made based on the skin symptoms, a characteristic urinary porphyrin excretion profile, and the detection of isocoproporphyrin in the feces. In red blood cells of individuals with type II PCT, UROD activity is decreased by approximately 50% due to heterozygous mutations in the UROD gene. Here we provide an update on clinical, diagnostic and therapeutic aspects of PCT, a disorder that affects both skin and liver. PMID- 20955975 TI - Hereditary liver disease: gallstones. AB - Gallstones are common in Western countries and due to pain and complications pose a substantial burden on health care systems. In general, cholesterol gallstones are distinguished from bilirubin gallstones. Bilirubin gallstones form if the ion product of unconjugated bilirubin and calcium in gallbladder bile exceeds the solubilisation capacities of mixed micelles and vesicles. Cholesterol gallstones develop if the amount of cholesterol in gallbladder bile exceeds the maximum concentration that is soluble at the given concentration of bile salts and phospholipids. In addition, cholesterol gallstone formation requires hypomotility of the gallbladder and a mucin gel as nucleation matrix for monohydrate crystals. The individual risk of gallstone formation is determined by interactions of lithogenic alleles of gallstone susceptibility genes and multiple environmental factors. For asymptomatic gallstones, expectant management is recommended, whereas an episode of gallstone-associated pain substantially increases the risk of complications such as cholecystitis, cholangitis and pancreatitis and therefore necessitates cholecystectomy. PMID- 20955976 TI - Laparoscopic total hysterectomy vs supracervical hysterectomy: turn, turn, turn. PMID- 20955977 TI - Is uterine retroversion and retroflexion a disease that requires surgical correction? PMID- 20955978 TI - Instituting an office-based surgery program in the gynecologist's office. AB - Office-based surgery (OBS) provides many advantages for the patient, physician, operating room team, and health care system. Newer technologies provide an array of procedures appropriate to the office setting, and with careful preparation, many can be performed without compromising patient safety or comfort. Several states have specific regulatory requirements for OBS, although half of them provide neither guidelines nor regulation. The Federation of State Medical Boards provides current regulatory information across the United States; the American College of Obstetrics and Gynecology has recently issued guidelines that provide recommendations for instituting an OBS practice, and the American Medical Association and the American Society of Anesthesiologists provide guidelines that promote patient safety and comfort in the office setting. Many issues must be considered before instituting an OBS program. Practices that perform invasive procedures requiring more than minimal sedation are encouraged to seek formal accreditation because it assures patients of quality of care. Residency programs and professional societies are encouraged to provide training in OBS surgery and to develop programs to mentor the next generation of physicians. PMID- 20955979 TI - Degenerating uterine myomas mimic ovarian dermoid cysts in a postmenopausal woman. PMID- 20955980 TI - Successful laparoscopic management of adnexal torsion during week 15 of a single pregnancy. PMID- 20955981 TI - Hysteroscopy without anesthesia: review of recent literature. AB - The need for anesthesia or analgesia for performing hysteroscopy is still matter of debate. Many factors explain the lack of agreement about anesthesia in hysteroscopy depending on the instrumentation, technique employed, need of performing surgical procedure, operator skill and patients' characteristics. Diagnostic minihysteroscopy (3.5 mm or less in size) is less painful and easier to perform than hysteroscopy performed with instruments sized around 5 mm. Thanks to miniaturized instruments, office hysteroscopy allows a growing number of women to be treated in an office setting avoiding the operating room. The main limitation to its widespread use is pain and low patient tolerance. Intrauterine surgical procedures involving only the endometrial mucosa (biopsies, adhesiolisis, cervical and endometrial polyectomies) are not painful. For endometrial polypectomy size of polyps (<2.2m) and duration of the procedure (more than 15 min) are limiting factors. Most literature suggests that office hysteroscopy in experienced hands is a well-tolerated technique and requires the use of analgesics only in selected patients like women with previous caesarean section, history of chronic pelvic pain, anxiety and in menopause. PMID- 20955982 TI - Use of local anesthesia for office diagnostic and operative hysteroscopy. AB - BACKGROUND: There is a variety of potential advantages to performing hysteroscopically-directed procedures on an awake patient in an office procedure room setting that include increased safety, reduced utilization of resources, and improved patient satisfaction. However, the ideal approach to local uterine anesthesia has/have yet to be determined. OBJECTIVE: Identification, categorization, and evaluation of published randomized clinical trials (RCTs) comparing local anesthesia to placebo or no treatment for the performance of hysteroscopy. METHODS: The Cochrane database of systematic reviews, MEDLINE, and ACP Journal Club were queried for related RCTs. In addition, we located a number of additional studies by identifying and reviewing references in selected papers. These were then reviewed for appropriateness and categorized by allocating them to one of the following types of local anesthesia: Intracervical, paracervical, topical intracavitary, topical cervical, and combined approaches. Each were evaluated for patient factors as well as anesthetic location, anesthetic agent, time from application to procedure, instrument features, and the procedures performed. RESULTS: A total of 36 studies were identified of which 19 met the criteria for our review; 6 paracervical, 4 intracervical, 7 topical intracavitary, 2 topical cervical; there was also one systematic review of RCTs. Overall, there was substantial heterogeneity in technique in all groups and only with paracervical anesthesia was there a consistent anesthetic effect demonstrated. Many studies were performed with application to procedure times that were less than the time required for maximal anesthetic effect. There were no studies identified where more than one technique was used. CONCLUSIONS: It appears that paracervical anesthesia is useful but the value of other techniques is difficult to evaluate because of limitations of technique and research design. Future investigation should be designed to evaluate longer application to procedure times, a variety of anesthetic agents, concentrations and volumes, and, given the complex innervation of the uterus, strategies that target more than one site. Pain outcomes should be stratified to identify the impact on various components of the procedure. Published studies have largely been limited to diagnostic hysteroscopy so there is also a need to evaluate a greater variety of hysteroscopic procedures. PMID- 20955984 TI - Fourteen-year experience with laparoscopic ventrosuspension in patients with retroverted and retroflected uterus and pelvic pain syndromes. AB - BACKGROUND: In women with a retroverted uterus, who have dyspareunia, chronic pelvic pain, or dysmenorrhea, laparoscopic ventrosuspension of the uterus has been reported effective in achieving symptom relief. STUDY OBJECTIVE: To critically review our experience with our method of laparoscopic ventrosuspension. DESIGN: Cohort study (Canadian Task Force classification II-3). SETTING: Tertiary care center. PATIENTS: Sixty-three women who had undergone laparoscopic ventrosuspension for treatment of pain syndromes during 1995 through 2008. INTERVENTIONS: Laparoscopic ventrosuspension, and a questionnaire about the long-term outcome of the operation. MEASUREMENTS AND MAIN RESULTS: There were no adverse events except for 2 repeat operations within 3 postoperative days. Forty nine women (77.8%) answered the questionnaire about long-term outcome, and in these patients, significant pain relief was achieved (p <.001). Pain levels decreased, based on a numeric rating scale, from a mean (SD) of 6.35 (1.92) to 0.97 (1.40) in patients without endometriosis, and from 6.93 (2.09) to 3.80 (2.08) in those with endometriosis. Of 34 patients without endometriosis, 1 (2.9%) stated that the operation had not led to symptom relief, compared with 4 of 15 (26.7%) with endometriosis (p = .03). CONCLUSION: Laparoscopic ventrosuspension is clearly beneficial in women with a retroverted and retroflected uterus who have pelvic pain syndromes, even in the long term. PMID- 20955983 TI - Learning curve and surgical outcome for robotic-assisted hysterectomy with lymphadenectomy: case-matched controlled comparison with laparoscopy and laparotomy for treatment of endometrial cancer. AB - STUDY OBJECTIVE: To determine the learning curve for robotic-assisted hysterectomy with lymphadenectomy for surgical treatment of endometrial cancer. DESIGN: An analysis of robotic-assisted hysterectomy with lymphadenectomy vs total laparoscopic hysterectomy with lymphadenectomy and laparotomy with total abdominal hysterectomy with lymphadenectomy (Canadian Task Force classification II-1). SETTING: Solo, experienced, minimally invasive gynecologic oncology practice in a tertiary hospital. PATIENTS: One hundred forty-eight patients including 56 patients who underwent robotic-assisted hysterectomy with bilateral pelvic and paraaortic lymph node dissection, 56 patients who underwent total laparoscopic hysterectomy with bilateral pelvic and paraaortic lymph node dissection, and 36 patients who underwent traditional total abdominal hysterectomy with bilateral pelvic and paraaortic lymph node dissection performed by the same surgeon for treatment of endometrial cancer. INTERVENTIONS: Robotic assisted hysterectomy with bilateral lymphadenectomy, total laparoscopic hysterectomy with bilateral lymphadenectomy, and traditional total abdominal hysterectomy with bilateral lymphadenectomy were performed. Data were categorized by chronologic order of cases into groups of 20 patients each. The learning curve of the surgical procedure was estimated by measuring operative time with respect to chronologic order of each patient who had undergone the respective procedure. MEASUREMENTS AND MAIN RESULTS: For the 3 surgical procedures, data analyzed included mean age, body mass index, operative time, blood loss, lymph node retrieval, and complications. Mean (SD); 95% confidence interval [CI]) operative time for the 3 procedures was statistically significant: 162.5 (53) minutes (95% CI, 148.6-176.4]), 192.3 (55.5) minutes (95% CI, 177.6-207.0), and 136.9 (32.3) minutes (95% CI, 126.3-147.5), respectively. Analysis of operative time for robotic-assisted hysterectomy with bilateral lymph node dissection with respect to chronologic order of each group of 20 cases demonstrated a decrease in operative time: 183.2 (69) minutes (95% CI; 153.0-213.4) for cases 1 to 20, 152.7 (39.8) minutes (95% CI, 135.3-170.1) for cases 21 to 40, and 148.8 (36.7) minutes (95% CI, 130.8-166.8) for cases 41 to 56. For the groups with laparoscopic hysterectomy with lymphadenectomy and traditional total abdominal hysterectomy with lymphadenectomy, there was no difference in operative time with respect to chronologic group order of cases. There was a difference between the number of lymph nodes retrieved between robotic-assisted hysterectomy with bilateral lymphadenectomy (26.7 [12.8]; 95% CI, 23.3-30.1) compared with laparoscopic hysterectomy with bilateral lymphadenectomy (45.1 [20.9]; 95% CI, 39.6-50.6) and traditional total abdominal hysterectomy with lymphadenectomy (55.8 [23.4]; 95% CI, 48.2-63.4). The rate of intraoperative complications for laparoscopic hysterectomy with bilateral lymphadenectomy was 12.5% (7 of 56) compared with 0 % for robotic-assisted hysterectomy with bilateral lymphadenectomy. The rate of postoperative complications was 14.3% (8 of 56), 21.4% (12 of 56), and 19.4% (7 of 36), respectively, for the 3 groups. There was less blood loss with robotic assisted hysterectomy with bilateral lymphadenectomy (89.3 [45.4]; 95% CI, 77.4 101.2) compared with laparoscopic hysterectomy with bilateral lymphadenectomy (209.1 [91.8]; 95% CI, 185.1-233.1) and traditional total abdominal hysterectomy with lymphadenectomy (266.0 [145.1]; 95% CI, 218.6-313.4). Duration of hospitalization was shorter in the group with robotic-assisted hysterectomy with bilateral lymphadenectomy (1.6 [0.7]; 95% CI, 1.4-1.8) compared with the groups who underwent laparoscopic hysterectomy with bilateral lymphadenectomy (2.6 [0.9]; 95% CI, 2.4-2.8) or traditional total abdominal hysterectomy with lymphadenectomy (4.9 [1.9]; 95% CI, (4.3-5.5). CONCLUSION: The learning curve for robotic-assisted hysterectomy with lymph node dissection seems to be easier compared with that for laparoscopic hysterectomy with lymph node dissection for surgical management of endometrial cancer. PMID- 20955985 TI - Use of a No. 11 blade scalpel and reusable blunt trocar to establish pneumoperitoneum: description of a safe and inexpensive technique. AB - First access is crucial in laparoscopic surgery because of its potentially life threatening complications. A number of procedures using a variety of instruments have been previously described; however, the safest approach remains uncertain. Herein, we describe a simple and inexpensive method for direct trocar insertion using reusable instruments that was developed over 10 years in a series of 4721 consecutive gynecologic laparoscopic procedures. Observed data revealed that the technique is feasible, rapidly performed, and safe, with a likely cost savings, using a small set of reusable instruments. This procedure should be compared with other access methods in randomized studies to confirm the observed advantages. PMID- 20955986 TI - Isobaric laparoendoscopic single-site assisted extracorporeal cystectomy in treatment of selected adnexal tumors: initial experience and technique. AB - Laparoscopic-assisted ovarian cystectomy with exteriorization is a minimally invasive procedure. However, applicability of this procedure for transumbilical laparoendoscopic single-site (LESS) surgery is not well established. Herein, we describe our initial experience with isobaric (gasless) LESS-assisted extracorporeal cystectomy in management of selected adnexal tumors. Of 17 consecutive adnexal tumors, 15 (88.2%) (dermoid cyst, 10; serous cystadenoma, 2; mucinous cystadenoma, 1; and paraovarian cyst, 2) were successfully managed with isobaric LESS-assisted extracorporeal cystectomy. Two dermoid cysts required intracorporeal LESS cystectomy because of poor mobility of the adnexal tissue. No conversion to either conventional laparoscopic surgery or laparotomy was necessary in this series. PMID- 20955987 TI - Implementing an advanced laparoscopic procedure by monitoring with a visiting surgeon. AB - STUDY OBJECTIVE: To investigate the feasibility of safely implementing a total laparoscopic hysterectomy (LH) in established gynecologists' practices with on site coaching and monitoring of the learning curve by an experienced visiting surgeon. DESIGN: Multicenter prospective feasibility and implementation study (Canadian Task Force classification II-2). SETTING: Eleven general gynecologists in 8 hospitals (1 university hospital and 7 regional hospitals) participated. PATIENTS: Laparoscopic hysterectomy was performed in 83 patients during the learning curve, and in 83 patients after the learning curve. INTERVENTIONS: During the learning curve, an experienced visiting laparoscopist was available for coaching during each LH. A competence score was marked on an Objective Structured Assessment of Technical Skills (OSATS) form. Complications were recorded intraoperatively and postoperatively for 6 weeks after surgery in all patients. MEASUREMENTS AND MAIN RESULTS: Nine of 11 gynecologists reached the competence score of at least 28 points during the study, from January 2005 to January 2007. A major complication occurred in 3 of 83 LH procedures (4%) performed during the learning curve, and in 5 of 83 LH procedures (6%) performed after the learning curve (p = .72). CONCLUSION: The concept of a visiting surgeon for on-site coaching and monitoring of established gynecologists during the learning curve of an advanced laparoscopic procedure using Objectively Structured Assessment of Technical Skills is feasible. According to the observed complication rate during and after the learning curve, on-site coaching is a useful tool when implementing a new laparoscopic technique in established gynecologists' practices. PMID- 20955988 TI - Symptomatic vaginal bleeding in a postmenopausal woman revealing colon adenocarcinoma metastasizing exclusively to the vagina. AB - Vaginal carcinomas are rare entities, accounting for 2% of all malignant cancers of the female genital tract, and the vast majority are metastatic. Adenocarcinoma of the colon metastasizing to the vagina is extremely rare, only 5 cases have been reported. We present the case of a woman who experienced vaginal bleeding as an isolated symptom of vaginal metastasis of colorectal adenocarcinoma. Vaginal localization of metastasis from colorectal cancer significantly worsens the survival prognosis, and a standard treatment has not yet been proposed. Potential mechanisms of spread of colorectal cancer to the vagina and therapeutic approaches are discussed. In this case, treatment included surgery and chemotherapy. PMID- 20955989 TI - Familial cystic teratomas: four case reports and review of the literature. AB - Mature cystic teratomas (MCTs) are some of the most common ovarian neoplasms in women of reproductive age. However, familial teratomas are exceedingly rare. We present 4 cases of dermoid cysts seen in a mother and her 3 daughters with left MCTs. None of the patients had symptoms at the time of diagnosis, but all of them were diagnosed in their twenties during an annual gynecologic examination. In this report, we elaborate on MCTs familial incidence, genetic linkage, theories of pathogenesis, diagnosis, complications, and surgical management. To our knowledge, after extensive review of the literature, there have been only 2 cases, in addition to the present case, of unilateral MCTs across generations reported. PMID- 20955990 TI - Hernia uterine inguinale: an uncommon cause of pelvic pain in the adult female patient. AB - Hernia uterine inguinale is a rare condition often presenting within the first few years of life as an asymptomatic palpable mass in the inguinal/groin area. This type of hernia contains uterine tissue and may contain oviducts, ovaries, and rarely the bladder. We report a case of a woman with a history of pelvic pain, found to have a rudimentary uterine horn herniating through the internal inguinal ring. A 24-year-old woman presented with noncyclic pelvic pain and irregular menses. Imaging revealed a solid 6- * 2-cm mass posterolateral to the ascending colon at the level of the pelvic brim in addition to absent right kidney and suspected unicornuate uterus. Laparoscopy with excision of the pelvic mass and appendectomy was performed. Surgical findings revealed a right rudimentary uterine horn herniating through the internal inguinal ring, attached to an elongated ovary/and an oviduct tightly tethered to the pelvic side wall. The result of pathologic study was consistent with rudimentary uterine horn, ovary with multiple cortical cysts, normal oviduct, and normal appendix. Hernia uterine inguinale is a rare condition and an even more uncommon cause of pelvic pain, instead presenting as an asymptomatic palpable groin mass early in life. This has been reported most commonly in the literature as both persistent mullerian duct syndrome and male pseudohermaphroditism. It is most often seen in a phenotypically normal male infant having both testes and uterine tissue present. Few cases have been documented to occur in the female sex, the adult patient, or as a cause of pelvic pain. Abdominal and pelvic imaging is useful in the diagnosis of this condition because it may aid in identifying patients with coexisting mullerian malformations. This subset may be at higher risk for hernia uterine inguinale, and, if presenting with complaints of pain or inguinal mass, it should likewise be considered in the differential diagnosis. PMID- 20955991 TI - Endometrial stromal sarcoma diagnosed after uterine morcellation in laparoscopic supracervical hysterectomy. AB - Endometrial stromal sarcoma is a rare uterine cancer with no reliable method for preoperative diagnosis. A 30-year-old parous woman underwent laparoscopic supracervical hysterectomy because of a leiomyoma. The uterus was removed from the abdominal cavity with an electric morcellator with a spinning blade. The pathology report revealed low-grade endometrial stromal sarcoma. Two months after the initial surgery, a second laparoscopic procedure was performed. The final pathology report confirmed low-grade endometrial stromal sarcoma involving the ovary, fallopian tube, and ovarian artery. It was concluded that morcellation of leiomyomas at laparoscopic supracervical hysterectomy may potentially increase metastasis if the tumor is a sarcoma. PMID- 20955992 TI - Successful laparoscopic management of early splenic pregnancy: case report and review of literature. AB - Splenic pregnancy is the least common form of ectopic pregnancy. A 32-year-old woman, gravida 5, para 2, had not menstruated for 46 days, and had spotty bleeding for 6 days and lower abdominal pain for 2 days. The initial beta-human chorionic gonadotropin concentration was 38,913.3 IU/L. Transvaginal ultrasound examination demonstrated an empty uterine cavity, and a gestational sac 4.3 * 4.0 mm in diameter, with no fetal pole or yolk sac, located just adjacent to the splenic region. Laparoscopic surgery demonstrated intact pelvic organs and an ectopic mass on the spleen. The splenic pregnancy was successfully treated via laparoscopic embryo methotrexate injection, with preservation of the uterus and spleen. As evidenced in this case, laparoscopic embryo methotrexate injection is a minimally invasive and effective method of diagnosis and treatment of early splenic pregnancy. PMID- 20955993 TI - Laparoendoscopic single-site combined cholecystectomy and hysterectomy. AB - Laparoendoscopic single-site (LESS) surgery has gained increased acceptance among surgeons in various specialties. The universal nature of port placement in the umbilicus during LESS surgery may enable concomitant procedures to be performed in these surgical specialties via this single incision. This case report presents a 37-year-old woman who underwent concomitant LESS cholecystectomy and hysterectomy to treat a symptomatic fibroid uterus and symptoms of cholelithiasis. The surgical procedure was performed in approximately 3 hours without any complications, and the patient was discharge to home 18 hours after the procedure. This case demonstrates that increasingly complex concomitant procedures can be performed using a LESS surgical approach. PMID- 20955994 TI - Laparoscopic management of tailgut cyst: case report and review of literature. AB - Tailgut cyst, also called retrorectal hamartoma, is a rare congenital lesion that arises from the remnants of the postanal primitive gut and is usually located anterior to the sacrum and posterior to the rectum. It is usually asymptomatic or demonstrates mass effects, and preoperatively is frequently misdiagnosed as adnexal tumor. Treatment is complete surgical resection. The English-language literature contains only limited reports of the laparoendoscopic approach to retrorectal cystic tumor and tailgut cyst. Herein, we report our experience with successful laparoscopic management of a tailgut cyst, discuss the laparoscopic resection technique, and present a review of the literature. PMID- 20955995 TI - Algorithm for nonvisible strings of levonorgestrel intrauterine system. AB - We present a case with nonvisible strings of her levonorgestrel intrauterine system (LNG-IUS) in the cervix. The LNG-IUS was subsequently found in the omentum and retrieved laparoscopically. An algorithm for missing strings of an intrauterine devised is proposed. PMID- 20955996 TI - Comments on ovariopexy. PMID- 20955997 TI - Treatment of splenic contusion: practices in France are they "Americanized"? PMID- 20955999 TI - Plasma nanostructuring of porous polymer membranes. AB - Several methods for membrane modification have been presented. Chemical modification of a neat polymer followed by membrane formation and modification of just formed membranes have been compared to plasma action. The following plasma modes are discussed in detail: treatment with non-polymerizable gases, treatment with vapors and plasma initiated grafting. Some examples of modified membrane properties are given. Finally, it was concluded that plasma treatment offers the fastest, environment friendly and versatile method that allows tailoring brand new membranes. PMID- 20955998 TI - Dissecting the clock: understanding the mechanisms of timing across tasks and temporal intervals. AB - Currently, it is unclear what model of timing best describes temporal processing across millisecond and second timescales in tasks with different response requirements. In the present set of experiments, we assessed whether the popular dedicated scalar model of timing accounts for performance across a restricted timescale surrounding the 1-second duration for different tasks. The first two experiments evaluate whether temporal variability scales proportionally with the timed duration within temporal reproduction. The third experiment compares timing across millisecond and second timescales using temporal reproduction and discrimination tasks designed with parallel structures. The data exhibit violations of the assumptions of a single scalar timekeeper across millisecond and second timescales within temporal reproduction; these violations are less apparent for temporal discrimination. The finding of differences across tasks suggests that task demands influence the mechanisms that are engaged for keeping time. PMID- 20956000 TI - What support can community mental health nurses deliver to carers of people diagnosed with schizophrenia? Findings from a review of the literature. AB - OBJECTIVES: The purpose of this review was to determine the nature of support that mental health nurses could deliver to carers of people diagnosed with schizophrenia. The aim was to identify approaches that could be delivered within community practice to reduce burden and increase knowledge, mental health and coping. QUESTIONS ADDRESSED: What effect did support have on carer burden and other needs? What were the key elements of effective support? What effective supports could mental health nurses deliver within practice? DESIGN: This review covers the international scientific literature published between 1980 and 2008. DATA SOURCES: Searches were made of electronic databases relevant to nursing. All papers, published in English, were assessed. Hand searches of review papers and references were also carried out. Sixty-eight studies were included. STUDY APPRAISAL AND SYNTHESIS: Only comparative studies providing a quantitative assessment of carer outcomes were included. Findings were synthesised in narrative format and grouped by intervention type. RESULTS: Of the 68 emerging studies, 12 (18%) directly included nurses in delivering the intervention and 16 (24%) included nurses as part of a multidisciplinary team. There is fairly robust evidence that education improves carer knowledge of schizophrenia. There is, however, little evidence that it addresses more substantive areas such as burden, coping or mental health. Supportive family education moves beyond information giving by developing coping. As might be expected these approaches can reduce burden. More intensive programmes such as behavioural family therapy aim to address stressful relationships which commonly occur in families of people diagnosed with schizophrenia. These programmes are particularly effective in reducing burden and can also improve mental health. Community support such as intensive outreach is also effective in reducing burden. Finally, there is some evidence that mutual support groups reduce burden and improve coping. CONCLUSIONS: Research on effective support for carers of people diagnosed with schizophrenia is emerging. Although findings were mixed, there was some evidence supporting a range of approaches that mental health nurses could offer to carers. There is, however, still a need for pragmatic studies to determine the extent that these approaches can be delivered within nursing practice. PMID- 20956001 TI - Complexity theory as an approach to explanation in healthcare: a critical discussion. AB - The reception of complexity theory in health care is characterised by a tendency to reify the idea of a complex system, which is basically an abstraction. This paper argues for three principal theses: first, to invoke complexity, to refer to complex systems, is to proffer a form of explanation; second, in the context of the social sciences, the form of explanation that complexity represents belongs to a family of explanations which the recent theoretical literature associates with social mechanisms; and, third, complexity explanations refer to a specific type of social mechanism, whose features differentiate it from the other members of the family. The most significant of these features is the jettisoning of the default link between order and design, which is precisely the principle omitted by an influential series of papers in the BMJ. Having defended these claims, the paper presents a brief case study illustrating the analysis. PMID- 20956002 TI - Upregulation of scavenger receptor class B type I expression by activation of FXR in hepatocyte. AB - OBJECTIVE: The farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has been proposed to play an important role in the pathogenesis of cardiovascular diseases by regulating the metabolism and transport of cholesterol and triglyceride. Scavenger receptor class B type I (SR-BI), a high-density lipoprotein receptor, plays an important role in decreasing lipid metabolism associated cardiovascular diseases by regulating reverse cholesterol transport. Recent studies have shown that SR-BI expression is upregulated by several nuclear receptors. However, the role of FXR in the regulation of SR-BI expression is not well known. In the present study, we investigate the regulation of SR-BI by FXR in hepatocyte and the corresponding mechanism. METHODS AND RESULTS: Treatment of human hepatoma cell line HepG2 with FXR ligands resulted in upregulation of SR-BI at the levels of both mRNA and protein. Reporter assays showed that activation of FXR significantly enhanced the SR-BI promoter activity. Electrophoretic mobility shift and chromatin immunoprecipitation assays indicated that FXR induced SR-BI expression by binding to a novel FXR element (FXRE), a directed repeat DNA motif, DR8 (-703 AGGCCAcgttctagAGCTCA -684). The in vivo experiment demonstrated that gavaging mice with a natural ligand of FXR increased SR-BI expression in liver tissues. CONCLUSIONS: FXR can directly upregulate SR-BI expression in hepatocyte, and DR8 is a likely novel FXRE that is involved in SR-BI regulation. FXR may serve as a novel molecular target for manipulating SR-BI expression in hepatocyte. PMID- 20956003 TI - Enhanced cyclooxygenase 2-mediated vasorelaxation in coronary arteries from insulin-resistant obese Zucker rats. AB - Obesity and metabolic syndrome increase the risk of coronary heart disease and lead to a proinflammatory state of the vascular wall. Endothelial dysfunction is associated with up-regulation of cyclooxygenase-2 (COX-2) and enhanced synthesis of constrictor prostaglandins in systemic arteries in diabetes. The present study assessed whether changes in the arachidonic acid (AA) metabolism via COX-1 and COX-2 may affect endothelial function of coronary arteries in obesity. Intramyocardial arteries from obese Zucker rats (OZR) and from lean Zucker rats (LZR) were mounted in microvascular myographs to assess vascular function and COX expression was determined by both immunohistochemistry and Western blot. AA elicited relaxations of similar magnitude in arteries from LZR and OZR which were abolished by endothelial cell removal. Selective inhibition of COX-1 enhanced the AA relaxant responses and inhibited the 5-hydroxytryptamine (5-HT)-induced vasoconstriction in arteries from both LZR and OZR. Antagonism of the TXA(2)/PGH(2) (TP) receptor mimicked the effects of COX-1 blockade in arteries from LZR but not OZR. Selective inhibition of COX-2 markedly reduced the vasodilatation induced by AA in OZR, but not in LZR, without altering 5-HT or ACh responses. COX-1 was widely distributed throughout the endothelial layer of coronary arteries from both LZR and OZR, while COX-2 protein, which was predominantly expressed in the endothelium, was significantly increased in arteries from OZR. Whereas AA is mainly metabolised to vasoconstrictor prostanoids via COX-1 in coronary arteries from healthy animals, endothelial COX 2 is up-regulated to produce vasodilator prostaglandins thus protecting coronary arteries in insulin resistant obese rats. PMID- 20956004 TI - Magnetic solid-phase extraction of hydrophobic analytes in environmental samples by a surface hydrophilic carbon-ferromagnetic nanocomposite. AB - A new sorbent of carbon-ferromagnetic nanocomposite was proposed for the extraction of polycyclic aromatic hydrocarbons (PAHs) in environmental samples. The sorbent was specially designed with a hydrophobic sublayer and a hydrophilic surface, which endows the sorbent some unique features. The former shows high extraction capability for the PAHs and the latter provides benign compatibility with the sample matrix. The sorbent can be easily dispersed in aqueous solutions for extraction and no additional stirring or shaking was necessary to facilitate the dispersion, which may bring operational convenience especially for on-site sampling and extraction. Parameters affecting the extraction efficiency were investigated in detail. The optimal conditions were as follows: 10mg of nanoparticles, 40mmol/L of sodium chloride, 30min of extraction time without shaking, hexane as the desorption solvent and 15min as the desorption-sonication time. The results demonstrate that enrichment factors ranging from 35- to 133 fold were obtained for the analytes. The limits of detection and the limits of quantification are in the range of 0.015-0.335ng/mL and 0.05-1.14ng/mL, respectively. Finally, the new sorbent was successfully used for the extraction of PAHs in lake water samples. PMID- 20956005 TI - Evaluation of dispersive liquid-liquid microextraction for the simultaneous determination of chlorophenols and haloanisoles in wines and cork stoppers using gas chromatography-mass spectrometry. AB - Dispersive liquid-liquid microextraction (DLLME) coupled with gas chromatography mass spectrometry (GC-MS) was evaluated for the simultaneous determination of five chlorophenols and seven haloanisoles in wines and cork stoppers. Parameters, such as the nature and volume of the extracting and disperser solvents, extraction time, salt addition, centrifugation time and sample volume or mass, affecting the DLLME were carefully optimized to extract and preconcentrate chlorophenols, in the form of their acetylated derivatives, and haloanisoles. In this extraction method, 1mL of acetone (disperser solvent) containing 30MUL of carbon tetrachloride (extraction solvent) was rapidly injected by a syringe into 5mL of sample solution containing 200MUL of acetic anhydride (derivatizing reagent) and 0.5mL of phosphate buffer solution, thereby forming a cloudy solution. After extraction, phase separation was performed by centrifugation, and a volume of 4MUL of the sedimented phase was analyzed by GC-MS. The wine samples were directly used for the DLLME extraction (red wines required a 1:1 dilution with water). For cork samples, the target analytes were first extracted with pentane, the solvent was evaporated and the residue reconstituted with acetone before DLLME. The use of an internal standard (2,4-dibromoanisole) notably improved the repeatability of the procedure. Under the optimized conditions, detection limits ranged from 0.004 to 0.108ngmL(-1) in wine samples (24-220pgg( 1) in corks), depending on the compound and the sample analyzed. The enrichment factors for haloanisoles were in the 380-700-fold range. PMID- 20956006 TI - Use of peak decay analysis and affinity microcolumns containing silica monoliths for rapid determination of drug-protein dissociation rates. AB - This report examined the use of silica monoliths in affinity microcolumns containing human serum albumin (HSA) to measure the dissociation rates for various drugs from this protein. Immobilized HSA and control monolith columns with dimensions of 1 mm * 4.6 mm i.d. were prepared for this work and used with a noncompetitive peak decay method. Several drugs known to bind HSA were examined, such as warfarin, diazepam, imipramine, acetohexamide, and tolbutamide. Items that were studied and optimized in this method included the sample volume, sample concentration, and elution flow rate. It was found that flow rates up to 10 mL/min could be used in this approach. Work with HSA silica monoliths at these high flow rates made it possible to provide dissociation rate constants for drugs such as warfarin in less than 40s. The dissociation rate constants that were measured gave good agreement with values reported in the literature or that had been obtained with other solutes that had similar binding affinities for HSA. This approach is a general one that should be useful in examining the dissociation of other drugs from HSA and in providing a high-throughput method for screening drug-protein interactions. PMID- 20956007 TI - Effects of urea induced protein conformational changes on ion exchange chromatographic behavior. AB - Urea is widely employed to facilitate protein separations in ion exchange chromatography at various scales. In this work, five model proteins were used to examine the chromatographic effects of protein conformational changes induced by urea in ion exchange chromatography. Linear gradient experiments were carried out at various urea concentrations and the protein secondary and tertiary structures were evaluated by far UV CD and fluorescence measurements, respectively. The results indicated that chromatographic retention times were well correlated with structural changes and that they were more sensitive to tertiary structural change. Steric Mass Action (SMA) isotherm parameters were also examined and the results indicated that urea induced protein conformational changes could affect both the characteristic charge and equilibrium constants in these systems. Dynamic light scattering analysis of changes in protein size due to urea-induced unfolding indicated that the size of the protein was not correlated with SMA parameter changes. These results indicate that while urea-induced structural changes can have a marked effect on protein chromatographic behavior in IEX, this behavior can be quite complicated and protein specific. These differences in protein behavior may provide insight into how these partially unfolded proteins are interacting with the resin material. PMID- 20956008 TI - An experimental hut evaluation of PermaNet((r)) 3.0, a deltamethrin-piperonyl butoxide combination net, against pyrethroid-resistant Anopheles gambiae and Culex quinquefasciatus mosquitoes in southern Benin. AB - PermaNet 3.0 is a long-lasting combination net with deltamethrin present on the sides and a mixture of deltamethrin and piperonyl butoxide (PBO), an oxidase synergist, on the top panel. An experimental hut trial comparing unwashed and 20 times washed PermaNet 3.0 and PermaNet 2.0, Olyset Net and a conventional deltamethrin-treated net washed three times was conducted in southern Benin. Anopheles gambiae and Culex quinquefasciatus from this area are highly resistant to pyrethroids through kdr and cytochrome P450 mechanisms. The unwashed PermaNet 3.0 killed slightly more A. gambiae (52%) than the unwashed PermaNet 2.0 (44%) (P=0.036), indicating only partial synergism of resistance. After washing there was significant loss of activity to a similar level, with PermaNet 3.0 killing 31%, PermaNet 2.0 killing 29% and the conventional net killing 26%. Blood-feeding rates were partially inhibited for unwashed PermaNet 3.0 and Olyset Net (27% inhibition). Personal protection against A. gambiae derived from PermaNet 3.0 was similar to that from PermaNet 2.0 before washing (50% vs. 47%), and after 20 washes it decreased to 30%. Against C. quinquefasciatus, no treatment killed >24% entering the huts. The synergism from unwashed PermaNet 3.0 was lower than expected, probably due to an unidentified resistance mechanism unaffected by PBO. PMID- 20956009 TI - DNA condensates organized by the capsid protein VP15 in White Spot Syndrome Virus. AB - The White Spot Syndrome Virus (WSSV) has a large circular double-stranded DNA genome of around 300kb and it replicates in the nucleus of the host cells. The machinery of how the viral DNA is packaged has been remained unclear. VP15, a highly basic protein, is one of the major capsid proteins found in the virus. Previously, it was shown to be a DNA binding protein and was hypothesized to participate in the viral DNA packaging process. Using Atomic Force Microscopy imaging, we show that the viral DNA is associated with a (or more) capsid proteins. The organized viral DNA qualitatively resembles the conformations of VP15 induced DNA condensates in vitro. Furthermore, single-DNA manipulation experiments revealed that VP15 is able to condense single DNA against forces of a few pico Newtons. Our results suggest that VP15 may aid in the viral DNA packaging process by directly condensing DNA. PMID- 20956010 TI - Influenza virus genome C4 promoter/origin attenuates its transcription and replication activity by the low polymerase recognition activity. AB - A natural variation is observed at position 4 of the 3'-end of influenza A virus genomes, where U (U4) or C (C4) is present. The replicon activity of C4 was 28% of U4. We compared the transcription and replication activity of U4 [v84(U4)], C4 [v84(C4)] and the complimentary RNA (c84) using the purified influenza virus RNA polymerase in vitro. ApG-primed replication activities of v84(C4) and c84 were 23.8% and 7.8% of v84(U4). Globin mRNA-primed transcription activities of v84(C4) and c84 were 36.9% and 6.81% of v84(U4). De novo replication activities of v84(C4) and c84 were 21.3 and 10.2% of v84(U4). This difference came from their polymerase binding activity. When all the eight genome segments of WSN strain were changed to U4, the virus titer was 760 times higher than the wild type. However, its pathogenicity in mice was lower than the wild type. PMID- 20956012 TI - Combination of Advanced Oxidation Processes and biological treatments for wastewater decontamination--a review. AB - Nowadays there is a continuously increasing worldwide concern for development of alternative water reuse technologies, mainly focused on agriculture and industry. In this context, Advanced Oxidation Processes (AOPs) are considered a highly competitive water treatment technology for the removal of those organic pollutants not treatable by conventional techniques due to their high chemical stability and/or low biodegradability. Although chemical oxidation for complete mineralization is usually expensive, its combination with a biological treatment is widely reported to reduce operating costs. This paper reviews recent research combining AOPs (as a pre-treatment or post-treatment stage) and bioremediation technologies for the decontamination of a wide range of synthetic and real industrial wastewater. Special emphasis is also placed on recent studies and large-scale combination schemes developed in Mediterranean countries for non biodegradable wastewater treatment and reuse. The main conclusions arrived at from the overall assessment of the literature are that more work needs to be done on degradation kinetics and reactor modeling of the combined process, and also dynamics of the initial attack on primary contaminants and intermediate species generation. Furthermore, better economic models must be developed to estimate how the cost of this combined process varies with specific industrial wastewater characteristics, the overall decontamination efficiency and the relative cost of the AOP versus biological treatment. PMID- 20956011 TI - Adaptation of HIV-1 to cells expressing rhesus monkey TRIM5alpha. AB - The cross-species transmission of retroviruses is limited by host restriction factors that exhibit inter-species diversity. For example, the TRIM5alpha proteins of Old World monkeys block the early, post-entry steps in human immunodeficiency virus (HIV-1) infection. We adapted an HIV-1 isolate to replicate in cells expressing TRIM5alpha(rh) from rhesus monkeys, an Old World species. A single amino acid change in the cyclophilin-binding loop of the HIV-1 capsid protein allowed virus replication in cells expressing TRIM5alpha(rh). The capsid of the escape virus exhibited a reduced affinity for TRIM5alpha(rh), but retained the ability to bind cyclophilin A efficiently. Thus, a preferred HIV-1 escape pathway involves decreased binding to TRIM5alpha, a capsid-destabilizing factor, and retention of binding to cyclophilin A, a capsid-stabilizing factor. PMID- 20956013 TI - Postoperative whole pelvic radiotherapy plus concurrent chemotherapy versus extended-field irradiation for early-stage cervical cancer patients with multiple pelvic lymph node metastases. AB - OBJECTIVES: The aim of this study was to compare the efficacy of postoperative pelvic radiotherapy plus concurrent chemotherapy with that of extended-field irradiation (EFRT) in patients with FIGO Stage IA2-IIb cervical cancer with multiple pelvic lymph node metastases. METHODS: We retrospectively reviewed the medical records of patients with FIGO Stage IA2-IIb cervical cancer who had undergone radical surgery between April 1997 and March 2008. Of these, 55 patients who demonstrated multiple pelvic lymph node metastases were treated postoperatively with pelvic radiotherapy plus concurrent chemotherapy (n=29) or EFRT (n=26). Thirty-six patients with single pelvic node metastasis were also treated postoperatively with pelvic radiotherapy plus concurrent chemotherapy. The recurrence rate, progression free survival (PFS), and overall survival (OS) were compared between the treatment groups. RESULTS: Pelvic radiotherapy plus concurrent chemotherapy was significantly superior to EFRT with regard to recurrence rate (37.9% vs 69.2%, p=0.0306), PFS (log-rank, p=0.0236), and OS (log rank, p=0.0279). When the patients were treated with pelvic radiotherapy plus concurrent chemotherapy, there was no significant difference in PFS or OS between the patients with multiple lymph node metastases and those with single node metastases. With regards to grade 3-4 acute or late toxicities, no statistically significant difference was observed between the two treatment groups. CONCLUSIONS: Postoperative pelvic radiotherapy plus concurrent chemotherapy is superior to EFRT for treating patients with FIGO Stage IA2-IIb cervical cancer displaying multiple pelvic lymph node metastases. PMID- 20956014 TI - Charcot-Leyden crystals associated with acute myeloid leukemia: case report and literature review. PMID- 20956015 TI - Transient marked increase in lymphocytosis during acute illness in chronic lymphocytic leukemia. PMID- 20956016 TI - Arsenic trioxide and low-dose cytarabine for patients with intermediate-2 and high-risk myelodysplastic syndrome. AB - Advanced myelodysplastic syndrome (MDS) carries a poor prognosis. In this phase I/II study, arsenic trioxide was combined with low-dose cytarabine in 49 previously untreated patients with intermediate-2 and high-risk MDS. Complete remission was achieved in 8 (17%) patients, including 3/14 (21%) with treatment related disease, 4/31 (13%) with unfavorable cytogenetics and 2/36 (6%) with baseline poor performance status. Mortality within the first 4 weeks was 8%. The regimen was active and had a tolerable extramedullary toxicity profile, but it was cumbersome and intensive compared to other currently available treatments. PMID- 20956017 TI - Exposure to bushfire smoke during prescribed burns and wildfires: firefighters' exposure risks and options. AB - Firefighters are exposed to known health-damaging air pollutants present in bushfire smoke and poorly managed exposure can result in serious health issues. A better understanding of exposure levels and the major factors influencing exposures is crucial for the development of mitigation strategies to minimise exposure risks and adverse health impacts. This study monitored air toxics within the breathing zone of firefighters at prescribed burns and at wildfires in Australia. The results showed that exposure levels were highly variable, with higher exposures (sometimes exceeding occupational exposure standards) associated with particular work tasks (such as patrol and suppression) and with certain burn conditions. The majority of firefighter's exposures were at low and moderate levels (~60%), however considerable attention should be given to the high (~30%) and very high (6%) exposure risk situations for which acute and chronic health risks are very likely and for which control strategies should be developed and implemented to minimise health risks. PMID- 20956018 TI - The PH domain adaptor protein Bam32/DAPP1 functions in mast cells to restrain FcERI-induced calcium flux and granule release. AB - Mast cell activation triggered by IgE binding to its high affinity receptor FcERI is highly dependent on signaling via phosphoinositde 3-kinases (PI3K). The phosphoinositide phosphatase SHIP controls mast cell activation by regulating accumulation of D3 phosphoinositide second messengers generated by PI3K. The PH domain adaptor protein Bam32/DAPP1 binds specifically to the D3 phosphoinositides PI(3,4,5)P3 and PI(3,4)P2 (the substrate and product of SHIP respectively). In B cells, Bam32 is phosphorylated by Src family kinases including Lyn, and is required for antigen receptor-induced activation; however the function of Bam32 in mast cells is unknown. Here we report that Bam32 is expressed in mast cells, is recruited to the plasma membrane upon stimulation and functions in FcERI signaling. Examination of bone marrow-derived mast cells (BMMC) isolated from Bam32-deficient mice revealed enhanced FcERI-induced degranulation and IL-6 production, indicating that Bam32 may function to restrain signaling via FcERI. These enhanced degranulation responses were PI3K-dependent, as indicated by blockade with PI3K inhibitors wortmannin or IC87114. While Bam32-deficient BMMC showed reduced FcERI-induced activation of mitogen-activated protein kinases ERK and JNK, FcERI-induced calcium flux and phosphorylation of PLCgamma1 and Akt were increased. Bam32-deficient BMMC showed significantly reduced phosphorylation of Lyn and SHIP, indicating reduced activity of inhibitory signaling pathways. Together our results identify Bam32 as a novel regulator of mast cell activation, potentially functioning in membrane-proximal integration of positive and negative signaling pathways. PMID- 20956019 TI - Differential regulation of TLR4 expression in human B cells and monocytes. AB - Toll-like receptor 4 (TLR4) is an innate immune receptor that is constitutively and inducibly activated in monocytes. Although TLR4 is expressed at very low levels on human B cells from healthy individuals, recent reports showed that TLR4 expression and function is elevated in B cells from inflammatory disease patients. New data showed that TLR4 expression on B cells is increased upon stimulation through surface IgMU and CD40 in combination with IL-4. In contrast, monocyte stimulation through CD40 and IL-4 receptors decreased TLR4 surface expression. Analysis of molecular signatures of TLR4 activation in stimulated B cells suggested that TLR4 is regulated by different mechanisms in B cells compared to monocytes. PU.1 and interferon regulatory factor association with the TLR4 promoter are sufficient for TLR4 transcription, but are not sufficient for surface TLR4 expression on B cells. In contrast, the PU.1/IRF combination is sufficient for surface TLR4 expression on monocytes. These data identify mechanisms that can activate B cell TLR4 expression in inflammatory disease patients, and demonstrate that B cells have additional layers of TLR4 regulation absent in monocytes. PMID- 20956020 TI - Subthreshold anxiety better defined by symptom self-report than by diagnostic interview. AB - BACKGROUND: There is no consensus on how to define subthreshold anxiety. Based on functional impairment, we aim to evaluate the use of a diagnostic instrument and an anxiety severity questionnaire to derive an empirical cut-off for defining clinically relevant, subthreshold anxiety. METHODS: Our sample consisted of 1788 subjects without full-syndromal anxiety disorders from the Netherlands Study of Depression and Anxiety (NESDA). We used ANCOVA to compare the Composite International Diagnostic Interview (CIDI) and the Beck Anxiety Inventory (BAI) in their association with functional impairment, measured by the World Health Organization Disability Assessment Schedule (WHODAS II). The BAI was selected over the Fear Questionnaire (FQ) and the Penn State Worry Questionnaire (PSWQ) for its highest associations with anxiety disorders. ROC analysis determined the percentage of functionally impaired with subthreshold anxiety based on found cut offs. RESULTS: The CIDI was very modestly associated with functional impairment, possibly because of skip rules, wording or scoring, while the BAI was highly correlated to functional impairment. A score of 11 on the BAI defined clinically relevant subthreshold anxiety. This cut-off identified 36.0% of the most functionally impaired as having subthreshold anxiety. LIMITATIONS: No "natural" cut-off on the BAI for determining subthreshold anxiety could be determined. The cut-off point of 11, based on a large effect size relative to normal anxiety, thus remains somewhat arbitrary. CONCLUSIONS: The questionnaire BAI is more suitable than the interview CIDI to measure clinically relevant, subthreshold anxiety. The BAI score of 11 appeared to be the most appropriate cut-off for identifying clinically relevant subthreshold anxiety. PMID- 20956021 TI - A review of immune transfer by the placenta. AB - Feto-maternal immune transfer occurs via both the placenta in utero and colostrum after birth. The layers between the maternal and fetal circulation systems, known as the placental barrier, regulate immune transfer to the fetus via the placenta. The placental barrier, as well as the type of placental structure, is species specific. The extent of transfer of antibodies from mother to fetus is related to the number of placental barrier layers. Passive immunity via the colostrum is essential in species in which the type of placentation impedes contact between maternal and fetal circulation systems, hindering the transfer of antibodies. In these species, susceptibility to neonatal infections is increased if colostrum is not ingested. Acquired antibodies are of extreme importance for adaptation of the neonate to the extrauterine environment. Based on the aforementioned factors, it was observed that in synepitheliochorial and epitheliochorial placentas immune transfer via the placenta is not possible, except in cases of placental alteration (e.g., placentitis). On the other hand, the mechanism of transfer in endothelial and hemochorial placentas is facilitated compared with other placentas. We conclude that there are no appreciable qualitative differences between the two mechanisms of transfer (placenta and colostrum) and that immune protection in the neonate can be attained by either mechanism. PMID- 20956022 TI - Polymorphisms in VEGF, progesterone receptor and IL-1 receptor genes in women with recurrent spontaneous abortion. AB - Hormonal, inflammatory and vascular alterations during pregnancy are thought to be involved in pregnancy loss. The role of progesterone, the actions of which involve cytokines and vascular endothelial growth factor (VEGF), has been thoroughly studied. Genetic factors are involved in modulation of these molecules, and several genes have been associated with recurrent spontaneous abortion (RSA), as well other obstetric conditions. Here we investigate the relationship between RSA and gene polymorphisms of the progesterone receptor (PROGINS), interleukin-1 receptor 1 (PstI) and vascular endothelial growth factor (VEGF) (-634, 936). This case-controlled study comprised a total of 89 women with idiopathic RSA and a control group of 191 women with at least two successful pregnancies and no miscarriages. Genomic DNA was extracted from whole blood, and polymorphism genotyping was conducted by digesting PCR products with specific restriction endonucleases. No correlations were found in any of the investigated polymorphisms, even among dominant, co-dominant and additive inheritance models and alleles. Our results support the hypothesis that these specific gene polymorphisms are not the major determinant of pregnancy success. Although we did not find any correlations, the investigation of these and other polymorphisms remains a challenge in the evaluation of RSA. PMID- 20956023 TI - Preoperative N-terminal pro-B type natriuretic peptide level can predict the regression of left ventricular mass after valvular surgery in patients with chronic severe mitral regurgitation: one-year follow-up. AB - BACKGROUND: The aim of this study was to investigate preoperative clinical and echocardiographic characteristics and N-terminal pro-B type natriuretic peptide (NT-proBNP) levels as prognostic factors for regression of the left ventricular (LV) mass after valvular surgery in patients with chronic severe mitral regurgitation (MR). METHODS: One hundred seventeen patients undergoing surgery for chronic severe MR were included. Plasma NT-proBNP measurements and echocardiography were performed preoperatively, immediately postoperatively, and at six and 12 months after surgery. Any regression of the LV mass was evaluated by echocardiography. RESULTS: During follow-up, 90 patients (77%) were classified as an LV mass regression group (LVMR), defined as having a postoperative reduction in LV mass indexed against body surface area (LVMI). The remaining 27 (23%) patients were classified as NON-LVMR. The LVMR group was younger (p=0.029) and had significantly lower ratios of patients with hypertension (p=0.045) and diuretic use (p=0.005) than the NON-LVMR group. They also had lower levels of NT proBNP (median: 446.4 pg/ml versus 1394.0 pg/ml, p=0.001). In multivariate analysis, higher preoperative NT-proBNP levels were independent predictors of no significant regression of the LV mass (odds ratio=1.731, 95% confidence intervals 1.052-2.844, p=0.010). CONCLUSIONS: A lower preoperative NT-proBNP level predicted the regression of LV mass after valvular surgery in patients with chronic severe MR. This measure could be used as a biomarker for predicting the postoperative course in such patients. PMID- 20956024 TI - A prospective study on canine hip dysplasia and growth in a cohort of four large breeds in Norway (1998-2001). AB - The study-objective was to measure the effect of weight and growth related parameters on the risk of development of Canine Hip Dysplasia (CHD). The hypothesis was that heavy and fast growing dogs of large sized breeds were at increased risk of development of CHD compared to lighter and slower growing dogs. A prospective cohort study was conducted among dogs of four large breeds: Newfoundland (NF), Leonberger (LEO), Labrador retriever (LR), and Irish wolfhound (IW). The dogs were privately owned with individualized nutrition and environment, and they were followed from birth and throughout the growth period until the official screening for CHD was performed. The study sample consisted of 501 dogs from 103 litters, with the breed distribution 125 NF, 180 LEO, 133 LR, and 63 IW. Because the dogs were clustered in litters a multivariable random effects logistic regression model was used to assess statistically significant growth-related risk factors for CHD. The estimated incidence risk of CHD was 36% in NF, 25% in LEO, 20% in LR, and 10% in IW. Based upon the final multilevel model it appears that the odds of CHD among both LR and IW (odds ratio (OR) 0.22) are about one-fifth of the odds for NF. The odds for LEO (OR 0.60) are not significantly different from NF. There appeared to be an inverse relationship between body weight at 3 months of age and odds of CHD, with an OR of 0.89 (P=0.044). The degree of clustering at the litter-level was high (22.6%) and highly significant (P<0.001). Findings failed to support the hypothesis that heavy and fast growing dogs from four large sized breeds were at increased risk for development of CHD. There might be other unmeasured environmental risk factors for CHD in this cohort of dogs, although the contribution of the genetic variance to the litter-level clustering also needs further investigation. PMID- 20956026 TI - IL-15 induces CD8+ T cells to acquire functional NK receptors capable of modulating cytotoxicity and cytokine secretion. AB - During the last years several authors have described a small population of CD8+ T cells expressing NK receptors (NKRs). Although their origin remains largely unknown, we have recently demonstrated that IL-15 is capable of inducing NKR expression in purified human CD8+CD56- T cells. In this study we show that IL-15 driven NKR induction in CD8+ T cells was linked with CD56 de novo acquisition, consistent with an effector-memory phenotype, increased anti-apoptotic levels, high granzyme B/perforin expression and with the ability of displaying in vitro NK-like cytotoxicity. Interestingly, dissection of NKR functional outcome in IL 15-cultured CD8+ T cells revealed: (i) that NKG2D cross-linking was able per se to upregulate degranulation levels and (ii) that KIR and NKG2A cross-linking upregulated secretion of cytokines such as IFN-gamma, TNF-alpha, IL-1beta and IL 10. These results suggest that IL-15 is capable of differentiating CD8+ T cells into NK-like T cells displaying a regulatory phenotype. PMID- 20956027 TI - Transgressive segregation for very low and high levels of basal resistance to powdery mildew in barley. AB - Basal resistance of barley to powdery mildew is a quantitatively inherited trait that limits the growth and sporulation of barley powdery mildew pathogen by a non hypersensitive mechanism of defense. Two experimental barley lines were developed with a very high (ErBgh) and low (EsBgh) level of basal resistance to powdery mildew by cycles of convergent crossing and phenotypic selection between the most resistant and between the most susceptible lines, respectively, from four mapping populations of barley. Phenotypic selection in convergent crossing was highly effective in producing contrasting phenotypes for basal resistance and susceptibility. In ErBgh, almost 90% of infection units failed to form a primary haustorium in the epidermal cells in association with papilla formation, but in EsBgh only 33% of infection units failed to form a primary haustorium. The contrast between ErBgh and EsBgh for successful formation of secondary and subsequent haustoria was much less obvious (69% versus 79% successful secondary haustorium formation). In an earlier investigation, we determined seven QTLs for basal resistance in the four mapping populations. Checking the peak markers of these QTLs indicated that only four out of seven QTLs were confirmed to be present in the selected resistant lines and only four QTLs for susceptibility were confirmed to be present in the selected susceptible lines. Surprisingly, none of the expected QTLs could be detected in the resistant line ErBgh. We discuss some reasons why marker aided selection might be less efficient in raising levels of basal resistance than phenotypic selection. The very resistant and susceptible lines developed here are valuable material to be used in further experiments to characterize the molecular basis of basal resistance to powdery mildew. PMID- 20956025 TI - Suppression of dendritic cell activation by diabetes autoantigens linked to the cholera toxin B subunit. AB - Antigen presenting cells, specifically dendritic cells (DCs) are a focal point in the delicate balance between T cell tolerance and immune responses contributing to the onset of type I diabetes (T1D). Weak adjuvant proteins like the cholera toxin B subunit when linked to autoantigens may sufficiently alter the balance of this initial immune response to suppress the development of autoimmunity. To assess adjuvant enhancement of autoantigen mediated immune suppression of Type 1 diabetes, we examined the cholera toxin B subunit (CTB)-proinsulin fusion protein (CTB-INS) activation of immature dendritic cells (iDC) at the earliest detectable stage of the human immune response. In this study, Incubation of human umbilical cord blood monocyte-derived immature DCs with CTB-INS autoantigen fusion protein increased the surface membrane expression of DC Toll-like receptor (TLR-2) while no significant upregulation in TLR-4 expression was detected. Inoculation of iDCs with CTB stimulated the biosynthesis of both CD86 and CD83 co-stimulatory factors demonstrating an immunostimulatory role for CTB in both DC activation and maturation. In contrast, incubation of iDCs with proinsulin partially suppressed CD86 co-stimulatory factor mediated DC activation, while incubation of iDCs with CTB-INS fusion protein completely suppressed iDC biosynthesis of both CD86 and CD83 costimulatory factors. The incubation of iDCs with increasing amounts of insulin did not increase the level of immune suppression but rather activated DC maturation by stimulating increased biosynthesis of both CD86 and CD83 costimulatory factors. Inoculation of iDCs with CTB-INS fusion protein dramatically increased secretion of the immunosuppressive cytokine IL-10 and suppressed synthesis of the pro-inflammatory cytokine IL12/23 p40 subunit protein suggesting that linkage of CTB to insulin (INS) may play an important role in mediating DC guidance of cognate naive Th0 cell development into immunosuppressive T lymphocytes. Taken together, the experimental data suggests Toll like receptor 2 (TLR-2) plays a dominant role in CTB mediated INS inhibition of DC induced type 1 diabetes onset in human Type 1 diabetes autoimmunity. Further, fusion of CTB to the autoantigen was found to be essential for enhancement of immune suppression as co-delivery of CTB and insulin did not significantly inhibit DC costimulatory factor biosynthesis. The experimental data presented supports the hypotheses that adjuvant enhancement of autoantigen mediated suppression of islet beta cell inflammation is dependent on CTB stimulation of dendritic cell TLR2 receptor activation and co-processing of both CTB and the autoantigen in the same dendritic cell. PMID- 20956028 TI - The protein kinase MEK1/2 participates in the regulation of ascorbate and glutathione content by jasmonic acid in Agropyron cristatum leaves. AB - This study investigated the role of the protein kinase MEK1/2 in the regulation of ascorbate and glutathione content by jasmonic acid in Agropyron cristatum leaves. The results showed that JA induced increases in the transcript levels and activities of APX, GR, MDHAR, DHAR, GalLDH and gamma-ECS, the contents of AsA, GSH, total ascorbate and total glutathione, and the ratios of AsA/DHA and GSH/GSSG, and reduced the E(GSSG/2GSH). The increases, except for the transcript level and activity of gamma-ECS and the reduction in E(GSSG/2GSH,) were all suppressed by pre-treatment with the MEK1/2 inhibitors PD98059 and U0126. The results of western blot analyses showed that JA induced increases in the phosphorylation level of MEK1/2. Our results suggest that JA could induce the activation of MEK1/2 by increasing the phosphorylation level, which, in turn, resulted in the up-regulation of ascorbate and glutathione content in A. cristatum leaves. PMID- 20956029 TI - Embryo vaccination of chickens using a novel adjuvant formulation stimulates protective immunity against Eimeria maxima infection. AB - Our previous study demonstrated that chickens immunized subcutaneously with an Eimeria recombinant profilin protein vaccine emulsified in a Quil A/cholesterol/DDA/Carbopol (QCDC) adjuvant developed partial protection against experimental avian coccidiosis compared with animals immunized with profilin alone. Because in ovo vaccination is presently used in commercial applications worldwide throughout the poultry industry, the current study was undertaken to investigate chicken embryo vaccination with profilin plus QCDC adjuvant. Eighteen day-old embryos were immunized with isotonic saline (control), profilin alone, QCDC alone, or profilin plus QCDC, and orally challenged with live Eimeria maxima at 7 days post-hatch. Body weight gain, fecal oocyst output, and intestinal cytokine transcript levels were assessed as measures of protective immunity. While immunization with profilin alone or QCDC alone did not alter body weight gain of infected chickens compared with the saline control group, vaccination with profilin plus QCDC increased body weight gain such that it was equal to the uninfected controls. Immunization with profilin plus QCDC also reduced fecal oocyst shedding compared with unimmunized controls, although in this case QCDC failed to provide an adjuvant effect since no difference was observed between the profilin-only and profilin/QCDC groups. Finally, increased levels of transcripts encoding IL-1beta, IL-15, and IFN-gamma were seen in the intestinal tissues of animals given profilin plus QCDC compared with the profilin-only or QCDC-only groups. In summary, this study demonstrates an adjuvant effect of QCDC on body weight gain and intestinal cytokine responses following in ovo vaccination of chickens with an Eimeria profilin vaccine. PMID- 20956030 TI - First-time fathers' experiences of childbirth--a phenomenological study. AB - OBJECTIVE: To describe fathers' experiences during childbirth. DESIGN: Qualitative method with phenomenological lifeworld approach. A re-enactment interview method, with open-ended questions analysed with a phenomenological method, was used. PARTICIPANTS AND SETTING: 10 First-time fathers from two hospitals were interviewed four to six weeks after childbirth in Southwest Sweden during the autumn of 2008. FINDINGS: The essential meaning of first-time fathers' lived experience of childbirth was described as an interwoven process pendulating between euphoria and agony. The four themes constituting the essence was: 'a process into the unknown', 'a mutually shared experience', 'to guard and support the woman' and 'in an exposed position with hidden strong emotions'. KEY CONCLUSIONS: Childbirth was experienced as a mutually shared process for the couple. The fathers' high involvement in childbirth, in cooperation with the midwife, and being engaged in support and care for his partner in her suffering is fulfilling for both partners, although the experience of the woman's pain, fear of the unknown and the gendered preconceptions of masculine hegemony can be difficult to bear for the father-to-be. IMPLICATIONS FOR PRACTICE: In order to maintain and strengthen childbirth as a mutually shared experience for the couple, the father needs to be recognised and supported as a parent-to-be. Midwives have to acknowledge fathers as valued participants and support their significant position. PMID- 20956031 TI - Computational model of the lumbar spine musculature: implications of spinal surgery. AB - BACKGROUND: The development of a comprehensive and detailed model of the musculature of the lumbar region is required if biomechanical models are to accurately predict the forces and moments experienced by the lumbar spine. METHODS: A new anatomical model representing the nine major muscles of the lumbar spine and the thoracolumbar fascia is presented. These nine muscles are modeled as numerous fascicles, each with its own force producing potential based on size and line of action. The simulated spine is fully deformable, allowing rotation in any direction, while respecting the physical constraints imposed by the skeletal structure. Maximal moments were predicted by implementing the model using a pseudo force distribution algorithm. Three types of surgery that affect the spinal musculature were simulated: posterior spinal surgery, anterior surgery, and total hip replacement. FINDINGS: Predicted moments matched published data from maximum isometric exertions in male volunteers. The biomechanical changes for the three different types of surgery demonstrated several common features: decreased spinal compression and production of asymmetric moments during symmetric tasks. INTERPRETATION: This type of analysis provides new opportunities to explore the effect of different patterns of muscle activity including muscle injury on the biomechanics of the spine. PMID- 20956032 TI - Part 8: Advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 20956033 TI - Part 7: CPR techniques and devices: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 20956034 TI - Part 6: Defibrillation: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. PMID- 20956035 TI - Part 5: Adult basic life support: 2010 International consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. PMID- 20956037 TI - Part 3: Evidence evaluation process: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 20956036 TI - Part 4: Conflict of interest management before, during, and after the 2010 International Consensus Conference on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 20956038 TI - Part 12: Education, implementation, and teams: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 20956040 TI - Part 2: International collaboration in resuscitation science: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 20956039 TI - Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 20956041 TI - Part 10: Paediatric basic and advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 20956042 TI - Part 1: Executive summary: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. PMID- 20956043 TI - European Resuscitation Council Guidelines for Resuscitation 2010 Section 10. The ethics of resuscitation and end-of-life decisions. PMID- 20956044 TI - European Resuscitation Council Guidelines for Resuscitation 2010 Section 9. Principles of education in resuscitation. PMID- 20956045 TI - European Resuscitation Council Guidelines for Resuscitation 2010 Section 8. Cardiac arrest in special circumstances: Electrolyte abnormalities, poisoning, drowning, accidental hypothermia, hyperthermia, asthma, anaphylaxis, cardiac surgery, trauma, pregnancy, electrocution. PMID- 20956046 TI - European Resuscitation Council Guidelines for Resuscitation 2010 Section 7. Resuscitation of babies at birth. PMID- 20956047 TI - European Resuscitation Council Guidelines for Resuscitation 2010 Section 6. Paediatric life support. PMID- 20956048 TI - European Resuscitation Council Guidelines for Resuscitation 2010 Section 5. Initial management of acute coronary syndromes. PMID- 20956049 TI - European Resuscitation Council Guidelines for Resuscitation 2010 Section 4. Adult advanced life support. PMID- 20956050 TI - European Resuscitation Council Guidelines for Resuscitation 2010 Section 3. Electrical therapies: automated external defibrillators, defibrillation, cardioversion and pacing. PMID- 20956051 TI - European Resuscitation Council Guidelines for Resuscitation 2010 Section 2. Adult basic life support and use of automated external defibrillators. PMID- 20956052 TI - European Resuscitation Council Guidelines for Resuscitation 2010 Section 1. Executive summary. PMID- 20956053 TI - Neurosurgical research in Pakistan: trends of publication and quality of evidence. AB - OBJECTIVE: To analyze the output and quality of neurosurgical research published from Pakistan in indexed peer reviewed journals. METHODS: Indexed peer reviewed publications from 2003 to 2008 were searched for neurosurgical contributions from Pakistan. The retrieved articles were evaluated to analyze the trends of publication and quality of evidence. RESULTS: Sixty-two neurosurgical research papers (10.3 per year, range 8-13) were published from Pakistan during the study period. Twenty-four (38.7%) publications were the contribution of just four primary authors; 25 (45.3%) of the publications were original research articles and 30 (48.4%) were either case reports or case series; and 38 (61.3%) of all the publications were from just three institutions in the country. Majority of publications were pertaining to neurooncology (n=23, 37.1%) and neurosurgical trauma (n=16, 25.8%). Overall, 48 (77.4%) papers were published in local indexed journals and only 14 (22.6%) in international journals. There were no basic science studies, and no papers offering level 1 or 2 evidence were published during the study period. CONCLUSION: Neurosurgical research in Pakistan over the past six years has been unsatisfactory, both in terms of number and quality of publications. Analysis of six year publications also did not show any significant improvement in research trends. PMID- 20956054 TI - Technique to minimize paraspinal muscle atrophy after posterior cervical fusion. AB - OBJECTIVE: Paraspinal muscle atrophy (PMA) after posterior cervical fusion is a known complication that causes considerable morbidity. It has been shown in the lumbar spine that preservation of the posterior ramus of the spinal nerve is important in minimizing paraspinal muscle atrophy. During posterior cervical spine fusions, we modified the exposure of the dorsal cervical spine by exposing only the medial two-thirds of the lateral mass utilizing a low electrocautery setting. In a retrospective analysis, we compared the incidence of paraspinal muscle atrophy using this modified technique with historical cohorts who underwent posterior cervical fusion using the standard technique of exposure of the entire lateral mass. MATERIALS AND METHODS: All patients who underwent posterior cervical fusion and internal fixation between 1999 and 2007 were included. Patients operated from 1999 to 2003 who underwent the standard exposure of the lateral mass formed Group 1 (n=31). Group 2 (n=32) included patients whose lateral masses were exposed using the modified technique of limiting the exposure only to the medial two-thirds of the lateral mass with the cautery on a low setting. All patients were assessed for PMA at six months after surgery. Atrophy was graded as no atrophy, mild atrophy (minimal midline atrophy), moderate atrophy (muscle lost without palpable hardware) and severe atrophy (hardware palpable). Before initiating the study, no atrophy and mild atrophy were grouped together as a non-significant atrophy and moderate atrophy and severe atrophy were grouped together as significant atrophy. RESULTS: We found a statistically lower incidence of paraspinal atrophy using this modified exposure of the lateral mass (p<0.03). CONCLUSIONS: This modified technique of cervical spine exposure is associated with lower paraspinal muscle atrophy secondary to the preservation of the innervation of the paraspinal musculature. PMID- 20956055 TI - Rate of loss of insecticides during soil solarization and soil biosolarization. AB - This paper reports the use of solarization and biosolarization to decontaminate a soil polluted with six insecticides (buprofezin, pirimicarb, pirimiphos methyl, pyridaben, pyriproxyfen and tebufenpyrad). In the experiment, 17-L pots filled with clay-loam soil were placed in a greenhouse during the summer season and then contaminated with the insecticides of interest. Treatments consisted of different solarization and biosolarization treatments, including a control without disinfection. For both solarization and biosolarization treatments, low-density polyethylene film was used as cover; the biosolarization treatment involving application of a mixture of sheep and chicken manures at a rate of 400 g pot(-1). Five pots per treatment were sampled periodically up to 90 d after the beginning of each treatment. The results showed that both solarization and biosolarization enhanced the degradation rates of most of the insecticides tested compared with the control, probably as a result of the increased soil temperature. Pirimicarb, pirimiphos methyl, tebufenpyrad, pyriproxyfen and pyridaben were degraded to a greater extent in the biosolarization than in the solarization treatment. The results confirm that both solarization and biosolarization can be considered as a remediation tool for soils polluted by these insecticides. PMID- 20956056 TI - An environmental friendly recovery production line of waste toner cartridges. AB - Quantity of waste toner cartridges has been generated following the increasing demand for printer and duplicator. Waste toner cartridge contains abundant valuable metals, plastics as well as toxic residual toner. Therefore, the recovery of waste toner cartridges is a meaningful subject, not only from waste treatment but also from environment protection. This study proposed a mechanical production line for recovering waste toner cartridges. The recovery process involved shearing process, magnetic separation, and eddy current separation. The recovery rates of steel (magnet), toner, aluminum, and plastic were 98.4%, 95%, 97.5%, and 98.8%, respectively. The results of the comparison between the production line and full manual dismantling indicated that the production line succeed in recovering waste toner cartridges. In addition, the proposed production line is an efficient and environmental friendly way for recovering waste toner cartridges. PMID- 20956057 TI - Arbuscular mycorrhizal phytoremediation of soils contaminated with phenanthrene and pyrene. AB - An available remediation technique--arbuscular mycorrhizal phytoremediation (AMPR)--is further proposed for soils contaminated with phenanthrene and pyrene as representative polycyclic aromatic hydrocarbons (PAHs) utilizing a greenhouse pot experiment. The initial concentrations of phenanthrene and/or pyrene in soils were 103 mg kg(-1) and 74 mg kg(-1), respectively. The host plant was alfalfa (Medicago sativa L.), and the experimental arbuscular mycorrhizal fungi (AMF) were Glomus mosseae and G. etunicatum. More than 98.6% and 88.1% of phenanthrene and pyrene were degraded after 70 days in soils with AMPR. Use of multiple mycorrhizal species significantly promoted degradation of PAHs in soils. The co contaminant (pyrene) present clearly inhibited the degradation of a single PAH (phenanthrene) in soil. Mycorrhizal colonization caused increased accumulation of PAHs in plant roots but a decrease in shoot. However, plant uptake contributed negligibly to PAH dissipation in AMPR, and plant accumulated PAHs amounted to less than 3.24% of total PAH degradation in mycorrhizal soils. In contrast, the optimized microbiota in mycorrhizal association was responsible for PAH degradation in AMPR. The high rate of PAH dissipation in mycorrhizal soils, the evident promotion of PAH degradation by AM colonization, and the healthy plant growth suggest encouraging opportunities for AMPR of PAH-contaminated soils. PMID- 20956058 TI - Biological effects and photodegradation by TiO(2) of terpenes present in industrial wastewater. AB - The aim of this work was to study the biological effects of four monoterpenes, i.e. alpha-pinene, beta-pinene, 3-carene and D-limonene present in the wastewater of a citrus transformation factory. The study was carried out by exposing V79 Chinese hamster cells to single terpene or to the mixture of four terpenes at concentrations corresponding to those in the wastewater evaluated by head space solid phase micro extraction and gas chromatography (HS-SPME-GC) analyses. Treatments with single or combined terpenes similarly affected cell vitality, but only the combined treatments induced the 6-thioguanine resistant mutants. Moreover the photocatalytic degradation of the four terpenes was successfully achieved with the photocatalyst TiO(2) Degussa P25 in both the actual effluent and in synthetic solutions. PMID- 20956059 TI - Metal catalysts impregnated on porous media for aqueous phenol decomposition within three-phase fluidized-bed reactor. AB - Performance of metal catalysts to decompose aqueous phenol was experimentally investigated. Comparison of the phenol decomposition rates within three-phase fluidized-bed reactors utilizing only O(3), TiO(2) deposited on silica beads, metal catalyst (Ni or Co) impregnated on mesoporous carbon beads, or O(3) in combination with each catalyst was thoroughly examined. It was found that the use of Co catalyst with the presence of O(3) led to the best removal condition which aqueous phenol was completely decomposed within 10 min (k = 0.1944 min(-1)). In contrast, the use of TiO(2) without O(3) resulted in the worst decomposition of phenol (k = 0.0066 min(-1)). Some intermediate products, such as hydroquinone and catechol, were also detected but their final concentrations were negligibly low. PMID- 20956060 TI - Characterization of Cd- and Pb-resistant fungal endophyte Mucor sp. CBRF59 isolated from rapes (Brassica chinensis) in a metal-contaminated soil. AB - To better understand the characteristics of fungal endophytes in the development of effective phytoremediation of heavy metals, the objectives of this study were to isolate a fungal endophyte tolerant Cd and Pb from rape roots grown in a heavy metal-contaminated soil, to characterize the metal-resistant fungal endophyte, and to assess its potential applications in removal of Cd and Pb from contaminated solutions and experimental soil. The isolate CBRF59 was identified as Mucor sp. based on morphological characteristics and phylogenetic analysis. From a Cd solution of 2.0mM, the maximum biosorption capacity of Cd by dead biomass of Mucor sp. CBRF59 was 108 mg g(-1). Under the same conditions, the bioaccumulation capacity of Cd by active biomass of the strain was 173 mg g(-1). The bioaccumulation capacity of Pb by active biomass of the strain was significantly lower than that by dead biomass in the initial Pb concentrations from 1.0 to 2.0mM. The ratio of Pb to Cd and initial pH values in the mixed Cd+Pb solutions affected the bioaccumulation and biosorption capacities of the metals by CBRF59. The addition of the active mycelia of CBRF59 significantly increased the availability of soil Pb and Cd by 77% and 11.5-fold, respectively. The results showed that the endophytic fungus was potentially applicable for the decontamination of metal-polluted media. PMID- 20956061 TI - No evidence for involvement of sheep in the epidemiology of cattle virulent epizootic hemorrhagic disease virus. AB - Epizootic hemorrhagic disease virus (EHDV) is an Orbivirus. While not previously considered as an important disease in cattle, several EHDV serotypes (EHDV-6 and 7) have recently been implicated in disease outbreaks. The involvement of sheep in the epidemiology of EHDV is still not understood. In this study we compared the prevalence of antibodies to EHDV and bluetongue virus (BTV) in sheep to their prevalence in cattle after an outbreak of EHDV that occurred in Israel during 2006. Sixty-six sheep and lambs scattered in seven herds were compared to 114 cows and calves scattered in 13 dairy cattle herds, matched to the sheep herds by location. While antibody prevalence to EHDV was high in cattle (35.2% within the outbreak zone) no evidence of exposure to EHDV was found in sheep (p<0.0001). Antibodies to BTV were apparent in both cattle and sheep though in the former it was significantly higher (63.2%, 16.7% respectively, p<0.0001), suggesting higher exposure of cattle to biting Culicoides midges. Taken together, these results imply that sheep have a negligible role in the epidemiology of EHDV. PMID- 20956062 TI - Epizotiology and phylogeny of equine arteritis virus in hucul horses. AB - The aim of the study was to determine the situation of equine arteritis virus (EAV) infections in hucul horses. A total of 176 horses (154 mares and 22 stallions) from the biggest hucul horse stud in Poland were tested. Antibodies against EAV were detected in 97 (55.1%) horses. The EAV seroprevalence among mares was 53.2% while in stallions - 68.2%. The percentage of positive mares increased with their age, thus amongst the mares of less than 2 years of age the percentage was 32.5%, while in the group of 3-5 years old increased to 59.4% and in the mares in the age of 6-10 years and older than 10 years 89.5% and 95% were seropositive, respectively. Among 11 seropositive stallions five were supposed to be shedders of EAV with their semen. It is likely that those persistently infected stallions were the reservoirs of the virus in the stud. Genetic studies using of ORF5 gene showed high homology between the viruses detected in the semen of those stallions what suggested lateral transmission between the stallions sharing the same stable. Persistent infection in an immature stallion, which has not yet been used for breeding, was established as a result of infection via respiratory route. Phylogenetic analysis confirmed that all hucul viruses shared the same ancestor and as most of EAV strains dominating in Polish horse population belonged to the European origin EAV subgroup (EU-1). PMID- 20956063 TI - Fetal and neonatal liver tumours. AB - Liver tumours are rare in children and account for about 5% of all tumours in the fetus and newborn. The most frequently occurring are benign vascular tumours and mesenchymal hamartomas although malignancy in the form of hepatoblastoma is a possibility. While the diagnosis can be suspected antenatally (by ultrasound and MR scan), a precise diagnosis is often difficult due to the complexity of the tumours. Inutero development of such tumours may be associated with polyhydramnios, fetal hydrops and extreme cases the maternal mirror syndrome. Postnatal symptoms may include abdominal distension, cardiac failure, consumptive coagulopathy and bleeding due to tumour rupture, but is dependent on the nature of the actual tumour. Treatment options may include watchful waiting, surgical resection, hepatic artery embolisation/ligation and chemotherapy. PMID- 20956064 TI - Induced cooperation between marine nitrifiers and anaerobic ammonium-oxidizing bacteria by incremental exposure to oxygen. AB - In oxygen-limited marine ecosystems cooperation between marine nitrifiers and anaerobic ammonium-oxidizing (anammox) bacteria is of importance to nitrogen cycling. Strong evidence for cooperation between anammox bacteria and nitrifiers has been provided by environmental studies but little is known about the development of such communities, the effects of environmental parameters and the physiological traits of their constituents. In this study, a marine laboratory model system was developed. Cooperation between marine nitrifiers and anammox bacteria was induced by incremental exposure of a marine anammox community dominated by Scalindua species to oxygen in a bioreactor set-up under high ammonium (40 mM influent) conditions. Changes in the activities of the relevant functional groups (anammox bacteria, aerobic ammonia oxidizers and nitrite oxidizers) were monitored by batch tests. Changes in community composition were followed by Fluorescence in situ Hybridization (FISH) and by amplification and sequencing of 16S rRNA and amoA genes. A co-culture of Scalindua sp., an aerobic ammonia-oxidizing Nitrosomonas-like species, and an aerobic (most likely Nitrospira sp.) nitrite oxidizer was obtained. Aerobic ammonia oxidizers became active immediately upon exposure to oxygen and their numbers increased 60-fold. Crenarchaea closely related to the ammonia-oxidizer Candidatus 'Nitrosopumilus maritimus' were detected in very low numbers and their contribution to nitrification was assumed negligible. Activity of anammox bacteria was not inhibited by the increased oxygen availability. The developed marine model system proved an effective tool to study the interactions between marine anammox bacteria and nitrifiers and their responses to changes in environmentally relevant conditions. PMID- 20956065 TI - Do beliefs about the utility of worry facilitate worry? AB - Various theoretical models have pointed out the role of positive beliefs in the worry process (Dugas, Gagnon, Ladouceur, & Freeston, 1998; Wells, 1995). Two studies were conducted to search for experimental support for this possibility. After trait worry was controlled, a persuasion procedure was used to induce diverse beliefs about worry (positive, negative, or neutral). It was hypothesized that participants persuaded of the usefulness of worry would be more worried and more anxious after listening to a worrisome message. In the first study, 90 participants (62 females and 28 males) were exposed to a novel worrisome message, and in the second study, 60 participants (34 females and 26 males) were exposed to a more personally relevant worry. Results indicate that persuasion about the utility of worry does not trigger worry, and when prior positive beliefs about worry were controlled, they do not correlate with the change in anxiety after worrisome induction. PMID- 20956066 TI - Gender differences in PTSD symptoms: an exploration of peritraumatic mechanisms. AB - Females are at higher risk than males for developing posttraumatic stress disorder symptoms (PTSS) following exposure to trauma, which may stem from gender differences in initial physiological and psychological responses to trauma. The present study aimed to examine a number of peri- and initial posttraumatic reactions to motor vehicle accidents (MVAs) to determine the extent to which they contributed to gender differences in PTSS. 356 adult MVA survivors (211 males and 145 females) reported on peritraumatic dissociation, perception of life threat and initial PTSS. In addition, heart rate and urinary cortisol levels were collected in-hospital. 6 weeks and 6 months later, PTSS were assessed via clinical interviews. Results suggested that initial PTSS and peritraumatic dissociation were marginally significant mediators at 6-week follow-up and significant mediators at 6-month follow-up, providing partial support for the hypothesis that initial responses to trauma may account for observed gender differences in PTSS development. PMID- 20956067 TI - The influence of motor impairment on autonomic heart rate modulation among children with cerebral palsy. AB - The study of heart rate variability is an important tool for a noninvasive evaluation of the neurocardiac integrity. The present study aims to evaluate the autonomic heart rate modulation in supine and standing positions in 12 children diagnosed with cerebral palsy and 16 children with typical motor development (control group), as well as to relate the level of motor impairment in children with cerebral palsy, as classified by to the Gross Motor Function Classification System, to the heart rate variability indices. The heart rate variability was analyzed by linear model in the frequency domain, at low and high frequency bands in normalized units and low and high frequency ratio. The results indicate that children with cerebral palsy present lower heart rate variability indices, indicating sympathovagal imbalance. The decrease of heart rate variability in children with cerebral palsy is related to the motor impairment level. PMID- 20956068 TI - Development and validation of a fine-motor assessment tool for use with young children in a Chinese population. AB - OBJECTIVES: Most of the fine-motor assessment tools used in Hong Kong have been designed in Western countries, so there is a need to develop a standardized assessment which is relevant to the culture and daily living tasks of the local (that is, Chinese) population. This study aimed to (1) develop a fine-motor assessment tool (the Hong Kong Preschool Fine-Motor Developmental Assessment [HK PFMDA]) for use with young children in a Chinese population and (2) examine the HK-PFMDA's psychometric properties. METHOD: The HK-PFMDA was developed by a group of occupational therapists specializing in the area of developmental disabilities in Hong Kong. A panel of 21 experts reviewed the content validity of the instrument. Rasch item analysis was used to examine the model fit of items against the rating scale model, and to explore the dimensionality of the test. Intra- and interrater reliability, convergent validity, and criterion-related validity were examined. The participants included 783 children without disabilities, 45 with autistic spectrum disorder, and 35 with developmental delay. RESULTS: The Rasch analysis suggested that the 87-item HK-PFMDA had a unidimensional structure, as the items explained most (91.6%) of the variance. The HK-PFMDA demonstrated excellent intra- (ICC = .99) and interrater reliability (ICC = .99), and internal consistency (alpha ranging from .83 to .92). In terms of validity, the HK-PFMDA had significant positive correlations with both age and the convergent measures of the Peabody Developmental Motor Scales (PDMS-2). CONCLUSION: A set of normative data for local children aged from birth to 6 years was established. The HK-PFMDA has shown excellent psychometric properties and is suitable for clinical application by occupational therapists in the assessment of fine-motor skills development of young children in Chinese populations. PMID- 20956069 TI - Application of mesenchymal stem cells derived from bone marrow and umbilical cord in human hair multiplication. AB - BACKGROUND: The methods currently used for treating alopecia have some limitations. The drug treatment is so temporary that medication discontinuance may progress depilation immediately. The number of hair transplantation restricts because total transplantable hair number is no increase. To overcome these problems, researchers have attempted the in vitro culturing of hair follicle cells and implanting these cells in the treatment area. OBJECTIVES: In the present study, culture-expanded mesenchymal stem cells (MSCs) that do not possess aggregative activity were used to produce self-aggregated cell-aggregated spheroidal dermal papilla like tissues (DPLTs) with the aid of a special culture condition in vitro, and hair bulb structure inductive capacity pertinent to the aggregative activity was then evaluated. Then hair inducing activity of self aggregated DPLTs employing MSCs was tested in athymic mice. METHODS: We isolated and cultivated MSCs from bone marrow and umbilical cord in vitro. After propagated MSCs underwent preconditioning in dermal papilla forming medium (DPFM), then subcultured MSCs formed self-aggregated DPLTs. We compared real human scalp dermal papilla cells (hDPCs) with DPLTs employing DPCs, DPLTs employing hBM-MSCs and DPLTs employing hUC-MSCs. RESULTS: Light microscopy and immunohistochemical staining were used to confirm that reconstructed DPLTs generated by this procedure had the size, shape, and expression of protein similar to actual DP. CONCLUSIONS: The DPLTs have the same hair bulb structure inductive ability as natural DPLTs in vitro. Transplanted DPLTs can induce new hair follicle in athymic mice. As a result, UC-MSCs and BM-MSCs may be an applicable and novel cell source for the generation of human hair cell therapy. PMID- 20956070 TI - Effect of the antimicrobial decapeptide KSL on the growth of oral pathogens and Streptococcus mutans biofilm. AB - Dental caries and periodontitis are common oral bacterial infectious diseases. Their prevention and treatment requires control of the causative pathogens, such as Streptococcus mutans and Porphyromonas gingivalis, that exist within dental plaque. As one of the attractive future substitutes for conventional antibiotics, antimicrobial peptides (AMPs), both natural and synthetic, have been widely tested and used for controlling bacterial infections. In this study, we investigated the antimicrobial activity of KSL (KKVVFKVKFK-NH(2)), a novel AMP, against several major cariogenic and periodontopathogenic bacteria as well as Candida albicans in vitro. Streptococcus mutans, the causative agent of dental caries, was chosen for in-depth testing. Bacterial susceptibility and time-kill assays were performed to investigate the sensitivity of S. mutans to KSL. The effect of KSL on biofilm formation and on pre-formed biofilm was also examined. For biofilm studies, confocal laser scanning microscopy (CLSM) was used to observe and analyse bacterial biofilm. The results showed that KSL had antimicrobial activity against a variety of oral bacteria and fungi. Streptococcus mutans and Lactobacillus acidophilus were the most susceptible strains to KSL peptide [minimum inhibitory concentration (MIC) of 0.0625 mg/mL] compared with other species tested (MICs of 0.125-1mg/mL). KSL also inhibited S. mutans biofilm formation, with a minimum biofilm inhibition concentration of 0.0625-0.125 mg/mL, and reduced 1-day-old developed S. mutans biofilm, with a minimum biofilm reduction concentration of 0.25-0.5mg/mL. CLSM images showed that KSL significantly reduced the viability of biofilm cells. This study suggests that KSL may have a potential clinical application in treating dental caries by killing S. mutans within dental plaque. PMID- 20956071 TI - 2-Year course of bipolar disorder type I patients in outpatient care: factors associated with remission and functional recovery. AB - EMBLEM is a 2-year, prospective, observational study that enrolled patients initiating/changing oral treatment for an acute manic/mixed episode. This paper analysed remission and functional recovery in 1656 patients who entered the 2 year long-term phase. Cox models identified variables significantly associated with achieving remission and functional recovery at 2years. Of these patients, 64% achieved remission and 34% achieved functional recovery. Patients with a higher CGI-BP overall score at baseline, who had depressive episodes in the year before inclusion and who had poor social functioning (work or social impairment, not living independently or without a spouse/partner) were less likely to achieve remission or recovery. Prescription of typical antipsychotics and prescription of antidepressants at the first visit of the long-term treatment phase (12weeks) were independent predictors of lower remission and recovery rates. In conclusion, functional recovery occurred in approximately half of those who achieved remission. Impairment of work and social functioning was consistently associated with lower remission and recovery rates. PMID- 20956072 TI - Reduced placental docosahexaenoic acid levels associated with increased levels of sFlt-1 in preeclampsia. AB - Our earlier studies, in preeclamptic women have shown altered levels of long chain polyunsaturated fatty acids (LCPUFA), essential constituents of the cell membrane lipids responsible for membrane stability as one of the key factors contributing to the pathophysiology of preeclampsia. We have also reported elevated levels of sFlt-1 in preeclampsia. The present study examines the levels of LCPUFA and their association with sFlt-1 levels in 69 pre-eclamptic women and 40 normotensive women. DHA and omega 3 fatty acid levels were lower (p<0.001) while arachidonic acid and omega 6 fatty acid levels were higher (p<0.05) in preeclamptic women as compared to normotensive women. Maternal plasma sFlt-1 levels were higher (p<0.05) in preeclamptic women and were negatively associated with DHA (p=0.008) and omega 3 fatty acids concentrations (p=0.031). Our results suggest that altered placental LCPUFA may result in altered membrane lipid fatty acid composition leading to increased release of sFlt-1 in circulation. PMID- 20956073 TI - Regulation of the immune response. PMID- 20956074 TI - Syringe exchange in community pharmacies--The Portuguese experience. AB - BACKGROUND: Since 1993 the participation of Portuguese pharmacies to the national Syringe Exchange Programme (SEP) has remained high. However, no national guidelines or standard procedures are available regarding the provision of this service. We aimed to describe practices and attitudes toward syringe dispensing and other harm reduction strategies in Portuguese pharmacies. METHODS: A cross sectional survey was conducted using an anonymous self-administered questionnaire. All pharmacies in Portugal (n=2775) were invited to participate. The questionnaire addressed SEP ever involvement and discontinuation; injection equipment policies; problems and needs in service provision. RESULTS: Participation rates were 69.6% among pharmacies involved in SEP and 42.7% in those not involved in the programme. Among current providers, 64.3% followed a strict "one-for-one" policy and 21.6% established limits on the number of syringes distributed. Syringe selling was reported by 76.2%. One-tenth of pharmacies supervised methadone consumption Problems in service provision were experienced by 12.8% of respondents. Need for increased training and improvement of referral pathways were frequently reported. CONCLUSIONS: Pharmacy-based harm reduction interventions in Portugal have tended to follow strict policies favouring conservative approaches. Training and feedback adaptation seem indispensable to avoid service discontinuation and boost an activity with an essential humanitarian dimension. PMID- 20956075 TI - A venue analysis of predictors of alcohol use prior to sexual intercourse among female sex workers in Senggigi, Indonesia. AB - BACKGROUND: Female sex workers' (FSWs') use of alcohol, a known disinhibitor to risk behaviour, has been largely understudied. Knowledge of how various sex work venues influence FSW's alcohol consumption before engaging in commercial sex is even rarer. Our analysis identifies those factors across three types of sex-work venues that predict alcohol use among FSWs prior to paid sexual intercourse with clients. Our data were collected through structured interviews with FSWs engaging in commercial sex in Senggigi Beach, Lombok Island in the eastern Indonesian province of West Nusa Tenggara. METHODS: Employing a cross-sectional and multilevel design, three categories of venues where FSWs meet clients in Senggigi were sampled: (1) discotheques and bars (freelance), (2) brothels, and (3) recreational enterprises such as karaoke establishments and massage parlors. The sample consisted of 115 women "nested" within 16 sex work venues. The FSWs reported on 326 clients interactions. RESULTS: Results show that FSWs consumed alcohol before commercial sex with 157 (48%) of the 326 clients interactions. Alcohol use varied by differences in HIV policies and services offered at the sex work venue, the FSW's educational level and age, and client characteristics. CONCLUSION: Alcohol use is common prior to sexual intercourse among FSWs and their clients in Senggigi, and the venue where FSWs meet their clients influences the women's alcohol use. Freelancers were likelier to use alcohol than those who work at brothels and recreational enterprises. Given the recognized links between alcohol use prior to sex and high risk behaviour, HIV prevention programmes that discourage alcohol use should be introduced to both women who engage in commercial sex and also sex-work venue managers, owners, and clients. PMID- 20956076 TI - Effects of government registration on unprotected sex amongst female sex workers in Tijuana; Mexico. AB - BACKGROUND: Sex work is partially regulated in Tijuana, but little is known of its health effects. A recent behavioural intervention amongst female sex workers (FSWs) decreased incidence of HIV/STIs by 40%. We evaluated effects of sex worker regulation on condom use amongst FSWs randomized to this intervention. METHODS: FSWs aged >=18 years who reported unprotected sex with >=1 client in the last 2 months and whether they were registered with Tijuana's Municipal Health Department underwent a brief, theory-based behavioural intervention to increase condom use. At baseline and 6 months, women underwent interviews and testing for HIV, syphilis, Chlamydia trachomatis and Neisseria gonorrhoeae. Negative binomial regression was used to determine the effect of registration on numbers of unprotected sex acts and cumulative HIV/STI incidence. RESULTS: Of 187 women, 83 (44%) were registered. Lack of registration was associated with higher rates of unprotected sex (rate ratio: 1.7, 95% CI: 1.2-2.3), compared to FSWs who were registered, after controlling for potential confounders. CONCLUSIONS: Registration predicted increased condom use amongst FSWs enrolled in a behavioural intervention. Public health programmes designed to improve condom use amongst FSWs may benefit from understanding the impact of existing regulation systems on HIV risk behaviours. PMID- 20956077 TI - "Should I stay or should I go?" Coming off methadone and buprenorphine treatment. AB - BACKGROUND: This study aimed to investigate patient perspectives regarding coming off maintenance opioid substitution treatment (OST). The study explored previous experiences, current interest and concerns about stopping treatment, and perceptions of how and when coming off treatment should be supported. METHODS: A cross-sectional survey was used. Participants were 145 patients receiving OST at public opioid treatment clinics in Sydney, Australia. RESULTS: Sixty-two percent reported high interest in coming off treatment in the next 6 months. High interest was associated with having discussed coming off treatment with a greater number of categories of people (OR=1.72), not citing concern about heroin relapse (OR=3.18), and shorter duration of current treatment episode (OR=0.99). Seventy one percent reported previous withdrawal attempts and 23% had achieved opioid abstinence for >=3 months following a previous withdrawal attempt. Attempts most commonly involved jumping off (59%), and doctor-controlled (52%) or self controlled (48%) gradual reduction. For future attempts respondents were most interested in doctor-controlled (68%) or self-controlled (41%) gradual reduction. Concerns regarding coming off treatment included withdrawal discomfort (68%), increased pain (50%), and relapse to heroin use (48%). CONCLUSION: While some patients may require lifetime maintenance, the issue of coming off treatment is important to many patients and should be discussed regularly throughout treatment and where appropriate supported by a menu of clinical options. PMID- 20956078 TI - Rapid electrochemical detection of polyaniline-labeled Escherichia coli O157:H7. AB - There is a high demand for rapid, sensitive, and field-ready detection methods for Escherichia coli O157:H7, a highly infectious and potentially fatal food and water borne pathogen. In this study, E. coli O157:H7 cells are isolated via immunomagnetic separation (IMS) and labeled with biofunctionalized electroactive polyaniline (immuno-PANI). Labeled cell complexes are deposited onto a disposable screen-printed carbon electrode (SPCE) sensor and pulled to the electrode surface by an external magnetic field, to amplify the electrochemical signal generated by the polyaniline. Cyclic voltammetry is used to detect polyaniline and signal magnitude indicates the presence or absence of E. coli O157:H7. As few as 7CFU of E. coli O157:H7 (corresponding to an original concentration of 70 CFU/ml) were successfully detected on the SPCE sensor. The assay requires 70 min from sampling to detection, giving it a major advantage over standard culture methods in applications requiring high-throughput screening of samples and rapid results. The method can be performed with portable, handheld instrumentation and no biological modification of the sensor surface is required. Potential applications include field-based pathogen detection for food and water safety, environmental monitoring, healthcare, and biodefense. PMID- 20956079 TI - The structural diversity and promise of antiparasitic marine invertebrate-derived small molecules. AB - This review focuses on six important parasitic diseases that adversely affect the health and lives of over one billion people worldwide. In light of the global human impact of these neglected tropical diseases (NTDs), several initiatives and campaigns have been mounted to eradicate these infections once and for all. Currently available therapeutics summarized herein are either ineffective and/or have severe and deleterious side effects. Resistant strains continue to emerge and there is an overall unmet and urgent need for new antiparasitic drugs. Marine derived small molecules (MDSMs) from invertebrates comprise an extremely diverse and promising source of compounds from a wide variety of structural classes. New discoveries of marine natural product privileged structures and compound classes that are being made via natural product library screening using whole cell in vitro assays are highlighted. It is striking to note that for the first time in history the entire genomes of all six parasites have been sequenced and additional transcriptome and proteomic analyses are available. Furthermore, open and shared, publicly available databases of the genome sequences, compounds, screening assays, and druggable molecular targets are being used by the worldwide research community. A combined assessment of all of the above factors, especially of current discoveries in marine natural products, implies a brighter future with more effective, affordable, and benign antiparasitic therapeutics. PMID- 20956080 TI - The expanding role of marine microbes in pharmaceutical development. AB - Marine microbes have received growing attention as sources of bioactive metabolites and offer a unique opportunity to both increase the number of marine natural products in clinical trials as well as expedite their development. This review focuses specifically on those molecules currently in the clinical pipeline that are established or highly likely to be produced by bacteria based on expanding circumstantial evidence. We also include an example of how compounds from harmful algal blooms may yield both tools for measuring environmental change as well as leads for pharmaceutical development. An example of the karlotoxin class of compounds isolated from the dinoflagellate Karlodinium veneficum reveals a significant environmental impact in the form of massive fish kills, but also provides opportunities to construct new molecules for the control of cancer and serum cholesterol assisted by tools associated with rational drug design. PMID- 20956081 TI - Understanding the temporal codes of intra-cellular signals. AB - The health of organisms and cells depends on appropriate responses to diverse internal and external cues, stimuli, or challenges, such as changes in hormone or cytokine levels, or exposure to a pathogen. Cellular responses must be tailored to the identity and intensity of the stimulus and therefore intra-cellular signals must carry information about both. However, signaling mediators often form intricate networks that react to multiple stimuli yet manage to produce stimulus-specific responses. The multi-functionality ('functional pleiotropism') of signaling nodes suggests that biological networks have evolved ways of passing physiologically relevant stimulus information through shared channels. Increasing evidence supports the notion that this is achieved in part through temporal regulation of signaling mediators' activities. The present challenge is to identify the features of temporal activity profile that represent information about a given stimulus and understand how cells read the temporal codes to control their responses. PMID- 20956082 TI - Reading, writing and editing methylated lysines on histone tails: new insights from recent structural studies. AB - The phenotypes of different cell types are governed by their differential gene expression programmes, which are prominently influenced by epigenetic gene regulation featuring heritable chromatin states. Different epigenetic states are associated with distinctive patterns of post-translational modifications of the histone tails, which in turn influence the recruitment of chromatin-modifying effectors and local chromatin structure. Despite rapid advances in understanding how particular histone marks correlate with transcriptional output, many of the molecular details on how the maintenance and alteration of these modifications relate to fundamental processes such as replication, DNA repair, and transcription remain to be elucidated. Here, we review recent advances in the structural description of the reading, writing, and editing of two histone methylation marks with opposite functions: at histone H3 lysine 4 (H3K4) associated with actively transcribed genes, and at histone H3 lysine 27 (H3K27)-a hallmark of silenced chromatin. These two marks are associated with trithorax and polycomb, respectively, prototypes of the genes involved in epigenetic inheritance in Drosophila. We also briefly discuss some recent examples of how the readout of particular marks is influenced by the presence of other modifications. PMID- 20956083 TI - A method for reliability analysis of speed-related repeated measures gait data. AB - Reliability should be addressed for measures used in gait studies. Many protocols designed for experimental or clinical research request subjects to walk repeatedly at different steady-state walking speeds. Such data lend themselves to reliability analysis, rendering a separate reliability test session superfluous. Thus human and time resources are saved, and the reported reliability relates directly to the study population and occasion at hand. In this report a procedure is introduced where residuals from individual speed related curve estimates are regarded as measurement error. If there is no speed related trend in data, the procedure will yield identical results to a usual repeated measures reliability analysis where all within-subject variability is regarded as measurement error. PMID- 20956084 TI - A potential role for insulin-like growth factor signaling in induction of pluripotent stem cell formation. AB - Recent success in reprogramming somatic cells into induced pluripotent stem cells (iPS cells) with a cluster of nuclear transcription factors, such as Oct4, Sox2, Klf4, and c-myc, opens up a new era in regenerative medicine. However, reportedly poor efficiency and slow kinetics of the reprogramming process by viral transfection of the nuclear factors may create an obstacle that hampers clinical application of the iPS cell technology. Furthermore, the viral transfection may induce mutagenesis and raises the risk for cancer development. Hence, generation of iPS cells using a non-viral approach appears to be an important prerequisite for iPS cell-based regenerative medicine. Through its receptor/phosphoinositide 3 kinase (PI3-K) signaling pathway, insulin-like growth factor (IGF) plays a critical role in promotion of survival and proliferation in a diversity of cell types, including both embryonic and adult stem cells. In addition, IGF may enhance expression of reprogramming or surviving factors in reprogramming somatic cells. This review summarizes recent advances in IGF research and discusses the potential for IGF to act as a co-stimulatory factor for somatic cell reprogramming and iPS cell development. Currently available evidence from experimental animal and human studies highly suggests that IGF may contribute to reprogramming of somatic cells into iPS cell generation, and enhancement of iPS cell survival and growth, which will be instrumental in regenerative medicine. PMID- 20956085 TI - Membrane transport of sepiapterin and dihydrobiopterin by equilibrative nucleoside transporters: a plausible gateway for the salvage pathway of tetrahydrobiopterin biosynthesis. AB - Tetrahydrobiopterin (BH(4)) is synthesized de novo in particular cells, but in the case of a systemic or local BH(4) deficiency, BH(4) supplementation therapy is applied. BH(4)-responsive PKU has also been effectively treated with BH(4) supplementation. However, the rapid clearance of the supplemented BH(4) has prevented the therapy from being widely accepted. Deposition of BH(4) after supplementation involves oxidation of BH(4) to dihydrobiopterin (BH(2)) and subsequent conversion to BH(4) by the salvage pathway. This pathway is known to be almost ubiquitous in the body. However, the mechanism for the redistribution and exclusion of BH(4) across the plasma membrane remains unclear. The aim of this work was to search for the key transporter of the uptake precursor of the salvage pathway. Based on the observed sensitivity of pterin transport to nitrobenzylthioinosine (NBMPR), we examined the ability of ENT1 and ENT2, representative equilibrative nucleoside transporters, to transport sepiapterin (SP), BH(2) or BH(4) using HeLa cell and Xenopus oocyte expression systems. hENT2 was capable of transporting the pterins with an efficiency of SP>BH(2)>BH(4). hENT1 could also transport the pterins but less efficiently. Non-transfected HeLa cells and rat aortic endothelial cells were able to incorporate the pterins and accumulate BH(4) via uptake that is likely mediated by ENT2 (SP>BH(2)>BH(4)). When exogenous BH(2) was given to mice, it was efficiently converted to BH(4) and its tissue deposition was similar to that of sepiapterin as reported (Sawabe et al., 2004). BH(4) deposition after BH(2) administration was influenced by prior treatment with NBMPR, suggesting that the distribution of the administered BH(2) was largely mediated by ENT2, although urinary excretion appeared to be managed by other mechanisms. The molecular basis of the transport of SP, BH(2), and BH(4) across the plasma membrane has now been described for the first time: ENT2 is a transporter of these pterins and is a plausible gateway to the salvage pathway of BH(4) biosynthesis, at least under conditions of exogenous pterin supplementation. The significance of the gateway was discussed in terms of BH(2) uptake for BH(4) accumulation and the release for modifying the intracellular BH(2)/BH(4) ratio. PMID- 20956086 TI - Groundwater arsenic contamination in one of the 107 arsenic-affected blocks in West Bengal, India: Status, distribution, health effects and factors responsible for arsenic poisoning. AB - A somewhat detailed study was carried out in Gaighata, one of the 107 arsenic affected blocks in West Bengal, India, to determine the degree of groundwater contamination with arsenic, its depth wise distribution, correlation with iron, arsenical health effects to the inhabitants and the factors responsible for arsenic poisoning. Groundwater in all the 107 mouzas over 13 gram-panchayets in Gaighata block contains arsenic above 0.01mgl(-1) and in 91 mouzas, arsenic concentration has been found above 0.05mgl(-1). About 59.2 and 40.3% of the tubewell water samples contain arsenic above 0.01 and 0.05mgl(-1), respectively. The approximate population drinking arsenic-contaminated water above 0.01 and 0.05mgl(-1) are 106,560 and 72,540, respectively. The tubewells that were installed within the depth range of 15.4-30.3m are mostly arsenic-contaminated. Even the shallow groundwater level (7.87-15.1m) is arsenic-contaminated. Both arsenic and iron concentrations in groundwater gradually increase from lower depth to higher depth up to 39.4m, and then decrease with increasing depth. About 58% of the deep tubewell water samples (depth range 122-182m, n=31) contain arsenic >=0.05mgl(-1). About 72% of the arsenic-contaminated deep tubewells (n=18) were safe when surveyed first time. But within a span of 2-5 years, they became contaminated with arsenic. The linear regression shows direct correlation between arsenic and iron concentrations in groundwater (r(2)=0.8114, p<0.0001, n=912). Intakes of inorganic arsenic from water by an adult male and female in the surveyed areas are 11.7 and 13.1MUg/kg body wt./day, respectively and these values are higher than the WHO recommended PTDI value of inorganic arsenic (2.1MUg/kg body wt./day). Mean arsenic concentrations in urine, hair and nail samples, collected from the inhabitants of Gutri mouza are higher than their normal level and the values are 292MUgl(-1) (range: 8.35-1024MUg l(-1), n=193), 2.50mgkg(-1) (range: 0.17-5.99mgkg(-1), n=132), and 6.05mgkg(-1) (range: 0.55 16.7mgkg(-1), n=116), respectively. About 83% and 68% of the urine samples (n=250) contain arsenic above 100 and 200MUgl(-1), respectively. Linear regressions show very good correlations between arsenic concentrations in water vs. urine, hair and nail samples from the inhabitants (n=103) of Gutri mouza. About 18.3% of the population (n=930) were registered with arsenical skin lesions. PMID- 20956087 TI - Effectiveness of the biological monitoring of chemical exposure in the workplace: results of a survey in an area of Northern Italy. AB - A survey of biological monitoring results from 2000 to 2008 was carried out as a part of institutional activities performed by the Workplace Prevention and Safety Service (SPSAL) of the south area of Modena district (Italy). The survey involved 18 companies employing 945 workers altogether. According to workplace exposure, routine biological monitoring had been carried out yearly or 6-monthly in private laboratories chosen by each company. Analysis of consecutive data from six plants showed fluctuating biomarker levels inconsistent with expected occupational exposure and sometimes exceeding biological exposure indices. Surveillance samplings were thus organized for comparison to be carried out in a public reference laboratory. Overall results showed systematic underestimation of marker levels by the laboratories in charge of routine biomonitoring that, together with inappropriate biomarker selection and timing of sample collection, led to insufficient and/or ineffective corrective measures. These results raise major concerns on the reliability of laboratory assessments performed for the routine biomonitoring of exposed workers. Continuous surveillance of the consistency between biological and ambient monitoring data, together with the systematic evaluation of the analytical quality of laboratory results, would be essential for a reliable assessment of health risk in the workplace. PMID- 20956088 TI - Assessment of valvular heart disease by cardiovascular magnetic resonance imaging: a review. AB - CMR is a comprehensive non-invasive tool capable of evaluating all aspects of valvular heart disease. It has advantages over echo including direct quantification of regurgitant lesions, highly accurate assessment of ventricular size and function, visualisation myocardial scar, and interrogation of extracardiac abnormalities. Although these gains can be realised with current scanning techniques, CMR's full potential has yet to be realised, and further studies of clinical outcomes are needed before CMR data can be integrated into the management algorithms for patients with significant valvular lesions. PMID- 20956089 TI - Glucose and insulin abnormalities in patients with heart failure. AB - The proportion of patients with heart failure (HF) who have diabetes is increasing. Patients with HF not known to be diabetic are at high risk of developing insulin resistance and impaired glucose tolerance, although the true prevalence and incidence are unknown. Despite the frequent co-occurrence of these conditions we have little evidence to direct prevention, screening and management of these patients, although earlier identification is advocated. This clinical update will define abnormal glucose levels and insulin resistance, review the pathophysiology, prevalence and incidence of glucose and insulin abnormalities in patients with HF, discuss prognostic implications, and make recommendations for clinical practice. PMID- 20956090 TI - Risk factors for increased in-hospital mortality: a cohort study among cardiac surgery patients. AB - BACKGROUND: Mortality is an important healthcare index for assessing the quality and the effectiveness of the provided nursing care. AIM: The aim of this study was to identify the risk factors for increased in-hospital mortality among cardiac surgery patients. METHODS: We followed up prospectively 313 consecutive patients who were admitted to the cardiac surgery intensive care unit (ICU) of a general, tertiary hospital in Athens during a 1 year period. Data collection was performed by using a short questionnaire and two instruments, the Nursing Activities Score (NAS) and the logistic EuroSCORE for assessing the nursing workload (NWL) and the perioperative risk for each patient respectively. RESULTS: Patients with a high 1st day NAS had an almost 3.3 times greater probability of death during their hospitalization (OR 3.3, 95%CI 1.4-8). Moreover, patients with increased perioperative risk (OR 4.2, 95%CI 1.50-12) and ICU length of stay (ICU LOS) (OR 16.8, 95%CI 4.8-58.6) had statistically significant higher in-hospital mortality. CONCLUSION: Increased level of NWL, patient perioperative risk and ICU LOS are closely associated with increased in-hospital mortality of cardiac surgery patients. The correlation between NWL and mortality represents the strong link of the nursing profession with the improvement of the effectiveness and quality of care. PMID- 20956092 TI - A break is not the End; insight into the damage response to DNA double strand breaks. PMID- 20956091 TI - High levels of Crohn's disease-associated anti-microbial antibodies are present and independent of colitis in chronic granulomatous disease. AB - Chronic granulomatous disease (CGD) and inflammatory bowel disease (IBD) have overlapping gastrointestinal manifestations. Serum antibodies to intestinal microbial antigens in IBD are thought to reflect a loss of tolerance in the setting of genetically encoded innate immune defects. CGD subjects studied here, with or without colitis, had considerably higher levels of ASCA IgA, ASCA IgG, anti-OmpC, anti-I2, and anti-CBir1, but absent to low pANCA, compared to IBD predictive cutoffs. Higher antibody levels were not associated with a history of colitis. Except for higher ASCA IgG in subjects <18 years, antibody levels were not age-dependent. In comparison, 7 HIES subjects expressed negative to low antibody levels to all of these antigens; none had colitis. Our results suggest that markedly elevated levels of antimicrobial antibodies in CGD do not correlate with a history of colitis but may reflect a specific defect in innate immunity in the face of chronic antigenic stimulation. PMID- 20956093 TI - Development and validation of an HPLC-MS/MS method to determine clopidogrel in human plasma. Use of incurred samples to test back-conversion. AB - Quantitative methods using LC-MS/MS allow achievement of adequate sensitivity for pharmacokinetic studies with clopidogrel; three such methods, with LLOQs as low as 5 pg/mL, were developed and fully validated according to the well established FDA 2001 guidelines. The chromatographic separations were performed on reversed phase columns Ascentis RP-Amide (15 cm x 2.1 mm, 5 MUm), Ascentis Express C8 (10 cm x 2.1 mm, 2.7 MUm) and Ascentis Express RP Amide (10 cm x 2.1 mm, 2.7 MUm), respectively. Positive electrospray ionization in MRM mode was employed for the detection and a deuterated analogue (d3-clopidogrel) was used as internal standard. Linearity, precision, extraction recovery, matrix effects and stability tests on blank plasma spiked with clopidogrel and stored in different conditions met the acceptance criteria. During the analysis of the real samples from the first pharmacokinetic study, a significant increase (>100%) of the measured clopidogrel concentrations in the extracts kept in the autosampler at 10 degrees C was observed. Investigations led to the conclusion that most probably a back conversion of one or more of the clopidogrel metabolites is occurring. The next methods were optimized in order to minimize this back-conversion. After a series of experiments, the adjustment of the sample preparation (e.g. processing at low temperature and introducing a clean-up step on Supelco HybridSPE-Precipitation cartridges) has proven to be the most effective in order to improve the stability of the extracts. Incurred samples of real subjects were successfully used in the validation of the last two analytical methods to evaluate the back-conversion, while tests using only the known metabolites could not detect this important problem. PMID- 20956094 TI - Determination of benzimidazole residues in bovine milk by ultra-high performance liquid chromatography-tandem mass spectrometry. AB - A method based on ultra-high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UHPLC-MS/MS) for the simultaneous determination of benzimidazole residues in bovine milk has been optimized and validated. Rapid chromatographic separation of 13 analytes in 8 min was obtained by means of UHPLC. The samples were subject to Oasis MCX solid-phase extraction cartridges for extraction and clean-up. Matrix-matched calibration curves were performed to compensate for the matrix effect and loss in sample preparation. Mean recoveries ranged from 80% to 101% and inter-day precision was lower than 14%. Limit of detection and limit of quantification of the method ranged from 0.01 to 0.5 MUg L-1 and from 0.1 to 1.0 MUg L-1, respectively. PMID- 20956095 TI - 2D-HPLC and MALDI-TOF/TOF analysis of barley proteins glycated during brewing. AB - The barley proteins have been the subject of interests of many research groups dealing with barley grains, malt and beer. The proteins which remain intact after harsh malting conditions influence the quality and flavor of beer. The characteristic feature of the proteins present in malt and beer is their extensive modification with carbohydrates, mainly glucose that comes from the starch degradation during technological processes. The degree of the protein glycation has an effect on the quality of malt and beer and on the properties of the beer foam. A combination of two-dimensional high performance liquid chromatography (2D-HPLC) and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF MS) was used for the analysis of the protein extracts that were reduced, alkylated, and degraded enzymatically without prior protein separation. This so-called "shot-gun" approach enabled us to determine glycation sites in one third of the proteins identified in the study and to propose potential glycation markers for fast and efficient monitoring during malting. PMID- 20956096 TI - Should diabetes be commissioned through multidisciplinary networks, rather than Practice Based Commissioning? AB - AIMS: Diabetes is recognized as a complex, long term, largely asymptomatic condition requiring self management skills, a range of health care professionals and articulated health services. Diabetes Networks have been introduced to provide guidance from people with diabetes and local health professionals with different skills to ensure that diabetes care is well organized, sustainable and delivers quality care. We have considered the role of Diabetes Networks in the English setting. METHODS: Drawing on studies of health service organization and health policy, we describe the context in which diabetes commissioning is currently occurring in England, the role of Diabetes Networks and key components for an effective Diabetes Network. RESULTS: We have identified that Diabetes Networks are not currently mandatory and discovered policy approaches that are likely to work against safe, timely, integrated approaches to diabetes services with potentially harmful impacts on people with diabetes in the future. Practice Based Commissioning, where it sidelines Diabetes Networks, is a particular concern. We have identified key components of Diabetes Networks including explicit frameworks for leadership, membership, funding, decision making, communication and action. CONCLUSIONS: Diabetes is a condition requiring collaboration between all involved. Diabetes Networks include patients and all relevant health professionals and should dictate what and how diabetes care should be commissioned within the local health economy. PMID- 20956097 TI - Anti-carcinogenic effects of sulforaphane in association with its apoptosis inducing and anti-inflammatory properties in human cervical cancer cells. AB - BACKGROUND: The multistep process of carcinogenesis is characterized by progressive disorganization and occurrence of initiation, promotion, and progression events. Several new strategies such as chemoprevention are being developed for treatment and prevention at various stages of carcinogenesis. Sulforaphane, a potential chemopreventive agent, possesses anti-proliferative, anti-inflammatory, anti-oxidant and anti-cancer activities and has attracted extensive interest for better cancer management. METHODS: We evaluated the effect of sulforaphane alone or in combination with gemcitabine on HeLa cells by cell viability assay and confirmed the results by apoptosis assay. Further we analyzed the effect of sulforaphane on the expression of Bcl-2, COX-2 and IL-1beta by RT PCR on HeLa cells. RESULTS: In the present study, sulforaphane was found to induce dose-dependent selective cytotoxicity in HeLa cells in comparison to normal cells pointing to its safe cytotoxicity profile. Additionally, a combination of sulforaphane and gemcitabine was found to increase the growth inhibition in a synergistic manner in HeLa cells compared to the individual drugs. Also, the expression analysis of genes involved in apoptosis and inflammation revealed significant downregulation of Bcl-2, COX-2 and IL-1beta upon treatment with sulforaphane. CONCLUSION: Our results suggest that sulforaphane exerts its anticancer activities via apoptosis induction and anti inflammatory properties and provides the first evidence demonstrating synergism between sulforaphane and gemcitabine which may enhance the therapeutic index of prevention and/or treatment of cervical cancer. PMID- 20956098 TI - Congenital linear porokeratosis with pseudoainhum. PMID- 20956099 TI - Amelanotic melanoma presenting as contact dermatitis. PMID- 20956100 TI - Rituximab for primary cutaneous diffuse large B-cell lymphoma-leg type. AB - Primary cutaneous diffuse large B-cell lymphoma leg type (PCDLBCL-LT) is a rare type of lymphoma, of poor prognosis, which affects elderly people. Rituximab is an anti-CD20 monoclonal antibody and has demonstrated its efficiency in the treatment of nodal lymphomas. Rituximab with polychemotherapy has been reported in PCDLBCL-LT with a good response but many adverse effects. We evaluated the risk-benefit ratio of treatment with single-agent rituximab in a retrospective study on 8 patients with PCDLBCL-LT treated with rituximab. The main evaluation clinical endpoint was the rate of objective responses to the treatment. The secondary endpoints were the adverse effects, disease-free survival and overall survival. After 4 courses of single-agent rituximab, 75% of objective responses were achieved. 100% of patients relapsed (median disease-free survival: 5.25 months, median follow-up: 17.7 months). The tolerance was excellent with one adverse event (Grade I). Rituximab monotherapy induces a rate of objective responses which is less than rituximab with polychemotherapy, with no lasting therapeutic response. The tolerance of rituximab monotherapy is higher than rituximab with polychemotherapy. The risk-benefit ratio is a bit lower but rituximab is well tolerated and may be useful for short term palliative treatment. PMID- 20956101 TI - The different psychological profiles of subjects attending melanoma screening campaigns and those delaying diagnosis: an aid for designing preventive campaigns? AB - Patient delay in seeking medical attention for melanoma (MM) constitutes one of the main challenges in designing prevention campaigns. No conclusive studies exploring psychological aspects of those patients, using standardized psychometric instruments, are currently available. We hypothesized that the attitude toward illness of subjects attending the melanoma screening day (EMD) would differ from patients diagnosed with MM following the usual clinical pathways. Five psychometric tests, assessing attitude toward illness, were administered both to EMD and MM groups, this latter further divided into two subgroups (good and bad detectors, GD and BD) considering the histo-clinical characteristics of the lesion. The Mann-Whitney U Test and Pearson Chi Square test were used to compare EMD patients with the other groups and to compare psychometric scores between GD and BD. BD and GD groups showed significant differences. Interestingly, the BD group was characterized by higher scores in Temperament and Character Inventory Fearful subscale, Multidimensional Health Locus of Control Powerful Others scale and Illness Behaviour Questionnaire General Hypochondriasis, Affective Disturbance and Irritability subscales. BD patients tend to react in a phobic manner to medical recommendations and they appear to favour external and more assertive help, which would suggest choosing a more direct approach in proposing a prevention campaign. Although this is a pilot study and further studies are needed, it gives new insight to build up more effective prevention campaigns for those patients. PMID- 20956102 TI - Papular eruption of male genitalia. PMID- 20956103 TI - Facial eruption related to snorting Ecstasy. PMID- 20956104 TI - Treatment of scleromyxedema with intravenous immunoglobulin. PMID- 20956105 TI - Biotin deficiency in dizygotic twins due to amino acid formula nutrition. PMID- 20956106 TI - Nevus lipomatosus cutaneous superficialis of the vulva. PMID- 20956107 TI - Chronic vasculitis urticaria associated to a monoclonal gammopathy of IgM and IgA type, a Schnitzler Syndrome? PMID- 20956108 TI - Extension of a malignant tailgut cyst to a subcutaneous space in the buttock. AB - Tailgut cysts are rare benign cystic lesions of the retrorectal space. The recommended treatment is complete resection because these cysts have occasionally shown malignant transformation. However, a high index of clinical suspicion is required to reach a diagnosis. We report a 68-year-old man complaining of a subcutaneous mass in his right buttock. Magnetic resonance imaging (MRI) showed a large cystic mass extending 25.7 cm from the pelvis to the buttock. Radiological features indicated a benign cystic tumor, but the level of serum carcinoembryonic antigen (CEA) (87.5 ng/mL) was increased. An incisional biopsy did not define the true histological nature of the lesion and was not useful for surgical planning. Although MRI could not detect malignant changes, the elevated serum CEA indicated malignant degeneration. The patient required a Miles operation for complete resection. Surgical pathology revealed focal areas of high-grade adenomatous and adenocarcinomatous changes in the cyst wall. After surgery, the serum CEA level decreased to below the normal range. The case presented here shows that early malignant degeneration of TGC is difficult to detect by MRI. Thus, a tailgut cyst should be completely removed, even if radiological examination cannot detect malignant features. Measurement of serum CEA may be helpful when the tumor expresses this antigen. PMID- 20956109 TI - Hyperkeratotic eczema of the nipple and areola associated with sorafenib treatment. PMID- 20956110 TI - Pseudoxanthoma elasticum: case report with arterial stiffness evaluated by a research cardiovascular profiling system. AB - Pseudoxanthoma elasticum (PXE) is an inherited systemic disorder characterized by calcification of elastic tissue, affecting the skin, the eyes and vascular system. The aim of our study was to specify the cardiovascular changes in a case of pseudoxanthoma elasticum by a non-invasive haemodynamic evaluation. We present a 50-year-old woman with a clinical diagnosis of pseudoxanthoma elasticum. Except for hypertension, treated over the past four years, there was no other modifiable cardiovascular risk factor. The patient had a familiar history of early cardiovascular death. In the physical examination, typical skin lesions were present and also an angioid streak of the retina. The patient and a control group were evaluated by the CR-2000 Research Cardiovascular Profiling System. A lower elasticity in large arteries (p = 0.006), a higher cardiac output (p = 0.006) and a higher total vascular impedance (p = 0.006) were observed with respect to the control group. There was no difference comparing this value with an elderly control group. We suggest that patients with PXE present vascular changes comparable with elderly patients and that these differences can not be explained by hypertension. PMID- 20956111 TI - Lichen ruber planus following connective tissue massage. PMID- 20956112 TI - Metastatic basal cell carcinoma and Turner syndrome: an unusual coincidence. PMID- 20956113 TI - Verrucous epidermal nevus successfully treated with photodynamic therapy. PMID- 20956114 TI - More pressure on pulmonary hypertension. PMID- 20956115 TI - Management of pulmonary arteriovenous malformations in pulmonary hypertensive patients: a pressure to embolise? PMID- 20956116 TI - Trends in pulmonary arterial hypertension. PMID- 20956117 TI - High-altitude pulmonary hypertension. AB - High-altitude pulmonary hypertension (HAPH) is a specific disease affecting populations that live at high elevations. The prevalence of HAPH among those residing at high altitudes needs to be further defined. Whereas reduction in nitric oxide production may be one mechanism for the development of HAPH, the roles of endothelin-1 and prostaglandin I2 pathways in the pathogenesis of HAPH deserve further study. Although some studies have suggested that genetic factors contribute to the pathogenesis of HAPH, data published to date are insufficient for the identification of a significant number of gene polymorphims in HAPH. The clinical presentation of HAPH is nonspecific. Exertional dyspnoea is the most common symptom and signs related to right heart failure are common in late stages of HAPH. Echocardiography is the most useful screening tool and right heart catheterisation is the gold standard for the diagnosis of HAPH. The ideal management for HAPH is migration to lower altitudes. Phosphodiesterase 5 is an attractive drug target for the treatment of HAPH. In addition, acetazolamide is a promising therapeutic agent for high-altitude pulmonary hypertension. To date, no evidence has confirmed whether endothelin-receptor antagonists have efficacy in the treatment of high-altitude pulmonary hypertension. PMID- 20956118 TI - Paediatric pulmonary hypertension: monitoring progress and identifying unmet needs. AB - Recent advances in the field of pulmonary hypertension (PH) have provided clinicians with a range of treatment options, but effective disease management in children presents a unique challenge. The present article will discuss the steps being taken to address unmet needs in paediatric PH. Understanding the epidemiology of paediatric PH is essential to guide management decisions, but such epidemiological data are scarce. The first international paediatric PH registry, Tracking Outcomes in Paediatric Pulmonary Hypertension (TOPP), promises to become a vital resource. Studies of PH therapies are rare in children, and treatment of paediatric PH is generally guided by the adult treatment algorithm, with some adaptations. However, invasive management options, such as continuous prostacyclin infusion, even if effective, are challenging in children, and further research is required to develop appropriate treatment strategies, formulations and doses for paediatric PH. Measures of treatment success must also be defined, and the applicability of end-points from adult clinical studies remains an open question. In summary, further epidemiological and treatment data are needed for paediatric pulmonary hypertension. The international TOPP registry will provide a valuable insight, but this must be complemented by research and development of adapted paediatric therapies. Dedicated childhood pulmonary hypertension services would optimise the diagnosis and management of this life threatening disease. PMID- 20956119 TI - Managing chronic thromboembolic pulmonary hypertension: pharmacological treatment options. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition in which organised thrombi obstruct the pulmonary vessels, causing increased pulmonary vascular resistance, progressive pulmonary hypertension (PH) and right heart failure. The treatment of choice is pulmonary endarterectomy, which restores pulmonary haemodynamics with acceptable periprocedural mortality rates in the majority of suitable patients. However, CTEPH may be inoperable owing to surgically inaccessible thrombi or comorbid diseases that confer an unacceptably high risk. Pharmacotherapies, although not yet approved, may be useful in this situation or for treating residual or recurrent PH following surgery. Vasodilator drugs for PH are attracting growing interest as potential treatments for CTEPH because this disease has recently been labelled as a "dual" pulmonary vascular disorder: major vessel obstruction and remodelling is combined with a small vessel arteriopathy that is histologically indistinguishable from the classical pulmonary arteriopathy observed in pulmonary arterial hypertension. Of three completed randomised controlled trials in patients with CTEPH, only one was powered to detect a treatment effect. The BENEFIT trial employed the dual endothelin-receptor antagonist bosentan. Although haemodynamics improved significantly, the second component of the primary end-point, exercise capacity, was not met. More evidence is required to resolve whether vasodilator treatments are beneficial for inoperable chronic thromboembolic pulmonary hypertension. PMID- 20956120 TI - Inhaled iloprost for the treatment of pulmonary hypertension. AB - Prostacyclin and its analogues (prostanoids) are potent vasodilators, and exhibit antithrombotic, antiproliferative and anti-inflammatory properties. Pulmonary arterial hypertension (PAH) is characterised by vasoconstriction, thrombosis and proliferation, and is associated with reduced synthesis of endogenous prostacyclin. This provides a strong rationale for the use of prostanoids to treat PAH, a concept that is now supported by more than two decades of clinical research and experience. Intravenous and subcutaneous prostanoids have clearly demonstrated efficacy in severe PAH, but adverse events related to the drug delivery system, systemic side-effects and tachyphylaxis have driven research into alternative prostanoid treatments. Iloprost is administered by inhalation, and thus avoids most of the systemic side-effects associated with i.v. or subcutaneous prostanoid infusion. Two randomised controlled 12-week trials in patients with PAH have demonstrated efficacy and a favourable safety profile for iloprost as monotherapy (the AIR trial) and in combination with oral bosentan (STEP). Open-label uncontrolled long-term studies of inhaled iloprost therapy indicate that this treatment may improve long-term outcomes in PAH. PMID- 20956121 TI - Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy. AB - The prognosis for patients with pulmonary hypertension remains poor despite recent treatment advances, and there is a need for therapies with new modes of action. Nitric oxide (NO) is an endogenous vasodilator, the levels of which are regulated throughout the lung to ensure preferential perfusion of well-ventilated regions. Drugs that act in synergy with endogenous NO would therefore promote pulmonary vasodilation while maintaining optimal gas exchange. Riociguat is an oral stimulator of the NO receptor soluble guanylate cyclase. It synergises with NO and has demonstrated vasodilatory and antiremodelling properties in preclinical studies. Riociguat has been shown to have a favourable safety profile in healthy volunteers and in patients with pulmonary hypertension. Pharmacokinetic analyses have revealed substantial interindividual variation, suggesting that individual dose titration will be required. In a proof-of-concept study of patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension, riociguat improved cardiopulmonary haemodynamics from baseline. It also caused systemic vasodilation, which was well tolerated but should be monitored in future studies. Dose titration of riociguat should promote pulmonary vasodilation while maintaining control of systemic effects, and has been investigated in a phase-II study of patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Preliminary results indicate that phase-III trials are warranted. PMID- 20956122 TI - Fatal rupture of pulmonary arteriovenous malformation in hereditary haemorrhagic telangiectasis and severe PAH. AB - A 29-yr-old patient with hereditary haemorrhagic telangiectasia was referred to the present authors' centre with progressive exertional dyspnoea. Pulmonary arterial hypertension (PAH) was suspected on Doppler echocardiography and confirmed by right heart catheterisation demonstrating severe PAH. Genetic analysis found an activin receptor-like kinase-1 gene missense mutation. Chest radiography and computed tomodensitometry of the chest revealed a pulmonary arteriovenous malformation with a 5-mm diameter feeding artery in the right lower lobe. Embolisation of the arteriovenous malformation was discussed, but was considered a very high-risk procedure that could aggravate PAH and was therefore not performed. Haemodynamics were improved by dual endothelin receptor antagonist and inhaled iloprost but the patient subsequently died suddenly of a rupture of the arteriovenous malformation into the pleural cavity. Severe PAH is generally considered a contraindication to performing pulmonary arteriovenous malformation embolisation because of the risk of worsening of PAH. However, given the significant risk of rupture, paradoxical embolism and haemoptysis, and the lack of data regarding the evolution of pulmonary pressure after embolisation in PAH, pulmonary arteriovenous malformation embolisation should not be absolutely contraindicated and might be considered in patients with stable PAH. PMID- 20956123 TI - Pulmonary necrobiotic nodules: a rare extraintestinal manifestation of Crohn's disease. AB - The present article reports the case of a 22-yr-old female with new onset Crohn's colitis, anterior uveitis and multiple pulmonary nodules which, on histological examination, were necrobiotic nodules. This is a rare but recognised pulmonary extraintestinal manifestation of Crohn's disease and only the fourth reported case. The present case report is followed by a brief review of the relevant literature. PMID- 20956124 TI - Biologics in severe difficult-to-treat asthma: find the right niche! PMID- 20956125 TI - Activity limitation: a major consequence of dyspnoea in COPD. PMID- 20956126 TI - Update on severe asthma: what we know and what we need. PMID- 20956127 TI - A physiological model of patient-reported breathlessness during daily activities in COPD. AB - Breathlessness during daily activities has a significant impact on quality of life in chronic obstructive pulmonary disease. Herein, we present a physiological model of patient-reported breathlessness based on the relationship between ventilatory load, respiratory muscle capacity, neural respiratory drive and neuromechanical dissociation during daily activities. This model should facilitate an understanding of the mechanisms driving increased intensity of breathlessness during daily activities and the relief of breathlessness following medical or surgical interventions. The model should also provide a structure on which to base the development of patient-reported outcome instruments to measure the severity of breathlessness during daily activities in chronic obstructive pulmonary disease. PMID- 20956128 TI - Update on the roles of distal airways in asthma. AB - The present review is the summary of an expert workshop that took place in Vence (France) in 2007 on the role of distal airways in asthma. The evidence showing inflammation and remodelling in distal airways, and their possible involvement in asthma control and natural history, was reviewed. The usefulness and limitations of various techniques used for assessing distal airways were also evaluated, including pulmonary function tests and imaging. Finally, the available data studying the benefit of treatment better targeting distal airways in asthma was examined. It was concluded that both proximal and distal airways were involved in asthma and that distal airways were the major determinant of airflow obstruction. Inflammation in distal airways appeared more intense in severe and uncontrolled asthma. Distal airways were poorly attained by conventional aerosol of asthma medications owing to their granulometry, being composed of 3-5 MUm particles. Both proximal and distal airways might be targeted either by delivering medications systemically or by aerosol of extra-fine particles. Extra fine aerosols of long-acting beta-agonists, inhaled corticosteroids or inhaled corticosteroid/long-acting beta-agonist combinations have been shown in short term studies to be not inferior to non-extra-fine aerosols of comparators. However, available studies have not yet demonstrated that extra-fine inhaled medications offer increased benefit compared with usual aerosols in asthmatic patients. PMID- 20956129 TI - Biomarkers in the management of COPD. AB - Chronic obstructive pulmonary disease (COPD) is still a leading cause of morbidity and mortality worldwide, with a huge socioeconomic impact. New strategies for the management of COPD are required, not only for identifying the origin of the exacerbation episodes, but also to assess an individual risk for each patient. A promising approach is to measure systemic biomarkers and correlate their levels with exacerbation characteristics and clinical prognosis of the disease. Several biomarkers have clearly correlated with the aetiology of lower respiratory tract infections and the response to antibiotic treatment, indicating a potential utility in COPD exacerbation. Nevertheless, the results available at the moment, together with the absence of a gold standard for identifying the aetiological origin of an exacerbation, impedes establishing the real utility of these biomarkers for this concrete task. Regarding the clinical evolution and prognosis, several clinical characteristics have been correlated to biomarker levels. The potential influence of many factors (severity of the disease, presence of comorbidities and treatment) leads to the conclusion that, in the future, the best option would be to monitor levels individually, rather than establishing cut-off points for the general COPD population. PMID- 20956130 TI - Prevalence of asthma control among adults in France, Germany, Italy, Spain and the UK. AB - The objectives of this article were to estimate the prevalence of asthma control and describe the characteristics of at least well-controlled (ALWC) versus not well-controlled (NWC) asthmatics. Data were obtained from the European National Health and Wellness Survey, an internet-based, cross-sectional study of 37,476 adults in France, Germany, Italy, Spain and the UK. Analysis was limited to 2,337 respondents who self-reported a physician diagnosis. Based on the Asthma Control Test (ACT), respondents were grouped as ALWC (ACT >=20) and NWC (ACT <=19). The prevalence of diagnosed asthma across five countries was estimated to be 5.8% (14 million extrapolated for the European Union population). Of these, 50.4% (7.1 million) were NWC. Compared with ALWC, NWC were older (15.8 versus 15.0%; p<0.001), less likely to be college educated (28.7 versus 36.3%; p<0.001) and more likely to be obese (30.0 versus 22.7%; p<0.001), experience depression (28.0 versus 18.7%; p<0.001) and smoke (34.7 versus 25.0%; p<0.001). The NWC had more occasions of contact with healthcare providers and were more likely to use controller and rescue medications, but with less adherence. A substantial portion of asthmatics are NWC. However, the proportion of NWC asthmatics found in this study was less than in previously reported. Patients and physicians need to be educated on the importance of asthma control and adherence to treatments. PMID- 20956131 TI - Pulmonary arterial hypertension in a patient with stage II sarcoidosis and Hashitoxicosis. AB - Although pulmonary arterial hypertension is usually associated with advanced stages of sarcoidosis, its occurrence in early stage disease is rare. Herein, a case of associated pulmonary arterial hypertension in the setting of Hashitoxicosis and stage II pulmonary sarcoidosis is reported. The case of associated pulmonary arterial hypertension occurred in a young female without clinically significant medical history and who completely recovered after receiving oral corticotherapy only. Furthermore, this case report suggests the presence of an interaction between pulmonary arterial hypertension, sarcoidosis and Hashitoxicosis. PMID- 20956132 TI - Acute exacerbation of idiopathic pulmonary fibrosis as the initial presentation of the disease. AB - The clinical course of patients with idiopathic pulmonary fibrosis (IPF) is generally marked by a decline in pulmonary function over time, although recently there is increasing recognition that fatal deterioration from acute exacerbation can occur at any stage. The patient described in the present case study was a 65 yr-old male who presented with exertional dyspnoea and fever of 2 weeks' duration. He had no history of chronic lung disease or physiological or radiological hallmarks of pre-existing disease. He underwent surgical lung biopsy and the histological examination showed a background pattern of usual interstitial pneumonia (UIP) with a pattern of focal acute diffuse alveolar damage (DAD) in the area where normal lung architecture was preserved. It is notable that the pathological diagnosis of this rapidly progressive interstitial pneumonia was DAD on UIP, which is typically seen in acute exacerbations of IPF. Unusual findings on high-resolution computed tomography scan were also noted. We presume that in this case acute exacerbation developed in the very early course of IPF. Given the possibility that similar cases may have arisen among patients diagnosed with acute interstitial pneumonia or acute respiratory distress syndrome, the histopathology of rapidly progressive interstitial pneumonia may need to be revisited. PMID- 20956133 TI - Combining evidence and experience in pulmonary hypertension. PMID- 20956134 TI - Update on acute pulmonary embolism. PMID- 20956135 TI - The use of combination therapy in pulmonary arterial hypertension: new developments. AB - There is a strong clinical rationale for combination therapy in pulmonary arterial hypertension (PAH), as several pathological pathways have been implicated in its pathogenesis and no single agent has yet been shown to deliver completely satisfactory results. Registry data indicate that use of combination therapy is in fact common in existing clinical practice, even though support has been largely empirical or derived from small-scale observational studies. Data from large, adequately powered, randomised controlled trials of combination therapy in PAH are now emerging and suggest that combination therapy may be clinically beneficial. Studies of bosentan in combination with prostanoids and phosphodiesterase (PDE)-5 inhibitors show consistent evidence of improvements in exercise capacity compared with placebo. Similar improvements have been observed with PDE-5 inhibitors in combination with prostanoids. The appropriate timing of combination therapy requires further evaluation but goal-oriented therapy using combinations of oral and inhaled drugs has been shown to provide acceptable long term results in patients with advanced PAH. Monitoring should be performed regularly and be based on repeatable, noninvasive, measurable parameters that have prognostic value. PMID- 20956136 TI - Pulmonary arterial hypertension in paediatric and adult patients with congenital heart disease. AB - Pulmonary arterial hypertension (PAH) commonly arises in patients with congenital heart disease (CHD). Greater numbers of patients with PAH associated with CHD (PAH-CHD) are now surviving into adulthood, many with increasingly complex cardiac defects. Patients with cardiac defects which result in left-to-right shunting are at risk of developing PAH, owing to the increased shear stress and circumferential stretch induced by increased pulmonary blood flow, which leads to endothelial dysfunction and progressive vascular remodelling and, thus, increased pulmonary vascular resistance. Although PAH-CHD shares similar lung histology with idiopathic PAH, differences do exist between these aetiologies. Management of PAH-CHD can involve surgical correction of the cardiac defect and/or treatment of the PAH, depending on the underlying cardiac defect and status of disease progression. Transplantation surgery can be curative but is not without limitations. The timing of intervention in patients with PAH-CHD is important, but the optimums are sometimes difficult to define, with limited robust data to inform management decisions. Uncontrolled studies suggest that prostacyclin analogues and phosphodiesterase type-5 inhibitors may have benefits in advanced pulmonary vascular disease. In the only randomised controlled trial dedicated to end-stage PAH-CHD, bosentan significantly reduced pulmonary vascular resistance and significantly increased 6-minute walk distance without compromising peripheral oxygen saturation, in patients with Eisenmenger syndrome. These data suggest that targeted therapies are beneficial in the PAH-CHD population, and warrant further research. PMID- 20956137 TI - Screening for pulmonary arterial hypertension in systemic sclerosis. AB - The onset and progression of pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc) can be particularly aggressive; however, effective treatments are available. Therefore, early identification of patients with suspected PAH, confirmation of diagnosis, and intervention is essential. PAH may be challenging to diagnose in its earliest stages, particularly in populations that have multiple causes of breathlessness, and, therefore, screening is required. The optimal screening tools and methodology are, as yet, unknown, and this is confounded by a lack of consensus over which patients to screen. Current practice favours annual screening of all SSc patients using Doppler echocardiography to detect elevated right heart pressures. This will typically identify most patients with the various forms of pulmonary hypertension found in SSc. The optimum thresholds for Doppler echocardiography are still subject to investigation, especially for patients with mild pulmonary hypertension, and this technique may, therefore, yield a significant number of false-positives and a currently unknown number of false-negatives. Confirmatory right heart catheterisation remains necessary in all suspected cases. Further research is needed to identify the optimal tools and the screening approach with greatest specificity and selectivity. PMID- 20956138 TI - Chronic thromboembolic pulmonary hypertension as a cause of dyspnoea in an older patient with a complex history. AB - A full diagnostic work-up for patients with pulmonary hypertension (PH) is vital. Classification and diagnosis of the underlying cause is important to ensure optimal management, but may be complicated by overlapping signs and symptoms. This case study describes how a full work-up identified chronic thromboembolic PH (CTEPH) as the cause of dyspnoea in a 68-yr-old male with a history of pulmonary embolism and an original diagnosis of chronic obstructive pulmonary disease. Key indicators included decreased tricuspid annular plane systolic excursion, increased Tei index and elevated systolic pulmonary artery pressure. Multi-slice spiral chest computed tomography and pulmonary angiography showed severe chronic thromboembolic pulmonary disease, both centrally and distally. Diffusing capacity of the lung for carbon monoxide was reduced and blood gas analysis revealed a wide alveolar-arterial oxygen pressure difference, which is typical of CTEPH. The patient was eligible for pulmonary endarterectomy according to established criteria. Residual PH after surgery was successfully managed with bosentan. PMID- 20956139 TI - Unusual presentation for a patent ductus arteriosus. AB - A 63-yr-old black female, with a 1-yr history of hepatitis C and ascites was referred to an expert centre with suspicion of portopulmonary hypertension (PPHTN). Her poor condition made a rapid diagnosis imperative and precluded a normal diagnostic work-up. Echocardiography confirmed severe pulmonary hypertension (PH). A hepatic scintigraphy and an abdominal echo-Doppler study excluded liver cirrhosis and portal hypertension. Cardiac magnetic resonance imaging showed marked dilation of the right ventricle with significant hypertrophy of the free wall, a finding that is uncommon in idiopathic pulmonary arterial hypertension or PPHTN. Right heart catheterisation demonstrated severe pre-capillary PH without response to acute vasodilator testing. Finally the patient underwent computed tomography angiography, which showed marked dilation of the pulmonary artery without thromboembolic disease and, unexpectedly, a partially calcified large patent ductus arteriosus. The correct diagnosis of the underlying cause of pulmonary arterial hypertension is essential. Patients with underlying heart defects may have an atypical presentation and be referred to expert centres with an incorrect diagnosis. A full investigation is necessary; careful examination of right ventricular anatomy can provide clues about the aetiology of PH, and it is important to exclude intra- and extracardiac shunts during haemodynamic studies. PMID- 20956140 TI - Pulmonary veno-occlusive disease misdiagnosed as idiopathic pulmonary arterial hypertension. AB - A 27-yr-old female with a 6-month diagnosis of idiopathic pulmonary arterial hypertension (PAH) confirmed elsewhere was referred to our centre with worsening dyspnoea. On examination, the patient had low systemic oxygen saturation despite high oxygen flow and reduced exercise capacity. Haemodynamics were indicative of severe pre-capillary PAH. High-resolution computed tomography revealed diffuse ground-glass opacity with thickening interlobular septa, and haemosiderin-laden macrophages were identified by bronchoalveolar lavage. Based on clinical and diagnostic findings, the patient was re-diagnosed with pulmonary veno-occlusive disease (PVOD). Treatment with high-dose diuretics and the endothelin-receptor antagonist bosentan improved the patient's exercise capacity, haemodynamics and quality of life. However, 1 yr later there was a progressive, slow deterioration in the patient's functional capacity and oxygen saturation, and inhaled prostanoid and oxygen therapy were initiated. Despite some subjective improvements, the patient's haemodynamics and oxygen saturation continued to decline and she underwent lung transplantation. This case emphasises that PVOD is an under-recognised and often misdiagnosed form of pulmonary hypertension. Therefore, accurate diagnosis of PVOD requires comprehensive clinical and diagnostic work-up. While lung transplantation remains the treatment of choice for patients with PVOD, targeted therapies for PAH in addition to high doses of diuretics merit evaluation. PMID- 20956141 TI - Fatal dissection of the pulmonary artery in pulmonary arterial hypertension. AB - A 41-yr-old patient with chronic stable idiopathic pulmonary arterial hypertension (PAH) presented with sudden chest pain and unusual dyspnoea during physical exertion. The patient had been diagnosed with PAH at the age of 12 yrs and was in New York Heart Association functional class I/II. The patient was being treated with an anticoagulant regimen, low-dose diuretics and continuous intravenous epoprostenol therapy. A computed tomography scan showed ancient massive thrombi in dilated central pulmonary arteries, which were not haemodynamically significant (perfusion lung scans did not demonstrate segmental or larger defects), and extensive dissection of the right pulmonary artery starting from the intermediate branch. Due to the extensiveness of the dissection, the patient was immediately considered for heart-lung transplantation, but died 72 h after the onset of symptoms. Permission for post mortem examination was denied. Pulmonary artery dissection should be suspected in PAH patients presenting with chest pain and worsening dyspnoea. In the current case, the factors possibly associated with increased risk for dissection may include dilatation of the pulmonary artery, local inflammation favoured by in situ thrombosis, and acute increase of pulmonary pressure secondary to physical exertion. Extensive pulmonary artery dissection is a life threatening complication of PAH, and urgent heart/lung transplantation might be the treatment of choice in eligible patients. In addition, better identification of the risk factors for pulmonary artery dissection may help in considering transplantation for selected patients at risk. PMID- 20956142 TI - Inflammatory pseudotumoural endotracheal mucormycosis with cartilage damage. AB - Mucormycosis is a rare opportunistic infection usually associated with immunosuppression, diabetes mellitus or haematological malignancy. Herein, we report an unusual case of mucormycosis in a 46-yr-old male patient with diabetes presenting with an endotracheal mass obstructing the trachea and cartilage damage. Histological examination of the bronchoscopy biopsy specimens revealed invasive mucormycosis. The patient was treated with intravenous amphotericin B followed by removal of the lesion via bronchoscopy. PMID- 20956143 TI - Near-fatal haemorrhage from pulmonary arteriovenous malformation in HHT with increased cardiac output. PMID- 20956144 TI - Multidrug- and extensively drug-resistant tuberculosis: an emerging threat. PMID- 20956145 TI - Recent advances in COPD: pathophysiology, respiratory physiology and clinical aspects, including comorbidities. PMID- 20956146 TI - Epidemiology of COPD. AB - Chronic obstructive pulmonary disease (COPD) is responsible for early mortality, high death rates and significant cost to health systems. The projection for 2020 indicates that COPD will be the third leading cause of death worldwide (from sixth in 1990) and fifth leading cause of years lost through early mortality or handicap (disability-adjusted life years) (12th in 1990). Active smoking remains the main risk factor, but other factors are becoming better known, such as occupational factors, infections and the role of air pollution. Prevalence of COPD varies according to country, age and sex. This disease is also associated with significant comorbidities. COPD is a disorder that includes various phenotypes, the continuum of which remains under debate. The major challenge in the coming years will be to prevent onset of smoking along with early detection of the disease in the general population. PMID- 20956147 TI - Pharmacological actions of statins: potential utility in COPD. AB - Chronic obstructive pulmonary disease (COPD) is characterised by minimally reversible airflow limitation and features of systemic inflammation. Current therapies for COPD have been shown to reduce symptoms and infective exacerbations and to improve quality of life. However, these drugs have little effect on the natural history of the disease (progressive decline in lung function and exercise tolerance) and do not improve mortality. The anti-inflammatory effects of statins on both pulmonary and systemic inflammation through inhibition of guanosine triphosphatase and nuclear factor-kappaB mediated activation of inflammatory and matrix remodelling pathways could have substantial benefits in patients with COPD due to the following. 1) Inhibition of cytokine production (tumour necrosis factor-alpha, interleukin (IL)-6 and IL-8) and neutrophil infiltration into the lung; 2) inhibition of the fibrotic activity in the lung leading to small airways fibrosis and irreversible airflow limitation; 3) antioxidant and anti inflammatory (IL-6 mediated) effects on skeletal muscle; 4) reduced inflammatory response to pulmonary infection; and 5) inhibition of the development (or reversal) of epithelial-mesenchymal transition, a precursor event to lung cancer. This review examines the pleiotropic pharmacological action of statins which inhibit key inflammatory and remodelling pathways in COPD and concludes that statins have considerable potential as adjunct therapy in COPD. PMID- 20956148 TI - Gastro-oesophageal reflux disease and non-asthma lung disease. AB - Gastro-oesophageal reflux disease (GERD) is a common disorder in Western countries, and its relationship to airways disorders (e.g. asthma) has been well established. Lung diseases other than asthma have also been associated with GERD, but the nature and scope of this relationship has not been fully defined. Diseases that have been associated with GERD include bronchiolitis syndromes, idiopathic pulmonary fibrosis, scleroderma and nontubercular mycobacterial infection. Diagnostic evaluation centres upon proving both reflux and pulmonary aspiration, which may be accomplished in some cases by lung biopsy. However, in many cases a compatible clinical and radiographic picture coupled with proof of proximal reflux by combined oesophageal probe testing may suffice for a provisional diagnosis and allow institution of anti-reflux measures. Proton-pump inhibitors are the medications of choice for GERD; other interventions shown to reduce reflux are weight loss, elevation of the head of the bed and avoidance of recumbency after meals. However, acid suppression therapy does not address non acid reflux that may be important in disease pathogenesis in select patients, and lifestyle modifications often fail. Laparoscopic fundoplication is the procedure of choice for medically refractory GERD with excellent short-term results with respect to respiratory symptoms associated with GERD; however, long-term studies document a significant percentage of patients requiring ongoing acid suppression therapy. PMID- 20956149 TI - Mechanisms controlling the volume of pleural fluid and extravascular lung water. AB - Pleural and interstitial lung fluid volumes are strictly controlled and maintained at the minimum thanks to the ability of lymphatics to match the increase in filtration rate. In the pleural cavity, fluid accumulation is easily accommodated by retraction of lung and chest wall (high compliance of the pleural space); the increase of lymph flow per unit increase in pleural fluid volume is high due to the great extension of the parietal lymphatic. However, for the lung interstitium, the increase in lymph flow to match increased filtration does not need to be so great. In fact, increased filtration only causes a minor increase in extravascular water volume (<10%) due to a marked increase in interstitial pulmonary pressure (low compliance of the extracellular matrix) which, in turn, buffers further filtration. Accordingly, a less extended lymphatic network is needed. The efficiency of lymphatic control is achieved through a high lymphatic conductance in the pleural fluid and through a low interstitial compliance for the lung interstitium. Fluid volume in both compartments is so strictly controlled that it is difficult to detect initial deviations from the physiological state; thus, a great physiological advantage turns to be a disadvantage on a clinical basis as it prevents an early diagnosis of developing disease. PMID- 20956150 TI - Long-term outcome in pulmonary arterial hypertension: a plea for earlier parenteral prostacyclin therapy. AB - The present review aims to examine the effect of specific drugs on long-term outcome of pulmonary arterial hypertension (PAH), to critically review the available data, and to derive useful information for daily patient care. PAH is an intrinsic disease of the pulmonary circulation with a malignant evolution as a consequence of progressive right heart failure. Without specific therapy, median survival is only 2.8 yrs. The intravenous prostacyclin analogue epoprostenol is the only treatment with a demonstrated effect on survival, observed during a single 12-week randomised placebo-controlled trial. Three long term observational studies have also shown that median survival is raised above 6 yrs with this therapy. Subcutaneous treprostinil appears to have similar beneficial effects on survival, as reported in two long-term observational studies. This is not the case for inhaled iloprost, as shown in one study in which a high proportion of patients needed the addition of, or the switch to, another therapy. Among the oral agents, long-term data have only been published for bosentan. The three studies including patients from expert centres also showed very good survival data, but again with a broad use of combination therapy. In less expert hands, with limited access to more complex therapies, reported survival seems much worse. In these studies, baseline New York Heart Association class and 6-min walk distance are repeatedly shown to be important predictors of survival. Finally, there is emerging data that prostanoid therapy results in a tendency to normalise C-reactive protein levels, a factor associated with improved long-term outcomes. PMID- 20956151 TI - The endothelin system in pulmonary and renal vasculopathy: les liaisons dangereuses. AB - Endothelial cells regulate vascular tone largely by the actions of endothelin-1. Endothelin-1 is a potent vasoconstrictor, with effects that are dependent on the receptors to which it binds as well as their location. Endothelin-1 dysregulation is implicated in pathological conditions, including those of the pulmonary vasculature and the kidney. In this review, we describe the physiology and actions of endothelin-1 in lung and renal tissues and discuss therapies that disrupt these interactions in disease states. We provide an overview of the current clinical progress of these targeted agents and provide perspectives on the treatment of pulmonary and renal diseases with endothelin receptor antagonists. PMID- 20956152 TI - Implementing the ESC/ERS pulmonary hypertension guidelines: real-life cases from a national referral centre. AB - Pulmonary hypertension (PH) comprises a heterogeneous group of disorders characterised by increased pulmonary vascular resistance that results in progressive right ventricular failure. In order to translate current evidence into routine clinical practice, the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) have recently jointly proposed evidence-based guidelines for the optimal management of different PH patient groups. This article describes a series of clinical cases of PH due to various aetiologies that were referred to a large national PH expert referral centre. In each case, the assessment and therapeutic approach undertaken is described in the context of the new ECS/ERS guidelines. The routine diagnostic work-up of suspected idiopathic pulmonary arterial hypertension (PAH) and recommended treatments for patients with functional class II, III and IV disease is emphasised. Familial screening and management of heritable PAH is discussed. Appropriate investigation and therapeutic strategies for patients with chronic thromboembolic disease and PH that is associated with congenital heart disease, pulmonary veno-occlusive disease and systemic sclerosis are also highlighted. PMID- 20956153 TI - Disseminated multiorgan MDR-TB resistant to virtually all first-line drugs. AB - The emergence of multidrug-resistant tuberculosis (MDR-TB) is a major global concern since, despite a complex treatment regime, it still remains a lethal threat. A 21-yr-old male HIV-negative migrant from Burma presented with a disseminated tuberculosis affecting the lung, spleen, liver, mediastinal and abdominal lymph nodes. This particular strain of Mycobacterium tuberculosis proved to be resistant to all but one (pyrazinamide) of the first-line drugs, i.e. rifampicin, isoniazid and ethambutol, plus streptomycin, rifabutin and ofloxacin. On the mere account of its susceptibility concerning kanamycin it could not be labelled as extensively drug-resistant tuberculosis. After 1month of a standard first-line four-drug regimen and a subsequent 4months of second-line treatment with amikacin, moxifloxacin, terizidone, protionamide, linezolid and pyrazinamide, sputum cultures eventually yielded constantly negative results. Likewise, the organ manifestations decreased significantly, so as to be virtually undetectable in computed tomography scans after 1yr of continuous treatment. A moderate pancytopenia reversed completely after dose adjustment of linezolid. Disseminated tuberculosis manifestations without typical pulmonary cavernous lesions are likely to represent primary infection rather than reactivation. Even a multiorgan disseminated MDR-TB with an extensive resistance pattern (including fluoroquinolones) can be successfully treated with an individual second-line treatment and result in considerably few adverse events. PMID- 20956154 TI - Paradoxical reactions in non-HIV tuberculosis presenting as endobronchial obstruction. AB - Paradoxical reaction (PR) in tuberculosis (TB) is common and may affect up to 25% of patients. PR has the potential to cause significant morbidity and, on occasion, death. Although PR has been recognised for some time, the pathophysiology, especially in HIV-negative patients, is not well understood. We present two cases of PR in HIV-negative patients with TB presenting as significant airway obstruction secondary to a florid endobronchial component. These cases demonstrate that PR should be considered in all patients presenting with airway symptoms who have started TB treatment. The outcomes of the cases illustrate the need for wider recognition of this condition and more research to characterise patients who may be at risk, in order to gain a greater understanding of the mechanisms involved and to make or predict this diagnosis earlier. PMID- 20956155 TI - Disseminated nontuberculous infections with Mycobacterium genavense during sarcoidosis. AB - Sarcoidosis is a chronic disease characterised by the development and accumulation of granulomas in multiple organs. We report two observations of disseminated Mycobacterium genavense infection in patients with proven sarcoidosis. High fever and abdominal pain appeared at 8 and 18 months following the initiation of immunosuppressive therapy. Abdominal computed tomography scans of the patients showed diffuse mesenteric lymphadenitis and splenomegaly. The diagnosis was obtained on bone marrow specimens for both patients with numerous acid-fast bacteria at direct examination and positive specific mycobacterial identification by nucleic acid amplification test. Despite prompt antimycobacterial therapy, occurrence of complications (peritonitis post splenectomy surgery and lung carcinoma) resulted in a fatal outcome for both patients. These cases highlight that opportunistic infections like M. genavense or other nontuberculous mycobacterial infections should be considered for long standing immunocompromised patients with sarcoidosis. PMID- 20956156 TI - An unusual cause of haemoptysis in a patient with asthma. PMID- 20956159 TI - Lighter than air: heliox breathing improves exercise tolerance in COPD. PMID- 20956160 TI - Treatment of right heart failure on pulmonary arterial hypertension: is going left a step in the right direction? PMID- 20956161 TI - Treatment of COPD: from pharmacological to instrumental therapies. PMID- 20956162 TI - Exercise training and pulmonary rehabilitation: new insights and remaining challenges. AB - Pulmonary rehabilitation is now regarded as an evidence-based treatment for symptomatic patients with chronic obstructive pulmonary disease. It has been shown to enhance exercise tolerance, improve symptoms and health-related quality of life, and reduce exacerbations in patients with recurrent exacerbations. In this article we review the mechanisms through which exercise training results in beneficial effects. We also review three challenges that currently remain: 1) the fine tuning of exercise training and multidisciplinary programmes; 2) the timing of rehabilitation; and 3) efforts to enhance the accessibility and adherence to pulmonary rehabilitation programmes. Further research is needed in order to apply the now well-established principles of pulmonary rehabilitation to unusual patient populations, or patient populations that are unlikely to participate in conventional outpatient programmes. PMID- 20956163 TI - Heliox, dyspnoea and exercise in COPD. AB - One of the most important determinants of physical and mental well-being of people with chronic obstructive pulmonary disease (COPD) is participation in physical activity. The ability to alter the sensation of dyspnoea during exercise may improve both exercise duration and intensity. Despite the low density, inert nature, strong safety profile and multiple applications of helium gas, the potential benefit of helium-oxygen gas mixtures as an adjunct therapy to modify disease symptoms and exercise capabilities in obstructive lung diseases has only recently been explored. This is a systematic review of the available peer reviewed evidence exploring whether symptom modification (perceived levels of dyspnoea) and exercise performance in COPD (either intensity or duration of work) are modified by inhalation of Heliox. Eight experimental studies met inclusion for this review. A variety of methodologies and outcome variables were used negating meta-analysis and hampering direct comparison between interventions. Overall, there was high level of evidence with a low risk of bias supporting Heliox's effectiveness in improving the intensity and endurance of exercise when compared to room air for people with COPD. Little conclusive evidence was found to determine whether Heliox altered the sensation of dyspnoea during exercise. PMID- 20956164 TI - Noninvasive positive pressure ventilation in acute asthmatic attack. AB - Asthma is characterised by reversible airway obstruction. In most patients, control of disease activity is easily achieved. However, in a small minority, asthma may be fatal. Between the two extremes lie patients with severe asthmatic attacks, refractory to standard treatment. These patients are at an increased risk of recurrent severe attacks, with respiratory failure, and mechanical ventilation. Invasive mechanical ventilation of the asthmatic patient is associated with a higher risk of complications and, therefore, is a measure of last resort. Noninvasive positive pressure ventilation (NPPV) is another treatment modality that may be beneficial in patients with severe asthmatic attack who are at an increased risk of developing respiratory failure. These patients have the potential to benefit from early respiratory support in the form of NPPV. However, reports of NPPV in asthmatic patients are scarce, and its usage in asthmatic attacks is, therefore, still controversial. Only a few reports of NPPV in asthma have been published over the last decade. These studies mostly involve small numbers of patients and those who have problematic methodology. In this article we review the available evidence for NPPV in asthma and try to formulate our recommendations for NPPV application in asthma based on the available evidence and reports. PMID- 20956165 TI - Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma. AB - Asthma is a complex, persistent, inflammatory disease characterised by airway hyperresponsiveness in association with airway inflammation. Studies suggest that regular use of high-dose inhaled corticosteroids and long-acting bronchodilators or omalizumab (a humanised monoclonal antibody that binds to immunoglobulin E and is often used as next-step therapy) may not be sufficient to provide asthma control in all patients, highlighting an important unmet need. Interleukin-4, interleukin-13, and the signal transducer and activator of transcription factor-6 are key components in the development of airway inflammation, mucus production, and airway hyperresponsiveness in asthma. Biological compounds targeting these molecules may provide a new therapeutic modality for patients with uncontrolled severe asthma. The purpose of this review is to summarise current studies of compounds targeting the interleukin-4/interleukin-13 pathway and to provide a rationale for the development of such compounds for this use. PMID- 20956166 TI - Diagnostic testing to guide the management of chronic thromboembolic pulmonary hypertension: state of the art. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening and debilitating disease affecting up to 5% of survivors of pulmonary embolism. Diagnostic testing is important to distinguish it from other forms of pulmonary hypertension and to assess the feasibility of pulmonary endarterectomy. This review provides an up-to-date perspective on the diagnosis and assessment of the disease. Patients with CTEPH often have a history of pulmonary embolism, deep vein thrombosis, thrombophilia, splenectomy, ventriculo-atrial shunt, inflammatory bowel disease or malignancy. Chest radiography may reveal pulmonary infarcts. CTEPH is often diagnosed as a wedge-shaped perfusion defect with normal ventilation scan during ventilation-perfusion scintigraphy, but multi-slice computed tomography angiography may be needed for differential diagnosis. Right heart catheterisation is required for diagnostic confirmation. Suitability for surgery is assessed by evaluating the number of obstructed vessels which could be disobliterated in the context of the pulmonary vascular resistance. Pulmonary vascular resistance that is out of proportion to evident obstructions is indicative of distal disease. Conventional pulmonary angiography, multi-slice computed tomography angiography and, potentially, magnetic resonance imaging can aid the decision to operate, but risk stratification systems are needed. In conclusion, CTEPH can be cured surgically, providing that patients are diagnosed and assessed using the appropriate techniques. PMID- 20956167 TI - Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: pathophysiology. AB - Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are two of the key subgroups of pulmonary hypertension. They are characterised by different risk factors. PAH can be associated with mutations in the gene encoding bone morphogenetic protein receptor type II (BMPR2), HIV infection, congenital heart disease, connective tissue disease (such as systemic sclerosis), and exposure to particular drugs and toxins including fenfluramine derivatives. In contrast, CTEPH can be associated with anti-phospholipid antibodies, splenectomy and the presence of a ventriculo-atrial shunt or an infected pacemaker. The first-line therapies used to treat PAH and CTEPH also differ. While medical therapy tends to be used for patients with PAH, pulmonary endarterectomy is the treatment of choice for patients with CTEPH. However, there are possible common mechanisms behind the two diseases, including endothelial cell dysfunction and distal pulmonary artery remodelling. Further research into these similarities is needed to assist the development of targeted pharmacological therapies for patients with inoperable CTEPH and patients who have persistent pulmonary hypertension after endarterectomy. PMID- 20956168 TI - Surgical and post-operative treatment of chronic thromboembolic pulmonary hypertension. AB - Patients with chronic thromboembolic pulmonary hypertension (CTEPH) have fibrous obstructions in their proximal pulmonary arteries, as well as a variable degree of secondary vascular remodelling of distal, surgically inaccessible, small pulmonary vessels. Pulmonary endarterectomy (PEA) is currently the only potentially curative treatment option for CTEPH, although it is not known whether it has a beneficial effect on established secondary remodelling. Medical pre treatment with therapies specific for pulmonary hypertension is often used as a bridge to PEA. The aim of PEA is the mechanical removal of the proximal fibrous pulmonary artery obstruction as completely as possible while avoiding vascular injury within the lung. The challenge is to find and follow the correct pulmonary artery endarterectomy plane in the time allowed during brief periods of circulatory arrest. Learning the operative technique is a complex process and, thus, early mortality after PEA decreases with increasing levels of surgical training and experience. Most patients experience lasting symptomatic and haemodynamic improvements after PEA, with only 10-20% having persistent or recurrent pulmonary hypertension after surgery. PMID- 20956169 TI - Riociguat: an upcoming therapy in chronic thromboembolic pulmonary hypertension? AB - Although pulmonary endarterectomy remains the treatment of choice for patients with chronic thromboembolic pulmonary hypertension (CTEPH), not all patients will benefit from or receive this highly specialised surgery. Patients whose CTEPH is deemed inoperable by an experienced centre and patients with persistent pulmonary hypertension after surgery are candidates for trial of pulmonary arterial hypertension (PAH) specific pharmacotherapies. However, the currently available PAH specific pharmacotherapies have not demonstrated a clear benefit in either of these patient groups. Accordingly, PAH therapies remain off-label for use in CTEPH. Riociguat (BAY 63-2521) is a stimulator of soluble guanylate cyclase, and may represent a novel agent in the treatment of select patients with CTEPH. Pre clinical and human phase II studies with riociguat have reported promising results, and a multinational, randomised, controlled, double-blinded phase III study is currently underway to investigate the effect of riociguat in patients with inoperable CTEPH and those with persistent or recurrent pulmonary hypertension following pulmonary endarterectomy. PMID- 20956170 TI - Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart. AB - Right heart function is the main determinant of prognosis in pulmonary arterial hypertension (PAH). At present, no treatments are currently available that directly target the right ventricle, as we will demonstrate in this article. Meta analysis of clinical trials in PAH revealed that current PAH medication seems to have limited cardiac-specific effects when analysed by the pump-function graph. Driven by the hypothesis that "left" and right heart failure might share important underlying pathophysiological mechanisms, we evaluated the clinical potential of left heart failure (LHF) therapies for PAH, based on currently available literature. As in LHF, the sympathetic nervous system and the renin angiotension-aldosterone system are highly activated in PAH. From LHF we know that intervening in this process, e.g. by angiotensin-converting enzyme inhibition or beta-blockade, is beneficial in the long run. Therefore, these medications could be also beneficial in PAH. Furthermore, the incidence of sudden cardiac death in PAH could be reduced by implantable cardioverter-defibrillators. Finally, pilot studies have demonstrated that interventricular dyssynchrony, present at end-stage PAH, responded favourably to cardiac resynchronisation therapy as well. In conclusion, therapies for LHF might be relevant for PAH. However, before they can be implemented in PAH management, safety and efficacy should be evaluated first in well-designed clinical trials. PMID- 20956171 TI - A 47-year-old female with shortness of breath and "reversed halo sign". AB - A 47-yr-old female was referred to a tertiary centre for further evaluation of chronic cough, fever, progressive exertional dyspnoea and fatigue. From a respiratory point of view she had been well until 7 months previously when she had started to experience systemic fatigue, low-grade fever and chronic dry cough. A computed tomography scan of the chest demonstrated diffuse bilateral ground-glass, ill-defined pulmonary opacities affecting all lobes. Some had central ground-glass hazy density with peripheral areas of increased opacity, which is consistent with "reversed halo sign". Cryptogenic organising pneumonia (COP) is a clinical, radiological and pathological diagnosis which is made when no definite cause, such as infection or connective tissue disease, is found. It is characterised histopathologically by the presence of patchy distribution of granulation tissue, which consists of fibroblasts and myofibroblasts embedded in a loose connective matrix, present in the lumen of the distal airspaces including alveoli, alveolar ducts and bronchioles. This case report illustrates the association of the reversed halo sign with COP. Although only seen in one fifth of patients with the disease, it appears to suggest the diagnosis of COP and, with proper clinical correlation, it may be another diagnostic adjunct. PMID- 20956172 TI - Pulmonary Langerhans cell histiocytosis associated with Hodgkin's lymphoma. PMID- 20956175 TI - Interstitial lung disease: new challenges and evolving phenotypes. PMID- 20956176 TI - Mucus hypersecretion in COPD: should we only rely on symptoms? PMID- 20956177 TI - Update on diffuse parenchymal lung disease. PMID- 20956178 TI - Revisited role for mucus hypersecretion in the pathogenesis of COPD. AB - Chronic obstructive pulmonary disease (COPD) is a heterogeneous and complex disease of which the basic pathophysiological mechanisms remain largely unknown. On the basis of recent results from pathological studies and large clinical trials, the presence of airway inflammation does not seem to be sufficient to explain the complexity of the disease and the relatively poor response to treatment. It is probably time to abandon the concept of COPD as a unique disease and define, identify and treat the various aspects, which may differ between individuals. Among the different phenotypic distinctions, the classical distinction "chronic bronchitis" has mucus hypersecretion as the key presenting symptom. Its role in COPD has been the subject of an ongoing debate; however, it now appears to be being re-evaluated due to findings from recent epidemiological and pathological studies. In this context, the view that chronic mucus hypersecretion plays a secondary role in the pathogenesis of COPD should be abandoned and instead, drugs targeting mucus hypersecretion should be considered as a treatment option. PMID- 20956179 TI - Impact of exacerbations on COPD. AB - Exacerbations of chronic obstructive pulmonary disease (COPD) determine disease associated morbidity, mortality, resource burden and healthcare costs. Acute exacerbation care requirements range from unscheduled primary care visits to emergency room, inpatient or intensive care, generating significant costs in COPD. Even after an exacerbation resolves, respiratory, physical, social and emotional impairment may persist for prolonged time. Frequent exacerbations, mainly in patients with severe COPD, accelerate disease progression and mortality. Thus, patients with frequent exacerbations have a more rapid decline in lung function, worse quality of life and decreased exercise performance. Management of COPD directed to reduce incidence and severity of exacerbations improves long-term health status and conserves health care resources and costs. PMID- 20956180 TI - Prevention of exacerbations of COPD with pharmacotherapy. AB - Exacerbations are a frequent event in the evolution of chronic obstructive pulmonary disease (COPD) patients. Individuals with COPD have a mean of 1-3 episodes per year, some of which lead to hospital admission and may even be a cause of death. The importance of COPD exacerbations has become increasingly apparent due to the impact these episodes have on the natural history of disease. It is now known that frequent exacerbations can adversely affect health-related quality of life and short- and long-term pulmonary function. Optimising treatment for stable COPD will help to reduce exacerbations. Long-acting bronchodilators, alone or combined with inhaled corticosteroids, have demonstrated efficacy in reducing the rate of exacerbations in patients with COPD. Other innovative approaches are being investigated, such as the long-term use of macrolides or the use of antibiotics in an effort to suppress bronchial colonisation and consequent exacerbations. Other drugs, such as mucolytics and immunomodulators, have recently provided positive results. Non-pharmacological interventions such as rehabilitation, self-management plans and the maintenance of high levels of physical activity in daily life are also useful strategies to prevent exacerbations in patients with COPD and should be implemented in regular clinical practice. PMID- 20956181 TI - Mucoactive drugs. AB - Mucus hypersecretion is a clinical feature of severe respiratory diseases such as asthma, cystic fibrosis and chronic obstructive pulmonary disease. Airway mucosal infection and/or inflammation associated with these diseases often gives rise to inflammatory products, including neutrophil-derived DNA and filamentous actin, in addition to bacteria, apoptotic cells and cellular debris, that may collectively increase mucus production and viscosity. Mucoactive agents have been the medication of choice for the treatment of respiratory diseases in which mucus hypersecretion is a clinical complication. The main purpose of mucoactive drugs is to increase the ability to expectorate sputum and/or decrease mucus hypersecretion. Many mucoactive drugs are currently available and can be classified according to their putative mechanism of action. Mucoactive medications include expectorants, mucoregulators, mucolytics and mucokinetics. By developing our understanding of the specific effects of mucoactive agents, we may result in improved therapeutic use of these drugs. The present review provides a summary of the most clinically relevant mucoactive drugs in addition to their potential mechanism of action. PMID- 20956182 TI - Mucoactive therapy in COPD. AB - It has been shown that mucus hypersecretion is associated with greater susceptibility for chronic obstructive pulmonary disease (COPD), excess forced expiratory volume in 1 s decline, hospitalisations and excess mortality. The effects of mucoactive drugs on outcomes have been reviewed in several meta analyses, the largest one including 26 studies. 21 studies were performed in patients with chronic bronchitis and five in patients with COPD. The majority of these trials were performed with N-acetylcysteine (n = 13) and carbocysteine (n = 3). Overall, there was a significant reduction in exacerbations (0.05 per patient per month) and the number of days with disability (0.56 days per patient per month). Mucolytics were well tolerated and the number of adverse events was lower than with placebo (odds ratio 0.78). In the largest and best designed study with N-acetylcysteine in 523 patients with COPD, the reduction in exacerbations was only observed in patients not taking inhaled corticosteroids. In addition, a 374 mL reduction in functional residual capacity was found. A recent large study (n = 709) with high-dose carbocysteine (1,500 mg.day-1) demonstrated a significant effect on exacerbations (25% reduction) and also reported an improvement in health-related quality of life (-4.06 units in St George's Respiratory Questionnaire). It is unclear what the mechanisms underlying these effects may be and which phenotypes benefit from this treatment. On the basis of this evidence mucoactive drugs may deserve consideration in the long-term treatment of COPD. PMID- 20956183 TI - Descending necrotising mediastinitis: two case reports and review of the literature. AB - Descending necrotising mediastinitis is a rare and serious infection with a high mortality rate, which complicates pharyngeal or odontogenic infection. Early recognition and treatment are essential in order to minimise morbidity. Evaluation with computed tomography is necessary to confirm the diagnosis and facilitate surgical planning. In addition to prompt empirical antibiotic therapy, surgical intervention is necessary in nearly all cases. Surgical drainage and debridement may be performed through cervicotomy alone, or through combined cervicotomy and thoracotomy, depending upon the extent of disease. Hyperbaric oxygen therapy may play an auxiliary role. We present two recent cases with characteristic imaging findings, and review the relevant literature. PMID- 20956184 TI - Update on asthma control in five European countries: results of a 2008 survey. AB - The 2006 European National Health and Wellness Survey (NHWS) showed that a large proportion of asthmatics had uncontrolled asthma. The current analysis estimated the prevalence of asthma and asthma control (Asthma Control TestTM (ACT); QualityMetric Inc., Lincoln, RI, USA) in five European countries using the 2008 NHWS. Health-related quality of life (HRQoL), using the Short Form-12 (SF-12) health survey, and work productivity/activity impairment were assessed. Of 3,619 respondents aged >=18 yrs, the prevalence of self-reported physician diagnosis of asthma was 6.1% (15 million people); 56.6% of treated asthmatics were not well controlled (NWC; ACT score <=19). Individual components of the ACT showed that, compared with at least well-controlled patients (ALWC; ACT score >=20), NWC patients had activity limitations at least some of the time (40.8% versus 1.5%, p<0.001), were breathless >=3 times per week (72.5% versus 5.4%, p<0.001), suffered sleep difficulties due to asthma at least once per week (60.3% versus 4.6%, p<0.001) and required rescue medication >=2-3 times per week (77.4% versus 15.9%, p<0.001). NWC patients had also received more healthcare contact in the past 6 ;months, including hospitalisation (17.4% versus 9.9%, p<0.001). The SF-12 physical and mental summary scores were 7.46 and 4.73 points higher, respectively, for ALWC patients compared with NWC patients (p<0.001). ALWC patients reported less absenteeism (5.5% versus 12.2%) and work impairment (15.4% versus 30.0%) than NWC patients (both p<0.001). The proportion of asthmatics with NWC asthma has not improved since 2006. ALWC asthma is associated with a significant positive impact on healthcare resource use, HRQoL and work productivity. PMID- 20956185 TI - Retrosternal and pleural "bridging" fibrosis mimicking malignancy in a patient exposed to asbestos. AB - Mediastinal fibrosis is a rare, benign disorder characterised by proliferation of fibrous tissue within the mediastinum. It can present as diffuse mediastinal infiltration or, more frequently, as a localised soft tissue mass, usually in the right paratracheal or subcarinal areas. 18-fluorodeoxyglucose (18-FDG) positron emission tomography (PET) imaging has only been reported in a few case reports with variable aspects. Herein, we present an unusual pattern of mediastinal fibrosis, presenting as a thick retrosternal mass contiguous with pleural thickening. 18-FDG PET showed intensely increased uptake in the mass. Both the location of fibrosis and PET imaging were confusing with malignancy. Histopathological proof of benign fibrosis was obtained by surgery. The patient had been exposed to asbestos and the possible relationship of this particular pattern of fibrosis with asbestos exposure will be discussed. PMID- 20956186 TI - Organising pneumonia can be the inaugural manifestation in connective tissue diseases, including Sjogren's syndrome. AB - Connective tissue diseases are known to be one of the causes of organising pneumonia (OP). However, this association is rare and signs of OP usually occur in the context of an already diagnosed disease. We report three cases of OP preceding the articular symptoms of the underlying connective tissue disease by 3 6 months in two cases of rheumatoid arthritis and by 36 months in one patient with primary Sjogren's syndrome. The diagnosis of post-infectious OP had initially been suspected in the three cases and the patients had not been followed up further. The occurrence of OP preceding articular or any other extrapulmonary involvement of connective tissue disease had been reported in only four cases in the literature and, to our knowledge, no case preceding Sjogren's syndrome had ever been reported. These observations suggest that exhaustive investigations should be considered when OP is diagnosed, including antinuclear auto-antibodies and investigations for Sjogren's syndrome, even when there are no clinical signs suggesting an underlying connective tissue disease. These investigations should also be repeated during the course of the disease, especially in the case of OP continuing to progress under treatment and, of course, if signs of connective tissue disease appear. PMID- 20956187 TI - Multiple pulmonary nodules in a male with psoriatic arthritis. PMID- 20956188 TI - Talcosis due to abundant use of cosmetic talcum powder. PMID- 20956189 TI - Emergency treatments in pulmonary arterial hypertension: a place for algorithms and for education programmes. PMID- 20956190 TI - Update on nonsmall cell lung cancer. PMID- 20956191 TI - The challenge of targeting EGFR: experience with gefitinib in nonsmall cell lung cancer. AB - As the first approved epidermal growth factor receptor (EGFR)-targeted therapy for nonsmall cell lung cancer (NSCLC), the clinical development of gefitinib was complex. Advances in scientific understanding of the target biology during its clinical development enabled the identification of a biomarker to define patients most likely to derive benefit from gefitinib. Initial phase II trials showed clinically meaningful anti-tumour activity in 12-18% of unselected pretreated patients with advanced NSCLC at the optimum biological dose (250 mg). Subgroup analyses of these and subsequent phase III trials in unselected patients suggested that EGFR mutation and some clinical characteristics associated with a higher incidence of EGFR mutation (Asian ethnicity, adenocarcinoma histology, never-smoking and female sex) were linked with increased response to gefitinib. Consequently, the IRESSA Pan-Asia Study (IPASS) was conducted in never-smokers or former light-smokers in East Asia who had adenocarcinoma of the lung. IPASS showed that EGFR mutation was the strongest predictor of improved progression free survival (mutation-positive subgroup hazard ratio (HR) 0.48, 95% CI 0.36 0.64 (p<0.001, n = 261); mutation-negative subgroup HR 2.85, 95% CI 2.05-3.98 (p<0.001, n = 176); interaction test p<0.001) with gefitinib versus carboplatin/paclitaxel as first-line therapy for advanced NSCLC. Important lessons for the development of future personalised medicines are discussed. PMID- 20956192 TI - The arterial load in pulmonary hypertension. AB - The anatomical differences between the pulmonary and systemic arterial system are the main cause of the difference in distribution of compliance. In the pulmonary arterial system compliance is distributed over the entire arterial system, and stands at the basis of the constancy of the RC-time. This distribution depends on the number of peripheral vessels, which is ~8-10 times more in the pulmonary system than the systemic tree. In the systemic arterial tree the compliance is mainly located in the aorta (80% of total compliance in thoracic-abdominal aorta). The constant RC-time in the pulmonary bed results in proportionality of systolic and diastolic pressure with mean pressure and, in turn, in the constant ratio of oscillatory and mean power. PMID- 20956193 TI - Optimising the management of pulmonary arterial hypertension patients: emergency treatments. AB - Pulmonary arterial hypertension (PAH) is a rare and potentially fatal disease whose management is usually restricted to a few specialised centres. As patients do not necessarily live in the neighbourhood of these centres, daily care and emergencies have to be delegated to first and second lines. Treatment guidelines do not usually provide recommendations for acute emergency situations as evidence is scarce. This short review provides a description of our therapeutic protocols based on available data. A model of transmural organisation of care for PAH patients, currently applied in Belgium, is described. Thereafter, based on an analysis of the reasons of death in the PAH population, a review of the main emergencies is provided. Cardiac arrest and resuscitation, decompensated right heart failure, respiratory failure, arrhythmia, pericardial effusion, haemoptysis, surgery and drug-related adverse events will be discussed successively. Case reports showing the precariousness of PAH patients will enforce our thesis of the need for optimal patient management organisation. PMID- 20956194 TI - Endoscopy: a clinical state of the art. PMID- 20956195 TI - Why you do or do not need thoracoscopy. AB - Thoracoscopy is an old but still very valuable technique for the evaluation of pleural pathology and, especially for the further investigation of the aetiology of pleural fluid. It remains of great importance, since it is able to not only provide an exact diagnosis, but also can have therapeutic potential. In this review, the differential diagnostic aspects of transudate versus exudate are further elaborated, and the role of thoracoscopy is compared to closed pleural biopsy and image guided biopsy. PMID- 20956196 TI - Spontaneous pneumothorax: epidemiology, pathophysiology and cause. AB - Spontaneous pneumothorax represents a common clinical problem. An overview of relevant and updated information on epidemiology, pathophysiology and cause(s) of spontaneous (primary and secondary) pneumothorax is described. PMID- 20956197 TI - Empyema thoracis: new insights into an old disease. AB - Pleural infection is a disease of historical importance and is still a modern menace, with incidences rising in adults and children, and a significant mortality in adults. Basic research is hampered by limitations with in vivo models, and the bacteriology of empyema is complex. The role of thoracic ultrasound in guiding investigation and drainage of empyema is clear. Prompt treatment with appropriate systemic antibiotics and chest tube drainage are the key; in cases of failure of these measures, thoracic surgery is of proven efficacy in the treatment of this age-old disease. PMID- 20956198 TI - Diagnostic bronchoscopy: state of the art. AB - Since the introduction of the flexible fibreoptic bronchoscope in the late 1960s there have been relatively few technological advances for three decades, aside from the development of a white light video bronchoscope with a miniature charge coupled device built in its tip replacing the fibreoptics. White light flexible videobronchoscopy with its ancillary devices (forceps biopsy, bronchial brushing, bronchoalveolar lavage, bronchial washings and transbronchial needle aspiration) has long been the only established diagnostic bronchoscopic technique. With the advances in microtechnology over the past two decades, recent technical developments such as autofluorescence bronchoscopy and endoscopic ultrasound allow better evaluation of endobronchial, mediastinal and parenchymal lesions. PMID- 20956199 TI - The clinical utility of bronchoalveolar lavage in diffuse parenchymal lung disease. AB - Bronchoalveolar lavage (BAL) has been used in diagnostic and prognostic evaluation in diffuse parenchymal lung disease for three decades and has a central role in the diagnosis of a number of rare disorders and in excluding opportunistic infection in treated patients. It also has an important place in the personal diagnostic algorithms of many experienced clinicians in the diagnosis of the more prevalent disorders, including sarcoidosis, hypersensitivity pneumonitis and idiopathic pulmonary fibrosis. This use of BAL is not well captured in the medical literature, as most published studies pre date changes in disease classification and fail to integrate BAL data with other clinical and radiological information. Further studies to quantify the value added by bronchoalveolar lavage in routine practice are urgently required. PMID- 20956200 TI - Lung volume reduction for severe emphysema: do we need a scalpel or a scope? AB - Resectional lung volume reduction has proven to be superior to medical treatment in reducing dyspnoea and in increasing lung function, survival and quality of life in a very well selected, low risk group of hyperinflated patients with heterogeneous emphysema predominantly in the upper lobe. Nevertheless, this intervention is hampered by an important pulmonary (30%) and cardiovascular (20%) morbidity, mainly as a result of prolonged (>7 days) air leak, and a 5% risk of death as a result of the surgical intervention. Results from ongoing randomised trials are awaited in order to determine whether less invasive, non-resectional lung volume treatment of emphysema via the bronchoscope using endobronchial valves, airway bypass stents or biological adhesives/heated water vapour will yield similar improvement with less morbidity and reduced mortality, compared with surgical resection. Furthermore, it is hoped that endoscopic lung volume reduction techniques may help patients with homogeneous emphysema currently excluded by most teams for the resectional procedure. PMID- 20956201 TI - Intussusception of small intestine due to metastasis of large cell carcinoma of the lung with a rhabdoid phenotype. AB - Large cell carcinoma of the lung with a rhabdoid phenotype is a rare type of lung cancer, and does not commonly metastasize to the small intestine. Herein we describe a 63-yr-old Japanese male with ileus resulting from small intestinal metastasis from lung cancer. Tumour enlargement was rapid and could not be treated with chemotherapy. PMID- 20956202 TI - Isolated splenic metastasis from lung cancer: ringleader of continuous fever. AB - The spleen is an infrequent metastatic organ of solid tumours, the prevalence of which ranges between 2.3% and 7.1% in populations with cancer as determined through autopsy. The most common sources of metastasis are breast, lung, colorectal and ovarian carcinoma and melanoma. Isolated metastasis of the spleen is rarely reported with only 93 cases from all sources having been reported up to 2007. Therefore, isolated splenic metastasis from primary lung cancer is exceedingly rare with only 11 cases reported to date. Herein, we report a rare case of isolated splenic metastasis in a 49-yr-old female 3 months after lobectomy for an undifferentiated large cell carcinoma in the right lung (pT(2a)N0M0). The only symptom the patient presented with was continuous high fever, which had never been previously reported. This patient presented diagnostic challenges due to the presentation of high fever, leukoapenia after chemotherapy and the cystic splenic mass, all of which led to the initial consideration of splenic abscess. The patient's high fever resolved rapidly after splenectomy and splenic metastasis was confirmed by pathological findings. We also reviewed all 11 reported previously cases and summarised the characteristics and appropriate management of isolated splenic metastasis from lung cancer. PMID- 20956203 TI - Nebuliser solution bottle cap presenting as a foreign body in the subglottic airway. PMID- 20956204 TI - Cardiovascular effects of 1 year of progressive and vigorous exercise training in previously sedentary individuals older than 65 years of age. AB - BACKGROUND: Healthy but sedentary aging leads to cardiovascular stiffening, whereas life-long endurance training preserves left ventricular (LV) compliance. However, it is unknown whether exercise training started later in life can reverse the effects of sedentary behavior on the heart. METHODS AND RESULTS: Twelve sedentary seniors and 12 Masters athletes were thoroughly screened for comorbidities. Subjects underwent invasive hemodynamic measurements with pulmonary artery catheterization to define Starling and LV pressure-volume curves; secondary functional outcomes included Doppler echocardiography, magnetic resonance imaging assessment of cardiac morphology, arterial stiffness (total aortic compliance and arterial elastance), and maximal exercise testing. Nine of 12 sedentary seniors (70.6+/-3 years; 6 male, 3 female) completed 1 year of endurance training followed by repeat measurements. Pulmonary capillary wedge pressures and LV end-diastolic volumes were measured at baseline, during decreased cardiac filling with lower-body negative pressure, and increased filling with saline infusion. LV compliance was assessed by the slope of the pressure-volume curve. Before training, Vo(2)max, LV mass, LV end-diastolic volume, and stroke volume were significantly smaller and the LV was less compliant in sedentary seniors than Masters athletes. One year of exercise training had little effect on cardiac compliance. However, it reduced arterial elastance and improved Vo(2)max by 19% (22.8+/-3.4 versus 27.2+/-4.3 mL/kg/mL; P<0.001). LV mass increased (10%, 64.5+/-7.9 versus 71.2+/-12.3 g/m(2); P=0.037) with no change in the mass-volume ratio. CONCLUSIONS: Although 1 year of vigorous exercise training did not appear to favorably reverse cardiac stiffening in sedentary seniors, it nonetheless induced physiological LV remodeling and imparted favorable effects on arterial function and aerobic exercise capacity. PMID- 20956205 TI - Cardiac arrest and resuscitation: an opportunity to align research prioritization and public health need. PMID- 20956206 TI - Modulation of calcium-activated potassium channels induces cardiogenesis of pluripotent stem cells and enrichment of pacemaker-like cells. AB - BACKGROUND: Ion channels are key determinants for the function of excitable cells, but little is known about their role and involvement during cardiac development. Earlier work identified Ca(2+)-activated potassium channels of small and intermediate conductance (SKCas) as important regulators of neural stem cell fate. Here we have investigated their impact on the differentiation of pluripotent cells toward the cardiac lineage. METHODS AND RESULTS: We have applied the SKCa activator 1-ethyl-2-benzimidazolinone on embryonic stem cells and identified this particular ion channel family as a new critical target involved in the generation of cardiac pacemaker-like cells: SKCa activation led to rapid remodeling of the actin cytoskeleton, inhibition of proliferation, induction of differentiation, and diminished teratoma formation. Time-restricted SKCa activation induced cardiac mesoderm and commitment to the cardiac lineage as shown by gene regulation, protein, and functional electrophysiological studies. In addition, the differentiation into cardiomyocytes was modulated in a qualitative fashion, resulting in a strong enrichment of pacemaker-like cells. This was accompanied by induction of the sino-atrial gene program and in parallel by a loss of the chamber-specific myocardium. In addition, SKCa activity induced activation of the Ras-Mek-Erk signaling cascade, a signaling pathway involved in the 1-ethyl-2-benzimidazolinone-induced effects. CONCLUSIONS: SKCa activation drives the fate of pluripotent cells toward mesoderm commitment and cardiomyocyte specification, preferentially into nodal-like cardiomyocytes. This provides a novel strategy for the enrichment of cardiomyocytes and in particular, the generation of a specific subtype of cardiomyocytes, pacemaker-like cells, without genetic modification. PMID- 20956207 TI - Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. AB - BACKGROUND: Inflammation and activation of immune cells are key mechanisms in the development of atherosclerosis. Previous data indicate important roles for monocytes and T lymphocytes in lesion formation, whereas the contribution of neutrophils remains to be firmly established. Here, we investigate the effect of hypercholesterolemia on peripheral neutrophil counts, neutrophil recruitment to atherosclerotic lesions, and the importance of neutrophils in atherosclerotic lesion formation in Apoe(-/-) mice. METHODS AND RESULTS: Hypercholesterolemia induces neutrophilia, which was attributable to enhanced granulopoiesis and enhanced mobilization from the bone marrow. The degree of hypercholesterolemia induced neutrophilia was positively correlated with the extent of early atherosclerotic lesion formation. In turn, neutropenic mice display reduced plaque sizes at early but not late stages of atherosclerotic lesion formation. Flow cytometry of enzymatically digested aortas further shows altered cellular plaque composition in neutropenic mice with reduced numbers of inflammatory monocytes and macrophages. Aortic neutrophil infiltration peaks 4 weeks after the start of a high-fat diet and decreases afterward. The recruitment of neutrophils to large arteries was found to depend on CCR1, CCR2, CCR5, and CXCR2, which contrasts to peripheral venous recruitment, which requires CCR2 and CXCR2 only. The involvement of CCR1 and CCR5 corresponded to the endothelial deposition of the platelet-derived chemokine CCL5 in arteries but not in veins. CONCLUSIONS: Our data provide evidence that hypercholesterolemia-induced neutrophilia is multifactorial and that neutrophils infiltrate arteries primarily during early stages of atherosclerosis. Collectively, these data suggest an important role of neutrophils in the initiation of atherosclerosis. PMID- 20956208 TI - Acetaminophen increases blood pressure in patients with coronary artery disease. AB - BACKGROUND: Because traditional nonsteroidal antiinflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, particularly in patients at increased cardiovascular risk. Hence, the aim of this study was to evaluate the safety of acetaminophen in patients with coronary artery disease. METHODS AND RESULTS: The 33 patients with coronary artery disease included in this randomized, double-blind, placebo controlled, crossover study received acetaminophen (1 g TID) on top of standard cardiovascular therapy for 2 weeks. Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin system, inflammation, and oxidative stress were determined at baseline and after each treatment period. Treatment with acetaminophen resulted in a significant increase in mean systolic (from 122.4+/-11.9 to 125.3+/-12.0 mm Hg P=0.02 versus placebo) and diastolic (from 73.2+/-6.9 to 75.4+/-7.9 mm Hg P=0.02 versus placebo) ambulatory blood pressures. On the other hand, heart rate, endothelial function, early endothelial progenitor cells, and platelet function did not change. CONCLUSIONS: This study demonstrates for the first time that acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease. Thus, the use of acetaminophen should be evaluated as rigorously as traditional nonsteroidal antiinflammatory drugs and cyclooxygenase 2 inhibitors, particularly in patients at increased cardiovascular risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00534651. PMID- 20956209 TI - Vascular dysfunction in women with a history of preeclampsia and intrauterine growth restriction: insights into future vascular risk. AB - BACKGROUND: Women with a history of placental disease are at increased risk for the future development of vascular disease. It is unknown whether preexisting endothelial dysfunction underlies both the predisposition to placental disease and the later development of vascular disease. The aim of this study was to assess vascular function in postpartum women and to determine whether differences emerged depending on the presentation of placental disease. METHODS AND RESULTS: Women with a history of early-onset preeclampsia (n=15), late-onset preeclampsia (n=9), intrauterine growth restriction without preeclampsia (n=9), and prior normal pregnancy (n=16) were studied 6 to 24 months postpartum. Flow-mediated vasodilatation and flow-independent (glyceryl trinitrate-induced) vasodilatation were studied through the use of high-resolution vascular ultrasound examination of the brachial artery. Arterial stiffness was assessed by pulse-wave analysis (augmentation index). Laboratory assessment included circulating angiogenic factors (vascular endothelial growth factor, soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin). Flow-mediated vasodilatation was significantly reduced in women with previous early-onset preeclampsia and intrauterine growth restriction compared with women with previous late-onset preeclampsia and control subjects (3.2+/-2.7% and 2.1+/-1.2% versus 7.9+/-3.8% and 9.1+/-3.5%, respectively; P<0.0001). Flow-independent vasodilatation was similar among all groups. Similarly, the radial augmentation index was significantly increased among women with previous early-onset preeclampsia and intrauterine growth restriction, but not among late preeclamptic women and control subjects (P=0.0105). Circulating angiogenic factors were similar in all groups. CONCLUSION: Only women with a history of early-onset preeclampsia or intrauterine growth restriction without preeclampsia exhibit impaired vascular function, which might explain their predisposition to placental disease and their higher risk of future vascular disease. PMID- 20956210 TI - Intrinsic coagulation activation and the risk of arterial thrombosis in young women: results from the Risk of Arterial Thrombosis in relation to Oral contraceptives (RATIO) case-control study. AB - BACKGROUND: Classically, intrinsic coagulation proteins are thought to have a minor role in hemostasis. Recently, these proteins, especially FXII, were implicated as possible key players in the pathogenesis of arterial thrombosis. This study aims to determine the risks of arterial thrombosis conferred by increased activation of intrinsic coagulation proteins in young women and the effect of oral contraceptive use on this association. METHODS AND RESULTS: The Risk of Arterial Thrombosis In relation to Oral contraceptives (RATIO) study is a population-based case-control study including young women (age 18 to 50 years) with myocardial infarction (n=205) and ischemic stroke (n=175) and 638 healthy controls. Intrinsic coagulation protein activation was determined by measuring activated protein-inhibitor complexes. This complex is with C1 esterase inhibitor (FXIIa-C1-INH, FXIa-C1-INH, Kallikrein-C1-INH) or antitrypsin inhibitor (FXIa-AT INH). Odds ratios (ORs) and corresponding confidence intervals (95% CIs) were calculated with logistic regression. High levels of protein activation (>90th percentile of controls) showed an increased risk of ischemic stroke: FXIIa-C1-INH (OR, 2.1; 95% CI, 1.3 to 3.5), FXIa-C1-INH (OR, 2.8; 95% CI, 1.6 to 4.7), FXIa-AT INH (OR, 2.3; 95% CI, 1.4 to 4.0), and Kallikrein-C1 (OR, 4.3; 95% CI, 2.6 to 7.2). If anything, myocardial infarction risk was only increased by Kallikrein-C1 INH (OR, 1.5; 95% CI, 0.9 to 2.5). Oral contraceptive use further increased the risks. CONCLUSIONS: High levels of activated proteins of the intrinsic coagulation system are associated with arterial thrombosis, whereas the strength of these associations differs for myocardial infarction and ischemic stroke. This contradicts similar analyses among men in the Northwick Park Heart Study. Together with the finding that oral contraceptive use further increases the risks, the question of whether the role of intrinsic coagulation proteins in the pathogenesis of arterial thrombosis is sex-specific is raised. PMID- 20956211 TI - Improved outcomes with early collaborative care of ambulatory heart failure patients discharged from the emergency department. AB - BACKGROUND: The type of outpatient physician care after an emergency department visit for heart failure may affect patients' outcomes. METHODS AND RESULTS: Using the National Ambulatory Care Reporting System, we examined the care and outcomes of heart failure patients who visited and were discharged from the emergency department in Ontario, Canada (April 2004 to March 2007). Early collaborative care by a cardiologist and primary care (PC) physician within 30 days after discharge was compared with PC alone. Care for 10 599 patients (age, 74.9+/-11.9 years; 50.2% male) was provided by PC alone (n=6596), cardiologist alone (n=535), or concurrently by both cardiologist and PC (n=1478); 1990 did not visit a physician. Collaborative care patients were more likely to undergo assessment of left ventricular function (57.4% versus 28.7%), noninvasive stress testing (20.1% versus 7.8%), and cardiac catheterization (11.6% versus 2.7%) compared with PC. Drug prescriptions (patients >=65 years of age) demonstrated higher use of angiotensin-converting enzyme inhibitors (58.8% versus 54.6%), angiotensin receptor blockers (22.7% versus 18.1%), beta-adrenoceptor antagonists (63.4% versus 48.0%), loop diuretics (84.2% versus 79.6%), metolazone (4.8% versus 3.4%), and spironolactone (19.8% versus 12.7%) within 100 days after emergency department discharge for collaborative care compared with PC. In a propensity matched model, mortality was lower with PC compared with no physician visit (hazard ratio, 0.75; 95% confidence interval, 0.64 to 0.87; P<0.001). Collaborative care reduced mortality compared with PC (hazard ratio, 0.79; 95% confidence interval, 0.63 to 1.00; P=0.045). Sole cardiology care conferred a trend to increased mortality (hazard ratio, 1.41 versus collaborative care; 95% confidence interval, 0.98 to 2.03; P=0.067). CONCLUSIONS: Early collaborative heart failure care was associated with increased use of drug therapies and cardiovascular diagnostic tests and better outcomes compared with PC alone. PMID- 20956212 TI - Association between aneurysm shoulder stress and abdominal aortic aneurysm expansion: a longitudinal follow-up study. AB - BACKGROUND: Aneurysm expansion rate is an important indicator of the potential risk of abdominal aortic aneurysm (AAA) rupture. Stress within the AAA wall is also thought to be a trigger for its rupture. However, the association between aneurysm wall stresses and expansion of AAA is unclear. METHODS AND RESULTS: Forty-four patients with AAAs were included in this longitudinal follow-up study. They were assessed by serial abdominal ultrasonography and computed tomography scans if a critical size was reached or a rapid expansion occurred. Patient specific 3-dimensional AAA geometries were reconstructed from the follow-up computed tomography images. Structural analysis was performed to calculate the wall stresses of the AAA models at both baseline and final visit. A nonlinear large-strain finite element method was used to compute the wall-stress distribution. The relationship between wall stresses and expansion rate was investigated. Slowly and rapidly expanding aneurysms had comparable baseline maximum diameters (median, 4.35 cm [interquartile range, 4.12 to 5.0 cm] versus 4.6 cm [interquartile range, 4.2 to 5.0 cm]; P=0.32). Rapidly expanding AAAs had significantly higher shoulder stresses than slowly expanding AAAs (median, 300 kPa [interquartile range, 280 to 320 kPa] versus 225 kPa [interquartile range, 211 to 249 kPa]; P=0.0001). A good correlation between shoulder stress at baseline and expansion rate was found (r=0.71; P=0.0001). CONCLUSION: A higher shoulder stress was found to have an association with a rapidly expanding AAA. Therefore, it may be useful for estimating the expansion of AAAs and improve risk stratification of patients with AAAs. PMID- 20956213 TI - Neutrophils, hypercholesterolemia, and atherogenesis. PMID- 20956214 TI - Blood pressure destabilization on nonsteroidal antiinflammatory agents: acetaminophen exposed? PMID- 20956215 TI - Postdischarge assessment after a heart failure hospitalization: the next step forward. PMID- 20956217 TI - Part 1: executive summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. AB - The goal of therapy for bradycardia or tachycardia is to rapidly identify and treat patients who are hemodynamically unstable or symptomatic due to the arrhythmia. Drugs or, when appropriate, pacing may be used to control unstable or symptomatic bradycardia. Cardioversion or drugs or both may be used to control unstable or symptomatic tachycardia. ACLS providers should closely monitor stable patients pending expert consultation and should be prepared to aggressively treat those with evidence of decompensation. PMID- 20956218 TI - Part 2: evidence evaluation and management of potential or perceived conflicts of interest: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. AB - In summary, the evidence review process has attempted to provide a systematic review of the scientific literature using a priori defined methods. The details and steps of the literature review are transparent and replicable. External opinions and community critique are highly valued, and the final products represent the combined labor of hundreds of participants. PMID- 20956219 TI - Part 3: ethics: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. PMID- 20956220 TI - Part 4: CPR overview: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. PMID- 20956221 TI - Part 5: adult basic life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. AB - The critical lifesaving steps of BLS are ? Immediate Recognition and Activation of the emergency response system ? Early CPR and ? Rapid Defibrillation for VF. When an adult suddenly collapses, whoever is nearby should activate the emergency system and begin chest compressions (regardless of training). Trained lay rescuers who are able and healthcare providers should provide compressions and ventilations. Contrary to the belief of too many in this situation, CPR is not harmful. Inaction is harmful and CPR can be lifesaving. However, the quality of CPR is critical. Chest compressions should be delivered by pushing hard and fast in the center of the chest (ie, chest compressions should be of adequate rate and depth). Rescuers should allow complete chest recoil after each compression and minimize interruptions in chest compressions. They should also avoid excessive ventilation. If and when available, an AED should be applied and used without delaying chest compressions. With prompt and effective provision of these actions, lives are saved every day. PMID- 20956222 TI - Part 6: electrical therapies: automated external defibrillators, defibrillation, cardioversion, and pacing: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. AB - The recommendations for electrical therapies described in this section are designed to improve survival from SCA and life-threatening arrhythmias. Whenever defibrillation is attempted, rescuers must coordinate high-quality CPR with defibrillation to minimize interruptions in chest compressions and to ensure immediate resumption of chest compressions after shock delivery. The high first shock efficacy of newer biphasic defibrillators led to the recommendation of single shocks plus immediate CPR instead of 3-shock sequences that were recommended prior to 2005 to treat VF. Further data are needed to refine recommendations for energy levels for defibrillation and cardioversion using biphasic waveforms. PMID- 20956223 TI - Part 7: CPR techniques and devices: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. AB - A variety of CPR techniques and devices may improve hemodynamics or short-term survival when used by well-trained providers in selected patients. All of these techniques and devices have the potential to delay chest compressions and defibrillation. In order to prevent delays and maximize efficiency, initial training, ongoing monitoring, and retraining programs should be offered to providers on a frequent and ongoing basis. To date, no adjunct has consistently been shown to be superior to standard conventional (manual) CPR for out-of hospital basic life support, and no device other than a defibrillator has consistently improved long-term survival from out-of-hospital cardiac arrest. PMID- 20956224 TI - Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. AB - The goal of therapy for bradycardia or tachycardia is to rapidly identify and treat patients who are hemodynamically unstable or symptomatic due to the arrhythmia. Drugs or, when appropriate, pacing may be used to control unstable or symptomatic bradycardia. Cardioversion or drugs or both may be used to control unstable or symptomatic tachycardia. ACLS providers should closely monitor stable patients pending expert consultation and should be prepared to aggressively treat those with evidence of decompensation. PMID- 20956225 TI - Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. AB - The goal of immediate post-cardiac arrest care is to optimize systemic perfusion, restore metabolic homeostasis, and support organ system function to increase the likelihood of intact neurological survival. The post-cardiac arrest period is often marked by hemodynamic instability as well as metabolic abnormalities. Support and treatment of acute myocardial dysfunction and acute myocardial ischemia can increase the probability of survival. Interventions to reduce secondary brain injury, such as therapeutic hypothermia, can improve survival and neurological recovery. Every organ system is at risk during this period, and patients are at risk of developing multiorgan dysfunction. The comprehensive treatment of diverse problems after cardiac arrest involves multidisciplinary aspects of critical care, cardiology, and neurology. For this reason, it is important to admit patients to appropriate critical-care units with a prospective plan of care to anticipate, monitor, and treat each of these diverse problems. It is also important to appreciate the relative strengths and weaknesses of different tools for estimating the prognosis of patients after cardiac arrest. PMID- 20956226 TI - Part 10: acute coronary syndromes: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. AB - There has been tremendous progress in reducing disability and death from ACS. But many patients still die before reaching the hospital because patients and family members fail to recognize the signs of ACS and fail to activate the EMS system. Once the patient with ACS contacts the healthcare system, providers must focus on support of cardiorespiratory function, rapid transport, and early classification of the patient based on ECG characteristics. Patients with STEMI require prompt reperfusion; the shorter the interval from symptom onset to reperfusion, the greater the benefit. In the STEMI population, mechanical reperfusion with percutaenous coronary intervention improves survival and decreases major cardiovascular events compared to fibrinolysis. Patients with UA/NSTEMI (non STEMI ACS) or nonspecific or normal ECGs require risk stratification and appropriate monitoring and therapy. Healthcare providers can improve survival rates and myocardial function of patients with ACS by providing skilled, efficient, and coordinated out-of-hospital and in-hospital care. PMID- 20956227 TI - Part 11: adult stroke: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. AB - Advances in stroke care will have the greatest effect on stroke outcome if care is delivered within a regional stroke system designed to improve both efficiency and effectiveness. The ultimate goal of stroke care is to minimize ongoing injury, emergently recanalize acute vascular occlusions, and begin secondary measures to maximize functional recovery. These efforts will provide stroke patients with the greatest opportunity for a return to previous quality of life and decrease the overall societal burden of stroke. PMID- 20956228 TI - Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. PMID- 20956230 TI - Part 14: pediatric advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. PMID- 20956231 TI - Part 15: neonatal resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. PMID- 20956229 TI - Part 13: pediatric basic life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. PMID- 20956232 TI - Part 16: education, implementation, and teams: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. AB - Optimizing the links in the Chain of Survival improves outcomes and saves lives. The use of evidence-based education and implementation strategies will allow organizations and communities to strengthen these links in the most effective and efficient manner. PMID- 20956233 TI - Part 17: first aid: 2010 American Heart Association and American Red Cross Guidelines for First Aid. PMID- 20956234 TI - Medical therapy alone produces regression of combined aortic and mitral valve involvement in hypereosinophilic syndrome. PMID- 20956235 TI - Letter by Hill et al. regarding article, "Mortality in first 5 years in infants with functional single ventricle born in Texas, 1996 to 2003". PMID- 20956237 TI - Ambulatory arrhythmia monitoring: choosing the right device. PMID- 20956238 TI - Exercise and physical activity: clinical outcomes and applications. PMID- 20956239 TI - Pacemaker reuse: an initiative to alleviate the burden of symptomatic bradyarrhythmia in impoverished nations around the world. PMID- 20956240 TI - Rupture of the right ventricle after closed-chest cardiac massage. PMID- 20956241 TI - Flapjack--graphical genotype visualization. AB - SUMMARY: New software tools for graphical genotyping are required that can routinely handle the large data volumes generated by the high-throughput single nucleotide polymorphism (SNP) platforms, genotyping-by-sequencing and other comparable genotyping technologies. Flapjack has been developed to facilitate analysis of these data, providing real time rendering with rapid navigation and comparisons between lines, markers and chromosomes, with visualization, sorting and querying based on associated data, such as phenotypes, quantitative trait loci or other mappable features. AVAILABILITY: Flapjack is freely available for Microsoft Windows, Mac OS X, Linux and Solaris, and can be downloaded from http://bioinf.scri.ac.uk/flapjack . PMID- 20956242 TI - FILTREST3D: discrimination of structural models using restraints from experimental data. AB - SUMMARY: Automatic methods for macromolecular structure prediction (fold recognition, de novo folding and docking programs) produce large sets of alternative models. These large model sets often include many native-like structures, which are often scored as false positives. Such native-like models can be more easily identified based on data from experimental analyses used as structural restraints (e.g. identification of nearby residues by cross-linking, chemical modification, site-directed mutagenesis, deuterium exchange coupled with mass spectrometry, etc.). We present a simple server for scoring and ranking of models according to their agreement with user-defined restraints. AVAILABILITY: FILTREST3D is freely available for users as a web server and standalone software at: http://filtrest3d.genesilico.pl/ CONTACT: iamb@genesilico.pl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 20956243 TI - SPLATCHE2: a spatially explicit simulation framework for complex demography, genetic admixture and recombination. AB - SUMMARY: SPLATCHE2 is a program to simulate the demography of populations and the resulting molecular diversity for a wide range of evolutionary scenarios. The spatially explicit simulation framework can account for environmental heterogeneity and fluctuations, and it can manage multiple population sources. A coalescent-based approach is used to generate genetic markers mostly used in population genetics studies (DNA sequences, SNPs, STRs or RFLPs). Various combinations of independent, fully or partially linked genetic markers can be produced under a recombination model based on the ancestral recombination graph. Competition between two populations (or species) can also be simulated with user defined levels of admixture between the two populations. SPLATCHE2 may be used to generate the expected genetic diversity under complex demographic scenarios and can thus serve to test null hypotheses. For model parameter estimation, SPLATCHE2 can easily be integrated into an Approximate Bayesian Computation (ABC) framework. AVAILABILITY AND IMPLEMENTATION: SPLATCHE2 is a C++ program compiled for Windows and Linux platforms. It is freely available at www.splatche.com, together with its related documentation and example data. CONTACT: mathias.currat@unige.ch PMID- 20956244 TI - Interactive microbial genome visualization with GView. AB - SUMMARY: GView is a Java application for viewing and examining prokaryotic genomes in a circular or linear context. It accepts standard sequence file formats and an optional style specification file to generate customizable, publication quality genome maps in bitmap and scalable vector graphics formats. GView features an interactive pan-and-zoom interface, a command-line interface for incorporation in genome analysis pipelines, and a public Application Programming Interface for incorporation in other Java applications. AVAILABILITY: GView is a freely available application licensed under the GNU Public License. The application, source code, documentation, file specifications, tutorials and image galleries are available at http://gview.ca. PMID- 20956245 TI - High-quality annotation of promoter regions for 913 bacterial genomes. AB - MOTIVATION: The number of bacterial genomes being sequenced is increasing very rapidly and hence, it is crucial to have procedures for rapid and reliable annotation of their functional elements such as promoter regions, which control the expression of each gene or each transcription unit of the genome. The present work addresses this requirement and presents a generic method applicable across organisms. RESULTS: Relative stability of the DNA double helical sequences has been used to discriminate promoter regions from non-promoter regions. Based on the difference in stability between neighboring regions, an algorithm has been implemented to predict promoter regions on a large scale over 913 microbial genome sequences. The average free energy values for the promoter regions as well as their downstream regions are found to differ, depending on their GC content. Threshold values to identify promoter regions have been derived using sequences flanking a subset of translation start sites from all microbial genomes and then used to predict promoters over the complete genome sequences. An average recall value of 72% (which indicates the percentage of protein and RNA coding genes with predicted promoter regions assigned to them) and precision of 56% is achieved over the 913 microbial genome dataset. AVAILABILITY: The binary executable for 'PromPredict' algorithm (implemented in PERL and supported on Linux and MS Windows) and the predicted promoter data for all 913 microbial genomes are available at http://nucleix.mbu.iisc.ernet.in/prombase/. PMID- 20956246 TI - State reduction for network intervention in probabilistic Boolean networks. AB - MOTIVATION: A key goal of studying biological systems is to design therapeutic intervention strategies. Probabilistic Boolean networks (PBNs) constitute a mathematical model which enables modeling, predicting and intervening in their long-run behavior using Markov chain theory. The long-run dynamics of a PBN, as represented by its steady-state distribution (SSD), can guide the design of effective intervention strategies for the modeled systems. A major obstacle for its application is the large state space of the underlying Markov chain, which poses a serious computational challenge. Hence, it is critical to reduce the model complexity of PBNs for practical applications. RESULTS: We propose a strategy to reduce the state space of the underlying Markov chain of a PBN based on a criterion that the reduction least distorts the proportional change of stationary masses for critical states, for instance, the network attractors. In comparison to previous reduction methods, we reduce the state space directly, without deleting genes. We then derive stationary control policies on the reduced network that can be naturally induced back to the original network. Computational experiments study the effects of the reduction on model complexity and the performance of designed control policies which is measured by the shift of stationary mass away from undesirable states, those associated with undesirable phenotypes. We consider randomly generated networks as well as a 17-gene gastrointestinal cancer network, which, if not reduced, has a 2(17) * 2(17) transition probability matrix. Such a dimension is too large for direct application of many previously proposed PBN intervention strategies. PMID- 20956247 TI - Identifying functional miRNA-mRNA regulatory modules with correspondence latent dirichlet allocation. AB - MOTIVATION: MicroRNAs (miRNAs) are small non-coding RNAs that cause mRNA degradation and translational inhibition. They are important regulators of development and cellular homeostasis through their control of diverse processes. Recently, great efforts have been made to elucidate their regulatory mechanism, but the functions of most miRNAs and their precise regulatory mechanisms remain elusive. With more and more matched expression profiles of miRNAs and mRNAs having been made available, it is of great interest to utilize both expression profiles to discover the functional regulatory networks of miRNAs and their target mRNAs for potential biological processes that they may participate in. RESULTS: We present a probabilistic graphical model to discover functional miRNA regulatory modules at potential biological levels by integrating heterogeneous datasets, including expression profiles of miRNAs and mRNAs, with or without the prior target binding information. We applied this model to a mouse mammary dataset. It effectively captured several biological process specific modules involving miRNAs and their target mRNAs. Furthermore, without using prior target binding information, the identified miRNAs and mRNAs in each module show a large proportion of overlap with predicted miRNA target relationships, suggesting that expression profiles are crucial for both target identification and discovery of regulatory modules. PMID- 20956249 TI - Part 1: Executive summary: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. PMID- 20956250 TI - Part 2: International collaboration in resuscitation science: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. PMID- 20956251 TI - Part 3: Evidence evaluation process: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. PMID- 20956252 TI - Part 4: Conflict of interest management before, during, and after the 2010 International Consensus Conference on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. PMID- 20956253 TI - Part 5: Adult basic life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. PMID- 20956254 TI - Part 6: Defibrillation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. PMID- 20956255 TI - Part 7: CPR techniques and devices: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. PMID- 20956256 TI - Part 8: Advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. PMID- 20956257 TI - Part 9: Acute coronary syndromes: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. PMID- 20956259 TI - Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. PMID- 20956261 TI - Part 13: First aid: 2010 American Heart Association and American Red Cross International Consensus on First Aid Science With Treatment Recommendations. PMID- 20956260 TI - Part 12: Education, implementation, and teams: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. PMID- 20956263 TI - Countrywide campaign to prevent soccer injuries in Swiss amateur players. AB - BACKGROUND: In Switzerland, the national accident insurance company registered a total of 42 262 soccer injuries, resulting in costs of approximately 145 million Swiss francs (~US$130 million) in 2003. Research on injury prevention has shown that exercise-based programs can reduce the incidence of soccer injuries. PURPOSE: This study was conducted to assess the implementation and effects of a countrywide campaign to reduce the incidence of soccer injuries in Swiss amateur players. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: All coaches of the Schweizerischer Fussballverband (SFV) received information material and were instructed to implement the injury prevention program "The 11" in their training of amateur players. After the instruction, the coaches were asked to rate the quality and the feasibility of "The 11." Before the start of the intervention and 4 years later, a representative sample of about 1000 Swiss soccer coaches were interviewed about the frequency and characteristics of injuries in their teams. Teams that did or did not practice "The 11" were compared with respect to the incidence of soccer injuries. RESULTS: A total of 5549 coaches for amateur players were instructed to perform "The 11" in the training with their teams. The ratings of the teaching session and the prevention program were overall very positive. In 2008, 80% of all SFV coaches knew the prevention campaign "The 11" and 57% performed the program or most parts of it. Teams performing "The 11" had an 11.5% lower incidence of match injuries and a 25.3% lower incidence of training injuries than other teams; noncontact injuries in particular were prevented by the program. CONCLUSION: "The 11" was successfully implemented in a countrywide campaign and proved effective in reducing soccer injuries in amateur players. An effect of the prevention program was also observed in the population-based insurance data and health-care costs. PMID- 20956264 TI - Adenoviral-mediated gene transfer of human bone morphogenetic protein-13 does not improve rotator cuff healing in a rat model. AB - BACKGROUND: Rotator cuff tendon-to-bone healing occurs by formation of a scar tissue interface after repair, which makes it prone to failure. Bone morphogenetic protein-13 (BMP-13) has been implicated in tendon and cartilage repair, and thus may augment rotator cuff repairs. The purpose of this study was to determine if the application of mesenchymal stem cells (MSCs) transduced with BMP-13 could improve regeneration of the tendon-bone insertion site in a rat rotator cuff repair model. HYPOTHESIS: Mesenchymal stem cells genetically modified to overexpress BMP-13 will improve rotator cuff healing based on histologic and biomechanical outcomes. STUDY DESIGN: Controlled laboratory study. METHODS: Sixty Lewis rats underwent unilateral detachment and repair of the supraspinatus tendon and 10 rats were used for MSC harvest. Animals were randomized into 2 groups (30 animals/group). The experimental group received 106 MSCs transduced with adenoviral-mediated gene transfer of human BMP-13 (Ad-BMP 13). The second group received untransduced MSCs. Fifteen animals in each group were sacrificed at 2 and 4 weeks. At each time point, 12 animals were allocated for biomechanical testing, and 3 for histomorphometric analysis. RESULTS: There were no differences in the amount of new cartilage formation or collagen fiber organization between groups at either time point. There were also no differences in the biomechanical strength of the repairs, the cross-sectional area, peak stress at failure, or stiffness. CONCLUSION: Application of MSCs genetically modified to overexpress BMP-13 did not improve healing in a rat model of rotator cuff repair. CLINICAL RELEVANCE: Further studies are needed to evaluate various growth factors and combinations of growth factors to determine the optimal factor for the biologic augmentation of rotator cuff repairs. PMID- 20956265 TI - Knee rotational laxity in a randomized comparison of single- versus double-bundle anterior cruciate ligament reconstruction. AB - BACKGROUND: While single-bundle anterior cruciate ligament reconstruction reduces anterior-posterior laxity, studies have demonstrated residual rotational instability. Improved pivot-shift results have been shown with the double-bundle graft; however, no study has compared rotational laxity outcome of these surgical techniques in vivo under quantified, isolated torsional loading. HYPOTHESIS: The anterior cruciate ligament-deficient knee exhibits greater rotational laxity than the contralateral uninjured knee. The double-bundle reconstruction restores rotational joint stability to a greater extent than single-bundle surgery. STUDY DESIGN: Controlled laboratory study. METHODS: Rotational laxity of 32 patients with unilateral anterior cruciate ligament injury was assessed in both knees at full extension and 30 degrees of flexion using a magnetic resonance imaging compatible torsional loading device. Patients were randomly allocated either a single- or double-bundle reconstruction and reassessed 5 months after surgery. RESULTS: The anterior cruciate ligament-deficient knees demonstrated greater laxity to internal rotational torque in the extended position, but not in the 30 degrees flexed position. No significant differences in rotational laxity were found between single- and double-bundle reconstructions. In extension, excessive internal rotational laxity of injured compared with contralateral knees was reduced by anterior cruciate ligament reconstruction. The single-bundle reconstruction did not affect internal rotation compared with contralateral or preoperative groups. In response to internal rotational torque in the flexed knee position, the double-bundle reconstruction reduced laxity to 10.8 degrees from the pre-operative value of 15.3 degrees (P = .058); postoperative rotation was also significantly less than the contralateral laxity of 16.4 degrees (P = .022). CONCLUSION: The ruptured anterior cruciate ligament resulted in increased internal rotational laxity only in the extended position. The single-bundle reconstruction did not affect rotational restraint compared with contralateral or preoperative groups. The double-bundle procedure significantly reduced internal laxity in the flexed position when compared with normal. CLINICAL RELEVANCE: As the anterior cruciate ligament is not the primary restraint to rotation, its contribution to joint stability is limited under isolated torsional load. While the double-bundle graft demonstrates superior rotational constraint, this may be excessive for isolated anterior cruciate ligament rupture. PMID- 20956266 TI - Impairment of ovarian function and associated health-related abnormalities are attributable to low social status in premenopausal monkeys and not mitigated by a high-isoflavone soy diet. AB - BACKGROUND: Psychological stress may impair premenopausal ovarian function and contribute to risk for chronic disease. Soy isoflavones may also influence ovarian function and affect health. Here, we report the effects of a psychological stressor (subordinate social status) and dietary soy on reproductive function and related health indices in female monkeys. We hypothesized that reproductive compromise and adverse health outcomes would be induced in subordinate when compared with dominant monkeys and be mitigated by exposure to soy. METHODS: Subjects were 95 adult cynomolgus monkeys (Macaca fascicularis) housed in social groups of five or six. Animals consumed a soy free, animal protein-based diet during an 8-month Baseline phase and then, during a 32-month Treatment phase, consumed either the baseline diet or an identical diet that substituted high-isoflavone soy protein for animal protein. RESULTS: Across more than 1200 menstrual cycles, subordinate monkeys consistently exhibited ovarian impairment [increased cycle length (P < 0.02) and variability (P < 0.02) and reduced levels of progesterone (P < 0.04) and estradiol (P < 0.04)]. Subordinate status was confirmed behaviorally and was associated with elevated cortisol (P < 0.04) and relative osteopenia (P < 0.05). Consumption of the soy diet had no significant effects. CONCLUSIONS: (i) Psychological stress adversely affects ovarian function and related health indices in a well-accepted animal model of women's health; (ii) Similar effects may extend to women experiencing reproductive impairment of psychogenic origin; (iii) soy protein and isoflavones neither exacerbate nor mitigate the effects of an adverse psychosocial environment; and (iv) this study was limited by an inability to investigate the genetic and developmental determinants of social status. PMID- 20956267 TI - SB203580, a p38 mitogen-activated protein kinase inhibitor, suppresses the development of endometriosis by down-regulating proinflammatory cytokines and proteolytic factors in a mouse model. AB - BACKGROUND: p38 mitogen-activated protein kinase (p38 MAPK), a regulator of inflammation, may play a role in the pathogenesis of endometriosis (EM). We studied the effect of SB203580, a p38 MAPK inhibitor, on the development of EM in a mouse model. METHODS: EM was induced in BALB/c mice by peritoneal injection of endometrium-rich fragments. Mice (n = 15) were injected i.p. for 24 days with SB203580 and 15 mice served as positive controls (EM group). Sham-operated mice received carrier only. Peritoneal fluid (PF) cells were collected for protein/mRNA analysis. Interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, matrix metalloproteinase-2 (MMP-2) and MMP-9 proteins were measured using enzyme linked immunosorbent assay and mRNAs by RT-PCR. Phosphorylation of p38 MAPK was evaluated by western blotting. RESULTS: SB203580 decreased the weight and size (P < 0.05 versus EM) of endometriotic lesions in BALB/c mice. IL-1beta, TNF-alpha, MMP-2 and MMP-9 mRNA levels were decreased in peritoneal cells of the SB203580 versus EM group (P < 0.01, P < 0.05, P < 0.05 and P < 0.05, respectively). Concentrations of IL-1beta, TNF-alpha, MMP-2 and MMP-9 proteins in PF were reduced in the SB203580 versus EM group (P < 0.05, P < 0.01, P < 0.05 and P < 0.05, respectively). Compared with the sham-operated group, phosphorylation of p38 MAPK in the EM group was increased, and this was down-regulated by SB203580 (P < 0.01). CONCLUSIONS: SB203580 may suppress the development of EM by inhibiting expression of proinflammatory cytokines and proteolytic factors. p38 MAPK might play a key role in progression of EM. PMID- 20956268 TI - Viral screening of couples undergoing partner donation in assisted reproduction with regard to EU Directives 2004/23/EC, 2006/17/EC and 2006/86/EC: what is the evidence for repeated screening? AB - BACKGROUND: This paper concerns the requirements of the EU Tissue and Cells Directives with regard to the biological screening of donors of reproductive cells which are to be used for partner donation. METHODS: We review the evidence regarding the risks of transmission of blood-borne viruses [hepatitis B (HBV), hepatitis C (HCV) and human immunodeficiency virus (HIV)] in the assisted reproductive technology (ART) setting. We document the experience in seven Irish ART clinics since the introduction of the legislation. RESULTS: Even among those known to be HBV-, HCV- or HIV-positive, when current best practice ART procedures are employed for gamete and embryo processing, cross-contamination in the ART facility or horizontal or vertical transmission to a partner or neonate has never been documented. When samples are processed and high-security straws are used for cryopreservation, transmission of virus and cross-contamination in storage have not been reported. CONCLUSIONS: While initial screening of those about to embark on ART treatment is good practice, we can find no medical or scientific evidence to support re-screening prior to each treatment cycle for individuals undergoing partner donation in ART. It would seem more appropriate to focus on risk reduction using a combination of initial baseline screening (with a reduced frequency of re-testing), appropriate sample processing and best possible containment systems for cryostorage. PMID- 20956269 TI - FSH, LH, inhibin B and estradiol levels in Turner syndrome depend on age and karyotype: longitudinal study of 70 Turner girls with or without spontaneous puberty. AB - BACKGROUND: Ovarian function in Turner syndrome (TS) patients depends on the specific karyotype. This retrospective clinical study evaluates the pituitary gonadal axis during infancy, childhood and adolescence in TS patients according to karyotype and ovarian function. METHODS: A cohort of 70 TS patients (0-16 years) followed at a tertiary referral centre for paediatric endocrinology were included. Longitudinal measurements of reproductive hormones (FSH, LH, inhibin B and estradiol) prior to hormonal replacement treatment in 66 patients related to karyotype (A, 45,X; or B, miscellaneous karyotypes) and ovarian function (spontaneous puberty or absent spontaneous puberty) were compared with an age matched reference range of 2406 healthy Danish females. RESULTS: The prevalence of spontaneous puberty was 6% for 45,X and 54% for miscellaneous karyotypes, P = 0.001. In all TS patients, gonadotrophins were higher during infancy and at expected puberty compared with levels at mid-childhood, where 21/25 and 23/27 had FSH and LH levels, respectively, within the reference range. In patients with absent spontaneous puberty, 10/12 had FSH in the reference range during the mid childhood nadir. 45,X-TS patients had undetectable inhibin B at 0-16 years. Ovarian failure was predicted in 20/20 patients with exclusively undetectable inhibin B, while 9/10 with detectable inhibin B entered puberty spontaneously. Estradiol levels were elevated from 4 to 8 years. CONCLUSIONS: Ovarian function in TS patients is associated with the specific karyotype, and multiple undetectable inhibin B values during mid-childhood may predict absence of spontaneous puberty, although the specificity of the test is low. The biphasic age pattern of gonadotrophins was preserved in all patients, and spontaneous gonadotrophins are not useful as a diagnostic marker for TS in girls aged 6-10 years. PMID- 20956270 TI - Rules and regulations in reproductive medicine: sensible requirements that should start with evidence. PMID- 20956271 TI - Agreement of visual field interpretation among glaucoma specialists and comprehensive ophthalmologists: comparison of time and methods. AB - AIMS: To evaluate interobserver agreement and interpretation time for three clinically available formats of visual field presentation: serial Humphrey visual field (HVF), STATPAC2 and PROGRESSOR. METHODS: 40 field series from the Advanced Glaucoma Intervention Study were presented to eight glaucoma specialists and eight comprehensive ophthalmologists to determine whether each field series was stable or progressive. Interobserver agreement and agreement with Hodapp-Parrish Anderson criteria were evaluated using kappa statistics, and the interpretation time was compared. RESULTS: For glaucoma specialists, median kappa values for interobserver agreement were 0.47, 0.60 and 0.43 for HVF, STATPAC2 and PROGRESSOR, respectively. Respective kappa values for comprehensive ophthalmologists were 0.43, 0.43 and 0.35. For glaucoma specialists, median kappa values for agreement with Hodapp-Parrish-Anderson criteria were 0.52, 0.67 and 0.52 for HVF, STATPAC2 and PROGRESSOR, respectively. Respective kappa values for comprehensive ophthalmologists were 0.41, 0.47 and 0.33. For glaucoma specialists, the mean+/-SD interpretation time for the series of 40 fields was 63.4+/-35.9, 57.1+/-23.1 and 41.1+/-15.3 min using HVF, STATPAC2 and PROGRESSOR, respectively. Respective interpretation times for comprehensive ophthalmologists were 72.9+/-38.3, 68.6+/-30.6 and 51+/-24.1 min. Interpretation time was decreased when STATPAC2 or PROGRESSOR was used rather than HVF. Time reduction was significant for glaucoma specialists using PROGRESSOR (p=0.02). CONCLUSIONS: For glaucoma specialists, interobserver agreement and agreement with HPA criteria were moderate to substantial. For comprehensive ophthalmologists, interobserver agreement and agreement with HPA criteria were fair to moderate. Field interpretation time may be reduced clinically when using STATPAC2 or PROGRESSOR rather than HVF. PMID- 20956258 TI - Part 10: Pediatric basic and advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. PMID- 20956272 TI - Evaluation of histamine-induced conjunctival oedema in guinea pigs by means of image analysis. AB - BACKGROUND: Conjunctival oedema is commonly observed in patients with allergic conjunctivitis and can be induced by histamine. In animal models of allergic conjunctivitis, conjunctival oedema is generally evaluated by measuring the extravasation of Evans blue dye into the conjunctiva. A limitation of this method is that it only allows evaluation at a single time point. The aim of the present study was to investigate kinetic changes in histamine-induced bulbar oedema. METHODS: Evans blue dye was injected intravenously into male guinea pigs. Histamine eye-drops were administered 30 min later. One group of animals received levocabastine (an antihistamine) eye-drops 10 min before histamine challenge. A digital camera was used to obtain images of the bulbar conjunctiva at 1 min intervals until 30 min after histamine challenge. The conjunctivas were then harvested, and the concentration of Evans blue was measured. The ImageJ software was used to analyse the images by counting the number of absolute pixel values. RESULTS: The degree of conjunctival oedema increased progressively until 20 min after histamine challenge and then stabilised. Correspondingly, the number of absolute pixel values increased significantly until 5 min after histamine challenge, then increased gradually until the 20 min time point and finally plateaued. Pixel values were significantly lower in animals treated with levocabastine than in control animals. A significant correlation was observed between the pixel values of the conjunctival images and the concentration of Evans blue in the conjunctiva. CONCLUSIONS: This is the first study to have quantitatively evaluated kinetic changes in histamine-induced bulbar oedema by means of image analysis. PMID- 20956273 TI - Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1. AB - OBJECTIVES: To identify CRB1 mutations in a large cohort of patients with recessive retinal dystrophies and to document the retinal phenotype and visual prognosis. DESIGN: A hospital-based cross-sectional study of children and adults with recessive retinal dystrophies. PARTICIPANTS: Three hundred and six patients with Leber congenital amaurosis (LCA), early-onset childhood retinal dystrophy or juvenile onset retinitis pigmentosa were recruited to the study and gave blood samples for molecular genetic analysis. METHODS: A detailed clinical examination was performed, including: logMAR visual acuity, refraction, Goldmann visual fields, slit-lamp biomicroscopy, fundus photography, autofluorescence imaging and optical coherence tomography. The results of electrophysiology testing were available in all patients. DNA was obtained for molecular genetic analysis. Initial screening for mutations was performed using the LCA chip. Patients who had one or more CRB1 mutations identified on the chip, and other patients whose phenotype suggested a CRB1 genotype, underwent direct sequencing. In addition, consanguineous families segregating recessive RP underwent a whole genome scan using Affymetrix gene chips, and affected family members showing linkage to the RP12 locus underwent sequencing of the CRB1 gene. MAIN OUTCOME MEASURES: Identification of patients with mutations in CRB1 and detailed documentation of the clinical phenotype. RESULTS: Mutations in CRB1, including 17 novel mutations, were identified in 41 patients from 32 families. The authors identified both disease mutations in 34 patients from 26 families, and these patients underwent detailed phenotyping. Common phenotypic features included hypermetropic refractive error, nummular pigmentation at the level of the RPE and increased retinal thickness on optical coherence tomography. Most patients had a clinical and electrophysiological phenotype consistent with a diagnosis of LCA or rod-cone dystrophy, but three patients had electroretinogram evidence of cone-rod degeneration. A minority of patients developed peripheral retinal telangiectasia, which in some cases led to seclusio pupillae and angle-closure glaucoma. CONCLUSION: Mutations in CRB1 are associated with a range of recessively inherited retinal dystrophies, including LCA, childhood- and juvenile-onset rod cone and cone-rod dystrophies. Although the phenotype is usually severe, in milder cases there is a window of opportunity for therapeutic intervention in early childhood. PMID- 20956274 TI - Negative refraction power causes underestimation of peripapillary retinal nerve fibre layer thickness in spectral-domain optical coherence tomography. AB - BACKGROUND/AIMS: Although studies using optical coherence tomography (OCT) reported that the retinal nerve fibre layer (RNFL) thickness of myopic eyes was thinner than those of normal controls, it was unclear if this finding indicated the difference in actual structural thickness or that created by sources affecting accuracy of OCT measurement. This study's aim was to evaluate the effect of refraction power on the measurement of the RNFL thickness using spectral-domain OCT. METHODS: OCT scans to measure RNFL thickness were repeated in 15 cycloplegic eyes of 15 participants, while different refraction powers were induced by wearing soft contact lenses of eight different dioptres (-6 to +8). RESULTS: Measured RNFL thicknesses decreased significantly with soft contact lenses of higher plus dioptres and increased with those of more minus dioptres. This finding was consistent with or without controlling factors including the signal strength and test-retest variability of the machine. Measurement of peripapillary RNFL thicknesses was not varied between scans performed with and without plano contact lenses. CONCLUSIONS: In spectral-domain OCT, RNFL thickness was underestimated in eyes with increasing negative refraction power and overestimated with increasing positive refraction power. PMID- 20956275 TI - Histological evaluation and biomechanical characterisation of an acellular porcine cornea scaffold. AB - PURPOSE: To optimise a protocol to produce an acellular porcine cornea scaffold and investigate its mechanical integrity and biocompatibility. METHODS: Fresh porcine corneas were decellularised with different detergents over a range of concentrations. Morphological and histological examinations were carried out to detect the major structure of the cornea. Completely acellular cornea scaffolds were subjected to uniaxial tensile testing and reseeding assay. RESULTS: Most protocols resulted in the retention of large numbers of whole cells and cell fragments. Only sodium dodecyl sulfate (SDS; 0.5% or 1%) resulted in total decellularisation at 24h. Histological analysis of the acellular matrix showed that the corneal stromal cells had been completely removed, collagen fibres were arranged in an orderly fashion, and Bowman's layer and Descemet's membrane were both intact after decellularisation. The ultimate tensile strength of acellular matrix treated with 0.5% SDS for 24h was not affected significantly compared with that of fresh cornea (p>0.05), whereas there was a significant difference between fresh cornea and cornea treated with 1% SDS (p<0.05). Clusters of corneal epithelial cells were observed on the surface of the matrix. CONCLUSION: Protocols using SDS (0.5% or 1% for 24h) were successful for cornea decellularisation. Biomechanical analysis and recellularisation showed that treatment with 0.5% SDS for 24h was optimal. PMID- 20956276 TI - Validation of a fornix depth measurer: a putative tool for the assessment of progressive cicatrising conjunctivitis. AB - BACKGROUND/AIMS: Documentation of conjunctival forniceal foreshortening in cases of progressive cicatrising conjunctivitis (PCC) is important in ascertaining disease stage and progression. Lower fornix shortening is often documented subjectively or semi-objectively, whereas upper forniceal obliteration is seldom quantified. Although tools such as fornix depth measurers (FDMs) have been described, their designs limit upper fornix measurement. The purpose of this study was to custom-design a FDM to evaluate the upper fornix and to assess variability in gauging fornix depth. METHODS: A polymethylmethacrylate FDM was constructed using industry-standard jewellery computer software and machinery. Two observers undertook a prospective independent evaluation of central lower fornix depth in a heterogeneous cohort of patients with clinically normal and abnormal conjunctival fornices both subjectively and by using the FDM (in mm). Upper central fornix depth was also measured. Agreement was assessed using Bland Altman plots. RESULTS: Fifty-one eyes were evaluated. There was 100% intraobserver agreement to within 1 mm for each observer for lower fornix measurement. The mean difference in fornix depth loss using the FDM between observer 1 and 2 was 1.19%, with 95% confidence of agreement (+/-2SD) of -15% to +20%. In total, 86% (44/51) of measurements taken by the two observers agreed to within 10% of total lower fornix depth (ie, +/-1 mm) versus only 63% (32/51) of the subjective measurements. Mean upper fornix difference was 0.57 mm, with 95% confidence of agreement of between -2 and +3 mm. CONCLUSIONS: This custom designed FDM is well tolerated by patients and shows low intraobserver and interobserver variability. This enables repeatable and reproducible measurement of upper and lower fornix depths, facilitating improved rates of detection and better monitoring of progression of conjunctival scarring. PMID- 20956278 TI - Subthreshold laser treatment for retinal arterial macroaneurysm. AB - PURPOSE: To assess the effects of subthreshold laser treatment (STLT) for retinal arterial macroaneurysms (RAM) associated with foveal exudative manifestations and visual acuity deterioration. METHODS: Patients with RAM associated with foveal exudative manifestations and best-corrected visual acuity (BCVA) worse than 20/80 Snellen equivalent underwent a ophthalmological examination, including ETDRS visual acuity, optical coherence tomography (OCT) and fluorescein angiography. The patients were prospectively observed for 4 months, and in absence of spontaneous improvement, they underwent STLT using an infrared diode laser. RESULTS: Primary outcome measures were a reduction in mean central point thickness (CPT) and BCVA changes at the 12-month examination. Secondary outcomes included changes in mean total macular volume (TMV) and central subfield thickness (CST). Nine patients were enrolled and prospectively followed up. The mean baseline values of BCVA, CPT, TMV and CST were 0.8 +/- 0.1 (logMAR +/- SD), 340 +/- 49 MUm, 7.14 +/- 0.05 mm(3) and 366 +/- 37 MUm, respectively. At the 4 month examination following STLT, the mean BCVA improved to 0.6 +/- 0.2, whereas the mean CPT, TMV, and CST decreased to 274 +/- 29 MUm, 6.87 +/- 0.11 mm(3) and 296 +/- 33 MUm. At the 12-month examination, the mean BCVA was 0.36 +/- 0.2, the mean CPT was 195 +/-11 MUm, the mean TMV was 6.55 +/- 0.19 mm(3), and the mean CST was 239 +/- 14 MUm, respectively. No side-effects were noted. In particular, no sign of retinal thinning and underlying backscattering typical of conventional laser treatment could be detected at the site of the laser application on OCT. CONCLUSION: The current pilot investigation of STLT for the treatment of symptomatic RAM revelas encouraging data. A randomised clinical trial is required to ascertain the real efficacy of this technique and the most appropriate settings to be employed. PMID- 20956277 TI - Evidence of outer retinal changes in glaucoma patients as revealed by ultrahigh resolution in vivo retinal imaging. AB - AIMS; It is well established that glaucoma results in a thinning of the inner retina. To investigate whether the outer retina is also involved, ultrahigh resolution retinal imaging techniques were utilised. METHODS: Eyes from 10 glaucoma patients (25-78 years old), were imaged using three research-grade instruments: (1) ultrahigh-resolution Fourier-domain optical coherence tomography (UHR-FD-OCT), (2) adaptive optics (AO) UHR-FD-OCT and (3) AO-flood illuminated fundus camera (AO-FC). UHR-FD-OCT and AO-UHR-FD-OCT B-scans were examined for any abnormalities in the retinal layers. On some patients, cone density measurements were made from the AO-FC en face images. Correlations between retinal structure and visual sensitivity were measured by Humphrey visual-field (VF) testing made at the corresponding retinal locations. RESULTS: All three in vivo imaging modalities revealed evidence of outer retinal changes along with the expected thinning of the inner retina in glaucomatous eyes with VF loss. AO-UHR-FD-OCT images identified the exact location of structural changes within the cone photoreceptor layer with the AO-FC en face images showing dark areas in the cone mosaic at the same retinal locations with reduced visual sensitivity. CONCLUSION: Losses in cone density along with expected inner retinal changes were demonstrated in well-characterised glaucoma patients with VF loss. PMID- 20956279 TI - Cerebrospinal fluid dynamics between the basal cisterns and the subarachnoid space of the optic nerve in patients with papilloedema. AB - AIMS: To determine cerebrospinal fluid (CSF) dynamics between intracranial CSF spaces and CSF in the subarachnoid space (SAS) of optic nerves (ONs) in 10 patients with papilloedema. METHODS: Prospective assessment of 10 patients with papilloedema and two control subjects using CT cisternography and analysis of CSF for the presence of lipocalin-like prostaglandin D synthase (betatrace protein). RESULTS: CT cisternography showed a progressively reduced influx of contrast loaded CSF from intracranial CSF spaces into the SAS. The lowest concentration of contrast-loaded CSF was found in the region of the ON immediately behind the globe, where the ON sheath was widened (possibly by unfolding) in all patients compared with normal subjects. The concentration of lipocalin-like prostaglandin D synthase differed between the spinal CSF and the CSF in the SAS, with a markedly higher concentration in the SAS. CONCLUSION: The results of this study suggest that CSF turnover in the SAS of the ON is reduced in patients with papilloedema from various causes and that the composition of CSF differs between spinal CSF and that surrounding the ON. PMID- 20956280 TI - Expression of HSP 90, PTEN and Bcl-2 in conjunctival melanoma. AB - BACKGROUND: In conjunctival melanoma, little is known about the tumour biology and protein-expression patterns. In this study, the authors analysed the expression of the antiapoptotic oncoprotein B cell leukaemia/lymphoma-2 protein (Bcl-2), the tumour-suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN), and the heat-shock-protein HSP-90 in conjunctival melanoma (CoM) and conjunctival nevi (CoN) by immunohistochemistry (IHC). MATERIAL AND METHODS: IHC was performed on 70 samples of CoM and 12 samples of CoN. Expression patterns between the diagnosis groups were compared. A receiver operating characteristic analysis was performed to determine the diagnostic value of the antigens. RESULTS: HSP-90 (p<0.0001) and PTEN (p=0.001) showed the potential to differentiate between CoM and CoN. Bcl-2 expression was higher in CoM than in CoN (p=0.04). The loss of nuclear PTEN expression was more pronounced in the malignant melanomas than in CoN (p=0.02). Tumours located at unfavourable sites (fornix, palpebral conjunctiva, caruncle) that had developed recurrences expressed almost twice as much HSP-90 than recurrence-free tumours. CONCLUSIONS: Conjunctival melanocytes differentially express Bcl-2, HSP-90 and PTEN, depending on their entity. HSP-90- and PTEN expression may add relevant information for the differentiation between conjunctival melanoma and nevi. PMID- 20956281 TI - Impact of early and late age-related macular degeneration on vision-specific functioning. AB - AIM: To assess the impact of early and late age-related macular degeneration (AMD) on vision-specific functioning in Singapore Malays. METHODS: AMD was assessed from fundus photographs. The following endpoints were considered for (a) AMD: no AMD, early AMD, and late AMD; (b) drusen: absence and presence; and (c) retinal pigment epithelium (RPE) abnormality: absence and presence. Vision functioning was assessed using the modified VF-11 scale validated using the Rasch analysis. The overall functioning score was used as the main outcome measure. RESULTS: Retinal photographs and vision functioning data were available only for 3252 participants. After age standardisation, the prevalence of early AMD was 3.5% and late AMD 0.34%. In multivariate models, after adjusting for age, gender, education, level of income, smoking status, ocular condition and hypertension, only late AMD was independently associated with poorer vision functioning when compared with no AMD or early AMD (beta (beta regression coefficient)=-6.4 (CI 11.7 to -2.1; p=0.01)). Early AMD or its principal components, drusen or RPE abnormality, were not independently associated with vision functioning (p>0.05). In adjusted multinomial logistic regression models, people with late AMD were twice as likely (OR=2.23; 95% CI 1.16 to 7.11) to have low overall functioning than those without AMD. CONCLUSIONS: Late AMD has a significant impact on visual functioning, but early AMD, drusen and RPE changes have no impact. These data highlight the importance of preventive public health strategies targeting patients with early AMD signs in order to prevent progression to late AMD when visual function is compromised. PMID- 20956282 TI - Probability of bystander effect induced by alpha-particles emitted by radon progeny using the analytical model of tracheobronchial tree. AB - Radiation-induced biological bystander effects have become a phenomenon associated with the interaction of radiation with cells. There is a need to include the influence of biological effects in the dosimetry of the human lung. With this aim, the purpose of this work is to calculate the probability of bystander effect induced by alpha-particle radiation on sensitive cells of the human lung. Probability was calculated by applying the analytical model cylinder bifurcation, which was created to simulate the geometry of the human lung with the geometric distribution of cell nuclei in the airway wall of the tracheobronchial tree. This analytical model of the human tracheobronchial tree represents the extension of the ICRP 66 model, and follows it as much as possible. Reported probabilities are calculated for various targets and alpha particle energies. Probability of bystander effect has been calculated for alpha particles with 6 and 7.69 MeV energies, which are emitted in the (222)Rn chain. The application of these results may enhance current dose risk estimation approaches in the sense of the inclusion of the influence of the biological effects. PMID- 20956283 TI - Counseling overweight patients: analysis of preventive encounters in primary care. AB - OBJECTIVE: The increasing prevalence of obesity requires particularly primary care providers to take action. The aim of this study was to analyze general practitioners (GPs) encounters with overweight and obese patients in primary care to test the hypothesis that patients with a BMI >= 30 kg/m2 would have longer consultations focusing on lifestyle-related issues like nutrition and physical activity than those with a BMI < 30 kg/m2. DESIGN: Cross sectional comparison of audiotaped encounters of patients with a BMI >= 30 kg/m2 and those with a BMI < 30 kg/m2. SETTING: Twelve GP surgeries in Berlin, Germany. PARTICIPANTS: Fifty patients who agreed to have preventive check-up encounters audiotaped. MAIN OUTCOME MEASURES: Based on the Roter Interaction ANALYSIS: System (RIAS) we assessed duration of encounter and the prevalence of GP statements regarding cardiovascular risks, nutrition and physical activity. RESULTS: An increased BMI was found to be a predictor for the length of encounters (P = 0.01), whereas the content of talks was mainly determined by the individual of GP and sex of the GP. Statements regarding cardiovascular risks were most frequent, followed by those regarding nutrition and physical activity. In this study the assessed physiological parameters were not associated with the specific contents of preventive encounters like nutrition or physical activity (P > 0.05). CONCLUSIONS: Our results indicate that GPs rarely use the check-up program to conduct lifestyle consultations with obese patients. Barriers to lifestyle counseling and possible solutions are discussed with a view to promoting individualized and target management of overweight patients. PMID- 20956284 TI - Finding common ground? Evaluating an intervention to improve teamwork among primary health-care professionals. AB - OBJECTIVE: Multidisciplinary care has been shown as the most effective option for chronic disease. The aim of the Team-link study was to assess the effectiveness of an intervention to improve teamwork among general practitioners (GPs), practice staff and allied health professionals (AHPs). This paper describes changes to teamwork using qualitative data collected in the study. DESIGN: Qualitative data about changes in internal and external professional collaboration were collected from facilitators' observations, GPs' reports and responses to a survey of AHPs assessing multidisciplinary teamwork. SETTING: Multidisciplinary teams within general practices and external collaborations with AHPs including dietitians, diabetic educators, exercise physiologists, podiatrists, psychologists and physiotherapists. PARTICIPANTS: GPs, practice nurses, practice staff, AHPs. INTERVENTION: A 6-month intervention consisting of an educational workshop and structured facilitation using specially designed materials, backed up by informal telephone support, was delivered to 26 practices. MAIN OUTCOME MEASURE: Data were analysed thematically using an approach based on identifying actors and associated collaborative actions. RESULTS: New and enhanced communication pathways were observed between GPs, practice staff, patients and AHPs following the intervention. The enhanced information sharing expedited communication and improved interprofessional collaboration within general practices and with AHPs. There was evidence of increased patient participation and empowerment in the care process and improved collaboration by practice staff and allied health providers. CONCLUSION: The Team link intervention improved professional collaboration among GPs, practice staff, AHPs and patients, increasing understanding and trust and enhancing multidisciplinary teamwork for chronic disease care in primary care settings. PMID- 20956285 TI - How are medication errors defined? A systematic literature review of definitions and characteristics. AB - OBJECTIVE: Multiplicity in terminology has been suggested as a possible explanation for the variation in the prevalence of medication errors. So far, few empirical studies have challenged this assertion. The objective of this review was, therefore, to describe the extent and characteristics of medication error definitions in hospitals and to consider the consequences for measuring the prevalence of medication errors. DATA SOURCES AND STUDY SELECTION: and data extraction Studies were searched for in PubMed, PsychINFO, Embase and CINAHL employing primary search terms such as 'medication errors' and 'adverse drug events'. Peer-reviewed articles containing these terms as primary end-points were included. Study country, year, aim, design, data-collection methods, sample-size, interventions and MAIN RESULT: were extracted. Result of data synthesis Forty five of 203 relevant studies provided a generic definition of medication errors including 26 different forms of wordings. The studies conducted in nine countries represented a variety of clinical settings and the approach was mainly descriptive. Of utmost importance is the documented prevalence of medication errors, which ranged from 2 to 75% with no associations found between definitions and prevalence. CONCLUSION: Inconsistency in defining medication errors has been confirmed. It appears that definitions and methods of detection rather than being reproducible and reliable methods are subject to the individual researcher's preferences. Thus, application of a clear-cut definition, standardized terminology and reliable methods has the potential to greatly improve the quality and consistency of medication error reporting. Efforts to achieve a common accepted definition that defines the scope and content are therefore needed. PMID- 20956286 TI - Telomere deficiencies on chromosomes 9p, 15p, 15q and Xp: potential biomarkers for breast cancer risk. AB - Although telomere dysfunction is a characteristic of breast cancer cells, the relationship between deficiency on individual chromosomal telomeres in normal somatic cells and breast cancer risk has not been characterized. A case-control study was conducted to examine the associations between individual lengths of 92 telomeres in the human genome and the risk of breast cancer in 204 newly diagnosed breast cancer patients and 236 healthy controls. Chromosome arm specific telomere lengths were measured by telomere quantitative fluorescent in situ hybridization. Unconditional logistic regression was used to estimate the risk associations. This genome-wide screen identified that shorter telomere lengths on chromosomes Xp and 15p were associated with breast cancer risk in pre menopausal women, with adjusted odds ratios (aORs) of 2.5 (95% CI = 1.3, 4.8) and 2.6 (1.3, 5.0), respectively. The study also revealed that greater length differences between homologous telomeres on chromosomes 9p, 15p and 15q were associated with breast cancer risk in pre-menopausal women, with aORs of 4.6 (2.3, 9.2), 3.1 (1.6, 6.0) and 2.8 (1.4, 5.4), respectively. When the subjects were categorized into quartiles, a dose-response relationship was observed for all of the above telomeres (P-for-trend <= 0.005). This study revealed that telomere deficiencies on chromosomes 9p, 15p, 15q and Xp were associated with breast cancer risk in pre-menopausal women. If confirmed in future studies, chromosomal arm-specific telomeres are likely to be a useful panel of blood-based biomarkers for breast cancer risk assessment, given their strong associations with breast cancer risk. PMID- 20956287 TI - SHEP1 partners with CasL to promote marginal zone B-cell maturation. AB - The marginal zone is a cellular niche bordering the marginal sinus of the spleen that contains specialized B-cell and macrophage subsets poised to capture bloodborne antigens. Marginal zone B cells are retained in this niche by integrin mediated signaling induced by G protein-coupled receptors (GPCRs) and, likely, the B-cell receptor (BCR). Sphingosine-1-phosphate (S1P) signaling via the S1P family of GPCRs is known to be essential for B-cell localization in the marginal zone, but little is known about the downstream signaling events involved. Here, we demonstrate that the adaptor protein SHEP1 is required for marginal zone B cell maturation. SHEP1 functions in concert with the scaffolding protein CasL, because we show that SHEP1 and CasL are constitutively associated in B cells. SHEP1 association is required for the BCR or S1P receptor(s) to induce the conversion of CasL into its serine/threonine hyperphosphorylated form, which is important for lymphocyte adhesion and motility. Thus, SHEP1 orchestrates marginal zone B-cell movement and retention as a key downstream effector of the BCR and S1P receptors. PMID- 20956288 TI - An essential transcription factor, SciP, enhances robustness of Caulobacter cell cycle regulation. AB - A cyclical control circuit composed of four master regulators drives the Caulobacter cell cycle. We report that SciP, a helix-turn-helix transcription factor, is an essential component of this circuit. SciP is cell cycle-controlled and co-conserved with the global cell cycle regulator CtrA in the alpha proteobacteria. SciP is expressed late in the cell cycle and accumulates preferentially in the daughter swarmer cell. At least 58 genes, including many flagellar and chemotaxis genes, are regulated by a type 1 incoherent feedforward motif in which CtrA activates sciP, followed by SciP repression of ctrA and CtrA target genes. We demonstrate that SciP binds to DNA at a motif distinct from the CtrA binding motif that is present in the promoters of genes co-regulated by SciP and CtrA. SciP overexpression disrupts the balance between activation and repression of the CtrA-SciP coregulated genes yielding filamentous cells and loss of viability. The type 1 incoherent feedforward circuit motif enhances the pulse like expression of the downstream genes, and the negative feedback to ctrA expression reduces peak CtrA accumulation. The presence of SciP in the control network enhances the robustness of the cell cycle to varying growth rates. PMID- 20956289 TI - GRIP1 and 2 regulate activity-dependent AMPA receptor recycling via exocyst complex interactions. AB - PSD-95/SAP90/DLG/ZO-1 (PDZ) domain-mediated protein-protein interactions play important roles in regulating AMPA receptor trafficking and neuronal plasticity. GRIP1 and GRIP2 are homologous multi-PDZ domain-containing proteins that bind to the C-termini of AMPA-R GluA2 and GluA3 subunits. Previous attempts to determine the cellular roles of GRIP1 and GRIP2 in neurons have been complicated by nonspecific reagents, and by the embryonic lethality of conventional GRIP1 KO mice. To circumvent these issues we developed a conditional targeted deletion strategy to knock out GRIP1 in postnatal neurons derived from GRIP2 KO mice. Loss of GRIP1 and 2 did not affect normal AMPA-R steady-state trafficking and endocytosis, but strikingly impaired activity-dependent AMPA-R recycling. This previously uncharacterized role for GRIP1 appears to be mediated by novel interactions with the cellular trafficking machinery via the exocyst protein complex. Indeed, disruption of GRIP1-exocyst binding caused a strikingly similar deficit in AMPA-R recycling. Together these findings reveal a previously unidentified role for AMPA-R-GRIP1-exocyst protein complexes in activity dependent AMPA-R trafficking. PMID- 20956290 TI - Connectivity-driven white matter scaling and folding in primate cerebral cortex. AB - Larger brains have an increasingly folded cerebral cortex whose white matter scales up faster than the gray matter. Here we analyze the cellular composition of the subcortical white matter in 11 primate species, including humans, and one Scandentia, and show that the mass of the white matter scales linearly across species with its number of nonneuronal cells, which is expected to be proportional to the total length of myelinated axons in the white matter. This result implies that the average axonal cross-section area in the white matter, a, does not scale significantly with the number of neurons in the gray matter, N. The surface area of the white matter increases with N(0.87), not N(1.0). Because this surface can be defined as the product of N, a, and the fraction n of cortical neurons connected through the white matter, we deduce that connectivity decreases in larger cerebral cortices as a slowly diminishing fraction of neurons, which varies with N(-0.16), sends myelinated axons into the white matter. Decreased connectivity is compatible with previous suggestions that neurons in the cerebral cortex are connected as a small-world network and should slow down the increase in global conduction delay in cortices with larger numbers of neurons. Further, a simple model shows that connectivity and cortical folding are directly related across species. We offer a white matter-based mechanism to account for increased cortical folding across species, which we propose to be driven by connectivity-related tension in the white matter, pulling down on the gray matter. PMID- 20956291 TI - Endosomal sorting of readily releasable synaptic vesicles. AB - Neurotransmitter release is achieved through the fusion of synaptic vesicles with the neuronal plasma membrane (exocytosis). Vesicles are then retrieved from the plasma membrane (endocytosis). It was hypothesized more than 3 decades ago that endosomes participate in vesicle recycling, constituting a slow endocytosis pathway required especially after prolonged stimulation. This recycling model predicts that newly endocytosed vesicles fuse with an endosome, which sorts (organizes) the molecules and buds exocytosis-competent vesicles. We analyzed here the endosome function using hippocampal neurons, isolated nerve terminals (synaptosomes), and PC12 cells by stimulated emission depletion microscopy, photooxidation EM, and several conventional microscopy assays. Surprisingly, we found that endosomal sorting is a rapid pathway, which appeared to be involved in the recycling of the initial vesicles to be released on stimulation, the readily releasable pool. In agreement with the endosomal model, the vesicle composition changed after endocytosis, with the newly formed vesicles being enriched in plasma membrane proteins. Vesicle proteins were organized in clusters both in the plasma membrane (on exocytosis) and in the endosome. In the latter compartment, they segregated from plasma membrane components in a process that is likely important for sorting/budding of newly developed vesicles from the endosome. PMID- 20956292 TI - Chronology of the Grotte du Renne (France) and implications for the context of ornaments and human remains within the Chatelperronian. AB - There is extensive debate concerning the cognitive and behavioral adaptation of Neanderthals, especially in the period when the earliest anatomically modern humans dispersed into Western Europe, around 35,000-40,000 B.P. The site of the Grotte du Renne (at Arcy-sur-Cure) is of great importance because it provides the most persuasive evidence for behavioral complexity among Neanderthals. A range of ornaments and tools usually associated with modern human industries, such as the Aurignacian, were excavated from three of the Chatelperronian levels at the site, along with Neanderthal fossil remains (mainly teeth). This extremely rare occurrence has been taken to suggest that Neanderthals were the creators of these items. Whether Neanderthals independently achieved this level of behavioral complexity and whether this was culturally transmitted or mimicked via incoming modern humans has been contentious. At the heart of this discussion lies an assumption regarding the integrity of the excavated remains. One means of testing this is by radiocarbon dating; however, until recently, our ability to generate both accurate and precise results for this period has been compromised. A series of 31 accelerator mass spectrometry ultrafiltered dates on bones, antlers, artifacts, and teeth from six key archaeological levels shows an unexpected degree of variation. This suggests that some mixing of material may have occurred, which implies a more complex depositional history at the site and makes it difficult to be confident about the association of artifacts with human remains in the Chatelperronian levels. PMID- 20956293 TI - Vaccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct viral subtypes. AB - Current influenza virus vaccines protect mostly against homologous virus strains; thus, regular immunization with updated vaccine formulations is necessary to guard against the virus' hallmark remodeling of regions that mediate neutralization. Development of a broadly protective influenza vaccine would mark a significant advance in human infectious diseases research. Antibodies with broad neutralizing activity (nAbs) against multiple influenza virus strains or subtypes have been reported to bind the stalk of the viral hemagglutinin, suggesting that a vaccine based on this region could elicit a broadly protective immune response. Here we describe a hemagglutinin subunit 2 protein (HA2)-based synthetic peptide vaccine that provides protection in mice against influenza viruses of the structurally divergent subtypes H3N2, H1N1, and H5N1. The immunogen is based on the binding site of the recently described nAb 12D1, which neutralizes H3 subtype viruses, demonstrates protective activity in vivo, and, in contrast to a majority of described nAbs, appears to bind to residues within a single alpha-helical portion of the HA2 protein. Our data further demonstrate that the specific design of our immunogen is integral in the induction of broadly active anti-hemagglutinin antibodies. These results provide proof of concept for an HA2-based influenza vaccine that could diminish the threat of pandemic influenza disease and generally reduce the significance of influenza viruses as human pathogens. PMID- 20956294 TI - Arginine methylation mediated by the Arabidopsis homolog of PRMT5 is essential for proper pre-mRNA splicing. AB - Protein arginine methylation, one of the most abundant and important posttranslational modifications, is involved in a multitude of biological processes in eukaryotes, such as transcriptional regulation and RNA processing. Symmetric arginine dimethylation is required for snRNP biogenesis and is assumed to be essential for pre-mRNA splicing; however, except for in vitro evidence, whether it affects splicing in vivo remains elusive. Mutation in an Arabidopsis symmetric arginine dimethyltransferase, AtPRMT5, causes pleiotropic developmental defects, including late flowering, but the underlying molecular mechanism is largely unknown. Here we show that AtPRMT5 methylates a wide spectrum of substrates, including some RNA binding or processing factors and U snRNP AtSmD1, D3, and AtLSm4 proteins, which are involved in RNA metabolism. RNA-seq analyses reveal that AtPRMT5 deficiency causes splicing defects in hundreds of genes involved in multiple biological processes. The splicing defects are identified in transcripts of several RNA processing factors involved in regulating flowering time. In particular, splicing defects at the flowering regulator flowering locus KH domain (FLK) in atprmt5 mutants reduce its functional transcript and protein levels, resulting in the up-regulation of a flowering repressor flowering locus C (FLC) and consequently late flowering. Taken together, our findings uncover an essential role for arginine methylation in proper pre-mRNA splicing that impacts diverse developmental processes. PMID- 20956295 TI - Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema. AB - Chronic obstructive pulmonary disease (COPD) is a debilitating disease caused by chronic exposure to cigarette smoke (CS), which involves airway obstruction and alveolar loss (i.e., emphysema). The mechanisms of COPD pathogenesis remain unclear. Our previous studies demonstrated elevated autophagy in human COPD lung, and as a cellular and tissue response to CS exposure in an experimental model of emphysema in vivo. We identified the autophagic protein microtubule-associated protein 1 light chain-3B (LC3B) as a positive regulator of CS-induced lung epithelial cell death. We now extend these initial observations to explore the mechanism by which LC3B mediates CS-induced apoptosis and emphysema development in vivo. Here, we observed that LC3B(-/-) mice had significantly decreased levels of apoptosis in the lungs after CS exposure, and displayed resistance to CS induced airspace enlargement, relative to WT littermate mice. We found that LC3B associated with the extrinsic apoptotic factor Fas in lipid rafts in an interaction mediated by caveolin-1 (Cav-1). The siRNA-dependent knockdown of Cav 1 sensitized epithelial cells to CS-induced apoptosis, as evidenced by enhanced death-inducing signaling complex formation and caspase activation. Furthermore, Cav-1(-/-) mice exhibited higher levels of autophagy and apoptosis in the lung in response to chronic CS exposure in vivo. In conclusion, we demonstrate a pivotal role for the autophagic protein LC3B in CS-induced apoptosis and emphysema, suggestive of novel therapeutic targets for COPD treatment. This study also introduces a mechanism by which LC3B, through interactions with Cav-1 and Fas, can regulate apoptosis. PMID- 20956296 TI - Multiple mating and its relationship to alternative modes of gestation in male pregnant versus female-pregnant fish species. AB - We construct a verbal and graphical theory (the "fecundity-limitation hypothesis") about how constraints on the brooding space for embryos probably truncate individual fecundity in male-pregnant and female-pregnant species in ways that should differentially influence selection pressures for multiple mating by males or by females. We then review the empirical literature on genetically deduced rates of multiple mating by the embryo-brooding parent in various fish species with three alternative categories of pregnancy: internal gestation by males, internal gestation by females, and external gestation (in nests) by males. Multiple mating by the brooding gender was common in all three forms of pregnancy. However, rates of multiple mating as well as mate numbers for the pregnant parent averaged higher in species with external as compared with internal male pregnancy, and also for dams in female-pregnant species versus sires in male-pregnant species. These outcomes are all consistent with the theory that different types of pregnancy have predictable consequences for a parent's brood space, its effective fecundity, its opportunities and rewards for producing half-sib clutches, and thereby its exposure to selection pressures for seeking multiple mates. Overall, we try to fit these fecundity-limitation phenomena into a broader conceptual framework for mating-system evolution that also includes anisogamy, sexual-selection gradients, parental investment, and other selective factors that can influence the relative proclivities of males versus females to seek multiple sexual partners. PMID- 20956297 TI - Neurophysiological origin of human brain asymmetry for speech and language. AB - The physiological basis of human cerebral asymmetry for language remains mysterious. We have used simultaneous physiological and anatomical measurements to investigate the issue. Concentrating on neural oscillatory activity in speech specific frequency bands and exploring interactions between gestural (motor) and auditory-evoked activity, we find, in the absence of language-related processing, that left auditory, somatosensory, articulatory motor, and inferior parietal cortices show specific, lateralized, speech-related physiological properties. With the addition of ecologically valid audiovisual stimulation, activity in auditory cortex synchronizes with left-dominant input from the motor cortex at frequencies corresponding to syllabic, but not phonemic, speech rhythms. Our results support theories of language lateralization that posit a major role for intrinsic, hardwired perceptuomotor processing in syllabic parsing and are compatible both with the evolutionary view that speech arose from a combination of syllable-sized vocalizations and meaningful hand gestures and with developmental observations suggesting phonemic analysis is a developmentally acquired process. PMID- 20956298 TI - A seed coat bedding assay shows that RGL2-dependent release of abscisic acid by the endosperm controls embryo growth in Arabidopsis dormant seeds. AB - Seed dormancy is an ecologically important adaptive trait in plants whereby germination is repressed even under favorable germination conditions such as imbibition with water. In Arabidopsis and most plant species, dormancy absolutely requires an unidentified seed coat germination-repressive activity and constitutively higher abscisic acid (ABA) levels upon seed imbibition. The mechanisms underlying these processes and their possible relationship are incompletely understood. We developed a "seed coat bedding" assay monitoring the growth of dissected embryos cultured on a layer of seed coats, allowing combinatorial experiments using dormant, nondormant, and various genetically modified seed coat and embryonic materials. This assay, combined with direct ABA measurements, revealed that, upon imbibition, dormant coats, unlike nondormant coats, actively produce and release ABA to repress embryo germination, whatever the embryo origin, i.e., from dormant, nondormant, or never dormant aba seeds, unable to synthesize ABA. The persistent high ABA levels in imbibed dormant seeds requires the permanent expression of the DELLA gene RGL2, where it remains insensitive to gibberellins (GA) unlike in nondormant seeds. These findings present the seed coat as an organ actively controlling germination upon seed imbibition and provide a framework to investigate how environmental factors break seed dormancy. PMID- 20956299 TI - Crystal and solution structures of an odorant-binding protein from the southern house mosquito complexed with an oviposition pheromone. AB - Culex mosquitoes introduce the pathogens responsible for filariasis, West Nile virus, St. Louis encephalitis, and other diseases into humans. Currently, traps baited with oviposition semiochemicals play an important role in detection efforts and could provide an environmentally friendly approach to controlling their populations. The odorant binding proteins (OBPs) in the female's antenna play a crucial, if yet imperfectly understood, role in sensing oviposition cues. Here, we report the X-ray crystallography and NMR 3D structures of OBP1 for Culex quinquefasciatus (CquiOBP1) bound to an oviposition pheromone (5R,6S)-6-acetoxy-5 hexadecanolide (MOP). In both studies, CquiOBP1 had the same overall six-helix structure seen in other insect OBPs, but a detailed analysis revealed an important previously undescribed feature. There are two models for OBP-mediated signal transduction: (i) direct release of the pheromone from an internal binding pocket in a pH-dependent fashion and (ii) detection of a pheromone-induced conformational change in the OBP.pheromone complex. Although CquiOBP1 binds MOP in a pH-dependent fashion, it lacks the C terminus required for the pH-dependent release model. This study shows that CquiOBP binds MOP in an unprecedented fashion using both a small central cavity for the lactone head group and a long hydrophobic channel for its tail. PMID- 20956300 TI - QnAs with Peter N. Devreotes. Interview by Prashant Nair. PMID- 20956301 TI - Neuronal Abelson helper integration site-1 (Ahi1) deficiency in mice alters TrkB signaling with a depressive phenotype. AB - Recent studies suggest that the human Abelson helper integration site-1 (AHI1) gene on chromosome 6 is associated with susceptibility to schizophrenia and autism, two common neuropsychological disorders with depression symptoms. Mouse Ahi1 protein is abundant in the hypothalamus and amygdala, which are important brain regions for controlling emotion. However, the neuronal function of Ahi1 remains unclear. With the Cre-loxP system, we created a mouse model that selectively reduces Ahi1 expression in neuronal cells. Mice with neuronal Ahi1 deficiency show reduced TrkB level in the brain and depressive phenotypes, which can be alleviated by antidepressant drugs or by overexpression of TrkB in the amygdala. Ahi1 deficiency promotes the degradation of endocytic TrkB and reduces TrkB signaling in neuronal cells. Our findings suggest that impaired endocytic sorting and increased degradation of TrkB can induce depression and that this impaired pathway may serve as a previously uncharacterized therapeutic target for depression. PMID- 20956302 TI - Attractive noncovalent interactions in asymmetric catalysis: links between enzymes and small molecule catalysts. AB - Catalysis by neutral, organic, small molecules capable of binding and activating substrates solely via noncovalent interactions--particularly H-bonding--has emerged as an important approach in organocatalysis. The mechanisms by which such small molecule catalysts induce high enantioselectivity may be quite different from those used by catalysts that rely on covalent interactions with substrates. Attractive noncovalent interactions are weaker, less distance dependent, less directional, and more affected by entropy than covalent interactions. However, the conformational constraint required for high stereoinduction may be achieved, in principle, if multiple noncovalent attractive interactions are operating in concert. This perspective will outline some recent efforts to elucidate the cooperative mechanisms responsible for stereoinduction in highly enantioselective reactions promoted by noncovalent catalysts. PMID- 20956303 TI - Adaptation and extinction in experimentally fragmented landscapes. AB - Competition and disturbance are potent ecological forces that shape evolutionary trajectories. These forces typically work in opposition: when disturbance is infrequent, densities are high and competition is intense. In contrast, frequent disturbance creates a low-density environment in which competition is weak and good dispersal essential. We exploited recent advances in genomic research to quantify the response to selection by these powerful ecological forces at the phenotypic and molecular genetic level in experimental landscapes. We grew the annual plant Arabidopsis thaliana in discrete patches embedded in a hostile matrix and varied the number and size of patches and the intensity of disturbance, by creating both static and dynamic landscapes. In static landscapes all patches were undisturbed, whereas in dynamic landscapes all patches were destroyed in each generation, forcing seeds to disperse to new locations. We measured the resulting changes in phenotypic, genetic, and genotypic diversity after five generations of selection. Simulations revealed that the observed loss of genetic diversity dwarfed that expected under drift, with dramatic diversity loss, particularly from dynamic landscapes. In line with ecological theory, static landscapes favored good competitors; however, competitive ability was linked to growth rate and not, as expected, to seed mass. In dynamic landscapes, there was strong selection for increased dispersal ability in the form of increased inflorescence height and reduced seed mass. The most competitive genotypes were almost eliminated from highly disturbed landscapes, raising concern over the impact of increased levels of human-induced disturbance in natural landscapes. PMID- 20956304 TI - Skeletal development in sloths and the evolution of mammalian vertebral patterning. AB - Mammals show a very low level of variation in vertebral count, particularly in the neck. Phenotypes exhibited at various stages during the development of the axial skeleton may play a key role in testing mechanisms recently proposed to explain this conservatism. Here, we provide osteogenetic data that identify developmental criteria with which to recognize cervical vs. noncervical vertebrae in mammals. Except for sloths, all mammals show the late ossification of the caudal-most centra in the neck after other centra and neural arches. In sloths with 8-10 ribless neck vertebrae, the caudal-most neck centra ossify early, matching the pattern observed in cranial thoracic vertebrae of other mammals. Accordingly, we interpret the ribless neck vertebrae of three-toed sloths caudal to V7 as thoracic based on our developmental criterion. Applied to the unusual vertebral phenotype of long-necked sloths, these data support the interpretation that elements of the axial skeleton with origins from distinct mesodermal tissues have repatterned over the course of evolution. PMID- 20956305 TI - Retinoic acid regulates bone morphogenic protein signal duration by promoting the degradation of phosphorylated Smad1. AB - The proper function of the bone morphogenic protein (BMP) pathway during embryonic development and organ maintenance requires its communication with other signaling pathways. Unlike the well-documented regulation of the BMP pathway by FGF/MAPK and Wnt/GSK3 signals, cross-talk between BMP/Smad and retinoic acid (RA)/RA receptor (RAR) pathways is poorly understood. Here, we show that RA represses BMP signal duration by reducing the level of phosphorylated Smad1 (pSmad1). Through its nuclear receptor-mediated transcription, RA enhances the interaction between pSmad1 and its ubiquitin E3 ligases, thereby promoting pSmad1 ubiquitination and proteasomal degradation. This regulation depends on the RA increased Gadd45 expression and MAPK activation. During the neural development in chicken embryo, the RA/RAR pathway also suppresses BMP signaling to antagonize BMP-regulated proliferation and differentiation of neural progenitor cells. Furthermore, this cross-talk between RA and BMP pathways is involved in the proper patterning of dorsal neural tube of chicken embryo. Our results reveal a mechanism by which RA suppresses BMP signaling through regulation of pSmad1 stability. PMID- 20956306 TI - CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function. AB - MyoD, a master regulator of myogenesis, exhibits a circadian rhythm in its mRNA and protein levels, suggesting a possible role in the daily maintenance of muscle phenotype and function. We report that MyoD is a direct target of the circadian transcriptional activators CLOCK and BMAL1, which bind in a rhythmic manner to the core enhancer of the MyoD promoter. Skeletal muscle of Clock(Delta19) and Bmal1(-/-) mutant mice exhibited ~30% reductions in normalized maximal force. A similar reduction in force was observed at the single-fiber level. Electron microscopy (EM) showed that the myofilament architecture was disrupted in skeletal muscle of Clock(Delta19), Bmal1(-/-), and MyoD(-/-) mice. The alteration in myofilament organization was associated with decreased expression of actin, myosins, titin, and several MyoD target genes. EM analysis also demonstrated that muscle from both Clock(Delta19) and Bmal1(-/-) mice had a 40% reduction in mitochondrial volume. The remaining mitochondria in these mutant mice displayed aberrant morphology and increased uncoupling of respiration. This mitochondrial pathology was not seen in muscle of MyoD(-/-) mice. We suggest that altered expression of both Pgc-1alpha and Pgc-1beta in Clock(Delta19) and Bmal1(-/-) mice may underlie this pathology. Taken together, our results demonstrate that disruption of CLOCK or BMAL1 leads to structural and functional alterations at the cellular level in skeletal muscle. The identification of MyoD as a clock controlled gene provides a mechanism by which the circadian clock may generate a muscle-specific circadian transcriptome in an adaptive role for the daily maintenance of adult skeletal muscle. PMID- 20956307 TI - Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a progressive and fatal genetic disorder of muscle degeneration. Patients with DMD lack expression of the protein dystrophin as a result of mutations in the X-linked dystrophin gene. The loss of dystrophin leads to severe skeletal muscle pathologies as well as cardiomyopathy, which manifests as congestive heart failure and arrhythmias. Like humans, dystrophin deficient mice (mdx mice) show cardiac dysfunction as evidenced by a decrease in diastolic function followed by systolic dysfunction later in life. We have investigated whether sildenafil citrate (Viagra), a phosphodiesterase 5 (PDE5) inhibitor, can be used to ameliorate the age-related cardiac dysfunction present in the mdx mice. By using echocardiography, we show that chronic sildenafil treatment reduces functional deficits in the cardiac performance of aged mdx mice, with no effect on normal cardiac function in WT controls. More importantly, when sildenafil treatment was started after cardiomyopathy had developed, the established symptoms were rapidly reversed within a few days. It is recognized that PDE5 inhibitors can have cardioprotective effects in other models of cardiac damage, but the present study reports a prevention and reversal of pathological cardiac dysfunction as measured by functional analysis in a mouse model of DMD. Overall, the data suggest that PDE5 inhibitors may be a useful treatment for the cardiomyopathy affecting patients with DMD at early and late stages of the disease. PMID- 20956308 TI - Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model. AB - Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder. Early in the pathophysiology of AD, synaptic function is disrupted by soluble Abeta oligomers, possibly through Abeta-mediated internalization of NMDA receptors. Striatal-enriched phosphatase (STEP) is a tyrosine phosphatase that regulates the internalization of NMDA receptors. Recent work shows that STEP is elevated in the prefrontal cortex of human AD patients and in animal models of AD. Here, we use genetic manipulations to reduce STEP activity in a triple transgenic AD mouse model and show that a decrease in STEP levels reverses cognitive and cellular deficits observed in these mice. Our results suggest that STEP inhibitors may prove therapeutic for this devastating disorder. PMID- 20956309 TI - Push-and-pull regulation of the fusion pore by synaptotagmin-7. AB - In chromaffin cells, Ca(2+) binding to synaptotagmin-1 and -7 triggers exocytosis by promoting fusion pore opening and fusion pore expansion. Synaptotagmins contain two C2 domains that both bind Ca(2+) and contribute to exocytosis; however, it remains unknown whether the C2 domains act similarly or differentially to promote opening and expansion of fusion pores. Here, we use patch amperometry measurements in WT and synaptotagmin-7-mutant chromaffin cells to analyze the role of Ca(2+) binding to the two synaptotagmin-7 C2 domains in exocytosis. We show that, surprisingly, Ca(2+) binding to the C2A domain suffices to trigger fusion pore opening but that the resulting fusion pores are unstable and collapse, causing a dramatic increase in kiss-and-run fusion events. Thus, synaptotagmin-7 controls fusion pore dynamics during exocytosis via a push-and pull mechanism in which Ca(2+) binding to both C2 domains promotes fusion pore opening, but the C2B domain is selectively essential for continuous expansion of an otherwise unstable fusion pore. PMID- 20956310 TI - Endothelial histamine H1 receptor signaling reduces blood-brain barrier permeability and susceptibility to autoimmune encephalomyelitis. AB - Disruption of the blood-brain barrier (BBB) underlies the development of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. Environmental factors, such as Bordetella pertussis, are thought to sensitize central endothelium to biogenic amines like histamine, thereby leading to increased BBB permeability. B. pertussis-induced histamine sensitization (Bphs) is a monogenic intermediate phenotype of EAE controlled by histamine H(1) receptor (Hrh1/H(1)R). Here, we transgenically overexpressed H(1)R in endothelial cells of Hrh1-KO (H(1)RKO) mice to test the role of endothelial H(1)R directly in Bphs and EAE. Unexpectedly, transgenic H(1)RKO mice expressing endothelial H(1)R under control of the von Willebrand factor promoter (H(1)RKO-vWF(H1R) Tg) were Bphs-resistant. Moreover, H(1)RKO-vWF(H1R) Tg mice exhibited decreased BBB permeability and enhanced protection from EAE compared with H(1)RKO mice. Thus, contrary to prevailing assumptions, our results show that endothelial H(1)R expression reduces BBB permeability, suggesting that endothelial H(1)R signaling may be important in the maintenance of cerebrovascular integrity. PMID- 20956311 TI - Divergent and nonuniform gene expression patterns in mouse brain. AB - Considerable progress has been made in understanding variations in gene sequence and expression level associated with phenotype, yet how genetic diversity translates into complex phenotypic differences remains poorly understood. Here, we examine the relationship between genetic background and spatial patterns of gene expression across seven strains of mice, providing the most extensive cellular-resolution comparative analysis of gene expression in the mammalian brain to date. Using comprehensive brainwide anatomic coverage (more than 200 brain regions), we applied in situ hybridization to analyze the spatial expression patterns of 49 genes encoding well-known pharmaceutical drug targets. Remarkably, over 50% of the genes examined showed interstrain expression variation. In addition, the variability was nonuniformly distributed across strain and neuroanatomic region, suggesting certain organizing principles. First, the degree of expression variance among strains mirrors genealogic relationships. Second, expression pattern differences were concentrated in higher-order brain regions such as the cortex and hippocampus. Divergence in gene expression patterns across the brain could contribute significantly to variations in behavior and responses to neuroactive drugs in laboratory mouse strains and may help to explain individual differences in human responsiveness to neuroactive drugs. PMID- 20956312 TI - Direct involvement of sigma-1 receptors in the dopamine D1 receptor-mediated effects of cocaine. AB - It is well known that cocaine blocks the dopamine transporter. This mechanism should lead to a general increase in dopaminergic neurotransmission, and yet dopamine D(1) receptors (D(1)Rs) play a more significant role in the behavioral effects of cocaine than the other dopamine receptor subtypes. Cocaine also binds to sigma-1 receptors, the physiological role of which is largely unknown. In the present study, D(1)R and sigma(1)R were found to heteromerize in transfected cells, where cocaine robustly potentiated D(1)R-mediated adenylyl cyclase activation, induced MAPK activation per se and counteracted MAPK activation induced by D(1)R stimulation in a dopamine transporter-independent and sigma(1)R dependent manner. Some of these effects were also demonstrated in murine striatal slices and were absent in sigma(1)R KO mice, providing evidence for the existence of sigma(1)R-D(1)R heteromers in the brain. Therefore, these results provide a molecular explanation for which D(1)R plays a more significant role in the behavioral effects of cocaine, through sigma(1)R-D(1)R heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction. PMID- 20956313 TI - Mucosal host immune response predicts the severity and duration of herpes simplex virus-2 genital tract shedding episodes. AB - Herpes simplex virus-2 (HSV-2) shedding episodes in humans vary markedly in duration and virologic titer within an infected person over time, an observation that is unexplained. To evaluate whether host or virological factors more closely accounted for this variability, we combined measures of viral replication and CD8(+) lymphocyte density in genital biopsies, with a stochastic mathematical model of HSV-2 infection. Model simulations reproduced quantities of virus and duration of shedding detected in 1,003 episodes among 386 persons. In the simulations, local CD8(+) lymphocyte density in the mucosa at episode onset predicted peak HSV DNA copy number and whether genital lesions or subclinical shedding occurred. High density of CD8(+) T cells in the mucosa correlated with decreased infected cell lifespan and fewer infected epithelial cells before episode clearance. If infected cell lifespan increased by 15 min because of CD8(+) lymphocyte decay, then there was potential for a thousandfold increase in the number of infected cells. The model suggests that the rate of containment of infected cells by the peripheral mucosal immune system is the major driver of duration and severity of HSV-2 reactivation in the immunocompetent host. PMID- 20956314 TI - Single amino acid change alters the ability to specify male or female organ identity. AB - The molecular mechanisms underlying the developmental processes that shape living organisms provide a basis to understand the evolution of biological complexity. Gene duplication allows biological functions to become separated, leading to increased complexity through subfunctionalization. Recently, the relative contributions to morphological evolution of changes to the regulatory and/or coding regions of duplicated genes have been the subject of debate. Duplication generated multiple copies of the MADS-box transcription factor genes that play essential roles in specifying organ identity in the flower, making this evolutionary novelty a good model to investigate the nature of the changes necessary to drive subfunctionalization. Here, we show that naturally occurring variation at a single amino acid in a MADS-box transcription factor switches its ability to specify male and female reproductive organs by altering its repertoire of protein-protein interactions. However, these different developmental fates are only manifest because of an underlying variation in the expression pattern of interacting proteins. This shows that the morphological outcomes of changes to protein sequence and gene expression must be interpreted in the context of the wider regulatory network. It also suggests an explanation for the surprisingly widespread duplications of some of the floral transcription factors. PMID- 20956317 TI - Thirty thousand-year-old evidence of plant food processing. AB - European Paleolithic subsistence is assumed to have been largely based on animal protein and fat, whereas evidence for plant consumption is rare. We present evidence of starch grains from various wild plants on the surfaces of grinding tools at the sites of Bilancino II (Italy), Kostenki 16-Uglyanka (Russia), and Pavlov VI (Czech Republic). The samples originate from a variety of geographical and environmental contexts, ranging from northeastern Europe to the central Mediterranean, and dated to the Mid-Upper Paleolithic (Gravettian and Gorodtsovian). The three sites suggest that vegetal food processing, and possibly the production of flour, was a common practice, widespread across Europe from at least ~30,000 y ago. It is likely that high energy content plant foods were available and were used as components of the food economy of these mobile hunter gatherers. PMID- 20956316 TI - Quaking I controls a unique cytoplasmic pathway that regulates alternative splicing of myelin-associated glycoprotein. AB - Precise control of alternative splicing governs oligodendrocyte (OL) differentiation and myelination in the central nervous system (CNS). A well-known example is the developmentally regulated expression of splice variants encoding myelin-associated glycoprotein (MAG), which generates two protein isoforms that associate with distinct cellular components crucial for axon-glial recognition during myelinogenesis and axon-myelin stability. In the quakingviable (qk(v)) hypomyelination mutant mouse, diminished expression of isoforms of the selective RNA-binding protein quaking I (QKI) leads to severe dysregulation of MAG splicing. The nuclear isoform QKI-5 was previously shown to bind an intronic element of MAG and modulate alternative exon inclusion from a MAG minigene reporter. Thus, QKI-5 deficiency was thought to underlie the defects of MAG splicing in the qk(v) mutant. Surprisingly, we found that transgenic expression of the cytoplasmic isoform QKI-6 in the qk(v) OLs completely rescues the dysregulation of MAG splicing without increasing expression or nuclear abundance of QKI-5. In addition, cytoplasmic QKI-6 selectively associates with the mRNA that encodes heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), a well characterized splicing factor. Furthermore, QKI deficiency in the qk(v) mutant results in abnormally enhanced hnRNPA1 translation and overproduction of the hnRNPA1 protein but not hnRNPA1 mRNA, which can be successfully rescued by the QKI-6 transgene. Finally, we show that hnRNPA1 binds MAG pre-mRNA and modulates alternative inclusion of MAG exons. Together, these results reveal a unique cytoplasmic pathway in which QKI-6 controls translation of the splicing factor hnRNPA1 to govern alternative splicing in CNS myelination. PMID- 20956315 TI - EGLN1 involvement in high-altitude adaptation revealed through genetic analysis of extreme constitution types defined in Ayurveda. AB - It is being realized that identification of subgroups within normal controls corresponding to contrasting disease susceptibility is likely to lead to more effective predictive marker discovery. We have previously used the Ayurvedic concept of Prakriti, which relates to phenotypic differences in normal individuals, including response to external environment as well as susceptibility to diseases, to explore molecular differences between three contrasting Prakriti types: Vata, Pitta, and Kapha. EGLN1 was one among 251 differentially expressed genes between the Prakriti types. In the present study, we report a link between high-altitude adaptation and common variations rs479200 (C/T) and rs480902 (T/C) in the EGLN1 gene. Furthermore, the TT genotype of rs479200, which was more frequent in Kapha types and correlated with higher expression of EGLN1, was associated with patients suffering from high-altitude pulmonary edema, whereas it was present at a significantly lower frequency in Pitta and nearly absent in natives of high altitude. Analysis of Human Genome Diversity Panel-Centre d'Etude du Polymorphisme Humain (HGDP-CEPH) and Indian Genome Variation Consortium panels showed that disparate genetic lineages at high altitudes share the same ancestral allele (T) of rs480902 that is overrepresented in Pitta and positively correlated with altitude globally (P < 0.001), including in India. Thus, EGLN1 polymorphisms are associated with high-altitude adaptation, and a genotype rare in highlanders but overrepresented in a subgroup of normal lowlanders discernable by Ayurveda may confer increased risk for high-altitude pulmonary edema. PMID- 20956318 TI - 3-Ketoacyl thiolase delays aging of Caenorhabditis elegans and is required for lifespan extension mediated by sir-2.1. AB - Studies of long-lived Caenorhabditis elegans mutants have identified several genes that function to limit lifespan, i.e., loss-of-function mutations in these genes promote longevity. By contrast, little is known about genes that normally act to delay aging and that when mutated cause premature aging (progeria). To seek such genes, we performed a genetic screen for C. elegans mutants that age prematurely. We found that loss-of-function mutations of the ketoacyl thiolase gene kat-1 result in an increased accumulation of the lipofuscin-like fluorescent aging pigment, shortened lifespan, early behavioral decline, and other abnormalities characteristic of premature aging. These findings suggest that kat 1 acts to delay C. elegans aging. kat-1 encodes a conserved metabolic enzyme that catalyzes the last step of fatty acid oxidation and was previously shown to regulate fat accumulation in worms. We observed that kat-1 is required for the extension of lifespan and enhanced thermotolerance mediated by extra copies of the deacetylase gene sir-2.1. kat-1 acts independently of other known pathways that affect longevity. Our findings suggest that defects in fatty acid oxidation can limit lifespan and accelerate aging in C. elegans and that kat-1-mediated fatty acid oxidation is crucial for overexpressed sir-2.1 to delay aging. PMID- 20956319 TI - Hierarchical order of coexisting pre- and postsynaptic forms of long-term potentiation at synapses in amygdala. AB - Synaptic rules that may determine the interaction between coexisting forms of long-term potentiation (LTP) at glutamatergic central synapses remain unknown. Here, we show that two mechanistically distinct forms of LTP could be induced in thalamic input to the lateral nucleus of the amygdala (LA) with an identical presynaptic stimulation protocol, depending on the level of postsynaptic membrane polarization. One form of LTP, resulting from pairing of postsynaptic depolarization and low-frequency presynaptic stimulation, was both induced and expressed postsynaptically ("post-LTP"). The same stimulation in the absence of postsynaptic depolarization led to LTP, which was induced and expressed presynaptically ("pre-LTP"). The inducibility of coexisting pre- and postsynaptic forms of LTP at synapses in thalamic input followed a well-defined hierarchical order, such that pre-LTP was suppressed when post-LTP was induced. This interaction was mediated by activation of cannabinoid type 1 receptors by endogenous cannabinoids released in the lateral nucleus of the amygdala in response to activation of the type 1 metabotropic glutamate receptor. These results suggest a previously unknown mechanism by which the hierarchy of coexisting forms of long-term synaptic plasticity in the neural circuits of learned fear could be established, possibly reflecting the hierarchy of memories for the previously experienced fearful events according to their aversiveness level. PMID- 20956320 TI - Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. AB - Reduced functional bladder capacity and concomitant increased micturition frequency (pollakisuria) are common lower urinary tract symptoms associated with conditions such as cystitis, prostatic hyperplasia, neurological disease, and overactive bladder syndrome. These symptoms can profoundly affect the quality of life of afflicted individuals, but available pharmacological treatments are often unsatisfactory. Recent work has demonstrated that the cation channel TRPV4 is highly expressed in urothelial cells and plays a role in sensing the normal filling state of the bladder. In this article, we show that the development of cystitis-induced bladder dysfunction is strongly impaired in Trpv4(-/-) mice. Moreover, we describe HC-067047, a previously uncharacterized, potent, and selective TRPV4 antagonist that increases functional bladder capacity and reduces micturition frequency in WT mice and rats with cystitis. HC-067047 did not affect bladder function in Trpv4(-/-) mice, demonstrating that its in vivo effects are on target. These results indicate that TRPV4 antagonists may provide a promising means of treating bladder dysfunction. PMID- 20956321 TI - LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. AB - LKB1 loss-of-function mutations, observed in ~30% of human lung adenocarcinomas, contribute significantly to lung cancer malignancy progression. We show that lysyl oxidase (LOX), negatively regulated by LKB1 through mTOR-HIF-1alpha signaling axis, mediates lung cancer progression. Inhibition of LOX activity dramatically alleviates lung cancer malignancy progression. Up-regulated LOX expression triggers excess collagen deposition in Lkb1-deficient lung tumors, and thereafter results in enhanced cancer cell proliferation and invasiveness through activation of beta1 integrin signaling. High LOX level and activity correlate with poor prognosis and metastasis. Our findings provide evidence of how LKB1 loss of function promotes lung cancer malignancy through remodeling of extracellular matrix microenvironment, and identify LOX as a potential target for disease treatment in lung cancer patients. PMID- 20956322 TI - Neutralization of West Nile virus by cross-linking of its surface proteins with Fab fragments of the human monoclonal antibody CR4354. AB - Many flaviviruses are significant human pathogens, with the humoral immune response playing an essential role in restricting infection and disease. CR4354, a human monoclonal antibody isolated from a patient, neutralizes West Nile virus (WNV) infection at a postattachment stage in the viral life-cycle. Here, we determined the structure of WNV complexed with Fab fragments of CR4354 using cryoelectron microscopy. The outer glycoprotein shell of a mature WNV particle is formed by 30 rafts of three homodimers of the viral surface protein E. CR4354 binds to a discontinuous epitope formed by protein segments from two neighboring E molecules, but does not cause any detectable structural disturbance on the viral surface. The epitope occurs at two independent positions within an icosahedral asymmetric unit, resulting in 120 binding sites on the viral surface. The cross-linking of the six E monomers within one raft by four CR4354 Fab fragments suggests that the antibody neutralizes WNV by blocking the pH-induced rearrangement of the E protein required for virus fusion with the endosomal membrane. PMID- 20956323 TI - Role of the hippocampus in remembering the past and imagining the future. AB - It has been proposed that a core network of brain regions, including the hippocampus, supports both past remembering and future imagining. We investigated the importance of the hippocampus for these functions. Five patients with bilateral hippocampal damage and one patient with large medial temporal lobe lesions were tested for their ability to recount autobiographical episodes from the remote past, the recent past, and to imagine plausible episodes in the near future. The patients with hippocampal damage had intact remote autobiographical memory, modestly impaired recent memory, and an intact ability to imagine the future. The patient with large medial temporal lobe lesions had intact remote memory, markedly impaired recent memory, and also had an intact ability to imagine the future. The findings suggest that the capacity for imagining the future, like the capacity for remembering the remote past, is independent of the hippocampus. PMID- 20956325 TI - Bacillus anthracis produces membrane-derived vesicles containing biologically active toxins. AB - Extracellular vesicle production is a ubiquitous process in Gram-negative bacteria, but little is known about such process in Gram-positive bacteria. We report the isolation of extracellular vesicles from the supernatants of Bacillus anthracis, a Gram-positive bacillus that is a powerful agent for biological warfare. B. anthracis vesicles formed at the outer layer of the bacterial cell had double-membrane spheres and ranged from 50 to 150 nm in diameter. Immunoelectron microscopy with mAbs to protective antigen, lethal factor, edema toxin, and anthrolysin revealed toxin components and anthrolysin in vesicles, with some vesicles containing more than one toxin component. Toxin-containing vesicles were also visualized inside B. anthracis-infected macrophages. ELISA and immunoblot analysis of vesicle preparations confirmed the presence of B. anthracis toxin components. A mAb to protective antigen protected macrophages against vesicles from an anthrolysin-deficient strain, but not against vesicles from Sterne 34F2 and Sterne deltaT strains, consistent with the notion that vesicles delivered both toxin and anthrolysin to host cells. Vesicles were immunogenic in BALB/c mice, which produced a robust IgM response to toxin components. Furthermore, vesicle-immunized mice lived significantly longer than controls after B. anthracis challenge. Our results indicate that toxin secretion in B. anthracis is, at least, partially vesicle-associated, thus allowing concentrated delivery of toxin components to target host cells, a mechanism that may increase toxin potency. Our observations may have important implications for the design of vaccines, for passive antibody strategies, and provide a previously unexplored system for studying secretory pathways in Gram-positive bacteria. PMID- 20956326 TI - Mental models and human reasoning. AB - To be rational is to be able to reason. Thirty years ago psychologists believed that human reasoning depended on formal rules of inference akin to those of a logical calculus. This hypothesis ran into difficulties, which led to an alternative view: reasoning depends on envisaging the possibilities consistent with the starting point--a perception of the world, a set of assertions, a memory, or some mixture of them. We construct mental models of each distinct possibility and derive a conclusion from them. The theory predicts systematic errors in our reasoning, and the evidence corroborates this prediction. Yet, our ability to use counterexamples to refute invalid inferences provides a foundation for rationality. On this account, reasoning is a simulation of the world fleshed out with our knowledge, not a formal rearrangement of the logical skeletons of sentences. PMID- 20956328 TI - White matter maturation reshapes structural connectivity in the late developing human brain. AB - From toddler to late teenager, the macroscopic pattern of axonal projections in the human brain remains largely unchanged while undergoing dramatic functional modifications that lead to network refinement. These functional modifications are mediated by increasing myelination and changes in axonal diameter and synaptic density, as well as changes in neurochemical mediators. Here we explore the contribution of white matter maturation to the development of connectivity between ages 2 and 18 y using high b-value diffusion MRI tractography and connectivity analysis. We measured changes in connection efficacy as the inverse of the average diffusivity along a fiber tract. We observed significant refinement in specific metrics of network topology, including a significant increase in node strength and efficiency along with a decrease in clustering. Major structural modules and hubs were in place by 2 y of age, and they continued to strengthen their profile during subsequent development. Recording resting state functional MRI from a subset of subjects, we confirmed a positive correlation between structural and functional connectivity, and in addition observed that this relationship strengthened with age. Continuously increasing integration and decreasing segregation of structural connectivity with age suggests that network refinement mediated by white matter maturation promotes increased global efficiency. In addition, the strengthening of the correlation between structural and functional connectivity with age suggests that white matter connectivity in combination with other factors, such as differential modulation of axonal diameter and myelin thickness, that are partially captured by inverse average diffusivity, play an increasingly important role in creating brain-wide coherence and synchrony. PMID- 20956327 TI - B-cell activating factor and v-Myc myelocytomatosis viral oncogene homolog (c Myc) influence progression of chronic lymphocytic leukemia. AB - Mice bearing a v-Myc myelocytomatosis viral oncogene homolog (c-Myc) transgene controlled by an Ig-alpha heavy-chain enhancer (iMyc(Calpha) mice) rarely develop lymphomas but instead have increased rates of memory B-cell turnover and impaired antibody responses to antigen. We found that male progeny of iMyc(Calpha) mice mated with mice transgenic (Tg) for CD257 (B-cell activating factor, BAFF) developed CD5(+) B-cell leukemia resembling human chronic lymphocytic leukemia (CLL), which also displays a male gender bias. Surprisingly, leukemic cells of Myc/Baff Tg mice expressed higher levels of c-Myc than did B cells of iMyc(Calpha) mice. We found that CLL cells of many patients with progressive disease also expressed high amounts of c-MYC, particularly CLL cells whose survival depends on nurse-like cells (NLC), which express high-levels of BAFF. We find that BAFF could enhance CLL-cell expression of c-MYC via activation the canonical IkappaB kinase (IKK)/NF-kappaB pathway. Inhibition of the IKK/NF-kappaB pathway in mouse or human leukemia cells blocked the capacity of BAFF to induce c MYC or promote leukemia-cell survival and significantly impaired disease progression in Myc/Baff Tg mice. This study reveals an important relationship between BAFF and c-MYC in CLL which may affect disease development and progression, and suggests that inhibitors of the canonical NF-kappaB pathway may be effective in treatment of patients with this disease. PMID- 20956329 TI - T-cell receptor-driven lymphomagenesis in mice derived from a reprogrammed T cell. AB - The conversion of mature somatic cells into pluripotent stem cells, both by nuclear transfer and transduction with specific "reprogramming" genes, represents a major advance in regenerative medicine. Pluripotent stem cell lines can now be generated from an individual's own cells, facilitating the generation of immunologically acceptable stem cell-based therapeutics. Many cell types can undergo nuclear reprogramming, leading to the question of whether the identity of the reprogrammed cell of origin has a biological consequence. Peripheral blood, containing a mixture of T, B, NK, and myeloid cell types, represents one potential source of reprogrammable cells. In this study, we describe the unique case of mice derived from a reprogrammed T cell. These mice have prerearranged T cell receptor (TCR) genes in all cells. Surprisingly, ~50% of mice with prerearranged TCR genes develop spontaneous T cell lymphomas, which originate in the thymus. The lymphomas arise from developing T cells, and contain activated Notch1, similar to most human and mouse T-cell acute lymphoblastic lymphomas. Furthermore, lymphomagenesis requires the expression of both prerearranged TCRalpha and TCRbeta genes, indicating a critical role for TCR signaling. Furthermore, inhibitors of multiple branches of TCR signaling suppress lymphoma growth, implicating TCR signaling as an essential component in lymphoma proliferation. The lymphomagenesis in mice derived from a reprogrammed T cell demonstrates the deleterious consequences of misregulation of the TCR rearrangement and signaling pathways and illustrates one case of cellular reprogramming where the identity of the cell of origin has profound consequences. PMID- 20956330 TI - Homolog of tocopherol C methyltransferases catalyzes N methylation in anticancer alkaloid biosynthesis. AB - Madagascar periwinkle (Catharanthus roseus) is the sole source of the anticancer drugs vinblastine and vincristine, bisindole alkaloids derived from the dimerization of the terpenoid indole alkaloids vindoline and catharanthine. Full elucidation of the biosynthetic pathways of these compounds is a prerequisite for metabolic engineering efforts that will improve production of these costly molecules. However, despite the medical and commercial importance of these natural products, the biosynthetic pathways remain poorly understood. Here we report the identification and characterization of a C. roseus cDNA encoding an S adenosyl-L-methionine-dependent N methyltransferase that catalyzes a nitrogen methylation involved in vindoline biosynthesis. Recombinant enzyme produced in Escherichia coli is highly substrate specific, displaying a strict requirement for a 2,3-dihydro bond in the aspidosperma skeleton. The corresponding gene transcript is induced in methyl jasmonate-elicited seedlings, along with the other known vindoline biosynthetic transcripts. Intriguingly, this unique N methyltransferase is most similar at the amino acid level to the plastidic gamma tocopherol C methyltransferases of vitamin E biosynthesis, suggesting an evolutionary link between these two functionally disparate methyltransferases. PMID- 20956331 TI - Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals. AB - Recognition and repair of cellular damage is crucial if organisms are to survive harmful environmental conditions. In mammals, the Keap1 protein orchestrates this response, but how it perceives adverse circumstances is not fully understood. Herein, we implicate NO, Zn(2+), and alkenals, endogenously occurring chemicals whose concentrations increase during stress, in this process. By combining molecular modeling with phylogenetic, chemical, and functional analyses, we show that Keap1 directly recognizes NO, Zn(2+), and alkenals through three distinct sensors. The C288 alkenal sensor is of ancient origin, having evolved in a common ancestor of bilaterans. The Zn(2+) sensor minimally comprises H225, C226, and C613. The most recent sensor, the NO sensor, emerged coincident with an expansion of the NOS gene family in vertebrates. It comprises a cluster of basic amino acids (H129, K131, R135, K150, and H154) that facilitate S-nitrosation of C151. Taken together, our data suggest that Keap1 is a specialized sensor that quantifies stress by monitoring the intracellular concentrations of NO, Zn(2+), and alkenals, which collectively serve as second messengers that may signify danger and/or damage. PMID- 20956332 TI - Electrical detection of pathogenic bacteria via immobilized antimicrobial peptides. AB - The development of a robust and portable biosensor for the detection of pathogenic bacteria could impact areas ranging from water-quality monitoring to testing of pharmaceutical products for bacterial contamination. Of particular interest are detectors that combine the natural specificity of biological recognition with sensitive, label-free sensors providing electronic readout. Evolution has tailored antimicrobial peptides to exhibit broad-spectrum activity against pathogenic bacteria, while retaining a high degree of robustness. Here, we report selective and sensitive detection of infectious agents via electronic detection based on antimicrobial peptide-functionalized microcapacitive electrode arrays. The semiselective antimicrobial peptide magainin I--which occurs naturally on the skin of African clawed frogs--was immobilized on gold microelectrodes via a C-terminal cysteine residue. Significantly, exposing the sensor to various concentrations of pathogenic Escherichia coli revealed detection limits of approximately 1 bacterium/MUL, a clinically useful detection range. The peptide-microcapacitive hybrid device was further able to demonstrate both Gram-selective detection as well as interbacterial strain differentiation, while maintaining recognition capabilities toward pathogenic strains of E. coli and Salmonella. Finally, we report a simulated "water-sampling" chip, consisting of a microfluidic flow cell integrated onto the hybrid sensor, which demonstrates real-time on-chip monitoring of the interaction of E. coli cells with the antimicrobial peptides. The combination of robust, evolutionarily tailored peptides with electronic read-out monitoring electrodes may open exciting avenues in both fundamental studies of the interactions of bacteria with antimicrobial peptides, as well as the practical use of these devices as portable pathogen detectors. PMID- 20956333 TI - Engineering of a synthetic electron conduit in living cells. AB - Engineering efficient, directional electronic communication between living and nonliving systems has the potential to combine the unique characteristics of both materials for advanced biotechnological applications. However, the cell membrane is designed by nature to be an insulator, restricting the flow of charged species; therefore, introducing a biocompatible pathway for transferring electrons across the membrane without disrupting the cell is a significant challenge. Here we describe a genetic strategy to move intracellular electrons to an inorganic extracellular acceptor along a molecularly defined route. To do so, we reconstitute a portion of the extracellular electron transfer chain of Shewanella oneidensis MR-1 into the model microbe Escherichia coli. This engineered E. coli can reduce metal ions and solid metal oxides ~8* and ~4* faster than its parental strain. We also find that metal oxide reduction is more efficient when the extracellular electron acceptor has nanoscale dimensions. This work demonstrates that a genetic cassette can create a conduit for electronic communication from living cells to inorganic materials, and it highlights the importance of matching the size scale of the protein donors to inorganic acceptors. PMID- 20956335 TI - Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles. AB - Using a diverse collection of small molecules generated from a variety of sources, we measured protein-binding activities of each individual compound against each of 100 diverse (sequence-unrelated) proteins using small-molecule microarrays. We also analyzed structural features, including complexity, of the small molecules. We found that compounds from different sources (commercial, academic, natural) have different protein-binding behaviors and that these behaviors correlate with general trends in stereochemical and shape descriptors for these compound collections. Increasing the content of sp(3)-hybridized and stereogenic atoms relative to compounds from commercial sources, which comprise the majority of current screening collections, improved binding selectivity and frequency. The results suggest structural features that synthetic chemists can target when synthesizing screening collections for biological discovery. Because binding proteins selectively can be a key feature of high-value probes and drugs, synthesizing compounds having features identified in this study may result in improved performance of screening collections. PMID- 20956336 TI - Single-particle cryoelectron microscopy analysis reveals the HIV-1 spike as a tripod structure. AB - The HIV-1 spike is a trimer of the transmembrane gp41 and the peripheral gp120 subunit pair. It is activated for virus-cell membrane fusion by binding sequentially to CD4 and to a chemokine receptor. Here we have studied the structural transition of the trimeric spike during the activation process. We solubilized and isolated unliganded and CD4-bound spikes from virus-like particles and used cryoelectron microscopy to reconstruct their 3D structures. In order to increase the yield and stability of the spike, we used an endodomain deleted and gp120-gp41 disulfide-linked variant. The unliganded spike displayed a hollow cage-like structure where the gp120-gp41 protomeric units formed a roof and bottom, and separated lobes and legs on the sides. The tripod structure was verified by fitting the recent atomic core structure of gp120 with intact N- and C-terminal ends into the spike density map. This defined the lobe as gp120 core, showed that the legs contained the polypeptide termini, and suggested the deleted variable loops V1/V2 and V3 to occupy the roof and gp41 the bottom. CD4 binding shifted the roof density peripherally and condensed the bottom density centrally. Fitting with a V3 containing gp120 core suggested that the V1/V2 loops in the roof were displaced laterally and the V3 lifted up, while the core and leg were kept in place. The loop displacements probably prepared the spike for coreceptor interaction and roof opening so that a new fusion-active gp41 structure, assembled at the center of the cage bottom, could reach the target membrane. PMID- 20956337 TI - Myeloid-derived suppressor cells prevent type 1 diabetes in murine models. AB - Effective immunotherapy for type 1 diabetes (T1D) relies on active induction of peripheral tolerance. Myeloid-derived suppressor cells (MDSCs) play a critical role in suppressing immune responses in various pathologic settings via multiple mechanisms, including expansion of regulatory T cells (Tregs). In this study, we investigated whether MDSCs could act as APCs to induce expansion of Ag-specific Tregs, suppress T cell proliferation, and prevent autoimmune T1D development. We found that MDSC-mediated expansion of Tregs and T cell suppression required MHC dependent Ag presentation. A murine T1D model was established in INS-HA/RAG(-/-) mice in which animals received CD4-HA-TCR transgenic T cells via adoptive transfer. We found a significant reduction in the incidence of diabetes in recipients receiving MDSC plus HA, but not OVA peptide, leading to 75% diabetes free mice among the treated animals. To test further whether MDSCs could prevent diabetes onset in NOD mice, nondiabetic NOD/SCID mice were injected with inflammatory T cells from diabetic NOD mice. MDSCs significantly prevented diabetes onset, and 60% of MDSC-treated mice remained diabetes free. The pancreata of treated mice showed significantly lower levels of lymphocyte infiltration in islet and less insulitis compared with that of the control groups. The protective effects of MDSCs might be mediated by inducing anergy in autoreactive T cells and the development of CD4(+)CD25(+)Foxp3(+) Tregs. Thist study demonstrates a remarkable capacity of transferred MDSCs to downregulate Ag specific autoimmune responses and prevent diabetes onset, suggesting that MDSCs possess great potential as a novel cell-based tolerogenic therapy in the control of T1D and other autoimmune diseases. PMID- 20956338 TI - Cutting edge: A critical functional role for IL-23 in psoriasis. AB - Interleukin-23 is a key cytokine involved in the generation of Th17 effector cells. Clinical efficacy of an anti-p40 mAb blocking both IL-12 and IL-23 and disease association with single nucleotide polymorphisms in the IL23R gene raise the question of a functional role of IL-23 in psoriasis. In this study, we provide a comprehensive analysis of IL-23 and its receptor in psoriasis and demonstrate its functional importance in a disease-relevant model system. The expression of IL-23 and its receptor was increased in the tissues of patients with psoriasis. Injection of a mAb specifically neutralizing human IL-23 showed IL-23-dependent inhibition of psoriasis development comparable to the use of anti TNF blockers in a clinically relevant xenotransplant mouse model of psoriasis. Together, our results identify a critical functional role for IL-23 in psoriasis and provide the rationale for new treatment strategies in chronic epithelial inflammatory disorders. PMID- 20956340 TI - Collectin 11 (CL-11, CL-K1) is a MASP-1/3-associated plasma collectin with microbial-binding activity. AB - Collectins play important roles in the innate immune defense against microorganisms. Recently, a new collectin, collectin 11 (CL-11 or CL-K1), was identified via database searches. In present work, we characterize the structural and functional properties of CL-11. Under nonreducing conditions, in gel permeation chromatography recombinant CL-11 forms disulfide-linked oligomers of 100 and 200 kDa. A mAb-based ELISA estimates the concentration of CL-11 in plasma to be 2.1 MUg/ml, and the presence of CL-11 in plasma was further verified by Western blotting and mass spectrometry. Mannan-binding lectin-associated serine protease 1 (MASP-1) copurified with CL-11 and the interaction in plasma with MASP 1 and/or MASP-3 was further demonstrated using ELISA. We identified the adrenal glands, the kidneys, and the liver as primary sites of expression. CL-11 lectin activity was demonstrated by ELISA and showed that CL-11 has preference for l fucose and d-mannose. We finally show that CL-11 binds to intact bacteria, fungi, and viruses and that CL-11 decreases influenza A virus infectivity and forms complexes with DNA. On the basis of the significant concentration of CL-11 in circulation and CL-11's interaction with various microorganisms and MASP-1 and/or MASP-3, it is conceivable that CL-11 plays a role in activation of the complement system and in the defense against invading microorganisms. PMID- 20956339 TI - TIM-3: a novel regulatory molecule of alloimmune activation. AB - T cell Ig domain and mucin domain (TIM)-3 has previously been established as a central regulator of Th1 responses and immune tolerance. In this study, we examined its functions in allograft rejection in a murine model of vascularized cardiac transplantation. TIM-3 was constitutively expressed on dendritic cells and natural regulatory T cells (Tregs) but only detected on CD4(+)FoxP3(-) and CD8(+) T cells in acutely rejecting graft recipients. A blocking anti-TIM-3 mAb accelerated allograft rejection only in the presence of host CD4(+) T cells. Accelerated rejection was accompanied by increased frequencies of alloreactive IFN-gamma-, IL-6-, and IL-17-producing splenocytes, enhanced CD8(+) cytotoxicity against alloantigen, increased alloantibody production, and a decline in peripheral and intragraft Treg/effector T cell ratio. Enhanced IL-6 production by CD4(+) T cells after TIM-3 blockade plays a central role in acceleration of rejection. Using an established alloreactivity TCR transgenic model, blockade of TIM-3 increased allospecific effector T cells, enhanced Th1 and Th17 polarization, and resulted in a decreased frequency of overall number of allospecific Tregs. The latter is due to inhibition in induction of adaptive Tregs rather than prevention of expansion of allospecific natural Tregs. In vitro, targeting TIM-3 did not inhibit nTreg-mediated suppression of Th1 alloreactive cells but increased IL-17 production by effector T cells. In summary, TIM-3 is a key regulatory molecule of alloimmunity through its ability to broadly modulate CD4(+) T cell differentiation, thus recalibrating the effector and regulatory arms of the alloimmune response. PMID- 20956341 TI - IL-31 receptor (IL-31RA) knockout mice exhibit elevated responsiveness to oncostatin M. AB - IL-31 signals through the heterodimeric receptor IL-31RA and oncostatin M receptor (OSMR), and has been linked with the development of atopic dermatitis, a Th2 cytokine-associated disease in humans. However, recent studies of IL-31RA knockout (KO) mice have suggested that IL-31 signaling may be required to negatively regulate Th2 type responses rather than exacerbate them. Because those studies were performed on genetically modified mice, we examined whether neutralizing IL-31 with a specific mAb would give similar results to IL-31RA KO mice in two Th2 cytokine-associated immune models. We report no difference in lymphocyte Th2-type cytokine production after Ag immunization between IL-31RA KO mice, mice treated with the IL-31 mAb, or control animals. Second, we tested whether the absence of the IL-31RA subunit in IL-31RA KO mice may allow for increased pairing of the OSMR subunit with another cytokine receptor, gp130, resulting in overrepresentation of the heterodimeric receptor for OSM and increased responsiveness to OSM protein. We found that intranasal OSM challenge of IL-31RA KO mice resulted in increased IL-6 and vascular endothelial growth factor production in the lung compared with wild-type littermate control animals. Moreover, PBS-challenged IL-31RA KO mice already had increased levels of vascular endothelial growth factor, which were further increased by OSM challenge. These data imply that IL-31RA-deficient mice produce increased levels of OSM-inducible cytokines during airway sensitization and challenge, which may be the driving force behind the apparent exacerbation of Th2-type inflammatory responses previously observed in these mice. PMID- 20956342 TI - Sialylation of 3-methylcholanthrene-induced fibrosarcoma determines antitumor immune responses during immunoediting. AB - Sialylation of tumor cells is involved in various aspects of their malignancy (proliferation, motility, invasion, and metastasis); however, its effect on the process of immunoediting that affects tumor cell immunogenicity has not been studied. We have shown that in mice with impaired immunoediting, such as in IL 1alpha(-/-) and IFNgamma(-/-) mice, 3-methylcholanthrene-induced fibrosarcoma cells are immunogenic and concomitantly bear low levels of surface sialylation, whereas tumor cells derived from wild type mice are nonimmunogenic and bear higher levels of surface sialylation. To study immune mechanisms whose interaction with tumor cells involves surface sialic acid residues, we used highly sialylated 3-methylcholanthrene-induced nonimmunogenic fibrosarcoma cell lines from wild type mice, which were treated with sialidase to mimic immunogenic tumor cell variants. In vivo and in vitro experiments revealed that desialylation of tumor cells reduced their growth and induced cytotoxicity by NK cells. Moreover, sialidase-treated tumor cells better activated NK cells for IFN-gamma secretion. The NKG2D-activating receptor on NK cells was shown to be involved in interactions with desialylated ligands on tumor cells, the nature of which is still not known. Thus, the degree of sialylation on tumor cells, which is selected during the process of immunoediting, has possibly evolved as an important mechanism of tumor cells with low intrinsic immunogenicity or select for tumor cells that can evade the immune system or subvert its function. When immunoediting is impaired, such as in IFN-gamma(-/-) and IL-1alpha(-/-) mice, the overt tumor consists of desialylayed tumor cells that interact better with immunosurveillance cells. PMID- 20956343 TI - Domain swapping reveals complement control protein modules critical for imparting cofactor and decay-accelerating activities in vaccinia virus complement control protein. AB - Vaccinia virus encodes a structural and functional homolog of human complement regulators named vaccinia virus complement control protein (VCP). This four complement control protein domain containing secretory protein is known to inhibit complement activation by supporting the factor I-mediated inactivation of complement proteins, proteolytically cleaved form of C3 (C3b) and proteolytically cleaved form of C4 (C4b) (termed cofactor activity), and by accelerating the irreversible decay of the classical and to a limited extent of the alternative pathway C3 convertases (termed decay-accelerating activity [DAA]). In this study, we have mapped the VCP domains important for its cofactor activity and DAA by swapping its individual domains with those of human decay-accelerating factor (CD55) and membrane cofactor protein (MCP; CD46). Our data indicate the following: 1) swapping of VCP domain 2 or 3, but not 1, with homologous domains of decay-accelerating factor results in loss in its C3b and C4b cofactor activities; 2) swapping of VCP domain 1, but not 2, 3, or 4 with corresponding domains of MCP results in abrogation in its classical pathway DAA; and 3) swapping of VCP domain 1, 2, or 3, but not 4, with homologous MCP domains have marked effect on its alternative pathway DAA. These functional data together with binding studies with C3b and C4b suggest that in VCP, domains 2 and 3 provide binding surface for factor I interaction, whereas domain 1 mediates dissociation of C2a and Bb from the classical and alternative pathway C3 convertases, respectively. PMID- 20956344 TI - Store-operated Ca2+ entry through ORAI1 is critical for T cell-mediated autoimmunity and allograft rejection. AB - ORAI1 is the pore-forming subunit of the Ca(2+) release-activated Ca(2+) (CRAC) channel, which is responsible for store-operated Ca(2+) entry in lymphocytes. A role for ORAI1 in T cell function in vivo has been inferred from in vitro studies of T cells from human immunodeficient patients with mutations in ORAI1 and Orai1( /-) mice, but a detailed analysis of T cell-mediated immune responses in vivo in mice lacking functional ORAI1 has been missing. We therefore generated Orai1 knock-in mice (Orai1(KI/KI)) expressing a nonfunctional ORAI1-R93W protein. Homozygosity for the equivalent ORAI1-R91W mutation abolishes CRAC channel function in human T cells resulting in severe immunodeficiency. Homozygous Orai1(KI/KI) mice die neonatally, but Orai1(KI/KI) fetal liver chimeric mice are viable and show normal lymphocyte development. T and B cells from Orai1(KI/KI) mice display severely impaired store-operated Ca(2+) entry and CRAC channel function resulting in a strongly reduced expression of several key cytokines including IL-2, IL-4, IL-17, IFN-gamma, and TNF-alpha in CD4(+) and CD8(+) T cells. Cell-mediated immune responses in vivo that depend on Th1, Th2, and Th17 cell function were severely attenuated in ORAI1-deficient mice. Orai1(KI/KI) mice lacked detectable contact hypersensitivity responses and tolerated skin allografts significantly longer than wild-type mice. In addition, T cells from Orai1(KI/KI) mice failed to induce colitis in an adoptive transfer model of inflammatory bowel disease. These findings reaffirm the critical role of ORAI1 for T cell function and provide important insights into the in vivo functions of CRAC channels for T cell-mediated immunity. PMID- 20956345 TI - The peritoneal cavity B-2 antibody repertoire appears to reflect many of the same selective pressures that shape the B-1a and B-1b repertoires. AB - To assess the extent and nature of somatic categorical selection of CDR-3 of the Ig H chain (CDR-H3) content in peritoneal cavity (PerC) B cells, we analyzed the composition of V(H)7183DJCMU transcripts derived from sorted PerC B-1a, B-1b, and B-2 cells. We divided these sequences into those that contained N nucleotides (N(+)) and those that did not (N(-)) and then compared them with sequences cloned from sorted IgM(+)IgD(+) B cells from neonatal liver and both wild-type and TdT deficient adult bone marrow. We found that the PerC B-1a N(-) repertoire is enriched for the signatures of CDR-H3 sequences present in neonatal liver and shares many features with the B-1b N(-) repertoire, whereas the PerC B-1a N(+), B 1b N(+), and B-2 N(+) repertoires are enriched for adult bone marrow sequence signatures. However, we also found several sequence signatures that were not shared with other mature perinatal or adult B cell subsets but were either unique or variably shared between the two or even among all three of the PerC subsets that we examined. These signatures included more sequences lacking N nucleotides in the B-2 population and an increased use of D(H) reading frame 2, which created CDR-H3s of greater average hydrophobicity. These findings provide support for both ontogenetic origin and shared Ag receptor-influenced selection as the mechanisms that shape the unique composition of the B-1a, B-1b, and B-2 repertoires. The PerC may thus serve as a general reservoir for B cells with Ag binding specificities that are uncommon in other mature compartments. PMID- 20956346 TI - Major differences in the responses of primary human leukocyte subsets to IFN beta. AB - Treatment of cell lines with type I IFNs activates the formation of IFN stimulated gene factor 3 (STAT1/STAT2/IFN regulatory factor-9), which induces the expression of many genes. To study this response in primary cells, we treated fresh human blood with IFN-beta and used flow cytometry to analyze phosphorylated STAT1, STAT3, and STAT5 in CD4(+) and CD8(+) T cells, B cells, and monocytes. The activation of STAT1 was remarkably different among these leukocyte subsets. In contrast to monocytes and CD4(+) and CD8(+) T cells, few B cells activated STAT1 in response to IFN-beta, a finding that could not be explained by decreased levels of IFNAR2 or STAT1 or enhanced levels of suppressor of cytokine signaling 1 or relevant protein tyrosine phosphatases in B cells. Microarray and real-time PCR analyses revealed the induction of STAT1-dependent proapoptotic mRNAs in monocytes but not in B cells. These data show that IFN-stimulated gene factor 3 or STAT1 homodimers are not the main activators of gene expression in primary B cells of healthy humans. Notably, in B cells and, especially in CD4(+) T cells, IFN-beta activated STAT5 in addition to STAT3, with biological effects often opposite from those driven by activated STAT1. These data help to explain why IFN beta increases the survival of primary human B cells and CD4(+) T cells but enhances the apoptosis of monocytes, as well as to understand how leukocyte subsets are differentially affected by endogenous type I IFNs during viral or bacterial infections and by type I IFN treatment of patients with multiple sclerosis, hepatitis, or cancer. PMID- 20956347 TI - Influenza A infection enhances cross-priming of CD8+ T cells to cell-associated antigens in a TLR7- and type I IFN-dependent fashion. AB - The initiation of antitumor immunity relies on dendritic cells (DCs) to cross present cell-associated tumor Ag to CD8(+) T cells (T(CD8+)) due to a lack of costimulatory molecules on tumor cells. Innate danger signals have been demonstrated to enhance cross-priming of T(CD8+) to soluble as well as virally encoded Ags; however, their effect on enhancing T(CD8+) cross-priming to cell genome-encoded Ags remains unknown. Furthermore, influenza A virus (IAV) has not been shown to enhance antitumor immunity. Using influenza-infected allogeneic cell lines, we show in this study that T(CD8+) responses to cell-associated Ags can be dramatically enhanced due to enhanced T(CD8+) expansion. This enhanced cross-priming in part involves TLR7- but not TLR3-mediated sensing of IAV and is entirely dependent on MyD88 and IFN signaling pathways. We also showed that the inflammasome-induced IL-1 and IFN-gamma did not play a role in enhancing cross priming in our system. We further demonstrated in our ex vivo system that CD8(+) DCs are the only APCs able to prime TCR-transgenic T(CD8+). Importantly, plasmacytoid DCs and CD8(-) DCs were both able to enhance such priming when provided in coculture. These observations suggest that IAV infection of tumor cells may facilitate improved cross-presentation of tumor Ags and may be used to augment clinical vaccine efficacy. PMID- 20956349 TI - Expanded numbers of circulating myeloid dendritic cells in patent human filarial infection reflect lower CCR1 expression. AB - APC dysfunction has been postulated to mediate some of the parasite-specific T cell unresponsiveness seen in patent filarial infection. We have shown that live microfilariae of Brugia malayi induce caspase-dependent apoptosis in human monocyte-derived dendritic cells (DCs) in vitro. This study addresses whether apoptosis observed in vitro extends to patent filarial infections in humans and is reflected in the number of circulating myeloid DCs (mDCs; CD11c(-)CD123(lo)) in peripheral blood of infected microfilaremic individuals. Utilizing flow cytometry to identify DC subpopulations (mDCs and plasmacytoid DCs [pDCs]) based on expression of CD11c and CD123, we found a significant increase in numbers of circulating mDCs (CD11c(+)CD123(lo)) in filaria-infected individuals compared with uninfected controls from the same filaria-endemic region of Mali. Total numbers of pDCs, monocytes, and lymphocytes did not differ between the two groups. To investigate potential causes of differences in mDC numbers between the two groups, we assessed chemokine receptor expression on mDCs. Our data indicate that filaria-infected individuals had a lower percentage of circulating CCR1(+) mDCs and a higher percentage of circulating CCR5(+) mDCs and pDCs. Finally, live microfilariae of B. malayi were able to downregulate cell-surface expression of CCR1 on monocyte-derived DCs and diminish their calcium flux in response to stimulation by a CCR1 ligand. These findings suggest that microfilaria are capable of altering mDC migration through downregulation of expression of some chemokine receptors and their signaling functions. These observations have major implications for regulation of immune responses to these long-lived parasites. PMID- 20956348 TI - The CDR-H3 repertoire from TdT-deficient adult bone marrow is a close, but not exact, homologue of the CDR-H3 repertoire from perinatal liver. AB - Compared with adult bone marrow (BM), the composition of the perinatal liver CDR 3 of the Ig H chain (CDR-H3) repertoire is marked by a paucity of N nucleotides and by enrichment for use of J(H) proximal DQ52 and D(H) proximal V(H) and J(H) gene segments. To test the extent to which these differences reflect limited perinatal TdT activity versus differences in the fetal/adult environment, we used the Hardy scheme to sort fractions B-F B lineage cells from TdT-deficient BALB/c adult BM. V(H)7183-containing VDJCMU transcripts from these cells were amplified, cloned, sequenced, and compared with transcripts from wild-type perinatal liver and adult BM. The pattern of V(H)DJ(H) usage in TdT-deficient BM largely matched that of TdT-sufficient adult cells. What minor differences were detected in the pro-B cell stage tended to diminish with B cell maturation, suggesting strong environmental or Ag-driven pressure to achieve a specific range of V(H)DJ(H) usage regardless of the extent of N nucleotide addition. However, although the patterns of V(H)DJ(H) usage in the TdT-deficient B lineage cells paralleled that of wild-type adult cells, the length distribution, global amino acid composition, and charge distribution of the CDR-H3 repertoire proved to be a close, although not exact, homologue of the CDR-H3 repertoire first expressed by late pre-B cells in the TdT-insufficient perinatal liver. Thus, although differing in V(H) content, TdT-deficient mice appear to represent a good, although not perfect, model for testing the role of perinatal CDR-H3 limitations on late B cell development and Ab responses. PMID- 20956351 TI - IL-17A-producing gammadeltaT cells promote CTL responses against Listeria monocytogenes infection by enhancing dendritic cell cross-presentation. AB - Interleukin-17A-producing T cells, especially Th17, have been shown to be involved in inflammatory autoimmune diseases and host defense against extracellular infections. However, whether and how IL-17A or IL-17A-producing cells can help protection against intracellular bacteria remains controversial, especially how it regulates the adaptive immunity besides recruitment of neutrophils in the innate immune system. By infecting IL-17A-deficient mice with Listeria monocytogenes, we show in this study that IL-17A is required for the generation of Ag-specific CD8(+) CTL response against primary infection, but not for the generation of memory CD8(+) T cells against secondary challenge. Interestingly, we identify gammadeltaT cells, but not conventional CD4(+) Th17 cells, as the main cells for innate IL-17A production during L. monocytogenes infection. Furthermore, gammadeltaT cells are found to promote Ag-specific CD8(+) T cell proliferation by enhancing cross-presentation of dendritic cells through IL-17A. Adoptive transfer of Il17a(+/+) gammadeltaT cells, but not Il17a(-/-) gammadeltaT cells or Il17a(+/+) CD4(+) T cells, were sufficient to recover dendritic cells cross-presentation and defective CD8(+) T cell response in Il17a( /-) mice. Our findings indicate an important role of infection-inducible IL-17A producing gammadeltaT cells and their derived IL-17A against intracellular bacterial infection, providing a mechanism of IL-17A for regulation of innate and adaptive immunity. PMID- 20956352 TI - Evaluating societal preferences for human papillomavirus vaccine and cervical smear test screening programme. AB - BACKGROUND: Cervical cancer and genital warts are diseases associated with human papillomavirus (HPV) infection. Cervical smear testing is used as a cervical cancer screening tool in most countries worldwide. The newly introduced vaccines that prevent HPV infections are the quadrivalent vaccine (Gardasil), which prevents genital warts and cervical cancer, and the bivalent vaccine (Cervarix), which prevents cervical cancer only. Public preferences for HPV vaccines and smear test screening were determined using a discrete choice experiment. METHODS: Participants from across Canada completed a choice-based questionnaire to measure preferences from which willingness to pay (WTP) was calculated for the following: (1) lifetime risk of cervical cancer and genital warts, (2) frequency of smear testing, (3) need for vaccine booster, (4) target group to vaccinate, (5) frequency of side effects and (6) cost of the vaccine (from 2008). A mixed effect logistic model was used to analyse the data. RESULTS: Of the 1157 participants, the mean age was 44 years (SD 15) and 49% were women. Respondents preferred a vaccine that gave lifelong immunity, a vaccination programme that targeted boys and girls and a vaccine that gave protection from genital warts and cervical cancer. Respondents were averse to yearly smear testing. On average, respondents were willing to pay $C53 and $C22 to avoid a 1% increase in the risk of cervical cancer and genital warts, respectively. CONCLUSIONS: Society agrees with the introduction of the HPV vaccination programme, but would prefer a programme that targets boys and girls with the quadrivalent vaccine. PMID- 20956350 TI - Domain V peptides inhibit beta2-glycoprotein I-mediated mesenteric ischemia/reperfusion-induced tissue damage and inflammation. AB - Reperfusion of ischemic tissue induces significant tissue damage in multiple conditions, including myocardial infarctions, stroke, and transplantation. Although not as common, the mortality rate of mesenteric ischemia/reperfusion (IR) remains >70%. Although complement and naturally occurring Abs are known to mediate significant damage during IR, the target Ags are intracellular molecules. We investigated the role of the serum protein, beta2-glycoprotein I as an initiating Ag for Ab recognition and beta2-glycoprotein I (beta2-GPI) peptides as a therapeutic for mesenteric IR. The time course of beta2-GPI binding to the tissue indicated binding and complement activation within 15 min postreperfusion. Treatment of wild-type mice with peptides corresponding to the lipid binding domain V of beta2-GPI blocked intestinal injury and inflammation, including cellular influx and cytokine and eicosanoid production. The optimal therapeutic peptide (peptide 296) contained the lysine-rich region of domain V. In addition, damage and most inflammation were also blocked by peptide 305, which overlaps with peptide 296 but does not contain the lysine-rich, phospholipid-binding region. Importantly, peptide 296 retained efficacy after replacement of cysteine residues with serine. In addition, infusion of wild-type serum containing reduced levels of anti-beta2-GPI Abs into Rag-1(-/-) mice prevented IR-induced intestinal damage and inflammation. Taken together, these data suggest that the serum protein beta2-GPI initiates the IR-induced intestinal damage and inflammatory response and as such is a critical therapeutic target for IR-induced damage and inflammation. PMID- 20956353 TI - Evaluation of e-Bug, an educational pack, teaching about prudent antibiotic use and hygiene, in the Czech Republic, France and England. AB - OBJECTIVES: e-Bug, a junior and senior school educational programme to decrease the spread of infection and unnecessary antibiotic use, was developed and consisted of eight sections providing information on the spread, treatment and prevention of infection as well as basic information on microbes, both useful and harmful. Each section comprised teacher background information, lesson plans and an interactive student activity, and extension activities were also available for more able students. This study aimed to evaluate the effectiveness of the e-Bug pack in improving children's knowledge in these key areas, when used within the National Curriculum in England, France and the Czech Republic. METHODS: Junior (9 11 years) and senior (12-15 years) school classes were divided into either control or intervention groups for evaluation of the resource. Students were required to complete identical knowledge questionnaires at three timepoints (before, immediately after and 6 weeks after teaching), to assess knowledge change and retention. Teaching, using the e-Bug pack, was given by junior and senior school teachers. RESULTS: The junior e-Bug teaching pack demonstrated a significant improvement in student's knowledge in all sections and there was no significant decrease in student knowledge observed after a 6 week period. Knowledge improvement with the senior e-Bug pack varied between regions, although consistent improvement was observed for Gloucestershire (England) and Ostrava (Czech Republic). CONCLUSIONS: Although a success, modifications are required in both packs to further improve student knowledge and make the packs more appealing. PMID- 20956354 TI - Mechanism of interaction of sitamaquine with Leishmania donovani. AB - OBJECTIVES: This study focuses on the mechanism of interaction of sitamaquine with Leishmania donovani membranes, and its accumulation within the parasites. METHODS: A biomimetic model of the outer layer of a Leishmania plasma membrane was used to examine the interactions of sitamaquine with lipids. The plasma membranes of L. donovani promastigotes were depleted of sterol using cholesterol oxidase, in order to assess the importance of sterols in drug-membrane interactions. Sterols were quantified and sitamaquine susceptibility was assessed using the MTT test. Kinetics of sitamaquine accumulation and efflux were measured under different conditions. RESULTS: Sitamaquine interacts first with phospholipid anionic polar head groups and then with phospholipid acyl chains to insert within biological membranes and accumulates rapidly in the Leishmania cytosol according to a sterol-independent process. The rapid sitamaquine efflux observed was related to an energy-dependent mechanism since the intracellular amount of sitamaquine was enhanced three times in the absence of glucose and the efflux was inhibited in energy-depleted conditions. (1)H NMR analysis of motile lipid showed that sitamaquine did not affect lipid trafficking in Leishmania. CONCLUSIONS: We propose that sitamaquine rapidly accumulates in Leishmania by diffusion along an electrical gradient and is concentrated in the cytosol by an energy- and sterol-independent process. The affinity of sitamaquine for membranes was transitory and an energy-dependent efflux was demonstrated, suggesting the presence of an as yet uncharacterized transporter. PMID- 20956355 TI - Social identities, group norms, and threat: on the malleability of ingroup bias. AB - Ingroup bias is one of the most basic intergroup phenomena and has been consistently demonstrated to be increased under conditions of existential threat. In the present research the authors question the omnipresence of ingroup bias under threat and test the assumptions that these effects depend on the content of social identity and group norm salient in a situation. In the first two studies cross-categorization and recategorization manipulations eliminated and even reversed mortality salience effects on bias in relations between English and Scottish students (Study 1) as well as English and French people (Study 2). In the third study the specific normative content of a given social identity (collectivism vs. individualism) was shown to moderate mortality salience effects on ingroup bias. The results of these studies suggest a social identity perspective on terror management processes. PMID- 20956356 TI - Look at me, I'm happy and creative: The effect of impression management on behavior in social presence. AB - The present research tested competing approaches to individual differences in impression management (as measured with social desirability scales) and their implication for behavior in social contexts. A defensiveness approach argues that impression management is a source of defensive self-presentation, which causes performance impairment in public social settings. The competing adjustment approach argues that impression management measures friendliness and self control, which should bring about performance facilitation in public social settings. To decide between these approaches, two experiments utilized a social facilitation paradigm, whereby task performance was compared between an alone and a public condition. The results supported the predictions of the adjustment approach. Across different tasks, a high impression management score was associated with performance facilitation in social presence, expressed in greater creativity, positive implicit affect, and high self-control. The results reveal previously unnoticed constructive effects of impression management, supporting the reframing of the trait as reflecting interpersonally oriented self-control. PMID- 20956357 TI - Iron chelators of the di-2-pyridylketone thiosemicarbazone and 2-benzoylpyridine thiosemicarbazone series inhibit HIV-1 transcription: identification of novel cellular targets--iron, cyclin-dependent kinase (CDK) 2, and CDK9. AB - HIV-1 transcription is activated by HIV-1 Tat protein, which recruits cyclin dependent kinase 9 (CDK9)/cyclin T1 and other host transcriptional coactivators to the HIV-1 promoter. Tat itself is phosphorylated by CDK2, and inhibition of CDK2 by small interfering RNA, the iron chelator 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), and the iron chelator deferasirox (ICL670) inhibits HIV-1 transcription. Here we have analyzed a group of novel di-2 pyridylketone thiosemicarbazone- and 2-benzoylpyridine thiosemicarbazone-based iron chelators that exhibit marked anticancer activity in vitro and in vivo (Proc Natl Acad Sci USA 103:7670-7675, 2006; J Med Chem 50:3716-3729, 2007). Several of these iron chelators, in particular 2-benzoylpyridine 4-allyl-3-thiosemicarbazone (Bp4aT) and 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), inhibited HIV 1 transcription and replication at much lower concentrations than did 311 and ICL670. Neither Bp4aT nor Bp4eT were toxic after a 24-h incubation. However, longer incubations for 48 h or 72 h resulted in cytotoxicity. Analysis of the molecular mechanism of HIV-1 inhibition showed that the novel iron chelators inhibited basal HIV-1 transcription, but not the nuclear factor-kappaB-dependent transcription or transcription from an HIV-1 promoter with inactivated SP1 sites. The chelators inhibited the activities of CDK2 and CDK9/cyclin T1, suggesting that inhibition of CDK9 may contribute to the inhibition of HIV-1 transcription. Our study suggests the potential usefulness of Bp4aT or Bp4eT in antiretroviral regimens, particularly where resistance to standard treatment occurs. PMID- 20956358 TI - Phylogeographic history of white spruce during the last glacial maximum: uncovering cryptic refugia. AB - Although a recent study of white spruce using chloroplast DNA uncovered the presence of a glacial refuge in Alaska, chloroplast failed to provide information on the number or specific localities of refugia. Recent studies have demonstrated the utility of nuclear microsatellites to refine insights into postglacial histories. The greater relative rate of mutation may allow finer scale resolution of historic dynamics, including the number, location, and sizes of refugia. Genetic data were acquired from screening 6 microsatellite loci on approximately 14 trees from each of 22 populations located across the central and western boreal forests of Canada and Alaska. Our studies combining microsatellites with Bayesian analyses of population structure in white spruce support the phylogeographic patterns uncovered using chloroplast, separating Alaskan from non Alaskan regions. Results also support the idea that north-central Alaska served as a glacial refugium during the last glacial maximum. Additionally, the relationship between the degree of genetic differentiation and geographic distance indicated that gene flow played a more important role in structuring non Alaskan populations, whereas drift played a more important role in structuring Alaskan populations (R(ST)'s for non-Alaskan populations 0.029 +/- 0.007 and 0.083 +/- 0.012 for Alaskan populations). Microsatellites also substantiate the bidirectional patterns of gene flow previously uncovered using chloroplast DNA but indicate much greater movement and mixing. Results from our Bayesian analyses also suggest the existence of additional cryptic refugia. However, the locations have been obscured by high gene flow (R(ST) averaging 0.057 +/- 0.004). PMID- 20956359 TI - C-terminal armadillo repeats are essential and sufficient for association of the plant U-box armadillo E3 ubiquitin ligase SAUL1 with the plasma membrane. AB - Ubiquitination plays important roles in plant growth and development. Whereas ubiquitin-dependent protein degradation and modulation in the cytoplasm and nucleus are well established in plants, ubiquitination events mediated by E3 ubiquitin ligases at the plasma membrane are largely unknown. Here, it is demonstrated that the suppressor of premature senescence and cell death SENESCENCE-ASSOCIATED UBIQUITIN LIGASE 1 (SAUL1), a plant U-box armadillo repeat (PUB-ARM) E3 ubiquitin ligase, localizes at the plasma membrane. Among the members of the PUB-ARM protein family, this localization is unique to SAUL1 and its two closest homologues. A novel armadillo repeat domain was identified at the SAUL1 C-terminus that directs specific association with the plasma membrane and is crucial for SAUL1 function in vivo. The data suggest that a small subgroup of PUB-ARM proteins including SAUL1 have functions at the plasma membrane probably by modifying target proteins by ubiquitination. PMID- 20956362 TI - Water and society: past, present and future. PMID- 20956360 TI - Restoration of photosystem II photochemistry and carbon assimilation and related changes in chlorophyll and protein contents during the rehydration of desiccated Xerophyta scabrida leaves. AB - Recovery of photosynthesis in rehydrating desiccated leaves of the poikilochlorophyllous desiccation-tolerant plant Xerophyta scabrida was investigated. Detached leaves were remoistened under 12 h light/dark cycles for 96 h. Water, chlorophyll (Chl), and protein contents, Chl fluorescence, photosynthesis-CO(2) concentration response, and the amount and activity of Rubisco were measured at intervals during the rehydration period. Leaf relative water contents reached 87% in 12 h and full turgor in 96 h. Chl synthesis was slower before than after 24 h, and Chla:Chlb ratios changed from 0.13 to 2.6 in 48 h. The maximum quantum efficiency recovered faster during rehydration than the photosystem II operating efficiency and the efficiency factor, which is known to depend mainly on the use of the electron transport chain products. From 24 h to 96 h of rehydration, net carbon fixation was Rubisco limited, rather than electron transport limited. Total Rubisco activity increased during rehydration more than the Rubisco protein content. Desiccated leaves contained, in a close to functional state, more than half the amount of the Rubisco protein present in rehydrated leaves. The results suggest that in X. scabrida leaves Rubisco adopts a special, protective conformation and recovers its activity during rehydration through modifications in redox status. PMID- 20956363 TI - Water and society in Jordan and Israel today: an introductory overview. AB - Increasing population levels and demand for water have led to a global water shortage, with more than one billion people unable to access safe drinking water. The Middle East is particularly vulnerable to water stress because of its dense population, variable climate and vulnerable groundwater resources. In Jordan, for example, if current trends in population continue, the water per capita will halve-putting the country in the category of having an absolute water shortage. This opening paper summarizes the climate and hydrology of Jordan and Israel, describes how water is managed at a national level in Jordan and reflects briefly on the broader international context. PMID- 20956364 TI - How uncertain are climate model projections of water availability indicators across the Middle East? AB - The projection of robust regional climate changes over the next 50 years presents a considerable challenge for the current generation of climate models. Water cycle changes are particularly difficult to model in this area because major uncertainties exist in the representation of processes such as large-scale and convective rainfall and their feedback with surface conditions. We present climate model projections and uncertainties in water availability indicators (precipitation, run-off and drought index) for the 1961-1990 and 2021-2050 periods. Ensembles from two global climate models (GCMs) and one regional climate model (RCM) are used to examine different elements of uncertainty. Although all three ensembles capture the general distribution of observed annual precipitation across the Middle East, the RCM is consistently wetter than observations, especially over the mountainous areas. All future projections show decreasing precipitation (ensemble median between -5 and -25%) in coastal Turkey and parts of Lebanon, Syria and Israel and consistent run-off and drought index changes. The Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4) GCM ensemble exhibits drying across the north of the region, whereas the Met Office Hadley Centre work Quantifying Uncertainties in Model ProjectionsAtmospheric (QUMP-A) GCM and RCM ensembles show slight drying in the north and significant wetting in the south. RCM projections also show greater sensitivity (both wetter and drier) and a wider uncertainty range than QUMP-A. The nature of these uncertainties suggests that both large-scale circulation patterns, which influence region-wide drying/wetting patterns, and regional-scale processes, which affect localized water availability, are important sources of uncertainty in these projections. To reduce large uncertainties in water availability projections, it is suggested that efforts would be well placed to focus on the understanding and modelling of both large-scale processes and their teleconnections with Middle East climate and localized processes involved in orographic precipitation. PMID- 20956365 TI - Water cycle changes over the Mediterranean: a comparison study of a super-high resolution global model with CMIP3. AB - Water cycle components over the Mediterranean for both a current run (1979-2007) and a future run (2075-2099) are studied with the Japan Meteorological Agency's 20 km grid global climate model. Results are compared with another study using the Coupled Model Intercomparison Project Phase 3 ensemble model (hereafter, the Mariotti model). Our results are surprisingly close to Mariotti's. The projected mean annual change rates of precipitation (P) between the future and the current run for sea and land are -11 per cent and -10 per cent, respectively, which are not as high as Mariotti's. Projected changes for evaporation (E) are +9.3 per cent and -3.6 per cent, compared with +7.2 per cent and -8.1 per cent in Mariotti's study, respectively. However, no significant difference in the change in P-E over the sea body was found between these two studies. The increased E over the eastern Mediterranean was found to be higher than that in the western Mediterranean, but the P decrease was lower. The net moisture budget, P-E, shows that the eastern Mediterranean will become even drier than the western Mediterranean. The river model suggests decreasing water inflow to the Mediterranean of approximately 36 per cent (excluding the Nile). PMID- 20956366 TI - A model-based assessment of the effects of projected climate change on the water resources of Jordan. AB - This paper is concerned with the quantification of the likely effect of anthropogenic climate change on the water resources of Jordan by the end of the twenty-first century. Specifically, a suite of hydrological models are used in conjunction with modelled outcomes from a regional climate model, HadRM3, and a weather generator to determine how future flows in the upper River Jordan and in the Wadi Faynan may change. The results indicate that groundwater will play an important role in the water security of the country as irrigation demands increase. Given future projections of reduced winter rainfall and increased near surface air temperatures, the already low groundwater recharge will decrease further. Interestingly, the modelled discharge at the Wadi Faynan indicates that extreme flood flows will increase in magnitude, despite a decrease in the mean annual rainfall. Simulations projected no increase in flood magnitude in the upper River Jordan. Discussion focuses on the utility of the modelling framework, the problems of making quantitative forecasts and the implications of reduced water availability in Jordan. PMID- 20956367 TI - Past, present and future precipitation in the Middle East: insights from models and observations. AB - Anthropogenic changes in precipitation pose a serious threat to society particularly in regions such as the Middle East that already face serious water shortages. However, climate model projections of regional precipitation remain highly uncertain. Moreover, standard resolution climate models have particular difficulty representing precipitation in the Middle East, which is modulated by complex topography, inland water bodies and proximity to the Mediterranean Sea. Here we compare precipitation changes over the twenty-first century against both millennial variability during the Holocene and interannual variability in the present day. In order to assess the climate model and to make consistent comparisons, this study uses new regional climate model simulations of the past, present and future in conjunction with proxy and historical observations. We show that the pattern of precipitation change within Europe and the Middle East projected by the end of the twenty-first century has some similarities to that which occurred during the Holocene. In both cases, a poleward shift of the North Atlantic storm track and a weakening of the Mediterranean storm track appear to cause decreased winter rainfall in southern Europe and the Middle East and increased rainfall further north. In contrast, on an interannual time scale, anomalously dry seasons in the Middle East are associated with a strengthening and focusing of the storm track in the north Mediterranean and hence wet conditions throughout southern Europe. PMID- 20956368 TI - Some physical drivers of changes in the winter storm tracks over the North Atlantic and Mediterranean during the Holocene. AB - The winter climate of Europe and the Mediterranean is dominated by the weather systems of the mid-latitude storm tracks. The behaviour of the storm tracks is highly variable, particularly in the eastern North Atlantic, and has a profound impact on the hydroclimate of the Mediterranean region. A deeper understanding of the storm tracks and the factors that drive them is therefore crucial for interpreting past changes in Mediterranean climate and the civilizations it has supported over the last 12 000 years (broadly the Holocene period). This paper presents a discussion of how changes in climate forcing (e.g. orbital variations, greenhouse gases, ice sheet cover) may have impacted on the 'basic ingredients' controlling the mid-latitude storm tracks over the North Atlantic and the Mediterranean on intermillennial time scales. Idealized simulations using the HadAM3 atmospheric general circulation model (GCM) are used to explore the basic processes, while a series of timeslice simulations from a similar atmospheric GCM coupled to a thermodynamic slab ocean (HadSM3) are examined to identify the impact these drivers have on the storm track during the Holocene. The results suggest that the North Atlantic storm track has moved northward and strengthened with time since the Early to Mid-Holocene. In contrast, the Mediterranean storm track may have weakened over the same period. It is, however, emphasized that much remains still to be understood about the evolution of the North Atlantic and Mediterranean storm tracks during the Holocene period. PMID- 20956369 TI - Palaeoenvironmental reconstruction in the Southern Levant: synthesis, challenges, recent developments and perspectives. AB - Palaeoenvironmental research in the Southern Levant presents a series of challenges, partly due to the unequal distribution of palaeoenvironmental records and potential archives throughout the region. Our knowledge of climatic evolution, during the last approximately 25,000 years, is of crucial importance to understand cultural developments. More local, well-dated, multi-proxy studies are much needed to obtain an accurate picture of environmental change in respect of the Late Pleistocene and the Holocene. This contribution reviews the current state of knowledge regarding Late Quaternary palaeoenvironmental changes in the Southern Levant, including some examples of more recent developments in palaeoenvironmental reconstruction in Israel and the Dead Sea area, and introduces the major challenges researchers face in the region. It also presents the first results of a new case study in Jordan, based on an analysis of peaty deposits located in the mountain slopes east of the Dead Sea. Such new studies help refine our knowledge of local environmental changes in the Southern Levant and especially the more arid areas, for which little information is presently available. More material suitable for palaeoenvironmental research, for example extensive tufa and travertine series, still awaits consideration in Jordan, opening up exciting perspectives for future research in the area. PMID- 20956370 TI - The domestication of water: water management in the ancient world and its prehistoric origins in the Jordan Valley. AB - The ancient civilizations were dependent upon sophisticated systems of water management. The hydraulic engineering works found in ancient Angkor (ninth to thirteenth century AD), the Aztec city of Tenochtitlan (thirteenth to fifteenth century AD), Byzantine Constantinople (fourth to sixth century AD) and Nabatean Petra (sixth century BC to AD 106) are particularly striking because each of these is in localities of the world that are once again facing a water crisis. Without water management, such ancient cities would never have emerged, nor would the urban communities and towns from which they developed. Indeed, the 'domestication' of water marked a key turning point in the cultural trajectory of each region of the world where state societies developed. This is illustrated by examining the prehistory of water management in the Jordan Valley, identifying the later Neolithic (approx. 8300-6500 years ago) as a key period when significant investment in water management occurred, laying the foundation for the development of the first urban communities of the Early Bronze Age. PMID- 20956371 TI - Land use, water and Mediterranean landscapes: modelling long-term dynamics of complex socio-ecological systems. AB - The evolution of Mediterranean landscapes during the Holocene has been increasingly governed by the complex interactions of water and human land use. Different land-use practices change the amount of water flowing across the surface and infiltrating the soil, and change water's ability to move surface sediments. Conversely, water amplifies the impacts of human land use and extends the ecological footprint of human activities far beyond the borders of towns and fields. Advances in computational modelling offer new tools to study the complex feedbacks between land use, land cover, topography and surface water. The Mediterranean Landscape Dynamics project (MedLand) is building a modelling laboratory where experiments can be carried out on the long-term impacts of agropastoral land use, and whose results can be tested against the archaeological record. These computational experiments are providing new insights into the socio ecological consequences of human decisions at varying temporal and spatial scales. PMID- 20956372 TI - Issues of water supply and contemporary urban society: the case of Greater Amman, Jordan. AB - Over the last two decades, Jordan has suffered a chronic water crisis, and is the tenth most water-scarce nation on Earth. Such water stress has been well illustrated in the case of Greater Amman, the capital, which has grown dramatically from a population of around 2000 in the 1920s, to 2.17 million today. One of the distinctive characteristics of the water supply regime of Greater Amman is that since 1987 it has been based on a system of rationing, with households receiving water once a week for various durations. Amman is highly polarized socio-economically, and by means of household surveys, both quantitative and qualitative, conducted in high- and low-income divisions of the city, a detailed empirical evaluation of the storage and use of water, the strategies used by households to manage water and overall satisfaction with water supply issues is provided in this paper, looking specifically at issues of social equity. The analysis demonstrates the social and economic costs of water rationing and consequent management to be high, as well as emphasizing that issues of water quality are of central importance to all consumers regardless of their socio-economic status within the city. PMID- 20956373 TI - Water reuse for irrigated agriculture in Jordan: challenges of soil sustainability and the role of management strategies. AB - Reclaimed water provides an important contribution to the water balance in water scarce Jordan, but the quality of this water presents both benefits and challenges. Careful management of reclaimed water is required to maximize the nutrient benefits while minimizing the salinity risks. This work uses a multi disciplinary research approach to show that soil response to irrigation with reclaimed water is a function of the management strategies adopted on the farm by the water user. The adoption of management methods to maintain soil productivity can be seen to be a result of farmers' awareness to potentially plant-toxic ions in the irrigation water (70% of Jordan Valley farmers identified salinization as a hazard from irrigation with reclaimed water). However, the work also suggests that farmers' management capacity is affected by the institutional management of water. About a third (35%) of farmers in the Jordan Valley claimed that their ability to manage salinization was limited by water shortages. Organizational interviews revealed that institutional awareness of soil management challenges was quite high (34% of interviewees described salinization as a risk from water reuse), but strategies to address this challenge at the institutional level require greater development. PMID- 20956374 TI - The aesthetics of water and land: a promising concept for managing scarce water resources under climate change. AB - The eastern Mediterranean faces a severe water crisis: water supply decreases due to climate change, while demand increases due to rapid population growth. The GLOWA Jordan River project generates science-based management strategies for maximizing water productivity under global climate change. We use a novel definition of water productivity as the full range of services provided by landscapes per unit blue (surface) and green (in plants and soil) water. Our combined results from climatological, ecological, economic and hydrological studies suggest that, in Israel, certain landscapes provide high returns as ecosystem services for little input of additional blue water. Specifically, cultural services such as recreation may by far exceed that of food production. Interestingly, some highly valued landscapes (e.g. rangeland) appear resistant to climate change, making them an ideal candidate for adaptive land management. Vice versa, expanding irrigated agriculture is unlikely to be sustainable under global climate change. We advocate the inclusion of a large range of ecosystem services into integrated land and water resources management. The focus on cultural services and integration of irrigation demand will lead to entirely different but productive water and land allocation schemes that may be suitable for withstanding the problems caused by climate change. PMID- 20956375 TI - Progressive development of water resources in the Middle East for sustainable water supply in a period of climate change. AB - The history of the Middle East has been influenced by past global climatic changes. Warm periods caused droughts, resulting in desertification, migration and war. Cold periods were humid and brought prosperity and agricultural settlement to the desert fringes. The forecast based on this correlation is that the present global warming will cause the drying up of the Middle East. As in the past, this negative impact should be mitigated by using the groundwater resources stored from past wetter times. This will involve deep drilling, pumping and modern irrigation methods within the framework of a new policy of 'progressive development', which will entail the use of currently undeveloped natural water resources beyond that of present water replenishment. While the use of the one time groundwater reserves is taking place, a master long-term comprehensive progressive development plan for the Middle East will be prepared. This plan will include the step-by-step development of other water resources such as treated effluents, desalinated brackish groundwater and desalination of seawater. PMID- 20956376 TI - Jiahuai Han: aflame on inflammation and p38. PMID- 20956377 TI - Cells in tight spaces: the role of cell shape in cell function. AB - In this issue, Pitaval et al. (2010. J. Cell Biol. doi:10.1083/jcb.201004003) demonstrate that cell geometry can regulate the elaboration of a primary cilium. Their findings and approaches are part of a historical line of inquiry investigating the role of cell shape in intracellular organization and cellular function. PMID- 20956379 TI - Cell shape and contractility regulate ciliogenesis in cell cycle-arrested cells. AB - In most lineages, cell cycle exit is correlated with the growth of a primary cilium. We analyzed cell cycle exit and ciliogenesis in human retinal cells and found that, contrary to the classical view, not all cells exiting the cell division cycle generate a primary cilium. Using adhesive micropatterns to control individual cell spreading, we demonstrate that cell spatial confinement is a major regulator of ciliogenesis. When spatially confined, cells assemble a contractile actin network along their ventral surface and a protrusive network along their dorsal surface. The nucleus-centrosome axis in confined cells is oriented toward the dorsal surface where the primary cilium is formed. In contrast, highly spread cells assemble mostly contractile actin bundles. The nucleus-centrosome axis of spread cells is oriented toward the ventral surface, where contractility prevented primary cilium growth. These results indicate that cell geometrical confinement affects cell polarity via the modulation of actin network architecture and thereby regulates basal body positioning and primary cilium growth. PMID- 20956378 TI - The cell biology of touch. AB - The sense of touch detects forces that bombard the body's surface. In metazoans, an assortment of morphologically and functionally distinct mechanosensory cell types are tuned to selectively respond to diverse mechanical stimuli, such as vibration, stretch, and pressure. A comparative evolutionary approach across mechanosensory cell types and genetically tractable species is beginning to uncover the cellular logic of touch reception. PMID- 20956380 TI - Cdc20 hypomorphic mice fail to counteract de novo synthesis of cyclin B1 in mitosis. AB - Cdc20 is an activator of the anaphase-promoting complex/cyclosome that initiates anaphase onset by ordering the destruction of cyclin B1 and securin in metaphase. To study the physiological significance of Cdc20 in higher eukaryotes, we generated hypomorphic mice that express small amounts of this essential cell cycle regulator. In this study, we show that these mice are healthy and not prone to cancer despite substantial aneuploidy. Cdc20 hypomorphism causes chromatin bridging and chromosome misalignment, revealing a requirement for Cdc20 in efficient sister chromosome separation and chromosome-microtubule attachment. We find that cyclin B1 is newly synthesized during mitosis via cytoplasmic polyadenylation element-binding protein-dependent translation, causing its rapid accumulation between prometaphase and metaphase of Cdc20 hypomorphic cells. Anaphase onset is significantly delayed in Cdc20 hypomorphic cells but not when translation is inhibited during mitosis. These data reveal that Cdc20 is particularly rate limiting for cyclin B1 destruction because of regulated de novo synthesis of this cyclin after prometaphase onset. PMID- 20956381 TI - Cep120 is asymmetrically localized to the daughter centriole and is essential for centriole assembly. AB - Centrioles form the core of the centrosome in animal cells and function as basal bodies that nucleate and anchor cilia at the plasma membrane. In this paper, we report that Cep120 (Ccdc100), a protein previously shown to be involved in maintaining the neural progenitor pool in mouse brain, is associated with centriole structure and function. Cep120 is up-regulated sevenfold during differentiation of mouse tracheal epithelial cells (MTECs) and localizes to basal bodies. Cep120 localizes preferentially to the daughter centriole in cycling cells, and this asymmetry between mother and daughter centrioles is relieved coincident with new centriole assembly. Photobleaching recovery analysis identifies two pools of Cep120, differing in their halftime at the centriole. We find that Cep120 is required for centriole duplication in cycling cells, centriole amplification in MTECs, and centriole overduplication in S phase arrested cells. We propose that Cep120 is required for centriole assembly and that the observed defect in neuronal migration might derive from a defect in this process. PMID- 20956382 TI - MyoD regulates apoptosis of myoblasts through microRNA-mediated down-regulation of Pax3. AB - The molecules that regulate the apoptosis cascade are also involved in differentiation and syncytial fusion in skeletal muscle. MyoD is a myogenic transcription factor that plays essential roles in muscle differentiation. We noticed that MyoD(-/-) myoblasts display remarkable resistance to apoptosis by down-regulation of miR-1 (microRNA-1) and miR-206 and by up-regulation of Pax3. This resulted in transcriptional activation of antiapoptotic factors Bcl-2 and Bcl-xL. Forced MyoD expression induces up-regulation of miR-1 and miR-206 and down-regulation of Pax3, Bcl-2, and Bcl-xL along with increased apoptosis in MyoD(-/-) myoblasts. In contrast, MyoD gene knockdown increases cell survival of wild-type myoblasts. The 3' untranslated region of Pax3 mRNA contains two conserved miR-1/miR-206-binding sites, which are required for targeting of these microRNAs (miRNAs). Therefore, these data suggest that MyoD not only regulates terminal differentiation but also apoptosis through miRNA-mediated down regulation of Pax3. Finally, MyoD, miR-1, and miR-206 are all down-regulated in quiescent satellite cells, which may be required for maintenance of muscle stem cells. PMID- 20956383 TI - Ankyrin G restricts ion channel diffusion at the axonal initial segment before the establishment of the diffusion barrier. AB - In mammalian neurons, the precise accumulation of sodium channels at the axonal initial segment (AIS) ensures action potential initiation. This accumulation precedes the immobilization of membrane proteins and lipids by a diffusion barrier at the AIS. Using single-particle tracking, we measured the mobility of a chimeric ion channel bearing the ankyrin-binding motif of the Nav1.2 sodium channel. We found that ankyrin G (ankG) limits membrane diffusion of ion channels when coexpressed in neuroblastoma cells. Site-directed mutants with decreased affinity for ankG exhibit increased diffusion speeds. In immature hippocampal neurons, we demonstrated that ion channel immobilization by ankG is regulated by protein kinase CK2 and occurs as soon as ankG accumulates at the AIS of elongating axons. Once the diffusion barrier is formed, ankG is still required to stabilize ion channels. In conclusion, our findings indicate that specific binding to ankG constitutes the initial step for Nav channel immobilization at the AIS membrane and precedes the establishment of the diffusion barrier. PMID- 20956384 TI - A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes. AB - In vertebrates, Hedgehog (Hh) signaling initiated in primary cilia activates the membrane protein Smoothened (Smo) and leads to activation of Gli proteins, the transcriptional effectors of the pathway. In the absence of signaling, Gli proteins are inhibited by the cytoplasmic protein Suppressor of Fused (SuFu). It is unclear how Hh activates Gli and whether it directly regulates SuFu. We find that Hh stimulation quickly recruits endogenous SuFu-Gli complexes to cilia, suggesting a model in which Smo activates Gli by relieving inhibition by SuFu. In support of this model, we find that Hh causes rapid dissociation of the SuFu-Gli complex, thus allowing Gli to enter the nucleus and activate transcription. Activation of protein kinase A (PKA), an inhibitor of Hh signaling, blocks ciliary localization of SuFu-Gli complexes, which in turn prevents their dissociation by signaling. Our results support a simple mechanism in which Hh signals at vertebrate cilia cause dissociation of inactive SuFu-Gli complexes, a process inhibited by PKA. PMID- 20956385 TI - Treatment effects of the R-appliance and twin block in Class II division 1 malocclusion. AB - The purpose of this study was to compare the effects of a differently designed functional appliance (the R-appliance) with a twin-block (TB)-treated group. Thirty patients (18 girls and 12 boys) with a mean age of 10.5+/-0.7 years were treated with the R-appliance for 16.2+/-0.3 months and 25 (11 boys and 14 girls) with a mean age of 11.2+/-1.3 years with a TB for 16.1+/-1.4 months (control). All had a Class II division 1 malocclusion due to mandibular deficiency. Lateral cephalograms obtained at the beginning (T1) and end (T2) of the study were analysed. Paired t-tests showed that SNB significantly increased in both groups. The incisor mandibular plane angle (IMPA) was reduced in the R-appliance group by 1.9+/-4.9 degrees (P<0.04) but increased by 0.5+/-5.1 degrees (P<0.6) in the TB group. SNA in the R-appliance group showed an increase of 0.2+/-1.8 degrees (P<0.5), while it was decreased by 0.2+/-1.3 degrees (P<0.3) in the TB group. Both treatment modalities were successful in moving the mandible forward. However, with the R-appliance, this was achieved without retroclination of the lower incisors. PMID- 20956386 TI - Prevalence and determinant factors of malocclusion in children with special needs. AB - Careful attention to malocclusion in children with special needs leads to a considerable improvement in the quality of life. The present study analysed the prevalence of malocclusion in children with Down syndrome (DS) and cerebral palsy (CP) as well as associations with individual, socio-economic, and behavioural factors. A cross-sectional study was carried out that included 181 mothers and their children with DS and CP (aged 3-12 years) at two institutions for individuals with special needs in Rio de Janeiro, Brazil. Data were collected using a questionnaire administered to the mothers and a dental examination of the children. Clinical examination recorded the following: anterior/posterior crossbite and anterior openbite (AOB). The control variables were the mother's level of education as well as the gender and age of the child. Statistical analysis of the data was performed using the chi-square test and multiple logistic regression. An anterior crossbite was present in 20.4 percent, a posterior crossbite in 21.5 percent, and an AOB in 29.8 percent. The presence of DS, bottle feeding, and non-nutritive sucking habits for 24 months or more was determinant factors for an anterior crossbite and the presence of DS, bottle feeding and non-nutritive sucking habits for 24 months or more, and respiratory infection in the previous 6 months was determinant factors for a posterior crossbite. The presence of CP and non-nutritive sucking habits for 24 months or more was determinant factors for an AOB. Thus, the prevalence of malocclusion in children with special needs was associated with the type of disability, use of bottle feeding and non-nutritive sucking habits for 24 months or more, and respiratory infection in the previous 6 months. PMID- 20956387 TI - Moments generated by simple V-bends in nickel titanium wires. AB - This study compared the moments produced by V-bends placed in rectangular nickel titanium (NiTi) orthodontic wire to those produced in titanium-molybdenum alloy (TMA). V-bends that included angles of 135, 150, and 165 degrees were heat set into 0.017*0.025 and 0.016*0.025 inch NiTi alloy wires and identical bends bent into TMA wires with a dimension of 0.018*0.025 and 0.016*0.022 inch. There were five specimens per group (N=60). The moments produced by each specimen were tested on a custom jig that aligned two lower incisor brackets with zero tip or torque at an interbracket distance of 15 mm. The upper bracket was connected to a moment transducer. The V-bend position for each specimen was varied in 1 mm increments towards the moment transducer. The moments produced by TMA wires were linear, which increased as the V-bend approached the transducer, while NiTi exhibited a non-linear curve characterized by a flattening of the moment value. The point of dissociation (where the moment experienced by the bracket became zero) was estimated for both wire types using linear mixed model analysis. For TMA wires, this point was similar to that reported in the literature but was significantly less for NiTi wire when compared with TMA. The moments produced by TMA generally increased with the magnitude of the V-bend, whereas this was not the case for NiTi. PMID- 20956388 TI - CSLEX (Sialyl Lewis X) is a useful tumor marker for monitoring of breast cancer patients. AB - BACKGROUND: CSLEX is a type II carbohydrate antigen that interacts with the CSLEX 1 monoclonal antibody. CSLEX in combination with carbohydrate antigen 15-3 may be more useful than Carcinoembryonic Antigen with carbohydrate antigen 15-3 as tumor markers for monitoring of breast cancer. METHODS: The serum levels of tumor markers, including CSLEX, were measured in 480 consecutive breast cancer patients with or without metastasis who visited the outpatient clinic of the Division of Breast and Endocrine Surgery, Shinshu University Hospital, between April 2007 and September 2007. RESULTS: Serum levels of each of the tumor markers correlated significantly with the status of metastasis (P < 0.01). Combinations of Carcinoembryonic Antigen and carbohydrate antigen 15-3, Carcinoembryonic Antigen and Nation Cancer Center-Stomach-439, Carcinoembryonic Antigen and CSLEX, carbohydrate antigen 15-3 and Nation Cancer Center-Stomach-439, and carbohydrate antigen 15-3 and CSLEX levels also correlated significantly with the status of metastasis (P < 0.01). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were almost the same for CSLEX and Nation Cancer Center-Stomach-439, which are both type II carbohydrate antigens. The cutoff indexes of serum CSLEX and Nation Cancer Center-Stomach-439 for detection of breast cancer metastasis were 38.8 +/- 52.7-fold and 22.1 +/- 27.8-fold, respectively (P = 0.16). CONCLUSIONS: These data suggest that the diagnostic values of CSLEX and Nation Cancer Center-Stomach-439 are similar in single or combined use. However, the cutoff index of serum CSLEX tended to be higher than that of Nation Cancer Center-Stomach-439, which may make CSLEX more useful for detection of breast cancer metastasis. PMID- 20956389 TI - Is return of spontaneous circulation always the best outcome in cardiac arrest? PMID- 20956390 TI - Reasons for not using intraosseous access in critical illness. AB - AIM: To identify reasons for not using intraosseous access (IO) when intravenous access is difficult during resuscitation. METHODS: Questionnaire made available to members of selected Scandinavian medical societies. RESULTS: Of 759 responders to the questionnaire, 23.5% (n=178) had experienced one or more situations where there was a need for IO but none was placed. The most common stated reasons for not performing IO were a lack of equipment (48.3%), a lack of knowledge about the procedure (32.6%), and intravenous access preferred over IO (23.0%). CONCLUSIONS: The main reasons for not using IO were lack of equipment and lack of training. The authors recommend increased training in IO use and greater availability of IO equipment for front-line staff in Scandinavian countries. The use of non-purpose designed needles for IO should be evaluated. PMID- 20956391 TI - Paramedics and the effects of shift work on sleep: a literature review. AB - INTRODUCTION: This paper investigates the literature regarding the impact of shift work on prehospital emergency providers. While the issue of shift work has been thoroughly investigated in other health disciplines, this is not the case for the paramedic discipline, particularly in the Australian context. OBJECTIVE: To identify the literature available on prehospital providers regarding the effects of shift work on sleep. METHOD: Electronic databases used were the Cochrane Database of Systematic Reviews, Ovid MEDLINE, Proquest, AMED and CINAHL. The following MeSH terms and keywords with truncation were used in the search strategy: 'shift work'; 'sleep disorder'; 'sleep deprivation'; 'circadian rhythm'; 'fatigue'; 'occupational stress'. RESULTS: The electronic databases cited 226 articles, of which nine met the inclusion criteria with another three articles sourced from references in the retrieved papers. There is a lack of literature describing the effect of shift work on sleep in the prehospital arena, with only one paper exploring paramedics in the Australian setting. These findings suggest that further work is required to examine shift hours and workforce health and safety in the prehospital setting. CONCLUSIONS: Shift work can affect health and well-being on a variety of levels, both physiologically and psychologically, affecting aspects of work and personal life. Further research is warranted to prevent the issues of patient safety, work-related fatigue and the cumulative effects of shift work. PMID- 20956392 TI - Penetrating chest injury from hammer splinter. PMID- 20956393 TI - Oral montelukast in acute asthma exacerbations: a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Although leukotriene receptor antagonists have an established role in the management of patients with chronic asthma, their efficacy in an acute asthma exacerbation is not fully known. METHODS: 87 adults with acute asthma requiring hospitalisation were randomly assigned to receive either montelukast 10 mg or placebo on admission and every evening thereafter for 4 weeks (when they were reviewed as outpatients). All patients were admitted under the care of a consultant chest physician and received full care for acute asthma according to the British Thoracic Society guidelines. The primary end point was the difference in peak expiratory flow (PEF) between active and placebo treatment the morning following admission. RESULTS: Primary end point data were analysed for 73 patients. At study entry, patients who received montelukast (n=37) had a mean (+/ SD) PEF of 227.6 (+/-56.9) l/min (47.6% predicted) and those who received placebo (n=36) had a PEF of 240.3 (+/-99.8) l/min (49.6% predicted). The morning after admission, patients who received montelukast achieved a PEF of 389.6 (+/-109.7) l/min (81.4% predicted) compared with 332.3 (+/-124.9) l/min (69.8% predicted) for placebo (p=0.046). The mean difference between treatment groups was 57.4 l/min (95% CI of 1.15 to 113.6 l/min or 1.95-21.2% predicted). CONCLUSION: In acute asthma exacerbations the additional administration of oral montelukast results in a significantly higher PEF the morning after admission than that achievable with current standard treatment. Clinical trial number NCT01011452. PMID- 20956395 TI - Should glycated haemoglobin (HbA1c) be used to detect people with type 2 diabetes mellitus and impaired glucose regulation? AB - There is a need to simplify screening tests for type 2 diabetes mellitus (T2DM) so patients can be identified earlier and more efficiently. Glycated haemoglobin (HbA1c) has been recommended by some international organisations as a diagnostic tool for detecting T2DM and impaired glucose regulation (IGR, also termed prediabetes and includes impaired fasting glucose and/or impaired glucose tolerance). The HbA1c cut-point of >=6.5% (48 mmol/mol) has been selected as diagnostic for T2DM, while the cut-points for IGR are debated by the different international organisations: an International Expert Committee has suggested using HbA1c 6.0-6.4% (42-46 mmol/mol); however, the American Diabetes Association has recommended using HbA1c 5.7-6.4% (39-46 mmol/mol). Some countries will adopt a new method of reporting HbA1c values in millimoles per mole (mmol/mol). Use of HbA1c has some logistical advantages over using an oral glucose tolerance test (OGTT). As patients do not need to fast, appointments do not need to be limited to the morning. The HbA1c result reflects longer term glycaemia and is less affected by recent physical/emotional stress. However, there is some debate as to whether HbA1c should replace fasting plasma glucose or the OGTT. As the two tests detect different people, some individuals with diabetes detected on OGTT will no longer be classified as having T2DM using HbA1c >=6.5% criteria. Furthermore, some medical conditions can result in HbA1c assay measurements not reflecting glycaemic control over the last 2-3 months; these include haematological disorders, renal failure, and chronic excess alcohol consumption. PMID- 20956394 TI - Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years. AB - BACKGROUND: Little is known about whether patterns of early growth are associated with altered respiratory and immune development. This study relates prenatal and infant growth patterns to wheeze and atopy at age 3 years. METHODS: Birth weight and length were measured in 1548 children born at term. Conditional fetal head and abdominal circumference growth velocities were calculated from antenatal ultrasound measurements. Conditional postnatal growth velocities were calculated from infant weight, length and adiposity data. Measures of size and conditional growth were related to parentally-reported infant and early childhood wheeze and to atopic status at age 3 years. RESULTS: The risk of atopy increased by 46% per SD increase in abdominal circumference growth velocity from 11 to 19 weeks gestation but by 20% per SD decrease in abdominal growth velocity from 19 to 34 weeks (p=0.007 and p=0.011, respectively). The risk of atopic wheeze increased by 20% per SD decrease in 19-34-week abdominal growth (p=0.046). The risk of non atopic wheeze increased by 10% per SD decrease in 11-19-week head circumference growth. Greater relative infant weight and adiposity gains were associated with both atopic and non-atopic wheeze. CONCLUSIONS: A rapid growth trajectory during 11-19 weeks gestation followed by late gestation growth faltering is associated with atopy, suggesting that influences affecting fetal growth may also alter immune development. A lower early fetal growth trajectory is associated with non atopic wheeze, possibly reflecting an association with smaller airways. An association between postnatal adiposity gain and wheeze may partly reflect prenatal influences that cause fetal growth to falter but are then followed by postnatal adiposity gain. PMID- 20956396 TI - Right ventricular myocardial infarction: pathophysiology, diagnosis, and management. AB - Right ventricular (RV) ischaemia complicates up to 50% of inferior myocardial infarctions (MIs), though isolated RV myocardial infarction (RVMI) is extremely rare. Although the RV shows good long term recovery, in the short term RV involvement portends a worse prognosis to uncomplicated inferior MI, with haemodynamic and electrophysiologic complications increasing in-hospital morbidity and mortality. Acute RV shock has an equally high mortality to left ventricular (LV) shock. Identification of RV involvement, particularly in the setting of hypotension, can help anticipate and prevent complications and has important management implications which are distinct from the management of patients presenting with LV infarction. Reperfusion therapy, particularly by primary percutaneous coronary intervention, hastens and enhances RV functional recovery that occurs to near normality in most patients. The diagnostic methods for RVMI are discussed, including clinical, electrocardiographic, and various imaging modalities as well as the RV pathophysiology that underpins the specifics of RVMI management. PMID- 20956397 TI - Tricuspid regurgitation: contemporary management of a neglected valvular lesion. AB - Right-sided cardiac valvular disease has traditionally been considered less clinically important than mitral or aortic valve pathology. However, detectable tricuspid regurgitation (TR) is common and recent data suggest that significant TR can lead to functional impairment and reduced survival, particularly in patients with concomitant left-sided valvular disease. The tricuspid valve is a complex anatomical structure and advances in three dimensional echocardiography and cardiac MRI have contributed to a greater understanding of tricuspid valve pathology. These imaging techniques are invaluable in determining the aetiology and severity of TR, and provide an assessment of right ventricular function and pulmonary artery pressure. TR is more prevalent in women and those with a history of myocardial infarction and heart failure. It also occurs in about 10% of patients with rheumatic heart disease. Chronic severe TR may have a prolonged clinical course culminating in the development of fatigue and poor exercise tolerance due to a reduced cardiac output. Approximately 90% of cases of TR are secondary to either pulmonary hypertension or intrinsic right ventricular pathology and about 10% are due to primary tricuspid valve disease. Primary causes such as Ebstein's anomaly, rheumatic disease, myxomatous changes, carcinoid syndrome, endomyocardial fibrosis, and degenerative disease have characteristic morphological features readily identifiable by echocardiography. Ascertaining an accurate right ventricular systolic pressure is important in separating primary from secondary causes as significant TR with a pressure <40 mm Hg implies intrinsic valve disease. Cardiac MRI may be indicated in those with inadequate echocardiographic images and is also the gold standard for the evaluation of right ventricular function and morphology. The assessment of leaflet morphology, annular dimensions, and pulmonary artery pressure are particularly important for determining subsequent management. Along with appropriate treatment of the underlying cause of TR and pulmonary hypertension, management guidelines indicate a move towards more aggressive treatment of TR. In those undergoing left-sided valve surgery, tricuspid valve repair is universally recommended in the presence of severe coexistent TR; in those with isolated severe TR, surgery is recommended in the presence of symptoms or progressive right ventricular dilatation or dysfunction. PMID- 20956398 TI - How can we as researchers promote a clear discourse in public health research, practice and policy? PMID- 20956399 TI - Cognitive impairment in relation to MRI metrics in patients with clinically isolated syndrome. AB - BACKGROUND: Cognitive deficits are frequent in multiple sclerosis (MS) and have been associated with morphologic brain changes. Less information exists on their extent and relation to MRI findings in clinically isolated syndrome (CIS). It is also unclear if structural changes as detected by magnetization transfer (MT) imaging may provide an additional explanation for cognitive dysfunction. OBJECTIVE: To analyse the extent of cognitive deficits and their relation to MRI metrics including MT imaging in CIS compared to relapsing-remitting MS (RRMS). METHODS: Forty-four CIS and 80 RRMS patients underwent the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) and a 3 T MRI scan. RESULTS: BRB-N subtests revealed similar results in CIS and RRMS. Impaired mental processing speed was most prevalent in both groups (CIS 13.6%; RRMS 16.3%) and thus served for correlation with MRI metrics. Using stepwise linear regression analyses, the strongest predictor for decreased mental processing speed was normalized cortex volume (p < 0.001) followed by T2-lesion load (p < 0.05) in RRMS, whereas cortical MT ratio was the only MRI parameter associated with decreased mental processing speed in CIS (p < 0.005). CONCLUSION: Cognitive dysfunction occurs in CIS in a pattern similar to RRMS, with impaired mental processing speed being most prevalent. Cortical MT-ratio changes may be an early sign for tissue changes related to impaired mental processing speed in CIS while this association shifts to increased signs of cortical atrophy and lesion load in RRMS. PMID- 20956400 TI - Biochemical endocrinology of the hypogonadal male. AB - Hypogonadism in the male results from inadequate testicular function, especially defects in androgen synthesis and secretion, or action. Androgen action is important throughout normal male development: in the fetus, puberty, adult life and old age. Regulation is by variable activity of the hypothalamo-pituitary axis at different phases of the life span. Clinical aspects include: genetic aspects presenting at birth and pubertal failure/arrest. Aspects in adult life embrace sexuality, somatic symptoms and osteoporosis. Acquired causes of hypogonadism may arise from various forms of testicular damage (primary hypogonadism), pituitary and hypothalamic disorders, as well as aetiologies acting at several sites. Measurement of testosterone (T) is crucial to the diagnosis of hypogonadism and the technologies continue to develop, with recent major advances. A growing problem relates to the diagnosis and treatment of hypogonadism in the ageing male. T therapy is available in several forms, with major improvements in more newly available modalities. PMID- 20956401 TI - Trans-catheter aortic valve implantation--early recovery of left and preservation of right ventricular function. AB - This study aimed to assess the early effect of trans-catheter aortic valve implantation (TAVI) on right (RV) and left ventricular (LV) function in severe aortic stenosis (AS) patients. Twenty AS patients (age 79+/-6 years) were examined before, one week and six weeks after TAVI using Doppler echocardiography. LV ejection fraction (EF), long-axis [mitral annular plane systolic excursion (MAPSE)] and RV long-axis [tricuspid annular plane systolic excursion (TAPSE)] function, septal radial motion were studied. Results were compared with 30 AS patients before and one week after aortic valve replacement (AVR) as well as 30 normals (reference group). Before TAVI, LVEF was reduced and E/A was higher than the reference and AVR groups (P<0.05 for all). MAPSE, TAPSE and septal motion were equally reduced in TAVI and AVR patients (P<0.05 for all). One week after the TAVI, EF increased in patients with values <50% before the procedure. In contrast, AVR resulted in reversed septal motion (P<0.001) and depressed TAPSE (P<0.001). The extent of reversed septal motion correlated with that of TAPSE in the patients group as a whole after procedures (r=0.78, P<0.001). Six weeks after TAVI, RV function remained unchanged, but LVEF increased and E/A decreased (P<0.05 for both). Thus, TAVI procedure results in significant early improvement of LV systolic and diastolic function particularly in patients with reduced EF and preserves RV systolic function. PMID- 20956402 TI - Left main artery dissection as a clinical sign of the aortic rupture following aortic valve replacement for fulminant aortic endocarditis. AB - Aortic valve endocarditis with perivalvular abscess formation remains a demanding condition and the results of the surgery are not optimal. Abscess localized in the aortic basis area can weaken the aortic wall, leading to further deterioration and rupture. The presented case allows us to recommend a maximal aggressive approach in patients, in whom the aortic wall seems to be rearranged due to abscess formation. Sometimes only the resection of the abscess hole and replacement of the entire ascending aorta offers a safe therapy option. PMID- 20956403 TI - Synchronous B3 thymoma and lung bronchoalveolar carcinoma. AB - The association between thymic tumors and other intrathoracic or extrathoracic neoplasms is relatively rare; the synchronous occurrence of thymoma and bronchoalveolar carcinoma of the lung has never been described so far. A huge B3 cystic thymoma was found at thoracotomy to be associated with stage IV bronchoalveolar carcinoma (intraparenchymal and pleural metastases). The thymic tumor was completely resected; lung cancer was biopsied only for diagnosis and staging purposes. After an uneventful postoperative course the patient underwent chemotherapy; she is still alive and well one year after surgery. PMID- 20956404 TI - Familial hemicrania continua. AB - There are now three known causative genes for familial hemiplegic migraine and increasing evidence to support a genetic predisposition to the more common types of migraine with and without aura, and for cluster headache. We present the first reported case of familial hemicrania continua. A mother and daughter developed hemicrania continua at the same time of life. Both showed an absolute response to indometacin and at similar doses. Both also suffered from migraine with aura. We discuss the increasing support for a genetic predisposition to dysfunction of the pain system within the brain manifesting as primary headache. PMID- 20956405 TI - Statins inhibit the antirheumatic effects of rituximab in rheumatoid arthritis: results from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. PMID- 20956406 TI - Prevalence of cardiovascular diseases in psoriatic arthritis resembles that of rheumatoid arthritis. PMID- 20956407 TI - Bone metabolism is altered in preclinical rheumatoid arthritis. PMID- 20956408 TI - Neonatal nurse practitioners: distribution, roles and scope of practice. AB - OBJECTIVE: We sought to determine the distribution and scope of practice of the neonatal nurse practitioner (NNP) workforce across the United States. METHODS: To determine distribution, we used counts of certified NNPs from the National Certification Corp (Chicago, IL). We calculated state NNP/child population ratios as the number of NNPs divided by the state population 0 to 17 years of age. We calculated NNP/NICU bed ratios as the number of NNPs divided by the total number of NICU beds per state. To characterize roles and scope of practice, we conducted a mail survey of a random national sample of 300 NNPs in states that license nurse practitioners to practice independently and 350 NNPs in states that require physician involvement. RESULTS: The greatest concentrations of NNPs per capita were in the Midwest, South, and Mid-Atlantic region. Thirty-one states had <100 total NNPs. The survey response rate was 77.1%. More than one-half of NNP respondents (54% [n = 211]) reported that they spent the majority of their time in a community hospital, whereas more than one-third (37% [n = 144]) were in an academic health center. Only 2% (n = 7) reported that they engaged in independent practice. CONCLUSIONS: As with many health care professionals, the supply of NNPs may not be distributed according to need. With increasing concern regarding the availability of NNPs, comprehensive studies that examine the demand for NNPs and the roles of other clinicians in the NICU should provide a greater understanding of appropriate NICU workforce capacity and needs. PMID- 20956410 TI - Relationship between bed sharing and breastfeeding: longitudinal, population based analysis. AB - OBJECTIVES: This is an investigation into the longitudinal patterns of bed sharing, the characteristics associated with those patterns, and the relationship with breastfeeding. METHODS: The study used prospective, population-based data from the United Kingdom to investigate nocturnal bed sharing at 5 time points from birth to 4 years of age. Of 14 062 live births, 7447 (53%) had data available for all time points. RESULTS: Latent class analysis identified 4 mutually exclusive groups, broadly described as nonsharers (66%), early bed sharers (only in infancy) (13%), late bed sharers (after the first year) (15%), and constant bed sharers (throughout the 4 years) (6%). The boy/girl ratio and the proportion of families of nonwhite ethnicity were slightly higher in all 3 bed-sharing groups, compared with the non-bed-sharing group. Higher maternal educational achievement and higher social class were positively associated with early bed sharing, negatively associated with late bed sharing, and not associated with constant bed sharing. The 3 bed-sharing patterns were related significantly to breastfeeding at 12 months (P < .001), whether the families shared beds late (odds ratio: 1.72 [95% confidence interval: 1.36-2.18]), early (odds ratio: 2.36 [95% confidence interval: 1.87-2.97]), or for the whole period (odds ratio: 5.29 [95% confidence interval: 4.05-6.91]). The prevalence of breastfeeding was significantly higher among the groups that shared beds constantly or early for each of the first 15 months after birth. CONCLUSIONS: Advice on whether bed sharing should be discouraged needs to take into account the important relationship with breastfeeding. PMID- 20956411 TI - Family nurse practitioners: roles and scope of practice in the care of pediatric patients. AB - OBJECTIVE: The goal was to characterize the pediatric role and scope of practice of family nurse practitioners (FNPs). METHODS: A mail survey of a random national sample of 1000 FNPs, stratified according to states that license nurse practitioners to practice independently, was performed. Frequencies were calculated and bivariate analyses were performed to determine the level of association between practice characteristics and practice state, practice location (urban versus rural), and type of care provided (primary versus specialty). RESULTS: The overall response rate was 75.9%. Sixty-six percent of respondents (n = 416) reported that they currently provided care to children, and 18% (n = 110) reported that they had never provided care to children. Fifty-four percent of FNPs who provided care to children (n = 222) reported that children represented <= 25% of their current patient populations. Few FNPs (9% [n = 39]) reported that children represented >75% of their total patient populations. CONCLUSIONS: Among FNPs who provide care to children, pediatric patients represent only a small fraction of their patient populations. FNPs are unlikely to have a significant impact on the availability of either primary or subspecialty care for children in the near future. PMID- 20956412 TI - Association between Medicaid reimbursement and child influenza vaccination rates. AB - OBJECTIVE: We examined associations between influenza vaccination rates and Medicaid reimbursement rates for vaccine administration among poor children who were eligible for Medicaid (<100% of the federal poverty level in all states). METHODS: We analyzed 3 consecutive National Immunization Surveys (NISs) to assess influenza vaccination rates among nationally representative children 6 to 23 months of age during the 2005-2006 (unweighted N = 12 885), 2006-2007 (unweighted N = 9238), and 2007-2008 (unweighted N = 11 785) influenza seasons (weighted N = 3.3-4.0 million per season). We categorized children into 3 income levels (poor, near-poor, or nonpoor). We performed analyses with full influenza vaccination as the dependent variable and state Medicaid reimbursement rates (continuous covariate ranging from $2 to $17.86 per vaccination) and terms with income levels as key covariates. RESULTS: In total, 21.0%, 21.3%, and 28.9% of all US children and 11.7%, 11.6%, and 18.8% of poor children were fully vaccinated in the 2006, 2007, and 2008 NISs, respectively. Multivariate analyses of all 3 seasons found positive significant (all P < .05) associations between state-level Medicaid reimbursement and influenza vaccination rates among poor children. A $10 increase, from $8 per influenza vaccination (the US average) to $18 (the highest state reimbursement), in the Medicaid reimbursement rate was associated with 6.0 , 9.2-, and 6.4-percentage point increases in full vaccination rates among poor children in the 2006, 2007, and 2008 NIS analyses, respectively. CONCLUSION: Medicaid reimbursement rates are strongly associated with influenza vaccination rates. PMID- 20956413 TI - Pediatric physician assistants: distribution and scope of practice. AB - BACKGROUND: Physician assistants (PAs) are licensed to practice with physician supervision. PAs do not specialize or subspecialize as part of their formal standard training; consequently, their license is not limited to a specific specialty. As such, PAs can, and do, change their practice settings at will. Some researchers have projected plans for the future use of the pediatric PA workforce. However, the information on which those projections have been based is limited. OBJECTIVE: To provide information regarding the current status of pediatric PAs and to inform future workforce deliberations, we studied their current distribution and scope of practice. METHODS: Data from the American Association of Physician Assistants and the US Census Bureau were used to map the per-capita national distribution of pediatric PAs. We conducted a mail survey of a random sample of 350 PAs working in general pediatrics and 300 working in pediatric subspecialties. RESULTS: Most states have <50 pediatric PAs, and there is significant variation in their distribution across the nation. The overall survey response rate was 83.5%; 82% (n = 359) were female. More than half of the respondents (57% [n = 247]) reported that they currently are working in pediatric primary care, mostly in private-practice settings. CONCLUSIONS: PAs can, and do, play an important role in the care of children in the United States. However, the impact of that role is limited by the relative scarcity of PAs currently engaged in pediatric practice. PMID- 20956409 TI - Multiple courses of antenatal corticosteroids for preterm birth study: 2-year outcomes. AB - OBJECTIVE: The aim of this study was to determine the effects of repeated courses of prenatal corticosteroid therapy versus placebo on death or neurologic impairment among the children enrolled in the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study, at 18 to 24 months of age. METHODS: A total of 2305 infants were eligible for follow-up evaluation; 2104 infants (1069 in the prenatal corticosteroid therapy group and 1035 in the placebo group) were monitored. The primary outcome was death or neurologic impairment, defined as either cerebral palsy or cognitive delay, at 18 to 24 months of age. The secondary outcomes were measurements of growth (height, weight, and head circumference). RESULTS: Children exposed to multiple courses of prenatal corticosteroid therapy had similar rates of death or neurologic impairment, compared with children exposed to placebo (148 children [13.8%] vs 142 children [13.7%]; odds ratio: 1.001[95% confidence interval: 0.75-1.30]; P = .95). They had a mean weight of 11.94 kg, compared with 12.14 kg in the placebo group (P = .04), a mean height of 85.51 cm, compared with 85.46 cm (P = .87), and a mean head circumference of 48.18 cm, compared with 48.25 cm (P = .45). CONCLUSIONS: Multiple courses of prenatal corticosteroid therapy, given every 14 days, did not increase or decrease the risk of death or neurologic impairment at 18 to 24 months of age, compared with a single course of prenatal corticosteroid therapy. Continued follow-up monitoring of these children is necessary to assess neurobehavioral function, school performance, and possible susceptibility to disease. PMID- 20956414 TI - Vision of Pediatrics 2020: the AAP's role in maintaining focus and creating the future. PMID- 20956415 TI - Physiologic and clinical benefits of noninvasive ventilation in infants with Pierre Robin sequence. AB - OBJECTIVE: The objective of the study was to determine the clinical and physiologic benefits of noninvasive respiratory support (NRS) (continuous positive airway pressure or noninvasive positive pressure ventilation) for infants with a Pierre Robin sequence (PRS). METHODS: Breathing patterns, respiratory efforts, and gas exchange were analyzed for 7 infants with a PRS during spontaneous breathing and during NRS. Clinical outcomes with duration of NRS and need for a tracheotomy and/or nutritional support was evaluated. RESULTS: Compared with spontaneous breathing, breathing patterns, respiratory efforts, and transcutaneous carbon dioxide pressures improved during NRS; the mean respiratory rate decreased from 55 +/- 9 to 37 +/- 7 breaths per minute (P = .063), the mean inspiratory time/total duty cycle decreased from 59 +/- 9% to 40 +/- 7% (P = .018), the mean esophageal pressure swing decreased from 29 +/- 13 to 9 +/- 4 cm H(2)O (P = .017), the diaphragmatic pressure-time product decreased from 844 +/- 308 to 245 +/- 126 cm H(2)O-second per minute (P = .018), and the mean transcutaneous carbon dioxide pressure during sleep decreased from 57 +/- 7 to 31 +/- 7 mm Hg (P = .043). All of the patients could be discharged successfully from the hospital with NRS. The mean duration of NRS was 16.7 +/- 12.2 months. Six patients could be weaned from nutritional support, and none required a tracheotomy. CONCLUSIONS: NRS is able to improve breathing patterns and respiratory outcomes for infants with severe upper airway obstruction attributable to a PRS, which supports its use as a first-line treatment. PMID- 20956416 TI - Vision of Pediatrics 2020: lessons learned from a Christmas Carol. PMID- 20956417 TI - Peering into the future: pediatrics in a changing world. AB - Over the last decade, health care has experienced continuous, capricious, and ever-accelerating change. In response, the American Academy of Pediatrics convened the Vision of Pediatrics (VOP) 2020 Task Force in 2008. This task force was charged with identifying forces that affect child and adolescent health and the implications for the field of pediatrics. It determined that shifts in demographics, socioeconomics, health status, health care delivery, and scientific advances mandate creative responses to these current trends. Eight megatrends were identified as foci for the profession to address over the coming decade. Given the unpredictable speed and direction of change, the VOP 2020 Task Force concluded that our profession needs to adopt an ongoing process to prepare for and lead change. The task force proposed that pediatric clinicians, practices, organizations, and interest groups embark on a continual process of preparing, envisioning, engaging, and reshaping (PEER) change. This PEER cycle involves (1) preparing our capacity to actively participate in change efforts, (2) envisioning possible futures and potential strategies through ongoing conversations, (3) engaging change strategies to lead any prioritized changes, and (4) reshaping our futures on the basis of results of any change strategies and novel trends in the field. By illustrating this process as a cycle of inquiry and action, we deliberately capture the continuous aspects of successful change processes that attempt to peer into a multiplicity of futures to anticipate and lead change. PMID- 20956418 TI - Referral to the emergency department by a primary care provider predicts severity of illness. AB - OBJECTIVE: The purpose of this study was to assess whether referral to a pediatric emergency department (PED) by a primary care provider was associated with greater severity of illness, as determined on the basis of clinical measures and increased resource utilization. METHODS: A retrospective study of data for 121 088 children who presented to a PED with abdominal pain, fever, or respiratory complaints during a 5-year period was performed. Demographic data, referral status, and proxy markers of illness severity were collected from the medical records and analyzed. RESULTS: A total of 26.3% of all patients seen in the PED presented with these 3 complaint categories. With adjustment for age, gender, race, and insurance class, referred patients were significantly more likely to have high triage acuity designations, higher rates of very abnormal vital signs, and higher admission rates, compared with patients who were self referred. Referred patients were more likely to undergo testing (laboratory or radiologic), to receive intravenous fluid therapy and pain medications, and to be assigned higher-severity discharge diagnoses, such as appendicitis, septic shock, or status asthmaticus. CONCLUSIONS: Referral by a primary care provider to a PED was significantly and independently associated with greater severity of illness and resource utilization. Referral status should be considered in algorithms used to triage cases for evaluation in the PED. PMID- 20956419 TI - Pediatric nurse practitioners: roles and scope of practice. AB - BACKGROUND: There are ~ 13,000 pediatric nurse practitioners (PNPs) in the United States. PNPs have been suggested as professionals who could provide care to the growing cadre of children with chronic illnesses and expand the pool of subspecialty care providers. Little is known about current roles of PNPs in primary or subspecialty care. OBJECTIVE: To gain a better understanding of the roles, focus of practice, professional setting, and professional responsibilities of PNPs. METHODS: We conducted a mail survey of a random national sample of 1200 PNPs stratified according to states that license NPs to practice independently. chi(2) statistics were used to assess responses from PNPs in states that allow independent practice versus those that do not and on PNPs in primary versus specialty care. RESULTS: The overall response rate was 82.4%. Ninety-six percent (n = 636) of the PNPs were female. More than half of all the respondents (59% [n = 391]) worked in primary care, and almost two-thirds (64% [n = 394]) did not provide care in inpatient settings. Only 11% of the PNPs in states that allow independent practice, practiced independently. CONCLUSIONS: The majority of PNPs currently work in primary care, and most do not have any inpatient roles. It does not seem that independent PNP practices are responsible for a significant portion of pediatric visits. For those who posit that PNPs will help alleviate the currently perceived shortage of pediatric subspecialists, our findings indicate that it likely will not occur without a significant change in the PNP workforce distribution. PMID- 20956420 TI - Neurocognitive and endothelial dysfunction in children with obstructive sleep apnea. AB - OBJECTIVE: Pediatric obstructive sleep apnea syndrome (OSAS) is associated with neurocognitive and endothelial dysfunction. However, it is unclear whether these 2 frequent morbidities of OSAS in children represent similar or different underlying pathophysiological processes, because they have never been concurrently assessed in children. METHODS: Consecutive children (ages 5-8 years) with polysomnographically based OSAS underwent cognitive battery evaluation (Differential Ability Scales and the NeuroPsychological Assessment Battery) and cuff-occlusion hyperemic tests for assessment of endothelial function. The presence of neurocognitive deficits (NC(+)) was defined on the basis of the presence of >= 2 abnormal cognitive test results. Endothelial dysfunction (ED(+)) was defined as a time to maximal postocclusive hyperemic response of >= 45 seconds (T(max)). RESULTS: Twenty-one control children and 87 children with OSAS completed both cognitive and endothelial tests. Of these children, 48 were NC(+) and 50 had a T(max) of >= 45 seconds, and at least 80% of these children were in both groups. Conversely, among children in whom there was no presence of neurocognitive deficits (NC(-)), only 25.6% were ED(+), whereas among those without endothelial dysfunction (ED(-)) only 21.6% were NC(+). Furthermore, approximately one-third of the children with OSAS was NC(-) and ED(-). Thus, findings on hyperemic vascular responses were highly predictive of neurocognitive status. CONCLUSIONS: Endothelial dysfunction and neurocognitive deficits are more likely to coexist than otherwise predicted from the frequency of each of these morbidities alone in pediatric OSAS. Thus, both of these morbid consequences may share similar pathogenetic mechanisms. Furthermore, a simple test such as the postocclusive hyperemic vascular response may help detect at-risk patients for neuropsychological deficits. PMID- 20956421 TI - Highly variable clinical phenotypes of hypomorphic RAG1 mutations. AB - Hypomorphic mutations that lead to "leaky" severe combined immunodeficiency presentation with partial protein function are increasingly being identified. Mutations in recombination-activating genes (RAGs) 1 and 2 cause immunodeficiency and dysregulation ranging from severe combined immunodeficiency to Omenn syndrome to more mild immunodeficiencies. We report here the cases of 3 patients with hypomorphic RAG1 mutations with distinct presentations. One patient had granulomatous skin disease and disseminated nontuberculous mycobacteria; the second patient presented with predominantly autoimmune manifestations; and the third patient presented with relatively late onset of infections and had isolated T-cell lymphopenia. These disparate and atypical presentations of hypomorphic RAG1 mutations highlight the role of RAG1 in immune function and autoimmunity and expand the disease spectrum linked to these genes. PMID- 20956422 TI - Maternal or paternal suicide and offspring's psychiatric and suicide-attempt hospitalization risk. AB - OBJECTIVE: We examined whether the risk for psychiatric morbidity requiring inpatient care was higher for offspring who experienced parental suicide, compared with offspring of fatal accident decedents, and whether the association varied according to the deceased parent's gender. METHODS: Children and adolescents (0-17 years of age) who experienced maternal (N = 5600) or paternal (N = 17,847) suicide in 1973-2003 in Sweden were identified by using national, longitudinal, population-based registries. Cox regression modeling was used to compare psychiatric hospitalization risks among offspring of suicide decedents and propensity score-matched offspring of accident decedents. RESULTS: Offspring of maternal suicide decedents had increased risk of suicide-attempt hospitalization, after controlling for psychiatric hospitalization for decedents and surviving parents, compared with offspring of maternal accidental decedents. Offspring of paternal suicide decedents had similar risk of suicide-attempt hospitalization, compared with offspring of accident decedents, but had increased risk of hospitalization attributable to depressive and anxiety disorders. The magnitude of risks for offspring suicide-attempt hospitalization was greater for those who experienced maternal versus paternal suicide, compared with their respective control offspring (interaction P = .05; offspring of maternal decedents, adjusted hazard ratio: 1.80 [95% confidence interval: 1.19-2.74]; offspring of paternal decedents, adjusted hazard ratio: 1.14 [95% confidence interval: 0.96-1.35]). CONCLUSIONS: Maternal suicide is associated with increased risk of suicide-attempt hospitalization for offspring, beyond the risk associated with maternal accidental death. However, paternal suicide is not associated with suicide-attempt hospitalization. Future studies should examine factors that might differ between offspring who experience maternal versus paternal suicide, including genetic or early environmental determinants. PMID- 20956423 TI - Helping mothers prevent influenza illness in their infants. PMID- 20956424 TI - Pediatrics in the year 2020 and beyond: preparing for plausible futures. AB - Although the future of pediatrics is uncertain, the organizations that lead pediatrics, and the professionals who practice within it, have embraced the notion that the pediatric community must anticipate and lead change to ultimately improve the health of children and adolescents. In an attempt to proactively prepare for a variety of conceivable futures, the board of directors of the American Academy of Pediatrics established the Vision of Pediatrics 2020 Task Force in 2008. This group was charged to think broadly about the future of pediatrics, to gather input on key trends that are influencing the future, to create likely scenarios of the future, and to recommend strategies to best prepare pediatric clinicians and pediatric organizations for a range of potential futures. The work of this task force led to the development of 8 "megatrends" that were identified as highly likely to have a profound influence on the future of pediatrics. A separate list of "wild-card" scenarios was created of trends with the potential to have a substantial influence but are less likely to occur. The process of scenario-planning was used to consider the effects of the 8 megatrends on pediatrics in the year 2020 and beyond. Consideration of these possible scenarios affords the opportunity to determine potential future pediatric needs, to identify potential solutions to address those needs, and, ultimately, to proactively prepare the profession to thrive if these or other future scenarios become realities. PMID- 20956425 TI - The association between developmental coordination disorder and other developmental traits. AB - OBJECTIVE: To explore associations between developmental coordination disorder (DCD) and attention, language, social skills, and academic ability in a population-based cohort. METHODS: We analyzed data (N = 6902) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Probable DCD was defined as children below the 15th centile of the ALSPAC Coordination Test aged 7 years with functional impairment in activities of daily living or handwriting, excluding children with neurologic difficulties or an IQ of <70. Four developmental domains were assessed by using standardized tests between the ages of 7.5 and 9 years: attention; language skills (expressive language, comprehension, short-term memory); social skills (nonverbal skills and social communication); and academic ability (reading and spelling). The worst 5% of each trait was used to define impairment. We used multiple logistic regression models to assess the association between probable DCD and each trait. Our final model controlled for IQ, socioeconomic factors, and other developmental traits not in the domain assessed. RESULTS: A total of 346 (5.0%) children met criteria for probable DCD. Probable DCD was associated with difficulties in attention (odds ratio [OR]: 1.94 [95% confidence interval (CI): 1.17-3.24]), nonword repetition (OR: 1.83 [95% CI: 1.26 2.66]), social communication (OR: 1.87 [95% CI: 1.15-3.04]), reading (OR: 3.35 [95% CI: 2.36-4.77]), and spelling (OR: 2.81 [95% CI: 2.03-3.90]). CONCLUSIONS: Children with probable DCD had an increased risk of difficulties in attention, social skills, reading, and spelling. These additional difficulties need to be screened for during assessment and considered when formulating interventions. PMID- 20956426 TI - A case of atrial fibrillation induced by inhaled fluticasone propionate. AB - Atrial fibrillation (AF) is the most common rhythm disorder observed in clinical practice. Several case reports and case-control studies have associated this condition with the use of systemic corticosteroids. However, to our knowledge, no case of AF induced by inhaled corticosteroids has been reported in the literature. We describe here the case of a 15-year-old boy who reported a paroxysmal AF with fast ventricular response after the administration of fluticasone propionate, which resolved after discontinuation of the drug. Use of the Naranjo adverse-drug-reaction probability scale indicated a possible relationship between the patient's development of AF and fluticasone propionate therapy. More studies are needed to confirm the association between this arrhythmia and the use of high doses of inhaled corticosteroids. Data from this report already suggest that clinicians should be aware of the possibility of adverse cardiovascular reactions when corticosteroids are prescribed also as inhaled preparations. PMID- 20956427 TI - Costs and consequences of universal sibling screening for vesicoureteral reflux: decision analysis. AB - OBJECTIVE: Our objective was to evaluate screening for vesicoureteral reflux (VUR) among siblings of patients with VUR, in terms of cost, radiation exposure, and number of febrile urinary tract infections (fUTIs) averted. METHODS: We constructed a Markov model to evaluate 2 competing management options, that is, universal screening (cystographic evaluation of all siblings without symptoms) and usual care (cystographic evaluation of siblings only after fUTIs). Published data were used to inform all model inputs. Costs were estimated by using a societal perspective. RESULTS: Universal screening yielded 2980 fUTIs, whereas usual care yielded 6330. Therefore, universal screening for VUR in a cohort of 100,000 siblings 1 year of age without symptoms resulted in the prevention of 1 initial fUTI per 3360 siblings, at an excess cost of $55,600 per averted fUTI, in comparison with usual care. These estimates were heavily dependent on screening age and the effectiveness of antibiotic prophylaxis; prevention of a single fUTI would require screening of 166 siblings 5 years of age and 694 siblings 10 years of age. Similarly, if prophylaxis was ineffective in preventing fUTIs, then up to 10,000 siblings would need to be screened for prevention of a single fUTI. CONCLUSIONS: Prevention of a single fUTI would require screening of 30 to 430 siblings 1 year of age without symptoms, at an estimated excess cost of $56,000 to $820,000 per averted fUTI. These estimates are heavily dependent on screening age and the effectiveness of antibiotic prophylaxis. PMID- 20956428 TI - The clinical problem of hyperinsulinemic hypoglycemia and resultant infantile spasms. AB - Hyperinsulinemic hypoglycemia (HH) is a cause of severe hypoglycemia in the newborn and infancy period and is associated with a high risk of neurologic handicap and epilepsy. Infantile spasms after exposure to HH is rare and has been described in only 1 previous report. We report the clinical, biochemical, and neurodevelopmental characteristics of 5 patients with neonatal-onset HH who subsequently developed infantile spasms. All 5 patients had neonatal-onset HH of varying severity and duration. These patients presented with the characteristic ictal pattern of spasms in clusters at a mean age of 6.6 months. Characteristic hypsarrhythmia was noted in only 3 of 5 patients. Structural abnormality was found in only 1 of 4 patients who underwent MRI of the brain. Infantile spasms responded to medical treatment in 3 patients, spasms in 1 patient were refractory to antiepileptic drugs, and treatment duration was insufficient for us to comment on the response in 1 patient. Developmental delay was evident in all of them. In conclusion neonatal HH of varying severity is associated with later (after a latent period) development of infantile spasms. The latent period before the onset of the spasms can be variable; hence, long-term neurodevelopmental follow up (until 1 year of age) is necessary. PMID- 20956429 TI - Racial differences among children with primary hypertension. AB - OBJECTIVE: Race is a known risk factor for hypertension and cardiovascular disease in adults and influences blood pressure (BP) in children. We sought to determine if there are differences in clinical, laboratory, or echocardiographic characteristics among children with primary hypertension from different racial groups. PATIENTS AND METHODS: Study participants were 184 children aged 3 to 20 years with a diagnosis of primary hypertension who were examined at 1 of 3 participating centers at the time of initial evaluation of elevated BP. Black children were categorized as African American (AA) and nonblack children as non AA. Comparisons were made for the entire group and after stratification according to age (<13 or >= 13 years). RESULTS: Overall, children categorized as AA had a higher prevalence of overweight/obesity and left ventricular hypertrophy and had higher plasma renin activity than children who were categorized as non-AA. After age stratification, these differences remained only in the children younger than 13 years old; there were no differences in these findings among children aged 13 years or older. AA children who were aged 13 years or older, however, had higher BPs for both casual and ambulatory measurements. Specifically, they had higher casual diastolic BP, higher 24-hour diastolic BP, higher daytime systolic and diastolic BP, and higher BP loads at night and over a 24-hour period compared with non-AA children who were aged 13 years or older. CONCLUSIONS: These data indicate that black children with primary hypertension may be at increased cardiovascular risk compared with nonblack children with primary hypertension. However, the high prevalence of overweight/obesity and left ventricular hypertrophy in all youth with primary hypertension demonstrates the need for greater preventive and therapeutic efforts aimed at reducing cardiovascular risk in this vulnerable population. PMID- 20956431 TI - Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 20956430 TI - Pediatric basic life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. PMID- 20956432 TI - Neonatal resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. PMID- 20956434 TI - Pediatric advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. PMID- 20956435 TI - Heterogeneity in the responsiveness to long-term lifestyle intervention and predictability in obese women with polycystic ovary syndrome. AB - BACKGROUND: Treatment of obesity improves all features of the polycystic ovary syndrome (PCOS). There is, however, a heterogeneous response to weight loss, and predictive factors are unknown. Objective This follow-up study aimed to investigate obese women with PCOS treated with a long-term lifestyle program to evaluate responsiveness and predictability. METHODS: One hundred PCOS women meeting the criteria for selection were invited to participate and 65 of them agreed. Lifestyle intervention had consisted of a 1200-1400 kcal/day diet for 6 months, followed by mild calorie restriction and physical activity. The protocol, which was similar at baseline and follow-up, included anthropometry, clinical evaluation, pelvic ultrasound, and laboratory investigations. The mean follow-up period was 20.4+/-12.5 months. RESULTS: After the follow-up period, women were reclassified into three groups according to the persistence (group 1, 15.4%), partial (group 2, 47.7%), or complete (group 3, 36.9%) disappearance of the categorical features of PCOS (hyperandrogenism, menses, and ovulatory dysfunctions). Duration of the follow-up and extent of weight loss were similar among the three groups, as were fasting and glucose-stimulated insulin and indices of insulin resistance. Baseline waist circumference, waist to hip ratio (WHR), and androstenedione blood levels were negatively correlated with a better outcome in the univariate analysis. However, only basal androstenedione values persisted to a highly significant extent (P<0.001) in the multivariate analysis. CONCLUSIONS: Responsiveness to weight loss in overweight/obese PCOS women varies considerably and more than one third of women may achieve full recovery. These findings add new perspectives to the impact of obesity on the pathophysiology of PCOS. PMID- 20956437 TI - Childhood psychological abuse and adult aggression: the mediating role of self capacities. AB - The current study examines the utility of self-trauma theory for explaining the long-term impact of childhood psychological abuse on aggression. Specifically, the self-capacities of interpersonal relatedness, identity, and affect regulation are tested as mediators of the impact of psychological abuse on various types of aggression in adulthood. Hierarchical regression analyses are used to examine data collected from 268 university students who completed the Personality Assessment Inventory, Comprehensive Child Maltreatment Scale, and the Inventory of Altered Self-Capacities. Results show that self-capacities were predicted by maltreatment, particularly psychological abuse. Altered self-capacities fully mediate the impact of child maltreatment on various forms of aggression. Problems with interpersonal relationships play the most significant role in mediating the relationship between child maltreatment and aggression. Results suggest more frequent maltreating experiences predict more dysfunctional self-capacities, which increases the probability of displaying various forms of aggression. PMID- 20956436 TI - Natural history of the transition from euthyroidism to overt autoimmune hypo- or hyperthyroidism: a prospective study. AB - OBJECTIVE: To evaluate the progression in time from euthyroidism to overt autoimmune hypothyroidism or to overt autoimmune hyperthyroidism. SUBJECTS AND METHODS: The design is that of a nested case-control study within the prospective Amsterdam autoimmune thyroid disease (AITD) cohort study in which 790 healthy euthyroid women with at least one first or second degree relative with documented AITD were followed for 5 years. Thyroid function tests were assessed annually. Contrast between cases (overt hypothyroidism - TSH>5.7 mU/l and free thyroxine (FT(4))<9.3 pmol/l and overt hyperthyroidism - TSH<0.4 mU/l and FT(4)>20.1 pmol/l, also referred to as events) and controls (matched for age and duration of follow-up). RESULTS: At baseline, the 38 hypothyroid cases had already higher TSH and lower FT(4) concentrations than their 76 controls, and the difference between both the groups persisted 1 year before occurrence of the event. In contrast, neither TSH nor FT(4) values differed between the 13 hyperthyroid cases and their 26 controls at baseline or 1 year before the event. The prevalence of thyroid peroxidase-Ab was higher in both hypothyroid and hyperthyroid cases than in controls. At the time of event, hypothyroid cases were less common among current smokers (P=0.083) and more common in the postpartum period (P=0.006) than their controls, whereas hyperthyroid cases were pregnant more frequently (P=0.063). CONCLUSIONS: The data suggest that progression toward overt autoimmune hypothyroidism is a gradual process taking several years, but in contrast overt autoimmune hyperthyroidism develops faster in terms of months. PMID- 20956438 TI - Words that hurt: a qualitative study of s parental verbal abuse in the Philippines. AB - This article investigated opinions on what constitute parental abuse with interviews of 30 high school students, 30 parents, and 28 counselors. Despite increased reported cases of emotional abuses and child maltreatments in the Philippines, few empirical studies have explored the exact nature of parental verbal abuses in this country. This study is designed to address this gap in the literature. The results revealed nine categories of parental verbal abuses namely: (a) Put downs and shaming, (b) Rejection, (c) Blaming, (d) Fault Exaggerating, (e) Threat, (f) Invoking harm, (g) Regrets, (h) Unfair comparison, and (i) Negative prediction. Implications for research and practice were discussed. PMID- 20956439 TI - Sexual assault of older women by strangers. AB - This study examines victim, offender, and offence characteristics associated with sexual assaults by strangers of older women compared to those against younger women. Cases are obtained from the Serious Crime Analysis Section of the United Kingdom National Policing Improvement Agency (NPIA; formerly Centrex). All possible cases of rape, attempted rape, and lesser sexual assault involving a single female victim aged 60 or older are selected (n = 53). These are matched with a sample of sexual assaults against women aged between 20 to 45 years ( n = 53). Research findings reveal significant differences in relation to a number of variables, including ethnicity of the offender, number of previous convictions of the offender, and characteristics associated with the assault itself. The results of this research reveal new information about violent sexual assaults on older women by strangers and have implications for practitioners dealing with such cases. PMID- 20956440 TI - The counselor's trauma as counseling motivation: vulnerability or stress inoculation? AB - Should counselors with interpersonal trauma histories work with similarly traumatized clients? How does the work affect them? Current research is inconsistent. This study examines 101 sexual assault and domestic violence counselors' recalled motivations for trauma work, their reported subjective personal changes, and their secondary and vicarious trauma symptoms and burnout. Counselors motivated by interpersonal trauma report both more symptoms and positive changes (including dealing with their own trauma). Those seeking personal meaning report becoming more hypervigilant and self-isolating. Those saying they learned from clients rate symptoms lower, suggesting stress inoculation. Supervisors of trauma counselors should facilitate learning from clients separately from processing the counselor's trauma. PMID- 20956441 TI - The influence of stereotypical beliefs, participant gender, and survivor weight on sexual assault response. AB - The present study explored the influence of survivor weight and participant gender, rape myth acceptance, and antifat attitudes on perceptions of sexual assault. Using an online survey tool, a community sample of 413 adult Canadian residents reviewed a hypothetical sexual assault scenario and completed a series of evaluations and attitudinal questionnaires. Generalized linear model analyses revealed that participants were more likely to hold the survivor responsible, excuse the perpetrator's actions, and respond more negatively toward the survivor and more positively toward the perpetrator when the survivor was depicted as thin versus overweight. Interactions were found between rape myth acceptance and survivor weight, gender and survivor weight, and gender and antifat attitudes, for certain dependent variables. In addition, men and those with higher levels of rape myth acceptance and antifat attitudes were found to make more negative evaluations of the survivor and more positive evaluations of the perpetrator. Recommendations for future research and interventions are discussed. PMID- 20956442 TI - Routine activities and victimization at school: the significance of gender. AB - Routine activities theory has not fully considered the role of gender in shaping victimization and yet, the research literature clearly demonstrates that gender is associated with an individual's risk of victimization. In addition to the pervasive effect of gender on victimization, gender shapes an individual's daily routines and thus may create a gender-specific relationship with victimization. This article explores the importance of gender in understanding the relationship between student's participation in extracurricular routine activities (e.g., student government, clubs, sports, and etc.) and the risk of victimization. From the Education Longitudinal Study of 2002, a sample of 10th-grade students was drawn for analyses. Hierarchical Generalized Linear Modeling was employed to explore the role of gender in the relationship between extracurricular routine activities and victimization at school. The results reveal that students' gender indeed interacts with several of the extracurricular routine activities creating gender-specific risks of victimization. This article highlights the importance of gender in explaining victimization and suggests researchers should consider how gender may interact with other routine activities and victimization. PMID- 20956443 TI - African American adolescents living and coping with community violence on Chicago's southside. AB - This study explores community violence exposures among African American adolescents and whether coping strategies were gendered. In-depth interviews are conducted with a sample of 32 African American high school students. Data are analyzed using a thematic analysis. The primary forms of violence exposures are physical attacks, fighting, and incidents involving police, gun violence, and murders. Boys report more exposure to violence as victims and witnesses, whereas girls are more likely to hear about violent acts. Coping styles range from "getting through," which included both an acceptance of community conditions; "getting along," which included self-defense techniques; "getting away," which included avoidance coping strategies; and "getting back," which consisted of confrontational coping strategies. Boys report more confrontational coping styles than are girls, who utilized more avoidance approaches. Widespread school-based interventions are warranted, given the high prevalence of community violence exposure among these youth and may provide important supports for coping against such trauma. PMID- 20956444 TI - Antenatal haemoglobinopathy screening. PMID- 20956445 TI - Have we heeded the lessons from Shipman? PMID- 20956446 TI - Changes in university funding for medical education in England. PMID- 20956447 TI - Improve chest compressions to reduce deaths from cardiac arrest, new guidance says. PMID- 20956452 TI - Hospital layoffs in US are "worst in decade," statistics show. PMID- 20956433 TI - Pediatric basic and advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 20956453 TI - Four million lives could be saved over next four years if more was done to tackle tuberculosis, partnership says. PMID- 20956454 TI - Court gives go ahead for 20 states to challenge US health reform. PMID- 20956456 TI - Ethnic differences in common carotid intima-media thickness, and the relationship to cardiovascular risk factors and peripheral arterial disease: the Ethnic Echocardiographic Heart of England Screening Study. AB - OBJECTIVE: To compare the mean and maximum common carotid intima-media thickness (CCIMT) in Blacks (Black Caribbean and Black African) and South Asians (People originating from India, Pakistan and Bangladesh) in a population survey and make associations with established cardiovascular risk factors and peripheral arterial disease (PAD). PATIENTS AND METHODS: A subset of 492 (293 South Asians and 199 Blacks) out of 572 participants aged >= 45 years recruited in a sub-study to the Ethnic-Echocardiographic Heart of England Screening (E-ECHOES) epidemiological study had mean and maximum CCIMT measured. A questionnaire, anthropometric measurements and Ankle Brachial Pressure Index (ABPI) and Intermittent Claudication assessments were made. RESULTS: Black participants had greater mean but not maximum CCIMT when compared to South Asians overall (P = 0.022), in men (P = 0.04) and in women (P = 0.044). Black ethnicity was an independent predictor of CCIMT even after adjustment for traditional cardiovascular risk factors (P < 0.05). After adjustment for age, ethnicity and traditional cardiovascular risk factors, the presence of PAD remained independently predictive of mean (P = 0.019) and maximum (P = 0.012) CCIMT. CONCLUSION: Black ethnicity is related to greater mean and maximum CCIMT when compared to South Asians, even after adjusting for traditional cardiovascular risk factors. The presence of PAD independently predicts mean and maximum CCIMT adjusting for ethnicity, age and cardiovascular risk factors. PMID- 20956457 TI - Accelerated total dose infusion of low molecular weight iron dextran is safe and efficacious in chronic kidney disease patients. AB - BACKGROUND: Low molecular weight iron dextran (LMWID) is licensed for use as a total dose infusion (TDI) over 4-6 h. In order to improve patient convenience and cost-effectiveness of therapy, we investigated the safety and efficacy of adopting accelerated dosing regimens and compared this with a standard rate LMWID infusion. METHODS: A retrospective study of patients undergoing accelerated and standard rate TDI of LMWID was conducted across three centres. A total of 1904 doses of LMWID were administered at an accelerated rate of 1 g over 1 h 40 min. This was compared with 395 patients who had standard rate infusion of 1 g LMWID over 3-4 h. RESULTS: There were eight minor adverse events in patients receiving accelerated dose LMWID (8/1904, 0.42%) in comparison to one adverse event in patients receiving a standard regimen (1/395, 0.25%). No serious adverse events occurred. Serum haemoglobin and ferritin significantly improved in both groups. CONCLUSION: TDI LMWID is a safe and efficacious method of iron replacement. Accelerated infusion regimen is safe and compares well with standard rate infusion regimen. Furthermore, accelerated TDI of LMWID enables greater numbers of patients to be treated and consequently there appear to be advantages for both patient and health resources. PMID- 20956458 TI - No evidence of RET germline mutations in familial pituitary adenoma. AB - Pituitary adenomas are common in the general population. Although most of them are sporadic, some occur in a familial setting. In familial pituitary adenoma patients it is common that no germline defects are found after screening of aryl hydrocarbon receptor interacting protein (AIP) and other genes known to underlie the condition, suggesting the existence of yet unknown predisposition genes. Recently, the RET proto-oncogene was found to be a novel in vivo interaction partner of AIP in the pituitary gland. Here, we have screened patients from 16 AIP mutation negative (AIPmut-) pituitary adenoma families for RET germline mutations to assess whether RET could play a role in pituitary adenoma predisposition, similar to AIP. We found five novel germline RET changes: one in RET Exon 4 and the rest in noncoding regions of RET. Two changes, c.1560*G > A and -1285 G > A, were segregated in affected family members. We also analyzed the RET region with enhancer element locator (EEL) to identify RET regulatory elements, and to see whether the changes resided in these. None of the variants mapped to the regions predicted by EEL. Expression of RET was examined in ten AIPmut- and seven AIP mutation positive (AIPmut+) somatotropinomas by immunohistochemistry, with a trend showing reduced expression in the latter (P = 0.05). We conclude that the RET variants are presumably not related to pituitary adenoma predisposition, although reduced RET expression may play a role in AIP related genesis of somatotropinomas. PMID- 20956459 TI - Role of p21 and cyclin E in normal and secalonic acid D-inhibited proliferation of human embryonic palatal mesenchymal cells. AB - Secalonic acid D (SAD), a cleft palate-inducing teratogen, has been shown to inhibit proliferation/cell cycle progression in association with alteration in the levels of cell cycle regulators, p21 and cyclin E. These studies were conducted to test the hypotheses that p21 and cyclin E play an important functional role in normal human embryonic palatal mesenchymal (HEPM) cell cycle and that their up- and down-regulation, respectively, by SAD is functionally significant to its cell cycle block. Using small interfering RNA (siRNA) to silence p21 gene and transient transfection to overexpress cyclin E in control & SAD-treated HEPM cells, cell proliferation was assessed using a combination of cell numbers, thymidine uptake, CDK2 activity and Ki-67 expression. The results showed that silencing of p21 gene, although increased cell proliferation/numbers and CDK2 activity in normal HEPM cells, failed to counteract SAD-induced anti proliferative effect despite inducing partial recovery of CDK2 activity. Similar effects were apparent with cyclin E overexpression. It is concluded that p21 and cyclin E are important for normal HEPM cell proliferation. However, SAD-induced deregulation of either protein, singly, may not be sufficient to induce anti proliferative effect. Involvement of other cell cycle proteins such as cyclin D1 or of multiple proteins in SAD-induced cell cycle block needs to be examined. PMID- 20956460 TI - Protective effects of Chinese and Brazilian propolis treatment against hepatorenal lesion in diabetic rats. AB - Diabetes mellitus promoted an overproduction of free radicals and an increased incidence of both diabetic nephropathy and liver disease. In this report, we evaluated the effects of Chinese and Brazilian propolis on streptozotocin-induced hepatorenal injury in rats. The results demonstrated that Chinese propolis treated rats had a 7.4% reduction in the glycated hemoglobin (HbAlc) level compared with untreated diabetic rats. Additionally, Chinese propolis induced an increase in the serum superoxide dismutase (SOD) level significantly while Brazilian propolis raised serum SOD and reduced level of malonaldehyde (MDA) and nitric synthetase (NOS). Of the measurable decrease in serum alanine transaminase (ALT), aspartate transaminase (AST) and microalbuminuria demonstrated the propolis-mediated improvement of hepatorenal function, which was further confirmed by histological examination. We also observed that Chinese and Brazilian propolis increased hepatorenal glutathione peroxidase (GSH-px) level and inhibited MDA production significantly. These results suggested that propolis may prevent hepatorenal injury by inhibiting lipid peroxidation and enhancing the activities of antioxidant enzymes. PMID- 20956461 TI - Strategic involvement of facial colliculus in SLE. PMID- 20956463 TI - Transient myopic shifting in systemic lupus erythematosus. PMID- 20956462 TI - Complicated systemic lupus erythematosus pancreatitis: pseudocyst, pseudoaneurysm, but real bleeding. AB - We report the case of a 25-year-old patient with systemic lupus erythematosus (SLE) pancreatitis which was complicated by pseudocyst and pseudoaneurysm formation. The pseudoaneurysm progressed to intra-abdominal bleeding requiring endovascular coil embolization of the gastroduodenal artery. The pseudocyst and hematoma formed two large abdominal fluid collections causing symptoms due to a mass effect. These fluid collections were treated conservatively, while active SLE was treated with steroids, azathioprine, and immunoglobulins. She finally made a full recovery. To the best of our knowledge, this is the first report of a bleeding pseudoaneurysm complicating SLE pancreatitis. Although anecdotal, this case may serve as a useful example of the possible complications of SLE pancreatitis, including considerations on optimal management. PMID- 20956464 TI - Diffuse alveolar hemorrhage in systemic lupus erythematosus: risk factors and clinical outcome: results from affiliated hospitals of Catholic University of Korea. AB - This study was undertaken to investigate clinical characteristics of diffuse alveolar hemorrhage (DAH) in patients with systemic lupus erythematosus (SLE) and to determine risk factors and clinical outcomes of DAH in SLE patients. Among the 1521 patients with SLE admitted between January 1993 and June 2009 to affiliated hospitals of Catholic University of Korea, 21 SLE were admitted for DAH. The inclusion criteria for DAH was defined as new infiltrates on chest radiographs, an acute hemoglobin drop of at least 1.5 g/dl in the absence of an obvious source of bleeding, and one or more of the following signs: hemoptysis, hypoxemia, bronchoscopic or biopsy evidence of DAH. Included as disease controls were 83 SLE patients, matched for age and sex, who were admitted for other manifestations. Data based on medical records were analyzed retrospectively. There were no significantly differing demographic characteristics between SLE patients with DAH and those with other manifestations. Multivariate analysis demonstrated coexisting neuropsychiatric lupus (p = 0.002) and high SLE disease activity index scores (SLEDAI > 10) as independent risk factors in the development of DAH (p = 0.029). Among the 21 SLE patients with DAH, 13 died during the admission period (in-hospital mortality rate: 61.9%). Mortality was associated with infection and requirements of mechanical ventilation. Collectively, SLE patients who have neuropsychiatric manifestations or are in the active stage of the disease have an increased risk for developing DAH. Due to the high mortality of SLE patients with DAH, early recognition of risk factors and appropriate intervention is essential. PMID- 20956465 TI - Radiolabeled bicyclic somatostatin-based analogs: a novel class of potential radiotracers for SPECT/PET of neuroendocrine tumors. AB - A variety of radiolabeled somatostatin analogs have been developed for targeting of somatostatin receptor (sst)-positive tumors. Bicyclic somatostatin-based radiopeptides have not been studied yet. Hypothesizing that the introduction of conformational constraints may lead to receptor subtype selectivity or may help to delineate structural features determining pansomatostatin potency, we developed and evaluated first examples of this new class of potential radiotracers for imaging or therapy of neuroendocrine tumors. METHODS: The bicyclic peptides were synthesized by standard solid-phase peptide synthesis. DOTA was coupled to the resin-assembled peptide for labeling with (177)Lu and (68)Ga. Binding affinity and receptor subtype profile were determined using human ssts. Ca(2+) flux, internalization, and efflux were studied in human embryonic kidney (HEK)-sst(2) and HEK-sst(3) cell lines. Biodistribution and PET/CT studies were performed in corresponding nude mice models. RESULTS: Some of the new analogs showed high affinity for sst(2) and sst(3) and moderate affinity for sst(1), sst(4), and sst(5), while exhibiting agonistic properties. The analog AM3, comprising an octreotide ring and a head-to-tail-coupled Arg-diaminobutyric acid(DOTA) cycle, showed the highest receptor affinity and agonist potency. (177)Lu-AM3 showed high and receptor-mediated uptake in vivo in sst(2) and sst(3) tumors with low background. Kidneys were the only other tissue accumulating radioactivity that could be reduced by a preinjection of lysine. PET/CT studies of (68)Ga-AM3 at 1 h after injection were characterized by clear localization of the tumor, visualization of the kidneys, and negligible background. CONCLUSION: The high rigidity of these new bicyclic somatostatin-based radiopeptides led to agonistic ligands with good affinity for all 5 ssts. The pharmacokinetic data of (177)Lu/(68)Ga-AM3 make this peptide an excellent candidate as an imaging--and especially as a PET--radiotracer. PMID- 20956466 TI - Detection of hepatocellular carcinoma with PET/CT: a prospective comparison of 18F-fluorocholine and 18F-FDG in patients with cirrhosis or chronic liver disease. AB - This prospective study aimed to compare the diagnostic performance of (18)F fluorocholine and (18)F-FDG for detecting and staging hepatocellular carcinoma (HCC) in patients with chronic liver disease and suspected liver nodules. METHODS: Whole-body PET/CT was performed in a random order at 10 min after injection of 4 MBq of (18)F-fluorocholine per kilogram and at 1 h after injection of 5 MBq of (18)F-FDG per kilogram. PET/CT results were read in a masked manner by 2 specialists, and diagnostic performance was assessed from the results of consensus masked reading. Those focal lesions appearing with increased or decreased activity, compared with background, on (18)F-fluorocholine PET/CT were considered positive for malignancy. The standard of truth was determined on a per site basis using data from a histologic examination and a follow-up period of more than 6 mo; on a per-patient basis, the Barcelona criteria were also accepted as a proof of HCC in 5 patients. RESULTS: Eighty-one patients were recruited; standard of truth was determined in 59 cases. HCC was diagnosed in 34 patients. Therefore, sensitivity was 88% for (18)F-fluorocholine and 68% for (18)F-FDG (P = 0.07), and in 70 sites, sensitivity was 84% for (18)F-fluorocholine, significantly better than the 67% for (18)F-FDG (P = 0.01). Of the 11 patients with well-differentiated HCC, 6 had a positive result with (18)F-fluorocholine alone, whereas (18)F-FDG was never positive alone; corresponding site-based sensitivity was 94% for (18)F-fluorocholine and 59% for (18)F-FDG (P = 0.001). The detection rate of 18 sites corresponding to other malignancies was 78% for (18)F-fluorocholine and 89% for (18)F-FDG. In nonmalignant sites, (18)F fluorocholine appeared less specific than (18)F-FDG (62% vs. 91% P < 0.01) because of uptake by focal nodular hyperplasia. CONCLUSION: (18)F-fluorocholine was significantly more sensitive than (18)F-FDG at detecting HCC, in particular in well-differentiated forms. In contrast, (18)F-FDG appeared somewhat more sensitive at detecting other malignancies and was negative in focal nodular hyperplasia. Thus (18)F-fluorocholine appears to be a useful PET/CT tracer for the detection and surveillance of HCC; however, performing PET/CT with both radiopharmaceuticals seems to be the best option. PMID- 20956467 TI - 17beta-estradiol augments 18F-FDG uptake and glycolysis of T47D breast cancer cells via membrane-initiated rapid PI3K-Akt activation. AB - Use of (18)F-FDG uptake as a surrogate marker of therapeutic response requires the recognition of biologic factors that influence cancer cell glucose metabolism. Estrogen is a potent stimulator of breast cancer proliferation, a process that requires sufficient energy, which is likely met by increased glycolysis. We thus explored the effect of estrogen on (18)F-FDG uptake in responsive breast cancer cells and investigated the mediating molecular mechanisms. METHODS: T47D breast cancer cells were stimulated with 17beta estradiol (E(2)) or bovine serum albumin (BSA)-E(2) and measured for (18)F-FDG uptake, lactate release, and mitochondrial hexokinase activity. The effects of antiestrogens, cycloheximide, and major protein kinase inhibitors were investigated. Immunoblots were performed for membrane glucose transporter type 1, phosphorylated phosphatidylinositol 3-kinase (PI3K), and Akt. RESULTS: E(2) augmented T47D cell (18)F-FDG uptake in a dose- and time-dependent manner that preceded and surpassed its proliferative effect. With exposure to 10 nM E(2), protein content-corrected (18)F-FDG uptake reached 172.7% +/- 6.6% and 294.4% +/- 9.5% of controls by 24 and 48 h, respectively. Lactate release reached 110.9% +/- 7.3% and 145.2% +/- 10.5% of controls at 24 and 48 h, and mitochondrial hexokinase activity increased to 187.1% +/- 31.6% at 24 h. Membrane glucose transporter type 1 expression was unaltered. The effect was absent in estrogen receptor (ER)-negative breast cancer cells and was abrogated by ICI182780, indicating ER dependence. The E(2) effect was not blocked by tamoxifen and was mimicked by membrane-impermeable BSA-E(2), consistent with nongenomic membrane initiated E(2) action. Inhibition by cycloheximide demonstrated the requirement of a new protein synthesis. Immunoblots displayed rapid phosphorylation of PI3K and Akt within minutes of E(2) treatment, and the specific PI3K inhibitors wortmannin and LY294002 abolished the ability of E(2) to elevate (18)F-FDG uptake. CONCLUSION: Estrogen augments breast cancer cell (18)F-FDG uptake by stimulating glycolysis and hexokinase activity via membrane-initiated E(2) action that activates the PI3K-Akt pathway. These findings yield important insight into our understanding of the biology of breast cancer metabolism and may have potential implications for (18)F-FDG uptake as a surrogate marker of therapeutic response. PMID- 20956468 TI - Molecular imaging of MDM2 messenger RNA with 99mTc-labeled antisense oligonucleotides in experimental human breast cancer xenografts. AB - The mouse double-minute 2 (MDM2) oncogene, amplified or overexpressed in many human cancers, has been suggested to be a novel target for cancer therapy. Visualization of MDM2 expression using radionuclide targeting can provide important diagnostic information in malignant tumors. The overall aim of this study was to evaluate whether liposome-coated (99m)Tc-radiolabeled antisense oligonucleotides (ASONs) targeting MDM2 messenger RNA (mRNA) could be used for imaging of MDM2 expression in vivo. METHODS: ASON and mismatch oligonucleotide (ASONM) targeted to MDM2 mRNA were synthesized and radiolabeled with (99m)Tc using the bifunctional chelator hydrazinonicotinamide (HYNIC). Then the radiolabeled probe was characterized in vitro. Reverse-transcriptase polymerase chain reaction and Western blotting were performed to assay the MDM2 mRNA and protein level after MCF-7 (human breast adenocarcinoma cell line) cells were incubated with liposome-coated (99m)Tc-HYNIC-ASON/ASONM at various concentrations for 24 h. Following established MCF-7-bearing nude mice models, the biodistribution of liposome-coated (99m)Tc-HYNIC-ASON/ASONM was investigated, and in vivo tumor scintigraphic images were acquired for these animal models. All data were analyzed by statistical software. RESULTS: The labeling efficiencies of (99m)Tc-HYNIC-ASON and (99m)Tc-HYNIC-ASONM were 57.2% +/- 2.98% and 56.3% +/- 3.01%, respectively; the specific activities were 1,450 +/- 60.2 and 1,370 +/- 55.4 kBq/MUg, respectively; and the radiochemical purity for both was above 95%. The radiolabeled ASON still had the ability to hybridize to the sense oligonucleotide. In comparison with the mismatch probe, the antisense probe had an obvious effect on the levels of MDM2 mRNA and protein. The levels of mRNA and protein were significantly different for different concentration antisense probe groups (P < 0.01). The excretion of the antisense and mismatch probe was mainly through the liver and kidneys. The tumor radioactivity uptake of the antisense probe was significantly higher than that of the mismatch probe (P < 0.01). At 1 10 h after injection of the antisense probe, the tumor could be clearly visualized, whereas the tumors were not imaged at any time after injection of the mismatch probe. CONCLUSION: The accumulation of liposome-coated (99m)Tc-labeled ASONs in breast cancer tissue is specific. The antisense imaging with liposome coated (99m)Tc-HYNIC-ASON may be a promising method for visualization of MDM2 expression in human breast cancer. PMID- 20956469 TI - A new 18F-labeled folic acid derivative with improved properties for the PET imaging of folate receptor-positive tumors. AB - The folate receptor is a proven target for folate-based diagnosis and treatment of cancer. Several folic acid conjugates have been developed as radiopharmaceuticals, but a suitable (18)F-labeled folic acid derivative for routine clinical use is still lacking. The purpose of this study was to investigate the potential of 2'-(18)F-fluorofolic acid as a PET agent for folate receptor-positive tumors. METHODS: The binding affinity of the cold reference compound 2'-fluorofolic acid was determined by in vitro displacement assays using human folate receptor-positive KB cells and (3)H-folic acid. (18)F labeling of 2' fluorofolic acid was accomplished via a direct nucleophilic aromatic substitution of N(2)-(N,N-dimethylamino-methylene)-2'-nitrofolic acid di-tert-butylester followed by acidic cleavage of the amino and carboxylic protecting groups. The new radiofolate was evaluated in nude mice bearing KB tumor xenografts under control and blocking conditions. Animals were either scanned from 75 to 105 min after injection of the radiotracer or sacrificed 75 min after injection for ex vivo biodistribution studies. RESULTS: 2'-fluorofolic acid showed a high binding affinity (inhibition constant, 1.8 +/- 0.1 nM) for the folate receptor. Direct aromatic (18)F labeling of 2'-fluorofolic acid was achieved within 80 min via a convenient 2-step procedure in satisfactory radiochemical yields. The new radiotracer exhibited excellent pharmacokinetics with fast renal clearance and only moderate hepatobiliary elimination. Uptake of 2'-(18)F-fluorofolic acid in folate receptor-positive KB tumors was high and specific, allowing a clear-cut visualization by PET. CONCLUSION: 2'-(18)F-fluorofolic acid, obtained via an integrated approach, is a promising PET agent for folate receptor-positive tumors and outperforms previously reported (18)F-labeled folates. PMID- 20956470 TI - Radiosynthesis and evaluation of 11C-CIMBI-5 as a 5-HT2A receptor agonist radioligand for PET. AB - PET brain imaging of the serotonin 2A (5-hydroxytryptamine 2A, or 5-HT(2A)) receptor has been widely used in clinical studies, and currently, several well validated radiolabeled antagonist tracers are used for in vivo imaging of the cerebral 5-HT(2A) receptor. Access to 5-HT(2A) receptor agonist PET tracers would, however, enable imaging of the active, high-affinity state of receptors, which may provide a more meaningful assessment of membrane-bound receptors. In this study, we radiolabel the high-affinity 5-HT(2A) receptor agonist 2-(4-iodo 2,5-dimethoxyphenyl)-N-(2-[(11)C-OCH(3)]methoxybenzyl)ethanamine ((11)C-CIMBI-5) and investigate its potential as a PET tracer. METHODS: The in vitro binding and activation at 5-HT(2A) receptors by CIMBI-5 was measured with binding and phosphoinositide hydrolysis assays. Ex vivo brain distribution of (11)C-CIMBI-5 was investigated in rats, and PET with (11)C-CIMBI-5 was conducted in pigs. RESULTS: In vitro assays showed that CIMBI-5 was a high-affinity agonist at the 5 HT(2A) receptor. After intravenous injections of (11)C-CIMBI-5, ex vivo rat studies showed a specific binding ratio of 0.77 +/- 0.07 in the frontal cortex, which was reduced to cerebellar levels after ketanserin treatment, thus indicating that (11)C-CIMBI-5 binds selectively to the 5-HT(2A) receptor in the rat brain. The PET studies showed that the binding pattern of (11)C-CIMBI-5 in the pig brain was in accordance with the expected 5-HT(2A) receptor distribution. (11)C-CIMBI-5 gave rise to a cortical binding potential of 0.46 +/- 0.12, and the target-to-background ratio was similar to that of the widely used 5-HT(2A) receptor antagonist PET tracer (18)F-altanserin. Ketanserin treatment reduced the cortical binding potentials to cerebellar levels, indicating that in vivo (11)C CIMBI-5 binds selectively to the 5-HT(2A) receptor in the pig brain. CONCLUSION: (11)C-CIMBI-5 showed a cortex-to-cerebellum binding ratio equal to the widely used 5-HT(2A) antagonist PET tracer (18)F-altanserin, indicating that (11)C-CIMBI 5 has a sufficient target-to-background ratio for future clinical use and is displaceable by ketanserin in both rats and pigs. Thus, (11)C-CIMBI-5 is a promising tool for investigation of 5-HT(2A) agonist binding in the living human brain. PMID- 20956471 TI - Phenotyping of tumor biology in patients by multimodality multiparametric imaging: relationship of microcirculation, alphavbeta3 expression, and glucose metabolism. AB - Both dynamic contrast-enhanced (DCE) MRI and PET provide quantitative information on tumor biology in living organisms. However, imaging biomarkers often neglect tissue heterogeneity by focusing on distributional summary statistics. We analyzed the spatial relationship of alpha(v)beta(3) expression, glucose metabolism, and perfusion by PET and DCE MRI, focusing on tumor heterogeneity. METHODS: Thirteen patients with primary or metastasized cancer (non-small cell lung cancer, n = 9; others, n = 4) were examined with DCE MRI and with PET using (18)F-galacto-RGD and (18)F-FDG. Twenty-three different regions of interest were defined by cluster analysis based on the heterogeneity of tracer uptake. In these regions, the initial area under the gadopentetate dimeglumine concentration-time curve (IAUGC), as well as the regional blood volume (rBV) and regional blood flow (rBF), were estimated from DCE MRI and correlated with standardized uptake values from PET. RESULTS: Regions with simultaneously high uptake of (18)F-galacto-RGD and (18)F-FDG showed higher functional MRI data (IAUGC, 0.35 +/- 0.04 mM.s; rBF, 70.2 +/- 12.7 mL/min/100 g; rBV, 23.3 +/- 2.7 mL/100 g) than did areas with low uptake of both tracers (IAUGC, 0.15 +/- 0.04 mM.s [P < 0.01]; rBF, 28.3 +/- 10.8 mL/min/100 g; rBV, 9.9 +/- 1.9 mL/100 g [P < 0.01]). There was a weak to moderate correlation between the functional MRI parameters and (18)F-galacto-RGD (r = 0.30 0.62) and also (18)F-FDG (r = 0.44-0.52); these correlations were significant (P < 0.05), except for (18)F-galacto-RGD versus rBF (P = 0.17). CONCLUSION: These data show that multiparametric assessment of tumor heterogeneity is feasible by combining PET and MRI. Perfusion is highest in tumor areas with simultaneously high alpha(v)beta(3) expression and high glucose metabolism and restricted in areas with both low alpha(v)beta(3) expression and low glucose metabolism. The current limitations resulting from imaging with separate scanners might be overcome by future hybrid PET/MRI scanners. PMID- 20956473 TI - Are health economics making us sick? PMID- 20956472 TI - 111In-bevacizumab imaging of renal cell cancer and evaluation of neoadjuvant treatment with the vascular endothelial growth factor receptor inhibitor sorafenib. AB - Clear cell renal cell cancer (ccRCC) prominently expresses vascular endothelial growth factor-A (VEGF-A), and new treatment strategies for renal cell cancer (RCC) aim at the inhibition of VEGF-VEGF receptor signaling. This study explores the ability of (111)In-bevacizumab scintigraphy to depict RCC and to evaluate response to neoadjuvant treatment with sorafenib, a VEGF receptor inhibitor. METHODS: The ability to depict RCC with (111)In-bevacizumab scintigraphy was tested in 14 patients scheduled to undergo a tumor nephrectomy; of these, 9 RCC patients were treated in a neoadjuvant setting with sorafenib (400 mg orally twice a day). In the latter group, baseline and posttreatment (111)In-bevacizumab scans were compared. The intratumoral distribution of (111)In-bevacizumab was determined scintigraphically ex vivo in a 1-cm lamella of the resected tumorous kidney. Expression of VEGF-A, glucose transporter-1, carbonic anhydrase IX, alpha smooth-muscle actin, and Ki67 was determined by immunohistochemistry and compared with the local concentration of (111)In-bevacizumab. Additionally, the VEGF-A content in tumor samples was determined quantitatively by enzyme-linked immunosorbent assay. RESULTS: In all 5 non-neoadjuvant-treated patients, preferential accumulation of (111)In-bevacizumab was observed in the tumors. All ccRCC lesions with enhanced (111)In-bevacizumab targeting expressed high levels of VEGF-A. Treatment with sorafenib resulted in a significant decrease of (111)In bevacizumab uptake in the tumor in the patients with ccRCC (mean change, -60.5%; range, +1.5% to -90.1%). The decrease in uptake was due to destruction of the tumor neovasculature, whereas the VEGF-A expression remained intact. In the patient with papillary RCC, limited uptake without change after sorafenib was observed. CONCLUSION: RCC lesions were clearly delineated with (111)In bevacizumab scintigraphy. Neoadjuvant treatment with sorafenib resulted in a significant decrease of (111)In-bevacizumab uptake in RCC. (111)In-bevacizumab scintigraphy can be an attractive biomarker for response and needs further study. PMID- 20956474 TI - In vivo assay of folate receptors in nonfunctional pituitary adenomas with 99mTc folate SPECT/CT. AB - The objective of this study was to evaluate the in vivo assay of folate receptors in nonfunctional pituitary adenomas using preoperative (99m)Tc-folate SPECT/CT and Western blot analysis (WBA) of surgical specimens as the standard. METHODS: Fifty-six patients (29 men, 27 women; age range, 29-82 y) with clinically nonfunctional pituitary adenomas on MRI underwent preoperative imaging using 666 MBq (18 mCi) of (99m)Tc-folate. SPECT/CT images and whole-body and lateral head planar images were acquired approximately 2 h after injection. Surgical resection took place within a week. WBA on a portion of the excised specimens assessed folate receptor expression in 49 patients. Attenuation-corrected (99m)Tc-folate SPECT/CT images were assessed qualitatively and quantitatively (maximal adenoma counts to background), with WBA as a standard. RESULTS: Integrated CT was useful for uptake localization and assisted region-of-interest placement. Qualitative interpretation of planar imaging yielded a sensitivity of 81% and specificity of 72%. Qualitative SPECT/CT yielded a sensitivity of 94% and specificity of 61%. Receiver-operating-characteristic curve analysis of quantitative uptake yielded a tumor-to-background cutoff ratio of 3.5, with a sensitivity of 81% and specificity of 83%. Scalp uptake yielded consistent results (over the brain, neck, and choroid plexus) for background when SPECT/CT misalignment artifacts were avoided. Detection of pituitary uptake on anterior-posterior and lateral images was hampered by facial uptake, which varied between patients. CONCLUSION: SPECT/CT of (99m)Tc-folate is an accurate method of assaying folate receptors in vivo and may provide a quantitative marker for identifying folate receptor positive tumors. This method may also prove beneficial in selecting patients for folate-targeted therapy of clinically nonfunctional pituitary adenomas, for which there is currently no medical therapy. PMID- 20956475 TI - PET of tumor CXCR4 expression with 4-18F-T140. AB - Expression of the chemokine receptor CXCR4 by cancers has been shown to correlate with tumor aggressiveness and poor prognosis and may also contribute to metastatic seeding of organs that express its ligand SDF-1. However, fully optimized PET agents for determining CXCR4 expression by tumor cells in vivo are not yet available. This study aims to develop a stable, (18)F-labeled peptide that enables in vivo quantification of CXCR4 in cancer. METHODS: 4-F-benzoyl TN14003 (4-F-T140), a short peptide antagonist of CXCR4 with 1-(4,4-dimethyl-2,6 dioxocyclohexylidene)ethyl protecting groups on the epsilon-amino groups of the lysine residues, was labeled with (18)F-fluoride via N-succinimidyl-4-(18)F fluorobenzoate conjugation, followed by deprotection to give 4-(18)F-T140 that was exclusively labeled on the alpha-amine at the N terminus. Cell binding, migration, biodistribution, and small-animal PET studies of 4-(18)F-T140 were performed. RESULTS: 4-F-T140 was radiolabeled by coupling with N-succinimidyl-4 (18)F-fluorobenzoate, with an overall decay-corrected radiochemical yield of 15% +/- 5% calculated from the start of synthesis. The mean measured specific activity (+/-SD) was 7 +/- 2 GBq/MUmol (0.19 +/- 0.05 Ci/MUmol), and radiochemical purity was greater than 99%. 4-(18)F-T140 was found to bind specifically to red blood cells in vitro and in vivo. The binding of 4-(18)F-T140 to red blood cells was blocked with a small amount of cold 4-F-T140, which led to higher uptake of 4-(18)F-T140 by Chinese hamster ovarian (CHO)-CXCR4 tumors. Biodistribution experiments at 3 h after injection with the addition of 10 MUg of cold 4-F-T140 showed a 3.03 +/- 0.31 percentage injected dose per gram uptake in CHO-CXCR4 tumors, with a tumor-to-blood ratio of 27.1 +/- 8.7 and a tumor-to muscle ratio of 21.6 +/- 7.1. PET studies demonstrated clear visualization of CXCR4-transfected, but not CXCR4-negative, CHO tumors. CONCLUSION: 4-(18)F-T140 can be used as a PET tracer to image tumor expression of CXCR4, with a high tumor to-background ratio. The knowledge of whether tumors express or do not express CXCR4 might be beneficial in determining appropriate treatment and monitoring. PMID- 20956476 TI - Breast cancer and hormonal stimulation: is glycolysis the first sign of response? PMID- 20956477 TI - Functional imaging of localized prostate cancer aggressiveness using 11C-acetate PET/CT and 1H-MR spectroscopy. AB - We assessed the ability of (11)C-acetate PET/CT, MRI, and proton MR spectroscopy ((1)H-MRS) to image localized prostate cancer and detect its aggressiveness, using qualitative and quantitative approaches. METHODS: Twenty-one patients with untreated localized prostate cancer, diagnosed using transrectal ultrasound guided biopsy, were prospectively enrolled. Cancer laterality was based on the percentage of cancer and the highest Gleason score determined from biopsies. In addition to PET/CT, 3-dimensional (1)H-MRS of the entire prostate volume using a quantitative approach was performed. The imaging and histologic findings of 8 patients undergoing subsequent prostatectomy were compared on a sextant level. For each lobe and sextant, standardized uptake values (SUVs) and (choline + creatine + polyamines)-to-citrate (CCP/C) ratios were obtained from (11)C-acetate PET/CT and (1)H-MRS, respectively. The visual and quantitative findings on PET/CT and MRI data were compared with cancer laterality and aggressiveness based on the Gleason score and with prostate-specific antigen (PSA) velocity and international risk group classification. RESULTS: The sensitivity, specificity, and accuracy, on a lobar level using visual analysis, of (11)C-acetate PET/CT were 80%, 29%, 71%, respectively, and 89%, 29%, 79%, respectively, using contrast-enhanced MRI. The sensitivity and accuracy of (11)C-acetate PET/CT decreased to 64% and 63% and specificity increased to 62% when sextant analysis was performed. The agreement between prostate cancer laterality based on biopsy findings and visual interpretation of (11)C-acetate PET/CT and contrast-enhanced MRI was similar at 71%. The mean SUV maximum and CCP/C maximum for the dominant tumor lesion were 5.5 and 1.48, respectively, and did not differ significantly from values in the nondominant lobe. The dominant-lesion SUVs or CCP/C values were not associated with histologically determined prostate cancer aggressiveness, nor did PSA velocity correlate with the SUV or CCP/C values from the entire gland. CONCLUSION: (11)C-acetate PET/CT, MRI, and (1)H-MRS enable detection of localized prostate cancer with comparable and limited accuracy but fail to provide information on cancer aggressiveness. PMID- 20956478 TI - Quantitative upright-supine high-speed SPECT myocardial perfusion imaging for detection of coronary artery disease: correlation with invasive coronary angiography. AB - A recently developed camera system for high-speed SPECT (HS-SPECT) myocardial perfusion imaging shows excellent correlation with conventional SPECT. Our goal was to test the diagnostic accuracy of an automated quantification of combined upright and supine myocardial SPECT for detection of coronary artery disease (CAD) (>= 70% luminal diameter stenosis or, in left main coronary artery, >= 50% luminal diameter stenosis) in comparison to invasive coronary angiography (ICA). METHODS: We studied 142 patients undergoing upright and supine HS-SPECT, including 56 consecutive patients (63% men; mean age +/- SD, 64 +/- 13 y; 45% exercise stress) without known CAD who underwent diagnostic ICA within 6 mo of HS SPECT and 86 consecutive patients with a low likelihood of CAD. Reference limits for upright and supine HS-SPECT were created from studies of patients with a low likelihood of CAD. Automated software adopted from supine-prone analysis was used to quantify the severity and extent of perfusion abnormality and was expressed as total perfusion deficit (TPD). TPD was obtained for upright (U-TPD), supine (S TPD), and combined upright-supine acquisitions (C-TPD). Stress U-TPD >= 5%, S-TPD >= 5%, and C-TPD >= 3% myocardium were considered abnormal for per-patient analysis, and U-TPD, S-TPD, and C-TPD >= 2% in each coronary artery territory were considered abnormal for per-vessel analysis. RESULTS: On a per-patient basis, the sensitivity was 91%, 88%, and 94% for U-TPD, S-TPD, and C-TPD, respectively, and specificity was 59%, 73%, and 86% for U-TPD, S-TPD, and C-TPD, respectively. C-TPD had a larger area under the receiver-operating-characteristic curve than U-TPD or S-TPD for identification of stenosis >= 70% (0.94 vs. 0.88 and 0.89, P < 0.05 and not significant, respectively). On a per-vessel basis, the sensitivity was 67%, 66%, and 69% for U-TPD, S-TPD, and C-TPD, respectively, and specificity was 91%, 94%, and 97% for U-TPD, S-TPD, and C-TPD, respectively (P = 0.02 for specificity U-TPD vs. C-TPD). CONCLUSION: In this first comparison of HS SPECT with ICA, new automated quantification of combined upright and supine HS SPECT shows high diagnostic accuracy for detecting clinically significant CAD, with findings comparable to those reported using conventional SPECT. PMID- 20956479 TI - Apoptosis imaging: beyond annexin V. AB - Induction of apoptosis is the primary mechanism through which most chemotherapies cause tumor cell death. Early assessment of tumor response is required to manage patients in terms of quality of life versus intensive chemotherapy. Although imaging with radiolabeled annexin V has been intensively investigated, it is still not sufficiently mature for clinical application. This article will summarize various alternative imaging techniques for visualization of phosphatidylserine externalization, activity of caspases, and mitochondrial membrane potential. Such imaging studies will promote the identification of novel molecular targets and the development of highly specific apoptosis-detecting imaging probes with potential clinical applications. It is highly possible that quantitative imaging of apoptosis will greatly improve clinical decision making in apoptosis-related diseases. PMID- 20956480 TI - Quantitative parametric perfusion images using 15O-labeled water and a clinical PET/CT scanner: test-retest variability in lung cancer. AB - Quantification of tumor perfusion using radioactive water (H(2)(15)O) and PET is a promising method for monitoring treatment with antiangiogenic agents. However, use of dynamic H(2)(15)O scans together with a fully 3-dimensional clinical PET/CT scanner needs to be validated. The purpose of the present study was to assess validity and reproducibility of dynamic H(2)(15)O PET/CT scans for measuring tumor perfusion and validate the quantitative accuracy of parametric perfusion images. METHODS: Eleven patients with non-small cell lung cancer were included in this study. Patients underwent 2 dynamic H(2)(15)O (370 MBq) PET scans on the same day. During the first scan, arterial blood was withdrawn continuously. Input functions were derived from blood sampler data and the ascending aorta as seen in the images themselves (image-derived input function [IDIF]). Parametric perfusion images were computed using a basis function implementation of the standard single-tissue-compartment model. Volumes of interest (VOIs) were delineated on low-dose CT (LD-CT) and parametric perfusion images. RESULTS: VOIs could be accurately delineated on both LD-CT and parametric perfusion images. These parametric perfusion images had excellent image quality and quantitative accuracy when compared with perfusion values determined by nonlinear regression. Good correlation between perfusion values derived from the blood sampler input function and IDIF was found (Pearson correlation coefficient, r = 0.964; P < 0.001). Test-retest variability of tumor perfusion was 16% and 20% when delineated on LD-CT and parametric perfusion images, respectively. CONCLUSION: The use of ascending aorta IDIFs is an accurate alternative to arterial blood sampling for quantification of tumor perfusion. Image quality obtained with a clinical PET/CT scanner enables generation of accurate parametric perfusion images. VOIs delineated on LD-CT have the highest reproducibility, and changes of more than 16% in tumor perfusion are likely to represent treatment effects. PMID- 20956481 TI - Brief intraperitoneal radioimmunotherapy of small peritoneal carcinomatosis using high activities of noninternalizing 125I-labeled monoclonal antibodies. AB - We assessed the efficiency and toxicity of brief intraperitoneal radioimmunotherapy using high activities of (125)I-labeled monoclonal antibody (mAb) in the treatment of small-volume peritoneal carcinomatosis. METHODS: Brief intraperitoneal radioimmunotherapy consisted of a 185-MBq (740 MBq/mg) intraperitoneal injection of (125)I-35A7 (an anti-carcinoembryonic antigen mAb) into athymic nude mice 4 d after peritoneal tumor xenografting and, after 1 h, abundant washing of the peritoneal cavity with saline solution to remove unbound radioactivity. Another group of mice received this treatment plus a 37-MBq intravenous injection of (125)I-35A7 on day 7 or 11 after grafting. Control groups received a brief treatment followed by an additional intravenous injection on day 7 of either saline solution or irrelevant (125)I-PX. Tumor growth was monitored by bioluminescence imaging and SPECT/CT, and hematologic toxicity was evaluated by complete blood counts. Survival time was reported, and the mice were sacrificed when the bioluminescence signal reached 4.5 * 10(7) photons/s. The biodistribution of (125)I-35A7 mAb after intravenous or brief treatment was assessed, and the mean absorbed irradiation dose by organs and tumors was calculated using the MIRD formalism. RESULTS: Mild, transient hematologic toxicity was observed after the brief treatment plus intravenous (125)I-mAb, with no weight loss. Median survival increased from 32 d in the control groups, to 46 d in the brief treatment group, to 66 d in the group additionally receiving intravenous treatment on day 11, to 73 d in the group additionally receiving intravenous treatment on day 7. The brief treatment alone resulted in a 3-fold higher tumor-to-blood uptake ratio than did the standard intravenous treatment, and the mean absorbed irradiation doses by tumors were 11.6 Gy for the brief treatment and 16.7 Gy for the additional intravenous treatment. For healthy tissues other than blood, the mean absorbed irradiation dose did not exceed 1 Gy after brief treatment and 4.2 Gy after intravenous treatment. CONCLUSION: The efficiency, low toxicity, and high tumor-to-healthy tissue uptake ratio associated with brief intraperitoneal (125)I-35A7 radioimmunotherapy suggest that this method can be used in combination with radiation-synergistic drugs in the therapy of small-volume peritoneal carcinomatosis after cytoreductive surgery. PMID- 20956482 TI - Perivascular delivery of blebbistatin reduces neointimal hyperplasia after carotid injury in the mouse. AB - Proliferation and migration of smooth muscle cells (SMC) require myosin II activity; thus, we examined whether blebbistatin, a cell-permeable selective inhibitor of myosin II ATP activity, would impair neointimal hyperplasia after vascular injury. Delivery of blebbistatin via a perivascular polymer cuff reduced neointimal formation by 73% and luminal obstruction by 75% after carotid denudation injury in C57BL/6 mice. Blebbistatin treatment was also associated with a reduction in cell density within the neointima; total number of cells (76 +/- 7 to 27 +/- 3 cells/high-powered field) and actin-positive cells (64 +/- 4 to 24 +/- 2 cells/high-powered field) in the neointima were reduced in blebbistatin treated mice compared with vehicle-treated mice. In a model of vascular injury with an intact endothelium, implantation of a blebbistatin-secreting cuff after carotid ligation in FVB/N mice was associated with a 61% decrease in neointimal area and a significant decrease in luminal obstruction (88 +/- 4% in vehicle treated mice versus 36 +/- 4% in blebbistatin-treated mice; p < 0.0001). In cultured rat aortic SMC, blebbistatin disrupted cellular morphology and actin cytoskeleton structure, and these effects were rapid and completely reversible. Blebbistatin had a dose-dependent inhibitory effect on DNA replication and cell proliferative responses to platelet-derived growth factor-BB, angiotensin II, and alpha-thrombin, migratory responses to serum, and migratory responses after blunt injury. In summary, perivascular delivery of blebbistatin reduced neointimal hyperplasia after carotid injury in the mouse. PMID- 20956483 TI - Endocarditis on the bicuspid aortic valve: what's the risk? PMID- 20956484 TI - Biological valves: is durability really the bottle neck? PMID- 20956485 TI - Dual antiplatelet therapy in cardiovascular disease: does aspirin increase clinical risk in the presence of potent P2Y12 receptor antagonists? AB - Aspirin is now widely accepted as the first-line antithrombotic platelet therapy for at-risk individuals. During the last decade or so it has also become established that co-administering antagonists of the ADP receptor P2Y(12) with aspirin further reduces the risk of acute thrombotic events. By the nature of its evolution, this therapeutic approach assumes that P2Y(12) receptor antagonists will be added to aspirin, and this therefore dominates the design of clinical trials. This strategy has resulted in the generation of a large body of clinical evidence showing the benefit of aspirin plus P2Y(12) receptor antagonists, largely from studies with clopidogrel and more recently from those with prasugrel and ticagrelor, but with obvious limitations in terms of residual ischaemic event rates and bleeding complications. It is our hypothesis, however, that when administered in the presence of potent P2Y(12) receptor antagonists, aspirin could actually increase total cardiovascular risk, although this has never been tested in large outcome studies. Clearly, this potentially negative interaction could be of relevance to millions of patients. PMID- 20956486 TI - Effect of postconditioning on infarct size in patients with ST elevation myocardial infarction. AB - BACKGROUND: Small studies suggest that postconditioning reperfusion interrupted by brief repetitive cycles of reocclusions, may protect the myocardium in the clinical setting. OBJECTIVE: To test the hypothesis that postconditioning limits infarct size in relation to the area at risk in patients with ST elevation myocardial infarction (STEMI). METHODS: 76 patients (aged 37-87 years) eligible for primary percutaneous coronary intervention due to STEMI were randomised to standard percutaneous coronary intervention (n = 38) or postconditioning, consisting of four cycles of 60 s reperfusion and 60 s of reocclusion before permanent reperfusion (n = 38). RESULTS: The area at risk was determined from angiographic abnormally contracting segments. Infarct size was quantified from delayed enhancement MRI on days 6-9. Infarct size, expressed in relation to the area at risk, did not differ between the control group (44%; 30, 56) (median and quartiles) and the post-conditioned group (47%; 23, 63). The slope of the regression lines relating infarct size to the area at risk differed between the two groups. Infarct size was significantly (p = 0.001) reduced by postconditioning in patients with large areas at risk. The area under the curve and peak troponin T release and CKMB during 48 h did not differ between patients in the control and postconditioning groups. CONCLUSIONS: This prospective, randomised trial suggests that postconditioning does not reduce infarct size in patients with STEMI in the overall study group. The data indicate that postconditioning may be of value in patients with large areas at risk. Clinical trial registration information Karolinska Clinical Trial Registration (http://www.kctr.se). Unique identifier: CT20080014. PMID- 20956487 TI - Increased expression and plasma levels of myeloperoxidase are closely related to the presence of angiographically-detected complex lesion morphology in unstable angina. AB - BACKGROUND: Myeloperoxidase (MPO) is a leucocyte enzyme that catalyses the formation of a number of reactive oxidant species. OBJECTIVE: The purpose of this study is to evaluate the relationship between angiographic coronary plaque morphology in patients with unstable angina pectoris (UAP) or stable angina pectoris (SAP) and MPO levels. PATIENTS AND DESIGN: Plasma MPO levels on admission were measured in 236 patients with UAP, 146 with SAP and 85 control subjects using an ELISA kit. The angiographic morphology of the culprit lesion was classified into two types, simple or complex, based on the Ambrose classification. In addition, 61 atherectomy specimens obtained from a different cohort of patients with UAP and SAP were studied immunohistochemically for MPO. RESULTS: Median (IQR) plasma MPO levels in patients with UAP with a complex lesion were significantly higher than in patients with a simple lesion (41.9 (21.7-73.7) ng/ml vs 20.5 (15.9-27.9) ng/ml, p<0.0001), but there was no significant difference between the two groups in patients with SAP. On multivariate analysis, raised plasma MPO levels and Braunwald class III were independent factors for angiographically-detected complex lesions (adjusted OR 12.49, 95% CI 3.24 to 48.17, p=0.0002). In the atherectomy specimens the number of MPO-positive cells in patients with UAP with complex lesions was significantly higher (p<0.0005) than in patients with simple lesions. Moreover, in this cohort, plasma MPO levels were positively correlated with the number of MPO-positive cells in atherectomy specimens (R=0.42, p=0.024). CONCLUSIONS: This study shows that increased expression and plasma MPO levels are closely related to the presence of angiographically-detected complex lesion morphology in patients with UAP. PMID- 20956488 TI - Microsimulation and clinical outcomes analysis support a lower age threshold for use of biological valves. AB - OBJECTIVE: To characterise contemporary results of aortic valve replacement in relation to type of prosthesis and subsequent competing hazards. METHODS: 5470 procedures in 5433 consecutive patients with aortic valve replacement +/- coronary artery bypass grafting (CABG) were studied. Microsimulation of survival and valve-related outcomes was performed based on meta-analysis and patient data inputs, with separate models for age, gender and CABG. Survival was validated against the UK Heart Valve Registry. RESULTS: Patient survival at 1, 5 and 10 years was 90%, 78% and 57%, respectively. The crossover points at which bioprostheses and mechanical prostheses conferred similar life expectancy (LE) was 59 years for men and women (no significant difference between prosthesis types between the ages of 56 and 69 for men, and 58 an 63 for women). The improvement in event-free LE for mechanical valves was greater at younger ages with a crossover point of 66 years for men and 67 years for women. Long-term survival was independently influenced by age, male gender and concomitant CABG, but not by type of prosthesis. In bioprostheses the most common long-term occurrence was structural deterioration. For men aged 55, 65 and 75 at initial operation it had a lifetime incidence of 50%, 30% and 13%, respectively. The simulation output showed excellent agreement with registry data. CONCLUSION: Bioprostheses can be implanted selectively in patients as young as 56 without significant adverse effects on life expectancy, although event-free life expectancy remains significantly lower with bioprostheses up to age of implant of 63. PMID- 20956489 TI - Left ventricular rotational mechanics in patients with coronary artery disease: differences in subendocardial and subepicardial layers. AB - OBJECTIVE: Subendocardial and subepicardial layers have opposite orientation of the myofibres and they are differently affected by coronary artery disease. This study investigated the differences in subendocardial and subepicardial left ventricular (LV) twist in patients with coronary artery disease. METHODS: 214 patients were included in the study: 60 with first ST elevation myocardial infarction (STEMI), 111 with chronic ischaemic heart failure (HF) and 43 normal subjects. Real-time three-dimensional echocardiography provided LV volumes and function. Two-dimensional speckle tracking echocardiography differentiating the subendocardial and subepicardial layers was used for the assessment of LV twist. Patients with STEMI were divided into two groups (small and large STEMI). RESULTS: Compared with normal subjects, peak subendocardial LV twist was significantly impaired in patients with STEMI (11.2 +/- 6.0 degrees vs 15.3 +/- 2.7 degrees , p<0.001). In patients with chronic HF, peak subendocardial LV twist was even more impaired (4.6 +/- 3.4 degrees , p<0.001 vs normal subjects and patients with STEMI). Conversely, peak subepicardial LV twist was not statistically different between normal subjects and patients with STEMI (8.9 +/- 1.9 degrees vs 8.4 +/- 4.4 degrees , p=0.98), whereas it was significantly impaired in patients with chronic HF (2.6 +/- 2.5 degrees , p<0.001 vs normal subjects and patients with STEMI). Peak subendocardial LV twist was not statistically different between large and small STEMI, whereas peak subepicardial LV twist was significantly lower in large STEMI than in small STEMI (7.1 +/- 4.8 degrees vs 9.6 +/- 3.6 degrees , p=0.025). CONCLUSIONS: Subendocardial LV twist is reduced in patients with STEMI and chronic ischaemic HF whereas subepicardial LV twist is reduced only in chronic ischaemic HF. When STEMI are divided into large and small infarctions, it becomes evident that subepicardial LV twist is only reduced in large infarctions. PMID- 20956490 TI - Gender differences in the implementation of cardiovascular prevention measures after an acute coronary event. AB - OBJECTIVE: To compare gender-related lifestyle changes and risk factor management after hospitalisation for a coronary event or revascularisation intervention in Europe. METHOD: The EUROASPIRE III survey was carried out in 22 European countries in 2006-2007. Consecutive patients having had a coronary event or revascularisation before the age of 80 were identified. A total of 8966 patients (25.3% women) were interviewed and underwent clinical and biochemical tests at least 6 months after hospital admission. Trends in cardiovascular risk management were assessed on the basis of the 1994-1995, 1999-2000 and 2006-2007 EUROASPIRE surveys. RESULTS: Female survey participants were generally older and had a lower educational level than male participants (p<0.0001). The prevalences of obesity (p<0.0001), high blood pressure (BP) (p=0.001), elevated low-density lipoprotein (LDL)-cholesterol (p<0.0001) and diabetes (p<0.0001) were significantly higher in women than in men, whereas current smoking (p<0.0001) was significantly more common in men. The use of antihypertensive and antidiabetic drugs (but not that of other drugs) was more common in women than in men. However, BP (p<0.0001), LDL cholesterol (p<0.0001) and HbA1c (p<0.0001) targets were less often achieved in women than in men. Between 1994 and 2007, cholesterol control improved less in women than in men (interaction: p=0.009), whereas trends in BP control (p=0.32) and glycaemia (p=0.36) were similar for both genders. CONCLUSION: The EUROASPIRE III results show that despite similarities in medication exposure, women are less likely than men to achieve BP, LDL-cholesterol and HbA1c targets after a coronary event. This gap did not appear to narrow between 1994 and 2007. PMID- 20956491 TI - Late hepatic complications after Fontan operation; non-invasive markers of hepatic fibrosis and risk factors. AB - OBJECTIVE: To identify the prevalence, clinical characteristics, risk factors of hepatic complications after a Fontan operation. METHODS: This was a cross sectional study of 139 Fontan patients who underwent cardiac CT scans out of a total of 204 patients who had undergone the Fontan procedure between 1986 and 2003. Mean age was 19.0 +/- 6.3 years and mean elapsed time since the initial Fontan operation was 11.5 +/- 4.7 years. Subjects' clinical features, echocardiograms, radiological features and biochemical test results were reviewed. Various non-invasive hepatic fibrosis blood markers were also evaluated. RESULTS: Fifty-seven patients had hepatic complications, including radiological features of liver cirrhosis (25.9%), thrombocytopenia (7.2%), hyperbilirubinaemia (20.9%) and hepatic masses (2.9%). Hepatic complications were also significantly associated with ventricular dysfunction (p=0.020), absence of fenestration (p=0.004), thrombus in the Fontan tract (p=0.027), sinus node dysfunction (p=0.034) and tachyarrhythmia (p<0.001). In a multivariate analysis, the elapsed time since the initial Fontan operation was the only measure that was correlated with hepatic complications; the odds ratio of the post-Fontan duration of 16-20 years to that of 0-5 years was 9.00 (CI 2.24 to 36.17). The non-invasive hepatic fibrosis blood marker (Forns index) was also correlated with the elapsed time since the initial Fontan operation (r=0.718, p<0.001). CONCLUSION: Late hepatic dysfunction and cirrhotic change were often seen in Fontan patients. Moreover, hepatic complications were correlated with the duration of Fontan circulation. Therefore, after a Fontan operation, regular evaluation of the hepatic condition is required--for which some non-invasive hepatic fibrosis markers can be effectively used. PMID- 20956492 TI - Main pulmonary artery dilation in association with congenital bicuspid aortic valve in the absence of pulmonary valve abnormality. AB - BACKGROUND: Main pulmonary artery (MPA) dilation is reported to occur in association with pulmonary valve (PV) abnormalities and in genetic diseases of connective tissue. AIM: To determine whether MPA dilation occurs with bicuspid aortic valve (BAV) in the absence of PV abnormality. METHODS: MPA and aortic dimensions were investigated in 194 subjects with BAV and 178 controls matched for age, sex and body surface area (BSA) using transthoracic two-dimensional echocardiography. Using control measurements, linear regression of each parameter versus age, gender, and BSA(2/3) provided expected values. For each subject with BAV, the percentage divergence from expected value ((observed--expected value)/expected value) for each dimension was analysed. RESULTS: MPA and aortic measurements showed normal distribution in all subjects. PV annulus and MPA were larger in BAV; 17.7% positive divergence of MPA dimension from expected was found in diastole, and 16.7% in systole. Aortic dimensions at all levels measured were larger in BAV; divergence was greater distally than proximally (10% divergence at annulus, 31% at ascending aorta). In BAV, divergence of ascending aortic dimensions from expected values increased with age (r(2)=0.142, p=0.02), but MPA divergence from expected values did not increase with age (r(2)=0.001, p=0.296). CONCLUSIONS: MPA dilation occurs in association with BAV in the absence of PV abnormality, suggesting primary vessel wall pathology predisposing to arterial dilation. A systemic abnormality of connective tissue common to both arteries may be responsible, or the dilation may result from a common developmental exposure as both originate from the embryologic cono-truncus. PMID- 20956493 TI - Cut junk food, says NICE guidance on cardiovascular disease prevention. PMID- 20956494 TI - Myocardial disease: The patient with hypertrophic cardiomyopathy. PMID- 20956495 TI - Heart failure: Diagnosis of heart failure in primary care. PMID- 20956496 TI - Unplanned redundant publication. A consequence of too many cardiovascular journals? PMID- 20956497 TI - Lipid-induced insulin resistance affects women less than men and is not accompanied by inflammation or impaired proximal insulin signaling. AB - OBJECTIVE: We have previously shown that overnight fasted women have higher insulin-stimulated whole body and leg glucose uptake despite a higher intramyocellular triacylglycerol concentration than men. Women also express higher muscle mRNA levels of proteins related to lipid metabolism than men. We therefore hypothesized that women would be less prone to lipid-induced insulin resistance. RESEARCH DESIGN AND METHODS: Insulin sensitivity of whole-body and leg glucose disposal was studied in 16 young well-matched healthy men and women infused with intralipid or saline for 7 h. Muscle biopsies were obtained before and during a euglycemic-hyperinsulinemic clamp (1.42 mU . kg-1 . min-1). RESULTS: Intralipid infusion reduced whole-body glucose infusion rate by 26% in women and 38% in men (P < 0.05), and insulin-stimulated leg glucose uptake was reduced significantly less in women (45%) than men (60%) after intralipid infusion. Hepatic glucose production was decreased during the clamp similarly in women and men irrespective of intralipid infusion. Intralipid did not impair insulin or AMPK signaling in muscle and subcutaneous fat, did not cause accumulation of muscle lipid intermediates, and did not impair insulin-stimulated glycogen synthase activity in muscle or increase plasma concentrations of inflammatory cytokines. In vitro glucose transport in giant sarcolemmal vesicles was not decreased by acute exposure to fatty acids. Leg lactate release was increased and respiratory exchange ratio was decreased by intralipid. CONCLUSIONS: Intralipid infusion causes less insulin resistance of muscle glucose uptake in women than in men. This insulin resistance is not due to decreased canonical insulin signaling, accumulation of lipid intermediates, inflammation, or direct inhibition of GLUT activity. Rather, a higher leg lactate release and lower glucose oxidation with intralipid infusion may suggest a metabolic feedback regulation of glucose metabolism. PMID- 20956498 TI - OCT1 Expression in adipocytes could contribute to increased metformin action in obese subjects. AB - OBJECTIVE: Metformin has been well characterized in vitro as a substrate of liver expressed organic cation transporters (OCTs). We investigated the gene expression and protein levels of OCT-1 and OCT-2 in adipose tissue and during adipogenesis and evaluated their possible role in metformin action on adipocytes. RESEARCH DESIGN AND METHODS: OCT1 and OCT2 gene expressions were analyzed in 118 adipose tissue samples (57 visceral and 61 subcutaneous depots) and during human preadipocyte differentiation. To test the possible role of OCT1 mediating the response of adipocytes to metformin, cotreatments with cimetidine (OCT blocker, 0.5 and 5 mmol/l) and metformin were made on human preadipocytes and subcutaneous adipose tissue (SAT). RESULTS: OCT1 gene was expressed in both subcutaneous and visceral adipose tissue. In both fat depots, OCT1 gene expression and protein levels were significantly increased in obese subjects. OCT1 gene expression in isolated preadipocytes significantly increased during differentiation in parallel to adipogenic genes. Metformin (5 mmol/l) decreased the expression of lipogenic genes and lipid droplets accumulation while increasing AMP-activated protein kinase (AMPK) activation, preventing differentiation of human preadipocytes. Cotreatment with cimetidine restored adipogenesis. Furthermore, metformin decreased IL-6 and MCP-1 gene expression in comparison with differentiated adipocytes. Metformin (0.1 and 1 mmol/l) decreased adipogenic and inflammatory genes in SAT. OCT2 gene expression was not detected in adipose tissue and was very small in isolated preadipocytes, disappearing during adipogenesis. CONCLUSIONS: OCT1 gene expression and protein levels are detectable in adipose tissue. Increased OCT1 gene expression in adipose tissue of obese subjects might contribute to increased metformin action in these subjects. PMID- 20956499 TI - The portal theory supported by venous drainage-selective fat transplantation. AB - OBJECTIVE: The "portal hypothesis" proposes that the liver is directly exposed to free fatty acids and cytokines increasingly released from visceral fat tissue into the portal vein of obese subjects, thus rendering visceral fat accumulation particularly hazardous for the development of hepatic insulin resistance and type 2 diabetes. In the present study, we used a fat transplantation paradigm to (artificially) increase intra-abdominal fat mass to test the hypothesis that venous drainage of fat tissue determines its impact on glucose homeostasis. RESEARCH DESIGN AND METHODS: Epididymal fat pads of C57Bl6/J donor mice were transplanted into littermates, either to the parietal peritoneum (caval/systemic venous drainage) or, by using a novel approach, to the mesenterium, which confers portal venous drainage. RESULTS: Only mice receiving the portal drained fat transplant developed impaired glucose tolerance and hepatic insulin resistance. mRNA expression of proinflammatory cytokines was increased in both portally and systemically transplanted fat pads. However, portal vein (but not systemic) plasma levels of interleukin (IL)-6 were elevated only in mice receiving a portal fat transplant. Intriguingly, mice receiving portal drained transplants from IL-6 knockout mice showed normal glucose tolerance. CONCLUSIONS: These results demonstrate that the metabolic fate of intra-abdominal fat tissue transplantation is determined by the delivery of inflammatory cytokines to the liver specifically via the portal system, providing direct evidence in support of the portal hypothesis. PMID- 20956500 TI - Prevalence of seroprotection against the pandemic (H1N1) virus after the 2009 pandemic. AB - BACKGROUND: Before pandemic (H1N1) 2009, less than 10% of serum samples collected from all age groups in the Lower Mainland of British Columbia, Canada, showed seroprotection against the pandemic (H1N1) 2009 virus, except those from very elderly people. We reassessed this profile of seroprotection by age in the same region six months after the fall 2009 pandemic and vaccination campaign. METHODS: We evaluated 100 anonymized serum samples per 10-year age group based on convenience sampling. We measured levels of antibody against the pandemic virus by hemagglutination inhibition and microneutralization assays. We assessed geometric mean titres and the proportion of people with seroprotective antibody levels (hemagglutination inhibition titre >= 40). We performed sensitivity analyses to evaluate titre thresholds of 80, 20 and 10. RESULTS: Serum samples from 1127 people aged 9 months to 101 years were obtained. The overall age standardized proportion of people with seroprotective antibody levels was 46%. A U-shaped age distribution was identified regardless of assay or titre threshold applied. Among those less than 20 years old and those 80 years and older, the prevalence of seroprotection was comparably high at about 70%. Seroprotection was 44% among those aged 20-49 and 30% among those 50-79 years. It was lowest among people aged 70-79 years (21%) and highest among those 90 years and older (88%). INTERPRETATION: We measured much higher levels of seroprotection after the 2009 pandemic compared than before the pandemic, with a U-shaped age distribution now evident. These findings, particularly the low levels of seroprotection among people aged 50-79 years, should be confirmed in other settings and closer to the influenza season. PMID- 20956501 TI - Pandemic (H1N1) 2009: assessing the response. PMID- 20956504 TI - Thrombus aspiration in primary coronary intervention. PMID- 20956505 TI - Eosinophilic gastroenteritis in a young man. PMID- 20956506 TI - Effect of soy isoflavones on breast cancer recurrence and death for patients receiving adjuvant endocrine therapy. AB - BACKGROUND: The intake of soy isoflavones among women with breast cancer has become a public health concern, because these compounds have weak estrogenic effects. There is little clinical evidence about their safety for patients with breast cancer who are receiving adjuvant endocrine therapy. METHODS: For patients who underwent surgery for breast cancer between August 2002 and July 2003 and who were receiving adjuvant endocrine therapy, we examined associations between dietary intake of soy isoflavones and recurrence of breast cancer and death. We measured dietary intake of soy isoflavones at baseline using a validated food frequency questionnaire. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) by means of multivariable Cox proportional hazards regression models. We further stratified the analyses by hormonal receptor status and endocrine therapy. RESULTS: The median follow-up period for the 524 patients in this study was 5.1 years. Among premenopausal patients, the overall death rate (30.6%) was not related to intake of soy isoflavones (HR = 1.05, 95% CI 0.78-1.71 for the highest quartile [> 42.3 mg/day] v. the lowest quartile [< 15.2 mg/day], p for trend = 0.87). Relative to post-menopausal patients in the lowest quartile of soy isoflavone intake, the risk of recurrence for post-menopausal patients in the highest quartile was significantly lower (HR = 0.67, 95% CI 0.54-0.85, p for trend = 0.02). Inverse associations were observed in patients with estrogen and progesterone receptor positive disease and those receiving anastrozole therapy. INTERPRETATION: High dietary intake of soy isoflavones was associated with lower risk of recurrence among post-menopausal patients with breast cancer positive for estrogen and progesterone receptor and those who were receiving anastrozole as endocrine therapy. PMID- 20956507 TI - Global tuberculosis partnership says industrialized world must do more. PMID- 20956508 TI - Seeking order out of global health chaos. PMID- 20956509 TI - Big city blues: health disparities within the world's largest urban centres. PMID- 20956510 TI - "The best or the worst" end up in product development partnerships. PMID- 20956511 TI - The short answer is "more". PMID- 20956512 TI - Energy drinks: beverage industry response. PMID- 20956513 TI - Getting them off the battlefield. PMID- 20956515 TI - Cholesterol microembolization syndrome. PMID- 20956516 TI - Bravo and beware. PMID- 20956517 TI - Frataxin depletion in yeast triggers up-regulation of iron transport systems before affecting iron-sulfur enzyme activities. AB - The primary function of frataxin, a mitochondrial protein involved in iron homeostasis, remains controversial. Using a yeast model of conditional expression of the frataxin homologue YFH1, we analyzed the primary effects of YFH1 depletion. The main conclusion unambiguously points to the up-regulation of iron transport systems as a primary effect of YFH1 down-regulation. We observed that inactivation of aconitase, an iron-sulfur enzyme, occurs long after the iron uptake system has been activated. Decreased aconitase activity should be considered part of a group of secondary events promoted by iron overloading, which includes decreased superoxide dismutase activity and increased protein carbonyl formation. Impaired manganese uptake, which contributes to superoxide dismutase deficiency, has also been observed in YFH1-deficient cells. This low manganese content can be attributed to the down-regulation of the metal ion transporter Smf2. Low Smf2 levels were not observed in AFT1/YFH1 double mutants, indicating that high iron levels could be responsible for the Smf2 decline. In summary, the results presented here indicate that decreased iron-sulfur enzyme activities in YFH1-deficient cells are the consequence of the oxidative stress conditions suffered by these cells. PMID- 20956518 TI - The peptidomimetic CXCR4 antagonist TC14012 recruits beta-arrestin to CXCR7: roles of receptor domains. AB - CXCR7 is an atypical chemokine receptor that signals through beta-arrestin in response to agonists without detectable activation of heterotrimeric G-proteins. Its cognate chemokine ligand CXCL12 also binds CXCR4, a chemokine receptor of considerable clinical interest. Here we report that TC14012, a peptidomimetic inverse agonist of CXCR4, is an agonist on CXCR7. The potency of beta-arrestin recruitment to CXCR7 by TC14012 is much higher than that of the previously reported CXCR4 antagonist AMD3100 and differs only by one log from that of the natural ligand CXCL12 (EC(50) 350 nM for TC14012, as compared with 30 nM for CXCL12 and 140 MUM for AMD3100). Moreover, like CXCL12, TC14012 leads to Erk 1/2 activation in U373 glioma cells that express only CXCR7, but not CXCR4. Given that with TC14012 and AMD3100 two structurally unrelated CXCR4 antagonists turn out to be agonists on CXCR7, this likely reflects differences in the activation mechanism of the arrestin pathway by both receptors. To identify the receptor domain responsible for these opposed effects, we investigated CXCR4 and CXCR7 C terminus-swapping chimeras. Using quantitative bioluminescence resonance energy transfer, we find that the CXCR7 receptor core formed by the seven-transmembrane domains and the connecting loops determines the agonistic activity of both TC14012 and AMD3100. Moreover, we find that the CXCR7 chimera bearing the CXCR4 C terminal constitutively associates with arrestin in the absence of ligands. Our data suggest that the CXCR4 and CXCR7 cores share ligand-binding surfaces for the binding of the synthetic ligands, indicating that CXCR4 inhibitors should be tested also on CXCR7. PMID- 20956519 TI - Exogenous recombinant dimeric neuropilin-1 is sufficient to drive angiogenesis. AB - Neuropilin-1 (NRP-1) is present on the cell surface of endothelial cells, or as a soluble truncated variant. Membrane NRP-1 is proposed to enhance angiogenesis by promoting the formation of a signaling complex between vascular endothelial growth factor-A(165) (VEGF-A(165)), VEGF receptor-2 (VEGFR-2) and heparan sulfate, whereas the soluble NRP-1 is thought to act as an antagonist of signaling complex formation. We have analyzed the angiogenic potential of a chimera comprising the entire extracellular NRP-1 region dimerized through an Fc IgG domain and a monomeric truncated NRP-1 variant. Both NRP-1 proteins stimulated tubular morphogenesis and cell migration in HDMECs and HUVECs. Fc rNRP 1 was able to induce VEGFR-2 phosphorylation and expression of the VEGFR-2 specific target, regulator of calcineurin-1 (RCAN1.4). siRNA mediated gene silencing of VEGFR-2 revealed that VEGFR-2 was required for Fc rNRP-1 mediated activation of the intracellular signaling proteins PLC-gamma, AKT, and MAPK and tubular morphogenesis. The stimulatory activity was independent of VEGF-A(165). This was evidenced by depleting the cell culture of exogenous VEGF-A(165), and using instead for routine culture VEGF-A(121), which does not interact with NRP 1, and by the inability of VEGF-A sequestering antibodies to inhibit the angiogenic activity of the NRP proteins. Analysis of angiogenesis over a period of 6 days in an in vitro fibroblast/endothelial co-culture model revealed that Fc rNRP-1 could induce endothelial cell tubular morphogenesis. Thus, we conclude that soluble Fc rNRP-1 is a VEGF-A(165)-independent agonist of VEGFR-2 and stimulates angiogenesis in endothelial cells. PMID- 20956520 TI - The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic-acid methyl ester has potent anti-diabetic effects in diet-induced diabetic mice and Lepr(db/db) mice. AB - The triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic-acid (CDDO) and its methyl ester (CDDO-Me) are undergoing clinical trials in cancer and leukemia therapy. Here we report that CDDO-Me ameliorates diabetes in high fat diet-fed type 2 diabetic mice and in Lepr(db/db) mice. CDDO-Me reduces proinflammatory cytokine expression in these animals. Oral CDDO-Me administration reduces total body fat, plasma triglyceride, and free fatty acid levels. It also improves glucose tolerance and insulin tolerance tests. Its potent glucose-lowering activity results from enhanced insulin action. Hyperinsulinemic-euglycemic clamp reveals an increased glucose infusion rate required to maintain euglycemia and showed a significant increase in muscle-specific insulin-stimulated glucose uptake (71% soleus, 58% gastrocnemius) and peripheral glucose clearance as documented by a 48% increase in glucose disposal rate. CDDO-Me activates AMP activated protein kinase (AMPK) and via LKB1 activation in muscle and liver in vivo. Treatment of isolated hepatocytes with CDDO-Me directly stimulates AMPK activity and LKB1 phosphorylation and decreases acetyl-coA carboxylase activity; it also down-regulates lipogenic gene expression, suppresses gluconeogenesis, and increases glucose uptake. Inhibition of AMPK phosphorylation using compound C and lentiviral-mediated knockdown of AMPK completely blocks the CDDO-Me-induced effect on hepatocytes as well as C(2)C(12) cells. We conclude that the triterpenoid CDDO-Me has potent anti-diabetic action in diabetic mouse models that is mediated at least in part through AMPK activation. The in vivo anti diabetogenic effects occur at a dose substantially lower than that used for anti leukemia therapy. We suggest that CDDO-Me holds promise as a potential anti diabetic agent. PMID- 20956521 TI - The essential role of clathrin-mediated endocytosis in the infectious entry of human enterovirus 71. AB - Little is currently known about the infectious entry process of human enterovirus 71 (HEV71) into host cells, which may represent potential anti-viral targeting sites. In this study a targeted small-interfering RNA (siRNA) screening platform assay was established and validated to identify and profile key cellular genes involved in processes of endocytosis, cytoskeletal dynamics, and endosomal trafficking essential for HEV71 infection. Screen evaluation was conducted via the expression of well characterized dominant-negative mutants, bioimaging studies (double-labeled immunofluorescence assays, transmission electron microscopy analysis), secondary siRNA-based dosage dependence studies, and drug inhibition assays. The infectious entry of HEV71 into rhabdomyosarcoma cells was shown to be significantly inhibited by siRNAs targeting genes associated with clathrin-mediated endocytosis (CME) that include AP2A1, ARRB1, CLTC, CLTCL1, SYNJ1, ARPC5, PAK1, ROCK1, and WASF1. The functional role of CME was verified by the observation of strong co-localization between HEV71 particles and clathrin as well as dose-dependent inhibition of HEV71 infection upon siRNA knockdown of CME associated genes. HEV71 entry by CME was further confirmed via inhibition by dominant-negative EPS15 mutants and treatment of CME drug inhibitors, with more than 80% inhibition observed at 20 MUm chlorpromazine. Furthermore, HEV71 infection was shown to be sensitive to the disruption of human genes in regulating early to late endosomal trafficking as well as endosomal acidic pH. The identification of clathrin-mediated endocytosis as the entry pathway for HEV71 infection of susceptible host cells contributes to a better understanding of HEV71 pathogenesis and enables future development of anti-viral strategies against HEV71 infection. PMID- 20956522 TI - Binding of calmodulin to the HIV-1 matrix protein triggers myristate exposure. AB - Steady progress has been made in defining both the viral and cellular determinants of retroviral assembly and release. Although it is widely accepted that targeting of the Gag polypeptide to the plasma membrane is critical for proper assembly of HIV-1, the intracellular interactions and trafficking of Gag to its assembly sites in the infected cell are poorly understood. HIV-1 Gag was shown to interact and co-localize with calmodulin (CaM), a ubiquitous and highly conserved Ca(2+)-binding protein expressed in all eukaryotic cells, and is implicated in a variety of cellular functions. Binding of HIV-1 Gag to CaM is dependent on calcium and is mediated by the N-terminally myristoylated matrix (myr(+)MA) domain. Herein, we demonstrate that CaM binds to myr(+)MA with a dissociation constant (K(d)) of ~2 MUm and 1:1 stoichiometry. Strikingly, our data revealed that CaM binding to MA induces the extrusion of the myr group. However, in contrast to all known examples of CaM-binding myristoylated proteins, our data show that the myr group is exposed to solvent and not involved in CaM binding. The interactions between CaM and myr(+)MA are endothermic and entropically driven, suggesting that hydrophobic contacts are critical for binding. As revealed by NMR data, both CaM and MA appear to engage substantial regions and/or undergo significant conformational changes upon binding. We believe that our findings will provide new insights on how Gag may interact with CaM during the HIV replication cycle. PMID- 20956523 TI - Prefoldin 5 is required for normal sensory and neuronal development in a murine model. AB - Molecular chaperones and co-chaperones are crucial for cellular development and maintenance as they assist in protein folding and stabilization of unfolded or misfolded proteins. Prefoldin (PFDN), a ubiquitously expressed heterohexameric co chaperone, is necessary for proper folding of nascent proteins, in particular, tubulin and actin. Here we show that a genetic disruption in the murine Pfdn5 gene, a subunit of prefoldin, causes a syndrome characterized by photoreceptor degeneration, central nervous system abnormalities, and male infertility. Our data indicate that a missense mutation in Pfdn5, may cause these phenotypes through a reduction in formation of microtubules and microfilaments, which are necessary for the development of cilia and cytoskeletal structures, respectively. The diversity of phenotypes demonstrated by models carrying mutations in different PFDN subunits suggests that each PFDN subunit must confer a distinct substrate specificity to the prefoldin holocomplex. PMID- 20956524 TI - Transcriptional regulation of selenoprotein W by MyoD during early skeletal muscle differentiation. AB - Selenoprotein W (SelW) is expressed in various tissues, but it is especially high in the skeletal muscle of mammals. Such tissue-specific protein expression implies regulation by a tissue-specific factor. In this study, we investigated SelW expression during myogenic C2C12 cell differentiation using RT-PCR, quantitative PCR, and Western blot analysis. Both the protein and mRNA levels of SelW were increased during C2C12 cell differentiation, particularly during the early stage. Sequence analysis of the SelW promoter revealed four putative E boxes, E1, E2, E3, and E4, which are known binding sites for MyoD, a myogenic transcriptional factor. Luciferase reporter assay showed that E1 and E4 were crucial for MyoD-dependent promoter activity. Using EMSA analysis, we observed that MyoD bound directly to E1 but not to E4, even though E4 mutation reduced SelW promoter activity in the luciferase reporter assay. Binding of MyoD to E1 was further investigated by ChIP assay. These results suggest that the SelW gene was activated by the binding of MyoD to a specific E-box during early skeletal muscle differentiation. PMID- 20956525 TI - Role of interferon {alpha} (IFN{alpha})-inducible Schlafen-5 in regulation of anchorage-independent growth and invasion of malignant melanoma cells. AB - IFNalpha exerts potent inhibitory activities against malignant melanoma cells in vitro and in vivo, but the mechanisms by which it generates its antitumor effects remain unknown. We examined the effects of interferon alpha (IFNalpha) on the expression of human members of the Schlafen (SLFN) family of genes, a group of cell cycle regulators that mediate growth-inhibitory responses. Using quantitative RT-real time PCR, we found detectable basal expression of all the different human SLFN genes examined (SLFN5, SLFN11, SLFN12, SLFN13, and SLFN14), in malignant melanoma cells and primary normal human melanocytes, but SLFN5 basal expression was suppressed in all analyzed melanoma cell lines. Treatment of melanoma cells with IFNalpha resulted in induction of expression of SLFN5 in malignant cells, suggesting a potential involvement of this gene in the antitumor effects of IFNalpha. Importantly, stable knockdown of SLFN5 in malignant melanoma cells resulted in increased anchorage-independent growth, as evidenced by enhanced colony formation in soft agar assays. Moreover, SLFN5 knockdown also resulted in increased invasion in three-dimensional collagen, suggesting a dual role for SLFN5 in the regulation of invasion and anchorage-independent growth of melanoma cells. Altogether, our findings suggest an important role for the SLFN family of proteins in the generation of the anti-melanoma effects of IFNalpha and for the first time directly implicate a member of the human SLFN family in the regulation of cell invasion. PMID- 20956527 TI - Smac mimetic compounds potentiate interleukin-1beta-mediated cell death. AB - Smac mimetic compounds (SMCs) potentiate TNFalpha-mediated cancer cell death by targeting the inhibitor of apoptosis (IAP) proteins. In addition to TNFalpha, the tumor microenvironment is exposed to a number of pro-inflammatory cytokines, including IL-1beta. Here, we investigated the potential impact of IL-1beta on SMC mediated death of cancer cells. Synergy was seen in a subset of a diverse panel of 21 cancer cell lines to the combination of SMC and IL-1beta treatment, which required IL-1beta-induced activation of the NF-kappaB pathway. Elevated NF-kappaB activity resulted in the production of TNFalpha, which led to apoptosis dependent on caspase-8 and RIP1. In addition, concurrent silencing of cIAP1, cIAP2, and X linked IAP by siRNA was most effective for triggering IL-1beta-mediated cell death. Importantly, SMC-resistant cells that produced TNFalpha in response to IL 1beta treatment were converted to an SMC-sensitive phenotype by c-FLIP knockdown. Reciprocally, ectopic expression of c-FLIP blocked cell death caused by combined SMC and IL-1beta treatment in sensitive cancer cells. Together, our study indicates that a positive feed-forward loop by pro-inflammatory cytokines can be exploited by SMCs to induce apoptosis in cancer cells. PMID- 20956526 TI - Endogenous ligands for nuclear receptors: digging deeper. AB - Nuclear receptors (NRs) are hormone-sensing transcription factors that translate dietary or endocrine signals into changes in gene expression. Therefore, the adoption of orphan NRs through the identification of their endogenous ligands is a key element for our understanding of their biology. In this minireview, we give an update on recent progress in regard to endogenous ligands for a cluster of NRs with high sequence homology, namely peroxisome proliferator-activated receptors alpha and gamma, Rev-erbalpha, and related receptors. This knowledge about the nature and physiology of these ligands may create new opportunities for therapeutic drug development. PMID- 20956528 TI - Genetic evidence for functional interaction of the Escherichia coli signal recognition particle receptor with acidic lipids in vivo. AB - The mechanism underlying the interaction of the Escherichia coli signal recognition particle receptor FtsY with the cytoplasmic membrane has been studied in detail. Recently, we proposed that FtsY requires functional interaction with inner membrane lipids at a late stage of the signal recognition particle pathway. In addition, an essential lipid-binding alpha-helix was identified in FtsY of various origins. Theoretical considerations and in vitro studies have suggested that it interacts with acidic lipids, but this notion is not yet fully supported by in vivo experimental evidence. Here, we present an unbiased genetic clue, obtained by serendipity, supporting the involvement of acidic lipids. Utilizing a dominant negative mutant of FtsY (termed NG), which is defective in its functional interaction with lipids, we screened for E. coli genes that suppress the negative dominant phenotype. In addition to several unrelated phenotype suppressor genes, we identified pgsA, which encodes the enzyme phosphatidylglycerophosphate synthase (PgsA). PgsA is an integral membrane protein that catalyzes the committed step to acidic phospholipid synthesis, and we show that its overexpression increases the contents of cardiolipin and phosphatidylglycerol. Remarkably, expression of PgsA also stabilizes NG and restores its biological function. Collectively, our results strongly support the notion that FtsY functionally interacts with acidic lipids. PMID- 20956529 TI - Transcription elongation regulator 1 is a co-integrator of the cell fate determination factor Dachshund homolog 1. AB - DACH1 (Dachshund homolog 1) is a key component of the retinal determination gene network and regulates gene expression either indirectly as a co-integrator or through direct DNA binding. The current studies were conducted to understand, at a higher level of resolution, the mechanisms governing DACH1-mediated transcriptional repression via DNA sequence-specific binding. DACH1 repressed gene transcription driven by the DACH1-responsive element (DRE). Recent genome wide ChIP-Seq analysis demonstrated DACH1 binding sites co-localized with Forkhead protein (FOX) binding sites. Herein, DACH1 repressed, whereas FOX proteins enhanced, both DRE and FOXA-responsive element-driven gene expression. Reduced DACH1 expression using a shRNA approach enhanced FOX protein activity. As DACH1 antagonized FOX target gene expression and attenuated FOX signaling, we sought to identify limiting co-integrator proteins governing DACH1 signaling. Proteomic analysis identified transcription elongation regulator 1 (TCERG1) as the transcriptional co-regulator of DACH1 activity. The FF2 domain of TCERG1 was required for DACH1 binding, and the deletion of FF2 abolished DACH1 trans repression function. The carboxyl terminus of DACH1 was necessary and sufficient for TCERG1 binding. Thus, DACH1 represses gene transcription through direct DNA binding to the promoter region of target genes by recruiting the transcriptional co-regulator, TCERG1. PMID- 20956530 TI - Induced pluripotent stem cells can be used to model the genomic imprinting disorder Prader-Willi syndrome. AB - The recent discovery of induced pluripotent stem cell (iPSC) technology provides an invaluable tool for creating in vitro representations of human genetic conditions. This is particularly relevant for those diseases that lack adequate animal models or where the species comparison is difficult, e.g. imprinting diseases such as the neurogenetic disorder Prader-Willi syndrome (PWS). However, recent reports have unveiled transcriptional and functional differences between iPSCs and embryonic stem cells that in cases are attributable to imprinting errors. This has suggested that human iPSCs may not be useful to model genetic imprinting diseases. Here, we describe the generation of iPSCs from a patient with PWS bearing a partial translocation of the paternally expressed chromosome 15q11-q13 region to chromosome 4. The resulting iPSCs match all standard criteria of bona fide reprogramming and could be readily differentiated into tissues derived from the three germ layers, including neurons. Moreover, these iPSCs retain a high level of DNA methylation in the imprinting center of the maternal allele and show concomitant reduced expression of the disease-associated small nucleolar RNA HBII-85/SNORD116. These results indicate that iPSCs may be a useful tool to study PWS and perhaps other genetic imprinting diseases as well. PMID- 20956531 TI - Identification and characterization of oxalate oxidoreductase, a novel thiamine pyrophosphate-dependent 2-oxoacid oxidoreductase that enables anaerobic growth on oxalate. AB - Moorella thermoacetica is an anaerobic acetogen, a class of bacteria that is found in the soil, the animal gastrointestinal tract, and the rumen. This organism engages the Wood-Ljungdahl pathway of anaerobic CO(2) fixation for heterotrophic or autotrophic growth. This paper describes a novel enzyme, oxalate oxidoreductase (OOR), that enables M. thermoacetica to grow on oxalate, which is produced in soil and is a common component of kidney stones. Exposure to oxalate leads to the induction of three proteins that are subunits of OOR, which oxidizes oxalate coupled to the production of two electrons and CO(2) or bicarbonate. Like other members of the 2-oxoacid:ferredoxin oxidoreductase family, OOR contains thiamine pyrophosphate and three [Fe(4)S(4)] clusters. However, unlike previously characterized members of this family, OOR does not use coenzyme A as a substrate. Oxalate is oxidized with a k(cat) of 0.09 s(-1) and a K(m) of 58 MUM at pH 8. OOR also oxidizes a few other 2-oxoacids (which do not induce OOR) also without any requirement for CoA. The enzyme transfers its reducing equivalents to a broad range of electron acceptors, including ferredoxin and the nickel-dependent carbon monoxide dehydrogenase. In conjunction with the well characterized Wood-Ljungdahl pathway, OOR should be sufficient for oxalate metabolism by M. thermoacetica, and it constitutes a novel pathway for oxalate metabolism. PMID- 20956532 TI - Estrogen signaling via estrogen receptor {beta}. AB - Estrogens act by binding to and activating two estrogen receptors (ERs), ERalpha and ERbeta. Transcriptional regulation by ERs is controlled by a complex array of factors such as ER-ligand binding, the DNA sequence bound by ERs, ER-interacting cofactors, and chromatin context. This minireview will provide an overview of the most recent advances in the identification of ERbeta-regulated target gene networks and ERbeta DNA-binding sites. We also highlight the recent work establishing new roles of ERbeta signaling, including protective functions in the epithelial-mesenchymal transition and in atherosclerosis, as well as regulation of cell proliferation in the colon. PMID- 20956533 TI - Inhibition of deoxyhypusine synthase enhances islet {beta} cell function and survival in the setting of endoplasmic reticulum stress and type 2 diabetes. AB - Islet beta cell dysfunction resulting from inflammation, ER stress, and oxidative stress is a key determinant in the progression from insulin resistance to type 2 diabetes mellitus. It was recently shown that the enzyme deoxyhypusine synthase (DHS) promotes early cytokine-induced inflammation in the beta cell. DHS catalyzes the conversion of lysine to hypusine, an amino acid that is unique to the translational elongation factor eIF5A. Here, we sought to determine whether DHS activity contributes to beta cell dysfunction in models of type 2 diabetes in mice and beta cell lines. A 2-week treatment of obese diabetic C57BLKS/J-db/db mice with the DHS inhibitor GC7 resulted in improved glucose tolerance, increased insulin release, and enhanced beta cell mass. Thapsigargin treatment of beta cells in vitro induces a picture of ER stress and apoptosis similar to that seen in db/db mice; in this setting, DHS inhibition led to a block in CHOP (CAAT/enhancer binding protein homologous protein) production despite >30-fold activation of Chop gene transcription. Blockage of CHOP translation resulted in reduction of downstream caspase-3 cleavage and near-complete protection of cells from apoptotic death. DHS inhibition appeared to prevent the cytoplasmic co localization of eIF5A with the ER, possibly precluding the participation of eIF5A in translational elongation at ER-based ribosomes. We conclude that hypusination by DHS is required for the ongoing production of proteins, particularly CHOP, in response to ER stress in the beta cell. PMID- 20956534 TI - Fetuin-A ({alpha}2HS-glycoprotein) is a major serum adhesive protein that mediates growth signaling in breast tumor cells. AB - The identity of the cell adhesive factors in fetal bovine serum, commonly used to supplement growth media, remains a mystery due to the plethora of serum proteins. In the present analyses, we showed that fetuin-A, whose function in cellular attachment in tissue culture has been debated for many years, is indeed a major serum cell attachment factor particularly for tumor cells. We are able to report this because of a new purification strategy that has for the first time given us a homogeneous protein band in colloidal Coomassie-stained gels that retains biological activity. The tumor cells adhered to immobilized fetuin-A and not alpha(2)-macroglobulin, its major contaminant. The interaction of cells with fetuin-A was driven mainly by Ca(2+) ions, and cells growing in regular medium supplemented with fetal bovine serum were just as sensitive to loss of extracellular Ca(2+) ions as cells growing in fetuin-A. Fractionation of human serum revealed that cell attachment was confined to the fractions that had fetuin A. Interestingly, the tumor cells also took up fetuin-A and secreted it back to the medium using an unknown mechanism that can be observed in live cells. The attachment of tumor cells to fetuin-A was accompanied by phosphatidylinositol 3 kinase/Akt activation that was down-regulated in cells that lack annexin-A6, one of the cell surface receptors for fetuin-A. Taken together, our data show the significance of fetuin-A in tumor cell growth mechanisms in vitro and open new research vistas for this protein. PMID- 20956535 TI - Hepatitis B virus induces expression of antioxidant response element-regulated genes by activation of Nrf2. AB - The expression of a variety of cytoprotective genes is regulated by short cis acting elements in their promoters, called antioxidant response elements (AREs). A central regulator of ARE-mediated gene expression is the NF-E2-related factor 2 (Nrf2). Human hepatitis B virus (HBV) induces a strong activation of Nrf2/ARE regulated genes in vitro and in vivo. This is triggered by the HBV-regulatory proteins (HBx and LHBs) via c-Raf and MEK. The Nrf2/ARE-mediated induction of cytoprotective genes by HBV results in a better protection of HBV-positive cells against oxidative damage as compared with control cells. Furthermore, there is a significantly increased expression of the Nrf2/ARE-regulated proteasomal subunit PSMB5 in HBV-positive cells that is associated with a decreased level of the immunoproteasome subunit PSMB5i. In accordance with this finding, HBV-positive cells display a higher constitutive proteasome activity and a decreased activity of the immunoproteasome as compared with control cells even after interferon alpha/gamma treatment. The HBV-dependent induction of Nrf2/ARE-regulated genes might ensure survival of the infected cell, shape the immune response to HBV, and thereby promote establishment of the infection. PMID- 20956536 TI - CAMDI, a novel disrupted in schizophrenia 1 (DISC1)-binding protein, is required for radial migration. AB - Centrosomes play a crucial role in the directed migration of developing neurons. However, the underlying mechanism is poorly understood. This study has identified a novel disrupted in schizophrenia 1 (DISC1)-interacting protein, named CAMDI after coiled-coil protein associated with myosin II and DISC1, which translocates to the centrosome in a DISC1-dependent manner. Knockdown of CAMDI by shRNA revealed severely impaired radial migration with disoriented centrosomes. A yeast two-hybrid screen identified myosin II as a binding protein of CAMDI. CAMDI interacts preferentially with phosphomyosin II and induces an accumulation of phosphomyosin II at the centrosome in a DISC1-dependent manner. Interestingly, one single nucleotide polymorphism of the CAMDI gene (R828W) is identified, and its gene product was found to reduce the binding ability to phosphomyosin II. Furthermore, mice with overexpression of R828W in neurons exhibit an impaired radial migration. Our findings indicate that CAMDI is required for radial migration probably through DISC1 and myosin II-mediated centrosome positioning during neuronal development. PMID- 20956537 TI - Regulation of Syk by phosphorylation on serine in the linker insert. AB - The Syk protein-tyrosine kinase is phosphorylated on multiple tyrosines after the aggregation of the B cell antigen receptor. However, metabolic labeling experiments indicate that Syk is inducibly phosphorylated to an even greater extent on serine after receptor ligation. A combination of phosphopeptide mapping and mass spectrometric analyses indicates that serine 291 is a major site of phosphorylation. Serine 291 lies within a 23-amino acid insert located within the linker B region that distinguishes Syk from SykB and Zap-70. The phosphorylation of serine-291 by protein kinase C enhances the ability of Syk to couple the antigen receptor to the activation of the transcription factors NFAT and Elk-1. Protein interaction studies indicate a role for the phosphorylated linker insert in promoting an interaction between Syk and the chaperone protein, prohibitin. PMID- 20956538 TI - Steroid receptor coactivator (SRC) family: masters of systems biology. AB - The three members of the p160 family of steroid receptor coactivators (SRC-1, SRC 2, and SRC-3) steer the functional output of numerous genetic programs and serve as pleiotropic rheostats for diverse physiological processes. Since their discovery ~15 years ago, the extraordinary sum of examination of SRC function has shaped the foundation of our knowledge for the now 350+ coregulators that have been identified to date. In this perspective, we retrace our steps into the field of coregulators and provide a summary of selected seminal work that helped define the SRCs as masters of systems biology. PMID- 20956539 TI - Gradient of increasing Aurora B kinase activity is required for cells to execute mitosis. AB - INCENP, Borealin, Survivin, and Aurora B kinase comprise the chromosomal passenger complex, an essential regulator of mitotic events. INCENP (inner centromere protein) binds and activates Aurora B through a feedback loop involving phosphorylation of a Thr-Ser-Ser (TSS) motif near the INCENP C terminus. Here, we have examined the role of the TSS motif in vertebrate cells using an DT40 INCENP(ON/OFF) conditional knock-out cell line in which mutants are expressed in the absence of wild-type INCENP. Our analysis confirms that regulated phosphorylation of the two serine residues (presumably by Aurora B) is critical for full activation of the kinase and is essential for cell viability. Cells expressing INCENP mutants bearing either phospho-null (TAA) or phospho mimetic (TEE) mutations exhibit significant levels of Aurora B kinase activity but fail to undergo normal spindle elongation or complete cytokinesis. This work confirms previous suggestions that INCENP can act as a rheostat, with different INCENP mutants promoting differing degrees of kinase activation. Our results also reveal that mitotic progression is accompanied by a requirement for progressively higher levels of Aurora B kinase activity. PMID- 20956540 TI - Sphingolipid-mediated inhibition of apoptotic cell clearance by alveolar macrophages. AB - A decreased clearance of apoptotic cells (efferocytosis) by alveolar macrophages (AM) may contribute to inflammation in emphysema. The up-regulation of ceramides in response to cigarette smoking (CS) has been linked to AM accumulation and increased detection of apoptotic alveolar epithelial and endothelial cells in lung parenchyma. We hypothesized that ceramides inhibit the AM phagocytosis of apoptotic cells. Release of endogenous ceramides via sphingomyelinase or exogenous ceramide treatments dose-dependently impaired apoptotic Jurkat cell phagocytosis by primary rat or human AM, irrespective of the molecular species of ceramide. Similarly, in vivo augmentation of lung ceramides via intratracheal instillation in rats significantly decreased the engulfment of instilled target apoptotic thymocytes by resident AM. The mechanism of ceramide-induced efferocytosis impairment was dependent on generation of sphingosine via ceramidase. Sphingosine treatment recapitulated the effects of ceramide, dose dependently inhibiting apoptotic cell clearance. The effect of ceramide on efferocytosis was associated with decreased membrane ruffle formation and attenuated Rac1 plasma membrane recruitment. Constitutively active Rac1 overexpression rescued AM efferocytosis against the effects of ceramide. CS exposure significantly increased AM ceramides and recapitulated the effect of ceramides on Rac1 membrane recruitment in a sphingosine-dependent manner. Importantly, CS profoundly inhibited AM efferocytosis via ceramide-dependent sphingosine production. These results suggest that excessive lung ceramides may amplify lung injury in emphysema by causing both apoptosis of structural cells and inhibition of their clearance by AM. PMID- 20956541 TI - Syntaxin 4 is required for acid sphingomyelinase activity and apoptotic function. AB - Acid sphingomyelinase (A-SMase) is an important enzyme in sphingolipid metabolism and plays key roles in apoptosis, immunity, development, and cancer. In addition, it mediates cytotoxicity of cisplatin and some other chemotherapeutic drugs. The mechanism of A-SMase activation is still undefined. We now demonstrate that, upon CD95 stimulation, A-SMase is activated through translocation from intracellular compartments to the plasma membrane in an exocytic pathway requiring the t-SNARE protein syntaxin 4. Indeed, down-regulation of syntaxin 4 inhibits A-SMase translocation and activation induced by CD95 stimulation. This leads to inhibition of the CD95-triggered signaling events, including caspase 3 and 9 activation and apoptosis, activation of the survival pathway involving the protein kinase Akt, and important changes in cell cycle and proliferation. The molecular interaction between A-SMase and syntaxin 4 was not known and clarifies the mechanism of A-SMase activation. The novel actions of syntaxin 4 in sphingolipid metabolism and exocytosis we describe here define signaling mechanisms of broad relevance in cell pathophysiology. PMID- 20956542 TI - {Omega}-oxidation of {alpha}-chlorinated fatty acids: identification of {alpha} chlorinated dicarboxylic acids. AB - Myeloperoxidase-derived HOCl targets tissue- and lipoprotein-associated plasmalogens to generate alpha-chlorinated fatty aldehydes, including 2 chlorohexadecanal. Under physiological conditions, 2-chlorohexadecanal is oxidized to 2-chlorohexadecanoic acid (2-ClHA). This study demonstrates the catabolism of 2-ClHA by omega-oxidation and subsequent beta-oxidation from the omega-end. Mass spectrometric analyses revealed that 2-ClHA is omega-oxidized in the presence of liver microsomes with initial omega-hydroxylation of 2-ClHA. Subsequent oxidation steps were examined in a human hepatocellular cell line (HepG2). Three different alpha-chlorinated dicarboxylic acids, 2-chlorohexadecane (1,16)-dioic acid, 2-chlorotetradecane-(1,14)-dioic acid, and 2-chloroadipic acid (2-ClAdA), were identified. Levels of 2-chlorohexadecane-(1,16)-dioic acid, 2 chlorotetradecane-(1,14)-dioic acid, and 2-ClAdA produced by HepG2 cells were dependent on the concentration of 2-ClHA and the incubation time. Synthetic stable isotope-labeled 2-ClHA was used to demonstrate a precursor-product relationship between 2-ClHA and the alpha-chlorinated dicarboxylic acids. We also report the identification of endogenous 2-ClAdA in human and rat urine and elevations in stable isotope-labeled urinary 2-ClAdA in rats subjected to intraperitoneal administration of stable isotope-labeled 2-ClHA. Furthermore, urinary 2-ClAdA and plasma 2-ClHA levels are increased in LPS-treated rats. Taken together, these data show that 2-ClHA is omega-oxidized to generate alpha chlorinated dicarboxylic acids, which include alpha-chloroadipic acid that is excreted in the urine. PMID- 20956543 TI - Human Cdc14A phosphatase modulates the G2/M transition through Cdc25A and Cdc25B. AB - The Cdc14 family of serine-threonine phosphatases antagonizes CDK activity by reversing CDK-dependent phosphorylation events. It is well established that the yeast members of this family bring about the M/G1 transition. Budding yeast Cdc14 is essential for CDK inactivation at the end of mitosis and fission yeast Cdc14 homologue Flp1/Clp1 down-regulates Cdc25 to ensure the inactivation of mitotic CDK complexes to trigger cell division. However, the functions of human Cdc14 homologues remain poorly understood. Here we have tested the hypothesis that Cdc14A might regulate Cdc25 mitotic inducers in human cells. We found that increasing levels of Cdc14A delay entry into mitosis by inhibiting Cdk1-cyclin B1 activity. By contrast, lowering the levels of Cdc14A accelerates mitotic entry. Biochemical analyses revealed that Cdc14A acts through key Cdk1-cyclin B1 regulators. We observed that Cdc14A directly bound to and dephosphorylated Cdc25B, inhibiting its catalytic activity. Cdc14A also regulated the activity of Cdc25A at the G2/M transition. Our results indicate that Cdc14A phosphatase prevents premature activation of Cdk1 regulating Cdc25A and Cdc25B at the entry into mitosis. PMID- 20956544 TI - ErbB2 stabilizes epidermal growth factor receptor (EGFR) expression via Erk and Sprouty2 in extracellular matrix-detached cells. AB - Epithelial cells are dependent on extracellular matrix (ECM) attachment for maintenance of metabolic activity and suppression of apoptosis. Here we show that loss of ECM attachment causes down-regulation of epidermal growth factor receptor (EGFR) and beta1 integrin protein and mRNA expression and that ErbB2, which is amplified in 25% of breast tumors, reverses these effects of ECM deprivation. ErbB2 rescue of beta1 integrin mRNA and protein in suspended cells is dependent on EGFR, however, the rescue of EGFR expression does not require beta1 integrin. We show that there is a significant decrease in the stability of EGFR in ECM detached cells that is reversed by ErbB2 overexpression. Rescue of both EGFR and beta1 integrin protein by ErbB2 is dependent on Erk activity and induction of its downstream target Sprouty2, a protein known to regulate EGFR protein stability. Interestingly, expression of EGFR and beta1 integrin protein is more dependent on Erk/Sprouty2 in ECM-detached ErbB2-overexpressing cells when compared with ECM attached cells. These results provide further insight into the ErbB2-driven anchorage independence of tumor cells and provide a new mechanism for regulation of EGFR and beta1 integrin expression in ECM-detached cells. PMID- 20956545 TI - The surface protein HvgA mediates group B streptococcus hypervirulence and meningeal tropism in neonates. AB - Streptococcus agalactiae (group B streptococcus; GBS) is a normal constituent of the intestinal microflora and the major cause of human neonatal meningitis. A single clone, GBS ST-17, is strongly associated with a deadly form of the infection called late-onset disease (LOD), which is characterized by meningitis in infants after the first week of life. The pathophysiology of LOD remains poorly understood, but our epidemiological and histopathological results point to an oral route of infection. Here, we identify a novel ST-17-specific surface anchored protein that we call hypervirulent GBS adhesin (HvgA), and demonstrate that its expression is required for GBS hypervirulence. GBS strains that express HvgA adhered more efficiently to intestinal epithelial cells, choroid plexus epithelial cells, and microvascular endothelial cells that constitute the blood brain barrier (BBB), than did strains that do not express HvgA. Heterologous expression of HvgA in nonadhesive bacteria conferred the ability to adhere to intestinal barrier and BBB-constituting cells. In orally inoculated mice, HvgA was required for intestinal colonization and translocation across the intestinal barrier and the BBB, leading to meningitis. In conclusion, HvgA is a critical virulence trait of GBS in the neonatal context and stands as a promising target for the development of novel diagnostic and antibacterial strategies. PMID- 20956546 TI - STAT6-mediated displacement of polycomb by trithorax complex establishes long term maintenance of GATA3 expression in T helper type 2 cells. AB - Polycomb group (PcG) and trithorax group (TrxG) complexes exert opposing effects on the maintenance of the transcriptional status of the developmentally regulated Hox genes. In this study, we show that activation of STAT6 induces displacement of the PcG complex by the TrxG complex at the upstream region of the gene encoding GATA3, a transcription factor essential for T helper type 2 (Th2) cell differentiation. Once Th2 cells differentiate, TrxG complex associated with the TrxG component Menin binds to the whole GATA3 gene locus, and this binding is required for the long-term maintenance of expression of GATA3 and Th2 cytokine. Thus, STAT6-mediated displacement of PcG by the TrxG complex establishes subsequent STAT6-independent maintenance of GATA3 expression in Th2 cells via the recruitment of the Menin-TrxG complex. PMID- 20956547 TI - Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases. AB - The inositol phosphatases phosphatase and tensin homologue (PTEN) and Src homology 2 domain-containing inositol phosphatase (SHIP) negatively regulate phosphatidylinositol-3-kinase (PI3K)-mediated growth, survival, and proliferation of hematopoietic cells. Although deletion of PTEN in mouse T cells results in lethal T cell lymphomas, we find that animals lacking PTEN or SHIP in B cells show no evidence of malignancy. However, concomitant deletion of PTEN and SHIP (bPTEN/SHIP(-/-)) results in spontaneous and lethal mature B cell neoplasms consistent with marginal zone lymphoma or, less frequently, follicular or centroblastic lymphoma. bPTEN/SHIP(-/-) B cells exhibit enhanced survival and express more MCL1 and less Bim. These cells also express low amounts of p27(kip1) and high amounts of cyclin D3 and thus appear poised to undergo proliferative expansion. Unlike normal B cells, bPTEN/SHIP(-/-) B cells proliferate to the prosurvival factor B cell activating factor (BAFF). Interestingly, although BAFF availability may promote lymphoma progression, we demonstrate that BAFF is not required for the expansion of transferred bPTEN/SHIP(-/-) B cells. This study reveals that PTEN and SHIP act cooperatively to suppress B cell lymphoma and provides the first direct evidence that SHIP is a tumor suppressor. As such, assessment of both PTEN and SHIP function are relevant to understanding the etiology of human B cell malignancies that exhibit augmented activation of the PI3K pathway. PMID- 20956548 TI - Huh-7 or HepG2 cells: which is the better model for studying human apolipoprotein B100 assembly and secretion? AB - Apolipoprotein-B100 (apoB100) is the essential protein for the assembly and secretion of very low density lipoproteins (VLDL) from liver. The hepatoma HepG2 cell line has been the cell line of choice for the study of synthesis and secretion of human apoB-100. Despite the general use of HepG2 cells to study apoB100 metabolism, they secrete relatively dense, lipid-poor particles compared with VLDL secreted in vivo. Recently, Huh-7 cells were adopted as an alternative model to HepG2 cells, with the implicit assumption that Huh-7 cells were superior in some respects of lipoprotein metabolism, including VLDL secretion. In this study we addressed the hypothesis that the spectrum of apoB100 lipoprotein particles secreted by Huh-7 cells more closely resembles the native state in human liver. We find that Huh-7 cells resemble HepG2 cells in the effects of exogenous lipids, microsomal triglyceride transfer protein (MTP)-inhibition, and proteasome inhibitors of apoB100 secretion, recovery, and degradation. In contrast to HepG2 cells, however, MEK-ERK inhibition does not correct the defect in VLDL secretion. Huh-7 cells do not appear to offer any advantages over HepG2 cells as a general model of human apoB100-lipoprotein metabolism. PMID- 20956549 TI - Are 15-oxygenated sterols present in the human circulation? PMID- 20956553 TI - Genomic collaboration of estrogen receptor alpha and extracellular signal regulated kinase 2 in regulating gene and proliferation programs. AB - The nuclear hormone receptor, estrogen receptor alpha (ERalpha), and mitogen activated protein kinases (MAPKs) play key roles in hormone-dependent cancers, and yet their interplay and the integration of their signaling inputs remain poorly understood. In these studies, we document that estrogen-occupied ERalpha activates and interacts with extracellular signal-regulated kinase 2 (ERK2), a downstream effector in the MAPK pathway, resulting in ERK2 and ERalpha colocalization at chromatin binding sites across the genome of breast cancer cells. This genomic colocalization, predominantly at conserved distal enhancer sites, requires the activation of both ERalpha and ERK2 and enables ERK2 modulation of estrogen-dependent gene expression and proliferation programs. The ERK2 substrate CREB1 was also activated and recruited to ERK2-bound chromatin following estrogen treatment and found to cooperate with ERalpha/ERK2 in regulating gene transcription and cell cycle progression. Our study reveals a novel paradigm with convergence of ERK2 and ERalpha at the chromatin level that positions this kinase to support nuclear receptor activities in crucial and direct ways, a mode of collaboration likely to underlie MAPK regulation of gene expression by other nuclear receptors as well. PMID- 20956554 TI - Cyclin D3 is selectively required for proliferative expansion of germinal center B cells. AB - The generation of robust T-cell-dependent humoral immune responses requires the formation and expansion of germinal center structures within the follicular regions of the secondary lymphoid tissues. B-cell proliferation in the germinal center drives ongoing antigen-dependent selection and the generation of high affinity class-switched plasma and memory B cells. However, the mechanisms regulating B-cell proliferation within this microenvironment are largely unknown. Here, we report that cyclin D3 is uniquely required for germinal center progression. Ccnd3(-/-) mice exhibit a B-cell-intrinsic defect in germinal center maturation and fail to generate an affinity-matured IgG response. We determined that the defect resulted from failed proliferative expansion of GL7(+) IgD(-) PNA(+) B cells. Mechanistically, sustained expression of cyclin D3 was found to be regulated at the level of protein stability and controlled by glycogen synthase kinase 3 in a cyclic AMP-protein kinase A-dependent manner. The specific defect in proliferative expansion of GL7(+) IgD(-) PNA(+) B cells in Ccnd3(-/-) mice defines an underappreciated step in germinal center progression and solidifies a role for cyclin D3 in the immune response, and as a potential therapeutic target for germinal center-derived B-cell malignancies. PMID- 20956555 TI - Sipl1 and Rbck1 are novel Eya1-binding proteins with a role in craniofacial development. AB - The eyes absent 1 protein (Eya1) plays an essential role in the development of various organs in both invertebrates and vertebrates. Mutations in the human EYA1 gene are linked to BOR (branchio-oto-renal) syndrome, characterized by kidney defects, hearing loss, and branchial arch anomalies. For a better understanding of Eya1's function, we have set out to identify new Eya1-interacting proteins. Here we report the identification of the related proteins Sipl1 (Shank interacting protein-like 1) and Rbck1 (RBCC protein interacting with PKC1) as novel interaction partners of Eya1. We confirmed the interactions by glutathione S-transferase (GST) pulldown analysis and coimmunoprecipitation. A first mechanistic insight is provided by the demonstration that Sipl1 and Rbck1 enhance the function of Eya proteins to act as coactivators for the Six transcription factors. Using reverse transcriptase PCR (RT-PCR) and in situ hybridization, we show that Sipl1 and Rbck1 are coexpressed with Eya1 in several organs during embryogenesis of both the mouse and zebrafish. By morpholino-mediated knockdown, we demonstrate that the Sipl1 and Rbck1 orthologs are involved in different aspects of zebrafish development. In particular, knockdown of one Sipl1 ortholog as well as one Rbck1 ortholog led to a BOR syndrome-like phenotype, with characteristic defects in ear and branchial arch formation. PMID- 20956556 TI - Requirement of the ATM/p53 tumor suppressor pathway for glucose homeostasis. AB - Ataxia telangiectasia (A-T) patients can develop multiple clinical pathologies, including neuronal degeneration, an elevated risk of cancer, telangiectasias, and growth retardation. Patients with A-T can also exhibit an increased risk of insulin resistance and type 2 diabetes. The ATM protein kinase, the product of the gene mutated in A-T patients (Atm), has been implicated in metabolic disease, which is characterized by insulin resistance and increased cholesterol and lipid levels, blood pressure, and atherosclerosis. ATM phosphorylates the p53 tumor suppressor on a site (Ser15) that regulates transcription activity. To test whether the ATM pathway that regulates insulin resistance is mediated by p53 phosphorylation, we examined insulin sensitivity in mice with a germ line mutation that replaces the p53 phosphorylation site with alanine. The loss of p53 Ser18 (murine Ser15) led to increased metabolic stress, including severe defects in glucose homeostasis. The mice developed glucose intolerance and insulin resistance. The insulin resistance correlated with the loss of antioxidant gene expression and decreased insulin signaling. N-Acetyl cysteine (NAC) treatment restored insulin signaling in late-passage primary fibroblasts. The addition of an antioxidant in the diet rendered the p53 Ser18-deficient mice glucose tolerant. This analysis demonstrates that p53 phosphorylation on an ATM site is an important mechanism in the physiological regulation of glucose homeostasis. PMID- 20956557 TI - Splicing factor Cwc22 is required for the function of Prp2 and for the spliceosome to escape from a futile pathway. AB - Cwc22 was previously identified to associate with the pre-mRNA splicing factor Cef1/Ntc85, a component of the Prp19-associated complex (nineteen complex [NTC]) involved in spliceosome activation. We show here that Cwc22 is required for pre mRNA splicing both in vivo and in vitro but is neither tightly associated with the NTC nor required for spliceosome activation. Cwc22 is associated with the spliceosome prior to catalytic steps and remains associated throughout the reaction. The stable association of Cwc22 with the spliceosome requires the presence of the NTC but is independent of Prp2. Although Cwc22 is not required for the recruitment of Prp2 to the spliceosome, it is essential for the function of Prp2 in promoting the release of the U2 components SF3a and SF3b. In the absence of Cwc22, Prp2 can bind to the spliceosome but is dissociated upon ATP hydrolysis without promoting the release of SF3a/b. Thus, Cwc22 represents a novel ATP-dependent step one factor besides Prp2 and Spp2 and has a distinct role from that of Spp2 in mediating the function of Prp2. PMID- 20956558 TI - Targeted inactivation of Mapk4 in mice reveals specific nonredundant functions of Erk3/Erk4 subfamily mitogen-activated protein kinases. AB - Erk4 and Erk3 are atypical members of the mitogen-activated protein (MAP) kinase family. The high sequence identity of Erk4 and Erk3 proteins and the similar organization of their genes imply that the two protein kinases are paralogs. Recently, we have shown that Erk3 function is essential for neonatal survival and critical for the establishment of fetal growth potential and pulmonary function. To investigate the specific functions of Erk4, we have generated mice with a targeted disruption of the Mapk4 gene. We show that Erk4-deficient mice are viable and fertile and exhibit no gross morphological or physiological anomalies. Loss of Erk4 is not compensated by changes in Erk3 expression or activity during embryogenesis or in adult tissues. We further demonstrate that additional loss of Erk4 does not exacerbate the fetal growth restriction and pulmonary immaturity phenotypes of Erk3(-/-) mice and does not compromise the viability of Erk3(+/-) neonates. Interestingly, behavioral phenotyping revealed that Erk4-deficient mice manifest depression-like behavior in the forced-swimming test. Our analysis indicates that the MAP kinase Erk4 is dispensable for mouse embryonic development and reveals that Erk3 and Erk4 have acquired specialized functions through evolutionary diversification. PMID- 20956559 TI - Sequential recruitment of SAGA and TFIID in a genomic response to DNA damage in Saccharomyces cerevisiae. AB - Eukaryotic genes respond to their environment by changing the expression of selected genes. The question we address here is whether distinct transcriptional responses to different environmental signals elicit distinct modes of assembly of the transcription machinery. In particular, we examine transcription complex assembly by the stress-directed SAGA complex versus the housekeeping assembly factor TFIID. We focus on genomic responses to the DNA damaging agent methyl methanesulfonate (MMS) in comparison to responses to acute heat shock, looking at changes in genome-wide factor occupancy measured by chromatin immunoprecipitation microchip (ChIP-chip) and ChIP-sequencing analyses. Our data suggest that MMS induced genes undergo transcription complex assembly sequentially, first involving SAGA and then involving a slower TFIID recruitment, whereas heat shock genes utilize the SAGA and TFIID pathways rapidly and in parallel. Also Crt1, the repressor of model MMS-inducible ribonucleotide reductase genes, was found not to play a wider role in repression of DNA damage-inducible genes. Taken together, our findings reveal a distinct involvement of gene and chromatin regulatory factors in response to DNA damage versus heat shock and suggest different implementations of the SAGA and TFIID assembly pathways that may depend upon whether a sustained or transient change in gene expression ensues. PMID- 20956560 TI - Nek10 mediates G2/M cell cycle arrest and MEK autoactivation in response to UV irradiation. AB - Appropriate cell cycle checkpoint control is essential for the maintenance of cell and organismal homeostasis. Members of the Nek (NIMA-related kinase) family of serine/threonine protein kinases have been implicated in the regulation of various aspects of the cell cycle. We explored the cellular functions of Nek10, a novel member of the Nek family, and demonstrate a role for Nek10 in the cellular UV response. Nek10 was required for the activation of extracellular signal regulated kinase 1/2 (ERK1/2) signaling upon UV irradiation but not in response to mitogens, such as epidermal growth factor stimulation. Nek10 physically associated with Raf-1 and MEK1 in a Raf-1-dependent manner, and the formation of this complex was necessary for Nek10-mediated MEK1 activation. Nek10 did not affect the kinase activity of Raf-1 but instead promoted the autophosphorylation dependent activation of MEK1. The appropriate maintenance of the G(2)/M checkpoint following UV irradiation required Nek10 expression and ERK1/2 activation. Taken together, our results uncover a role for Nek10 in the cellular response to UV irradiation. PMID- 20956561 TI - Endocytosis of the aspartic acid/glutamic acid transporter Dip5 is triggered by substrate-dependent recruitment of the Rsp5 ubiquitin ligase via the arrestin like protein Aly2. AB - Endocytosis of nutrient transporters is stimulated under various conditions, such as elevated nutrient availability. In Saccharomyces cerevisiae, endocytosis is triggered by ubiquitination of transporters catalyzed by the E3 ubiquitin ligase Rsp5. However, how the ubiquitination is accelerated under certain conditions remains obscure. Here we demonstrate that closely related proteins Aly2/Art3 and Aly1/Art6, which are poorly characterized members of the arrestin-like protein family, mediate endocytosis of the aspartic acid/glutamic acid transporter Dip5. In aly2Delta cells, Dip5 is stabilized at the plasma membrane and is not endocytosed efficiently. Efficient ubiquitination of Dip5 is dependent on Aly2. aly1Delta cells also show deficiency in Dip5 endocytosis, although less remarkably than aly2Delta cells. Aly2 physically interacts in vivo with Rsp5 at its PY motif and also with Dip5, thus serving as an adaptor linking Rsp5 with Dip5 to achieve Dip5 ubiquitination. Importantly, the interaction between Aly2 and Dip5 is accelerated in response to elevated aspartic acid availability. This result indicates that the regulation of Dip5 endocytosis is accomplished by dynamic recruitment of Rsp5 via Aly2. PMID- 20956562 TI - Identification of a male-specific RNA binding protein that regulates sex-specific splicing of Bmdsx by increasing RNA binding activity of BmPSI. AB - Bmdsx is a sex-determining gene in the silkworm and is alternatively spliced in males and females. CE1 is a splicing silencer element responsible for the sex specific splicing of Bmdsx. To identify sex-specific factors implicated in the sex-specific splicing of Bmdsx, we performed RNA affinity chromatography using CE1 RNA as a ligand. We have identified BmIMP, a Bombyx homolog of IGF-II mRNA binding protein (IMP), as a male-specific factor that specifically binds to CE1. The gene encoding BmIMP is localized on the Z chromosome and is male-specifically expressed in various tissues. Antisense inhibition of BmIMP expression increased female-specific splicing of Bmdsx pre-mRNA. Coimmunoprecipitation and glutathione S-transferase (GST) pulldown analyses demonstrated that BmIMP physically interacts with BmPSI, which has been identified as a factor implicated in the sex specific splicing of Bmdsx, through the KH domains of BmIMP. The functional consequence of this interaction was examined using RNA mobility shift analysis. BmIMP increased BmPSI-CE1 RNA binding activity by decreasing the rate of BmPSI dissociation from CE1 RNA. Truncation analysis of BmIMP suggested that the KH domains are responsible for enhancing BmPSI-CE1 RNA binding activity. These results suggest that BmIMP may enhance the male-specific splicing of Bmdsx pre mRNA by increasing RNA binding activity of BmPSI. PMID- 20956563 TI - cis-Regulatory remodeling of the SCL locus during vertebrate evolution. AB - Development progresses through a sequence of cellular identities which are determined by the activities of networks of transcription factor genes. Alterations in cis-regulatory elements of these genes play a major role in evolutionary change, but little is known about the mechanisms responsible for maintaining conserved patterns of gene expression. We have studied the evolution of cis-regulatory mechanisms controlling the SCL gene, which encodes a key transcriptional regulator of blood, vasculature, and brain development and exhibits conserved function and pattern of expression throughout vertebrate evolution. SCL cis-regulatory elements are conserved between frog and chicken but accrued alterations at an accelerated rate between 310 and 200 million years ago, with subsequent fixation of a new cis-regulatory pattern at the beginning of the mammalian radiation. As a consequence, orthologous elements shared by mammals and lower vertebrates exhibit functional differences and binding site turnover between widely separated cis-regulatory modules. However, the net effect of these alterations is constancy of overall regulatory inputs and of expression pattern. Our data demonstrate remarkable cis-regulatory remodelling across the SCL locus and indicate that stable patterns of expression can mask extensive regulatory change. These insights illuminate our understanding of vertebrate evolution. PMID- 20956564 TI - The mammalian Sin3 proteins are required for muscle development and sarcomere specification. AB - The highly related mammalian Sin3A and Sin3B proteins provide a versatile platform for chromatin-modifying activities. Sin3-containing complexes play a role in gene repression through deacetylation of nucleosomes. Here, we explore a role for Sin3 in myogenesis by examining the phenotypes resulting from acute somatic deletion of both isoforms in vivo and from primary myotubes in vitro. Myotubes ablated for Sin3A alone, but not Sin3B, displayed gross defects in sarcomere structure that were considerably enhanced upon simultaneous ablation of both isoforms. Massively parallel sequencing of Sin3A- and Sin3B-bound genomic loci revealed a subset of target genes directly involved in sarcomere function that are positively regulated by Sin3A and Sin3B proteins. Both proteins were coordinately recruited to a substantial number of genes. Interestingly, depletion of Sin3B led to compensatory increases in Sin3A recruitment at certain target loci, but Sin3B was never found to compensate for Sin3A loss. Thus, our analyses describe a novel transcriptional role for Sin3A and Sin3B proteins associated with maintenance of differentiated muscle cells. PMID- 20956565 TI - Role of the RNA-binding protein IMP-2 in muscle cell motility. AB - Insulin-like growth factor 2 (IGF-2) mRNA-binding proteins (IMPs) are a family of posttranscriptional regulatory factors with well-understood roles in embryonic development and cancer but with poorly characterized functions in normal adult cells and tissues. We now show that IMP-2, the most ubiquitously expressed member of the family, is abundant in human and mouse adult skeletal myoblasts, where it is indispensable for cell motility and for stabilization of microtubules. To explore the functions of IMP-2, we analyzed the transcripts that were differentially regulated in IMP-2-depleted myoblasts and bound to IMP-2 in normal myoblasts. Among them were the mRNAs of PINCH-2, an important mediator of cell adhesion and motility, and MURF-3, a microtubule-stabilizing protein. By gain- and loss-of-function assays and gel shift experiments, we show that IMP-2 regulates the expression of PINCH-2 and MURF-3 proteins via direct binding to their mRNAs. Upregulation of PINCH-2 in IMP-2-depleted myoblasts is the key event responsible for their decreased motility. Our data reveal how the posttranscriptional regulation of gene expression by IMP-2 contributes to the control of adhesion structures and stable microtubules and demonstrate an important function for IMP-2 in cellular motility. PMID- 20956566 TI - A Kunitz protease inhibitor from Dermacentor variabilis, a vector for spotted fever group rickettsiae, limits Rickettsia montanensis invasion. AB - A defining facet of tick-Rickettsia symbioses is the molecular strategy employed by each partner to ensure its own survival. Ticks must control rickettsial colonization to avoid immediate death. In the current study, we show that rickettsial abundance in the tick midgut increases once the expression of a Kunitz-type serine protease inhibitor from the American dog tick (Dermacentor variabilis) (DvKPI) is suppressed by small interfering RNA (siRNA). A series of in vitro invasion assays suggested that DvKPI limits rickettsial colonization during host cell entry. Interestingly, we observed that DvKPI associates with rickettsiae in vitro as well as in the tick midgut. Collectively, our data demonstrate that DvKPI limits host cell invasion by Rickettsia montanensis, possibly through an association with the bacterium. PMID- 20956567 TI - Nontypeable Haemophilus influenzae initiates formation of neutrophil extracellular traps. AB - Nontypeable Haemophilus influenzae (NTHI) is a leading cause of otitis media infections, which are often chronic and/or recurrent in nature. NTHI and other bacterial species persist in vivo within biofilms during otitis media and other persistent infections. These biofilms have a significant host component that includes neutrophil extracellular traps (NETs). These NETs do not mediate clearance of NTHI, which survives within NET structures by means of specific subpopulations of lipooligosaccharides on the bacterial surface that are determinants of biofilm formation in vitro. In this study, the ability of NTHI and NTHI components to initiate NET formation was examined using an in vitro model system. Both viable and nonviable NTHI strains were shown to promote NET formation, as did preparations of bacterial DNA, outer membrane proteins, and lipooligosaccharide (endotoxin). However, only endotoxin from a parental strain of NTHI exhibited equivalent potency in NET formation to that of NTHI. Additional studies showed that NTHI entrapped within NET structures is resistant to both extracellular killing within NETs and phagocytic killing by incoming neutrophils, due to oligosaccharide moieties within the lipooligosaccharides. Thus, we concluded that NTHI elicits NET formation by means of multiple pathogen associated molecular patterns (most notably endotoxin) and is highly resistant to killing within NET structures. These data support the conclusion that, for NTHI, formation of NET structures may be a persistence determinant by providing a niche within the middle-ear chamber. PMID- 20956568 TI - Generation of a neutralizing human monoclonal antibody Fab fragment to surface antigen 1 of Toxoplasma gondii tachyzoites. AB - A combinatorial immunoglobulin gene library was constructed from lymphocytes in peripheral blood of a patient with toxoplasmosis and screened for production of human monoclonal antibody Fab fragments to recombinant surface antigen 1 (SAG1) of Toxoplasma gondii. Two Fab clones, Tox203 and Tox1403, which consisted of a common heavy chain and different light chains, showed positive staining on the entire surface of tachyzoites in confocal microscopy. Sequence analysis of the heavy-chain gene revealed that the closest germ line V segments were VH3-23. The germ line D segment was D1-7, and the closest germ line J segment was JH4. In the light-chain genes, the closest germ line V segment was Vkappa1-17 with the Jkappa1 or Jkappa4 segments. The dissociation constants of these Fab fragments with recombinant SAG1 were 3.09 * 10(-9) M for Tox203 and 2.01 * 10(-8) M for Tox1403, indicating that the affinity of Tox203 was 7 times higher than that of Tox1403. Preincubation of T. gondii tachyzoites with Tox203 significantly inhibited their attachment to cultured MDBK cells. Passive immunization of mice with Tox203 also significantly reduced mortality after challenge with T. gondii tachyzoites. This is the first report of bacterial expression of human monoclonal antibody Fab fragments to SAG1 of T. gondii. These results also demonstrate that human Fab fragments to SAG1 might be applicable for immunoprophylaxis of toxoplasmosis. PMID- 20956569 TI - Meningococcal internalization into human endothelial and epithelial cells is triggered by the influx of extracellular L-glutamate via GltT L-glutamate ABC transporter in Neisseria meningitidis. AB - Meningococcal internalization into human cells is likely to be a consequence of meningococcal adhesion to human epithelial and endothelial cells. Here, we identified three transposon mutants of Neisseria meningitidis that were primarily defective in the internalization of human brain microvascular endothelial cells (HBMEC), with insertions occurring in the gltT (a sodium-independent L-glutamate transporter) gene or its neighboring gene, NMB1964 (unknown function). NMB1964 was tentatively named gltM in this study because of the presence of a mammalian cell entry (MCE)-related domain in the deduced amino acid sequences. The null DeltagltT-DeltagltM N. meningitidis mutant was also defective in the internalization into human umbilical vein endothelial cells and the human lung carcinoma epithelial cell line A549, and the defect was suppressed by transcomplementation of the mutants with gltT(+)-gltM(+) genes. The intracellular survival of the DeltagltT-DeltagltM mutant in HBMEC was not largely different from that of the wild-type strain under our experimental conditions. Introduction of a1-bp deletion and amber or ochre mutations in gltT-gltM genes resulted in the loss of efficient internalization into HBMEC. The defect in meningococcal internalization into HBMEC and L-glutamate uptake in the DeltagltT-DeltagltM mutant were suppressed only in strains expressing both GltT and GltM proteins. The efficiency of meningococcal invasion to HBMEC decreased under L-glutamate depleted conditions. Furthermore, ezrin, a key membrane-cytoskeleton linker, accumulated beneath colonies of the gltT(+)-gltM(+) N. meningitidis strain but not of the DeltagltT-DeltagltM mutant. These findings suggest that l-glutamate influx via the GltT-GltM L-glutamate ABC transporter serves as a cue for N. meningitidis internalization into host cells. PMID- 20956570 TI - Identification of immunodominant antigens by probing a whole Chlamydia trachomatis open reading frame proteome microarray using sera from immunized mice. AB - Chlamydia trachomatis infections can lead to severe chronic complications, including trachoma, ectopic pregnancy, and infertility. The only effective approach to disease control is vaccination. The goal of this work was to identify new potential vaccine candidates through a proteomics approach. We constructed a protein chip array (Antigen Discovery, Inc.) by expressing the open reading frames (ORFs) from C. trachomatis mouse pneumonitis (MoPn) genomic and plasmid DNA and tested it with serum samples from MoPn-immunized mice. Two groups of BALB/c female mice were immunized either intranasally or intravaginally with live elementary bodies (EB). Another two groups were immunized by a combination of the intramuscular and subcutaneous routes with UV-treated EB (UV-EB), using either CpG and Montanide as adjuvants to favor a Th1 response or alum to elicit a Th2 response. Serum samples collected at regular intervals postimmunization were tested in the proteome array. The microarray included the expression products of 909 proteins from a total of 921 ORFs of the Chlamydia MoPn genome and plasmid. A total of 185 immunodominant proteins elicited an early and sustained antibody response in the mice immunized with live EB, and of these, 71 were also recognized by the sera from mice immunized with UV-EB. The reactive antigens included some proteins that were previously described as immunogenic, such as the major outer membrane protein, OmpB, Hsp60, and IncA and proteins from the type III secretion system. In addition, we identified in mice several new immunogens, including 75 hypothetical proteins. In summary, we have identified a new group of immunodominant chlamydial proteins that can be tested for their ability to induce protection. PMID- 20956571 TI - Heat shock factor 1 protects mice from rapid death during Listeria monocytogenes infection by regulating expression of tumor necrosis factor alpha during fever. AB - Heat shock factor 1 (HSF1) is a stress-induced transcription factor that promotes expression of genes that protect mammalian cells from the lethal effects of severely elevated temperatures (>42 degrees C). However, we recently showed that HSF1 is activated at a lower temperature (39.5 degrees C) in T cells, suggesting that HSF1 may be important for preserving T cell function during pathogen-induced fever responses. To test this, we examined the role of HSF1 in clearance of Listeria monocytogenes, an intracellular bacterial pathogen that elicits a strong CD8(+) T cell response in mice. Using temperature transponder microchips, we showed that the core body temperature increased approximately 2 degrees C in L. monocytogenes-infected mice and that the fever response was maintained for at least 24 h. HSF1-deficient mice cleared a low-dose infection with slightly slower kinetics than did HSF1(+/+) littermate controls but were significantly more susceptible to challenges with higher doses of bacteria. Surprisingly, HSF1 deficient mice did not show a defect in CD8(+) T cell responses following sublethal infection. However, when HSF1-deficient mice were challenged with high doses of L. monocytogenes, increased levels of serum tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) compared to those of littermate control mice were observed, and rapid death of the animals occurred within 48 to 60 h of infection. Neutralization of TNF-alpha enhanced the survival of HSF1 deficient mice. These results suggest that HSF1 is needed to prevent the overproduction of proinflammatory cytokines and subsequent death due to septic shock that can result following high-dose challenge with bacterial pathogens. PMID- 20956572 TI - Pasteurella multocida toxin-stimulated osteoclast differentiation is B cell dependent. AB - Pasteurella multocida is a Gram-negative bacillus that infects a number of wild and domestic animals, causing respiratory diseases. Toxigenic Pasteurella multocida strains produce a protein toxin (PMT) that leads to atrophic rhinitis in swine due to enhanced osteoclastogenesis and the inhibition of osteoblast function. We show that PMT-induced osteoclastogenesis is promoted by an as-yet uncharacterized B-cell population. The toxin, however, is not acting at the level of hematopoietic stem cells, since purified CD117(+) cells from murine hematopoietic progenitor cells cultivated with PMT did not mature into osteoclasts. The early macrophages contained within this cell population (CD117(+)/CD11b(+)) did not further differentiate into osteoclasts but survived and were able to phagocytose. Within the CD117(-) population, however, we detected PMT-induced generation of a B220(+)/CD19(+) and B220(+)/IgM(+) B-cell population that was able to take up fluorescently labeled PMT. Using purified B cell and macrophage populations, we show that these B cells are needed to efficiently generate osteoclasts from macrophages. Cells of the immune system are thought to affect osteoclast formation and function by secreting cytokines and growth factors. We show here that PMT-stimulated B cells produce elevated levels of the osteoclastogenic factors interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor alpha, and receptor activator of nuclear factor receptor ligand (RANKL) compared to B cells generated through incubation with IL-7. These results suggest that the osteoclastic properties characteristic for PMT may result from a cross talk between bone cells and lymphoid cells and that B cells might be an important target of Pasteurella multocida. PMID- 20956573 TI - Host DNA repair proteins in response to Pseudomonas aeruginosa in lung epithelial cells and in mice. AB - Although DNA repair proteins in bacteria are critical for pathogens' genome stability and for subverting the host defense, the role of host DNA repair proteins in response to bacterial infection is poorly defined. Here, we demonstrate, for the first time, that infection with the Gram-negative bacterium Pseudomonas aeruginosa significantly altered the expression and enzymatic activity of 8-oxoguanine DNA glycosylase (OGG1) in lung epithelial cells. Downregulation of OGG1 by a small interfering RNA strategy resulted in severe DNA damage and cell death. In addition, acetylation of OGG1 is required for host responses to bacterial genotoxicity, as mutations of OGG1 acetylation sites increased Cockayne syndrome group B (CSB) protein expression. These results also indicate that CSB may be involved in DNA repair activity during infection. Furthermore, OGG1 knockout mice exhibited increased lung injury after infection with P. aeruginosa, as demonstrated by higher myeloperoxidase activity and lipid peroxidation. Together, our studies indicate that P. aeruginosa infection induces significant DNA damage in host cells and that DNA repair proteins play a critical role in the host response to P. aeruginosa infection, serving as promising targets for the treatment of this condition and perhaps more broadly Gram negative bacterial infections. PMID- 20956574 TI - Granulocyte-macrophage colony-stimulating factor- and tumor necrosis factor alpha mediated matrix metalloproteinase production by human osteoblasts and monocytes after infection with Brucella abortus. AB - Osteoarticular complications are common in human brucellosis, but the pathogenic mechanisms involved are largely unknown. Since matrix metalloproteinases (MMPs) are involved in joint and bone damage in inflammatory and infectious diseases, we investigated the production of MMPs by human osteoblasts and monocytes, either upon Brucella abortus infection or upon reciprocal stimulation with factors produced by each infected cell type. B. abortus infection of the normal human osteoblastic cell line hFOB 1.19 triggered a significant release of MMP-2, which was mediated in part by granulocyte-macrophage colony-stimulating factor (GM-CSF) acting on these same cells. Supernatants from infected osteoblasts exhibited increased levels of monocyte chemoattractant protein 1 and induced the migration of human monocytes (THP-1 cell line). Infection with B. abortus induced a high MMP-9 secretion in monocytes, which was also induced by heat-killed B. abortus and by the Omp19 lipoprotein from B. abortus. These effects were mediated by Toll like receptor 2 and by the action of tumor necrosis factor alpha (TNF-alpha) produced by these same cells. Supernatants from B. abortus-infected monocytes induced MMP-2 secretion in uninfected osteoblasts, and this effect was mediated by TNF-alpha. Similarly, supernatants from infected osteoblasts induced MMP-9 secretion in uninfected monocytes. This effect was mediated by GM-CSF, which induced TNF-alpha production by monocytes, which in turn induced MMP-9 in these cells. These results suggest that MMPs could be potentially involved in the tissue damage observed in osteoarticular brucellosis. PMID- 20956575 TI - Preclinical evaluation of the Pht proteins as potential cross-protective pneumococcal vaccine antigens. AB - Current pneumococcal vaccines are composed of capsular polysaccharides (PS) of various serotypes, either as free PS or as protein-PS conjugates. The use of pneumococcus protein antigens that are able to afford protection across the majority of serotypes is envisaged as a relevant alternative and/or complement to the polysaccharides. In this context, based on several studies, the Pht protein family emerged as relevant vaccine candidates. The purpose of the present study was to evaluate the Pht protein family in several preclinical mouse models. Immunization with these antigens was compared with immunization with other pneumococcal antigens, such as CbpA, PspA, and PsaA. In a nasopharyngeal colonization model and in a lung colonization model, the Phts were found to be superior to the other candidates in terms of efficacy of protection and serotype coverage. Likewise, vaccination with PhtD allowed higher animal survival rates after lethal intranasal challenge. Finally, a passive transfer model in which natural anti-PhtD human antibodies were transferred into mice demonstrated significant protection against lethal intranasal challenge. This indicates that natural anti-PhtD human antibodies are able to protect against pneumococcal infection. Our findings, together with the serotype-independent occurrence of the Phts, designate this protein family as valid candidate antigens to be incorporated in protein-based pneumococcal vaccines. PMID- 20956576 TI - Murine fetoplacental infection models. PMID- 20956577 TI - Sperm quality assessments for endangered razorback suckers Xyrauchen texanus. AB - Flow cytometry (FCM) and computer-assisted sperm motion analysis (CASA) methods were developed and validated for use with endangered razorback suckers Xyrauchen texanus collected (n=64) during the 2006 spawning season. Sperm motility could be activated within osmolality ranges noted during milt collections (here 167-343 mOsm/kg). We hypothesized that sperm quality of milt collected into isoosmotic (302 mOsm/kg) or hyperosmotic (500 mOsm/kg) Hanks' balanced salt solution would not differ. Pre-freeze viabilities were similar between osmolalities (79%+/-6 (s.e.m.) and 76%+/-7); however, post-thaw values were greater in hyperosmotic buffer (27%+/-3 and 12%+/-2; P=0.0065), as was mitochondrial membrane potential (33%+/-4 and 13%+/-2; P=0.0048). Visual estimates of pre-freeze motility correlated with total (r=0.7589; range 23-82%) and progressive motility (r=0.7449) by CASA and were associated with greater viability (r=0.5985; P<0.0001). Count (FCM) was negatively correlated with post-thaw viability (r= 0.83; P=0.0116) and mitochondrial function (r=-0.91; P=0.0016). By FCM-based assessments of DNA integrity, whereby increased fluorochrome binding indicated more fragmentation, higher levels were negatively correlated with count (r=-0.77; P<0.0001) and pre-freeze viabilities (r=-0.66; P=0.0004). Fragmentation was higher in isotonic buffer (P=0.0234). To increase reproductive capacity of natural populations, the strategy and protocols developed can serve as a template for use with other imperiled fish species, biomonitoring, and genome banking. PMID- 20956578 TI - Endocrinology of the mammalian fetal testis. AB - The testes are essential endocrine regulators of fetal masculinization and male development and are, themselves, subject to hormonal regulation during gestation. This review focuses, primarily, on this latter control of testicular function. Data available suggest that, in most mammalian species, the testis goes through a period of independent function before the fetal hypothalamic-pituitary-gonadal axis develops at around 50% of gestation. This pituitary-independent phase coincides with the most critical period of fetal masculinization. Thereafter, the fetal testes appear to become pituitary hormone-dependent, concurrent with declining Leydig cell function, but increasing Sertoli cell numbers. The two orders of mammals most commonly used for these types of studies (rodents and primates) appear to represent special cases within this general hypothesis. In terms of testicular function, rodents are born 'early' before the pituitary dependent phase of fetal development, while the primate testis is dependent upon placental gonadotropin released during the pituitary-independent phase of development. PMID- 20956579 TI - Helping students with disabilities better address teasing and bullying situations: a MASNRN study. AB - Students with disabilities are more likely to be chronically teased or bullied and develop related psychosocial problems. Proactive interventions help these youths develop coping skills and become more resilient in handling such situations. The specific aims of this study were to (a) identify children with disabilities, who are at risk for being chronically teased or bullied and (b) intervene using a web-based program to build resiliency for managing teasing and bullying situations. Using materials from the U.S. Health Services Resources Administration's Stop Bullying Now campaign, 11 school nurses conducted a 12 session, biweekly support/discussion group intervention for 65 students with disabilities. Results indicated that after participating in serial brief interventions using a school nurse-led support group model, students reported being significantly less bothered by teasing and possessed significantly improved self-concepts, thus becoming more resilient in managing teasing and bullying situations. This study was conducted by MASNRN: the Massachusetts School Nurse Research Network. PMID- 20956580 TI - Understanding and identifying the child at risk for auditory processing disorders: a case method approach in examining the interdisciplinary role of the school nurse. AB - Despite receiving increased professional and public awareness since the initial American Speech Language Hearing Association (ASHA) statement defining Auditory Processing Disorders (APDs) in 1993 and the subsequent ASHA statement (2005), many misconceptions remain regarding APDs in school-age children among health and academic professionals. While many disorders account for why a child has difficulty understanding auditory content, this article will provide an overview of the history of APDs, current clinical presentations, distinguish between the common and often coexisting disorders seen in school-age children, and discuss how an audiological evaluation is used to detect the presence of APDs. Using a case method approach, a clinical case scenario describing the elusive nature of APDs, the importance of comprehensive audiological testing, and the interdisciplinary role of health professionals, with emphasis on the distinct role of the school nurse will be highlighted. PMID- 20956581 TI - Students feeling unsafe in school: fifth graders' experiences. AB - Children of late elementary school age (fifth grade) provide evidence that many do not feel safe in their schools. The purpose of this study was to examine how children express their experiences of feeling unsafe in school. Questions guiding the study were What percentage of children in this sample report feeling unsafe at school? What are the aftereffects of feeling unsafe? and How do children describe what makes them feel unsafe? Participants included 243 fifth-grade students who, as part of their participation in a larger study, were asked, "Have you felt unsafe at school?" Children responding affirmatively described what made them feel unsafe. Fifty-seven (23.8%) participants indicated they sometimes or always felt unsafe at school, citing teasing, bullying, or other threats that typically occurred when adults were not present. Of these, nearly a third reported being stressed and almost half felt at slight or great risk because of feeling unsafe. When children feel unsafe in school, there are implications for schools, neighborhoods, and larger communities. The related potential for children's increased involvement in health risk behaviors because they feel unsafe merits immediate and thoughtfully planned action. PMID- 20956582 TI - Relationships among social support, professional empowerment, and nursing career development of male nurses: a cross-sectional analysis. AB - The purpose of this study is to explore the relationships among social support, professional empowerment, and nursing career development and to identify the significant factors that affect nursing career development among male nurses. A cross-sectional survey design was used with 314 male nurses in Taiwan. Social support and professional empowerment were significantly and positively correlated with nursing career development among male nurses. Social support, professional empowerment, salary, type of institution, type of clinical level, and nursing discipline were identified as factors that significantly influenced nursing career development. Together, they accounted for 55.9% of the total variation. Professional empowerment was the most critical predictor of nursing career development and accounted for 47.7% of the variation. Nursing managers should follow male nurses' empowerment with interest and specifically address professional empowerment to promote male nurses' career development. PMID- 20956583 TI - Effects of mindfulness-based stress reduction (MBSR) on health among breast cancer survivors. AB - The purpose of this study was to examine the effects of a MBSR program on physiological and psychological outcomes among early-stage breast cancer survivors. A quasi-experimental, pre-and posttest control group design was selected. The intervention group received the MBSR intervention. The control group received no MBSR intervention. ANOVA and ANCOVA were used to analyze data. The intervention group demonstrated statistically significant improvement in physiological and psychological outcomes including reduced blood pressure, heart rate, and respiratory rate and increased mindfulness state at the level of p = .05 to p = .001. The effects of MBSR on reducing stress in this sample were statistically significant on the physiological outcome (morning cortisol) at the measurement after the intervention completion, but this effect was not sustained at 1-month follow-up. MBSR showed a trend toward improving psychological outcomes by reducing mood disturbance in this sample. PMID- 20956584 TI - Transformational leadership required to design and sustain evidence-based practice: a system exemplar. AB - In a pay-for-performance environment, implementing and sustaining evidence-based practice (EBP) is no longer a luxury but a necessity. A critical driving force for EBP is that our communities-the people we serve-expect to receive care based on the best available evidence. Transformational nursing leadership is required to create an infrastructure that influences organizational factors, processes and expectations, thus enabling the sustainability of EBP. The American Nurses Credentialing Center and the American Organization of Nurse Executives provide a framework for nursing leaders to consider when designing EBP implementation structures. This exemplar illustrates nursing leadership competencies with regard to implementation and sustainability of EBP within a multihospital system. PMID- 20956585 TI - Contribution of specific amino acid changes in penicillin binding protein 1 to amoxicillin resistance in clinical Helicobacter pylori isolates. AB - Amoxicillin is commonly used to treat Helicobacter pylori, a major cause of peptic ulcers, stomach cancer, and B-cell mucosa-associated lymphoid tissue lymphoma. Amoxicillin resistance in H. pylori is increasing steadily, especially in developing countries, leading to treatment failures. In this study, we characterize the mechanism of amoxicillin resistance in the U.S. clinical isolate B258. Transformation of amoxicillin-susceptible strain 26695 with the penicillin binding protein 1 gene (pbp1) from B258 increased the amoxicillin resistance of 26695 to equal that of B258, while studies using biotinylated amoxicillin showed a decrease in the binding of amoxicillin to the PBP1 of B258. Transformation with 4 pbp1 fragments, each encompassing several amino acid substitutions, combined with site-directed mutagenesis studies, identified 3 amino acid substitutions in PBP1 of B258 which affected amoxicillin susceptibility (Val 469 Met, Phe 473 Leu, and Ser 543 Arg). Homology modeling showed the spatial orientation of these specific amino acid changes in PBP1 from 26695 and B258. The results of these studies demonstrate that amoxicillin resistance in the clinical U.S. isolate B258 is due solely to an altered PBP1 protein with a lower binding affinity for amoxicillin. Homology modeling analyses using previously identified amino acid substitutions of amoxicillin-resistant PBP1s demonstrate the importance of specific amino acid substitutions in PBP1 that affect the binding of amoxicillin in the putative binding cleft, defining those substitutions deemed most important in amoxicillin resistance. PMID- 20956587 TI - Flow cytometry as a tool to determine the effects of cell wall-active antibiotics on vancomycin-susceptible and -resistant Enterococcus faecalis strains. AB - Flow cytometry and confocal microscopy were used to study the effects of vancomycin, daptomycin, telavancin, and PA1409, a new investigational vancomyquine, on the morphology, membrane potential, and permeability of glycopeptide-susceptible and -resistant Enterococcus faecalis strains. Daptomycin exerted the most pronounced effects on bacterial size and bacterial permeability against susceptible and resistant strains. PMID- 20956586 TI - Anti-Inflammatory benefits of antibiotic-induced neutrophil apoptosis: tulathromycin induces caspase-3-dependent neutrophil programmed cell death and inhibits NF-kappaB signaling and CXCL8 transcription. AB - Clearance of apoptotic neutrophils is a central feature of the resolution of inflammation. Findings indicate that immuno-modulation and induction of neutrophil apoptosis by macrolide antibiotics generate anti-inflammatory benefits via mechanisms that remain obscure. Tulathromycin (TUL), a new antimicrobial agent for bovine respiratory disease, offers superior clinical efficacy for reasons not fully understood. The aim of this study was to identify the immuno modulating effects of tulathromycin and, in this process, to establish tulathromycin as a new model for characterizing the novel anti-inflammatory properties of antibiotics. Bronchoalveolar lavage specimens were collected from Holstein calves 3 and 24 h postinfection, challenged intratracheally with live Mannheimia haemolytica (2 * 10(7) CFU), and treated with vehicle or tulathromycin (2.5 mg/kg body weight). Terminal deoxynucleotidyltransferase-mediated dUTP biotin nick end labeling (TUNEL) staining and enzyme-linked immunosorbent assay (ELISA) revealed that tulathromycin treatment significantly increased leukocyte apoptosis and reduced levels of proinflammatory leukotriene B(4) in M. haemolytica-challenged calves. In vitro, tulathromycin concentration dependently induced apoptosis in freshly isolated bovine neutrophils from healthy steers in a capase-3-dependent manner but failed to induce apoptosis in bovine fibroblasts, epithelial cells, and endothelial cells, as well as freshly isolated bovine blood monocytes and monocyte-derived macrophages. The proapoptotic effects of TUL were also, in part, drug specific; equimolar concentrations of penicillin G, oxytetracycline, and ceftiofur failed to cause apoptosis in bovine neutrophils. In addition, tulathromycin significantly reduced levels of phosphorylated IkappaBalpha, nuclear translocation of NF-kappaB p65, and mRNA levels of proinflammatory interleukin-8 in lipopolysaccharide (LPS)-stimulated bovine neutrophils. The findings illustrate novel mechanisms through which tulathromycin confers anti-inflammatory benefits. PMID- 20956589 TI - Carbapenem-hydrolyzing GES-type extended-spectrum beta-lactamase in Acinetobacter baumannii. AB - Acinetobacter baumannii isolate AP was recovered from a bronchial lavage of a patient hospitalized in Paris, France. A. baumannii AP was resistant to all beta lactams, including carbapenems, and produced the extended-spectrum beta-lactamase (ESBL) GES-14, which differs from GES-1 by two substitutions, Gly170Ser and Gly243Ala. Cloning of the bla(GES-14) gene followed by its expression in Escherichia coli showed that GES-14 compromised significantly the efficacy of all beta-lactams, including cephalosporins, aztreonam, and carbapenems. The carbapenemase activity of purified GES-14 was confirmed by kinetic studies. The bla(GES-14) gene was located into a class 1 integron structure and located onto a ca. 95-kb self-transferable plasmid. This study identified a very broad-spectrum beta-lactamase in A. baumannii. PMID- 20956588 TI - Population pharmacokinetics of nevirapine in HIV-1-infected pregnant women and their neonates. AB - The aim of the present study was to describe the nevirapine (NVP) pharmacokinetics (PK) in pregnant women and their neonates and to evaluate the transplacental drug transfer and administration scheme for the prevention of mother-to-child transmission. Thirty-eight HIV-1-infected pregnant women were administered one tablet of NVP (200 mg) and two tablets of tenofovir emtricitabine (Truvada) at the initiation of labor. Children were given NVP syrup (2 mg/kg of body weight) as a single dose (sdNVP) on the first day of life. By pair, NVP concentrations were measured in 11 maternal, 1 cord blood, and 2 neonatal plasma samples and analyzed by a population approach. A one-compartment model was used for mothers and neonates; the absorption rate constants for mothers and neonates were 0.95 h(-1) (intersubject variability, 111%) and 0.39 h( 1), respectively; the apparent elimination clearances were 1.42 liter.h(-1) (intersubject variability, 22%) and 0.035 liter.h(-1), respectively; and apparent volumes of distribution were 87.3 liters (intersubject variability, 25%) and 5.65 liters, respectively. An effect compartment was linked to maternal circulation by mother-to-cord and cord-to-mother rate constants of 1.10 h(-1) and 1.43 h(-1), respectively. Placental transfer, expressed as the fetal-to-maternal area under the curve ratio, was 75%. Neonates had a very long half-lives (110 h) compared to adults. In the 38 mothers, the simulated median individual predicted time during which the NVP concentration remained above the half-maximal inhibitory concentration (IC(50)) was 13.2 days (range, 12 to 19.2 days). Thus, the administration of tenofovir-emtricitabine for at least 3 weeks after delivery should be considered to prevent the emergence of resistant viruses. The neonate must receive sdNVP immediately after birth when the infant is born less than 30 min after maternal drug intake to keep NVP concentrations above the IC(50). PMID- 20956590 TI - Prevalence and mechanism of resistance to antimicrobial agents in group G streptococcal isolates from China. AB - Eighty group G streptococcal stains were collected from Chinese children. Susceptibility testing was done by a double-dilution and a disk diffusion method. PCR was used to test drug-resistant genes, and the chi(2) test and definite probability methods were used to test for statistically significant differences among the three groups. Thirty-four isolates (42.5%) showed resistance to erythromycin. There are differences between the resistance characteristics of group G streptococci from different regions of China. PMID- 20956591 TI - Structure of the Mycobacterium tuberculosis D-alanine:D-alanine ligase, a target of the antituberculosis drug D-cycloserine. AB - D-alanine:D-alanine ligase (EC 6.3.2.4; Ddl) catalyzes the ATP-driven ligation of two D-alanine (D-Ala) molecules to form the D-alanyl:D-alanine dipeptide. This molecule is a key building block in peptidoglycan biosynthesis, making Ddl an attractive target for drug development. D-Cycloserine (DCS), an analog of D-Ala and a prototype Ddl inhibitor, has shown promise for the treatment of tuberculosis. Here, we report the crystal structure of Mycobacterium tuberculosis Ddl at a resolution of 2.1 A. This structure indicates that Ddl is a dimer and consists of three discrete domains; the ligand binding cavity is at the intersection of all three domains and conjoined by several loop regions. The M. tuberculosis apo Ddl structure shows a novel conformation that has not yet been observed in Ddl enzymes from other species. The nucleotide and D-alanine binding pockets are flexible, requiring significant structural rearrangement of the bordering regions for entry and binding of both ATP and D-Ala molecules. Solution affinity and kinetic studies showed that DCS interacts with Ddl in a manner similar to that observed for D-Ala. Each ligand binds to two binding sites that have significant differences in affinity, with the first binding site exhibiting high affinity. DCS inhibits the enzyme, with a 50% inhibitory concentration (IC(50)) of 0.37 mM under standard assay conditions, implicating a preferential and weak inhibition at the second, lower-affinity binding site. Moreover, DCS binding is tighter at higher ATP concentrations. The crystal structure illustrates potential drugable sites that may result in the development of more effective Ddl inhibitors. PMID- 20956592 TI - Recombinant anthrax toxin receptor-Fc fusion proteins produced in plants protect rabbits against inhalational anthrax. AB - Inhalational anthrax, a zoonotic disease caused by the inhalation of Bacillus anthracis spores, has a ~50% fatality rate even when treated with antibiotics. Pathogenesis is dependent on the activity of two toxic noncovalent complexes: edema toxin (EdTx) and lethal toxin (LeTx). Protective antigen (PA), an essential component of both complexes, binds with high affinity to the major receptor mediating the lethality of anthrax toxin in vivo, capillary morphogenesis protein 2 (CMG2). Certain antibodies against PA have been shown to protect against anthrax in vivo. As an alternative to anti-PA antibodies, we produced a fusion of the extracellular domain of human CMG2 and human IgG Fc, using both transient and stable tobacco plant expression systems. Optimized expression led to the CMG2-Fc fusion protein being produced at high levels: 730 mg/kg fresh leaf weight in Nicotiana benthamiana and 65 mg/kg in N. tabacum. CMG2-Fc, purified from tobacco plants, fully protected rabbits against a lethal challenge with B. anthracis spores at a dose of 2 mg/kg body weight administered at the time of challenge. Treatment with CMG2-Fc did not interfere with the development of the animals' own immunity to anthrax, as treated animals that survived an initial challenge also survived a rechallenge 30 days later. The glycosylation of the Fc (or lack thereof) had no significant effect on the protective potency of CMG2-Fc in rabbits or on its serum half-life, which was about 5 days. Significantly, CMG2-Fc effectively neutralized, in vitro, LeTx-containing mutant forms of PA that were not neutralized by anti-PA monoclonal antibodies. PMID- 20956593 TI - Spontaneous mutations in the Plasmodium falciparum sarcoplasmic/ endoplasmic reticulum Ca2+-ATPase (PfATP6) gene among geographically widespread parasite populations unexposed to artemisinin-based combination therapies. AB - Recent reports on the decline of the efficacy of artemisinin-based combination therapies (ACTs) indicate a serious threat to malaria control. The endoplasmic/sarcoplasmic reticulum Ca(2+)-ATPase ortholog of Plasmodium falciparum (PfSERCA) has been suggested to be the target of artemisinin and its derivatives. It is assumed that continuous artemisinin pressure will affect polymorphism of the PfSERCA gene (serca) if the protein is the target. Here, we investigated the polymorphism of serca in parasite populations unexposed to ACTs to obtain baseline information for the study of potential artemisinin-driven selection of resistant parasites. Analysis of 656 full-length sequences from 13 parasite populations in Africa, Asia, Oceania, and South America revealed 64 single nucleotide polymorphisms (SNPs), of which 43 were newly identified and 38 resulted in amino acid substitutions. No isolates showed L263E and S769N substitutions, which were reportedly associated with artemisinin resistance. Among the four continents, the number of SNPs was highest in Africa. In Africa, Asia, and Oceania, common SNPs, or those with a minor allele frequency of >=0.05, were less prevalent, with most SNPs noted to be continent specific, whereas in South America, common SNPs were highly prevalent and often shared with those in Africa. Of 50 amino acid haplotypes observed, only one haplotype (3D7 sequence) was seen in all four continents (64%). Forty-eight haplotypes had frequencies of less than 5%, and 40 haplotypes were continent specific. The geographical difference in the diversity and distribution of serca SNPs and haplotypes lays the groundwork for assessing whether some artemisinin resistance-associated mutations and haplotypes are selected by ACTs. PMID- 20956594 TI - Sequence of pR3521, an IncB plasmid from Escherichia coli encoding ACC-4, SCO-1, and TEM-1 beta-lactamases. AB - The sequence of pR3521, a self-transmissible plasmid from Escherichia coli, was determined. pR3521 (110,416 bp) comprised a contiguous IncB sequence (84,034 bp) sharing extensive similarities with IncI replicons and an acquired region (26,382 bp) carrying sequences of diverse origin, containing bla(ACC-4), bla(SCO-1), bla(TEM-1b) (two copies), strA, strB, sul2, and aacC2. PMID- 20956595 TI - qnrB19 gene bracketed by IS26 on a 40-kilobase IncR plasmid from an Escherichia coli isolate from a veal calf. PMID- 20956596 TI - The antibiotic gentamicin inhibits specific protein trafficking functions of the Arf1/2 family of GTPases. AB - Gentamicin is a highly efficacious antibiotic against Gram-negative bacteria. However, its usefulness in treating infections is compromised by its poorly understood renal toxicity. Toxic effects are also seen in a variety of other organisms. While the yeast Saccharomyces cerevisiae is relatively insensitive to gentamicin, mutations in any one of ~20 genes cause a dramatic decrease in resistance. Many of these genes encode proteins important for translation termination or specific protein-trafficking complexes. Subsequent inspection of the physical and genetic interactions of the remaining gentamicin-sensitive mutants revealed a network centered on chitin synthase and the Arf GTPases. Further analysis has demonstrated that some conditional arf1 and gea1 alleles make cells hypersensitive to gentamicin under permissive conditions. These results suggest that one consequence of gentamicin exposure is disruption of Arf dependent protein trafficking. PMID- 20956597 TI - Tracking origins and spread of sulfadoxine-resistant Plasmodium falciparum dhps alleles in Thailand. AB - The emergence and spread of drug-resistant Plasmodium falciparum have been a major impediment for the control of malaria worldwide. Earlier studies have shown that similar to chloroquine (CQ) resistance, high levels of pyrimethamine resistance in P. falciparum originated independently 4 to 5 times globally, including one origin at the Thailand-Cambodia border. In this study we describe the origins and spread of sulfadoxine-resistance-conferring dihydropteroate synthase (dhps) alleles in Thailand. The dhps mutations and flanking microsatellite loci were genotyped for P. falciparum isolates collected from 11 Thai provinces along the Burma, Cambodia, and Malaysia borders. Results indicated that resistant dhps alleles were fixed in Thailand, predominantly being the SGEGA, AGEAA, and SGNGA triple mutants and the AGKAA double mutant (mutated codons are underlined). These alleles had different geographical distributions. The SGEGA alleles were found mostly at the Burma border, while the SGNGA alleles occurred mainly at the Cambodia border and nearby provinces. Microsatellite data suggested that there were two major genetic lineages of the triple mutants in Thailand, one common for SGEGA/SGNGA alleles and another one independent for AGEAA. Importantly, the newly reported SGNGA alleles possibly originated at the Thailand-Cambodia border. All parasites in the Yala province (Malaysia border) had AGKAA alleles with almost identical flanking microsatellites haplotypes. They were also identical at putatively neutral loci on chromosomes 2 and 3, suggesting a clonal nature of the parasite population in Yala. In summary, this study suggests multiple and independent origins of resistant dhps alleles in Thailand. PMID- 20956598 TI - Activity of deferasirox in Mucorales: influences of species and exogenous iron. AB - Differences in deferasirox susceptibility among members of the order Mucorales are unknown. Here we show that Cunninghamella bertholletiae (four isolates) and Mucor species (five isolates) display higher deferasirox MICs and minimal fungicidal concentrations compared to Rhizopus species (six isolates). Exogenous iron further attenuated the deferasirox susceptibility of Mucorales isolates with low MICs. Vital staining revealed damage to subapical compartments in susceptible strains. PMID- 20956599 TI - Emergence of Klebsiella pneumoniae coproducing KPC-2 and 16S rRNA methylase ArmA in Poland. AB - A Klebsiella pneumoniae epidemic strain that coproduced carbapenemase KPC-2 (K. pneumoniae carbapenemase 2) and 16S rRNA methylase ArmA has emerged in Poland. Four nonduplicate isolates from patients in a hospital in Warsaw, Poland, were found to carry the bla(KPC-2) and armA genes on ca. 50-kb and 90-kb plasmids, respectively. Tn4401 with a 100-bp deletion in the variable region was detected in all the isolates. XbaI pulsed-field gel electrophoresis (PFGE) revealed 93.2% similarity of the isolates. All the isolates were resistant to carbapenems and 4,6-disubstituted 2-deoxystreptamines. PMID- 20956600 TI - Cross-resistance profile determination of two second-generation HIV-1 integrase inhibitors using a panel of recombinant viruses derived from raltegravir-treated clinical isolates. AB - The integrase inhibitor raltegravir (RAL) is currently used for the treatment of both treatment-naive and treatment-experienced HIV-1-infected patients. Elvitegravir (EVG) is in late phases of clinical development. Since significant cross-resistance between RAL and EVG is observed, there is a need for second generation integrase inhibitors (INIs) with a higher genetic barrier and limited cross-resistance to RAL/EVG. A panel of HIV-1 integrase recombinants, derived from plasma samples from raltegravir-treated patients (baseline and follow-up samples), were used to study the cross-resistance profile of two second generation integrase inhibitors, MK-2048 and compound G. Samples with Q148H/R mutations had elevated fold change values with all compounds tested. Although samples with the Y143R/C mutation had reduced susceptibility to RAL, they remained susceptible to MK-2048 and compound G. Samples with the N155H mutation had no reduced susceptibility to compound G. In conclusion, our results allowed ranking of the INIs on the basis of the antiviral activities using recombinant virus stocks from RAL-treated patient viruses. The order according to decreasing susceptibility is compound G, MK-2048, and EVG. PMID- 20956601 TI - Differential effects of paromomycin on ribosomes of Leishmania mexicana and mammalian cells. AB - Paromomycin, an aminoglycoside antibiotic having low mammalian cell toxicity, is one of the drugs currently used in the chemotherapy of cutaneous and visceral leishmaniasis. In order to understand the mode of action of this antibiotic at the molecular level, we have investigated the effects of paromomycin on protein synthesis in Leishmania and its mammalian hosts. We were able to demonstrate that in vivo protein synthesis in the promastigote stage of the parasite and its proliferation rate are markedly inhibited by paromomycin while being only slightly affected by other aminoglycoside antibiotics, such as streptomycin and neomycin B. Furthermore, both in vitro polypeptide synthesis induced by poly(U) as mRNA and accuracy of translation are significantly decreased by paromomycin in cell-free systems containing ribosomal particles of Leishmania promastigotes. Conversely, when ribosomes from mammalian cells are used instead of the protozoan particles, polyphenylalanine synthesis is only barely reduced by the antibiotic and the translation misreading remains almost unaltered. Surface plasmon resonance analysis of the interaction between paromomycin and protozoan or mammalian cell ribosomal RNAs shows a strong binding of antibiotic to the parasite ribosomal decoding site and practically no interaction with the mammalian cell counterpart. Our results indicating differential effects of paromomycin on the translation processes of the Leishmania parasite and its mammalian hosts can explain the therapeutic efficiency of this antibiotic as an antileishmaniasis agent. PMID- 20956602 TI - Structural features governing the activity of lactoferricin-derived peptides that act in synergy with antibiotics against Pseudomonas aeruginosa in vitro and in vivo. AB - Pseudomonas aeruginosa is naturally resistant to many antibiotics, and infections caused by this organism are a serious threat, especially to hospitalized patients. The intrinsic low permeability of P. aeruginosa to antibiotics results from the coordinated action of several mechanisms, such as the presence of restrictive porins and the expression of multidrug efflux pump systems. Our goal was to develop antimicrobial peptides with an improved bacterial membrane permeabilizing ability, so that they enhance the antibacterial activity of antibiotics. We carried out a structure activity relationship analysis to investigate the parameters that govern the permeabilizing activity of short (8- to 12-amino-acid) lactoferricin-derived peptides. We used a new class of constitutional and sequence-dependent descriptors called PEDES (peptide descriptors from sequence) that allowed us to predict (Spearman's rho = 0.74; P < 0.001) the permeabilizing activity of a new peptide generation. To study if peptide-mediated permeabilization could neutralize antibiotic resistance mechanisms, the most potent peptides were combined with antibiotics, and the antimicrobial activities of the combinations were determined on P. aeruginosa strains whose mechanisms of resistance to those antibiotics had been previously characterized. A subinhibitory concentration of compound P2-15 or P2-27 sensitized P. aeruginosa to most classes of antibiotics tested and counteracted several mechanisms of antibiotic resistance, including loss of the OprD porin and overexpression of several multidrug efflux pump systems. Using a mouse model of lethal infection, we demonstrated that whereas P2-15 and erythromycin were unable to protect mice when administered separately, concomitant administration of the compounds afforded long-lasting protection to one-third of the animals. PMID- 20956604 TI - Failure of vancomycin continuous infusion against experimental endocarditis due to vancomycin-intermediate Staphylococcus aureus. AB - Continuous infusion of vancomycin was evaluated against experimental endocarditis due to heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) and VISA. Animals were infected with hVISA PC1 (vancomycin MIC, 2 mg/liter) or VISA PC3 (vancomycin MIC, 8 mg/liter) and treated for 5 days with constant serum levels of 20 or 40 mg/liter. Vancomycin continuous infusion was unsuccessful, as 20 mg/liter was barely active against PC1 (6 of 13 sterile vegetations) and 40 mg/liter failed against PC3 (2 of 9 sterile vegetations). PMID- 20956603 TI - Potent strategy to inhibit HIV-1 by binding both gp120 and gp41. AB - The development of an anti-HIV microbicide is critical in the fight against the spread of HIV. It is shown here that the covalent linking of compounds that bind gp120 with compounds that bind gp41 can inhibit HIV entry even more potently than individual inhibitors or noncovalent combinations. The most striking example involves griffithsin, a potent HIV inhibitor that binds to the surface of HIV gp120. While griffithsin inhibits HIV Env-mediated fusion in a CCR5-tropic cell cell fusion assay with a 50% inhibitory concentration (IC(50)) of 1.31 +/- 0.87 nM and the gp41-binding peptide C37 shows an IC(50) of 18.2 +/- 7.6 nM, the covalently linked combination of griffithsin with C37 (Griff37) has an IC(50) of 0.15 +/- 0.05 nM, exhibiting a potency 8.7-fold greater than that of griffithsin alone. Similarly, in CXCR4-tropic cell-cell fusion assays, Griff37 is 5.2-fold more potent than griffithsin alone. In viral assays, both griffithsin and Griff37 inhibit HIV replication at midpicomolar levels, but the linked compound Griff37 is severalfold more potent than griffithsin alone against both CCR5- and CXCR4 tropic virus strains. Another example of this strategy is the covalently linked combination of peptide C37 with a variant of the gp120-binding peptide CD4M33 (L. Martin et al., Nat. Biotechnol. 21:71-76, 2003). Also, nuclear magnetic resonance (NMR) spectra for several of these compounds are shown, including, to our knowledge, the first published NMR spectrum for griffithsin. PMID- 20956605 TI - Functional antibodies targeting IsaA of Staphylococcus aureus augment host immune response and open new perspectives for antibacterial therapy. AB - Staphylococcus aureus is the most common cause of nosocomial infections. Multiple antibiotic resistance and severe clinical outcomes provide a strong rationale for development of immunoglobulin-based strategies. Traditionally, novel immunological approaches against bacterial pathogens involve antibodies directed against cell surface-exposed virulence-associated epitopes or toxins. In this study, we generated a monoclonal antibody targeting the housekeeping protein IsaA, a suggested soluble lytic transglycosylase of S. aureus, and tested its therapeutic efficacy in two experimental mouse infection models. A murine anti IsaA antibody of the IgG1 subclass (UK-66P) showed the highest binding affinity in Biacore analysis. This antibody recognized all S. aureus strains tested, including hospital-acquired and community-acquired methicillin-resistant S. aureus strains. Therapeutic efficacy in vivo in mice was analyzed using a central venous catheter-related infection model and a sepsis survival model. In both models, anti-IsaA IgG1 conferred protection against staphylococcal infection. Ex vivo, UK-66P activates professional phagocytes and induces highly microbicidal reactive oxygen metabolites in a dose-dependent manner, resulting in bacterial killing. The study provides proof of concept that monoclonal IgG1 antibodies with high affinity to the ubiquitously expressed, single-epitope-targeting IsaA are effective in the treatment of staphylococcal infection in different mouse models. Anti-IsaA antibodies might be a useful component in an antibody-based therapeutic for prophylaxis or adjunctive treatment of human cases of S. aureus infections. PMID- 20956606 TI - In vitro antibiotic synergy in extensively drug-resistant Acinetobacter baumannii: the effect of testing by time-kill, checkerboard, and Etest methods. AB - This study examined the in vitro effects of polymyxin B, tigecycline, and rifampin combinations on 16 isolates of extensively drug-resistant Acinetobacter baumannii, including four polymyxin-resistant strains. In vitro synergy was demonstrated in 19 (40%) of a possible 48 isolate-antibiotic combinations by time kill methods, 8 (17%) by checkerboard methods, and only 1 (2%) by Etest methods. There was only slight agreement between Etest and checkerboard methods and no agreement between results obtained by other methods. PMID- 20956607 TI - Short alkylated peptoid mimics of antimicrobial lipopeptides. AB - We report the creation of alkylated poly-N-substituted glycine (peptoid) mimics of antimicrobial lipopeptides with alkyl tails ranging from 5 to 13 carbons. In several cases, alkylation significantly improved the selectivity of the peptoids with no loss in antimicrobial potency. Using this technique, we synthesized an antimicrobial peptoid only 5 monomers in length with selective, broad-spectrum antimicrobial activity as potent as previously reported dodecameric peptoids and the antimicrobial peptide pexiganan. PMID- 20956608 TI - Molecular characterization of fluoroquinolone resistance in Mycobacterium tuberculosis: functional analysis of gyrA mutation at position 74. AB - A PCR-sequencing assay was evaluated for direct detection of mutations in the quinolone resistance-determining region (QRDR) of gyrase A (gyrA) gene in fluoroquinolone-resistant Mycobacterium tuberculosis in respiratory specimens. As determined by gyrA QRDR analysis, complete concordance of genotypic and phenotypic fluoroquinolone resistance was demonstrated. Our results indicate that the assay is a rapid and reliable method for the diagnosis of fluoroquinolone resistant tuberculosis, facilitating timely clinical management and public health control. Using the assay, we detected a novel gyrA Ala74Ser mutation in M. tuberculosis directly from sputum specimens. The functional effect of the Ala74Ser mutant was verified through the study of the DNA supercoiling inhibitory activity of fluoroquinolones against the recombinant gyrase. The drug-mediated gyrase-DNA cleavage complex model suggests perturbation of the gyrA-gyrA dimer interface caused by the Ala74Ser mutation probably disturbs the putative quinolone binding pocket and leads to the reduction of the drug binding affinity. A number of gyrA mutations (Glu21Gln, Ser95Thr, and Gly668Asp) were also characterized to be natural polymorphisms not associated with fluoroquinolone resistance. PMID- 20956609 TI - Using positive deviance for determining successful weight-control practices. AB - Based on positive deviance (examining the practices of successful individuals), we identified five primary themes from 36 strategies that help to maintain long term weight loss (weight control) in 61 people. We conducted in-depth interviews to determine what successful individuals did and/or thought about regularly to control their weight. The themes included weight-control practices related to (a) nutrition: increase water, fruit, and vegetable intake, and consistent meal timing and content; (b) physical activity: follow and track an exercise routine at least 3x/week; (c) restraint: practice restraint by limiting and/or avoiding unhealthy foods; (d) self-monitor: plan meals, and track calories/weight progress; and (e) motivation: participate in motivational programs and cognitive processes that affect weight-control behavior. Using the extensive data involving both the practices and practice implementation, we used positive deviance to create a comprehensive list of practices to develop interventions for individuals to control their weight. PMID- 20956610 TI - Complex genetic effects in quantitative trait locus identification: a computationally tractable random model for use in F(2) populations. AB - Methodology for mapping quantitative trait loci (QTL) has focused primarily on treating the QTL as a fixed effect. These methods differ from the usual models of genetic variation that treat genetic effects as random. Computationally expensive methods that allow QTL to be treated as random have been explicitly developed for additive genetic and dominance effects. By extending these methods with a variance component method (VCM), multiple QTL can be mapped. We focused on an F(2) crossbred population derived from inbred lines and estimated effects for each individual and their corresponding marker-derived genetic covariances. We present extensions to pairwise epistatic effects, which are computationally intensive because a great many individual effects must be estimated. But by replacing individual genetic effects with average genetic effects for each marker class, genetic covariances are approximated. This substantially reduces the computational burden by reducing the dimensions of covariance matrices of genetic effects, resulting in a remarkable gain in the speed of estimating the variance components and evaluating the residual log-likelihood. Preliminary results from simulations indicate competitiveness of the reduced model with multiple-interval mapping, regression interval mapping, and VCM with individual genetic effects in its estimated QTL positions and experimental power. PMID- 20956611 TI - Surprising fitness consequences of GC-biased gene conversion. II. Heterosis. AB - Heterosis is a widespread phenomenon corresponding to the increase in fitness following crosses between individuals from different populations or lines relative to their parents. Its genetic basis has been a topic of controversy since the early 20th century. The masking of recessive deleterious mutations in hybrids likely explains a substantial part of heterosis. The dynamics and consequences of these mutations have thus been studied in depth. Recently, it was suggested that GC-biased gene conversion (gBGC) might strongly affect the fate of deleterious mutations and may have significant fitness consequences. gBGC is a recombination-associated process mimicking selection in favor of G and C alleles, which can interfere with selection, for instance by increasing the frequency of GC deleterious mutations. I investigated how gBGC could affect the amount and genetic structure of heterosis through an analysis of the interaction between gBGC and selection in subdivided populations. To do so, I analyzed the infinite island model both by numerical computations and by analytical approximations. I showed that gBGC might have little impact on the total amount of heterosis but could greatly affect its genetic basis. PMID- 20956612 TI - MicroRNAs in resolution of acute inflammation: identification of novel resolvin D1-miRNA circuits. AB - Mechanisms controlling resolution of acute inflammation are of wide interest. Here, we investigated microRNAs (miRNAs) in self-limited acute inflammatory exudates and their regulation by resolvin D1 (RvD1). Using real-time PCR analysis, we found in resolving exudates that miR-21, miR-146b, miR-208a, miR 203, miR-142, miR-302d, and miR-219 were selectively regulated (P<0.05) in self limited murine peritonitis. RvD1 (300 ng/mouse or 15 MUg kg(-1)) reduced zymosan elicited neutrophil infiltration into the peritoneum 25-50% and shortened the resolution interval (R(i)) by ~4 h. In peritonitis at 12 h, RvD1 up-regulated miR 21, miR-146b, and miR-219 and down-regulated miR-208a in vivo. In human macrophages overexpressing recombinant RvD1 receptors ALX/FPR2 or GPR32, these same miRNAs were significantly regulated (P<0.05) by RvD1 at concentrations as low as 10 nM, recapitulating the in vivo circuit. In addition, RvD1-miRNAs identified herein target cytokines and proteins involved in the immune system, e.g., miR-146b targeted NF-kappaB signaling, and miR-219 targeted 5-lipoxygenase and reduced leukotriene production. RvD1 also reduced nuclear translocation of NF kappaB and SMAD and down-regulated phospho-IkappaB. Taken together, these results indicate that resolvin-regulated specific miRNAs target genes involved in resolution and establish a novel resolution circuit involving RvD1 receptor dependent regulation of specific miRNAs. PMID- 20956613 TI - ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS. AB - A large noncoding RNA called ANRIL (for antisense noncoding RNA in the INK4 locus) has been identified within the p15/CDKN2B-p16/CDKN2A-p14/ARF gene cluster. While the exact role of ANRIL awaited further elucidation, common disease genomewide association studies (GWAS) have surprisingly identified the ANRIL gene as a genetic susceptibility locus shared associated by coronary disease, intracranial aneurysm and also type 2 diabetes. Expression studies have confirmed the coregulation of p15/CDKN2B, p16/CDKN2A, p14/ARF, and ANRIL. Among the cluster, ANRIL expression showed the strongest association with the multiple phenotypes linked to the 9p21.3 region. More recent GWAS also identified ANRIL as a risk locus for gliomas and basal cell carcinomas in accordance with the princeps observation. Moreover, a mouse model has confirmed the pivotal role of ANRIL in regulation of CDKN2A/B expression through a cis-acting mechanism and its implication in proliferation and senescence. The implication of ANRIL in cellular aging has provided an attractive unifying hypothesis to explain its association with various susceptibility risk factors. ANRIL identification emphasizes the underestimated role of long noncoding RNAs. Many GWAS have identified trait associated SNPs that felt in noncoding genomic regions. It is conceivable to anticipate that long, noncoding RNAs will map to many of these "gene deserts." PMID- 20956614 TI - Neural correlates of developing and adapting behavioral biases in speeded choice reactions--an fMRI study on predictive motor coding. AB - In reaction-time (RT) tasks with unequally probable stimuli, people respond faster and more accurately in high-probability trials than in low-probability trials. We used functional magnetic resonance imaging to investigate brain activity during the acquisition and adaptation of such biases. Participants responded to arrows pointing to either side with different and previously unknown probabilities across blocks, which were covertly reversed in the middle of some blocks. Changes in response bias were modeled using the development of the selective RT bias at the beginning of a block and after the reversal as parametric regressors. Both fresh development and reversal of an existing response bias were associated with bilateral activations in inferior parietal lobule, intraparietal sulcus, and supplementary motor cortex. Further activations were observed in right temporoparietal junction, dorsolateral prefrontal cortex, and dorsal premotor cortex. Only during initial development of biases at the beginning of a block, we observed additional activity in ventral premotor cortex and anterior insula, whereas the basal ganglia (bilaterally) were recruited when the bias was adapted to reversed probabilities. Taken together, these areas constitute a network that updates and applies implicit predictions to create an attention and motor bias according to environmental probabilities that transform into specific facilitation. PMID- 20956615 TI - Deubiquitylase, deSUMOylase, and deISGylase activity microarrays for assay of substrate preference and functional modifiers. AB - Microarray-based proteomics expanded the information potential of DNA arrays to the level of protein translation and interaction, but so far, not much beyond. Although enzymatic activity from immobilized proteins has been reliably studied using surface plasmon resonance, a microarray of catalytically competent enzymes would facilitate high throughput, parallel study of their function. The ability to localize activity from soluble substrates has frustrated development of such an array. Here, we report the novel use of previously developed, highly specific suicide substrates for three families of enzymes: deubiquitylases, deSUMOylases, and deISGylases. We show specificity of each family to its cognate substrate, and demonstrate utility of the array in a secondary screen of small molecule inhibitors. PMID- 20956616 TI - Anthracycline cardiotoxicity in the elderly cancer patient: a SIOG expert position paper. AB - BACKGROUND: Comorbidities and risk factors likely to complicate treatment are common in elderly cancer patients. Anthracyclines remain the cornerstone of first line therapy for non-Hodgkin's lymphoma (NHL) and metastatic and early breast cancer but can cause congestive heart failure. Elderly patients are at increased risk of this event and measures to reduce it should be considered. METHODS: A committee of experts in breast cancer and NHL met under the auspices of the International Society for Geriatric Oncology to review the literature and make recommendations, based on level of evidence, for the assessment, treatment and monitoring of elderly patients requiring anthracyclines. RESULTS AND RECOMMENDATIONS: Use of anthracycline-based chemotherapy illustrates many of the dilemmas facing elderly cancer patients. Age in itself should not prevent access to potentially curative treatment or treatment that prolongs life or improves its quality. The risk of cardiotoxicity with conventional anthracyclines is increased by the following factors: an existing or history of heart failure or cardiac dysfunction; hypertension, diabetes and coronary artery disease; older age (independent of comorbidities and performance status); prior treatment with anthracyclines; higher cumulative dose of anthracyclines and short infusion duration. The fact that cumulative and irreversible cardiotoxicity is likely to be greater in this population than among younger patients calls for effective pretreatment screening for risk factors, rigorous monitoring of cardiac function and early intervention. Use of liposomal anthracycline formulations, prolonging the infusion time for conventional anthracyclines and cardioprotective measures should be considered. However, when treatment is being given with curative intent, care should be taken to ensure reduced cardiotoxicity is not achieved at the expense of efficacy. PMID- 20956617 TI - Urine metabolite analysis offers potential early diagnosis of ovarian and breast cancers. AB - PURPOSE: Metabolomics is a new, rapidly expanding field dedicated to the global study of metabolites in biological systems. In this article metabolomics is applied to find urinary biomarkers for breast and ovarian cancer. EXPERIMENTAL DESIGN: Urine samples were collected from early- and late-stage breast and ovarian cancer patients during presurgical examinations and randomly from females with no known cancer. After quantitatively measuring a set of metabolites using nuclear magnetic resonance spectroscopy, both univariate and multivariate statistical analyses were employed to determine significant differences. RESULTS: Metabolic phenotypes of breast and ovarian cancers in comparison with normal urine and with each other revealed significance at Bonferroni-corrected significance levels resulting in unique metabolite patterns for breast and ovarian cancer. Intermediates of the tricarboxylic acid cycle and metabolites relating to energy metabolism, amino acids, and gut microbial metabolism were perturbed. CONCLUSIONS: The results presented here illustrate that urinary metabolomics may be useful for detecting early-stage breast and ovarian cancer. PMID- 20956618 TI - High blood neutrophil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy. AB - PURPOSE: Asbestos-induced chronic inflammation is implicated in the pathogenesis of malignant mesothelioma (MM). We have investigated blood neutrophil-to lymphocyte ratio (NLR), an index of systemic inflammation, as a prognostic factor in MM patients. EXPERIMENTAL DESIGN: Patients with MM who had systemic therapy at participating institutes were studied. Potential prognostic factors such as age, gender, performance status, histologic subtype, and baseline laboratory parameters, including NLR, were analyzed. Overall survival from commencement of therapy was determined by the Kaplan-Meier method. Multivariate analyses using Cox Regression model were performed with significant factors (P <= 0.05) to determine their independent effect. RESULTS: A total of 173 MM patients undergoing systemic therapy including 119 patients receiving first-line therapy and 54 patients receiving second- or third-line therapy were included in this retrospective evaluation. Forty-two percent of patients had an elevated NLR at baseline. The following variables were predictive of survival: female gender (P = 0.044), epithelioid histologic subtype (P < 0.001), baseline white blood cell count less than 8.3 * 109/L (P = 0.008), baseline platelet count 400 * 109/L or less (P = 0.05), and NLR of 5 or less (P < 0.001). After multivariate analysis, histologic epithelioid subtype [hazard ratio (HR) = 2.0; 95% confidence interval (CI) = 1.3-2.9; P = 0.001], and NLR less than 5 (HR = 2.7; 95% CI = 1.8-3.9; P < 0.001) remained independent predictors. The 1-year survival rate was 60% versus 26%, whereas the 2-year survival rate was 34% versus 10% for NLR less than 5 and 5 or greater, respectively. In the separate analyses of chemotherapy-naive and previously treated patient groups, NLR was an independent predictor of survival in both groups. CONCLUSION: Our results indicate that NLR is an independent predictor of survival for patients with MM undergoing systemic therapy. PMID- 20956619 TI - Genotoxicity in filling station attendants exposed to petroleum hydrocarbons. AB - OBJECTIVES: Biomonitoring of exposure in workplaces has gained importance in evaluation of human health hazards. Since occupational exposure to petroleum hydrocarbons may have deleterious effects, genotoxicity risk among 200 fuel filling station attendants (FFSAs) and 200 matched controls was investigated. METHODS: The probable genetic damage was determined by comet assay and micronucleus test in peripheral blood lymphocytes (PBL) of study subjects. Air and blood sample analysis was done to estimate the benzene, toluene, and xylene (BTX) concentrations using gas chromatography-mass spectrometry. The effect of exposure on antioxidant enzymes was also studied by determining the levels of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and rate of lipid peroxidation measured as concentration of malondialdehyde (MDA) formed. RESULTS: The results of the present study suggest that there was a statistically significant increase in mean comet tail length (25.09 versus 10.27 MUm) and frequency of micronuclei in PBL (11.83 versus 5.83 per thousand; P < 0.05) of FFSAs as compared to controls. BTX concentrations were found to be significantly higher in ambient air of petrol pumps and FFSAs showed elevated levels of these compounds in their breathing zone in comparison to controls (P < 0.05). Blood BTX levels were found to be significantly enhanced in FFSAs. SOD and GPx were significantly decreased with an increased rate of CAT and MDA in FFSAs as compared to controls. CONCLUSIONS: The results of our study suggest that exposure to BTX has the potential to cause genetic changes in the exposed subjects. The data highlight the need to maintain safety measures and intervention to minimize exposure. PMID- 20956620 TI - Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma. AB - PURPOSE: Phase II clinical studies suggest that hypoxic modification with carbogen and nicotinamide (CON) may increase the efficacy of radiotherapy (RT). PATIENTS AND METHODS: Three hundred thirty-three patients with locally advanced bladder carcinoma were randomly assigned to RT alone versus RT with CON. A schedule of either 55 Gy in 20 fractions in 4 weeks or 64 Gy in 32 fractions in 6.5 weeks was used. The primary end point was cystoscopic control at 6 months (CC(6m)) and secondary end points were overall survival (OS), local relapse-free survival (RFS), urinary and rectal morbidity. RESULTS: CC(6m) was 81% for RT + CON and 76% for RT alone (P = .3); however, just more than half of patients underwent cystoscopy at that time. Three-year estimates of OS were 59% and 46% (P = .04) and 3-year estimates of RFS were 54% and 43% (P = .06) for RT + CON versus RT alone. Risk of death was 14% lower with RT + CON (P = .04). In multivariate comparison, RT + CON significantly reduced the risk of relapse (P = .05) and death (P = .03). There was no evidence that differences in late urinary or GI morbidity between treatment groups or between fractionation schedules were significant. CONCLUSION: RT + CON produced a small nonsignificant improvement in CC(6m). Differences in OS, risk of death, and local relapse were significantly in favor of RT + CON. Late morbidity was similar in both trial arms. Results indicate a benefit of adding CON to radical RT. PMID- 20956621 TI - Infrequent tumor initiative of the Children's Oncology Group: initial lessons learned and their impact on future plans. AB - The merger of the Pediatric Oncology Group, Children's Cancer Group, the Intergroup Rhabdomyosarcoma Study Group, and the National Wilms Tumor Study Group in 2000 offered the newly formed Children's Oncology Group (COG), an opportunity to study rare cancers that had not been the subject of organized evaluation within the context of a cooperative group. In 2002, the COG formed the rare tumor committee which is comprised of four subcommittees. This article details the experience of the infrequent tumor subcommittee for the period of 2002 to 2007. During the initial implementation of this strategy, we have observed low rates of registration within the COG registry and low levels of participation in open banking, biology, and first-line therapeutic studies. This initial experience has allowed us to develop alternative strategies to increase registration rates and clinical trial enrollments. It is hoped that these new plans will allow us to increase our ability to better understand the biology and improve the treatment outcome of young patients with infrequent cancers. Furthermore, our initial experience has demonstrated to us the potential power of expanded cooperation and collaboration at a global level. PMID- 20956622 TI - Dose escalation of lenalidomide in relapsed or refractory acute leukemias. AB - PURPOSE: Lenalidomide is effective in myeloma and low-risk myelodysplastic syndromes with deletion 5q. We report results of a phase I dose-escalation trial of lenalidomide in relapsed or refractory acute leukemia. PATIENTS AND METHODS: Thirty-one adults with acute myeloid leukemia (AML) and four adults with acute lymphoblastic leukemia (ALL) were enrolled. Lenalidomide was given orally at escalating doses of 25 to 75 mg daily on days 1 through 21 of 28-day cycles to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD), as well as to provide pharmacokinetic and preliminary efficacy data. RESULTS: Patients had a median age of 63 years (range, 22 to 79 years) and a median of two prior therapies (range, one to four therapies). The DLT was fatigue; 50 mg/d was the MTD. Infectious complications were frequent. Plasma lenalidomide concentration increased proportionally with dose. In AML, five (16%) of 31 patients achieved complete remission (CR); three of three patients with cytogenetic abnormalities achieved cytogenetic CR (none with deletion 5q). Response duration ranged from 5.6 to 14 months. All responses occurred in AML with low presenting WBC count. No patient with ALL responded. Two of four patients who received lenalidomide as initial therapy for AML relapse after allogeneic transplantation achieved durable CR after development of cutaneous graft-versus-host disease, without donor leukocyte infusion. CONCLUSION: Lenalidomide was safely escalated to 50 mg daily for 21 days, every 4 weeks, and was active with relatively low toxicity in patients with relapsed/refractory AML. Remissions achieved after transplantation suggest a possible immunomodulatory effect of lenalidomide, and results provide enthusiasm for further studies in AML, either alone or in combination with conventional agents or other immunotherapies. PMID- 20956624 TI - Nilotinib in a patient with postnecrotic liver cirrhosis related to imatinib. PMID- 20956623 TI - Prognostic factors in patients with metastatic germ cell tumors who experienced treatment failure with cisplatin-based first-line chemotherapy. AB - PURPOSE: To develop a prognostic model in patients with germ cell tumors (GCT) who experience treatment failure with cisplatin-based first-line chemotherapy. PATIENTS AND METHODS: Data from 1,984 patients with GCT who progressed after at least three cisplatin-based cycles and were treated with cisplatin-based conventional-dose or carboplatin-based high-dose salvage chemotherapy was retrospectively collected from 38 centers/groups worldwide. One thousand five hundred ninety-four (80%) of 1,984 eligible patients were randomly divided into a training set of 1,067 patients (67%) and a validation set of 527 patients (33%). Seminomas were set aside for posthoc analyses. Primary end point was the 2-year progression-free survival after salvage treatment. RESULTS: Overall, 990 patients (62%) relapsed and 604 patients (38%) remained relapse free. Histology, primary tumor location, response, and progression-free interval after first-line treatment, as well as levels of alpha fetoprotein, human chorionic gonadotrophin, and the presence of liver, bone, or brain metastases at salvage were identified as independent prognostic variables and used to build a prognostic model in the training set. Survival rates in the training and validation set were very similar. The estimated 2-year progression-free survival rates in patients not included in the training set was 75% in very low risk, 51% in low risk, 40% in intermediate risk, 26% in high risk, and only 6% in very high-risk patients. Due to missing values in individual variables, 69 patients could not reliably be classified into one of these categories. CONCLUSION: Prognostic variables are important in patients with GCT who experienced treatment failure with cisplatin based first-line chemotherapy and can be used to construct a prognostic model to guide salvage strategies. PMID- 20956626 TI - Allogeneic stem-cell transplantation in patients with Waldenstrom macroglobulinemia: report from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. AB - PURPOSE: Allogeneic stem-cell transplantation (alloSCT) is a curative therapeutic option for patients with low-grade lymphoid malignancies. Information regarding alloSCT in Waldenstrom macroglobulinemia (WM) is limited. This study presents the long-term outcome of a large series of patients with WM treated with alloSCT. PATIENTS AND METHODS: A total of 86 patients received allograft by using either myeloablative (MAC; n = 37) or reduced-intensity conditioning (RIC; n = 49) regimens and were retrospectively studied. The median age was 49 years (range, 23 to 64 years); 47 patients had received three or more previous lines of therapy, and eight patients had experienced failure on a prior autologous stem-cell transplantation. A total of 59 patients (68.6%) had chemotherapy-sensitive disease at the time of alloSCT. Median follow-up of the surviving patients was 50 months (7 to 142 months). RESULTS: Nonrelapse mortality (NRM) at 3 years was 33% for MAC and 23% for RIC. The overall response rate was 75.6%. The relapse rates (RRs) at 3 years were 11% for MAC and 25% for RIC. Fourteen patients received donor lymphocyte infusions (DLIs) for disease relapse. PFS and OS at 5 years were 56% and 62% for MAC and 49% and 64% for RIC, respectively. The occurrence of chronic graft-versus-host disease (cGVHD) was associated with a higher NRM and a lower RR, leading to an improvement in PFS. CONCLUSION: alloSCT can induce durable remissions in a selected population of young and heavily pretreated patients with WM. The low RR, the achievement of additional disease responses after DLIs, and the lower RR in patients developing cGVHD suggest the existence of a clinically relevant graft-versus-WM effect. PMID- 20956625 TI - Impact of overall treatment time on survival and local control in patients with anal cancer: a pooled data analysis of Radiation Therapy Oncology Group trials 87 04 and 98-11. AB - PURPOSE: To determine whether increased duration of radiation therapy (RT) and overall treatment (RX) time has a detrimental effect in anal cancer. PATIENTS AND METHODS: Data from Radiation Therapy Oncology Group (RTOG) 87-04 and RTOG 98-11 trials were combined to form three treatment groups: RT/fluorouracil (FU)/mitomycin (n = 472), RT/FU/cisplatin (n = 320), and RT/FU (n = 145). Cox proportional hazards models were used with the following variables: RT duration, RT intensity, RX duration, treatment group, age, sex, Karnofsky performance score (KPS), T stage, N stage, and RT dose. RESULTS: In the univariate analysis, there was a significant association between RX duration and colostomy failure (CF; hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.14; P = .02), local failure (HR = 1.52; 95% CI, 1.14 to 2.03; P = .005), locoregional failure (HR = 1.51; 95% CI, 1.15 to 1.98; P = .003), and time to failure (HR = 1.40; 95% CI, 1.10 to 1.79; P = .007). The significance of RX duration was maintained after adjusting for treatment group. In multivariate modeling there was a trend toward an association between RX duration and CF (HR = 1.57; 95% CI, 0.98 to 2.50; P = .06) and a statistically significant association with local failure (HR = 1.96; 95% CI, 1.34 to 2.87; P = .0006). Age, sex, KPS, T stage, N stage, and RT dose, but not RT duration, RT intensity, or RX duration, were found to be statistically significant predictors of OS and colostomy-free survival. CONCLUSION: Total treatment time, but not duration of radiation therapy, seems to have a detrimental effect on local failure and colostomy rate in anal cancer. Induction chemotherapy may contribute to local failure by increasing total treatment time. PMID- 20956627 TI - Clinical relapse in a patient with multiple myeloma presenting as an atrial plasmacytoma. PMID- 20956628 TI - The future of radiation oncology in the United States from 2010 to 2020: will supply keep pace with demand? AB - PURPOSE: Prior studies forecasted an incipient shortage of medical oncologists as a result of the aging US population, but the radiation oncology workforce has not been studied. Accordingly, we projected demand for radiation therapy and supply of radiation oncologists in 2010 and 2020 to determine whether a similar shortage may exist for this specialty. METHODS: Demand for radiation therapy in 2010 and 2020 was estimated by multiplying current radiation utilization rates (as calculated with Surveillance, Epidemiology, and End Results data) by population projections from the Census Bureau. Supply of radiation oncologists was projected using data from the American Board of Radiology inclusive of current radiation oncologists and active residents, accounting for variation in full-time equivalent status and expected survival by age and sex. RESULTS: Between 2010 and 2020, the total number of patients receiving radiation therapy during their initial treatment course is expected to increase by 22%, from 470,000 per year to 575,000 per year. In contrast, assuming that the current graduation rate of 140 residents per year remains constant, the number of full-time equivalent radiation oncologists is expected to increase by only 2%, from 3,943 to 4,022. The size of residency training classes for the years 2014 to 2019 would have to double to 280 residents per year in order for growth in supply of radiation oncologists to equal expected growth in demand. CONCLUSION: Demand for radiation therapy is expected to grow 10 times faster than supply between 2010 and 2020. Research is needed to explore strategies to enhance capacity to deliver quality radiation therapy despite increased patient loads. PMID- 20956629 TI - Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. AB - Renal impairment is a common complication of multiple myeloma (MM). The estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula is the recommended method for the assessment of renal function in patients with MM with stabilized serum creatinine. In acute renal injury, the RIFLE (risk, injury, failure, loss and end-stage kidney disease) and Acute Renal Injury Network criteria seem to be appropriate to define the severity of renal impairment. Novel criteria based on eGFR measurements are recommended for the definition of the reversibility of renal impairment. Rapid intervention to reverse renal dysfunction is critical for the management of these patients, especially for those with light chain cast nephropathy. Bortezomib with high-dose dexamethasone is considered as the treatment of choice for such patients. There is limited experience with thalidomide in patients with myeloma with renal impairment. Thus, thalidomide can be carefully administered, mainly in the context of well-designed clinical trials, to evaluate if it can improve the rapidity and probability of response that is produced by the combination with bortezomib and high-dose dexamethasone. Lenalidomide is effective in this setting and can reverse renal insufficiency in a significant subset of patients, when it is given at reduced doses, according to renal function. The role of plasma exchange in patients with suspected light chain cast nephropathy and renal impairment is controversial. High-dose melphalan (140 mg/m(2)) and autologous stem-cell transplantation should be limited to younger patients with chemosensitive disease. PMID- 20956630 TI - Small-cell carcinoma of the parotid gland. PMID- 20956631 TI - Factors associated with successful matching to dermatology residency programs by reapplicants and other applicants who previously graduated from medical school. AB - OBJECTIVES: To identify factors associated with and not associated with successful matching and matriculation (hereinafter "matching") to dermatology residency programs for applicants who previously graduated from medical school and to distinguish which factors are within applicants' control. DESIGN: Observational cohort study. SETTING: Six accredited academic dermatology residency training programs in the United States. PARTICIPANTS: A total of 221 residency applicants who previously graduated from medical school and who applied through standardized electronic application to 1 or more of the participating residency training programs. MAIN OUTCOME MEASURE: Matriculation to a dermatology residency program by August 2008 following the 2006 residency application period. RESULTS: Forty-six of 221 former medical school graduates included in this study matched to a dermatology residency program. Factors strongly associated with matching included United States Medical Licensing Examination Step 3 score; submission of letters written by dermatologists from institutions that train dermatology residents; completion of preliminary medicine internships rather than transitional or other internship types; listing of research experience; publishing of medical manuscripts; and completion of non-Accreditation Council for Graduate Medical Examination dermatology fellowships. Factors not associated with increased matching included volunteer work; PhD status; sex; number of posters or presentations at dermatology conferences; quality of journal publications; and first authorship. Most successful applicants limited personal statements to 1 page and did not mention previously failing to match. The study sample represented at least 86% of such nontraditional applicants who matched in 2006. CONCLUSIONS: For candidates seeking to match into dermatology residency programs after graduating from medical school, there are factors within their control that are associated with higher rates of match success. This study provides evidence to assist mentors who counsel such candidates. PMID- 20956632 TI - Immediate reduction in sweat secretion with electric current application in primary palmar hyperhidrosis. PMID- 20956633 TI - The performance of MelaFind: a prospective multicenter study. AB - OBJECTIVE: To demonstrate the safety and effectiveness of MelaFind, a noninvasive and objective computer-vision system designed to aid in detection of early pigmented cutaneous melanoma. DESIGN: A prospective, multicenter, blinded study. The diagnostic performance of MelaFind and of study clinicians was evaluated using the histologic reference standard. Standard images and patient information for a subset of 50 randomly selected lesions (25 melanomas) were used in a reader study of 39 independent dermatologists to estimate clinicians' biopsy sensitivity to melanoma. SETTING: Three academic and 4 community practices in the United States with expertise in management of pigmented skin lesions. PATIENTS: A total of 1383 patients with 1831 lesions enrolled from January 2007 to July 2008; 1632 lesions (including 127 melanomas-45% in situ-with median Breslow thickness of invasive lesions, 0.36 mm) were eligible and evaluable for the study end points. MAIN OUTCOME MEASURES: Sensitivity of MelaFind; specificities and biopsy ratios for MelaFind and the study investigators; and biopsy sensitivities of independent dermatologists in the reader study. RESULTS: The measured sensitivity of MelaFind was 98.4% (125 of 127 melanomas) with a 95% lower confidence bound at 95.6% and a biopsy ratio of 10.8:1; the average biopsy sensitivity of dermatologists was 78% in the reader study. Including borderline lesions (high-grade dysplastic nevi, atypical melanocytic proliferations, or hyperplasias), MelaFind's sensitivity was 98.3% (172 of 175), with a biopsy ratio of 7.6:1. On lesions biopsied mostly to rule out melanoma, MelaFind's average specificity (9.9%) was superior to that of clinicians (3.7%) (P=.02). CONCLUSION: MelaFind is a safe and effective tool to assist in the evaluation of pigmented skin lesions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00434057. PMID- 20956634 TI - Multiple facial milia in patients with Loeys-Dietz syndrome. AB - BACKGROUND: Loeys-Dietz syndrome (LDS) results from mutations in the TGFBR1 or TGFBR2 genes and is known to cause aggressive cardiovascular disease, including aortic aneurysms and dissections at an early age. Currently, craniofacial, skeletal, and cardiovascular findings play an important role in early recognition of the disease. While many patients do have recognizable cutaneous features of LDS, little information about associated skin findings has been reported. OBSERVATIONS: Four unrelated patients with LDS due to a mutation in the TGFBR2 gene were observed to have numerous facial milia. All 4 patients reported that the milia had been present since early childhood and had increased in number with time. In some cases, affected relatives were reported to have similar findings. CONCLUSIONS: To our knowledge, the association of LDS and facial milia has not been previously reported. Recognition of LDS is important because the aggressive aortic and arterial disease warrants early surgical therapy. Facial milia and other cutaneous findings may possibly differentiate LDS from Marfan syndrome and other related disorders, thereby facilitating early diagnosis. Interestingly, each of the 4 patients with LDS and facial milia had a mutation in TGFBR2 despite widespread variability in other features of the disease. PMID- 20956635 TI - A randomized comparison of methods of selecting narrowband UV-B starting dose to treat chronic psoriasis. AB - OBJECTIVES: To compare narrowband UV-B (TL-01 lamp) phototherapy for psoriasis with individual patient starting doses based on minimal erythemal dose (MED) determination vs a standard fixed starting dose and to compare the efficacy of 70% of MED vs 50% of MED starting dose regimens. DESIGN: Single-center, randomized, double-blind, clinical trial. SETTING: Department of Dermatology, Ninewells Hospital and Medical School, Dundee, Scotland. PATIENTS: A total of 210 adult patients (207 of skin phototypes I to III) referred for narrowband UV-B to treat chronic psoriasis. The study was designed to have 90% power to detect a difference of 3 or more treatments to clearance and/or minimal residual activity (MRA) between groups. INTERVENTIONS: Narrowband UV-B phototherapy was given according to 3 standard regimens, differing only by starting dose selection method. The randomly allocated starting doses were (1) a fixed starting dose, (2) 70% of individual MED, and (3) 50% of individual MED. All patients were MED tested to ensure blinding and for safety reasons. MAIN OUTCOME MEASURES: The number of treatments to clearance and/or MRA of psoriasis was the primary efficacy outcome measure, with changes in Psoriasis Area and Severity Index and Psoriasis Disability Index scores as secondary measures. Adverse effects were recorded. RESULTS: There were no significant differences in the number of treatments to clearance and/or MRA across all 3 groups or in the percentages achieving clearance in each group. More uncomfortable erythemas occurred in the 50% of MED starting dose group (39%) than in the 70% of MED starting dose group (24%) or the fixed starting dose group (24%) (P=.07). CONCLUSIONS: The methods of determining the starting dose in this predominantly skin phototype I and II population, treated 3 times weekly, with a 20% followed by 10% incremental reduction in dose, did not significantly influence the effectiveness of treatment. Had there been a clinically important difference in efficacy, we would have expected to identify this. Thus, basing starting dose on individual MED assessments may not influence the treatment's efficacy in a skin phototype I to III population, although it remains important for patient safety. It remains possible that in populations containing individuals with a broader range of erythemal sensitivity, basing the starting dose on MED testing could have an important impact on treatment effectiveness. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN84614024. PMID- 20956636 TI - Chondrodermatitis nodularis helicis successfully treated with photodynamic therapy. PMID- 20956637 TI - Acral melanocytic nevi: prevalence and distribution of gross morphologic features in white and black adults. AB - OBJECTIVE: To determine prevalence and morphologic features of acral melanocytic nevi in white and black adults. DESIGN: Point prevalence survey. SETTING: Outpatient dermatology clinic. PATIENTS: Convenience sample of subjects 18 years or older. MAIN OUTCOME MEASURES: Prevalence and morphologic features based on ethnicity, sex, and age. RESULTS: Palmar or plantar nevi were detected in 42.0% of blacks (50 of 119) vs 23.0% of whites (79 of 343) (P < .001). Palmar or plantar nevi of 6-mm diameter or larger were detected in 3.4% of blacks (4 of 119) vs 0.6% of whites (2 of 343) (P = .04). Diffusely black acral nevi were uncommon in whites (0 of 343) and blacks (1 of 119). The prevalence of palmar or plantar nevi increased directly with degree of skin pigmentation (P < .001). In whites, this prevalence was greater in women (27.1%, 51 of 188) than in men (18.1%, 28 of 155) (P = .047); in subjects younger than 50 years (30.8%, 57 of 185) than in those 50 years or older (13.9%, 22 of 158) (P < .001); in subjects with a history of atypical nevus removal than in those without (odds ratio [OR], 3.6; 95% confidence interval [CI], 1.9-6.9); in those with at least 1 extant atypical nevus than in those without (OR, 3.2; 95% CI, 1.7-6.0); and in those with at least 20 nevi of 2-mm diameter or larger than in those without (OR, 3.0; 95% CI, 1.6-5.6). CONCLUSIONS: Acral nevi appear to be associated with ethnicity, pigmentation, age, and cutaneous melanoma (CM) risk factors. While relatively large and/or very darkly pigmented acral nevi appear to be more common in blacks than in whites, diffusely black acral nevi are uncommon in both groups. These findings are relevant to the assessment of pigmented lesions in the differential diagnosis of acral CM. PMID- 20956639 TI - The influence of age and sex on reasons for seeking and expected benefits of skin cancer screening. AB - OBJECTIVE: To determine the influence of age and sex on why individuals seek skin cancer screening and their understanding of its benefits. DESIGN: Voluntary survey. SETTING: Academic dermatology department. PARTICIPANTS: Individuals 18 years or older being seen for skin cancer screening from May to October 2009. MAIN OUTCOME MEASURES: Patients' reasons for seeking and perceived benefits of skin cancer screening and understanding of screening recommendations. RESULTS: Of 546 patients, 487 eligible individuals (89.2%) participated in the survey. Most (80.6%) sought screening without a particular lesion of concern. Women were more likely than men to present with a lesion they believed could be skin cancer (24.6% vs 11.9%; P < .001) or because they were concerned about previous sun exposure (34.3% vs 23.8%; P < .05). Individuals younger than 50 years were more likely than older patients to seek screening because of a family history of melanoma (30% vs 18.9%; P < .01). Men 50 years or older were more likely than other patients to seek skin cancer screening because of a previous skin cancer diagnosis (64.6% vs 40.8%; P < .001). Most patients believed that screening reduces the risk of death from skin cancer and prevents skin cancer. There was no consensus among patients regarding the frequency with which healthy adults should be screened for skin cancer. CONCLUSIONS: There is a need for better educational campaigns with specific recommendation for who should be screened for skin cancer. Men 50 years or older, the group at highest risk for death from melanoma, are most likely to seek screening only after being diagnosed as having a skin cancer. PMID- 20956640 TI - Overscreening and underscreening for melanoma: comment on "the influence of age and sex on reasons for seeking and expected benefits of skin cancer screening". PMID- 20956642 TI - Subacute cutaneous lupus erythematosus exacerbated or induced by chemotherapy. AB - BACKGROUND: Subacute cutaneous lupus erythematosus (SCLE), characterized by nonscarring, photodistributed, annular or papulosquamous plaques, is occasionally induced by medication. It has been strongly associated with antihypertensive medications and terbinafine hydrochloride. OBSERVATION: We describe 3 women with breast cancer who developed SCLE-like eruptions after being administered doxorubicin hydrochloride and cyclophosphamide. Biopsy specimens of all 3 patients demonstrated an interface dermatitis. Treatment consisted of topical and/or systemic corticosteroids, photoprotection, and switching the chemotherapeutic regimens. CONCLUSIONS: Based on clinicopathologic correlation and timing of chemotherapy exposure, the patients were believed to have drug induced SCLE. Although cutaneous eruption, pruritus, and photosensitivity are known adverse effects of doxorubicin, to our knowledge there has been only 1 previously reported case of doxorubicin-induced SCLE. PMID- 20956641 TI - High prevalence of vitamin D deficiency in patients with basal cell nevus syndrome. AB - OBJECTIVES: To evaluate vitamin D status in patients with basal cell nevus syndrome (BCNS) who practice photoprotection because of their genetic predisposition to skin cancer and to determine risk factors for deficiency. DESIGN: Retrospective cohort study. SETTING: Academic medical centers. PATIENTS: Forty-one ambulatory patients with BCNS who participated in a 2-year chemoprevention clinical trial. Population-based controls (n = 360) were selected and matched by age, sex, Fitzpatrick skin type, and season/geography. MAIN OUTCOME MEASURES: Levels of 25-hydroxyvitamin D (25[OH]D) and vitamin D deficiency (defined as a 25[OH]D level of <=20 ng/mL). RESULTS: Twenty-three patients with BCNS (56%) were vitamin D deficient. Patients with BCNS had mean 25(OH)D levels below those of the general population (-3 ng/mL; P = .02) and were 3 times more likely to be vitamin D deficient (56% vs 18%; P < .001). Levels of 25(OH)D were lower in patients who were overweight (-3.0 ng/mL; P = .04) and who had blood collected in the winter compared with the summer (-7.1 ng/mL; P < .001). CONCLUSION: Patients with BCNS may be at increased risk for vitamin D deficiency, depending on their adherence to photoprotection practices. PMID- 20956643 TI - Circulating benign nevus cells detected by ISET technique: warning for melanoma molecular diagnosis. AB - BACKGROUND: The notion that only malignant melanoma cells circulate and diffuse is shared by oncologists and pathologists. Isolation by size of epithelial tumor cells (ISET) allows the identification of circulating tumor cells by filtration according to size. OBSERVATIONS: During a study of identification of circulating melanoma cells using ISET, blood samples from a 69-year-old man with an atypical melanocytic lesion on his back were evaluated. Binucleated and multinucleated cells that fulfilled the criteria for circulating tumor cells were found. The morphological features were similar to those of the excised skin tissue specimen, and the patient was subsequently diagnosed as having a congenital melanocytic nevus. BRAF (V600E)-mutated DNA was detected in both plasma and formalin-fixed tissue specimens, and the blood samples demonstrated an increase in tyrosinase messenger RNA levels. CONCLUSION: The finding that benign nevus cells may circulate in blood brings into question the value of tyrosinase or other melanocytic markers as a molecular surrogate for circulating melanoma cells. PMID- 20956645 TI - Pemphigus and osteoporosis: a case-control study. AB - OBJECTIVE: To investigate the association between pemphigus and osteoporosis. DESIGN: Case-control study. SETTING: A large health care provider organization in Israel. PARTICIPANTS: Patients with pemphigus older than 20 years (hereinafter, pemphigus patients) were compared with a sample of age- and sex-matched controls. Interventions Data retrieval from a large community-based medical database regarding health-related lifestyles, comorbidities, use of medications, bone mineral density scans, and drugs for osteoporosis. MAIN OUTCOME MEASURES: The prevalence of osteoporosis in patients and controls, use of bone mineral density scans, and drugs for osteoporosis. RESULTS: The study included 255 pemphigus patients and 509 controls older than 20 years. Osteoporosis was diagnosed among 40.4% of pemphigus patients compared with 6.5% of controls (P < .001; odds ratio [OR], 9.77; 95% confidence interval [CI], 6.34-15.10). After controlling for confounders, including age, sex, and duration of glucocorticosteroid therapy and proton pump inhibitor therapy, the associations with osteoporosis persisted (OR, 4.27; 95% CI, 2.44-7.47; P < .001). Similar results were obtained when using cumulative glucocorticosteroid dose. Only 73 pemphigus patients with osteoporosis (70.9%) had undergone a bone mineral density test within the past 10 years. While most pemphigus patients with osteoporosis purchased medications for osteoporosis, including calcium (95.1% of patients), cholecalciferol (89.3%), bisphosphonates (90.3%), or raloxiphene (8.8%), the duration of therapy was short. CONCLUSIONS: We found an association between pemphigus and osteoporosis, which persisted after controlling for glucocorticosteroid use. Monitoring and treatment of osteoporosis in pemphigus patients was suboptimal in this study. PMID- 20956646 TI - Underutilization of prophylaxis for osteoporosis: comment on "pemphigus and osteoporosis". PMID- 20956647 TI - Pityriasis versicolor: a systematic review of interventions. AB - OBJECTIVE: To determine the efficacy of topical or systemic agents in the treatment and prevention of pityriasis versicolor. DESIGN: Systematic review and meta-analysis. DATA SOURCES: The Cochrane Skin Group Specialized Register (to June 2008), Cochrane Central Register of Controlled Trials, MEDLINE (1950 to June 2008), EMBASE (1974 to June 2008), LILACS (to March 2009), the gray literature, and sources for registered trials to November 2008. Reference lists of all retrieved trials and review articles were checked for additional trials. STUDY SELECTION: Controlled trials that examined therapies used in children or adults with a clinical or microscopic diagnosis of pityriasis versicolor. DATA EXTRACTION: The primary outcome measure included a negative result from mycological evaluation of participants with direct microscopy using potassium hydroxide smear. The secondary outcome measures were findings from Wood's light examination and a negative clinical evaluation result, with disappearance of visual signs (except pigmentary defects) and symptoms. DATA SYNTHESIS: Results of treatment and prevention of pityriasis versicolor infection in 8327 participants in 93 controlled trials were examined. Overall, trials investigating the efficacy of therapeutic and prophylactic treatments for pityriasis versicolor are poorly reported and may be of low quality. Most trials did not adequately report the methods of randomization, concealment of allocation, and blinding, and many did not use intention-to-treat analysis. Most topical treatments used to treat pityriasis versicolor are effective compared with placebo, with numbers needed to treat of 1 to 3. Data suggest that longer durations of treatment and higher concentrations of active agents produce greater cure rates. CONCLUSIONS: Most topical and systemic treatments used for pityriasis versicolor are effective compared with placebo. Randomized controlled clinical trials are needed to establish relative efficacy of topical and systemic agents used for treatment and prevention of pityriasis versicolor. PMID- 20956648 TI - Failure to use available evidence to guide tinea versicolor treatment: comment on "pityriasis versicolor". PMID- 20956649 TI - Efficacy and safety of finasteride therapy for androgenetic alopecia: a systematic review. AB - CONTEXT: Androgenetic alopecia is the most common form of alopecia in men. OBJECTIVE: To determine the efficacy and safety of finasteride therapy for patients with androgenetic alopecia. DATA SOURCES: MEDLINE, EMBASE, CINAHL, Cochrane Registers, and LILACS were searched for randomized controlled trials reported in any language that evaluated the efficacy and safety of finasteride therapy in comparison to treatment with placebo in adults with androgenetic alopecia. STUDY SELECTION AND DATA EXTRACTION: Two reviewers independently evaluated eligibility and collected the data, including assessment of methodological quality (Jadad score). Outcome measures included patient self assessment, hair count, investigator clinical assessment, global photographic assessment, and adverse effects at short term (<=12 months) and long term (>=24 months). Heterogeneity was explored by testing a priori hypotheses. DATA SYNTHESIS: Twelve studies fulfilled the eligibility criteria (3927 male patients), 10 of which demonstrated a Jadad score of 3 or more. The proportion of patients reporting an improvement in scalp hair was greater with finasteride therapy than with placebo treatment in the short term (relative risk [RR], 1.81 [95% confidence interval (CI), 1.42-2.32]; I2, 64%) and in the long term (RR, 1.71 [95% CI, 1.15-2.53]; I2, 16%); both results were considered to have moderate quality evidence. The number needed to treat for 1 patient to perceive himself as improved was 5.6 (95% CI, 4.6-7.0) in the short term and 3.4 (95% CI, 2.6-5.1) in the long term. Moderate-quality evidence suggested that finasteride therapy increased the mean hair count from baseline in comparison to placebo treatment, expressed as a percentage of the initial count in each individual, at short term (mean difference [MD], 9.42% [95% CI, 7.95%-10.90%]; I2, 50%) and at long term (MD, 24.3% [95% CI, 17.92%-30.60%]; I2, 0%). Also, the proportion of patients reported as improved by investigator assessment was greater in the short term (RR, 1.80 [95% CI, 1.43-2.26]; number needed to treat, 3.7 [95% CI, 3.2-4.3]; I2, 82%) (moderate-quality evidence). Moderate-quality evidence suggested an increase in erectile dysfunction (RR, 2.22 [95% CI, 1.03-4.78]; I2, 1%; number needed to harm, 82.1 [95% CI, 56-231]) and a possible increase in the risk of any sexual disturbances (RR, 1.39 [95% CI, 0.99-1.95]; I2, 0%). The risk of discontinuing treatment because of sexual adverse effects was similar to that of placebo (RR, 0.88 [95% CI, 0.51-1.49]; I2, 5%) (moderate-quality evidence). CONCLUSION: Moderate-quality evidence suggests that daily use of oral finasteride increases hair count and improves patient and investigator assessment of hair appearance, while increasing the risk of sexual dysfunction. PMID- 20956650 TI - Is etanercept safe for treating plaque psoriasis in a patient with chronic hepatitis C virus infection? PMID- 20956651 TI - ISET device: a useful tool to answer some questions about the biologic behavior of melanocytic nevus cells. PMID- 20956652 TI - Gap-based education, changing competence, and dermatology simulation: a glimpse at the future of CME. PMID- 20956653 TI - Introducing the practice gap commentary section. PMID- 20956654 TI - Evidence-based medicine, the research-practice gap, and biases in medical and surgical decision making in dermatology. AB - The objectives of this article are to promote a better understanding of a group of biases that influence therapeutic decision making by physicians/dermatologists and to raise the awareness that these biases contribute to a research-practice gap that has an impact on physicians and treatment solutions. The literature included a wide range of peer-reviewed articles dealing with biases in decision making, evidence-based medicine, randomized controlled clinical trials, and the research-practice gap. Bias against new therapies, bias in favor of indirect harm or omission, and bias against change when multiple new choices are offered may unconsciously affect therapeutic decision making. Although there is no comprehensive understanding or theory as to how choices are made by physicians, recognition of certain cognition patterns and their associated biases will help narrow the research-practice gap and optimize decision making regarding therapeutic choices. PMID- 20956655 TI - Identifying biases: comment on "evidence-based medicine, the research-practice gap, and biases in medical and surgical decision making in dermatology". PMID- 20956656 TI - Fine wrinkling of the thighs and axillae--quiz case. Middermal elastolysis. PMID- 20956657 TI - Asymptomatic tumors in a 64-year-old man--quiz case. CD4(+)/CD56(+) hematodermic neoplasm. PMID- 20956658 TI - Adult-onset unilateral segmental vascular patches--quiz case. Unilateral nevoid telangiectasia. PMID- 20956659 TI - Lower extremity purpura in a woman with psychosis--quiz case. Scurvy. PMID- 20956660 TI - Medical student detection of melanoma: clinical skills. PMID- 20956661 TI - Lack of knowledge of type of skin cancer diagnosis. PMID- 20956662 TI - Effect of oral acetylsalicylic acid on burning caused by tacrolimus ointment in patients with atopic dermatitis. PMID- 20956663 TI - Inadequate biopsy technique and specimen size: an alarming trend that compromises patient care and an appeal to our clinical colleagues. PMID- 20956664 TI - Practice gaps--performing inadequate biopsy: comment on "inadequate biopsy technique and specimen size". PMID- 20956665 TI - Why the first step should be abandoned! PMID- 20956666 TI - Adherence to treatment: still the forgotten variable. PMID- 20956667 TI - Teaching dermatology using 3-dimensional virtual reality. PMID- 20956668 TI - Treatment of sebaceous adenoma with topical photodynamic therapy. PMID- 20956670 TI - A tooth for an eye: cicatricial pemphigoid and the osteo-odonto-keratoprosthesis. PMID- 20956669 TI - Moist toilet paper: allergy to the nonhalogenated derivative methylisothiazolinone preservative alone. PMID- 20956671 TI - Madura foot caused by Actinomadura madurae in a pregnant woman. PMID- 20956672 TI - Docetaxel recall phenomenon at the site of previous drug extravasation. PMID- 20956673 TI - Successful treatment of Morgellons disease with pimozide therapy. PMID- 20956674 TI - Disseminated superficial porokeratosis secondary to immunosuppression induced by etanercept for extensive psoriasis. PMID- 20956675 TI - Mexican beer dermatitis: a unique variant of lime phytophotodermatitis attributable to contemporary beer-drinking practices. PMID- 20956676 TI - Toxic effects of fluorouracil cream ingestion on dogs and cats. PMID- 20956677 TI - Regression of cutaneous warts in a patient with WILD syndrome following recombinant quadrivalent human papillomavirus vaccination. PMID- 20956678 TI - Dermoscopy of longitudinal leukonychia in Hailey-Hailey disease. PMID- 20956679 TI - Residency training at a crossroads: duty-hour standards 2010. AB - In 2003, the Accreditation Council for Graduate Medical Education (ACGME) implemented a single duty-hour standard nationwide. The evidence to date suggests that this neither improved nor worsened patient outcomes. In June 2010, the ACGME proposed a new set of duty-hour standards for implementation in July 2011. The main disadvantage of this approach is that there is no ability to determine whether different standards would have worked better to reduce resident fatigue while improving patient safety. Many unanswered questions remain about how to design duty-hour standards, but relatively little evidence exists. In addition, the same approach may not work in all specialties and all hospitals. A more flexible, dynamic policy that emphasizes ongoing testing and evaluation would be more likely to achieve improvements in clinical and educational outcomes. PMID- 20956680 TI - Taylorized medicine. PMID- 20956681 TI - Obesity in menopausal women: more than you might think. PMID- 20956682 TI - Stratford 2010 relived. PMID- 20956683 TI - Effects of ovariectomy and estrogen replacement therapy on visceral adipose tissue and serum adiponectin levels in rats. AB - BACKGROUND: Excess visceral adipose tissue accumulation after menopause is closely associated with decreased insulin sensitivity and adiponectin levels. OBJECTIVE: The purpose of this study was to determine the effect of ovariectomy and estrogen replacement on visceral fat and serum adiponectin levels in ovariectomized (OVX) rats. METHOD: Forty 11-week-old female Wistar rats were divided into the four following groups (n = 10 rats per group): sham-operated control (SHAM); sedentary OVX (OVX-SED); OVX with estrogen replacement (OVX-ER); and OVX with sesame oil treatment (OVX-C). Rats in OVX-ER and OVX-C groups received 17beta-estradiol valerate (30 ug/kg, subcutaneously) and sesame oil as vehicle, five days a week, respectively. All animals were sacrificed after eight weeks of intervention. RESULTS: Ovariectomy after eight weeks increased body weight and visceral fat (P < 0.05) in OVX-SED and OVX-C groups compared with SHAM rats with no change in plasma adiponectin levels. Estrogen replacement in OVX animals decreased body weight (13.4%, P < 0.05) and visceral fat (10.4%). Although they were not statistically significant, adiponectin, insulin sensitivity and lipid profile of OVX rats were ameliorated with estrogen treatment. CONCLUSION: We conclude that ovarian hormone withdrawal leads to higher body weight and visceral adipose tissue in rats, but surprisingly does not change adiponectin levels. Although a substantial decrease in body weight was achieved by estrogen replacement therapy in OVX animals, the beneficial metabolic effects of weight loss seems to be only mechanical, having a tendency to improve insulin sensitivity without elevating adiponectin production. PMID- 20956684 TI - Obesity is related to increased menopausal symptoms among Spanish women. AB - OBJECTIVE: To assess the metabolic syndrome (METS) and its components in postmenopausal women using updated diagnostic criteria and explore their relation to menopausal symptom severity. METHOD: Medical records of the first visit of 574 postmenopausal Caucasian Spanish women attending a menopause clinic were retrospectively reviewed. Recorded information included general demographic data, type of menopause, menopausal symptom intensity (Kupperman index) and baseline hormonal and metabolic parameters. METS was established if three or more of the following criteria were met: body mass index (BMI) >28.8 kg/m(2), fasting glycaemia >=100 mg/dL, high-density lipoprotein cholesterol (HDL-C) <50 mg/dL, triglycerides >=150 mg/dL and blood pressure >=130/85 mmHg. RESULTS: Mean +/- SD age of the whole cohort was 49.9 +/- 6.1 years, 66% had natural menopause and 38.9% were obese. In all, 23.1% met diagnostic criteria for METS who were significantly older and displayed higher rates of being married, obesity and abnormal glucose, triglyceride, HDL-C, low-density lipoprotein cholesterol and blood pressure values, when compared with those without the syndrome. The mean Kupperman index score for the whole sample was 26.4+/-10.6, with 73.8% displaying moderate to severe scores (20 or more). Logistic regression analysis determined that obesity and marriage status were independent risk factors related to more severe menopausal symptoms (Kupperman index scores of 20 or more). CONCLUSION: Although METS was observed in a lower frequency than previous reports, obesity was associated with more severe menopausal symptoms among postmenopausal Spanish women. PMID- 20956685 TI - Lowering the age at menarche and risk of early menarche in a population of Spanish postmenopausal women during the past two decades. AB - AIM: The purpose of this study is to confirm in our population the decreasing secular trend in the age of menarche (AAM) observed in other European countries. Another aim is to investigate the association between early menarche and breast cancer, metabolic disorders risk or early menopause. MATERIALS AND METHODS: We conducted a nationwide population-based study of 1980 Caucasoid Spanish postmenopausal women from 2003 to 2006 to investigate the AAM, the duration of the fertile period and the relation of early menarche with breast cancer and some metabolic disorders. RESULTS: Regression analysis of AAM demonstrates a trend towards the younger AAM in our population during the past decades (P > 0.001). Parallel to this decrease we observe a significant increase in the fertility period and the height of our population (P < 0.001). In the women with AAM less than 11 years, there is an increased risk of hypercholesterolaemia, being overweight and obesity. However, early menarche does not raise the risk of adult onset diabetes, hypertension or breast cancer. CONCLUSIONS: These data indicate a decreasing secular trend of AAM in a Spanish population in the last decades. Furthermore, hypercholesterolaemia and obesity, but not breast cancer, appears to be influenced by younger AAM. Only women who have their menarche at the age of nine years or less are more likely to have an earlier menopause. PMID- 20956686 TI - A study of new referrals to a menopause clinic and their initial outcomes: how can we improve the service we provide? AB - This retrospective case-note study was performed to examine the ways in which an already established menopause clinic could improve service to its patients. The management of 151 patients was examined. Most were referred by their general practitioner and the most common reason for referral was to seek an alternative to hormone replacement therapy (HRT). The consultant saw 17% of the patients, and with the trainee was most likely to discharge the patient. Better information on alternatives to HRT, more consultant input and better use of telephone consultation for follow-up would enhance the service provided by the menopause clinic. PMID- 20956687 TI - Vulval disease in the postmenopausal patient: a guide to current management. AB - In spite of overwhelming evidence that vulvovaginal symptoms plague up to 46% of menopausal and perimenopausal women, and that there persists a reluctance to seek help among patients, adequate vulval and sexual histories are still woefully rare in general gynaecology clinics. This review aims to present the key points of an effective vulval history and an overview of the accepted current management of vulval disease postmenopause, in order that our patients feel encouraged to present with their problems. PMID- 20956688 TI - Tissue-selective agents: selective estrogen receptor modulators and the tissue selective estrogen complex. AB - Menopause has been associated with vasomotor symptoms, vulvar-vaginal atrophy and osteoporosis. One of the goals in exploring the potential of selective estrogen receptor modulators (SERMs) was to determine if they could prevent fractures, reduce menopausal symptoms and treat vaginal atrophy, while being neutral or protective on the uterus, breast and cardiovascular system. However, no SERM to date has achieved this goal. More recently, the idea of pairing a SERM with estrogen(s), known as a tissue-selective estrogen complex (TSEC), has been studied in postmenopausal women. A TSEC combines the complementary tissue selective activities of a SERM and estrogen(s), in an attempt to gain the benefits of each with better overall tolerability. The Selective estrogen Menopause And Response to Therapy (SMART) trials were multicentre, randomized, double-blind, placebo- and active-controlled phase 3 studies evaluating the safety and efficacy of the SERM, bazedoxifene (BZA) paired with conjugated estrogens (CEs) in healthy postmenopausal women. In the first SMART trial, BZA/CE protected the endometrium from estrogenic stimulation, relieved hot flushes and maintained bone mass, with rates of amenorrhea, breast pain and overall adverse events similar to those with placebo in more than 3400 women over two years. BZA 20 mg was the lowest effective dose of BZA in BZA/CE to protect the endometrium and maintain bone mass when paired with CE 0.625 mg and CE 0.45 mg. In SMART-2, these BZA/CE doses significantly reduced the frequency and severity of hot flushes over 12 weeks. Collectively, these data support the TSEC containing BZA/CE as a new paradigm for treating menopausal symptoms and preventing osteoporosis while protecting the endometrium from unopposed estrogenic stimulation. PMID- 20956689 TI - Practice observed. PMID- 20956690 TI - Post-reproductive health and lifestyle consultations. PMID- 20956691 TI - Summaries for patients. Invasive dental treatment and risk for vascular events. PMID- 20956692 TI - Summaries for patients. Can patients with diabetes help each other get better? PMID- 20956693 TI - Summaries for patients. Incidence of hospital admissions with multidrug-resistant and extensively drug-resistant tuberculosis among South African health care workers. PMID- 20956694 TI - ACP Journal Club. Review: Vibration testing and monofilament testing are most accurate for diagnosing large-fiber peripheral neuropathy in diabetes. PMID- 20956695 TI - ACP Journal Club. Individual and combined confrontation visual field tests performed poorly as a screen for visual field abnormalities. PMID- 20956696 TI - ACP Journal Club. Concurrent PPIs and antibiotics for incident C. difficile infection were associated with increased risk for recurrent infection. PMID- 20956697 TI - ACP Journal Club. A 9-factor score predicted 2-year risk for bleeding in outpatients with, or at high risk for, atherothrombosis. PMID- 20956698 TI - ACP Journal Club. Benazepril plus amlodipine reduced CV events more than benazepril plus hydrochlorothiazide in hypertension with or without diabetes. PMID- 20956699 TI - ACP Journal Club. Prior intensive insulin treatment reduced long-term risk for peripheral neuropathy in type 1 diabetes. PMID- 20956700 TI - ACP Journal Club. Once-only flexible sigmoidoscopy screening reduced colorectal cancer incidence and mortality. PMID- 20956701 TI - ACP Journal Club. Colorectal cancer screening with fecal immunochemical testing had higher adherence than screening with guaiac-based FOBT. PMID- 20956702 TI - ACP Journal Club. Early use of transjugular intrahepatic portosystemic shunts improved outcomes in patients with cirrhosis and variceal bleeding. PMID- 20956703 TI - ACP Journal Club. Aspirin alone or combined with nadroparin did not increase live birth rates in women with unexplained recurrent miscarriage. PMID- 20956704 TI - ACP Journal Club. Review: Evidence for the effectiveness of prophylactic drugs for tension-type headache in adults is limited. PMID- 20956705 TI - ACP Journal Club. CT coronary angiography was more accurate than stress testing for diagnosing CAD, especially in patients at intermediate risk. PMID- 20956706 TI - Invasive dental treatment and risk for vascular events: a self-controlled case series. AB - BACKGROUND: Treatment of periodontal disease may reduce cardiovascular risk in the longer term, but studies have suggested a link among dental procedures, acute inflammation, and endothelial dysfunction. However, whether such acute inflammatory effects translate into a short-lived increased risk for vascular events is not known. OBJECTIVE: To investigate whether invasive dental treatment transiently increases the risk for vascular events. DESIGN: Self-controlled case series. SETTING: Data came from the U.S. Medicaid claims database. PATIENTS: All persons exposed to invasive dental treatment with a primary hospital discharge diagnosis of ischemic stroke (n = 650) or myocardial infarction (n = 525) from 2002 to 2006. MEASUREMENTS: The incidence of ischemic stroke and myocardial infarction in periods immediately after invasive dental treatment was compared with the incidence in all other observed time periods. Incidence ratios and 95% CIs were calculated. RESULTS: The rate of vascular events significantly increased in the first 4 weeks after invasive dental treatment (incidence ratio, 1.50 [95% CI, 1.09 to 2.06]) and gradually returned to the baseline rate within 6 months. The positive association remained after exclusion of persons with diabetes, hypertension, or coronary artery disease or persons with prescriptions for antiplatelet or salicylate drugs before treatment. LIMITATIONS: Power to examine the effects of invasive dental treatment on stroke and myocardial infarction separately was limited because of the low frequency of invasive dental procedures. Lack of information about use of over-the-counter drugs limited the ability to assess confounding by possible withholding of antiplatelet or salicylate drugs before invasive dental treatment or by the use of nonsteroidal anti-inflammatory drugs after treatment. CONCLUSION: Invasive dental treatment may be associated with a transient increase in the risk for vascular events. However, the absolute risks are minimal, and the long-term benefits on vascular health will probably outweigh the short-lived adverse effects. PMID- 20956707 TI - Diabetes control with reciprocal peer support versus nurse care management: a randomized trial. AB - BACKGROUND: Resource barriers complicate diabetes care management. Support from peers may help patients manage their diabetes. OBJECTIVE: To compare a reciprocal peer-support (RPS) program with nurse care management (NCM). DESIGN: Randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00320112) SETTING: 2 U.S. Department of Veterans Affairs health care facilities. PATIENTS: 244 men with hemoglobin A(1c) (HbA(1c)) levels greater than 7.5% during the previous 6 months. MEASUREMENTS: The primary outcome was 6-month change in HbA(1c) level. Secondary outcomes were changes in insulin therapy; blood pressure; and patient reports of medication adherence, diabetes-related support, and emotional distress. INTERVENTION: Patients in the RPS group attended an initial group session to set diabetes-related behavioral goals, receive peer communication skills training, and be paired with another age-matched peer patient. Peers were encouraged to talk weekly using a telephone platform that recorded call occurrence and provided reminders to promote peer contact. These patients could also participate in optional group sessions at 1, 3, and 6 months. Patients in the NCM group attended a 1.5-hour educational session and were assigned to a nurse care manager. RESULTS: Of the 244 patients enrolled, 216 (89%) completed the HbA(1c) assessments and 231 (95%) completed the survey assessments at 6 months. Mean HbA(1c) level decreased from 8.02% to 7.73% (change, -0.29%) in the RPS group and increased from 7.93% to 8.22% (change, 0.29%) in the NCM group. The difference in HbA(1c) change between groups was 0.58% (P = 0.004). Among patients with a baseline HbA(1c) level greater than 8.0%, those in the RPS group had a mean decrease of 0.88%, compared with a 0.07% decrease among those in the NCM group (between-group difference, 0.81%; P < 0.001). Eight patients in the RPS group started insulin therapy, compared with 1 patient in the NCM group (P = 0.020). Groups did not differ in blood pressure, self-reported medication adherence, or diabetes-specific distress, but the RPS group reported improvement in diabetes social support. LIMITATION: The study included only male veterans and lasted only 6 months. CONCLUSION: Reciprocal peer support holds promise as a method for diabetes care management. PMID- 20956708 TI - High incidence of hospital admissions with multidrug-resistant and extensively drug-resistant tuberculosis among South African health care workers. AB - BACKGROUND: Nosocomial transmission has been described in extensively drug resistant tuberculosis (XDR-TB) and HIV co-infected patients in South Africa. However, little is known about the rates of drug-resistant tuberculosis among health care workers in countries with high tuberculosis and HIV burden. OBJECTIVE: To estimate rates of multidrug-resistant tuberculosis (MDR-TB) and XDR TB hospitalizations among health care workers in KwaZulu-Natal, South Africa. DESIGN: Retrospective study of patients with drug-resistant tuberculosis who were admitted from 2003 to 2008 for the initiation of drug-resistant tuberculosis therapy. SETTING: A public tuberculosis referral hospital in KwaZulu-Natal, South Africa. PARTICIPANTS: 231 health care workers and 4151 non-health care workers admitted for initiation of MDR-TB or XDR-TB treatment. MEASUREMENTS: Hospital admission rates and hospital admission incidence rate ratios. RESULTS: Estimated incidence of MDR-TB hospitalization was 64.8 per 100,000 health care workers versus 11.9 per 100,000 non-health care workers (incidence rate ratio, 5.46 [95% CI, 4.75 to 6.28]). Estimated incidence of XDR-TB hospitalizations was 7.2 per 100,000 health care workers versus 1.1 per 100,000 non-health care workers (incidence rate ratio, 6.69 [CI, 4.38 to 10.20]). A higher percentage of health care workers than non-health care workers with MDR-TB or XDR-TB were women (78% vs. 47%; P < 0.001), and health care workers were less likely to report previous tuberculosis treatment (41% vs. 92%; P < 0.001). HIV infection did not differ between health care workers and non-health care workers (55% vs. 57%); however, among HIV-infected patients, a higher percentage of health care workers were receiving antiretroviral medications (63% vs. 47%; P < 0.001). LIMITATION: The study had an observational retrospective design, is subject to referral bias, and had no information on type of health care work or duration of occupational exposure to tuberculosis. CONCLUSION: Health care workers in this HIV-endemic area were substantially more likely to be hospitalized with either MDR-TB or XDR TB than were non-health care workers. The increased risk may be explained by occupational exposure, underlining the urgent need for tuberculosis infection control programs. PMID- 20956709 TI - Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism. AB - BACKGROUND: In patients with a first unprovoked venous thromboembolism (VTE), an elevated d-dimer level after anticoagulation is stopped is a risk factor for recurrent VTE. However, questions remain about the utility of measuring d-dimer in clinical practice. PURPOSE: To determine whether the timing of testing, patient age, and the cut point used to define a positive or negative result affect the ability of d-dimer testing to distinguish risk for recurrent disease. DATA SOURCES: Comprehensive search of electronic databases (MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials) until July 2010, supplemented by reviewing conference abstracts and contacting content experts. STUDY SELECTION: 7 prospective studies that investigated an association between d dimer, measured after stopping anticoagulation, and disease recurrence in patients with a first unprovoked VTE (proximal deep venous thrombosis, pulmonary embolism, or both). DATA EXTRACTION: Patient-level databases were obtained, transferred to a central database, checked, completed with further information provided by study investigators, and pooled into a single database. DATA SYNTHESIS: 1818 patients with a first unprovoked VTE were followed for a mean of 26.9 months (SD, 19.1). A study-stratified multivariate Cox regression model, which included patient age, sex, hormone therapy use at the time of the index event, body mass index, timing of postanticoagulation d-dimer testing, and inherited thrombophilia as possible confounders, indicated that the hazard ratio for d-dimer status (positive vs. negative) was 2.59 (95% CI, 1.90 to 3.52). Only male sex had a significant effect on risk for recurrent VTE independent of d dimer status. The Cox regression model and the log-rank test confirmed that the risk for recurrent VTE was higher in patients with a positive d-dimer result than in those with a negative result, regardless of the timing of postanticoagulation d-dimer testing or patient age. No study- or assay-specific d-dimer effect was found, and reassessing the analysis after recoding data according to specific quantitative d-dimer cut points (500 ug/L and 250 ug/L) did not change the results. LIMITATIONS: Unmeasured variables could have affected the risk for recurrent VTE. The study population was predominantly white. CONCLUSION: In patients with a first unprovoked VTE who have their d-dimer level measured after stopping anticoagulation, the timing of d-dimer testing, patient age, and the assay cut point used do not affect the ability of d-dimer to distinguish patients with a higher or lower risk for recurrent VTE. PMID- 20956710 TI - What's in placebos: who knows? Analysis of randomized, controlled trials. AB - BACKGROUND: No regulations govern placebo composition. The composition of placebos can influence trial outcomes and merits reporting. PURPOSE: To assess how often investigators specify the composition of placebos in randomized, placebo-controlled trials. DATA SOURCES: 4 English-language general and internal medicine journals with high impact factors. STUDY SELECTION: 3 reviewers screened titles and abstracts of the journals to identify randomized, placebo-controlled trials published from January 2008 to December 2009. DATA EXTRACTION: Reviewers independently abstracted data from the introduction and methods sections of identified articles, recording treatment type (pill, injection, or other) and whether placebo composition was stated. Discrepancies were resolved by consensus. DATA SYNTHESIS: Most studies did not disclose the composition of the study placebo. Disclosure was less common for pills than for injections and other treatments (8.2% vs. 26.7%; P = 0.002). LIMITATION: Journals with high impact factors may not be representative. CONCLUSION: Placebos were seldom described in randomized, controlled trials of pills or capsules. Because the nature of the placebo can influence trial outcomes, placebo formulation should be disclosed in reports of placebo-controlled trials. PMID- 20956711 TI - Invasive dental treatment and risk for vascular events: have we bitten off more than we can chew? PMID- 20956712 TI - The role of peer patients in chronic disease management. PMID- 20956713 TI - A mother in Haiti. PMID- 20956714 TI - What bugs you? PMID- 20956715 TI - Sexually transmitted diseases among users of erectile dysfunction drugs. PMID- 20956716 TI - Two additional implications of an HIV nucleic acid testing program with automated Internet and voicemail systems to deliver results. PMID- 20956717 TI - Metastatic breast carcinoma diagnosed by nerve root biopsy for the cauda equina syndrome. PMID- 20956718 TI - Physician views on the use of comparative effectiveness research: a national survey. PMID- 20956719 TI - Examination of the pregnancy-associated plasma protein-A assay on the Beckman Coulter Access((r)) platform: suitability for use in first trimester Down's syndrome screening. AB - OBJECTIVE: To explore the clinical validity of the new Access((r)) pregnancy associated plasma protein-A (PAPP-A) assay for Down's syndrome screening. SETTING: Academic hospital. METHOD: Residual serum samples (n = 416) received for routine first trimester Down's syndrome screening (10-13 weeks) were retrieved from freezer storage and tested using two PAPP-A immunoassay methods. The new Access((r)) assay was specifically compared, on a subset of these samples (n = 194), with an assay proven to give acceptable Down's syndrome screening performance, the PerkinElmer (PE) AutoDELFIA method. Access((r)) PAPP-A levels were examined in relation to gestational age and maternal weight, and were compared with the PE method by regression and Bland-Altman analyses. RESULTS: Access((r)) PAPP-A assay results were highly correlated with the PE AutoDELFIA method (r = 0.97). PAPP-A levels obtained using the Access((r)) assay increased with advancing gestational age and were inversely related to maternal weight, as expected. The distribution of multiples of the median (MoM) values fit a log Gaussian distribution and the standard deviation of the log MoM (0.2331) matched published estimates. PAPP-A MoM levels in Down's syndrome pregnancies (n = 6, median 0.30) showed the expected reduction. CONCLUSION: Using an appropriate gestational age-specific median equation, the Access((r)) PAPP-A assay is expected to perform acceptably in first trimester Down's syndrome screening. PMID- 20956720 TI - Improvements to the newborn bloodspot screening service are required to meet national standards. AB - OBJECTIVES: The UK Newborn Screening Programme has standards to facilitate the early identification and treatment of five specific diseases to prevent lifelong impairment or death. This audit aimed to assess the newborn bloodspot screening programme in an inner London borough and to make recommendations for service improvement. METHODS: Data on babies registered with a general practitioner in the borough between April 2008 and March 2009 were obtained from the borough's health database and the laboratory result systems and compared with national screening standards. Interviews were conducted with the leads of each service providing components of newborn screening. RESULTS: A total of 292 (8%) out of 3636 babies registered within the audit period had no result on the database (average 1 in 13). Regional reports revealed that over the previous three years the borough, like many others, had consistently failed to achieve the core standards for newborn bloodspot screening. Major areas of concern identified by this audit pertained to the quality of the bloodspot sample, response to requests for repeat samples, timely identification of untested babies and communication of results to parents. CONCLUSION: The audit revealed that for the majority of children registered in the borough, screening was successfully carried out. However, gaps in the service meant that with current practice one affected child could be missed every seven years. Recommendations include staff training, frequent data reviews, and providing a coordinating officer to oversee the programme and follow up missing results. PMID- 20956721 TI - Effect of temperature changes on the occurrence of congenital hypothyroidism. AB - OBJECTIVES: To investigate an association between seasonal changes in temperature and the prevalence of congenital hypothyroidism (CH) in the Southwest of Iran. METHODS: A prospective two-year study conducted from March 2007 to March 2009 during the nationwide screening programme for CH in Ahvaz, the biggest city in southwest Iran. Blood samples were taken from almost all newborns by heel-stick and used in a thyroid-stimulating hormone (TSH)-enzyme-linked immunosorbent assay (ELISA). Serum thyroxine (T4) and TSH were measured if the ELISA-TSH was >5 mIU/L (suspicious cases). Infants were considered to have CH with T4 <6.0 ug/dL and TSH > 10 mIU/L, or with normal T4 values and persistent high TSH values for >2 months (subclinical hypothyroidism). Date of birth and sex were recorded. Detailed temperature data were obtained from the meteorological organization. The relationship between the monthly incidence of CH and the average monthly temperature was investigated. RESULTS: From 47,075 (50.92% male) newborns, 1131 were referred (recall rate = 2.4%) and 142 infants (51.4% male) were confirmed to have CH. The seasonal distribution of CH cases was 32.4% in the warm period and 67.6% in the cold period of the year (19%, 13.4%, 32.4% and 35.2% in spring, summer, fall and winter, respectively; P = 0.001). A statistical difference was seen between mid-summer (2.8%, warmest time) and early winter (15.5%, coldest time). The above-mentioned difference was the same for suspicious individuals (P < 0.001). The odds of being affected were increased by 4% for each fall of 1 degrees C. CONCLUSION: The prevalence of CH has a significant negative correlation with the temperature in the tropical area of Iran. PMID- 20956722 TI - Ethnic disparities in knowledge of cancer screening programmes in the UK. AB - OBJECTIVE: The aim of the study was to examine awareness of the three National Cancer Screening Programmes (breast, cervical, bowel) among white and ethnic minority groups in the UK. SETTING: Data were from two surveys in which the screening questions were added: (i) the Office of National Statistics (ONS) Opinions Survey, carried out in September and October 2008; and (ii) the EthnibusTM survey of the main ethnic minority groups in England, conducted in October and November 2008. METHODS: The ONS sample consisted of 2216 adults selected using stratified probability sampling to obtain a population representative sample. The EthnibusTM sample was obtained by quota sampling and included 1500 adults from the six largest ethnic minority groups in England (Indian, Pakistani, Bangladeshi, Caribbean, African and Chinese). Participants completed questions on awareness of cancer screening programmes as part of the wider Cancer Awareness Measure (CAM) in home-based, face-to-face interviews. RESULTS: Awareness of breast and cervical cancer screening was high in the white ONS participants (89% breast and 84% cervical), lower in the ONS ethnic minority sample (74% for both breast and cervical) and lowest in the EthnibusTM sample (69% breast and 66% cervical). Ethnic disparities persisted after controlling for age, gender and occupational group. In both groups, knowledge of breast and cervical screening was lower among men and more socioeconomically deprived groups. Awareness of the new bowel cancer screening programme was less than 30% in both white and ethnic minority groups. CONCLUSIONS: Ethnic disparities in knowledge of breast and cervical cancer screening should be addressed. Strategies to engage ethnic minority and socioeconomically deprived groups in bowel cancer screening should be instigated to avoid the emergence of disparities. PMID- 20956723 TI - A simple method to estimate the episode and programme sensitivity of breast cancer screening programmes. AB - BACKGROUND: The estimation of breast cancer screening sensitivity is a major aim in the quality assessment of screening programmes. The proportional incidence method for the estimation of the sensitivity of breast cancer screening programmes is rarely used to estimate the underlying incidence rates. METHODS: We present a method to estimate episode and programme sensitivity of screening programmes, based solely on cancers detected within screening cycles (excluding breast cancer cases at prevalent screening round) and on the number of incident cases in the total target population (steady state). The assumptions, strengths and limitations of the method are discussed. An example of calculation of episode and programme sensitivities is given, on the basis of the data from the IMPACT study, a large observational study of breast cancer screening programmes in Italy. RESULTS: The programme sensitivity from the fifth year of screening onwards ranged between 41% and 48% of the total number of cases in the target population. At steady state episode sensitivity was 0.70, with a trend across age groups, with lowest values in women aged 50-54 years (0.52) and highest in those 65-69 (0.77). CONCLUSIONS: The method is a very serviceable tool for estimating sensitivity in service screening programmes, and the results are comparable with those of other methods of estimation. PMID- 20956724 TI - Breast and cervical cancer screening programme implementation in 16 countries. AB - OBJECTIVES: There is a continuing need to monitor and evaluate the impact of organized screening programmes on cancer incidence and mortality. We report results from a programme assessment conducted within the International Cancer Screening Network (ICSN) to understand the characteristics of cervical screening programmes within countries that have established population-based breast cancer screening programmes. METHODS: In 2007-2008, we asked 26 ICSN country representatives to complete a web-based survey that included questions on breast and cervical cancer screening programmes. We summarized information from 16 countries with both types of organized programmes. RESULTS: In 63% of these countries, the organization of the cervical cancer screening programme was similar to that of the breast cancer screening programme in the same country. There were differences in programme characteristics, including year established (1962-2003 cervical; 1986-2002 breast) and ages covered (15-70+ cervical; 40-75+ breast). Adoption of new screening technologies was evident (44% liquid-based Pap tests; 13% human papillomavirus (HPV)-triage tests cervical; 56% digital mammography breast). There was wide variation in participation rates for both programme types (<4-80% cervical; 12-88% breast), and participation rates tended to be higher for cervical (70-80%) than for breast (60-70%) cancer screening programmes. Eleven ICSN member countries had approved the HPV vaccine and five more were considering its use in their organized programmes. CONCLUSION: Overall, there were similarities and differences in the organization of breast and cervical cancer screening programmes among ICSN countries. This assessment can assist established and new screening programmes in understanding the organization and structure of cancer screening programmes. PMID- 20956725 TI - Mortality reductions produced by sustained prostate cancer screening have been underestimated. AB - BACKGROUND: The recently published European Randomized Study of Screening for Prostate Cancer (ERSPC) reported prostate specific antigen (PSA)-based screening to have reduced the prostate cancer death rate by only 20%. However, this is an underestimate caused by (i) including in the 20% the years before the impact of the first screen becomes manifest, and (ii) not having full information for the follow-up years where the effects of the screening are most apparent. This paper provides a re-analysis of the results using time-specific measures, which avoid the first of these sources of error. METHODS: Mortality rate ratios for follow-up years 1-12 were derived from the yearly numbers of prostate cancer deaths and numbers of men being followed in each arm of the ERSPC. To reduce statistical noise, they were based on moving three-year intervals, and a smooth rate ratio curve was fitted to the yearly data, in order to measure the steady state reduction in mortality and to identify the time at which it reached this level. RESULTS: The re-analysis suggests that the sustained reduction in prostate cancer mortality may be more than 50%. CONCLUSION: Re-analysis of the ERSPC data suggests that if screening is carried out for several years, and if follow-up is pursued until the reduction becomes manifest, the reduction in mortality will be 50-60%. An analysis that includes the 2007-2008 follow-up data is required to quantify more precisely the impact of this intervention. PMID- 20956726 TI - Improving colorectal cancer screening outcomes: proceedings of the second meeting of the International Colorectal Cancer Screening Network, a global quality initiative. AB - The International Colorectal Cancer Screening Network (ICRCSN) is a global consortium of initiatives delivering organized colorectal cancer (CRC) screening to their populations. The aim of the Network is to promote improvements in quality assurance (QA) and programme evaluation to maximize the benefit and to minimize the risk associated with CRC screening. ICRCSN currently includes 41 member initiatives from 27 countries. The ICRCSN held its second international meeting in Oxford in September 2008 with representatives from 24 countries. This report summarizes the presentations and discussions, the feedback from participants on their current and future needs and the potential role of the ICRCSN in supporting those needs. PMID- 20956727 TI - Breast screening: why estimates differ by a factor of 20-25. PMID- 20956729 TI - Knowing hypertension awareness and psychological distress in primary prevention. PMID- 20956730 TI - Macrocirculation meets microcirculation. PMID- 20956732 TI - Learning from the placenta: acute atherosis and vascular remodeling in preeclampsia-novel aspects for atherosclerosis and future cardiovascular health. AB - Preeclampsia is a common and potentially lethal pregnancy complication for women and offspring. Women who develop preeclampsia also run a long-term augmented risk of cardiovascular disease and premature death, and two theories are discussed. Women developing preeclampsia and persons developing cardiovascular disease may have common risk factors, which are unmasked by the "stress" of pregnancy. Alternatively, a new risk factor might occur de novo during the preeclamptic pregnancy. In preeclampsia, lipid deposition in walls of the maternal uterine arteries leading to the placenta, named spiral arteries, regularly occurs. These vascular lesions resemble early stages of atherosclerosis and are named "acute atherosis" and is thought to regress after delivery. The mechanisms that contribute to acute atherosis in preeclampsia are largely unknown, but are related to the impaired vascular remodeling of the spiral arteries in the first half of pregnancy. One striking feature is that the development of these "atherosclerosis-like" lesions requires a few months in pregnancy and may be partly linked to invasion of trophoblasts (specialized fetally derived placenta cells). We summarize normal and pathological vessel remodeling in pregnancy and discuss similarities and differences between preeclampsia and arteriosclerosis. The transient appearance of acute atherosis of uterine wall spiral arteries seen in pregnancy complications and the molecular interaction between trophoblast, smooth muscle and vascular cells could add important elements to explain arteriosclerosis and stenosis in cardiovascular disease. Further understanding of the process underlying spiral artery atherosis in the months of pregnancy may cast light on development of cardiovascular disease later in life. PMID- 20956731 TI - Suppression of the nitric oxide pathway in metastatic renal cell carcinoma patients receiving vascular endothelial growth factor-signaling inhibitors. AB - Therapies that target the vascular endothelial growth factor (VEGF) pathway cause hypertension, but the mechanism remains unknown. This cross-sectional study tested the hypothesis that VEGF inhibition causes hypertension by suppressing VEGF-mediated vasodilatory pathways. Urine was collected from 80 patients with metastatic renal cell carcinoma from 2002 to 2009, 40 at baseline and 40 while on VEGF inhibitors. Measured urinary biomarkers include albumin, metabolites of the nitric oxide (NO) pathway and its downstream effector cGMP, and prostaglandin pathway biomarkers prostaglandin E2, 6-keto prostaglandin F1alpha, and cAMP, all normalized to urinary creatinine. The mean age in both groups was 61.8 years, 76% were men, and urinary albumin was higher in patients receiving VEGF inhibitors (median: 18.4 versus 4.6 mg/g; P = 0.009). cGMP/creatinine was suppressed in patients on VEGF inhibitors (0.28 versus 0.39 pmol/MUg; P = 0.01), with a trend toward suppression of nitrate/creatinine (0.46 versus 0.62 MUmol/mg; P = 0.09). Both comparisons were strengthened when patients on bevacizumab were excluded, and only those receiving small molecule tyrosine kinase inhibitors were analyzed (cGMP/creatinine: P = 0.003; nitrate/creatinine: P = 0.01). Prostaglandin E2, 6 keto prostaglandin F1alpha, and cAMP did not differ between groups. These results suggest that hypertension induced by VEGF inhibitors is mediated by suppression of NO production. Prospective studies are needed to explore whether these biomarkers may be useful predictors of efficacy in patients receiving VEGF targeted therapies. PMID- 20956734 TI - Attitudes toward Olfaction: A Cross-regional Study. AB - This study aimed to determine whether there are regional influences on attitudes toward olfaction. A total of 1082 participants aged 21-50 years from 4 different regions (Mexican, Korean, Czech, and German) were asked to rate general attitudes toward olfaction in everyday life. To examine affective attitudes to odors (i.e., pleasantness), participants were also asked to list 3 odors as being the most pleasant or unpleasant, respectively. Next, the mentioned odor names were attributed to 1 of 4 main categories: "Food & Drink," "Social relationship," "Nature," and "Civilization" and the distribution of these categories was compared across regions. Mexicans were significantly different to the other regions in their general attitudes toward olfaction. In addition, in all regions, in comparison with men, women indicated a higher interest in the sense of smell. Moreover, a significant positive correlation was present between individuals' self-rating of olfactory sensitivity and general attitudes toward olfaction. Finally, there were significant cross-regional differences in affective attitudes toward specific categories of odors. In conclusion, our findings support and extend the notion that regions affect attitudes toward the olfactory world. PMID- 20956733 TI - Conservation of indole responsive odorant receptors in mosquitoes reveals an ancient olfactory trait. AB - Aedes aegypti and Anopheles gambiae are among the best-characterized mosquito species within the Culicinae and Anophelinae mosquito clades which diverged ~150 million years ago. Despite this evolutionary distance, the olfactory systems of these mosquitoes exhibit similar morphological and physiological adaptations. Paradoxically, mosquito odorant receptors, which lie at the heart of chemosensory signal transduction pathways, belong to a large and highly divergent gene family. We have used 2 heterologous expression systems to investigate the functional characteristics of a highly conserved subset of Ors between Ae. aegypti and An. gambiae to investigate whether protein homology correlates with odorant-induced activation. We find that these receptors share similar odorant response profiles and that indole, a common and ecologically relevant olfactory cue, elicits strong responses from these homologous receptors. The identification of other highly conserved members of this Or clade from mosquito species of varying phylogenetic relatedness supports a model in which high sensitivity to indole represents an ancient ecological adaptation that has been preserved as a result of its life cycle importance. These results provide an understanding of how similarities and disparities among homologous OR proteins relate to olfactory function, which can lead to greater insights into the design of successful strategies for the control of mosquito-borne diseases. PMID- 20956735 TI - Different BOLD responses to intragastric load of L-glutamate and inosine monophosphate in conscious rats. AB - In this study, we compared the blood oxygen level-dependent (BOLD) signal changes between intragastric load of monosodium L-glutamate (MSG) and inosine monophosphate (IMP), which elicit the umami taste. An intragastric load of 30 mM IMP or 60 mM MSG induced a BOLD signal increase in several brain regions, including the nucleus of the solitary tract (NTS), lateral hypothalamus (LH), and insular cortex. Only MSG increased the BOLD signal in the amygdala (AMG). The time course of the BOLD signal changes in the NTS and the LH in the IMP group was different from that of the MSG group. We further compared the brain regions correlated with the BOLD signal change in the NTS between MSG and IMP groups. The BOLD responses in the hippocampus and the orbital cortex were associated with activation of the NTS in both MSG and IMP groups, but the association in the AMG and the pyriform was only in MSG group. These results indicate that gut stimulation with MSG and IMP evoked BOLD responses in distinct regions with different temporal patterns and that the mechanism of perception of L-glutamate and IMP in the gastrointestinal tract differed from that in the taste-sensing system. PMID- 20956736 TI - Ontogeny of odor liking during childhood and its relation to language development. AB - One important aspect of odor hedonics is its plasticity during human development. The present study set out to probe the modulators of such olfactory change during that period by testing the hypothesis that language and semantic representations of objects are strong organizers of odor liking. To this end, 15 three-year-old children were tested in a longitudinal study. Participants were exposed to exactly the same 12 odorants once a year over a 3-year period. At each experimental session, they were asked to answer 2 questions: 1) "Do you like or dislike this odor?" and 2) "Can you tell me what it is?" The level of language production was assessed on a standardized test. The 3-year-old children were found to categorize the same number of odorants as liked and as disliked. The follow-up study, in contrast, showed that at 5 years of age they categorized more of these odors as liked and that the shift was significant only in the children with higher language production skills. Taken as a whole, these findings suggest that the 3- to 5-year age range, when children begin to master language, is a turning point in the construction of olfactory hedonic categories during childhood. PMID- 20956737 TI - Alteration of mouse urinary odor by ingestion of the xenobiotic monoterpene citronellal. AB - Body odors provide a rich source of sensory information for other animals. There is considerable evidence to suggest that short-term fluctuations in body odor can be caused by diet; however, few, if any, previous studies have demonstrated that specific compounds can directly mask or alter mouse urinary odor when ingested and thus alter another animal's behavior. To investigate whether the ingestion of citronellal, a monoterpene aldehyde that produces an intense aroma detected by both humans and mice, can alter mouse urinary odor, mice (C57BL6J) were trained in a Y maze to discriminate between the urinary odors of male donor mice that had ingested either citronellal in aqueous solution or a control solution. Trained mice could discriminate between urinary odors from the citronellal ingestion and control groups. A series of generalization tests revealed that citronellal ingestion directly altered mouse urinary odor. Moreover, trained mice that had successfully discriminated between urinary odors from donor mice of different ages failed to detect age-related changes in urine from male mice that had ingested 50 ppm of citronellal. This study is the first to show that ingestion of a xenobiotic can alter mouse urinary odor and confuse the behavioral responses of trained mice to age-related scents. PMID- 20956738 TI - What is otolaryngology-head and neck surgery? PMID- 20956739 TI - Professional burnout among microvascular and reconstructive free-flap head and neck surgeons in the United States. AB - OBJECTIVES: To determine the prevalence of professional burnout among microvascular free-flap (MVFF) head and neck surgeons and to identify modifiable risk factors with the intent to reduce MVFF surgeon burnout. DESIGN: A cross sectional, observational study. SETTING: A questionnaire mailed to MVFF surgeons in the United States. PARTICIPANTS: A total of 60 MVFF surgeons. MAIN OUTCOMES MEASURES: Professional burnout was quantified using the Maslach Burnout Inventory Human Services Study questionnaire, which defines burnout as the triad of high emotional exhaustion (EE), high depersonalization (DP), and low personal accomplishment. Additional data included demographic information and subjective assessment of professional stressors, satisfaction, self-efficacy, and support systems using Likert score scales. Potential risk factors for burnout were determined via significant association (P < .05) by Fisher exact tests and analyses of variance. RESULTS: Of the 141 mailed surveys, 72 were returned, for a response rate of 51%, and 60 of the respondents were practicing MVFF surgeons. Two percent of the responding MVFF surgeons experienced high burnout (n = 1); 73%, moderate burnout (n = 44); and 25%, low burnout (n = 15). Compared with other otolaryngology academic faculty and department chairs, MVFF surgeons had similar or lower levels of burnout. On average, MVFF surgeons had low to moderate EE and DP scores. High EE was associated with excess workload, inadequate administration time, work invading family life, inability to care for personal health, poor perception of control over professional life, and frequency of irritable behavior toward loved ones (P < .001). On average, MVFF surgeons experienced high personal accomplishment. CONCLUSIONS: Most MVFF surgeons experience moderate professional burnout secondary to moderate EE and DP. This may be a problem of proper balance between professional obligations and personal life goals. Most MVFF surgeons, nonetheless, experience a high level of personal accomplishment in their profession. PMID- 20956740 TI - Thoracodorsal artery scapular tip autogenous transplant: vascularized bone with a long pedicle and flexible soft tissue. AB - OBJECTIVE: To demonstrate that the 3 reconstructive advantages of the thoracodorsal artery scapular tip transplant (Tdast), a long pedicle, independently mobile tissue components, and the 3-dimensional nature of the scapular tip, will improve the quality and success of complex reconstructions by avoiding vein grafting, preventing the need for 2 separate transplants, and facilitating bony inset. DESIGN: Prospective case series. SETTING: Tertiary care academic medical center. PATIENTS: Twenty-one patients (male to female ratio, 16:5; mean age, 52 years) underwent reconstruction of the upper, middle, and lower face from 2001 through 2006. Indications for reconstruction were tumor ablation in 11 patients, secondary reconstruction in 4 patients, osteoradionecrosis in 4, and posttraumatic reconstruction in 2. Seventeen patients underwent radiation. INTERVENTIONS: All patients underwent harvest of an autogenous transplant of scapular tip bone and latissimus dorsi soft tissue based on the thoracodorsal artery. The mean bone length was 5.2 cm (range, 2.5-9.0 cm), and the mean cutaneous surface area was 68 cm2 (range, 20-250 cm2). MAIN OUTCOME MEASURES: Reduction of vein grafting, avoidance of 2 transplants, use of the triangular shape of the scapular tip in reconstruction, complications, and shoulder function. RESULTS: The success rate of transplantation was 100%. The use of this transplant avoided vein grafting in 16 patients and the need for 2 separate transplants in 11 patients, and the 3-dimensional nature of the scapular tip facilitated inset in 13 patients. In 14 patients, more than 1 of these reconstructive advantages was achieved. In 6 patients, all 3 were accomplished. Eleven patients experienced a complication. The major complication rate was 33%, and the minor complication rate was 33%. The mean Constant-Murley test of shoulder function score was 87 of 100 (range, 74-100). CONCLUSIONS: The Tdast is an excellent choice for reconstruction in the head and neck as an alternative to procedures requiring vein grafting and multiple free tissue transplants, or in which the 3-dimensional contour of the scapular tip aids in reconstruction. The complication rate should be assessed in the context of the risk factors of the patient population and the outcome with respect to stable employment, increasing body mass index, and maintenance of shoulder function. PMID- 20956741 TI - Nerve-muscle pedicle flap implantation combined with arytenoid adduction. AB - OBJECTIVES: To describe a new technique of nerve-muscle pedicle (NMP) flap implantation combined with arytenoid adduction (AA) to treat dysphonia due to unilateral vocal fold paralysis and to examine postoperative vocal function. STUDY DESIGN: Retrospective review of clinical records. SETTING: Tertiary academic center. PATIENTS: Twenty-two consecutive patients underwent NMP flap implantation with AA and were followed up short term over a period of 1 to 6 months (mean, 2.9 months) and long term over a period of 7 to 36 months (mean, 21.4 months). INTERVENTIONS: An NMP flap was made using an ansa cervicalis branch and a piece of the sternohyoid muscle. A window was opened in the thyroid ala at the level of the vocal fold. Then, AA was performed and the NMP flap was securely implanted onto the thyroarytenoid muscle through the window under microscopic guidance. MAIN OUTCOME MEASURES: The maximum phonation time, mean airflow rate, pitch range, and acoustic parameters (jitter, shimmer, and harmonics to noise ratio) were evaluated before surgery and twice after surgery. RESULTS: All parameters improved significantly after surgery (P < .01). The measurements for maximum phonation time, mean airflow rate, and harmonics to noise ratio were within normal ranges after surgery. Furthermore, the maximum phonation time and jitter were significantly improved after long-term follow-up compared with early postoperative measurements (P < .01 and P < .05, respectively). CONCLUSIONS: Precise harvest of an NMP flap and its placement directly onto the thyroarytenoid muscle combined with AA provided excellent vocal function. The NMP method may have played a certain role in the improvement of postoperative vocal function, although further study with electromyographic examination is required to clarify the innervation status of the thyroarytenoid muscle. PMID- 20956742 TI - Mandibular segmental defect regenerated with macroporous biphasic calcium phosphate, collagen membrane, and bone marrow graft in dogs. AB - OBJECTIVE: To reconstruct segmental mandibulectomy using calcium phosphate ceramics and collagen membrane with a delayed bone marrow grafting in experimental animals. DESIGN: Defects of segmental mandibulectomy were filled with calcium phosphate granules and wrapped with a collagen membrane in 4 dogs and left empty as a control in 2 dogs. Two months later, a bone marrow graft was injected into the center of the implants. Animals were humanely killed after a 16 week delay. SUBJECTS: Six adult beagles were included in this study. INTERVENTION: Segmental mandibulectomy. MAIN OUTCOME MEASURE: Bone ingrowth and material resorption in the reconstructed segment. RESULTS: Successful osseous colonization bridged the whole length of the defects. The good new bone formation at the center and the periosteum-like formation at the periphery suggest the osteoinductive role of the bone marrow graft and the healing scaffold role of the membrane. CONCLUSIONS: This model succeeded in regenerating a large segmental defect in the mandible. An investigation with a postimplantation radiation delivery schedule is required with the use of this model, which should be considered as a preclinical study for a bone tissue engineering approach in patients with cancer-related bone defects. PMID- 20956743 TI - Use of the King LT for emergency airway management. AB - OBJECTIVE: To discuss the role of the King LT reusable supraglottic airway in emergency airway management. DESIGN: Retrospective case series review. SETTING: Tertiary academic medical facility. PATIENTS: We studied patients who presented to the emergency trauma center having undergone intubation at an outside facility or at the scene of the incident. The otolaryngology service was consulted for definitive management of the airway. MAIN OUTCOME MEASURE: Airway evaluation and management once the King LT has been placed. RESULTS: Six patients with known prehospitalization use of the King LT presented to the emergency trauma center and subsequently required emergency tracheostomy for establishment of a secure airway. Fiberoptic and/or direct laryngoscopic evaluation performed with the tube in place failed to reveal whether safe oral endotracheal intubation could be performed because of visualization problems. Examination after tracheostomy and removal of the King LT revealed that in 2 patients, orotracheal intubation would have been difficult or impossible, whereas another 4 patients could have been intubated. One patient had prehospitalization placement of a King LT, which resulted in subcutaneous emphysema because of placement within the mediastinum. The patient was able to be successfully intubated and did not require tracheostomy. CONCLUSIONS: The King LT offers benefits in emergency situations, but evaluation of the airway is challenging and often necessitates tracheostomy for establishment of a safe and secure airway. Even if tracheostomy is not required, serious complications may occur. PMID- 20956744 TI - Evolving therapies to treat retroglossal and base-of-tongue obstruction in pediatric obstructive sleep apnea. AB - OBJECTIVE: To describe our experience treating retroglossal and base-of-tongue collapse in children and young adults with obstructive sleep apnea using combined genioglossus advancement (Repose THS; MedtronicENT, Jacksonville, Florida) and radiofrequency ablation of the tongue base. DESIGN: Retrospective institutional review board-approved analysis of 31 operations. SETTING: Tertiary pediatric medical center. PATIENTS: Thirty-one patients with a mean age of 11.5 years (age range, 3.1-23.0 years). INTERVENTIONS: Combined genioglossus advancement and radiofrequency ablation. MAIN OUTCOME MEASURES: Preoperative and postoperative polysomnographic data were evaluated for each patient. Success of surgery was determined using the criteria of a postoperative apnea-hypopnea index of 5 or fewer events per hour, without evidence of hypoxemia (oxygen saturation as measured by pulse oximetry), and without prolonged hypercarbia (end-tidal carbon dioxide). RESULTS: Thirty-one patients who underwent genioglossus advancement were analyzed. Nineteen (61%) had Down syndrome. The overall success rate was 61% (19 of 31) (58% [12 of 19] success among patients with Down syndrome and 66% [7 of 12] success among patients without Down syndrome). Overall, the mean apnea hypopnea index improved from 14.1 to 6.4 events per hour (P < .001); the mean nadir oxygen saturation as measured by pulse oximetry during apnea improved from 87.4% to 90.9% (P = .07). CONCLUSIONS: Pediatric obstructive sleep apnea refractory to adenotonsillectomy that is due to retroglossal and base-of-tongue collapse remains difficult to treat. However, most patients in this analysis benefited from combined genioglossus advancement and radiofrequency ablation. PMID- 20956745 TI - Cystic fibrosis and endoscopic sinus surgery: Relationship between nasal polyposis and likelihood of revision endoscopic sinus surgery in patients with cystic fibrosis. AB - OBJECTIVES: To observe the extent of nasal polyposis endoscopically in a cystic fibrosis population before the first surgical intervention and to grade the extent using a modified Malm scale, to observe patients prospectively and record the need for revision endoscopic sinus surgery (ESS), and to compare this among the individual polyp grading groupings. DESIGN: Retrospective medical record review of data collected prospectively. SETTING: Tertiary care hospital. PATIENTS: Forty-nine consecutive patients with a clinical preoperative diagnosis of cystic fibrosis and sinusitis. MAIN OUTCOME MEASURES: Using a modified Malm scale, the extent of polyps was prospectively graded into 3 groups before the first surgical intervention. The number of patients needing revision ESS and the mean time to revision ESS were compared among the 3 groups. RESULTS: Forty-nine consecutive patients underwent ESS between 1992 and 2007. We used a 3-stage system for extent of polyposis: 16 patients were noted to have no polyps (grade A), 14 had mild polyposis (grade B), and 19 had extensive polyposis (grade C). During the study, 14 patients required revision surgery: 3 with mild polyps and 11 with extensive polyps. Mean time to revision surgery was 39.7 months for those with grade B and 23.8 months for those with grade C. In the overall statistical analysis, the rate of revision ESS was significantly different among the 3 groups (P < .001). In pairwise comparisons, there were significant differences between those with grades A and C (P < .001) and between those with grades B and C (P = .04) and a trend toward significance between those with grades A and B (P = .052). There were no complications from ESS. CONCLUSION: Preoperative grading of nasal polyposis in patients with cystic fibrosis can help assess the future likelihood of revision ESS. PMID- 20956746 TI - Current techniques in management of postmeningitic deafness in children. AB - OBJECTIVES: To determine pneumococcal vaccination status of children with recent postmeningitic deafness and to review our current approach for achieving early implantation in this special population that is at significant risk for cochlear ossification. DESIGN: Review of imaging studies and test results. SETTING: Tertiary care/referral children's hospital. PATIENTS: Five children ranging in age from 15 months to 10 years who experienced recent onset of profound bilateral sensorineural hearing loss due to pneumococcal meningitis. INTERVENTIONS: All children underwent preoperative magnetic resonance imaging with 3-dimensional heavily T2-weighted steady-state free precession sequences. Four children underwent auditory steady-state response testing. All underwent bilateral cochlear implantation. MAIN OUTCOME MEASURE: Degree of electrode insertion using standard surgical procedures. RESULTS: All children developed meningitis despite a history of pneumococcal vaccination. Complete electrode insertion in both ears was achieved. CONCLUSIONS: Pneumococcal vaccination has reduced but not eliminated childhood deafness secondary to pneumococcal disease. Auditory steady state response testing and 3-dimensional steady-state free precession imaging are modalities that expedite candidacy evaluation of this population. Early bilateral simultaneous implantation increases the likelihood of binaural hearing and ensures implantation of the better ear in this population of children whose course is often complicated by formation of scar tissue and ossification within the cochlea. PMID- 20956747 TI - Sensorineural hearing loss in a pediatric population: association of congenital cytomegalovirus infection with intracranial abnormalities. AB - OBJECTIVES: To examine the incidence of congenital cytomegalovirus (CMV) infection relative to common genetic etiologies of hearing loss in a pediatric population with sensorineural hearing loss (SNHL), and to characterize intracranial radiological abnormalities in patients with CMV-associated hearing loss. DESIGN: Retrospective study. SETTING: Academic tertiary care center. PATIENTS: A total of 112 pediatric patients with confirmed SNHL. MAIN OUTCOME MEASURES: The association of congenital CMV infection status with abnormal brain magnetic resonance imaging (MRI) scans and the frequencies of congenital CMV infection, gap junction beta-2 (GJB2) mutations, and the mitochondrial DNA (mtDNA) 1555A>G mutation in children with SNHL. RESULTS: Of 109 patients, 11 (10%) had positive results for CMV DNA; 10 of the 11 had normal GJB2 sequence and had negative test results for the mtDNA 1555A>G mutation. Brain MRI scans for 97 patients demonstrated a higher proportion of abnormalities in patients with positive CMV test results (80%) compared with those with no detectable CMV DNA (33%) (P = .006). GJB2 mutations and the mtDNA 1555A>G mutation were seen in 10 of 88 patients (11%) and 1 of 97 patients (1%) with SNHL, respectively. CONCLUSIONS: The presence of brain abnormalities in most patients with congenital CMV infection suggests that neurological damage in otherwise asymptomatic patients may not be limited to SNHL. Congenital CMV infection accounted for a significant proportion of patients with SNHL, with an incidence rate comparable with that of GJB2-related SNHL. PMID- 20956748 TI - Stapedectomy in children: causes and surgical results in 35 cases. AB - OBJECTIVES: To study children who had undergone stapedectomy at an age younger than 16 years to determine the causes (particularly frequency of congenital anomalies vs otosclerosis) and to analyze the functional results over the short term, 1-year, and long-term postsurgery time course. DESIGN: Ten-year retrospective study covering 1998 to 2008. SETTING: Pediatric tertiary care centers. PATIENTS: A total of 33 patients (35 ears) underwent stapes surgery from October 1998 to October 2008. MAIN OUTCOME MEASURE: Sex, age, preoperative and postoperative audiometric test results, associated anomalies, type of surgery (stapedotomy or partial stapedectomy), method of stapes surgery, and complications. RESULTS: The median age of patients at surgery was 13.4 years, ranging from 3.3 to 15.9 years. The major cause, which was found in 25 of 35 ears (71%), was nonprogressive conductive hearing loss due to congenital stapes fixation. The second most common cause, which was found in 6 of 35 ears (17%), was otosclerosis with progressive conductive or mixed hearing loss. Three ears presented posttraumatic stapes luxation (1 child aged 3.3 years at surgery). In 1 ear, the cause was osteogenesis imperfecta. Twenty-two ears were treated via the drill or laser-assisted small fenestra technique, and 13 ears were treated by a partial removal of the footplate covered by fascia. Early functional results were good, with a median postoperative air-bone gap of 9.8 dB, and 94% of the results were considered good or very good. There was no significant difference between early, 1-year, and longer-term audiometric results. CONCLUSIONS: Congenital fixation is the major indication for stapedectomy in children younger than 16 years. Functional results are good and remain stable over time. PMID- 20956749 TI - The association between semicircular canal dehiscence and Chiari type I malformation. AB - OBJECTIVE: To investigate the association between semicircular canal dehiscence (SCD) and Chiari type I malformation (CM-I). DESIGN: Retrospective case series. SETTING: Military tertiary referral center. PATIENTS: Adult patients with SCD. INTERVENTION: Review of records of patients diagnosed as having SCD for the radiologic diagnosis of CM-I and presenting symptoms. MAIN OUTCOME MEASURES: The prevalence of CM-I among patients with SCD and the presenting symptoms of patients with SCD with and without a coexistent CM-I. RESULTS: Of 32 patients diagnosed as having SCD, 30 underwent magnetic resonance imaging of the brain. Seven patients (23%; 95% confidence interval [CI], 12%-41%) were found to have a CM-I. Chiari type I malformation was associated with superior SCD in 3 of 26 patients (12%; 95% CI, 3%-30%). Of 10 patients with bilateral superior SCD, 2 (20%; 95% CI, 5%-52%) had a CM-I. Five of 6 patients (83%; 95% CI, 42%-99%) had a CM-I with unilateral or bilateral posterior SCD. Twenty-nine records were reviewed for presenting symptoms, and no significant difference was observed between patients with SCD alone and those with an associated CM-I (P = .09-.64). CONCLUSIONS: Among patients with SCD, the prevalence of CM-I is elevated. This association is especially marked in patients with posterior SCD. This finding suggests a relationship between CM-I and SCD, particularly with posterior SCD. PMID- 20956750 TI - Prognostic value of anterior rhinomanometry in diode laser turbinoplasty. AB - OBJECTIVE: To identify objective criteria predicting the success of diode laser assisted turbinoplasty. DESIGN: Prospective before-and-after trial with follow-up of 8 weeks. SETTING: Outpatient department of a tertiary referral center. PATIENTS: Forty-one patients with nasal obstruction caused by hyperplastic inferior nasal turbinates. INTERVENTION: Active anterior rhinomanometry with and without decongestion was used to assess the patients both before and after diode laser-assisted turbinate surgery. Surgery was performed under local anesthesia in "contact mode" using a continuous diode laser. In addition, a questionnaire assessed the subjective postoperative benefit. MAIN OUTCOME MEASURES: Presurgical effect of topical decongestion was correlated with postoperative improvement of nasal airflow and patients' subjective satisfaction. RESULTS: Turbinoplasty significantly improved the mean (SD) nasal airflow by 37.1% (52.4%) (95% confidence interval [CI], 20.6%-53.7%), from 509.8 (189.2) cm3/s (95% CI, 450.1 569.5) to 660.9 (285.4) cm3/s (95% CI, 570.8-751.0) (P < .001). There was no significant correlation between patients' subjective satisfaction and improvement of nasal airflow postoperatively (r(s) = -0.01; P = .93). There was a strong correlation between the presurgical effect of topical decongestion and the improvement of nasal airflow by surgery (r(s) = 0.42; P = .01). The correlation was even stronger when the absolute values were adjusted by the preoperative nasal airflow baseline (r(s) = 0.55; P = .01). CONCLUSIONS: Rhinomanometry with topical decongestion has a high predictive value for the objective outcome of diode laser-assisted turbinoplasty. Thus, performing a rhinomanometry with topical decongestion and calculating the relative spread of decongestion can help to estimate the patients' benefit from diode laser-assisted turbinate surgery. PMID- 20956751 TI - Obstructive sleep apnea syndrome and postoperative complications: clinical use of the STOP-BANG questionnaire. AB - OBJECTIVE: To determine whether high risk scores on preoperative STOP-BANG (Snoring, Tiredness during daytime, Observed apnea, high blood Pressure, Body mass index, Age, Neck circumference, Gender) questionnaires during preoperative evaluation correlated with a higher rate of complications of obstructive sleep apnea syndrome (OSAS). DESIGN: Historical cohort study. SETTING: Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. PATIENTS: Adult patients undergoing elective surgery at a tertiary care center who were administered the STOP-BANG questionnaire for 3 consecutive days in May 2008. MAIN OUTCOME MEASURES: Number and types of complications. RESULTS: A total of 135 patients were included in the study, of whom 56 (41.5%) had high risk scores for OSAS. The mean (SD) age of patients was 57.9 (14.4) years; 60 (44.4%) were men. Patients at high risk of OSAS had a higher rate of postoperative complications compared with patients at low risk (19.6% vs 1.3%; P < .001). Age, American Society of Anesthesiologists class of 3 or higher, and obesity were associated with an increased risk of postoperative complications. On multivariate analysis, high risk of OSAS and American Society of Anesthesiologists class 3 or higher were associated with higher odds of complications. CONCLUSION: The STOP-BANG questionnaire is useful for preoperative identification of patients at higher than normal risk for surgical complications, probably because it identifies patients with occult OSAS. PMID- 20956752 TI - Epileptic laryngospasm presenting as a primary sleep disturbance. PMID- 20956753 TI - Costello syndrome and the importance of cancer screening. PMID- 20956754 TI - Radiology quiz case 1. Chronic sclerosing sialadenitis of the submandibular gland. PMID- 20956755 TI - Radiology quiz case 2. Fetal goitrous hypothyroidism. PMID- 20956756 TI - Radiology case quiz case 3. Right maxillary sinus foreign body. PMID- 20956757 TI - Pathology quiz case 1. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) of the LDS. PMID- 20956758 TI - Pathology quiz case 2. Subcutaneous Sweet syndrome of the neck. PMID- 20956759 TI - Comparing treatments using observational study designs: what can we do about selection bias? PMID- 20956760 TI - Secondary stroke prevention in the era of carotid stenting: update on recent trials. AB - Stroke is a leading cause of morbidity and mortality worldwide. Traditional therapy for extracranial carotid artery occlusive disease, a significant risk factor for stroke, consists of optimal medical management and selective surgical treatment with carotid endarterectomy (CEA) for stroke risk reduction. Buoyed by the widespread application of percutaneous interventions for the treatment of coronary artery disease, carotid artery stenting (CAS) has steadily developed during the past decade as an alternative to CEA for patients who might benefit from surgical treatment. With greater operator experience have come advances in CAS techniques and patient selection criteria, and several single-center studies and industry-sponsored stent registries have demonstrated excellent results for CAS, especially compared with the landmark randomized CEA trials of the 1980s. Nevertheless, CAS has emerged as one of the most controversial procedures in the era of modern medicine, and recently published randomized trials from Europe have only stoked the fires of controversy. This study reviews the best available data for CAS as an alternative therapy to CEA for stroke risk reduction and gives an overview of eagerly anticipated large randomized trials. PMID- 20956761 TI - Introduction to propensity scores: A case study on the comparative effectiveness of laparoscopic vs open appendectomy. AB - OBJECTIVE: To demonstrate the use of propensity scores to evaluate the comparative effectiveness of laparoscopic and open appendectomy. DESIGN: Retrospective cohort study. SETTING: Academic and private hospitals. PATIENTS: All patients undergoing open or laparoscopic appendectomy (n = 21 475) in the Public Use File of the American College of Surgeons National Surgical Quality Improvement Program were included in the study. We first evaluated the surgical approach (laparoscopic vs open) using multivariate logistic regression. We next generated propensity scores and compared outcomes for open and laparoscopic appendectomy in a 1:1 matched cohort. Covariates in the model for propensity scores included comorbidities, age, sex, race, and evidence of perforation. MAIN OUTCOME MEASURES: Patient morbidity and mortality, rate of return to operating room, and hospital length of stay. RESULTS: Twenty-eight percent of patients underwent open appendectomy, and 72% had a laparoscopic approach; 33% (open) vs 14% (laparoscopic) had evidence of a ruptured appendix. In the propensity-matched cohort, there was no difference in mortality (0.3% vs 0.2%), reoperation (1.8% vs 1.5%), or incidence of major complications (5.9% vs 5.4%) between groups. Patients undergoing laparoscopic appendectomy experienced fewer wound infections (odds ratio [OR], 0.4; 95% confidence interval [CI], 0.3-0.5) and fewer episodes of sepsis (0.8; 0.6-1.0) but had a greater risk of intra-abdominal abscess (1.7; 1.3-2.2). An analysis using multivariate adjustment resulted in similar findings. CONCLUSIONS: After accounting for patient severity, open and laparoscopic appendectomy had similar clinical outcomes. In this case study, propensity score methods and multivariate adjustment yielded nearly identical results. PMID- 20956762 TI - Influence of psychiatric comorbidity on surgical mortality. AB - OBJECTIVE: To examine the potential effect of 5 existing psychiatric comorbidities on postsurgical mortality. DESIGN: Retrospective cohort. SETTING: Intensive care units of all Veterans Health Administration hospitals designated as providing acute care. PATIENTS: We studied 35 539 surgical patients admitted to intensive care units from October 1, 2003, through September 30, 2006. MAIN OUTCOME MEASURES: Psychiatric comorbidity (depression, anxiety, posttraumatic stress disorder, bipolar disease, and schizophrenia) was identified using outpatient encounters in the 12 months preceding the index admission. End points included in-hospital and 30-day mortality. Generalized estimating equations accounted for hospital clustering and adjusted mortality for demographics, type of surgery, medical comorbidity, and disease severity. RESULTS: We identified 8922 patients (25.1%) with an existing psychiatric comorbidity on admission. Unadjusted 30-day mortality rates were similar among patients with and without psychiatric comorbidity (3.8% vs 4.0%, P = .56). After adjustment, 30-day mortality was higher for patients with psychiatric comorbidity (odds ratio, 1.21; 95% confidence interval, 1.07-1.37; P = .003). In individual analyses, patients with depression and anxiety had higher odds of 30-day mortality (P = .01 and P = .02, respectively) but the odds were similar for the other conditions. CONCLUSION: Existing psychiatric comorbidity was associated with a modest increased risk of death among postsurgical patients. Estimates of the increased risk across the individual conditions were highest for anxiety and depression. The higher mortality may reflect higher unmeasured severity or unique management issues in patients with psychiatric comorbidity. PMID- 20956763 TI - Cost-effectiveness of groin hernia surgery in the Western Region of Ghana. AB - OBJECTIVE: To calculate the cost-effectiveness of tension-free inguinal hernia repair with mosquito net mesh in the Western Region of Ghana. DESIGN: Prospective study. SETTING: Four district hospitals in the Western Region of Ghana. PATIENTS: A total of 113 referred or presenting patients from rural areas with inguinal hernias of various sizes. INTERVENTION: Lichtenstein method of tension-free repair using mosquito net mesh by European and African surgeons. Main Outcome Measure Disability-adjusted life-years (DALYs) averted with counterfactual definitions based on precedent and expert opinion. RESULTS: All operations were performed as day cases, with 81 of the patients (71.7%) under local anesthesia and few complications. An average of 9.3 (95% confidence interval [CI], 8.0-10.7) DALYs were averted per person, with a total of 1052 averted in the study. Average cost per patient was $120.02 (95% CI, $117.66-$122.39) from a provider perspective and $102.88 ($88.47-$117.29) from a patient perspective. Cost effectiveness was $12.88 per DALY averted (95% CI, $10.98-$14.78), which is well below the Ghanaian per capita gross national income ($590). Results were robust to sensitivity analysis and may be refined as further work is done on the burden of disease due to hernias in Africa. CONCLUSIONS: Inguinal hernia repair was cost effective in the Western Region of Ghana through international collaboration. Research in other settings should test the generalizability of results. PMID- 20956764 TI - Screening of Helicobacter pylori infection after gastrectomy for cancer or peptic ulcer: results of a cohort study. AB - BACKGROUND: Gastric cancer commonly follows a long-standing inflammation, mainly due to Helicobacter pylori (HP) infection. After resection, the stump develops precancerous alterations. DESIGN: Prospective study of patients undergoing endoscopy from April 1, 2000, through March 31, 2006. SETTING: University departments of Surgery and Experimental Medicine and Pathology. PATIENTS: One hundred eighty-seven patients receiving upper gastrointestinal tract endoscopy many years after surgery for duodenal ulcer or gastric cancer. Ten to 12 postoperative endoscopic biopsy samples were taken from the remnant stomach. MAIN OUTCOME MEASURE: The risk of gastric cancer precursor lesions associated with HP infection. RESULTS: The gastric cancer precursor lesions were more common in the entire HP-positive population (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.25-4.49; P = .007). However, HP-positive patients undergoing resection for cancer had a higher risk of the precursor lesions compared with HP-negative patients in the same diagnostic group (OR, 4.20; 95% CI, 1.10-15.96) and all patients undergoing resection for duodenal ulcer (OR, 1.59; 95% CI, 0.44-5.73). CONCLUSION: The results of this investigation support the role of HP in gastric carcinogenesis and suggest that the HP eradication therapy might prevent the development of metachronous gastric cancer after gastric resection. PMID- 20956765 TI - Decreased peritoneal expression of active transforming growth factor beta1 during laparoscopic cholecystectomy with heated carbon dioxide. AB - BACKGROUND: Laparoscopic surgery involves the establishment of a pneumoperitoneum, mostly using carbon dioxide. Cooling of the peritoneum, due to insufflation, may traumatize the peritoneum and disturb local biological processes. The current study was performed to assess the effect of the temperature of carbon dioxide on peritoneal transforming growth factor beta1 (TGF beta1) expression. DESIGN: Patients were randomized into 2 groups. In one group, a pneumoperitoneum was created with carbon dioxide at room temperature; in the other, with carbon dioxide at body temperature. Peritoneal biopsy specimens were taken at the start and end of surgery. SETTING: Community hospital. PATIENTS: Thirty patients scheduled for laparoscopic cholecystectomy. MAIN OUTCOME MEASURES: Tissue concentrations of total and active TGF-beta1 were measured using enzyme-linked immunosorbent assays. RESULTS: At the start of surgery, there were no significant differences between groups in the total and active fractions of TGF-beta1. At the end of the procedure, the peritoneal active TGF-beta1 concentrations were significantly lower (P = .03) in patients receiving carbon dioxide at body temperature. In contrast, the concentrations of total TGF-beta1 did not differ between groups. A slight, nonsignificant increase in total and active TGF-beta1 levels was observed in patients receiving unheated carbon dioxide. The ratio of active to total TGF-beta1 did not change during procedures, and there were no differences between groups. CONCLUSIONS: Heating of carbon dioxide, used for insufflation, to body temperature decreases the expression of active TGF-beta1 in the peritoneum. Considering the broad biological effects of TGF-beta1, including the regulation of peritoneal healing and oncological processes, this observation might have clinical repercussions. PMID- 20956766 TI - Effect of blood products transfusion on the development of postinjury multiple organ failure. AB - HYPOTHESIS: Transfusion of fresh frozen plasma (FFP) and platelets is independently associated with the development of multiple organ failure (MOF) in critically injured patients. DESIGN: Prospective cohort study. SETTING: Academic regional level I trauma center. PATIENTS: From 1992 to 2004, a total of 1440 critically injured patients were admitted to our surgical intensive care unit and survived at least 48 hours. Of these, 1415 had complete data on age, Injury Severity Score (ISS), and units of FFP, platelets, and packed red blood cells (PRBCs) transfused. Multiple organ failure was defined using the Denver MOF score. Multiple logistic regression analysis was used to adjust transfusion of FFP, platelets, and PRBCs for known MOF risk factors. MAIN OUTCOME MEASURE: Multiple organ failure. RESULTS: The mean (SD) ISS was 29.3 (11.3), and the mean (SD) patient age was 37.4 (16.6) years. Among 1440 patients, 346 (24.0%) developed MOF, and 118 (8.2%) died. Multiple logistic regression analysis detected a significant interaction between units of FFP and PRBCs transfused (P < .001). Regardless of the units of PRBCs transfused, FFP transfusion was independently associated with the development of MOF. However, the deleterious effect associated with FFP transfusion was more prominent among patients receiving fewer than 6 U of PRBCs. Platelet transfusion was unassociated with MOF after adjustment for age, ISS, and FFP and PRBC transfusion. CONCLUSIONS: Early transfusion of FFP is associated with an increased risk of postinjury MOF, even after adjusting for age, ISS, and PRBC transfusion. Caution is warranted in developing protocols for empirical FFP transfusion. Specifically, transfusion triggers for FFP should be reexamined, as well as the practice of delivering FFP in fixed ratios to the units of PRBCs transfused. PMID- 20956767 TI - Wrong-site and wrong-patient procedures in the universal protocol era: analysis of a prospective database of physician self-reported occurrences. AB - OBJECTIVE: To determine the frequency, root cause, and outcome of wrong-site and wrong-patient procedures in the era of the Universal Protocol. DESIGN: Analysis of a prospective physician insurance database performed from January 1, 2002, to June 1, 2008. Deidentified cases were screened using predefined taxonomy filters, and data were analyzed by evaluation criteria defined a priori. SETTING: Colorado. PATIENTS: Database contained 27 370 physician self-reported adverse occurrences. MAIN OUTCOME MEASURES: Descriptive statistics were generated to examine the characteristics of the reporting physicians, the number of adverse events reported per year, and the root causes and occurrence-related patient outcomes. RESULTS: A total of 25 wrong-patient and 107 wrong-site procedures were identified during the study period. Significant harm was inflicted in 5 wrong patient procedures (20.0%) and 38 wrong-site procedures (35.5%). One patient died secondary to a wrong-site procedure (0.9%). The main root causes leading to wrong patient procedures were errors in diagnosis (56.0%) and errors in communication (100%), whereas wrong-site occurrences were related to errors in judgment (85.0%) and the lack of performing a "time-out" (72.0%). Nonsurgical specialties were involved in the cause of wrong-patient procedures and contributed equally with surgical disciplines to adverse outcome related to wrong-site occurrences. CONCLUSIONS: These data reveal a persisting high frequency of surgical "never events." Strict adherence to the Universal Protocol must be expanded to nonsurgical specialties to promote a zero-tolerance philosophy for these preventable incidents. PMID- 20956768 TI - Accelerating the pace of surgical quality improvement: the power of hospital collaboration. AB - HYPOTHESIS: A regional collaborative approach is an efficient platform for surgical quality improvement. DESIGN: Retrospective cohort study. SETTING: Academic research. PATIENTS: Patients undergoing general and vascular surgical procedures in 16 hospitals of the Michigan Surgical Quality Collaborative (MSQC) were evaluated quarterly to discuss surgical quality, to identify best practices, and to assess problems with process implementation. MAIN OUTCOME MEASURES: Results among MSQC patients were compared with those among 126 non-Michigan hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) over the same interval. RESULTS: A total of 315 699 patients were included in the analysis. To assess improvement, patients were stratified into 2 periods (T1 and T2). The 35 422 MSQC patients (10.7% morbidity in T1 vs 9.7% in T2 [9.0% reduction], P = .002) showed improvement, while 280 277 non-Michigan ACS NSQIP patients did not (12.4% morbidity in T1 and T2, P = .49). No improvements in mortality rates were noted in either group. Overall, the odds of experiencing a complication in T2 compared with T1 were significantly less in the MSQC group (odds ratio, 0.898) than in the non-Michigan ACS NSQIP group (odds ratio, 1.000) (P=.004). CONCLUSION: A statewide surgical quality improvement collaborative supported by a third-party payer showed significant improvement in quality and high levels of participant satisfaction. PMID- 20956769 TI - Reduced access to care resulting from centers of excellence initiatives in bariatric surgery. AB - OBJECTIVE: To determine the effect on travel distance for Medicare patients before and after Centers for Medicare & Medicaid Services required that bariatric procedures be performed at Centers of Excellence (COEs). DESIGN: We calculated the distance traveled to our medical center for the 2 years prior (2004-2005) and 2 years after (2006-2007) COE status was required by Medicare. We also compared the proportion of bariatric cases done in large hospitals with those for esophageal and pancreatic resections, procedures whose effects regionalization would have on patient access have been modeled. SETTING: University of Texas Southwestern Medical Center, a high-volume tertiary referral center for bariatric surgery. PATIENTS: Patients undergoing bariatric procedures. MAIN OUTCOME MEASURE: Travel distances. RESULTS: Depending on insurance status, before COEs were required, patients traveled a median of 16 to 25 miles to undergo bariatric operations at University of Texas Southwestern. After COEs were required, the median distance Medicare patients were required to travel increased 76% to 44 miles. CONCLUSIONS: Center of Excellence requirements have increased the travel distance required for Medicare patients. Prior research has shown that outcomes at COEs are no different than those at non-COEs suggesting that the reduced access to care resulting from requiring COE status is not beneficial. PMID- 20956770 TI - Hospital process compliance and surgical outcomes in medicare beneficiaries. AB - OBJECTIVES: To determine whether high rates of compliance with perioperative processes of care used for public reporting and pay-for-performance are associated with lower rates of risk-adjusted mortality and high-risk surgical complications. DESIGN: Retrospective analysis of Medicare inpatient claims data (from January 1, 2005, through December 31, 2006). Hierarchical logistic regression models assessed the relationship between adverse outcomes and hospital compliance with the surgical processes of care reported on the Hospital Compare Web site. SETTING: Two thousand US hospitals. PARTICIPANTS: Beneficiaries who underwent 1 of 6 high-risk operations in 2005 and 2006. MAIN OUTCOME MEASURES: Thirty-day postoperative mortality rate, venous thromboembolism, and surgical site infection. RESULTS: Process compliance ranged from 53.7% in low compliance hospitals to 91.4% in high compliance hospitals. Risk-adjusted outcomes did not vary at high compliance hospitals relative to medium compliance hospitals for mortality rate (odds ratio, 0.98; 95% confidence interval, 0.92-1.05), surgical site infection (1.01; 0.90-1.13), or venous thromboembolism (1.04; 0.89-1.20). Outcomes also did not vary at low compliance hospitals. Stratified analyses by operation type confirm these trends for the 6 procedures individually. CONCLUSIONS: Currently available information on the Hospital Compare Web site will not help patients identify hospitals with better outcomes for high-risk surgery. The Centers for Medicare and Medicaid Services needs to identify higher leverage process measures and devote greater attention to profiling hospitals based on outcomes to improve public reporting and pay-for-performance efforts. PMID- 20956771 TI - Thoracic aortic endografting for trauma: a current appraisal. AB - OBJECTIVE: To explore this newer treatment modality's benefits, technical concerns, and complications as currently understood during the management of patients with blunt aortic injury (BAI). DATA SOURCES: Data sources included relevant articles from published medical journals and current published texts. STUDY SELECTION: Assimilation of the pertinent world's literature into a select representation of the current status of thoracic aortic endografting for trauma's (TAET) performance and outcomes. DATA EXTRACTION: Comprehensive review of the current literature on BAI. DATA SYNTHESIS: Comparison and critical evaluation of the current literature. CONCLUSIONS: Endografting is the most frequently used method for repair of BAI. The use of TAET has led to reductions in operative mortality and spinal cord ischemia. Although experience seems promising, a new array of early and late complications must be considered. The positive experience with TAET thus far has provided impetus for endograft engineering and clinical trials specifically for BAI therapy. The ultimate late durability of TAET remains to be defined. PMID- 20956772 TI - Prevalence of burnout among surgical residents and surgeons in Switzerland. AB - Burnout is a pathologic reaction in response to long-term work-related stress. The aim of this study was 2-fold: first, to assess the prevalence and degree of burnout among surgical residents and surgeons in Switzerland and, second, to identify predictors of burnout in the surgical community. Four hundred five of 618 anonymous questionnaires (65.5%) were returned. Among respondents, 3.7% and 35.1% showed high and moderate degrees of burnout, respectively. Respondents with high and moderate degrees of burnout had higher summary scores of perceived stress (P < .001). In multiple logistic regression analysis, the strongest predictors of burnout were poor interaction with nurses, disturbances due to telephone consultations, and high overall workload. To reduce burnout, new work models should be sought, in addition to decreasing work intensity and workload rather than restricting work hours alone. PMID- 20956773 TI - Image of the month--quiz case. Antiphospholipid antibody syndrome. PMID- 20956774 TI - Image of the month--quiz case. Gastric duplication cyst. PMID- 20956775 TI - Open mesh repair of ventral incisional hernias with tacker with less complication. PMID- 20956776 TI - Energized dissection, energized hemostasis. PMID- 20956777 TI - Micrometastasis and axillary dissection in breast cancer. PMID- 20956778 TI - Surgical innovators past and present. PMID- 20956779 TI - Teaching hospital status and operative mortality in the United States. PMID- 20956780 TI - Failure to consider the number of dissected sides can bias complication rate calculations of central lymph node dissection for thyroid cancer. PMID- 20956781 TI - Genetics and breast cancer risk prediction--are we there yet? PMID- 20956783 TI - Teaching NeuroImages: hemispheric-onset Creutzfeldt-Jakob disease with concordant MRI and EEG findings. PMID- 20956782 TI - Assessment of clinical validity of a breast cancer risk model combining genetic and clinical information. AB - BACKGROUND: The Gail model is widely used for the assessment of risk of invasive breast cancer based on recognized clinical risk factors. In recent years, a substantial number of single-nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified. However, it remains unclear how to effectively integrate clinical and genetic risk factors for risk assessment. METHODS: Seven SNPs associated with breast cancer risk were selected from the literature and genotyped in white non-Hispanic women in a nested case-control cohort of 1664 case patients and 1636 control subjects within the Women's Health Initiative Clinical Trial. SNP risk scores were computed based on previously published odds ratios assuming a multiplicative model. Combined risk scores were calculated by multiplying Gail risk estimates by the SNP risk scores. The independence of Gail risk and SNP risk was evaluated by logistic regression. Calibration of relative risks was evaluated using the Hosmer-Lemeshow test. The performance of the combined risk scores was evaluated using receiver operating characteristic curves. The net reclassification improvement (NRI) was used to assess improvement in classification of women into low (<1.5%), intermediate (1.5%-2%), and high (>2%) categories of 5-year risk. All tests of statistical significance were two-sided. RESULTS: The SNP risk score was nearly independent of Gail risk. There was good agreement between predicted and observed SNP relative risks. In the analysis for receiver operating characteristic curves, the combined risk score was more discriminating, with area under the curve of 0.594 compared with area under the curve of 0.557 for Gail risk alone (P < .001). Classification also improved for 5.6% of case patients and 2.9% of control subjects, showing an NRI value of 0.085 (P = 1.0 * 10-5). Focusing on women with intermediate Gail risk resulted in an improved NRI of 0.195 (P = 8.6 * 10-5). CONCLUSIONS: Combining validated common genetic risk factors with clinical risk factors resulted in modest improvement in classification of breast cancer risks in white non-Hispanic postmenopausal women. Classification performance was further improved by focusing on women at intermediate risk. PMID- 20956784 TI - Teaching NeuroImages: ultrasound findings in giant-cell arteritis. PMID- 20956785 TI - Beauty and the beast: B12, homocysteine, and the brain: a bemusing saga! PMID- 20956786 TI - Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study. AB - OBJECTIVE: To examine the relation between serum levels of homocysteine (tHcy) and holotranscobalamin (holoTC), the active fraction of vitamin B12, and risk of incident Alzheimer disease (AD) in a sample of Finnish community-dwelling elderly. METHODS: A dementia-free sample of 271 subjects aged 65-79 years derived from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study was followed up for 7 years to detect incident AD. The association between serum tHcy and holoTC with AD was analyzed with multiple logistic regression after adjusting for several potential confounders, including common vascular risk factors. RESULTS: The odds ratios (ORs) (95% confidence interval [CI]) for AD were 1.16 (1.04-1.31) per increase of 1 MUmol/L of tHcy at baseline and 0.980 (0.965-0.995) for each increase of 1 pmol/L baseline holoTC. Adjustment for several potential confounders including age, sex, education, APOE epsilon4 allele, body mass index, Mini-Mental State Examination, smoking, stroke, and blood pressure did not alter the associations: ORs (95% CI) for AD became 1.19 (1.01-1.39) for tHcy and 0.977 (0.958-0.997) for holoTC. Adjusting for holoTC attenuated the tHcy-AD link (OR changed from 1.16 to 1.10, 95% CI 0.96-1.25). The holoTC-AD relationship was less influenced by controlling for tHcy (OR changed from 0.980 to 0.984, 95% CI 0.968 1.000). Addition of folate did not change any of the results. CONCLUSIONS: This study suggests that both tHcy and holoTC may be involved in the development of AD. The tHcy-AD link may be partly explained by serum holoTC. The role of holoTC in AD should be further investigated. PMID- 20956787 TI - Premorbid cognitive leisure independently contributes to cognitive reserve in multiple sclerosis. AB - OBJECTIVE: Consistent with the cognitive reserve hypothesis, higher education and vocabulary help persons with Alzheimer disease (AD) and multiple sclerosis (MS) better withstand neuropathology before developing cognitive impairment. Also, premorbid cognitive leisure (e.g., reading, hobbies) is an independent source of cognitive reserve for elders with AD, but there is no research on the contribution of leisure activity to cognition in MS. We investigated whether premorbid cognitive leisure protects patients with MS from cognitive impairment. METHODS: Premorbid cognitive leisure was surveyed in 36 patients with MS. Neurologic disease severity was estimated with brain atrophy, measured as third ventricle width on high-resolution MRI. Cognitive status was measured with a composite score of processing speed and memory. RESULTS: Controlling for brain atrophy, premorbid cognitive leisure was positively associated with current cognitive status (r(p) = 0.49, p < 0.01), even when controlling for vocabulary (r(p) = 0.39, p < 0.05) and education (r(p) = 0.47, p < 0.01). Also, premorbid cognitive leisure was unrelated to brain atrophy (r = 0.03, p > 0.5), but a positive partial correlation between leisure and atrophy emerged when controlling for cognitive status (r(p) = 0.37, p < 0.05), which remained when also controlling for vocabulary (r(p) = 0.34, p < 0.05) and education (r(p) = 0.35, p < 0.05). CONCLUSIONS: Premorbid cognitive leisure contributes to cognitive status in patients with MS independently of vocabulary and education. Also, patients with MS who engaged in more cognitive leisure were able to withstand more severe brain atrophy at a given cognitive status. Premorbid cognitive leisure is supported as an independent source of cognitive reserve in patients with MS. PMID- 20956788 TI - Prevalence of multiple sclerosis in Korea. AB - OBJECTIVE: The aim of this study was to estimate the prevalence of multiple sclerosis (MS) in Korea through a nationwide survey. METHODS: We estimated the prevalence of MS in Korea using several sources collected between 2000 and 2005: verified cases from 38 major referral hospitals across the nation, the National Health Insurance (NHI) payment request data from NHI Corporation of Korea, and the national mortality dataset from Statistics Korea. We established a network of neurologists from 38 major referral hospitals and performed a nationwide hospital survey for MS cases. The diagnoses of MS were validated according to the McDonald criteria. The diagnostic validity of each hospital was evaluated from hospital survey data to reduce the uncertainty of NHI data and was applied to estimate the prevalence using novel statistical methods. RESULTS: The estimated numbers of MS cases in Korea through 2 different statistical methods which adjust NHI data by the diagnostic validity of each hospital were very similar: 1,681 (95% confidence interval [CI] 1,490-1,902) by the stratification method and 1,640 (95% CI 1,402 1,789) by the linear regression method. The crude MS prevalence was 3.5-3.6 cases per 100,000 individuals. The estimated female-to-male ratio was 1.26. CONCLUSION: This study is the first nationwide survey for the prevalence of MS in Korea utilizing a national database in complementary way. We found an increase in the prevalence of MS that is consistent with reports from neighboring Asian countries. PMID- 20956789 TI - Predictors of seizure freedom after incomplete resection in children. AB - OBJECTIVE: Incomplete resection of the epileptogenic zone (EZ) is the most important predictor of poor outcome after resective surgery for intractable epilepsy. We analyzed the contribution of preoperative and perioperative variables including MRI and EEG data as predictors of seizure-free (SF) outcome after incomplete resection. METHODS: We retrospectively reviewed patients <18 years of age with incomplete resection for epilepsy with 2 years of follow-up. Fourteen preoperative and perioperative variables were compared in SF and non-SF (NSF) patients. We compared lesional patients, categorized by reason for incompleteness, to lesional patients with complete resection. We analyzed for effect of complete EEG resection on SF outcome in patients with incompletely resected MRI lesions and vice versa. RESULTS: Eighty-three patients with incomplete resection were included with 41% becoming SF. Forty-eight lesional patients with complete resection were included. Thirty-eight percent (57/151) of patients with incomplete resection and 34% (47/138) with complete resection were excluded secondary to lack of follow-up or incomplete records. Contiguous MRI lesions were predictive of seizure freedom after incomplete resection. Fifty seven percent of patients incomplete by MRI alone, 52% incomplete by EEG alone, and 24% incomplete by both became SF compared to 77% of patients with complete resection (p = 0.0005). CONCLUSIONS: Complete resection of the MRI- and EEG defined EZ is the best predictor of seizure freedom, though patients incomplete by EEG or MRI alone have better outcome compared to patients incomplete by both. More than one-third of patients with incomplete resection become SF, with contiguous MRI lesions a predictor of SF outcome. PMID- 20956790 TI - SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain. AB - BACKGROUND: Inherited and de novo mutations in sodium channel genes underlie a variety of channelopathies. Mutations in SCN2A, encoding the brain sodium channel Na(V)1.2, have previously been reported to be associated with benign familial neonatal infantile seizures, febrile seizures plus, and intractable epilepsy of infancy. METHODS: We evaluated the clinical characteristics in a patient with a neonatal-onset complex episodic neurologic phenotype. We screened SCN2A for mutations and carried out in vitro electrophysiologic analyses to study the consequences of the identified mutation. We studied the developmental expression of Na(V)1.2 in cerebellum by immunohistochemical analysis. RESULTS: The patient presented with neonatal-onset seizures and variable episodes of ataxia, myoclonia, headache, and back pain after 18 months of age. The patient carries a de novo missense mutation (p.Ala263Val) in SCN2A, which leads to a pronounced gain-of-function, in particular an increased persistent Na(+) current. Immunohistochemical studies suggest a developmentally increasing expression of Na(V)1.2 in granule cell axons projecting to Purkinje neurons. CONCLUSIONS: These results can explain a neuronal hyperexcitability resulting in seizures and other episodic symptoms extending the spectrum of SCN2A-associated phenotypes. The developmentally increasing expression of Na(V)1.2 in cerebellum may be responsible for the later onset of episodic ataxia. PMID- 20956791 TI - Pontocerebellar hypoplasia: clinical, pathologic, and genetic studies. AB - BACKGROUND: Mutations in genes encoding subunits of the tRNA-splicing endonuclease (TSEN) complex were identified in patients with pontocerebellar hypoplasia 2 (PCH2) and pontocerebellar hypoplasia 4 (PCH4). OBJECTIVE: We report molecular genetic findings in 12 Italian patients with clinical and MRI findings compatible with PCH2 and PCH4. METHODS: We retrospectively selected a cohort of 12 children from 9 Italian families with MRI of hypoplastic pontocerebellar structures and clinical manifestations suggesting either PCH2 or PCH4 and submitted them to direct sequencing of the genes encoding the 4 subunits of the TSEN complex, namely TSEN54, TSEN34, TSEN15, and TSEN2. RESULTS: In a cohort of 12 children, we detected the common p.A307S mutation in TSEN54 in 9/12 available patients from nine unrelated families. We also detected a novel c.1170_1183del (p. V390fs39X) in compound heterozygosity with the common p.A307S in a child with a severe PCH4 phenotype. In another severely affected patient, the second mutant allele was not identified. Two sibs without mutations in the TSEN complex were unlinked to the PCH3 locus. In addition to typical clinical and neuroradiologic features of PCH2, both children were affected by a tubulopathy resembling Bartter syndrome. CONCLUSIONS: We confirm that the common p.A307S mutation in TSEN54 is responsible for most of the patients with a PCH2 phenotype. The presence of a heterozygous in/del variant correlates with a more severe phenotype as PCH4. In addition, we describe a new clinical form of PCH in 2 sibs with clinical and MRI features of PCH2. PMID- 20956793 TI - Histamine in the CNS: multiple functions and potential neurologic implications. PMID- 20956792 TI - Transcranial magnetic brain stimulation modulates blepharospasm: a randomized controlled study. AB - BACKGROUND: Benign essential blepharospasm (BEB) is a common form of focal dystonia. Besides pathology in the basal ganglia, accumulating evidence suggests pathologic changes in the anterior cingulate cortex (ACC). METHODS: This is a randomized, sham-controlled, observer-blinded prospective study. In 12 patients with BEB, we evaluated the effects of a 15-minute session of low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS) over the ACC with stimulation intensities at 100% active motor threshold with 3 stimulation coils: a conventional circular coil (C-coil), a sham coil (S-coil), and a Hesed coil (H coil, which allows stimulation of deeper brain regions. Primary outcome was the clinical effects on BEB (blink rate, number of spasms rated by a blinded physician and patient rating before, immediately after, and 1 hour after stimulation); secondary outcome was the blink reflex recovery curve. RESULTS: Subjective stimulation comfort was similar for each coil with no stimulation associated adverse events. Stimulation with the H- and C-coils resulted in a significant improvement in all 3 outcome measures and was still detectable in physician rating and patient rating 1 hour after stimulation. S-coil stimulation had no effects. The active motor threshold was significantly lower for the H-coil compared to the other 2 coils. CONCLUSIONS: rTMS could be used as a therapeutic tool in BEB. Further studies will be necessary to show whether repeated stimulation applications result in lasting clinical effects. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with BEB, H- and C-coil rTMS is safe and improves clinical symptoms of BEB immediately and 1 hour after stimulation. PMID- 20956794 TI - Neuroimages. Hypertrichosis in alopecia universalis and complex regional pain syndrome. PMID- 20956795 TI - Spinal cord stimulation failed to relieve akinesia or restore locomotion in Parkinson disease. PMID- 20956798 TI - Gender relations and applied research on aging. AB - As a concept in gerontology, gender appears as lists of traits learned through socialization when theorized at all. I argue for a framework that theorizes the intersections of relations of gender inequality with those of age. This framework holds that men and women gain resources and bear responsibilities, in relation to one another, by virtue of mundane categorization into naturalized stratified groups. Current research shows that this approach allows explanation of gender differences, which appear in many reports but which usually go untheorized, as responses to social inequality. I illustrate applications to research and practice in relation to three areas of old age experiences: financial security, spousal care work, and health. Throughout, I discuss implications of focusing on inequality to enhance our abilities to engage in effective research, practice, and policy for older people, women and men alike. For instance, an understanding of the gender division of labor and workplace discrimination makes clear that financial status in later life cannot be reduced to individual choices concerning paid labor or retirement planning. And understanding that people orient their behaviors to gender ideals allows us to see that men and women perform spousal care in similar and different ways that require varied responses from practitioners; it also reveals contexts in which men engage in positive health behaviors. Finally, I argue that gerontologists interested in facilitating favorable outcomes for old people should consider research and practice that would disrupt, not reinforce, the bases of gender inequalities in later life. PMID- 20956799 TI - Monocytes from HTLV-1-infected patients are unable to fully mature into dendritic cells. AB - Human T-cell lymphotropic virus type 1 (HTLV-1) is a causative agent of adult T cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. HTLV 1-associated myelopathy/tropical spastic paraparesis is a chronic inflammatory disease characterized by loss of motor movement in response to spinal marrow cell destruction by T lymphocytes. To perform their cellular function, T cells need to be activated by antigen-presenting cells, such as dendritic cells (DCs). The aim of this work was to analyze DC differentiation and activation from monocytes of HTLV-1-infected individuals. We demonstrated that monocytes from HTLV-1-infected patients who had been stimulated to differentiate had an impaired loss of CD14 expression, expressed low levels of CD1a, and maintained secretion of tumor necrosis factor-alpha compared with monocytes from noninfected donors. We further evaluated DC activation by tumor necrosis factor-alpha. We observed that in response to activation, DCs that were derived from noninfected donors had an increase in the percentage of CD83(+), CD86(+), and human leukocyte antigen-DR(+) cells, whereas in DCs derived from HTLV-1-infected patients, the percentage of CD83(+), CD86(+), and human leukocyte antigen-DR(+) cells remained similar to that of nonactivated cells. Moreover, these cells had an impaired capacity to stimulate allogeneic T lymphocytes. We demonstrated that DC maturation was altered in HTLV-1-infected patients, which could contribute to the development of HTLV-1-associated diseases. PMID- 20956800 TI - Histone deacetylase inhibitors impair innate immune responses to Toll-like receptor agonists and to infection. AB - Regulated by histone acetyltransferases and deacetylases (HDACs), histone acetylation is a key epigenetic mechanism controlling chromatin structure, DNA accessibility, and gene expression. HDAC inhibitors induce growth arrest, differentiation, and apoptosis of tumor cells and are used as anticancer agents. Here we describe the effects of HDAC inhibitors on microbial sensing by macrophages and dendritic cells in vitro and host defenses against infection in vivo. HDAC inhibitors down-regulated the expression of numerous host defense genes, including pattern recognition receptors, kinases, transcription regulators, cytokines, chemokines, growth factors, and costimulatory molecules as assessed by genome-wide microarray analyses or innate immune responses of macrophages and dendritic cells stimulated with Toll-like receptor agonists. HDAC inhibitors induced the expression of Mi-2beta and enhanced the DNA-binding activity of the Mi-2/NuRD complex that acts as a transcriptional repressor of macrophage cytokine production. In vivo, HDAC inhibitors increased the susceptibility to bacterial and fungal infections but conferred protection against toxic and septic shock. Thus, these data identify an essential role for HDAC inhibitors in the regulation of the expression of innate immune genes and host defenses against microbial pathogens. PMID- 20956801 TI - Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice. AB - As a central regulator of iron metabolism, hepcidin inhibits dietary iron absorption and macrophage iron recycling. Its expression is regulated by multiple factors including iron availability and erythropoietic activity. To investigate the role of transferrin (Tf) in the regulation of hepcidin expression by these factors in vivo, we employed the hypotransferrinemic (hpx) mouse. These Tf deficient mice have severe microcytic anemia, tissue iron overload, and hepcidin deficiency. To determine the relationship of Tf levels and erythropoiesis to hepcidin expression, we subjected hpx mutant and control mice to a number of experimental manipulations. Treatment of hpx mice with Tf injections corrected their anemia and restored hepcidin expression. To investigate the effect of erythropoiesis on hepcidin expression, we suppressed erythropoiesis with blood transfusions or myeloablation with chemotherapeutic drugs. Transfusion of hpx animals with wild-type red blood cells led to increased hepcidin expression, while hepcidin expression in myeloablated hpx mice increased only if Tf was administered postablation. These results suggest that hepcidin expression in hpx mice is regulated both by Tf-restricted erythropoiesis and by Tf through a mechanism independent of its role in erythropoiesis. PMID- 20956802 TI - Combinatorial and distinct roles of alpha5 and alpha4 integrins in stress erythropoiesis in mice. AB - To delineate the role of specific members of beta1 integrins in stress erythropoiesis in the adult, we compared the response to phenylhydrazine stress in 3 genetically deficient models. The survival of beta1-conditionally deficient mice after phenylhydrazine is severely compromised because of their inability to mount a successful life saving splenic erythroid response, a phenotype reproduced in beta1(Delta/Delta) reconstituted animals. The response of bone marrow to phenylhydrazine-induced stress was, unlike that of spleen, appropriate in terms of progenitor cell expansion and mobilization to peripheral blood although late differentiation defects qualitatively similar to those in spleen were present in bone marrow. In contrast to beta1-deficient mice, alpha4(Delta/Delta) mice showed only a kinetic delay in recovery and similar to beta1(Delta/Delta), terminal maturation defects in both bone marrow and spleen, which were not present in VCAM 1(Delta/Delta) mice. Convergence of information from these comparative studies lends new insight to the distinct in vivo roles of alpha4 and alpha5 integrins in erythroid stress, suggesting that the presence of mainly alpha5beta1 integrin in all hematopoietic progenitor cells interacting with splenic microenvironmental ligands/cells is instrumental for their survival and accumulation during hemolytic stress, whereas presence of alpha4 or of both alpha5 and alpha4, is important for completion of terminal maturation steps. PMID- 20956803 TI - Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation. AB - Bortezomib induces remissions in 30%-50% of patients with relapsed mantle cell lymphoma (MCL). Conversely, more than half of patients' tumors are intrinsically resistant to bortezomib. The molecular mechanism of resistance has not been defined. We generated a model of bortezomib-adapted subclones of the MCL cell lines JEKO and HBL2 that were 40- to 80-fold less sensitive to bortezomib than the parental cells. Acquisition of bortezomib resistance was gradual and reversible. Bortezomib-adapted subclones showed increased proteasome activity and tolerated lower proteasome capacity than the parental lines. Using gene expression profiling, we discovered that bortezomib resistance was associated with plasmacytic differentiation, including up-regulation of IRF4 and CD38 and expression of CD138. In contrast to plasma cells, plasmacytic MCL cells did not increase immunoglobulin secretion. Intrinsically bortezomib-resistant MCL cell lines and primary tumor cells from MCL patients with inferior clinical response to bortezomib also expressed plasmacytic features. Knockdown of IRF4 was toxic for the subset of MCL cells with plasmacytic differentiation, but only slightly sensitized cells to bortezomib. We conclude that plasmacytic differentiation in the absence of an increased secretory load can enable cells to withstand the stress of proteasome inhibition. Expression of CD38 and IRF4 could serve as markers of bortezomib resistance in MCL. This study has been registered at http://clinicaltrials.gov as NCT00131976. PMID- 20956804 TI - Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis. AB - Dendritic cells (DCs) play a pivotal role in the pathogenesis of inflammatory disorders, so suppressing the activity of DCs is instrumental in treating such diseases. In the present study, we show that a proteasome inhibitor, bortezomib, suppresses the survival and immunostimulatory function of human plasmacytoid DCs (pDCs) by targeting 2 critical points, intracellular trafficking of nucleic acid sensingToll-like receptors (TLRs) and endoplasmic reticulum (ER) homeostasis. Among the immune cells in blood, pDCs were the most susceptible to the killing effect of bortezomib. This correlates with a decrease in the spliced form of a transcription factor XBP1, which rescues cells from apoptosis by maintaining ER homeostasis. Bortezomib suppressed the production of interferon-alpha and interleukin-6 by pDCs activated with a TLR9-stimulating CpG DNA and a TLR7 stimulating influenza virus, which appears to be partially independent of apoptosis. Bortezomib inhibited translocation of TLR9 from the ER to endolysosomes but not of an ER membrane protein, Unc93B1, that delivers TLR9 to endolysosomes. Thus, bortezomib suppresses the activity of pDCs by inhibiting intracellular trafficking of TLRs through disrupting the coordinated translocation of TLRs and Unc93B1 and by disturbing ER homeostasis. This study suggests that proteasome inhibitors may alleviate inflammatory disorders such as lupus and psoriasis that involve pDCs. PMID- 20956805 TI - The prolyl isomerase Pin1 acts as a novel molecular switch for TNF-alpha-induced priming of the NADPH oxidase in human neutrophils. AB - Neutrophils play a key role in host defense by releasing reactive oxygen species (ROS). However, excessive ROS production by neutrophil nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can damage bystander tissues, thereby contributing to inflammatory diseases. Tumor necrosis factor-alpha (TNF-alpha), a major mediator of inflammation, does not activate NADPH oxidase but induces a state of hyperresponsiveness to subsequent stimuli, an action known as priming. The molecular mechanisms by which TNF-alpha primes the NADPH oxidase are unknown. Here we show that Pin1, a unique cis-trans prolyl isomerase, is a previously unrecognized regulator of TNF-alpha-induced NADPH oxidase hyperactivation. We first showed that Pin1 is expressed in neutrophil cytosol and that its activity is markedly enhanced by TNF-alpha. Inhibition of Pin1 activity with juglone or with a specific peptide inhibitor abrogated TNF-alpha-induced priming of neutrophil ROS production induced by N-formyl-methionyl-leucyl-phenylalanine peptide (fMLF). TNF-alpha enhanced fMLF-induced Pin1 and p47phox translocation to the membranes and juglone inhibited this process. Pin1 binds to p47phox via phosphorylated Ser345, thereby inducing conformational changes that facilitate p47phox phosphorylation on other sites by protein kinase C. These findings indicate that Pin1 is critical for TNF-alpha-induced priming of NADPH oxidase and for excessive ROS production. Pin1 inhibition could potentially represent a novel anti-inflammatory strategy. PMID- 20956806 TI - Evolution of protein phosphorylation for distinct functional modules in vertebrate genomes. AB - Recent publications have revealed that the evolution of phosphosites is influenced by the local protein structures and whether the phosphosites have characterized functions or not. With knowledge of the wide functional range of phosphorylation, we attempted to clarify whether the evolutionary conservation of phosphosites is different among distinct functional modules. We grouped the phosphosites in the human genome into the modules according to the functional categories of KEGG (Kyoto Encyclopedia of Genes and Genomes) and investigated their evolutionary conservation in vertebrate genomes from mouse to zebrafish. We have found that the phosphosites in the vertebrate-specific functional modules (VFMs), such as cellular signaling processes and responses to stimuli, are evolutionarily more conserved than those in the basic functional modules (BFMs), such as metabolic and genetic processes. The phosphosites in the VFMs are also significantly more conserved than their flanking regions, whereas those in the BFMs are not. These results hold for both serine/threonine and tyrosine residues, although the fraction of phosphorylated tyrosine residues is increased in the VFMs. Moreover, the difference in the evolutionary conservation of the phosphosites between the VFMs and BFMs could not be explained by the difference in the local protein structures. There is also a higher fraction of phosphosites with known functions in the VFMs than BFMs. Based on these findings, we have concluded that protein phosphorylation may play more dominant roles for the VFMs than BFMs during the vertebrate evolution. As phosphorylation is a quite rapid biological reaction, the VFMs that quickly respond to outer stimuli and inner signals might heavily depend on this regulatory mechanism. Our results imply that phosphorylation may have an essential role in the evolution of vertebrates. PMID- 20956807 TI - Effect of age and affection status on blood pressure, serum potassium and stature in familial hyperkalaemia and hypertension. AB - BACKGROUND: The rare autosomal dominant genetic disorder familial hyperkalemia and hypertension which is caused by mutations in WNK4 kinase, is characterized by childhood hyperkalemia and hypercalciuria, and appearance of hypertension in the third to fourth decade. Accompanying short stature is often described. METHODS: We determined height, blood pressure and blood and urinary biochemical parameters in members of a very large family of FHHt with the WNK4 Q565E mutation. RESULTS: The family has 57 members, 30 of whom (including 14 children) are affected. Prehypertension occurred in 7/11 affected and 1/10 unaffected children (P = 0.024). Serum potassium (SK) was ~0.5 mmol/L higher in affected children vs adults [5.98 +/- 0.42 vs 5.46 +/- 0.40 mmol/L, respectively (P < 0.0001)] (33 samples from 11 children and 36 samples from eight adults). SK of >= 6.0 mmol/L occurred in 16/33 children's samples and in 3/36 adults' samples (P = 0.0003). Hyperkalaemia in children is currently untreated. Children also had more severe hyperchloraemia and hypercalciuria. The family contains four large subfamilies, and each includes 8-10 siblings. In one subfamily, height Z-score was lower in affected vs unaffected subjects [- 2.69 +/- 0.36 vs -1.05 +/- 0.16, respectively (P < 0.0001)]. In the other three subfamilies, no such difference was found. CONCLUSIONS: Short stature is not part of FHHt with the WNK4 Q565E mutation. Children affected with FHHt have a high prevalence of prehypertension, and their hyperkalaemia is more severe than that of affected adults. Children may have a more severe defect in the basic mechanism that produces hyperkalaemia. We suggest that, in affected adults, the attenuation of hyperkalaemia and appearance of hypertension may be the result of a late rise in the activity of renal transporters or channels such as the epithelial sodium channel. PMID- 20956808 TI - Circulating cells and dialysis: improving cell number or increasing session number? PMID- 20956809 TI - Defining acute kidney injury: playing hide-and-seek with the unknown man? PMID- 20956810 TI - Vascular calcification and 25-hydroxyvitamin D levels in non-dialysis patients with chronic kidney disease stages 4 and 5. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death among chronic kidney disease (CKD) patients. Vascular calcification is highly prevalent in this population and is an independent predictor of cardiovascular mortality. Vascular calcification in uraemic patients is known to be an active and regulated process subject to the action of many promoting and inhibitory factors. The role of vitamin D in this process remains controversial. We evaluated the relationship between serum levels of 25-hydroxyvitamin D (25(OH)D) and vascular calcification evaluated by plain X-ray images, in predialysis patients with CKD stages 4 and 5. METHODS: We performed a cross-sectional study with 210 CKD patients stages 4 and 5 managed at our predialysis unit. Patients were 63.5 +/- 13 years of age, 60.5% males, 64.8% diabetics and 47.1% with a history of CVD. Plain X-ray images of pelvis, hands and lateral lumbar spine from all subjects were studied for calculation of semiquantitative vascular calcification scores as described by Adragao and Kauppila. RESULTS: We found a high prevalence of vascular calcification in our population. Adragao scores revealed only 47 patients (22.4%) without vascular calcification and 120 (57.1%) with scores higher than 3. Kauppila scores revealed only 29 patients (13.8%) without aortic calcifications and 114 patients (54.3%) with scores higher than 7. Higher vascular calcification scores were related to older age, diabetes, history of CVD and lower levels of 25(OH)D. Only 18.5% of patients had adequate levels of 25(OH)D (> 30 ng/mL), 53.7% of them had insufficient levels (15-30 ng/mL) and 27.8% had deficient levels (< 15 ng/mL). Multivariate analysis showed that age, diabetes and CVD were directly associated and 25(OH)D levels were inversely associated with vascular calcifications. CONCLUSIONS: Our results show an independent and negative association between serum levels of 25(OH)D and vascular calcification. Further and larger prospective studies are needed to clarify the possible role of vitamin D deficiency in the development of vascular calcification in CKD patients. PMID- 20956812 TI - National Institutes of Health State-of-the-Science Conference on the Management and Diagnosis of Ductal Carcinoma in Situ: a call to action. PMID- 20956811 TI - Bisphenol A impairs follicle growth, inhibits steroidogenesis, and downregulates rate-limiting enzymes in the estradiol biosynthesis pathway. AB - Bisphenol A (BPA) is used as the backbone for plastics and epoxy resins, including various food and beverage containers. BPA has also been detected in 95% of random urine samples and ovarian follicular fluid of adult women. Few studies have investigated the effects of BPA on antral follicles, the main producers of sex steroid hormones and the only follicles capable of ovulation. Thus, this study tested the hypothesis that postnatal BPA exposure inhibits antral follicle growth and steroidogenesis. To test this hypothesis, antral follicles isolated from 32-day-old FVB mice were cultured with vehicle control (dimethyl sulfoxide [DMSO]), BPA (4.4-440 MUM), pregnenolone (10 MUg/ml), pregnenolone + BPA 44 MUM, and pregnenolone + BPA 440 MUM. During the culture, follicles were measured for growth daily. After the culture, media was subjected to ELISA for hormones in the estradiol biosynthesis pathway, and follicles were processed for quantitative real-time PCR of steroidogenic enzymes. The results indicate that BPA (440 MUM) inhibits follicle growth and that pregnenolone cotreatment was unable to restore/maintain growth. Furthermore, BPA 44 and 440 MUM inhibit progesterone, dehydroepiandrosterone, androstenedione, estrone, testosterone, and estradiol production. Pregnenolone cotreatment was able to increase production of pregnenolone, progesterone, and dehydroepiandrosterone and maintain androstenedione and estrone levels in BPA-treated follicles compared with DMSO controls but was unable to protect testosterone or estradiol levels. Furthermore, pregnenolone was unable to protect follicles from BPA-(44-440 MUM) induced inhibition of steroidogenic enzymes compared with the DMSO control. Collectively, these data show that BPA targets the estradiol biosynthesis pathway in the ovary. PMID- 20956813 TI - Ductal carcinoma in situ: risk factors and impact of screening. AB - BACKGROUND: The National Institutes of Health Office of Medical Applications of Research commissioned a structured literature review on the incidence of ductal carcinoma in situ (DCIS) as a background paper for the State of the Science Conference on Diagnosis and Management of DCIS. METHODS: Published studies were abstracted from MEDLINE and other sources. We include articles published through January 31, 2009; 92 publications were abstracted. RESULTS: DCIS incidence rose from 1.87 per 100,000 in 1973-1975 to 32.5 per 100,000 in 2005. Increases in incidence were greatest in tumors without comedo necrosis. Incidence increased in all ages but more in women older than 50 years. Increased use of mammography explains some but not all of the increased incidence. Risk factors for incident DCIS include older age and positive family history. Whereas tamoxifen prevents both invasive breast cancer and DCIS, raloxifene is associated with decreased invasive breast cancer but not decreased DCIS. CONCLUSIONS: Scientific questions deserving further investigation include the relationship between mammography use and DCIS incidence and the role of chemoprevention for reducing the incidence of DCIS and invasive breast cancer. PMID- 20956814 TI - The impact of sentinel lymph node biopsy and magnetic resonance imaging on important outcomes among patients with ductal carcinoma in situ. AB - The objective of this systematic review was to determine the impact of sentinel lymph node (SLN) biopsy and breast magnetic resonance imaging (MRI) on important outcomes for patients with ductal carcinoma in situ. We identified no study that directly evaluated important outcomes for SLN biopsy. So, we determined the incidence of SLN metastases among patients with ductal carcinoma in situ. Using American Joint Committee on Cancer criteria, the incidence of pN1 and pN1(mic) SLN metastases were 0.9% and 1.5%, respectively. Because the incidence of SLN metastasis is very low, SLN biopsy is not likely to affect important outcomes. We identified one study that directly evaluated important outcomes after breast MRI. In this study, the use of MRI did not affect local recurrence rates after breast conserving surgery and radiation. Although MRI may identify occult multicentric or contralateral breast cancer in some patients, it may also lead to unnecessary biopsies and overtreatment. PMID- 20956816 TI - The impact of surgery, radiation, and systemic treatment on outcomes in patients with ductal carcinoma in situ. AB - BACKGROUND: Ductal carcinoma in situ (DCIS) is associated with low rates of mortality. Outcomes are generally assessed in terms of recurrence. METHODS: Published studies were abstracted from MEDLINE and other sources. We include articles published through January 31, 2009; 10 publications of five randomized controlled trials and 133 publications of 64 observational studies were reviewed. RESULTS: Whole-breast radiation therapy following breast-conserving surgery (BCS) was consistently associated with a reduced incidence of local DCIS recurrence and local invasive carcinoma. Women undergoing mastectomy were less likely than women undergoing lumpectomy with or without radiation to experience local DCIS or invasive recurrence. Tamoxifen use reduced risk of recurrent DCIS or invasive carcinoma. CONCLUSIONS: BCS plus radiation and mastectomy appear to yield equivalent outcomes, whereas BCS alone tends to be inferior to mastectomy. Tamoxifen seems helpful in treating DCIS. PMID- 20956815 TI - Association between patient and tumor characteristics with clinical outcomes in women with ductal carcinoma in situ. AB - We synthesized the evidence of the association between patient and tumor characteristics with clinical outcomes in women with ductal carcinoma in situ of the breast. We identified five randomized controlled clinical trials and 64 observational studies that were published in English from January 1970 to January 2009. Younger women with clinically presented ductal carcinoma in situ had higher risk of ipsilateral recurrent cancer. African Americans had higher mortality and greater rates of advanced recurrent cancer. Women with larger tumor size, comedo necrosis, worse pathological grading, positive surgical margins, and at a higher risk category, using a composite prognostic index, had worse outcomes. Inconsistent evidence suggested that positive HER2 receptor and negative estrogen receptor status were associated with worse outcomes. Synthesis of evidence was hampered by low statistical power to detect significant differences in predictor categories and inconsistent adjustment practices across the studies. Future research should address composite prediction indices among race groups for all outcomes. PMID- 20956817 TI - Ductal carcinoma in situ: terminology, classification, and natural history. AB - Ductal carcinoma in situ (DCIS) refers to breast epithelial cells that have become "cancerous" but still reside in their normal place in the ducts and lobules. In this setting, cancerous means that there is an abnormal increase in the growth of the epithelial cells, which accumulate within and greatly expand the ducts and lobules. DCIS is a nonlethal type of cancer because it stays in its normal place. However, DCIS is very important because it is the immediate precursor of invasive breast cancers, which are potentially lethal. This article provides a general overview of DCIS, including historical perspective, methods of classification, current perspective, and future goals. PMID- 20956818 TI - Epidemiology of ductal carcinoma in situ. AB - Ductal carcinoma in situ (DCIS) is a relatively common diagnosis among women undergoing screening mammography. The greatest increases in DCIS incidence have been in non-comedo subtypes of DCIS that are not associated with subsequent invasive cancer. After a 500% increase in DCIS from 1983 to 2003, the incidence of DCIS declined in women aged 50 years and older, whereas the incidence in women younger than age 50 continues to increase. Having undergone mammography is one of the strongest and most prevalent risk factors associated with a diagnosis of DCIS. Other risk factors for DCIS are similar to that for invasive cancer including increasing age, family history of breast cancer, high mammographic breast density, and postmenopausal hormone therapy use. Treatment for DCIS is relatively aggressive with the use of both surgery and radiation therapy and most recently adjuvant hormonal therapy. Breast cancer mortality is low and similar with all types of treatment. New information regarding incidence of DCIS and subtypes of DCIS according to frequency of mammography and risk factors could lead to insights into the biology of DCIS. PMID- 20956819 TI - Mode of detection and secular time for ductal carcinoma in situ. AB - In this article, the published literature on the role of screening mammography in the detection of ductal carcinoma in situ (DCIS) is reviewed. This includes what is known about the detection of DCIS in different demographic groups. Finally the author describes her views on how the field might be advanced. PMID- 20956820 TI - Sentinel lymph node biopsy and management of the axilla in ductal carcinoma in situ. AB - Ductal carcinoma in situ (DCIS) of the breast historically has been a disease detected by physical examination, diagnosed by open surgical biopsy, and treated by mastectomy and axillary dissection. It is now increasingly detected by screening mammography, diagnosed by needle core biopsy, and treated by lumpectomy, with axillary dissection having been abandoned and sentinel node biopsy being used in axillary staging. However, outcomes related to sentinel node biopsy in DCIS have not been validated in well-controlled clinical trials. Current guideline recommendations are to use sentinel node biopsy when needle core biopsy is highly suspicious for invasive cancer or where there is a high risk DCIS when lumpectomy identifies invasive breast cancer with the DCIS, or when mastectomy is performed for extensive DCIS. Routine use of sentinel node biopsy for DCIS is not supported. PMID- 20956821 TI - Magnetic resonance imaging in the evaluation of ductal carcinoma in situ. AB - Before 2000, breast magnetic resonance imaging (MRI) was considered a relatively poor imaging tool for ductal carcinoma in situ (DCIS), as a high percentage of false-negative magnetic resonance examinations were cases of DCIS. Three specific shifts in breast MRI occurred, which changed this assessment: 1) a shift from high temporal to high spatial imaging, revealing specific morphological features on MRI suspicious for DCIS; 2) a shift from diagnostic studies of patients with cancers identified on mammography to screening studies of high-risk patients, allowing more accurate comparisons of mammography vs MRI in detecting the full spectrum of breast cancers regardless of appearance on mammography; and 3) a shift from emphasis on masses to improved understanding of features of non-mass like malignant lesions, distinct from benign background parenchymal enhancement patterns. Over the last decade, research has confirmed that of all imaging tools, MRI has the highest sensitivity in detection of DCIS (compared with mammography and ultrasound). Future studies are needed to clarify how best to use this tool for improved patient outcomes. PMID- 20956822 TI - Local control of ductal carcinoma in situ based on tumor and patient characteristics: the surgeon's perspective. AB - Ductal carcinoma in situ (DCIS) is a disease whose manifestations are largely confined to in-breast pathology. Management strategies therefore focus on various combinations of local therapy: mastectomy, lumpectomy alone, and lumpectomy followed by breast irradiation. Although DCIS does not carry an inherent risk of distant organ metastasis, optimal local control is essential because any in breast or chest wall recurrence may occur as an invasive lesion. Local recurrence has been reported following breast-conserving surgery as well as mastectomy. Breast radiation is therefore generally recommended following breast-conserving surgery, and in selected circumstances, mastectomy may be the preferred treatment strategy. This article reviews the surgical and associated clinicopathologic issues related to initial biopsy and perioperative planning that should be considered for all DCIS cases to optimize local control. PMID- 20956823 TI - Local outcomes in ductal carcinoma in situ based on patient and tumor characteristics. AB - The term ductal carcinoma in situ (DCIS) encompasses a heterogeneous group of lesions that differ in their clinical behavior. Clinical factors such as symptomatic presentation and young age are associated with an increased risk of local recurrence in patients with DCIS managed with breast-conserving therapy. Treatment factors such as wider surgical margins, the use of radiation therapy, and the use of tamoxifen reduce the local recurrence risk. Pathological characteristics such as larger lesion size, high nuclear grade, comedo necrosis, and involved margins are associated with an increased risk of local recurrence in many studies. However, there are complex interactions between these pathological risk factors and other parameters such as treatment and length of follow-up. In fact, the magnitude of the effect of these pathological features on local recurrence risk is modified by these other factors. Analysis of genetic and molecular alterations as well as study of the microenvironment associated with DCIS are important avenues of research that may provide new insights into DCIS recurrence and progression risk, and this in turn may lead to new strategies for treatment and prevention. PMID- 20956825 TI - Local and systemic outcomes in DCIS based on tumor and patient characteristics: the radiation oncologist's perspective. AB - Four randomized clinical trials have shown unanimously the benefit of 50 Gy whole breast radiotherapy in breast-conserving therapy (BCT) for ductal carcinoma in situ (DCIS). The risk of both DCIS and invasive local recurrence is reduced with about 50%, and this effect is similar for all clinical and histological subgroups analyzed. Younger age and involved margin status are the most important factors for an increased risk of local recurrence. In these subgroups, even with radiotherapy, the observed local recurrence rates are more than 20% at 10 years, which is considerably higher than reported local recurrence rates after BCT for invasive breast cancer. The optimal radiotherapy dose in BCT for DCIS has yet to be established. Also, at present, a subgroup of lesions in which the recurrence rate is so low that radiotherapy can be safely omitted has not yet been identified. PMID- 20956826 TI - Carcinoma in situ outcomes in National Surgical Adjuvant Breast and Bowel Project Breast Cancer Chemoprevention Trials. AB - BACKGROUND: In the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT), the reduction in risk of noninvasive breast cancer was 50%. There were 93 cases in women receiving placebo and 60 in those receiving tamoxifen (P = .008). Through 7 years of follow-up, the cumulative incidence of noninvasive breast cancer among the placebo group was 15.8 per 1000 women vs 10.2 per 1000 women in the tamoxifen group. In the initial report of the Study of Tamoxifen and Raloxifene (STAR trial), the rate for noninvasive breast cancer was 1.51 per 1000 women assigned to tamoxifen and 2.11 per 1000 women assigned to raloxifene (risk ratio, 1.40; 95% confidence interval = 0.98 to 2.00). METHODS: Additional follow-up of the NSABP STAR trial through March 31, 2009 is reported with a focus on noninvasive breast cancer events. RESULTS: Through 81 months of median follow-up in the NSABP STAR trial, there are 137 cases of noninvasive breast cancer in the raloxifene group compared with 111 cases in the tamoxifen group (risk ratio = 1.02, 95% confidence interval = 0.61 to 1.70). The occurrence of ductal carcinoma in situ with raloxifene was seen more frequently among women with lower baseline Gail scores and no atypical hyperplasia than in women taking tamoxifen therapy. Raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive breast cancer. CONCLUSIONS: Although these data indicate that raloxifene offers less protection than tamoxifen for postmenopausal women who are at increased risk for both invasive and noninvasive breast cancer, the favorable risk-benefit profile for raloxifene affords acceptable clinical reduction in the risk of in situ cancers among postmenopausal women. PMID- 20956827 TI - The impact of adding radiation treatment after breast conservation surgery for ductal carcinoma in situ of the breast. AB - Ductal carcinoma in situ (DCIS; intraductal carcinoma) is most commonly detected as suspicious microcalcifications on routine screening mammography in an asymptomatic woman. As most women with newly diagnosed DCIS are eligible for breast conservation treatment, a major decision for most women is whether or not to add radiation treatment after surgical excision (lumpectomy). In four prospective randomized clinical trials, the addition of radiation treatment after lumpectomy reduced the risk of local recurrence by approximately 50%, both for overall local recurrence and for the subset of invasive local recurrence. Nonetheless, efforts have continued to attempt to identify a subset of patients with favorable DCIS who are at sufficiently low risk of local recurrence that omitting radiation treatment is reasonable. Prospective and retrospective studies have demonstrated excellent long-term outcomes at 10 and 15 years after breast conservation treatment with radiation. Careful follow-up, including yearly surveillance mammography, after initial breast conservation treatment with radiation is warranted for the early detection of potentially salvageable local and local-regional recurrences. PMID- 20956828 TI - Choosing treatment for patients with ductal carcinoma in situ: fine tuning the University of Southern California/Van Nuys Prognostic Index. AB - The University of Southern California/Van Nuys Prognostic Index is an algorithm that quantifies five measurable prognostic factors known to be important in predicting local recurrence in conservatively treated patients with ductal carcinoma in situ (tumor size, margin width, nuclear grade, age, and comedonecrosis). With three times as many patients since originally developed, sufficient numbers now exist for analysis by individual scores rather than groups of scores. To achieve a local recurrence rate of less than 20% at 12 years, these data support excision alone for all patients scoring 4, 5, or 6 and patients who score 7 but have margin widths >= 3 mm. Excision plus RT achieves the less than 20% local recurrence requirement at 12 years for patients who score 7 and have margins < 3 mm, patients who score 8 and have margins >= 3 mm, and for patients who score 9 and have margins >= 5 mm. Mastectomy is required for patients who score 8 and have margins < 3 mm, who score 9 and have margins < 5 mm, and for all patients who score 10, 11, or 12 to keep the local recurrence rate less than 20% at 12 years. These recommendations in this article represent substantial changes from those previously published. PMID- 20956829 TI - The impact of surgery on ductal carcinoma in situ outcomes: the use of mastectomy. AB - Mastectomy has been the historical mainstay of treatment for ductal carcinoma in situ (DCIS), but over time, there have been significant changes in its use for preinvasive breast cancer. Although there was an early reduction in mastectomy rates for DCIS with the introduction of breast-conserving surgery, in some groups, the rates of both mastectomy and contralateral mastectomy for DCIS have increased in recent years. Due to advances in breast cancer screening as well as improvements in breast reconstruction, mastectomy will continue to be an important and acceptable treatment option. Recurrence is rare following mastectomy for DCIS. Nevertheless, there remains a need to follow patients for in breast, nodal, or contralateral breast events, which can occur long after the index DCIS has been treated. Since up to 70% of women with newly diagnosed DCIS have disease that can be managed with breast-conserving surgery, patient counseling is imperative to ensure the best use of this option for DCIS, given that mastectomy does not significantly impact survival in this setting. PMID- 20956830 TI - The impact of systemic therapy following ductal carcinoma in situ. AB - Following local therapy for ductal carcinoma in situ (DCIS), tamoxifen reduces the risk of ipsilateral and contralateral breast cancer by 30%-50%. Studies of tamoxifen in women with resected DCIS have not shown any effect on overall or cancer-specific survival. The adverse event profile of tamoxifen is well characterized, and individual risks and benefits should be assessed to guide decision making. We review the results of the phase III trials of tamoxifen in DCIS as well as the emerging risk reduction therapies. PMID- 20956831 TI - Communication between patients and providers and informed decision making. AB - Women with ductal carcinoma in situ (DCIS) need to comprehend the meaning of the diagnosis and the potential benefits and harms of treatment options. Full and understandable information is a requirement, not an option. However, with DCIS, as with many areas of medicine, a high level of uncertainty about the disease remains. In this article, we define informed medical decision making, review challenges to its implementation, and provide suggestions on how to improve communication with women about the diagnosis and treatment of DCIS. PMID- 20956832 TI - Molecular markers for the diagnosis and management of ductal carcinoma in situ. AB - Ductal carcinoma in situ (DCIS) is a heterogeneous group of lesions reflecting the proliferation of malignant cells within the ducts of the breast without invasion through the basement membrane. Numerous studies analyzing the molecular profiles of DCIS using genome-wide unbiased and candidate gene approaches have been conducted with the aim of identifying clinically useful markers that would predict the risk of progression to invasion. Results of these investigations defined the heterogeneity of DCIS at the molecular level, but a gene signature predictive of invasive progression has not been identified. Major diagnostic criteria that differentiate DCIS from invasive cancer are the presence of intact basement membrane and myoepithelial cell layer. Based on this, perturbation of normal myoepithelial cell differentiation has been proposed to explain progression to invasion. Comprehensive molecular studies analyzing large cohorts of DCIS with long-term clinical follow-up are necessary to resolve the many remaining questions. PMID- 20956833 TI - Imaging for the diagnosis and management of ductal carcinoma in situ. AB - Diagnosis of ductal carcinoma in situ (DCIS) has increased dramatically in parallel with the increased use of screening mammography. There are specific mammographic findings, most associated with shapes (amorphous, fine and coarse pleomorphic, and fine linear) and distributions (linear and segmental) of calcifications that permit a reasonable sensitivity for detection of DCIS without an unreasonable decrease in specificity, especially in view of the dramatic decrease in breast cancer mortality associated with early detection. While some DCIS may never progress to invasive disease, at this time, we cannot make that separation. This should be an active area for research. PMID- 20956834 TI - Quality-of-life issues in patients with ductal carcinoma in situ. AB - Ductal carcinoma in situ (DCIS) as we know it today is a clinical entity that is primarily discovered through the finding of microscopic calcifications on a screening mammogram. Asymptomatic women who are found to have DCIS receive treatments that are similar to women with invasive breast cancer and experience substantial psychological distress in spite of having an excellent prognosis and normal life expectancy. More research is needed to determine the best way to communicate with women about this condition and to match the extent of treatment with the risk of serious future disease. Clinical and research efforts should focus on reducing the anxiety and psychological distress associated with the diagnosis of DCIS. PMID- 20956835 TI - Inclusion understood from the perspectives of children with disability. AB - This study explored the perspectives of children with disabilities regarding the concept of inclusion in physical activity. Participants were children (two girls, nine boys, Mage = 10 years, five months, age range: 8-12 years) with disabilities, including cerebral palsy, fine and gross motor delays, developmental coordination disorder, muscular dystrophy, nemaline myopathy, brachial plexus injury, and severe asthma. Children's perspectives on inclusion in physical activity (e.g., sports, games, and play) were explored through semistructured interviews. Interviews were digitally audio taped and transcribed verbatim. Data were analyzed through content analysis. Three themes emerged from the data: gaining entry to play, feeling like a legitimate participant, and having friends. These themes were associated with feeling included to varying degrees in sports, games, and play. In essence, it was the actions of others that were the prominent features identified by children that contributed to feeling more or less included in physical activity contexts. These results are discussed in relation to inclusion in physical education, recreation, and unstructured free play. PMID- 20956836 TI - Multidimensional physical self-concept of athletes with physical disabilities. AB - The purposes of this investigation were first to predict reported PA (physical activity) behavior and self-esteem using a multidimensional physical self-concept model and second to describe perceptions of multidimensional physical self concept (e.g., strength, endurance, sport competence) among athletes with physical disabilities. Athletes (N = 36, M age = 16.11, SD age = 2.8) completed the Physical Self-Description Questionnaire. Participants reported mostly positive perceptions of self-esteem, global physical self-concept, endurance, body fat, sport competence, strength, flexibility, and physical activity (Ms ranging from 3.9 to 5.6 out of 6). Correlations indicated a number of significant relationships among self-esteem and reported PA and various dimensions of physical self-concept. Using physical self-concept, strength, endurance, and flexibility in the first regression equation and sport competence and endurance simultaneously in the second equation, 47 and 31% of the variance was accounted for in self-esteem and reported PA, respectively. The findings support the value of examining multidimensional physical self-concept as different aspects of the physical self appear to have different influences on reported PA engagement versus self-esteem. PMID- 20956837 TI - Physical fitness and physical activity in adolescents with asperger syndrome: a comparative study. AB - While physical activity is beneficial for youth with developmental disabilities, little is known about those individuals' fitness profile and levels of activity. Therefore the purpose of this study was to investigate the physical fitness profile and physical activity level of 30 adolescents with and without Asperger syndrome (AS). Evaluations were done using the Eurofit physical fitness test and the Baecke Habitual Physical Activity questionnaire. A 2 x 2 MANOVA indicated that adolescents with AS scored significantly lower than the comparison group on all physical fitness subtests, including balance, coordination, flexibility, muscular strength, running speed, and cardio-respiratory endurance (p < .001). Adolescents with AS were also less physically active (p < .001). Engagement in physical activities is therefore recommended. PMID- 20956824 TI - Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. AB - Individual patient data were available for all four of the randomized trials that began before 1995, and that compared adjuvant radiotherapy vs no radiotherapy following breast-conserving surgery for ductal carcinoma in situ (DCIS). A total of 3729 women were eligible for analysis. Radiotherapy reduced the absolute 10 year risk of any ipsilateral breast event (ie, either recurrent DCIS or invasive cancer) by 15.2% (SE 1.6%, 12.9% vs 28.1% 2 P <.00001), and it was effective regardless of the age at diagnosis, extent of breast-conserving surgery, use of tamoxifen, method of DCIS detection, margin status, focality, grade, comedonecrosis, architecture, or tumor size. The proportional reduction in ipsilateral breast events was greater in older than in younger women (2P < .0004 for difference between proportional reductions; 10-year absolute risks: 18.5% vs 29.1% at ages <50 years, 10.8% vs 27.8% at ages >= 50 years) but did not differ significantly according to any other available factor. Even for women with negative margins and small low-grade tumors, the absolute reduction in the 10 year risk of ipsilateral breast events was 18.0% (SE 5.5, 12.1% vs 30.1%, 2P = .002). After 10 years of follow-up, there was, however, no significant effect on breast cancer mortality, mortality from causes other than breast cancer, or all cause mortality. PMID- 20956838 TI - The accuracy of pedometers for adults with Down syndrome. AB - The purpose of this study was to examine the accuracy of spring-levered and piezoelectric pedometers for adults with and without Down syndrome (DS). Twenty adults with DS and 24 adults without a disability walked for two minute periods on a predetermined indoor course at a self-selected, slower and faster pace. Pedometer recorded and criterion observed steps were compared to determine pedometer error. There was a significant interaction between pedometer model and walking speed. Piezoelectric pedometers demonstrated significantly less measurement error than spring-levered pedometers, particularly at slower walking speeds. There were also significant differences in pedometer error between adults with and without DS. The study concludes that pedometer measurement error is significantly different for adults with DS but also that piezoelectric pedometers can be used in the future to measure walking activity for adults with and without DS. PMID- 20956840 TI - Correlates of physical activity participation in community-dwelling older adults. AB - The authors examined factors related to participation in walking, gardening or yard work, and sports or exercise in 686 community-dwelling adults 60-95 years of age from Wave IV of the population-based Americans' Changing Lives Study. Logistic regression revealed that male gender, being married, and better functional health were associated with greater likelihood of participating in gardening or yard work (p < .05). Male gender, better functional health, and lower body-mass index were independently associated with greater likelihood of walking (p < .05). Increasing age, male gender, higher education, and better functional health were associated with greater likelihood of participating in sports or exercise (p < .05). Subsequent analyses yielded an interaction of functional health by gender in sport or exercise participation (p = .06), suggesting a greater association between functional health and participation in men. Gender and functional health appear to be particularly important for physical activity participation, which may be useful in guiding future research. Attention to different subgroups may be needed to promote participation in specific activities. PMID- 20956839 TI - Fitness level and gross motor performance of children with attention-deficit hyperactivity disorder. AB - The purpose of this study was to assess fitness and gross motor performance of children with ADHD, including users and nonusers of methylphenidate medication. Seventy boys took part in the study. Fitness level of children with ADHD using medication or not, including body composition, flexibility, and muscular endurance, was similar to that of a control group. The only difference was observed for body mass index, which was lower in children with ADHD using medication. Aerobic capacity was also similar when measured by a treadmill test. A lower performance was observed when aerobic capacity was estimated using a field shuttle test, however, suggesting that the methodology used is important. Finally, both groups of children with ADHD presented significantly lower scores for locomotion skills. PMID- 20956841 TI - The influence of familiarization sessions on the stability of ramp and ballistic isometric torque in older adults. AB - Ramp isometric contractions determine peak torque (PT) and neuromuscular activation (NA), and ballistic contractions can be used to evaluate rate of torque development (RTD) and electrical mechanical delay (EMD). The purposes of this study were to assess the number of sessions required to stabilize ramp and ballistic PT and to compare PT and NA between contractions in older adults. Thirty-five older men and women (age 63.7 +/- 3.7 yr, body mass 64.3 +/- 10.7 kg, height 159.2 +/- 6.6 cm) performed 4 sessions of unilateral ramp and ballistic isometric knee extension, 48 hr apart. PT significantly increased (main time effect p < .05) from the first to the third session, with no further improvements thereafter. There was a trend toward higher PT in ballistic than in ramp contractions. No difference between contraction types on EMG values was observed. Therefore, the authors suggest that 3 familiarization sessions be performed to correctly assess PT. In addition, PT, NA, RTD, and EMD can be assessed with ballistic contraction in older adults. PMID- 20956842 TI - The effect of functional circuit training on physical frailty in frail older adults: a randomized controlled trial. AB - The purpose of this study was to evaluate whether a 12-wk functional circuit training program (FCT) could alter markers of physical frailty in a group of frail community-dwelling adults. Fifty-one individuals (31 women, 20 men), mean age (+/- SD) 84 (+/- 2.9) yr, met frailty criteria and were randomly assigned into groups (FCT = 26, control group [CG] = 25). FCT underwent a 12-wk exercise program. CG met once a week for health education meetings. Measures of physical frailty, function, strength, balance, and gait speed were assessed at Weeks 0, 12, and 36. Physical-frailty measures in FCT showed significant (p < .05) improvements relative to those in CG (Barthel Index at Weeks 0 and 36: 73.41 (+/- 2.35) and 77.0 (+/- 2.38) for the FCT and 70.79 (+/- 2.53) and 66.73 (+/- 2.73) for the CG. These data indicate that an FCT program is effective in improving measures of function and reducing physical frailty among frail older adults. PMID- 20956843 TI - The impact of a national strategy to increase physical activity among older adults on national organizations. AB - This study was designed to evaluate the impact of the National Blueprint (NB) on the policies, programs, and organizational culture of selected national organizations. The theoretical model selected to assess the impact of the NB on organizational behavior was Burke's system theory of organizational change. Three organizations, AARP, the American College of Sports Medicine (ACSM), and the Administration on Aging (AoA), were selected for the study. Two individuals in each of these organizations were selected for interview. Semistructured interviews and document reviews were used in the data-collection process. Findings showed that the publication and establishment of the NB resulted in changes in the operating procedures of AARP, ACSM, and AoA. The results were broadly consistent with Burke's system theory of organizational change. The publication of the NB was shown to affect the behavior of organizational leaders, organizational culture, policies, programs, and individual and organizational performance. The new information generated has increased our understanding of the impact of health campaigns on organizational behavior. PMID- 20956844 TI - Individual progress toward self-selected goals among older adults enrolled in a physical activity counseling intervention. AB - The purpose of this study was to examine what happens to goals over the course of a physical activity counseling trial in older veterans. At baseline, participants (N = 313) identified 1 health-related goal and 1 walking goal for their participation in the study and rated where they perceived themselves to be relative to that goal at the current time. They rated their current status on these same goals again at 6 and 12 mo. Growth-curve analyses were used to examine longitudinal change in perceived goal status. Although both the intervention and control groups demonstrated improvement in their perceived proximity to their health-related and walking goals (L = 1.19, p < .001), the rates of change were significantly greater in the intervention group (beta = -.30, p < .05). Our results demonstrate that this physical activity counseling intervention had a positive impact on self-selected goals over the course of the intervention. PMID- 20956845 TI - Physical activity and cognition in older adults: the potential of Tai Chi Chuan. AB - The purpose of this article is to review the potential of Tai Chi Chuan as a mode of physical activity that could have cognitive benefits for older adults and to provide potential directions for future research. A brief introduction to Tai Chi Chuan and its related physical benefits is provided. In addition, the empirical literature related to Tai Chi Chuan and cognition is reviewed. Potential mediators of the relationship between Tai Chi Chuan and cognition, including physical resources, disease status, and mental resources, are discussed. Based on the limitations of the extant literature, it is argued that future research in this area must provide more detailed descriptions of Tai Chi Chuan, particularly in terms of intensity and program progression. Consideration of the specific type of cognition that is expected to benefit is also encouraged, and approaches for further efforts to understand how Tai Chi Chuan affects cognition are recommended. PMID- 20956850 TI - Anterior urethral strictures: a brief review of the current surgical treatment. AB - A review of the recent literature on the surgical management of anterior urethral stricture was performed. The literature was searched via PubMed using the search terms 'urethral stricture' and 'urethroplasty' from 1996 to 2009. The management of anterior urethral strictures is changing rapidly in the sense that the reconstructive procedures have evolved greatly. Penile skin, because of its location and because it is hairless, has been popular and used for a long time. Since the early 1990s, buccal mucosa graft (BMG) was introduced in urethral reconstructive surgery and has become the first choice of most practicing urologists. Recently, there has been an increase in the use of lingual mucosa graft with various doctors reporting easy harvesting and lesser morbidity in comparison to BMG. Also, fibrin glue has recently been used to fix the graft with promising results. With the success of tissue-engineered materials that are still in the experimental phase, the urologist would no longer be limited by the quantity of the graft. These substitutes will also boost the appealing scarless endoscopic urethroplasty. This article provides a brief up-to-date review of the main surgical techniques in the management of anterior urethral stricture disease for the contemporary practicing urologists. Present controversies have been given special emphasis. The possible future techniques and the future of the anterior urethral stricture surgery are also discussed in brief. PMID- 20956851 TI - Progression of a giant omphalocele in utero: ultrasound and fetal magnetic resonance imaging findings. AB - A 34-year-old Hispanic woman was referred to us at 18 weeks' gestation for prenatal ultrasound. Sonographic evaluation showed a large omphalocele similar in size to the abdomen. Ultrasonographic and MRI images illustrating the typical appearance of a giant omphalocele are provided. PMID- 20956852 TI - The role of calcium-dependent gene expression in autism spectrum disorders: lessons from MeCP2, Ube3a and beyond. AB - During the last decade, autism spectrum disorders (ASD) have become the center of attention where several branches of modern biology unexpectedly meet, such as neural development, molecular biology, epigenetics, neurophysiology and psychiatry. This review will focus on the molecular mechanism by which calcium dependent gene expression regulates brain development and how ASD may occur if this process is compromised. Specifically, the studies of the calcium-dependent transcriptional repressor MeCP2 gave us much insight about how abnormal development may lead to ASD. Most recently, studies about Ube3a, a critical component of the ubiquitination system enzyme, shed light on how neural activity regulates synapse function through the protein degradation pathway. Taken together, these studies suggest that ASD may be caused by the incapability of neurons to generate adaptive responses via regulating gene expression upon incoming activity. PMID- 20956853 TI - Rapid progression of diabetic nephropathy is linked to inflammation and episodes of acute renal failure. AB - BACKGROUND/AIMS: Chronic kidney disease (CKD) from diabetic nephropathy is characterized by progressive loss of renal function. The renal decline has been viewed as a linear fall, presumably dependent on metabolic, hemodynamic and dietary stresses. However, renal injury in diabetic nephropathy can be rapidly aggravated by unpredictable external and internal factors, a state of affairs inconsistent with a linear loss of function. Acute renal injury and subsequent inflammation are potential factors, and we investigated their presence in renal biopsies from patients with nephropathy. METHODS: In a protocol approved by the Indiana University School of Medicine Institutional Review Board, renal biopsy specimens, estimated GFR, proteinuria and renal survival were examined in patients with diabetic nephropathy. RESULTS: Prominent clusters of inflammatory cells, particularly macrophages, were detected in the renal biopsy specimens. CKD progressed rapidly but not linearly, in that CKD was characterized by a succession of seemingly random episodes of self-limited acute renal failure. Episodes of acute kidney injury were associated with progression to end-stage renal disease. CONCLUSIONS: We propose that diabetic nephropathy is complicated by unpredictable and possibly random episodes of usually self-limited acute renal failure, and by subsequent renal inflammation, which appear to accelerate progression and eventual kidney loss. PMID- 20956855 TI - Protection of mice by a lambda-based therapeutic vaccine against cancer associated with human papillomavirus type 16. AB - OBJECTIVE: Human papillomavirus (HPV) oncoproteins (i.e. E6 and E7) are constitutively expressed in cervical cancer cells. The proteins are ideal targets to be used for developing therapeutic vaccines against existing HPV-associated carcinomas. To date, whole bacteriophage ('phage')-lambda particles, rather than purified 'naked' DNA, have been described as highly efficient delivery vehicles for a DNA vaccine. METHODS: In this study, a safe and efficient lambda-based therapeutic cancer vaccine, recombinant lambda-ZAP E7 phage, was developed by inserting a HPV16 E7 gene into the Lambda ZAP(r) cytomegalovirus vector. lambda ZAP E7 phages were employed to immunize mice against the E7-expressing murine tumor cell line (TC-1), which is used as a tumor model in an H-2b murine system. RESULTS: The tumor-bearing mice indicated a significant inhibition of tumor growth after 3 injections of 2 * 10(12) particles of recombinant phages. Released lactate dehydrogenase, interferon-gamma and granzyme B from spleen cells and lymphocyte proliferation of spleen cells, which all demonstrate the enhancement of cell-mediated immunity, suggested the phages could be a potent gene delivery system in animal models. CONCLUSION: Our results suggest the recombinant phages can be used as effective biological tools for inducing E7-specific protective immune responses. Hence, the study introduces a possible therapeutic strategy against cervical cancer and other HPV-related neoplasia. PMID- 20956854 TI - Prevalence of mild cognitive impairment and its subtypes in the Heinz Nixdorf Recall study cohort. AB - AIMS: We investigated the prevalence of mild cognitive impairment (MCI) and its subtypes according to the original (MCI-original) and modified (MCI-modified; neglecting cognitive complaints) Petersen criteria. METHODS: 4,145 subjects (aged 50-80 years) from a German population-based study completed a cognitive screening test and were poststratified into 2 groups with sample sizes of 1,125 for impaired and 3,020 for age-appropriate performance. Random samples of 445 impaired participants and 211 age-appropriate participants received a detailed neuropsychological evaluation. The prevalence of MCI was estimated by a bias correction estimator based on stratum weights. The association between MCI and age, gender and education was analyzed in a logistic regression model. RESULTS: The estimated MCI prevalence was 7.8% (95% CI: 5.7-9.9%) for the original, and 12.1% (95% CI: 9.8-14.4%) for the modified criteria. In the MCI-original group, amnestic MCI subtypes were slightly less common than non-amnestic MCI subtypes (3.5 vs. 4.3%). MCI-original was associated with lower education and older age. In the MCI-modified group, the amnestic subtypes were more common than the non amnestic MCI subtypes (7.8 vs. 4.3%), and MCI was associated with age, gender and education. CONCLUSIONS: Prevalence rates of MCI are high in the general population and vary considerably according to the criteria applied. PMID- 20956856 TI - An overview of physical growth and maturation. AB - An understanding of physical growth and maturation is relevant to many disciplines, including exercise and sport science, anthropology, human biology, medicine, psychology and education. Growth and maturation is governed by a complex interaction between genetic and environmental factors. There is increasing evidence that physical activity plays an important role in normal growth, development, health and well-being of children and youth, however, caution is required in the activity setting so that growth and maturation is not jeopardized. To appreciate the impact of physical activity and/or exercise on growth and maturation, a thorough understanding of the general principles of auxology is useful. Following an introduction to terminology, an overview of physical growth and development is provided in the context of morphological changes. Detailed information is provided regarding individual variability in growth and development along with sexual dimorphism. A small degree of sexual dimorphism exists at birth however striking differences develop during the pubertal years. Sexual dimorphism in body composition is largely regulated by endocrine factors with critical roles played by growth hormone and gonadal steroids. PMID- 20956857 TI - Role of various cytokines and growth factors in pubertal development. AB - Historical data suggest that body composition is intricately involved in pubertal development. Progression through puberty is dependent on the interaction between the growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis, reproductive and metabolic hormones as well as pro- and anti-inflammatory cytokines which induce alterations in feedback mechanisms and therefore mediate body composition and growth. Simultaneous increases in GH and IGF-1, and the concomitant changes in the hormonal milieu (i.e. reproductive hormones, testosterone and estrogen, and insulin)are the major contributors to anabolic effects seen throughout the pubertal transition, and are affected by various factors including (but not limited to) energy status and body composition. Orexigenic agents (i.e. ghrelin and leptin) also play a role at the level of the hypothalamus affecting not only energy intake, but also pubertal onset and progression. Effects of cytokines, many of which may be considered catabolic, extend beyond their traditionally viewed role involving the immune system, accompanying reproductive maturity further regulating aspects of energy and bone metabolism. As such, the signal(s) initiating the hypothalamic response that triggers puberty is likely reliant on a number of neural, metabolic and endocrine networks, all of which are at least partially influenced by pubertal growth factors, and act independently, antagonistically and/or synergistically to regulate anabolic pathways, therefore modifying body composition trajectory and growth during adolescence. PMID- 20956858 TI - Body composition differences in normal weight, obese-overweight and anorexic adolescents: role of adipocytokines. AB - Adipocytokines are signaling molecules released by adipose tissue with numerous functions, including regulation of metabolism, inflammatory process, and body mass. They are particularly interesting in youth, considering the rising prevalence of overweight/obesity and the linkage of this condition to inflammation. This chapter examines the relationship between body composition and select adipocytokines: leptin, adiponectin, IL-6, TNF-alpha, and resistin, in overweight, normal weight and anorexic youth. Leptin, which stimulates energy expenditure and promotes satiety, is highest in overweight youth, followed by normal weight and lastly anorexic youth. Adiponectin has similar functions to leptin but is negatively correlated with measures of body composition. Anorexic youth have the highest adiponectin per kg fat mass, followed by normal weight and overweight. Conversely, IL-6 is positively associated with body composition; however, research in anorexic youth is inconclusive. It has some pro-inflammatory effects and promotes glucose and fat use, therefore beneficial for maintenance of normal weight status. TNF-alpha is also a pro-inflammatory adipocytokine thought to be somewhat protective against cancer. TNF-alpha is highest in overweight, followed by normal weight and anorexic youth, similar to leptin. Finally, resistin is also involved in the pro-inflammatory response and the development of insulin resistance. However, far less research exists on this adipocytokine and its relation to body composition in overweight or anorexic youth is equivocal. In conclusion, several consistent relationships exist regarding adipocytokines and body composition; however, there is a need for additional research on these relationships in youth especially at extremes of adiposity such as overweight and anorexics. PMID- 20956859 TI - Inflammatory cytokines and metabolic risk factors during growth and maturation: influence of physical activity. AB - Cytokines influence tissue and cell physiology in positive and negative ways. Our aim in this chapter is to briefly present on select cytokines and their relationship to disease, metabolic risk factors, and physical activity in youth. We discuss the association of adiponectin, interleukin-6 (IL-6), resistin, tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) with metabolic risk factors in youth, and whether circulating concentrations of these cytokines are different based on being physically active or engaging in exercise training. Results from several studies show that adiponectin concentrations are reduced with increased adiposity, while others show that TNF-alpha, IL-6, resistin and CRP concentrations may be elevated with increased adiposity. Results from studies link decreased adiponectin with increased insulin resistance, while some evidence links increased TNF-alpha and resistin with increased insulin resistance. Several studies relate higher blood pressures to decreased adiponectin, increased TNF alpha, and CRP concentrations. The only lipids associated with the cytokines appear to be triglycerides and HDL cholesterol. Higher levels of habitual physical activity are associated with higher adiponectin and perhaps decreased TNF-alpha and resistin concentrations. Exercise training also appears to positively influence the concentrations of these cytokines. In conclusion, the role of these cytokines is still somewhat unclear as is their associations with metabolic risk factors. However, the available evidence indicates that chronic inflammatory states such as obesity in childhood are associated with a pro inflammatory profile and the presence of increased risk factors for disease while physical activity or exercise training elicit a protective role relative to this profile. PMID- 20956860 TI - Visfatin and adiponectin levels in children: relationships with physical activity and metabolic parameters. AB - Childhood obesity is increasing throughout the world and increases in adipose tissue are related to insulin resistance, cardiovascular diseases and metablic syndrome. Adipose tissue is not simply a storage depot for surplus energy but rather, is an active organ that modulates various biological functions and synthesizes and secretes multiple cytokines into the circulation. Adiponectin and visfatin are two cytokines which are considered to be possible links between obesity, insulin resistance and the metabolic syndrome. In turn, concentrations of adiponectin and visfatin are mainly influenced by the overall body fat mass which is one of the main determinants of insulin resistance and cardiovascular diseases. In contrast, physical activity and exercise are negatively related to body fat mass and also have an influence on cytokine concentrations in the blood. It is of particular interest whether physical activity or lifestyle interventions have a positive effect on adiponectin and visfatin concentrations in the blood. The aim of this review is to provide an overview of the contribution of vistafin and adiponectin to various metabolic parameters and their relationship with different physical activity patterns in children and adolescents. PMID- 20956861 TI - Ghrelin and obestatin concentrations during puberty: relationships with adiposity, nutrition and physical activity. AB - Ghrelin and obestatin are two peptides associated with appetite control and the regulation of energy balance in adults. It is intuitive that they have an important role in growth and development during puberty. Therefore, it is acknowledged that these peptides, in addition to others, form part of the substrate underlying energy homeostasis which in turn will contribute to body weight regulation and could explain changes in energy balance during puberty. Both peptides originate from the stomach; hence, it is intuitive that they are involved in generating signals from tissue stores which influence food intake. This could be manifested via alterations in the drive to eat (i.e. hunger), eating behaviors and appetite regulation. Furthermore, there is some evidence that these peptides might also be associated with physical activity behaviors and metabolism. Anecdotally, children and adolescents experience behavioral and metabolic changes during growth and development which will be associated with physiological changes. PMID- 20956862 TI - Menstrual irregularities and energy deficiency in physically active women: the role of ghrelin, PYY and adipocytokines. AB - Menstrual cycle irregularities are often observed among physically active women and athletes who participate in physical activity ranging from recreational to competitive exercise training. Further, such irregularities have been casually linked to an energy deficiency where caloric intake is inadequate for exercise energy expenditure resulting in a suppressive effect on growth and reproduction. Adaptations consistent with chronic energy deficiency, including reductions in resting energy expenditure and total triiodothyronine, have been observed in exercising women with functional hypothalamic amenorrhea (FHA). Gut peptides and adipocytokines also appear to be altered in exercising women with FHA and have been hypothesized to be involved in the etiology of FHA. Ghrelin concentrations are elevated in exercising women with FHA. Interestingly, while fasting ghrelin, an orexigenic peptide, is elevated in women with FHA, PYY, an orexigenic peptide, is paradoxically also elevated in women with anorexia nervosa and exercising women with FHA. Leptin, an adipocytokine, is also suppressed in FHA associated with exercise and anorexia. A critical leptin concentration threshold is suggested to be necessary for regular menses to occur. Ghrelin, PYY, and leptin all have the ability to cross the blood brain barrier and, in the hypothalamus, can modulate appetite and food intake, and are hypothesized to affect the hypothalamic-pituitary-ovarian axis. Future studies are needed to determine if ghrelin, PYY, or leptin play a direct role in the regulation of the hypothalamic pituitary-ovarian axis, and if these signals can be altered by improving energy status secondary to increasing caloric intake and initiate the reversal of amenorrhea. PMID- 20956863 TI - Influence of ghrelin and adipocytokines on bone mineral density in adolescent female athletes with amenorrhea and eumenorrheic athletes. AB - Adolescent female athletes are at increased risk for low bone mineral density (BMD) secondary to exercise-induced hypogonadism. Of particular concern is that the adolescent years are also a critical time for bone accrual, and deficits incurred during this period could lead to suboptimal peak bone mass acquisition and subsequent fracture risk in later life. Although weight-bearing exercise is typically associated with an increase in BMD, amenorrheic athletes have lower BMD than eumenorrheic athletes and nonathletic controls as a consequence of low energy availability and subsequent hypogonadism. It is important to recognize that critical interactions exist between net energy availability and the hypothalamo-pituitary-gonadal (H-P-G) axis that are key to the development of a hypogonadal state when energy intake cannot keep pace with expenditure. While the link between energy availability and gonadtotropin pulsatility patterns is well established, the actual metabolic signals that link the two are less clear. Decreased energy availability in athletes is associated with decreases in fat mass, and alterations in adipokines (such as leptin and adiponectin) and fat regulated hormones (such as ghrelin and peptide YY). These hormones impact the H P-G axis in animal models, and it is possible that in athletes alterations in fat related hormones signal the state of energy availability to the hypothalamus and contribute to suppression of gonadotropin pulsatility, hypothalamic amenorrhea and consequent decreased BMD. A better understanding of pathways linking low energy availability with functional hypothalamic amenorrhea and low BMD is critical for the development of future therapeutic strategies addressing these issues in amenorrheic athletes. PMID- 20956864 TI - Bone turnover markers during pubertal development: relationships with growth factors and adipocytokines. AB - The rapid increase in skeletal mass that occurs during puberty is caused by increases in longitudinal growth as well as cortical thickness. The measurement of growth changes during puberty using two-dimensional (dual-energy X-ray absorptiometry) and/or three-dimensional (computed tomography, magnetic resonance imaging) measurement devices provides only a static representation of bone tissue parameters. The measurement of bone turnover markers provides a more dynamic picture of the nature of bone tissue that can be repeated at much shorter intervals during puberty. The bone turnover markers are products of osteoblasts and osteoclasts which can be measured in urine or blood. The increase in different markers of bone turnover coincides with the pubertal growth spurt and thereafter markers decline until they converge into adult values. The initiation of puberty is accompanied by increases in androgens and estrogens. The effects of sex hormones on bone mineral accrual are mediated mainly by growth hormone and insulin-like growth factor-1, but they also exert a direct effect on bone metabolism. Important determinants of bone mineral accrual during puberty include optimal nutritional status, body composition parameters and physical activity pattern. All of these determinants are related to the state of energy balance, while peripheral indicators of energy balance, such as different growth factors and adipocytokines, may also have a positive influence of the growing skeleton. Taken together, bone mineral accrual during puberty is a complex interaction between physical activity pattern, various body composition parameters, specific growth factors and adipocytokines, and also sex hormones. PMID- 20956865 TI - Exercise training, physical fitness and the growth hormone-insulin-like growth factor-1 axis and cytokine balance. AB - The effect of exercise training on anabolic hormones and inflammatory mediators is particularly important during childhood and puberty, since during this period there is a spontaneous increase in anabolic hormones that leads to the marked puberty-related growth spurt. Therefore, any training-associated hormonal and/or inflammatory effect during this critical period may have profound consequences on growth and development, especially if the effect is maintained for long periods. Several studies suggest the hypothesis that a sudden imposition of a training program which is associated with substantial increase in energy expenditure leads initially to an increase in pro-inflammatory cytokines, and as a consequence, to decreases in IGF-1 levels. Further, if the training adaptation is successful, the proinflammatory cytokines fall, and with that decrease, the suppression of IGF-1 diminishes, an anabolic 'rebound' in the GH-IGF-1 axis may ensue, and IGF-1 level exceed the pretraining level. Exactly how and when this switch takes place, and whether the initial catabolic-type stage is necessary for the ultimate anabolic adaptation remains unknown. Consistent with the two phases hypothesis, longer periods of training were indeed associated with stable or with increases in circulating GH and IGF-1 levels. Despite the early training-associated decrease in circulating IGF-1 levels, there is an increase in muscle mass and fitness may improve, suggesting that the local tissue effect of exercise on growth factors differ from systemic effects. Total caloric intake as well as macronutrient content, consumption and timing influence the anabolic and inflammatory response to training. Finally, changes in the balance of anabolic and catabolic hormones and inflammatory mediators during the training season may help elite athletes and their coaches in their training and preparation for competition. PMID- 20956866 TI - Growth hormone-insulin-like growth factor-1 and inflammatory response to a single exercise bout in children and adolescents. AB - Physical activity plays an important role in tissue anabolism, growth and development, but the mechanisms that link patterns of exercise with tissue anabolism are not completely understood. The effectiveness of physical training depends on the training load and on the individual ability to tolerate it, and an imbalance between the two may lead to under or over-training. Therefore, many efforts have been made to find objective parameters to quantify the balance between training load and the athlete's tolerance. One of the unique features of exercise is that it leads to a simultaneous increase of antagonistic mediators. On the one hand, exercise stimulates anabolic components of the growth hormone (GH) -> IGF-1 (insulin-like growth factor-1) axis. On the other hand, exercise elevates catabolic pro-inflammatory cytokines such as interleukin-6 (IL-6), IL-1 and tumor necrosis factor-alpha (TNF-alpha). This emphasizes probably the importance of optimal adaptation to exercise in particularly during adolescence. The very fine balance between the anabolic and inflammatory/catabolic response to exercise will determine the effectiveness of exercise training and the health consequences of exercise. If the anabolic response is stronger, exercise will probably lead ultimately to increased muscle mass and improved fitness. A greater catabolic response, in particularly if persists for long duration, may lead to overtraining. Therefore, changes in the anabolic-catabolic hormonal balance and in circulating inflammatory cytokines can be used by adolescent athletes and/or their coaches to gauge the training intensity in individual and team sports. PMID- 20956867 TI - Effect of acute and chronic exercise on ghrelin and adipocytokines during pubertal development. AB - It is important to understand the factors that regulate the development of obesity during adolescence due to the increased risk of adult obesity, metabolic syndrome and the deleterious health effects of early puberty which may increase the risk of breast cancer later in life. Leptin, ghrelin, and adiponectin are peptides that affect energy homeostasis and insulin action. Similar to findings in adults, steady-state exercise does not change leptin concentrations and aerobic training without a change in body weight. A small amount of available data suggest that acute exercise does not increase circulating adiponectin concentrations in adolescents; however, it is very possible that more rigorous exercise protocols could acutely affect circulating adiponectin levels. Training studies indicate that shorter lengths of exercise training have a stronger effect on increases in adiponectin concentrations in male than female adolescents. It appears that if training is extended, increases in adiponectin levels will accompany improvements in insulin sensitivity. There are no studies of acute or chronic exercise on high-molecular weight adiponectin in adolescents and since this is thought to be the bioactive form of adiponectin, these studies are definitely needed. Investigations have demonstrated that exercise training increases total ghrelin levels in adolescents and that ghrelin is sensitive to reductions in body fat or increases in energy expenditure in this population. These findings are similar to those in adults. Moreover, there is evidence that luteinizing hormone is a predictor of total ghrelin levels in girls and suggests that ghrelin is a biomarker of energy imbalance across the menstrual cycle. PMID- 20956868 TI - Venous thromboembolism and port-related thrombosis in metastatic colorectal cancer patients: a monocenter experience. AB - Venous thromboembolism (VTE) may occur during the natural history of neoplastic disease and is a common cause of mortality and morbidity in cancer patients. Major risk factors for VTE in cancer patients include surgery, immobilization, hospitalization, and the administration of granulopoietic and/or erythropoietic (stimulatory) agents. Chemotherapy is a supplementary independent risk factor for VTE and the use of central venous catheters (CVC) in clinical practice has increased the risk of thromboembolic events. We conducted a retrospective study to evaluate CVC-related thrombosis and the VTE rate in 145 consecutive metastatic colorectal cancer patients. We observed only 2 cases of symptomatic CVC- related thrombotic events (1.38%) and 10 cases of thromboembolic events (6.9%) in our series. Only surgery for metastases was found to be significantly related to the development of VTE, with an incidence of 16.1% vs. 4.4 in patients who did not undergo surgery (p = 0.037). In addition, a history of VTE seems to be a supplementary risk factor for CVC-related thrombosis (p = 0.055). PMID- 20956869 TI - [Community-acquired pneumonia: a budget impact model]. AB - Community-acquired pneumonia (CAP) is an infectious disease with high morbidity and mortality and a major social and economic impact. A budget impact model was developed to estimate the impact on hospital direct costs of different antibiotic therapies suggested by international and national (FADOI) guidelines on treatment of patients hospitalized with CAP. The model includes the costs of drugs, staffing, consumables and in-patient stays in two different scenarios: intravenous therapy only and switch therapy; it compares levofloxacin (monotherapy) versus other combination therapies as suggested by the guidelines and includes the cost of failure of first-line treatment. Budget impact analysis shows that the cost of CAP-hospitalized patients in Italy consists mainly in the cost of treatment failure while that of antibiotics is just a small component of total direct costs incurred by hospitals. PMID- 20956870 TI - [Prevalence of intestinal parasitosis in Reggio Emilia (Italy) during 2009]. AB - The purpose of this survey is to assess the prevalence of intestinal parasites in Reggio Emilia during 2009. We analyzed 1961 samples from 1503 subjects: a copro parasitological standard examination was performed in 1416 of the subjects and the scotch-test in the remaining 87. Of the 1503 subjects examined, 111 (7.4%) were positive for one or more parasites. Pathogenic parasites were found in 44 subjects (39.6% of all positive subjects) and non-pathogenic protozoa were found in 67 subjects (60.4% of all positive subjects). The most commonly found species were, of the protozoa, Blastocystis hominis, Dientamoeba fragilis and Giardia intestinalis and, of the helminths, Enterobius vermicularis and Taenia Spp. This epidemiological survey shows the need to pay more attention to immigrants and travellers to endemic areas as potential carriers of major parasitic infections in the community. PMID- 20956871 TI - [Study on in-vitro susceptibility of ESBL-positive Escherichia coli isolated from urine specimens]. AB - Treatment of infections by beta-lactamase-producing microorganisms is very difficult. Our aim was to determine the in vitro susceptibility of 430 ESBL positive Escherichia coli strains isolated from urinary tract infections. All the microorganisms were isolated in the Microbiology Unit at the Ospedale dell'Angelo in Mestre (Venice) between May 2008 and September 2009 and were confirmed by the double-disk test. All microorganisms were sensitive to imipenem and meropenem, 98.4% to tigecycline, 95.1% to amikacin, 89.3% to nitrofurantoin, 67.5% to gentamycin and 63.2% to piperacillin/tazobactam. Only 22.6% were sensitive to cotrimoxazole, while fluoroquinolone (norfloxacin and levofloxacin) activity was found to be very low (6%). PMID- 20956872 TI - [Clinical, virological and epidemiological aspects of acute B hepatitis in the Catania area (Italy)]. AB - Starting from January 1997 we prospectively evaluated all cases of acute hepatitis B admitted to two of the main Infectious Diseases Units in Catania (eastern Sicily). The survey was extended throughout a 10-year period up to December 2007. Between 1997 and 1999 we observed 21 cases of acute hepatitis B; between 2000 and 2002 18 cases; between 2003 and 2005 22 cases and, finally, 37 cases were reported in the period 2006-2007. We found an increase in acute hepatitis B cases among people aged 26 to 44 years (from 38% in 1997-99 to 70% in 2006-07). A progressive decrease in intravenous drug abuse as a risk factor for acute hepatitis B was also observed (from 61% to 14%) together with a parallel increase in cases due to sexual transmission (from 19% to 56%) and outpatient cosmetic surgical procedures. Mean time to serum HBsAg negativization was longer in the last period (2006-07), with 6 cases out of 37 showing HBsAg persistence beyond 12 months from the clinical onset. Furthermore, in 2006-07 there were 12 cases (42%) of acute hepatitis due to HBV genotypes A and F. In our area, a progressive drop of hepatitis B cases due to intravenous drug abuse occurred, whereas heterosexual and iatrogenic cases increased. Cases due to HBV non-D genotypes may well be related to migration from endemic areas towards Sicily. PMID- 20956873 TI - Aural myiasis in an infant. AB - Aural myiasis is a rare clinical state that usually occurs in developing countries and in patients who mentally retarded or have poor personal hygiene. However, the prevalence has decreased over the years, and now it is very rare. The authors describe a case of aural myiasis caused by Wohlfartia magnifica in a five-month-old infant. The treatment used was a combination of suctioning and microsurgical forceps under an operative microscope. Additionally, topical and oral antibiotics were given to avoid secondary infection. PMID- 20956875 TI - Intrathecal colistin for treatment of multidrug resistant (MDR) Pseudomonas aeruginosa after neurosurgical ventriculitis. AB - Cerebrospinal fluid (CSF) shunts significantly improve the quality of life in patients with acute hydrocephalus. However, infections associated with a CSF shunt constitute a severe complication with high morbidity and mortality. We describe a case of CFS shunt infection cured with intrathecal colistin. PMID- 20956874 TI - Coexistent cervical spine fusion and thoracic disc herniations with acute myelitis. AB - Thoracic disc herniations are commonly found in asymptomatic individuals, sometimes with genetic predisposition. Congenital fusions of cervical vertebrae occur in Klippel-Feil syndrome, which may be asymptomatic or cause compressive myelitis due to cervical instability or associated herniated discs. We report the case of a 72-year-old man with monophasic acute transverse myelitis probably caused by herpes simplex virus, coexistent with fused cervical vertebrae (C4-C5) and thoracic herniated discs. Establishment of the aetiology in cases of transverse acute myelitis can constitute a challenge in patients with cervical spine anomaly and disc herniations. PMID- 20956876 TI - Neurological impairment and arthritis in an immunocompetent child with human parvovirus B19 chronic infection. AB - Human parvovirus B19 (HPV-B19) is usually a self-limiting infection in immunocompetent children. In this case report, instead, we describe an immunocompotent child with evidence of persistent HPV-B19 infection, arthritis and neurological impairment. He was first admitted to hospital for HPV-B19 infection and sent home in good clinical condition after anti-inflammatory therapy. Eight months later he was re-admitted to hospital for episodes of arthritis and weakness, myalgia, tremors in his legs and hands, and was unable to walk unaided. In both plasma and serum, HPV-B19 DNA, detected by polymerase chain reaction, was still present. For neurological symptoms, he underwent magnetic resonance, which showed increased signal intensity at the spinal roots in the lumbar region, compatible with polyradiculoneuritis. After immunoglobulin therapy he had an excellent response in clinical and radiological terms, suggesting an association between neurological impairment and HPV-B19 infection. Eleven months after the second admission, the patient was still in good clinical condition. PMID- 20956877 TI - Necrotizing soft-tissue infections in a general hospital. PMID- 20956878 TI - Chloramphenicol and rifampin may be the only options against Stenotrophomonas maltophilia. A tale of a colonized bladder device in a patient with myelofibrosis. PMID- 20956879 TI - [Whipple's disease in an AIDS patient with Kaposi's sarcoma. Report of a case]. PMID- 20956880 TI - The plague of the Philistines and other pestilences in the Ancient World: exploring relations between the religious-literary tradition, artistic evidence and scientific proof. AB - In ancient times the term pestilence referred not only to infectious disease caused by Yersinia pestis, but also to several different epidemics. We explore the relations between references in the Bible and recent scientific evidence concerning some infectious diseases, especially the so-called Plague of the Philistines and leprosy. In addition, some considerations regarding possible connections among likely infectious epidemic diseases and the Ten Plagues of Egypt are reported. Evidence suggesting the presence of the rat in the Nile Valley in the II millennium BC is shown; a possible role of the rat in the plague spreading already in this historical period should be confirmed by these data. While the biblical tale in the Book of Samuel may well report an epidemic event resembling the plague, as to date this infectious disease remains unknown, it is not conceivable to confirm the presence of leprosy in the same age, because the little palaeopathologic evidence of the latter disease, in the geographic area corresponding to Egypt and Palestine, is late, dating back only to the II century AD. PMID- 20956881 TI - False negative and positive motor evoked potentials in one patient: is single motor evoked potential monitoring reliable method? A case report and literature review. AB - STUDY DESIGN: A case report and literature review. OBJECTIVE: To report a false negative and delayed positive motor-evoked potential (MEP) in 1 patient. SUMMARY OF BACKGROUND DATA: An unreliable MEP can result in fatal outcomes because surgeons have recently begun to depend on the MEP for intraoperative decision making. METHODS: We report a case of a false MEP during scoliosis surgery that showed false negative and positive MEPs during a series of operations. RESULTS: A 23-year-old man with a history of spondyloepiphyseal dysplasia presented with severe kyphoscoliosis. The initial neurologic examination did not reveal any neurologic abnormalities. Surgical correction and fusion were performed with transcranial MEP monitoring. During the entire procedure, the MEP did not reveal any signs of cord injury. However, lower limb paralysis and paresthesia was observed when the patient awakened. After 2 additional surgical procedures to recover the neurologic deficit, the MEP did not show any signs of cord injury but the patient's neurologic status had recovered slightly. At postoperative day 8, the neurologic status recovered, and a third operation was performed to fix the long rods. However, there were abnormal amplitudes in both lower limbs but the patient's neurologic status was almost normal. CONCLUSION: From our experience of false negative and positive MEP in 1 patient, it is concluded that undesirable events can occur with use of MEP in scoliosis or other spinal surgery. Therefore, we warn the surgeons too heavily rely on the MEP monitoring, and propose a further prospective study as well as use of alternative method that can improve the reliability of single MEP. PMID- 20956883 TI - Preparation of a carbon-based solid acid catalyst by sulfonating activated carbon in a chemical reduction process. AB - Sulfonated (SO(3)H-bearing) activated carbon (AC-SO(3)H) was synthesized by an aryl diazonium salt reduction process. The obtained material had a SO(3)H density of 0.64 mmol.g-1 and a specific surface area of 602 m2.g-1. The catalytic properties of AC-SO(3)H were compared with that of two commercial solid acid catalysts, Nafion NR50 and Amberlyst-15. In a 10-h esterification reaction of acetic acid with ethanol, the acid conversion with AC-SO(3)H (78%) was lower than that of Amberlyst-15 (86%), which could be attributed to the fact that the SO(3)H density of the sulfonated carbon was lower than that of Amberlyst-15 (4.60 mmol.g 1). However, AC-SO(3)H exhibited comparable and even much higher catalytic activities than the commercial catalysts in the esterification of aliphatic acids with longer carbon chains such as hexanoic acid and decanoic acid, which may be due to the large specific surface area and mesoporous structures of the activated carbon. The disadvantage of AC-SO(3)H is the leaching of SO(3)H group during the reactions. PMID- 20956884 TI - Small interfering RNA effectively inhibits the expression of SARS coronavirus membrane gene at two novel targeting sites. AB - Small interfering RNA (siRNA) is a class of duplex RNA molecules of 21-25 nt nucleotides in length functioning post-transcriptionally to downregulate targeted gene expression. The membrane (M) protein of severe acute respiratory syndrome associated coronavirus (SARS-CoV) is highly abundant during viral infections and is a critical element for viral assembly. Nucleotide substitution in the viral genome occurs frequently during SARS-CoV infection. In the current study, we analyzed the M gene sequences derived from 15 SARS-CoV isolates and uncovered six nucleotide substitutions among these isolates. Interestingly, these nucleotide substitutions are all located at the 5' half of the M gene. Based on this information and previous reports, we created two novel siRNAs targeting two unexplored and well conserved regions in the M gene. The effects of these two siRNAs were tested by semi-quantitative RT-PCR and EGFP-M fusion gene expression. The results demonstrated that both siRNAs effectively and specifically blocked the targeted gene expression. Real time quantitative RT-PCR (qRT-PCR) revealed that siRNA targeting the 3' half of the M gene (si-M2) induced more potent inhibition than that targeting the 5' half (si-M1). Both si-M1 and si-M2 significantly downregulated M gene mediated upregulation of interferon b expression. Thus, our results indicate that SARS-CoV M gene specific siRNA might function in a sequence-dependent manner. PMID- 20956885 TI - Urinary tract infection in children in a tertiary level hospital in bangladesh. AB - An observation study was carried out in the department of Paediatrics in Mymensingh Medical College Hospital, Mymensingh regarding urinary tract infection (UTI) in children aged <=15 years from January 2008 to December 2008. The objectives of this study were to review symptoms, causative agents, antimicrobial sensitivity test, abnormalities of urinary tract and treatment of children with UTI. Fifty cases of childhood UTI, based on urine routine examination and culture, were analyzed and male female ratio was 1:1.3. Sixteen (32%) children were less than one year old. Fever was the most common clinical presentation (82%). Pyuria was detected in 92% of cases. Most common causative organism was Eschericia coli (E. coli) (70%). Susceptibility of E. coli to ceftriaxone, levofloxacin, amikacin and nitrofurantoin was greater than 80% and less susceptible to cotrimoxazole, ampicillin, cephradine and ciprofloxacin. Most of the patients became afebrile within 5 days after starting antimicrobial therapy. PMID- 20956886 TI - Detection of biofilm formation among the isolates of staphylococcus epidermidis by modified microtiter- plate test. AB - The present study was done to detect biofilm formation among the strains of Staphylococcus epidermidis isolated from different clinical specimens and healthy controls in the department of Microbiology, Mymensingh Medical College between July 2007 to June 2008. A total of 62 Staphylococcus epidermidis isolates were identified by standard microbiological technique. Among them 32 S. epidermidis were isolated from cases and 30 were from healthy controls. Antimicrobial susceptibility of the isolates was carried out by disk diffusion method as per recommendation of Clinical and Laboratory Standard Institute 2007. Biofilm production was detected by Modified microtiter-plate test. Out of 32 clinical isolates of S. epidermidis, 13 strains found to produce biofilm. On the other hand out of 30 S. epidermidis from healthy controls, only 5 strains produced biofilm. So detection rate of biofilm production of S. epidermidis by Modified microtiter plate test in clinical isolates was significantly higher than that of control group. PMID- 20956887 TI - Refractive status of medical students of mymensingh medical college. AB - This study is done to find out the refractive status of medical students of Mymensingh Medical College (MMC), Mymensingh, Bangladesh. They are of the age of 17-19 years. This is a nonrandom purposive cross sectional study done at late part of the November 2008. Visual acuity estimation, automated refraction, streak retinoscopy, fundoscopy using +78D volk lens were done according to the need of the cases. Out of 175 students 53.14% are emmetropic and 46.86% are ametropic, ametropia is nearly equal in both sexes (male 51.22%, female 48.78%). About all students are of highest academic attainment (GPA 5). About one quarter of the ametropic students (21.61%) are not using spectacles. Simple myopia (81.70%) and myopic astigmatism (18.30%) are the types of ametropia. Out of 67 simple myopic students 56 are of bilateral involvement and 11 are of unilateral involvement. There is similarity in the distribution of sex & refractive status in between general population & medical students of Bangladesh. Myopia and myopic astigmatism are prevalent among medical students. PMID- 20956888 TI - Metastasis in differentiated thyroid carcinoma. AB - Seventy patients of differentiated thyroid carcinoma (DTC) irrespective of age and sex were selected in ENT Department of Bangabandhu Sheikh Mujib Medical University, Dhaka Medical College Hospital and Rangpur Medical College Hospital who were admitted from March 2003 to March 2005. Female were more commonly affected (2.6:1) Papillary carcinoma was more common in 31-50 years of age and follicular carcinoma (ca) common in 41-50 years of age. Among the differentiated thyroid carcinoma papillary carcinoma found 77.15% and follicular ca. found 22.85%. Lymph node metastasis was more common in papillary (35%) than follicular carcinoma (12.5%). But distant metastasis was more common in follicular (12.5%) than papillary carcinoma (3.70). Maximum lymph node metastasis was found in level 3(55%), level 2(45%). PMID- 20956889 TI - Morphometry of purkinje cell body of cerebellum in bangladeshi cadaver. AB - This cross sectional descriptive study was performed by examining 30 (thirty) relatively fresh cerebellum. Out of them 20 postmortem human cerebellum collected from Bangladeshi cadavers of both sexes (male 10 and female 10) age ranging from 5 to 60 years and 10 cerebellums from caesarian section of dead fetuses of both sexes (male 6 and female 4) age ranging from 34 weeks to 41 weeks. Specimen containing cerebellum was collected from dead bodies autopsied on different dates from April'2009 to September'2009 at the autopsy laboratory of department of Forensic Medicine and Gynaecology and Obstetrics of Mymensingh Medical College, Mymensingh. Samples were collected by using nonprobability sampling technique. The collected sample was grouped in to three age groups like Group A (34 to 41 weeks of gestation), Group B (5 to 30 years) and Group C (31 to 60 years) and two sex groups (male and female). Ten cerebellums were studied from each age group for this histological study. Sections were processed following standard histological procedure and were stained with Hematoxylin and Eosin stain. Slides were examined under 15X40 magnifications and measurement of vertical and transverse diameter of the cell body were taken with the help of ocular micrometer. In this study, the mean difference of mean vertical and transverse diameter of Purkinje cell body between Groups A & B and Groups A & C was statistically highly significant (p<0.001) but differences between Groups B & C was statistically significant only in case of transverse diameter. PMID- 20956890 TI - Genetic Testing for Huntington's Disease in Parkinsonism. AB - The study was conducted to find out Huntington's disease (HD) by genetic analysis from those presenting with parkinsonism in the Neurology department of Mymensingh Medical College & Hospital. A sample of about 5ml blood was collected by veni puncture in EDTA tube with informed consent from 9 patients & 7 healthy individuals after approval of the institutional ethics committee for genetic study. The neurological disorder along with a complete history and physical findings were recorded in a prescribed questionnaire by the neurologists of Mymensingh Medical College & Hospital. Extraction of genomic DNA from the venous blood using FlexiGene DNA kit (Qiagen, Japan) was performed in Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh. The extracted DNA was stored and accumulated and then these DNA were sent to Division of Clinical Genetics, Department of Medical Genetics, Osaka University Medical School, Suita, Osaka 565 0871, Japan for PCR and further analysis. PCR amplification of the CAG repeat in the 1T15 gene was performed with primers HD1 and HD3. HD PCR products revealed the DNA product of about 110bp (no. of CAG repeats=21) to 150bp (no. of CAG repeats=34) in both healthy individual and suspected PD patient DNA. PMID- 20956891 TI - Seroprevalence of Hepatitis B, Hepatitis C, HIV Infections in Blood Donors of Khulna, Bangladesh. AB - To determine changes (Trends) in infection rates of Hepatitis B surface antigen (HBsAg), Hepatitis C virus (HCV) and Human immunodeficiency virus (HIV) in blood donors of Khulna Population. Specimens of 34953 voluntary blood donors & party or relative donors in Transfusion Medicine Department of Khulna Medical College Hospital from 2007 to 2009 were screened for HBsAg, anti-HCV, anti-HIV 1 & 2 reactivity in a cross-sectional survey by rapid test method. Reactive samples were verified using a recognized confirmatory test which consisted of a second generation enzyme immune assay (HBsAg), anti-HCV antibodies by anti-HCV EIA & for HIV by western Blot, respectively. The seroprevalence of HBsAg, Anti-HCV, HIV antibody 1 & 2 was 1.4%, 0.09% & 0.03% respectively in all blood donors. Prevalence of confirmed positivity was 0.62% for HBsAg, 0.04 % for Anti-HCV, 0.02% for HIV Western Blot. Between 2007 to 2009 a decreasing trend was observed in HBsAg frequency, HCV frequency decreased in 2009 compared to 2007. One HIV positivity found in 2009. Although the frequency of transfusion transmitted infections is low, party or relative donors have some risk factors than voluntary blood donors. Through more scrutiny in donor selection, improved serological test & reevaluation of infections routes in donor, infection reduction can be achieved. PMID- 20956892 TI - Knowledge and practice about TT vaccination among undergraduate female medical students. AB - Neonatal Tetanus (NT) is a clinical form of tetanus, generally occurs through infection via unhealed umbilicus. Newborns can be successfully protected against tetanus by vaccinating women with Tetanus Toxoid (TT). In our country, target groups for vaccination are vaccinated at Out-reach Centres (ORCs) and fixed centres (health facilities) free of cost. All women of reproductive age group, regardless of their marital and pregnancy status, are accessible to the vaccination programme. Illiteracy is one of the known important factors that stand in the way of vaccination. This descriptive, cross-sectional study was intended to assess knowledge about EPI diseases and vaccines, and TT vaccination status among 62 purposively selected undergraduate female students of Mymensingh Medical College (MMC), Mymensingh of session 2006-2007. Semi-structured interview schedule was used for data collection. Data were managed manually by using master sheet and scientific calculator. Out of sixty-two, 44(70.97%) female students started to receive TT vaccination after completion of 15 years. Of them, only 5(11.36%) had completed the five dose schedule till the conduction of the study. Educational status of women is vital for effective utilization of available preventive health services. Vaccination programme is geographically, economically and culturally accessible in our country. Literacy status of our respondents was very high. Nonetheless, access rate for TT vaccine was very much dissatisfactory. So based on these findings, it can be concluded that creating community awareness is an important factor to improve utilization status of preventive programmes including vaccination. PMID- 20956893 TI - Haemodynamic and end tidal CO2 changes state after inflation and deflation of pneumatic tourniquet on extremities. AB - The use of a tourniquet for obtaining a bloodless field is an essential and accepted tool for extremity surgery. A prospective study was done on 30 adult patients undergoing elective limb surgery requiring tourniquet application for haemodynamic and End tidal CO2 (EtCO2) changes. After the induction of general anaesthesia a tourniquet was applied on the limb. There was gradual increase in heart rate & EtCO2 through out the whole period of tourniquet inflation. There was also significant increase of mean arterial pressure during the inflation period. At the end of surgery tourniquet was deflated. Tourniquet time was 76.83+/-16.94 minutes. After deflation of the tourniquet, heart rate & EtCO2 value increased & the values were maximum at 5 minutes. These values came down to the base line at 15 minutes. There was significant decrease of mean arterial pressure (MAP) at 5 minute; it also came to the base at 15 minute. These changes are usually benign but can be significant in patients with co-existing cardiovascular & intracranial diseases. In conclusion, we recommend the haemodynamic and End tidal CO2 monitoring as well as rapid fluid infusion along with hyperventilation for 15-30 minutes after deflation of tourniquet. PMID- 20956894 TI - Kala azar in Pregnancy. AB - Kala azar (KA) is one of the most important tropical diseases. More so is the issue of KA in pregnancy. In this retrospective study we tried to find out the out come of pregnant patient treated with Sodium Antimony Gluconate (SAG) for KA in one of the most endemic area of Bangladesh, Fulbaria. SAG is the available and registered drug for treatment of KA patient with pregnancy in Bangladesh. A total of 16 pregnant women presented with KA during the study period of 2005 to 2009. Out of the 16 patients 11 had abortion and they were all with in the 16 to 22nd week of pregnancy. The abortion took place mostly on the 22nd to 24th day of treatment when the patient had become afebrile. Rest of the 5 patients was in their 30 to 34th week of pregnancy and had good obstetric outcome. All the 16 patients were clinically cured at the end of treatment. No follow up records were available and there was no data regarding the 5 children. It is of our opinion that the abortions were induced by SAG and therefore we recommend that SAG should not be used in early or mid pregnancy for treating KA. PMID- 20956895 TI - Baker's method in the management of equinus deformity in cerebral palsy. AB - This prospective study was conducted in the department of orthopedic surgery in Bangabandhu Sheikh Mujib Medical University (BSMMU) Dhaka, Bangladesh, from January 2005 to December 2007. Total number of 20 patients with 37 feet of equinus deformity due to cerebral palsy was managed by Baker's method. Equinus deformity in cerebral palsy is not uncommon in our outpatient department. Before operation patient walks on tip toes and after operation by Baker's method by apponeurotic lengthening of gastrocnemius muscle, with extensive physiotherapy, patients can able to walk normally in plantigrade feet. Among 20 patients only the spastic diplegic or hemiplegic equinus deformity in cerebral palsy was between 3 years to 12 years with a mean age of 5 years 9.6 months (SD+/-2 years 4.97 months). There were 3(15%) unilateral and 17(85%) bilateral cases. Among 20 cases, 13(65%) were male and 7(35%) were female. All cases were followed up for period ranging from 4 month to 28 months. Final clinical outcome was satisfactory (excellent and good) in 34(92%) feet and unsatisfactory (fair plus poor) in 3(8%) feet (p<0.001). PMID- 20956896 TI - Doppler prediction of perinatal outcome in pregnancy induced hypertension and intrauterine growth retardation. AB - This study is done for the pulsatility index (PI) and resistance index (RI) of the "umbilical artery" during pregnancy. We determine the normal range (mean+/ 2SD) for various indices in our population and statistical significance of these values in pregnancy induced hypertension and small for gestational age (SGA) babies. One hundred twenty random pregnancies were screened at various periods of gestations. A color Doppler scanner with a carrier frequency of 3.5 MHz was used for studying the umbilical artery. Pregnancies with a normal outcome were used for calculating the normal range of various indices and for testing the specificity and negative predictive value (NPV) of the study. Those pregnancies with an abnormal outcome PIH and SGA babies were used for calculating the sensitivity and positive predictive value (PPV) of the study. In normal pregnancies, the flow velocity waveforms (FVWs) showed a good diastolic flow. A low diastolic flow and high indices characterized the pregnancies with abnormal outcomes. Among the umbilical indices, the PI had the highest sensitivity and specificity of 83.33 and 64.28 respectively. Doppler provides a non-invasive method of assessing the fetal and maternal circulation during pregnancy. PMID- 20956897 TI - Plasma Renin in ipsilateral renal vein in patients with chronic unilateral pelvic ureteric junction obstruction. AB - Acute experimental hydronephrosis induces increased output of renin from ipsilateral kidney. In most clinical presentation of unilateral hydronephrosis the patients are however, normotensive with normal circulating plasma renin activity. In consideration of this argument we undertook this prospective study of ipsilateral renal vein renin activity in children with congenital Pelvic Ureteric Junction Obstruction (PUJO) and compared with other wise normal children. In this prospective cross-sectional study, started from July 99 to June 2001, twenty patients, age upto 12 years, with unilateral hydronephrosis and in control group ten patients without hydronephrosis were taken. 2ml blood was taken from the renal vein in study group and from infrarenal portion of inferior vena cava during exploratory laparotomy from the control group. All the patients had advanced grade of hydronephrosis and two patients (13%) had mild hypertension. In this study the mean plasma renin activity (PRA) was 45.58 ng/ml/hr (range: 11.69 67.56 ng/ml/hr) in study group. The mean PRA in control group was 5.9ng/ml/hr. The result of study group was significantly higher than normal (P value 0.0003). In Bangladesh we are doing more conservative kidney preserving surgery for PUJO, but need long term follow up of the patients undergoing surgery for PUJO in childhood for potential of developing renin-angiotensin induced hypertension in later life. PMID- 20956898 TI - Prevalence of obesity among affluent school children in Dhaka. AB - A cross sectional study was conducted in September 2006 in one of the private schools in Dhaka, Bangladesh to see the prevalence of obesity among affluent school children and adolescents. Informed consent was taken from school authority to take anthropometric measurement of all school children. Standing height was measured with a stadiometer and weight with a bathroom scale. Waist and hip circumference were measured with a measuring tape. The body mass index (BMI) was calculated using weight in kilogram/(height in meter)2 formula. Obesity was defined as BMI>=95th percentile for age and sex, over weight as BMI>=85th percentile for age and sex, normal weight as BMI between 5th and 84th percentile and underweight as BMI <5th percentile. Official centers for disease control (CDC) growth chart for boys and girls age 2-20 years was used. Children and adolescents were divided into group 1(3-5 years), Group 2(6-9years), group 3(10 13 years) and group 4(14-18 years). There were a total of 468 children and adolescents (male 266, female 202). In group 1 there were 110 children, in group 2 there were177 children, in group 3 and 4 there were 149 and 32 adolescents respectively. The prevalence of obesity was 17.9%, higher among males (19.9%), compared to females (15.3%). Obesity was highest (27.7%) in group 2, 14.5% in group 1, 10.7% in group 3 and 9.4% in group 4. PMID- 20956899 TI - Congenital muscular torticollis: experience of 14 cases. AB - Congenital Muscular Torticollis (CMT) is a postural deformity of head and neck detected at birth or shortly after birth, primarily resulting from unilateral shortening of Sternocleidomastoid Muscle (SCM). In neonates and infants, patient may cure conservatively by physiotherapy but surgery is the treatment of choice for children and adolescents. There are various techniques of surgery. Here we show our experience regarding management of congenital muscular torticollis. In the present retrospective case series, fourteen patients of congenital muscular torticollis were treated. The cases were enrolled between Nov' 2005 to Oct' 2007 in Bangabandhu Sheikh Mujib Medical University, Gonosasthaya Somaj Vittik Medical College Hospital, Dhaka and different private clinics of Dhaka city of Bangladesh. Neonates and infants were treated conservatively with physiotherapy and others treated surgically by transection of both sternal and clavicular head of SCM under general anesthesia. Operated patients were released on following post operative day with advised to do physiotherapy. Patients age range from 7 days to 15 years of which ten were female and four male. SCM was shortened in all cases (8 on right side and 6 on left side). Eleven were female and three male. Of 14 patients, 2 neonates, 7 infants and 5 were more than 1 year age. There was no associated anomaly. Out of 9 neonates and infants 8 cured conservatively with physiotherapy and another one significantly improved. Six were treated surgically including one failed physiotherapy. Post operative period was uneventful and there was no complication. Results were evaluated clinically and comments of peers. Most of the patient of congenital muscular torticollis can be treated conservatively during infancy. Division of both sternal and clavicular head of SCM is easy and safe surgical technique for the treatment of CMT of older children and adolescents. PMID- 20956900 TI - Anthropometric measurements of the arm span and their correlation with the stature of bangladeshi adult muslim females. AB - Anthropometry is the science that deals with the measurement of size, weight and proportion of the human body. Stature is natural heights of a person in an upright position. This can be estimated from arm span length. In the last 50 years of the 20th century various mass disasters such as different powerful storm, flood, plane crash, train accident was increased. Very recently in Chittagong and southern Bangladesh many people were killed through land slides and Seder. As so many disasters were occurring it is possible to identify a missing person if a part of his or her body is available. The arm span lengths can be used as a basis for estimating age-related loss in stature and as an alternative measure to stature. The study was done for the estimation of stature from the arm span on one hundred and fifty Bangladeshi adult Muslim females. Subject was collected from Bangabandhu Sheikh Mujib Medical University, Dhaka and some urban region of Dhaka, Bangladesh. The present study showed significant (p<0.001) positive correlation between the stature and the arm span. PMID- 20956901 TI - Sistrunk's operation for the treatment of thyroglossal cyst. AB - Effective Treatment of thyroglossal cyst requires knowledge of its embryological background and anatomical disposition of the thyroglossal duct and its remnants. Equally important is the expertise of the surgeon to ensure total excision of the remnants of thyroglossal duct. We have operated 12 cases of both primary and recurrent thyroglossal cysts in the department of Surgery, BSMMU, Dhaka, Bangladesh from January 2001 to September 2008. We performed the Sistruk's operation on all the 12 cases. Under general anaesthesia the thyroglossal cyst, 10 mm of the central part of the body of the hyoid bone and a core of tissue in the suprahyoid region up to the foramen caecum were removed. There was no need for blood transfusion. There was neither mortality nor any significant morbidity. Average hospital stay after operation was three days. After mean follow up of 3 years there was no recurrence. We found that the Sistrunk operation is a safe and effective procedure. PMID- 20956902 TI - Prolonged analgesia by adding midazolam and hyperbaric bupivacaine in subarachnoid block for lower uterine caesarian section. AB - Antinociceptive effect and safety of sub-arachnoid (SAB) midazolam is well established in animals and human beings. In this randomized, prospective placebo control clinical study, we investigated the addition of 2.5mg midazolam to bupivacaine on the quality of surgical anaesthesia and duration of first analgesic in the post operative period after lower uterine caesarean section (LUCS). Sixty ASA I or II pregnant women scheduled for elective lower uterine caesarean section were selected for the study. The patients were randomly allocated to receive 2ml of 0.5% hyperbaric bupivacaine with either 0.5ml of 5% dextrose in aqua or 2.5 mg (0.5ml) midazolam. The duration of first analgesic demand, quality of anaesthesia, haemodynamic changes and neonatal condition were assessed. The duration of analgesia (the time interval in minutes between the sub arachnoid injection and the first analgesic demand by the patient) was significantly longer in the Group II than Group I (197min vs. 112min; p<0.001). The quality of surgical anaesthesia was excellent or good throughout the surgical procedure in 90% (n = 27) of the patients in Group II (p = 0.01). Systolic Blood pressure was significantly lower in the group I at 10 min and 20 min after administration of SAB than group II (p = 0.005 and p = 0.007) but comparable at other times. Sedation level, Apgar score was comparable in both groups. No neurological deficit or other significant adverse effects were recorded. The addition of midazolam with hyperbaric low dose bupivacaine in SAB significantly improves the quality of surgical anaesthesia and prolongs the duration of analgesia without any adverse effects. PMID- 20956903 TI - Microbes responsible for acute exacerbation of COPD. AB - This study was designed to find out the microbes responsible for acute exacerbation of chronic obstructive pulmonary disease (COPD). This study was carried out in the National Institute of Diseases of the Chest & Hospital (NIDCH), Dhaka during the period of January 2003 to December 2003. The study was a prospective case control study. There were 88 male and 2 female patients. The majority of the study subjects fell within the range of 50-70 years. All were smokers. 30 stable COPD patients were taken as control for comparison of sputum culture results of acute exacerbated COPD patients. A standard proforma with questionnaire was designed and filled to select patient with COPD. The patients were selected according to the predetermined criteria viz FEV1<70% predicted and FEV1/FVC % <70% of predicted. Morning specimen of sputum was collected after appropriate preparation and physical character of the sputum were noted. Sputum was immediately sent to microbiology lab for culture. Out of 30 stable COPD patients 6(20%) showed positive sputum culture for bacteria, Pseudomonas 3, Klebsiella 1, Streptococcus pneumoniae 1 and Haemophilus influenza 1. Majority of them were Gram-negative organism. Out of 60 patients with acute exacerbation of COPD 39 patients (65%) showed positive culture for bacteria. Pseudomonas 15, Klebsiella 8, Acinetobacter 4, Enterobacter 2, Moraxella catarrhalis 2 and mixed organisms like, Pseudomonas + Klebsiella 2 and Pseudononas + Acinobacter 1. Majority were Gram-negative bacilli viz. Pseudomonas and Klebsiella spp. species. From this study it was concluded that the prevalence of lower airway bacterial colonization in outpatients with stable COPD is high and is mainly due to Gram negative bacilli like Pseudomonas spp. The greater rate of isolation of pathogenic bacteria in exacerbated COPD than in stable COPD in this study, supports the pathogenic role of bacteria in a proportion of acute exacerbations of chronic obstructive pulmonary disease. The organism commonly play pathogenic role in acute exacerbations of COPD are Pseudomonas and Klebsiella. Acinobacter Moraxella catarrhalis and Enterobacter also contributed in exacerbation of COPD. PMID- 20956904 TI - Intrathecal neostigmine for postoperatrive analgesia in caesarean section. AB - This study was done for intrathecal adjuncts often are used to enhance small dose spinal bupivacaine anaesthesia. We designed this study to evaluate the postoperative analgesic efficacy and safety of intrathecal neostigmine. A randomized, double-blind prospective study was conducted in 90 healthy term pregnant patients scheduled to undergoing elective caesarean section using spinal anaesthesia. Women were administered 12.5 mg bupivacaine alone or with 75 microgram and 150 microgram of neostigmine as intrathecal drug. Parametric data were analyzed using ANOVA. Chi-square test was used to analyze the incidence data. Neostigmine significantly increased the duration sensory and motor block (p<0.05) and the time until for achieving discharge criteria. The addition of neostigmine produced dose-dependent nausea and vomiting and had no significant effect on haemodynamic or respiratory parameters. Addition of neostigmine to intrathecal bupivacaine extends the duration of postoperative analgesia with fewer side-effects without adverse effects on fetus following caesarean section. PMID- 20956905 TI - Evaluation of surgical management of primary spinal tumours. AB - Spinal tumours, which are 5-10% of skeletal tumours, cause considerable morbidity and present challenging situations in their management. Surgery is often used in the treatment of spinal tumours. Now a day only few specialized spinal care centers have developed in Bangladesh. The prospective study regarding surgical management of primary spinal tumour might be beneficial for proper planning and patient management. All patients who underwent surgical resection of a primary tumor of the spine between July 2006 and May 2008, at the Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Patients were uniformly staged before surgery and baseline demographic and surgical variables were recorded, as well as an evaluation of general health related quality of life were done. Thirty-two patients (16 males and 16 females) were eligible for the study. Average age was 43.25 (range 15 to 85). There were 8(25%) vertebral body and pedicle tumors and 3(9.37%) extradural, 16(50%) intradural-extramedullary and 05(15.67%) intradural intramedullary. Only 5(15.63%) developed complication. In this series out of 32 patients, 15(46.88%) achieved excellent result and 10(31.25%) got good result and 5(15.5%) achieved fair and remaining 2(6.25%) patients achieved poor results after the management. Complete neurological involvement of patient did not show complete recovery. In addition to surgery, radiotherapy and chemotherapy are needed to sterilize the tumour bed. Early detection and surgery of primary spinal tumour give satisfactory results and patient can return to their normal life. PMID- 20956906 TI - Uroflowmetry before and after transurethral resection of prostate for bladder outlet obstruction. AB - This prospective study evaluates the effectiveness of uroflowmetry to follow up the patients of benign prostatic hyperplasia treated by transurethral resection of prostate. Total sixty eight patients of 50 to 70 years age group attending for the treatment of BPH with bladder outlet obstruction in the department of Urology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka were recruited for the study. All the TURP's were performed by experienced urologist. Patients were advised to come after 3 months and 6 months for follow up visits. In each visit, the patients were evaluated through history, physical examination and relevant investigations including IPSS and uroflowmetry. Significant improvement was observed in term of Qmax, voided volume, and voiding time in all patients after TURP. Mean (+/-SD) IPSS change in pre to post TURP was 16.2(+/ 0.76) (p<0.05). The objective parameters of uroflowmetry correlated well with the subjective parameters represented by IPSS in this study. PMID- 20956907 TI - Correlation between severity of coronary artery stenosis and perfusion defect assessed by SPECT myocardial perfusion imaging. AB - Numerous non-invasive techniques are developed to assess the severity of coronary artery disease (CAD). Coronary angiography (CAG) is an established method for the diagnosis and to quantify the severity of coronary artery stenosis. Single photon emission computed tomography-myocardial perfusion imaging (SPECT-MPI) using Technetium-99m (Tc-99m) tetrofosmin is also a useful established technique for the assessment of severity of CAD. This prospective observational study was carried out in Bangabandhu Sheikh Mujib Medical University (BSMMU) to assess the severity of coronary artery stenosis using Tc-99m Single Photon Emission Computed Tomography myocardial perfusion imaging (SPECT-MPI) in comparison with CAG. Eighty two (82) consecutive patients with mean age 53.51(SD+/-7.08) years and Candian Cardiovascular Society (CCS) class I and II severity of chest pain, male: female ratio (4.8:1) was studied. Tc-99m SPECT-MPI was performed by one-day exercise stress and rest protocol. A total of two hundred and forty six coronary artery territories examined in this study. By CAG normal coronary arteries were found in seventy six, moderate stenosis in twenty four and severe stenosis in one hundred and forty-six coronary artery territories whereas SPECT-MPI found normal perfusion in twenty seven, mild perfusion abnormality in seventeen, moderate perfusion abnormality in thirty two and severe perfusion abnormality in one hundred and sixty five coronary artery territories. Sensitivity and specificity of SPECT-MPI using Tc-99m tetrofosmin in detecting coronary artery stenosis were 87.09% and 80.95% respectively. The positive predictive value, negative predictive value and accuracy of the test were 91.01%, 73.91% and 85.18% respectively. From this study it can be concluded that Tc-99m SPECT-MPI was a safe, effective and excellent non-invasive tool for the detection of severity of coronary artery lesion and can be used to predict severity of CAD. PMID- 20956908 TI - A case report of right ventricular mass. AB - Primary Cardiac tumors are uncommon during infancy and childhood. Myxomas originating in the right ventricles are even less common in paediatric patient. Our patient baby Rani, 3 months of age presented with shortness of breath and chest indrawing. Antenatal history and delivery was uneventful. The baby was under weight and also malnourished but there was no cyanosis and clubbing. Her respiratory rate was 25/minute. On precordium examination, first heart sound (S1) was normal but pulmonary component of second heart sound (P2) was soft. There was an ejection systolic murmur (Grade-3/6) in the left upper para-sternal area. Chest X-ray revealed cardiomegaly. Echocardiogram revealed a large mass (11x10mm) in the right ventricle, dynamically obstructing the right ventricular out-flow tract and compressing the left ventricle. There was a Tricuspid regurgitation (Grade-2) and moderate pulmonary hypertension (PASP-50 mmHg). PMID- 20956909 TI - A young lady with secondary tuberculosis of breast. AB - Tuberculosis of breast is an extremly rare form of extrapulmonary tuberculosis even in endemic area like Bangladesh and the incidence is 0.25-4.5% of all breast lesions. The diagnosis is difficult because of nonspecific clinical, radiological and histopathological findings. Very often biopsy specimens are inadequate and microscopy or culture is negative. It is usually suspected in a multiparous woman who may be immunocompromised. We report a case of breast tuberculosis in a 26 years old multiparous lady who previously present with two times attack of right sided breast lump and then diagnosed as a case of breast abscess and treated by incision and drainage with antibiotics in a nearby local hospital. During her third time attack she admitted into Mymensingh Medical College Hospital with right sided breast lump with multiple discharging sinuses for one month. Biopsy was taken from the lump and sinus tract and histopathological report confirmed the diagnosis as a case of tuberculosis of breast. Her X-ray chest showed tubercular lesion in lungs. So this is a case of secondary breast tuberculosis. This case highlights how difficult is the diagnosis of a case of breast tuberculosis for which the patient may require even mastectomy at very late case. So this case is reported. PMID- 20956910 TI - Neck swelling with renal stone. AB - Since the advent of screening of calcium and imaging techniques (CT and MRI), hyperparathyroidism has been detected with increasing frequency. Although in the past, most patients present with severe bone and renal diseases, a large number of patients are asymptomatic. Number of parathyroid glands and their ectopic locations in individuals are the problem of its management. Parathyroid adenoma or hyperplasia may be a part of Multiple Endocrine neoplasia type II. This is the story of a boy of 18 years who had got admitted in the department of Otolaryngology, Mymensingh Medical College Hospital with the complaints of a neck swelling, abdominal discomfort, inability to walk, frequency of micturation for almost same duration of 1 year. After search, hypercalcaemia, bilateral renal stone, raised parathormone level and enlarged one parathyroid gland in lower pole of left thyroid lobe was identified. Clinically it was diagnosed as parathyroid adenoma which was proved histologically after surgical excision. Many controversies still exist regarding the treatment policy of parathyroid adenoma. PMID- 20956911 TI - Oral rehabilitation in ectodermal dysplasia. AB - Ectodermal dysplasia (ED) is an inherited heterogenous group of disorders causing mal formation of all tissues originating from ectoderm, like defect in hair, teeth, nail and sweat gland function. Numerous types have been described. Hypohydrotic ectodermal dysplasia (HED) is one of the common type; characterized by hypohidrosis, hypotrichosis (abnormal hair), onychodysplasia (abnormal nail) and hypodontia or anodontia (abnormal dentition). The significance of this disease lies in severe hypodontia. Dental clinicians can be the first to diagnose such cases. The dental team should be aware of its sign and symptoms in order to provide the correct therapies for the functional and psychologic needs of these patients. Here we have discussed oral rehabilitation of a 10 year old boy with ectodermal dysplasia. The objective of this case report is to make aware the people about such rare genetic disease and different methods of oral Rehabilitation of these patients for better social living, self esteem oral function. PMID- 20956912 TI - Testosterone secreting adrenal adenoma in an adult female patient. AB - Adrenal tumours that secrete testosterone are extremely rare and we describe such a case in a 35 years old female with virilization. She had steroid biochemical profile in normal limit, except increased serum testosterone level. She had left adrenal adenoma 7.5 X 6.4 cm in size, her ovaries were normal. After left adrenalectomy the serum testosterone level returns to normal and has remained in the normal range. Hirsutism decreasing gradually and menstruation restarts after 3 months. Histopathological examination confirmed the diagnosis of adrenal adenoma. PMID- 20956913 TI - Congenital sideroblastic anemia treated as thalassemia major. AB - Sideroblastic anemia is a rare cause of microcytic hypochromic anemia. In Bangladesh, most common causes of microcytic anemia are iron deficiency anemia, anemia of chronic diseases and thalassemia. Serum ferritin is usually done to differentiate them. If serum ferritin is low, the diagnosis of iron deficiency is entertained. When serum ferritin is raised but erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are normal - anemia of chronic disease is excluded. The next investigation is Hb-electrophoresis. Normal Hb-electroporesis excludes thalassemia. Then bone marrow examination with iron stain is done for the diagnosis of sideroblastic anemia. Here we report a case of a 14 year old girl presenting with intermittent leg pain and anemia. Her blood flim showed microcytic hypochromic anemia with raised serum ferritin and normal Hb electroporesis. Initially she was labeled as a case of unusual type of thalassemia and treated with blood transfusion. Finally bone marrow examination with iron stain was done and she was diagnosed as a case of congenital sideroblastic anemia. We reviewed the literature and discussed the management as well. PMID- 20956914 TI - Diagnosis and management of solid pseudopapillary tumours of the pancreas. AB - The finding of a solid or cystic mass in the pancreas is becoming more common secondary to the increasing use of cross-sectional imaging and the improved sensitivity of such studies for the detection of pancreatic abnormalities. Because of the aggressive natural history of pancreatic cancer, this has caused concern that all pancreatic abnormalities may be cancer as well as confusion over proper diagnostic and treatment algorithms. This review provides an overview of the natural history, diagnostic considerations, and treatment recommendations for the less common tumor of the pancreas which can be misinterpreted as pancreatic cancer: solid pseudopapillary tumors (SPT). A Medline search was conducted to identify studies investigating the clinicopath-ologic features, molecular genetics, pathogenesis, diagnosis, and treatment of SPT. It is often possible to obtain an accurate pretreatment diagnosis for this unusual pancreatic tumor and to successfully differentiate them from the more common pancreatic malignancies. PMID- 20956915 TI - Recent Advances in the Management of Chemotherapy-induced Nausea and Vomiting: A Case Study Compendium. PMID- 20956918 TI - Dysphagia in severe traumatic brain injury. AB - Dysphagia, or swallowing difficulty, is a common problem following severe traumatic brain injury and is associated with an increased risk of malnutrition and pneumonia. Management of patients with dysphagia following head injury is complicated by the presence of cognitive, communication, and behavioral impairments. The purpose of this review article is to help physicians taking care of traumatic brain injury patients understand and manage dysphagia. The article reviews the history of the study of swallowing, stages of swallowing, impairments of swallowing, neural control of swallowing, and the evaluation of patients with swallowing difficulties and their management. In addition to the general principles of dysphagia management, this article covers the management of dysphagic patients with tracheostomy and their nutritional management. PMID- 20956920 TI - Assessment of autonomic function in epileptic patients. AB - OBJECTIVE: To use spectral analysis to assess the autonomic activity of epileptic patients compared with normal patients, and to assess the clinical usefulness of the applied methods of signal processing. METHODS: Forty-eight patients with generalized tonic-clonic seizures and who were not taking any medications, and 48 age and gender matched controls participated in this study from July to September 2007 at Johns Hopkins Hospital, Baltimore, Maryland, and the Medical Center, Cookeville, Tennessee, United States of America. All subjects consented to participate in the research prior to their inclusion in the study, and the local ethics committee approved the study protocol. The study design was to measure peripheral blood flow (PBF) and respiration signals as well as the heart rate variability (HRV) signals derived from the ECG during supine and standing positions. RESULTS: The results clearly indicate that in patients with epilepsy, the coherence values are less than in the control group in both low frequency and high frequency bands at coherence spectra between HRV and PBF as well as HRV and respiration in both the supine and standing position. CONCLUSION: Autopower and coherence spectra analysis for patients with epilepsy compared to normal subjects seems useful in the assessment of autonomic function for epileptic patients. Further studies are needed using other tests and methods of signal analysis. PMID- 20956919 TI - Allicin can reduce neuronal death and ameliorate the spatial memory impairment in Alzheimer's disease models. AB - OBJECTIVE: To investigate the mechanisms and protective effects of allicin on learning and memory in a mouse model of Alzheimer's disease (AD). METHODS: This study took place in the Institute of Medicine of Jishou University, Jishou, China, between January and September 2009. Allicin was given as preventive administration after AD was induced by amyloid beta (Abeta[1-42]), and the protective effects of Allicin against learning and memory impairment were investigated. Sixty mice were randomly divided into 3 groups including the sham operated+phosphate buffer solution (PBS) group, the Abeta(1-42)+PBS group, and the Abeta(1-42)+allicin group. The Abeta(1-42) (1 uL = 4ug) was injected into the bilateral hippocampi. Sham-operated mice were infused with PBS. Allicin or PBS was then injected intraperitoneally for 14 days. The animals were trained, and learning and memory abilities tested using the Morris Water-Maze. The changes of Abeta(1-42) and P38 mitogen-activated protein kinase (p38MAPK) were recorded to explore the mechanism of allicin's protective effects on learning and memory deficits. RESULTS: The Abeta(1-42)-infused allicin-treated group showed significantly shorter latency times than the PBS treated Abeta(1-42)-infused group from the second day of learning sessions (p=0.031), accompanied with significant reduction of malondialdehyde (MDA) (p=0.035) and an increase of superoxide dismutase (SOD) activity (p=0.041). Allicin also decreased Abeta and p38MAPK expressions in the cerebral cortex of AD mice model (p=0.031). CONCLUSION: Preventive administration of allicin prevented learning and memory impairment, the mechanism may be due to an increase in the activity of SOD, a reduction in the levels of MDA and the expressions of Abeta and p38MAPK in the brain. PMID- 20956921 TI - Validity and reliability of the Persian epilepsy quality of life questionnaire. AB - OBJECTIVE: To translate and test the reliability and validity of the 31-item epilepsy quality of life questionnaire (QOLIE-31) in Iranian epileptic patients. METHODS: In order to standardize the questionnaire, using a standard "forward backward" translation, cognitive debriefing, and cultural adaptation procedure, the English version of the QOLIE-31 was translated to Persian (the Iranian official language). The subjects were Epileptic patients, over 18 years old, referred to the Motaharri Clinic, Shiraz, Southern Iran from March 2007 to March 2008. The reliability and internal consistency of the questionnaire were assessed by Cronbach's alpha coefficient. Validity was assessed using convergent and disconvergent validity through Spearman's correlation. RESULTS: Two hundred and eleven epileptic patients (88 females [41.7%], 123 males [58.3%]), with a mean +/ SD age of 28.7+/-11.6 years were enrolled in the study. Reliability analysis showed a satisfactory result (Cronbach's alpha=0.890). Internal consistency was satisfactory for both demographic and patients' clinical characteristics (alpha>=0.70). The scaling success rates were 100% for convergent validity of each scale. Disconvergent validity for all 7 scales was good. CONCLUSION: The Persian version of the QOLIE-31 questionnaire has good structural characteristics, is a reliable and valid instrument, and can be used for measuring the effect of epilepsy on the quality of life. PMID- 20956922 TI - Prevalence of anxiety and depression in Iranian kidney transplant recipients. AB - OBJECTIVE: To evaluate the prevalence of depression and anxiety in Iranian patients receiving a kidney transplant. METHODS: A cross-sectional study was undertaken in Shiraz Organ Transplant Center, Shiraz University of Medical Sciences, Shiraz, Iran between September 2006 and July 2007. We evaluated depression and anxiety in renal transplant recipients who had a follow-up appointment scheduled. The study participants consisted of 109 male and 91 female renal transplant patients, age ranged from 17-73 years with a mean age of 39.64 years (SD = 12.85). All patients were assessed using validated Beck Depression Inventory and Beck Anxiety Inventory. RESULTS: Out of 200 patients, 75% showed depression and 50% had anxiety. Among variables, donor type, pretransplant dialysis period, posttransplant period, and rejection had a significant relationship with depression and anxiety. CONCLUSION: The frequency of depression and anxiety is high in renal transplantation. Psychiatric evaluation should be a routine part of most pre-transplant candidacy workups. Transplant patients with a history of rejection should receive more attention for psychiatric problems. The type of the graft donor was also found to be an important factor affecting anxiety and depression in renal transplant patients. PMID- 20956923 TI - Etiological characteristics of people with intellectual disability in Iran. AB - OBJECTIVE: To describe the etiological characteristics of intellectual disability in one Iranian center. METHODS: In a cross-sectional study, 64 cases with mental retardation (MR) were examined in the Intellectual Rehabilitation & Welfare Care Center of Vardavard, Iran between April and September 2008. Cases were diagnosed with MR or showed delay/regression of developmental milestones. We studied the records of patients and interviewed their families. RESULTS: A total of 64 cases were screened (most were children). The number of male patients was 19 (29.7%) and the females was 45 (70.3%). First degree relatives with mental retardation were found in the families of studied patients, among these relatives 48% were female and 52% were male. Up to 77% of the marriages were between relatives, approximately half between first cousins. The illiteracy rate reached 34% in the families of MR children. Hard labor, hypoxia during labor, mother's preexisting systemic disease, and maternal and neonatal infection were the most important factors for MR. Furthermore, most of the families were found to have low socioeconomic class. CONCLUSION: Cognitive disabilities in children are multifactorial. Consanguinity was the main risk factor for MR and considering its high rate in our country due to traditional marriages, it should be modified. PMID- 20956924 TI - Prognostic factors of neurological sequel in adult patients with tuberculous meningitis. AB - OBJECTIVE: To evaluate the predictors of neurological sequel in tuberculous meningitis (TBM). METHODS: This study was carried out at the Department of Clinical Microbiology and Infectious Diseases, Haseki Training and Research Hospital, Istanbul, Turkey, between January 1998 and March 2009. Neurological sequels at 6 months of 160 adult patients with TBM who had been followed up were assessed retrospectively. The prognostic role of various demographic, clinical, laboratory, and radiological findings on admission, in prediction of neurological sequel development, were studied using a multivariate logistic regression. Clinical and therapeutic outcomes at 6 months were determined using a modified Barthel Index. RESULTS: Twenty-seven (17%) patients died and 20 (13%) survivors had neurological sequelae at 6 months. Cranial nerve palsy, presence of tuberculoma, younger age, and basal meningitis were found to be significant predictors of neurological sequelae in univariate analysis, but only younger age (odds ratio [OR] 2.9, 95% confidence intervals [CI] 1.0-8.6, p=0.049), cranial nerve palsy (OR 3.9, 95% CI 1.8-8.8, p=0.001), and presence of tuberculoma (OR 1.9, 95% CI 1.0-4.2, p=0.048) were found to be significant predictors using multivariable logistic regression analysis. CONCLUSION: Neurological sequelae were more common in patients with tuberculoma and cranial nerve palsy on admission. Development of neurological complications may be seen despite timely and effective anti-tuberculous therapy especially in younger patients. PMID- 20956925 TI - Do obstetrical brachial plexus injuries affect proprioceptive sense? AB - OBJECTIVE: To evaluate the proprioceptive sensory input in the shoulder joint affected by obstetrical brachial plexus injuries (OBPI). METHODS: This controlled study included 39, 7-12-year-old children with upper and/or middle trunk OBPI, and it took place in the Department of Physiotherapy and Rehabilitation, Faculty of Health Science, Hacettepe University, Ankara, Turkey between January 2008 and September 2009. The proprioceptive evaluation was carried at both affected and normal sides, at predetermined target angles, which were determined as 10%, 30%, and 90% of the shoulder passive abduction angle and at the rate of 2 degrees/s speed. RESULTS: A statistically significant difference was observed between affected and normal sides at 10% and 30% of the target angles. Absolute values of the affected side proprioception score were found to be higher compared to the normal side. CONCLUSION: A decrease in the proprioceptive sense in OBPI was observed. Therefore, a deteriorated proprioceptive network will eventually, over time, affect functionality in this type of injury. PMID- 20956926 TI - Successful treatment of severe stenosis of the posterior cerebral artery with percutaneous transluminal angioplasty and stenting. AB - Cerebral arterial stenosis is a major cause of stroke and of insufficient blood supply to the vertebral basilar system. Percutaneous transluminal cerebral angioplasty and stenting (PTCAS) have been used to preliminarily treat vertebrobasilar stenosis. However, the feasibility to treat the posterior cerebral arterial stenosis by PTCAS has not been fully established. We report a case of a 64-year-old man with a severe stenosis of the posterior cerebral artery that was treated successfully using a PTCAS procedure. PMID- 20956927 TI - Unusual appearance of a cerebral hydatid cyst as a hemorrhagic infarct. AB - We herein present a 32-year-old Lebanese woman with a history of cardiac hydatid cyst presenting with headache, confusion, and right arm clumsiness. A CT of the head showed hemorrhagic infarct of the left fronto-parietal lobe. Eleven months later, the subsequent development of hydatid cysts within the necrotic area of the infracted hemisphere suggested a cerebral hydatid embolism of cardiac origin. In patients with a positive history of hydatid disease, hydatid embolism should be considered in the differential diagnosis of stroke in young patients. PMID- 20956928 TI - Arachnoid cyst of the posterior fossa. AB - Arachnoid cysts of the posterior fossa are uncommon. Our case of a 49-year-old man presented with a 2 month history of headaches, nausea, and vertigo associated with walking instability. An MRI revealed a median well-circumscribed cystic lesion of the posterior fossa, with similar signal characteristics to CSF, and without connection to the fourth ventricle. This aspect suggested either arachnoid or hydatid cysts. Direct open surgery was performed allowing complete removal of the cyst wall, with a good outcome. PMID- 20956929 TI - Aneurysmal bone cyst concomitant with fibrous dysplasia in the frontal bone. AB - Secondary aneurysmal bone cyst in fibrous dysplasia is exceedingly rare, especially in the skull and particularly in the frontal bone. We present a case of aneurysmal bone cyst concomitant with fibrous dysplasia in the frontal bone in a 15-year-old male patient presenting with headache and euphoria with an uncharacteristic imaging appearance and treated successfully by total resection. PMID- 20956930 TI - Thyroiditis of Hashimoto and myotonia. AB - Hypothyroidism is frequently associated with different neuromuscular disorders. However, myotonia is rarely a revealing feature. We report a case of hypothyroidism secondary to Hashimoto's thyroiditis and myotonia. The patient is a 45-year-old woman who consulted for a progressive myotonia. Blood and thyroid assessments revealed peripheral hypothyroidism with low free thyroxine, high thyroid-stimulating hormone levels and high titers of anti-thyroperoxidase antibodies. Outcome was favorable with thyroid hormone substitution. Hashimoto's thyroiditis is a common cause of hypothyroidism. The frequency of myopathy during hypothyroidism ranges from 30-80%. The main symptoms related are weakness, muscular cramps, and myalgia. Myotonia may reveal hypothyroidism. The pathogenic mechanism of this myotonia is still unknown. Good outcome of hypothyroid manifestations with thyroid hormone substitution requires systematic thyroid hormone screening in patients presenting with neuromuscular manifestations. PMID- 20956931 TI - Bulky subependymal giant cell astrocytoma with profuse blood supply without tuberous sclerosis. PMID- 20956932 TI - Fibromyalgia, co-morbid psychiatric disorder and gender. A study based on General Health Questionnaire (GHQ-12) and (GHQ-30). PMID- 20956933 TI - Effects of lemon essential oil aroma on the learning behaviors of rats. PMID- 20956934 TI - An unusual time pattern of central nervous system anomalies in Northwestern Iran. PMID- 20956935 TI - Phenytoin induced status epilepticus. PMID- 20956936 TI - Chronic childhood ataxia: ataxia-telangiectasia. PMID- 20956937 TI - NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response. AB - Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in regenerating nicotinamide adenine dinucleotide (NAD(+)) from nicotinamide in mammals. NAMPT has crucial roles for many cellular functions by regulating NAD(+) dependent SIRT1 deacetylase. However, roles of NAMPT in cancer are poorly defined. In this study, we show that NAMPT is prominently overexpressed in human prostate cancer cells along with SIRT1. Elevation of NAMPT expression occurs early for the prostate neoplasia. Inhibition of NAMPT significantly suppresses cell growth in culture, soft agar colony formation, cell invasion and growth of xenografted prostate cancer cells in mice. NAMPT knockdown sensitizes prostate cancer cells to oxidative stress caused by H(2)O(2) or chemotherapeutic treatment. Overexpression of NAMPT increases prostate cancer cell resistance to oxidative stress, which is partially blocked by SIRT1 knockdown. We demonstrate that in addition to modulating SIRT1 functions, the NAMPT inhibition reduces forkhead box, class 'O' (FOXO)3a protein expression and its downstream anti oxidant genes catalase and manganese superoxide dismutase. Our results suggest important roles of concomitant upregulation of NAMPT and SIRT1 along with increased FOXO3a protein level for prostate carcinogenesis and their contribution to oxidative stress resistance of prostate cancer cells. These findings may have implications for exploring the NAMPT pathway for prostate cancer prevention and treatment. PMID- 20956939 TI - MicroRNA-101-mediated Akt activation and estrogen-independent growth. AB - MicroRNAs are gene regulators that work through a posttranscriptional repression mechanism. Dysregulation of microRNA expression could lead to a variety of disorders, in particular, human cancer, and has also been implicated in antihormone therapy resistance. However, little is known whether microRNAs have a role in estrogen-independent growth, leading to tamoxifen resistance in estrogen receptor (ER)-positive tumors. In this study, we use an in vivo selection system against a microRNA library using the MCF-7 model and demonstrate that miR-101 promotes estrogen-independent growth and causes the upregulation of phosphorylated Akt (pAkt) without impacting the ER level or activity. Importantly, although miR-101 suppresses cell growth in normal estradiol (E2) containing medium, it promotes cell growth in E2-free medium. Moreover, estrogen deprivation greatly enhances miR-101-mediated Akt activation. Finally, we show that MAGI-2 (membrane-associated guanylate kinase), a scaffold protein required for PTEN (phosphatase and tensin homolog) activity, is a direct target for miR 101; suppression of MAGI-2 by miR-101 reduces PTEN activity, leading to Akt activation. Taken together, these results not only establish a role for miR-101 in estrogen-independent signaling but also provide a mechanistic link between miR 101 and Akt activation. PMID- 20956938 TI - Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab. AB - KRAS mutation is a predictive biomarker for resistance to cetuximab (Erbitux) in metastatic colorectal cancer (mCRC). This study sought to determine if KRAS mutant CRC lines could be sensitized to cetuximab using dasatinib (BMS-354825, Sprycel), a potent, orally bioavailable inhibitor of several tyrosine kinases, including the Src family kinases (SFKs). We analyzed 16 CRC lines for: (1) KRAS mutation status, (2) dependence on mutant KRAS signaling and (3) expression level of epidermal growth factor receptor (EGFR) and SFKs. From these analyses, we selected three KRAS mutant (LS180, LoVo and HCT116) cell lines and two KRAS wild type cell lines (SW48 and CaCo2). In vitro, using poly-D-lysine/laminin plates, KRAS mutant cell lines were resistant to cetuximab, whereas KRAS wild-type lines showed sensitivity to cetuximab. Treatment with cetuximab and dasatinib showed a greater antiproliferative effect on KRAS mutant lines when compared with either agent alone in vitro and in vivo. To investigate potential mechanisms for this antiproliferative response in the combinatorial therapy, we performed Human Phospho-Kinase Antibody Array analysis, measuring the relative phosphorylation levels of 39 intracellular proteins in untreated, cetuximab, dasatinib or the combinatorial treatment in the KRAS mutant lines LS180, LoVo and HCT116 cells. The results of this experiment showed a decrease in a broad spectrum of kinases centered on the beta-catenin pathway, the mitogen-activated protein kinase (MAPK) pathway, AKT/mammalian target of rapamycin (mTOR) pathway and the family of signal transducers and activators of transcription (STATs) when compared with the untreated control or monotherapy treatments. Next, we analyzed tumor growth with cetuximab, dasatinib or their combination in vivo. KRAS mutant xenografts showed resistance to cetuximab therapy, whereas KRAS wild type demonstrated an antitumor response when treated with cetuximab. KRAS mutant tumors exhibited minimal response to dasatinib monotherapy. However, as in vitro, KRAS mutant lines exhibited a response to the combination of cetuximab and dasatinib. Combinatorial treatment of KRAS mutant xenografts resulted in decreased cell proliferation, as measured by Ki67, and higher rates of apoptosis, as measured by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling). The data presented in this study indicate that dasatinib can sensitize KRAS mutant CRC tumors to cetuximab and may do so by altering the activity of several key signaling pathways. Furthermore, these results suggest that signaling via EGFR and SFKs may be necessary for cell proliferation and survival of KRAS mutant CRC tumors. These data strengthen the rationale for clinical trials combining cetuximab and dasatinib in the KRAS mutant CRC genetic setting. PMID- 20956940 TI - Epigenetic inactivation of the RASSF10 candidate tumor suppressor gene is a frequent and an early event in gliomagenesis. AB - We have recently described the N-terminal RAS association domain family of genes, RASSF7-10. Previously, we cloned the N-terminal RASSF10 gene and demonstrated frequent methylation of the associated 5'-CpG island in acute lymphoblastic leukemia. To characterize RASSF10 gene expression, we demonstrate that in developing Xenopus embryos, RASSF10 shows a very striking pattern in the rhombencephalon (hind brain). It is also expressed in other parts of the brain and other organs. Due to the well-defined expression pattern in the brain of Xenopus embryos, we analyzed the methylation status of the RASSF10-associated 5' CpG island in astrocytic gliomas. RASSF10 was frequently methylated in WHO grade II-III astrocytomas and WHO grade IV primary glioblastomas (67.5%), but was unmethylated in grade I astrocytomas and in DNA from age matched control brain samples. RASSF10 gene expression both at the mRNA and protein levels could be switched back on in methylated glioma cell lines after treatment with 5-aza-2' deoxycytidine. In secondary glioblastomas (sGBM), RASSF10 methylation was an independent prognostic factor associated with worst progression-free survival and overall survival and occurred at an early stage in their development. In cell culture experiments, overexpression of RASSF10 mediated a reduction in the colony forming ability of two RASSF10-methylated glioma cell lines. Conversely, RNAi mediated knockdown of RASSF10-stimulated anchorage-independent growth of U87 glioma cells, increased their viability and caused an increase in the cells' proliferative ability. We generated and characterized a RASSF10-specific antibody and demonstrated for the first time that RASSF10 subcellular localization is cell cycle dependent with RASSF10 colocalizing to centrosomes and associated microtubules during mitosis. This is the first report demonstrating that RASSF10 can act as a tumor suppressor gene and is frequently methylated in gliomas and can potentially be developed into a prognostic marker for sGBM. PMID- 20956941 TI - Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants. AB - The WTX, Wilms tumor-associated tumor-suppressor gene, is present on the X chromosome and a single WTX mutation may be sufficient to promote carcinogenesis. Unlike the WT1 tumor suppressor, a transcription factor, WTX lacks conserved functional protein domains. To study the function of WTX, we constructed inducible cell lines expressing WTX and tumor-associated WTX mutants. Induction of WTX inhibited cell growth and caused G(1)/G(0) arrest. In contrast, a short, tumor-associated truncation mutant of WTX358 only slightly inhibited cell growth without a significant cell-cycle arrest, although expression of a longer truncation mutant WTX565 led to the growth inhibition and cell-cycle arrest to a similar extent as wild-type WTX. Like WT1, WTX slowed growth and caused cell cycle arrest through p21 induction. Gene expression profiling showed that these two tumor-suppressors regulated genes in similar pathways, including those implicated in control of the cellular growth, cell cycle, cell death, cancer and cardiovascular system development. When gene expression changes mediated by wild type WTX were compared with those affected by mutant forms, WTX565 showed a 55% overlap (228 genes) in differentially regulated genes, whereas WTX358 regulated only two genes affected by wild-type WTX, implying that amino-acid residues 358 561 are critical for WTX function. PMID- 20956942 TI - Thyroid hormone receptor beta1 domains responsible for the antagonism with the ras oncogene: role of corepressors. AB - The thyroid hormone receptor (TR) is a suppressor of ras-mediated responses. To characterize the receptor domains involved in this function, we analyzed a panel of TRbeta1 mutants for their ability to interfere with ras-driven cyclin D1 activation, formation of transformation foci and tumor growth in nude mice. Our results show that the domains and mechanisms responsible for the anti transforming and anti-tumorigenic actions of the receptor are divergent from those operating in classical T3-dependent transcriptional activation. TRbeta1 mutants that do not bind coactivators and do not transactivate retained the capacity of suppressing cellular transformation and tumor growth, whereas selective mutations in the hinge region affecting corepressors recruitment abolished these actions, while preserving ligand-dependent transcription. There was a strict parallelism between anti-transforming activity of the various mutants and their ability to antagonize cyclin D1 stimulation by ras, indicating that transrepression mechanisms may have an important function in suppression of the transforming effects of the oncogene by TRbeta1. The inhibitory action of T3 on transformation was further enhanced after over-expression of corepressors, while corepressor depletion by means of small-interference RNA reversed significantly hormonal action. This shows an important functional role of endogenous corepressors in suppression of ras-mediated transformation and tumorigenesis by TRbeta1. PMID- 20956943 TI - c-Src differentially regulates the functions of microtentacles and invadopodia. AB - During metastasis, invading cells produce various actin-based membrane protrusions that promote directional migration and proteolysis of extracellular matrix (ECM). Observations of actin staining within thin, tubulin-based microtentacle (McTN) protrusions in suspended MDA-MB-231 tumor cells, prompted an investigation of whether McTNs are structural or functional analogs of invadopodia. We show here that MDA-MB-231 cells are capable of producing invadopodia and McTNs, both of which contain F-actin. Invadopodium formation was enhanced by the expression of a constitutively active c-Src kinase, and repressed by the expression of dominant-negative, catalytically inactive form of c-Src. In contrast, expression of inactive c-Src significantly increased McTN formation. Direct inhibition of c-Src with the SU6656 inhibitor compound also significantly enhanced McTN formation, but suppressed invadopodia, including the appearance of F-actin cores and phospho-cortactin foci, as well as completely blocking focal degradation of ECM. In addition, silencing of Tks5 in Src-transformed fibroblasts blocked invadopodia without affecting McTNs. Genetic modification of c-Src activity that promoted McTN formation augmented capillary retention of circulating tumor cells in vivo and rapid re-attachment of suspended cells in vitro, even though invadopodia were strongly suppressed. These results indicate that McTNs are capable of enhancing tumor cell reattachment, even in the absence of Tks5 and active Src, and define separate cytoskeletal mechanisms and functions for McTNs and invadopodia. PMID- 20956944 TI - MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin beta8. AB - It has been reported that the miR-106b~25 cluster, a paralog of the miR-17~92 cluster, possesses oncogenic activities. However, the precise role of each microRNA (miRNA) in the miR-106b~25 cluster is not yet known. In this study, we examined the function of miR-93, one of the microRNAs within the miR-106b~25 cluster, in angiogenesis and tumor formation. We found that miR-93 enhanced cell survival, promoted sphere formation and augmented tumor growth. Most strikingly, when miR-93-overexpressing U87 cells were co-cultured with endothelial cells, they supported endothelial cell spreading, growth, migration and tube formation. In vivo studies revealed that miR-93-expressing cells induced blood vessel formation, allowing blood vessels to extend to tumor tissues in high densities. Angiogenesis promoted by miR-93 in return facilitated cell survival, resulting in enhanced tumor growth. We further showed that integrin-beta8 is a target of miR 93. Higher levels of integrin-beta8 are associated with cell death in tumor mass and in human glioblastoma. Silencing of integrin-beta8 expression using small interfering RNA promoted cell proliferation, whereas ectopic expression of integrin-beta8 decreased cell growth. These findings showed that miR-93 promotes tumor growth and angiogenesis by suppressing, at least in part, integrin-beta8 expression. Our results suggest that inhibition of miR-93 function may be a feasible approach to suppress angiogenesis and tumor growth. PMID- 20956945 TI - Upregulation of miR-21 by Ras in vivo and its role in tumor growth. AB - miR-21 is a microRNA (miRNA) frequently overexpressed in human cancers. Here we show that miR-21 is upregulated both in vitro and in vivo by oncogenic Ras, thus linking this miRNA to one of the most frequently activated oncogenes in human cancers. Ras regulation of miR-21 occurs with a delayed kinetic and requires at least two Ras downstream pathways. A screen of human thyroid cancers and non small-cell lung cancers for the expression of miR-21 reveals that it is overexpressed mainly in anaplastic thyroid carcinomas, the most aggressive form of thyroid cancer, whereas in lung its overexpression appears to be inversely correlated with tumor progression. We also show that a LNA directed against miR 21 slows down tumor growth in mice. Consistently, a search for mRNAs downregulated by miR-21 shows an enrichment for mRNAs encoding cell cycle checkpoints regulators, suggesting an important role for miR-21 in oncogenic Ras induced cell proliferation. PMID- 20956946 TI - Milk fat globule--epidermal growth factor--factor VIII (MFGE8)/lactadherin promotes bladder tumor development. AB - Milk fat globule-epidermal growth factor-factor VIII (MFGE8), also called lactadherin or SED1, is a secreted integrin-binding protein that promotes elimination of apoptotic cells by phagocytes leading to tolerogenic immune responses, and vascular endothelial growth factor (VEGF)-induced angiogenesis: two important processes for cancer development. Here, by transcriptomic analysis of 228 biopsies of bladder carcinomas, we observed overexpression of MFGE8 during tumor development, correlated with expression of genes involved in cell adhesion or migration and in immune responses, but not in VEGF-mediated angiogenesis. To test whether MFGE8 expression was instrumental in bladder tumor development, or a simple consequence of this development, we used genetic ablation in a mouse model of carcinogen-induced bladder carcinoma. We showed that Mfge8 was also upregulated in mouse carcinoma, and that in its absence, Mfge8-deficient animals developed less advanced tumors. Angiogenesis was similar in carcinogen-treated Mfge8-expressing or -deficient bladders, thus ruling out a major role of the proangiogenic function of Mfge8 for its protumoral role. By contrast, the tumor promoting role of Mfge8 was not observed anymore in mice devoid of adaptive immune system, and human tumors overexpressing MFGE8 where invaded with macrophages and regulatory T cells, thus suggesting that MFGE8/lactadherin favors development of bladder tumors at least partly by an immune system-dependent mechanism. Our observations suggest future use of MFGE8-inhibiting molecules as therapies of bladder carcinomas, and of a limited number of other human cancers, in which our analysis of public databases also revealed overexpression of MFGE8. PMID- 20956947 TI - Proteasome inhibitors induce nucleolar aggregation of proteasome target proteins and polyadenylated RNA by altering ubiquitin availability. AB - The ubiquitin-proteasome pathway is essential for most cellular processes, including protein quality control, cell cycle, transcription, signaling, protein transport, DNA repair and stress responses. Hampered proteasome activity leads to the accumulation of polyubiquitylated proteins, endoplastic reticulum (ER) stress and even cell death. The ability of chemical proteasome inhibitors (PIs) to induce apoptosis is utilized in cancer therapy. During PI treatment, misfolded proteins accrue to cytoplasmic aggresomes. The formation of aggresome-like structures in the nucleus has remained obscure. We identify here a nucleolus associated RNA-protein aggregate (NoA) formed by the inhibition of proteasome activity in mammalian cells. The aggregate forms within the nucleolus and is dependent on nucleolar integrity, yet is a separate structure, lacking nucleolar marker proteins, ribosomal RNA (rRNA) and rRNA synthesis activity. The NoAs contain polyadenylated RNA, conjugated ubiquitin and numerous nucleoplasmic proteasome target proteins. Several of these are key factors in oncogenesis, including transcription factors p53 and retinoblastoma protein (Rb), several cell cycle-regulating cyclins and cyclin-dependent kinases (CDKs), and stress response kinases ataxia-telangiectasia mutated (ATM) and Chk1. The aggregate formation depends on ubiquitin availability, as shown by modulating the levels of ubiquitin and deubiquitinases. Furthermore, inhibition of chromosome region maintenance 1 protein homolog (CRM1) export pathway aggravates the formation of NoAs. Taken together, we identify here a novel nuclear stress body, which forms upon proteasome inactivity within the nucleolus and is detectable in mammalian cell lines and in human tissue. These findings show that the nucleolus controls protein and RNA surveillance and export by the ubiquitin pathway in a previously unidentified manner, and provide mechanistic insight into the cellular effects of PIs. PMID- 20956948 TI - PKB/Akt promotes DSB repair in cancer cells through upregulating Mre11 expression following ionizing radiation. AB - An elevated DNA-repair capacity in cancer cells leads to radiation resistance and severely limits the efficacy of radiation therapy. Activation of Akt is tightly associated with resistance to radiotherapy, and Mre11 protein has important role during the repair of DNA double-strand breaks (DSBs). In this report, our results showed that inhibition of Akt activity impaired the repair of DSBs in CNE2 cells, whereas activated Akt promoted the repair of DSBs in HeLa cells. Knockdown of Mre11 also impaired the process of DSB repair in both these two cell lines. More importantly, we found that Akt could regulate Mre11 expression. Inhibition of Akt activity by small interfering RNA or LY294002 efficiently downregulated the Mre11 expression in CNE2 cells, and transfection with myr-Akt plasmid in HeLa cells upregulated the Mre11 expression. In addition, luciferase reporter analysis revealed that Mre11 reporter activity increased after transfection with myr-Akt1 plasmids, and this myr-Akt1-induced transcriptional activity was blocked in the presence of LY294002. Further study showed GSK3beta/beta-catenin/LEF-1 pathway was involved in this regulation. Knockdown of beta-catenin or LEF-1 led to the downregulation of Mre11, whereas overexpression of beta-catenin led to upregulation of Mre11. The chromatin immunoprecipitation assay assay showed beta catenin/LEF-1 heterodimer could directly bind to the promoter of Mre11 in vivo. And the luciferase activity of the pGL3-Mre11 and pGL3-Lef increased in HeLa cells following beta-catenin plasmid co-transfected, but was abolished when the LEF-1-binding conserved sequences of Mre11 promoter were mutated. These results together support Akt can upregulate the expression of Mre11 through GSK3beta/ beta-catenin/LEF pathway to elevate DSB-repair capacity in cancer cells. PMID- 20956951 TI - Paraproteinaemia after allo-SCT, association with alemtuzumab-based conditioning and CMV reactivation. AB - Paraproteinaemia following allo-SCT is common. We analysed 91 consecutive patients undergoing allo-SCT; conditioning included alemtuzumab in 42% of the patients. Paraproteinaemia incidence at 2 years was 32%. In univariate analysis paraproteinaemia was associated with unrelated donor, age, recipient seropositivity for CMV and alemtuzumab conditioning (hazard ratio (HR) 3.93, P=0.0006). Paraproteinaemia was not associated with haematological diagnosis; disease status at transplant; varicella zoster, herpes simplex or EBV serology; reduced-intensity vs myeloablative conditioning or GVHD. CMV reactivation-more frequent in alemtuzumab recipients-was associated with paraproteinaemia (HR 7.52, P<0.0001). In multivariate analysis, only increasing age (HR 1.04 per year, P=0.048) and CMV reactivation (HR 5.74, P=0.001) were significantly associated with paraproteinaemia. Alemtuzumab without CMV reactivation, however, resulted in significantly more paraproteinaemia, suggesting an effect that is independent of CMV reactivation. OS was poorer in patients with paraproteinaemia (HR 2.54, P=0.04) and relapse increased (HR 2.38, P=0.087). Paraproteinaemia was not significantly independently associated with decreased survival on multivariate analysis. Post transplant paraproteinaemia is associated with CMV reactivation, is more frequent in alemtuzumab-conditioned transplants and is not associated with improved OS. PMID- 20956952 TI - Ancestim (r-metHuSCF) plus filgrastim and/or chemotherapy for mobilization of blood progenitors in 513 poorly mobilizing cancer patients: the French compassionate experience. AB - Ancestim (r-MetHuSCF) is available in France for compassionate use in patients who are candidates for high-dose chemotherapy and autologous transplantation, and who failed in previous attempts at mobilization and collection. We report here data from 513 adult patients who benefited from this program, between January 1998 and July 2007. Given with systematic premedication, ancestim was generally well tolerated, although severe but not life-threatening adverse events were reported in 12 individuals. Overall, a graft was obtained or completed for 235 patients (46%). The median number of collected CD34+ cells was 3.00 * 10(6)/kg (range: 0.03-39.50). The target threshold of 2 * 10(6) CD34+ cells/kg was reached in 161 patients (31%). Factors associated with collection were diagnosis of myeloma, no previous autologous transplant, no more than one previous failed attempt and a mobilization regimen including cytotoxic agents. A total of 207 patients (40%) proceeded to high-dose chemotherapy and autologous transplantation. The median time to reach 0.5 * 10(9)/L neutrophils and 20 * 10(9)/L platelets was 12 (6-40) and 13 (0-31) days, respectively. We conclude that a combination of ancestim with filgrastim successfully mobilized CD34+ cells in peripheral blood, and allowed adequate collection in preparation for autologous transplantation in approximately one-third of poorly mobilizing patients. PMID- 20956953 TI - Reduced-intensity SCT for chronic active EBV infection: excellent outcomes should trigger future investigations on how EBV-positive recipient cells are eradicated. PMID- 20956954 TI - Ischemic stroke associated with the infusion of DMSO-cryopreserved auto-PBSCs. PMID- 20956955 TI - A second course of high-dose melphalan and auto-SCT for the treatment of relapsed AL amyloidosis. AB - High-dose melphalan and auto-SCT (HDM/SCT) induces hematological complete responses (HCRs) in 40% of patients with immunoglobulin light chain (AL) amyloidosis. However, relapses occur in 8% of patients who initially achieve HCR. We conducted a study to explore the feasibility and efficacy of a second HDM/SCT in this setting. Eleven patients were enrolled. Five patients underwent repeat stem cell mobilization with G-CSF; the others had stem cells cryopreserved from the first mobilization. Six patients received 200 mg/m(2) HDM; five patients received modified HDM at 140 mg/m(2). Engraftment occurred at a median of 10 days for neutrophils and 12 days for platelets. There was no treatment-related mortality or death within the first year, but significant grade III/IV non hematological toxicities occurred. In all, 4 of 11 patients (36%) achieved HCR at 1 year. Two of these patients are in continuous remission at 3 and 6 years; the other two relapsed at 2 and 3 years. Of the four patients who achieved partial hematological response at 1 year, three have relapsed at a median of 3 years. Three patients died of progressive disease at 1-2 years. In conclusion, one-third of patients with AL amyloidosis who relapse after HDM/SCT can achieve HCR with a second SCT. PMID- 20956956 TI - Alternative donor marrow transplantation in children with aplastic anemia using low-dose irradiation and fludarabine-based conditioning. PMID- 20956957 TI - Temporal relationship between HHV 6 and graft vs host disease in a patient after haplo-identical SCT and severe T-cell depletion. PMID- 20956958 TI - Sarcoidosis-associated MHC Ags and the development of cutaneous and nodal granulomas following allogeneic hematopoietic cell transplant. PMID- 20956959 TI - Allogeneic haematopoietic stem-cell transplantation with reduced intensity conditioning for advanced stage Hodgkin's lymphoma in Sweden: high incidence of post transplant lymphoproliferative disorder. AB - Allogeneic transplantation after reduced intensity conditioning (allo-RIC) is a treatment option for patients with Hodgkin's lymphoma (HL) relapsing after autologous transplantation. In all, 23 adult patients with HL underwent allo-RIC in Sweden between 2000 and 2007. The median number of previous treatment lines was five and 20 patients (87%) were previously autografted. TRM at 100 days and at 1 year was 13 and 22% respectively. Acute GVHD grades II-IV developed in 7 out of 23 patients (30%) and chronic GVHD in 10 out of 20 patients at risk (50%). The OS and EFS at three years was 59 and 27%, respectively. Four patients (17%) developed post transplant lymphoproliferative disease (PTLD) after a median time of 55 days (range 38-95); two of these patients later died. The study confirmed that allo-RIC is feasible, but associated with a substantial relapse rate: only 20% of the patients were still alive 7 years after the transplant. A finding of high incidence of PTLD needs to be confirmed in a larger trial that includes patients with non-HL and CLL. PMID- 20956961 TI - Differences Among ACE Inhibitors. PMID- 20956962 TI - Salt intake and the nitric oxide-cyclic AMP signaling pathway in renin secreting cells. PMID- 20956963 TI - Early life exposure to hypoxia: a developmental insult critical to the programming of cardiovascular risk. PMID- 20956965 TI - Putting data to work. PMID- 20956966 TI - A large-scale protein-function database. PMID- 20956968 TI - Protein engineering: Check nature first, then evolve. PMID- 20956969 TI - Structural biology: Toward the ATP synthase mechanism. PMID- 20956970 TI - Biosynthesis: A new (old) way of hijacking tRNA. PMID- 20956971 TI - RHAMM/ERK interaction induces proliferative activities of cementifying fibroma cells through a mechanism based on the CD44-EGFR. AB - We have previously established immortalized cells (HCF) from cementifying fibroma of the jaw bone. Here, we found that the receptor for hyaluronan (HA)-mediated motility (RHAMM) and epiregulin, a ligand for the epidermal growth factor receptor (EGFR), were highly expressed in HCF cells in comparison with osteoblasts by conducting a microarray analysis. The cell growth of HCF cells was significantly decreased by the knockdown of RHAMM using small interfering RNA (siRNA). RHAMM was associated with extracellular signal-regulated kinase (ERK) and essential for ERK phosphorylation. HCF cells had characteristic growth mechanisms in which epiregulin functions in an extracellular autocrine loop. Interestingly, exogenous HA induced the phosphorylation of EGFR, which was mainly dependent on CD44. The results raise the novel idea that the EGFR may activate Raf-MEK-ERK signaling in response to the binding of HA to CD44. Moreover, RHAMM was able to associate with TPX2 in the nucleus and was required for HA-induced activation of the Aurora A kinase. The results suggest that RHAMM has a predominant role in the cell cycle in HCF. Here, we report the new machinery by which RHAMM/ERK interaction induces the proliferative activity of cementifying fibroma cells via a specific signaling pathway through the CD44-EGFR axis. PMID- 20956972 TI - Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet induced nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is an emerging disease with a broad spectrum of liver conditions. The complex molecular pathogenesis of NAFLD is still unclear. In this study, we conducted an analysis of microRNA (miRNA) expression profiles in liver of rats made NAFLD by different diets. To this aim, Sprague-Dawley rats were fed ad libitum for 3 months with different diets: standard diet (SD), diet enriched in fats and low in carbohydrates (HFD), SD with high fructose (SD-HF) and diet with high levels of fats and fructose (HFD-HF). Our results demonstrated that the treatment with different dietetic regimens caused a significant increase of the body weight and the alteration of some metabolic parameters compared with control animals, as well as various liver injuries. The miRNAs analysis showed the significant downregulation of three miRNAs (miR-122, miR-451 and miR-27) and the upregulation of miR-200a, miR-200b and miR-429 in HFD, SD-HF and HFD-HF rats. Besides, miR-21 expression was significantly decreased only in fructose-enriched diets. These miRNAs target molecules involved in the control of lipid and carbohydrate metabolism, signal transduction, cytokine and chemokine-mediated signaling pathway and apoptosis. Western blot analysis of PKCdelta, LITAF, ALDOLASE-A, p38MAPK, PTEN, LIPIN1, EPHRIN-A1, EPHA2 and FLT1 showed a diet-induced deregulation of all these proteins. Interestingly, the expression pattern of LITAF, PTEN, LIPIN1, EPHRIN A1, EPHA2 and FLT1 might be well explained by the trend of their specific mRNAs, by potentially regulatory miRNAs, or both. In conclusion, we highlight for the first time the potential involvement of novel determinants (miRNAs and proteins) in the molecular pathogenesis of diet-induced NAFLD. PMID- 20956973 TI - Role of nitric oxide synthases in elastase-induced emphysema. AB - Nitric oxide (NO) in combination with superoxide produces peroxynitrites and induces protein nitration, which participates in a number of chronic degenerative diseases. NO is produced at high levels in the human emphysematous lung, but its role in this disease is unknown. The aim of this study was to determine whether the NO synthases contribute to the development of elastase-induced emphysema in mice. nNOS, iNOS, and eNOS were quantified and immunolocalized in the lung after a tracheal instillation of elastase in mice. To determine whether eNOS or iNOS had a role in the development of emphysema, mice bearing a germline deletion of the eNOS and iNOS genes and mice treated with a pharmacological iNOS inhibitor were exposed to elastase. Protein nitration was determined by immunofluorescence, protein oxidation was determined by ELISA. Inflammation and MMP activity were quantified by cell counts, RT-PCR and zymography in bronchoalveolar lavage fluid. Cell proliferation was determined by Ki67 immunostaining. Emphysema was quantified morphometrically. iNOS and eNOS were diffusely upregulated in the lung of elastase-treated mice and a 12-fold increase in the number of 3-nitrotyrosine expressing cells was observed. Over 80% of these cells were alveolar type 2 cells. In elastase-instilled mice, iNOS inactivation reduced protein nitration and increased protein oxidation but had no effect on inflammation, MMP activity, cell proliferation or the subsequent development of emphysema. eNOS inactivation had no effect. In conclusion, in the elastase-injured lung, iNOS mediates protein nitration in alveolar type 2 cells and alleviates oxidative injury. Neither eNOS nor iNOS are required for the development of elastase-induced emphysema. PMID- 20956974 TI - Yersinia enterocolitica induces epithelial barrier dysfunction through regional tight junction changes in colonic HT-29/B6 cell monolayers. AB - Yersinia enterocolitica is a common cause of acute gastroenteritis. This study aimed to clarify the mechanisms leading to barrier dysfunction and diarrhea. Exposure of human colonic HT-29/B6 cells to Y. enterocolitica resulted in a decrease in transepithelial resistance from 404+/-23 to 163+/-21 Omega cm2 (P<0.001) in parallel with an increase in mannitol (182 Da) and fluorescein (332 Da) permeability, whereas short circuit current did not change. This effect was time dependent, required the presence of living bacteria, could not be triggered by bacterial supernatants and was not due to Yersinia outer proteins. Concomitantly, Y. enterocolitica induced necrosis as indicated by an increase in lactate dehydrogenase-release, whereas epithelial apoptosis was not upregulated. Local changes in conductivity were detected by conductance scanning, indicating 'leaky regions' within the epithelium that were visualized by biotinylation and confocal microscopy. In these regions, claudin-3 and -4 and, especially claudin 8, were redistributed off the tight junction (TJ) into the cytoplasm. In addition, the expression of claudin-2, -3, -8, -10 and ZO-1 was diminished as quantified by immunoblotting. Moreover, we found claudin-8 to be regulated by the c-Jun N-terminal kinase, the inhibition of which attenuated the Y. enterocolitica induced decrease in transepithelial resistance and restored claudin-8 protein level. In conclusion, barrier dysfunction in Y. enterocolitica infection is due to circumscribed epithelial TJ protein changes and necrotic cell loss, as a consequence of which leak flux diarrhea and antigen-uptake provoking extraintestinal arthritis may be triggered. PMID- 20956975 TI - DNA binding-dependent glucocorticoid receptor activity promotes adipogenesis via Kruppel-like factor 15 gene expression. AB - Glucocorticoids, such as dexamethasone, have been used as in vitro inducers of adipogenesis. However, the roles of the glucocorticoid receptor (GR) in adipogenesis have not been well characterized yet. Here, we show that inhibition of GR activity using the GR antagonist RU486 prevents human mesenchymal stem cell and mouse embryonic fibroblast (MEF) differentiation into adipocytes. Moreover, in MEFs isolated from GR knockout (GR(null)) and GR(dim) mice deficient in GR DNA binding activity, adipogenesis was blocked. We identified glucocorticoid response element sites in the first intron of KLF15 by bioinformatical promoter analysis and confirmed their functional relevance by demonstrating GR interaction by chromatin immunoprecipitation. Moreover, transfection of MEFs with siRNA for KLF15 significantly attenuated the expressions of adipogenic-marker genes and the lipid accumulation. Our results provide a new mechanism for understanding glucocorticoids-dependent adipogenesis and that GR promotes adipogenesis via KLF15 gene expression as a transcriptional direct target. PMID- 20956976 TI - Inhibition of matrix metalloproteinases reduces ischemia-reperfusion acute kidney injury. AB - Matrix metalloproteinases (MMPs) are endopeptidases that degrade extracellular matrix and involved in ischemic organ injuries. The present study was designed to determine the role of MMP-2 in the development of ischemic acute kidney injury (AKI). AKI was induced in MMP-2 wild-type (MMP-2(+/+)) mice by 30, 60, 90, and 120 min renal ischemia and reperfusion. Renal histology, expression and activity of MMP-2 and MMP-9, and renal function were examined during the development of AKI. AKI was also induced in MMP-2-deficient (MMP-2(-/-)) mice and MMP-2(+/+) mice treated with inhibitor of MMPs (minocycline and synthetic peptide MMP inhibitor). In MMP-2(+/+) mice, MMP-2 and MMP-9 activities increased significantly at 2 to 24 h, peaked at 6 h, after reperfusion. Immunohistochemical analysis identified MMP-2 in the interstitium around tubules and peritubular capillaries in the outer medulla. Acute tubular injury (ATI), including apoptosis and necrosis, was evident in the outer medulla at 24 h, along with renal dysfunction. As ischemia period increases, MMP-2 and MMP-9 activities at 6 h and severity of AKI at 24 h increased depending on the duration of ischemia between 30 and 120 min. However, the kidneys of MMP-2(-/-) mice showed minimal ATI; serum creatinine 24 h after reperfusion was significantly low in these mice. Inhibitors of MMPs reduced ATI and improved renal dysfunction at 24 h. We conclude that MMPs, especially MMP-2 have a pathogenic role in ischemia-reperfusion AKI, and that inhibitors of MMPs can protect against ischemic AKI. PMID- 20956977 TI - Ablation of the decorin gene enhances experimental hepatic fibrosis and impairs hepatic healing in mice. AB - Accumulation of connective tissue is a typical feature of chronic liver diseases. Decorin, a small leucine-rich proteoglycan, regulates collagen fibrillogenesis during development, and by directly blocking the bioactivity of transforming growth factor-beta1 (TGFbeta1), it exerts a protective effect against fibrosis. However, no in vivo investigations on the role of decorin in liver have been performed before. In this study we used decorin-null (Dcn-/-) mice to establish the role of decorin in experimental liver fibrosis and repair. Not only the extent of experimentally induced liver fibrosis was more severe in Dcn-/- animals, but also the healing process was significantly delayed vis-a-vis wild type mice. Collagen I, III, and IV mRNA levels in Dcn-/- livers were higher than those of wild-type livers only in the first 2 months, but no difference was observed after 4 months of fibrosis induction, suggesting that the elevation of these proteins reflects a specific impairment of their degradation. Gelatinase assays confirmed this hypothesis as we found decreased MMP-2 and MMP-9 activity and higher expression of TIMP-1 and PAI-1 mRNA in Dcn-/- livers. In contrast, at the end of the recovery phase increased production rather than impaired degradation was found to be responsible for the excessive connective tissue deposition in livers of Dcn-/- mice. Higher expression of TGFbeta1-inducible early responsive gene in decorin-null livers indicated enhanced bioactivity of TGFbeta1 known to upregulate TIMP-1 and PAI-1 as well. Moreover, two main axes of TGFbeta1-evoked signaling pathways were affected by decorin deficiency, namely the Erk1/2 and Smad3 were activated in Dcn-/- samples, whereas no significant difference in phospho-Smad2 was observed between mice with different genotypes. Collectively, our results indicate that the lack of decorin favors the development of hepatic fibrosis and attenuates its subsequent healing process at least in part by affecting the bioactivity of TGFbeta1. PMID- 20956978 TI - A theoretical molecular network for dyslexia: integrating available genetic findings. AB - Developmental dyslexia is a common specific childhood learning disorder with a strong heritable component. Previous studies using different genetic approaches have identified several genetic loci and candidate genes for dyslexia. In this article, we have integrated the current knowledge on 14 dyslexia candidate genes suggested by cytogenetic findings, linkage and association studies. We found that 10 of the 14 dyslexia candidate genes (ROBO1, KIAA0319, KIAA0319L, S100B, DOCK4, FMR1, DIP2A, GTF2I, DYX1C1 and DCDC2) fit into a theoretical molecular network involved in neuronal migration and neurite outgrowth. Based on this, we also propose three novel dyslexia candidate genes (SLIT2, HMGB1 and VAPA) from known linkage regions, and we discuss the possible involvement of genes emerging from the two reported genome-wide association studies for reading impairment-related phenotypes in the identified network. PMID- 20956979 TI - Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways. AB - Dysbindin-1 regulates D2-receptor trafficking and is implicated in schizophrenia and related cognitive abnormalities, but whether this molecular effect mediates the clinical manifestations of the disorder is unknown. We explored in dysbindin 1-deficient mice (dys-/-) (1) schizophrenia-related behaviors, (2) molecular and electrophysiological changes in medial prefrontal cortex (mPFC) and (3) the dependence of these on D2-receptor stimulation. Dysbindin-1 disruption altered dopamine-related behaviors and impaired working memory under challenging/stressful conditions. Dys-/- pyramidal neurons in mPFC layers II/III were hyperexcitable at baseline but hypoexcitable following D2 stimulation. Dys-/ were also respectively more and less sensitive to D2 agonist- and antagonist induced behavioral effects. Dys-/- had reduced expression of Ca(2+)/calmodulin dependent protein kinase II (CaMKII) and CaMKKbeta in mPFC. Chronic D2 agonist treatment reproduced these changes in protein expression, and some of the dys-/- behavioral effects. These results elucidate dysbindin's modulation of D2-related behavior, cortical activity and mPFC CaMK components, implicating cellular and molecular mechanisms of the association of dysbindin with psychosis. PMID- 20956980 TI - Molecular mechanisms of metastasis in breast cancer--clinical applications. AB - The metastatic cascade is a series of biological processes that enable the movement of tumor cells from the primary site to a distant location and the establishment of a new cancer growth. Circulating tumor cells (CTCs) have a crucial role in tumor dissemination. The role of CTCs in treatment failure and disease progression can be explained by their relation to biological processes, including the epithelial-to-mesenchymal transition and 'self seeding', defined as reinfiltration of the primary tumor or established metastasis by more aggressive CTCs. CTCs are a unique and heterogeneous cell population with established prognostic and predictive value in certain clinical situations. The possibility of collecting sequential blood samples for real-time monitoring of systemic therapy efficacy presents new possibilities to evaluate targeted therapies based on the genomic profiling of CTCs and to improve the clinical management of patients by personalized therapy. Interruption of the metastatic cascade via the targeting of CTCs might be a promising therapeutic strategy. PMID- 20956981 TI - Synthetic lethal approaches to breast cancer therapy. AB - The promise of personalized therapy for breast cancer is that therapeutic efficacy will be increased while toxic effects are reduced to a minimum. To achieve this goal, there is now an emphasis on the design of therapies that are based not only on the clinical manifestations of the disease, but also on the underlying molecular and cellular biology of cancer. However, identifying targets for personalized therapies in breast cancer is challenging. Here, we describe how biological concepts such as synthetic lethality and oncogene addiction can be used to identify new therapeutic targets and approaches. We discuss the current clinical developments in implementing synthetic lethality therapies, and highlight new ways in which this approach could be used to target specific subsets of breast cancer. PMID- 20956982 TI - BRCA mutations in the management of breast cancer: the state of the art. AB - Genetic testing for BRCA1 and BRCA2 mutations is gaining acceptance in clinical oncology worldwide and may help target unaffected high-risk women for prevention and for close surveillance. Annual screening with MRI seems to be an effective surveillance strategy, but the long term follow-up of women with small MRI detected breast cancers is necessary to establish its ultimate value. Women with cancer and a BRCA mutation may benefit from tailored treatments, such as cisplatin or olaparib. The treatment goals for a woman with a BRCA-associated breast cancer should be to prevent recurrence of the initial cancer and to prevent second primary breast and ovarian cancers. Mutations in BRCA1 and BRCA2 are presented throughout the world and it is important that the benefits of genetic testing and of targeted therapies be extended to women who live outside of North America and Western Europe. PMID- 20956983 TI - Prognostic factors in chronic lymphocytic leukemia-what do we need to know? AB - Of all leukemias, chronic lymphocytic leukemia (CLL) shows the highest variability in its clinical presentation and course. CLL can present as an aggressive and life threatening leukemia or as an indolent form that will not require treatment over decades. The currently available clinical staging systems for CLL are simple and inexpensive but lack accuracy to predict disease progression and survival on an individual basis. The increased understanding of the key events of molecular pathogenesis has provided a plethora of novel molecular and biological factors that correlate with the outcome of CLL. This Review provides a concise discussion of the most important discoveries and gives guidance on how to implement novel prognostic tools in the clinical management of CLL by applying the criteria of evidence, relevance, and simplicity to the selection of prognostic markers. PMID- 20956985 TI - Quantifying subcellular distribution of fluorescent fusion proteins in cells migrating within tissues. AB - The movement of proteins within cells can provide dynamic indications of cell signaling and cell polarity, but methods are needed to track and quantify subcellular protein movement within tissue environments. Here we present a semiautomated approach to quantify subcellular protein location for hundreds of migrating cells within intact living tissue using retrovirally expressed fluorescent fusion proteins and time-lapse two-photon microscopy of intact thymic lobes. We have validated the method using GFP-PKCzeta, a marker for cell polarity, and LAT-GFP, a marker for T-cell receptor signaling, and have related the asymmetric distribution of these proteins to the direction and speed of cell migration. These approaches could be readily adapted to other fluorescent fusion proteins, tissues and biological questions. PMID- 20956984 TI - Induced pluripotent stem cells: developmental biology to regenerative medicine. AB - Nuclear reprogramming of somatic cells with ectopic stemness factors to bioengineer pluripotent autologous stem cells signals a new era in regenerative medicine. The study of developmental biology has provided a roadmap for cardiac differentiation from embryonic tissue formation to adult heart muscle rejuvenation. Understanding the molecular mechanisms of stem-cell-derived cardiogenesis enables the reproducible generation, isolation, and monitoring of progenitors that have the capacity to recapitulate embryogenesis and differentiate into mature cardiac tissue. With the advent of induced pluripotent stem (iPS) cell technology, patient-specific stem cells provide a reference point to systematically decipher cardiogenic differentiation through discrete stages of development. Interrogation of iPS cells and their progeny from selected cohorts of patients is an innovative approach towards uncovering the molecular mechanisms of disease. Thus, the principles of cardiogenesis can now be applied to regenerative medicine in order to optimize personalized therapeutics, diagnostics, and discovery-based science for the development of novel clinical applications. PMID- 20956986 TI - Human immunodeficiency virus-1 vaccine design: where do we go now? AB - Numerous human immunodeficiency virus (HIV)-1 vaccines have been developed over the last three decades, but to date an effective HIV-1 vaccine that can be used for prophylactic or therapeutic purposes in humans has not been identified. The failures and limited successes of HIV-1 vaccines have highlighted the gaps in our knowledge with regard to fundamental immunity against HIV-1 and have provided insights for vaccine strategies that may be implemented for designing more effective HIV-1 vaccines in the future. Recent studies have shown that robust mucosal immunity, high avidity and polyfunctional T cells, and broadly neutralizing antibodies are important factors governing the induction of protective immunity against HIV-1. Furthermore, optimization of vaccine delivery methods for DNA or live viral vector-based vaccines, elucidating the immune responses of individuals who remain resistant to HIV-1 infections and also understanding the core immune responses mediating protection against simian immunodeficiency viruses (SIV) and HIV-1 in animal models following vaccination, are key aspects to be regarded for designing more effective HIV-1 vaccines in the future. PMID- 20956987 TI - Host genetic background affects regulatory T-cell activity that influences the magnitude of cellular immune response against Mycobacterium tuberculosis. AB - Using two mouse strains with different abilities to generate interferon (IFN) gamma production after Mycobacterium tuberculosis infection, we tested the hypothesis that the frequency and activity of regulatory T (Treg) cells are influenced by genetic background. Our results demonstrated that the suppressive activity of spleen Treg cells from infected or uninfected BALB/c mice was enhanced, inhibiting IFN-gamma and interleukin (IL)-2 production. Infected C57BL/6 mice exhibited a decrease in the frequency of lung Treg cells and an increased ratio CD4(+):CD4(+)Foxp3(+) cells compared with infected BALB/c mice and uninfected C57BL/6 mice. Moreover, infected C57BL/6 mice also had a decrease in the immunosuppressive capacity of spleen Treg cells, higher lung IFN-gamma and IL-17 production, and restricted the infection better than BALB/c mice. Adoptive transfer of BALB/c Treg cells into BALB/c mice induced an increase in bacterial colony-forming unit (CFU) counts. Furthermore, BALB/c mice treated with anti-CD25 antibody exhibited lung CFU counts significantly lower than mice treated with irrelevant antibody. Our results show that in BALB/c mice, the Treg cells have a stronger influence than that in C57BL/6 mice. These data suggest that BALB/c and C57BL/6 mice may use some different mechanisms to control M. tuberculosis infection. Therefore, the role of Treg cells should be explored during the development of immune modulators, both from the perspective of the pathogen and the host. PMID- 20956988 TI - Molecular and genetic parameters defining T-cell clonal selection. AB - Clonal selection of T cells occurs in the thymus and is responsible for generating a useful and functional repertoire of T cells. Aberrations in clonal selection result in altered T-cell homeostasis in the secondary lymphoid organs ranging from an absence of T cells to an overabundance of autoreactive T cells. The advent of new technologies facilitating the manipulation of the mouse genome has helped refine our understanding of the molecular and genetic pathways involved in clonal selection and has also revealed a high degree of complexity. Herein, we attempt to review recent advances in thymic selection processes, achieved mostly through genetic manipulations. PMID- 20956989 TI - Antigen-driven T-cell repertoire selection during adaptive immune responses. AB - Protective immunity against a variety of infections depends on the amplification and differentiation of rare naive antigen-specific CD4 and CD8 T cells. Recent evidence indicates that the clonotypic composition of the responding T-cell compartment has a critical role in the immune defense against pathogens. The present review compares and contrasts how naive CD4 and CD8 T cells recognize their cognate antigen, and discusses the factors that regulate the genesis and maintenance of the CD4 and CD8 T-cell receptor repertoire diversity. PMID- 20956990 TI - MRI for the assessment and monitoring of RA--what can it tell us? AB - The past 15 years has seen an exponential rise in the use of MRI for the assessment of rheumatoid arthritis (RA). In this Perspectives article, we review the current and potential future role of MRI in the diagnosis, prognosis and monitoring of RA. We also review the impact of MRI research on the understanding of disease mechanisms. In our view, the pivotal role of synovitis in RA and its predilection for sonographically accessible joints makes it likely that MRI will be used diagnostically in joints that are inaccessible to ultrasonography or where the differential diagnosis is unclear. Additionally, MRI will probably assume an even more prominent role in clinical trials where the aim of therapy is the complete ablation of synovitis. Given the ever-increasing sophistication of MRI, we anticipate that it will continue to be a key research tool in the coming years. PMID- 20956991 TI - Could uric acid have a pathogenic role in pre-eclampsia? AB - Interest has been renewed over the role of uric acid in the pathogenesis of hypertension, endothelial dysfunction and renal dysfunction, which are all features of pre-eclampsia. Uric acid is not a consistent predictive factor for the development of pre-eclampsia but its levels generally increase once the disease manifests, and plasma levels of uric acid approximately correlate with disease severity. Hyperuricemia in pre-eclampsia was once thought to result solely from reduced renal clearance, but levels of uric acid are now also thought to increase through increased uric acid production caused by trophoblast breakdown, cytokine release and ischemia. Uric acid can promote endothelial dysfunction, damage and inflammation, which leads to oxidation. Pre-eclampsia, which is characterized by widespread endothelial dysfunction and inflammation, might be propagated by uric acid through these known in vitro activities. Of note, however, uric acid can also act as a scavenger of oxygen free radicals. Plasma urate measurements are currently used to support the diagnosis of pre eclampsia during pregnancy. As further studies define the role of uric acid in the development of pre-eclampsia, monitoring levels of this factor may again become essential to the future treatment of pre-eclampsia. PMID- 20956992 TI - Iron supplementation to treat anemia in patients with chronic kidney disease. AB - Iron deficiency is prevalent in patients with chronic kidney disease (CKD), and use of oral and intravenous iron in patients with CKD who do not require dialysis might obviate or delay the need for treatment with eythropoiesis-stimulating agents (ESAs). Patients on hemodialysis have lower intestinal iron absorption, greater iron losses, and require greater iron turnover to maintain the ESA-driven red cell mass than do healthy individuals. In these patients, intravenous iron reduces ESA dose requirements and increases the likelihood of maintaining levels of hemoglobin within the desired range. Oral iron is inferior to intravenous iron in patients on hemodialysis, in part because elevated serum levels of hepcidin prevent intestinal absorption of iron. Increased levels of hepcidin also impair the normal recycling of iron through the reticuloendothelial system. Levels of serum ferritin and transferrin saturation below 450 pmol/l and 20%, respectively are indicative of iron deficiency, but values above the normal range lack diagnostic value in patients with CKD on dialysis. The availability of various iron preparations and new developments in delivering iron should enable adequate provision of iron to patients with CKD. This Review examines the efficacy, safety and use of iron supplementation therapy for the treatment of anemia in patients with CKD. PMID- 20956993 TI - Network analysis of transcriptional regulation in response to intramuscular interferon-beta-1a multiple sclerosis treatment. AB - Interferon-beta (IFN-beta) is one of the major drugs for multiple sclerosis (MS) treatment. The purpose of this study was to characterize the transcriptional effects induced by intramuscular IFN-beta-1a therapy in patients with relapsing remitting form of MS. By using Affymetrix DNA microarrays, we obtained genome wide expression profiles of peripheral blood mononuclear cells of 24 MS patients within the first 4 weeks of IFN-beta administration. We identified 121 genes that were significantly up- or downregulated compared with baseline, with stronger changed expression at 1 week after start of therapy. Eleven transcription factor binding sites (TFBS) are overrepresented in the regulatory regions of these genes, including those of IFN regulatory factors and NF-kappaB. We then applied TFBS-integrating least angle regression, a novel integrative algorithm for deriving gene regulatory networks from gene expression data and TFBS information, to reconstruct the underlying network of molecular interactions. An NF-kappaB centered sub-network of genes was highly expressed in patients with IFN-beta related side effects. Expression alterations were confirmed by real-time PCR and literature mining was applied to evaluate network inference accuracy. PMID- 20956994 TI - Complementary medicine use by men with prostate cancer: a systematic review of prevalence studies. AB - Men with prostate cancer are reported as commonly using complementary and alternative medicine (CAM) but surveys have not recently been subjected to a rigorous systematic review incorporating quality assessment. Six electronic databases were searched using pre-defined terms. Detailed information was extracted systematically from each relevant article. Study reporting quality was assessed using a quality assessment tool, which demonstrated acceptable inter rater reliability and produces a percentage score. In all, 42 studies are reviewed. All were published in English between 1999 and 2009; 60% were conducted in the United States. The reporting quality was mixed (median score = 66%, range 23-94%). Significant heterogeneity precluded formal meta-analysis. In all, 39 studies covering 11,736 men reported overall prevalence of CAM use; this ranged from 8 to 90% (median=30%). In all, 10 studies reported prevalence of CAM use specifically for cancer care; this ranged from 8 to 50% (median = 30%). Some evidence suggested CAM use is more common in men with higher education/incomes and more severe disease. The prevalence of CAM use among men with prostate cancer varies greatly across studies. Future studies should use standardised and validated data collection techniques to reduce bias and enhance comparability. PMID- 20956995 TI - Does diabetes mellitus increase the risk of high-grade prostate cancer in patients undergoing radical prostatectomy? AB - The objective was to test the hypothesis that in patients with prostate cancer undergoing radical prostatectomy (RP), diabetic patients are at a higher risk of harboring a high-grade tumor than non-diabetic patients. We examined 2060 consecutive men who underwent RP between 2001 and 2009. Of them, 7.1% had type 2 diabetes mellitus (DM). A high-grade tumor was defined as having a Gleason score >= 8. Univariable and multivariable logistic regression analyses were used to test the relationship between type 2 DM and high-grade tumor. Mean patient age was 64 years (range: 45-85). Mean total PSA level was 9 ng ml(-1) (range: 1 89.5). A significantly higher percentage of diabetic patients had high-grade tumor on biopsy (16.3 vs 7.6%; P = 0.001) and on RP specimen (21.1 vs 11.7%; P = 0.001) in comparison with non-diabetic patients. In multivariable analyses, DM was an independent predictor of high-grade tumor on biopsy (odds ratio = 2.31, P = 0.001) and on final pathological specimen (odds ratio = 2.22, P = 0.002). In patients undergoing RP, those with type 2 DM had a higher risk of harboring a poorly differentiated tumor on final pathological examination. PMID- 20956997 TI - The GTPase-activating protein Rap1GAP: a new player to modulate Ret signaling. PMID- 20956996 TI - Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration. AB - Oncostatin M (OSM) is a cytokine of the interleukin-6 family and plays important roles during inflammation. However, its roles in myoblast differentiation and muscle regeneration remain unexplored. We show here that OSM potently inhibited myoblast differentiation mainly by activating the JAK1/STAT1/STAT3 pathway. OSM downregulated myocyte enhancer-binding factor 2A (MEF2A), upregulated the expression of Id1 and Id2, and inhibited the transcriptional activity of MyoD and MEF2. In addition, OSM also enhanced the expression of STAT3 and OSM receptor, which constituted a positive feedback loop to further amplify OSM-induced signaling. Moreover, we found that STAT1 physically associated with MEF2 and repressed its transcriptional activity, which could account for the OSM-mediated repression of MEF2. Although undetectable in normal muscles in vivo, OSM was rapidly induced on muscle injury and then promptly downregulated just before the majority of myoblasts differentiate. Prolonged expression of OSM in muscles compromised the regeneration process without affecting myoblast proliferation, suggesting that OSM functions to prevent proliferating myoblasts from premature differentiation during the early phase of muscle regeneration. PMID- 20956998 TI - Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. AB - The introduction of four transcription factors Oct4, Klf4, Sox2 and c-Myc by viral transduction can induce reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), but the use of iPSCs is hindered by the use of viral delivery systems. Chemical-induced reprogramming offers a novel approach to generating iPSCs without any viral vector-based genetic modification. Previous reports showed that several small molecules could replace some of the reprogramming factors although at least two transcription factors, Oct4 and Klf4, are still required to generate iPSCs from mouse embryonic fibroblasts. Here, we identify a specific chemical combination, which is sufficient to permit reprogramming from mouse embryonic and adult fibroblasts in the presence of a single transcription factor, Oct4, within 20 days, replacing Sox2, Klf4 and c Myc. The iPSCs generated using this treatment resembled mouse embryonic stem cells in terms of global gene expression profile, epigenetic status and pluripotency both in vitro and in vivo. We also found that 8 days of Oct4 induction was sufficient to enable Oct4-induced reprogramming in the presence of the small molecules, which suggests that reprogramming was initiated within the first 8 days and was independent of continuous exogenous Oct4 expression. These discoveries will aid in the future generation of iPSCs without genetic modification, as well as elucidating the molecular mechanisms that underlie the reprogramming process. PMID- 20957000 TI - Klinefelter syndrome presenting as behavioral problems in a young adult. AB - BACKGROUND: An 18-year-old Somali man presented to a primary care clinic to investigate a potential pathophysiological reason for behavioral problems at school that had arisen in the past 1-2 years. A previous physical examination at school revealed the patient to have small, firm testicles which prompted further testing. INVESTIGATION: Thyroid function and levels of prolactin, total testosterone, follicle-stimulating hormone and luteinizing hormone were determined. Testes were measured. Chromosome analysis testing was performed to determine the patient's karyotype. DIAGNOSIS: Klinefelter syndrome with a 47,XXY karyotype. MANAGEMENT: Testosterone replacement therapy was recommended, but the patient declined treatment. PMID- 20956999 TI - Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. AB - Growth hormone (GH), insulin-like growth factor (IGF)-I and insulin have potent growth-promoting and anabolic actions. Their potential involvement in tumor promotion and progression has been of concern for several decades. The evidence that GH, IGF-I and insulin can promote and contribute to cancer progression comes from various sources, including transgenic and knockout mouse models and animal and human cell lines derived from cancers. Assessments of the GH-IGF axis in healthy individuals followed up to assess cancer incidence provide direct evidence of this risk; raised IGF-I levels in blood are associated with a slightly increased risk of some cancers. Studies of human diseases characterized by excess growth factor secretion or treated with growth factors have produced reassuring data, with no notable increases in de novo cancers in children treated with GH. Although follow-up for the vast majority of these children does not yet extend beyond young adulthood, a slight increase in cancers in those with long standing excess GH secretion (as seen in patients with acromegaly) and no overall increase in cancer with insulin treatment, have been observed. Nevertheless, long term surveillance for cancer incidence in all populations exposed to increased levels of GH is vitally important. PMID- 20957002 TI - [Effect of synthesized GYY4137, a slowly releasing hydrogen sulfide donor, on cell viability and distribution of hydrogen sulfide in mice]. AB - OBJECTIVE: To improve a method of a new hydrogen sulfide slow-releasing donor, to observe its cellular toxicity in HepG2 cells and tissue distribution and metabolic pathway after administration of the donor by intraperitoneal injection in ICR mice and to afford experimental evidences for rationally using this donor in hydrogen sulfide research. METHODS: We synthesized the new chemical compound which slowly released hydrogen sulfide. After administration of the donor, the cell toxicity was evaluated for cell viability using trypan blue staining in HepG2 cells and lactate dehydrogenase (LDH) activity in culture medium. After administration of this donor by intrasperitoneal injection, we measured the tissue hydrogen sulfide content in the liver, heart, kidney and brain using sensitive-sulfur electrode assay. RESULTS: We successfully prepared the donor which could release hydrogen sulfide. The releasing ability of the donor solution stored at 4 degrees C or 20 degrees C did not change as compared with the freshly-prepared one. Treated at various concentrations of the donor (0.062 5, 0.125, 0.25, 0.5, 1 and 2 mmol/L) for 24 hours in HepG2 cells, the cell viability and LDH leak from the cells were not different as compared with the controls. The donor (2 mmol/L) was administrated everyday and the culture medium was changed every 3 days. After 9 days, the cell viability and LDH leak did not change. Administration of the donor (200 MUmol/kg) quickly increased the tissue hydrogen sulfide concentrations in the liver and heart and maintained about 20 min; the hydrogen sulfide level in the kidney elevated and maintained a longer time, then recovered after 2 hours, which implicated that the donor might exclude the kidney; the hydrogen sulfide concentration in the brain did not change in the present study, which suggested that the donor could not pass the blood-brain barrier. Long time (4 weeks) treatment with this compound might induce hepatic or cutaneous injury. CONCLUSION: The new chemical compound is a relative stable, slow-releasing donor of hydrogen sulfide with low cellular toxicity, which may be used to study the regulatory role of hydrogen sulfide in the cellular physiological and pathophysiological mechanism of the animal model with acute diseases. PMID- 20957001 TI - The metabolic actions of glucagon revisited. AB - The initial identification of glucagon as a counter-regulatory hormone to insulin revealed this hormone to be of largely singular physiological and pharmacological purpose. Glucagon agonism, however, has also been shown to exert effects on lipid metabolism, energy balance, body adipose tissue mass and food intake. The ability of glucagon to stimulate energy expenditure, along with its hypolipidemic and satiating effects, in particular, make this hormone an attractive pharmaceutical agent for the treatment of dyslipidemia and obesity. Studies that describe novel preclinical applications of glucagon, alone and in concert with glucagon-like peptide 1 agonism, have revealed potential benefits of glucagon agonism in the treatment of the metabolic syndrome. Collectively, these observations challenge us to thoroughly investigate the physiology and therapeutic potential of insulin's long-known opponent. PMID- 20957004 TI - [Construction of periostin shRNA vectors and their effects on the expression of periostin in fibroblasts]. AB - OBJECTIVE: For studying the functions of periostin (POSTN) further, the recombinant plasmid and lentiviral vector for human periostin were constructed. The mRNA and protein expressions of POSTN were tested after the infection with the shRNA plasmid and lentivirus of POSTN in primary keloid fibroblasts (KFb). METHODS: We designed a specific sequence of small hair RNA targeting POSTN gene which containing both sense and antisense oligo DNA of the targeting sequence. It was cloned into the vectors to construct a plasmid and a lentiviral vector. The plasmid was converted into the competent DH5alpha E.coli, which confirmed by PCR and sequencing. Then the viral vector and the packed systemic vector were co transfected 293T cells to get the lentivirus. KFb was infected with the plasmid and lentivirus. The expressions of POSTN in KFb were detected by RT-PCR and Western blotting. MTT was used to examine the proliferation of KFb and SFb. RESULTS: The expression of POSTN mRNA in KFb infected with plasmid reduced 43% compared with negative control cells (1.98+/-0.03 vs 1.12+/-0.03, F=688.291, P<0.001). The mRNA and protein levels of POSTN in KFb infected with the lentivirus reduced 46% (0.44+/-0.09 vs 0.81+/-0.07, F=90.06, P<0.001) and 45% (0.29+/-0.04 vs 0.53+/-0.09, F=33.43, P<0.001), respectively, compared with negative control cells. Compared with negative control cells, the decreased proliferation rates were 19%, 14%, 18% in 48 h, 72 h, 96 h, respectively in KFb infected with the lentivirus. CONCLUSION: The expression of POSTN in primary keloid fibroblasts reduced after infecting plasmid or lentiviral shRNA expression vector targeting human POSTN, which will be a basis to the further function study of POSTN. PMID- 20957003 TI - [Strong association between the NINJ2 gene polymorphism and the susceptibility of stroke in Chinese Han population in Fangshan district]. AB - OBJECTIVE: To investigate the association between the NINJ2 gene rs11833579 polymorphism and stroke in Han Chinese population. METHODS: This study was a population-based cross-sectional case-control study. Polymerase chain reaction restriction fragment length polymorphism (RFLP) and sequencing were used for the detection of NINJ2 genotypes in 790 patients with stroke (679 ischemic stroke) which were Han Chinese population from Fangshan First Hospital and 811 controls which were healthy Han Chinese population without family history of stroke in Fangshan district rural area. RESULTS: In rs11833579 locus of the NINJ2 gene, the frequencies of GG genotype and allele G were higher in ischemic stroke patients than that in controls (P<0.001). The frequency of allele G of the NINJ2 gene was higher in cerebral hemorrhage patients than that in controls (P=0.005). Genotype had little effect on the glucose, total cholesterol and triglyceride. CONCLUSION: There is significant association between rs11833579 site polymorphism of the NINJ2 gene and risk for stroke in Han Chinese population from Fangshan district. PMID- 20957005 TI - [Early production of interleukin-17 in airway upon Chlamydia trachomatis infection increases the local secretion of IL-6 and MIP-2]. AB - OBJECTIVE: To evaluate the early interleukin-17 (IL-17) production in airway upon Chlamydia trachomatis infection and its relationship with the secretion of interleukin-6 (IL-6) and macrophage inflammatory protein 2 (MIP-2) in local site. METHODS: In vivo, a murine model of pneumonia induced by intranasal inoculation with Chlamydia trachomatis mouse pneumonitis (MoPn, now classified as a new species C. muridarum) was used for the study. Chlamydial growth in the lung was assessed by inoculating HeLa cell monolayer with lung homogenates followed by enzyme-linked immunosorbent assay (IFA). IL-17, IL-6 and MIP-2 were measured by enzyme-linked immunosorbent assay (ELISA). Mice without infection acted as the control group. In vitro, L929 cells were pretreated with recombinant murine IL-17 (rmIL-17) at a dose ranging from 20, 100 to 500 MUg/L for 24 h then infected with MoPn for 24 h. The supernatants were harvested and tested for IL-6 and MIP-2 concentration using ELISA. The cells were assayed for the number of inclusion forming unit (IFU) by IFA. L929 cells without pretreatment with rmIL-17 but infected with MoPn was the control group. RESULTS: The study showed that in vivo, Chlamydial growth in the lung was found on day 1 after infection, and reached its peak at day 8 (6.49+/-0.19, lg IFU/lung) with subsequent decline in quantity. IL 17 peaked at 48 h (83.0 ng/L+/-35.8 ng/L) while IL-6 peaked on day 3 [(3.98+/ 0.04) MUg/L], MIP-2 peaked on day 8 [(2.19+/-0.71) MUg/L]. The study showed that in vitro, compared with control group [(55.10+/-16.54) ng/L for IL-6 production and (13.71+/-0.84) ng/L for MIP-2], L929 cells pretreated with rmIL-17 at the different concentrations of 20, 100 and 500 MUg/L for 24 h then infected with MoPn for 24 h, could significantly increase IL-6 (P <0.01) and MIP-2 secretion (P <0.05). The productions of IL-6 in the supernatants were (531.65+/-24.40), (629.95+/-7.71), and (646.51+/-35.92) ng/L. Meanwhile, the productions of MIP-2 were (107.21+/-28.40), (181.95+/-25.51), and (221.90+/-17.32) ng/L, respectively. RmIL-17 alone had no effect on IL-6 and MIP-2 secretion, and no direct effect on growth of chlamydial inclusion body was demonstrated either. CONCLUSION: IL-17 was produced early in airway upon Chlamydia trachomatis, and rmIL-17could induce IL-6 and MIP-2 production in L929 cells after infection with MoPn. These suggest that an early IL-17 response may play an important role by inducing the secretion of IL-6 and MIP-2 in initiating host defense against infection with Chlamydia trachomatis in the airway. PMID- 20957006 TI - [Characteristics of lipolysis in epididymal adipose tissues of OLETF rats with spontaneous type 2 diabetic mellitus]. AB - OBJECTIVE: To observe the characteristics of lipolysis in epididymal adipose tissues of spontaneously type 2 diabetic animal model-Otsuka Long-Evans Tokushima Fatty (OLETF) rats-in different stages of disease and explore the possible molecular mechanism. METHODS: We adopted OLETF rats as subjects, and Long-Evans Tokushima Otsuka (LETO) rats were used as age-matched normal controls. Oral glucose tolerance tests (OGTT) and fasting serum insulin levels were performed respectively at the ages of 8, 18 and 28 weeks. The animals were sacrificed and epididymal fat pads were obtained in corresponding weeks. Glycerol released in the culture medium was determined by use of a colorimetric assay and served as an index of lipolysis. The protein levels of hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), perilipin, extracellular signal-regulated kinase (ERK) and its phosphorylated form (p-ERK) in epididymal fat were examined by immunoblotting. RESULTS: (1) Compared with the age-matched normal control, the ratio of epididymal adipose tissues to total body weight was heavier at the end of 18 weeks [(1.80+/-0.09)% vs (1.23+/-0.07)%, P<0.01] and 28 weeks [(2.51+/ 0.12)% vs (1.56+/-0.08)%, P<0.01]; In OGTT 1 h plasma glucose levels of OLETF rats were higher at the age of 18 weeks [(26.00+/-3.09) vs (10.50+/-0.82) mmol/L, P<0.01] and 28 weeks [(23.15+/-0.55) vs (9.72+/-0.17) mmol/L, P<0.01] and 2 h plasma glucose levels were higher at the age of 18 weeks [(16.19+/-1.22) vs (7.47+/-0.35) mmol/L, P<0.01] and 28 weeks [(17.96+/-2.00) vs (9.24+/-0.47) mmol/L, P<0.01]. The level of fasting insulin was higher in OLETF rats than that of LETO rats only at the age of 28 weeks [(68.17+/-13.35)*10(-3) vs (19.61+/ 0.20)*10(-3) U/L, P<0.01]. (2) Glycerol released from epididymal adipose tissues of OLETF rats was increased by 34.7% compared with LETO rats at the age of 18 weeks [(213.0+/-12.5) vs (158.2+/-11.7) nmol/(g*h), P<0.05], whereas at the age of 28 weeks, it was reduced by 33.5% [(210.2+/-37.8) vs (315.9+/-25.0) nmol/(g*h), P<0.05]. (3) In OLETF rats, HSL protein level was not altered at the age of 18 weeks, but down-regulated at the age of 28 weeks. Nevertheless, the expressions of ATGL and perilipin were decreased, while p-ERK protein expression was increased at the age of both 18 and 28 weeks. CONCLUSION: With the development of disease in spontaneously type 2 diabetic animal model of OLETF rats, the lipolysis in epididymal adipose tissue presented a pattern of initial increase followed by subsequent reduction. The earlier augment may contribute to the higher expression of p-ERK and the lower content of perilipin, however the later decrease may result from the reduction of both HSL and ATGL level. PMID- 20957007 TI - [Clinic pathologic analysis and evaluation of fibrosis in 17 cases of idiopathic interstitial pneumonia]. AB - OBJECTIVE: To explore the general principles and the significance of histopathology for idiopathic interstitial pneumonia (IIP) diagnosis; and to investigate the quantitative parameters in evaluation of fibrosis degree of IIP. METHODS: 17 cases of IIP were collected from Peking University 1st Hospital between 2004 and 2009, which had relatively integrated clinical, radiological and pathological materials. Combining clinical and radiological characteristics, histological manifestations and fibrosis degree were analyzed according to American Thoracic Society/European Respiratory Society (ATS/ERS) international consensus classification. Immunohistochemical staining for CD34 and SMA were performed and the correlation between their expressive extent and fibrosis degree were analyzed. RESULTS: 17 cases of IIP were diagnosed by clinical-radiological pathological comprehensive analysis, which included 9 cases of usual interstitial pneumonia, 5 cases of cryptogenic organizing pneumonia and 3 cases of nonspecific interstitial pneumonia; SMA expression showed positive correlation with degree of fibrosis (r=0.928, P=0.01), and CD34 expression showed negative correlation with degree of fibrosis (r=-0.606, P=0.01). CONCLUSION: Histopathology plays an important role in the diagnosis and classification of IIP. By combining histopathologic pattern, clinical and radiological features, a definite type of IIP can be confirmed. Proper and sufficient biopsy specimens are the premise of right diagnosis.CD34 and SMA immunohistochemical staining can be used in routine practice to evaluate the fibrosis degree of IIP. PMID- 20957008 TI - [Activities of Akt pathway and their correlation with pathological changes in myotonic dystrophy]. AB - OBJECTIVE: To investigate the expression of Akt pathway and their correlation with pathological changes in the skeletal muscle of myotonic dystrophy 1 (DM1) patients. METHODS: We chose 7 DM1 patients who were confirmed through clinical, electrophysiological and pathological data as DM1 patients group, and 7 patients without muscle pathological change as control group. The age range of DM1 patients group was from 6 to 35 years and disease duration was from 1 to 20 years. The clinical spectrum included distal myotonia, muscle weakness and atrophy. The serum creatine kinase ranged from 271 to 1 325 U/L; Electromyography showed myopathic changes together with diffusive myotonic discharges. We performed muscle biopsies in all the patients and tested total Akt, phosphorelated Akt, phosphorelated p70s6k in skeletal muscle specimens. We compared the Akt pathway activity of DM1 patients group with that of the control group and analyzed their correlation with the ratio of muscular hypertrophy, internal nuclei and basophilic sarcoplasmic masses. RESULTS: Skeletal muscle biopsies revealed muscular dystrophic changes accompanied by peripherally placed sarcoplasmic masses and numerous internal nuclei. Increased optical density (D) of Akt, p-Akt, p-p70s6k had been noted in DM1 patients as compared with the controls (Akt: t=4.110, P=0.006; p-Akt: t=4.408, P=0.004; p-p70s6k: t=4.113, P=0.005; p-Akt/Akt: t=4.055, P=0.002). A positive linear correlation was observed between Akt pathway activity and muscle hypertrophy proportion (Akt group: r=0.825, P=0.015; p-Akt group: r=0.914, P=0.004; p-p70s6k group: r=0.916, P=0.004). But, no correlation was observed between Akt pathway and sarcoplasmic masses or internal nuclei. CONCLUSION: Akt signaling pathway activity increased diffusively in skeletal muscle of the DM1 patient. Such elevation might be the cause of pathological muscle hypertrophy. PMID- 20957009 TI - [Effects of highly selective dorsal rootlets rhizotomy on bladder function and penis erection in SD rats]. AB - OBJECTIVE: To study the highly selective dorsal rhizotomy influence on bladder and penis erection function of SD rats. METHODS: Forty mature male SD rats of clean grades, with weight range of 300-350 g were selected. Ten rats were chosen to do electrophysiology study on dorsal rootlets of L6 and S1 segment. Changes in intravesical pressure (IVP) and intracavernous pressure (ICP) were investigated to define main segments which conducted to bladder and corpus cavernosum. Thirty rats were divided into two groups (A and B) on average at random. In group A, we made highly selective dorsal rhizotomy on the fascicle of conduction bladder detrusor muscle. In group B, we made highly selective dorsal rhizotomy on the fascicle of conduction corpus cavernosum. Changes of IVP and ICP after rhizotomy were investigated and recorded. RESULTS: The changes of IVP during electrostimulation were of no significant variation between L6 and S1 (P=0.972). With the changes of ICP during electrostimulation, S1 segment was of more significant variation than L6 segment, DeltaICP of S1 was (13.05+/-8.41) cmH2O (1 cmH2O=0.098 kPa), while DeltaICP of L6 was (6.88+/-2.76) cmH2O (P<0.01). There was no reasonable variation in IVP and ICP on the left and right dorsal rootlets of S1 segment (P was 0.623 and 0.828 respectively). In group A, there was significant variation in IVP, DeltaIVP of before rhizotomy was (14.37+/-4.89) cmH2O, while after rhizotomy was (3.25+/-1.29) cmH2O (P<0.001) while no obvious variation in ICP (P=0.153) after highly selective rhizotomy on S1 dorsal rootlets. In group B, there was significant variation in ICP, DeltaICP of before rhizotomy was (11.97+/-4.41) cmH2O, while after rhizotomy was (2.68+/-1.01) cmH2O (P<0.001), but no obvious variation in IVP (P=0.162) after highly selective rhizotomy on S1 dorsal rootlets. CONCLUSION: SD rats' different rootlets of S1 dorsal rootlets can be distinguished by microanatomy and electrostimulation. The IVP and ICP had distinct changes after highly selective dorsal rhizotomy. It could provide an experimental support to treat spastic bladder after spinal cord injury and retain at maximum reflexible erection function in the clinic. PMID- 20957010 TI - [Varying concentration of ropivacaine with stimulating catheters on sciatic nerve blocking for postoperative analgesia: comparison of efficacy]. AB - OBJECTIVE: To determine the most suitable concentration of ropivacaine on sciatic nerve blocks with stimulating catheters. METHODS: Sixty adult patients undergoing surgeries involving the foot and ankle were randomly divided into 3 groups (n=20): The patients in group A were given 0.1% ropivacaine, the patients in groups B and C received 0.125% and 0.15% ropivacaine respectively. We combined ultrasound and nerve stimulators for popliteal sciatic nerve blocks, and then placed stimulating catheters for postoperative analgesia. VAS and adverse effects were monitored 6 h, 12 h, 24 h and 48 h after surgery. RESULTS: The difference of VAS was of significance in statistics 6 h and 12 h postoperation. VAS in Group A at postoperative 6 h and 12 h was significantly higher than that in Groups B and C(P<0.05). The incidence of motor disturbance and limbs numbness in Group C was significantly higher than that in Groups A and B (P<0.05). There was no significant difference in the satisfaction of the three groups (P>0.05). CONCLUSION: The most suitable concentration of ropivacaine on sciatic nerve blocks with stimulating catheters is 0.125%. PMID- 20957011 TI - [Evaluation of capsule endoscopy on the diagnosis of gastrointestinal diseases]. AB - OBJECTIVE: To investigate the diagnostic value of capsule endoscopy in patients with gastrointestinal diseases of unknown causes (especially with small intestinal diseases). METHODS: The clinical data and images from M2A capsule endoscopy of 100 consecutive patients from 2004 to 2009 in Peking University Third Hospital were analyzed. These patients were followed up by telephone. RESULTS: The patients with metoclopramide (10 mg, intramuscular injection) had a significantly shorter gastric transit time in capsule endoscopy than those without metoclopramide (15.0 min vs 30.5 min, P=0.019). Among the patients with obscure gastrointestinal bleeding (n=40), abdominal pain or discomfort (n=35) and diarrhea (n=18), the rate of definitive diagnosis was 60.0%, 80.0% and 72.2%, respectively. The overall diagnostic yield of capsule endoscopy was 67.6%, 42.9% and 44.4%. The accuracy of capsule endoscopy was 75.0%, 92.9% and 84.6%. The sensitivity of capsule endoscopy for small intestinal diseases was 77.3%, 87.5% and 66.7%. The specificity was 50.0%, 95.0% and 90.0%. The positive predictive value was 94.4%, 87.5% and 66.7%. The negative predictive value was 16.7%, 95.0% and 90.0%, respectively. CONCLUSION: M2A capsule endoscopy with its high diagnostic value was a good method in the diagnosis of gastrointestinal diseases, especially in the patients with small intestinal diseases. There were differences in aspect of the diagnostic value among patients with different indications. Metoclopramide was helpful to reduce the gastric transit time of patients referred for capsule endoscopy. PMID- 20957012 TI - [Relationship among pathological change of gastric mucous, body mass index and the serum levels of ghrelin and leptin]. AB - OBJECTIVE: To investigate serum ghrelin and leptin levels in relation to pathology change of gastric mucous membrane and body mass index (BMI). METHODS: A total of 156 patients were studied from Apr. 2009 to Jul. 2009. Blood serum ghrelin and leptin levels were assessed by ELISA method. All patients underwent gastroscopy with biopsies from gastric antrum and gastric body in order to evaluate pathology change of gastric mucous membrane. RESULTS: Serum ghrelin levels (250.14 ng/L vs 386.65 ng/L) and leptin levels (4.12 MUg/L vs 4.31 MUg/L) in male subjects were lower than in female ones. There was significant difference in ghrelin levels (P=0.003), but not in leptin levels (P=0.681). ghrelin levels in <=35-year-old group, 36 to 54-year-old group and >=55-year-old group were 408.93 ng/L, 309.16 ng/L and 236.76 ng/L respectively, with significant difference (P=0.007). While leptin levels in <=35-year-old group, 36 to 54-year old group and >=55-year-old group were 4.26 MUg/L, 4.41 MUg/L and 3.86 MUg/L respectively, without significant difference (P=0.549). Serum ghrelin levels (308.40 ng/L vs 344.88 ng/L) and leptin levels (4.17 MUg/L vs 4.35 MUg/L) were both lower in chronic superficial gastritis patients than in chronic atrophy gastritis patients. But no statistically significant difference of ghrelin and leptin levels emerged either in chronic superficial gastritis group or in chronic atrophy gastritis group (P=0.870 and 0.436, respectively). There was a negative correlation between ghrelin and BMI (P=0.000), but a positive correlation between leptin and BMI (P=0.000). CONCLUSION: Gender and age have influence on serum ghrelin levels. Meanwhile, serum ghrelin and leptin levels were associated with neither chronic superficial gastritis nor chronic atrophy gastritis. Serum ghrelin levels decrease and leptin levels increase with the increase of BMI. PMID- 20957013 TI - [Pharmacodynamic interaction between propofol and remifentanil on the tolerance response to electrical tetanus stimuli]. AB - OBJECTIVE: To describe the pharmacodynamic interaction between propofol and remifentanil in suppressing somatic and hemodynamic responses to electrical tetanus stimuli (ETS) during induction of intravenous anesthesia with response surface method. METHODS: Seventy patients of ASA I or II, aged 18-65 years, scheduled for elective surgery were anesthetized by propofol and remifentanil. Propofol was administered with a target-controlled infusion (TCI) device at a target concentration that remained constant throughout the study, and remifentanil was administered with a TCI device at increasing staircase target concentrations. The somatic and hemodynamic responses to electrical tetanus stimuli were assessed multiple times after allowing for plasma effect site equilibration. The pharmacodynamic interaction between propofol and remifentanil was analyzed by response surface method. The three-dimensional response surfaces were constructed with Minitab Software. Model parameters were estimated with NONMEM. RESULTS: Response surface method characterized the pharmacodynamic interactions between propofol (0-9 mg/L) and remifentanil (0-10 MUg/L) qualitatively and quantitatively. The three-dimensional response surfaces showed considerable synergy between propofol and remifentani for blunting somatic and hemodynamic responses to ETS. When the target concentration of remifentani was 1 MUg/L, 2 MUg/L and 3 MUg/L, the C50 of propofol for blunting somatic responses to ETS decreased by 40.1%, 71.5% and 82.1% respectively; and the C50 of propofol for blunting hemodynamic responses to ETS decreased by 45.0%, 72.8% and 83.7% respectively. However, further increases in remifentanil only modestly reduced the C50 of propofol associated with loss of response to ETS. Ceiling effect was seen. CONCLUSION: Response surface method can analyze the pharmacodynamic interactions qualitatively and quantitatively. The response surface models revealed the significant synergy between propofol (<=9 mg/L) and remifentanil (<=10 MUg/L) for blunting somatic and hemodynamic responses to electrical tetanus stimuli. The ceiling effects of remifentanil were demonstrated in the reduction of propofol C50 regarding tolerance of responses to ETS. PMID- 20957014 TI - [Synthesis of G3.5 dendrimer-2-aminoethyl beta-D-galactopyranoside conjugates and its specificity on hepatocyte targeting in vitro]. AB - OBJECTIVE: To prepare a valuable nanodevice targeting for hepatic parenchymal cells to improve the effects of drugs for treatment of hepatitis B and liver cancer. METHODS: Generation 3.5 dendrimer (G3.5 PAMAM) was conjugated with fluoresceine isothiocyanate (FITC) to obtain G3.5 PAMAM-FITC, which was then conjugated with 2-aminoethyl beta-D-galactopyranoside (Dgal) in different molar ratios (1:5, 1:10, 1:15, 1:20) to obtain Dgal(n)-PAMAM-FITC. Flow cytometry was applied to examine which of the molar ratios was the best. RESULTS: Through active ester method, we got conjugates in different molar ratios of G3.5 PAMAM FITC to Dgal (1:5, 1:10, 1:15, 1:20). Cellular entry of FITC-labeled PAMAM conjugated with different numbers of Dgal was evaluated in vitro by using rat hepatocytes with flow cytometry, and it was found that one molecule of PAMAM conjugated with 20 molecules of Dgal was the best ratio. CONCLUSION: Dgal(20) G3.5 PAMAM-FITC can be used for liver-targeting drug delivery system. PMID- 20957015 TI - [Preparation and in vitro evaluation of tanshinone IIA pulsatile release pellets]. AB - OBJECTIVE: To develop pulsatile release pellets using tanshinone II as model drug and evaluate their properties in vitro. METHODS: The tanshinone II pusatile release pellets with rupturable coatings were prepared by fluid bed. Hydroxy propyl methyl cellulose (HPMC), low-substituted hydroxy propyl cellulose (L HPC)/HPMC, and HPMC/Sureleae were used as swelling agents respectively, and aqueous ethylcellulose dispersion Surelease as the material of controlled layer. Dissolution experiments were employed to evaluate the effects of different swelling agents and weight gain of each coating layer. Cross-sections of pellets with different swelling agents were observed by scanning electron microscope (SEM). The release profiles of tanshinone II from the coated pellets were fitted into various mathematic models. RESULTS: Pellets with HPMC or L-HPC/HPMC as swelling agents could not present a significant release lag time. However, the pellets with the mixture of HPMC and Surelease as swelling agents could. As the ratio of Surelease increased in swelling layer, the lag time could be extended. As to the controlled layer, the thicker the controlled layer, the longer the lag time could be. When the controlled layer was coated by 30%-40% weight gains, 3-5 h lag time was realized. The fitted model suggested that first order equation could explain the drug release from tanshinone II pulsatile release pellets. CONCLUSION: Using HPMC/Surelease mixture as swelling agents, and Surelease as the material of controlled layer, tanshinone II pulsatile release pellets with 3-5 h lag time were successfully prepared. PMID- 20957016 TI - [Determinants of household healthcare expenditure of rural floating population in Beijing: a Tobit model approach]. AB - OBJECTIVE: To explain the household healthcare expenditure among the rural floating population in Beijing and analyze the determinants of a household total healthcare consumption. METHODS: The data came from the special investigation about rural floating population in Beijing which is part of The Fourth National Health Service Investigation of China. A total of 4 698-native rural migrants (2,728 families) in Beijing were chosen as subjects and a Tobit model was used to analyze the data. Base on the censored characteristics, we use the censored least absolute deviations (CLAD) method to estimate the parameters. RESULTS: Compared with the general urban population, the population under investigation has a high proportion of male and unmarried, but low educated group of young people. The average household healthcare expenditure per month was 21.26 Yuan, and about 74% of the households had made no healthcare expenditure 3 months preceding the survey. The household healthcare expenditure was influenced by the household's education level, household's income level, household size, Engel's coefficient, head's choice of medical institutions and so on. CONCLUSION: The level of household healthcare expenditure is low with the determinants in the floating population, such as the household's economic circumstances and so on. We should make and develop relevant policies and improve the healthcare utilization of the floating population. PMID- 20957017 TI - [Clinical study on modified maxillomandibular advancement for the treatment of obstructive sleep apnea syndrome]. AB - OBJECTIVE: To evaluate the modified maxillomandibular advancement (MMMA) technique for the treatment of obstructive sleep apnea syndrome (OSAS) in yellow race of convex profile. METHODS: Eight patients underwent MMMA for the treatment of OSAHS. All the patients underwent pre-surgical and postsurgical polysomnography, cephalometric analysis and objective results assessment. RESULTS: The preoperative polysomnography results of the patients were as follows: apnea-hypopnea index, (40.1+/-16.1) per hour; lowest oxygen saturation, (72.4+/-7.2)%. The postoperative polysomnography results were as follows: apnea hypopnea index, (5.4+/-3.8) per hour; lowest oxygen saturation, (90.6+/-2.1)%. The mean preoperative SNA was (80.9+/- 1.7) degrees , and the mean postoperative SNA was (82.9+/-1.5) degrees . The mean preoperative SNB was (72.5+/-2.6) degrees , and the mean postoperative SNB was (81.5+/-1.7) degrees . The mean preoperative PAS was (5.3 +/-1.6) mm, and the mean postoperative PAS was (10.8 +/-1.8) mm. CONCLUSION: The preliminary review has demonstrated that the modified MMA technique for the treatment of OSAS is highly effective in the treatment of severe OSAS without the significant facial profile change commonly associated with the traditional MMA technique. With the introduction of this modified MMA technique for the treatment of OSAS, skeletal surgery may be less perceived as an unattractive treatment modality due to the markedly reduced anticipated facial changes after surgery. PMID- 20957018 TI - [Restore two posterior teeth with modified resin-bonded-bridge]. AB - OBJECTIVE: To restore two posterior teeth with resin-bond-bridge with attachments. METHODS: Twenty patients were selected with two adjacent posterior teeth missing and the opposite teeth were natural teeth. The mean age was 45.6 years old, 9 male and 11 female. The maxillary cases were 12 and mandibules case were 8. The female part of attachment was attached with the retainer on the bicuspid teeth; the male part was attached with the pontic. After try-in, the two parts were adhered to the abutments separately and joined by the attachment. RESULTS: The mean survival time of the 20 cases was 28.8 months, and the max was 42 months. In only one case the posterior part debonded, and it resumed being used after rebonding. CONCLUSION: In recent years the successful rate of resin bond-bridge has got close to that of the traditional bridge. Most RBB were used to restore the single missing tooth. Now RBB with non-rigid connector can restore two missing teeth. When the teeth get stress, the directions of stress are different. The longer span of RBB with rigid connector, the bigger interbutment stress on the adhere layer. With the non-rigid connector the stress between the retainer and the adhesive layer can be reduced. Our clinic treatment showed that this kind of method got good results and even the service time was not very long. PMID- 20957019 TI - [A comparison of skeletal changes between adult and adolescent with skeletal class II malocclusions before and after therapy]. AB - OBJECTIVE: To compare skeletal changes after orthodontic treatment between adults and adolescents skeletal class II malocclusions with average mandible plane angle. METHODS: In our study, 30 adolescent girls and 30 adult females who had skeletal class II and Angle class II, division 1 malocclusions were selected. The two groups were matched by gender, treatment period and method. Cephalometric radiographs taken before and after treatment were traced and measured. Student's t-test was used. RESULTS: After treatment, SNA, SNB and ANB decreased in both groups, but no significant difference was found between the two groups. The length of mandible, anterior and posterior facial heights increased significantly in adolescents, but the ratio of lower and total anterior and posterior facial heights remained unchanged and no difference was found between the two groups. CONCLUSION: Although some maxillary and mandibular growths were found in adolescents, the skeletal changes during treatment in skeletal class II malocclusion with average mandible plane showed no difference between adults and adolescents. PMID- 20957020 TI - [Effect of filler content of composite resins on polymerization shrinkage measured by a video imaging apparatus (Acuvol)]. AB - OBJECTIVE: To investigate the effect of filler content on the polymerization shrinkage of resins and to evaluate whether Acuvol is a simple and easy method in volumetric shrinkage measurement. METHODS: Six experimental resins with filler contents of 80%, 78%, 76%, 70%, 60%, and 50% were made. Three commercial resins were Syn D6 with 80% filler content, Syn Compact Nano with 74% filler content and Syn Flow with 55% filler content(using the mass fraction to express the filler content). Small semi-sphere samples of these composites were manually formed and light cured for 40 s using a quartz tungsten halogen unit at 650 mW/cm2 (n=10). The volumetric shrinkage was measured in both SVVR and MVVR modes using Acuvol. RESULTS: The volumetric shrinkage of the three commercial resins were: Syn Flow > Syn Compact Nano > Syn D6. The shrinkage values of the six experimental resins with different filler contents were: 50% > 60% > 70% > 76% > 78% > 80%. The negative correlation between filler content and volumetric shrinkage of commercial and experimental resins were strongly (-0.982 and -0.968 respectively, P<0.001). No significant difference between SVVR and MVVR modes (t=0.385, P>0.05). CONCLUSION: The present results support the view that filler content is one of the most important factors influencing polymerization shrinkage of composites. Acuvol provides an easy method for measuring polymerization shrinkage of composites. Both SVVR and MVVR modes of Acuvol give reproducible results. PMID- 20957021 TI - [A case report of a successfully rescued patient with respiratory failure in late pregnancy]. AB - Respiratory problem is a common concomitant disease during pregnancy. Puerpera with respiratory failure has a high risk of morbidity and mortality. During pregnancy, a puerpera usually experienced obvious respiratory changes, which make the mother carry out enough oxygen to provide the fetus and meet its increasing need, and ensure that the mother will remove the excess of carbon dioxide produced by the elevated metabolic demands as the fetus grows mature. The normal value of arterial carbon dioxide tension(PaCO2 )is around 28 to 34 mmHg during noncomplicated pregnancies. The case we reported here was a 26-year-old woman, with G1P0. Emergency admission to Peking University Third Hospital because of chest suffocating for about 6 months. She was diagnosed as "Intrauterine pregnancy over 34 weeks, with respiratory failure type II and acidosis". The PaCO2 of the puerpera reached 74 mmHg before delivery and 94 mmHg after delivery. The doctors from several departments conducted cooperative management, undertook combined spinal and epidural anesthesia in the sitting position, controlled the anesthesia level and applied low concentration oxygen therapy. The baby was delivered successfully and the mother's condition was kept stable. Both the mother and the baby were discharged safely 11 days after operation. Although we carried out a series of checks, the exact cause of the disease remained unclear. PMID- 20957022 TI - [A case report of monitoring on carbamazepine in breast feeding woman]. AB - To evaluate the safety of oral cabamazepine during breast milk feeding. The carbamazepine concentration in breast milk of one epilepsy maternal patient was assayed by high performance liquid chromatography, and the literature was reviewed to find the nursing evidence in the use of cabamazepine. The carbamazepine concentration in breast milk ranged from 0.34-0.86 mg/L. The neonate daily dose intake was estimated ranging from 0.34 mg to 0.86 mg through breast-feeding in theory. The literature showed that carbamazepine was generally considered safe for use during breast feeding; however, adverse effects should be monitored as recommended. It is better to avoid feeding at high concentration level to minimize the harm of carbamazepine to the baby. PMID- 20957023 TI - [Methods of BMP immobilization and evaluation for Ti-based dental implant surface modification]. AB - Ti-based biomaterial has been widely used as dental and bone implant material although its bioactivity still needs improvement especially for dental implant. The bone morphogenetic proteins(BMPs) bound to Ti-based materials will attract the mesenchymal stem cells to differentiate into osteoblast cells, which benefits the response to the protein-material surface, and finally leads to new bone formation. Several methods including physically mixing, coating, plasma immobilization and cross-linking were used to investigate how BMPs bind to Ti based biomaterials. The latest research papers are focused on the structure and function of BMPs, and the methods to bind BMPs to Ti-based biomaterial and the evaluation methods after protein immobilization are reviewed in this paper. PMID- 20957024 TI - [Molecular mechanism of proteinuria caused progression of chronic renal disease]. AB - Increasing numbers of clinical and experimental studies have proved that proteinuria plays a key role in the progression of chronic renal disease. In recent years, some molecular mechanisms of how proteinuria causes further kidney injuries have been revealed by many researches, although there are still many questions to be answered. Proteinuria triggers chemokine expression of tubular epithelial cells and activates complements, which result in interstitial inflammation and fibrosis; proteinuria also induces the apoptosis of tubular epithelial cells. Albumin in urine is considered as the main culprit, but other elements in proteinuria have also been suspected to cause renal damage, too. On the other hand, serum proteins leaking from glomerular barrier also adversely affect podocytes. Ultrafiltered serum proteins induce morphological changes and functional impairment of podocytes, resulting in exacerbating proteinuria; furthermore, TGF-beta1 up-regulated by podocytes in response to protein overload contributes to the sclerosis of glomeruli. Studies on the mechanism of how proteinuria accelerates kidney diseases are important because they may offer novel therapeutic targets for controlling chronic kidney disease. For example, targeting directly on the complement synthesis and activation in proximal tubules, or chemokine production in tubular cells might be beneficial for preventing the progression of chronic proteinuric kidney disease to end stage renal disease. PMID- 20957025 TI - [Primary and secondary hypocholesterolemia]. AB - Hypocholesterolemia is characterized by serum total cholesterol that is lower than the 5th percentile for age and sex, or the cut-off value which predicts the adverse prognosis by epidemiological study. Unlike hypercholesterolemia, physicians pay less attention to the morbidity, causes and consequences of hypocholesterolemia in clinical practice. In fact, hypocholesterolemia is a common dislipidemia, and mainly results from secondary factors. The causes of primary hypocholesterolemia are some disorders owing to genetic mutation in the pathway of cholesterol absorption, biosynthesis or metabolism, including abetalipoproteinemia, hypobetalipoproteinemia, Tangier disease, chylomicron retention disease and inherited disorders of cholesterol biosynthesis. The causes of secondary hypocholesterolemia comprise anemia, hyperthyroidism, malignancy, live disease, critical illness, serious stress, malabsorption or malnutrition, acute or chronic infection, chronic inflammation, and use of some drugs. In addition, what's more important is that hypocholesterolemia can result in some adverse events, such as increased mortality, intracerebral hemorrhage, cancer, infection, adrenal failure, suicide and mental disorder. Therefore, with the practice of intensive lipid-lowering treatment and the tendency to the increased indications of statins, it's high time that physicians attached more importance to hypocholesterolemia. PMID- 20957026 TI - [Research progress of radionuclide tracing in small interference RNA imaging in vivo]. AB - RNA interference has emerged as one of the most promising gene silencing techniques in gene function and gene therapy researches. However, the in- vivo application of small interference RNA (siRNA) requires an effective noninvasive method to evaluate its delivery in vivo. Nuclear imaging, luciferase imaging and bioluminescence imaging have potential values in this area. Applied widely in clinic and research, nuclear imaging has the advantages of noninvasiveness, high sensitivity and good safety, and it can be used in the large animal, even the human body. Moreover, nuclear imaging provides the information of biodistribution and semi-quantitative or quantitative evaluation in gene interference. The recent progress in in-vivo application basis, protection, radiolabeling methods, biodistribution, and nuclear imaging of siRNA is reviewed here, in order to help the development of siRNA based imaging and therapy researches. PMID- 20957027 TI - The crystal structure of the Dachshund domain of human SnoN reveals flexibility in the putative protein interaction surface. AB - The human SnoN is an oncoprotein that interacts with several transcription regulatory proteins such as the histone-deacetylase, N-CoR containing co repressor complex and Smad proteins. This study presents the crystal structure of the Dachshund homology domain of human SnoN. The structure reveals a groove composed of conserved residues with characteristic properties of a protein interaction surface. A comparison of the 12 monomers in the asymmetric unit reveals the presence of two major conformations: an open conformation with a well accessible groove and a tight conformation with a less accessible groove. The variability in the backbone between the open and the tight conformations matches the differences seen in previously determined structures of individual Dachshund homology domains, suggesting a general plasticity within this fold family. The flexibility observed in the putative protein binding groove may enable SnoN to recognize multiple interaction partners. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1. PMID- 20957028 TI - Wide-field motion integration in fly VS cells: insights from an inverse approach. AB - Fly lobula plate tangential cells are known to perform wide-field motion integration. It is assumed that the shape of these neurons, and in particular the shape of the subclass of VS cells, is responsible for this type of computation. We employed an inverse approach to investigate the morphology-function relationship underlying wide-field motion integration in VS cells. In the inverse approach detailed, model neurons are optimized to perform a predefined computation: here, wide-field motion integration. We embedded the model neurons to be optimized in a biologically plausible model of fly motion detection to provide realistic inputs, and subsequently optimized model neuron with and without active conductances (g(Na), g(K), g(K(Na))) along their dendrites to perform this computation. We found that both passive and active optimized model neurons perform well as wide-field motion integrators. In addition, all optimized morphologies share the same blueprint as real VS cells. In addition, we also found a recurring blueprint for the distribution of g(K) and g(Na) in the active models. Moreover, we demonstrate how this morphology and distribution of conductances contribute to wide-field motion integration. As such, by using the inverse approach we can predict the still unknown distribution of g(K) and g(Na) and their role in motion integration in VS cells. PMID- 20957029 TI - PP2A mediated AMPK inhibition promotes HSP70 expression in heat shock response. AB - BACKGROUND: Under stress, AMP-activated protein kinase (AMPK) plays a central role in energy balance, and the heat shock response is a protective mechanism for cell survival. The relationship between AMPK activity and heat shock protein (HSP) expression under stress is unclear. METHODOLOGY/PRINCIPAL FINDINGS: We found that heat stress induced dephosphorylation of AMPKalpha subunit (AMPKalpha) in various cell types from human and rodent. In HepG2 cells, the dephosphorylation of AMPKalpha under heat stress in turn caused dephosphorylation of acetyl-CoA carboxylase and upregulation of phosphoenolpyruvate carboxykinase, two downstream targets of AMPK, confirming the inhibition of AMPK activity by heat stress. Treatment of HepG2 cells with phosphatase 2A (PP2A) inhibitor okadaic acid or inhibition of PP2A expression by RNA interference efficiently reversed heat stress-induced AMPKalpha dephosphorylation, suggesting that heat stress inhibited AMPK through activation of PP2A. Heat stress- and other HSP inducer (CdCl(2), celastrol, MG132)-induced HSP70 expression could be inhibited by AICAR, an AMPK specific activator. Inhibition of AMPKalpha expression by RNA interference reversed the inhibitory effect of AICAR on HSP70 expression under heat stress. These results indicate that AMPK inhibition under stress contribute to HSP70 expression. Mechanistic studies showed that activation of AMPK by AICAR had no effect on heat stress-induced HSF1 nuclear translocation, phosphorylation and binding with heat response element in the promoter region of HSP70 gene, but significantly decreased HSP70 mRNA stability. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that during heat shock response, PP2A mediated AMPK inhibition upregulates HSP70 expression at least partially through stabilizing its mRNA, which suggests a novel mechanism for HSP induction under stress. PMID- 20957030 TI - Temporal gene expression profiling during rat femoral marrow ablation-induced intramembranous bone regeneration. AB - Enhanced understanding of differential gene expression and biological pathways associated with distinct phases of intramembranous bone regeneration following femoral marrow ablation surgery will improve future advancements regarding osseointegration of joint replacement implants, biomaterials design, and bone tissue engineering. A rat femoral marrow ablation model was performed and genome wide microarray data were obtained from samples at 1, 3, 5, 7, 10, 14, 28, and 56 days post-ablation, with intact bones serving as controls at Day 0. Bayesian model-based clustering produced eight distinct groups amongst 9,062 significant gene probe sets based on similar temporal expression profiles, which were further categorized into three major temporal classes of increased, variable, and decreased expression. Osteoblastic- and osteoclastic-associated genes were found to be significantly expressed within the increased expression groups. Chondrogenesis was not detected histologically. Adipogenic marker genes were found within variable/decreased expression groups, emphasizing that adipogenesis was inhibited during osteogenesis. Differential biological processes and pathways associated with each major temporal group were identified, and significantly expressed genes involved were visually represented by heat maps. It was determined that the increased expression group exclusively contains genes involved in pathways for matrix metalloproteinases (MMPs), Wnt signaling, TGF beta signaling, and inflammatory pathways. Only the variable expression group contains genes associated with glycolysis and gluconeogenesis, the notch signaling pathway, natural killer cell mediated cytotoxicity, and the B cell receptor signaling pathway. The decreased group exclusively consists of genes involved in heme biosynthesis, the p53 signaling pathway, and the hematopoietic cell lineage. Significant biological pathways and transcription factors expressed at each time point post-ablation were also identified. These data present the first temporal gene expression profiling analysis of the rat genome during intramembranous bone regeneration induced by femoral marrow ablation. PMID- 20957032 TI - Role of host immune response and viral load in the differential outcome of pandemic H1N1 (2009) influenza virus infection in Indian patients. AB - BACKGROUND: An unusually high number of severe pneumonia cases with considerable mortality is being observed with the pandemic H1N1 2009 virus infections globally. In India, all mild as well as critically ill cases were admitted and treated in the government hospitals during the initial phase of the pandemic. The present study was undertaken during this early phase of the pandemic. METHODOLOGY: The role of viral load and host factors in the pathogenesis were assessed by examining 26 mild (MP), 15 critically ill patients (CIP) and 20 healthy controls from Pune, India. Sequential blood and lung aspirate samples were collected from CIP. Viral load and cytokines/chemokine levels were determined from the plasma and lung aspirates of the patients. TLR levels were determined by staining and FACS analysis. Gene profiling was done for both cells in the lung aspirates and PBMCs using TaqMan Low Density arrays. Antibody titres and isotyping was done using HA protein based ELISAs. PRINCIPAL FINDINGS: 13/15 critically ill patients expired. All plasma samples were negative for the virus irrespective of the patient's category. Sequential lung samples from CIP showed lower viral loads questioning association of viral replication with the severity. Anti-rpH1N1-09-HA-IgG titres were significantly higher in critically ill patients and both categories circulated exclusively IgG1 isotype. Critically ill patients exhibited increase in TLR-3, 4, 7 and decrease in TLR-2 expressions. The disease severity correlated with increased plasma levels of IL1RA, IL2, IL6, CCL3, CCL4 and IL10. Majority of the immune-function genes were down-regulated in the PBMCs and up-regulated in the cells from lung aspirates of critically ill patients. No distinct pattern differentiating fatal and surviving patients was observed when sequential samples were examined for various parameters. CONCLUSIONS: Disease severity was associated with pronounced impairment of host immune response. PMID- 20957031 TI - cDNA microarray gene expression profiling of hedgehog signaling pathway inhibition in human colon cancer cells. AB - BACKGROUND: Hedgehog (HH) signaling plays a critical role in normal cellular processes, in normal mammalian gastrointestinal development and differentiation, and in oncogenesis and maintenance of the malignant phenotype in a variety of human cancers. Increasing evidence further implicates the involvement of HH signaling in oncogenesis and metastatic behavior of colon cancers. However, genomic approaches to elucidate the role of HH signaling in cancers in general are lacking, and data derived on HH signaling in colon cancer is extremely limited. METHODOLOGY/PRINCIPAL FINDINGS: To identify unique downstream targets of the GLI genes, the transcriptional regulators of HH signaling, in the context of colon carcinoma, we employed a small molecule inhibitor of both GLI1 and GLI2, GANT61, in two human colon cancer cell lines, HT29 and GC3/c1. Cell cycle analysis demonstrated accumulation of GANT61-treated cells at the G1/S boundary. cDNA microarray gene expression profiling of 18,401 genes identified Differentially Expressed Genes (DEGs) both common and unique to HT29 and GC3/c1. Analyses using GenomeStudio (statistics), Matlab (heat map), Ingenuity (canonical pathway analysis), or by qRT-PCR, identified p21(Cip1) (CDKN1A) and p15(Ink4b) (CDKN2B), which play a role in the G1/S checkpoint, as up-regulated genes at the G1/S boundary. Genes that determine further cell cycle progression at G1/S including E2F2, CYCLIN E2 (CCNE2), CDC25A and CDK2, and genes that regulate passage of cells through G2/M (CYCLIN A2 [CCNA2], CDC25C, CYCLIN B2 [CCNB2], CDC20 and CDC2 [CDK1], were down-regulated. In addition, novel genes involved in stress response, DNA damage response, DNA replication and DNA repair were identified following inhibition of HH signaling. CONCLUSIONS/SIGNIFICANCE: This study identifies genes that are involved in HH-dependent cellular proliferation in colon cancer cells, and following its inhibition, genes that regulate cell cycle progression and events downstream of the G1/S boundary. PMID- 20957033 TI - Biological role of Nardonella endosymbiont in its weevil host. AB - Weevils constitute the most species-rich animal group with over 60,000 described species, many of which possess specialized symbiotic organs and harbor bacterial endosymbionts. Among the diverse microbial associates of weevils, Nardonella spp. represent the most ancient and widespread endosymbiont lineage, having co speciated with the host weevils for over 125 million years. Thus far, however, no empirical work on the role of Nardonella for weevil biology has been reported. Here we investigated the biological role of the Nardonella endosymbiont for the West Indian sweet potato weevil, Euscepes postfasciatus. This insect is an experimentally tractable pest insect that can easily be reared on a natural diet of sweet potato root as well as on an agar-based artificial diet. By larval feeding on an antibiotic-containing artificial diet, Nardonella infection was effectively eliminated from the treated insects. The antibiotic-treated insects exhibited significantly lighter body weight and lower growth rate than the control insects. Then, the antibiotic-treated insects and the control insects were respectively allowed to mate and oviposit on fresh sweet potatoes without the antibiotic. The offspring of the antibiotic-treated insects, which were all Nardonella-negative, exhibited significantly lighter body weight, smaller body size, lower growth rate and paler body color in comparison with the offspring of the control insects, which were all Nardonella-positive. In conclusion, the Nardonella endosymbiont is involved in normal growth and development of the host weevil. The biological role of the endosymbiont probably underlies the long lasting host-symbiont co-speciation in the evolutionary course of weevils. PMID- 20957034 TI - Modeling oncogenic signaling in colon tumors by multidirectional analyses of microarray data directed for maximization of analytical reliability. AB - BACKGROUND: Clinical progression of colorectal cancers (CRC) may occur in parallel with distinctive signaling alterations. We designed multidirectional analyses integrating microarray-based data with biostatistics and bioinformatics to elucidate the signaling and metabolic alterations underlying CRC development in the adenoma-carcinoma sequence. METHODOLOGY/PRINCIPAL FINDINGS: Studies were performed on normal mucosa, adenoma, and carcinoma samples obtained during surgery or colonoscopy. Collections of cryostat sections prepared from the tissue samples were evaluated by a pathologist to control the relative cell type content. The measurements were done using Affymetrix GeneChip HG-U133plus2, and probe set data was generated using two normalization algorithms: MAS5.0 and GCRMA with least-variant set (LVS). The data was evaluated using pair-wise comparisons and data decomposition into singular value decomposition (SVD) modes. The method selected for the functional analysis used the Kolmogorov-Smirnov test. Expressional profiles obtained in 105 samples of whole tissue sections were used to establish oncogenic signaling alterations in progression of CRC, while those representing 40 microdissected specimens were used to select differences in KEGG pathways between epithelium and mucosa. Based on a consensus of the results obtained by two normalization algorithms, and two probe set sorting criteria, we identified 14 and 17 KEGG signaling and metabolic pathways that are significantly altered between normal and tumor samples and between benign and malignant tumors, respectively. Several of them were also selected from the raw microarray data of 2 recently published studies (GSE4183 and GSE8671). CONCLUSION/SIGNIFICANCE: Although the proposed strategy is computationally complex and labor-intensive, it may reduce the number of false results. PMID- 20957035 TI - Monomerization of cytosolic mature smac attenuates interaction with IAPs and potentiation of caspase activation. AB - The four residues at the amino-terminus of mature Smac/DIABLO are an IAP binding motif (IBM). Upon exit from mitochondria, mature Smac interacts with inhibitor of apoptosis proteins (IAPs), abrogating caspase inhibition. We used the ubiquitin fusion model to express mature Smac in the cytosol. Transiently expressed mature Smac56-239 (called Smac56) and Smac60-239 (called Smac60), which lacks the IBM, interacted with X-linked inhibitor of apoptosis protein (XIAP). However, stable expression produced wild type Smac56 that failed to homodimerize, interact with XIAP, and potentiate caspase activation. Cytosolic Smac60 retained these functions. Cytosolic Smac56 apparently becomes posttranslationally modified at the dimer interface region, which obliterated the epitope for a monoclonal antibody. Cytosolic Smacdelta, which has the IBM but lacks amino acids 62-105, homodimerized and weakly interacted with XIAP, but failed to potentiate apoptosis. These findings suggest that the IBM of Smac is a recognition point for a posttranslational modification(s) that blocks homodimerization and IAP interaction, and that amino acids 62-105 are required for the proapoptotic function of Smac. PMID- 20957036 TI - Methanol assimilation in Methylobacterium extorquens AM1: demonstration of all enzymes and their regulation. AB - BACKGROUND: Methylobacterium extorquens AM1 is an aerobic facultative methylotrophic alpha-proteobacterium that can use reduced one-carbon compounds such as methanol, but also multi-carbon substrates like acetate (C2) or succinate (C4) as sole carbon and energy source. The organism has gained interest as future biotechnological production platform based on methanol as feedstock. METHODOLOGY/PRINCIPAL FINDINGS: We present a comprehensive study of all postulated enzymes for the assimilation of methanol and their regulation in response to the carbon source. Formaldehyde, which is derived from methanol oxidation, is assimilated via the serine cycle, which starts with glyoxylate and forms acetyl-CoA. Acetyl-CoA is assimilated via the proposed ethylmalonyl-CoA pathway, which thereby regenerates glyoxylate. To further the understanding of the central carbon metabolism we identified and quantified all enzymes of the pathways involved in methanol assimilation. We observed a strict differential regulation of their activity level depending on whether C1, C2 or C4 compounds are used. The enzymes, which are specifically required for the utilization of the individual substrates, were several-fold up-regulated and those not required were down-regulated. The enzymes of the ethylmalonyl-CoA pathway showed specific activities, which were higher than the calculated minimal values that can account for the observed growth rate. Yet, some enzymes of the serine cycle, notably its first and last enzymes serine hydroxymethyl transferase and malate thiokinase, exhibit much lower values and probably are rate limiting during methylotrophic growth. We identified the natural C1 carrying coenzyme as tetrahydropteroyl tetraglutamate rather than tetrahydrofolate. CONCLUSION/SIGNIFICANCE: This study provides the first complete picture of the enzymes required for methanol assimilation, the regulation of their activity levels in response to the growth substrate, and the identification of potential growth limiting steps. PMID- 20957037 TI - Electrophysiological effects of SKF83959 on hippocampal CA1 pyramidal neurons: potential mechanisms for the drug's neuroprotective effects. AB - Although the potent anti-parkinsonian action of the atypical D1-like receptor agonist SKF83959 has been attributed to the selective activation of phosphoinositol(PI)-linked D1 receptor, whereas the mechanism underlying its potent neuroprotective effect is not fully understood. In the present study, the actions of SKF83959 on neuronal membrane potential and neuronal excitability were investigated in CA1 pyramidal neurons of rat hippocampal slices. SKF83959 (10-100 uM) caused a concentration-dependent depolarization, associated with a reduction of input resistance in CA1 pyramidal neurons. The depolarization was blocked neither by antagonists for D1, D2, 5-HT(2A/2C) receptors and alpha1-adrenoceptor, nor by intracellular dialysis of GDP-beta-S. However, the specific HCN channel blocker ZD7288 (10 uM) antagonized both the depolarization and reduction of input resistance caused by SKF83959. In voltage-clamp experiments, SKF83959 (10-100 uM) caused a concentration-dependent increase of Ih current in CA1 pyramidal neurons, which was independent of D1 receptor activation. Moreover, SKF83959 (50 uM) caused a 6 mV positive shift in the activation curve of Ih and significantly accelerated the activation of Ih current. In addition, SKF83959 also reduced the neuronal excitability of CA1 pyramidal neurons, which was manifested by the decrease in the number and amplitude of action potentials evoked by depolarizing currents, and by the increase of firing threshold and rhoebase current. The above results suggest that SKF83959 increased Ih current through a D1 receptor independent mechanism, which led to the depolarization of hippocampal CA1 pyramidal neurons. These findings provide a novel mechanism for the drug's neuroprotective effects, which may contributes to its therapeutic benefits in Parkinson's disease. PMID- 20957038 TI - RNAi experiments in D. melanogaster: solutions to the overlooked problem of off targets shared by independent dsRNAs. AB - BACKGROUND: RNAi technology is widely used to downregulate specific gene products. Investigating the phenotype induced by downregulation of gene products provides essential information about the function of the specific gene of interest. When RNAi is applied in Drosophila melanogaster or Caenorhabditis elegans, often large dsRNAs are used. One of the drawbacks of RNAi technology is that unwanted gene products with sequence similarity to the gene of interest can be down regulated too. To verify the outcome of an RNAi experiment and to avoid these unwanted off-target effects, an additional non-overlapping dsRNA can be used to down-regulate the same gene. However it has never been tested whether this approach is sufficient to reduce the risk of off-targets. METHODOLOGY: We created a novel tool to analyse the occurrence of off-target effects in Drosophila and we analyzed 99 randomly chosen genes. PRINCIPAL FINDINGS: Here we show that nearly all genes contain non-overlapping internal sequences that do show overlap in a common off-target gene. CONCLUSION: Based on our in silico findings, off-target effects should not be ignored and our presented on-line tool enables the identification of two RNA interference constructs, free of overlapping off-targets, from any gene of interest. PMID- 20957040 TI - An assassin among predators: the relationship between plant-ants, their host Myrmecophytes and the Reduviidae Zelus annulosus. AB - Tropical plants frequently live in association with ants that protect their foliage from defoliators. Among them, myrmecophytes have evolved mutualisms with a limited number of plant-ants that they shelter and feed, and, in return, benefit from some protection. Hirtella physophora (Chrysobalanaceae), for example, houses Allomerus decemarticulatus (Myrmicinae) that build gallery-shaped traps to catch large prey. In French Guiana, we frequently observed the assassin bug Zelus annulosus (Reduviidae, Harpactorinae) on the leaves of H. physophora. Here, we studied the distribution of Zelus annulosus among understory plants in the Guianese rainforest and found it only on pubescent plants, including H. Physophora, whether or not it was sheltering an A. decemarticulatus colony, but only rarely on other myrmecophytes. The relationship between Z. annulosus and its host plants is, then, also mutualistic, as the plant trichomes act as an enemy free space protecting the nymphs from large predatory ants, while the nymphs protect their host-plants from herbivorous insects. Through their relationship with A. decemarticulatus colonies, Z. annulosus individuals are protected from army ants, while furnishing nothing in return. In those cases where H. physophora sheltered both an A. decemarticulatus colony and Z. annulosus nymphs, certain plant individuals repeatedly sheltered nymphs, indicating that female bugs may select not only pubescent plants but also particular H. physophora treelets having characteristics more favourable to the development of their progeny. PMID- 20957039 TI - PHOX2B-mediated regulation of ALK expression: in vitro identification of a functional relationship between two genes involved in neuroblastoma. AB - BACKGROUND: Neuroblastoma (NB) is a severe pediatric tumor originating from neural crest derivatives and accounting for 15% of childhood cancer mortality. The heterogeneous and complex genetic etiology has been confirmed with the identification of mutations in two genes, encoding for the receptor tyrosine kinase Anaplastic Lymphoma Kinase (ALK) and the transcription factor Paired-like Homeobox 2B (PHOX2B), in a limited proportion of NB patients. Interestingly, these two genes are overexpressed in the great majority of primary NB samples and cell lines. These observations led us to test the hypothesis of a regulatory or functional relationship between ALK and PHOX2B underlying NB pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Following this possibility, we first confirmed a striking correlation between the transcription levels of ALK, PHOX2B and its direct target PHOX2A in a panel of NB cell lines. Then, we manipulated their expression in NB cell lines by siRNA-mediated knock-down and forced over expression of each gene under analysis. Surprisingly, PHOX2B- and PHOX2A-directed siRNAs efficiently downregulated each other as well as ALK gene and, consistently, the enhanced expression of PHOX2B in NB cells yielded an increment of ALK protein. We finally demonstrated that PHOX2B drives ALK gene transcription by directly binding its promoter, which therefore represents a novel PHOX2B target. CONCLUSIONS/SIGNIFICANCE: These findings provide a compelling explanation of the concurrent involvement of these two genes in NB pathogenesis and are going to foster a better understanding of molecular interactions at the base of the disease. Moreover, this work opens new perspectives for NBs refractory to conventional therapies that may benefit from the design of novel therapeutic RNAi based approaches for multiple gene targets. PMID- 20957041 TI - Failure of effector function of human CD8+ T Cells in NOD/SCID/JAK3-/- immunodeficient mice transplanted with human CD34+ hematopoietic stem cells. AB - Humanized mice, which are generated by transplanting human CD34+ hematopoietic stem cells into immunodeficient mice, are expected to be useful for the research on human immune responses. It is reported that antigen-specific T cell responses occur in immunodeficient mice transplanted with both human fetal thymus/liver tissues and CD34+ fetal cells, but it remains unclear whether antigen-specific T cell responses occur in those transplanted with only human CD34+ hematopoietic stem cells (HSCs). Here we investigated the differentiation and function of human CD8+ T cells reconstituted in NOD/SCID/Jak3-/- mice transplanted with human CD34+ HSCs (hNOK mice). Multicolor flow cytometric analysis demonstrated that human CD8+ T cells generated from the CD34+ HSCs comprised only 3 subtypes, i.e., CD27(high)CD28+CD45RA+CCR7+, CD27+CD28+CD45RA-CCR7+, and CD27+CD28+CD45RA-CCR7 and had 3 phenotypes for 3 lytic molecules, i.e., perforin(Per)-granzymeA(GraA) granzymeB(GraB)-, Per-GraA+GraB-, and Per(low)GraA+GraB+. These CD8+ T cells failed to produce IFN-gamma and to proliferate after stimulation with alloantigens. These results indicate that the antigen-specific T cell response cannot be elicited in mice transplanted with only human CD34+ HSCs, because the T cells fail to develop normally in such mice. PMID- 20957042 TI - Increased dependence of humans on ecosystem services and biodiversity. AB - Humans have altered ecosystems more rapidly and extensively than ever, largely to meet rapidly growing demands for resources along with economic development. These demands have been considered important drivers of ecosystem degradation and biodiversity loss. Are humans becoming less dependent on ecosystem services and biodiversity following economic development? Here, we used roundwood production, hydroelectricity generation and tourism investment in 92 biodiversity hotspot and 60 non-hotspot countries as cases to seek the answer. In 1980-2005, annual growth rates of roundwood production, hydroelectricity generation and tourism investment were higher in hotspot countries (5.2, 9.1 and 7.5%) than in non-hotspot countries (3.4, 5.9 and 5.6%), when GDP grew more rapidly in hotspot countries than non-hotspot countries. Annual growth rates of per capita hydropower and per capita tourism investment were higher in hotspot countries (5.3% and 6.1%) than in non-hotspot countries (3.5% and 4.3%); however, the annual growth rate of per capita roundwood production in hotspot countries (1%) was lower than in non hotspot countries (1.4%). The dependence of humans on cultural services has increased more rapidly than on regulating services, while the dependence on provisioning services has reduced. This pattern is projected to continue during 2005-2020. Our preliminary results show that economic growth has actually made humans more dependent upon ecosystem services and biodiversity. As a consequence, the policies and implementations of both economic development and ecosystems/biodiversity conservation should be formulated and carried out in the context of the increased dependence of humans on ecosystem services along with economic development. PMID- 20957043 TI - Use of ITS2 region as the universal DNA barcode for plants and animals. AB - BACKGROUND: The internal transcribed spacer 2 (ITS2) region of nuclear ribosomal DNA is regarded as one of the candidate DNA barcodes because it possesses a number of valuable characteristics, such as the availability of conserved regions for designing universal primers, the ease of its amplification, and sufficient variability to distinguish even closely related species. However, a general analysis of its ability to discriminate species in a comprehensive sample set is lacking. METHODOLOGY/PRINCIPAL FINDINGS: In the current study, 50,790 plant and 12,221 animal ITS2 sequences downloaded from GenBank were evaluated according to sequence length, GC content, intra- and inter-specific divergence, and efficiency of identification. The results show that the inter-specific divergence of congeneric species in plants and animals was greater than its corresponding intra specific variations. The success rates for using the ITS2 region to identify dicotyledons, monocotyledons, gymnosperms, ferns, mosses, and animals were 76.1%, 74.2%, 67.1%, 88.1%, 77.4%, and 91.7% at the species level, respectively. The ITS2 region unveiled a different ability to identify closely related species within different families and genera. The secondary structure of the ITS2 region could provide useful information for species identification and could be considered as a molecular morphological characteristic. CONCLUSIONS/SIGNIFICANCE: As one of the most popular phylogenetic markers for eukaryota, we propose that the ITS2 locus should be used as a universal DNA barcode for identifying plant species and as a complementary locus for CO1 to identify animal species. We have also developed a web application to facilitate ITS2-based cross-kingdom species identification (http://its2-plantidit.dnsalias.org). PMID- 20957044 TI - Increased ROS production: a component of the longevity equation in the male mygalomorph, Brachypelma albopilosa. AB - BACKGROUND: The diversity of longevities encountered in wildlife is one of the most intriguing problems in biology. Evolutionary biologists have proposed different theories to explain how longevity variability may be driven by bad genes expression in late life or by gene pleiotropic effects. This reflexion has stimulated, in the last ten years, an active research on the proximal mechanisms that can shape lifespan. Reactive oxygen species (ROS), i.e., the by-products of oxidative metabolism, have emerged as the main proximate cause of ageing. Because ROS are mainly produced by the mitochondria, their production is linked to metabolic rate, and this may explain the differences in longevity between large and small species. However, their implication in the sex difference in longevity within a species has never been tested, despite the fact that these differences are widespread in the animal kingdom. METHODOLOGY/PRINCIPAL FINDINGS: Mitochondrial superoxide production of hemolymph immune cells and antioxidant and oxidative damages plasma levels were measured in adult male and female B. albopilosa at different ages. We found that female spiders are producing less mitochondrial superoxide, are better protected against oxidative attack and are then suffering less oxidative damages than males at adulthood. CONCLUSIONS/SIGNIFICANCE: In tarantulas, once reaching sexual maturity, males have a life expectancy reduced to 1 to 2 years, while females can still live for 20 years, in spite of the fact that females continue to grow and moult. This study evidences an increased exposure of males to oxidative stress due to an increase in mitochondrial superoxide production and a decrease in hemolymph antioxidant defences. Such a phenomenon is likely to be part of the explanation for the sharp reduction of longevity accompanying male tarantula maturity. This opens several fundamental research roads in the future to better understand how reproduction and longevity are linked in an original ageing model. PMID- 20957045 TI - Insight into antigenic diversity of VAR2CSA-DBL5epsilon domain from multiple Plasmodium falciparum placental isolates. AB - BACKGROUND: Protection against pregnancy associated malaria (PAM) is associated with high levels of anti-VAR2CSA antibodies. This protection is obtained by the parity dependent acquisition of anti-VAR2CSA antibodies. Distinct parity associated molecular signatures have been identified in VAR2CSA domains. These two observations combined point to the importance of identifying VAR2CSA sequence variation, which facilitate parasitic evasion or subversion of host immune response. Highly conserved domains of VAR2CSA such as DBL5epsilon are likely to contain conserved epitopes, and therefore do constitute attractive targets for vaccine development. METHODOLOGY/PRINCIPAL FINDINGS: VAR2CSA DBL5epsilon-domain sequences obtained from cDNA of 40 placental isolates were analysed by a combination of experimental and in silico methods. Competition ELISA assays on two DBL5epsilon variants, using plasma samples from women from two different areas and specific mice hyperimmune plasma, indicated that DBL5epsilon possess conserved and cross-reactive B cell epitopes. Peptide ELISA identified conserved areas that are recognised by naturally acquired antibodies. Specific antibodies against these peptides labelled the native proteins on the surface of placental parasites. Despite high DBL5epsilon sequence homology among parasite isolates, sequence analyses identified motifs in DBL5epsilon that discriminate parasites according to donor's parity. Moreover, recombinant proteins of two VAR2CSA DBL5epsilon variants displayed diverse recognition patterns by plasma from malaria-exposed women, and diverse proteoglycan binding abilities. CONCLUSIONS/SIGNIFICANCE: This study provides insights into conserved and exposed B cell epitopes in DBL5epsilon that might be a focus for cross reactivity. The importance of sequence variation in VAR2CSA as a critical challenge for vaccine development is highlighted. VAR2CSA conformation seems to be essential to its functionality. Therefore, identification of sequence variation sites in distinct locations within VAR2CSA, affecting antigenicity and/or binding properties, is critical to the effort of developing an efficient VAR2CSA-based vaccine. Motifs associated with parasite segregation according to parity constitute one such site. PMID- 20957046 TI - The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor. AB - BACKGROUND: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxicity and biological activity of dioxins and related chemicals. The AhR influences a variety of processes involved in cellular growth and differentiation, and recent studies have suggested that the AhR is a potential target for immune-mediated diseases. METHODOLOGY/PRINCIPAL FINDINGS: During a screen for molecules that activate the AhR, leflunomide, an immunomodulatory drug presently used in the clinic for the treatment of rheumatoid arthritis, was identified as an AhR agonist. We aimed to determine whether any biological activity of leflunomide could be attributed to a previously unappreciated interaction with the AhR. The currently established mechanism of action of leflunomide involves its metabolism to A771726, possibly by cytochrome P450 enzymes, followed by inhibition of de novo pyrimidine biosynthesis by A771726. Our results demonstrate that leflunomide, but not its metabolite A771726, caused nuclear translocation of AhR into the nucleus and increased expression of AhR-responsive reporter genes and endogenous AhR target genes in an AhR-dependent manner. In silico Molecular Docking studies employing AhR ligand binding domain revealed favorable binding energy for leflunomide, but not for A771726. Further, leflunomide, but not A771726, inhibited in vivo epimorphic regeneration in a zebrafish model of tissue regeneration in an AhR dependent manner. However, suppression of lymphocyte proliferation by leflunomide or A771726 was not dependent on AhR. CONCLUSIONS: These data reveal that leflunomide, an anti-inflammatory drug, is an agonist of the AhR. Our findings link AhR activation by leflunomide to inhibition of fin regeneration in zebrafish. Identification of alternative AhR agonists is a critical step in evaluating the AhR as a therapeutic target for the treatment of immune disorders. PMID- 20957047 TI - Casein kinase 2 dependent phosphorylation of neprilysin regulates receptor tyrosine kinase signaling to Akt. AB - Neprilysin (NEP) is a type II membrane metalloproteinase that cleaves physiologically active peptides at the cell surface thus regulating the local concentration of these peptides available for receptor binding and signal transduction. In addition, the cytoplasmic N-terminal domain of NEP interacts with the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) thereby regulating intracellular signaling via Akt. Thus, NEP serves dual functions in extracellular and intracellular signal transduction. Here, we show that NEP undergoes phosphorylation at serine residue 6 within the N-terminal cytoplasmic domain. In vitro and cell culture experiments demonstrate that Ser 6 is efficiently phosphorylated by protein kinase CK2. The phosphorylation of the cytoplasmic domain of NEP inhibits its interaction with PTEN. Interestingly, expression of a pseudophosphorylated NEP variant (Ser6Asp) abrogates the inhibitory effect of NEP on insulin/insulin-like growth factor-1 (IGF-1) stimulated activation of Akt. Thus, our data demonstrate a regulatory role of CK2 in the interaction of NEP with PTEN and insulin/IGF-1 signaling. PMID- 20957048 TI - Setup of an in vitro test system for basic studies on biofilm behavior of mixed species cultures with dental and periodontal pathogens. AB - BACKGROUND: Caries and periodontitis are important human diseases associated with formation of multi-species biofilms. The involved bacteria are intensively studied to understand the molecular basis of the interactions in such biofilms. This study established a basic in vitro single and mixed-species culture model for oral bacteria combining three complimentary methods. The setup allows a rapid screening for effects in the mutual species interaction. Furthermore, it is easy to handle, inexpensive, and reproducible. METHODS: Streptococcus mitis, S. salivarius and S. sanguinis, typical inhabitants of the healthy oral cavity, S. mutans as main carriogenic species, and Porphyromonas gingivalis, Fusobacterium nucleatum, Parvimonas micra, S. intermedius and Aggregatibacter actinomycetemcomitans as periodontitis-associated bacteria, were investigated for their biofilm forming ability. Different liquid growth media were evaluated. Safranin-staining allowed monitoring of biofilm formation under the chosen conditions. Viable counts and microscopy permitted investigation of biofilm behavior in mixed-species and transwell setups. FINDINGS: S. mitis, F. nucleatum, P. gingivalis and P. micra failed to form biofilm structures. S. mutans, S. sanguinis, S. intermedius and S. salivarius established abundant biofilm masses in CDM/sucrose. A. actinomycetemcomitans formed patchy monolayers. For in depth analysis S. mitis, S. mutans and A. actinomycetemcomitans were chosen, because i) they are representatives of the physiological-, cariogenic and periodontitis associated bacterial flora, respectively and ii) their difference in their biofilm forming ability. Microscopic analysis confirmed the results of safranin staining. Investigation of two species combinations of S. mitis with either S. mutans or A. actinomycetemcomitans revealed bacterial interactions influencing biofilm mass, biofilm structure and cell viability. CONCLUSIONS: This setup shows safranin staining, microscopic analysis and viable counts together are crucial for basic examination and evaluation of biofilms. Our experiment generated meaningful results, exemplified by the noted S. mitis influence, and allows a fast decision about the most important bacterial interactions which should be investigated in depth. PMID- 20957049 TI - A rapid murine coma and behavior scale for quantitative assessment of murine cerebral malaria. AB - BACKGROUND: Cerebral malaria (CM) is a neurological syndrome that includes coma and seizures following malaria parasite infection. The pathophysiology is not fully understood and cannot be accounted for by infection alone: patients still succumb to CM, even if the underlying parasite infection has resolved. To that effect, there is no known adjuvant therapy for CM. Current murine CM (MCM) models do not allow for rapid clinical identification of affected animals following infection. An animal model that more closely mimics the clinical features of human CM would be helpful in elucidating potential mechanisms of disease pathogenesis and evaluating new adjuvant therapies. METHODOLOGY/PRINCIPAL FINDINGS: A quantitative, rapid murine coma and behavior scale (RMCBS) comprised of 10 parameters was developed to assess MCM manifested in C57BL/6 mice infected with Plasmodium berghei ANKA (PbA). Using this method a single mouse can be completely assessed within 3 minutes. The RMCBS enables the operator to follow the evolution of the clinical syndrome, validated here by correlations with intracerebral hemorrhages. It provides a tool by which subjects can be identified as symptomatic prior to the initiation of trial treatment. CONCLUSIONS/SIGNIFICANCE: Since the RMCBS enables an operator to rapidly follow the course of disease, label a subject as affected or not, and correlate the level of illness with neuropathologic injury, it can ultimately be used to guide the initiation of treatment after the onset of cerebral disease (thus emulating the situation in the field). The RMCBS is a tool by which an adjuvant therapy can be objectively assessed. PMID- 20957050 TI - uFBI: a microfluidic bead-based immunoassay for multiplexed detection of proteins from a uL sample volume. AB - BACKGROUND: Over the last ten years, miniaturized multiplexed immunoassays have become robust, reliable research tools that enable researchers to simultaneously determine a multitude of parameters. Among the numerous analytical protein arrays available, bead-based assay systems have evolved into a key technology that enables the quantitative protein profiling of biological samples whilst requiring only a minimal amount of sample material. METHODOLOGY/PRINCIPAL FINDINGS: A microfluidic bead-based immunoassay, uFBI, was developed to perform bead-based multiplexed sandwich immunoassays in a capillary. This setup allows the simultaneous detection of several parameters and only requires 200 ng of tissue lysate in a 1 uL assay volume. In addition, only 1 uL of detection antibodies and 1 uL of the reporter molecule Streptavidin-Phycoerythrin were required. The uFBI was used to compare the expression of seven receptor tyrosine kinases and their degree of tyrosine phosphorylation in breast cancer tissue and in normal tissue lysates. The total amount of HER-2, as well the degree of tyrosine phosphorylation was much higher in breast cancer tissue than in normal tissue. uFBI and a standard bead-based assay led to identical protein expression data. Moreover, it was possible to reduce the quantity of sample material required by a factor of 100 and the quantity of reagents by a factor of 30. CONCLUSIONS/SIGNIFICANCE: The uFBI, microfluidic bead-based immunoassay, allows the analysis of multiple parameters from a very small amount of sample material, such as tumor biopsies or tissue sections. PMID- 20957051 TI - Gene Variant of the Bradykinin B2 Receptor Influences Pulmonary Arterial Pressures in Heart Failure Patients. AB - BACKGROUND: Pulmonary arterial pressure (PAP) varies considerably in heart failure (HF) despite similar degrees of left ventricular (LV) dysfunction. Bradykinin alters vascular tone and common variations in the kinin B2 receptor (BDKRB2) gene exists. We hypothesized that genetic variation in this receptor would influence PAP in HF. METHODS: 131 HF patients (>1yr history systolic HF), without COPD, not currently smoking, BMI < 40, without atrial fibrillation completed the study which included a blood draw for genotyping and neurohormones (ACE, A-II, Bradykinin, ANP, BNP, and catecholamines), an echocardiogram for cardiac function and systolic PAP (PAPsys). RESULTS: Mean LVEF was 29% +/- 12%, NYHA class 2 +/- 1, age 56 +/- 12 yr, BMI 28 +/- 5 kg/m(2). Forty-six patients (35%) were homozygous for the +9 allele, 58 (44%) were heterozygous (+9/-9) and 27 (21%) were homozygous for the -9 allele of the BDKRB2. PAPsys averaged 42 +/- 13, 38 +/- 12, and 35 +/- 11 mmHg for +9/+9, +9/-9 and -9/-9, respectively (p = 0.03). There was a trend towards gene effect for plasma ACE with the highest values in +9/+9 and lowest in -9/-9 patients (9.5 +/- 10.7, 7.1 +/- 8.7, and 5.4 +/- 6.4 U/L, respectively, p = 0.06). There were no differences in plasma bradykinin or A-II, LVEF, or NYHA across genotypes. CONCLUSION: These data suggest the +9/+9 polymorphism of the BDKRB2 receptor influences pulmonary vascular tone in stable HF. PMID- 20957052 TI - Choroidal osteoma with choroidal neovascular membrane: Successful treatment with intravitreal bevacizumab. AB - An otherwise healthy 27-year-old woman presented with complaints of sudden painless blurred vision in the right eye for one week. On examination, visual acuity was 20/30 in the right eye and 20/20 in left eye. Fundus examination OS was normal, but OD demonstrated an elevated, opaque, yellowish parapapillary choroidal lesion with grayish membrane associated with minimal subretinal fluid, suggestive of a choroidal neovascular membrane in the center. B-scan ultrasonography revealed findings consistent with a choroidal osteoma. Fundus fluorescein angiography of the right eye revealed a relatively well defined area of hyperfluorescence that increased in size and intensity in the later phases, suggestive of active extrafoveal choroidal neovascular membrane. Optical coherence tomography confirmed the extrafoveal choroidal neovascular membrane with subfoveal fluid. She was treated with intravitreal bevacizumab OD. At the two-week visit, vision OD improved to 20/20. Fluorescein angiography and optical coherence tomography revealed a resolved choroidal neovascular membrane. Intravitreal bevacizumab may be an effective alternative in the management of choroidal neovascular membrane secondary to choroidal osteoma. PMID- 20957053 TI - Bilateral sporadic aniridia: review of management. AB - PURPOSE: To report a rare case of bilateral sporadic aniridia in an African child and review the management modalities. PRESENTATION: We report a case of bilateral sporadic aniridia with horizontal nystagmus, axial cataract optic disc, and fovea hypoplasia in a 5-year-old female patient. She was managed conservatively. Various modalities of treatment are reviewed. PMID- 20957054 TI - Feasibility of motivational interviewing delivered by a glaucoma educator to improve medication adherence. AB - INTRODUCTION: Adherence to glaucoma treatment is poor, potentially reducing therapeutic effects. A glaucoma educator was trained to use motivational interviewing (MI), a patient-centered counseling style, to improve adherence. This study was designed to evaluate whether MI was feasible in a busy ophthalmology practice. METHODS: Feasibility was assessed using five criteria from the National Institutes of Health Behavior Change consortium: fidelity of intervention components to MI theory; success of the training process; delivery of MI-consistent interventions by the glaucoma educator; patient receipt of the intervention based on enrollment, attrition, and satisfaction; and patient enactment of changes in motivation and adherence over the course of the intervention. RESULTS: A treatment manual was designed by a multidisciplinary team with expertise in health psychology, public health, and ophthalmology. The glaucoma educator received 6 hours of training including role-play exercises, self-study, and individual supervision. His MI-related knowledge and skills increased following training, and he delivered exclusively MI-consistent interventions in 66% of patient encounters. 86% (12/14) of eligible patients agreed to be randomized into glaucoma educator support or a control condition. All 8 patients assigned to the glaucoma educator completed at least 2 of 6 planned contacts, and 50% (4/8) completed all 6 contacts. Patients assigned to the glaucoma educator improved over time in both motivation and adherence. CONCLUSION: The introduction of a glaucoma educator was feasible in a busy ophthalmology practice. Patients improved their adherence while participating in the glaucoma educator program, although this study was not designed to show a causal effect. The use of a glaucoma educator to improve glaucoma patients' medication adherence may be feasible at other ophthalmology clinics, and can be implemented with a standardized training approach. Pilot data show the intervention can be implemented with fidelity, is acceptable to patients and providers, and has the potential to improve adherence. PMID- 20957055 TI - Surgical treatment of a transorbital penetrating brain injury. AB - Penetrating injury of the skull and brain are relatively uncommon events, representing about 0.4% of all head injuries. Transorbital penetrating brain injury is an unusual occurrence in emergency practice and presents with controversial management. We report the case of a 10-year-old boy who fell forward on a bamboo stick while playing with other children, causing a penetrating transorbital injury, resulting in meningitis. We performed a combined surgical approach with neurosurgeons and ophthalmogic surgeons. Upon discharge, the patient had a Glasgow Coma Scale score of 15, no motor deficit and no visual loss. We discuss the management of this case and review current literature. PMID- 20957056 TI - Relaxing retinotomies and retinectomies in the management of retinal detachment with severe proliferative vitreoretinopathy (PVR). AB - Relaxing retinotomies and retinectomies are used in the presence of retinal shortening resulting from retinal incarceration or fibrous proliferation and contraction that prevents contact of the retina with the retinal pigment epithelium. The peripheral retina is usually cut or excised to preserve function of the posterior retina which is more visually significant. OBJECTIVE: To investigate the techniques, therapeutic effects, indications, and complications of relaxing retinotomies and retinectomies for complicated retinal detachment with severe proliferative vitreoretinopathy (PVR). METHODS: Thirty eight eyes of 38 patients of complicated retinal detachment with severe PVR were recruited for a noncomparative retrospective study. They were operated on and followed-up for at least six months. The operative technique included buckling, vitrectomy, peeling, relaxing retinotomy and/or retinectomy, intraocular tamponade, and laser treatment. RESULTS: Retina was reattached in 34 (89.5%) eyes in operations. Retinal detachment was recurrent in seven eyes in follow-up, in which the retina was reattached again in two eyes by a second operation. The final success rate was 76.3% (29 eyes out of 38 eyes). Visual acuity was perception of light with bad projection in 35 (92%) eyes and hand motion in three (8%) eyes before operation. Visual acuity was better than 4/60 in 23 eyes (60.5%) after operation. The complications included iatrogenic retinal breaks, bleeding from the retinotomy site, hypotony, and recurrent fibrous proliferation from the retinotomy site. CONCLUSION: Retinotomy and retinectomy can improve the curative effect of complicated retinal detachment. There are potentially serious complications of these maneuvers and they should not be performed if less aggressive measures will suffice. PMID- 20957057 TI - Transient tractional retinal detachment in an eye with retinitis pigmentosa. AB - We present a case of retinitis pigmentosa with vitreoretinal traction-associated retinal detachment. The retinal detachment was detected in the nasal periphery. No retinal breaks and no active vascular leakage were observed by fundus scopy and fluorescein angiography, respectively. However, 8 months later, the tractional retinal detachment was spontaneously resolved with posterior vitreous detachment. PMID- 20957058 TI - Dose uniformity of topical corticosteroid preparations: difluprednate ophthalmic emulsion 0.05% versus branded and generic prednisolone acetate ophthalmic suspension 1%. AB - PURPOSE: To compare the dose uniformity of difluprednate ophthalmic emulsion 0.05% (Durezol((r))) with both branded and generic prednisolone acetate ophthalmic suspension 1% under different simulated patient usage conditions. METHODS: Drug concentrations of difluprednate emulsion, branded prednisolone acetate suspension (Pred Forte((r))) and generic prednisolone acetate suspension following three storage conditions (upright, then shaken; upright, not shaken; inverted, not shaken) were analyzed by high performance liquid chromatography assay and results were reported as percent of declared concentration. Two drops were dispensed every four hours four times daily. RESULTS: Regardless of bottle orientation and shaking, all difluprednate emulsion concentrations at each time point analyzed were within 15% of declared concentration. Both branded and generic prednisolone acetate suspension concentrations varied substantially throughout the study. For the bottle stored upright and not shaken, 46% of the branded concentrations were not within 15% of declared concentration; for the bottle stored upright and shaken prior to use, 60% failed to meet this criterion. None of the branded concentrations from the inverted and not shaken bottle was within 15% of declared concentration. Generic prednisolone concentrations demonstrated the poorest dose uniformity, with 96% of the concentrations from the inverted and not shaken bottle not within 15% of declared concentration; 94% of the concentrations from the upright and shaken bottle and 87% from the upright and not shaken bottle similarly failed to meet this criterion. CONCLUSIONS: Dose uniformity of Durezol emulsion was predictable in all simulated patient usage conditions, whereas the drop concentrations of Pred Forte and generic prednisolone acetate suspensions were highly variable throughout the study. Drop concentrations are more predictable with Durezol emulsion than with either prednisolone acetate suspension. PMID- 20957059 TI - Fixed combination of bimatoprost and timolol in patients with primary open-angle glaucoma or ocular hypertension with inadequate IOP adjustment. AB - OBJECTIVE: To assess the efficacy and tolerability of a fixed combination of bimatoprost and timolol (BTFC) in a large patient sample in a clinical setting. METHODS: In this multicenter, observational, noncontrolled, open-label study, patients (n = 1862) with primary open-angle glaucoma or ocular hypertension were treated with BTFC. Assessments were made at baseline, six weeks, and three months. RESULTS: Prior to starting BTFC, 92.3% of patients were taking other ocular hypotensive medications. In the overall group at three months, mean intraocular pressure was reduced from baseline (21.7 +/- 4.5 mmHg and 21.8 +/- 4.9 mmHg for the right and left eye, respectively) to 16.1 +/- 3.0 mmHg for each eye (P < 0.0001). The majority of patients (92%) reported no adverse events. The most commonly reported adverse events (in >1% of patients) were eye irritation, and ocular and conjunctival hyperemia. Adherence to treatment was generally better than (35.4%) or the same as (57.5%) with prior therapy. BTFC tolerability was rated as excellent or good by 92.3% of physicians and 85.8% of patients. CONCLUSIONS: In a large group of patients with primary open-angle glaucoma or ocular hypertension, treatment with BTFC was associated with consistent reductions in IOP, improved adherence to treatment, and good tolerability. PMID- 20957060 TI - Paired-eye comparison of medical therapies for glaucoma. AB - OBJECTIVE: To evaluate efficacy and patient preference retrospectively among intraocular pressure (IOP)-lowering prostamide and prostaglandin medications in a real-world clinical setting. METHODS: Chart review of patients with uncontrolled glaucoma or ocular hypertension seen at a private practice clinic (n = 55) who received bimatoprost 0.03% once daily in one eye and either travoprost 0.004% or latanoprost 0.005% once daily in the fellow eye. IOP was evaluated at the initial visit and at a follow-up visit scheduled 4-6 weeks later. At the follow-up visit, each patient discussed the clinical results with their physician, chose which medication they preferred to continue using, and were queried regarding the reason for their choice. This paired-eye comparison method is used routinely in clinical practice to assess clinical response and involve patients in decisions regarding treatment. Change in mean IOP from baseline and patient medication choice were the outcome measures. RESULTS: Bimatoprost-treated eyes (n = 52) had a mean IOP reduction of 2.7 mmHg and travoprost-treated eyes (n = 47) had an average decrease of 1.7 mmHg (P = 0.230). Bimatoprost significantly reduced mean IOP (from 19.8 mmHg at baseline to 17.1 mmHg at follow-up, P < 0.0001), as did travoprost (from 19.4 mmHg at baseline to 17.7 mmHg at follow-up, P = 0.009). Latanoprost-treated eyes were excluded from the efficacy analysis due to small sample size (n = 5). For continued therapy, patients chose bimatoprost over travoprost by a factor of 2.4 to 1. Of the 15 patients who gave a reason for their choice, 80% said their decision was based primarily on IOP change. CONCLUSIONS: Bimatoprost and travoprost were efficacious in reducing IOP among patients with uncontrolled glaucoma and ocular hypertension. Patients preferred bimatoprost over travoprost when trialed in fellow eyes. PMID- 20957061 TI - Two-year treatment patterns and costs in glaucoma patients initiating treatment with prostaglandin analogs. AB - OBJECTIVE: To determine treatment patterns and costs over a two-year period among new initiators of topical prostaglandin analogs in a managed care population by retrospective cohort analysis of an insurance claims database. METHODS: Patients who initiated therapy with a prostaglandin analog between September 2006 and March 2007 were identified. The use of monotherapy and adjunctive therapies were compared by index prostaglandin. Days to initiation of adjunctive therapy and rates of glaucoma surgical procedures were also calculated. Medical costs (antiglaucoma medications and ophthalmic visits) over the two-year period were estimated. RESULTS: The analysis identified 5018 patients with at least one prostaglandin analog prescription (bimatoprost, n = 747; latanoprost, n = 1651; benzalkonium chloride (BAK)-free travoprost, n = 203). The majority (51%-54%) had repeat prescriptions. Among those with repeat prescriptions, 52% were female (not significant) and mean age was 64 years (P < 0.01). Rates of adjunctive therapy use varied across groups (bimatoprost 51%, latanoprost 37%, and BAK- free travoprost 35%, P < 0.0001). Median and mean days to initiation of adjunctive therapy were 83 and 140 for bimatoprost, 101 and 181 for latanoprost, and 113 and 221 for BAK- free travoprost. Two-year medical costs were $3147, $2843, and $2557 for patients initiating treatment with bimatoprost, latanoprost, and BAK-free travoprost, respectively. Use of glaucoma surgical procedures across the treatment groups was similar over the two-year period. CONCLUSIONS: Over a two year period, the rate and time to initiation of adjunctive therapy use, as well as medical costs, varied between index prostaglandins. However, the rate of glaucoma surgical interventions did not vary significantly across index medications. PMID- 20957062 TI - Enucleation following treatment with intravenous pentamidine for Acanthamoeba sclerokeratitis. AB - PURPOSE: To describe the course and outcome of treatment of advanced Acanthamoeba sclerokeratitis with intravenous pentamidine. METHODS: A case of advanced Acanthamoeba sclerokeratitis was resistant to conventional therapy and was treated with intravenous pentamidine. The eye was later removed due to incapacitating pain. RESULTS: The eye showed Acanthamoeba organisms within the cornea and evidence of acute and chronic inflammation throughout the remainder of the eye. The patient has survived without orbital recurrence for 2 years. CONCLUSIONS: This case demonstrates late inflammation with active Acanthameoba keratitis following systemic pentamidine therapy. PMID- 20957063 TI - Indicators of Self-rated Driving across 3 Years among a Community-based Sample of Older Adults. AB - These secondary analyses were conducted to identify predictors of self-rated driving ability over three years in community-dwelling older adults. From the Staying Keen in Later Life (SKILL) study, baseline and 3-year follow-up data for 426 older drivers were analyzed. Health, visual, physical, psychological and cognitive abilities were examined as prospective predictors of self-rated driving ability over a 3-year period, controlling for baseline self-rated driving. Results indicated that lower baseline ratings of self-efficacy and a diagnosis of osteoporosis independently predicted lower self-rated driving ability at 3-year follow-up. Interestingly, functional performance, such as visual, physical and cognitive abilities, were not predictive of self-ratings of driving ability across three years. Older drivers' self-ratings are more reflective of perceived self-efficacy rather than functional abilities. Self-screening tools for older drivers may be effective in improving the correspondence between perceived ability and actual ability in order to promote better informed decisions about driving regulation. PMID- 20957064 TI - A model for Structure and Thermodynamics of ssDNA and dsDNA Near a Surface: a Coarse Grained Approach. AB - New methods based on surfaces or beads have allowed measurement of properties of single DNA molecules in very accurate ways. Theoretical coarse grained models have been developed to understand the behavior of single stranded and double stranded DNA. These models have been shown to be accurate and relatively simple for very short systems of 6-8 base pairs near surfaces. Comparatively less is known about the influence of a surface on the secondary structures of longer molecules important to many technologies. Surface fields due to either applied potentials and/or dielectric boundaries are not in current surface mounted coarse grained models. To gain insight into longer and surface mounted sequences we parameterized a discretized worm-like chain model. Each link is considered a sphere of 6 base pairs in length for dsDNA, and 1.5 bases for ssDNA (requiring an always even number of spheres). For this demonstration of the model, the chain is tethered to a surface by a fixed length, non-interacting 0.536 nm linker. Configurational sampling was achieved via Monte-Carlo simulation. Our model successfully reproduces end to end distance averages from experimental results, in agreement with polymer theory and all atom simulations. Our average tilt results are also in agreement with all atom simulations for the case of dense systems. PMID- 20957065 TI - A new perspective on in vitro assessment method for evaluating quantum dot toxicity by using microfluidics technology. AB - In this study, we demonstrate a new perspective on in vitro assessment method for evaluating quantum dot (QD) toxicity by using microfluidics technology. A new biomimetic approach, based on the flow exposure condition, was applied in order to characterize the cytotoxic potential of QD. In addition, the outcomes obtained from the flow exposure condition were compared to those of the static exposure condition. An in vitro cell array system was established that used an integrated multicompartmented microfluidic device to develop a sensitive flow exposure condition. QDs modified with cetyltrimethyl ammonium bromide/trioctylphosphine oxide were used for the cytotoxicity assessment. The results suggested noticeable differences in the number of detached and deformed cells and the viability percentages between two different exposure conditions. The intracellular production of reactive oxygen species and release of cadmium were found to be the possible causes of QD-induced cytotoxicity, irrespective of the types of exposure condition. In contrast to the static exposure, the flow exposure apparently avoided the gravitational settling of particles and probably assisted in the homogeneous distribution of nanoparticles in the culture medium during exposure time. Moreover, the flow exposure condition resembled in vivo physiological conditions very closely, and thus, the flow exposure condition can offer potential advantages for nanotoxicity research. PMID- 20957066 TI - Long-period fiber gratings spontaneously written by a mechanism markedly different from Hill grating formation. AB - Pumping a nonlinear germanosilicate fiber with intense near-infrared femtosecond laser pulses for supercontinuum generation may invoke multiphoton-assisted photosensitivity of glasses to write a long-period fiber grating. In sharp contrast to the spontaneous formation of a Hill grating that resonates with the writing wavelength through first-order diffraction, the long-period fiber grating resonates with the writing wavelength through second-order diffraction. This finding highlights the surprising light-matter interaction in a waveguide. PMID- 20957067 TI - Multicolor fluorescence enhancement from a photonics crystal surface. AB - A photonic crystal substrate exhibiting resonant enhancement of multiple fluorophores has been demonstrated. The device, fabricated uniformly from plastic materials over a ~3*5 in.(2) surface area by nanoreplica molding, utilizes two distinct resonant modes to enhance electric field stimulation of a dye excited by a lambda=632.8 nm laser (cyanine-5) and a dye excited by a lambda=532 nm laser (cyanine-3). Resonant coupling of the laser excitation to the photonic crystal surface is obtained for each wavelength at a distinct incident angle. Compared to detection of a dye-labeled protein on an ordinary glass surface, the photonic crystal surface exhibited a 32* increase in fluorescent signal intensity for cyanine-5 conjugated streptavidin labeling, while a 25* increase was obtained for cyanine-3 conjugated streptavidin labeling. The photonic crystal is capable of amplifying the output of any fluorescent dye with an excitation wavelength in the 532 nm=16 at baseline, 79.5% and 66.9% of subjects presented with prominent manic and depressive symptoms, respectively, and 46.4% presented with mixed symptoms. Approximately half (45%) of subjects were taking adjunctive mood stabilizers and/or antidepressants. Paliperidone ER was found to be effective in improving psychotic and mood symptoms in these subjects. Paliperidone ER was also effective as monotherapy or adjunctive to mood stabilizers and/or antidepressants for subjects with prominent manic, depressive, or mixed symptoms at baseline. No new tolerability signals were observed in this population. To the best of our awareness, these pooled data provide the largest data set of patients with schizoaffective disorder, and extend our knowledge of disease characteristics and treatment response. PMID- 20957128 TI - Lifestyle diseases and cardiovascular risk factors are interrelated to deficiencies of major substrates in ATP synthesis. AB - Recent studies on diabetes and metabolic syndrome indicate a common disturbance of inorganic phosphate (Pi) metabolism. Pi is an important substrate in the formation of adenosine triphosphate (ATP), and many lifestyle diseases and cardiovascular risk factors similarly show deficiencies in either 1 or 2 major components of ATP synthesis. Age, male gender, hypertension, obesity, hypertriglyceridemia, metabolic syndrome, and diabetes mellitus are all associated with hypophosphatemia. In addition, tobacco smoking, hyperchylomicronemia, hypertension, and diabetes may involve defects in tissue oxygen delivery. Hypophosphatemia may lead to a critical decrease in intracellular Pi and to mitochondrial dysfunction, which might be counter-acted by the pharmacological use of fructose 1,6-diphosphate. PMID- 20957129 TI - Screening for type 2 diabetes in a multiethnic setting using known risk factors to identify those at high risk: a cross-sectional study. AB - INTRODUCTION: Screening enables the identification of type 2 diabetes mellitus (T2DM) during its asymptomatic stage and therefore allows early intervention which may lead to fewer complications and improve outcomes. A targeted screening program was carried out in a United Kingdom (UK) multiethnic population to identify those with abnormal glucose tolerance. METHODS: A sample of individuals aged 25-75 years (40-75 white European) with at least one risk factor for T2DM were invited for screening from 17 Leicestershire (UK) general practices or through a health awareness campaign. All participants received a 75 g oral glucose tolerance test, cardiovascular risk assessment, detailed medical and family histories and anthropometric measurements. RESULTS: In the 3,225 participants who were screened. 640 (20%) were found to have some form of abnormal glucose tolerance of whom 4% had T2DM, 3% impaired fasting glucose (IFG), 10% impaired glucose tolerance (IGT) and 3% both IFG and IGT. The odds of detecting IGT was approximately 60% greater (confounder-adjusted odds ratios [OR] 1.67 [1.22-2.29]) in the South Asian population. CONCLUSIONS: Around one in five people who had targeted screening have IGT, IFG or T2DM, with a higher prevalence in those of South Asian origin. The prevalence of undetected T2DM is lower in South Asians compared to previously published studies and maybe due to increased awareness of this group being at high risk. PMID- 20957130 TI - Benefits of statin therapy and compliance in high risk cardiovascular patients. AB - Cardiovascular disease (CVD) remains the top cause of global mortality. There is considerable evidence that supports the mortality and morbidity benefit of statin therapy in coronary heart disease (CHD) and stroke, both in primary and secondary prevention settings. Data also exist pointing to the advantage of statin treatment in other high-risk CVD conditions, such as diabetes, CKD, CHF, and PVD. National and international clinical guidelines in the management of these CVD conditions all advocate for the utilization of statin therapy in appropriate patients. However, overall compliance to statin therapy remains suboptimal. Patient-, physician-, and economic-related factors all play a role. These factors need to be considered in devising approaches to enhance adherence to guideline based therapies. To fully reap the benefits of statin therapy, interventions which improve long-term treatment compliance in real-world settings should be encouraged. PMID- 20957131 TI - Prevention of the renarrowing of coronary arteries using drug-eluting stents in the perioperative period: an update. AB - The management of patients scheduled for surgery with a coronary stent, and receiving 1 or more antiplatelet drugs, has many controversies. The premature discontinuation of antiplatelet drugs substantially increases the risk of stent thrombosis (ST), myocardial infarction, and cardiac death, and surgery under an altered platelet function could also lead to an increased risk of bleeding in the perioperative period. Because of the conflict in the recommendations, this article reviews the current antiplatelet protocols after positioning a coronary stent, the evidence of increased risk of ST associated with the withdrawal of antiplatelet drugs and increased bleeding risk associated with its maintenance, the different perioperative antiplatelet protocols when patients are scheduled for surgery or need an urgent operation, and the therapeutic options if excessive bleeding occurs. PMID- 20957132 TI - New class of agents for treatment of hypertension: focus on direct renin inhibition. AB - Aliskiren, the first orally active direct renin inhibitor, is an effective antihypertensive drug with distinctive characteristics, including good blockade of the renin-angiotensin system, a prolonged duration of action, pharmacologic effects that persist after drug discontinuation, and favorable tolerability comparable with placebo. The blood pressure-lowering effect of aliskiren monotherapy is similar, if not superior, to that of other first-line antihypertensive agents, and is greatly enhanced when aliskiren is combined with various other antihypertensive medications, without any adverse drug interactions. Aliskiren is also an effective and well tolerated therapy in special populations, including diabetic, obese, and elderly hypertensives. Beyond its blood pressure-lowering efficacy, results from experimental and clinical trials suggest that aliskiren has positive effects on markers of cardiovascular and renal damage. The ASPIRE (Aliskiren Study in Post-MI patients to Reduce rEmodelling) HIGHER clinical trials program is further assessing whether the promising pharmacologic properties of aliskiren translate into reduced risk of adverse cardiovascular and renal outcomes. PMID- 20957133 TI - Costs and outcomes of noncardioembolic ischemic stroke in a managed care population. AB - PURPOSE: To evaluate the clinical outcomes and incremental health care costs of ischemic stroke in a US managed care population. PATIENTS AND METHODS: A retrospective cohort analysis was done on patients (aged 18+ years) hospitalized with noncardioembolic ischemic stroke from January 1, 2002, through December 31, 2003, identified from commercial health plan administrative claims. New or recurrent stroke was based on history in the previous 12 months, with index date defined as first date of indication of stroke. A control group without stroke or transient ischemic attack (TIA) was matched (1:3) on age, sex, and geographic region, with an index date defined as the first medical claim during the patient identification period. Patients with atrial fibrillation or mitral value abnormalities were excluded. Ischemic stroke and control cohorts were compared on 4-year clinical outcomes and 1-year costs. RESULTS: Of 2180 ischemic stroke patients, 1808 (82.9%) had new stroke and 372 (17.1%) had a recurrent stroke. Stroke patients had higher unadjusted rates of additional stroke, TIA, and fatal outcomes compared with the 6540 matched controls. Recurrent stroke patients had higher rates of adverse clinical outcomes compared with new stroke patients; costs attributed to recurrent stroke were also higher. Stroke patients were 2.4 times more likely to be hospitalized in follow-up compared with controls (hazard ratio [HR] 2.4, 95% confidence interval [CI]: 2.2, 2.6). Occurrence of stroke following discharge was 21 times more likely among patients with index stroke compared with controls (HR 21.0, 95% CI: 16.1, 27.3). Stroke was also predictive of death (HR 1.8, 95% CI: 1.3, 2.5). Controlling for covariates, stroke patients had significantly higher costs compared with control patients in the year following the index event. CONCLUSION: Noncardioembolic ischemic stroke patients had significantly poorer outcomes and higher costs compared with controls. Recurrent stroke appears to contribute substantially to these higher rates of adverse outcomes and costs. PMID- 20957134 TI - Role of tipranavir in treatment of patients with multidrug-resistant HIV. AB - The worldwide emergence of multidrug-resistant human immunodeficiency virus (HIV) 1 strains has the driven the development of new antiretroviral (ARV) agents. Over the past 5 years, HIV-entry and integrase inhibitor ARVs, as well as improved non nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), have become available for treatment. It is important to assess how these new ARVs might be most judiciously used, paying close attention to viral susceptibility patterns, pharmacodynamic parameters, and the likelihood that patients will adhere to their therapy. Herein we review published material in Medline, EMBASE, and ISI for each antiretroviral agent/classes currently approved and summarize the available data on their efficacy, safety, and pharmacologic parameters. We focus on the role of tipranavir, a recently approved nonpeptidic PI, for treating HIV-infected children, adolescents, and adults with a history of multidrug-resistant HIV. PMID- 20957135 TI - Microbial contamination of nonsterile pharmaceuticals in public hospital settings. AB - PURPOSE: Contamination of pharmaceuticals with microorganisms irrespective whether they are harmful or nonpathogenic can bring about changes in physicochemical characteristics of the medicines. Although sterility is not a requirement in official compendia for nonsterile pharmaceuticals, bioburdens need to be within acceptable limits. Therefore, this study investigated microbial contamination of 10 nonsterile pharmaceuticals frequently delivered to outpatients by identifying and quantifying microbial contaminants and susceptibility pattern testing on the microbes isolated. METHODS: The study was carried out at Amana Municipal Hospital in Dar es Salaam, Tanzania. The protocol for the study involved structured selection of representative tablets, syrups, and capsules from the hospital's outpatient pharmacy. Constitutive microorganisms were elaborated and enumerated using standard microbiologic procedures. RESULTS: Results showed that 50% of all tested products were heavily contaminated, and the predominant contaminants comprised Klebsiella, Bacillus, and Candida species. Furthermore, the results showed that the isolated Bacillus and Klebsiella species were resistant to Augmentin (r) and cloxacillin. The differences in means for cfu/mL and zones of inhibition among the microorganisms isolated were considered significant at P < 0.05. CONCLUSION: The nonsterile pharmaceuticals were presumably microbiologically contaminated due to poor handling during dispensing, repackaging, and/or nonadherence to good manufacturing practice. Therefore, training and educating the dispensers, as well as patients, on the proper handling and use of medicines cannot be overemphasized, because these are key aspects in controlling cross-contamination of medicines. PMID- 20957136 TI - Intravenous lipid emulsion for treatment of local anesthetic toxicity. AB - CLINICAL QUESTION: Is intravenous lipid emulsion a safe and effective therapy for the reversal and treatment of local anesthetic toxicity? RESULTS: Systematic reviews, human case reports, and experimental animal studies have demonstrated the efficacy of intravenous lipid emulsion therapy in successfully reversing cardiac arrhythmias, cardiac arrest, and cardiac collapse seen with severe systemic local anesthetic toxicity. There are fewer data to support treatment of neurologic toxicities associated with local anesthetics. IMPLEMENTATION: Intravenous lipid emulsion 20% should be available whenever patients receive large doses of local anesthetics in operating rooms and emergency departments. Various dosing protocols have been published in the medical literature. Although the dosing protocols are based on low-level evidence, a lack of major adverse events makes lipid emulsion an appropriate therapy for treating cardiotoxic symptoms induced by local anesthetics. PMID- 20957137 TI - Gastrointestinal stromal tumor (GIST) recurrence following surgery: review of the clinical utility of imatinib treatment. AB - Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Surgery with complete removal of the tumor is the primary treatment for resectable GIST and the only chance of cure. However, recurrence after surgery is common. The 2 main prognostic factors are the mitotic activity and the size of the tumor. Tumor rupture is also a risk factor for postoperative recurrence, and extra care should be taken while manipulating this soft and friable tumor. Imatinib mesylate (IM, Gleevec((r)), Novartis, Basel, Switzerland) is a tyrosine kinase inhibitor and was first studied in the palliative setting for metastatic GIST patients in the year 2000. It is now the cornerstone of metastatic GIST treatment. IM also plays an important role as an adjuvant treatment for resectable GIST and has been shown to increase the recurrence-free survival in phase III studies. However, some points remain to be clarified. Notably, the ideal duration of adjuvant IM after surgery is still unclear. It is also difficult to determine the exact place of surgery in metastatic or recurrent GIST patients in the IM era. A multidisciplinary approach is, therefore, mandatory to offer GIST patients the best treatment available. PMID- 20957138 TI - An improved delivery system for bladder irrigation. AB - INTRODUCTION: Occasionally, urologists may see patients requiring temporary bladder irrigation at hospitals without stocks of specialist irrigation apparatus. One option is to transfer the patient to a urology ward, but often there are outstanding medical issues that require continued specialist input. Here, we describe an improved system for delivering temporary bladder irrigation by utilizing readily available components and the novel modification of a sphygmomanometer blub. This option is good for bladder irrigation in patients with moderate or severe gross hematuria due to various causes. MATERIALS AND METHODS: In this prospective study from March 2007 to April 2009, we used our new system in eligible cases. In this system, an irrigant bag with 1 L of normal saline was suspended 80 cm above the indwelled 3-way Foley catheter, and its drainage tube was inserted into the irrigant port of the catheter. To increase the flow rate of the irrigant system, we inserted a traditional sphygmomanometer bulb at the top of the irrigant bag. This closed system was used for continuous bladder irrigation (CBI) in patients who underwent open prostatectomy, transurethral resection of the prostate (TURP), or transurethral resection of the bladder (TURB). This high-pressure system is also used for irrigation during cystourethroscopy, internal urethrotomy, and transurethral lithotripsy. Our 831 eligible cases were divided into two groups: group 1 were endourologic cases and group 2 were open prostatectomy, TURP, and TURB cases. The maximum and average flow rates were evaluated. The efficacy of our new system was compared prospectively with the previous traditional system used in 545 cases. RESULTS: In group 1, we had clear vision at the time of endourologic procedures. The success rate of this system was 99.5%. In group 2, the incidence of clot retention decreased two fold in comparison to traditional gravity-dependent bladder flow system. These changes were statistically significant (P = 0.001). We did not observe any adverse effects such as bladder perforation due to our high-pressure, high-flow system. CONCLUSION: A pressurized irrigant system has better visualization during endourologic procedures, and prevents clot formation after open prostatectomy, TURP, and TURB without any adverse effects. PMID- 20957141 TI - Cystoid macular edema secondary to immune recovery uveitis in a man with cytomegalovirus retinitis and AIDS. AB - Cytomegalovirus (CMV) is the most common intraocular opportunistic infection in profoundly immunocompromised patients with AIDS. It is characterized by an acute, progressive, necrotizing retinitis in patients with a CD4 count of <50 cells/MUL. Although the incidence of CMV retinitis has declined because of the introduction of antiretroviral therapy (ART), a new syndrome of intraocular inflammation has emerged in patients with rising CD4 lymphocyte counts following ART. This is called immune recovery uveitis (IRU). It is thought to occur as a result of restored immunity to various infectious agents, commonly mycobacterial, Cryptococcus, and herpes virus infections. We report a man who was treated for CMV retinitis and later developed IRU in the form of cystoid macular edema (CMO) even though his CMV retinitis remained inactive. His CMO resolved and visual acuity improved 2 years after the onset of CMO without any treatment interventions. PMID- 20957139 TI - Pegylated liposomal doxorubicin in the management of ovarian cancer. AB - Among the pharmaceutical options available for treatment of ovarian cancer, much attention has been progressively focused on pegylated liposomal doxorubicin (PLD), whose unique formulation, which entraps conventional doxorubicin in a bilayer lipidic sphere surrounded by a polyethylene glycol layer, prolongs the persistence of the drug in the circulation and potentiates intratumor drug accumulation. These properties enable this drug to sustain its very favorable toxicity profile and to be used safely in combination with other drugs. PLD has been already approved for treatment of advanced ovarian cancer patients failing first-line platinum-based treatment. Moreover, phase III trials have been already completed, and results are eagerly awaited, which hopefully will expand the range of PLD clinical application in this neoplasia both in front-line treatment, and in the salvage setting in combination with other drugs. Moreover, attempts are continuing to enable this drug to be combined with novel cytotoxic drugs and target-based agents. This review aims at summarizing the available evidence and the new perspectives for the clinical role of PLD in the management of patients with epithelial ovarian cancer. PMID- 20957140 TI - Resistance and the management of complicated skin and skin structure infections: the role of ceftobiprole. AB - Antimicrobial resistant bacteria are an increasing concern due to the resulting increase in morbidity, mortality, and health-care costs associated with the administration of inadequate or delayed antimicrobial therapy. The implications of inadequate antimicrobial therapy in complicated skin and skin structure infections (cSSSIs) have gained more attention recently, most likely due to the recent emergence of community-acquired methicillin resistant Staphylococcus aureus (MRSA) and the already high prevalence of MRSA in the nosocomial setting. Due to the continuous threat of resistance arising and the limitations of currently available agents for the treatment of cSSSIs, it is necessary to develop new antimicrobials for this indication. Ceftobiprole medocaril, the prodrug of ceftobiprole, is a parental investigational cephalosporin for the treatment of cSSSIs displaying a wide-spectrum of activity against both Gram positive and Gram-negative species, including MRSA. Ceftobiprole displays noncomplex linear pharmacokinetics, is eliminated primarily by glomerular filtration, and distributes to extracellular fluid. Additionally, it has been shown that the extent of distribution to the site of action with regard to cSSSIs, ie, the extracellular space fluid of subcutaneous adipose tissue and skeletal muscle, is expected to be efficacious, as free concentrations meet efficacy targets for most pathogens. Similar to other beta-lactams, it displays an excellent safety and tolerability profile with the primary adverse events being dysgeusia in healthy volunteers, resulting from the conversion of the prodrug to the active, and nausea in patients. Ceftobiprole has demonstrated noninferiority in two large-scale pivotal studies comparing it to vancomycin, clinical cure rates 93.3% vs 93.5%, respectively, or vancomycin plus ceftazidime, clinical cure rates 90.5% vs 90.2%, respectively. Given the pharmacokinetic and pharmacodynamic properties, ceftobiprole is a promising new agent for the treatment of cSSSIs and has the potential to be used as a single agent for empiric treatment. PMID- 20957142 TI - Epithelial growth over the optic surface of the type 1 Boston Keratoprosthesis: histopathology and implications for biointegration. AB - We report the histopathology of epithelial overgrowth in the Boston type I keratoprosthesis. The epithelium shows an inconsistent number of layers and basement membrane and goblet cells are absent. Epithelialization of the keratoprosthesis optic would have multiple advantages, but the limitation of vision makes tolerating the overgrowth difficult. PMID- 20957143 TI - Lucentis using Visudyne study: determining the threshold-dose fluence of verteporfin photodynamic therapy combined with intravitreal ranibizumab for exudative macular degeneration. AB - PURPOSE: Combination verteporfin photodynamic therapy (vPDT) and antivascular endothelial growth factor (anti-VEGF) therapy may decrease the need for injections while maintaining visual acuity in exudative age-related macular degeneration. This pilot study was designed to determine the threshold fluence dose of vPDT (the dose required to demonstrate an effect on choroidal perfusion) combined with ranibizumab. METHODS: Seven patients were randomized to sham vPDT (two patients), 20% fluence vPDT (two patients), or 40% fluence vPDT (three patients) in combination with three-monthly intravitreal 0.5 mg ranibizumab injections. Intravitreal ranibizumab was reinjected if disease activity was seen on fluorescein angiography, optical coherence tomography, or clinical examination. Indocyanine green-determined choroidal hypoperfusion was graded in a masked fashion. RESULTS: Patients with 20% vPDT had mild hypoperfusion defects at seven days that resolved by week 4 (threshold dose); patients with 40% fluence vPDT had marked hypoperfusion at seven days that persisted as long as 12 months. Recruitment was stopped after limited efficacy was observed. One patient with 20% fluence vPDT lost 19 letters at one year; no other patient lost or gained >10 letters. Central retinal thickness decreased in six of seven patients, but ranibizumab injections did not decrease. CONCLUSION: This pilot study shows that the threshold fluence dose of vPDT (when combined with ranibizumab) is approximately 20% standard fluence, and that mild and transient choroidal hypoperfusion can occur. Forty percent fluence vPDT causes a more prolonged and striking hypoperfusion. Despite hypoperfusion, no decrease in visual acuity or injections required was noted, suggesting that even higher fluence levels of vPDT may be necessary to decrease the number of anti-VEGF injections. PMID- 20957144 TI - Interactions between exposure to environmental polycyclic aromatic hydrocarbons and DNA repair gene polymorphisms on bulky DNA adducts in human sperm. AB - BACKGROUND: Nucleotide excision repair (NER) and base excision repair (BER) are the primary mechanisms for repair of bulky adducts caused by chemical agents, such as PAHs. It is expected that polymorphisms in NER or BER genes may modulate individual susceptibility to PAHs exposure. Here, we evaluate the effects of PAHs exposure and polymorphisms in NER and BER pathway, alone or combined, on polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adducts in human sperm. METHODOLOGY/PRINCIPAL FINDINGS: Sperm PAH-DNA adducts were measured by immunofluorescent assay using flow cytometry in a sample of 465 infertile adults. Polymorphisms of XPA, XPD, ERCC1, XPF, and XRCC1 were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques. The PAHs exposure was detected as urinary 1-hydroxypyrene (1-OHP) levels. In multivariate models adjusted for potential confounders, we observed that XRCC1 5'pUTR -T/C, Arg194Trp, Arg399Gln polymorphisms were associated with increased sperm adduct levels. Furthermore, the stratified analysis indicated that adverse effects of XRCC1 Arg194Trp, Arg399Gln polymorphisms on PAH-DNA adducts were detected only in the high PAHs exposure group. CONCLUSIONS/SIGNIFICANCE: These findings provided the first evidence that polymorphisms of XRCC1 may modify sperm PAH-DNA adduct levels and may be useful biomarkers to identify individuals susceptible to DNA damage resulting from PAHs exposure. PMID- 20957145 TI - Metabolomics-based discovery of diagnostic biomarkers for onchocerciasis. AB - BACKGROUND: Development of robust, sensitive, and reproducible diagnostic tests for understanding the epidemiology of neglected tropical diseases is an integral aspect of the success of worldwide control and elimination programs. In the treatment of onchocerciasis, clinical diagnostics that can function in an elimination scenario are non-existent and desperately needed. Due to its sensitivity and quantitative reproducibility, liquid chromatography-mass spectrometry (LC-MS) based metabolomics is a powerful approach to this problem. METHODOLOGY/PRINCIPAL FINDINGS: Analysis of an African sample set comprised of 73 serum and plasma samples revealed a set of 14 biomarkers that showed excellent discrimination between Onchocerca volvulus-positive and negative individuals by multivariate statistical analysis. Application of this biomarker set to an additional sample set from onchocerciasis endemic areas where long-term ivermectin treatment has been successful revealed that the biomarker set may also distinguish individuals with worms of compromised viability from those with active infection. Machine learning extended the utility of the biomarker set from a complex multivariate analysis to a binary format applicable for adaptation to a field-based diagnostic, validating the use of complex data mining tools applied to infectious disease biomarker discovery and diagnostic development. CONCLUSIONS/SIGNIFICANCE: An LC-MS metabolomics-based diagnostic has the potential to monitor the progression of onchocerciasis in both endemic and non endemic geographic areas, as well as provide an essential tool to multinational programs in the ongoing fight against this neglected tropical disease. Ultimately this technology can be expanded for the diagnosis of other filarial and/or neglected tropical diseases. PMID- 20957147 TI - Profound and sustained reduction in Chlamydia trachomatis in The Gambia: a five year longitudinal study of trachoma endemic communities. AB - BACKGROUND: The elimination of blinding trachoma focuses on controlling Chlamydia trachomatis infection through mass antibiotic treatment and measures to limit transmission. As the prevalence of disease declines, uncertainty increases over the most effective strategy for treatment. There are little long-term data on the effect of treatment on infection, especially in low prevalence settings, on which to base guidelines. METHODOLOGY/PRINCIPAL FINDINGS: The population of a cluster of 14 Gambian villages with endemic trachoma was examined on seven occasions over five years (baseline, 2, 6, 12, 17, 30 and 60 months). Mass antibiotic treatment was given at baseline only. All families had accessible clean water all year round. New latrines were installed in each household after 17 months. Conjunctival swab samples were collected and tested for C. trachomatis by PCR. Before treatment the village-level prevalence of follicular trachoma in 1 to 9 year olds (TF(%1-9)) was 15.4% and C. trachomatis was 9.7%. Antibiotic treatment coverage was 83% of the population. In 12 villages all baseline infection cleared and few sporadic cases were detected during the following five years. In the other two villages treatment was followed by increased infection at two months, which was associated with extensive contact with other untreated communities. The prevalence of infection subsequently dropped to 0% in these 2 villages and 0.6% for the whole population by the end of the study in the absence of any further antibiotic treatment. However, several villages had a TF(%1-9) of >10%, the threshold for initiating or continuing mass antibiotic treatment, in the absence of any detectable C. trachomatis. CONCLUSIONS/SIGNIFICANCE: A single round of mass antibiotic treatment may be sufficient in low prevalence settings to control C. trachomatis infection when combined with environmental conditions, which suppress transmission, such as a good water supply and sanitation. PMID- 20957146 TI - Zip4 (Slc39a4) expression is activated in hepatocellular carcinomas and functions to repress apoptosis, enhance cell cycle and increase migration. AB - BACKGROUND: The zinc transporter ZIP4 (Slc39a4) is important for proper mammalian development and is an essential gene in mice. Recent studies suggest that this gene may also play a role in pancreatic cancer. METHODS/PRINCIPAL FINDINGS: Herein, we present evidence that this essential zinc transporter is expressed in hepatocellular carcinomas. Zip4 mRNA and protein were dramatically elevated in hepatocytes in the majority of human hepatocellular carcinomas relative to noncancerous surrounding tissues, as well as in hepatocytes in hepatocellular carcinomas occurring in farnesoid X receptor-knockout mice. Interestingly, meta analysis of microarray data in the Geo and Oncomine databases suggests that Zip4 mRNA may also be elevated in many types of cancer. Potential mechanisms of action of ZIP4 were examined in cultured cell lines. RNAi knockdown of Zip4 in mouse Hepa cells significantly increased apoptosis and modestly slowed progression from G(0)/G(1) to S phase when cells were released from hydroxyurea block into zinc deficient medium. Cell migration assays revealed that RNAi knockdown of Zip4 in Hepa cells depressed in vitro migration whereas forced over-expression in Hepa cells and MCF-7 cells enhanced in vitro migration. CONCLUSIONS: ZIP4 may play a role in the acquisition of zinc by hepatocellular carcinomas, and potentially many different cancerous cell-types, leading to repressed apoptosis, enhanced growth rate and enhanced invasive behavior. PMID- 20957148 TI - Chagas disease risk in Texas. AB - BACKGROUND: Chagas disease, caused by Trypanosoma cruzi, remains a serious public health concern in many areas of Latin America, including Mexico. It is also endemic in Texas with an autochthonous canine cycle, abundant vectors (Triatoma species) in many counties, and established domestic and peridomestic cycles which make competent reservoirs available throughout the state. Yet, Chagas disease is not reportable in Texas, blood donor screening is not mandatory, and the serological profiles of human and canine populations remain unknown. The purpose of this analysis was to provide a formal risk assessment, including risk maps, which recommends the removal of these lacunae. METHODS AND FINDINGS: The spatial relative risk of the establishment of autochthonous Chagas disease cycles in Texas was assessed using a five-stage analysis. 1. Ecological risk for Chagas disease was established at a fine spatial resolution using a maximum entropy algorithm that takes as input occurrence points of vectors and environmental layers. The analysis was restricted to triatomine vector species for which new data were generated through field collection and through collation of post-1960 museum records in both Mexico and the United States with sufficiently low georeferenced error to be admissible given the spatial resolution of the analysis (1 arc-minute). The new data extended the distribution of vector species to 10 new Texas counties. The models predicted that Triatoma gerstaeckeri has a large region of contiguous suitable habitat in the southern United States and Mexico, T. lecticularia has a diffuse suitable habitat distribution along both coasts of the same region, and T. sanguisuga has a disjoint suitable habitat distribution along the coasts of the United States. The ecological risk is highest in south Texas. 2. Incidence-based relative risk was computed at the county level using the Bayesian Besag-York-Mollie model and post-1960 T. cruzi incidence data. This risk is concentrated in south Texas. 3. The ecological and incidence-based risks were analyzed together in a multi-criteria dominance analysis of all counties and those counties in which there were as yet no reports of parasite incidence. Both analyses picked out counties in south Texas as those at highest risk. 4. As an alternative to the multi-criteria analysis, the ecological and incidence-based risks were compounded in a multiplicative composite risk model. Counties in south Texas emerged as those with the highest risk. 5. Risk as the relative expected exposure rate was computed using a multiplicative model for the composite risk and a scaled population county map for Texas. Counties with highest risk were those in south Texas and a few counties with high human populations in north, east, and central Texas showing that, though Chagas disease risk is concentrated in south Texas, it is not restricted to it. CONCLUSIONS: For all of Texas, Chagas disease should be designated as reportable, as it is in Arizona and Massachusetts. At least for south Texas, lower than N, blood donor screening should be mandatory, and the serological profiles of human and canine populations should be established. It is also recommended that a joint initiative be undertaken by the United States and Mexico to combat Chagas disease in the trans border region. The methodology developed for this analysis can be easily exported to other geographical and disease contexts in which risk assessment is of potential value. PMID- 20957149 TI - Synaptic plasticity in medial vestibular nucleus neurons: comparison with computational requirements of VOR adaptation. AB - BACKGROUND: Vestibulo-ocular reflex (VOR) gain adaptation, a longstanding experimental model of cerebellar learning, utilizes sites of plasticity in both cerebellar cortex and brainstem. However, the mechanisms by which the activity of cortical Purkinje cells may guide synaptic plasticity in brainstem vestibular neurons are unclear. Theoretical analyses indicate that vestibular plasticity should depend upon the correlation between Purkinje cell and vestibular afferent inputs, so that, in gain-down learning for example, increased cortical activity should induce long-term depression (LTD) at vestibular synapses. METHODOLOGY/PRINCIPAL FINDINGS: Here we expressed this correlational learning rule in its simplest form, as an anti-Hebbian, heterosynaptic spike-timing dependent plasticity interaction between excitatory (vestibular) and inhibitory (floccular) inputs converging on medial vestibular nucleus (MVN) neurons (input spike-timing dependent plasticity, iSTDP). To test this rule, we stimulated vestibular afferents to evoke EPSCs in rat MVN neurons in vitro. Control EPSC recordings were followed by an induction protocol where membrane hyperpolarizing pulses, mimicking IPSPs evoked by flocculus inputs, were paired with single vestibular nerve stimuli. A robust LTD developed at vestibular synapses when the afferent EPSPs coincided with membrane hyperpolarization, while EPSPs occurring before or after the simulated IPSPs induced no lasting change. Furthermore, the iSTDP rule also successfully predicted the effects of a complex protocol using EPSP trains designed to mimic classical conditioning. CONCLUSIONS: These results, in strong support of theoretical predictions, suggest that the cerebellum alters the strength of vestibular synapses on MVN neurons through hetero-synaptic, anti Hebbian iSTDP. Since the iSTDP rule does not depend on post-synaptic firing, it suggests a possible mechanism for VOR adaptation without compromising gaze holding and VOR performance in vivo. PMID- 20957150 TI - Adaptive evolution of the Chlamydia trachomatis dominant antigen reveals distinct evolutionary scenarios for B- and T-cell epitopes: worldwide survey. AB - BACKGROUND: Chlamydia trachomatis is one of the most disseminated human pathogens, for which no vaccine is available yet. Understanding the impact of the host pressure on pathogen antigens is crucial, but so far it was only assessed for highly-restricted geographic areas. We aimed to evaluate the evolutionary picture of the chlamydial key antigen (MOMP), which is one of the leading multi subunit vaccine candidates, in a worldwide basis. METHODOLOGY/PRINCIPAL FINDINGS: Using genetics, molecular evolution methods and mathematical modelling, we analyzed all MOMP sequences reported worldwide, composed by 5026 strains from 33 geographic regions of five continents. Overall, 35.9% of variants were detected. The evolutionary pattern of MOMP amino acid gains/losses was found to differ from the remaining chromosome, reflecting the demanding constraints of this porin, adhesin and dominant antigen. Amino acid changes were 4.3-fold more frequent in host-interacting domains (P<10-12), specifically within B-cell epitopes (P<10-5), where 25% of them are at fixation (P<10-5). According to the typical pathogen host arms race, this rampant B-cell antigenic variation likely represents neutralization escape mutants, as some mutations were previously shown to abrogate neutralization of chlamydial infectivity in vitro. In contrast, T-cell clusters of diverse HLA specificities are under purifying selection, suggesting a strategy that may lead to immune subversion. Moreover, several silent mutations are at fixation, generating preferential codons that may influence expression, and may also reflect recombination-derived 'hitchhiking-effect' from favourable nonsilent changes. Interestingly, the most prevalent C. trachomatis genotypes, E and F, showed a mutation rate 22.3-fold lower than that of the remainder (P<10 20), suggesting more fitted antigenic profiles. CONCLUSIONS/SIGNIFICANCE: Globally, the adaptive evolution of the C. trachomatis dominant antigen is likely driven by its complex pathogenesis-related function and reflects distinct evolutionary antigenic scenarios that may benefit the pathogen, and thus should be taking into account in the development of a MOMP-based vaccine. PMID- 20957151 TI - Identification of restricted subsets of mature microRNA abnormally expressed in inactive colonic mucosa of patients with inflammatory bowel disease. AB - BACKGROUND: Ulcerative Colitis (UC) and Crohn's Disease (CD) are two chronic Inflammatory Bowel Diseases (IBD) affecting the intestinal mucosa. Current understanding of IBD pathogenesis points out the interplay of genetic events and environmental cues in the dysregulated immune response. We hypothesized that dysregulated microRNA (miRNA) expression may contribute to IBD pathogenesis. miRNAs are small, non-coding RNAs which prevent protein synthesis through translational suppression or mRNAs degradation, and regulate several physiological processes. METHODOLOGY/FINDINGS: Expression of mature miRNAs was studied by Q-PCR in inactive colonic mucosa of patients with UC (8), CD (8) and expressed relative to that observed in healthy controls (10). Only miRNAs with highly altered expression (>5 or <0.2 -fold relative to control) were considered when Q-PCR data were analyzed. Two subsets of 14 (UC) and 23 (CD) miRNAs with highly altered expression (5.2->100 -fold and 0.05-0.19 -fold for over- and under expression, respectively; 0.00190% of these deaths occur in developing countries where few children have access to life-saving serotype-based vaccines. Understanding the serotype epidemiology of invasive pneumococcal disease (IPD) among children is necessary for vaccine development and introduction policies. The aim of this study was to systematically estimate the global and regional distributions of serotypes causing IPD in children <5 years of age. METHODS AND FINDINGS: We systematically reviewed studies with IPD serotype data among children <5 years of age from the published literature and unpublished data provided by researchers. Studies conducted prior to pneumococcal conjugate vaccine (PCV) introduction, from 1980 to 2007, with >=12 months of surveillance, and reporting >=20 serotyped isolates were included. Serotype-specific proportions were pooled in a random effects meta analysis and combined with PD incidence and mortality estimates to infer global and regional serotype-specific PD burden. Of 1,292, studies reviewed, 169 were included comprising 60,090 isolates from 70 countries. Globally and regionally, six to 11 serotypes accounted for >=70% of IPD. Seven serotypes (1, 5, 6A, 6B, 14, 19F, 23F) were the most common globally; and based on year 2000 incidence and mortality estimates these seven serotypes accounted for >300,000 deaths in Africa and 200,000 deaths in Asia. Serotypes included in both the 10- and 13-valent PCVs accounted for 10 million cases and 600,000 deaths worldwide. CONCLUSIONS: A limited number of serotypes cause most IPD worldwide. The serotypes included in existing PCV formulations account for 49%-88% of deaths in Africa and Asia where PD morbidity and mortality are the highest, but few children have access to these life-saving vaccines. Please see later in the article for the Editors' Summary. PMID- 20957192 TI - Endoplasmic reticulum calcium regulates the retrotranslocation of Trypanosoma cruzi calreticulin to the cytosol. AB - For most secretory pathway proteins, crossing the endoplasmic reticulum (ER) membrane is an irreversible process. However, in some cases this flow can be reversed. For instance, misfolded proteins retained in the ER are retrotranslocated to the cytosol to be degraded by the proteasome. This mechanism, known as ER associated degradation (ERAD), is exploited by several bacterial toxins to gain access to the cytosol. Interestingly, some ER resident proteins can also be detected in the cytosol or nucleus, calreticulin (CRT) being the most studied. Here we show that in Trypanosoma cruzi a minor fraction of CRT localized to the cytosol. ER calcium depletion, but not increasing cytosolic calcium, triggered the retrotranslocation of CRT in a relatively short period of time. Cytosolic CRT was subsequently degraded by the proteasome. Interestingly, the single disulfide bridge of CRT is reduced when the protein is located in the cytosol. The effect exerted by ER calcium was strictly dependent on the C terminal domain (CRT-C), since a CRT lacking it was totally retained in the ER, whereas the localization of an unrelated protein fused to CRT-C mirrored that of endogenous CRT. This finding expands the regulatory mechanisms of protein sorting and may represent a new crossroad between diverse physiological processes. PMID- 20957193 TI - Enhanced case detection and improved diagnosis of PKDL in a Kala-azar-endemic area of Bangladesh. AB - OBJECTIVES: To support the Bangladesh National Kala-azar Elimination Programme (NKEP), we investigated the feasibility of using trained village volunteers for detecting post-kala-azar dermal leishmaniasis (PKDL) cases, using polymerase chain reaction (PCR) for confirmation of diagnosis and treatment compliance by PKDL patients in Kanthal union of Trishal sub-district, Mymensingh, Bangladesh. METHODS: In this cross-sectional study, Field Research Assistants (FRAs) conducted census in the study area, and the research team trained village volunteers on how to look for PKDL suspects. The trained village volunteers (TVVs) visited each household in the study area for PKDL suspects and referred the suspected PKDL cases to the study clinic. The suspected cases underwent physical examinations by a qualified doctor and rK39 strip testing by the FRAs and, if positive, slit skin examination (SSE), culture, and PCR of skin specimens and peripheral buffy coat were done. Those with evidence of Leishmania donovani (LD) were referred for treatment. All the cases were followed for one year. RESULTS: The total population of the study area was 29,226 from 6,566 households. The TVVs referred 52 PKDL suspects. Probable PKDL was diagnosed in 18 of the 52 PKDL suspect cases, and PKDL was confirmed in 9 of the 18 probable PKDL cases. The prevalence of probable PKDL was 6.2 per 10,000 people in the study area. Thirteen PKDL suspects self-reported from outside the study area, and probable and confirmed PKDL was diagnosed in 10 of the 13 suspects and in 5 of 10 probable PKDL cases respectively. All probable PKDL cases had hypopigmented macules. The median time for PKDL development was 36 months (IQR, 24-48). Evidence of the LD parasite was documented by SSE and PCR in 3.6% and 64.3% of the cases, respectively. PCR positivity was associated with gender and severity of disease. Those who were untreated had an increased risk (odds ratio = 3.33, 95%CI 1.29 8.59) of having persistent skin lesions compared to those who were treated. Patients' treatment-seeking behavior and treatment compliance were poor. CONCLUSION: Improved detection of PKDL cases by TVVs is feasible and useful. The NKEP should promote PCR for the diagnosis of PKDL and should find ways for improving treatment compliance by patients. PMID- 20957194 TI - 2nd International external quality control assessment for the molecular diagnosis of dengue infections. AB - BACKGROUND: Currently dengue viruses (DENV) pose an increasing threat to over 2.5 billion people in over 100 tropical and sub-tropical countries worldwide. International air travel is facilitating rapid global movement of DENV, increasing the risk of severe dengue epidemics by introducing different serotypes. Accurate diagnosis is critical for early initiation of preventive measures. Different reverse transcriptase PCR (RT-PCR) methods are available, which should be evaluated and standardized. Epidemiological and laboratory-based surveillance is required to monitor and guide dengue prevention and control programmes, i.e., by mosquito control or possible vaccination (as soon as an effective and safe vaccine becomes available). OBJECTIVE: The purpose of the external quality assurance (EQA) study described is to assess the efficiency and accuracy of dengue molecular diagnosis methods applied by expert laboratories. STUDY DESIGN: A panel of 12 human plasma samples was distributed and tested for DENV-specific RNA. The panel comprised 9 samples spiked with different DENV serotypes (DENV-1 to DENV-4), including 10-fold dilution series of DENV-1 and DENV-3. Two specificity controls consisted of a sample with a pool of 4 other flaviviruses and a sample with chikungunya virus. A negative control sample was also included. RESULTS: Thirty-seven laboratories (from Europe, Middle East Asia, Asia, the Americas/Caribbean, and Africa) participated in this EQA study, and reports including 46 sets of results were returned. Performance among laboratories varied according to methodologies used. Only 5 (10.9%) data sets met all criteria with optimal performance, and 4 (8.7%) with acceptable performance, while 37 (80.4%) reported results showed the need for improvement regarding accomplishment of dengue molecular diagnosis. Failures were mainly due to lack of sensitivity and the presence of false positives. CONCLUSIONS: The EQA provides information on each laboratory's efficacy of RT-PCR techniques for dengue diagnosis and indicates for most laboratories an urgent need to improve sensitivity and specificity. PMID- 20957195 TI - French experience of 2009 A/H1N1v influenza in pregnant women. AB - BACKGROUND: The first reports on the pandemic influenza 2009 A/H1N1v from the USA, Mexico, and Australia indicated that this disease was associated with a high mortality in pregnant women. The aim of this study was to describe and compare the characteristics of severe critically ill and non-severe pregnant women with 2009 A/H1N1v-related illness in France. METHODOLOGY/PRINCIPAL FINDINGS: A national registry was created to screen pregnant women with laboratory-confirmed 2009 A/H1N1v influenza. Three hundred and fifteen patients from 46 French hospitals were included: 40 patients were admitted to intensive care units (severe outcomes), 111 were hospitalized in obstetric or medical wards (moderate outcomes), and 164 were outpatients (mild outcomes). The 2009 A/H1N1v influenza illness occurred during all pregnancy trimesters, but most women (54%), notably the severe patients (70%), were in the third trimester. Among the severe patients, twenty (50%) underwent mechanical ventilation, and eleven (28%) were treated with extracorporeal membrane oxygenation. Three women died from A/H1N1v influenza. We found a strong association between the development of a severe outcome and both co-existing illnesses (adjusted odds ratio [OR], 5.1; 95% confidence interval [CI], 2.2-11.8) and a delay in oseltamivir treatment after the onset of symptoms (>3 or 5 days) (adjusted OR, 4.8; 95% CI, 1.9-12.1 and 61.2, 95% CI; 14.4-261.3, respectively). Among the 140 deliveries after 22 weeks of gestation known to date, 19 neonates (14%) were admitted to a neonatal intensive care unit, mainly for preterm delivery, and two neonates died. None of these neonates developed 2009 A/H1N1v infection. CONCLUSIONS: This series confirms the high incidence of complications in pregnant women infected with pandemic A/H1N1v observed in other countries but depicts a lower overall maternal and neonatal mortality and morbidity than indicated in the USA or Australia. Moreover, our data demonstrate the benefit of early oseltamivir treatment in this specific population. PMID- 20957196 TI - Mass treatment with azithromycin for trachoma control: participation clusters in households. AB - BACKGROUND: Mass treatment to trachoma endemic communities is a critical part of the World Health Organization SAFE strategy. However, non-participation may not be at random, affecting coverage surveys and effectiveness if infection is differential. METHODOLOGY/PRINCIPAL FINDINGS: As part of the Partnership for Rapid Elimination of Trachoma (PRET), 32 communities in Tanzania, and 48 in The Gambia had a detailed census taken followed by mass treatment with azithromycin. The target coverage in each community was >80% of children ages <10 years. Community treatment assistants observed treatment and recorded compliance, thus coverage at the community, household, and individual level could be determined. Within each community, we determined the actual proportions of households where all, some, or none of the children were treated. Assuming the coverage in children <10 years of the community was as observed and non-participation was at random, we did 500 simulations to derive expected proportions of households where all, some, or none of the children were treated. Clustering of household treatment was detected comparing greater-than-expected proportions of households where none or all of children were treated, and the intraclass correlation (ICC) was calculated. Tanzanian and Gambian mass treatment coverages for children <10 years of age ranged from 82-100% and 62-99%, respectively. Clustering of households where all children were treated or no children were treated was greater than expected. Compared to model simulations, all Tanzanian communities and 44 of 48 (91.7%) Gambian communities had significantly higher proportions of households where all children were treated. Furthermore, 30 of 32 (93.8%) Tanzanian communities and 34 of 48 (70.8%) Gambian communities had a significantly elevated proportion of households compared to the expected proportion where no children were treated. The ICC for Tanzania was 0.77 (95% CI 0.74-0.81) and for The Gambia was 0.55 (95% CI 0.51-0.59). CONCLUSIONS/SIGNIFICANCE: In programs aiming for high coverage, complete compliance or non-compliance with mass treatment clusters within households. Non compliance cannot be assumed to be at random. PMID- 20957197 TI - Genetic variation of the Fc gamma receptor 3B gene and association with rheumatoid arthritis. AB - BACKGROUND: Fc gamma receptors (FcgammaRs) play a crucial role in immunity by linking IgG antibody-mediated responses with cellular effector and regulatory functions. Genetic variants in these receptors have been previously identified as risk factors for several chronic inflammatory conditions. The present study aimed to investigate the presence of copy number variations (CNVs) in the FCGR3B gene and its potential association with the autoimmune disease rheumatoid arthritis (RA). METHODOLOGY/PRINCIPAL FINDINGS: CNV of the FCGR3B gene was studied using Multiplex Ligation Dependent Probe Amplification (MLPA) in 518 Dutch RA patients and 304 healthy controls. Surprisingly, three independent MLPA probes targeting the FCGR3B promoter measured different CNV frequencies, with probe#1 and #2 measuring 0 to 5 gene copies and probe#3 showing little evidence of CNV. Quantitative-PCR correlated with the copy number results from MLPA probe#2, which detected low copy number (1 copy) in 6.7% and high copy number (>=3 copies) in 9.4% of the control population. No significant difference was observed between RA patients and the healthy controls, neither in the low copy nor the high copy number groups (p-values = 0.36 and 0.71, respectively). Sequencing of the FCGR3B promoter region revealed an insertion/deletion (indel) that explained the disparate CNV results of MLPA probe#1. Finally, a non-significant trend was found between the novel -256A>TG indel and RA (40.7% in healthy controls versus 35.9% in RA patients; P = 0.08). CONCLUSIONS/SIGNIFICANCE: The current study highlights the complexity and poor characterization of the FCGR3B gene sequence, indicating that the design and interpretation of genotyping assays based on specific probe sequences must be performed with caution. Nonetheless, we confirmed the presence of CNV and identified novel polymorphisms in the FCGR3B gene in the Dutch population. Although no association was found between RA and FCGR3B CNV, the possible protective effect of the -256A>TG indel polymorphism must be addressed in larger studies. PMID- 20957198 TI - Expression of glycogen phosphorylase isoforms in cultured muscle from patients with McArdle's disease carrying the p.R771PfsX33 PYGM mutation. AB - BACKGROUND: Mutations in the PYGM gene encoding skeletal muscle glycogen phosphorylase (GP) cause a metabolic disorder known as McArdle's disease. Previous studies in muscle biopsies and cultured muscle cells from McArdle patients have shown that PYGM mutations abolish GP activity in skeletal muscle, but that the enzyme activity reappears when muscle cells are in culture. The identification of the GP isoenzyme that accounts for this activity remains controversial. METHODOLOGY/PRINCIPAL FINDINGS: In this study we present two related patients harbouring a novel PYGM mutation, p.R771PfsX33. In the patients' skeletal muscle biopsies, PYGM mRNA levels were ~60% lower than those observed in two matched healthy controls; biochemical analysis of a patient muscle biopsy resulted in undetectable GP protein and GP activity. A strong reduction of the PYGM mRNA was observed in cultured muscle cells from patients and controls, as compared to the levels observed in muscle tissue. In cultured cells, PYGM mRNA levels were negligible regardless of the differentiation stage. After a 12 day period of differentiation similar expression of the brain and liver isoforms were observed at the mRNA level in cells from patients and controls. Total GP activity (measured with AMP) was not different either; however, the active GP activity and immunoreactive GP protein levels were lower in patients' cell cultures. GP immunoreactivity was mainly due to brain and liver GP but muscle GP seemed to be responsible for the differences. CONCLUSIONS/SIGNIFICANCE: These results indicate that in both patients' and controls' cell cultures, unlike in skeletal muscle tissue, most of the protein and GP activities result from the expression of brain GP and liver GP genes, although there is still some activity resulting from the expression of the muscle GP gene. More research is necessary to clarify the differential mechanisms of metabolic adaptations that McArdle cultures undergo in vitro. PMID- 20957199 TI - Molecular mechanisms of persistence of mutualistic bacteria Photorhabdus in the entomopathogenic nematode host. AB - Symbioses between microbes and animals are ubiquitous, yet little is known about the intricate mechanisms maintaining such associations. In an emerging mutualistic model system, insect-pathogenic bacteria Photorhabdus and their insect-parasitic nematode partner Heterorhabditis, we found that the bacteria undergo major transcriptional reshaping in the nematode intestine. Besides general starvation mechanisms, the bacteria induce cellular acidification to slow down growth, switch to pentose phosphate pathway to overcome oxidative stress and nutrition limitation, and shed motility but develop biofilm to persist in the nematode intestine until being released into the insect hemolymph. These findings demonstrate how the symbiotic bacteria reduce their nutritional dependence on the enduring nematode partner to ensure successful transmission of the couple to the next insect host. PMID- 20957200 TI - Prion replication in the hematopoietic compartment is not required for neuroinvasion in scrapie mouse model. AB - Fatal neurodegenerative prion diseases are caused by the transmissible PrP(Sc) prion agent whose initial replication after peripheral inoculation takes place in follicular dendritic cells present in germinal centers of lymphoid organs. However, prion replication also occurs in lymphoid cells. To assess the role of the hematopoietic compartment in neuroinvasion and prion replication, we generated chimeric mice, on a uniform congenic C57/BL6J background, by bone marrow replacement with hematopoietic cells expressing different levels of PrP protein. Nine different types of chimeric mice were inoculated intraperitoneally either with the lymphotropic Rocky Mountain Laboratory (RML) strain or the non lymphotropic ME-7 scrapie strain, at different doses. Here, we clearly demonstrate that overexpression of PrP by the hematopoietic system, or the lack of PrP expression by the bone marrow derived cells, does not change the incubation time period of the disease, even when the mice are infected at limiting doses. We conclude that the hematopoietic compartment is more or less permissive to prion replication, both for RML and ME-7, but does not play a role in neuroinvasion. PMID- 20957202 TI - Identification of Leishmania proteins preferentially released in infected cells using change mediated antigen technology (CMAT). AB - Although Leishmania parasites have been shown to modulate their host cell's responses to multiple stimuli, there is limited evidence that parasite molecules are released into infected cells. In this study, we present an implementation of the change mediated antigen technology (CMAT) to identify parasite molecules that are preferentially expressed in infected cells. Sera from mice immunized with cell lysates prepared from L. donovani or L. pifanoi-infected macrophages were adsorbed with lysates of axenically grown amastigotes of L. donovani or L. pifanoi, respectively, as well as uninfected macrophages. The sera were then used to screen inducible parasite expression libraries constructed with genomic DNA. Eleven clones from the L. pifanoi and the L. donovani screen were selected to evaluate the characteristics of the molecules identified by this approach. The CMAT screen identified genes whose homologs encode molecules with unknown function as well as genes that had previously been shown to be preferentially expressed in the amastigote form of the parasite. In addition a variant of Tryparedoxin peroxidase that is preferentially expressed within infected cells was identified. Antisera that were then raised to recombinant products of the clones were used to validate that the endogenous molecules are preferentially expressed in infected cells. Evaluation of the distribution of the endogenous molecules in infected cells showed that some of these molecules are secreted into parasitophorous vacuoles (PVs) and that they then traffic out of PVs in vesicles with distinct morphologies. This study is a proof of concept study that the CMAT approach can be applied to identify putative Leishmania parasite effectors molecules that are preferentially expressed in infected cells. In addition we provide evidence that Leishmania molecules traffic out of the PV into the host cell cytosol and nucleus. PMID- 20957201 TI - TcTASV: a novel protein family in trypanosoma cruzi identified from a subtractive trypomastigote cDNA library. AB - BACKGROUND: The identification and characterization of antigens expressed in Trypanosoma cruzi stages that parasitize mammals are essential steps for the development of new vaccines and diagnostics. Genes that are preferentially expressed in trypomastigotes may be involved in key processes that define the biology of trypomastigotes, like cell invasion and immune system evasion. METHODOLOGY/PRINCIPAL FINDINGS: With the initial aim of identifying trypomastigote-specific expressed tags, we constructed and sequenced an epimastigote-subtracted trypomastigote cDNA library (library TcT-E). More than 45% of the sequenced clones of the library could not be mapped to previously annotated mRNAs or proteins. We validated the presence of these transcripts by reverse northern blot and northern blot experiments, therefore providing novel information about the mRNA expression of these genes in trypomastigotes. A 280-bp consensus element (TcT-E element, TcT-Eelem) located at the 3' untranslated region (3' UTR) of many different open reading frames (ORFs) was identified after clustering the TcT-E dataset. Using an RT-PCR approach, we were able to amplify different mature mRNAs containing the same TcT-Eelem in the 3' UTR. The proteins encoded by these ORFs are members of a novel surface protein family in T. cruzi, (which we named TcTASV for T. cruzi Trypomastigote, Alanine, Serine and Valine rich proteins). All members of the TcTASV family have conserved coding amino- and carboxy-termini, and a central variable core that allows partitioning of TcTASV proteins into three subfamilies. Analysis of the T. cruzi genome database resulted in the identification of 38 genes/ORFs for the whole TcTASV family in the reference CL-Brener strain (lineage II). Because this protein family was not found in other trypanosomatids, we also looked for the presence of TcTASV genes in other evolutionary lineages of T. cruzi, sequencing 48 and 28 TcTASVs members from the RA (lineage II) and Dm28 (lineage I) T. cruzi strains respectively. Detailed phylogenetic analyses of TcTASV gene products show that this gene family is different from previously characterized mucin (TcMUCII), mucin-like, and MASP protein families. CONCLUSIONS/SIGNIFICANCE: We identified TcTASV, a new gene family of surface proteins in T. cruzi. PMID- 20957204 TI - When action meets emotions: how facial displays of emotion influence goal-related behavior. AB - Many authors have proposed that facial expressions, by conveying emotional states of the person we are interacting with, influence the interaction behavior. We aimed at verifying how specific the effect is of the facial expressions of emotions of an individual (both their valence and relevance/specificity for the purpose of the action) with respect to how the action aimed at the same individual is executed. In addition, we investigated whether and how the effects of emotions on action execution are modulated by participants' empathic attitudes. We used a kinematic approach to analyze the simulation of feeding others, which consisted of recording the "feeding trajectory" by using a computer mouse. Actors could express different highly arousing emotions, namely happiness, disgust, anger, or a neutral expression. Response time was sensitive to the interaction between valence and relevance/specificity of emotion: disgust caused faster response. In addition, happiness induced slower feeding time and longer time to peak velocity, but only in blocks where it alternated with expressions of disgust. The kinematic profiles described how the effect of the specificity of the emotional context for feeding, namely a modulation of accuracy requirements, occurs. An early acceleration in kinematic relative-to-neutral feeding profiles occurred when actors expressed positive emotions (happiness) in blocks with specific-to-feeding negative emotions (disgust). On the other hand, the end-part of the action was slower when feeding happy with respect to neutral faces, confirming the increase of accuracy requirements and motor control. These kinematic effects were modulated by participants' empathic attitudes. In conclusion, the social dimension of emotions, that is, their ability to modulate others' action planning/execution, strictly depends on their relevance and specificity to the purpose of the action. This finding argues against a strict distinction between social and nonsocial emotions. PMID- 20957203 TI - Yersinia virulence factor YopM induces sustained RSK activation by interfering with dephosphorylation. AB - BACKGROUND: Pathogenic yersiniae inject several effector proteins (Yops) into host cells, which subverts immune functions and enables the bacteria to survive within the host organism. YopM, whose deletion in enteropathogenic yersiniae results in a dramatic loss of virulence, has previously been shown to form a complex with and activate the multifunctional kinases PKN2 and RSK1 in transfected cells. METHODOLOGY/PRINCIPAL FINDINGS: In a near physiological approach with double-affinity-tagged YopM being translocated into the macrophage cell line J774A.1 via the natural type three secretion system of Yersinia we verified the interaction of YopM with PKN2 and RSK1 and detected association with additional PKN and RSK isoforms. In transfected and infected cells YopM induced sustained phosphorylation of RSK at its activation sites serine-380 and serine 221 even in the absence of signalling from its upstream kinase ERK1/2, suggesting inhibition of dephosphorylation. ATP-depletion and in vitro assays using purified components directly confirmed that YopM shields RSK isoforms from phosphatase activity towards serines 380 and 221. CONCLUSIONS/SIGNIFICANCE: Our study suggests that during Yersinia infection YopM induces sustained activation of RSK by blocking dephosphorylation of its activatory phosphorylation sites. This may represent a novel mode of action of a bacterial virulence factor. PMID- 20957205 TI - Trachoma rapid assessments in Unity and Northern Bahr-el-Ghazal States, Southern Sudan. AB - BACKGROUND: Trachoma is thought to be endemic over large parts of Southern Sudan, but empirical evidence is limited. While some areas east of the Nile have been identified as highly endemic, few trachoma surveys have been conducted in the remainder of the country. This study aimed to determine whether trachoma constitutes a problem to public health in Northern Bahr-el-Ghazal and Unity State, both located west of the Nile. METHODS AND PRINCIPAL FINDINGS: Trachoma rapid assessments (TRA) were conducted between July and September 2009. Seven villages in Northern Bahr-el-Ghazal State and 13 villages in Unity State were surveyed; an average of 50 children (age 1-9 years) and 44 women (age 15 years and above) were examined per village. Samples for analysis using the APTIMA Combo 2 nucleic acid amplification test (NAAT) were collected from participants with active trachoma in eight villages in Unity State. In Northern Bahr-el-Ghazal State, only three children with active trachoma (trachomatous inflammation follicular (TF) and/or trachomatous inflammation intense (TI)) and two women with trichiasis (TT) were found, in two of the seven villages surveyed. In Unity State, trachoma was endemic in all thirteen villages surveyed; the proportion of children with active trachoma ranged from 33% to 75% between villages, while TF in children ranged from 16% to 44%. Between 4% to 51% of examined women showed signs of TT. Samples from active trachoma cases tested using the NAAT were positive for Chlamydia trachomatis infection for 46.6% of children and 19.0% of women. CONCLUSIONS: Trachoma presents a major problem to public health Unity State, while the disease is of low priority in Northern-Bahr-el-Ghazal State. Implementation of a population-based prevalence survey is now required in Unity State to generate baseline prevalence data so that trachoma interventions can be initiated and monitored over time. PMID- 20957206 TI - Viewing ageing eyes: diverse sites of amyloid Beta accumulation in the ageing mouse retina and the up-regulation of macrophages. AB - BACKGROUND: Amyloid beta (Abeta) accumulates in the ageing central nervous system and is associated with a number of age-related diseases, including age-related macular degeneration (AMD) in the eye. AMD is characterised by accumulation of extracellular deposits called drusen in which Abeta is a key constituent. Abeta activates the complement cascade and its deposition is associated with activated macrophages. So far, little is known about the quantitative measurements of Abeta accumulation and definitions of its relative sites of ocular deposition in the normal ageing mouse. METHODOLOGY/PRINCIPAL FINDINGS: We have traced Abeta accumulation quantitatively in the ageing mouse retina using immunohistochemistry and Western blot analysis. We reveal that it is not only deposited at Bruch's membrane and along blood vessels, but unexpectedly, it also coats photoreceptor outer segments. While Abeta is present at all sites of deposition from 3 months of age, it increases markedly from 6 months onward. Progressive accumulation of deposits on outer segments was confirmed with scanning electron microscopy, revealing age-related changes in their morphology. Such progress of accumulation of Abeta on photoreceptor outer segments with age was also confirmed in human retinae using immunohistochemistry. We also chart the macrophage response to increases in Abeta showing up-regulation in their numbers using both confocal laser imaging of the eye in vivo followed by in vitro immunostaining. With age macrophages become bloated with cellular debris including Abeta, however, their increasing numbers fail to stop Abeta accumulation. CONCLUSIONS: Increasing Abeta deposition in blood vessels and Bruch's membrane will impact upon retinal perfusion and clearance of cellular waste products from the outer retina, a region of very high metabolic activity. This accumulation of Abeta may contribute to the 30% reduction of photoreceptors found throughout life and the shortening of those that remain. The coating of Abeta on outer segments may also have an impact upon visual function with age. PMID- 20957207 TI - Characterization of a novel esterase Rv0045c from Mycobacterium tuberculosis. AB - BACKGROUND: It was proposed that there are at least 250 enzymes in M. tuberculosis involved in lipid metabolism. Rv0045c was predicted to be a hydrolase by amino acid sequence similarity, although its precise biochemical characterization and function remained to be defined. METHODOLOGY/PRINCIPAL FINDINGS: We expressed the Rv0045c protein to high levels in E. coli and purified the protein to high purity. We confirmed that the prepared protein was the Rv0045c protein by mass spectrometry analysis. Circular dichroism spectroscopy analysis showed that the protein possessed abundant beta-sheet secondary structure, and confirmed that its conformation was stable in the range pH 6.0 10.0 and at temperatures <= 40 degrees C. Enzyme activity analysis indicated that the Rv0045c protein could efficiently hydrolyze short chain p-nitrophenyl esters (C2-C8), and its suitable substrate was p-nitrophenyl caproate (C6) with optimal catalytic conditions of 39 degrees C and pH 8.0. CONCLUSIONS/SIGNIFICANCE: Our results demonstrated that the Rv0045c protein is a novel esterase. These experiments will be helpful in understanding ester/lipid metabolism related to M. tuberculosis. PMID- 20957208 TI - Species diversity and distribution patterns of the ants of Amazonian Ecuador. AB - Ants are among the most diverse, abundant and ecologically significant organisms on earth. Although their species richness appears to be greatest in the New World tropics, global patterns of ant diversity and distribution are not well understood. We comprehensively surveyed ant diversity in a lowland primary rainforest in Western Amazonia, Ecuador using canopy fogging, pitfall traps, baits, hand collecting, mini-Winkler devices and subterranean probes to sample ants. A total of 489 ant species comprising 64 genera in nine subfamilies were identified from samples collected in only 0.16 square kilometers. The most species-rich genera were Camponotus, Pheidole, Pseudomyrmex, Pachycondyla, Brachymyrmex, and Crematogaster. Camponotus and Pseudomyrmex were most diverse in the canopy, while Pheidole was most diverse on the ground. The three most abundant ground-dwelling ant genera were Pheidole, Solenopsis and Pyramica. Crematogaster carinata was the most abundant ant species in the canopy; Wasmannia auropunctata was most abundant on the ground, and the army ant Labidus coecus was the most abundant subterranean species. Ant species composition among strata was significantly different: 80% of species were found in only one stratum, 17% in two strata, and 3% in all three strata. Elevation and the number of logs and twigs available as nest sites were significant predictors of ground-dwelling ant species richness. Canopy species richness was not correlated with any ecological variable measured. Subterranean species richness was negatively correlated with depth in the soil. When ant species were categorized using a functional group matrix based on diet, nest-site preference and foraging ecology, the greatest diversity was found in Omnivorous Canopy Nesters. Our study indicates ant species richness is exceptionally high at Tiputini. We project 647-736 ant species in this global hotspot of biodiversity. Considering the relatively small area surveyed, this region of western Amazonia appears to support the most diverse ant fauna yet recorded. PMID- 20957209 TI - Intermediate levels of hippocampal activity appear optimal for associative memory formation. AB - BACKGROUND: It is well established that hippocampal activity is positively related to effective associative memory formation. However, in biological systems often optimal levels of activity are contrasted by both sub- and supra-optimal levels. Sub-optimal levels of hippocampal activity are commonly attributed to unsuccessful memory formation, whereas the supra-optimal levels of hippocampal activity related to unsuccessful memory formation have been rarely studied. It is still unclear under what circumstances such supra-optimal levels of hippocampal activity occur. To clarify this issue, we aimed at creating a condition, in which supra-optimal hippocampal activity is associated with encoding failure. We assumed that such supra-optimal activity occurs when task-relevant information is embedded in task-irrelevant, distracting information, which can be considered as noise. METHODOLOGY/PRINCIPAL FINDINGS: In the present fMRI study, we probed neural correlates of associative memory formation in a full-factorial design with associative memory (subsequently remembered versus forgotten) and noise (induced by high versus low distraction) as factors. Results showed that encoding failure was associated with supra-optimal activity in the high-distraction condition and with sub-optimal activity in the low distraction condition. Thus, we revealed evidence for a bell-shape function relating hippocampal activity with associative encoding success. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that intermediate levels of hippocampal activity are optimal while both too low and too high levels appear detrimental for associative memory formation. Supra optimal levels of hippocampal activity seem to occur when task-irrelevant information is added to task-relevant signal. If such task-irrelevant noise is reduced adequately, hippocampal activity is lower and thus optimal for associative memory formation. PMID- 20957210 TI - A preliminary investigation regarding the effect of tennis grunting: does white noise during a tennis shot have a negative impact on shot perception? AB - BACKGROUND: There is a growing chorus of critics who complain that many of the top-ranked professional tennis players who grunt when they hit the ball gain an unfair advantage because the sound of the grunt interferes with their opponent's game. However, there is no scientific evidence to support this claim. METHODOLOGY/PRINCIPAL FINDINGS: We explored this potential detrimental effect of grunting by presenting videos of a tennis player hitting a ball to either side of a tennis court; the shot either did, or did not, contain a brief sound that occurred at the same time as contact. The participants' task was to respond as quickly as possible, indicating whether the ball was being hit to the left- or right-side of the court. The results were unequivocal: The presence of an extraneous sound interfered with a participants' performance, making their responses both slower and less accurate. CONCLUSIONS/SIGNIFICANCE: Our data suggest that a grunting player has a competitive edge on the professional tennis tour. The mechanism that underlies this effect is a topic for future investigation. Viable alternatives are discussed. For example, the possibility that the interfering auditory stimulus masks the sound of the ball being struck by the racket or it distracts an opponent's attention away from the sound of the ball. PMID- 20957211 TI - Neutralisation of interleukin-13 in mice prevents airway pathology caused by chronic exposure to house dust mite. AB - BACKGROUND: Repeated exposure to inhaled allergen can cause airway inflammation, remodeling and dysfunction that manifests as the symptoms of allergic asthma. We have investigated the role of the cytokine interleukin-13 (IL-13) in the generation and persistence of airway cellular inflammation, bronchial remodeling and deterioration in airway function in a model of allergic asthma caused by chronic exposure to the aeroallergen House Dust Mite (HDM). METHODOLOGY/PRINCIPAL FINDINGS: Mice were exposed to HDM via the intranasal route for 4 consecutive days per week for up to 8 consecutive weeks. Mice were treated either prophylactically or therapeutically with a potent neutralising anti-IL-13 monoclonal antibody (mAb) administered subcutaneously (s.c.). Airway cellular inflammation was assessed by flow cytometry, peribronchial collagen deposition by histocytochemistry and airway hyperreactivity (AHR) by invasive measurement of lung resistance (R(L)) and dynamic compliance (C(dyn)). Both prophylactic and therapeutic treatment with an anti-IL-13 mAb significantly inhibited (P<0.05) the generation and maintenance of chronic HDM-induced airway cellular inflammation, peribronchial collagen deposition, epithelial goblet cell upregulation. AHR to inhaled methacholine was reversed by prophylactic but not therapeutic treatment with anti-IL-13 mAb. Both prophylactic and therapeutic treatment with anti-IL-13 mAb significantly reversed (P<0.05) the increase in baseline R(L) and the decrease in baseline C(dyn) caused by chronic exposure to inhaled HDM. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that in a model of allergic lung disease driven by chronic exposure to a clinically relevant aeroallergen, IL-13 plays a significant role in the generation and persistence of airway inflammation, remodeling and dysfunction. PMID- 20957212 TI - A second dimension to the leaf economics spectrum predicts edaphic habitat association in a tropical forest. AB - BACKGROUND: Strong patterns of habitat association are frequent among tropical forest trees and contribute to the maintenance of biodiversity. The relation of edaphic differentiation to tradeoffs among leaf functional traits is less clear, but may provide insights into mechanisms of habitat partitioning in these species rich assemblages. METHODOLOGY/PRINCIPAL FINDINGS: We quantify the leaf economics spectrum (LES) for 16 tree species within a Bornean forest characterized by highly pronounced habitat specialization. Our findings suggest that the primary axis of trait variation in light-limited, lowland tropical forests was identical to the LES and corresponds with the shade tolerance continuum. There was no separation with respect to edaphic variation along this primary axis of trait variation. However, a second orthogonal axis determined largely by foliar P concentrations resulted in a near-perfect separation of species occupying distinct soil types within the forest. CONCLUSIONS/SIGNIFICANCE: We suggest that this second axis of leaf trait variation represents a "leaf edaphic habitat spectrum" related to foliar P and potentially other nutrients closely linked to geological substrate, and may generally occur in plant communities characterized by strong edaphic resource gradients. PMID- 20957213 TI - Safety and efficacy of azacitidine in myelodysplastic syndromes. AB - PURPOSE: The clinical efficacy, different dosages, treatment schedules, and safety of azacitidine are reviewed. SUMMARY: Azacitidine is the first drug FDA approved for the treatment of myelodysplastic syndromes that has demonstrated improvements in overall survival and delaying time to progression to acute myelogenous leukemia. The recommended dosage of azacitidine is 75 mg/m(2) daily for 7 days, with different treatment schedules validated. It appears to be well tolerated, with the most common adverse effects being myelosuppression. Several other off-label recommendations were also analyzed. CONCLUSION: Azacitidine is the first DNA hypomethylating agent approved by FDA for the treatment of myelodysplastic syndromes with demonstrated efficacy. PMID- 20957214 TI - Chimeric design, synthesis, and biological assays of a new nonpeptide insulin mimetic vanadium compound to inhibit protein tyrosine phosphatase 1B. AB - Prior to its total synthesis, a new vanadium coordination compound, called TSAG0101, was computationally designed to inhibit the enzyme protein tyrosine phosphatase 1B (PTP1B). The PTP1B acts as a negative regulator of insulin signaling by blocking the active site where phosphate hydrolysis of the insulin receptor takes place. TSAG001, [V(V)O(2)(OH)(picolinamide)], was characterized by infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy; IR: nu/cm(-1) 3,570 (NH), 1,627 (C=O, coordinated), 1,417 (C-N), 970/842 (O=V=O), 727 delta (pyridine ring); (13)C NMR: 5 bands between 122 and 151 ppm and carbonyl C shifted to 180 ppm; and (1)H NMR: 4 broad bands from 7.6 to 8.2 ppm and NH(2) shifted to 8.8 ppm. In aqueous solution, in presence or absence of sodium citrate as a biologically relevant and ubiquitous chelator, TSAG0101 undergoes neither ligand exchange nor reduction of its central vanadium atom during 24 hours. TSAG0101 shows blood glucose lowering effects in rats but it produced no alteration of basal- or glucose-induced insulin secretion on beta cells during in vitro tests, all of which excludes a direct mechanism evidencing the extrapancreatic nature of its activity. The lethal dose (LD(50)) of TSAG0101 was determined in Wistar mice yielding a value of 412 mg/kg. This value is one of the highest among vanadium compounds and classifies it as a mild toxicity agent when compared with literature data. Due to its nonsubstituted, small-sized scaffold design, its remarkable complex stability, and low toxicity; TSAG0101 should be considered as an innovative insulin-mimetic principle with promising properties and, therefore, could become a new lead compound for potential nonpeptide PTP1B inhibitors in antidiabetic drug research. In view of the present work, the inhibitory concentration (IC(50)) and extended solution stability will be tested. PMID- 20957215 TI - Current and developing therapeutic agents in the treatment of Chagas disease. AB - Chagas disease must be treated in all its stages: acute, indeterminate, chronic, and initial and middle determinant chronic, due to the fact that DNA of the parasite can be demonstrated by PCR in chronic cases, where optical microscopy does not detect parasites. Nifurtimox (NF) and benznidazole (BNZ) are the drugs accepted to treat humans based upon ethical considerations and efficiency. However, both the drugs produce secondary effects in 30% of the cases, and the treatment must be given for at least 30-60 days. Other useful drugs are itraconazole and posaconazole. The latter may be the drug to treat Chagas disease in the future when all the investigations related to it are finished. At present, there is no criterion of cure for chronic cases since in the majority, the serology remains positive, although it may decrease. In acute cases, 70% cure with NF and 75% with BNZ is achieved. In congenital cases, 100% cure is obtained if the treatment is performed during the first year of life. In chronic acquired cases, 20% cure and 50% improvement of the electrocardiographic changes are obtained with itraconazole. PMID- 20957216 TI - Thermosensitive Pluronic hydrogel: prolonged injectable formulation for drug abuse. AB - OBJECTIVE: The main objective of this study was to investigate thermosensitive Pluronic F-127 (PF-127) hydrogel for the modified release of a potent alcohol and opioid antagonist, naltrexone (NTX) hydrochloride, in a subcutaneous injectable dosage form. METHODS: The NTX hydrogels were prepared by the cold method, and the in vitro release profiles of various formulations were evaluated at 37 degrees C using the Franz diffusion cell system. We examined the different PF-127 concentrations, pH of solution, and inorganic salts on drug release from these gels. RESULTS: The data showed an increase in PF-127 content from 20% to 35%, resulting in a decrease in the rate of NTX release. Among the formulations prepared in different pH solutions, pH 7.4 produced the slowest drug release rate. The addition of inorganic salts had no significant effect on drug release. However, these factors appeared to have limited effects on drug release rate. Therefore, to achieve a sustained-release formulation, a NTX and triacetyl beta cyclodextrin (TAbetaCD) complex was evaluated. The binary systems of NTX/TAbetaCD in different molar ratios were prepared by the kneading method, and complex formation was demonstrated by differential scanning calorimetry. CONCLUSION: The results of the current in vitro study indicate that PF-127 gel formulations containing drug complexes with hydrophobic cyclodextrin could be useful for the preparation of a controlled delivery system of water-soluble drugs such as NTX, for a period of more than 140 hours. PMID- 20957217 TI - Human serum albumin nanoparticles as an efficient noscapine drug delivery system for potential use in breast cancer: preparation and in vitro analysis. AB - Drug delivery systems such as nanoparticles can provide enhanced efficacy for anticancer agents. Noscapine, a widely used cough suppressant for decades has recently been shown to cause significant inhibition and regression of tumor volumes without any detectable toxicity in cells or tissues. Nanoparticles made of human serum albumin (HSA) represent promising strategy for targeted drug delivery to tumor cells by enhancing the drug's bioavailability and distribution, and reducing the body's response towards drug resistance. In the present study, we report for the first time the incorporation and delivery of noscapine-loaded HSA nanoparticles to tumor cells. The nanoparticles were designed and optimized to achieve a particle size in the range of 150-300 nm with a drug-loading efficiency of 85%-96%. The nanoparticles were evaluated in vitro for their anticancer activity and efficacy on breast cancer cells. PMID- 20957218 TI - Preparation, characterization, and in vitro targeted delivery of folate-decorated paclitaxel-loaded bovine serum albumin nanoparticles. AB - Paclitaxel (Taxol((r))) is an important anticancer drug in clinical use for treatment of a variety of cancers. Because of its low solubility, it is formulated in high concentration in Cremophor EL((r)) which induces hypersensitivity reactions. In this study, targeted delivery of paclitaxel-loaded nanoparticles was prepared by a desolvation procedure, crosslinked on the wall material of bovine serum albumin, and subsequently decorated by folic acid. The characteristics of the nanoparticles, such as amount of folate conjugation, surface morphology, drug entrapment efficiency, drug loading efficiency, and release kinetics were investigated in vitro. The targeting effect was investigated in vitro by cancer cell uptake of fluorescein isothiocyanate-labeled nanoparticles. The spherical nanoparticles obtained were negatively charged with a zeta potential of about -30 mV, and characterized around 210 nm with a narrow size distribution. Drug entrapment efficiency and drug loading efficiency were approximately 95.3% and 27.2%, respectively. The amount of folate conjugation was 9.22 MUg/mg of bovine serum albumin. The folate-decorated nanoparticles targeted a human prostate cancer cell line effectively. PMID- 20957219 TI - Modification of composition of a nanoemulsion with different cholesteryl ester molecular species: effects on stability, peroxidation, and cell uptake. AB - PURPOSE: Use of lipid nanoemulsions as carriers of drugs for therapeutic or diagnostic purposes has been increasingly studied. Here, it was tested whether modifications of core particle constitution could affect the characteristics and biologic properties of lipid nanoemulsions. METHODS: Three nanoemulsions were prepared using cholesteryl oleate, cholesteryl stearate, or cholesteryl linoleate as main core constituents. Particle size, stability, pH, peroxidation of the nanoemulsions, and cell survival and uptake by different cell lines were evaluated. RESULTS: It was shown that cholesteryl stearate nanoemulsions had the greatest particle size and all three nanoemulsions were stable during the 237-day observation period. The pH of the three nanoemulsion preparations tended to decrease over time, but the decrease in pH of cholesteryl stearate was smaller than that of cholesteryl oleate and cholesteryl linoleate. Lipoperoxidation was greater in cholesteryl linoleate than in cholesteryl oleate and cholesteryl stearate. After four hours' incubation of human umbilical vein endothelial cells (HUVEC) with nanoemulsions, peroxidation was minimal in the presence of cholesteryl oleate and more pronounced with cholesteryl linoleate and cholesteryl stearate. In contrast, macrophage incubates showed the highest peroxidation rates with cholesteryl oleate. Cholesteryl linoleate induced the highest cell peroxidation rates, except in macrophages. Uptake of cholesteryl oleate nanoemulsion by HUVEC and fibroblasts was greater than that of cholesteryl linoleate and cholesteryl stearate. Uptake of the three nanoemulsions by monocytes was equal. Uptake of cholesteryl oleate and cholesteryl linoleate by macrophages was negligible, but macrophage uptake of cholesteryl stearate was higher. In H292 tumor cells, cholesteryl oleate showed the highest uptakes. HUVEC showed higher survival rates when incubated with cholesteryl stearate and smaller survival with cholesteryl linoleate. H292 survival was greater with cholesteryl stearate. CONCLUSION: Although all three nanoemulsion types were stable for a long period, considerable differences were observed in size, oxidation status, and cell survival and nanoemulsion uptake in all tested cell lines. Those differences may be helpful in protocol planning and interpretation of data from experiments with lipid nanoemulsions. PMID- 20957220 TI - Effects of TAT-conjugated platinum nanoparticles on lifespan of mitochondrial electron transport complex I-deficient Caenorhabditis elegans, nuo-1. AB - Platinum nanoparticle (Pt-np) species are superoxide dismutase/catalase mimetics and also have an activity similar to that of mitochondrial electron transport complex I. To examine if this complex I-like activity functions in vivo, we studied the effects of Pt-nps on the lifespan of a mitochondrial complex I deficient Caenorhabditis elegans mutant, nuo-1 (LB25) compared with wild-type N2. We synthesized a fusion protein of a cell-penetrating peptide, human immunodeficiency virus-1 TAT (48-60), C-terminally linked to a peptide with a high affinity to platinum (GRKKRRQRRRPPQ-DRTSTWR). Pt-nps were functionalized by conjugation with this fusion protein at a 1:1 ratio of TAT-PtBP to Pt atoms. Adult worms were treated with conjugated Pt-nps for 10 days. The mean lifespan of untreated N2 and LB25 was 19.6 +/- 0.4 and 11.8 +/- 0.3 days, respectively. Using 5 MUM of conjugated Pt-nps, the lifespan of N2 and LB25 was maximally extended. This maximal lifespan extension of LB25 was 31.9 +/- 2.6%, which was significantly greater than that of N2 (21.1 +/- 1.7%, P < 0.05 by Student's t test). Internalization of Pt into the whole body and mitochondria was similar between these two strains. Excessive accumulation of reactive oxygen species was not observed in the cytosol or mitochondria of untreated LB25. Treatment for five days with 5 MUM conjugated Pt-nps decreased cytosolic and mitochondrial reactive oxygen species in N2 and LB25 to a similar extent. The ratio of [NAD(+)]/[NADH] was very low in the whole body and mitochondria of control LB25. After five days of treatment with 5 MUM conjugated Pt-nps, the ratio of [NAD(+)]/[NADH] was increased in N2 and LB25. However, the degree of the increase was much higher in LB25 than in N2. Pt-nps function as NADH oxidase and recover the [NAD(+)]/[NADH] ratio in LB25, leading to effective extension of the lifespan of LB25. PMID- 20957221 TI - Luteinizing hormone-releasing hormone receptor-mediated delivery of mitoxantrone using LHRH analogs modified with PEGylated liposomes. AB - A sterically stabilized, mitoxantrone-loaded liposome, tailored to target luteinizing hormone-releasing hormone (LHRH) receptor overexpressing cells, was developed to promote the efficiency of intracellular delivery of mitoxantrone through receptor-mediated endocytosis. Liposomes were prepared by lipid film hydration and an ultrasound dispersion process. Thiolated gonadorelin with affinity for the LHRH receptor was chemically coupled to N-[(3-maleimide-1 oxopropyl) aminopropyl polyethylene glycol-carbamyl] distearoyl-l-phosphatidyl ethanolamine via a thioether bond and subsequently inserted into polyethylene glycol-grafted liposomes. The liposome was characterized in terms of its size, ligand density, drug loading, and leakage properties. The targeting nature and antitumor effects of the liposomes were evaluated in vitro using cultured MCF-7 breast cancer cells. A protein assay of ligand coupling to the liposomal surface indicated that more than 60% of the LHRH peptides were inserted into the liposome bilayer. Up to 1.0 mg/mL of stable liposomal mitoxantrone loading was achieved, with approximately 98% of this being entrapped within the liposomes. In vitro cell culture studies revealed that the gonadorelin-modified liposomes bound to their target cells had significantly higher affinity and better antitumor efficiency than generic drug-loaded liposomes. These events were presumed to occur through specific interactions of the LHRH with its cognate receptors on the cell surface. It was concluded that the targeting properties of the delivery system would potentially improve the therapeutic benefits of mitoxantrone, as compared with nontargeted liposomes. PMID- 20957222 TI - Synthesis and evaluation of nanoglobule-cystamine-(Gd-DO3A), a biodegradable nanosized magnetic resonance contrast agent for dynamic contrast-enhanced magnetic resonance urography. AB - Dynamic contrast-enhanced magnetic resonance imaging has been recently shown to be effective for diagnostic urography. High-resolution urographic images can be acquired with T1 contrast agents for the kidney and urinary tract with minimal noise in the abdomen. Currently, clinical contrast agents are low molecular weight agents and can rapidly extravasate from blood circulation, leading to slow contrast agent elimination through kidney and consequently providing limited contrast enhancement in urinary tract. In this study, a new biodegradable macromolecular contrast agent, nanoglobule-G4-cystamine-(Gd-DO3A), was prepared by conjugating Gd-DO3A chelates on the surface of a generation 4 nanoglobule, poly-L-lysine octa(3-aminopropyl)silsesquioxane dendrimer, via a disulfide spacer, where the carrier had a precisely defined nanosize that is far smaller than the renal filtration threshold. The in vivo contrast enhancement and dynamic imaging of the urinary tract of the agent was evaluated in nude mice using a low molecular weight agent Gd(DTPA-BMA) as a control. The agent eliminated rapidly from blood circulation and accumulated more abundantly in urinary tract than Gd(DTPA-BMA). The fast elimination kinetics is ideal for functional evaluation of the kidneys. The morphology of the kidneys and urinary tract was better visualized by the biodegradable nanoglobular contrast agent than Gd(DTPA-BMA). The agent also resulted in low liver contrast enhancement, indicating low nonspecific tissue deposition. These features render the G4 nanoglobule-cystamine (Gd-DO3A) conjugate a promising contrast agent for magnetic resonance urography. PMID- 20957225 TI - Genomic instability of I elements of Drosophila melanogaster in absence of dysgenic crosses. AB - Retrotranspostion of I factors in the female germline of Drosophila melanogaster is responsible for the so called I-R hybrid dysgenesis, a phenomenon that produces a broad spectrum of genetic abnormalities including reduced fertility, increased frequency of mutations and chromosome loss. Transposition of I factor depends on cellular conditions that are established in the oocytes of the reactive females and transmitted to their daughters. The so-called reactivity is a cellular state that may exhibit variable levels of expression and represents a permissive condition for I transposition at high levels. Defective I elements have been proposed to be the genetic determinants of reactivity and, through their differential expression, to modulate transposition of active copies in somatic and/or germ line cells. Recently, control of transposable element activity in the germ line has been found to depend on pi-RNAs, small repressive RNAs interacting with Piwi-family proteins and derived from larger transposable elements (TE)-derived primary transcripts. In particular, maternally transmitted I-element piRNAs originating from the 42AB region of polytene chromosomes were found to be involved in control of I element mobility. In the present work, we use a combination of cytological and molecular approaches to study the activity of I elements in three sublines of the inducer y; cn bw; sp isogenic strain and in dysgenic and non-dysgenic genetic backgrounds. Overall, the results of FISH and Southern blotting experiments clearly show that I elements are highly unstable in the Montpellier subline in the absence of classical dysgenic conditions. Such instability appears to be correlated to the amount of 5' and 3' I element transcripts detected by quantitative and real-time RT-PCR. The results of this study indicate that I elements can be highly active in the absence of a dysgenic crosses. Moreover, in the light of our results caution should be taken to assimilate the genomic annotation data on transposable elements to all y; cn bw sp sublines. PMID- 20957226 TI - A scientometric prediction of the discovery of the first potentially habitable planet with a mass similar to Earth. AB - BACKGROUND: The search for a habitable extrasolar planet has long interested scientists, but only recently have the tools become available to search for such planets. In the past decades, the number of known extrasolar planets has ballooned into the hundreds, and with it, the expectation that the discovery of the first Earth-like extrasolar planet is not far off. METHODOLOGY/PRINCIPAL FINDINGS: Here, we develop a novel metric of habitability for discovered planets and use this to arrive at a prediction for when the first habitable planet will be discovered. Using a bootstrap analysis of currently discovered exoplanets, we predict the discovery of the first Earth-like planet to be announced in the first half of 2011, with the likeliest date being early May 2011. CONCLUSIONS/SIGNIFICANCE: Our predictions, using only the properties of previously discovered exoplanets, accord well with external estimates for the discovery of the first potentially habitable extrasolar planet and highlight the the usefulness of predictive scientometric techniques to understand the pace of scientific discovery in many fields. PMID- 20957227 TI - Generation of human antigen-specific monoclonal IgM antibodies using vaccinated "human immune system" mice. AB - BACKGROUND: Passive transfer of antibodies not only provides immediate short-term protection against disease, but also can be exploited as a therapeutic tool. However, the 'humanization' of murine monoclonal antibodies (mAbs) is a time consuming and expensive process that has the inherent drawback of potentially altering antigenic specificity and/or affinity. The immortalization of human B cells represents an alternative for obtaining human mAbs, but relies on the availability of biological samples from vaccinated individuals or convalescent patients. In this work we describe a novel approach to generate fully human mAbs by combining a humanized mouse model with a new B cell immortalization technique. METHODOLOGY/PRINCIPAL FINDINGS: After transplantation with CD34+CD38- human hematopoietic progenitor cells, BALB/c Rag2-/-IL-2Rgammac-/- mice acquire a human immune system and harbor B cells with a diverse IgM repertoire. "Human Immune System" mice were then immunized with two commercial vaccine antigens, tetanus toxoid and hepatitis B surface antigen. Sorted human CD19+CD27+ B cells were retrovirally transduced with the human B cell lymphoma (BCL)-6 and BCL-XL genes, and subsequently cultured in the presence of CD40-ligand and IL-21. This procedure allows generating stable B cell receptor-positive B cells that secrete immunoglobulins. We recovered stable B cell clones that produced IgM specific for tetanus toxoid and the hepatitis B surface antigen, respectively. CONCLUSION/SIGNIFICANCE: This work provides the proof-of-concept for the usefulness of this novel method based on the immunization of humanized mice for the rapid generation of human mAbs against a wide range of antigens. PMID- 20957228 TI - Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity. AB - BACKGROUND: Recently, there has been a surge of interest in developing compounds selectively targeting mitochondria for the treatment of neoplasms. The critical role of mitochondria in cellular metabolism and respiration supports this therapeutic rationale. Dysfunction in the processes of energy production and metabolism contributes to attenuation of response to pro-apoptotic stimuli and increased ROS production both of which are implicated in the initiation and progression of most human cancers. METHODOLOGY/PRINCIPAL FINDINGS: A high throughput MTT-based screen of over 10,000 drug-like small molecules for anti proliferative activity identified the phosphonium salts TP187, 197 and 421 as having IC50 concentrations in the submicromolar range. TP treatment induced cell cycle arrest independent of p53 status, as determined by analysis of DNA content in propidium iodide stained cells. In a mouse model of human breast cancer, TP treated mice showed significantly decreased tumor growth compared to vehicle or paclitaxel treated mice. No toxicities or organ damage were observed following TP treatment. Immunohistochemical staining of tissue sections from TP187-treated tumors demonstrated a decrease in cellular proliferation and increased caspase-3 cleavage. The fluorescent properties of analog TP421 were exploited to assess subcellular uptake of TP compounds, demonstrating mitochondrial localization. Following mitochondrial uptake cells exhibited decreased oxygen consumption and concomittant increase in mitochondrial superoxide production. Proteomics analysis of results from a 600 target antibody microarray demonstrated that TP compounds significantly affected signaling pathways relevant to growth and proliferation. CONCLUSIONS/SIGNIFICANCE: Through our continued interest in designing compounds targeting cancer-cell metabolism, the Warburg effect, and mitochondria we recently discovered a series of novel, small-molecule compounds containing a triphenylphosphine moiety that show remarkable activity in a panel of cancer cell lines as well as in a mouse model of human breast cancer. The mechanism of action includes mitochondrial localization causing decreased oxygen consumption, increased superoxide production and attenuated growth factor signaling. PMID- 20957229 TI - A network approach to predict pathogenic genes for Fusarium graminearum. AB - Fusarium graminearum is the pathogenic agent of Fusarium head blight (FHB), which is a destructive disease on wheat and barley, thereby causing huge economic loss and health problems to human by contaminating foods. Identifying pathogenic genes can shed light on pathogenesis underlying the interaction between F. graminearum and its plant host. However, it is difficult to detect pathogenic genes for this destructive pathogen by time-consuming and expensive molecular biological experiments in lab. On the other hand, computational methods provide an alternative way to solve this problem. Since pathogenesis is a complicated procedure that involves complex regulations and interactions, the molecular interaction network of F. graminearum can give clues to potential pathogenic genes. Furthermore, the gene expression data of F. graminearum before and after its invasion into plant host can also provide useful information. In this paper, a novel systems biology approach is presented to predict pathogenic genes of F. graminearum based on molecular interaction network and gene expression data. With a small number of known pathogenic genes as seed genes, a subnetwork that consists of potential pathogenic genes is identified from the protein-protein interaction network (PPIN) of F. graminearum, where the genes in the subnetwork are further required to be differentially expressed before and after the invasion of the pathogenic fungus. Therefore, the candidate genes in the subnetwork are expected to be involved in the same biological processes as seed genes, which imply that they are potential pathogenic genes. The prediction results show that most of the pathogenic genes of F. graminearum are enriched in two important signal transduction pathways, including G protein coupled receptor pathway and MAPK signaling pathway, which are known related to pathogenesis in other fungi. In addition, several pathogenic genes predicted by our method are verified in other pathogenic fungi, which demonstrate the effectiveness of the proposed method. The results presented in this paper not only can provide guidelines for future experimental verification, but also shed light on the pathogenesis of the destructive fungus F. graminearum. PMID- 20957230 TI - Variation in courtship ultrasounds of three Ostrinia moths with different sex pheromones. AB - Moths use ultrasounds as well as pheromones for sexual communication. In closely related moth species, variations in ultrasounds and pheromones are likely to profoundly affect mate recognition, reproductive isolation, and speciation. The European corn borer, Ostrinia nubilalis, and its Asian congeners, Ostrinia furnacalis and Ostrinia scapulalis, exhibit within-species and between-species variation in their pheromone communication. Recently, we reported ultrasound communication in O. furnacalis; however, variations in ultrasounds in the three congeners have not been addressed to date. Here we investigated features of ultrasound production and hearing in O. nubilalis and O. scapulalis, and compared them with those of O. furnacalis. As in O. furnacalis, males of O. nubilalis and O. scapulalis produced ultrasounds during courtship by rubbing specialized scales on the wings against scales on the thorax. The covering of these scales with nail polish muffled the sounds and significantly reduced mating success in O. nubilalis, showing the importance of ultrasound signaling in mating. The ultrasounds produced by O. nubilalis and O. scapulalis were similar, consisting of long trains of pairs of pulses with a main energy at 40 kHz, but distinctly different from the ultrasound produced by O. furnacalis, consisting of groups of pulses peaking at 50 kHz and with substantially more energy up to 80 kHz. Despite overall similarities, temporal features and patterns of amplitude modulation differed significantly among the geographic populations of O. nubilalis and O. scapulalis, which differed in pheromone type. In contrast, no significant difference in hearing was found among the three species with regard to the most sensitive frequencies and hearing threshold levels. The patterns of variations in the songs and pheromones well reflected those of the phylogenetic relationships, implying that ultrasound and pheromone communications have diverged concordantly. Our results suggest that concordant evolution in sexual signals such as courtship ultrasounds and sex pheromones occurs in moths. PMID- 20957231 TI - Enterococcus faecalis endocarditis severity in rabbits is reduced by IgG Fabs interfering with aggregation substance. AB - BACKGROUND: Enterococcus faecalis is a significant cause of infective endocarditis, an infection of the heart endothelium leading to vegetation formation (microbes, fibrin, platelets, and host cells attached to underlying endothelial tissue). Our previous research determined that enterococcal aggregation substance (AS) is an important virulence factor in causation of endocarditis, although endocarditis may occur in the absence of AS production. Production of AS by E. faecalis causes the organism to form aggregates through AS binding to enterococcal binding substance. In this study, we assessed the ability of IgGs and IgG Fabs against AS to provide protection against AS+ E. faecalis endocarditis. METHODOLOGY/PRINCIPAL FINDINGS: When challenged with AS+ E. faecalis, 10 rabbits actively immunized against AS+ E. faecalis developed more significant vegetations than 9 animals immunized against AS-E. faecalis, and 9/10 succumbed compared to 2/9 (p<0.005), suggesting enhanced aggregation by IgG contributes significantly to disease. IgG antibodies against AS also enhanced enterococcal aggregation as tested in vitro. In contrast, Fab fragments of IgG from rabbits immunized against purified AS, when passively administered to rabbits (6/group) immediately before challenge with AS+E. faecalis, reduced total vegetation (endocarditis lesion) microbial counts (7.9 x 106 versus 2.0 x 105, p = 0.02) and size (40 mg versus 10, p = 0.05). In vitro, the Fabs prevented enterococcal aggregation. CONCLUSIONS/SIGNIFICANCE: The data confirm the role of AS in infective endocarditis formation and suggest that use of Fabs against AS will provide partial protection from AS+E. faecalis illness. PMID- 20957232 TI - Distribution of Phoxinus eos, Phoxinus neogaeus, and their asexually-reproducing hybrids (Pisces: Cyprinidae) in Algonquin Provincial Park, Ontario. AB - Hybrid Phoxinus are one of the few asexually reproducing vertebrates species. The distribution of hybrid Phoxinus among lakes in Algonquin Park, Ontario, was evaluated relative to the distribution of parental species and relative to physiochemical lake characteristics. No association between the distribution of hybrids and the distribution of parental species was found, suggesting that the hybrids can successfully coexist with either parental species. In addition, we found no association between hybrid distribution and the physiochemical characteristics of lakes, suggesting that the hybrids are generalists with respect to the ecological niches available in Algonquin Park. There was a difference between the physiochemical characteristics of lakes with and without the parental species P. neogaeus. The lakes containing P. neogaeus were lower elevation than the lakes containing the other parental species, P. eos. The difference in distribution between the parental species may therefore be due to different dispersal abilities, to later arrival following post-glacial dispersal, or to differences in ecology. These results suggest that asexual reproduction is a successful strategy for hybrid Phoxinus in Algonquin Park because these sperm dependent asexual hybrids are able to survive and persist regardless of which parental species is present, and regardless of the physiochemical characteristics of their habitat. PMID- 20957233 TI - Natural killer cell tolerance persists despite significant reduction of self MHC class I on normal target cells in mice. AB - BACKGROUND: A major group of murine inhibitory receptors on Natural Killer (NK) cells belong to the Ly49 receptor family and recognize MHC class I molecules. Infected or transformed target cells frequently downmodulate MHC class I molecules and can thus avoid CD8(+) T cell attack, but may at the same time develop NK cell sensitivity, due to failure to express inhibitory ligands for Ly49 receptors. The extent of MHC class I downregulation needed on normal cells to trigger NK cell effector functions is not known. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we show that cells expressing MHC class I to levels well below half of the host level are tolerated in an in vivo assay in mice. Hemizygous expression (expression from only one allele) of MHC class I was sufficient to induce Ly49 receptor downmodulation on NK cells to a similar degree as homozygous expression, despite a strongly reduced cell surface level of MHC class I. Co-expression of weaker MHC class I ligands in the host did not have any further effect on the degree of Ly49 downmodulation. Furthermore, a single MHC class I allele could downmodulate up to three Ly49 receptors on individual NK cells. Only when NK cells simultaneously expressed several Ly49 receptors and hemizygous MHC class I levels, a putative threshold for Ly49 downmodulation was reached. CONCLUSION: Collectively, our findings suggest that in interactions between NK cells and normal untransformed cells, MHC class I molecules are in most cases expressed in excess compared to what is functionally needed to ensure self tolerance and to induce maximal Ly49 downmodulation. We speculate that the reason for this is to maintain a safety margin for otherwise normal, autologous cells over a range of MHC class I expression levels, in order to ensure robustness in NK cell tolerance. PMID- 20957234 TI - Nanoparticle based enhancement of electrochemical DNA hybridization signal using nanoporous electrodes. AB - A novel nanoparticle-based enhanced methodology for the detection of ssDNA using nanoporous alumina filter membranes, containing pores of 200 nm in diameter, is reported. The blockage of the pores due to the hybridization is detected by measuring the decrease in the differential pulse voltammetric response of the [Fe(CN)(6)](4-/3-) redox indicator and using screen-printed carbon electrodes as transducing platform. Furthermore, 20 nm gold nanoparticle (AuNPs) tags are used in order to increase the sensitivity of the assay. The enhancement mechanism of DNA detection is due to an additional blocking effect induced by hybridization reaction by bringing AuNPs inside the pores. The developed methodology can be extended to other biosensing systems with interest not only for DNA but also for proteins and cells. The developed nanochannel/nanoparticle biosensing system would have enormous potential in future miniaturized designs adapted to mass production technologies such as screen-printing technology. PMID- 20957235 TI - Artificial light-harvesting antennae: electronic energy transfer by way of molecular funnels. AB - Electronic energy transfer (EET) plays a critical role in many biological processes and is used by nature to direct energy to a site where chemical reactions need to be initiated. Such EET can occur over large distances and can involve many individual molecules of identical, similar or disparate chemical identity. Advances in spectroscopy and data processing have allowed the rates of EET to be measured on extremely fast timescales such that improved mechanistic insight becomes feasible. At the same time, highly sophisticated synthetic operations have been devised that facilitate the isolation and purification of elaborate multi-component molecular arrays. A key feature of these arrays concerns the logical positioning of individual units in a way that favours directed EET along the molecular axis or along some other preferred pathway. The availability of these novel molecular materials allows close examination of popular theoretical models and paves the way for the development of advanced molecular sensors, artificial light harvesters, fluorescent labels and sensitizers. Of particular interest is the spectacular growth in the application of boron dipyrromethene dyes as basic reagents in such artificial photon collectors and these compounds have dominated the market in recent years because of their synthetic versatility and valuable photophysical properties. In this article, recent developments in the field are highlighted in terms of synthesis and subsequent spectroscopic exploration. PMID- 20957236 TI - Metal-ion responsive redox polyelectrolyte multilayers. AB - We present polyelectrolyte multilayer modified electrodes exhibiting novel chemically responsive redox behaviour due to the combination of both redox and metal-ion-ligand functionalities on the same sites. PMID- 20957237 TI - Hoveyda-Grubbs catalyst confined in the nanocages of SBA-1: enhanced recyclability for olefin metathesis. AB - Via a simple adsorption, the second generation Hoveyda-Grubbs catalyst was successfully immobilized on a mesoporous material SBA-1, leading to a highly recyclable solid catalyst for olefin metathesis. PMID- 20957238 TI - Powder X-ray diffraction observations of ice crystals formed from disaccharide solutions. AB - Powder X-ray diffraction (PXRD) measurements on rapid freezing samples of disaccharide (trehalose, sucrose, and maltose) solutions indicated that the crystalline phases in the sample were both hexagonal and cubic ice. The cubic ice existed at a higher ratio in the higher disaccharide concentration samples. The temperature ramping experiments revealed that the cubic ice was stable below 233 K, which was obviously higher than the temperature expected for a pure water system. The diffraction peak width of the hexagonal ice crystal was independent in the disaccharide concentrations. This indicated that the crystallite size of the hexagonal ice was more than several hundreds of nanometre, which coincided with the ice particle size previously observed in the freeze-fractured replica samples. The comparison of the present PXRD data with the replica observations by transmission electron microscope in an earlier study allows us to conclude that the cubic ice was formed at the grain boundary between the hexagonal ice and the coexisted non-crystalline disaccharide phase. PMID- 20957239 TI - Synthesis and characterisation of low valent Mn-complexes as models for Mn catalases. AB - In this work we report the synthesis of two novel manganese complexes, [L1(3)Mn(II)(6)](ClO(4))(6) (1.(ClO(4))(6)) and [L2Mn(II)(2)(MU-OAc)(MU Cl)](ClO(4))(2) (2.(ClO(4))(2)), where L1(2-) is the 2,2'-(1,3 phenylenebis(methylene))bis((2-(bis(pyridin-2 ylmethyl)amino)ethyl)azanediyl)diacetic acid anion and L2 is N1,N1'-(1,3 phenylenebis(methylene))bis(N2,N2'-bis(pyridin-2-ylmethyl)ethane-1,2-diamine). The ligands Na(2)L1 and L2 are built on the same backbone, L2 only contains nitrogen donors, while two carboxylate arms have been introduced in Na(2)L1. The two complexes have been characterized by single-crystal X-ray diffraction, magnetic susceptibility, EPR spectroscopy, and electrochemistry. X-Ray crystallography revealed that 1 is a manganese(II) hexamer and 2 is a manganese(II) dimer featuring an unprecedented mono-MU-acetato, mono-MU-chlorido bridging motif. The ability of the complexes to catalyse H(2)O(2) disproportionation, thereby acting as models for manganese catalases, has been investigated and compared to the activity of two other related manganese complexes. The introduction of carboxylate donors in the ligands, leading to increased denticity, resulted in a drop in H(2)O(2) disproportionation activity. PMID- 20957240 TI - Generation of benzyne from benzoic acid using C-H activation. AB - ortho C-H activation of benzoic acids with Pd(II) generates an oxapalladacycle that can decarboxylate to produce a palladium-associated aryne. The arynes then undergo [2+2+2] trimerisation to afford triphenylenes. PMID- 20957241 TI - Electrochemical formation and investigation of a self-assembled [60]fullerene monolayer. AB - The formation and characterisation of a C(60) monolayer at the electrode|electrolyte interface has been studied by cyclic voltammetry, potential step chronoamperometry and ac voltammetry. The presence of the monolayer is evidenced by the presence of a very sharp peak P in the voltammogram, attributed to the faradaic phase formation of an ordered monolayer, and of a reduction post peak Q associated with the reduction of adsorbed species. The chronoamperograms exhibit a well-defined maximum, characteristic of a nucleation and growth mechanism. By comparison with existing models of phase transitions, a progressive polynucleation and growth mechanism is demonstrated. The monolayer is proposed to consist of a 2D fulleride salt. It is suggested that the formation of the monolayer can take place for a broad range of solution compositions, but requires an atomically smooth substrate such as mercury. PMID- 20957242 TI - Unsaturation and variable hapticity in binuclear azulene manganese carbonyl complexes. AB - Azulene is reported to react with Mn(2)(CO)(10) to give trans C(10)H(8)Mn(2)(CO)(6), which has been shown by X-ray crystallography to have a bis(pentahapto) structure with no metal-metal bond. This structure is found by density functional theory to be the lowest energy C(10)H(8)Mn(2)(CO)(6) structure. However, a corresponding bis(pentahapto) cis-C(10)H(8)Mn(2)(CO)(6) structure, also without an Mn...Mn bond, lies within ~1 kcal mol(-1) of this global minimum. The lowest energy C(10)H(8)Mn(2)(CO)(5) structure is singlet cis eta(5),eta(5)-C(10)H(8)Mn(2)(CO)(5) with an Mn->Mn dative bond from the Mn(CO)(3) group to the Mn(CO)(2) group. However, a singlet cis-eta(6),eta(4) C(10)H(8)Mn(2)(CO)(5) structure with a normal Mn-Mn single bond lies within ~6 kcal mol(-1) of this global minimum. The lowest energy structures of the more highly unsaturated C(10)H(8)Mn(2)(CO)(n) (n = 4, 3, 2) systems all have cis geometries and manganese-manganese bonds of various orders. The corresponding global minima are triplet cis-eta(5),eta(3)-C(10)H(8)Mn(2)(CO)(3)(eta(2)-MU-CO) for the tetracarbonyl with a four-electron donor bridging carbonyl group, singlet cis-eta(5),eta(5)-C(10)H(8)Mn(2)(CO)(3) for the tricarbonyl, and triplet cis eta(6),eta(4)-C(10)H(8)Mn(2)(CO)(eta(2)-MU-CO) for the dicarbonyl. PMID- 20957244 TI - Polymer adsorption onto a micro-sphere from optical tweezers electrophoresis. AB - We explore the design and operation of an optical-tweezers electrophoresis apparatus to resolve polymer adsorption dynamics onto a single micro-sphere in a micro-fluidic environment. Our model system represents a broader class of micro fluidic electrophoresis experiments for biosensing and fundamental colloid and surface science diagnostics. We track the adsorption of 100 kDa poly(ethylene oxide) homopolymer onto a colloidal silica sphere that is optically trapped in a crossed parallel-plate micro-channel. The adsorption dynamics are probed on the ~1 MUm particle length scale with ~1 s temporal resolution. Because the particle electrophoretic mobility and channel electro-osmotic flow are exquisitely sensitive to the polymer layer hydrodynamic thickness, particle dynamics can be complicated by polymer adsorption onto the micro-channel walls. Nevertheless, using experiments and a theoretical model of electro-osmotic flow in channels with non-uniform wall zeta-potentials, we show that such influences can be mitigated by adopting a symmetrical flow configuration. The equilibrium hydrodynamic layer thickness of 100 kDa poly(ethylene oxide) on colloidal silica is ~10 nm at polymer concentrations ?10 ppm (weight percent), with the dynamics reflecting polymer solution concentration, flow rate, and polydispersity. PMID- 20957243 TI - Luminescent ruthenium probe for the determination of acetyl phosphate in complex biological matrices. AB - The first probe for the fluorogenic determination of acetyl phosphate (AcP), (bpy)(2)Ru(1,10-phenanthroline-5,6-dione dioxime) (RuPDO), was prepared and its reaction with AcP was studied in detail. The emission of the weakly luminescent RuPDO is red shifted and strongly enhanced upon reaction with AcP in the presence of metal cations like Zn(2+) or Cu(2+). The reaction occurs within 60 min incubation time under highly biocompatible conditions (aqueous buffer of pH 7, 37 degrees C). A linear dynamic range from 10 to 200 umol L(-1) is observed with an LOD of AcP of 3.4 umol L(-1) (for RuPDO-Zn). Other bio-phosphates studied show only weak interference. Furthermore, the applicability of the probe in complex biological matrices was evaluated. PMID- 20957246 TI - Protein glycosylation--an evolutionary crossroad between genes and environment. AB - The majority of molecular processes in higher organisms are performed by various proteins and are thus determined by genes that encode these proteins. However, a significant structural component of at least half of all cellular proteins is not a polypeptide encoded by a single gene, but an oligosaccharide (glycan) synthesized by a network of proteins, resulting from the expression of hundreds of different genes. Relationships between hundreds of individual proteins that participate in glycan biosynthesis are very complex which enables the influence of environmental factors on the final structure of glycans, either by direct effects on individual enzymatic processes, or by induction of epigenetic changes that modify gene expression patterns. Until recently, the complexity of glycan structures prevented large scale studies of protein glycosylation, but recent advances in both glycan analysis and genotyping technologies, enabled the first insights into the intricate field of complex genetics of protein glycosylation. Mutations which inactivate genes involved in the synthesis of common N-glycan precursors are embryonically lethal. However, mutations in genes involved in modifications of glycan antennas are common and apparently contribute largely to individual phenotypic variations that exist in humans and other higher organisms. Some of these variations can be recognized as specific glyco-phenotypes that might represent specific evolutionary advantages or disadvantages. They are however, amenable to environmental influences and are thus less pre-determined than classical Mendelian mutations. PMID- 20957245 TI - Photonics-on-a-chip: recent advances in integrated waveguides as enabling detection elements for real-world, lab-on-a-chip biosensing applications. AB - By leveraging advances in semiconductor microfabrication technologies, chip integrated optical biosensors are poised to make an impact as scalable and multiplexable bioanalytical measurement tools for lab-on-a-chip applications. In particular, waveguide-based optical sensing technology appears to be exceptionally amenable to chip integration and miniaturization, and, as a result, the recent literature is replete with examples of chip-integrated waveguide sensing platforms developed to address a wide range of contemporary analytical challenges. As an overview of the most recent advances within this dynamic field, this review highlights work from the last 2-3 years in the areas of grating coupled, interferometric, photonic crystal, and microresonator waveguide sensors. With a focus towards device integration, particular emphasis is placed on demonstrations of biosensing using these technologies within microfluidically controlled environments. In addition, examples of multiplexed detection and sensing within complex matrices--important features for real-world applicability- are given special attention. PMID- 20957247 TI - Galactosyl conjugated N-succinyl-chitosan-graft-polyethylenimine for targeting gene transfer. AB - Through incorporating lactobionic acid (LA) bearing a galactose group to N succinyl-chitosan-graft-polyethylenimine (NSC-g-PEI), NSC-g-PEI-LA copolymers were synthesized as gene vectors with hepatocyte targeting properties. The molecular weight and composition of NSC-g-PEI-LA copolymers were characterized using gel permeation chromatography (GPC) and (1)H nuclear magnetic resonance spectroscopy ((1)H NMR) respectively. Agarose gel electrophoresis assays showed good DNA binding ability of NSC-g-PEI-LA, and the particle size of the NSC-g-PEI LA/DNA complexes were between 150 and 400 nm as determined by a Zeta sizer. The NSC-g-PEI-LA/DNA complexes observed by scanning electron microscopy (SEM) exhibited a compact and spherical morphology. The zeta potentials of these complexes were increased with the weight ratio of NSC-g-PEI-LA/DNA. NSC-g-PEI-LA has a lower cytotoxicity than PEI (25 kDa) and the toxicity decreased with increasing substitution of LA. The transfection efficiency of different complexes was evaluated by luciferase assay. Compared with PEI (25 kDa) and NSC-g-PEI/DNA, NSC-g-PEI-LA showed good transfection activity and cell specificity to HepG2 cells. The results suggested that NSC-g-PEI-LA has the potential to be used as a safe and effective targeting gene vector. PMID- 20957248 TI - A self-assembled, luminescent europium cholate hydrogel: a novel approach towards lanthanide sensitization. AB - We propose a new self-assembly based strategy for the design of novel lanthanide based luminescent materials. In this approach a europium hydrogel is prepared and sensitization is achieved by doping the gel with pyrene in a non-coordinated fashion. PMID- 20957249 TI - Pasteur's quasiracemates in 2D: chiral conflict between structurally different enantiomers induces single-handed enantiomorphism. AB - During two-dimensional chiral conglomerate formation of tartaric acid on the copper(110) surface, the growth of one enantiomorph is suppressed by the opposite chirality of a coadsorbed malic acid enantiomer, forming a quasi-racemic, semi ordered mixture. PMID- 20957250 TI - New insights into the acid mediated disproportionation of pentavalent uranyl. AB - The reaction of benzoic acid with the uranyl(V) complex [(UO(2)Py(5))(KI(2)Py(2))] in pyridine leads to immediate disproportionation with formation of a hexanuclear U(IV) benzoate cluster, a bis-benzoate complex of uranyl(VI) and water. PMID- 20957251 TI - Simple fabrication of hydrophilic nanochannels using the chemical bonding between activated ultrathin PDMS layer and cover glass by oxygen plasma. AB - This study describes a simple and low cost method for fabricating enclosed transparent hydrophilic nanochannels by coating low-viscosity PDMS (monoglycidyl ether-terminated polydimethylsiloxane) as an adhesion layer onto the surface of the nanotrenches that are molded with a urethane-based UV-curable polymer, Norland Optical Adhesive (NOA 63). In detail, the nanotrenches made of NOA 63 were replicated from a Si master mold and coated with 6 nm thick layer of PDMS. These nanotrenches underwent an oxygen plasma treatment and finally were bound to a cover glass by chemical bonding between silanol and hydroxyl groups. Hydrophobic recovery that is observed in the bulk PDMS was not observed in the thin film of PDMS on the mold and the PDMS-coated nanochannel maintained its surface hydrophilicity for at least one month. The potentials of the nanochannels for bioapplications were demonstrated by stretching lambda-DNA (48,502 bp) in the channels. Therefore, this fabrication approach provides a practical solution for the simple fabrication of the nanochannels for bioapplications. PMID- 20957252 TI - Derivation of a solubility condition for proteins from an analysis of the competition between folding and aggregation. AB - Failure in maintaining protein solubility in vivo impairs protein homeostasis and results in protein misfolding and aggregation, which are often associated with severe neurodegenerative and systemic disorders that include Alzheimer's and Parkinson's diseases and type II diabetes. In this work we formulate a model of the competition between folding and aggregation, and derive a condition on the solubility of proteins in terms of the stability of their folded states, their aggregation propensities and their degradation rates. From our model, the bistability between folding and aggregation emerges as an intrinsic aspect of protein homeostasis. The analysis of the conditions that determine such a bistability provides a rationalization of the recently observed relationship between the cellular abundance and the aggregation propensity of proteins. We then discuss how the solubility condition that we derive can help rationalise the correlation that has been reported between evolutionary rates and expression levels or proteins, as well as in vivo protein solubility and expression level measurements, and recently elucidated trends of proteome evolution. PMID- 20957253 TI - A highly porous flexible Metal-Organic Framework with corundum topology. AB - A flexible Metal-Organic Framework Zn(4)O(BenzTB)(3/2) (DUT-13) was obtained by combination of a tetratopic linker and Zn(4)O(6+) as connector. The material has a corundum topology and shows the highest pore volume among flexible MOFs. PMID- 20957254 TI - Ultrasonication-assisted spray ionization mass spectrometry for on-line monitoring of organic reactions. AB - A straightforward on-line monitoring of organic reactions by ultrasonication assisted spray ionization mass spectrometry (UASI MS) is demonstrated in this work. PMID- 20957255 TI - Increasing the stability of an enzyme toward hostile organic solvents by directed evolution based on iterative saturation mutagenesis using the B-FIT method. AB - Mutants of the lipase from Bacillus subtilis, previously engineered for enhanced thermostability using directed evolution based on the B-FIT method, show significantly increased tolerance to hostile organic solvents. PMID- 20957256 TI - Intramolecular heterolytic dihydrogen cleavage by a bifunctional frustrated pyrazolylborane Lewis pair. AB - The reaction of bis(pentafluorophenyl)borane, HB(C(6)F(5))(2), with 3,5-di-tert butyl-1H-pyrazole (3) affords the zwitterionic pyrazolium-borate trans-5 and, after dehydrogenation by use of the frustrated carbene-borane Lewis pair 1/B(C(6)F(5))(3), the bifunctional pyrazolylborane 6, which is able to cleave dihydrogen heterolytically with the formation of a mixture of cis-5 and trans-5. PMID- 20957257 TI - Reactive thermoresponsive copolymer scaffolds. AB - Thermoresponsive copolymer scaffolds containing reactive aldehyde functions were prepared and a selection of organic residues conjugated to these copolymer scaffolds through oxime/hydrazone formation. The conjugation of hydrophobic residues affords copolymers whose lower solution critical temperatures are in most cases higher than that of the parent copolymer scaffold. PMID- 20957258 TI - Observation of two-step nucleation in methane hydrates. AB - In this work we show that homogeneous nucleation of methane hydrate can, under appropriate conditions, be a very rapid process, achieved within tens of nanoseconds. In agreement with recent experimental results on different systems, we find that the nucleation of a gas hydrate crystal appears as a two-step process. It starts with the formation of disordered solid-like structures, which will then spontaneously evolve to more recognizable crystalline forms. This previously elusive first-stage state is confirmed to be post-critical in the nucleation process, and is characterized as processing reasonable short-range structure but essentially no long-range order. Its energy, molecular diffusion and local structure reflect a solid-like character, although it does exhibit mobility over longer (tens of ns) timescales. We provide insights into the controversial issue of memory effects in methane hydrates. We show that areas locally richer in methane will nucleate much more readily, and no 'memory' of the crystal is required for fast re-crystallization. We anticipate that much richer polycrystallinity and novel methane hydrate phases could be possible. PMID- 20957259 TI - Structure and dynamics of binary and ternary lanthanide(III) and actinide(III) tris[4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione] (TTA) complexes. Part 2, the structure and dynamics of binary and ternary complexes in the Y(III)/Eu(III)-TTA tributylphosphate (TBP) system in chloroform as studied by NMR spectroscopy. AB - The stoichiometric reaction mechanisms, rate constants and activation parameters for inter- and intramolecular ligand exchange reactions in the binary Y/Eu(TTA)(3)(OH(2))(2)-HTTA and the ternary Y/Eu(TTA)(3)(OH(2))(2)-TBP systems have been studied in chloroform using (1)H and (31)P NMR methods. Most complexes contain coordinated water that is in very fast exchange with water in the chloroform solvent. The exchange reactions involving TTA/HTTA and TBP are also fast, but can be studied at lower temperature. The rate constant and activation parameters for the intramolecular exchange between two structure isomers in Y(TTA)(3)(OH(2))(2) and Y(TTA)(3)(TBP)(OH(2)) were determined from the line broadening of the methine protons in coordinated TTA. The rate equations for the intermolecular exchange between coordinated TTA and free HTTA in both complexes are consistent with a two-step mechanism where the first step is a fast complex formation of HTTA, followed by a rate determining step involving proton transfer from coordinated HTTA to TTA. The rate constants for both the inter- and intramolecular exchange reactions are significantly smaller in the TBP system. The same is true for the activation parameters in the Y(TTA)(3)(OH(2))(2)-HTTA and the ternary Y/Eu(TTA)(3)(TBP)(OH(2))-HTTA systems, which are DeltaH(?) = 71.8 +/- 2.8 kJ mol(-1), DeltaS(?) = 62.4 +/- 10.3 J mol(-1) K(-1) and DeltaH(?) = 38.8 +/- 0.6 kJ mol(-1), DeltaS(?) = -93.0 +/- 3.3 J mol(-1) K(-1), respectively. The large difference in the activation parameters does not seem to be related to a difference in mechanism as judged by the rate equation; this point will be discussed in a following communication. The rate and mechanism for the exchange between free and coordinated TBP follows a two-step mechanism, involving the formation of Y(TTA)(3)(TBP)(2). PMID- 20957260 TI - Electronic peculiarities of the excited states of [RuN5C]+ vs. [RuN6]2+ polypyridine complexes: insight from theory. AB - The ground state, oxidized ground state, (3)MLCT and (3)MC excited states have been studied by DFT and TDDFT for two Ru(II) complexes bearing an N(6) or N(5)C coordination sphere. The effect of replacing one Ru-N dative bond by one Ru-C covalent bond have been studied and quantified on their ground state by the means of geometry optimization, NBO analysis and calculation of their IR vibrations. IR fingerprints of the Ru-C bond have been found at 945 and 1113 cm(-1). In addition, this study confirmed and quantified the effects of N->C(-) substitution on the spectroscopic properties of the [RuN(5)C](+) complex: a broader and bathochromically-shifted absorption spectrum, a smaller ground-(3)MLCT energy gap and a highly energetic (3)MC state are the major characteristics of the carbon containing monocationic complex. PMID- 20957261 TI - Ligands derived from tetrathiafulvalene: building blocks for multifunctional materials. AB - The last decade has witnessed many advances in the coordination chemistry of tetrathiafulvalene (TTF). Various ligands, in which a metal-binding functionality is attached to the TTF unit, have been synthesized and used for the preparation of metal complexes. This Perspective summarizes the main types of TTF-containing ligands and their metal complexes and outlines the potential for the use of these building blocks in the design and assembly of multifunctional molecular materials. PMID- 20957262 TI - Tricarbonylrhenium(I) complexes of highly symmetric hexaazatrinaphthylene ligands (HATN): structural, electrochemical and spectroscopic properties. AB - The new mononuclear and dinuclear tricarbonylrhenium(I) complexes [(HATN)Re(CO)(3)Cl] (1-Cl) and [(MU-Me(6)-HATN)[Re(CO)(3)Cl](2)] (2-Cl(2)) of highly symmetric ligands HATN and Me(6)-HATN were synthesized and structurally characterized. X-Ray crystal structures reveal identical strained aromatic systems and out of the plane fac-Re(CO)(3)Cl units for both complexes. The packing geometry in the unit cell of 1 suggests intermolecular pi-pi association. Infrared spectroelectrochemistry (SEC) experiments confirmed ligand-based reductions. To get more insight into the reduction mechanism the triflate salts, [(HATN)Re(CO)(3)](OTf) (1-OTf) and [(MU-Me(6)HATN){Re(CO)(3)}(2)](OTf)(2) (2 OTf(2)), were synthesized. Their electrochemical and spectroelectrochemical behavior also exhibits reduction of the aromatic systems. The electronic absorption spectral features of the one electron reduced species were studied by UV-vis-NIR spectroscopy, which shows a broad shoulder at 1500 nm, confirming intra-ligand charge transfer (ILCT). Density functional theory (DFT) calculations on the complexes 1-Cl and 2-Cl(2) for structural optimization show good agreement with experimental bond lengths and bond angles. The spin density plot shows a metal based HOMO and HATN ligand centered LUMO. PMID- 20957263 TI - Aqueous coordination chemistry and photochemistry of uranyl(VI) oxalate revisited: a density functional theory study. AB - Using density functional theory (DFT) calculations, we revisited a classical problem of uranyl(VI) oxalate photochemical decomposition. Photoreactivities of uranyl(VI) oxalate complexes are found to correlate largely with ligand structural arrangements. Importantly, the intramolecular photochemical reaction is inhibited when oxalate is bound to uranium exclusively in chelate binding mode. Previously proposed mechanisms involving a UO(2)(C(2)O(4))(2)(2-) (1:2) complex as the main photoreactive species are thus unlikely to apply, because the two oxalic acids are bound to uranium in a chelating binding mode. Our DFT results suggest that the relevant photoreactive species are UO(2)(C(2)O(4))(3)(4 ) (1:3) and (UO(2))(2)(C(2)O(4))(5)(6-) (2:5) complexes binding uranium in an unidentate fashion. These species go through decarboxylation upon excitation to the triplet state, which ensues the release of CO(2) and reduction of U(vi) to U(v). The calculations also suggest an alternative intermolecular pathway at low pH via an electron transfer between the excited state *UO(2)(2+) and hydrogen oxalate (HC(2)O(4)(-)) which eventually leads to the production of CO and OH(-) with no net reduction of U(VI). The calculated results are consistent with previous experimental findings that CO is only detected at low pH while U(IV) is detected only at high pH. PMID- 20957264 TI - Non-trivial solution chemistry between amido-pyridylcalix[4]arenes and some metal salts. AB - Mercury ion complexation reactions were carried out between 3 and various mercury(II) salts. (1)H NMR studies showed that the role of solvent, the anion chosen and the initial reaction conditions were critical and that the formation of a "simple" mercury(II) complex was non-trivial. The mercury(II) ion can cause either (i) the formation of an ion-pair system, which have a characteristic doubling of all signals in the (1)H NMR spectrum, (ii) a cleavage reaction to occur resulting in the reformation of the calix[4]arene diester compound 2, but only when the reaction is heated and (iii) "simple" mercury binding to the pyridine rings when the binding studies are carried out using NMR titration techniques. The electrochemistry results, on the same systems, show that the initial reaction involves the removal of the phenoxide protons followed by the resulting catalysis of the mercury species. This proton removal is not observed in the NMR spectra of any of the mercury reactions. It was also found that 3 could bind silver and zinc salts and was not selective for mercury(II) as was previously described. PMID- 20957265 TI - The chemistry and biology of organic guanidine derivatives. PMID- 20957266 TI - Single-walled carbon nanohorns and their applications. AB - Single-walled carbon nanohorns (SWCNHs) are horn-shaped single-walled tubules with a conical tip. They are generally synthesized by laser ablation of pure graphite without using metal catalyst with high production rate and high yield, and typically form radial aggregates. SWCNHs are essentially metal-free and very pure, which avoids cumbersome purification and makes them user-friendly and environmentally benign. Currently, SWCNHs have been widely studied for various applications, such as gas storage, adsorption, catalyst support, drug delivery system, magnetic resonance analysis, electrochemistry, biosensing application, photovoltaics and photoelectrochemical cells, photodynamic therapy, fuel cells, and so on. This review outlines the research progress on SWCNHs, including their properties, functionalization, applications, and outlook. PMID- 20957267 TI - An efficient and high-throughput electroporation microchip applicable for siRNA delivery. AB - Here we report a novel electroporation microchip with great performance and compatibility with the standard multi-well plate used in biological research. The novel annular interdigitated electrode design makes it possible to achieve efficient cell transfection as high as 90% under low-strength electrical pulses, thereby circumventing the many adverse effects of conventional cuvette-type and previously reported microchip-based electroporation devices. Using this system, we demonstrated substantially improved cell transfection efficacy and viability in cultured and primary cells, for both plasmid and synthetic siRNA. Improvements of this system open new opportunities for high-throughput applications of siRNA technology in basic and biomedical research. PMID- 20957268 TI - Autocatalytic membrane-amplification on a pre-existing vesicular surface. AB - In water, phosphoric membrane molecule (V(-)) self-assembled to form an anionic giant vesicle, the surface of which served as a catalyst for the autocatalytic formation of V(-) from its membrane precursor (V*), and the amplified V(-) produced a new vesicle using the original vesicle as a scaffold. PMID- 20957269 TI - Monoclinic CuO nanoflowers on resin support: recyclable catalyst to obtain perylene compound. AB - Monoclinic CuO crystallite in grams has been obtained from resin bound Cu(II) 1,10-phenanthroline complex, R(-)[Cu(1,10-phen)(2)](2+) that becomes a recyclable catalyst for oxidative phenol coupling (OPC) reaction. Thus an exclusively intuitive blue fluorescing perylene derivative is derived from colorless 2,7 dihydroxynaphthalene (2,7-DHN) in high yield. PMID- 20957270 TI - Photochemical H2 with noble-metal-free molecular devices comprising a porphyrin photosensitizer and a cobaloxime catalyst. AB - Among three noble-metal-free molecular devices (1-3) containing a porphyrin photosensitizer and a cobaloxime catalyst, the one with a zinc porphyrin unit displayed apparently higher efficiency for photoinduced H(2) production than complex 2 with a magnesium porphyrin and 3 with a free-base porphyrin, possibly due to the formation of a TEAZnPor-Co triad in solution. PMID- 20957271 TI - CdSe quantum dot (QD) and molecular dye hybrid sensitizers for TiO2 mesoporous solar cells: working together with a common hole carrier of cobalt complexes. AB - Redox couples based on cobalt complexes were found to be effective in regenerating both inorganic CdSe quantum dot- and organic dye-sensitizers. The hybrid sensitizer composed of CdSe QD and ruthenium sensitizer (Z907Na) dye showed a maximum power conversion efficiency of 4.76% on using cobalt(o phen)(3)(2+/3+) as a common redox mediator. PMID- 20957272 TI - Resonance Raman and surface- and tip-enhanced Raman spectroscopy methods to study solid catalysts and heterogeneous catalytic reactions. AB - Resonance Raman (RR) spectroscopy has several advantages over the normal Raman spectroscopy (RS) widely used for in situ characterization of solid catalysts and catalytic reactions. Compared with RS, RR can provide much higher sensitivity and selectivity in detecting catalytically-significant surface metal oxides. RR can potentially give useful information on the nature of excited states relevant to photocatalysis and on the anharmonic potential of the ground state. In this critical review a detailed discussion is presented on several types of RR experimental systems, three distinct sources of so-called Raman (fluorescence) background, detection limits for RR compared to other techniques (EXAFS, PM-IRAS, SFG), and three well-known methods to assign UV-vis absorption bands and a band specific unified method that is derived mainly from RR results. In addition, the virtues and challenges of surface-enhanced Raman spectroscopy (SERS) are discussed for detecting molecular adsorbates at catalytically relevant interfaces. Tip-enhanced Raman spectroscopy (TERS), which is a combination of SERS and near-field scanning probe microscopy and has the capability of probing molecular adsorbates at specific catalytic sites with an enormous surface sensitivity and nanometre spatial resolution, is also reviewed (300 references). PMID- 20957273 TI - Multistage-multiorifice flow fractionation (MS-MOFF): continuous size-based separation of microspheres using multiple series of contraction/expansion microchannels. AB - Previously we introduced a novel hydrodynamic method using a multi-orifice microchannel for size-based particle separation, which is called a multi-orifice flow fractionation (MOFF). The MOFF has several advantages such as continuous, non-intrusive, and minimal power consumption. However, it has a limitation that the recovery yield is relatively low. Although the recovery may be increased by adjusting parameters such as the Reynolds number and central collecting region, poor purity inevitably followed. We newly designed and fabricated a microfluidic channel for multi-stage multi-orifice flow fractionation (MS-MOFF), which is made by combining three multi-orifice segments, and consists of 3 inlets, 3 filters, 3 multi-orifice segments and 5 outlets. The structure and dimensions of the MS-MOFF were determined by the hydrodynamic principles to have constant Reynolds numbers at each multi-orifice segment. Polystyrene microspheres of two different sizes (7 MUm and 15 MUm) were tested. With this device, we made an attempt to improve recovery and minimize loss of purity by collecting and re-separating non-selected particles of the first separation. The final recovery successfully increased from 73.2% to 88.7% while the final purity slightly decreased from 91.4% to 89.1% (for 15 MUm). These values were never achievable with the single-stage MOFF (SS-MOFF) having only one multi-orifice segment in our previous work. The MS-MOFF channel will be useful for clinical applications, such as separation of circulating tumor cells (CTC) or rare cells from human blood samples. PMID- 20957274 TI - Enhancement by optical force of separation in pinched flow fractionation. AB - A method for improving the size-based particle separation technique known as pinched flow fractionation (PFF) has been demonstrated experimentally and analyzed by performing numerical calculations. Since the particles in the pinched region are pushed by an optical scattering force, the original particle position with respect to the wall is modulated. This position modulation in the pinched region is amplified in the broadened region along the streamline. This enhancement of separation is achieved by imposing an optical force on the original PFF design. Three different polystyrene latexes (PSLs) with diameters of 2, 5, and 10 MUm were separated with PFF and optically enhanced PFF (OEPFF) devices. The separations achieved with the two devices were compared and enhancements in the separation distance by factors of up to approximately 15 were achieved. Theoretical calculations were also performed to interpret these results. PMID- 20957275 TI - Superquenching acridinium ester chemiluminescence by gold nanoparticles for DNA detection. AB - It was found that the chemiluminescence of acridinium ester (AE) was quenched effectively by gold nanoparticles (AuNPs) with Stern-Volmer constants approaching 10(10) M(-1), which was exploited to realize sequence-specific DNA detection based on the preferential absorption of AE-tagged single-strand probe on unmodified AuNPs over the hybrids of probe and target DNA. PMID- 20957276 TI - Biological applications of microfluidic gradient devices. AB - Molecular gradients play an important role in diverse physiological and pathological phenomena such as immune response, wound healing, development and cancer metastasis. In the past 10 years, engineering tools have been increasingly used to develop experimental platforms that capture important aspects of cellular microenvironments to allow quantitative and reproducible characterization of cellular response to gradients. This review discusses the emergence of microfluidics-based gradient generators and their applications in enhancing our understanding of fundamental biological processes such as chemotaxis and morphogenesis. The principles and applications of microfluidic gradient generation in both 2D and 3D cellular microenvironments are discussed with emphasis on approaches to manipulate spatial and temporal distribution of signaling molecules. PMID- 20957277 TI - Force applied to a single molecule at a single nanogate molecule filter. AB - We have investigated the origin of molecule filtering system based on a chemical potential barrier produced by thermodynamically driven molecular flow in a nanoscopic space at nanogates. Single molecule tracking experiments prove that the highly localized potential barrier allows for selective manipulation of the target molecule. We propose the presence of a force, a few fN per molecule, to decelerate the molecule's movement at the nanogate, which is comparable to or larger than the force applied by conventional electrophoretic operation. The present force can be tuned by changing the nanogate width at the nanometre level. These findings allow us to propose an accurate design of novel devices for molecular manipulation on an ultra small scale using a very small number of molecules without any external biases. PMID- 20957278 TI - Programming nanostructures of polymer brushes by dip-pen nanodisplacement lithography (DNL). AB - We report a facile and versatile scanning probe based approach-dip-pen nanodisplacement lithography (DNL)--for manipulating nanostructures of polymer brushes. Nanostructured polymer brushes with sizes as small as 25 nm are made by DNL patterning of the initiator molecules and subsequent surface-initiated polymerization. Nanoconfinement effects including chain collapsing and spreading are observed in the nanopatterned polymer brushes. In addition to chemical structure, size, topography and shape, our approach can also readily program the grafting density, chain configuration, hierarchical structure and multiplexing of the polymer brushes, which allows for the realization of complex chemical surfaces. PMID- 20957279 TI - Adsorption and binding of capping molecules for highly luminescent CdSe nanocrystals--DFT simulation studies. AB - During CdSe nanocrystal growth, loss of surface capping molecules occurs leading to a decrease of photoluminescence (PL) quantum yield. In general, aliphatic capping molecules are applied to passivate the surface of CdSe nanocrystals to modulate the optical properties of the CdSe. In this work, two kinds of alkylamine (n-butylamine (n-BA) and n-hexylamine (n-HA)) and oleic acid (OA) were used to modify the surfaces of the CdSe nanocrystals. From the PL spectra and quantum yield analyses, we observed that the PL emission peak positions of the modified CdSe nanocrystals have blue shifted for all three capping molecules. However, the PL quantum yield of the CdSe nanocrystals increased after introduction of the alkylamine molecules, but decreased with oleic acid. The detailed mechanism was not clear until now. In this study, a density function theory (DFT) simulation was employed to demonstrate binding energy and charge analyses of CdSe with n-BA, n-HA and OA. By comparing the binding energy of the bare CdSe nanocrystals to that of the CdSe with the capping molecules, it was shown that n-BA and n-HA as capping molecules help to increase the charge on Se and decrease it on cadmium of the CdSe. PMID- 20957280 TI - TEMPO-oxidized cellulose nanofibers. AB - Native wood celluloses can be converted to individual nanofibers 3-4 nm wide that are at least several microns in length, i.e. with aspect ratios>100, by TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl radical)-mediated oxidation and successive mild disintegration in water. Preparation methods and fundamental characteristics of TEMPO-oxidized cellulose nanofibers (TOCN) are reviewed in this paper. Significant amounts of C6 carboxylate groups are selectively formed on each cellulose microfibril surface by TEMPO-mediated oxidation without any changes to the original crystallinity (~74%) or crystal width of wood celluloses. Electrostatic repulsion and/or osmotic effects working between anionically charged cellulose microfibrils, the zeta-potentials of which are approximately 75 mV in water, cause the formation of completely individualized TOCN dispersed in water by gentle mechanical disintegration treatment of TEMPO-oxidized wood cellulose fibers. Self-standing TOCN films are transparent and flexible, with high tensile strengths of 200-300 MPa and elastic moduli of 6-7 GPa. Moreover, TOCN-coated poly(lactic acid) films have extremely low oxygen permeability. The new cellulose-based nanofibers formed by size reduction process of native cellulose fibers by TEMPO-mediated oxidation have potential application as environmentally friendly and new bio-based nanomaterials in high-tech fields. PMID- 20957281 TI - Access to beta,gamma-diamino acids. Application to the synthesis of 3 deoxyaminostatine. AB - The synthesis of orthogonally protected diastereo- and enantiopure beta,gamma diamino acids starting from natural alpha-amino acids is described, as well as its application to the synthesis of fully protected 3-deoxyaminostatine. PMID- 20957282 TI - Asymmetric total synthesis of (+)-swainsonine. AB - A concise asymmetric synthesis of (+)-swainsonine (ent-1) is described starting from 2, which was readily prepared from commercially available l-glutamic acid. The method features installation of the indolizidine ring via an intramolecular cyclisation of alpha-sulfinyl carbanion as a key step. (+)-Swainsonine was obtained in 11.8% overall yield in 10 steps. PMID- 20957283 TI - Insects and their chemical weaponry: new potential for drug discovery. PMID- 20957284 TI - Electrochemical biosensors based on redox carbon nanotubes prepared by noncovalent functionalization with 1,10-phenanthroline-5,6-dione. AB - To improve the electrocatalytic activities of carbon nanotubes (CNT) towards the oxidation of nicotinamide adenine dinucleotide (NADH), we derive them with a redox mediator, 1,10-phenanthroline-5,6-dione (PD), by the noncovalent functionalization method. The redox carbon nanotubes (PD/CNT/GC) show excellent electrocatalytic activities towards the oxidation of NADH (catalytic reaction rate constant, k(h) = 7.26 * 10(3) M(-1) s(-1)), so the determination of NADH can be achieved with a high sensitivity of 8.77 MUA mM(-1) under the potential of 0.0 V with minimal interference. We also develop an amperometric ethanol biosensor by integration of alcohol dehydrogenase (ADH) within the redox carbon nanotubes (PD/CNT/GC). The ethanol biosensor exhibits a wide linear range up to 7 mM with a lower detection limit of 0.30 mM as well as a high sensitivity of 10.85 nA mM( 1). PMID- 20957285 TI - The activity and expression of microRNAs in prostate cancers. AB - Recent studies have shown that microRNA (miRNA) inhibitory activity can be quantified by examining their target mRNA expression levels. The accumulated evidence of differential miRNA activities between cancer subtypes necessitates the systematical comparison of miRNA expressions and activities. In this study, we integrated 8 mRNA microarray datasets to infer and compare the miRNA activities between prostate cancers (PCs) and normal tissues (NTs). Gene expression analyses show that miRNA activity is stronger in PCs. This conclusion is consolidated by target protein expression. We simultaneously collected 6 independent miRNA expression datasets, where great inconsistency is present in the expression difference between PCs and NTs. The overall correlation between miRNA activity and expression is very weak. However, meta-analysis demonstrated that the expressions of 114 individual miRNAs agree with their activities. Additionally, we detected two other factors associated with higher miRNA activity in PCs. One is deregulation of some key miRNA-repression related genes, such as the over-expression of Dicer, TRBP and Ago2, and the under-expression of IRP1 in PCs. The other is that miRNA-mRNA binding site efficacy has significant positive correlation with miRNA activity, whereas no correlation with miRNA expression. Furthermore, miRNA activity is more reproducible than miRNA expression across different datasets, which allows miRNA activity to be a good feature for the classification of cancer subtypes. We expect our analysis can improve the methods for inferring miRNA activity and further, provide some clues to the role of miRNA in tumorigenesis. PMID- 20957286 TI - Environmental monitoring to enhance comprehension and control of infectious diseases. AB - In a world of emerging and resurging infectious diseases, dominated by zoonoses, environmental monitoring plays a vital role in our understanding their dynamics and their spillover to humans. Here, we critically review the ecology, epidemiology and need for monitoring of a variety of directly transmitted (Sin Nombre virus, Avian Influenza) and vector-borne (Ross River virus, West Nile virus, Lyme disease, anaplasmosis and babesiosis) zoonoses. We focus on the valuable role that existing monitoring plays in the understanding of these zoonoses, the demands for new monitoring, and how improvements can be made to existing monitoring. We also identify the fruitful outcomes which would result from implementation of the monitoring demands we have highlighted. This review aims to promote improvements in our understanding of zoonoses, their management, and public health by encouraging discussion among researchers and public health officials. PMID- 20957287 TI - A neuron-benign microfluidic gradient generator for studying the response of mammalian neurons towards axon guidance factors. AB - Investigation of biochemical cues in isolation or in combinations in cell culture systems is crucial for unraveling the mechanisms that govern neural development and repair. The most widely used experimental paradigms that elicit axon guidance in vitro utilize as the source of the gradient a pulsatile pipette, transfected cells, or a loaded gel, producing time-varying gradients of poor reproducibility which are not well suited for studying slow-growing mammalian cells. Although microfluidic device design have allowed for generating stable, complex gradients of diffusible molecules, the flow-induced shear forces in a microchannel has made it impossible to maintain viable mammalian neuronal cultures for sufficiently long times. In this paper, we describe axonal responses of mouse cortical neurons in a "neuron-benign" gradient-generator device based on an open chamber that can establish highly stable gradients of diffusible molecules for at least 6 h with negligible shear stress, and also allows the neurons to thrive for at least 2 weeks. Except for the period when the gradient is on, the cells in the gradient are under the same conditions as the cells on the control surfaces, which ensure a consistent set of micro-environmental variables. The gradient stability and uniformity over the cell culture surface achieved by the device, together with our software platform for acquiring, post-processing and quantitatively analyzing the large number of images allowed us to extract valuable information even from small datasets. We report a directed response of primary mammalian neurons (from E14 embryonic mice cortex) to a diffusible gradient of netrin in vitro. We infer from our studies that a large majority (~73%) of the neurons that extend axons during the gradient application grow towards the netrin source, and our data analysis also indicates that netrin acts as a growth factor for this same population of neurons. PMID- 20957288 TI - Design and dynamic characterization of "single-stroke" peristaltic PDMS micropumps. AB - In this paper, we present a monolithic PDMS micropump that generates peristaltic flow using a single control channel that actuates a group of different-sized microvalves. An elastomeric microvalve design with a raised seat, which improves bonding reliability, is incorporated into the micropump. Pump performance is evaluated based on several design parameters--size, number, and connection of successive microvalves along with control channel pressure at various operating frequencies. Flow rates ranging 0-5.87 uL min(-1) were observed. The micropump design demonstrated here represents a substantial reduction in the number of/real estate taken up by the control lines that are required to run a peristaltic pump, hence it should become a widespread tool for parallel fluid processing in high throughput microfluidics. PMID- 20957289 TI - A micro surface tension pump (MISPU) in a glass microchip. AB - A non-membrane micro surface tension pump (MISPU) was fabricated on a glass microchip by one-step glass etching. It needs no material other than glass and is driven by digital gas pressure. The MISPU can be seen working like a piston pump inside the glass microchip under a microscope. The design of the valves (MISVA) and pistons (MISTON) was based on the surface tension theory of the micro surface tension alveolus (MISTA). The digital gas pressure controls the moving gas-liquid interface to open or close the input and output MISVAs to refill or drive the MISTON for pumping a liquid. Without any moving parts, a MISPU is a kind of long lasting micro pump for micro chips that does not lose its water pumping efficiency over a 20-day period. The volumetric pump output varied from 0 to 10 nl s(-1) when the pump cycle time decreased from 5 min to 15 s. The pump head pressure was 1 kPa. PMID- 20957290 TI - High-throughput single-cell quantification using simple microwell-based cell docking and programmable time-course live-cell imaging. AB - Extracting single-cell information during cellular responses to external signals in a high-throughput manner is an essential step for quantitative single-cell analyses. Here, we have developed a simple yet robust microfluidic platform for measuring time-course single-cell response on a large scale. Our method combines a simple microwell-based cell docking process inside a patterned microfluidic channel, with programmable time-course live-cell imaging and software-aided fluorescent image processing. The budding yeast, Saccharomyces cerevisiae (S. cerevisiae), cells were individually captured in microwells by multiple sweeping processes, in which a cell-containing solution plug was actively migrating back and forth several times by a finger-pressure induced receding meniscus. To optimize cell docking efficiency while minimizing unnecessary flooding in subsequent steps, circular microwells of various channel dimensions (4-24 um diameter, 8 um depth) along with different densities of cell solution (1.5-6.0 * 10(9) cells per mL) were tested. It was found that the microwells of 8 um diameter and 8 um depth allowed for an optimal docking efficiency (>90%) without notable flooding issues. For quantitative single-cell analysis, time-course (time interval 15 minute, for 2 hours) fluorescent images of the cells stimulated by mating pheromone were captured using computerized fluorescence microscope and the captured images were processed using a commercially available image processing software. Here, real-time cellular responses of the mating MAPK pathway were monitored at various concentrations (1 nM-100 uM) of mating pheromone at single cell resolution, revealing that individual cells in the population showed non uniform signaling response kinetics. PMID- 20957291 TI - Droplet-on-a-wristband: chip-to-chip digital microfluidic interfaces between replaceable and flexible electrowetting modules. AB - We present a long (204 mm), curved (curvature of 0.04 mm(-1)), and closed droplet pathway in "droplet-on-a-wristband" (DOW) with the designed digital microfluidic modular interfaces for electric signal and droplet connections based on the study of electrowetting-on-dielectric (EWOD) in inclined and curved devices. Instead of using sealed and leakage-proof pipes to transmit liquid and pumping pressure, the demonstrated modular interface for electrowetting-driven digital microfluidics provides simply electric and fluidic connections between two adjacent parallel plate modules which are easy-to-attach/detach, showing the advantages of using droplets for microfluidic connections between modules. With the previously reported digital-to-channel interfaces (Abdelgawad et al., Lab Chip, 2009, 9, 1046-1051), the chip-to-chip interface presented here would be further applied to continuous microfluidics. Droplet pumping across a single top plate gap and through a modular interface with two gaps between overlapping plates are investigated. To ensure the droplet transportation in the DOW, we actuate droplets against gravity in an inclined or curved device fabricated on flexible PET substrates prepared by a special razor blade cutter and low temperature processes. Pumping a 2.5 MUl droplet at a speed above 105 mm s(-1) is achieved by sequentially switching the entire 136 driving electrodes (1.5 mm * 1.5 mm) along the four flexible modules of the DOW fabricated by 4-inch wafer facilities. PMID- 20957298 TI - Introduction to the mechanisms of directed cell migration themed issue. PMID- 20957299 TI - The growing burden of cardiovascular disease: role of the arterial-cardiac interaction. PMID- 20957300 TI - Epidemiology and management of surgical upper limb infections in patients with end-stage renal failure. AB - INTRODUCTION: Hand infections in patients with end-stage renal failure (ESRF) are more diffi cult to treat and have had the worse outcomes. This paper examines the epidemiology, bacteriology and outcomes of surgically managed upper limb infections in these vulnerable patients. MATERIALS AND METHODS: All patients from a single centre with surgically-managed upper limb infections between 2001 and 2007 were reviewed. We collected epidemiological data on demographics, type and site of infection, bacteriology, surgical treatment, complications and mortality. RESULTS: Forty-seven out of 803 (6%) patients with surgically managed upper limb infections in the study period had ESRF. The average age was 59 years. ESRF was secondary to diabetes in 88% of cases. Patients presented on average 7 days after onset of symptoms. Abscesses (34%), wet gangrene (26%) and osteomyelitis (11%) were the commonest infections. Methicillin-resistant Staphylococcus aureus (MRSA) was the commonest pathogen (29%), occurring either in isolation or with other organisms. Eighteen percent of single organisms cultured were gram-negative. Multiple organisms occurred in 29%. A median of 2 operations were required. Thirty-six percent of all cases required amputation. Twenty-fi ve percent of patients had a life-threatening event (myocardial infarction or septic shock) during treatment. CONCLUSIONS: ESRF patients present late with severe upper limb infections. Nosocomial infections are common. Initial empirical antibiotic treatment should cover MRSA and gram-negative bacteria. Immediate referral to a hand surgery unit is recommended. Multi-disciplinary management of the patient with input from physicians and anaesthetists or intensivists in the perioperative period is necessary to optimise the patient for surgery and to manage active medical comorbidities and complications after surgery. PMID- 20957301 TI - The influence of maternal ethnic group and diet on breast milk fatty acid composition. AB - INTRODUCTION: Breast milk fatty acids play a major role in infant development. However, no data have compared the breast milk composition of different ethnic groups living in the same environment. We aimed to (i) investigate breast milk fatty acid composition of three ethnic groups in Singapore and (ii) determine dietary fatty acid patterns in these groups and any association with breast milk fatty acid composition. MATERIALS AND METHODS: This was a prospective study conducted at a tertiary hospital in Singapore. Healthy pregnant women with the intention to breastfeed were recruited. Diet profile was studied using a standard validated 3-day food diary. Breast milk was collected from mothers at 1 to 2 weeks and 6 to 8 weeks postnatally. Agilent gas chromatograph (6870N) equipped with a mass spectrometer (5975) and an automatic liquid sampler (ALS) system with a split mode was used for analysis. RESULTS: Seventy-two breast milk samples were obtained from 52 subjects. Analysis showed that breast milk ETA (Eicosatetraenoic acid) and ETA:EA (Eicosatrienoic acid) ratio were significantly different among the races (P = 0.031 and P = 0.020), with ETA being the highest among Indians and the lowest among Malays. Docosahexaenoic acid was significantly higher among Chinese compared to Indians and Malays. No difference was demonstrated in n3 and n6 levels in the food diet analysis among the 3 ethnic groups. CONCLUSIONS: Differences exist in breast milk fatty acid composition in different ethnic groups in the same region, although no difference was demonstrated in the diet analysis. Factors other than maternal diet may play a role in breast milk fatty acid composition. PMID- 20957302 TI - The deep inferior epigastric perforator flap for breast reconstruction: Is this the ideal flap for Asian women? AB - INTRODUCTION: This study aims to evaluate the outcome and safety of the deep inferior epigastric perforator (DIEP) flap for breast reconstruction in a group of Southeast Asian women treated in our unit and to identify risk factors for breast reconstruction using the DIEP flap in this population. MATERIALS AND METHODS: This is a prospective study on 50 consecutive DIEP flap breast reconstructions by a single surgeon in an academic institution between July 1999 and July 2006. Data on patient demographics, diagnosis, procedure type, adjuvant and neoadjuvant treatments, risk factors and complications were prospectively collected and registered in a clinical database. Outcome variables include total flap loss, partial flap loss, fat necrosis and minor complications related to the donor site or flap. Known risk factors are analysed to determine if they affect outcome in terms of complication rate in this group of patients. RESULTS: Total flap loss, partial flap loss and fat necrosis complication rates were 6%, 4% and 10%, respectively. Flap complication rates were comparable to those quoted by previous studies done worldwide. Obesity (BMI >27) is a statistically significant factor associated with development of DIEP flap complications in our population. CONCLUSION: Breast reconstruction with DIEP flap is a safe and reliable method when used in Southeast Asian women, offering optimal results with less donor site morbidity. Obesity increases the incidence of flap complication in this group of patients. PMID- 20957303 TI - The pedagogical value of a student-run community-based experiential learning project: The Yong Loo Lin School of Medicine Public Health Screening. AB - INTRODUCTION: We assessed the pedagogical value of a student-led community-based experiential learning project called the Public Health Screening (PHS) run by medical and nursing students of the National University of Singapore's Yong Loo Lin School of Medicine (NUS YLLSoM). MATERIALS AND METHODS: We conducted a cross sectional study using a self-administered anonymised questionnaire on medical and nursing students who participated in PHS using the Fund for the Improvement of Postsecondary Education (FIPSE) Survey Instrument. Participants also gave an overall score for their learning experience at the PHS. RESULTS: The participation rate was 93.1% (576/619) for medical students and 100% (37/37) for nursing students. All participants gave the PHS learning experience a high rating (median = 8 out of maximum of 10, inter-quartile range, 7 to 9). A majority of participants felt that PHS had helped them to improve across all domains surveyed. For medical students, those in preclinical years and females were independently more likely to feel that PHS had helped them to improve in communication skills, teamwork, ability to identify social issues, taking action, and gaining and applying their knowledge than those in clinical years and males. Improved ability to interact with patients (beta=1.64, 95%CI, 1.01-2.27), appreciation of challenges to healthcare faced by Singaporeans from lower income groups (beta=0.93, 95%CI, 0.49-1.37), thinking of others (beta=0.70, 95%CI, 0.04 1.37) and tolerance of different people (beta =0.63, 95%CI, 0.17-1.10) were strongly associated with the overall rating score. CONCLUSION: PHS was a positive learning experience in a wide range of domains for all students involved. This suggests that student-organised community-based experiential learning projects have potential educational value for both medical and nursing students. PMID- 20957304 TI - A survey of local preclinical and clinical medical students' attitudes towards radiology. AB - INTRODUCTION: This study compares the attitudes between preclinical and clinical medical students towards radiology, following the introduction of a new radiology curriculum for 1st year students. MATERIALS AND METHODS: Revision of the 1st year medical school curriculum for the academic year of 2008/9 with the inclusion of 13 one-hour formal radiology lectures integrated with each body system was done in an undergraduate Southeast Asian medical school. In the old curriculum, 1st and 2nd year medical students are not exposed to radiology. They received limited radiology teaching in their 3rd and 5th years with 2 one-hour lectures as part of their medicine and surgery rotations. In the 4th year, they have a one week non examinable posting in radiology. A survey was administered to preclinical (new curriculum) and clinical (old curriculum) students. Survey responses were tabulated and attitudes between preclinical and clinical students were compared. RESULTS: More than half of the preclinical students (155 out of 270 students, 59%) and 90 out of 720 clinical students (12.5%) responded. Students exposed to the new curriculum had attended one or two dedicated radiology lectures and were considering radiology as a clinical elective. Both groups of students did not feel familiar with radiology as with other specialties, were not considering radiology as a career, but felt that radiology was interesting and important to the overall practice of medicine. CONCLUSIONS: Exposure of 1st year students to radiology increases their interest in the subject. Further intervention, fi ne tuning of the curriculum and follow-up surveys will be carried out to see if this interest persists throughout their clinical years. PMID- 20957305 TI - Bone marrow cytogenetics workup: Application of lean management system to determine if additional cell workup is helpful and necessary to analysis. AB - INTRODUCTION: High workload volumes in a Cytogenetics laboratory can lead to long result turn-around times (TAT). This study aimed to improve laboratory efficiency by adopting Lean Management System initiatives to increase productivity through the elimination of wastes. This study examined if the prerequisite 20-cell analysis was sufficient for a conclusive result or if additional cell workup was necessary to ascertain the presence of a previous chromosome abnormality among cases on follow-up, or when a single abnormal cell was encountered during the analysis to determine the presence of a clone. MATERIALS AND METHODS: The karyotype results of cases that had additional workup were retrieved from among 8040 bone marrow cases of various haematological disorders performed between June 2003 and June 2008. RESULTS: Of 8040 cases analysed, 2915 cases (36.3%) had additional cell workup. Only 49 cases (1.7%) led to the establishment of a clone. The majority of these cases could have been resolved without the additional workup, especially if fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR)-based assays had been utilised. CONCLUSION: This study shows that the additional workup procedure is redundant. The time saved by discontinuing the workup procedure can be used to analyse other cases, leading to increased laboratory efficiency and a faster TAT without compromise to patient care. The practice of additional workup over and above the 20- cell analysis should be dispensed with as little benefit was derived for the amount of additional manpower expended. FISH or PCR-based assays should be utilised to elucidate a case further. PMID- 20957306 TI - Urotensin 2 and retinoic acid receptor alpha (RARA) gene expression in IgA nephropathy. AB - INTRODUCTION: IgA nephropathy is a disease where the pathogenesis is still poorly understood. Deoxyribonucleic acid (DNA) microarray technique allows tens of thousands of gene expressions to be examined at the same time. Commercial availability of microarray genechips has made this powerful tool accessible for wider utilisation in the study of diseases. MATERIALS AND METHODS: Seven patients with IgA nephropathy, 6 with minimal change nephrotic syndrome (MCNS) as patient controls and 7 normal healthy subjects were screened for the differential expression of genes, genome-wide. The Human Genome U133 Plus 2.0 Arrays (Affymetrix, USA) were used to quantitate the differential expression of 38,500 well-characterised human genes. RESULTS: A total of 7761 gene expressions were identified that have an IgAN/Normal gene expression ratio of 0.06-fold to 5.58 fold. About 35% of the altered gene expressions have no gene title or just a hypothetical protein label such as FLJ30679. Most of the remaining 65% are identified proteins where their importance to IgAN is not immediately apparent at this time. Among the 30 most upregulated and 30 most downregulated genes are Urotensin 2 (upregulated 3.09-fold, P <0.05) and Fatty-acid binding protein 6 (downregulated to 0.12-fold, P <0.05). Retinoic acid receptor alpha (vitamin A receptor) was also found downregulated to 0.41-fold (P <0.005). Taqman realtime polymerase chain reaction (PCR) for urotensin 2 and retinoic acid receptor alpha (RARA) were performed on 20 patients with IgA nephropathy and 11 with Minimal Change Disease and the data correlated with various clinical indices. CONCLUSIONS: The findings suggest that there may be a therapeutic role for retinoic acid receptor alpha (RARA) in IgA nephropathy and a clinical monitoring role for Urotensin 2 in Minimal Change Disease. PMID- 20957307 TI - Botulinum toxin a for idiopathic detrusor overactivity. AB - INTRODUCTION: This prospective study aims to evaluate botulinum toxin type A (BTX A, Botox (r)) as a treatment for idiopathic detrusor overactivity (IDO) for patients with symptoms of overactive bladder (OAB). MATERIALS AND METHODS: Nineteen patients with IDO were treated with intradetrusal injection of 200 units of BTX-A under cystoscopic guidance. There were 10 males and 9 females, with a mean age of 60 years (range, 38 to 87). Subjective responses were measured using the International Prostate Symptom Score and quality of life (QOL) score, as well as incontinent episodes, functional capacity and voiding intervals obtained from the voiding diary. They were recorded prior to, and at 6 weeks, 3, 6 and 9 months after BTX-A injections. Urodynamic studies were performed between 6 weeks to 3 months post-treatment. RESULTS: There was statistically significant improvement in subjective parameters at 3 months post-treatment involving QOL (P = 0.002), incontinence episodes (P = 0.004), functional capacity (P = 0.01) and voiding interval (P <0.001). Reflex volume was significantly increased (P = 0.003), and maximal detrusal pressure (P = 0.001) as well as leak volume (P = 0.013) were significantly decreased during follow-up. Results of a gender-based subgroup analysis reveal that BTX-A may be more efficacious in females. Observed side effects included a patient who needed to perform CISC for about 3 months, a patient who had gross haematuria needed bladder washout and 3 patients who required treatments for urinary tract infection. CONCLUSION: Overall BTX-A, which is well received by most patients, has become a very important part of the armamentarium for the treatment of IDO. PMID- 20957308 TI - Colorectal cancer liver metastases - understanding the differences in the management of synchronous and metachronous disease. AB - INTRODUCTION: Metastatic disease to the liver in colorectal cancer is a common entity that may present synchronously or metachronously. While increasing surgical experience has improved survival outcomes, some evidence suggest that synchronous lesions should be managed differently. This review aims to update current literature on differences between the outcomes and management of synchronous and metachronous disease. MATERIALS AND METHODS: Systematic review of MEDLINE database up till November 2008. RESULTS: Discrete differences in tumour biology have been identified in separate studies. Twenty-one articles comparing outcomes were reviewed. Definitions of metachronicity varied from anytime after primary tumour evaluation to 1 year after surgery for primary tumour. Most studies reported that synchronous lesions were associated with poorer survival rates (8% to 16% reduction over 5 years). Sixteen articles comparing combined vs staged resections for synchronous tumour showed comparable morbidity and mortality. Benefits over staged resections included shorter hospital stays and earlier initiation of chemotherapy. Suitability for combined resection depended on patient age and constitution, primary tumour characteristics, size and the number of liver metastases, and the extent of liver involvement. CONCLUSIONS: Surgery remains the only treatment option that offers a chance of long-term survival for patients amenable to curative resection. Synchronicity suggests more aggressive disease although a unifying theory for biological differences explaining the disparity in tumour behaviour has not been found. Combined resection of primary tumour and synchronous metastases is a viable option pending careful patient selection and institutional experience. Given the current evidence, management of synchronous and metachronous colorectal liver metastases needs to be individualised to the needs of each patient. PMID- 20957309 TI - Hepatocellular carcinoma peritoneal metastases: report of three cases and collective review of the literature. AB - INTRODUCTION: Patients with peritoneal metastases (PM) from hepatocellular carcinoma (HCC) often experience a rapid demise even after a complete removal of intrahepatic tumour. Localised PM may now be adequately controlled and managed with cytoreductive surgery (CRS). TREATMENT: Three patients underwent CRS for HCC PM. OUTCOME: The first patient survived 21 months from the time of CRS and is alive with the disease. The second patient died 4 months after CRS. The third patient survived 10 months since CRS and is also alive with the disease. Collectively, the survival of 24 patients with HCC PM extracted through a collective literature review who were treated with cytoreductive surgery had 1- and 2-year survival percentages of 83% and 71%, respectively. CONCLUSION: Careful selection of patients with localised disease to the peritoneal cavity for CRS, taking into consideration the performance status, liver function and tumour biology may lead to a successful outcome in patients with HCC PM. PMID- 20957310 TI - Temporary tattoo associated type IV delayed hypersensitivity dermatitis in a child - a case report and call for parental caution in Singapore. PMID- 20957311 TI - Chewing-induced facial dystonia. PMID- 20957312 TI - An unexpected outcome following radial head excision for Jeffrey type II fracture dislocation of the proximal radius in a child. PMID- 20957313 TI - Durian seed masquerading as gallstone ileus on computed tomography. PMID- 20957314 TI - Psychiatric sub-specialization in Africa--introduction to a series. PMID- 20957315 TI - Mental health policy implementation in Ghana and in Zambia. PMID- 20957316 TI - "Communication by impact" and other forms of non-verbal communication: a review of transference, countertransference and projective identification. AB - This article aims to review the importance, place and especially the emotional impact of non-verbal communication in psychiatry. The paper argues that while biological psychiatry is in the ascendency with increasing discoveries being made about the functioning of the brain and psycho-pharmacology, it is important to try and understand what is happening between psychiatrist and patient. The importance of being aware of the subtleties of this interaction is argued, as are the roles of phenomena such as transference, counter-transference and projective identification. The workings and use of these phenomena are explored as central in the doctor-patient interaction, as well as the consequences of failure to utilize and understand these phenomena. The author reviews - amongst others - the work of the analysts Casement, Gabbard, Goldstein, Ogden and Symington. PMID- 20957317 TI - From mental health policy development in Ghana to implementation: what are the barriers? AB - OBJECTIVE: This paper identifies the key barriers to mental health policy implementation in Ghana and suggests ways of overcoming them. METHOD: The study used both quantitative and qualitative methods. Quantitatively, the WHO Mental Health Policy and Plan Checklist and the WHO Mental Health Legislation Checklist were employed to analyse the content of mental health policy, plans and legislation in Ghana. Qualitative data was gathered using in-depth interviews and focus group discussions with key stakeholders in mental health at the macro, meso and micro levels. These were used to identify barriers to the implementation of mental health policy, and steps to overcoming these. RESULTS: Barriers to mental health policy implementation identified by participants include: low priority and lack of political commitment to mental health; limited human and financial resources: lack of intersectoral collaboration and consultation; inadequate policy dissemination; and an absence of research-based evidence to inform mental health policy. Suggested steps to overcoming the barriers include: revision of mental health policy and legislation; training and capacity development and wider consultation. CONCLUSION: These results call for well-articulated plans to address the barriers to the implementation of mental health policy in Ghana to reduce the burden associated with mental disorders. PMID- 20957318 TI - Mental illness--stigma and discrimination in Zambia. AB - OBJECTIVE: The aim of this qualitative study was to explore the presence, causes and means of addressing individual and systemic stigma and discrimination against people with mental illness in Zambia. This is to facilitate the development of tailor-made antistigma initiatives that are culturally sensitive for Zambia and other low-income African countries. This is the first in-depth study on mental illness stigma in Zambia. METHOD: Fifty semi-structured interviews and 6 focus group discussions were conducted with key stakeholders drawn from 3 districts in Zambia (Lusaka, Kabwe and Sinazongwe). Transcripts were analyzed using a grounded theory approach. RESULTS: Mental illness stigma and discrimination is pervasive across Zambian society, prevailing within the general community, amongst family members, amid general and mental health care providers, and at the level of government. Such stigma appears to be fuelled by misunderstandings of mental illness aetiology; fears of contagion and the perceived dangerousness of people with mental illness; and associations between HIV/AIDS and mental illness. Strategies suggested for reducing stigma and discrimination in Zambia included education campaigns, the transformation of mental health policy and legislation and expanding the social and economic opportunities of the mentally ill. CONCLUSION: In Zambia, as in many other low-income African countries, very little attention is devoted to addressing the negative beliefs and behaviours surrounding mental illness, despite the devastating costs that ensue. The results from this study underscore the need for greater commitment from governments and policy-makers in African countries to start prioritizing mental illness stigma as a major public health and development issue. PMID- 20957319 TI - Diagnosis and treatment of schizophrenia in a general hospital based acute psychiatric ward. AB - OBJECTIVES: To review and describe the clinical profile and acute in-patient treatment of patients diagnosed with schizophrenia over a four-year period; to review and describe the documented evidence for the diagnosis of schizophrenia; and to identify possible associated or predictive factors in the acute in-patient treatment outcome of patients at an acute (designated for 72-hour assessments) ward - within a general hospital, Helen Joseph Hospital (HJH). METHOD: Routine discharge summaries were used in a retrospective clinical review of patients with schizophrenia. The demographic, clinical and treatment profile of these patients were described and the documented evidence for the diagnosis of schizophrenia was reviewed using descriptive and comparative statistics. Factors were evaluated to assess their association with the length of stay (LOS) as outcome variable, using "Generalized Linear Latent and Mixed Models" (GLLAMM). RESULTS: A total of 436 patients were diagnosed with schizophrenia, constituting on average about 20% of the total numbers of admissions. The overall mean LOS was 19.5 days. Considering DSM IV-TR criteria for schizophrenia, behavior problems were confirmed in 71.8% (n=313), perceptual disturbances in 29% (n=126) and thought disorders in 83.5% (n=364). The duration of symptoms were specified in 68% (n=298) patients. Age (p<0.001), gender (p<0.019), substance abuse (p<0.019) and follow-up referral (p<0.000) were significantly associated with LOS. CONCLUSION: The study contributed by identifying these predictive indicators for the acute in-patient treatment outcome of patients with schizophrenia. Future standard operational procedures for diagnostic and treatment processes in acute wards may have to include structured interviews in order to enhance the quality of the routine process of diagnosis and treatment of patients with schizophrenia. PMID- 20957320 TI - Profile of mortality of patients admitted to Weskoppies Psychiatric Hospital in South Africa over a 5-year period (2001-2005). AB - OBJECTIVE: Mortality in the psychiatric population, both from natural and unnatural causes, is higher than in the general population and this is despite an improvement in the delivery of care and treatment of mental illness in recent years. The study was conducted to determine a profile of mortality and standardized mortality rates within our psychiatric hospital. METHOD: A retrospective clinical case audit was conducted of deaths that occurred at Weskoppies Hospital between 1st January 2001 and 31st December 2005. Direct standardised mortality rates were calculated (gender specific adjusted for age according to the South African population). RESULTS: A total of 164 deaths were observed during this period. The gender-specific all cause mortality rates, standardised to the South African population, were 0.0177 (95% CI 0.0141, 0.0213) and 0.0163 (95% CI 0.0121, 0.0206) for males and females respectively. The all cause mortality rates for the South African male and female population were 0.0188 and 0.0170 respectively (not significantly different as it falls within the 95% confidence interval of the standardised rates). The predominant natural cause of mortality was infection. Ten of the deaths were due to unnatural causes, of these 7 were suicides. The mortality ratio for unnatural causes was 0.47. CONCLUSION: Mortality studies are important tools for determining quality of health care provisions to patients. Studies of this nature assist in making recommendations for optimal clinical practice and aid in developing preventative measures. PMID- 20957321 TI - A comparison between the efficacy of dydrogesterone and calcium plus vitamin D in improving women's general health. AB - OBJECTIVE: The aim of this randomized, double-blind, placebo-controlled clinical trial was to evaluate the effect of dydrogesterone and calcium plus vitamin D on young women's general health. METHOD: One hundred and eighty students studying at Shiraz University were recruited. Students completed the General Health Questionnaires (GHQ-28) prior to participation. They were then randomly assigned to take a tablet containing either 5 mg of dydrogesterone, 500 mg of calcium plus 200 mg of vitamin D, or a placebo twice daily from the 15th to the 24th day of their menstrual cycle for 2 consecutive cycles, and to complete the same questionnaires during both the intervention cycles. RESULTS: The effects of dydrogesterone and calcium plus vitamin D on general health scores were similar during the first month of intervention (11.41 +/- 4.28, 12.23 +/- 3.76, respectively) (p>0.05) and both of them were more effective than placebo (16.69 +/- 3.28) (p<0.05). However, dydrogesterone was more effective than calcium plus vitamin D and placebo during the second month of intervention (4.33 +/- 2.69, 6.2 +/- 3.55, 14.39 +/- 3.45, respectively) (p<0.05). No significant differences between groups regarding drugs' side effects (p>0.05) were found. CONCLUSION: Both dydrogesterone and calcium D were more effective than placebo in promoting women's general health. Dydrogesterone was, however, more efficient than calcium plus vitamin D. PMID- 20957322 TI - Anhedonia in acute schizophrenia. PMID- 20957323 TI - The role of the neuropsychological assessment in relinquishing decision making rights. PMID- 20957324 TI - First rank symptoms: concepts and diagnostic utility. AB - First Rank Symptoms (FRS) were first defined by Schneider as diagnostic of schizophrenia. Since then, there has been an immense debate on their diagnostic and prognostic utility. This review attempts to understand the concepts of FRS as depicted over the years and the diagnostic and prognostic implications of FRS in mental illnesses including schizophrenia. Review of relevant material showed that there are wide variations in the concepts of FRS which may be classified according to broad and narrow definitions. These variations have also led to the differences in the diagnostic systems currently being used. Although the diagnostic utility of FRS in schizophrenia remains, it is not clearly so with other mental illnesses in which these symptoms may also be observed. In addition there is controversy over the prognostic implications with evidence divided between poor and no influence on outcome. PMID- 20957325 TI - Psychopatholgy, fundamental assumptions and CD4 T lymphocyte counts in HIV positive patients. AB - OBJECTIVE: We investigated whether psychopathology in HIV-positive patients was associated with more negative fundamental assumptions than in healthy controls. In addition, we explored whether psychopathology and negative fundamental assumptions in HIV-positive patients were associated with lower CD4 T-lymphocyte counts. METHOD: Self-rating questionnaires to assess depressive symptoms, posttraumatic stress symptoms, alcohol abuse, general psychopathology and fundamental assumptions, were completed by 123 HIV-positive patients and 84 uninfected clinic attendees at three primary health care clinics in the Western Cape, South Africa. CD4 T-lymphocyte counts were obtained from chart records. RESULTS: HIV-positive patients reported more depressive and posttraumatic symptoms than uninfected individuals. However when controlling for socio-economic status, the number of traumatic events experienced and other potential confounds, no differences remained. Fundamental assumptions (FA) were mainly positive in both HIV-positive patients and controls and no correlations were found between fundamental assumptions, psychiatric symptoms and CD4 levels. However, in infected patients FA and psychopathology were negatively associated with all participants scoring in the positive range of the FA scale. CONCLUSION: The positive scores on the FA scale indicate that positive assumptions are related to less psychopathology. Longitudinal studies investigating the association between the valence of fundamental assumptions and HIV morbidity are needed. PMID- 20957326 TI - Adherence to highly active antiretroviral therapy in depressed patients with HIV/AIDS attending a Nigerian university teaching hospital clinic. AB - OBJECTIVE: To determine the prevalence of depressive disorder in patients with HIV/AIDS receiving HAART; to determine the effect of depressive disorder on adherence to antiretroviral therapy; and to determine the significance of the association. METHOD: The study was conducted amongst outpatients of Ahmadu Bello University Teaching Hospital, Zaria. A sociodemographic and drug adherence questionnaire was administered. The Centre for Epidemiological Studies Depression Scale (CES-D) was used to screen for depressive symptoms while the Schedule for Clinical Assessment in Neuropsychiatry (SCAN) was used to confirm the diagnosis of depressive disorder. RESULTS: A total of 310 patients with HIV/AIDS receiving HAART participated in the study. 68.4% were female and the mean age was 35.5 (+/- 8.97 years). 37.4% had secondary education, while 27.1% had tertiary education. Sixty-six participants (21.3%) had significant depressive symptoms while 14.2% met ICD-10 diagnostic criteria for depressive disorder. Overall, 73% of participants had good adherence to HAART. 63.6% of participants with depressive disorder had poor adherence to HAART compared to 21.1% of participants without depressive disorder (p<0.05). CONCLUSION: Depressive disorder in patients with HIV/AIDS is associated with poor adherence to antiretroviral medication. Early identification and treatment of depression in such patients may improve antiretroviral medication adherence and treatment outcomes. PMID- 20957327 TI - HIV-infection as a self-reported risk factor for attempted suicide in South Africa. AB - OBJECTIVE: The aim of this study was to examine variables associated with recently diagnosed HIV-infection as a self-reported attempted suicide risk factor. METHOD: The study cohort consisted of 112 general hospital in-patients who attempted suicide because of HIV-infection. All the patients were subject to a comprehensive mental state examination and administration of a semi-structured questionnaire to obtain biographical, sociodemographic and other relevant information. Pearson uncorrected Chi-square (X(2)) or Fisher's Exact Probability Test were used to analyze data utilising Epicalc 2000, version 1.02. RESULTS: Most patients expressed a heterosexual preference. The average age was 34.9 years. Females predominated and in both genders depression and substance abuse (mainly alcohol-related) accounted for the most common psychiatric diagnoses. Less than half of the patients were married. Partner relational problems was a statistically significant variable. The most prevalent co-morbid stressors were poor social support, fear of disclosure/stigmatization and socio-economic pressures. Cognitive deficits included problems with cognitive flexibility, concentration and memory. Based on estimated national suicidal behaviour prevalence rates, a descriptive HIV-related attempted suicide rate of 67.2 per 100 000 and an increased risk for attempted suicide of 13.33% to 18.87% were calculated. CONCLUSION: HIV-infection can be an underestimated suicide risk factor. Effective management and prevention programmes should include as imperatives early diagnosis of HIV-related suicidal behaviour, recognition of underlying psychopathology, neurocognitive deficits, associated stressors, the dynamics of partner relationship problems, as well as cultural awareness and sensitivity. Potential neurocognitive complications that can act as additional risk factors require further research. PMID- 20957328 TI - Explanatory models of mental disorders and treatment practices among traditional healers in Mpumulanga, South Africa. AB - OBJECTIVE: In many traditional belief systems in Africa, including South Africa, mental health problems may be attributed to the influence of ancestors or to bewitchment. Traditional healers are viewed as having the expertise to address these causes. However, there is limited information on their explanatory models and consequent treatment practices. The present study examines traditional healers' explanatory models (EMs) and treatment practices for psychotic and non psychotic mental illnesses. METHOD: 4 focus group discussions (8 healers in each group) and 18 in-depth interviews were conducted. Four vignettes were presented (schizophrenia, depression, panic and somatisation) and traditional healers' views on the nature of the problem, cause, consequence, treatment and patient expectations were elicited. RESULTS: Traditional healers held multiple explanatory models for psychotic and non-psychotic disorders. Psychotic illnesses appear to be the main exemplar of mental illness and were treated with traditional medicine, while nonpsychotic illnesses were not viewed as a mental illness at all. Additionally, traditional healers do not only use herbs and substances solely from "traditional" sources but rather have incorporated into their treatment practices modern ingredients that are potentially toxic. CONCLUSION: Interventions aimed at increasing the mental health literacy of traditional healers are essential. In addition, investigations of the effectiveness of traditional healer treatment for psychiatric disorders should be conducted. PMID- 20957329 TI - Predictors of outcome in patients with common mental disorders receiving a brief psychological treatment: an exploratory analysis of a randomized controlled trial from Goa, India. AB - OBJECTIVE: A randomized placebo-controlled trial of treatment for common mental disorders in Goa, India found that psychological treatment (problem-solving) was no more effective than placebo. The study aimed to identify factors predicting outcome amongst participants receiving the psychological treatment, as measured by score on the Revised Clinical Interview Schedule (CISR). METHOD: The CISR scores at 2 months, 6 months and 12 months were modelled using multiple linear regression with a random effect for patients. Two types of variables were examined. Patient variables were age; sex; religion; education; marital status; severity of psychiatric morbidity at recruitment; and severity of social and life problems faced by the subject. Treatment variables were number of sessions attended and the hospital site. RESULTS: About half the participants had a depressive disorder; most of the remainder had mixed anxiety-depression. Overall adherence with the intervention was low; more than a third of patients attended only one session. Attending a greater number of sessions and facing a severe life problem were significantly associated with a worse outcome (p<0.005). CONCLUSION: The severe nature of life problems faced by some patients with common mental disorders may limit the efficacy of clinic-based psychological treatments in low income countries. PMID- 20957330 TI - Psychosis and relapse in bipolar disorder are related to GRM3, DAOA, and GRIN2B genotype. AB - OBJECTIVE: Dysfunction in glutamate signalling is thought to play a role in the pathophysiology of bipolar disorder (BD). There is evidence of associations between single nucleotide polymorphisms (SNPs) in GRM3, GRIN2B, and DAOA genes and the diagnosis of BD. In this pilot study, we investigated the frequency of SNP variants in these 3 genes within South African population groups, and assessed interactions between genes and phenotypes of BD disease severity. METHOD: Multiplex SNaPshotTM PCR was used to genotype 191 case and 188 control samples. Cases comprised of 191 individuals in a South African cohort of mixed ancestry and Caucasians, with BD Type 1. Phenotypes of BD disease severity were: age of onset, number of illness episodes, number of hospitalisations for depression or mania and history of psychotic symptoms. RESULTS: There were no significant difference in SNP allele frequencies between cases and controls. In the case-only analysis, the GRM3 rs6465084 heterozygote was associated with a 4 fold increased risk of lifetime history of psychotic symptoms, and the specific variants within the gene pair, DAOA and GRIN2B, had a significant interaction with the number of hospitalisations for mania, with lowest admission rates associated with both pairs of ancestral alleles. CONCLUSION: In BD, variations in glutamatergic genes may influence phenotypes related to the severity of illness. Speculatively, newly derived genes associated with various evolutionary advantages, may also increase the risk for more severe BD. These preliminary findings deserve validation in a larger cohort. PMID- 20957331 TI - Testing the effectiveness of existing psycho-educational material (The Alliance Programme) for patients suffering from schizophrenia in the South African context. AB - OBJECTIVE: The objective of this study was to test the effectiveness of the existing psycho-educational material (The Alliance Programme) for patients suffering from schizophrenia in the South African context. METHOD: A qualitative research approach was used. Fifteen Setswana speaking participants, with a diagnosis of schizophrenia were exposed to the programme. Semi-structured and screening interviews were used to collect demographic and clinical data. The participants were divided into two groups and were exposed to either the Alliance Programme or on adapted version of the programme. Participatory communication instruments including focus groups, were used to assess comprehension and knowledge retention of the material over time. RESULTS: Participants who were exposed to the original Alliance Programme experienced the contents of the programme to be technical, difficult to read or recall. They were unable to relate their previous symptoms to the psycho-education given. Participants who were exposed to the adapted version faired much better, gained more insight and were able to relate better to their illnesses. Participants preferred booklets with examples and illustrations, video clips and films over formal lectures. CONCLUSION: Psycho-education material given to people suffering from schizophrenia and their caregivers has to be adapted to their context to be effective. PMID- 20957332 TI - Obsessive auditory imagery: a case report. PMID- 20957333 TI - Intraventricular neurocysticercosis causing acute unilateral hydrocephalus. PMID- 20957334 TI - Inhibition of aldehyde dehydrogenase 2 by oxidative stress is associated with cardiac dysfunction in diabetic rats. AB - Left ventricular (LV) dysfunction is a common comorbidity in diabetic patients, although the molecular mechanisms underlying this cardiomyopathic feature are not completely understood. Aldehyde dehydrogenase 2 (ALDH2) has been considered a key cardioprotective enzyme susceptible to oxidative inactivation. We hypothesized that hyperglycemia-induced oxidative stress would influence ALDH2 activity, and ALDH2 inhibition would lead to cardiac functional alterations in diabetic rats. Diabetes was induced by intraperitoneal (i.p.) injection of 60 mg/kg streptozotocin. Rats were divided randomly into four groups: control, untreated diabetic, diabetic treated with N-acetylcysteine (NAC) and diabetic treated with alpha-lipoic acid (alpha-LA). Cardiac contractile function, oxidative stress markers and reactive oxygen species (ROS) levels were assessed. ALDH2 activity and expression also were determined. The role of ALDH2 activity in change in hyperglycemia-induced mitochondrial membrane potential (Deltapsi) was tested in cultured neonatal cardiomyocytes. Myocardial MDA content and ROS were significantly higher in diabetic rats than in controls, whereas GSH content and Mn-SOD activity were decreased in diabetic rats. Compared with controls, diabetic rats exhibited significant reduction in LV ejection fraction and fractional shortening, accompanied by decreases in ALDH2 activity and expression. NAC and alpha-LA attenuated these changes. Mitochondrial Deltapsi was decreased greatly with hyperglycemia treatment, and high glucose combined with ALDH2 inhibition with daidzin further decreased Deltapsi. The ALDH2 activity can be regulated by oxidative stress in the diabetic rat heart. ALDH2 inhibition may be associated with LV reduced contractility, and mitochondrial impairment aggravated by ALDH2 inhibition might reflect an underlying mechanism which causes cardiac dysfunction in diabetic rats. PMID- 20957335 TI - Activation of membrane androgen receptors in colon cancer inhibits the prosurvival signals Akt/bad in vitro and in vivo and blocks migration via vinculin/actin signaling. AB - Recently, we reported that membrane androgen receptors (mARs) are expressed in colon tumors triggering strong apoptotic responses. In the present study, we analyzed mAR-induced downstream effectors controlling cell survival and migration of Caco2 colon cancer cells. We show that long-term activation of mAR downregulated the activity of PI-3K and Akt and induced de phosphorylation/activation of the proapoptotic Bad (p-Bad). Moreover, treatment of APC(Min/+) mice, which spontaneously develop intestinal tumors, with mAR activating testosterone conjugates reduced the tumor incidence by 80% and significantly decreased the expression of p-Akt and p-Bad levels in tumor tissue. Furthermore, mAR activation strongly inhibited Caco2 cell migration. In accordance with these findings, vinculin, a protein controlling cell adhesion and actin reorganization, was effectively phosphorylated upon mAR activation. Phosphorylation inhibitors genistein and PP2 inhibited actin reorganization and restored motility. Moreover, silencing vinculin by appropriate siRNA's, or blocking actin reorganization by cytochalasin B, restored the migration potential. From these results we conclude that mAR activation inhibits the prosurvival signals Akt/Bad in vitro and in vivo and blocks migration of colon cancer cells via regulation of vinculin signaling and actin reorganization, supporting the powerful tumoristatic effect of those receptors. PMID- 20957336 TI - CYP1A2*1F and GSTM1 alleles are associated with susceptibility to porphyria cutanea tarda. AB - Porphyria cutanea tarda (PCT) is a cutaneous porphyria with sporadic (type 1) and familial (type 2) subtypes, both resulting from decreased hepatic uroporphyrinogen decarboxylase (UROD) activity. Environmental and genetic factors are involved in the development of PCT, and genetic variants in the cytochrome P450 (CYP ) genes, CYP1A1 and CYP1A2, have been implicated. We investigated the association between PCT and variants in CYP1A1, CYP1A2 and CYP2E1, and the glutathione-S-transferase (GST ) genes, GSTM1 and GSTT1. PCT diagnosis was based on urinary or plasma porphyrin profiles. Patients were classified as type 1 or 2 PCT based on UROD mutation analysis. The CYP1A2*1F promoter A allele frequency was significantly higher (P < 0.022) and the A/A genotype frequency marginally higher in PCT patients overall (P < 0.057), with the A/A genotype significantly more common in type 1 PCT (P < 0.043). The presence of the wild-type GSTM1 allele also was associated significantly with PCT (P < 0.019). Neither hemochromatosis (HFE) mutations, tobacco smoking, hepatitis C and HIV infection, ethanol consumption, nor estrogen use were associated with these allelic variants. Age at onset was significantly lower in type 2 PCT patients (P < 0.001), as observed previously. Thus, positive associations between PCT and the CYP1A2*1F promoter A allele and A/A genotype and the wild-type GSTM1 allele indicates that these functional hepatic biotransformation enzymes are risk factors for the development of this disease. PMID- 20957338 TI - Lower respiratory tract infections: serious or self-limiting acute cough? PMID- 20957339 TI - [A rare tumour of the auricle]. AB - We report on a patient suffering from a mesenchymal tumour located at the antihelix. Histopathology of the tissue specimens derived from this lesion reported a myofibroblastic sarcoma, a rare tumour entity with a slight predominance of occurrence in the area of the head and neck. Grading of these tumours can be challenging since benign as well as malign phenotypes have been described. Therefore, beside complete resection of the lesion additional radiotherapy should be discussed individually. PMID- 20957337 TI - Inhibition of Sonic hedgehog and Notch pathways enhances sensitivity of CD133(+) glioma stem cells to temozolomide therapy. AB - Malignant gliomas are currently treated with temozolomide (TMZ), but often exhibit resistance to this agent. CD133(+) cancer stem cells, a population believed to contribute to the tumor's chemoresistance, bear the activation of Notch and Sonic hedgehog (SHH) pathways. In this study, we examined whether inhibition of both pathways enhances the efficacy of TMZ monotherapy in the context of glioma stem cells. Transcriptional analysis of Notch and SHH pathways in CD133(+)-enriched glioma cell populations showed the activity of these pathways. CD133(+) cells were less susceptible to TMZ treatment than the unsorted glioma counterparts. Interestingly, Notch and SHH pathway transcriptional activity in CD133(+) glioma cells was further enhanced by TMZ exposure, which led to NOTCH 1, NCOR2, and GLI1 upregulation (6.64-, 3.73-, and 2.79-fold, respectively) and CFLAR downregulation (4.22-fold). The therapeutic effect of TMZ was enhanced by Notch and SHH pathway pharmacological antagonism with GSI-1 and cyclopamine. More importantly, simultaneous treatment involving TMZ with both of these compounds led to a significant increase in CD133(+) glioma cytotoxicity than treatment with any of these agents alone (P < 0.05). In conclusion, CD133(+) glioma cells overexpress genes involved in Notch and SHH pathways. These pathways contribute to the chemoresistant phenotype of CD133(+) glioma cells, as their antagonism leads to an additive effect when used in combination with TMZ. PMID- 20957340 TI - [Auditory verbal learning in children with suspected auditory processing deficits]. AB - BACKGROUND: As unanimously found in several consensus papers, other conditions such as learning disorders need to be ruled out prior to labelling a child as having an auditory processing disorder (APD). METHODS: In a retrospective study data from 386 children (245 boys, 141 girls) aged 6;0-9;11 years were investigated. All children were referred for behavioural problems suspected to be due to APD. The German auditory verbal learning test (Verbaler Lern- und Merkfahigkeitstest, VLMT) was administered. Results in a range of more than one/two standard deviations from the mean were regarded as deviant/pathological, while a test result under 15.8 was considered below normal. RESULTS: The VLMT short term component was impaired in 202 children, the long term component (loss after interference) in 83 children and the recognition component in 298 children. DISCUSSION: Compared with previously published results, our results suggest that approximately half of all children referred for APD diagnosis suffer from short term memory deficit. We suggest the VLMT, and thus testing of short- and long term memory skills, be administered routinely for thorough APD assessments. PMID- 20957341 TI - Overproduction of cyclo-oxygenase-2 (COX-2) is involved in the resistance to apoptosis in vascular smooth muscle cells from diabetic patients: a link between inflammation and apoptosis. AB - AIMS/HYPOTHESIS: Inflammation is a common feature in cardiovascular diseases, including diabetes mellitus. In addition to the well-known inflammatory role of cyclo-oxygenase-2 (COX-2), this protein has also been implicated in apoptosis resistance in tumour cells. Vascular smooth muscle cells (VSMC) from diabetic patients are also resistant to apoptosis because of an increased abundance of B cell lymphoma 2 protein (BCL2). In this work, we investigated whether overproduction of COX-2 was involved in the resistance to apoptosis in VSMC from diabetic patients. METHODS: VSMC were obtained from internal mammary arteries from patients who had undergone coronary artery bypass graft surgery. Apoptosis was measured by DNA fragmentation, BCL2 degradation and cytochrome c release. RESULTS: Apoptosis induced by C-reactive protein in cells from non-diabetic patients was mediated by COX-2. VSMC from diabetic patients showed higher basal levels of COX-2 compared with those from non-diabetic patients. Transfection of VSMC from non-diabetic patients with a plasmid containing COX-2 (also known as PTGS2) increased basal production of COX-2 and BCL2 and mimicked the resistance to apoptosis that occurs in diabetic patients. We also found a significant correlation (R = 0.846, p = 0.016) between COX-2 and BCL2 production in arterial rings from diabetic patients measured by confocal microscopy. However, inhibition of COX-2 production by small interfering RNA proved unable to reverse BCL2 production in diabetic VSMC. CONCLUSIONS/INTERPRETATION: These results suggest a link between inflammation (COX-2) and apoptosis resistance (BCL2) in the arteries of diabetic patients. This relationship is not causative and the common production of these two proteins may be co-regulated by shared regulatory elements in diabetes. PMID- 20957342 TI - Relationship between ulcer healing after hyperbaric oxygen therapy and transcutaneous oximetry, toe blood pressure and ankle-brachial index in patients with diabetes and chronic foot ulcers. AB - AIMS/HYPOTHESIS: The randomised, double-blind, placebo-controlled Hyperbaric Oxygen Therapy (HBOT) in Diabetic Patients with Chronic Foot Ulcers (HODFU) study showed beneficial effect of HBOT. As this treatment is expensive and time consuming, being able to select patients for therapy would be very useful. The aim of this study was to evaluate whether circulatory variables could help in predicting outcome of HBOT. METHODS: All HODFU study participants who completed therapy, predefined as receiving at least 36 out of 40 scheduled HBOT/placebo sessions, were included in this study (n = 75). Baseline transcutaneous oximetry (TcPO2), toe blood pressure (TBP) and ankle-brachial index (ABI) were measured. Ulcer healing rate was registered at the 9-month follow-up visit. An ulcer was considered healed when it was completely epithelialised and remained so at the 12 month follow-up. RESULTS: In the HBOT group TcPO2 were significantly lower for patients whose ulcer did not heal as compared with those whose ulcers healed. A significantly increased healing frequency was seen with increasing TcPO(2) levels in the HBOT group (TcPO2/healing rate: <25 mmHg/0%; 26-50 mmHg/50%; 51-75 mmHg/73%; and >75 mmHg/100%). No statistically significant relation between the level of TBP or ABI and healing frequency was seen. CONCLUSIONS/INTERPRETATION: Our results indicate that TcPO2 in contrast to ABI and TBP correlates to ulcer healing following HBOT. We suggest HBOT as a feasible adjunctive treatment modality in diabetic patients with chronic non-healing foot ulcers when basal TcPO2 at the dorsum of the foot is above 25 mmHg. TRIAL REGISTRATION: NCT00953186 FUNDING: Mrs Thelma Zoegas Foundation and Faculty of Medicine, Lund University. PMID- 20957343 TI - Carriers of the TCF7L2 rs7903146 TT genotype have elevated levels of plasma glucose, serum proinsulin and plasma gastric inhibitory polypeptide (GIP) during a meal test. AB - AIMS/HYPOTHESIS: The transcription factor 7-like 2 (TCF7L2) rs7903146 T allele associates with type 2 diabetes in several populations, possibly mediated via decreased incretin secretion and/or action and altered beta and alpha cell function. We aimed to study circulating levels of glucose, proinsulin, insulin, C peptide, glucagon, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP 2) and gastric inhibitory polypeptide (GIP) among individuals carrying the high risk rs7903146 TT genotype and low-risk CC genotype following a meal test. METHODS: A meal challenge was performed in 31 glucose-tolerant men (age 54 +/- 7 years and BMI 26 +/- 3 kg/m2) with rs7903146 TT genotype and 31 glucose-tolerant age- and BMI-matched men with CC genotype (age 53 +/- 6 years and BMI 26 +/- 3 kg/m2). Serum proinsulin, insulin, C-peptide and plasma glucose, glucagon, GLP-1, GLP-2 and GIP were obtained 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 180, 210, and 240 min after ingestion of a standardised breakfast meal. RESULTS: An elevated incremental AUC for plasma glucose was observed among TT genotype carriers (CC carriers 21.8 +/- 101.9 mmol/l * min vs TT carriers 97.9 +/- 89.2 mmol/l * min, p = 0.001). TT carriers also had increased AUCs for proinsulin (CC carriers 6,030 +/- 3,001 pmol/l * min vs TT carriers 6,917 +/- 4,820 pmol/l * min, p = 0.03), C-peptide (CC carriers 397.6 +/- 131.9 nmol/l * min vs TT carriers 417.1 +/- 109.3 nmol/l * min, p = 0.04) and GIP (CC carriers 12,310 +/- 3,840 pmol/l * min vs TT carriers 14,590 +/- 5,910 pmol/l * min, p = 0.004). CONCLUSIONS/INTERPRETATION: Middle-aged normoglycaemic individuals carrying the rs7903146 TCF7L2 risk TT genotype show early signs of dysregulated glucose metabolism, decreased processing of proinsulin and elevated GIP secretion following a meal challenge. PMID- 20957344 TI - Diabetes-induced peroxynitrite impairs the balance of pro-nerve growth factor and nerve growth factor, and causes neurovascular injury. AB - AIMS/HYPOTHESIS: Diabetic retinopathy, the leading cause of blindness in working age Americans, is characterised by reduced neurotrophic support and increased proinflammatory cytokines, resulting in neurotoxicity and vascular permeability. We sought to elucidate how oxidative stress impairs homeostasis of nerve growth factor (NGF) and its precursor, proform of NGF (proNGF), to cause neurovascular dysfunction in the eye of diabetic patients. METHODS: Levels of NGF and proNGF were examined in samples from human patients, from retinal Muller glial cell line culture cells and from streptozotocin-induced diabetic animals treated with and without atorvastatin (10 mg/kg daily, per os) or 5,10,15,20-tetrakis (4 sulfonatophenyl)porphyrinato iron (III) chloride (FeTPPs) (15 mg/kg daily, i.p.) for 4 weeks. Neuronal death and vascular permeability were assessed by TUNEL and extravasation of BSA-fluorescein. RESULTS: Diabetes-induced peroxynitrite formation impaired production and activity of matrix metalloproteinase-7 (MMP-7), which cleaves proNGF extracellularly, leading to accumulation of proNGF and reducing NGF in samples from diabetic retinopathy patients and experimental models. Treatment of diabetic animals with atorvastatin exerted similar protective effects that blocked peroxynitrite using FeTPPs, restoring activity of MMP-7 and hence the balance between proNGF and NGF. These effects were associated with preservation of blood-retinal barrier integrity, preventing neuronal cell death and blocking activation of RhoA and p38 mitogen-activated protein kinase (p38MAPK) in experimental and human samples. CONCLUSIONS/INTERPRETATION: Oxidative stress plays an unrecognised role in causing accumulation of proNGF, which can activate a common pathway, RhoA/p38MAPK, to mediate neurovascular injury. Oral statin therapy shows promise for treatment of diabetic retinopathy. PMID- 20957345 TI - Estrogenic response in male bullfrog (Rana catesbeiana) hepatocytes after single or combined exposure to cadmium (Cd) and 17beta-estradiol (E2). AB - Contamination by heavy metals and sex hormones in a water environment is an important health issue. In this study, we investigated the estrogenic effects of cadmium (Cd) administration alone and in combination with 17beta-estradiol (E2) on the hepatocytes of male Bullfrog (Rana catesbeiana). Their vitellogenin (VTG) expression and reactive oxygen species (ROS) were analyzed upon exposure to Cd alone or to both Cd and E2. Our results suggest that the VTG levels induced by the co-treatment of 100 nM E2 and 100 nM CdCl(2) were significantly higher than those induced by 100 nM E2 alone (p < 0.05), and were comparable to vitellogenin induction observed with 1 MUM E2. A similar result was observed by western blot analysis in the culture medium of hepatocytes. Meanwhile, Cd (but not E2) increased the ROS levels. These results suggest that Cd has a cooperative effect with E2 in the induction of VTG, thus acting as an estrogenic disruptor. Cd also causes oxidative stress that occurs with the enhanced vitellogenesis. PMID- 20957346 TI - Effect of the antiviral drug oseltamivir (Tamiflu) on the bacterial community structure of a surface water ecosystem analyzed using fluorescence in situ hybridization. AB - The antiviral drug Tamiflu has received particular attention because of its recommended use against the influenza A H5N1 and H1N1 viruses. Given its resistance to degradation and its hydrophilicity the active metabolite, Oseltamivir Carboxylate (OC), is expected to enter the aquatic ecosystem from sewage treatment plants. In the present paper the bacterial community of surface water samples, treated with OC (1.5 mg L-1), was characterized by Fluorescence In Situ Hybridization (FISH) in microcosm experiments. The alpha-, beta- and gamma Proteobacteria increased in OC-treated versus non-treated water samples during the incubation period, suggesting these bacterial groups had an active role in OC degradation. PMID- 20957347 TI - Distribution and normalization of some metals in surface sediments from South Caspian Sea. AB - Surface sediments along the south of Caspian Sea were collected to evaluate the contamination of heavy metals. The result ranged (MUg/g, Fe% dw): Pb(13.06 33.48); Ni(18.01-69.63); Cd(0.62-1.5); Zn(30.11-87.88); Cu(5.86-26.37) and Fe(1.8 4%) respectively. Cadmium showed higher EF when compared to other sites. Geoaccumulation Index value for Cd in most stations was classified as moderately contaminated and moderately to strongly contaminated, as well as the average of I(geo) of Cd (1.77 +/- 0.35) suggested that surface sediments of Caspian coast were moderately polluted by this metal. The result of the Pearson correlation showed that there were significant positive associations between Ni, Cd and Zn (r = 0.44-0.76; p < 0.01). PMID- 20957348 TI - Production, purification and structural characterization of an exopolysaccharide produced by a probiotic Lactobacillus plantarum MTCC 9510. AB - Exopolysaccharides (EPS) from lactic acid bacteria contribute to specific rheology and texture of fermented milk products and finds applications even in non-dairy foods and in therapeutics. Box-Behnken model of response surface methodology (RSM) was employed to formulate the production medium for exopolysaccharide (EPS). FT-IR spectral analysis of the purified EPS from Lactobacillus plantarum MTCC 9510 revealed prominent characteristic groups corresponding to polyhydric alcohols. The degradation temperature (Td) of the polysaccharide was found to be 260 degrees C with the help of thermo gravimetric analysis (TGA). Structure elucidation of the EPS showed that it consists of a trisaccharide repeating unit of alpha-D: -glucose, beta-D: -glucose and alpha-D: mannose. PMID- 20957349 TI - Myosin heavy chain expression pattern as a marker for anabolic potency: desoxymethyltestosterone (madol), norandrostenedione and testosterone repress MHC IIb expression and stimulate MHC-IId/x expression in orchiectomized rat gastrocnemius muscle. AB - Both 19-norandrostenedione (estr-4-ene-3,17-dione, NOR) and desoxymethyltestosterone (17alpha-methyl-5alpha-androst-2-en-17beta-ol, DMT or "madol") are 'designer steroids' misused for doping purposes in the bodybuilding scene. We have previously characterized the pharmacological profile of madol and identified potential adverse side effects. The aim of this study was to investigate the anabolic potency of NOR, madol and the reference substance testosterone propionate (TP). Besides wet weight of the M.levator ani (LA), we examined the effects on muscle fiber type composition and myosin heavy chain (MHC) expression in the M.gastrocnemius (Gas) muscle as additional markers for anabolic potency. A Hershberger assay was performed, where orchiectomized (orchi) male Wistar rats were treated subcutaneously with NOR, madol, TP or vehicle control (all 1 mg/kg BW/day) for 12 days. Wet weights of the Gas, LA, prostate and seminal vesicle were examined to determine anabolic and androgenic effects. Fiber type composition of the Gas muscle was analyzed using ATPase staining, and MHC protein profiles were determined by silver stain and Western blot analysis. NOR and madol exhibited strong anabolic and weak androgenic potency by stimulating growth of the LA but not the prostate and seminal vesicle. Skeletal muscle fiber type composition characterized by ATPase staining was not significantly altered between the treatment groups, although there was a tendency toward lower levels of type IIB and increased type IIA fibers in all treatment groups relative to orchi. MHC protein expression determined by Western blot and silver stain analysis revealed that MHC IId/x was significantly up-regulated, while MHC IIb was significantly down-regulated in NOR, madol and TP groups relative to orchi. There were no significant differences for MHC IIa and MHC I expression between groups. Results suggest that the observed MHC expression shift could serve as a molecular marker to determine anabolic activity of anabolic steroids at least in skeletal muscle of orchi rats. The molecular mechanisms as well as the androgen-dependent regulation of MHC expression in intact skeletal muscle remain to be further investigated. PMID- 20957350 TI - Extrasynaptic GABAA receptor activation reverses recognition memory deficits in an animal model of schizophrenia. AB - RATIONALE: Schizophrenia is a complex psychiatric disorder comprised of three main classes of symptoms: positive, negative and cognitive symptoms. Currently, no approved treatment exists for the cognitive symptoms. There is thus a great need for research aiming at identifying novel targets for treatment of this indication. Several neurotransmitter systems are affected in schizophrenia patients, including the gamma-amino butyric acid (GABAergic) system, demonstrated by reduced parvalbumin-containing interneurons, glutamate decarboxylase (GAD) and the GABA transporter GAT-1. Furthermore, gene expression of several GABA(A) receptor sub-units, such as alpha1, alpha4 and delta is reduced in the dorsolateral prefrontal cortex of schizophrenia patients. OBJECTIVES: The psychotomimetic NMDA receptor antagonist phencyclidine (PCP) is frequently employed to model schizophrenia in animal disease models. Sub-chronic PCP treatment of female hooded Lister rats has repeatedly been shown to induce impairments in object recognition memory, and this model was therefore chosen for the examination of the potential of positive modulation of extrasynaptic GABA(A) receptors in alleviating the PCP-induced deficit. RESULTS: Rats treated sub chronically with PCP showed significant impairments in recognition memory. This deficit was reversed by positive modulation of extrasynaptic GABA(A) receptors. CONCLUSION: The present study shows that extrasynaptic GABA(A) receptors may present a novel target for the development of therapeutics aimed at improving cognitive deficits in schizophrenia. PMID- 20957352 TI - Effects of cadmium and phenanthrene mixtures on aquatic fungi and microbially mediated leaf litter decomposition. AB - Urbanization and industrial activities have contributed to widespread contamination by metals and polycyclic aromatic hydrocarbons, but the combined effects of these toxics on aquatic biota and processes are poorly understood. We examined the effects of cadmium (Cd) and phenanthrene on the activity and diversity of fungi associated with decomposing leaf litter in streams. Leaves of Alnus glutinosa were immersed for 10 days in an unpolluted low-order stream in northwest Portugal to allow microbial colonization. Leaves were then exposed in microcosms for 14 days to Cd (0.06-4.5 mg L(-1)) and phenanthrene (0.2 mg L(-1)) either alone or in mixture. A total of 19 aquatic hyphomycete species were found sporulating on leaves during the whole study. The dominant species was Articulospora tetracladia, followed by Alatospora pulchella, Clavatospora longibrachiata, and Tetrachaetum elegans. Exposure to Cd and phenanthrene decreased the contribution of A. tetracladia to the total conidial production, whereas it increased that of A. pulchella. Fungal diversity, assessed as denaturing gradient gel electrophoresis fingerprinting or conidial morphology, was decreased by the exposure to Cd and/or phenanthrene. Moreover, increased Cd concentrations decreased leaf decomposition and fungal reproduction but did not inhibit fungal biomass production. Exposure to phenanthrene potentiated the negative effects of Cd on fungal diversity and activity, suggesting that the co occurrence of these stressors may pose additional risk to aquatic biodiversity and stream ecosystem functioning. PMID- 20957351 TI - The use of peripheral vision to guide perturbation-evoked reach-to-grasp balance recovery reactions. AB - For a reach-to-grasp reaction to prevent a fall, it must be executed very rapidly, but with sufficient accuracy to achieve a functional grip. Recent findings suggest that the CNS may avoid potential time delays associated with saccade-guided arm movements by instead relying on peripheral vision (PV). However, studies of volitional arm movements have shown that reaching is slower and/or less accurate when guided by PV, rather than central vision (CV). The present study investigated how the CNS resolves speed-accuracy trade-offs when forced to use PV to guide perturbation-evoked reach-to-grasp balance-recovery reactions. These reactions were evoked, in 12 healthy young adults, via sudden unpredictable antero-posterior platform translation (barriers deterred stepping reactions). In PV trials, subjects were required to look straight-ahead at a visual target while a small cylindrical handhold (length 25%> hand-width) moved intermittently and unpredictably along a transverse axis before stopping at a visual angle of 20 degrees , 30 degrees , or 40 degrees . The perturbation was then delivered after a random delay. In CV trials, subjects fixated on the handhold throughout the trial. A concurrent visuo-cognitive task was performed in 50% of PV trials but had little impact on reach-to-grasp timing or accuracy. Forced reliance on PV did not significantly affect response initiation times, but did lead to longer movement times, longer time-after-peak-velocity and less direct trajectories (compared to CV trials) at the larger visual angles. Despite these effects, forced reliance on PV did not compromise ability to achieve a functional grasp and recover equilibrium, for the moderately large perturbations and healthy young adults tested in this initial study. PMID- 20957353 TI - Micronuclei assay in exfoliated buccal cells from individuals exposed to arsenic in Argentina. AB - Drinking arsenic (As)-laden water for a long time affects a population's health and leads to chronic hydroarsenicism, which is associated with an increased incidence of different types of cancer. To determine the potential genotoxic risk associated with different degrees of environmental exposure to inorganic As by way of drinking water, micronuclei (MN) frequency in exfoliated buccal cells was evaluated in Argentina among rural populations of Santiago del Estero and urban populations of Buenos Aires. The exposed group in Santiago del Estero (La Firmeza and Santos Lugares localities) showed a significant increase in MN frequency in epithelial cells compared with controls (Monte Quemado and Urutau localities) (p = 0.0005). With regard to the Buenos Aires groups, Navarro individuals (the exposed group) exhibited a significant difference compared with controls (Ciudad Autonoma de Buenos Aires) (p = 0.0002). Comparison of MN frequencies between Santiago del Estero and Buenos Aires individuals showed that genotoxic effects of As in drinking water exhibit variation between rural and urban groups, probably due to individual susceptibility being an important incidence factor. The results clearly show that MN assay in buccal mucosa cells is an ideal methodology with which to measure potential genetic risk related to environmental As exposure in humans. PMID- 20957354 TI - A review-biosynthesis of optically pure ethyl (S)-4-chloro-3-hydroxybutanoate ester: recent advances and future perspectives. AB - Ethyl (S)-4-chloro-3-hydroxybutanoate ester ((S)-CHBE) is a precursor of enantiopure intermediates used for the production of chiral drugs, including the cholesterol-lowering 3-hydroxy-3-methyl-glutaryl CoA reductase inhibitors (statins). The asymmetric reduction of ethyl 4-chloro-3-oxobutanoate ester (COBE) to (S)-CHBE by biocatalysis has several positive attributes, including low cost, mild reaction conditions, high yield, and a high level of enantioselectivity. During genome database mining of the yeast Pichia stipitis, our group found two novel carbonyl reductases (PsCRI and PsCRII) that have a promising future for the industrial production of (S)-CHBE with >99% enantiomeric excess. This review covers the main process of biosynthesis of (S)-CHBE: screening of microorganisms that catalyze the reduction of COBE to (S)-CHBE (I); gene cloning, expression, and characterization of carbonyl reductases for the production of (S)-CHBE in Escherichia coli (II); development of cofactor generation systems for regenerating cofactors (III); and biocatalysis of COBE to (S)-CHBE by recombinant E. coli (IV). PMID- 20957356 TI - Bioavailability of organic compounds solubilized in nonionic surfactant micelles. AB - Whether direct availability of organic compound solubilized in nonionic surfactant micelles (bioavailability) in a bioremediation or biotransformation process is uncertain to some extent, which is partially attributed to the difficulty by direct experimental determination. In another point of view, it should be ascribed to the fuzzy concept about the solubilization of organic compound in a nonionic surfactant micelle aqueous solution. In this mini-review, the solubilization of organic compound in surfactant micelles aqueous solution is fully discussed; especially saturated solubilization and unsaturated solubilization have been emphasized. Then the current methods for estimation of bioavailability of organic compounds solubilized in micelles are introduced, in which the possible drawbacks of each method are stressed. Finally, the conclusion that organic compound solubilized in micelles is unavailable directly by microbes has been drawn and the intensification of bioremediation or biotransformation by nonionic surfactant micelle aqueous solution is contributed to enhancement of the hydrophobic organic compounds dissolution. PMID- 20957355 TI - Elimination of carbon catabolite repression in Klebsiella oxytoca for efficient 2,3-butanediol production from glucose-xylose mixtures. AB - Microbial preference for glucose implies incomplete and/or slow utilization of lignocellulose hydrolysates, which is caused by the regulatory mechanism named carbon catabolite repression (CCR). In this study, a 2,3-butanediol (2,3-BD) producing Klebsiella oxytoca strain was engineered to eliminate glucose repression of xylose utilization. The crp(in) gene, encoding the mutant cyclic adenosine monophosphate (cAMP) receptor protein CRP(in), which does not require cAMP for functioning, was characterized and overexpressed in K. oxytoca. The engineered recombinant could utilize a mixture of glucose and xylose simultaneously, without CCR. The profiles of sugar consumption and 2,3-BD production by the engineered recombinant, in glucose and xylose mixtures, were examined and showed that glucose and xylose could be consumed simultaneously to produce 2,3-BD. This study offers a metabolic engineering strategy to achieve highly efficient utilization of sugar mixtures derived from the lignocellulosic biomass for the production of bio-based chemicals using enteric bacteria. PMID- 20957357 TI - Disruption of ten protease genes in the filamentous fungus Aspergillus oryzae highly improves production of heterologous proteins. AB - Proteolytic degradation by secreted proteases into the culture medium is one of the significant problems to be solved in heterologous protein production by filamentous fungi including Aspergillus oryzae. Double (tppA, and pepE) and quintuple (tppA, pepE, nptB, dppIV, and dppV) disruption of protease genes enhanced human lysozyme (HLY) and bovine chymosin (CHY) production by A. oryzae. In this study, we used a quintuple protease gene disruptant and performed successive rounds of disruption for five additional protease genes (alpA, pepA, AopepAa, AopepAd, and cpI), which were previously investigated by DNA microarray analyses for their expression. Gene disruption was performed by pyrG marker recycling with a highly efficient gene-targeting background (?ligD) as previously reported. As a result, the maximum yields of recombinant CHY and HLY produced by a decuple protease gene disruptant were approximately 30% and 35%, respectively, higher than those produced by a quintuple protease gene disruptant. Thus, we successfully constructed a decuple protease gene disruptant possessing highly improved capability of heterologous protein production. This is the first report on decuple protease gene disruption that improved the levels of heterologous protein production by the filamentous fungus A. oryzae. PMID- 20957358 TI - DNA restriction-modification systems in the ethanologen, Zymomonas mobilis ZM4. AB - To better understand the DNA restriction-modification (R-M) systems for more amenable strain development of the alternative industrial ethanologen, Zymomonas mobilis, three gene knockout mutants were constructed. The gene knockout mutants were tested for their DNA restriction activities by the determination of transformation efficiency using methylated and unmethylated foreign plasmid DNAs. Inactivation of a putative mrr gene encoded by ZMO0028 (zmrr) resulted in a 60 fold increase in the transformation efficiency when unmethylated plasmid DNA was used. This indicated that the putative mrr gene may serve as a type IV restriction-modification system in Z. mobilis ZM4. To assign the function of a putative type I DNA methyltransferase encoded by ZMO1933 (putative S subunit) and ZMO1934 (putative M subunit), the putative S subunit was inactivated. The gene inactivation of ZMO1933 resulted in a 30-fold increase in the transformation efficiency when methylated plasmid DNA was introduced, indicating that the putative S subunit possibly serves as a part of functional type I R-M system(s). Growth studies performed on the mutant strains indicate inactivation of the type I S subunit resulted in a lower maximum specific glucose consumption rate and biomass yield, while inactivation of the type IV Zmrr had the opposite effect, with an increase in the maximum specific growth rate and biomass yield. PMID- 20957359 TI - Recombinant expression, affinity purification and functional characterization of Scots pine defensin 1. AB - Plants produce a variety of molecules to defend themselves from fungal pathogens. Defensins belong to the family of antimicrobial peptides that play a central role in innate immunity in all species of plants. We have previously reported the purification of antimicrobial peptides from Scots pine seedlings and the identification of some of them, including defensin, by mass spectrometry. In this study, we extend our original study on molecular cloning of Pinus sylvestris defensin 1 (PsDef1) by presenting the expression and affinity purification of recombinant defensin 1 (rPsDef1). The full-length coding sequence of PsDef1 has an open reading frame capable to encode a protein of 83 amino residues, including a signal peptide of 33 aa, followed by a characteristic defensin domain of 50 amino acids representing its active form. The calculated molecular weight of the mature form of PsDef1 is 5,601.6 Da. We have employed pET system to express mature form of PsDef1 fussed to GST. As GST-PsDef1 fusion protein was not biologically active, we removed GST moiety from the mature defensin 1 peptide by proteolytic cleavage with Factor Xa. The resulting rPsDef1 protein exhibited strong antifungal activity against a panel of pathogenic fungi which is comparable to that of endogenous Scots pine defensin 1. In addition, rPsDef1 was used to produce specific polyclonal antibodies. Using generated antibodies, we found that the level of PsDef1 is significantly increased in Scots pine seedlings during germination and in their response to pathogenic infection with Heterobasidion annosum. PMID- 20957360 TI - Limitations of Tc99m-MIBI-SPECT imaging scans in persistent primary hyperparathyroidism. AB - BACKGROUND: In primary hyperparathyroidism (PHPT) the predictive value of technetium 99m sestamibi single emission computed tomography (Tc99m-MIBI-SPECT) for localizing pathological parathyroid glands before a first parathyroidectomy (PTx) is 83-100%. Data are scarce in patients undergoing reoperative parathyroidectomy for persistent hyperparathyroidism. The aim of the present study was to determine the value of Tc99m-MIBI-SPECT in localizing residual hyperactive parathyroid tissue in patients with persistent primary hyperparathyroidism (PHPT) after initial excision of one or more pathological glands. METHOD: We retrospectively evaluated the localizing accuracy of Tc99m MIBI-SPECT scans in 19 consecutive patients with persistent PHPT who had a scan before reoperative parathyroidectomy. We used as controls 23 patients with sporadic PHPT who had a scan before initial surgery. RESULTS: In patients with persistent PHPT, Tc99m-MIBI-SPECT accurately localized a pathological parathyroid gland in 33% of cases before reoperative parathyroidectomy, compared to 61% before first PTx for sporadic PHPT. The Tc99m-MIBI-SPECT scan accurately localized intra-thyroidal glands in 2 of 7 cases and a mediastinal gland in 1 of 3 cases either before initial or reoperative parathyroidectomy. CONCLUSIONS: Our data suggest that the accuracy of Tc99m-MIBI-SPECT in localizing residual hyperactive glands is significantly lower before reoperative parathyroidectomy for persistent PHPT than before initial surgery for sporadic PHPT. These findings should be taken in consideration in the preoperative workup of patients with persistent primary hyperparathyroidism. PMID- 20957361 TI - Tailored or routine addition of an antireflux fundoplication in laparoscopic large hiatal hernia repair: a comparative cohort study. AB - BACKGROUND: There is controversy about the tailored or routine addition of an antireflux fundoplication in large hiatal hernia (type II-IV) repair. We investigated the strategy of selective addition of a fundoplication in patients with a large hiatal hernia and concomitant gastroesophageal reflux disease. METHODS: Between 2002 and 2008, 60 patients with a large hiatal hernia were evaluated preoperatively and 12 months after surgery by reflux-related symptoms, upper endoscopy, and esophageal 24-h pH monitoring. In patients with preoperatively documented gastroesophageal reflux disease, an antireflux fundoplication was added during hiatal hernia repair. RESULTS: An antireflux procedure was added in 35 patients and 25 patients underwent hiatal hernia repair only. Preoperative symptoms were improved or resolved in 31 patients (88.6%) in the group who had fundoplication and in 20 patients (87.0%) in the group who did not have fundoplication. In patients with fundoplication, esophagitis was present in 6 patients (22.2%) after surgery and abnormal esophageal acid exposure persisted in 11 (39.3%). Seven patients (38.9%) with hernia repair only developed abnormal esophageal acid exposure, and esophagitis was postoperatively generated in five (27.8%). In neither group did patients have new onset of daily heartburn or dysphagia. CONCLUSIONS: In patients with a large hiatal hernia associated with gastroesophageal reflux disease, addition of a fundoplication during hernia repair yields acceptable reduction of symptoms and does not generate symptomatic side effects. Objective control of reflux, however, is only moderate. Omission of an antireflux procedure in the absence of gastroesophageal reflux disease induced esophagitis in 28% and abnormal esophageal acid exposure in 39% of patients. Therefore, routine addition of an antireflux fundoplication should be recommended. PMID- 20957362 TI - Outcomes from prehospital cardiac arrest in blunt trauma patients. AB - BACKGROUND: There are few strategies for treating patients who have suffered cardiopulmonary arrest due to blunt trauma (BT-CPA). The aim of this population based case series observational study was to clarify the outcome of BT-CPA patients treated with a standardized strategy that included an emergency department thoracotomy (EDT) under an emergency medical service (EMS) system with a rapid transportation system. METHODS: The 477 BT-CPA registry data were augmented by a review of the detailed medical records in our emergency department (ED) and action reports in the prehospital EMS records. RESULTS: Of those, 76% were witnessed and 20% were CPA after leaving the scene. In all, 18% of the patients went to the intensive care unit (ICU), the transcatheter arterial embolization (TAE) room, or the operating room (OR). Only 3% survived to be discharged. Among the 363 witnessed patients-11 of whom had ventricular fibrillation (VF) as the initial rhythm, 134 exhibiting pulseless electrical activity (PEA), and 221 with asystole-13, 1, and 3%, respectively, survived to discharge. The most common initial rhythm just after collapse was not VF but PEA, and asystole increased over the 7 min after collapse. There were no differences in the interval between arrival at the hospital and the return of spontaneous circulation between the patients that survived to discharge and deceased patients in the ED, OR, TAE room, or ICU. The longest interval was 17 min. CONCLUSIONS: In BT-CPA patients, a 20-min resuscitation effort and termination of the effort are thought to be relevant. The initial rhythm is not a prognostic indicator. We believe that the decision on whether to undertake aggressive resuscitation efforts should be made on a case-by-case basis. PMID- 20957363 TI - Effect of surgery on quality of life with operable breast cancer in limited resource environment. PMID- 20957364 TI - The metalloprotease, NN-PF3 from Naja naja venom inhibits platelet aggregation primarily by affecting alpha2beta1 integrin. AB - NN-PF3 is a non-toxic, anticoagulant, high-molecular-mass (67.81 kDa) metalloprotease from Indian cobra (Naja naja) venom. In the present study, NN-PF3 was investigated for the mechanism of inhibition of collagen-induced aggregation of human platelets. The complete inhibition of collagen-induced aggregation and partial inhibition of ADP- and epinephrine-induced aggregation has the respective IC(50) of 75 +/- 5, 185 +/- 10, and 232 +/- 12 nM, whereas no inhibition of thrombin-, arachidonic acid-, and ristocetin-induced aggregation of platelets was observed in platelet-rich plasma. Further, native NN-PF3 and EDTA-inactivated NN PF3 inhibited collagen-induced aggregation of washed platelets with respective IC(50) of 75 +/- 4 and 180 +/- 6 nM. The higher inhibitory effect of native NN PF3 compared with EDTA-inactivated NN-PF3 suggests the enzymatic and non enzymatic mechanism of inhibition. NN-PF3 pretreatment affected the collagen binding but not the fibrinogen, and fibronectin binding of washed platelets in adhesion assay suggested that the collagen receptors are affected. Western blot study using anti-integrin alpha2beta1 mAb 6F1 suggested that NN-PF3 binds to integrin alpha2beta1 in a primary structure-dependent manner only and is not cleaved. There was a drastic reduction in the intensity of several intracellular signaling phosphotyrosine protein bands when monoclonal anti-phosphotyrosine antibody was used, suggesting that the major activation pathway of platelets get affected, which occurs through glycoprotein VI. NN-PF3 did not bind to collagen as revealed by Western blot using anti-collagen mAb. Furthermore, neither the proteolytic cleavage of fibrinogen nor its degradation products by NN-PF3 contributed for the collagen-induced platelet aggregation inhibition. PMID- 20957365 TI - Random skin biopsy and bone marrow biopsy for diagnosis of intravascular large B cell lymphoma. AB - Intravascular lymphoma (IVL) is a rare type of extranodal lymphoma in which the lymphoma cells proliferate exclusively in the lumina of small vessels. The diagnosis of IVL requires histological confirmation. Although random skin biopsy from healthy-appearing skin in patients with suspected IVL appeared to be useful, the sensitivity of this method for the diagnosis of IVL remains unknown. We performed a random skin biopsy from 12 consecutive cases of IVL diagnosed at our institution over the past 4 years and evaluate its relevance of clinical and laboratory characteristics, presence or absence of skin lesions, and bone marrow involvement. All 12 patients were diagnosed antemortem by either random skin biopsy or bone marrow biopsy and treated with rituximab-containing chemotherapy. Random skin biopsy was performed in all 12 patients, and the results were positive in ten patients (83.3%). Erythematous skin lesions were seen in 3 of 12 patients, but biopsy was positive for lymphoma lesion in two patients. Bone marrow invasion was seen in 11 of the 12 patients (91.6%) by bone marrow smear and/or flow cytometric analysis, but was detected in only half of the patients by trephine biopsy. We concluded that random skin biopsy from normal-appearing skin is highly sensitive in the diagnosis of IVL comparable to bone marrow trephine biopsy. It should be performed irrespective of the presence or absence of skin lesions in patients who were suspicious of IVL. PMID- 20957366 TI - CXCR4 expression on transplanted peripheral blood CD34+ cells: relationship to engraftment after autologous transplantation in a cohort of multiple myeloma patients. AB - Expression of the chemokine receptor CXCR4 by haematopoietic stem cells (HSCs) is believed to influence the process of these cells 'homing' back to the bone marrow post-transplantation, in response to the stromal cell-derived factor-1 gradient, followed by engraftment. The primary aim of this retrospective study was to compare reinfused CD34(+) cell dose, assessed from the fresh collection, with the post-thaw viable (v) CD34(+) and vCD34/CXCR4(+) dual positive cell dose as predictors of haematopoietic recovery in multiple myeloma patients undergoing autologous stem cell transplantation. Cryopreserved samples from stem cell collections of 27 myeloma patients were analysed for CD34 and CXCR4 expression and times to haematological engraftment measured. Dosage of transplanted vCD34(+) cells was on average 79% of the original calculation from the fresh collection bag (range 29-98%). The median percentage of vCD34+ cells co-expressing CXCR4 was 37% (3.7-97%). Surface expression of CXCR4 by thawed vCD34(+) cells was closely correlated to complementary DNA levels. The median dose of CD34/CXCR4(+) cells in the autografts was 1.2 * 10(6)/kg (0.2-3.0 * 10(6)/kg) compared with 3.3 * 10(6)/kg for transplanted vCD34(+) cells (1.2-5.5 * 10(6)/kg). Both CD34 and vCD34 doses correlated with neutrophil engraftment (p < 0.005) although vCD34/CXCR4(+) dose did not. However, patients given a higher dose of CD34/CXCR4(+) cells (>=1.75 * 10(6)/kg) showed a faster time to platelet recovery (p < 0.05) than those given a lower dose (<=0.42 * 10(6)/kg). These results warrant further study of CD34/CXCR4 expression by mobilised HSCs and the relationship to platelet recovery post-transplantation on a larger cohort of patients. PMID- 20957367 TI - Genetic polymorphisms of tumor necrosis factor-alpha and lymphotoxin-alpha in Chinese patients with non-Hodgkin lymphoma. PMID- 20957368 TI - Expression, purification, and characterization of an iron chaperon protein CyaY from Acidithiobacillus ferrooxidans. AB - CyaY is the bacterial homolog of frataxin, proposed to be involved in the assembly of iron-sulfur clusters. While, the physiological iron donor for the iron-sulfur clusters assembly remains controversial. In this study, the gene of CyaY from Acidithiobacillus ferrooxidans was cloned and expressed in Escherichia coli, the protein was purified by one-step affinity chromatography to homogeneity. The CyaY protein can bind ferric iron and serve as an iron donor for the biogenesis of iron-sulfur clusters on the scaffold protein IscU in the presence of IscS and L-cysteine in vitro. PMID- 20957369 TI - Effects of prolonged chlorine exposures upon PCR detection of Helicobacter pylori DNA. AB - The effect of low doses of free chlorine on the detection of Helicobacter pylori (H. pylori) cells by qPCR in tap water was monitored. Detection of sequences targeted to the ureA gene from preparations containing 107 cells/ml decreased about 2-4 logs by days 9 and 14, respectively. When duplicate suspensions of the 107 cells/ml were exposed to higher levels of chlorine, 0.2-2.2 mg/l, by day 9 and 14 there were 5 and 6 log decreases, respectively, in the detection of ureA gene. H. pylori target sequences (within suspended, intact cells at densities of 102-103 cells /ml) were rendered undetectable by qPCR analysis after 17 h of continuous exposure to low chlorine levels common to treated drinking water distribution systems. The persistence of DNA sequences within treated distribution systems detectable by qPCR may be as brief as 17 h especially for bacteria such as H. pylori which are known to occur in very low numbers within treated distribution systems. This study suggests that degradation of H. pylori DNA target sequences by chlorine levels commonly found within treated water distribution systems occurs within the average water retention times (2-3 days) commonly found in these systems. PMID- 20957370 TI - Design of regulation and dynamics in simple biochemical pathways. AB - Complex regulation of biochemical pathways in a cell is brought about by the interaction of simpler regulatory structures. Among the basic regulatory designs, feedback inhibition of gene expression is the most common motif in gene regulation and a ubiquitous control structure found in nature. In this work, we have studied a common structural feature (delayed feedback) in gene organisation and shown, both theoretically and experimentally, its subtle but important functional role in gene expression kinetics in a negatively auto-regulated system. Using simple deterministic and stochastic models with varying levels of realism, we present detailed theoretical representations of negatively auto regulated transcriptional circuits with increasing delays in the establishment of feedback of repression. The models of the circuits with and without delay are studied analytically as well as numerically for variation of parameters and delay lengths. The positive invariance, boundedness of the solutions, local and global asymptotic stability of both the systems around the unique positive steady state are studied analytically. Existence of transient temporal dynamics is shown mathematically. Comparison of the two types of model circuits shows that even though the long-term dynamics is stable and not affected by delays in repression, there is interesting variation in the transient dynamical features with increasing delays. Theoretical predictions are validated through experimentally constructed gene circuits of similar designs. This combined theoretical and experimental study helps delineate the opposing effects of delay-induced instability, and the stability-enhancing property of negative feedback in the pathway behaviour, and gives rationale for the abundance of similar designs in real biochemical pathways. PMID- 20957371 TI - Modeling the formation of in vitro filopodia. AB - Filopodia are bundles of actin filaments that extend out ahead of the leading edge of a crawling cell to probe its upcoming environment. In vitro experiments (Vignjevic et al. in J Cell Biol 160:951-962, 2003) have determined the minimal ingredients required for the formation of filopodia from the dendritic-like morphology of the leading edge. We model these experiments using kinetic aggregation equations for the density of growing bundle tips. In mean field, we determine the bundle size distribution to be broad for bundle sizes smaller than a characteristic bundle size above which the distribution decays exponentially. Two-dimensional simulations incorporating both bundling and cross-linking measure a bundle size distribution that agrees qualitatively with mean field. The simulations also demonstrate a nonmonotonicity in the radial extent of the dendritic region as a function of capping protein concentration, as was observed in experiments, due to the interplay between percolation and the ratcheting of growing filaments off a spherical obstacle. PMID- 20957372 TI - Consequences of fluctuating group size for the evolution of cooperation. AB - Studies of cooperation have traditionally focused on discrete games such as the well-known prisoner's dilemma, in which players choose between two pure strategies: cooperation and defection. Increasingly, however, cooperation is being studied in continuous games that feature a continuum of strategies determining the level of cooperative investment. For the continuous snowdrift game, it has been shown that a gradually evolving monomorphic population may undergo evolutionary branching, resulting in the emergence of a defector strategy that coexists with a cooperator strategy. This phenomenon has been dubbed the 'tragedy of the commune'. Here we study the effects of fluctuating group size on the tragedy of the commune and derive analytical conditions for evolutionary branching. Our results show that the effects of fluctuating group size on evolutionary dynamics critically depend on the structure of payoff functions. For games with additively separable benefits and costs, fluctuations in group size make evolutionary branching less likely, and sufficiently large fluctuations in group size can always turn an evolutionary branching point into a locally evolutionarily stable strategy. For games with multiplicatively separable benefits and costs, fluctuations in group size can either prevent or induce the tragedy of the commune. For games with general interactions between benefits and costs, we derive a general classification scheme based on second derivatives of the payoff function, to elucidate when fluctuations in group size help or hinder cooperation. PMID- 20957373 TI - Arboreal habitat structure affects route choice by rat snakes. AB - In arboreal habitats gaps between branches and branch structure profoundly affect the ability of animals to move; hence, an ability to perceive such attributes could facilitate choosing routes that enhance the speed and ease of locomotion. Although many snakes are arboreal, no previous study has determined whether they can perceive structural variation of branches that is mechanically relevant to their locomotion. We tested whether the gap distance, location, and attributes of two destination perches on the far side of a crossable gap affected the route travelled by North American rat snakes (Pantherophis), which are proficient climbers. Snakes usually chose routes with shorter gaps. Within a horizontal plane, the snakes usually went straight rather than crossing an equal distance gap with a 90 degrees turn, which was consistent with our finding that crossing a straight gap was easier. However, decreasing the distance of the gap with a 90 degrees turn eliminated the preference for going straight. Additional factors, such as the width of the landing surface and the complexity of branching of the destination perches, resulted in non-random route choice. Thus, many of the observed biases in route choice suggested abilities to perceive structural variation and select routes that are mechanically beneficial. PMID- 20957375 TI - Direct and indirect medical costs of functional constipation: a population-based study. AB - BACKGROUND: Constipation causes a large number of medical visits each year and imposes significant financial toll on healthcare systems worldwide. So the present community-based study was conducted in order to estimate attributable direct and indirect costs to functional constipation (FC) and to provide an overview of related physician visits in general population of Iran. METHODS: From May 2006 to December 2007, a total of 19,200 adult persons (aged 16 and above) were drawn randomly in Tehran province, Iran (response rate 94%). Participants who reported any gastrointestinal symptoms (2,790 persons) were referred to assigned physicians to be questioned about symptoms of functional bowel disorders according to the Rome III criteria. Direct and indirect costs to FC were calculated. Attributable costs were reported as purchasing power parity dollars (PPP$). RESULTS: Of the total 18,180 consenting participants in this study, 435 (2.4%) had FC according to Rome III criteria. Mean total cost of constipation per person was 146.84 PPP$, of which 128.68 PPP$ was related to direct costs and 18.16 PPP$ to indirect costs. Higher educated persons (189.75 PPP$), those above 64 years of age (373.42 PPP$), subjects with BMI of less than 18.5 kg/m(2) (510.84 PPP$), and widowed persons (258.50 PPP$) had the highest costs. CONCLUSIONS: This study determined that although the economic burden of FC does not seem to be substantial in comparison to other major health problems, it still exacts a substantial toll on the health system for two reasons: chronicity and ambiguity of symptoms. PMID- 20957374 TI - Neonatal tumours. PMID- 20957376 TI - Sciatic pain after rubber band ligation of haemorrhoids. PMID- 20957378 TI - A cortical form of CADASIL with cerebral Abeta amyloidosis. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was diagnosed by genetic testing in a 53-year-old patient, 10 years before death. Following two strokes with partial recovery, he developed rapidly progressive cognitive decline 3 years before death. Neuropathology confirmed CADASIL. Characteristic arteriolar changes were associated with subcortical infarcts, and status cribrosus in basal ganglia and the cortico-subcortical junctions. Leukoencephalopathy was very mild. Severe arteriolar changes in the cerebral cortex and leptomeninges were associated with numerous intracortical microinfarcts. There was abundant Abeta deposition throughout the cerebral cortex, mainly as Abeta42 diffuse plaques, frequently periarteriolar. There was no cerebral amyloid angiopathy apart from rare Abeta40 deposits around Notch3-positive deposits. Amyloid plaques were rare. Tau pathology was minimal. Alzheimer disease associated with CADASIL has been described, but the few reported cases had abundant amyloid plaques, amyloid angiopathy, fibrillar plaques and neurofibrillary tangles. Abeta accumulation could result from abnormal Abeta synthesis or impaired elimination due to the arteriolar changes of CADASIL. We did not find Abeta deposits in our other CADASIL cases with milder cortical arteriolar changes. Additional genetic predisposing factors were not identified. This case suggests that besides the classical, purely subcortical form of CADASIL, a "cortical" form with numerous lacunar infarcts and Abeta deposition in the cerebral cortex may occur and may be difficult to differentiate clinically from Alzheimer disease. PMID- 20957377 TI - AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer's disease and other tauopathies. AB - Tauopathies represent a class of neurodegenerative disorders characterized by abnormal tau phosphorylation and aggregation into neuronal paired helical filaments (PHFs) and neurofibrillary tangles. AMP-activated protein kinase (AMPK) is a metabolic sensor expressed in most mammalian cell types. In the brain, AMPK controls neuronal maintenance and is overactivated during metabolic stress. Here, we show that activated AMPK (p-AMPK) is abnormally accumulated in cerebral neurons in 3R+4R and 3R tauopathies, such as Alzheimer's disease (AD), tangle predominant dementia, Guam Parkinson dementia complex, Pick's disease, and frontotemporal dementia with parkinsonism linked to chromosome 17, and to a lesser extent in some neuronal and glial populations in the 4R tauopathies, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease. In AD brains, p-AMPK accumulation decorated neuropil threads and dystrophic neurites surrounding amyloid plaques, and appeared in more than 90% of neurons bearing pre-tangles and tangles. Granular p-AMPK immunoreactivity was also observed in several tauopathies in apparently unaffected neurons devoid of tau inclusion, suggesting that AMPK activation preceded tau accumulation. Less p-AMPK pathology was observed in PSP and CBD, where minimal p-AMPK accumulation was also found in tangle-positive glial cells. p-AMPK was not found in purified PHFs, indicating that p-AMPK did not co aggregate with tau in tangles. Finally, in vitro assays showed that AMPK can directly phosphorylate tau at Thr-231 and Ser-396/404. Thus, activated AMPK abnormally accumulated in tangle- and pre-tangle-bearing neurons in all major tauopathies. By controlling tau phosphorylation, AMPK might regulate neurodegeneration and therefore could represent a novel common determinant in tauopathies. PMID- 20957379 TI - Pilot study into the efficacy of foetal fibronectin testing in minimising hospital admissions in women presenting with symptoms of preterm labour: a randomised controlled trial of obstetric and neonatal outcomes. AB - AIMS: The purpose of this pilot study was to determine the role of foetal fibronectin (fFN) testing in women presenting to hospital with symptoms of preterm labour in reducing the hospital admissions, without significantly increasing the risk of preterm birth and neonatal respiratory distress syndrome. METHODS: Women with symptoms of preterm labour were assigned randomly to receive fFN (n = 44) or to preterm labour management without fFN (n = 44). In the testing arm, the result of the test was revealed to the clinician. Clinical outcomes were compared in the two groups. The time period covered by the randomised controlled trial (RCT) was from December 2007 to March 2009. The RCT was conducted in two large maternity units in the west of Scotland, one in Glasgow the other in Ayrshire. RESULTS: All the women with fibronectin positive got admitted while only 32.4% of the fibronectin negatives were admitted (P = 0.002). There was a significant difference in the mean length of stay between the fibronectin positives which was 47.17 h, and the negatives which was 12.9 h (P = 0.018). Overall the control and testing arms did not differ in respect to admissions and length of stay. 5 out of 7 positives and 11 out of 37 negatives had corticosteroids (P = 0.089). 2 out of 7 positives and 1 out of 37 negatives had tocolytics (P = 0.073). CONCLUSIONS: Those who had the fFN test done were less likely to be admitted in the hospital and had a shorter length of stay, without any increase in the adverse maternal or foetal effects, avoiding unnecessary admissions. PMID- 20957380 TI - Rituximab CHOP for successful management of diffuse large B-cell lymphoma of the ovary. PMID- 20957381 TI - Is there a personalized medicine for mood disorders? AB - Major Depressive Disorder (MDD) and antidepressant therapy response are largely based on behavioral criteria, which are known to correlate at best modestly with biological measures. Therefore, it is not surprising that the search for peripheral biological markers (biomarkers) being assessed in distant biological systems such as body fluids has not yet resulted in clinically convincing measures for MDD diagnostics or treatment evaluation. Imaging genetics studies, however, have been successful in the search for intermediate imaging phenotypes of MDD and treatment response that are directly related to the neurobiological underpinnings of MDD, but are not suitable for a broad clinical use today. Hence, we argue that intermediate phenotypes derived from imaging genetics studies should be utilized as substitutes of behaviorally assessed psychiatric diagnoses or therapy response in the search for easily accessible peripheral biomarkers. This article will further cover the current state of peripheral and neural biomarker research. PMID- 20957382 TI - Herpes simplex virus type 2 meningitis and symptomatic migraine. PMID- 20957383 TI - Diffusion-weighted ASPECTS as an independent marker for predicting functional outcome. AB - Whether lesion volume on diffusion-weighted MRI imaging (DWI) can reliably predict functional outcome in acute ischemic stroke is controversial. The aim of our study was to assess whether the Alberta Stroke Program Early CT Score (ASPECTS) on DWI is useful for predicting functional outcome in patients with anterior circulation infarction with a broad range of severities. Three-hundred and fifty patients with first-ever ischemic stroke in the anterior circulation within 24 h of onset were enrolled. We compared background characteristics, vital signs, laboratory data, and MRI findings between favorable (F) and unfavorable (U) outcome groups at 3 months, according to the modified Rankin Scale (mRS). The F and U groups were defined as having a mRS of 0-2 and 3-6, respectively. DWI ASPECTS was scored by DWI obtained 3-24 h after onset. Two-hundred and eighteen patients (62.3%) were classified into the F group and 132 patients (37.7%) into the U group. On univariate analysis, the F group patients were younger, had lower score of the National Institutes of Health Stroke Scale (NIHSS) at entry (5.7 +/- 3.3 vs. 14.2 +/- 6.0), male predominance, longer time after onset, lower rate of prior antithrombotic therapy, higher hematocrit and lower fibrinogen than the U group patients. Stroke subtype was different between the two groups, and F group patients had higher DWI ASPECTS score, lower leukoaraiosis and medial temporal atrophy score, and lower rate of early neurological deterioration (END) than the U group patients. Multiple logistic regression analysis revealed that NIHSS (p < 0.001), prior antithrombotic therapy (p = 0.013), ASPECTS (p = 0.002), and END (p < 0.001) were independent predictors of functional outcome. DWI ASPECTS can be an independent predictor for functional outcome, along with other clinical variables. PMID- 20957384 TI - Impact of psychiatric symptoms and sleep disorders on the quality of life of patients with Parkinson's disease. AB - The objective of this study is to assess how the non-motor symptoms of Parkinson's disease (PD), such as depression, cognitive deterioration, neuropsychiatric and sleep disorders, affect the quality of life, and to compare them with the motor symptoms in order to determine their real impact. A cross sectional study was designed including 99 patients (mean age 68.5 +/- 9.9 years, duration of disease 8.7 +/- 6.2 years). Demographic data, onset of PD, years on treatment with levodopa (LD), class of dopaminergic drug prescribed, and dosages were obtained. The following scales were used: quality of life (PDQ-39), Unified Parkinson's Disease Rating Scale (UPDRS I-IV), Parkinson Disease Sleep Scale (PDSS) and daytime sleepiness (Epworth), Mini-Mental State Examination, depression (HAM-D), and the neuropsychiatric inventory (NPI-10). The PDQ-39 summary index (PDQ-39 SI) was 24.7 +/- 13.2. A linear regression model including all variables showed that four independent variables accounted for 67.2% of the variance in the PDQ-39 SI (F = 33,277; p < 0.001): NPI, PDSS, UPDRS IV, and UPDRS I. When sub-items of the NPI, PDSS and UPDRS IV scales are analyzed, significant correlations (p < 0.001) are found between the PDQ-39 SI and depression, agitation, apathy, anxiety, hallucinations, delusions, incontinence of urine, morning painful posturing, restlessness in bed, morning fatigue, duration of off periods, unpredictable and predictable off periods, early morning dystonia, and sudden off periods. Neuropsychiatric symptoms, especially depression, nighttime sleep disorders such as urinary incontinence, nighttime restlessness, morning fatigue and somnolence, off-period dystonia and motor fluctuations are the variables that most affect the quality of life of patients with PD. PMID- 20957385 TI - Korbinian Brodmann (1868-1918). PMID- 20957387 TI - Farewell. PMID- 20957386 TI - Decreased retinal nerve fiber layer thickness in patients with obstructive sleep apnea/hypopnea syndrome. AB - BACKGROUND: To compare parameters for retinal nerve fiber layer (RNFL) thickness, optic nerve head (ONH) measurements, and macular thickness in patients with different severities of obstructive sleep apnea/hypopnea syndrome (OSAHS) versus normal controls. METHODS: Patients presenting with snoring and daytime sleepiness who underwent overnight polysomnography to determine OSAHS severity were recruited, and subsequently referred for ophthalmologic evaluation. Optical coherence tomography was used to evaluate the retinal nerve fiber layer (RNFL), optic nerve head topography, and macular thickness for early detection of glaucoma. Patients determined not to have OSAHS were included as controls. RESULTS: A total of 127 subjects were recruited, including 105 patients with OSAHS and 22 normal control subjects. RNFL thickness was significantly lower for the severe OSAHS group than for the control and mild OSAHS groups in the average (p < 0.0001) and in the superior quadrant (p = 0.0007). When subjects without OSAHS or with mild disease (AHI < 15) were grouped together and compared with patients with moderate/severe OSAHS (AHI ? 15), RNFL thickness measurements for the latter group were significantly lower in the average (p < 0.0001), and in the superior (p = 0.001), inferior (p = 0.029), and temporal (p = 0.007) quadrants. Positive correlations were identified between lowest oxygenation saturation on PSG and RNFL thickness in the average (r = 0.260), superior (r = 0.200) and nasal (r = 0.156) quadrants. CONCLUSIONS: Compared to patients without OSAHS or those with mild disease, RNFL thickness was lower in patients with moderate/severe OSAHS. Lowest saturation of oxygen in the moderate/severe OSAHS group correlated with decreased RNFL thickness. Patients with moderate and severe OSAHS are at increased risk for glaucoma. PMID- 20957388 TI - Reply to: The parabolic power-velocity relationship does apply to fatigued states. PMID- 20957389 TI - Performance and physiological responses to repeated-sprint exercise: a novel multiple-set approach. AB - We investigated the acute and chronic responses to multiple sets of repeated sprint exercise (RSE), focusing on changes in acceleration, intermittent running capacity and physiological responses. Ten healthy young adults (7 males, 3 females) performed an incremental test, a Yo-Yo intermittent recovery test level1 (Yo-Yo IR1), and one session of RSE. RSE comprised three sets of 5 * 4-s maximal sprints on a non-motorised treadmill, with 20 s of passive recovery between repetitions and 4.5 min of passive recovery between sets. After ten repeated sprint training sessions, participants repeated all tests. During RSE, performance was determined by measuring acceleration, mean and peak power/velocity. Recovery heart rate (HR), HR variability, and finger-tip capillary lactate concentration ([Lac(-)]) were measured. Performance progressively decreased across the three sets of RSE, with the indices of repeated-sprint ability being impaired to a different extent before and after training. Training induced a significant increase (p < 0.05) in all indices of performance, particularly acceleration (21.9, 14.7 and 15.2% during sets 1, 2 and 3, respectively). Training significantly increased Yo-Yo IR1 performance by 8% and decreased Delta[Lac(-)]/work ratio (-15.2, -15.5, -9.4% during sets 1, 2 and 3, respectively) and recovery HR during RSE. There were strong correlations between Yo-Yo IR1 performance and indices of RSE performance, especially acceleration post-training (r = 0.88, p = 0.004). Repeated-sprint training, comprising only 10 min of exercise overall, effectively improved performance during multiple-set RSE. This exercise model better reflects team-sport activities than single-set RSE. The rapid training-induced improvement in acceleration, quantified here for the first time, has wide applications for professional and recreational sport activities. PMID- 20957390 TI - Expression of Hox genes during the larval development of the snail, Gibbula varia (L.)-further evidence of non-colinearity in molluscs. AB - Hox transcription factors, a subfamily of homeobox genes, are expressed in distinct, often overlapping domains along the anterior-posterior body axis of animal embryos. Here, we report the sequence and expression pattern of Hox2, Hox3, Hox4, Hox5, Lox5, Hox7, Lox4, and Lox2 in different larval stages during the encapsulated development of the marine gastropod Gibbula varia. Our results show that all Gva-Hox genes are expressed in ectoderm-derived cells. Hox2, Hox3, Hox4, Hox5, and Hox7 are expressed in overlapping patterns in the pedal, pleural, oesophageal, and visceral ganglia, supporting the ancestral role of Hox genes in the neurogenesis processes in bilaterians. Gva-Hox1, Gva-Post2, and Gva-Post1 genes are involved in shell morphogenesis and have apparently lost their role in neurogangliogenesis. Lox5, Lox4, and Lox2 are expressed in different cells of the apical organ during the earlier larval stage (trochophore) and the cerebral ganglia during later larval stages (veliger). These results support the hypothesis that apical organ neurosensory cells contribute to the formation of cerebral ganglia commissures during metamorphosis. Gva-Hox7 and Gva-Lox4 are additionally expressed in the prototroch of the trochophore and in the velar area of the veliger larvae. This contradicts with the expression of these genes in the annelids, where most of Hox genes are expressed in the posttrochal area and are involved in segmental determination. Therefore, expression of Hox genes may serve as an example of co-option and plasticity of gene function during evolution of gastropods. PMID- 20957391 TI - Metabolic syndrome, adipokines and ghrelin in overweight and obese schoolchildren: results of a 1-year lifestyle intervention programme. AB - The aim of this study was to evaluate the effect of a lifestyle intervention programme (nutrition and exercise counselling) on metabolic syndrome (MS) components, adipokines (leptin, adiponectin) and ghrelin levels in overweight children. A total of 61 overweight children aged 7-9 years (>= 85th body mass index (BMI) percentile; 27 boys/34 girls) were randomly assigned and completed a 1-year individual (IT) or group-based treatment (GT). Anthropometric and biochemical parameters were assessed at baseline, at 6 months and at 1 year. Twenty-two normal weight children (<85th BMI percentile; 7-9 years old; 13 boys/nine girls) were also evaluated at baseline. Insulin resistance (IR) was determined by the homeostasis model assessment of IR (HOMA-IR). Overweight children presented significantly higher blood pressure, triglycerides, apolipoprotein B, insulin, HOMA-IR, leptin, C-reactive protein and homocysteine levels, while apolipoprotein A-I was significantly lower. At baseline, MS was present in ten overweight children, of which only five maintained it at 1 year. Leptin and ghrelin levels were associated with IR and MS components. MS was predicted by apolipoprotein A-I, insulin and pre-puberty. The lifestyle intervention led to a significant improvement in standard deviation score of BMI, waist circumference/height ratio and lipid profile. Changes in insulin, HOMA-IR, leptin and adiponectin were not significant. Ghrelin behaved differently between IT and GT. The GT intervention seems to be more successful, with a decrease in BMI Z-score and an improvement of metabolic parameters. In conclusion, overweight children have multiple risk factors associated with MS. A lifestyle intervention programme seems to be an effective mean for reducing obesity and MS components and improving adipokines concentrations. PMID- 20957393 TI - [Health services research project "action alliance pain-free city Munster" : Objectives and methods]. AB - Inadequate pain care in health care facilities is still a major concern. Due to structural and organizational shortcomings the potential of modern analgesia is far from being exhausted. The project "Action Alliance Pain-free City Munster" is designed to analyze the multiprofessional pain management in health care facilities in the model City of Munster in an epidemiologic study and aims to optimize pain management in accordance with nursing standards and medical guidelines. Hospitals, nursing homes, outpatient nursing services, hospices and pain care centers will be examined. After an analysis of the current state on the basis of a pre-test, the necessary optimization measures will be developed and implemented. Subsequently, the pain management will be reevaluated in a post test. In partly still unexplored health care areas of Germany, epidemiologic data will be generated, barriers to the implementation of standards and guidelines revealed and measures of improvements developed and tested. In addition, interface problems between the evaluated sectors will be identified. In this article the objective and the methods of the project are described. PMID- 20957392 TI - Determining microsatellite genotyping reliability and mutation detection ability: an approach using small-pool PCR from sperm DNA. AB - Microsatellite genotyping from trace DNA is now common in fields as diverse as medicine, forensics and wildlife genetics. Conversely, small-pool PCR (SP-PCR) has been used to investigate microsatellite mutation mechanisms in human DNA, but has had only limited application to non-human species. Trace DNA and SP-PCR studies share many challenges, including problems associated with allelic drop out, false alleles and other PCR artefacts, and the need to reliably identify genuine alleles and/or mutations. We provide a framework for the validation of such studies without a multiple tube approach and demonstrate the utility of that approach with an analysis of microsatellite mutations in the tammar wallaby (Macropus eugenii). Specifically, we amplified three autosomal microsatellites from somatic DNA to characterise efficiency and reliability of PCR from low template DNA. Reconstruction experiments determined our ability to discriminate mutations from parental alleles. We then developed rules to guide data interpretation. We estimated mutation rates in sperm DNA to range from 1.5 * 10( 2) to 2.2 * 10(-3) mutations per locus per generation. Large multi-step mutations were observed, providing evidence for complex mutation processes at microsatellites and potentially violating key assumptions in the stepwise mutation model. Our data demonstrate the necessity of actively searching for large mutation events when investigating microsatellite evolution and highlight the need for a thorough understanding of microsatellite amplification characteristics before embarking on SP-PCR or trace DNA studies. PMID- 20957394 TI - Prospective comparison of the prognostic utility of the Mini Mental State Examination and the Montreal Cognitive Assessment in patients with brain metastases. AB - PURPOSE: The Mini Mental State Examination (MMSE) is the most commonly chosen cognitive screening test (CST) in clinical practice and trials, despite its poor sensitivity, likely because of its prognostic utility. The Montreal Cognitive Assessment (MoCA) is an alternative CST, is more sensitive, and is better correlated with quality of life. METHODS: Sixty-five patients with brain metastases were prospectively accrued and completed both the MMSE and MoCA. We compared the prognostic utility of both CSTs. RESULTS: The mean age of patients was 59.0 years; 42.0% had single brain metastases. Median MMSE and MoCA scores were 28 and 22, respectively. Median overall survival (OS) was worse for individuals with below- versus above-average MMSE scores (10.4 versus 36.3 weeks, p = 0.007). Likewise, below- versus above-average MoCA scores were prognostic (6.3 versus 50.0 weeks, p < 0.001). Median OS for MoCA scores <22, 22-26, and >26 were 6.3, 30.9, and 61.7 weeks, respectively (p < 0.001). On multivariable analysis, below-average MMSE scores were no longer prognostic (hazard ratio [HR] = 1.71 [0.90-3.26]), though below-average MoCA scores were (HR = 5.44 [2.70 10.94]). Furthermore, the MoCA demonstrated superior prognostic utility when comparing multivariable models with continuous CST scores. CONCLUSIONS: Our results indicate that the MoCA is a superior prognostic indicator than the MMSE. Furthermore, given its superior sensitivity and better correlation with quality of life, the MoCA should be preferentially chosen in clinical practice and trials. PMID- 20957395 TI - Advanced glycation endproducts: from precursors to RAGE: round and round we go. AB - The formation of advanced glycation endproducts (AGEs) occurs in diverse settings such as diabetes, aging, renal failure, inflammation and hypoxia. The chief cellular receptor for AGEs, RAGE, transduces the effects of AGEs via signal transduction, at least in part via processes requiring the RAGE cytoplasmic domain binding partner, diaphanous-1 or mDia1. Data suggest that RAGE perpetuates the inflammatory signals initiated by AGEs via multiple mechanisms. AGE-RAGE interaction stimulates generation of reactive oxygen species and inflammation- mechanisms which enhance AGE formation. Further, recent data in type 1 diabetic kidney reveal that deletion of RAGE prevents methylglyoxal accumulation, at least in part via RAGE-dependent regulation of glyoxalase-1, a major enzyme involved in methylglyoxal detoxification. Taken together, these considerations place RAGE in the center of biochemical and molecular stresses that characterize the complications of diabetes and chronic disease. Stopping RAGE-dependent signaling may hold the key to interrupting cycles of cellular perturbation and tissue damage in these disorders. PMID- 20957396 TI - Lipid glycation and protein glycation in diabetes and atherosclerosis. AB - Recent instrumental analyses using a hybrid quadrupole/linear ion trap spectrometer in LC-MS/MS have demonstrated that the Maillard reaction progresses not only on proteins but also on amino residues of membrane lipids such as phosphatidylethanolamine (PE), thus forming Amadori-PE (deoxy-D: -fructosyl PE) as the principal products. The plasma Amadori-PE level is 0.08 mol% of the total PE in healthy subjects and 0.15-0.29 mol% in diabetic patients. Pyridoxal 5' phosphate and pyridoxal are the most effective lipid glycation inhibitors, and the PE-pyridoxal 5'-phosphate adduct is detectable in human red blood cells. These findings are beneficial for developing a potential clinical marker for glycemic control as well as potential compounds to prevent the pathogenesis of diabetic complications and atherosclerosis. Glucose and other aldehydes, such as glyoxal, methylglyoxal, and glycolaldehyde, react with the amino residues of proteins to form Amadori products and Heynes rearrangement products. Because several advanced glycation end-product (AGE) inhibitors such as pyridoxamine and benfotiamine inhibit the development of retinopathy and neuropathy in streptozotocin (STZ)-induced diabetic rats, AGEs may play a role in the development of diabetic complications. In the present review, we describe the recent progress and future applications of the Maillard reaction research regarding lipid and protein modifications in diabetes and atherosclerosis. PMID- 20957397 TI - Down-regulation of the ubiquitin-proteasome proteolysis system by amino acids and insulin involves the adenosine monophosphate-activated protein kinase and mammalian target of rapamycin pathways in rat hepatocytes. AB - The purpose of this work was to examine whether changes in dietary protein levels could elicit differential responses of tissue proteolysis and the pathway involved in this response. In rats fed with a high protein diet (55%) for 14 days, the liver was the main organ where adaptations occurred, characterized by an increased protein pool and a strong, meal-induced inhibition of the protein breakdown rate when compared to the normal protein diet (14%). This was associated with a decrease in the key-proteins involved in expression of the ubiquitin-proteasome and autophagy pathway gene and a reduction in the level of hepatic ubiquitinated protein. In hepatocytes, we demonstrated that the increase in amino acid (AA) levels was sufficient to down-regulate the ubiquitin proteasome pathway, but this inhibition was more potent in the presence of insulin. Interestingly, AICAR, an adenosine monophosphate-activated protein kinase (AMPK) activator, reversed the inhibition of protein ubiquination induced by insulin at high AA concentrations. Rapamycin, an mammalian target of rapamycin (mTOR) inhibitor, reversed the inhibition of protein ubiquination induced by a rise in insulin levels with both high and low AA concentrations. Moreover, in both low and high AA concentrations in the presence of insulin, AICAR decreased the mTOR phosphorylation, and in the presence of both AICAR and rapamycin, AICAR reversed the effects of rapamycin. These results demonstrate that the inhibition of AMPK and the activation of mTOR transduction pathways, are required for the down-regulation of protein ubiquitination in response to high amino acid and insulin concentrations. PMID- 20957398 TI - Gender differences in outcomes of acute mania: a 12-month follow-up study. AB - This study aimed to assess short-term (12 weeks) and long-term (12 months) gender differences in the outcomes of patients experiencing an episode of mania in the course of bipolar disorder. European Mania in Bipolar Longitudinal Evaluation of Medication was a 2-year, prospective, observational study of the outcomes of patients with a manic or mixed episode conducted in 14 European countries. Data were collected during the acute phase (12 weeks) and during a follow-up period (up to 12 months). Analyses were carried out in the subgroup of patients identified with a pure manic episode at baseline. Kaplan-Meier survival analysis estimated time to first occurrence of mania improvement, worsening, recovery and depressive episode, and Cox's proportional hazards models were used to analyse factors associated with these outcomes. Overall, 2,485 patients (46.6% men, 53.4% women) were included in the analysis. Frequency of substance abuse was higher in men than women. No significant gender differences were found in the severity of manic symptoms at baseline. There were no gender differences in assessment of mania improvement, worsening or recovery over 12 weeks, but more women than men showed mania improvement over 12 months (95.4% vs. 89.2%; p < 0.01). Significantly more women developed a depressive episode over 12 weeks (14.9% vs. 9.7%; p < 0.01) and over 12 months (27.7% vs. 21.5%; p < 0.001). In conclusion, the results show that there are small gender differences in the course of patients experiencing a pure manic episode. Women had a faster time to mania improvement and a higher risk of developing a depressive episode during the 12 month follow-up period. PMID- 20957399 TI - Parecoxib sodium in the treatment of postoperative pain after Lichtenstein tension-free mesh inguinal hernia repair. AB - PURPOSE: This prospective, randomized, double-blind study compared the analgesic efficacy and safety of parecoxib sodium versus lornoxicam and diclofenac, after Lichtenstein tension-free mesh inguinal hernia repair. METHODS: Patients were randomly assigned to receive parecoxib 80 mg daily i.v. (Group A), lornoxicam 16 mg daily i.v. (Group B) or diclofenac 150 mg daily i.m. (Group C). Rescue analgesia in all groups consisted of pethidine 25 mg i.m. Pain was measured with an analogue scale (pain intensity score). RESULTS: Patients treated with parecoxib 80 mg reported significantly lower summed pain intensity scores compared with lornoxicam and diclofenac-treated patients. Duration of analgesia was also significantly longer with parecoxib than with lornoxicam and diclofenac. Adverse events were significantly less common in the parecoxib and lornoxicam group, compared with diclofenac group. CONCLUSIONS: Multiple-day administration of parecoxib 40 mg twice daily is more effective than equivalent doses of lornoxicam and diclofenac, and generally better tolerated than diclofenac after Lichtenstein tension-free mesh inguinal hernia repair. PMID- 20957400 TI - Assessment of endothelial function in patients with fibromyalgia--cardiac ultrasound study. AB - In patients with fibromyalgia (FM) syndrome, stress and pain may chronically enhance sympathetic activity, altering cardiovascular response and inducing endothelial dysfunction. We investigated endothelial function in FM patients using echocardiography and analyzed whether endothelial function was affected by the clinical parameters of FM. Fifty-five postmenopausal women with FM and 35 healthy controls were included. Endothelial function was examined by brachial artery flow-mediated dilatation (FMD, endothelium dependent) and response to 40 MUg of sublingual nitroglycerine (NTG-induced dilatation, endothelium independent). FM patients underwent manual tender point survey and completed visual analogue scale (VAS) of pain and fibromyalgia impact questionnaire (FIQ). The study participants were subdivided into two groups based on the sum of the FIQ score (group A, FIQ >= 50, group B, <50). The FMD value (5.7 +/- 3.9% vs. 7.0 +/- 1.4%, P = 0.008) and NTG-induced dilatation (12.5 +/- 5.1% vs. 14.7 +/- 2.5%, P = 0.006) were significantly lower in FM group than healthy control. There were no significant differences in FMD between groups A and B (5.4 +/- 3.3% vs. 6.6 +/ 3.5%, P = 0.19). However, significant decreases were noted in NTG-induced dilatation values of group A compared with those of group B (11.0 +/- 4.4% vs. 14.3 +/- 3.8%, P = 0.004). FMD and NTG-induced dilatation showed a significant inverse association with pain VAS and FIQ. Pain exerts a negative effect on endothelial function in FM patients, and that effect was significantly different according to the FIQ score. PMID- 20957401 TI - Idiopathic retroperitoneal fibrosis (RPF): clinical features of 61 cases and literature review. AB - The objective of this study is to describe the clinical characteristics of patients with idiopathic retroperitoneal fibrosis (RPF). A retrospective analysis of patients diagnosed with idiopathic RPF in Chinese People's Liberation Army General Hospital was conducted. Sixty-one patients with idiopathic RPF were identified. Male to female ratio was 3.7: 1. The mean age was 55.7 years. One patient had polymyositis and two patients had a family history of idiopathic RPF. Back pain and abdominal pain are the most common symptoms. Forty-seven patients (77.1%) had retroperitoneal soft tissue shadow or ureteral obstruction on computed tomography or magnetic resonance imaging. Thirty-eight patients (62.3%) had histological diagnosis of idiopathic RPF. Thirty-four patients (55.7%) received surgical interventions. Five patients (8.2%) had palliative percutaneous nephrostomy. Ten patients (16.4%) received medical treatment alone including corticosteroids, immunosuppressants, and tamoxifen. Four patients (6.6%) received corticosteroids after surgical intervention. Two patients (3.3%) required renal dialysis. There were two cases of death. Surgery and medical treatments are effective for idiopathic RPF. In conclusion, long-term low dose corticosteroids and immunosuppressants may prevent relapse of idiopathic RPF. PMID- 20957402 TI - Implications of the up-regulation of genes encoding protein degradation enzymes and heat shock protein 90 for intertidal green macroalga Ulva fasciata against hypersalinity-induced protein oxidation. AB - The molecular acclimation of intertidal green macroalga Ulva fasciata Delile to high salinity stress were examined by the construction of a forward cDNA library via the suppressive subtractive hybridization between 300/00 and 900/00 (24 h) and by the time course dynamics of several abundantly expressed genes. Among the genes with known sequences, the expressed sequence tags are abundant in the function of protein synthesis (ribosomal protein) and destination. The cDNAs of ATP-dependent Clp protease (UfClpC), 20S proteasome beta-subunit type 1 domain (UfPbf1), ubiquitin-conjugating enzyme E2 I (UfUbc9), and heat shock protein 90A (UfHsp90A) were cloned. UfClpC transcript increased 3 h after 900/00 treatment, followed by a decrease, while UfPbf1 and UfUbc9 transcripts increased after 12 h and decreased at 48 h. The transcripts of UfHsp90A increased 1 h after 900/00 treatment, followed by a drop and to the control level at 48 h. Protease activity increased 3 h after 900/00 treatment and decreased to the control level at 48 h. H2O2 contents increased 1 h after 900/00 treatment and then remained unchanged, but protein carbonyl group contents increased after 48 h. The treatments of reactive oxygen species scavengers partially alleviated 900/00 damage (partial growth rescue) and suppressed the increases in H2O2 content, protein carbonyl group content, protease activity, and UfClpC, UfPbf1, UfUbc9, and UfHsp90A transcripts by 900/00. The induction of specific chaperones and proteases at the molecular level for protein quality control can be considered as one of the molecular mechanisms of hypersalinity acclimation in U. fasciata. PMID- 20957404 TI - Melting of polymer single crystals studied by dynamic Monte Carlo simulations. AB - We report dynamic Monte Carlo simulations of lattice polymers melting from a metastable chain-folded lamellar single crystal. The single crystal was raised and then melted in an ultrathin film of polymers wetting on a solid substrate, mimicking the melting observations made by using Atomic Force Microscopy. We observed that the thickness distribution of the single crystal appears quite inhomogeneous and the thickness increases gradually from facetted edges to the center. Therefore, at low melting temperatures, melting stops at a certain crystal thickness, and melting-recrystallization occurs when allowing crystal thickening; at intermediate temperatures, melting maintains the crystal shape and exhibits different speeds in two stages; at high temperatures, fast melting makes a melting hole in the thinnest region, as well as a saw-tooth-like pattern at the crystal edges. In addition, the linear melting rates at low temperatures align on the curve extrapolated from the linear crystal growth rates. The temperature dependence of the melting rates exhibits a regime transition similar to crystal growth. Such kinetic symmetry persists in the melting rates with variable frictional barriers for c -slip diffusion in the crystal as well as with variable chain lengths. Visual inspections revealed highly frequent reversals upon melting of single chains at the wedge-shaped lateral front of the lamellar crystal. We concluded that the melting kinetics is dominated by the reverse process of intramolecular secondary crystal nucleation of polymers. PMID- 20957403 TI - Clinical and functional evaluation of patients with rectocele and mucosal prolapse treated with transanal repair of rectocele and rectal mucosectomy with a single circular stapler (TRREMS). AB - BACKGROUND: The aim of the present study was to make a preoperative and postoperative clinical and functional evaluation of patients who underwent transanal repair of rectocele and rectal mucosectomy with a single circular stapler (TRREMS procedure) as treatment for obstructed defecation syndrome (ODS) caused by rectocele and rectal mucosal prolapse (RMP). METHODS: This prospective study included 35 female patients, 34 multiparous and one nulliparous, with an average age of 47.5 years (range 31-67 years), rectocele grade II (n = 13/37.1%) or grade III (n = 22/62.9%), associated with RMP. The study parameters included ODS, constipation, functional continence scores and pre- and postoperative cinedefecographic findings. RESULTS: The average preoperative ODS score, the constipation score and the functional continence score were significantly reduced after surgery from 10.63 to 2.91 (p = 0.001), 15.23 to 4.46 (p = 0.001) and 2.77 to 1.71 (p = 0.001), respectively. Between the first and the eighth postoperative day, the average visual analog scale pain score fell from 5.23 to 1.20 (p = 0.001). Satisfaction with treatment outcome was 79.97, 86.54, 87.65 and 88.06 at 1, 3, 6 and 12 months, respectively. Cinedefecography revealed average reductions in rectocele size from 19.23 +/- 8.84 mm (3-42) to 6.68 +/- 3.65 mm (range 0-7) at rest and from 34.89 +/- 12.30 mm (range 20-70) to 10.94 +/- 5.97 mm (range 0 25) during evacuation (both P = 0.001). CONCLUSION: The TRREMS procedure is a safe and efficient technique associated with satisfactory anatomic and functional results and with a low incidence of postoperative pain and complications. PMID- 20957405 TI - Femoral-head vascularity after hip surface arthroplasty. AB - BACKGROUND: iatrogenic devascularization of the femoral head is as an area of concern following hip resurfacing arthroplasty, with probable implications on short-term failure and long-term survival of the implant. MATERIALS AND METHODS: we assessed the vascularity of 25 resurfaced femoral heads in 20 patients by comparison with preoperative and postoperative Tc-99m methylene diphosphonate (MDP) bone scintigraphy images, the postoperative scans being done 9 months after the surgery. RESULTS: eight out of 25 hips (32%) showed <55% of their preoperative uptake at a mean of 9 months after surgery and were categorized as showing reduced vascularity. CONCLUSION: our study reveals reduction in vascularity of the femoral-head remnant as a frequent occurrence after hip resurfacing. Our study also highlights the role of bone scintigraphy as tool in assessing the vascularity of resurfaced femoral heads. PMID- 20957407 TI - Gliosarcoma with bone infiltration and extracranial growth: case report and review of literature. AB - Gliosarcoma is a relatively rare and highly malignant brain tumor consisting of both a glioblastoma and a mesenchymal component. Because of the natural barrier of the dura mater, that prevents intra or extradural neoplasm dissemination, cases of penetration of the dura and cranium by gliosarcomas without previous surgery or radiation are very rarely reported. We report an unusual case of gliosarcoma that involved the temporal skull base and the dura without antecedent radiation or surgery, although the lesion traversed the dura without radiologic or gross interruption of the dura. Remarkable in our case is the initial integrity of cerebral parenchyma. Follow-up revealed a tumorous infiltration of the temporal lobe almost one year after initial diagnosis. Thus the origin of the gliosarcoma in our case seemed to be extradural in the temporal skull base. Furthermore, this report demonstrates that extensive multi-modality treatment might be effective in patients with gliosarcomas and poor prognostic factors, for example unmethylated MGMT status. PMID- 20957408 TI - The efficacy of gamma knife radiosurgery for advanced gastric cancer with brain metastases. AB - The aim of this study was to retrospectively investigate the efficacy of gamma knife radiosurgery for brain metastases from advanced gastric cancer (AGC) comparing whole brain radiotherapy (WBRT). Between January 1991 and May 2008, 56 patients with brain metastases from AGC, treated with GKR or WBRT, were reviewed to assess prognostic factors affecting survival. Most brain metastases were diagnosed based on MRI, both metachronous and synchronous brain metastases, adenocarcinoma and signet ring carcinoma were included, but excluded cases of gastric lymphoma. Fifteen patients with a median age of 54.0 years (range, 42-67 years) were treated with GKR: 11 were treated with GKR only, 2 with surgery plus GKR, 1 with repeated GKR, 1 with GKR plus WBRT, and the other 1 with WBRT plus GKR. Forty-one were treated with WBRT only. The median number of metastatic brain lesions was 3 (range, 1-15), and treatment involved 17.0 Gy (range 14-23.6 Gy), or 30 Gy with fractionated radiotherapy. The median survival after brain metastases for GKR treatment was 40.0 weeks [95% confidence interval (CI) 44.9 132.1 weeks] and WBRT was 9.0 weeks 95% CI, 8.8-21.9 weeks). The progression free survival of 15 GKR treated patients was 56.5 weeks (95% CI 33.4-79.5 weeks). The recursive partitioning analysis (RPA) (class 2 vs. class 3) and use of GKR were correlated with prolonged survival in univariate and multivariate analyses. Age, sex, pathology, leptomeningeal seeding, tumor size (>=3 cm), extracranial metastases, single metastasis, chemotherapy, and synchronous metastases were not correlated with a good prognosis in both univariate and multivariate analysis. Based on our study, the use of GKR and RPA class 2 resulted in more favorable clinical outcomes in patients with brain metastases from AGC. PMID- 20957409 TI - Influence of zinc and zinc chelator on HT-29 colorectal cell line. AB - Trace elements are involved in many key pathways involving cell cycle control. The influence of zinc and zinc chelator (TPEN) on transcription levels of the main zinc transporters (ZnT1 and ZIP1) in the HT-29 colorectal cell line has not been reported. Proliferation of HT-29 cells was measured using the methylene blue assay after exposure to zinc (two concentrations), TPEN (two concentrations), or a combination of zinc and TPEN (simultaneously and sequentially) for 4 h, 8 h, and 24 h. The transcription levels of ZnT1, ZIP1, vascular endothelial growth factor (VEGF), and caspase-3 were determined using reverse transcriptase real time polymerase chain reaction (RT-PCR) after exposure of cells to zinc and TPEN. The zinc content in the substrate (medium used for culture) was determined using atomic absorption spectrometry. TPEN decreased cellular proliferation causing complete cell death by 8 h. Zinc had a protective effect against short periods of exposure to TPEN. There was no correlation between the transcripts of main zinc transporters and the zinc content in the substrate. The zinc content in the substrate remained constant after varying periods of cell culture. TPEN decreased the transcript levels of caspase-3 and VEGF, which are surrogate markers for apoptosis and angiogenesis. Zinc chelation of HT-29 cells causes cell death. Zinc appears to be protective for short periods of exposure to TPEN but has no protective effect on prolonged exposure. HT-29 cells are not able to counteract the effect of intracellular chelation of zinc by altering zinc transport. Further research into the mechanisms of these findings is necessary and may lead to novel therapeutic options. PMID- 20957410 TI - Aerobic cometabolic degradation of trichloroethene by methane and ammonia oxidizing microorganisms naturally associated with Carex comosa roots. AB - The degradation potential of trichloroethene by the aerobic methane- and ammonia oxidizing microorganisms naturally associated with wetland plant (Carex comosa) roots was examined in this study. In bench-scale microcosm experiments with washed (soil free) Carex comosa roots, the activity of root-associated methane- and ammonia-oxidizing microorganisms, which were naturally present on the root surface and/or embedded within the roots, was investigated. Significant methane and ammonia oxidation were observed reproducibly in batch reactors with washed roots incubated in growth media, where methane oxidation developed faster (2 weeks) compared to ammonia oxidation (4 weeks) in live microcosms. After enrichment, the methane oxidizers demonstrated their ability to degrade 150 MUg l(-1) TCE effectively at 1.9 mg l(-1) of aqueous CH(4). In contrast, ammonia oxidizers showed a rapid and complete inhibition of ammonia oxidation with 150 MUg l(-1) TCE at 20 mg l(-1) of NH(4)(+)-N, which may be attributed to greater sensitivity of ammonia oxidizers to TCE or its degradation product. No such inhibitory effect of TCE degradation was detected on methane oxidation at the above experimental conditions. The results presented here suggest that microorganisms associated with wetland plant roots can assist in the natural attenuation of TCE in contaminated aquatic environments. PMID- 20957411 TI - Early postnatal development of rat brain is accompanied by generation of lipofuscin-like pigments. AB - The increased generation of free radicals results in the formation of fluorescent end-products of lipid peroxidation, lipofuscin-like pigments (LFPs). The authors observed that LFPs are generated in rat brain after a normal birth during 5 postnatal days. The experimental design of the study comprised 10 groups of animals. The authors measured prenatal values 1 day and 7 days before birth, and then the animals were sampled on postnatal day 1, 2, 5, 10, 15, 25, 35, and 90. Maximum LFP concentration is achieved on the postnatal day 2. Starting from postnatal day 10, LFP concentration returns to prenatal values. A new rise in LFP concentration is observed at 3 months of age. This is associated with the beginning of the aging process. LFPs were characterized by fluorescence spectroscopy using tridimensional excitation spectra, synchronous spectra and their derivatives, and HPLC with fluorescence detection. It was possible to discern several tens of fluorescent compounds of unknown structure that are generated and metabolized during early development. The authors suggest that LFPs are formed after respiratory burst of microglia phagocytosing apoptotic cells. PMID- 20957412 TI - Spatial and temporal expression of hypoxia-inducible factor-1alpha during myogenesis in vivo and in vitro. AB - We investigated the spatial and temporal expression patterns of hypoxia-inducible factor-1alpha (HIF-1alpha) during muscle regeneration and myogenesis in a C2C12 cell culture system. The expression of HIF-1alpha synchronized with that of myogenic regulatory genes during muscle regeneration at both the mRNA and protein levels. The HIF-1alpha protein was localized in the nuclei of newly formed regenerating myofibers in three different muscle injury models, including freezing, bupivacaine injection, and muscular dystrophy. In myogenic cell culture, the HIF-1alpha protein was localized in the nucleus and cytoplasm of the majority of myoblasts and myotubes. HIF-1alpha protein expression decreased concomitant with the increased expression of MyoD and myogenin proteins after the induction of myogenic differentiation. We investigated the adaptive response of myoblasts to hypoxia-like conditions induced by treatment of cobalt chloride. This treatment allowed HIF-1alpha to accumulate and translocate to the nucleus to activate transcription of its target genes, suggesting that myoblasts adapted to acute hypoxia-like conditions through enhancing an HIF-1-dependent pathway. Our results provide insight into the possible involvement of HIF-1alpha in myogenesis in vivo and in vitro. PMID- 20957413 TI - The effect of NF-kappaB pathway on proliferation and apoptosis of human umbilical vein endothelial cells induced by intermittent high glucose. AB - Our previous study found that blocking nuclear factor (NF)-kappaB signaling could protect human umbilical vein endothelial cells (HUVECs) from apoptosis and proliferation inhibition due to high glucose (HG). Intermittent HG makes glucose toxicity more significant. In this study, we aimed to investigate the effect of NF-kappaB pathway on HUVECs induced by intermittent HG (a daily alternating 5.5 or 30.5 mmol/l glucose). A recombinant adenovirus containing a RNAi cassette targeting the NF-kappaB/p65 gene was produced, and its silencing effect on p65 gene was detected by Western blot analysis in HUVECs cultured with intermittent HG. The subsequent effect on proliferation of HUVECs in the indicated conditions was measured by the AlamarBlue assay. The Bcl-2 expression was also detected by Western blot. The results showed that the expression of p65 protein could be inhibited efficiently by the RNAi adenovirus. Intermittent HG also induced the translocation of NF-kappaB in HUVECs. Inhibition of NF-kappaB with the RNAi adenovirus could prevent the effects. At the 6th day after HUVECs were exposed to intermittent HG, the proliferation of HUVECs with Ad-1566 was significantly higher than that of HUVECs with Ad-DEST (P < 0.01). Knockdown of NF-kappaB/p65 up regulated the Bcl-2 expression of HUVECs under intermittent HG conditions (P < 0.01). These findings concluded that the NF-kappaB/p65-targeting RNAi adenovirus is an important tool, which can efficiently inhibit the expression of p65 gene in HUVECs. Intermittent HG reduces HUVECs proliferation with a concomitant increase in apoptosis. Knockdown of NF-kappaB/p65 partly protected HUVECs from proliferation inhibition and may reduce apoptosis. PMID- 20957414 TI - Rhipicephalus sanguineus on dogs: relationships between attachment sites and tick developmental stages. AB - The brown dog tick, Rhipicephalus sanguineus, is the most widespread tick in the world and infests primarily domestic dogs. Studies on the bio-ecology of R. sanguineus have been carried out worldwide, but little is known of the on-dog relationships of tick developmental stages and their possible role on tick feeding performance, reproduction and pathogen transmission. We studied the relationships between different developmental stages of R. sanguineus on particular body areas of naturally infested dogs. In addition, we assessed whether these relationships could vary according to sex and breed of the dogs. Over 2,200 tick records were analyzed and the results showed that attachment sites of males and females are strongly positively correlated whereas attachment sites of nymphs and adults tend to be negatively correlated. Our findings indicate that adult ticks generally feed on sites (e.g., ears) that make it difficult for dogs to remove them, whereas immatures feed on lower areas of the dog's body (e.g., belly, rump, and hind legs), probably because of their more limited mobility. Further research on the possible on-dog interactions of adult and immature ticks is needed to better understand why their attachment sites tend to be negatively correlated and to assess their possible implications for pathogen transmission. PMID- 20957415 TI - Physiological effects upon Amblyomma americanum (Acari: Ixodidae) infected with Beauveria bassiana (Ascomycota: Hypocreales). AB - Unfed adult Amblyomma americanum were exposed to the entomopathogenic fungus Beauveria bassiana. Ticks exposed to the fungus exhibited reduced survival and increased water loss as indicated by change in weight. Treated ticks survived 7.2 +/- 0.22 days (mean +/- SE) and controls survived 17.9 +/- 0.73 days (P = 0.01; df = 57). At death, ticks exposed to the fungus had lost 25.2 +/- 0.84% of their starting weight; control ticks had lost 14.1 +/- 0.85% of their starting weight (P = 0.01; df = 96). Water loss was highest immediately following inoculation, although losses continued to be higher than in uninoculated ticks. This suggests that fungal penetration causes sufficient cuticle damage to cause desiccation, although other water-loss avenues exist, including increased time of spiracular opening. Additionally this study did not eliminate the possibility of a negative impact on water vapor uptake. This is the first study to investigate the effect of an entomopathogenic fungus on the water balance of a tick. PMID- 20957416 TI - Lung cancer detection by native fluorescence spectra of body fluids--a preliminary study. AB - Lung cancer takes a heavy toll every year, since the survival rate is not more than 15%. In this paper, we present results of a novel technique based on the autofluorescence of body fluids like blood plasma, acetone extract of cellular components, sputa and urine of lung cancer patients (N=27). A set of ratio parameters based on the fluorescence peaks of tryptophan and elastin, in plasma and sputum; flavin, NADH (reduced nicotinamide adenine dinucleotide) and porphyrin in urine; porphyrin alone in acetone extract of formed elements, were all evaluated. Similar sets of ratios were obtained for age adjusted normal controls (N=27) and all these ratios were given as inputs to multivariate (principle component and discriminant) analyses, which showed that the two groups could be classified with an accuracy of about 90%. Since the instrumentation involved was an ordinary steady state Xe lamp based spectrofluorometer, the technique is of significant advantage in screening and early detection of lung cancer in high risk population such as heavy smokers. PMID- 20957417 TI - Determination of iron(III) by room temperature ionic liquids/surfactant sensitized fluorescence quenching method. AB - A new method for the determination of iron (III) has been described. The analytical procedure was based on the fluorescence quenching of salicylfluorone (SAF) by iron (III) and the fluorescence quenching value (DeltaF) could be increased in the medium of room temperature ionic liquids (RTILs) (1-ethyl-3 methylimidazolium ethyl sulfate)/SDS (sodium dodecyl sulfate). The main factors influencing the fluorescence quenching (DeltaF) were investigated in detail. Under the optimal conditions, the linear equation was [Formula: see text](c:MUg.mL(-1), r = 0.9936). The linear range of calibration curve was 0.2 1.1 MUg.mL(-1) and the detection limit was 8.3 ng.mL(-1). The preliminary sensitized mechanism was discussed with distribution coefficient and fluorescence quantum yield in different media. The method has been applied to the determination of Fe (III) in water samples with satisfactory results. PMID- 20957418 TI - Nicotine stimulated dendritic cells could achieve anti-tumor effects in mouse lung and liver cancer. AB - INTRODUCTION: Our previous studies have revealed that nicotine-treated immature dendritic cells (imDCs) have anti-tumor effects in murine lymphoma models. The present study is to explore the preventive and therapeutic anti-tumor effects of nicotine-treated imDCs in murine lung and liver cancer. MATERIALS AND METHODS: To address this objection, bone marrow-derived imDCs were firstly stimulated by nicotine in vitro and the expressions of CD80, CD86, CD40, CD11b, MHC class I and II were determined by flow cytometry. Then, DCs-dependent tumor-lysate-specific T cell proliferation, IL-12(p40+p70) secretion were determined by BrdU cell proliferation assay and enzyme-linked immunosorbent assay, respectively. The anti tumor effects of such imDCs were further explored by intraperitoneal transfer against tumor challenge or implantation. By using kinase inhibitors, the mechanism of nicotine upregulating CD80 was finally explored by flow cytometry. RESULTS: The results showed that: firstly, nicotine could upregulate the expressions of CD80, CD86, CD40,CD11b, MHC class I and II molecules in imDCs. Secondly, nicotine could promote imDCs-dependent T cell priming and IL-12 secretion. Most importantly, systemic transfer of ex vivo nicotine-stimulated imDCs, which enhanced CD80 expression through PI3K activation, could reveal preventive and effectively therapeutic effects on tumor development. CONCLUSIONS: Ex vivo nicotine stimulation can significantly improve imDCs efficacy for adaptive therapy of cancer. Nicotine-treated imDCs might be considered as a potential candidate for therapeutic tumor immunotherapy for lung and liver cancer. PMID- 20957419 TI - Therapeutic effect of a novel anti-parkinsonian agent zonisamide against MPTP (1 methyl-4-phenyl-1,2,3,6- tetrahydropyridine) neurotoxicity in mice. AB - We investigated the therapeutic effect of zonisamide against 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice, using Western blot analysis, immunohistochemistry and behavioral test. Our Western blot analysis and immunohistochemical study showed that the post-treatment with zonisamide prevented significantly dopaminergic cell damage, the depletion of tyrosine hydroxylase (TH) protein levels and the proliferation of microglia in the striatum and/or substantia nigra 8 days after MPTP treatment. Furthermore, our behavioral study showed that the post-treatment with zonisamide attenuated significantly the motor deficits 7 days after MPTP treatment. These results show that zonisamide has the therapeutic effect in the MPTP model of Parkinson's disease (PD) in mice. Our study also demonstrates the neuroprotective effect of zonisamide against dopaminergic cell damage after MPTP treatment in mice. Thus our present findings suggest that therapeutic strategies targeted to the activation of TH protein and/or the inhibition of microglial activation with zonisamide may offer a great potential for restoring the functional capacity of the surviving dopaminergic neurons in individuals affected with PD. PMID- 20957420 TI - Migraine headaches following catheter ablation for atrial fibrillation. AB - BACKGROUND: Atrial septal defects (ASD), including patent foramen ovale, have been linked to an increased prevalence of migraine headaches in the general population. A similar association with migraine is speculated for iatrogenic ASD due to atrial septal puncture during catheter ablation for atrial fibrillation (AF). METHODS: A total of 2,069 patients who underwent catheter ablation for AF at Mayo Clinic, Rochester, MN between January 2001 and December 2008 were scheduled for follow-up at least at 3 months and annually thereafter. Data were collected from the questionnaires patients answered at follow-up inquiring about presence and characteristics of any headaches following the procedure and further chart review. Definite migraine was diagnosed based on clinical features per the International Classification of Headache Disorder-II definition. RESULTS: Twenty two patients (1.1%) had a new-onset definite migraine, 12 (0.6%) had a new-onset probable migraine, ten (0.5%) with a previous history of migraine had worsened headaches, and four (0.2%) had headache due to an alternate identifiable cause; a total of 48 patients (2.3%) reported post-procedural headaches. Nineteen of 22 patients (86%) with definite migraine had complete resolution of symptoms at 1- to 2-year follow-up. CONCLUSION: New-onset migraine is an uncommon and usually temporary side effect of catheter ablation for AF. The mechanism for post procedure headache remains unclear. PMID- 20957421 TI - Older female caregivers and HIV/AIDS-related secondary stigma in rural South Africa. AB - South Africa's HIV/AIDS epidemic poses a major public health threat with multi faceted harmful impacts and 'socially complex' outcomes. While some outcomes relate to structural issues, others stem from society's attitudinal milieu. Due to negative attitudes toward People Living with HIV/AIDS, stigmatisation mars their own experience and often extends to those close to them, in particular their caregivers. Many of the caregivers in South Africa are older women; thus, older women are the focus of this paper, which aims to examine HIV/AIDS-related stigma from their perspective. This paper explores secondary stigma as a socio cultural impact of HIV/AIDS through repeated semistructured interviews with 60 women aged 50-75 in the MRC/Wits Rural Public Health and Health Transitions Unit research site (Agincourt), many of whom had cared for a family member with HIV/AIDS. Respondents' narratives reveal that many older persons attribute high rates of death in their community to young persons' lack of respect for societal norms and traditions. The findings illustrate the forms and expressions of HIV/AIDS-related secondary stigma and their impacts on older female caregivers. The types of secondary stigma experienced by the respondents include physical stigma in the form of isolation and separation from family members; social stigma in the form of voyeurism and social isolation; and verbal stigma in the form of being gossiped about, finger-pointing and jeering at them. Despite mixed reports about community responses toward infected and affected people, HIV/AIDS-related stigma remains a cause for concern, as evidenced by the reports of older women in this study. PMID- 20957422 TI - Gender differences in satisfaction with life in patients with coronary heart disease: physical activity as a possible mediating factor. AB - The objective of the present study was to examine if time varying, mediating effect of physical activity plays an important role in the gender-satisfaction with life relationship. Six hundred four male and 197 female patients were included. Principal outcomes of interest were self-report satisfaction with life and physical activity at baseline, 6, 12 and 24 months. The Krull and MacKinnon procedure for hierarchical linear modeling showed that the change in physical activity mediated the gender-satisfaction with life over a 2 year period. Results from the current study suggest that increased physical activity partially explains why males report having increased well-being than females after hospitalization. This suggests that future interventions need to focus on reducing the gender disparity in physical activity to improve differences noted in satisfaction with life. If higher physical activity levels impact satisfaction with life positively, the importance of physical activity for female patients is warranted. PMID- 20957423 TI - A preliminary randomized controlled trial of a nurse-delivered medication adherence intervention among HIV-positive outpatients initiating antiretroviral therapy in Beijing, China. AB - We evaluated a nurse-delivered adherence intervention in a preliminary randomized controlled trial among 70 HIV-positive outpatients initiating antiretroviral therapy (ART) in Beijing, China. In both arms, participants received a 30-min educational session, a pillbox, and a referral to a peer support group. In the enhanced arm, participants could choose an electronic reminder device, three sessions of counseling either alone or with a treatment adherence partner, or both reminder and counseling. Survey assessments and blood draws occurred at baseline, post-intervention (13 weeks), and follow-up (25 weeks). Primary outcomes were 7-day and 30-day adherence assessed by self-report and electronic drug monitoring (EDM), and secondary outcomes were HIV-1 RNA viral load and CD4 count. The intervention was feasible and well received. It led to some improvement in self-reported and EDM-assessed adherence but not the biological outcomes. Providing counseling and facilitating the use of electronic reminders to patients initiating ART merits further investigation as a culturally viable means of promoting adherence in China. PMID- 20957424 TI - Notes on the frequency of routinely collected and self-reported behavioral data in HIV prevention trials. AB - HIV prevention trials typically randomize thousands of participants to active or control intervention arms, with regular (e.g. monthly) clinic visits over one or more years of follow-up. Because HIV infection rates are often lower than 3 per 100 person-years even in high prevalence settings, tens of thousands of clinic visits may take place before the number of infections required to achieve adequate study power has been observed. In addition to clinical outcomes, the multitude of study visits provides an opportunity to assess adherence and related participant behaviors in great detail. These data may be used to refine counseling messages, gain insight into patterns of behavior, and perform supporting analyses in an attempt to obtain more precise estimates of treatment efficacy. Exploratory analyses were performed to assess how our understanding of participant behaviors and their relationships to biological outcomes in two recent prevention trials might have been impacted had the frequency of routine behavioral data collection been reduced from monthly to just months 1, 3, 6, 9, and 12. Results were comparably informative in the reduced case, suggesting that unnecessarily extensive amounts of routine behavioral data may be collected in these trials. PMID- 20957425 TI - Toward the effective and efficient measurement of implementation fidelity. AB - Implementation science in mental health is informed by other academic disciplines and industries. Conceptual and methodological territory charted in psychotherapy research is pertinent to two elements of the conceptual model of implementation posited by Aarons and colleagues (2010)--implementation fidelity and innovation feedback systems. Key characteristics of scientifically validated fidelity instruments, and of the feasibility of their use in routine care, are presented. The challenges of ensuring fidelity measurement methods are both effective (scientifically validated) and efficient (feasible and useful in routine care) are identified as are examples of implementation research attempting to balance these attributes of fidelity measurement. PMID- 20957426 TI - Outcomes for implementation research: conceptual distinctions, measurement challenges, and research agenda. AB - An unresolved issue in the field of implementation research is how to conceptualize and evaluate successful implementation. This paper advances the concept of "implementation outcomes" distinct from service system and clinical treatment outcomes. This paper proposes a heuristic, working "taxonomy" of eight conceptually distinct implementation outcomes-acceptability, adoption, appropriateness, feasibility, fidelity, implementation cost, penetration, and sustainability-along with their nominal definitions. We propose a two-pronged agenda for research on implementation outcomes. Conceptualizing and measuring implementation outcomes will advance understanding of implementation processes, enhance efficiency in implementation research, and pave the way for studies of the comparative effectiveness of implementation strategies. PMID- 20957427 TI - A collaborative approach to identifying effective incentives for mental health clinicians to improve depression care in a large managed behavioral healthcare organization. AB - This descriptive study used stakeholder input to prioritize evidence-based strategies for improving depression care and to select incentives for mental health clinicians to adopt those strategies, and to conduct a feasibility test of an incentive-based program in a managed behavioral healthcare organization (MBHO). In two rounds of interviews and a stakeholder meeting, MBHO administrators and clinicians selected increasing combination treatment (antidepressant plus psychotherapy) rates as the program goal; and paying a bonus for case reviews, clinician feedback, and clinician education as incentives. We assessed program feasibility with case review and clinician surveys from a large independent practice association that contracts with the MBHO. Findings suggest that providing incentives for mental health clinicians is feasible and the incentive program did increase awareness. However, adoption may be challenging because of administrative barriers and limited clinical data available to MBHOs. PMID- 20957428 TI - The utility of home problem pervasiveness and severity in classifying children identified with attention-deficit/hyperactivity disorder. AB - Given the propensity for clinical assessment of Attention-Deficit/Hyperactivity Disorder (ADHD) to focus on core behavioral symptoms, the current study examined how well other predictors classified children who were diagnosed with ADHD by licensed practitioners. Participants were 91 children (39 ADHD-identified, 52 without ADHD), aged 8 to 13 years. In addition to significantly more ADHD symptoms, the ADHD-identified group exhibited significantly more externalizing problems and internalizing symptoms, less adaptive functioning, and greater problem pervasiveness and severity. Binary logistic regression analyses indicated that problem pervasiveness and severity significantly predicted diagnostic group membership when controlling for other predictors, and pervasiveness added unique variance beyond measures of core ADHD symptoms. Diagnostic utility analyses showed measurement of problem pervasiveness and severity to be a useful tool in the identification of ADHD. Findings provide support for the practical use of a parent-report measure of impairment in the home as part of evidence-based assessment of ADHD. PMID- 20957429 TI - Discriminatory accuracy and potential clinical utility of genomic profiling for breast cancer risk in BRCA-negative women. AB - Several single nucleotide polymorphisms (SNPs) are associated with an increased risk of breast cancer. The clinical utility of genotyping individuals at these loci is not known. Subjects were 519 unaffected women without BRCA mutations. Gail, Claus, and IBIS models were used to estimate absolute breast cancer risks. Subjects were then genotyped at 15 independent risk loci. Published per-allele and genotype-specific odds ratios were used to calculate the composite cumulative genomic risk (CGR) for each subject. Affected age- and ethnicity-matched BRCA mutation-negative women were also genotyped as a comparison group for the calculation of discriminatory accuracy. The CGR was used to adjust absolute breast cancer risks calculated by Gail, Claus and IBIS models to determine the proportion of subjects whose recommendations for chemoprevention or MRI screening might be altered (reclassified) by such adjustment. Mean lifetime breast cancer risks calculated using the Gail, Claus, and IBIS models were 19.4, 13.0, and 17.7%, respectively. CGR did not correlate with breast cancer risk as calculated using any model. CGR was significantly higher in affected women (mean 3.35 vs. 3.12, P = 0.009). The discriminatory accuracy of the CGR alone was 0.55 (SE 0.019; P = 0.006). CGR adjustment of model-derived absolute risk estimates would have altered clinical recommendations for chemoprevention in 11-19% of subjects and for MRI screening in 8-32%. CGR has limited discriminatory accuracy. However, the use of a genomic risk term to adjust model-derived estimates has the potential to alter individual recommendations. These observations warrant investigation to evaluate the calibration of adjusted risk estimates. PMID- 20957430 TI - Immunohistochemistry compared to cytosol assays for determination of estrogen receptor and prediction of the long-term effect of adjuvant tamoxifen. AB - The purpose of this study is to compare immunohistochemistry (IHC) and cytosol based assays for determination of estrogen receptor (ER) and prediction of response to adjuvant tamoxifen treatment in postmenopausal women with early-stage invasive breast cancer. The Stockholm Breast Cancer Study Group conducted a randomized trial during 1976 through 1990 comparing adjuvant tamoxifen versus control. The patients were stratified according to tumor size and lymph node status in high-risk and low-risk groups. In this study we evaluated 683 patients with "low risk" breast cancer (size <=30 mm, lymph node-negative) for whom ER status had been determined by both the cytosol assays and IHC at one pathology laboratory. The median follow-up was 17 years. Six hundred eighty-three patients had tumors with ER determined by both methods, 536 (78.5%) were ER-positive by cytosol assays using the cutoff level at >=0.05 fmol/MUg DNA and 539 patients were ER-positive (79%) by IHC using the cutoff level at >=10% cell stained. Thirty-nine tumors (5.7%) were ER-positive by cytosol but not by IHC, whereas the opposite pattern was found for 42 cases (6.1%). Only seven tumors had stained cells between 0 and 9% by IHC. The concordance between IHC and cytosol assays was high (88%). The kappa statistic was 0.65, 95% CI 0.58-0.72. Among patients classified as ER-negative no therapeutic benefit from tamoxifen was observed. Among patients with ER-expressing tumors, tamoxifen resulted in significantly better recurrence-free survival irrespective of the method (IHC: HR, 0.53, P < 0.001; cytosol: HR, 0.53, P < 0.001). The effect on overall survival was not statistically significant probably due to the limited sample size. Both IHC and cytosol assay accurately predict long-term response to adjuvant tamoxifen. PMID- 20957431 TI - Asian ethnicity and breast cancer subtypes: a study from the California Cancer Registry. AB - The distribution of breast cancer molecular subtypes has been shown to vary by race/ethnicity, highlighting the importance of host factors in breast tumor biology. We undertook the current analysis to determine population-based distributions of breast cancer subtypes among six ethnic Asian groups in California. We defined immunohistochemical (IHC) surrogates for each breast cancer subtype among Chinese, Japanese, Filipina, Korean, Vietnamese, and South Asian patients diagnosed with incident, primary, invasive breast cancer between 2002 and 2007 in the California Cancer Registry as: hormone receptor-positive (HR+)/HER2- [estrogen receptor-positive (ER+) and/or progesterone receptor positive (PR+), human epidermal growth factor receptor 2-negative (HER2-)], triple-negative (ER-, PR-, and HER2-), and HER2-positive (ER+/-, PR+/-, and HER2+). We calculated frequencies of breast cancer subtypes among Asian ethnic groups and evaluated their associations with clinical and demographic factors. Complete IHC data were available for 8,140 Asian women. Compared to non-Hispanic White women, Korean [odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.5 2.2], Filipina (OR = 1.3, 95% CI = 1.2-1.5), Vietnamese (OR = 1.3, 95% CI = 1.1 1.6), and Chinese (OR = 1.1, 95% CI = 1.0-1.3) women had a significantly increased risk of being diagnosed with HER2-positive breast cancer subtypes after adjusting for age, stage, grade, socioeconomic status, histology, diagnosis year, nativity, and hospital ownership status. We report a significant ethnic disparity in HER2-positive breast cancer in a large population-based cohort enriched for Asian-Americans. Given the poor prognosis and high treatment costs of HER2 positive breast cancer, our results have implications for healthcare resource utilization, cancer biology, and clinical care. PMID- 20957432 TI - Optimization and evaluation of electroporation delivery of siRNA in the human leukemic CEM cell line. AB - In order to study nucleoside analog activation in the CEM cell line, a transfection protocol had to be optimized in order to silence an enzyme involved in nucleoside analog activation. Hematopoetic cell lines can be difficult to transfect with traditional lipid-based transfection, so the electroporation technique was used. Field strength, pulse length, temperature, electroporation media, siRNA concentration, among other conditions were tested in order to obtain approximately 70-80% mRNA and enzyme activity downregulation of the cytosolic enzyme deoxycytidine kinase (dCK), necessary for nucleoside analog activation. Downregulation was assessed at mRNA and enzyme activity levels. After optimizing the protocol, a microarray analysis was performed in order to investigate whether the downregulation was specific. Additionally two genes were differentially expressed besides the downregulation of dCK. These were however of unknown function. The leakage of intracellular nucleotides was also addressed in the electroporated cells since it can affect the DNA repair mechansism and the efficiency of nucleoside analogs. Three of these pools were increased compared to untreated, unelectroporated cells. The siRNA transfected cells with reduced dCK expression and activity showed reduced sensitivity to several nucleoside analogs as expected. The multidrug resistance to other drugs, as seen in nucleoside analog-induced resistant cells, was not seen with this model. PMID- 20957433 TI - Clinical correlation of nitric oxide levels with acute rejection in renal transplantation. AB - BACKGROUND: The objective of this study was to examine whether there was an association between acute rejection (AR) and nitric oxide (NO) levels and also to evaluate the clinical impact of NO measurement as a noninvasive marker for early detection of AR. METHODS: Fifty consecutive patients aged 17-62 years old received a living-related kidney graft. Serum levels of total nitrite and nitrate (NOx) were measured 30 min after graft reperfusion (NOx 1) and on days 1 (NOx 2), 5 (NOx 3), and 10 (NOx 4) post-transplantation (Tx). If clinically indicated, graft biopsy was performed. RESULTS: Acute humoral rejection was diagnosed by biopsy on 3rd post-Tx day in one patient. His serum NOx 2 levels were remarkably higher (380%) compared with his NOx 1 measurement. At the same time, NOx 1-2 measurements in uncomplicated group showed lower levels (-12%). Additionally, during the first month post-Tx, 5 cases of acute cellular rejection (ACR) were diagnosed. The mean percent change of NOx 3-4 levels in ACR group was 180.7 versus 16.1 in uncomplicated patients (P < 0.01). In addition, >70 MUmol/L change in NOx levels in consecutive samples had a sensitivity of 100% and a specificity of 97.7% in predicting AR episodes. CONCLUSION: Our study reports significant increase in serum NOx levels in episodes of AR. NOx might be an useful noninvasive marker for early diagnosis of AR. PMID- 20957434 TI - Juvenile psychopathic personality traits are associated with poor reading achievement. AB - The current study sought to further the understanding of the linkage between maladaptive behavior and cognitive problems by examining the relations between psychopathic personality traits and reading comprehension performance. Data were derived from a study of 432 predominately African-American and Hispanic middle school students. Dependent variables consisted of three measures of reading comprehension. Psychopathy measures included the Inventory of Callous-Unemotional traits (ICU-teacher rated) and the self-reported Youth Psychopathic traits Inventory (YPI). Findings from regression models indicated that self-report and teacher ratings of psychopathy were statistically significant inverse predictors of reading performance. Specifically, affective facets of psychopathy were potent predictors of reading comprehension over and above ADHD, IQ, and an impulsivity component of psychopathy. Study results extend the utility of psychopathy construct generally and affective traits specifically to reading achievement, which has broad implications. Findings are discussed with respect to future research and prevention. PMID- 20957435 TI - Psychiatric correlates of behavioral indicators of school disengagement in the United States. AB - The current study examined relations between behavioral indicators of school disengagement and psychiatric disorders. Data was derived from a nationally representative sample of U.S. adults (N = 43,093). Indicators of school disengagement and diagnoses of personality, substance use, mood, and anxiety disorders were assessed with the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV-version. Findings from multinomial logistic regression analyses revealed that cumulative school disengagement is associated with increased odds of reporting a lifetime psychiatric disorder and general antisociality. Behavioral indicators of school disengagement such as absenteeism and cutting class are potentially important signs of psychiatric distress and conduct problems. In addition to attending to academic achievement outcomes school disengagement prevention strategies should consider targeting these psychiatric conditions in order to reduce school dropout. PMID- 20957436 TI - Application of high throughput perfusion micro 3-D cell culture platform for the precise study of cellular responses to extracellular conditions -effect of serum concentrations on the physiology of articular chondrocytes. AB - Mammalian cells are sensitive to extracellular microenvironments. In order to faithfully explore the physiological responses of cells to extracellular conditions, a steady, homogenous, and three-dimensional (3-D) culture environment is required because it can provide a more quantifiable and biologically-relevant culture condition. To achieve this, this study reports a perfusion micro cell culture platform encompassing 22 microbioreactor units for high throughput 3-D cell culture. The cell culture platform structurally consisting of a plug and a microbioreactor chamber module was simply fabricated by replica molding of polydimethylsiloxane (PDMS) polymer. The platform features in the proposed plug module with multiple molds incorporated, facilitating the preparation of cell encapsulated 3-D hydrogel constructs in a precise and efficient manner. This trait is found particularly useful for high-precision and high-throughput micro 3 D cell culture-based assay. In this study, the real value of the proposed platform to maintain a stable and homogenous culture condition was discussed. Besides, the application of the presented platform for precisely investigating the effect of serum concentration on the metabolic activities and biosynthetic abilities of articular chondrocytes was also demonstrated. As a whole, the proposed device has paved an alternative route to carry out high throughput micro scale 3-D perfusion cell culture in a simple, cost-effective and precise manner. The promising applications include 3-D cell culture-based high throughput drug or toxicity testing/screening, or other investigations on the cell biology, where the precise quantification of the links between the cellular responses and extracellular conditions is required. PMID- 20957437 TI - Designing of a Si-MEMS device with an integrated skeletal muscle cell-based bio actuator. AB - With the aim of designing a mechanical drug delivery system involving a bio actuator, we fabricated a Micro Electro Mechanical Systems (MEMS) device that can be driven through contraction of skeletal muscle cells. The device is composed of a Si-MEMS with springs and ratchets, UV-crosslinked collagen film for cell attachment, and C2C12 muscle cells. The Si-MEMS device is 600 MUm x 1000 MUm in size and the width of the collagen film is 250 ~ 350 MUm, which may allow the device to go through small blood vessels. To position the collagen film on the MEMS device, a thermo-sensitive polymer was used as the sacrifice-layer which was selectively removed with O2 plasma at the positions where the collagen film was glued. The C2C12 myoblasts were seeded on the collagen film, where they proliferated and formed myotubes after induction of differentiation. When C2C12 myotubes were stimulated with electric pulses, contraction of the collagen film C2C12 myotube complex was observed. When the edge of the Si-MEMS device was observed, displacement of ~8 MUm was observed, demonstrating the possibility of locomotive movement when the device is placed on a track of adequate width. Here, we propose that the C2C12-collagen film complex is a new generation actuator for MEMS devices that utilize glucose as fuel, which will be useful in environments in which glucose is abundant such as inside a blood vessel. PMID- 20957441 TI - The value of postoperative parathyroid hormone levels in predicting the need for long-term vitamin D supplementation after total thyroidectomy. AB - BACKGROUND: Few studies have examined the need for vitamin D supplementation after total thyroidectomy. This study examines the role of postoperative day (POD) 1 serum calcium and parathyroid hormone (PTH) levels in predicting the need for long-term vitamin D supplementation after total thyroidectomy. METHODS: A retrospective, single institutional study of patients who underwent total thyroidectomy between January 2007 and December 2008 was performed. Data collected included extent of surgery, final pathology, postoperative calcium (mg/dl) and PTH (pg/ml) values, and duration of vitamin D supplementation. Patients were divided into 4 groups based on POD1 PTH values: group 1 (<5.0); group 2 (5.0-10); group 3 (10.1-20); and group 4 (>20). RESULTS: Of the 104 patients, 26 were in group 1, 12 in group 2, 18 in group 3, and 48 in group 4, with median PTH values of <2.5, 8.2, 14.1, and 30 pg/ml, respectively. All 7 (7%) patients who required vitamin D supplementation >1 month were in group 1. The positive predictive value of POD1 PTH <5.0 in predicting supplementation >1 month was 27% (sensitivity 100%, specificity 80%). Seventy-eight patients had a POD1 PTH level >=5, and none required vitamin D supplementation >1 month (100% negative predictive value). The positive predictive value of various POD1 calcium thresholds (<7.5, <8.0, and <8.5 mg/dl) was 17, 14, and 15%, respectively. CONCLUSIONS: Postoperative PTH levels better predict long-term hypocalcemia requiring vitamin D supplementation than serum calcium levels. A PTH level >=5.0 may identify patients who can be safely discharged without routine vitamin D supplementation. PMID- 20957442 TI - Role of survivin gene promoter polymorphism (-31G>C) in susceptibility and survival of esophageal cancer in northern India. AB - BACKGROUND AND AIM: Survivin is an upregulated inhibitor of apoptosis protein in esophageal cancer (EC), and a promoter region polymorphism (-31G>C) in the survivin gene has been reported as a modulator of gene expression. We aim to explore the role of survivin -31G>C polymorphism in susceptibility and survival of EC patients in northern Indian population. MATERIALS AND METHODS: A case control study was performed in 500 subjects (250 EC patients and 250 controls), and genotyping was done by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) method. RESULTS: Survivin CC genotype was found to be significantly associated with EC susceptibility [odds ratio (OR) = 2.29; 95% confidence interval (CI) = 1.27-4.14; P = 0.006], particularly in males (OR = 4.91; 95% CI = 2.19-11.02; P = 0.0001) having squamous cell carcinoma (SCC) histopathology (OR = 2.4; 95% CI = 1.36-4.21; P = 0.002) at middle third esophagus location (OR = 2.60; 95% CI = 1.40-4.82; P = 0.002). Patients carrying CC genotype were found to have higher susceptibility to lymph node metastasis (OR = 2.82; 95% CI = 1.46-5.48; P = 0.002). However, on survival analysis, no prognostic role of survivin -31G>C polymorphism was detected. In case-only analysis, no gene-environment interaction was observed. CONCLUSION: Survivin promoter region polymorphism (-31G>C) is associated with susceptibility and clinical characteristics but not prognosis of esophageal cancer in northern Indian population. PMID- 20957443 TI - Monitoring the longitudinal intra-tumor physiological impulse response to VEGFR2 blockade in breast tumors using DCE-CT. AB - PURPOSE: The purpose of this study was to quantify and model the longitudinal intra-tumor physiological response to a single dose of a monoclonal antibody specific to the VEGFR2 using dynamic contrast-enhanced CT. MATERIAL AND METHODS: Dynamic contrast-enhanced CT imaging was performed on athymic nude mice bearing xenograft VEGF-transfected MCF-7 tumors (MCF7(VEGF)) to quantify intra-tumor physiology pre- and post-injection (days 2, 7, and 14) of a nonspecific (IgG1, controls) and specific (DC101, treated) monoclonal antibody targeting VEGFR2. Parametrical maps of tumor physiology-perfusion (F), permeability surface area (PS), fractional plasma (f(p)), and interstitial space (f (is))-were obtained at four time points over a 2-week period. RESULTS: A temporal multistage recovery process whereby a decoupling of the fractional change in physiological parameters (f (p), F) was observed when comparing treated to control tumors: f (p) and perfusion decreased by a combined 27% (P < 0.01) and 65% (P < 0.01) on day 2, while only perfusion remained reduced by 46% (P < 0.01) on day 7. Intra-tumor heterogeneity defined by the change in variance of perfusion decreased on days 2 and 7; no change in the variance of f(p) was observed. Analysis based on a mathematical model linking perfusion and vascular morphology indicates that a decrease in f(p) and perfusion was consistent with a reduction in blood vessel radius, followed by an increase in the vascular radius and tortuosity resulting in the decoupling of f(p) and perfusion before returning to control levels. CONCLUSION: Inhibiting VEGFR2 activity results in a temporal decoupling of physiological parameters, which can be explained by a combination of morphological changes influencing perfusion. Such a decoupling has the potential to significantly impact the delivery of pharmaceuticals and oxygen within solid tumors, critical factors in combined anti-angiogenic and radio- and chemotherapies. PMID- 20957444 TI - A videoendoscopic evaluation of the upper airway in South East Asian adults with obstructive sleep apnea. AB - OBJECTIVES: We aimed to evaluate the severity of upper airway obstruction at the retropalatal and retroglossal regions in obstructive sleep apnea (OSA) patients. METHODOLOGY: This is a descriptive cross-sectional study at the Sleep Clinic, Department of Otorhinolaryngology-Head and Neck Surgery. Flexible nasopharyngolaryngoscopy was performed in seated erect and supine position. Retropalatal and retroglossal regions were continuously recorded during quiet breathing and Mueller's maneuver in both positions. Captured images were measured using Scion Image software and narrowing rate was calculated. Level of each site was classified based on Fujita classification and severity of obstruction using Sher scoring system for Mueller's maneuver. RESULTS: A total of 59 patients participated in this study. Twenty-nine (49.2%) participants had type 1 (retropalatal) obstruction, 23 (38.9%) had type 2 (retropalatal and retroglossal), and seven (11.9%) in type 3 (retroglossal) obstruction. Fifty (84.7%) of the patients have severe obstruction at the retropalatal region in supine position (SRP) followed by 35 (59.3%) at retropalatal region in erect position (ERP), 27 (45.8%) at retroglossal region in supine position (SRG) and eight (13.5%) at retroglossal region in erect position (ERG). The average oxygen saturation showed significant association in ERP (P = 0.012) and SRP (P < 0.001), but not significant in ERG and SRG. CONCLUSIONS: Videoendoscopy utilizing flexible nasopharyngolaryngoscopy and Scion Image software is reliable, minimally invasive, and useful as an office procedure in evaluating the multilevel obstruction of upper airway in OSA patients. The retropalatal region has more severe obstruction compared with retroglossal region either in erect or supine position. PMID- 20957445 TI - The prediction of novel multiple lipid-binding regions in protein translocation motor proteins: a possible general feature. AB - Protein translocation is an important cellular process. SecA is an essential protein component in the Sec system, as it contains the molecular motor that facilitates protein translocation. In this study, a bioinformatics approach was applied in the search for possible lipid-binding helix regions in protein translocation motor proteins. Novel lipid-binding regions in Escherichia coli SecA were identified. Remarkably, multiple lipid-binding sites were also identified in other motor proteins such as BiP, which is involved in ER protein translocation. The prokaryotic signal recognition particle receptor FtsY, though not a motor protein, is in many ways related to SecA, and was therefore included in this study. The results demonstrate a possible general feature for motor proteins involved in protein translocation. PMID- 20957446 TI - Massachusetts health disparities: key lessons for the nation. PMID- 20957447 TI - Weight loss after Roux-en-Y gastric bypass in obese patients heterozygous for MC4R mutations. AB - BACKGROUND: Heterozygous mutations in melanocortin-4 receptor (MC4R) are the most frequent genetic cause of obesity. Bariatric surgery is a successful treatment for severe obesity. The mechanisms of weight loss after bariatric surgery are not well understood. METHODS: Ninety-two patients who had Roux-en-Y gastric bypass (RYGB) surgery were screened for MC4R mutations. We compared percent excess weight loss (%EWL) in the four MC4R mutation carriers with that of two control groups: 8 matched controls and with the remaining 80 patients who underwent RYGB. RESULTS: Four patients were heterozygous for functionally significant MC4R mutations. In patients with MC4R mutations, the %EWL after RYGB (66% EWL) was not significantly different compared to matched controls (70% EWL) and non-matched controls (60% EWL) after 1 year of follow-up. CONCLUSIONS: This study suggests that patients with heterozygous MC4R mutations also benefit from RYGB and that weight loss may be independent of the presence of such mutations. PMID- 20957448 TI - The impairment of liver DNA conformation and liver apoptosis of mice caused by CeCl3. AB - Cerium (Ce) was shown to cause various toxic effects both in rats and mice; however, the molecular mechanism by which Ce exert theirs toxicity is still understood. In this report, the impairment of liver DNA conformation and liver apoptosis of mice caused by CeCl(3) was studied in vivo using inductively coupled plasma-mass spectrometry, various spectral methods, gel electrophoresis, and transmission electron micrograph. We found that the coefficients of liver to body weight of the mice treated with CeCl(3) were significantly increased. Ce(3+) could be significantly accumulated in the liver, and it insert itself into DNA base pairs and/or bind to DNA nucleotide, and alter the conformation of DNA. Furthermore, the evaluation by gel electrophoresis and transmission electron micrograph showed that higher dose of Ce(3+) could cause DNA cleavage and hepatocyte apoptosis in mice. Therefore, our study aroused the attention of Ce application and exposure effects especially on human liver for long-term and low dose treatment. PMID- 20957449 TI - Trace elements in obese Turkish children. AB - The quality of the diet of obese children is poor. Eating habits may alter micronutrient status in obese patients. In this study, we determined the serum levels of selenium, zinc, vanadium, molybdenum, iron, copper, beryllium, boron, chromium, manganese, cobalt, silver, barium, aluminum, nickel, cadmium, mercury, and lead in obese Turkish children. Thirty-four obese and 33 healthy control subjects were enrolled in the study. Serum vanadium and cobalt levels of obese children were significantly lower than those of the control group (0.244 +/- 0.0179 vs. 0.261 +/- 0.012 MUg/l, p < 0.001, and 0.14 +/- 0.13 vs. 0.24 +/- 0.15 MUg/l, p = 0.011, respectively). There was no significant difference between groups regarding the other serum trace element levels. In conclusion, there may be alterations in the serum levels of trace elements in obese children and these alterations may have a role in the pathogenesis of obesity. PMID- 20957450 TI - Production of recombinant porcine interferon alpha using PHB-intein-mediated protein purification strategy. AB - Interferons (IFNs) are involved in the pathogenesis and recovery of viral and other infectious diseases. Recombinant IFNs have been used as anti-infectious agents exhibiting a broad range of antiviral and immunomodulatory properties in both human and domestic animals. In this report, we describe a highly efficient and economical approach to purify porcine IFN alpha (PoIFNalpha) using polyhydroxybutyrate (PHB) as the affinity carrier and intein for self-cleaving removal of the affinity tag. Additionally, the conditions of protein expression and purification have been optimized. Our results suggested that culture medium containing 1.62% (w/v) of sodium lactate dramatically increases the accumulation of PHB binding protein in Escherichia coli cells. High yields of recombinant PoIFNalpha (30-35 mg/L, 97% purity by high-performance liquid chromatography) were obtained using intein-mediated self-cleaving conditions using a cleavage inducing buffer with a pH of 6.5 at 20 degrees C for 24-36 h. The antiviral activity of the recovered recombinant PoIFNalpha was up to 1.4 x 106 IU/mg of protein ascertained using recombinant human IFNalpha1 as a standard. This report also demonstrates that large-scale production of intein-mediated purification of highly pure and active recombinant PoIFNalpha is feasible for the purposes of experimental studies, veterinary clinic therapeutics, and swine infectious disease control. PMID- 20957451 TI - Gastric adenocarcinoma? Looks similar but behaves differently! PMID- 20957453 TI - Mechanical stretch activates signaling events for protein translation initiation and elongation in C2C12 myoblasts. AB - It has been proposed that mechanically induced tension is the critical factor in the induction of muscle hypertrophy. However, the molecular mechanisms involved in this process are still under investigation. In the present study, the effect of mechanical stretch on intracellular signaling for protein translation initiation and elongation was studied in C2C12 myoblasts. Cells were grown on a silicone elastomer chamber and subjected to 30-min of 5 or 15% constant static or cyclic (60 cycles/min) uniaxial stretch. Western blot analyses revealed that p70 S6 kinase (p70S6K) and eukaryotic elongation factor 2 (eEF2), which are the markers for translation initiation and peptide chain elongation, respectively, were activated by both static and cyclic stretch. The magnitude of activation was greater in response to the 15% cyclic stretch. Cyclic stretch also increased the phosphorylation of MAP kinases (p38 MAPK, ERK1/2 and JNK). However, the pharmacological inhibition of MAP kinases did not block the stretch-induced activation of p70S6K and eEF2. An inhibitor of the mammalian target of rapamycin (mTOR) blocked the stretch-induced phosphorylation of p70S6K but did not affect the eEF2 activation. A broad-range tyrosine kinase inhibitor, genistein, blocked the stretch-induced activation of p70S6K and eEF2, whereas Src tyrosine kinase and Janus kinase (JAK) inhibitors did not. These results suggest that the stretch induced activation of protein translation initiation and elongation in mouse myoblast cell lines is mediated by tyrosine kinase(s), except for Src kinase or JAK. PMID- 20957454 TI - Backbone (1)H, (15)N, and (13)C resonance assignments and secondary structure of the Tollip CUE domain. AB - The Toll-interacting protein (Tollip) is a negative regulator of the Toll-like receptor (TLR)-mediated inflammation response. Tollip is a modular protein that contains an Nterminal Tom1-binding domain (TBD), a central conserved domain 2 (C2), and a C-terminal coupling of ubiquitin to endoplasmic reticulum degradation (CUE) domain. Here, we report the sequence-specific backbone (1)H, (15)N, and (13)C assignments of the human Tollip CUE domain. The CUE domain was found to be a stable dimer as determined by size-exclusion chromatography and molecular crosslinking studies. Analysis of the backbone chemical shift data indicated that the CUE domain exhibits three helical elements corresponding to 52% of the protein backbone. Circular dichroism spectrum analysis confirmed the helical nature of this domain. Comparison of the location of these helical regions with those reported for yeast CUE domains suggest differences in length for all helical elements. We expect the structural analysis presented here will be the foundation for future studies on the biological significance of the Tollip CUE domain, its molecular interactions, and the mechanisms that modulate its function during the inflammatory response. PMID- 20957452 TI - Seeing is believing: are cancer stem cells the Loch Ness monster of tumor biology? AB - Tumors are complex systems with a diversity of cell phenotypes essential to tumor initiation and maintenance. With the heterogeneity present within the neoplastic compartment as its foundation, the cancer stem cell hypothesis posits that a fraction of tumor cells has the capacity to recapitulate the parental tumor upon transplantation. Over the last decade, the cancer stem cell hypothesis has gained support and shown to be relevant in many highly lethal solid tumors. However, the cancer stem cell hypothesis is not without its controversies and critics question the validity of this hypothesis based upon comparisons to normal somatic stem cells. Cancer stem cells may have direct therapeutic relevance due to resistance to current treatment paradigms, suggesting novel multimodal therapies targeting the cancer stem cells may improve patient outcomes. In this review, we will use the most common primary brain tumor, glioblastoma multiforme, as an example to illustrate why studying cancer stem cells holds great promise for more effective therapies to highly lethal tumors. In addition, we will discuss why the abilities of self-renewal and tumor propagation are the critical defining properties of cancer stem cells. Furthermore, we will examine recent progress in defining appropriate cell surface selection markers and mouse models which explore the potential cell(s) or origin for GBMs. What remains clear is that a population of cells is present in many tumors which are resistant to conventional therapies and must be considered in the design of the next generation of cancer treatments. PMID- 20957455 TI - Extracellular domain of V-set and immunoglobulin domain containing 1 (VSIG1) interacts with sertoli cell membrane protein, while its PDZ-binding motif forms a complex with ZO-1. AB - V-set and immunoglobulin domain containing 1 (VSIG1) is a newly discovered member of the junctional adhesion molecule (JAM) family; it is encoded by a gene located on human chromosome X and preferentially expressed in a variety of cancers in humans. Little is known about its physiological function. To determine the role(s) of VSIG1 in mammalian spermatogenesis, we first generated a specific antibody against mouse VSIG1 and examined the presence and localization of the protein in tissues. RTRCR and Western blot analysis of the mouse tissues indicated that VSIG1 was specifically expressed in the testis. Furthermore, the results of our trypsinization and biotinylation assays strongly support the assumption that VSIG1 is localized on the testicular germ cell surface. In order to determine whether VSIG1 is capable of participation in homotypic interactions, we performed a GST-pull down assay by using recombinant GST-fusion and Histagging proteins. The pull-down assay revealed that each GST-fusion Ig-like domain shows homotypic binding. We further show that mVSIG1 can adhere to the Sertoli cells through its first Ig-like domain. To identify the protein that interacted with cytoplasmic domain, we next performed co-immunoprecipitation analysis. This analysis showed that ZO-1, which is the central structural protein of the tight junction, is the binding partner of the cytoplasmic domain of mouse VSIG1. Our findings suggest that mouse VSIG1 interacts with Sertoli cells by heterophilic adhesion via its first Ig-like domain. In addition, its cytoplasmic domain is critical for binding to ZO-1. PMID- 20957456 TI - Secretion of EGF-like domain of heregulinbeta promotes axonal growth and functional recovery of injured sciatic nerve. AB - Neuregulin 1 (NRG1) and epidermal growth factor receptor (ErbB) signaling pathways control Schwann cells during axonal regeneration in an injured peripheral nervous system. We investigated whether a persistent supply of recombinant NRG1 to the injury site could improve axonal growth and recovery of sensory and motor functions in rats during nerve regeneration. We generated a recombinant adenovirus expressing a secreted form of EGF-like domain from Heregulinbeta (sHRGbetaE-Ad). This virus, sHRGbetaE-Ad allowed for the secretion of 30-50 ng of small sHRGbetaE peptides per 10(7-8) virus particle outside cells and was able to phosphorylate ErbB receptors. Transduction of the concentrated sHRGbetaE-Ad into an axotomy model of sciatic nerve damage caused an effective promotion of nerve regeneration, as shown by histological features of the axons and Schwann cells, as well as increased expression of neurofilaments, GAP43 and S100 in the distal stump of the injury site. This result is consistent with longer axon lengths and thicker calibers observed in the sHRGbetaE-Ad treated animals. Furthermore, sensory and motor functions were significantly improved in sHRGbetaE-Ad treated animals when evaluated by a behavioral test. These results suggest a therapeutic potential for sHRGbetaE-Ad in treatment of peripheral nerve injury. PMID- 20957457 TI - Metabolic syndrome: from the genetics to the pathophysiology. AB - The metabolic syndrome (MS) constitutes a combination of underlying risk factors for an adverse outcome, cardiovascular disease. Thus, the clinical behavior of the MS can be regarded as a whole. Nevertheless, from a pathogenic point of view, understanding of the underlying mechanisms of each MS intermediate phenotype is far beyond their understanding as an integrative process. Systems biology introduces a new concept for revealing the pathogenesis of human disorders and suggests the presence of common physiologic processes and molecular networks influencing the risk of a disease. This paper shows a model of this concept to explain the genetic determinants of MS-associated phenotypes. Based on the hypothesis that common physiologic processes and molecular networks may influence the risk of MS disease components, we propose two systems-biology approaches: a gene enrichment analysis and the use of a protein-protein interaction network. Our results show that a network driven by many members of the nuclear receptor superfamily of proteins, including retinoid X receptor and farnesoid X receptor (FXR), may be implicated in the pathogenesis of the MS by its interactions at multiple levels of complexity with genes associated with metabolism, cell differentiation, and oxidative stress. In addition, we review two alternative genetic mechanisms that are gaining acceptance in the physiopathology of the MS: the regulation of transcriptional and post-transcriptional gene expression by microRNAs and epigenetic modifications such as DNA methylation. PMID- 20957458 TI - Dietary fructose and hypertension. AB - The association between fructose and increased blood pressure is still incompletely defined, because experimental studies have produced dissimilar conclusions. Amplified vasopressor responses to minimal stimuli and differing responses to fructose in peripheral versus central sites may explain the controversy. Fructose induces systemic hypertension through several mechanisms mainly associated with deleterious effects on target organs (kidney, endothelium, heart) exerted by the byproducts of its metabolism, such as uric acid. The kidney is particularly sensitive to the effects of fructose because high loads of this sugar reach renal tissue. In addition, fructose increases reabsorption of salt and water in the small intestine and kidney; thus the combination of salt and fructose has a synergistic effect in the development of hypertension. Clinical and epidemiologic studies have also linked fructose consumption with hypertension. Further studies are warranted in order to understand the role of fructose in the development of hypertension. PMID- 20957459 TI - The need for axillary dissection in patients with positive axillary sentinel lymph nodes. AB - The need for completion axillary dissection after a positive sentinel node biopsy continues to be challenged. In the 2 years since we last reviewed this subject, a number of authors have shared their experiences about micrometastatic disease and isolated tumor cells, opining both for and against axillary treatment. Data from the ACOSOG Z0011 trial and other small studies do not appear to support the use of completion axillary dissection even for macro-metastatic disease in patients with clinically node-negative (N0) disease. While existing guidelines still recommend axillary dissection for patients with clinically positive nodes, even when conversion to clinically negative disease following neoadjuvant chemotherapy has occurred, this concept is being questioned in ACOSOG Z1071 and in several other recent small trials. The surgical approach to the treatment of breast cancer continues to move away from the traditional Halstedian concept. PMID- 20957460 TI - Epinephrine autoinjector refill history in an HMO. AB - Epinephrine can be lifesaving in episodes of anaphylaxis, yet it is underprescribed and underused. Tracking of epinephrine refills over time for patients with a diagnosis of anaphylaxis has not been reported. This study reports on the refill history of 14,677 patients in a large HMO who received an initial dispensing of EpiPen (Dey Pharma, Basking Ridge, NJ) or EpiPen Jr between 2000 and 2006. A total of 6,776 (46%) refilled at least once. Twenty-five percent of the patients who were in the cohort for 5 years or more refilled multiple times, and 11% refilled consistently at all expected refill times. Infants through children 12 years of age were more likely to receive a refill dispensing (63%) compared with teenagers and adults (40%). The most common ICD-9 codes that were linked to the initial epinephrine dispensing were allergic disorder (37%), miscellaneous anaphylaxis/angioedema (23%), hymenoptera/insect bite or sting (14%), and specific or nonspecific food allergy (11%). A total of 79% of patients with a food-related ICD-9 code and 59% of patients with an insect sting-related ICD-9 code refilled epinephrine at least once. An opportunity exists to identify system-based as well as personal barriers in an ongoing effort to provide patients at risk with the tools and empowerment that could reduce their risk during life-threatening anaphylactic reactions. PMID- 20957461 TI - Towards an expansive hybrid psychology: integrating theories of the mediated mind. AB - This article develops an integrative theory of the mind by examining how the mind, understood as a set of skills and dispositions, depends upon four sources of mediators. Harre's hybrid psychology is taken as a meta-theoretical starting point, but is expanded significantly by including the four sources of mediators that are the brain, the body, social practices and technological artefacts. It is argued that the mind is normative in the sense that mental processes do not simply happen, but can be done more or less well, and thus are subject to normative appraisal. The expanded hybrid psychology is meant to assist in integrating theoretical perspectives and research interests that are often thought of as incompatible, among them neuroscience, phenomenology of the body, social practice theory and technology studies. A main point of the article is that these perspectives each are necessary for an integrative approach to the human mind. PMID- 20957462 TI - Kyphectomy in children with myelomeningocele. AB - BACKGROUND: Patients with myelomeningocele and rigid lumbar and thoracolumbar kyphosis face substantial functional difficulties with sitting and lying supine and are prone to skin breakdown over the gibbus and risk of infection. Kyphectomy, along with cordotomy and segmental spinal instrumentation down to the pelvis, is one alternative that can provide reliable correction of the deformity but also can maintain that correction over a period of time. QUESTIONS/PURPOSES: We determined the fusion rates, deformity correction and maintenance, and perioperative complications of kyphectomy with long segmental spinal instrumentation using the Warner and Fackler technique. METHODS: We retrospectively reviewed the charts and radiographs of 33 patients with myelomeningocele who had kyphectomy with segmental spinal instrumentation down to the pelvis between 1991 and 2006. The average age at surgery was 7.6 years (range, 3-19 years). Twenty-one patients had a minimum 2-year followup (average, 7.0 years; range, 2.4-15.7 years). RESULTS: The average preoperative kyphosis of 124 degrees (range, 75 degrees -210 degrees ) improved at last followup to 22 degrees (range, 3 degrees -55 degrees ) with an average correction of 81% (range, 59%-98%). We identified 17 postoperative complications. Wound and skin complications were most common; 11 secondary surgeries were performed in 10 patients. CONCLUSIONS: Surgery for myelomeningocele kyphosis is technically demanding and carries substantial risk. Kyphectomy and posterior spinal fusion and instrumentation with the Warner and Fackler technique allow correction and maintenance of sagittal alignment. PMID- 20957464 TI - Letter to the editor: Do "premium" joint implants add value?: analysis of high cost joint implants in a community registry. PMID- 20957465 TI - Orthopaedic case of the month: medial knee pain in a 69-year-old man. PMID- 20957466 TI - Early definitive spinal fusion in young children: what we have learned. AB - BACKGROUND: Early-onset scoliosis, when left untreated, leads to severe deformity. Until the last decade, treatment of progressive curves in young children often consisted of definitive spinal fusion. The recognition of thoracic insufficiency syndrome associated with definitive early fusion has led to the development of new surgical techniques developed to preserve spinal and thoracic growth in young patients with progressive scoliosis. QUESTIONS/PURPOSES: We asked: (1) Does early definitive fusion arrest progression of spinal deformity? To what extent does early definitive spinal fusion influence (2) pulmonary function and (3) thoracic growth? METHODS: A Medline search of the published literature on early-onset scoliosis, congenital scoliosis, and infantile scoliosis between 2008 and 2010 was performed on spinal fusion for early-onset scoliosis, focusing on studies reporting pulmonary function at followup. RESULTS: Spinal deformity is apparently not well controlled by early fusion since revision surgery has been required in 24% to 39% of patients who underwent presumed definitive fusion in early childhood. Restrictive pulmonary disease, defined as forced vital capacity less than 50% of normal, occurs in 43% to 64% of patients who undergo early fusion surgery with those children who have extensive thoracic fusions and whose fusions involve the proximal thoracic spine at highest risk. Thoracic growth after early surgery is an average of 50% of that seen in children with scoliosis who do not have early surgery. Diminished thoracic spinal height correlates with decreased forced vital capacity. CONCLUSIONS: The literature does not support routine definitive fusion of thoracic spinal deformity at an early age in children with scoliosis. PMID- 20957468 TI - [Primary hydatid cyst of the adrenal gland in a patient with situs inversus. A one-case report]. AB - Primary hydatid cyst of the adrenal gland remains an exceptional localization. The adrenal gland is an uncommon site even in our country in which echinococcal disease is endemic. We report the case of a 38-year-old woman who consulted for left back pain. The CT scan showed a cystic mass in the left retroperitoneal area with a calcified wall. The patient underwent surgery which confirmed a diagnosis of hydatid cyst of the left adrenal gland. The surgical treatment consisted on a total resection of the cyst, without rupture of the cystic wall and preserving the gland. The diagnosis was confirmed on macroscopic and histological examination of the resected piece. The postoperative course was uneventful. No recurrence had occurred after 36 months of follow-up. PMID- 20957467 TI - The attitude of oncology physicians and nurses to the acceptance of new drugs for gene therapy. AB - With the efficacy of gene therapy verified in phase III trials, cancer patients will consider whether to accept gene therapy sooner or later. The purpose of this study is to investigate the attitudes of oncology physicians and nurses regarding effective gene therapy. A questionnaire was administered to 368 oncology physicians and nurses. A total of 328 valid questionnaires were returned (response rate, 89.1%). Gene therapy was considered as very safe or safe by 256 (78.0%) participants. Regardless of the stage of cancer, participants who advised patients to enroll in clinical trials and considered gene therapy as safe tended to accept the effective gene therapy. Gene therapy is considered to be a safe treatment. Most participants are willing to accept effective and verified gene therapy on the assumption that they themselves suffer from cancers. PMID- 20957470 TI - Cleanup strategies and advantages in the determination of several therapeutic classes of pharmaceuticals in wastewater samples by SPE-LC-MS/MS. AB - This work describes the development and validation of an offline solid-phase extraction with simultaneous cleanup capability, followed by liquid chromatography-(electrospray ionisation)-ion trap mass spectrometry, enabling the concurrent determination of 23 pharmaceuticals of diverse chemical nature, among the most consumed in Portugal, in wastewater samples. Several cleanup strategies, exploiting the physical and chemical properties of the analytes vs. interferences, alongside with the use of internal standards, were assayed in order to minimise the influence of matrix components in the ionisation efficiency of target analytes. After testing all combinations of adsorbents (normal-phase, ion exchange and mixed composition) and elution solvents, the best results were achieved with the mixed-anion exchange Oasis MAX cartridges. They provided recovery rates generally higher than 60%. The precision of the method ranged from 2% to 18% and 4% to 19% (except for diclofenac (22%) and simvastatin (26%)) for intra- and inter-day analysis, respectively. Method detection limits varied between 1 and 20 ng L(-1), while method quantification limits were <85 ng L(-1) (both excluding ibuprofen). This analytical method was applied to gather preliminary results on influents and effluents of two wastewater treatment plants (WWTPs) located in the urban region of Porto (Portugal). Typically, paracetamol, hydrochlorothiazide, furosemide, naproxen, ibuprofen, diclofenac and bezafibrate were detected in concentrations ranging from 1 to 20 MUg L(-1), while gemfibrozil, simvastatin, ketoprofen, azithromycin, bisoprolol, lorazepam and paroxetine were quantified in levels below 1 MUg L(-1). These WWTPs were given particular attention since they discharge their effluents into the Douro river, where water is extracted for the production of drinking water. Some sampling spots in this river were also analysed. PMID- 20957469 TI - Multimodal approach to postoperative pain control in patients undergoing rotator cuff repair. AB - PURPOSE: This prospective study was undertaken to compare the effectiveness and safety of a multimodal pain control protocol with those of intravenous patient controlled analgesia in rotator cuff repair. METHODS: Seventy patients scheduled for rotator cuff repair were randomized to either a multimodal pain control group (group 1, 40 patients) or an intravenous patient-controlled analgesia group (group 2, 30 patients). We compared these two groups with respect to level of pain before surgery to the fifth postoperative day, duration of postoperative rehabilitation, consumption of additional analgesics, and adverse effects. RESULTS: Mean visual analogue scale scores immediately after surgery (day 0) and on postoperative days 1-5 were 6.9, 5.5, 4.3, 3.3, 3.0, and 2.6 in group 1 and 7.8, 5.9, 4.4, 4.7, 4.3, and 3.7 in group 2. Pain relief was significantly better in group 1 on days 0, 3, 4, and 5 (P = 0.026, 0.006, 0.010, and 0.009, respectively). Furthermore, functional recovery occurred earlier in group 1. No significant differences were observed between the two groups with respect to nausea, vomiting, urinary retention, and headache (n.s.), but group 1 was found to be significantly less likely to experience dizziness or urticaria (P = 0.007, 0.017, respectively). One other significant difference was observed: 1 patient (2.5%) in group 1 and 6 patients (20%) in group 2 discontinued regimen because of medication-related adverse effects (P = 0.016). CONCLUSION: The multimodal pain control protocol was found to offer more effective postoperative pain control with fewer adverse effects than intravenous patient-controlled analgesia. However, achieving adequate pain control within the first 48 h of surgery remains challenging, and thus, the developments of more effective and safer multimodal pain control protocols are required. PMID- 20957472 TI - Raman chemical mapping reveals site of action of HIV protease inhibitors in HPV16 E6 expressing cervical carcinoma cells. AB - It has been shown that the HIV protease inhibitors indinavir and lopinavir may have activity against the human papilloma virus (HPV) type 16 inhibiting HPV E6 mediated proteasomal degradation of p53 in cultured cervical carcinoma cells. However, their mode and site of action is unknown. HPV-negative C33A cervical carcinoma cells and the same cells stably transfected with E6 (C33AE6) were exposed to indinavir and lopinavir at concentrations of 1 mM and 30 MUM, respectively. The intracellular distribution of metabolites and metabolic changes induced by these treatments were investigated by Raman microspectroscopic imaging combined with the analysis of cell fractionation products by liquid chromatography-mass spectrometry (LC-MS). A uniform cellular distribution of proteins was found in drug-treated cells irrespective of cell type. Indinavir was observed to co-localise with nucleic acid in the nucleus, but only in E6 expressing cells. Principal components analysis (PCA) score maps generated on the full Raman hypercube and the corresponding PCA loadings plots revealed that the majority of metabolic variations influenced by the drug exposure within the cells were associated with changes in nucleic acids. Analysis of cell fractionation products by LC-MS confirmed that the level of indinavir in nuclear extracts was approximately eight-fold greater than in the cytoplasm. These data demonstrate that indinavir undergoes enhanced nuclear accumulation in E6-expressing cells, which suggests that this is the most likely site of action for this compound against HPV. PMID- 20957471 TI - A targeted mass spectrometry-based approach for the identification and characterization of proteins containing alpha-aminoadipic and gamma-glutamic semialdehyde residues. AB - The site-specific identification of alpha-aminoadipic semialdehyde (AAS) and gamma-glutamic semialdehyde (GGS) residues in proteins is reported. Semialdehydic protein modifications result from the metal-catalyzed oxidation of Lys or Arg and Pro residues, respectively. Most of the analytical methods for the analysis of protein carbonylation measure change to the global level of carbonylation and fail to provide details regarding protein identity, site, and chemical nature of the carbonylation. In this work, we used a targeted approach, which combines chemical labeling, enrichment, and tandem mass spectrometric analysis, for the site-specific identification of AAS and GGS sites in proteins. The approach is applied to in vitro oxidized glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and an untreated biological sample, namely cardiac mitochondrial proteins. The analysis of GAPDH resulted in the site-specific identification of two AAA and four GGS residues. Computational evaluation of the identified AAS and GGS sites in GAPDH indicated that these sites are located in flexible regions, show high solvent accessibility values, and are in proximity with possible metal ion binding sites. The targeted proteomic analysis of semialdehydic modifications in cardiac mitochondria yielded nine AAS modification sites which were unambiguously assigned to distinct lysine residues in the following proteins: ATP/ATP translocase isoforms 1 and 2, ubiquinol cytochrome-c reductase core protein 2, and ATP synthase alpha-subunit. PMID- 20957474 TI - Predictors of retrograde aortic arch obstruction after hybrid palliation of hypoplastic left heart syndrome. AB - A potential complication after hybrid stage 1 palliation for hypoplastic left heart syndrome (HLHS) is retrograde aortic arch obstruction (RAAO). This can lead to increased morbidity and unplanned surgical or interventional procedures in the interstage period. This study aimed to identify potential predictors of RAAO by analyzing initial echocardiograms and angiograms before hybrid stage 1 palliation. For this study, 96 patients who underwent hybrid stage 1 palliation between July 2002 and July 2009 were reviewed, 68 of which had standard HLHS and met the inclusion criteria. The initial echocardiogram, hybrid stage 1 angiograms, and follow-up echocardiograms were reviewed. Anatomic and hemodynamic measurements were obtained by both modalities, and comparisons were made between those who developed RAAO and those who did not. Of the 68 patients, 20 (29%) had RAAO. The mean aortic root size was smaller for the patients who had RAAO (3.6 vs 4.4 mm; p = 0.036). The angiographic angle between the aortic isthmus and the patent ductus arteriosus (PDA) was significantly larger in the RAAO group (86 degrees vs 63 degrees ; p = 0.008). The retrograde aortic arch velocities were higher in the RAAO group. Patients with RAAO have a smaller aortic root and higher retrograde velocities on initial echocardiogram. Patients with RAAO show a larger angle between the retrograde arch and PDA on angiogram. Because RAAO is an important potential complication after hybrid stage 1 palliation for HLHS, identification of predictors of RAAO may lead to improved care and outcome for patients with RAAO. PMID- 20957475 TI - Origin of an anomalous left coronary artery from a left hilar pulmonary artery. AB - Anomalous coronaries arising in nontruncal regions of the pulmonary artery are exceedingly rare. We report an autopsy case of an anomalous left coronary artery that arose from the distal pulmonary artery at the hilum of the left lung in an infant with complex congenital heart disease. To the best of our knowledge, this is the first such report. This previously unknown coronary malformation led to a fatal intraoperative complication during a pulmonary angioplasty procedure. PMID- 20957473 TI - Application of flow field-flow fractionation for the characterization of macromolecules of biological interest: a review. AB - An overview is given of the recent literature on (bio) analytical applications of flow field-flow fractionation (FlFFF). FlFFF is a liquid-phase separation technique that can separate macromolecules and particles according to size. The technique is increasingly used on a routine basis in a variety of application fields. In food analysis, FlFFF is applied to determine the molecular size distribution of starches and modified celluloses, or to study protein aggregation during food processing. In industrial analysis, it is applied for the characterization of polysaccharides that are used as thickeners and dispersing agents. In pharmaceutical and biomedical laboratories, FlFFF is used to monitor the refolding of recombinant proteins, to detect aggregates of antibodies, or to determine the size distribution of drug carrier particles. In environmental studies, FlFFF is used to characterize natural colloids in water streams, and especially to study trace metal distributions over colloidal particles. In this review, first a short discussion of the state of the art in instrumentation is given. Developments in the coupling of FlFFF to various detection modes are then highlighted. Finally, application studies are discussed and ordered according to the type of (bio) macromolecules or bioparticles that are fractionated. PMID- 20957476 TI - Newborn with persistent truncus arteriosus and interrupted aortic arch demonstrating reverse left subclavian artery flow. PMID- 20957477 TI - Cardiac troponin T in children with acute rheumatic carditis. AB - The existence of cardiac damage in active rheumatic carditis patients is unknown, especially in those without pericarditis. The aim of this study was to determine cardiac myocyte damage using cardiac troponin T (cTnT) measurements in active rheumatic carditis. The levels of creatine kinase MB isoenzyme (CK-MB), cTnT, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), cardiothoracic ratio (CTR), and fractional shortening (FS) were compared using Mann-Whitney U test between 28 patients with active rheumatic carditis and 32 controls (healthy children). Association of cTnT levels with ESR, CRP, and CTR was evaluated with Spearman correlation analysis. ESR, CRP, cTnT levels, and CTR were statistically higher in the patients than in the controls. There were no differences between the groups for CK-MB levels and FS. No relationships were found between cTnT levels and ESR, CRP, and CTR in the patient group. The results of the study suggest that when cTnT levels are within non-pathological range, there is no serious cardiac damage; however, statistically significant increases in cTnT levels may indicate minor damages in patients with active carditis due to acute rheumatic fever. PMID- 20957478 TI - Acute-phase reactants and a supplemental diagnostic aid for Kawasaki disease. AB - The diagnosis of acute Kawasaki disease (KD) is based on characteristic clinical signs and not on a specific diagnostic test. The authors performed a comprehensive evaluation of acute-phase reactants in KD to determine which of the acute-phase reactants would most accurately distinguish KD from other febrile illnesses. Blood was collected from 218 cases of febrile children with KD (64 cases); bacterial pneumonia (74 cases); hand, foot, and mouth disease (31 cases); and upper respiratory tract infection (49 cases) in acute-stage illness before any therapy. The demographics, body temperature, and laboratory markers including white blood cell count, red blood cell count, and levels of hemoglobin, platelets, C-reactive protein, haptoglobin, apolipoprotein A-I, and apolipoprotein B were evaluated. Using post hoc analysis, the platelet count (10(3)/MUl) and haptoglobin/apolipoprotein A-I ratio were significantly higher for the KD patients (404.64 +/- 161.68, P = 0.004; 4.74 +/- 2.73, P < 0.001) than for the other groups including patients with pneumonia (272.76 +/- 115.07, 2.03 +/- 1.88); hand, foot, and mouth disease (274 +/- 105.9, 2.24 +/- 1.19); and upper respiratory tract infection (282.06 +/- 107.72, 1.4 +/- 0.98). The best cutoff value of the haptoglobin/apolipoprotein A-I ratio obtained from receiver operating characteristics (ROC) curves for KD was 2 (area under the ROC curve, 0.88; 95% confidence interval, 0.801-0.955), with a sensitivity of 89.7% and a specificity of 85.6% for detecting KD. Our data indicate that the serum haptoglobin/apolipoprotein A-I ratio could be a useful supplemental laboratory marker for the acute phase of KD. PMID- 20957479 TI - Peak circulatory power as an indicator of clinical status in children after Fontan procedure. AB - Peak circulatory power (CircP), a product of peak exercise oxygen uptake (VO(2)) and peak mean or systolic arterial blood pressure, has proved to be a strong predictor of poor outcome in adults with congenital heart disease. This study sought to compare CircP with other cardiopulmonary exercise (CPX) test variables and to assess whether CircP is superior in categorizing patients into well functioning vs. poorly functioning at-risk groups in the pediatric population after a Fontan procedure. The CPX test reports of 50 patients were retrospectively reviewed after the Fontan procedure. The patients were divided into two groups. The well-functioning group included patients in New York Heart Association (NYHA) classes 1 and 2 (n = 36). The poorly functioning at-risk group included patients in NYHA classes 3 and 4 and those with significant indicators or outcomes of a poor prognosis (n = 14). The patients in the well-functioning group had significantly higher CircP values based on mean blood pressure (MBP) (P < 0.001), higher CircP values based on systolic blood pressure (SBP) (P < 0.001), and higher peak VO(2) (P = 0.004) than those in the poorly functioning at-risk group. At a cutoff value less than 2100.4 mmHg/mlO(2)/kg/min, CircP MBP had a sensitivity of 85% in categorizing children to the poorly functioning at-risk group. CircP correlated well with the clinical status of our patients. CircP and peak VO(2) did not differ significantly in ability to identify poorly functioning patients. Further prospective analysis is needed to assess whether CircP can serve as a prognostic marker for the pediatric population after Fontan procedure. PMID- 20957480 TI - UGT1A1*1/*28 and *1/*6 genotypes have no effects on the efficacy and toxicity of FOLFIRI in Japanese patients with advanced colorectal cancer. AB - PURPOSE: Differences in efficacy and toxicity between UDP-glucuronosyltransferase (UGT) 1A1*1/*1 and *1/*6 or *1/*28 genotypes remain unclear in Japanese patients. METHODS: Patients with advanced colorectal cancer who received irinotecan combined with 5-fluorouracil plus l-leucovorin (FOLFIRI) as first-line therapy were divided into two groups: those with UGT1A1*1/*1 genotype and those with UGT1A1*1/*6 or *1/*28 genotype. Efficacy and toxicity were compared between these groups retrospectively. RESULTS: Forty-two patients (24 *1/*1 and 18 *1/*6 or *1/*28) were evaluated. The response rate was 48% in *1/*1 group and 56% in *1/*6 or *1/*28 group (P = 0.847). Median progression-free survival was 8.6 months in *1/*1 group and 8.5 months in *1/*6 or *1/*28 group (P = 0.888). No hematologic or non-hematologic toxic effects were clearly related to UGT1A1*1/*6 or *1/*28 during the first cycle or throughout the entire course of chemotherapy. CONCLUSIONS: There were no significant differences in the efficacy or toxicity of FOLFIRI between patients with UGT1A1*1/*1 genotype and those with UGT1A1*1/*6 or *1/*28 genotype. Our results suggest that patients with the latter genotypes can receive FOLFIRI at the same dose of irinotecan as those with the UGT1A1*1/*1 genotype receive. PMID- 20957481 TI - Nilotinib in patients with GIST who failed imatinib and sunitinib: importance of prior surgery on drug bioavailability. AB - PURPOSE: To evaluate the efficacy of nilotinib in patients with advanced gastrointestinal stromal tumors (GISTs) resistant or intolerant to both imatinib and sunitinib and to explore the potential relationship between nilotinib pharmacokinetics and clinical outcomes. PATIENTS AND METHODS: We analyzed the efficacy, tolerability and pharmacokinetic parameters of nilotinib (400 mg twice daily) in 17 GIST patients with histories of prior gastrointestinal surgery. RESULTS: Median patient age was 59 years (range, 35-71 years), 14 of 17 patients (82.4%) were male, and mean body weight was 59.4 kg. Of the 17 patients, 2 (11.8%) had partial responses (PR), 10 (58.8%) had stable disease (SD), and 5 (29.4%) had progressive disease (PD), with a clinical benefit rate (CR + PR + SD) at 24 weeks of 47.0%. Median progression-free survival (PFS) and overall survival (OS) were 23.6 weeks (95% confidence interval [CI] 0.0-50.6 weeks) and 74.0 weeks (95% CI 27.4-120.6 weeks), respectively. Most observed adverse events were mild (grade 1, 41.2%; grade 2, 52.9%), with no grade 3/4 events. Pharmacokinetic parameters of nilotinib were as follows: C (max) of 1,754 +/- 970 MUg/L, T(1/2) of 13.4 +/- 8.94 h and AUC (0-12 h) of 14,190 +/- 6,853 h MUg/L. The AUC (0-12 h) of nilotinib was significantly lower in the 4 patients with prior major (total or subtotal) gastrectomy than in the other 13 patients (8,526 +/- 7,869 h MUg/L vs. 15,930 +/- 5,759 h MUg/L, P = 0.014). Of the 4 gastrectomized patients, two (50%) showed markedly decreased nilotinib exposure (AUC (0-12 h) of 1,914 and 3,194 h MUg/L) and rapid disease progression (PFS of 4.6 and 7.1 weeks). CONCLUSION: Nilotinib was active and safe in patients with advanced GIST resistant to both imatinib and sunitinib. Major gastrectomy decreased the bioavailability of nilotinib and, in some patients, lowered its clinical activity. PMID- 20957482 TI - Radiation dose of cardiac computed tomography - what has been achieved and what needs to be done. AB - This review highlights the recently introduced techniques by manufacturers and various research workers to reduce radiation dose in coronary CT. It discusses in detail the development of ECG-based tube current modulation, the application of low tube voltage protocols and prospective ECG-gating. It also briefly discusses two further methods of dose reduction, namely minimisation of the x-y anatomical coverage and adaptive statistical iterative reconstruction. PMID- 20957483 TI - [Structures of long-term care facilities: a study in nursing homes in Leipzig]. AB - BACKGROUND: In order to provide guidelines for the organization and design of nursing homes, it is important to evaluate current care facilities. The aim of the study was to describe the structures of nursing homes in the German city of Leipzig. MATERIALS AND METHODS: As part of a cross-sectional design, 47 nursing homes participated in a written survey. RESULTS: The majority of nursing homes focus on caring for residents diagnosed with dementia. Only a few special care units exist. A precise description of the structure of nursing homes, concepts and nursing methods, however, is rare. Established concepts exist in a small number of institutions. Approved service offers are largely available, but do not apply specifically to the large group of nursing home residents with dementia. CONCLUSION: The study showed not only the diversity of the stationary nursing homes in a large city, but also their resources and limitations. PMID- 20957484 TI - Impact of troponin I-autoantibodies in chronic dilated and ischemic cardiomyopathy. AB - The aim of this study was to investigate the prognostic value of circulating troponin I (TNI)-autoantibodies in plasma of patients with chronic heart failure. Sera of 390 heart failure patients were tested for the presence of anti-TNI antibodies by enzyme-linked immunosorbent assay (ELISA), including 249 (63.8% of total) patients with dilated cardiomyopathy (DCM) and 141 (36.2% of total) patients with ischemic cardiomyopathy (ICM). A total of 72 patients (18.5% of total) were female and 318 (81.5% of total) were male. Mean patient age was 54.6 +/- 11.3 years and mean follow-up time was 3.8 +/- 3.2 years. TNI-autoantibodies (titer of >=1:40) were detected in 73 out of 390 patients (18.7% of total). In TNI-autoantibody positive patients mean left ventricular ejection fraction (LVEF) was 27.6 +/- 5.8%, compared to 25.8 +/- 5.9% in TNI-autoantibody negative patients, P = 0.03. The combined end-point of death (n = 118, 30.3% of total) or heart transplantation (HTX) (n = 44, 11.3% of total) was reached in 162 patients (41.5% of total). Kaplan-Meier analysis demonstrated superior survival (combined end-point of death or HTX) in patients with DCM versus ICM (P = 0.0198) and TNI autoantibody positive patients versus TNI-autoantibody negative patients (P = 0.0348). Further subgroup analysis revealed a favorable outcome in TNI-positive patients with heart failure if the patients suffered from DCM (P = 0.0334), whereas TNI-autoantibody status in patients with ICM was not associated with survival (P = 0.8486). In subsequent multivariate Weibull-analysis, a positive TNI serostatus was associated with a significantly lower all-cause mortality in DCM patients (P = 0.0492). The presence of TNI-autoantibodies in plasma is associated with an improved survival in patients with chronic DCM, but not ICM. This might possibly indicate a prophylactic effect of TNI-autoantibodies in this subgroup of patients, encouraging further studies into possible protective effects of antibodies against certain cardiac target structures. PMID- 20957485 TI - "One-shot" CO2 versus Er:YAG laser stapedotomy: is the outcome the same? AB - To assess and compare the functional results obtained by means of multiple-shot Erbium: yttrium-aluminum-garnet (Er:YAG) laser to those obtained using "one-shot" CO(2) laser stapedotomy in patients affected by otosclerosis. A retrospective case review was performed. Of the total number of 123 patients (114 ears) who underwent primary small-fenestra stapedotomy from January 2006 to September 2008, seven patients who received multiple-shot laser CO(2) stapedotomy were excluded from the study. The remaining 116 patients (104 ears) were sorted, and "one-shot" CO(2) laser stapedotomy (group A) was performed in 35/104 and Er:YAG laser stapedotomy (group B) in 69/104. After surgery, air conduction-pure tone average (AC-PTA) and air-bone gap (ABG) improved significantly in both groups, whereas sensorineural hearing loss (SNHL) and bone conduction (BC)-PTA did not change in both the groups. In group A, the postoperative ABG was significantly better (12.63 vs. 14.86 dB). Moreover, after "one-shot" stapedotomy, the AC-PTA significantly improved in all tested frequencies. On the contrary, in group B the AC-PTA improved significantly only in two frequencies (0.5 and 1 kHz). Consistent with previous reports, our findings confirm that laser stapedotomy is a safe and effective surgery, regardless of the technique. Based on our functional results, the "one-shot" CO(2) laser technique seems to be associated with a significantly better postoperative ABG if compared to Er:YAG laser stapedotomy. PMID- 20957486 TI - Surgical versus percutaneous tracheostomy: an evidence-based approach. AB - The choice between surgical (ST) and percutaneous tracheostomy (PT) is not often based on evidence. The aim is to evaluate the quality of evidence in published articles comparing the two methods. A MEDLINE search was done. From 298 articles found, 37 fulfilled the inclusion criteria and 35 were further analyzed. No study was based on type I evidence, 13 (37%) represented type II, in 1 (3%) a clear-cut definition between type II or III was not possible and 21 (60%) represented type III or IV evidence. Taking into account the complication rate of the 13 type II evidence studies, 7 are in favor of PT and 3 in favor of ST. The majority of studies comparing PT with ST are of type III or IV level of evidence. Even if only type II studies are analyzed, outcomes are controversial. Any claims by clinicians in favor of a particular treatment are still debatable. PMID- 20957487 TI - The impacts of open-mouth breathing on upper airway space in obstructive sleep apnea: 3-D MDCT analysis. AB - Open-mouth breathing during sleep is a risk factor for obstructive sleep apnea (OSA) and is associated with increased disease severity and upper airway collapsibility. The aim of this study was to investigate the effect of open-mouth breathing on the upper airway space in patients with OSA using three-dimensional multi-detector computed tomography (3-D MDCT). The study design included a case control study with planned data collection. The study was performed at a tertiary medical center. 3-D MDCT analysis was conducted on 52 patients with OSA under two experimental conditions: mouth closed and mouth open. Under these conditions, we measured the minimal cross-sectional area of the retropalatal and retroglossal regions (mXSA-RP, mXSA-RG), as well as the upper airway length (UAL), defined as the vertical dimension from hard palate to hyoid. We also computed the volume of the upper airway space by 3-D reconstruction of both conditions. When the mouth was open, mXSA-RP and mXSA-RG significantly decreased and the UAL significantly increased, irrespective of the severity of OSA. However, between the closed- and open-mouth states, there was no significant change in upper airway volume at any severity of OSA. Results suggest that the more elongated and narrow upper airway during open-mouth breathing may aggravate the collapsibility of the upper airway and, thus, negatively affect OSA severity. PMID- 20957488 TI - Effects of tumour stage, comorbidity and therapy on survival of laryngeal cancer patients: a systematic review and a meta-analysis. AB - Laryngeal cancer is the second most common cancer of the respiratory tract with a relative 5-year survival over all tumour sites in the USA (61.6%; SEER 2009), which is much better than other head and neck cancers. The aim of this paper is to review and summarise data on the survival of laryngeal cancer patients. Literature search was conducted to identify articles in PubMed up to June 2009. Thirty studies with different study aims including sufficient information on survival of laryngeal cancer patients were identified. The 5-year overall survival ranged from 0 to 100%, depending on the T- and N-category, therapeutic approach and tumour location. The involvement of other factors such as genetics, nutrition and lifestyle habits remains uncertain. Our meta-analysis on a subgroup of published studies yielded an overall 5-year relative survival rate of 64.2% (95% confidence interval 63.7-64.7%). Different study aims and patient selection criteria prohibit general conclusions. However, this review may provide an actual picture of the complexity of factors influencing the survival of laryngeal cancer patients. PMID- 20957489 TI - Association of occupation with prevalent hypertension in an elderly East German population: an exploratory cross-sectional analysis. AB - PURPOSE: Hypertension is one of the most relevant risk factors for cardiovascular disease; however, little is known about differences in hypertension by occupation. The aim of this study was to explore the association between occupational group and prevalent hypertension. METHODS: Cross-sectional data of the CARLA study were used, a representative sample of an East German population aged 45-83. Job titles of the current or last held occupation of 967 men and 808 women were coded using the German classification of occupation. Hypertension was defined as blood pressure of >=140 mmHg (systolic), >=90 mmHg (diastolic) or use of antihypertensives. Sex-stratified, age-adjusted prevalence risk ratios (PR) with 95% confidence intervals (CI) were calculated for 31 occupational groups. RESULTS: Hypertension was prevalent in 79% of the population. In men, highest age adjusted prevalence ratios were observed in metal-processing workers, carpenters/painters, and electricians with PRs of 1.31 (CI 1.04-1.65), 1.28 (CI 1.00-1.64), and 1.21 (0.95-1.53), respectively, compared to office clerks. In women, highest PRs were found in technicians/forewomen, scrutinisers/storekeepers, and food-processing occupations with PR 1.28 (1.09 1.49), 1.23 (0.99-1.51), and 1.22 (1.01-1.48), respectively. Adjustment for education, smoking, body mass index, and current work hours did not fully explain occupational differences. Excluding currently non-working subjects lead to decreased PRs in men and to increased PR in women. CONCLUSIONS: Differences in the prevalences of hypertension by occupational group were only partly explained by conventional risk factors and may require workplace interventions targeted at high-risk occupations. Longitudinal data with large cohorts and work-related exposure assessment are needed to confirm a temporal relationship between occupation and incident hypertension. PMID- 20957490 TI - MTHFR C677T polymorphism and differential methylation status in gastric cancer: an association with Helicobacter pylori infection. AB - MTHFR C677T and Helicobacter pylori infection are believed to play critical roles in the DNA methylation process, an epigenetic feature frequently found in gastric cancer. The aim of this study was to verify the associations between the MTHFR C677T polymorphism and the methylation status of three gastric cancer-related genes. The influence of H. pylori strains was also assessed. DNA extracted from 71 gastric tumor samples was available for MTHFR C677T genotyping by PCR-RFLP, promoter methylation identification by MS-PCR and H. pylori detection and posterior subtyping (cagA and vacA genes) by PCR. In the distal tumors, a positive correlation was found between the methylation of CDKN2A and the allele T carriers (r=0.357; p=0.009). Considering the eldest patients (age >=60 years old), this correlation was even higher (r=0,417; p=0.014). H. pylori infection by highly pathogenic strains (cagA+/vacAs1m1) was also found correlated to promoter methylation of CDKN2A and the allele T carriers in distal tumors (r=0.484; p=0.026). No significant correlation was verified between MTHFR C677T genotype and promoter methylation status when we analyzed the general sample. DNA methylation in CDKN2A associated to the MTHFR 677T carrier is suggested to be a distal tumor characteristic, especially in those 60 years old or older, and it seems to depend on the infection by H. pylori cagA/vacAs1m1 strains. PMID- 20957491 TI - Paratesticular fibrous pseudotumor--an IgG4-related disorder? AB - Paratesticular fibrous pseudotumor (nodular periorchitis, inflammatory pseudotumor of the spermatic cord) is a rare, benign condition of unknown etiology characterized by solitary or multiple intrascrotal nodules composed of dense fibrous tissue with a variable, sometimes sparse inflammatory infiltrate. Based on certain similarities to other fibroinflammatory disorders characterized by infiltrates of IgG4-expressing plasma cells and recently subsumed under the heading of IgG4-mediated diseases, we investigated the plasma cell distribution and immunoglobulin isotypes in three cases of paratesticular fibrous and inflammatory pseudotumor. All three cases showed a high number of IgG4-positive plasma cells with an IgG4 to IgG ratio of 44-48%. This finding indicates that paratesticular fibrous pseudotumor might belong to the growing list of IgG4 related diseases, which by now includes such diverse entities as retroperitoneal fibrosis, sclerosing pancreatitis and cholangitis, Riedel's thyroiditis, or sclerosing sialadenitis. PMID- 20957494 TI - Atrophy in the parahippocampal gyrus as an early biomarker of Alzheimer's disease. AB - The main aim of the present study was to compare volume differences in the hippocampus and parahippocampal gyrus as biomarkers of Alzheimer's disease (AD). Based on the previous findings, we hypothesized that there would be significant volume differences between cases of healthy aging, amnestic mild cognitive impairment (aMCI), and mild AD. Furthermore, we hypothesized that there would be larger volume differences in the parahippocampal gyrus than in the hippocampus. In addition, we investigated differences between the anterior, middle, and posterior parts of both structures. We studied three groups of participants: 18 healthy participants without memory decline, 18 patients with aMCI, and 18 patients with mild AD. 3 T T1-weighted MRI scans were acquired and gray matter volumes of the anterior, middle, and posterior parts of both the hippocampus and parahippocampal gyrus were measured using a manual tracing approach. Volumes of both the hippocampus and parahippocampal gyrus were significantly different between the groups in the following order: healthy>aMCI>AD. Volume differences between the groups were relatively larger in the parahippocampal gyrus than in the hippocampus, in particular, when we compared healthy with aMCI. No substantial differences were found between the anterior, middle, and posterior parts of both structures. Our results suggest that parahippocampal volume discriminates better than hippocampal volume between cases of healthy aging, aMCI, and mild AD, in particular, in the early phase of the disease. The present results stress the importance of parahippocampal atrophy as an early biomarker of AD. PMID- 20957493 TI - Interaction of Snail and p38 mitogen-activated protein kinase results in shorter overall survival of ovarian cancer patients. AB - Epithelial ovarian cancer is a highly metastatic disease and the leading cause of death among cancer of the female genital tract. Abnormal epidermal growth factor receptor (EGFR) signalling has been shown to be involved in epithelial mesenchymal transition (EMT), an early step during metastasis. Additionally, over expression of the E-cadherin repressor Snail, a key regulator of EMT, has previously been found to be associated with unfavourable prognostic features. Thus, the aim of our study was to elucidate the role of EGFR-dependent signalling pathways for Snail expression in ovarian cancer. For this purpose, we analysed 25 formalin-fixed and paraffin-embedded (FFPE) primary tumours and their corresponding metastases for the expression of 25 signalling pathway molecules by reverse phase protein arrays. We found a significant correlation of Snail with EGFR((Tyr1086)) and p38 MAPK((Thr180/Tyr182)) in primary ovarian carcinoma and with EGFR((Tyr1086)) in their corresponding metastasis. Additionally, we showed that high expression levels of Snail in primary tumours combined with high expression levels of the phosphorylated p38 MAPK((Thr180/Tyr182)) in metastasis lead to an increased risk for death in ovarian carcinoma patients. Thus, for future combinatorial cancer therapy, drug combinations that best target the deregulated protein network in each individual patient should be selected. PMID- 20957495 TI - Localization of an endocannabinoid system in the hypophysial pars tuberalis and pars distalis of man. AB - The hypophysial pars tuberalis (PT) acts as an important interface between neuroendocrine brain centers (hypothalamus, pineal organ) and the pars distalis (PD) of the hypophysis. Recently, we have identified an endocannabinoid system in the PT of hamsters and provided evidence that 2-arachidonoylglycerol is a messenger molecule that appears to play an essential role in seasonal reproduction and prolactin release by acting on the cannabinoid receptors in the PD. We now demonstrate the enzymes involved in endocannabinoid synthesis and degradation, namely sn-1-selective diacylglycerol lipase alpha, N acylphosphatidylethanolamine-specific phospholipase D, and monoacylglycerol lipase, in the PT of man by means of immunohistochemistry. High-performance liquid chromatography coupled with tandem mass spectrometry revealed 2 arachidonoylglycerol and other endocannabinoids in the human PT. Furthermore, we detected the expression of the cannabinoid receptor 1 (CB1), a primary receptor for endocannabinoids, in the PD. Double-immunofluorescence staining for CB1 and various hypophysial hormones or S-100, a marker for folliculostellate (FS) cells, revealed that CB1 immunoreactivity was mainly localized to corticotrophs and FS cells. A limited number of lactotrophs and somatotrophs also showed CB1 immunoreactivity, which was however absent from gonadotrophs and thyrotrophs. Our data thus indicate that the human PT comprises an endocannabinoid system, and that corticotrophs and FS-cells are the main target cells for endocannabinoids. The functional significance of this newly discovered pathway remains to be elucidated in man; it might be related to the control of stress responses and/or reflect a remnant seasonal control of hypophysial hormonal secretion. PMID- 20957496 TI - Cellular and subcellular localization of aquaporins 1, 3, 8, and 9 in amniotic membranes during pregnancy in mice. AB - The amniotic membrane encloses the amniotic fluid and plays roles in the regulation of amniotic fluid flux through the intramembranous pathway during pregnancy. Aquaporins (AQPs) 1, 3, 8, and 9 are expressed in amniotic membranes. AQPs are water channel proteins that facilitate the rapid flux of water or small molecules across the plasma membrane. Recently, additional roles of AQPs in facilitating cell migration, proliferation, and apoptosis have been suggested, with AQPs being distributed in the appropriate subcellular regions for their functions. The cellular and subcellular distributions of AQPs in the amniotic membrane however remain unclear. We have examined the cellular and subcellular localization of AQPs in amniotic membranes during pregnancy in mice. After embryonic day 12 (E12), AQP1 was distributed in the plasma membrane of finely branched cell processes in the amniotic fibroblasts. AQP3 was present in both epithelial cells and fibroblasts between E10 and E12. The distribution of AQP3 in the epithelial cells dynamically changed as follows: at E14 in the lateral membrane and apical junction; at E16 in the lateral membrane alone; at E17 in the lateral membrane and cytoplasm. AQP8 was expressed in the epithelial cells and complementarily localized in the apical junction and the lateral membrane. AQP9 was detected only in the apoptotic cells of the epithelium. These cellular and subcellular localizations of amniotic AQPs indicate that each AQP plays distinct functional roles, such as in water and urea transport, cell migration, cell proliferation, and apoptosis, for amniotic fluid homeostasis or tissue remodeling of amniotic membranes. PMID- 20957497 TI - Hepatic progenitor cells. AB - Liver diseases are associated with a marked reduction in the viable mass of hepatocytes. The most severe cases of liver disease (liver failure) are treated by orthotopic liver transplantation. One alternative to whole organ transplantation for patients with hepatic failure (and hereditary liver disease) is hepatocyte transplantation. However, there is a serious limitation to the treatment of liver diseases either by whole organ or hepatocyte transplantation, and that is the shortage of organ donors. Therefore, to overcome the problem of organ shortage, additional sources of hepatocytes must be found. Alternative sources of cells for transplantation have been proposed including embryonic stem cells, immortalised liver cells and differentiated cells. One other source of cells for transplantation found in the adult liver is the progeny of stem cells. These cells are termed hepatic progenitor cells (HPCs). The therapeutic potential of HPCs lies in their ability to proliferate and differentiate into hepatocytes and cholangiocytes. However, using HPCs as a cell therapy cannot be exploited fully until the mechanisms governing hepatocyte differentiation are elucidated. Here, we discuss the fundamental cellular and molecular elements required for HPC differentiation to hepatocytes. PMID- 20957498 TI - Proton pump inhibitor versus prokinetic therapy in patients with functional dyspepsia: is therapeutic response predicted by Rome III subgroups? AB - BACKGROUND: The comparative effectiveness of proton pump inhibitor versus prokinetic therapy in relieving the symptoms of patients with functional dyspepsia remains unknown. Whether the Rome III subgroups predict therapeutic response has not been investigated. METHODS: This was an open-label, parallel randomized controlled trial. A total of 329 adult outpatients fulfilling the Rome III criteria for functional dyspepsia were randomly allocated to receive either lansoprazole 30 mg once daily (n = 166) or mosapride 5 mg thrice daily (n = 163) for 2 weeks. Enrolled patients were evaluated with the validated Hong Kong Index questionnaire for symptom severity at baseline and at the end of the trial. The primary outcome was symptom relief as defined by the Hong Kong Index, and the secondary outcome was decrease of symptom scores. Post-hoc multivariate logistic regression analysis was conducted to identify independent predictors for therapeutic response. RESULTS: After 2-week therapy, 50.6% (84/166) and 47.85% (78/163) of the patients treated with lansoprazole and mosapride, respectively, achieved significant symptom relief (odds ratio 1.12, 95% confidence interval 0.72-1.72, p = 0.62). Differences in decreases of symptom scores between lansoprazole and mosapride receivers were also insignificant (-0.08, 95% confidence interval -1.25 to 1.09, p = 0.89). Therapeutic responses to either pharmacotherapy did not differ in the subgroup of patients fulfilling the criteria for epigastric pain syndrome (n = 256) or in those fulfilling the criteria for postprandial distress syndrome (n = 161). Multivariate logistic regression confirmed that the treatment allocation and Rome III subgroup were unrelated to treatment outcome. CONCLUSIONS: The effectiveness of proton pump inhibitor therapy and that of prokinetic therapy in functional dyspepsia are not different, and cannot be predicted by Rome III subgroups (ClinicalTrials.gov number, NCT00663897). PMID- 20957499 TI - Genetic background of autoimmune hepatitis in Japan. AB - Autoimmune hepatitis (AIH) is an organ-specific autoimmune disease characterized by chronic inflammation of the liver. Several studies from ethnically different countries have clarified that the genetic predisposition to type 1 AIH is linked mainly to human leukocyte antigen (HLA)-class II genes. Recently, molecular analysis using polymerase chain reaction (PCR)-based DNA typing has revealed that susceptibility to type 1 AIH is primarily associated with the HLA class II DRB1 locus, which encodes a polymorphic beta chain of the HLA-DR antigen. However, additional susceptibility genes (either HLA or non-HLA) and/or environmental factors may also contribute to the development of type 1 AIH; in Japanese type 1 AIH patients, although the most influential gene in disease susceptibility is HLA DRB1*04:05, several other genes have been identified as being involved in AIH pathogenesis or resistance and are the currently the focus of single nucleotide polymorphism analysis. PMID- 20957500 TI - The cnidarian nematocyst: a miniature extracellular matrix within a secretory vesicle. AB - Nematocysts are the taxon-defining features of all cnidarians including jellyfish, sea anemones, and corals. They are highly sophisticated organelles used for the capture of prey and defense. The nematocyst capsule is produced within a giant post-Golgi vesicle, which is continuously fed by proteins from the secretory pathway. Mature nematocysts consist of a hollow capsule body in which a long tubule is coiled up that, upon discharge, is expelled in a harpoon-like fashion. This is accompanied by the release of a toxin cocktail stored in the capsule matrix. Nematocyst discharge, which is one of the fastest processes in biology, is driven by an extreme osmotic pressure of about 150 bar. The molecular analysis of the nematocyst has from the beginning indicated a collagenous nature of the capsule structure. In particular, a large family of unusual minicollagens has been demonstrated to form the highly resistant scaffold of the capsule. Recent findings on the molecular composition of Hydra nematocysts have confirmed the notion of a specialized extracellular matrix, which is assembled during an intracellular secretion process to form the most complex predatory apparatus at the cellular level. PMID- 20957502 TI - A new scheme to calculate isotope effects. AB - We present a new scheme to calculate isotope effects. Only selected frequencies at the target level of theory are calculated. The frequencies are selected by an analysis of the Hessian from a lower level of theory. We obtain accurate isotope effects without calculating the full Hessian at the target level of theory. The calculated frequencies are very accurate. The scheme converges to the correct isotope effect. PMID- 20957501 TI - Methyl jasmonate counteracts boron toxicity by preventing oxidative stress and regulating antioxidant enzyme activities and artemisinin biosynthesis in Artemisia annua L. AB - Boron is an essential plant micronutrient, but it is phytotoxic if present in excessive amounts in soil for certain plants such as Artemisia annua L. that contains artemisinin (an important antimalarial drug) in its areal parts. Artemisinin is a sesquiterpene lactone with an endoperoxide bridge. It is quite expensive compound because the only commercial source available is A. annua and the compound present in the plant is in very low concentration. Since A. annua is a major source of the antimalarial drug and B stress is a deadly threat to its cultivation, the present research was conducted to determine whether the exogenous application of methyl jasmonate (MeJA) could combat the ill effects of excessive B present in the soil. According to the results obtained, the B toxicity induced oxidative stress and reduced the stem height as well as fresh and dry masses of the plant remarkably. The excessive amounts of soil B also lowered the net photosynthetic rate, stomatal conductance, internal CO(2) concentration and total chlorophyll content in the leaves. In contrast, the foliar application of MeJA enhanced the growth and photosynthetic efficiency both in the stressed and non-stressed plants. The excessive B levels also increased the activities of antioxidant enzymes, such as catalase, peroxidase and superoxide dismutase. Endogenous H(2)O(2) and O(2)(-) levels were also high in the stressed plants. However, the MeJA application to the stressed plants reduced the amount of lipid peroxidation and stimulated the synthesis of antioxidant enzymes, enhancing the content and yield of artemisinin as well. Thus, it was concluded that MeJA might be utilized in mitigating the B toxicity and improving the content and yield of artemisinin in A. annua plant. PMID- 20957503 TI - The mechanism of methanol decomposition by CuO. A theoretical study based on the reaction force and reaction electronic flux analysis. AB - A theoretical study of methanol decomposition using a model representing the initial step of the reaction CH3OH + CuO -> CH2O + H2O + Cu is presented. Theoretical calculations using B3LYP/6-31 G along with Lanl2DZ pseudopotentials on metallic centers were performed and the results discussed within the framework of the reaction force analysis. It has been found that the reaction takes place following a stepwise mechanism: first, copper reduction (Cu+2 -> Cu+) accompanies the oxygen transposition and then a second reduction takes place (Cu+ -> Cu0) together with a proton transfer that produce formaldehyde and release a water molecule. PMID- 20957504 TI - Hypoxic tissues are associated with microvessel density following brain ischemia reperfusion. AB - Hypoxic tissue has been observed in the surrounding areas of the ischemic core following cerebral infarction. The underlying mechanisms for this potentially reversible ischemic region remain to be determined. In this study, we generated permanent brain ischemia (PI) and reperfusion after inducing ischemia for 1.5 h (ischemia-reperfusion or IR) in a rat model of middle cerebral artery occlusion. Using immunofluorescence, we observed hypoxic tissue in ischemic brains and assessed microvessel density in and surrounding the hypoxic tissue. We found that the hypoxic tissues were observed at 1 and 3 days in PI rats and at 1, 3, 7, and 14 days in IR rats. The hypoxic tissue gradually decreased over time. The microvessel density increased in a time-dependent manner in focal brain ischemic tissue in PI and IR rats. Furthermore, IR induced a significant increase in microvessel density when compared with PI rats (P < 0.05). Microvessel density surrounding hypoxic tissue was significantly higher when compared with within the hypoxic tissue (P < 0.05). These data demonstrate that hypoxic tissue may exist for a long period (14 days) following brain IR and indicate that hypoxic tissue usually existed with low microvessel density. Furthermore, the duration of hypoxic tissue was partially dependent on the degree of microvessel proliferation. PMID- 20957505 TI - Prescription of lipophilic statins to Alzheimer's disease patients: some controversies to consider. AB - Alzheimer's disease (AD) is the most common disorder causing cognitive decline in old age. It is a progressive and irreversible neuropathology with a diagnosis often missed or delayed. Cholesterol represents an important determinant of the physical state of biological membranes and in AD brains, specific changes in its membrane-ordering and Raft-organizing effects take place. A recent publication shows downregulation of Seladin-1 (selective Alzheimer's disease indicator, also called DHCR24), which catalyzes the last step of cholesterol biosynthesis in affected neurons in AD. Postmortem analysis of AD brains revealed a loss in membrane cholesterol content and this finding makes the therapeutical use of statins (especially the lipophilic ones) quite a lot controversial. Some clinical studies suggest that risk of Alzheimer's disease is substantially reduced in users of statins; however, because these studies are not randomized trials, they provide insufficient evidence to recommend statin family therapy. PMID- 20957506 TI - Concurrent development of the head and pinnae and the acoustical cues to sound location in a precocious species, the chinchilla (Chinchilla lanigera). AB - Sounds are filtered in a spatial- and frequency-dependent manner by the head and pinna giving rise to the acoustical cues to sound source location. These spectral and temporal transformations are dependent on the physical dimensions of the head and pinna. Therefore, the magnitudes of binaural sound location cues-the interaural time (ITD) and level (ILD) differences-are hypothesized to systematically increase while the lower frequency limit of substantial ILD production is expected to decrease due to the increase in head and pinna size during development. The frequency ranges of the monaural spectral notch cues to source elevation are also expected to decrease. This hypothesis was tested here by measuring directional transfer functions (DTFs), the directional components of head-related transfer functions, and the linear dimensions of the head and pinnae for chinchillas from birth through adulthood. Dimensions of the head and pinna increased by factors of 1.8 and 2.42, respectively, reaching adult values by ~6 weeks. From the DTFs, the ITDs, ILDs, and spectral shape cues were computed. Maximum ITDs increased by a factor of 1.75, from ~160 MUs at birth (P0-1, first postnatal day) to 280 MUs in adults. ILDs depended on source location and frequency exhibiting a shift in the frequency range of substantial ILD (>10 dB) from higher to lower frequencies with increasing head and pinnae size. Similar trends were observed for the spectral notch frequencies which ranged from 14.7 33.4 kHz at P0-1 to 5.3-19.1 kHz in adults. The development of the spectral notch cues, the spatial- and frequency-dependent distributions of DTF amplitude gain, acoustic directionality, maximum gain, and the acoustic axis were systematically related to the dimensions of the head and pinnae. The dimension of the head and pinnae in the chinchilla as well as the acoustical properties associated with them are mature by ~6 weeks. PMID- 20957507 TI - Using the cochlear microphonic as a tool to evaluate cochlear function in mouse models of hearing. AB - The cochlear microphonic (CM) can be a useful analytical tool, but many investigators may not be fully familiar with its unique properties to interpret it accurately in mouse models of hearing. The purpose of this report is to develop a model for generation of the CM in wild-type (WT) and prestin knockout mice. Data and modeling results indicate that in the majority of cases, the CM is a passive response, and in the absence of outer hair cell (OHC) damage, mice lacking amplification are expected to generate WT levels of CM for inputs less than approximately 30 kHz. Hence, this cochlear potential is not a useful metric to estimate changes in amplifier gain. This modeling analysis may explain much of the paradoxical data in the literature. For example, various manipulations, including the application of salicylate and activation of the crossed olivocochlear bundle, reduce the compound action potential but increase or do not change the CM. Based on this current evaluation, CM measurements are consistent with early descriptions where this AC cochlear potential is dominated by basal OHCs, when recorded at the round window. PMID- 20957508 TI - Nitric oxide stimulates human neural progenitor cell migration via cGMP-mediated signal transduction. AB - Neuronal migration is one of the most critical processes during early brain development. The gaseous messenger nitric oxide (NO) has been shown to modulate neuronal and glial migration in various experimental models. Here, we analyze a potential role for NO signaling in the migration of fetal human neural progenitor cells. Cells migrate out of cultured neurospheres and differentiate into both neuronal and glial cells. The neurosphere cultures express neuronal nitric oxide synthase and soluble guanylyl cyclase that produces cGMP upon activation with NO. By employing small bioactive enzyme activators and inhibitors in both gain and loss of function experiments, we show NO/cGMP signaling as a positive regulator of migration in neurosphere cultures of early developing human brain cells. Since NO signaling regulates cell movements from developing insects to mammalian nervous systems, this transduction pathway may have evolutionary conserved functions. PMID- 20957509 TI - Cooperative interactions between odorant-binding proteins of Anopheles gambiae. AB - To understand olfactory discrimination in Anopheles gambiae, we made six purified recombinant OBPs and investigated their ligand-binding properties. All OBPs were expressed in bacteria with additional production of OBP47 in the yeast Kluveromyces lactis. Ligand-binding experiments, performed with a diverse set of organic compounds, revealed marked differences between the OBPs. Using the fluorescent probe N-phenyl-1-naphthylamine, we also measured the binding curves for binary mixtures of OBPs and obtained, in some cases, unexpected behaviour, which could only be explained by the OBPs forming heterodimers with binding characteristics different from those of the component proteins. This shows that OBPs in mosquitoes can form complexes with novel ligand specificities, thus amplifying the repertoire of OBPs and the number of semiochemicals that can be discriminated. Confirmation of the likely role of heterodimers was demonstrated by in situ hybridisation, suggesting that OBP1 and OBP4 are co-expressed in some antennal sensilla of A. gambiae. PMID- 20957510 TI - An ordered EST catalogue and gene expression profiles of cassava (Manihot esculenta) at key growth stages. AB - A cDNA library was constructed from the root tissues of cassava variety Huanan 124 at the root bulking stage. A total of 9,600 cDNA clones from the library were sequenced with single-pass from the 5'-terminus to establish a catalogue of expressed sequence tags (ESTs). Assembly of the resulting EST sequences resulted in 2,878 putative unigenes. Blastn analysis showed that 62.6% of the unigenes matched with known cassava ESTs and the rest had no 'hits' against the cassava database in the integrative PlantGDB database. Blastx analysis showed that 1,715 (59.59%) of the unigenes matched with one or more GenBank protein entries and 1,163 (40.41%) had no 'hits'. A cDNA microarray with 2,878 unigenes was developed and used to analyze gene expression profiling of Huanan 124 at key growth stages including seedling, formation of root system, root bulking, and starch maturity. Array data analysis revealed that (1) the higher ratio of up-regulated ribosome related genes was accompanied by a high ratio of up-regulated ubiquitin, proteasome-related and protease genes in cassava roots; (2) starch formation and degradation simultaneously occur at the early stages of root development but starch degradation is declined partially due to decrease in UDP-glucose dehydrogenase activity with root maturity; (3) starch may also be synthesized in situ in roots; (4) starch synthesis, translocation, and accumulation are also associated probably with signaling pathways that parallel Wnt, LAM, TCS and ErbB signaling pathways in animals; (5) constitutive expression of stress-responsive genes may be due to the adaptation of cassava to harsh environments during long term evolution. PMID- 20957511 TI - Thermography based breast cancer detection using texture features and Support Vector Machine. AB - Breast cancer is a leading cause of death nowadays in women throughout the world. In developed countries, it is the most common type of cancer in women, and it is the second or third most common malignancy in developing countries. The cancer incidence is gradually increasing and remains a significant public health concern. The limitations of mammography as a screening and diagnostic modality, especially in young women with dense breasts, necessitated the development of novel and more effective strategies with high sensitivity and specificity. Thermal imaging (thermography) is a noninvasive imaging procedure used to record the thermal patterns using Infrared (IR) camera. The aim of this study is to evaluate the feasibility of using thermal imaging as a potential tool for detecting breast cancer. In this work, we have used 50 IR breast images (25 normal and 25 cancerous) collected from Singapore General Hospital, Singapore. Texture features were extracted from co-occurrence matrix and run length matrix. Subsequently, these features were fed to the Support Vector Machine (SVM) classifier for automatic classification of normal and malignant breast conditions. Our proposed system gave an accuracy of 88.10%, sensitivity and specificity of 85.71% and 90.48% respectively. PMID- 20957512 TI - Antenatal depressive symptomatology, family conflict and social support among Chengdu Chinese women. AB - To investigate the association between demo-socio-economic status, obstetric variables, family conflict, social support and antenatal depressive symptoms among 1,609 Chinese women from four regional public hospitals during their second trimester of pregnancy in Chengdu. The vulnerable factors of depressive symptoms were explored in terms of their demo-socio-economic, obstetric, and Chinese family relational aspects, as well as in terms of social support. The women were identified as having depressive symptoms using the Edinburgh Postnatal Depression Scale. Marital conflict and parent-in-law conflict were assessed using the Dyadic Adjustment Scale and the Stryker Adjustment Checklist, respectively. The Interpersonal Support Evaluation List was used to measure the functional aspects of the perceived availability of social support. The prevalence rates of antenatal mild to severe and severe depressive symptoms were 35.9 and 7.3%, respectively. The logistic regression analysis revealed that participants who had been married for a shorter time, had a single source of financial support, a poor marital and mother-in-law relationship, and who lacked social support were more likely to have mild to severe depressive symptoms (P<0.05). Participants who were younger, who had lived in Chengdu for a shorter period of time, had a shorter duration of marriage, solo financial support, poor marital relationship, and poor social support were more likely to have severe depressive symptoms (P<0.05). The findings provide important information for prenatal screening, public health and social policies to help in the reduction of antenatal depressive symptoms among the Chengdu population. PMID- 20957513 TI - Association between health beliefs and health behavior in early pregnancy. AB - Folate-supplementation significantly reduces the risk of neural tube defects. The aim of this research was to reveal associations between health beliefs and folate -supplementation as well as other elements of health behavior among Hungarian women early in their pregnancy. Three-hundred and seven women in early pregnancy completed the second part of Health and Illness Scale. Factor structure of health beliefs was established and associations of factors with pregnancy planning, folate-intake, vitamin-intake, smoking-habits and alcohol-consumption were tested. A six factor health model was formulated; the factor named 'mental capacities and abilities' was associated with greater chance on folate-intake, vitamin-intake and prepared pregnancy, as well as a reduced chance of smoking. The factors 'destiny', 'measures aiming at prevention', and 'relatives and acquaintances' related to lower chance on folate-intake. The health belief factor representing Internal Health Locus of Control was associated with more than one component of healthy behavior, while factors of external dimensions (Powerful Others Health Locus of Control and Chance Health Locus of Control) were predictive on unhealthy behavioral tendencies. New approaches aiming to shift one's health beliefs and health locus of control from external causes to internal dimensions are needed in order to reach greater openness towards health-improving interventions. PMID- 20957514 TI - First steps for mommy and me: a pilot intervention to improve nutrition and physical activity behaviors of postpartum mothers and their infants. AB - To assess the feasibility of a pediatric primary care based intervention to promote healthful behaviors among 0-6 month old infants and their mothers. We enrolled two intervention practices (60 mother-infant pairs) and one usual care control practice (24 pairs) in a non-randomized controlled trial. We completed visits and interviews with 80 (95%) pairs at birth and 6 months. The intervention included (1) brief focused negotiation by pediatricians, (2) motivational counseling by a health educator, and (3) group parenting workshops. We evaluated the intervention effects on infant feeding, sleep duration, TV viewing, and mothers' responsiveness to satiety cues. Maternal behavioral targets included postpartum diet, physical activity, TV and sleep. At 6 months, fewer intervention than control infants had been introduced to solid foods (57% vs. 82%; P=0.04), and intervention infants viewed less TV (mean 1.2 vs. 1.5 h/d; P=0.07). Compared to control infants, intervention infants had larger increases in their nocturnal sleep duration from baseline to follow up (mean increase 1.9 vs. 1.3 h/d; P=0.05); larger reductions in settling time (mean reduction -0.70 vs. -0.10 h/d; P=0.02); and larger reductions in hours/day of nighttime wakefulness (mean reduction -2.9 vs. -1.5 h/d; P=0.08). There were no differences in breastfeeding, response to satiety cues, or maternal health behaviors. A program of brief focused negotiation by pediatricians, individual coaching by health educators using motivational interviewing, and group parenting workshops tended to improve infant feeding, sleep and media exposure, but had less impact on mothers' own health-related behaviors. PMID- 20957515 TI - Parental marital discord and treatment response in depressed adolescents. AB - Evidence suggests that parental marital discord contributes to the development of internalizing and externalizing symptoms in children and adolescents. Few studies, however, have examined the association between parental marital discord and youth's response to treatment. The present study examined the impact of interparental discord on treatment response in a randomized control trial of adolescents with major depression enrolled in the Treatment for Adolescents with Depression Study (TADS). Participants were 260 adolescents from two-parent households randomly assigned to one of four treatment groups: fluoxetine (FLX), cognitive behavior therapy (CBT), their combination (COMB), or placebo (PBO). Logistic regressions revealed that parental marital discord interacted with youth gender and co-morbid oppositionality symptoms to predict group differences in treatment response. PMID- 20957516 TI - Aerosol size distributions in urban Jinan: seasonal characteristics and variations between weekdays and weekends in a heavily polluted atmosphere. AB - Aerosol size distributions, trace gas, and PM(2.5) concentrations have been measured in urban Jinan, China, over 6 months in 2007 and 2008, covering spring, summer, fall, and winter time periods. Number concentrations of particles (10 2,500 nm) were 16,200, 13,900, 11,200, and 21,600 cm( -3) in spring, summer, fall, and winter, respectively. Compared with other urban studies, Jinan has higher number concentrations of accumulation-mode particles (100-500 nm) and particles (10-2,500 nm), but lower concentrations of ultrafine particles (10-100 nm). The number, surface and volume concentrations, and size distributions of particles showed obvious seasonal variation and are also influenced by traffic emissions. Through correlation analysis, traffic emissions are proposed to be a more important contributor to Atkien-mode and accumulation-mode particles than coal firing. Around midday, the presence of nanoparticles and new particle formation is limited to pre-existing particles from traffic emissions and the mass transport of particles from suburban and rural areas. Compared with other studies in urban areas of Europe and the USA, the variation of particle number concentration and related gas concentration in Jinan between weekdays and weekends is smaller and the reasons has been deduced. PMID- 20957517 TI - Assessment of enrichment factors and grain size influence on the metal distribution in riverbed sediments (Anllons River, NW Spain). AB - The metals distribution in the bed sediments of the Anllons River was studied, with special emphasis on the evaluation of the metal distribution as a function of the granulometric fraction chosen for the analysis. Statistical significant differences between the distribution of K, Ca, Cr, Mn, As, Rb, Sr and Nb in the bulk (<2 mm) and fine fraction (<63 MUm) were not found. Fe, Ni, Cu, Ga, Zr, Zn and Pb commonly appear in higher concentrations in the fine fraction, whereas Ti appears in higher concentrations in the bulk fraction. In general, it was observed that contamination phenomena tend to equalise the concentrations of both fractions, and this was mainly explained as the result of two processes. First, the formation of coatings over sands and, second, the formation of large aggregates (pseudo-sands) at sites located over basic rocks, whose chemical behaviour is closer to that of clays and could be responsible for significant adsorption processes. Normalisation techniques to evaluate contamination were applied by testing Nb, Sr, Rb or Ga as normaliser elements and by using crustal or shale average values for background concentrations. The most satisfactory result was obtained when using shale average values and Ga as the normaliser element. Arsenic was identified as the main contaminant of the basin, exceeding in all cases the low-effect reference values proposed by sediment quality guidelines and in two cases the medium-effect reference values. These sites were identified by multivariate techniques, which allow differentiating site 10 as affected by anthropogenic inputs related to past mining activities. PMID- 20957518 TI - Myocardial scar extent evaluated by cardiac magnetic resonance imaging in ICD patients: relationship to spontaneous VT during long-term follow-up. AB - Patients with ischemic cardiomyopathy have an increased risk for ventricular arrhythmia, since myocardial infarction can be the substrate for re-entrant arrhythmias. Contrast-enhanced cardiac magnetic resonance imaging (CMR) has proven to reliably quantify myocardial infarction. Aim of our study was to evaluate correlations between functional and contrast-enhanced CMR findings and spontaneous ventricular tachy-arrhythmias in patients with ischemic cardiomyopathy who underwent implantable cardioverter-defibrillator (ICD) therapy. Forty-one patients with ischemic cardiomyopathy and indication for ICD therapy underwent cine and late gadolinium enhancement CMR for quantification of left ventricular volumes, function and scar tissue before subsequent implantation of ICD device. During a follow-up period of 1184 +/- 442 days 68 monomorphic and 14 polymorphic types of ventricular tachycardia (VT) could be observed in 12 patients. Patients with monomorphic VT had larger scar volumes (25.3 +/- 11.3 vs. 11.8 +/- 7.5% of myocardial mass, P < 0.05) than patients with polymorphic VT. Moreover myocardial infarction involved more segments in the LAD perfusion territory (86 vs. 20%, P < 0.05) than in patients with polymorphic VT. Patients with spontaneous monomorphic VT during the long-term follow-up period had more infarcted tissue, which was more often present in the LAD perfusion territory than patients with polymorphic events. These data strengthen the diagnostic benefit of CMR in patients with ischemic cardiomyopathy. CMR may be used for better risk stratification in patients with ischemic cardiomyopathy undergoing ICD therapy. PMID- 20957519 TI - Analgesic and anti-inflammatory activities of 18-acetoxy-ent-kaur-16-ene from Annona squamosa L. bark. AB - The Annona squamosa L. bark was collected from Ahmednagar district, India. 18 Acetoxy-ent-kaur-16-ene was isolated from petroleum ether extract (PE) and studied for its analgesic and anti-inflammatory activities. 18-Acetoxy-ent-kaur 16-ene at the doses of 12.5 and 25 mg/kg, and PE at a dose of 50 mg/kg exhibited significant analgesic along with anti-inflammatory activity. PMID- 20957520 TI - Immunology as it pertains to drugs of abuse, AIDS and the neuroimmune axis: mediators and traffic. AB - The interactions between the immune and nervous systems are very complex, and yet our understanding of these interactions is still relatively limited. The neuroinflammatory reaction that can accompany HIV infection occurs because of a cascade of events that appears to require the migration of HIV-infected cells across the blood-brain barrier. In susceptible individuals, this leads to inflammatory processes which can include substantial changes in neuronal function. It is possible to consider the inflammatory events to be composed of two essential processes. The first process is cellular traffic, and the second, is the expression and recognition of the various pro-inflammatory and/or toxic mediators. The added complication of drug abuse adds complexity to the traffic and mediator release events, and depending on the specific drug being abused, the disease can be exacerbated in these individuals. An understanding of the fine details of these mediator and traffic processes should provide useful targets for therapeutic intervention to attenuate disease associated with HIV infection. PMID- 20957521 TI - Improving venous thromboembolic disease prophylaxis in medical inpatients: a role for education and audit. AB - BACKGROUND: Venous thromboembolic disease (VTED) prophylaxis is a key strategy in reducing preventable deaths in medical inpatients. We assessed compliance with internationally published guidelines for VTED prophylaxis in at-risk medical patients before and 1 month after an educational intervention to enhance compliance with such guidelines. RESULTS: One hundred and fifty patients were assessed on each occasion. Pre-intervention, VTED prophylaxis was prescribed in only 48% of at-risk cases. Compliance was best among patients under stroke services and worst for those under acute medical teams. Patients within specialist units were more likely to be prescribed prophylaxis than those in general wards (75 vs. 53%; p = 0.0019). Post-intervention, overall compliance improved to 63% (p = 0.041 for comparison). There was a significant improvement among general medical teams (48 vs. 75%; p = 0.001), and in general wards (52 vs. 74%; p = 0.003). CONCLUSIONS: Thromboprophylaxis is under-prescribed in medical inpatients, but compliance with international guidelines can be significantly enhanced with targeted educational intervention. PMID- 20957522 TI - A proteomic investigation of B lymphocytes in an autistic family: a pilot study of exposure to natural rubber latex (NRL) may lead to autism. AB - Autism is a multi-factorial neurodevelopmental disorder. We have investigated the molecular mechanism involved in a Chinese family with autism by a proteomic approach. Antibody chips containing 500 spots of human protein antibodies were used to screen for differentially expressed proteins in the peripheral B lymphocytes between autistic and non-autistic siblings in this family. Four proteins relevant to immuno-pathway, including IKKalpha that was up-regulated and Tyk2, EIF4G1 and PRKCI that were down-regulated, were identified differentially expressed in autistic versus non-autistic siblings. Western blot analysis and reverse transcription quantitative polymerase chain reaction validated the differential expression of these four proteins. Based on the function of these differentially expressed proteins, relevant studies on immunoglobulin E (IgE) level, nuclear factor kappa B signaling activation and cell cycle were conducted in both autistic and non-autistic children of this family. Considering the fact that the family members were in close contact with natural rubber latex (NRL) and that IgE-mediated cross-reactions could be triggered by Hevea brasiliensis (Hev b) proteins in NRL, we hypothesize that immune reactions triggered by close contact with NRL might influence the functions of B lymphocytes by altering expression of certain proteins identified in our experiments thus contributing to the occurrence of autism. PMID- 20957523 TI - Effects of SMYD3 over-expression on cell cycle acceleration and cell proliferation in MDA-MB-231 human breast cancer cells. AB - SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase that plays an important role in transcriptional regulation in human carcinogenesis. It can specifically methylate histone H3 at lysine 4 and activate the transcription of a set of downstream genes, including several oncogenes (e.g., N-myc, CrkL, Wnt10b, RIZ and hTERT) and genes involved in the control of cell cycle (e.g., CyclinG1 and CDK2) and signal transduction (e.g., STAT1, MAP3K11 and PIK3CB). To determine the effects of SMYD3 over-expression on cell proliferation, we transfected SMYD3 into MDA-MB-231 cells and found that these cells showed several transformed phenotypes as demonstrated by colony growth in soft agar. Besides, we show here that down-regulation of SMYD3 could induce G1 phase cell cycle arrest, indicating the potent induction of apoptosis by SMYD3 knockdown. These results suggest the regulatory mechanisms of SMYD3 on the acceleration of cell cycle and facilitate the development of strategies that may inhibit the progression of cell cycle in breast cancer cells. PMID- 20957525 TI - CIDE-3 interacts with lipopolysaccharide-induced tumor necrosis factor, and overexpression increases apoptosis in hepatocellular carcinoma. AB - Cell death-inducing DFF45-like effector-3 (CIDE-3) is a novel member of an apoptosis-inducing protein family, but its function is unknown. CIDE-3 shows a different distribution pattern in hepatocellular carcinoma (HCC) tissues and normal adjacent tissues. Therefore, this work tested the hypothesis that CIDE-3 induces apoptosis in HCC cells, inhibiting oncogenesis and tumor development. We used immunohistochemistry to evaluate the expression of CIDE-3 in 82 HCC samples and 51 adjacent liver tissues. Overexpression of CIDE-3 induced apoptosis, as detected by flow cytometry, in the HCC cell line SMMC-7721, which had undetectable levels of CIDE-3 in the absence of CIDE-3 overexpression. A yeast two-hybrid system was employed to screen for proteins that interact with CIDE-3. The expression of CIDE-3 was decreased in HCC tissue, compared to adjacent normal tissues, and CIDE-3 expression and HCC differentiation were positively correlated. CIDE-3 expression levels were lower in poorly differentiated HCC tissue than in well-differentiated HCC tissue. Overexpressed CIDE-3 inhibited proliferation and induced apoptosis in HCC cells. We found that lipopolysaccharide-induced tumor necrosis factor (LITAF) interacted with CIDE-3 in hepatic cells. This is the first demonstrated interaction between CIDE-3 and LITAF, and the first report that CIDE-3 induces apoptosis in hepatocellular carcinoma. PMID- 20957524 TI - Prognostic significance and mechanisms of patterned matrix vasculogenic mimicry in hepatocellular carcinoma. AB - Vasculogenic mimicry (VM), including tubular VM and patterned matrix VM, has been generally recognized as a new pattern of tumor neovascularization. Pilot studies of tubular VM showed that it was present in hepatocellular carcinoma (HCC) and associated with poor clinical prognosis. However, whether patterned matrix VM is clinically significant in HCC is unknown. To elucidate the effects of patterned matrix VM on prognosis of HCC and the mechanisms involved in VM formation, we examined 151 cases of surgically resected human HCC by immunohistochemistry and transmission electron microscopy and conducted hypoxic experiments on human HCC cell line MHCC97-H. We observed 31 of 151 (20.5%) cases exhibited evidence of patterned matrix VM. The expression of patterned matrix VM was associated with larger tumors (P = 0.042), vascular invasion (P = 0.016), high-grade HCC (P = 0.022), and late-stage HCC (P = 0.013). Kaplan-Meier survival analysis revealed that cases of the VM group had lower overall survival (OS) rate (P < 0.001) and disease-free survival (DFS) rate (P = 0.002) than that of the non-VM group. Univariate and multivariate analysis indicated that the presence of patterned matrix VM was independent adverse prognostic factor for both OS (P = 0.004) and DFS (P = 0.011). Expression of hypoxia-inducible factor 1 alpha (HIF-1alpha), matrix metalloproteinase (MMP)-2, and MMP-9 were higher in the VM group than in the non-VM group (P = 0.001, P = 0.030, P = 0.007, respectively). After VM formation was induced by hypoxia, up-regulated expression of HIF-1alpha, MMP-2, and MMP-9 was also detected in cells cultured under hypoxia condition. Our results indicate that patterned matrix VM exists in HCC, and it might serve as an unfavorable prognostic factor for HCC patients. It is possible that hypoxia via induction of expression of HIF-1alpha, MMP-2, and MMP-9 may enhance VM formation in HCC. PMID- 20957526 TI - Improvement of image resolution of brain SPECT by use of the wide-angle offset acquisition method. AB - OBJECTIVE: Cerebral SPECT images require high spatial and contrast resolution for precise evaluation of the abnormal tracer distribution in the brain. A shorter data acquisition time is preferable so that artifacts due to patient movement are avoided. We tried to shorten data acquisition time applying larger sampling angle and offset acquisition method, in which half degree of the step angle was shifted in the opposite gamma camera of the dual-detector SPECT system. METHODS: A simulation study was performed with a 3-dimensional mathematical phantom. The phantom studies were performed with a hot-rod phantom and a brain phantom. A clinical study with 99(m)Tc-ECD SPECT was also performed on a patient who had a cerebral infarction. Reconstruction of images was done for the normal 6 degrees and 12 degrees onset and 12 degrees offset. Data for the 12 degrees offset were acquired by shifting of sampling angles of the opposite detector by half (6 degrees ) of the sampling angles of 12 degrees . The MLEM algorithm was used for image reconstruction. Image qualities in the simulation study, the phantom studies, and the clinical study were compared for the 6 degrees and 12 degrees onset, and for the 12 degrees offset by quantitative analysis with use of profile curves. RESULTS: Analysis of the profile curves revealed that the image quality of the 12 degrees offset was better than that of the 12 degrees onset and compared to that of the 6 degrees onset in the simulation study, the phantom studies, and the clinical study. CONCLUSIONS: The present study indicates that wide-angle offset data acquisition improves the image resolution of brain SPECT compared to onset data acquisition with the same sampling time. PMID- 20957527 TI - Is contrast material needed after treatment of malignant lymphoma in positron emission tomography/computed tomography? AB - PURPOSE: Positron emission tomography (PET)/computed tomography (CT) with (18)F fluorodeoxyglucose is widely used for post-therapeutic surveillance of malignant lymphoma. Debate still exists as to whether intravenous contrast media during the CT stage of a PET/CT scan should be used. The purpose of this study was to investigate the clinical value of contrast agent in PET/CT in patients with lymphoma following treatment. PATIENTS AND METHODS: One hundred and twenty-two consecutive patients with malignant lymphoma underwent 146 PET/CT scans to monitor therapeutic response (n = 57) or surveillance during follow-up (n = 89). All patients had a conventional PET/CT scan with low-dose CT without contrast (ldCT), and then a full-dose CT scan with contrast (ceCT). Two datasets were interpreted separately and prevalence of discrepant results between the two methods was evaluated. In addition, differences of diagnostic performance were investigated for restaging. RESULTS: Both PET + ldCT and PET + ceCT were positive in 22 cases and negative in 35 cases when monitoring response to therapy. There were no cases in which these techniques demonstrated inconsistent findings. For restaging, the patient-based sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of PET + ldCT were 70, 91, 76, 87, and 84%, respectively, and those of PET + ceCT were 74, 92, 81, 89, and 87%, respectively. Discrepant results between the two methods occurred in only 2 of 89 cases (2%). CONCLUSION: PET/ceCT yielded more accurate findings than PET/ldCT in a limited number of cases. PET/ldCT may, therefore, be sufficient for routine PET/CT scanning for post-therapeutic assessment or restaging of lymphoma patients. PMID- 20957529 TI - The integration of information across lexical and sublexical processes in spelling. AB - We report on a brain-injured subject, LAT, who made phonologically plausible errors in word spelling (e.g., "bouquet" spelled as BOUKET). Although many of his errors are phonologically plausible they contained low-frequency (yet lexically correct) spellings (/ei/ spelled as ET in BOUK ET). Because these errors are phonologically plausible they do not appear to have been generated by the lexical process, yet because they contain low probability, lexically correct elements they do not appear to be have been generated by the sublexical process. We present analyses that specifically support the conclusion that many of LAT's phonologically plausible responses to word stimuli consist of the integrated output of elements generated by both the lexical and sublexical processes. This evidence constitutes strong support for the notion that lexical and sublexical processes share information during the course of spelling a familiar word. PMID- 20957528 TI - Multidimensional atomic force microscopy: a versatile novel technology for nanopharmacology research. AB - Nanotechnology is giving us a glimpse into a nascent field of nanopharmacology that deals with pharmacological phenomena at molecular scale. This review presents our perspective on the use of scanning probe microscopy techniques with special emphasis to multidimensional atomic force microscopy (m-AFM) to explore this new field with a particular emphasis to define targets, design therapeutics, and track outcomes of molecular-scale pharmacological interactions. The approach will be to first discuss operating principles of m-AFM and provide representative examples of studies to understand human health and disease at the molecular level and then to address different strategies in defining target macromolecules, screening potential drug candidates, developing and characterizing of drug delivery systems, and monitoring target-drug interactions. Finally, we will discuss some future directions including AFM tip-based parallel sensors integrated with other high-throughput technologies which could be a powerful platform for drug discovery. PMID- 20957530 TI - The effects of rotation and inversion on face processing in prosopagnosia. AB - The current study investigated the sensitivity of face recognition to two changes of the stimulus, a rotation in depth and an inversion, by comparing the performance of two prosopagnosic patients, RN and CR, with non-neurological control subjects on a face-matching task. The control subjects showed an effect of depth rotation, with errors and reaction times increasing systematically with rotation angle, and the traditional inversion effect, with errors and reaction times increasing under inverted conditions. In contrast, RN showed no effect of rotation or inversion on his error data but did show a less sensitively graded effect of rotation and the traditional inversion effect on reaction times. CR did not show a graded effect of rotation on his errors or reaction times. Although CR showed the traditional inversion effect on his error data, he displayed an inversion superiority effect on his reaction time data, which supports the claim that the damaged holistic processing systems continue to dominate face processing in prosopagnosia even though they are malfunctioning. These results suggest that the damage that occurs to the ventral temporal cortex in prosopagnosia may have forced the patients to rely on sources of information that are not dependent on the view of the face and, moreover, cannot be adapted to deal with rotated faces under both upright and inverted conditions. PMID- 20957531 TI - Early selection induced by perceptual load in a patient with frontal lobe damage: External vs. internal modulation of processing control. AB - We examined effects of interference from task-irrelevant information in a patient with frontal and temporal lobe damage (FK), using Simon and reverse-Simon tasks. FK responded to the meaning or location of a word (LEFT or RIGHT), while ignoring the irrelevant dimension. When the dimensions were incongruent, FK showed large interference effects. However, when noninformative distractors (e.g., XXXX) were presented as a perceptual load in the reverse-Simon task, the size of the interference effect reduced as a function of the number of distractors. RT distribution analyses revealed that the reduction of interference was due to increased correct responses in the fast end of the distribution. Opposite effects occurred in the standard Simon task. These results are consistent with perceptual load leading to early visual selection (Lavie, 1995). The results suggest that FK has intact processing of the location and meaning of words, but there is impaired internal control of attentional resources to the task-relevant information. In contrast, resources can be controlled externally, by increasing the perceptual load. We discuss the implications for understanding attentional modulation of visual processing. PMID- 20957532 TI - Neuropsychological evidence for a convergent route model for action. AB - We present a detailed analysis of the relations between acting, naming, and recognising objects from vision, touch, and verbal labels, in a series of three cases. We demonstrate that: (1) there can be better "use" than gesturing of objects even in a patient with impaired semantic information for the objects; (2) this is contingent on direct proprioceptive feedback in action; and (3) there are impaired gestures to "non-action" parts of objects even when the patients can gesture to names and can identify the objects. These results are consistent with a "convergent route" model of action, which holds that direct, modality-specific associations between objects and actions constrain the retrieval of actions from semantic representations. PMID- 20957533 TI - Visual perception and verbal descriptions as sources for generating mental representations: Evidence from representational neglect. AB - In the majority of investigations of representational neglect, patients are asked to report information derived from long-term visual knowledge. In contrast, studies of perceptual neglect involve reporting the contents of relatively novel scenes in the immediate environment. The present study aimed to establish how representational neglect might affect (a) immediate recall of recently perceived, novel visual layouts, and (b) immediate recall of novel layouts presented only as auditory verbal descriptions. These conditions were contrasted with reports from visual perception and a test of immediate recall of verbal material. Data were obtained from 11 neglect patients (9 with representational neglect), 6 right hemisphere lesion control patients with no evidence of neglect, and 15 healthy controls. In the perception, memory following perception, and memory following layout description conditions, the neglect patients showed poorer report of items depicted or described on the left than on the right of each layout. The lateralised error pattern was not evident in the non-neglect patients or healthy controls, and there was no difference among the three groups on immediate verbal memory. One patient showed pure representational neglect, with ceiling performance in the perception condition, but with lateralised errors for memory following perception or following verbal description. Overall, the results indicate that representational neglect does not depend on the presence of perceptual neglect, that visual perception and visual mental representations are less closely linked than has been thought hitherto, and that visuospatial mental representations have similar functional characteristics whether they are derived from visual perception or from auditory linguistic descriptive inputs. PMID- 20957534 TI - Preservation of memory for people in semantic memory disorder: Further category specific semantic dissociation. AB - ML, a 70-year-old right-handed woman, presented with a history of semantic memory difficulties and a profound anomia affecting both proper nouns and common nouns following a left-hemisphere CVA some years earlier. She was found to show a striking contrast between her ability to make fine-grained semantic distinctions between objects and animals, on the one hand, and famous faces and names, on the other. Although she was impaired on a series of picture and word semantic comprehension tests when the stimuli consisted of exemplars of object and animal categories, her performance was intact when the materials comprised famous faces and names, suggesting a dissociation between the representation of person specific knowledge and other categories of semantic information. A number of cases have been reported in which person-specific knowledge has been selectively impaired, but we would suggest that our case provides the clearest evidence so far of the reverse dissociation, in which person-specific knowledge is selectively preserved. We speculate on possible differences in the ways in which person-specific knowledge may be represented, relative to information about objects and animals. PMID- 20957535 TI - Temporally graded semantic memory loss in amnesia and semantic dementia: Further evidence for opposite gradients. AB - The consolidation theory of long-term memory (e.g., Squire, 1992) predicts that damage to the medial temporal lobes will result in temporally graded retrograde memory loss, with a disproportionate impairment of recent relative to remote knowledge; in contrast, severe atrophy of the temporal neocortex is predicted to result in the reverse temporally graded pattern, with a selective sparing of recent memory (K.S. Graham & Hodges, 1997). Previously, we reported evidence that autobiographical episodic memory does not follow this temporal pattern (Westmacott, Leach, Freedman, & Moscovitch, 2001). In the present study, we found evidence suggesting that semantic memory loss does follow the predicted temporal pattern. We used a set of tasks that tap implicit and explicit memory for famous names and English vocabulary terms from across the 20th century. KC, a person with medial temporal amnesia, consistently demonstrated across tasks a selective deficit for famous names and vocabulary terms from the 5-year period just prior to injury; this deficit was particularly profound for elaborated semantic knowledge (e.g., word definitions, occupation of famous person). However, when asked to guess on unfamiliar items, KC's performance for names and words from this 5-year time period increased substantially, suggesting that he retains some of this knowledge at an implicit or rudimentary level. Conversely, EL, a semantic dementia patient with temporal neocortical atrophy and relative sparing of the medial temporal lobe, demonstrated a selective sparing of names and words from the most recent time period. However, this selective sparing of recent semantic memory was demonstrated in the implicit tasks only; performance on explicit tasks suggested an equally severe impairment of semantics across all time periods. Unlike the data from our previous study of autobiographical episodic memory, these findings are consistent with the predictions both of consolidation theory (Hodges & Graham, 1998; Squire, 1992) and multiple trace theory (Nadel & Moscovitch, 1999) that the hippocampus plays a timelimited role in the acquisition and representation of long-term semantic memories. Moreover, our findings suggest that tasks requiring minimal verbal production and explicit recall may provide a more sensitive and comprehensive assessment of intact memory capacity in brain-damaged individuals. PMID- 20957536 TI - Evidence for a context-sensitive word retrieval disorder in a case of nonfluent aphasia. AB - We describe a patient (BM) with nonfluent aphasia who presents with sparse, fragmented spontaneous speech but normal or near-normal performance on standard naming tasks. However, more detailed investigation revealed some unusual features to BM's naming: On a task involving repeated naming of a small set of targets, his performance degenerated when the targets were semantically blocked, particularly at fast rates of presentation. This semantic blocking effect was not observed in an analogous wordpicture matching task. Also, it was not present on a task where a set of words had to be named repeatedly in a fixed, predictable sequence. Finally, a fluent aphasic patient who presented with a classic "output" anomia failed to show the semantic blocking and predictability effects. It is suggested that BM suffers from a context-sensitive word retrieval disorder. The disorder is attributed to a difficulty in modulating activation within the lexical network. Implications for nonfluent aphasia, as well as for models of lexical retrieval, are discussed. PMID- 20957537 TI - Imageability effects, phonological errors, and the relationship between auditory repetition and picture naming: Implications for models of auditory repetition. AB - Hanley and Kay (1997) reported the case of a patient (PS) who showed effects of imageability on tests of auditory repetition, but whose errors were phonological rather than semantic. They argued that this pattern of performance could be explained in terms of a partial impairment to both lexical and nonlexical repetition routes so long as some interaction between the two routes was allowed, consistent with Hillis and Caramazza's (1991) "summation" hypothesis. The present paper investigates the performance of a new patient (MF) who also makes a large number of phonological errors when repeating words of low imageability. MF performs at a similar level to PS on tests of picture naming, but is less impaired than PS when repeating words and nonwords. It is argued that the pattern of performance that MF demonstrates on these and on a wide range of other tests of word production and comprehension can be readily accommodated in terms of the dual-route account of impaired auditory repetition that Hanley and Kay (1997) put forward. However, we argue that it is difficult to explain these patients' performance in terms of models of auditory word repetition that do not incorporate a separate nonlexical repetition route (Dell, Schwartz, Martin, Saffran, & Gagnon, 1997; Foygel & Dell, 2000). PMID- 20957538 TI - The syntax of single words: Evidence from a patient with a selective function word reading deficit. AB - We describe the reading performance of a patient who has selective deficits for reading nonwords, function words, and morphologically complex words in isolation. His reading of highly abstract nouns and verbs, however, is relatively well preserved. He can recognise and comprehend the meaning of written function words, of derivational morphology, and of most inflectional morphology. We suggest that his deficit in reading grammatical morphemes is unrelated to his problems in reading nonwords and cannot be explained by their low semanticity and imageability. The patient's speech is ungrammatical but is not devoid of grammatical morphemes and his reading of functional elements improves when these are presented within the context of sentences. We argue that syntactic information relevant to individual lexical items including information about how the word may potentially be used within a phrase must be accessed during single word reading tasks (e.g., Levelt, 1989). This is particularly difficult for function words due to their linguistic specification, which is different from that of lexical categories (Chomsky, 1995). Both linguistic theory and Garrett's (e.g., 1982) model of sentence processing account for the patient's improved reading of function words in the context of sentences. PMID- 20957539 TI - The role of semantic, orthographic, and phonological prime information in unilateral visual neglect. AB - The present study examined what type of lexical information could be extracted from the patient's neglected field. Patients (N =32) and age-matched controls (N =32) were required to name a foveally presented word after a parafoveal prime was presented either to the left or right visual field. Primes were identical to the target (KITE-KITE), related to the target at the level of semantics (DOG-CAT), orthography (LEMON-DEMON), phonology (ACHE-LAKE), or both orthography and phonology (HIDE-RIDE). Only when the target was semantically related to the prime were consistently reliable priming effects found in the patients, even in the patients' neglected visual field. These results demonstrate that semantic information can be extracted from the patients' neglected field. PMID- 20957540 TI - A new multiword naming deficit: Evidence and interpretation. AB - This study analyses the naming performance of MP, a nonfluent aphasic speaker, and demonstrates that she has a context-sensitive naming deficit, which manifests in worse naming of a target set when multiple targets are depicted at once and a multiname utterance is prepared. Experiments 1 and 2 documented the effect in composite-picture descriptions, compared to standard naming. Experiment 3 documented it in the naming of picture lists of length 2 and 3, compared to 1; and Experiment 4 documented it in the naming of one of two pictured items, under conditions that encouraged preparation of both item names. Several alternative accounts are considered and an argument is made for a type of multiword naming deficit that has not been described before. The deficit involves interference at the lexeme stage of retrieval, arising when multiple lemmas are co-activated during the preparation of a multiword utterance. PMID- 20957541 TI - An evaluation of statistical procedures for comparing an individual's performance with that of a group of controls. AB - The single case methodology that is widely used in cognitive neuropsychology often requires a comparison of data from a single individual (the patient) with that from a group of controls, in order to ascertain whether the patient's mean score can be viewed as significantly different from that of controls. This article reviews methods that have been used to deal with such data. Although Analysis of Variance (ANOVA) provides one possible solution of comparing group means, unequal group sizes and differences in variability between patient and controls can violate the assumptions of the test. Using Monte Carlo simulations, it was found that differences in group size and a group of N = 1 did not significantly affect the reliability of the analysis. In contrast, unacceptably high Type I errors were obtained when, in addition to unequal group sizes, there were relatively modest differences between the variance of the patient and that of the controls. We suggest that ANOVA can be used for the comparison of the mean score of an individual with that of a group of controls, but that when there is a difference in variability between the two groups, revised F criteria should be used in order to make the analysis reliable. A table of modified F values is given, which can be used for various departures from homogeneity of variance. PMID- 20957542 TI - The fur of the crocodile and the mooing sheep: A study of a patient with a category-specific impairment for biological things. AB - We report a single case study of a brain-damaged patient, ER, who showed a remarkably consistent category-specific deficit for living things. His impairment was observed across tasks (naming, definition, matching, drawing from memory, questionnaires), input modalities (visual, verbal, nonverbal auditory), and output modalities (verbal vs. pointing or visual matching responses) as well as for different types of knowledge. Although visual knowledge of living things was severely affected, his category-specific impairment in nonverbal sound recognition is inconsistent with models of category-specific deficits based on pre-semantic visual descriptions. ER's deficit cannot fully be explained by item typicality, word frequency, visual complexity, homomorphy, age of acquisition, value to perceiver, or modality of transaction. Furthermore, in ER, contextual cues were even slightly detrimental for the recognition of animals. ER's naming and recognition errors were constrained by the categorical structure of the knowledge base: In most cases they respected both the second- and first-order superordinates. In particular, ER's knowledge of shared categorical properties related to biological function was almost spared. This result is compatible with the idea that, for living things, shared functional properties and shared perceptual properties are strongly correlated. Feature-based models assuming perceptual vs. functional semantic components cannot account for ER's deficit, since for living things he was impaired on both kinds of features to a similar extent. ER's behaviour is quite consistent with the notion that conceptual knowledge is organised categorically in the brain, with one or several specialised subsystems for biologically related entities. PMID- 20957543 TI - A PET investigation of lexicality and phonotactic frequency in oral language processing. AB - Lexicality and phonotactic frequency effects are observed in many cognitive studies on language processing, but little is known about their underlying neural substrates, especially with regard to phonotactic frequency effects. Here, we conducted a positron emission tomography (PET) study in which 11 right-handed volunteers had either to repeat or to listen to lists of words, high phonotactic frequency nonwords, and low phonotactic frequency nonwords. The comparison of word versus nonword processing consistently confirmed previous findings of left temporal and prefrontal activations classically ascribed to lexicosemantic processing. Higher activation was found in the right posterior superior temporal gyrus when comparing high phonotactic frequency nonwords to words, but not when comparing low phonotactic frequency nonwords to words. We propose that this region is implicated in the formation of temporary phonological representations for high-probability phonological events, which may support processing of high phonotactic frequency nonwords. PMID- 20957544 TI - Transient binding by time: Neuropsychological evidence from anti-extinction. AB - Anti-extinction occurs when there is poor report of a single stimulus presented on the contralesional side of space, but better report of the same item when it occurs concurrently with a stimulus on the ipsilesional side (Goodrich & Ward, 1997). We report a series of experiments that examine the factors that lead to anti-extinction in a patient GK, who has bilateral parietal lesions but more impaired identification of left-side stimuli. We show a pattern of anti extinction when stimuli are briefly presented, which is followed by an extinction effect when stimuli are left for longer in the visual field. In Experiments 1 and 2 we present evidence that the anti-extinction effects are determined by stimuli onsetting together, and it is not apparent when stimuli are defined by offsets. In Experiments 3 and 4 we report that performance is not strongly affected by whether the same or different tasks are performed on the ipsi- and contralesional stimuli, and the anti-extinction effect also survives trials where eye movements are made to right-side stimuli. Experiment 5 provides evidence that anti extinction is due to temporal grouping between stimuli, rather than to increased arousal or cueing attention to the contralesional side. Experiment 6 demonstrates that anti-extinction dissociates from GK's conscious perception of when contra- and ipsilesional stimuli occur together. We interpret the data as indicating that there is unconscious and transient temporal binding in vision. PMID- 20957545 TI - Independent representations for cursive and print style: Evidence from dysgraphia in Alzheimer's disease. AB - In this paper we describe two mild Alzheimer's disease patients (AF and EZ) who show a double dissociation in written production of cursive and print styles. We analysed their performance on a number of different tasks. Both had no major difficulty in reading, direct copying, or spelling but displayed contrasting patterns of impairment in writing using different styles. AF was impaired when asked to write in cursive, whereas EZ was impaired when requested to write in print. The patients showed no general impairment in retrieving visual forms, but both failed a letter form judgement task, only for the affected style. Evidence from their overall performance adds support to opposing patterns of impairments in both patients. The double dissociation shown by AF's and EZ's performance strengthens previous arguments for independent representations of cursive and print style. PMID- 20957546 TI - The role of premorbid expertise on object identification in a patient with category-specific visual agnosia. AB - The role of premorbid expertise in object identification was investigated in the category-specific visual agnosia patient ELM. For several years prior to his stroke ELM played bugle in a military band. We surmised that band membership would lead to preferential exposure to, and expertise for, brass instruments relative to other musical-instrument families. To test this hypothesis we assessed ELM's musical instrument identification capability for brass and stringed instruments. Testing was conducted 14 years post-stroke. ELM listed significantly more correct attributes for five brass instruments than for five stringed instruments. On a picture-word matching task ELM showed significantly better identification of brass, relative to stringed, musical instruments. Finally, when ELM was required to pair novel shapes with labels denoting brass or stringed instruments, he made significantly more errors in the stringed instrument condition than in the brass-instrument condition. We conclude that the elevated attribute knowledge accompanying expertise serves to increase the visual and semantic distance between objects within a category, thereby protecting them against identification deficits in the context of category-specific visual agnosia. PMID- 20957547 TI - Lexical effects in left neglect dyslexia: A study in Italian patients. AB - This study investigated whether and to what extent the reading performance of six Italian right-brain-damaged patients with left neglect dyslexia was affected by lexical variables. The lexicality of responses (either words or nonwords) and the distribution of substitution vs. omission neglect errors were measured. Patients were given the following tasks: (1) reading aloud monomorphemic words of different frequencies and nonwords with different degrees of similarity to real words (Experiment 1); (2) reading aloud morphologically complex (suffixed) derived words and morphologically complex (suffixed) nonwords (Experiment 2). Patients could be distinguished in terms of their sensitivity to the lexical status of the target. Four patients exhibited lexicality effects in their reading performance, while two patients did not. The dissociation is discussed in terms of the interaction between defective visuospatial analysis, which characterises neglect, and higher-order lexical knowledge. The suggestion is made that lexical effects in neglect dyslexia reflect a relative preservation of visuospatial processing of the left side of the letter string, its absence a more severe neglect disorder. This interpretation of the occurrence of lexical effects in left neglect dyslexia in terms of severity of the spatial disorder is specific to the domain of reading, however, and does not extend to other manifestations of unilateral spatial neglect. Finally, the relationship between error type (omissions vs. substitutions) and the absence vs. presence of lexical effects is considered. PMID- 20957548 TI - Visual selection and action in Balint's syndrome. AB - We examined the relations between attention and action in a patient with Balint's syndrome following bilateral damage involving the parietal lobes. The first two experiments used prolonged stimulus exposures and showed that unlike normals, the patient GK made independent actions to bilateral stimuli, even when explicitly instructed to make coordinated reaches. In contrast, bimanual actions to a single stimulus were coordinated in time. Experiments 3 and 4 employed reduced stimulus exposures to produce visual extinction. We found comparable extinction effects in detection and action, along with improved bimanual movements when the stimuli were grouped by collinearity and surface contrast, plus better coordination with bilateral stimuli proximity. The results are discussed in relation to the common role of visual selection processes in perception and action. PMID- 20957549 TI - An attribute is worth more than a category: Testing different semantic memory organisation hy potheses in relation to the living/nonliving things dissociation. AB - The present paper contrasted categorical and featural hypotheses of semantic memory organisation in relation to the living/nonliving things dissociation phenomenon. In the three experiments reported, normal subjects decided if word pairs representing living, nonliving, or both (mixed pairs) shared a particular perceptual (i.e., four legs, size, and hardness) or functional attribute (i.e., dangerousness, speed, and usefulness). The overall pattern of results is more in accordance with a general featural perspective and also emphasises the role of functional attributes. Both a categorical perspective and an attribute-category connection hypothesis have more difficulties in explaining the observed data. Implications for the study of semantic memory organisation and for the explanation of living/nonliving things dissociation cases are also considered. PMID- 20957550 TI - Why semantic dementia drives you to the dogs (but not to the horses): A theoretical account. AB - This paper describes a patient (IH) with semantic dementia and severe impairment in all semantic categories except for numerical knowledge, which was preserved. IH showed a severe deficit in reading and writing non-number words (e.g., candle, juice) and nonwords, and preservation of reading and writing number words (e.g., one, forty) and numerals (e.g., 1, 40). IH's pattern of performance can be explained by the combination of a selective sparing of one semantic category- i.e., numbers--with a total deficit of nonsemantic processes for mapping letters and sounds. As number was the only spared semantic category in the presence of these other nonsemantic deficits, it follows that the semantic route is sufficient for accurate reading and spelling. Our data clarify the nature of reading and writing processes and support the functional and neuroanatomical independence of the number domain. PMID- 20957551 TI - Representing arithmetic table facts in memory: Evidence from acquired impairments. AB - In this article we explore how arithmetic table facts (e.g., 6 * 9 = 54) are stored in memory and evaluate the possibility that arithmetic facts are exclusively stored in a phonological or sound-based form. We present two single case studies of brain-damaged patients who suffer specific number processing impairments. Both patients often retrieve the correct answer to simple arithmetic problems from memory when unable to generate the phonological representation of either the arithmetic problem or the answer to that problem. We argue that this pattern of performance is incompatible with the hypothesis that arithmetic facts are stored and retrieved from memory exclusively in a phonological form. Accounts consistent with out findings are proposed. PMID- 20957552 TI - Regions of neural dysfunction associated with impaired naming of actions and objects in acute stroke. AB - The proposal that there are distinct neural regions devoted to the representation or processing of names of objects versus actions has received support from a variety of sources. However, there have been conflicting results regarding the localisation of the postulated mechanisms that are more crucial for one category or the other. There is also controversy as to whether the separation of mechanisms devoted to object versus action naming arises at the level of lexical semantics or at the level of accessing lexical representations for output. We addressed these issues by testing oral naming and word comprehension of object and action names in 33 right-handed patients with acute left-hemisphere stroke, and by obtaining magnetic resonance (MR) perfusion-weighted and diffusion weighted imaging of each patient at the same time. We identified regions of abnormal blood flow or infarction associated with impaired naming (with and without impaired word comprehension) of objects, of actions, or of both, using Fisher Exact tests. We found both neural regions shared by networks underlying naming of actions and networks underlying naming of objects, and other neural regions that were crucial to only one network or the other. One of the shared components (in the left superior temporal gyrus) was also essential to comprehension of action and object names (as tested by word/picture verification). These results converge with evidence from chronic lesion studies and functional imaging studies, indicating that some components of the neural networks for accessing lexical representations for output are more important for object names (e.g., left temporal cortex) and others more important for action names (e.g., left posterior frontal cortex). PMID- 20957553 TI - Sequential and parallel letter processing in letter-by-letter dyslexia. AB - Four experiments are reported that focus on the issue of sequential vs. parallel letter processing in letter-by-letter (LBL) dyslexia; these were conducted on patient IH. Expt. 1 showed a large linear reduction of word naming times with an increase in the number of orthographic neighbours of the target (i.e., words of the same length differing by just one letter; N size). Given the large negative linear correlation existing between word length and N size, this result raises the possibility that the large word length effect diagnostic of LBL dyslexia may be, in fact, an artefact of uncontrolled N size. Expt. 2 falsified this possibility by showing that the word length effect is unaffected by whether N size is controlled for or not. This result also suggested that the facilitatory effect of increased N size in LBL dyslexia is based on the parallel processing of the constituent letters of the target. Further supporting a contribution of parallel letter processing to overt word recognition performance in the disorder, Expt. 3 showed significant but independent effects of word length and letter confusability (i.e., similarity of the constituent letters of the target word with other letters of the alphabet). The letter confusability effect therefore appears to rest on the parallel analysis of the letters in the target word. Finally, Expt. 4 showed that the facilitatory effect of N size is prevented with high letter-confusability targets. These observations suggest that LBL dyslexia rests on an impairment of letter encoding that results in an excessive level of background noise in the activation of lexical-orthographic representations when letters are processed in parallel. This prevents overt identification of the target and forces sequential letter processing in order to achieve this goal. PMID- 20957554 TI - Standing on the gateway to memory: Shouldn't we step in? AB - The book by Gluck and Myers (Gateway to memory: An introduction to neural network modelling of the hippocampus and learning, 2001) provides a clear and well organised description of a particular connectionist approach to modelling hippocampal function. We argue that such an approach may help conceptualise the function described, but does not have the power to explain the relations between the function and the neural structure that subserves it. PMID- 20957555 TI - From "Cinquante-Six" to "5quante-Six": The origin of intrusion errors in a patient with probable alzheimer disease. AB - This paper presents a detailed single-case study of a patient (BT) with dementia of the Alzheimer's type who showed impairments in number processing. Numeral comprehension and calculation abilities were largely preserved but the patient encountered substantial difficulties in transcoding tasks. In addition to syntactic errors, she produced numerous perseverations and intrusion errors, especially when she had to transcode arabic numerals into written verbal numerals and vice versa. In the present study, we show that these errors are concomitant with but not dependent on the syntactic deficit. We also demonstrate that their production is not exclusive to the numerical domain but clearly depend on the attentional processing load as well as on the familiarity of the transcoding task. To account for these data, we suggest that perseverations and intrusion errors are attentional in nature and originate from a unique impairment in selective attention capacities. PMID- 20957556 TI - Graded modality-specific specialisation in semantics: A computational account of optic aphasia. AB - A long-standing debate regarding the representation of semantic knowledge is whether such knowledge is represented in a single, amodal system or whether it is organised into multiple subsystems based on modality of input or type of information. The current paper presents a distributed connectionist model of semantics that constitutes a middle ground between these unitary- versus multiple semantics accounts. In the model, semantic representations develop under the pressure of learning to mediate between multiple input and output modalities in performing various tasks. The system has a topographic bias on learning that favours short connections, leading to a graded degree of modality-specific functional specialisation within semantics. The model is applied to the specific empirical phenomena of optic aphasia--a neuropsychological disorder in which patients exhibit a selective deficit in naming visually presented objects that is not attributable to more generalised impairments in object recognition (visual agnosia) or naming (anomia). As a result of the topographic bias in the model, as well as the relative degrees of systematicity among tasks, damage to connections from vision to regions of semantics near phonology impairs visual object naming far more than visual gesturing or tactile naming, as observed in optic aphasia. Moreover, as in optic aphasia, the system is better at generating the name of an action associated with an object than at generating the name of the object itself, because action naming receives interactive support from the activation of action representations. The ability of the model to account for the pattern of performance observed in optic aphasia across the full range of severity of impairment provides support for the claim that semantic representations exhibit graded functional specialisation rather than being entirely amodal or modality specific. PMID- 20957557 TI - Impaired recognition of fear in a Chinese man with bilateral cingulate and unilateral amygdala damage. AB - LJM, a 41-year-old schizophrenic Chinese man with bilateral anterior cingulate gyrus (Brodmann's area 24) lesions and also a small lesion in right amygdala after an operation, was compared with normal as well as brain-damaged and schizophrenic controls in identification of morphed facial expressions of six basic emotions. In repeated administrations of the test for recognition of facial emotions, over a 1- year period, LJM performed significantly worse for expressions of fear compared with the three groups of controls. Recognition of other emotions was not significantly different from that of the controls, except that his recognition of disgust during the first session (but not in two subsequent sessions) was worse than normal and brain-damaged controls but not worse than schizophrenic controls. The dissociation between recognition of fear and other emotions supported the view that the brain has separable networks for processing different emotions, and that the right amygdala as well as the anterior part of bilateral cingulate gyrus are possible substrates involved in the special network for perception of fear. The results from the various groups of Chinese subjects indicate that they perceive emotions in a categorical manner, and that the six basic emotions are likely to be cross-cultural universals. PMID- 20957558 TI - The interaction of lexical and sublexical information in spelling: What's the point? AB - Most theories of spelling propose two major processes for translating between orthography and phonology: a lexical process for retrieving the spellings of familiar words and a sublexical process for assembling the spellings of unfamiliar letter strings based on knowledge of the systematic correspondences between phonemes and graphemes. We investigated how the lexical and sublexical processes function and interact in spelling by selectively interfering with the sublexical process in a dysgraphic individual. By comparing spelling performance under normal conditions and under conditions of sublexical disruption we were able to gain insight into the functioning and the unique contributions of the sublexical process. The results support the hypothesis that the sublexical process serves to strengthen a target word and provide it with a competitive advantage over orthographically and phonologically similar word neighbours that are in competition with the target for selection. PMID- 20957559 TI - Words are more than the sum of their parts: evidence for detrimental effects of word-level information in alexia. AB - The effects of sequential letter presentation on reading were investigated with both normal readers and an alexic patient. Normal readers showed longer naming latencies when words were presented letter-by-letter than when all the letters were presented simultaneously. In contrast, naming latencies for the alexic reader were shorter when words were presented letter-by-letter (error rates did not differ for the patient and the controls). Further experiments provided evidence for the patient being abnormally affected by lateral masking between stimuli, though she could access phonology from subword functional spelling units. The experiments demonstrate that, for alexic and normal readers alike, words are more than the sum of their individual letters; however, for normal readers a supra-letter reading strategy is useful whereas it can be detrimental in alexia. PMID- 20957560 TI - Rigid and nonrigid objects in canonical and noncanonical views: hemisphere specific effects on object identification. AB - We compared the performance in a picture-name matching task of 10 patients suffering from left cerebral hemisphere (LH) damage and 10 from right hemisphere (RH) damage. The tasks showed detailed figures of nonrigid objects (animals) and rigid objects (artefacts), and each object was shown in two separate views: a noncanonical view (an unusual perspective for rigid objects or a contorted pose for the nonrigid ones) and a canonical view (a typical perspective and pose). Patients with LH damage were specifically impaired in identifying noncanonical (contorted) poses of nonrigid objects (animals). In a second picture-name matching experiment, using the divided visual field technique, normal subjects matched names to images of nonrigid shapes (animals) shown in canonical and noncanonical perspectives of noncontorted, typical poses of the animals. It was found that the normal subjects' RH identified these perspectives better than their LH. We conclude that computationally different problems are solved by different cerebral mechanisms when identifying flexible objects and when identifying rigid objects. We propose the idea that identifying flexible objects when their shapes contort relies on accessing stored descriptions of objects' parts and their "categorical" spatial relations and that both types of information are encoded better by the LH. In contrast, we propose that the RH is more adept at identifying different perspectives of rigid objects (and flexible objects when their shapes do not contort) because of this hemisphere's superiority in encoding specific global shapes and their views, and in coordinate spatial transformation. PMID- 20957561 TI - Implicit location encoding via stored representations of familiar objects: neuropsychological evidence. AB - We report data on the visual localisation ability of a patient with Balint's syndrome, GK. We show that, with relatively long exposures of displays, GK is better able to judge the spatial relations between separate objects (a "between object judgement") than the spatial relations between a part and a whole object (a "within-object judgement") (Experiments 1-3). This dissociation occurred even when the same stimulus was used for both judgements, and the task instructions biased GK to parse the stimulus as either a single or as two separate objects (Experiments 2 and 6). However, when he could use a stored representation to make a within-object judgement, then performance was better than on a comparable spatial judgement of the relations between two separate objects (Experiments 4 7). The data demonstrate that stored representations of objects can support the spatial coding of parts to perceptual wholes. In the absence of stored representations, part-whole relations must be explicitly coded by attention, a process that is impaired in this patient. PMID- 20957562 TI - Agnosia for global patterns: When the cross-talk between grouping and visual selective attention failS. AB - We present a single case study of a 72-year-old mild AD patient, MC, with a highly specific deficit in deriving the global pattern of visual stimuli, in the absence of visuospatial neglect. MC shows a specific difficulty in segregating overlapping figures, in object decision, and in all neuropsychological tasks requiring perception of a global structure from local cues, such as the Street Completion Test and the perception of illusory contours and of the global level of hierarchical stimuli. The detailed neuropsychological assessment prompted a psychophysical experiment aiming to quantify the limits of perceptual grouping in MC. We measured the thresholds of integration for a closed chain of Gabor Patches as a function of background noise using stimuli with different values of the distance between the local elements. When compared to normal controls, the patient displays a statistically significant drop of performance for stimuli with the larger interelement distance. The data are interpreted in the context of the "association field" theory (Field, Hayes, & Hess, 1993). As MC presents with a marked atrophy of the right temporoparietal junction, we interpret our data as providing further evidence of a neuromodulatory role of the right temporoparietal junction over the occipital cortices, in line with recent functional evidence (Fink et al., 1997a). The study also highlights the benefits of complementing classical neuropsychological investigations with more quantitative psychophysical procedures. PMID- 20957563 TI - A duck with four legs: Investigating the structure of conceptual knowledge using picture drawing in semantic dementia. AB - In Study 1, six patients with semantic dementia were asked to produce drawings of concrete concepts from dictation of their names. The drawings were characterised by a loss of distinctive features. In the artefact domain, this feature loss resulted in representations that were increasingly box-like. In the living domain, as well as distinctive features being lost, there was a tendency for patients to include incorrect features that resulted in more familiar and "prototypical" representations. A second study included two further conditions in the drawing assessment: immediate and delayed copying of line drawings of concrete concepts. Analysis of the drawings produced by three patients with semantic dementia confirmed that overall performance was significantly influenced by the task condition (immediate delayed) and severity of disease. The rate of intruding features, but not of omitted ones, was influenced by the domain of the item, with a greater proportion of intrusions in the living than in the nonliving domain. There was also a significant effect of feature distinctiveness on the proportions of these error types: Intruded features were most likely to come from the pool of properties that are shared across domain. PMID- 20957564 TI - Assessing the Role of Hemispheric Specialisation, Serial-Position Processing, and Retinal Eccentricity in Lateralised Word RecognitioN. AB - The advantage for words in the right visual hemifield (RVF) has been assigned parallel orthographic processing by the left hemisphere and sequential by the right. However, an examination of previous studies of serial position performance suggests that orthographic processing in each hemifield is modulated by retinal eccentricity. To investigate this issue, we presented words at eccentricities of 1, 2, 3, and 4 degrees. Serial position performance was measured using the Reicher-Wheeler task to suppress influences of guesswork and an eye-tracker controlled fixation location. Greater eccentricities produced lower overall levels of performance in each hemifield although RVF advantages for words obtained at each eccentricity (Experiments 1 and 2). However, performance in both hemifields revealed similar U-shaped serial position performance at all eccentricities. Moreover, this performance was not influenced by lexical constraint (high, low; Experiment 2) or status (word, nonword; Experiment 3), although only words (not nonwords) produced an RVF advantage. These findings suggest that although each RVF advantage was produced by left-hemisphere function, the same pattern of orthographic analysis was used by each hemisphere at each eccentricity. PMID- 20957565 TI - On hemispheric specialisation and visual field effects in the perception of print: A comment on Jordan, Patching, and Thomas. AB - Introduction Due to structural characteristics of the visual pathways, stimuli that are presented in the right half of the visual field (RVF) are initially projected to the left cerebral hemisphere, while those presented in the left half of the visual field (LVF) are projected to the right cerebral hemisphere. This anatomical feature has frequently been taken to support the notion that the well documented RVF advantage in recognising printed words is a reflection of functional differences between the two hemispheres; notably that of the dominance of the left hemisphere for processing language. Word stimuli that are sent straight to the left hemisphere are believed to profit from more efficient processing than those sent initially to the right hemisphere, because the latter stimuli must follow a longer and more noisy pathway before reaching the language dominant hemisphere. In the work by Jordan, Patching, and Thomas (2003) the above notion is further developed to speculate that the point of entry of visual information into the cortex may determine the procedure that will underlie the ensuing word recognition process: "... the left hemisphere can process words by mapping orthographic information in parallel onto lexical entries whereas the right hemisphere has a more rudimentary process, that can only map orthographic information sequentially" (p. 50). PMID- 20957566 TI - Asymmetries and eccentricities in studies of lateralised word recognition: a response to nazir. AB - The anatomical arrangement of the human visual system offers considerable scope for investigating functional asymmetries in hemispheric processing. In particular, because each hemisphere receives information initially from the contralateral visual hemifield, visual stimuli presented to the left of a central fixation point can be projected directly to the right hemisphere and visual stimuli presented to the right of a central fixation point can be projected directly to the left hemisphere. Numerous studies using displays of this type suggest that, for the vast majority of individuals, written words produce different patterns of performance when presented to different hemifields and these findings have inspired considerable debate about the processes available for word recognition in each hemisphere. PMID- 20957567 TI - Vowels in the buffer: a case study of acquired dysgraphia with selective vowel substitutions. AB - We report the case of a patient who recovered from a clinical picture of fluent aphasia to selective dysgraphia. The features of the writing disorder were compatible with a graphemic output buffer dysfunction (errors in all spelling tasks and for all type of material, affected by word length and consisting mostly of graphemic deviations), with the exception of the lack of transposition errors and position preference. Further, the spelling disorder was selective for vowels, replicating the original observation by Cubelli (1991). A similar, although milder, error pattern was also observed in reading tasks, in particular for nonwords, suggesting that the locus of dysfunction involves a processing stage shared by reading and writing. These findings support the notion that the consonant-vowel status is a property of graphemic representations, and is compatible with that a common buffer is involved in spelling and reading. We discuss the implications of selective vowel disorders for current models of the spelling system. PMID- 20957568 TI - Normal and impaired spelling in a connectionist dual-route architecture. AB - This paper presents a dual-route connectionist model of spelling, in which one route maps directly from sound to spelling (phonemes to graphemes), while in the other route the mapping is mediated by a further level of representation. The direct route is implemented as a two-layer associative network, with syllabically structured phonemic (input) and graphemic (output) representations, which comes to behave as a productive sound-to-spelling conversion mechanism through the exposure to a corpus of monosyllabic words. The mediated route is modelled as a frequency-sensitive lexical pathway. Nodes representing more frequent words become activated more rapidly than those of lower-frequency words. Access to both routes occurs in parallel, and the final spelling is determined by the combined output of both routes. We show that the model accounts for a wide range of data from normal spellers (including nonword spelling, the variability in vowel spelling and the effect of surrounding phonological context, frequency effect and its interaction with spelling regularity). We also investigate the effect of a selective lesion to the lexical route in which the ceiling of lexical activation is lowered. This manipulation produces a model with surface dysgraphic characteristics, which is tested against data from two impaired subjects. As well as simulating the classic surface dysgraphic profile, including a frequency by regularity interaction, the model exhibits a phenomenon that has only recently been reported, and which provides strong evidence for the idea that multiple routes are active in parallel, and combine to produce the final spelling. PMID- 20957569 TI - An influence of syntactic and semantic variables on word form retrieval. AB - We report the case of DPI, an aphasic patient who shows a phonological impairment in production that spares certain syntactic and semantic categories. On a picture naming task, he produces mostly phono-logical paraphasias, and the probability of producing a correct response depends on the frequency and length of the target word. This deficit occurs in the presence of spared ability to find the grammatical gender of the items that he cannot name, intact conceptual knowledge, and very good reading and word repetition. Therefore, we conclude that DPI's deficit is restricted to the phonological retrieval of a correctly selected lexical entry. However, production errors are not uniform across semantic and syntactic domains. Numerals and names of days and months are totally spared compared to matched controls. In addition, abstract nouns and verbs are significantly less affected than concrete nouns, even when variables affecting phonological retrieval (frequency, length, syllabic structure) are controlled for. This suggests that a functional organisation in terms of semantic and syntactic variables exists at the level of phonological retrieval. We discuss these findings in light of current models of speech production. PMID- 20957570 TI - Neuropsychological and neuroimaging perspectives on conceptual knowledge: an introduction. PMID- 20957571 TI - What are the facts of semantic category-specific deficits? A critical review of the clinical evidence. AB - In this study we provide a critical review of the clinical evidence available to date in the field of semantic category-specific deficits. The motivation for undertaking this review is that not all the data reported in the literature are useful for adjudicating among extant theories. This project is an attempt to answer two basic questions: (1) what are the categories of category-specific deficits, and (2) is there an interaction between impairment for a type of knowledge (e.g., visual, functional, etc.) and impairment for a given category of objects (e.g., biological, artefacts, etc.). Of the 79 case studies in which the reported data are sufficiently informative with respect to the aims of our study, 61 presented a disproportionate impairment for biological categories and 18 presented a disproportionate impairment for artefacts. Less than half of the reported cases provide statistically and theoretically interpretable data. Each case is commented upon individually. The facts that emerge from our critical review are that (1) the categories of category-specific semantic deficits are animate objects, inanimate biological objects, and artefacts (the domain of biological objects fractionates into two independent semantic categories: animals, and fruit/vegetables); (2) the types of category-specific deficits are not associated with specific types of conceptual knowledge deficits. Other conclusions that emerge from our review are that the evidence in favour of the existence of cases of reliable category-specific agnosia or anomia is not very strong, and that the visual structural description system functions relatively autonomously from conceptual knowledge about object form. PMID- 20957572 TI - A case series analysis of "category-specific" deficits of living things:the hit account. AB - We report a case series analysis of a group of seven patients with apparent "category-specific" disorders affecting living things. On standard diagnostic tests, a range of deficits were apparent, with some cases appearing to have impaired visual access to stored knowledge, some with impaired semantic knowledge (across modalities), and some with an impairment primarily at a name retrieval stage. Patients with a semantic deficit were impaired for both visual and associative/functional knowledge about living things, whilst patients with a modality-specific access deficit showed worse performance when stored visual knowledge was probed. In addition, patients with impaired access to visual knowledge were affected when perceptual input was degraded by masking, and all patients showed an interaction between perceptual similarity and category when matching pictures to names or defining statements. We discuss the results in terms of the Hierarchical Interactive Theory (HIT) of object recognition and naming (Humphreys & Forde, 2001). We also discuss evidence on lesion sites in relation to research from functional brain imaging on category differences in object identification in normal observers. PMID- 20957573 TI - Semantic dementia with category specificity:acomparative case-series study. AB - Patients with semantic dementia, the temporal variant of frontotemporal dementia, are relevant to both the neuroanatomical and neuropsychological debates in the category-specific literature. These patients present with a selective and progressive semantic deficit consequent on circumscribed atrophy of the inferolateral polar temporal lobes bilaterally, including the inferotemporal gyrus. In this study, a patient KH with a significant advantage for artefacts over living things was compared to five other semantic dementia patients with commensurate levels of semantic impairment. KH demonstrated a consistent category difference in favour of artefacts across all the expressive and receptive semantic tests. This difference was reliable even when familiarity, frequency, and other potential confounding factors were controlled. While KH demonstrated an association between poor knowledge of sensory attributes and a consistently greater impairment on living things than artefacts, the other patients did not. As observed in a number of previous studies, all five of the patients, contrasted to KH, exhibited an advantage for functional/associative over sensory attributes but without demonstrating the category-specific deficit that the sensory functional theory (and the locus of their atrophy) might predict. The results of this and other studies are discussed in relation to four accounts of category specificity: the sensory-functional theory, domain-specific knowledge systems, intercorrelated features, and individual differences. PMID- 20957574 TI - Category specificity and feature knowledge:evidence from new sensory-quality categories. AB - Category-specific deficits and their relation to types of feature knowledge are addressed with respect to three semantic domains: artefacts, living things, and mass-kinds. The performance of a herpes encephalitic patient with a classic category-specific pattern of knowledge, MU, was compared to that of the other HSE patients and normal subjects. In a feature verification task involving over 4000 questions, MU showed a severe impairment with the mass-kind category, where his sensory features knowledge was at chance and much worse than his functional knowledge. In the feature production task, however, MU was grossly impaired with respect to sensory relative to functional features across all categories. Control experiments suggest that the deficits were of knowledge. Overall, these findings give some support to the sensory-functional theory, and are difficult to explain on the domain-specific knowledge theory. However, an account is still needed of the differences observed in MU's performance between the two paradigms. PMID- 20957575 TI - The selective impairment of fruit and vegetable knowledge:amultiple processing channels account of fine-grain category specificity. AB - We report the case of a gentleman, FAV, who developed a grave anomia and selective comprehension deficit following a left temporo-occipital infarction. His word retrieval abilities were significantly more impaired for living things than for man-made artefacts. There was no difference between his performance when naming to confrontation and naming to verbal description. However, further assessment revealed a more fine-grain deficit at the level of comprehension. FAV had significantly more difficulty with fruit and vegetables than animals or nonliving foods on a number of tests probing semantic knowledge. These results are discussed within the context of current theories of the organisation of conceptual knowledge. We conclude that this pattern of performance and other fine grain category effects within the realms of living and nonliving things are best explained by a multiple processing pathways account. PMID- 20957576 TI - A case of impaired knowledge for fruit and vegetables. AB - In this paper, we report the case of RS, a brain-damaged patient presenting with a disproportionate conceptual impairment for fruit and vegetables in comparison to animals and artefacts. We argue that such a finer-grained category-specific deficit than the living/nonliving dichotomy provides a source of critical evidence for assessing current alternative theories of conceptual organisation in the brain. The case study was designed to evaluate distinct expectations derived from the categorical and the knowledge-specific accounts for category-specific semantic deficits. In particular, the integrity of object-colour knowledge has been assessed in order to determine whether the patient's deficit for fruit and vegetables was associated with a deficit for that kind of knowledge, which has been claimed to be highly diagnostic for fruit and vegetables. The results showed that the patient's pattern of performance is consistent with theories assuming a topographical category-like organisation of conceptual knowledge in the brain. PMID- 20957577 TI - Genetic and environmental influences on the organisation of semantic memory in the brain:is "living things" an innate category? AB - The organisation of semantic memory into separately lesionable or imageable components must be determined by some combination of genetic and environmental factors. Little is known about the relative contributions of these two factors in establishing the functional architecture of semantic memory. By assessing the semantic memory impairment of an individual who sustained brain damage as a newborn, it is possible to place an upper bound on the contribution of post-natal experience. The present case study demonstrates a profound and enduring impairment in knowledge of "living things" following posterior cerebral artery infarctions at approximately 1 day of age. The design of the two experiments reported here allows us to characterise the subject's semantic memory impairment in terms of its scope and selectivity. The impairment affects both the naming of pictures of living things and the retrieval of verbal information about living things. It cannot be accounted for by differences in the difficulty of retrieving knowledge of living and nonliving things, as the living and nonliving items were equated for difficulty in each experiment. When visual and nonvisual information were queried separately for living and nonliving things, the impairment was manifest for both kinds of information about living things, but for neither kind of information about nonliving things. Because this impairment resulted from brain damage sustained too early for experience to have contributed to the organisation of semantic memory, this case study supports a genetic basis for the living-nonliving distinction in semantic memory. PMID- 20957578 TI - Neural correlates of conceptual knowledge for actions. AB - The neural correlates of conceptual knowledge for actions are not well understood. To begin to address this knowledge gap, we tested the hypothesis that the retrieval of conceptual knowledge for actions depends on neural systems located in higher-order association cortices of left premotor/prefrontal, parietal, and posterior middle temporal regions. The investigation used the lesion method and involved 90 subjects with damage to various regions of the left or right hemisphere. The experimental tasks measured retrieval of knowledge for actions, in a nonverbal format: Subjects evaluated attributes of pictured actions, and compared and matched pictures of actions. In support of our hypothesis, we found that the regions of highest lesion overlap in subjects with impaired retrieval of conceptual knowledge for actions were in the left premotor/prefrontal sector, the left parietal region, and in the white matter underneath the left posterior middle temporal region. These sites are partially distinct from those identified previously as being important for the retrieval of words for actions. We propose that a key function of the sites is to operate as two-way intermediaries between perception and concept retrieval, to promote the retrieval of the multidimensional aspects of knowledge that are necessary and sufficient for the mental representation of a concept of a given action. PMID- 20957579 TI - Constraining questions about the organisation and representation of conceptual knowledge. AB - In this article we assume a domain-specific organisation of conceptual knowledge and consider two questions: How does this architecture constrain further assumptions that might be made regarding (1) the organisation of conceptual knowledge in the brain, and (2) the representation of conceptual knowledge in the brain? Data from category-specific semantic deficits, functional neuroimaging, and apraxia are recruited in attempt to clarify these questions. It is shown that the domain-specific hypothesis can account for the extant facts. Furthermore, we outline one possible theoretical framework that imposes empirical constraints on proposals that might be advanced in response to the two questions raised above. PMID- 20957580 TI - The similarity-in-topography principle: reconciling theories of conceptual deficits. AB - Three theories currently compete to explain the conceptual deficits that result from brain damage: sensory-functional theory, domain-specific theory, and conceptual structure theory. We argue that all three theories capture important aspects of conceptual deficits, and offer different insights into their origins. Conceptual topography theory (CTT) integrates these insights, beginning with A. R. Damasio's (1989) convergence zone theory and elaborating it with the similarity-in-topography (SIT) principle. According to CTT, feature maps in sensory-motor systems represent the features of a category's exemplars. A hierarchical system of convergence zones then conjoins these features to form both property and category representations. According to the SIT principle, the proximity of two conjunctive neurons in a convergence zone increases with the similarity of the features they conjoin. As a result, conjunctive neurons become topographically organised into local regions that represent properties and categories. Depending on the level and location of a lesion in this system, a wide variety of deficits is possible. Consistent with the literature, these deficits range from the loss of a single category to the loss of multiple categories that share sensory-motor properties. PMID- 20957581 TI - Three parietal circuits for number processing. AB - Did evolution endow the human brain with a predisposition to represent and acquire knowledge about numbers? Although the parietal lobe has been suggested as a potential substrate for a domain-specific representation of quantities, it is also engaged in verbal, spatial, and attentional functions that may contribute to calculation. To clarify the organisation of number-related processes in the parietal lobe, we examine the three-dimensional intersection of fMRI activations during various numerical tasks, and also review the corresponding neuropsychological evidence. On this basis, we propose a tentative tripartite organisation. The horizontal segment of the intraparietal sulcus (HIPS) appears as a plausible candidate for domain specificity: It is systematically activated whenever numbers are manipulated, independently of number notation, and with increasing activation as the task puts greater emphasis on quantity processing. Depending on task demands, we speculate that this core quantity system, analogous to an internal "number line," can be supplemented by two other circuits. A left angular gyrus area, in connection with other left-hemispheric perisylvian areas, supports the manipulation of numbers in verbal form. Finally, a bilateral posterior superior parietal system supports attentional orientation on the mental number line, just like on any other spatial dimension. PMID- 20957582 TI - The influence of conceptual knowledge on visual discrimination. AB - Does conceptual knowledge about objects influence their perceptual processing? There is some evidence for interactions between semantic and visual knowledge in tasks requiring both long-term memory and lexical access. Here we assessed whether similar perceptual/semantic interactions arise during sequential visual matching, a task that does not require access to semantic information. Matching of two-dimensional or three-dimensional novel objects was facilitated when the objects were associated with arbitrarily assigned distinctive artificial semantic concepts as compared to similar semantic concepts. In contrast to prior demonstrations, this effect was obtained in a task that did not require naming objects, and was not affected by participants rehearsing consonant strings, suggesting a direct influence from semantic associations on visual object recognition. PMID- 20957583 TI - Role of mental imagery in a property verification task: FMRI evidence for perceptual representations of conceptual knowledge. AB - Is our knowledge about the appearance of objects more closely related to verbal thought or to perception? In a behavioural study using a property verification task, Kosslyn (1976) reported that there are both amodal and perceptual representations of concepts, but that amodal representations may be more easily accessed. However, Solomon (1997) argued that due to the nature of Kosslyn's stimuli, subjects may be able to bypass semantics entirely and perform this task using differences in the strength of association between words in true trials (e.g., cat-whiskers) and those in false trials (e.g., mouse-stinger). Solomon found no evidence for amodal representations when the task materials were altered to include associated false trials (e.g., cat-litter), which require semantic processing, as opposed to associative strategies. In the current study, we used fMRI to examine the response of regions of visual association cortex while subjects performed a property verification task with either associated or unassociated false trials. We found reliable activity across subjects within the left fusiform gyrus when true trials were intermixed with associated false trials but not when true trials were intermixed with unassociated false trials. Our data support the idea that conceptual knowledge is organised visually and that it is grounded in the perceptual system. PMID- 20957584 TI - Do semantic categories activate distinct cortical regions? Evidence for a distributed neural semantic system. AB - A key issue in cognitive neuroscience concerns the neural representation of conceptual knowledge. Currently, debate focuses around the issue of whether there are neural regions specialised for the processing of specific semantic attributes or categories, or whether concepts are represented in an undifferentiated neural system. Neuropsychological studies of patients with selective semantic deficits and previous neuroimaging studies do not unequivocally support either account. We carried out a PET study to determine whether there is any regional specialisation for the processing of concepts from different semantic categories using picture stimuli and a semantic categorisation task. We found robust activation of a large semantic network extending from left inferior frontal cortex into the inferior temporal lobe and including occipital cortex and the fusiform gyrus. The only category effect that we found was additional activation for animals in the right occipital cortex, which we interpret as being due to the extra visual processing demands required in order to differentiate one animal from another. We also carried out analyses in specific cortical regions that have been claimed to be preferentially activated for various categories, but found no evidence of any differential activation as a function of category. We interpret these data within the framework of cognitive accounts in which conceptual knowledge is represented within a nondifferentiated distributed system. PMID- 20957585 TI - How is the fusiform gyrus related to category-specificity? AB - There is growing evidence from functional imaging studies that distinct regions in the fusiform gyri are differentially sensitive to object category. In this paper, we investigate how the areas that are more sensitive to animals than tools respond to other visual and semantic variables. We illustrate that (1) category effects in the fusiform areas are stronger for pictures of objects than their written names; (2) retrieving information on the colour or size of objects activates a left lateralised fusiform area that lies anterior to the category sensitive areas; and (3) both left and right category-sensitive areas respond strongly to visual feature detection on false fonts-meaningless visual stimuli with no semantic associations. These results dissociate the responses in two fusiform areas: The posterior category-sensitive areas are primarily modulated by visual input, whereas a more anterior polymodal region is involved in the retrieval of visual information. In addition, we demonstrate that the posterior areas which are more active for animals than tools are also more active for fruits than tools. Our data are therefore consistent with the proposal that activation in the lateral posterior fusiform gyri reflects the demands on structural differentiation. Since animals and fruits tend to have more structurally similar neighbours than man-made kinds of objects, category effects are likely to be observed during most picture identification tasks. In contrast, when the stimuli are written or auditory names, category effects may only be observed when the task requires access to fine spatial details in the objects' structures. PMID- 20957586 TI - A Case Study of Visual Agnosia without Perceptual Processing or Structural Descriptions Impairment. AB - We report a new case of visual associative agnosia. Our patient (DJ) was impaired in several tasks assessing visual processing of real objects, colour pictures, and line drawings. The deficit was present both with naming and gesturing responses. Object processing in other modalities (verbal, auditory nonverbal, and tactile) was intact. Semantic processing was impaired in the visual but not in the verbal modality. Picture-word matching was better than single picture identification. DJ's visual perceptual processing, was intact in several tasks such as visual attributes discrimination, shape discrimination, illusory contours perception, segmentation, embedded figures processing and matching objects under different viewpoints. Most importantly, we show that there was no impairment of stored structural descriptions and that the patient was able to build new visual representations. These results are considered in the context of Farah's (1990, 1991) proposals about visual associative agnosia. PMID- 20957587 TI - Autobiographical Memory and Autoneotic Consciousness in a case of Semantic Dementia. AB - Investigations of retrograde amnesia have contributed to a better understanding of the cerebral structures involved in remote memory. Such studies have suggested that neocortical regions such as the anterior temporal lobe play a major role in both the storage and retrieval of remote episodic and semantic information. Semantic dementia (SD), characterised as a focal anterior temporal lobe atrophy, offers an opportunity to study episodic remote memory, especially in the absence of day-to-day memory dysfunctioning, which takes place in permanent amnesic syndromes. Few studies have investigated autobiographical retrograde amnesia in SD. We present the findings from a patient (AT) at the early stage of SD. First, we have compared episodic and semantic components of autobiographical memory using two specially designed fluency tasks. The results demonstrated good recall of autobiographical events from all time periods and poor retrieval of names of acquaintances, albeit to a lesser degree, with respect to recent life. Second, we have investigated strictly episodic autobiographical memory and autonoetic consciousness by means of a sophisticated autobiographical test and the Remember/Know procedure which used a more stringent criterion of episodicity. The results demonstrated a relatively good recall of autobiographical memories (whatever their nature) but poor retrieval of remote specific detailed memories compared to recent ones. Moreover, patient AT provided Remember judgements to the same extent as control subjects regardless of the time interval covered although his responses were not justified in terms of the actual contextual information retrieved beyond the last 5 years. These findings provide further evidence that strictly episodic recollection is restricted to the recent past in SD. These data are discussed according to their relevance to the episodic and semantic distinction and to models of long-term memory consolidation. PMID- 20957588 TI - Visual and Spatial Short-term Memory in Integrative Agnosia. AB - The extent to which imagery and perceptual processes overlap in the brain has been the focus of a number of studies using different experimental methodologies (e.g., studies of functional brain activation and studies of patients with selective deficits following brain damage). Here we report the results of a number of different experimental investigations exploring visual memory in a patient with a severe perceptual deficit (HJA). We demonstrate that HJA can perform imagery tasks well that require judgements about a single object or object part; however, he experiences difficulty on tasks where he has to respond to the spatial relations between the local parts of objects. He experiences similar difficulties in perceptual processing. We argue that the bottom-up coding of visual images is influenced by the same intermediate visual processes that serve object recognition. PMID- 20957589 TI - Attentional functions in dorsal and ventral simultanagnosia. AB - Whole report of brief letter arrays is used to analyse basic attentional deficits in dorsal and ventral variants of simultanagnosia. Using Bundesen's Theory of Visual Attention (TVA), a number of previous theoretical suggestions are formalised and tested, including primary deficit in processing more than one display element, attentional stickiness, foveal bias, and global weakness of the visual representation. Interestingly, data from two cases, one dorsal and one ventral, show little true deficit in simultaneous perception, or selective deficit in those TVA parameters (short-term memory capacity, attentional weighting) specifically associated with multi-element displays. Instead there is a general reduction in speed of visual processing (processing rate in TVA), effective even for a single display element but compounded when two or more elements compete. PMID- 20957590 TI - Lost for words or loss of memories? Autobiographical memory in semantic dementia. AB - Recent reports have suggested that patients with semantic dementia show a loss of early (remote) auto-biographical memories with pronounced sparing of recent memories (Graham & Hodges, 1997; Snowden, Griffiths, & Neary, 1996), i.e., a 'reversed' temporal gradient or 'Ribot effect'. At first sight, these findings suggest that the deficits in 'semantic' dementia go beyond the semantic domain, involving aspects of autobiographical (episodic) memory. It has also been proposed that there is a 'step-like' function with personal memories preserved for 18 months to 2 years in the immediate past. This view is consistent with the theory that the hippocampal complex/medial temporal lobe (relatively intact in semantic dementia) plays a time-limited role in the acquisition and storage of memories, while the temporal neocortex (damaged in semantic dementia) is required for long-term storage and retrieval. In this study we ask whether (a) previous tests have underestimated the integrity of remote memory in semantic dementia as a result of not allowing for these patients' comprehension and language production difficulties, and (b) whether a recency effect, if obtained, is genuinely step-like or more graded. We used a cued autobiographical memory interview with semantic dementia patient, IH, to examine the effect of providing increasingly specific lexical cues to probe salient events throughout his lifespan. Results demonstrated that the provision of specific cues enabled IH to access and express memories from his childhood and early adulthood as well as from more recent times. There was a gentle recency effect only for intermediate levels of cueing, indicating that recent memories were easier to retrieve and/or express in the absence of specific cues, but this effect was graded, with no evidence of a step-like cut-off at 18 months or 2 years before testing. In brief, our findings are consistent with the view that the deficits in semantic dementia are predominantly or exclusively semantic, rather than involving the storage of autobiographical memories per se. PMID- 20957591 TI - Endogenous and exogenous attention in patients with conversion paresis. AB - Endogenous and exogenous attention of patients with conversion paresis was investigated using Posner's 'covert orienting of visual attention' task. In the light of previous evidence showing that inhibition of higher-level control functions plays a role in conversion paralysis (e.g., Marshall, Halligan, Fink, Wade, & Frackowiak, 1997), patients were expected to display weaker cue effects in the endogenous condition and weaker inhibition of return (IOR) in the exogenous condition. Eight patients with conversion paresis in one or more limbs and eight healthy controls were administered the attention task in a verbal response condition and in a limb response condition in which subjects responded with each limb separately. When responding verbally, patients showed relatively weakened endogenous cue effects on a 150-ms stimulus onset asynchronicity (SOA) and no IOR in the exogenous condition. Comparable effects emerged when patients responded with affected limbs but not when they responded with unaffected limbs. The findings suggest impairment in voluntary attention. High-level inhibition is suggested to interfere with the orientation to stimuli that prime responses with affected limbs. The fact that similar results were found for verbal responses is interpreted as supporting the view that attention deficits are manifested on a high, abstract level of cognitive processing. PMID- 20957592 TI - [Social medicine education, graduate education and continuing education]. PMID- 20957593 TI - [Feedback as key element of a new culture of teaching and learning. Part 1: theoretical background]. PMID- 20957594 TI - [Targeted methods for measuring patient satisfaction in a radiological center]. AB - PURPOSE: To investigate two event-oriented methods for evaluating patient satisfaction with radiological services like outpatient computed tomography (CT) examinations. MATERIALS AND METHODS: 159 patients (55% men, 45% women) were asked to complete a questionnaire to provide information about their satisfaction with their examination. At first, patients were asked to spontaneously recall notably positive and negative aspects (so-called "critical incidents", critical incident technique = CIT) of the examination. Subsequently a flow chart containing all single steps of the examination procedure was shown to all patients. They were asked to point out the positive and negative aspects they perceived at each step (so-called sequential incident technique = SIT). RESULTS: The CIT-based part of the questionnaire yielded 356 comments (183 positive and 173 negative), which were assigned to one of four categories: interaction of staff with patient, procedure and organization, CT examination, and overall setting of the examination. Significantly more detailed comments regarding individual aspects of the CT examination were elicited in the second part of the survey, which was based on the SIT. There were 1413 statements with a significantly higher number of positive comments (n = 939, 66%) versus negative comments (n = 474, 34%; p < 0.001). CONCLUSION: The critical and sequential incident techniques are suitable to measure the subjective satisfaction with the delivery of radiological services such as CT examinations. Positive comments confirm the adequacy of the existing procedures, while negative comments provide direct information about how service quality can be improved. PMID- 20957595 TI - Toxicogenomics for the prediction of toxicity related to herbs from traditional Chinese medicine. AB - Toxicogenomics represents the integration of genomics and toxicology to investigate the interaction between genes and environmental stress in human health. It is a scientific field that studies how the genome is involved in responses to environmental stressors and toxicants. The patterns of altered gene expression that are caused by specific exposures or disease outcomes reveal how toxicants may act and cause disease. Nowadays, toxicogenomics faces great challenges in discriminating the molecular basis of toxicity. We do believe that advances in this field will eventually allow us to describe all the toxicological interactions that occur within a living system. Toxicogenomic responses of a toxic agent in one species (e.g., laboratory animals) may predict the mode of action in another species (e.g., humans) (predictive toxicology). Development and application of toxicogenomic databases and new bioinformatics tools are among the most important aspects of toxicogenomic research which will facilitate sharing and interpretation of the huge amount of biological information generated in this field. Medicinal herbs have played an important role in pharmacy from ancient to modern times. Nowadays, there is a revival of interest in medicinal plants and an increasing scientific interest in bioactive natural products. Medicinal herbs are usually considered to be nontoxic. However, the consumption of herbs could produce prominent toxic effects either due to inherent toxicity or to contaminants (heavy metals, microorganisms, pesticides, toxic organic solvents, radioactivity, etc.). Therefore, a critical assessment of their toxicity is an urgent issue. This review explores the field of toxicogenomics, pinpoints some of its research approaches and describes the challenges it faces. In particular, Chinese herbal preparations have been implicated. PMID- 20957596 TI - Plant products in the treatment and control of filariasis and other helminth infections and assay systems for antifilarial/anthelmintic activity. AB - Lymphatic filariasis, onchocerciasis, loaisis, and other helminth infections cause serious health problems especially in resource-limited tropical and subtropical developing countries of the world, and more than 2 billion people are infected with at least one helminth species. From times immemorial, man looked up to the plant kingdom in search of anthelmintics, antifilarials, and remedies for parasite-induced health problems. Although more than 50 % of drugs in modern medicine are derived from plants or leads from plants, a success story of plant based anthelminthics or antifilarials is yet to be told. In the last 5 decades, more than 100 plant products were reported to be beneficial in the treatment or control of these parasitic infections but they could not be developed into viable drugs for a variety of reasons. This review focuses on the plant products reported to be useful in the control and treatment of human helminth infections with the main emphasis on filariasis and the in vitro and in vivo systems available for assaying anthelmintic activity. PMID- 20957597 TI - PPARalpha activation by culinary herbs and spices. AB - Hyper- and dyslipidemia are risk factors for cardiovascular disease, the primary cause of death in industrialized countries. Peroxisome proliferators-activated receptor (PPAR)alpha activation is involved in various mechanisms that improve the lipid profile. We tested various plant extracts and their compounds to determine whether they stimulated PPARalpha activity in vitro. Out of 34 tested plant extracts, nine exhibited low to moderate PPARalpha transactivation, including caraway, chili pepper, nutmeg, licorice, black and white pepper, paprika, coriander, saffron, and stevia tea. The active components of black pepper and chili pepper, piperine, and capsaicin exerted the highest transactivational activities with EC50 values of 84 uM and 49 uM, respectively. The chalcones, including 2-hydroxychalcone, 2'-hydroxychalcone, 4 hydroxychalcone, and 4-methoxychalcone, moderately transactivated PPARalpha. Resveratrol and apigenin only slightly transactivated PPARalpha. These results suggest that a diet rich in fruit, herbs, and spices provides a number of PPARalpha agonists that might contribute to an improved lipid profile. PMID- 20957599 TI - [Clinical views on biosignal processing of ventilation in sleep medicine]. AB - Biological signals recorded by polysomnography such as electroencephalograms (EEG), electrooculograms (EOG) und electromyograms (EMG), airflow, thoracic and abdominal motions, O(2) saturation and heart frequency pass through a processing chain with amplification and filtering of the measured variables. In the signal processing the original signal is manipulated to extract information in order to correlate various parameters and to visualise the signal in different representations. The task of the clinician is now to take advantage of the information available and to come to clinical conclusions. Therefore the characteristics, especially the methodology of the signal processing in the devices, should be disclosed by the manufacturers and thus be verifiable. In this review for the example of O(2) saturation, the consequence of different processing criteria with regard to the apnea/hypopnea index is presented. Biosignals such as the respiratory flow are also increasingly being used to control therapy equipment for automatic CPAP devices (APAP). However, the implemented algorithms are often not known, and cannot directly be derived from the polysomnographic records under APAP therapy. In model experiments with a flow generator, defined flow patterns can be simulated. Using bench tests with simulated apneas and waking periods, diagnosed from the flow characteristics, the methods of signal processing can be verified by measuring the pressure profiles and made more transparent for the clinician. PMID- 20957598 TI - Flavonoid pharmacokinetics and tissue distribution after repeated dosing of the roots of Scutellaria baicalensis in rats. AB - Scutellariae Radix (root of Scutellaria baicalensis, SR) contains numerous flavonoids such as baicalin, baicalein, and wogonin. This study investigated the pharmacokinetics and tissue distribution of flavonoids and their metabolites in rats after repeated dosing of a SR decoction. Sprague-Dawley rats were orally administered SR at 2 g/kg for seven doses. After the 7th dose, blood samples were withdrawn at specific times and organs, including the liver, kidney, lung, and brain, and collected. The concentrations of baicalein and wogonin in the serum and various tissues were assayed by HPLC before and after hydrolysis with glucuronidase and sulfatase. Baicalein and wogonin were not detected in the serum, and the molecules found were their glucuronides/sulfates. In tissues, the free forms of baicalein and wogonin appeared in the liver, kidney, and lung in addition to their glucuronides/sulfates. Baicalein was the major form in the lung, whereas baicalein glucuronides/sulfates were the major forms in the liver and kidney. Wogonin was the major form in the liver, kidney, lung, and traces of wogonin glucuronides/sulfates were detected in the kidney and liver. Neither baicalein and wogonin nor their glucuronides/sulfates were detected in the brain. In conclusion, the glucuronides/sulfates of baicalein and wogonin were exclusively present in the circulation, whereas their free forms appeared in the lung, liver, and kidney. PMID- 20957600 TI - Effect of fat supplementation on the maintenance of gut integrity in elemental diet-fed rats. AB - AIMS: The aims of this study were to investigate the mechanism of atrophic change in ileal mucosa supplied with an elemental diet (ED) and to assess the value of supplemented fat emulsion in the prevention of atrophic change. MATERIALS AND METHODS: In experiment 1, 25 male Wistar rats with a body weight of 160-180 g were divided into 3 groups. The first group was fed regular rat chow (Control group, n=5). The second group was given ED containing 0.6% long-chain triglycerides (ED group, n=10). The third group was provided with fat-enriched ED (FED) containing 3.5% long-chain triglycerides (FED group, n=10). Each group received an isocaloric diet (300 kcal/kg/day). 4 weeks later, after euthanization, ileal samples were taken for light and electron microscopic examinations. The morphological changes of the intestinal mucosa and the crypt cell proliferation rate (CCPR) were determined. In experiment 2, to determine the site of fat absorption, 9 rats were fed ED for 1 week. After 24 h of food deprivation, all rats were given 2 ml of FED through a gastric tube. Then 1, 2, and 3 h(s) later, groups of 3 rats each were euthanized, and the total small intestine was obtained from each rat. The proximal and distal jejunum and distal ileum were stained with oil red O. RESULTS: In experiment 1, the samples had almost the same morphological appearance irrespective of the type of feeding. The CCPR was significantly diminished in the ED group compared with the Control group, while there was no statistical difference between the FED and Control groups. In experiment 2, the oil red O stain was positive in the proximal and distal jejunum, but was completely negative in the distal ileum. CONCLUSIONS: The introduction of ED does not soon result in an atrophic morphological change of the ileum but will decrease the CCPR. An additive fat emulsion which was rapidly absorbed by the distal jejunum could play a role in maintaining ileal mucosa integrity through some mechanism independent of absorption. PMID- 20957601 TI - Open versus laparoscopic pyloromyotomy for pyloric stenosis: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: Aim of the study was to compare the outcomes after laparoscopic pyloromyotomy (LP) with those of open pyloromyotomy (OP) for infantile pyloric stenosis. METHOD: We conducted searches until February 2009 in multiple databases and identified randomized controlled trials comparing LP with OP for pyloric stenosis. Results were expressed using the odds ratio (OR) for categorical variables and standard weighted mean differences (SMD) for continuous outcomes. Study quality was assessed using the Cochrane Handbook 5.0.1 guidelines and statistical analysis was performed using RevMan 5.0.8 software. RESULTS: 3 studies totaling 492 infants were included. The results showed no significant differences in complications between the groups with regard to wound infection (OR: 1.77, 95% CI 0.58-5.35), mucosal perforations (OR: 0.96, 95% CI: 0.22-4.26), incisional hernia or granuloma (OR: 1.39, 95% CI: 0.41-4.73), incomplete pyloromyotomy (OR: 0.13, 95% CI: 0.02-1.07), substantial vomiting (OR: 0.67, 95% CI: 0.30-1.52) and total complications (OR: 0.91, 95% CI: 0.54-1.53). Although the combined result of 2 studies also indicated an insignificant discrepancy in time-related outcomes for full time to feeds, length of stay after surgery and operating time (SMD: 0.78, 95% CI: -0.50-2.06; SMD: 1.27, 95% CI: -1.56-4.10; SMD: -0.46, 95% CI: -1.11-0.20, respectively), another study indicated shorter times for LP procedures (p=0.002, 0.027, and 0.008, respectively). CONCLUSIONS: Only a few trials were available for analysis. Heterogeneity was seen between studies, but the available trials were of high quality. The present study shows that both OP and LP are equally safe and effective procedures for the management of pyloric stenosis in children. However, there was a trend in LP toward shorter time time-related outcomes. PMID- 20957602 TI - Slippage of the proximal femoral epiphysis related to multiple enchondromatosis: treatment with staged surgical dislocation and epiphyseal realignement. A case report at seven years follow up. PMID- 20957603 TI - Prospecting candidate SNPs for backfat in Canchim beef cattle. AB - Canchim is a composite cattle breed developed in Brazil for beef production. One of the breeding objectives is to increase fat deposition. QTLs for fat thickness and/or marbling have been reported on BTA4 and BTA14. The IGFBP3 and DDEF1 genes, mapped to BTA4 and BTA14, respectively, affect adipogenesis. We looked for SNPs in the IGFBP3 and DDEF1 genes that could be associated with backfat thickness in Canchim beef cattle. For SNP identification, sires with the highest accuracy were ranked according to expected breeding value for fat thickness; the 12 extremes (six sires with the highest and six with the lowest expected breeding value for the trait) were chosen. Six regions of the IGFBP3 and 14 regions of the DDEF1 were sequenced using the Sanger method. Nine SNPs were identified in IGFBP3 and 76 in the DDEF1. After an initial analysis, two SNPs were selected to be genotyped for the whole population; these were DDEF1g.279401A>G and IGFBP3c.4394T>C(Trp>Arg). We found a significant effect (P <= 0.05) of allele substitution on backfat thickness; however, the IGFBP3 SNP did not significantly affect this trait. PMID- 20957604 TI - Giant panda ribosomal protein S14: cDNA, genomic sequence cloning, sequence analysis, and overexpression. AB - RPS14 is a component of the 40S ribosomal subunit encoded by the RPS14 gene and is required for its maturation. The cDNA and the genomic sequence of RPS14 were cloned successfully from the giant panda (Ailuropoda melanoleuca) using RT-PCR technology and touchdown-PCR, respectively; they were both sequenced and analyzed. The length of the cloned cDNA fragment was 492 bp; it contained an open reading frame of 456 bp, encoding 151 amino acids. The length of the genomic sequence is 3421 bp; it contains four exons and three introns. Alignment analysis indicates that the nucleotide sequence shares a high degree of homology with those of Homo sapiens, Bos taurus, Mus musculus, Rattus norvegicus, Gallus gallus, Xenopus laevis, and Danio rerio (93.64, 83.37, 92.54, 91.89, 87.28, 84.21, and 84.87%, respectively). Comparison of the deduced amino acid sequences of the giant panda with those of these other species revealed that the RPS14 of giant panda is highly homologous with those of B. taurus, R. norvegicus and D. rerio (85.99, 99.34 and 99.34%, respectively), and is 100% identical with the others. This degree of conservation of RPS14 suggests evolutionary selection. Topology prediction shows that there are two N-glycosylation sites, three protein kinase C phosphorylation sites, two casein kinase II phosphorylation sites, four N-myristoylation sites, two amidation sites, and one ribosomal protein S11 signature in the RPS14 protein of the giant panda. The RPS14 gene can be readily expressed in Escherichia coli. When it was fused with the N-terminally His-tagged protein, it gave rise to accumulation of an expected 22-kDa polypeptide, in good agreement with the predicted molecular weight. The expression product obtained can be purified for studies of its function. PMID- 20957605 TI - M13-microsatellite PCR and rDNA sequence markers for identification of Trichoderma (Hypocreaceae) species in Saudi Arabian soil. AB - Seven fungal isolates were identified as pan-global Hypocrea/Trichoderma species, from section Trichoderma, on the basis of their morphology. These species were H. lixii/T. harzianum and H. orientalis/T. longibrachiatum. PCR-based markers with primer M13 (core sequence of phage M13) and internal-transcribed spacer sequences of ribosomal DNA were used to confirm the identity of the two Trichoderma species. Sequence identification was performed using the TrichOKEY version 2.0 barcode program and the multilocus similarity search database TrichoBLAST. Sequences from the ribosomal DNA internal-transcribed spacer regions showed limited variation among the Trichoderma species. This analysis divided the isolates into two main groups. Grouping the isolates based on cluster analysis of their DNA profiles matched the grouping based on morphological taxonomy. Molecular data obtained from analyses of gene sequences are essential to distinguish phonetically cryptic species in this group and to establish phylogenetic relationships. PMID- 20957606 TI - Differential diagnosis of active hypodermal and hematopoietic necrosis virus based on gene choice and reverse transcription coupled with PCR. AB - The Pacific whiteleg shrimp Litopenaeus vannamei (Penaeidae) is one of the most important cultivated species in world aquaculture. In Brazil, the northeastern states are home to the main shrimp producers. As shrimp aquaculture has expanded and intensified, diseases have progressively become one of the most serious threats to this industry. Infectious hypodermal and hematopoietic necrosis virus (IHHNV) is an enzootic viral agent in Brazilian shrimp farms. Its is usually diagnosed by histological methods. However, to detect sub-clinical or acute IHHNV infection, more refined methods based on molecular techniques have been utilized. We found that by using "universal" primers and a single-step PCR diagnostic test, it was difficult to distinguish between non-infective forms of the virus and active IHHNV. Detection of IHHNV was more accurate when we used two alternative molecular strategies, namely 1) single-step PCR amplification based on gene choice and 2) reverse transcription coupled with PCR. PMID- 20957607 TI - An interspecific QTL study of Drosophila wing size and shape variation to investigate the genetic basis of morphological differences. AB - The Drosophila wing has been used as a model in studies of morphogenesis and evolution; the use of such models can contribute to our understanding of mechanisms that promote morphological divergence among populations and species. We mapped quantitative trait loci (QTL) affecting wing size and shape traits using highly inbred introgression lines between D. simulans and D. sechellia, two sibling species of the melanogaster subgroup. Eighteen QTL peaks that are associated with 12 wing traits were identified, including two principal components. The wings of D. simulans and D. sechellia significantly diverged in size; two of the QTL peaks could account for part of this interspecific divergence. Both of these putative QTLs were mapped at the same cytological regions as other QTLs for intraspecific wing size variation identified in D. melanogaster studies. In these regions, one or more loci could account for intra- and interspecific variation in the size of Drosophila wings. Three other QTL peaks were related to a pattern of interspecific variation in wing size and shape traits that is summarized by one principal component. In addition, we observed that female wings are significantly larger and longer than male wings and the second, fourth and fifth longitudinal veins are closer together at the distal wing area. This pattern was summarized by another principal component, for which one QTL was mapped. PMID- 20957608 TI - Bacterial culture and antibiotic susceptibility testing. AB - Complicated bacterial infections should prompt clinicians to pursue a definitive diagnosis. Two methods of bacterial culture and antibiotic susceptibility testing are commonly used in veterinary medicine: (1) the disk diffusion technique and (2) the broth dilution technique. Both methods identify the infecting pathogen and the antibiotics that are likely to inhibit its growth. The broth dilution test also provides the minimal inhibitory concentration, which can help in making the best antibiotic choice. PMID- 20957609 TI - Fluoroquinolones: then and now. AB - Fluoroquinolones were discovered in the 1960s as a derivative of the antimalarial drug chloroquine. Over the past 40 years, many fluoroquinolones have been developed for use in human and veterinary medicine. As with all classes of antibiotics, resistance to fluoroquinolones is a serious concern, and multiple avenues for resistance are being investigated. Resistance-associated point mutations in bacterial DNA and, more recently, plasmid-mediated resistance have been reported in both human and veterinary bacterial isolates. This article reviews the history and most current literature on fluoroquinolones approved for use in dogs and cats and the spectra of activity, mechanisms of action, resistance patterns, and recommendations for appropriate clinical use of these drugs. PMID- 20957610 TI - Gastroesophageal intussusception in a German shepherd. PMID- 20957611 TI - Giardia infection in cats. AB - The protozoon Giardia duodenalis is a common gastrointestinal parasite of cats. While most Giardia-infected cats are asymptomatic, acute small bowel diarrhea, occasionally with concomitant weight loss, may occur. Giardia poses a diagnostic challenge, but newer tests, including a commercially available ELISA kit, have improved clinicians' ability to obtain an accurate diagnosis. Several treatment options have been reported, and although none has been shown to be universally effective, most cases can be successfully managed with drug therapy, supportive measures, and environmental control. Current recommendations suggest that combination therapy with fenbendazole and metronidazole may be the safest, most effective treatment option for symptomatic cats. PMID- 20957612 TI - The final diagnosis: the veterinarian-client bond--stronger than expected. PMID- 20957613 TI - Evaluation of the potential use of adipose-derived mesenchymal stromal cells in the treatment of canine atopic dermatitis: a pilot study. AB - Stem cells and their potential therapeutic uses in human and veterinary medicine have generated considerable interest. These cells have a number of potentially unique immunologic properties; most notable are their reported regenerative and antiinflammatory capabilities. The aim of this prospective pilot study was to evaluate the efficacy of intravenously administered autogenous adipose-derived mesenchymal stem cells (AD-MSCs) in the treatment of canine atopic dermatitis. AD MSCs administered intravenously at a dose of 1.3 million cells/kg did not significantly reduce the clinical signs of canine atopic dermatitis or the owner assessed pruritus level. PMID- 20957614 TI - Antimicrobial activity of tulathromycin and 14 other antimicrobials against virulent Rhodococcus equi in vitro. AB - This study determined the antimicrobial activity of tulathromycin against Rhodococcus equi in vitro. Ninety-eight virulent isolates of R. equi from equine clinical cases were examined, of which 20 isolates were macrolide resistant. A custom 96-well antimicrobial susceptibility testing plate was used, allowing 14 additional antimicrobials to be tested against R. equi. Isolates were cultured with various concentrations of antimicrobials, and minimal inhibitory concentration (MIC) values were determined. Tulathromycin was found to have poor activity in vitro against R. equi isolates susceptible or resistant to macrolides, with MIC50 and MIC90 values >64 ug/mL for all isolates. MIC values for other macrolides tested were similar to previously published data. PMID- 20957615 TI - Ex vivo viability of canine and feline sarcomas: a pilot study. AB - Assay-based chemotherapeutic protocols are common in human gynecologic oncology, most notably for patients with ovarian or breast cancer. The current study examines ex vivo incubation conditions necessary for the assessment of sarcomatous tumor response to potential chemotherapeutic drugs. Slices of sarcomatous tumors were incubated in one of two culture media. Viability indices were measured and compared across time and between media. Neither medium was sufficient to support the growth of sarcomatous tumor tissue slices based on the indices studied. It is likely that sarcomatous tumors require a different approach for ex vivo assessment than their epithelial counterparts. Our long-term goal is to incubate tumor slices with chemotherapeutic agents to predict the in vivo tumor response based on the maintenance or loss of slice viability within this system. PMID- 20957616 TI - Protection against feline leukemia virus challenge for at least 2 years after vaccination with an inactivated feline leukemia virus vaccine. AB - Twelve cats were vaccinated at 8 and 11 weeks of age with a commercially available inactivated FeLV vaccine (Nobivac FeLV, Intervet/Schering-Plough Animal Health). Eleven cats served as age-matched, placebo-vaccinated controls. All cats were kept in isolation for 2 years after vaccination and were then challenged with virulent FeLV to evaluate vaccine efficacy and duration of immunity. Cats were monitored for 12 weeks after challenge for development of persistent viremia using a commercial FeLV p27 ELISA. Persistent viremia developed in all 11 (100%) of the control cats, whereas 10 of 12 (83%) vaccinated cats were fully protected from persistent viremia following challenge. The results demonstrate that the vaccine used in this study protects cats from persistent FeLV viremia for at least 2 years after vaccination. PMID- 20957617 TI - A noninferiority clinical trial comparing fluconazole and ketoconazole in combination with cephalexin for the treatment of dogs with Malassezia dermatitis. AB - This double-blinded noninferiority clinical trial evaluated the use of oral fluconazole for the treatment of Malassezia dermatitis in dogs by comparing it with use of an accepted therapeutic agent, ketoconazole. Dogs presenting with Malassezia dermatitis were treated with either fluconazole or ketoconazole in addition to cephalexin for concurrent bacterial dermatitis. Statistically significant improvements in cytologic yeast count, clinical signs associated with Malassezia dermatitis, and pruritus were seen with both antifungal treatments. There was no statistical difference between the treatments with regard to the magnitude of reduction in these parameters. These results suggest that fluconazole is at least as effective as ketoconazole for the treatment of dogs with Malassezia dermatitis. PMID- 20957618 TI - Why PMO? Towards functionality and utility of periodic mesoporous organosilicas. AB - Creative synthetic chemistry has endowed the class of periodic mesoporous organosilica materials, dubbed PMO, with a variety of new and exciting compositions, properties, and functions since its inception a decade ago. Using a handful of recent trendsetting case histories, the multidisciplinary applications of PMO materials in chemistry and physics, materials science and engineering, biology, and medicine are demonstrated in a most powerful way. In doing so, this Review aims to inspire more collaborative and ambitious endeavors in the second decade of PMO research. PMID- 20957619 TI - Logic-embedded vectors for intracellular partitioning, endosomal escape, and exocytosis of nanoparticles. AB - A new generation of nanocarriers, logic-embedded vectors (LEVs), is endowed with the ability to localize components at multiple intracellular sites, thus creating an opportunity for synergistic control of redundant or dual-hit pathways. LEV encoding elements include size, shape, charge, and surface chemistry. In this study, LEVs consist of porous silicon nanocarriers, programmed for cellular uptake and trafficking along the endosomal pathway, and surface-tailored iron oxide nanoparticles, programmed for endosomal sorting and partitioning of particles into unique cellular locations. In the presence of persistent endosomal localization of silicon nanocarriers, amine-functionalized nanoparticles are sorted into multiple vesicular bodies that form novel membrane-bound compartments compatible with cellular secretion, while chitosan-coated nanoparticles escape from endosomes and enter the cytosol. Encapsulation within the porous silicon matrix protects these nanoparticle surface-tailored properties, and enhances endosomal escape of chitosan-coated nanoparticles. Thus, LEVs provide a mechanism for shielded transport of nanoparticles to the lesion, cellular manipulation at multiple levels, and a means for targeting both within and between cells. PMID- 20957620 TI - Rapid patterning of single-wall carbon nanotubes by interlayer lithography. PMID- 20957621 TI - Bismuth-doped ordered mesoporous TiO2: visible-light catalyst for simultaneous degradation of phenol and chromium. AB - A controllable and reproducible synthesis of highly ordered two-dimensional hexagonal mesoporous, crystalline bismuth-doped TiO(2) nanocomposites with variable Bi ratios is reported here. Analyses by transmission electron microscopy, X-ray diffraction, Raman, and X-ray photoelectron spectroscopy reveal that the well-ordered mesostructure is doped with Bi, which exists as Bi(3+) and Bi((3+x+)). The Bi-doped mesoporous TiO(2) (ms-TiO(2)) samples exhibit improved photocatalytic activities for simultaneous phenol oxidation and chromium reduction in aqueous suspension under visible and UV light over the pure ms TiO(2), P-25, and conventional Bi-doped titania. The high catalytic activity is due to both the unique structural characteristics and the Bi doping. This new material extends the spectral response from UV to the visible region, and reduces electron-hole recombination, which renders the 2.0% Bi-doped ms-TiO(2) photocatalyst highly responsive to visible light. PMID- 20957622 TI - On the origin of altered diastereomeric ratios for anionic versus neutral reaction conditions in the oxy-Cope/ene reaction: an interplay of experiment and computational modeling. AB - We report herein a detailed investigation into the reaction mechanism for a sequential oxy-Cope/ene reaction under anionic conditions. With DFT calculations and ab initio molecular dynamics simulations, the observed diastereoselectivity is shown to be the result of an isomerization of the enolate olefin, which would evidently not occur under neutral conditions. The potential energy surface was thoroughly mapped out for the reaction pathways and the proposed mechanism confirmed the different product distributions observed under neutral and anionic oxy-Cope conditions. In addition, other possible pathways are shown to be higher in energy and experimental evidence is given that supports the olefin isomerization pathway. PMID- 20957623 TI - High-pressure investigations under CO/H2 of rhodium complexes containing hemispherical diphosphites. AB - The two rhodium complexes [Rh(acac)(L(R))] (L(R)=(S,S)-5,11,17,23-tetra-tert butyl-25,27-di(OR)-26,28-bis(1,1'-binaphthyl-2,2' dioxyphosphanyloxy)calix[4]arene; 6: R=benzyl, 7: R=fluorenyl), each based on a hemispherical chelator forming a pocket about the metal centre upon chelation, are active in the hydroformylation of 1-octene and styrene. As expected for this family of diphosphanes, both complexes resulted in remarkably high selectivity towards the linear aldehyde in the hydroformylation of 1-octene (l/b~15 for both complexes). Linear aldehyde selectivity was also observed when using styrene, but surprisingly only 6 displayed a marked preference for the linear product (l/b=12.4 (6) vs. 1.9 (7)). A detailed study of the structure of the complexes under CO or CO/H(2) in toluene was performed by high-pressure NMR (HP NMR) and FT IR (HP-IR) spectroscopies. The spectroscopic data revealed that treatment of 6 with CO gave [Rh(acac)(CO)(eta(1)-L(benzyl))] (8), in which the diphosphite behaves as a unidentate ligand. Subsequent addition of H(2) to the solution resulted in a well-defined chelate complex with the formula [RhH(CO)(2)(L(benzyl))] (9). Unlike 6, treatment of complex 7 with CO only led to ligand dissociation and concomitant formation of [Rh(acac)(CO)(2)], but upon addition of H(2) a chelate complex analogous to 9 was formed quantitatively. In both [RhH(CO)(2)(L(R))] complexes the diphosphite adopts the bis-equatorial coordination mode, a structural feature known to favour the formation of linear aldehydes. As revealed by variable-temperature NMR spectroscopy, these complexes show the typical fluxionality of trigonal bipyramidal [RhH(CO)(2)(diphosphane)] complexes. The lower linear selectivity of 7 versus 6 in the hydroformylation of styrene was assigned to steric effects, due to the pocket in which the catalysis takes place being less adapted to accommodate CO or larger olefins and, therefore, possibly leading to facile ligand decoordination. This interpretation was corroborated by an X-ray structure determination carried out for 7. PMID- 20957624 TI - Tetra- to dodecanuclear oxomolybdate complexes with functionalized bisphosphonate ligands: activity in killing tumor cells. AB - We report the synthesis and characterization of five novel Mo-containing polyoxometalate (POM) bisphosphonate complexes with nuclearities ranging from 4 to 12 and with fully reduced, fully oxidized, or mixed-valent (Mo(V), Mo(VI)) molybdenum, in which the bisphosphonates bind to the POM cluster through their two phosphonate groups and a deprotonated 1-OH group. The compounds were synthesized in water by treating [Mo(V)(2)O(4)(H(2)O)(6)](2+) or [Mo(VI)O(4)](2-) with H(2)O(3)PC(C(3)H(6)NH(2))OPO(3)H(2) (alendronic acid) or its aminophenol derivative, and were characterized by single-crystal X-ray diffraction and (31)P NMR spectroscopy. (NH(4))(6)[(Mo(V)(2)O(4))(Mo(VI)(2)O(6))(2)(O(3)PC(C(3)H(6)NH(3))OPO(3))(2)].12H( )O (1) is an insoluble mixed-valent species. [(C(2)H(5))(2)NH(2)](4)[Mo(V)(4)O(8)(O(3)PC(C(3)H(6)NH(3))OPO(3))(2)].6H(2)O (2) and [(C(2)H(5))(2)NH(2)](6)[Mo(V)(4)O(8)(O(3)PC(C(10)H(14)NO)OPO(3))(2)].18H(2)O (4) contain similar tetranuclear reduced frameworks. Li(8)[(Mo(V)(2)O(4)(H(2)O))(4)(O(3)PC(C(3)H(6)NH(3))OPO(3))(4)].45H(2)O (3) and Na(2)Rb(6)[(Mo(VI)(3)O(8))(4)(O(3)PC(C(3)H(6)NH(3))OPO(3))(4)].26H(2)O (5) are alkali metal salts of fully reduced octanuclear and fully oxidized dodecanuclear POMs, respectively. The activities of 2-5 (which are water-soluble) against three human tumor cell lines were investigated in vitro. Although 2-4 have weak but measurable activity, 5 has IC(50) values of about 10 MUM, which is about four times the activity of the parent alendronate molecule on a per-alendronate basis, which opens up the possibility of developing novel drug leads based on Mo bisphosphonate clusters. PMID- 20957625 TI - [Ln(binolam)3].(OTf)3, a new class of propeller-shaped lanthanide(III) salt complexes as enantioselective catalysts: structure, dynamics and mechanistic insight. AB - The ligand 3,3'-bis(diethylaminomethyl)-1,1'-bi-2-naphthol (binolam) contains an arrayed Bronsted acid-Bronsted base (BABB) system, which is responsible for the original shape of its lanthanide compounds. The solution structure of Pr, Nd and Yb compounds is solved by means of paramagnetic NMR spectroscopy and it is demonstrated that they are substantially isostructural, but with a completely new fold compared to the apparently similar heterobimetallic systems based on 1,1' bis(2-naphthol) (binol) and alkali cations. The aromatic nuclei lie in a region equatorial with respect to the C(3) symmetry axis, whereas the alkylamine chain stretches almost parallel to C(3), above (and below) Ln(3+). This is also found in the crystal structure of the binolamo-scandium complex. A detailed study of the proton-exchange processes within the network of BABBs present in the complex is reported, which provides insight into the mechanism of the enantioselective Henry reaction promoted by these systems. PMID- 20957626 TI - Regulation of tissue- and stimulus-specific cell fate decisions by p53 in vivo. AB - The tumour suppressor p53 pathway is often inactivated by multiple mechanisms in the genesis of human cancers. Aberrant cellular proliferation, DNA damage, hypoxia, and ribosomal stress cause activation of the p53 tumour suppressor with multiple possible consequences to the cell: cell death, cell cycle arrest, or senescence. These mechanisms ultimately ensure that the cell does not replicate, and are thus potent tumour suppressor mechanisms. An important question that has eluded the field is how p53 makes these cell fate decisions. This review summarizes the current status of knowledge regarding p53-mediated stress and tissue-dependent cell fate decisions in mouse models and human tumours. PMID- 20957627 TI - The dynamic roles of TGF-beta in cancer. AB - The transforming growth factor-beta (TGF-beta) signalling pathway plays a critical and dual role in the progression of human cancer. During the early phase of tumour progression, TGF-beta acts as a tumour suppressor, exemplified by deletions or mutations in the core components of the TGF-beta signalling pathway. On the contrary, TGF-beta also promotes processes that support tumour progression such as tumour cell invasion, dissemination, and immune evasion. Consequently, the functional outcome of the TGF-beta response is strongly context-dependent including cell, tissue, and cancer type. In this review, we describe the molecular signalling pathways employed by TGF-beta in cancer and how these, when perturbed, may lead to the development of cancer. Concomitantly with our increased appreciation of the molecular mechanisms that govern TGF-beta signalling, the potential to therapeutically target specific oncogenic sub-arms of the TGF-beta pathway increases. Indeed, clinical trials with systemic TGF-beta signalling inhibitors for treatment of cancer patients have been initiated. However, considering the important role of TGF-beta in cardiovascular and many other tissues, careful screening of patients is warranted to minimize unwanted on target side effects. PMID- 20957628 TI - Matrix metalloproteinase-9 is associated with disease-free survival and overall survival in patients with gastric cancer. AB - Matrix metalloproteinase-9 is a member of the Matrix metalloproteinases (MMP) family, which is overexpressed in some solid tumor and thought to enhance the tumor invasion and metastasis ability. Our study is to investigate the association of MMP-9 expression with disease-free survival and overall survival of patients with gastric cancer. Clinical gastric cancer specimens and adjacent normal tissues from 286 patients who had not received neoadjuvant chemotherapy were investigated by immunohistochemistry assay. Staining evaluation results were analyzed statistically in relation to various clinicopathological characters, disease-free survival and overall survival. High level of MMP-9 expression was detected in gastric cancer, significantly more than in adjacent normal epithelial cells. In gastric cancer, MMP-9 was significantly positively correlated with depth of invasion, lymph node metastasis and distant metastasis. However, no correlations between MMP-9 expression and patients' age, sex, tumor location or differentiation status were detected. The disease-free survival and overall survival were significantly shorter for patients with MMP-9 positive than those with MMP-9 negative tumors. Multivariate analysis identified MMP-9 was an independent prognostic factor for both disease-free survival and overall survival. Our findings provided convincing evidence for MMP-9 as an important role in human gastric cancer recurrence and prognosis. It might also serve as a novel target for both prognostic prediction and therapeutics. PMID- 20957629 TI - Bacillus Calmette-Guerin immunotherapy of bladder cancer induces selection of human leukocyte antigen class I-deficient tumor cells. AB - Bacillus Calmette-Guerin (BCG) immunotherapy is a standard treatment for high risk non-muscle-infiltrating bladder cancer patients. Although the outcomes are good, cancer relapse is observed in around 40% of patients. We present the comparative analysis of human leukocyte antigen (HLA) class I expression in recurrent bladder tumors in patients treated with mitomycin or BCG. HLA class I expression was analyzed by RT-Q-PCR and immunohistochemical techniques. Loss of heterozygosity (LOH) was determined by microsatellite amplification of markers in chromosome 6 and 15. More profound alterations in HLA class I expression were found in post-BCG recurrent tumors than in pre-BCG lesions, whereas mitomycin treatment did not change the HLA class I expression pattern. Post-BCG recurrent tumors also showed a higher incidence of structural defects underlying altered HLA class I expression. We hypothesize that the immunotherapy-activated immune system recognizes and eliminates tumor cells with reversible ("soft") HLA class I changes but not transformed cells with additional, irreversible ("hard") alterations. To our knowledge, this is the first clinical evidence of immunotherapy-induced immunoselection of HLA class I loss tumor variants in bladder cancer, although the study involved a small number of patients. PMID- 20957630 TI - Cancer registration and healthcare access in West Bank, Palestine: a GIS analysis of childhood cancer, 1998-2007. AB - In low and middle income countries (LMIC), high-quality disease registration is difficult to achieve in the setting of inadequate healthcare infrastructure and political or economical instability. In this article, we explore the potential of geographic information systems (GIS) to add value to the understanding of childhood cancer patterns in the West Bank, despite a variety of obstacles to disease registration. All incidence cases of childhood cancers (under the age 15) from 1998 to 2007 were collected from the West Bank Cancer Registry. Temporal, spatial and space-time analyses were performed using the SatScan software developed by Martin Kulldorff and the National Cancer Institute (NCI). The analyses were categorized into the following groups: all childhood cancer, leukemias, acute lymphocytic leukemia, lymphomas, brain and central nervous system (CNS) cancers and remaining cancers (excluding leukemia, lymphoma and CNS tumors). The temporal analysis revealed that cancer registration was more complete from 1998 to 2000 (p=0.0162), and that leukemia registration was severely deficient from 2003 to 2005 (p=0.0012). The spatial analysis showed a concentration of cancer in metropolitan districts where referral hospitals are based. Under registration was detected in the northern districts of Jenin and Tulkarm (RR=0.59, p=0.0059), more prominent from 2002 to 2005 (RR=0.33, p=0.0006). The analysis for high rates found a cluster of lymphoma in town of Dura and its surrounding agricultural villages (RR=4.10, p=0.0023). Our study reveals that the application of GIS tools to registry data in LMIC can help to identify geographical patterns in cancer registration and healthcare accessibility, generating priorities for future health research and policy in resource-limited areas. PMID- 20957631 TI - A comparison of human papillomavirus testing of clinician-collected and self collected samples during follow-up after screen-and-treat. AB - Screen-and-treat cervical cancer prevention programs based on high-risk human papillomavirus (HPV) testing and cryotherapy have been shown to be effective in resource-limited settings. However, because cryotherapy is not 100% effective, follow-up is needed after treatment to detect post-treatment failures. We compared the test performances of high-risk HPV testing (Hybrid Capture 2) using self-collected and clinician-collected samples as well as cervical cytology for identifying cervical intraepithelial neoplasia grades 2 or 3 or invasive cervical cancer (CIN2+) among women who did (n=812) and did not (n=1858) undergo cryotherapy in a South African screen-and-treat trial. At 6 months after enrolment (and after cryotherapy, if performed), women were tested using all three screening methods and then underwent colposcopy/biopsy. A predefined subset of women (n=1,455) had extended follow-up with colposcopy/biopsy at 12 months. A total of 33 and 91 cases of CIN2+ were detected among treated and untreated women, respectively. The sensitivity of HPV testing using clinician-collected samples and cervical cytology did not differ by treatment status. HPV testing of clinician-collected samples detected the most cases of CIN2+ among both treated (85%) and untreated (91%) women (p=0.31). Cytology (at a cutoff of atypical squamous cells of undetermined significance or greater) detected 76% of cases among both treated and untreated women. However, the sensitivity of HPV testing using self-collected samples was significantly lower among treated versus untreated women (55% vs. 78%, p=0.01). HPV testing using self-collected vaginal specimens may be useful in primary screening but performs poorly for detecting post-treatment failures. PMID- 20957632 TI - Oral contraceptives, menopausal hormone therapy use and risk of B-cell non Hodgkin lymphoma in the California Teachers Study. AB - We examined oral contraceptive (OC) and menopausal hormonal therapy (MHT) use in relation to risk of B-cell non-Hodgkin lymphoma (NHL). Women under age 85 years participating in the California Teachers Study with no history of hematopoietic cancer were followed from 1995 through 2007. A total of 516 of 114,131 women eligible for OC use analysis and 402 of 54,758 postmenopausal women eligible for MHT use analysis developed B-cell NHL. Multivariable adjusted and age stratified Cox proportional hazards models were fit to estimate relative risks (RRs) and 95% confidence intervals (95% CI). Ever versus never OC use was marginally associated with lower B-cell NHL risk, particularly among women first using OCs before age 25 years (RR=0.72, 95% CI=0.51-0.99); yet, no duration-response effect was observed. No association was observed for ever versus never MHT use among postmenopausal women (RR=1.05, 95% CI=0.83-1.33) overall or by formulation (estrogen alone, ET, or estrogen plus progestin, EPT). Among women with no MHT use, having bilateral oophorectomy plus hysterectomy was associated with greater B-cell NHL risk than having natural menopause (RR=3.15, 95% CI=1.62-6.13). Bilateral oophorectomy plus hysterectomy was not associated with risk among women who used ET or EPT. These results indicate that exogenous hormone use does not strongly influence B-cell NHL risk. PMID- 20957633 TI - Response assessment in gastrointestinal stromal tumor. AB - Imatinib is standard first-line treatment for patients with advanced gastrointestinal stromal tumor (GIST). Initial responses are not always accompanied by reductions in tumor size; consequently, other parameters should be considered in response assessments. Conventional size-based criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate responses to imatinib and have poor predictive value for outcome. Imatinib-responding tumors demonstrate decreased metabolic activity on positron emission tomography within the first weeks of treatment, often showing reduced density and greater homogeneity on computed tomography (CT) scans regardless of initial changes in tumor size. New criteria, based on reductions in tumor size or in tumor density on CT, seem more sensitive and specific for detecting early responses to imatinib, and more predictive of time to tumor progression and disease-specific survival. Compared with conventional size-based criteria, new CT-based criteria may potentially offer improved response assessment and be predictive of outcome in GIST. However, such emerging criteria should be further explored and validated in large, multicenter trials with imatinib and other kinase inhibitors in GIST and in other solid tumors. PMID- 20957634 TI - Anticancer drugs that target metabolism: Is dichloroacetate the new paradigm? AB - Recent findings in the fields of oncogenic regulation of metabolism, mitochondrial function and macromolecular synthesis have brought tumor metabolism and the Warburg effect back into the scientific limelight. A number of metabolic pathways that seem to be important for tumor growth are being touted as novel targets for anticancer drug development. One of the candidates in this class of drugs being investigated is dichloroacetate (DCA), a molecule used for over 25 years in the treatment of children with inborn errors in mitochondrial function. This pyruvate mimetic compound stimulates mitochondrial function by inhibiting the family of regulatory pyruvate dehydrogenase kinases (PDK1-4). The stimulation of mitochondrial function, at the expense of glycolysis, reverses the Warburg effect and is thought to block the growth advantage of highly glycolytic tumors. Interestingly, some of the recent in vitro findings have shown very modest "antitumor cell activity" of DCA when cells are treated in a dish. However, several studies have reported "antitumor activity" in model tumors. This apparent paradox raises the question, how do we evaluate cancer drugs designed to target tumor metabolism? Traditional approaches in cancer drug development have used in vitro assays as a first pass to evaluate potential lead compounds. The fact that DCA has better in vivo activity than in vitro activity suggests that there are unique aspects of solid tumor growth and metabolism that are difficult to recapitulate in vitro and may be important in determining the effectiveness of this class of drugs. PMID- 20957635 TI - Radiolabeled cetuximab: dose optimization for epidermal growth factor receptor imaging in a head-and-neck squamous cell carcinoma model. AB - Noninvasive imaging of the epidermal growth factor receptor (EGFR) in head-and neck squamous cell carcinoma could be of value to select patients for EGFR targeted therapy. We assessed dose optimization of (111) Indium-DTPA-cetuximab ((111) In-cetuximab) for EGFR imaging in a head-and-neck squamous cell carcinoma xenograft model. (111) In-cetuximab slowly internalized into FaDu cells in vitro, amounting to 1.0 * 10(4) molecules cetuximab per cell after 24 hr (15.8% of added activity). In nude mice with subcutaneous FaDu xenograft tumors, a protein dose escalation study with (111) In-cetuximab showed highest specific accumulation in tumors at protein doses between 1 and 30 MUg per mouse (mean tumor uptake 33.1 +/ 3.1%ID/g, 3 days postinjection (p.i.)). The biodistribution of (111) In cetuximab and (125) I-cetuximab was determined at 1, 3 and 7 days p.i. at optimal protein dose. Tumor uptake was favorable for (111) In-cetuximab compared to (125) I-cetuximab. With pixel-by-pixel analysis, good correlations were found between intratumoral distribution of (111) In-cetuximab as determined by autoradiography and EGFR expression in the same tumor sections as determined immunohistochemically (mean r = 0.74 +/- 0.14; all correlations p < 0.0001). Micro Single Photon Emission Computed Tomography (MicroSPECT) scans clearly visualized FaDu tumors from 1 day p.i. onward and tumor-to-background contrast increased until 7 days p.i. (tumor-to-liver ratios 0.58 +/- 0.24, 3.42 +/- 0.66, 8.99 +/- 4.66 and 16.33 +/- 11.56, at day 0, day 1, day 3 and day 7 p.i., respectively). Our study suggests that, at optimal cetuximab imaging dose, (111) In-cetuximab can be used for visualization of EGFR expression in head-and-neck squamous cell carcinoma using SPECT. PMID- 20957636 TI - Methods for distinguishing nitrosative and oxidative chemistry of reactive nitrogen oxide species derived from nitric oxide. AB - NO-derived intermediates formed under aerobic conditions may engage in complex chemical reactions with biologically important molecules. The outcomes of these reactions and their ultimate effect on biological systems depend on the selectivity of the species and the concentrations of different substances present and whether the reaction takes place in the gas or aqueous phase. In this unit conversion of two different compounds to fluorescent products is used to distinguish between oxidative and nitrosative chemistry of different reactive nitrogen oxide species. PMID- 20957637 TI - Inducible nitric oxide synthase expression. AB - This unit contains three protocols that can be used to determine iNOS expression in mouse macrophage-like cells, RAW 264.7, by measuring end product, protein, and mRNA. A bacterial product, lipopolysaccharide (LPS), stimulates iNOS expression in RAW 264.7 cells. PMID- 20957638 TI - Overview of neurotoxicology. AB - Environmental exposure to chemicals such as lead, mercury, organic solvents, pesticides, as well as naturally occurring compounds have neurotoxic effects. This unit is an overview of the structure and function of the nervous system, including a discussion of critical issues in defining neurotoxic effects and neurotoxicological risk assessment. PMID- 20957639 TI - Neurobehavioral screening in rodents. AB - Neurobehavioral evaluations are an important component of screening for neurotoxicological effects. A neurobehavioral test battery is chosen to assess a variety of endpoints, including autonomic, neuromuscular, sensory, and excitability functions. Such a battery includes observation of gait and posture, reactivity and arousal, gait and postural characteristics, involuntary/abnormal motor movements, clinical signs and manipulation of neurological reflexes and reactions and neuromuscular activity and postural reactions. Finally, the battery includes assessment of sensory responses. PMID- 20957640 TI - Assessment of spatial memory. AB - Behavioral tasks must be evaluated in terms of the cognitive functions they require. The tasks described in this unit are useful for detecting stimulation by drugs or a small electrical current, impairment of normal function by production of lesions or administration of a pharmacologic or toxicologic agent, recording activity during performance of a specific task, or behavioral phenotyping of transgenic or knockout mice. The radial arm maze test is used for basic working memory or working memory versus reference memory; the water maze task is used for spatial memory, spatial probe trials, or working memory; and the T-maze test is used for spatial memory, working versus reference memory, or spontaneous alternation. PMID- 20957641 TI - Advanced behavioral testing in rodents: assessment of cognitive function in animals. AB - In risk assessment of a neurotoxic chemical, it may be necessary to assess its effect on cognitive function, the information-processing capacity of the animal. Such effects may be inferred from behavioral effects only after other explanations have been ruled out. Learning, memory, attention, and performance are elements of cognitive function that can be assessed in a variety of tests described in this unit: autoshaping the lever-press response, repeated acquisition in the radial maze, delayed matching to position, two-light visual discrimination, visual signal detection, and multiple fixed interval/fixed ratio operant schedule. PMID- 20957642 TI - Testing for organophosphate-induced delayed polyneuropathy. AB - Organophosphorous compounds may cause two distinct types of toxicity: acute cholinergic toxicity and organophosphate-induced delayed polyneuropathy (OPIDP). The ability of a compound to cause OPIDP is assessed as described by administering the compound to hens and screening the brain, spinal cord, and peripheral nerves for neuropathy target esterase activity to detect OPIDP and acetylcholinesterase activity to rule out the acute toxicity. This assay can also be used as part of a screen for protective agents. PMID- 20957643 TI - Risk assessment and neurotoxicology. AB - Risk assessment refers to the use of toxicological data to define the relationship between the exposure to an agent and an adverse health outcome. This unit describes the factors involved in the study and evaluation of neurotoxicants to assess the risks associated with exposure. PMID- 20957644 TI - Neurobehavioral testing in humans. AB - The evaluation of the effects of chemical exposures on humans is a worldwide concern, and most chemicals have not been evaluated for neurotoxic effect. Human neurobehavioral research or clinical evaluations of populations exposed to chemicals must be carefully planned and structured. This unit describes the steps required to create such a study, select the appropriate measures, and evaluate the results. PMID- 20957645 TI - Mouse models of global cerebral ischemia. AB - Use of rodent models of hippocampal neurodegeneration are recommended for use in studies to understand the pathophysiology and molecular mechanisms involved. This unit includes protocols for two-vessel occlusion, three-vessel occlusion, and permanent bilateral vertebral artery occlusion plus methods for histological techniques for preparation of brain tissue and analysis of hippocampal injury. PMID- 20957646 TI - Genetic analysis of "leucine-rich repeat (LRR) and immunoglobulin (Ig) domain containing, Nogo receptor-interacting protein-1 (LINGO1)" in two independent Chinese parkinson's disease populations. AB - A large genome-wide association study has shown that the "leucine-rich repeat (LRR) and immunoglobulin (Ig) domain-containing, Nogo receptor-interacting protein-1 (LINGO1) gene" is associated with an increased risk for essential tremor (ET) recently. Given the clinical phenotype overlap between Parkinson's disease (PD) and ET, and LINGO1 had also been demonstrated to play roles in the structural plasticity and integrity of the DA neurons as well as survival of dopaminergic neurons in PD animal models, it has been suggested that the LINGO1 variant could be associated with PD. Here, we report the first analysis of the LINGO1 variant rs9652490 (A > G) in two independent case-control cohorts in ethnic Chinese populations involving a total of 1,305 subjects (649 PD patients and 656 controls) from Taiwan and Singapore. We were unable to demonstrate any significant association between genotype distribution and allele frequency with risk of PD in each case-control study and in the pooled analysis. Further meta analysis including all published data and ours failed to demonstrate any modulatory role of rs9652490 GG genotype or G allele. LINGO1 variant rs9652490 (A > G) is unlikely to play a major role in PD in our Chinese populations. PMID- 20957648 TI - Childhood maltreatment, the corticotropin-releasing hormone receptor gene and adult depression in the general population. AB - Dysregulations of the hypothalamic-pituitary-adrenal (HPA) axis have been implicated in the pathogenesis of depressive disorders and the corticotropin releasing hormone (CRH) was found to modulate emotional memory consolidation. Recently, two studies have reported an interaction between childhood abuse and the TAT-haplotype of the CRH-Receptor Gene (CRHR1) connecting childhood adversities and genetic susceptibility to adult depression. We tested the hypothesis of an interaction of childhood maltreatment with single nucleotide polymorphisms (SNPs) and haplotypes of the CRHR1 gene not previously investigated. Caucasian subjects (n = 1,638) from the German general population (Study of Health in Pomerania, SHIP) were analyzed. As in the previous studies, childhood abuse and neglect were assessed with the Childhood Trauma Questionnaire (CTQ) and depression with the Beck Depression Inventory (BDI-2). The CRHR1-SNPs were genotyped on the Affymetrix Genome-Wide Human SNP Array 6.0 platform. We identified an interaction between the TAT-haplotype and childhood physical neglect. The interaction with physical neglect showed significant (P < 0.05) results in 23 of the 28 SNPs, with rs17689882 (P = 0.0013) reaching "gene-wide" significance. Although we did not replicate the specific interaction of abuse and the TAT-haplotype of the CRHR1 gene we confirmed the relevance of an interplay between variants within the CRHR1 gene and childhood adversities in the modulation of depression in adults. The largest effect was found for rs17689882, a SNP previously not analyzed. Relevant sample differences between this and prior studies like lower BDI-2 scores, less childhood maltreatment and higher psychosocial functioning may account for the differences in gene-environment interaction findings. (c) 2010 Wiley-Liss, Inc. PMID- 20957647 TI - Fine-mapping reveals novel alternative splicing of the dopamine transporter. AB - The dopamine transporter gene (SLC6A3, DAT) has been implicated in the pathogenesis of numerous psychiatric and neurodevelopmental disorders, including schizophrenia (SZ). We previously detected association between SZ and intronic SLC6A3 variants that replicated in two independent Caucasian samples, but had no obvious function. In follow-up analyses, we sequenced the coding and intronic regions of SLC6A3 to identify complete linkage disequilibrium patterns of common variations. We genotyped 78 polymorphisms, narrowing the potentially causal region to two correlated clusters of associated SNPs localized predominantly to introns 3 and 4. Our computational analysis of these intronic regions predicted a novel cassette exon within intron 3, designated E3b, which is conserved among primates. We confirmed alternative splicing of E3b in post-mortem human substantia nigra (SN). As E3b introduces multiple in-frame stop codons, the SLC6A3 open reading frame is truncated and the spliced product may undergo nonsense mediated decay. Thus, factors that increase E3b splicing could reduce the amount of unspliced product available for translation. Observations consistent with this prediction were made using cellular assays and in post mortem human SN. In mini-gene constructs, the extent of splicing is also influenced by at least two common haplotypes, so the alternative splicing was evaluated in relation to SZ risk. Meta-analyses across genome-wide association studies did not support the initial associations and further post-mortem studies did not suggest case-control differences in splicing. These studies do not provide a compelling link to schizophrenia. However, the impact of the alternative splicing on other neuropsychiatric disorders should be investigated. (c) 2010 Wiley-Liss, Inc. PMID- 20957649 TI - The impact of a genome-wide supported psychosis variant in the ZNF804A gene on memory function in schizophrenia. AB - A recent genome-wide association study showed that a variant (rs1344706) in the ZNF804A gene was associated with schizophrenia and bipolar disorder. Replication studies supported the evidence for association between this variant in the ZNF804A gene and schizophrenia and that this variant is the most likely susceptibility variant. Subsequent functional magnetic resonance imaging studies in healthy subjects demonstrated the association of the high-risk ZNF804A variant with neural activation during a memory task and a theory of mind task. As these cognitive performances are disturbed in patients with schizophrenia, this gene may play a role in cognitive dysfunction in schizophrenia. The aim of the current study was to investigate the potential relationship between this ZNF804A polymorphism and memory function. The effects of the high-risk ZNF804A genotype, diagnosis, and genotype-diagnosis interaction on verbal memory, visual memory (VisM), attention/concentration, and delayed recall (measured by the Wechsler Memory Scale-Revised) were analyzed by two-way analysis of covariance in 113 patients with schizophrenia and 184 healthy subjects. Consistent with previous studies, patients with schizophrenia exhibited poorer performance on all indices as compared to healthy control subjects (P < 0.001). A significant ZNF804A genotype-diagnosis interaction was found for VisM performance (P = 0.0012). Patients with the high-risk T/T genotype scored significantly lower on VisM than G carriers did (P = 0.018). In contrast, there was no genotype effect for any index in the healthy control subjects (P > 0.05). Our data suggest that rs1344706 may be related to memory dysfunction in schizophrenia. (c) 2010 Wiley-Liss, Inc. PMID- 20957650 TI - Effects of the BDNF val66met polymorphism on prefrontal brain function in a population at high genetic risk of schizophrenia. AB - A single nucleotide polymorphism (val66met) in the brain derived neurotrophic factor (BDNF) gene has been shown to be a risk factor for a number of psychiatric disorders, including schizophrenia. This polymorphism has also been shown to have effects on prefrontal brain morphology and function. This study aims to clarify the effects of the val66met polymorphism on prefrontal brain function in a population at high genetic risk for schizophrenia. The Edinburgh High Risk Study has followed young individuals who had one first- or second-degree relative with schizophrenia and a minimum of one further genetic relative with the illness. A sample of 62 individuals provided both genetic and functional imaging data using the Hayling sentence completion task. Individuals with the BDNF ValVal (presumed risk) genotype (n = 41) showed relatively increased activation of the anterior cingulate cortex in relation to Met carrier individuals (n = 21) during sentence completion conditions versus baseline, against a background of similar levels of task performance. It appeared from further investigation that this relatively increased activation was attributable to a failure to disengage or suppress activation in the high risk ValVal group during the task condition, suggesting that BDNF may contribute to the abnormal default network reported in schizophrenia. These results suggest that this gene affects prefrontal brain function in those at high genetic risk for the disorder, unconfounded by medication effects. BDNF may therefore be one of the heritable factors involved in the development of abnormal prefrontal function in schizophrenia. (c) 2010 Wiley-Liss, Inc. PMID- 20957651 TI - Osteopontin--an important downstream effector of S100A4-mediated invasion and metastasis. AB - Substantial evidence has linked the small calcium-binding protein S100A4 to metastatic progression. S100A4-mediated effects include stimulation of angiogenesis, regulation of cell death and increased cell motility and invasion, but the exact molecular mechanisms by which the protein exerts these effects are incompletely elucidated. In the present study, we demonstrate that S100A4 induces NF-kappaB-dependent expression and secretion of osteopontin (OPN) in a selection of osteosarcoma cell lines. OPN is, as S100A4, known to result in a variety of cellular effects potentially leading to increased angiogenesis and metastasis, and several of the activated signaling pathways are common for the two proteins. In our study, extracellular S100A4 was found to upregulate enzymes of the plasminogen activator system and matrix metalloproteinase (MMP) family, especially urokinase plasminogen activator and MMP-13. Furthermore, increased motility and invasion was observed in vitro as a result of S100A4 treatment. OPN expression was inhibited by the use of siRNA molecules, and a partial blocking of S100A4-induced effects on protease expression and invasive capacity was detected. In conclusion, our results suggest regulation of OPN as a downstream molecular mechanism of S100A4 signaling. This novel finding adds more information to how S100A4 mediates tumor development and metastatic progression. The observation of a link between S100A4 and OPN, and also identification of common downstream effect molecules, highlights them, their receptors or downstream proteins, as targets for therapeutic approaches. PMID- 20957652 TI - Characterization of a mouse Scube3 reporter line. AB - The SCUBE gene family encode secreted, extracellular proteins that share a distinct domain organization of at least five recognizable motifs, including an amino-terminal signal peptide sequence, multiple EGF-like domains, a large spacer region containing multiple N-linked glycosylation sites, three repeated stretches of six-cysteine residues and a carboxy-terminal CUB domain. We describe a Scube3(tm1Dge/H) targeted allele, which replaces the entire coding region for Exons 2 and 3 with a neomycin-lacZ selectable marker cassette predicted to delete the first two EGF-like domains of the transcribed protein. Scube3(+/tm1Dge/H) embryos demonstrate strong beta-galactosidase activity in the early facial epithelium, including the branchial arches and facial processes, the otic vesicle, limb buds, and neural tube. In addition, strong reporter activity was identified in the epithelial compartments of developing teeth and hair follicles. However, analysis of the Scube3(tm1Dge/H) allele revealed that it encodes a truncated protein, which contains part of the spacer region and CUB domain. It is likely that this protein retains functionality because our analysis reveals that Scube3(tm1Dge/H; tm1Dge/H) mice are phenotypically normal. Whilst acting as a useful reporter, these mice do not provide any insight into the potential role of Scube3 during embryonic development. PMID- 20957654 TI - Asbestos is still with us: Repeat call for a universal ban. PMID- 20957655 TI - Ascertainment of occupational histories in the working population: the occupational history calendar approach. AB - BACKGROUND: self-reported occupational histories are an important means for collecting historical data in epidemiological studies. An occupational history calendar (OHC) has been developed for use alongside a national occupational hazard surveillance tool. This study presents the systematic development of the OHC and compares work histories collected via this calendar to those collected via a traditional questionnaire. METHODS: the paper describes the systematic development of an OHC for use in the general working population. A comparison of data quality and recall was undertaken in 51 participants where both tools were administered. RESULTS: the OHC enhanced job recall compared with the traditional questionnaire. Good agreement in the data captured by both tools was observed, with the exception of hazard exposures. CONCLUSIONS: a calendar approach is suitable for collecting occupational histories from the general working population. Despite enhancing job recall the OHC approach has some shortcomings outweighing this advantage in large-scale population surveillance. PMID- 20957653 TI - Effects of the A(-115)G variant on CREB1 promoter activity in two brain cell lines: Interactions with gonadal steroids. AB - Major depressive disorder (MDD) is a leading contributor to disease burden worldwide. Previous genetic studies have revealed significant evidence of linkage of the CREB1 region to mood disorders among women from families with recurrent, early-onset MDD (RE-MDD), a severe and familial subtype of MDD. Systematic resequencing of the CREB1 gene in affected members of these families has identified rare sequence variants at positions -656 and -115 that appear to cosegregate with unipolar mood disorders in two large multigenerational families and three small nuclear families, respectively. Results from previous transfection experiments that employed constructs containing the wild-type or variant CREB1 promoters coupled to a reporter gene support the hypothesis that the A(-656) allele contributes to the development of MDD in women by selectively increasing the activity of the CREB1 promoter in brain cell lines exposed to 17 beta-estradiol. Analogous transfection experiments described in the current study revealed that the G(-115) promoter variant reduced promoter activity in CATH.a neuronal cells regardless of the hormonal environment, consistent with the observation that increased risk for unipolar mood disorders conferred by this allele was not limited by sex. The effects of CREB1 promoter variants on promoter activity, their influence on the development of mood disorders and related clinical features, and the interaction of their phenotypic expression with sex seem likely to be complex and allele-specific rather than a general property of the CREB1 locus. (c) 2010 Wiley-Liss, Inc. PMID- 20957656 TI - Clean STD-NMR spectrum for improved detection of ligand-protein interactions at low concentration of protein. AB - Saturation transfer difference (STD)-NMR has been widely used to screen ligand compound libraries for their binding activities to proteins and to determine the binding epitopes of the ligands. We report herein, a Clean STD-NMR method developed to overcome false positives (artifacts) observed in the STD-NMR spectrum due to the power spillover of RF irradiation. The method achieved higher degree of resonance saturation through digital editing of two STD-NMR spectra to generate a concatenated difference spectrum and three times of sensitivity enhancement for a loose binding complex involving DNA oligonucleotide and an RNA binding protein, CUGBP-1ab (25.2 kDa). The interesting binding characteristics of the complex dCTGTCT-CUGBP1ab were obtained. The method was applied to a mixture of small ligand and bovine serum albumin protein (BSA, 66.3 kDa), and detected the intermolecular contacts at a BSA concentration as low as 0.1 uM, a working concentration useful for the detection of proteins of low solubility at biologically relevant conditions. PMID- 20957658 TI - Systematic review and meta-analysis: anti-tumor necrosis factor alpha therapy and cardiovascular events in rheumatoid arthritis. AB - OBJECTIVE: Control of rheumatoid arthritis (RA) may reduce the risk of cardiovascular events. We sought to systematically assess the association between anti-tumor necrosis factor alpha (anti-TNFalpha) therapy in RA and cardiovascular event rates. METHODS: Observational cohorts and randomized controlled trials (RCTs) reporting on cardiovascular events (all events, myocardial infarction [MI], congestive heart failure, and cerebrovascular accident [CVA]) in RA patients treated with anti-TNFalpha therapy compared to traditional disease modifying antirheumatic drugs were identified from a search of PubMed (1950 to November 2009), EMBase (1980 to November 2009), and conference abstracts. Relative risks (RRs) or hazard ratios and 95% confidence intervals (95% CIs) were extracted. If the incidence was reported, additional data were extracted to calculate an incidence density ratio and its variance. RESULTS: The systematic review and meta-analysis include 16 and 11 publications, respectively. In cohort studies, anti-TNFalpha therapy was associated with a reduced risk for all cardiovascular events (pooled adjusted RR 0.46; 95% CI 0.28, 0.77), MI (pooled adjusted RR 0.81; 95% CI 0.68, 0.96), and CVA (pooled adjusted RR 0.69; 95% CI 0.53, 0.89). Meta-analysis of RCTs also produced a point estimate indicating lower risk of cardiovascular events, but this was not statistically significant (pooled RR 0.85; 95% CI 0.28, 2.59). CONCLUSION: Anti-TNFalpha therapy is associated with a reduced risk of all cardiovascular events, MI, and CVA in observational cohorts. There was heterogeneity among cohort studies and possible publication bias. The point estimate of the effect from RCTs is underpowered with wide 95% CIs, and cardiovascular events were secondary outcomes, but RCTs also demonstrated a trend toward decreased risk. PMID- 20957657 TI - Rates of change and sensitivity to change in cartilage morphology in healthy knees and in knees with mild, moderate, and end-stage radiographic osteoarthritis: results from 831 participants from the Osteoarthritis Initiative. AB - OBJECTIVE: To study the longitudinal rate of (and sensitivity to) change of knee cartilage thickness across defined stages of radiographic osteoarthritis (OA), specifically healthy knees and knees with end-stage radiographic OA. METHODS: One knee of 831 Osteoarthritis Initiative participants was examined: 112 healthy knees, without radiographic OA or risk factors for knee OA, and 719 radiographic OA knees (310 calculated Kellgren/Lawrence [K/L] grade 2, 300 calculated K/L grade 3, and 109 calculated K/L grade 4). Subregional change in thickness was assessed after segmentation of weight-bearing femorotibial cartilage at baseline and 1 year from coronal magnetic resonance imaging (MRI). Regional and ordered values (OVs) of change were compared by baseline radiographic OA status. RESULTS: Healthy knees displayed small changes in plates and subregions (+/-0.7%; standardized response mean [SRM] +/-0.15), with OVs being symmetrically distributed close to zero. In calculated K/L grade 2 knees, changes in cartilage thickness were small (<1%; minimal SRM -0.22) and not significantly different from healthy knees. Knees with calculated K/L grade 3 showed substantial loss of cartilage thickness (up to -2.5%; minimal SRM -0.35), with OV1 changes being significantly (P < 0.05) greater than those in healthy knees. Calculated K/L grade 4 knees displayed the largest rate of loss across radiographic OA grades (up to -3.9%; minimal SRM -0.51), with OV1 changes also significantly (P < 0.05) greater than in healthy knees. CONCLUSION: MRI-based cartilage thickness showed high rates of loss in knees with moderate and end-stage radiographic OA, and small rates (indistinguishable from healthy knees) in mild radiographic OA. From the perspective of sensitivity to change, end-stage radiographic OA knees need not be excluded from longitudinal studies using MRI cartilage morphology as an end point. PMID- 20957659 TI - Safety and efficacy of etanercept beyond 10 years of therapy in North American patients with early and longstanding rheumatoid arthritis. AB - OBJECTIVE: To evaluate the long-term safety and efficacy of etanercept therapy in rheumatoid arthritis (RA) patients. METHODS: Adult patients with early RA or longstanding RA received etanercept in open-label extension studies following initial double-blind trials of etanercept. RESULTS: Of 558 early RA patients and 714 longstanding RA patients who received at least 1 dose of etanercept, a total of 194 early RA patients and 217 longstanding RA patients were treated with 25 mg of etanercept twice weekly through 10 years. Five opportunistic infections were reported: in early RA, 1 Candida septicemia; in longstanding RA, 1 herpes zoster, 1 atypical mycobacterium infection, 1 meningoencephalitis (unspecified), and 1 fungal sepsis (unspecified). Twenty-nine cases of sepsis occurred (10 early RA, 19 longstanding RA). Occurrence of all malignancies was similar to that expected in the general population, but the occurrence of lymphomas was higher than expected in the general population. Fourteen lymphomas (7 early RA, 7 longstanding RA) and 2 cases of demyelinating disease (1 early RA, 1 longstanding RA) were reported. Deaths occurred in 18 early RA patients and 43 longstanding RA patients. Both patient groups showed sustained improvement in American College of Rheumatology responses, swollen joint counts, Health Assessment Questionnaire disability index scores, and C-reactive protein levels. CONCLUSION: Etanercept maintained therapeutic benefits beyond 10 years of therapy in both early RA and longstanding RA patients, suggesting that etanercept is well tolerated and effective as a long-term, continuous therapy for the treatment of RA, with a favorable risk/benefit ratio. PMID- 20957660 TI - Pain sensitivity and pain reactivity in osteoarthritis. AB - OBJECTIVE: To assess experimental pain sensitivity and compare the inflammatory response to pain in 26 osteoarthritis (OA) patients and 33 age- and sex-matched controls from the general population in order to examine the nature of the association between pain and inflammation in OA. METHODS: The participants underwent psychophysical pain testing to assess pain sensitivity in response to heat, cold, and mechanical stimuli. Blood samples were taken at baseline and at 4 time points after testing to determine the effect of acute pain on C-reactive protein (CRP), interleukin-6 (IL-6), IL-1beta, and tumor necrosis factor alpha levels. RESULTS: OA patients had lower pressure pain thresholds (P <= 0.003) and higher heat pain ratings (P <= 0.04) than controls across multiple body sites. OA patients had higher CRP levels than controls (P = 0.007). CRP levels did not change in response to pain testing. Although not statistically significant, OA patients tended to have higher IL-6 levels than controls (P = 0.12). IL-6 levels increased after pain testing in OA patients and controls (P < 0.0001), but the amount of increase was not different between the 2 groups. Among OA patients, heightened pain sensitivity was associated with elevated CRP and IL-6 levels (P <= 0.05). CONCLUSION: Compared with controls, OA patients are more sensitive to experimental pain at multiple body sites. IL-6 levels in OA patients and controls exhibited reactivity to acute painful stimuli, increasing at similar rates after psychophysical pain testing. PMID- 20957661 TI - Patient repositioning reproducibility of joint space width measurements on hand radiographs. AB - OBJECTIVE: Computer-based methods to measure radiographic joint space width (JSW) have the potential to improve the longitudinal assessment of rheumatoid arthritis (RA). The purpose of this report was to measure the long-term patient repositioning reproducibility of software-measured radiographic JSW. METHODS: Patients underwent baseline and followup hand radiography examinations with a followup time of <=3 years. To eliminate any JSW change due to real disease progression, the evaluation was performed on "unaffected" joints, defined as having JSW and erosion Sharp scores of 0 at both baseline and followup. The root mean square SD (RMSSD) and coefficient of variation (CV) were used as the reproducibility metrics. RESULTS: The RMSSD was 0.14 mm (CV 10.5%) for all joints, 0.18 mm (CV 10.9%) for the metacarpophalangeal (MCP) joints, and 0.08 mm (CV 8.3%) for the proximal interphalangeal (PIP) joints. The distribution of JSW change was asymmetric, suggesting that narrowing due to RA progression occurred for several joints. A second analysis was performed, excluding joints where the loss of JSW was greater than 3 SDs. For this analysis, the RMSSD was 0.10 mm (CV 7.5%) for all joints, 0.12 mm (CV 7.3%) for the MCP joints, and 0.07 mm (CV 7.1%) for the PIP joints. CONCLUSION: Repositioning reproducibility is very good but is likely to be a dominating factor compared to reader and software reproducibility. Additionally, further evidence is given that a software method is able to detect changes in some joints for which the Sharp score is insensitive. PMID- 20957662 TI - Modulatory effects of lipoic acid and selenium against cadmium-induced biochemical alterations in testicular steroidogenesis. AB - Exposure to toxic metals including cadmium has become an increasingly recognized source of illness worldwide. Cadmium (Cd(2+) ) is one of the environmental pollutants affecting various tissues and organs including testis. The protective effect of lipoic acid and selenium on Cd(2+) -induced testicular damage was investigated. Accordingly, male Wistar rats were allocated into four groups (n = 8; each). Gp I: (control), whereas the other 3 groups received CdCl(2) (2 mg/kg, i.p. for 28 days) alone or in combination with either (i) lipoic acid (35 mg/kg, p.o) or (ii) selenium (0.35 mg/kg, p.o) throughout the experiment. Serum testosterone, luteinizing hormone and follicle-stimulating hormone levels significantly decreased in the Cd(2+) -exposed rats. The activities of testicular key androgenic enzymes, 3beta-hydroxysteroid dehydrogenase and 17 beta-HSD significantly decreased in Cd(2) exposed rats compared to the control counterparts. In addition, the activities of testicular marker enzymes were significantly altered in cadmium-treated animals. Significant reductions in body and testicular weight as well as antioxidant status were also observed in Cd(2+) exposed rats. Moreover, some testicular metal levels were altered. Lipoic acid and selenium significantly increased serum testosterone level and restored testicular activity of 3beta-HSD and 17 beta-HSD and were effective in modulation of most of the measured biochemical parameters. The biochemical parameters were further confirmed with histopathological findings. In conclusion, the present study demonstrated the beneficial influences of lipoic acid and selenium in reducing harmful effects of Cd(2+) in rats' testes. PMID- 20957663 TI - Effects of gallic acid on brain lipid peroxide and lipid metabolism in streptozotocin-induced diabetic Wistar rats. AB - This study evaluated the protective effects of gallic acid on brain lipid peroxidation products, antioxidant system, and lipids in streptozotocin-induced type II diabetes mellitus. Streptozotocin-induced diabetic rats showed a significant increase in the levels of blood glucose, brain lipid peroxidation products, and lipids and a significant decrease in the activities of brain enzymic antioxidants. Oral treatment with gallic acid (10 mg and 20 mg/kg) for 21 days significantly decreased the levels of blood glucose, brain lipid peroxidation products, and lipids and significantly increased the activities of brain enzymic antioxidants in diabetic rats. Histopathology of brain confirmed the protective effects of gallic acid. Furthermore, in vitro study revealed the free radical scavenging action of gallic acid. Thus, our study shows the beneficial effects of gallic acid on brain metabolism in streptozotocin-induced type II diabetic rats. A diet containing gallic acid may be beneficial to type II diabetic patients. PMID- 20957665 TI - Intent-to-treat: further insight. PMID- 20957666 TI - The development and psychometric analysis of the short-form Pulmonary Functional Status Scale (PFSS-11). AB - This article describes the development and psychometric evaluation of the short form Pulmonary Functional Status Scale (PFSS-11(c)) derived from the previously validated 35-item PFSS, using data from 179 subjects (120 Chronic Obstructive Pulmonary Disease [COPD]/59 normative, non-COPD). Items were extracted based on item-response distribution and commonality >.60. Factor analysis yielded a three factor solution, accounting for 65.6% of total variance. Construct validity was supported by PFSS-11(c) scores for COPD versus norms (p < .001). The PFSS-11(c) was robustly associated with the PFSS-35 (r = .93), accounting for 88% of variance in the longer version. Internal consistency was satisfactory and significant response to treatment was shown by score changes pre/post rehabilitation. The PFSS-11(c) has solid psychometric properties useful in research and clinical practice, similar to the PFSS-35. PMID- 20957667 TI - Lung cancer and occupation: A New Zealand cancer registry-based case-control study. AB - BACKGROUND: There are many proven and suspected occupational causes of lung cancer, which will become relatively more important over time, as smoking prevalence decreases. METHODS: We interviewed 457 cases aged 20-75 years notified to the New Zealand Cancer Registry during 2007-2008, and 792 population controls. We collected information on demographic details, potential confounders, and employment history. Associations were estimated using logistic regression adjusted for gender, age, ethnicity, smoking, and socio-economic status. RESULTS: Among occupations of a priori interest, elevated odds ratios (ORs) were observed for sawmill, wood panel and related wood-processing plant operators (OR 4.63; 95% CI 1.05-20.29), butchers (OR 8.77, 95% CI 1.06-72.55), rubber and plastics products machine operators (4.27; 1.16-15.66), heavy truck drivers (2.24; 1.19 4.21) and workers in petroleum, coal, chemical and associated product manufacturing (1.80; 1.11-2.90); non-significantly elevated risks were also observed for loggers (4.67; 0.81-27.03), welders and flame-cutters (2.50; 0.86 7.25), pressers (5.74; 0.96-34.42), and electric and electronic equipment assemblers (3.61; 0.96-13.57). Several occupations and industries not of a priori interest also showed increased risks, including nursing associate professionals (5.45; 2.29-12.99), enrolled nurses (7.95; 3.10-20.42), care givers (3.47; 1.40 8.59), plant and machine operators and assemblers (1.61; 1.20-2.16), stationary machine operators and assemblers (1.67; 1.22-2.28), food and related products processing machine operators (1.98; 1.23-3.19), laborers and related elementary service workers (1.45; 1.05-2.00), manufacturing (1.34; 1.02-1.77), car retailing (3.08; 1.36-6.94), and road freight transport (3.02; 1.45-6.27). CONCLUSIONS: Certain occupations and industries have increased lung cancer risks in New Zealand, including wood workers, metal workers, meat workers, textile workers and drivers. Am. J. Ind. Med. 54:89-101, 2011. (c) 2010 Wiley-Liss, Inc. PMID- 20957668 TI - Effect of dopamine transporter genotype on caudate volume in childhood ADHD and controls. AB - Polymorphism of the dopamine transporter genotype (DAT1) confers a small but significant susceptibility to attention deficit hyperactivity disorder (ADHD). We examined whether the volume of the head of caudate, a striatal structure with high DAT expression that is important for inhibitory function, differs by DAT1 in children diagnosed with the disorder relative to age and IQ matched controls. Volume of the head of caudate was delineated in the right and left hemisphere and compared between 7- and 13-year-old children with and without ADHD (combined type) who were carriers of two (10/10) or one (9/10) copy of the 10-repeat DAT1 allele. Caudate volumes were overall smaller in 10/10 than 9/10 children, particularly in the left than right hemisphere. While DAT1 effects did not vary by ADHD diagnosis, overall caudate volumes were smaller in ADHD relative to control children. Altered caudate development associated with 10-repeat homozygosity of DAT1 may contribute susceptibility to ADHD. PMID- 20957669 TI - Early carotid endarterectomy following thrombolysis in the hyperacute treatment of stroke. AB - BACKGROUND: Thrombolysis with intravenous recombinant tissue plasminogen activator improves the probability of complete neurological recovery if given promptly following the onset of acute ischaemic stroke. Carotid endarterectomy (CEA) can reduce the risk of further embolic stroke in selected patients and is most effective within 14 days of the incident event. The safety of surgery so soon after thrombolysis is unknown. The aim of this study was to report the immediate outcomes of this management strategy early in the unit experience and to encourage pooling of data, recognizing that this will be an uncommon procedure even in busy stoke units with an active lysis programme. METHODS: Data were extracted from two prospectively collected databases, and included patient demographics, type of stroke, type and timing of surgical procedure, and immediate outcome. On presentation with a stroke, all patients underwent urgent computed tomography (CT) of the brain. Those eligible received thrombolysis according to the unit protocol. They underwent CT angiography 24 h after thrombolysis and patients with a severe carotid stenosis had surgery. RESULTS: Ten of a cohort of 450 patients who had received lysis underwent CEA. Seven of these were women and eight of the procedures were carried out under local anaesthetic. Surgery was performed a median of 8 (range 2-23) days after the index event; there were no major complications. CONCLUSION: Few patients with acute stroke are eligible, but CEA performed soon after thrombolytic therapy for stroke appears to be safe. PMID- 20957670 TI - Dickkopf-1 (DKK-1) stimulated prostate cancer growth and metastasis and inhibited bone formation in osteoblastic bone metastases. AB - BACKGROUND: Osteoblastic bone metastasis is the predominant phenotype observed in prostate cancer patients and is associated with high patient mortality and morbidity. However, the mechanisms determining the development of this phenotype are not well understood. Prostate cancer cells secrete several osteogenic factors including Wnt proteins, which are not only osteoinductive but also oncogenic. Therefore, the purpose of the study was to investigate the contribution of the Wnt signaling pathway in prostate cancer growth, incidence of bone metastases, and osteoblastic phenotype of bone metastases. The strategy involved overexpressing the Wnt antagonist, DKK-1, in the mixed osteoblastic and osteolytic Ace-1 prostate cancer cells. METHODS: Ace-1 prostate cancer cells stably expressing human DKK-1 or empty vector were established and transduced with lentiviral yellow fluorescent protein (YFP)-luciferase (Luc). The Ace 1/vector(YFP-LUC) and Ace-1/DKK-1(YFP-LUC) cells were injected subcutaneously, intratibially, or in the left cardiac ventricle in athymic mice. RESULTS: Unexpectedly, DKK-1 significantly increased Ace-1 subcutaneous tumor mass and the incidence of bone metastases after intracardiac injection of Ace-1 cells. DKK-1 increased Ace-1 tumor growth associated with increased phospho46 c-Jun amino terminal kinase by the Wnt noncanonical pathway. As expected, DKK-1 decreased the Ace-1 osteoblastic phenotype of bone metastases, as confirmed by radiographic, histopathologic, and microcomputed tomographic analysis. DKK-1 decreased osteoblastic activity via the Wnt canonical pathway evidenced by an inhibition of T-cell factor activity in murine osteoblast precursor ST2 cells. CONCLUSION: The present study showed that DKK-1 is a potent inhibitor of bone growth in prostate cancer-induced osteoblastic metastases. PMID- 20957671 TI - No evidence of FGFR3 mutations in prostate cancer. AB - BACKGROUND: FGFR3 mutations are associated with a good clinical disease course in bladder tumors. Currently, prognostic markers to stratify prostate cancer (PCa) patients for conservative management are lacking. Conflicting results have been found on the presence of FGFR3 mutations in PCa. Our objective was to determine the prevalence of FGFR3 mutations in a subset of prostate tumors. Next, determine the prevalence of FGFR3 mutations in PCa patients with coexistent tumors in other tissues. METHODS: Primary and locally advanced prostate tumors (n =132) were collected at our medical center. From the 132 PCa patients, 28 (21%) were diagnosed with coexistent primary tumors (bladder, skin, pancreas, renal cell, gastric, colon, hepatic, and lung). Tumors were analyzed by FGFR3 mutation analysis on exon 7, 10, and 15, known to harbor the most frequent mutations. RESULTS: The prevalence of FGFR3 mutations in patients with only PCa was 0%. Most PCa patients presented with coexistent bladder (n=12) and bladder and skin tumors (n =7). Other coexistent tumors in PCa patients included: bladder and pancreatic cancer (n=1); bladder and renal cell carcinoma (n=1); bladder and gastric carcinoma (n=1); skin cancer (n=1); colon cancer (n= 3); hepatic carcinoma (n=1); and lung cancer (n = 1). FGFR3 mutations were detected in 9/15 (60%) analyzed bladder tumors. CONCLUSIONS: FGFR3 mutations were absent in the investigated prostate tumors, suggesting a minor role of these mutations in tumorigenesis. Hence, FGFR3 mutation analysis is not suitable to select patients for conservative management. Interestingly, if a prostate tumor coincided with other tumors these were mostly bladder and skin. PMID- 20957672 TI - LL-37 as a therapeutic target for late stage prostate cancer. AB - BACKGROUND: The antimicrobial peptide, leucine-leucine-37 (LL-37), stimulates proliferation, angiogenesis, and cellular migration, inhibits apoptosis and is associated with inflammation. Since these functional processes are often exaggerated in cancer, the aim of the present study was to investigate the expression and role of LL-37 in prostate cancer (PCa) and establish its value as a therapeutic target. METHODS: We evaluated the expression of LL-37 and the murine orthologue, cathelicidin-related antimicrobial peptide (CRAMP) in human and murine prostate tumors, respectively. Compared to normal/benign prostate tissue, both LL-37 and CRAMP were increasingly over-expressed with advancing grades of primary PCa and its metastasis in human tissues and in the transgenic adenocarcinoma mouse prostate (TRAMP) model, correspondingly. We subsequently knocked-down CRAMP in the highly tumorigenic TRAMP-C1 cell line via a RNA interference strategy to examine the importance of CRAMP on cellular proliferation, angiogenesis, invasion, apoptosis, activation of signaling pathways and tumor kinetics. RESULTS: Abrogation of CRAMP expression led to decreased proliferation, invasion, type IV collagenase, and the amount of phosphorylated Erk1/2 and Akt signaling in vitro. These results were paralleled in vivo. Syngenic implantation of TRAMP-C1 cells subjected to CRAMP knock-down resulted in a decreased tumor incidence and size, and the down-regulation of pro tumorigenic mechanisms. CONCLUSIONS: CRAMP knock-down in a murine PCa model analogously demonstrated the tumorigenic contributions of LL-37 in PCa and its potential as a novel therapeutic target for the treatment of PCa and potentially, other cancers over-expressing the peptide. PMID- 20957673 TI - A multiplex model of combining gene-based, protein-based, and metabolite-based with positive and negative markers in urine for the early diagnosis of prostate cancer. AB - BACKGROUND: Multiplex urine-based assay emerged outperforms single biomarker (e.g., prostate-specific antigen, PSA) for predicting prostate cancer (CaP), whereas its combined mode has to be fully optimized. Our aim is to determine whether a strategy of combining gene-based, protein-based, metabolite-based with positive, negative makers in urine could optimize a multiplex model for detecting CaP. METHODS: Using quantitative PCR, Western blot, and liquid chromatography mass spectrometry, expression patterns of PCA3, TMPRSS2: ERG, Annexin A3, Sarcosine, and urine PSA were evaluated in urine samples from 86 untreated patients with CaP and 45 patients with no evidence of malignancy. Multivariate logistic regression analysis was used to generate a final model and receiver operating characteristic (ROC) analysis and special bootstrap software to assess diagnostic performance of tested variables. RESULTS: The expression patterns of PCA3, TMPRSS2: ERG, Annexin A3, Sarcosine, and a panel including these biomarkers were significant predictors of CaP both in patients with PSA 4-10 ng/ml and in all patients (all P < 0.05). Employing ROC analysis, the area under the curves of the panel in these both cohorts were 0.840 and 0.856, respectively, which outperform that of any single biomarker (PCA3: 0.733 and 0.739; TMPRSS2: ERG: 0.720 and 0.732; Annexin A3: 0.716 and 0.728; Sarcosine: 0.659 and 0.665, respectively). CONCLUSIONS: Compared with single biomarker, the multiplex model including PCA3, TMPRSS2: ERG, Annexin A3 and Sarcosine adds even more to the diagnostic performance for predicting CaP. Further validation experiments and optimization for the strategy of constructing this model are warranted. PMID- 20957674 TI - Civil engineering airman at increased risk for injuries and injury-related musculoskeletal disorders. AB - BACKGROUND: With the advent of electronic records, the opportunity to conduct research on workplace-related injuries and musculoskeletal disorders has increased dramatically. The purpose of this study was to examine the United States Air Force Civil Engineering career field to determine if they are negatively impacted by their work environment. Specifically, the objective of this study was to determine if enlisted Civil Engineering Airmen (n = 25,385) were at increased risk for injury or injury-related musculoskeletal disorders compared to enlisted Information Management/Communications Airmen (n = 28,947). METHODS: Using an historical prospective design, electronic data were assembled and analyzed using Cox's proportional hazards modeling. Models were stratified by gender and adjusted for race/ethnicity, marital status, birth year, and deployment status. RESULTS: Male Civil Engineers were observed to be at greater risk for both inpatient injury-related musculoskeletal disorders (HR = 1.86; 95% CI = 1.54-2.26) and injuries (HR = 1.77; 95% CI = 1.48-2.11), while female Civil Engineers were more than double the risk for both inpatient injury-related musculoskeletal disorders (HR = 2.18; 95% CI = 1.28-3.73) and injuries (HR = 2.22; 95% CI = 1.27-3.88) compared to Information Management/Communications Airmen. CONCLUSIONS: Although analyses do not allow exploration of specific causes, they highlight the utility of using electronic data to identify occupations for further evaluation. Based on these results, additional resources were allocated to survey Civil Engineers on their physical work demands and job requirements to identify key problem areas for further study and mitigation. PMID- 20957675 TI - Nickel metal not associated with lung cancer risk. PMID- 20957676 TI - Interpreting borderline BeLPT results. AB - BACKGROUND: The beryllium lymphocyte proliferation test (BeLPT) identifies persons sensitized to beryllium (BeS) and thus at risk for chronic beryllium disease (CBD). BeLPT test results are abnormal (AB), borderline (BL), or normal (NL). This manuscript addresses the predictive value and interpretation of BL BeLPT results. METHODS: The various three-result combinations that meet or exceed a nominal referral criteria of 1 AB + 1 BL are assessed with probability modeling and compared. RESULTS: At 2% prevalence, the three-result combinations that meet or exceed this referral criteria and associated probabilities of BeS are: (a) 1 AB + 1 BL + 1 NL (72%); (b) 3 BL (91%); (c) 2 AB + 1 NL (95%); (d) 1 AB + 2 BL (99%); (e) 2 AB + 1 BL (100%); and (f) 3 AB (100%). CONCLUSION: These results suggest that BL results are meaningful and that three BL results predict BeS across a broad range of population prevalences. An analysis of longitudinal BeLPT results and clinical findings from an actual surveillance program is warranted to confirm the model's predictions. PMID- 20957677 TI - Airway response to chlorine inhalation (bleach) among cleaning workers with and without bronchial hyperresponsiveness. AB - BACKGROUND: Symptoms of obstructive lung disease in domestic cleaning staff have been related to the use of bleach and other irritant cleaning products. MATERIAL AND METHODS: Included in the study were thirteen cleaning employees with work related asthma-like symptoms, three asthmatic controls and three atopic subjects without bronchial hyperresponsiveness (BHR) who had no exposure to cleaning products. The study protocol consisted of a methacholine test, sputum induction and fraction of exhaled nitric oxide measurement (FENO) both at baseline and 24 hr after a 1-hr inhalation challenge with either placebo or bleach at a concentration of 0.4 ppm of chlorine. RESULTS: The inhalation of the placebo caused no bronchial reactions. Mean maximum fall in FEV(1) during challenge testing with bleach was significantly higher than the values obtained during the placebo challenge. Inhalation challenge with bleach elicited two isolated late asthmatic reactions and one dual asthmatic reaction. Of all the patients who underwent challenge testing with bleach, only one had a >=2-fold decrease in methacholine PC(20) 24 hr after the challenge. No significant correlation was found between maximum fall in FEV(1) and PC(20) methacholine. Following challenge testing with bleach, no clinically significant changes in sputum cell counts or FENO were detected. CONCLUSIONS: These results suggest that bleach inhalation at a concentration of 0.4 ppm-a concentration below 8-hr permissible occupational exposure level-brings about a substantial decrease in FEV1 in subjects with and without BHR. Some subjects have a positive challenge response to bleach inhalation. PMID- 20957678 TI - Prevalence of connective tissue disease in silicosis (1985-2006)-a report from the state of Michigan surveillance system for silicosis. AB - BACKGROUND: The risk of developing clinical connective tissue disease (CTD) has been reported to be increased among individuals with silica exposure. METHODS: We reviewed the medical records of individuals reported to the Michigan Silicosis Surveillance system from 1985 to 2006 to confirm the diagnosis of silicosis and determine the presence of CTDs. RESULTS: From 1985 to 2006, 1,022 cases were confirmed to have silicosis. Medical records of 790 cases were available. Thirty three individuals had rheumatoid arthritis (RA) [prevalence 4.2% (prevalence ratio (RR) ranged from 2.26, 95% CI: 1.57-3.25 to 6.96, 95% CI: 2.93-16.53) depending on the reference rate used], two had scleroderma [prevalence 0.3% (RR 28.3, 95% CI: 6.09-129.98)], one had systemic lupus erythematosus [prevalence 0.1% (RR 2.53, 95% CI: 0.30-21.64)], two had Sjogrens syndrome [prevalence 0.3% (RR 0.42, 95% CI: 0.09-2.08)], and six had anti-neutrophil cytoplasm antibody (ANCA) vasculitis [prevalence 0.8% (RR 25.3, 95% CI: 6.34-101.04)]. There was no difference between those with and without CTD with respect to age, race, industry type, history of tuberculosis, application for workers' compensation, or severity of fibrotic changes on chest X-ray. CONCLUSIONS: A two- to eightfold risk for RA and systemic lupus erythematosus, with a greater than 24-fold risk for scleroderma and ANCA vasculitis was found in individuals with silicosis. The most common CTD among silicotics in the Michigan disease registry was RA. Though not classically included in the category of CTD, ANCA-associated vasculitis was found to have a much greater prevalence amongst silicosis patients than the general population. PMID- 20957679 TI - Prooxidant activity of fisetin: effects on energy metabolism in the rat liver. AB - Flavonols, which possess the B-catechol ring, as quercetin, are capable of producing o-hemiquinones and to oxidize NADH in a variety of mammalian cells. The purpose of this study was to investigate whether fisetin affects the liver energy metabolism and the mitochondrial NADH to NAD+ ratio. The action of fisetin on hepatic energy metabolism was investigated in the perfused rat liver and isolated mitochondria. In isolated mitochondria, fisetin decreased the respiratory control and ADP/O ratios with the substrates alpha-ketoglutarate and succinate. In the presence of ADP, respiration of isolated mitochondria was inhibited with both substrates, indicating an inhibitory action on the ATP-synthase. The stimulation of the ATPase activity of coupled mitochondria and the inhibition of NADH-oxidase activity pointed toward a possible uncoupling action and the interference of fisetin with mitochondrial energy transduction mechanisms. In livers from fasted rats, fisetin inhibited ketogenesis from endogenous sources. The beta hydroxybutyrate/ acetoacetate ratio, which reflects the mitochondrial NADH/NAD+ redox ratio, was also decreased. In addition, fisetin (200 MUM) increased the production of (14)CO2 from exogenous oleate. The results of this investigation suggest that fisetin causes a shift in the mitochondrial redox potential toward a more oxidized state with a clear predominance of its prooxidant activity. PMID- 20957680 TI - Thymoquinone supplementation attenuates cyclophosphamide-induced cardiotoxicity in rats. AB - This study examined the possible protective effects of thymoquinone (TQ), the main constituent of the volatile oil of black seed (Nigella sativa), against cyclophosphamide (CP)-induced cardiotoxicity. Adult male Wistar albino rats were divided into four treatment groups. Rats in the first group were served as control. Rats in the second group received TQ (50 mg/L in drinking water) for 12 days. Animals in the third group were injected with a single dose of CP (200 mg/kg, IP) at day 5. Rats in the fourth group received TQ (50 mg/L in drinking water) for 5 days before a single dose of CP (200 mg/kg, IP) and continued thereafter throughout the experiment. On day 13, animals were sacrificed; serum and hearts were isolated and analyzed. Cyclophosphamide resulted in a significant increase in serum creatine kinase, lactate dehydrogenase, cholesterol, triglycerides, creatinine, urea, and tumor necrosis factor-alpha. In heart tissues, CP resulted in a significant increase in thiobarbituric acid reactive substances and total nitrate/nitrite and a significant decrease in reduced glutathione, glutathione peroxidase, catalase, and adenosine triphosphate levels. Interestingly, TQ supplementation resulted in a complete reversal of all the biochemical changes induced by CP to their control values. Data from this study suggest that TQ supplementation attenuates CP-induced cardiotoxicity by a mechanism related, at least in part, to its ability to decrease oxidative and nitrosative stress and to preserve the activity of antioxidant enzymes as well as its ability to improve the mitochondrial function and energy production. . PMID- 20957681 TI - Spectroscopic identification of interactions of formaldehyde with bovine serum albumin. AB - The mechanism of formaldehyde-protein interactions was investigated by determining the effects of formaldehyde on the common protein bovine serum albumin (BSA). The effects at the molecular level were determined by fluorescence, ultraviolet absorption, and circular dichroism (CD) spectrometry. Formaldehyde could decrease the amount of alpha-helix, leading to loosening of the protein skeleton. In the loose structure, internal amino acids are exposed and the characteristic fluorescence of BSA is obviously quenched. The spectroscopic results reveal that formaldehyde exposure induces changes in the microenvironment and conformation of serum albumin, which could lead to toxic effects on the organism. PMID- 20957682 TI - Effect of histidine on autotaxin activity in experimentally induced liver fibrosis. AB - The aim of this study was to explain whether serum autotaxin (ATX) activity might be a target for regulation of liver fibrosis and to evaluate the hepatoprotective and antifibrotic effects of histidine in thioacetamide (TAA)-induced liver fibrosis in rats. This study was carried out on 100 Wistar Albino rats, classified into five groups, each containing 20 rats: Group I (control group), Group II: rats were given histidine intraperitoneally, Group III: rats were injected intraperitoneally with TAA, Group IV: rats were injected with L histidine together with TAA, and Group V: rats were injected with TAA for 1 month then treated with intraperitoneal injection of L-histidine for another month. At the end of experiment, blood and liver were collected for determination of some liver enzymes, plasma total antioxidant capacity (TAC), serum ATX activity, and liver tissue hydroxyproline. Thioacetamide treatment caused significant increases in liver enzymes, ATX activities, and liver hydroxyproline, but a significant decrease in plasma's TAC. Upon treatment with histidine, a significant decrease in liver enzymes, ATX activities, and liver hydroxyproline was observed with a significant increase in plasma TAC in Group IV and a significant decrease in Group V. Histidine as an antioxidant has a protective effect on TAA-induced liver fibrosis; it is beneficial in rats not only by inhibition of collagen synthesis and increasing TAC but also by inhibition of ATX activities thus reducing its capacity to produce lysophosphatidic acid, which has a role in liver fibrosis. PMID- 20957684 TI - Dyslexia in regular orthographies: manifestation and causation. AB - This article summarizes our research on the manifestation of dyslexia in German and on cognitive deficits, which may account for the severe reading speed deficit and the poor orthographic spelling performance that characterize dyslexia in regular orthographies. An only limited causal role of phonological deficits (phonological awareness, phonological STM, and rapid naming) for the emergence of reading fluency and spelling deficits is inferred from two large longitudinal studies with assessments of phonology before learning to read. A review of our cross-sectional studies provides no support for several cognitive deficits (visual-attention deficit, magnocellular dysfunction, skill automatization deficit, and visual-sequential memory deficit), which were proposed as alternatives to the phonological deficit account. Finally, a revised version of the phonological deficit account in terms of a dysfunction in orthographic phonological connectivity is proposed. PMID- 20957683 TI - The acute toxicity of fenitrothion on narrow-clawed crayfish (Astacus leptodactylus Eschscholtz, 1823) in association with biomarkers of lipid peroxidation. AB - The aim of this research was to evaluate the acute toxicity of fenitrothion to the crayfish (Astacus leptodactylus Eschscholtz, 1823), which is chosen as an alternative aquatic organism to fish by using the static test system and evaluate the basic lipid peroxidation parameters for the first 24 h. Crayfish of 27.3 +/- 0.56 g mean weight and 10.0 +/- 0.72 cm mean length were selected for the bioassay experiments. The experiments were repeated three times in 20 liters of tap water. The temperature of water was 21 +/- 1 degrees C. The data obtained were statistically evaluated by using a computer program developed by the United States Environmental Protection Agency, based on Finney's probit analysis method and the 96-h LC(50) value for crayfish was calculated to be 15.75 MUg/L. The 95% lower and upper confidence limits for the LC(50) were 9.45 to 25.01 MUg/L. In addition to the acute toxicity bioassay experiments, 24-h oxidative stress parameters such as malondialdehyde (MDA) levels and ferrous oxidation assay (FOX HP [hydrogen peroxide] equivalents) were also determined. Only MDA levels of hepatopancreas decreased at 5, 10, and 20 MUg/L of fenitrothion doses. We can conclude that fenitrothion is highly toxic to crayfish, a nontarget organism in the ecosystem, and the lipid peroxidation indicators can be easily used for monitoring environmental effects. PMID- 20957685 TI - Is there a causal link from a phonological awareness deficit to reading failure in children at familial risk for dyslexia? AB - The knowledge that reading and phonological awareness are mainly reciprocally related has hardly influenced the status of a phonological awareness deficit as the main cause of a reading deficit in dyslexia. Because direct proofs for this theory are still lacking we investigated children at familial risk for dyslexia in kindergarten and first grade. The familial risk was genuine; 40% developed reading deficits in first grade. However, we did not find any relationship between a phonological awareness or other phonological processing deficits in kindergarten and reading deficits in first grade. Finally, we did not find evidence for the claim that a phonological awareness deficit assumedly causes a reading deficit via 'unstable' or otherwise corrupted letter-speech sound associations. Although earlier research indicated letter knowledge as another significant determinant of later reading deficits, we found no support for this claim. Letter knowledge learning and learning to associate and integrate letters and speech sound are different processes and only problems in the latter process seem directly linked to the development of a reading deficit. The nature of this deficit and the impact it might have on multisensory processing in the whole reading network presents a major challenge to future reading and dyslexia research. PMID- 20957686 TI - Exploring dyslexics' phonological deficit III: foreign speech perception and production. AB - This study investigates French dyslexic and control adult participants' ability to perceive and produce two different non-native contrasts (one segmental and one prosodic), across several conditions varying short-term memory load. For this purpose, we selected Korean plosive voicing (whose categories conflict with French ones) as the segmental contrast and lexical stress as the prosodic contrast (French does not use contrastive lexical stress). We also used a French (native) segmental contrast as a control. Tasks were either auditory discrimination or repetition of CVCV nonsense words. Short-term memory load was varied by presenting the stimuli either in isolation, in sequences of two, or in sequences of three. Our results show overall few differences between dyslexic and control participants. In particular, dyslexic participants performed similarly to controls in all tasks involving Korean plosives, whether in discrimination or in production, and regardless of short-term memory load. However, some group differences emerged with respect to lexical stress, in the discrimination task at greater short-term memory load. Various analyses suggest that dyslexic participants' difficulties are due to the meta-phonological nature of the task and to short-term memory load. PMID- 20957687 TI - Coherence motion perception in developmental dyslexia: a meta-analysis of behavioral studies. AB - The magnitude of the association between developmental dyslexia (DD) and motion sensitivity is evaluated in 35 studies, which investigated coherence motion perception in DD. A first analysis is conducted on the differences between DD groups and age-matched control (C) groups. In a second analysis, the relationship between motion coherence threshold and reading ability is considered. Globally, the mean effect size (ES) is moderate (d = 0.675, 2334 subjects) with a large value (d = 0.747) for the between-groups differences in motion perception and a smaller mean ES (d = 0.178) for the correlational studies. The influence on ES of the stimuli parameters and subjects age is analyzed. The number of dots, the age of the subjects, and the type of analysis (i.e. between-group or correlational) are significantly related to the ES. Looking at the ES values, a smaller number of dots constituting the stimuli are associated with larger ES and, interestingly, the children studies are associated with lower ES in comparison with the researches evaluating adults. The large ES value supports the importance of studying motion perception deficits in DD groups, consistently with the claim that dorsal impairment/noise-exclusion deficit could be one of the risk factor of reading difficulties. PMID- 20957688 TI - Striking the right balance: motor difficulties in children and adults with dyslexia. AB - Balance difficulties are an enduring feature of dyslexia research, however results have been inconsistent. We propose that between-study heterogeneity may be attributable to variability in balance tasks, balance measurement, participant age, and inclusion of comorbid disorders such as ADHD. This study attempted to clarify these issues, employing quantitative, continuous measures of balance and blindfolded balance, and using both adult and child participants without comorbid ADHD. Eighty-seven individuals participated: dyslexic adults (n = 17), matched adult controls (n = 30), dyslexic children (n = 16) and matched child controls (n = 24). The study found significant balance deficits for the child dyslexic group in the eyes-open task and a result approaching significance in the blindfolded task. By contrast, the adult dyslexic group showed significant deficits in the blindfolded task only. This result is interpreted in terms of lack of sensitivity of the non-blindfolded balance task for adults, owing to ceiling effects. This highlights the need for the use of age-appropriate tests, and may explain some of the heterogeneity in the literature. It is concluded that there is a significant incidence of balance difficulties in children and adults with dyslexia, even for those without comorbid attention deficit. PMID- 20957689 TI - Introduction to this issue: Adjudicative competencies. PMID- 20957690 TI - "Good and bad, I defined these terms, quite clear no doubt somehow": Neuroimaging and competency to be executed after Panetti. AB - There has been little consideration, in either the caselaw or the scholarly literature, of the potential impact of neuroimaging on cases assessing whether a seriously mentally disabled death row defendant is competent to be executed. The Supreme Court's 2007 decision in Panetti v. Quarterman significantly expanded its jurisprudence by ruling that such a defendant had a constitutional right to make a showing that his mental illness "obstruct[ed] a rational understanding of the State's reason for his execution." This article considers the impact of neuroimaging testimony on post-Panetti competency determination hearings, and looks at multiple questions of admissibility of evidence, adequacy of counsel, availability of expert assistance, juror attitudes, trial tactics, and application of the Daubert doctrine, and also considers the implications of the lesser-known Panetti holding (that enhances the role of expert witnesses in all competency-to-be-executed inquiries). It warns that the power of the testimony in question has the capacity to inappropriately affect fact-finders in ways that may lead "to outcomes that are both factually and legally inaccurate and constitutionally flawed." PMID- 20957691 TI - Factors affecting jail detention of defendants adjudicated incompetent to proceed. AB - The movement of defendants through the legal process who have been adjudicated incompetent to proceed is little studied, yet it is important. The purpose of this study was to provide empirical data regarding factors that affected the amount of time defendants adjudicated incompetent to proceed and ordered to undergo hospitalization remained in jail while awaiting transfer to a state hospital. Statewide data collected in Florida between July 2005 and June 2008 were used to determine the lengths of time incompetent defendants spent at certain stages in the legal process. The addition of forensic bed capacity following media attention and litigation resulted in a significant decrease in the amount of time defendants adjudicated incompetent to proceed waited in jail for transfer to a state hospital for treatment. The amount of time it took for completed commitment orders to be submitted to the state mental health authority by the Clerks of Court of each county accounted for a meaningful portion of days defendants spent in jail awaiting transfer to a state hospital, with considerable variation across counties with respect to waiting times. These findings reflect how various stakeholders can affect the amount of time defendants spend in jail while awaiting hospitalization. These issues are discussed in the context of controversy related to Florida's forensic mental health system, as well as issues related to the political process and funding of the state's mental health authority. PMID- 20957692 TI - Impact of early onset dementia on caregivers: a review. AB - OBJECTIVE: When it comes to dementia, caregiving can have adverse effects on the psychological and physical health of the informal caregiver. As yet, little is known about the impact of caring for a young dementia patient. This review provides an overview of the literature concerning the impact of early onset dementia (EOD) on informal caregivers and on children of EOD patients. The available literature comparing the impact on EOD and late onset dementia (LOD) caregivers will also be provided. METHODS: PubMed, Psychinfo, and Cinahl were searched for articles that considered the psychological or psychosocial impact of EOD on informal caregivers and children. The methodological quality of the studies was assessed in order to make better judgments about the value of each article. RESULTS: Seventeen articles were included, of which the overall methodological quality was limited. The results showed that EOD caregivers experienced high levels of burden, stress, and depression. When compared with LOD caregivers, results were inconclusive. Furthermore, the caregivers of EOD patients experienced a variety of psychosocial problems, including relational problems, family conflict, problems with employment, financial difficulties, and problems concerning diagnosis. CONCLUSIONS: Whether there is a difference in impact between EOD and LOD on caregivers is still unclear. The studies conducted are methodologically too limited to answer this question. Nevertheless, it is clear that EOD caregivers do seem to experience high levels of psychological suffering and specific problems related to their phase in life. PMID- 20957693 TI - Treating depression to remission in older adults: a controlled evaluation of combined escitalopram with interpersonal psychotherapy versus escitalopram with depression care management. AB - OBJECTIVE: More than half of the older adults respond only partially to first line antidepressant pharmacotherapy. Our objective was to test the hypothesis that a depression-specific psychotherapy, Interpersonal Psychotherapy (IPT), when used adjunctively with escitalopram, would lead to a higher rate of remission and faster resolution of symptoms in partial responders than escitalopram with depression care management (DCM). METHOD: We conducted a 16-week randomized clinical trial of IPT and DCM in partial responders to escitalopram, enrolling 124 outpatients aged 60 and older. The primary outcome, remission, was defined as three consecutive weekly scores of 7 or less on the Hamilton rating scale for depression (17-item). We conducted Cox regression analyses of time to remission and logistic modeling for rates of remission. We tested group differences in Hamilton depression ratings over time via mixed-effects modeling. RESULTS: Remission rates for escitalopram with IPT and with DCM were similar in intention to-treat (IPT vs. DCM: 58 [95% CI: 46, 71] vs. 45% [33,58]; p = 0.14) and completer analyses (IPT vs. DCM: 58% [95% CI: 44,72] vs. 43% [30,57]; p = 0.20). Rapidity of symptom improvement did not differ in the two treatments. CONCLUSION: No added advantage of IPT over DCM was shown. DCM is a clinically useful strategy to achieve full remission in about 50% of partial responders. PMID- 20957694 TI - Relation between frontal lobe symptoms and dementia severity within and across diagnostic dementia categories. AB - BACKGROUND: To study frontal lobe symptoms in relation to dementia severity within and across diagnostic dementia categories, a cross-sectional analysis of behavioural data was performed. METHODS: Patients with probable Alzheimer's disease (AD) (n = 456), frontotemporal dementia (FTD) (n = 55) and dementia with Lewy bodies (DLB) (n = 48) were included. Dementia severity and frontal lobe symptoms were assessed by means of the global deterioration scale and the Middelheim frontality score (MFS). RESULTS: In FTD, no difference in MFS total scores between patients belonging to the mild and severe dementia stages was found (p = 0.828). In AD and DLB groups, significantly higher MFS total scores were found in severe dementia stages compared to mild dementia stages (p < 0.001). Comparing MFS total scores between FTD and AD patients, significantly higher scores were achieved in FTD patients, irrespective of dementia severity (p < 0.001). CONCLUSIONS: In FTD patients, frontal lobe symptoms were severe in the mild, moderate and severe dementia stages although the nature of frontal lobe symptoms depended on disease severity. AD and DLB patients displayed more frontal lobe symptoms in the advanced disease stages as compared to disease onset, suggesting gradual frontal lobe involvement as the disease progresses. The nature of frontal lobe symptoms related to dementia severity differed between AD, DLB and FTD patients, suggesting different patterns of frontal lobe involvement. Last but not the least, these data point to the potential diagnostic value of behavioural observation of frontal lobe symptoms for (differential) dementia diagnosis, especially at the earliest disease stages. These findings await confirmation through a prospective, longitudinal study. PMID- 20957695 TI - Thyroid function, cognition, functional independence and behavioural and psychological symptoms of dementia in Alzheimer's disease. PMID- 20957696 TI - Is every shared psychosis a folie a deux? PMID- 20957697 TI - Screening for dementia in populations with little education. PMID- 20957698 TI - Advanced polymers for stem cell biology and medicine. PMID- 20957699 TI - Electrochemical polymerization of (2-dodecyl-4, 7-di (thiophen-2-yl)-2H benzo[d][1,2,3] triazole): a novel matrix for biomolecule immobilization. AB - A recently synthesized conducting polymer [poly(2-dodecyl-4,7-di(thiophen-2-yl) 2H-benzo[d][1,2,3]triazole (PTBT)] was tested as a platform for biomolecule immobilization. After electrochemical polymerization of the monomer (TBT) on graphite electrodes, immobilization of glucose oxidase (GOx,beta-D-glucose: oxygen-1-oxidoreductase, EC 1.1.3.4) was carried out. To improve the interactions between the enzyme and hydrophobic alkyl chain on the polymeric structure, GOx and isoleucine (Ile) amino acid were mixed in sodium phosphate buffer (pH 7.0) with a high ionic strength (250 * 10(-3) M). The solution is then casted on the polymer film, and the amino groups in the protein structure were crosslinked using glutaraldehyde (GA) as the bifunctional agent. Finally, the surface was covered with a perm-selective membrane. Consequently, cross-linked enzyme crystal (CLEC) like assembles with regular shapes were observed after immobilization. Microscopic techniques such as scanning electron microscopy (SEM) and fluorescence microscopy were used to monitor the surface morphologies of both the polymer and the bioactive layer. Electrochemical responses of the enzyme electrodes were measured by monitoring O(2) consumption in the presence of glucose at -0.7 V. The optimized biosensor showed a very good linearity between 0.05 and 2.5 * 10(-3) M with a 52 s response time and a detection limit (LOD) of 0.029 * 10(-3) M to glucose. Also, kinetic parameters, operational and storage stabilities were determined. K(m) and I(max) values were found as 4.6 * 10(-3) M and 2.49 uA, respectively. It was also shown that no activity was lost during operational and storage conditions. Finally, proposed system was applied for glucose biomonitoring during fermentation in yeast culture where HPLC was used as the reference method to verify the data obtained by the proposed biosensor. PMID- 20957700 TI - Electric-field-induced resistive switching in a family of mott insulators: Towards a new class of RRAM memories. PMID- 20957701 TI - Weight suppression as a predictor variable in treatment trials of bulimia nervosa and binge eating disorder. AB - OBJECTIVE: The purpose of this study was to examine weight suppression (WS) as a predictor of treatment outcome among individuals with binge eating disorder (BED) and bulimia nervosa (BN). METHOD: Participants were diagnosed with BED or BN and took part in separate treatment studies. The current study examined WS as a predictor of treatment completion, weight change during treatment, and symptomatic abstinence, as well as percent reduction in binge eating and purging frequency. RESULTS: WS did not significantly predict treatment completion or treatment outcome in either group. DISCUSSION: Contrary to some previous findings, these results failed to demonstrate that WS was predictive of outcome at the end of treatment in BN. In addition, WS was not predictive of treatment outcome or dropout status in BED. PMID- 20957702 TI - Children's eating attitudes test: validation in a sample of Spanish schoolchildren. AB - OBJECTIVE: To validate the Spanish version of the Children's Eating Attitudes Test (ChEAT). METHOD: The factor structure and other psychometric characteristics of the questionnaire were examined using the answers of 38,554 schoolchildren. Diagnostic efficiency was based on a standardized clinical interview of 968 schoolchildren who had previously completed the questionnaire. RESULTS: Five factors ("preoccupation with thinness," "dieting," "social pressure to eat," "purging," and "preoccupation with food and oral control") explained 46% of the variance. Cronbach's alpha was .858 for the total scale. The area under the receiver operating characteristic curve was .851. Sensitivity (SE) was 27% and specificity (SP) 96% for a cut-off of 20. A more appropriate cut-off was 15, where SE and SP were 62% and 90% respectively, and the positive and negative predictive values 27 and 98%. DISCUSSION: The ChEAT psychometric characteristics are adequate. The questionnaire is valid. A cut-off point of 15 is recommended for adolescents. PMID- 20957703 TI - Bivariate analysis of disordered eating characteristics in adolescence and young adulthood. AB - OBJECTIVE: We examined the etiology of two disordered eating characteristics. METHOD: Participants included 1,470 female adolescent and young adult twins and their female nontwin siblings. Phenotypic factor analyses of a seven-item eating pathology screening tool yielded two factors: weight and shape concerns and behaviors (WSCB) and binge eating (BE). Univariate and bivariate extended twin analyses (including cotwins and nontwin siblings) were used to estimate the magnitude of genetic and environmental influences on these characteristics. RESULTS: Analyses indicated that individual differences in WSCB and BE could be explained by additive genetic influences (a2 = 0.43 (95% CI: 0.33-0.52) and 0.49 (95% CI: 0.36-0.58), respectively), with the remaining variance due to nonshared environmental influences. The genetic correlation between WSCB and BE was estimated at 0.64; the nonshared environmental correlation was estimated at 0.27. DISCUSSION: These results corroborate previous findings on genetic and environmental influences on disordered eating characteristics and suggest that findings can be extended to nontwin populations. PMID- 20957704 TI - Evoked facial emotional expression and emotional experience in people with anorexia nervosa. AB - OBJECTIVE: To use an experimental paradigm to assess facial expression, subjective experience of emotion and the relationship between them in people with anorexia nervosa (AN). METHOD: Film clips are used to elicit emotion and participants' facial expression and subjective experience are recorded. Thirty inpatients with AN and 34 healthy control (HC) women are included in the study. RESULTS: People with AN are less facially expressive than HC while watching positive and negative film clips and report feeling less positive emotion than HC but not less negative emotion. People with AN look away significantly more than HC during the negative film clip. Duration of illness and depression relate to attenuated positive facial expression and eating pathology to attenuated negative facial expression. DISCUSSION: This experimental study supports self report studies showing people with AN attenuate emotional expression and avoid negative affect. Such behavior may affect social interaction and contribute to the maintenance of the disorder. PMID- 20957705 TI - Predictive significance of changes in dietary restraint in obese patients with binge eating disorder during treatment. AB - OBJECTIVE: To examine whether changes in different aspects of dietary restraint in obese patients with binge eating disorder (BED) participating in a treatment study predict outcomes. METHOD: Fifty obese patients with BED in a randomized controlled study of orlistat administered with cognitive-behavioral therapy, guided-self-help (CBTgsh) completed dietary restraint measures at baseline, during- and post-treatment, and three-month follow-up. RESULTS: Change in the restraint scale of the Eating Disorder Examination-Questionnaire did not predict binge abstinence or 5% weight loss. Increased flexible restraint subscale of the Three Factor Eating Questionnaire (TFEQ) during treatment significantly predicted binge abstinence at post-treatment and three-month follow-up and 5% weight loss at post-treatment. Change in the rigid restraint subscale of the TFEQ predicted binge abstinence at post-treatment. DISCUSSION: Our findings clarify further pathologic and adaptive aspects of restraint and suggest the importance of enhancing flexible restraint in order to improve both binge eating and weight loss outcomes. PMID- 20957707 TI - Efficient quantification of the importance of contacts for the dynamical stability of proteins. AB - Understanding the stability of the native state and the dynamics of a protein is of great importance for all areas of biomolecular design. The efficient estimation of the influence of individual contacts between amino acids in a protein structure is a first step in the reengineering of a particular protein for technological or pharmacological purposes. At the same time, the functional annotation of molecular evolution can be facilitated by such insight. Here, we use a recently suggested, information theoretical measure in biomolecular design the Kullback-Leibler-divergence - to quantify and therefore rank residue-residue contacts within proteins according to their overall contribution to the molecular mechanics. We implement this protocol on the basis of a reduced molecular model, which allows us to use a well-known lemma of linear algebra to speed up the computation. The increase in computational performance is around 10(1)- to 10(4) fold. We applied the method to two proteins to illustrate the protocol and its results. We found that our method can reliably identify key residues in the molecular mechanics and the protein fold in comparison to well-known properties in the serine protease inhibitor. We found significant correlations to experimental results, e.g., dissociation constants and Phi values. PMID- 20957706 TI - Correlates of weight instability across the lifespan in a population-based sample. AB - OBJECTIVE: Research from overweight/obese clinical samples links weight instability to poor health. This study investigated whether negative health outcomes were associated with weight instability in a population-based sample. METHOD: One thousand five hundred ten women and 1,111 men from the Mid-Atlantic Twin Registry completed questionnaires assessing demographics, body size in childhood, adolescence, and adulthood, health satisfaction, and disordered eating. Noneating disorder psychiatric diagnoses were assessed via clinical interviews. RESULTS: Weight instability was related to lower health satisfaction and self-esteem, and higher body dissatisfaction, dieting, and binge eating for both sexes. Weight unstable women were more likely to meet criteria for lifetime major depressive disorder, generalized anxiety disorder, and eating disorders. Weight stable women were more likely to abuse alcohol; however, two of these associations [e.g. weight instability and generalized anxiety disorder (GAD) and weight stability and alcohol abuse] became nonsignificant once lifetime binge eating was accounted for, indicating that these forms of psychopathology are more strongly related to binge eating than weight instability itself. No associations between weight stability and psychiatric diagnoses were found in men. DISCUSSION: Weight instability is related to mental and physical health concerns for both sexes. It was also specifically associated with depression and eating pathology in women. PMID- 20957708 TI - A simple approach to coordination compounds of the pentacyanocyclopentadienide anion. AB - Deprotonation of [Et(3)NH][C(5)(CN)(5)] with metal bases provides a very simple approach to coordination compounds containing the pentacyanocyclopentadienide anion [C(5)(CN)(5)](-) (1). The three-dimensional polymer [Na(thf)(1.5)(1)](infinity) and the molecular dimer [{(tmeda)(2)Na(1)}(2)] are obtained by reaction of this precursor with NaH in the presence of thf or tmeda (Me(2)NCH(2)CH(2)NMe(2)). Their single-crystal X-ray structures both reveal sigma bonded C=N-Na arrangements and pi stacking between [C(5)(CN)(5)](-) ions. DFT calculations on the [C(5)(CN)(5)](-) ion have been used to investigate the structures and bonding in [Na(thf)(1.5)(1)](infinity) and [{(tmeda)(2)Na(1)}(2)]. The absence of pi bonding of the metal ions in both complexes is due to dispersion of the negative charge from the C(5) ring unit to the C[triple chemical bond]N groups in the [C(5)(CN)(5)](-) ion, making the coordination chemistry of this anion distinctly different from that of cyclopentadienide C(5)H(5)(-). PMID- 20957709 TI - Salen-complex-mediated formation of cyclic carbonates by cycloaddition of CO2 to epoxides. AB - Metal complexes of salen ligands are an important class of compounds, and they have been widely studied in the past. Among their successful catalytic applications, the synthesis of cyclic carbonates by the coupling reaction of epoxides with CO(2) has received increased attention; this is mostly due to the importance of using a greenhouse gas as a feedstock for the synthesis of useful molecules. Herein the most relevant past and present research surrounding this topic is presented. PMID- 20957711 TI - Smart self-assemblies based on a surfactant-encapsulated photoresponsive polyoxometalate complex. PMID- 20957710 TI - Rapid three-dimensional MAS NMR spectroscopy at critical sensitivity. PMID- 20957713 TI - Photochemistry of methyl ethyl ketone: quantum yields and S1/S0-diradical mechanism of photodissociation. AB - Pulsed laser photolysis (PLP) at lambda=248 and 308 nm coupled with gas chromatographic analysis is applied to determine the photodissociation quantum yield (QY) of methyl ethyl ketone (MEK). Temperature dependent UV absorption cross-sections [sigma(MEK)(lambda,T)] are also determined. At 308 nm, the QY decreases with decreasing temperature (T=323-233 K) and with increasing pressure (P=67-998 mbar synthetic air). Stern-Volmer (SV) analysis of the T and P dependent QYs provides the experimental estimate of E(S1)=398+/-9 kJ mol(-1) (=300+/-6 nm) for the barrier of the first excited singlet state (S(1)). The QY at 248 nm is close to unity and independent of pressure (T=298 K). Theoretical reaction pathways are examined systematically on the basis of CASPT2/6-31+G* calculations. Among three possible pathways, a S(1)/S(0)-diradical mechanism, which involves H atom transfer on the S(1) surface, followed by a nonadiabatic transition at a diradical isomer of MEK, explains the experimental data very well. Therefore, this unusual mechanism, which is not seen in any smaller carbonyl compounds, is proposed as an important pathway for the MEK dissociation. Our study supports the view that both the absorption cross-sections and the QYs of carbonyls have significant temperature dependences that should be taken into account for accurate modelling of atmospheric chemistry. PMID- 20957712 TI - Conformational control of integrin-subtype selectivity in isoDGR peptide motifs: a biological switch. PMID- 20957714 TI - Refractive index of liquid mixtures: theory and experiment. AB - An innovative approach is presented to interpret the refractive index of binary liquid mixtures. The concept of refractive index "before mixing" is introduced and shown to be given by the volume-fraction mixing rule of the pure-component refractive indices (Arago-Biot formula). The refractive index of thermodynamically ideal liquid mixtures is demonstrated to be given by the volume fraction mixing rule of the pure-component squared refractive indices (Newton formula). This theoretical formulation entails a positive change of refractive index upon ideal mixing, which is interpreted in terms of dissimilar London dispersion forces centred in the dissimilar molecules making up the mixture. For real liquid mixtures, the refractive index of mixing and the excess refractive index are introduced in a thermodynamic manner. Examples of mixtures are cited for which excess refractive indices and excess molar volumes show all of the four possible sign combinations, a fact that jeopardises the finding of a general equation linking these two excess properties. Refractive indices of 69 mixtures of water with the amphiphile (R,S)-1-propoxypropan-2-ol are reported at five temperatures in the range 283-303 K. The ideal and real refractive properties of this binary system are discussed. Pear-shaped plots of excess refractive indices against excess molar volumes show that extreme positive values of excess refractive index occur at a substantially lower mole fraction of the amphiphile than extreme negative values of excess molar volume. Analysis of these plots provides insights into the mixing schemes that occur in different composition segments. A nearly linear variation is found when Balankina's ratios between excess and ideal values of refractive indices are plotted against ratios between excess and ideal values of molar volumes. It is concluded that, when coupled with volumetric properties, the new thermodynamic functions defined for the analysis of refractive indices of liquid mixtures give important complementary information on the mixing process over the whole composition range. PMID- 20957715 TI - Tunable electronic properties of a proton-responsive N,N-dimethylaminoazobenzene fullerene (C60) dyad. AB - A basic N,N-dimethylaminoazobenzene-fullerene (C(60)) dyad molecular skeleton is modelled and synthesized. In spite of the myriad use of azobenzene as a photo- and electrochromic moiety, the idea presented herein is to adopt a conceptually different path by using it as a bridge in a donor-bridge-acceptor single molecular skeleton, connecting the electron acceptor N-methylfulleropyrrolidine with an electron donor N,N-dimethylaniline. Addition of trifluoroacetic acid (TFA) results in a drastic colour change of the dyad from yellow to pink in dichloromethane (DCM). The structure of the protonated species are established from electronic spectroscopy and time-dependent density functional theory (TD DFT) calculations. UV/Vis spectroscopic investigations reveal the disappearance of the 409 nm (1)(pi->pi*) transition with appearance of new features at 520 and 540 nm, attributed to protonated beta and alpha nitrogens, respectively, along with a finite weight of the C(60) pyrrolidinic nitrogen. Calculations reveal intermixing of n((N=N))->pi*((N=N)) and charge transfer (CT) transitions in the neutral dyad, whereas, the n((N=N))->pi*((N=N)) transition in the protonated dyad is buried under the dominant (1)(pi ->pi*) feature and is red-shifted upon Gaussian deconvolution. The experimental binding constants involved in the protonation of N,N-dimethylanilineazobenzene and the dyad imply an almost equal probability of existence of both alpha- and beta-protonated forms. Larger binding constants for the protonated dyads imply more stable dyad complexes than for the donor counterparts. One of the most significant findings upon protonation resulted in frontier molecular orbital (FMO) switching with the dyad LUMO located on the donor part, evidenced from electrochemical investigations. The appearance of a new peak, prior to the first reduction potential of N methylfulleropyrrolidine, clearly indicates location of the first incoming electron on the donor-centred LUMO of the dyad, corroborated by unrestricted DFT calculations performed on the monoanions of the protonated dyad. The protonation of the basic azo nitrogens thus enables a rational control over the energetics and location of the FMOs, indispensable for electron transport across molecular junctions in realizing futuristic current switching devices. PMID- 20957716 TI - Modulating the photochemistry of bipyridylic compounds by symmetric substitutions. AB - A quantum electronic study of the effect of substituents on (2,2'-bipyridyl)-3,3' diol and (2,2'-bipyridyl)-3,3'-diamine is presented. A large difference in the photochemical behavior between the original and the substituted selected systems is expected. For the sake of simplicity, the study is restricted to the symmetrically bi-substituted compounds: fluorine, the more electronegative atom and thus a strong sigma-acceptor but also a weak pi-donor group, and NO(2), a strong pi-acceptor substituent. Among the large set of compounds studied, two receive special attention: 5,5'-dinitro-(2,2'-bipyridyl)-3,3'-diamine and 6,6' difluoro-(2,2'-bipyridyl)-3,3'-diol. While in the former case the nitro substitution transforms (2,2'-bipyridyl)-3,3'-diamine, previously suggested to behave as a photomemory material, into a simple fluorescent species, the latter substitution turns (2,2'-bipyridyl)-3,3'-diol into a fresh new candidate for a photomemory device. PMID- 20957717 TI - Modeling and biological investigations of an unusual behavior of novel synthesized acridine-based polyamine ligands in the binding of double helix and G quadruplex DNA. AB - Three novel 2,7-substituted acridine derivatives were designed and synthesized to investigate the effect of this functionalization on their interaction with double stranded and G-quadruplex DNA. Detailed investigations of their ability to bind both forms of DNA were carried out by using spectrophotometric, electrophoretic, and computational approaches. The ligands in this study are characterized by an open-chain (L1) or a macrocyclic (L2, L3) framework. The aliphatic amine groups in the macrocycles are joined by ethylene (L2) or propylene chains (L3). L1 behaved similarly to the lead compound m-AMSA, efficiently intercalating into dsDNA, but stabilizing G-quadruplex structures poorly, probably due to the modest stabilization effect exerted by its protonated polyamine chains. L2 and L3, containing small polyamine macrocyclic frameworks, are known to adopt a rather bent and rigid conformation; thus they are generally expected to be sterically impeded from recognizing dsDNA according to an intercalative binding mode. This was confirmed to be true for L3. Nevertheless, we show that L2 can give rise to efficient pi-pi and H-bonding interactions with dsDNA. Additionally, stacking interactions allowed L2 to stabilize the G-quadruplex structure: using the human telomeric sequence, we observed the preferential induction of tetrameric G quadruplex forms. Thus, the presence of short ethylene spacers seems to be essential for obtaining a correct match between the binding sites of L2 and the nucleobases on both DNA forms investigated. Furthermore, current modeling methodologies, including docking and MD simulations and free energy calculations, provide structural evidence of an interaction mode for L2 that is different from that of L3; this could explain the unusual stabilizing ability of the ligands (L2>L3>L1) toward G-quadruplex that was observed in this study. PMID- 20957718 TI - Double click reaction for the acquisition of a highly potent and selective mPTPB inhibitor. AB - Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), is a major worldwide threat to public health. Mycobacterium protein tyrosine phosphatase B (mPTPB) is a virulent phosphatase secreted by Mtb, which is essential for the survival and persistence of the bacterium in the host. Consequently, small-molecule inhibitors of mPTPB are expected to serve as anti-TB agents with a novel mode of action. Herein, we report the discovery of highly potent and selective mPTPB inhibitors using a novel, double Click chemistry strategy. The most potent mPTPB inhibitor from this approach possesses a K(i) value of 160 nM and a >25-fold selectivity for mPTPB over 19 other protein tyrosine phosphatases (PTBs). Molecular docking study of the enzyme-inhibitor complex provides a rationale for the high potency and selectivity of the lead compound and reveals an unusual binding mode, which may guide further optimization effort. PMID- 20957719 TI - Differentiation of bulk and surface contribution to supercapacitance in amorphous and crystalline NiO. PMID- 20957720 TI - Dynamin self-assembly and the vesicle scission mechanism: how dynamin oligomers cleave the membrane neck of clathrin-coated pits during endocytosis. AB - Recently, Gao et al. and Chappie et al. elucidated the crystal structures of the polytetrameric stalk domain of the dynamin-like virus resistance protein, MxA, and of the G-domain dimer of the large, membrane-deforming GTPase, dynamin, respectively. Combined, they provide a hypothetical oligomeric structure for the complete dynamin protein. Here, it is discussed how the oligomers are expected to form and how they participate in dynamin mediated vesicle fission during the process of endocytosis. The proposed oligomeric structure is compared with the novel mechanochemical model of dynamin function recently proposed by Bashkirov et al. and Pucadyil and Schmid. In conclusion, the new model of the dynamin oligomer has the potential to explain how short self-limiting fissogenic dynamin assemblies are formed and how concerted GTP hydrolysis is achieved. The oligomerisation of two other dynamin superfamily proteins, the guanylate binding proteins (GBPs) and the immunity-related GTPases (IRGs), is addressed briefly. PMID- 20957721 TI - Improved outcome of patients with low- and intermediate-risk cytogenetics acute myeloid leukemia (AML) in first relapse with gemtuzumab and cytarabine versus cytarabine: results of a retrospective comparative study. AB - BACKGROUND: Acute myeloid leukemia (AML) in first relapse is associated with a poor outcome even when treated with intermediate- to high-dose cytarabine (IHDAraC). Gemtuzumab ozogamycin (GO) used as a single agent has clinical activity in relapsed and refractory AML. Various combination regimens of GO have been developed, but few data are available regarding their efficacy compared with IHDAraC-based regimens. METHODS: The authors performed a retrospective analysis of response and survival in 90 AML patients in first relapse treated with either IHDAraC (n = 56) or IHDAraC + GO (n = 34). Patient characteristics of the two groups were comparable. RESULTS: Median follow-up was 37 months. Compared with IHDAraC, IHDAraC + GO induction was associated with a better response rate (68% vs 45%, P = .04), a better overall survival (median, 35 months vs 6 months, P = .001), and a better event-free survival (24 months vs 6 months, P = .002). This effect was limited to patients with low-risk and intermediate-risk cytogenetics. In multivariate analysis, age, cytogenetic risk, first complete remission duration, and the use of IHDAraC + GO were independently associated with better results. CONCLUSIONS: This study showed that the addition of GO to IHDAraC is associated with a better efficacy for patients in first relapse of AML with low- or intermediate-risk cytogenetics. Prospective controlled studies of GO in this population are warranted. Patients with high-risk cytogenetics should be offered investigational new drugs. PMID- 20957722 TI - Using claims-based measures to predict performance status score in patients with lung cancer. AB - BACKGROUND: Performance status (PS) is a good prognostic factor in lung cancer and is used to assess chemotherapy appropriateness. Researchers studying chemotherapy use are often hindered by the unavailability of PS in automated data sources. To the authors' knowledge, no attempts have been made to estimate PS using claims-based measures. The current study explored the ability to estimate PS using routinely available measures. METHODS: A cohort of insured patients aged >=50 years who were diagnosed with American Joint Committee on Cancer stage II through IV lung cancer between 2000 and 2007 was identified via a tumor registry (n = 552). PS was abstracted from medical records. Automated medical and pharmaceutical claims from the year preceding diagnosis were linked to tumor registry data. A logistic regression model was fit to estimate good versus poor PS in a random half of the sample. C statistics, sensitivity, specificity, and R2 were used to compare the predictive ability of models that included demographic factors, comorbidity measures, and claims-based utilization variables. Model fit was evaluated in the other half of the sample. RESULTS: PS was available in 80% of medical records. The multivariable regression model predicted good PS with high sensitivity (0.88 or 0.94 depending on how good PS was defined), but moderate specificity (0.45 or 0.32) with a 0.50 prediction cutoff, and good sensitivity (0.64 or 0.83) and specificity (0.69 or 0.55) when the cutoff was 0.70. The goodness-of-fit c statistic was 0.76 or 0.78. CONCLUSIONS: PS can be estimated, with some accuracy, using claims-based measures. Emphasis should be placed on documenting PS in medical records and tumor registries. PMID- 20957724 TI - Animal models of early life stress: implications for understanding resilience. AB - In the mid-1950s, Levine and his colleagues reported that brief intermittent exposure to early life stress diminished indications of subsequent emotionality in rats. Here we review ongoing studies of a similar process in squirrel monkeys. Results from these animal models suggest that brief intermittent exposure to stress promotes the development of arousal regulation and resilience. Implications for programs designed to enhance resilience in human development are discussed. PMID- 20957725 TI - What's in a name? Brain activity reveals categorization processes differ across languages. AB - The linguistic relativity hypothesis proposes that speakers of different languages perceive and conceptualize the world differently, but do their brains reflect these differences? In English, most nouns do not provide linguistic clues to their categories, whereas most Mandarin Chinese nouns provide explicit category information, either morphologically (e.g., the morpheme "vehicle" che1 in the noun "train" huo3che1) or orthographically (e.g., the radical "bug" chong2 in the character for the noun "butterfly" hu2die2). When asked to judge the membership of atypical (e.g., train) vs. typical (e.g., car) pictorial exemplars of a category (e.g., vehicle), English speakers (N = 26) showed larger N300 and N400 event-related potential (ERP) component differences, whereas Mandarin speakers (N = 27) showed no such differences. Further investigation with Mandarin speakers only (N = 22) found that it was the morphologically transparent items that did not show a typicality effect, whereas orthographically transparent items elicited moderate N300 and N400 effects. In a follow-up study with English speakers only (N = 25), morphologically transparent items also showed different patterns of N300 and N400 activation than nontransparent items even for English speakers. Together, these results demonstrate that even for pictorial stimuli, how and whether category information is embedded in object names affects the extent to which typicality is used in category judgments, as shown in N300 and N400 responses. PMID- 20957726 TI - Asbestosis and mesothelioma among British asbestos workers (1971-2005). AB - BACKGROUND: Ascertainment of asbestosis and mesothelioma from underlying cause of death underestimates the burden of these diseases. The aims of this study were to estimate the true frequency of asbestosis and mesothelioma among asbestos workers in Great Britain (GB), and to identify factors associated with the risk of death with these diseases. METHODS: The GB Asbestos Survey was established in 1971 to monitor long-term health outcomes among workers covered by regulations to control asbestos at work. Asbestosis and mesothelioma cases were defined by multiple cause of death, and were ascertained by identifying asbestos workers on the GB Asbestosis and Mesothelioma Registers. Standardized mortality ratios (SMRs) were calculated; the risks of asbestosis and mesothelioma were modeled with Poisson regression analysis. Deaths to the end of 2005 were included. RESULTS: There were 15,557 deaths between 1971 and 2005 among the 98,912 workers. Altogether 477 asbestosis and 649 mesothelioma cases were identified. The SMR for all causes was 1.42, for asbestosis 51.3, and for mesothelioma 13.5. In multiply adjusted analysis, age, sex, job, and birth cohort were significantly associated with asbestosis and mesothelioma. For asbestosis year of first exposure, and for mesothelioma latency, were also statistically significant. CONCLUSIONS: The asbestos workers experienced high mortality from all causes, asbestosis, and mesothelioma. There was some evidence that the risk of asbestosis and mesothelioma was lower in later birth cohorts and among those first occupationally exposed to asbestos more recently. Due to the long latency of both diseases, further follow-up is required to confirm these trends. PMID- 20957727 TI - Job stress and healthy behavior among male Japanese office workers. AB - BACKGROUND: Lifestyle modification in healthy workers is challenging. We aim to investigate associations between job stress and healthy behavior change among workers. METHODS: This cross-sectional study investigated 1,183 Japanese male white-collar workers in 2008 during health checkups for Metabolic Syndrome. Healthy behavior included either a calorie-focused diet or regular exercise. Job stress was measured by Job Content Questionnaire based on the job demands-control model and tension-anxiety and anger-hostility scales on the Profile of Mood States. RESULTS: Healthy behaviors were confirmed in 54% of study subjects. Multivariate logistic model showed that healthy behaviors were positively associated with a higher degree of work control and negatively associated with greater work demand. Work control and support were negatively correlated with tension-anxiety and depression, whereas work demand and strain were positively correlated with these two emotion domains (all P's < 0.0001). CONCLUSIONS: It is suggested that addressing job stress is of clinical importance to promote healthy behaviors. PMID- 20957728 TI - A structural equation model relating work stress, coping resource, and quality of life among Chinese medical professionals. AB - BACKGROUND: Work stress and coping resource may contribute to the quality of life in medical professionals. This study is to determine the relationships among work stressor, personal strain, coping resource and the quality of life (QOL) and its two dimensions in medical professionals. METHODS: The Chinese version of Short Form-36 Health Survey was used to measure QOL, the modified edition of the Occupational Stress Inventory was applied to evaluate the work stressor, personal strain and coping resources among 2,721 medical professionals. The structural equation model was established to assess the relationships among these variables. RESULTS: Work stressor and coping resources had both direct and indirect effects on QOL and its two dimensions, the indirect effects were mediated by personal strain. Personal strain had a negative direct effect on QOL and its two dimensions. CONCLUSIONS: This study confirmed a complex relationship among these variables. Countermeasures targeting work stressor, reducing personal strain and strengthening coping resources are necessary in order to improve the QOL among medical professionals. PMID- 20957729 TI - Porous tantalum stimulates the proliferation and osteogenesis of osteoblasts from elderly female patients. AB - Porous tantalum (Ta) implants have been successful in various orthopedic procedures for patients with compromised bone-forming abilities. Previous studies demonstrated that human osteoblast (HOB) cultures from older female patients produced less bone on implant materials in vitro compared to HOBs from age matched male and younger female patients. In this study, the responses of HOBs from younger (< 45) and older (> 60 years old) female patients were compared on Ta, titanium fiber mesh (TFM) and tissue culture plastic. Adhesion, proliferation, and mineralization were greater in cells from younger patients than from older patients. Cell adhesion was slightly higher on Ta than TFM or plastic. However, Ta highly stimulated cell proliferation with a 4- and 6-fold increase compared to TFM for cells from younger and older patients, respectively, and 12- and 16-fold increase in proliferation compared to cells on plastic (p <= 0.001). At 3 weeks, mineralization was significantly higher on Ta compared to TFM for HOBs from older patients (p <= 0.05). Expression levels of bone matrix markers demonstrated differences dependent on age and substrate. Scanning electron micrographs revealed HOBs covering the surfaces and entering the pores of both Ta and TFM. In conclusion, tantalum greatly stimulates cell proliferation, and improves the ability of HOBs from older patients to form bone. PMID- 20957730 TI - Toxic effect on tissues and differentially expressed genes in hepatopancreas identified by suppression subtractive hybridization of freshwater pearl mussel (Hyriopsis cumingii) following microcystin-LR challenge. AB - Microcystins are a family of potent hepatotoxins produced by freshwater cyanobacteria and can cause animal intoxications and human diseases. In this study, the effect of microcystin-LR (MC-LR) on the tissues of freshwater pearl mussel (Hyriopsis cumingii) was evaluated and differentially expressed genes in the hepatopancreas of the mussel exposed to MC-LR were identified. HPLC analysis of cell extracts from various tissues of the mussel indicated that the hepatopancreas had the highest MC-LR levels (55.78 +/- 6.73 MUg g-1 DW) after 15 day exposure. The MC-LR concentration in gill or muscle was an order of magnitude less than in hepatopancreas or gonad. Subtractive cDNA library was constructed by suppression subtractive hybridization (SSH), and ~400 positive clones were sequenced, from which 98 high quality sequences were obtained by BLAST analysis. The screening identified numerous genes involved in apoptosis, signal transduction, cytoskeletal remodel, innate immunity, material and energy metabolism, translation and transcription which were extensively discussed. The results of this study add large amount of information to the mussel genome data, and for the first time present the basic data on toxicity effect of MC-LR on mussel. PMID- 20957731 TI - The medial-lateral force distribution in the ovine stifle joint during walking. AB - Knowledge of the load distribution in the knee is essential for understanding the interaction between mechanics and biology in both the healthy and diseased joint. While the sheep stifle joint is a predominant model for better understanding regeneration after injury, little is known about the compartmental force distribution between the medial and lateral condyles. By including sheep specific anatomy and gait analyses, we used computational musculoskeletal analyses to estimate the medial-lateral joint contact force distribution in ovine stifle joints during walking by simplifying the system of equations into a 2D problem that was solved directly. Gait analysis was conducted using bone markers in three female Merino-mix sheep. Joint contact forces were computed with respect to the specific anatomy of the ovine tibia, resulting in low (<0.13 bodyweight) mean anteroposterior shear forces throughout the gait cycle, with mean peak contact forces perpendicular to the tibial plateau of 2.2 times bodyweight. The medial lateral compartmental load distribution across the tibial condyles was determined and revealed loading predominantly on the medial condyle, bearing approximately 75% of the total load during phases of peak loading. By considering the anatomical characteristics of the ovine stifle joint, together with the dynamic forces during gait, this study provides evidence for predominantly medial loading in sheep, somewhat similar to the distribution reported in man. However, the exact conditions under which the loading in the ovine stifle joint is representative of the human situation will need to be elucidated in further studies. PMID- 20957732 TI - Hyaluronan up-regulates IL-10 expression in fibroblast-like synoviocytes from patients with tibia plateau fracture. AB - Progression to osteoarthritis (OA) is a frequent sequela of severe articular fracture, particularly when weight-bearing joints are involved. Prevention from post-traumatic OA remains a challenge. Hyaluronan (HA) therapy is reported to represent a safe and effective treatment for patients with OA and rheumatoid arthritis. However, the capacity of HA to prevent the occurrence of osteoarthritic changes in fractured joints has not been demonstrated. The present study was undertaken to examine the effects of HA on expression of six OA-related proteins in fibroblast-like synoviocytes (FLS) from 10 patients with tibia plateau fracture. OA-related factors were quantified using a sandwich enzyme linked immunosorbent assay. Regardless of induction of the FLS with interleukin (IL)-1beta, HA was found to down-regulate expression of catabolic factors (IL 1beta, matrix metalloproteinase-3, and tumor necrosis factor-alpha) and to up regulate production of anti-catabolic factors (tissue inhibitors of metalloproteinase-1 and metalloproteinase-2). HA also enhanced expression of IL 10, an anti-inflammatory cytokine, in FLS. Our results indicated that HA can promote the expression of both antiinflammatory and structure-protective factors in FLS of patients with tibia plateau fracture. PMID- 20957733 TI - Use of the term "superficial femoral vein" in ultrasound. AB - PURPOSE: To determine the frequency of use of the term "superficial femoral vein" (SFV) in the radiologic reports from a sample of sonographic investigations for suspected deep vein thrombosis and to assess the potential for clinical error in their interpretation. METHODS: Retrospective review of 425 consecutive reports from medical patients attending the Imaging Department over a 6-month period for the presence of the term "superficial femoral vein" and for the presence of thrombus. A questionnaire was sent to a sample of referring clinicians to assess their understanding of the anatomy of the deep venous system of the leg and indications for anticoagulant treatment. RESULTS: Of the 425 sonographic investigations reviewed, 90 (21.2%) used the term "superficial femoral vein," and 12 (13.3%) were positive for SFV thrombus. Among 87 clinicians, 74.7% believed the SFV to be part of the superficial venous system and that its thrombosis did not require anticoagulant treatment, although anticoagulation is now indicated in selected cases of superficial venous thrombosis. CONCLUSION: Seventy-five percent of clinicians do not recognize the SFV as being part of the deep venous system and that its thrombosis requires anticoagulant treatment. In this study, 13% of SFV examined were positive for thrombus, and four patients (4.4%) had an isolated SFV thrombus that could have been left untreated due to this misunderstanding. Use of the term "superficial femoral vein" is prone to misinterpretation by clinicians and potentially hazardous to patients. It should be replaced by "common femoral vein" and "femoral vein" in reports. PMID- 20957734 TI - Adult human articular chondrocytes in a microcarrier-based culture system: expansion and redifferentiation. AB - Expanding human chondrocytes in vitro while maintaining their ability to form cartilage remains a key challenge in cartilage tissue engineering. One promising approach to address this is to use microcarriers as substrates for chondrocyte expansion. While microcarriers have shown beneficial effects for expansion of animal and ectopic human chondrocytes, their utility has not been determined for freshly isolated adult human articular chondrocytes. Thus, we investigated the proliferation and subsequent chondrogenic differentiation of these clinically relevant cells on porous gelatin microcarriers and compared them to those expanded using traditional monolayers. Chondrocytes attached to microcarriers within 2 days and remained viable over 4 weeks of culture in spinner flasks. Cells on microcarriers exhibited a spread morphology and initially proliferated faster than cells in monolayer culture, however, with prolonged expansion they were less proliferative. Cells expanded for 1 month and enzymatically released from microcarriers formed cartilaginous tissue in micromass pellet cultures, which was similar to tissue formed by monolayer-expanded cells. Cells left attached to microcarriers did not exhibit chondrogenic capacity. Culture conditions, such as microcarrier material, oxygen tension, and mechanical stimulation require further investigation to facilitate the efficient expansion of clinically relevant human articular chondrocytes that maintain chondrogenic potential for cartilage regeneration applications. (c) 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:539-546, 2011. PMID- 20957735 TI - Sonographically guided percutaneous excision of clinically benign breast masses. AB - PURPOSE: To report our experience with a vacuum-assisted biopsy device system in percutaneous excision of clinically benign breast masses under sonographic guidance. METHODS: Percutaneous removal of 79 masses in 58 patients was performed with a vacuum-assisted biopsy device under sonographic guidance from April 2008 to September 2008. The lesions were category 3 lesions on sonogram, according to Breast Imaging Reporting and Data System (n = 74), or had been confirmed as benign by a previous core needle biopsy (n = 5). RESULTS: All procedures were technically successful. Confirmed as benign were 98.7% (78/79) lesions on pathology after resection, and 93.7% (74/79) lesions were excised completely as demonstrated by follow-up sonographic examination. The duration of the procedure ranged from 2 to 19 minutes (mean +/- SD, 9.6 +/- 9.3). CONCLUSIONS: Percutaneous excision using a vacuum-assisted biopsy device is an alternative to surgical excision of benign breast masses. PMID- 20957736 TI - The chorionic bump: Radiologic and pathologic correlation. AB - Chorionic bump is a rare abnormal condition of the gestational sac seen in the first trimester of pregnancies, extending from the choriodecidual surface to the gestational sac. We report the sonographic and histopathologic findings in a case involving three "chorionic bumps" extending from the choriodecidual surface to the gestational sac. Chorionic bump can be associated with a poor prognosis for the pregnancy. Therefore, cases with chorionic bumps must be followed with serial ultrasound examinations throughout the first trimester. PMID- 20957737 TI - Four-dimensional and Doppler sonography in the diagnosis and surveillance of a true cord knot. AB - Prenatal diagnosis of a true knot of the umbilical cord is often an incidental observation at ultrasound with a difficult differential diagnosis between true and false knots. Furthermore, little is known about the optimal management of these cases. We report the importance of color Doppler and four-dimensional ultrasound for the differential diagnosis in the case of true cord knot and the role of Doppler flow velocimetry in the management of that case. PMID- 20957738 TI - Effect of in vitro stress-deprivation and cyclic loading on the length of tendon cell cilia in situ. AB - To determine the effect of loading conditions on the length of primary cilia in tendon cells in situ, freshly harvested rat tail tendons were stress-deprived (SD) for up to 72 h, cyclically loaded at 3% strain at 0.17 Hz for 24 h, or SD for 24 h followed by cyclic loading (CL) for 24 h. Tendon sections were stained for tubulin, and cilia measured microscopically. In fresh control tendons, cilia length ranged from 0.6 to 2.0 um with a mean length of 1.1 um. Following SD, cilia demonstrated an increase (p < 0.001) in overall length at 24 h when compared to controls. Cilia length did not increase with time of SD (p = 0.329). Cilia in cyclically loaded tendons were shorter (p < 0.001) compared to all SD time periods, but were not different from 0 time controls (p = 0.472). CL for 24 h decreased cilia length in 24 h SD tendons (p < 0.001) to levels similar to those of fresh controls (p = 0.274). The results of this study demonstrate that SD resulted in an immediate and significant increase in the length of primary cilia of tendon cells, which can be reversed by cyclic tensile loading. This suggests that, as in other tissues, cilia length in tendon cells is affected by mechanical signaling from the extracellular matrix. PMID- 20957739 TI - Mesenchymal stromal cells expressing heme oxygenase-1 reverse pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) remains a serious disease, and although current treatments may prolong and improve quality of life, search for novel and effective therapies is warranted. Using genetically modified mouse lines, we tested the ability of bone marrow-derived stromal cells (mesenchymal stem cells [MSCs]) to treat chronic hypoxia-induced PAH. Recipient mice were exposed for 5 weeks to normobaric hypoxia (8%-10% O(2)), MSC preparations were delivered through jugular vein injection and their effect on PAH was assessed after two additional weeks in hypoxia. Donor MSCs derived from wild-type (WT) mice or heme oxygenase-1 (HO-1) null mice (Hmox1(KO)) conferred partial protection from PAH when transplanted into WT or Hmox1(KO) recipients, whereas treatment with MSCs isolated from transgenic mice harboring a human HO-1 transgene under the control of surfactant protein C promoter (SH01 line) reversed established disease in WT recipients. SH01-MSC treatment of Hmox1(KO) animals, which develop right ventricular (RV) infarction under prolonged hypoxia, resulted in normal RV systolic pressure, significant reduction of RV hypertrophy and prevention of RV infarction. Donor MSCs isolated from a bitransgenic mouse line with doxycycline inducible, lung-specific expression of HO-1 exhibited similar therapeutic efficacy only on doxycycline treatment of the recipients. In vitro experiments indicate that potential mechanisms of MSC action include modulation of hypoxia induced lung inflammation and inhibition of smooth muscle cell proliferation. Cumulatively, our results demonstrate that MSCs ameliorate chronic hypoxia induced PAH and their efficacy is highly augmented by lung-specific HO-1 expression in the transplanted cells, suggesting an interplay between HO-1 dependent and HO-1-independent protective pathways. PMID- 20957740 TI - From hair to cornea: toward the therapeutic use of hair follicle-derived stem cells in the treatment of limbal stem cell deficiency. AB - Limbal stem cell deficiency (LSCD) leads to severe ocular surface abnormalities that can result in the loss of vision. The most successful therapy currently being used is transplantation of limbal epithelial cell sheets cultivated from a limbal biopsy obtained from the patient's healthy, contralateral eye or cadaveric tissue. In this study, we investigated the therapeutic potential of murine vibrissae hair follicle bulge-derived stem cells (HFSCs) as an autologous stem cell (SC) source for ocular surface reconstruction in patients bilaterally affected by LSCD. This study is an expansion of our previously published work showing transdifferentiation of HFSCs into cells of a corneal epithelial phenotype in an in vitro system. In this study, we used a transgenic mouse model, K12(rtTA/rtTA) /tetO-cre/ROSA(mTmG) , which allows for HFSCs to change color, from red to green, once differentiation to corneal epithelial cells occurs and Krt12, the corneal epithelial-specific differentiation marker, is expressed. HFSCs were isolated from transgenic mice, amplified by clonal expansion on a 3T3 feeder layer, and transplanted on a fibrin carrier to the eye of LSCD wild-type mice (n = 31). The HFSC transplant was able to reconstruct the ocular surface in 80% of the transplanted animals; differentiating into cells with a corneal epithelial phenotype, expressing Krt12, and repopulating the corneal SC pool while suppressing vascularization and conjunctival ingrowth. These data highlight the therapeutic properties of using HFSC to treat LSCD in a mouse model while demonstrating a strong translational potential and points to the niche as a key factor for determining stem cell differentiation. PMID- 20957741 TI - The histone deacetylase inhibitor vorinostat selectively sensitizes fibrosarcoma cells to chemotherapy. AB - Soft tissue sarcoma (STS) is a rare malignancy that is generally resistant to chemotherapy. We investigated the ability of the histone deacetylase inhibitor vorinostat to sensitize STS cells versus normal fibroblasts to chemotherapy. Fibrosarcoma, leiomyosarcoma, and liposarcoma cells and normal fibroblasts were treated with vorinostat to determine effects on proliferation and basal apoptosis as measured by total cell number and cleaved caspase 3 staining. Effects on histone deacetylases (HDAC) activity were confirmed by Western blotting for acetylated histone H3. A clinically relevant dose of vorinostat that had no effect on basal apoptosis was selected to examine altered sensitivity to doxorubicin. The effects of vorinostat, doxorubicin, or the combination on fibrosarcoma growth in vivo were determined in a xenograft model. Tumor volume was measured biweekly and HDAC activity and cell death were assessed by immunohistochemical analysis of acetylated histone H3, cleaved caspase 3, and TUNEL staining. Vorinostat inhibited proliferation and induced histone acetylation without affecting basal apoptosis levels. Combined treatment with vorinostat and doxorubicin synergistically induced apoptosis in vitro in fibrosarcoma but not leiomyosarcoma, liposarcoma, or normal fibroblasts. In nude mice, the combination of vorinostat and doxorubicin inhibited fibrosarcoma xenograft growth further than either agent alone. Cell death, as measured by cleaved caspase 3 and TUNEL staining, was greatest in xenografts from mice treated with vorinostat and doxorubicin. Vorinostat inhibits growth and induces chemosensitivity in fibrosarcoma cells in vitro and in vivo, suggesting that the combination of vorinostat and chemotherapy may represent a novel treatment option for this STS subtype. (c) 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:623-632, 2011. PMID- 20957742 TI - Effects of preexisting microdamage, collagen cross-links, degree of mineralization, age, and architecture on compressive mechanical properties of elderly human vertebral trabecular bone. AB - Previous studies have shown that the mechanical properties of trabecular bone are determined by bone volume fraction (BV/TV) and microarchitecture. The purpose of this study was to explore other possible determinants of the mechanical properties of vertebral trabecular bone, namely collagen cross-link content, microdamage, and mineralization. Trabecular bone cores were collected from human L2 vertebrae (n = 49) from recently deceased donors 54-95 years of age (21 men and 27 women). Two trabecular cores were obtained from each vertebra, one for preexisting microdamage and mineralization measurements, and one for BV/TV and quasi-static compression tests. Collagen cross-link content (PYD, DPD, and PEN) was measured on surrounding trabecular bone. Advancing age was associated with impaired mechanical properties, and with increased microdamage, even after adjustment by BV/TV. BV/TV was the strongest determinant of elastic modulus and ultimate strength (r2 = 0.44 and 0.55, respectively). Microdamage, mineralization parameters, and collagen cross-link content were not associated with mechanical properties. These data indicate that the compressive strength of human vertebral trabecular bone is primarily determined by the amount of trabecular bone, and notably unaffected by normal variation in other factors, such as cross-link profile, microdamage and mineralization. PMID- 20957743 TI - Activation of cyclic amp/protein kinase: a signaling pathway enhances osteoblast cell adhesion on biomaterials for regenerative engineering. AB - Osteoblast cell adhesion on biomaterials is an important goal for implants to be useful in bone regeneration technologies. The adhesion of osteoblastic cells to biomaterials has been investigated in the field of bone regenerative engineering. Previous work from our group demonstrated that osteoblastic cells adhering to biodegradable biomaterials require the expression of integrins on the cell surface. However, the underlying molecular signaling mechanism is still not fully clear. We report here that cyclic adenosine monophosphate (cAMP), a small signaling molecule, regulates osteoblast cell adhesion to biomaterial surfaces. We used an in vitro cell adhesion assay to demonstrate that at 0.1 mM, 8-Br-cAMP, a cell-permeable cAMP analog, significantly enhances osteoblast-like cells' (MC3T3-E1) adherence to biomaterials. Moreover, we demonstrate that a commonly used cAMP-elevating agent, forskolin, promotes cell adhesion similar to that of the cell permeable cAMP analog. By using different target-specific cAMP analogs: 8-CPT-2Me-cAMP which specifically activates exchange protein activated by cAMP (Epac), and 6-Bnz-cAMP which specifically activates protein kinase A (PKA), we observed that the PKA signaling pathway plays a dominant role in this process. Thus, this report suggests a new method to enhance osteoblast cell adhesion on biodegradable biomaterials for bone regenerative engineering applications. PMID- 20957744 TI - Motion-derived coordinate systems reduce inter-subject variability of elbow flexion kinematics. AB - The selection of a joint coordinate system affects the outcome of motion pathways. We developed coordinate systems for the ulna and humerus, which are generated from upper extremity motion. These Motion-Derived Coordinate Systems (CS) were compared to traditional Anatomy-Derived CS created using surface digitizations of anatomical features. Within-subject repeatability of creating Motion-Derived CS was quantified. In vitro elbow flexion was generated in the gravity-dependent position using an active upper extremity motion simulator. Kinematic pathways of those motions were calculated in terms of valgus angulation and internal rotation of the ulna relative to the humerus, using both CS. The method of creating Motion-Derived CS was highly repeatable-less than 0.5 mm and 1 degrees for all coordinate directions measured. Inter-subject variability of active flexion pathways was reduced with Motion-Derived CS compared to Anatomy Derived CS (p < 0.05). The decrease in inter-subject kinematic variability when using Motion-Derived CS may increase the statistical power of biomechanical studies and allow for reduced sample sizes. This minimally invasive method, which also determines the elbow flexion and forearm rotation axes and center of the capitellum, may also be applicable in computer-navigated surgery of the upper limb. PMID- 20957745 TI - Probing bis-ANS binding sites of different affinity on aggregated IgG by steady state fluorescence, time-resolved fluorescence and isothermal titration calorimetry. AB - Fluorescent dyes, for example, 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid dipotassium salt (bis-ANS) are extensively used to detect nonnative protein structures in therapeutic protein products, for example, during formulation development by monitoring the greatly enhanced dye fluorescence upon binding to nonnative species. Our aim was to characterize the level of heterogeneity of bis ANS binding sites in a thermally stressed monoclonal antibody (IgG) formulation by steady-state fluorescence, time-resolved fluorescence and isothermal titration calorimetry (ITC), and to obtain apparent dissociation constants (Kd ) by data fitting. Because the methods differ in their underlying measurement principles, they provide different information on binding properties of bis-ANS to thermally stressed IgG. We found very heterogeneous bis-ANS binding sites on thermally stressed IgG, with apparent Kd values ranging from as low as 50 nM (time-resolved fluorescence) to 63 MUM (ITC). Steady-state fluorescence and ITC gave insight into an overall binding affinity of a wide population of dye binding sites with micromolar Kd values. Time-resolved fluorescence was particularly sensitive to high-affinity binding sites with nanomolar Kd s. The heterogeneity of the bis-ANS binding sites reflects the complex, heterogeneous nature of the heat-stressed IgG used in this study. To probe such heterogeneity adequately, one should apply complementary analytical methods under various experimental conditions as presented in this paper. (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:1294-1305, 2011. PMID- 20957746 TI - Terahertz in-line sensor for direct coating thickness measurement of individual tablets during film coating in real-time. AB - We present a new in-line measurement technique to determine the coating thickness of individual pharmaceutical tablets during film coating in a pan coating unit using pulsed terahertz technology. Results of these real-time terahertz measurements acquired during a production scale coating run are validated using both off-line high-resolution terahertz pulsed imaging of the whole dosage form as well as weight-gain measurements made on sample tablets removed at discrete time intervals during the process run. The terahertz measurements provide a direct method of determining the coating thickness, and no chemometric calibration models are required for the quantification. The results, and their repeatability, demonstrate that real-time monitoring of pharmaceutical tablet coating is not only possible but also provides substantially more information of the coating quality than the standard quality control method. Rather than providing the average coating thickness of a large number of tablets, the terahertz sensor provides the thickness of up to 100 individual tablet coatings per minute. Using this information, the operator can get additional information about the thickness distribution in the coating pan and adjust the process accordingly. At present, a minimum coating thickness of 40 MUm is required to determine the coating thickness. The technique is applicable for coatings up to 1 mm in thickness. Within that range, it provides thickness measurements of sub micron resolution. Terahertz in-line coating process measurements show considerable potential for applications in real-time release, process analytical technology and quality by design. PMID- 20957747 TI - In vitro conversion of model sulfenamide prodrugs in the presence of small molecule thiols. AB - Sulfenamide prodrugs of amide and urea functional group containing drugs have recently been proposed as a means of altering the physical and bioproperties of problematic drug molecules containing these two functionalities. Sulfenamides have been shown to revert to the parent drug via reaction with thiols. Explored here is the mechanism for this reaction. The stoichiometry and pH dependency of the in vitro reversion of two model prodrugs of the oxazolidinone, linezolid, and a sulfenamide of phthalimide were studied at 25 degrees C in the presence of thiols, including cysteine and glutathione, of varying basicity. High performance/pressure liquid chromatography and liquid chromatography-mass spectrometry results showed the near quantitative reversion of the sulfenamides to the parent drug with simultaneous formation of a mixed disulfide. The pH and the dependency of the reaction on the basicity of the thiol strongly supported the role of the thiolate species in the conversion. The reaction is consistent with an S(N)2 type mechanism seen in the reaction of some thiols with disulfides. PMID- 20957748 TI - CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells. AB - We studied early NK-cell recovery in 29 allografted patients undergoing different lymphoreductive regimens. Already at 2 wk after graft take, the number of NK cells had reached (supra)normal levels but NK-cell subsets were skewed. The number of CD56(dim) CD16(bright) NK cells was low and correlated strongly with the level of hematopoiesis, whereas the number of the more abundant NK cells expressing high levels of CD56 did not. Post-transplant CD56(bright) NK cells (ptCD56(bright)) differed from CD56(bright) NK cells in normal controls (CD56(bright)) in being HLA-DR- and perforin-positive, CCR7(-), CD27(-), CD127(-) and mostly c-kit(-). CD56(bright) from normal controls stimulated by IL-15 in vitro (NK(IL-15)) acquired all the characteristics distinguishing CD56(bright) from ptCD56(bright). IL-2 exerted similar effects. Moreover, when cultured without cytokines, ptCD56(bright), CD56(bright) and NK(IL-15) responded similarly by upregulating CD127 and c-kit but not CCR7. IL-12 stimulated IFN-gamma production in ptCD56(bright), whereas CD56(bright) responded only to IL-12 plus IL-15. Hence, ptCD56(bright) have all the features of cytokine-stimulated CD56(bright). Because only patients with low numbers of T cells had high numbers of ptCD56(bright), we conclude that ptCD56(bright) are activated CD56(bright) that expand while competing with T cells for the elevated post-transplant level of IL-15. PMID- 20957749 TI - HPK1 competes with ADAP for SLP-76 binding and via Rap1 negatively affects T-cell adhesion. AB - The hematopoietic progenitor kinase 1 (HPK1) signals into MAPK and NFkappaB pathways downstream of immunoreceptors, but enigmatically is a negative regulator of leukocytes. Here, we report a novel role for HPK1 in regulating the activation of the adhesion molecule leukocyte function-associated antigen-1 (LFA-1). Upon TCR stimulation, mediated by binding of adhesion and degranulation promoting adaptor protein (ADAP) to SLP-76, a ternary complex composed of ADAP/55-kDa src kinase associated phosphoprotein (SKAP-55) and RIAM translocates to the membrane and causes membrane recruitment of the active small GTPase Ras-related protein 1 (Rap1). Active Rap1, via its binding to RapL (regulator for cell adhesion and polarization enriched in lymphoid tissues), mediates LFA-1 integrin activation. We show here that HPK1, which also binds SLP-76, compete with ADAP for SLP-76 binding. In addition, HPK1 dampens Rap1 activation, resulting in decreased LFA-1 activity. Analysis of HPK1-deficient T cells revealed increased ADAP recruitment to SLP-76 and elevated Rap1 activation in those cells, leading to increased adhesion to ICAM-1 and cell spreading. Altogether, these results describe a novel function for HPK1 in linking TCR signaling to cell adhesion regulation and provide a mechanistic explanation for the negative regulatory role of HPK1 in T cell biology. PMID- 20957750 TI - TLR3-mediated IFN-beta gene induction is negatively regulated by the TLR adaptor MyD88 adaptor-like. AB - There is limited insight into the mechanisms involved in the counterregulation of TLR. Given the important role of TLR3/TIR domain-containing adaptor-inducing IFN beta (TRIF)-dependent signalling in innate immunity, novel insights into its modulation is of significance in the context of many physiological and pathological processes. Herein, we sought to perform analysis to definitively assign a mechanistic role for MyD88 adaptor-like (Mal), an activator of TLR2/4 signalling, in the negative regulation of TLR3/TRIF signalling. Biochemical and functional analysis demonstrates that Mal negatively regulates TLR3, but not TLR4, mediated IFN-beta production. Co-immunoprecipitation experiments demonstrate that Mal associates with IRF7 (IRF, IFN regulatory factor), not IRF3, and Mal specifically blocks IRF7 activation. In doing so, Mal impedes TLR3 ligand induced IFN-beta induction. Interestingly, Mal does not affect the induction of IL-6 and TNF-alpha upon TLR3 ligand engagement. Together, these data show that the TLR adaptor Mal interacts with IRF7 and, in doing so, impairs IFN-beta induction through the positive regulatory domains I-III enhancer element of the IFN-beta gene following poly(I:C) stimulation. Our findings offer a new mechanistic insight into TLR3/TRIF signalling through a hitherto unknown mechanism whereby Mal inhibits poly(I:C)-induced IRF7 activation and concomitant IFN-beta production. Thus, Mal is essential in restricting TLR3 signalling thereby protecting the host from unwanted immunopathologies associated with excessive IFN-beta production. PMID- 20957751 TI - Granulocyte-colony stimulating factor drives the in vitro differentiation of human dendritic cells that induce anergy in naive T cells. AB - G-CSF is a modulator of T-cell and DC functions. Previous reports show that monocytes from G-CSF-treated (post-G) healthy donors differentiate into tolerogenic DC in vitro in the presence of autologous serum, containing high levels of IL-10 and IFN-alpha, and in turn induce type 1 Treg (Tr1) cells. However, the direct effect of G-CSF on DC differentiation was not investigated. Here, we show that monocytes differentiated in the presence of exogenous G-CSF (G DC) remain CD14(+) CD1a(-) , but acquire a DC-like morphology, express CD83 and CD86 and low levels of the tolerogenic markers Ig-like transcript (ILT)4 and HLA G. G-DC spontaneously produce IL-10 and, upon stimulation, low levels of IL-12. G DC display low stimulatory capacity and induce anergy in naive T cells, but do not confer suppressive function. Therefore, in vitro differentiation of monocyte derived DC in the presence of G-CSF can replicate some but not all features of post-G DC. These findings indicate that the tolerogenic properties of G-CSF do not exclusively reside in its direct effect on DC, which in turn induce T-cell anergy, but also in its ability to generate a tolerogenic milieu in vivo, which is necessary for Tr1 cell induction and cannot be replicated in vitro. PMID- 20957752 TI - Modulation of systemic antigen-specific immune responses by oral antigen in humans. AB - Oral antigen uptake can induce systemic immune responses ranging from tolerance to immunity. However, the underlying mechanisms are poorly understood, especially in humans. Here, keyhole limpet hemocyanin (KLH), a neoantigen which has been used in earlier studies of oral tolerance, was fed in a repeated low-dose and a single high-dose protocol to healthy volunteers. KLH-specific CD4(+) T-cell proliferation and cytokine production, as well as KLH-specific serum Ab and the effects of oral KLH on a subsequent parenterally induced systemic immune response, were analyzed. Repeated low-dose oral KLH alone induced antigen specific CD4(+) T cells positive predominantly for the gut-homing receptor integrin beta7 and the cytokines IL-2 and TNF-alpha; some CD4(+) T cells also produced IL-4. Oral feeding of KLH accelerated a subsequent parenterally induced systemic CD4(+) T-cell response. The cytokine pattern of KLH-specific CD4(+) T cells shifted toward more IL-4- and IL-10- and less IFN-gamma-, IL-2- and TNF alpha-producing cells. The parenterally induced systemic KLH-specific B-cell response was accelerated and amplified by oral KLH. The impact of single high dose oral KLH on antigen-specific immune responses was less pronounced compared with repeated low-dose oral KLH. These findings suggest that oral antigen can effectively modulate subsequently induced systemic antigen-specific immune responses. Immunomodulation by oral antigen may offer new therapeutic strategies for Th type1-mediated inflammatory diseases and for the development of vaccination strategies. PMID- 20957753 TI - Proteomic analysis of Pteris vittata fronds: two arbuscular mycorrhizal fungi differentially modulate protein expression under arsenic contamination. AB - Arbuscular mycorrhizae (AM) are the most widespread mutualistic symbioses between the roots of most land plants and a phylum of soil fungi. AM are known to influence plant performance by improving mineral nutrition, protecting against pathogens and enhancing resistance or tolerance to biotic and abiotic stresses. The aim of this study was to investigate the frond proteome of the arsenic hyperaccumulator fern Pteris vittata in plants that had been inoculated with one of the two AM fungi (Glomus mosseae or Gigaspora margarita) with and without arsenic treatment. A protective role for AM fungi colonisation in the absence of arsenic was indicated by the down-regulation of oxidative damage-related proteins. Arsenic treatment of mycorrhizal ferns induced the differential expression of 130 leaf proteins with specific responses in G. mosseae- and Gi. margarita-colonised plants. Up-regulation of multiple forms of glyceraldehyde-3 phosphate dehydrogenase, phosphoglycerate kinase, and enolase, primarily in G. mosseae-inoculated plants, suggests a central role for glycolytic enzymes in arsenic metabolism. Moreover, a putative arsenic transporter, PgPOR29, has been identified as an up-regulated protein by arsenic treatment. PMID- 20957754 TI - Mitochondrial comparative proteomics of human ovarian cancer cells and their platinum-resistant sublines. AB - Resistance to platinum-based chemotherapy is the major obstacle to successful treatment of ovarian cancer. It is evident that mitochondrial defects and the dysfunctions of oxidative phosphorylation and energy production in ovarian cancer cells were directly related to their resistance to platinum drugs. Using 2-D DIGE, we compared mitochondrial proteins from two platinum-sensitive human ovarian cancer cell lines (SKOV3 and A2780) with that of four platinum-resistant sublines (SKOV3/CDDP, SKOV3/CBP, A2780/CDDP, and A2780/CBP). Among the 236 differentially expressed spots, five mitochondrial proteins (ATP-alpha, PRDX3, PHB, ETF, and ALDH) that participate in the electron transport respiratory chain were identified through mass spectrometry. All of them are downregulated in one or two of the platinum-resistant cell lines. Three proteins (ATP-alpha, PRDX3, and PHB) were validated by using western blot and immunohistochemistry. There is a significant decrease of PHB in tumor tissues from ovarian cancer patients who were resistant to platinum-based chemotherapies. This is the first direct mitochondrial proteomic comparison between platinum-sensitive and resistant ovarian cancer cells. These studies demonstrated that 2-D DIGE-based proteomic analysis could be a powerful tool to investigate limited mitochondrial proteins, and the association of PHB expression with platinum resistance indicates that mitochondria defects may contribute to platinum resistance in ovarian cancer cells. PMID- 20957755 TI - Long term bed rest with and without vibration exercise countermeasures: effects on human muscle protein dysregulation. AB - The present investigation, the first in the field, was aimed at analyzing differentially, on individual samples, the effects of 55 days of horizontal bed rest, a model for microgravity, on myosin heavy and myosin light chain isoforms distribution (by SDS) and on the proteome (by 2-D DIGE and MS) in the vastus lateralis (VL), a mixed type II/I (~50:50%) head of the quadriceps and in the calf soleus (SOL), a predominantly slow (~35:65%) twitch muscle. Two separate studies were performed on six subjects without (BR) and six with resistive vibration exercise (RVE) countermeasures, respectively. Both VL and SOL underwent in BR decrements of ~15% in cross-sectional area and of ~22% in maximal torque that were prevented by RVE. Myosin heavy chain distribution showed increased type I and decreased type IIA in BR both in VL and in SOL, the opposite with RVE. A substantial downregulation of proteins involved in aerobic metabolism characterized both in SOL and VL in BR. RVE reversed the pattern more in VL than in SOL, whereas proteins involved in anaerobic glycolysis were upregulated. Proteins from the Z-disk region and from costamers were differently dysregulated during bed rest (both BR and RVE), particularly in VL. PMID- 20957756 TI - Proteomic and PROTEOMEX profiling of mammary cancer progression in a HER-2/neu oncogene-driven animal model system. AB - The prevention of mammary carcinoma by immunological strategies targeting the HER 2/neu receptor has proved to be effective in preclinical models. Thus, a well characterized HER-2/neu oncogene-driven mammary carcinogenesis model was analysed by various profiling strategies following "triplex" vaccination to identify new candidate targets for breast cancer immunoprevention. 2-DE-based proteomic profiling of preneoplastic and tumour lesions versus normal and aged mammary tissue demonstrated that tumour progression was associated with an up-regulation of molecular chaperones including glucose-regulated protein (GRP)78 and of proteins favouring cell motility, which was in line with the corresponding transcriptomic profiling data. Furthermore, PROTEOMEX analyses suggested that naturally induced autoantibody responses occur during early phases of mammary cancer progression. Most of the cancer progression-induced antibodies targeted proteins of normal and preneoplastic mammary glands. However, three proteins were only recognized by sera obtained from vaccinated mice, including 2 isoforms of annexin A6. The distinct expression patterns for annexin A6 and GRP78 during tumour progression were further verified by western blot and/or immunoprecipitation. In addition, an inhibitor-mediated blockade of GRP78 expression in a model cell line caused a reduced cell growth. Thus, the proteome based approaches applied in the murine BALB-NeuT model might indeed provide candidates for immunoprevention strategies in breast cancer. PMID- 20957757 TI - The proteome of lysosomes. AB - Lysosomes are organelles of eukaryotic cells that are critically involved in the degradation of macromolecules mainly delivered by endocytosis and autophagocytosis. Degradation is achieved by more than 60 hydrolases sequestered by a single phospholipid bilayer. The lysosomal membrane facilitates interaction and fusion with other compartments and harbours transport proteins catalysing the export of catabolites, thereby allowing their recycling. Lysosomal proteins have been addressed in various proteomic studies that are compared in this review regarding the source of material, the organelle/protein purification scheme, the proteomic methodology applied and the proteins identified. Distinguishing true constituents of an organelle from co-purifying contaminants is a central issue in subcellular proteomics, with additional implications for lysosomes as being the site of degradation of many cellular and extracellular proteins. Although many of the lysosomal hydrolases were identified by classical biochemical approaches, the knowledge about the protein composition of the lysosomal membrane has remained fragmentary for a long time. Using proteomics many novel lysosomal candidate proteins have been discovered and it can be expected that their functional characterisation will help to understand functions of lysosomes at a molecular level that have been characterised only phenomenologically so far and to generally deepen our understanding of this indispensable organelle. PMID- 20957758 TI - Biochips that sequentially capture and focus antigens for immunoaffinity MALDI TOF MS: a new tool for biomarker verification. AB - A novel approach to immunoaffinity MS is described wherein antibodies are appended to a patterned gold Biochip surface. The Biochip surface is patterned with an array of concentric immunocapture zones composed of highly hydrophilic central zones surrounded by moderately hydrophilic zones that reside on a non wetting background, with protein attachment via electrochemically cleavable linkers. After linker cleavage, matrix application forms a discrete spot suitable for MALDI-TOF-MS. Use of the Biochip to purify transthyretin from human serum allowed a distinct resolution of four disulfide conjugates and one truncated form isoforms with good mass resolution and sensitivity. PMID- 20957759 TI - Influence of internal structure and composition of liquid crystalline phases on topical delivery of paclitaxel. AB - This study aimed to evaluate whether and how the internal structure and composition of liquid crystalline systems can be tailored to maximize paclitaxel cutaneous delivery. Liquid crystalline phases of water, Brij-97, and medium-chain mono/diglycerides (MCG) were characterized by polarized light microscopy. Lamellar phases containing 20% (w/w) water and MCG at 10% (LP-10) or 20% (LP-20), and a hexagonal phase (HP) with 45% water and 10% MCG were selected; paclitaxel was incorporated at 0.5% (w/w). Compared with drug solution in myvacet oil, LP-20 provided the highest paclitaxel cutaneous delivery (threefold), and LP-10 the highest transdermal delivery (fourfold). Using a fluorescent drug derivative [at 0.5%, (w/w)], we observed that penetration occurred through intact stratum corneum. To evaluate whether penetration results relate to drug release differences, paclitaxel self-diffusion coefficient (D) and in vitro release were studied. D was the highest in LP-20, but release from LP-20 and LP-10 was similar. The low D in HP was associated with the lowest drug release. As an index of efficacy, we assessed the cytotoxicity of paclitaxel-loaded LP-20 against fibroblasts. Cell viability was 1.3-2 times smaller with LP-20 than with drug solution. Our results demonstrate that LP-20 provides optimization of paclitaxel cutaneous delivery and efficient cytotoxicity. PMID- 20957760 TI - Ratiometric optical sensing of chloride ions with organic fluorophore-gold nanoparticle hybrids: a systematic study of design parameters and surface charge effects. AB - Colloidal nanoparticles are often stabilized by high surface charges. These create an electrical potential that may strongly affect the concentration of dissolved ions, which presents a formidable problem for the use of nanoparticles in ion-sensing applications. This effect is investigated systematically with organic fluorophore-gold nanoparticle hybrids, which have a chloride-sensitive fluorophore attached at varying distances from their surface. The distance dependent fluorescence response is quantitatively assessed using fluorescence spectroscopy. PMID- 20957761 TI - Nanoparticle layer deposition for plasmonic tuning of microstructured optical fibers. AB - Plasmonic nanoparticles with spectral properties in the UV-to-near-IR range have a large potential for the development of innovative optical devices. Similarly, microstructured optical fibers (MOFs) represent a promising platform technology for fully integrated, next-generation plasmonic devices; therefore, the combination of MOFs and plasmonic nanoparticles would open the way for novel applications, especially in sensing applications. In this Full Paper, a cost effective, innovative nanoparticle layer deposition (NLD) technique is demonstrated for the preparation of well-defined plasmonic layers of selected particles inside the channels of MOFs. This dynamic chemical deposition method utilizes a combination of microfluidics and self-assembled monolayer (SAM) techniques, leading to a longitudinal homogeneous particle density as long as several meters. By using particles with predefined plasmonic properties, such as the resonance wavelength, fibers with particle-adequate spectral characteristics can be prepared. The application of such fibers for refractive-index sensing yields a sensitivity of about 78 nm per refractive index unit (RIU). These novel, plasmonically tuned optical fibers with freely selected, application-tailored optical properties present extensive possibilities for applications in localized surface plasmon resonance (LSPR) sensing. PMID- 20957762 TI - Chemically induced, thermally controlled peel-off of the external walls of double walled carbon nanotubes. PMID- 20957763 TI - Effect of molecular adsorption on the electrical conductance of single au nanowires fabricated by electron-beam lithography and focused ion beam etching. AB - Metal nanowires are one of the potential candidates for nanostructured sensing elements used in future portable devices for chemical detection; however, the optimal methods for fabrication have yet to be fully explored. Two routes to nanowire fabrication, electron-beam lithography (EBL) and focused ion beam (FIB) etching, are studied, and their electrical and chemical sensing properties are compared. Although nanowires fabricated by both techniques exhibit ohmic conductance, I-V characterization indicates that nanowires fabricated by FIB etching exhibit abnormally high resistivity. In addition, the resistivity of nanowires fabricated by FIB etching shows very low sensitivity toward molecular adsorption, while those fabricated by EBL exhibit sensitive resistance change upon exposure to solution-phase adsorbates. The mean grain sizes of nanowires prepared by FIB etching are much smaller than those fabricated by EBL, so their resistance is dominated by grain-boundary scattering. As a result, these nanowires are much less sensitive to molecular adsorption, which mediates nanowire conduction through surface scattering. The much reduced mean grain sizes of these nanowires correlate with Ga ion damage caused during the ion milling process. Thus, even though the nanowires prepared by FIB etching can be smaller than their EBL counterparts, their reduced sensitivity to adsorption suggests that nanowires produced by EBL are preferred for chemical and biochemical sensing applications. PMID- 20957764 TI - Inkjet printing of TIPS-PEN on soluble polymer insulating films: a route to high performance thin-film transistors. PMID- 20957765 TI - Silver clusters embedded in glass as a perennial high capacity optical recording medium. PMID- 20957766 TI - Size effects on magnetic actuation in Ni-Mn-Ga shape-memory alloys. AB - The off-stoichiometric Ni(2)MnGa Heusler alloy is a magnetic shape-memory alloy capable of reversible magnetic-field-induced strains (MFIS). These are generated by twin boundaries moving under the influence of an internal stress produced by a magnetic field through the magnetocrystalline anisotropy. While MFIS are very large (up to 10%) for monocrystalline Ni-Mn-Ga, they are near zero (<0.01%) in fine-grained polycrystals due to incompatibilities during twinning of neighboring grains and the resulting internal geometrical constraints. By growing the grains and/or shrinking the sample, the grain size becomes comparable to one or more characteristic sample sizes (film thickness, wire or strut diameter, ribbon width, particle diameter, etc), and the grains become surrounded by free space. This reduces the incompatibilities between neighboring grains and can favor twinning and thus increase the MFIS. This approach was validated recently with very large MFIS (0.2-8%) measured in Ni-Mn-Ga fibers and foams with bamboo grains with dimensions similar to the fiber or strut diameters and in thin plates where grain diameters are comparable to plate thickness. Here, we review processing, micro- and macrostructure, and magneto-mechanical properties of (i) Ni-Mn-Ga powders, fibers, ribbons and films with one or more small dimension, which are amenable to the growth of bamboo grains leading to large MFIS, and (ii) "constructs" from these structural elements (e.g., mats, laminates, textiles, foams and composites). Various strategies are proposed to accentuate this geometric effect which enables large MFIS in polycrystalline Ni-Mn-Ga by matching grain and sample sizes. PMID- 20957767 TI - Alzheimer's disease genetics: current knowledge and future challenges. AB - Alzheimer's disease (AD) is highly heritable, but genetically complex. Recently, three large-scale genome-wide association studies have made substantial breakthroughs in disentangling the genetic architecture of the disease. These studies combined include data from over 43 000 independent individuals and provide compelling evidence that variants in four novel susceptibility genes (CLU, PICALM, CR1, BIN1) are associated with disease risk. These findings are tremendously exciting, not only in providing new avenues for exploration, but also highlighting the potential for further gene discovery when larger samples are analysed. Here we discuss progress to date in identifying risk genes for dementia, ways forward and how current findings are refining previous ideas and defining new putative primary disease mechanisms. PMID- 20957768 TI - Expressed emotion measure adaptation into a foreign language. AB - Expressed emotion (EE) measures have been created in English; adaptation into a foreign language is difficult. The aim of this study was to adapt the five minutes speech sample (FMSS), with a designed procedure ensuring optimum quality of the adaptation, and thus better trans-cultural validity. A strategy for improving inter-rater agreement comprised three phases: (1) phase of initial ratings (70 French samples), (2) experimental phase in two steps: ratings of 40 other samples in French, followed by analysis of differences between the French language ratings and English-language ratings and (3) final rating phase of the initial 70 samples. For each phase, the kappa coefficients measuring inter-rater agreement were calculated and compared using a bootstrap procedure. The improvements between these scorings were significant at p < 0.05 (phase 2 initial versus phase 2 final and phases 1 versus 3). The French inter-rater agreement significantly improved after this procedure. PMID- 20957769 TI - Effectiveness for interpersonal problem-solving is reduced in women with binge eating disorder. AB - OBJECTIVE: Therapeutic programs for binge eating disorder (BED) often include the mediation of problem-solving skills to deal with the desire to binge. In women with BED, problem-solving abilities have not been studied yet. Knowing that reasons for binge episodes are often linked to interpersonal topics, we expected women with BED to have poorer problem-solving abilities than healthy controls (HC). METHODS: Twenty-five women with BED and 30 overweight HC were given a shortened version of the Means-Ends Problem-Solving Procedure (MEPS). Dependent variables were the number of relevant means, the effectiveness and the specificity of the generated solution. RESULTS: Generated solutions in the group of women with BED were significantly less effective and less specific compared to HC. Moreover, reduced effectiveness of interpersonal problem-solving was related to increased binge frequency. CONCLUSIONS: The results support the importance of teaching problem-solving ability in individuals with BED to promote behaviour change. PMID- 20957770 TI - Invalidating childhood environments and core beliefs in women with eating disorders. AB - It can be hypothesised that invalidating environments in childhood influence the negative core beliefs that are found in the eating disorders. This study of eating-disordered women aimed to test the relationships between perceived childhood invalidating environments and negative core beliefs. Forty-one eating disordered females completed the measures of childhood invalidating experiences and core beliefs. Such core beliefs were most closely related to the individuals' perceptions of having grown up in a 'chaotic' family environment. Future clinical practice should continue to target core beliefs in formulating cases of eating disorders. Explaining those core beliefs may depend on understanding the individual's experiences of invalidation in early years. PMID- 20957771 TI - Conceptualizing the cross-cultural gaps in managing international aid: HIV/AIDS and TB project delivery in Southern Africa. AB - There appears to be a gap between the billions of dollars inputted into fighting HIV/AIDS and TB and outcomes. This in part can be attributed to the lack of attention in International Development to managing programmes and projects within complex levels of cross-cultural interactions. International Development often ignores management issues, yet Management Studies is left wanting through a lack of engagement with development issues including the fight against disease and poverty. This paper attempts to link these two disciplines towards mutual benefit, through a critical cross-cultural approach. It provides contextualization of international development policies/strategies; conceptualization of dominant paradigms; structural analysis of how a programme/project fits into the global governance structure; analysis of complexities and levels of cross-cultural interaction and their consequences and the process and implications of knowledge transfer across cultural distances. It concludes with implications for policy and practice, as well as what is needed from cross-disciplinary research. This includes how feedback loops can be strengthened from local to global, how indigenous knowledge may be better understood and integrated, how power relations within the global governance structure could be managed, how cross-cultural interaction could be better understood, and how knowledge transfer/sharing should be critically managed. PMID- 20957772 TI - From gastric aspiration to airway inflammation. AB - The airways are poorly protected from potentially damaging agents contained within gastric contents. While digestive factors are obvious damaging agents, gastric aspiration may also deliver microbial agents, cytokines or food antigens to airway tissues. Direct damage or the triggering of the inflammatory cascade by gastric aspiration is believed to drive airways disease onset and/or progression. Evidence exists from experimental models demonstrating direct instillation of damaging factors to a range of airways epithelia causes damage and/or an inflammatory response. Clinical longitudinal studies have also noted an association between the presence of biomarkers of reflux in airways samples and disease progression. A shared pathophysiology of many chronic airways diseases is a more negative intrathoracic pressure. Such changes would drive an increased abdominothoracic pressure gradient. These changes in respiratory mechanics mean that chronic lung disease patients may be predisposed to reflux and subsequent aspiration. Therefore, it appears that gastric aspiration and airways disease progression may be linked not solely as cause and effect, but seemingly within a vicious cycle. A range of physiological factors govern both occurrence of gastric reflux into the pharynx/larynx and could also increase the susceptibility of certain individuals to disease progression. A range of long-term surgical and pharmacological intervention studies are necessary to test the benefit of such therapies in reducing disease progression or driving symptom improvement. Such studies may be hampered by the reliability of available therapies in halting gastric aspiration and the difficulty in the clinical or biochemical assessment of gastric aspiration. PMID- 20957773 TI - [Development of emotional competence in the preschool age]. PMID- 20957775 TI - [The development of emotional understanding and behavioral self-regulation in kindergarten children from German and immigrant families]. AB - The present study explores whether kindergarten children with and without immigrant parents in Germany differ in respect to their emotion understanding (TEC) and their behavioral self-regulation (HTKS). 356 three-to-six-year-olds with germanborn parents were contrasted with 155 children with at least one parent who was born abroad. In addition, influences of children's age, gender, and their receptive understanding of the German language were included in the analyses. There were strong effects for migration background and no main effects for gender. When children's language abilities were included in the analyses, the significant influence of having at least one immigrant parent on emotion understanding and behavioral self regulation disappeared. Moreover: receptive language skills that are related to parents' migration status exerted themselves a significant influence. Children with at least one non-german parent were on average less proficient in their receptive language abilities, their emotion understanding, and their behavioral self-regulation than children of two germanborn parents. The function of language for the acquisition of emotion understanding and self regulation is discussed. PMID- 20957774 TI - [Emotion understanding of victimized and bullying children in kindergarten- starting points for a prevention?]. AB - Being victimized by peers is one of the most negative social experiences of childhood and adolescence. Emotions play a central role in these kinds of interaction. Surprisingly however, socio-affective skills of victimized and bullying children have only rarely been the subject of investigation. In this study, the emotion understanding of Swiss kindergarten children between the ages of four and seven years was probed with the Test of Emotion Comprehension (TEC) and an emotion recognition task. Individual scores in victimization and bullying behavior were determined using teacher ratings. Ordinal regression analyses showed that problems in recognizing mimic emotions (specifically anger, sadness and fear), understanding external causes of emotions and understanding the possibility of hiding emotions were predictive of more victimization. Likewise, problems in understanding external causes of emotions were related to more bullying behavior. Implications of these results for the prevention of bullying are discussed. PMID- 20957776 TI - [The development of moral emotions in early childhood]. AB - We investigated the development of young children's moral emotions, i.e., sympathy and guilt, within a multi-informant longitudinal research design. One hundred and seventy-five 6-year-old Swiss children participated at the first assessment (T1; re-assessed after one year; T2). Mothers and teachers participated as well. Sympathy was measured with self- and other reports and within children's play narratives. Guilt feelings were assessed by emotion attributions to protagonists and self-as-protagonist following different hypothetical moral transgressions. Mother-rated sympathy at T2 was positively related to guilt feelings at T2, whereas no relations between sympathy and guilt were found at T1. Sympathy ratings within informant were stable over a year. Guilt feelings to protagonists and self-as-protagonist were stable over a year as well. Guilt feelings predicted subsequent guilt feelings, whereas earlier sympathy did not predict guilt feelings. The results are discussed in regard to the differential development of moral emotions. PMID- 20957777 TI - [Which is the best way for not feeling fear? Young children's strategies to regulate fear]. AB - Over the past decade several studies have demonstrated children's rich knowledge of emotions. In contrast, less is known about children's knowledge about strategies to regulate their own emotional states. While questionnaire data suggest a rather late development of strategies to regulate emotions, not beginning before middle childhood, theory-of-mind research suggests the possibility of an earlier development. The present study examines whether children from age three on are able to distinguish effective from ineffective strategies of emotion regulation. A total of 64 children (16 3-, 4,-5-, and 6 year-olds) were given six stories all depicting a child protagonist facing a fear eliciting situation. For each story, two effective and two ineffective strategies were presented. The children's task was to judge whether the strategy would be helpful for not feeling scared. With the exception of the 3-year-olds, children of all age groups were better in understanding the mental strategies than the behavioral strategies. Thus, the results are in accordance with theory of mind research and indicate that recognizing effective behavioral and mental strategies begins to develop from three years onward. PMID- 20957778 TI - [Neuropsychological issues in child psychology and child psychiatry]. AB - Neuropsychological aspects are of relevance to a variety of psychological concerns, especially in assessments. But is this trend represented in journals which do not explicitly refer to neuropsychologists? To investigate this question, publications in 2008 and 2009 editions of representative German journals on child psychology and psychiatry were bibliometrically analyzed. Main topics of neuropsychological publications were attention disorders and diagnostic issues. Neuropsychological findings support the development of assessment instruments and interventions and help improve the basic understanding of disorders and treatment limitations. For example, reduced attention or memory resources are possible hindrances for individual progress in cognitive behavioral intervention. An intensified dialogue of the disciplines is essential for developing advanced guidelines for diagnostics and therapy. PMID- 20957779 TI - [A morbidly obese patient: what causes the conspicuous skin changes?]. PMID- 20957780 TI - [The final impetus for the E-card is still missing. The health card: two steps forward, one back?]. PMID- 20957781 TI - [Kyphoplasty after osteoporotic vertebral fractures. A common intervention of no use?]. PMID- 20957782 TI - [Tears, rage, silence: patients in state of emergency]. PMID- 20957783 TI - [The speechless patient]. PMID- 20957784 TI - [The weeping patient]. PMID- 20957785 TI - [The aggressive patient]. PMID- 20957786 TI - [Sleep apnoea: more patients, less sleep diagnostic centers]. PMID- 20957787 TI - [Urticaria--clinical overview]. PMID- 20957788 TI - [Blood coagulation self management facilitates anticoagulant therapy. Reduces risk of complications and mortality]. PMID- 20957789 TI - [Growing pains in children]. AB - Growing pains refer to intermittently recurring pains locating in the lower extremities and causing arousal from sleep mostly in the evening or at night. This is an innocuous, albeit inconvenient ailment. Growing pains affect children at the age of 3 to 12 years and frequencies of occurrence vary from two to fifty percent. The cause of growing pains is not known, and no organic disease is assignable as an underlying cause. Although the diagnosis is often clear, certain differential diagnostic alternatives should be kept in mind. Despite their name, growing pains are not associated with the child's growth. PMID- 20957790 TI - [Risk symptoms of psychosis in the young]. AB - Early intervention may postpone or even prevent the onset of psychosis and relieve symptom-related anxiety. Support and follow-up observation requires up-to date knowledge of the nature of the risk symptoms of psychosis and of the therapy of the person having symptoms within the healthcare system. Healthcare professionals should be aware of the limitations of present research information in order to assess the correct magnitude of the risk of psychosis. Although a person assigned by current methods to the risk group presents a higher than tenfold risk compared with the rest of the population, improvement of prognostic accuracy remains as the central research issue. PMID- 20957791 TI - [Diagnosis and treatment of chylothorax]. AB - In chylothorax, chyle has accumulated into the pleural clarity. Chylothorax is a fairly rare finding, most commonly arising after procedures within the thoracic cavity. Suspicion of chylothorax is based on anamnesis and clinical picture, with chest radiograph and pleural fluid puncture as the basic tests. Treatment should be started immediately after a confirmed diagnosis. In the early stages it is vital that the production of chyle is minimized and the fluid is drained. If the conservative treatment fails, surgery is recommended PMID- 20957792 TI - [Myofascial pain syndrome--fascial muscle pain]. AB - Symptoms of myofascial pain syndrome, i.e. fascial muscle pain may occur in several areas of the body, particularly in the neck-shoulder region. The muscle pain symptom in the neck-shoulder region is commonly termed tension neck pain or nonspecific neck pain, but myofascial pain syndrome can also be distinguished into its own diagnosis. This review deals with the clinical picture of myofascial pain syndrome along with pathophysiological hypotheses and treatment options. PMID- 20957793 TI - [Judgment of the level of evidence and strength of recommendations in healthcare according to the GRADE working group]. AB - Finnish doctors are pioneers in the production and utilization of evidence-based recommendations in healthcare. Doctor's databases were established by the end of the 1980s and Current Care guidelines have been devised since 1994. In evidence based recommendations it is essential to provide the user with a description of the quality of research data used as the basis for the recommendation. Consistent, applicable and transparent methods are helpful in the judgment of the quality of studies and strength of evidence. In this article we describe the judgment of the level of evidence and the strength of recommendations according to the international GRADE working group. PMID- 20957794 TI - [Elbow pain]. AB - Pain and disability in the elbow are not as common as in the neck, shoulder or wrist, for example. The elbow may, however, present disorders that may in a prolonged state be difficult and cause significant loss of working capacity. These include epicondylitis, osteoarthritis and entrapment of the ulnar nerve. PMID- 20957795 TI - [Damage of teres minor branch of axillary nerve]. AB - Atrophy demarcating to musculus teres minor is seen in magnetic resonance imaging of the shoulder region in 3 to 5.5% of investigations. We describe seven patients with prolonged or recurrent pain of the shoulder region, who were diagnosed in ENMG with damage of the axillary nerve brand to m. teres minor. Probable causes included tear of the rotator cuff, luxation of the shoulder joint, nerve entrapment in the quadrilateral space, neuritis of the brachial plexus and iatrogenic damage associated with shoulder arthroscopy. This nerve damage cannot be proved clinically. PMID- 20957796 TI - [Update on current care guidelines. Diagnosis, treatment and follow-up of cytological changes in the cervix, vagina and vulva]. AB - Approximately 150 cervical cancer cases are diagnosed in Finland annually. Both incidence and mortality have decreased by 80% since organised screening began. Recently, screening based on primary HPV-testing with Pap-smear triage has been shown to be more sensitive and more specific among women over 35 years old in randomised studies and thus may be implemented in routine. Abnormal findings in Pap smears indicate management. Confirmed CIN1 lesions are followed up and CIN2 and worse lesions treated. Follow-up after treatment should be reliably arranged, because elevated risk of cancer remains over 20 years after treatment. Quality control is of utmost importance. PMID- 20957797 TI - [Culture and knowledge of scientific nurses]. PMID- 20957798 TI - [Epistemologic reflections on human sciences, medicine, and nursing science]. PMID- 20957799 TI - [Disciplinary anchorage, formation, current thoughts]. PMID- 20957800 TI - [The semi-structured interview: at the border of public health and anthropology]. AB - The interview is the tool for data collection the most used in the context of research conducted in health sciences, human sciences and social sciences. After completing some generalities about the different types of interviews, the focus is on semi-structured interview during its various stages including the processing and data analysis, this from the return of a lived experience of research in work on the border of the field of public health and that of anthropology. If this approach and contextualized the semistructured interview may a priori appear specific, the reader interested in the development of qualitative research in a humanistic perspective and the implementation of multidisciplinary strategies to ascertain its universal character. PMID- 20957801 TI - [Conceptual charts: a creative tool in pedagogy]. PMID- 20957802 TI - [Effect of using an instrument for continuous evaluation of nursing quality in terms of employment satisfaction and of their affective implications]. AB - Medical staff are directly concerned by improving the quality of care. The goal of this study is to assess qualitatively the effects of the application of a Global Assessment Instrument for the Quality of Care on thirty nurses divided in two groups: an experimental group--who participated in the IGE-QSI--and another "witness" group--who participated in another project. The theory developed with the research involves the affective implication and satisfaction at work. Affective implication is the emotional attachment of the employee vis-a-vis the hospital. Satisfaction at work is a positive answer of the worker to their professional environment. The results of the research show that satisfaction in the workplace could be the result of professional experience and maturity. Hence, there could be a link between personal values and attitude that could encourage the implication of the staff in management. Responsibilities, recognition and the feeling of belonging to a group are part of the positive incentives and help develop management objectives. PMID- 20957803 TI - [Impact of hospitalization of an infant during breast-feeding: mother-child investigation]. AB - A real health priority for governments, breastfeeding has prompted WHO and UNICEF to create the "Baby-Friendly Hospital Initiative" for maternity units respecting the "ten steps to successful breastfeeding". This effort does not include pediatric departments. However, as the properties of breast milk enhance recovery of the infant, it is also important to promote breastfeeding in this branch. Furthermore, few studies have analyzed the constraints of hospitalization on the breastfeeding process. The aim of this study is to identify the constraints imposed by hospitalization on the process of breastfeeding in infants aged 29 days to 6 months suffering from acute disease, during hospitalization and within a week following their return home. This prospective study was conducted between October 1st and December 31st, 2008 in a pediatric department through interviews and questionnaires from breastfeeding mothers and health professionals. 51 mother infant pairs and 35 caregivers were included in the study. During hospitalization; direct breastfeeding was interrupted for 31 mothers. After hospitalization, 3 mothers had weaned their babies, 12 went from exclusive breastfeeding to mixed feeding and 13 had experienced difficulties. Caregivers partially meet WHO's recommendations. The hospitalization of an infant disrupts the continuation of breastfeeding. To overcome this, actions must be taken in relation with hospitals, departments and professionals. The study's small sample does not prove that the original training of caregivers influence theirs practices. PMID- 20957804 TI - [Apprenticeship of caring in student baccalaureate nurses in a program of formation of competence]. AB - The nursing profession and university nursing programs both took great strides after universities first introduced nursing programs in and around the 1950s. The purpose of this phenomenological qualitative study was to describe the meaning of the apprenticeship of caring through in the Bachelor of Science in Nursing program. Watson's human caring philosophy (2008) suggested that researchers explore the meaning persons ascribe to phenomena. Based on semi-structured interviews this phenomenological study described the essence of the phenomenon and revealed that the apprenticeship of caring meant the harmonisation of the "self-perceived" and the "self-lived" that allows the embodiment of caring. The results of this research are available to teachers who may wish to consider its recommendations when planning and developing assessment and training programs for various kinds of nursing clienteles. PMID- 20957805 TI - [Exploratory research on applied research in nursing sciences: complementary and final assessments]. PMID- 20957806 TI - [Development of research competence]. AB - The implementation of the new reference system of training in nursing care requires from trainers to develop new educational skills. These allow to help students to transfer their experience in new situations of care. The study is based on the experience of two training institutes in nursing care which participated in programmes of European exchanges. In this presentation, we shall be interested in the one that participated in the Leonardo daVinci programme. The analysis shows that the confrontation with a new reference field, Europe, leads the trainers to modify their position by developing reflexive analysis and by using interactive educational methods. Therefore, they move from the "teaching" to the "training" process. The reference to concepts enhances the status of trainers who then become aware of their skills. Upstream to the project, it falls under IFSI head's responsibility to implement the conditions favourable to its success. This project integrated into that of the institution then becomes a training-action. PMID- 20957807 TI - [Impact of central nurses on the perception of the body image of anorexic patients. Prospective study of fifty hospitalized patients]. PMID- 20957808 TI - [Concerning construction of a research problem on the production of knowledge: elements of comprehension]. PMID- 20957809 TI - [Those who know: of what use is it at the end of studies for nursing students]. PMID- 20957810 TI - [Perception of nursing cultural science]. PMID- 20957811 TI - [Mothers' perception of their children's obesity]. AB - OBJECTIVE: Assess mother's perceptions of their children's weight. METHODS: Cross sectional study. We included demographic variables and children's height and weight and used a series of sketches to assess the mother's perception. Among overweight or obese children we collected blood samples to determine glucose, cholesterol and triglycerides levels. RESULTS: Of the 525 children, 52% were female with an average age of 6.4 +/- 3.2 years. Thirteen and 17% of participating children were overweight or obese. There was a higher frequency of obese children if the mother was obese. Fifty seven percent of the mothers correctly assessed their children's weight. Among 357 children with normal weight children, 64% of the mothers perceived their child weight as normal. Of the 72 overweight children, only 29% believed that their child was overweight and of the 90 obese children, 52% of mothers perceived them as obese. Mothers of male children significantly perceived a higher weight for their children than mothers with female children (56 versus 45.6%, p = 0.001). Among overweight and obese children, the frequency of hyperglycemia, hypercholesterolemia and hipertriglyceridemia was 9, 2.3 and 3.8% respectively. CONCLUSIONS: Half of the mothers that we surveyed failed to perceive their child's weight. A better understanding of how mothers perceive the problem of excess weight in their children is needed in order to achieve success in preventive interventions of childhood obesity. PMID- 20957812 TI - [Teen pregnancy in migrants: socioeconomic, gynecobstetric, and neonatal variables]. AB - OBJECTIVE: Identify and correlate characteristics of adolescent mothers in a border city of Mexico with their migratory status. METHODS: We surveyed post partum adolescent mothers in the discharge rooms of two public hospitals in Tijuana, Mexico. We assessed obstetric, gynecologic, socioeconomic and neonatal variables. Mothers living fewer than 5 years in the area were designated as 'migrant.' RESULTS: 324 adolescent mothers were identified; 86% had healthy babies; 27% had previous pregnancies; age of onset of sexual activity was 15.5 +/ 1.4 years. 115 (36%) were identified as 'migrant,' among whom we found they had interrupted their studies (24% vs. 33%; OR 2.62: CI 95% 1.39-4.94), had a higher incidence of failure to use contraception (74% vs. 62%; OR 1.79: C.I. 95% 1.07 3.01) and a lower incidence of prenatal care (28% vs. 38%; OR 1.8: C.I. 95% 1.04 3.15). A larger percentage of migrant adolescents already lived with their partner (39% vs. 24%; OR 2.00: C.I. 95% 1.21-3.30) and expressed a desire to become pregnant (55% vs. 37%; OR 2.10: C.I. 95% 1.31-3.37). The observed association persisted in multivariate analysis. We did not observe differences between other ob-gyn and neonatal variables. CONCLUSIONS: Being a female migrant should be considered a risk factor in the reproductive health of adolescent mothers. PMID- 20957813 TI - [Laryngeal function as node metastasis predictor in patients with cancer of the larynx]. AB - INTRODUCTION: Although the possibility of developing cervical node metastases (CNM) in patients with squamous cell carcinoma of the larynx (SCCL) depends on the site of tumor origin, other factors may be associated, even in glottic tumors. The objective of this study was to determine factors associated with CNM. METHODS: We carried out a retrospective analysis of a series of patients with SCCL. We analyzed the following variables: T-staging, tumor site, and arytenoid mobility/fixation. and correlated them with histopathological node status. Statistical significance was assessed using chi2 tests. RESULTS: 91 patients were included 82 were male and 9 female; median age was 66 years. The most frequently affected site was the glottic-subglottic region (38) followed by the glottis (22). The most frequent T stage was T3 (46%) followed by T4 (25%); 81% were NO and 19% N+. 76 (83%) had arytenoid fixation. Factors associated with CNM included glottic-supraglottic infiltration (65%) and arytenoid fixation (17% vs. 0, p = 0.048). None of the patients with arytenoid mobility had CNM. Tumor infiltration to thyroid gland was observed among 14% of patients studied The most important risk factor was subglottic extension (17%; p = 0.5). CONCLUSIONS: Lack of mobility of the arytenoid cartilage is a factor associated with CNM among SCCL patients. A subglottic tumor is a risk factor for thyroid infiltration PMID- 20957814 TI - [Early-onset type 2 diabetes mellitus. The experience from a third level medical institution]. AB - OBJECTIVE: Describe the clinical, metabolic and psychosocial characteristics observed among patients with early onset type 2 diabetes (T2DM). METHODS: We included 80 consecutive patients with early onset T2DM. All had a medical record, completed a battery of questionnaires and had blood and urine tests. RESULTS: Mean age was 49 +/- 12 years, 57.5% were women, 76.2% had a family history of diabetes and 68.8% a personal history of obesity. Diabetes was diagnosed at the mean age of 32 +/- 6 years with a mean duration of 17 +/- 11 years. Most patients (66.2%) were on poor glycemic control (Alc > 9.0%) and 30% were depressed. Insulin was commonly needed (80% of the patients) and started on average 9 years after diagnosis Significant diabetes related complications were common (71.3% of patients). A longer diabetes duration was the variable most significantly associated with developing complications (p < 0.00001). CONCLUSIONS: Patients with early onset T2DM constitute 27.8% of the total number of diabetic patients attending our clinic; they are characterized by a stronger family history of diabetes, a personal history of obesity and co-morbidities associated with metabolic syndrome. Longer disease course and poor glycemic control contribute to a high prevalence of diabetes related complications and high rates of mortality. PMID- 20957815 TI - [Non-classical cellular and molecular deficits in cancer development]. AB - A wide number of genetic and epigenetic changes are required to drive normal cells towards malignancy. These changes participate in oncogenic intracellular pathways that allow tumor cells proliferation and dissemination. Hanahan and Weinberg' in their seminal paper "The hallmarks of cancer" described the classic cell hallmarks acquired in cancer development and progression: self-sufficiency in growth signals, insensitivity to anti-growth signals, evading apoptosis, limitless replication potential, sustained angiogenesis, tissue invasion and metastasis. This review covers other recently described biological characteristics associated with the emergence of cancer. Some of the main non classical hallmarks of cancer that are broadly accepted include: genetic instability, evasion of cell senescence, epigenetic alterations of cancer related genes, RNA interference alterations in the expression of cancer related-genes, changes in glucose and glutamine metabolism, participation of cancer stem cells in cellular proliferation, stromal cell participation in the tumor's micro environment, and changes in antigenic presentation and immunosuppression due to cytokines in the tumor's micro-environment. The identification of molecular biomarkers of classical and non classical tumor processes in a specific tumor will allow a better understanding of its pathophysiology. It will also permit the design of ad-hoc therapeutic strategies. PMID- 20957816 TI - [The origin of the genetic variability of influenza viruses]. AB - To better understand the significant variability displayed by influenza viruses, we need to be aware not only of its genetic characteristics, but also of the effect this genetic makeup has on proteins associated with viral replication and antigenicity. The origin of such diversity is due first and foremost to its segmented genome that allows segment reassortment (antigenic shift) and second to the error prone viral polymerase (antigenic drift) responsible of copying the genes enclosed in these segments. These two combined mechanisms confer a genetic plasticity that often leads to the emergence of new influenza viruses in nature. PMID- 20957817 TI - [A seven-month-old infant with hepatomegaly, hypoglycemia and short stature]. PMID- 20957818 TI - [Mammary gland Rosai Dorfman disease. A case report and literature review]. AB - Rosai-Dorfman disease (RDD) is an uncommon idiopathic, benign histiocytic lesion. It generally involves the cervical lymph nodes and, less often the extranodal sites. Involvement of the breast is rare, with about 18 cases reported in the English literature to date. We describe a case of breast involvement by extranodal RDD. The patient was a 67 year old woman with a solid breast lesion that was detected during mammography screening. Microscopically, the lesion was well-circumscribed, and made of sheets of S-100 protein-positive large histiocytes displaying lymphocytophagocytosis. Because the clinical presentation and imaging characteristics of RDD frequently mimics invasive breast carcinoma, awareness and appropriate diagnosis of this entity is essential for proper treatment. PMID- 20957819 TI - [Mediastinal ganglioneuroma in an adult patient. A case report and literature review]. AB - We describe the case of an adult patient with a mediastinal ganglioneuroma as a finding in the pathological study and compare its biological behavior with literature findings. A histopathological diagnosis of ganglioneuroma is made possible in the presence of adequate characteristic macroscopic and microscopic variables; nevertheless our case differs with some conventional findings, which made diagnosis during surgery cumbersome. We carried out a literature search to look beyond conventional findings that would enable us to understand its impact on the tumor's biological behavior. PMID- 20957820 TI - [Historical analysis of the hospital bed]. AB - Until now the bed has been the basic physical resource in hospitals. This type of furniture has served to study and treat patients, through out the centuries it has undergone changes in the materials they are made of dimensions, functionality, accessories, aesthetic, and design. The hospital bed history is not well known, there are thousands of documents about the evolution of hospitals, but not enough is known about hospital beds, a link between the past and the present. The medical, anthropological, technological, social, and economic dynamics and knowledge have produced a variety of beds in general and hospital beds in particular. From instinctive, rustic, poor and irregular "sites" that have differed in shape and size they had evolved into ergonomic equipment. The history of the hospital bed reflects the culture, techniques and human thinking. Current hospital beds include several types: for adults, for children, for labor, for intensive therapy, emergency purposes, census and non census beds etc. PMID- 20957821 TI - [Cleft lobe sign. A curious clinical sign or an ischemic heart disease marker?]. AB - The majority of studies have demonstrated a correlation between diagonal earlobe creases sign with coronary artery disease and atheroscleosis. Diagonal earlobe creases run from the lower pole of the external meatus, diagonally backwards to the edge of the lobe at approximately 45. The objective of this paper is review the evidence related to this interesting clinical sign. PMID- 20957822 TI - [Embryo donation in developing countries]. AB - In theory there are three things that can happen to surplus embryos: cryopreservation, discarding, or donation. Embryo donation has three different aims: clinical use (generally infertility therapy), research (basic biomedical research, stem cell research, etc.) or teaching (mainly used by clinical embryologists). We present a literature review that analyzes empirical data from developed countries (Germany, Australia, Belgium, Canada, Denmark, Spain, U.S.A., Finland, France, Italy, New Zealand, United Kingdom, Sweden and Switzerland) regarding the probable fate of surplus embryos. According to the literature, embryos are most often discarded or donated for research. PMID- 20957823 TI - [Conversion of pancreatic alpha-cells to beta-cells]. PMID- 20957824 TI - [Opening ceremony of the CXLVII academic year of the Mexican National Academy of Medicine. Inaugural speech]. PMID- 20957825 TI - Autarky/Autarchy: genetics, food production, and the building of Fascism. PMID- 20957826 TI - Genetics as a modernization program: biological research at the Kaiser Wilhelm Institutes and the political economy of the Nazi State. AB - During the Third Reich, the biological institutes of the Kaiser Wilhelm Society (KWG, Kaiser-Wilhelm-Gesellschaft) underwent a substantial reorganization and modernization. This paper discusses the development of projects in the fields of biochemical genetics, virus research, radiation genetics, and plant genetics that were initiated in those years. These cases exemplify, on the one hand, the political conditions for biological research in the Nazi state. They highlight how leading scientists advanced their projects by building close ties with politicians and science-funding organizations and companies. On the other hand, the study examines how the contents of research were shaped by, and how they contributed to, the aims and needs of the political economy of the Nazi system. This paper therefore aims not only to highlight basic aspects of scientific development under Nazism, but also to provide general insights into the structure of the Third Reich and the dynamics of its war economy. PMID- 20957827 TI - Diffusively coupled bursters: effects of cell heterogeneity. AB - The interaction of a pair of weakly coupled biological bursters is examined.Bursting refers to oscillations in which an observable slowly alternates between phases of relative quiescence and rapid oscillatory behavior. The motivation for this work is to understand the role of electrical coupling in promoting the synchronization of bursting electrical activity (BEA) observed in the -cells of the islet of Langerhans, which secrete insulin in response to glucose. By studying the coupled fast subsystem of a model of BEA, we focus on the interaction that occurs during the rapid oscillatory phase. Coupling is weak, diffusive and non-scalar. In addition,non-identical oscillators are permitted. Using perturbation methods with the assumption that the uncoupled oscillators are near a Hopf bifurcation, a reduced system of equations is obtained. A detailed bifurcation study of this reduced system reveals a variety of patterns but suggests that asymmetrically phase-locked solutions are the most typical. Finally, the results are applied to the unreduced full bursting system and used to predict the burst pattern for a pair of cells with a given coupling strength and degree of heterogeneity. PMID- 20957828 TI - Fascist labscapes: geneticists, wheat, and the landscapes of Fascism in Italy and Portugal. AB - This paper explores the role of scientists in the building of fascist regimes in Italy and Portugal by focusing on plant geneticists' participation in the Italian and Portuguese wheat wars for bread self-sufficiency. It looks closely at the work undertaken by Nazareno Strampelli at the National Institute of Genetics for Grain Cultivation (Italy) and by Antonio Sousa da Camara at the National Agronomic Experiment Station (Portugal), both of whom took wheat as their prime experimental object of genetics research. The main argument is that the production of standardized organisms-the breeder's elite seeds-in laboratory spaces is deeply entangled with their circulation through extended distribution networks that allowed for their massive presence in Italian and Portuguese landscapes such as the Po Valley and the Alentejo. The narrative pays particular attention to the historical development of fascist regimes in the two countries, advancing the argument that breeders' artifacts were key components of the institutionalization of the new political regimes. PMID- 20957829 TI - One grain, one nation: rice genetics and the corporate state in early Francoist Spain (1939-1952. AB - This paper aims to show the links between rice genetics and the corporatist political economy of early Francoism. After investigating the transition from prewar rice producers' associations to a new federation embedded in a vertical union, I identify three main novelties of the new organization: its national scope, its need to address lack of supply rather than overproduction, and its hierarchical functioning. I then focus on the one state-owned agricultural station devoted to rice research, showing how its agricultural scientists shaped, and relied on, the state-controlled unions, both for producing and distributing new varieties of rice and for controlling the seeds farmers used. Finally, I explore how this relationship made it possible for the scientists to test, multiply, and distribute throughout the Spanish landscape the seeds they produced at the laboratory, thus putting hierarchical unity and autarky to work and demonstrating the role of scientists as active agents of state formation and landscape transformation within a corporatist political economy. PMID- 20957830 TI - Purifying landscapes: the Vichy Regime and the genetic modernization of France. AB - This article argues that "genetic modernism" in seeds was simultaneously a technoscientific and a political project that materialized under wartime Vichy's proto-fascist regime and that contributed to shaping and legitimizing Vichy as a "planner state." The constitution of the genetically homogeneous cultivar as a scientific object, a market commodity, and a state policy object went hand in hand during the Vichy regime. A new biopolitical connection between state and seeds emerged, in which seeds were considered a priority target for state intervention because they were seen as the easiest path toward transforming agricultural practices so as to meet pressing needs for a sufficient and autonomous food supply (autarky). The state acquired the power of life and death over plant genomes in the nation's landscapes and enacted a phytoeugenics that was both positive (aiming to encourage the diffusion of varieties deemed healthy or higher yielding) and negative (aiming to suppress varieties deemed obsolete). The ontology of "genetic modernism" considered living beings as having an intrinsic genetic identity, sealed off from the vagaries of the environment, and favored serial and stable forms of life, which were achieved materially through the production of plant populations composed of isogenotypic individuals (clones, pure lines, F1 hybrids). Such pure line ontology, planned seed-economy practices, and metrological arrangements articulated a biopolitics geared towards superseding a nexus of biocultural crop evolutionary processes under farmers' management with centralized planning of genetic progress. This turned Vichy France into a huge biopolitical laboratory. It also left major legacies in the post-World War II decades. PMID- 20957831 TI - The fate of peasant-friendly plant breeding in Nazi Germany. AB - The peasantry played a central role in National Socialist ideology, as both a source of racial strength and a foundation of the economy. In this paper I explore the extent to which the regime's policies actually favored peasant farming. The first section looks at the overall character of agricultural policy and demonstrates that although peasant farmers were targeted for special assistance from 1933 until 1936, they were neglected thereafter as the economy geared up for war. In the second section I focus upon a particular set of policies--the regime's attempts to promote the use of high-quality seed--and show that while farmers as a whole probably gained from these measures, peasants appear not to have benefited differentially. In the third section I examine agricultural officials' attempts to establish a "division of labor" between public-sector plant breeding institutions and commercial breeders. I demonstrate that although the former had been successfully developing new varieties specifically designed for peasant farmers since the turn of the century, this work was henceforth to be curtailed so as not to "compete" with the private sector. In the conclusion I argue that neither the regime's policies on plant breeding nor the highly centralized character of agricultural policy-making can be regarded as specifically fascist. PMID- 20957832 TI - Veterinary investment act clears the House. PMID- 20957833 TI - Castration clinics fight unwanted horse problem. States, national coalition offering them at no, low cost to owners. PMID- 20957834 TI - More on the economics behind feral cat control. PMID- 20957835 TI - That which must not, can not be... A reply to the EChA and EDF responses to the REACH analysis of animal use and costs. PMID- 20957836 TI - [Eager learning and living long]. PMID- 20957837 TI - [End of reports about work]. PMID- 20957838 TI - [The Sanitation Service for Bovines and the Swiss Medical Association for ruminants have fused. The roads that begin from here are whatever people have attributed to them]. PMID- 20957839 TI - Sleep apnea: why should we look for cardiac biomarkers? PMID- 20957840 TI - High prevalence of restless legs syndrome among patients with fibromyalgia: a controlled cross-sectional study. AB - STUDY OBJECTIVES: To investigate the prevalence of restless legs syndrome (RLS) in fibromyalgia (FM) and determine the presence and amount of sleep disruption in FM patients with RLS. RLS and FM have been associated in uncontrolled studies using a variety of RLS definitions. We explored this relationship using a cross sectional study design. METHODS: FM cases that met the American College of Rheumatology diagnostic criteria were recruited through an academic referral clinic and advertising. Pain- and fatigue-free controls were recruited from the Seattle metropolitan area. We enrolled 172 FM patients (mean age 50 years, 93% female) and 63 pain- and fatigue-free controls (mean age 41 years, 56% female). RLS was ascertained by a self-administered validated diagnostic interview. RESULTS: The age- and gender-adjusted prevalence of RLS was higher in the FM group than the control group (33.0%; 95% CI: 25.9, 40.1 vs. 3.1%; 95% CI: 0.0, 7.4; p = 0.001). Likewise, the FM group was more likely to report RLS (OR = 11.7; 95% CI: 2.6, 53.0), even after adjusting for age and gender. The mean Pittsburgh Sleep Quality Index score was higher among FM patients with RLS than those without (11.8 vs. 9.9; p = 0.01) but subjective limb pain measures did not differ between these 2 groups. CONCLUSIONS: There is a higher prevalence and odds of RLS in those with FM compared to controls. Clinicians should routinely query FM patients regarding RLS symptoms because treatment of RLS can potentially improve sleep and quality of life in these patients. PMID- 20957841 TI - Higher prevalence of periodic limb movements of sleep in patients with history of stroke. AB - STUDY OBJECTIVES: The association between obstructive sleep apnea and stroke is well established. Less is known about the relationship between stroke and periodic limb movements of sleep (PLMS). This study sought to assess the frequency of PLMS in patients with a history of stroke. METHODS: We reviewed the medical and polysomnographic records of 40 patients with a history of stroke and 40 control patients matched for age, sex, and risk factors. RESULTS: 19 patients with a history of stroke (47.5%) and 5 control patients (12.5%) had a PLMS index > 5/h (p < 0.001). The average PLMS index was also lower in control patients than patients with stroke (1.9 +/- 0.7 and 11.7 +/- 3.4; p = 0.006). CONCLUSIONS: Our patients with a history of stroke had a greater prevalence and severity of PLMS than control patients. These limb movements may have implications for secondary stroke prevention as well as stroke recovery. PMID- 20957842 TI - Clinical and polysomnographic characteristics of high frequency leg movements. AB - STUDY OBJECTIVES: The aim of this study was to describe the clinical and polysomnographic characteristics of patients with high frequency leg movements (HFLM) on polysomnographic recording. METHODS: Among 486 patients (male 232, female 254) referred for overnight diagnostic PSG over a 9-month period, 37 patients demonstrated HFLM: 19 males (8.2% of PSGs) and 18 females (7.1% of PSGs). An equal number of age- and sex-matched consecutive patients who did not show HFLM were selected. HFLM was defined as > or = 4 discrete leg movements occurring at a frequency of 0.3-4.0 Hz. RESULTS: Two-thirds (64.3%) of all HFLMs occurred during waking; 35.7% occurred during sleep. Of those HFLM episodes occurring during sleep, 44.8% occurred during stage 1, 45.1% during stage 2, 0.6% during stages 3 and 4, and 9.5% during REM. The movements usually appeared unilaterally, but sometimes they showed a bilateral pattern. The mean frequency was 1.6 +/- 0.6 Hz (range 0.4-3.7), the mean number of episodes of HFLM per subject per night was 26.5 +/- 30.5 (range 2-111), and the mean duration per episode was 17.6 +/- 35.4 sec (range 1.5 sec-6.1 minutes). The mean HFLM index, (total number of HFLM divided by the time in bed, in hours), was 107.7 +/- 254.5 (range 2.0-1078.3). Patients with HFLM complained of RLS symptoms significantly more often than the group without HFLM (p < 0.05). CONCLUSION: Further studies are needed to establish criteria for scoring HFLM. Examination of other patient cohorts with HFLM will be needed to determine whether HFLM are in fact associated with RLS. PMID- 20957843 TI - Sleep quality and sleep hygiene behaviors of adolescents during chemotherapy. AB - STUDY OBJECTIVES: Describe the self-reported sleep quality and sleep hygiene behaviors of adolescents before diagnosis and during chemotherapy (CTX), compare their sleep quality and sleep hygiene behaviors with published normative data for healthy adolescents and adolescents with chronic pain, and explore factors that predict sleep quality. METHODS: Subjects were 51 adolescents (10 to 19 years) receiving CTX for cancer. A questionnaire was used to assess sleep patterns prior to the adolescent's cancer diagnosis, and a 7-day sleep diary was used to assess subjective sleep-wake activity during CTX. Sleep quality was assessed using the Adolescent Sleep Wake Scale, and sleep-facilitating and sleep-inhibiting behaviors using the Adolescent Sleep Hygiene Scale. RESULTS: Adolescents receiving CTX reported significantly worse sleep quality and sleep hygiene behaviors than healthy adolescents, and better sleep quality but similar sleep hygiene behaviors to adolescents with chronic pain. Significant interactions were found between bedtimes and wake-times on weekdays and weekends before diagnosis and during CTX. Sleep hygiene and demographic variables accounted for 24% of the variance in sleep quality. The cognitive and emotional subscales of the sleep hygiene scale and demographic variables accounted for 36% of the variance in sleep quality. CONCLUSIONS: Both the weekday and weekend sleep-wake patterns of adolescents receiving CTX resembled their weekend sleep patterns prior to diagnosis. PMID- 20957844 TI - Impaired quality of sleep in Meniere's disease patients. AB - OBJECTIVE: To evaluate the quality of sleep in Meniere's disease patients with the use of polysomnography. STUDY DESIGN: Prospective study using polysomnography administered in patients diagnosed as "Definite Meniere's disease cases" according to the guidelines of the American Academy of Otolaryngology-Head and Neck Surgery. METHODS: Thirty-five patients, 17 male and 18 female, aged 31 to 71 (58 average) years with active, unilateral, cochleovestibular Meniere's disease refractory to medical management underwent polysomnography. The results were compared with 35 healthy controls matched for age and sex. All participants underwent full-night polysomnography, and a sleep medicine physician interpreted the results. RESULTS: Total sleeping time in Meniere's disease was significantly higher than in controls. Stage 2 sleep was significantly longer and stage 3+4 shorter in Meniere's disease than controls, while there was no difference of stage 1 and REM. Arousal index was significantly higher in Meniere's disease than in controls. Five cases of severe OSAS were found in Meniere's disease and 4 cases in controls; 4 cases of PLMD were found in patients and 3 in controls. CONCLUSIONS: Our finding of decreased deep sleep and an elevated arousal index is a striking new finding in Meniere's disease. This poor quality of sleep in Meniere's disease patients has received little attention in the past, but may cause additional stress and lead to a negative spiral of symptoms. PMID- 20957845 TI - Tolerability and efficacy of armodafinil in naive patients with excessive sleepiness associated with obstructive sleep apnea, shift work disorder, or narcolepsy: a 12-month, open-label, flexible-dose study with an extension period. AB - STUDY OBJECTIVES: This 12-month, open-label, flexible-dose study with an extension period evaluated the tolerability and efficacy of armodafinil in patients with excessive sleepiness associated with treated obstructive sleep apnea (OSA), shift work disorder (SWD), or narcolepsy. METHODS: Armodafinil naive, adult patients with excessive sleepiness associated with treated OSA (n = 170), SWD (n = 108), or narcolepsy (n = 50) received armodafinil (100-250 mg) once daily (treated OSA or narcolepsy) or before night shifts (SWD). Patients with OSA were regular users of continuous positive airway pressure (CPAP) therapy. Efficacy measures included the Clinical Global Impression of Improvement (CGI-I) and the Epworth Sleepiness Scale (ESS). RESULTS: Across the diagnosis groups, the most commonly occurring adverse event was headache (14%-24%). Forty three patients (13%) and 13 patients (4%) were withdrawn because of adverse events and insufficient efficacy, respectively. Armodafinil did not adversely affect CPAP therapy. At the final visit, 80% (95% CI: 74.1, 86.7) of patients with treated OSA and 84% (72.7, 94.8) of patients with narcolepsy were rated on the CGI-I as at least minimally improved with regard to overall clinical condition; 98% (95.2, 100.0) of patients with SWD were rated as improved with regard to sleepiness during night shifts, including the commute to and from work. Armodafinil improved ESS total scores in patients with treated OSA (mean [SD] [95% CI] change from baseline, -7.3 [5.6] [-8.39, -6.30]) and patients with narcolepsy (-4.7 [6.0] [-7.41, -1.93]). CONCLUSIONS: Armodafinil administered for 12 months or more was generally well tolerated and improved wakefulness in patients with excessive sleepiness associated with treated OSA, SWD, or narcolepsy. Armodafinil improved the overall clinical condition of patients with treated OSA or narcolepsy. PMID- 20957846 TI - The long-term tolerability and efficacy of armodafinil in patients with excessive sleepiness associated with treated obstructive sleep apnea, shift work disorder, or narcolepsy: an open-label extension study. AB - STUDY OBJECTIVES: Armodafinil is a wakefulness-promoting medication. Its efficacy and tolerability have been established in 12-week studies of patients with excessive sleepiness (ES) associated with treated obstructive sleep apnea (OSA), shift work disorder (SWD), or narcolepsy. This study evaluated the tolerability and efficacy of armodafinil for > or = 12 months. METHODS: Patients with ES associated with treated OSA, SWD, or narcolepsy who completed one of four 12 week, double-blind studies were eligible for this multicenter, open-label study of > or = 12 months' duration of treatment with armodafinil (50 to 250 mg/day). Adverse events and other criteria of tolerability were monitored throughout the study. Efficacy assessments included the Clinical Global Impression of Change (CGI-C), Brief Fatigue Inventory (BFI), and Epworth Sleepiness Scale (ESS). RESULTS: Of 743 enrolled patients (474 with treated OSA, 113 with SWD, and 156 with narcolepsy), 57% of patients (420/743) completed 12 months or more of treatment. Discontinuations due to adverse events occurred in 13% of patients (95/743) during the initial 12-month period. Throughout the > or = 12-month study, adverse events were generally of mild-to-moderate intensity; headache (25% [180/731]), nasopharyngitis (17% [123/731]), and insomnia (14% [99/731]) were the most common. Modest increases were observed in vital sign measurements (blood pressure [3.6/2.3 mm Hg], heart rate [6.7 beats per minute]) across all patient groups; most of the changes occurred by month 3. Improvements from baseline in efficacy assessments started at month 1 and were maintained throughout the study. CONCLUSIONS: Armodafinil remained effective and was generally well tolerated. Increased monitoring of blood pressure may be appropriate in patients on armodafinil. Armodafinil represents an option for long-term treatment of patients with ES associated with treated OSA, SWD, or narcolepsy. PMID- 20957847 TI - Risk assessment of obstructive sleep apnea in a population of patients undergoing ambulatory surgery. AB - STUDY OBJECTIVES: The aims of this study were to: (a) assess the prevalence of diagnosed OSA and symptoms of undiagnosed OSA in a cohort of ambulatory surgical patients, and (b) characterize the frequency of postoperative complications in outpatients with a diagnosis of or a propensity to OSA. METHODS: Patients presenting for ambulatory surgery completed a self-administered questionnaire. Using a previously validated prediction model, the probability for OSA was determined. Patients with > or = 70% propensities were considered to be at high risk of having the disorder. Relevant perioperative data and complications were tracked and recorded, and differences in median estimated propensities for OSA were considered by these data. RESULTS: Three-thousand five hundred fifty-three patients 'completed the preoperative survey. A total of 2139 patients had perioperative data and estimated propensity scores. Ninety-four of the 2139 (4.4%) patients gave a self-reported prior diagnosis of OSA. One hundred three (4.8%) patients were found to be at high risk of OSA based on the survey and prediction model. Seventy-five percent of the patients with > 70% propensity for OSA had not yet been diagnosed. There was no association between OSA propensity scores and unplanned hospital admission, however there was an association of increased propensity with difficult intubation, intraoperative use of pressors, and postoperative oxygen saturation in the PACU. CONCLUSION: The results of this study suggest that undiagnosed OSA may be relatively common in an ambulatory surgical population. There was no relationship between unplanned hospital admission and diagnosis of or increased risk of OSA. However, there was an association of increased perioperative events requiring additional anesthetic management in patients with a diagnosis of, or with a higher propensity to OSA. PMID- 20957848 TI - The value of assessing risk of obstructive sleep apnea in surgical patients: it only takes one. PMID- 20957849 TI - Does snoring intensity correlate with the severity of obstructive sleep apnea? AB - STUDY OBJECTIVES: It is commonly believed that louder snoring is associated with more severe obstructive sleep apnea (OSA). We evaluated the association between snoring intensity and the severity of OSA to better understand this clinical correlation. We also investigated the relationships between body mass index (BMI), neck size, sleep stage, and body position with the intensity of snoring. METHODS: Overnight polysomnography, including objective measurement of snoring intensity, in 1643 habitual snorers referred for evaluation of sleep apnea. RESULTS: Sixty-five percent of patients were male; the cohort had a mean age of 48.7 +/- 13.7 y and BMI of 30.9 +/- 8.8 kg/m2. The mean apnea-hypopnea index (AHI) was 28.2 +/- 26. The severity of OSA was graded as no OSA (AHI < 5), mild (AHI 5 to 15), moderate (AHI 15 to 30), severe (AHI 30 to 50), and very severe OSA (AHI > 50). Snoring intensity increased progressively across all 5 categories of AHI frequency and ranged from 46.3 +/- 3.6 db in patients with AHI < 5 to 60.5 +/- 6.4 db in those with AHI > 50. Furthermore, there was a positive correlation between the intensity of snoring and the AHI (r = 0.66, p < 0.01). CONCLUSIONS: The intensity of snoring increases as OSA becomes more severe. PMID- 20957850 TI - A two-year weight reduction program in obese sleep apnea patients. AB - STUDY OBJECTIVES: To evaluate the effects of a 2-year weight reduction program on respiratory disturbances, arousal index, daytime sleepiness, metabolic status, and quality of life in obese patients with obstructive sleep apnea syndrome (OSAS). METHODS: Prospective intervention study of 33 consecutive obese OSAS patients (24 men, 9 women); 19 subjects used continuous positive airway pressure and 4 used mandibular retaining device, except during nights with sleep recording. The program consisted of 8 weeks of low calorie diet followed by group meetings with behavioral change support. RESULTS: Seventy percent of the patients completed the program; 67% completed the sleep recordings. The success rate for the apnea-hypopnea index (AHI) (< 20 and reduction > or = 50%) was 15% in the intention to treat (ITT) analysis. The AHI showed a nonsignificant decrease in mean values, from 43 to 28. The oxygen desaturation index (ODI) decreased from 42 to 23 (p = 0.010), arousal index from 24 to 11 (p = 0.019), body mass index from 40 to 35 (p = 0.003) and the Epworth Sleepiness Scale (ESS) from 9 to 5 (p = 0.026), all ITT. Metabolic status, physical functioning, and vitality evaluations improved only in the per protocol analysis. Reduction in weight correlated significantly to reductions in ESS (p = 0.038) and insulin levels (p = 0.002), respectively. There were no differences based on gender or use/non-use of OSAS treatment device. CONCLUSIONS: Our weight reduction program showed a limited success in reducing AHI. However, there were significant improvements in weight, ODI, arousal index, and subjective symptoms. We recommend the program as an adjunct treatment for well-motivated obese OSAS patients. PMID- 20957851 TI - Nightmare reduction in a Vietnam veteran using imagery rehearsal therapy. AB - Following exposure to traumatic events, approximately 19% of combat veterans develop posttraumatic stress disorder. One of the main symptoms of this mental illness is reexperiencing the trauma, which is commonly expressed in the form of chronic trauma-related nightmares. In these patients, nightmares can fragment sleep, decrease sleep quality, and even cause fear about going to sleep. One promising psychological treatment for chronic nightmares is imagery rehearsal therapy. Imagery rehearsal therapy presumes that nightmares are a learned behavior and that activating the visual imagery system may facilitate emotional processing of the trauma. This treatment involves deliberately rewriting a nightmare and mentally rehearsing images from the newly rescripted scenario while awake. Imagery rehearsal therapy has been found to reduce nightmares and associated distress. We present a case study demonstrating the use of imagery rehearsal therapy in a Vietnam-era veteran with posttraumatic stress disorder and chronic nightmares. Nightmares were considerably reduced and the quality of sleep greatly improved after treatment. PMID- 20957852 TI - Alleviation of severe restless legs syndrome (RLS) symptoms by cigarette smoking. AB - Cigarette smoking is in general considered an aggravating factor for restless legs syndrome (RLS). The author presents a case in which cigarette smoking has produced for many years a consistent and effective alleviation of RLS symptoms. PMID- 20957854 TI - The ambivalent sleeper. PMID- 20957853 TI - Best clinical practices for the sleep center adjustment of noninvasive positive pressure ventilation (NPPV) in stable chronic alveolar hypoventilation syndromes. AB - Noninvasive positive pressure ventilation (NPPV) devices are used during sleep to treat patients with diurnal chronic alveolar hypoventilation (CAH). Bilevel positive airway pressure (BPAP) using a mask interface is the most commonly used method to provide ventilatory support in these patients. BPAP devices deliver separately adjustable inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP). The IPAP and EPAP levels are adjusted to maintain upper airway patency, and the pressure support (PS = IPAP-EPAP) augments ventilation. NPPV devices can be used in the spontaneous mode (the patient cycles the device from EPAP to IPAP), the spontaneous timed (ST) mode (a backup rate is available to deliver IPAP for the set inspiratory time if the patient does not trigger an IPAP/EPAP cycle within a set time window), and the timed (T) mode (inspiratory time and respiratory rate are fxed). During NPPV titration with polysomnography (PSG), the pressure settings, backup rate, and inspiratory time (if applicable) are adjusted to maintain upper airway patency and support ventilation. However, there are no widely available guidelines for the titration of NPPV in the sleep center. A NPPV Titration Task Force of the American Academy of Sleep Medicine reviewed the available literature and developed recommendations based on consensus and published evidence when available. The major recommendations derived by this consensus process are as follows: General Recommendations: 1. The indications, goals of treatment, and side effects of NPPV treatment should be discussed in detail with the patient prior to the NPPV titration study. 2. Careful mask fitting and a period of acclimatization to low pressure prior to the titration should be included as part of the NPPV protocol. 3. NPPV titration with PSG is the recommended method to determine an effective level of nocturnal ventilatory support in patients with CAH. In circumstances in which NPPV treatment is initiated and adjusted empirically in the outpatient setting based on clinical judgment, a PSG should be utilized if possible to confirm that the final NPPV settings are effective or to make adjustments as necessary. 4. NPPV treatment goals should be individualized but typically include prevention of worsening of hypoventilation during sleep, improvement in sleep quality, relief of nocturnal dyspnea, and providing respiratory muscle rest. 5. When OSA coexists with CAH, pressure settings for treatment of OSA may be determined during attended NPPV titration PSG following AASM Clinical Guidelines for the Manual Titration of Positive Airway Pressure in Patients with Obstructive Sleep Apnea. 6. Attended NPPV titration with PSG is the recommended method to identify optimal treatment pressure settings for patients with the obesity hypoventilation syndrome (OHS), CAH due to restrictive chest wall disease (RTCD), and acquired or central CAH syndromes in whom NPPV treatment is indicated. 7. Attended NPPV titration with PSG allows definitive identification of an adequate level of ventilatory support for patients with neuromuscular disease (NMD) in whom NPPV treatment is planned. Recommendations for NPPV Titration Equipment: 1. The NPPV device used for titration should have the capability of operating in the spontaneous, spontaneous timed, and timed mode. 2. The airflow, tidal volume, leak, and delivered pressure signals from the NPPV device should be monitored and recorded if possible. The airflow signal should be used to detect apnea and hypopnea, while the tidal volume signal and respiratory rate are used to assess ventilation. 3. Transcutaneous or end-tidal PCO2 may be used to adjust NPPV settings if adequately calibrated and ideally validated with arterial blood gas testing. 4. An adequate assortment of masks (nasal, oral, and oronasal) in both adult and pediatric sizes (if children are being titrated), a source of supplemental oxygen, and heated humidification should be available. Recommendations for Limits of IPAP, EPAP, and PS Settings: 1. The recommended minimum starting IPAP and EPAP should be 8 cm H2O and 4 cm H2O, respectively. 2. The recommended maximum IPAP should be 30 cm H2O for patients > or = 12 years and 20 cm H2O for patients < 12 years. 3. The recommended minimum and maximum levels of PS are 4 cm H2O and 20 cm H2O, respectively. 4. The minimum and maximum incremental changes in PS should be 1 and 2 cm H2O, respectively. Recommendations for Adjustment of IPAP, EPAP, and PS: 1. IPAP and/or EPAP should be increased as described in AASM Clinical Guidelines for the Manual Titration of Positive Airway Pressure in Patients with Obstructive Sleep Apnea until the following obstructive respiratory events are eliminated (no specific order): apneas, hypopneas, respiratory effort-related arousals, and snoring. 2. The pressure support (PS) should be increased every 5 minutes if the tidal volume is low (< 6 to 8 mL/kg) 3. The PS should be increased if the arterial PCO2 remains 10 mm Hg or more above the PCO, goal at the current settings for 10 minutes or more. An acceptable goal for PCO, is a value less than or equal to the awake PCO2. 4. The PS may be increased if respiratory muscle rest has not been achieved by NPPV treatment at the current settings for 10 minutes of more. 5. The PS may be increased if the SpO, remains below 90% for 5 minutes or more and tidal volume is low (< 6 to 8 mL/kg). Recommendations for Use and Adjustment of the Backup Rate/ Respiratory Rate: 1. A backup rate (i.e., ST mode) should be used in all patients with central hypoventilation, those with a significant number of central apneas or an inappropriately low respiratory rate, and those who unreliably trigger IPAP/EPAP cycles due to muscle weakness. 2. The ST mode may be used if adequate ventilation or adequate respiratory muscle rest is not achieved with the maximum (or maximum tolerated) PS in the spontaneous mode. 3. The starting backup rate should be equal to or slightly less than the spontaneous sleeping respiratory rate (minimum of 10 bpm). 4. The backup rate should be increased in 1 to 2 bpm increments every 10 minutes if the desired goal of the backup rate has not been attained. 5. The IPAP time (inspiratory time) should be set based on the respiratory rate to provide an inspiratory time (IPAP time) between 30% and 40% of the cycle time (60/respiratory rate in breaths per minute). 6. If the spontaneous timed mode is not successful at meeting titration goals then the timed mode can be tried. Recommendations Concerning Supplemental Oxygen: 1. Supplemental oxygen may be added in patients with an awake SpO2 < 88% or when the PS and respiratory rate have been optimized but the SpO2 remains < 90% for 5 minutes or more. 2. The minimum starting supplemental oxygen rate should be 1 L/minute and increased in increments of 1 L/minute about every 5 minutes until an adequate SpO2 is attained (> 90%). Recommendations to Improve Patient Comfort and Patient-NPPV Device Synchrony: 1. If the patient awakens and complains that the IPAP and/or EPAP is too high, pressure should be lowered to a level comfortable enough to allow return to sleep. 2. NPPV device parameters (when available) such as pressure relief, rise time, maximum and minimum IPAP durations should be adjusted for patient comfort and to optimize synchrony between the patient and the NPPV device. 3. During the NPPV titration mask refit, adjustment, or change in mask type should be performed whenever any significant unintentional leak is observed or the patient complains of mask discomfort. If mouth leak is present and is causing significant symptoms (e.g., arousals) use of an oronasal mask or chin strap may be tried. Heated humidification should be added if the patient complains of dryness or significant nasal congestion. Recommendations for Follow Up: 1. Close follow-up after initiation of NPPV by appropriately trained health care providers is indicated to establish effective utilization patterns, remediate side effects, and assess measures of ventilation and oxygenation to determine if adjustment to NPPV is indicated. PMID- 20957855 TI - Comments on board review corner: the early riser. PMID- 20957856 TI - Most experts predict higher volumes with reform--EDs must prepare now. AB - Most ED managers believe volumes will increase under the health care reform law. You can't prevent a growing number of patients from coming to your ED, but there are steps you can take to make your department more efficient. If no beds are available upstairs, move patients to the floors of other units. Make sure you have a strategy in place for when your ED becomes too crowded. Use Lean tools to identify and eliminate unnecessary process steps and standardize placement of equipment in your rooms. PMID- 20957857 TI - Best practices boost efficiency. PMID- 20957858 TI - Cardiac MRI in obs lowers admissions. AB - A study conducted by researchers at Wake Forest University Baptist Medical Center showed that using a cardiac MRI in the ED's observation unit enabled providers to manage most patients without admitting them, resulting in lower cost at the hospital of about $588 per patient. It also allowed diagnosis and prevention of all cardiac events that might have occurred within 30 days of the visit. Cardiac MRI can reveal edema, allow a view of wall motion, allow profusion testing at rest and during stress, and offer delayed enhancement looks at areas of cardiac scarring or recent infarction. Placing moderate and high-risk patients in the observation unit frees up beds in the ED. Cardiac MRI allows the opportunity to bill for observation care, which is higher in terms of professional fees. PMID- 20957859 TI - Propofol is part of a larger issue. AB - The"Propofol" issue initiated by a ruling from the Centers for Medicare and Medicaid Services (CMS) is about much more than that ruling, i.e., who is qualified to administer procedural sedation, say observers. This issue has set up challenges for ED managers, anesthesia departments, and administration. Sit down and work out an agreement with your anesthesia department about administering procedural sedation in the ED. Remind administration that anesthesia must have input, but that they are not compelled to prohibit administration of Propofol by ED staff. Emphasize the greater safety and efficiency of Propofol, and ask the administrators what kind of care they would prefer if they were a patient. PMID- 20957860 TI - System restricts nurses' overtime. AB - Noting concern over patient safety and staff well-being, Emory Healthcare in Atlanta has instituted a new policy that restricts overtime hours for nurses, including those in the ED. Here are some of the ways in which the system ensures their nurses get adequate rest: Nurses who want to work overtime cannot be on duty more than 60 hours a week. A central staffing center has been established to cover shifts. A number of the nurses have ED experience. Steps have been taken to ensure that nurses can take their 30-minute lunches and 15-minute breaks. PMID- 20957861 TI - Proactive managers buoy satisfaction. AB - The ED leaders at St. Clair Hospital in Pittsburgh, PA, say that"managing by walking around"was one of the keys to their earning a ranking from Press Ganey as the no. 1 ED in patient satisfaction for EDs with more than 50,000 annual visits. The director selects and talks with random patients, following up on their care and making sure they're satisfied. Staff members are asked specific questions based on the Press Ganey priority indices. If there are patient complaints about a staff member, confidential meetings are held to discuss ways to improve. PMID- 20957862 TI - If you lead. PMID- 20957864 TI - Hurman factors. PMID- 20957863 TI - Want a job? Get flu vaccine. PMID- 20957865 TI - Finance. New Medicare cuts will force hospitals to plug major revenue leak. PMID- 20957866 TI - Access & coverage. Outreach progran helps patients get covered. PMID- 20957867 TI - From coma, safety evangelist emerges. PMID- 20957868 TI - Quality. Executive treatment urged to drive down infection rates. PMID- 20957869 TI - Technology. Checking vital signs? There's an app for that. PMID- 20957870 TI - Regulation. 50 states, 50 IT plans? PMID- 20957871 TI - The happy meal problem. PMID- 20957872 TI - Smart leadership! Finding the right mix of minds to manage the future. AB - American health care is about to undergo the most dramatic transformation in many a decade. And the hard work begins right in your own C-suite. As a hospital leader, take a hard look at your executive team-including yourself-to make sure you have the right mix of skills for this new era. You might need to add new titles to your leadership mix. Current executives will need to rethink their roles to meet the mandates for integration, technology and more. PMID- 20957873 TI - Creating a cardiac care continuum. PMID- 20957874 TI - McLeod Regional Medical Center. Florence, SC. The drive to continuously improve. PMID- 20957875 TI - Henry Ford Hospital & Health Network. Detroit. 'You can achieve dramatic results'. PMID- 20957876 TI - Queens Hospital Center. New York. A staffwide sense of ownership. PMID- 20957877 TI - The two paths to PHRs. AB - Hospitals pick up the pace on patient health records. Should you take the "true" route, opt for a portal or consider a combination of the two? PMID- 20957878 TI - AHA environmental scan 2011. PMID- 20957879 TI - New tools for governance. PMID- 20957880 TI - A rich resource on the history of Medicare. PMID- 20957881 TI - Physicians' Rx for health-care reform. PMID- 20957882 TI - It's all about the attitude. PMID- 20957883 TI - Nursing educators: the view from here. PMID- 20957884 TI - Building successful mentoring relationships. PMID- 20957886 TI - From witness to social justice advocate. PMID- 20957887 TI - Contribution of US and CT for diagnosis of intraperitoneal focal fat infarction (IFFI): a pictorial review. AB - The term IFFI--for intraperitoneal focal fat infarction--includes various acute abdominal clinical conditions in which focal fatty tissue necrosis represents the common pathologic denominator. Only differing by their various anatomical locations and dimensions, all cases nevertheless present rather similar clinical signs, aetiology, radiological features and prognosis. In clinical practise, most cases of IFFI concern torsion and/or infarction of the greater omentum or epiploic appendages. Rarer types of torsion and/or infarction of lipomatous appendages of the hepatic falciform ligament and of the lesser omentum have also been reported. Cases are finally described in the paediatric population. US and merely CT have been shown having a high sensitivity and specificity for the diagnosis of IFFI and in most cases the clinical evolution is spontaneously favourable. For these two reasons, the option of conservative treatment after specific imaging diagnosis now represents the other common denominator of IFFI. Such a safe and unambiguous imaging diagnosis of IFFI represents thus an important challenge for each abdominal radiologist with the intention of persuading the referent clinician to avoid unnecessary surgery for their patients. The aim of this pictorial review is to extensively explore not only the classical imaging findings of various types of IFFI but also to review the normal US and MDCT anatomy of the fatty abdominal structures being usually implicated in IFFI. More rare or atypical presentations are also illustrated as well as subacute findings and sequels. All reported patients were collected in our department during a 7-year-period and most were successfully treated conservatively. PMID- 20957888 TI - An unusual cause of pelvic hemorrhage: multidetector CT diagnosis of inferior mesenteric vein injury. AB - Pelvic trauma can lead to uncontrollable bleeding and even death. Although significantly decreased with the application of novel treament modalities and the use of state-of-the-art imaging equipment, pelvic trauma and subsequent bleeding remains to stay as a major source of morbidity and mortality. In this case we present a patient suffering from pelvic bleeding from the inferior mesenteric vein due to sigmoid mesocolon injury. Similar finding has not been reported as an isolated source of pelvic hemorrhage. We also propose that the routine use of reformatted images obtained with multidetector CT scanners in patients with hemoperitoneum may be a highly useful adjunct for the correct identification of the source of hemorrhage. PMID- 20957889 TI - Post-traumatic hepatic arterial pseudoaneurysm and arterioportal shunt. AB - The authors report the case of a 21-year-old man who suffered from a blunt abdominal trauma. Initial imaging revealed a liver laceration at the right lobe, a perirenal hematoma of the right kidney and a hematoma of the right adrenal gland. Follow-up MDCT-scan on day 10 after admission showed at the arterial-phase contrast-enhanced study perfusion alterations and two hepatic pseudoaneurysms. The diagnosis of pseudoaneurysm was confirmed and treated angiographically with superselective coil embolization. A follow-up CT-scan on day 17 showed at a nontreated area an arterioportal shunt and a wedge-shaped transient hepatic parenchymal enhancement. This was confirmed angiographically and subsequently treated with coil embolization. PMID- 20957890 TI - Leiomyomatosis peritonealis disseminata in a 50-year-old woman: imaging findings. AB - Leiomyomatosis peritonealis disseminata (LPD)--or diffuse abdominal leiomyomatosis--is a very rare benign abdominal entity. Only a little more than 100 cases have been reported in the English literature since its first description in 1965. Middle aged female are typically affected and the clinical presentation is rather aspecific. The differential diagnosis between benign LPD and diffuse peritoneal carcinomatosis or abdominal disseminated malignancy represents the crucial diagnostic challenge that can only definitively be made through biopsy and histologic analysis. Multimodal imaging features (ultrasound, CT, MR and PET) of a case of LPD diagnosed in a 50-year-old female are presented with review the literature. PMID- 20957891 TI - Intracranial germ cell tumor. AB - Germ cell tumours represent about 3 to 8% of pediatric brain tumours. Occurrence of diabetes insipidus is common in the case of suprasellar germ cell tumors. The diagnosis may be advanced by MRI owing to the location and relatively univocal characteristics of the lesion signal. The existence of a bifocal mass developed in both suprasellar region and pineal zone is highly suggestive of a germinoma. The most important notion is to recognize that at the time of diabetes insipidus diagnosis in a child, the cerebral mass might be too small to be identified by MRI. In such patients, repeating imaging study should be obtained. PMID- 20957892 TI - Spontaneous cholecystocutaneous abscess. AB - Spontaneous cholecystocutaneous abscesses or fistulae are rare complications of neglected biliary calculous disease which have become extremely rare during the last decades. We report a case of spontaneous cholecystocutaneous abscess in a 69 year-old male who presented with a mass in the right subcostal region.The diagnosis was made by CT scan with multiplanar reformating. Treatment consisted of incision and drainage of the abdominal wall abscess followed by cholecystectomy in a one-stage protocol. PMID- 20957893 TI - Small bowel obstruction due to an internal herniation through a defect of the broad ligament. AB - We report on a case of internal hernia through a defect of the broad ligament of the uterus. Early diagnostic may be possible with multidetector CT and lead to early treatment. MDCT can help achieving early preoperative diagnostic and allows early laparoscopic treatment with prompt recovery. PMID- 20957894 TI - Acetabular osteoid osteoma treated by percutaneous radiofrequency ablation: delayed articular cartilage damage. AB - The authors report the case of an osteoid osteoma of the acetabular roof in a 17 year-old sportsgirl successfully treated by radiofrequency ablation, with a mid term evidence of cartilage loss. Extra-articular access and exact positioning of the needle electrode exclude direct operative chondral damage. Intense physical activity could be an aggravating factor for the chondropathy. It is difficult to determine whether the acetabular cartilage joint was damaged only by thermo ablation or if it had also been weakened before by the O.O. The authors caution practitioners from using this technique for para-articular lesions, especially near weight-bearing joints. PMID- 20957895 TI - Pigmented villonodular synovitis of the midfoot. AB - A 60-year-old man presented with a longstanding slowly growing swelling at the dorsal aspect of the left midfoot. The lesion was imaged with CT, ultrasound, and MR. On CT bony erosions were evident. On MR the lesions appeared bifocal and one component was hypointense on T2 weighted images suggesting hemosiderin deposits. The other component was hyperintense on T2 which is more unusual for PVNS. Imaging findings, however, suggested PVNS which was pathologically confirmed. A unique finding in this case is the late age of presentation of the disorder. Also the bifocal nature of the lesion is relatively uncommon. PMID- 20957896 TI - X-ray control of borders and of internal security. AB - OBJECTIVE: Security control with X-rays means exposure to ionising radiation and creates the possibility of access to personal privacy. Internal security concerns the police and secret services. The used technologies and their possibilities are described. MATERIAL AND METHOD: Observations and additional information have been collected. The exposure dose has been measured. RESULTS: Several technical set ups are in use: Transmission imaging (fluoroscopy), backscatter imaging, computed tomography and several combinations. The search of persons concerns the interior of the human body, its surface and the clothing together with the luggage. One looks for weapons, explosives and drugs. The exposure dose is low compared to the exposure dose by a flight or due to a holiday in a country with higher environmental radiation by external sources like Finland. CONCLUSION: In the future, the security control will increase. Using X-rays creates the possibility to inspect privacy. PMID- 20957897 TI - Vascular liver anatomy and main variants: what the radiologist must know. AB - Advances in surgical techniques are extremely demanding regarding the accuracy and level of detail expected for display of the vascular anatomy of the liver. Precise knowledge of the arterial, portal and hepatic vein territories are mandatory whenever a liver intervention is planned. Sectional anatomy can now be routinely performed on multidetector computed tomography (MDCT) with volumetric data and isotropic voxel display, by means of sub-millimetric slice thickness acquisition. The relevant vascular information can thus be gathered, reviewed and post-processed with unprecedented clarity, obviating the need for digital subtraction angiography. The scope of the present paper is to review the normal vascular liver anatomy, its most relevant variants including additional sources of vascular inflow. Apart from providing the surgeon with a detailed vascular and parenchymal roadmap knowledge of imaging findings may avoid potential confusion with pathologic processes. PMID- 20957898 TI - Detachable coiling for embolotherapy of high-flow pulmonary arteriovenous malformation: case report and review of the literature. AB - Pulmonary arteriovenous malformations (PAVMs) are very rare anomalies of the lung parenchyma. Although many patients are asymptomatic, it carries a high risk of severe cerebral complications, and rarely fatal outcome due to rupture of the malformation. There is a strong association with the Rendu-Osler-Weber disease. The patients should be treated in case of symptomatic PAVMs (paradoxical emboli), and also preventively, when the feeding artery is at least 3 mm in diameter. Embolization is a well-established treatment, which can be very challenging when dealing with very high-flow fistulas, where there is a risk of inadvertent migration of the embolization material in the left cavities of the heart and in the aorta. This report emphasizes the importance of the diagnosis and the embolization indication in pulmonary arteriovenous malformations, and the usefulness of detachable coils in case of high-flow fistulas. PMID- 20957899 TI - CT imaging of ascaris lumbricoides. PMID- 20957900 TI - An uncommon cause of asyptomatic crazy paving pattern: exogenous lipoid pneumonia. PMID- 20957901 TI - Mycotic aneurysm of the superior mesenteric artery. PMID- 20957902 TI - Bithalamic acute stroke: artery of Percheron. PMID- 20957903 TI - Gallstone ileus. PMID- 20957904 TI - The admiral and the General. PMID- 20957905 TI - Blackwater fever: divine retribution or genetic happenstance? PMID- 20957906 TI - Curbing healthcare-associated infections. PMID- 20957907 TI - Healthcare-associated infections: what can be done to reduce risk to our patients? PMID- 20957908 TI - Reducing the incidence of Clostridium difficile infections: can we do it? PMID- 20957909 TI - The growing problem of methicillin-resistant Staphylococcus aureus: will hospitals prevail? PMID- 20957910 TI - Increasing annual influenza vaccinations among healthcare workers in Rhode Island: a social marketing approach. PMID- 20957911 TI - Prevention and control of multi-drug resistant organisms using standardized cross setting communication. PMID- 20957912 TI - Public reporting of hospital-acquired infections. PMID- 20957913 TI - Spontaneous pneumomediastinum: an uncommon cause of chest pain. PMID- 20957915 TI - The cleansing of blunt language. PMID- 20957914 TI - Central line-associated bloodstream infections (CLABSI) in Rhode Island. PMID- 20957916 TI - Caring for school kids. PMID- 20957917 TI - New twist on school screening. PMID- 20957918 TI - Hospital helps school districts. PMID- 20957919 TI - Class is in session (in the hospital). PMID- 20957920 TI - Beyond gym class. PMID- 20957921 TI - School-based clinics. PMID- 20957922 TI - The Abuela's knee. PMID- 20957923 TI - Removing junk food and beverages from school vending machines. PMID- 20957924 TI - The 2009 H1N1 influenza pandemic and Minnesota's K-12 schools: public health lessons learned. AB - Prior to 2009, influenza pandemic planners had primarily planned for a virus that would originate in a location other than North America, giving public health officials in the United States time to determine its severity before widespread disease occurred here. Thus, response plans for schools focused on closure in the case of a severe pandemic and potential closure in the event of a moderate one. The 2009 H1N1 pandemic, however, presented a different scenario. The severity of 2009 H1N1 was initially unknown and later was determined to be mild to moderate. Thus, as the pandemic unfolded, state and national public health entities found themselves adapting their recommendations for school closure. This article reviews Minnesota's experience with 2009 H1N1, focusing on the pandemic among school-aged children during the spring (April to August 2009) and fall (September 2009 to April 2010), and it chronicles how outbreak surveillance policies and recommendations for K-12 schools changed over the course of the pandemic. PMID- 20957925 TI - Counseling parents of difficult adolescents. AB - The relationship between parent and child changes during adolescence. During that transition time, some youths may be challenging rules, engaging in risky behaviors, or failing to disclose their activities to their parents. Physicians and other health care providers are in a position to counsel not only youths about problem behaviors but also parents about how to more effectively deal with their children. One of the things they can recommend is an approach known as authoritative parenting. This approach has been shown to promote higher school achievement and self-esteem, and result in less depression and anxiety and more self-reliance among youths. This article describes the approach and offers physicians tips about what they can say to parents. PMID- 20957926 TI - Community-acquired methicillin-resistant Staphylococcus aureus necrotizing fasciitis in a healthy adolescent male. AB - Recently, the rate of severe, invasive community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infection has been increasing in healthy children. The single most common cause of necrotizing fasciitis in children is group A Streptococcus. Empiric therapy is usually targeted at this organism, which is uniformly sensitive to penicillin. Necrotizing fasciitis caused by CA MRSA is a potentially life-threatening infection that has not been extensively reported in the U.S. pediatric population. The limited literature includes reports of neonatal cases and reports of pediatric cases embedded in articles about adults with underlying risk factors. We present a case of CA-MRSA necrotizing fasciitis in a previously healthy 11-year-old male with no risk factors. PMID- 20957927 TI - Trends in drug abuse among Minnesota youths. AB - Young people have long been confronted with choices about whether to use alcohol and other drugs. Today, however, they are having to make those decisions at a younger age, and they are encountering substances that were unheard of by members of their parents' generation. This article describes trends in abuse of alcohol, marijuana, synthetic marijuana, and prescription drugs among youths in the United States and Minnesota. PMID- 20957928 TI - Now is the time to step up to the plate. PMID- 20957929 TI - Dennis Manning calls on ADA Board, House to speak with 'unified voice'. Interviewed by Walter Lamacki. PMID- 20957930 TI - Online learning. CDS to present debut webinar on Direct Resin Pearls. PMID- 20957931 TI - The value of virtual assistants. PMID- 20957932 TI - Employee problems you never envisioned. PMID- 20957933 TI - CDS Foundation grants foster access to care. PMID- 20957934 TI - Goldie's Place. Student-run dental clinic offers eye-opening experience. PMID- 20957935 TI - Chocolate facts and fiction. PMID- 20957936 TI - Dr. Truman Brophy was a pioneer in cleft palate surgery. PMID- 20957937 TI - Don't take your stress out on your mouth. PMID- 20957938 TI - Don't underestimate the value of dignity. PMID- 20957939 TI - Breaking Bergmann's rule: truncation of Northwest Atlantic marine fish body sizes. AB - A strictly species-centric view of human impacts on ecological communities may conceal important trait changes key to ecosystem functioning and stability. Analyses of body size and community composition data for 326 Northwest Atlantic fish species sampled across > 900000 km2 over three decades revealed a rapid and widespread reduction of body sizes driven by declines within species and changes in relative abundances. The changes were unrelated to species richness but of sufficient magnitude to eliminate biogeographic scale gradients of increasing body size with latitude commonly characterized as Bergmann's rule. These changes have persisted despite reduced potential for intraspecific competition and favorable bottom water temperatures, both of which should lead to increased growth rates. The aggregate body sizes in these Northwest Atlantic fish communities may now represent a mismatch between the environmental variability characteristic of the Northwest Atlantic and the historical body size, life history traits, and productivity of species across this region. We discuss how these changes may jeopardize the potential for recovery of these important temperate/subarctic ecosystems. PMID- 20957940 TI - Experimental test of parasitism hypothesis for population cycles of a forest lepidopteran. AB - Population cycles of herbivores are thought to be driven by trophic interaction mechanisms, either between food plant and herbivore or between the herbivorous prey and its natural enemies. Observational data have indicated that hymenopteran parasitoids cause delayed density-dependent mortality in cyclic autumnal moth (Epirrita autumnata) populations. We experimentally tested the parasitism hypothesis of moth population cycles by establishing a four-year parasitoid exclusion experiment, with parasitoid-proof exclosures, parasitoid-permeable exclosures, and control plots. The exclusion of parasitoids led to high autumnal moth abundances, while the declining abundance in both the parasitoid-permeable exclosures and the control plots paralleled the naturally declining density in the study area and could be explained by high rates of parasitism. Our results provide firm experimental support for the hypothesis that hymenopteran parasitoids have a causal relationship with the delayed density-dependent component required in the generation of autumnal moth population cycles. PMID- 20957941 TI - Modeling species co-occurrence by multivariate logistic regression generates new hypotheses on fungal interactions. AB - Signals of species interactions can be inferred from survey data by asking if some species occur more or less often together than what would be expected by random, or more generally, if any structural aspect of the community deviates from that expected from a set of independent species. However, a positive (or negative) association between two species does not necessarily signify a direct or indirect interaction, as it can result simply from the species having similar (or dissimilar) habitat requirements. We show how these two factors can be separated by multivariate logistic regression, with the regression part accounting for species-specific habitat requirements, and a correlation matrix for the positive or negative residual associations. We parameterize the model using Bayesian inference with data on 22 species of wood-decaying fungi acquired in 14 dissimilar forest sites. Our analyses reveal that some of the species commonly found to occur together in the same logs are likely to do so merely by similar habitat requirements, whereas other species combinations are systematically either over- or underrepresented also or only after accounting for the habitat requirements. We use our results to derive hypotheses on species interactions that can be tested in future experimental work. PMID- 20957942 TI - Meta-analyses and mega-mistakes: calling time on meta-analysis of the species richness-productivity relationship. AB - The form of the species richness-productivity relationship (SRPR) is both theoretically important and contentious. In an effort to distill general patterns, ecologists have undertaken meta-analyses, within which each SRPR data set is first classified into one of five alternative forms: positive, humped (unimodal), negative, U-shaped (unimodal), and no relationship. Herein, I first provide a critique of this approach, based on 68 plant data sets/ studies used in three meta-analyses published in Ecology. The meta-analyses are shown to have resulted in highly divergent outcomes, inconsistent and often highly inappropriate classification of data sets, and the introduction and multiplication of errors from one meta-analysis to the next. I therefore call on the ecological community at large to adopt a far more rigorous and critical attitude to the use of meta-analysis. Second, I develop the argument that the literature on the SRPR continues to be bedeviled by a common failing to appreciate the fundamental importance of the scale of analysis, beginning with the confusion evident between concepts of grain, focus, and extent. I postulate that variation in the form of the SRPR at fine scales of analysis owes much to artifacts of the sampling regime adopted. An improved understanding may emerge from combining sampling theory with an understanding of the factors controlling the form of species abundance distributions and species accumulation curves. PMID- 20957943 TI - Evidence and inference: shapes of species richness-productivity curves. PMID- 20957944 TI - Repeatability and transparency in ecological research. PMID- 20957945 TI - Understanding species richness-productivity relationships: the importance of meta analyses. PMID- 20957946 TI - A critique for meta-analyses and the productivity-diversity relationship. PMID- 20957947 TI - Mega mistakes in meta-analyses: devil in the detail. PMID- 20957948 TI - A statistical view of synthesizing patterns of species richness along productivity gradients: devils, forests, and trees. PMID- 20957949 TI - Achieving synthesis with meta-analysis by combining and comparing all available studies. PMID- 20957950 TI - The productivity-diversity relationship: varying aims and approaches. PMID- 20957951 TI - In the dragon's den: a response to the meta-analysis forum contributions. PMID- 20957952 TI - Foliar fungal pathogens and grassland biodiversity. AB - By attacking plants, herbivorous mammals, insects, and belowground pathogens are known to play an important role in maintaining biodiversity in grasslands. Foliar fungal pathogens are ubiquitous in grassland ecosystems, but little is known about their role as drivers of community composition and diversity. Here we excluded foliar fungal pathogens from perennial grassland by using fungicide to determine the effect of natural levels of disease on an otherwise undisturbed plant community. Importantly, we excluded foliar fungal pathogens along with rabbits, insects, and mollusks in a full factorial design, which allowed a comparison of pathogen effects along with those of better studied plant enemies. This revealed that fungal pathogens substantially reduced aboveground plant biomass and promoted plant diversity and that this especially benefited legumes. The scale of pathogen effects on productivity and biodiversity was similar to that of rabbits and insects, but different plant species responded to the exclusion of the three plant enemies. These results suggest that theories of plant coexistence and management of biodiversity in grasslands should consider foliar fungal pathogens as potentially important drivers of community composition. PMID- 20957953 TI - Mycorrhizal benefit differs among the sexes in a gynodioecious species. AB - Both plant sex and arbuscular mycorrhizal (AM) symbiosis influence resource acquisition and allocation in plants, but the interaction between these two components is not well established. As the different plant sexes differ in their resource needs and allocation patterns, it is logical to presume that they might differ in their relationship with AM as well. We investigate whether the association with AM symbiosis is different according to the host plant sex in the gynodioecious Geranium sylvaticum, of which, besides female and hermaphrodite plants, intermediate plants are also recognized. Specifically, we examine the effects of two different AM fungi in plant mass allocation and phosphorus acquisition using a factorial greenhouse/common garden experiment. Cloned G. sylvaticum material was grown in symbiosis with AM fungi or in non-mycorrhizal condition. We evaluated both the symbiotic plant benefit in terms of plant mass and plant P content and the fungal benefit in terms of AM colonization intensity in the plant roots and spore production. Our results suggest that G. sylvaticum plants benefit from the symbiosis with both AM fungal species tested but that the benefits gained from the symbiosis depend on the sex of the plant and on the trait investigated. Hermaphrodites suffered most from the lack of AM symbiosis as the proportion of flowering plants was dramatically reduced by the absence of AM fungi. However, females and intermediates benefited from the symbiosis relatively more than hermaphrodites in terms of higher P acquisition. The two AM fungal species differed in the amount of resources accumulated, and the fungal benefit was also dependent on the sex of the host plant. This study provides the first evidence of sex-specific benefits from mycorrhizal symbiosis in a gynodioecious plant species. PMID- 20957954 TI - Specificity between Neotropical tree seedlings and their fungal mutualists leads to plant-soil feedback. AB - A growing body of evidence obtained largely from temperate grassland studies suggests that feedbacks occurring between plants and their associated soil biota are important to plant community assemblage. However, few studies have examined the importance of soil organisms in driving plant-soil feedbacks in forested systems. In a tropical forest in central Panama, we examined whether interactions between tree seedlings and their associated arbuscular mycorrhizal fungi (AMF) lead to plant-soil feedback. Specifically, do tropical seedlings modify their own AMF communities in a manner that either favors or inhibits the next cohort of conspecific seedlings (i.e., positive or negative feedback, respectively)? Seedlings of two shade-tolerant tree species (Eugenia nesiotica, Virola surinamensis) and two pioneer tree species (Luehea seemannii, Apeiba aspera) were grown in pots containing identical AMF communities composed of equal amounts of inoculum of six co-occurring AMF species. The different AMF-host combinations were all exposed to two light levels. Under low light (2% PAR), only two of the six AMF species sporulated, and we found that host identity did not influence composition of AMF spore communities. However, relative abundances of three of the four AMF species that produced spores were influenced by host identity when grown under high light (20% PAR). Furthermore, spores of one of the AMF species, Glomus geosporum, were common in soils of Luehea and Eugenia but absent in soils of Apeiba and Virola. We then conducted a reciprocal experiment to test whether AMF communities previously modified by Luehea and Apeiba differentially affected the growth of conspecific and heterospecific seedlings. Luehea seedling growth did not differ between soils containing AMF communities modified by Luehea and Apeiba. However, Apeiba seedlings were significantly larger when grown with Apeiba-modified AMF communities, as compared to Apeiba seedlings grown with Luehea-modifed AMF communities. Our experiments suggest that interactions between tropical trees and their associated AMF are species-specific and that these interactions may shape both tree and AMF communities through plant-soil feedback. PMID- 20957955 TI - Tropical forest soil microbial communities couple iron and carbon biogeochemistry. AB - We report that iron-reducing bacteria are primary mediators of anaerobic carbon oxidation in upland tropical soils spanning a rainfall gradient (3500-5000 mm/yr) in northeast Puerto Rico. The abundant rainfall and high net primary productivity of these tropical forests provide optimal soil habitat for iron-reducing and iron oxidizing bacteria. Spatially and temporally dynamic redox conditions make iron transforming microbial communities central to the belowground carbon cycle in these wet tropical forests. The exceedingly high abundance of iron-reducing bacteria (up to 1.2 x 10(9) cells per gram soil) indicated that they possess extensive metabolic capacity to catalyze the reduction of iron minerals. In soils from the higher rainfall sites, measured rates of ferric iron reduction could account for up to 44% of organic carbon oxidation. Iron reducers appeared to compete with methanogens when labile carbon availability was limited. We found large numbers of bacteria that oxidize reduced iron at sites with high rates of iron reduction and large numbers of iron reducers. The coexistence of large populations of iron-reducing and iron-oxidizing bacteria is evidence for rapid iron cycling between its reduced and oxidized states and suggests that mutualistic interactions among these bacteria ultimately fuel organic carbon oxidation and inhibit CH4 production in these upland tropical forests. PMID- 20957956 TI - Resprouting as a persistence strategy of tropical forest trees: relations with carbohydrate storage and shade tolerance. AB - Resprouting is an important persistence strategy for woody species and represents a dominant pathway of regeneration in many plant communities, with potentially large consequences for vegetation dynamics, community composition, and species coexistence. Most of our knowledge of resprouting strategies comes from fire prone systems, but this cannot be readily applied to other systems where disturbances are less intense. In this study we evaluated sapling responses to stem snapping for 49 moist-forest species and 36 dry-forest species from two Bolivian tropical forests. To this end we compared in a field experiment the survival and height growth of clipped and control saplings for a two-year period, and related this to the shade tolerance, carbohydrate reserves, and the morphological traits (wood density, leaf size) of the species. Nearly all saplings resprouted readily after stem damage, although dry-forest species realized, on average, a better survival and growth after stem damage compared to moist-forest species. Shade-tolerant species were better at resprouting than light-demanding species in moist forest. This resprouting ability is an important prerequisite for successful regeneration in the shaded understory, where saplings frequently suffer damage from falling debris. Survival after stem damage was, surprisingly, only modestly related to stem reserves, and much more strongly related to wood density, possibly because a high wood density enables plants to resist fungi and pathogens and to reduce stem decay. Correlations between sampling performance and functional traits were similar for the two forest types, and for phylogenetically independent contrasts and for cross-species analyses. The consistency of these results suggests that tropical forest species face similar trade-offs in different sites and converge on similar sets of solutions. A high resprouting ability, as well as investments in stem defense and storage reserves, form part of a suite of co-evolved traits that underlies the growth survival trade-off, and contributes to light gradient partitioning and species coexistence. These links with shade tolerance are important in the moist evergreen forest, which casts a deep, more persistent shade, but tend to diminish in dry deciduous forest where light is a less limiting resource. PMID- 20957957 TI - Induced responses to competition and herbivory: natural selection on multi-trait phenotypic plasticity. AB - Herbivory and competition are two of the most common biotic stressors for plants. When occurring simultaneously, responses to one interaction can constrain the induction of responses to the other interaction due to resource limitation and other interactive effects. Thus, to maximize fitness when interacting with competitors and herbivores, plants are likely to express particular combinations of plastic responses. This study reports the interactive effects of herbivory and competition on responses induced in Tithonia tubaeformis plants and describes how natural selection acts on particular plastic responses and on their different combinations. Competition induced a stem elongation response, expressed through an increase in height and mean internode length, together with a decrease in basal diameter. Interestingly, realized resistance increased in both competition and herbivory treatments, suggesting a plastic response in both constitutive and induced resistance traits. Particular combinations of plastic responses defined three plant phenotypes: vigorous, elongated, and resistant plants. The ecological context in which plants grew modified the traits and the particular combinations of plastic responses that were favored by selection. Vigorous plants were favored by selection in all environments, except when they were damaged by herbivores in the absence of neighbors. The combination of responses defining an elongated plant phenotype was favored by selection in crowded conditions. Resistance was negatively selected in the absence of competition and herbivory but favored in the presence of both interactions. In addition, contextual analyses detected that population structure in heterogeneous environments can also influence the outcomes of selection. These findings suggest that natural selection can act on particular combinations of plastic responses, which may allow plants to adjust their phenotypes to those that promote greater fitness under particular ecological conditions. PMID- 20957958 TI - Flower color influences insect visitation in alpine New Zealand. AB - Despite a long-standing belief that insect pollinators can select for certain flower colors, there are few experimental demonstrations that free-flying insects choose between natural flowers based on color. We investigated responses of insect visitors to experimental manipulations of flower color in the New Zealand alpine. Native syrphid flies (Allograpta and Platycheirus) and solitary bees (Hylaeus and Leioproctus) showed distinct preferences for visiting certain flower species. These responses were determined, in part, by flower color, as insects also responded to experimental manipulations of visible petal color in 7 out of 11 tests with different combinations of flower species and insect type. When preferences were detected, syrphid flies chose yellow over white petals regardless of flower species, whereas Hylaeus chose white over yellow Ourisia glandulosa. In some cases, the strength and direction of color preference depended on the context of other floral traits, in which case the response usually favored the familiar, normal combination of traits. Syrphid flies also visited in response to floral morphological traits but did not show preference based on UV reflectance. The unusually high preponderance of white flowers in the New Zealand alpine is not explained by complete generalization of flower color choice. Instead, the insect visitors show preferences based on color, including colors other than white, along with other floral traits. Furthermore, they can respond in complex ways to combinations of floral cues, suggesting that traits may act in nonadditive ways in determining pollinator visitation. PMID- 20957959 TI - Associations of plant fitness, leaf chemistry, and damage suggest selection mosaic in plant-herbivore interactions. AB - The geographic mosaic theory of coevolution states that variation in species interactions forms the raw material for coevolutionary processes, which take place over large geographic scales. One key assumption underlying the process of coevolution in plant-herbivore interactions is that herbivores exert selection on their host plants and that this selection varies among plant populations. We examined spatial variation in the existence and strength of phenotypic selection on host plant resistance exerted by specialist herbivores in 17 archipelago populations of the perennial herb Vincetoxicum hirundinaria (Asclepiadaceae). In these highly fragmented populations, V. hirundinaria is consumed by the larvae of two specialist herbivores: the folivorous moth Abrostola asclepiadis and the seed predator Euphranta connexa. Selection imposed on host plants by these herbivores was examined by analyzing the associations between levels of herbivory, plant fitness, and contents of a number of leaf chemicals reflecting plant resistance to and quality for the herbivores. We found extensive spatial variation in the levels of herbivory and in plant fitness. More importantly, the impact of both leaf herbivory and seed predation on plant fitness varied among plant populations, indicating spatial variation in phenotypic selection. In addition, leaf chemistry varied widely among plant populations, reflecting spatial variation in plant quality as food for the herbivores. However, leaf compounds influenced folivory similarly in all the studied plant populations, and interestingly, some of the compounds were associated with the intensity of seed predation. Finally, some of the leaf compounds were associated with plant fitness, and the strength and direction of these associations varied among plant populations. The observed spatial variation in the strength of the interactions between V. hirundinaria and its specialist herbivores suggests a geographic selection mosaic. Because the occurrence and strength of spatial variation varied between the two specialist herbivores, our results highlight the importance of considering multiple enemies when trying to understand evolution of interactions between plants and their herbivores. PMID- 20957960 TI - Spatial location dominates over host plant genotype in structuring an herbivore community. AB - Recent work has shown a potential role for both host plant genotype and spatial context in structuring insect communities. In this study, we use three separate data sets on herbivorous insects on oak (Quercus robur) to estimate the relative effects of host plant genotype (G), location (E), and the G x E interaction on herbivore community structure: a common garden experiment replicated at the landscape scale (approximately 5 km2); two common gardens separated at the regional scale (approximately 10 000 km2); and survey data on wild trees in various spatial settings. Our experiments and survey reveal that, at the landscape scale, the insect community is strongly affected by the spatial setting, with 32% of the variation in species richness explained by spatial connectivity. In contrast, G and G x E play minor roles in structuring the insect community. Results remained similar when extending the spatial scale of the study from the more local (landscape) level to the regional level. We conclude that in our study system, spatial processes play a major role in structuring these insect communities at both the landscape and regional scales, whereas host plant genotype seems of secondary importance. PMID- 20957961 TI - The functional response of a hoarding seed predator to mast seeding. AB - Mast seeding involves the episodic and synchronous production of large seed crops by perennial plants. The predator satiation hypothesis proposes that mast seeding maximizes seed escape because seed predators consume a decreasing proportion of available seeds with increasing seed production. However, the seed escape benefits of masting depend not only on whether predators are satiated at high levels of seed production, but also on the shape of their functional response (type II vs. type III), and the actual proportion of available seeds that they consume at different levels of seed production. North American red squirrels (Tamiasciurus hudsonicus) are the primary vertebrate predator of white spruce (Picea glauca) mast seed crops in many boreal regions because they hoard unopened cones in underground locations, preempting the normal sequence of cone opening, seed dispersal, and seed germination. We document the functional response of cone hoarding by red squirrels across three non-mast years and one mast year by estimating the number of cones present in the territories of individual red squirrels and the proportion of these cones that they hoarded each autumn. Even though red squirrels are not constrained by the ingestive and on-body (fat reserves) energy reserve limitations experienced by animals that consume seeds directly, most squirrels hoarded < 10% of the cones present on their territories under mast conditions. Cone availability during non-mast years also reached levels that satiated the hoarding activity of red squirrels; however, this occurred only on the highest-quality territories. Squirrels switched to mushroom hoarding when cone production was low and mushrooms were abundant. This resulted in type III functional response whereby the proportional harvest of cones was highest at levels of cone availability that were intermediate within non-mast years. Overall, more cones escaped squirrel cone-hoarding during a mast event than when cone production was low in non-mast years, which supports the predator satiation hypothesis. However, the highly variable seed escape in non-mast years may help to explain why all spruce cone production is not concentrated into fewer, larger, mast years. PMID- 20957962 TI - Seed dispersal by pulp consumers, not "legitimate" seed dispersers, increases Guettarda viburnoides population growth. AB - We examined the effect of seed dispersal by Purplish Jays (Cyanocorax cyanomelas; pulp consumers) and the Chestnut-eared Aracari (Pteroglossus castanotis; "legitimate" seed dispersers) on population growth of the small tree Guettarda viburnoides (Rubiaceae) in northeastern Bolivian savannas. Because each bird species differs with respect to feeding and post-feeding behavior, we hypothesized that seed dispersal by each species will contribute differently to the rate of increase of G. viburnoides, but that seed dispersal by either species will increase population growth when compared to a scenario with no seed dispersal. To examine the effects of individual dispersers on the future population size of G. viburnoides, we projected population growth rate using demographic models for G. viburnoides that explicitly incorporate data on quantitative and qualitative aspects of seed dispersal by each frugivore species. Our model suggests that seed dispersal by C. cyanomelas leads to positive population growth of G. viburnoides, whereas seed dispersal by P. castanotis has a detrimental effect on the population growth of this species. To our knowledge, this is the first study to report negative effects of a "legitimate" seed disperser on the population dynamics of the plant it consumes. Our results stress the importance of incorporating frugivore effects into population projection matrices, to allow a comprehensive analysis of the effectiveness of different dispersers for plant population dynamics. PMID- 20957963 TI - Comparing ecosystem engineering efficiency of two plant species with contrasting growth strategies. AB - Many ecosystems are greatly affected by ecosystem engineering, such as coastal salt marshes, where macrophytes trap sediment by reducing hydrodynamic energy. Nevertheless, little is known about the costs and benefits that are imposed on engineering species by the traits that underlie their ecosystem engineering capacity. We addressed this topic by comparing ecosystem engineering efficiency defined as the benefit-cost ratio per unit of biomass investment for two species from the intertidal habitat: the stiff grass Spartina anglica and the flexible grass Puccinellia maritima. These species were selected for their ability to modify their habitat by trapping large quantities of sediment despite their contrasting growth form. On a biomass basis, dissipation of hydrodynamic energy from waves (a proxy for benefits associated with ecosystem engineering capability as it relates to the sediment trapping capability) was strikingly similar for both salt marsh species, indicating that both species are equally effective in modifying their habitat. The drag forces per unit biomass (a proxy for costs associated with ecosystem engineering ability as it relates to the requirements on tissue construction and shoot anchoring to prevent breaking and/or washing away) were slightly higher in the species with flexible shoots. As a result, stiff Spartina vegetation had slightly higher ecosystem engineering efficiency, due to lower engineering costs rather than to a higher engineering effect. Thus, Spartina is a slightly more efficient rather than a more effective ecosystem engineer. Ecosystem engineering efficiency was found to be a species-specific characteristic, independent of vegetation density and relatively constant in space. Analyzing ecosystem engineering by quantifying trade-offs offers a useful way toward developing a better understanding of different engineering strategies. PMID- 20957964 TI - Comparative water use of native and invasive plants at multiple scales: a global meta-analysis. AB - Ecohydrology and invasive ecology have become increasingly important in the context of global climate change. This study presents the first in-depth analysis of the water use of invasive and native plants of the same growth form at multiple scales: leaf, plant, and ecosystem. We reanalyzed data for several hundred native and invasive species from over 40 published studies worldwide to glean global trends and to highlight how patterns vary depending on both scale and climate. We analyzed all pairwise combinations of co-occurring native and invasive species for higher comparative resolution of the likelihood of an invasive species using more water than a native species and tested for significance using bootstrap methods. At each scale, we found several-fold differences in water use between specific paired invasive and native species. At the leaf scale, we found a strong tendency for invasive species to have greater stomatal conductance than native species. At the plant scale, however, natives and invasives were equally likely to have the higher sap flow rates. Available data were much fewer for the ecosystem scale; nevertheless, we found that invasive-dominated ecosystems were more likely to have higher sap flow rates per unit ground area than native-dominated ecosystems. Ecosystem-scale evapotranspiration, on the other hand, was equally likely to be greater for systems dominated by invasive and native species of the same growth form. The inherent disconnects in the determination of water use when changing scales from leaf to plant to ecosystem reveal hypotheses for future studies and a critical need for more ecosystem-scale water use measurements in invasive- vs. native dominated systems. The differences in water use of native and invasive species also depended strongly on climate, with the greater water use of invasives enhanced in hotter, wetter climates at the coarser scales. PMID- 20957965 TI - Similar cation exchange capacities among bryophyte species refute a presumed mechanism of peatland acidification. AB - Fen-bog succession is accompanied by strong increases of carbon accumulation rates. We tested the prevailing hypothesis that living Sphagna have extraordinarily high cation exchange capacity (CEC) and therefore acidify their environment by exchanging tissue-bound protons for basic cations in soil water. As Sphagnum invasion in a peatland usually coincides with succession from a brown moss-dominated alkaline fen to an acidic bog, the CEC of Sphagna is widely believed to play an important role in this acidification process. However, Sphagnum CEC has never been compared explicitly to that of a wide range of other bryophyte taxa. Whether high CEC directly leads to the ability to acidify the environment in situ also remains to be tested. We screened 20 predominant subarctic bryophyte species, including fen brown mosses and bog Sphagna for CEC, in situ soil water acidification capacity (AC), and peat acid neutralizing capacity (ANC). All these bryophyte species possessed substantial CEC, which was remarkably similar for brown mosses and Sphagna. This refutes the commonly accepted idea of living Sphagnum CEC being responsible for peatland acidification, as Sphagnum's ecological predecessors, brown mosses, can do the same job. Sphagnum AC was several times higher than that of other bryophytes, suggesting that CE (cation exchange) sites of Sphagna in situ are not saturated with basic cations, probably due to the virtual absence of these cations in the bog water. Together, these results suggest that Sphagna can not realize their CEC in bogs, while fen mosses can do so in fens. The fen peat ANC was 65% higher than bog ANC, indicating that acidity released by brown mosses in the CE process was neutralized, maintaining an alkaline environment. We propose two successional pathways indicating boundaries for a fen-bog shift with respect to bryophyte CEC. In neither of them is Sphagnum CE an important factor. We conclude that living Sphagnum CEC does not play any considerable role in the fen-bog shift. Alternatively, we propose that exclusively indirect effects of Sphagnum expansion such as peat accumulation and subsequent blocking of upward alkaline soil water transport are keys to the fen-bog succession and therefore for bog-associated carbon accumulation. PMID- 20957966 TI - Species dispersal rates alter diversity and ecosystem stability in pond metacommunities. AB - Metacommunity theory suggests that relationships between diversity and ecosystem stability can be determined by the rate of species dispersal among local communities. The predicted relationships, however, may depend upon the relative strength of local environmental processes and disturbance. Here we evaluate the role of dispersal frequency and local predation perturbations in affecting patterns of diversity and stability in pond plankton metacommunities. Pond metacommunities were composed of three mesocosm communities: one of the three communities maintained constant "press" predation from a selective predator, bluegill sunfish (Lepomis macrochirus); the second community maintained "press" conditions without predation; and the third community experienced recurrent "pulsed" predation from bluegill sunfish. The triads of pond communities were connected at either no, low (0.7%/d), or high (20%/d) planktonic dispersal. Richness and composition of zooplankton and stability of plankton biomass and ecosystem productivity were measured at local and regional spatial scales. Dispersal significantly affected diversity such that local and regional biotas at the low dispersal rate maintained the greatest number of species. The unimodal local dispersal-diversity relationship was predator-dependent, however, as selective press predation excluded species regardless of dispersal. Further, there was no effect of dispersal on beta diversity because predation generated local conditions that selected for distinct community assemblages. Spatial and temporal ecosystem stability responded to dispersal frequency but not predation. Low dispersal destabilized the spatial stability of producer biomass but stabilized temporal ecosystem productivity. The results indicate that selective predation can prevent species augmentation from mass effects but has no apparent influence on stability. Dispersal rates, in contrast, can have significant effects on both species diversity and ecosystem stability at multiple spatial scales in metacommunities. PMID- 20957967 TI - Are wolves saving Yellowstone's aspen? A landscape-level test of a behaviorally mediated trophic cascade. AB - Behaviorally mediated trophic cascades (BMTCs) occur when the fear of predation among herbivores enhances plant productivity. Based primarily on systems involving small-bodied predators, BMTCs have been proposed as both strong and ubiquitous in natural ecosystems. Recently, however, synthetic work has suggested that the existence of BMTCs may be mediated by predator hunting mode, whereby passive (sit-and-wait) predators have much stronger effects than active (coursing) predators. One BMTC that has been proposed for a wide-ranging active predator system involves the reintroduction of wolves (Canis lupus) to Yellowstone National Park, USA, which is thought to be leading to a recovery of trembling aspen (Populus tremuloides) by causing elk (Cervus elaphus) to avoid foraging in risky areas. Although this BMTC has been generally accepted and highly popularized, it has never been adequately tested. We assessed whether wolves influence aspen by obtaining detailed demographic data on aspen Stands using tree rings and by monitoring browsing levels in experimental elk exclosures arrayed across a gradient of predation risk for three years. Our study demonstrates that the historical failure of aspen to regenerate varied widely among stands (last recruitment year ranged from 1892 to 1956), and our data do not indicate an abrupt cessation of recruitment. This pattern of recruitment failure appears more consistent with a gradual increase in elk numbers rather than a rapid behavioral shift in elk foraging following wolf extirpation. In addition, our estimates of relative survivorship of young browsable aspen indicate that aspen are not currently recovering in Yellowstone, even in the presence of a large wolf population. Finally, in an experimental test of the BMTC hypothesis we found that the impacts of elk browsing on aspen demography are not diminished in sites where elk are at higher risk of predation by wolves. These findings suggest the need to further evaluate how trophic cascades are mediated by predator-prey life history and ecological context. PMID- 20957968 TI - Adaptive changes in size and age at metamorphosis can qualitatively vary with predator type and available defenses. AB - In many taxa the timing of metamorphosis is plastic in response to predation risk during the pre-metamorphic stage, and trends in both age and body size at metamorphosis have been the subject of much study. The responses to cues of predators are predominantly to be larger or equal-sized at the same age or older at metamorphosis. These observations are in direct contrast with existing theoretical treatments of this plasticity, which mostly predict earlier and smaller metamorphosis and never later and larger metamorphosis without invoking indirect effects on growth rate. Here we resolve the discrepancy between theory and observation using a dynamic state-dependent model that incorporates morphological and behavioral responses to predation risk. We allow prey to choose the optimal activity level and/or investment in defense over the growth period. We show that under certain conditions, metamorphosis at a larger size and later time is likely to be optimal. Our analysis allows us to make testable predictions about the changes in activity level of prey as they grow and how the effect of providing refuges will vary with predator type. Several of these predictions are supported by a meta-analysis of metamorphic responses to caged predators by larval amphibians and insects. Our predictions lead to insights about the feedback effects of antipredator responses on growth and subsequent implications for life history. PMID- 20957969 TI - Spatial heterogeneity in distribution and ecology of Western Palearctic birds. AB - Species vary in abundance and heterogeneity of spatial distribution, and the ecological and evolutionary consequences of such variability are poorly known. Evolutionary adaptation to heterogeneously distributed resources may arise from local adaptation with individuals of such locally adapted populations rarely dispersing long distances and hence having small populations and small overall ranges. We quantified mean population density and spatial heterogeneity in population density of 197 bird species across 12 similarly sized regions in the Western Palearctic. Variance in population density among regions differed significantly from a Poisson distribution, suggesting that random processes cannot explain the observed patterns. National estimates of means and variances in population density were positively correlated with continental estimates, suggesting that means and variances were maintained across spatial scales. We used Morisita's index of population abundance as an estimate of heterogeneity in distribution among regions to test a number of predictions. Heterogeneously distributed passerine bird species as reflected by Morisita's index had small populations, low population densities, and small breeding ranges. Their breeding populations had been consistently maintained at low levels for considerable periods of time, because the degree of genetic variation in a subsample of non passerines and passerines was significantly negatively related to heterogeneity in distribution. Heterogeneously distributed passerine species were not more often habitat specialists than homogeneously distributed species. Furthermore, heterogeneously distributed passerine species had high annual adult survival rates but did not differ in annual fecundity from homogeneously distributed species. Heterogeneously distributed passerine species rarely colonized urban habitats. Finally, homogeneously distributed bird species were hosts to a greater diversity of blood parasite species than heterogeneously distributed species. In conclusion, small breeding ranges, population sizes, and population densities of heterogeneously distributed passerine bird species, combined with their low degree of genetic variability, and their inability to colonize urban areas may render such species particularly susceptible to human-influenced global climatic changes. PMID- 20957970 TI - Phylogeny and metabolic scaling in mammals. AB - The scaling of metabolic rates to body size is widely considered to be of great biological and ecological importance, and much attention has been devoted to determining its theoretical and empirical value. Most debate centers on whether the underlying power law describing metabolic rates is 2/3 (as predicted by scaling of surface area/volume relationships) or 3/4 ("Kleiber's law"). Although recent evidence suggests that empirically derived exponents vary among clades with radically different metabolic strategies, such as ectotherms and endotherms, models, such as the metabolic theory of ecology, depend on the assumption that there is at least a predominant, if not universal, metabolic scaling exponent. Most analyses claimed to support the predictions of general models, however, failed to control for phylogeny. We used phylogenetic generalized least-squares models to estimate allometric slopes for both basal metabolic rate (BMR) and field metabolic rate (FMR) in mammals. Metabolic rate scaling conformed to no single theoretical prediction, but varied significantly among phylogenetic lineages. In some lineages we found a 3/4 exponent, in others a 2/3 exponent, and in yet others exponents differed significantly from both theoretical values. Analysis of the phylogenetic signal in the data indicated that the assumptions of neither species-level analysis nor independent contrasts were met. Analyses that assumed no phylogenetic signal in the data (species-level analysis) or a strong phylogenetic signal (independent contrasts), therefore, returned estimates of allometric slopes that were erroneous in 30% and 50% of cases, respectively. Hence, quantitative estimation of the phylogenetic signal is essential for determining scaling exponents. The lack of evidence for a predominant scaling exponent in these analyses suggests that general models of metabolic scaling, and macro-ecological theories that depend on them, have little explanatory power. PMID- 20957971 TI - Inferential permutation tests for maximum entropy models in ecology. AB - Maximum entropy (maxent) models assign probabilities to states that (1) agree with measured macroscopic constraints on attributes of the states and (2) are otherwise maximally uninformative and are thus as close as possible to a specified prior distribution. Such models have recently become popular in ecology, but classical inferential statistical tests require assumptions of independence during the allocation of entities to states that are rarely fulfilled in ecology. This paper describes a new permutation test for such maxent models that is appropriate for very general prior distributions and for cases in which many states have zero abundance and that can be used to test for conditional relevance of subsets of constraints. Simulations show that the test gives correct probability estimates under the null hypothesis. Power under the alternative hypothesis depends primarily on the number and strength of the constraints and on the number of states in the model; the number of empty states has only a small effect on power. The test is illustrated using two empirical data sets to test the community assembly model of B. Shipley, D. Vile, and E. Garnier and the species abundance distribution models of S. Pueyo, F. He, and T. Zillio. PMID- 20957972 TI - Historical archives. PMID- 20957973 TI - Electrical stimulation and electrode properties. Part 1: clinical electrodes. PMID- 20957974 TI - Brain computer interface (BCI) tools developed in a clinical environment. AB - Brain computer interfaces are devices that collect signals from a subject's cortical surface and interpret these signals to control a computer Recently much development has been done on these devices with the help of epilepsy patients and the clinical staff who treat these patients. The types of data collected from epilepsy patients, particularly the invasive data give a unique opportunity to researchers in this area. The clinical staff has a unique opportunity to use the treatment of one patient population to help another PMID- 20957975 TI - Potential neurological risk during a titanium rib procedure and appropriate intraoperative neurophysiologic monitoring modalities. AB - The titanium rib procedure is a safe and effective way of surgically treating pediatric patients with thoracic insufficiency syndrome and scoliosis. As with any invasive surgical procedure, it is not without risks. This article explains the potential risks to neurological structures while outlining the surgical approach and the neurological anatomy in the vicinity of the implanted instrumentation. The types of potential nerve injury involve ischemia, trauma, compression, and stretch. Furthermore, a suitable compilation of modalities of intraoperative neurophysiologic monitoring is recommended to detect and avoid long-term nerve or spinal cord insult. Monitoring modalities that would be appropriate for this procedure are discussed. PMID- 20957976 TI - Electrical status epilepticus during sleep: a case report and review of the literature. AB - We present the case of a 5-year-old male who other than being six weeks premature at birth had no significant early medical problems, and had normal physical and cognitive development until preschool. It was then that his teacher noticed the child was having learning difficulties, staring spells, and difficulty expressing himself He had a single generalized tonic-clonic seizure (GTCS) in September of 2008. A routine EEG revealed very frequent epileptiform discharges. He was started on levetiracetam and four months later his EEG showed continuous spike wave discharges during sleep. The spike wave discharges occurred in long runs, lasting a minute or more, without clear ictal evolution. The spike wave discharges were seen in a generalized distribution, maximal bifronto-temporally with some asymmetry (right greater than left). When the patient was subsequently awakened, the EEG dramatically improved and the spike wave discharges almost completely resolved. The spike and wave discharges recurred as the patient became drowsy again. Authors have described this as electrographic status during sleep (ESES) which is a typical childhood process of generalization of paroxysmal activity and can be seen with specific childhood epileptic encephalopathies. Treatment with levetiracetam was increased and his EEG and language subsequently returned to normal. PMID- 20957977 TI - Effects of anesthetic regimens and other confounding factors affecting the interpretation of motor evoked potentials during pediatric spine surgery. AB - Children undergoing corrective spine surgery are at risk of serious neurologic injury. Monitoring transcranial electric motor evoked potentials (TCeMEPs) during these procedures may identify and help prevent injury to motor pathways. The difficulty in obtaining consistent motor evoked potential (MEP) responses during pediatric spine surgery can result in part to the suppression of evoked responses caused by volatile inhalational anesthetics, elevated levels of propofol, and/or physiologic variables. Data obtained from 140 pediatric patients who underwent spine surgery with MEP monitoring were retrospectively analyzed and evaluated for age and anesthetic effects on stimulation variables. MEPs acquired under inhalational anesthetic agents required greater stimulation compared to intravenous propofol anesthesia. Additionally, the responses were more variable when inhalational agents were used. These effects were more prominent in younger age patients. The number of alerts of MEP loss or reduction related to anesthetic levels or blood pressure changes was higher under inhalational agents. PMID- 20957978 TI - Neurocysticercosis: fireflies in the central nervous system. PMID- 20957979 TI - Waveform window #18. Troubleshoot this. PMID- 20957980 TI - Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials. AB - Ipilimumab is a fully human, monoclonal antibody that blocks cytotoxic T lymphocyte antigen-4 to potentiate an antitumor T-cell response. This agent improved overall survival in a phase III trial in previously treated patients with advanced melanoma. Because the mechanism of action for ipilimumab is thought to be HLA independent, most trials enrolled patients without regard to HLA subtype. However, enrollment in the phase III trial was restricted to class-I HLA A*0201-positive patients because two of the three arms contained an HLA-A*0201 restricted gp100 vaccine. HLA typing was also performed prospectively in several phase II trials and was available for 93.5% of patients. In this retrospective analysis, pooled efficacy and safety data are presented according to HLA-A*0201 status and dose from pretreated patients randomized to 0.3, 3, or 10 mg/kg ipilimumab in four phase II trials. Median overall survival (OS) was similar for the 187 HLA-A*0201-positive [9.3 months, 95% CI (confidence interval) 7.4-11.5] and 266 HLA-A*0201-negative patients [11.4 months, 95% CI 9.3-15.1] randomized to ipilimumab at all doses across the four phase II trials. These data are comparable to the OS for the 137 HLA-A*0201-positive patients randomized to ipilimumab in the phase III study [10.1 months, 95% CI 8.0-13.8]. Ipilimumab induced adverse events and immune-related adverse events (skin, gastrointestinal, hepatic, other) also occurred at similar frequencies among patients in the phase II and III trials, regardless of HLA-A*0201 status. These findings support the hypothesis that ipilimumab-treated patients with advanced melanoma have similar outcomes regardless of their HLA-A*0201 status. PMID- 20957981 TI - Mass transportation mechanism in electric-biased carbon nanotubes. AB - The mass transportation mechanism in electric-biased carbon nanotubes (CNTs) is investigated experimentally. Except for the widely accepted electromigration mechanism, we find out the thermal effect can also induce the mass transportation in the form of thermomigration or thermal evaporation. Moreover, the convincing in situ transmission electron microscope experiment results show the thermal gradient force overrides the electromigration force in most conditions, according to specific parameters of the CNTs and "cargos". A full analysis on the thermal gradient force and electromigration force imposed on the cargos is given, thus our experimental results are well explained and understood. PMID- 20957982 TI - Extraordinary all-dielectric light enhancement over large volumes. AB - We present resonant dielectric structures exhibiting arbitrarily large optical field enhancement, only limited by fabrication imperfections. Three different arrangements are investigated, based upon dielectric waveguides, dielectric particle arrays, and a combination of these two structures. Experimental confirmation of enhancement in a waveguide resonator is achieved by measuring the luminescence of quantum dots dispersed in the hot optical region of the structure. The performance of these systems can be readily controlled by simply changing geometrical parameters, which allows obtaining remarkable values of the intensity enhancement approaching 105 relative to the incident intensity over large volumes under feasible experimental conditions. This opens new avenues for all-optical switching and biosensing. PMID- 20957983 TI - Single-molecule kinetics and super-resolution microscopy by fluorescence imaging of transient binding on DNA origami. AB - DNA origami is a powerful method for the programmable assembly of nanoscale molecular structures. For applications of these structures as functional biomaterials, the study of reaction kinetics and dynamic processes in real time and with high spatial resolution becomes increasingly important. We present a single-molecule assay for the study of binding and unbinding kinetics on DNA origami. We find that the kinetics of hybridization to single-stranded extensions on DNA origami is similar to isolated substrate-immobilized DNA with a slight position dependence on the origami. On the basis of the knowledge of the kinetics, we exploit reversible specific binding of labeled oligonucleotides to DNA nanostructures for PAINT (points accumulation for imaging in nanoscale topography) imaging with <30 nm resolution. The method is demonstrated for flat monomeric DNA structures as well as multimeric, ribbon-like DNA structures. PMID- 20957984 TI - Time-resolved three-dimensional molecular tracking in live cells. AB - We report a method for tracking individual quantum dot (QD) labeled proteins inside of live cells that uses four overlapping confocal volume elements and active feedback once every 5 ms to follow three-dimensional molecular motion. This method has substantial advantages over three-dimensional molecular tracking methods based upon charge-coupled device cameras, including increased Z-tracking range (10 MUm demonstrated here), substantially lower excitation powers (15 MUW used here), and the ability to perform time-resolved spectroscopy (such as fluorescence lifetime measurements or fluorescence correlation spectroscopy) on the molecules being tracked. In particular, we show for the first time fluorescence photon antibunching of individual QD labeled proteins in live cells and demonstrate the ability to track individual dye-labeled nucleotides (Cy5 dUTP) at biologically relevant transport rates. To demonstrate the power of these methods for exploring the spatiotemporal dynamics of live cells, we follow individual QD-labeled IgE-FcepsilonRI receptors both on and inside rat mast cells. Trajectories of receptors on the plasma membrane reveal three-dimensional, nanoscale features of the cell surface topology. During later stages of the signal transduction cascade, clusters of QD labeled IgE-FcepsilonRI were captured in the act of ligand-mediated endocytosis and tracked during rapid (~950 nm/s) vesicular transit through the cell. PMID- 20957985 TI - Graphene films with large domain size by a two-step chemical vapor deposition process. AB - The fundamental properties of graphene are making it an attractive material for a wide variety of applications. Various techniques have been developed to produce graphene and recently we discovered the synthesis of large area graphene by chemical vapor deposition (CVD) of methane on Cu foils. We also showed that graphene growth on Cu is a surface-mediated process and the films were polycrystalline with domains having an area of tens of square micrometers. In this paper, we report on the effect of growth parameters such as temperature, and methane flow rate and partial pressure on the growth rate, domain size, and surface coverage of graphene as determined by Raman spectroscopy, and transmission and scanning electron microscopy. On the basis of the results, we developed a two-step CVD process to synthesize graphene films with domains having an area of hundreds of square micrometers. Scanning electron microscopy and Raman spectroscopy clearly show an increase in domain size by changing the growth parameters. Transmission electron microscopy further shows that the domains are crystallographically rotated with respect to each other with a range of angles from about 13 to nearly 30 degrees . Electrical transport measurements performed on back-gated FETs show that overall films with larger domains tend to have higher carrier mobility up to about 16,000 cm(2) V(-1) s(-1) at room temperature. PMID- 20957986 TI - Caspase cascade regulated mitochondria mediated apoptosis in monocrotophos exposed PC12 cells. AB - Monocrotophos (MCP) is a commonly used organophosphorus (OP) pesticide. We studied apoptotic changes in PC12 cells exposed to MCP. A significant induction in reactive oxygen species (ROS), lipid peroxide (LPO), and the ratio of glutathione disulfide (GSSG)/reduced glutathione (GSH) was observed in cells exposed to selected doses of MCP. Following the exposure of PC12 cells to MCP, the levels of protein and mRNA expressions of Caspase-3, Caspase-9, Bax, p53, P(21), Puma, and cytochrome-c were significantly upregulated, whereas the levels of Bcl(2), Bcl(w), and Mcl1 were downregulated. TUNEL assay, DNA laddering, and micronuclei induction show that long-term exposure of PC12 cells to MCP at higher concentration (10(-5) M) decreases the number of apoptotic events due to an increase in the number of necrotic cells. MCP-induced translocation of Bax and cytochrome-c proteins between the cytoplasm and mitochondria confirmed the role of p53 and Puma in mitochondrial membrane permeability. Mitochondria mediated apoptosis induction was confirmed by the increased activity of caspase cascade. We believe that this is the first report showing MCP-induced apoptosis in PC12 cells, which is mitochondria mediated and regulated through the caspase cascade. Our data demonstrates that MCP induced the apoptotic cell death in neuronal cells and identifies the possible cellular and molecular mechanisms of organophosphate pesticide-induced apoptosis in neuronal cells. PMID- 20957987 TI - "Drawing with nanotubes": creating nanowires with complex geometries by pulsed electrodeposition on self-organized carbon nanotube patterns. AB - We present a new approach for the creation of nanowires with well-defined complex geometries by electrodeposition onto self-organized single-walled carbon nanotubes. The concept is demonstrated by generation of continuous Au nanowires with various geometries, including parallel arrays, serpentines, and coils. The generality of this approach is further illustrated by synthesizing Bi(2)Te(3) nanowires. Our concept of "drawing with nanotubes" offers to combine different material properties with complex geometries on the route to new functional nanosystems. PMID- 20957988 TI - Biotinylated analogue of the spin-trap 5,5-dimethyl-1-pyrroline-N-oxide for the detection of low-abundance protein radicals by mass spectrometry. AB - Protein radicals are implicated in oxidative stress and are associated with a wide range of diseases and disorders. In the present work, we describe the specific application of a newly synthesized nitrone spin trap, Bio-SS-DMPO, for the detection of these highly reactive species by mass spectrometry (MS). Bio-SS DMPO is a biotinylated analogue of the spin-trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) that allows for specific capture of the protein(s)/peptide(s) labeled by the spin-trap on a (strept)avidin-bound solid matrix. The disulfide bond in the linker arm joining biotin to DMPO can be cleaved to release captured spin-adduct peptide from the solid matrix. This (strept)avidin-based affinity purification reduces the complexity of the samples prior to MS analyses, thereby facilitating the location of the sites of spin trap addition. In addition, the biotin moiety on the spin-trap can efficiently be probed with (strept)avidin-conjugated reporter. This offers an effective means to visualize the presence of DMPO adducted proteins in intact cells. PMID- 20957989 TI - Biochemical filter with sigmoidal response: increasing the complexity of biomolecular logic. AB - The first realization of a designed, rather than natural, biochemical filter process is reported and analyzed as a promising network component for increasing the complexity of biomolecular logic systems. Key challenge in biochemical logic research has been achieving scalability for complex network designs. Various logic gates have been realized, but a "toolbox" of analog elements for interconnectivity and signal processing has remained elusive. Filters are important as network elements that allow control of noise in signal transmission and conversion. We report a versatile biochemical filtering mechanism designed to have sigmoidal response in combination with signal-conversion process. Horseradish peroxidase-catalyzed oxidation of chromogenic electron donor by H(2)O(2) was altered by adding ascorbate, allowing to selectively suppress the output signal, modifying the response from convex to sigmoidal. A kinetic model was developed for evaluation of the quality of filtering. The results offer improved capabilities for design of scalable biomolecular information processing systems. PMID- 20957990 TI - Isomorphous substitutions of rare earth elements for calcium in synthetic hydroxyapatites. AB - Polycrystalline hydroxyapatites Ca(10-x)REE(x)(PO(4))(6)(OH)(2-x)O(x) were synthesized and studied by X-ray powder diffraction, infrared absorption, diffuse reflectance spectroscopy, and thermogravimetry. The solubility limits x(max) of rare earth elements (REE) in Ca hydroxyapatites decreases with an increasing REE atomic number from x(max) = 2.00 for La, Pr, and Nd to x(max) = 0.20 for Yb at 1100 degrees C. Refinements of X-ray diffraction patterns by the Rietveld method show that REE atoms substitute for Ca preferentially at the Ca(2) sites of the apatite structure. The substitution decreases the Ca(2)-O(4) atomic distances in the calcium coordination polyhedra and increases the Ca(2)-O(1,2,3) distances. This observation shows that interatomic distances depend not only on radii of the ions involved in the substitution but also on their charges. PMID- 20957992 TI - Ru9Zn7Sb8: a structure with a 2 * 2 * 2 supercell of the half-Heusler phase. AB - The title compound Ru(9)Zn(7)Sb(8) was synthesized via a high-temperature reaction from the elements in a stoichiometric ratio, and its structure was solved by a single-crystal X-ray diffraction method. The structure [cubic, space group Fm3m, Pearson symbol cF96, a = 11.9062(14) A (293 K), and Z = 4] adopts a unique 2a(hh) * 2a(hh) * 2a(hh) supercell of a normal half-Heusler phase and shows abnormal features of atomic coordination against the Pauling rule. The formation of this superstructure was discussed in light of the valence electron concentration per unit cell. It is a metallic conductor [rho(300 K) = 16 MUOmega.m], and differential scanning calorimetry revealed that Ru(9)Zn(7)Sb(8) undergoes a transformation at 1356(1) K and melts, by all indications, congruently at 1386 K. At room temperature, its thermal conductivity is about 3 W/m.K, which is only one-quarter of that of most normal half-Heusler phases. Ru(9)Zn(7)Sb(8) as well as its analogues of iron-, cobalt-, rhodium-, and iridium containing compounds are expected to serve as a new structure type for exploring new thermoelectric materials. PMID- 20957993 TI - Vibronic coupling in J-aggregates and beyond: a direct means of determining the exciton coherence length from the photoluminescence spectrum. AB - Exciton coherence in a J-aggregate with exciton-phonon coupling involving a single intramolecular vibration is studied. For linear aggregates with no disorder and periodic boundary conditions, the 0-0 to 0-1 line strength ratio, S(R), corresponding to the low-temperature photoluminescence spectrum is rigorously equal to N/lambda2, where N is the number of chromophores comprising the aggregate and lambda2 is the Huang-Rhys factor of the coupled vibrational mode. The result is independent of exciton bandwidth and therefore remains exact from the weak to strong exciton-phonon coupling regimes. The simple relation between S(R) and N also holds for more complex morphologies, as long as the transition from the lowest exciton state to the vibrationless ground state is symmetry-allowed. For example, in herringbone aggregates with monoclinic unit cells, the line strength ratio, defined as SR = I(b)(0-0)/I(b)(0-1) (where I(b)(0 0) and I(b)(0-1) correspond to the b-polarized 0-0 and 0-1 line strengths, respectively) is rigorously equal to N/lambda2. In the presence of disorder and for T > 0 K, lambda2S(R) is closely approximated by the exciton coherence number N(coh), thereby providing a simple and direct way of extracting N(coh) from the photoluminescence spectrum. Increasing temperature in linear J-aggregates (and herringbone aggregates) generally leads to a demise in S(R) and therefore also the exciton coherence size. When no disorder is present, and under the fast scattering and thermodynamic limits, S(R) is equal to N(T)/lambda2, where the thermal coherence size is given by N(T) = 1 + [4piomega(c)/k(b)T](d/2) for an aggregate of dimension d, where omega(c) is the exciton band curvature at k = 0. PMID- 20957994 TI - Laser printing single gold nanoparticles. AB - Current colloidal synthesis is able to produce an extensive spectrum of nanoparticles with unique optoelectronic, magnetic, and catalytic properties. In order to exploit them in nanoscale devices, flexible methods are needed for the controlled integration of nanoparticles on surfaces with few-nanometer precision. Current technologies usually involve a combination of molecular self-assembly with surface patterning by diverse lithographic methods like UV, dip-pen, or microcontact printing.(1,2) Here we demonstrate the direct laser printing of individual colloidal nanoparticles by using optical forces for positioning and the van der Waals attraction for binding them to the substrate. As a proof-of concept, we print single spherical gold nanoparticles with a positioning precision of 50 nm. By analyzing the printing mechanism, we identify the key physical parameters controlling the method, which has the potential for the production of nanoscale devices and circuits with distinct nanoparticles. PMID- 20957995 TI - Lactoferrin-conjugated biodegradable polymersome holding doxorubicin and tetrandrine for chemotherapy of glioma rats. AB - The blood-brain barrier (BBB) and multidrug resistance (MDR) are the main causes for poor prognosis of glioma patients after chemotherapy. To explore the way for settling this problem, in this study, a novel antitumor agent loaded drug delivery system, lactoferrin-conjugated biodegradable polymersome holding doxorubicin and tetrandrine (Lf-PO-Dox/Tet), integrating both BBB and glioma targeting moiety and MDR inhibitor, was designed and its chemotherapy for glioma rats was evaluated. Biodegradable polymersome (PO) encapsulating both doxorubicin (Dox) and tetrandrine (Tet) was prepared by the thin-film hydration method (PO Dox/Tet) and then conjugated with lactoferrin (Lf) to yield Lf-PO-Dox/Tet with an average diameter around 220 nm and surface Lf molecule number per polymersome around 40. Compared with PO-DOX, PO-Dox/Tet, and Lf-PO-Dox, Lf-PO-Dox/Tet demonstrated the strongest cytotoxicity against C6 glioma cells and the greatest uptake index by C6 cells. In vivo imaging analysis indicated that Lf-PO labeled with a near-infrared dye could enter the brain and accumulate at the tumor site. Pharmacokinetics and tissue distribution results also showed that Lf-PO-Dox/Tet accumulated more in the right hemisphere than other groups of polymersomes. Pharmacodynamics results revealed that tumor volume of the Lf-PO-Dox/Tet group was significantly smaller than that of other therapeutic groups, and the median survival time of Lf-PO-Dox/Tet group was longer than that of Lf-PO-Dox group and significantly longer than those of the other three therapeutic groups. These results suggested that Lf-PO-Dox/Tet could have therapeutic potential for gliomas. PMID- 20957996 TI - Pulsed ultrasound enhances nanoparticle penetration into breast cancer spheroids. AB - Effective treatment of solid tumors requires homogeneous distribution of anticancer drugs within the entire tumor volume to deliver lethal concentrations to resistant cancer cells and tumor-initiating cancer stem cells. However, penetration of small molecular weight chemotherapeutic agents and drug-loaded polymeric and lipid particles into the hypoxic and necrotic regions of solid tumors remains a significant challenge. This article reports the results of pulsed ultrasound enhanced penetration of nanosized fluorescent particles into MCF-7 breast cancer spheroids (300-350 MUm diameter) as a function of particle size and charge. With pulsed ultrasound application in the presence of microbubbles, small (20 nm) particles achieve 6-20-fold higher penetration and concentration in the spheroid's core compared to those not exposed to ultrasound. Increase in particle size to 40 and 100 nm results in their effective penetration into the spheroid's core to 9- and 3-fold, respectively. In addition, anionic carboxylate particles achieved higher penetration (2.3-, 3.7-, and 4.7-fold) into the core of MCF-7 breast cancer spheroids compared to neutral (2.2-, 1.9-, and 2.4-fold) and cationic particles (1.5-, 1.4-, and 1.9-fold) upon US exposure for 30, 60, and 90 s under the same experimental conditions. These results demonstrate the feasibility of utilizing pulsed ultrasound to increase the penetration of nanosized particles into MCF-7 spheroids mimicking tumor tissue. The effects of particle properties on the penetration enhancement were also illustrated. PMID- 20957998 TI - Heterogeneous components of chitosans. AB - The main objectives of the research were to compare the components of partially N deacetylated chitins prepared identically from native chitin and a chitin regenerated from a heavily deacetylated chitosan. Additionally, to determine if any of the water-soluble components would serve as substrates in a study of a Chitinase isolated from soy bean hull. The brief heating of suspended chitins in 20% (w/w) NaOH resulted in similar degrees of N-deacetylation, the native chitin giving DAc 0.84 and the regenerated chitin DAc 0.79-0.72, with DAc indicating the proportion of glucosamine residues that are acetylated. Evidence for the nature of the hydrolysis of acetamido groups was provided by analyses of the water soluble and -insoluble Smith degradation products. The water-soluble fraction derived from the native chitin comprised very small amounts of erythrityl N acetyl glucosaminoside (GlcNAc1E), erythrityl N,N'-diacetyl chitobioside (GlcNAc2E), and erythrityl N,N',N''-triacetyl chitotrioside (GlcNAc3E), each identified by MALDI-TOF mass spectrometry of the butanoyl derivative. The water insoluble products, as analyzed by light scattering detection method of their butanoyl esters and corrected for their composition, had a molecular weight (Mw) of 25 kDa, corresponding to about 120 N-acetyl glucosaminyl repeating residues (DPw), contrasting to that of 140 kDa with DPw of 680 for the parent chitin. Much of the decrease in the molecular weight of the polymer occurs by the loss of sugar residues by alkaline peeling at reducing terminals. For the regenerated chitin (DAc 1.0), prepared by N-reacetylation of a commercial chitosan (DAc 0.15), the resulting Smith products comprised erythritol and a series of N-acetyl glucosaminyl erythritol homologues of up to at least 39 N-acetyl glucosaminyl repeating residues, reflecting greater heterogeneity in the hydrolysis of acetamido groups along the polymer chain than what was seen for the native chitin. Of the water-soluble Smith products, GlcNAc5-7E were good substrates for chitinase isolated from soybean hull. PMID- 20957997 TI - Doxorubicin as a molecular nanotheranostic agent: effect of doxorubicin encapsulation in micelles or nanoemulsions on the ultrasound-mediated intracellular delivery and nuclear trafficking. AB - Doxorubicin (DOX) is one of the most commonly used chemotherapeutic drugs and is a popular research tool due to the inherent fluorescence of the DOX molecule. After DOX injection, fluorescence imaging of organs or cells can provide information on drug biodistribution. Therapeutic and imaging capabilities combined in a DOX molecule make it an excellent theranostic agent. However, DOX fluorescence depends on a number of factors that should be taken into consideration when interpreting results of DOX fluorescence measurements. Discussing these problems is the main thrust of the current paper. The sensitivity of DOX fluorescence intensity to DOX concentration, local microenvironment, and interaction with model cellular components is illustrated by fluorescence spectra of paired DOX/phospholipid, DOX/histone, DOX/DNA, and triple DOX/histone/DNA and DOX/phospholipid/DNA systems. DOX fluorescence is dramatically quenched upon intercalation into the DNA; DOX fluorescence is also self-quenched at high concentrations of molecularly dissolved DOX; in contrast, DOX fluorescence is increased after binding to the histone or partitioning into the phospholipid phase of PEG-phospholipid micelles or hydrophobic cores of polymeric micelles. While flow cytometry is commonly used for characterization of DOX intracellular uptake, the above aspects of DOX fluorescence may significantly complicate interpretation of flow cytometry results. High cell fluorescence measured by flow cytometry may provide deceptive information on the actual intracellular DOX concentration and may not correlate with the therapeutic efficacy if DOX does not penetrate into the site of action in cell nuclei. These problems are illustrated in the experiments on the intracellular trafficking of DOX encapsulated in poly(ethylene glycol)-co-polycaprolactone (PEG-PCL) micelles or PEG-PCL stabilized perfluorocarbon nanodroplets, with and without the application of ultrasound used as an external trigger. For efficient encapsulation in micelle cores, DOX is usually deprotonated, which removes the positive charge and enhances hydrophobicity of DOX molecule. It was found that the deprotonated DOX accumulated in the cell cytoplasm but did not penetrate into the cell nuclei. The same was true for the DOX encapsulated in micelles or nanodroplets, which may explain their low therapeutic efficacy in the absence of ultrasound. Ultrasound triggers DOX trafficking into the cell nuclei, which is especially pronounced in the presence of nanoemulsions that convert into microbubbles under the ultrasound action. Microbubble cavitation results in the transient permeabilization of both plasma and nuclear membranes, thus allowing DOX penetration into the cell nuclei, which dramatically enhances therapeutic efficacy of DOX-loaded nanodroplet systems. PMID- 20957999 TI - Phosphoramidate end labeling of inorganic polyphosphates: facile manipulation of polyphosphate for investigating and modulating its biological activities. AB - Polyphosphates, linear polymers of inorganic phosphates linked by phosphoanhydride bonds, are widely present among organisms and play diverse roles in biology, including functioning as potent natural modulators of the human blood clotting system. However, studies of protein-polyphosphate interactions are hampered by a dearth of methods for derivatizing polyphosphate or immobilizing it onto solid supports. We now report that EDAC (1-ethyl-3-[3 (dimethylamino)propyl]carbodiimide) efficiently promotes the covalent attachment of a variety of primary amine-containing labels and probes to the terminal phosphates of polyphosphates via stable phosphoramidate linkages. Using (31)P NMR, we confirmed that EDAC-mediated reactions between primary amines and polyphosphate result in phosphoramidate linkages with the terminal phosphate groups. We show that polyphosphate can be biotinylated, labeled with fluorophores, and immobilized onto solid supports, that immobilized polyphosphate can be readily used to quantify protein binding affinities, that covalently derivatized or immobilized polyphosphate retains its ability to trigger blood clotting, and that derivatizing the ends of polyphosphate with spermidine protects it from exopolyphosphatase degradation. Our findings open up essentially the entire armamentarium of protein chemistry to modifying polyphosphate, which should greatly facilitate studies of its biological roles. PMID- 20958000 TI - Supramolecular hydrogels from cisplatin-loaded block copolymer nanoparticles and alpha-cyclodextrins with a stepwise delivery property. AB - A stepwise anticancer drug delivery system based on an injectable supramolecular hydrogel was presented. In this system, poly(ethylene glycol)-b-poly(acrylic acid) (PEG-b-PAA) block copolymer nanoparticles containing cisplatin were released by erosion of the hydrogels and then the cisplatin was released from the nanoparticles by exchanging with chloride ions. By mixing alpha-cyclodextrins (alpha-CDs) and the PEG-b-PAA micelles with their PAA cores loaded with the cisplatin in water, the novel supramolecular hydrogels were generated by threading alpha-CDs onto the PEG segments and forming physical cross-links of molecular necklaces. The gelation properties could be tuned by changing concentrations of the polymers and cisplatin, their feeds, and by adding PEG homopolymers or Pluronic copolymers as additives. Structures and properties of the supramolecular hydrogels containing cisplatin were studied by wide-angle X ray diffraction (XRD) and rheology measurements, respectively. The thixotropic effect of the hydrogels and their reversible sol-gel transition were confirmed. In vitro hydrogel erosion experiments were conducted and cisplatin release in saline and pure water was quantified. Hydrogel erosion produced discrete nanoparticles from which cisplatin was released completely in saline. In contrast, the hydrogels were eroded into nanoparticles in pure water, but no cisplatin could be released. In vitro cytotoxicity studies showed that the cisplatin-loaded hydrogels inhibited the growth of human bladder carcinoma EJ cells with a similar potency as that of the free cisplatin, whereas the hydrogels without cisplatin showed no cytotoxicity. These results suggested that the cisplatin-coordinated PEG-b-PAA/alpha-CD supramolecular hydrogels hold great potential as an injectable system for sustained delivery of cisplatin in cancer therapy. PMID- 20958001 TI - Time evolution of the aggregation process of peptides involved in neurodegenerative diseases and preventing aggregation effect of phosphorus dendrimers studied by EPR. AB - A key pathological event of prion and Alzheimer diseases is the formation of prion and amyloid plaques generated by peptide aggregation in the form of fibrils. Dendrimers have revealed their ability to prevent fibril formation and therefore cure neurodegenerative diseases. To provide information about the kinetics and the mechanism of peptide fibril formation and about the ability of the dendrimers to prevent peptide aggregation, we performed a computer-aided EPR analysis of the selected nitroxide spin probe 4-octyl-dimethylammonium,2,2,6,6 tetramethyl-piperidine-1-oxyl bromide (CAT8) in water solutions of the beta amyloid peptide Abeta 1-28 and the prion peptide PrP 185-208, which contain the fibril nucleation sites, in the absence and in the presence of phosphorus dendrimers. After a careful selection of the experimental conditions that allow aggregation to occur and to be monitored by EPR analysis over time, it was found that the Abeta 1-28 fibrils formed in 220 min at 0.5 mM peptide, 0.05 mM CAT8, 0.04 mg/mL heparin, and pH = 5. As a consequence, the interacting sites available for cooperative interactions with CAT8 were engaged in the peptide-peptide interactions and a fraction of the probe was extracted in the fluid fibril/water interphase, while another fraction was trapped at the peptide/peptide interphase, showing a decrease in mobility. Conversely, in the presence of the dendrimer (at the selected, after several trials, peptide/dendrimer molar ratio = 50), due to dipole-dipole interactions with peptide monomers, the probe remained at the dendrimer/peptide interphase and the spectral parameters negligibly changed over time. A fraction of probes inserted in PrP 185-208 low-packed aggregates and monitored their fast formation after 90 min. However, the binding organization of the prion peptide negligibly changed upon aggregation in comparison to Abeta 1 28. It is proposed that dendrimers mainly interfere in the lag (nucleation) phase of the prion peptide. PMID- 20958002 TI - Ultrahigh resolution mass spectrometry and indicator species analysis to identify marker components of soil- and plant biomass- derived organic matter fractions. AB - The chemical properties of organic matter affect important soil processes such as speciation, solubilization, and transport of plant nutrients and metals. This work uses ultrahigh resolution electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry to determine the molecular composition of three organic matter fractions of soils and aqueous extracts of crop biomass. Comparison of the van Krevelen plots allowed tracking the changes in organic matter with increasing humification. Aqueous plant biomass extracts contain a diverse mixture of lipids, proteins, and lignins. Soil aqueous extracts were marked by increases in lignin and carbohydrate components and decrease in the protein component as compared to the plant extract. Refractory humic acid fractions were marked by decrease in the lignin component and increases in the lipid and condensed aromatic components. The multivariate indicator species analysis was used to identify marker components of the four organic matter types investigated. The plant extract group had 772 marker components compared to 237 for soil aqueous extract, 92 for mobile humic acid, and 418 for calcium humic acid. This study demonstrates that ultrahigh resolution mass spectrometry and multivariate methods can be used to identify marker components to gain a molecular-scale description and understanding of C dynamics. PMID- 20958003 TI - Prediction of aqueous solubility, vapor pressure and critical micelle concentration for aquatic partitioning of perfluorinated chemicals. AB - The majority of perfluorinated chemicals (PFCs) are of increasing risk to biota and environment due to their physicochemical stability, wide transport in the environment and difficulty in biodegradation. It is necessary to identify and prioritize these harmful PFCs and to characterize their physicochemical properties that govern the solubility, distribution and fate of these chemicals in an aquatic ecosystem. Therefore, available experimental data (10-35 compounds) of three important properties: aqueous solubility (AqS), vapor pressure (VP) and critical micelle concentration (CMC) on per- and polyfluorinated compounds were collected for quantitative structure-property relationship (QSPR) modeling. Simple and robust models based on theoretical molecular descriptors were developed and externally validated for predictivity. Model predictions on selected PFCs were compared with available experimental data and other published in silico predictions. The structural applicability domains (AD) of the models were verified on a bigger data set of 221 compounds. The predicted properties of the chemicals that are within the AD, are reliable, and they help to reduce the wide data gap that exists. Moreover, the predictions of AqS, VP, and CMC of most common PFCs were evaluated to understand the aquatic partitioning and to derive a relation with the available experimental data of bioconcentration factor (BCF). PMID- 20958004 TI - A series of Cu(II)-azide polymers of Cu6 building units and the role of chelating diamine in controlling their dimensionality: synthesis, structures, and magnetic behavior. AB - Four new neutral copper-azido polymers [Cu(6)(N(3))(12)(aem)(2)](n)(1), [Cu(6)(N(3))(12)(dmeen)(2)(H(2)O)(2)](n) (2), [Cu(6)(N(3))(12)(N,N'-dmen)(2)](n) (3), and [Cu(6)(N(3))(12)(hmpz)(2)](n) (4) [aem = 4-(2-aminoethyl)morpholine; dmeen = N,N-dimethyl-N'-ethylethylenediamine; N,N'-dmen = N,N' dimethylethylenediamine and hmpz = homopiperazine] have been synthesized by using 0.33 mol equiv of the chelating diamine ligands with Cu(NO(3))(2).3H(2)O/CuCl(2).2H(2)O and an excess of NaN(3). Single crystal X-ray structures show that the basic unit of these complexes, especially 1-3, contains very similar Cu(II)(6) building blocks. But the overall structures of these complexes vary widely in dimensionality. While 1 is three-dimensional (3D) in nature, 2 and 3 have a two-dimensional (2D) arrangement (with different connectivity) and 4 has a one-dimensional (1D) structure. Cryomagnetic susceptibility measurements over a wide range of temperature exhibit dominant ferromagnetic behavior in all the four complexes. The experimental susceptibility data have been analyzed by some theoretical model equations. PMID- 20958005 TI - EXAFS studies on the reaction of gold (III) chloride complex ions with sodium hydroxide and glucose. AB - EXAFS and QEXAFS experiments were carried out at Hasylab laboratory in DESY center (X1 beamline, Hamburg, Germany) to monitor the course of the hydrolysis reactions of [AuCl(4)](-) complex ions as well as their reduction using glucose. As a result, changes in the spectra of [AuCl(4)](-) ions and disappearance of absorption Au-L(3) edge were registered. From the results of the experiments we have carried out, the changes in bond lengths between Au(3+) central ion and Cl( ) ligands as well as the reduction of Au(3+) to metallic form (colloidal gold was formed in the system) are evident. Good quality spectra obtained before and after the reactions gave a chance to determine the bond length characteristic of Au-Cl, Au-OH and Au-Au pairs. Additionally, the obtained results were compared with the simulated spectra of different gold (III) complex ions, possibly present in the solution. Finally, the mechanism of these reactions was suggested. Unfortunately, it was not possible to detect the changes in the structure of gold (III) complex ions within the time of reaction, because of too high rates of both processes (hydrolysis and reduction) as compared with the detection time. PMID- 20958006 TI - Dissociation and multiply charged silicon ejection in high abundance from hexamethyldisilane. AB - Quadruply charged, neon-like silicon and helium-like carbon were generated by the exposure of hexamethyldisilane to intense femtosecond laser pulses. Dissociation of the silicon-silicon bond, the formation of highly charged silicons, as well as the saturation intensity of their formation were studied by mass spectroscopy. The production of these ions in high abundance, but also with lower laser intensity than theoretically expected for the element, was accomplished by using organosilicon compounds. Multiply charged silicon was generated at low laser intensity because stripping electrons from organosilicon compounds is much easier than from pure silicon due to the loose binding of electrons belonging to molecular orbitals. Femtosecond laser ionization is a valuable methodology for producing highly charged ions in high abundance and is useful in many fields of interest. PMID- 20958007 TI - Long-range migration of a water molecule to catalyze a tautomerization in photoionization of the hydrated formamide cluster. AB - The dynamics on the vacuum-ultraviolet one-photon ionization of a formamide-water cluster is investigated by a combination of theoretical reaction-path search and infrared spectroscopic methods. A keto-enol tautomerization of the formamide moiety occurs after photoionization by a catalytic action of the water molecule accompanied with its long-distance migration; the water molecule in the cluster migrates almost one turn around the formamide moiety. During the migration, the water molecule abstracts the proton of CH in the formamide moiety and carries it to the O atom side in the carbonyl group through a "catch and release"-type catalytic action. PMID- 20958008 TI - Chiroptical study of alpha-aliphatic amino acid films in the vacuum ultraviolet region. AB - A series of natural circular dichroism (CD) and absorption spectra for films of alpha-aliphatic amino acids--such as alanine, aminobutyric acid, norvaline, norleucine, valine, leucine, and isoleucine--in the vacuum ultraviolet (VUV) region were observed with the absolute values of optical constants at the undulator-based CD beamline TERAS BL5. Preliminary predictions of some CD spectra were also performed, based on quantum-chemical calculations using the crystal structure. Although the absorption spectra show similar features to each other, significant differences between the CD spectra were found, especially in the 7-8 eV region. The CD spectra of aliphatic amino acids with branched alkyl groups in the side-chain--such as valine, leucine, and isoleucine--exhibit strong negative CD peaks in this energy region. In contrast, the corresponding CD peaks were weak or absent in the spectra of amino acids with straight alkyl groups. Our simple calculation, and the absorption spectra of alkanes, suggest that this difference partly originates from the contribution of the alkyl group. Clear discrepancies between the CD spectra of these amino acids in solutions and those in the solid state were also observed; this is probably caused by the different molecular structures in each state. Our results clearly indicated that CD spectra in the VUV region were very sensitive to the conformations of chiral molecules. PMID- 20958009 TI - Structural, electronic, and vibrational properties of amino-adamantane and rimantadine isomers. AB - We performed a first principles total energy investigation on the structural, electronic, and vibrational properties of adamantane molecules, functionalized with amine and ethanamine groups. We computed the vibrational signatures of amantadine and rimantadine isomers with the functional groups bonded to different carbon sites. By comparing our results with recent infrared and Raman spectroscopic data, we discuss the possible presence of different isomers in experimental samples. PMID- 20958010 TI - Excess electron and lithium atom solvation in water clusters at finite temperature: an ab initio molecular dynamics study of the structural, spectral, and dynamical behavior of (H2O)6- and Li(H2O)6. AB - The roles of hydrogen bonds in the solvation of an excess electron and a lithium atom in water hexamer cluster at 150 K have been studied by means of ab initio molecular dynamics simulations. It is found that the hydrogen bonded structures of (H(2)O)(6)(-) and Li(H(2)O)(6) clusters are very different from each other and they dynamically evolve from one conformer to other along their simulation trajectories. The populations of the single acceptor, double acceptor, and free type water molecules are found to be significantly high unlike that in pure water clusters. Free hydrogens of these type of water molecules primarily capture the unbound electron density in these clusters. It is found that the binding motifs of the free electron evolve with time and the vertical detachment energy of (H(2)O)(6)(-) and vertical ionization energy of Li(H(2)O)(6) also change with time. Assignments of the observed peaks in vibrational power spectra are done, and we found direct correlations between the time-averaged population of water molecules in different hydrogen bonding states and the spectral features. The dynamical aspects of these clusters have also been studied through calculations of time correlations of instantaneous stretch frequencies of OH modes which are obtained from the simulation trajectories through a time series analysis. PMID- 20958011 TI - A new mechanism of atomic manipulation: bond-selective molecular dissociation via thermally activated electron attachment. AB - We report a new mechanism of (bond-selective) atomic manipulation in the scanning tunneling microscope (STM). We demonstrate a channel for one-electron-induced C Cl bond dissociation in chlorobenzene molecules chemisorbed on the Si(111)-7 * 7 surface, at room temperature and above, which is thermally activated. We find an Arrhenius thermal energy barrier to one-electron dissociation of 0.8 +/- 0.2 eV, which we correlate explicitly with the barrier between chemisorbed and physisorbed precursor states of the molecule. Thermal excitation promotes the target molecule from a state where one-electron dissociation is suppressed to a transient state where efficient one-electron dissociation, analogous to the gas phase negative-ion resonance process, occurs. We expect the mechanism will be obtained in many surface systems, and not just in STM manipulation, but in photon and electron beam stimulated (selective) chemistry. PMID- 20958012 TI - Resist free patterning of nonpreferential buffer layers for block copolymer lithography. AB - We report the design of a direct electron beam patternable buffer layer to spatially control the orientation of the microdomains in an overlaying polystyrene-block-poly(methyl methacrylate) (PS-b-PMMA) block copolymer (BCP) film. The buffer layer consists of a surface anchored low molecular weight PS-b PMMA, with the PMMA segment anchored to the surface and a short PS block at the buffer layer/BCP interface. The block architecture of the buffer layer combines the essential features of "bottom up" and "top down" approaches as it functions as a nonpreferential layer to dictate perpendicular orientation of BCP domains from the substrate interface and as an e-beam resist to allow top-down lithographic process to spatially define the buffer layer on the substrate. The composition of the buffer layer can be tuned by changing the relative block lengths to create a nonpreferential surface which effectively induces perpendicular orientation of domains in an overlying BCP film. The grafted block copolymer can be locally shaved by e-beam lithography resulting in spatial control of domain orientation in the BCP film. The direct patterning approach reduces the number of steps involved in forming chemical patterns by conventional lithography. PMID- 20958014 TI - Triterpenes from Garcia parviflora. Cytotoxic evaluation of natural and semisynthetic friedelanes. AB - Three new friedelane-type triterpenes, 1,2-dehydro-2,3-secofriedelan-3-oic acid (1), 1beta-hydroxyfriedelin (2), and 3beta-hydroxyfriedelan-23-oic acid (3), and the known compounds friedelin-3,4-lactone (4), acetyl aleuritolic acid (5), 4 hydroxy-5-propionyl-1,3-di-O-methylpyrogallol, elemicin, and (-)-syringaresinol were isolated from the leaves of Garcia parviflora. The structures of 1-3 were elucidated by spectroscopic methods, including 1D and 2D NMR, HREIMS, X-ray, and CD analysis. Some derivatives of 2 (6-14) were prepared via oxidation, reduction, and esterification. The natural triterpenes and the semisynthetic friedelane derivatives were tested for cytotoxic activity against human cancer cell lines U251, PC-3, K562, HCT-15, MCF-7, and SKLU-1. Compound 5 was cytotoxic against U251 cells. PMID- 20958015 TI - High-performance field effect transistors from solution processed carbon nanotubes. AB - Nanoelectronic field effect transistors (FETs) are produced using solution processed individual carbon nanotubes (CNTs), synthesized by both arc discharge and laser ablation methods. We show that the performance of solution processed FETs approaches that of CVD-grown FETs if the nanotubes have minimal lattice defects and are free from surface contamination. This is achieved by treating the nanotubes to a high-temperature vacuum annealing process and using 1,2 dichloroethane for dispersion. We present CNT FETs with mobilities of up to 3546 cm(2)/(V s), transconductance of 4.22 MUS, on-state conductance of 9.35 MUS and on/off ratios as high as 10(6). High-resolution transmission electron microscopy is used to examine the presence of catalyst particles and amorphous carbon on the surface and Raman spectroscopy is used to examine the lattice defects, both of which lead to reduced device performance. PMID- 20958016 TI - Confined polymer dynamics on clay platelets. AB - The structure and dynamics of poly(ethylene oxide) adsorbed on dispersed clay platelets are investigated by small-angle neutron scattering and neutron spin echo spectroscopy. The intermediate scattering function has a mobile contribution described by the Zimm theory and an immobile contribution that is constant within the time window. The immobile fraction as a function of the scattering vector Q is described by a Lorentz function, from which a localization length is determined. The relaxation rates grow with polymer concentration in agreement with dielectric measurements but contrary to pure polymer gels. PMID- 20958017 TI - beta-cyclodextrin as the vehicle for forming ratiometric mercury ion sensor usable in aqueous media, biological fluids, and live cells. AB - The selective and sensitive detection methods for toxic transition-metal ions, which are rapid, facile, and applicable to the environmental and biological milieus, are of great importance. In this study, we designed a beta-CD-based ratiometric sensor for detecting mercury ions in aqueous media, some biological fluids, and live cells. In this sensing platform, the thiocarbamido-containing probe dye was covalently linked onto the hydrophilic beta-CD rim, which is conducive to complexing with metal ion, while the donor dye was anchored inside hydrophobic beta-CD cavity via the adamantyl moiety, which is good for avoiding self-aggregation and enhancing the quantum yield of the donor dye. Upon associating with mercury ion, the probe dye undergoes ring-opening process and serves as the energy acceptor and constitutes the FRET system with the donor dye; by this way ratiometric detection of mercury ion in water can be realized with the detection limit of 10 nM. The cyclodextrin plays a crucial role for the sensing system; it not only accommodates both the donor dye and the probe dye which can form FRET system upon addition of Hg(2+) but also makes the sensor water-soluble and cell membrane permeable. This nontoxic sensing platform can be used for mercury ion detection in aqueous medium, biological fluids, and live cells (L929 and Hela). We also found that, upon being taken up by L929 cells, the sensor exhibited no cytotoxicity, and the cell proliferation was not affected. PMID- 20958018 TI - Fabrication of microwell arrays based on two-dimensional ordered polystyrene microspheres for high-throughput single-cell analysis. AB - This paper describes a method of fabricating rounded bottom microwell arrays (MA) in poly(dimethylsiloxane) (PDMS) by molding a monolayer of ordered polystyrene (PS) microspheres. PS microspheres were self-assembled on a glass slide and partially melted mainly from the bottom at 240 degrees C to increase adhesive force with the substrate. The partially melted PS arrays were used as master to generate MA. Microwell sizes are tunable in the 10-20 MUm range with rounded bottoms; such a 3D structure is not readily obtainable through conventional soft lithography. Both adherent and nonadherent cell types can be retained in the microwells with high efficiency. As a demonstration of the advantage of real-time cell screening with this MA, single cell enzyme kinetic analysis was also carried out on trapped single cells. The PDMS MA may find applications in high-throughput drug screening, guided formation of cell clusters, and multicellular communication. PMID- 20958019 TI - Broad-specificity immunoassay for O,O-diethyl organophosphorus pesticides: application of molecular modeling to improve assay sensitivity and study antibody recognition. AB - A monoclonal antibody (mAb) against 4-(diethoxyphosphorothioyloxy)benzoic acid (hapten 1) was raised and used to develop a broad-specificity competitive indirect enzyme-linked immunosorbent assay (ciELISA) for 14 O,O-diethyl organophosphorus pesticides (OPs). Computer-assisted molecular modeling was used to model two-dimensional (2D) and three-dimensional (3D) quantitative structure activity relationships (QSARs) to study antibody recognition. On the basis of insights obtained from the QSAR models, two heterologous coating haptens, 4 (diethoxyphosphorothioylamino)butanoic acid (hapten 2) and 4 (diethoxyphosphorothioyloxy)-2-methylbenzoic acid (hapten 3) were designed, synthesized, and used to develop heterologous ciELISAs with significantly improved sensitivity. The heterologous ciELISA using hapten 2 as the coating hapten showed good sensitivity in a broad-specific manner for eight O,O-diethyl OPs and may be used as a screening method for the determination of these OPs. Our studies demonstrated that molecular modeling can provide insights into the spatial and electronic effects of molecular structures that are important for antibody activity, which can then be used to improve immunoassay sensitivity. PMID- 20958020 TI - Enzyme-responsive intracellular controlled release using nanometric silica mesoporous supports capped with "saccharides". AB - The synthesis of new capped silica mesoporous nanoparticles for on-command delivery applications is described. The gate-like functional hybrid systems consisted of nanoscopic MCM-41-based materials functionalized on the pore outlets with different "saccharide" derivatives and a dye contained in the mesopores. A series of hydrolyzed starch products as saccharides were selected. The mesoporous silica nanoparticles S1, S2, and S3 containing the grafted starch derivatives Glucidex 47, Gludicex 39, and Glucidex 29 were synthesized. Additionally, for comparative purposes solid S4 containing lactose was prepared. Delivery studies in pure water in the presence of pancreatin or beta-d-galactosidase were carried out for S1-S3 and S4, respectively. S1, S2, and especially S3 showed very low release in the absence of enzyme, but displayed cargo delivery in the presence of the corresponding enzyme. Moreover, nanoparticles of S1 were used to study the controlled release of the dye in intracellular media. Cell viability assays using HeLa and LLC-PK1 cells indicated that S1 nanoparticles were devoid of unspecific cell toxicity. The endocytosis process for S1 nanoparticle internalization in HeLa cells was confirmed, and the anchored starch was degraded by the lysosomal enzymes. Furthermore, a new mesoporous silica nanoparticle functionalized with Glucidex 47 and loaded with a cytotoxic, S1-DOX, was developed. The cell viability with S1-DOX decreased due to the internalization of the nanoparticle, enzyme-dependent opening of the saccharide molecular gate and the consequent release of the cytotoxic agent. As far as the authors know, this is the first example of enzyme-induced in-cell delivery using capped silica mesoporous nanoparticles. PMID- 20958021 TI - Supraparamagnetic, conductive, and processable multifunctional graphene nanosheets coated with high-density Fe3O4 nanoparticles. AB - The amazing properties of graphene are triggering extensive interests of both scientists and engineers, whereas how to fully utilize the unique attributes of graphene to construct novel graphene-based composites with tailor-made, integrated functions remains to be a challenge. Here, we report a facile approach to multifunctional iron oxide nanoparticle-attached graphene nanosheets (graphene@Fe(3)O(4)) which show the integrated properties of strong supraparamagnetism, electrical conductivity, highly chemical reactivity, good solubility, and excellent processability. The synthesis method is efficient, scalable, green, and controllable and has the feature of reduction of graphene oxide and formation of Fe(3)O(4) nanoparticles in one step. When the feed ratios are adjusted, the average diameter of Fe(3)O(4) nanoparticles (1.2-6.3 nm), the coverage density of Fe(3)O(4) nanoparticles on graphene nanosheets (5.3-57.9%), and the saturated magnetization of graphene@Fe(3)O(4) (0.5-44.1 emu/g) can be controlled readily. Because of the good solubility of the as-prepared graphene@Fe(3)O(4), highly flexible and multifunctional films composed of polyurethane and a high content of graphene@Fe(3)O(4) (up to 60 wt %) were fabricated by the solution-processing technique. The graphene@Fe(3)O(4) hybrid sheets showed electrical conductivity of 0.7 S/m and can be aligned into a layered-stacking pattern in an external magnetic field. The versatile graphene@Fe(3)O(4) nanosheets hold great promise in a wide range of fields, including magnetic resonance imaging, electromagnetic interference shielding, microwave absorbing, and so forth. PMID- 20958022 TI - European experience in chemicals management: integrating science into policy. AB - The European Union (EU) adopted the first legislation on chemicals management in 1967 with the Dangerous Substances Directive (DSD). Over time the underlying concepts evolved: from hazard identification over risk assessment to safety assessment. In 1981 a premarketing notification scheme was introduced. Approximately 10 years later a risk assessment program started for existing substances following a data collection and prioritization exercise. Integration of science into EU chemicals legislation occurred via several technical committees managed by the European Chemicals Bureau (ECB) and resulted in the Technical Guidance Document on Risk Assessment (TGD), which harmonized the risk assessment methodology. The TGD was revised several times to adapt to scientific developments. The revision process, and the risk assessments for new and existing substances, led to scientific research on chemical risk assessment and thus increased in complexity. The new EU chemicals policy REACH (Registration, Evaluation, Authorization and Restriction of CHemicals) builds on previous experiences and aims to further enhance health and safety. REACH places the burden of proof for chemical safety on industry focusing on managing risks. REACH formalizes the precautionary principle. Furthermore, it underlines a continued scientific underpinning in its implementation, also via stakeholder involvement, and a focus on aligning with international fora. PMID- 20958023 TI - Biofuels done right: land efficient animal feeds enable large environmental and energy benefits. AB - There is an intense ongoing debate regarding the potential scale of biofuel production without creating adverse effects on food supply. We explore the possibility of three land-efficient technologies for producing food (actually animal feed), including leaf protein concentrates, pretreated forages, and double crops to increase the total amount of plant biomass available for biofuels. Using less than 30% of total U.S. cropland, pasture, and range, 400 billion liters of ethanol can be produced annually without decreasing domestic food production or agricultural exports. This approach also reduces U.S. greenhouse gas emissions by 670 Tg CO2-equivalent per year, or over 10% of total U.S. annual emissions, while increasing soil fertility and promoting biodiversity. Thus we can replace a large fraction of U.S. petroleum consumption without indirect land use change. PMID- 20958024 TI - Chemical equilibrium modeling of organic acids, pH, aluminum, and iron in Swedish surface waters. AB - A consistent chemical equilibrium model that calculates pH from charge balance constraints and aluminum and iron speciation in the presence of natural organic matter is presented. The model requires input data for total aluminum, iron, organic carbon, fluoride, sulfate, and charge balance ANC. The model is calibrated to pH measurements (n = 322) by adjusting the fraction of active organic matter only, which results in an error of pH prediction on average below 0.2 pH units. The small systematic discrepancy between the analytical results for the monomeric aluminum fractionation and the model results is corrected for separately for two different fractionation techniques (n = 499) and validated on a large number (n = 3419) of geographically widely spread samples all over Sweden. The resulting average error for inorganic monomeric aluminum is around 1 uM. In its present form the model is the first internally consistent modeling approach for Sweden and may now be used as a tool for environmental quality management. Soil gibbsite with a log *Ks of 8.29 at 25 degrees C together with a pH dependent loading function that uses molar Al/C ratios describes the amount of aluminum in solution in the presence of organic matter if the pH is roughly above 6.0. PMID- 20958025 TI - Enhancement of indirect sulphation of limestone by steam addition. AB - The effect of water (H2O(g)) on in situ SO2 capture using limestone injection under (FBC) conditions was studied using a thermobalance and tube furnace. The indirect sulphation reaction was found to be greatly enhanced in the presence of H2O(g). Stoichiometric conversion of samples occurred when sulphated with a synthetic flue gas containing 15% H2O(g) in under 10 h, which is equivalent to a 45% increase in conversion as compared to sulphation without H2O(g). Using gas pycnometry and nitrogen adsorption methods, it was shown that limestone samples sulphated in the presence of H2O(g) undergo increased particle densification without any significant changes to pore area or volume. The microstructural changes and observed increase in conversion were attributed to enhanced solid state diffusion in CaO/CaSO4 in the presence of H2O(g). Given steam has been shown to have such a strong influence on sulphation, whereas it had been previously regarded as inert, may prompt a revisiting of the classically accepted sulphation models and phenomena. These findings also suggest that steam injection may be used to enhance sulfur capture performance in fluidized beds firing low moisture fuels such as petroleum coke. PMID- 20958027 TI - Nanoparticles change the ordering pattern of n-carboxylic acids into nanorods on HOPG. AB - This paper describes the formation of organic nanorods induced by monolayer protected inorganic nanoparticles. Alkanes and alkane derivatives, such as n carboxylic acids, self-assemble on highly oriented pyrolytic graphite (HOPG) into a persistent molecular packing structure that is dictated by the epitaxial interaction between the carbon chain plane and the HOPG basal plane. Carboxylic acids form 2-D crystalline layers consisting of nanostripe domains whose periodicity is one or two times the molecular chain length. However, when the molecular ordering occurs in the vicinity of a nanoparticle, this persistent HOPG dominated nanostripe pattern is disrupted, and nanorods attached to the nanoparticles become the dominant structure. In order to understand the underlying mechanism of the nanoparticle-mediated nanorod formation, the effects of film-forming conditions, carboxylic acid chain length, nanoparticle size, and chemical composition of the nanoparticle are examined. It is determined that carboxylic acid nanorods can be induced by nanoparticles of different core materials including CdSe, CdS, and Au, as long as the protecting monolayer allows sufficient dispersion and colloidal stability of the nanoparticles in solution. A carboxylic chain length range amenable to the nanorod formation is identified, as is the relationship between the nanoparticle size and the number of nanorods per nanoparticle. This study contributes to the understanding of seed-mediated crystallization and molecular ordering. Moreover, it defines the parameters governing solution-based formation of hybrid nanostructures and nanopatterns incorporating dual functionality as defined by the inorganic nanoparticle and organic nanorod, respectively. PMID- 20958028 TI - Local cooperativity in an amyloidogenic state of human lysozyme observed at atomic resolution. AB - The partial unfolding of human lysozyme underlies its conversion from the soluble state into amyloid fibrils observed in a fatal hereditary form of systemic amyloidosis. To understand the molecular origins of the disease, it is critical to characterize the structural and physicochemical properties of the amyloidogenic states of the protein. Here we provide a high-resolution view of the unfolding process at low pH for three different lysozyme variants, the wild type protein and the mutants I56T and I59T, which show variable stabilities and propensities to aggregate in vitro. Using a range of biophysical techniques that includes differential scanning calorimetry and nuclear magnetic resonance spectroscopy, we demonstrate that thermal unfolding under amyloidogenic solution conditions involves a cooperative loss of native tertiary structure, followed by progressive unfolding of a compact, molten globule-like denatured state ensemble as the temperature is increased. The width of the temperature window over which the denatured ensemble progressively unfolds correlates with the relative amyloidogenicity and stability of these variants, and the region of lysozyme that unfolds first maps to that which forms the core of the amyloid fibrils formed under similar conditions. Together, these results present a coherent picture at atomic resolution of the initial events underlying amyloid formation by a globular protein. PMID- 20958029 TI - Elementary building blocks of self-assembled peptide nanotubes. AB - In the world of biology, "self-assembly" is the ability of biological entities to interact with one another to form supramolecular structures. One basic group of self-assembled structures is peptide nanotubes (PNTs). However, the self-assembly mechanism, with its special characteristics, is not yet fully understood. An exceptional quantum-confined approach is shown here for the self-assembly mechanism in bio-inspired materials. We found the elementary building block of the studied PNT, which is self-assembled from short peptides composed of two phenylalanine residues, to be 0D-quantum-confined (can be related to confinement in 3D), also called a quantum dot (QD). This elementary building block can further self-assemble to a PNT formation. It has been observed that the assembly process of dots to tubes and the disassembly process of tubes to dots are reversible. We further show that a similar dipeptide can also self-assemble to a QD-like structure, with different dimensions. The presented peptide QD structures are nanometer-sized structures, with pronounced exciton effects, which may promote the use of an entirely new kind of organic QDs. PMID- 20958030 TI - Synthesis and shape control of CuInS(2) nanoparticles. AB - Cu(2)S-CuInS(2) hybrid nanostructures as well as pure CuInS(2) (CIS) nanocrystals were synthesized by methods of colloidal chemistry. The structure, the shape and the composition of these nanomaterials were investigated with transmission electron microscopy (TEM), powder X-ray diffraction (XRD) and energy dispersive X ray analysis (EDX). By changing the reaction conditions, CuInS(2) nanorods with different aspect ratio, dimeric nanorods as well as hexagonal discs and P-shaped particles could be synthesized. Under our reaction conditions, CIS nanoparticles crystallize in the hexagonal wurtzite structure, as confirmed by Rietveld analysis of the X-ray diffraction patterns. The formation of Cu(2)S-CuInS(2) hybrid nanostructures turned out to be an essential intermediate step in the growth of CIS nanoparticles, the copper sulphide part of the hybrid material playing an important role in the shape control of the CIS nanocrystals. By a treatment of Cu(2)S-CuInS(2) with 1,10-phenanthroline, Cu(2)S parts of the hybrid nanostructures could be removed, and pure CIS nanoparticles with shapes not accessible with other methods can be obtained. Our synthetic procedure turned out to be suitable to synthesize also other compounds, like CuInS(2)-ZnS alloys, and to modify, in this way, the optical properties of the nanocrystals. PMID- 20958031 TI - High-resolution (19)F MAS NMR spectroscopy: structural disorder and unusual J couplings in a fluorinated hydroxy-silicate. AB - High-resolution (19)F magic angle spinning (MAS) NMR spectroscopy is used to study disorder and bonding in a crystalline solid. (19)F MAS NMR reveals four distinct F sites in a 50% fluorine-substituted deuterated hydrous magnesium silicate (clinohumite, 4Mg(2)SiO(4).Mg(OD(1-x)F(x))(2) with x = 0.5), indicating extensive structural disorder. The four (19)F peaks can be assigned using density functional theory (DFT) calculations of NMR parameters for a number of structural models with a range of possible local F environments generated by F(-)/OH(-) substitution. These assignments are supported by two-dimensional (19)F double quantum MAS NMR experiments that correlate F sites based on either spatial proximity (via dipolar couplings) or through-bond connectivity (via scalar, or J, couplings). The observation of (19)F-(19)F J couplings is unexpected as the fluorines coordinate Mg atoms and the Mg-F interaction is normally considered to be ionic in character (i.e., there is no formal F-Mg-F covalent bonding arrangement). However, DFT calculations predict significant (19)F-(19)F J couplings, and these are in good agreement with the splittings observed in a (19)F J-resolved MAS NMR experiment. The existence of these J couplings is discussed in relation to both the nature of bonding in the solid state and the occurrence of so-called "through-space" (19)F-(19)F J couplings in solution. Finally, we note that we have found similar structural disorder and spin-spin interactions in both synthetic and naturally occurring clinohumite samples. PMID- 20958032 TI - Improved fitting of solution X-ray scattering data to macromolecular structures and structural ensembles by explicit water modeling. AB - A new procedure, AXES, is introduced for fitting small-angle X-ray scattering (SAXS) data to macromolecular structures and ensembles of structures. By using explicit water models to account for the effect of solvent, and by restricting the adjustable fitting parameters to those that dominate experimental uncertainties, including sample/buffer rescaling, detector dark current, and, within a narrow range, hydration layer density, superior fits between experimental high resolution structures and SAXS data are obtained. AXES results are found to be more discriminating than standard Crysol fitting of SAXS data when evaluating poorly or incorrectly modeled protein structures. AXES results for ensembles of structures previously generated for ubiquitin show improved fits over fitting of the individual members of these ensembles, indicating these ensembles capture the dynamic behavior of proteins in solution. PMID- 20958033 TI - Temperature jump and fast photochemical oxidation probe submillisecond protein folding. AB - We report a new mass-spectrometry-based approach for studying protein-folding dynamics on the submillisecond time scale. The strategy couples a temperature jump with fast photochemical oxidation of proteins (FPOP), whereby folding/unfolding is followed by changes in oxidative modifications by OH radical reactions. Using a flow system containing the protein barstar as a model, we altered the protein's equilibrium conformation by applying the temperature jump and demonstrated that its reactivity with OH free radicals serves as a reporter of the conformational change. Furthermore, we found that the time-dependent increase in mass resulting from free-radical oxidation is a measure of the rate constant for the transition from the unfolded to the first intermediate state. This advance offers the promise that, when extended with mass-spectrometry-based proteomic analysis, the sites and kinetics of folding/unfolding can also be followed on the submillisecond time scale. PMID- 20958034 TI - Acyclic chelate with ideal properties for (68)Ga PET imaging agent elaboration. AB - We have investigated novel bifunctional chelate alternatives to the aminocarboxylate macrocycles NOTA (N(3)O(3)) or DOTA (N(4)O(4)) for application of radioisotopes of Ga to diagnostic nuclear medicine and have found that the linear N(4)O(2) chelate H(2)dedpa coordinates (67)Ga quantitatively to form [(67)Ga(dedpa)](+) after 10 min at RT. Concentration-dependent coordination to H(2)dedpa of either (68)Ga or (67)Ga showed quantitative conversion to the desired products with ligand concentrations as low as 10(-7) M. With (68)Ga, specific activities as high as 9.8 mCi nmol(-1) were obtained without purification. In a 2 h competition experiment against human apo-transferrin, [(67)Ga(dedpa)](+) showed no decomposition. Two bifunctional versions of H(2)dedpa are also described, and these both coordinate to (67)Ga at RT within 10 min. Complete syntheses, characterizations, labeling studies, and biodistribution profiles of the (67)Ga complexes are presented for the new platform chelates. The stability of these platform chelates is higher than that of DOTA. PMID- 20958035 TI - Pronounced negative thermal expansion from a simple structure: cubic ScF(3). AB - Scandium trifluoride maintains a cubic ReO(3) type structure down to at least 10 K, although the pressure at which its cubic to rhombohedral phase transition occurs drops from >0.5 GPa at ~300 K to 0.1-0.2 GPa at 50 K. At low temperatures it shows strong negative thermal expansion (NTE) (60-110 K, alpha(l) ~ -14 ppm K( 1)). On heating, its coefficient of thermal expansion (CTE) smoothly increases, leading to a room temperature CTE that is similar to that of ZrW(2)O(8) and positive thermal expansion above ~1100 K. While the cubic ReO(3) structure type is often used as a simple illustration of how negative thermal expansion can arise from the thermally induced rocking of rigid structural units, ScF(3) is the first material with this structure to provide a clear experimental illustration of this mechanism for NTE. PMID- 20958036 TI - Total synthesis of isokidamycin. AB - The synthesis of isokidamycin, which represents the first total synthesis of a bis-C-aryl glycoside natural product in the pluramycin family, has been completed. The synthesis features the use of a silicon tether as a disposable regiocontrol element in an intramolecular Diels-Alder reaction between a substituted naphthyne and a glycosyl furan and a subsequent O->C-glycoside rearrangement. PMID- 20958038 TI - Electrophoretic mobilities of PEGylated gold NPs. AB - Electromigration of nanoparticles (NPs) is relevant to many technological and biological applications. We correlate the experimentally observed electromigration of Au NPs with a closed-form theoretical model that furnishes key NP characteristics, including the previously unknown values of Au NP core zeta-potential, PEG-corona permeability, and particle-hydrogel friction coefficient. More generally, the theory furnishes new understanding of NP electromigration in complex environments, establishing a robust and predictive model to guide the design and characterization of functionalized NPs. PMID- 20958041 TI - Catalytic enantioselective 1,3-dipolar cycloadditions of nitrones with propioloylpyrazoles and acryloylpyrazoles induced by chiral pi-cation catalysts. AB - A chiral copper(II) complex of 3-(2-naphthyl)-l-alanine amide successfully catalyzes the enantioselective 1,3-dipolar cycloaddition reaction of nitrones with propioloylpyrazole and acryloylpyrazole derivatives. The asymmetric environment created by intramolecular pi-cation interaction gives the corresponding adducts in high yields with excellent enantioselectivity. This is the first successful method for the catalytic enantioselective 1,3-dipolar cycloaddition of nitrones with acetylene derivatives. The 1,3-dipolar cycloadducts can be stereoselectively converted to beta-lactams via reductive cleavage of the N-O bond using SmI(2). PMID- 20958040 TI - Synthesis of amino acid derived enaminones via Wolff rearrangement using vinylogous amides as carbon nucleophiles. AB - Cyclic enaminones were synthesized in high yields from amino acids in two steps via Wolff rearrangement. The cyclization represents a rare 6-exo-dig cyclization involving a ketene as an electrophile. No racemization was observed during this reaction. PMID- 20958043 TI - Effect of the ionic strength of pulsed electric field treatment medium on the physicochemical and structural characteristics of lactoferrin. AB - Pulsed electric field (PEF) treatment (35 kV cm(-1) for 19.2 MUs using bipolar 2 MUs pulses) was conducted on bovine lactoferrin (LF; 0.4 mg mL(-1)) prepared in simulated milk ultrafiltrate (SMUF), at concentrations between 0.2* and 2* normal strength, with electrical conductivities ranging from 0.17 to 1.04 S m(-1). The physicochemical and structural characteristics (LF content by a spectrophotometric and an ELISA method, surface hydrophobicity, electrophoretic mobility, far-UV circular dichroism spectra, and tryptophan fluorescence) of LF dissolved in SMUF of all strengths tested were not changed after PEF treatment. The PEF treatment of LF in 0.2 strength SMUF did not cause the release of LF bound ferric ion into the aqueous phase, with a concentration of LF-bound iron being the same as that of the untreated LF control (174 MUg L(-1)). However, in treatment media with higher ionic strengths, ferric ion was released from the LF molecule into the aqueous phase. The concentration of LF-bound iron decreased from 174 MUg L(-1) for the LF treated in 0.2 strength SMUF to 80 MUg L(-1) for that treated in double-strength SMUF. The results suggest that the PEF-induced iron depletion of LF does not appear to cause an appreciable conformational change in LF molecules. PEF treatment could be developed as a novel physical way to produce iron-depleted LF, as an alternative to the existing chemical method. PMID- 20958044 TI - Efficiency of DNA typing methods for detection of smoked paprika "pimenton de la vera" adulteration used in the elaboration of dry-cured Iberian pork sausages. AB - The purpose of this work was to develop a PCR method for the identification of smoked paprika "Pimenton de la Vera" adulteration with paprika elaborated from varieties of pepper foreign to the la Vera region, in central western Spain. Three autochthonous varieties of pepper, Jaranda, Jariza, and Bola, and the varieties Papri Queen, Papri King, Sonora, PS9794, and Papri Ace, foreign to the La Vera region, were used in the study. Analyses of the ITS and 5.8S rDNA, RAPD PCR, SSR, and ISSR were tested. RAPD-PCR, SSR, and ISSR analyses allowed differentiation among the varieties of paprika analyzed. There was no difference in the sequence of ITS1-5.8S rDNA-ITS2. In addition, with the RAPD-PCR primers S13 and S22, two molecular markers were obtained of 641 and 704 bp, respectively, which allowed all of the smoked paprika varieties to be differentiated from paprikas elaborated with the five foreign varieties. These two molecular markers were investigated as a basis for detecting the adulteration of smoked paprika with paprika elaborated from foreign varieties of pepper. PMID- 20958045 TI - Flufenerim, a novel insecticide acting on diverse insect pests: biological mode of action and biochemical aspects. AB - A new chemical compound was tested for its insecticidal activity against several major insect pests. The compound, called "flufenerim", has a core pyrimidine structure and an unknown mode of action and showed potent activity against the sweet potato whitefly Bemisia tabaci (Gennadius), the green peach aphid Myzus persicae (Sulzer), and the African cotton leafworm Spodoptera littoralis (Boisduval); however, it did not show any activity against two thrips species: western flower thrips Frankliniella occidentalis (Pergande) and tobacco thrips Thrips tabaci (Lindeman). The compound was relatively potent against the three tested pests and caused mortality rates that reached up to 100% at concentrations under 10 mg of active ingredient (ai) L(-1). The action of the compound was very fast, and mortality was observed within 48 h after exposure of the insects to treated leaves. A unique characteristic of this compound is its very short residual activity, which approximates to 4 days after application under laboratory conditions and to 2 days under outdoor conditions for both B. tabaci and S. littoralis. Although this new compound's mode of action is yet unknown, its rapid and potent action against sap-sucking pests suggests that it acts on a very important target site in the insect body and possibly could be applied very close to harvesting. PMID- 20958047 TI - Luteolin ameliorates experimental lung fibrosis both in vivo and in vitro: implications for therapy of lung fibrosis. AB - Lonicera japonica (Caprifoliaceae) has been known as an anti-inflammatory herb in traditional Chinese medicine for thousands of years and is used constantly for upper respiratory tract infections. Luteolin, an active flavonoid compound isolated from Lonicera japonica, has a spectrum of biological activities, especially with antioxidative and anti-inflammatory properties. However, whether luteolin has a direct inhibitory effect on lung fibrosis has not been established. In this study, we examined the effects of luteolin on lung fibrosis both in vivo and in vitro. We found that oral administration of luteolin (10 mg/kg) efficiently suppressed the neutrophil infiltration as well as TNF-alpha and IL-6 elevation in the bronchoalveolar lavage fluid in bleomycin-instilled C57BL/6J mice. Luteolin also alleviated collagen deposition, TGF-beta1 expression, and lung fibrosis upon bleomycin instillation. A similar tendency was observed in both early and delayed luteolin-treated groups. Next, our in vitro studies showed that luteolin inhibited TGF-beta1-induced alpha-SMA, type I collagen, and vimentin expression in primary cultured mouse lung fibroblasts. Moreover, luteolin significantly blocked TGF-beta1-mediated epithelial marker (E cadherin) downregulation and mesenchymal cell markers (fibronectin and vimentin) upregulation, as well as retaining epithelial morphology in human alveolar epithelial-derived A549 cells. Additionally, luteolin could attenuate TGF-beta1 induced Smad3 phosphorylation in both lung fibroblasts and A549 cells. These findings suggest that luteolin has a potent antifibrotic activity; this effect was mediated, at least in part, by inhibition of lung inflammation and suppression of myofibroblast differentiation as well as epithelial-to-mesenchymal transition. PMID- 20958046 TI - Epoxygenated fatty acids and soluble epoxide hydrolase inhibition: novel mediators of pain reduction. AB - The soluble epoxide hydrolase (sEH) enzyme was discovered while investigating the metabolism of xenobiotic compounds in the Casida laboratory. However, an endogenous role of sEH is to regulate the levels of a group of potent bioactive lipids, epoxygenated fatty acids (EFAs), that have pleiotropic biological activities. The EFAs, in particular the arachidonic acid derived epoxy eicosatrienoic acids (EETs), are established autocrine and paracrine messengers. The most recently discovered outcome of inhibition of sEH and increased EFAs is their effects on the sensory system and in particular their ability to reduce pain. The inhibitors of sEH block both inflammatory and neuropathic pain. Elevation of EFAs, in both the central and peripheral nervous systems, blocks pain. Several laboratories have now published a number of potential mechanisms of action for the pain-reducing effects of EFAs. This paper provides a brief history of the discovery of the sEH enzyme and argues that inhibitors of sEH through several independent mechanisms display pain-reducing effects. PMID- 20958048 TI - Enhanced anti-inflammatory activities of Monascus pilosus fermented products by addition of ginger to the medium. AB - Hypercholesterolemia initiates the atherogenic process; however, chronic inflammation promotes atherogenesis. Monascus spp. fermented products are recognized for their anti-hypercholesterolemic effect, but their anti inflammatory activity is not as significant as that of many plant-derived foods. To enhance the anti-inflammatory function of Monascus pilosus fermented products, ginger was added to the PDB medium at a ratio of 20% (v/v). The mycelia and broth were collected, freeze-dried, and extracted by ethanol for assays. Macrophage RAW264.7 was challenged with lipopolysaccharide (LPS) and coincubated with the extracts of fermented product cultured in ginger-supplemented medium (MPG) or extracts of fermented product cultured in regular PDB medium (MP) for 18 h. Human umbilical vein endothelial cell HUVEC was challenged with tumor necrosis factor (TNF)-alpha and coincubated with the extracts of either MPG or MP for 6 h. The results showed that MPG significantly (p<0.05) lowered the production of macrophage pro-inflammatory cytokines TNF-alpha, nitric oxide (NO), interleukin (IL)-1, IL-6, and prostaglandin E2 (PGE2) by 68.53%, 84.29%, 32.55%, 84.49%, and 69.49%, respectively; however, MP had no inhibitory effect. MPG significantly downregulated the expression of p-IkappaB, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in macrophage by 42.16%, 50.87%, and 51.35%, respectively, while MP had no inhibition on COX-2 expression and only 16.64% and 19.22% downregulatory effect on iNOS and phosphorylated-IkappaB (p IkappaB), respectively. Moreover, MPG significantly suppressed the expression of vessel cell adhesion molecule-1 (VCAM-1) and p-IkappaB in endothelial cell by 63.48% and 63.41%, respectively. LC/MS/MS analysis indicated that 6-gingerdiol was formed in the ginger-modified medium during fermentation. The results of this study will facilitate the development of Monascus spp. fermented products as antiatherosclerotic nutraceuticals. PMID- 20958049 TI - Development, validation, and use of quantitative structure-activity relationship models of 5-hydroxytryptamine (2B) receptor ligands to identify novel receptor binders and putative valvulopathic compounds among common drugs. AB - Some antipsychotic drugs are known to cause valvular heart disease by activating serotonin 5-HT(2B) receptors. We have developed and validated binary classification QSAR models capable of predicting potential 5-HT(2B) actives. The classification accuracies of the models built to discriminate 5-HT(2B) actives from the inactives were as high as 80% for the external test set. These models were used to screen in silico 59,000 compounds included in the World Drug Index, and 122 compounds were predicted as actives with high confidence. Ten of them were tested in radioligand binding assays and nine were found active, suggesting a success rate of 90%. All validated actives were then tested in functional assays, and one compound was identified as a true 5-HT(2B) agonist. We suggest that the QSAR models developed in this study could be used as reliable predictors to flag drug candidates that are likely to cause valvulopathy. PMID- 20958051 TI - Origin of lyotropic liquid crystalline mesophase formation and liquid crystalline to mesostructured solid transformation in the metal nitrate salt-surfactant systems. AB - The zinc nitrate salt acts as a solvent in the ZnX-C(12)EO(10) (ZnX is [Zn(H(2)O)(6)](NO(3))(2) and C(12)EO(10) is C(12)H(25)(OCH(2)CH(2))(10)OH) lyotropic liquid crystalline (LLC) mesophase with a drastic dropping on the melting point of ZnX. The salt-surfactant LLC mesophase is stable down to -52 degrees C and undergoes a phase change into a solid mesostructured salt upon cooling below -52 degrees C; no phase separation is observed down to -190 degrees C. The ZnX-C(12)EO(10) mesophase displays a usual phase behavior with an increasing concentration of the solvent (ZnX) in the media with an order of bicontinuous cubic(V(1))-2D hexagonal(H(1))--a mixture of 2D hexagonal and micelle cubic(H(1) + I)-micelle cubic(I)-micelle(L(1)) phases. The phase behaviors, specifically at low temperatures, and the first phase diagram of the ZnX-C(12)EO(10) system was investigated using polarized optical microscopy (POM), X-ray diffraction (XRD), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), and Raman techniques and conductivity measurements. PMID- 20958050 TI - Structure-based design, synthesis, and structure-activity relationship studies of HIV-1 protease inhibitors incorporating phenyloxazolidinones. AB - A series of new HIV-1 protease inhibitors with the hydroxyethylamine core and different phenyloxazolidinone P2 ligands were designed and synthesized. Variation of phenyl substitutions at the P2 and P2' moieties significantly affected the binding affinity and antiviral potency of the inhibitors. In general, compounds with 2- and 4-substituted phenyloxazolidinones at P2 exhibited lower binding affinities than 3-substituted analogues. Crystal structure analyses of ligand enzyme complexes revealed different binding modes for 2- and 3-substituted P2 moieties in the protease S2 binding pocket, which may explain their different binding affinities. Several compounds with 3-substituted P2 moieties demonstrated picomolar binding affinity and low nanomolar antiviral potency against patient derived viruses from HIV-1 clades A, B, and C, and most retained potency against drug-resistant viruses. Further optimization of these compounds using structure based design may lead to the development of novel protease inhibitors with improved activity against drug-resistant strains of HIV-1. PMID- 20958054 TI - Nuclear permeable ruthenium(II) beta-carboline complexes induce autophagy to antagonize mitochondrial-mediated apoptosis. AB - The role of autophagy in cancer development and response to cancer therapy has been a subject of debate. Here we demonstrate that a series of ruthenium(II) complexes containing a beta-carboline alkaloid as ligand can simultaneously induce autophagy and apoptosis in tumor cells. These Ru(II) complexes are nuclear permeable and highly active against a panel of human cancer cell lines, with complex 3 displaying activities greater than those of cisplatin. The antiproliferative potentialities of 1-3 are in accordance with their relative lipophilicities, cell membrane penetration abilities, and in vitro DNA binding affinities. Complexes 1-3 trigger release of reactive oxygen species (ROS) and attenuation of ROS by scavengers reduced the sub-G1 population, suggesting ROS dependent apoptosis. Inhibition of ROS generation also reduces autophagy, indicating that ROS triggers autophagy. Further studies show that suppression of autophagy using pharmacological inhibitors (3-methyladenine and chloroquine) enhances apoptotic cell death. PMID- 20958056 TI - Cyanidin-3-O-glucoside protection against TNF-alpha-induced endothelial dysfunction: involvement of nuclear factor-kappaB signaling. AB - Oxidative stress and inflammation are considered to play a pivotal role in vascular endothelial dysfunction by triggering activation of transcription factors, such as NF-kappaB, functionally dependent on cellular redox status. The anthocyanin cyanidin-3-O-glucoside (C3G), as well as other phytochemicals recognized as potent antioxidants and free radical scavengers, may act as modulators of gene regulation and signal transduction pathways. This study demonstrates that C3G is able to protect human endothelial cells against alterations induced by TNF-alpha, including the activation of NF-kappaB, increased gene expression of adhesion molecules, leukocyte adhesion to endothelium, and intracellular accumulation of H2O2 and lipid peroxidation byproducts. These observations contribute to provide a conceptual background for the understanding of the mechanisms underlying the role of C3G, as well as other dietary plant polyphenols, in the prevention of diseases associated with inflammation and oxidative stress, including atherosclerosis. PMID- 20958055 TI - Exploration of the active site of neuronal nitric oxide synthase by the design and synthesis of pyrrolidinomethyl 2-aminopyridine derivatives. AB - Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure-activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((+/ )-32 and (+/-)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-[2''-(3''' fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-[2''-(3''' fluorophenethylamino)ethylamino]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) (J. Am. Chem. Soc. 2010, 132 (15), 5437 - 5442). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed. PMID- 20958057 TI - Effects of latitude-related factors and geographical origin on anthocyanidin concentrations in fruits of Vaccinium myrtillus L. (bilberries). AB - Two data sets are presented to identify the effect of growth location and origin of parental plant on anthocyanidin concentrations in Vaccinium myrtillus fruits. Bilberries were collected from wild populations growing at different latitudes and from cultivated plants originating from different geographical locations but grown in the same location for over 10 years. High-performance liquid chromatography analysis showed that anthocyanidin concentrations varied significantly with latitude and with geographical origin, with higher values form northern latitudes or from a more northerly origin of parent plants. The results show that anthocyanidin concentrations in bilberries are under strong genetic control but are also influenced by climatic factors. Furthermore, the proportions of specific anthocyanidins differed between latitudes and between plants with different parental origins. The diversity in anthocyanidin concentration and composition has important implications for plant breeders and for future development of varieties with high antioxidant capacity. PMID- 20958058 TI - Synthesis, characterization, and application of metal organic framework nanostructures. AB - The considerable number of important physical properties, including optical, electronic, and magnetic properties, of Prussian blue (PB) analogues have attracted fundamental and industrial interest. Nevertheless, the gas sorption properties of PB coordination compounds were only investigated very recently. In this work, we report the synthesis and gas sorption properties of PB nanocomposites with different size and shape obtained by using poly(vinylpyrrolidone) (PVP), chitosan, and dioctyl sodium sulfosuccinate (AOT) as stabilizers and structure directing agents. All three porous nanocrystals show high and selective CO(2) adsorption over CH(4) or N(2). No distinct relationship was found between the size (or shape) of the nanosorbents and their gas uptake capacities. To our knowledge, this is the first report on the use of PB nanocomposites for CO(2) capture applications. PMID- 20958059 TI - A water-soluble Xe@cryptophane-111 complex exhibits very high thermodynamic stability and a peculiar (129)Xe NMR chemical shift. AB - The known xenon-binding (+/-)-cryptophane-111 (1) has been functionalized with six [(eta(5)-C(5)Me(5))Ru(II)](+) ([Cp*Ru](+)) moieties to give, in 89% yield, the first water-soluble cryptophane-111 derivative, namely [(Cp*Ru)(6)1]Cl(6) ([2]Cl(6)). [2]Cl(6) exhibits a very high affinity for xenon in water, with a binding constant of 2.9(2) * 10(4) M(-1) as measured by hyperpolarized (129)Xe NMR spectroscopy. The (129)Xe NMR chemical shift of the aqueous Xe@[2](6+) species (308 ppm) resonates over 275 ppm downfield of the parent Xe@1 species in (CDCl(2))(2) and greatly broadens the practical (129)Xe NMR chemical shift range made available by xenon-binding molecular hosts. Single crystal structures of [2][CF(3)SO(3)](6).xsolvent and 0.75H(2)O@1.2CHCl(3) reveal the ability of the cryptophane-111 core to adapt its conformation to guests. PMID- 20958060 TI - Chirality organization of aniline oligomers through hydrogen bonds of amino acid moieties. AB - Aniline oligomers bearing amino acid moieties were designed by the introduction of L/D-Ala-OMe into aniline oligomers to induce chirality organization of the pi conjugated aniline oligomer moieties, wherein the formation of intramolecular hydrogen bonds was demonstrated to play an important role to regulate the aniline oligomer moieties conformationally. PMID- 20958061 TI - The constitutive activation of Jak2-V617F is mediated by a pi stacking mechanism involving phenylalanines 595 and 617. AB - Somatic mutations in the Jak2 allele that lead to constitutive kinase activation of the protein have been identified in human disease conditions such as the myeloproliferative neoplasms (MPNs). The most common mutation in these patients is a V617F substitution mutation, which is believed to play a causative role in the MPN pathogenesis. As such, identifying the molecular basis for the constitutive activation of Jak2-V617F is important for understanding its clinical implications and potential treatment. Here, we hypothesized that conversion of residue 617 from Val to Phe resulted in the formation of novel pi stacking interactions with neighboring Phe residues. To test this, we first examined the Jak2 structure via molecular modeling and identified a potential pi stacking interaction between F594, F595, and F617. Disruption of this interaction through site-directed mutagenesis impaired Jak2 autophosphorylation, Jak2-dependent gene transcription, and in vitro kinase activity of the Jak2-V617F protein. Further, substitution of F594 and F595 with Trp did not affect Jak2 function significantly, but replacement with charged residues did, showing the importance of aromaticity and hydropathy index conservation at these positions. Using molecular dynamics (MD) simulations, we found that the pi stacking interaction between residues 595 and 617 in the Jak2-V617F protein was of much greater energy and conformed to the properties of pi stacking, relative to the Jak2-WT or Jak2 V617F/F594A/F595A. In summary, we have identified a pi stacking interaction between F595 and F617 that is specific to and is critical for the constitutive activation of Jak2-V617F. PMID- 20958062 TI - Manipulating the stereoselectivity of limonene epoxide hydrolase by directed evolution based on iterative saturation mutagenesis. AB - Limonene epoxide hydrolase from Rhodococcus erythropolis DCL 14 (LEH) is known to be an exceptional epoxide hydrolase (EH) because it has an unusual secondary structure and catalyzes the hydrolysis of epoxides by a rare one-step mechanism in contrast to the usual two-step sequence. From a synthetic organic viewpoint it is unfortunate that LEH shows acceptable stereoselectivity essentially only in the hydrolysis of the natural substrate limonene epoxide, which means that this EH cannot be exploited as a catalyst in asymmetric transformations of other substrates. In the present study, directed evolution using iterative saturation mutagenesis (ISM) has been tested as a means to engineer LEH mutants showing broad substrate scope with high stereoselectivity. By grouping individual residues aligning the binding pocket correctly into randomization sites and performing saturation mutagenesis iteratively using a reduced amino acid alphabet, mutants were obtained which catalyze the desymmetrization of cyclopentene-oxide with stereoselective formation of either the (R,R)- or the (S,S)-diol on an optional basis. The mutants prove to be excellent catalysts for the desymmetrization of other meso-epoxides and for the hydrolytic kinetic resolution of racemic substrates, without performing new mutagenesis experiments. Since less than 5000 tranformants had to be screened for achieving these results, this study contributes to the generalization of ISM as a fast and reliable method for protein engineering. In order to explain some of the stereoselective consequences of the observed mutations, a simple model based on molecular dynamics simulations has been proposed. PMID- 20958063 TI - Crucial role of the reaction conditions in isolating several metastable phases in a Gd-Ce-Zr-O system. AB - A series of samples with composition Gd(2-y)Ce(y)Zr(2)O(7) (0.0 <= y <= 2.0) were prepared by the gel combustion method followed by high-temperature reduction. The details of the structural variations as a function of the composition, temperature, and oxygen stoichiometry have been investigated by X-ray diffraction (XRD), high-temperature XRD (HT-XRD), and thermogravimetry. A complete solubility of Gd(3+) in Ce(2)Zr(2)O(7) and Ce(2)Zr(2)O(8) could be achieved by this adaptive preparative method. Analysis of the XRD data revealed a sequential variation of the structural features with oxygen stoichiometry as well as Gd(3+) contents in these compositions. The variation in the unit cell parameter along the compositions has a strong influence on the oxygen uptake behavior in the Gd(2 y)Ce(y)Zr(2)O(7) system, as observed from the thermogravimetric and HT-XRD studies. The preparation and stability of various metastable phases in Gd-Ce-Zr-O have been addressed in detail. The details of the study will be useful for the design and application of a potential redox catalyst and an oxygen storage capacitor. PMID- 20958064 TI - Stacks of functional oxide thin films patterned by micromolding. AB - Stacks of up to five relief patterned functional oxide thin films were obtained by a low-cost and low-tech soft-lithographic patterning technique. Micromolding was used to pattern a film of a metal-organic precursor solution for Y-stabilized ZrO(2) (YSZO). Subsequent drying and pyrolysis yielded a line-patterned YSZO film. The process was repeated up to four times with a precursor solution for BaTiO(3) on top of the YSZO film, resulting in stacks of YSZO and BaTiO(3) lines with well-defined edges. This approach presents a step forward on the way to a versatile additive micropatterning technique with which simple multi-material device structures can be fabricated in a reliable, fast, and cost-effective manner. PMID- 20958065 TI - A DNA crystal designed to contain two molecules per asymmetric unit. AB - We describe the self-assembly of a DNA crystal that contains two tensegrity triangle molecules per asymmetric unit. We have used X-ray crystallography to determine its crystal structure. In addition, we have demonstrated control over the colors of the crystals by attaching either Cy3 dye (pink) or Cy5 dye (blue green) to the components of the crystal, yielding crystals of corresponding colors. Attaching the pair of dyes to the pair of molecules yields a purple crystal. PMID- 20958066 TI - Vibrational predissociation spectrum of the carbamate radical anion, C(5)H(5)N CO(2)(-), generated by reaction of pyridine with (CO(2))(m)(-). AB - We report the vibrational predissociation spectrum of C(5)H(5)N-CO(2)(-), a radical anion which is closely related to the key intermediates postulated to control activation of CO(2) in photoelectrocatalysis with pyridine (Py). The anion is prepared by the reaction of Py vapor with (CO(2))(m)(-) clusters carried out in an ionized, supersonic entrainment ion source. Comparison with the results of harmonic frequency calculations establishes that this species is a covalently bound molecular anion derived from the corresponding carbamate, C(5)H(5)N-CO(2)( ) (H(+)). These results confirm the structural assignment inferred in an earlier analysis of the cluster distributions and photoelectron spectra of the mixed Py(m)(CO(2))(n)(-) complexes [J. Chem. Phys. 2000, 113 (2), 596-601]. The spectra of the (CO(2))(m)(-) (m = 5 and 7) clusters are presented for the first time in the lower energy range (1000-2400 cm(-1)), which reveal several of the fundamental modes that had only been characterized previously by their overtones and combination bands. Comparison of these new spectra with those displayed by Py(CO(2))(n)(-) suggests that a small fraction of the Py(CO(2))(n)(-) ions are trapped entrance channel reaction intermediates in which the charge remains localized on the (CO(2))(m)(-) part of the cluster. PMID- 20958067 TI - Magnesium coordination-directed n-selective stereospecific alkylation of 2 pyridones, carbamates, and amides using alpha-halocarboxylic acids. AB - A general inversion-stereospecific, N-selective alkylation of substituted 2 pyridones (and analogues), amides, and carbamates using chiral alpha-chloro- or bromocarboxylic acids in the presence of KOt-Bu (or KHMDS) and Mg(Ot-Bu)(2) is reported. The resulting alpha-chiral carboxylic acid products were isolated by crystallization in good chemical yields and in high ee (>90% ee). Mechanistic evidence suggests that the reaction proceeds through 2-pyridone O-coordinated Mg carboxylate intermediates, which afford the product through an intramolecular S(N)2 alkylation. PMID- 20958068 TI - Organocatalyzed enantioselective protonation of silyl enol ethers: scope, limitations, and application to the preparation of enantioenriched homoisoflavones. AB - In the present work, enantioselective protonation of silyl enol ethers is reported by means of a variety of chiral nitrogen bases as catalysts, mainly derived from cinchona alkaloids, in the presence of various protic nucleophiles as proton source. A detailed study of the most relevant reaction parameters is disclosed allowing high enantioselectivities of up to 92% ee with excellent yields to be achieved under mild and eco-friendly conditions. The synthetic utility of this organocatalytic protonation was demonstrated during the preparation of two homoisoflavones 4a and 4b, isolated from Chlorophytum Inornatum and Scilla Nervosa, which were obtained with 81% and 78% ee, respectively. PMID- 20958069 TI - Solid-state photo-CIDNP effect observed in phototropin LOV1-C57S by (13)C magic angle spinning NMR spectroscopy. AB - Until now, the solid-state photo-CIDNP effect, discovered in 1994 by Zysmilich and McDermott, has been observed selectively in photosynthetic systems. Here we present the first observation of this effect in a nonphotosynthetic system, the blue-light photoreceptor phototropin LOV1-C57S using (13)C magic-angle spinning (MAS) NMR. PMID- 20958070 TI - Differential reactivity between two copper sites in peptidylglycine alpha hydroxylating monooxygenase. AB - Peptidylglycine alpha-hydroxylating monooxygenase (PHM) catalyzes the stereospecific hydroxylation of the Calpha of C-terminal glycine-extended peptides and proteins, the first step in the activation of many peptide hormones, growth factors, and neurotransmitters. The crystal structure of the enzyme revealed two nonequivalent Cu sites (Cu(M) and Cu(H)) separated by ~11 A. In the resting state of the enzyme, Cu(M) is coordinated in a distorted tetrahedral geometry by one methionine, two histidines, and a water molecule. The coordination site of the water molecule is the position where external ligands bind. The Cu(H) has a planar T-shaped geometry with three histidines residues and a vacant position that could potentially be occupied by a fourth ligand. Although the catalytic mechanism of PHM and the role of the metals are still being debated, Cu(M) is identified as the metal involved in catalysis, while Cu(H) is associated with electron transfer. To further probe the role of the metals, we studied how small molecules such as nitrite (NO(2)(-)), azide (N(3)(-)), and carbon monoxide (CO) interact with the PHM copper ions. The crystal structure of an oxidized nitrite-soaked PHMcc, obtained by soaking for 20 h in mother liquor supplemented with 300 mM NaNO(2), shows that nitrite anion coordinates Cu(M) in an asymmetric bidentate fashion. Surprisingly, nitrite does not bind Cu(H), despite the high concentration used in the experiments (nitrite/protein > 1000). Similarly, azide and carbon monoxide coordinate Cu(M) but not Cu(H) in the PHMcc crystal structures obtained by cocrystallization with 40 mM NaN(3) and by soaking CO under 3 atm of pressure for 30 min. This lack of reactivity at the Cu(H) is also observed in the reduced form of the enzyme: CO binds Cu(M) but not Cu(H) in the structure of PHMcc obtained by exposure of a crystal to 3 atm CO for 15 min in the presence of 5 mM ascorbic acid (reductant). The necessity of Cu(H) to maintain its redox potential in a narrow range compatible with its role as an electron-transfer site seems to explain the lack of coordination of small molecules to Cu(H); coordination of any external ligand will certainly modify its redox potential. PMID- 20958071 TI - Facile synthesis of 2-(phenylthio)phenols by copper(I)-catalyzed tandem transformation of C-S coupling/C-H functionalization. AB - 2-(Phenylthio)phenols were successfully synthesized from simple phenols and aromatic halides by using dimethyl sulfoxide as the oxidant. The transformation was accomplished via tandem copper(I)-catalyzed C-S coupling/C-H functionalization employing the CuI/L [L = (E)-3-(dimethylamino)-1-(2 hydroxyphenyl)prop-2-en-1-one] catalyst system. The mechanism of the reaction was elucidated based on an isotope labeling strategy. PMID- 20958073 TI - Determination of the metallic/semiconducting ratio in bulk single-wall carbon nanotube samples by cobalt porphyrin probe electron paramagnetic resonance spectroscopy. AB - A simple and quantitative, self-calibrating spectroscopic technique for the determination of the ratio of metallic to semiconducting single-wall carbon nanotubes (SWCNTs) in a bulk sample is presented. The technique is based on the measurement of the electron paramagnetic resonance (EPR) spectrum of the SWCNT sample to which cobalt(II)octaethylporphyrin (CoOEP) probe molecules have been added. This yields signals from both CoOEP molecules on metallic and on semiconducting tubes, which are easily distinguished and accurately characterized in this work. By applying this technique to a variety of SWCNT samples produced by different synthesis methods, it is shown that these signals for metallic and semiconducting tubes are independent of other factors such as tube length, defect density, and diameter, allowing the intensities of both signals for arbitrary samples to be retrieved by a straightforward least-squares regression. The technique is self-calibrating in that the EPR intensity can be directly related to the number of spins (number of CoOEP probe molecules), and as the adsorption of the CoOEP molecules is itself found to be unbiased toward metallic or semiconducting tubes, the measured intensities can be directly related to the mass percentage of metallic and semiconducting tubes in the bulk SWCNT sample. With the use of this method it was found that for some samples the metallic/semiconducting ratios strongly differed from the usual 1:2 ratio. PMID- 20958072 TI - Nanoplex delivery of siRNA and prodrug enzyme for multimodality image-guided molecular pathway targeted cancer therapy. AB - The ability to destroy cancer cells while sparing normal tissue is highly sought after in cancer therapy. Small interfering RNA (siRNA)-mediated silencing of cancer-cell-specific targets and the use of a prodrug enzyme delivered to the tumor to convert a nontoxic prodrug to an active drug are two promising approaches in achieving this goal. Combining both approaches into a single treatment strategy can amplify selective targeting of cancer cells while sparing normal tissue. Noninvasive imaging can assist in optimizing such a strategy by determining effective tumor delivery of the siRNA and prodrug enzyme to time prodrug administration and detecting target down-regulation by siRNA and prodrug conversion by the enzyme. In proof-of-principle studies, we synthesized a nanoplex carrying magnetic resonance imaging (MRI) reporters for in vivo detection and optical reporters for microscopy to image the delivery of siRNA and a functional prodrug enzyme in breast tumors and achieve image-guided molecular targeted cancer therapy. siRNA targeting of choline kinase-alpha (Chk-alpha), an enzyme significantly up-regulated in aggressive breast cancer cells, was combined with the prodrug enzyme bacterial cytosine deaminase (bCD) that converts the nontoxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU). In vivo MRI and optical imaging showed efficient intratumoral nanoplex delivery. siRNA-mediated down-regulation of Chk-alpha and the conversion of 5-FC to 5-FU by bCD were detected noninvasively with (1)H MR spectroscopic imaging and (19)F MR spectroscopy. Combined siRNA and prodrug enzyme activated treatment achieved higher growth delay than either treatment alone. The strategy can be expanded to target multiple pathways with siRNA. PMID- 20958076 TI - Design and reinforcement: vertically aligned carbon nanotube-based sandwich composites. AB - Carbon nanotube (CNT) reinforcement of polymer composites has not yielded optimum results in that the composite properties are typically compromised by poor dispersion and random orientation of CNTs in polymers. Given the short lengths available for nanotubes, opportunities lie in incorporating CNTs with other structural reinforcements such as carbon fibers (CFs) to achieve improvement over existing composite designs. Growth of vertically aligned CNTs (VACNTs) offers new avenues for designing high-performance composites by integrating CFs and nanotubes into layered 3D architectures. To obtain composites with high rigidity and damping, we have designed and fabricated VACNT-based sandwich composites from simply stacking the freestanding VACNTs and CF fabrics and infiltrating with epoxy matrix. Comparing with the CF/epoxy laminates, the VACNT-based sandwich composites exhibit higher flexural rigidity and damping, which is achieved due to the effective integration of the VACNTs as an interfacial layer between the CF stacks. Furthermore, the lighter weight of these VACNT-based sandwich composites offers advantages in aerospace and transportation applications. PMID- 20958074 TI - Drug resistance in breast cancer cells: biophysical characterization of and doxorubicin interactions with membrane lipids. AB - Understanding the role of lipids in drug transport is critical in cancer chemotherapy to overcome drug resistance. In this study, we isolated lipids from doxorubicin-sensitive (MCF-7) and -resistant (MCF-7/ADR) breast cancer cells to characterize the biophysical properties of membrane lipids (particularly lipid packing and membrane fluidity) and to understand the role of the interaction of cell membrane lipids with drug/nanocarrier on drug uptake and efficacy. Resistant cell membrane lipids showed significantly different composition and formed more condensed, less fluid monolayers than did lipids from sensitive cells. Doxorubicin, used as a model anticancer agent, showed a strong hydrophobic interaction with resistant cell membrane lipids but significantly less interaction, as well as a different pattern of interaction (i.e., ionic), with sensitive ones. The threshold intracellular doxorubicin concentration required to produce an antiproliferative effect was similar for both sensitive and resistant cell lines, suggesting that drug transport is a major barrier in determining drug efficacy in resistant cells. In addition to the biophysical characteristics of resistant cell membrane lipids, lipid-doxorubicin interactions appear to decrease intracellular drug transport via diffusion as the drug is trapped in the lipid bilayer. The rigid nature of resistant cell membranes also seems to influence endosomal functions that inhibit drug uptake when a liposomal formulation of doxorubicin is used. In conclusion, biophysical properties of resistant cell membrane lipids significantly influence drug transport, and hence drug efficacy. A better understanding of the mechanisms of cancer drug resistance is vital to developing more effective therapeutic interventions. In this regard, biophysical interaction studies with cell membrane lipids might be helpful to improve drug transport and efficacy through drug discovery and/or drug delivery approaches by overcoming the lipid barrier in resistant cells. PMID- 20958075 TI - Total synthesis of (+)-nankakurines A and B and (+/-)-5-epi-nankakurine A. AB - The first total syntheses of the Lycopodium alkaloids (+)-nankakurine A (2), (+) nankakurine B (3), and the originally purported structure 1 of nankakurine A were accomplished. The syntheses of 2 and 3 feature a demanding intramolecular azomethine imine cycloaddition as the key step for generating the octahydro-3,5 ethanoquinoline moiety and installing the correct relative configuration at the spiropiperidine ring juncture. The cyclization precursor was prepared from octahydronaphthalene ketone 50, which was assembled from enone (+)-9 and diene 48 by a cationic Diels-Alder reaction. The Diels-Alder reactants were synthesized from 5-hexyn-1-ol (16) and (+)-pulegone (49), respectively. The tetracyclic ring system of 1 was generated using an unprecedented nitrogen-terminated aza-Prins cyclization cascade. The enantioselective total syntheses of (+)-nankakurine A (2) and (+)-nankakurine B (3) establish the relative and absolute configuration of these alkaloids and are sufficiently concise that substantial quantities of 2 and 3 were prepared for biological studies. (+)-Nankakurine A and (+)-nankakurine B showed no effect on neurite outgrowth in rat hippocampal H-19 cells over a concentration range of 0.3-10 MUM. PMID- 20958077 TI - A nanochannel array-based electrochemical device for quantitative label-free DNA analysis. AB - A strategy for label-free oligonucleotide (DNA) analysis has been proposed by measuring the DNA-morpholino hybridization hindered diffusion flux of probe ions Fe(CN)(6)(3-) through nanochannels of a porous anodic alumina (PAA) membrane. The flux of Fe(CN)(6)(3-) passing through the PAA nanochannels is recorded using an Au film electrochemical detector sputtered at the end of the nanochannels. Hybridization of the end-tethered morpholino in the nanochannel with DNA forms a negatively charged DNA-morpholino complex, which hinders the diffusion of Fe(CN)(6)(3-) through the nanochannels and results in a decreased flux. This flux is strongly dependent on ionic strength, nanochannel aperture, and target DNA concentration, which indicates a synergetic effect of steric and electrostatic repulsion effects in the confined nanochannels. Further comparison of the probe flux with different charge passing through the nanochannels confirms that the electrostatic effect between the probe ions and DNA dominates the hindered diffusion process. Under optimal conditions, the present nanochannel array-based DNA biosensor gives a detection limit of 0.1 nM. PMID- 20958079 TI - Platinum(II) chloride-catalyzed stereoselective domino enyne isomerization/Diels Alder reaction. AB - Chiral 1,6-enynes were prepared via Ir-catalyzed allylic substitutions. Their platinum(II) chloride-catalyzed domino enyne isomerization/Diels-Alder reaction provided stereoselective access to complex heterocycles. Very high diastereoselectivity was induced by a chirality center of the enyne. PMID- 20958078 TI - Development of the Ireland-Claisen rearrangement of alkoxy- and aryloxy substituted allyl glycinates. AB - The Ireland-Claisen rearrangement of 3-alkoxy- and 3-aryloxy-substituted allyl glycinates is presented. This [3,3]-sigmatropic rearrangement route offers direct access to syn beta-alkoxy and beta-aryloxy alpha-amino acid systems. In particular, N,N-diboc glycine esters rearrange with excellent diastereoselectivities (dr > 25:1). The synthesis of substrates, rearrangement optimization, and a discussion of stereoselection are presented. PMID- 20958080 TI - Photothermal release of single-stranded DNA from the surface of gold nanoparticles through controlled denaturating and Au-S bond breaking. AB - Photothermal release of DNA from gold nanoparticles either by thermolysis of the Au-S bonds used to anchor the oligonucleotides to the nanoparticle or by thermal denaturation has great therapeutic potential, however, both processes have limitations (a decreased particle stability for the former process and a prohibitively slow rate of release for the latter). Here we show that these two mechanisms are not mutually exclusive and can be controlled by adjusting laser power and ionic strength. We show this using two different double-stranded (ds)DNA-nanoparticle conjugates, in which either the anchored sense strand or the complementary antisense strand was labeled with a fluorescent marker. The amounts of release due to the two mechanisms were evaluated using fluorescence spectroscopy and capillary electrophoresis, which showed that irradiation of the decorated particles in 200 mM NaOAc containing 10 mM Mg(OAc)(2) with a pulsed 532 nm laser operating at 100 mW favors denaturation over Au-S cleavage to an extent of more than six-to-one. Due to the use of a pulsed laser, the process occurs on the order of minutes rather than hours, which is typical for continuous wave lasers. These findings encourage continued research toward developing photothermal gene therapeutics. PMID- 20958081 TI - Targeted drug delivery to lymphocytes: a route to site-specific immunomodulation? AB - Lymphocytes are central to the progression of autoimmune disease, transplant rejection, leukemia, lymphoma and lymphocyte-resident viral diseases such as HIV/AIDs. Strategies to target drug treatments to lymphocytes, therefore, represent an opportunity to enhance therapeutic outcomes in disease states where many current treatment regimes are incompletely effective and promote significant toxicities. Here we demonstrate that highly lipophilic drug candidates that preferentially access the intestinal lymphatics after oral administration show significantly enhanced access to lymphocytes leading to improved immunomodulatory activity. When coadministered with such drugs, lipids enhance lymphocyte targeting via a three tiered action: promotion of drug absorption from the gastrointestinal tract, enhancement of lymphatic drug transport and stimulation of lymphocyte recruitment into the lymphatics. This strategy has been exemplified using a highly lipophilic immunosuppressant (JWH015) where coadministration with selected lipids led to significant increases in lymphatic transport, lymphocyte targeting and IL-4 and IL-10 expression in CD4+ and CD8+ lymphocytes after ex vivo mitogen stimulation. In contrast, administration of a 2.5-fold higher dose of JWH015 in a formulation that did not stimulate lymph transport had no effect on antiinflammatory cytokine levels, in spite of equivalent drug exposure in the blood. The current data suggest that complementary drug design and delivery strategies that combine highly lipophilic, lymphotropic drug candidates with lymph-directing formulations provide enhanced selectivity, potency and therapeutic potential for drug candidates with lymphocyte associated targets. PMID- 20958082 TI - Translocator protein (TSPO) ligand-Ara-C (cytarabine) conjugates as a strategy to deliver antineoplastic drugs and to enhance drug clinical potential. AB - The aim of this work was to evaluate TSPO ligand-Ara-C conjugation as an approach for the selective delivery of the antineoplastic agent to brain tumors as well as for overcome P-gp resistance induction observed for the majority of cytotoxic agents, enhancing the drug clinical potential. To this end, the novel N imidazopyridinacetyl-Ara-C conjugates 3a-c, 10 and 15 have been prepared and evaluated for their cytotoxicity against glioma cell lines. In contrast to that observed for 3a-c and 10, the conjugate 15 resulted stable in both phosphate buffer and physiological medium. In all cases, the release of free Ara-C from hydrolyzed conjugates was checked by HPLC and ESI-MS analysis. Conjugates 10 and 15 displayed very high in vitro TSPO affinity and selectivity, and, hence, they may possess potential for targeted brain delivery. Due to the favorable features displayed by the conjugate 15, it was further evaluated on glioma cell lines, expressing high levels of TSPO, in the presence and in the absence of specific nucleoside transport (NT) inhibitors. In contrast to that observed for the free Ara-C, the presence of NT inhibitors did not reduce the cytotoxic activity of 15. Moreover, conjugate 15, as N(4)-acyl derivative of Ara-C, should be resistant to inactivation by cytidine deaminase, and it may possess enhanced propensity to target brain tumor cells characterized by a reduced expression of NTs. In addition, this conjugate behaves as a clear P-gp modulator and thereby may be useful to reverse MDR. Transport studies across the MDCKII-MDR1 monolayer indicated that conjugate 15 should overcome the BBB by transcellular pathway. All these features may be useful for enhancing the clinical potential of the nucleoside drug Ara-C. PMID- 20958083 TI - Oriented immobilization of prion protein demonstrated via precise interfacial nanostructure measurements. AB - Nanopatterning of biomolecules on functionalized surfaces offers an excellent route for ultrasensitive protein immobilization, for interaction measurements, and for the fabrication of devices such as protein nanoarrays. An improved understanding of the physics and chemistry underlying the device properties and the recognition process is necessary for performance optimization. This is especially important for the recognition and immobilization of intrinsically disordered proteins (IDPs), like the prion protein (PrP), a partial IDP, whose folding and stability may be influenced by local environment and confinement. Atomic force microscopy allows for both highly controllable nanolithography and for sensitive and accurate direct detection, via precise topographic measurements on ultraflat surfaces, of protein interactions in a liquid environment, thus different environmental parameters affecting the biorecognition phenomenon can be investigated in situ. Using nanografting, a tip-induced lithographic technique, and an affinity immobilization strategy based on two different histidine tagged antibodies, with high nM affinity for two different regions of PrP, we successfully demonstrated the immobilization of recombinant mouse PrP onto nanostructured surfaces, in two different orientations. Clear discrimination of the two molecular orientations was shown by differential height (i.e., topographic) measurements, allowing for the estimation of binding parameters and the full characterization of the nanoscale biorecognition process. Our work opens the way to several high sensitivity diagnostic applications and, by controlling PrP orientation, allows for the investigation of unconventional interactions with partially folded proteins, and may serve as a platform for protein misfolding and refolding studies on PrP and other thermodynamically unstable, fibril forming, proteins. PMID- 20958084 TI - Multifunctional stable and pH-responsive polymer vesicles formed by heterofunctional triblock copolymer for targeted anticancer drug delivery and ultrasensitive MR imaging. AB - A multifunctional stable and pH-responsive polymer vesicle nanocarrier system was developed for combined tumor-targeted delivery of an anticancer drug and superparamagnetic iron oxide (SPIO) nanoparticles (NPs). These multifunctional polymer vesicles were formed by heterofunctional amphiphilic triblock copolymers, that is, R (folate (FA) or methoxy)-poly(ethylene glycol)(M(w):5000) poly(glutamate hydrozone doxorubicin)-poly(ethylene glycol) (M(w):2000)-acrylate (i.e., R (FA or methoxy)-PEG(114)-P(Glu-Hyd-DOX)-PEG(46)-acrylate). The amphiphilic triblock copolymers can self-assemble into stable vesicles in aqueous solution. It was found that the long PEG segments were mostly segregated into the outer hydrophilic PEG layers of the vesicles, thereby providing active tumor targeting via FA, while the short PEG segments were mostly segregated into the inner hydrophilic PEG layer of the vesicles, thereby making it possible to cross link the inner PEG layer via the acrylate groups for enhanced in vivo stability. The therapeutic drug, DOX, was conjugated onto the polyglutamate segment, which formed the hydrophobic membrane of the vesicles using a pH-sensitive hydrazone bond to achieve pH-responsive drug release, while the hydrophilic SPIO NPs were encapsulated into the aqueous core of the stable vesicles, allowing for ultrasensitive magnetic resonance imaging (MRI) detection. The SPIO/DOX-loaded vesicles demonstrated a much higher r(2) relaxivity value than Feridex, a commercially available SPIO-based T(2) contrast agent, which was attributed to the high SPIO NPs loading level and the SPIO clustering effect in the aqueous core of the vesicles. Results from flow cytometry and confocal laser scanning microscopy (CLSM) analysis showed that FA-conjugated vesicles exhibited higher cellular uptake than FA-free vesicles which also led to higher cytotoxicity. Thus, these tumor-targeting multifunctional SPIO/DOX-loaded vesicles will provide excellent in vivo stability, pH-controlled drug release, as well as enhanced MRI contrast, thereby making targeted cancer therapy and diagnosis possible. PMID- 20958085 TI - General and mild preparation of 2-aminopyridines. AB - A general and facile one-pot amination procedure for the synthesis of 2 aminopyridines from the corresponding pyridine-N-oxides is presented as a mild alternative to S(N)Ar chemistry. A variety of amines and heterocyclic-N-oxides participate effectively in this transformation which uses the phosphonium salt, PyBroP, as a means of substrate activation. PMID- 20958086 TI - A de novo approach to the synthesis of glycosylated methymycin analogues with structural and stereochemical diversity. AB - A divergent and highly stereoselective route to 11 glycosylated methymycin analogues has been developed. The key to the success of this method was the iterative use of the Pd-catalyzed glycosylation reaction and postglycosylation transformation. This unique application of Pd-catalyzed glycosylation demonstrates the breath of alpha/beta- and d/l-glycosylation of macrolides that can be efficiently prepared using a de novo asymmetric approach to the carbohydrate portion. PMID- 20958087 TI - Highly enantioselective mukaiyama aldol reactions catalyzed by a chiral oxazaborolidinium ion: total synthesis of (-)-inthomycin C. AB - A cationic oxazaborolidinium-catalyzed asymmetric Mukaiyama aldol reaction of (1 methoxy-2-methyl-propenyloxy)-trimethylsilane with various aldehydes including alpha,beta-disubstituted acroleins has been developed in high yields and enantioselectivities. The synthetic utility of this methodology was demonstrated in the first short synthesis of naturally occurring inthomycin C in high enantiopurity. PMID- 20958088 TI - Cross-reactivity virtual profiling of the human kinome by X-react(KIN): a chemical systems biology approach. AB - Many drug candidates fail in clinical development due to their insufficient selectivity that may cause undesired side effects. Therefore, modern drug discovery is routinely supported by computational techniques, which can identify alternate molecular targets with a significant potential for cross-reactivity. In particular, the development of highly selective kinase inhibitors is complicated by the strong conservation of the ATP-binding site across the kinase family. In this paper, we describe X-React(KIN), a new machine learning approach that extends the modeling and virtual screening of individual protein kinases to a system level in order to construct a cross-reactivity virtual profile for the human kinome. To maximize the coverage of the kinome, X-React(KIN) relies solely on the predicted target structures and employs state-of-the-art modeling techniques. Benchmark tests carried out against available selectivity data from high-throughput kinase profiling experiments demonstrate that, for almost 70% of the inhibitors, their alternate molecular targets can be effectively identified in the human kinome with a high (>0.5) sensitivity at the expense of a relatively low false positive rate (<0.5). Furthermore, in a case study, we demonstrate how X-React(KIN) can support the development of selective inhibitors by optimizing the selection of kinase targets for small-scale counter-screen experiments. The constructed cross-reactivity profiles for the human kinome are freely available to the academic community at http://cssb.biology.gatech.edu/kinomelhm/ . PMID- 20958089 TI - Catalytic asymmetric formal [4 + 1] annulation leading to optically active cis isoxazoline N-oxides. AB - The catalytic asymmetric synthesis of densely functionalized cis-isoxazoline N oxides was realized with novel use of an organocatalyst, (S)-2 (azidodiphenylmethyl)pyrrolidine (4e) (Tan, B.; Zhu, D.; Zhang, L.; Chua, P. J.; Zeng, X.; Zhong, G. Chem.-Eur. J. 2010, 16, 3842; Olivares-Romero, J. L.; Juaristi, E. Tetrahedron 2008, 64, 9992), via an elegant formal [4 + 1] annulation strategy using readily available 2-nitroacrylates and alpha iodoaldehydes. PMID- 20958090 TI - Electrophysiology of respiratory chain complexes and the ADP-ATP exchanger in native mitochondrial membranes. AB - Transport of protons and solutes across mitochondrial membranes is essential for many physiological processes. However, neither the proton-pumping respiratory chain complexes nor the mitochondrial secondary active solute transport proteins have been characterized electrophysiologically in their native environment. In this study, solid-supported membrane (SSM) technology was applied for electrical measurements of respiratory chain complexes CI, CII, CIII, and CIV, the F(O)F(1) ATPase/synthase (CV), and the adenine nucleotide translocase (ANT) in inner membranes of pig heart mitochondria. Specific substrates and inhibitors were used to validate the different assays, and the corresponding K(0.5) and IC(50) values were in good agreement with previously published results obtained with other methods. In combined measurements of CI-CV, it was possible to detect oxidative phosphorylation (OXPHOS), to measure differential effects of the uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP) on the respective protein activities, and to determine the corresponding IC(50) values. Moreover, the measurements revealed a tight functional coupling of CI and CIII. Coenzyme Q (CoQ) analogues decylubiquinone (DBQ) and idebenone (Ide) stimulated the CII- and CIII-specific electrical currents but had inverse effects on CI-CIII activity. In summary, the results describe the electrophysiological and pharmacological properties of respiratory chain complexes, OXPHOS, and ANT in native mitochondrial membranes and demonstrate that SSM-based electrophysiology provides new insights into a complex molecular mechanism of the respiratory chain and the associated transport proteins. Besides, the SSM-based approach is suited for highly sensitive and specific testing of diverse respiratory chain modulators such as inhibitors, CoQ analogues, and uncoupling agents. PMID- 20958091 TI - Differential histone modification and protein expression associated with cell wall removal and regeneration in rice (Oryza sativa). AB - The cell wall is a critical extracellular structure that provides protection and structural support in plant cells. To study the biological function of the cell wall and the regulation of cell wall resynthesis, we examined cellular responses to enzymatic removal of the cell wall in rice (Oryza sativa) suspension cells using proteomic approaches. We find that removal of cell wall stimulates cell wall synthesis from multiple sites in protoplasts instead of from a single site as in cytokinesis. Nucleus DAPI stain and MNase digestion further show that removal of the cell wall is concomitant with substantial chromatin reorganization. Histone post-translational modification studies using both Western blots and isotope labeling assisted quantitative mass spectrometry analyses reveal that substantial histone modification changes, particularly H3K18(AC) and H3K23(AC), are associated with the removal and regeneration of the cell wall. Label-free quantitative proteome analyses further reveal that chromatin associated proteins undergo dramatic changes upon removal of the cell wall, along with cytoskeleton, cell wall metabolism, and stress-response proteins. This study demonstrates that cell wall removal is associated with substantial chromatin change and may lead to stimulation of cell wall synthesis using a novel mechanism. PMID- 20958092 TI - Type 2 diabetes in the First Nations population: a case example of clinical practice guidelines. AB - CONTEXT: Type 2 diabetes (T2D) is a major public health concern and has reached epidemic proportions in the Canadian First Nation population. Reasons for this epidemic are the consequences of low socioeconomic status, and challenges to screening, primary prevention, management and access to care. ISSUE: This article presents the authors' opinions of the healthcare needs specific to the First Nation population in Canada with respect to management of T2D. LESSONS LEARNED: The authors argue that the current Canadian Diabetes Association Clinical Practice Guidelines are insufficient to provide a basis for health care and funding policies related to T2D management in the First Nation population. The authors present their own recommendations in relation to funding policies and the appropriateness of services for the First Nation population. PMID- 20958093 TI - International Standard Cytogenomic Array Consortium. Interview by Alyson Krokosky, Sharon F Terry. PMID- 20958095 TI - Brain targeting of risperidone-loaded solid lipid nanoparticles by intranasal route. AB - Intranasal drug delivery is known to overcome the blood-brain barrier (BBB) for delivery of drugs to brain. The objective of this study was to prepare risperidone (RSP)-loaded solid lipid nanoparticles (RSLNs) and explore the possibility of brain targeting by nose-to-brain delivery. RSLNs were prepared by solvent emulsification-solvent evaporation method and characterized for drug content, particle size and size distribution, zeta potential, and in vitro drug release study. The pharmacodynamic study of RSLNs, which was performed by paw test using Perspex platform, showed higher hindlimb retraction time (HRT) values as compared with RSP solution (RS) indicating the superiority of RSLNs over the RS for brain targeting. The pharmacokinetics and biodistribution studies in mice showed that brain/blood ratio 1 h post-administration of RSLNs (i.n.) was found to be 1.36 +/- 0.06 (nearly 10- and 5-fold higher) as compared with 0.17 +/- 0.05 for RS (i.v.) and 0.78 +/- 0.07 for RSLNs (i.v.), respectively. Gamma scintigraphy imaging of mice brain following intravenous and intranasal administration confirmed the localization of drug in brain. This finding substantiates the existence of direct nose-to-brain delivery route for nanoparticles administered to the nasal cavity. PMID- 20958097 TI - Systematic user-based assessment of "Navigated Control Spine" / Systematische, nutzerzentrierte Evaluation von "Navigated Control Spine". AB - The aim of this study was the systematic preclinical assessment of a new mill for spinal surgery. This mill automatically switches off at predefined workspace margins. The system is called the "Navigated Control Spine". The workspace is planned intraoperatively with fluoroscopic images. Assessment was performed in a simulated surgical scenario with real surgical instruments and equipment, and the following criteria were measured: "milling accuracy" and "surgical workflow parameters". To simulate the patient, an anatomical spine model was created with a Rapid Prototyping machine. The models included electronic components that simulate injuries to the structures at risk. For the workflow parameters, the results show differences between experienced and inexperienced surgeons. The maximum accuracy for experienced surgeons was +0.31 mm and for inexperienced surgeons +0.57 mm. The dura, as one of the structures at risk, was never injured. PMID- 20958096 TI - Nitrate and nitrite content of human, formula, bovine, and soy milks: implications for dietary nitrite and nitrate recommendations. AB - BACKGROUND: Estimation of nitrate and nitrite concentrations of milk sources may provide insight into potential health risks and benefits of these food sources for infants, children, and adults. The World Health Organization and American Academy of Pediatrics recommends exclusive consumption of human milk for the first 6 months of life. Human milk is known to confer significant nutritional and immunological benefits for the infant. Consumption of formula, cow's, and soy milk may be used as alternatives to human milk for infants. METHODS: We sought to estimate potential exposure to nitrate and nitrite in human, formula, bovine, and soy milk to inform total dietary exposure estimates and recommendations. Using sensitive quantitative methodologies, nitrite and nitrate were analyzed in different samples of milk. RESULTS: Human milk concentrations of colostrum (expressed days 1-3 postpartum; n=12), transition milk (expressed days 3-7 postpartum; n=17), and mature milk (expressed >7 days postpartum; n=50) were 0.08 mg/100 mL nitrite and 0.19 mg/100 mL nitrate, 0.001 mg/100 mL nitrite and 0.52 mg/100 mL nitrate, and 0.001 mg/100 mL nitrite and 0.3 mg/100 mL nitrate, respectively, revealing that the absolute amounts of these anions change as the composition of milk changes. When expressed as a percentage of the World Health Organization's Acceptable Daily Intake limits, Silk(r) Soy Vanilla (WhiteWave Foods, Broomfield, CO) intake could result in high nitrate intakes (104% of this standard), while intake of Bright Beginnings Soy Pediatric(r) formula (PBM Nutritionals, Georgia, VT) could result in the highest nitrite intakes (383% of this standard). CONCLUSIONS: The temporal relationship between the provision of nitrite in human milk and the development of commensal microbiota capable of reducing dietary nitrate to nitrite supports a hypothesis that humans are adapted to provide nitrite to the gastrointestinal tract from birth. These data support the hypothesis that the high concentrations of breastmilk nitrite and nitrate are evidence for a physiologic requirement to support gastrointestinal and immune homeostasis in the neonate. PMID- 20958098 TI - Diffusion loading and drug delivery characteristics of alginate gel microparticles produced by a novel impinging aerosols method. AB - Microencapsulation of a hydrophilic active (gentamicin sulphate (GS)) and a hydrophobic non-steroidal anti-inflammatory drug (ibuprofen) in alginate gel microparticles was accomplished by molecular diffusion of the drug species into microparticles produced by impinging aerosols of alginate solution and CaCl(2) cross-linking solution. A mean particle size in the range of 30-50 um was measured using laser light scattering and high drug loadings of around 35 and 29% weight/dry microparticle weight were obtained for GS and ibuprofen respectively. GS release was similar in simulated intestinal fluid (phosphate buffer saline (PBS), pH 7.4, 37 degrees C) and simulated gastric fluid (SGF) (HCl, pH 1.2, 37 degrees C) but was accelerated in PBS following incubation of microparticles in HCl. Ibuprofen release was restricted in SGF but occurred freely on transfer of microparticles into PBS with almost 100% efficiency. GS released in PBS over 7 h, following incubation of microparticles in HCl for 2 h was found to retain at least 80% activity against Staphylococcus epidermidis while Ibuprofen retained around 50% activity against Candida albicans. The impinging aerosols technique shows potential for producing alginate gel microparticles of utility for protection and controlled delivery of a range of therapeutic molecules. PMID- 20958099 TI - Nanomaterials as matrices for enzyme immobilization. AB - Nanomaterials constitute novel and interesting matrices for enzyme immobilization. While their high surface to volume ratio is an obvious advantage, their Brownian motion can impact the behavior of enzymes immobilized on these matrices. Carbon nanotubes, superparamagnetic nanoparticles, and mesoporous materials constitute some important classes of matrices. Such immobilized enzyme systems have been used in both aqueous and low water media for biocatalysis and resolution of racemates. This overview examines the behavior of enzymes immobilized on nanomaterials and discusses the results reported with such biocatalyst preparations. PMID- 20958100 TI - Evaluation of the effect of tolterodine on pupil diameter and anterior chamber parameters with the Pentacam. AB - BACKGROUND: To evaluate the effect of tolterodine on pupil diameter and anterior chamber parameters, including volume, depth, and angle, with the Pentacam. METHODS: The 56 eyes of 28 patients who were diagnosed as having overactive bladder and planned to be treated with tolterodine were followed up prospectively in the study. All the patients underwent full ophthalmic examination and scanning with the Pentacam (Oculus, Inc., Wetzlar, Germany) before and 4 weeks after the start date of tolterodine therapy. In addition, the 30 eyes of 15 healthy volunteers were analyzed twice as a control group for repeatability of the measurements. RESULTS: The quantitative descriptors of the anterior chamber before and after the treatment, respectively, were as follows: pupil diameter, 3.02 +/- 0.56 mm and 3.01 +/- 0.55 mm; anterior chamber depth, 2.74 +/- 0.35 mm and 2.75 +/- 0.34 mm; anterior chamber volume, 150.23 +/- 33.95 mm(3) and 150.27 +/- 34.48 mm(3); and anterior chamber angle, 34.56 degrees +/- 5.68 degrees and 35.03 degrees +/- 5.99 degrees . For all the measurements, the differences did not reach statistical significance (p > .05). Also, the comparison of the same parameters obtained from the first and second measurements of healthy volunteers was not statistically significant (p > .05). CONCLUSION: Our study demonstrates that tolterodine does not affect pupil diameter and anterior chamber parameters, including angle, volume, and depth. Most likely, it is an organ-selective agent, inhibiting muscarinic receptors in the bladder rather than in the anterior segment of the eye. PMID- 20958101 TI - Antidepressant drugs and breastfeeding: a review of the literature. AB - The use of antidepressants in breastfeeding mothers is controversial: Manufacters often routinely discourage breastfeeding for the nursing mother despite the well known positive impact that breastfeeding carries on the health of the nursing infant and on his or her family and society. We conducted a systematic review of drugs commonly used in the treatment of postpartum depression. For every single drug two sets of data were provided: (1) selected pharmacokinetic characteristics such as half-life, milk-to-plasma ratio, protein binding, and oral bioavailability and (2) information about lactational risk, according to some authoritative sources of the literature: Drugs in Pregnancy and Lactation edited by Briggs et al. (Lippincott Williams, Philadelphia, 2008), Medications and Mothers' Milk by Hale (Hale Publishing, Amarillo, TX, 2010), and the LactMed database of TOXNET ( www.pubmed.gov ; accessed June 2010). Notwithstanding a certain variability of advice, we found that (1) knowledge of pharmacokinetic characteristics are scarcely useful to assess safety and (2) the majority of antidepressants are not usually contraindicated: (a) Selective serotinin reuptake inhibitors and nortryptiline have a better safety profile during lactation, (b) fluoxetine must be used carefully, (c) the tricyclic doxepine and the atypical nefazodone should better be avoided, and (d) lithium, usually considered as contraindicated, has been recently rehabilitated. PMID- 20958102 TI - Development of a WIC single-user electric breast pump protocol. AB - OBJECTIVE: This project describes the development of a protocol that compared issuing multi-user electric breast pumps to single-user breast pumps for Special Supplemental Nutrition Program for Women, Infants and Children (WIC) participants. METHODS: Forty breastfeeding mothers participating in WIC who were separated from their infants >=30 hours a week, planned to offer breastmilk until their infants turned 1 year, and used a WIC-loaned electric breast pump for at least 1 month were enrolled in the project. RESULTS: Results of this project indicate that an appropriate protocol to administer single-user electric breast pumps was developed and may provide some benefits to both WIC and WIC mothers. CONCLUSION: Recommendations to successfully continue using the single-user breast pump protocol include strengthening policies, procedures, and future issuance criteria. PMID- 20958103 TI - An evaluation of hospital breastfeeding policies in the Philadelphia metropolitan area 1994-2009: a comparison with the baby-friendly hospital initiative ten steps. AB - OBJECTIVE: The purpose of this study was to describe current breastfeeding policies and practices among Philadelphia, PA metropolitan hospitals and changes in their policies and practices over time. METHODS: In-person group interviews were conducted to obtain a composite picture of actual breastfeeding policies and practices. One questionnaire per hospital was completed based on responses from group consensus. Twenty-five hospitals providing maternity care were contacted. Information was obtained from personnel representing different areas of maternity services. Hospitals were classified according to the degree to which they were implementing the Ten Steps to Successful Breastfeeding. RESULTS: Mean breastfeeding rates at suburban hospitals were significantly higher than urban hospitals (72% vs. 49%, p = 0.015). Most hospitals were classified as high or moderately high implementers on six of the Ten Steps, including staff training (67%), printed information distributed to breastfeeding mothers (94%), breastfeeding initiation (61%), oral breastfeeding instruction given to mothers (83%), infant feeding schedules (89%), and hospital postpartum support (83%). Most hospitals reported partial or low implementation on two maternity practices: infant formula supplementation (61%) and rooming-in (72%). CONCLUSIONS: In the past 15 years, hospitals in the Philadelphia area have an increased awareness about breastfeeding and enhanced support of breastfeeding by healthcare professionals. In spite of an increase in overall breastfeeding rates, formula supplementation in hospitals and contact time between mothers and their newborns continue to be areas of concern. PMID- 20958104 TI - Pharmacological treatment of obesity in children and adolescents: current status and perspectives. AB - IMPORTANCE OF THE FIELD: The prevalence of overweight and obesity in children and adolescents is increasing rapidly, while the short- and long-term morbid outcomes make these entities a major public health concern. Initial steps in therapy are based on dietary and lifestyle intervention. In the presence of an insufficient progress, medication or - eventually - surgery may be recommended. Three drugs are currently used: orlistat, metformin, and sibutramine; other candidates are in development. However, trials assessing the efficacy and safety of the current medications are frequently affected by methodological limitations, in particular insufficient power and period of follow-up. AREAS COVERED IN THIS REVIEW: The efficacy and safety of antiobesity drugs currently used for children and adolescents are reviewed. Additional information on upcoming agents is presented. WHAT THE READER WILL GAIN: This is an exhaustive review of current state on controversial issues regarding drugs used in children and adolescent obesity, specifically related with their efficacy and safety. TAKE HOME MESSAGE: The efficacy of these drugs is modest. Our knowledge of their efficacy and safety comes from clinical trials affected by insufficient follow-up (1 year or less); very often, these trials are of limited power. Further data from larger and longer well-designed clinical trials would be advisable. PMID- 20958105 TI - Interventions to increase the duration of breastfeeding in obese mothers: the Bassett Improving Breastfeeding Study. AB - OBJECTIVE: Maternal obesity is associated with poor breastfeeding outcomes, yet no intervention has been developed to improve them. To ascertain whether increased breastfeeding support or provision of a breast pump is a feasible, effective intervention to improve breastfeeding, we enrolled obese women who intended to breastfeed in two randomized trials. METHODS: In Bassett Improving Breastfeeding Study (BIBS) 1, 40 women received targeted breastfeeding support in the hospital and via telephone or usual care. Information regarding breastfeeding was collected via telephone for 7 days after delivery and at 30 and 90 days postpartum. In BIBS 2, 34 obese mothers received a manual or electric breast pump to use for 10-14 days or no pump; data collection was similar. RESULTS: In both experiments, randomization failed to distribute women of differing postpartum body mass index adequately among the treatment groups. When analyses were adjusted for this, there was no difference in BIBS 1 between targeted and usual care groups and in BIBS 2 among the treatment groups in the proportion of women still breastfeeding at the times studied. CONCLUSIONS: In future studies of obese women, stratified randomization may be necessary. Further development of interventions to help obese women achieve optimal breastfeeding outcomes is required. PMID- 20958106 TI - Intent to breastfeed: a population-based perspective. AB - BACKGROUND: Prenatal maternal intent to breastfeed can indicate postnatal breastfeeding practices and may serve to indicate potential barriers to breastfeeding. Breastfeeding rates in West Virginia, a primarily rural state, are among the lowest in the United States, and minimal research has been published to date on population-based prenatal intent to breastfeed among rural women. METHODS: Secondary data analysis of population-based data was conducted using two state-linked datasets. State data included all live singleton births from at least 20 weeks of gestation in West Virginia from 2004 to 2006, for a total of 52,899 births. RESULTS: Results from the logistic regression model for the population-based study indicate that variables predicting intent to breastfeed among pregnant women in West Virginia include insurance status, maternal education, maternal age, parity, marital status, timing of prenatal care initiation, and prenatal smoking status. CONCLUSIONS: Prenatal identification of characteristics associated with lack of intent to breastfeed can serve to inform healthcare providers of women who are at risk for not breastfeeding for directed breastfeeding promotion and intervention, complementing education of healthy lifestyle choices such as breastfeeding promotion with smoking cessation. PMID- 20958107 TI - In vivo cytogenetic studies on rat's bone-marrow cells of structurally related Schiff base complexes. AB - The in vivo interactions of structurally-related Ni(II) and Fe(III) Schiff base complexes based on N-(8-quinolyl)salicylaldimine (HL(1)) and N-(8 quinolyl)napthaldimine (HL(2)) ligands with DNA molecules in the bone-marrow cells of rats were demonstrated using chromosomal aberrations (CAs) assay. The complexes differ by one aromatic group on the aldehyde site of the Schiff base (basicity or lipophilicity), or by the type of the central metal ions (Ni(II) or Fe(III)). Animals were injected intraperitoneally (i.p) with different concentrations of each drug, and CAs were examined in bone-marrow cells, 15 hours later. A significant increase in the frequency of CAs was induced upon treatment with 15 mg / kg weight of L(1) complexes (P < 0.001), and not with L(2) complexes (P > 0.05). Also, the magnitude of aberrations induced by L(1)-Ni(II) was higher than that induced by L(1)-Fe(III) (P < 0.01). The binding data, estimated using UV-Visible absorption technique, showed that the metal binding of HL(1) was much greater than that of HL(2) and that the affinity of HL(1) towards Ni(II) is higher than that for Fe(III) ions. Thus, the trends in the presented in vivo results signify the important role of complex stability in predicting the clastogenicity of metal-ion-chelating Schiff base drugs. PMID- 20958109 TI - To switch (statins) or not to switch? That is the question. AB - Cost is an important consideration when deciding which drugs to prescribe. The problem is becoming more evident because effective, well-tolerated and evidence based generic drugs are now widely available. More specifically, switching to a cheaper statin formulation might result in less effective treatment in terms of event reduction or achievement of lipid goal. Better patient adherence to treatment is also not always achieved by switching to generics. This editorial considers this debate. PMID- 20958108 TI - Cytopede: a three-dimensional tool for modeling cell motility on a flat surface. AB - When cultured on flat surfaces, fibroblasts and many other cells spread to form thin lamellar sheets. Motion then occurs by extension of the sheet at the leading edge and retraction at the trailing edge. Comprehensive quantitative models of these phenomena have so far been lacking and to address this need, we have designed a three-dimensional code called Cytopede specialized for the simulation of the mechanical and signaling behavior of plated cells. Under assumptions by which the cytosol and the cytoskeleton are treated from a continuum mechanical perspective, Cytopede uses the finite element method to solve mass and momentum equations for each phase, and thus determine the time evolution of cellular models. We present the physical concepts that underlie Cytopede together with the algorithms used for their implementation. We then validate the approach by a computation of the spread of a viscous sessile droplet. Finally, to exemplify how Cytopede enables the testing of ideas about cell mechanics, we simulate a simple fibroblast model. We show how Cytopede allows computation, not only of basic characteristics of shape and velocity, but also of maps of cell thickness, cytoskeletal density, cytoskeletal flow, and substratum tractions that are readily compared with experimental data. PMID- 20958110 TI - Treating gestational trophoblastic disease. AB - IMPORTANCE OF THE FIELD: Gestational trophoblastic disease is one of the few human malignancies that is curable, even in advanced stages of the disease. However, appropriate management and follow-up are essential components in curing this disease. AREAS COVERED IN THIS REVIEW: Observational, retrospective and prospective studies evaluating the efficacy of medical and surgical management of gestational trophoblastic disease were analyzed to provide a comprehensive review of current and new treatment modalities. We searched PubMed, Medline and the Library of Congress from January 1965 to January 2010. WHAT THE READER WILL GAIN: The reader will obtain information on how to classify gestational trophoblastic neoplasia (GTN) into low- and high-risk groups, as well as learn the medical and surgical management of low- and high-risk GTN and recurrent GTN. The effectiveness of treatment regimens and subsequent fertility is also reviewed. TAKE HOME MESSAGE: GTN is highly responsive to chemotherapy. However, surgery is an important adjunct in select cases. Even in advanced-stage or recurrent disease, cure can be achieved and fertility preserved. PMID- 20958111 TI - Emerging sublingual immunotherapy drugs. AB - IMPORTANCE OF THE FIELD: There is epidemiological evidence that respiratory allergy has reached epidemic proportions; owing to the related socio-economic impact, this topic deserves particular attention. An integrated approach involving pharmacotherapy and the immunomodulatory effect of immunotherapy is expected to optimize the management of respiratory allergy, reducing its clinical and economic burdens. Sublingual immunotherapy (SLIT) has gained increasing interest for its efficacy comparable to traditional subcutaneous immunotherapy and its good safety profile. AREAS COVERED IN THIS REVIEW: A review of the up-to date state of the art concerning the key aspects of SLIT is provided; the critical issues are discussed in the light of the comprehensive revision of the recent World Allergy Organization position paper and the subsequent literature, paying particular attention to efficacy, safety, additional effects, adherence and clinical developments. WHAT THE READER WILL GAIN: The overview of current certainties and concerns, related to the use of SLIT, allows the reader's insight into the future directions of research and clinical applications of SLIT, aimed at covering current unmet needs. TAKE HOME MESSAGE: A large amount of experimental evidence sustains the use of SLIT, though some aspects still need to be clarified to provide clear, evidence-based recommendations. Unmet needs represent the basis for future research, while clinical hypotheses would open the search for new indications and modalities. PMID- 20958112 TI - Oxidative stress after sulfur mustard intoxication and its reduction by melatonin: efficacy of antioxidant therapy during serious intoxication. AB - Sulfur mustard (SM) is an important chemical warfare agent. The mechanism of SM toxicity still has not been fully recognized. However, oxidative stress and following the damaging of macromolecules in the human body is considered one of the crucial steps in SM toxicity. Rats intoxicated with pure (i.e., distilled) SM were used as a model organism. The doses, 0 (control), 5, 20, and 80 mg/kg of body weight, were applied intradermally. A hormone with strong antioxidant potency, melatonin, was applied (25 and 50 mg/kg, subcutaneously) into the other group of rats exposed with the same doses of SM. Total plasma protein, ferric reducing antioxidant power (FRAP), thiobarbituric-acid-reactive substances (TBARS), and plasma protein carbonyls were assayed in blood plasma. A significant decrease of total plasma proteins was found for control, and the lowest dose of SM was treated with melatonin. Melatonin was also able to enhance the production of low-molecular-weight antioxidants, as the SM-intoxicated rats had significantly (P <= 0.01) increasing FRAP levels after intoxication with SM in doses of 20 and 80 mg/kg, when compared to the control treated with melatonin. Melatonin also decreased TBARS level, representing reduced lipid peroxidation (LPO). However, LPO seems to be of less importance for SM toxic impact. The more reliable parameter was the level of total plasma protein carbonyls. The carbonyl levels were significantly increased due to SM, and the carbonylation was slowed due to melatonin intake. In conclusion, melatonin seems to be a prospective compound in reducing SM toxicity impact in the rat. PMID- 20958113 TI - Medication adherence with disease modifying treatments for multiple sclerosis among US employees. AB - OBJECTIVE: Medication adherence in chronic diseases like multiple sclerosis (MS) plays an important role in predicting long-term outcomes, yet existing data on adherence in employee populations are not found. The objective of this study is to compare adherence among employees treated with disease modifying treatments (DMTs) for MS in the year following treatment initiation. METHODS: A healthcare claims database of US employees from 2001 to 2008 was used to identify patients with MS based on two or more DMT prescriptions or one DMT prescription with an MS diagnosis (ICD-9 340.xx). Employees continuously employed and with health plan coverage for 1 year following DMT initiation were eligible. Two measures were used in estimating adherence after DMT initiation: (1) persistence (the number of days from DMT initiation to the first 30-day gap in supply) and, (2) annual compliance, assessed by the medication possession ratio (MPR = number of days with a medication supply in the year divided by 365 days). Wilcoxon tests on time to-event data and t-tests were used to compare persistence and MPR, respectively, between DMT groups. Other measures of resource utilization were also compared. RESULTS: Overall, 358 employees [179 interferon [IFN]-beta1a-IM (Avonex* = 'A'); 63 IFN-beta1b (Betaseron? = 'B'); 20 IFN-beta1a-SC (Rebif? = 'R'); 96 glatiramer acetate (CopaxoneS = 'C')] were eligible for analysis. No significant differences in age, gender, and certain job-related variables existed between cohorts. Persistence was better for 'A' than 'B' (p = 0.039), 'C' (p = 0.0007), and 'R' (p = 0.130). At 1 year, a greater proportion of 'A' employees were persistent (60.34%) than 'B' (42.86%, p = 0.016), 'C' (42.71%, p = 0.0052), and 'R' (45.00%, p = 0.190). 'A' also had the highest MPR (0.782) which was significantly higher than 'C' (MPR = 0.698, p = 0.0160) and statistically equivalent to 'B' (MPR = 0.705, p = 0.0576) and 'R' (MPR = 0.761, p = 0.7347). LIMITATIONS: The study has limitations characteristic of administrative claims database studies and small sample sizes. The population may not be representative of undiagnosed/untreated MS patients, those not able to maintain employment, and those not using the initial therapy. CONCLUSIONS/RELEVANCE: Among employees treated with 'A', 'B', 'C', and 'R' for MS, 'A' patients had significantly greater medication adherence. PMID- 20958114 TI - Modelling the clinical and economic implications of galantamine in the treatment of mild-to-moderate Alzheimer's disease in Germany. AB - OBJECTIVE: This analysis was to assess the long-term clinical and economic implications of galantamine in the treatment of mild-to-moderate Alzheimer's disease (AD) in Germany. METHODS: An economic model was developed using discrete event simulation to predict the course of AD through changes in cognition, behavioural disturbance, and function over time. It compares the costs and benefits of galantamine versus no-drug treatment and ginkgo biloba. Clinical data were mainly derived from analyses of pooled data from clinical trials. Epidemiological and cost data were obtained from literature and public data sources. Costs (2009 euros) from the perspective of the German Statutory Health Insurance were used. RESULTS: The mean survival time for the model population is about 3.44 years over 10 years of simulation. Galantamine delays average time to severe stage of the disease by 3.57 and 3.36 months, compared to no-drug treatment and ginkgo biloba, respectively. Galantamine reduces time spent in an institution by 2.34 and 2.21 months versus no-drug treatment and ginkgo biloba, respectively. The use of galantamine is projected to yield net savings of ?3,978 and ?3,972 per patient versus no-drug and ginkgo biloba treatments. These results, however, may be limited by lack of long-term comparative efficacy data as well as data on long-term care costs based on multiple outcome measures. CONCLUSION: Compared to no-drug treatment and ginkgo biloba, galantamine therapy provides clinical benefits and achieves savings in healthcare costs associated with care for patients with mild-to-moderate AD in Germany. PMID- 20958115 TI - The secretory mechanisms in equine platelets are independent of cytoskeletal polymerization and occur through membrane fusion. AB - Studies in animal models are useful to understand the basic mechanisms involved in hemostasis and the functional differences among species. Ultrastructural observations led us to predict differences in the activation and secretion mechanisms between equine and human platelets. The potential mechanisms involved have been comparatively explored in the present study. Equine and human platelets were activated with thrombin (0.5 U/ml) and collagen (20 ug/ml), for 90 seconds, and samples processed to evaluate: i) ultrastructural changes, by electron microscopy, ii) actin polymerization and cytoskeletal assembly, by polyacrylamide gel electrophoresis, and iii) specific molecules involved in activation and secretion, by western blot. In activated human platelets, centralization of granules, cytoskeletal assembly and fusion of granules with the open canalicular system were observed. In activated equine platelets, granules fused together forming an organelle chain that fused with the surface membrane and released its content directly outside the platelets. Human platelets responded to activation with actin polymerization and the assembly of other contractile proteins to the cytoskeleton. These events were almost undetectable in equine platelets. When exploring the involvement of the synaptosomal-associated protein-23 (SNAP-23), a known regulator of secretory granule/plasma membrane fusion events, it was present in both human and equine platelets. SNAP-23 was shown to be more activated in equine platelets than human platelets in response to activation, especially with collagen. Thus, there are significant differences in the secretion mechanisms between human and equine platelets. While in human platelets, activation and secretion of granules depend on mechanisms of internal contraction and membrane fusion, in equine platelets the fusion mechanisms seem to be predominant. PMID- 20958116 TI - Immune thrombocytopenic purpura occurred prior to multiple extranodal diffuse large B cell lymphoma. PMID- 20958118 TI - Pharmacotherapy of dyslipidemias in the adult population. AB - IMPORTANCE OF THE FIELD: Lipid-modifying drugs are therapeutic options that have been shown to reduce the biological and clinical burden related to atherosclerosis; they can be used to correct minor lipid abnormalities, as well as the more severe dyslipidemias that can be met in clinical practice. AREAS COVERED IN THIS REVIEW: HMG-CoA reductase inhibitors (statins) surely represent the choice agents, and must be utilized in relation to the global cardiovascular risk of a hypercholesterolemic subject. When treatment is only partly effective, association therapy is a reasonable solution or, alternatively, a shift towards other less effective 'rescue' drugs or nutraceutical 'ancillary remedies'. In every case, drug tolerability warrants consideration. WHAT THE READER WILL GAIN: Pharmacotherapy of lipid disorders cannot be separated from the knowledge of the main clinical trial results and the pharmacological characteristics of hypocholesterolemic drugs. An appropriate treatment protocol is proposed and examined. TAKE HOME MESSAGE: Hypolipidemic drugs must be added to therapeutic lifestyle changes, and not substituted for them; they may be prosecuted indefinitely, without any interruption; drug adherence is a prerequisite of efficacy and clinical monitoring is necessary for both compliance and safety issues. PMID- 20958117 TI - Dipyridamole synergizes with nitric oxide to prolong inhibition of thrombin induced platelet shape change. AB - We and others have previously demonstrated that nitric oxide (NO)-induced inhibition of platelet shape change is important in regulating platelet adhesion and aggregation, and therapeutic intervention of this pathway is clinically relevant for secondary prevention of stroke with dipyridamole. In the present study, we investigated whether dipyridamole affected the shape change of aspirinated platelets. Platelet shape change was inhibited using both authentic NO and sodium nitroprusside, as monitored by light scattering and mean platelet volume measurements. Dipyridamole synergized with NO, even at supra-therapeutic levels, to inhibit thrombin-induced shape change and further potentiated cAMP dependent protein kinase (PKA) mediated phosphorylation of vasodilator stimulated phosphoprotein (VASP) Ser157, even without altered levels of platelet cAMP. The effect of dipyridamole on NO-inhibited shape change depended on cGMP synthesis as evaluated by inhibition of soluble guanylyl cyclase. Measured increases in cGMP levels by dipyridamole and NO was assessed by mathematical modeling and found to be consistent with inhibition of phosphodiesterase 5 (PDE5). The model could explain the unexpected efficiency of dipyridamole in inhibiting PDE5 at the measured cGMP levels, by the majority of cGMP being bound to cGMP-dependent protein kinase (PKG). Still, selective activators of PKG failed to extend NO mediated inhibition of the thrombin-induced platelet shape change, suggesting that PKG was not responsible for the inhibitory effect of NO and dipyridamole on shape change. The effects of dipyridamole were independent of the prostanoid and ADP pathways. Thus, the effect of dipyridamole on NO-mediated inhibition of platelet shape change may be an important and additional beneficial therapeutic effect of dipyridamole, which we suggest, is acting though localized amplification of the NO/cGMP/Phosphodiesterase3/cAMP/PKA-pathway. Probably, the efficiency of dipyridamole could be amplified clinically with NO donors. PMID- 20958119 TI - Efficacy and safety of ciclesonide in patients with severe asthma: a 12-week, double-blind, randomized, parallel-group study with long-term (1-year) follow-up. AB - OBJECTIVE: To investigate the efficacy and safety of ciclesonide in patients with severe asthma over a 1-year period. RESEARCH DESIGN AND METHODS: Patients aged 18 - 75 years with persistent asthma were enrolled in a 12-week, double-blind, randomized study and treated with ciclesonide 320 or 640 MUg twice daily (b.i.d.) with the option of continuing in a 40-week extension phase (EP). MAIN OUTCOMES MEASURES: Change in morning peak expiratory flow (PEF) from baseline to 12 weeks and safety over 1 year. RESULTS: 365 patients were randomized and 275 continued into the EP. During 12 weeks' treatment, morning peak expiratory flow significantly increased by 16 l/min (p < 0.001) and 14 l/min (p = 0.001) in the 320 and 640 MUg b.i.d. groups, respectively. Both doses significantly reduced total asthma symptom scores by 0.29 (p < 0.0001). In both groups, the incidence of adverse effects (AEs) was low and mean cortisol levels in serum and urine were not suppressed during the EP. CONCLUSIONS: Ciclesonide 320 MUg b.i.d. sustained lung function and asthma symptoms in patients with severe asthma over 12 weeks' treatment, and maintained lung function during a 40-week EP; ciclesonide 640 MUg b.i.d. did not provide additional benefits. Long-term use of ciclesonide was not associated with increased local AEs or negative effects on cortisol levels. PMID- 20958120 TI - Paving the way for targeting RSK in cancer. AB - The 90 kDa ribosomal S6 kinase (RSK) family is a group of highly conserved Ser/Thr kinases that promote cell proliferation, growth, motility and survival. Deregulated RSK expression or activity has been associated with several human diseases, including cancer. RSK lies downstream of the Ras/mitogen-activated protein kinase (MAPK) signalling pathway and is directly phosphorylated by the extracellular signal-regulated kinases 1 and 2 (ERK1/2). Significant advances in the field of RSK signalling have occurred in the past few years, unravelling novel RSK cellular substrates and biological functions as well as new RSK regulatory mechanisms. Together, these findings suggest that RSK may be a promising therapeutic target for the treatment of cancer, particularly those characterized by oncogenic mutations in components of the Ras signalling pathway. This article briefly describes our current knowledge on the impact of RSK on cell growth and proliferation, as well as RSK-dependent mechanisms associated with tumourigenesis. The potential of targeting RSK in cancer is discussed in light of available data on the biological functions of each RSK family members. Targeting RSK with small molecule inhibitors appears to be a promising path for cancer therapy, but several considerations need to be evaluated and will be discussed in detail. PMID- 20958129 TI - Verapamil sustained release: new formulation and convolution. AB - A novel bead formulation of verapamil hydrochloride was developed comprising a combination of extrusion and spheronization to produce a relatively high drug load, followed by coating of the bead with an insoluble polymer (ethylcellulose) that contains a water soluble channeling agent (lactose), thus allowing the application of a sufficiently thick outer coating that is uniform and robust without 'shutting down' release of the relatively insoluble drug. The new formulation provided the unexpected benefit that by adjusting both coating thickness and ethylcellulose/lactose ratio, it is possible to obtain essentially non-agitation sensitive and approximately zero-order drug release up to 14 hours in either KCl or two pH media, at stirring speeds of either 75 or 200 rpm with either the USP basket or USP paddle stirring method. PMID- 20958130 TI - In vitro and in vivo evaluation of a hydrogel-based prototype transdermal patch system of alfuzosin hydrochloride. AB - The first-line therapy for moderate to severe benign prostatic hyperplasia is the oral therapy by alfuzosin hydrochloride. Unfortunately, the oral therapy of alfuzosin is associated with several route-specific systemic side-effects. The current study was aimed to develop a prototype transdermal patch system for alfuzosin using a hydrogel polymer and optimize the drug delivery through the skin for systemic therapy. The prospective of different chemical enhancers (polyethylene glycol (PEG 400), isopropyl myristate, propylene glycol, menthol and L-methionine; 5% w/v) and iontophoresis (0.3 mA/cm(2)) in the alfuzosin delivery across the full thickness rat skin was assessed in vitro. In vivo iontophoretic studies were carried out using selected patch system (PEG 400) for a period of 6 h in Sprague-Dawley rats. Passive permeation studies indicated that the incorporation of chemical agents have moderate effect (~4- to 7-fold) on the alfuzosin skin permeability and reduced the lag time. Combined approach of iontophoresis with chemical enhancers significantly augmented the drug transport (~ 43- to 72-fold). In vivo pharmacokinetic parameters revealed that the iontophoresis (transdermal patch with PEG 400) significantly enhanced the C(max) (~ 3-fold) and AUC(0-alpha) (~ 4-fold), when compared to control. The current study concludes that the application of iontophoresis (0.3 mA/cm(2)) using the newly developed agaorse-based prototype patch with PEG 400 could be utilized for the successful delivery of alfuzosin by transdermal route. PMID- 20958131 TI - The gastrointestinal manifestations with swine influenza (H1N1) in hospitalized adults. PMID- 20958133 TI - Vestibular tributaries to the vein of the vestibular aqueduct. AB - CONCLUSION: The vein of the vestibular aqueduct drains blood from areas extensively lined by vestibular dark cells (VDCs). A possible involvement in the pathogenesis of an impaired endolymphatic homeostasis can be envisioned at the level of the dark cells area. OBJECTIVES: The aim of this study was to investigate the vascular relationship between the vein of the vestibular aqueduct and the vestibular apparatus, with focus on the VDCs. METHODS: Sixteen male Wistar rats were divided into groups of 6 and 10. In the first group, 2 MUm thick sections including the vein of the vestibular aqueduct, utricle, and crista ampullaris of the lateral ampulla were examined by light microscopy and computer generated three-dimensional imaging. In the second group, ultrathin sections including venules and VDCs were examined by transmission electron microscopy. RESULTS: A microvascular network was observed in close relation to the VDCs in the utricle and the crista ampullaris of the lateral semicircular canal in the vestibular apparatus. One major vein emanated from these networks, which emptied into the vein of the vestibular aqueduct. Veins draining the saccule and the common crus of the superior and posterior semicircular canals were likewise observed to merge with the vein of the vestibular aqueduct. PMID- 20958132 TI - Ameliorative effect of purple bamboo salt-pharmaceutical acupuncture on cisplatin induced ototoxicity. AB - CONCLUSION: Our findings demonstrated that purple bamboo salt (PBS) pharmaceutical acupuncture has an ameliorative effect on cisplatin-induced ototoxicity. OBJECTIVES: We have previously reported that PBS exhibited anti allergic and anti-inflammatory actions in vitro and in vivo. Pharmaceutical acupuncture is a traditional oriental therapeutic technique that combines acupuncture with herbal treatment. The aim of this study was to investigate the protective effect and mechanism of PBS-pharmaceutical acupuncture against cisplatin-induced ototoxicity in the auditory cell line, HEI-OC1, and in vivo. METHODS: The ELISA method, a caspase-3 assay, an MTT assay, Western blot analysis, and a luciferase assay were utilized to investigate the effect of PBS in vivo and in vitro. RESULTS: When it was acupunctured at the Ermen acupoint (triple energizer meridian 21) after an administration of cisplatin, PBS pharmaceutical acupuncture significantly suppressed interleukin (IL)-6 production and caspase-3 activation induced by cisplatin in the cochlea. In addition, PBS significantly inhibited cisplatin-induced apoptosis and IL-6 production in HEI OC1 cells. PBS also suppressed cytochrome c release and caspase-3 activation, and it inhibited extracellular signal-related kinase and nuclear factor-kappaB activation in HEI-OC1 cells. PMID- 20958134 TI - Emergency ureteroscopic treatment for upper urinary tract calculi obstruction associated with acute renal failure: feasible or not? AB - PURPOSE: To determine the efficacy and safety of emergency ureteroscopy (URS) and holmium:yttrium-aluminum-garnet (Ho:YAG) laser lithotripsy for ureteral calculi that are associated with acute renal failure (ARF). PATIENTS AND METHODS: We retrospectively evaluated a cohort of 49 patients who underwent URS from November 2005 to November 2008 for ARF that was caused by calculi obstruction of the upper urinary tract. The mean (maximal diameter) stone size was 1.48 cm. Acute renal failure was demonstrated by oliguria or anuria and marked increase in serum creatinine and blood urea nitrogen levels. All the patients were treated with URS and Ho:YAG laser lithotripsy emergently. Ureteral stent placement was performed in all cases after lithotripsy. A plain film of the kidneys, ureters, and bladder and abdominal ultrasonography were performed to evaluate efficacy of treatment on the first day postoperatively. Serum creatinine and blood urea nitrogen levels and urine volume were successively monitored until they returned to normal. All patients had postoperative imaging, including ultrasonography and excretory urography, to confirm stone clearance and exclude late obstructive complications 3 months after URS. RESULTS: URS and laser lithotripsy were successfully performed in all patients. There were no major intraoperative complications, and no procedure was converted to open surgery. The mean operative time was 35 minutes. The successful fragmentation rate was 95.5%. The overall stone-free rate was 91.8%. Normal renal function returned in 46 (93.8%) patients within 7 days. No postoperative ureteral stricture occurred after 3 months. CONCLUSIONS: URS and Ho:YAG laser lithotripsy represent an effective and safe modality for treating patients with ARF that is caused by calculi obstruction of the upper urinary tract in strictly selected situations. PMID- 20958135 TI - NS-398 (a selective cyclooxygenase-2 inhibitor) decreases agonist-induced contraction of the human ureter via calcium channel inhibition. AB - PURPOSE: Recently, it has been demonstrated that ureteral obstruction is associated with increased cyclooxygenase (COX)-2 expression and that selective COX-2 inhibitors provide potent analgesia with fewer side effects in patients with ureteral stones. Moreover, selective COX-2 inhibitors have been shown to decrease in vitro contractility of the human ureter. We aimed at evaluating the effects of the selective COX-2 inhibitor NS-398 on human ureteral smooth muscle contractility and compare its potency with that of nonselective COX inhibitors, COX-1 inhibitors, and other COX-2 inhibitors. MATERIALS AND METHODS: Ureteral samples were obtained from human adult subjects undergoing radical nephrectomy. After isolating the upper ureteral strips, we analyzed the contractile responses of the ureteral strips to high potassium (KCl 35 mM) and Bay K 8644 and the relaxation responses of a nonspecific COX inhibitor (indomethacin), a COX-1 inhibitor (SC-560), and a COX-2 inhibitor (NS-398 and celecoxib) to KCl and Bay K 8644-induced contraction by measuring isometric tension. RESULTS: NS-398 produced dose-dependent (10-9-10-5 M) relaxation of KCl (35 mM)-precontracted strips of the ureter, whereas indomethacin (10-8-10-5 M) and SC-560 (10-9-10-5 M) did not. Both tonic and phasic contraction of Bay K 8644 (methyl-1,4-dihydro-2,6-dimethyl 3-nitro-4-2(trifluoromethylphenyl)pyridine-5-carboxylate) (1 MUM) were significantly inhibited by NS-398 (10-5 M). Another selective COX-2 inhibitor, celecoxib, did not show potent inhibitory effects as strong as those of NS-398. CONCLUSIONS: We concluded that NS-398 reduces tonic or phasic contraction by inhibiting the action of voltage-dependent calcium channels. NS-398 has dual inhibitory effects with COX-2 inhibition on ureteral spasms due to renal or ureteral colic. PMID- 20958140 TI - An animal model for assessment of heat distribution and neural damage around the endo shears coagulation device-applications for laparoscopic nerve-sparing surgery. AB - BACKGROUND AND PURPOSE: Current urologic laparoscopic procedures include preservation of locoregional nerve fibers. The use of electrical coagulation is limited because of tissue conductance of current and heat production. While ultrasonic coagulation does not use electricity, heat is still produced. We designed an animal model to characterize the heat spread around ultrasonic devices and assess whether it is neurodestructive. MATERIALS AND METHODS: 10 rats were anesthetized; their skin was reflected, exposing the muscles. An ultrasonic probe was introduced into the tissue, and coagulation was performed for 10 seconds. Tissue temperature was measured using four thermocouples, at distances of 4, 8, 12, and 16 mm from the probes and in a circumferential manner. Thermal mapping of the probes was performed with an infrared camera. Further, four rats were anesthetized; the skin above their inner thighs was reflected bilaterally exposing the "nervus ischiadicus." Coagulation was performed in varying distances from the nerve on one side while the other served as control. One week later, the animals were sacrificed, and the nerves were obtained. Silver staining was used to assess the vitality of the axons. RESULTS: In distances of 4 to 8 mm from the device, temperatures as high as 81 degrees C were recorded, and silver staining showed severe axonal damage. CONCLUSIONS: Although ultrasonic coagulation is efficient, local heat production may reach neurodestructive levels with a typical tissue distribution pattern. These features should be addressed during laparoscopic dissection and when considering nerve-sparing procedures. PMID- 20958141 TI - Systematic Review and Meta-Analysis of Nephrostomy Placement Versus Tubeless Percutaneous Nephrolithotomy. AB - Abstract Purpose: We performed a systemic review with meta-analysis to compare tubeless vs conventional percutaneous nephrolithotomy (PCNL) and assess the effectiveness and safety of this innovative procedure. Materials and Methods: A systematic review of PUBMED, EMBASE, LILACS, and Cochrane Library was performed to identify all randomized controlled trials (RCTs) that compared tubeless PCNL vs conventional PCNL. The analyzed outcomes were stone-free rate, pain assessment, analgesic medication requirements, operative time, hospitalization time, blood loss, and complications. Results: A total of 10 RCTs were identified that reported 621 patients. Seven studies analyzed stone-free rates. Meta analysis of the data resulted in no difference between tubeless and conventional PCNL. Operative time, blood transfusion, hemoglobin drop and postoperative fever did not differ between the groups. Meta-analysis of length of hospitalization and prolonged urinary drainage was analyzed and favored the tubeless PCNL group. Conclusions: Tubeless PCNL is a safe and effective procedure with a stone clearance rate comparable to that of conventional PCNL. Tubeless PCNL presented a shorter hospital stay and less postoperative urinary leakage. Pain reduction and minimization of analgesic requirements also were demonstrated. PMID- 20958142 TI - Optimization of a procedure used to measure aerosol characteristics of nebulized solutions using a cooled next generation impactor. AB - BACKGROUND: Cooling the Next Generation Impactor (NGI) is recommended to minimize evaporation due to heat transfer from impactor to aerosols when evaluating nebulized solutions. This methodology increases testing time for serial testing procedures. We hypothesize that after an initial prolonged cooling time, experiments could be repeated after shorter recooling times without sacrificing accuracy. METHODS: Three units of continuous output (HUDSON) and breath enhanced (PARI LC Plus) nebulizers were operated (6 L/min) with albuterol solution (2.5 mg/3 mL) into a cooled (4 degrees C) NGI (internal and external filters) calibrated at 15 L/min. Mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), % particles <5 MUm (P%<5), and % particles 1-3 MUm (P%1 3) were compared with three different protocols. Initial cooling of the NGI (90 min for all protocols) was followed by two measurements with recooling intervals of either 90 and 90 (protocol A), 60 and 60 (protocol B), or 30 and 30 min (protocol C). Albuterol was diluted and measured by spectrophotometry (276 nm). RESULTS: MMAD, GSD, P%<5, and P%1-3 for first measurements of all protocols (n = 9) were: 3.47 +/- 0.21 MUm, 2.31 +/- 0.07, 67.3 +/- 2.6%, and 40 +/- 2.3% (PARI) and 4.56 +/- 0.35 MUm, 2.16 +/- 0.08, 54 +/- 3.7%, and 22.4 +/- 2.8% (HUDSON). No differences were found between cooling protocols (p > 0.05). Percentage of variation from first measurement ranged from: -3.9 to +2.1% (PARI) and -4.1 to +2.9% (HUDSON) for MMAD; -5.6 to +2.6% (PARI) and -4.9 to +1.9% (HUDSON) for GSD; 0 to +4.6% (PARI) and -3.7% to +5.7% (HUDSON) for P%<5; and -2.4 to +5.2% (PARI) and -1.8 to +4.9% (HUDSON) for P%1-3. CONCLUSIONS: Aerosol characteristics of nebulized solutions determined by NGI are not affected by performing two repeat measurements after recooling the impactor for either 30 or 60 min after an initial 90-min time. PMID- 20958143 TI - Inhaled lidocaine for the treatment of asthma: lack of efficacy in two double blind, randomized, placebo-controlled clinical studies. AB - BACKGROUND: Asthma with severe or persistent exacerbations is treated with chronic oral corticosteroids (OCS), such as prednisone. Although efficacious, OCS treatment is often associated with side effects; thus, corticosteroid-sparing treatments are needed. METHODS: We conducted two double-blind, placebo controlled, clinical studies assessing lidocaine solution for inhalation (LSI; 40 mg twice daily; eFlow((r)) nebulizer) to treat asthma. Study 1-Mild/Moderate included 154 patients with mild-moderate asthma [forced expiratory volume in one second (FEV(1)) >=60% predicted, and >=12% improvement in FEV(1) (L) after short acting, inhaled beta-agonist; no OCS or inhaled corticosteroids (ICS) in previous month] and evaluated whether FEV(1) improved after 12 weeks of treatment. Study 2 OCS included 114 patients with more severe asthma (FEV(1) 35-85% of predicted values, treatment with OCS for >=6 months, average daily dose between 5 and 70 mg prednisone or equivalent, stable >=30 days) and evaluated whether 20 weeks of treatment had a corticosteroid-sparing effect, measured as reduced need for OCS. RESULTS: LSI did not improve pulmonary function in Study 1-Mild/Moderate, and did not have a corticosteroid-sparing effect in Study 2-OCS, when compared with placebo. Thus, the primary efficacy endpoints were not met. Significant improvements were not observed for asthma symptom scores, morning and evening peak expiratory flow values, FEV(1) % predicted, proportion of patients with asthma instability, and asthma quality-of-life scores at week 12 (Study 1 Mild/Moderate) or week 20 (Study 2-OCS). LSI was well tolerated. CONCLUSIONS: These results indicate that lidocaine solution for inhalation is not a useful treatment for asthma; it did not improve pulmonary function and did not have a corticosteroid-sparing effect. PMID- 20958144 TI - Delivery efficacy of a vibrating mesh nebulizer and a jet nebulizer under different configurations. AB - BACKGROUND: Jet nebulizers coupled to spacers are frequently used to promote drug lung deposition, but their clinical efficacy has not been established. Few in vivo studies have been performed with mesh nebulizers, commonly used to nebulize antibiotics. Our study compared inhaled mass and urinary drug concentration of amikacin by using three different nebulizer delivery configuration systems: a standard unvented jet nebulizer (Sidestream((r))) used alone or coupled to a 110 mL corrugated piece of tubing and a vibrating mesh nebulizer (e-Flow rapid((r))). METHOD: The inhaled mass of amikacin was assessed using the residual gravimetric method. Delivery efficacy was evaluated by assessing amikacin urinary drug concentration in six healthy spontaneously breathing volunteers. Urinary amikacin was monitored by fluorescent polarization immunoassay then cumulative excreted amount and antibiotic elimination rate were calculated. RESULTS AND CONCLUSIONS: The total daily amount of amikacin urinary excretion (Cu) was almost twice as high with eFlow rapid((r)) compared to Sidestream((r)) used alone; intermediate values being observed when the device was coupled to a corrugated piece of tubing. The latter configuration was also associated with a higher total daily amount of amikacin urinary excretion. In vivo drug output rate was around threefold higher with the eFlow Rapid((r)) than with the Sidestream((r)) used in any configuration. These results were concordant to those obtained with in vitro analysis comparing inhaled mass of amikacin for the three nebulizers. The elimination constant (Ke) and the mass median aerodynamic diameter (MMAD) did not differ between the three devices. In conclusion, the vibrating mesh nebulizer is more efficient, promoting larger urinary drug concentration and drug output. Coupling a corrugated piece of tubing to the standard jet nebulizer favors delivery efficacy. PMID- 20958153 TI - Dealing with retinal detachment in a patient with aphakia, an Artisan lens, and an ExPress valve in situ. AB - PURPOSE: To report our experience from a case with a retinal detachment in an eye with aphakia, an Artisan phakic anterior chamber lens, and an ExPress valve and describe its course after vitrectomy and gas tamponade. METHODS: Interventional case report. RESULTS: A 65-year-old man who had previously undergone cataract extraction, Artisan/Verisyse lens implantation, and ExPress valve insertion for the treatment of aphakia and refractory glaucoma presented with a superior retinal detachment. The patient underwent a 20-g pars plana 20g vitrectomy, cryotherapy, and sulfur hexafluoride (SF(6)) tamponade. Twenty days after vitrectomy, the Artisan lens remained in place and the retina attached. Twelve months postoperatively, the situation remained unchanged. CONCLUSION: Iris-claw lenses have been introduced in 2004 as an alternative option for the correction of aphakia. Vitreoretinal surgeons face a new therapeutic challenge since data with regard to retinal detachment repair in patients with Artisan lenses are very limited. In our case, all intraoperative vitrectomy manipulations were performed without difficulty through the Artisan lens, which remained stable during fluid air exchange as well as postoperatively, despite the movements of the gas bubble and the presence of the ExPress valve. Moreover, there was no displacement of the ExPress valve during the intraoperative manipulations of vitrectomy or dysfunction of the valve due to the existence of the gas in the postoperative period. PMID- 20958145 TI - The alkalizer citrate reduces serum uric Acid levels and improves renal function in hyperuricemic patients treated with the xanthine oxidase inhibitor allopurinol. AB - OBJECTIVE: Hyperuricemia, an integral component of metabolic syndrome, is a major health problem causing gout and renal damage. Urine alkalizers such as citrate preparations facilitate renal excretion of the uric acid, but its supportive effect on xanthine oxidase inhibitors has not been tested yet. We performed a randomized, prospective study of the effect of a combination of allopurinol and a citrate preparation on renal function in patients with hyperuricemia, employing 70 patients who had hyperuricemia with serum uric acid levels >=7.0 mg/dL, or those diagnosed as having hyperuricemia in the past. METHODS: They were randomly enrolled into two study groups: the allopurinol monotherapy (MT) group or combination treatment (CT) group with allopurinol and a citrate preparation. Allopurinol (100-200 mg/day) in the absence or presence of a citrate preparation (3 g/day) was administered for 12 weeks and levels of serum uric acid, its urinary clearance (Cua), and the renal glomerular filtration rates assessed with the creatinine clearance (Ccr) were evaluated before and after the treatment. RESULTS: Serum levels of uric acid decreased significantly in both groups, whereas the change observed was much greater in CT group. Cua was significantly increased in CT group but not in MT group. Ccr was not altered in both groups in general, whereas it was significantly increased in a fraction of CT group with decreased renal function. CONCLUSIONS: These results indicate that an additional use of citrate preparations with xanthine oxidase inhibitors is beneficial for patients with hyperuricemia, reducing circulating uric acid and improving their glomerular filtration rates. PMID- 20958157 TI - Practical poetry. PMID- 20958156 TI - Immunotoxicity of dibromoacetic acid administered via drinking water to female B6C3F1 mice. AB - Dibromoacetic acid (DBA) is a disinfection by-product commonly found in drinking water as a result of chlorination/ ozonation processes. The Environmental Protection Agency estimates that more than 200 million people consume disinfected water in the United States. This study was conducted to evaluate the potential immunotoxicological effects of DBA exposure when administered for 28 days via drinking water to B6C3F1 mice, at concentrations of 125, 500, and 1000 mg/L. Multiple endpoints were evaluated to assess innate, humoral, and cell-mediated immune components, as well as host resistance. Standard toxicological parameters were unaffected, with the exception of a dose-responsive increase in liver weight and a decrease in thymus weight at the two highest exposure levels. Splenocyte differentials were affected, although the effects were not dose-responsive. Exposure to DBA did not significantly affect humoral immunity (immunoglobulin M [IgM] plaque assay and serum IgM anti-sheep erythrocyte titers) or cell-mediated immunity (mixed-leukocyte response). No effects were observed on innate immune function in either interferon-gamma-induced in vitro macrophage cytotoxic activity or basal natural killer (NK)-cell activity. Augmented NK-cell activity (following exposure to polyinosinic-polycytidylic acid) was decreased at the low dose, however the effect was not dose-responsive. Finally, DBA exposure had no effect on resistance to infection with either Streptococcus pneumoniae or Plasmodium yoelii, or challenge with B16F10 melanoma cells. With the exception of changes in thymus weight, these results indicate that DBA exposure resulted in no immunotoxic effects at concentrations much larger than those considered acceptable in human drinking water. PMID- 20958158 TI - Escaping the phantom's ghostly grasp: on psychoanalysis as a performance art in the spirit world. PMID- 20958159 TI - Psychoanalysis as theater: the practical application of acting theory to psychotherapy and real life. PMID- 20958160 TI - The lessons of a classic revisited: Freud on Jensen's Gradiva. PMID- 20958161 TI - Freud, Frankenstein, and the art of loss. PMID- 20958162 TI - Samuel Clemens and Mark Twain: pseudonym as act of reparation. PMID- 20958163 TI - The bisexuality of Shakespeare's sonnets and implications for de Vere's authorship. PMID- 20958164 TI - "Stelle" in Henry James's, the 'Turn of the screw'. PMID- 20958167 TI - Microwave modified non-crosslinked pectin films with modulated drug release. AB - The effects of microwave on drug release properties of pectin films carrying sulfanilamide (SN-P), sulfathiazole (ST-P) and sulfamerazine (SM-P) of high to low aqueous solubilities were investigated. These films were prepared by solvent evaporation technique and treated by microwave at 80 W for 5-40 min. Their profiles of drug dissolution, drug content, matrix interaction and matrix crystallinity were determined by drug dissolution testing, drug content assay, differential scanning calorimetry, X-ray diffractometry and scanning electron microscopy techniques. Microwave induced an increase in matrix amorphousness but lower drug release propensity with a greater retardation extent in SN-P films, following a rise in strength of matrix interaction. A gain in amorphous structure does not necessarily increase the drug release of film. Microwave can possibly retard drug release of pectin film carrying water-soluble drug through modulating its state of matrix interaction. PMID- 20958168 TI - Personality disorder and violence: understand violence risk: an introduction to the special section personality disorder and violence. AB - This paper introduces the Special Section on personality disorder and violence. The first paper evaluates the impact of removing the Psychopathy Checklist (PCL R) as a mandatory element of a major approach to the assessment of violence risk the HCR-20. The second paper considers violence to self as well as violence to others; it examines the influence of dysfunctional personality traits in a sample of female offenders. The third paper provides a systematic framework for risk formulation, discussing how to bridge the gap between nomothetic research and the individual case. This paper concludes by arguing that there is a need to shift perspective from asking "what?" dysfunctional traits are relevant to future violence to "why?" are particular traits relevant. The "why?" question is particularly germane in the forensic arena where expert testimony must endeavor to provide a causal explanation of risk processes at the level of the individual. PMID- 20958169 TI - The role of psychopathic personality disorder in violence risk assessments using the HCR-20. AB - Antisocial and psychopathic traits are essential to evaluate when assessing risk for violence using the HCR-20. The role of the PCL-R on the HCR-20 was investigated using a series of meta-analytic tests. Across 34 samples in which both tools were rated, AUCs for violence were similar (~.69), and exclusion of the psychopathy item (H7) did not reduce the HCR-20's accuracy. Quantitative synthesis of results from multivariate analyses conducted in 7 raw datasets that used both tools demonstrated that the average probability of observing violence for every point increase on the HCR-20 (without H7), while controlling for the PCL-R, was 23%, whereas for the PCL-R it was -1%. The HCR-20 (without H7) added incremental validity to the PCL-R, whereas the converse was not true, and only the HCR-20 (without H7) possessed unique predictive validity. Results suggest the HCR-20's predictive validity was not negatively impacted by excluding the PCL-R. Areas for future study are discussed, including research on various ways to assess and incorporate into risk assessment personality traits related to violence. PMID- 20958170 TI - Suicidal and criminal behavior among female offenders: the role of abuse and psychopathology. AB - Childhood abuse is relatively prevalent among women and is an important risk factor for both criminal behavior and suicide-related behavior (SRB). Based on a sample of 266 female offenders, we address one theoretical and one practical issue. First, from a theoretical perspective, we assess whether internalizing (depression and anxiety) and externalizing (substance abuse and antisocial behavior) psychopathology mediate the relation between abuse on the one hand, and SRB or criminal behavior, on the other. Results indicate that externalizing problems mediate the relation between childhood abuse and both lifetime SRB (fully) and lifetime criminality (partially). Second, at a practical level, results indicate that a subscale of the Revised Psychopathy Checklist (PCL-R; Hare, 1991) that assesses lifetime criminal behavior adds incremental utility to postdicting SRB, beyond the variance accounted for by self-report measures of abuse and externalizing problems. However, none of the measures-including the PCL R-predicted future recidivism. PMID- 20958171 TI - Personality disorder and violence: making the link through risk formulation. AB - The extant research demonstrates that the combination of personality disorder and violence implies severe dysfunction, poor responsivity to treatment, more serious and persistent violence, and higher recidivism rates. Thus, it comes as no surprise that personality disorder is included in many of the available guidelines for assessing and managing violence. Unsurprisingly, the combination of personality pathology and violence frequently presents the greatest challenge to services, even those in whom violence risk assessment and management practice is established and routine. Conceptual and methodological limitations pervade the literature and a full explanation of the nature of the association between personality pathology and violence is still awaited. Furthermore, current approaches to risk assessment fail to provide a systematic framework for assessors to use to make sense of the heterogeneous presentations typically found in individuals with personality disorder and violence. In this paper, formulation is proposed as the critical process linking risk assessment and risk management. It is argued that assessors must move beyond a simple listing of risk factors and should instead produce detailed, comprehensive, individualized explanations of risk potential and risk management needs. Personality disorder is used in this paper to illustrate the important contribution of formulation to the risk assessment process, and in doing so, the link between personality pathology and violence is explored. PMID- 20958172 TI - Predictors of response and drop-out during intensive dialectical behavior therapy. AB - The purpose of this study was to examine the effectiveness, and predictors of response and drop-out during a four-week course of intensive dialectical behavior therapy (I-DBT) in 447 outpatients suffering from borderline personality disorder (BPD), over a 10-year period. Assessments included a diagnostic interview, the International Personality Disorder Examination Screening Questionnaire, the Beck Depression Inventory, and the Beck Hopelessness Scale. Among these participants, 103 started a second course of treatment. In agreement with previous reports, I DBT was effective in reducing levels of depression and hopelessness with a trend of increasing effectiveness over the study period. High schizoid scores and low narcissistic score predicted poor response. Treatment completion rate was high, and low education predicted dropout. A discussion on the usefulness of a second course of treatment should be held with patients and staff as it was not effective in reducing depression and hopelessness. PMID- 20958173 TI - Predicting self-injury in BPD: an investigation of the experiential avoidance model. AB - This study investigated the contribution of indices of experiential avoidance to prediction of frequency and lethality of self-injurious behaviour (SIB) in a female BPD sample (N = 71) with high levels of SIB and histories of poor treatment outcomes. The experiential avoidance model (EAM) tested included motivations for SIB, coping style and DSM-IV Avoidant PD criteria. Distinct findings for suicidal and non-suicidal SIB were noted. In partial support of the model, motivations related to relief from negative emotions positively predicted frequency of non-suicidal, but not suicidal, SIB. Avoidant PD traits predicted a pattern of more frequent, less risky non-suicidal SIB. However, reliance on avoidant coping strategies predicted lethality but not frequency of SIB, while self-blaming coping and SIB motivations related to a desire to influence others predicted frequency of non-suicidal SIB. Results suggest the need for investigation of a more complex model of the antecedents and functions of SIB that includes the contribution of Avoidant PD traits. PMID- 20958174 TI - Development of a borderline personality disorder-relevant picture stimulus set. AB - Individuals with borderline personality disorder (BPD) report erratic and poorly regulated emotional behavior. However, these abnormalities have not been confirmed in laboratory studies. This may be because the emotional stimuli employed have not been sufficiently relevant or evocative of psychological themes germane to BPD (e.g., threats to attachment). The aim of this study was to develop a picture stimulus set relevant to BPD that could be employed in research to examine emotion dysregulation thought to be central to BPD. Ninety pictures were initially selected from the International Affective Picture System that had putative interpersonal and social content across a range of pleasantness and intensity. The set was then rated by 19 clinical BPD research experts on two dimensions: How self-referential the picture would be to someone with BPD and the extent to which the picture represented an ideal-other to a prototypic BPD case. Two sets of pictures were generated for future research with BPD participants. PMID- 20958175 TI - Psychopathy in Iran: a cross-cultural study. AB - Few cross-cultural studies have assessed psychopathy and none have included a sample from non-western countries. This study investigated the factor structure of the Psychopathy Checklist: Screening Version (PCL:SV) in an Iranian sample, and compared the results with a western sample. Three hundred fifty-one Iranian prisoners were compared with 405 participants of the standardization sample of the PCL:SV. Confirmatory factor analysis and item response theory method were used for data analysis. The Iranian data fitted well with the hierarchical three factor model of psychopathy and neither two- nor four-factor models showed an adequate fit. Differential item functioning existed across samples, with discriminatory power of factor 1 (arrogant and deceitful interpersonal style) being lower in the Iranian sample that for factor 2 (deficient emotional experience) being greater in the Iranian sample than the standardization sample. Deficient emotional experience might be the most significant factor in diagnosing psychopathy, regardless of the studied culture. Other factors appear to be relatively culture-specific. PMID- 20958176 TI - External dacryocystorhinostomy: assessing factors that influence outcome. AB - PURPOSE: To present the experience of external dacryocystorhinostomy (DCR) at a tertiary referral center and investigate factors that may affect clinical outcomes. METHODS: The clinical records of all patients who underwent external DCR at Sydney Eye Hospital between May 2000 and August 2007 were reviewed. Data were collected in regards to patient demographics, preoperative assessment, operative details, surgical technique, postoperative management, and clinical outcomes. This information was then analyzed, with emphasis on factors that influence surgical outcomes and success. RESULTS: A total of 338 cases were reviewed. The mean age at time of surgery was 64.82 years and the majority of patients were female (65%). Epiphora was the major preoperative symptom. Assisted local anesthesia and day stay surgery were the most common surgical settings. There was a statistically significant difference in theatre time between consultant and trainee surgeons (P < 0.00001). The mean final follow-up time was 11 months. Overall, 77.3% of patients had full resolution of symptoms and 20.8% had partial resolution. Only five patients (1.9%) had no resolution of symptoms. There was no significant difference in outcomes between consultants and trainees. Patients with anatomical nasolacrimal obstruction had significantly better outcomes compared with functional obstruction (P = 0.04). The postoperative fluorescein dye disappearance test was a good predictor of clinical success (P = 0.005). Silicone intubation for greater than 6 months was associated with better outcomes (P = 0.002). CONCLUSIONS: The results at our tertiary center are comparable to results stated in the literature. In our series, only the amount of nasolacrimal obstruction and duration of postoperative intubation influenced surgical success. PMID- 20958177 TI - Tumors of the lacrimal drainage system. AB - Tumors of the lacrimal drainage system are rare, but potentially life threatening. They comprise a large and variable spectrum of entities grouped into three major categories of primary epithelial, primary nonepithelial and inflammatory lesions. The most common primary epithelial tumors include papilloma, squamous cell carcinoma and transitional cell carcinoma, the most frequent primary nonepithelial tumors fibrous histiocytoma, malignant lymphoma and malignant melanoma, and the most common inflammatory lesions sarcoidosis, Wegener granulomatosis and pyogenic granuloma. This review outlines the incidence, types, management and prognosis of tumors affecting the lacrimal drainage system. PMID- 20958178 TI - Determinants of physicians' communication behaviour in disability assessments. AB - PURPOSE: Knowledge about the determinants of communication behaviour of physicians during face-to-face consultations with patients might increase our understanding of communication behaviour, and provide insight into how training might be able to change their communication behaviour. For physicians who conduct work disability assessment interviews, referred to as 'social insurance physicians', communication with patients is their most important instrument. Therefore, the aim of this study was to understand the determinants of communication behaviour of social insurance physicians, by modelling the following constructs of the Theory of Planned Behaviour: attitudes, social influence, self-efficacy, skills, barriers and intentions concerning their communication with claimants in medical disability assessments. METHOD: Cross sectional data were collected by means of questionnaires. Analyses were performed with the LISREL maximum likelihood estimation procedure. RESULTS: The results showed a well-fitting model in which attitudes had a significant and substantial direct effect on two intentions. Self-efficacy had a significant, but smaller direct effect on one intention. CONCLUSIONS: Empirical support was found for a model that describes intentions of social insurance physicians, especially intentions to give information and to consider personal aspects. Attitudes were the main determinants of physicians' intentions and therefore these may be a promising focus of communication skills training. PMID- 20958179 TI - Engagement and learning: an exploratory study of situated practice in multi disciplinary stroke rehabilitation. AB - PURPOSE: Active participation is considered to be a key factor in stroke rehabilitation. Patient engagement in learning is an important part of this process. This study sets out to explore how active participation and engagement are 'produced' in the course of day-to-day multi-disciplinary stroke rehabilitation. METHOD: Ethnographic observation, analytic concepts drawn from discourse analysis (DA) and the perspective and methods of conversation analysis (CA) were applied to videotaped data from three sessions of rehabilitation therapy each for two patients with communication impairments (dysarthria, aphasia). FINDINGS: Engagement was facilitated (and hindered) through the interactional work of patients and healthcare professionals. An institutional ethos of 'right practice' was evidenced in the working practices of therapists and aligned with or resisted by patients; therapeutic activity type (impairment, activity or functional focus) impacted on the ways in which patient engagement was developed and sustained. CONCLUSIONS: This exploration of multi-disciplinary rehabilitation practice adds a new dimension to our understanding of the barriers and facilitators to patient engagement in the learning process and provides scope for further research. Harmonising the rehabilitation process across disciplines through more focused attention to ways in which patient participation is enhanced may help improve the consistency and quality of patient engagement. PMID- 20958180 TI - Multidisciplinary cognitive behavioural pain management programmes for people with a spinal cord injury: design and implementation. AB - PURPOSE: This article seeks to outline the design and implementation of cognitive behavioural pain management programmes (PMPs) for people with spinal cord injury (SCI), illustrated by the experiences in a recently evaluated programme (SpinalADAPT). It is hoped that this will provide an easily accessible account of the relevant design and implementation issues for those who seek to deliver such programmes to persons with a SCI. METHODS: A collaborative team of pain and SCI professionals developed a modified version of a standard cognitive behavioural pain management programme (ADAPT) based upon experiences of those with SCI who had previously attempted ADAPT. A number of structural and content elements of the programme were identified that required modification in order to accommodate the particular needs of those with SCI. RESULTS: The modified programme was subsequently successfully delivered by a combination of SCI and pain health professionals. Three groups of individuals completed the SpinalADAPT, and an evaluation of outcomes compared to standard care are reported elsewhere (Nicholson Perry et al., Clin J Pain 2010;26:206-216). CONCLUSIONS: It appears feasible to appropriately modify standard PMPs for participants with SCI, and that such programmes may offer benefits in terms of improved quality of life. Further revision and evaluation of such programmes is required. PMID- 20958181 TI - Wheelchair accessibility of public buildings: a review of the literature. AB - PURPOSE: The purpose of this review was to examine the wheelchair accessibility in public buildings and discuss the role of professional in this practice area. METHOD: Of the 85 originally identified publications from a search of major electronic bibliographic databases, 12 studies relating to wheelchair accessibility in public buildings were selected. The compliance rates with wheelchair accessibility in different areas were summarised. RESULTS: No study reported 100% wheelchair accessibility despite the enforcement of existing laws and regulations. Parking had the lowest compliance rate among all facilities in terms of accessibility, while entrances had the highest. CONCLUSIONS: A global review is needed of both new and old buildings regarding wheelchair accessibility. Professional in this practice area has an important role to play in advocating wheelchair accessibility and assisting wheelchair users to participate fully in all areas of the community. PMID- 20958182 TI - Mesenchymal stem cells and potential applications in treating ocular disease. AB - Mesenchymal stem cells (MSCs) are remarkable in stem cell biology. Not only do they have significant tissue regeneration potential, but more recently their paracrine effects (either innate or through genetic augmentation) have become increasingly recognized as useful therapeutic approaches. In particular, clinical roles for MSC therapy in neuroprotection and immune suppression are likely to emerge. These therapeutic effects will be particularly advantageous in work on neurological tissues, because MSC-based molecular therapy could overcome some of the difficulties of long-term drug delivery to tissues, such as the eye, which are relatively inaccessible to systemic delivery (for example due to the blood retina barrier). MSC therapy is, therefore, poised for significant impact in ocular molecular therapeutics, particularly for chronic diseases, such as retinal degeneration, glaucoma, and uveitis. Other molecular and tissue regeneration effects of MSCs are also likely to have impact in the management of ocular surface disease and oculoplastics. PMID- 20958183 TI - Single and multidose ocular kinetics and stability analysis of extemporaneous formulation of topical voriconazole in humans. AB - PURPOSE: The purpose of the present study was to evaluate the kinetics of single and multiple doses of topical, non-preserved voriconazole (VZ) in human eyes. METHODS: For single dose kinetics, 119 patients undergoing cataract surgery were divided into group I and group II and each group received a single drop (30 ul) of either 1% or 0.1% VZ formulation. Aqueous humor was collected at designated time intervals. For multidose kinetics, a single drop of 1% VZ was instilled 5 times either hourly or every 2 hr. The aqueous humor was tested for VZ at the 5th hr and 9th hr, respectively, after initial instillation. The stability and efficacy of the reconstituted VZ formulations were also evaluated after 30 days. RESULTS: Single dose ocular kinetics of 1% VZ resulted in a maximum mean aqueous concentration of 3.333 +/- 1.61 ug/ml in 30 min whereas 0.1% showed a maximum mean aqueous concentration of 0.817 +/-.36 ug/ml. In the multidose kinetic study, hourly and bi-hourly dosing resulted in mean aqueous concentrations of 7.47 +/- 2.14 ug/ml and 4.69 +/- 2.7 ug/ml, respectively. The reconstituted VZ formulations were stable at all studied temperatures, and their efficacy was maintained throughout the study period. CONCLUSION: The present study showed that the achieved mean concentration of VZ in both single dose and multi dose kinetic studies satisfactorily met the MIC(90) for almost all causative fungal organisms. The frequency of instillation may be designed for an "every 2 hr regimen" to maintain a therapeutic concentration for successful therapy. PMID- 20958184 TI - Changes in corneal curvatures and anterior segment parameters after descemet stripping automated endothelial keratoplasty. AB - PURPOSE: To evaluate the influence of Descemet stripping automated endothelial keratoplasty (DSAEK) on corneal curvature and the anterior segment parameters obtained with the Pentacam rotating Scheimpflug camera. METHODS: A total of 9 eyes of 9 consecutive patients (3 men, 6 women) were evaluated preoperatively, at 1 and 3 months postoperatively with the Pentacam. We compared preoperative and 1- and 3-month postoperative measurements of anterior and posterior corneal curvature, anterior and posterior corneal astigmatism, anterior chamber depth (ACD), anterior chamber volume (ACV), anterior chamber angle (ACA) width, central corneal thickness (CCT), and the corneal volume (CV). RESULTS: Preoperative CCT decreased from 687 +/- 85 microns to 631 +/- 68 microns at 3 months after surgery (p = 0.07). Anterior mean K reading of the cornea flattened from 43.3 +/- 1.65 diopter before surgery to 42.7 +/- 1.5 diopter at 3 months (p = 0.03). Anterior corneal astigmatism did not change significantly. Posterior mean K reading of the cornea steepened significantly from -5.6 +/- 0.6 diopter preoperatively to -7.2 +/- 0.4 diopter at 3 months (p = 0.007). Posterior corneal astigmatism increased accordingly from 0.52 +/- 0.17 diopter before surgery to 0.95 +/- 0.57 diopter at 3 months (p = 0.07). CV increased significantly from 65.8 +/- 5.6 ul before surgery to 85.2 +/- 4.2 ul at 3 months (p = 0.007). ACA, ACD, and ACV did not change significantly following DSAEK surgery. The average postoperative spherical equivalent changed from 0.5 +/- 2.5 D before surgery to 1.41 +/- 0.59 D three months after surgery (p = 0.05). CONCLUSIONS: DSAEK significantly increased posterior corneal k-reading, posterior corneal astigmatism, and corneal volume, resulting in a mild hyperopic shift. This observation should be taken into consideration when performing a triple procedure. PMID- 20958185 TI - Expression of MMP, HPSE, and FAP in stroma promoted corneal neovascularization induced by different etiological factors. AB - PURPOSE: To observe the relationship between the expression of matrix metalloproteinases (MMP-2, MMP-9), heparanase (HPSE), and fibroblast activation protein (FAP) in stroma and corneal neovascularization induced by different etiological factors. METHODS: Five models were established: alkaline burn, fungal infection, suturing, immunogen implantation, and tumor cell implantation. The ingrowth time and morphology of corneal neovascularization in each model was observed by slit lamp. Inflammation and neovascularization in the corneal stroma were examined by histopathology. MMP-2, MMP-9, HPSE, and FAP were detected by immunohistochemistry or double immunofluorescence staining. RESULTS: The neovascular vessels started to invade the cornea from the third day in each model. The corneal neovascularization presented dendritic-form, brush-form, and triangle-form in alkaline burn, fungal infection, and suturing models, respectively, and reached to the central cornea in the latter two models. The inflammatory cells appeared in the stroma on the first day, while neovascular vessels grew into the stroma from the third day and both of them accompanied each other from 3-14 days in each model. MMP-2, MMP-9, and HPSE appeared before the neovascularization on the first day and accompanied it from 3-14 days in each model. FAP(+) cells occurred mainly around CD31(+) vascular endothelial cells in each model. CONCLUSION: The corneal neovascularization induced by different etiological factors have different morphologies. The inflammation and the expression of MMP, HPSE, and FAP in stroma may serve as pioneers for the growth of corneal neovascularization. PMID- 20958186 TI - Human corneal basal epithelial cells express an embryonic stem cell marker OCT4. AB - PURPOSE: Transcription factors act as molecular switches to activate or repress specific genes, which in turn control cellular phenotype. Transcription factor OCT4 is critical for self-renewal and maintenance of embryonic stem cells. OCT4 expression is down-regulated in all differentiated somatic cell types in vitro and in vivo. Our aim is to investigate whether the human corneal epithelium expresses OCT4. MATERIALS AND METHODS: OCT4 protein was examined in nine human cornea specimens and in human testicular seminoma positive control samples by fluorescence immunohistochemistry. OCT4 mRNA was studied in human corneal epithelial as well as human embryonic stem cells (ESC). The RT-PCR products were further analyzed by DNA sequencing. RESULTS: All of the corneas displayed nuclear staining patterns, limited to the corneal epithelial basal layer. The OCT4 positive staining cells resided mainly in the limbal epithelial basal layer, but some were also found in the peri-limbal and central corneal epithelial basal layers. OCT4 mRNA was detected in the epithelium of all human corneas and human ESC cells. Neither OCT4 mRNA nor protein was detected from negative controls. The sequencing analysis showed that the base sequences of PCR products were 99.17% similar to the human OCT4 gene. CONCLUSION: The basal layer of corneal epithelium expresses OCT4. PMID- 20958187 TI - MRI in diagnosis of orbital masses. AB - PURPOSE: To evaluate the role of diffusion-weighted magnetic resonance imaging and proton magnetic resonance spectroscopy in diagnosis of different orbital masses and their advantages over conventional magnetic resonance imaging. METHODS: The study included 32 patients presenting with proptosis. Every patient was subjected to a clinical examination; conventional MRI "T1 weighted, T2 weighted, and post-contrast T1 weighted if needed;" diffusion-weighted MRI; and proton magnetic resonance spectroscopy. Orbitotomy was performed, the orbital mass was excised, and histopathological examination was performed. RESULTS: Diffusion-weighted MRI can be used to differentiate between benign lesions and malignant tumors in 75% of cases; however, overlap occurred in 25% of cases with benign tumors showing restricted diffusion while proton magnetic resonance spectroscopy could differentiate between benign and malignant tumors in 93.7% of cases. CONCLUSION: Diffusion-weighted MRI and proton magnetic resonance spectroscopy increased the accuracy of diagnosis of orbital masses through giving in vivo tissue characterization; with magnetic resonance spectroscopy being more accurate. PMID- 20958188 TI - Evaluation of the impact of diabetes on retinal metabolites by NMR spectroscopy. AB - PURPOSE/AIM OF THE STUDY: Diabetic retinopathy (DR) is a leading cause of blindness in working age adults in developed countries. Changes in metabolites and in metabolic pathways of the retina caused by hyperglycemia may compromise the physiology of the retina. Using nuclear magnetic resonance (NMR) spectroscopy, we aimed to investigate the effect of diabetes on the levels of intermediate metabolites in rat retinas and the metabolic pathways that could be affected. MATERIALS AND METHODS: Diabetes was induced in male Wistar rats with a single injection of streptozotocin (65 mg/Kg, i.p.). Metabolic alterations were analyzed in streptozotocin-induced diabetic rat retinas by (1)H NMR spectroscopy. Glucose uptake was measured with 2-deoxy-D-[1-(3)H]glucose. Lactate production was evaluated by (1)H NMR spectroscopy using [U-(13)C]glucose. RESULTS: Tissue levels of several metabolic intermediates were quantified, but no significant changes in the levels of most metabolites were detected, with the exceptions of glucose, significantly increased, and lactate, significantly reduced in diabetic rat retinas, as compared to age-matched controls. The cytosolic redox ratio, indirectly evaluated by lactate-to-pyruvate ratio, was significantly reduced in diabetic rat retinas, as well as glucose uptake. Parallel studies demonstrated that lactate production rates were significantly diminished, suggesting a reduction in the glycolytic flux. CONCLUSIONS: These results suggest that diabetes may significantly decrease glycolysis in the retina since higher intracellular glucose levels do not translate into higher intracellular lactate levels or into higher rates of lactate production. These changes may alter the normal functioning of the retina during diabetes and may contribute for vision loss in DR. PMID- 20958189 TI - ON-retinal bipolar cell survival in RCS rats. AB - PURPOSE: In retinitis pigmentosa (RP), the slow and progressive death of inner retinal neurons is thought to be inevitable after the death of photoreceptors. However, even in the advanced stage of RP, all inner retinal neurons are not completely lost. The morphological and electrophysiological modifications in ON retinal bipolar cells (ON-RBCs) of Royal College of Surgeons (RCS) rats (RCS-ON RBCs) were investigated to elucidate the mechanisms of survival of RCS-ON-RBCs in RP. METHODS: Control (CTR) and RCS rats were divided into age groups according to postnatal stage: postnatal day 21 (Pn21d), postnatal day 30 (Pn30d), postnatal day 60 (Pn60d), and postnatal day 90 (Pn90d). Lucifer yellow staining of single ON-RBCs and double-immunofluorescence of the retinal frozen sections were used to detect the morphological modifications and loss of RCS-ON-RBCs in different retinal regions. The whole-cell patch clamping technique was used to record the electrophysiological properties of ON-RBCs. RESULTS: There was a significant loss of RCS-ON-RBCs compared with CTR (p < 0.01) at Pn60d. Loss of the RCS-ON-RBCs differed by region. From Pn60d onwards, the loss was more severe in the peripheral retinal regions (p < 0.01). From Pn21d, the ectopic neurites from the RCS-ON-RBCs reached the outer and inner nuclear layers. At Pn60d, terminal branches of RCS-ON-RBCs axons vanished and ectopic neurites from the RCS-ON-RBCs became entwined. The resting membrane potential, input resistance and outward membrane current amplitude of RCS-ON-RBCs were significantly higher than those of the ON-RBCs of CTR rats at Pn60d (p < 0.05). CONCLUSION: Our results indicate that more RCS-ON-RBCs survived in the central retinal area near cone clusters, potentially as a result of ectopic neuritis. Meanwhile the surviving RCS-ON-RBCs remained immature and had no normal electrophysiological characteristics. PMID- 20958190 TI - Suppression of choroidal neovascularization by N-acetyl-cysteine in mice. AB - PURPOSE: N-acetyl-cysteine (NAC) is a potent antioxidant known to be a precursor of glutathione. The purpose of this study was to investigate the role of NAC in the development of choroidal neovascularization (CNV). METHODS: CNV was induced in C57BL/6 mice by laser photocoagulation of the ocular fundus. Mice were injected intraperitoneally with NAC or vehicle alone. The levels of 4-hydoroxy-2 nonenal (4-HNE)-modified protein and nucleus factor (NF)-kappaB were determined by wester blotting. The recruitment of macrophages and neutrophils after laser injury was analyzed immunohistochemically and in myeloperoxidase (MPO) assays. Enzyme-linked immunosorbent assays (ELISA) were used to measure monocyte chemotactic protein (MCP)-1, CXCL1, vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2. The extent of CNV was evaluated 7 d after laser injury by lectin staining. RESULTS: In NAC-treated mice with laser-induced injuries, the induction of 4-HNE-modified protein after 3 hr and the activation of NF-kappaB in nuclear extracts after 6 hr were markedly suppressed compared to vehicle-treated mice. Macrophage and neutrophil recruitment were inhibited and the levels of MCP-1, CXCL1, VEGF, and VEGFR-1 were also lower in NAC-treated mice compared to vehicle-treated mice. Furthermore, the extent of CNV induced was significantly lower in NAC-treated compared to vehicle-treated mice (p = 0.027). CONCLUSIONS: Our results clearly showed that NAC inhibited indicators of oxidative stress and the activation of NF-kappaB induced by laser injury, and, consequently, suppressed macrophage and neutrophil infiltration and the development of CNV. This suggests novel preventative and interventional therapeutic strategies for age-related macular degeneration. PMID- 20958192 TI - Repeated intraocular pressure measurement in awake Lewis rats does not bias retinal ganglion cell survival. AB - PURPOSE: The TonoPen applanation tonometry is an established method for intraocular pressure (IOP) measurement. The IOP is one of the main variables affecting retinal ganglion cell (RGC) loss in experimental animal models in ophthalmology and the main risk factor for human glaucoma. In this study, we examined if IOP measurements with the TonoPen itself lead to retinal ganglion cell loss or any other possible retina damages, such as intraocular bleedings or ablation, in Lewis rats. METHODS: Three groups of rats (n = 5 each) were formed. IOP monitoring, using a TonoPen XL, was performed on groups 1 and 3. Animals in groups 1 and 2 received funduscopies before and after one and two weeks of the study, in order to detect possible abnormalities. After two weeks, retinal flatmounts were stained to detect ganglion cells. RGCs were manually counted in eight predefined areas to compare mean RGC densities between groups 1 and 2 (IOP readings vs. no readings), using student t-test. RESULTS: No significant difference in RGC density between animals that underwent IOP readings and controls could be observed (p = 0.8). As expected, no IOP alterations were monitored in groups 1 and 3 throughout the study. No retinal abnormalities, such as bleeding or retina ablation, were detectable. CONCLUSION: We could detect no effects on retinal ganglion cell survival in Lewis rats or any other damages to the retina caused by IOP measurements using a TonoPen XL. This study proposes that repeated applanation tonometry does not affect RGC numbers, one of the main monitored variables in most glaucoma model studies. Therefore, the use of a TonoPen XL for repeated IOP monitoring in Lewis rats can be considered harmless. PMID- 20958191 TI - Inhibitory effect of epigallocatechin gallate (EGCG), resveratrol, and curcumin on proliferation of human retinal pigment epithelial cells in vitro. AB - PURPOSE: To investigate potential inhibitory effects of three polyphenolic agents, epigallocatechin gallate (EGCG; from green tea), resveratrol (from red wine), and curcumin (from turmeric), on the proliferation of human retinal pigment epithelial (RPE) cells and to elucidate unwanted effects. METHODS: ARPE19 cells and primary human RPE cells were cultured in the presence of various concentrations of EGCG, resveratrol, or curcumin, and compared with controls. The number of viable cells was determined after 24, 48, and 72 hr by flow cytometrical enumeration. Furthermore, cell division was measured by dye dilution assay using carboxyfluorescein succinimidyl ester (CFSE), cell death by Hoechst 33258 staining, and apoptosis by staining for active caspase 3/7 and 8. RESULTS: The three drugs inhibited the increase of RPE cell numbers at all time points, with resveratrol being the most efficient and curcumin being the least efficient. EGCG inhibited cell proliferation with intermediate efficiency, and showed little induction of cell death. Resveratrol almost completely suppressed cell proliferation, and induced RPE cell necrosis and caspase 3/7- and caspase 8 dependent apoptosis. Curcumin inhibited RPE cell increase exclusively by inducing caspase 3/7-dependent but caspase 8-independent cell death and necrosis. CONCLUSIONS: All three polyphenols tested reduced the absolute number of cells, but had different effects on cell proliferation, apoptosis, and necrosis. Resveratrol was most potent and EGCG induced the least cell death. These polyphenols may aid treatment of proliferative vitreoretinopathy (PVR). PMID- 20958193 TI - Correlation between UV absorption and riboflavin concentration in different depths of the cornea in CXL. PMID- 20958196 TI - Communication impairment and activity limitation in stroke patients with severe aphasia. AB - PURPOSE: This study investigated how patients with severe aphasia communicated in daily living, which verbal and non-verbal communication skills were spared and which were impaired, and whether activity limitations in communication are related to verbal impairments. METHODS: Twenty-seven patients with severe aphasia and 9 with moderate aphasia originating from a sample of 102 aphasic persons followed up in a French regional survey were assessed with a communication test and a communication activity limitation questionnaire 12-18 months after a first stroke. RESULTS: Patients with severe aphasia suffered severe activity limitations in communication, with performance 3-fold lower than that of patients with moderate aphasia, and 4-fold lower than scores attained by normals. Both aphasia severity and communication disability at follow-up were related to the initial severity of aphasia. Using a phone, credit card and a chequebook, reading and filling in administrative documents, and communication behaviours involved in social life were the most severely impaired. Non-verbal communication performance was not related to aphasia severity. CONCLUSIONS: We conclude that there is a great need for speech therapy research to develop new compensatory or alternative strategies for patients with severe aphasia. PMID- 20958197 TI - Assessing the cost of electronic health records: a review of cost indicators. AB - We systematically reviewed PubMed and EBSCO business, looking for cost indicators of electronic health record (EHR) implementations and their associated benefit indicators. We provide a set of the most common cost and benefit (CB) indicators used in the EHR literature, as well as an overall estimate of the CB related to EHR implementation. Overall, CB evaluation of EHR implementation showed a rapid capital-recovering process. On average, the annual benefits were 76.5% of the first-year costs and 308.6% of the annual costs. However, the initial investments were not recovered in a few studied implementations. Distinctions in reporting fixed and variable costs are suggested. PMID- 20958198 TI - The impact of telemedicine on greenhouse gas emissions at an academic health science center in Canada. AB - OBJECTIVE: This study estimates the reduction in greenhouse gas (GHG) emissions resulting from 840 telemedicine consultations completed in a 6-month time period. Our model considers GHG emissions for both vehicle and videoconferencing unit energy use. Cost avoidance factors are also discussed. MATERIALS AND METHODS: Travel distances in kilometers were calculated for each appointment using postal code data and Google MapsTM Web-based map calculator tools. RESULTS: Including return travel, an estimated 757,234 km were avoided, resulting in a GHG emissions savings of 185,159 kg (185 metric tons) of carbon dioxide equivalents in vehicle emissions. Approximately 360,444 g of other air pollutant emissions was also avoided. The GHG emissions produced by energy consumption for videoconference units were estimated to be 42 kg of carbon dioxide equivalents emitted for this sample. CONCLUSIONS: The overall GHG emissions associated with videoconferencing unit energy is minor when compared with those avoided from vehicle use. In addition to improved patient-centered care and cost savings, environmental benefits provide additional incentives for the adoption of telemedicine services. PMID- 20958199 TI - Development, validity and reliability of a postal questionnaire assessing health states relevant to young persons with stroke in Sweden. AB - PURPOSE: The aim was to develop and test a postal questionnaire, the Swedish MYS questionnaire, for validity and reliability in order to survey health states relevant to young persons with stroke. METHOD: The questionnaire was designed with the International Classification of Functioning, Disability and Health as a frame and tested for content validity, face validity and readability by a group of experts including an occupational therapist, a physician, a physiotherapist, a psychologist, a speech and language therapist, a welfare officer and a selected sample of young persons with stroke (n = 15). To test the questionnaire for reliability in terms of stability a test-retest was performed on a selected sample of young persons (n = 20) with stroke. RESULTS: The questionnaire was found to be valid in terms of content validity, face validity and readability and finally consisted of 59 questions encompassing health states relevant to young persons with stroke. The questionnaire was stable in the test-retest (kappa; 0.40 1.0) except for two questions and one alternative answer. CONCLUSION: The Swedish MYS questionnaire is a valid and reliable questionnaire that can be used in postal surveys of young persons with stroke except for two questions and one answering alternative, which need to be tested further. PMID- 20958200 TI - A web-based versus paper questionnaire on alcohol and tobacco in adolescents. AB - OBJECTIVE: Our study was aimed at comparing health behavior data collected from a Web-based self-administered questionnaire (Web SAQ) versus a paper-and-pencil self-administered questionnaire and assessing the feasibility of the application. MATERIALS AND METHODS: One hundred and ninety (n = 190) pupils (ages 14-16 years) of senior high schools anonymously completed a questionnaire, with demographics and queries about lifestyle, alcohol, and tobacco use. For each class, the adolescents were randomly assigned to complete either the paper version of the questionnaire or the equivalent Web-based one, which used a customized platform developed for the purposes of this survey. RESULTS: Females who filled out the Web SAQ required significantly less time and completed a significantly higher percentage of its items. Although the majority of questions on tobacco and alcohol did not differ significantly across the two administration modes, there were gender-related differences in some sensitive information. Male adolescents on the Web SAQ accounted higher per hour drink consumption (r = 0.27, p = 0.015) and more numerous episodes of inebriety (r = 0.26, p = 0.010), whereas females seemed to state a younger age of alcohol onset (r = 0.33, p = 0.002). Females were more likely to report being monthly smokers on the Web SAQ (odds ratio = 0.37). Adolescents felt significantly less observed and females referred being more independent while compiling the Web SAQ. CONCLUSIONS: The findings of the study suggest that differences in reporting of some behavior of adolescents when using a Web SAQ do exist, despite the small-to-medium effect sizes. Exploiting the Web requires further investigation for extensive comprehension of the reasons for such differences. PMID- 20958202 TI - Identifying child functioning from an ICF-CY perspective: everyday life situations explored in measures of participation. AB - PURPOSE: This study was part of a larger work to develop an authentic measure consisting of code sets for self- or proxy-report of child participation. The aim was to identify common everyday life situations of children and youth based on measures of participation. METHOD: The study was descriptive in nature and involved several stages: systematic search of literature to find articles presenting measures for children and youth with disabilities, identifying measures in selected articles, linking items in included measures to the ICF-CY, analysing content in measures presented as performance and participation and identifying aggregations of ICF-CY codes across these measures. RESULTS: A large number of measures for children and youth with disabilities were identified but only 12 fulfilled the inclusion criteria. A slight distinction in content and age appropriateness appeared. Measures presented as performance covered all the ICF CY Activities and Participation chapters, whereas measures presented as participation covered five of nine chapters. Three common everyday life situations emerged from the measures: Moving around, Engagement in play and Recreation and leisure. CONCLUSION: Only a small number of life situations for children and youth emerged from items in selected measures, thus, other sources are needed to identify more everyday life situations. PMID- 20958201 TI - The indonesian variants of CRF33_01B: Near-full length sequence analysis. AB - Cocirculation of subtype B and CRF01_AE in Southeast Asia has led to the establishment of new recombinant forms. In our previous study, we found five samples suspected of being recombinants between subtype B and CRF01_AE, and here, we analyzed near full-length sequences of two samples and compared them to known CRFs_01B, subtype B, and CRF01_AE. Five overlapped segments were amplified with nested PCR from PBMC DNA, sequenced, and analyzed for genome mosaicism. The two Indonesian samples, 07IDJKT189 and 07IDJKT194, showed genome-mosaic patterns similar to CRF33_01B references from Malaysia, with one short segment in the 3' end of the p31 integrase-coding region, which was rather more similar to subtype B than CRF01_AE, consisting of unclassified sequences. These results suggest gene specific continuous diversification and spread of the CRF33_01B genomes in Southeast Asia. PMID- 20958203 TI - Does training laparoscopic skills in a virtual reality simulator improve surgical performance? AB - BACKGROUND AND PURPOSE: Several different methods of teaching laparoscopic skills have been advocated, with virtual reality surgical simulation (VRSS) being the most popular. Its effectiveness in improving surgical performance is not a consensus yet, however. The purpose of this study was to determine whether practicing surgical skills in a virtual reality simulator results in improved surgical performance. MATERIALS AND METHODS: Fifteen medical students recruited for the study were divided into three groups. Group I (control) did not receive any VRSS training. For 10 weeks, group II trained basic laparoscopic skills (camera handling, cutting skill, peg transfer skill, and clipping skill) in a VRSS laparoscopic skills simulator. Group III practiced the same skills and, in addition, performed a simulated cholecystectomy. All students then performed a cholecystectomy in a swine model. Their performance was reviewed by two experienced surgeons. The following parameters were evaluated: Gallbladder pedicle dissection time, clipping time, time for cutting the pedicle, gallbladder removal time, total procedure time, and blood loss. RESULTS: With practice, there was improvement in most of the evaluated parameters by each of the individuals. There were no statistical differences in any of evaluated parameters between those who did and did not undergo VRSS training, however. CONCLUSION: VRSS training is assumed to be an effective tool for learning and practicing laparoscopic skills. In this study, we could not demonstrate that VRSS training resulted in improved surgical performance. It may be useful, however, in familiarizing surgeons with laparoscopic surgery. More effective methods of teaching laparoscopic skills should be evaluated to help in improving surgical performance. PMID- 20958204 TI - Prevalence of diabetes and cardiovascular risk factors among California Native American adults compared to other ethnicities: the 2005 California Health Interview Survey. AB - BACKGROUND: People with diabetes (DM) are at an increased risk of cardiovascular disease. Although Native American groups have been identified to have among the highest prevalences of DM, such as those located in Arizona, Oklahoma, and North/South Dakota, there is a lack of population data on DM and its cardiovascular risk factor correlates in Native Americans. We sought to examine the prevalence and its cardiovascular risk factor correlates in Native Americans residing in California. METHODS: In the California Health Interview Survey 2005 (CHIS), we examined in adults aged >=18 years (n = 43,020 projected to 26.4 million, 50.9% female) the prevalence and risk factor correlates of DM, based on self-reported telephone interview information available from CHIS. RESULTS: Among all ethnic groups, the prevalence of DM was highest in Native Americans (14.9%), compared to 10.1% in African Americans, 8.0% in Hispanics, 6.5% in Asians, and 6.0% in Caucasians. From multiple logistic regression, after adjusting for age, gender, other risk factors, and lifestyle characteristics, Native Americans still had the highest likelihood of DM [odds ratio (OR) = 3.09, confidence interval (CI), 1.92-4.96], P < 0.01, when compared to Caucasians). Among adults with DM, Native Americans had the highest prevalence of high cholesterol (42.1%). Age, male gender, lower intake of vegetables and fruits, and high blood pressure were the most important indicators of DM in Native Americans. CONCLUSIONS: California Native American adults are more likely to have DM compared to other ethnicities. Education on prevention and further investigation are needed. PMID- 20958205 TI - ENPP1/PC-1 K121Q and other predictors of posttransplant diabetes. AB - Diabetes mellitus is a major cause of morbidity and mortality among transplanted patients. This study evaluated the role of the ENPP1 K121Q polymorphism and other variables known to affect diabetes risk in 115 nondiabetic and unrelated patients who underwent kidney transplant at our institution and had consented for use of genetic material (30% whites, 48% blacks, and 22% Hispanics). Thirty-six of these patients (30%) developed posttransplant diabetes mellitus (PTDM) within 1 year of observation from transplant. Black race, ENPP1 K121Q polymorphism, age, body mass index (BMI), and immunosuppressive medications were found to have the strongest associations with PTDM in the logistic regression and receiver operator characteristic (ROC) analysis. However, because ENPP1 K121Q is more common in Hispanics and in blacks, who also have higher PTDM prevalence, the studied genetic polymorphism did not exert independent predictive effect, whereas ethnicity, specifically black versus non-black, was the most robust predictor of PTDM. The model with the largest ROC area under the curve (AUC) of 0.80 was comprised of black/non-black, age, BMI, and tacrolimus treatment as significant predictors. A reduced model containing only ethnicity (black/non-black) and age as predictors yielded similar results (ROC AUC 0.78). We conclude that black race and age are major and not modifiable risk factors for PTDM. The specific role of ENPP1 K121Q on ethnic susceptibility to PTDM deserves further investigation in larger cohorts of transplanted patients. PMID- 20958206 TI - Racial/ethnic differences in the association of triglycerides with other metabolic syndrome components: the Multi-Ethnic Study of Atherosclerosis. AB - OBJECTIVE: The aim of this study was to examine whether there are ethnic differences in the association of triglycerides (TG) with waist circumference (WC), blood pressure, high-density lipoprotein cholesterol (HDL-C), fasting glucose, and insulin resistance and to examine the disparities in the prevalence of the metabolic syndrome components between African Americans and non-Hispanic whites who do not have hypertriglyceridemia. METHODS: This study used the baseline data from the Multi-Ethnic Study of Atherosclerosis (MESA) study. The analysis included non-Hispanic whites (N = 2,427) and African Americans (N = 1,519) aged 45-84 years free of clinically evident cardiovascular disease and diabetes at baseline. The revised National Cholesterol Education Program (NCEP) criteria were used to define the metabolic syndrome and its components. RESULTS: African Americans had lower prevalence of elevated TG as compared with non Hispanic whites. The association of TG with other components of the metabolic syndrome appeared to be similar between African Americans and non-Hispanic whites except for one. There was significant association of TG with WC among white women but not among African American women after adjusting for demographic and other variables (P for interaction of TG with ethnicity <0.001). In participants with TG < 150 mg/dL, African American women had higher prevalence rates than white women of abdominal obesity, elevated blood pressure, low HDL-C, elevated fasting glucose and homeostasis model assessment of insulin resistance (HOMA-IR). In men, the prevalence rates of high blood pressure, elevated fasting glucose, and HOMA IR were significantly higher in African Americans than in whites. CONCLUSIONS: The study findings suggest that further evaluation is warranted regarding the cutoffs for elevated TG and its clustering effect with other cardiometabolic risk factors on predicting risk for diabetes and cardiovascular disease (CVD) in African Americans. PMID- 20958207 TI - Prevention of type 2 diabetes by dietary patterns: a systematic review of prospective studies and meta-analysis. AB - Lifestyle intervention may reduce the risk of type 2 diabetes. The aim of this study was to investigate the role of dietary patterns in the prevention of type 2 diabetes. We did an electronic search through November 30, 2009, for prospective studies that evaluated the role of dietary patterns in type 2 diabetes prevention. Ten large prospective studies were identified, comprising more than 190,000 subjects free of diabetes at baseline, followed for a time ranging from 2 to 23 years, and 8,932 cases of incident diabetes. All ten studies showed consistent results: Relative risk reduction of type 2 diabetes ranged from 83% to 15%. Overall, adherence to a healthy dietary pattern was associated with reduced risk of developing type 2 diabetes: Combined mean difference = -0.39, 95% confidence interval (CI) -0.54 to -0.24. The reduced risk of developing type 2 diabetes was still present after sensitivity analysis (-0.34, 95% CI -0.44 to 0.24). Dietary patterns characterized by high consumption of fruit and vegetables, whole grains, fish, and poultry, and by decreased consumption of red meat, processed foods, sugar-sweetened beverages, and starchy foods may retard the progression of type 2 diabetes. Healthy diets can help people to live more years without type 2 diabetes. PMID- 20958208 TI - Telethinking with Craig Lipset. Interview by Jamie Devereaux. PMID- 20958209 TI - How human factors can influence the elderly in the use of telemedicine. PMID- 20958210 TI - Circulating plasmacytoid dendritic cells in acutely infected patients with hepatitis C virus genotype 4 are normal in number and phenotype. AB - The incidence of hepatitis C virus (HCV) genotype 4 infection in Egypt provides a unique opportunity to study the innate immune response to symptomatic acute HCV infection. We investigated whether plasmacytoid dendritic cells (pDCs) are activated as a result of HCV infection. We demonstrate that, even during symptomatic acute infection, circulating pDCs maintained a similar precursor frequency and resting phenotype, compared with pDCs in healthy individuals. Moreover, stimulation with a Toll-like receptor 9 agonist resulted in an intact inflammatory response. These data support the growing consensus that pDCs are not directly activated by HCV and therefore are viable targets for immunotherapy throughout HCV infection. PMID- 20958211 TI - Mycobacterium tuberculosis-specific cellular immune profiles suggest bacillary persistence decades after spontaneous cure in untreated tuberculosis. AB - Individuals with self-healed tuberculosis from the preantibiotic era offer a unique insight into the natural history of and protective immunity to tuberculosis. In 27 such persons whose tuberculosis self-healed >50 years earlier, circulating Mycobacterium tuberculosis antigen-specific interferon gamma (IFN-gamma)- and interleukin 2 (IL-2)-secreting T cells were detected ex vivo in 16 and 19 individuals, respectively. The M. tuberculosis-specific T cell cytokine profile was dominated by effector memory T cells that secrete both IFN-gamma and IL-2 and included T cells that secrete only IFN-gamma or IL-2, suggesting persistence of antigen secreted by viable bacilli. Of 10 individuals with no M. tuberculosis antigen-specific IFN-gamma-secreting T cells detectable ex vivo, 7 had evidence of central memory T cells, consistent with clearance of infection. PMID- 20958212 TI - In vitro genetic analysis of an erythrocyte determinant of malaria infection. AB - Invasion of erythrocytes by Plasmodium falciparum is an obligatory step in the life cycle of the parasite. A major challenge is the unambiguous identification and characterization of host receptors. Because erythrocytes lack nuclei, direct genetic analyses have been limited. In this work, we combined an in vitro erythrocyte culture system, which supports P. falciparum invasion and growth, with lentiviral transduction to knock down gene expression. We genetically demonstrate, in an isogenic background, that glycophorin A is required for efficient strain-specific parasite invasion. We establish the feasibility of in vitro systematic functional analysis of essential erythrocyte determinants of malaria and erythrocyte biology. PMID- 20958213 TI - The American Academy of Implant Dentistry (AAID). PMID- 20958215 TI - Compensatory stepping responses in individuals with stroke: a pilot study. AB - Impaired postural control and a high incidence of falls are commonly observed following stroke. Compensatory stepping responses are critical to reactive balance control. We hypothesize that, following a stroke, individuals with unilateral limb dyscontrol will be faced with the unique challenge of controlling such rapid stepping reactions that may eventually be linked to the high rate of falling. The objectives of this exploratory pilot study were to investigate compensatory stepping in individuals poststroke with regard to: (1) choice of initial stepping limb (paretic or non-paretic); (2) step characteristics; and (3) differences in step characteristics when the initial step is taken with the paretic vs. the non-paretic limb. Four subjects following stroke (38-165 days post) and 11 healthy young adults were recruited. Anterior and posterior perturbations were delivered by using a weight drop system. Force plates recorded centre-of-pressure excursion prior to the onset of stepping and step timing. Of the four subjects, three only attempted to step with their non-paretic limb and one stepped with either limb. Time to foot-off was generally slow, whereas step onset time and swing time were comparable to healthy controls. Two of the four subjects executed multistep responses in every trial, and attempts to force stepping with the paretic limb were unsuccessful in three of the four subjects. Despite high clinical balance scores, these individuals with stroke demonstrated impaired compensatory stepping responses, suggesting that current clinical evaluations might not accurately reflect reactive balance control in this population. PMID- 20958217 TI - Differences between cellular and molecular profiles of induced pluripotent stem cells generated from mouse embryonic fibroblasts. AB - Induced pluripotent stem (iPS) cells are a new alternative for the development of patient-specific stem cells, and the aim of this study was to determine whether differences exist between the cellular and molecular profiles of iPS cells, generated using lentiviral vectors, compared to ES cells. The lentiviral infection efficiency differed according to the method of cell culture (adherent cells: 0.085%; suspended cells: 0.785%). Six iPS cell lines exhibited typical ES cell morphology and marker expression, but varied in their in vitro/in vivo differentiation ability. Global gene transcription analysis revealed that core pluripotency genes were expressed at lower levels in iPS cell lines compared to D3-ES cells (Pou5f1: x1.6~2.2-fold, Sox2: x2.58~10.0-fold, Eras: x1.08~2.54-fold, Dppa5a: x1.04~1.41-fold), while other genes showed higher expression in iPS cells (Lin28: x1.43~2.33-fold; Dnmt3b: x1.33~2.64-fold). This pattern was repeated in a survey of specific functional groups of genes (surface markers, cell death, JAK STAT and P13K-AKT signaling pathways, endothelial, cardiovascular, and neurogenesis genes). Among the iPS cell lines examined, only two showed similar characteristics to ES cells. These results demonstrated that, in addition to cellular characterization, the numerical evaluation of gene expression using DNA microarrays might help to identify the stem cell stability and pluripotency of iPS cells. PMID- 20958218 TI - Drug delivery technologies for autoimmune disease. AB - IMPORTANCE OF THE FIELD: Targeting autoimmune disease poses two main challenges. The first is to identify unique targets to suppress directly or indirectly autoreactive cells exclusively. The second is to penetrate target tissues to deliver specifically drugs to desired cells that can achieve a therapeutic outcome. AREAS COVERED IN THIS REVIEW: Herein, the range of drug delivery methods available and under development and how they can be useful to treat autoimmune diseases are discussed. Polymer delivery methods, as well as biological methods that include fusion proteins, targeted antibodies, recombinant viruses and cell products are compared. WHAT THE READER WILL GAIN: Readers will gain insight into the progression of clinical trials for different technologies and drug delivery methods useful for targeting and modulating the function of autoreactive immune cells. TAKE HOME MESSAGE: Several tissue-specific polymer-based and biologic drug delivery systems are now in Phase II/III clinical trials. Although these trials are focused mainly on cancer treatment, lessons from these trials can guide the use of the same agents for autoimmunity therapeutics. PMID- 20958219 TI - Short and long term anti-inflammatory effects of bosentan therapy in patients with pulmonary arterial hypertension: relation to clinical and hemodynamic responses. AB - OBJECTIVE: We sought to investigate the short- and long- term effects of bosentan therapy on endothelial, inflammatory and fibrotic markers in patients with pulmonary arterial hypertension (PAH) and the relation to clinical and hemodynamic responses. METHODS: We studied 16 patients with moderate-severe idiopathic PAH, in WHO functional class II-IV, despite conventional treatment. Patients received additional treatment with bosentan, 62.5 mg twice daily for 1 month, followed by 125 mg twice daily for 11 months. Study endpoints included 6 min walking distance (6MWD), mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and plasma levels of intracellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), IL-6 and brain natriuretic peptide (BNP). Patients were assessed at baseline, 2 months and 12 months after initiation of bosentan. RESULTS: At 2 months there was an improvement in 6MWD (p < 0.001) and functional class (p < 0.001) and a marked fall in PVR (p < 0.001), ICAM-1 (p < 0.001), IL-6 (p < 0.001)and BNP (p = 0.001). At 12 months, 6MWD was further improved (p < 0.001), PVR remained significantly improved (p < 0.001), mPAP was significantly decreased (p < 0.001) and ICAM-1, IL 6 and BNP remained significantly lower (p < 0.001). Significant correlations were found between changes in ICAM-1 and cardiac index (r = 0.59, p = 0.01), IL-6 and PVR (r = 0.51, p = 0.04), BNP and 6MWD (r = -0.53, p = 0.03) and BNP and PAP (r = 0.51, p = 0.04) between 2- and 12-months treatment. CONCLUSIONS: In patients with moderate-severe PAH, the addition of bosentan to therapy, exerts favorable anti inflammatory effects, which are associated with clinical and hemodynamic improvement. PMID- 20958221 TI - Mito-communications. PMID- 20958220 TI - Different radiosensitivity of CD4(+)CD25(+) regulatory T cells and effector T cells to low dose gamma irradiation in vitro. AB - PURPOSE: To determine the radiosensitivity difference of human Cluster of Differentiation (CD)4(+)CD25(+) regulatory T cells (Treg) and effector T cells to low dose gamma ray and elucidate the underlying mechanisms in vitro. MATERIALS AND METHODS: Blood samples were collected from five health subjects and five patients with advanced hepatocellular carcinoma (HCC). Treg and CD4(+)CD25- T cells were selected using magnetic microbeads. The proliferative profiles, cytokine secretion, and differential expressions of apoptosis-related proteins in Treg and CD4(+)CD25- T cells were compared using [3H]-thymidine incorporation, Luminex assay and flow cytometry when treated with various low doses of gamma ray. RESULTS: A dose-dependent reduction of proliferation in response to irradiation which paralleled the induction of apoptosis existed in Treg and CD4(+)CD25- T cells. Treg were more radiosensitive to low-dose irradiation (0.94 Gray [Gy]) than effector T cells. The interferon-gamma (IFNgamma) was significantly upregulated and interleukin 10 (IL-10) was significantly downregulated in irradiated Treg. An enhanced immune response to low dose gamma ray existed in the peripheral blood in patients with advanced HCC. Higher levels of active caspase-3, CD95, B cell lymphoma 2 (Bcl-2)-associated X protein (Bax) expression were observed in Treg compared to CD4(+)CD25- T cells. In addition, gamma irradiation activated CD4(+)CD25- T cells to express CD25. CONCLUSIONS: These studies revealed that Treg were more radiosensitive than CD4(+)CD25- T cells to low dose irradiation. Higher expressions of apoptosis-related proteins such as caspase-3, CD95 and Bax were observed in Treg when compared to CD4(+)CD25 T cells. Our results suggest that treatment with low doses of gamma irradiation may be a viable strategy to enhance immune response in patients with advanced HCC. PMID- 20958222 TI - The mitochondrial genome of Opilio parietinus (Arachnida: Opiliones). PMID- 20958223 TI - Complete mitochondrial genome of three Branchiostegus (Perciformes, Malacanthidae) species: genome description and phylogenetic considerations. AB - We cloned and sequenced the complete mitochondrial DNA (mtDNA) of three tilefishes (Branchiostegus albus, Branchiostegus argentatus, and Branchiostegus japonicus) to characterize and compare their mitochondrial genomes (mitogenomes). The mitogenomes of B. albus, B. argentatus, and B. japonicus were 16,532, 16,550, and 16,541 bp long, respectively, and all consisted of 37 genes (13 protein coding genes, 2 ribosomal RNA, and 22 transfer RNA (tRNAs)), which are typical for vertebrate mtDNA. As in other bony fishes, most genes were encoded on the H strand, except for the nad6 and eight tRNA genes that were encoded on the L strand. Among the 13 protein-coding genes of all three tilefishes, 2 reading frame overlaps were found on the same strand: atp8 and atp6 overlapped by 10 nucleotides, and nad4L and nad4 overlapped by 7 nucleotides. The identity of the nad4 gene between B. albus and B. argentatus was the lowest at 87%. Conversely, the identity of the nad6 gene between B. albus and B. japonicus was the highest at 99%. Most tRNA genes were similar in length among the three species, while the tRNA-Ser((AGY)) of B. japonicus was 9 bp longer than those of B. albus and B. argentatus. The control region of the mitogenome spanned 853, 862, and 856 bp in B. albus, B. argentatus, and B. japonicus, respectively. A maximum likelihood tree constructed using 11,035 sites contained five independent groups with bootstrap values of 100% in support of their divergence. All three tilefishes examined were clustered with the Pomacanthidae species in Group II. PMID- 20958224 TI - Mitochondrial genome of the cotton bollworm Helicoverpa armigera (Lepidoptera: Noctuidae) and comparison with other Lepidopterans. AB - We present the complete sequence of the mitochondrial genome (mitogenome) of the cotton bollworm Helicoverpa armigera. The 15,347-bp mitogenome of H. armigera was arranged in the same order described for all other sequenced lepidopterans, which differs from the most common type found in insects, due to the movement of trnM to a position 5'-upstream of trnI. The gene overlap in the H. armigera mitogenome is totally 23 bp in six locations. The H. armigera mitogenome has a total of 175 bp of intergenic spacer sequences spread over 14 regions ranging in size from 1 to 45 bp. The nucleotide composition of the whole mitogenome of H. armigera is highly A+T biased, accounting for 80.97%, with a slightly positive AT skewness and negative GC skewness, indicating the occurrence of more A than T, C more than G. The protein-encoding genes have typical mitochondrial start codons, except for cox1, which contains the unusual CGA. The cox1, cox2, and nad4 genes have incomplete stop codons (T). The lrRNA and srRNA genes are 1395 and 794-bp long, respectively. All tRNAs have a typical cloverleaf structure of mitochondrial tRNAs, except for trnS1(AGN), the dihydrouridine arm of which could not form a stable stem-loop structure. The H. armigera A+T-rich region contains a conserved structure combining the motif ATAGA and a 19-bp poly-T stretch, but absence of the 9-bp poly-A element upstream of trnM. PMID- 20958225 TI - Complete mitochondrial genome of the longtail tadpole shrimp Triops longicaudatus (Crustacea, Branchiopoda, Notostraca). PMID- 20958226 TI - The complete mitochondrial genome of the relict frog Leiopelma archeyi: insights into the root of the frog Tree of Life. AB - Determining the root of the anuran Tree of Life is still a contentious and open question in frog systematics. Two genera with disjunct distributions have been traditionally considered the most basal among extant frogs: Leiopelma, which is endemic to New Zealand, and Ascaphus, which lives in North America. However, their specific phylogenetic position is rather elusive because each genus shows many autapomorphies, and together they retain many symplesiomorphic characters. Therefore, several alternative hypotheses have been proposed regarding the relative phylogenetic position of both Leiopelma and Ascaphus. In order to distinguish among these competing phylogenetic hypotheses, we sequenced the complete mitochondrial (mt) genome of Leiopelma archeyi and used it along with previously reported frog mt genomes (including that of Ascaphus truei) to infer a robust phylogeny of major anuran lineages. The reconstructed maximum likelihood and Bayesian inference phylogenies recovered identical topology, which supports the sister group relationship of Ascaphus and Leiopelma, and the placement of this clade at the base of the anuran tree. Interestingly, the mt genome of L. archeyi displays a novel gene arrangement in frog mt genomes affecting the relative position of cytochrome b, trnT, NADH dehydrogenase subunit 6, trnE, and trnP genes. The tandem duplication-random loss model of gene order change explains the origin of this novel frog mt genome arrangement, which is convergent with others reported in some fishes and salamanders. These results, together with comparative data for other available vertebrate mt genomes, provide evidence that the 5' end of the control region is a hot spot for gene order rearrangement. PMID- 20958227 TI - The complete mitochondrial genome of Caprella scaura (Crustacea, Amphipoda, Caprellidea), with emphasis on the unique gene order pattern and duplicated control region. AB - The nucleotide and amino acid sequences and the gene order of the mitochondrial genome are highly informative for studying phylogeny, population genetics, and phylogeography. This study determined the complete mitochondrial genome of the caprellid species Caprella scaura. The mitochondrial genome of C. scaura has a total length of 15,079 bp, with an AT content of 66.43%. The mitochondrial genome contains typical gene components, including 13 protein-coding genes, 2 rRNA genes, and 22 tRNA genes. In comparison with the mitochondrial genome of a gammarid, some distinct characteristics were found. For example, the order of the two conserved gene blocks is inverted between Gammaridea and C. scaura. In addition, two copies of almost identical control regions were found in the mitochondrial genome of C. scaura. These unique characteristics will be useful for determining the evolutionary history of the Caprellidea. PMID- 20958228 TI - L-arginine supplementation in women with chronic hypertension: impact on blood pressure and maternal and neonatal complications. AB - OBJECTIVE: To evaluate L-arginine (L-Arg) supplementation in pregnant women with chronic hypertension and its effects on blood pressure (BP) and maternal and neonatal complications. METHODS: We enrolled 80 women affected by mild chronic hypertension referred to the High Risk Clinic of the Mother-Infant Department of the University of Modena and Reggio Emilia. Each woman after obtaining oral consent was randomized to receive oral L-Arg versus placebo and thereafter submitted to 24-h ambulatory BP monitoring. The primary outcome was BP change after 10-12 weeks of treatment. Secondary outcomes were as follows: percentage of women on antihypertensive treatment at delivery, maternal, and fetal outcome. RESULTS: The BP changes after 10-12 weeks of treatment did not differ between groups. A lower percentage of women received antihypertensive drugs in the L-Arg group than the placebo group. The incidence of superimposed preeclampsia indicated delivery before the 34th weeks and certain neonatal complications tended to be higher in the placebo group. CONCLUSIONS: L-Arg supplementation in pregnant women with mild chronic hypertension does not significantly affect overall BP but is associated with less need for antihypertensive medications and a trend toward fewer maternal and neonatal complications. The results of the study were limited by the small sample size and by the exclusion of women with severe chronic hypertension. In our policy, these patients needed many hypertensive drugs and were normally managed by the cardiologist. Nevertheless, considering the promising results on maternal and fetal outcome, we believe that further studies should be performed to confirm such data and to clarify the role of L-Arg as a protective supplement in high-risk pregnancy. PMID- 20958229 TI - Early compensatory adaptations in maternal undernourished pregnancies in rats: role of the aquaporins. AB - OBJECTIVE: To investigate the effect of maternal undernutrition (MUN) during pregnancy on fetal and placental weight, amniotic fluid (AF) volume, AF osmolality and ion concentrations at gestational ages E16 and E20. We also quantified protein expression of water channels (aquaporins; AQPs). METHODS: Pregnant rat dams were fed an ad libitum diet (AdLib; n = 6) or were 50% MUN (n = 6) beginning at E10 of gestation. At E16 and E20, we assessed the effect of MUN on fetal and placental weights, AF volume and osmolality, and placental expression of AQP1, 8 and 9. We focused on two uterine positions (proximal and mid-horns) with the extremes of nutrient/oxygen supply. We also separately studied the basal zone (hormone production) and the labyrinth zone (feto-maternal exchange). RESULTS: We showed that at E16, MUN fetal, and placental weights were unchanged and that, similarly, MUN AF volume, osmolality were comparable to AdLib. At E20, however, MUN fetal and placental zonal weights were significantly decreased. Inversely, due to MUN, maternal and fetal plasma osmolality and Na+ concentrations were significantly increased. Further, MUN AF volume was significantly reduced, while AF osmolality and Na+ concentration were increased at E20. CONCLUSION: Placental basal zone showed variable changes in AQP expression unrelated to position in the uterus or the gestational age (and thus severity of the fetal/placental growth restriction). In the labyrinth zone, MUN placental AQP1 was significantly decreased, whereas AQP8 and 9 expressions were significantly increased at E16 and E20. Dysregulation of AQPs' expression prior to the occurrence of oligohydramnios may represent a compensatory mechanism under conditions of early MUN. PMID- 20958230 TI - Molecular modelling studies of new potential human DNA polymerase alpha inhibitors. AB - The human polymerase alpha (pol alpha) is a promising target for the therapy of cancer e.g. of the skin. The authors recently built a homology model of the active site of human DNA pol alpha. This 3D model was now used for molecular modelling studies with eight novel analogues of 2-butylanilino-dATP, which is a highly selective nucleoside inhibitor of mammalian pol alpha. Our results suggest that a higher hydrophobicity of a carbohydrate side chain (pointing into a spacious hydrophobic cavity) may enhance the strength of the interaction with the target protein. Moreover, acyclic acyclovir-like derivatives outperformed those with a sugar-moiety, indicating that structural flexibility and higher conformational adaptability has a positive effect on the receptor affinity. Cytotoxicity tests confirmed our theoretical findings. Besides, one of our most promising compounds in the molecular modelling studies revealed high selectivity for the SCC-25 cell line derived from squamous cell carcinoma in man. PMID- 20958231 TI - Molecular and biologic markers of progression in monoclonal gammopathy of undetermined significance to multiple myeloma. AB - Multiple myeloma (MM) is a malignant plasma cell dyscrasia localized in the bone marrow. Recent studies have shown that MM is preceded in virtually all cases by a premalignant state called monoclonal gammopathy of undetermined significance (MGUS). This review focuses on non-IgM MGUS and its progression to MM. Although certain clinical markers of MGUS progression have been identified, it currently is not possible to accurately determine individual risk of progression. This review focuses on the various biologic and molecular markers that could be used to determine the risk of MM progression. A better understanding of the pathogenesis will allow us to define the biological high-risk precursor disease and, ultimately, to develop early intervention strategies designed to delay and prevent full-blown MM. PMID- 20958232 TI - Autologous stem cell transplant for immunoglobulin light chain amyloidosis: a status report. AB - High-dose chemotherapy for the management of immunoglobulin light chain amyloidosis remains an effective and viable treatment technique for selected patients with this disorder. We reviewed the medical records of 434 patients uniformly treated with high-dose chemotherapy and autologous stem cell transplant at Mayo Clinic, Rochester, Minnesota, between 8 March 1996 and 13 April 2010. Outcomes, engraftment, and predictors of early mortality were reviewed. Median survival has not been reached for the patients with a complete response, is 107 months for those with a partial response, and is 32 months for patients with no response (p < 0.001). The only predictor of survival was cardiac stage (p < 0.001). The hematologic response rate is predictive for organ response rates. Both hematologic and organ responses are associated with improved survival. PMID- 20958235 TI - [Cementless total hip arthroplasty: a review]. AB - The purpose of total hip replacement (THR) is the restoration of a painless functioning hip joint with the main focus on the biomechanical properties. Advances in surgical techniques and biomaterial properties currently allow predictable surgical results in most patients. Despite the overwhelming success of this surgical procedure, the debate continues surrounding the optimal choice of implants and fixation. Femoral and acetabular implants with varying geometries and fixation methods are currently available. Problems inherent with acrylic bone cement, however, have encouraged surgeons to use alternative surfaces to allow biologic fixation. Optimal primary and secondary fixation of cementless hip stems is a precondition for long-term stability. Important criteria to achieve primary stability are good rotational and axial stability by press-fit fixation. The objective of the cementless secondary fixation is the biological integration of the implant by bony ingrowth. Nevertheless, current investigations show excellent results of cementless fixation even in older patients with reduced osseous quality. The main advantages of cementless fixation include biological integration, reduced duration of surgery, no tissue damage by cement polymerization and reduction of intraoperative embolisms. In comparison to cemented THR both, cementless sockets and stems provide good long-term results. PMID- 20958236 TI - Subungual glomus tumor: surgical and histopathologic evaluation. AB - Glomus tumor is a rare and benign vascular tumor, arising from neuromyoarterial glomus bodies. It is generally localized on the hand and especially the nail bed and is usually solitary. Pain, tenderness, and temperature sensitivity are the classic triad of symptoms of a glomus tumor. Owing to the small lesions and absence of specific skin features in the nail bed and nail matrix localizations, glomus tumor may not be taken into consideration. In particular, presentation of patients to practitioners of different disciplines for treatment of pain may cause diagnostic delays. Surgical excision is the most effective treatment approach and provides histopathologic diagnosis and rapid improvement of symptoms. This article describes a patient with a subungual glomus tumor for which surgical excision was performed. PMID- 20958237 TI - Gastroretentive dosage forms: a review with special emphasis on floating drug delivery systems. AB - In the present era, gastroretentive dosage forms (GRDF) receive great attention because they can improve the performance of controlled release systems. An optimum GRDF system can be defined as a system which retains in the stomach for a sufficient time interval against all the physiological barriers, releases active moiety in a controlled manner, and finally is easily metabolized in the body. Physiological barriers like gastric motility and gastric retention time (GRT) act as obstacles in developing an efficient GRDF. Gastroretention can be achieved by developing different systems like high density systems, floating drug delivery systems (FDDS), mucoadhesive systems, expandable systems, superporous systems, and magnetic systems. All these systems have their own merits and demerits. This review focused on the various aspects useful in development of GRDF including the current trends and advancements. PMID- 20958244 TI - Evolving cardiac conduction phenotypes in developing zebrafish larvae: implications to drug sensitivity. AB - Cardiac arrhythmias include problems with impulse formation and/or conduction abnormalities. Zebrafish (Danio rerio) is an emerging model system for studying the cardiac conduction system. However, real-time recording of the electrocardiogram remains a challenge. In the present study, we assessed the feasibility of recording electrical cardiogram (ECG) signals from the zebrafish larvae using the micropipette electrodes, and demonstrated the dynamic changes in ECG signals and their sensitivity to Amiodarone during the developmental stages. We observed that ECG signals revealed P waves and QRS complexes at 7 days postfertilization (dpf). T waves started to develop at 14 dpf. Distinct P waves, QRS complexes, and T waves were similar to those of adult zebrafish at 35 dpf, accompanied by a statistically significant decrease in QRS intervals (from 256 +/ 16 ms at 7 dpf to 54 +/- 6 ms, p < 0.01, n = 5). In response to Amiodarone, ECG signals showed QRS prolongation from 7 to 35 dpf (p < 0.05, n = 5). Hence, micropipette electrodes can be applied to detect evolving ECG signals from the developing zebrafish larvae, thus providing a noninvasive and nonparalyzing approach to investigate cardiac conduction phenotypes in response to genetic, epigenetic, or pharmacologic perturbation. PMID- 20958245 TI - Characterization of sensor-specific stress response by transcriptional profiling of wsc1 and mid2 deletion strains and chimeric sensors in Saccharomyces cerevisiae. AB - Cell wall stress in the model yeast Saccharomyces cerevisiae is known to trigger an adaptive transcriptional response. This response is mediated by a specific MAPK cell wall integrity (CWI) signal transduction pathway and affects the expression of many genes whose products are involved in the remodeling of the cellular envelope. Cell wall damage is detected mainly by Wsc1 and Mid2, which are the dominant sensors of CWI pathway. Here, we first determined the transcriptional response to different cell stresses (Congo red, Caspofungin, and Zymolyase) in mid2Delta and wsc1Delta mutant strains using DNA microarrays. Mid2 turned out to be the main sensor involved in the detection of damage provoked by Congo Red, whereas the transcriptional response to Caspofungin is mediated almost exclusively by Wsc1. For stress caused by the degradation of cell wall glucans by Zymolyase, mid2Delta and wsc1Delta deletions show little effect, but the transcriptional response rather depends on the transmembrane protein Sho1, a component of the high-osmolarity glycerol (HOG) pathway. Using sensor chimeras of Wsc1 and Mid2 we studied the contribution of the cytoplasmic and extracellular regions of Mid2 and Wsc1 for sensing Caspofungin-cell wall stress. Genome-wide transcriptional characterization in addition to Slt2 MAPK phosphorylation and phenotypic analyses indicates an important role of the extracellular domain of Wsc1 in mediating signal specificity of this sensor to detect cell wall damage. PMID- 20958246 TI - Dynamics of protein damage in yeast frataxin mutant exposed to oxidative stress. AB - Oxidative stress and protein carbonylation is implicated in aging and various diseases such as neurodegenerative disorders, diabetes, and cancer. Therefore, the accurate identification and quantification of protein carbonylation may lead to the discovery of new biomarkers. We have developed a new method that combines avidin affinity selection of carbonylated proteins with iTRAQ labeling and LC fractionation of intact proteins. This simple LC-based workflow is an effective technique to reduce sample complexity, minimize technical variation, and enable simultaneous quantification of four samples. This method was used to determine protein oxidation in an iron accumulating mutant of Saccharomyces cerevisiae exposed to oxidative stress. Overall, 31 proteins were identified with 99% peptide confidence, and of those, 27 proteins were quantified. Most of the identified proteins were associated with energy metabolism (32.3%), and cellular defense, transport, and folding (38.7%), suggesting a drop in energy production and reducing power of the cells due to the damage of glycolytic enzymes and decrease in activity of enzymes involved in protein protection and regeneration. In addition, the oxidation sites of seven proteins were identified and their estimated position also indicated a potential impact on the enzymatic activities. Predicted 3D structures of peroxiredoxin (TSA1) and thioredoxin II (TRX2) revealed close proximity of all oxidized amino acid residues to the protein active sites. PMID- 20958247 TI - Constructing consensus genetic maps in comparative analysis. AB - The construction of consensus genetic maps is a very challenging problem in computational biology. Many computational approaches have been proposed on the basis of only the marker order relations provided by a given set of individual genetic maps. In this article, we propose a comparative approach to constructing consensus genetic maps for a genome, which further takes into account the order relations from a closely related genome when resolving ordering conflicts among individual genetic maps. It aims to retain as many order relations as possible from individual genetic maps while achieving the minimum rearrangement distance to the reference genome. We implement the proposed approach as an integer linear program and test it on both simulated and real biological datasets. The experimental results show that it is capable of constructing more accurate consensus genetic maps than the most recent approach called MergeMap. PMID- 20958248 TI - Ray: simultaneous assembly of reads from a mix of high-throughput sequencing technologies. AB - An accurate genome sequence of a desired species is now a pre-requisite for genome research. An important step in obtaining a high-quality genome sequence is to correctly assemble short reads into longer sequences accurately representing contiguous genomic regions. Current sequencing technologies continue to offer increases in throughput, and corresponding reductions in cost and time. Unfortunately, the benefit of obtaining a large number of reads is complicated by sequencing errors, with different biases being observed with each platform. Although software are available to assemble reads for each individual system, no procedure has been proposed for high-quality simultaneous assembly based on reads from a mix of different technologies. In this paper, we describe a parallel short read assembler, called Ray, which has been developed to assemble reads obtained from a combination of sequencing platforms. We compared its performance to other assemblers on simulated and real datasets. We used a combination of Roche/454 and Illumina reads to assemble three different genomes. We showed that mixing sequencing technologies systematically reduces the number of contigs and the number of errors. Because of its open nature, this new tool will hopefully serve as a basis to develop an assembler that can be of universal utilization (availability: http://deNovoAssembler.sf.Net/). For online Supplementary Material , see www.liebertonline.com. PMID- 20958249 TI - Markov logic networks in the analysis of genetic data. AB - Complex, non-additive genetic interactions are common and can be critical in determining phenotypes. Genome-wide association studies (GWAS) and similar statistical studies of linkage data, however, assume additive models of gene interactions in looking for genotype-phenotype associations. These statistical methods view the compound effects of multiple genes on a phenotype as a sum of influences of each gene and often miss a substantial part of the heritable effect. Such methods do not use any biological knowledge about underlying mechanisms. Modeling approaches from the artificial intelligence (AI) field that incorporate deterministic knowledge into models to perform statistical analysis can be applied to include prior knowledge in genetic analysis. We chose to use the most general such approach, Markov Logic Networks (MLNs), for combining deterministic knowledge with statistical analysis. Using simple, logistic regression-type MLNs we can replicate the results of traditional statistical methods, but we also show that we are able to go beyond finding independent markers linked to a phenotype by using joint inference without an independence assumption. The method is applied to genetic data on yeast sporulation, a complex phenotype with gene interactions. In addition to detecting all of the previously identified loci associated with sporulation, our method identifies four loci with smaller effects. Since their effect on sporulation is small, these four loci were not detected with methods that do not account for dependence between markers due to gene interactions. We show how gene interactions can be detected using more complex models, which can be used as a general framework for incorporating systems biology with genetics. PMID- 20958250 TI - Long-term results of percutaneous transhepatic cholangiographic drainage for palliation of malignant biliary obstruction. AB - INTRODUCTION: Percutaneous stenting is established in the palliation of malignant biliary obstruction. We examined the indications, success rate, complications, and long-term postoperative course of patients undergoing this procedure. METHODS: All patients undergoing percutaneous transhepatic cholangiography (PTC) and metal stenting over a 12-month period in a tertiary referral center were studied. Data regarding diagnosis, number and type of procedures, complications, and survival were collected from multidisciplinary case notes and general practitioner records. RESULTS: There were 21 patients of median age 70 (mean, 71; range, 54-93), 56.5% (11) had pancreatic cancer and 33% (7) cholangiocarcinoma. The mean number of PTC procedures was 2.43 and mean length of stay in hospital 20.66 days (range, 3-99). Serum bilirubin fell post drainage from 397 to 226 (MUmol/L; p < 0.001) on discharge, however, in 19% (4) there was no significant reduction. Complications included cholangitis (19%) and acute pancreatitis (10%). Mortality was high and 9 patients (43%) died within 30 days, of whom 2 died in the hospital (1 from ascending cholangitis and another from pneumonia). The median time between discharge and death was 25 days (mean, 59.1 days) and no patient was alive after 193 days. CONCLUSIONS: The prognosis following PTC stenting of malignant biliary obstruction is extremely poor despite adequate drainage. The procedure can lead to significant morbidity and a lengthy hospital stay. Patient selection is therefore of paramount importance and an expedient treatment protocol and early return home recommended. PMID- 20958252 TI - Pesticides as estrogen disruptors: QSAR for selective ERalpha and ERbeta binding of pesticides. AB - Evidence suggests that environmental exposure to estrogen-like compounds can cause adverse effects in humans and wildlife. The Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) has advised screening of 87,000 compounds in the interest of human safety. This may best be accomplished by pre-screening using quantitative structure-activity relationship (QSAR) modelling. The present study aimed to develop in silico QSARs based on natural, semi-synthetic, synthetic, and phytoestrogens, to predict the potential estrogenic toxicity of pesticides. A diverse set of 170 compounds including steroidal-, synthetic- and phytoestrogens, as well as pesticides was used to construct the QSAR models using artificial neural networks (ANNs). Mean correlation coefficients between experimentally measured and predicted binding affinities were all greater than 0.7 and models had few false negative results, an important consideration for screening tools. This study demonstrated the utility of ANNs as QSAR models for pre-screening of potential endocrine disruptors. PMID- 20958251 TI - Childhood abuse and later worries about the baby's health in pregnancy. AB - OBJECTIVE: to explore the associations between sexual and/or physical abuse in childhood and worries about the baby's health in pregnancy. DESIGN: cross sectional questionnaire study. Setting. Norwegian prospective pregnancy cohort. SAMPLE: an original sample of 58,139 pregnancies (1999-2006) covering about 43% of the pregnant population. METHODS: two self-reported questionnaires in the 17th and 30th week of gestation were merged with data from the Medical Birth Registry of Norway. Associations between physical and/or sexual childhood abuse and worries about the baby's health were assessed with multiple logistic regression analyses. MAIN OUTCOME MEASURES: strong worries about the baby's health in the 30th week of gestation among women with experience of childhood abuse. RESULTS: women who reported being exposed to physical or sexual childhood abuse or a combination of the two were at increased risk of strong worries about the baby's health compared to women who had not been similarly exposed (adjusted odds ratio (OR) = 1.62, 95% confidence interval (CI) 1.26-2.08; adjusted OR = 1.30, 95% CI 1.03-1.64; adjusted OR = 2.10, 95% CI 1.68-2.62, respectively). Marital status, adult abuse, pelvic pain, quality of antenatal care, self-efficacy and previous birth experiences were also associated with concern about the baby's health. CONCLUSIONS: there were significant associations between physical and/or sexual childhood abuse and strong concern about the baby's health. Worries about the baby's health are complex and associated with many elements of risk. PMID- 20958253 TI - Screening of antioxidant, antimicrobial activities and chemical contents of edible mushrooms wildly grown in the black sea region of Turkey. AB - The antioxidative activity of the methanol extracts obtained from twelve commonly consumed wild edible mushrooms was investigated according to the phosphomolybdenum method, inhibition of linoleic acid peroxidation, reducing power, metal chelating, O(2)(-), DPPH(), peroxide and H(2)O(2) scavenging activity in the Black Sea Region of Turky, and compared to standard antioxidant compounds such as a-tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and trolox. Total phenolic compounds, flavonoids, anthocyanins, ascorbic acid, beta-carotene and lycopene in the extracts were measured. The antimicrobial activities of extracts were also evalated against gram (-) and (+) bacteria and yeast with disc diffusion method. Hydnum repandum, Lactarius delicious, Lactarius camphoratus, Lactarius piperatus, Ramaria flava, and Agaricus bisporus were greater than alpha-tocopherol and BHT on antioxidant activity. The lipid peroxidation of L. camphoratus and Lactarius volemus was excellent, and was 58.05% and 61.44% respectively. The DPPH() scavenging effects decreased in the order of R. flava>BHT> Macrolepiota procera>L. camphoratus>L. piperatus>Lactarius volemus>a-tocopherol and were, at 500 ug/ml and were 80.38, 76.61, 69.74, 61.55, 61.47, 61.09, 60.65%, respectively. All the extracts of mushroom also had the stronger chelating effect according to standards. The O(2)( ) scavenging effect of extracts of the mushroom species was in order of R. flava>Boletus edulis>Leatiporus sulphureus>M. procera>standards. L. piperatus, L. camphorates, L. volemus, A. bisporus, Chanterellus cibarius, L. sulphureus, H. repandum showed strong antimicrobial activity, especially on E. coli. H. repandum exhibited to be more effective on P. aeruginosa than other bacterial strains. PMID- 20958254 TI - Determination of the antiretroviral drug nevirapine in diluted alkaline electrolyte by adsorptive stripping voltammetry at the mercury film electrode. AB - This paper describes a stripping method for the determination of nevirapine at the submicromolar concentration levels. The method is based on controlled adsorptive accumulation of nevirapine at thin-film mercury electrode, followed by a linear cyclic scan voltammetry measurement of the surface species. Optimal experimental conditions include a 2.0 x 10(-3) mol L(-1) NaOH solution (supporting electrolyte), an accumulation potential of -0.20 V, and a scan rate of 100 mV s(-1). The response of nevirapine is linear over the concentration range 0.01-0.14 ppm. For an accumulation time of 6 minutes, the detection limit was found to be 0.87 ppb (3.0 x 10(-9) mol L(-1)). More convenient methods to measure the nevirapine in presence of the efavirenz, acyclovir, didanosine, indinavir, nelfinavir, saquinavir, lamivudine, zidovudine and metals ions were also investigated. The utility of this method is demonstrated by the presence of nevirapine together with ATP or DNA. PMID- 20958255 TI - Ultrahigh-throughput screening system for directed glucose oxidase evolution in yeast cells. AB - A compartmentalized tyramide labeling system (CoaTi) employing flow cytometry for sorting of yeast cells was developed as ultrahigh-throughput screening for Glucose oxidase (GOx) from Aspergillus niger. CoaTi combines in vitro compartmentalization technology with the CARD reporter system which uses fluorescein tyramide labels for detection of peroxidase activity. Physical connection between cells and fluorescein tyramide radicals was achieved by compartmentalization of yeast cells inside microdroplets of single water-in-oil emulsions. After reaction cells were recovered from single emulsions and sorted by flow cytometry, an error prone PCR mutant library of Glucose oxidase (GOx) containing 10(7) cells and ~10(5) of different GOx variants was screened. Mutagenic conditions of GOx mutant library were selected to generate <1 % of active GOx population in order to explore influence of high mutation frequency on GOx activity. GOx variant Mut12 that contains 5 mutations (N2Y, K13E, T30V, I94V, K152R) showed a 1.2 times decreased K(m) (22.0 vs 18.1 mM) and a 2.7 fold increased k(cat) (150 s(-1) vs 54.8 s(-1)) compared to wt GOx. Compared to the employed parent B11 GOx (16 mM, 80 s(-1)) it has a slightly increased K(m) and 1.8 times increased k(cat). PMID- 20958256 TI - PLUXter: rapid discovery of metal-organic framework structures using PCA and HCA of high throughput synchrotron powder diffraction data. AB - This paper reports on a systematic method--called PLUXter--developed for screening and data mining of large numbers of potential metal-organic framework compounds that have been synthesized then subsequently analyzed with high throughput synchrotron radiation X-ray powder diffraction. The first part of the method utilizes principal components analysis (PCA), which allows materials to be ranked in order of crystallinity so that undesirable amorphous materials may be identified and eliminated. The second part allows structural grouping within and between samples to be observed using hierarchical cluster analysis (HCA). Classification using a single linkage distance produced unsatisfactory clusters however the dendrogram's structural relationships were used to establish and guide the boundaries of groups. The resultant grouping identities allowed further structure-property studies to be undertaken on representative structures from the clusters, significantly reducing time and the use of resources. PMID- 20958257 TI - Miniaturization of a panel of high-throughput yeast-cell-based nuclear receptor assays in 384- and 1536-well microplates. AB - A panel of luminescent Saccharomyces cerevisiae cell-based nuclear receptor assays, consisting of human estrogen receptors alpha and beta, androgen receptor, and aryl hydrocarbon receptor, was miniaturized from the standard 96-well microplate format to high-throughput 384- and 1536-well microplate formats. In these assays, firefly luciferase lacking the peroxisome targeting sequence was used as a reporter and D-luciferin substrate was pre-mixed with the yeast cells before the incubation step, eliminating cell lysis and substrate addition steps, and allowing multiple readings at any desired time point. All of the assays were highly functional in the 384-well format, and most functioned well in the 1536 well format. The detection limit of the estrogen receptor alpha assay was even lower in the miniaturized microplate formats than in the original 96-well format. The panel of yeast-cell-based nuclear receptor assays can be used for high throughput chemical testing and environmental monitoring of potential endocrine disrupting activity of compounds and samples. PMID- 20958258 TI - OPLS-DA as a suitable method for selecting a set of gene transcripts discriminating RAS- and PTPN11-mutated cells in acute lymphoblastic leukaemia. AB - OPLS discriminant analysis (OPLS-DA) was successfully applied for the selection of a limited number of gene transcripts necessary to discriminate PTPN11 and RAS mutated cells in acute lymphoblastic leukaemia (ALL) patients. The original set of 273 variables with VIP (1) values higher than 2.0 in the OPLS-DA model could be further reduced to 200 by elimination of less informative variables in the PCA class models adopted for SIMCA classification. The above 200 transcripts not only achieve a satisfactory discrimination accuracy between PTPN11 and RAS mutated cells but also indicate clearly that wild type samples belong to none of the mutated class models. In this list it was possible to identify candidate genes that could be involved in the molecular mechanisms discriminating PTPN11 and RAS mutations in ALL. Among them CBFA2T2, a member of the "ETO" family, is known because of its homology and association with the product of RUNX1-CBFA2T1 gene fusion generated by t(8;21) translocation, one frequent cause of acute myeloid leukemia. PMID- 20958259 TI - New invariant of DNA sequences based on a new matrix representation. AB - In this paper we propose a matrix depiction and two new invariants of DNA sequences. This approach is illustrated on the primate mitochondrial DNA sequences for 11 different species and 80 different H5N1 avian influenza virus DNA sequences. We also construct the dendrogram tree for them. These phylogenies obtained are generally consistent with evolutionary trees constructed in previous studies. PMID- 20958260 TI - Streamlined in vivo selection and screening of human prostate carcinoma avid phage particles for development of peptide based in vivo tumor imaging agents. AB - Bacteriophage (phage) display has been exploited for the purpose of discovering new cancer specific targeting peptides. However, this approach has resulted in only a small number of tumor targeting peptides useful as in vivo imaging agents. We hypothesize that in vivo screening for tumor uptake of fluorescently tagged phage particles displaying multiple copies of an in vivo selected tumor targeting peptide will expedite the development of peptide based imaging agents. In this study, both in vivo selection and in vivo screening of phage displaying foreign peptides were utilized to best predict peptides with the pharmacokinetic properties necessary for translation into efficacious in vivo imaging agents. An in vivo selection of phage display libraries was performed in SCID mice bearing human PC-3 prostate carcinoma tumors. Eight randomly selected phage clones and four control phage clones were fluorescently labeled with AlexaFluor 680 for subsequent in vivo screening and analyses. The corresponding peptides of six of these phage clones were tested as 111In-labeled peptide conjugates for single photon emission computed tomography (SPECT) imaging of PC-3 prostate carcinomas. Two peptide sequences, G1 and H5, were successful as in vivo imaging agents. The affinities of G1 and H5 peptides for cultured PC-3 cells were then analyzed via cell flow cytometry resulting in Kd values of 1.8 uM and 2.2 uM, respectively. The peptides bound preferentially to prostate tumor cell lines compared to that of other carcinoma and normal cell lines, and H5 appeared to possess cytotoxic properties. This study demonstrates the value of in vivo screening of fluorescently labeled phage for the prediction of the efficacy of the corresponding 111In-labeled synthetic peptide as an in vivo SPECT tumor imaging agent. PMID- 20958261 TI - Apoptosis induction by thalidomide: critical for limb teratogenicity but therapeutic potential in idiopathic pulmonary fibrosis? AB - Thalidomide is a powerful treatment for inflammatory and cancer-based diseases. However, its clinical use remains limited due to its teratogenic properties, which primarily affect limb development. A prerequisite for overcoming these limitations is to understand the cellular and molecular mechanisms underlying thalidomide teratogenicity, which involve induction of oxidative stress, suppression of ubiquitin-mediated protein degradation and disruption of angiogenesis. Here, we discuss the hypothesis that thalidomide-induced limb teratogenicity is primarily based on the generation of nuclear oxidative stress with subsequent induction of transient apoptosis in the outgrowing limb bud. To this end, we establish a model of the signaling network regulating cell proliferation, survival and endogenous apoptosis-induction required for correct limb outgrowth and patterning. We then summarize data showing how thalidomide interferes with this signaling network: thalidomide inhibits the activity of the redox-sensitive transcription factor NF-kappaB, shifts the balance of fibroblast growth factors and bone morphogenetic proteins (Bmps) towards pro-apoptotic Bmps, and suppresses Wnt/beta-catenin- and Akt-dependent survival signaling in the limb bud. Consequently, prechondrogenic precursor cells that determine skeletal elements are eliminated leading to the development of truncated limbs. We further discuss the involvement of thalidomide effects on ubiquitin-mediated protein degradation and angiogenesis in the induction of apoptosis in the limb bud. Finally, we discuss the paradox that the embryonic molecular pathology induced by thalidomide suggests this drug as a candidate for therapeutic application in idiopathic pulmonary fibrosis (IPF), a chronic and fatal lung disease characterized by downregulation of Bmp signaling, increased Wnt and Akt activity, and apoptosis resistance. PMID- 20958262 TI - HIF-1 as a target for cancer chemotherapy, chemosensitization and chemoprevention. AB - Cells in rapidly growing solid tumors are commonly exposed to chronic or intermittent hypoxia. Hypoxia can induce cell death by multiple mechanisms; however, some cells may adapt by orchestrating dramatic changes in gene expression patterns. In addition, hypoxia exerts a powerful selective pressure on tumor cells, resulting in the emergence of clonal populations whose defects in DNA repair mechanisms favor genomic instability and tumor progression, whereas disabling of apoptotic pathways makes them more resistant to both environmental stresses and therapeutic interventions. The transcriptional factor HIF-1 (Hypoxia Inducible Factor 1) is generally considered as the major regulator of the hypoxic adaptive response, and as such it is viewed as a viable prospective target for novel pharmacologic approaches to the clinical management of solid tumors. Several agents have been identified that inhibit HIF1 transcriptional activity, and some of them are currently undergoing clinical trials, mostly based on their antiangiogenic properties. This article reviews the role played by HIF-1 in tumorigenesis and chemoresistance and provides an overview of current and prospective pharmacologic strategies designed to inhibit HIF-1 activity, emphasizing their direct and indirect effects on tumor growth, as well as their potential for chemoprevention and chemosensitization. PMID- 20958263 TI - A highly stable Yarrowia lipolytica lipase formulation for the treatment of pancreatic exocrine insufficiency. AB - Yarrowia lipolytica lipase has been assumed to be a good candidate for the treatment of fat malabsorption in patients with pancreatic insufficiency. Nevertheless, no systematic studies on its stability under physiological conditions pertaining to the human GI (gastrointestinal) tract have been published. Stability of various Y. lipolytica lipase powder formulations at various physiological pH values as well as the effect of digestive proteases and bile salts on enzyme activity were investigated. Results were compared with those obtained from another competing fungal lipase sourced from Candida rugosa. Among the studied formulations, Y. lipolytica lipase stabilized with gum arabic and skimmed milk powder was the most promising powder formulation. Under acidic conditions (pH 3-5), this formulation showed higher stability than those observed with the other Y. lipolytica lipase formulations and C. rugosa lipase. In addition, in the presence of gum arabic and skimmed milk powder as additives, Y. lipolytica lipase exhibited markedly higher resistance to pepsin, trypsin and chymotrypsin actions. Resistance to proteolytic degradation by digestive proteases was also by far higher than that observed with C. rugosa lipase. Similar behaviour was, however, observed when these two fungal lipases were incubated with increased concentrations of bile salts. Residual lipase activity of both fungal lipases showed a slight decrease in NaTDC (sodium taurodeoxycholate) concentration above 4 mM. Consequently, Y. lipolytica lipase formulated with gum arabic and milk powder seemed to have great potential for use as a therapeutic tool for patients with pancreatic insufficiency. PMID- 20958264 TI - Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6 bisphosphatase 2 in prostate cancer cells. AB - Up-regulation of lipogenesis by androgen is one of the most characteristic metabolic features of LNCaP prostate cancer cells. The present study revealed that androgen increases glucose utilization for de novo lipogenesis in LNCaP cells through the activation of HK2 (hexokinase 2) and activation of the cardiac isoform of PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase). Activation of PKA (cAMP-dependent protein kinase) by androgen increased phosphorylation of CREB [CRE (cAMP-response element)-binding protein], which in turn bound to CRE on the promoter of the HK2 gene resulting in transcriptional activation of the HK2 gene. Up-regulation of PFKFB2 expression was mediated by the direct binding of ligand-activated androgen receptor to the PFKFB2 promoter. The activated PI3K (phosphoinositide 3-kinase)/Akt signalling pathway in LNCaP cells contributes to the phosphorylation of PFKFB2 at Ser466 and Ser483, resulting in the constitutive activation of PFK-2 (6-phosphofructo-2-kinase) activity. Glucose uptake and lipogenesis were severely blocked by knocking-down of PFKFB2 using siRNA (small interfering RNA) or by inhibition of PFK-2 activity with LY294002 treatment. Taken together, our results suggest that the induction of de novo lipid synthesis by androgen requires the transcriptional up-regulation of HK2 and PFKFB2, and phosphorylation of PFKFB2 generated by the PI3K/Akt signalling pathway to supply the source for lipogenesis from glucose in prostate cancer cells. PMID- 20958265 TI - Atherosclerosis and sex hormones: current concepts. AB - CVD (cardiovascular disease) is the leading cause of death for women. Considerable progress has been made in both our understanding of the complexities governing menopausal hormone therapy and our understanding of the cellular and molecular mechanisms underlying hormone and hormone receptor function. Understanding the interplay of atherosclerosis and sex steroid hormones and their cognate receptors at the level of the vessel wall has important ramifications for clinical practice. In the present review, we discuss the epidemiology of CVD in men and women, the clinical impact of sex hormones on CVD, and summarize our current understanding of the pathogenesis of atherosclerosis with a focus on gender differences in CVD, its clinical presentation and course, and pathobiology. The critical animal and human data that pertain to the role of oestrogens, androgens and progestins on the vessel wall is also reviewed, with particular attention to the actions of sex hormones on each of the three key cell types involved in atherogenesis: the endothelium, smooth muscle cells and macrophages. Where relevant, the systemic (metabolic) effects of sex hormones that influence atherogenesis, such as those involving vascular reactivity, inflammation and lipoprotein metabolism, are discussed. In addition, four key current concepts in the field are explored: (i) total hormone exposure time and coronary heart disease risk; (ii) the importance of tissue specificity of sex steroid hormones, critical timing and the stage of atherosclerosis in hormone action; (iii) biomarkers for atherosclerosis with regard to hormone therapy; and (iv) the complex role of sex steroids in inflammation. Future studies in this field will contribute to guiding clinical treatment recommendations for women and help define research priorities. PMID- 20958266 TI - Retraction of: Number and activity of endothelial progenitor cells from peripheral blood in patients with hypercholesterolaemia. PMID- 20958268 TI - Vitiligo, reactive oxygen species and T-cells. AB - The acquired depigmenting disorder of vitiligo affects an estimated 1% of the world population and constitutes one of the commonest dermatoses. Although essentially asymptomatic, the psychosocial impact of vitiligo can be severe. The cause of vitiligo remains enigmatic, hampering efforts at successful therapy. The underlying pathogenesis of the pigment loss has, however, been clarified to some extent in recent years, offering the prospect of effective treatment, accurate prognosis and rational preventative strategies. Vitiligo occurs when functioning melanocytes disappear from the epidermis. A single dominant pathway is unlikely to account for all cases of melanocyte loss in vitiligo; rather, it is the result of complex interactions of biochemical, environmental and immunological events, in a permissive genetic milieu. ROS (reactive oxygen species) and H2O2 in excess can damage biological processes, and this situation has been documented in active vitiligo skin. Tyrosinase activity is impaired by excess H2O2 through oxidation of methionine residues in this key melanogenic enzyme. Mechanisms for repairing this oxidant damage are also damaged by H2O2, compounding the effect. Numerous proteins and peptides, in addition to tyrosinase, are similarly affected. It is possible that oxidant stress is the principal cause of vitiligo. However, there is also ample evidence of immunological phenomena in vitiligo, particularly in established chronic and progressive disease. Both innate and adaptive arms of the immune system are involved, with a dominant role for T-cells. Sensitized CD8+ T cells are targeted to melanocyte differentiation antigens and destroy melanocytes either as the primary event in vitiligo or as a secondary promotive consequence. There is speculation on the interplay, if any, between ROS and the immune system in the pathogenesis of vitiligo. The present review focuses on the scientific evidence linking alterations in ROS and/or T-cells to vitiligo. PMID- 20958267 TI - Phosphate toxicity: new insights into an old problem. AB - Phosphorus is an essential nutrient required for critical biological reactions that maintain the normal homoeostatic control of the cell. This element is an important component of different cellular structures, including nucleic acids and cell membranes. Adequate phosphorus balance is vital for maintaining basic cellular functions, ranging from energy metabolism to cell signalling. In addition, many intracellular pathways utilize phosphate ions for important cellular reactions; therefore, homoeostatic control of phosphate is one of the most delicate biological regulations. Impaired phosphorus balance can affect the functionality of almost every human system, including musculoskeletal and cardiovascular systems, ultimately leading to an increase in morbidity and mortality of the affected patients. Human and experimental studies have found that delicate balance among circulating factors, like vitamin D, PTH (parathyroid hormone) and FGF23 (fibroblast growth factor 23), are essential for regulation of physiological phosphate balance. Dysregulation of these factors, either alone or in combination, can induce phosphorus imbalance. Recent studies have shown that suppression of the FGF23-klotho system can lead to hyperphosphataemia with extensive tissue damage caused by phosphate toxicity. The cause and consequences of phosphate toxicity will be briefly summarized in the present review. PMID- 20958269 TI - CXCL8 enhances the angiogenic activity of umbilical cord blood-derived outgrowth endothelial cells in vitro. AB - OECs (outgrowth endothelial cells), also known as late-EPCs (late-endothelial progenitor cells), have a high proliferation potential in addition to in vitro tube formation capability. In ischaemic animal models, injected OECs were integrated into regenerating blood vessels and improved neovascularization. Previous reports have demonstrated the expression of CXCL8 to be up-regulated in ischaemic tissues. It has also been documented that CXCL8 stimulates the angiogenic activity of mature ECs (endothelial cells). Therefore, it has been suggested that CXCL8 plays an important role in neovascularization in ischaemic tissues. However, it is still uncertain whether CXCL8 also stimulates the angiogenic activity of OECs. This study evaluated the effects of CXCL8 on the angiogenic activity of OECs in vitro. OECs were isolated from human UCB (umbilical cord blood)-derived mononuclear cells. Phenotypes of the OECs were assessed by flow cytometry, immunostaining, and real-time RT (reverse transcription)-PCR. The effects of CXCL8 on OECs were investigated by transwell migration assay and capillary tube formation assay on Matrigel. The OEC clones isolated from UCB expressed OEC phenotypes. In addition, CXCL8 receptors (CXCR1 and CXCR2) were expressed on these OEC clones. CXCL8 significantly stimulated the transwell migration and capillary tube formation of OECs. Neutralizing antibody against CXCR2, but not CXCR1, abolished a transwell migration of OECs induced by CXCL8, suggesting the involvement of CXCL8/CXCR2 axis in transwell migration. These results demonstrate that CXCL8 stimulates the angiogenic activity of UCB derived OECs in vitro. PMID- 20958270 TI - Preventing breast cancer in women with schizophrenia. AB - OBJECTIVE: To record risk factors for breast cancer in women with schizophrenia and recommend preventive actions. METHOD: A PubMed literature search (from 2005 to 2010) was conducted, using the search terms 'schizophrenia', 'antipsychotics', 'breast cancer' and 'risk factors'. RESULTS: Several risk factors of relevance to schizophrenia were identified: obesity, elevated prolactin levels, low participation in mammography screening, high prevalence of diabetes, comparatively low parity, low incidence of breastfeeding, social disadvantage, high levels of smoking and alcohol consumption, low activity levels. CONCLUSION: Awareness of breast cancer risk should lead to more accurate risk ascertainment, stronger linkage with primary care, regular monitoring and screening, judicious choice and low dose of antipsychotic treatment, concomitant use of adjunctive cognitive and psychosocial therapies, referral to diet and exercise programmes as well as smoking and drinking cessation programmes, avoidance of hormonal treatment and discussion with patient and family about the pros and cons of preventive measures in high-risk women. Psychiatrists are in a position to reverse many of the identified risk factors. PMID- 20958271 TI - A systematic review and meta-analysis of the fertility of patients with schizophrenia and their unaffected relatives. AB - OBJECTIVE: We aimed to systematically evaluate the empirical evidence for the commonly held view that the reduced reproductive output in patients with schizophrenia is compensated for by an increased fitness in unaffected relatives. Secondary aims were to quantify the magnitude of the fertility disadvantage and the apparent gender difference in fertility of patients with schizophrenia. METHOD: We carried out a systematic review and meta-analysis of studies investigating the fertility of patients with schizophrenia, their siblings, their parents and the general population. RESULTS: Patients with schizophrenia had reduced fertility compared with the general population, [Fertility Ratio (FR)=0.39 (95% Confidence Interval (CI)=0.35-0.44)]. Siblings of patients with schizophrenia had somewhat fewer offspring than the general population (FR=0.96, 95% CI=0.93-1.00). Parents of patients with schizophrenia had fertility similar to the general population (FR=1.17, 95% CI=0.94-1.46). Men had a greater impairment in fertility than women, both in patients (FR=0.54, 95% CI=0.50-0.57) and in their unaffected siblings (FR=0.81, 95% CI=0.71-0.92). CONCLUSION: Compensatory fitness advantage in siblings and parents cannot explain the maintenance of schizophrenia in the population. Alternative explanations include mutation-selection balance and the role of quantitative traits. PMID- 20958272 TI - Factors predictive of ten-year mortality in severe anorexia nervosa patients. AB - OBJECTIVE: Little is known concerning mortality and predictive factors for anorexia nervosa in-patients. This study aimed to establish mortality rates and identify predictors in a large sample of adults through a 10-year post in-patient treatment follow-up. METHOD: Vital status was established for 601 anorexia nervosa (DSM-IV) consecutive in-patients with initial evaluation at admission. Standardized mortality ratio (SMR) was calculated. Cox analyses for hypothesized predictors of mortality were performed. RESULTS: Forty deaths were recorded. SMR was 10.6 [CI 95% (7.6-14.4)]. Six factors at admission were associated with death: older age, longer eating disorder duration, history of suicide attempt, diuretic use, intensity of eating disorder symptoms, and desired body mass index at admission. CONCLUSION: Anorexia nervosa in-patients are at high risk of death. This risk can be predicted by both chronicity and seriousness of illness at hospitalization. These elements should be considered as warnings to adapt care provision and could be targeted by treatment. PMID- 20958273 TI - No functional psychopharmacology without functional psychopathology. PMID- 20958274 TI - Phenomenology is not enough. PMID- 20958275 TI - Use of thromboelastometry in the assessment of coagulation before epidural insertion after massive transfusion. AB - A British soldier presented to the UK Field Hospital, Afghanistan with bilateral traumatic lower limb amputations. Resuscitation and surgery followed accepted damage control principles. Blood component therapy was in keeping with UK military guidelines and included platelets and cryoprecipitate. The patient's trachea was extubated following insertion of an effective epidural. Ten days later, in the UK, he developed neurological symptoms and the presence of a subdural haematoma was confirmed on magnetic resonance imaging. Conventional laboratory coagulation results in this patient were above accepted limits for epidural insertion; however, thromboelastometry before insertion was suggestive of reduced platelet function. This case highlights the risk of relying solely on platelet count as a marker of platelet function following massive transfusion. Thromboelastometry provides additional information for the assessment of coagulation and should form part of the assessment of coagulation following massive transfusion before epidural insertion. PMID- 20958276 TI - A paramedic study comparing the use of the Airtraq, Airway Scope and Macintosh laryngoscopes in simulated prehospital airway scenarios. AB - In a randomised, cross-over study, we compared the use of the Airtraq , Airway Scope and Macintosh laryngoscopes by paramedics for tracheal intubation in three simulated prehospital scenarios. Fifty-four paramedics were invited to take part. When evaluated in a difficult airway manikin, median IQR [range] time to intubation with the Airtraq (21 (16-37 [6-80] s) and Airway Scope (16 (5-75 [12 23] s) was shorter than that with the Macintosh laryngoscope (39 (25-54 [7-120] s; p < 0.0001). The success rate within 30 s was greater with the Airtraq (61%) and Airway Scope (93%) than with the Macintosh laryngoscope (22%; p < 0.0001). When used for a standard intubation and in the sitting position, we found minimal differences among the three laryngoscopes. We conclude that the Airway Scope and Airtraq have significant advantages over the Macintosh laryngoscope and that of the two, the Airway Scope is the more effective device to use in the prehospital environment. PMID- 20958277 TI - The analgesic efficacy of continuous wound instillation with ropivacaine after open hepatic surgery. AB - The analgesic efficacy of continuous local anaesthetic wound instillation after open hepatic surgery was evaluated. Forty-eight patients scheduled for elective liver surgery were assigned to receive either ropivacaine 0.25% or saline infusion at 4 ml.h(-1) for 68 h via two multi-orifice indwelling catheters placed within the musculo-fascial layer before skin closure; plasma ropivacaine concentrations were measured during the infusion. Supplemental analgesia was provided by intravenous patient-controlled analgesia morphine. Patients in the ropivacaine group had decreased mean (SD) total morphine consumption (58 (30) mg vs 86 (44) mg, p = 0.01) and less pain at rest as well as after spirometry at 4, 12, 24, 48 and 72 h postoperatively (p < 0.01). Forced vital capacity was reduced postoperatively in both groups, but the reduction was greater in the saline group at 12 and 24 h (p = 0.03). The mean plasma concentration of ropivacaine increased to 2.05 (0.78) MUg.ml(-1) at the point when the infusion was terminated. PMID- 20958278 TI - Comparison of the LMA Supreme vs the i-gel in paralysed patients undergoing gynaecological laparoscopic surgery with controlled ventilation. AB - We compared the efficacy of the inflatable cuff of the LMA Supreme against the non-inflatable i-gel cuff in providing an adequate seal for laparoscopic surgery in the Trendelenburg position in 100 female patients. There was no difference in our primary outcome, oropharyngeal leak pressure, between the LMA Supreme and the i-gel (mean (SD) 26.4 (5.1) vs 25.0 (5.7) cmH(2) O, respectively; p = 0.18). Forty-seven (94%) LMA Supremes and 48 (96%) i-gels were successfully inserted on the first attempt, with similar ease, and comparable times to the first capnograph trace (mean (SD) 14.3 (4.7) s for the LMA Supreme vs 15.4 (8.2) s for the i-gel; p = 0.4). Gastric tube insertion was easier and achieved more quickly with the LMA Supreme vs the i-gel (9.0 (2.5) s vs 15.1 (7.3) s, respectively; p < 0.001). After creation of the pneumoperitoneum, there was a smaller difference between expired and inspired tidal volumes with the LMA Supreme (21.5 (15.2) ml) than with the i-gel (31.2 (23.5) ml; p = 0.009). There was blood on removal of two LMA Supremes and one i-gel. Four patients in the LMA Supreme group and one patient in the i-gel group experienced mild postoperative sore throat. PMID- 20958279 TI - Using magnetic resonance imaging to diagnose nondisplaced fractures of the second phalanx in horses. AB - Two horses presented with a history of severe lameness that was localised to the area around the second phalanx (P2) of one forelimb. Radiographs of the second phalanx of both horses were unremarkable, apart from some smooth periosteal new bone production on the dorsum of P2. Magnetic resonance imaging revealed a non displaced fracture of P2 in both horses. One horse was euthanased because of a poor prognosis for racing, but the second horse was treated conservatively and salvaged for breeding. Magnetic resonance imaging is a newer imaging modality in horses and may be useful in diagnosing cases of obscure lameness. PMID- 20958281 TI - A survey of aged horses in Queensland, Australia. Part 1: management and preventive health care. AB - OBJECTIVE: To describe management practices and routine preventive care of aged horses in Queensland, Australia, including effects of owner characteristics, affiliation to an equestrian group and retirement of the horse. METHODS: Owners of horses were contacted via Equestrian Australia (EA) and asked to complete a questionnaire about their aged horses (e.g. age, breed, sex and colour); their use and management, including preventive health care; and use of equine healthcare providers. RESULTS: Horses aged 15 years or greater represented one third of the total horses owned in the population sample. The median age of the horses was 20.7 years (range 15-44 years). Basic husbandry and preventive health care varied depending on demographic region, age of the horse and its use. Affiliation with EA was associated with the breed and use of the horse, but not with management or preventive health care other than frequency of hoof care visits. Retired horses had reduced basic husbandry and preventive health care compared with non-retired horses. There was reduced preventive health care in rural compared with urban areas. The majority (61%) of horses in the current study had not been visited by a veterinarian in the previous 12 months. CONCLUSION: Aged horses constitute a large subgroup of the Australian horse population. Although basic management is at a high level for most aged horses, it appears to be reduced following the horse's retirement and in the more rural areas. There was limited veterinary involvement in preventive healthcare strategies for aged horses, especially in rural areas. PMID- 20958282 TI - Two-dimensional and M-mode echocardiographic findings in healthy Thoroughbred foals. AB - OBJECTIVE: The aim of this study was to establish reference values for a series of conventional two-dimensional (2-D) and M-mode echocardiographic variables in Thoroughbred foals at increasing age intervals. DESIGN: Nineteen healthy Thoroughbred foals (11 males, 8 females) were examined at 1, 2, 4, 8, 12 and 16 weeks of life. Auscultatory findings were recorded and echocardiographic examinations (2-D and M-mode) were performed. Descriptive statistical analyses, including mean, standard deviation and 95% confidence interval for the means, were used to summarise the data. The relationships between selected echocardiographic variables and age, body weight and heart rate were analysed. RESULTS: Reference values were determined for 12 routinely used 2-D and M-mode echocardiographic variables in healthy Thoroughbred foals at increasing age intervals. Linear relationships between echocardiographic variables and age (P < 0.001) and body weight (P < 0.001) were found, with the linear relationships between echocardiographic variables and body weight being stronger than those with age. Weak (R(2) <= 0.37) but significant (P < 0.001) correlations between the echocardiographic variables and heart rate were identified. CONCLUSIONS: Reference values for 2-D and M-mode echocardiographic variables in clinically normal Thoroughbred foals up to 4 months of age and approximately 190 kg body weight may assist in the interpretation of echocardiograms of Thoroughbred foals of similar age and body weight with suspected congenital or acquired cardiac disease. PMID- 20958283 TI - Complete caecal bypass without ileal transection for caecal impaction in horses: seven clinical cases (1997-2007). AB - OBJECTIVES: To report the clinical outcome in seven horses following use of a newly described surgical technique for treating caecal impaction. METHODS: The medical records of seven horses with caecal impaction treated surgically using a stapling technique to create a complete caecal bypass without ileal transection were reviewed. Data were obtained from the records and through telephone interviews with case-associated personnel. RESULTS: The mean age was 10 years (range 2-22 years) and duration of colic ranged from 24 h to 2 weeks. Five horses had type II motility dysfunction and the remaining two had type I. Mean surgical time was 185 min (range 146-245 min) and the horses were hospitalised for a mean of 12.4 days (range 9-22 days); 71% (5/7) were discharged from hospital and all five were alive 60 days from the surgery date. One horse was lost to follow-up. The four (66.7%) available remaining horses were alive >= 1 year (long-term survivors). CONCLUSIONS: Complete caecal bypass without ileal transection for clinical cases of caecal impaction had comparable outcomes to complete bypass with ileal transection. The technique is easy to perform, has the potential to reduce surgical time, compared with traditional bypass techniques, and may reduce the risk of intraoperative abdominal contamination. It is recommended for use in clinical cases in which caecal bypass is desirable. PMID- 20958284 TI - Improved procedure for implanting radiotransmitters in the coelomic cavity of snakes. AB - OBJECTIVE: To investigate the expulsion of radiotransmitters in snakes and modify the surgical technique for coelomic implantation to prevent its occurrence. DESIGN: To enable monitoring of snakes for an ecological study, radiotransmitters were implanted in 23 south-west carpet pythons (Morelia spilota imbricata) using the standard surgical technique. In a further 23 pythons we used a refinement of the technique, which anchored the tracking device, using non-dissolvable sutures, to the snake's rib-cage. We also investigated the potential mechanisms for expelling the radiotransmitters in one snake that underwent an exploratory coeliotomy. RESULTS: Of the initial group of snakes, 12 (52%) expelled the radiotransmitter between 4 days and 3 years post implantation. In the later group, which underwent the refined technique of implantation, none of the radiotransmitters was expelled and no adverse responses were observed. CONCLUSION: An appropriately sized radiotransmitter anchored to the rib-cage of the snake will prevent expulsion of the device and appears to be well tolerated. Non-attachment of the tracking device enables it to migrate along the length of the body, particularly during feeding and reproduction. Caudal positioning of the transmitter's antenna provides a possible pathogenesis for expulsion into the cloaca. PMID- 20958285 TI - Tracheal resection and anastomosis in a red-tailed black cockatoo (Calyptorhynchus banksii banksii). AB - Tracheal stricture is an uncommon sequel to tracheitis in birds. We describe a case in a red-tailed black cockatoo that was attributed to a bacterial tracheitis associated with inhaled plant material and was successfully resolved by surgical resection and anastomosis of the trachea. PMID- 20958286 TI - Nasal myiasis in a cat caused by larvae of the nasal bot fly, Oestrus ovis. AB - An 8-year-old desexed male Burmese cat, which lived on a sheep-grazing property in central New South Wales, Australia, was presented following the sudden onset of dyspnoea, moist coughing and violent sneezing. The respiratory distress started several hours after the cat had made an outdoor excursion. Anterior rhinoscopy demonstrated small, white objects moving across oedematous and moderately inflamed nasal mucosa. These were retrieved via a series of vigorous nasal flushes and subsequently identified as larvae of the nasal bot fly, Oestrus ovis. The cat was treated with ivermectin followed by selamectin 7 days later. It went on to make a complete recovery over 2-3 weeks. PMID- 20958287 TI - Impaired neoangiogenesis in beta2-adrenoceptor gene-deficient mice: restoration by intravascular human beta2-adrenoceptor gene transfer and role of NFkappaB and CREB transcription factors. AB - BACKGROUND AND PURPOSE: There is much evidence supporting the role of beta2 adrenoceptors (beta2AR) in angiogenesis but the mechanisms underlying their effects have not been elucidated. Hence, we studied post-ischaemic angiogenesis in the hindlimb (HL) of beta2AR knock-out mice (beta2AR-/-) in vivo and explored possible molecular mechanisms in vitro. EXPERIMENTAL APPROACH: Femoral artery resection (FAR) was performed in wild-type and beta2AR-/- mice and adaptive responses to chronic HL ischaemia were explored; blood flow was measured by ultrasound and perfusion of dyed beads, bone rarefaction, muscle fibrosis and skin thickness were evaluated by immunoflourescence and morphometric analysis. Intrafemoral delivery of an adenovirus encoding the human beta2AR (ADbeta2AR) was used to reinstate beta2ARs in beta2AR-/- mice. Molecular mechanisms were investigated in mouse-derived aortic endothelial cells (EC) in vitro, focusing on NFkappaB activation and transcriptional activity. RESULTS: Angiogenesis was severely impaired in beta2AR-/- mice subjected to FAR, but was restored by gene therapy with ADbeta2AR. The proangiogenic responses to a variety of stimuli were impaired in beta2AR-/- EC in vitro. Moreover, removal of beta2ARs impaired the activation of NFkappaB, a transcription factor that promotes angiogenesis; neither isoprenaline (stimulates betaARs) nor TNFalpha induced NFkappaB activation in beta2AR(-/-) EC. Interestingly, cAMP response element binding protein (CREB), a transcription factor that counter regulates NFkappaB, was constitutively increased in beta2AR(-/-) ECs. ADbeta2AR administration restored beta2AR membrane density, reduced CREB activity and reinstated the NFkappaB response to isoprenaline and TNFalpha. CONCLUSIONS AND IMPLICATIONS: Our results suggest that beta2ARs control angiogenesis through the tight regulation of nuclear transcriptional activity. PMID- 20958288 TI - Vascular actions of calcimimetics: role of Ca2(+) -sensing receptors versus Ca2(+) influx through L-type Ca2(+) channels. AB - BACKGROUND AND PURPOSE: The calcimimetic, (R)-N-(3-(3 (trifluoromethyl)phenyl)propyl)-1-(1-napthyl)ethylamine hydrochloride (cinacalcet), which activates Ca2(+) -sensing receptors (CaR) in parathyroid glands, is used to treat hyperparathyroidism. Interestingly, CaR in perivascular nerves or endothelial cells is also thought to modulate vascular tone. This study aims to characterize the vascular actions of calcimimetics. EXPERIMENTAL APPROACH: In rat isolated small mesenteric arteries, the relaxant responses to the calcimimetics, cinacalcet and (R)-2-[[[1-(1-naphthyl)ethyl]amino]methyl]-1H indole hydrochloride (calindol) were characterized, with particular emphasis on the role of CaR, endothelium, perivascular nerves, K(+) channels and Ca2(+) channels. Effects of L-ornithine, which activates a Ca(2+) -sensitive receptor related to CaR (GPRC6A), were also tested. KEY RESULTS: Cinacalcet induced endothelium-independent relaxation (pEC50 5.58 +/- 0.07, E(max) 97 +/- 6%) that was insensitive to sensory nerve desensitization by capsaicin or blockade of large-conductance Ca2(+) -activated K(+) channels by iberiotoxin. Calindol, another calcimimetic, caused more potent relaxation (pEC50 6.10 +/- 0.10, E(max) 101 +/- 6%), which was attenuated by endothelial removal or capsaicin, but not iberiotoxin. The negative modulator of CaR, calhex 231 or changes in [Ca2(+) ](o) had negligible effect on relaxation to both calcimimetics. The calcimimetics relaxed vessels precontracted with high [K(+) ](o) and inhibited Ca2(+) influx in endothelium-denuded vessels stimulated by methoxamine, but not ionomycin. They also inhibited contractions to the L-type Ca2(+) channel activator, BayK8644. L ornithine induced small relaxation alone and had no effect on the responses to calcimimetics. CONCLUSION AND IMPLICATIONS: Cinacalcet and calindol are potent arterial relaxants. Under the experimental conditions used, they predominantly act by inhibiting Ca2(+) influx through L-type Ca2(+) channels into vascular smooth muscle, whereas Ca2(+) -sensitive receptors (CaR or GPRC6A) play a minor role. PMID- 20958289 TI - Involvement of decreased muscarinic receptor function in prepulse inhibition deficits in mice reared in social isolation. AB - BACKGROUND AND PURPOSE: We have previously reported that galantamine, a weak acetylcholinesterase inhibitor, improves prepulse inhibition (PPI) deficits in mice reared in social isolation. ACh receptors are involved in the underlying mechanism of PPI, but whether rearing in social isolation causes dysfunction of the cholinergic system is unknown. In this study, we examined the involvement of muscarinic receptors in the improvement of PPI deficits induced by galantamine, and whether the cholinergic system is altered in mice reared in isolation. EXPERIMENTAL APPROACH: Three-week-old male ddY mice were housed in isolated cages for 6 weeks before the initiation of experiments to create PPI deficits. Cholinergic functions were determined by measuring the behavioural and neurochemical responses to nicotinic and muscarinic receptor agonists. KEY RESULTS: The improvement by galantamine of social isolation-induced PPI deficits was blocked by scopolamine, a non-selective muscarinic antagonist, and telenzepine, a preferential M1 receptor antagonist. Activation of M1 receptors improved social isolation-induced PPI deficits. Social isolation did not affect choline acetyltransferase and acetylcholinesterase activities in the prefrontal cortex and hippocampus, but it reduced the locomotor-suppressive response to muscarinic agonist oxotremorine, but not to nicotine. The isolation also attenuated the M1 receptor agonist N-desmethylclozapine-induced increase in prefrontal dopamine release. CONCLUSIONS AND IMPLICATIONS: Galantamine improves PPI deficits of mice reared in social isolation via activation of M1 receptors. Social isolation reduces the muscarinic, especially M1, receptor function and this is involved in PPI deficits. PMID- 20958290 TI - Negative cooperativity in binding of muscarinic receptor agonists and GDP as a measure of agonist efficacy. AB - BACKGROUND AND PURPOSE: Conventional determination of agonist efficacy at G protein coupled receptors is measured by stimulation of guanosine-5'-gamma thiotriphosphate (GTPgammaS) binding. We analysed the role of guanosine diphosphate (GDP) in the process of activation of the M2 muscarinic acetylcholine receptor and provide evidence that negative cooperativity between agonist and GDP binding is an alternative measure of agonist efficacy. EXPERIMENTAL APPROACH: Filtration and scintillation proximity assays measured equilibrium binding as well as binding kinetics of [35S]GTPgammaS and [3H]GDP to a mixture of G-proteins as well as individual classes of G-proteins upon binding of structurally different agonists to the M2 muscarinic acetylcholine receptor. KEY RESULTS: Agonists displayed biphasic competition curves with the antagonist [3H]-N methylscopolamine. GTPgammaS (1 uM) changed the competition curves to monophasic with low affinity and 50 uM GDP produced a similar effect. Depletion of membrane bound GDP increased the proportion of agonist high-affinity sites. Carbachol accelerated the dissociation of [3H]GDP from membranes. The inverse agonist N methylscopolamine slowed GDP dissociation and GTPgammaS binding without changing affinity for GDP. Carbachol affected both GDP association with and dissociation from G(i/o) G-proteins but only its dissociation from G(s/olf) G-proteins. CONCLUSIONS AND IMPLICATIONS: These findings suggest the existence of a low affinity agonist-receptor conformation complexed with GDP-liganded G-protein. Also the negative cooperativity between GDP and agonist binding at the receptor/G protein complex determines agonist efficacy. GDP binding reveals differences in action of agonists versus inverse agonists as well as differences in activation of G(i/o) versus G(s/olf) G-proteins that are not identified by conventional GTPgammaS binding. PMID- 20958291 TI - Agonist activation of the G protein-coupled receptor GPR35 involves transmembrane domain III and is transduced via Galpha13 and beta-arrestin-2. AB - BACKGROUND AND PURPOSE: GPR35 is a poorly characterized G protein-coupled receptor at which kynurenic acid has been suggested to be the endogenous ligand. We wished to test this and develop assays appropriate for the study of this receptor. EXPERIMENTAL APPROACH: Human and rat orthologues of GPR35 were engineered and expressed and assays developed to assess interaction with beta arrestin-2, activation of Galpha13 and agonist-induced internalization. KEY RESULTS: GPR35-beta-arrestin-2 interaction assays confirmed that both the endogenous tryptophan metabolite kynurenic acid and the synthetic ligand zaprinast had agonist action at each orthologue. Zaprinast was substantially more potent than kynurenic acid at each and both agonists displayed substantially greater potency at rat GPR35. Two novel thiazolidinediones also displayed agonism and displayed similar potency at each GPR35 orthologue. The three ligand classes acted orthosterically with respect to each other, suggesting overlapping binding sites and, consistent with this, mutation to alanine of the conserved arginine at position 3.36 or tyrosine 3.32 in transmembrane domain III abolished beta arrestin-2 recruitment in response to each ligand at each orthologue. CONCLUSIONS AND IMPLICATIONS: These studies indicate that beta-arrestin-2 interaction assays are highly appropriate to explore the pharmacology of GPR35 and that Galpha13 activation is an alternative avenue of signal generation from GPR35. Arginine and tyrosine residues in transmembrane domain III are integral to agonist recognition and function of this receptor. The potency of kynurenic acid at human GPR35 is sufficiently low, however, to question whether it is likely to be the true endogenous ligand for this receptor. PMID- 20958292 TI - Pharmacology of structural changes at the GABA(A) receptor transmitter binding site. AB - BACKGROUND AND PURPOSE: The binding of transmitter to specialized binding pockets leads to rearrangements in the structure of the receptor eventually resulting in channel opening. We used voltage-clamp fluorometry to investigate the pharmacological basis and biophysical processes that underlie structural changes at the transmitter binding site of the rat alpha1beta2gamma2L GABA(A) receptor. EXPERIMENTAL APPROACH: Simultaneous electrophysiological and site-specific fluorescence measurements were conducted on receptors expressed in Xenopus oocytes and labelled with an environmentally-sensitive fluorophore, Alexa 546 maleimide, at the alpha1L127C site. KEY RESULTS: Receptors activated by GABA demonstrate a concentration-dependent increase in fluorescence intensity, indicating that the environment surrounding the fluorophore becomes less polar upon activation. Qualitatively similar responses were observed with other GABA site ligands such as piperidine-4-sulphonic acid, muscimol, beta-alanine and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol. Fluorescence changes were not affected by the direction of current flow. During long applications of GABA significant desensitization developed, which was not accompanied by additional changes in fluorescence. Pentobarbital was an efficacious agonist of the labelled mutant receptor but did not cause changes in fluorescence. Direct activation by etomidate or the steroid allopregnanolone also did not result in fluorescence changes. Functional potentiation of GABA-activated receptors by allopregnanolone or etomidate enhanced both the GABA-elicited functional response and the fluorescence change. In contrast, potentiation by pentobarbital was not accompanied by an enhanced fluorescence response. CONCLUSIONS AND IMPLICATIONS: The data indicate that there is no direct correlation between current flow or position of the activation gate and the structural changes as detected by Alexa 546-labelled alpha1L127Cbeta2gamma2L GABA(A) receptors. Channel potentiation by pentobarbital qualitatively differs from potentiation by etomidate or allopregnanolone. PMID- 20958293 TI - Ramipril retards development of aortic valve stenosis in a rabbit model: mechanistic considerations. AB - BACKGROUND AND PURPOSE: Aortic valve stenosis (AVS) is associated with significant cardiovascular morbidity and mortality. To date, no therapeutic modality has been shown to be effective in retarding AVS progression. We evaluated the effect of angiotensin-converting enzyme inhibition with ramipril on disease progression in a recently developed rabbit model of AVS. EXPERIMENTAL APPROACH: The effects of 8 weeks of treatment with either vitamin D2 at 25,000 IU for 4 days a week alone or in combination with ramipril (0.5 mg.kg-1) on aortic valve structure and function were examined in New Zealand white rabbits. Echocardiographic aortic valve backscatter (AV(BS)) and aortic valve:outflow tract flow velocity ratio were utilized to quantify changes in valve structure and function. KEY RESULTS: Treatment with ramipril significantly reduced AV(BS) and improved aortic valve :outflow tract flow velocity ratio. The intravalvular content of the pro-oxidant thioredoxin-interacting protein was decreased significantly with ramipril treatment. Endothelial function, as measured by asymmetric dimethylarginine concentrations and vascular responses to ACh, was improved significantly with ramipril treatment. CONCLUSIONS AND IMPLICATIONS: Ramipril retards the development of AVS, reduces valvular thioredoxin-interacting protein accumulation and limits endothelial dysfunction in this animal model. These findings provide important insights into the mechanisms of AVS development and an impetus for future human studies of AVS retardation using an angiotensin converting enzyme inhibitor. PMID- 20958294 TI - Method of injection of onabotulinumtoxinA for chronic migraine: a safe, well tolerated, and effective treatment paradigm based on the PREEMPT clinical program. AB - Chronic migraine (CM) is a prevalent and disabling neurological disorder. Few prophylactic treatments for CM have been investigated. OnabotulinumtoxinA, which inhibits the release of nociceptive mediators, such as glutamate, substance P, and calcitonin gene-related peptide, has been evaluated in randomized, placebo controlled studies for the preventive treatment of a variety of headache disorders, including CM. These studies have yielded insight into appropriate patient selection, injection sites, dosages, and technique. Initial approaches used a set of fixed sites for the pericranial injections. However, the treatment approach evolved to include other sites that corresponded to the location of pain and tenderness in the individual patient in addition to the fixed sites. The Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) injection paradigm uses both fixed and follow-the-pain sites, with additional specific follow-the-pain sites considered depending on individual symptoms. The PREEMPT paradigm for injecting onabotulinumtoxinA has been shown to be safe, well tolerated, and effective in well-designed, controlled clinical trials and is the evidence-based approach recommended to optimize clinical outcomes for patients with CM. PMID- 20958295 TI - Adverse childhood experiences and frequent headaches in adults. AB - BACKGROUND: A variety of studies have linked childhood maltreatment to headaches, including migraines, and to headache severity. This study assesses the relationship of adverse childhood experiences (ACEs) to frequent headaches during adulthood. METHODS: We used data from the Adverse Childhood Experiences (ACE) study, which included 17,337 adult members of the Kaiser Health Plan in San Diego, CA who were undergoing a comprehensive preventive medical evaluation. The study assessed 8 ACEs including abuse (emotional, physical, sexual), witnessing domestic violence, growing up with mentally ill, substance abusing, or criminal household members, and parental separation or divorce. Our measure of headaches came from the medical review of systems using the question: "Are you troubled by frequent headaches?" We used the number of ACEs (ACE score) as a measure of cumulative childhood stress and hypothesized a "dose-response" relationship of the ACE score to the prevalence and risk of frequent headaches. RESULTS: Each of the ACEs was associated with an increased prevalence and risk of frequent headaches. As the ACE score increased the prevalence and risk of frequent headaches increased in a "dose-response" fashion. The risk of frequent headaches increased more than 2-fold (odds ratio 2.1, 95% confidence interval 1.8-2.4) in persons with an ACE score >=5, compared to persons with and ACE score of 0. The dose-response relationship of the ACE score to frequent headaches was seen for both men and women. CONCLUSIONS: The number of ACEs showed a graded relationship to frequent headaches in adults. Future studies should examine general populations with headache, and carefully classify them. A better understanding of the link between ACEs and migraine may lead to new knowledge regarding pathophysiology and enhanced additional therapies for headache patients. PMID- 20958296 TI - Defining the pharmacologically intractable headache for clinical trials and clinical practice. AB - The terms refractory headache and intractable headache have been used interchangeably to describe persistent headache that is difficult to treat or fails to respond to standard and/or aggressive treatment modalities. A variety of definitions of intractability have been published, but as yet, an accepted/established definition is not available. To advance clinical and basic research in this population of patients, a universal and graded classification scheme of intractability is needed, and must include a definition of failure, to which and how many treatments the patient has failed, the level of headache related disability, and finally, the intended intervention (clinical or research) and intensity of the intervention. This paper addresses each of these variables with the intent of providing a graded classification scheme that can be used in defining intractability for clinical practice interventions and clinical research initiatives. PMID- 20958297 TI - Idiopathic intracranial hypertension in pregnancy. PMID- 20958298 TI - Brain imaging in migraine research. AB - Understanding the pathophysiology and pharmacology of migraine has been driven by astute clinical observations, elegant experimental medicine studies, and importantly by studying highly effective anti-migraine agents in the laboratory and the clinic. Significant progress has been made in the use of functional brain imaging to compliment observational studies of migraine phenotypes by highlighting pathways within the brain that may be involved in predisposition to migraine, modulating migraine pain or that could be sensitive to pharmacological or behavioral therapeutic intervention. In drug discovery, molecular imaging approaches compliment functional neuroimaging by visualizing migraine drug targets within the brain. Molecular imaging enables the selection and evaluation of drug candidates by confirming that they engage their targets sufficiently at well tolerated doses to test our therapeutic hypotheses. Migraine is a progressive disorder. Developing our knowledge of where drugs act in the brain and of how the brain is altered in both episodic migraine (interictal state and ictal state) and chronic migraine are important steps to understanding why there is such differential responsiveness to therapeutics among migraine patients and to improving how they are evaluated and treated. PMID- 20958299 TI - Insights into the pathophysiology of headache provided by recent functional imaging studies. PMID- 20958301 TI - Amniotic fluid embolism-apropos two consecutive cases. AB - Amniotic fluid embolism (AFE) is a sporadic, unpredictable, and usual fatal obstetric complication. The paper deals with two cases of maternal deaths because of AFE verified by medicolegal autopsy. In both the cases, several known risk factors associated with AFE, such as increased maternal age (41 and 35 years), diabetes, augmented labor, and cesarean delivery, were identified. Clinical features were typical, including sudden onset of cardiovascular and respiratory symptoms. In the patient who survived longer, both clinical and autopsy signs of disseminated intravascular coagulopathy were present, while they were absent in the case where death occurred rapidly. This paper describes briefly the particular features to look for at autopsy and stresses the importance of histology examination and staining techniques. PMID- 20958300 TI - Individual differences in the subjective experience of pain: new insights into mechanisms and models. AB - Individual differences in pain sensitivity have long remained a perplexing and challenging clinical problem. How can one individual have a sensory experience that is vastly different than that of another, even when they have received similar sensory input? Developing an understanding of such differences and the mechanisms that support them has progressed substantially as psychophysical findings are integrated with measures of brain activation provided by functional brain imaging techniques. Continued delineation of these mechanisms will contribute substantially to the development of combined psychophysical/psychological models that can be used to optimize pain treatment on an individual-by-individual basis. PMID- 20958302 TI - The development of analytical and interpretational protocols to facilitate the provenance establishment of polycarbonate headlamp lens material. AB - Despite the forensic significance of polycarbonate headlamp lenses, robust analytical protocols to facilitate their discrimination are scarce. In this study, laser ablation inductively coupled plasma mass spectrometry has been applied to the analysis of polycarbonate headlamp lenses with multivariate chemometrics techniques utilized to facilitate interpretation of the data. The analytical protocol involves the analysis of 46 analytes on material comprising the exterior surface of the lens. Using this data, it was found that although minor variation exists within a single headlamp lens, discrimination between lenses produced from a single manufacturing plant was still possible using iterative forward stepwise linear discriminant analysis processes. Discrimination between all headlamp lenses, with the exception of some lenses produced on the same day in a single plant, could be achieved using the analytical protocol. Furthermore, an interpretational protocol has been developed that has successfully classified all tested headlamp lens samples, within the discrimination limits of the analytical method. PMID- 20958303 TI - Resistance and recovery of soil microbial communities in the face of Alliaria petiolata invasions. AB - Invaders can gain ecological advantages because of their evolutionary novelty, but little is known about how these novel advantages will change over time as the invader and invaded community evolve in response to each other. Invasive plants often gain such an advantage through alteration of soil microbial communities. In soil communities sampled from sites along a gradient of invasion history with Alliaria petiolata, microbial richness tended to decline, but the community's resistance to A. petiolata's effects generally increased with increasing history of invasion. However, sensitive microbial taxa appeared to recover in the two oldest sites, leading to an increase in richness, but consequent decrease in resistance. This may be because of evolutionary changes in the A. petiolata populations, which tend to reduce their investment to allelopathic compounds over time. These results show that, over time, microbial communities can develop resistance to an invasive plant but at the cost of lower richness. However, over longer time-scales evolution in the invasive species may allow for the recovery of soil microbial communities. PMID- 20958304 TI - Differentiating between effects of invasion and diversity: impacts of aboveground plant communities on belowground fungal communities. AB - Exotic plant species can affect soil microbial communities with the potential for community and ecosystem feedbacks. Yet, separating the effects of exotics from confounded changes in plant community diversity still remains a challenge. We focused on how plant diversity and native or exotic life history affected root fungi because of their significant roles in community and ecosystem processes. Specifically, we examined how fungi colonizing plant roots were affected by plant richness (one, two or four species) replicated across a range of plant community mixtures (natives, exotics, native-exotic mixtures). Fungal biomass inside roots was affected independently by plant richness and mixture, while root fungal community composition was affected only by plant richness. Extraradical networks also increased in size with plant richness. By contrast, plant biomass was a function of plant mixture, with natives consistently smaller than exotics and native-exotic mixtures intermediate. Plant invasions may have an impact on the belowground community primarily through their effects on diversity, at least in the short-term. Disentangling the effects of diversity and invasion on belowground microbial communities can help us to understand both the controllers of belowground resilience and mechanisms of successful colonization and spread of exotic plants. PMID- 20958305 TI - Can we predict carbon stocks in tropical ecosystems from tree diversity? Comparing species and functional diversity in a plantation and a natural forest. AB - * Linking tree diversity to carbon storage can provide further motivation to conserve tropical forests and to design carbon-enriched plantations. Here, we examine the role of tree diversity and functional traits in determining carbon storage in a mixed-species plantation and in a natural tropical forest in Panama. * We used species richness, functional trait diversity, species dominance and functional trait dominance to predict tree carbon storage across these two forests. Then we compared the species ranking based on wood density, maximum diameter, maximum height, and leaf mass per area (LMA) between sites to reveal how these values changed between different forests. * Increased species richness, a higher proportion of nitrogen fixers and species with low LMA increased carbon storage in the mixed-species plantation, while a higher proportion of large trees and species with high LMA increased tree carbon storage in the natural forest. Furthermore, we found that tree species varied greatly in their absolute and relative values between study sites. * Different results in different forests mean that we cannot easily predict carbon storage capacity in natural forests using data from experimental plantations. Managers should be cautious when applying functional traits measured in natural populations in the design of carbon-enriched plantations. PMID- 20958306 TI - Hubs and bottlenecks in plant molecular signalling networks. AB - Conditional control of plant cell function and development relies on appropriate signal perception, signal integration and processing. The development of high throughput technologies such as proteomics and interactomics has enabled the identification of protein interaction networks that mediate signal processing from inputs to appropriate outputs. Such networks can be depicted in graphical representations using nodes and edges allowing for the immediate visualization and analysis of the network's topology. Hubs are network elements characterized by many edges (often degree grade k >= 5) which confer a degree of topological importance to them. The review introduces the concept of networks, hubs and bottlenecks and describes four examples from plant science in more detail, namely hubs in the redox regulatory network of the chloroplast with ferredoxin, thioredoxin and peroxiredoxin, in mitogen activated protein (MAP) kinase signal processing, in photomorphogenesis with the COP9 signalosome, COP1 and CDD, and monomeric GTPase function. Some guidance is provided to appropriate internet resources, web repositories, databases and their use. Plant networks can be generated from existing public databases and this type of analysis is valuable in support of existing hypotheses, or to allow for the generation of new concepts or ideas. However, intensive manual curating of in silico networks is still always necessary. PMID- 20958307 TI - ERP investigation of transient attentional selection of single and multiple locations within touch. AB - Mechanisms underlying pure tactile attentional selection were investigated. Tactile imperative stimuli were preceded by symbolic tactile cues directing attention to the left or right (directional cues), or to both hands (non directional cues). Comparison of ERP waveforms on directional and non-directional cue trials showed that attentional modulations at N140 and P200 components reflect mainly enhancement of stimuli at the attended, while longer latency modulations reflect mainly suppression of processing of stimuli at the unattended location. This pattern of results differs from analogous studies involving other modalities suggesting that different mechanisms underlie pure tactile attention. Furthermore, ERP waveforms on non-directional cue trials were enhanced in comparison to directional cue trials at the P100 component and at longer latencies, indicating that tactile attentional mechanisms may differ when attending to one compared to multiple locations. PMID- 20958308 TI - Psychophysiological and behavioral measures for detecting concealed information: the role of memory for crime details. AB - This study examined the role of memory for crime details in detecting concealed information using the electrodermal measure, Symptom Validity Test, and Number Guessing Test. Participants were randomly assigned to three groups: guilty, who committed a mock theft; informed-innocents, who were exposed to crime-relevant items; and uninformed-innocents, who had no crime-relevant information. Participants were tested immediately or 1 week later. Results showed (a) all tests detected the guilty in the immediate condition, and combining the tests improved detection efficiency; (b) tests' efficiency declined in the delayed condition, mainly for peripheral details; (c) no distinction between guilty and informed innocents was possible in the immediate, yet some distinction emerged in the delayed condition. These findings suggest that, while time delay may somewhat reduce the ability to detect the guilty, it also diminishes the danger of accusing informed-innocents. PMID- 20958309 TI - What do we mean when we write "senescence," "apoptosis," "necrosis," or "clearance of dying cells"? AB - The clearance of dying cells has become an important field of research. Apart from a significant increase in our understanding of the mechanisms for uptake, cell clearance is a basic mechanism in tissue homeostasis, cancer, resolution of inflammation, induction of tolerance, and autoimmunity. Phagocytosis of dying cells is a complex process, involving many interacting molecules on the dying cell and the phagocyte, and in the microenvironment. Although much is known on the subject, there are many questions and unknown variables that remain under investigation. Naturally, different terms were developed, among which some are misused, leading sometimes to pseudoconflicts of understanding. Several receptors were described as "phosphatidylserine receptor: are they all equal?" We will revise terms such as apoptosis, primary and secondary necrosis, lysed cells, senescent cells, clearance of apoptotic cells, efferocytosis, and more. We will try to point out misnomers, misunderstandings, and contradictions, and to define a consensual vocabulary. PMID- 20958310 TI - Apoptosis and autoimmune diseases. AB - Every day billions of cells die in our bodies to eliminate those that are harmful, useless, or senescent. The process can be divided into two steps: cell dying and cell clearance. In the first step, death machinery is activated in the cells and quickly kills them. During the second step, dead cells are engulfed by phagocytes, and their components are degraded in the lysosomes of the phagocytes. The death mechanism and the clearance of dead cells have been extensively studied. Mouse lines that are deficient in the death or clearance process have been established, and human patients carrying a mutation in the death machinery have been identified. Data from these mutant mice and human patients indicate that defects in cell death or dead-cell clearance leads to autoimmunity. This review examines the cell death and clearance processes and briefly discusses the diseases they cause. PMID- 20958311 TI - Anti-inflammatory functions of the "apoptotic" caspases. AB - The two main known functions of the caspases act antagonistically in regulating inflammation. "Inflammatory" caspases trigger inflammation by catalyzing the processing of IL-1beta precursors and other proinflammatory cytokines. In contrast, "apoptotic" caspases safeguard against the triggering of inflammation by imposing a cell-death form that withholds release of alarmins by dying cells and dictates generation of anti-inflammatory mediators. These antagonizing functions are exerted by evolution-related mechanisms. Studies of the function of caspase-8, an enzyme-mediating apoptotic cell-death induction in response to TNF family ligands, reveal that it blocks inflammation in additional ways. One way is by restricting activation of the RIG-I complex by foreign ribonucleic acid. Chronic skin inflammation in mice with caspase-8-deficient epidermis is associated with constitutive activation of the RIG-I complex in keratinocytes. This activation is apparently prompted by nucleic acids released from epidermal cells that disintegrate during cornification, and becomes chronic because it is not restricted by caspase-8. PMID- 20958312 TI - TAM receptors and the clearance of apoptotic cells. AB - The Tyro3, Axl, and Mer (TAM) receptor tyrosine kinases and their ligands Gas6 and Protein S are required for the optimal phagocytosis of apoptotic cells in the mature immune, nervous, and reproductive systems. Genetic analyses in mice, rats, and humans reveal that this receptor-ligand system plays an especially important role in the phagocytosis that is triggered by the "eat-me" signal phosphatidylserine. Deficiencies in TAM signaling lead to human retinal dystrophies and may contribute to lupus and other human autoimmune diseases. The TAM system appears to interact and cooperate with several other phagocytic networks, including scavenger receptor and integrin-based systems, and may serve as a signaling hub that integrates these systems. PMID- 20958313 TI - ELMO1 signaling in apoptotic germ cell clearance and spermatogenesis. AB - Apoptosis and the subsequent removal of dying cells are crucial processes for tissue development and maintenance. Although we are beginning to understand the signaling pathways that control the phagocytic clearance of apoptotic cells, the physiological relevance of these pathways is lacking. During spermatogenesis, over half of the developing germ cells eventually die by apoptosis, yet the signaling pathways that regulate the phagocytic clearance of these dying cells or the impact of this clearance on development and maintenance of the germ cell population is not well understood. The ELMO1/Dock180 proteins form an evolutionarily conserved signaling module that functions as a bipartite guanine nucleotide exchange factor for the small GTPase Rac. The subsequent Rac-dependent cytoskeletal changes play an important role in the physical engulfment of apoptotic cells. Recent findings demonstrate an in vivo role for ELMO1-dependent clearance in the testes, with implications for spermatogenesis. Here we will discuss the role of apoptotic cell clearance during spermatogenesis, with a particular emphasis on ELMO1/Dock180 signaling. PMID- 20958314 TI - Immune regulation by apoptotic cell clearance. AB - Apoptotic cell clearance by phagocytes is essential for the maintenance of self tolerance under physiological conditions. Consistent with this, the intravenous injection of apoptotic cells can induce cell-associated antigen-specific immunosuppression or tolerance. The intravenous injection of apoptotic cells expressed a fragment of myelin oligodendrocyte glycoprotein (MOG)-induced MOG specific T cell tolerance and suppressed the development of experimental autoimmune encephalomyelitis. However, the suppressive effects of the MOG expressing apoptotic cells were largely eliminated by masking phosphatidylserine (PS) exposed on the apoptotic cells, suggesting that the PS-dependent engulfment of apoptotic cells is required for the tolerance induction. We found that this mechanism of tolerance induction requires the contribution of two cell populations in the splenic marginal zone (MZ). The MZ contains two types of macrophages: marginal metallophilic macrophages and MZ macrophages. These macrophages contribute to the rapid clearance of cell corpses in blood flow. In addition, we also found that CD8alpha(+), CD103(+) dendritic cells localizing in the MZ selectively phagocytose blood-borne dead cells and subsequently present dead cell-associated antigens to induce antigen-specific immunosuppression or tolerance. PMID- 20958315 TI - Role of class A human thrombospondins in the clearance of dying cells and tolerance induction. AB - Mammalian thrombospondins (TSPs) are a group of large, secreted, calcium-binding glycoproteins of complex spatial structure that mediate a wide range of intercellular activities and participate in cell-matrix interactions. This family includes five proteins, divided into two subfamilies, that possess different roles and tissue expression. TSPs have complex roles in mediating cellular processes. Apoptotic cell and phagocyte interactions show a dynamic structure with expanding complexity. However, a vast majority of the consequences of these interactions can be mediated by a single protein. One of these signaling molecules is TSP-1, which binds to a wide variety of integrin and nonintegrin cell surface receptors and mediates both engulfment and immune modulation. This mechanism is not only important in homeostasis but may also be a major mechanism for inflammation downregulation and in avoiding autoimmunity. PMID- 20958316 TI - Apoptotic mimicry: phosphatidylserine-mediated macropinocytosis of vaccinia virus. AB - Viruses are obligatory intracellular parasites that rely on cellular processes and factors for most aspects of their replication cycle. For entry, most viruses take advantage of cellular endocytic activities to be transported from the cell surface into the cytoplasm where they penetrate into the host cell cytosol. It has recently emerged that vaccinia virus, the prototypic poxvirus, uses macropinocytosis to gain entry. The incoming virus particles activate a complex signaling network that triggers dramatic changes in the cortical actin network, resulting in membrane blebbing that facilitates virus entry. Phosphatidylserine in the virus membrane is required to trigger the signaling, blebbing, and macropinocytic event, suggesting that the vaccinia virus uses an entry mechanism based on mimicry of apoptotic bodies. PMID- 20958317 TI - Responding to infection and apoptosis--a task for TH17 cells. AB - Two of the critical cytokines required for the differentiation of T helper 17 (T(H)17) cells from naive CD4 T cells are transforming growth factor-beta (TGF beta) and interleukin-6 (IL-6). Innate recognition of apoptotic cells in the presence of Toll-like receptor engagement directs the simultaneous synthesis of these cytokines by antigen-presenting cells (APCs), and as such provides a cytokine milieu that favors T(H)17 cell induction. In this situation, APCs are activated in response to ligands derived from apoptotic cells, but also to those from the infecting pathogen. Induction of a T(H)17 response against Citrobacter rodentium infection was dependent on the ability of Citrobacter to induce apoptosis of intestinal epithelial cells. In this review, we will discuss how simultaneous activation of inflammatory and noninflammatory pattern recognition receptors on APCs impacts T helper cell differentiation, and what relevance this effect has on the immune response generated against bacterial infections that cause host cell apoptosis. PMID- 20958318 TI - Alpha (v) integrins license regulatory T cells to apoptotic cells and self associated antigens. AB - Defects in apoptotic cell clearance are thought to contribute to autoimmunity by failure to induce tolerance, coupled with accumulation of immunogenic material. However, little is known about the contribution of apoptosis to immune responses at mucosal sites, where regulatory T cells (T(reg) cells) and other immune cells play an essential active role in maintaining tolerance to self-associated antigens. In recent studies, we have found that alpha(v) integrins have an important role in apoptotic cell phagocytosis and induction of T(reg) cells in the intestine, and deletion of alpha(v) from myeloid cells causes colitis associated with failed apoptotic cell removal and loss of T(reg) cells. Our data show that activation of transforming growth factor (TGF)-beta by alpha(v) beta(8) on dendritic cells (DCs) is essential for generating T(reg) cells and inducing mucosal tolerance. These results provide a mechanism by which tolerance to apoptotic cell-derived and -associated antigens is maintained by DC "licensing" at sites of high TGF-beta expression. PMID- 20958319 TI - Surface-exposed calreticulin in the interaction between dying cells and phagocytes. AB - Phagocytosis is essential for pathogen elimination and for the removal of apoptotic corpses, a process that has been long considered immunologically silent. The phagocytic uptake of apoptotic/necrotic cells involves a plethora of molecules, including immunoglobulins, lectins, components of the complement system (all of which act as opsonins), as well as the phospholipid phosphatidylserine (PS) and the endoplasmic reticulum chaperone calreticulin (CRT), both of which can be exposed on the surface of dying cells. For a long time, surface-exposed CRT was believed to participate in phagocytosis, mostly as a (co)receptor for specific opsonins. Recently, this view has been challenged by the observations that, similar to PS, CRT acts as a facultative recognition ligand on apoptotic cells, and that cytotoxic agents such as anthracyclines induce the exposure of CRT on the surface of dying tumor cells, thereby generating an engulfment signal that stimulates the uptake of apoptotic corpses and the presentation of the corresponding antigens by dendritic cells. Here, we summarize the current knowledge on the role of CRT and CRT-interacting proteins during corpse removal. PMID- 20958320 TI - Redox remodeling: a candidate regulator of HMGB1 function in injured skeletal muscle. AB - High-mobility group box-1 (HMGB1) is a prototypical endogenous signal that links tissue necrosis and wound healing. Extracellular HMGB1 has apparently contrasting biological actions: it sustains inflammation (with the possible establishment of autoimmunity or of self-maintaining tissue damage) while activating and recruiting stem cells, which foster tissue repair. However, little is known about the role environmental cues play in the extracellular functions of HMGB1. The skeletal muscle is an optimal tissue model to help us unravel these underlying molecular events. Here, sterile injury triggers a potent inflammatory response that includes infiltration by inflammatory leukocytes and the parallel activation, proliferation, and fusion of muscle-specific stem cells. Recent data suggest that the regulation of environmental redox is critical for the bioactivity of HMGB1, which is extremely sensitive to oxidation. Moreover, data suggest a potential role for infiltrating alternatively activated macrophages to influence the outcome of inflammatory responses to sterile skeletal muscle necrosis. PMID- 20958322 TI - Desirable cell death during anticancer chemotherapy. AB - The concept of immunogenic chemotherapy that has recently emerged relies upon the capacity of a cytotoxic compound to trigger a cell-death modality. This modality elicits cross-priming by dendritic cells of tumor antigen-specific T cells that will contribute to the tumoricidal activity of the compound and protect the host against relapse. In contrast, most anticancer drugs elicit nonimmunogenic apoptosis that is not accompanied with an immunizing property. This review will discuss some molecular and metabolic changes required at the level of the tumor that must engage key pathways at the level of the host for the induction of Tc1 polarized-protective T cell responses during chemotherapy. We will summarize the immune adjuvants that can boost the immunogenicity of cell death to augment the efficacy of chemotherapy. PMID- 20958321 TI - A role for calreticulin in the pathogenesis of rheumatoid arthritis. AB - Calreticulin (CRT) plays a role in the clearance of dying cells and has been implicated in autoimmunity. Recent evidence indicates that cell surface CRT (csCRT) acts as a signal transducing receptor for the rheumatoid arthritis (RA) shared epitope (SE). The SE binding site on CRT has been mapped to amino acid residues 217-223 in the P-domain. Upon interaction with dendritic cells (DCs), the SE activates potent immune regulatory events. In CD8alpha(+) DCs, which express higher abundance of csCRT, the SE inhibits the tolerogenic enzyme indoleamine 2,3 dioxygenase with resultant inhibition of regulatory T (Treg) cell differentiation. In CD8alpha(-) DCs, the SE ligand increases secretion of IL-6 and IL-23 and facilitates generation of Th17 cells, a T cell subset known to play a role in autoimmunity. On the basis of these recent findings, we discuss the possibility that the csCRT may play a pathogenic role in RA by transducing SE activated Th17-polarizing signals. PMID- 20958323 TI - Ex vivo- and in vivo-induced dead tumor cells as modulators of antitumor responses. AB - Joint application of standard tumor therapies like radiotherapy and/or chemotherapy with immune therapy has long been considered not to fit. However, it has become accepted that immune responses may contribute to the elimination of cancer cells. We present how in vivo-induced tumor cell death by irradiation, chemotherapeutic agents, or hyperthermia can be rendered more immunogenic. High hydrostatic pressure is introduced as an innovative inactivation method for tumor cells used as vaccines. Annexin A5, being a natural occurring ligand for phosphatidylserine that is exposed by dying tumor cells, renders apoptotic tumor cells immunogenic and induces tumor regression. Combinations of irradiation with hyperthermia may also foster antitumor responses. For preparation of autologous tumor cell vaccines, high hydrostatic pressure is suitable to induce immunogenic cancer cell death. Future work will be aimed toward evaluating which combination and chronological sequence of radiotherapy, chemotherapy, hyperthermia, annexin A5, and/or autologous tumor cell vaccines will induce specific and long-lasting antitumor immunity. PMID- 20958324 TI - Intravenous apoptotic cell infusion as a cell-based therapy toward improving hematopoietic cell transplantation outcome. AB - Allogeneic hematopoietic cell transplantation (AHCT) is an efficient therapy for different malignant and nonmalignant hematological diseases. However, the use of this therapeutic approach is still limited by some severe toxic side effects, mainly graft-versus-host disease (GvHD). Today, the risk of fatal GvHD restrains the wider application of AHCT to many patients in need of an effective therapy for their high-risk hematologic malignancies. Thus, new strategies, including cell-based therapy approaches, are required. We propose to use intravenous donor apoptotic leukocyte infusion to improve AHCT outcome. In experimental AHCT models, we demonstrated that intravenous apoptotic leukocyte infusion, simultaneously with allogeneic bone marrow grafts, favors hematopoietic engraftment, prevents allo-immunization, and delays acute GvHD onset. Here, we review the different mechanisms and the potential beneficial effects associated with the immunomodulatory properties of apoptotic cells in the AHCT setting. PMID- 20958327 TI - Possible metabolic pathways of ethanol responsible for oxidative DNA damage in human peripheral lymphocytes. AB - BACKGROUND: Ethanol abuse, especially binge drinking, can be toxic to human organs. However, there have been few studies on the genotoxicity induced by ethanol in human peripheral lymphocytes under binge drinking conditions. The purpose of this study was to investigate the oxidative DNA damage induced by ethanol in human peripheral lymphocytes in vitro and the possible mechanism associated with ethanol metabolism. The concentrations of ethanol investigated in this study were 50 and 100 mM, which are equal to the ethanol concentrations in blood after binge drinking. The maximum concentration we used was 150 mM although it is not the typical blood ethanol concentration seen during binge drinking, and most people may die at such a high concentration. The purpose of using this maximum concentration was to obtain more detailed evidence about the genotoxicity induced by ethanol. The DNA repair process was also studied. METHODS: Peripheral lymphocytes were isolated from donors who were nonsmokers and not ethanol drinkers. Oxidative DNA damage, possible metabolic pathways of ethanol in human peripheral lymphocytes, and the repair system involved in the DNA auto-repair process were examined by comet assay, flow cytometry, time-of-flight mass spectrometry (TOF-MS), reverse transcription-polymerase chain reaction (RT-PCR), and western blotting. RESULTS: The results showed that ethanol at the concentrations of 50, 100, and 150 mM significantly induced the oxidative DNA damage in human peripheral lymphocytes in vitro, which was accompanied by a parallel increase in the generation of 8-OHdG, intracellular hydroxyl radical, and reactive oxygen species (iROS). The DNA damage induced by ethanol could be attenuated by alcohol dehydrogenase 1B (ADH1B) or acetaldehyde dehydrogenase 2 (ALDH2) inhibitor, and the mRNA expression levels of ADH1B and ALDH2 were increased markedly by ethanol. The inhibitor of cytochrome P450 2E1 (CYP2E1) had no effect on ethanol-induced DNA damage, and CYP2E1 mRNA expression was not affected by ethanol. Furthermore, ethanol-induced DNA damage could be auto repaired by lymphocytes. The expression of 8-oxoguanine DNA glycosylase 1 (OGG1) and the X-ray repair cross-complementation group 1 (XRCC1), 2 core enzymes in the base excision repair (BER) system, were increased in both of transcriptional and protein levels after ethanol treatment. CONCLUSIONS: This study provides direct evidence that ethanol can induce oxidative DNA damage in human peripheral lymphocytes in vitro, and its mechanism may be associated with the metabolism of ethanol by the ADH1B/ALDH2 pathway. Moreover, ethanol-induced DNA damage can be auto-repaired by human peripheral lymphocytes possibly mediated by the BER system. PMID- 20958325 TI - Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms. AB - RAS GTPases control a major signaling network implicated in several cellular functions, including cell fate determination, proliferation, survival, differentiation, migration, and senescence. Within this network, signal flow through the RAF-MEK-ERK pathway-the first identified mitogen-associated protein kinase (MAPK) cascade-mediates early and late developmental processes controlling morphology determination, organogenesis, synaptic plasticity, and growth. Signaling through the RAS-MAPK cascade is tightly controlled; and its enhanced activation represents a well-known event in oncogenesis. Unexpectedly, in the past few years, inherited dysregulation of this pathway has been recognized as the cause underlying a group of clinically related disorders sharing facial dysmorphism, cardiac defects, reduced postnatal growth, ectodermal anomalies, variable cognitive deficits, and susceptibility to certain malignancies as major features. These disorders are caused by heterozygosity for mutations in genes encoding RAS proteins, regulators of RAS function, modulators of RAS interaction with effectors, or downstream signal transducers. Here, we provide an overview of the phenotypic spectrum associated with germline mutations perturbing RAS-MAPK signaling, the unpredicted molecular mechanisms converging toward the dysregulation of this signaling cascade, and major genotype-phenotype correlations. PMID- 20958326 TI - Impact of Mendelian inheritance in cardiovascular disease. AB - Cardiovascular disease is a leading cause of mortality worldwide. While the etiology for the majority of cardiovascular disease is presumed to be a combination of genetic and environmental factors, developments in understanding the basic biology of cardiac disorders have been greatly advanced through discoveries made studying heart diseases that exhibit Mendelian forms of inheritance. Most of these diseases primarily affect children and young adults and include cardiomyopathies, arrhythmias, aortic aneurysms, and congenital heart defects. The discovery of the genetic etiologies for these diseases have had significant impact on our understanding of more complex forms of cardiovascular disease and in some cases have led to novel diagnostic and treatment modalities. In this review, we will summarize these seminal genetic discoveries, highlighting a few that have resulted in significant impact on human disease, and discuss the potential utility of studying Mendelian-inherited heart disease with the development of new genetic technologies and our increased understanding of the human genome. PMID- 20958328 TI - The investigation into CYP2E1 in relation to the level of response to alcohol through a combination of linkage and association analysis. AB - BACKGROUND: A low level of response to alcohol during an individual's early experience with alcohol is associated with an increase risk of alcoholism. A family-based genome-wide linkage analysis using sibling pairs that underwent an alcohol challenge where the level of response to alcohol was measured with the Subjective High Assessment Scale (SHAS) implicated the 10q terminal (10qter) region. CYP2E1, a gene known for its involvement with ethanol metabolism, maps to this region. METHODS: Variance component multipoint linkage analysis was performed on a combined map of single-nucleotide polymorphism (SNP) and microsatellite data. To account for the heterogeneity evident in the dataset, a calculation assuming locus heterogeneity was made using the Heterogeneity Log of Odds (HLOD) score. Association between SNP marker allele counts and copy number and SHAS scores were evaluated using a logistic regression model. RESULTS: Linkage analysis detected significant linkage to CYP2E1, which was diminished because of apparent locus heterogeneity traced to a single family with extreme phenotypes. In retrospect, circumstances recorded during testing for this family suggest that their phenotype data are likely to be unreliable. Significant allelic associations were detected for several CYP2E1 polymorphisms and the SHAS score. DNA sequencing from families that contributed the greatest evidence for linkage did not detect any changes directly affecting the primary amino acid sequence. With the removal of a single family, combined evidence from microsatellites and SNPs offers significant linkage between the level of response to alcohol and the region on the end of chromosome 10. CONCLUSION: Combined linkage and association indicate that sequence changes in or near CYP2E1 affect the level of response to alcohol providing a predictor of risk of alcoholism. The absence of coding sequence changes indicates that regulatory sequences are responsible. Implicating CYP2E1 in the level of response to alcohol allows inferences to be made about how the brain perceives alcohol. PMID- 20958330 TI - Adolescent substance abuse: the effects of alcohol and marijuana on neuropsychological performance. AB - BACKGROUND: Adolescence is a period in which cognition and brain undergo dramatic parallel development. Whereas chronic use of alcohol and marijuana is known to cause cognitive impairments in adults, far less is known about the effect of these substances of abuse on adolescent cognition, including possible interactions with developmental processes. METHODS: Neuropsychological performance, alcohol use, and marijuana use were assessed in 48 adolescents (ages 12 to 18), recruited in 3 groups: a healthy control group (HC, n = 15), a group diagnosed with substance abuse or dependence (SUD, n = 19), and a group with a family history positive for alcohol use disorder (AUD) but no personal substance use disorder (FHP, n = 14). Age, drinks per drinking day (DPDD), percentage days drinking, and percentage days using marijuana were considered as covariates in a MANCOVA in which 6 neuropsychological composites (Verbal Reasoning, Visuospatial Ability, Executive Function, Memory, Attention, and Processing Speed) served as dependent variables. RESULTS: More DPDD predicted poorer performance on Attention and Executive Function composites, and more frequent use of marijuana was associated with poorer Memory performance. In separate analyses, adolescents in the SUD group had lower scores on Attention, Memory, and Processing Speed composites, and FHP adolescents had poorer Visuospatial Ability. CONCLUSIONS: In combination, these analyses suggest that heavy alcohol use in adolescence leads to reduction in attention and executive functioning and that marijuana use exerts an independent deleterious effect on memory. At the same time, premorbid deficits associated with family history of AUD appeared to be specific to visuospatial ability. PMID- 20958329 TI - Upregulation of cannabinoid type 1 receptors in dopamine D2 receptor knockout mice is reversed by chronic forced ethanol consumption. AB - BACKGROUND: The anatomical proximity of the cannabinoid type 1 (CNR1/CB1R) and the dopamine D2 receptors (DRD2), their ability to form CB1R-DRD2 heteromers, their opposing roles in locomotion, and their involvement in ethanol's reinforcing and addictive properties prompted us to study the levels and distribution of CB1R after chronic ethanol intake, in the presence and absence of DRD2. METHODS: We monitored the drinking patterns and locomotor activity of Drd2+/+ and Drd2-/- mice consuming either water or a 20% (v/v) ethanol solution (forced ethanol intake) for 6 months and used the selective CB1 receptor antagonist [3H]SR141716A to quantify CB1R levels in different brain regions with in vitro receptor autoradiography. RESULTS: We found that the lack of DRD2 leads to a marked upregulation (approximately 2-fold increase) of CB1R in the cerebral cortex, the caudate-putamen, and the nucleus accumbens, which was reversed by chronic ethanol intake. CONCLUSIONS: The results suggest that DRD2-mediated dopaminergic neurotransmission and chronic ethanol intake exert an inhibitory effect on cannabinoid receptor expression in cortical and striatal regions implicated in the reinforcing and addictive properties of ethanol. PMID- 20958331 TI - Test of a clinical model of drinking and suicidal risk. AB - BACKGROUND: There are few data on the role of drinking patterns in suicidal thoughts or behavior among alcohol-dependent individuals (ADIs) and meager data on variables that may influence the role of drinking in suicidal thoughts and behavior. This study tested a heuristic model that predicts that drinking promotes suicidal thoughts and behavior, the association is mediated (accounted for) by depressive symptoms, and that anger moderates (increases) the risk associated with intense drinking. METHODS: Data from Project MATCH, a multisite alcohol use disorders treatment trial, were analyzed using structural equation modeling. There were 1,726 participants including 24% women and a mean age of 40.2 +/- 11.0 years. Subjects were assessed at baseline and at 3-, 9-, and 15 month follow-up. Two categorical measures (presence/absence) of suicidal ideation (SI) were used that were analyzed in separate models. Predictors of interest were continuous assessments of average drinking intensity (i.e., drinks per drinking day or DDD), drinking frequency (i.e., percent days abstinent or PDA), depression, and anger. RESULTS: Both DDD and PDA were associated with SI at a statistically significant level, with PDA showing an inverse association. Depression scores served as a partial mediator or a full mediator of the drinking SI relationship depending on the measure of SI used in the analysis. The models testing anger scores as a moderator fit the data poorly and did not support that anger serves as a moderator of the drinking-SI association. CONCLUSIONS: Greater drinking intensity and drinking frequency predict SI among ADIs and depression serves as a mediator of these associations, but anger does not appear to serve as a moderator. Further research is required to clarify whether depression serves as a partial or full mediator and to see whether the results herein extend to suicidal behavior (i.e., suicide attempt, suicide). PMID- 20958332 TI - The effects of maternal binge drinking during pregnancy on neural correlates of response inhibition and memory in childhood. AB - BACKGROUND: Although an extensive literature has documented a broad range of cognitive performance deficits in children with prenatal alcohol exposure, little is known about how the neurophysiological processes underlying these deficits may be affected. Event-related potentials (ERPs), which reflect task-specific changes in brain electrical activity, provide a method for examining multiple constituents of cognitive processing at the neural level. METHODS: We recorded ERPs in 217 children from Inuit communities in Arctic Quebec (M age = 11.3 years) during 2 different tasks-Go/No-go response inhibition and continuous recognition memory. Children were classified as either alcohol-exposed (ALC) or controls (CON) depending on whether the mother reported binge drinking during pregnancy. RESULTS: Both groups performed comparably in terms of accuracy and reaction time on the tasks, and both tasks elicited the expected effects on ERPs when responses were compared across conditions. However, the ALC group showed slower P2 latencies on Go/No-go, suggesting an altered neurophysiological response associated with initial visual processing of the stimuli. On the memory task, the ALC group showed reduced FN400 amplitude to New items, known as the familiarity effect, and reduced amplitude for the late positive component, possibly reflecting impairment in memory retrieval. CONCLUSIONS: These findings show that, even in tasks in which alcohol-exposed children exhibit behavioral performance that is comparable to controls, fetal alcohol exposure is associated with altered neurophysiological processing of response inhibition and recognition memory. The data suggest that fetal alcohol exposure is associated with reduced efficiency in the initial extracting of the meaning of a stimulus, reduced allocation of attention to the task, and poorer conscious, explicit recognition memory processing. PMID- 20958333 TI - Fibroblast function and wound breaking strength is impaired by acute ethanol intoxication. AB - BACKGROUND: Alcohol intoxication occurs in nearly half of all trauma patients and increases the morbidity, mortality, and healing complications of these patients. Prior studies in our laboratory and elsewhere have demonstrated impairments in re epithelialization, angiogenesis, and inflammation in wounds following acute ethanol exposure. Clinically, acute ethanol exposure has been shown to cause an increased breakdown of wounds. To date, the mechanisms by which acute ethanol exposure modifies wound strength have received little experimental attention. METHODS: To examine how ethanol influences functions critical to the development of wound strength, the effect of ethanol exposure on fibroblast proliferation and extracellular matrix production was examined. Normal human dermal fibroblasts (NHDF) were exposed to ethanol (100 mg/dl) and then examined for proliferative capacity and mRNA production of collagen I, collagen III, and lysyl oxidase (LOX). In in vivo studies, the wound breaking strength, LOX activity, collagen, and hyaluronic acid (HA) contents of wounds of ethanol-exposed (100 mg/dl) mice were examined. RESULTS: At 24, 48, and 72 hours after acute ethanol exposure (8 hours duration), NHDF displayed a significant impairment in proliferative capacity (up to 50% at 24 hours p < 0.001). After ethanol exposure, NHDF produced less collagen I and LOX mRNA, but more collagen III mRNA than control fibroblasts (p < 0.05). Ethanol exposure in vivo caused a reduction in wound breaking strength of up to 40% when compared to control mice (p < 0.01). LOX activity, collagen, and HA contents in the wounds of ethanol-exposed mice were significantly reduced (p < 0.01). CONCLUSIONS: These studies reveal that a single exposure to ethanol prior to injury can cause a significant decrease in wound breaking strength. Our studies suggest that ethanol directly impairs fibroblast function, leading to decreased collagen production. The results provide a possible explanation for how acute ethanol exposure might increase in wound complications and wound failure. PMID- 20958338 TI - Intracellular ethanol accumulation in yeast cells during aerobic fermentation: a Raman spectroscopic exploration. AB - AIMS: To investigate the intracellular ethanol accumulation in yeast cells by using laser tweezers Raman spectroscopy (LTRS). METHODS AND RESULTS: Ethanol accumulation in individual yeast cells during aerobic fermentation triggered by excess glucose was studied using LTRS. Its amount was obtained by comparing intracellular and extracellular ethanol concentrations during initial process of ethanol production. We found that (i) yeasts start to produce ethanol within 3 min after triggering aerobic fermentation, (ii) average ratio of intracellular to extracellular ethanol is 1.54 +/- 0.17 during the initial 3 h after addition of 10% (w/v) excess glucose and (iii) the accumulated intracellular ethanol is released when aerobic fermentation is stimulated with decreasing glucose concentration. CONCLUSIONS: Intracellular ethanol accumulation occurs in initial stage of a rapid aerobic fermentation and high glucose concentration may attribute to this accumulation process. SIGNIFICANCE AND IMPACT OF THE STUDY: This work demonstrates LTRS is a real-time, reagent-free, in situ technique and a powerful tool to study kinetic process of ethanol fermentation. This work also provides further information on the intracellular ethanol accumulation in yeast cells. PMID- 20958334 TI - Functional imaging of cognitive control during acute alcohol intoxication. AB - BACKGROUND: The anterior cingulate and several other prefrontal and parietal brain regions are implicated in error processing and cognitive control. The effects of different doses of alcohol on activity within these brain regions during a functional magnetic resonance imaging (fMRI) task where errors are frequently committed have not been fully explored. METHODS: This study examined the impact of a placebo [breath alcohol concentration (BrAC) = 0.00%], moderate (BrAC = 0.05%), and high (BrAC = 0.10%) doses of alcohol on brain hemodynamic activity during a functional MRI (fMRI) Go/No-Go task in 38 healthy volunteers. RESULTS: Alcohol increased reaction time and false alarm errors in a dose dependent manner. fMRI analyses showed alcohol decreased activity in anterior cingulate, lateral prefrontal cortex, insula, and parietal lobe regions during false alarm responses to No-Go stimuli. CONCLUSIONS: These findings indicate that brain regions implicated in error processing are affected by alcohol and might provide a neural basis for alcohol's effects on behavioral performance. PMID- 20958340 TI - Prevalence and simultaneous occurrence of periodontitis and dental caries. AB - AIM: The aim of the study was to evaluate the prevalence and simultaneous occurrence of periodontal disease and dental caries in Finnish adults. MATERIAL AND METHODS: The study was performed as part of the nationally representative Health 2000 Survey. The study population was 5255 subjects aged 30 years and older. Probing pocket depth (PPD) and untreated dentinal caries were recorded by tooth. Teeth with PPD 4mm and deeper indicated periodontal disease, and teeth with PPD 6mm and deeper indicated a severe periodontal disease. RESULTS: Sixty four percent of persons had periodontal disease, 21% had a severe periodontal disease, and 29% had dental caries. Persons having periodontal disease had significantly more often dental caries (33%) compared with those without periodontal disease (23%). This was even more evident in persons having severe periodontal disease (44%). Accordingly, persons having dental caries had significantly more often severe periodontal disease (31%) compared with those without dental caries (16%). The mean number of teeth with dental caries or periodontal disease per person was greater when the mean number of teeth with the other disease was also greater. CONCLUSIONS: These data indicate that especially severe periodontal disease and dental caries tend to accumulate in the same subjects. PMID- 20958339 TI - Interferon-gamma promoter hypomethylation and increased expression in chronic periodontitis. AB - AIM: The goal of this investigation was to determine whether epigenetic modifications in the IFNG promoter are associated with an increase of IFNG transcription in different stages of periodontal diseases. MATERIALS AND METHODS: DNA was extracted from gingival biopsy samples collected from 47 total sites from 47 different subjects: 23 periodontally healthy sites, 12 experimentally induced gingivitis sites and 12 chronic periodontitis sites. Levels of DNA methylation within the IFNG promoter containing six CpG dinucleotides were determined using pyrosequencing technology. Interferon gamma mRNA expression was analysed by quantitative polymerase chain reactions using isolated RNA from part of the biological samples mentioned above. RESULTS: The methylation level of all six analysed CpG sites within the IFNG promoter region in the periodontitis biopsies {52% [interquartile range, IQR (43.8%, 63%)]} was significantly lower than periodontally healthy samples {62% [IQR (51.3%, 74%)], p=0.007} and gingivitis biopsies {63% [IQR (55%, 74%)], p=0.02}. The transcriptional level of IFNG in periodontitis biopsies was 1.96-fold and significantly higher than tissues with periodontal health (p=0.04). Although the mRNA level from experimental gingivitis samples exhibited an 8.5-fold increase as compared with periodontally healthy samples, no significant methylation difference was observed in experimental gingivitis sample. CONCLUSIONS: A hypomethylation profile within IFNG promoter region is related to an increase of IFNG transcription present in the chronic periodontitis biopsies, while such an increase of IFNG in experimentally induced gingivitis seems independent of promoter methylation alteration. PMID- 20958341 TI - Third attempt to place implants in sites where previous surgeries have failed. AB - BACKGROUND: a lower survival rate for re-implantation in previously failed sites was reported. A third implant attempt in sites where previous implants have failed twice is rare; however, it may be necessary where other treatment alternatives are unacceptable. The aim of the present report is to explore the survival of implants placed three times at the same site. METHODS: patients in whom a third attempt of implant placement at sites where two implants failed previously were evaluated. Medical history and smoking were recorded. The implant dimension, characteristics and survival were documented. The same implant and surgeon were involved in all three attempts. RESULTS: fifteen third attempt implants in 12 patients were evaluated. The average age of the patients at first implantation was 48.8 +/- 14.1 years. Six of the 15 second re-do implants have failed (60.0% survival rate). Smoking was reported by two patients. The implants that survived were followed for 44.1 +/- 35 months (range 4-86). The mean implant length and diameter did not vary between attempts: the mean implant width/lengths were 3.6 +/- 0.3/12.2 +/- 1.4, 3.7 +/- 0.3/12.6 +/- 1.5 and 3.80 +/- 0.3/12.4 +/- 1.6 mm for the first, second and third attempts, respectively (p>0.05). CONCLUSIONS: a third attempt to place implants in sites where two implants had failed previously results in significantly lower survival rates compared with similar procedures in pristine sites. PMID- 20958343 TI - Editorial. PMID- 20958342 TI - Lip closing pressure and spoon management in passive spoon feeding. AB - To determine the sources of lip closing pressure (P(LC) ) generation during passive spoon feeding, we used a fine pressure transducer glued into a wooden spoon, as well as electromyography (EMG) of the upper and lower lips and the submental muscle complex, in normal adult volunteers (average age 24.5 years). An assistant fed a seated subject 0.6 mL of yogurt and then withdrew the spoon from the subject's closed mouth. The spoon was held at an angle of 0 degrees (i.e. in the naso-auricular plane) during serving and at either 0 degrees or 60 degrees during withdrawal. We detected simultaneous increases in P(LC) and in EMG activity in the lips and the submental muscle complex. The maximum P(LC) was significantly higher at 60 degrees [65 +/- 11 g cm(-2) (mean +/- s.e.m)] than at 0 degrees (42 +/- 8 g cm(-2)). The former was correlated with the maximum EMG amplitude, which was analysed by using the mean of the root-mean-square EMG and presented as a percentage of the maximum EMG obtained in the lower lip region and the submental muscle complex during subsequent swallowing in each subject. In conclusion, in healthy adult subjects, perioral muscles of the lower lip region and the submental muscle complex participate in P(LC) generation, particularly at a steep spoon withdrawal angle. The results suggest that a steep withdrawal angle not only increases P(LC) but also promotes these muscles' activities in passive spoon feeding. PMID- 20958344 TI - The sahel: an information crisis*. PMID- 20958345 TI - Emergency shelter. PMID- 20958346 TI - Living with earthquakes. PMID- 20958347 TI - Global systems and local disasters: the untapped power of peoples' science. PMID- 20958348 TI - Nutritional status and pressure on populations in the awash valley and hararghe mountains, ethiopia. PMID- 20958349 TI - Disaster housing in yugoslavia. PMID- 20958351 TI - Adelaide'S prediction. PMID- 20958350 TI - Some initial lessons from guatemala. PMID- 20958352 TI - Editorial. PMID- 20958353 TI - SAHEL NUTRITION SURVEYS, 1974 and 1975. PMID- 20958354 TI - Refugee camps and cAMP planning: the state of the art. PMID- 20958355 TI - The United nations and disaster relief in the sahel, 1973-75. AB - This research is part of an extensive study entitled 'International Disaster Response: The Sahelian Experience', which was made possible by a grant number 1711-520147 of the U.S. Agency for International Development and the U.S. Department of State. The opinions expressed are solely the responsibility of the researcher and do not necessarily represent the views of the organizations studied or the sponsoring institutions. PMID- 20958356 TI - Chinese earthquake policy. PMID- 20958357 TI - Comments from the dec. PMID- 20958359 TI - Predicting famine. PMID- 20958358 TI - Reconstruction in guatemala. PMID- 20958360 TI - Breast feeding: a key measure in large-scale disaster relief. PMID- 20958361 TI - Toowoomba: victims and helpers in an Australian hailstorm disaster. PMID- 20958362 TI - The role of emergency grain reserves*. PMID- 20958363 TI - Anthropometric measurements in a relief programme in niger: a tool for decision making at the community level. PMID- 20958364 TI - A struggle for meaning: reactions to disaster amongst cypriot refugees*. PMID- 20958365 TI - Some aspects of disaster research. PMID- 20958366 TI - Letters to the editor. PMID- 20958367 TI - Acts of nature or acts of man? PMID- 20958368 TI - Response to drought: the mursi of southwestern ethiopia*. PMID- 20958369 TI - TETRACHLORODIBENZO-p-DIOXIN RELEASE AT SEVESO. PMID- 20958370 TI - Haemorrhagic Fever in Africa due to marburg-ebola viruses. PMID- 20958371 TI - Toowoomba: the role of an Australian disaster unit. PMID- 20958372 TI - Letters to the editor. PMID- 20958373 TI - Editorial. PMID- 20958374 TI - Some epidemiologic features of disasters in guatemala. AB - Epidemiological procedures can be organised under disaster conditions by means of a simple surveillance system and with few personnel. In the aftermath of the 4 February 1976 earthquake in Guatemala, an information system was organized by which the requisite information for decision-making was obtained with adequate speed and promptness. The initial epidemiologic informution was based on reports collected during the early days on symptoms observed at hospitals and health centers and in localities and villages in the stricken area. At a second, post emergency stage a more elaborate surveillance system was instituted to provide guidance in the investigntwn of outbreaks, evaluate the health activities and establish basic criteria for preventive and control measures. PMID- 20958375 TI - Planning for urban floods. PMID- 20958376 TI - The reconstruction of darwin after cyclone tracy. AB - Learning from any process or past experience is one of the wing graces of mankind. In this context, the rebuilding of Darwin had been to ensure that the catastrophic events, wrought by nature, will not be repeated by bringing total devistation of a city and a way of life. The total engineered city is a unique product of the "rethink" process brought about by the rebuilding of Darwin. The future economic viability of this cyclone resistant city is of paramount importance, but the lessons to be learnt also include a social and psychological value that the people of any city have for their existing infrastructure, and life style. The economic well being of any population development goes hand in hand with the happiness and contentment that the settled population work towards. The following is an assessment of the background, problems and achievements in which the Commonwealth Department of Construction played a major role. The Author, during the whole of the rebuilding programme in Darwin, occupied the position of Associate Director in charge of a multidiscipline cell within the Departpent of Construction, whose sole purpose was to handle the majority of the reconsiruction work for the Darwin Reconstruction Commission. PMID- 20958378 TI - Disaster relief in sahel. PMID- 20958377 TI - The gediz earthquake: reconstruction between 1970 & 1977. AB - Our observations in Gediz weremadein 1970,1973,1975 and 1977. Information was collected in each of these trips but the fullest interviewing took place in 1977. Some of the people interviewed evaded our questions and many would not talk freely. This was mainly in New Gediz, where we were often referred to the mayor. Gediz has had three mayors since the earthquake, but the present mayor is fully informed on the aid which has arrived since the earthquake. He was generous with this information and his opinion Equally generous and gracious were the members of an informal association concerned with the revival of Old Gediz. In addition, we were able to talk to people in public places and to shopkeepers. Our contacts on the street were rather few We visited Akcaalan in 1975 and 1977, conducting interviews in both years. Much of the information and opinion was collected in two coffee shops. The mayor, Mr. M. Taskin, impressed us with his precision and graciousness. PMID- 20958379 TI - BREAST FEEDING and DISASTER RELIEF. PMID- 20958380 TI - An appeal for a significantly comparative method in disaster research. PMID- 20958382 TI - Editorial. PMID- 20958381 TI - Vitamin a assay in unicef foodmix. PMID- 20958383 TI - EMERGENCY MENTAL HEALTH SERVICES and A MAJOR AIRCRAFT ACCIDENT. PMID- 20958384 TI - Seveso: no answers yet. PMID- 20958385 TI - A classification scheme for evacuation. PMID- 20958386 TI - Editorial. PMID- 20958387 TI - Tabas-e-golshan (iran) catastrophic earthquake of 16 september 1978; a preliminary field report. PMID- 20958388 TI - Risk analysis of the 1970 san antonio diphtheria epidemic*. AB - Prediction of disease patterns for communicable diseases with low prevalence rates is difficult because of the random variations inherent in the data Smoothing of prevalence or incidence data prior to the analysis may facilitate these predictions. All of the analyses are based on census tract characterisiics. The disadvantages of this type of data are that the boundaries are arbitraty and lead to some heterogenous tracts. Also, the analyses depend totally on aggregate rather than individual data. The advantage of working with this type of data is its availability for all metropolitan areas. The San Antonio diphtheria epidemic has been previously referred to as an ethnic epidemic. This paper shows that it is even more an epidemic of lower socioeconomic groups. In this region of the country, socioeconomic characteristics are almost indistinguishable. PMID- 20958389 TI - The application of satellite remote sensing to monitoring of agricultural disasters. PMID- 20958390 TI - DISASTER and SOCIAL SCIENCE IN AUSTRALIA*. PMID- 20958391 TI - HOUSING and CULTURAL PRIORITIES: THE ASIA MINOR GREEK REFUGEES OF 1922*. PMID- 20958392 TI - Risk factors in social change. PMID- 20958393 TI - Catholic relief services: nutrition intervention program for the drought areas of kenya (1975-76). PMID- 20958394 TI - The lice earthquake. PMID- 20958395 TI - Editorial. PMID- 20958396 TI - Anthropology and disaster research. PMID- 20958397 TI - The social aetiology of disasters. PMID- 20958398 TI - Management of disaster victims and rehabilitation of uprooted communities. AB - The natural disasters which have so far dominated world attention are the least important in terms of number of victims. By far the most important problems, affecting tens of millions of people in non-industrialized countries, are the creeping and recurrent disasters, generally made and/or aggravated by man. Subsequent deprivations frequently lead to the process of uprooting. While a well organized and economically strong community can suffer severe set-backs from a disaster it will not be permanently disrupted. On the other hand, an uprooted community is by definition seriously disrupted by upheaval or crushing of its social system, leading to disorganization, disheartedness and dependence. This affects, to varying degrees, communities which have fled across ethnic or political borders and found themselves in a minority situation; as well as communities whose mode of life has been made obsolete or impossible by abrupt or slow ecological etc changes destroying their economy. The phenomenon of uprooting poses particular problems demanding particular attention. It is especially important to stop and reverse the process. This calls for adequate preparedness, and for relief and rehabilitation without delays and frustrations which will aggravate the uprooting. The planning should normally aim for balanced integration, and always avoid over- and under-aid. Also, in order to make the victimized communities self-reliant, it is crucial to assist them in the reconstruction of their social systems. Finally, the planning necessary for disaster preparedness coincides closely with what is needed for planning of development activities. PMID- 20958399 TI - Organizational adaptation to crises: mechanisms of coordination and structural change. PMID- 20958401 TI - Geological predictions*. PMID- 20958400 TI - Future disaster planning in the United kingdom*. AB - 1 An ideal integrated national disaster plan would include the following points: 2 First aid training for the general population. 3 Advanced training in critical care for ambulance men. 4 Principles of triage for all emergency services. 5 Application of triage by trained ambulance men. 6 Spreading the casualty load (where possible) to a number of receiving hospitals. 7 The setting up of local disaster co-ordinating committees. 8 The more widespread dissemination of disaster information and reports. PMID- 20958402 TI - Disaster in bali caused by earthquake 1976 (a report). PMID- 20958403 TI - Planning processes in disaster prone areas with reference to floods in Tunisia. PMID- 20958404 TI - The yungay avalanche of 1970: anthropological perspectives on disaster and social change*. PMID- 20958406 TI - Guest editorial. PMID- 20958405 TI - The 1975-76 drought in England and wales in perspective. PMID- 20958407 TI - Disaster relief operations in andhra pradesh, southern India, following the cyclone in november 1977. PMID- 20958408 TI - Planning basic health services in Nigeria. AB - This article does not deal directly with disasters, but as it is recognised that natural disasters most commonly occur and are most damaging in third world countries which are often still in the process of developing their health services; and since clearly a well-functioning health service is a valuable resource in pre-disaster planning and post-disaster relief and recovery, it is thought relevant to publish this study of one local health network which appears to answer effectively the basic needs of a rural population, within the means of the community. PMID- 20958409 TI - Education and training of medical students for mass casualties situations. AB - During the academic years I 9 75 and I 9 76 an interdisciplinary course in mass casualty management was given to sixth year medical students at the Hebrew University-Hadassah Medical School in Jerusalem. The course included introductory lectures in definition of types of disasters, objectives in disaster intervention, description of local and national rescue organizations. Special importance was paid to mage of casualties and to a centralized system of evacuation from the disaster site. Further, hospital planning and deployment, stressing the role of the Emergency Room physician. The specific approach to multiple injuries including neurosurgical, orthopedic, abdominal, chest and soft tissue wounds was discussed in a panel meeting. Stress intervention and a comprehensive lecture on public health problems concluded this part of the course. The last half-day was devoted to a practical exercise, simulating a town severely damaged by an earthquake. Although the course was an elective one, it was extremely well attended by the students, and its implementation was enthusiastically performed by both teachers and students. PMID- 20958410 TI - Pediatric morbidity and mortality in minas gerais, Brazil. PMID- 20958411 TI - Relief induced agonism. PMID- 20958412 TI - The vaiont dam overflow: a case study of extra-community responses in massive disasters. PMID- 20958414 TI - Flood losses: the significance of the commercial sector. PMID- 20958413 TI - Sanitary consequences of inundations. PMID- 20958415 TI - Equipment section. PMID- 20958416 TI - Guest editorial. PMID- 20958417 TI - Directions for social research in disaster prevention, mitigation and relief. PMID- 20958418 TI - Observations on the development of educational materials following the andhra pradesh cyclone, 1977. AB - It should be clearly understood that this report was written primarily to record the process and observations made in the production of specific educational materials. The conclusions are not definitive. The sampling used for the testing of the drawings was small (approximately 501; was not furry representative of the general population;and, because of the disaster circumstances under which the sampling was made, did not clearly isolate the variables or systematically examine all the options. The comments contained herein should be understood as observations of the staff associated with the project. PMID- 20958419 TI - Permanent post-disaster housing in honduras: aspects of vulnerability to future disasters. AB - To some degree it is unfair to evaluate a post-disaster housing program as to its effectiveness in decreasing vulnerability and preventing future disasters. As Burton states, "With rare exceptions, administrators and techniques have been trained to cope with disaster rather than to prevent it" [reference (2), p.197]. These were certainly not goals articulated by the agency responsible for constructing housing after Fifi. However, the authors feel that failure to evaluate specific projects by persons knowledgeable of the projects functioning, will only forestall the shift which Cuny calls for, "... from disaster response to disaster mitigation and prevention" [reference (4), p.123). In doing this we hope to add some specific case study data to the growing literature on disaster mitigation and prevention. Disaster vulnerability in Honduras is overwhelmingly related to flooding. More crucial than the materials and construction of housing is the issue of siting. If appropriately sited, houses made of bajarique, wood, or concrete block are able to withstand the heavy rains associated with a hurricane. Regarding the siting of the projects, the Honduras Project clearly has one positive and one negative accomplishment in the cases of Santa Rica and Flores, respectively. San Jose is less clear but is certainly a much safer site than those formerly occupied by the residents, in that there is no danger of flooding. The present site was not flooded during Fifi nor did it experience mudslides. However, the future is not so clear regarding the latter. Within the village proper a large amount of vegetation has been added which will tend to stabilise the soil on the steeper slopes. The streets, however, are seriously eroded and probably can not be maintained for vehicle usage, which does not pose a serious problem to the residents as none possess automobiles or trucks. One large gully bisects the village and receives run-off from the adjacent hills. It has been expanding, which would suggest that the slopes above the village could prove problematic in case of a Fifi-sized storm. Flores is located on a very poor site in reference to prevention and mitigation. It is located in a portion of the Sula Valley which is prone to flooding and, as mentioned before, was inundated by over 2m of water during hurricane Fifi. No prevention techniques were possible by NAEA/HEA and the houses were built on earthen mounds barely adequate to keep water out during the rainy season. The nearby dike which could possibly provide protection is non-functional due to poor maintainance. Given a storm of Fifi's magnitude, or possibly smaller, this site will again be flooded. Santa Rica is clearly well sited concerning flooding: it did not experience flooding during Fifi and is not flood prone. However, houses did experience some wall damage due to earthquakes following and associated with the Guatemalan quake of 1976. Due to the size and nature of the latter much "re-adjustment" occurred in the neighbouring fault system; however, damage to the houses was all superficial. We feel the residents were vocal about their concern due to the severity of the Guatemalan disaster and their lack of experience with concrete block houses. That the two sites (particularly Flores and partially San Jose) are vulnerable to future disasters cannot be considered solely the fault of an outside agency without local knowledge and understanding. In the engineering report issued during the construction it was explicitly stated that in Flores, "Future flooding remains a danger," [reference (6), p.49]. The future residents of Flores had gained access to the land from the National Agrarian Institute and were anxious to receive assistance in building homes. In fact, CARE, which had previously given these people tin roofing for houses, was threatening to take it back since the people had not yet started building. NAEA/HEA were responding to people in a rather desperate situation. But, on the other hand, they were responding to people who had been promised (not given) land by an agency of the Honduran national government which would be cognizant of the potential flooding at this site. Likewise, in San Jose, where mudslides and erosion remain a threat, the land was provided by a local government agency, the municipality. Although our goal in this discussion has not been to establish blame, we feel it imperative to mention the sequence of events that resulted in the questionable siting of Flores and San Jose. It is very easy and often accurate to place blame on outsiders who lack sophistication and knowledge about such matters. In this case local input did not result in post-disaster planning that is actually precautionary. This, we feel, illustrates the extreme complexity of cross-cultural aid, especially in the post-disaster period. It also points to the need for precautionary planning with reference to permanent post-disaster reconstruction. PMID- 20958420 TI - Flood prevention and mitigation in the people's republic of mozambique. PMID- 20958421 TI - Some needed cross-cultural studies of emergency time disaster behaviour: a first step*. PMID- 20958422 TI - Old theories don't apply: implications of communications in crises*. PMID- 20958423 TI - The lice earthquake. PMID- 20958424 TI - Guest editorial. PMID- 20958425 TI - Once the running stops: assimilation of angolan refugees into zambian border villages*. PMID- 20958426 TI - Managing refugees: zambia's response to angolan refugees 1966-1977*. PMID- 20958427 TI - Rural refugees in Africa: what the eye does not see. PMID- 20958428 TI - Settlement of rural refugees in Africa*. PMID- 20958429 TI - Angola: meeting health and health related needs with refugees. PMID- 20958430 TI - Practical evaluation of a pilot immunization campaign against typhoid Fever in a cambodian refugee cAMP. AB - An epidemic outbreak of typhoid fever in the largest refugee camp of the besieged capital of Phom-Penh, Cambodia; the concomitant lack of personal and public hygiene and the availability of a locally manufactured Tetanus-Typhoid Paratyphoid vaccine, prompted us to test the practicability of a mass immunization campaign by carrying out a trial in the smaller, well delineated refugee camp of Pochentong. Attendances by adults as well as children throughout the three or four inoculation rounds showed a steady decline with only 30 (20%) of the people completing the course. The general initial acceptance by the people on the other hand was good, due to a comprehensive service (information, health education and individual care of patients). It is concluded from these results that multi-injection immunization campaigns against typhoid-paratyphoid are a waste of money in a war-torn situation with an unstable population. PMID- 20958431 TI - Eritrea refugees in Sudan*. PMID- 20958432 TI - Women and men as refugees: differential assimilation of angolan refugees in zambia. PMID- 20958433 TI - Disastrous international relief failure a report on burmese refugees in bangladesh from may to december 1978. PMID- 20958434 TI - Emergency sanitation for refugees: experiences in the bangladesh refugee relief camps, India, 1971-1972. PMID- 20958435 TI - Space enclosures for emergencies in developing countries*. PMID- 20958436 TI - Evaluation of cmu/intertect a-frames as emergency shelter in bangladesh, march 1977. AB - From February 13th-19th 1977, a visit to Bangladesh was undertaken for the purpose of evaluating the emergency shelter units designed and built under the direction of the Carnegie Mellon University J INTERTECT Refugee Housing Team in 1975. PMID- 20958437 TI - Norwegian red cross in guatemala. PMID- 20958438 TI - The effects of disaster on health: a summary. PMID- 20958439 TI - Some observations on communication with non-literate communities. PMID- 20958440 TI - Some thoughts on communication. PMID- 20958441 TI - Materials for rural housing: the building materials work of the intermediate technology development group. PMID- 20958442 TI - The social consequences of Australian disasters. PMID- 20958443 TI - The United States government programme in emergency shelter for victims of disasters in foreign lands. PMID- 20958445 TI - New Look for Canada's Emergency Planning Digest. PMID- 20958444 TI - Inside the agencies:a report on a fact-finding mission to three countries in latin america. PMID- 20958446 TI - International disaster relief: developments in the European economic community. PMID- 20958447 TI - Anthropology groups. PMID- 20958448 TI - The consequences of the drought in bas-zaire, 1978. PMID- 20958449 TI - DROUGHT and CHANGE IN A TRIBAL ECONOMY: THE BERTI OF NORTHERN DARFUR. PMID- 20958450 TI - New organizational approaches for speeding food relief in international disasters: the potential contribution of technology*. PMID- 20958451 TI - User satisfaction with permanent post-disaster housing: two years after hurricane fifi in honduras. PMID- 20958452 TI - International disaster action: advancing slowly, but how surely? PMID- 20958453 TI - Thresholds of security in different societies*. PMID- 20958454 TI - Curative medicine or community health? Appropriate health services with refugees *. PMID- 20958455 TI - Letters to the editor. PMID- 20958457 TI - Editorial. PMID- 20958456 TI - The impact of food aid. PMID- 20958458 TI - Famine Prevention in Africa, a Conference/Workshop held in Kinshasa, Zaire, by the Centre National de Planification de Nutrition Humaine, 6-11 January 1980. PMID- 20958459 TI - Bangladesh Landsat Programme, Science and Technology Division, Government of the People's Republic of Bangladesh: Regional Workshop on Disaster Preparedness and Remote Sensing, Dacca, 9-11 December 1979. PMID- 20958460 TI - Disaster and the small dwelling, oxford, april 1978. PMID- 20958461 TI - The refugee experience, windsor, 22-24 february 1980. PMID- 20958463 TI - An ethiopian refugee cAMP in Sudan - the problem of tuberculosis. PMID- 20958462 TI - Sudan's Refugees, 1967-1980. PMID- 20958464 TI - Refugees and the u.s.a. PMID- 20958465 TI - Reconstruction following seismic disaster in venzone, friuli. PMID- 20958466 TI - Who bears the costs of natural disasters?- an Australian case study. PMID- 20958468 TI - Predisaster physical planning: integration of disaster risk analysis into physical planning - a case study in Tunisia. PMID- 20958467 TI - The effect of social influence on response to hurricane warnings*. PMID- 20958469 TI - The work of le centre d'etudes psychosociologiques des sinistres et de leur revention (cepsp) in france. PMID- 20958470 TI - NATURAL DISASTER and SOCIOECONOMIC CHANGE: POST-FROST ADJUSTMENTS IN PARANA, BRAZIL*. PMID- 20958472 TI - Editorial. PMID- 20958471 TI - Non-natural disasters - an epidemiological review. PMID- 20958474 TI - Letters to the editor. PMID- 20958475 TI - Editorial. PMID- 20958476 TI - International disaster institute news. PMID- 20958477 TI - Letter to the editor. PMID- 20958478 TI - Editorial. PMID- 20958479 TI - The source parameters, surface deformation and tectonic setting of three recent earthquakes: thessalonki (Greece), tabas-e-golshan (iran) and carlisle (u.k.). AB - Abstract- Three earthquakes have been studied. These are the Thessaloniki earthquake of 20th June 1978 (Ms = 6.4, Normal faulting), the Tabase-Golshan earthquake of 16th September 1978 (Ms = 7.7 Thrust faulting) and the Carlisle earth-quake of 26th December 1979 (Mb = 5.0, Thrust faulting). The techniques employed to determine source parameters included field studies of SUP face deformation, fault breaks, locations of locally recorded aftershocks and teleseismic studies including joint hypocentral location, first motion methods and waveform modelling. It is clear that these techniques applied together provide more information than the same methods used separately. The moment of the Thessaloniki earthquake determined teleseismically (Force moment 5.2 times 10(25) dyne cm. Geometric moment 1.72 times 10(8) m(3) ) is an order of magnitude greater than that determined using field data (surface ruptures and aftershock depths) (Force moment 4.5 times 10(24) dyne cm. Geometric moment 0.16 times 10(8) m(3) ). It is concluded that for this earthquake the surface rupture only partly reflects the processes on the main rupture plane. This view i s supported by a distribution of aftershocks and damage which extends well outside the region of ground rupture. However, the surface breaks consistently have the same slip vector direction as the fault plane solutions suggesting that they are in this respect related to to the main faulting and are not superficial slumping. Both field studies and waveform studies suggest a low stress drop which may explain the relatively little damage and loss of life as a result of the Thessaloniki earthquake. In contrast, the teleseismic moment of the Tabas-e-Golshan earthquake (Force moment 4.4 times 10(26) dyne cm. Geometric moment 1.5 times 10(9) m(3) ) is similar t o that determined from field studies (Force moment 10.2 times 10(26) dyne cm. Geometric moment 3.4 times 10(9) m(3) ) and the damage and after-shock distributions clearly relate to the surface faulting. It h a s also been observed that high aftershock activity appears beneath gaps in the surface rupture system. The Carlisle earthquake (Force moment 9 times 10(23) dyne cm. Geometric moment 3 times 10(6) m(3) ) produced no surface ruptures. However, dislocation model-ling suggests that surface deformation will be visible on a first order levelling line which passes very close t o the epicentre. A well controlled fault plane solution, the first in the British Isles, derived from an aftershock study shows north-south compression. All three studied earthquakes occurred along major faults which had been reactivated in geological times. The fault on which the Tabas-e-Golshan earthquake occurred could have been identified a s active from evidence of Quaternary motion and previous smaller earthquakes. However, there were no perceptible events in the 12 months preceeding the catastrophic earthquake. In both Thessaloniki and Carlisle, significant foreshocks did occur within 6 months prior to the main shock* PMID- 20958480 TI - Considerations on the new epidemic outbreak of human leptospirosis in greater recife, brasil, in 1975. AB - Abstract- A brief report was presented on a new outbreak of leptospirosis among the population of Greater Recife in 1975 in the wake of the floods that struck the city and its survivors in July of that year. A total of 107 cases were recorded, of which 105 were identified by sero-agglutination and 2 by hemoculture. Once again the serotype icterohaemorrhagiae was the predominant etiological agent, having been found in 55 cases, followed by ballum in 18, grippotyphosa in 9, and pyrogenes in 8 cases. PMID- 20958481 TI - The march 1980 eruptions of mt. St. Helens: citizen perceptions of volcano threat. PMID- 20958482 TI - Asthmatic bronchitis associated with a volcanic eruption in st. Vincent, west indies. PMID- 20958483 TI - Anthropology and action. PMID- 20958484 TI - The role of the health worker in refugee communities. PMID- 20958485 TI - The italian earthquake: relief operations. PMID- 20958486 TI - The message from Karamoja. PMID- 20958487 TI - A multi-hospital system for disaster situations*. AB - From a review of the literature, it can be concluded that it is always advantageous and usually necessary to distribute the casualties of a disaster to several hosp-hospitals rather than allowing 1 hospital, the nearest to the scene, to bear the whole load. The potential of these hospitals would be enhanced if their preparedness and planning included anticipation of their functioning as part of a framework of the entire capacity of the medical services of an entire small country, or a region of a larger one. For the smooth functioning of this framework, central co-ordination and control of the distribution of the load, the movements within it, the strengthening of its various component parts is necessary and services other than medical (transport, communications, etc.) are essential. The establishment of a multihospital system for disaster situations for a whole region is suggested. This would integrate all medical facilities and services of the region, as well as promoting additional services, first horizontally integrated and later vertically, and would have a central governing body with full authority to prepare the system for the calamity and to execute the implementation of the plan when disaster occurs. This body may find it useful to base some of its decision in the planning as well as the implementing stage, on an assumed population of casualties that is characteristic for the region and on implications that may be drawn from the population. PMID- 20958488 TI - The value of hazard zone mapping: Water Authority 'Section 24(5) surveys' in England and Wales. AB - Successful problem-solving is usually based upon a sound knowledge of the problem. Where the problem is a hazard, the impossibility of a 'solution' in terms of complete prevention is well known but proper problem assessment is still required. Detailed hazard zone mapping can be a valuable aid to planning to reduce hazards and to avoid disasters. A map is a powerful visual medium for conveying information where awareness of disaster proneness amongst public officials and others is limited. However, a map is also a comparatively limited medium for analysing risks and is most useful to planners if combined with detailed supporting documentation. Maps and related documents are particularly useful if they provide a complete assessment of risk, are periodically updated, are integrated with the planning process and are systematically compiled and presented at an appropriate scale. Map scale often presents problems. The larger the scale, the less limited the map will be in recording useful detail but updating becomes more costly and therefore less likely. The Water Authorities Section 24(5) surveys are remarkably detailed and are valuable planning and research materials. They demonstrate the widespread nature of flooding problems and the need for decades of flood alleviation and drainage expenditure in England and Wales. Further standardisation of content and presentation could enhance the value of the survey reports but their value depends ultimately upon regular and systematic updating. PMID- 20958489 TI - A model for urban post-earthquake fire hazard. PMID- 20958490 TI - 'Ethnic nationalism' and structured unemployment: refugees in the Orange Free State. PMID- 20958491 TI - An examination of health data following two major earthquakes in Russia. AB - Thus the hazards to health observed from these two earthquakes can be summarised as follows: (a) massive immediate damage, the main victims being women and children; (b) the seriously injured suffer mainly from fractures (17%), head injuries (15-30%) and soft tissue conusions with haemhorrage; (c) a change in the physical features of a country which unfavourably affect the environment; (d) some time after the earthquake the appearance of communicable disease; (e) increases in cases of cardiovascular disease neuroses and psychoses. PMID- 20958492 TI - The international relief union of 1932. PMID- 20958493 TI - From disaster to development: notes from India. PMID- 20958494 TI - Letters to the editor. PMID- 20958495 TI - UNDRO - Spot the difference. PMID- 20958496 TI - Editorial. PMID- 20958497 TI - The Italian Earthquake: narrowing the retrospective gap. PMID- 20958498 TI - Earthquake hazard and vulnerability in the northeastern Mediterranean: the Corinth earthquake sequence of February-March 1981. AB - Population density, building type and earthquake magnitude are the main factors on which the total building damage following an earthquake depend. For the Greece - Turkey region quantitative relations between these factors have been developed, which, in spite of the inaccuracies in the available data, allow crude estimates of the damage following a particular size earthquake to be made. This is demonstrated retrospectively for the Gulf of Corinth earthquakes in 1981. PMID- 20958499 TI - The historical seismicity of England. PMID- 20958500 TI - Preliminary assessment of landslides resulting from the earthquake of 23rd November 1980 in Southern Italy. AB - This paper examines the hazards, mechanisms and effects of landsliding provoked by the 1980 earthquake in Campania and Basilicata Regions, Southern Italy. The effects of seismically-induced mass-movement are assessed with respect to slope stability and damage to both settlements and roads. Whereas the mechanism of cyclic loading of soils, which can give rise to landslides, is different from the pore-pressure, gravity loading and strength-reduction mechanisms that normally cause slope failure, the morphology of slides is often indistinguishable and this made it difficult to identify which slides were directly caused by the earthquake. However, creep in potential shear planes undoubtably became more widespread, and the incidence of small, bowl-shaped slides Increased as a direct result of the earthquake. Although variations in the detailed stress-pattern within individual slopes meant that some very mobile soil and rock masses did not move, 36 settlements reported landslide damage and 29 roads were affected by landslides occurring during the earthquake and its immediate aftermath. A full assessment of the disaster, together with an explanation of the geography of the disaster area, can be found in Alexander (1982). PMID- 20958501 TI - What have New Zealanders learnt from earthquake disasters in their own country?*. PMID- 20958502 TI - Resolving the "sooner vs later" controversy surrounding the public announcement of earthquake predictions*. PMID- 20958503 TI - Epidemiological surveillance of diseases following the earthquake of 23rd November 1980 in Southern Italy. PMID- 20958504 TI - The thinness chart. PMID- 20958505 TI - Community planning for disaster relief. PMID- 20958506 TI - Information required on disaster warnings. PMID- 20958507 TI - On not buttering parsnips. PMID- 20958508 TI - Rural refugees in Africa: Past experience, future pointers. AB - Rapid change In rural Africa raises new policy problems In dealing with mass influxes of rural refugees. Self-settlement in agriculture has become less feasible and is less acceptable now that Its disadvantages are better understood. Organized smallholder settlement can be a better solution where it is economically viable, refugees have freedom of movement, and staff are suitable. But growing land shortage means that Increasing proportions of refugees are being placed in camps. To offset this trend, more attention is suggested to programmes for groups of refugees, categorized by time of arrival, by ability to self-settle or to farm, and by skills and experience. Practically-oriented social science research can contribute to these and other approaches which will require imagination and ingenuity. Solutions to future rural refugee problems should be linked with programmes of social and economic development which will make easier the achievement of humanitarian objectives. PMID- 20958509 TI - Unanticipated repercussions of international disaster relief. AB - Following the Peruvian earthquake of May 1970, the devastated provincial town of Huarez received massive amounts of disaster relief aid. The reconstruction process rapidly transformed the economic and social structure of the community by causing a shortlived boom which raised the expectations of the population. Once the relief agencies withdrew, the demand for goods and services fell sharply and the people were forced to readjust to a less prosperous life. It also appeared that their capacity to respond to future disasters had not been significantly unproved. This case study highlights the need for research into the long term consequences of disaster relief. PMID- 20958510 TI - The creation of vulnerability to natural disaster: Case studies from the Dominican Republic*. AB - This paper argues that natural disasters are not a category of events which can be separated from the broader Issues of development, since economic change can create vulnerability to natural disaster. The analysis of case studies from the Dominican Republic shows how the development of large scale commercialized agricultural production has created such vulnerability by reducing or restricting the resource base of certain sectors of the population. It b suggested that the vulnerable state of a population should be considered as much a cause of natural disaster as the extreme physical phenomena Involved. Therefore there Is a need both for a broader framework for analysis of disasters and for strategies to reduce such vulnerability to be an Integral part of long term development planning. PMID- 20958511 TI - Residents' preparedness and response to the Kalamazoo Tornado. AB - A survey was conducted of individuals residing directly in the path of the tornado that hit Kalamazoo, Michigan, on 13th May 1980. The residents' tornado preparedness and response were examined in an effort to evaluate the city's emergency warning system. The system was adequate for people on the east side of the city and lacking for west side residents. Other factors pertaining to the storm event and human response were also evaluated. PMID- 20958512 TI - The long-term impact of a man-made disaster: An examination of a small town in the aftermath of the Three Mile Island Nuclear Reactor Accident. AB - This paper explores the long-term effects of a nuclear accident on residents' perceptions of their physical and mental health, their trust of public officials, and their attitudes toward the future risks of nuclear power generation In their community. We find that in the period after the accident at Three Mile Island that there are constant or Increasing levels of distress reported by community residents. We conclude that the effects of a technological disaster may often be more enduring than those natural disaster and that greater research efforts should be made to Investigate the long-term consequences of man-made catastrophies of all types. PMID- 20958513 TI - Karamoja update. PMID- 20958514 TI - Poland'S crisis as a disaster: the private sector's response. PMID- 20958516 TI - A new famine research unit. PMID- 20958515 TI - Undro-a new decade. PMID- 20958518 TI - Forthcoming conferences, meetings and workshops. PMID- 20958517 TI - New publications. PMID- 20958519 TI - Society for computer simulation. PMID- 20958520 TI - Underreported flash flood. PMID- 20958521 TI - Charity falters at home: Afghan refugees and the U.K. PMID- 20958522 TI - Changes in housing in Guatemala following the 1976 earthquake: With special reference to earthen structures and how they are perceived by disaster victims*. AB - This paper reports on what has happened to earthen structures in 26 Guatemalan communities studied over a 4-year period since the 1976 earthquake. The data were obtained from three waves of personal interviews with 1472 randomly sampled household heads. The results show that adobe, which was the primary housing material before the earthquake was heavily damaged in that event. As a consequence the number of adobe structures and of other earthen structures has been drastically reduced. The people of Guatemala individually and because of agency housing programs have abandoned adobe as a building material and turned to concrete block and wood. Surviving earthen structures have not been improved substantially and remain with largely the same structural features as before the earthquake. The greatest improvement is in the use of comer posts or columns in the walls but most of these are made of untreated crude logs or lumber, subject to rot and termite damage. Little information on aseismic housing seems to have spread either within the earthquake area or in the unaffected areas surrounding it. A program to spread information on how to use adobe in aseismic designs needs to be conducted along with one to assist citizens to aquire the resources necessary to improve the earthquake vulnerability of houses. PMID- 20958523 TI - Recovery following the South Italian earthquake, November 1980: Two contrasting examples. AB - Recovery and reconstruction in two communities following the South Itallan earthquake is described and differences are related to factors such as pradisaster development levels, relief decisions made during the emergency phase, the kind of material aid received, local leadership and economic opportunities. The combination of appropriate aid and effective leadership appears to a potent force for recovery. PMID- 20958524 TI - Prisoners of armed conflict: Nicaragua an ICRC survey. AB - This paper examinee the role of the medical delegate of the ICRC. Part I outlines the diseases and conditions found during a survey of three Nicaraguan rural prisoner of war camps. This information should enable medical delegates to formulate better plans for the treatment of prisoners in future. Part II suggests an alternative health care system which relies on the use of medical kits and manuals In the hands of medical auxiliaries. Dividing responsibility in this way would leave the medical delegate free to perform tasks which make more use of his more sophisticated skills. PMID- 20958525 TI - Evacuation behavior and Three Mile Island. AB - The responses of the residents to the nuclear power plant arcident at Three Mile Island, Pennsylvania illustrate the factors influencing pre-impact coping responses of populations exposed to technological hazards. Confusion itnd ambiguous information influenced both the decision to evaluate and to remain in place. Proximity to the facility, stage in life cycle and the actions of friends and neighbors influenced the decision to evacuate. PMID- 20958527 TI - 'Correcting' earthquake damage data for population density. PMID- 20958526 TI - Attrition and housing improvements: A study of post-disaster housing after three years. AB - This research is part of an effort to monitor houses built for victims of hurricane Fifi in 1975. After 3 years (1978) we interviewed the residents to determine the rate of continued occupancy and the amount of housing improvement and the correlates of both. We found that a significant number of small families, Protestants, and families that had not participated in the construction of the housing had moved. From what we could determine, moving was primarily related to seeking work and improving one's financial position. Nearly 90% of the permanent occupants had improved their houses with either indigenous or manufactured materials. Non-improvement of houses was concentrated among families with few members. The largest number of unimproved houses was located in the project that sewed the poorest victims and contained the cheapest housing. PMID- 20958528 TI - Random rubble. PMID- 20958529 TI - Disaster relief at the un economic and social council: july 1982. PMID- 20958530 TI - Counter-disaster training in developing countries. AB - This paper discusses both the need for training within a wider context of community disaster preparedness and the major alternatives in methods of training. Emphasis is placed on the importance of compatibility between the resources within a given country and appropriate training programmes. PMID- 20958531 TI - The 'who' and 'what' of training far disaster relief. AB - This paper defines the various levels within government, the voluntary agencies and the community which might benefit from training and makes suggestions as to where the emphasis should be placed. It points out that training programmes should be designed to meet the expressed needs of a particular group of trainees as well as be related to the current or potential disaster situation. PMID- 20958533 TI - Bureaucratic and Political obstacles to disaster relief. PMID- 20958532 TI - Training of expatriate refugee health workers: Principles and practices. AB - Abstract-This paper describes in detail the separate components of an ideal expatriate refugee health worker training course. Emphasis is given to organizational aspects of such courses. PMID- 20958534 TI - The 1934 floods in Tabriz, N. W. Iran. AB - The disastrous floods of July 1934 in Tabriz are examined in the context of the history of floodinginthe city, which is crossed by a dry stream bed liable to sudden Inundation by mountain torrents from the southeast. Few details of past events have survived, suggesting that relatively little significance has been attached to them. Typically, flood dykes were inadequately maintained. This neglect, combined with a radical alteration in urban topography after 1925, when broad straight avenues were constructed through the old heart of the city, led to serious losses from flooding twice in 1929 and again in 1934. Enhanced perception of the flood risk finally found expression in the adoption of large scale engineering measures to mitigate future events, including strengthening protective dykes and widening the river channel through the city. These works have reduced vulnerability to flooding from river overflow. No long-term detrimental Impact of the 1934 flood has been observed. Some of the physical and social parameters that have influenced the vulnerability of Tabrizinthe past continue to be present both there and elsewhere in Iran, and they may be characteristic also of other regions with comparable natural environments or in a similar stage of socio-economic development. PMID- 20958535 TI - Aftermath of natural disasters: Coping through residential mobility. AB - Most studies of population movement have concentrated on the more developed nations and on trends that have not been influenced by man-made or natural disasters. The experience of developing countries in the Caribbean basin, as studied after the Guatemalan earthquake of 1976 and the impact of Hurricane David in the Dominican Republic of 1979, highlights the importance of socio-economic factors in the decision to make permanent migrations after a disaster, regardless of whether the migrant had personally suffered losses. In many cases the opportunities for personal betterment created by the disaster acted as a catalyst and accelerated a previously-existing trend of migration. PMID- 20958536 TI - The tragedy of Kampuchea. AB - This paper, abstracted from the final report of the Kampuchea Inquiry Commission, analyses the population losses in Cambodia prior to 1979 and goes on to describe some of the unwanted side effects of the international relief programmes in both Thailand and in Kampuchea. The paper concludes that various opposition movements to the present Vietnamese backed regime in Kampuchea have been strengthened by international aid. PMID- 20958537 TI - Bereavement and mourning after a shipping disaster: The case for intervention. AB - This paper describes the help given by the social services department of a shipping company to bereaved families following a shipping disaster. In the absence of clear, factual and prompt information from an authoritative source, there is a tendency for bereaved individuals to deny their loss and thereby delay the process of mourning and eventual recovery. Appropriate intervention and support can help to overcome this tendency as was seen in the Madasa case. PMID- 20958538 TI - The turkana of north west kenya. PMID- 20958539 TI - The bureau for overseas medical service. PMID- 20958540 TI - Editorial. PMID- 20958541 TI - The Pyrenees earthquake of 1660: Effects in France. AB - Until 1975 or so, scientists' knowledge of the major earthquake of 1660 in the Pyrenees (in Bigorre) was largely restricted to the meagre information repeated in the classical catalogues. Useful material published in local learned journals was mostly unknown, and has only been unearthed and interpreted since 1976, when two year's work of analysis was started for the "Projet Sismo-tectonique" in France. During and since that project, further routine work necessary for the revision of the historical seismicity of France, has brought to light a new wealth of information from archive sources. This new knowledge, at least from the French side, is used as the basis for a brief macroseismic review of the event north of the Pyrenees, putting forward proposals for the isoseismal lines. Emphasis is placed on the number and quality of the sources, some of which are quoted for evidence of major rockfalls in the meizoseismal region and the wide extent of the felt area, as far north as Salnt-Maixent in Poitou. PMID- 20958542 TI - Lake Elsinore disaster: The slings and arrows of outrageous fortune. AB - A case study of a flood which occurred at Lake Elsinore, California, February, 1980, focuses upon the assistance which the community received during both the flood and recovery periods. Relevant literature on disaster research is examined, including a model of disaster recovery, and the study places the events which occurred din Lake Elsinore within that recovery model. Implications for policy include the recommendation that decision-makers consider the pre-disaster growth of the community indecisions to support recovery assistance. PMID- 20958543 TI - Is the environment becoming more hazardous?-A global survey 1947 to 1980. AB - This paper examines the assertion that natural disasters are increasingly destructive using evidence from disaster reports during the period 1947-1980. The criteria for judging the impact of a given natural disaster are chiefly loss of life and the extent of the geographical area affected. In spite of uneveness and bias in the reporting of sudden impact disasters the conclusions are that both the frequency of disasters and number of people killed are increasing. Further research into the social consequences of disasters and the need for disaster preparedness training programmes are recommended. PMID- 20958544 TI - A preliminary investigation of socio-economic problems following the 1978 Thessaloniki (Greece) earthquake. AB - The consequences of social and economic disruption in the city of Thessaloniki following the large earthquake in 1978 are investigated. Specifically, the phenomenon of organized life in camps for Thessaloniki residents over a long period of time is studied. With the use of a questionnaire, all data regarding each person in the camps were assembled and processed with the correspondence analysis method. PMID- 20958545 TI - A microcomputer-based emergency response system*. AB - A microcomputer-based system was developed to provide local officials responsible for disaster management with assistance during the crucial period immediately following a disaster, a period when incorrect decisions could have an adverse impact on the surrounding community. While the paper focuses on a potential disaster resulting from an accident at a commercial nuclear power generating facility, the system can be applied to other disastrous situations. Decisions involving evacuation, shelter and the deployment of resources must be made in response to floods, earthquakes, accidents in the transportation of hazardous materials, and hurricanes to name a few examples. As a decision aid, the system was designed to enhance data display by presenting the data in the form of representations (i.e. road maps, evacuation routes, etc.) as well as in list or tabular form. The potential impact of the event (i.e. the release of radioactive material) was displayed in the form of a cloud, representing the dispersion of the radioactive material. In addition, an algorithm was developed to assist the manager in assigning response resources to demands. The capability for modelling the impact of a disaster is discussed briefly, with reference to a system installed in the communities surrounding the Indian Point nuclear power plant in New York State. Results demonstrate both the technical feasibility of incorporating microcomputers indecision support systems for radiological emergency response, and the acceptance of such systems by those public officials responsible for implementing the response plans. PMID- 20958546 TI - Editorial. PMID- 20958547 TI - Pollution by halogenated aromatic compounds at Trissino: A case study of groundwater contamination and rehabilitation. AB - An investigation is presented on industrial contamination by benzotrifluoride percolation into ground water used for drinking water, in a populated area of 20 km(2) at Trissino, north Italy, due to improper chemical waste disposal. Hydrogeological features of the situation are reported, as well as the emergency action taken, such as the surveys made and their analytical results. The epidemiology of the emergency is examined and rehabilitation measures are presented and discussed. Fortunately no major ecological or social disaster occurred, In part thanks to the speed and efficiency with which the affair was handled. It is notable that the authorities kept the public duly informed and thus retained their confidence. PMID- 20958548 TI - "How near were we to Ruine": the effects in England of the earthquake of 8th September 1692. AB - This paper attempts to Illustrate some of the advantages and disadvantages of using contemporary evidence in the study of historical seismicity. The event considered here is doubly significant-it was a large event by British standards, as well as arguably the best documented earthquake to have occurred before the mid-eighteenth century. At a time when an interdisciplinary approach to historical seismicity is still in its infancy this paper identifies those areas where the available sources can assist in the evaluation of early macroseismic data. PMID- 20958549 TI - Newspaper reporting of bush-fire disaster in south-eastern Australia-Ash Wednesday 1983. AB - Newspaper reports about a bushfire disaster in SE Australia were analysed in order to present some understanding of the images those reports conveyed to the victims and non-victims in one affected State. The results demonstrated that the newspapers gave limited prominence to reports containing warning or response information before or after the disaster. The newspapers reported most prominently case study descriptions of personal hardship or heroism which portrayed the victims as completely helpless during and after the event. The newspapers also devoted considerable prominence to reports describing the losses attributable to the bushfire, the factual details of which were accurate: this emphasis in content probably increased community perception of the danger of bushfire threat but, as little warning or response information was given, it is unlikely that the reports helped improve community preparedness for a future bushfire. PMID- 20958550 TI - Refugee health care: Similar but different? AB - The present review sets out to identify differences between refugees and other more stable communities living in less developed countries: demographic, mortality, morbidity, nutritional and selected epidemiological data are discussed. Although generalizations are difficult because of the variability of refugees and their differing circumstances, the health problems and diseases do not appear to differ qualitatively, although they may be quantitatively more severe. The areas of particular concern lie not so much with the problems but with approaches to their solutions: the need to respond rapidly and appropriately to emergencies, the importance of attending to the priorities of nutrition, shelter, sanitation and water; and the necessity of providing services which are sufficiently flexible and sensitive to the changing needs of the refugees as they move from the acute emergency to the long-term settlements. The review highlights certain areas where insufficient information is currently available, notably mental illness and the long-term issues of health and development, and outlines the implications of the conclusions for policy makers, with particular reference to training and research. PMID- 20958551 TI - Letter to the editor. PMID- 20958552 TI - Primitive poppycock? PMID- 20958553 TI - Sturzstrom in the upper rhone valley, Switzerland, 1584. PMID- 20958554 TI - Public health aspects of volcanic hazards; Evaluation and prevention of excessive morbidity and mortality due to natural disasters. AB - This is a summary of the proceedings of sessions on Volcanic Hazards at the First International Symposium on Public Health in Asia and the Pacific Basin, held 3 11th March 1983, in Honolulu, Hawaii. The Symposium was sponsored by the Association of Schools of Public Health, the U.S. Public Health Service and the Centers for Disease Control (CDC), the World Health Organization (WHO), the South Pacific Commission, and the East-West Center of the University of Hawaii. The full proceedings are being prepared for publication. The Symposium was supported in part by: The Pan American Health Organization and The Amoco Foundation. PMID- 20958556 TI - A new camp for vintage refugees? PMID- 20958555 TI - The long-term effects of the 1980 earthquake on the villages of Southern Italy. PMID- 20958557 TI - Where the exception confirms the rule: The cyclones of 1982-1983 in French Polynesia. AB - The island groups of French Polynesia, which had not experienced any really devastating cyclones since the beginning of the century, were hard hit several times between December 1982 and April 1983. This paper reviews the cost of damage from these cyclones and shows how lowered public awareness of the hazard in a low frequency area combined with the special economic conditions prevailing in the Territory to make the total cost much higher than it need have been. Ways and means of rehabilitation are analyzed. The development of the thermal imbalance in the Pacific, which appears to have triggered this series of natural disasters, only seemingly exceptional, is briefly discussed. PMID- 20958558 TI - Famine forecasting; Prices and peasant behaviour in Northern Ethiopia. AB - This paper, completed in January 1984, begins by briefly outlining the contrasting views of price behaviour during the last Ethiopian famine (1972-1974) put forward by Seaman and Holt (1980) and Sen (1981). A hypothesis is developed to account for peasant behaviour and price responses under developing famine conditions. This is then tested with data recently made available. The paper concludes by summarizing the findings and their implications for famine forecasting, and argues that famine conditions in Northern Ethiopia are likely to worsen during 1984. PMID- 20958559 TI - Lessons in logistics from Somalia. AB - By February 1981 the refugee relief operation in Somalia was close to breakdown. The Governor of Somalia and the United Nations High Commission for Refugees (UNHCR) contracted the agency CARE to manage the logistics of the operation. By August 1981 over 99 % of food received at Mogadishu was reaching the camps. Here we describe this apparent success, and attempt to diagnose the contributing factors. Chief among these are dynamic leadership, 'systems' management, adaptability of personnel, the use of professional Indian food monitors in the camps, and the support given by the Government. The chief qualification on the success of the operation has been the continued dependency on expatriate expertise. General conclusions are offered relating to the management of logistics in relief operations. The most important conclusion is that there is a prime need for logistics to be centralized in a single organization at the start of major emergencies. We point to the current inadequacy in an international relief system which fails to ensure this, and suggest that a new or existing part of the United Nations family be given a 'brief for in-country logistics' to become a UN Emergency Logistics Office. PMID- 20958560 TI - The disaster warning process: A study of the 1981 Gujarat cyclone. AB - This paper reports on the channels through which warning of the impending disastrous cyclone of October-November 1981 was received and disseminated in the districts and villages of Gujarat in Northwest India. The process is slow and laborious, and efforts are in hand to improve the speed and efficiency of warning methods. Some of the problems likely to be encountered are discussed. PMID- 20958561 TI - Australian disasters. PMID- 20958562 TI - Natural disasters in Australia. AB - The history of natural hazards in Australia and their physical, economic and social consequences are discussed in this paper. The lack of any national programme for hazard mitigation is identified, alongside an overview of Australia as a country where major disasters are accepted as a part of everyday life. PMID- 20958563 TI - The great Australian drought: 1982-1983*. AB - The development of drought over eastern Australia from April 1982 to February 1983 is described. National wheat production for the 1982-1983 season was 63 per cent of the average for the previous five years, while for New South Wales and Victoria production was 29 and 16 per cent respectively. Production of other grains was similarly reduced. Net value of rural production was reduced from over $4,000 million to $2,300 million nationally, the percentage reduction being much larger in drought-affected States. Methods of assessing drought severity are discussed and it is concluded that the 1982-1983 drought must be regarded as one of the most severe in the last 100 years. Impact of drought is also discussed, including that on wheat production and sheep and cattle populations since 1885. It is suggested that the limits of grain growing areas, and of sheep and cattle populations, beyond which environmental degradation may occur, have been exceeded during that period. The view is expressed that more attention should be given to the development of strategies to ameliorate drought impacts. PMID- 20958564 TI - Urban flooding in Australia: Policy development and implementation. AB - This paper presents a review of Australian urban riverine flooding. By world standards the Australian flood problem is relatively small, though there are pockets of development subject to regular severe inundation. In the past, government response to flooding was ad hoc and characterized by structural adjustments. The 1970s and 1980s, however, have seen a major shift in approach. The new approach emphasizes resource management rather than construction, and consists of the announcement of policies, enactment of enabling legislation, and the introduction of procedures to help ensure that the widest range of flood damage reduction measures are considered. The changes are evident at both the federal and state levels of government. Though problems remain, particularly at the local government level, where ultimate responsibility for policy implementation generally rests, the authors feel there are good grounds for optimism. Some suggestions for future policy are offered and the importance of public safety is stressed. PMID- 20958565 TI - Community response to hazard information. AB - The impact of flood hazard information on public acceptance of a selected flood mitigation strategy was assessed by an analysis of the content of newspaper reports of community reaction and letters to the editor. The impact of personal delivery of a flood hazard map on individual perception of risk and attitude to such information was assessed using personal interviews. The results indicated that media coverage of the flood hazard information reduced public criticism of the works. This result must be partially attributable to the dramatic style of media coverage and the fact that the media only emphasized the positive value of the works. The interview demonstrated that personal delivery of the information raised perception of risk, improved comprehension of flood risk, had no impact on acceptability of risk but discouraged some respondents from seeking such information in the future. Factors to explain the last negative change were identified to be the format of the map sheet and low salience of flood hazard. On the basis of all results, methods to improve community response to hazard information are provided. PMID- 20958566 TI - Australia's organized response to natural disaster: Background and theoretical analysis. AB - An analysis of organizations involved in response to disaster within Australia is offered. The location of these key organizations within the existing institutional framework, and a discussion of the functions of each, together with the relationships between them is provided. Particular emphasis is placed on the location and role of the State and Territory Emergency Service organizations (S/TES's) within this organizational network. The paper suggests there are a number of constraints that operate upon the S/TES's which prejudice both the effectiveness of this organizational type and that of the entire organizational network. These constraints are analyzed in terms of power and influence variables. The outcome of this discussion is the development of a taxonomy of Australia's counter-disaster organizations that is based on: (1) the ability of individual organizations within the network to determine the role which it will perform; and (2) the potential of the organization to influence the direction of the network. PMID- 20958567 TI - Letter to the editor. PMID- 20958568 TI - Editorial. PMID- 20958569 TI - Developments in the technique of combating winter hazards on European highways. PMID- 20958570 TI - Symposium on the problems and consequences of refugee migrations in the developing world: COMMISSION ON POPULATION GEOGRAPHY. PMID- 20958571 TI - Reflections on the late earthquake in North Wales on 19th July 1984. PMID- 20958572 TI - Spontaneous resettlement after drought: An Ethiopian example*. AB - Based upon two recent periods of fieldwork among a spontaneously resettled population of cattle herders in southwestern Ethiopia, this paper is an attempt to illustrate, by a particular case, the general proposition that external aid, if it is not to be counter-productive, must meet people's needs as they themselves define them. The people in question, the Mursi, have experienced, since 1970, their worst period of drought and hunger in living memory. They have responded to this experience with resilience and inventiveness and largely without external assistance. The paper concentrates on a recent, drought induced, migration of Mursi to higher land, outside their traditional territory, and shows how the migrants are adapting to a new way of life which brings them into direct conflict with some of their most cherished cultural traditions. PMID- 20958573 TI - A multi-hazard history of Antigua*. AB - Antigua experiences earthquakes, droughts and hurricanes. To isolate for study each of these as they occur, would be to over simplify the inter-relationships between the aftereffects of one and the occurrence and the effects of the next. Moreover, there will be conditions arising from factors outside the natural disaster spectrum which bear upon, and are themselves affected by, all of these phenomena. This interplay of events and conditions is readily illustrated in the case of island countries, which have a natural and clearly defined containment. Such interrelationships suggest a complex human-ecological system which must be recognized if environmental balance and compatability are to be maintained - particularly in respect of hazards. This documentary analysis of the colonial era in Antigua, has to conclude for the time being with questions concerning the environmental effectiveness of imported systems of administration which, with no knowledge of comparable natural hazards, assumed sectoral separation. PMID- 20958574 TI - Training Community Health Workers in refugee camps: A case study from Pakistan. AB - In October 1983 a training programme for refugee community health workers was begun as the major part of a primary health care programme for Afghan refugees in Pakistan. The programme began with a pilot period in Badaber camp, situated near to Peshawar. The general issues involved in training auxiliary health personnel were answered by the use of a "knowledge, attitudes and practices survey" and involvement of the refugees from the beginning of the programme. The development of the training programme is discussed with reference to these issues and the constraints arising from the special circumstances of the refugees, in addition to those common to most national training programmes, are reviewed. PMID- 20958575 TI - Vulnerable groups*. AB - As a rule, refugees arrive in their host country with a bare minimum of possessions; in this respect every refugee can be classified as vulnerable. However, a certain category is especially at risk, namely those persons who would be considered vulnerable in a "normal society." These people are doubly in need of assistance, firstly, inasmuch as they are refugees and secondly, insofar as they are vulnerable. If these refugees can be helped to overcome (or at least reduce) their handicaps, they can begin to become self-reliant and form an active, productive parts of their community, rather than remaining an extra burden to an already vulnerable part of the society in their country of asylum. Whilst their able-bodied companions work in the fields or the towns, part of this category can be trained and usefully employed in sectors of work that do not require great mobility or physical fitness (such as handicrafts, trade, teaching and services).. PMID- 20958576 TI - Australia's organized response to natural disaster: The constrained organization in two wildfires. PMID- 20958577 TI - Shelters from the storm: A note on the geography of hurricane shelters in Barbados, 1982. AB - Barbados, a small island of 166 square miles in the Caribbean, with a population of 246,416 persons, has a total of 177 emergency shelters with a known capacity of 20,623 persons. The average shelter capacity is 117 persons and the total known shelter capacity represents 8.4% of the population. The spatial arrangement of the grade I shelters, as seen relative to the 1980 population census map by grouped enumeration districts, reveals that there are many areas and persons, who, in time of emergency, will not be able to avail themselves of the protection of a shelter. PMID- 20958579 TI - Food crisis in Bangladesh? Report on a visit to Dhaka, 2nd-21st July 1984. PMID- 20958578 TI - Editorial: TEN YEAR HITCH. PMID- 20958580 TI - Planning against disasters with poor agrarian communities: An extension perspective. PMID- 20958581 TI - International flood hazard research: Lessons for Britain: Report on a Workshop. PMID- 20958582 TI - The second international conference on assistance to refugees in Africa, geneva, 9th to 11th july 1984. PMID- 20958583 TI - Methods of increasing food self-sufficiency following disasters in the commonwealth Caribbean*. AB - In the Caribbean, catastrophic events take their toll on food availability through loss of food crops and livestock, disruption in the channels of distribution and loss of foreign exchange earnings from export crops, which are used to procure imported foodstuffs. Nutritional consequences such as the protein energy malnutrition among children, pregnant and lactating women and hard-working males and females are likely to follow. Choice of crops and livestock systems following disasters should be such as to allow for a rapid rehabilitation of the agricultural production and distribution system to eliminate prolonged dependence on food aid. Opportunities should be provided for balanced meal plans including staples, legumes, vegetables, food from animals, fruits, oils and fats. These issues are addressed in this article. PMID- 20958584 TI - Hurricanes and agriculture: Losses and remedial actions*. AB - Hurricanes cause serious and long-term damage to the Agricultural sectors of Caribbean countries. Bananas and tree crops are defoliated, snapped or uprooted and food crops may be flooded or washed away. Recovery takes time and money as both the production bases and the infrastructure are damaged or destroyed. National economies do not have the resources to expedite recovery without aid. An account is given of the actions taken to estimate losses and prepare rehabilitation plans after Hurricanes David (1979) in Dominica and Allen (1980) in St. Lucia and St. Vincent. The implementation of funding agency-assisted agricultural rehabilitation programmes is also described. Some steps that farmers can take to reduce loss of food are suggested. PMID- 20958585 TI - The role of the individual administrator in famine relief: Three case studies. AB - A series of hypotheses on the role of the individual administrator in famine relief are proposed and three are examined with respect to case studies of famines in India (1896 and 1906-1907), Uganda (1908) and Lombok (1940). While the evidence is not conclusive, the focus upon the role of the individual administrator offers additional insights into the compexities of official response to famines. PMID- 20958586 TI - Emergency centers in Israel: A small community organizes to cope with war related crises*. AB - This paper focuses on community-wide emergencies caused by war-related events in Lebanon at the beginning of June 1982. Mobilization for the "Peace for Galilee" campaign began on Friday, 4th June. Overnight, families were disrupted, husbands and sons were in danger, and within 24 hours there were notifications of casualities and deaths. Families in crisis became a widespread phenomenon. In Herzlia, as in many other communities, a new service - the Emergency Center - emerged under the auspices of the Ministry of Labor and Social Affairs and the Municipality. The authors describe this process of getting organized, the populations served, how the Center was staffed, the role of citizen volunteers, and the types of interventions used to help vulnerable families as well as soldiers home on leave. Stress is placed on the unique type of short-term co operation achieved between social workers of the local Department of Social Welfare, the staff of the Department of Community Services (especially its Volunteer Bureau), the local liason officer of the Israel Defence Force, the municipal government, and public-spirited volunteers. Mention is made of conditions which made possible the activation of such a service within hours, of the Center's capacity to serve all segments of the population, and of how it was deactivated within a few weeks when the emergency ended. On the basis of lessons learned from this experience, the paper ends with a number of specific recommendations. The authors hope that such innovative forms of crisis intervention will become part of the helping technology widely available at the community level in future years. PMID- 20958587 TI - Relief workers and violations of humanitarian law: Some legal considerations. AB - This paper examines the various legal constraints upon action by relief workers when faced with violations of human rights or of humanitarian law. The unique status of the International Committee of the Red Cross (ICRC) and its delegates is explained and contrasted with the position of relief organizations and their personnel under the Geneva Conventions 1949 and their Additional Protocol I 1977. Proposals are made for the establishment of guidelines for action by relief workers when confronted with atrocities and for the training of relief workers in the relevant laws and procedures. PMID- 20958589 TI - Editorial. PMID- 20958588 TI - Welfare policy: A review. AB - This paper reviews the literature on disaster welfare policy. Analysis of the Australian disaster welfare response shows the different functions of government and voluntary welfare agencies. PMID- 20958590 TI - The politics of drought: The pauperization of lsiolo Boran. AB - Isiolo Boran are becoming a population of permanent paupers. During the colonial period they were protected from Somali incursions, and their way of life preserved. Since Independence, however, largely as a result of increasing government intervention and market integration, they have become caught in a vicious spiral of poverty and decline. PMID- 20958591 TI - The development and applications of a Drought Early Warning System in Botswana*. AB - This article describes the indicators and data sources used by the Botswana Drought Early Warning System formally established in early 1984, the main uses of the indicators in the assessment of drought conditions and the design of relief programmes are outlined. Limitations of the sources of data available are discussed, as is the feasibility of adding some possible further indicators. In conclusion, the importance of a functioning Early Warning System in a country highly susceptible to repeated droughts is stressed, in the context of die current effort to elaborate a comprehensive National Food Strategy and to establish a Regional Early Warning System for Southern Africa. PMID- 20958592 TI - Snow avalanche hazards in the Glen Nevis and Glen Coe areas of Scotland. AB - Until quite recently, snow avalanches in Britain had caused only a few deaths and the occasional destruction of property. Since about 1950, however, the number of people involved in avalanche accidents has risen sharply, particularly in Scotland. The main reason for this has been the growing popularity of mountaineering. This paper examines the situation in the Glen Nevis and Glen Coe areas of the Western Highlands. The types of avalanche occurring at these localities are briefly discussed and relationships between avalanche characteristics and accidents are examined. Mountaineers are the group chiefly responsible for the increase of avalanche deaths and injuries in the Glen Nevis and Glen Coe areas. Responses to the hazard are considered and these are shown to be inadequate. As elsewhere in Scotland, much more research is needed if a further worsening of the problem is to be avoided. PMID- 20958593 TI - Death and injury in earthquakes. AB - The assumption that the ratio of mortality to morbidity will approximate 1:3 in earthquake disasters is investigated. When it occurs, a 1:3 ratio is most likely to coincide with a Richter magnitude in the range 6.5-7.4, but many other ratios of death to injuries may instead be probable. For each individual disaster the pattern of casualties is likely to be very heterogeneous, but it would be easier to discover regularities if a more standardized definition of 'injury' could be found. PMID- 20958594 TI - Training refugees as primary health care workers: Past imperfect, future conditional. AB - Many problems have been encountered in the planning and implementation of health care in refugee camps, and more specifically in the training of refugees as primary health care workers. A review of the published literature and a "survey" of the opinions and experiences of refugee, national and international health personnel regarding training has therefore been undertaken to provide an overview of what has been done and to make recommendations for future work. The review highlights the need to reallocate resources away from high visibility emergency aid to development activities, such as training, that will create an infrastructure for primary health care and promote self-reliance. PMID- 20958595 TI - Emergency and institutional crisis in Peru during El Nino 1982-1983. AB - From December 1982 through July 1983, Peru was plagued by disastrous consequences of El Nino/Southern Oscillation phenomenon. While the northern part of the country was devastated by torrential rains and floods, central Andean Peru endured landslides and flash floods, the southern Altiplano suffered a severe drought. Hazard preparedness was nonexistent, and official disaster relief uncoordinated and slow in coming. Administrative inefficiency magnified the stress upon the populations under disaster conditions. Provisions of disaster training from specialized international organizations is recommended as a preventive measure and as a policy to improve catastrophe-coping abilities in developing nations. PMID- 20958596 TI - Letters to the editor. PMID- 20958597 TI - Editorial. PMID- 20958598 TI - The hazard of forest fires in southern France. AB - The annual hazard of fire in the forest, maquis and garrigue of southern France is related both to the fragile nature of the Mediterranean ecosystem and to man's activities. The Mediterranean vegetation is adapted to withstand the aridity of the summer months, but the combination of high temperatures, low precipitation, critical soil-moisture levels and occasional bouts of strong winds (mistral) desiccate the vegetation cover and create conditions in which outbreaks of forest fires are inevitable. Although the annual incidence and impact of forest fires are related to the occurrence of extreme weather conditions they are also exacerbated by depopulation of the remoter rural areas, the spread of urbanization and the growth of tourist facilities in the more accessible coastal zones, and above dl by man's carelessness. This article reviews the factors affecting the nature and severity of forest fires and discusses the attempts being made to prevent and control forest fires in the Mediterranean zone of southern France. PMID- 20958599 TI - Malnutrition among the Akamba of Kenya -Problem or response to a problem? AB - Two recent studies amongst the Kenyan Akamba are contrasted to illustrate how malnutrition can be regarded either as a response to a problem in the local environment, or as the problem itself, arising from general conditions of poverty and ignorance. Differences in methodology are compared and it is shown that nutrition studies often ignore local factors in reaching conclusions on nutritional status. Consequently, nutrition policy recommendations provide general solutions of limited value. It is suggested that factors in the local environment which may cause malnutrition be investigated by hypothesis testing, in order to provide specific information for community-based action. The category of the poor is not merely inadequate for evaluative exercises and a nuisance for causal analysis, it can also have distorting effects on policy matters. On the causal side, the lack of discrimination between different circumstances leading to poverty gives rise to a lack of focus in policy choice. PMID- 20958600 TI - A general assessment of the environmental impact of refugees in Somalia with attention to the refugee agricultural programme. AB - This paper attempts to examine the broad features of Somalia's harsh physical environment into which several hundreds of thousands of refugees, with mainly a nomadic or semi-nomadic life style and culture, dramatically descended six years ago. The thirty-six rural camps in which at least half of them live are described as is the refugee agricultural programme which is training several thousand families so that they may be "self-supporting." The four regions where the camps are located are each briefly summarized in terms of their soils, their climates, their natural vegetation, and the type of agriculture which the refugee farmers practice. A more detailed analysis is then given on the following critical environmental concerns: Vegetation and erosion on refugee farms, the growing problem of refugee livestock, the destruction of trees, and irrigation practices and salinity on refugee farms. The paper concludes with an argument to preserve Somalia's environment from careless and destructive exploitation, which is leading towards desertification, and calls for an in-depth study of the situation. PMID- 20958601 TI - The Spanish toxic oil syndrome: Some explanations for the pathology and an appraisal of the similarities with other episodes of food adulteration. AB - In 1981 in Madrid, a new disease was identified, and attributed to the fraudulent sale of adulterated, industrial-quality oil as olive oil. The competing hypotheses for the clinical symptoms and tissue changes are reviewed but it is also important to note the general similarities between this epidemic and those other incidents where food adulteration has presented an acute hazard. PMID- 20958602 TI - A review of poliomyelitis epidemics in Jamaica: The immunization policies and socio-economic implications. AB - The prevalence of communicable diseases in the English speaking Caribbean has declined considerably over the last two decades, creating a false sense of security and complacency in implementing continuous preventive measures such as immunization. Poliomyelitis is one such case in paint. The last case of paralytic poliomyelitis was reported in Jamaica in 1969. Then twelve years later, in May 1982, the Ministry of Health announced the outbreak of poliomyelitis in the parish of St. James, caused by the Type I virus. This paper traces the history of epidemics of poliomyelitis in Jamaica from 1954 to 1982, the Government's policies and strategies for immunization and demonstrates that preventive intervention through immunization is cheaper and preferable to crisis management caused by epidemics. The evaluation of the social and economic costs of the 1982 poliomyelitis epidemic in Jamaica provides conclusive evidence in support of preventive intervention. PMID- 20958603 TI - Eleventh regional seminar on earthquake engineering, granada, september 1984. AB - Some of the problems of combining macroseismic (descriptive) and instrumental information on modern and historical earthquakes are discussed, together with the relationships that have evolved between these two fields of study. The paper emphasises the dangers of transferring macroseismic information straight into computer databanks, without taking full account of the levels of confidence attached to the information and its suitability for earthquake risk analysis. PMID- 20958604 TI - The responses of professional fire-fighters to disaster. AB - This paper reports the results of a survey of the physical and mental reactions of a group (N= 72) of members of the South Australian Metropolitan Fire Service (MFS) who were engaged in fighting the bushfires close to Adelaide, 16th-19th February 1983. A questionnaire, designed to elicit reports on both physical and mental reactions to exposure to the fire, as well as perceptions of several measures of social strain and social support, was administered to the firefighters when they came off duty. The results reported show the possible influence of role strain factors in predicting mental reactions, and also demonstrate what may be mediating effects of perceived social support. The paper also discusses methodological problems affecting this and other studies of the reactions of emergency service personnel to disaster. PMID- 20958606 TI - Editorial. PMID- 20958605 TI - Letter to the editor. PMID- 20958607 TI - Cholera in Sudan: An account of an epidemic in a refugee camp in eastern Sudan, May-June 1985. AB - In 1985 cholera has been a serious problem in the horn of Africa, particularly affecting the many famine victims and refugees in that region. In this paper the history of cholera in Africa is briefly summarized, as is the background to the current refugee situation in eastern Sudan. A cholera epidemic involving 1,175 cases in two adjacent refugee camps in eastern Sudan is described. In this epidemic there were thirteen inpatient deaths and thirty-eight known home deaths from cholera. The management of the epidemic is described in detail. Overall an average of 8 1. of intravenous fluid was used per case, a higher figure than was anticipated, probably because of the unexpected degree of vomiting and the shortage of trained nursing staff. The relationship between cholera and malnutrition is explored and hypochlorhydria is suggested as the main reason for the increased susceptibility to cholera among malnourished populations. It was observed that severely malnourished adults and children appeared to nave less severe diarrhoea with their cholera, presumably because of reduced mucosal surface area and poor enterocyte function. Finally possible means of aborting cholera epidemics are discussed. PMID- 20958608 TI - The impact of refugees on the health status and health services of host communities: Compounding bad with worse? AB - Although there have been a number of recent developments in our understanding of refugee health problems that have influenced policies and action, the effects of refugees on the health status and services of host communities remain relatively neglected. This article sets out to explain why this is an important issue with implications for policy, planning surveillance and evaluation, training and research. The first sections outline some of the problems facing host governments and communities in Africa and discuss the changing rhetoric between the first and second International Conferences for Assistance to Refugees in Africa. A number of possible ways in which refugees could affect the individual, agent and environmental causes of disease are considered, as are the characteristics of the refugees, the host communities and the response which may all modify this impact. Policy implications of the impact of the refugees, both negative and positive, are discussed, and detailed consideration is given to the pros and cons of integrated and parallel approaches to health care provision. The need to monitor carefully the health status and services of host communities is emphasized and recommendations are made for this and other essential developments relating to training and research. PMID- 20958609 TI - The politics of disaster - Nicaragua. AB - The occurrence of natural disasters, such as floods and earthquakes, are, in themselves, beyond oar control. However, careful preparation before such events, and the correct management of the problem once it occurs, can both lead to major redaction of the suffering involved. Disaster preparation and emergency planning are both inextricably linked to politics and economics, both on a national and an international scale. Disasters themselves raise a number of issues of a political or economic nature, and die response to a natural disaster both in the short and the long term is largely determined by the political relations within a country, and between that country and the international community. This paper examines these issues by taking the examples of the earthquake of Managua, Nicaragua in 1972 and the flooding that occurred in Nicaragua in 1982. These two natural disasters occurred under different administrations in Nicaragua, and tills allows some interesting comparisons. PMID- 20958610 TI - Flood policy reversal in australia. AB - In 1977 the Government of New South Wales introduced a flood prone lands policy which attempted to break with the past emphasis on structural works. Cornerstones of the policy were the preparation of floodplain maps, and use of the 1:100 (100 year or 1%) flood to delineate floodplains and 1:20 flood for floodway definition. The fiscal and regulatory elements of the policy were to be applied more or less uniformly within the two zones. At first there was little effective opposition to the program, but this changed when large areas of Sydney, which had not been inundated since development, were mapped. Local government concern over issues of legal liability led to decisions which in turn prompted opposition to the policy from residents' action groups and property development interests. A perceived drop in property values provided the main motivation for action by residents. This pressure for change, which intensified just before the 1984 state election, saw the policy overturned. The new policy gives local government greater responsibility for floodplain management. State authorities have withdrawn from floodplain mapping, although technical advice will continue to be provided, and there are no longer any uniform floodplain or floodway definitions. Policy implementation is to be guided by a Manual which attempts to define flood hazard in terms of both physical and social criteria. PMID- 20958611 TI - Prospects for improved hurricane protection on oceanic islands: Hawaii after Hurricane Iwa *. AB - Hurricane Iwa (23rd November 1982) produced Hawaii's costliest natural disaster and revealed serious flaws in the area's hurricane preparedness, response and mitigation programs. Twenty-eight months later, a follow-up study showed that impacted communities and facilities had been reconstructed with only selective and limited attention to mitigating future coastal storm hazards. Prospects for the reduction of hazard vulnerability on oceanic islands through post-disaster mitigation measures are assessed in the light of Hawaii's experience. PMID- 20958613 TI - Educational development, basic human needs and disaster relief. Lessons from a few experiences. PMID- 20958612 TI - Climate hazards: Lessons from recent events in the United States. AB - Three recent cases of climate extremes are studied to identify human impacts and response strategies and to identify common characteristics that may help illuminate the nature of climate hazards. The 1980 heat wave in the central United States, 1981 cold wave in Boston, Massachusetts, and recent flooding and lake level rise in northern Utah, illustrate several important aspects of climate hazards that separate them from the more traditional set of catastrophic events (e.g. tornadoes, hurricanes and earthquakes) usually dealt with by hazards research and management. Among those characteristics are an emphasis on health impacts rather than physical damage, accumulative effects rather than short shocks, a tendency for impacts to accrue to certain socio-economic classes, and relatively slow onset. The management and research implications of these hazard characteristics are explored. PMID- 20958614 TI - A menu of possible educational responses in the context of disasters. PMID- 20958615 TI - Information and professionalism in disaster relief programmes. PMID- 20958616 TI - What has to be done to increase the effectiveness of disaster interventions. PMID- 20958617 TI - Establishing a national program of disaster preparedness, mitigution and prevention: The Jamaican experience. PMID- 20958618 TI - Reducing vulnerability to drought: The case of Seguenega. PMID- 20958619 TI - Development: An AFSC perspective. PMID- 20958620 TI - The role of academic institutions in training agency personnel. PMID- 20958621 TI - Training in disaster/development management. PMID- 20958622 TI - Institute on education for development in the context of disasters: summary remarks. PMID- 20958624 TI - Editorial. PMID- 20958623 TI - A reconceptualization of the linkages between disasters and development. PMID- 20958625 TI - From drought relief to post-disaster recovery: The case of Botswana. AB - This article discusses the initiative of the Government of Botswana in formulating and introducing a programme to assist recovery in rural areas after the present drought period as an important aspect of the national development effort. It examines the process by which this Post Drought Recovery Programme was arrived at, its limitations, the extent of its appropriateness to longer-term factors which render rural households more vulnerable to drought, and suggests conclusions which may be drawn to inform the design of similar programmes elsewhere. PMID- 20958626 TI - Recovery following the Gediz earthquake: a study of four villages of western Turkey. AB - This paper is the result of a social and economic survey of four villages in the Gediz region of South West Anatolia, Turkey, which was undertaken in two phases, October/November 1982 and March/April 1984. The specific aims of this survey were to define what was perceived as recovery in the local social, cultural and economic context and to measure recovery in communities which had suffered different degrees of distress and loss following the earthquake and, consequently, had received different amounts and kinds of assistance from the government. Essentially, therefore, the survey sought to answer the question - how far did the government programme of assistance promote recovery and over what period of time? The implications of such an inquiry concern what constitutes appropriate assistance following earthquake in rural communities. It is hoped that studies of this kind can help to guide decision making of both national governments and international humanitarian organizations on the role of material aid in the process of recovery. This is particularly urgent in view of the fact that preliminary investigations of other small rural and under-developed communities struck by earthquake suggest that material aid may actually preclude recovery in the longer term. PMID- 20958627 TI - Supplementary feeding for refugees and other displaced communities - questioning current orthodoxy. AB - Supplementary feeding programmes of one sort or another are an almost universal response to refugee displacements, particularly in Africa. The aim of this paper is to question some of the assumptions which underlie current approaches to providing this additional food. First, there is a brief description of recent general policy developments relating to refugee health care and an outline of the two main factors that are likely to affect the objectives of supplementary feeding programmes: the adoption of either the medical or the epidemiological model of malnutrition, and the identification of the major differences between refugees and stable communities in developing countries. The characteristics of vulnerable groups are then discussed, as is the need to place food supplements within a much broader context of appropriate interventions directed towards improving and maintaining the health and nutritional status of these vulnerable groups. At the same time, emphasis is placed on the non-nutritional value of food and the importance of allowing refugees to determine their own priorities and to use the available resources accordingly. Several unresolved questions about nutrition programmes are identified, in particular whether the focus of supplementary food should be high risk individuals or families, and whether supplements should be provided on a supervised or take home basis - or if they should merely be included as part of a basic ration determined by "need." Eight axioms of supplementary feeding programmes for refugees are stated and the implications of these for planning, training and research are discussed. PMID- 20958628 TI - Landfill gas - a potential environmental hazard. AB - Methane derived from the decomposition of organic material contained within a landfill may escape beyond the site boundary where it can pose an explosion or fire hazard. Methods are described to prevent die occurrence of such lateral gas migration. Problems due to the accumulation of gas in buildings, erected on landfill sites, have occurred and techniques are now available to overcome these at some sites. However, it is recognized that at other sites, redevelopment should not be allowed to take place on die grounds of safety. PMID- 20958630 TI - Letters to the editor. PMID- 20958629 TI - Co-ordination for disasters. AB - This paper was prepared in 1978 on the basis of a review of sociological and anthropological fieldwork conducted up to that time. Although theoretical in presentation its conclusions are formulated in accordance with the author's own extensive observations of organizational response to natural disasters in developing countries, especially those having sudden onset. Practical implications for co-ordination agencies and pre-disaster training are drawn. PMID- 20958631 TI - Editorial. PMID- 20958632 TI - Volcanic disasters in Latin America and the 13th November 1985 eruption of Nevado del Ruiz volcano in Colombia. AB - Volcanic eruptions in Latin America have claimed about 61,000 lives since 1600 A.D. and the region's volcanoes are responsible for about a quarter of the world's fatalities from this type of hazard. Nearly all loss of life from volcanism in Latin America is due to pyroclastic surges, pyroclastic flows and lahars or volcanic mudflows. Lahars generated during the 13th November, 1985 eruption of Nevado del Ruiz in Colombia claimed 25,000 lives, underscoring the great hazard from lahars, which can be generated from the fifty-six, active, ice capped Central and South American volcanoes during even very small eruptions. The probability of specific prediction of the timing of such events is currently low, whereas the probability of a general prediction of volcanic eruption is high, giving sufficient time to install telemetered lahar alarm systems, which could largely avoid the loss of life. PMID- 20958633 TI - The use of newspaper data in historical earthquake studies. AB - Studies of historical British earthquakes are an essential component of assessing seismic hazard in the U.K.; such studies rely heavily on macroseismic data obtained from printed newspapers. This paper discusses the ways in which newspapers have reported British earthquakes and the nature and limitations of the data that may be acquired from this source. Historical changes in the press as a source of macroseismic data are discussed. It is suggested that an understanding of the background and nature of newspaper data is an important component in the process of revaluating historical earthquakes from such data. PMID- 20958634 TI - Indigenous responses to drought in sub-Saharan Africa*. AB - Drought is a frequent occurrence in contemporary sub-Saharan Africa, and the existence of periodic drought can be documented over hundreds of years. As a consequence of the routine rainfall shortages that affect them, agricultural and pastoral societies have developed a number of social institutions and mechanisms for bridging temporary food production shortfalls caused by drought. Drawing on the literature and field data from southeastern Kenya, this paper discusses a number of regular indigenous responses to short-term drought in sub-Saharan Africa. Changes in these patterns in the present day are also discussed. It is concluded that market-based responses are now the most important strategies, but that traditional institutions remain significant and contribute to the viability of drought-affected societies. PMID- 20958635 TI - Toxicological mass disaster management - a hospital deployment scheme. AB - Toxicological mass disasters have occurred frequently in past years and constitute a permanent threat in urban areas. From the standpoint of hospital planning, special consideration is required to treat a large number of poisoned casualties in a relatively short period. Several unique medical aspects characterize toxicological mass disasters: casualties present a single disease entity with many "borderline" cases, most medical personnel are unfamiliar with the problem and casualties present a potential contamination hazard to the hospital. A hospital deployment scheme is presented recommending Decontamination, Triage and simple Treatment Algorithms to meet the medical and organizational challenge of such a mass casualty situation. A further specific deployment scheme for treatment of organophosphorus agents poisoning is described to illustrate the principles presented. PMID- 20958636 TI - Information systems and needs assessment in natural disasters: An approach for better disaster relief management. AB - The paper addresses the issue of information in disasters relief. It begins by establishing the need for planning and systematic organization in disaster action, in order to produce a long term effect on the vulnerability levels of communities. Information is introduced as a key element in any phase of disaster management. The different informational needs are described by phases; information types and possible sources are briefly described. The organizational network of information collection is presented and the immediate need for research in this field is emphasized. PMID- 20958637 TI - Letter to the editor. PMID- 20958638 TI - Editorial. PMID- 20958639 TI - The African food crisis of 1982-1986*. AB - The crisis cannot be attributed to any one cause, but rather it was the product of a number of interacting factors whose precise combination varied between countries. Drought, internal political and economic factors and an unfavourable external economic environment were significant contributory factors. Civil war and externally financed insurgency were primarily responsible for propelling a food crisis into a famine in four out of the six worst affected countries. Within the literature, there is a tendency for writers to emphasize the relative contribution of factors within their own disciplines. So far the literature on the responses, both within country and internationally, is comprised of eye witness accounts by journalists and evaluations by aid agencies of their performance. The international response by governments and the public was massive and unprecedented, but the response by governments, indigenous NGO's and the public within affected countries is often overlooked by the journalistic literature. Generalizations about "the African food crisis" have obscured the considerable diversity amongst countries. This is well illustrated by the experiences of Ethiopia, Kenya and Botswana. This diversity indicates the biased perspectives that arise from focussing on the extreme famines, as in Ethiopia. Research priorities should include studies of systems that coped during the crisis, historical analysis of the crisis, the way early warning information is processed within bureaucratic institutions, environmental degradation and fully integrated analysis of food production and consumption systems. PMID- 20958640 TI - Food aid and relief-development strategies*. AB - This paper begins by setting out the main arguments on which a proposal for "relief-development strategies" rest. The second part of the paper is concerned with a discussion of the way the objectives of a "relief-development strategy" might be achieved and the roles emergency food aid might have. In the third part of the paper, a number of strategic issues are discussed. A stylized account is presented of how a broad "relief development strategy" might be mounted. The last part of the paper draws together the discussion by considering how emergency projects should be assessed. If the principles on which this paper are based are accepted, then the evaluation of emergency projects should extend well beyond convention. PMID- 20958641 TI - Hunger, poverty and food aid in Sub-Saharan Africa: Retrospect and potential. AB - Frustrations and failures will continue to mount if we do not immediately summon the courage to revise the ways we think and take action-as well as maintaining essential services to support life and health ... Saving hundreds of thousands ... who are at risk of dying from malnutrition or infection is an immediate imperative. But it must be only one stage in the progress toward other activities, and one element in the truly comprehensive approach... The main intent of this paper is to explore aspects of the nature and evolution of poverty in Sub-Saharan Africa with special reference to food and hunger and their interaction with macro-economic policy. An attempt is made to outline the overall context within which food aid needs to be used in order to have a greater developmental impact. Following an Introductory Section I, Section II provides a sketch map of how recession and lagging food production - with cyclical weather crises superimposed - affect the human condition of poor people. Section III reviews die interaction between "standard" IMF stabilization and World Bank structural adjustment strategies and poverty/hunger. Improvements in the design of stabilization and adjustment programmes, and of the inter-relationship with them of emergency programmes, can be identified. A number turn on the broadened and more innovative or catalytic use of food aid. Section IV reviews aspects of facing a continuing series of emergencies and of designing life support programmes to facilitate rehabilitation of the households directly affected as well as of the national economies. From this base it explores a series of elements in achieving renewed development. The concluding Section seeks to explore the strengths, limitations and potentials of food aid in the context set by the previous sections. The standard criticisms of food aid appear to be overstated and/or to relate to particular modalities or approaches rather than to anything intrinsic. A number of criteria for improving the effectiveness of food aid - especially in respect to rehabilitation, recovery and renewed development - are set out. PMID- 20958642 TI - Food aid and food crisis in Sub-Saharan Africa: Statistical trends and implications*. AB - This paper documents the rapid expansion and changes in food aid flows to Sub Saharan Africa up to mid-1985. Trends for Sub-Saharan Africa as a whole and for the more seriously affected countries are examined, as are the comparative experiences of food aid of individual countries in the region. Table 11 lists the Sub-Saharan African countries and indicates the most seriously affected food short countries, as defined by the WFP/FAO task force. It should be borne in mind that some practical problems exist in compiling data on food aid. These include lack of availability of reliable data, especially of most recent data; lack of common terminology and definitions; and different accounting systems. These data problems are sometimes a source of confusion. However, the basic facts are clear: food aid gradually emerged during the early 1980s as a resource too often of considerable significance to many countries of Sub-Saharan Africa. These trends were only accelerated with the crisis of 1984-1985. These facts provide a point of reference for further analysis of the sources of the crisis, its actual dimensions and consequences. PMID- 20958643 TI - Editorial. PMID- 20958644 TI - Editorial. PMID- 20958645 TI - Editorial. PMID- 20958646 TI - Editorial. PMID- 20958647 TI - The qiongshan earthquake of july 1605. AB - In 1605 a destructive earthquake affected the northern region of Hainan Island and adjacent parts of the Chinese mainland. Based on a detailed analysis of contemporary chronicles, the authors present a revision of the effects of the earthquake, and show that a sequence of strong shocks throughout 1605 caused cumulative damage and relatively heavy loss of life in Qiongshan. The subsidence of large areas of coast round Puqian Bay and Dongzhai Port is shown to be due to a combination of liquefaction caused by the shock, the occurrence of a typhoon associated with flooding and exacerbated by a high surge tide, as well as a long term process of active tectonic movement in the area; the subsidence was not caused by downthrow of the earth's crust during the shock. Topographical changes in the area, traced from historical maps, suggest that subsidence is continuing, but a survey of the long-term seismicity of Hainan Island indicates that it is not an area of exceptional seismic risk. PMID- 20958648 TI - The performance of the sydney flood warning system, august 1986. AB - During August 1986 Sydney experienced its worst flooding for decades. Some 2,500 properties were flooded and transport was severely disrupted in much of the metropolitan area. The flood provided an opportunity to examine the operation of a warning system in a major Australian city. Pre-existing research into flood warnings was expanded to take advantage of the opportunity. The warning system is examined in terms of: its impact on flood losses; consumer satisfaction; and inefficiences or breakdowns within the system. Much of the flooded area was not covered by a formal warning system. For the area that was covered, performance could be improved. Problems were experienced with the data collection and transmission network. Warning dissemination was inadequate, and the majority of those surveyed claimed that they did not receive warnings. The actions of householders reduced the flood damage substantially, but this does not appear to be the result of official warnings. Key recommendations concern improving the reliability of the flood detection network and information management. PMID- 20958649 TI - Emergency service response and costs in british floods. AB - The costs of emergency response to flood disasters has received little attention. This paper presents and discusses a method for estimating the economic costs incurred through the use of the emergency services during flood events in Britain. First, a model of British emergency service response to flood events is presented. Secondly, cost evaluation principles relevant to each emergency service are discussed. Thirdly, a set of "standard" emergency service cost data are presented - these data are derived from research based upon the model of response and the evaluation principles. Finally, the "standard" data are applied to the case of the York and Selby floods of 1982 where data from research on the reported actions and costs of each emergency service are compared with those predicted through the use of the "standard" data. PMID- 20958650 TI - Nutrition assessment through the use of a nutritional scoring system. AB - In 1984 and 1985, Chad was affected by a large scale drought. In order to ensure rapid decision making for the allocation of food and because of the practical problems encountered when using the classical nutritional survey methods, a Nutritional Score System (N.S.S) was developed. This method was based on the use of social, economic and nutritional indicators and allowed comparison of nutritional status between communities. This paper discusses how the N.S.S. was developed and applied, and how it compared with the classical survey methods. PMID- 20958651 TI - Famine early warning systems and the use of socio-economic data. AB - Famine early warning systems using socio-economic data suffer from several problems. One is that they cannot, and do not attempt to, distinguish between qualitatively different kinds of famine. The second is that they cannot predict these either accurately or early enough. This is because all the socio-economic indicators produce both false positives and false negatives, the indicators themselves are "late" and because interpretation of the data is complex and time consuming. The third problem is that within the context of a famine that is occurring, these indicators cannot predict excess mortality. The argument is illustrated with examples from the 1984-5 famine in Darfur, Sudan. PMID- 20958652 TI - Gas bursts from cameroon crater lakes: a new natural hazard. AB - Gas bursts from tropical crater lakes constitute a hitherto unrecognized natural hazard, which claimed 37 lives around Lake Monoun in 1984 and 1,746 lives in 1986 around Lake Nyos in Cameroon, west Africa. Studies of these events indicate that the lethal gas clouds were dominantly CO(2) which exsolved catastrophically from deep waters of the lakes, producing in the case of Lake Nyos a gas cloud of 1.94 times 10(6) tons CO(2) . Carbon-isotope data indicate a magmatic source of the carbon dioxide, but the geochemistry of deep water and gases does not support a sudden injection of volcanic gas from a deep source into the lakes. Rather, it is proposed that the gas bursts were preceded by gradual build-up of dissolved bicarbonate in deep waters, where anoxic conditions in enclosed and stagnant basins led to low pH and pCO(2) close to saturation. Steady input from the Earth's mantle to submerged mofettes or CO(2) -rich soda springs within the lakes is most likely the primary source of carbon dioxide. Lethal effects of the gas bursts are almost entirely due to CO(2) -induced asphyxia. A small percentage of victims awoke from coma one or two days after the event, but most died. Unusual skin lesions on about 5% of victims arose from the comatose state. It is shown that the mass of gas required to account for the lethal effects and observed gas clouds is an order of magnitude less than the potential gas yield from the lakes. In view of the lethal gas bursts from the small Cameroon lakes, the potential hazard of future gas bursts from other much larger density-stratified equatorial lakes must be seriously considered, particularly in Lake Kivu in east Africa, where methane and carbon dioxide gas content is higher by two to four orders of magnitude than that of the Cameroon lakes. A gas burst from Lake Kivu would form a carbon dioxide cloud up to 340 km(3) in volume and expansion of the exsolving gas from deep water to atmospheric pressure would correspond to an energy release equivalent to 8 megatons of explosive. PMID- 20958653 TI - Nutritional status as an indicator of impending food stress*. AB - Famine early warning systems benefit from a variety of indicators which together signal the initial stages of food stress for particular population groups. Anthropometry has been used as an indicator in early warning systems, but there are inherent problems in its use which should be understood. Using data from Turkana pastoralists of northwest Kenya, this paper discusses the problems of: time lag between food shortages and changes in body size and composition; use of reference points; accurate age assessment; and establishment of baseline data. Diet composition data are suggested to be an additional nutrition-oriented indicator of impending food stress and one in which problems associated with anthropometry are not inherent. Both measures may be useful in monitoring a population, but their strengths and weaknesses should be appreciated. PMID- 20958654 TI - National organizations and famine early warning the case of mali(1). AB - In the Sahelian countries of West Africa, the problems of drought and famine are sufficiently long term to justify the existence of permanent food security agencies. Yet donors are reluctant to fund these agencies when there is not a crisis, forcing poor countries to use their own resources for food security and famine early warning efforts. To make more effective use of limited resources and since the data needs for effective famine early warning are similar to those for basic rural development, information systems to provide data simultaneously for development projects and famine early warning should be developed and supported. In Mali, one of the larger and poorer countries of the West African Sahel, basic information systems which gather a range of appropriate data already exist, but there need to be improvements in the quality of design and the timeliness of analysis to make the information more useful for either development or famine early warning. PMID- 20958655 TI - Refugee income generating projects and occupational health. AB - The shift from purely emergency relief for refugees in developing countries to aid within the context of development strategies is slowly gathering momentum (UN, 1983; UNHCR, 1984; Simmonds, 1984). Such a move implies that if self reliance is to be a realistic goal then employment for refugees is essential; a number of income-generating schemes are therefore being both proposed and developed (ILO, 1983 and 1984). Many of these schemes have implications for the health of the refugees, so this paper summarises some occupational health hazards and offers suggestions for future action. PMID- 20958656 TI - Natural Hazard Reporting in the UK Press. AB - Important sources of information concerning world natural hazards are provided by the mass media, especially newspapers. The nature, depth and consistency of the reporting, however, varies considerably depending upon the journalistic approach of the newspaper and on the perceived 'newsworthiness' of a disaster. Intensive events are much more likely to receive attention than pervasive hazards but other contributory factors play a part, such as the day, time, severity in terms of damage and loss of life, and location of the event. This paper reflects on the reporting of natural hazards in UK newspapers and is based on an analysis of press cuttings taken over a period of twelve months. The survey indicated that there is a very uneven coverage of world disasters, that location maps are scarce, and that valuable follow-up reporting is minimal. PMID- 20958657 TI - Valtellina landslide and flood emergency, northern Italy, 1987. AB - This report describes the progress of the landslide and flood emergency that occurred in Valtellina, in the northern Italian Alps, during July and August 1987. For the authorities, the critical problem was one of controlling the rise of a large lake impounded on the River Adda by landslide debris that threatened to breach catastrophically, releasing a major floodwave. Several lessons can be learned from the way in which the emergency was managed. First, helicopters played a critical role in evacuating survivors and moving supplies around the disaster area, but there was scope for better co-ordination of operations. Secondly, high levels of private car ownership allowed greater flexibility in designing mass evacutation plans for threatened communites, but such high personal mobility proved difficult to control in order to ensure public safety. In future, education programmes could be used to help people appreciate the dangers of driving during periods of great natural hazard risk. Thirdly, the Valtellina disaster coincided with a change of national government, including substitution of the Minister of Civil Protection. This led to a policy vacuum, sub-optimal decision making and erosion of public confidence in political leaders. Landslide-dammed lakes represent a widespread but rather unpredictable hazard: they therefore require flexible emergency repsonse, but not without decisive leadership. PMID- 20958658 TI - The scandinavian earthquakes of 22 december 1759 and 31 august 1819. AB - The two largest known pre-1850 Scandinavian earthquakes are the 22 December 1759 Kattegat event (located at 57.7 degrees N-11.1 degrees E) and the 31 August 1819 Nordland event (located at 66.4 degrees N-14.4 degrees E), the latter being the largest north European near-shore earthquake of the past few centuries. The 22 December 1759 event caused minor damage to buildings (MMIVII) on either side of the Kattegat in Northern Jutland and in the Swedish province ofBohuslan, and was felt up to 600 km away. The 31 August 1819 earthquake caused widespread damage (MMIVIII) to stone components of wooden buildings in the sparsely populated region of Nordland Norway, as well as very extensive rockfalls, liquefaction phenomena and a remarkable variety of disturbances in fjords and in the sea. The earthquake was felt throughout northern Scandinavia over distances of up to 800 km. PMID- 20958659 TI - Evaluative research in a refugee cAMP: the effectiveness of community health workers in khao I dang holding center, Thailand. AB - An evaluation of Khmer refugee public health services found a strong cultural preference for older females as Community Health Workers (CHWs), in contrast to the young males employed. Class conflicts were identified between educated, upper class CHWs and the uneducated camp majority. Poor community acceptance of the CHWs impaired their effectiveness, and was attributed to age, sex and socioeconomic barriers. Based on these evaluation findings, the refugee health program was restructured to include a preponderance of female workers. A repeat survey demonstrated enhanced program effectiveness following this change. Selection of refugee health workers should be based on intrinsic community roles, taking age, sex, socioeconomic and other group distinctions into account. Additional research is needed on the adaptation of community health principles to the refugee context. PMID- 20958660 TI - Limitations of anthropometry during acute food shortages: high mortality can mask refugees' deteriorating nutritional status. AB - Longitudinal comparison of anthropometric data from cross-sectional surveys is commonly used to assess nutritional status in relief operations. In a refugee camp in Sudan, assessment indicated a high level of childhood malnutrition, but nutritional status appeared relatively unchanged between cluster sample surveys in January (26.3% below 80% of median weight-for-height) and March 1985 (28.4% below 80% of median weight-for-height). However, in this interval, which was marked by irregular food supplies and relatively low energy (calorie) intake as well as by a high incidence of diarrhoeal disease and measles, nearly 13% of all children in the camp died. This deceptive appearance of stability in nutritional status in the face of high mortality may be explained by ongoing nutritional deterioration ("replacement malnutrition") among surviving children. These findings demonstrate that collection and analysis of mortality data are essential for the correct interpretation of anthropometric results during periods of uncertain food supply. PMID- 20958661 TI - Tuberculosis in a Refugee Camp: A campaign to reduce transmission. AB - In November 1985, tuberculosis was highly prevalent among the 6,250 Tigrayan refugees ofFau I camp in Eastern Sudan. It was therefore decided to launch an active case-finding campaign aimed at decreasing transmission, to be carried out by primary health care workers. The entire population of the camp was screened for symptoms of pulmonary tuberculosis and the sputum of people with productive cough was examined by direct microscopy. However, it was considered that this examination was insufficiently sensitive in the camp situation. For this reason, people with non-productive cough or sputum-negative were enrolled in a follow-up program whose length was determined by the severity of their symptoms. The campaign was interrupted by circumstances that are typical of refugee situations. On the basis of results obtained a few conclusions can nonetheless be made on the appropriateness of introducing an active screening program in situations where a stable refugee population has good access to basic health care of good quality. PMID- 20958662 TI - Practical experience with the management of a cholera outbreak in a refugee cAMP in eastern Sudan, 1985. AB - From May to November 1985 most refugee camps in Eastern Sudan were affected by cholera. This article summarizes the experience from the refugee camp Wad Sherife with the emphasis on the practical aspects of management of cholera in a refugee context. Paramedical personnel from the refugee community were used to a great extent both in curative and preventive measures. The home visitors played an important role in the early detection of the cases and in trying to prevent the spread of cholera in the camp. A total of 1793 cases were admitted during a three month period. The results show a case fatality rate of 1.8%. A significantly higher number of women were affected in the age group 15-44. As seen in other refugee camps in Eastern Sudan, there was a relatively high intravenous fluid consumption with an average of about 6 litres in adults. PMID- 20958663 TI - The persian famine of 1870-1872: prices and politics. AB - By whatever definitions one cares to classify food shortages and deaths resulting from lack of food, there can be little semantic difficulty in recognising a catastrophic famine in Persia (Iran) in the early 1870s. This paper briefly examines the famine in its natural, political and socio-economic context. Fluctuations in prices and in the supply of essential commodities responded primarily to weather conditions, but this response was exaggerated and in some instances triggered directly by actions in the political and economic sphere. PMID- 20958664 TI - Peasant survival strategies in ethiopia1. AB - This paper focuses on peasant farmers in Ethiopia, and their behaviour as serious famine sets in. In many of the last seventeen years the crop yields on rain-fed plots in drought-prone areas have failed to meet the requirements of the peasant farmers and their families. Significant numbers have received food aid either at distribution points or in the shelters which developed in 1973 and 1984. Seeking food relief from external sources, however, is the last resort of peasants who have managed their dwindling resources for months, if not years, in order to survive. PMID- 20958665 TI - The spatial and temporal variability of residential real estate values in response to flooding. AB - A relationship between residential property values and the incidence of flooding is represented, using a case study of two Californian communities that were flooded following a levee break. Analysis of the real estate market before and after the flood shows that the flood was capitalized into housing values, whereby both list and selling prices dropped immediately and have recently begun to recover. However, recovery of the market is not uniform throughout the floodplain. Houses that suffered eighteen inches of water recovered to near pre flood values in less than one year. In contrast, houses that had approximately ten feet of water in them have not recovered to the same extent, indicating that capitalization and recovery do not occur evenly. These findings suggest that policies and programs should address these spatial and temporal differences in recovery, which are expected to vary with different flood frequencies and magnitudes. PMID- 20958666 TI - Surveillance for adverse health effects following a chemical release in west virginia. AB - On 11 August 1985, a large inadvertent release occurred from a chemical manufacturing plant in Institute, West Virginia. The emission was related to overheating of a storage tank that contained chemicals for the production of aldicarb, a cholinesterase inhibiting pesticide. As a result of this emission, 136 persons were treated in five local emergency rooms, 29 of whom were hospitalized for one or more days, mostly for observation. No fatalities resulted. Interviews with treated persons and non-treated community residents confirmed that the health effects were transient and compatible with exposure to irritating vapors rather than with exposure to methyl isocyanate (a chemical used in the process) or to aldicarb. Only 5% of the treated persons and 5% of the community residents surveyed were adequately warned of the emission by the plant siren. Because persons in the nearby community are potentially vulnerable to chemical injury, we recommend the development of an improved warning system, a formal evacuation procedure, and other measures to limit exposure of persons in this area in the event of a future release. PMID- 20958667 TI - Patterns of giving and receiving help during severe winter conditions: a research note. AB - Severe winter conditions and blizzards may cause persons to be stranded, unable to move from one place to another. Being stranded under such conditions can be life-threatening and often requires help. This is a study of giving and receiving help among people who were stranded during severe winter conditions and blizzards in Bowling Green, Ohio, USA and the surrounding countryside in 1976-1977. Mail questionnaire data were collected from the Bowling Green, Ohio telephone directory which included listings from both rural and urban areas. The family, followed by friends and neighbors, were most important in the giving and receiving of help. There was little difference between the responses of rural and urban residents. Propinquity was found to be an important intervening variable. PMID- 20958668 TI - Agriculture and food security in ethiopia. AB - Food security in Ethiopia is discussed in the context of the repeated famines and the international responses both to them and to the socialist agricultural policies being pursued by Ethiopia. Increasing concern has been expressed by the international donor community regarding the ability of Ethiopia to absorb development funds without a major shift in emphasis in agricultural policy making. The background to Ethiopia's present vulnerability is shown both in terms of the size of the vulnerable population and in terms of the poor performance of the agricultural sector in the last decade. The author looks at the present agricultural and marketing policy reforms and questions whether they are sufficient to generate the sort of international response needed to create the level of food security that would be required to avert future famines. PMID- 20958669 TI - The Food and Nutrition Surveillance Systems of Chad and Mali: The "SAP" After Two Years. AB - The "Systemes d'Alerte Precoce" - the SAPs - of Chad and Mali have been in operation since April 1986. Their purpose is to forecast (or more realistically, detect as early as possible) food shortages in the drought-prone areas of each country. They are based on a multidisciplinary strategy, taking into account all relevant phenomena, from meteorology to nutritional status, and are implemented through the governmental networks. The present experience shows that, compared with the devastations due to famine and the cost of emergency food aid, they are not that expensive and they seem sustainable over the long term. "Faultless" prediction is not yet the rule, but several procedures permit progressive improvement in the ability of the systems to analyse and interpret. This paper explains the functioning process of the SAPs and presents several operational results. Additionally, it covers innovative concepts that have proved to be successful, such as the "participative information network". PMID- 20958670 TI - The relief operation in puno district, peru, after the 1986 floods of lake titicaca. AB - The 1985-86 rainy season in Peru was disastrous due to very high precipitation. Because of the unusual level of floods in the Lake Titicaca area and the increasing number of affected people, the Peruvian Government established an emergency relief plan and appealed for international aid. At that time the situation was already very critical. The lack of preparedness made the implementation of the relief operation difficult. Our paper describes the intervention of a French N.G.O. (Medecins Sans Trontieres), requested by the Peruvian authorities. The early phase of the relief programme and its methodology are described. Problems within this relief programme and the further long-term development action that should be undertaken are discussed. Au Perou, la saison des pluies 85-86 a ete catastrophique par l'importance des precipitations. Au cours des premiers mois de l'annee 1986, devant l'ampleur inhabituelle des inondations dans la region du lac Titicaca et le nombre sans cesse croissant de sinistres, le gouvernement pbruvien decide de mettre en route un plan national de secours d'urgence enfaisant appel a l'aide internationale. Mais la reponse est deja tardive et le manque de mesures preventives fait que l'organisation des secours se heurte a un grand nombre de difficultes. Notre etude se situe dans le cadre de l'intervention d'une organisation non gouvernementale europeenne, sollicitee par le gouvernement peruvien pour une collaboration dans la phase des premiers secours a cette population. Les problemes poses lors de cette operation et la suite a donner a l'assistance a moyen et a long terme sont discutes. PMID- 20958671 TI - The role of socio-economic data in food needs assessment and monitoring. AB - This paper reviews six case studies examined as part of a project to review targetting methodologies employed by non-government organisations in Africa during the 1984-6 food crisis. Most agencies have not yet fully evaluated the role of data in informing policy decisions during their respective emergency programmes. The case studies presented reflect a wide variety of approaches to targetting emergency food aid that are based largely on the use of 'socio economic' data. The recent emergency relief operations in Africa seem to indicate a change in relief agencies' approaches to the assessment and monitoring of needs of the affected populations. Earlier dependance on nutritional data has given way to an increasing reliance on the use of socio-economic indicators. There was a wide variation in the case studies of the type of indicators collected and utilised in needs assessment and monitoring. There were those who relied almost exclusively on nutritional data to target resources during the 1984-86 African crisis, and others whose experiences during that period lead them to attach more weight to socio-economic data. Other agencies appear to have recognised the problems of relying solely on nutritional data to target food aid during their 1984-86 emergency programmes, and thus more or less abandoned classical anthropometric surveys in their needs assessment and monitoring methodologies during this period. Thus nutritional data has a less significant role in the decision making process than previously had been the case. PMID- 20958672 TI - Diet and Nutrition during Drought-An Indian Experience. AB - In 1987 India experienced one of the century's worst droughts with two-thirds of its sown area receiving 'scanty' or 'deficient' rainfall. Delayed rains in some parts, though to some extent they relieved the water scarcity, did not brighten the prospects of agricultural production. In order to assess the diet and nutritional situation of the vulnerable population in the severely affected areas, rapid surveys were undertaken by the National Institute of Nutrition, Hyderabad, in five States of the country, namely Andhra Pradesh, Tamil Nadu, Karnataka, Orissa and Gujarat, during the months of October-December 1987. Results obtained during the current surveys are compared with the dietary situation observed in earlier droughts in the 1960s and 1970s, and it is concluded that the widespread hunger and its consequences encountered in earlier droughts could be averted, due mainly to the better food security and distribution mechanisms now available in the country. PMID- 20958673 TI - A case study of social behaviour in a natural disaster: the olivares landslide (Spain). AB - The modern sociological literature on disasters highlights the fact that many of the ideas about human behaviour in disasters which were long considered as valid, are wrong. The main discovery is based on the fact that situations of crisis increase people's moral principles and capability of response. This paper illustrates some of these ideas, in a case study of a village which was struck by a natural disaster in the north of Granada (Spain) in 1986. The population's attitude revealed a huge potential of resources that were underestimated by professionals of disaster management. The analysis shows that it is necessary to bring civil protection systems and the population's capability of response into close harmony. PMID- 20958674 TI - The October 1988 Elia Prefecture Earthquake (SW Greece): Seismic Environment, Building Types and Damage Patterns. AB - Earthquake disasters occur frequently in Greece, causing serious building damage and considerable loss of life. The latest event, on 16 October 1988, though not one of the most destructive, caused considerable damage. Strong motion records have been obtained near to the damaged region and this provides the opportunity to assess the extent of damage to various building types, and compare it with damage caused during another recent earthquake. The common characteristics of each building type are given, along with the typical damage patterns. Comments are also made about the seismicity of Greece and earthquake damage during this century. The building type distribution in various parts of the country is also discussed, with a view to future earthquake disaster prevention and mitigation. PMID- 20958675 TI - Humanitarian emergencies and military help: some conceptual observations. AB - In 1988 the International Peace Academy, New York, sponsored a study exploring the interface between security and the delivery of humanitarian aid. The aim was to evaluate the possible use of military help to support humanitarian relief workers during armed conflicts. As part of this pioneering work, the authors of this paper discuss the conceptual questions that must be raised before dealing with the associated practical difficulties. It examines those circumstances in which foreign military organizations might offer help in humanitarian emergencies; the nature of contemporary examples of humanitarian need that result in international responses; and the importance of factors which affect how these are perceived. The paper then analyses the pertinent functions that military units might undertake and finally examines the constraints that would apply if such forces were to become involved. PMID- 20958676 TI - Thought for Food: Suggestions for a systematised approach to emergency food distribution operations. AB - The following paper is a synopsis of a longer report, under the same name, aimed at the people responsible for implementing relief food operations. The report attempts to fill a perceived need for a manual covering the organisation of relief operations from planning to evaluation stages. Following the initial planning phase, the distribution of relief food can be viewed as a logistics operation sandwiched between two phases of data acquisition - one before the distribution of relief to targetted destinations, and the other after the distribution, to assess its efficacy and to identify problems. PMID- 20958677 TI - Design and validation of a practical index for trauma assessment. AB - In the past 20 years a variety of indices have been suggested for measuring the severity of trauma, however none of them meets the requirement of being a simple and objective instrument that can be utilized efficiently by lay persons and providers of health services without previous experience in triaging. A new system has been proposed which meets this requirement and which has been validated with 197 injured persons at the emergency ward of the Valle University Hospital in Call, Colombia. The instrument showed a high level of concordance with the conventional triaging method and classifies victims into four categories: critical with recovery unlikely, critical but recoverable, moderately serious, and ambulatory. There is discussion on the reliability of this instrument and it is recommended that it be validated with victims from larger disasters. Regardless, it has the advantage of being specific and free of the subjectivity that characterizes other indices. PMID- 20958678 TI - The Protection of China's Ancient Cities from Flood Damage. AB - Over many centuries, the repeated and serious flooding of many of China's ancient cities has led to the development of various measures to mitigate the impact of floods. These have included structural measures, such as the construction of walls, dams and dykes, with tree planting for soil consolidation; installation of drainage systems and water storage capacity; the raising of settlement levels and the strengthening of building materials. Non-structural measures include warning systems and planning for emergency evacuation. Urban planning and architectural design have evolved to reduce flood damage, and government officials have been appointed with specific responsibilities for managing the flood control systems. In view of the serious consequences of modern neglect of these well-tried methods, this paper examines China's historical experience of flooding and demonstrates its continuing relevance for today. A brief historical survey is followed by a detailed discussion of various flood prevention measures. The paper is illustrated by city plans from ancient local chronicles. PMID- 20958679 TI - Preserving the Identity of Small Settlements during Post-Disaster Reconstruction in Italy(1). AB - The nature of small, historic settlements in Apennine Italy is described and options for reconstructing them are discussed. Villages and towns are disproportionately vulnerable to damage by even small earthquakes, which can cause substantial changes to their distinctive character. Responses to such events are outlined, including various strategies of evacuation and the process of developing standardized methods for post-disaster architectural survey. Rationales for demolishing damaged buildings, and their role in causing decentralization of the settlements, are discussed. The effects of temporary shelter and contemporary reconstruction plans are evaluated in terms of their impact on the changing urban landscape of such towns. Finally, inconsistencies in government reconstruction funding are shown to be responsible for much of the variability of post-disaster recovery in Italy. Hence, existing theoretical models are of little use in predicting the course of reconstruction. PMID- 20958680 TI - Earthquake hazard assessment after Mexico (1985). AB - The 1985 Mexican earthquake ranks foremost amongst the major earthquake disasters of the twentieth century. One of the few positive aspects of the disaster is that it provided massive quantities of data that would otherwise have been unobtainable. Every opportunity should be taken to incorporate the findings from these data in earthquake hazard assessments. The purpose of this paper is to provide a succinct summary of some of the more important lessons from Mexico. It stems from detailed field investigations, and subsequent analyses, conducted by the author on the behalf of reinsurance companies. PMID- 20958681 TI - Migrations and nutritional status in the sahel. AB - In the Sahel, migration is of considerable importance. It permits the peasants to adjust to variable food conditions. In areas affected by food shortages, cluster sample studies of villages showed that, as the number of recently abandoned houses in a cluster increased, the prevalence of malnutrition decreased, and this linear trend was significant (p < 0.05). This phenomenon tends to reduce the prevalence of malnutrition in these areas, and it emphasizes the fact that the malnutrition rate is a late indicator when used for nutritional surveillance. The article provides also a brief description of the current migration patterns in the Sahel and underlines the effects droughts have had on them. PMID- 20958682 TI - The 1988 earthquake in soviet armenia: implications for earthquake preparedness. AB - An earthquake registering 6.9 on the Richter scale hit the northern part of the Armenian Republic of the Soviet Union on 7 December 1988, resulting in thousands of deaths and injuries. The majority of these resulted from the collapse of inadequately designed and constructed buildings. Analysis of the effects of the Armenian earthquake on the population, as well as of the rescue and medical response, has strong implications for earthquake preparedness and response in other seismically vulnerable parts of the world. Specifically, this paper will recommend a number of important endeavours deemed necessary to improve medical planning, preparedness and response to earthquakes. Strengthening the self reliance of the community in disaster preparedness is suggested as the best way to improve the effectiveness of relief operations. In earthquake-prone areas, training and education in basic first aid and methods of rescue should be an integral part of any community preparedness programme. PMID- 20958683 TI - Rapid post-disaster community needs assessment: a case study of guatemala after the civil strife of 1979-1983. AB - Disaster assessment and assistance activities are often hampered by organizational problems which diminish the effect of these efforts on the people they are intended to help. Inefficient targeting of relief causes reduced coverage of needy populations and inflated costs. In order to ensure that the most needy populations receive appropriate types and amounts of assistance, collection of assessment data must be at the lowest possible administrative unit. In addition, it is essential that disaster assessment be a dynamic process in which follow-up activities monitor possible changes in vulnerability and need in the targeted populations. This paper presents a method for post-disaster rapid needs assessment at the community level. Indigenous numerators are used to collect data with which communities are served and ranked according to need. Qualitative and quantitative methods are incorporated to provide rapidly a centralised database with which relief organizations can accurately target specific communities for assistance. PMID- 20958684 TI - Coping with riverbank erosion hazard and displacement in bangladesh: survival strategies and adjustments. AB - As a deltaic plain, Bangladesh annually experiences riverbank erosion hazard due to sudden and rapid channel shifting, particularly in the major floodplain areas of the country. Consequently, valuable cultivable land is lost; also village settlements, markets and towns are destroyed, displacing tens of thousands of people. This paper examines the magnitude of river channel migration and encroachment on land, and the nature of human adjustment systems in the Brahmaputra-Jamuna floodplain, by investigating aspects of the social and cultural dynamics of resettlement of the displaced people. Some policy measures are recommended to improve the ability of the people in the floodplain to cope with these hazards. PMID- 20958685 TI - Effects of floods on the use and condition of pit latrines in rural bangladesh. AB - The severe floods of 1987 in Bangladesh had devastating effects on many development activities. Here, the use and condition of improved sanitation facilities (double pit water sealed latrines) during the 1987 peak flood period are presented. Two surveys on the use and condition of the latrines were carried out in May (pre-flood) and September (post-flood) 1987 in a rural area 60 km north of Dhaka, with a population of about 4500. General usage of the latrines by the population aged five years or more decreased from 88% to 78% (p < 0.001) after the flood. Only 40% of the 343 latrines which were in use and had no damaged component at the time of the pre-flood survey still had no damaged components after the floods. Fencing was the component which suffered the most damage. It was the only component which was installed and maintained by the users, project staff being responsible for all other components. The estimated post-flood repair cost was approximately US $4.0 per latrine. Development of an affordable and durable fencing is recommended. PMID- 20958686 TI - Determining the future policies for disaster management in the southwest pacific. AB - There are still deficiencies in the delivery of disaster aid and the overall policies need further re-examination. This paper looks at the particular circumstances of the island nations of the Southwest Pacific. In their context, dependence on outside help for counter-disaster management is recognised, but in the light of the present economic, social, cultural and political characteristics of these countries, it is concluded that aid donors should shift the emphasis of their activities to the promotion of a greater self-help approach in the individual countries, as against the provision of emergency material aid from outside. The extent to which this policy could be adopted depends on the local resource base. Rather than relying mainly on emergency ad hoc aid delivery following each disaster, it is considered that donors would improve the disaster response through the previous provision of advice, training and funds. This would facilitate the growth and development of internal counter-disaster organizatons, and assist countries to make their own decisions on the timing and nature of the aid required. Such a policy could also meet concerns that arise about external interference. PMID- 20958687 TI - Displacements and reconstruction: the case of west beirut - Lebanon. AB - This paper focusses on the housing conditions of the displaced people who were forced to move to West Beirut due to the conflict in Lebanon which started in 1975. With the lack of any emergency housing provision, people have adopted two ways to shelter their families; either by occupying vacant buildings or by squatting on unused land (land squatting). The study is based on fieldwork undertaken in order to gain a deeper insight into the displaced people's housing conditions. The results of the survey analysis are believed to be common to other displaced people, as has been verified by comparison with the available information in newspaper reports, unpublished documents, and other accounts. The paper concludes with a reconstruction strategy, composed of two policies. First, a short-term policy which deals with the urgent needs of the people in the place of refuge. Thus mitigation and risk reduction are the aims of this policy. Second, a long-term policy which concentrates on future housing reconstruction; in which economic development, social integration and cultural identity are the basic features. PMID- 20958688 TI - Squatters' nightmare: the political economy of disasters and disaster response in zambia. AB - Despite the frequency with which disasters occur, very few if any third world countries have developed elaborate disaster mitigation networks. Most commonly, governments in these countries focus their attention on disaster relief rather than disaster mitigation and preparedness. It is the contention of this paper that apart from the political and economic instability which will result from government apathy, lack of sensitivity to the question of disasters and disaster preparedness will result in untold suffering for the millions of our people who live on the urban margins and who are the most exposed to the dangers of disasters. This paper is about disasters and disaster response in Zambia. PMID- 20958689 TI - The international decade for natural disaster reduction: background and objectives. PMID- 20958690 TI - Post-disaster housing reconstruction and social inequality: a challenge to policy and practice. AB - In post-disaster reconstruction the social aspects of housing provision are important for the success of both emergency shelters and permanent housing, particularly in settlements that have been permanently relocated or entirety rebuilt. The social dimensions of housing reconstruction after disaster are discussed in the context of the long-term effects of reconstruction after the Yungay, Peru Earthquake-Avalanche of 1970. Consideration of these issues presents questions regarding the tension between continuity and change in affected populations, the importance of pre-disaster socio-economic patterns for reconstruction and the criteria used for assessing the success of post-disaster reconstruction and development projects. The author contends that post-disaster housing reconstruction must avoid rebuilding structures which reflect, sustain and reproduce patterns of inequality and exploitation. PMID- 20958691 TI - The uses of satellite technology in disaster management. AB - Various kinds of Satellites, including communications, meteorology, remote sensing and geophysics satellites, are, or may become, useful tools in disaster prevention, preparedness and relief. They already provide operational capability for storm warnings and search-and-rescue efforts. Other capabilities, such as improved flood prediction and global mobile communications during relief, are close within reach. Still others, such as earthquake prediction, require considerable research. Close cooperation and communication between space technologists and disaster-management specialists will be needed in guiding research and designing and testing satellite systems. It is hoped that the International Decade for Natural Disaster Reduction can provide a framework for such activities. PMID- 20958692 TI - The role of the media in hazard mitigation and disaster management. AB - The International Decade for Natural Disaster Reduction, which began in January 1990, will embrace efforts to reduce death, injury and property losses stemming from rapid-onset natural disasters. Our expanding science and technology base makes possible this concerted cooperative international effort, and communications is a central part of that effort - for public education, early warning, evacuation and coordination of post-disaster relief. Mass communication is inextricably entwined with disasters and hazard mitigation. Reflecting the public's great interest and concern, the electronic and print media extensively cover natural disasters and significantly affect how and what the public learns about and how it perceives natural hazards. Improving the linkages between the media and disaster-mitigation researchers and practitioners could prepare the public to act promptly on warnings, helping to mitigate disasters. This could also accelerate the shift of the societal emphasis from post-disaster relief toward pre-disaster initiatives. PMID- 20958693 TI - The yellow Fever epidemic in Western mali, september-november 1987: why did epidemiological surveillance fail? AB - Recent yellow fever epidemics in West Africa have underlined the discrepancy between the official number of cases and deaths and those estimated by a retrospective epidemiological investigation. During the yellow fever epidemic that broke out in western Mali in September 1987, a total of 305 cases and 145 deaths were officially notified, but estimates revealed true figures abut five times higher. This paper attempts to discuss the factors that hindered early case detection and more complete reporting. They were, first, the insufficient training on the clinical diagnosis, the blood sampling method for laboratory confirmation, and the curative treatment of patients (resulting in low utilization of services); second, the lack of an action plan to prepare in advance a quick response to the epidemic, affecting reporting procedures at the peripheral level and active case-finding during the outbreak; and third, the lack of laboratory facilities for a quick confirmation of the disease. The difficulties experienced during the yellow fever epidemic in Mali demonstrated the importance of a preparedness strategy for epidemic control, based on an integrated approach of epidemiological surveillance within basic health service activities. The need for regional collaboration and for institutionalized funds in the donor community that could be mobilized for epidemic preparedness activities is also emphasized. PMID- 20958694 TI - Towards the evaluation of natural resource management projects in the sahel. AB - Recent drought in the Sahel has focussed attention on the important role played by natural resources in the rural economy and, together with the increasing environmental awareness of donors, has spawned a series of field projects aimed at improving the management of existing natural resources. This paper is a working document; a contribution to the discussion of how to evaluate the success or failure of natural resource management projects and of whether important components of successful projects can be replicated elsewhere. PMID- 20958695 TI - Putting people first again: non-governmental organisations and the 'new orthodoxy' for development. PMID- 20958696 TI - The Spitak (Armenia, USSR) Earthquake: Residential Building Typology and Seismic Behaviour. AB - The 1988 earthquake in Armenia was the most serious seismic disaster since the 1976 earthquake in Tangshan, China. At least 25,000 people lost their lives in a tremor of moderate magnitude and the USSR suffered a loss of more than 2.5 per cent of 1988's GDP. Research at the Martin Centre on the effects of earthquakes on human lives has shown an increase in global earthquake mortality rate, despite the well known improvements in some countries. The Armenian disaster was a warning to all of us concerned with natural or man-made disasters. Areas of potential high hazard are pointed out for the sub-Caucasian region. Construction practices similar to those in Armenia are certainly found in many other parts of the world, with some regional variations, and the fast assimilation of the lessons is an important target. The structural characteristics of all the residential building types existing in the affected area are presented in terms of their seismic vulnerability. Vulnerable points are discussed with a view to low cost interventions that will drastically improve the seismic safety of new buildings. PMID- 20958697 TI - Pastoral and environmental security in East Africa. AB - The most vulnerable people in Third World countries are often accused of destroying forests and fragile ecosystems and of practising destructive forms of agriculture and animal husbandry. The key to environmental sustainability, however, lies in more reliable production and food security at the local level. This article focuses on individual and household security amongst dryland herders in East Africa. The most crucial aspect of pastoral viability is the maintenance of a balance between family herd and size of household. Risk-spreading, through dependence on relatives, the borrowing of animals, redistribution through marriage etc. is a general principle of social behaviour amongst these peoples. Consideration of local-level security, furthermore, reveals the connection between ecological stress and political conflict. Only by establishing secure access to food for individuals and families can sustainable development and political security, not only at the local but also at the national and international levels, be achieved. PMID- 20958698 TI - Ecological stress and political coercion in the Sudan. AB - This article outlines the impact of state intervention on ecological relations in the Sudan. The establishment of large-scale mechanised agricultural schemes; population and livestock concentration around water sources; and the evolution of large urban centres with high demands for firewood and charcoal have all contributed to ecological degradation. These effects have been coupled with the use of coercive measures to displace traditional farmers and pastoralists from their lands in favour of large-scale farming schemes. The objectives of government policy have suffered a double retreat - from development to crisis management and from crisis management to the bare maintenance of compliance and order. The inability of the state to intervene on behalf of the victims of drought and famine has led to the use of coercion as the only means to legitimise its hold on power. PMID- 20958699 TI - Desertification, refugees and regional conflict in west Africa. AB - This article documents the potential for inter-state conflict in the migration of hundreds of thousands of famine refugees across international borders in West Africa. Nigeria and Ghana, for example, have to deal not only with the effects of land degradation in their northern territories but also with the influx of famine victims from Mali, Niger, Chad and Burkino Faso. These migrations put an enormous extra burden on the fragile and already overstretched social and economic infrastructures of the host countries. The construction of dams for irrigation and electricity generation in international river basins, is another cause of inter-state conflict related to land degradation. The capacity of West African states to find peaceful solutions to these problems is being undermined by the increasing impoverishment and marginalisation of their populations. A self serving neo-colonialist governing elite is caught in the economic stranglehold of the advanced capitalist nations. While there is thus no short term solution to the problem of land degradation, immediate steps should at least be taken to give legal protection to those who are forced to cross international borders because of drought and famine. PMID- 20958700 TI - Environmental degradation and political constraints in ethiopia. AB - The article begins by outlining the extent and origins of environmental degradation in northern Ethiopia. Soil conservation and related environmental rehabilitation measures adopted by the Ministry of Agriculture, with donor assistance, are outlined and shown to be inadequate to reverse the trend of environmental degradation. Their scope and financing are too limited, there are too few immediate production returns for the peasants, and the conventional 'top down' implementation of the measures means that peasants participate in rehabilitation programmes as paid workers (food-for-work) rather than as responsible landowners. The post-revolutionary government has continued the centralising and state-building policies of its predecessors, substituting the state for feudal lords as the appropriator of peasant production and labour. The wars in Eritrea and Tigray consume the lion's share of the state's resources and development programmes have become increasingly extractive (procurement of grain at low prices, labour campaigns, etc.) and penetrative (relocation of population, collectivisation of agriculture, etc). The problem of land degradation is ultimately a political one: how to find a political formula within which efficient development administration can be combined with power sharing and cultural pluralism. PMID- 20958701 TI - From emergency to social security in Sudan - part I: the problem. AB - This is the first part of a two-part article which stresses the need to move away from short term emergency measures to a more general system of social security. A weakness in much of the thinking on food security in Sudan is its conception of a normally self-provisioning peasantry which is pushed into distress only as a consequence of exceptional external conditions. Food catastrophes are therefore seen as, essentially, temporary phenomena requiring emergency interventions. This article proposes a different view: that the commercial development of Sudan has engendered a crisis of subsistence synonymous with the collapse of indigenous support systems, the spread of absolute poverty and the erosion of the country's resource base. In the North this situation has come about through economic means and in the South through war. The spread of absolute poverty and the resulting vicious struggle for scarce resources cannot, however, be separated from the decay in governance. Part I of the article attempts to establish the interconnections between these elements and thereby to indicate the problems which a system of social security would have to overcome. Part II will examine the institutional consequences of the crisis, namely the imposition of a donor led system of social security. PMID- 20958702 TI - Monitoring and responding to famine: lessons from the 1984 - 85 food crisis in kenya. AB - The geographic and temporal scale of institutional responses to food crises suggests three levels of food information or famine early warning system: a seasonal national food balance, baseline data on household food poverty and estimates of vulnerability to climatic and economic variations, and targeted interventions based on individual entitlements and food deprivation. Stimulating the demand for food information, beyond the need to forecast famines, is a crucial factor in the adoption of improved monitoring systems. Issues in the design of food information systems are illustrated by the experience in Kenya in 1984-85. The government of Kenya responded to the 1984 drought and ensuing food crisis to prevent widespread famine, largely through timely commercial imports of yellow maize. Although qualified by the nature of the drought and Kenya's economic development, this success story emphasises the need to improve food information systems. PMID- 20958703 TI - Redefining decision: implications for managing risk and uncertainty. AB - The standard risk analysis paradigm is one of choice among alternative actions, each with a defined list of possible outcomes which can be compared on a probability-weighted cost basis. The practice of extending this model into circumstances in which the possible outcomes are ill-defined (but potentially disastrous), their relative probabilities are defined only subjectively, and the parties concerned have conflicting objectives, is dangerously flawed. An alternative paradigm is proposed which models consequential decisions as a process of building commitment to a course of action, including commitment to manage its (unknown) consequences. An important criterion here is unmanageability: the extent to which a particular course of action may rapidly generate severe, indeterminately adverse consequences, not manageable with existing resources and technology. This approach appears able to provide new and better decision tools in disaster-vulnerable areas such as response to climatic change and regulation of potentially catastrophic technology. PMID- 20958704 TI - The vulnerability of small island States to sea level rise: the need for holistic strategies. AB - There is uncertainty about climate change and its socioenvironmental implications, but the vulnerability of small island states to hazardous events is likely to become increasingly significant. It will not be a normally benign sea that rises but the incidence of storms and cyclones can be assumed to increase with tropical sea-surface temperatures. The proportional socioeconomic impact of tropical cyclone disasters makes these of crucial significance to small islands and small island states. Sea-defences are of little use (and may not be feasible at all) against the damage caused by tropical cyclones and some sea-surges. Social and economic adjustments are also required to parallel erosion control; and disaster preparedness "longstops" must be further developed as a matter of urgency. Apparently small measures must not be displaced by images of ultimate, massive catastrophe; adjustments may serve other functions in society as well. International and bilateral measures are required to take account of migration and"ecological refugees" and national administrations may require modification to take appropriate account of this most crucial of environmental phenomena. PMID- 20958705 TI - The parameters of refugeeism and flight: the case of laos. AB - The circumstances of the flight of four ethnic groups from Laos are described and cornpared. It is found that different ethnic groups defined the fall of the Laotian government in 1975 differently. This affected why, how and when they fled. It is stressed that any explanation of refugee behavior must be in terms not only of individual motivation but also of group behavior. Conclusions are drawn about the role that social networks, sanctuary opportunities, perceptions of family unity, class, clanship, patron-client relationships and traditions of mobility can play in making the decision to flee. PMID- 20958706 TI - A pattern of disasters and victims. AB - Two three-dimensional conceptual models are presented that should help those concerned with disasters and disaster victims to integrate the numerous studies on the topic. The first, concerning disasters, involves matters ecological, technological and social scientific. It covers the elements earth, air, fire, water/liquid, and people. It includes the time dimensions of preparedness, response, recovery and mitigation. The second introduces a six-fold classification of victims, together with dimensions to cover the methods and kinds of delivery of different interventions that might be made available to help them. The suggestion is that, were the appropriately noted victim model placed within the larger disaster model according to the types of disaster study being examined, there might be useful academic, political, and professional implications. PMID- 20958707 TI - Planning for chemical disasters in Greece. AB - A mathematical model named DISASTER was applied in the Thessaloniki area for the assessment of potential hazards resulting from major accidents in local chemical industries. Some of these hazards are too severe to ignore and immediate measures are therefore required. Such measures need to comply with the EEC Directive 82/501/EEC on major accidents. The implementation of the Directive by the Greek authorities is examined and discussed. PMID- 20958708 TI - Social and Ecological Aspects of Resettlement and Villagization among the Konso of Southwestern Ethiopia. AB - TEKLEMARIAM AYELE(2) This is a study of the changing settlement and land use patterns of the Konso in three peasant associations in southwestern Ethiopia and an evaluation of their attitudes toward government-sponsored villagization in the lowlands. Over the years, the Konso have moved spontaneously from the overpopulated highlands toward lower elevations and have recently begun to cultivate on the Yanda plain, but without settling there. Fear of tropical diseases, armed conflict with pastoralists and the Konso perception of lowland living continue to be powerful deterrents to settlement in the lowlands. Major objectives of the government villagization programme are unlikely to be achieved in the Konso area and may instead lead to disaster unless this programme is drastically revised to provide suitable conditions for resettlement and to meet the specific needs of the population. PMID- 20958709 TI - From Emergency to Social Security in Sudan - Part II: The Donor Response. AB - In the first part of this article I examined the crisis of subsistence in Sudan resulting from the commercial development of the North and the war in the South. An attempt was also made to relate the deepening impoverishment that this represents to a decay in governance. There is a tendency amongst donor and government officials, which is reflected in the literature, to regard the unfolding crisis as the transitory result of exceptional circumstances rather than as irreversible and therefore warranting a major revaluation of policy. As a consequence, social security and emergency planning has generally been of an emergency type. In this, the final part of the article, I examine the donor response in more detail. In particular, I argue that the decay of governance is so extensive that a donor-led system of social security has been imposed on Sudan. This system has a number of characteristics, the most important of which is that it exists in the absence of the political renewal and democratisation that would be necessary for the technical solutions it advocates to be implemented. The result is that donor-led security, which is typical of the Horn of Africa, proceeds in a relation of antagonism to the sovereign power, a situation which significantly reduces the efficiency of the measures undertaken. PMID- 20958710 TI - The politics of AIDS and condoms for stable heterosexual relations in Africa: recent evidence from the local print media. AB - Although there has been considerable attention to increasing mortality rates and economic problems in areas of Africa hardest hit by AIDS, in this paper I examine the epidemic's impact on stable heterosexual relations. By identifying salient cultural themes pertaining to marriage and fertility, I examine people's emerging responses to policy injunctions to use condoms and limit their sexual partners. I draw policy conclusions for the fate of children whose mothers die from AIDS, threats to female education in the wake of the AIDS epidemic and the likelihood of condom acceptance. PMID- 20958711 TI - Successes and failures in post-disaster resettlement. AB - In this article I examine the problem of the resettlement of populations after disaster. After considering the complexity of the resettlement process in general and the reasons resettlement is often chosen by authorities following disaster, I discuss a theoretical perspective from development project resettlement which may have relevance for disaster research. This is followed by an examination of those factors in post-disaster resettlement projects which have proved important in affecting successful or unsuccessful outcomes. Site, layout, housing and popular input are presented as crucial issues in the determination of success or failure in post-disaster resettlement. Case material from Turkey, Iran and Peru is presented to illustrate how failure to attend to these issues produces unsuccessful resettlement villages. Case material from Turkey is used to illustrate how attention to these factors improves chances of success in resettlement. Material from cases of voluntary, spontaneous post-disaster resettlement in Guatemala is also presented to underscore the importance of popular participation for successful resettlement despite insufficiencies in design and material inputs. The article ends with a brief consideration of resistance to resettlement and alternative policies. PMID- 20958712 TI - Shelter, housing and recovery: a comparison of u.s. Disasters. AB - In this paper we examine the issues associated with the temporary sheltering and housing of victims after natural disasters in the United States. Specific topics addressed include differential access to shelter and housing aid according to social class, ethnicity and related demographic factors; the relationship between post-disaster shelter and housing and long-term recovery; the role of social support networks in the sheltering of victims; and the implications of the research for the provision of shelter and housing aid after disasters. PMID- 20958713 TI - Famine, impoverishment and the creation of a labor reserve in central Tanzania. AB - An often under-recognized response to drought by members of pastoral and mixed farming communities in Africa is semi-regular migration in search of wage employment. Among the Gogo of the Dodoma and Singida Regions of central Tanzania this strategy has increasingly, since the 1940s, been the response of individuals to a cycle of drought, loss of livestock, and impoverishment. Before World War II hardly any people left Ugogo for wage labor; by 1955 20 per cent of the population was estimated to be absent at any particular time, with the proportion rising sharply during years of drought. Today, local stereotypes depict the Wagogo as beggars and casual laborers throughout Tanzania. The transitional period between 1942 and 1955 was marked by four major famines in which thousands of people died of malnutrition and associated diseases. These famines also marked a dramatic change in the distribution of livestock ownership as wealthy cattle owners no longer used livestock to control the labor of food deficit households and individuals found themselves forced into migrant labor. Colonial policy during and after the war helped precipitate these changes through labor conscription and the demand for labor from the Groundnut Scheme in the Kongwa area of the region. PMID- 20958714 TI - Reducing vulnerability to drought and famine: developmental approaches to relief. AB - In this paper we present salient lessons learned through the International Relief/Development Project about the relationships between disasters and development. We discuss approaches to famine response and prevention, including the impact of global food distribution efforts on the capacities of people affected by famine and offer criteria for planning famine relief so that it will promote systemic, long term development of these capacities. We first describe a collaborative research project which showed that it is possible for international famine assistance either to promote the capacities of people who suffer from famine so that they are better able to handle future food crises, or to leave those it purports to help worse off and even more vulnerable to subsequent disasters. We then illustrate alternative strategies for promoting development in the midst of crisis by presenting information about a number of famine response programs and analyzing their impact on capacities and vulnerabilities. PMID- 20958715 TI - "Droughts have Different Tails": Response to Crises in Mukogodo Division, North Central Kenya, 1950s-1980s. AB - In this essay I discuss the response to crises of Maasai speaking pastoralists in Mukogodo Division, North Central Kenya. I begin with the reminder that the Maasai term currently translated as "drought", olamei, refers primarily to any situation of want of which meteorological drought is only one possible cause. It is therefore preferable to speak of crises, rather than of "droughts". 1 then review the crises which have affected Mukogodo pastoralism since the turn of the century in a wider socioeconomic and political perspective. I then show how the crises of 1981 and 1984 have led to a process of stratification, which locks the poorer half of the population into an unviable and residual "labour reserve pastoralism" with declining chances of recovery. PMID- 20958716 TI - Chaos, order and world view: tibetan refugees in Switzerland. AB - This article is about culturally specific responses to extreme events. The concept of social chaos and some criteria for distinguishing this concept are discussed. Social chaos refers to an extreme situation in which neither the rules of normal behaviour nor those for coping with unexpected problems apply. It is suggested that the concept of world view may be an asset in the study of social chaos. The case of Tibetan refugees in Switzerland is presented to show how the ability of a society to survive a disaster is related to the specific outlook on the world shared by members of that society. Finally, it is asked whether it would be possible to account for a society's response to disasters, on the basis of socio-cultural factors. PMID- 20958717 TI - The displaced poor and resettlement policies in bangladesh. AB - Bangladesh is a land of natural disasters. Every year the country is affected by flood, riverbank erosion, drought, coastal cyclone and tornado. Riverbank erosion alone displaces an estimated one million people annually. Based on research carried out in Bangladesh in 1984-85, this paper critically examines resettlement options of the displaced poor in the light of existing policies for developing more effective short and long-term resettlement and development strategies. PMID- 20958718 TI - Mobility due to natural disaster: theoretical considerations and preliminary analyses. AB - Relatively little of the work on natural disasters has focused on people who do not return to their pre-disaster homes. This study uses Annual Housing Survey data from 1974 through 1981 to examine moving households who attribute their moves to a natural disaster. The focus is on three issues: the characteristics of the movers and their recovery; a comparison with other involuntary movers (i.e., public and private displacees); and the amount of innovating or conserving behavior shown by different groups of movers and the impact of these behaviors on each group's recovery after the move. The paper compares disaster movers to all movers and to other forced movers. Distinct differences between the groups in their characteristics and housing recovery exist. The paper concludes with suggestions for continued analysis and policy implications. PMID- 20958719 TI - War famine and flight in Sudan I introduction. PMID- 20958720 TI - II Murahaleen Raids on the Dinka, 1985-89. AB - Successive Sudanese governments have used proxy forces, so-called militias, as an integral part of their war with the rebel Sudan People's Liberation Army (SPLA). The Rizeiqat and Misseriya of South Darfur and South Kordofan created armed bands, known as Murahaleen, in order to raid cattle from the Dinka to their south. Massive raids have depopulated swathes of territory south of the Bahr al Arab, killing tens of thousands of people and leading to the destruction and displacement of unknown numbers of others. Famine in western Sudan fuelled the early raids, but the scale of the devastation wrought from 1985 onwards was the result of government complicity and assistance. More recently, since the coming to power of the current military government in Khartoum in June 1989, the relationship between the army and the Murahleen has been formalized through the creation of Popular Defence Forces. PMID- 20958721 TI - III A Disaster for Whom?: Local Interests and International Donors During Famine Among the Dinka of Sudan. AB - The 1985-88 famine amongst the Dinka is described and shown to have been rooted in the long term exploitation of the south by northern Sudanese and international interests. This process of exploitation served, and continues to serve, important functions for particular groups. Some of the ways in which the 1985-88 famine was functional - for the central government, the army and merchants - are outlined and the implications for relief operations considered. It is argued that international donors had considerable "room for manoeuvre" which they could have used to adopt more effective policies. They only did so after the worst of the mortality was over. PMID- 20958722 TI - IV War Through the Eyes of the Dispossessed: Three Stories of Survival. PMID- 20958723 TI - Correspondence. PMID- 20958724 TI - Natural disasters: a framework for research and teaching. AB - Natural disasters are defined in this paper by relating the impact of extreme geophysical events to patterns of human vulnerability. Hazard perception is shown to be a factor that limits the mitigation of risk. The historical development of disaster studies is traced and five different schools of thought are identified. The current International Decade for Natural Disaster Reduction (IDNDR) is evaluated critically with regard to its potential for unifying the disparate strands of knowledge and its scope as a vehicle for education. A pedagogical framework for disaster studies is presented. Time and space provide valuable unifying factors, while the subject matter can be differentiated according to the continua and dichotomies that it presents. In disaster studies as in other branches of higher education, an ecocentric approach is preferable to a technocentric one, as many of the poorer nations of the world, which are most afflicted by natural catastrophe, will have to rely for mitigation on maintaining their ecological sustainability, instead of depending on sophisticated technology. Valuable insights into the impact of environmental extremes on mankind are gained from the study of disasters as human ecology. PMID- 20958725 TI - The risks from flooding: which risks and whose perception? AB - Four main groups are considered in relation to the risk from flooding: the engineers involved in the design of flood alleviation schemes, emergency planners, the public, including both the population at risk from flooding and the rest of the population who will bear all or most of the cost of flood alleviation schemes and the researchers, such as geographers and economists concerned with flood hazards and scheme appraisal. It is argued that these different groups vary significantly in their selection and definition of risks from flooding as a focus of concern and that their definition of risk influences their expectations about future events and the appropriate response to those events. But the different groups share two tendencies: the expectation that the future will be a replication of the past; and the neglect of "uncertain uncertainties" in favour of known uncertainties of risk. PMID- 20958726 TI - Effective Communication between the Scientific Community and the Media. AB - There are many accounts of hazard warnings which, although received by the target population, have not been appropriately understood and/or acted upon. In all such cases, what needs to be explored is a social relational failure rather than a technological one. Although the relationship between the mass media and the general public has been thoroughly explored, that between the media and the scientific community has been generally neglected. Scientists who communicate warning information to the media must recognise the background, commitments, values, needs and expectations of those they communicate with. Their efforts should be directed at conveying information in a way which is useful to the target population and, at the same time, which appeals to the media. Various "communication strategies" for the achievement of this goal are outlined. PMID- 20958727 TI - The structure of regional conflict in northern ethiopia. AB - A conventional view of regional conflict in Ethiopia is that it is the result of the domination and exploitation of conquered peoples by the central Ethiopian state. The pattern of regional conflict does not, however, fit this explanation. The most important threat to the central government today comes not from the recently conquered pastoral and sedentary peoples of southern Ethiopia but from the northern highlands (Eritrea, Tigray, northern Wollo and Gonder) which have been associated with the Ethiopian state for many centuries. A more satisfactory explanation needs to take into account both the political and economic bases of revolt in northern Ethiopia following the 1974 revolution. Politically, the people were alienated from a national government of which they had previously often been a dominant part. Economically, the progressive marginalisation and agricultural degradation of the northern highlands was accelerated by the policies of the post-1974 government, policies which brought immediate and important benefits to the southern regions. PMID- 20958728 TI - Warfare, vulnerability and survival: a case from southwestern ethiopia. AB - The Mursi are a small group of herders and cultivators living in the Lower Omo Valley of southwestern Ethiopia. Over the past 20 years they have suffered a disaster of classic proportions, involving drought, famine, migration and war. Measures taken to ensure the physical survival of people, and especially cattle, in the face of regular and expected attacks by their neighbours have made the economy of the Mursi more vulnerable to climatic uncertainty. A crude materialist explanation of warfare is not, therefore, supported by this case but it is clear also that warfare has played a key part in Mursi expansion northwards, over the past century, into the territory of the Bodi. Warfare, in this context, is a means of establishing and maintaining the separate political identities of neighbouring groups. The problem of survival does not present itself to the Mursi and their neighbours as a choice between political and physical survival: the only way they know of saving lives is to save their way of life. PMID- 20958729 TI - Correspondence. PMID- 20958730 TI - British disaster planning and management: an initial assessment. AB - The unprecedented series of damaging events experienced by Britain since the early 1980s has focussed attention on the country's arrangements for disaster prevention, planning and management. Until very recently the focus had been on planning for wartime emergencies, with events of the kind responsible for the current anxiety receiving much less attention. This is now changing and, following a wide ranging review, the government has appointed a Civil Emergencies Advisor to assist the national effort. The paper reviews these changes and makes an initial assessment of British disaster planning and management. This is not done at the operational level; rather it proceeds in terms of key issues emerging from the literature and the government review: organisational structure; information flow; national policy or guidelines; and learning from disasters. PMID- 20958731 TI - Disaster study of war. AB - In the first part of this article I argue that war should be considered as a disaster. A brief historical review of the relationship of the field of disaster studies to military concerns is presented in an effort to demonstrate that, in fact, war has been a familiar subject in the field. I then consider definitions of disaster and conclude that war is easily accommodated by them. In the main section of the article I attempt to uncover distinctive characteristics of war by submitting war to analysis within well known sociological frameworks for disasters. Finally, some methodological considerations for the study of war disasters are presented. PMID- 20958732 TI - Computer Simulation as a Means of Dialogue between Local Committees and Relief Agencies: A Case from Southern Sudan. AB - Computer simulations, using modest equipment - a portable computer with a familiar spreadsheet programme - can facilitate dialogue between local committees and relief agencies in the management of disasters. An example is given from the southern Sudan in which the outcomes of different relief strategies, some urged by the donors, were simulated. This helped the local committee to defend difficult choices and the donors to realise that the decision-making autonomy of the affected community should be respected. PMID- 20958733 TI - The impact of local elites on disaster preparedness planning: the location of flood shelters in northern bangladesh. AB - Disaster relief and preparedness organisations are concerned with allocating scarce resources in unstable environments, such as those prone to flooding and river erosion. The need to understand the role of powerful elites in such disaster prone environments is illustrated through an analysis of the actual location decisions and biases involved in siting four flood shelters in four communities in northern Bangladesh. The previously unrecognised implications of the location biases for employment, shelter, access and the utilisation of the flood shelter by the powerless people in the target group demonstrate the need for disaster organisations to include an analysis of the local power structure in project preparation and appraisal. PMID- 20958734 TI - The contribution of the relief and development institute to the evolution of the agenda on famine and emergency relief. PMID- 20958735 TI - Disaster relief or relief disaster? A challenge to the international community*. PMID- 20958736 TI - The impact of drought on production, consumption and nutrition in southwestern kenya. AB - In this paper I compare the effects of the 1984 drought on agricultural production, income, food consumption, and nutrition of farm and non-farm households in South Nyanza District, Kenya. Survey work covered the period 1984 to 1987. It was the late arrival of the long rains in spring 1984, rather than an absolute shortfall in rain, that caused most of the fluctuations in agricultural production. Agricultural households who were least affected by the drought were able to cope by increasing the amount of cultivated land and by relying more on coarse grain production. Coping strategies for the landless households in South Nyanza were more limited and this group of households therefore experienced greater fluctuations in income between the drought and non-drought periods than did most types of agricultural households. Surprisingly, changes in food consumption between the drought and non-drought periods were small for most households. In spite of differences in production, food availability and incomes, however, the health and nutritional status of pre-school-aged children was not significantly different in the two time periods. Differences in health and nutritional status appear to be influenced more by community-level health and sanitation factors than by differences in agricultural production and incomes in drought and non-drought years. PMID- 20958737 TI - The resilience of households to famine in el fasher, Sudan, 1982-89. AB - This paper examines issues related to famine resilience and describes the results of a survey of households who migrated from famine affected rural communities in Northern Darfur to the provincial capital, El Fasher, in western Sudan. It reveals that asset wealth did not enhance household resilience to famine; rather, the data indicate that households who reportedly practiced more numerous survival strategies before migrating to El Fasher were on the whole able to stay longer in their villages before migrating. The data also suggest that some households might have been better able to endure the deteriorating rural conditions by participating in intra-communal practices of sharing resources. An additional issue influencing the timing of migration to El Fasher is previous familiarity with the economic opportunities in the provincial capital. PMID- 20958738 TI - Mortality and morbidity in refugee camps in eastern Sudan: 1985-90. AB - Civil war has disrupted life in Ethiopia since the 1960s and many people have sought refuge in Eastern Sudan, particularly during the famine emergency of 1984 85. UNHCR has provided the main financial support for the refugee programme, but began scaling down operations in 1990. Nearly 300,000 refugees still live in camps and benefit from food and health programmes. Health services are co ordinated by the Sudanese Refugee Health Unit which operates a centralised health and nutrition surveillance system with the co-operation of the NGOs responsible for health care in the camps. A revision of the monthly reporting system and the establishment of a computer database in 1990 provided an opportunity to review the situation in the camps over the five years since the emergency. Child death rates for example, appear to have been reduced to levels below those expected in rural Africa. Patterns of mortality, morbidity, and nutritional status are outlined here and point to the general effectiveness of the health care programme. The surveillance system can, however, be used to identify those camps which have persistent problems, while monthly comparisons with the situation in previous years can provide early warning of deteriorating conditions. PMID- 20958739 TI - A comparison of health provision and status in ban napho refugee cAMP and nakhon phanom province, northeastern Thailand. AB - Health care provision and health status in Ban Napho Refugee Camp is compared with that of the surrounding Nakhon Phanom Province for the year 1988. Records for the period 1984-88 were also examined to compare trends in health status. Personal experience of health services in the Camp and visits made to local schools and health facilities were also used in the comparison. Although direct comparison was difficult (because of the mobile nature of the camp population and problems to do with the interpretation of statistics), it was found that health care for refugees was more comprehensive, at a primary level, than for the Thai population of the surrounding Province. Access to primary health care facilities in the Camp was, moreover, easier and free of charge. This may explain the higher use of health facilities in the Camp but, despite this, health and nutritional status appeared to be worse in the Camp than in the Province. Possible reasons for the difference in reported health status and the use of facilities are discussed. PMID- 20958740 TI - Rapid Nutrition Surveys: How Many Clusters are Enough? AB - On the basis of theoretical considerations, population-based nutrition surveys of 30 clusters of 30 children should provide reasonably valid estimates of the prevalence of malnutrition with at least 95 per cent confidence that the estimated prevalence differs from the true value by no more than 5 per cent. In areas of famine in Africa, where an urgent need often exists for rapid nutritional assessment to determine the extent and severity of the problem, visiting 30 sites is often logistically difficult. To determine the effects of using fewer than 30 clusters on the validity and precision of the estimated level of undernutrition, we used data from the 1983 Swaziland National Nutrition Survey and from rapid nutrition surveys performed in 1984 and 1985 in Burkina Faso, Guinea, and Niger. Fewer than 30 clusters may result in point prevalence estimates that differ dramatically from the true prevalence and, in most instances, are less precise. In contrast, little is gained by collecting more than 30 clusters. In summary, around 30 clusters provides relatively valid and precise estimates of the prevalence of undernutrition, and every effort should be made to obtain the logistic support required to study this number of clusters. PMID- 20958741 TI - Variations in disaster evacuation behavior: public responses versus private sector executive decision-making processes. AB - Data obtained from 65 executives working for tourism firms in three sample communities permitted comparison with the public warning response literature regarding three topics: disaster evacuation planning, initial warning responses, and disaster evacuation behavior. Disaster evacuation planning was reported by nearly all of these business executives, although it was highly variable in content, completeness, and formality. Managerial responses to post-disaster warnings paralleled the type of complex social processes that have been documented within the public response literature, except that warning sources and confirmation behavior were significantly affected by contact with authorities. Five key areas of difference were discovered in disaster evacuation behavior pertaining to: influence of planning, firm versus family priorities, shelter selection, looting concerns, and media contacts. PMID- 20958742 TI - Drought and development in marsabit district, kenya. AB - Extensive drought in the 1970s and 1980s prompted national and international development efforts aimed at the pastoralist populations of Marsabit District of Kenya. Famine relief efforts by the Catholic Church and the African Inland Mission contributed to the settling of former nomads and the growth of small towns, while international development efforts, including UNESCO's Integrated Project in Arid Lands (IPAL) focused on range conservation and the improvement of livestock marketing. The sedentarization of pastoralists has led to greater access to health care, education, and other social services, but has also contributed to economic differentiation and rural proletarianization. Local economies are now based on a combination of subsistence pastoralism, livestock marketing, and wage-labor, indicating that the process of sedentarization is a complex one with varying consequences for different sectors of the population. PMID- 20958743 TI - Should pastoralism continue as a way of life? AB - Pastoralism is unpopular with most African governments. It is widely regarded as environmentally destructive and even economically irrational. Yet most of the popular allegations against pastoralism are unfounded. In most of the areas in which it is practiced it is the only way to survive in marginal, semi-arid environments, and the majority of pastoralists have a deep respect and knowledge of their environment. The tragedy of pastoralism today derives from a misunderstanding of the position and motivation of pastoralists who, often in extreme circumstances, are trying to come to terms with a rapidly changing political, economic and natural environment. The only sensible pastoral development strategy in this context is to provide a facilitating environment for pastoralists, where they can be supported in the particular range of activities which they know best. Any more traditional, prescriptive 'range management' approach is likely to fail. PMID- 20958744 TI - Is famine a discrete event? PMID- 20958745 TI - Composite indicators for famine early warning systems. AB - Traditional famine early warning systems use a host of indicators to predict food crisis situations, from rainfall and increased rate of marketing of household durables to the behavior of birds and animals. Although many of these indicators are valid in general, limited understanding of the sensitivity and specificity of the distress signals makes food crisis prediction a highly subjective exercise. In order to make the system more effective and credible, we need to identify a limited number of 'composite' indicators, which naturally summarize most relevant food-related information contained in the specific predictors of food crisis. Considering the chronology of the food production and consumption chain, three composite indicators specific to three different stages of the chain have been identified. The satellite data based Normalized Deviation of Vegetative Index (NDVI), prices of major food grains, and malnutrition rates are found to be correlated not only with the quality and quantity of inputs of this process but also with the final outcome. Both NDVI and price data are widely used as important predictors of food crisis by famine warning systems. What we have demonstrated is that improved sensitivity of the indicators is likely to be due to their inherent capability of summarizing information from various specific measures. Child malnutrition rates also summarize inputs and outputs of the food consumption process very effectively, and therefore should be able to predict community level food crisis in an efficient manner. The empirical results confirm this conjecture by showing that malnutrition rates can predict food crisis probability three months into the future with a high degree of specificity. The use of 'composite' indicators not only simplifies the problem of aggregation, but is also likely to yield forecasts that are highly specific and sensitive. PMID- 20958746 TI - Pests and donors in mali, 1985-90. AB - Between 1985 and 1988 large-scale spray campaigns were carried out against migratory crop pests in the Sahel. The Malian government and its donors subsequently adopted this emergency response to a natural disaster as a long-term strategy for crop protection in Sahelian Mali. This is financially unsustainable, probably economically wasteful and stunts the development of other plant protection strategies. A similar process has occurred in Burkina Faso, Niger and Senegal. Donors should therefore exercise critical, collective control over the release of pesticide aid and should subject it to economic evaluation. PMID- 20958747 TI - Vulnerability to tropical cyclones: evidence from the april 1991 cyclone in coastal bangladesh. AB - In this article we report the results of a survey conducted in two coastal communities of Bangladesh less than two weeks after they were hit by the severe cyclone of April 29, 1991. It was found that almost all of the surveyed heads of households had received early warnings of the cyclone. Nevertheless, a majority of the respondents did not leave their homes to seek shelter. The two most common reasons given for this passive reaction were (i) fear of burglary and (ii) disbelief of the warnings. Thus, it appears that the existing system of early warnings is not having its intended effect and that it, and related disaster mitigation policies, need to be revised. Some suggestions are made as to what could be done. PMID- 20958748 TI - Livelihood patterns of displaced households in greater khartoum. AB - Members of impoverished households in Greater Khartoum, who have been displaced from their homelands by famine and civil war, gain a livelihood by utilising a wide variety of subsistence activities and sources. These include moonlighting, income diversification and pooling, exchange relations, scavenging, relief supplies from aid agencies and remittances from relatives working in other areas. This finding challenges the widely held view of the displaced as dependent and parasitic on the wider urban community. Several public policies are identified which have a detrimental effect on the livelihood of the displaced. PMID- 20958749 TI - The effects of flooding on residential property values in three new zealand communities. AB - Research on the effects of natural events on property values has focused primarily on experiences in the United States and has shown that these impacts must be evaluated in the context of both the hydrologic regime and local urban economic situations. It remains unclear if these relationships exist with different flood regimes and under different institutional arrangements. The research reported here analyzes the impacts of flooding on property values in Paeroa, Te Aroha, and Thames, New Zealand. The results indicate different experiences in the three communities, but suggest several common trends. Each community has distinct housing submarkets that exhibit different housing value characteristics, independent of hazardousness, which may either mask or exaggerate flood-related impacts. In addition, initial local impacts of events vary, but eventually differences in flooded and non-flooded properties decrease. Thus, at least over the long term, hazardousness is not a factor in housing value differentials. PMID- 20958750 TI - Food as an instrument of war in contemporary african famines: a review of the evidence. AB - Famine is conventionally portrayed as a natural disaster expressed in terms of food scarcity and culminating in starvation. This view has attracted criticism in recent years as the political, legal and social dimensions of famine have become more clearly understood. This paper draws upon these criticisms to understand the particular conditions of famine creation in conflict situations. Following an examination of six contemporary African famines, it is suggested that the use of food as a weapon of war by omission, commission and provision has contributed to the creation of famine in recent decades. Despite the optimism for peace engendered by the demise of the Cold War, the momentum for conflict would seem to be sustained by internal factors, including economic and environmental decline, political instability and ethnic rivalry. Within these conflicts, the strategic importance of food is likely to remain central. This study highlights the need to link concerns with food security and public health to those of development, human rights and international relations. PMID- 20958751 TI - Entitlements, coping mechanisms and indicators of access to food: wollo region, ethiopia, 1987-88. AB - Vulnerability to famine and traditional responses to food insecurity in Wollo Region, Ethiopia are described. The timeliness of anthropometric and socio economic indicators of access to food is then assessed, using data collected in Wollo by Save the Children Fund during 1987-88, a period of drought and subsequent food insecurity. The movements of different indicators are then examined for evidence of correspondence at sub-district level. The author concludes that although anthropometric status does not respond as early as crop yield or grain price, a deterioration in anthropometric status is detectable at a stage when livestock and migration indicators show little or no change and mortality rate remains unaffected. At sub-district level, changes in different indicators are not well-correlated. PMID- 20958752 TI - Childhood Immunisation in Rural Afghanistan: The EPI Programme, 1987-91. AB - A decade of outright war followed by civil strife and conflict has hindered the development of health care services for the population of rural Afghanistan. Despite the absence of a functional health care system and the fragmentation of the Afghan resistance, and despite widely held views to the contrary, it has proved possible to set up a technically valid and politically acceptable Expanded Programme of Immunisation (EPI). This paper discusses some of its technical and programmatic aspects and the rationale behind some of the very unusual choices made - such as the use of DPTP, the inclusion of girls 3-14 years old for TT immunisation, a vertical programme structure and a predominance of mobile and outreach strategies. The paper argues against the mindless use of global or handbook recipes. The keys to success have been strategic vision, intimate knowledge of the local context and pragmatic choices for options that are simple and effective. PMID- 20958753 TI - Deaths in natural hazards in the solomon islands. AB - Archival and library search techniques have been used to establish extensive databases on deaths and damage resulting from natural hazards in the Solomon Islands. Although the records of fatalities are certainly incomplete, volcanic eruptions, tropical cyclones, landslides, tsunami and earthquakes appear to have been the most important. Only 22 per cent of the recorded deaths have resulted from meteorological hazards but a single event could change this proportion significantly. Five events in the fatality database account for 88 per cent of the recorded deaths. Future death tolls are also likely to be dominated by a small number of events. While the expected number of deaths in a given period is dependent upon the length of record considered, it is clear that a disaster which kills one hundred or more people in the Solomons can be expected more frequently than once in a hundred years. PMID- 20958754 TI - Evacuation mapping: the utility of guidelines. AB - Maps provided to the public for preventive and protective evacuations should be an integral part of emergency plans. The map design criteria contained in the United States Federal Emergency Management Agency (FEMA) guidelines for nuclear power plants were examined and compared with the content and design of evacuation maps found in the public information publications of thirteen United States nuclear power plants. Results indicated that the graphic and descriptive content of these maps varied considerably. Four characteristics related chiefly to the FEMA guidelines capture some of the findings from this study: 1) failure to comply with Nuclear Regulatory Commission (NRQ/FEMA suggestions; 2) failure to comply with FEMA guidelines for map elements; 3) weaknesses present in the FEMA guidelines themselves; and 4) significant omissions in those guidelines. PMID- 20958755 TI - Economic effects of riverbank erosion: some evidence from bangladesh. AB - In this paper I investigate some of the economic effects of riverbank erosion in Bangladesh. The study was conducted in one village over the period 1979-89. Between these dates the village lost almost 20 per cent of its farmland to riverbank erosion. This resulted in a loss of more than 50 per cent of crop income (at 1989 prices). About 45 per cent of households were affected during the period. It appears, however, that there is little understanding among the relevant government agencies and non-governmental organisations of the severity of riverbank erosion in Bangladesh. This article aims to provide, therefore, some basic information on the various economic effects of this natural hazard. PMID- 20958756 TI - Coping with drought and food insecurity in ethiopia. AB - In this article I examine the impact of drought on farm households in Ethiopia and their response to crisis conditions. I ask whether every household in a community is equally affected by drought and what households do to mitigate the effects of drought and associated food insecurity. Information on production, income and food consumption is disaggregated by agroecological zone (highland and lowland), and by socioeconomic strata (relatively wealthy versus poor). Such detailed analysis permits an improved understanding of why the poor are much more vulnerable than the wealthy to drought and associated famines and why they need to be more effectively targeted by relief and development interventions. In a world of limited public resources for crisis intervention, such understanding is crucial to the design of improved policies and projects for reaching people most at risk. PMID- 20958757 TI - Operational value of anthropometric surveillance in famine early warning and relief: wollo region, ethiopia, 1987-88. AB - In this article I examine the operational implications of the findings reported in 'Entitlements, Coping Mechanisms and Indicators of Access to Food: Wollo Region, Ethiopia, 1987-88' (Kelly, 1992). The usefulness of anthropometric and other indicators for early warning and relief planning in Wollo is assessed by comparing the findings of Save the Children Fund's nutritional surveillance programme with those of the Early Warning and Planning Service of the Ethiopian government's Relief and Rehabilitation Commission. Case studies are used to illustrate the value of anthropometric and other indicators for targeting relief food and monitoring its effects. The costs of monitoring various indicators are then considered, and the cost of the Save the Children Fund programme is compared with that of other programmes. It is argued that in Wollo, anthropometric surveillance is a cost-effective means of improving early warning, planning, targeting and monitoring. PMID- 20958758 TI - Health response to a large and rapid influx of Albanian refugees in southern Italy, 1991. AB - Over a two-day period in March 1991, more than 23,000 Albanian refugees arrived without warning in the southern Italian port of Brindisi. A simple surveillance system was established within days of their arrival to monitor health problems that were expected to have a high frequency, were of concern to the Italian health care system because of potential spread to the local population, and were susceptible to therapeutic or preventive measures. The most commonly encountered health problems were pediculosis and scabies. Despite poor sanitary conditions, only one outbreak of gastrointestinal disease was reported. Obstetric events were common, and many resulted in adverse outcomes. Hospitalization rates were high, although in the early weeks of the emergency, many were unwarranted. This experience demonstrates the value of a simple, rapid surveillance system in prioritizing health problems and preventing rumors. In future, greater emphasis should be placed on outpatient management of simple medical problems. PMID- 20958759 TI - A computer assisted exercise in classifying nutritional status: a new tool for learning. PMID- 20958760 TI - Recovery after disaster: achieving sustainable development, mitigation and equity. AB - This paper reviews key findings and raises issues that are not fully addressed by the predominant disaster recovery literature. Achievement of equity, mitigation and sustainable development, particularly through local participation in redevelopment planning and institutional cooperation, is the central issue of the review. Previous research and past assumptions about the process by which communities rebuild after a disaster are reviewed. A conceptual model for understanding local disaster recovery efforts is then presented. The conceptual and practical significance of this model is then demonstrated by presenting case studies of local recovery experiences. Finally, conclusions on the current understanding of disaster redevelopment planning, as well as implications for public policy and future research are offered. PMID- 20958761 TI - Infant feeding in emergencies. AB - Recent experience of emergency relief operations in middle-income countries has shown that infant feeding issues can greatly complicate attempts to protect infant health. The two main problems are: how to protect and support breastfeeding in communities where it is no longer the norm and how to assist artificially fed infants without exposing them to the dramatically increased risks associated with artificial feeding under disaster conditions. This article explores the underlying issues and makes a number of recommendations for policy and programmes. PMID- 20958762 TI - New policy directions in disaster preparedness and response in ethiopia. AB - Following the fall of the government of Mengistu Haile Mariam in May 1991, the Transitional Government of Ethiopia has initiated new policy directions in relation to national disaster preparedness and response. Drawing on the lessons learnt from more than a decade's experience of famine and famine relief work in the north of the country, policies are emerging from the reconstituted Relief and Rehabilitation Commission that represent a new agenda for the conduct of assistance programs. These changes have important implications for the relationship between the Transitional Government, international aid organizations and local communities. PMID- 20958763 TI - Women at risk: gender and AIDS in Africa. AB - AIDS in Africa is a gender, development and rights issue involving power and differential access to resources. The risk situations for women in stressed development contexts of war, destabilisation and displacement, and the many contexts of transactional sex, are poorly understood by policy makers and the medical community. The dominant epidemiological paradigm has focused on female 'prostitutes' in a number of African cities. The limitations of this approach are discussed, as are the different contextualised meanings of sexual exchange. The importance of women's experience of sexually transmitted diseases and HIV and their perceptions of risk are stressed, as is the need for non-judgmental services linked to primary and comprehensive health care, and for sensitive, qualitative research. It is argued that all women who engage in unprotected penetrative sex are at risk. Most health promotion messages, however, construct an image of women as prostitutes ('Avoid prostitutes') or seek to mobilise women as carers and educators of families and communities. PMID- 20958764 TI - Health Effects of the 1991 Bangladesh Cyclone: Report of a UNICEF Evaluation Team. AB - To assess the impact on health of the cyclone and tidal wave that struck the southern coast of Bangladesh on the evening of 29 April 1991, a team of health professionals visited cyclone affected areas from 4-27 June, 1991. Team members met with health workers and officials of the Government of Bangladesh and with staff pom nongovernmental organizations, and conducted field surveys in two severely affected areas. Mortality among the 135 households surveyed (pre-cyclone population 1,123) was 14 per cent. At highest risk of deaths were children of less than 10 years (26 per cent mortality) and women of more than 40 (31 per cent mortality). Almost all deaths occurred as a result of drowning from the tidal wave that accompanied the cyclone. Although 95 per cent of the population surveyed had received warning of the cyclone four or more hours before it struck, the 300 existing cyclone shelters had capacity for only 450,000 of the 5,000,000 people affected by the cyclone. Deaths following the cyclone were few. Diarrhea caused by Vibrio cholerae and Shigella dysenteria type 1, both of which are endemic in Bangladesh, occurred in the post-cyclone period. Reports by the national Diarrhea Surveillance System of large increases in diarrheal incidence following the cyclone were difficult to assess because of inconsistencies in pre and post-cyclone reporting methods. No increase in other infectious diseases was identified. Although water availability had been a major concern following the cyclone, the tubewell system was functioning well in the area that was surveyed. Distribution of relief assistance by the Government of Bangladesh and by non governmental organizations was good, with 95 per cent of families surveyed receiving food aid within five days of the cyclone. The major health effect of this cyclone was acute deaths due to drowning. Preventing deaths during future cyclones will require increasing accessible shelter. PMID- 20958765 TI - Health effects of the 1991 bangladesh cyclone: a comment. PMID- 20958766 TI - Post disaster relief: the supply -management challenge. PMID- 20958767 TI - Recent trends in the international relief system. AB - Since 1991 the international relief system has been undergoing a process of rapid and fundamental change associated with the end of the Cold War period. The principal changes concern (i) the international community's approach to national sovereignty and the 'right' of armed intervention in support of humanitarian objectives, and (ii) organisatwnal changes aimed at improving the coordination and effectiveness of the response by donor organisations and the United Nations. This paper describes these changes and attempts to place them in the context of earlier trends within the international relief system, notably the enhanced role of non-governmental organisations, which occurred during the 1980s. PMID- 20958768 TI - Repatriation of 150,000 sudanese refugees from ethiopia: the manipulation of civilians in a situation of civil conflict. AB - This paper outlines the dramatic return to Sudan of 150,000 men, women and children from Itang Refugee Camp in Ethiopia in June 1991. These people were pawns in Sudan's civil war, manipulated by governments, military forces and the media - a state of affairs that the international community failed to deal with effectively. At the time of the return to Sudan, ICRC and the United Nations were working to assist the returnees in two different areas and each had a different access agreement and thus a different impact on the survival of the returnees. The paper focuses on the role of political awareness and negotiation in the protection of refugees and in the organisation of relief in the context of a civil war. PMID- 20958769 TI - Famine, gold and guns: the suri of southwestern ethiopia, 1985-91. AB - Over the past few years, the Suri have lived through a deep ecological and social crisis without substantial external aid from either the Ethiopian government or international aid agencies. They have experienced drought, cattle disease and an increasing level of violent conflict with their neighbours, leading to the severe disruption of their traditional agro-pastoral subsistence system and settlement pattern. Through migration, the exploitation of gold resources and investment in automatic weapons, however, they have managed virtually a full recovery of their economy and society. PMID- 20958770 TI - The 1992 'cairo earthquake': cause, effect and response. AB - This paper examines the geological and socio-political setting of the 1992 earthquake in northern Egypt. The main conclusions concern the importance of surface geology in controlling the nature of the earthquake impact, and the role of poor construction and maintenance standards (and lapses in building regulation enforcement) in influencing the vulnerability of buildings to failure. The heaviest human losses were associated with two main types of construction: firstly the old, dilapidated adobe houses of the poor in rural areas and in Cairo's inner city slums, and secondly certain modern, engineered (in some cases illegally) high-rise concrete constructions inhabited by the wealthy. The paper concludes by analysing the immediate response of the government and some non governmental organisations in Egypt to the earthquake. Politicisation of the event is linked to broader issues of economic and social reform in the country and to the rise of Islamic Fundamentalist activity in all its forms. PMID- 20958771 TI - An exposure-response method for assessing the long term health effects of the bhopal gas disaster. AB - Approximately 200,000 persons were exposed to methyl isocyanate in the Bhopal Gas leak in Bhopal, India. 4037 deaths have resulted and 30 per cent of the population are estimated to be suffering from long-term health effects. Though inflammatory damage to the eyes and lungs is the main cause of morbidity, other systems are also reported to be affected. For a disaster of this magnitude, there is a relative paucity of medical information. Very little information has been published on the late recovery period, a phase in which the detection of chronic and long-term effects is vital. Early cross-sectional studies suffer from a number of defects in study design, including validity and precision of exposure and outcome variables, selection of study and control groups, etc. By using exposure concentrations derived from Singh's analytic dispersion model, this paper outlines a strategy for doing community epidemiology in Bhopal using exposure strata for sampling. Pulmonary dose can be estimated from exposure concentration, duration and activity during exposure. For respiratory end-points, a sample size of 100/stratum will ensure study power of 90 per cent. Using multiple linear regression, data from the study can be used to build a model for prediction of lung function parameters. Exposure-stratified sampling techniques may provide valid estimates of exposure-response without including the total exposed community. PMID- 20958772 TI - The bangladesh cyclone of 1991: why so many people died. AB - Living with natural disasters has become a way of life in Bangladesh. On the night of 29 April 1991 a severe cyclonic storm, accompanied by tidal surges up to 30 feet high, battered the coastal areas of Bangladesh for 3-4 hours. Thousands of people were killed and property worth billions of dollars was destroyed. After the cyclone, several studies, using epidemiological and anthropological methods, looked at the impact of the cyclone. It was estimated that over 67,000 people lost their lives. Women, children and the elderly were much more at risk and so were those from the socio-economically disadvantaged section of the population. Cyclone shelters were few in relation to need but proved very helpful in saving lives. At least 20 per cent more deaths would have occurred in the absence of these shelters. The article documents impressive improvements in Bangladesh's ability to cope and makes recommendations for the future. PMID- 20958773 TI - Restocking refugee pastoralists in the horn of Africa. AB - Repeated and lingering famine in the Horn of Africa has produced enormous pastoralist refugee populations in a region where livestock production is a major form of land use. Permanently settling destitute pastoralists has a record of failure. It can disrupt host land-uses, causing social and ecological problems, and prevent the utilization of very large grazing areas where pastoralism may be the only ecologically and economically sustainable land-use. Herd reconstitution should be considered an option in relief and rehabilitation programmes for pastoralists. This paper examines a design where the most proven and immediate way of sustaining stockless pastoralists - farming - can be used to facilitate restocking objectives. Using data gathered in Somalia, estimates of livestock carrying capacity are linked with forage resources, land area, livestock units, and the frequency of good, average, and poor (drought) water years, to explore the possibilities for incorporating restocking into refugee rehabilitation efforts. PMID- 20958774 TI - Environmental influences on the distribution of the incidence of cholera: a case study in quelimane, mozambique. AB - Cholera continues to cause widespread suffering in many parts of the world. Previous research has mainly described modes of transmission and has correctly indicated the role of predisposing socio-economic conditions in affected areas. Little field research has been carried out, however, in endemic zones, on the contribution of physical characteristics in environmental reservoirs which prolong the survival time or increase the toxigeneity of Vibrio cholerae 01, despite substantial indication of their significance at laboratory scale. A study carried out in Quelimane, Mozambique, to test for such environmental influences on the spatial and temporal distribution of cholera incidence, is described. The role of population displacement in this relationship is also discussed. The practical implications of the results for prevention of primary infection and subsequent reinfection are outlined. PMID- 20958777 TI - Editorial. PMID- 20958778 TI - Editorial. PMID- 20958779 TI - Editorial. PMID- 20958780 TI - From Sustainability to Invulnerability Development: Justifications for a clear, Comprehensive and Appropriate Disaster Paradigm. PMID- 20958781 TI - Editorial: beyond seeds and tools: effective support to farmers in emergencies. PMID- 20958783 TI - Editorial: food security, complex emergencies and longer-term programming. PMID- 20958782 TI - The sphere project: the humanitarian charter and minimum standards in disaster response: introduction. PMID- 20958787 TI - Glyceraldehyde-3-phosphate dehydrogenase of the entomopathogenic fungus Metarhizium anisopliae: cell-surface localization and role in host adhesion. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a classic glycolytic enzyme that plays important roles in various cellular processes. Here, we report the sequence and transcriptional analyses of a regulated gene (gpdh1) encoding GAPDH in the entomopathogenic fungus Metarhizium anisopliae, a well-characterized biocontrol agent of a wide range of arthropod pests. Transcript and protein analyses of the gpdh1 showed a carbohydrate-dependent expression pattern in response to different carbon sources. A demonstration that GAPDH is localized at the cell surface is presented, and assays with insect wings show that this protein has adhesion-like activity. These results imply that GAPDH adhesion to the wing surface is specific and may play a role in the binding of conidia to a host. Our observations indicate new roles for GAPDH both physiologically and during the entomopathogen-host interaction. PMID- 20958788 TI - Metabolic stress-induced programmed cell death in Xanthomonas. AB - Xanthomonas campestris pv. glycines (Xcg), an etiological agent of the bacterial pustule disease of soybean, displayed nutritionally regulated caspase-dependent programmed cell death (PCD). Experiments showed that Xcg was under metabolic stress during PCD, as evident from the intracellular accumulation of NADH and ATP. Further, the accumulation of reactive oxygen species (ROS), as confirmed by 2',7'-dichlorofluorescein diacetate labeling, electron spin resonance spectroscopy, and scopoletin assay, was also observed along with the activation of caspase-3. ROS scavengers such as dimethylsulfoxide, glutathione, n-propyl gallate, and catalase significantly inhibited caspase biosynthesis as well as its activity, eventually leading to the inhibition of PCD. The presence of a sublethal concentration of an electron transport chain uncoupler, 2,4 dinitrophenol, was found to reduce the ROS generation and the increase in the cell survival. These results indicated that Xcg cells grown in a protein-rich medium experienced metabolic stress due to electron leakage from the electron transport chain, leading to the generation of ROS and the expression as well as the activation of caspase-3, and resulting in PCD. A bacterial DNA gyrase inhibitor, nalidixic acid, was also found to inhibit PCD. Gyrase, which regulates DNA superhelicity, and consequently DNA replication and cell multiplication, appears to be involved in the process. PMID- 20958789 TI - Ethnic inequity in neonatal survival: a case-referent study in northern Vietnam. AB - AIM: In this study from Quang Ninh province in northern Vietnam (sub-study of the trial Neonatal Health - Knowledge into Practice, NeoKIP, ISRCTN 44599712), we investigated determinants of neonatal mortality through a case-referent design, with special emphasis on socio-economic factors and health system utilization. METHODS: From July 2008 until December 2009, we included 183 neonatal mortality cases and 599 referents and their mothers were interviewed. RESULTS: Ethnicity was the main socio-economic determinant for neonatal mortality (OR 2.08, 95% CI 1.39-3.10, adjusted for mothers' education and household economic status). Health system utilization before and at delivery could partly explain the risk elevation, with an increased risk of neonatal mortality for mothers who did not attend antenatal care and who delivered at home (OR 4.79, 95% CI 2.98-7.71). However, even if mothers of an ethnic minority attended antenatal care or delivered at a health facility, the increased risk for this group was sustained. CONCLUSION: Our study demonstrates inequity in neonatal survival that is related to ethnicity rather than family economy or education level of the mother and highlights the need to include the ethnic dimension in the efforts to reduce neonatal mortality. PMID- 20958790 TI - Pulmonary blood volume in mitral regurgitation in Cavalier King Charles spaniels. AB - BACKGROUND: Pulmonary edema and venous congestion are well-recognized signs of congestive heart failure (CHF) in advanced canine chronic mitral regurgitation (MR). However, little is known about pulmonary blood volume (PBV), blood pulmonary transit time (PTT), and the regulation of these. OBJECTIVES: To measure and evaluate the relationships of PBV, forward stroke volume (FSV), and heart rate normalized blood pulmonary transit time (nPTT) in healthy dogs and dogs with MR. ANIMALS: Thirty-three Cavalier King Charles Spaniels; 11 healthy, 4 in modified New York Heart Association (NYHA) class I, 11 in class II, and 7 in CHF. METHODS: Heart rate normalized PTTs were measured by radionuclide angiocardiography. Left ventricular end diastolic and systolic diameter, left atrial/aortic root ratio, and FSV were measured by echocardiography. PBV and pulmonary blood volume index (PBVI) were calculated by established formulas. RESULTS: PBVI was 308+/-56 (mean+/-SD) mL/m2 for healthy dogs, 287+/-51 mL/m2 in NYHA class I, 360+/-66 mL/m2 in Class II, and 623+/-232 mL/m2 in CHF (P=.0008). Heart rate normalized PTT, not FSV, was a predictor of PBV (r=0.92 and 0.02, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Increased PBV, not decreased FSV, is the main cause of increased nPTT in MR. Increased nPTT can be used as an indicator of abnormal cardiopulmonary function in dogs with MR. PMID- 20958791 TI - The effects of deferoxamine mesylate on iron elimination after blood transfusion in neonatal foals. AB - BACKGROUND: Hepatic failure is one of the more common complications in foals requiring blood transfusion to treat neonatal isoerythrolysis. Iron intoxication is likely the cause of hepatic injury. OBJECTIVES: To determine the effects of deferoxamine on iron elimination in normal foals. ANIMALS: Thirteen neonatal foals. METHODS: Randomized-controlled trial. At 1-3 days of age, foals received either 3 L of washed packed dam's red blood cells (RBC) or 3 L of saline IV once. Foals were treated with deferoxamine (1 g) or saline (5 mL) SC twice daily for 14 days. Foals were randomly assigned to 1 of 3 groups: RBC/deferoxamine (deferoxamine), RBC/saline (placebo), or saline/saline (control). Blood and urine samples and liver biopsy specimens were collected for measurement of hematological, biochemical, and iron metabolism variables. RESULTS: There was a significant (P<.05) increase in hematocrit, RBC count, and hemoglobin in the groups transfused with packed RBC as compared with controls at all times. Biochemical variables and liver biopsy scores were not significantly different between groups at any time. Urine iron concentrations and fractional excretion of iron were significantly higher in deferoxamine treated foals. By 14 days after transfusion, liver iron concentrations in foals treated with deferoxamine (79.9+/ 30.9 ppm) were significantly lower than that of foals receiving placebo (145+/ 53.0 ppm) and similar to that of controls (44.8+/-4.09 ppm). CONCLUSIONS AND CLINICAL IMPORTANCE: Deferoxamine enhances urinary iron elimination and decreases hepatic iron accumulation after blood transfusion in foals. PMID- 20958792 TI - Clinical outcomes in patients with acute left circumflex/obtuse marginal occlusion presenting with myocardial infarction. AB - BACKGROUND: Acute occlusion of left circumflex (LCx) or obtuse marginal (OM) arteries can present as ST elevation myocardial infarction (STEMI) or non-ST elevation myocardial infarction (NSTEMI). NSTEMI patients (pts) with occlusions have worse outcomes than those without occlusions, but no studies specifically examine outcomes in acute myocardial infarction (AMI) pts with LCx/OM occlusion. This study aims to define the incidence of NSTEMI in pts presenting with LCx/OM occlusion and analyzes clinical characteristics and outcomes in those presenting with NSTEMI compared to STEMI. METHODS AND MATERIALS: A review of our catheterization and STEMI database was performed to identify AMI pts presenting with LCx or OM occlusion from 1/1/2007 to 7/31/2009 at the Medical College of Virginia. Patients were divided into STEMI and NSTEMI groups, and a chart review was performed. Primary end-points were in-hospital mortality (HM), cardiogenic shock (CS), and in-hospital CHF. Secondary end-points included peak CK-MB and time to catheterization, as well as combined end-points of 1-month mortality, and recurrent AMI and CHF. RESULTS: Fifty-six pts met inclusion criteria, 54% of whom presented with NSTEMI. STEMI pts were significantly more likely to meet the primary end-points, as well as the combined secondary end-points. They had shorter times to catheterization but larger infarct sizes. Patients with left or mixed coronary dominance were more likely to have STEMI. CONCLUSIONS: AMI pts with LCx/OM occlusion present with NSTEMI as often as STEMI. Those with NSTEMI have better outcomes, which may be related to right coronary dominance. SUMMARY: Patients with acute LCx or OM occlusion present with NSTEMI as often as STEMI, but those with STEMI have worse outcomes. The difference in presentation may be related to coronary dominance. PMID- 20958793 TI - Worldwide diffusion of FVII Arg304Gln coagulation defect (FVII Padua). AB - FVII Padua is a Type 2 defect owing to an Arg304Gln substitution in exon 8. The defect was originally discovered in an isolated valley in northeastern Italy. Subsequently, it was described in several other countries of the Mediterranean basin and Middle East. Recently, several proven or suspected cases have been described among Afro-Americans in the USA. This study has demonstrated the existence of at least a two-founder effect for this FVII abnormality, Mediterranean countries, and USA Afro-Americans. Patients are usually asymptomatic or only paucisymptomatic. The defect is characterized by low FVII activity when rabbit brain thromboplastins are used in the assay system. On the contrary, FVII levels are normal when ox-brain thromboplastins are used. FVII antigen is always normal. PMID- 20958794 TI - VWF and ADAMTS13 behavior in estradiol-treated HUVEC. AB - OBJECTIVES: In this study, the role of 17beta-estradiol (E2) in the regulation of von Willebrand factor (VWF) and ADAMTS13 synthesis, storage, and secretion was investigated in cultured human umbilical vein endothelial cells (HUVEC). METHODS: HUVEC were grown to 80-90% confluence and replaced with fresh medium containing E2 (1 nm) or vehicle for 24 h, after which the supernatant medium and cell lysates were collected to measure VWF and ADAMTS13. VWF was evaluated by VWF:Ag and multimeric analysis. ADAMTS13 was evaluated by SDS-PAGE. VWF and ADAMTS13 mRNA were quantified by real-time PCR after E2 or vehicle exposure for 18 h. A functional effect of ADAMTS13 on HUVEC VWF protein synthesis was further evaluated using a short hairpin RNA (shRNA) to knockdown the expression of endogenous ADAMTS13. RESULTS: E2 did not increase the release or intracellular VWF levels in HUVEC. However, E2 increased the production of intracellular ADAMTS13, although there was no evidence of significant effects of their release into culture medium. Incubation of HUVEC with E2 resulted in a significantly increased expression of VWF and ADAMTS13 mRNA. ADAMTS13 gene inactivation upregulates release and intracellular VWF levels in E2-treated HUVEC. CONCLUSION: The results demonstrated that E2 may play a role in the regulation of VWF and ADAMTS13 gene expression and in its production in human endothelial cells. The mechanism of the protective effects of E2 on the cardiovascular system could be explained by the intracellular regulation of VWF produced by ADAMTS13. PMID- 20958795 TI - Atomic force microscope imaging of red cell vesiculation. PMID- 20958796 TI - Allograft vasculopathy after allogeneic vascularized knee transplantation. AB - Composite tissue allotransplantation represents a new discipline in reconstructive surgery. Over the past 10 years, we have performed six human vascularized allogeneic knee transplantations. All of these grafts have been lost within the first 56 months. A histomorphologic assessment of the latest case resulted in the detection of diffuse concentric fibrous intimal thickening and occlusion of graft vessels. Findings are comparable with cardiac allograft vasculopathy. The lack of adequate tools for monitoring graft rejection might have allowed multiple untreated episodes of acute rejection, triggering myointimal proliferation and occlusion of graft vessels. Graft vasculopathy represents an obstacle to long-term vascularized bone and joint allograft survival, and adequate tools for monitoring need to be developed. PMID- 20958797 TI - What is simulated in the action observation network when we observe actions? AB - In the last decade there has been a great amount of research investigating the role of simulation in our ability to infer the underlying intentions of any observed action. The majority of studies have focussed on the role of mirror neurons and the network of cortical areas active during action observation (AON) in inferring the goal of an observed action. However, it remains unclear what precisely is simulated when we observe an action and how such simulations can enable the observer to infer the underlying intention of that action. In particular it is not known how simulation in the AON enables the inference of the same goal when the kinematics observed to achieve that goal differ, such as when reaching to grasp an object with the left or right hands. Here we performed a behavioural study with healthy human subjects to address this question. We show that the subjects were able to detect very subtle changes in the kinematics of an observed action. In addition, we fitted the behavioural responses with a model based on the predictive coding account of mirror neurons. This is a Bayesian account of action observation that can be explained by the free-energy principle. Here we show that we can model all the effects observed when the action observation system is considered within a predictive coding framework. PMID- 20958798 TI - Microvillous cells expressing IP3 receptor type 3 in the olfactory epithelium of mice. AB - Microvillous cells of the main olfactory epithelium have been described variously as primary olfactory neurons, secondary chemosensory cells or non-sensory cells. Here we generated an IP3R3(tm1(tauGFP)) mouse in which the coding region for a fusion protein of tau and green fluorescent protein replaces the first exon of the Itpr3 gene. We provide immunohistochemical and functional characterization of the cells expressing IP3 receptor type 3 in the olfactory epithelium. These cells bear microvilli at their apex, and we therefore termed them IP3R3 MV cells. The cell body of these IP3R3 MV cells lies in the upper third of the main olfactory epithelium; a long thick basal process projects towards the base of the epithelium without penetrating the basal lamina. Retrograde labeling and unilateral bulbectomy corroborated that these IP3R3 MV cells do not extend axons to the olfactory bulb and therefore are not olfactory sensory neurons. The immunohistochemical features of IP3R3 MV cells varied, suggesting either developmental stages or the existence of subsets of these cells. Thus, for example, subsets of the IP3R3 MV cells make contact with substance P fibers or express the purinergic receptor P2X3. In addition, in recordings of intracellular calcium, these cells respond to ATP and substance P as well as to a variety of odors. The characterization of IP3R3 MV cells as non-neuronal chemoresponsive cells helps to explain the differing descriptions of microvillous cells in the literature. PMID- 20958799 TI - Inositol 1,4,5-trisphosphate signaling maintains the activity of glutamate uptake in Bergmann glia. AB - The maintenance of synaptic functions is essential for neuronal information processing in the adult brain. Astrocytes express glutamate transporters that rapidly remove glutamate from the extracellular space and they play a critical role in the precise operation of glutamatergic transmission. However, how the glutamate clearance function of astrocytes is maintained remains elusive. Here, we describe a maintenance mechanism for the glutamate uptake capacity of Bergmann glial cells (BGs) in the cerebellum. When inositol 1,4,5-trisphosphate (IP(3) ) signaling was chronically and selectively inhibited in BGs in vivo, the retention time of glutamate around parallel fiber-Purkinje cell synapses was increased. Under these conditions, a decrease in the level of the glutamate/aspartate transporter (GLAST) in BGs was observed. The same effects were observed after chronic in vivo inhibition of purinergic P2 receptors in the cerebellar cortex. These results suggest that the IP(3) signaling cascade is involved in regulating GLAST levels in BGs to maintain glutamate clearance in the mature cerebellum. PMID- 20958800 TI - Cytology quiz: 'distorting the truth'--can you figure out the truth? PMID- 20958803 TI - Factors associated with patient and visitor violence experienced by nurses in general hospitals in Switzerland: a cross-sectional survey. AB - AIMS: To explore nurses' experiences with patient and visitor violence, as well as other related factors, in Swiss general hospital settings. BACKGROUND: Patient and visitor violence is a complex occupational hazard among health care professions, with nursing in general, experiencing the highest rate of patient and visitor violence. International research has found that staff and patient attributes, interaction between staff and patients, as well as environmental characteristics are important factors associated with the occurrence of patient and visitor violence. Previous studies, however, have only partially described these factors in the general hospital setting. Mainland European general hospital settings are even less well researched. DESIGN: A retrospective cross-sectional survey was conducted in 2007. METHODS: A total of 291 nurses working in different clinical departments in general hospitals provided data. The questionnaire used was a modified German version of the Survey of Violence Experienced by Staff. RESULTS: The findings revealed that 72% of nurses had experienced verbal patient and visitor violence and 42% physical patient and visitor violence in the past 12 months. Also, 23% were physically injured and 1.4% took one or more days of sick leave. Patient and visitor violence was distressing for the nursing staff. A higher risk for patient and visitor violence was observed with registered nurses nursing anxious or cognitively impaired patients, for rehabilitation units with longer-term nurse-patient/nurse-relative interactions and for workplaces with an absence of formal procedures for patient and visitor violence. CONCLUSIONS: The results indicate that the clinical setting has little impact on the occurrence of patient and visitor violence. Patient and visitor violence appears to be influenced more by the additional factors specific to the type of interaction and situation. Research should follow up on these specific findings to further improve policies, procedures and intervention strategies. RELEVANCE TO CLINICAL PRACTICE: To prevent patient and visitor violence, Swiss general hospitals should take into consideration the risk factors associated with patient and visitor violence. Existing policies, procedures and staff education should be improved on. PMID- 20958804 TI - Fostering real-world clinical mental health research. AB - AIMS AND OBJECTIVES: In this article, we identify key aspects for enhancing real world research in mental health care clinical settings and broadly discuss some practicalities and issues that must be considered beforehand. BACKGROUND: Practice which is evidence-based uses interventions or treatment methods that are supported by research findings for their quality and efficacy. Modern mental health settings endorse evidence-based practice and welcome the development of innovative, evidence-based approaches to care. Often, however, research findings are inaccessible, inconclusive, inconsistent, contradictory and overwhelming in sheer volume. Further, where there is no evidence, the absence of evidence is frequently mistaken for evidence of absence of the effectiveness of services. DESIGN: Discursive paper. METHOD: The main themes expressed in the literature were collated by the authors into themes, and their relevance to the development of real-world clinical mental health research is summarised with the aid of a vignette. CONCLUSIONS: Ideally, research should be part of mainstream activities and as such constitute core business. Staff in mental health services should be encouraged to be research productive, and prospective clinical researchers should consider linking their studies to higher research degree programmes so that they can access resources, support and expertise to sustain motivation and morale. RELEVANCE TO CLINICAL PRACTICE: For research findings to make the leap to evidence-based practice, the research needs to include real-world consumers and families typical of clinical practice supported by clinically relevant outcomes. Clinical and research leaders should create opportunities for academic and clinical nurses to collaborate in research, and researchers should ensure that clinically relevant outcomes are presented in ways that are meaningful and accessible to clinicians. PMID- 20958805 TI - ICU nurses' experiences and perspectives of caring for obstetric patients in intensive care: a qualitative study. AB - AIMS AND OBJECTIVES: The aim of this study was to gain an understanding of the experiences and perspectives of intensive care nurses caring for critically ill obstetric patients. BACKGROUND: Current literature suggests critically ill obstetric patients need specialised, technically appropriate care to meet their specific needs with which many intensive care nurses are unfamiliar. Furthermore, there is little research and evidence to guide the care of this distinct patient group. DESIGN: This study used a descriptive qualitative design. METHODS: Two focus groups were used to collect data from 10 Australian intensive care units nurses in May 2007. Open-ended questions were used to guide the discussion. Latent content analysis was used to analyse the data set. Each interview lasted no longer than 60 minutes and was recorded using audio tape. The full interviews were transcribed prior to in-depth analysis to identify major themes. RESULTS: The themes identified from the focus group interviews were competence with knowledge and skills for managing obstetric patients in the intensive care unit, confidence in caring for obstetric patients admitted to the intensive care unit and acceptance of an expanded scope of practice perceived to include fundamental midwifery knowledge and skills. CONCLUSION: The expressed lack of confidence and competence in meeting the obstetric and support needs of critically ill obstetric women indicates a clear need for greater assistance and education of intensive care nurses. This in turn may encourage critical care nurses to accept an expanded role of clinical practice in caring for critically ill obstetric patients. RELEVANCE TO CLINICAL PRACTICE: Recognition of the issues for nurses in successfully caring for obstetric patients admitted to an adult intensive care setting provides direction for designing education packages, ensuring specific carepaths and guidelines are in place and that support from a multidisciplinary team is available including midwifery staff. PMID- 20958806 TI - Neuropeptide precursor gene discovery in the Chagas disease vector Rhodnius prolixus. AB - We show a straightforward workflow combining homology search in Rhodnius prolixus genome sequence with cloning by rapid amplification of cDNA ends and mass spectrometry. We have identified 32 genes and their transcripts that encode a number of neuropeptide precursors leading to 194 putative peptides. We validated by mass spectrometry 82 of those predicted neuropeptides in the brain of R. prolixus to achieve the first comprehensive genomic, transcriptomic and neuropeptidomic analysis of an insect disease vector. Comparisons of available insect neuropeptide sequences revealed that the R. prolixus genome contains most of the conserved neuropeptides in insects, many of them displaying specific features at the sequence level. Some gene families reported here are identified for the first time in the order Hemiptera, a highly biodiverse group of insects that includes many human, animal and plant disease agents. PMID- 20958807 TI - Profile of the mosaic element BTMR1 in the genome of the bumble bee Bombus terrestris (Hymenoptera: Apidae). AB - Co-evolution involving a mariner transposon, Botmar1 and the other repeats contained in the Bombus terrestris genome was investigated. We found that the 5' region of Botmar1 forms one of the components of a mosaic element, known as B. terrestris mosaic repeat 1 (BTMR1), which is also composed of inner segments originating from two different retrotransposons and a pseudogene corresponding to an RNA methyltransferase cDNA. The fact that BTMR1 is interspersed within chromosomes and the differences in its abundance in different species indicate that it is very probably a mobile element. Nevertheless, the absences of direct or inverted repeats at its ends and of target site duplication indicate that its mobility is not ensured by a cardinal transposable element, but putatively by a Crypton-like element. PMID- 20958808 TI - The RNA-Seq approach to studying the expression of mosquito mitochondrial genes. AB - In this study, we used extensive expressed sequence tag evidence obtained through 454 and Solexa next-generation sequencing to explore mtDNA transcription in male and female first instar larvae of Aedes aegypti and adults of Aedes aegypti, Anopheles gambiae, and Anopheles quadrimaculatus. Relative abundances of individual transcripts differed considerably within each sample, consistent with the differential stability of messenger RNA species. Large differences were also observed between species and between larval and adult stages; however, the male and female larval samples were remarkably similar. Quantitative PCR analysis of selected genes, cox1, l-rRNA and nd5, in larvae and adults of Ae. aegypti and in An. gambiae adults was consistent with the RNA-Seq-based quantification of expression. Finally, the absence of a conserved mtDNA region involved in transcriptional control in other dipterans suggests that mosquitoes have evolved a distinct mechanism of regulation of gene expression in the mitochondrion. PMID- 20958809 TI - Navigating the unknown: model selection in phylogeography. Models of population structure: tools for thinkers. AB - Despite the widespread use and obvious strengths of model-based methods for phylogeographic study, a persistent concern for such analyses is related to the definition of the model itself. The study by Peter et al. (2010) in this issue of Molecular Ecology demonstrates an approach for overcoming such hurdles. The authors were motivated by a deceptively simple goal; they sought to infer whether a population has remained at a low and stable size or has undergone a decline, and certainly there is no shortage of software packages for such a task (e.g., see list of programs in Excoffier & Heckel 2006). However, each of these software packages makes basic assumptions about the underling population (e.g., is the population subdivided or panmictic); these assumptions are explicit to any model based approach but can bias parameter estimates and produce misleading inferences if the model does not approximate the actual demographic history in a reasonable manner. Rather than guessing which model might be best for analyzing the data (microsatellite data from samples of chimpanzees), Peter et al. (2010) quantify the relative fit of competing models for estimating the population genetic parameters of interest. Complemented by a revealing simulation study, the authors highlight the peril inherent to model-based inferences that lack a statistical evaluation of the fit of a model to the data, while also demonstrating an approach for model selection with broad applicability to phylogeographic analysis. PMID- 20958810 TI - Gradual speciation in a global hotspot of plant diversity. AB - The speciation process that underlies recent, rapid radiations of plants is controversial, and suggested mechanisms range from pollinator or ecological niche differentiation to allopatry and nonadaptive divergence. Phylogenetic approaches to locating the most appropriate speciation models have been constrained by the low levels of molecular divergence between recently diverged species, which are typical of recent, rapid radiations. In this issue of Molecular Ecology, Rymer et al. (2010) used coalescence analyses of sequence data and genome scans of Amplified Fragment Length Polymorphism (AFLP) loci to demonstrate that in a species complex in the irid genus Gladiolus, a member of the hyper diverse Cape flora of southern Africa, speciation is a gradual process. Older divergences are genetically more differentiated, and show a greater difference in flowering time and floral morphology, than taxa that diverged more recently. There is no evidence of any abrupt events. Gene flow is limited by shifts in flowering time and floral morphology; thus, by pre-zygotic rather than by post-zygotic mechanisms, these evolved together with the occupation of somewhat different habitats. This research gives the first critical insight into how the remarkable diversity in a diversity hotspot could have arisen. More importantly, it demonstrates that the speciation process in recent, rapid radiations is tractable and can be investigated with suitable genetic tools. PMID- 20958811 TI - Bayesian statistical treatment of the fluorescence of AFLP bands leads to accurate genetic structure inference. AB - Ever since the introduction of allozymes in the 1960s, evolutionary biologists and ecologists have continued to search for more powerful molecular markers to estimate important parameters such as effective population size and migration rates and to make inferences about the demographic history of populations, the relationships between individuals and the genetic architecture of phenotypic variation (Bensch & Akesson 2005; Bonin et al. 2007). Choosing a marker requires a thorough consideration of the trade-offs associated with the different techniques and the type of data obtained from them. Some markers can be very informative but require substantial amounts of start-up time (e.g. microsatellites), while others require very little time but are much less polymorphic. Amplified fragment length polymorphism (AFLP) is a firmly established molecular marker technique that falls in this latter category. AFLPs are widely distributed throughout the genome and can be used on organisms for which there is no a priori sequence information (Meudt & Clarke 2007). These properties together with their moderate cost and short start-up time have made them the method of choice for many molecular ecology studies of wild species (Bensch & Akesson 2005). However, they have a major disadvantage, they are dominant. This represents a very important limitation because many statistical genetics methods appropriate for molecular ecology studies require the use of codominant markers. In this issue, Foll et al. (2010) present an innovative hierarchical Bayesian method that overcomes this limitation. The proposed approach represents a comprehensive statistical treatment of the fluorescence of AFLP bands and leads to accurate inferences about the genetic structure of natural populations. Besides allowing a quasi-codominant treatment of AFLPs, this new method also solves the difficult problems posed by subjectivity in the scoring of AFLP bands. PMID- 20958813 TI - Range-wide population genetic structure of the European bitterling (Rhodeus amarus) based on microsatellite and mitochondrial DNA analysis. AB - An understanding of recent evolutionary processes is essential for the successful conservation and management of contemporary populations, especially where they concern the introduction or invasion of species outside their natural range. However, the potentially negative implications of intraspecific introductions and invasions have attracted less attention, although they also represent a potential threat to biodiversity, and are commonly facilitated through human activities. The European bitterling (Rhodeus amarus) is a small cyprinid fish that decreased greatly in its distribution during the 1970s and 1980s and was subsequently included on many European conservation lists. This decline appears to have reversed, and the extent of its distribution now exceeds its former range. We used a combination of 12 microsatellite markers and cytochrome b sequences on a large data set (693 individuals) across the current range of the European bitterling to investigate possible scenarios for its colonization of Europe. We show that the inferred history of colonization of Europe was largely congruent between mitochondrial and nuclear markers. The most divergent mtDNA lineages occur in the Aegean region but probably are not reproductively isolated as the Aegean populations also displayed mtDNA haplotypes from other lineages and nuclear data indicated their close relationship to Danubian populations. Much of Europe is currently populated by descendants of two main lineages that came to natural secondary contact in western Europe. An approximate Bayesian computation analysis indicates different dates for admixture events among western and central European populations ranging from the last deglaciation (natural) to the last few centuries (human-assisted translocations). PMID- 20958812 TI - Multiple hybridization events between Drosophila simulans and Drosophila mauritiana are supported by mtDNA introgression. AB - The study of speciation has advanced considerably in the last decades because of the increased application of molecular tools. In particular, the quantification of gene flow between recently diverged species could be addressed. Drosophila simulans and Drosophila mauritiana diverged, probably allopatrically, from a common ancestor approximately 250,000 years ago. However, these species share one mitochondrial DNA (mtDNA) haplotype indicative of a recent episode of introgression. To study the extent of gene flow between these species, we took advantage of a large sample of D. mauritiana and employed a range of different markers, i.e. nuclear and mitochondrial sequences, and microsatellites. This allowed us to detect two new mtDNA haplotypes (MAU3 and MAU4). These haplotypes diverged quite recently from haplotypes of the siII group present in cosmopolitan populations of D. simulans. The mean divergence time of the most diverged haplotype (MAU4) is approximately 127,000 years, which is more than 100,000 years before the assumed speciation time. Interestingly, we also found some evidence for gene flow at the nuclear level because an excess of putatively neutral loci shows significantly reduced differentiation between D. simulans and D. mauritiana. Our results suggest that these species are exchanging genes more frequently than previously thought. PMID- 20958814 TI - The invasion route for an insect pest species: the tobacco aphid in the New World. AB - Biological invasions are rapid evolutionary events in which populations are usually subject to a founder event during introduction followed by rapid adaptation to the new environment. Molecular tools and Bayesian approaches have shown their utility in exploring different evolutionary scenarios regarding the invasion routes of introduced species. We examined the situation for the tobacco aphid, Myzus persicae nicotianae, a recently introduced aphid species in Chile. Using seven microsatellite loci and approximate Bayesian computation, we studied populations of the tobacco aphid sampled from several American and European countries, identifying the most likely source populations and tracking the route of introduction to Chile. Our population genetic data are consistent with available historical information, pointing to an introduction route of the tobacco aphid from Europe and/or from other putative populations (e.g. Asia) with subsequent introduction through North America to South America. Evidence of multiple introductions to North America from different genetic pools, with successive loss of genetic diversity from Europe towards North America and a strong bottleneck during the southward introduction to South America, was also found. Additionally, we examined the special case of a widespread multilocus genotype that was found in all American countries examined. This case provides further evidence for the existence of highly successful genotypes or 'superclones' in asexually reproducing organisms. PMID- 20958815 TI - Plio-Pleistocene history of West African Sudanian savanna and the phylogeography of the Praomys daltoni complex (Rodentia): the environment/geography/genetic interplay. AB - Rodents of the Praomys daltoni complex are typical inhabitants of the Sudanian savanna ecosystem in western Africa and represent a suitable model for testing the effects of Quaternary climatic oscillations on extant genetic variation patterns. Phylogeographical analyses of mitochondrial DNA sequences (cytochrome b) across the distribution range of the complex revealed several well-defined clades that do not support the division of the clade into the two species currently recognized on the basis of morphology, i.e. P. daltoni (Thomas, 1892) and Praomys derooi (Van der Straeten & Verheyen 1978). The observed genetic structure fits the refuge hypothesis, suggesting that only a small number of populations repeatedly survived in distinct forest-savanna mosaic blocks during the arid phases of the Pleistocene, and then expanded again during moister periods. West African rivers may also have contributed to genetic differentiation, especially by forming barriers after secondary contact of expanding populations. The combination of three types of genetic markers (mtDNA sequences, microsatellite loci, cytogenetic data) provides evidence for the presence of up to three lineages, which most probably represent distinct biological species. Furthermore, incongruence between nuclear and mtDNA markers in some individuals unambiguously points towards a past introgression event. Our results highlight the importance of combining different molecular markers for an accurate interpretation of genetic data. PMID- 20958816 TI - Evidence of extreme habitat stability in a Southeast Asian biodiversity hotspot based on the evolutionary analysis of neotenic net-winged beetles. AB - The diversification of neotenic beetle lineages has not been studied, despite the potential for defining biodiversity hotspots and elucidating the history of regional faunas. Additionally, neotenics may provide insight into the process of speciation in small populations with extremely low dispersal ability and a limited range. Here, we used two rDNA and three mtDNA markers to investigate the phylogeny of Scarelus, a neotenic lineage endemic to Southeast Asian rainforests. Most genetic differentiation was associated with Palaeogene geographical divisions, which remain distinct despite temporary connections. Dispersal events were rare, with only two inferred for Scarelus: from Borneo to the Philippines 28.3 million years ago (Ma) and from Sumatra to Java 13.9 Ma. We suggest that speciation resulted from allopatric range fragmentation, and Scarelus diversified readily when conditions were favourable; in this case, at different times in the eastern (19.3-39.1 Ma) and western (3.5-13.9 Ma) parts of Sundaland. The observed strong phenotypic similarity was preserved under speciation through complete allopatry. Neotenic Lycidae have survived for a long time in very stable habitats, and extremely low dispersal activity has not limited their persistence; however, the long-term diversification rate of neotenics is low and diversification is nonexistent under stable conditions. The modern ranges of neotenic lineages are indicative of ancient rainforest refugia and may be used in biodiversity conservation management. Most neotenics are at risk of extinction because of their small ranges and a low dispersal potential. PMID- 20958817 TI - Surfing the wave on a borrowed board: range expansion and spread of introgressed organellar genomes in the seaweed Fucus ceranoides L. AB - For many taxa, introgression represents an important source of genetic variation, but the specific contexts allowing locally introgressed material to spread and largely replace native allelic lineages throughout a species range remain poorly understood. Recent demographic-genetic simulations of spatial expansions show that the stochastic surfing of alien alleles during range expansions may constitute a general mechanism leading to extensive introgression, but empirical evidence remain scarce and difficult to distinguish from selection. In this study, we report a compelling case of such a phenomenon in the estuarine alga Fucus ceranoides. We re-assessed the phylogenetic relationships among F. ceranoides and its marine congeners F. vesiculosus and F. spiralis using nuclear, mitochondrial and chloroplast sequence data, and conducted a mtDNA phylogeographic survey in F. ceranoides. Our phylogenetic analyses revealed a recent and asymmetric introgression of a single F. vesiculosus cytoplasm into F. ceranoides. The phylogeographic scope of introgression was striking, with native and introgressed mtDNA displaying disjunct distributions south and north of the English Channel. A putative Pleistocene climatic refugium was detected in NW Iberia, and the extensive and exclusive spread of the alien cytoplasm throughout Northern Europe was inferred to have occurred concurrently with the species post glacial, northwards range expansion. This massive spread of a foreign organelle throughout the entire post-glacial recolonization range represents good empirical evidence of an alien cytoplasm surfing the wave of a range expansion and the first description of such a phenomenon in the marine realm. PMID- 20958818 TI - Pollen foraging behaviour of solitary Hawaiian bees revealed through molecular pollen analysis. AB - Obtaining quantitative information concerning pollinator behaviour has become a primary objective of pollination studies, but methodological limitations hinder progress towards this goal. Here, we use molecular genetic methods in an ecological context to demonstrate that endemic Hawaiian Hylaeus bees (Hymenoptera: Colletidae) selectively collect pollen from native plant species in Haleakala and Hawaii Volcanoes National Parks. We identified pollen DNA from the crops (internal storage organs) of 21 Hylaeus specimens stored in ethanol for up to 3 years. Genetic analyses reveal high fidelity in pollen foraging despite the availability of pollen from multiple plant species present at each study site. At high elevations in Haleakala, pollen was available from more than 12 species of flowering plants, but Hawaiian silversword (Argyroxiphium sandwicense subsp. macrocephalum) comprised 86% of all pollen samples removed from bee crops. At lower elevations in both parks, we only detected pukiawe (Leptecophylla (Styphelia) tameiameiae) pollen in Hylaeus crops despite the presence of other plant species in flower during our study. Furthermore, 100% of Hylaeus crops from which we successfully identified pollen contained native plant pollen. The molecular approaches developed in this study provide species-level information about floral visitation of Hawaiian Hylaeus that does not require specialized palynological expertise needed for high-throughput visual pollen identification. Building upon this approach, future studies can thus develop appropriate and customized criteria for assessing mixed pollen loads from a broader range of sources and from other global regions. PMID- 20958819 TI - Refugial persistence and postglacial recolonization of North America by the cold tolerant herbaceous plant Orthilia secunda. AB - Previous phylogeographical and palaeontological studies on the biota of northern North America have revealed a complex scenario of glacial survival in multiple refugia and differing patterns of postglacial recolonization. Many putative refugial regions have been proposed both north and south of the ice sheets for species during the Last Glacial Maximum, but the locations of many of these refugia remain a topic of great debate. In this study, we used a phylogeographical approach to elucidate the refugial and recolonization history of the herbaceous plant species Orthilia secunda in North America, which is found in disjunct areas in the west and east of the continent, most of which were either glaciated or lay close to the limits of the ice sheets. Analysis of 596 bp of the chloroplast trnS-trnG intergenic spacer and five microsatellite loci in 84 populations spanning the species' range in North America suggests that O. secunda persisted through the Last Glacial Maximum (LGM) in western refugia, even though palaeodistribution modelling indicated a suitable climate envelope across the entire south of the continent. The present distribution of the species has resulted from recolonization from refugia north and south of the ice sheets, most likely in Beringia or coastal regions of Alaska and British Columbia, the Washington/Oregon region in the northwest USA, and possibly from the region associated with the putative 'ice-free corridor' between the Laurentide and Cordilleran ice sheets. Our findings also highlight the importance of the Pacific Northwest as an important centre of intraspecific genetic diversity, owing to a combination of refugial persistence in the area and recolonization from other refugia. PMID- 20958820 TI - Extremely high molecular diversity within the East Asian nematode Caenorhabditis sp. 5. AB - Most relatives of the self-fertilizing hermaphroditic nematode model organism Caenorhabditis elegans reproduce via obligate outbreeding between males and females, which also represents the ancestral mode of reproduction within the genus. However, little is known about the scope of genetic diversity and differentiation within such gonochoristic species, especially those found outside of temperate Europe and North America. It is critical to understand the evolutionary processes operating in these species to provide a framework for deciphering the evolution of hermaphroditism and a baseline for the application of outcrossing Caenorhabditis to problems in evolutionary genetics. Here, we investigate for the first time molecular sequence variation for Caenorhabditis sp. 5, a species found commonly in eastern Asia. We identify enormous levels of standing genetic variation that approach the levels observed in the marine broadcast-spawning sea squirt, Ciona savignyi. Although we document significant isolation by distance, we demonstrate that the high polymorphism within C. sp. 5 is not because of strong differentiation among populations or to the presence of cryptic species. These findings illustrate that molecular population genetic approaches to studying obligately outbreeding species of Caenorhabditis will prove powerful in identifying and characterizing functionally and evolutionarily important features of the genome. PMID- 20958821 TI - To sleep, perchance to dream. PMID- 20958822 TI - A new-born with massive abdominal distension. PMID- 20958823 TI - Missing the cue: recognising parents with English as second language. PMID- 20958824 TI - The first case of congenital leishmaniasis in a female infant in Greece. PMID- 20958825 TI - Multiple sclerosis in association with Williams-Beuren syndrome. PMID- 20958827 TI - Ventricular tachycardia in the era of ventricular assist devices. AB - Sustained ventricular tachycardia (VT) in patients with advanced cardiomyopathy is a potentially life-threatening arrhythmia. Newer treatment strategies have evolved that combine the use of catheter ablation to target the substrate for VT and ventricular assist devices (VADs) to hemodynamically support the failing ventricle. This editorial is targeted to the practicing clinician caring for these difficult patients. The current article reviews the use of percutaneous VADs to support catheter ablation of VT, the use of durable VADs to support the failing heart in patients with recurrent VT, ventricular arrhythmias in patients with durable VADs, and the use of catheter ablation to treat VT in patients with durable VADs. PMID- 20958828 TI - Spinal cord stimulation causes potentiation of right vagus nerve effects on atrial chronotropic function and repolarization in canines. AB - INTRODUCTION: Experimental evidence suggests that spinal cord stimulation (SCS) can cause augmentation of parasympathetic influences on the heart via enhanced vagus nerve (VgN) activity. Herein, we investigated whether this might lead to enhanced inducibility of vagally mediated atrial tachyarrhythmias (AT) and whether such actions depend on intact autonomic neural connections with central neurons. METHOD AND RESULTS: Epidural SCS electrodes were implanted at T1-T4 in anesthetized canines. Sinus cycle length prolongation, atrial repolarization changes (191 epicardial electrode sites), and AT inducibility in response to right VgN stimuli applied at the cervical level were determined before and during SCS. VgN-induced sinus cycle length prolongation was potentiated during SCS among the animals with intact neural connections or bilateral vagotomy proximal to the stimulation site, whereas such prolongation was unaffected by SCS among animals with bilateral decentralization of stellate ganglia. Likewise, the atrial surface area in which VgN-induced repolarization wave form changes were identified was significantly augmented during SCS among the former but not among the latter. AT facilitation occurred during SCS in the majority of animals with intact neural connections, particularly among those displaying relatively greater potentiation of vagally mediated sinus cycle length prolongation. CONCLUSION: The data indicate that SCS may cause potentiation of parasympathetic influences on the atria in response to cervical VgN stimulation. Such SCS effects appear to be mediated via decreased tonic inhibitory sympathetic influences in the presence of intact stellate ganglion connections to central neurons. PMID- 20958829 TI - Utility of esophageal temperature monitoring during pulmonary vein isolation for atrial fibrillation using duty-cycled phased radiofrequency ablation. AB - INTRODUCTION: A novel ablation system has been introduced for rapid treatment of atrial fibrillation (AF). This system delivers duty-cycled phased radiofrequency (RF) energy via an over-the-wire catheter (PVAC(r) , Medtronic) to achieve pulmonary vein (PV) isolation. Lower power and depth control suggests that collateral damage might be minimized. However, no studies have investigated the potential for thermal effect and damage to the esophagus. METHODS AND RESULTS: Ninety consecutive patients undergoing PV-isolation were evaluated. Group A (48 patients) had continuous luminal esophageal temperature (LET) monitoring using a temperature probe with 3 metal electrodes located in the vicinity of the targeted PV ostia. Ablation ceased when LET exceeded 40 degrees C. Only patients with LET >= 39 degrees C underwent endoscopic evaluation to assess esophageal damage. Group B (42 patients) excluded LET monitoring but all patients underwent endoscopy. In Group A, 27 (56%) patients showed LET >= 39 degrees C (mean LET 40.5 degrees C). Endoscopy revealed esophageal alterations in 5 (8%) (3 erythema and 2 intramural bleeding). One hundred eighty-nine out of 190 (99.5%) targeted PVs were successfully isolated, with 1 PV unsuccessful due to high LET. In Group B all 165 targeted PVs (100%) were successfully isolated. Endoscopy in Group 2 revealed no esophageal alterations. CONCLUSIONS: Using a duty-cycled, phased RF ablation system is safe and effective to isolate PVs. No Eso alteration was documented after ablation when LET was not monitored. This suggests that the LET probe may contribute to the thermal effect. Whether the documented increments in LET are due to direct tissue heating or possible interaction between the LET probe requires further investigation. PMID- 20958830 TI - Noncontact electroanatomic mapping to characterize typical atrial flutter: participation of right atrial posterior wall in the reentrant circuit. AB - BACKGROUND: Reentry utilizing cavotricuspid isthmus (CTI) is accepted as the mechanism underlying typical atrial flutter (AFLT). However, it is unclear how the right atrial (RA) posterior wall (PW) participates in AFLT circuit. We sought to investigate this by using noncontact electroanatomic mapping. METHODS: Fifteen patients (pts) undergoing ablation for typical AFLT participated. Multipolar catheters were deployed in RA and coronary sinus. RA shell was created during AFLT. Entrainment was performed to confirm CTI dependence and assess participation of various RA regions (septum-Sep, PW, lateral wall-LW). Data were analyzed for (1) RA activation patterns and (2) conduction time (CT) through various RA regions. RESULTS: Mean pt age was 70 +/- 13 years (all males; CCW = 10; CW = 5). Mean AFLT cycle length was 255 +/- 15 ms. Single activation wave front traversing sequentially CTI, Sep, and LW was seen in all pts and in 12 (80%; 9 CCW, 3 CW) this also traversed PW. Entrainment confirmed PW participation in 7 of these. Mean CT (in ms) through various RA regions was as follows: CTI = 69 +/- 27, Sep = 50 +/- 39, PW = 65 +/- 35, and LW = 76 +/- 35; P = NS. CONCLUSION: These observations offer new insights regarding the participation of PW in the reentrant circuit of typical AFLT in some patients. PMID- 20958831 TI - Combining shock reduction strategies to enhance ICD therapy: a role for computer modeling. AB - OBJECTIVES: To develop a computer model to test shock reduction strategies such as antitachycardia pacing and shock withholding for supraventricular rhythms, oversensing, and nonsustained ventricular tachycardia. BACKGROUND: While the implantable cardioverter defibrillator (ICD) can reduce mortality, inappropriate ICD shocks remain a limitation. Randomized trials provide evidence of efficacy, but they are not always practical. Computer models provide an alternative approach, and are particularly useful when evaluating multiple interventions. METHODS: A computer model was developed using clinical data and validated in a large ICD data set (EMPIRIC). After validation, the model was applied to 736 adjudicated clinical episodes from the ICD arm of Sudden Cardiac Death Heart Failure Trial (SCD-HeFT). RESULTS: The shock reduction strategies hypothetically reduced the number of VT/VF shocked episodes in SCD-HeFT by an estimated 59% (from 952 observed to 395 modeled shocks, probability of >0.999) at detection duration settings (18 of 24 intervals). The percentage of patients experiencing inappropriate shocks over 5 years was decreased by 15% (23.5-8.4%), and the number of shocks for non-VT/VF episodes was decreased from 423 to 77 (82% reduction). The percentage of patients receiving shocks for VT/VF was reduced from 30.7% (SCD-HeFT) to 26.1% with the addition of ATP. Extended detection (24 of 32 or 30 of 40 intervals) showed modest additional improvement compared to 18 of 24 intervals. CONCLUSION: Computer modeling is able to predict the results of a known clinical trial and demonstrate that shock reduction strategies have the potential to significantly reduce inappropriate and unnecessary ICD shocks versus the mandated programming used in SCD-HeFT. PMID- 20958832 TI - Improved endothelial function in patients with atrial fibrillation through maintenance of sinus rhythm by successful catheter ablation. AB - BACKGROUND: Although atrial fibrillation (AF) is a risk factor for endothelial dysfunction (ED), the effect of catheter ablation (CA) on AF-associated ED has not been evaluated. The aims of this study are to determine if the degree of ED predicts the outcome of AF ablation and to evaluate whether ED can be improved through restoring sinus rhythm (SR) by successful CA. METHODS: This study prospectively enrolled 80 subjects who underwent CA for AF (paroxysmal AF = 61, persistent AF = 19). Eighty subjects with no history of AF were enrolled as controls, all of whom were matched by age, gender, body mass index, and atherosclerotic risk factor distribution. Brachial artery flow-mediated dilatation (FMD) was measured at baseline, and at 1 month and 6 months post CA in AF subjects who remained in SR. Among controls, FMD was measured at baseline and at 6 months. We used high sensitivity C-reactive protein (hs-CRP), interleukin-6, soluble E- or P-selectin, and endothelin-1 as biomarker indices for inflammation and/or ED. RESULTS: Compared with controls, AF subjects had lower FMD at baseline (FMD(baseline), P < 0.001). After successful CA, FMD was significantly improved at 1 month and 6 months, nearly approaching control levels. A multivariate analysis revealed that FMD(baseline), hs-CRP, and left atrial volume (LAV) were independent predictors for arrhythmia recurrence after CA. Other biomarkers were not related to rhythm outcome. CONCLUSION: AF subjects have significantly impaired FMD, which can be reversed through maintenance of SR by successful CA. FMD(baseline), hs-CRP, and LAV are important predictors for AF recurrence after CA. PMID- 20958833 TI - Outcome of invasive electrophysiological procedures and gender: are males and females the same? AB - The aim of this review is to summarize the available evidence on gender-related differences in outcome of invasive electrophysiological procedures. Gender exerts significant influences on the epidemiology, pathophysiology, and clinical presentation of many cardiac rhythm disorders. Women with supraventricular arrhythmias have a higher incidence of atrioventricular nodal reentrant tachycardia, a lower prevalence of atrioventricular accessory pathways, and increased arrhythmia inducibility during luteal phases of the menstrual cycle. Catheter ablation of supraventricular arrhythmias appears equally effective in the 2 genders, although women present to catheter ablation later, with more symptoms, and after having failed more antiarrhythmic drugs. The outcome of catheter ablation of atrial fibrillation in women has been reported worse than in men, which may be explained by a later referral. Accordingly, women present to catheter ablation with a higher incidence of long-standing persistent atrial fibrillation. Of note, the outcome of catheter ablation of atrial flutter does not seem to differ between genders. To date, with regard to ventricular arrhythmias, no gender-related differences in outcome of catheter ablation procedures have been reported. However, pathophysiology and risk factors underlying ventricular arrhythmias appear different in the two genders. Severe left ventricular dysfunction does not perform equally as a predictor for sudden cardiac death in women as compared to men, and the survival benefit of prophylactic implantable cardioverter-defibrillator (ICD) implantation in women is inconclusive. On the other hand, the clinical outcome after cardiac resynchronization therapy seems to be more favorable in women, who experience a greater degree of reverse left ventricular remodeling. PMID- 20958834 TI - Catheter ablation for atrial fibrillation on uninterrupted warfarin: NEED it be done WITH echo guidance? PMID- 20958835 TI - Catheter ablation of cardiac fat pads attenuates Bezold-Jarisch reflex in dogs. AB - BACKGROUND: Bezold-Jarisch reflex (BJR) plays an important role in the pathophysiology of several cardiovascular disorders. Radiofrequency catheter ablation (RFCA) of the vagal ganglia in cardiac fat pads (FPs) may attenuate BJR. The purpose of this study was to examine the effects of RFCA of the cardiac FPs on veratridine-induced BJR in dogs. METHODS AND RESULTS: This study was performed in 30 pentobarbital-anesthetized and open-chest dogs: control group received no ablation (n = 15); and ablation group (n = 15) received epicardial ablation of the 3 FPs located near the right pulmonary vein, the inferior vena cava, and the aortic root. The BJR was induced by injection of veratridine (15 MUg/kg) into the left ventricle. Before injection of veratridine, there were no significant differences in heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricle end-diastolic pressure (LVEDP), left ventricular peak systolic and diastolic velocity (+/-dp/dt(max)) between these 2 groups (P > 0.05). However, the veratridine-induced decrease of HR in ablation group was significantly lower than that in control group (22.9 +/- 8.5 bpm vs 93.3 +/- 18.4 bpm, P < 0.01). There were no differences in the reduction of SAP, DAP, MAP, LVSP, LVEDP and dp/dt(max) between both groups (P > 0.05). CONCLUSIONS: RFCA of the cardiac FPs significantly attenuated veratridine-induced cardio-vagal component but not the vasodepressor component of the BJR. This might have therapeutic implications in BJR-related disorders such as cardio-inhibitory vasovagal syncope. PMID- 20958836 TI - Ablation of paroxysmal and persistent atrial fibrillation: 1-year follow-up through continuous subcutaneous monitoring. AB - BACKGROUND: The aim of this prospective observational study was to identify responders to ablation through continuous subcutaneous monitoring for 1 year after ablation in patients with paroxysmal atrial fibrillation (PAF) or persistent AF (PersAF). METHOD: Patients with symptomatic drug refractory AF were enrolled. Real-time three-dimensional (3D) left atrium maps were reconstructed by using a nonfluoroscopic navigation system (CARTO, Biosense-Webster Inc., Diamond Bar, CA, USA). The ipsilateral left and right pulmonary veins (PVs) were encircled in 1 lesion line by circumferential PV isolation. All patients were implanted with Reveal XT (Medtronic Inc.) for continuous AF monitoring and data collected every month during the 12-month follow-up. RESULTS: We enrolled 129 patients (56 +/- 9 years, 102 males), all of whom were followed-up for 12 months after the last ablation procedure: 58 (45%) had a history of PersAF. After only 1 ablation procedure, 76 (59%) of the 129 patients were AF-free at 12-month: 48 out of 71 (68%) in the PAF group and 28 out of 58 (48%) in the PersAF group. After 1 or more ablation procedures, 94 (73%) of the 129 patients were AF-free 12 months after the last procedure: 57 out of 71 (80%) in the PAF group and 37 out of 58 (64%) in the PersAF group. CONCLUSION: Ablation is highly effective in treating AF, as assessed through detailed 1-year continuous monitoring: success rate is higher in PAF than in PersAF patients. The use of subcutaneous monitors is a valuable means of identifying responders and nonresponders, and can potentially guide antiarrhythmic and antithrombotic therapies. PMID- 20958837 TI - H1N1 influenza A virus induced atrioventricular block. AB - We report a case of an 18-year-old female who presented with respiratory failure secondary to H1N1 infection, and who subsequently developed high-degree atrioventricular (AV) block. The conduction abnormalities persisted over 2 weeks following complete resolution of respiratory symptoms. A permanent pacemaker was implanted for safety and subsequent pacemaker follow-up suggested reversibility of the conduction abnormality. This case highlights the potential impact of the H1N1 influenza virus on the cardiac conduction system. PMID- 20958838 TI - Relationship between arrhythmogenic pulmonary veins and the surrounding atrial substrate in patients with paroxysmal atrial fibrillation. AB - INTRODUCTION: The relationship between pulmonary veins (PVs) with atrial fibrillation (AF) initiating triggers and their surrounding atrial substrate has not been elucidated. We aimed to clarify the atrial substrate properties around the PVs. METHODS AND RESULTS: Twenty-three paroxysmal AF patients were studied with the identification of PV initiating triggers. High-density mapping of the dominant frequency (DF, 1200 Hz) and the mean degree of the complex fractionated electrograms (CFE mean interval over 6 seconds) was evaluated in 2 zones (zone 1: < 5 mm, zone 2: 5-15 mm from the PVs) and the left atrial (LA) using a NavX system prior to the PV isolation. High-DFs (>8 Hz) and continuous CFEs (<50 ms) were identified in 1.5 +/- 0.9 and 2.3 +/- 1.1 regions per patient, respectively. Most of the high-DF regions (86%) and continuous CFE regions (77%) were located within 15 mm of the PV ostia. Of those, 75% of the high-DF regions and 54% of the continuous CFE regions were related to arrhythmogenic PVs. There was a significant DF gradient from arrhythmogenic PV zone 1 to zone 2, while the mean CFE exhibited a significant gradient between arrhythmogenic PV zone 2 and the rest of the LA. Additionally, 69% of the procedural AF termination sites were at arrhythmogenic PV zone 2. CONCLUSION: Evaluation of the atrial substrate properties may be useful for locating arrhythmogenic PVs during AF and defining the extent of the circumferential PV isolation. PMID- 20958839 TI - The esophageal temperature probe: helpful monitoring device or inadvertent amplifier of risk? PMID- 20958840 TI - Examining differences in substance use among rural and urban pregnant women. AB - Substance use during pregnancy is a major public health concern. This study examined differences in substance use among pregnant women from rural and urban areas. Participants were 114 pregnant women entering a hospital-based inpatient detoxification unit primarily for Opiate Dependence who voluntarily agreed to a face-to-face interview. Substance use measures were based on the Addiction Severity Index gathering information about lifetime, past 12 months, and 30 days prior to admission. Rural pregnant women had higher rates of illicit opiate use, illicit sedative/benzodiazepine use, and injection drug use (IDU) in the 30 days prior to admission. Additionally, a greater proportion of rural pregnant women reported the use of multiple illegal/illicit substances in the 30 days prior to entering detoxification. More specifically, pregnant women from rural areas were 8.4 times more likely to report illicit opiate use, 5.9 times more likely to report IDU, 3.3 times more likely to report illicit sedative/benzodiazepine use, and 2.8 times more likely to report the use of multiple illegal/illicit substances in the 30 days prior to entering inpatient detoxification, after adjustment for socio-demographic characteristics (including education and income), pregnancy characteristics, physical and mental health indicators, and criminal justice system involvement. The increased rates of prescription opiate and benzodiazepine use as well as IDU among rural pregnant women are concerning. In order to begin to understand the elevated rates of substance abuse among rural pregnant women, substance use must be considered within the context of demographic, geographic, social, and economic conditions of the region. PMID- 20958841 TI - Reasons for substance use among adolescents with bipolar disorder. AB - We examined whether children and adolescents with bipolar disorder (BPD) "self medicate" with cigarettes, alcohol, or other substances of abuse. One hundred and five adolescents with BPD and 98 controls were comprehensively assessed with a structured psychiatric diagnostic interview for psychopathology and the Drug Use Screening Inventory (DUSI) for self-medication. Thirteen control (mean +/- standard deviation [SD]= 15.31 +/- 1.18 years) and 27 BPD (15.30 +/- 2.09 years) subjects endorsed use of one of the listed drugs in the DUSI Section A within the past year and were included in all analyses. BPD adolescents were more likely than nonmood disordered, substance-using controls to report starting to use their preferred drug for mood-altering effects. There were no differences between groups in motivation for use with respect to starting substances to sleep better or get high, or in continuing substances to change mood, sleep better, or get high. These data may contribute to increased prevention of substance use disorders and to the treatment of adolescent BPD. Further studies clarifying the characteristics of self-medication are necessary. PMID- 20958842 TI - A placebo-controlled trial of atomoxetine in marijuana-dependent individuals with attention deficit hyperactivity disorder. AB - This study evaluated the effects of atomoxetine on the symptoms of attention deficit hyperactivity disorder (ADHD) and marijuana use in marijuana-dependent adults. In conjunction with motivational interviewing, participants received either atomoxetine (n = 19) or matching placebo (n = 19) for 12 weeks. Participants randomized to atomoxetine had greater improvement in ADHD on the Clinical Global Impression-Improvement scale than participants treated with placebo. No treatment group differences in self-rated ADHD symptoms, overall Wender-Reimherr Adult Attention Deficit Disorder Scale scores, or marijuana use outcomes were noted. These results suggest that atomoxetine may improve some ADHD symptoms but does not reduce marijuana use in this population. PMID- 20958843 TI - The association of trauma and PTSD with the substance use profiles of alcohol- and cocaine-dependent out-of-treatment women. AB - The association of trauma and posttraumatic stress disorder (PTSD) with alcohol and cocaine use is explored to determine if there is additive risk associated with dual dependence. Data were collected from out-of-treatment women enrolled in an HIV-prevention study. Women who experienced a DSM-IV qualifying event (n = 791) were stratified into four substance use groups based on lifetime alcohol and cocaine use. Women with lifetime comorbid alcohol and cocaine dependence experienced significantly more traumatic events and had a higher prevalence of violent events and lifetime diagnosis of PTSD and PTSD-related impairment. There is added risk for associated trauma and subsequent PTSD among women who have dual substance dependence. PMID- 20958844 TI - Counselor attitudes toward the use of motivational incentives in addiction treatment. AB - Counselor attitudes toward evidence-based practices, such as motivational incentives/contingency management (MI/CM), are important in bridging the gap between research and practice. Mailed surveys from 1,959 substance abuse treatment counselors showed ambivalence toward MI/CM and strong disagreement with using monetary rewards for achievement of treatment goals. Attitudes were associated with counselors' educational attainment, a 12-step treatment ideology, affiliation with NIDA's Clinical Trials Network, and working in opioid treatment programs. Exposure to MI/CM via training was more strongly associated with attitudes when counselors worked in programs that had adopted MI/CM. While there is substantial resistance to MI/CM, dissemination and training about the essential elements of MI/CM may enhance counselors' receptivity toward this intervention. PMID- 20958845 TI - Substance use in patients with sexually transmitted infections: results from a national U.S. survey. AB - Little is known about the prevalence and correlates of substance use in patients diagnosed with sexually transmitted infections (STIs) in the general population. We examined the relationship between STIs and substance use. Of the 54,623 respondents, 1% reported a past-year STI. STI was associated with alcohol abuse/dependence (AOR 1.8, 95% CI 1.1-3.3), and marijuana use (AOR 2.0, 95% CI 1.4-3.0); but not with past-year alcohol use, cocaine use, nonmedical use of prescription opioids, or past-month binge or heavy drinking. A diagnosis of an STI should prompt clinicians to screen for substance use, in particular, alcohol abuse/dependence and marijuana use. PMID- 20958846 TI - An examination of drug craving over time in abstinent methamphetamine users. AB - Craving for addictive drugs may predict relapse in abstinent addicts. To assess relationships between craving and use, we examined changes in craving for methamphetamine (MA) in a sample of 865 outpatients in a multisite 16-week MA treatment study. Craving was assessed on a 0-100 scale, and MA use was assessed by self-report and confirmed by urinalysis. We hypothesized that the magnitude of craving would decline (decay) with increased time of abstinence, and that decay would be greater for more frequent MA users, and greater for intravenous (IV) users and smokers as compared to those who used MA intranasally. Craving declined significantly as the number of weeks of consecutive abstinence increased. Rate of decay was greater for IV users and smokers as compared to both intranasal users and oral users, but not for more frequent users of MA. Rate of decay was independent of age, gender, and race/ethnicity. The trajectory to 0 (no) craving was 1 week shorter for females than males because females had significantly lower pretreatment craving scores compared to males. This study confirms that the sooner MA-dependent people are able to quit using and the longer that they are able to stay abstinent, the more likely it is that their craving for MA will decrease over time. PMID- 20958848 TI - Pilot study of a preliminary criterion standard for prescription opioid misuse. AB - Multidisciplinary experts created a behaviorally defined preliminary criterion standard definition of probable prescription opioid misuse (PPOM) that could be rated from material found in administrative, pharmacy, and electronic health record databases. They then derived a scoring system to identify PPOM patients requiring referral to a specialist. Experts next rated cases of misuse and nonmisuse. Rater no. 1 correctly differentiated 37 of 40 cases (92.5%); kappa coefficient was .79 (CI: .57, 1.00). Rater no. 2 correctly identified 39 of 40 cases (97.5%); kappa was .94 (CI: .81, 1.00). Kappa for comparing raters was .73 (CI: .49, .98). This preliminary study demonstrates that multidisciplinary raters can use behaviorally based criteria to identify patients with known PPOM from health plan databases. PMID- 20958847 TI - Prescription use disorders in older adults. AB - The number of older adults needing substance abuse treatment is projected to rise significantly in the next few decades. This paper will focus on the epidemic of prescription use disorders in older adults. Particular vulnerabilities of older adults to addiction will be considered. Specifically, the prevalence and patterns of use of opioids, stimulants, and benzodiazepines will be explored, including the effects of these substances on morbidity and mortality. Treatment intervention strategies will be briefly discussed, and areas for future research are suggested. PMID- 20958849 TI - Physician views regarding substance use-related participation in a state physician health program. AB - Physician Health Programs (PHPs) safeguard the public by monitoring impaired physicians, but participation is not always voluntary, and many physicians resist referral. In this study, 80 physicians (85.1% male) who were referred to a state PHP for substance use-related problems completed an anonymous online survey regarding their experiences in the program. Results indicated that 78.1% of program completers had a 5-year contract, with 100% including random drug screening. In addition, 84.8% continued participation in 12-step fellowships after the required monitoring period. Participants were generally satisfied with the program, and 92.5% indicated that they would recommend it to others. They provided suggestions to increase the acceptability and efficacy of PHPs for physicians. PMID- 20958850 TI - The Relationship between parental alcohol use, early and late adolescent alcohol use, and young adult psychological symptoms: a longitudinal study. AB - We tested the hypothesis that there is a mediational pathway from parental alcohol use during the participants' adolescence to the participants' psychological symptoms in young adulthood. This pathway includes the participants' alcohol use and their psychological symptoms, both during adolescence. The participants are inner city African American and Puerto Rican early adolescents followed until young adulthood. They reported their own and their parents' behavior. Structural equation modeling showed that parental alcohol use was related to early adolescent alcohol use, which was associated with late adolescent alcohol use. Late adolescent alcohol use was related to psychological symptoms in late adolescence, which predicted young adult psychological symptoms. Males reported more alcohol use and more psychological symptoms than females in late adolescence and more psychological symptoms in young adulthood. Findings suggest that parents' and adolescents' alcohol use should be a focus in interventions designed to prevent or treat psychological symptoms in late adolescence and young adulthood. PMID- 20958851 TI - Changes in coping moderate substance abuse outcomes differentially across behavioral treatment modality. AB - In this secondary data analytic study, we examined whether the relationship between changes in coping and treatment outcome differed between women enrolled in either the Women's Recovery Group (WRG) (n = 29), a new manualized group treatment for women with substance use disorders, or Group Drug Counseling (GDC) (n = 7), an empirically supported mixed-gender group treatment. We examined subscales of the Ways of Coping Questionnaire and found that while changes in coping did not differ significantly across treatment groups, the association between changes in coping and substance abuse outcome was related to treatment condition. Increases in problem-focused coping were associated with decreased drinking days in WRG, but paradoxically with increased drinking days in GDC. For both groups, increases in wishful thinking were associated with increases in substance use, and increases in social support coping associated with decreases in use, but these associations were greater in GDC. Our results highlight the importance of examining the impact of treatment modality on coping, as well as contextual factors that may help to explain the specific pattern of results. PMID- 20958853 TI - Buprenorphine-based regimens and methadone for the medical management of opioid dependence: selecting the appropriate drug for treatment. AB - Maintenance therapy with methadone or buprenorphine-based regimens reduces opioid dependence and associated harms. The perception that methadone is more effective than buprenorphine for maintenance treatment has been based on low buprenorphine doses and excessively slow induction regimens used in early buprenorphine trials. Subsequent studies show that the efficacy of buprenorphine sublingual tablet (Subutex(r)) or buprenorphine/naloxone sublingual tablet (Suboxone(r)) is equivalent to that of methadone when sufficient buprenorphine doses, rapid induction, and flexible dosing are used. Although methadone remains an essential maintenance therapy option, buprenorphine-based regimens increase access to care and provide safer, more appropriate treatment than methadone for some patients. PMID- 20958852 TI - Pathological gamblers respond equally well to cognitive-behavioral therapy regardless of other mental health treatment status. AB - Data consistently demonstrate comorbidity between pathological gambling and psychiatric disorders. This study compares severity of gambling and psychosocial problems and gambling treatment outcomes in treatment-seeking pathological gamblers (n = 231) based on their self-reported mental health treatment utilization. As expected, participants currently receiving mental health treatment demonstrated the most psychiatric problems, and those with no mental health treatment the least. Although preferred gambling activity differed according to mental health treatment status, severity of gambling problems, and gambling treatment outcomes did not. Individual cognitive-behavioral therapy was efficacious in reducing gambling problems irrespective of mental health treatment utilization. PMID- 20958854 TI - Stimulant formulation and motivation for nonmedical use of prescription attention deficit/hyperactivity disorder medications in a college-aged population. AB - There is relatively little research examining motives for nonmedical use (NMU) of attention-deficit/hyperactivity disorder (ADHD) medications and predictors of motivation. We present results of a secondary analysis of an Internet-based epidemiological survey to explore the relationship between stimulant formulation and motivation for NMU of ADHD stimulant medications in a college-aged population. Demographic predictors of motivation to engage in NMU were also explored to investigate the potential correlates of recreational versus performance-enhancement motivations. Respondents scoring higher on the Adult ADHD Self-Report Scale were significantly more likely to engage in NMU of ADHD stimulant medications. Those using extended release (ER) stimulant formulations were less likely to endorse "staying awake" as a reason for NMU compared to those using immediate release (IR) stimulant formulations. PMID- 20958855 TI - Human vocal cord infection with the Microsporidium Anncaliia algerae. AB - We describe a biopsy proven case of microsporidial infection of the false vocal cords in a 69-yr-old male with a history of chronic lymphocytic leukemia. The patient had hoarseness for several weeks before his admission to the hospital for shortness of breath. He had received chemotherapy with fludarabine 6 wk before this hospital admission. A biopsy of vocal cord nodules demonstrated an organism that was identified as Anncaliia algerae by electron microscopy. Molecular analysis of the small subunit RNA gene amplified by polymerase chain reaction further confirmed the identification of this organism as A. algerae. This case illustrates the ability of this insect pathogen to cause disease in immune compromised mammalian hosts. PMID- 20958857 TI - Case of acute cerebellar ataxia associated with primary Epstein-Barr virus infection. PMID- 20958856 TI - A prospective randomized study of 980 nm diode laser-assisted venous ulcer healing on 34 patients. AB - Venous ulcers are chronic wounds affecting up to 1% of adults in developed countries. Considering that noncontact normothermic therapy has been shown to modify the wound healing process, we conducted a prospective comparative clinical trial aimed at evaluating 980 nm diode laser in laser-assisted venous ulcer healing. Thirty-four Caucasian patients with venous leg ulcers were included in the study and separated into two homogenous groups based on age, sex ratio, size, and etiologies of the ulcers. In the laser group, 980 nm InGasAs diode laser (power 15 W, spot size 8 mm, time 3 seconds, fluence 90 J/cm(2) ) was applied weekly for 9 weeks to the ulcers in a homogenous standardized manner, resulting in a local temperature of 45-50 degrees C, which was controlled with a thermal infrared camera. Complete healing, reduction in size, and pain during and between each procedure were evaluated each time. Of the 18 patients in the laser group, three (16.7%) were completely healed during laser treatment. In the control group (16 patients), the healing was complete for four patients (25%). This difference was not significant (p=0.62). At the ninth follow-up visit, in the control group, the ulcers had decreased on an average to 94.3% of the original area of the ulcers. In the laser group, the decrease was to 74.2% of the original area of the ulcers. Again, this difference was not significant (p=0.60). The mean VAS score between each treatment was 2.7 (0.5-4.4) in the laser group compared with 3.8 (2.3-5.0) in the control group (0.13= 37.5 degrees C) or history of fever. To assess the time to re-infection, a blood film was also systematically obtained from pre-treated children every 2 weeks. RESULTS: The mean time to the first malaria infection was 36 days in the SP arm and 26 days in the AL arm (P=0.006). The incidence density of malaria infection was similar in both groups (86.5%vs. 92.3%, P=0.52). The mean time to the first malaria episode was 47 days in the SP arm and 32 days in the AL arm (P<0.001). The incidence of malaria episodes was significantly higher in the group pre treated with AL (45.7 per 1000 child days-at-risk CI 95% [35-56]) than in the control group (10.7 per 1000 child days-at-risk CI 95% [7-15]); P<0.001). CONCLUSIONS: Our findings suggest that the radical clearance of parasitemia with AL may increase susceptibility to malaria infection and clinical malaria episodes. PMID- 20958889 TI - High failure rate of the dissolution tests for 500-mg amoxicillin capsules sold in Cambodia: is it because of the product or the test method? AB - OBJECTIVES: During the survey of substandard medicines in Cambodia in 2007, it was found that more than 90% of 500-mg amoxicillin (AMPC) capsules failed the United States Pharmacopeia (USP) 30 TEST 1 dissolution test. In the USP, several monographs provide multiple methods for performing the dissolution test. By using the 500-mg AMPC capsule as an example, we aimed to identify the problems and implications of the USP methods adopted for the dissolution test as a global standard. METHODS: All AMPC samples were collected from the Cambodian market in 2007. For the quantitative test, we referred to USP 30. We performed the USP 28 and USP 30 TEST 2 dissolution tests and compared these results with those of the USP 30 TEST 1. RESULTS: All 500-mg AMPC capsules used for the comparison passed the quantitative test. Samples that passed the USP 28 and USP 30 TEST 2 dissolution tests were identical, and the pass rate was 97.1% (34/35), whereas the pass rate with the USP 30 TEST 1 was 8.6% (3/35). The difference in the dissolution results between the three methods was significant (P<0.0001). CONCLUSION: This study revealed that many users would select the most stringent method when multiple methods exist in the USP. This may lead to a high failure rate of the tests. Because USP is a global standard, we recommend that it take into consideration the developing countries and create a more detailed user friendly manual for selection for appropriate methods. PMID- 20958890 TI - Randomized controlled trial of zinc and vitamin A as co-adjuvants for the treatment of pulmonary tuberculosis. AB - OBJECTIVE: To assess the efficacy of weekly zinc or zinc plus retinol as adjuncts for the treatment of pulmonary tuberculosis. METHODS: Double-blind, randomized, placebo-controlled trial in 350 patients >15 years old with smear-positive tuberculosis in Nigeria (ISRCTN36636609). In addition to antituberculous treatment, patients were randomly allocated to weekly supplements of zinc (90 mg), zinc plus retinol (5000 IU) or placebos for 6 months. Primary outcomes were time to sputum smear conversion and resolution of radiographic abnormalities. RESULTS: After 8 weeks of treatment, 68% had achieved sputum smear conversion, and the median conversion time was 6.5 weeks. Hazard ratios (HR, 95%CI) for sputum conversion relative to the placebo group were not significant for zinc (1.07, 0.92-1.29) or zinc plus retinol (0.89, 0.76-1.07). Significant predictors of time to sputum conversion were lung abnormality score, sputum smear grade, age and serum C-reactive protein. HIV co-infection and gender were not independent predictors of time to sputum conversion. There were no significant differences between supplement groups in clinical, radiological or laboratory outcomes at 2 months or 6 months. There were 9, 9 and 2 deaths in patients receiving zinc, zinc plus retinol or placebos, respectively. Mortality in those who received zinc (HR 1.71, 0.88-3.58) or zinc plus retinol (HR 1.54, 0.78-3.26) did not differ significantly from those who received placebos. Most deaths occurred in patients co-infected with HIV. CONCLUSIONS: Supplementation with zinc or zinc plus retinol did not lead to better outcomes than placebos, and caution is warranted regarding routine micronutrient supplementation, particularly in patients co infected with HIV. PMID- 20958891 TI - Costs of HIV/AIDS outpatient services delivered through Zambian public health facilities. AB - OBJECTIVE: To present evidence on unit and total costs of outpatient HIV/AIDS services in ZPCT-supported facilities in Zambia; specifically, to measure unit costs of selected outpatient HIV/AIDS services, and to estimate total annual costs of antiretroviral therapy (ART) and prevention of mother-to-child transmission (PMTCT) in Zambia. METHODS: Cost data from 2008 were collected in 12 ZPCT-supported facilities (hospitals and health centres) in four provinces. Costs of all resources used to produce ART, PMTCT and CT visits were included, using the perspective of the provider. All shared costs were distributed to clinic visits using appropriate allocation variables. Estimates of annual costs of HIV/AIDS services were made using ZPCT and Ministry of Health data on numbers of persons receiving services in 2009. RESULTS: Unit costs of visits were driven by costs of drugs, laboratory tests and clinical labour, while variability in visit costs across facilities was explained mainly by differences in utilization. First year costs of ART per client ranged from US$278 to US$523 depending on drug regimen and facility type; costs of a complete course of antenatal care (ANC) including PMTCT were approximately US$114. Annual costs of ART provided in ZPCT supported facilities were estimated at US$14.7-$40.1 million depending on regimen, and annual costs of antenatal care including PMTCT were estimated at US$16 million. In Zambia as a whole, the respective estimates were US$41.0-114.2 million for ART and US$57.7 million for ANC including PMTCT. CONCLUSIONS: Consistent with the literature, total costs of services were dominated by drugs, laboratory tests and clinical labour. For each visit type, variability across facilities in total costs and cost components suggests that some potential exists to reduce costs through greater harmonization of care protocols and more intensive use of fixed resources. Improving facility-level information on the costs of resources used to produce services should be emphasized as an element of health systems strengthening. PMID- 20958892 TI - Predictive diagnostic value of the tourniquet test for the diagnosis of dengue infection in adults. AB - OBJECTIVE: To examine the accuracy of the admission tourniquet test in the diagnosis of dengue infection among Lao adults. METHODS: Prospective assessment of the predictive diagnostic value of the tourniquet test for the diagnosis of dengue infection, as defined by IgM, IgG and NS1 ELISAs (Panbio Ltd, Australia), among Lao adult inpatients with clinically suspected dengue infection. RESULTS: Of 234 patients with clinically suspected dengue infection on admission, 73% were serologically confirmed to have dengue, while 64 patients with negative dengue serology were diagnosed as having scrub typhus (39%), murine typhus (11%), undetermined typhus (12%), Japanese encephalitis virus (5%), undetermined flavivirus (5%) and typhoid fever (3%); 25% had no identifiable aetiology. The tourniquet test was positive in 29.1% (95% CI = 23.2-34.9%) of all patients and in 34.1% (95% CI = 27.0-41.2%) of dengue-seropositive patients, in 32.7% (95% CI = 23.5-41.8) of those with dengue fever and in 36.4% (95% CI = 24.7-48.0) of those with dengue haemorrhagic fever. Interobserver agreement for the tourniquet test was 90.2% (95% CI = 86.4-94.0) (Kappa = 0.76). Using ELISAs as the diagnostic gold standard, the sensitivity of the tourniquet test was 33.5-34%; its specificity was 84-91%. The positive and negative predictive values were 85 90% and 32.5-34%, respectively. CONCLUSIONS: The admission tourniquet test has low sensitivity and adds relatively little value to the diagnosis of dengue among Lao adult inpatients with suspected dengue. Although a positive tourniquet test suggests dengue and that treatment of alternative diagnoses may not be needed, a negative test result does not exclude dengue. PMID- 20958893 TI - Matrix metalloproteinase-9 and intercellular adhesion molecule 1 are powerful staging markers for human African trypanosomiasis. AB - OBJECTIVES: A critical step before treatment of human African trypanosomiasis (HAT) is the correct staging of the disease. As late stage is established when trypanosomes cross the blood-brain barrier and invade the central nervous system, we hypothesized that matrix metalloproteinases and cell adhesion molecules could indicate, alone or in combination, the disease progression from the first to the second stage of HAT. METHODS: We measured the levels of MMP-2, MMP-9, ICAM-1, VCAM-1 and E-selectin in the cerebrospinal fluid (CSF) of 63 Trypanosoma brucei gambiense-infected patients (15 stage 1 and 48 stage 2). Staging was based on counting of white blood cells (WBC) and/or parasite detection in CSF. Concentrations were obtained either by ELISA or multiplex bead suspension assays, and results were compared with three known HAT staging markers (CXCL10, CXCL8 and H-FABP). RESULTS: ICAM-1 and MMP-9 accurately discriminated between stage 1 and stage 2 patients with HAT with 95% sensitivity (SE) for 100% specificity (SP), which was better than CXCL10 (93% SE for 100% SP), one of the most promising known markers. Combination of ICAM-1 and MMP-9 with H-FABP provided a panel that resulted in 100% of SE and SP for staging HAT. CONCLUSIONS: ICAM-1 and MMP-9, alone or in combination, appeared as powerful CSF staging markers of HAT. Final validation of all newly discovered staging markers on a large multi-centric cohort including both forms of the disease as well as patients with others infections should be performed. PMID- 20958894 TI - Migration and child health inequities in Nigeria: a multilevel analysis of contextual- and individual-level factors. AB - OBJECTIVE: To assess the role of rural-urban migration in the risks of under-five death; to identify possible mechanisms through which migration may influence mortality; and to determine individual- and community-level relationships between migration status and under-five death. METHOD: Multilevel Cox regression analysis was used on a nationally representative sample of 6029 children from 2735 mothers aged 15-49 years and nested within 365 communities from the 2003 Nigeria Demographic and Health Survey. Hazard ratios with 95% confidence intervals were used to express the measures of association between the characteristics, and intra-class coefficients were used to express the measures of variation. RESULTS: Children of rural non-migrant mothers had significantly lower risks of under-five death than children of rural-urban migrant mothers. The disruption of family and community ties, low socio-economic position and vulnerability, and the difficulties migrants face in adapting into the new urban environment, may predispose the children of rural-urban migrants to higher mortality. CONCLUSION: Our results stress the need for community-level and socio-economic interventions targeted at migrant groups within urban areas to improve their access to health care services, maternal education, as well as the general socio-economic situation of women. PMID- 20958895 TI - Linking migration, mobility and HIV. AB - Population mobility is commonly identified as a key driver of the HIV epidemic, both linking geographically separate epidemics and intensifying transmission through inducing riskier sexual behaviours. However, beyond the well-known case studies of South African miners and East African truck drivers, the evidence on the links between HIV and mobility is nuanced, contradictory and inconclusive and is in part attributed to the abstract definitions of mobility used in different studies. This problematic conception of mobility, with no reference to who moves, their motivations for moving, or the characteristics of sending and receiving areas, can have a dramatic impact on how one understands the influence which this structural factor has on HIV risk in different settings. Future research on mobility and HIV transmission must incorporate an understanding of migration and mobility as dynamic processes and link different patterns and forms of mobility with location-specific sexual networks and HIV epidemiology. PMID- 20958896 TI - A community-randomised controlled trial promoting waterless hand sanitizer and handwashing with soap, Dhaka, Bangladesh. AB - OBJECTIVES: To pilot two intensive hand hygiene promotion interventions, one using soap and one using a waterless hand sanitizer, in low-income housing compounds in Dhaka, Bangladesh and assess subsequent changes in handwashing behaviour and hand microbiology. METHODS: Fieldworkers randomized 30 housing compounds: 10 received handwashing promotion with free soap, 10 received handwashing promotion with free waterless hand sanitizer and 10 were non intervention controls. Fieldworkers assessed handwashing behaviour by structured observation and collected hand rinse specimens. RESULTS: At baseline, compound residents washed their hands with soap 26% of the time after defecation and 30% after cleaning a child's anus but <1% at other times. Compared with baseline, residents of soap intervention compounds were much more likely to wash their hands with soap after faecal contact (85-91%), before preparing food (26%) and before eating (26%). Compounds that received waterless hand sanitizer cleansed their hands more commonly than control compounds that used soap (10.4%vs. 2.3%), but less commonly than soap intervention compounds used soap (25%). Post intervention hand rinse samples from soap and sanitizer compounds had lower concentrations of faecal indicator bacteria compared with baseline and control compounds. CONCLUSIONS: Waterless hand sanitizer was readily adopted by this low income community and reduced hand contamination but did not improve the frequency of handwashing compared with soap. Future deployments of waterless hand sanitizers may improve hand hygiene more effectively by targeting settings where soap and water is unavailable. PMID- 20958897 TI - Providing universal access to antiretroviral therapy in Thyolo, Malawi through task shifting and decentralization of HIV/AIDS care. AB - OBJECTIVE: To describe how district-wide access to HIV/AIDS care was achieved and maintained in Thyolo District, Malawi. METHOD: In mid-2003, the Ministry of Health and Medecins Sans Frontieres developed a model of care for Thyolo district (population 587, 455) based on decentralization of care to health centres and community sites and task shifting. RESULTS: After delegating HIV testing and counseling to lay counsellors, uptake of testing increased from 1300 tests per month in 2003 to 6500 in 2009. Shifting responsibility for antiretroviral therapy (ART) initiations to non-physician clinicians almost doubled ART enrollment, with a majority of initiations performed in peripheral health centres. By the end 2009, 23, 261 people had initiated ART of whom 11, 042 received ART care at health-centre level. By the end of 2007, the universal access targets were achieved, with nearly 9000 patients alive and on ART. The average annual cost for achieving these targets was ? 2.6 per inhabitant/year. CONCLUSION: The Thyolo programme has demonstrated the feasibility of district-wide access to ART in a setting with limited resources for health. Expansion and decentralization of HIV/AIDS service-capacity to the primary care level, combined with task shifting, resulted in increased access to HIV services with good programme outcomes despite staff shortages. PMID- 20958898 TI - Challenges in the diagnosis of meningitis in low-resource settings. PMID- 20958899 TI - Whither therapeutic drug monitoring? PMID- 20958900 TI - Use of oral ketamine in a patient with systemic mastocytosis. PMID- 20958901 TI - Successful treatment of metastatic squamous cell carcinoma of the skin with chemoradiation followed by surgery. PMID- 20958903 TI - No evidence of an epidemic of Parkinson's disease in rural Western Australia. PMID- 20958904 TI - Meta-analysis reveals negative yet variable effects of ocean acidification on marine organisms. AB - Ocean acidification is a pervasive stressor that could affect many marine organisms and cause profound ecological shifts. A variety of biological responses to ocean acidification have been measured across a range of taxa, but this information exists as case studies and has not been synthesized into meaningful comparisons amongst response variables and functional groups. We used meta analytic techniques to explore the biological responses to ocean acidification, and found negative effects on survival, calcification, growth and reproduction. However, there was significant variation in the sensitivity of marine organisms. Calcifying organisms generally exhibited larger negative responses than non calcifying organisms across numerous response variables, with the exception of crustaceans, which calcify but were not negatively affected. Calcification responses varied significantly amongst organisms using different mineral forms of calcium carbonate. Organisms using one of the more soluble forms of calcium carbonate (high-magnesium calcite) can be more resilient to ocean acidification than less soluble forms (calcite and aragonite). Additionally, there was variation in the sensitivities of different developmental stages, but this variation was dependent on the taxonomic group. Our analyses suggest that the biological effects of ocean acidification are generally large and negative, but the variation in sensitivity amongst organisms has important implications for ecosystem responses. PMID- 20958905 TI - Are we reporting ileal pouch biopsies correctly? AB - AIM: The accuracy of ileo-anal pouch biopsy reporting was assessed. METHOD: The pathology reports of 100 consecutive pouch biopsies were reviewed to assess the accuracy and consistency with which the St Mark's histological scoring criteria were applied. The quality of pouch biopsy sampling and provision of clinical and endoscopic information on pathology request forms was also assessed. RESULTS: In 27% of cases no relevant endoscopic or clinical information was provided with the pathology request form. Separately labelled biopsies from the prepouch ileum, pouch and columnar cuff were submitted in only 4% of cases. In 32% of pathology reports, no acute or chronic St Mark's score was included. In 2% of cases the St Mark's scoring criteria were applied inappropriately. Twenty per cent of cases histologically diagnosed as pouchitis did not include a numerical score. In 30% of cases diagnosed histologically as pouchitis, an acute inflammatory score of < 4 (i.e. insufficient for this diagnosis) was included in the report. CONCLUSION: Pouchitis is a combined clinical, endoscopic and histological diagnosis. The correct interpretation and application of the St Mark's histological scoring criteria for pouch biopsies is an important part of this diagnostic process. PMID- 20958906 TI - Perioperative care: a survey of New Zealand and Australian colorectal surgeons. AB - AIM: Recent surveys in Europe and North America have demonstrated significant challenges in the implementation of evidence-based surgical practice. METHOD: A survey of New Zealand and Australian colorectal surgeons was conducted to help understand current practice and perceived barriers to interventions in this region. Questions were based around elective colorectal resection care. RESULTS: There were 152 eligible participants identified. Over a 60-day period, 82 (54%) surgeons responded but only 76 (50%) of the questionnaires were complete; they were used for data analysis. The majority of surgeons indicated a preference for laparoscopic techniques. Barriers to laparoscopy include lack of operating time, lack of adequate training and institutional pressures. Only 28 (37%) indicated that they cared for patients in a formalized enhanced recovery programme (ERAS). Barriers to implementing ERAS included lack of support from institutions and other specialities. Routine oral 'mechanical' bowel preparation for colon and rectal resection was preferred by 28% and 63%, respectively. Drainage after routine colon and rectal resection was not used by 62 (83%) and 39 (53%). Prophylactic nasogastric intubation afterwards was not used by 66 (87%) responders. The preferred mode of analgesia was patient-controlled opioid analgesia (PCA) for 52%. A 'restrictive' intravenous fluid therapy was preferred by 34 (49%) while 33 (48%) preferred no fluid restriction. A prolonged 'nil by mouth' status was preferred by 28%. CONCLUSION: There appears to be a high rate of evidence in agreement with some interventions but not others. The systemic barriers to implementing evidence-based perioperative care need attention. PMID- 20958907 TI - Standard protocol for assessment of colon cancer improves the quality of pathology. AB - AIM: Tumour stage is the most important prognostic factor in colon cancer. The aim of this study was to examine the impact on the quality of pathology of the use of a standardized pathological and anatomical (PAD) protocol. METHOD: A standardized PAD protocol for colorectal cancer was developed and all patients subjected to colon resection due to adenocarcinomas between 2004 and 2006 were analysed regarding lymph node status, circumferential resection margin (CRM), and intravascular and perineural growth. Moreover, usage of the PAD protocol and whether a pathologist or biomedicine analytical technician (BMA) performed the lymph node dissection was noted, and also whether the surgical procedure was elective or acute. RESULTS: During the study period 302 colon resections were carried out. The standard protocol was employed in 68% of the cases, varying from 0% to 100% between pathologists. The median number of investigated lymph nodes was 16 +/- 11. When the lymph node dissection was performed by a BMA, significantly more lymph nodes were examined; 22 +/- 15 and 14 +/- 9, respectively (P < 0.01). There was a positive correlation between application of the standard protocol and the number of analysed lymph nodes (< 0.05). Comments on CRM, perineural growth and intravascular growth were also significantly more frequent when the protocol was used. Emergency surgery did not influence the handling of the specimens. CONCLUSION: Minor changes in procedure in terms of a standard protocol for pathology and specimen dissection by BMAs, leading to an increased quality of the PAD-report, may also improve the long-term outcome for patients. PMID- 20958908 TI - Isolated colonic inertia is not usually the cause of chronic constipation. AB - AIM: Chronic constipation is classified as outlet obstruction, colonic inertia or both. We aimed to determine the incidence of isolated colonic inertia in chronic constipation and to study symptom pattern in those with prolonged colonic transit time. METHODS: Chronic constipation patients were classified radiologically by surgeon-reported defaecating proctography and transit study into four groups: isolated outlet obstruction, isolated colonic inertia, outlet obstruction plus colonic inertia, or normal. Symptom patterns were defined as stool infrequency (twice weekly or less) or frequent unsuccessful evacuations (more than twice weekly). RESULTS: Of 541 patients with chronic constipation, 289 (53%) were classified as isolated outlet obstruction, 26 (5%) as isolated colonic inertia, 159 (29%) as outlet obstruction plus colonic inertia and 67 (12%) as normal. Of 448 patients (83%) with outlet obstruction, 35% had additional colonic inertia. Only 14% of those with prolonged colonic transit time had isolated colonic inertia. Frequent unsuccessful evacuations rather than stool infrequency was the commonest symptom pattern in all three disease groups (isolated outlet obstruction 86%, isolated colonic inertia 54% and outlet obstruction plus colonic inertia 63%). CONCLUSION: Isolated colonic inertia is an unusual cause of chronic constipation. Most patients with colonic inertia have associated outlet obstruction. These data question the clinical significance of isolated colonic inertia. PMID- 20958909 TI - Primary amyloid of the colon mimicking ischemic colitis. PMID- 20958910 TI - Is routine histopathological examination of appendectomy specimens useful? A systematic review of the literature. AB - AIM: Histopathological examination of the appendix after appendectomy is routinely performed. The object of this systematic review is to determine whether routine histopathological examination of the appendix is justified. METHOD: PubMed, EMBASE, Web of Science and the Cochrane library were searched without language restriction up to 1 October 2009. All articles that reported on the incidence of histopathologically proven aberrant appendiceal pathology were included. RESULTS: Nineteen case series reported the incidence of a benign neoplasm [0.5%, weighted mean (WM)], malignant neoplasm (0.2%, WM) and other pathology (0-14%). Nine articles reported the sensitivity of the intra-operative findings to detect aberrant diagnoses. Parasitic infection was detected in 0-19%, endometriosis in 0% and granulomatosis in 0-11% of cases. Five articles addressed the consequences of aberrant pathology. Most patients with parasite infection, granulomatosis and malignant neoplasms underwent additional investigation or treatment, in contrast to patients with a benign neoplasm. CONCLUSION: The incidence of unexpected findings in appendectomy specimens is low and the intra operative diagnosis alone appears insufficient for identifying unexpected disease. The benefit of histopathology is studied inadequately. From the present available evidence, routine histopathology cannot be judged as useless. PMID- 20958911 TI - Enterolithiasis associated with sigmoid stenosis caused by foreign body introduction. PMID- 20958912 TI - Intra-operative perforation is an important predictor of local recurrence and impaired survival after abdominoperineal resection for rectal cancer. AB - AIM: Abdominoperineal resection for rectal cancer is associated with higher rates of local recurrence and poorer survival than anterior resection. The aim of this study was to evaluate the outcome of conventional abdominoperineal resection in a large national series. METHOD: The study was based on the Danish National Colorectal Cancer Database and included patients treated with abdominoperineal resection between 1 May 2001 and 31 December 2006. Follow up in the departments was supplemented with vital status in the Civil Registration System. The analysis included actuarial local and distant recurrence, and overall and cancer-specific survival. Risk factors for local recurrence, distant metastases, overall survival and cancer-specific survival were identified using multivariate analyses. RESULTS: A total of 1125 patients were followed up for a median of 57 (25-93) months. Intra-operative perforation was reported in 108 (10%) patients. The cumulative 5-year local recurrence rate was 11% [95% confidence interval (CI), 7 13)], overall survival was 56% (95% CI, 53-60) and cancer-specific survival was 68% (95% CI, 65-71). Multivariate analysis showed that perforation, tumour stage and nonradical surgery were independent risk factors for local recurrence; tumour fixation to other organs, perforation and tumour stage were independent risk factors for distant metastases; and risk factors for impaired overall survival and cancer-specific survival were age, tumour perforation, tumour stage, lymph node metastases and nonradical surgery. CONCLUSION: Intra-operative perforation is a major risk factor for local and distant recurrence and survival and therefore should be avoided. PMID- 20958914 TI - Adenocarcinoma arising in a retrorectal teratoma: case report and review of the literature. PMID- 20958913 TI - Preoperative tumour staging with multidisciplinary team assessment improves the outcome in locally advanced primary rectal cancer. AB - AIM: Multidisciplinary team meetings have been introduced as a result of developments in preoperative radiological tumour staging and neoadjuvant treatment. Multidisciplinary team recommendations will influence treatment decisions but their effect on patient outcome is unknown. The aim of this study was to assess outcome in relation to preoperative local and distant staging, with or without multidisciplinary team assessment. METHODS: A population-based registry of all patients with rectal cancer, treated in the Stockholm region from 1995 to 2004, identified 303 patients with locally advanced primary rectal cancer. The patients were classified into three groups: group 1, preoperative local and distant radiological tumour staging with discussion at a multidisciplinary team meeting; group 2, preoperative staging but no multidisciplinary team assessment; and group 3, no proper preoperative radiological staging. RESULTS: Neoadjuvant treatment was more prevalent in groups 1 and 2 than in group 3. The incidence of R0 resection differed significantly between the groups (52% in group 1, 43% in group 2 and 21% in group 3; P < 0.001). Local tumour control was achieved in 57%, 36%, and 19% of patients in groups 1, 2 and 3, respectively (P < 0.001). The estimated overall 5-year survival of patients was 30%, 28% and 12% in groups 1, 2 and 3, respectively. CONCLUSION: Preoperative radiological tumour staging in patients with locally advanced primary rectal cancer and discussion at a multidisciplinary team meeting increases the proportion of patients receiving neoadjuvant treatment and cancer specific end-points. PMID- 20958915 TI - Characteristics of primary care processes for the treatment of faecal incontinence in an urban area. AB - AIM: In this study, we investigated the adequacy of the healthcare response systems to detect and treat faecal incontinence in patients in the primary care areas (PCAs) in a core urban area of Barcelona. METHOD: Patients with a diagnosis of faecal incontinence in the study area were identified from the electronic register of diagnostic codes, and from a manual review of electronic medical records of a random sample of the study population. The remaining variables were obtained through a structured telephone interview. RESULTS: In the study population (n = 65,023) with a previously estimated prevalence of faecal incontinence of 13% [95% confidence interval (CI) 10-17%], 68 cases of faecal incontinence were detected by the health care system (prevalence: 0.10%; 95% CI, 0.08-0.13). Of these, 39 patients (68% women, 68 +/- 18 years of age) were interviewed: 18 (46%) reported symptoms lasting for longer than 5-10 years and 20 (51%) had waited for more than 5 years before seeking medical advice. Only 8 (18%) had received any treatment for faecal incontinence, and 18 (46%) reported persistent faecal incontinence at the time of the interview (Vaizey severity score 13 +/- 4/24). CONCLUSION: The detection and treatment of faecal incontinence is insufficient in primary care services. Strategies to correct this are needed. PMID- 20958916 TI - Intestinal barrier function in patients undergoing colectomy. AB - AIM: The aim of this pilot study was to determine whether the type of approach (open or laparoscopic) and the order of devascularization during laparoscopic colectomy affect intestinal barrier function, local inflammatory response and clinical outcome. METHOD: Twenty-two patients undergoing elective colectomy from April 2006 to July 2008 were randomized to two sequences of vascular ligation, starting with either the inferior mesenteric artery or the ileocolic artery. Eighteen patients scheduled for open surgery served as a prospective control group. To assess the intestinal barrier function, release of intestinal fatty acid binding protein (I-FABP; a marker of mucosal injury and ischaemia) was measured pre- and postoperatively. Mesenteric lymph nodes were harvested to assess the expression of inflammatory mediator-related genes using multiplex ligation probe amplification. The study was registered under NTR1025. RESULTS: Laparoscopic devascularization starting at the ileocolic artery resulted in a significantly increased excretion of I-FABP over time (P = 0.002). In this group, the I-FABP levels were significantly increased on postoperative days 1 and 3 compared with preoperative values (P = 0.011 and P = 0.001, respectively). There were no differences in expression of inflammatory mediator-related genes or postoperative morbidity among the groups. CONCLUSIONS: In this pilot study, devascularization commencing at the ileocolic artery during laparoscopic colectomy was associated with prolonged intestinal mucosal ischaemia. PMID- 20958917 TI - Long-term follow-up of Wilson disease: natural history, treatment, mutations analysis and phenotypic correlation. AB - BACKGROUND AND AIMS: Wilson disease (WD) is an inherited disorder of copper metabolism. When treated, the outcome can be excellent, although the long-term survival has yet to be well documented. The aim of this study was to describe the long-term outcome of a cohort of patients with WD and to assess those factors affecting the phenotypic manifestation of WD. METHODS: The presence of mutations to the ATP7B gene, the clinical manifestations, treatments and the long-term outcomes were analysed retrospectively in 117 patients with WD (59 men and 58 women, aged at evaluation 38.5 +/- 11, range 16-63 years). RESULTS: Fifty-five patients with a neurological presentation, 51 patients with a hepatic presentation and 11 asymptomatic patients were followed up for an average of 15.1 +/- 10 years (median 12 years, range 1-41 years). The H1069Q ATP7B gene mutation was the most frequent genetic variant (54.3%); the frequency of this mutation did not differ between patients with either the hepatic or the neurological presentation (P = 0.099). d-penicillamine or zinc salts (81 and 17% respectively) were used for treatment, and three patients underwent liver transplantation. The majority of symptomatic patients became asymptomatic, or improved, during the follow-up (82% patients with hepatic presentation, 69% with neurological presentation). The long-term survival of patients with WD did not differ from that of the general Czech population (P = 0.95). CONCLUSIONS: Long-term follow-up shows a satisfactory response in the great majority of adequately treated patients with WD and survival coincides with that of the general population. PMID- 20958918 TI - Altered aquaporin expression and role in apoptosis during hepatic stellate cell activation. AB - BACKGROUND: Hepatic stellate cells (HSCs) are effector cells of hepatic fibrosis contributing to excessive collagen deposition and scar matrix formation. Sustained HSC activation leads to hepatic cirrhosis, a leading cause of liver related death. Reversal of hepatic fibrosis has been attributed to the induction of HSC apoptosis. Aquaporins (AQPs) are critical proteinacious channels that mediate cellular water loss during the initiation and progression of apoptosis. AIMS: This study examined AQP expression in quiescent and activated HSCs and determined the responsiveness to AQP-dependent apoptosis. METHODS: Aquaporin gene and protein expressions in quiescent and activated HSCs were determined by reverse transcription polymerase chain reaction and Western blot analyses. AQP function was determined by cell swelling and apoptotic assays in the absence and presence of HgCl(2) , a non-specific AQP inhibitor. RESULTS: In this study, we report that activated HSCs showed no detectable expression of AQP 1, 5, 8, 9 and 12 mRNAs but expression was observed in quiescent HSCs. Similarly, AQP 0, 1, 8 and 9 protein was not detected in activated HSCs but was measured in quiescent HSCs. Dual fluorescent immunohistochemistry confirmed that AQP expression is decreased in activated HSCs in a model of liver injury. Functional studies demonstrated that quiescent HSCs were highly susceptible to osmotic challenge and apoptotic stimulus, whereas activated HSCs were less responsive. Finally, apoptosis was abrogated by the inhibition of AQP-dependent water movement. CONCLUSIONS: These findings demonstrate that increased resistance to apoptosis in activated HSCs is due, at least in part, to the changes in AQP expression and function that occur following HSC activation. PMID- 20958920 TI - Chemical space sampling in virtual screening by different crystal structures. AB - Retrospective virtual screening experiments were carried out to investigate the effects of combining hit lists from different crystal structures of the same target using consensus scoring. An in-house High Throughput Screening (HTS) dataset from PI3K-gamma was used and docked against five diverse PI3K-gamma crystal structures. The results show that consensus scoring prioritizes compounds that score moderately against individual crystal structures and is thus complementary to individual crystal structure screening leading to an increase in the diversity of hits. Enrichment factors (EFs) of the consensus score for two or three structures are often as high as or higher than the EF of the individual structures used in the consensus score. Combining four or five structures in the consensus score generally yields lower enrichments. Compounds in the top 500 of the consensus score that are also found in the top 500 of an individual X-ray structure used in the consensus score calculations yield the largest number of hits with the lowest number of false positives. PMID- 20958919 TI - Low-molecular-weight heparin in patients with advanced cirrhosis. AB - BACKGROUND & AIMS: The use of low-molecular-weight heparins (LMWH) in patients with advanced liver diseases is frequently avoided because of the enhanced risk of bleeding complications. However, many patients with impaired liver function are at a high risk of thrombosis or have an indication for therapeutic anticoagulation. Therefore, the aim of this study was to evaluate the pharmacokinetics of LMWH in patients with cirrhosis. METHODS: Eighty-four consecutive patients with cirrhosis and a clinical indication for prophylactic or therapeutic anticoagulation were included. The LMWH doses were chosen according to current guidelines. Antifactor Xa activity (anti-Xa) was assessed on two consecutive days, 4 h after drug administration. The severity of liver disease was quantified using Child-Turcotte-Pugh score, the MELD score and clinical features and was correlated with the anti-Xa value and the occurrence of complications. RESULTS: Antifactor Xa activity was negatively correlated with the severity of the liver disease, and a positive correlation was observed between antithrombin-III (AT) levels and anti-Xa value. AT itself was negatively correlated with the severity of liver disease. Seven patients had an episode of variceal bleeding. No patient died during the observation interval and no thromboembolic events occurred. CONCLUSION: Prophylactic use of LMWH in patients with cirrhosis appears to be safe. A decreased anti-Xa value in cirrhotic patients and a negative correlation with liver function challenge the unconditional use of anti-Xa assays in LMWH monitoring in cirrhotic patients and reveals a potential limitation of anti-Xa analysis in these patients. Low levels of AT, because of reduced hepatic synthesis, are the most likely cause of this phenomenon. PMID- 20958921 TI - Quantitative structure activity relationship study of 2,4,6-trisubstituted-s triazine derivatives as antimalarial inhibitors of Plasmodium falciparum dihydrofolate reductase. AB - This study presents a quantitative structure activity relationships (QSAR) study on a pool of 19 bio-active s-triazine compounds. Molecular descriptors, kappa {1kappa}, chi {3chi}, x component of the dipole moment (MU(x) ), Coulson charge (q(N) ) on the nitrogen atom sandwiched between the two substituted carbons of the triazine ring, and total energy (E(T) ) obtained from AM1 calculations provide valuable information and have a significant role in the assessment of dihydrofolate reductase (DHFR) inhibitory activity of the compounds. By using the Genetic Function Approach (GFA) technique, five QSAR models have been drawn up with the help of these calculated descriptors and DHFR inhibitory activity data of the molecules. Among the obtained QSAR models presented in the study, statistically the most significant one is a four-parameter linear equation with the Lack-of-Fit value 0.5624, squared correlation coefficient R2 value of 0.7697, and the squared cross-validated correlation coefficient R2(CV) value of 0.6469. The results are discussed in light of the main factors that influence the DHFR inhibitory activity. PMID- 20958922 TI - Selenopeptide analogs of EETI-II retain potent trypsin inhibitory activities. AB - Three-disulfide-bridged Ecballium elaterium trypsin inhibitor II (EETI-II) is a 28-residue peptide that belongs to the squash family of canonical trypsin inhibitors. Herein, we report synthesis and biological activity of three EETI-II analogs. In each of analog, a pair of cysteine residues forming a native disulfide bridge was individually replaced by a pair of selenocysteine residues. All selenopeptide analogs were chemically synthesized using the Fmoc protocol and subsequently folded in the presence of oxidized and reduced glutathione. The analogs containing a diselenide bridge displayed association constants with trypsin that ranged from 2.6 x 10(9) to 5.1 x 10(9) [M(-1) ]. Our results suggest that the selenopeptide analogs retained low nanomolar inhibitory potencies, and only the diselenide bridge adjacent to the inhibitory binding loop weakened the interactions with trypsin by approximately fivefold. We discuss these findings in the context of a broader use of selenopeptide analogs as proxies to study cysteine-rich peptides. PMID- 20958923 TI - Temperature dependence of haemoglobin-oxygen affinity in heterothermic vertebrates: mechanisms and biological significance. AB - As demonstrated by August Krogh et al. a century ago, the oxygen-binding reaction of vertebrate haemoglobin is cooperative (described by sigmoid O(2) equilibrium curves) and modulated by CO(2) and protons (lowered pH) that - in conjunction with later discovered allosteric effectors (chloride, lactate and organic phosphate anions) - enhance O(2) unloading from blood in relatively acidic and oxygen-poor tissues. Based on the exothermic nature of the oxygenation of the haem groups, haemoglobin-O(2) affinity also decreases with rising temperature. This thermal sensitivity favours oxygen unloading in warm working muscles, but may become detrimental in regionally heterothermic animals, for example in cold tolerant birds and mammals and warm-bodied fish, where it may perturb the balance between O(2) unloading and O(2) requirement in organs with substantially different temperatures than at the respiratory organs and thus commonly is reduced or obliterated. Given that the oxygenation of haemoglobin is linked with the endothermic release of allosteric effectors, increased effector interaction is an effective strategy that is widely exploited to achieve adaptive reductions in the temperature dependence of blood-O(2) affinity. The molecular mechanisms implicated in heterothermic vertebrates from different taxonomic groups reveal remarkable variability, both as regards the effectors implicated (protons in tunas, organic phosphates in sharks and billfish, chloride ions in ruminants and chloride and phosphate anions in the extinct woolly mammoth, etc.) and binding sites for the same effectors, indicating multiple evolutionary origins, but convergent physiological functionality (reductions in temperature dependence of O(2) -binding affinity that safeguard tissue O(2) supply). PMID- 20958924 TI - Old proteins - new locations: myoglobin, haemoglobin, neuroglobin and cytoglobin in solid tumours and cancer cells. AB - AIM: The unexpected identification of myoglobin (MB) in breast cancer prompted us to evaluate the clinico-pathological value of MB, haemoglobin (HB) and cytoglobin (CYGB) in human breast carcinoma cases. We further screened for the presence of neuroglobin (NGB) and CYGB in tumours of diverse origin, and assessed the O(2) response of HB, MB and CYGB mRNAs in cancer cell lines, to better elicit the links between this ectopic globin expression and tumour hypoxia. METHODS: Breast tumours were analysed by immunohistochemistry for HB, MB and CYGB and correlated with clinico-pathological parameters. Screening for CYGB and NGB mRNA expression in tumour entities was performed by hybridization, quantitative PCR (qPCR) and bioinformatics. Hypoxic or anoxic responses of HB, MB and CYGB mRNAs was analysed by qPCR in human Hep3B, MCF7, HeLa and RCC4 cancer cell lines. RESULTS: 78.8% of breast cancer cases were positive for MB, 77.9% were positive for HB and 55.4% expressed CYGB. The closest correlation with markers of hypoxia was observed for CYGB. Compared to the weakly positive status of MB in healthy breast tissues, invasive tumours either lost or up-regulated MB. Breast carcinomas showed the tendency to silence CYGB. HB was not seen in normal tissues and up-regulated in tumours. Beyond breast malignancies, expression levels of NGB and CYGB mRNAs were extremely low in brain tumours (glioblastoma, astrocytoma). NGB was not observed in non-brain tumours. CYGB mRNA, readily detectable in breast cancer and other tumours, is down-regulated in lung adenocarcinomas. Alpha1 globin (alpha1 globin) and Mb were co-expressed in MCF7 and HeLa cells; CYGB transcription was anoxia inducible in Hep3B and RCC4 cells. CONCLUSIONS: This is the first time that HB and CYGB are reported in breast cancer. Neither NGB nor CYGB are systematically up-regulated in tumours. The down-regulated CYGB expression in breast and lung tumours is in line with a tumour-suppressor role. Each of the screened cancer cells expresses at least one globin (i.e. main globin species: CYGB in Hep3B; alpha1 globin + MB in MCF7 and HeLa). Thus, globins exist in a wide variety of solid tumours. However, the generally weak expression of the endogenous proteins in the cancer argues against a significant contribution to tumour oxygenation. Future studies should consider that cancer-expressed globins might function in ways not directly linked to the binding and transport of oxygen. PMID- 20958925 TI - A collection of scientific reports: international symposium on neglected influenza viruses February 3-5, 2010, Amelia Island, FL, USA. PMID- 20958927 TI - Equine influenza - surveillance and control. AB - Equine influenza virus (EIV) is considered the most important respiratory virus of horses because it is highly contagious and has the potential to disrupt major equestrian events. Equine influenza (EI) can be controlled by vaccination but it has been demonstrated repeatedly in the field that antigenic drift impacts on vaccine efficacy. EI surveillance maintains awareness of emergence and international spread of antigenic variants. It not only serves as an early warning system for horse owners, trainers and veterinary clinicians but is fundamental to influenza control programmes based on vaccination. Data on outbreaks of EI and strain characterisation is reviewed annually by an Expert Surveillance Panel (ESP) including representatives from OIE and WHO. This panel makes recommendations on the need to update vaccines based on analysis of evidence of disease in well vaccinated horses, antigenic changes, genetic changes and when possible, experimental challenge data. However, the disparity in the level of surveillance and virus collection in different countries results in potentially biased information about the relative prevalence of different viruses. There is a need for increased surveillance on a global level and a greater awareness of the benefits of updating the vaccines. The vaccine companies have traditionally been slow to respond to the ESP recommendations. Veterinary clinicians have a major role to play in purchasing vaccines with epidemiologically relevant strains and promoting their benefits to their clients. PMID- 20958926 TI - Historical thoughts on influenza viral ecosystems, or behold a pale horse, dead dogs, failing fowl, and sick swine. AB - OBJECTIVES: To understand human influenza in a historical context of viral circulation in avian species, mammals, and in the environment. DESIGN: Historical review. SETTING: Global events in a variety of circumstances over more than 3,000 years time. SAMPLE: Comprehensive review of the historical literature including all major publications on pandemic and panzootic influenza. MAIN OUTCOME MEASURES: Influenza pandemics, panzootics, major epidemics and epizootics, and instances of interspecies transmission of influenza A. RESULTS: Extensive documentation of human and animal influenza over many centuries suggests that influenza A viruses have adapted to a variety of species and environmental milieu and are capable of switching between many different hosts under widely varying circumstances. CONCLUSIONS: The genetic elements of influenza A viruses circulate globally in an extensive ecosystem comprised of many avian and mammalian species and a spectrum of environments. Unstable gene constellations found in avian species become stable viruses only upon switching to secondary hosts, but may then adapt and circulate independently. It may be desirable to think of influenza A viruses as existing and evolving in a large ecosystem involving multiple hosts and environments. Implications for understanding human influenza are discussed. PMID- 20958928 TI - Infectivity and pathogenicity of canine H3N8 influenza A virus in horses. AB - BACKGROUND: Equine H3N8 influenza A viruses (EIVs) cause respiratory disease in horses and circulate among horses worldwide. In 2004, an outbreak of canine H3N8 influenza A virus (CIV) occurred among dogs in Florida and has spread among dogs in the United States (US). Genetic analyses revealed that this CIV is closely related to the recent EIVs. Although CIV-infected dogs could be the source of H3N8 influenza A virus for horses, it remains unclear whether the CIV circulating in the United States still maintains its infectivity and/or pathogenicity in horses. To address this, we investigated the infectivity and pathogenicity of CIV in horses and the receptor binding specificity of CIV. MATERIALS AND METHODS: Three horses were inoculated with A/canine/Colorado/30604/2006 (CO06, H3N8). Clinical signs and nasal swabs were recorded or collected every day. We also evaluated the virus binding to alpha2-3-linked 5-N-acetylneuraminic acid (NeuAcalpha2-3Gal) and 5-N-glycolylneuraminic acid (NeuGcalpha2-3Gal) receptor analogues. RESULTS: Although all the three horses inoculated with CO06 seroconverted, they showed only mild clinical signs and two of them showed no virus shedding. CO06 had reduced binding to NeuGcalpha2-3Gal. DISCUSSION: Our results demonstrated that CO06 had reduced proliferation ability and pathogenicity in horses. As the recognition of NeuGcalpha2-3Gal by EIV is known to be essential for binding to the equine respiratory system, the decreased binding of CO06 to NeuGcalpha2-3Gal may be one of the important factors that reduces the proliferation ability and pathogenicity of CO06 in horses. PMID- 20958929 TI - The pathogenesis of H3N8 canine influenza virus in chickens, turkeys and ducks. AB - BACKGROUND: Canine influenza virus (CIV) of the H3N8 subtype has emerged in dog populations throughout the United States where it has become endemic in kennels and animal shelters in some regions. It has not previously been determined whether the canine-adapted H3N8 influenza virus can be transmitted to chickens, turkeys or ducks which are economically important animals that are susceptible to type A influenza virus from numerous species. METHODS: Four-week-old specific pathogen-free (SPF) chickens, 3-week-old SPF turkeys and 2-week-old commercial Pekin ducks were inoculated with 10(5.2) 50% tissue culture infectious doses of CIV per bird by the intra-choanal route. The birds were observed daily, and at 2 and 4 days post-inoculation (DPI), two inoculated birds and one sham-inoculated control bird were euthanized and necropsied to evaluate gross lesions and to collect tissues for microscopic examination. Cloacal and oral swabs were collected at 2, 4 and 7 DPI to evaluate virus shed by real-time RT-PCR (rRT-PCR). Two weeks post-infection, sera were collected from all remaining birds for type A influenza antibody detection by hemagglutination inhibition assay. RESULTS: Clinical signs and gross lesions were not observed in any of the birds of any species nor did any seroconvert. Oral and Cloacal swab material was negative for virus by rRT-PCR. CONCLUSIONS: Chickens, turkeys and Pekin ducks are not susceptible to infection with CIV by simulated respiratory exposure route with the dose administered. PMID- 20958930 TI - A comparative antibody study of the potential susceptibility of Thoroughbred and non-Thoroughbred horse populations in Ireland to equine influenza virus. AB - BACKGROUND: In Ireland, horses may be protected against equine influenza virus (EIV) as a result of natural exposure or vaccination. Current mandatory vaccination programmes are targeted at highly mobile horses. A correlation between antibody levels as measured by single radial haemolysis (SRH) and protective immunity against EIV has been established. OBJECTIVES: The objective of this study was to determine the susceptibility of selected populations of horses by quantifying their antibodies to EIV. METHODS: Blood samples were collected from Thoroughbred weanlings, yearlings, racehorses and broodmares, teaser stallions and non-Thoroughbred horses. Antibodies against EIV H3N8 and H7N7 were measured by SRH. RESULTS: The order of susceptibility to Equine Influenza (EI) in the populations examined in Ireland was as follows: Thoroughbred weanlings > teasers > non-Thoroughbred horses and ponies > Thoroughbred yearlings > Thoroughbred horses in training > Thoroughbred broodmares. The H3N8 antibody levels of the weanlings, yearlings, broodmares and horses in training were similar to their H7N7 antibody levels, suggesting that their antibodies were primarily vaccinal in origin. The teasers and non Thoroughbreds had higher H3N8 antibody levels than H7N7 antibody levels, suggesting that the majority of seropositive horses in these populations had been exposed to H3N8 by natural infection. CONCLUSIONS: Weanlings, teasers and non Thoroughbred horses were identified as most susceptible to EIV. The results suggest that it would be advisable that weanlings are vaccinated prior to attendance at public sales, that teaser stallions are vaccinated prior to each breeding season and that mandatory vaccination be implemented for participation in non-Thoroughbred events. PMID- 20958931 TI - An avian outbreak associated with panzootic equine influenza in 1872: an early example of highly pathogenic avian influenza? AB - BACKGROUND: An explosive fatal epizootic in poultry, prairie chickens, turkeys, ducks and geese, occurred over much of the populated United States between 15 November and 15 December 1872. To our knowledge the scientific literature contains no mention of the nationwide 1872 poultry outbreak. OBJECTIVE: To understand avian influenza in a historical context. RESULTS: The epizootic progressed in temporal-geographic association with a well-reported panzootic of equine influenza that had begun in Canada during the last few days of September 1872. The 1872 avian epizootic was universally attributed at the time to equine influenza, a disease then of unknown etiology but widely believed to be caused by the same transmissible respiratory agent that caused human influenza. CONCLUSIONS: Another microbial agent could have caused the avian outbreak; however, its strong temporal and geographic association with the equine panzootic, and its clinical and epidemiologic features, are most consistent with highly pathogenic avian influenza. The avian epizootic could thus have been an early instance of highly pathogenic avian influenza. PMID- 20958932 TI - Systemic influenza virus H5N1 infection in cats after gastrointestinal exposure. AB - BACKGROUND: Highly pathogenic avian influenza virus (HPAIV) H5N1 infections in felids have been reported in several countries. Feeding on infected birds has been suggested as potential source of infection. OBJECTIVES: The study aimed to verify gastrointestinal infection as possible portal of entry for HPAIV H5N1 in cats. METHODS: Four cats were infected oculo-nasopharyngeally with 106 50% egg infectious dose (EID(50) ) of HPAIV H5N1 A/cat/Germany/R606/2006. Two cats were infected intravenously with 106 EID(50) and two cats were inoculated orally with 107 EID(50) HPAIV embedded in gelatine capsules to mimic gastrointestinal exposure and to avoid virus contact to oropharyngeal or respiratory tissues. Cats were monitored for 6 days by physical examination, virus excretion, and peripheral blood lymphocyte counts. Blood chemical parameters (including AST, ALT, CPK, and TBIL) and viral excretion using pharyngeal and rectal swabs were analyzed. RESULTS: Infected cats showed elevated body temperature up to 41.3 degrees C starting from day 1 or 2 p.i. All infected cats excreted virus in pharyngeal swabs within 2 days p.i. co-inciding with the development of clinical signs (anorexia, depression, and labored breathing) irrespective of the infection route. Virus dissemination occurred through cell-free and cell-associated viremia. Infected cats developed lymphopenia, hepatic necrosis, pneumonia, and significantly elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine phosphokinase (CPK), and TBIL. CONCLUSIONS: The experiments show that the gastrointestinal tract can serve as portal for the entry of HPAIV H5N1 into cats. Infection routes used did not influence viral tissue tropism and course of disease. PMID- 20958933 TI - Transmission of influenza A viruses between pigs and people, Iowa, 2002-2004. AB - BACKGROUND: Triple-reassortant (tr) viruses of human, avian, and swine origin, including H1N1, H1N2, and H3N2 subtypes, emerged in North American swine herds in 1998 and have become predominant. While sporadic human infections with classical influenza A (H1N1) and with tr-swine influenza viruses have been reported, relatively few have been documented in occupationally exposed swine workers (SW). METHODS: We conducted a 2-year (2002-2004) prospective cohort study of transmission of influenza viruses between pigs and SW from a single pork production company in Iowa. Respiratory samples were collected and tested for influenza viruses from SW and from pigs under their care through surveillance for influenza-like illnesses (ILI). Serial blood samples from study participants were tested by hemagglutination inhibition (HI) for antibody seroconversion against human and swine influenza viruses (SIV), and antibody seroprevalence was compared to age-matched urban Iowa blood donors. RESULTS: During the first year, 15 of 88 SW had ILI and were sampled; all were culture-negative for influenza. During the second year, 11 of 76 SW had ILI and were sampled; one was culture-positive for a human seasonal H3N2 virus. Among 20 swine herd ILI outbreaks sampled, influenza A virus was detected by rRT-PCR from 17 with 11 trH1N1 and five trH3N2 virus isolates cultured. During both years, HI geometric mean titers were significantly higher among SW compared to blood donor controls for three SIV: classical swine Sw/WI/238/97 (H1N1), tr Sw/IN/9K035/99 (H1N2), and trSw/IA/H02NJ56371/02 (H1N1)] (P < 0.0001). CONCLUSIONS: SW had serologic evidence for infection with both swine and human influenza viruses and were exposed to diverse influenza virus strains circulating in pigs. Influenza virus surveillance among pigs and SW should be encouraged to better understand cross-species transmission and diversity of influenza viruses at the human-swine interface. PMID- 20958934 TI - Rapid detection of the pandemic 2009 H1N1 virus M gene by real-time and gel-based RT-PCR assays. AB - BACKGROUND: Since the first pandemic 2009 H1N1 (pH1N1) virus was isolated from humans, it has also been detected in other mammalian (pigs, cats, dogs, ferrets) and avian (turkey) species, most likely because of cross-species transmission from humans. The pH1N1 contains six genes derived from swine influenza viruses (SIVs) currently circulating in North America of human- (PB1), avian- (PB2, PA), and swine- (HA, NP, and NS) origin and two genes (NA and M) derived from Eurasian SIVs. The novel genetic composition of pH1N1 necessitates development of novel molecular and serological assays to differentiate the pH1N1 virus from circulating human, swine, turkey, canine, and feline influenza viruses. METHODS: To detect and discriminate the pH1N1 from currently circulating SIVs in North America, we developed and evaluated a TaqMan probe-based real-time and a gel based RT-PCR assay, both targeting the pH1N1 matrix gene. RESULTS: The real-time and gel-based RT-PCR assays were able to specifically detect the pH1N1 M gene and differentiate it from SIVs circulating in North America, including the classical and novel human-like H1N1 influenza virus as well as H1, H2, and H3 subtype triple reassortant SIVs. Both assays were highly sensitive and specific for the pH1N1 virus. CONCLUSIONS: The newly developed pH1N1-specific real-time and gel based RT-PCR assays can be used to detect and differentiate the pH1N1 virus from currently circulating SIVs in North America. We suggest a combinational diagnostic approach where the real-time RT-PCR is used for high-throughput detection of influenza positive or suspect samples and the gel-based RT-PCR for confirmation and sequencing of the M-gene. PMID- 20958935 TI - A matrix gene-based multiplex real-time RT-PCR for detection and differentiation of 2009 pandemic H1N1 and other influenza A viruses in North America. AB - BACKGROUND: The emergence in humans of pandemic (H1N1) 2009 (pH1N1) with similarities to swine influenza viruses (SIVs) caused much concern for both human and animal health as potential for interspecies transmission was initially unknown. OBJECTIVES: The goal of this study was to develop a real-time RT-PCR test for the detection and differentiation of 2009 pH1N1 and endemic influenza A viruses in North America. METHODS: Matrix (M) gene sequences from U.S. human pH1N1 cases and U.S. SIVs were aligned to determine a suitable region for an assay target. Primers were selected to amplify all influenza A. Two probes were designed to differentiate pH1N1 (EA matrix) from endemic (NA matrix) SIVs. The assay was validated using the first U.S. pH1N1 strain, 10 human pH1N1-positive specimens and nine U.S. SIV isolates, then evaluated on 165 specimens of swine and other animal origin submitted to the Iowa State University Veterinary Diagnostic Laboratory. Results were compared to other influenza A PCR assays. Sequences from additional pH1N1 strains and contemporary H1N1 SIVs were used to assess robustness of the selected primers and probes for the intended purpose. RESULTS: The new assay's results from clinical specimens concurred with confirmatory PCR testing. The additional probe designed from sequence analysis improved detection of the NA matrix subtype when added to the reaction mixture. CONCLUSION: This assay detects and differentiates pH1N1 and US influenza A viruses in various sample matrices and species. Good bioinformatics support is critical when designing RT-PCR assays and monitoring their performance. PMID- 20958936 TI - MChip, a low density microarray, differentiates among seasonal human H1N1, North American swine H1N1, and the 2009 pandemic H1N1. AB - BACKGROUND: The MChip uses data from the hybridization of amplified viral RNA to 15 distinct oligonucleotides that target the influenza A matrix (M) gene segment. An artificial neural network (ANN) automates the interpretation of subtle differences in fluorescence intensity patterns from the microarray. The complete process from clinical specimen to identification including amplification of viral RNA can be completed in <8 hours for under US$10. OBJECTIVES: The work presented here represents an effort to expand and test the capabilities of the MChip to differentiate influenza A/H1N1 of various species origin. METHODS: The MChip ANN was trained to recognize fluorescence image patterns of a variety of known influenza A viruses, including examples of human H1N1, human H3N2, swine H1N1, 2009 pandemic influenza A H1N1, and a wide variety of avian, equine, canine, and swine influenza viruses. Robustness of the MChip ANN was evaluated using 296 blinded isolates. RESULTS: Training of the ANN was expanded by the addition of 71 well-characterized influenza A isolates and yielded relatively high accuracy (little misclassification) in distinguishing unique H1N1 strains: nine human A/H1N1 (88.9% correct), 35 human A/H3N2 (97.1% correct), 31 North American swine A/H1N1 (80.6% correct), 14 2009 pandemic A/H1N1 (87.7% correct), and 23 negative samples (91.3% correct). Genetic diversity among the swine H1N1 isolates may have contributed to the lower success rate for these viruses. CONCLUSIONS: The current study demonstrates the MChip has the capability to differentiate the genetic variations among influenza viruses with appropriate ANN training. Further selective enrichment of the ANN will improve its ability to rapidly and reliably characterize influenza viruses of unknown origin. PMID- 20958937 TI - A review of methods of analysis in contouring studies for radiation oncology. AB - Inter-observer variability in anatomical contouring is the biggest contributor to uncertainty in radiation treatment planning. Contouring studies are frequently performed to investigate the differences between multiple contours on common datasets. There is, however, no widely accepted method for contour comparisons. The purpose of this study is to review the literature on contouring studies in the context of radiation oncology, with particular consideration of the contouring comparison methods they employ. A literature search, not limited by date, was conducted using Medline and Google Scholar with key words: contour, variation, delineation, inter/intra observer, uncertainty and trial dummy-run. This review includes a description of the contouring processes and contour comparison metrics used. The use of different processes and metrics according to tumour site and other factors were also investigated with limitations described. A total of 69 relevant studies were identified. The most common tumour sites were prostate (26), lung (10), head and neck cancers (8) and breast (7).The most common metric of comparison was volume used 59 times, followed by dimension and shape used 36 times, and centre of volume used 19 times. Of all 69 publications, 67 used a combination of metrics and two used only one metric for comparison. No clear relationships between tumour site or any other factors that may influence the contouring process and the metrics used to compare contours were observed from the literature. Further studies are needed to assess the advantages and disadvantages of each metric in various situations. PMID- 20958938 TI - Voice recognition versus transcriptionist: error rates and productivity in MRI reporting. AB - PURPOSE: Despite the frequent introduction of voice recognition (VR) into radiology departments, little evidence still exists about its impact on workflow, error rates and costs. We designed a study to compare typographical errors, turnaround times (TAT) from reported to verified and productivity for VR generated reports versus transcriptionist-generated reports in MRI. METHODS: Fifty MRI reports generated by VR and 50 finalized MRI reports generated by the transcriptionist, of two radiologists, were sampled retrospectively. Two hundred reports were scrutinised for typographical errors and the average TAT from dictated to final approval. To assess productivity, the average MRI reports per hour for one of the radiologists was calculated using data from extra weekend reporting sessions. RESULTS: Forty-two % and 30% of the finalized VR reports for each of the radiologists investigated contained errors. Only 6% and 8% of the transcriptionist-generated reports contained errors. The average TAT for VR was 0 h, and for the transcriptionist reports TAT was 89 and 38.9 h. Productivity was calculated at 8.6 MRI reports per hour using VR and 13.3 MRI reports using the transcriptionist, representing a 55% increase in productivity. CONCLUSION: Our results demonstrate that VR is not an effective method of generating reports for MRI. Ideally, we would have the report error rate and productivity of a transcriptionist and the TAT of VR. PMID- 20958939 TI - Variation in mammographic appearance between projections of small breast cancers compared with radial scars. AB - AIMS: The study aims to assess variation in appearance between mammographic projections (conspicuity variation) for invasive breast cancers (IBCs) compared with radial scars (RS). Conspicuity variation has been previously described as characteristic of RS. The lesions were also compared with respect to breast density and the proportion of cases detected by one of two readers and required a third (consensus) read. MATERIALS AND METHODS: The study was approved by the BreastScreen Victoria research committee. Mammograms of 75 randomly selected invasive breast cancers, with histological diameter <=10 mm (IBC), were mixed with 67 consecutively detected RS, all from a double-reading population-based breast cancer screening programme. On blinded review, these 142 lesions were classified for mammographic findings and assessed for marked or minor conspicuity variation between views. We assessed the associations between lesion type, lesion spicules and centres, breast density, conspicuity variation and proportion detected by one reader only. RESULTS: Marked conspicuity variation was common, but not statistically different for IBC and RS (64% vs. 66%, chi(2) = 0.8, P = 0.04). Conspicuity variation did not correlate with spiculation type (long, fine or short, broad based) or lesion centres (lucent or dense) (rho < 0.05, P = 0.5), and showed no significant change with increasing Breast Imaging Reporting and Data System breast density (IBC, chi(2) = 2.3, P = 0.5; RS, chi(2) = 0.95, P = 0.6). Density did not vary by lesion type. In the screening programme, 29% of IBC (125 of 431) versus 43% of RS (32 of 75) had been detected by one of two readers (chi(2) = 2.7, P = 0.098). CONCLUSIONS: Two-thirds of small IBCs displayed marked conspicuity variation, similar to RS. Therefore, conspicuity variation does not discriminate between IBC and RS. PMID- 20958940 TI - Diagnostic accuracy of contrast-enhanced ultrasound in differentiating benign and malignant focal liver lesions: a retrospective study. AB - PURPOSE: The purpose of this study was to assess the diagnostic accuracy of our early experience with contrast-enhanced ultrasound (CEUS) in the characterisation of focal liver lesions (FLLs) using histopathology, contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI) or other imaging follow-up as the standard of reference. MATERIALS AND METHODS: Seventy-three patients with 82 FLLs who underwent liver CEUS from January 2006 to December 2008 were retrospectively reviewed. CEUS was performed with up to 4.8 mL of SonoVue(r) (Bracco, Milan, Italy) using a low mechanical index mode. The CEUS findings were compared with histopathology, or where histopathology was not available, clinical and imaging follow-up over at least 12 months was used as the standard of reference. RESULTS: Of the 82 FLLs, 50 were malignant and 32 were benign at final diagnosis. CEUS correctly identified 43 malignant FLLs, with final diagnosis confirmed by histopathology in 13 lesions and clinico-radiological follow-up in 30 lesions. Twenty-nine lesions were correctly identified as benign on CEUS, with all these lesions confirmed on clinico-radiological follow-up. CEUS demonstrated a sensitivity of 86.0% and a specificity of 90.6% in the characterisation of liver lesions as malignant, with an overall accuracy of 87.8% (P < 0.05). CONCLUSION: Our early experience has shown that CEUS can be accurate in differentiating malignant from benign FLLs and may become a useful first-line imaging tool where CT or MRI are not available or contra-indicated. PMID- 20958941 TI - Diagnostic yield of computed tomography of the brain in first episode psychosis. AB - INTRODUCTION: Brain computed tomography (CT) is inconsistently recommended worldwide in the investigative algorithm of patients presenting with first episode psychosis (FEP). The objective of this study is to investigate the clinical efficacy of brain CT in patients presenting with FEP without neurological signs in a major metropolitan teaching hospital. METHODS: The CT brain scan reports of 237 consecutive patients, for which the imaging requests or reports provided a history of FEP but no focal neurological signs, were retrospectively identified within a 6-year period in a 750-bed tertiary referral teaching hospital using the radiology information system text-search function (170 male, 67 female; mean age, 28.3 years). All reports were authored or approved by consultant radiologist. They were reviewed for the presence of any lesion that could cause psychosis and hence alter clinical management. Minor neuroradiological abnormalities were also noted. Hospital Ethics Committee registration and approval were obtained and patient informed consent was not required. RESULTS: No focal brain lesion potentially responsible for the psychosis or focal lesion requiring surgical intervention was identified in any patient. Findings unable to be directly linked to the psychosis such as evidence of small vessel ischaemic disease, arachnoid cysts, cerebral atrophy, and normal variants were present in 17.6% of patients (45 of 237 studies), none of which led to an alteration of clinical management. CONCLUSION: The results of this study postulate that brain CT should not be universally performed in the initial assessment of patients with first episode psychosis without neurological signs. PMID- 20958942 TI - Susceptibility weighted imaging: a pictorial review. AB - Susceptibility weighted imaging (SWI) is a valuable technique in the evaluation of a wide variety of intracranial pathologies. SWI is a gradient echo sequence utilising both phase and magnitude data to achieve exquisite sensitivity to tissue magnetic susceptibility effects. Normal SWI appearances and common artefacts are illustrated. Examples of SWI in common intracranial pathologies such as subarachnoid, intraventricular and intraparenchymal haemorrhage, intra axial and extra-axial tumours, pyogenic and non-pyogenic infections, trauma, neurodegenerative diseases and vascular disease including aneurysms, vascular malformations are illustrated and discussed. This pictorial essay will enable radiologists to recognise the normal, artefactual and common intracranial pathological appearances of SWI. PMID- 20958943 TI - Pictorial review: 'fishtail deformity' of the elbow. AB - Fishtail deformity of the elbow is characterised by a contour abnormality of the distal humerus, which develops when the lateral trochlear ossification centres fails to develop or resorbs. It is an uncommon complication usually following a distal humeral fracture in childhood. Whilst initially presumed to be a benign condition, long-term follow-up suggests that patients with fishtail deformity are prone to functional impairment, ongoing pain and the development of early osteoarthrosis. This paper reviews the imaging findings in fishtail deformity, the proposed aetiology and the potential long-term complications. PMID- 20958944 TI - Isolated left brachiocephalic vein aneurysm presenting as a symptomatic mediastinal mass. AB - Thoracic venous aneurysms arising from the mediastinal systemic veins are very rare conditions. We report a case of a 42-year-old female who presented with dull aching pain in the left infraclavicular region, dyspnea and palpitation since 4-5 month. Chest roentgenogram revealed superior mediastinal widening secondary to a mass. Contrast enhanced CT scan revealed a homogenously enhancing superior mediastinal mass. Selective left brachiocephalic vein venography confirmed the diagnosis of an isolated large left brachiocephalic vein saccular aneurysm. The patient is being followed up without surgical treatment. Although rare a diagnosis of innominate vein aneurysm should be considered when a uniformly attenuating mediastinal mass is seen on CT so that unnecessary biopsy and surgery can be avoided. PMID- 20958945 TI - The implementation of diagnostic reference levels to Australian radiology practice. AB - At the present time, there is no national surveillance of the increasing ionising radiation dose to the population from diagnostic imaging procedures. As the number of procedures undertaken is increasing, it is expected that the population dose will also increase. A substantial component of that contribution is from multi-detector computed tomography (MDCT) systems. The Australian Radiation Protection & Nuclear Safety Agency (ARPANSA) estimates that the growth in MDCT scans, based on Medicare Benefits Schedule data, is increasing at approximately 9% per annum, with over 2 million MDCT scans being performed in 2009. The caput effective dose (mSv) from this modality is expected to be approaching 1.2 mSv per annum. If current dose-detriment models are accurate, the risk of induction of carcinogenic detriment from current MDCT scanning patterns is a significant public health issue that requires a concerted and ongoing response. For the application of ionising radiation in medicine, the International Commission on Radiological Protection recommends the conservative philosophy of Justification and Optimisation via the measurement of 'Diagnostic Reference Levels' to limit the potential overexposure of patients and decrease the overall population burden. The Australian government has commissioned ARPANSA to survey, calculate and construct representative national diagnostic reference levels for diagnostic imaging modalities that use ionising radiation. This will be achieved in close consultation with the professional organisations who represent the professionals responsible for the use of ionising radiation in diagnostic imaging. PMID- 20958946 TI - For discussion: obtaining consent for ionising radiation: has the time come? AB - The aim of this paper is to promote debate on the issues surrounding the provision of information to, and the obtaining of valid consent from patients exposed to ionising radiation (IR) from diagnostic and interventional imaging procedures. This is especially pertinent in view of recent interest in the risks of IR expressed in the medical and lay press. PMID- 20958947 TI - Microcystic adnexal carcinoma of the skin: the role of adjuvant radiotherapy. AB - INTRODUCTION: Microcystic adnexal carcinoma (MAC) is a rare cutaneous tumour where the role of radiotherapy remains undefined. We contrast our institutional experience with current literature, define the local control rate and suggest a role for adjuvant radiotherapy in the treatment of this cancer. METHODS: From 1992-2008, a retrospective review was undertaken for MAC treated with curative intent involving surgery and adjuvant radiotherapy at the Royal Brisbane Hospital and Mater Hospital Brisbane. Clinical, pathologic and treatment details as well as patterns of recurrence were analysed. RESULTS: Fourteen cases of MAC received local excision and adjuvant radiotherapy. The median age was 71 years old, with nine of the cases in men. All cases occurred in the head and neck region with mean tumour size of 20.5 mm and mean depth of invasion of 9.9 mm. Peri-neural invasion occurred in 56% of cases and 69% had positive surgical margins. Various adjuvant radiotherapy schedules were used to treat the primary site resulting in a crude local control rate of 93%. Primary and nodal relapses were subsequently salvaged with further treatment. CONCLUSION: While Mohs micrographic surgery may be considered the gold standard, wide local excision and adjuvant radiotherapy offers comparable control rates. Doses of 50 Gy or greater should be prescribed with generous margins (3-5 cm) owing to its tendency for peri-neural and deep invasion. There was no evidence that radiotherapy can cause aggressive transformation of the tumour. The role for definitive radiotherapy remains uncertain. PMID- 20958948 TI - Involved-field radiotherapy with concurrent chemotherapy for limited-stage small cell lung cancer: disease control, patterns of failure and survival. AB - INTRODUCTION: Major randomised trials have employed elective nodal irradiation as part of combined modality therapy for limited-stage small-cell lung cancer (SCLC). The present investigation describes patterns of failure, disease control, and survival outcomes for involved-field radiotherapy with concurrent chemotherapy, without elective irradiation of uninvolved mediastinal nodal regions. METHODS: Retrospective analysis of SCLC patients treated with curative intent accelerated, twice-daily radiotherapy and concurrent platinum-based chemotherapy at an academic institution. Treatment fields were reviewed, and patients who completed >=42 Gy in 1.5 Gy twice-daily fractions to involved fields (without elective irradiation of uninvolved mediastinal lymphatic regions) were included in the present analysis. Initial patterns of failure, disease control and overall survival were recorded. RESULTS: Fifty-two patients fulfilled study criteria and were included in the present analysis. All but one patient completed three to four cycles of chemotherapy, and 10 patients experienced grade 3 acute esophagitis. At a median survivor follow-up of 35 months (range 5.5-91.9), 22 patients were alive (15 without recurrence) and 30 had died (23 of/with disease, four of unknown cause, two of other cause and one of treatment toxicity). Initial site(s) of disease failure were loco-regional only (11 patients), distant only (14) and loco-regional plus distant (3). There were no cases of isolated out-of field mediastinal recurrence in the absence of supraclavicular or more distant disease. The estimated 3-year disease-free and overall survivals were 36% and 44%, respectively. CONCLUSIONS: Involved-field radiotherapy did not appear to have an adverse impact on the anticipated patterns of failure, disease control, or overall survival in this population of limited-stage SCLC patients. PMID- 20958949 TI - Radiotherapy in treatment of carcinoma of the parotid gland, an approach for the medically or technically inoperable patient. AB - INTRODUCTION: Initial surgical resection is considered the standard of care for patients diagnosed with tumours involving the salivary glands. We reviewed our institutional outcomes of patients treated with initial radiation therapy (RT) for diagnosed carcinoma of the parotid gland. METHODS: This review examined seventeen patients that received RT as initial therapy for tumours involving the parotid gland. Fifteen patients had primary salivary gland cancer, and two patients had metastatic carcinoma to the parotid gland. Sixteen patients (94.1%) following surgical evaluation had operative risk of facial nerve impairment or sacrifice with initial surgery, four (23.5%) had clinical objective evidence of nerve involvement at evaluation, five (29.4%) were poor surgical candidates and three (17.6%) refused initial surgery. Primary tumour stages ranged T2-T4b, and disease stages ranged II-IVb. RT median dose was 70 Gy, and median follow-up was 12 months. RESULTS: Eleven patients (64.7%) achieved a clinical complete response (CR) to therapy. Of these CR patients eight (72.7%) received definitive RT and three (27.3%) underwent surgery following RT. Two surgical patients avoided facial nerve impairment while one required nerve sacrifice. The other six patients (35.3%) achieved an unfavourable response to RT and had unresectable or metastatic disease at follow-up. No long-term complications were reported. CONCLUSION: Initial radiation therapy for tumours involving the parotid gland is effective to achieve clinical CR, eliminate surgical resection for many patients, and decrease risk of facial nerve impairment or sacrifice for those patients requiring surgery following RT. PMID- 20958950 TI - The dosimetric consequences of anatomic changes in head and neck radiotherapy patients. AB - INTRODUCTION: To investigate anatomical response-related changes in the head and neck region during a course of radical radiotherapy and their impact on the planned dosimetry. METHODS: The study consisted of 10 patients with primary mucosal carcinoma. Patients' nutritional requirements were managed as per departmental protocol to minimise weight loss during treatment. Kilovoltage computed tomography (CT) scans were acquired once 40 to 50 Gy had been delivered. Gross tumour volumes (GTV) and organs at risk were delineated and the initial optimised treatment plan was overlaid on the repeat CT. Comparisons were made between scans and absolute volume variations, centres of structures, dice similarity coefficients and the subsequent dosimetric impact were assessed. RESULTS: Median weight loss at second scan was 3%. Primary and lymph node GTVs reduced by 49.9% (range 21.3-82%) and 73.7% (range 61.7-88.6%), respectively, yet continued to receive the prescribed dose. Maximum dose to spinal cord and brainstem changed minimally. Spared and un-spared parotid gland volumes reduced by median 23.5% and 20.5%, respectively, with no consistent translational displacement direction and minimal change in the mean dose. CONCLUSIONS: Despite some significant geometric changes, nutritional management ensured patient size and shape was maintained in these consecutively selected patients and subsequently there was no apparent under-dosing of targets or over-dosing of normal structures with this technique. Further investigations which model gradual change and allow cumulative dosimetry are required to better characterise what occurs during the treatment course. PMID- 20958951 TI - Variations in cone beam CT numbers as a function of patient size: in vivo demonstration in bladder cancer patients. AB - We determined Hounsfield numbers, using cone beam CT (CBCT), in the bladder of 27 muscle invasive bladder cancer patients treated with online adaptive radiotherapy using a Varian linear accelerator. The CBCT number of urine was found to increase by 130 from the thinnest to the largest patient (249 mm to 346 mm average diameter) demonstrating the effect of patient size on Hounsfield number in CBCT in vivo. PMID- 20958952 TI - RE: faculty of radiation oncology endorsed guidelines for informed consent: risk description. PMID- 20958953 TI - The redox--biochemistry of human hair pigmentation. AB - The biochemistry of hair pigmentation is a complex field involving a plethora of protein and peptide mechanisms. The in loco factory for melanin formation is the hair follicle melanocyte, but it is common knowledge that melanogenesis results from a fine tuned concerted interaction between the cells of the entire dermal papilla in the anagen hair follicle. The key enzyme is tyrosinase to initiate the active pigmentation machinery. Hence, an intricate understanding from transcription of mRNA to enzyme activity, including enzyme kinetics, substrate supply, optimal pH, cAMP signaling, is a must. Moreover, the role of reactive oxygen species on enzyme regulation and functionality needs to be taken into account. So far our knowledge on the entire hair cycle relies on the murine model of the C57BL/6 mouse. Whether this data can be translated into humans still needs to be shown. This article aims to focus on the effect of H(2)O(2)-redox homeostasis on hair follicle pigmentation via tyrosinase, its substrate supply and signal transduction as well as the role of methionine sulfoxide repair via methionine sulfoxide reductases A and B (MSRA and B). PMID- 20958954 TI - Melatonin and vitamin C increase umbilical blood flow via nitric oxide-dependent mechanisms. AB - Inadequate umbilical blood flow leads to intrauterine growth restriction, a major killer in perinatal medicine today. Nitric oxide (NO) is important in the maintenance of umbilical blood flow, and antioxidants increase NO bioavailability. What remains unknown is whether antioxidants can increase umbilical blood flow. Melatonin participates in circadian, seasonal, and reproductive physiology, but has also been reported to act as a potent endogenous antioxidant. We tested the hypothesis that treatment during pregnancy with melatonin increases umbilical blood flow via NO-dependent mechanisms. This was tested in pregnant sheep by investigating in vivo the effects on continuous measurement of umbilical blood flow of melatonin before and after NO blockade with a NO clamp. These effects of melatonin were compared with those of the traditional antioxidant, vitamin C. Under anesthesia, 12 pregnant sheep and their fetuses (0.8 of gestation) were fitted with catheters and a Transonic probe around an umbilical artery, inside the fetal abdomen. Following 5 days of recovery, cardiovascular variables were recorded during fetal i.v. treatment with either melatonin (n=6, 0.5+/-0.1 MUg/kg/min) or vitamin C (n=6, 8.9+/-0.4 mg/kg/min) before and after fetal NO blockade with the NO clamp. Fetal treatment with melatonin or vitamin C increased umbilical blood flow, independent of changes in fetal arterial blood pressure. Fetal NO blockade prevented the increase in umbilical blood flow induced by melatonin or vitamin C. Antioxidant treatment could be a useful clinical tool to increase or maintain umbilical blood flow in complicated pregnancy. PMID- 20958955 TI - Has information technology finally been adopted in Flemish intensive care units? AB - BACKGROUND: Information technology (IT) may improve the quality, safety and efficiency of medicine, and is especially useful in intensive Care Units (ICUs) as these are extremely data-rich environments with round-the-clock changing parameters. However, data regarding the implementation rates of IT in ICUs are scarce, and restricted to non-European countries. The current paper aims to provide relevant information regarding implementation of IT in Flemish ICU's (Flanders, Belgium). METHODS: The current study is based on two separate but complementary surveys conducted in the region of Flanders (Belgium): a written questionnaire in 2005 followed by a telephone survey in October 2008. We have evaluated the actual health IT adoption rate, as well as its evolution over a 3 year time frame. In addition, we documented the main benefits and obstacles for taking the decision to implement an Intensive Care Information System (ICIS). RESULTS: Currently, the computerized display of laboratory and radiology results is almost omnipresent in Flemish ICUs, (100% and 93.5%, respectively), but the computerized physician order entry (CPOE) of these examinations is rarely used. Sixty-five % of Flemish ICUs use an electronic patient record, 41.3% use CPOE for medication prescriptions, and 27% use computerized medication administration recording. The implementation rate of a dedicated ICIS has doubled over the last 3 years from 9.3% to 19%, and another 31.7% have plans to implement an ICIS within the next 3 years. Half of the tertiary non-academic hospitals and all university hospitals have implemented an ICIS, general hospitals are lagging behind with 8% implementation, however. The main reasons for postponing ICIS implementation are: (i) the substantial initial investment costs, (ii) integration problems with the hospital information system, (iii) concerns about user-friendly interfaces, (iv) the need for dedicated personnel and (v) the questionable cost-benefit ratio. CONCLUSIONS: Most ICUs in Flanders use hospital IT systems such as computerized laboratory and radiology displays. The adoption rate of ICISs has doubled over the last 3 years but is still surprisingly low, especially in general hospitals. The major reason for not implementing an ICIS is the substantial financial cost, together with the lack of arguments to ensure the cost/benefit. PMID- 20958956 TI - Pim-selective inhibitor DHPCC-9 reveals Pim kinases as potent stimulators of cancer cell migration and invasion. AB - BACKGROUND: Pim family kinases are small constitutively active serine/threonine specific kinases, elevated levels of which have been detected in human hematopoietic malignancies as well as in solid tumours. While we and others have previously shown that the oncogenic Pim kinases stimulate survival of hematopoietic cells, we now examined their putative role in regulating motility of adherent cancer cells. For this purpose, we inhibited Pim kinase activity using a small molecule compound, 1,10-dihydropyrrolo[2,3-a]carbazole-3 carbaldehyde (DHPCC-9), which we had recently identified as a potent and selective inhibitor for all Pim family members. RESULTS: We now demonstrate that the Pim kinase inhibitor DHPCC-9 is very effective also in cell-based assays. DHPCC-9 impairs the anti-apoptotic effects of Pim-1 in cytokine-deprived myeloid cells and inhibits intracellular phosphorylation of Pim substrates such as Bad. Moreover, DHPCC-9 slows down migration and invasion of cancer cells derived from either prostate cancer or squamocellular carcinoma patients. Silencing of Pim expression reduces cell motility, while Pim overexpression enhances it, strongly suggesting that the observed effects of DHPCC-9 are dependent on Pim kinase activity. Interestingly, DHPCC-9 also abrogates NFATc-dependent migration of cancer cells, implying that NFATc factors mediate at least part of the pro migratory effects of Pim kinases. CONCLUSIONS: Altogether, our data indicate that DHPCC-9 is not only a powerful tool to investigate physiological effects of the oncogenic Pim family kinases, but also an attractive molecule for drug development to inhibit invasiveness of Pim-overexpressing cancer cells. PMID- 20958957 TI - Fulminant necrotizing fasciitis following the use of herbal concoction: a case report. AB - INTRODUCTION: Necrotizing fasciitis is a rare and life-threatening rapidly progressive soft tissue infection. A fulminant case could involve muscle and bone. Necrotizing fasciitis after corticosteroid therapy and intramuscular injection of non-steroidal anti-inflammatory drugs has been reported. We present a case of fulminant necrotizing fasciitis occurring in a patient who used a herbal concoction to treat a chronic leg ulcer. CASE PRESENTATION: A 20-year-old Ibo woman from Nigeria presented with a three-year history of recurrent chronic ulcer of the right leg. She started applying a herbal concoction to dress the wound two weeks prior to presentation. This resulted in rapidly progressive soft tissue necrosis that spread from the soft tissue to the bone, despite aggressive emergency debridement. As a result she underwent above-knee amputation. CONCLUSION: The herbal concoction used is toxic, and can initiate and exacerbate necrotizing fasciitis. Its use for wound dressing should be discouraged. PMID- 20958958 TI - Assertive community treatment for elderly people with severe mental illness. AB - BACKGROUND: Adults aged 65 and older with severe mental illnesses are a growing segment of the Dutch population. Some of them have a range of serious problems and are also difficult to engage. While assertive community treatment is a common model for treating difficult to engage severe mental illnesses patients, no special form of it is available for the elderly. A special assertive community treatment team for the elderly is developed in Rotterdam, the Netherlands and tested for its effectiveness. METHODS: We will use a randomized controlled trial design to compare the effects of assertive community treatment for the elderly with those of care as usual. Primary outcome measures will be the number of dropouts, the number of patients engaged in care and patient's psychiatric symptoms, somatic symptoms, and social functioning. Secondary outcome measures are the number of unmet needs, the subjective quality of life and patients' satisfaction. Other secondary outcomes include the number of crisis contacts, rates of voluntary and involuntary admission, and length of stay. Inclusion criteria are aged 65 plus, the presence of a mental disorder, a lack of motivation for treatment and at least four suspected problems with functioning (addiction, somatic problems, daily living activities, housing etc.). If patients meet the inclusion criteria, they will be randomly allocated to either assertive community treatment for the elderly or care as usual. Trained assessors will use mainly observational instruments at the following time points: at baseline, after 9 and 18 months. DISCUSSION: This study will help establish whether assertive community treatment for the elderly produces better results than care as usual in elderly people with severe mental illnesses who are difficult to engage. When assertive community treatment for the elderly proves valuable in these respects, it can be tested and implemented more widely, and mechanisms for its effects investigated. TRIAL REGISTRATION: The Netherlands National Trial Register NTR1620. PMID- 20958959 TI - Right subclavian vein catheterism complication due to a 'foreign body': a case report. AB - INTRODUCTION: Central venous access devices are widely used in hospital practice. Complications associated with their use are well described and reviewed. In this paper, we report a former complication that in turn created a new complication during a standardized procedure. CASE PRESENTATION: We report the case of an 81 year-old Caucasian woman requiring total parenteral nutrition due to a high-debt enterocutaneous fistula. In a previous right subclavian catheterization a fragmentation of the tip of the catheter, probably not recognized at the time, provoked an extrinsic compression of the vessel. CONCLUSION: Fragmentation of a central venous catheter is a possible complication of catheterization and can be missed. Control of a catheter is imperative after its removal, even if not always practiced. PMID- 20958960 TI - Raloxifene inhibits tumor growth and lymph node metastasis in a xenograft model of metastatic mammary cancer. AB - BACKGROUND: The effects of raloxifene, a novel selective estrogen receptor modulator, were studied in a mouse metastatic mammary cancer model expressing cytoplasmic ERalpha. METHODS: Mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879luc2 cells, were subsequently treated with raloxifene at 0, 18 and 27 mg/kg/day using mini-osmotic pumps. RESULTS: In vitro study demonstrated that the ERalpha in BJMC3879luc2 cells was smaller (between 50 and 64 kDa) than the normal-sized ERalpha (66 kDa) and showed cytoplasmic localization. A statistically significant but weak estradiol response was observed in this cell line. When BJMC3879luc2 tumors were implanted into mice, the ERalpha mRNA levels were significantly higher in females than in males. In vitro studies showed that raloxifene induced mitochondria-mediated apoptosis and cell-cycle arrest in the G1-phase and a decrease in the cell population in the S phase. In animal experiments, tumor volumes were significantly suppressed in the raloxifene-treated groups. The multiplicity of lymph node metastasis was significantly decreased in the 27 mg/kg group. Levels of apoptosis were significantly increased in the raloxifene-treated groups, whereas the levels of DNA synthesis were significantly decreased in these groups. No differences in microvessel density in tumors were observed between the control and raloxifene treated groups. The numbers of dilated lymphatic vessels containing intraluminal tumor cells were significantly reduced in mammary tumors in the raloxifene treated groups. The levels of ERalpha mRNA in mammary tumors tended to be decreased in the raloxifene-treated groups. CONCLUSION: These results suggest that the antimetastatic activity of raloxifene in mammary cancer expressing cytoplasmic ERalpha may be a crucial finding with clinical applications and that raloxifene may be useful as an adjuvant therapy and for the chemoprevention of breast cancer development. PMID- 20958961 TI - Proliferation of epithelial rests of Malassez following auto-transplantation of third molars: a case report. AB - INTRODUCTION: Auto-transplantation of third molars is frequently undertaken in order to restore a perfect occlusion and to improve mastication following a substantial loss of molars. However, little is known about the precise role of the periodontal membrane during this procedure. Therefore, we investigated if the epithelial rests of Malassez persist in the periodontal ligament of auto transplanted teeth and, if so, whether these may show signs of a neuro-epithelial relationship. CASE PRESENTATION: We report a case of a 21-year-old Caucasian woman who underwent an auto-transplantation of two third molars. After two years, renewed progressive caries of the auto-transplanted teeth led to the removal of the auto-transplanted elements. The periodontal ligament was removed and studied with a light and transmission electron microscope. CONCLUSION: In this report we examined the ultrastructure of the periodontal ligament after auto transplantation in order to see if the periodontal ligament recovers completely from this intervention. We observed fully developed blood vessels and a re innervation of the epithelial rests of Malassez which were proliferating following auto-transplantation. This proliferation might be critical in the remodelling of the alveolar socket in order to provide a perfect fit for the transplanted tooth. In order to minimalise the damage to the epithelial rests of Malassez, the extraction of the tooth should be as atraumatic as possible in order to provide an optimal conservation of the periodontal ligament which will be beneficial to the healing-process. PMID- 20958962 TI - Residues at the tip of the pore loop of NR3B-containing NMDA receptors determine Ca2+ permeability and Mg2+ block. AB - BACKGROUND: Members of the complex N-methyl-D-aspartate receptor (NMDAR) subfamily of ionotropic glutamate receptors (iGluRs) conventionally assemble from NR1 and NR2 subunits, the composition of which determines receptor properties. Hallmark features of conventional NMDARs include the requirement for a coagonist, voltage-dependent block by Mg2+, and high permeability for Ca2+. Both Mg2+ sensitivity and Ca2+ permeability are critically dependent on the amino acids at the N and N+1 positions of NR1 and NR2. The recently discovered NR3 subunits feature an unprecedented glycine-arginine combination at those critical sites within the pore. Diheteromers assembled from NR1 and NR3 are not blocked by Mg2+ and are not permeable for Ca2+. RESULTS: Employing site-directed mutagenesis of receptor subunits, electrophysiological characterization of mutants in a heterologous expression system, and molecular modeling of the NMDAR pore region, we have investigated the contribution of the unusual NR3 N and N+1 site residues to the unique functional characteristics of receptors containing these subunits. Contrary to previous studies, we provide evidence that both the NR3 N and N+1 site amino acids are critically involved in mediating the unique pore properties. Ca2+ permeability could be rescued by mutating the NR3 N site glycine to the NR1 like asparagine. Voltage-dependent Mg2+ block could be established by providing an Mg2+ coordination site at either the NR3 N or N+1 positions. Conversely, "conventional" receptors assembled from NR1 and NR2 could be made Mg2+ insensitive and Ca2+ impermeable by equipping either subunit with the NR3-like glycine at their N positions, with a stronger contribution of the NR1 subunit. CONCLUSIONS: This study sheds light on the structure-function relationship of the least characterized member of the NMDAR subfamily. Contrary to previous reports, we provide evidence for a critical functional involvement of the NR3 N and N+1 site amino acids, and propose them to be the essential determinants for the unique pore properties mediated by this subunit. PMID- 20958963 TI - Successful treatment of a free-moving abdominal mass with radiation therapy guided by cone-beam computed tomography: a case report. AB - INTRODUCTION: Because tumors in the abdomen can change position, targeting these tumors for radiation therapy should be done with caution; use of daily image guided radiation therapy is advised. CASE PRESENTATION: We report the case of a 72-year-old Caucasian man with recurrent mantle cell lymphoma who was referred for palliative radiation therapy for an abdominopelvic tumor. Computed tomography was used to generate images for radiation treatment planning. Comparison of those planning images with a positron emission tomography/computed tomography scan ordered during the planning period revealed that the tumor had moved from one side of the abdomen to the other during the three-day interval between scans. To account for this unusual tumor movement, we obtained a second set of planning computed tomography scans and used a Varian cone-beam computed tomography scanner with on-board imaging capability to target the tumor before each daily treatment session, leading to successful treatment and complete resolution of the mass. CONCLUSION: Abdominal masses associated with the mesentery should be considered highly mobile; thus, radiation therapy for such masses should be used with the utmost caution. Modern radiation therapy techniques offer the ability to verify the tumor location in real time and shift the treatment ports accordingly over the course of treatment. PMID- 20958964 TI - Long term follow up results of sequential left internal thoracic artery grafts on severe left anterior descending artery disease. AB - PURPOSE: Several alternative procedures have been proposed to achieve complete revascularization in the presence of diffuse left anterior descending coronary artery (LAD) disease. With the extensive use of internal thoracic artery grafts in coronary artery bypass procedures, sequential anastomosis of the left internal thoracic artery (LITA) to LAD has gained popularity in these challenging cases. The long term results of sequential LITA to LAD anstomosis were examined in this study. PATIENTS AND METHODS: In order to determine the long term results of the sequential revascularization of LAD by LITA graft, 41 out of 49 patients operated between January 2001 and December 2005 were selected for control coronary arteriography. The median period for control coronary arteriography was 64 months. RESULTS: Seventy five anastomoses were found to be fully patent (91,46%) among the 82 sequential LITA anastomoses (41 LITA grafts) on the LAD at a median follow-up period of 64 months (53 to 123 months). Among the 41 LITA grafts used for this purpose, 36 were found intact (complete patency of the proximal and distal anastomoses) (87,8%). Two LITA grafts (4 anastomoses) were found to be totally occluded (4,87%). The proximal anastomosis of the LITA graft was observed to be 90% stenotic in one patient (1,21%). In one patient tight stenosis of the distal anastomosis line was observed (1,21%), while in another patient 70% narrowing of LITA lumen after the proximal anastomosis was detected (1,21%). CONCLUSION: We strongly beleive that sequential LITA grafting of LAD is a safe alternative in the presence of severe LAD disease to achieve complete revascularization of the anterior myocardium with patency rates not much differing from conventional single LITA to LAD anastomosis. PMID- 20958965 TI - Effects of olive oil and its minor phenolic constituents on obesity-induced cardiac metabolic changes. AB - BACKGROUND: Olive oil and its minor constituents have been recommended as important dietary therapeutic interventions in preventive medicine. However, a question remains to be addressed: what are the effects of olive oil and its phenolic compounds on obesity-induced cardiac metabolic changes? METHODS: Male Wistar rats were divided into two groups (n = 24/group): (C) receiving standard chow; (Ob) receiving hypercaloric-chow. After 21 days C and Ob groups were divided into four subgroups (n = 6/group):(C) standard-chow and saline; (C Olive)standard-chow and olive-oil (3.0 g/kg.day); (C-Oleuropein)standard-chow and oleuropein (0.023 mg/kg/day); (C-Cafeic) standard-chow and cafeic-acid (2.66 mg/kg/day); (Ob)receiving hypercaloric-chow and saline;(Ob-Olive) hypercaloric chow and olive-oil;(Ob-Oleuropein) hypercaloric-chow and oleuropein;(Ob-Cafeic) hypercaloric-chow and cafeic-acid. Treatments were given twice a week during 21 days. RESULTS: After 42 days, obesity was evidenced in Ob rats from enhanced body weight, surface-area, and body-mass-index. Energy-expenditure, oxygen consumption(VO2) and fat-oxidation were lower in Ob-group than in C. Despite no morphometric changes, Ob-Olive, Ob-Oleuropein and Ob-Cafeic groups had higher VO2, fat-oxidation, myocardial beta-hydroxyacyl coenzyme-A dehydrogenase and lower respiratory-quotient than Ob. Citrate-synthase was highest in Ob-Olive group. Myocardial lipid-hydroperoxide(LH) and antioxidant enzymes were unaffected by olive-oil and its compounds in obesity condition, whereas LH was lower and total-antioxidant-substances were higher in C-Olive and C-Oleuropein than in C. CONCLUSIONS: The present study demonstrated for the first time that olive-oil, oleuropein and cafeic-acid enhanced fat-oxidation and optimized cardiac energy metabolism in obesity conditions. Olive oil and its phenolic compounds improved myocardial oxidative stress in standard-fed conditions. PMID- 20958966 TI - PIST regulates the intracellular trafficking and plasma membrane expression of cadherin 23. AB - BACKGROUND: The atypical cadherin protein cadherin 23 (CDH23) is crucial for proper function of retinal photoreceptors and inner ear hair cells. As we obtain more and more information about the specific roles of cadherin 23 in photoreceptors and hair cells, the regulatory mechanisms responsible for the transport of this protein to the plasma membrane are largely unknown. RESULTS: PIST, a Golgi-associated, PDZ domain-containing protein, interacted with cadherin 23 via the PDZ domain of PIST and the C-terminal PDZ domain-binding interface (PBI) of cadherin 23. By binding to cadherin 23, PIST retained cadherin 23 in the trans-Golgi network of cultured cells. The retention was released when either of the two known cadherin 23-binding proteins MAGI-1 and harmonin was co-expressed. Similar to MAGI-1 and harmonin, PIST was detected in mouse inner ear sensory hair cells. CONCLUSIONS: PIST binds cadherin 23 via its PDZ domain and retains cadherin 23 in trans-Golgi network. MAGI-1 and harmonin can compete with PIST for binding cadherin 23 and release cadherin 23 from PIST's retention. Our finding suggests that PIST, MAGI-1 and harmonin collaborate in intracellular trafficking of cadherin 23 and regulate the plasma membrane expression of cadherin 23. PMID- 20958967 TI - The imprint of the Slave Trade in an African American population: mitochondrial DNA, Y chromosome and HTLV-1 analysis in the Noir Marron of French Guiana. AB - BACKGROUND: Retracing the genetic histories of the descendant populations of the Slave Trade (16th-19th centuries) is particularly challenging due to the diversity of African ethnic groups involved and the different hybridisation processes with Europeans and Amerindians, which have blurred their original genetic inheritances. The Noir Marron in French Guiana are the direct descendants of maroons who escaped from Dutch plantations in the current day Surinam. They represent an original ethnic group with a highly blended culture. Uniparental markers (mtDNA and NRY) coupled with HTLV-1 sequences (env and LTR) were studied to establish the genetic relationships linking them to African American and African populations. RESULTS: All genetic systems presented a high conservation of the African gene pool (African ancestry: mtDNA = 99.3%; NRY = 97.6%; HTLV-1 env = 20/23; HTLV-1 LTR = 6/8). Neither founder effect nor genetic drift was detected and the genetic diversity is within a range commonly observed in Africa. Higher genetic similarities were observed with the populations inhabiting the Bight of Benin (from Ivory Coast to Benin). Other ancestries were identified but they presented an interesting sex-bias. Whilst male origins spread throughout the north of the bight (from Benin to Senegal), female origins were spread throughout the south (from the Ivory Coast to Angola). CONCLUSIONS: The Noir Marron are unique in having conserved their African genetic ancestry, despite major cultural exchanges with Amerindians and Europeans through inhabiting the same region for four centuries. Their maroon identity and the important number of slaves deported in this region have maintained the original African diversity. All these characteristics permit to identify a major origin located in the former region of the Gold Coast and the Bight of Benin; regions highly impacted by slavery, from which goes a sex-biased longitudinal gradient of ancestry. PMID- 20958968 TI - Severe burn injury in Europe: a systematic review of the incidence, etiology, morbidity, and mortality. AB - INTRODUCTION: Burn injury is a serious pathology, potentially leading to severe morbidity and significant mortality, but it also has a considerable health economic impact. The aim of this study was to describe the European hospitalized population with severe burn injury, including the incidence, etiology, risk factors, mortality, and causes of death. METHODS: The systematic literature search (1985 to 2009) involved PubMed, the Web of Science, and the search engine Google. The reference lists and the Science Citation Index were used for hand searching (snowballing). Only studies dealing with epidemiologic issues (for example, incidence and outcome) as their major topic, on hospitalized populations with severe burn injury (in secondary and tertiary care) in Europe were included. Language restrictions were set on English, French, and Dutch. RESULTS: The search led to 76 eligible studies, including more than 186,500 patients in total. The annual incidence of severe burns was 0.2 to 2.9/10,000 inhabitants with a decreasing trend in time. Almost 50% of patients were younger than 16 years, and ~60% were male patients. Flames, scalds, and contact burns were the most prevalent causes in the total population, but in children, scalds clearly dominated. Mortality was usually between 1.4% and 18% and is decreasing in time. Major risk factors for death were older age and a higher total percentage of burned surface area, as well as chronic diseases. (Multi) organ failure and sepsis were the most frequently reported causes of death. The main causes of early death (< 48 hours) were burn shock and inhalation injury. CONCLUSIONS: Despite the lack of a large-scale European registration of burn injury, more epidemiologic information is available about the hospitalized population with severe burn injury than is generally presumed. National and international registration systems nevertheless remain necessary to allow better targeting of prevention campaigns and further improvement of cost-effectiveness in total burn care. PMID- 20958969 TI - Western diet enhances hepatic inflammation in mice exposed to cecal ligation and puncture. AB - BACKGROUND: Obese patients display an exaggerated morbidity during sepsis. Since consumption of a western-style diet (WD) is a major factor for obesity in the United States, the purpose of the present study was to examine the influence of chronic WD consumption on hepatic inflammation in mice made septic via cecal ligation and puncture (CLP). Feeding mice diets high in fat has been shown to enhance evidence of TLR signaling and this pathway also mediates the hepatic response to invading bacteria. Therefore, we hypothesized that the combined effects of sepsis and feeding WD on TRL-4 signaling would exacerbate hepatic inflammation. Male C57BL/6 mice were fed purified control diet (CD) or WD that was enriched in butter fat (34.4% of calories) for 3 weeks prior to CLP. Intravital microscopy was used to evaluate leukocyte adhesion in the hepatic microcirculation. To demonstrate the direct effect of saturated fatty acid on hepatocytes, C3A human hepatocytes were cultured in medium containing 100 MUM palmitic acid (PA). Quantitative real-time PCR was used to assess mRNA expression of tumor necrosis factor-alpha (TNF-alpha, monocyte chemotactic protein-1 (MCP 1), intercellular adhesion molecule-1 (ICAM-1), toll-like receptor-4 (TLR-4) and interleukin-8 (IL-8). RESULTS: Feeding WD increased firm adhesion of leukocytes in the sinusoids and terminal hepatic venules by 8-fold six hours after CLP; the increase in platelet adhesion was similar to the response observed with leukocytes. Adhesion was accompanied by enhanced expression of TNF-alpha, MCP-1 and ICAM-1. Messenger RNA expression of TLR-4 was also exacerbated in the WD+CLP group. Exposure of C3A cells to PA up-regulated IL-8 and TLR-4 expression. In addition, PA stimulated the static adhesion of U937 monocytes to C3A cells, a phenomenon blocked by inclusion of an anti-TLR-4/MD2 antibody in the culture medium. CONCLUSIONS: These findings indicate a link between obesity-enhanced susceptibility to sepsis and consumption of a western-style diet. PMID- 20958970 TI - MediPlEx - a tool to combine in silico & experimental gene expression profiles of the model legume Medicago truncatula. AB - BACKGROUND: Expressed Sequence Tags (ESTs) are in general used to gain a first insight into gene activities from a species of interest. Subsequently, and typically based on a combination of EST and genome sequences, microarray-based expression analyses are performed for a variety of conditions. In some cases, a multitude of EST and microarray experiments are conducted for one species, covering different tissues, cell states, and cell types. Under these circumstances, the challenge arises to combine results derived from the different expression profiling strategies, with the goal to uncover novel information on the basis of the integrated datasets. FINDINGS: Using our new analysis tool, MediPlEx (MEDIcago truncatula multiPLe EXpression analysis), expression data from EST experiments, oligonucleotide microarrays and Affymetrix GeneChips(r) can be combined and analyzed, leading to a novel approach to integrated transcriptome analysis. We have validated our tool via the identification of a set of well characterized AM-specific and AM-induced marker genes, identified by MediPlEx on the basis of in silico and experimental gene expression profiles from roots colonized with AM fungi. CONCLUSIONS: MediPlEx offers an integrated analysis pipeline for different sets of expression data generated for the model legume Medicago truncatula. As expected, in silico and experimental gene expression data that cover the same biological condition correlate well. The collection of differentially expressed genes identified via MediPlEx provides a starting point for functional studies in plant mutants. MediPlEx can freely be used at http://www.cebitec.uni-bielefeld.de/mediplex. PMID- 20958971 TI - The aconitate hydratase family from Citrus. AB - BACKGROUND: Research on citrus fruit ripening has received considerable attention because of the importance of citrus fruits for the human diet. Organic acids are among the main determinants of taste and organoleptic quality of fruits and hence the control of fruit acidity loss has a strong economical relevance. In citrus, organic acids accumulate in the juice sac cells of developing fruits and are catabolized thereafter during ripening. Aconitase, that transforms citrate to isocitrate, is the first step of citric acid catabolism and a major component of the citrate utilization machinery. In this work, the citrus aconitase gene family was first characterized and a phylogenetic analysis was then carried out in order to understand the evolutionary history of this family in plants. Gene expression analyses of the citrus aconitase family were subsequently performed in several acidic and acidless genotypes to elucidate their involvement in acid homeostasis. RESULTS: Analysis of 460,000 citrus ESTs, followed by sequencing of complete cDNA clones, identified in citrus 3 transcription units coding for putatively active aconitate hydratase proteins, named as CcAco1, CcAco2 and CcAco3. A phylogenetic study carried on the Aco family in 14 plant species, shows the presence of 5 Aco subfamilies, and that the ancestor of monocot and dicot species shared at least one Aco gene. Real-time RT-PCR expression analyses of the three aconitase citrus genes were performed in pulp tissues along fruit development in acidic and acidless citrus varieties such as mandarins, oranges and lemons. While CcAco3 expression was always low, CcAco1 and CcAco2 genes were generally induced during the rapid phase of fruit growth along with the maximum in acidity and the beginning of the acid reduction. Two exceptions to this general pattern were found: 1) Clemenules mandarin failed inducing CcAco2 although acid levels were rapidly reduced; and 2) the acidless "Sucrena" orange showed unusually high levels of expression of both aconitases, an observation correlating with the acidless phenotype. However, in the acidless "Dulce" lemon aconitase expression was normal suggesting that the acidless trait in this variety is not dependent upon aconitases. CONCLUSIONS: Phylogenetic studies showed the occurrence of five different subfamilies of aconitate hydratase in plants and sequence analyses identified three active genes in citrus. The pattern of expression of two of these genes, CcAco1 and CcAco2, was normally associated with the timing of acid content reduction in most genotypes. Two exceptions to this general observation suggest the occurrence of additional regulatory steps of citrate homeostasis in citrus. PMID- 20958972 TI - Effectiveness of a hand-held fan for breathlessness: a randomised phase II trial. AB - BACKGROUND: Breathlessness is common and distressing in advanced disease. This phase II study aimed to determine the use and acceptance of a hand-held fan (HHF) to relieve breathlessness, to test the effectiveness of the HHF and to evaluate the recruitment into the study. METHODS: RCT embedded within a longitudinal study testing a HHF over time compared to a wristband. Patients were included in the longitudinal study when suffering from breathlessness due to advanced cancer or COPD III/IV and could opt in the RCT. Primary outcome was use of the HHF and the wristband after two months. Secondary outcomes were recruitment into the trial and change of breathlessness severity after two months, measured on the modified Borg scale. Baseline data were collected in a personal interview and follow-up data by monthly postal questionnaires. RESULTS: 109 patients were recruited in the longitudinal study of which 70 patients (64%) participated in the RCT. Non participants had statistically significant less breathlessness (Borg mean 2.6 (SD 1.48) versus 3.7 (SD 1.83); p = 0.003) and a better functional status (Karnofsky status mean 61.9 (SD 11.2) versus 66.7 (SD 11.0); p = 0.03). Attrition due to drop out or death was high in both groups. After two months, about half of the patients used the HHF but only 20% the wristband without a statistical difference (Fisher's exact test p = 0.2). 9/16 patients judged the HHF as helpful after two months and 4/5 patients the wristband. There was no difference in mean breathlessness change scores between the HHF (Borg change score: mean 0.6 (SD 2.10)) and the wristband (mean 0.8 (SD 2.67)) after two months (p = 0.90). CONCLUSIONS: Symptom burden and low functional status did not restrain patients from participation in the study. Finding a control for a visible intervention is challenging and needs careful consideration to what is acceptable to patients. The preliminary evidence of effectiveness of the HHF could not be proved. Patients often stopped using the HHF but a small group seemed to benefit which was not necessarily related to a relief in breathlessness. Therefore, more work is necessary on selecting and identifying those who might benefit from the HHF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01123902. PMID- 20958973 TI - Low back pain in junior Australian rules football: a cross-sectional survey of elite juniors, non-elite juniors and non-football playing controls. AB - BACKGROUND: Low back pain in junior Australian Rules footballers has not been investigated despite findings that back pain is more prevalent, severe and frequent in senior footballers than non-athletic controls and findings that adolescent back pain is a strong predictor for adult back pain. The aim of this study was to determine the prevalence, intensity, quality and frequency of low back pain in junior Australian Rules footballers and a control group and to compare this data between groups. METHODS: A cross-sectional survey of male non elite junior (n = 60) and elite junior players (n = 102) was conducted along with a convenience sample of non-footballers (school children) (n = 100). Subjects completed a self-reported questionnaire on low back pain incorporating the Quadruple Visual Analogue Scale and McGill Pain Questionnaire (short form), along with additional questions adapted from an Australian epidemiological study. Linear Mixed Model (Residual Maximum Likelihood) methods were used to compare differences between groups. Log-linear models were used in the analysis of contingency tables. RESULTS: For current, average and best low back pain levels, elite junior players had higher pain levels (p < 0.001), with no difference noted between non-elite juniors and controls for average and best low back pain. For low back pain at worst, there were significant differences in the mean pain scores. The difference between elite juniors and non-elite juniors (p = 0.040) and between elite juniors and controls (p < 0.001) was significant, but not between non-elite juniors and controls. The chance of suffering low back pain increases from 45% for controls, through 55% for non-elite juniors to 66.7% for elite juniors. The chance that a pain sufferer experiences chronic pain is 16% for controls and 41% for non-elite junior and elite junior players. Elite junior players experienced low back pain more frequently (p = 0.002), with no difference in frequency noted between non-elite juniors and controls. Over 25% of elite junior and non-elite junior players reported that back pain impacted their performance some of the time or greater. CONCLUSIONS: This study demonstrated that when compared with non-elite junior players and non-footballers of a similar age, elite junior players experience back pain more severely and frequently and have higher prevalence and chronicity rates. PMID- 20958974 TI - The effects of time-released garlic powder tablets on multifunctional cardiovascular risk in patients with coronary artery disease. AB - The double-blinded placebo-controlled randomized study has been performed in 51 coronary heart disease (CHD) patients to estimate the effects of time-released garlic powder tablets Allicor on the values of 10-year prognostic risk of acute myocardial infarction (fatal and non-fatal) and sudden death, with the respect of secondary CHD prevention. It has been demonstrated that 12-month treatment with Allicor results in the significant decrease of cardiovascular risk by 1.5-fold in men (p < 0.05), and by 1.3-fold in women. The above results were equitable also in terms of relative risks. The main effect that played a role in cardiovascular risk reduction was the decrease in LDL cholesterol by 32.9 mg/dl in men (p < 0.05), and by 27.3 mg/dl in women. Thus, the most significant effects were observed in men, while in women the decrease of cardiovascular risk appeared as a trend that might be due presumably to the insufficient sample size. Since Allicor is the remedy of natural origin, it is safe with the respect to adverse effects and allows even perpetual administration that may be crucial for the secondary prevention of atherosclerotic diseases in CHD patients. PMID- 20958975 TI - Effects of legal and illegal use of benzodiazepines at acute admission to a psychiatric acute department. AB - BACKGROUND: In the psychiatric acute and emergency services patients present in severe crisis often complicated by behavioral problems, substance use, and multiple axis 1 diagnoses. In these clinical settings both legal and illegal use of benzodiazepines are difficult to evaluate since benzodiazepines could in some patients be regarded as first line treatment and in other patients as the cause of the acute psychiatric condition. The aims of this study were to evaluate the frequency and clinical effects of both legal and illegal use of benzodiazepines at admittance to a psychiatric acute department. METHODS: All patients acutely admitted to a Norwegian acute psychiatric university department serving a catchment area were asked about use of benzodiazepines, other medications and substances before admission. Patients were asked to give urine samples for analyses of benzodiazepines and substances. RESULTS: In 227 consecutive admissions there was legal use of benzodiazepines before admission in 39%, illegal use in 13% and no use in 48%. Patients with legal use of benzodiazepines were older, used more often antidepressants and a higher number of prescribed psychotropic medications. Illegal users of benzodiazepines more often used other illegal substances, were evaluated as clinically affected by a substance at admittance and were diagnosed with a substance use disorder. Patients with psychoses or major affective disorders treated with adequate medication (antidepressants, antipsychotics or mood-stabilizers) before admission more often received benzodiazepines than patients without adequate medication. CONCLUSIONS: The patients using benzodiazepines at admittance to psychiatric acute departments could be divided in illegal and legal users. The illegal users were young, used illegal substances and were more often regarded clinically affected by substances at admittance. The legal users were older, did not use other substances and were not regarded as clinically affected by substances at admittance. Benzodiazepines were used as adjuvant therapy to specific pharmacological treatment with antidepressants, antipsychotics or mood stabilizers for major psychiatric disorders. TRIAL REGISTRATION: NCT 00184119/NCT 00184132. PMID- 20958976 TI - Acute exposure of mice to high-dose ultrafine carbon black decreases susceptibility to pneumococcal pneumonia. AB - BACKGROUND: Epidemiological studies suggest that inhalation of carbonaceous particulate matter from biomass combustion increases susceptibility to bacterial pneumonia. In vitro studies report that phagocytosis of carbon black by alveolar macrophages (AM) impairs killing of Streptococcus pneumoniae. We have previously reported high levels of black carbon in AM from biomass smoke-exposed children and adults. We therefore aimed to use a mouse model to test the hypothesis that high levels of carbon loading of AM in vivo increases susceptibility to pneumococcal pneumonia. METHODS: Female outbred mice were treated with either intranasal phosphate buffered saline (PBS) or ultrafine carbon black (UF-CB in PBS; 500 MUg on day 1 and day 4), and then infected with S. pneumoniae strain D39 on day 5. Survival was assessed over 72 h. The effect of UF-CB on AM carbon loading, airway inflammation, and a urinary marker of pulmonary oxidative stress was assessed in uninfected animals. RESULTS: Instillation of UF-CB in mice resulted a pattern of AM carbon loading similar to that of biomass-smoke exposed humans. In uninfected animals, UF-CB treated animals had increased urinary 8 oxodG (P = 0.055), and an increased airway neutrophil differential count (P < 0.01). All PBS-treated mice died within 72 h after infection with S. pneumoniae, whereas morbidity and mortality after infection was reduced in UF-CB treated animals (median survival 48 h vs. 30 h, P < 0.001). At 24 hr post-infection, UF CB treated mice had lower lung and the blood S. pneumoniae colony forming unit counts, and lower airway levels of keratinocyte-derived chemokine/growth-related oncogene (KC/GRO), and interferon gamma. CONCLUSION: Acute high level loading of AM with ultrafine carbon black particles per se does not increase the susceptibility of mice to pneumococcal infection in vivo. PMID- 20958977 TI - Physiological relation between respiration activity and heterologous expression of selected benzoylformate decarboxylase variants in Escherichia coli. AB - BACKGROUND: The benzoylformate decarboxylase (BFD) from Pseudomonas putida is a biotechnologically interesting biocatalyst. It catalyses the formation of chiral 2-hydroxy ketones, which are important building blocks for stereoselective syntheses. To optimise the enzyme function often the amino acid composition is modified to improve the performance of the enzyme. So far it was assumed that a relatively small modification of the amino acid composition of a protein does not significantly influence the level of expression or media requirements. To determine, which effects these modifications might have on cultivation and product formation, six different BFD-variants with one or two altered amino acids and the wild type BFD were expressed in Escherichia coli SG13009 pKK233-2. The oxygen transfer rate (OTR) as parameter for growth and metabolic activity of the different E. coli clones was monitored on-line in LB, TB and modified PanG mineral medium with the Respiratory Activity MOnitoring System (RAMOS). RESULTS: Although the E. coli clones were genetically nearly identical, the kinetics of their metabolic activity surprisingly differed in the standard media applied. Three different types of OTR curves could be distinguished. Whereas the first type (clones expressing Leu476Pro-Ser181Thr or Leu476Pro) had typical OTR curves, the second type (clones expressing the wild type BFD, Ser181Thr or His281Ala) showed an early drop of OTR in LB and TB medium and a drastically reduced maximum OTR in modified PanG mineral medium. The third type (clone expressing Leu476Gln) behaved variable. Depending on the cultivation conditions, its OTR curve was similar to the first or the second type. It was shown, that the kinetics of the metabolic activity of the first type depended on the concentration of thiamine, which is a cofactor of BFD, in the medium. It was demonstrated that the cofactor binding strength of the different BFD-variants correlated with the differences in metabolic activity of their respective host strain. CONCLUSIONS: The BFD-variants with high cofactor binding affinity (wild type, His281Ala, Ser181Thr) obviously extract thiamine from the medium and bind it tightly to the enzyme. This might explain the hampered growth of these clones. In contrast, growth of clones expressing variants with low cofactor binding affinity (Leu476His, Leu476Pro, Leu476Pro-Ser181Thr) is not impaired. Leu476Gln has an intermediate cofactor binding strength, thus, growth of its host strain depends on the specific cultivation conditions. This paper shows that slight differences of the amino acid composition can affect protein expression and cultivation and might require an adaptation of media components. Effects such as the observed are hardly foreseeable and difficult to detect in conventional screening processes. Via small scale experiments with on-line measurements in shake flasks such effects influencing the cultivation and product formation can be detected and avoided. PMID- 20958978 TI - The spatial distribution of cis regulatory elements in yeast promoters and its implications for transcriptional regulation. AB - BACKGROUND: How the transcription factor binding sites (TFBSs) are distributed in the promoter region have implications for gene regulation. Previous studies used the translation start codon as the reference point to infer the TFBS distribution. However, it is biologically more relevant to use the transcription start site (TSS) as the reference point. In this study, we reexamined the spatial distribution of TFBSs, investigated various promoter features that may affect the distribution, and studied the effect of TFBS distribution on transcriptional regulation. RESULTS: We found a sharp peak for the distribution of TFBSs at ~115 bp upstream of the TSS, but no clear peak when the translation start codon was used as the reference point. Our analysis of sequence variation data among 63 yeast strains revealed very low deletion polymorphisms in the region between the distribution peak and the TSS, suggesting that the distances between TFBSs and the TSS have been selectively constrained in evolution. As in previous studies, we found that the nucleosome occupancy and the presence/absence of TATA-box in the promoter region affect the TFBS distribution pattern. In addition, we found that there exists a correlation between the 5'UTR length and the TFBS distribution pattern and we showed that the TFBS distribution pattern affects gene transcription level and plasticity. CONCLUSIONS: The spatial distribution of TFBSs obtained using the TSS as the reference point shows a much sharper peak than does the distribution obtained using the translation start codon as the reference point. The TFBS distribution pattern is affected by nucleosome occupancy and presence of TATA-box and it affects the transcription level and transcription plasticity of the gene. PMID- 20958979 TI - Evaluation of the endoplasmic reticulum-stress response in eIF2B-mutated lymphocytes and lymphoblasts from CACH/VWM patients. AB - BACKGROUND: Eukaryotic translation initiation factor 2B (eIF2B), a guanine nucleotide exchange factor (GEF) and a key regulator of translation initiation under normal and stress conditions, causes an autosomal recessive leukodystrophy of a wide clinical spectrum. EBV-immortalised lymphocytes (EIL) from eIF2B mutated patients exhibit a decrease in eIF2B GEF activity. eIF2B-mutated primary fibroblasts have a hyper-induction of activating transcription factor 4 (ATF4) which is involved in the protective unfolded protein response (UPR), also known as the ER-stress response. We tested the hypothesis that EIL from eIF2B-mutated patients also exhibit a heightened ER-stress response. METHODS: We used thapsigargin as an ER-stress agent and looked at polysomal profiles, rate of protein synthesis, translational activation of ATF4, and transcriptional induction of stress-specific mRNAs (ATF4, CHOP, ASNS, GRP78) in normal and eIF2B mutated EIL. We also compared the level of stress-specific mRNAs between EIL and primary lymphocytes (PL). RESULTS: Despite the low eIF2B GEF activity in the 12 eIF2B-mutated EIL cell lines tested (range 40-70% of normal), these cell lines did not differ from normal EIL in their ATF4-mediated ER-stress response. The absence of hyper-induction of ATF4-mediated ER-stress response in eIF2B-mutated EIL in contrast to primary fibroblasts is not related to their transformation by EBV. Indeed, PL exhibited a higher induction of the stress-specific mRNAs in comparison to EIL, but no hyper-induction of the UPR was noticed in the eIF2B mutated cell lines in comparison to controls. CONCLUSIONS: Taken together with work of others, our results demonstrate the absence of a major difference in ER stress response between controls and eIF2B-mutated cells. Therefore, components of the ER-stress response cannot be used as discriminatory markers in eIF2B related disorders. PMID- 20958980 TI - An effective and safe innovation for the management of vault prolapse. AB - OBJECTIVE: Considering the great variety of techniques and disagreement about the ideal route, there is a need for a simple, safe and effective method for the management of vault prolapse. STUDY DESIGN: 51 cases of post- hysterectomy vault prolapse: 45 following vaginal and 6 after total abdominal hysterectomy were treated surgically by anterior abdominal wall colpopexy with autogenous rectus fascia strips. RESULTS: Except for minor complaints like vomiting, fever and urinary retention in 3.92% cases each (n = 2 each), no major complications were encountered. Moreover, no recurrence, thus far, on follow-up. CONCLUSION: Using autogenous rectus fascia strips in anterior abdominal wall colpopexy is not only simple, cheap and effective method of treating apical prolapse but is also devoid of any serious complications as described with other techniques. PMID- 20958981 TI - Development and validation of an ELISA using a protein encoded by ORF2 antigenic domain of porcine circovirus type 2. AB - BACKGROUND: The capsid protein (ORF2) is a major structural protein of porcine circovirus type 2 (PCV2). A simple and reliable diagnostic method based on ORF2 protein immunoreactivity would serve as a valuable diagnostic method for detecting serum antibodies to PCV2 and monitoring PCV infection. Here, we reported an indirect enzyme-linked immunosorbent assay (I-ELISA) by using an antigenic domain (113-147AA) of ORF2-encoded antigen, expressed in E. coli, for diagnosis of PCV infection. RESULTS: The ELISA was performed on 288 serum samples collected from different porcine herds and compared with an indirect immunofluorescent assay (IFA). In total, 262 of 288 samples were positive as indicated by both I-ELISA and IFA. The specificity and sensitivity of I-ELISA were 87.7% and 93.57%. CONCLUSIONS: This ELISA is suitable for detection and discrimination of PCV2 infection in both SPF and farm antisera. PMID- 20958983 TI - Functional blockade of alpha5beta1 integrin induces scattering and genomic landscape remodeling of hepatic progenitor cells. AB - BACKGROUND: Cell scattering is a physiological process executed by stem and progenitor cells during embryonic liver development and postnatal organ regeneration. Here, we investigated the genomic events occurring during this process induced by functional blockade of alpha5beta1 integrin in liver progenitor cells. RESULTS: Cells treated with a specific antibody against alpha5beta1 integrin exhibited cell spreading and scattering, over-expression of liver stem/progenitor cell markers and activation of the ERK1/2 and p38 MAPKs signaling cascades, in a similar manner to the process triggered by HGF/SF1 stimulation. Gene expression profiling revealed marked transcriptional changes of genes involved in cell adhesion and migration, as well as genes encoding chromatin remodeling factors. These responses were accompanied by conspicuous spatial reorganization of centromeres, while integrin genes conserved their spatial positioning in the interphase nucleus. CONCLUSION: Collectively, our results demonstrate that alpha5beta1 integrin functional blockade induces cell migration of hepatic progenitor cells, and that this involves a dramatic remodeling of the nuclear landscape. PMID- 20958984 TI - The physical and functional borders of transit peptide-like sequences in secondary endosymbionts. AB - BACKGROUND: Plastids rely on protein supply by their host cells. In plastids surrounded by two membranes (primary plastids) targeting of these proteins is facilitated by an N-terminal targeting signal, the transit peptide. In secondary plastids (surrounded by three or four membranes), transit peptide-like regions are an essential part of a bipartite topogenic signal sequence (BTS), and generally found adjacent to a N-terminally located signal peptide of the plastid pre-proteins. As in primary plastids, for which no wealth of functional information about transit peptide features exists, the transit peptide-like regions used for import into secondary ones show some common features only, which are also poorly characterized. RESULTS: We modified the BTS (in the transit peptide-like region) of the plastid precursor fucoxanthin-chlorophyll a/c binding protein D (FcpD) fused to GFP as model substrate for the characterization of pre protein import into the secondary plastids of diatoms. Thereby we show that (i) pre-protein import is highly charge dependent. Positive net charge is necessary for transport across the plastid envelope, but not across the periplastid membrane. Acidic net charge perturbs pre-protein import within the ER. Moreover, we show that (ii) the mature domain of the pre-protein can provide intrinsic transit peptide functions. CONCLUSIONS: Our results indicate important characteristics of targeting signals of proteins imported into secondary plastids surrounded by four membranes. In addition, we show a self-targeting mechanism, in which the mature protein domain contributes to the transit peptide function. Thus, this phenomenon lowers the demand for pre-sequences evolved during the course of endosymbiosis. PMID- 20958985 TI - Dispersion of single-walled carbon nanotubes by a natural lung surfactant for pulmonary in vitro and in vivo toxicity studies. AB - BACKGROUND: Accumulating evidence indicate that the degree of dispersion of nanoparticles has a strong influence on their biological activities. The aims of this study were to develop a simple and rapid method of nanoparticle dispersion using a natural lung surfactant and to evaluate the effect of dispersion status of SWCNT on cytotoxicity and fibrogenicity in vitro and in vivo. RESULTS: The natural lung surfactant Survanta(r) was used to disperse single-walled carbon nanotubes (SWCNT) in a biological medium. At physiologically relevant concentrations, Survanta(r) produced well dispersed SWCNT without causing a cytotoxic or fibrogenic effect. In vitro studies show that Survanta(r)-dispersed SWCNT (SD-SWCNT) stimulated proliferation of lung epithelial cells at low doses (0.04-0.12 MUg/ml or 0.02-0.06 MUg/cm2 exposed surface area) but had a suppressive effect at high doses. Non-dispersed SWCNT (ND-SWCNT) did not exhibit these effects, suggesting the importance of dispersion status of SWCNT on bioactivities. Studies using cultured human lung fibroblasts show that SD-SWCNT stimulated collagen production of the cells. This result is supported by a similar observation using Acetone/sonication dispersed SWCNT (AD-SWCNT), suggesting that Survanta(r) did not mask the bioactivity of SWCNT. Likewise, in vivo studies show that both SD-SWCNT and AD-SWCNT induced lung fibrosis in mice, whereas the dispersing agent Survanta(r) alone or Survanta(r)-dispersed control ultrafine carbon black had no effect. CONCLUSIONS: The results indicate that Survanta(r) was effective in dispersing SWCNT in biological media without causing cytotoxic effects at the test concentrations used in this study. SD-SWCNT stimulated collagen production of lung fibroblasts in vitro and induced lung fibrosis in vivo. Similar results were observed with AD-SWCNT, supporting the conclusion that Survanta(r) did not mask the bioactivities of SWCNT and thus can be used as an effective dispersing agent. Since excessive collagen production is a hallmark of lung fibrosis, the results of this study suggest that the in vitro model using lung fibroblasts may be an effective and rapid screening tool for prediction of the fibrogenic potential of SWCNT in vivo. PMID- 20958986 TI - Ultrasound-guided central venous catheterization in cancer patients improves the success rate of cannulation and reduces mechanical complications: a prospective observational study of 1,978 consecutive catheterizations. AB - BACKGROUND: A central venous catheter (CVC) currently represents the most frequently adopted intravenous line for patients undergoing infusional chemotherapy and/or high-dose chemotherapy with hematopoietic stem-cell transplantation and parenteral nutrition. CVC insertion represents a risk for pneumothorax, nerve or arterial punctures. The aim of this prospective observational study was to explore the safety and efficacy of CVC insertion under ultrasound (US) guidance and to confirm its utility in clinical practice in cancer patients. METHODS: Consecutive adult patients attending the oncology hematology department were eligible if they had solid or hematologic malignancies and required CVC insertion. Four types of possible complication were defined a priore: mechanical, thrombotic, infection and malfunctioning. The patient was placed in Trendelenburg's position, a 7.5 MHZ puncturing US probe was placed in the supraclavicular site and a 16-gauge needle was advanced under real-time US guidance into the last portion of internal jugular vein. The Seldinger technique was used to place the catheter, which was advanced into the superior vena cava until insertion into right atrium. Within two hours after each procedure, an upright chest X-ray and ultrasound scanning were carried out to confirm the CVC position and to rule out a pneumotorax. CVC-related infections, symptomatic vein thrombosis and malfunctioning were recorded. RESULTS: From December 2000 to January 2009, 1,978 CVC insertional procedures were applied to 1,660 consecutive patients. The procedure was performed 580 times in patients with hematologic malignancies and 1,398 times those with solid tumors. A single-needle puncture of the vein was performed on 1,948 of 1,978 procedures (98.48%); only eighteen attempts among 1,978 failed (0.9%). No pneumotorax, no major bleeding, and no nerve puncture were reported; four cases (0.2%) showed self-limiting hematomas. The mean lifespan of CVC was 189.7 +/- 18.6 days (range 7-701). Symptomatic deep vein thrombosis of the upper limbs developed in 48 patients (2.42%). Catheter related infections occurred in 197 (9.96%) of the catheters inserted. They were successfully treated with antibiotics and only in 48 (2.9%) patients definitive CVC removal was required for infection and/or thrombosis or malfunctioning. CONCLUSIONS: This study represents the largest published series of consecutive patients with cancer undergoing CVC insertion under US guidance; this procedure allowed the completion of the therapeutic program for 1,930/1,978 (97.6%) of the catheters inserted. The absence of pneumotorax and other major complications indicates that US guidance should be mandatory for CVC insertion in patients with cancer. PMID- 20958982 TI - Differential gene expression during the moult cycle of Antarctic krill (Euphausia superba). AB - BACKGROUND: All crustaceans periodically moult to renew their exoskeleton. In krill this involves partial digestion and resorption of the old exoskeleton and synthesis of new cuticle. Molecular events that underlie the moult cycle are poorly understood in calcifying crustaceans and even less so in non-calcifying organisms such as krill. To address this we constructed an Antarctic krill cDNA microarray in order to generate gene expression profiles across the moult cycle and identify possible activation pathways. RESULTS: A total of 26 different cuticle genes were identified that showed differential gene expression across the moult cycle. Almost all cuticle genes were up regulated during premoult and down regulated during late intermoult. There were a number of transcripts with significant sequence homology to genes potentially involved in the synthesis, breakdown and resorption of chitin. During early premoult glutamine synthetase, a gene involved in generating an amino acid used in the synthesis of glucosamine, a constituent of chitin, was up regulated more than twofold. Mannosyltransferase 1, a member of the glycosyltransferase family of enzymes that includes chitin synthase was also up regulated during early premoult. Transcripts homologous to a beta-N-acetylglucosaminidase (beta-NAGase) precursor were expressed at a higher level during late intermoult (prior to apolysis) than during premoult. This observation coincided with the up regulation during late intermoult, of a coatomer subunit epsilon involved in the production of vesicles that maybe used to transport the beta-NAGase precursors into the exuvial cleft. Trypsin, known to activate the beta-NAGase precursor, was up regulated more than fourfold during premoult. The up regulation of a predicted oligopeptide transporter during premoult may allow the transport of chitin breakdown products across the newly synthesised epi- and exocuticle layers. CONCLUSION: We have identified many genes differentially expressed across the moult cycle of krill that correspond with known phenotypic structural changes. This study has provided a better understanding of the processes involved in krill moulting and how they may be controlled at the gene expression level. PMID- 20958987 TI - Interleukin-33 contributes to both M1 and M2 chemokine marker expression in human macrophages. AB - BACKGROUND: Interleukin-33 is a member of the IL-1 cytokine family whose functions are mediated and modulated by the ST2 receptor. IL-33-ST2 expression and interactions have been explored in mouse macrophages but little is known about the effect of IL-33 on human macrophages. The expression of ST2 transcript and protein levels, and IL-33-mediated effects on M1 (i.e. classical activation) and M2 (i.e. alternative activation) chemokine marker expression in human bone marrow-derived macrophages were examined. RESULTS: Human macrophages constitutively expressed the membrane-associated (i.e. ST2L) and the soluble (i.e. sST2) ST2 receptors. M2 (IL-4 + IL-13) skewing stimuli markedly increased the expression of ST2L, but neither polarizing cytokine treatment promoted the release of sST2 from these cells. When added to naive macrophages alone, IL-33 directly enhanced the expression of CCL3. In combination with LPS, IL-33 blocked the expression of the M2 chemokine marker CCL18, but did not alter CCL3 expression in these naive cells. The addition of IL-33 to M1 macrophages markedly increased the expression of CCL18 above that detected in untreated M1 macrophages. Similarly, alternatively activated human macrophages treated with IL 33 exhibited enhanced expression of CCL18 and the M2 marker mannose receptor above that detected in M2 macrophages alone. CONCLUSIONS: Together, these data suggest that primary responses to IL-33 in bone marrow derived human macrophages favors M1 chemokine generation while its addition to polarized human macrophages promotes or amplifies M2 chemokine expression. PMID- 20958988 TI - Analysis of a new strain of Euphorbia mosaic virus with distinct replication specificity unveils a lineage of begomoviruses with short Rep sequences in the DNA-B intergenic region. AB - BACKGROUND: Euphorbia mosaic virus (EuMV) is a member of the SLCV clade, a lineage of New World begomoviruses that display distinctive features in their replication-associated protein (Rep) and virion-strand replication origin. The first entirely characterized EuMV isolate is native from Yucatan Peninsula, Mexico; subsequently, EuMV was detected in weeds and pepper plants from another region of Mexico, and partial DNA-A sequences revealed significant differences in their putative replication specificity determinants with respect to EuMV-YP. This study was aimed to investigate the replication compatibility between two EuMV isolates from the same country. RESULTS: A new isolate of EuMV was obtained from pepper plants collected at Jalisco, Mexico. Full-length clones of both genomic components of EuMV-Jal were biolistically inoculated into plants of three different species, which developed symptoms indistinguishable from those induced by EuMV-YP. Pseudorecombination experiments with EuMV-Jal and EuMV-YP genomic components demonstrated that these viruses do not form infectious reassortants in Nicotiana benthamiana, presumably because of Rep-iteron incompatibility. Sequence analysis of the EuMV-Jal DNA-B intergenic region (IR) led to the unexpected discovery of a 35-nt-long sequence that is identical to a segment of the rep gene in the cognate viral DNA-A. Similar short rep sequences ranging from 35- to 51-nt in length were identified in all EuMV isolates and in three distinct viruses from South America related to EuMV. These short rep sequences in the DNA-B IR are positioned downstream to a ~160-nt non-coding domain highly similar to the CP promoter of begomoviruses belonging to the SLCV clade. CONCLUSIONS: EuMV strains are not compatible in replication, indicating that this begomovirus species probably is not a replicating lineage in nature. The genomic analysis of EuMV-Jal led to the discovery of a subgroup of SLCV clade viruses that contain in the non coding region of their DNA-B component, short rep gene sequences located downstream to a CP-promoter-like domain. This assemblage of DNA-A-related sequences within the DNA-B IR is reminiscent of polyomavirus microRNAs and could be involved in the posttranscriptional regulation of the cognate viral rep gene, an intriguing possibility that should be experimentally explored. PMID- 20958989 TI - Study on administration of 1,5-anhydro-D-fructose in C57BL/6J mice challenged with high-fat diet. AB - 1,5-Anhydro-D-fructose (AF) is a mono-saccharide directly formed from starch and glycogen by the action of alpha-1,4-glucan lyase (EC 4.2.2.13). Our previous study has indicated that AF increases glucose tolerance and insulin secretion in NMRI mice after administration through a gastric gavage in a single dose at 150 mg per mouse. In this study, we used high-fat feeding of C57BL/6J mice to examine the influence of long-term administration of AF on glucose-stimulated insulin secretion in vivo and in vitro. We found that 8-weeks of high-fat feeding increased body weight, fasting blood glucose and insulin levels in C57BL/6J mice when compared to mice fed normal diet. Impaired glucose tolerance was also observed in mice receiving 8-weeks of high-fat diet. In contrast, AF (1.5 g/kg/day), administered through drinking water for 8-weeks, did not affect body weight or food and water intake in mice fed either the high-fat or normal diet. There was no difference in basal blood glucose or insulin levels between AF treated and control group. Oral glucose tolerance test (OGTT) showed that AF did not affect glucose-stimulated insulin secretion in mice. In in vitro studies with isolated islets, AF did not influence glucose-stimulated insulin secretion in mice receiving either high-fat or normal diet. We therefore conclude that when given through drinking water for 8 weeks at 1.5 g/kg/day, AF has no effect on glucose-stimulated insulin secretion in C57BL/6J mice challenged with a high-fat diet. PMID- 20958990 TI - Reliability and concurrent validity of the Dutch hip and knee replacement expectations surveys. AB - BACKGROUND: Preoperative expectations of outcome of total hip and knee arthroplasty are important determinants of patients' satisfaction and functional outcome. Aims of the study were (1) to translate the Hospital for Special Surgery Hip Replacement Expectations Survey and Knee Replacement Expectations Survey into Dutch and (2) to study test-retest reliability and concurrent validity. METHODS: Patients scheduled for total hip (N = 112) or knee replacement (N = 101) were sent the Dutch Expectations Surveys twice with a 2 week interval to determine test-retest reliability. To determine concurrent validity, the Expectation WOMAC was sent. RESULTS: The results for the Dutch Hip Replacement Expectations Survey revealed good test-retest reliability (ICC 0.87), no bias and good internal consistency (alpha 0.86) (N = 72). The correlation between the Hip Expectations Score and the Expectation WOMAC score was 0.59 (N = 86). The results for the Dutch Knee Replacement Expectations Survey revealed good test-retest reliability (ICC 0.79), no bias and good internal consistency (alpha 0.91) (N = 46). The correlation with the Expectation WOMAC score was 0.52 (N = 57). CONCLUSIONS: Both Dutch Expectations Surveys are reliable instruments to determine patients' expectations before total hip or knee arthroplasty. As for concurrent validity, the correlation between both surveys and the Expectation WOMAC was moderate confirming that the same construct was determined. However, patients scored systematically lower on the Expectation WOMAC compared to the Dutch Expectation Surveys. Research on patients' expectations before total hip and knee replacement has only been performed in a limited amount of countries. With the Dutch Expectations Surveys it is now possible to determine patients' expectations in another culture and healthcare setting. PMID- 20958991 TI - Prominent crista terminalis mimicking a right atrial mass: case report. AB - The crista terminalis is a normal anatomical structure within the right atrium that is not normally visualised in the standard views obtained while performing a transthoracic echocardiogram. In this case report, transthoracic echocardiography suggested the presence of a right atrial mass in a patient with end stage renal disease. However, subsequent transesophageal echocardiography revealed that the right atrial mass was actually a thick muscular bridge in the right atrium consistent with a prominent crista terminalis. An understanding of the anatomy and the echocardiographic appearance of a prominent crista terminalis will minimize the misdiagnosis of this structure avoiding unnecessary expensive additional tests. PMID- 20958992 TI - "Poker" association of weekly alternating 5-fluorouracil, irinotecan, bevacizumab and oxaliplatin (FIr-B/FOx) in first line treatment of metastatic colorectal cancer: a phase II study. AB - BACKGROUND: This phase II study investigated efficacy and safety of weekly alternating Bevacizumab (BEV)/Irinotecan (CPT-11) or Oxaliplatin (OHP) associated to weekly 5-Fluorouracil (5-FU) in first line treatment of metastatic colorectal carcinoma (MCRC). METHODS: Simon two-step design: delta 20% (p0 50%, p1 70%), power 80%, alpha 5%, beta 20%. Projected objective responses (ORR): I step, 8/15 patients (pts); II step 26/43 pts. Schedule: weekly 12 h-timed-flat-infusion/5-FU 900 mg/m2, days 1-2, 8-9, 15-16, 22-23; CPT-11 160 mg/m2 plus BEV 5 mg/kg, days 1,15; OHP at three dose-levels, 60-70-80 mg/m2, days 8, 22; every 4 weeks. RESULTS: Fifty consecutive, unselected pts < 75 years were enrolled: median age 63; young-elderly (yE) 24 (48%); liver metastases (LM) 33 pts, 66% Achieved OHP recommended dose, 80 mg/m2. ORR 82% intent-to-treat and 84% as-treated analysis. Median progression-free survival 12 months. Equivalent efficacy was obtained in yE pts. Liver metastasectomies were performed in 26% of all pts and in 39% of pts with LM. After a median follow-up of 21 months, median overall survival was 28 months. Cumulative G3-4 toxicities per patient: diarrhea 28%, mucositis 6%, neutropenia 10%, hypertension 2%. They were equivalent in yE pts. Limiting toxicity syndromes (LTS), consisting of the dose-limiting toxicity, associated or not to G2 or limiting toxicities: 44% overall, 46% in yE. Multiple versus single site LTS, respectively: overall, 24% versus 20%; yE pts, 37.5% versus 8%. CONCLUSION: Poker combination shows high activity and efficacy in first line treatment of MCRC. It increases liver metastasectomies rate and can be safely administered. TRIAL REGISTRATION: Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2007-004946-34. PMID- 20958993 TI - Development of a syngeneic mouse model of epithelial ovarian cancer. AB - BACKGROUND: Most cases of ovarian cancer are epithelial in origin and diagnosed at advanced stage when the cancer is widely disseminated in the peritoneal cavity. The objective of this study was to establish an immunocompetent syngeneic mouse model of disseminated epithelial ovarian cancer (EOC) to facilitate laboratory-based studies of ovarian tumor biology and preclinical therapeutic strategies. METHODS: Individual lines of TgMISIIR-TAg transgenic mice were phenotypically characterized and backcrossed to inbred C57BL/6 mice. In addition to a previously described line of EOC-prone mice, two lines (TgMISIIR-TAg-Low) were isolated that express the oncogenic transgene, but have little or no susceptibility to tumor development. Independent murine ovarian carcinoma (MOVCAR) cell lines were established from the ascites of tumor-bearing C57BL/6 TgMISIIR-TAg transgenic mice, characterized and tested for engraftment in the following recipient mice: 1) severe immunocompromised immunodeficient (SCID), 2) wild type C57BL/6, 3) oophorectomized tumor-prone C57BL/6 TgMISIIR-TAg transgenic and 4) non-tumor prone C57BL/6 TgMISIIR-TAg-Low transgenic. Lastly, MOVCAR cells transduced with a luciferase reporter were implanted in TgMISIIR-TAg-Low mice and in vivo tumor growth monitored by non-invasive optical imaging. RESULTS: Engraftment of MOVCAR cells by i.p. injection resulted in the development of disseminated peritoneal carcinomatosis in SCID, but not wild type C57BL/6 mice. Oophorectomized tumor-prone TgMISIIR-TAg mice developed peritoneal carcinomas with high frequency, rendering them unsuitable as allograft recipients. Orthotopic or pseudo-orthotopic implantation of MOVCAR cells in TgMISIIR-TAg-Low mice resulted in the development of disseminated peritoneal tumors, frequently accompanied by the production of malignant ascites. Tumors arising in the engrafted mice bore histopathological resemblance to human high-grade serous EOC and exhibited a similar pattern of peritoneal disease spread. CONCLUSIONS: A syngeneic mouse model of human EOC was created by pseudo-orthotopic and orthotopic implantation of MOVCAR cells in a susceptible inbred transgenic host. This immunocompetent syngeneic mouse model presents a flexible system that can be used to study the consequences of altered gene expression (e.g., by ectopic expression or RNA interference strategies) in an established MOVCAR tumor cell line within the ovarian tumor microenvironment and for the development and analysis of preclinical therapeutic agents including EOC vaccines and immunotherapeutic agents. PMID- 20958994 TI - Role of LOX-1 and ROS in oxidized low-density lipoprotein induced epithelial mesenchymal transition of NRK52E. AB - BACKGROUND: To investigate the effect of oxidized low density lipoprotein receptor-1 (LOX-1) on tubular epithelial-mesenchymal transition (TEMT) induced by oxidized low-density lipoprotein (ox-LDL) and its mechanism. METHODS: NRK-52E cells were incubated with ox-LDL (0, 25, 50, and 100 MUg/ml) for 24 hours or pre treated with the chemical inhibitor of the LOX-1 receptor polyinosinic acid (poly I) and carrageenan or the antioxidant N-acetyl-L-cysteine (NAC), the cells were then exposed to 50 MUg/ml of ox-LDL.The expression of LOX-I, E-cadherin, alpha smooth muscle actin (alpha-SMA) and reactive oxygen species (ROS) were analyzed by real-time PCR, western blotting analysis, immunofluorescence and confocal laser scanning microscopy. RESULTS: Ox-LDL increased the expression of LOX-1 mRNA and protein in a dose-dependent manner from 0 to 100 MUg/ml (P < 0.05). Following the increase in the LOX-1 protein level, the lipid intake, ROS generation and alpha-SMA expression increased; however, the E-cadherin level decreased. The pre treatment with poly I or carrageenan or NAC significantly inhibited the LOX-1 expression, alpha-SMA expression, the lipid intake and ROS generation and reversed decrease of E-cadherin expression induced by ox-LDL. Meanwhile, the ROS generation were associated with a increase in the LOX-1 expression. The alpha-SMA expression was positively correlated with the ROS generation and LOX-1 expression, and the E-cadherin expression was negatively correlated with the ROS generation and LOX-1 expression. CONCLUSIONS: LOX-1 and ROS may play a important role in epithelial-mesenchymal transition of NRK52E induced by OX-LDL. PMID- 20958996 TI - Discover protein complexes in protein-protein interaction networks using parametric local modularity. AB - BACKGROUND: Recent advances in proteomic technologies have enabled us to create detailed protein-protein interaction maps in multiple species and in both normal and diseased cells. As the size of the interaction dataset increases, powerful computational methods are required in order to effectively distil network models from large-scale interactome data. RESULTS: We present an algorithm, miPALM (Module Inference by Parametric Local Modularity), to infer protein complexes in a protein-protein interaction network. The algorithm uses a novel graph theoretic measure, parametric local modularity, to identify highly connected sub-networks as candidate protein complexes. Using gold standard sets of protein complexes and protein function and localization annotations, we show our algorithm achieved an overall improvement over previous algorithms in terms of precision, recall, and biological relevance of the predicted complexes. We applied our algorithm to predict and characterize a set of 138 novel protein complexes in S. cerevisiae. CONCLUSIONS: miPALM is a novel algorithm for detecting protein complexes from large protein-protein interaction networks with improved accuracy than previous methods. The software is implemented in Matlab and is freely available at http://www.medicine.uiowa.edu/Labs/tan/software.html. PMID- 20958995 TI - Ankle manual therapy for individuals with post-acute ankle sprains: description of a randomized, placebo-controlled clinical trial. AB - BACKGROUND: Ankle sprains are common within the general population and can result in prolonged disablement. Limited talocrural dorsiflexion range of motion (DF ROM) is a common consequence of ankle sprain. Limited talocrural DF ROM may contribute to persistent symptoms, disability, and an elevated risk for re injury. As a result, many health care practitioners use hands-on passive procedures with the intention of improving talocrural joint DF ROM in individuals following ankle sprains. Dosage of passive hands-on procedures involves a continuum of treatment speeds. Recent evidence suggests both slow- and fast-speed treatments may be effective to address disablement following ankle sprains. However, these interventions have yet to be longitudinally compared against a placebo study condition. METHODS/DESIGN: We developed a randomized, placebo controlled clinical trial designed to test the hypotheses that hands-on treatment procedures administered to individuals following ankle sprains during the post acute injury period can improve short-, intermediate-, and long-term disablement, as well as reduce the risk for re-injury. DISCUSSION: This study is designed to measure the clinical effects of hands-on passive stretching treatment procedures directed to the talocrural joint that vary in treatment speed during the post acute injury period, compared to hands-on placebo control intervention. TRIAL REGISTRATION: http://www.clinicaltrials.gov identifier NCT00888498. PMID- 20958997 TI - Study protocol to a nationwide prospective cohort study on return to gainful occupation after stroke in Denmark 1996 - 2006. AB - BACKGROUND: Successful return to work is regarded as one of the most important outcome factors for working-age post stroke patients. The present study will estimate the effect of various predictors on the odds of returning to work after stroke. Nearly twenty thousand 20-57 year-old stroke patients in Denmark who were gainfully occupied prior to the stroke will be included in the study. METHODS/DESIGN: Stroke patients will be followed prospectively through national registers. Multi-level logistic regression will be used to model the odds of being gainfully occupied ca. two years after the stroke as a function of the following predictors: Age (20-49 years, 50-57 years) gender, occupational class, self-employment (yes; no), onset calendar year (1996, 1997, ..., 2006), diagnosis (subarachnoid haemorrhage; intracerebral haemorrhage; cerebral infarction; stroke, not specified as haemorrhage or infarction) and 'type of municipality' (the variable is set to 1 if the person lived in a municipality which had a brain injury rehabilitation centre at the time of the stroke. Otherwise it is set to 0). Municipalities will be treated as the subjects while individual observations within municipalities are treated as correlated repeated measurements. DISCUSSION: Since our follow-up is done through registers and all people in the target population are included, the study is free from sampling bias, recall bias and non-response bias. The study is also strengthened by its size. The major weakness of the study is that it does not contain any stroke severity measures. Thus, it cannot accurately predict whether a particular stroke patient will in fact return to work. The study is, however, quite useful from a public health perspective. It can be used to estimate the proportion of patients in a certain group that is expected to return to work, and thereby provide a comparison material, which e.g. municipalities can use to evaluate their success in returning their stroke patients to work. PMID- 20958998 TI - Brown adipose tissue: is it affected by intermittent hypoxia? AB - BACKGROUND: Intermittent hypoxia (IH), a model of sleep apnea, produces weight loss in animals. We hypothesized that changes in brown adipose tissue (BAT) function are involved in such phenomenon. We investigated the effect of IH, during 35 days, on body weight, brown adipose tissue wet weight (BATww) and total protein concentration (TPC) of BAT. METHODS: We exposed Balb/c mice to 35 days of IH (n = 12) or sham intermittent hypoxia (SIH; n = 12), alternating 30 seconds of progressive hypoxia to a nadir of 6%, followed by 30 seconds of normoxia. During 8 hours, the rodents underwent a total of 480 cycles of hypoxia/reoxygenation, equivalent to an apnea index of 60/hour. BAT was dissected and weighed while wet. Protein was measured using the Lowry protein assay. RESULTS: Body weight was significantly reduced in animals exposed to IH, at day 35, from 24.4 +/- 3.3 to 20.2 +/- 2.2 g (p = 0.0004), while in the SIH group it increased from 23.3 +/- 3.81 to 24.1 +/- 2.96 g (p = 0.23). BATww was also lower in IH than in SIH group (p = 0.00003). TPC of BAT, however, was similar in IH (204.4 +/- 44.3 MUg/100 MUL) and SIH groups (213.2 +/- 78.7 MUg/100 MUL; p = 0.74) and correlated neither with body weight nor with BATww. TPC appeared to be unaffected by exposure to IH also in multivariate analysis, adjusting for body weight and BATww. The correlation between body weight and BATww is significant (rho= 0.63) for the whole sample. When IH and SIH groups are tested separately, the correlations are no longer significant (rho = 0.48 and 0.05, respectively). CONCLUSION: IH during 35 days in a mice model of sleep apnea causes weight loss, BATww reduction, and no change in TPC of BATww. The mechanisms of weight loss under IH demands further investigation. PMID- 20958999 TI - Oxidative stress in skin fibroblasts cultures from patients with Parkinson's disease. AB - BACKGROUND: In the substantia nigra of Parkinson's disease (PD) patients, increased lipid peroxidation, decreased activities of the mitochondrial complex I of the respiratory chain, catalase and glutathione-peroxidase, and decreased levels of reduced glutathione have been reported. These observations suggest that oxidative stress and mitochondrial dysfunction play a role in the neurodegeneration in PD. We assessed enzymatic activities of respiratory chain and other enzymes involved in oxidative processes in skin fibroblasts cultures of patients with PD. METHODS: We studied respiratory chain enzyme activities, activities of total, Cu/Zn- and Mn-superoxide-dismutase, gluthatione-peroxidase and catalase, and coenzyme Q10 levels in skin fibroblasts cultures from 20 Parkinson's disease (PD) patients and 19 age- and sex- matched healthy controls. RESULTS: When compared with controls, PD patients showed significantly lower specific activities for complex V (both corrected by citrate synthase activity and protein concentrations). Oxidized, reduced and total coenzyme Q10 levels (both corrected by citrate synthase and protein concentrations), and activities of total, Cu/Zn- and Mn-superoxide-dismutase, gluthatione-peroxidase and catalase, did not differ significantly between PD-patients and control groups. Values for enzyme activities in the PD group did not correlate with age at onset, duration, scores of the Unified Parkinson's Disease Rating scales and Hoehn-Yahr staging. CONCLUSIONS: The main result of this study was the decreased activity of complex V in PD patients. This complex synthesizes ATP from ADP using an electrochemical gradient generated by complexes I-IV. These results suggest decreased energetic metabolism in fibroblasts of patients with PD. PMID- 20959000 TI - Pesticide use and opportunities of exposure among farmers and their families: cross-sectional studies 1998-2006 from Hebron governorate, occupied Palestinian territory. AB - BACKGROUND: Adverse health effects caused by pesticide exposure have been reported in occupied Palestinian territory and the world at large. The objective of this paper is to compare patterns of pesticide use in Beit-U'mmar village, West Bank, between 1998 and 2006. METHODS: We studied two populations in Beit U'mmar village, comprised of: 1) 61 male farmers and their wives in 1998 and 2) 250 male farmers in 2006. Both populations completed a structured interview, which included questions about socio-demographic factors, types of farming tasks, as well as compounds, quantities, and handling of pesticides. Using the 1998 population as a reference, we applied generalized linear regression models (GLM) and 95% confidence intervals (CI) in order to estimate prevalence differences (PD) between the two populations. RESULTS: In 1998, farmers used 47 formulated pesticides on their crops. In 2006, 16 of these pesticides were still in use, including five internationally banned compounds. There were positive changes with less use of large quantities of pesticides (>40 units/year) (PD -51; CI -0.60, 0.43), in applying the recommended dosage of pesticides (PD +0.57; CI +0.48, +0.68) and complying with the safety period (PD +0.89; CI+0.83, +0.95). Changes also included farmers' habits while applying pesticides, such as less smoking (PD -0.20; CI-0.34, -0.07) and eating at the work place (PD -0.33; CI-0.47, -0.19). No significant changes were found from 1998 to 2006 regarding use of personal protective equipment, pesticide storage, farmers' habits after applying pesticides, and in using some highly hazardous pesticides. CONCLUSIONS: The results were based on two cross-sectional surveys and should be interpreted with caution due to potential validity problems. The results of the study suggest some positive changes in the handling of pesticides amongst participants in 2006, which could be due to different policy interventions and regulations that were implemented after 1998. However, farm workers in Beit -U'mmar village are still at risk of health effects because of ongoing exposure to pesticides. To the best of our knowledge, no studies on long-term changes in pesticide use have been reported from developing countries. PMID- 20959001 TI - Male gender, Charnley class C, and severity of bone defects predict the risk for aseptic loosening in the cup of ABG I hip arthroplasty. AB - BACKGROUND: We studied which factor could predict aseptic loosening in ABG I hip prosthesis with hydroxyapatite coating. Aseptic loosening and periprosthetic osteolysis are believed to be caused, at least in part, by increased polyethylene (PE) wear rate via particle disease. Based on it, increased PE wear rate should be associated with aseptic loosening regardless of the type of implant. METHODS: We analyzed data from 155 revisions of ABG I hip prostheses to examine the influence of patient, implant, surgery, and wear related factors on the rate of aseptic loosening at the site of the cup. This was calculated by stepwise logistic regression analysis. The stability of the implant and severity of bone defects were evaluated intraoperatively. RESULTS: We found that men (odds ratio, OR = 5.6; p = 0.004), patients with Charnley class C (OR = 6.71; p = 0.013), those having more severe acetabular bone defects (OR = 4 for each degree of severity; p = 0.002), and longer time to revision surgery (OR = 1.51 for each additional year; p = 0.012) had a greater chance of aseptic loosening of the cup. However, aseptic loosening was not directly predicted by polyethylene wear rate in our patients. CONCLUSION: Severity of bone defects predicts the risk for aseptic loosening in ABG I cup. Factors potentially associated with the quality of bone bed and biomechanics of the hip might influence on the risk of aseptic loosening in this implant. PMID- 20959002 TI - Toxicogenomic analysis of exposure to TCDD, PCB126 and PCB153: identification of genomic biomarkers of exposure to AhR ligands. AB - BACKGROUND: Two year cancer bioassays conducted by the National Toxicology Program have shown chronic exposure to dioxin-like compounds (DLCs) to lead to the development of both neoplastic and non-neoplastic lesions in the hepatic tissue of female Sprague Dawley rats. Most, if not all, of the hepatotoxic effects induced by DLC's are believed to involve the binding and activation of the transcription factor, the aryl hydrocarbon receptor (AhR). Toxicogenomics was implemented to identify genomic responses that may be contributing to the development of hepatotoxicity in rats. RESULTS: Through comparative analysis of time-course microarray data, unique hepatic gene expression signatures were identified for the DLCs, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (100 ng/kg/day) and 3,3',4,4',5-pentachlorobiphenyl (PCB126) (1000 ng/kg/day) and the non-DLC 2,2',4,4',5,5',-hexachlorobiphenyl (PCB153) (1000 MUg/kg/day). A common time independent signature of 41 AhR genomic biomarkers was identified which exhibited at least a 2-fold change in expression following subchronic (13-wk) and chronic (52-wk) p.o. exposure to TCDD and PCB126, but not the non DLC, PCB153. Real time qPCR analysis validated that 30 of these genes also exhibited at least a 2-fold change in hepatic expression at 24 hr following a single exposure to TCDD (5 MUg/kg, po). Phenotypic anchoring was conducted which identified forty six genes that were differently expressed both following chronic p.o. exposure to DLCs and in previously reported studies of cholangiocarcinoma or hepatocellular adenoma. CONCLUSIONS: Together these analyses provide a comprehensive description of the genomic responses which occur in rat hepatic tissue with exposure to AhR ligands and will help to isolate those genomic responses which are contributing to the hepatotoxicity observed with exposure to DLCs. In addition, the time independent gene expression signature of the AhR ligands may assist in identifying other agents with the potential to elicit dioxin-like hepatotoxic responses. PMID- 20959004 TI - Characterization of human adenovirus 35 and derivation of complex vectors. AB - BACKGROUND: Replication-deficient recombinant adenoviral vectors based on human serotype 35 (Ad35) are desirable due to the relatively low prevalence of neutralizing antibodies in the human population. The structure of the viral genome and life cycle of Ad35 differs from the better characterized Ad5 and these differences require differences in the strategies for the generation of vectors for gene delivery. RESULTS: Sequences essential for E1 and E4 function were identified and removed and the effects of the deletions on viral gene transcription were determined. In addition, the non-essential E3 region was deleted from rAd35 vectors and a sequence was found that did not have an effect on viability but reduced viral fitness. The packaging capacity of rAd35 was dependent on pIX and vectors were generated with stable genome sizes of up to 104% of the wild type genome size. These data were used to make an E1-, E3-, E4 deleted rAd35 vector. This rAd35 vector with multiple gene deletions has the advantages of multiple blocks to viral replication (i.e., E1 and E4 deletions) and a transgene packaging capacity of 7.6 Kb, comparable to rAd5 vectors. CONCLUSIONS: The results reported here allow the generation of larger capacity rAd35 vectors and will guide the derivation of adenovirus vectors from other serotypes. PMID- 20959003 TI - A detailed genome-wide reconstruction of mouse metabolism based on human Recon 1. AB - BACKGROUND: Well-curated and validated network reconstructions are extremely valuable tools in systems biology. Detailed metabolic reconstructions of mammals have recently emerged, including human reconstructions. They raise the question if the various successful applications of microbial reconstructions can be replicated in complex organisms. RESULTS: We mapped the published, detailed reconstruction of human metabolism (Recon 1) to other mammals. By searching for genes homologous to Recon 1 genes within mammalian genomes, we were able to create draft metabolic reconstructions of five mammals, including the mouse. Each draft reconstruction was created in compartmentalized and non-compartmentalized version via two different approaches. Using gap-filling algorithms, we were able to produce all cellular components with three out of four versions of the mouse metabolic reconstruction. We finalized a functional model by iterative testing until it passed a predefined set of 260 validation tests. The reconstruction is the largest, most comprehensive mouse reconstruction to-date, accounting for 1,415 genes coding for 2,212 gene-associated reactions and 1,514 non-gene associated reactions.We tested the mouse model for phenotype prediction capabilities. The majority of predicted essential genes were also essential in vivo. However, our non-tissue specific model was unable to predict gene essentiality for many of the metabolic genes shown to be essential in vivo. Our knockout simulation of the lipoprotein lipase gene correlated well with experimental results, suggesting that softer phenotypes can also be simulated. CONCLUSIONS: We have created a high-quality mouse genome-scale metabolic reconstruction, iMM1415 (Mus Musculus, 1415 genes). We demonstrate that the mouse model can be used to perform phenotype simulations, similar to models of microbe metabolism. Since the mouse is an important experimental organism, this model should become an essential tool for studying metabolic phenotypes in mice, including outcomes from drug screening. PMID- 20959005 TI - Study of quality of life and its determinants in patients after urinary stone fragmentation. AB - BACKGROUND: This study was designed to evaluate the health-related quality of life (HRQOL) of patients who had undergone lithotripsy for treatment of urinary stones and to identify factors that significantly affect the HRQOL of these patients. METHODS: A comparative cross-sectional study was performed at the main university and main Ministry of health hospitals in Riyadh, Saudi Arabia. All patients admitted to the urology service and who underwent lithotripsy for urinary stones during a 9-month period were included in the study. An observation period of 3-15 months following the last treatment was allowed before patients completed the QOL questionnaire. Information on socio-demographic, and medical characteristics, and number and type of lithotripsies were collected. The Medical Outcome Study Short-Form 36-item survey (SF-36) was used to assess HRQoL. For comparison, the HRQoL in an equal number of healthy individuals was investigated; multivariate analysis of variance was used for comparisons between groups. RESULTS: Compared with healthy subjects, lithotripsy patients had significantly higher mean scores in the different subscales of the SF-36 questionnaire such as physical functioning, vitality, role-physical, role-emotional and mental health, indicating a better HRQOL. Compared with patients who underwent ureteroscopic or extracorporeal shock-wave lithotripsies, those who underwent percutaneous lithotripsy had significantly worse mean scores for all the SF-36 scales, except for body pain. Factors impacting HRQOL of the patients were age, obesity, diabetes mellitus, and stone characteristics such as localization (in the kidney) and recurrence (multiple lithotripsies). CONCLUSIONS: Post-lithotripsy, patients have a favorable HRQOL compared with healthy volunteers. Further prospective studies are warranted to confirm these results owing to the inherent limitations of the cross-sectional design and backward analysis of this study. PMID- 20959006 TI - Comparison of mitotic cell death by chromosome fragmentation to premature chromosome condensation. AB - Mitotic cell death is an important form of cell death, particularly in cancer. Chromosome fragmentation is a major form of mitotic cell death which is identifiable during common cytogenetic analysis by its unique phenotype of progressively degraded chromosomes. This morphology however, can appear similar to the morphology of premature chromosome condensation (PCC) and thus, PCC has been at times confused with chromosome fragmentation. In this analysis the phenomena of chromosome fragmentation and PCC are reviewed and their similarities and differences are discussed in order to facilitate differentiation of the similar morphologies. Furthermore, chromosome pulverization, which has been used almost synonymously with PCC, is re-examined. Interestingly, many past reports of chromosome pulverization are identified here as chromosome fragmentation and not PCC. These reports describe broad ranging mechanisms of pulverization induction and agree with recent evidence showing chromosome fragmentation is a cellular response to stress. Finally, biological aspects of chromosome fragmentation are discussed, including its application as one form of non-clonal chromosome aberration (NCCA), the driving force of cancer evolution. PMID- 20959007 TI - Modifiers of notch transcriptional activity identified by genome-wide RNAi. AB - BACKGROUND: The Notch signaling pathway regulates a diverse array of developmental processes, and aberrant Notch signaling can lead to diseases, including cancer. To obtain a more comprehensive understanding of the genetic network that integrates into Notch signaling, we performed a genome-wide RNAi screen in Drosophila cell culture to identify genes that modify Notch-dependent transcription. RESULTS: Employing complementary data analyses, we found 399 putative modifiers: 189 promoting and 210 antagonizing Notch activated transcription. These modifiers included several known Notch interactors, validating the robustness of the assay. Many novel modifiers were also identified, covering a range of cellular localizations from the extracellular matrix to the nucleus, as well as a large number of proteins with unknown function. Chromatin-modifying proteins represent a major class of genes identified, including histone deacetylase and demethylase complex components and other chromatin modifying, remodeling and replacement factors. A protein-protein interaction map of the Notch-dependent transcription modifiers revealed that a large number of the identified proteins interact physically with these core chromatin components. CONCLUSIONS: The genome-wide RNAi screen identified many genes that can modulate Notch transcriptional output. A protein interaction map of the identified genes highlighted a network of chromatin-modifying enzymes and remodelers that regulate Notch transcription. Our results open new avenues to explore the mechanisms of Notch signal regulation and the integration of this pathway into diverse cellular processes. PMID- 20959008 TI - Measuring newborn foot length to identify small babies in need of extra care: a cross sectional hospital based study with community follow-up in Tanzania. AB - BACKGROUND: Neonatal mortality because of low birth weight or prematurity remains high in many developing country settings. This research aimed to estimate the sensitivity and specificity, and the positive and negative predictive values of newborn foot length to identify babies who are low birth weight or premature and in need of extra care in a rural African setting. METHODS: A cross-sectional study of newborn babies in hospital, with community follow-up on the fifth day of life, was carried out between 13 July and 16 October 2009 in southern Tanzania. Foot length, birth weight and gestational age were estimated on the first day and foot length remeasured on the fifth day of life. RESULTS: In hospital 529 babies were recruited and measured within 24 hours of birth, 183 of whom were also followed-up at home on the fifth day. Day one foot length <7 cm at birth was 75% sensitive (95%CI 36-100) and 99% specific (95%CI 97-99) to identify very small babies (birth weight <1500 grams); foot length <8 cm had sensitivity and specificity of 87% (95%CI 79-94) and 60% (95%CI 55-64) to identify those with low birth weight (<2500 grams), and 93% (95%CI 82-99) and 58% (95%CI 53-62) to identify those born premature (<37 weeks). Mean foot length on the first day was 7.8 cm (standard deviation 0.47); the mean difference between first and fifth day foot lengths was 0.1 cm (standard deviation 0.3): foot length measured on or before the fifth day of life identified more than three-quarters of babies who were born low birth weight. CONCLUSION: Measurement of newborn foot length for home births in resource poor settings has the potential to be used by birth attendants, community volunteers or parents as a screening tool to identify low birth weight or premature newborns in order that they can receive targeted interventions for improved survival. PMID- 20959010 TI - Hypercalcemia and huge splenomegaly presenting in an elderly patient with B-cell non-Hodgkin's lymphoma: a case report. AB - INTRODUCTION: Hypercalcemia is the major electrolyte abnormality in patients with malignant tumors. It can be due to localized osteolytic hypercalcemia or elaboration of humoral substances such as parathyroid hormone-related protein from tumoral cells. In hematological malignancies, a third mechanism of uncontrolled synthesis and secretion of 1-25(OH)2D3 from tumoral cells or neighboring macrophages may contribute to the problem. However, hypercalcemia is quite unusual in patients with B-cell non-Hodgkin's lymphoma. CASE PRESENTATION: An 85-year-old Caucasian woman presented with low grade fever, anorexia, abdominal discomfort and fullness in her left abdomen for the last six months. She was mildly anemic and complained of fatigability. She had huge splenomegaly and was hypercalcemic. After correction of her hypercalcemia, she had a splenectomy. Microscopic evaluation revealed a malignant lymphoma. Her immunohistochemistry was positive for leukocyte common antigen, CD20 and parathyroid hormone-related peptide. CONCLUSION: Immunopositivity for parathyroid hormone-related peptide clearly demonstrates that hypersecretion of a parathyroid hormone-like substance from the tumor had led to hypercalcemia in this case. High serum calcium is seen in only seven to eight percent of patients with B-cell non Hodgkin's lymphoma, apparently due to different mechanisms. Evaluation of serum parathyroid hormone-related protein and 1-25(OH)2D3 can be helpful in diagnosis and management. It should be noted that presentation with hypercalcemia has a serious impact on prognosis and survival. PMID- 20959009 TI - Within-trial economic evaluation of diabetes-specific cognitive behaviour therapy in patients with type 2 diabetes and subthreshold depression. AB - BACKGROUND: Despite the high prevalence of subthreshold depression in patients with type 2 diabetes, evidence on cost-effectiveness of different therapy options for these patients is currently lacking. METHODS/DESIGN: Within-trial economic evaluation of the diabetes-specific cognitive behaviour therapy for subthreshold depression. Patients with diabetes and subthreshold depression are randomly assigned to either 2 weeks of diabetes-specific cognitive behaviour group therapy (n = 104) or to standard diabetes education programme only (n = 104). Patients are followed for 12 months. During this period data on total health sector costs, patient costs and societal productivity costs are collected in addition to clinical data. Health related quality of life (the SF-36 and the EQ-5D) is measured at baseline, immediately after the intervention, at 6 and at 12 months after the intervention. Quality adjusted life years (QALYs), and cumulative costs will be estimated for each arm of the trial. Cost-effectiveness of the diabetes specific cognitive behaviour group therapy will be analysed from the perspective of the German statutory health insurance and from the societal perspective. To this end, incremental cost-effectiveness ratio (ICER) in terms of cost per QALY gained will be calculated. DISCUSSION: Some methodological issues of the described economic evaluation are discussed. TRIAL REGISTRATION: The trial has been registered at the Clinical Trials Register (NCT01009138). PMID- 20959011 TI - Expression and purification of ELP-intein-tagged target proteins in high cell density E. coli fermentation. AB - BACKGROUND: Elastin-like polypeptides (ELPs) are useful tools that can be used to non-chromatographically purify proteins. When paired with self-cleaving inteins, they can be used as economical self-cleaving purification tags. However, ELPs and ELP-tagged target proteins have been traditionally expressed using highly enriched media in shake flask cultures, which are generally not amenable to scale up. RESULTS: In this work, we describe the high cell-density expression of self cleaving ELP-tagged targets in a supplemented minimal medium at a 2.5 liter fermentation scale, with increased yields and purity compared to traditional shake flask cultures. This demonstration of ELP expression in supplemented minimal media is juxtaposed to previous expression of ELP tags in extract-based rich media. We also describe several sets of fed-batch conditions and their impact on ELP expression and growth medium cost. CONCLUSIONS: By using fed batch E. coli fermentation at high cell density, ELP-intein-tagged proteins can be expressed and purified at high yield with low cost. Further, the impact of media components and fermentation design can significantly impact the overall process cost, particularly at large scale. This work thus demonstrates an important advances in the scale up of self-cleaving ELP tag-mediated processes. PMID- 20959012 TI - Obstetric near-miss and maternal mortality in maternity university hospital, Damascus, Syria: a retrospective study. AB - BACKGROUND: Investigating severe maternal morbidity (near-miss) is a newly recognised tool that identifies women at highest risk of maternal death and helps allocate resources especially in low income countries. This study aims to i. document the frequency and nature of maternal near-miss at hospital level in Damascus, Capital of Syria, ii. evaluate the level of care at maternal life saving emergency services by comparatively analysing near-misses and maternal mortalities. METHODS: Retrospective facility-based review of cases of near-miss and maternal mortality that took place in the years 2006-2007 at Damascus Maternity University Hospital, Syria. Near-miss cases were defined based on disease-specific criteria (Filippi 2005) including: haemorrhage, hypertensive disorders in pregnancy, dystocia, infection and anaemia. Main outcomes included maternal mortality ratio (MMR), maternal near miss ratio (MNMR), mortality indices and proportion of near-miss cases and mortality cases to hospital admissions. RESULTS: There were 28,025 deliveries, 15 maternal deaths and 901 near-miss cases. The study showed a MNMR of 32.9/1000 live births, a MMR of 54.8/100,000 live births and a relatively low mortality index of 1.7%. Hypertensive disorders (52%) and haemorrhage (34%) were the top causes of near misses. Late pregnancy haemorrhage was the leading cause of maternal mortality (60%) while sepsis had the highest mortality index (7.4%). Most cases (93%) were referred in critical conditions from other facilities; namely traditional birth attendants homes (67%), primary (5%) and secondary (10%) healthcare unites and private practices (11%). 26% of near-miss cases were admitted to Intensive Care Unit (ICU). CONCLUSION: Near-miss analyses provide valuable information on obstetric care. The study highlights the need to improve antenatal care which would help early identification of high risk pregnancies. It also emphasises the importance of both: developing protocols to prevent/manage post-partum haemorrhage and training health care professionals to manage infrequent but fatal conditions like sepsis. An urgent review of the referral system and the emergency obstetric care in Syria is highly recommended. PMID- 20959013 TI - An inventory of the Aspergillus niger secretome by combining in silico predictions with shotgun proteomics data. AB - BACKGROUND: The ecological niche occupied by a fungal species, its pathogenicity and its usefulness as a microbial cell factory to a large degree depends on its secretome. Protein secretion usually requires the presence of a N-terminal signal peptide (SP) and by scanning for this feature using available highly accurate SP prediction tools, the fraction of potentially secreted proteins can be directly predicted. However, prediction of a SP does not guarantee that the protein is actually secreted and current in silico prediction methods suffer from gene-model errors introduced during genome annotation. RESULTS: A majority rule based classifier that also evaluates signal peptide predictions from the best homologs of three neighbouring Aspergillus species was developed to create an improved list of potential signal peptide containing proteins encoded by the Aspergillus niger genome. As a complement to these in silico predictions, the secretome associated with growth and upon carbon source depletion was determined using a shotgun proteomics approach. Overall, some 200 proteins with a predicted signal peptide were identified to be secreted proteins. Concordant changes in the secretome state were observed as a response to changes in growth/culture conditions. Additionally, two proteins secreted via a non-classical route operating in A. niger were identified. CONCLUSIONS: We were able to improve the in silico inventory of A. niger secretory proteins by combining different gene model predictions from neighbouring Aspergilli and thereby avoiding prediction conflicts associated with inaccurate gene-models. The expected accuracy of signal peptide prediction for proteins that lack homologous sequences in the proteomes of related species is 85%. An experimental validation of the predicted proteome confirmed in silico predictions. PMID- 20959014 TI - Robust peak recognition in intracranial pressure signals. AB - BACKGROUND: The waveform morphology of intracranial pressure pulses (ICP) is an essential indicator for monitoring, and forecasting critical intracranial and cerebrovascular pathophysiological variations. While current ICP pulse analysis frameworks offer satisfying results on most of the pulses, we observed that the performance of several of them deteriorates significantly on abnormal, or simply more challenging pulses. METHODS: This paper provides two contributions to this problem. First, it introduces MOCAIP++, a generic ICP pulse processing framework that generalizes MOCAIP (Morphological Clustering and Analysis of ICP Pulse). Its strength is to integrate several peak recognition methods to describe ICP morphology, and to exploit different ICP features to improve peak recognition. Second, it investigates the effect of incorporating, automatically identified, challenging pulses into the training set of peak recognition models. RESULTS: Experiments on a large dataset of ICP signals, as well as on a representative collection of sampled challenging ICP pulses, demonstrate that both contributions are complementary and significantly improve peak recognition performance in clinical conditions. CONCLUSION: The proposed framework allows to extract more reliable statistics about the ICP waveform morphology on challenging pulses to investigate the predictive power of these pulses on the condition of the patient. PMID- 20959015 TI - Analyzing spatial aggregation error in statistical models of late-stage cancer risk: a Monte Carlo simulation approach. AB - PURPOSE: This paper examines the effect of spatial aggregation error on statistical estimates of the association between spatial access to health care and late-stage cancer. METHODS: Monte Carlo simulation was used to disaggregate cancer cases for two Illinois counties from zip code to census block in proportion to the age-race composition of the block population. After the disaggregation, a hierarchical logistic model was estimated examining the relationship between late-stage breast cancer and risk factors including travel distance to mammography, at both the zip code and census block levels. Model coefficients were compared between the two levels to assess the impact of spatial aggregation error. RESULTS: We found that spatial aggregation error influences the coefficients of regression-type models at the zip code level, and this impact is highly dependent on the study area. In one study area (Kane County), block level coefficients were very similar to those estimated on the basis of zip code data; whereas in the other study area (Peoria County), the two sets of coefficients differed substantially raising the possibility of drawing inaccurate inferences about the association between distance to mammography and late-stage cancer risk. CONCLUSIONS: Spatial aggregation error can significantly affect the coefficient values and inferences drawn from statistical models of the association between cancer outcomes and spatial and non-spatial variables. Relying on data at the zip code level may lead to inaccurate findings on health risk factors. PMID- 20959016 TI - 'Choosing shoes': a preliminary study into the challenges facing clinicians in assessing footwear for rheumatoid patients. AB - BACKGROUND: Footwear has been accepted as a therapeutic intervention for the foot affected by rheumatoid arthritis (RA). Evidence relating to the objective assessment of footwear in patients with RA is limited. The aims of this study were to identify current footwear styles, footwear characteristics, and factors that influence footwear choice experienced by patients with RA. METHODS: Eighty patients with RA were recruited from rheumatology clinics during the summer months. Clinical characteristics, global function, and foot impairment and disability measures were recorded. Current footwear, footwear characteristics and the factors associated with choice of footwear were identified. Suitability of footwear was recorded using pre-determined criteria for assessing footwear type, based on a previous study of foot pain. RESULTS: The patients had longstanding RA with moderate-to severe disability and impairment. The foot and ankle assessment demonstrated a low-arch profile with both forefoot and rearfoot structural deformities. Over 50% of shoes worn by patients were open-type footwear. More than 70% of patients' footwear was defined as being poor. Poor footwear characteristics such as heel rigidity and sole hardness were observed. Patients reported comfort (17%) and fit (14%) as important factors in choosing their own footwear. Only five percent (5%) of patients wore therapeutic footwear. CONCLUSIONS: The majority of patients with RA wear footwear that has been previously described as poor. Future work needs to aim to define and justify the specific features of footwear that may be of benefit to foot health for people with RA. PMID- 20959017 TI - Genetic diversity and striatal gene networks: focus on the heterogeneous stock collaborative cross (HS-CC) mouse. AB - BACKGROUND: The current study focused on the extent genetic diversity within a species (Mus musculus) affects gene co-expression network structure. To examine this issue, we have created a new mouse resource, a heterogeneous stock (HS) formed from the same eight inbred strains that have been used to create the collaborative cross (CC). The eight inbred strains capture > 90% of the genetic diversity available within the species. For contrast with the HS-CC, a C57BL/6J (B6) * DBA/2J (D2) F2 intercross and the HS4, derived from crossing the B6, D2, BALB/cJ and LP/J strains, were used. Brain (striatum) gene expression data were obtained using the Illumina Mouse WG 6.1 array, and the data sets were interrogated using a weighted gene co-expression network analysis (WGCNA). RESULTS: Genes reliably detected as expressed were similar in all three data sets as was the variability of expression. As measured by the WGCNA, the modular structure of the transcriptome networks was also preserved both on the basis of module assignment and from the perspective of the topological overlap maps. Details of the HS-CC gene modules are provided; essentially identical results were obtained for the HS4 and F2 modules. Gene ontology annotation of the modules revealed a significant overrepresentation in some modules for neuronal processes, e.g., central nervous system development. Integration with known protein-protein interactions data indicated significant enrichment among co-expressed genes. We also noted significant overlap with markers of central nervous system cell types (neurons, oligodendrocytes and astrocytes). Using the Allen Brain Atlas, we found evidence of spatial co-localization within the striatum for several modules. Finally, for some modules it was possible to detect an enrichment of transcription binding sites. The binding site for Wt1, which is associated with neurodegeneration, was the most significantly overrepresented. CONCLUSIONS: Despite the marked differences in genetic diversity, the transcriptome structure was remarkably similar for the F2, HS4 and HS-CC. These data suggest that it should be possible to integrate network data from simple and complex crosses. A careful examination of the HS-CC transcriptome revealed the expected structure for striatal gene expression. Importantly, we demonstrate the integration of anatomical and network expression data. PMID- 20959018 TI - Preferential antitumor effect of the Src inhibitor dasatinib associated with a decreased proportion of aldehyde dehydrogenase 1-positive cells in breast cancer cells of the basal B subtype. AB - BACKGROUND: Recent studies have suggested that the Src inhibitor dasatinib preferentially inhibits the growth of breast cancer cells of the basal-like subtype. To clarify this finding and further investigate combined antitumor effects of dasatinib with cytotoxic agents, a panel of breast cancer cell lines of various subtypes was treated with dasatinib and/or chemotherapeutic agents. METHODS: Seven human breast cancer cell lines were treated with dasatinib and/or seven chemotherapeutic agents. Effects of the treatments on c-Src activation, cell growth, cell cycle, apoptosis and the proportion of aldehyde dehydrogenase (ALDH) 1-positive cells were examined. RESULTS: The 50%-growth inhibitory concentrations (IC50s) of dasatinib were much lower in two basal B cell lines than those in the other cell lines. The IC50s of chemotherapeutic agents were not substantially different among the cell lines. Dasatinib enhanced antitumor activity of etoposide in the basal B cell lines. Dasatinib induced a G1-S blockade with a slight apoptosis, and a combined treatment of dasatinib with etoposide also induced a G1-S blockade in the basal B cell lines. Dasatinib decreased the expression levels of phosphorylated Src in all cell lines. Interestingly, dasatinib significantly decreased the proportion of ALDH1-positive cells in the basal B cell lines but not in the other cell lines. CONCLUSIONS: The present study indicates that dasatinib preferentially inhibits the growth of breast cancer cells of the basal B subtype associated with a significant loss of putative cancer stem cell population. A combined use of dasatinib with etoposide additively inhibits their growth. Further studies targeting breast cancers of the basal B subtype using dasatinib with cytotoxic agents are warranted. PMID- 20959019 TI - Transcriptome changes in grapevine (Vitis vinifera L.) cv. Malbec leaves induced by ultraviolet-B radiation. AB - BACKGROUND: Ultraviolet-B radiation (UV-B, 280-315 nm) is a natural component of sunlight, which has numerous regulatory effects on plant physiology. The nature of the response to UV-B is dependent on fluence rate, dose, duration and wavelength of the UV-B treatment. Some reports have analyzed the changes in gene expression caused by UV-B light on several plant species using microarray technology. However, there is no information on the transcriptome response triggered by UV-B in grapevine. In this paper we investigate the gene expression responses of leaves from in vitro cultured Vitis vinifera cv. Malbec plants subjected to the same dose of biologically effective UV-B radiation (4.75 kJ m-2 d-1) administered at two different fluence rates (16 h at ? 8.25 MUW cm-2, 4 h at ? 33 MUW cm-2) using a new custom made GrapeGen Affymetrix GeneChip(r). RESULTS: The number of genes modulated by high fluence rate UV-B doubled the number of genes modulated by low fluence UV-B. Their functional analyses revealed several functional categories commonly regulated by both UV-B treatments as well as categories more specifically modulated depending on UV-B fluence rate. General protective responses, namely the induction of pathways regulating synthesis of UV B absorbing compounds such as the Phenylpropanoid pathway, the induction of different antioxidant defense systems and the activation of pathways commonly associated with pathogen defense and abiotic stress responses seem to play critical roles in grapevine responses against UV-B radiation. Furthermore, high fluence rate UV-B seemed to specifically modulate additional pathways and processes in order to protect grapevine plantlets against UV-B-induced oxidative stress, stop the cell cycle progression, and control protein degradation. On the other hand, low fluence rate UV-B regulated the expression of specific responses in the metabolism of auxin and abscisic acid as well as in the modification of cell walls that could be involved in UV-B acclimation-like processes. CONCLUSION: Our results show the UV-B radiation effects on the leaf transcriptome of grapevine (Vitis vinifera cv. Malbec) plantlets. Functional categories commonly modulated under both UV-B treatments as well as transcripts specifically regulated in an UV-B-intensity dependent way were identified. While high fluence rate UV-B had regulatory effects mainly on defense or general multiple-stress responses pathways, low fluence rate UV-B promoted the expression of genes that could be involved in UV-B protection or the amelioration of the UV-B-induced damage. This study also provides an extensive list of genes regulating multiple metabolic pathways involved in the response of grapevine to UV-B that can be used for future researches. PMID- 20959021 TI - Hepatitis B virus core protein with hot-spot mutations inhibit MxA gene transcription but has no effect on inhibition of virus replication by interferon alpha. AB - It has been reported that hepatitis B virus (HBV) core protein (HBc) can inhibit the transcription of human interferon-induced MxA gene. In this study, we investigated whether HBc protein mutations at hot spots (L60V, S87G and I97L) could still inhibit MxA transcription and the potential significance of this inhibition in virus replication in vitro. Our data indicated that the IFN-induced MxA mRNA expression level and MxA promoter activity was significantly down regulated by mutant protein of HBc(I97L), compared to WT and the other two mutated HBc proteins(L60V or S87G). However, in Huh7 cells stably expressing WT or the mutated HBc proteins (L60V, S87G or I97L), IFN-alpha could inhibit the extra- and intracellular HBV DNA level and HBsAg secretion to a similar level compared to that in cells transfected with control plasmids. In conclusion, HBc protein with I97L mutation may play an special role in suppressing the transcription of MxA gene. Moreover, the inhibitory effect on MxA gene transcription by the WT or mutated HBc proteins (L60V, S87G and I97L) has no impact on inhibition of HBV replication by IFN-alpha in Huh7 cells. The clinical significance of the inhibitory effect of MxA gene transcription by HBc protein requires further study. PMID- 20959020 TI - Genetic diversity and C2-like subgenogroup strains of enterovirus 71, Taiwan, 2008. AB - BACKGROUND: Human enterovirus 71 (EV-71) is known of having caused numerous outbreaks of hand-foot-mouth disease, and other clinical manifestations globally. In 2008, 989 EV-71 strains were isolated in Taiwan. RESULTS: In this study, the genetic and antigenic properties of these strains were analyzed and the genetic diversity of EV-71 subgenogroups surfacing in Taiwan was depicted, which includes 3 previously reported subgenogroups of C5, B5, and C4, and one C2-like subgenogroup. Based on the phylogenetic analyses using their complete genome nucleotide sequences and neutralization tests, the C2-like subgenogroup forms a genetically distinct cluster from other subgenogroups, and the antisera show a maximum of 128-fold decrease of neutralization titer against this subgenogroup. In addition, the subgenogroup C4 isolates of 2008 were found quite similar genetically to the Chinese strains that caused outbreaks in recent years and thus they should be carefully watched. CONCLUSIONS: Other than to be the first report describing the existence of C2-like subgenogroup of EV-71 in Taiwan, this article also foresees a potential of subgenogroup C4 outbreaks in Taiwan in the near future. PMID- 20959022 TI - Capturing the dynamic epigenome. AB - Traditional methods for epigenomic analysis provide a static picture of chromatin, which is actually a highly dynamic assemblage. Recent approaches have allowed direct measurements of chromatin dynamics, providing deeper insights into processes such as transcription, DNA replication and epigenetic inheritance. PMID- 20959024 TI - Elevated excitatory neurotransmitter levels in the fibromyalgia brain. AB - Consistent brain imaging findings demonstrate that neurobiological factors may contribute to the pathology of 'central' pain states such as fibromyalgia (FM). Studies using proton magnetic resonance spectroscopy suggest that glutamate (Glu), a key excitatory neurotransmitter, may be present in higher concentrations within the brains of FM patients. This neurotransmitter imbalance is present in multiple brain regions that have been implicated in processing pain information. However, it is unknown if elevated Glu is acting at the synapse. New investigations are needed to investigate the molecular action of Glu in FM and to investigate these findings during treatment that modulates glutamatergic neurotransmission. PMID- 20959023 TI - Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. AB - Osteoarthritis is characterized by a progressive degradation of articular cartilage leading to loss of joint function. The molecular mechanisms regulating pathogenesis and progression of osteoarthritis are poorly understood. Remarkably, some characteristics of this joint disease resemble chondrocyte differentiation processes during skeletal development by endochondral ossification. In healthy articular cartilage, chondrocytes resist proliferation and terminal differentiation. By contrast, chondrocytes in diseased cartilage progressively proliferate and develop hypertrophy. Moreover, vascularization and focal calcification of joint cartilage are initiated. Signaling molecules that regulate chondrocyte activities in both growth cartilage and permanent articular cartilage during osteoarthritis are thus interesting targets for disease-modifying osteoarthritis therapies. PMID- 20959025 TI - Histone deacetylases in RA: epigenetics and epiphenomena. AB - Reduced synovial expression of histone deacetylases (HDACs) is proposed to contribute to pathology in rheumatoid arthritis (RA) by enhancing histone dependent access of transcription factors to promoters of inflammatory genes. In the previous issue of Arthritis Research & Therapy, Kawabata and colleagues provided independent evidence that HDAC activity is increased in the synovium and fibroblast-like synoviocytes (FLSs) of patients with RA and is paralleled by increased HDAC1 expression and synovial tumor necrosis factor-alpha (TNFalpha) production. Remarkably, stimulation of RA FLSs with TNFalpha specifically increases HDAC activity and HDAC1 expression, suggesting that changes in synovial HDAC activity and expression may be secondary to local inflammatory status. PMID- 20959026 TI - Genetic control of mammalian T-cell proliferation with a synthetic RNA regulatory system - illusion or reality? AB - Synthetic RNA-based regulatory systems are used to program higher-level biological functions that could be exploited, among many applications, for in vivo diagnostic and therapeutic applications. Chen and colleagues have recently reported a significant technological advance by producing an RNA modular device based on a hammerhead ribozyme and successfully tested its ability to control the proliferation of mammalian T lymphocytes. Like all exciting research, this work raises a lot of significant questions. How quickly will such knowledge be translated into clinical practice? How efficient will this system be in human clinical trials involving adaptive T-cell therapy? We discuss the possible advantages of using such new technologies for specific therapeutic applications. PMID- 20959027 TI - Comparing different thrombolytic dosing regimens for treatment of acute pulmonary embolism. PMID- 20959028 TI - The genetics of generalized vitiligo: autoimmune pathways and an inverse relationship with malignant melanoma. AB - Generalized vitiligo (GV) is the most common pigmentation disease, in which white spots of skin and overlying hair result from loss of melanocytes from the involved regions. GV is a complex disease involving both genetic predisposition and unknown environmental triggers. Whereas various pathogenetic mechanisms have been suggested, most evidence supports an autoimmune basis for this disease. Recently, three different genome-wide association studies of GV have been reported, identifying a total of 17 confirmed GV susceptibility loci. Almost all of these genes encode immunoregulatory proteins, together highlighting pathways by which melanocytes might be recognized and killed. Moreover, the biological interaction between two of these GV susceptibility genes, HLA-A and TYR (encoding tyrosinase), points to an apparent inverse relationship between susceptibility to GV versus malignant melanoma, suggesting that GV may result, in part, from dysregulation of normal processes of immune surveillance against melanoma. PMID- 20959029 TI - Advances in the genetics of endometriosis. AB - Endometriosis is a gynecological disease characterized by implantation of endometrial tissue outside of the uterus. Early familial aggregation and twin studies noted a higher risk of endometriosis among relatives. Studies on the roles of the environment, genetics and aberrant regulation in the endometrium and endometriotic lesions of women with endometriosis suggest that endometriosis arises from the interplay between genetic variants and environmental factors. Elucidating the hereditary component has proven difficult because multiple genes seem to produce a susceptibility to developing endometriosis. Molecular techniques, including linkage and genome-wide analysis, have identified candidate genes located near known loci related to development and regulation of the female reproductive tract. As new candidate genes are discovered and hereditary pathways identified using technologies such as genome-wide analysis, the possibility of prevention and treatment becomes more tangible for millions of women affected by endometriosis. Here, we discuss the advances of genetic research in endometriosis and describe technologies that have contributed to the current understanding of the genetic variability in endometriosis, variability that includes regulatory polymorphisms in key genes. PMID- 20959030 TI - Chondrogenesis of mesenchymal stem cells: role of tissue source and inducing factors. AB - Multipotent mesenchymal stromal cells (MSCs) are an attractive cell source for cell therapy in cartilage. Although their therapeutic potential is clear, the requirements and conditions for effective induction of chondrogenesis in MSCs and for the production of a stable cartilaginous tissue by these cells are far from being understood. Different sources of MSCs have been considered for cartilage tissue engineering, mainly based on criteria of availability, as for adipose tissue, or of proximity to cartilage and the joint environment in vivo, as for bone marrow and synovial tissues. Focussing on human MSCs, this review will provide an overview of studies featuring comparative analysis of the chondrogenic differentiation of MSCs from different sources. In particular, it will examine the influence of the cells' origin on the requirements for the induction of chondrogenesis and on the phenotype achieved by the cells after differentiation. PMID- 20959032 TI - Central role of glia in disease research. PMID- 20959031 TI - Advances in gout: some answers, more questions. AB - In a previous issue of the journal, Becker and colleagues present efficacy and safety data from a large study comparing febuxostat to allopurinol. The study showed non-inferiority of febuxostat 40 mg/day in lowering serum urate compared to allopurinol 200 to 300 mg/day. More importantly, the study showed a similar frequency of important cardiovascular adverse events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) for febuxostat 40 mg/day (0%), febuxostat 80 mg/day (0.4%) and allopurinol groups (0.4%). Other cardiac adverse event rates (unstable angina, coronary revascularization, cerebral revascularization, transient ischemic attack, venous and peripheral arterial vascular thrombotic event, congestive heart failure, and arrhythmia) were also similar for febuxostat 40 mg/day (1.3%), febuxostat 80 mg/day (1.2%) and allopurinol groups (0.9%). A meta-analysis of safety data from published studies is presented. PMID- 20959033 TI - Oxidation and age-related macular degeneration: insights from molecular biology. AB - Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. It is a multifactorial disease, and current therapy predominantly limits damage only when it has already occurred. The macula is a source of high metabolic activity, and is therefore exposed to correspondingly high levels of reactive oxygen species (ROS). With age, the balance between production of ROS and local antioxidant levels is shifted, and damage ensues. Systemic ROS and antioxidant levels in AMD reflect these local processes. Genetic studies investigating mutations in antioxidant genes in AMD are inconclusive and further studies are indicated, especially to determine the role of mitochondria. Oral antioxidant supplements could be beneficial, and diet modification may help. Future treatments might either increase antioxidant capacity or reduce the production of ROS, using methods such as genetic manipulation. This article reviews the role of oxidative stress in AMD and the potential therapies that might have a role in preventing the blindness resulting from this disease. PMID- 20959034 TI - Penile granuloma following intravesical bacillus Calmette-Guerin (BCG) therapy. AB - We present a case of penile granuloma following intravesical bacillus Calmette Guerin (BCG) therapy that is unique in its presentation and management. The patient presented with a subcutaneous cystic lump with no overlying skin changes, inguinal lymphadenopathy or systemic upset. The treatment was excision alone. PMID- 20959035 TI - A rare cause of spontaneous intra-abdominal haemorrhage due to coeliac artery stenosis. AB - Coeliac artery stenosis is associated with the formation of collateral vessels from the superior mesenteric artery. High pressure within collateral vessels can lead to the formation of visceral artery aneurysms. Haemorrhage from such aneurysms can be catastrophic if they are not identified and managed promptly. We describe successful arterial embolisation of a pseudoaneurysm arising from a branch of the gastroduodenal artery secondary to coeliac artery stenosis. To the best of our knowledge this is thefirst such reported case in the literature. PMID- 20959036 TI - Hyperbilirubinemia in newborns with gestation >=35 weeks. PMID- 20959037 TI - [Relationship between ACE gene insertion or deletion polymorphism and left ventricular mass in newborns admitted to the neonatal intensive care unit]. AB - OBJECTIVE: To study the relationship between angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and left ventricular mass (LVM) in newborns admitted to the neonatal intensive care unit (NICU). METHODS: Seventy two newborns admitted to the NICU were enrolled. ACE genotypes were determined by genomic DNA which was isolated from heel-prick blood. Disease status of the newborns was evaluated by the Neonatal Critical Score (draft) on postnatal day 1. LVM and LVM index (LVMI) were evaluated by echocardiography on postnatal days 1 3. RESULTS: DD genotype was identified in 11 cases, ID genotype in 31 cases, and II genotype in 30 cases. There were no significant differences in clinical characteristics, critical score and body measurements in newborns with different genotypes. The DD genotype group showed significantly lower LVMI than the group with ID+II genotypes (29+/-4 g/m2 vs 35+/-8 g/m2; P<0.05). CONCLUSIONS: ACE gene polymorphism is associated with the LVMI in newborns admitted to the NICU. The LVMI of DD genotype carriers is significantly lower than that of ID+II genotypes carriers, which suggests that D allele may be associated with the growth and development of left ventricular. PMID- 20959038 TI - [Umbilical cord serum levels of insulin-like growth factor-1, insulin and growth hormone in neonates with intrauterine growth retardation]. AB - OBJECTIVE: To investigate the levels of insulin-like growth factor-1(IGF-1), insulin (INS)and growth hormone (GH) in the cord blood of neonates with intrauterine growth retardation (IUGR), and to assess the effects of the endocrine environment on IUGR. METHODS: Sixty-three newborn infants were selected, including 37 males and 26 females. According to birth weight, they were classified into IUGR group (n=33) and control group (normal birth weight, n=30). The levels of IGF-1, INS and GH in the cord blood were measured. RESULTS: Umbilical cord serum levels of IGF-1 and INS in the IUGR group were significantly lower than those in the control group. In contrast, umbilical cord serum GH levels in the IUGR group were significantly higher than those in the control group. Birth weight was positively correlated with umbilical cord serum IGF-1 levels (r=0.625, P<0.01) and negatively correlated with GH levels (r=-0.257, P<0.05). Gestational age was positively correlated with umbilical cord serum IGF 1 levels (r=0.271, P<0.05). Multiple linear stepwise regression analysis showed that umbilical cord serum IGF-1 and INS levels were significant influential factors for birth weight. CONCLUSIONS: The endocrine environment controls the growth and development of the fetus. The levels of IGF-1 and INS in the cord blood are associated with fetal weight. The low umbilical cord serum levels of IGF-1 may be one of the reasons for resulting in IUGR. PMID- 20959039 TI - [Digital retinal camera for screening of retinopathy of prematurity]. AB - OBJECTIVE: To evaluate the practicability and efficacy of digital retinal camera (RetCam) as a method for early diagnosis of retinopathy of prematurity (ROP). METHODS: One hundred and twelve preterm infants admitted to the First Hospital of Jilin University from June 2007 to March 2008 were enrolled. Fundus examinations were performed by indirect ophthalmoscope and RetCam respectively. The results from RetCam were compared with those from indirect ophthalmoscopy which was a "gold standard" for ROP screening. RESULTS: ROP was identified in 46 eyes by RetCam, and in 43 eyes by indirect ophthalmoscope. The sensitivity of RetCamII was 97.7% (43/44) and the specificity was 98.3% (177/180), and the positive and negative predictive values were 93.5% and 99.4%, respectively. The concordance rate for identification of ROP between RetCam and indirect ophthalmoscopy was 97.3%. CONCLUSIONS: RetCam is an effective method for the identification of ROP and is worth recommending. PMID- 20959040 TI - [Risk factors for adverse neonatal outcomes in 254 twins]. AB - OBJECTIVE: The aim of this study was to identify the risk factors for adverse neonatal outcome in twins in order to provide a basis for the improvement of the survival and neonatal outcomes of twins. METHODS: Data from 254 twins admitted to Nanfang Hospital of Southern Medical University From January 2005 to December 2009 were retrospectively studied. Risk factors for adverse neonatal outcomes were assessed by logistic regression analysis. RESULTS: Of the 254 twins, 84 (33.1%) had an adverse outcome, including 10 (3.9%) neonatal deaths. Logistic regression analysis demonstrated that gestational age (<=34 weeks), cord abnormalities, meconium-stained amniotic fluid and 5-min Apgar scores (<=7) were independent risk factors for adverse neonatal outcomes (OR=4.434, 4.731, 3.424, 18.958, respectively; P=0.021, 0.001, 0.037, 0.011, respectively). Conception by assisted reproductive technology was shown as a protective factor for adverse neonatal outcomes (OR=0.389, P=0.037). CONCLUSIONS: The twins with gestational age <=34 weeks, cord abnormalities, meconium-stained amniotic fluid or 5-min Apgar scores (<=7) are subject to adverse neonatal outcome. PMID- 20959041 TI - [Characteristics of developmental regression in autistic children]. AB - OBJECTIVE: About 30% of autistic cases experience developmental regression around 2 years of age. The clinical course and manifestations of autistic children with regression remain unclear. This study investigated the clinical features of a group of autistic children with regression. METHODS: One hundred and fifty-two children at ages of 2.5-6.5 years confirmed with autism based on DSM-IV diagnostic criteria were enrolled. They were grouped according to language development: normal or regression. The perinatal history, developmental history and characteristics of regression were investigated. The symptoms were compared between the two groups. RESULTS: Regressions were observed in 33 children (21.7%) at age of between 16 and 21 months, with loss both in communicative skills and social engagement. The regressive group was scored significantly higher on the Childhood Autism Rating Scale (CARS) (P<0.05) and had a relatively higher proportion of severely ill children (66.7% vs 45.4%; P<0.05)compared with the non regressive group. CONCLUSIONS: Regression as a characteristic symptom occurs in some autistic children and is of value for diagnosis of autism. The autistic children with regression display more severe social and language impairments than those without regression. Regressive autism may be a special subtype. PMID- 20959042 TI - [WASP gene mutation analysis of a family of X-linked thrombocytopenia]. AB - OBJECTIVE: This study investigated the history and gene mutations of a family with X-linked thrombocytopenia, in order to understand the clinical characteristic and molecular pathogenesis of the disease. METHODS: A three generation X-linked thrombocytopenia family with 13 family members was investigated using PCR-DNA direct sequencing method to screen the exons of WASP gene for mutation analysis. RESULTS: The WASP gene sequencing of the proband revealed a missense mutation in exon 2 (G291A), resulting in a change of amino acid 86 from arginine to histidine. The patient's mother was the carrier of the heterozygosis mutation in X-chromosome. CONCLUSIONS: WASP mutations may be attributed to the molecular mechanism of X-linked thrombocytopenia. G291A is one of the mutations of WASP. PMID- 20959043 TI - [Relationship of 24-hour ambulatory blood pressure and rennin-angiotensin aldosterone system in children with primary nephrotic syndrome]. AB - OBJECTIVE: To investigate the changes of blood pressure by 24-hour ambulatory blood pressure (ABP) monitoring in children with primary nephrotic syndrome (PNS) and explore the relationship of the changes in blood pressure with rennin angiotensin-aldosterone system (RAAS) in these children. METHODS: ABP and casual blood pressure (CBP) monitoring were performed in 114 children with PNS. Plasma levels of rennin activity (PRA), angiotensin II (AngII) and aldosterone (ALD) were measured. The correlation of plasma levels of PRA, AngII and ALD with ABP was evaluated. RESULTS: Of the 114 children with PNS, 101 (88.6%) presented elevated blood pressure. Mild or severe masked hypertension was found in 45 children (39.5%). Eighty (70.2%) children showed non-dipper blood pressure. The index and load of systolic blood pressure were higher than those of diastolic blood pressure. The blood pressure index and blood pressure load during sleep were higher than those during wakefulness. The boy presented higher diastolic blood pressure index and load than girls. Decubitus blood PRA, AngII and ALD levels in children with PNS were significantly higher than normal controls. The group with elevated blood pressure presented significantly higher decubitus blood PRA, AngII and ALD levels than the group with normal blood pressure. AngII level was significantly positively correlated with the index and load of both systolic blood pressure and diastolic blood pressure. CONCLUSIONS: The children with PNS present a high incidence of hypertension, with a large percentage of masked hypertension and non-dipper blood pressure. Systolic blood pressure increases more significantly than diastolic blood pressure. Blood pressure during sleep increases more significantly than that during wakefulness. Diastolic blood pressure increases more significantly in boys than in girls. RAAS activity is elevated and the elevated RAAS activity might increase the blood pressure mainly by AngII in children with PNS. PMID- 20959044 TI - [Digestive system manifestations in children infected with novel influenza A (H1N1) virus]. AB - OBJECTIVE: To study the digestive system manifestations in children infected with novel influenza A (H1N1) virus. METHODS: A prospective study of 153 children infected with novel influenza A (H1N1) virus in Shenzhen Children's Hospital from November 2009 to January 2010 was conducted. The clinical features and outcomes of 69 children with digestive system manifestations were analyzed. RESULTS: The children presenting with digestive system manifestations accounted for 45% (69 cases) in the 153 hospitalized children with novel influenza A (H1N1) infection. Gastrointestinal manifestations were observed in 50 cases (33%) and liver function abnormality in 19 cases (12%). The incidence rate of coma, neurological complications, increase in creative kinase level, ICU admission, and death in the patients with digestive system manifestations were significantly higher than those without digestive system manifestations (P<0.05). In the 69 patients with digestive system manifestations, 5 died from severe complications and 64 recovered fully. Gastrointestinal manifestations disappeared through 1 to 3 days and abnormal liver function recovered through 4 to 7 days. CONCLUSIONS: Digestive system manifestations are common in children infected with novel influenza A (H1N1) virus. Neurological system involvements are more common in the patients with digestive system manifestations than those without. PMID- 20959045 TI - [Economic evaluation on diagnosis of congenital cytomegalovirus infection by fluorescent quantitative polymerase chain reaction in neonates]. AB - OBJECTIVE: To explore the cost-effectiveness of the diagnosis of congenital cytomegalovirus (CMV) infection by fluorescent quantitative polymerase chain reaction (FQ-PCR) in neonates. METHODS: Serum CMV immunoglobulin M (CMV-IgM) and CMV-IgG were detected using ELISA in 610 neonates aged less than 14 days. CMV DNA content was detected by FQ-PCR. The cost-effectiveness analysis was then performed. RESULTS: The positive rate of FQ-PCR in neonates with positive CMV-IgM was 42.9% (15/35), while, 2.9% (16/547) in neonates with positive CMV-IgG. The mean logarithm values of CMV DNA in neonates with positive CMV-IgM were higher than those in neonates with positive CMV-IgG (5.79+/-1.24 vs 4.11+/-0.87; P<0.01). The costs of the diagnosis of CMV infection by FQ-PCR were 256 RMB/case in neonates with positive CMV-IgM, and 3 760 RMB/case in neonates with positive CMV-IgG. CONCLUSIONS: The CMV DNA content in neonates with positive CMV-IgM is higher than that in neonates with positive CMV-IgG. Diagnosis of congenital CMV infection by FQ-PCR in neonates with positive CMV-IgG is not suitable for large scale epidemiological survey because of high cost-effectiveness ratio. PMID- 20959046 TI - [Lung fibrosis induced by mechanical ventilation with different tidal volume in neonatal rats]. AB - OBJECTIVE: To study the changes of collagen synthesis following mechanical ventilation with different tidal volume and the possible mechanism. METHODS: Twenty-four neonatal Sprague-Dawley rats were randomized to hyperventilation (tidal volume 25 mL/kg), conventional ventilation (tidal volume 10 mL/kg) and no mechanical ventilation (control group) (n=8 each group). They were sacrificed 5 hrs after ventilation. Left lung samples were used for histopathologic examinations and the detection of connective tissue growth factor (CTGF) expression by immunohistochemistry. Right lung samples were used for the detection of expression of procollagenIII mRNA(PcolIII mRNA), cysteinyl leukotriene mRNA(CysLT1 mRNA)and CTGF mRNA by PCR. RESULTS: The severity of lung injury and fibrosis increased significantly with the increasing tidal volume compared with the control group. Lung CTGF mRNA expression in the hyperventilation group was significantly higher than that in the control group (P<0.05). Lung PcolIII mRNA and CysLT1 mRNA levels increased with the increasing tidal volume when compared with the control group. The differences in PcolIII mRNA and CysLT1 mRNA levels between groups were significant (P<0.05). There was a positive correlation between lung PcolIII mRNA expression and the severity of lung injury (r=0.78,P<0.01). CTGF and CysLT levels were positively correlated with PcolIII expression (r = 0.59,0.86,P<0.01). CONCLUSIONS: Mechanical ventilation using different tidal volume leads to different severities of lung injury, followed by the occurrence of lung fibrosis. The degree of lung fibrosis is consistent with the severity of lung injury. CysLT and CTGF may be involved in the development of lung fibrosis. PMID- 20959048 TI - [Effect of oral glutamine on intestinal barrier function in young rats with endotoxemia]. AB - OBJECTIVE: To study the effect of glutamine on intestinal barrier function by examining the changes of plasma D-lactic levels and diamine oxidase (DAO) levels in plasma and intestinal tissue after glutamine intervention in young rats with endotoxemia. METHODS: Eighty 18-day-old rats were randomly divided into endotoxemia and glutamine intervention groups (n=40 each). Endotoxemia was induced by lipopolysaccharide (LPS) injection. Plasma and small intestine homogenate were collected 1.5, 6, 24 and 72 hrs and 7 days after LPS injection. The glutamine intervention group was immediately administered with oral glutamine (2 g/kg) after LPS injection. Afterwards, glutamine was administered once daily. Plasma D-lactic and DAO levels and intestinal DAO levels were measured. RESULTS: Plasma DAO activity in the glutamine intervention group was significantly lower than that in the endotoxemia group 6 and 72 hrs after LPS injection (P<0.05). In contrast, the intestinal DAO activity in the glutamine intervention group was significantly higher than that in the endotoxemia group 6, 24 and 72 hrs and 7 days after LPS injection (P<0.05 or 0.01). Plasma D-lactic levels in the glutamine intervention group were significantly lower than those in the endotoxemia group 6, 24 and 72 hrs and 7 days after LPS injection (P<0.01). CONCLUSIONS: Glutamine may reduce the permeability of intestinal mucosa, and thus provides protective effects on intestinal barrier function in rats with endotoxemia. PMID- 20959047 TI - [NF-kappaB levels in the liver of young rats with endotoxemic liver injury]. AB - OBJECTIVE: To study hepatic NF-kappaB level following endotoxemic liver injury, and its relationship with hepatic TNF-alpha and IL-6 levels in young rats. METHODS: Forty 18-day-old rats were randomly assigned to a normal control and an endotoxemia group. Endotoxemia was induced by lipopolysaccharide injection (LPS, 5 mg/kg). The endotoxemia group was subdivided into four groups sampled at 2, 6, 12 and 24 hrs after LPS injection (n=8 each). Pathological changes in liver cells were observed under a light microscope. TNF-alpha and IL-6 levels in liver tissue homogenates were measured using ELISA. Reitman-Frankel was used to measure serum ALT concentrations. NF-kappaB activation level in liver tissues was detected by immunohistochemistry. RESULTS: Liver tissue injury was the most obvious 6 hrs after LPS injection under the light microscope, and the damage rating of liver tissues was significantly higher in the endotoxemia group than that in the normal control group at all time points (P<0.05). ALT levels in the endotoxemia group were significantly higher than those in the normal control group 6, 12 and 24 hrs after LPS injection (P<0.05). NF-kappaB p65 protein expression in liver cells (percentage of nuclear positive cells) in the endotoxemia groups was significantly higher than that in the normal control group (P<0.05). TNF-alpha and IL-6 levels in liver tissue homogenates in the endotoxemia groups were significantly higher than those in the normal control group 6 and 12 hrs after LPS injection (P<0.05). CONCLUSIONS: Endotoxemia can cause liver injury, resulting in liver cell damage and changes in liver function. NF-kappaB activation is involved in endotoxemic liver injury which may be mediated by inflammatory cytokines TNF-alpha and IL-6 synthesis. PMID- 20959049 TI - [Protection of PD-1 against LPS-induced endotoxemia and the underlying mechanism]. AB - OBJECTIVE: Gram-negative bacteria-induced multiple organ failure/dysfunction syndrome (MOF/MODS) is one of the leading causes of death through the world. The member of immunoglobulin family programmed death-1 (PD-1) is a negative immune regulator. This study investigated the protective effect of PD-1 as well as the underlying mechanism in LPS-induced endotoxemia. METHODS: Ten PD-1(+/+) and ten PD-1 knockout (PD-1(-/-)) mice were injected peritoneally with LPS (10 mg/kg), and the survival was observed within 72 hrs after LPS injection. The other 40 PD 1(+/+) and 40 PD-1(-/-) mice were injected peritoneally with LPS (5 mg/kg). Blood samples were collected before injection and 1.5, 3 and 6 hrs after LPS injection (n=10 each time point). Serum levels of various inflammatory mediators were measured using ELISA. RESULTS: The survival rate in PD-1(-/-) mice was noticeably lower than that in PD-1(+/+) mice after 10 mg/kg LPS injection. Serum levels of inflammatory mediators TNF-alpha, IL-1beta, IL-12 and IL-17 in PD-1/mice were higher than those in PD-1(+/+) mice after 5 mg/kg LPS injection. CONCLUSIONS: PD 1 can protect mice from LPS-induced endotoxemia probably through its regulation on inflammatory mediator production. PMID- 20959050 TI - [Effects of inhaled budesonide on the bronchial-pulmonary pathology and expression of thymic stromal lymphopoietin in lung tissues in asthmatic rats]. AB - OBJECTIVE: Thymic stromal lymphopoietin (TSLP) plays an important role in initiating dendritic cell mediated allergic inflammation. This study was designed to examine the effects of inhaled budesonide on TSLP expression in the lung tissues and on the bronchial-pulmonary pathology in asthmatic rats. METHODS: Thirty-two female Sprague-Dawley rats were sensitized and challenged with inhaled ovalbumin (OVA) to induce asthma. The asthmatic rats were randomly divided into 2 groups on the 22nd day of OVA challenge: a budesonide treatment group that received inhaled budesonide at 0.32 mg/kg daily for 7 days and an asthma control group that received inhaled 0.9% normal saline for 7 days. TSLP expression in the lung tissues was measured by Western blot and fluorescent-immunohistochemistry 29 and 36 days after OVA challenge. Bronchial-pulmonary pathological changes were evaluated by hematoxylin & eosin and periodic acid-schiff staining. RESULTS: Budesonide treatment alleviated airway inflammation when compared with the asthma control group 29 days after OVA challenge. However, the airway inflammatory reactions were aggravated in the budesonide treatment group 36 days after OVA challenge (7 days after budesonide discontinuance). TSLP expression in the lung tissues was significantly lower in the budesonide treatment group than that in the asthma control group both 29 and 36 days after OVA challenge (P<0.05). CONCLUSIONS: Inhaled budesonide can inhibit the TSLP expression in the lung tissues and alleviate lung inflammatory reactions in asthmatic rats, but there is end-of-dose failure. PMID- 20959052 TI - [Arrhythmia following the transcatheter closure of atrial defect]. PMID- 20959051 TI - [Suppression subtractive hybridization for the identification of differentially expressed genes in the hippocampus of the offsprings of lead exposed female rats]. AB - OBJECTIVE: To screen and identify differentially expressed genes in the hippocampus of the offsprings of lead exposed female rats in order to provide a theoretical basis for identifying learning and memory deficits related genes. METHODS: RNA was extracted from the hippocampus of young rats with learning and memory deficits due to maternal lead exposure. Suppression subtractive hybridization was used to identify the differentially expressed genes in the hippocampus. RESULTS: An effective subtracted library was constructed which consisted of approximately 200 clones. Sequencing for the library identified 93 clones harboring insertion fragments which included 43 different genes and 4 unknown genes. These genes might be related to learning and memory deficits due to maternal lead exposure. CONCLUSIONS: The up-regulated genes in the hippocampus of young rats from pregnant rats under lead exposure include some housekeeping genes and some proteins involved in cellular protein folding, signal transduction, stress response and DNA methylation. These proteins might be directly related to a significant reduction in learning and memory abilities in the young rats. PMID- 20959053 TI - [Contents of exhaled nitric oxide and serum nitric oxide in children with asthma before and after treatment]. PMID- 20959054 TI - [Acquired immunocompromise in children with serious influenza A (H1N1)]. PMID- 20959055 TI - [Findings of digital chest radiography in 493 neonates]. PMID- 20959056 TI - [Investigation on bacterial infections and drug resistance in neonatal intensive care units]. PMID- 20959057 TI - [Acute myocardial infarction in a 13-year-old girl]. PMID- 20959058 TI - [A case report of propionic academia]. PMID- 20959059 TI - [Childhood hemiplegia associated with influenza A (H1N1) infection: a case report]. PMID- 20959060 TI - [Enlightenment for pediatric continuing education from the University of Sydney DHC project]. PMID- 20959061 TI - [Research advance in genetic-associated genes of tuberculosis]. PMID- 20959062 TI - [Study on the molecular mechanisms of dlk1 stimulated lung cancer cell proliferation]. AB - BACKGROUND: The imprinted gene dlk1 has been recognized as a cancer related gene since it aberrantly expressed in a series of cancer tissues, but its role in lung cancer is still unknown. The aim of this study is to examine dlk1's expression in non-small cell lung cancers (NSCLCs) and investigate the molecular mechanism by which dlk1 could accelerate the proliferation of the cells in lung cancer cell lines (H520). METHODS: The relative expression of dlk1 among 30 NSCLC specimens and their adjacent normal lung tissues were analyzed by RT-PCR. A cell model that stably expressed exogenous dlk1 was established following that the dlk1 gene was cloned into a eukaryotic expression vector and then transfected into the lung cancer cells H520. CCK8 analysis and colony forming assay were employed to investigate the effect of dlk1 on cell proliferation. The expression of CyclinB1 was detected by Western blot. RESULTS: dlk1 aberrantly expressed in 36.7% (11/30) of the tumor tissues of NSCLC compared with their adjacent cancer lung tissues. CCK8 analysis showed that overexpression of dlk1 could promote the proliferation of H520 cells (P < 0.05) and the results was further confirmed by colony forming assay. Western blot analysis found that over expression of dlk1 could up-regulate the expression of CyclinB1 (P < 0.05). CONCLUSIONS: dlk1 aberrantly expressed in NSCLCs. The Overexpression of dlk1 could accelerate the proliferation of lung cancer cells H520 in vitro, probably through up-regulating the expression of cell cycle protein CyclinB1. PMID- 20959063 TI - [Comparative proteomics study on human high-metastatic large cell lung cancer cell lines before and after transfecting with nm23-H1 gene]. AB - BACKGROUND: As a tumor metastasis suppressor gene, the functions of nm23-H1 gene are still unclear. The aim of this study is to better understand the mechanism of lung cancer metastasis and to find new biomarkers for early diagnosis and new target for therapy by conducting comparative proteomics between the human high metastatic large cell lung cancer cell lines (L9981) and L9981-nm23-H1 (constructed with transfecting nm23-H1 gene into the L9981 cell line). METHODS: The total proteins of L9981 and L9981-nm23-H1 were separated by immobilized pH gradient (IPG)-based 2-dimensional electrophoresis (2-DE); the significantly differently expressed proteins were examined by mass spectrometry and analyzed by bioinformatics. RESULTS: It was observed that nm23-H1 gene transfection caused remarkable changes of the proteome of L9981 compared with L9981-nm23-H1 cells: 5 proteins were deleted, 9 proteins appeared, 16 proteins downregulated, and 12 proteins up-regulated. These proteins are involved in cell framework, signal transduction, metabolism, proliferation and metastasis. CONCLUSIONS: After nm23 H1 gene is transfected into L9981, proteome in L9981 is remarkably changed. These changes of the proteome could serve as a basis for reversing the invasive and metastatic phenotype in lung cancer and elucidating the mechanisms of the metastasis of lung cancer. PMID- 20959064 TI - [Effects of the spider venom on proliferation of human lung adenocarcinoma cell A549]. AB - BACKGROUND AND OBJECTIVE: The spider venom may inspire new drugs to treat cancer. The aim of this study is to investigate the effects and mechanisms of spider venom on lung adenocarcinoma cell A549. METHODS: The proliferation of lung adenocarcinoma A549 cells was detected by MTT. The apoptosis rate was observed with MTT assay and flow cytometer. The activity of catalase was detected by colorimetry. The malondialdehyde (MDA) content was determined by improved thiobarbituric acid fluorometric method. The expression of P38MAPK protein was analyzed with Western blot. RESULTS: Spider venom can remarkably inhibite the proliferation of lung adenocarcinoma A549 cells, increased activity of catalase and MDA content, down-regulated expression of P38MAPK compared with the control group. CONCLUSIONS: The reduced proliferation of lung adenocarcinoma A549 cells by spider venom is may be associated with the increased of activity of catalase and MDA content and decreased expression of P38MAPK. PMID- 20959065 TI - [Paclitaxel blocks immunologic escape through up-regulating TAP-1, TAP-2 and eliminatiing Treg cells in 3LL-bearing mice]. AB - BACKGROUND AND OBJECTIVE: Until now, there are still some questions that chemotherapy could block cancer immunologic escape or not. The aim of this study is to explore the mechanism of paclitaxel in the blocking of immunologic escape in 3LL bearing mice. METHODS: MHC class I components were detected by FACS antibodies TAP-1 and TAP-2 in 3LL group and 3LL pretreated with 5*10(-8) mmol/L paclitaxel. C57BL/6 mice were divided into 3 groups: tumor -bearing group, paclitaxel-treating group and tumor-free group. 3LL cells (0.3*10(6)) were injected via tail vein of mice. On day 8, paclitaxel (0.012 5 mg) was injected subcutaneously in the treatment group. On day 21, murine lung cells were suspended. With FACS triple staining, we analyzed expression of Treg in each group. RESULTS: The expression of TAP-1 (5.68%+/-0.65%), TAP-2 (89.54%+/-4.8%) was remarkably higher in paclitaxel-pretreating 3LL group than that in 3LL bearing mice group with TAP-1 (1.93%+/-0.25%), TAP-2 (67.78%+/-5.08%), P=0.006, P=0.036 respectively. The expression of regulatory T cells (Treg) in tumor bearing mice was significantly higher (25.46%+/-2.23%) than that of in normal mice (12.46%+/-1.21%) (P < 0.001). Expression of Treg in paclitaxel treated mice was remarkably inhibited (17.53%+/-1.24%) compared with that in 3LL bearing mice group (P=0.004). CONCLUSIONS: Paclitaxel may block immunologic escape in the treatment of 3LL bearing mice partly through up-regulation TAP-1, TAP-2 and eliminating Treg cells. PMID- 20959066 TI - [BAG family gene and its relationship with lung adenocarcinoma susceptibility]. AB - BACKGROUND AND OBJECTIVE: BAG genes (Bcl-2-associated athanogene) belong to a recently discovered multifunctional anti-apoptosis gene family that regulate various physiological processes which include apoptosis, tumorigenesis, neural differentiation, stress response and cell cycle and so on. The expression status of BAG family genes are related to certain tumor incidence and prognosis. The aim of this study is to explore the association of the BAG family gene expression status with the susceptibility of lung adenocarcinoma. METHODS: The gene expression data of BAG family genes from 29 cases of lung adenocarcinoma tissues and matched pericancerous lung tissues were generated by microarray chips. Cox regression was used to analyze the association between the expression of BAG family genes and the susceptibility of lung adenocarcinoma and the results were verified by GEO database. RESULTS: The expression levels of BAG-1, BAG-2, BAG-5 in cancer tissues were significantly downregulated compared with matched pericancerous lung tissues and were protective factors of lung adenocarcinoma (P < 0.05, OR < 1); while the expression level of BAG-4 in cancer tissues were remarkably upregulated compared with the matched pericancerous lung tissues and was risk factor of lung adenocarcinoma (P < 0.05, OR > 1). CONCLUSIONS: BAG-1, BAG-2, BAG-5 might be the potential protective factors while BAG-4 is possible risk factor of lung adenocarcinoma. PMID- 20959067 TI - [Diagnostic value of bone metabolic markers ICTP and BAP in lung cancer patients with bone metastases]. AB - BACKGROUND AND OBJECTIVE: Bone metabolic markers are biomarkers derived from bone matrix or osteocyte reflecting bone metabolic situation. The aim of this study is to explore the diagnostic value of bone markers, cross-linked telopeptide of type I collage (ICTP) and bone-specific alkaline phosphatase (BAP) in lung cancer patients with bone metastases (B.M). METHODS: As a prospective control study, 110 cases were enrolled and divided into 3 groups. Totally 90 pre-treated, stage IV lung cancer cases were divided into two groups: 50 cases with bone metastases, 40 cases without bone metastases, as well as 20 healthy subjects were included as control. Serum ICTP was detected by enzyme-linked immunoassay (ELISA) and serum BAP was detected by electrochemiluminescence immunoassay. The relationships between factors of B.M and serum levels of ICTP, BAP were analyzed. RESULTS: The levels of serum ICTP and BAP in lung cancer patients with B.M were significantly higher than those in the healthy controls and those without B.M (P < 0.05). The level of serum BAP in patients with multiple B.M (lesions>=3) was significantly higher than that in patients with few B.M (lesions < 3) (P < 0.05). The level of serum BAP in patients with mixed pattern was significantly higher than that with lytic pattern. The sensibility of ICTP and BAP in the diagnosis of B.M in lung cancer patients was 18% and 40% respectively. The specificity of ICTP and BAP was 98.3% and 95% respectively. The accuracy rates of ICTP and BAP were 61.8% and 70.0% respectively. Joint detection of ICTP and BAP had improved sensibility and accuracy in the diagnosis of bone metastases in lung cancer patients (52% and 74.5% respectively). CONCLUSIONS: Serum bone biochemical markers ICTP and BAP have diagnostic values for B.M in lung cancer patients with lower costs, noninvasiveness and convenience. PMID- 20959068 TI - [Clinical significance of serum cytokeratin 19 fragment in the prediction of chemotherapy efficacy and prognosis in patients with advanced non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: RECIST (Response Evaluation Criteria in Solid Tumors) criteria could not be used to detect viable tumor tissue and is not an accurate tool for evaluation of objective response (OR) in non-small cell lung cancer (NSCLC) patients without measurable lesions. The aim of this study is to detect the pre- and post-chemotherapy serum cytokeratin 19 fragment (CYFRA21-1) expression levels in advanced NSCLC patients to evaluate the clinical value of CYFRA21-1 in the prediction of chemotherapy response and prognosis in NSCLC patients. METHODS: A automatic electrochemiluminescence immunoassay analyzer was applied to detect the pre- and post-chemotherapy serum CYFRA21-1 expression levels in 112 cases of initial treatment patients with NSCLC. Application of receiver operating characteristics curve (ROC) curve in evaluation the significance of serum CYFRA21-1 response in the diagnosis of OR and its correlation with prognosis. RESULTS: After 2 cycles of platinum-based combined chemotherapy, post-chemotherapy serum CYFRA21-1 significantly decreased compared with baseline levels. 80 patients were evaluable for radiological and serological efficacy, and 26.3% (21/80) patients achieved radiological OR. The decrease ratio of post-chemotherapy serum CYFRA21-1 with CYFRA21-1 response was 40.0% (32/80). There was significant correlation between serum CYFRA21-1 response and OR (P < 0.001). The median survival time of all patients was 9.9 months; the survival of patients with CYFRA21-1 response were significantly longer than those without CYFRA21-1 responders (12.3 months vs 8.9 months, P < 0.001). Univariate survival analysis showed that PS score, OR, baseline serum CYFRA21-1 level and CYFRA21-1 response were important prognostic factors. Cox multivariate survival analysis confirmed that only the PS score, serum CYFRA21-1 baseline levels and CYFRA21-1 response were independent prognostic factors of NSCLC patients; OR was not an independent prognostic factor. CONCLUSIONS: Serum CYFRA21-1 level can be sensitive to reflect changes in tumor volume, which may be a reliable substitution index for evaluation the chemotherapy efficacy in advanced NSCLC patients and a good indicator for prediction the prognosis of survival. PMID- 20959069 TI - [Expression and clinical significance of CD8+natural killer T cell stimulatory receptor NKG2D in peripheral blood of lung cancer patients]. AB - BACKGROUND AND OBJECTIVE: NKG2D-expressing CD8+NKT cells and soluble major histocompatibility complex class I-related chain A (sMICA) is one of recently emerged general interests in tumor research area. The aim of this study is to investigate the levels of NKG2D-expressing CD8+NKT cells in peripheral blood of lung cancer patients, which are remarkably related to clinical significance, and to analyze the correlation between NKG2D-expressing CD8+NKT cells and sMICA levels, and to explore the role of NKG2D and sMICA in immune surveillance. METHODS: Flow cytometry was used to determine the percentage of NKG2D-expressing CD8+NKT cells, and ELISA was used to measure the levels of sMICA in peripheral blood of 82 untreated lung cancer patients and 45 healthy controls. The association of NKG2D levels with clinical features was analyzed. RESULTS: The expression of NKG2D on CD8+NKT cells in lung cancer group was significantly lower than that in healthy group, with statistically significant difference (P < 0.001). And with the increase of TNM stage, NKG2D expression rate reduced gradually. NKG2D expression in stage IV disease was significantly lower than which stage I-II and III disease (P < 0.001). The expression of NKG2D on CD8+NKT cells was remarkably lower in that in smokers than that in non-smokers, with statistically significant difference (P < 0.05). NKG2D exhibited negative correlation with sMICA (r=-0.598, P < 0.001). CONCLUSIONS: Lung cancer has low expression of NKG2D in CD8+NKT cells which correlate with pathological stage. Detection of NKG2D and sMICA might be helpful to understand immune functions and provide evaluation of combined treatment for clinical cancer. PMID- 20959070 TI - [Impact of anemia on chemotherapy efficacy and prognosis in patients with advanced non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Cancer-related anemia is the common complication of non small cell lung cancer (NSCLC), which affects the quality of life (QOL), chemotherapy efficacy and prognosis in patients with NSCLC. In this study, we statistically analysed the incidence of anemia in NSCLC patients before and after chemotherapy and related risk factors, and investigated the impact of anemia on QOL, chemotherapy efficacy and prognosis in patients with NSCLC. METHODS: Clinical data of 140 patients with NSCLC from January 2007 to December 2008 were collected and retrospectively analysed for the changes in hemoglobin levels before and after chemotherapy, the risk factors of anemia, and the relationship with chemotherapy efficacy and prognosis. Application of QOL scale (EORTCQLQ-C30, Chinese version) to evaluate the impact of anemia on QOL in patients with advanced NSCLC. RESULTS: Total 140 cases of NSCLC patients, the incidence of anemia after two cycles of chemotherapy was significantly higher than that before chemotherapy (71.4% vs 47.1%, P < 0.001), and the severity of anemia increased simultaneously with the cycles of chemotherapy. According to univariete and multivariate Logstic regression analysis, age, clinical stage, PS score and albumin levels were closely related to pre-treatment cancerrelated anemia. However, multivariate Logistic regression analysis confirmed that only albumin levels was the risk factors of anemia. QOL scores on physical function, symptoms and overall quality of life were significantly different in anemia and nonanemic patients (P < 0.05). Anemia occurred before and after chemotherapy were significantly lower chemotherapy efficacy in patients with advanced NSCLC. Cancer related anemia obviously impacted on the prognosis of patients, the median survival of cancer-related anemia patients was significantly shorter than those without anemia (7 months vs 13 months, P < 0.001), and the median survival of cancer-related anemia patients before chemotherapy was significantly longer than those with anemia (7 months vs 11 months, P < 0.001). Cox multivariate regression analysis confirmed that anemia, clinical stage, PS score, albumin level were the independent prognostic factors in advanced NSCLC. CONCLUSIONS: NSCLC patients had a higher incidence of anemia, especially the incidence of chemotherapy-related anemia, age, clinical stage, PS score, albumin levels were the risk factors of pre-treatment cancer-related anemia. NSCLC patients with anemia had lower QOL and chemotherapy efficacy, and shorter lifetime. Anemia was an independent prognostic factor in NSCLC patients. PMID- 20959071 TI - [Prevention of refractory cough with mediastinal fat to fill the residual cavity after radical systematic mediastinal lymphadenectomy in patients with right lung cancer]. AB - BACKGROUND AND OBJECTIVE: The aim of this study is to analyze the impact on the cough after radical systematic mediastinal lymphadenectomy and prevention of refractory cough with mediastinal fat to fill the residual cavity after radical systematic mediastinal lymphadenectomy. METHODS: Sixty patients clinically diagnosed of lung cancer were selected according to the adopt standardization, from January 2008 to December 2008. All of the patients were divided into two groups randomly: the filling-fat group and the non-filling-fat group. The surgical information such as operation duration time bleeding volume during operation, post-operation bleeding volume were recorded. After one month, FACT-L and LCQ were completed. RESULTS: There are no remarkably differences between the operation duration time, bleeding volume in operation and 1st postoperation day's drainage volume of the two groups. There's significant difference in the scores of cough at night after taking off the chest tube, as well as in the scores of LCQ after one month and in the scores of last items of FACT-L. CONCLUSIONS: Filling the fat of the mediastinal to cover the residual cavity left by completely systematic mediastinal lymphadenectomy can reduce the refractory cough after surgery, and can also improve the quality of the life. It has no effect on the the operation duration time, bleeding volume in operation and 1st post operation day's drainage volume of the patients. PMID- 20959072 TI - [The roles of signal transducer and activator of transcription 3 in tumor metastasis]. PMID- 20959073 TI - [Advances on diagnosis and treatment of malignant thymic tumors]. PMID- 20959074 TI - [Comparative values of different imaging methods in lung cancer screening]. AB - Radiology is the primary lung cancer screening technique. Whether the mortality rate of lung cancer could be markedly reduce by radiological screening was still unknown to us. It was suggested that high-risk individuals should take regular radiological examinations to detect early lung cancers, followed by suitable treatment. In this review, we compared the values of different radiological methods in lung cancer screening. PMID- 20959075 TI - How long does it take to establish a morphogen gradient? AB - A morphogen gradient is defined as a concentration field of a molecule that acts as a dose-dependent regulator of cell differentiation. One of the key questions in studies of morphogen gradients is whether they reach steady states on timescales relevant for developmental patterning. We propose a systematic approach for addressing this question and illustrate it by analyzing several models that account for diffusion and degradation of locally produced chemical signals. PMID- 20959076 TI - Activity and dynamics of an enzyme, pig liver esterase, in near-anhydrous conditions. AB - Water is widely assumed to be essential for life, although the exact molecular basis of this requirement is unclear. Water facilitates protein motions, and although enzyme activity has been demonstrated at low hydrations in organic solvents, such nonaqueous solvents may allow the necessary motions for catalysis. To examine enzyme function in the absence of solvation and bypass diffusional constraints we have tested the ability of an enzyme, pig liver esterase, to catalyze alcoholysis as an anhydrous powder, in a reaction system of defined water content and where the substrates and products are gaseous. At hydrations of 3 (+/-2) molecules of water per molecule of enzyme, activity is several orders-of magnitude greater than nonenzymatic catalysis. Neutron spectroscopy indicates that the fast (<=nanosecond) global anharmonic dynamics of the anhydrous functional enzyme are suppressed. This indicates that neither hydration water nor fast anharmonic dynamics are required for catalysis by this enzyme, implying that one of the biological requirements of water may lie with its role as a diffusion medium rather than any of its more specific properties. PMID- 20959077 TI - Size-dependent rheology of type-I collagen networks. AB - We investigate the system size-dependent rheological response of branched type I collagen gels. When subjected to a shear strain, the highly interconnected mesh dynamically reorients, resulting in overall stiffening of the network. When a continuous shear strain is applied to a collagen network, we observe that the local apparent modulus, in the strain-stiffening regime, is strongly dependent on the gel thickness. In addition, we demonstrate that the overall network failure is determined by the ratio of the gel thickness to the mesh size. These findings have broad implications for cell-matrix interactions, the interpretation of rheological tissue data, and the engineering of biomimetic scaffolds. PMID- 20959078 TI - Monte carlo simulations of tau proteins: effect of phosphorylation. AB - We perform Monte Carlo simulations of tau proteins bound to a cylinder that mimics a microtubule (MT), and then study them in solution. Tau protein binds to a highly anionic MT surface to stabilize the cylindrical structure of MT. The negatively charged tail domain floats away from the anionic MT surface while positively charged tau segments localize near the MT surface. Monte Carlo simulations demonstrate that, in 3RS tau isoform (which has three imperfect repeats (R) short (S) isoform), amino acids are more condensed near a highly charged interface compared to 4RL isoform (which has four imperfect repeats (R) long (L) isoform). In 4RL isoform, amino acids in tail domain stay mostly apart from the MT surface. In the bulk solution, dephosphorylated taus are separated due to Coulomb repulsion between similarly charged isoforms. Moderate phosphorylation of 3RS isoform decreases average intermolecular distance between dephosphorylated and phosphorylated taus and lead to their overlap. Further phosphorylation does not change noticeably the intermolecular distances. PMID- 20959079 TI - SANS investigation of the photosynthetic machinery of Chloroflexus aurantiacus. AB - Green photosynthetic bacteria harvest light and perform photosynthesis in low light environments, and contain specialized antenna complexes to adapt to this condition. We performed small-angle neutron scattering (SANS) studies to obtain structural information about the photosynthetic apparatus, including the peripheral light-harvesting chlorosome complex, the integral membrane light harvesting B808-866 complex, and the reaction center (RC) in the thermophilic green phototrophic bacterium Chloroflexus aurantiacus. Using contrast variation in SANS measurements, we found that the B808-866 complex is wrapped around the RC in Cfx. aurantiacus, and the overall size and conformation of the B808-866 complex of Cfx. aurantiacus is roughly comparable to the LH1 antenna complex of the purple bacteria. A similar size of the isolated B808-866 complex was suggested by dynamic light scattering measurements, and a smaller size of the RC of Cfx. aurantiacus compared to the RC of the purple bacteria was observed. Further, our SANS measurements indicate that the chlorosome is a lipid body with a rod-like shape, and that the self-assembly of bacteriochlorophylls, the major component of the chlorosome, is lipid-like. Finally, two populations of chlorosome particles are suggested in our SANS measurements. PMID- 20959080 TI - Accurate prediction of gene expression by integration of DNA sequence statistics with detailed modeling of transcription regulation. AB - Gene regulation involves a hierarchy of events that extend from specific protein DNA interactions to the combinatorial assembly of nucleoprotein complexes. The effects of DNA sequence on these processes have typically been studied based either on its quantitative connection with single-domain binding free energies or on empirical rules that combine different DNA motifs to predict gene expression trends on a genomic scale. The middle-point approach that quantitatively bridges these two extremes, however, remains largely unexplored. Here, we provide an integrated approach to accurately predict gene expression from statistical sequence information in combination with detailed biophysical modeling of transcription regulation by multidomain binding on multiple DNA sites. For the regulation of the prototypical lac operon, this approach predicts within 0.3-fold accuracy transcriptional activity over a 10,000-fold range from DNA sequence statistics for different intracellular conditions. PMID- 20959081 TI - Variability in G-protein-coupled signaling studied with microfluidic devices. AB - Different cells, even those that are genetically identical, can respond differently to identical stimuli, but the precise source of this variability remains obscure. To study this problem, we built a microfluidic experimental system which can track responses of individual cells across multiple stimulations. We used this system to determine that amplitude variation in G protein-activated calcium release in RAW264.7 macrophages is generally extrinsic, i.e., they arise from long-lived variations between cells and not from stochastic activation of signaling components. In the case of responses linked to P2Y family purine receptors, we estimate that approximately one-third of the observed variability in calcium release is receptor-specific. We further demonstrate that the signaling apparatus downstream of P2Y6 receptor activation is moderately saturable. These observations will be useful in constructing and constraining single-cell models of G protein-coupled calcium dynamics. PMID- 20959082 TI - Actin cross-linkers and the shape of stereocilia. AB - Stereocilia are actin-based cellular protrusions essential for hearing. We propose that they are shaped by the detachment dynamics of actin cross-linkers, in particular espin. We account for experimentally observed stereocilium shapes, treadmilling velocity to length relationship, espin 1 localization profile, and microvillus length to espin level relationship. If the cross-linkers are allowed to reattach, our model yields a dynamical phase transition toward unbounded growth. Considering the simplified case of a noninteracting, one-filament system, we calculate the length probability distribution in the growing phase and its stationary form in a continuum approximation of the finite-length phase. Numerical simulations of interacting filaments suggest an anomalous power-law divergence of the protrusion length at the growth transition, which could be a universal feature of cross-linked depolymerizing systems. PMID- 20959083 TI - Stiffening of human skin fibroblasts with age. AB - Changes in mechanical properties are an essential characteristic of the aging process of human skin. Previous studies attribute these changes predominantly to the altered collagen and elastin organization and density of the extracellular matrix. Here, we show that individual dermal fibroblasts also exhibit a significant increase in stiffness during aging in vivo. With the laser-based optical cell stretcher we examined the viscoelastic biomechanics of dermal fibroblasts isolated from 14 human donors aged 27 to 80. Increasing age was clearly accompanied by a stiffening of the investigated cells. We found that fibroblasts from old donors exhibited an increase in rigidity of ~60% with respect to cells of the youngest donors. A FACS analysis of the content of the cytoskeletal polymers shows a shift from monomeric G-actin to polymerized, filamentous F-actin, but no significant changes in the vimentin and microtubule content. The rheological analysis of fibroblast-populated collagen gels demonstrates that cell stiffening directly results in altered viscoelastic properties of the collagen matrix. These results identify a new mechanism that may contribute to the age-related impairment of elastic properties in human skin. The altered mechanical behavior might influence cell functions involving the cytoskeleton, such as contractility, motility, and proliferation, which are essential for reorganization of the extracellular matrix. PMID- 20959084 TI - FRAP analysis of membrane-associated proteins: lateral diffusion and membrane cytoplasmic exchange. AB - Obtaining quantitative kinetic parameters from fluorescence recovery after photobleaching (FRAP) experiments generally requires a theoretical analysis of protein mobility and appropriate solutions for FRAP recovery derived for a given geometry. Here we provide a treatment of FRAP recovery for a molecule undergoing a combined process of reversible membrane association and lateral diffusion on the plasma membrane for two commonly used bleach geometries: stripes, and boxes. Such analysis is complicated by the fact that diffusion of a molecule during photobleaching can lead to broadening of the bleach area, resulting in significant deviations of the actual bleach shape from the desired bleach geometry, which creates difficulty in accurately measuring kinetic parameters. Here we overcome the problem of deviations between actual and idealized bleach geometries by parameterizing, more accurately, the initial postbleach state. This allows for reconstruction of an accurate and analytically tractable approximation of the actual fluorescence distribution. Through simulated FRAP experiments, we demonstrate that this method can be used to accurately measure a broad range of combinations of diffusion constants and exchange rates. Use of this method to analyze the plextrin homology domain of PLC-delta1 in Caenorhabditis elegans results in quantitative agreement with prior analysis of this domain in other cells using other methods. Because of the flexibility, relative ease of implementation, and its use of standard, easily obtainable bleach geometries, this method should be broadly applicable to investigation of protein dynamics at the plasma membrane. PMID- 20959085 TI - Spatial distribution of the state of water in frozen mammalian cells. AB - We describe direct determination of the state of intracellular water, measurement of the intercellular concentration of a cryoprotectant agent (dimethylsulfoxide), and the distribution of organic material in frozen mammalian cells. Confocal Raman microspectroscopy was utilized at cryogenic temperatures with single live cells to conduct high spatial resolution measurements (350 * 350 * 700 nm), which yielded two, we believe, novel observations: 1), intracellular ice formation during fast cooling (50 degrees C/min) causes more pronounced intracellular dehydration than slow cooling (1 degrees C/min); and 2), intracellular dimethylsulfoxide concentration is lower (by as much as 50%) during fast cooling, decreasing the propensity for intracellular vitrification. These observations have a very significant impact for developing successful biopreservation protocols for cells used for therapeutic purposes and for cellular biofluids. PMID- 20959086 TI - Mechanical force affects expression of an in vitro metastasis-like phenotype in HCT-8 cells. AB - Cancer deaths are primarily caused by metastases, not by the parent tumor. During metastasis, malignant cells detach from the parent tumor, and spread through the circulatory system to invade new tissues and organs. The physical-chemical mechanisms and parameters within the cellular microenvironment that initiate the onset of metastasis, however, are not understood. Here we show that human colon carcinoma (HCT-8) cells can exhibit a dissociative, metastasis-like phenotype (MLP) in vitro when cultured on substrates with appropriate mechanical stiffness. This rather remarkable phenotype is observed when HCT-8 cells are cultured on gels with intermediate-stiffness (physiologically relevant 21-47 kPa), but not on very soft (1 kPa) and very stiff (3.6 GPa) substrates. The cell-cell adhesion molecule E-Cadherin, a metastasis hallmark, decreases 4.73 +/- 1.43 times on cell membranes in concert with disassociation. Both specific and nonspecific cell adhesion decrease once the cells have disassociated. After reculturing the disassociated cells on fresh substrates, they retain the disassociated phenotype regardless of substrate stiffness. Inducing E-Cadherin overexpression in MLP cells only partially reverses the MLP phenotype in a minority population of the dissociated cells. This important experiment reveals that E-Cadherin does not play a significant role in the upstream regulation of the mechanosensing cascade. Our results indicate, during culture on the appropriate mechanical microenvironment, HCT-8 cells undergo a stable cell-state transition with increased in vitro metastasis-like characteristics as compared to parent cells grown on standard, very stiff tissue culture dishes. Nuclear staining reveals that a large nuclear deformation (major/minor axis ratio, 2:5) occurs in HCT-8 cells when cells are cultured on polystyrene substrates, but it is markedly reduced (ratio, 1:3) in cells grown on 21 kPa substrates, suggesting the cells are experiencing different intracellular forces when grown on stiff as compared to soft substrates. Furthermore, MLP can be inhibited by blebbistatin, which inactivates myosin II activity and relaxes intracellular forces. This novel finding suggests that the onset of metastasis may, in part, be linked to the intracellular forces and the mechanical microenvironment of the tumor. PMID- 20959087 TI - Shear-stabilized rolling behavior of E. coli examined with simulations. AB - Escherichia coli exhibit both shear-stabilized rolling and a transition to stationary adhesion while adhering in fluid flow. Understanding the mechanism by which this shear-enhanced adhesion occurs is an important step in understanding bacterial pathogenesis. In this work, simulations are used to investigate the relative contributions of fimbrial deformation and bond transitions to the rolling and stationary adhesion of E. coli. Each E. coli body is surrounded by many long, thin fimbriae terminating in a single FimH receptor that is capable of forming a catch bond with mannose. As simulated cells progress along a mannosylated surface under flow, the fimbriae bend and buckle as they interact with the surface, and FimH-mannose bonds form and break according to a two-state, allosteric catch-bond model. In simulations, shear-stabilized rolling resulted from an increase in the low-affinity bond number due to increased fimbrial deformation with shear. Catch-bond formation did not occur during cell rolling, but instead led to the transition to stationary adhesion. In contrast, in leukocyte and platelet systems, catch bonds appear to be involved in the stabilization of rolling, and integrin activation is required for stationary adhesion. PMID- 20959088 TI - Mesenchymal stem cell mechanics from the attached to the suspended state. AB - Human mesenchymal stem cells (hMSCs) are therapeutically useful cells that are typically expanded in vitro on stiff substrata before reimplantation. Here we explore MSC mechanical and structural changes via atomic force microscopy and optical stretching during extended passaging, and we demonstrate that cytoskeletal organization and mechanical stiffness of attached MSC populations are strongly modulated over >15 population doublings in vitro. Cytoskeletal actin networks exhibit significant coarsening, attendant with decreasing average mechanical compliance and differentiation potential of these cells, although expression of molecular surface markers does not significantly decline. These mechanical changes are not observed in the suspended state, indicating that the changes manifest themselves as alterations in stress fiber arrangement rather than cortical cytoskeleton arrangement. Additionally, optical stretching is capable of investigating a previously unquantified structural transition: remodeling-induced stiffening over tens of minutes after adherent cells are suspended. Finally, we find that optically stretched hMSCs exhibit power-law rheology during both loading and recovery; this evidence appears to be the first to originate from a biophysical measurement technique not involving cell-probe or cell-substratum contact. Together, these quantitative assessments of attached and suspended MSCs define the extremes of the extracellular environment while probing intracellular mechanisms that contribute to cell mechanical response. PMID- 20959089 TI - Role of the S4-S5 linker in CNG channel activation. AB - Cyclic nucleotide-gated (CNG) channels mediate sensory signal transduction in retinal and olfactory cells. The channels are activated by the binding of cyclic nucleotides to a cyclic nucleotide-binding domain (CNBD) in the C-terminus that is located at the intracellular side. The molecular events translating the ligand binding to the pore opening are still unknown. We investigated the role of the S4 S5 linker in the activation process by quantifying its interaction with other intracellular regions. To this end, we constructed chimeric channels in which the N-terminus, the S4-S5 linker, the C-linker, and the CNBD of the retinal CNGA1 subunit were systematically replaced by the respective regions of the olfactory CNGA2 subunit. Macroscopic concentration-response relations were analyzed, yielding the apparent affinity to cGMP and the Hill coefficient. The degree of functional coupling of intracellular regions in the activation gating was determined by thermodynamic double-mutant cycle analysis. We observed that all four intracellular regions, including the relatively short S4-S5 linker, are involved in controlling the apparent affinity of the channel to cGMP and, moreover, in determining the degree of cooperativity between the subunits, as derived from the Hill coefficient. The interaction energies reveal an interaction of the S4-S5 linker with both the N-terminus and the C-linker, but no interaction with the CNBD. PMID- 20959090 TI - Pulsed electron spin resonance resolves the coordination site of Cu2(+) ions in alpha1-glycine receptor. AB - Herein, we identify the coordination environment of Cu2(+) in the human alpha1 glycine receptor (GlyR). GlyRs are members of the pentameric ligand-gated ion channel superfamily (pLGIC) that mediate fast signaling at synapses. Metal ions like Zn2(+) and Cu2(+) significantly modulate the activity of pLGICs, and metal ion coordination is essential for proper physiological postsynaptic inhibition by GlyR in vivo. Zn2(+) can either potentiate or inhibit GlyR activity depending on its concentration, while Cu2(+) is inhibitory. To better understand the molecular basis of the inhibitory effect we have used electron spin resonance to directly examine Cu2(+) coordination and stoichiometry. We show that Cu2(+) has one binding site per alpha1 subunit, and that five Cu2(+) can be coordinated per GlyR. Cu2(+) binds to E192 and H215 in each subunit of GlyR with a 40 MUM apparent dissociation constant, consistent with earlier functional measurements. However, the coordination site does not include several residues of the agonist/antagonist binding site that were previously suggested to have roles in Cu2(+) coordination by functional measurements. Intriguingly, the E192/H215 site has been proposed as the potentiating Zn2(+) site. The opposing modulatory actions of these cations at a shared binding site highlight the sensitive allosteric nature of GlyR. PMID- 20959091 TI - NMR structures of the histidine-rich peptide LAH4 in micellar environments: membrane insertion, pH-dependent mode of antimicrobial action, and DNA transfection. AB - The LAH4 family of histidine-rich peptides exhibits potent antimicrobial and DNA transfection activities, both of which require interactions with cellular membranes. The bilayer association of the peptides has been shown to be strongly pH-dependent, with in-planar alignments under acidic conditions and transmembrane orientations when the histidines are discharged. Therefore, we investigated the pH- and temperature-dependent conformations of LAH4 in DPC micellar solutions and in a TFE/PBS solvent mixture. In the presence of detergent and at pH 4.1, LAH4 adopts helical conformations between residues 9 and 24 concomitantly with a high hydrophobic moment. At pH 6.1, a helix-loop-helix structure forms with a hinge encompassing residues His10-Ala13. The data suggest that the high density of histidine residues and the resulting electrostatic repulsion lead to both a decrease in the pK values of the histidines and a less stable alpha-helical conformation of this region. The hinged structure at pH 6.1 facilitates membrane anchoring and insertion. At pH 7.8, the histidines are uncharged and an extended helical conformation including residues 4-21 is again obtained. LAH4 thus exhibits a high degree of conformational plasticity. The structures provide a stroboscopic view of the conformational changes that occur during membrane insertion, and are discussed in the context of antimicrobial activity and DNA transfection. PMID- 20959092 TI - Electrostatic interactions and binding orientation of HIV-1 matrix studied by neutron reflectivity. AB - The N-terminal matrix (MA) domain of the HIV-1 Gag protein is responsible for binding to the plasma membrane of host cells during viral assembly. The putative membrane-binding interface of MA was previously mapped by means of mutagenesis and analysis of its trimeric crystal structure. However, the orientation of MA on membranes has not been directly determined by experimental measurements. We present neutron reflectivity measurements that resolve the one-dimensional scattering length density profile of MA bound to a biomimetic of the native viral membrane. A molecular refinement procedure was developed using atomic structures of MA to determine the orientation of the protein on the membrane. The orientation defines a lipid-binding interface consistent with previous mutagenesis results. The MA protein maintains this orientation without the presence of a myristate group, driven only by electrostatic interactions. Furthermore, MA is found to penetrate the membrane headgroup region peripherally such that only the side chains of specific Lys and Arg residues interact with the surface. The results suggest that electrostatic interactions are sufficient to favorably orient MA on viral membrane mimics. The spatial determination of the membrane-bound protein demonstrates the ability of neutron reflectivity to discern orientation and penetration under physiologically relevant conditions. PMID- 20959093 TI - Cell-penetrating peptide induces leaky fusion of liposomes containing late endosome-specific anionic lipid. AB - Cationic cell-penetrating peptides (CPPs) are a promising vehicle for the delivery of macromolecular drugs. Although many studies have indicated that CPPs enter cells by endocytosis, the mechanisms by which they cross endosomal membranes remain elusive. On the basis of experiments with liposomes, we propose that CPP escape into the cytosol is based on leaky fusion (i.e., fusion associated with the permeabilization of membranes) of the bis(monoacylglycero)phosphate (BMP)-enriched membranes of late endosomes. In our experiments, prototypic CPP HIV-1 TAT peptide did not interact with liposomes mimicking the outer leaflet of the plasma membrane, but it did induce lipid mixing and membrane leakage as it translocated into liposomes mimicking the lipid composition of late endosome. Both membrane leakage and lipid mixing depended on the BMP content and were promoted at acidic pH, which is characteristic of late endosomes. Substitution of BMP with its structural isomer, phosphatidylglycerol (PG), significantly reduced both leakage of the aqueous probe from liposomes and lipid mixing between liposomes. Although affinity of binding to TAT was similar for BMP and PG, BMP exhibited a higher tendency to support the inverted hexagonal phase than PG. Finally, membrane leakage and peptide translocation were both inhibited by inhibitors of lipid mixing, further substantiating the hypothesis that cationic peptides cross BMP-enriched membranes by inducing leaky fusion between them. PMID- 20959094 TI - The energetics of transmembrane helix insertion into a lipid bilayer. AB - Free energy profiles for insertion of a hydrophobic transmembrane protein alpha helix (M2 from CFTR) into a lipid bilayer have been calculated using coarse grained molecular dynamics simulations and umbrella sampling to yield potentials of mean force along a reaction path corresponding to translation of a helix across a lipid bilayer. The calculated free energy of insertion is smaller when a bilayer with a thinner hydrophobic region is used. The free energies of insertion from the potentials of mean force are compared with those derived from a number of hydrophobicity scales and with those derived from translocon-mediated insertion. This comparison supports recent models of translocon-mediated insertion and in particular suggests that: 1), helices in an about-to-be-inserted state may be located in a hydrophobic region somewhat thinner than the core of a lipid bilayer; and/or 2), helices in a not-to-be-inserted state may experience an environment more akin (e.g., in polarity/hydrophobicity) to the bilayer/water interface than to bulk water. PMID- 20959095 TI - Residue-specific side-chain packing determines the backbone dynamics of transmembrane model helices. AB - The transmembrane domains (TMDs) of membrane-fusogenic proteins contain an overabundance of beta-branched residues. In a previous effort to systematically study the relation among valine content, fusogenicity, and helix dynamics, we developed model TMDs that we termed LV-peptides. The content and position of valine in LV-peptides determine their fusogenicity and backbone dynamics, as shown experimentally. Here, we analyze their conformational dynamics and the underlying molecular forces using molecular-dynamics simulations. Our study reveals that backbone dynamics is correlated with the efficiency of side-chain to side-chain van der Waals packing between consecutive turns of the helix. Leu side chains rapidly interconvert between two rotameric states, thus favoring contacts to its i+/-3 and i+/-4 neighbors. Stereochemical restraints acting on valine side chains in the alpha-helix force both beta-substituents into an orientation where i,i+/-3 interactions are less favorable than i,i+/-4 interactions, thus inducing a local packing deficiency at VV3 motifs. We provide a quantitative molecular model to explain the relationship among chain connectivity, side-chain mobility, and backbone flexibility. We expect that this mechanism also defines the backbone flexibility of natural TMDs. PMID- 20959096 TI - Interaction of synaptotagmin with lipid bilayers, analyzed by single-molecule force spectroscopy. AB - Synaptotagmin I is the major Ca2(+) sensor for membrane fusion during neurotransmitter release. The cytoplasmic domain of synaptotagmin consists of two C2 domains, C2A and C2B. On binding Ca2(+), the tips of the two C2 domains rapidly and synchronously penetrate lipid bilayers. We investigated the forces of interaction between synaptotagmin and lipid bilayers using single-molecule force spectroscopy. Glutathione-S-transferase-tagged proteins were attached to an atomic force microscope cantilever via a glutathione-derivatized polyethylene glycol linker. With wild-type C2AB, the force profile for a bilayer containing phosphatidylserine had both Ca2(+)-dependent and Ca2(+)-independent components. No force was detected when the bilayer lacked phosphatidylserine, even in the presence of Ca2(+). The binding characteristics of C2A and C2B indicated that the two C2 domains cooperate in binding synaptotagmin to the bilayer, and that the relatively weak Ca2(+)-independent force depends only on C2A. When the lysine residues K189-192 and K326, 327 were mutated to alanine, the strong Ca2(+) dependent binding interaction was either absent or greatly reduced. We conclude that synaptotagmin binds to the bilayer via C2A even in absence of Ca2(+), and also that positively charged regions of both C2A and C2B are essential for the strong Ca2(+)-dependent binding of synaptotagmin to the bilayer. PMID- 20959097 TI - Molecular organization of the tear fluid lipid layer. AB - The tear fluid protects the corneal epithelium from drying out as well as from invasion by pathogens. It also provides cell nutrients. Similarly to lung surfactant, it is composed of an aqueous phase covered by a lipid layer. Here we describe the molecular organization of the anterior lipid layer of the tear film. Artificial tear fluid lipid layers (ATFLLs) composed of egg yolk phosphatidylcholine (60 mol %), free fatty acids (20 mol %), cholesteryl oleate (10 mol %), and triglycerides (10 mol %) were deposited on the air-water interface and their physico-chemical behavior was compared to egg-yolk phosphatidylcholine monolayers by using Langmuir-film balance techniques, x-ray diffraction, and imaging techniques as well as in silico molecular level simulations. At low surface pressures, ATFLLs were organized at the air-water interface as heterogeneous monomolecular films. Upon compression the ATFLLs collapsed toward the air phase and formed hemispherelike lipid aggregates. This transition was reversible upon relaxation. These results were confirmed by molecular-level simulations of ATFLL, which further provided molecular-scale insight into the molecular distributions inside and dynamics of the tear film. Similar type of behavior is observed in lung surfactant but the folding takes place toward the aqueous phase. The results provide novel information of the function of lipids in the tear fluid. PMID- 20959098 TI - Molecular dynamics simulations of Arp2/3 complex activation. AB - Actin-related protein 2 and 3 (Arp2/3) complex forms a dendritic network of actin filaments during endocytosis and cellular locomotion by nucleating branches on the sides of preexisting actin filaments. Reconstructions of electron tomograms of branch junctions show how Arp2/3 complex anchors the branch, with Arp2 and Arp3 serving as the first two subunits of the branch. Our aim was to characterize the massive conformational change that moves Arp2 ~30 A from its position in crystal structures of inactive Arp2/3 complex to its position in branch junctions. Starting with the inactive crystal structure, we used atomistic-scale molecular dynamics simulations to drive Arp2 toward the position observed in branch junctions. When we applied forces to Arp2 while restraining Arp3, one block of structure (Arp2, subunit ARPC1, the globular domain of ARPC4 and ARPC5) rotated counterclockwise by 30 degrees around a pivot point in an alpha-helix of ARPC4 (Glu81-Asn100) to align Arp2 next to Arp3 in a second block of structure including ARPC3 and the globular domains of ARPC2. This active structure buried more surface area than the inactive conformation. The complex was stable in all simulations. In most simulations, collisions of subdomain 2 of Arp2 with Arp3 impeded the movement of Arp2. PMID- 20959099 TI - RNA polymerase II with open and closed trigger loops: active site dynamics and nucleic acid translocation. AB - RNA polymerase II is the central eukaryotic enzyme in transcription from DNA to RNA. The dynamics of RNA polymerase II is described from molecular-dynamics simulations started from two crystal structures with open and closed trigger loop (TL) forms. Dynamic transitions between neutral and forward translocated states were observed, especially for the downstream DNA duplex. Dynamic rearrangements were also seen in the active site environment, including conformations in which the active site nucleotide assumed a possibly precatalytic conformation in close proximity to the terminal 3'-hydroxyl of the nascent RNA. Because nucleic acid translocation was observed primarily in the simulations with an open TL structure, whereas close approach of the active site nucleotide to the terminal RNA ribose predominantly occurred in the closed TL structure, a modified Brownian ratchet mechanism is proposed whereby thermally driven translocation is only possible with an open TL, and fidelity control and catalysis require TL closing. PMID- 20959100 TI - Chromatin ionic atmosphere analyzed by a mesoscale electrostatic approach. AB - Characterizing the ionic distribution around chromatin is important for understanding the electrostatic forces governing chromatin structure and function. Here we develop an electrostatic model to handle multivalent ions and compute the ionic distribution around a mesoscale chromatin model as a function of conformation, number of nucleosome cores, and ionic strength and species using Poisson-Boltzmann theory. This approach enables us to visualize and measure the complex patterns of counterion condensation around chromatin by examining ionic densities, free energies, shielding charges, and correlations of shielding charges around the nucleosome core and various oligonucleosome conformations. We show that: counterions, especially divalent cations, predominantly condense around the nucleosomal and linker DNA, unburied regions of histone tails, and exposed chromatin surfaces; ionic screening is sensitively influenced by local and global conformations, with a wide ranging net nucleosome core screening charge (56-100e); and screening charge correlations reveal conformational flexibility and interactions among chromatin subunits, especially between the histone tails and parental nucleosome cores. These results provide complementary and detailed views of ionic effects on chromatin structure for modest computational resources. The electrostatic model developed here is applicable to other coarse-grained macromolecular complexes. PMID- 20959101 TI - A lattice model for transcription factor access to nucleosomal DNA. AB - Nucleosomes, the basic repeating unit of chromatin, consist of 147 basepairs of DNA that are wrapped in almost two turns around a histone protein octamer core. Because ~3/4 of the human genomic DNA is found within nucleosomes, their position and DNA interaction is an essential determinant for the DNA access of gene specific transcription factors and other proteins. Here, a DNA lattice model was developed for describing ligand binding in the presence of a nucleosome. The model takes into account intermediate states, in which DNA is partially unwrapped from the histone octamer. This facilitates access of transcription factors to up to 60 DNA basepairs located in the outer turn of nucleosomal DNA, while the inner DNA turn was found to be more resistant to competitive ligand binding. As deduced from quantitative comparisons with recently published experimental data, our model provides a better description than the previously used all-or-none lattice binding model. Importantly, nucleosome-occupancy maps predicted by the nucleosome unwrapping model also differed significantly when partial unwrapping of nucleosomal DNA was considered. In addition, large effects on the cooperative binding of transcription factors to multiple binding sites occluded by the nucleosome were apparent. These findings indicate that partial unwrapping of DNA from the histone octamer needs to be taken into account in quantitative models of gene regulation in chromatin. PMID- 20959102 TI - Cation charge dependence of the forces driving DNA assembly. AB - Understanding the strength and specificity of interactions among biologically important macromolecules that control cellular functions requires quantitative knowledge of intermolecular forces. Controlled DNA condensation and assembly are particularly critical for biology, with separate repulsive and attractive intermolecular forces determining the extent of DNA compaction. How these forces depend on the charge of the condensing ion has not been determined, but such knowledge is fundamental for understanding the basis of DNA-DNA interactions. Here, we measure DNA force-distance curves for a homologous set of arginine peptides. All forces are well fit as the sum of two exponentials with 2.4- and 4.8-A decay lengths. The shorter-decay-length force is always repulsive, with an amplitude that varies slightly with length or charge. The longer-decay-length force varies strongly with cation charge, changing from repulsion with Arg1 to attraction with Arg2. Force curves for a series of homologous polyamines and the heterogeneous protein protamine are quite similar, demonstrating the universality of these forces for DNA assembly. Repulsive amplitudes of the shorter-decay length force are species-dependent but nearly independent of charge within each species. A striking observation was that the attractive force amplitudes for all samples collapse to a single curve, varying linearly with the inverse of the cation charge. PMID- 20959103 TI - Evaluating elastic network models of crystalline biological molecules with temperature factors, correlated motions, and diffuse x-ray scattering. AB - In this study, the variance-covariance matrix of protein motions is used to compare several elastic network models within the theoretical framework of x-ray scattering from crystals. A set of 33 ultra-high resolution structures is used to characterize the average scaling behavior of the vibrational density of states and make comparisons between experimental and theoretical temperature factors. Detailed investigations of the vibrational density of states, correlations, and predicted diffuse x-ray scatter are carried out for crystalline Staphylococcal nuclease; correlations and diffuse x-ray scatter are also compared to predictions from the translation, libration, screw model and a liquid-like dynamics model. We show that elastic network models developed to best predict temperature factors without regard for the crystal environment have relatively strong long-range interactions that yield very short-ranged atom-atom correlations. Further, we find that the low-frequency modes dominate the variance-covariance matrix only for those models with a physically reasonable vibrational density of states, and the fraction of modes required to converge the correlations is higher than that typically used for elastic network model studies. The practical implications are explored using computed diffuse x-ray scatter, which can be measured experimentally. PMID- 20959105 TI - NMR studies on domain diffusion and alignment in modular GB1 repeats. AB - Modular proteins contain individual domains that are often connected by flexible, unstructured linkers. Using a model system based on the GB1 domain, we constructed tandem repeat proteins and investigated the rotational diffusion and long-range angular ordering behavior of individual domains by measuring NMR relaxation parameters and residual dipolar couplings. Although they display almost identical protein-solvent interfaces, each domain exhibits distinct rotational diffusion and alignment properties. The diffusion tensor anisotropy of the N-terminal domain (NTD) is D(||)/D(?) = 1.5-1.6, similar to that of single GB1 domains (D(||)/D(?) = 1.6-1.7), whereas the value for the C-terminal domain (CTD) is D(||)/D(?) = 2.0-2.2. In addition, the two domains have different rotational correlation times. These effects are observed for linkers of three to 24 residues, irrespective of linker length. The NTD and CTD also differ in their degree of magnetic alignment, even with a flexible linker of 18 residues, exhibiting D(a) values of 7.7 Hz and 9.7 Hz, respectively. Our results suggest that diffusion differences and long-range influences may persist in modular protein systems, even for systems that have highly flexible linkers and exhibit no domain-domain or domain-linker interactions. PMID- 20959104 TI - Human GLTP: Three distinct functions for the three tryptophans in a novel peripheral amphitropic fold. AB - Human glycolipid transfer protein (GLTP) serves as the GLTP-fold prototype, a novel, to our knowledge, peripheral amphitropic fold and structurally unique lipid binding motif that defines the GLTP superfamily. Despite conservation of all three intrinsic Trps in vertebrate GLTPs, the Trp functional role(s) remains unclear. Herein, the issue is addressed using circular dichroism and fluorescence spectroscopy along with an atypical Trp point mutation strategy. Far-ultraviolet and near-ultraviolet circular dichroism spectroscopic analyses showed that W96F W142Y-GLTP and W96Y-GLTP retain their native conformation and stability, whereas W85Y-W96F-GLTP is slightly altered, in agreement with relative glycolipid transfer activities of >90%, ~85%, and ~45%, respectively. In silico three dimensional modeling and acrylamide quenching of Trp fluorescence supported a nativelike folding conformation. With the Trp96-less mutants, changes in emission intensity, wavelength maximum, lifetime, and time-resolved anisotropy decay induced by phosphoglyceride membranes lacking or containing glycolipid and by excitation at different wavelengths along the absorption-spectrum red edge indicated differing functions for W142 and W85. The data suggest that W142 acts as a shallow-penetration anchor during docking with membrane interfaces, whereas the buried W85 indole helps maintain proper folding and possibly regulates membrane-induced transitioning to a glycolipid-acquiring conformation. The findings illustrate remarkable versatility for Trp, providing three distinct intramolecular functions in the novel amphitropic GLTP fold. PMID- 20959106 TI - The binding interface of cytochrome c and cytochrome c1 in the bc1 complex: rationalizing the role of key residues. AB - The interaction of cytochrome c with ubiquinol-cytochrome c oxidoreductase (bc1 complex) has been studied for >30 years, yet many aspects remain unclear or controversial. We report the first molecular dynamic simulations of the cyt c-bc1 complex interaction. Contrary to the results of crystallographic studies, our results show that there are multiple dynamic hydrogen bonds and salt bridges in the cyt c-c1 interface. These include most of the basic cyt c residues previously implicated in chemical modification studies. We suggest that the static nature of x-ray structures can obscure the quantitative significance of electrostatic interactions between highly mobile residues. This provides a clear resolution of the discrepancy between the structural data and functional studies. It also suggests a general need to consider dynamic interactions of charged residues in protein-protein interfaces. In addition, a novel structural change in cyt c is reported, involving residues 21-25, which may be responsible for cyt c destabilization upon binding. We also propose a mechanism of interaction between cyt c1 monomers responsible for limiting the binding of cyt c to only one molecule per bc1 dimer by altering the affinity of the cytochrome c binding site on the second cyt c1 monomer. PMID- 20959107 TI - Diffusion and sedimentation interaction parameters for measuring the second virial coefficient and their utility as predictors of protein aggregation. AB - The concentration-dependence of the diffusion and sedimentation coefficients (k(D) and k(s), respectively) of a protein can be used to determine the second virial coefficient (B2), a parameter valuable in predicting protein-protein interactions. Accurate measurement of B2 under physiologically and pharmaceutically relevant conditions, however, requires independent measurement of k(D) and k(s) via orthogonal techniques. We demonstrate this by utilizing sedimentation velocity (SV) and dynamic light scattering (DLS) to analyze solutions of hen-egg white lysozyme (HEWL) and a monoclonal antibody (mAb1) in different salt solutions. The accuracy of the SV-DLS method was established by comparing measured and literature B2 values for HEWL. In contrast to the assumptions necessary for determining k(D) and k(s) via SV alone, k(D) and ks were of comparable magnitudes, and solution conditions were noted for both HEWL and mAb1 under which 1), k(D) and k(s) assumed opposite signs; and 2), k(D) >=k(s). Further, we demonstrate the utility of k(D) and k(s) as qualitative predictors of protein aggregation through agitation and accelerated stability studies. Aggregation of mAb1 correlated well with B2, k(D), and k(s), thus establishing the potential for k(D) to serve as a high-throughput predictor of protein aggregation. PMID- 20959108 TI - Thermal fluctuation spectroscopy of DNA thermal denaturation. AB - We have developed the technique of thermal fluctuation spectroscopy to measure the thermal fluctuations in a system. This technique is particularly useful to study the denaturation dynamics of biomolecules like DNA. Here we present a study of the thermal fluctuations during the thermal denaturation (or melting) of double-stranded DNA. We find that the thermal denaturation of heteropolymeric DNA is accompanied by large, non-Gaussian thermal fluctuations. The thermal fluctuations show a two-peak structure as a function of temperature. Calculations of enthalpy exchanged show that the first peak comes from the denaturation of AT rich regions and the second peak from denaturation of GC rich regions. The large fluctuations are almost absent in homopolymeric DNA. We suggest that bubble formation and cooperative opening and closing dynamics of basepairs causes the additional fluctuation at the first peak and a large cooperative transition from a partially molten DNA to a completely denatured state causes the additional fluctuation at the second peak. PMID- 20959109 TI - Balbiani ring mRNPs diffuse through and bind to clusters of large intranuclear molecular structures. AB - A detailed conception of intranuclear messenger ribonucleoprotein particle (mRNP) dynamics is required for the understanding of mRNP processing and gene expression outcome. We used complementary state-of-the-art fluorescence techniques to quantify native mRNP mobility at the single particle level in living salivary gland cell nuclei. Molecular beacons and fluorescent oligonucleotides were used to specifically label BR2.1 mRNPs by an in vivo fluorescence in situ hybridization approach. We characterized two major mobility components of the BR2.1 mRNPs. These components with diffusion coefficients of 0.3 +/- 0.02 MUm2/s and 0.73 +/- 0.03 MUm2/s were observed independently of the staining method and measurement technique used. The mobility analysis of inert tracer molecules revealed that the gland cell nuclei contain large molecular nonchromatin structures, which hinder the mobility of large molecules and particles. The mRNPs are not only hindered by these mobility barriers, but in addition also interact presumably with these structures, what further reduces their mobility and effectively leads to the occurrence of the two diffusion coefficients. In addition, we provide evidence that the remarkably high mobility of the large, 50 nm-sized BR2.1 mRNPs was due to the absence of retarding chromatin. PMID- 20959110 TI - Multicolor fluorescence nanoscopy in fixed and living cells by exciting conventional fluorophores with a single wavelength. AB - Current far-field fluorescence nanoscopes provide subdiffraction resolution by exploiting a mechanism of fluorescence inhibition. This mechanism is implemented such that features closer than the diffraction limit emit separately when simultaneously exposed to excitation light. A basic mechanism for such transient fluorescence inhibition is the depletion of the fluorophore ground state by transferring it (via a triplet) in a dark state, a mechanism which is workable in most standard dyes. Here we show that microscopy based on ground state depletion followed by individual molecule return (GSDIM) can effectively provide multicolor diffraction-unlimited resolution imaging of immunolabeled fixed and SNAP-tag labeled living cells. Implemented with standard labeling techniques, GSDIM is demonstrated to separate up to four different conventional fluorophores using just two detection channels and a single laser line. The method can be expanded to even more colors by choosing optimized dichroic mirrors and selecting marker molecules with negligible inhomogeneous emission broadening. PMID- 20959111 TI - Label-free cellular imaging by broadband coherent anti-Stokes Raman scattering microscopy. AB - Raman microspectroscopy can provide the chemical contrast needed to characterize the complex intracellular environment and macromolecular organization in cells without exogenous labels. It has shown a remarkable ability to detect chemical changes underlying cell differentiation and pathology-related chemical changes in tissues but has not been widely adopted for imaging, largely due to low signal levels. Broadband coherent anti-Stokes Raman scattering (B-CARS) offers the same inherent chemical contrast as spontaneous Raman but with increased acquisition rates. To date, however, only spectrally resolved signals from the strong CH related vibrations have been used for CARS imaging. Here, we obtain Raman spectral images of single cells with a spectral range of 600-3200 cm-1, including signatures from weakly scattering modes as well as CH vibrations. We also show that B-CARS imaging can be used to measure spectral signatures of individual cells at least fivefold faster than spontaneous Raman microspectroscopy and can be used to generate maps of biochemical species in cells. This improved spectral range and signal intensity opens the door for more widespread use of vibrational spectroscopic imaging in biology and clinical diagnostics. PMID- 20959112 TI - Quantitative measurement of Ca2(+) in the sarcoplasmic reticulum lumen of mammalian skeletal muscle. AB - Skeletal muscle stores Ca2(+) in the sarcoplasmic reticulum (SR) and releases it to initiate contraction, but the concentration of luminal Ca2(+) in the SR ([Ca2(+)](SR)) and the amount that is released by physiological or pharmacological stimulation has been difficult to measure. Here we present a novel, yet simple and direct, method that provides the first quantitative estimates of static content and dynamic changes in [Ca2(+)](SR) in mammalian skeletal muscle, to our knowledge. The method uses fluo-5N loaded into the SR of single, mammalian skeletal muscle cells (murine flexor digitorum brevis myofibers) and confocal imaging to detect and calibrate the signals. Using this method, we have determined that [Ca2(+)](SR, free) is 390 MUM. 4-Chloro-m-cresol, an activator of the skeletal muscle ryanodine receptor, reduces [Ca2(+)](SR, free) to ~8 MUM, when values are corrected for background fluorescence from cytoplasmic pools of dye. Prolonged electrical stimulation (10 s) at 50 Hz releases 88% of the SR Ca2(+) content, whereas stimulation at 1 Hz (10 s) releases only 20%. Our results lay the foundation for molecular modeling of the dynamics of luminal SR Ca2(+) and for future studies of the role of SR Ca2(+) in healthy and diseased mammalian muscle. PMID- 20959113 TI - Spin labeling of the Escherichia coli NADH ubiquinone oxidoreductase (complex I). AB - The proton-pumping NADH:ubiquinone oxidoreductase, the respiratory complex I, couples the transfer of electrons from NADH to ubiquinone with the translocation of protons across the membrane. Electron microscopy revealed the two-part structure of the complex with a peripheral arm involved in electron transfer and a membrane arm most likely involved in proton translocation. It was proposed that the quinone binding site is located at the joint of the two arms. Most likely, proton translocation in the membrane arm is enabled by the energy of the electron transfer reaction in the peripheral arm transmitted by conformational changes. For the detection of the conformational changes and the localization of the quinone binding site, we set up a combination of site-directed spin labeling and EPR spectroscopy. Cysteine residues were introduced to the surface of the Escherichia coli complex I. The spin label (1-oxyl-2,2,5,5-tetramethyl-Delta3 pyrroline-3-methyl)-methanethiosulfonate (MTSL) was exclusively bound to the engineered positions. Neither the mutation nor the labeling had an effect on the NADH:decyl-ubiquinone oxidoreductase activity. The characteristic signals of the spin label were detected by EPR spectroscopy, which did not change by reducing the preparation with NADH. A decyl-ubiquinone derivative with the spin label covalently attached to the alkyl chain was synthesized in order to localize the quinone binding site. The distance between a MTSL labeled complex I variant and the bound quinone was determined by continuous-wave (cw) EPR allowing an inference on the location of the quinone binding site. The distances between the labeled quinone and other complex I variants will be determined in future experiments to receive further geometry information by triangulation. PMID- 20959114 TI - Kinetics of degradation of dipalmitoylphosphatidylcholine (DPPC) bilayers as a result of vipoxin phospholipase A2 activity: an atomic force microscopy (AFM) approach. AB - In this paper we used AFM as an analytical tool to visualize the degradation of a phospholipid bilayer undergoing hydrolysis of the vipoxin's PLA(2). We obtained time series images during the degradation process of supported 1, 2 dipalmitoylphosphatidylcholine (DPPC) bilayers and evaluated the occurrence and the growth rate of the bilayer defects. The special resolution of the AFM images allowed us to measure the area and the perimeter length of these defects and to draw conclusions about the kinetics of the enzyme reaction. Moreover, we also report for some unique characteristics discovered during the vipoxin's PLA(2) action. Experimentally for the first time, we observed the appearance and the growth of three-dimensional (3D), crystal-like structures within the formed defects of the degraded bilayer. In an effort to explain their nature, we applied bearing image analysis to estimate the volume of these crystals and we found that their growth rate follows a similar kinetic pattern as the degradation rate of the supported bilayer. PMID- 20959115 TI - Influence of renal compensatory hypertrophy on mitochondrial energetics and redox status. AB - A reduction in functional renal mass is common in numerous renal diseases and aging. The remaining functional renal tissue undergoes compensatory growth primarily due to hypertrophy. This is associated with a series of physiological, morphological and biochemical changes similar to those observed after uninephrectomy. Previous work showed that compensatory renal cellular hypertrophy resulted in an increase in susceptibility to several drugs and environmental chemicals and appeared to be associated with oxidative stress. Compensatory renal cellular hypertrophy was also associated with increases in mitochondrial metabolic activity, uptake of glutathione (GSH) across renal plasma and mitochondrial inner membranes, and intracellular GSH concentrations. Based on these observations, we hypothesize that the morphological, physiological and biochemical changes in the hypertrophied kidney are associated with marked alterations in renal cellular energetics, redox status and renal function in vivo. In this study, we used a uninephrectomized (NPX) rat model to induce compensatory renal growth. Our results show alterations in renal physiological parameters consistent with modest renal injury, altered renal cellular energetics, upregulation of certain renal plasma membrane transporters, including some that have been observed to transport GSH, and evidence of increased oxidative stress in mitochondria from the remnant kidney of NPX rats. These studies provide additional insight into the molecular changes that occur in compensatory renal hypertrophy and should help in the development of novel therapeutic approaches for patients with reduced renal mass. PMID- 20959116 TI - Differential sensitivity to adrenergic stimulation underlies the sexual dimorphism in the development of diabetes caused by Irs-2 deficiency. AB - The diabetic phenotype caused by the deletion of insulin receptor substrate-2 (Irs-2) in mice displays a sexual dimorphism. Whereas the majority of male Irs-2( /-) mice are overtly diabetic by 12 weeks of age, female Irs-2(-/-) animals develop mild obesity and progress less rapidly to diabetes. Here we investigated beta-cell function and lipolysis as potential explanations for the gender-related differences in this model. Glucose-stimulated insulin secretion was enhanced in islets from male null mice as compared to male WT whereas this response in female Irs-2(-/-) islets was identical to that of female controls. The ability of alpha(2)-adrenoceptor (alpha(2)-AR) agonists to inhibit insulin secretion was attenuated in male Irs2 null mice. Consistent with this, the expression of the alpha(2A)-AR was reduced in male Irs-2(-/-) islets. The response of male Irs-2(-/ ) islets to forskolin was enhanced, owing to increased production of cAMP. Basal lipolysis was increased in male Irs-2(-/-) but decreased in female Irs-2(-/-) mice, concordant with the observation that adipose tissue is sparse in males whereas female Irs2 null mice are mildly obese. Adipocytes from both male and female Irs-2(-/-) were resistant to the anti-lipolytic effects of insulin but female Irs-2(-/-) fat cells were additionally resistant to the catabolic effects of beta-adrenergic agonists. This catecholamine resistance was associated with impaired generation of cAMP. Consequently, targets of cAMP-dependent protein kinase (PKA) which mediate lipolysis were not phosphorylated in adipose tissue of female Irs-2(-/-) mice. Our findings suggest that IRS-2 deficiency in mice alters the expression and/or sensitivity of components of adrenergic signaling. PMID- 20959117 TI - Sodium salicylate is a novel catalytic inhibitor of human DNA topoisomerase II alpha. AB - We have previously reported that pretreatment of human lymphoblastoid cells with the hydroxyl radical scavenger, N-acetyl cysteine, attenuates doxorubicin-induced DNA damage signalling through the ATM protein kinase. We sought to extend these studies to examine the effects of other hydroxyl radical scavengers in human breast cancer cells. Using MCF-7 cells, we observed that doxorubicin treatment triggered autophosphorylation of ATM on serine 1981 and the ATM-dependent activation of its downstream effectors p53, Chk2, and SMC1. Furthermore, we demonstrate that this effect was attenuated by pretreatment of cells with the hydroxyl radical scavengers sodium benzoate, sodium salicylate and, to a lesser extent, N-acetyl cysteine, but not TroloxTM. Intriguingly, these effects were independent of doxorubicin's ability to redox cycle, were observed with multiple classes of topoisomerase II poisons, but did not represent a general damage attenuating response. In addition, the observed effects were independent of the ability of sodium salicylate to inhibit cyclooxygenase-2 or NFkappaB. We demonstrate that sodium salicylate prevented doxorubicin-induced DNA double strand break generation, which was attributable to inhibition of doxorubicin stabilized topoisomerase IIalpha-DNA cleavable complex formation in vivo. Using topoisomerase IIalpha-DNA cleavage and decatenation assays, we determined that sodium salicylate is a catalytic inhibitor of topoisomerase IIalpha. Consistent with the observed inhibition of double-strand break formation, pretreatment of cells with sodium salicylate attenuated doxorubicin and etoposide cytotoxicity. These results demonstrate a novel mechanism of action for sodium salicylate and suggest that further study on the mechanism of topoisomerase II inhibition and the effects of related therapeutics on doxorubicin and etoposide cytotoxicity are warranted. PMID- 20959118 TI - Rho-kinase inhibitor upregulates migration by altering focal adhesion formation via the Akt pathway in colon cancer cells. AB - Although Rho-kinase is reportedly implicated in carcinogenesis and the progression of human cancers, its precise mechanism has not been fully elucidated. We recently reported that Rho-kinase negatively regulates epidermal growth factor (EGF)-stimulated cancer progression in SW480 colon cancer cells. In the present study, we investigated the effect of Rho-kinase on the migration of SW480 colon cancer cells and the mechanism underlying the involvement of Rho kinase. Interestingly, (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl) cyclohexanecarboxamide, 2HCl (Y27632), a specific inhibitor of Rho-kinase, dose dependently enhanced cell migration. SW480 cells spontaneously release vascular endothelial growth factor (VEGF), however, Y27632 had little effect on its release. While Rho-kinase, which is generally phosphorylated in unstimulated cells, was clearly suppressed by Y27632, exogenous VEGF did not affect its phosphorylation. Immunofluorescence microscopy revealed that Y27632 caused a dramatic change in the localization of focal adhesion components, vinculin, phosphorylated caveolin-1 and tyrosine-phosphorylated proteins in SW480 cells. Furthermore, Akt inhibitor restored the loss of vinculin-stained focal adhesion formation induced by Y27632. We also observed similar effects for Y27632 on the migration and localization of focal adhesion components such as vinculin in another colon cancer cell line, HT29. Taken together, these results strongly suggest that Rho-kinase negatively regulates the migration of colon cancer cells by altering focal adhesion formation via the Akt pathway. PMID- 20959119 TI - Effects of beta-adrenoceptor antagonists on anaphylactic hypotension in conscious rats. AB - Anaphylactic shock is sometimes fatal or resistant to therapy in patients treated with propranolol, a nonselective beta-adrenoceptor antagonist, against cardiovascular diseases. However, it remains unknown which subtype of beta adrenoceptors, beta(1)- or beta(2)-adrenoceptor, is primarily responsible for the detrimental effects of propranolol on anaphylactic hypotension. Effects of beta(1)- and beta(2)-adrenoceptor antagonists were therefore determined on the survival rate and systemic hypotension in conscious Sprague-Dawley rats that suffered from anaphylactic shock. Mean arterial pressure and portal venous pressure were simultaneously measured. The control rats showed a decrease in mean arterial pressure and an increase in portal venous pressure, but did not die within 48h after an injection of ovalbumin antigen. The survival rate of the rats pretreated with propranolol (1mg/kg; n=7), the selective beta(2)-adrenoceptor antagonist ICI 118,551 (0.5mg/kg; n=7), or adrenalectomy (n=7) was significantly smaller than that with the selective beta(1)-adrenoceptor antagonist atenolol (2mg/kg; n=7). However, the changes in mean arterial pressure and portal venous pressure were similar for 10min after antigen among any groups, although propranolol and atenolol attenuated the antigen-induced increase in heart rate. Furthermore, bolus injections of epinephrine (3MUg/kg) at 3 and 5min after antigen prevented the death of the atenolol-pretreated rats, but only marginally prolonged the survival rates for the ICI 118,551- or propranolol-pretreated and adrenalectomized rats. In conclusion, in rat anaphylactic shock, inhibition of beta(2)-adrenoceptor causes more detrimental effects than that of the beta(1) adrenoceptor. These beta-adrenoceptor antagonists may exert detrimental effects on rat systemic anaphylaxis via inhibiting beneficial actions of catecholamines endogenously released from the adrenal gland. PMID- 20959121 TI - Modified Golgi-Cox method for micrometer scale sectioning of the whole mouse brain. AB - One of the major challenges of connectomics is obtaining a physical map of the neurons that comprise a circuit and the sites within the whole mouse brain. However, there is no report that addresses the preparation of whole mouse brain tissue for microsectioning. In this paper, such tissue is prepared by a modified Golgi-Cox method in which the staining time is prolonged to half a year, the darkening solution is changed to 1% LiOH, and the brain is embedded in resin. Projections of several coronal sections are reconstructed by serial 1-MUm sectioning and simultaneous imaging of the specimen. This approach ensures that the stained neurons are present throughout the whole mouse brain from superficial to deep layers and that the neuronal soma and traces of the processes can be distinguished in local magnification. PMID- 20959120 TI - Nicorandil normalizes prolonged repolarisation in the first transgenic rabbit model with Long-QT syndrome 1 both in vitro and in vivo. AB - Transgenic rabbits expressing loss-of-function pore mutants of the human gene KCNQ1 (K(v)LQT1-Y315S) have a Long QT-Syndrome 1 (LQT1) phenotype. We evaluated for the first time the effect of nicorandil, an opener of ATP-sensitive potassium channels, and of isoproterenol on cardiac action potential duration and heart rate dependent dispersion of repolarisation in transgenic LQT1 rabbits. In vivo LQT1 and littermate control were subjected to transvenous electrophysiological studies; in vitro monophasic action potentials were recorded from explanted Langendorff-perfused hearts. In vivo ventricular effective refractory periods (VERP) at the right ventricular base were significantly prolonged in LQT1 as compared to littermate control, resulting in a more pronounced VERP dispersion in LQT1. This difference in VERP dispersion between LQT1 and littermate control disappeared after infusion of nicorandil. In vitro, mean action potential durations (APD(75) and APD(90)) of LQT1 were significantly prolonged compared to littermate control at baseline. Nicorandil decreased APD(75) and APD(90) in LQT1 and littermate control at all stimulated heart rates. After adding nicorandil, the APD(90) at all hearts rates and the APD(75) at high heart rates were no longer different. Dispersion of repolarisation (?APD(75) and ?APD(90)) was heart rate dependently decreased after nicorandil at all tested stimulation cycle lengths only in LQT1. We demonstrated phenotypic differences of LQT1 and littermate control in vivo and in vitro. Nicorandil 20MUmol/l improved repolarisation abnormalities and heterogeneities in transgenic LQT1 rabbits. PMID- 20959122 TI - Preserved insulin secretion capacity and graft function of cryostored encapsulated rat islets. AB - Encapsulation of pancreatic islets before transplantation enables survival and function in an immunocompetent recipient without immunosuppression. However, the insufficient availability of allogenic islet tissue is a major problem. One concept to overcome these shortcomings is the cryopreservation of microencapsulated allogenic islets, to allow their unlimited collection and use on demand. Therefore, this report outlines the development of a cryopreservation protocol for CD rat islets encapsulated in an alginate-based microcapsule-system. We determined RPMI-medium plus 10% FCS as freezing medium, equilibration at 0 degrees C for 15 min with the cryoprotectant dimethyl sulfoxide (DMSO; final concentration 2.0M), and a stepwise removal of DMSO by sucrose dilution after thawing, as best protocol for cryopreservation of encapsulated islets. Importantly, the cryopreserved encapsulated islets showed post thawing in vitro an insulin increase upon a glucose challenge comparable to that of non cryopreserved encapsulated islets. Moreover, a stable graft function without the need of immunosuppression was detected after transplantation of 2500 cryopreserved encapsulated CD rat islets in streptozotocin-diabetic Wistar rats. Finally, the glucose clearance rate during an IPGTT 4 weeks after transplantation was comparable to that of rats transplanted with non-cryopreserved encapsulated islets. In conclusion, our study demonstrates for the first time that cryopreservation of encapsulated rat islets is possible without substantial losses on graft function. Future studies will now have to carry on this approach to human islets, aiming to apply such a bioartificial pancreas consisting of cryopreserved encapsulated islets in humans. PMID- 20959123 TI - Distribution of neuropeptides in endocrine and exocrine pancreas of long-legged buzzard (Buteo rufinus): an immunohistochemical study. AB - This study aimed to determine the existence and distribution of certain neuropeptides in endocrine and exocrine pancreas of the long-legged buzzard by using immunohistochemical methods. SOM-14-, NPY- and CGRP-IR endocrine cells were determined in both central and peripheral regions in A-islets within the pancreas, while SP-IR endocrine cells were found only in the central region, and CCK-8- and galanin-IR endocrine cells were only detected in peripheral region. On the other hand, in B-islets; SP-, NPY- and CGRP-IRendocrine cells were determined in both central and peripheral regions, while SOM-14- CCK-8- and galanin IRendocrine cells were found only in the peripheral region. In addition; SOM-14-, NPY-, CGRP-, CCK-8- and galanin-IR cells were also observed in exocrine pancreas. This distribution pattern in the pancreas of the long-legged buzzard demonstrates that neuropeptides perform their probable affects through endocrine and/or paracrine mechanisms. In conclusion, the existence and distribution of neuropeptides in the pancreas of long-legged buzzard have been introduced in this study for the first time and this bird species has also been found to differ from other types of avian species. PMID- 20959124 TI - Co-operative effects of angiotensin II and caerulein in NFkappaB activation in pancreatic acinar cells in vitro. AB - Angiotensin II is a vasoactive peptide that controls blood pressure and homeostasis. Emerging evidence shows that locally generated angiotensin II plays a crucial role in normal physiology, as well as pathophysiological conditions such as pancreatitis. We recently reported that angiotensin II activates pancreatic NFkappaB in obstructive pancreatitis. However, the specific cell type responsible for this activation remains unclear. In this study, we investigated whether pancreatic acinar cells respond to angiotensin II. These cells are the most abundant pancreatic cells and the most vulnerable to pancreatitis. Pancreatic acinar AR42J cells were used as an in vitro model of pancreatic inflammation. Our results demonstrated that treatment with caerulein, a cholecystokinin receptor agonist, induced hypersecretion and NFkappaB activation, as demonstrated by elevated amylase secretion and degradation of inhibitor of NFkappaB (IkappaBbeta). Angiotensin II, either alone or in combination with caerulein, augmented IkappaBbeta degradation. Pre-treatment with losartan, an antagonist of the angiotensin type I (AT1) receptor, abolished NFkappaB activation by angiotensin II and caerulein in a dose-dependent manner. Treatment with PD123319, a blocker of the angiotensin type II (AT2) receptor, enhanced the activation of NFkappaB by angiotensin II and caerulein. Preliminary data further demonstrated that angiotensin II could extend caerulein-induced ERK1/2 activation in acinar cells. These results indicated that inflammation triggered by hyperstimulation of pancreatic acinar cells is enhanced by angiotensin II, via the AT1 receptor. In contrast, stimulation of the AT2 receptor protects against caerulein-induced NFkappaB activation. The differential roles of the AT1 and AT2 receptors might be useful in developing potential therapies for pancreatic inflammation. PMID- 20959125 TI - Induction of cell growth arrest by atmospheric non-thermal plasma in colorectal cancer cells. AB - Plasma is generated by ionizing neutral gas molecules, resulting in a mixture of energy particles, including electrons and ions. Recent progress in the understanding of non-thermal atmospheric plasma has led to applications in biomedicine. However, the exact molecular mechanisms involved in plasma-induced cell growth arrest are unclear. In this study, we investigated the feasibility of non-thermal atmospheric plasma treatment for cancer therapy and examined the mechanism by which plasma induces anti-proliferative properties and cell death in human colorectal cancer cells. Non-thermal atmospheric plasma induced cell growth arrest and induced apoptosis. In addition, plasma reduced cell migration and invasion activities. As a result, we found that plasma treatment to the cells increases beta-catenin phosphorylation, suggesting that beta-catenin degradation plays a role at least in part in plasma-induced anti-proliferative activity. Therefore, non-thermal atmospheric plasma constitutes a new biologic tool with the potential for therapeutic applications that modulate cell signaling and function. PMID- 20959126 TI - Thermostabilization of Bacillus circulans xylanase: computational optimization of unstable residues based on thermal fluctuation analysis. AB - Low thermostability often hampers the applications of xylanases in industrial processes operated at high temperature, such as degradation of biomass or pulp bleaching. Thermostability of enzymes can be improved by the optimization of unstable residues via protein engineering. In this study, computational modeling instead of random mutagenesis was used to optimize unstable residues of Bacillus circulans xylanase (Bcx). The thermal fluctuations of unstable residues known as important to the thermal unfolding of Bcx were investigated by the molecular dynamics (MD) simulations at 300 K and 330 K to identify promising residues. The N52 site in unstable regions showed the highest thermal fluctuations. Subsequently, computational design was conducted to predict the optimal sequences of unstable residues. Five optimal single mutants were predicted by the computational design, and the N52Y mutation showed the thermostabilization effect. The N52 residue is conserved in Bacillus species xylanases and the structure analysis revealed that the N52Y mutation introduced more hydrophobic clusters for thermostability, as well as a more favorable aromatic stacking environment for substrate binding. We confirm that flexible residues at high temperature in unstable regions can be promising targets to improve thermostability of enzymes. PMID- 20959127 TI - Enhanced secretory production of hemolysin-mediated cyclodextrin glucanotransferase in Escherichia coli by random mutagenesis of the ABC transporter system. AB - The hemolysin transport system was found to mediate the release of cyclodextrin glucanotransferase (CGTase) into the extracellular medium when it was fused to the C-terminal 61 amino acids of HlyA (HlyAs(61)). To produce an improved secretion variant, the hly components (hlyAs, hlyB and hlyD) were engineered by directed evolution using error-prone PCR. Hly mutants were screened on solid LB starch plate for halo zone larger than the parent strain. Through screening of about 1 * 10(4) Escherichia coli BL21(DE3) transformants, we succeeded in isolating five mutants that showed a 35-217% increase in the secretion level of CGTase-HlyAs(61) relative to the wild-type strain. The mutation sites of each mutant were located at HlyB, primarily along the transmembrane domain, implying that the corresponding region was important for the improved secretion of the target protein. In this study we describe the finding of novel site(s) of HlyB responsible for enhancing secretion of CGTase in E. coli. PMID- 20959128 TI - Promiscuous protease-catalyzed aldol reactions: a facile biocatalytic protocol for carbon-carbon bond formation in aqueous media. AB - Several proteases, especially pepsin, were observed to directly catalyze asymmetric aldol reactions. Pepsin, which displays well-documented proteolytic activity under acidic conditions, exhibited distinct catalytic activity in a crossed aldol reaction between acetone and 4-nitrobenzaldehyde with high yield and moderate enantioselectivity. Fluorescence experiments indicated that under neutral pH conditions, pepsin maintains its native conformation and that the natural structure plays an important role in biocatalytic promiscuity. Moreover, no significant loss of enantioselectivity was found even after four cycles of catalyst recycling, showing the high stability of pepsin under the selected aqueous reaction conditions. This case of biocatalytic promiscuity not only expands the application of proteases to new chemical transformations, but also could be developed into a potentially valuable method for green organic synthesis. PMID- 20959129 TI - Internal translation initiation stimulates expression of the ARF/core+1 open reading frame of HCV genotype 1b. AB - The hepatitis C virus possesses an alternative open reading frame overlapping the Core gene, whose products are referred to as Core+1 or alternative reading frame (ARF) or F protein(s). Extensive studies on genotype HCV-1a demonstrated that ribosomal frameshifting supports the synthesis of core+1 protein, when ten consecutive As are present within core codons 9-11 whereas, in the absence of this motif, expression of the core+1 ORF is mediated mainly by internal translation initiation. However, in HCV-1b, no Core+1 isoforms produced by internal translation initiation have been described. Using constructs which contain the Core/Core+1(342-770) region from previously described HCV-1b clinical isolates from liver biopsies, we provide evidence for the synthesis of Core+1 proteins by internal translation initiation in transiently transfected mammalian cells using nuclear or cytoplasmic expression systems. Site directed mutagenesis analyses revealed that (a) the synthesis of Core+1 proteins is independent from the polyprotein expression, as we observed an increase of Core+1 protein expression from constructs lacking the polyprotein translation initiator, (b) the main Core+1 product is expressed from AUG(85), similarly to the Core+1/S protein of HCV-1a, (c) synthesis of Core+1 isoforms is also mediated from GUG(58) or under certain conditions GUG(26) internal codons, albeit at lower efficiency. Finally, comparable to HCV-1a Core+1 proteins, the HCV-1b Core+1 products are negatively regulated by core expression and the proteaosomal pathway. The expression of Core+1 ORF from HCV-1b clinical isolates and the preservation of translation initiation mechanism that stimulates its expression encourage investigating the role of these proteins in HCV pathogenesis. PMID- 20959130 TI - Oral TNF-alpha gene silencing using a polymeric microsphere-based delivery system for the treatment of inflammatory bowel disease. AB - The purpose of this study was to evaluate down-regulation of tumor necrosis factor (TNF)-alpha by oral RNA interference therapy. Control (scrambled sequence) or TNF-alpha specific small interfering RNA (siRNA) was encapsulated in type B gelatin nanoparticles and further entrapped in poly(epsilon-caprolactone) (PCL) microspheres to form a nanoparticles-in-microsphere oral system (NiMOS). Upon confirmation of the dextran sulfate sodium (DSS)-induced acute colitis model, mice were divided into several treatment groups receiving no treatment, blank NiMOS, NiMOS with scramble siRNA, or NiMOS with TNF-alpha silencing siRNA by oral administration. Successful gene silencing led to decreased colonic levels of TNF alpha, suppressed expression of other pro-inflammatory cytokines (e.g., interleukin (IL)-1beta, interferon (IFN)-gamma) and chemokines (MCP-1), an increase in body weight, and reduced tissue myeloperoxidase activity. Results of this study established the clinical potential of a NiMOS-based oral TNF-alpha gene silencing system for the treatment of inflammatory bowel disease as demonstrated in an acute colitis model. PMID- 20959132 TI - Somatodendritic serotonin release and re-uptake in mouse embryonic stem cell derived serotonergic neurons. AB - Serotonergic neurotransmission plays an important role during neural development. Serotonergic dysfunction is observed in various psychiatric disorders and many psychoactive drugs target proteins on serotonergic neurons. Serotonergic neurons are located in the raphe nuclei and densely innervate the whole brain. The low number and the intricate accessibility of these neurons do not allow to culture them and therefore to date it was impossible to study drug-target interactions on bona fide serotonergic neurons. In order to circumvent such problems we have developed a protocol that allows the rapid and efficient generation of serotonergic neurons from mouse embryonic stem cells. Neuronal precursors were obtained by neuronal stem sphere formation in floating culture in the presence of various mitogens. Differentiation into neurons was induced by withdrawal of the mitogens. About 90% of the resulting neurons exhibited a serotonergic phenotype as judged by immunostaining against serotonin, its synthesising enzyme tryptophan hydroxylase 2, the serotonin transporter as well as 5-HT1(A) and 5-HT1(B) autoreceptors. In addition, we found expression of the vesicular monoamine transporter vMAT2 and the presynaptic protein Bassoon, which is involved in organizing the assembly of the presynaptic active zone. Depolarisation-induced calcium influx was visualised by Fluo-4, and accompanying exocytotic events by FM dye staining. Proteins involved in 5-HT release and re-uptake as well as depolarisation evoked exocytosis were evenly co-distributed on neurites and cell bodies suggesting that ES cell-derived serotonergic neurons also exhibit somatodendritic release comparable to serotonergic neurons in the raphe nuclei. PMID- 20959131 TI - Trait anxiety, but not trait anger, predisposes obese individuals to emotional eating. AB - The present study examined whether trait anxiety and trait anger are associated with vulnerability to emotional eating, particularly among obese individuals. Lean (n = 37) and obese (n = 24) participants engaged in a laboratory study where they completed measures of trait anxiety and trait anger at screening and then completed 3 counterbalanced experimental sessions involving different mood inductions (neutral, anxiety, anger). Following each mood induction, participants were provided with snack foods in a sham taste test. Models predicting snack intake revealed a significant trait anxiety*body mass index group interaction, such that high trait anxiety was positively associated with food intake for obese individuals, but not their lean counterparts. Contrary to the hypothesis, trait anger was not associated with food intake for obese or lean participants. Results suggest that trait anxiety may be a risk factor for emotional eating among obese individuals. PMID- 20959133 TI - Adhesive performance of a caries infiltrant on sound and demineralised enamel. AB - OBJECTIVE: Resin infiltration is considered as a treatment option for initial caries lesions. As cavitated early lesions might require additional restorative intervention, a caries infiltrant might be also used for enamel conditioning prior to composite insertion. This study aimed to analyse the shear bond strength of a flowable composite to sound and demineralised enamel pretreated with a caries infiltrant, a conventional adhesive or a combination of both. METHODS: Flattened bovine enamel specimens (n=120) were either demineralised (14 d, acidic buffer, pH 5) or remained untreated. Sound and demineralised specimens (each n=20) were then treated with: (1) 35% phosphoric acid, conventional adhesive, (2) 15% hydrochloric acid, caries infiltrant or (3) 15% hydrochloric acid, caries infiltrant, conventional adhesive. Shear bond strength of a flowable composite was tested after 24 h water storage (37 degrees C) and statistically analysed (ANOVA, p<=0.05). The mode of failure was assessed microscopically at 25* magnification. RESULTS: On demineralised enamel, the combination of caries infiltrant and conventional adhesive showed significantly higher shear bond strength values than the conventional adhesive alone, while both being not significantly different from group 2. No significant differences between the groups could be detected on sound specimens. A higher percentage of cohesive failures could be observed in demineralised samples of group 2 (40%) and 3 (65%), while all other specimens presented almost only adhesive failures. CONCLUSION: The use of a caries infiltrant before application of a conventional adhesive did not impair bonding to sound and demineralised enamel and might be beneficial as a pretreatment in demineralised enamel. PMID- 20959134 TI - Processing of novel identifiability and duration in children and adults. AB - In a passive auditory oddball paradigm identifiability and duration of task irrelevant novel sounds (novels) were varied in children aged 7-8 and in adults. Event-related potentials (ERPs) elicited by identifiable novels were augmented compared to ERPs elicited by non-identifiable novels around 200ms after stimulus onset. This identifiability effect occurs in children and adults, showing that identifiable novels are processed differently from non-identifiable novels in both age groups. However, only in children the identifiability effect continued for short novels after 300ms. This indicates that children cannot inhibit processing of meaningful task-irrelevant information as efficiently as adults. Moreover, long novels caused more positive amplitudes than short novels in a time window of 400-600ms in children but not in adults, showing children's increased susceptibility to physically rich sounds. Results are discussed in the framework of current models of involuntary attention referring to the ERP-components N1/Mismatch Negativity, P2, early P3a, and late P3a. PMID- 20959136 TI - Effect of masticating chewing gum on postural stability during upright standing. AB - The purpose of this study was to investigate the effect of masticating chewing gum on postural stability during upright standing. To address this issue, 12 healthy subjects performed quiet standing on a force platform for the posturography study. The subjects were instructed to stand as stable as possible on the force platform in order to record the trajectory of the center-of-pressure (COP). After measuring the postural sway in the initial condition (pre condition), the subjects were asked to stand while masticating chewing gum (gum condition). Following the gum-condition, quiet standing without mastication was evaluated (post-condition) to ensure the effect of masticating chewing gum on postural stability. The trajectory and velocity of the COP were analyzed for each condition. We found that the postural stability tended to enhance during mastication of chewing gum. The rectangle area of the COP trajectory significantly diminished in the gum-condition and significantly enlarged in the post-condition. A similar effect was observed in the maximum velocity and standard deviation (SD) of the fore-aft amplitude of the COP trajectory. The values were significantly smaller in the gum-condition compared to those in the post-condition. These findings suggest that mastication of chewing gum affects the postural control by enhancing the postural stability during upright standing. PMID- 20959135 TI - Loss of thyroid hormone receptor beta is associated with increased progenitor proliferation and NeuroD positive cell number in the adult hippocampus. AB - Adult hippocampal neurogenesis is modulated by perturbations in thyroid hormone status; however the role of specific thyroid hormone receptors (TRs) in this process is not completely understood. We show here that loss of the TRbeta gene results in a significant increase in the proliferation of adult hippocampal progenitors, without any change in immature neuron number or in the neuronal and glial differentiation of progenitors. Using the mitotic marker 5'-bromo-2 deoxyuridine (BrdU) or the endogenous cell cycle marker, proliferating cell nuclear antigen (PCNA), we find a significant increase in the number of BrdU- and PCNA-immunopositive cells within the subgranular zone (SGZ) of the dentate gyrus subfield in TRbeta-/- mice. Further, we find that TRbeta-/- mice exhibit a significant increase in the numbers of NeuroD-positive cells within the SGZ, suggesting that the increased numbers of proliferating progenitors translate into enhanced numbers of neuroblasts. Interestingly, the number of BrdU-positive cells that persist 4 weeks post-BrdU injection is unaltered in TRbeta-/- mice, indicating that the enhanced proliferation does not result in increased hippocampal neurogenesis. This is also supported by the evidence of no change in the numbers of cells expressing markers of immature neurons such as doublecortin or polysialylated neural cell adhesion molecule. Furthermore, no change is observed in the neuronal or glial differentiation of BrdU-positive cells in the TRbeta-/- mice. Taken together, our results provide novel evidence for a role of TRbeta in modulating hippocampal progenitor cell division, and implicate this receptor in the effects of thyroid hormone on adult hippocampal neurogenesis. PMID- 20959137 TI - Effects of Kaempferia parviflora Wall. Ex Baker on endothelial dysfunction in streptozotocin-induced diabetic rats. AB - AIM OF THE STUDY: The aim of the present study was to investigate an ethanolic extract of Kaempferia parviflora (KPE) reduces oxidative stress and preserves endothelial function in aortae from diabetic rats. MATERIALS AND METHODS: Diabetes was induced in Sprague-Dawley rats by streptozotocin (STZ) treatment (55 mg/kg i.v.). Vascular reactivity and superoxide generation were assessed in aortic rings using standard organ bath techniques and lucigenin-enhanced chemiluminescence, respectively. RESULTS: Eight weeks after STZ treatment blood glucose was elevated compared to citrate treated control rats and there was an increased aortic generation of superoxide anion. In aortic rings acetylcholine induced relaxation was impaired whereas endothelium-independent relaxation to sodium nitroprusside was unaffected. When aortic rings were acutely exposed to KPE (1, 10 and 100 MUg/ml) there was a significant reduction in the detection of superoxide anion and enhanced relaxation to acetylcholine. Two separate groups of rats (control and diabetic) were orally administered daily with KPE (100 mg/kg body weight) for 4 weeks. KPE treatment reduced superoxide generation and increased the nitrite levels in diabetic aortae, and enhanced acetylcholine induced relaxation. In the presence of N(G)-nitro-L-arginine (L-NNA), the relaxation to acetylcholine in aortic rings of diabetic rats was only partially inhibited, but was totally abolished in aortic rings from the KPE-treated diabetic rats. Indomethacin did not affect relaxation to acetylcholine in aortic rings of any group. CONCLUSIONS: These results suggest that KPE, acutely in vitro or after 4 weeks administration in vivo, reduces oxidant stress, increases NO bioavailability and preserves endothelium-dependent relaxation in aortae from diabetic rats. PMID- 20959138 TI - A biotechnological perspective on the application of iron oxide magnetic colloids modified with polysaccharides. AB - Iron oxide magnetic nanoparticles (MNPs) alone are suitable for a broad spectrum of applications, but the low stability and heterogeneous size distribution in aqueous medium represent major setbacks. These setbacks can however be reduced or diminished through the coating of MNPs with various polymers, especially biopolymers such as polysaccharides. Polysaccharides are biocompatible, non-toxic and renewable; in addition, they possess chemical groups that permit further functionalization of the MNPs. Multifunctional entities can be created through decoration with specific molecules e.g. proteins, peptides, drugs, antibodies, biomimetic ligands, transfection agents, cells, and other ligands. This development opens a whole range of applications for iron oxide nanoparticles. In this review the properties of magnetic structures composed of MNPs and several polysaccharides (Agarose, Alginate, Carrageenan, Chitosan, Dextran, Heparin, Gum Arabic, Pullulan and Starch) will be discussed, in view of their recent and future biomedical and biotechnological applications. PMID- 20959139 TI - Enhanced levels of endogenous endothelin-1 contribute to the over expression of Gialpha protein in vascular smooth muscle cells from SHR: Role of growth factor receptor activation. AB - We earlier showed that vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit increased expression of Gi proteins. Since the levels of endothelin-1 (ET-1) are enhanced in VSMC from SHR, we undertook the present study to examine the implication of endogenous ET-1 and the underlying mechanisms in the enhanced expression of Gialpha proteins in VSMC from SHR. The enhanced expression of Gialpha-2 and Gialpha-3 proteins in VSMC from SHR was inhibited by ET(A) and ET(B) receptor antagonists, BQ123 and BQ788 respectively. In addition, these antagonists also attenuated the enhanced inhibition of forskolin-stimulated adenylyl cyclase activity by low concentrations of GTPgammaS and by inhibitory hormones in VSMC from SHR compared to WKY. Furthermore, AG1295, AG1024 and PP2, inhibitors of platelet derived growth factor receptor (PDGFR), insulin-like growth factor 1 receptor (IGF-1R) and c-Src respectively, inhibited the enhanced expression of Gialpha protein and the enhanced phosphorylation of PDGFR and IGF-1R in VSMC from SHR to WKY levels. In addition, NAD(P)H oxidase inhibitor DPI and N-acetylcysteine (NAC), a scavenger of superoxide anion (O2-) also inhibited the enhanced phosphorylation of PDGFR and IGF-1R and c-Src in VSMC from SHR to control levels. Furthermore, the augmented phosphorylation of ERK1/2 in VSMC from SHR was attenuated by BQ123 and BQ788, growth factor receptors inhibitors and PP2. These results suggest that the enhanced levels of endogenous ET-1 in VSMC from SHR increase oxidative stress, which through c-Src-mediated activation of growth factor receptors and associated MAP kinase signaling, contribute to the enhanced expression of Gialpha proteins. PMID- 20959140 TI - Bone morphogenetic proteins: a critical review. AB - Bone Morphogenetic Proteins (BMPs) are potent growth factors belonging to the Transforming Growth Factor Beta superfamily. To date over 20 members have been identified in humans with varying functions during processes such as embryogenesis, skeletal formation, hematopoiesis and neurogenesis. Though their functions have been identified, less is known regarding levels of regulation at the extracellular matrix, membrane surface, and receptor activation. Further, current models of activation lack the integration of these regulatory mechanisms. This review focuses on the different levels of regulation, ranging from the release of BMPs into the extracellular components to receptor activation for different BMPs. It also highlights areas in research that is lacking or contradictory. PMID- 20959141 TI - Bone morphogenetic protein signalling in airway epithelial cells during regeneration. AB - Mechanisms of lung regeneration after injury remain poorly understood. Bone morphogenetic protein 4 (BMP4) is critical for lung morphogenesis and regulates differentiation of the airway epithelium during development, although its mechanism of action is unknown. The role of BMPs in adult lungs is unclear. We hypothesised that BMP signalling is involved in regeneration of damaged adult airways after injury. Our aims were to characterise the regeneration process in 1 nitronaphthalene (1-NN) injured airways, to determine if and when BMP signalling is activated during this process and investigate the effects of BMP4 on normal adult airway epithelial cells (AECs). Rats were injected with 50 mg/kg 1-NN and protein expression in AECs was examined by Western blotting of lung lysis lavage, and by immunofluorescence, at 6, 24, 48 and 96 h post injection. Expression of signalling molecules p-ERK-1, p-ERK-2 and p-Smad1/5/8 in AECs peaked at 6 h post injection, coincident with maximal inflammation and prior to airway denudation which occurred at 24 h. While airways were re-epithelialised by 48h, AEC proliferation peaked later at 96 h post 1-NN injection. In vitro, BMP4 induced a mesenchymal-like morphology in normal AECs, downregulated E-cadherin expression and increased migration in a wound closure assay. Thus, following acute injury, increased BMP signalling in AECs coincides with inflammation and precedes airway denudation and re-epithelialisation. Our data indicate that, similar to its role in controlling tissue architecture during development, BMP signalling regulates regeneration of the airways following acute injury, involving downregulation of E cadherin and induction of migration in AECs. PMID- 20959143 TI - Proteomic analysis highlights the molecular complexities of native Kv4 channel macromolecular complexes. AB - Voltage-gated K(+) (Kv) channels are key determinants of membrane excitability in the nervous and cardiovascular systems, functioning to control resting membrane potentials, shape action potential waveforms and influence the responses to neurotransmitters and neurohormones. Consistent with this functional diversity, multiple types of Kv currents, with distinct biophysical properties and cellular/subcellular distributions, have been identified. Rapidly activating and inactivating Kv currents, typically referred to as I(A) (A-type) in neurons, for example, regulate repetitive firing rates, action potential back-propagation (into dendrites) and modulate synaptic responses. Currents with similar properties, referred to as I(to,f) (fast transient outward), expressed in cardiomyocytes, control the early phase of myocardial action potential repolarization. A number of studies have demonstrated critical roles for pore forming (alpha) subunits of the Kv4 subfamily in the generation of native neuronal I(A) and cardiac I(to,f) channels. Studies in heterologous cells have also suggested important roles for a number of Kv channel accessory and regulatory proteins in the generation of functional I(A) and I(to,f) channels. Quantitative mass spectrometry-based proteomic analysis is increasingly recognized as a rapid and, importantly, unbiased, approach to identify the components of native macromolecular protein complexes. The recent application of proteomic approaches to identify the components of native neuronal (and cardiac) Kv4 channel complexes has revealed even greater complexity than anticipated. The continued emphasis on development of improved biochemical and analytical proteomic methods seems certain to accelerate progress and to provide important new insights into the molecular determinants of native ion channel protein complexes. PMID- 20959142 TI - Epidermal growth factor-mediated proliferation and sodium transport in normal and PKD epithelial cells. AB - Members of the epidermal growth factor (EGF) family bind to ErbB (EGFR) family receptors which play an important role in the regulation of various fundamental cell processes including cell proliferation and differentiation. The normal rodent kidney has been shown to express at least three members of the ErbB receptor family and is a major site of EGF ligand synthesis. Polycystic kidney disease (PKD) is a group of diseases caused by mutations in single genes and is characterized by enlarged kidneys due to the formation of multiple cysts in both kidneys. Tubule cells proliferate, causing segmental dilation, in association with the abnormal deposition of several proteins. One of the first abnormalities described in cell biological studies of PKD pathogenesis was the abnormal mislocalization of the EGFR in cyst lining epithelial cells. The kidney collecting duct (CD) is predominantly an absorptive epithelium where electrogenic Na(+) entry is mediated by the epithelial Na(+) channel (ENaC). ENaC-mediated sodium absorption represents an important ion transport pathway in the CD that might be involved in the development of PKD. A role for EGF in the regulation of ENaC-mediated sodium absorption has been proposed. However, several investigations have reported contradictory results indicating opposite effects of EGF and its related factors on ENaC activity and sodium transport. Recent advances in understanding how proteins in the EGF family regulate the proliferation and sodium transport in normal and PKD epithelial cells are discussed here. This article is part of a Special Issue entitled: Polycystic Kidney Disease. PMID- 20959144 TI - Cloning of a nitric oxide synthase from green shore crab, Carcinus maenas: a comparative study of the effects of eyestalk ablation on expression in the molting glands (Y-organs) of C. maenas, and blackback land crab, Gecarcinus lateralis. AB - Molting in decapod crustaceans is regulated by ecdysteroids produced by a pair of Y-organs (YOs) located in the cephalothorax. YO ecdysteroidogenesis is suppressed by molt-inhibiting hormone (MIH), a neuropeptide produced in the X-organ of the eyestalk (ES) ganglia. MIH signaling may involve nitric oxide synthase (NOS) and NO-sensitive guanylyl cyclase (GC-I). A full-length cDNA encoding Carcinus maenas NOS (Cm-NOS; 3836 base pairs) of 1164 amino acid residues (estimated mass 131,833 Da) was cloned with 88% identity to Gecarcinus lateralis NOS (Gl-NOS). End-point reverse transcription-polymerase chain reaction (RT-PCR) showed that Cm-NOS was expressed at varying levels in the YO, testis, ovary, hepatopancreas, midgut, hindgut, heart, thoracic ganglion, and skeletal muscle and was not detected in the gill. Immunofluorescence microscopy showed localization of NOS and cGMP in the steroidogenic cells and the surrounding connective tissue layer of the C. maenas YO. ES ablation (ESA) induced molting in G. lateralis; hemolymph ecdysteroid titers increased during premolt and reached a peak of about 400 pg/MUL at 20 days and 24 days post-ESA. By contrast, ESA did not induce molting in C. maenas; hemolymph ecdysteroid titers increased about 2-fold (53 to 121 pg/MUL) by 3 days post-ESA and remained at that level at 7 days post-ESA. Real time PCR was used to quantify the effects of ESA on the expression of NOS in C. maenas and G. lateralis YOs. ESA caused 32-fold and 5-fold increases in Gl-NOS and Cm-NOS transcripts by 24 days and 7 days post-ESA, respectively, which were correlated with hemolymph ecdysteroid levels. In addition, GC-I catalytic subunit (Gl-GC-Ibeta) mRNA level increased 7.4-fold by 24 days post-ESA, but there was no significant effect of ESA on membrane GC (Gl-GC-II) mRNA level. These data indicate that the YO up-regulates NO signaling components in response to withdrawal of ES neuropeptides. PMID- 20959145 TI - Involvement of apolipophorin III in antibacterial defense of Galleria mellonella larvae. AB - Apolipophorin III (apoLp-III) is an abundant hemolymph protein involved in lipid transport and immune response in insects. We investigated involvement of apoLp III in the antibacterial response in Galleria mellonella larvae. Immune challenge with Gram-negative (Escherichia coli, Klebsiella pneumoniae) and Gram-positive (Micrococcus luteus) bacteria led to an increase in the level of apoLp-III in G. mellonella hemolymph, 0.5-2h and 8h after treatment, respectively. ApoLp-III purified from larval hemolymph as well as that present in hemolymph extracts adsorbed on the surface of different bacteria. The adsorption capacity of apoLp III on bacterial cells prompted us to investigate the effect of this phenomenon on bacterial growth. Our results demonstrate antibacterial activity of apoLp-III against selected Gram-positive and Gram-negative bacteria in vitro. Among bacteria tested, Salmonella typhimurium and K. pneumoniae were the most sensitive to apoLp-III. LIVE/DEAD staining of bacteria incubated with purified apoLp-III revealed their growth inhibition; however, neither morphological changes in the cell shape nor formation of cell aggregates was noticed. The results suggest that apoLp-III is a multifunctional protein in G. mellonella hemolymph. PMID- 20959146 TI - Isolation and identification of fetuin-B-like protein from rainbow trout seminal plasma and its localization in the reproductive system. AB - Seminal plasma of rainbow trout (Oncorhynchus mykiss, Salmonidae) contains an inhibitory system consisting of three fractions (I-III) characterized by different electrophoretic migration rates. Using a two-step isolation procedure we purified (20- and 43-fold to homogeneity) and characterized the two subforms of inhibitor I (Ia and Ib). On the basis of the homology alignment of the amino acid sequences, inhibitor I was classified to the family of cysteine proteinase inhibitors - fetuins. The molecular masses were determined to be 61,146.5Da and 63,096.0Da, and the isoelectric points were estimated to be 6.04 and 6.22 for inhibitor Ia and Ib. Both inhibitors were glycoproteins with a carbohydrate content about 13% for inhibitor Ia and 19% for inhibitor Ib. The equilibrium association constant of inhibitor Ib with cod trypsin was determined to be 7.1*10(8)M(-1). Except for the cod trypsin inhibition, the inhibitor Ib effectively inhibited papain belonging to the cysteine proteainases. Comparative studies of the distribution of inhibitor I and the previously described inhibitor II were performed. The presence of inhibitor I in the seminal plasma was a common feature of several Salmoniformes, which was contrary to inhibitor II detected in seminal plasma of other fish families. Inhibitors I and II showed different expression patterns in the testes and spermatic duct of the rainbow trout. PMID- 20959147 TI - Adaptive response to oxidative stress: Bacteria, fungi, plants and animals. AB - Reactive oxygen species (ROS) are continuously produced and eliminated by living organisms normally maintaining ROS at certain steady-state levels. Under some circumstances, the balance between ROS generation and elimination is disturbed leading to enhanced ROS level called "oxidative stress". The primary goal of this review is to characterize two principal mechanisms of protection against oxidative stress - regulation of membrane permeability and antioxidant potential. The ancillary goals of this work are to describe up to date knowledge on the regulation of the previously mentioned mechanisms and to identify areas of prospective research and emerging directions in investigation of adaptation to oxidative stress. The ubiquity for challenges leading to oxidative stress development calls for identification of common mechanisms. They are cysteine residues and [Fe,S]-clusters of specific regulatory proteins. The latter mechanism is realized via SoxR bacterial protein, whereas the former mechanism is involved in operation of bacterial OxyR regulon, yeast H(2)O(2)-stimulon, plant NPR1/TGA and Rap2.4a systems, and animal Keap1/Nrf2, NF-kappaB and AP-1, and others. Although hundreds of studies have been carried out in the field with different taxa, the comparative analysis of adaptive response is quite incomplete and therefore, this work aims to cover a plethora of phylogenetic groups to delineate common mechanisms. In addition, this article raises some questions to be elucidated and points out future directions of this research. The comparative approach is used to shed light on fundamental principles and mechanisms of regulation of antioxidant systems. The idea is to provide starting points from which we can develop novel tools and hypothesis to facilitate meaningful investigations in the physiology and biochemistry of organismic response to oxidative stress. PMID- 20959148 TI - Evaluation of the taxonomic utility of six-enzyme pulsed-field gel electrophoresis in reconstructing Salmonella subspecies phylogeny. AB - Pulsed-field gel electrophoresis (PFGE) remains an important tool in the molecular epidemiological evaluation of strains emerging from disease outbreak clusters. Recent studies of Escherichia coli O157:H7 and Salmonella Enteritidis have noted marked improvements in the discriminatory power of PFGE when combining band profiles from up to six restriction enzyme datasets into a single concatenated analysis. This approach has provided more accurate assignments of genetic relationships among closely related strains and allowed effective phylogenetic inference of host and geographical reservoirs. Although this approach enhances epidemiological congruence among closely related strains, it remains unclear to what extent six-enzyme PFGE pattern similarity reiterates evolutionary relatedness among more distantly related Salmonella strains (i.e., serovar or subspecies levels). Here, taxonomic accuracy of six-enzyme PFGE is tested phylogenetically across two distinct Salmonella enterica populations Salmonella reference collection B (SARB), representing the breadth of taxonomic diversity of S. enterica subspecies I only, and Salmonella reference collection C (SARC), comprising the seven disparate subspecies of S. enterica plus S. bongori. Cladistic analysis of SAR strains revealed substantial polyphyly between the two strain collections such that numerous SARB strains clustered more closely with diverged SARC subspecies rather than with other members of subspecies I. Also, in several cases, SARC sibling strains from the same subspecies were evolutionary obscured-broken into distant locales on the most parsimonious six-enzyme trees. Genetic diversity among SARB and SARC strains was comparable at 45% and 47%, respectively, while congruence testing revealed discordance among individual enzyme datasets. While six-enzyme PFGE is effective in ascertaining accurate genetic relationships for more closely related strains (e.g., strains within the same serovar), reconstitution of evolutionarily meaningful strain groupings may be elusive for Salmonella at the serovar level and above. Thus, caution is warranted when applying PFGE with a limited number of enzymes as the primary phylogenetic marker in these instances. PMID- 20959149 TI - Autoimmune uveitis: the associated proinflammatory molecules and the search for immunoregulation. AB - Uveitis is an intraocular inflammatory disease causing a significant visual impairment. The disease can be idiopathic, associated with infectious and systemic disorders or arisen from an unknown cause. Over the last 20years the model of EAU in mice has contributed significantly for the establishment of parameters for diagnostic evaluations and therapies for posterior uveitis in human. Many studies using recently discovered molecules which present proinflammatory and anti-inflammatory effects have been described. Moreover, new approaches of research provided by the increasing body of knowledge on components of immune responses such as cytokines, T-cell subpopulations and their associated functions have contributed for the further understanding of uveitis and possible treatment. PMID- 20959150 TI - The increased in vitro osteoclastogenesis in patients with rheumatoid arthritis is due to increased percentage of precursors and decreased apoptosis - the In Vitro Osteoclast Differentiation in Arthritis (IODA) study. AB - Increases in local and systemic bone resorption are hallmarks of rheumatoid arthritis (RA). Osteoclasts are implicated in these processes and their enhanced differentiation may contribute to bone destruction. We observed that in vitro osteoclastogenesis varies among healthy individuals and hypothesized that increased osteoclastogenesis could be a marker for the presence of RA. Our objective in the present study was to determine if in vitro osteoclastogenesis from peripheral blood mononuclear cells (PBMCs) was different in patients with RA compared to healthy controls and osteoarthritis (OA) patients. Expression of CD14 in PBMCs was quantified and PBMCs were incubated for 21 days in the presence of the osteoclastogenic cytokines M-CSF and RANKL. Differentiation on cortical bone slices permitted the analysis of bone resorption while apoptotic potential was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. In vitro osteoclastogenesis was higher in PBMCs from RA patients compared to controls, and a similar increase was observed in the percentage of osteoclast precursors in RA patients. Osteoclasts from RA patients showed lower apoptotic rates than osteoclasts from healthy controls. No difference was observed in bone resorption activity between RA patients and controls. Interestingly, the difference in osteoclast number and apoptosis rate allowed the implementation of an algorithm capable of distinguishing patients with RA from controls. In conclusion, our study shows that osteoclast differentiation from PBMCs is enhanced in patients with RA, and this difference can be explained by both a higher percentage of osteoclast precursors in the blood and by the reduced apoptotic potential of mature osteoclasts. PMID- 20959151 TI - NELL1 promotes high-quality bone regeneration in rat femoral distraction osteogenesis model. AB - NELL1 (NEL-like molecule-1; NEL [a protein strongly expressed in neural tissue encoding epidermal growth factor like domain]) is a cranisynostosis-associated molecule directly regulated by Runx2, the master molecule in controlling osteoblastic differentiation. NELL1 has exhibited potent osteoinductive activity for bone regeneration in several animal models. However, its capacity for promoting repair of long-bone defects remains unknown. In this study, we investigated the osteogenic effects of NELL1 on femoral distraction osteogenesis using adenoviral gene delivery and multiple approaches of in vivo analysis. Thirty Sprague-Dawley (SD) rats were randomly assigned to 3 groups for treatment (n=10 each): adenovirus-green fluorescent protein (Ad-GFP)-NELL1 or Ad-GFP at 1*109 plaque-forming units/ml diluted in saline, or saline alone. The femoral distraction was at a speed of 0.25 mm every 12h for 14 days, and a single injection of Ad-GFP-NELL1 or Ad-GFP was given at the mid-distraction period. The effective NELL1 delivery in vivo after Ad-GFP-NELL1 injection was evaluated by optical imaging. The bone regeneration was assessed quantitatively at days 21, 28, 42, and 56 by live 3-D micro-computed tomography (micro-CT), and animals were sacrificed at day 56 for biomechanical testing and histological analysis. Exogenous NELL1 was expressed in the distracted gap for at least 14 days after Ad GFP-NELL1 transfection. The bone union rate in the distracted gap was significantly higher with Ad-GFP-NELL1 than with Ad-GFP (9/9 vs. 4/9 rats) or saline alone (5/9 rats) at day 56. The serial 3-D micro-CT images and quantitation obtained with the development and application of radiolucent external fixators showed less callus but more mature cortical bones formed with Ad-GFP-NELL1 than with Ad-GFP transfection and saline administration during distraction osteogenesis. The biomechanical properties of femur samples with Ad GFP-NELL1 transfection were better than samples with Ad-GFP transfection or saline treatment, and were similar with unoperated femurs. Histology revealed cartilaginous tissues in the middle of distraction gaps with Ad-GFP transfection and saline treatment but only bony bridges with Ad-GFP-NELL1 transfection at the final time point (day 56). Coincidently, the expression of Runx2, BMP2, and BMP7 did not differ among groups at day 56, whereas the expression of osteocalcin and osteopontin was slightly higher with Ad-GFP-NELL1 transfection. Thus, sustained Ad-NELL1 protein delivery into a local area of a rat femoral distraction osteogenesis model remarkably improved regeneration of good-quality bones and accelerated bone union at a high rate. Acquiring serial micro-CT data during rat femoral distraction osteogenesis and regional adenovirus delivery of NELL1 may facilitate future in vivo studies. PMID- 20959153 TI - A novel triple adjuvant formulation promotes strong, Th1-biased immune responses and significant antigen retention at the site of injection. AB - Ovalbumin (OVA) was labeled with a near infra-red dye (*OVA) and formulated with the host defense peptide indolicidin (Indol), CpG oligodeoxynucleotide (ODN) 1826 (CpG) and/or poly(p-dicarboxylatophenoxy)-phosphazene (PP4). The immunogenicity of these *OVA formulations was evaluated in mice. All double and triple adjuvant combinations elicited strong antibody responses. *OVA formulated with CpG ODN in combination with indolicidin, PP4 or both induced only IFN-gamma, while formulations with indolicidin and/or PP4 promoted predominantly IL-5 production. Overall, both IgG and IFN-gamma production was superior when *OVA was combined with CpG/Indol/PP4. Furthermore, mice injected with *OVA formulated with CpG/Indol/PP4 contained detectable *OVA in the injection site two months post immunization. These results indicate that the CpG/Indol/PP4 combination promotes prolonged antigen retention and strong, antigen-specific Th1-biased immune responses. PMID- 20959152 TI - Identification and characterisation of the BPI/LBP/PLUNC-like gene repertoire in chickens reveals the absence of a LBP gene. AB - Palate, lung and nasal epithelial clone (PLUNC) proteins are structural homologues to the innate defence molecules LPS-binding protein (LBP) and bactericidal/permeability-increasing protein (BPI). PLUNCs make up the largest portion of the wider BPI/LBP/PLUNC-like protein family and are amongst the most rapidly evolving mammalian genes. In this study we systematically identified and characterised BPI/LBP/PLUNC-like protein-encoding genes in the chicken genome. We identified eleven complete genes (and a pseudogene). Five of them are clustered on a >50 kb locus on chromosome 20, immediately adjacent to BPI. In addition to BPI, we have identified presumptive orthologues LPLUNCs 2, 3, 4 and 6, and BPIL 2. We find no evidence for the existence of single domain containing proteins in birds. Strikingly our analysis also suggests that there is no LBP orthologue in chicken. This observation may in part account for the relative resistance to LPS toxicity observed in birds. Our results indicate significant differences between the avian and mammalian repertoires of BPI/LBP/PLUNC-like genes at the genomic and transcriptional levels and provide a framework for further functional analyses of this gene family in chickens. PMID- 20959154 TI - A tetravalent recombinant dengue domain III protein vaccine stimulates neutralizing and enhancing antibodies in mice. AB - Dengue viruses co-circulate as four serologically distinct viruses (DENV1-4) that commonly infect individuals sequentially. Current DENV candidate vaccines incorporate the entire virion envelope E protein (E) ectodomain thereby stimulating both DENV serotype-specific and cross-reactive antibodies. Because the latter may enhance naturally acquired infection, such vaccine formulations must be tetravalent. We evaluated the neutralizing and enhancing antibody response to E domain III (dIII) proteins, in which serotype-specific neutralizing determinants are concentrated. Mice immunized with insect cell-secreted recombinant DENV-dIII proteins individually, and in tetravalent combination, produced serotype-specific IgG1 neutralizing antibodies that nevertheless exhibited measurable DENV enhancing activity in FcgammaR-bearing cells. Vaccine strategies directed to DENV-dIII-targeted neutralizing antibody production remain attractive but will likely require further modifications to induce safe, protective immunity. PMID- 20959155 TI - Formononetin accelerates wound repair by the regulation of early growth response factor-1 transcription factor through the phosphorylation of the ERK and p38 MAPK pathways. AB - Formononetin, a phytoestrogen from the root of Astragalus membranaceus, is used as a blood enhancer and to improve blood microcirculation in complementary and alternative medicine. The present study investigated the influence of formononetin on the expression of early growth response factor-1 (Egr-1) and growth factors contributing to wound healing. Formononetin significantly increased growth factors such as transforming growth factor-beta 1 (TGF-beta1), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) in human umbilical vein endothelial cells (HUVECs). Formononetin also increased the expression of Egr-1 transcription factor by 3.2- and 10.5-fold, compared with recombinant VEGF(125) in HUVECs. The formononetin-mediated 12%-43% increase induced endothelial cell proliferation and recovered the migration of wounded HUVECs. In an ex vivo angiogenesis assay, formononetin produced a larger capillary sprouting area than produced using recombinant VEGF(125). Cell proliferation and migration of HUVECs were also greater in the presence of formonectin than VEGF(125). Western blot analysis of scratch-wounded confluent HUVECs showed that formononetin induced the phosphorylation of extracellular signal-regulated kinase (ERK) and slightly inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK). The formononetin-mediated sustained activation of Egr-1 was suppressed by the ERK inhibitor PD98059 and the p38 inhibitor SB203580. PD98059 inhibited the formononetin-induced endothelial proliferation and repair in scratch-wounded HUVECs, SB203580 increased the cell proliferation and wound healing. Formononetin accelerate wound closure rate as early as day 3 after surgery and consistently observed until day 10 after in wound animal model. These data suggest that formononetin promotes endothelial repair and wound healing in a process involving the over-expression of Egr-1 transcription factor through the regulation of the ERK1/2 and p38 MAPK pathways. PMID- 20959156 TI - Temporal change in deep-sea benthic ecosystems: a review of the evidence from recent time-series studies. AB - Societal concerns over the potential impacts of recent global change have prompted renewed interest in the long-term ecological monitoring of large ecosystems. The deep sea is the largest ecosystem on the planet, the least accessible, and perhaps the least understood. Nevertheless, deep-sea data collected over the last few decades are now being synthesised with a view to both measuring global change and predicting the future impacts of further rises in atmospheric carbon dioxide concentrations. For many years, it was assumed by many that the deep sea is a stable habitat, buffered from short-term changes in the atmosphere or upper ocean. However, recent studies suggest that deep-seafloor ecosystems may respond relatively quickly to seasonal, inter-annual and decadal scale shifts in upper-ocean variables. In this review, we assess the evidence for these long-term (i.e. inter-annual to decadal-scale) changes both in biologically driven, sedimented, deep-sea ecosystems (e.g. abyssal plains) and in chemosynthetic ecosystems that are partially geologically driven, such as hydrothermal vents and cold seeps. We have identified 11 deep-sea sedimented ecosystems for which published analyses of long-term biological data exist. At three of these, we have found evidence for a progressive trend that could be potentially linked to recent climate change, although the evidence is not conclusive. At the other sites, we have concluded that the changes were either not significant, or were stochastically variable without being clearly linked to climate change or climate variability indices. For chemosynthetic ecosystems, we have identified 14 sites for which there are some published long-term data. Data for temporal changes at chemosynthetic ecosystems are scarce, with few sites being subjected to repeated visits. However, the limited evidence from hydrothermal vents suggests that at fast-spreading centres such as the East Pacific Rise, vent communities are impacted on decadal scales by stochastic events such as volcanic eruptions, with associated fauna showing complex patterns of community succession. For the slow-spreading centres such as the Mid-Atlantic Ridge, vent sites appear to be stable over the time periods measured, with no discernable long-term trend. At cold seeps, inferences based on spatial studies in the Gulf of Mexico, and data on organism longevity, suggest that these sites are stable over many hundreds of years. However, at the Haakon Mosby mud volcano, a large, well-studied seep in the Barents Sea, periodic mud slides associated with gas and fluid venting may disrupt benthic communities, leading to successional sequences over time. For chemosynthetic ecosystems of biogenic origin (e.g. whale-falls), it is likely that the longevity of the habitat depends mainly on the size of the carcass and the ecological setting, with large remains persisting as a distinct seafloor habitat for up to 100 years. Studies of shallow water analogs of deep-sea ecosystems such as marine caves may also yield insights into temporal processes. Although it is obvious from the geological record that past climate change has impacted deep-sea faunas, the evidence that recent climate change or climate variability has altered deep-sea benthic communities is extremely limited. This mainly reflects the lack of remote sensing of this vast seafloor habitat. Current and future advances in deep-ocean benthic science involve new remote observing technologies that combine a high temporal resolution (e.g. cabled observatories) with spatial capabilities (e.g. autonomous vehicles undertaking image surveys of the seabed). PMID- 20959157 TI - The biology and fisheries of European hake, Merluccius merluccius, in the north east Atlantic. AB - The aim of this chapter is to review the biology and fishery, including the management, of European hake in the north-east Atlantic. The European hake is widely distributed throughout the north-east Atlantic, from Norway in the north to the Guinea Gulf in the south, and throughout the Mediterranean and Black Sea, being more abundant from the British Isles to the south of Spain. In this area, ICES (International Council for the Exploration of the Sea) recognises the existence of two stocks: the northern stock and the southern stock. Both stocks have been extensively and intensively harvested and since the beginning of the 90s have been considered to be outside safe biological limits. The northern stock, however, is currently considered to lie within safe biological limits. In any case, recovery plans were implemented for the northern stock in 2004 and for the southern stock in 2006. Despite its commercial importance, knowledge of the biology and ecology of the European hake in the North Atlantic is still quite scarce. For example, recent investigations suggest that European hake grows much faster, by a factor of two, than was considered previously. This faster growth also affects the maturity-at-age pattern of hake and the agreed maturity-at-age ogive used in the assessments. European hake is a top predator in the demersal community in the north-east Atlantic area; mainly preying on blue whiting, horse mackerel and other cupleids. In relation to the reproductive biology, European hake is considered to be a batch spawner species with indeterminate fecundity and spawning activity all year round. All these characteristics could, in turn, be interpreted as European hake adopting a more opportunistic life strategy, which is unusual for a gadoid and demersal species, and raises several questions about hake biology and ecology that require further investigation. PMID- 20959158 TI - Chronobiology of deep-water decapod crustaceans on continental margins. AB - Species have evolved biological rhythms in behaviour and physiology with a 24-h periodicity in order to increase their fitness, anticipating the onset of unfavourable habitat conditions. In marine organisms inhabiting deep-water continental margins (i.e. the submerged outer edges of continents), day-night activity rhythms are often referred to in three ways: vertical water column migrations (i.e. pelagic), horizontal displacements within benthic boundary layer of the continental margin, along bathymetric gradients (i.e. nektobenthic), and endobenthic movements (i.e. rhythmic emergence from the substrate). Many studies have been conducted on crustacean decapods that migrate vertically in the water column, but much less information is available for other endobenthic and nektobenthic species. Also, the types of displacement and major life habits of most marine species are still largely unknown, especially in deep-water continental margins, where steep clines in habitat factors (i.e. light intensity and its spectral quality, sediment characteristics, and hydrography) take place. This is the result of technical difficulties in performing temporally scheduled sampling and laboratory testing on living specimens. According to this scenario, there are several major issues that still need extensive research in deep-water crustacean decapods. First, the regulation of their behaviour and physiology by a biological clock is almost unknown compared to data for coastal species that are easily accessible to direct observation and sampling. Second, biological rhythms may change at different life stages (i.e. size-related variations) or at different moments of the reproductive cycle (e.g. at egg-bearing) based on different intra- and interspecific interactions. Third, there is still a major lack of knowledge on the links that exist among the observed bathymetric distributions of species and selected autoecological traits that are controlled by their biological clock, such as the diel rhythm of behaviour. Species evolved in a photically variable environment where intra- and inter-specific interactions change along with the community structure over 24 h. Accordingly, the regulation of their biology through a biological clock may be the major evolutionary constraint that is responsible for their reported bathymetric distributions. In this review, our aim is to propose a series of innovative guidelines for a discussion of the modulation of behavioural rhythms of adult decapod crustaceans, focusing on the deep waters of the continental margin areas of the Mediterranean as a paradigm for other marine zones of the world. PMID- 20959159 TI - The Patagonian toothfish: biology, ecology and fishery. AB - Patagonian toothfish (Dissostichus eleginoides) is a large notothenioid fish that supports valuable fisheries throughout the Southern Ocean. D. eleginoides are found on the southern shelves and slopes of South America and around the sub Antarctic islands of the Southern Ocean. Patagonian toothfish are a long-lived species (>50 years), which initially grow rapidly on the shallow shelf areas, before undertaking an ontogenetic migration into deeper water. Although they are active predators and scavengers, there is no evidence of large-scale geographic migrations, and studies using genetics, biochemistry, parasite fauna and tagging indicate a high degree of isolation between populations in the Indian Ocean, South Georgia and the Patagonian Shelf. Patagonian toothfish spawn in deep water (ca. 1000 m) during the austral winter, producing pelagic eggs and larvae. Larvae switch to a demersal habitat at around 100 mm (1-year-old) and inhabit relatively shallow water (<300 m) until 6-7 years of age, when they begin a gradual migration into deeper water. As juveniles in shallow water, toothfish are primarily piscivorous, consuming the most abundant suitably sized local prey. With increasing size and habitat depth, the diet diversifies and includes more scavenging. Toothfish have weakly mineralised skeletons and a high fat content in muscle, which helps neutral buoyancy, but limits swimming capacity. Toothfish generally swim with labriform motion, but are capable of more rapid sub carangiform swimming when startled. Toothfish were first caught as a by-catch (as juveniles) in shallow trawl fisheries, but following the development of deep water longlining, fisheries rapidly developed throughout the Southern Ocean. The initial rapid expansion of the fishery, which led to a peak of over 40,000 tonnes in reported landings in 1995, was accompanied by problems of bird by-catch and overexploitation as a consequence of illegal, unreported and unregulated fishing (IUU). These problems have now largely been addressed, but continued vigilance is required to ensure that the species is sustainably exploited and the ecosystem effects of the fisheries are minimised. PMID- 20959160 TI - Preface. Aspects of eye development: advances over the past twenty years. PMID- 20959161 TI - Retinal determination the beginning of eye development. AB - The road to producing an eye begins with the decision to commit a population of cells to adopting an eye tissue fate, the process of retinal determination. Over the past decade and a half, a network of transcription factors has been found to mediate this process in all seeing animals. This retinal determination network is known to regulate not only tissue fate but also cell proliferation, pattern formation, compartment boundary establishment, and even retinal cell specification. The compound eye of the fruit fly, Drosophila melanogaster, has proven to be an excellent experimental system to study the mechanisms by which this network regulates organogenesis and tissue patterning. In fact the founding members of most of the gene families that make up this network were first isolated in Drosophila based on loss-of-function phenotypes that affect the eye. This chapter will highlight the history of discovery of the retinal determination network and will draw attention to the molecular and biochemical mechanisms that underlie our understanding of how the fate of the retina is determined. PMID- 20959162 TI - Eye field specification in Xenopus laevis. AB - Vertebrate eyes begin as a small patch of cells at the most anterior end of the early brain called the eye field. If these cells are removed from an amphibian embryo, the eyes do not form. If the eye field is transplanted to another location on the embryo or cultured in a dish, it forms eyes. These simple cut and paste experiments were performed at the beginning of the last century and helped to define the embryonic origin of the vertebrate eye. The genes necessary for eye field specification and eventual eye formation, by contrast, have only recently been identified. These genes and the molecular mechanisms regulating the initial formation of the Xenopus laevis eye field are the subjects of this review. PMID- 20959164 TI - Two themes on the assembly of the Drosophila eye. AB - Cells are sequentially recruited during formation of the Drosophila compound eye. A few simple rules are reiteratively utilized to control successive steps of eye assembly. Two themes emerge: the interplay between cell signaling and competence determines diversity of cell types and selective cell adhesion determines spatial patterns of cells. Cell signaling through competence creates signaling relays, which sequentially trigger differentiation of all cell types. Selective cell adhesion, on the other hand, provides forces to drive cells into energy-favored spatial configurations. Organ formation is nevertheless a complex process. The complexity lies in the spatial, temporal, and quantitative precision of gene expression. Many challenging questions remain. PMID- 20959163 TI - Eye morphogenesis and patterning of the optic vesicle. AB - Organogenesis of the eye is a multistep process that starts with the formation of optic vesicles followed by invagination of the distal domain of the vesicles and the overlying lens placode resulting in morphogenesis of the optic cup. The late optic vesicle becomes patterned into distinct ocular tissues: the neural retina, retinal pigment epithelium (RPE), and optic stalk. Multiple congenital eye disorders, including anophthalmia or microphthalmia, aniridia, coloboma, and retinal dysplasia, stem from disruptions in embryonic eye development. Thus, it is critical to understand the mechanisms that lead to initial specification and differentiation of ocular tissues. An accumulating number of studies demonstrate that a complex interplay between inductive signals provided by tissue-tissue interactions and cell-intrinsic factors is critical to ensuring proper specification of ocular tissues as well as maintenance of RPE cell fate. While several of the extrinsic and intrinsic determinants have been identified, we are just at the beginning in understanding how these signals are integrated. In addition, we know very little about the actual output of these interactions. In this chapter, we provide an update of the mechanisms controlling the early steps of eye development in vertebrates, with emphasis on optic vesicle evagination, specification of neural retina and RPE at the optic vesicle stage, the process of invagination during morphogenesis of the optic cup, and maintenance of the RPE cell fate. PMID- 20959166 TI - Retinal progenitor cells, differentiation, and barriers to cell cycle reentry. AB - Neurogenesis in the retina occurs via the coordination of proliferation, cell cycle exit and differentiation of retinal progenitor cells. Until recently, it was widely assumed that once a retinal progenitor cell produced a postmitotic neuron, there was no possibility for cell-cycle re-entry. However, recent studies have shown that mature differentiated horizontal neurons with reduced Rb pathway function can re-enter the cell cycle and proliferate while maintaining their differentiated features. This chapter will explore the molecular and cellular mechanisms that help to keep differentiated retinal neurons and glia postmitotic. We propose that there are cell-type specific barriers to cell-cycle re-entry by differentiated neurons and these may include apoptosis, chromatin/epigenetics mechanisms, cellular morphology and/or metabolic demands that are distinct across cell populations. Our data suggest that differentiated neurons span a continuum of cellular properties related to their ability to re-enter the cell cycle and undergo cytokinesis while maintaining their differentiated features. A deeper understanding of these processes may allow us to begin to explain the cell type specificity of neuronal cell death and tumor susceptibility. For example, neurons that have more barriers to cell-cycle re-entry may be less likely to form tumors but more likely to undergo degeneration. Conversely, neurons that have fewer barriers to cell-cycle re-entry may be more likely to form tumors but less likely to undergo degeneration. PMID- 20959168 TI - Milestones and mechanisms for generating specific synaptic connections between the eyes and the brain. AB - All information about the visual world is conveyed to the brain by a single type of neurons at the back of the eye called retinal ganglion cells (RGCs). Understanding how RGC axons locate and wire up with their targets is therefore critical to understanding visual development. In recent years, several important technological and conceptual advances have been made in this area, and yet, many fundamental questions remain unanswered. Indeed, while much is now known about how RGC axons pathfind at the optic chiasm and form retinotopic maps within their targets, how RGCs select their overall targets in the first place is poorly understood. Moreover, the signals that direct mammalian RGC axons to their appropriate layer within those targets remain unknown. The recent advent of genetic tools to selectively label and manipulate defined groups of RGCs is starting to provide a way to resolve these and other important questions about RGC wiring specificity. This field is therefore positioned to reveal new principles of visual circuit development that no doubt will extend to other regions of the CNS. PMID- 20959165 TI - Building a fly eye: terminal differentiation events of the retina, corneal lens, and pigmented epithelia. AB - In the past, vast differences in ocular structure, development, and physiology throughout the animal kingdom led to the widely accepted notion that eyes are polyphyletic, that is, they have independently arisen multiple times during evolution. Despite the dissimilarity between vertebrate and invertebrate eyes, it is becoming increasingly evident that the development of the eye in both groups shares more similarity at the genetic level than was previously assumed, forcing a reexamination of eye evolution. Understanding the molecular underpinnings of cell type specification during Drosophila eye development has been a focus of research for many labs over the past 25 years, and many of these findings are nicely reviewed in Chapters 1 and 4. A somewhat less explored area of research, however, considers how these cells, once specified, develop into functional ocular structures. This review aims to summarize the current knowledge related to the terminal differentiation events of the retina, corneal lens, and pigmented epithelia in the fly eye. In addition, we discuss emerging evidence that the different functional components of the fly eye share developmental pathways and functions with the vertebrate eye. PMID- 20959169 TI - Part 9: Acute coronary syndromes: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 20959170 TI - Intravenous administration of hyperoxygenated solution attenuates pulmonary edema formation in phosgene-induced acute lung injury in rabbits. AB - BACKGROUND: The aim of this study was to investigate the post-treatment effect of intravenous hyperoxygenated solution (HOS) on pulmonary parameters in rabbits whole-body-exposed to the toxic gas phosgene. MATERIALS AND METHODS: Twenty-four New Zealand rabbits were divided into four groups randomly: rabbits were exposed whole-body to either filtered room air or 539 ppm phosgene for 5 minutes followed by room air washout for 5 minutes. Phosgene-exposed group (exposed to phosgene without treatment, PH group); Control group (exposed to air, Control group); Lactate Ringer's solution (LRS)-treated group (intravenous infusion of LRS by 30 ml.kg-1 after phosgene exposure, LRS group); Hyperoxygenated solution (HOS) treated group (intravenous infusion of HOS after phosgene exposure by 30 mL.kg-1, HOS group). Arterial blood was collected for blood gas analysis at 1, 3, 8, and 12 hours after phosgene or air exposure. Rabbits were put to death 12 hours after exposure. Lung edema was assessed gravimetrically by measuring tissue wet/dry weight ratio (W/D) and lung coefficient (LC). Bronchoalveolar lavage (BAL) was performed and fluid was analyzed for total maloaldehyde (MDA), glutathione peroxidase (GSH-Px), and protein concentration. Lungs were perfused with saline to remove blood, snap-frozen in liquid nitrogen (N2), analyzed for tissue reduced glutathione (GSH) and oxidized glutathione (GSSG). Parts of lung tissues were reserved for histopathology examination. RESULTS: In the PH, LRS, and HOS groups, phosgene inhalation caused serious lung edema, W/D and LC, lung tissue GSSG, BALF MDA, and protein content increased significantly. Meanwhile, PaO2, lung tissue GSH, and BALF GSH-Px decreased markedly. However, after HOS treatment in the HOS group, PaO2 was clearly higher than that in the PH group and LRS group at 3, 8, 12 hours (P < 0.01). W/D and LC, lung tissue GSSG, BALF MDA, and protein content in the HOS group were apparently lower than that in the PH group and LRS group (P < 0.01). In the HOS group, lung tissue GSH and BALF GSH-Px increased compared with both PH and LRS group, respectively. There was no difference on lung tissue GSH among the PH, LRS, and HOS groups (P > 0.05). CONCLUSIONS: Intravenous HOS infusion after phosgene exposure can clearly lessen phosgene-induced lung edema formation, lipid peroxidatic reaction, and ameliorate hypoxemia associated with phosgenismus; it is a safe, simple, and effective measure to protect animals from phosgene-induced lung injury. PMID- 20959171 TI - Dehydration improves cryopreservation of coconut (Cocos nucifera L.). AB - Cryopreservation of coconut can be used as a strategy to back up the establishment of living collections which are expensive to maintain and are under constant threat from biotic and abiotic factors. Unfortunately, cryopreservation protocols still need to be developed that are capable of producing a sizeable number of field-grown plants. Therefore, we report on the development of an improved cryopreservation protocol which can be used on a wide range of coconut cultivars. The cryopreservation of zygotic embryos and their recovery to soil growing plants was achieved through the application of four optimised steps viz.: (i) rapid dehydration; (ii) rapid cooling; (iii) rapid warming and recovery in vitro and (iv) acclimatization and soil-supported growth. The thermal properties of water within the embryos were monitored using differential scanning calorimetry (DSC) in order to ensure that the freezable component was kept to a minimum. The feasibility of the protocol was assessed using the Malayan Yellow Dwarf (MYD) cultivar in Australia and then tested on a range of cultivars which were freshly harvested and studied in Indonesia. The most efficient protocol was one based on an 8-h rapid dehydration step followed by rapid cooling step. Best recovery percentages were obtained when a rapid warming step and an optimised in vitro culture step were used. Following this protocol, 20% (when cryopreserved 12 days after harvesting) and 40% (when cryopreserved at the time of harvest) of all MYD embryos cryopreserved could be returned to normal seedlings growing in soil. DSC showed that this protocol induced a drop in embryo fresh weight to 19% and significantly reduced the amount of water remaining that could produce ice crystals (0.1%). Of the 20 cultivars tested, 16 were found to produce between 10% and 40% normal seedlings while four cultivars generated between 0% and 10% normal seedlings after cryopreservation. This new protocol is applicable to a wide range of coconut cultivars and is useful for the routine cryopreservation of coconut genetic resources. PMID- 20959172 TI - [Influence of obesity on dyspepsia symptoms]. AB - BACKGROUND: There is a high prevalence of dyspepsia and obesity in Mexican population. A relationship between obesity and dyspeptic symptoms has been proposed. OBJECTIVE: To determine prevalence of dyspeptic symptoms in patients with normal weight, overweight and obesity. METHODS: Prospective study on consecutive patients who attend for medical assistance for any reason in a first level medical center. Weight, height, and body mass index (BMI) were measured. A validated questionnaire for dyspepsia was applied. RESULTS: Three-hundred and twenty patients were included (61.6% women, n = 197). The mean patient age was 37 +/- 14.4 years old. Mean BMI was 26.68 with 42.2% of patients (n = 135) overweight, 35.6% (n = 114) with normal weight and 22.2% (n = 71) were obese. Compared to patients with normal weight and overweight the obesity group showed a higher prevalence of gastritis symptoms, pain, stomachache, heartburn, a worst quality of life, and a higher frequency of medication intake. Patients with overweight presented a higher score in quality of life and treatment compared with normal weight patients. CONCLUSIONS: Obese patients showed a higher prevalence of dyspeptic symptoms compared to normal weight and overweight patients. PMID- 20959167 TI - Planar cell polarity signaling in the Drosophila eye. AB - Planar cell polarity (PCP) signaling regulates the establishment of polarity within the plane of an epithelium and allows cells to obtain directional information. Its results are as diverse as the determination of cell fates, the generation of asymmetric but highly aligned structures (e.g., stereocilia in the human ear or hairs on a fly wing), or the directional migration of cells during convergent extension during vertebrate gastrulation. Aberrant PCP establishment can lead to human birth defects or kidney disease. PCP signaling is governed by the noncanonical Wnt or Fz/PCP pathway. Traditionally, PCP establishment has been best studied in Drosophila, mainly due to the versatility of the fly as a genetic model system. In Drosophila, PCP is essential for the orientation of wing and abdominal hairs, the orientation of the division axis of sensory organ precursors, and the polarization of ommatidia in the eye, the latter requiring a highly coordinated movement of groups of photoreceptor cells during the process of ommatidial rotation. Here, I review our current understanding of PCP signaling in the Drosophila eye and allude to parallels in vertebrates. PMID- 20959173 TI - [Gastric adenocarcinoma in young adults; comparative study with older patients]. AB - BACKGROUND: Gastric adenocarcinoma (GA) has been considered a disease of elderly age and has been rarely reported in patients younger than 35 years of age. The aim of thisOmega demographic, clinicopathological and prognosis of gastric cancer in young patients and to compare their features with the behavior in elder adults. METHODS: Between 1993 and 2008, 1536 patients with GA were enrolled in a retrospective database. Clinical and pathologic features of thirty patients aged 35 years or less (young group) were compared with those of 458 aged 75 years or more (elder group). RESULTS: Mean patient age was 31 and 80-years old in the young and elder groups, respectively, with a predominance of females in the last group (61%). Lauren diffuse type carcinoma was more frequent in people younger than 35 years (70%) than in older patients (17.4%). Main symptoms were dyspepsia (40%) and hemorrhage (20%). The most common T stage in young and elder patients was T3 (52.9% and 56.7% respectively). Surgical resection was performed in 68% of cases and the rest received only systemic chemotherapy. CONCLUSION: Gastric adenocarcinoma is rare in young patients and most cases presented at advanced clinical stage similar to elderly patients, so the prognosis in both age groups is poor. For this reason is important to be aware of alarm symptoms and risk factors in order to perform an early endoscopic diagnosis and a treatment with curative intent. PMID- 20959174 TI - [Acute abdominal pain in elderly patients evaluated in the emergency department at a tertiary level]. AB - BACKGROUND: Life expectancy in Mexico has increased in the last decades with a remarkable increase in geriatric population. Acute abdominal pain (AAP) in elderly people compared with young people has different clinical presentation because of the concomitant chronic diseases, the use of medications, history of abdominal surgeries and decrease in perception of pain and immunity. OBJECTIVE: To know the cause and associated mortality of acute abdominal pain in geriatric patients who attend the emergency room. METHODS: Geriatric patients' files with acute abdominal pain admitted from January 2004 to December 2008 were retrospectively reviewed. Age, gender, presence of chronic diseases, use of medications, history of surgical procedures, definitive diagnosis causative of the symptoms and the associated mortality were recorded. RESULTS: 17 524 patients were admitted, of whom 324 (1.8%) were geriatric patients with AAP: 110 were men (36.9) and 214 were women (66%), with a mean age of 78 years (range 60 to 102 years). The most common causes of AAP were acute cholecystitis in 49 patients (15.1%), irritable bowel syndrome in 42 (12.9%), ulcerative syndrome in 40 (12.3%), intestinal obstruction in 35 (10.8%) and diverticulitis in 23 (10.8%). Nine patients died (2.7%). CONCLUSIONS: In our hospital the most common cause of AAP in geriatric patients is related to biliary disease followed by functional gastrointestinal disorder and ulcerative syndrome. Mortality is low. PMID- 20959175 TI - [Endoscopic cholangiopancreatography in the elderly: a prospective comparative study in northern Mexico]. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a widely used technique for the diagnosis and treatment of bilio-pancreatic diseases. According to Mexican Statistics, there is increasing life expectancy in Mexican population. The incidence of biliary tract pathologies is also increasing, leading to an increased demand of ERCP. AIM: Compare the utility and safety of ERCP in elderly and younger patients. METHODS: Prospective and comparative study including 450 patients who underwent ERCP during 2007. Patients were divided into two groups: 65 years age and older (group A) and less than 65 years old (group B). We registered gender, age, indication and length of the endoscopic procedure, morbidity and mortality. RESULTS: Mean patient age was 74.5 +/- 6.9 and 43.0 +/- 13.5 years old in groups A and B respectively. Choledocholithiasis was the more frequent diagnosis in both groups (48.62 %), followed by benign biliary stenosis (22.02 %) and malignant biliary obstruction (16.28 %). In 428 patients (98.16%) therapeutic procedures were performed. Endoscopic complications occurred in 1.37 % and there were not significant differences between groups (p = 0.218). There was no mortality. CONCLUSION: ERCP is a safe procedure in elderly patients with a very low rate of complications and excellent therapeutic efficacy. PMID- 20959176 TI - [Difficulty to cannulate papilla of Vater in the presence of periampullary duodenal diverticulum]. AB - BACKGROUND: There are conflicting results in the literature regarding the impact of duodenal diverticula on the technical success and complications of endoscopic retrograde cholangiopancreatography (ERCP). AIM: To evaluate if the presence of periampullary duodenal diverticulum increases the risk of failure of ampulla cannulation. METHODS: Patients who underwent ERCP between January 2008 and December 2009 were evaluated. They were divided in group A (without duodenal diverticulum) or group B (with duodenal diverticulum). Gender, age, endoscopic and radiological diagnosis, difficulty to cannulate, endoscopic sphincterotomy, precut technique, therapeutic procedure and complications were documented. RESULTS: 1159 patients were included: 1100 in group A and 59 in group B. A successful cannulation was obtained in 1061 patients of group A and 53 of group B (96.46 vs. 89.83%, p < 0.0001, OR 0.03). The failure of cannulation was observed in 39 patients of group A and 6 of group B (3.54 vs. 10.17%, p= 0.021, OR 2.94). The presence of intradiverticular papilla was the cause of failure in all cases. The therapeutic procedures showed statistical differences in choledocholithiasis clearance as well as endoscopic sphincterotomy and biliary stents insertion, but there was no significant difference in complications. We found statistical significant differences in biliary lithiasis, malignant stenosis, mechanical lithotripsy and insertion of biliary stents. CONCLUSIONS: Periampullary duodenal diverticula increase the risk of failure for cannulation of ampulla. However, it should not be considered as contraindication for ERCP. PMID- 20959177 TI - [Three prognostic utility scales to determine early mortality in patients with alcoholic hepatitis in the General Hospital of Mexico]. AB - BACKGROUND: There are many models to predict survival in patients with alcoholic hepatitis (AH). The most commonly used are the modified Maddrey's index, the Glasgow scale and the Model for End stage Liver Disease (MELD). OBJECTIVE: To evaluate three prognostic scales ability to predict early mortality (first 30 days) in patients with AH. METHODS: We retrospectively reviewed the database of hospitalized patients with AH during a 3-years period. Seventy one patients were included. We calculated the modified Maddrey's index, the Glasgow scale and the MELD scores. We evaluated if the scales predicted early (30-day) mortality. For each scale we determined sensitivity, specificity, positive and negative values (PPV and NPV) and likelihood value of each scale. RESULTS: For modified Maddrey's index, the values obtained were sensitivity 98.8%, specificity 11.7%, PPV 61.6%, NPV 87.5% and likelihood ratio 1.12. For Glasgow scale corresponding values were sensitivity 98.8%, specificity 61.7%, PPV 78.7%, NPV 97.4% and likelihood ratio 2.64. For the MELD scale sensitivity 98.8%, specificity 0.1%, PPV 59%, NPV 50% and likelihood ratio 1. CONCLUSIONS: The three scales were very sensitive. Glasgow's scale was the most specific and, maybe, the most exact test. PMID- 20959178 TI - [Distribution of genotypes of hepatitis C in the city of Cordoba, Argentina]. AB - BACKGROUND: Knowledge of Hepatitis C virus genotype (HCV) present in a patient has an epidemiological interest. In addition, it has an important prognostic value that guides the duration and success of treatment. AIMS: To analyze the distribution of genotypes in HCV-positive patients and linking them with the viral load before and after treatment, evaluating sustained viral response. PATIENTS AND METHODS: We retrospectively analyzed the results of genotyping and HCV viral load of 71 patients during the period January 2001 to May 2009. The genotypes were determined by RFLP (restriction fragment length polymorphism) and the viral load by NASBA HVC quantitative. Statistical analysis was performed using the Infostat program. RESULTS: 59% of patients were women. The frequency of genotypes was: 39% type 1, 58% type 2 and 3% type 3. We do not find a cutoff value of viral load to identify the different genotypes, although patients with genotype 1 had a higher number of viral copies than those of genotype 2 (p <0.0001). After treatment, 95% of patients with genotype 2 had a sustained viral response versus 67% of patients with genotype 1. CONCLUSIONS: The genotype 2 was the most prevalent in our population. It also confirmed the impact of knowledge of HCV genotype on sustained viral response, which was related related surgical interventions to infection with HCV type 2. PMID- 20959179 TI - [Prevalence of positive markers for hepatitis B (HBV Ags) and hepatitis C (Anti HCV) in health personnel at the Social Security Institute of Mexico State and Municipalities]. AB - BACKGROUND: The prevalence of serum markers of viral hepatitis in health-care workers seems to be similar to that described in the general population, even though this group would appear at increased risk because exposure to potentially infectious material. There is scarce information available in Mexico in this regard. AIM: To define the prevalence of serum markers for hepatitis C (anti-HCV antibodies) and hepatitis B (hepatitis B surface antigen, HBsAg) in health-care workers at the Instituto de Seguridad Social del Estado de Mexico y Municipios (ISSEMYM) and to establish the presence of viremia in subjects with positive serum markers. METHOD: Health-care workers from ISSEMyM with unknown hepatitis serologic status participated voluntarily in this trial. They completed a written questionnaire detailing potential risk factors for viral hepatitis and provided a blood sample. RESULTS: A total of 374 health-care workers were included. Seven subjects (1.8%) were positive, 5 for anti-HCV antibodies (1.3%) and 2 for HBsAg (0.5%). None of these subjects had detectable serum HCV RNA or HBV DNA on further testing. CONCLUSIONS: The frequency of positive serum markers for viral hepatitis in this group of healthcare workers is similar to the estimated prevalence among the general population in Mexico. No case of active infection defined by positive viremia was encountered in this group of subjects. PMID- 20959180 TI - [Indications for corticosteroids in gastroenterology]. AB - Since the discovery of anti- inflammatory and immunosuppressive properties of glucocorticoids in the late 40's, these drugs have been a cornerstone in the treatment of a variety of autoimmune and inflammatory diseases, being one of the most prescribed drugs in spite of their side effects occurring in up to 80% of patients treated. In Gastroenterology, as in other medical specialties, glucocorticoids are a widely used tool for the treatment of various diseases affecting the gastrointestinal tract, liver, bile ducts and pancreas, making it necessary to establish when and in which patients are indicated, as well as the glucocorticoid type, dose, route of administration and duration of treatment, taking into account that the long-term use without adequate control produces complications that may outweigh their beneficial effects. PMID- 20959181 TI - [Surgical treatment of rectal cancer]. AB - Rectal affection accounts for 30% of colorectal cancer. The standard of treatment is surgical resection, which often is curative. For superior and middle-rectal involvement, low anterior resection (LAR) is the preferred procedure. For tumors involving the lower portion of the rectum, abdominoperineal resection (APR) or LAR are the options of treatment, depending on sphincter involvement. The main surgical objective is to achieve a R0 resection with an appropriated total mesorrectal excision, greater number of lymph nodes and negative distal and radial margins. These surgical parameters have been used as quality indicators and have prognostic implications in terms of overall and disease-free survival. Total mesorectal excision with preservation of hypogastric nerves has shown a reduction in rates of sexual and bladder dysfunction as well as lower local recurrence. At specialized centers such procedures are performed by minimal invasive surgery; however the number of meta-analysis is scarce. PMID- 20959182 TI - [Clinical Images. Gastric infection by Strongyloides]. PMID- 20959183 TI - [Clinical Images. Endoscopic removal of fish bone in the cervical esophagus]. PMID- 20959184 TI - [Clinical Images. Radiological evidence of right subphrenic air, is it always pneumoperitoneum?]. PMID- 20959185 TI - [Clinical Images. Spontaneous rupture of jejunal GIST]. PMID- 20959186 TI - [Lower gastrointestinal bleeding secondary to rectal gastrointestinal stromal tumor]. AB - Gastrointestinal stromal tumors are the most frequent mesenchymal digestive tract neoplasms, but represent only 1 to3% of all GI tract neoplasms. We report an uncommon case of stromal rectal tumor because of its atypical location. PMID- 20959187 TI - [Local resection and radiofrequency hepatic epithelioid hemangioendothelioma]. AB - Epithelioid hemangioendothelioma is an uncommon tumor of vascular endothelial cell origin with a clinical course between hemangioma and angiosarcoma. Clinical manifestations and radiological findings are nonspecific, and histopathologic examination is required to establish a definitive diagnosis. Currently, hepatic resection or liver transplantation is the best therapeutic options. Because of its unknown biological behavior, local resection and radio-frequency ablation, although an uncommon treatment method, can be performed in the absence of extrahepatic or diffuse involvement. PMID- 20959188 TI - Endoscopic biliary large-balloon dilation after endoscopic sphincterotomy for the treatment of large common bile duct stones. Case report. AB - Common bile duct (CBD) stones extraction is usually performed by endoscopic sphincterotomy followed by removal by either a Dormia basket or extraction balloon catheter. However, some stones due to their size are not amenable to these procedures and extracorporeal or mechanical lithotripsy devices need to be used. Mechanical lithotripsy involves usage of a basket that will be inevitably destroyed which increases cost to the patient and endoscopy unit. The use of extracorporeal wave shock lithotripsy is an alternative; however it is not available widely. Reports about the use of hydrostatic large caliber balloon dilator (HLCBD) aiding in the extraction of large caliber CBD stones have concluded that is a safe and feasible therapeutic alternative. We present the case of a 25 mm x 30 mm CBD stone that could not be extracted using conventional methods. CBD dilation using HLCBD was performed after endoscopic sphincterotomy in an attempt to avoid mechanical lithotripsy. PMID- 20959189 TI - [Hepatic actinomycosis ; presentation a case in a diabetic patient]. AB - We report the case of an Hispanic female diabetic patient admitted to our hospital complaining of progressive abdominal pain, weight loss, nausea and vomiting. Work-up included an abdominal computed tomography (CT) scan which reported a large liver mass consistent with atypical abscess. Serum alpha fetoprotein value was normal, so a fine needle aspiration biopsy of the liver was performed and the report was consistent with an actinomycosis-induced abscess. Patient was treated with intravenous and oral amoxicillin with satisfactory clinical response. PMID- 20959190 TI - [Phytobezoar as a cause of intestinal occlusion. Presentation of a case]. AB - Eighty per cent of the intestinal occlusions in the small bowel are the result of adhesions, neoplasms or hernias. Approximately 4.3% of bowel occlusions are due to some type of bezoar. We report an 83 years old male who presented with a clinical picture of intestinal obstruction. He underwent hand-assisted laparoscopic exploration identifying an intraluminal non-fixed mass. Enterotomy was performed and a 3 x 4 cm yellowish mass was extracted. Histological analysis demonstrated a vegetal bezoar. Laparoscopic surgery is increasing its role in the management of intestinal occlusion. PMID- 20959191 TI - [Low back pain as a manifestation of an intra-abdominal desmoplastic small round cell tumor]. AB - The desmoplastic small round cell tumor is infrequent.That mainly affects male youngsters and is normally located at the abdomino-pelvic cavity, being its clinic unspecific. The diagnosis is confirmed by the presence of a specific chromosomal translocation: t (11; 22), (p13; q12). As to its treatment, it is mostly recommended to follow a multimodal aggressive one. We present the case of a man, whose atypicality is due to his advanced age (63 years old) and the symptoms he presents (lumbar ache). PMID- 20959192 TI - Diagnosis of pancreatic plasmacytoma by endoscopic ultrasound-fine needle aspiration. AB - Plasmacytoma presents more frequently in middle age men with aerodigestive tract involvement, especially in the head and the neck. Gastrointestinal tract involvement is uncommon, but the organ most commonly involved is the stomach. We report the first case in the literature in which final diagnosis was made by fine needle aspiration biopsy guided by endoscopic ultrasound with adequate sample for pathologic analysis. The treatment of this entity is systemic chemotherapy but its effectiveness is limited. Plasmacytoma should be taken into account in differential diagnosis of pancreatic masses. PMID- 20959193 TI - Pyloric gland adenoma: case report. AB - Pyloric gland adenoma (PGA), also called adenoma with gastric differentiation, is a rare neoplasm of the gastric mucosa that can appear as gastric heterotopia in several organs. A 49-year-old woman presented with gastric reflux and chronic elevation of liver enzymes. She had a history of type 2 diabetes mellitus, hypothyroidism and an unspecified allergy treated with deflazacor, and a family history of autoimmune diseases. A liver biopsy showed macro- and microvesicular steatohepatitis. Hepatitis B and virus serum tests were negative. Autoimmune hepatitis was suspected and investigated. As an evaluation for dyspeptic symptoms an upper gastrointestinal endoscopy was performed, showing diffuse gastroduodenitis. A few polyps were found and resected from the gastric fundus; histopathology revealed a pyloric gland adenoma. There is very few clinical data on this tumor type because it is frequently underdiagnosed and reported as dysplasia. Further research is needed on the pathophysiology of this disease. PMID- 20959194 TI - Cholecystectomy for gallbladder polyps. PMID- 20959195 TI - [Upper GI tract diseases I. GERD: extra-esophageal syndromes]. PMID- 20959196 TI - [Upper GI tract diseases I. Barrett's esophagus]. PMID- 20959197 TI - [Upper GI tract diseases I. Non-erosive reflux disease]. PMID- 20959198 TI - [Upper GI tract diseases I. New technologies for the diagnosis of esophageal diseases]. PMID- 20959199 TI - [Upper GI tract diseases I. Pharmacologic treatment of GERD (PPI and anti-reflux treatment)]. PMID- 20959200 TI - [Upper GI tract diseases II. Eosinophilic esophagitis]. PMID- 20959201 TI - [Upper GI tract diseases II. What is new in H. pylori infection?]. PMID- 20959202 TI - [Upper GI tract diseases II. Gastrointestinal injury caused by NSAID / COXIB and its treatment]. PMID- 20959203 TI - [Upper GI tract diseases II. H. pylori-negative peptic ulcer]. PMID- 20959204 TI - [Bowel diseases. Chronic diarrhea]. PMID- 20959205 TI - [Bowel diseases. Celiac disease]. PMID- 20959206 TI - [Bowel diseases. Microscopic colitis]. PMID- 20959207 TI - [Functional digestive disorders. Esophageal hypersensitivity and functional pyrosis]. PMID- 20959208 TI - [Functional digestive disorders. Functional dispepsia]. PMID- 20959209 TI - [Functional digestive disorders. Irritable bowel syndrome: advances in 2010]. PMID- 20959210 TI - [Functional digestive disorders. Constipation and fecal incontinence]. PMID- 20959211 TI - [Gastrointestinal oncology. Esophageal cancer]. PMID- 20959212 TI - [Gastrointestinal oncology. Gastric cancer]. PMID- 20959213 TI - [Gastrointestinal oncology. Colon cancer]. PMID- 20959214 TI - [Gastrointestinal oncology. Hepatocellular carcinoma]. PMID- 20959215 TI - [Gastrointestinal oncology. Pancreatic cancer]. PMID- 20959216 TI - [AGA plenary sessions. Quality in gastroenterology]. PMID- 20959217 TI - [AGA plenary sessions. Advances in basic science with clinical relevance]. PMID- 20959218 TI - [AGA plenary sessions. Advances in clinical research]. PMID- 20959219 TI - [AGA plenary sessions. Advances in GI surgery]. PMID- 20959220 TI - [GI bleeding. Non-variceal GI bleeding]. PMID- 20959221 TI - [GI bleeding. Variceal bleeding]. PMID- 20959222 TI - [GI bleeding. Obscure GI bleeding]. PMID- 20959223 TI - [GI bleeding. Lower GI bleeding]. PMID- 20959224 TI - [GI bleeding. Surgery in GI bleeding]. PMID- 20959225 TI - [GI infections and parasitoses. Protozoarian infections: is there something new?]. PMID- 20959226 TI - [GI infections and parasitoses. HIV and associated gastrointestinal diseases]. PMID- 20959227 TI - [GI infections and parasitoses. Acute infectious diarrhea]. PMID- 20959228 TI - [GI infections and parasitoses. Pseudomembranous colitis: are new toxins involved?]. PMID- 20959229 TI - [Colorectal diseases. Intestinal bacterial colonization]. PMID- 20959230 TI - [Colorectal diseases. Colon polyps]. PMID- 20959231 TI - [Colorectal diseases. Colon diverticular disease]. PMID- 20959232 TI - [Colorectal diseases. Rectal and anal cancer]. PMID- 20959233 TI - [Inflammatory bowel disease. Ulcerative colitis: latest news]. PMID- 20959234 TI - [Inflammatory bowel disease. Crohn's disease]. PMID- 20959236 TI - [GI endoscopy. Interventional EUS]. PMID- 20959235 TI - [Inflammatory bowel disease. Current treatment for IBS]. PMID- 20959237 TI - [GI endoscopy. Endoscopic mucosal resection and endoscopic submucosal dissection]. PMID- 20959238 TI - [GI endoscopy. GI bleeding: are there advances?]. PMID- 20959239 TI - [GI endoscopy. Endoscopic ablation of Barrett's esophagus]. PMID- 20959240 TI - [GI endoscopy. Capsule endoscopy]. PMID- 20959241 TI - [ASGE plenary sessions. Chromoendoscopy]. PMID- 20959242 TI - [ASGE plenary sessions. Enteroscopy]. PMID- 20959243 TI - [ASGE plenary sessions. Anti-reflux endoscopic procedures: state of the art]. PMID- 20959244 TI - [Liver diseases. Non-alcoholic fatty liver disease]. PMID- 20959245 TI - [Liver diseases. Hepatitis B]. PMID- 20959246 TI - [Liver diseases. Autoimmune liver diseases]. PMID- 20959247 TI - [Liver diseases. Hepatic encephalopathy]. PMID- 20959248 TI - [Biliary tract diseases. Cholestasis]. PMID- 20959249 TI - [Biliary tract diseases. Current trends biliary tract imaging]. PMID- 20959250 TI - [Biliary tract diseases. Gallbladder and biliary duct cancer]. PMID- 20959251 TI - [Biliary tract diseases. ERCP: to do or not to do?]. PMID- 20959252 TI - [Gastrointestinal surgery. Bariatric surgery]. PMID- 20959253 TI - [Gastrointestinal surgery. Liver transplant]. PMID- 20959254 TI - [Gastrointestinal surgery. Endoscopic surgery through natural orifice]. PMID- 20959255 TI - [Gastrointestinal surgery. Anti-reflux surgery: to whom and when]. PMID- 20959256 TI - [AASLD plenary sessions. Hepatitis C infection: what's new?]. PMID- 20959257 TI - [AASLD plenary sessions. Liver fibrosis in the plenary sessions of the AASLD-AGA 2010]. PMID- 20959258 TI - [AASLD plenary sessions. Advances in hepatocellular carcinoma]. PMID- 20959259 TI - A 3-d 160-site microelectrode array for cochlear nucleus mapping. AB - A 3-D application-specific microelectrode array has been developed for physiological studies in guinea pig cochlear nucleus (CN). The batch-fabricated silicon probes contain integrated parylene cables and use a boron etch-stop to define 15MUm-thick shanks and limit tissue displacement. Targeting the ventral (three probes) and dorsal (two probes) subnuclei, the custom four-shank 32-site probes are combined in a slotted block platform having a 1.18-mm (2) footprint. The device has permitted, for the first time, high-density 3-D in vivo studies of ventral CN to dorsal CN connections, stimulating with 1000 MUm (2) sites in one subnucleus while recording with 177 MUm (2) sites in the other. Through these experiments, it has demonstrated the efficacy of bimodal silicon arrays to better understand the central nervous system at the circuit level. The 160 electrode sites also provide a high-density neural interface, which is an essential aspect of auditory prosthesis prototypes. PMID- 20959260 TI - Variable time-delay estimation for anesthesia control during intensive care. AB - The presence of artifacts plays a crucial role in automatic sedation systems and may introduce variable time delays (TDs) in the closed-loop-control structures. This paper presents a successful procedure to estimate the varying TD of the bispectral index (BIS) monitor used in closed-loop control during intensive care. The TD estimation (TDE) is based on the cross-correlation analysis technique and the method is validated with real measured signals of propofol and BIS. Extended prediction self-adaptive control is used in combination with a Smith predictor to reduce the computational burden imposed by the variable TD. The conclusion is that an online TDE of the BIS monitor improves the performance of the closed-loop system for reference tracking, disturbance rejection, and overall stability. PMID- 20959261 TI - An efficient 3-D eddy-current solver using an independent impedance method for transcranial magnetic stimulation. AB - In many important bioelectromagnetic problem settings, eddy-current simulations are required. Examples are the reduction of eddy-current artifacts in magnetic resonance imaging and techniques, whereby the eddy currents interact with the biological system, like the alteration of the neurophysiology due to transcranial magnetic stimulation (TMS). TMS has become an important tool for the diagnosis and treatment of neurological diseases and psychiatric disorders. A widely applied method for simulating the eddy currents is the impedance method (IM). However, this method has to contend with an ill conditioned problem and consequently a long convergence time. When dealing with optimal design problems and sensitivity control, the convergence rate becomes even more crucial since the eddy-current solver needs to be evaluated in an iterative loop. Therefore, we introduce an independent IM (IIM), which improves the conditionality and speeds up the numerical convergence. This paper shows how IIM is based on IM and what are the advantages. Moreover, the method is applied to the efficient simulation of TMS. The proposed IIM achieves superior convergence properties with high time efficiency, compared to the traditional IM and is therefore a useful tool for accurate and fast TMS simulations. PMID- 20959262 TI - Experimental validation of a tissue-joining implant providing flexible adaptation to the thickness of the stomach wall. AB - Endoscopy is gradually replacing open surgery in the gastrointestinal tract. Therefore, novel medical devices and instrumentation are required, such as flexible miniaturized mechanisms for tissue joining and manipulation. In this paper, an absorbable implant for the purpose of long-term tissue fixation is presented. An experimental validation of the implant design and functionality is introduced. The implant achieves tissue penetration and provides flexible adaptation according to the thickness of two stomach walls. This mechanism is easy as it is based on push-pull principle using unidirectional forces. The shape optimization of each implant part occurs by varying design-influencing factors. The load transmission on postmortem porcine tissue was measured in the frame of the experimental setup. The feasibility of the implant was tested, and the forces needed for the intended application quantified. The implant successfully achieves tissue penetration, load transmission, adjustment, and fixation. It is a new alternative to conventional tissue-joining mechanisms. PMID- 20959263 TI - Design of a semi-implantable hearing device for direct acoustic cochlear stimulation. AB - A new hearing therapy based on direct acoustic cochlear stimulation was developed for the treatment of severe to profound mixed hearing loss. The device efficacy was validated in an initial clinical trial with four patients. This semi implantable investigational device consists of an externally worn audio processor, a percutaneous connector, and an implantable microactuator. The actuator is placed in the mastoid bone, right behind the external auditory canal. It generates vibrations that are directly coupled to the inner ear fluids and that, therefore, bypass the external and the middle ear. The system is able to provide an equivalent sound pressure level of 125 dB over the frequency range between 125 and 8000 Hz. The hermetically sealed actuator is designed to provide maximal output power by keeping its dimensions small enough to enable implantation. A network model is used to simulate the dynamic characteristics of the actuator to adjust its transfer function to the characteristics of the middle ear. The geometry of the different actuator components is optimized using finite element modeling. PMID- 20959264 TI - Frequency-offset Cartesian feedback for MRI power amplifier linearization. AB - High-quality magnetic resonance imaging (MRI) requires precise control of the transmit radio-frequency (RF) field. In parallel excitation applications such as transmit SENSE, high RF power linearity is essential to cancel aliased excitations. In widely-employed class AB power amplifiers, gain compression, cross-over distortion, memory effects, and thermal drift all distort the RF field modulation and can degrade image quality. Cartesian feedback (CF) linearization can mitigate these effects in MRI, if the quadrature mismatch and dc offset imperfections inherent in the architecture can be minimized. In this paper, we present a modified Cartesian feedback technique called "frequency-offset Cartesian feedback" (FOCF) that significantly reduces these problems. In the FOCF architecture, the feedback control is performed at a low intermediate frequency rather than dc, so that quadrature ghosts and dc errors are shifted outside the control bandwidth. FOCF linearization is demonstrated with a variety of typical MRI pulses. Simulation of the magnetization obtained with the Bloch equation demonstrates that high-fidelity RF reproduction can be obtained even with inexpensive class AB amplifiers. Finally, the enhanced RF fidelity of FOCF over CF is demonstrated with actual images obtained in a 1.5 T MRI system. PMID- 20959265 TI - Optimization methods for spiking neurons and networks. AB - Spiking neurons and spiking neural circuits are finding uses in a multitude of tasks such as robotic locomotion control, neuroprosthetics, visual sensory processing, and audition. The desired neural output is achieved through the use of complex neuron models, or by combining multiple simple neurons into a network. In either case, a means for configuring the neuron or neural circuit is required. Manual manipulation of parameters is both time consuming and non-intuitive due to the nonlinear relationship between parameters and the neuron's output. The complexity rises even further as the neurons are networked and the systems often become mathematically intractable. In large circuits, the desired behavior and timing of action potential trains may be known but the timing of the individual action potentials is unknown and unimportant, whereas in single neuron systems the timing of individual action potentials is critical. In this paper, we automate the process of finding parameters. To configure a single neuron we derive a maximum likelihood method for configuring a neuron model, specifically the Mihalas-Niebur Neuron. Similarly, to configure neural circuits, we show how we use genetic algorithms (GAs) to configure parameters for a network of simple integrate and fire with adaptation neurons. The GA approach is demonstrated both in software simulation and hardware implementation on a reconfigurable custom very large scale integration chip. PMID- 20959266 TI - Condensed vector machines: learning fast machine for large data. AB - Scalability is one of the main challenges for kernel-based methods and support vector machines (SVMs). The quadratic demand in memory for storing kernel matrices makes it impossible for training on million-size data. Sophisticated decomposition algorithms have been proposed to efficiently train SVMs using only important examples, which ideally are the final support vectors (SVs). However, the ability of the decomposition method is limited to large-scale applications where the number of SVs is still too large for a computer's capacity. From another perspective, the large number of SVs slows down SVMs in the testing phase, making it impractical for many applications. In this paper, we introduce the integration of a vector combination scheme to simplify the SVM solution into an incremental working set selection for SVM training. The main objective of the integration is to maintain a minimal number of final SVs, bringing a minimum resource demand and faster training time. Consequently, the learning machines are more compact and run faster thanks to the small number of vectors included in their solution. Experimental results on large benchmark datasets shows that the proposed condensed SVMs achieve both training and testing efficiency while maintaining a generalization ability equivalent to that of normal SVMs. PMID- 20959267 TI - IMAGE resolution enhancement by using discrete and stationary wavelet decomposition. AB - In this correspondence, the authors propose an image resolution enhancement technique based on interpolation of the high frequency subband images obtained by discrete wavelet transform (DWT) and the input image. The edges are enhanced by introducing an intermediate stage by using stationary wavelet transform (SWT). DWT is applied in order to decompose an input image into different subbands. Then the high frequency subbands as well as the input image are interpolated. The estimated high frequency subbands are being modified by using high frequency subband obtained through SWT. Then all these subbands are combined to generate a new high resolution image by using inverse DWT (IDWT). The quantitative and visual results are showing the superiority of the proposed technique over the conventional and state-of-art image resolution enhancement techniques. PMID- 20959268 TI - In search of perceptually salient groupings. AB - Finding meaningful groupings of image primitives has been a long-standing problem in computer vision. This paper studies how salient groupings can be produced using established theories in the field of visual perception alone. The major contribution is a novel definition of the Gestalt principle of Pragnanz, based upon Koffka's definition that image descriptions should be both stable and simple. Our method is global in the sense that it operates over all primitives in an image at once. It works regardless of the type of image primitives and is generally independent of image properties such as intensity, color, and texture. A novel experiment is designed to quantitatively evaluate the groupings outputs by our method, which takes human disagreement into account and is generic to outputs of any grouper. We also demonstrate the value of our method in an image segmentation application and quantitatively show that segmentations deliver promising results when benchmarked using the Berkeley Segmentation Dataset (BSDS). PMID- 20959269 TI - Inverse halftoning based on the bayesian theorem. AB - This study proposes a method which can generate high quality inverse halftone images from halftone images. This method can be employed prior to any signal processing over a halftone image or the inverse halftoning used in JBIG2. The proposed method utilizes the least-mean-square (LMS) algorithm to establish a relationship between the current processing position and its corresponding neighboring positions in each type of halftone image, including direct binary search, error diffusion, dot diffusion, and ordered dithering. After which, a referenced region called a support region (SR) is used to extract features. The SR can be obtained by relabeling the LMS-trained filters with the order of importance. Moreover, the probability of black pixel occurrence is considered as a feature in this work. According to this feature, the probabilities of all possible grayscale values at the current processing position can be obtained by the Bayesian theorem. Consequently, the final output at this position is the grayscale value with the highest probability. Experimental results show that the proposed method offers better visual quality than that of Mese-Vaidyanathan's and Chang et al's methods in terms of human-visual peak signal-to-noise ratio (HPSNR). In addition, the memory consumption is also superior to Mese Vaidyanathan's method. PMID- 20959270 TI - Real-time discriminative background subtraction. AB - The authors examine the problem of segmenting foreground objects in live video when background scene textures change over time. In particular, we formulate background subtraction as minimizing a penalized instantaneous risk functional- yielding a local online discriminative algorithm that can quickly adapt to temporal changes. We analyze the algorithm's convergence, discuss its robustness to nonstationarity, and provide an efficient nonlinear extension via sparse kernels. To accommodate interactions among neighboring pixels, a global algorithm is then derived that explicitly distinguishes objects versus background using maximum a posteriori inference in a Markov random field (implemented via graph cuts). By exploiting the parallel nature of the proposed algorithms, we develop an implementation that can run efficiently on the highly parallel graphics processing unit (GPU). Empirical studies on a wide variety of datasets demonstrate that the proposed approach achieves quality that is comparable to state-of-the-art offline methods, while still being suitable for real-time video analysis ( >= 75 fps on a mid-range GPU). PMID- 20959271 TI - Early-onset basal cell carcinoma in a case of Ivemark syndrome. PMID- 20959272 TI - Systemic absorption of sodium cromoglicate from a new cutaneous emulsion (Altoderm (r)) in children with atopic dermatitis. PMID- 20959273 TI - CD56 highCD16 - NK cell involvement in cutaneous lichen planus. AB - Lichen planus is an inflammatory disease of the skin and mucous membranes characterized by vacuolization of basal keratinocytes associated with a prominent junctional lymphocyte infiltrate which comprises T lymphocytes, NK cells, myeloid and plasmacytoid dendritic cells. Basal keratinocyte damage is considered as being a consequence of a lymphocytic cytotoxic attack, mostly mediated by perforin+CD8+ T lymphocytes. NK cells have been described to infiltrate inflamed skin and significantly contribute to the amplification of immune-mediated skin diseases, thanks to their cytotoxic activity and the release of pro-inflammatory cytokines. Here, we investigated the characteristics and functional properties of NK lymphocytes involved in lichen planus. Double staining immunohistochemistry showed a considerable number (6.42 +/- 2.2% of the total cellular infiltrate) of CD3-CD56+ cells in early lichen planus lesions, mostly distributed in the papillary dermis and at the epidermal-dermal interface. Skin NK cells isolated from lichen planus lesions belong to the CD56highCD16- subset, are highly positive for perforin and natural cytotoxic receptors NKG2D and NKp44, and, in accordance with their phenotype, are negative for KIRs receptors CD158a and CD158b. Skin CD56highCD16- NK cells display a CCR6+CXCR3+CCR5+ChemR23+ chemokine receptor asset for homing into inflamed skin. In terms of cytokine release, skin CD56highCD16- NK cells are able to secrete IFN-gamma, TNF-alpha and hardly release IL-22, IL-17 and IL-4. Overall, our data propose a pro-inflammatory role of NK lymphocytes in lichen planus. PMID- 20959274 TI - Multidisciplinary team meetings in Oncology: first analysis of benefits and evaluation of activity in a Dermatology unit in France. AB - Improving Multi-Disciplinary Meetings (MDM) is one of the 70 clauses of the French Cancer Plan of 2003-2007. The French High Authority of Health (HAS) and the National Cancer Institute (INCa) have established guidelines to standardize MDM concerning cancer care. No objective assessment of cutaneous cancer (dermato oncology) MDM has been published yet, despite the growing numbers in the incidence of skin cancers. This study aims to analyze two of our center's MDM concerns: its decisions and its compliance with HAS guidelines. A retrospective study of all skin tumors discussed in MDM held at Amiens University Hospital between 2006-2007 analyzed epidemiological data, MDM decisions (recommendations), and their compliance. 349 MDM conclusion reports concerning 228 patients were analyzed. The cases consisted of 132 melanomas, 27 basal cell carcinomas, 19 squamous cell carcinomas, 5 Merkel cell carcinomas, 8 sarcomas, 16 cutaneous lymphomas, and 21 other tumors. 45.7% of MDM had at least 3 different specialists present. Patients were present in 49.4% of discussions. 88% of the MDMs' recommendations were implemented. More than 94% of these decisions were according to the guidelines. MDM recommendations contributed to: making 13.6% of diagnoses, 74.7% of treatment decisions, 45.6% of investigations requested, and 48.2% of long-term follow-up decisions. Treatment recommendations were: surgery in 50.6% of patients, chemotherapy in 45.0% and radiotherapy in 12.5%. The MDM's therapeutic decisions tended to follow the specialty of the referring physician; e.g. patients were likely to have surgery when referred by a surgeon, etc (p < 0.0001). Dermato-oncology MDM at Amiens University Hospital comply with most of the guidelines, however, patient attendance at MDM, participation of different specialists and the formal function and structure, all have room for improvement. PMID- 20959275 TI - Ischemic fasciitis with MRI findings. PMID- 20959276 TI - Scurvy in a housewife manifesting as anemia and ecchymoses. PMID- 20959277 TI - Palmoplantar keratoderma in keratosis follicularis spinulosa decalvans. PMID- 20959278 TI - Upper airway tract and upper gastrointestinal tract involvement in patients with pemphigus vulgaris. AB - Pemphigus vulgaris (PV) is an autoimmune disease involving the skin and mucous membranes. The frequency of upper airway tract (UAT) and upper gastrointestinal tract (UGIT) involvement in PV is not clearly known. Our aim was to determine the incidence of UAT and UGIT involvement in patients with PV. Thirty-seven patients who were diagnosed with PV and treated between March 2008 and April 2009 at the Dermatology Department of the Vakif Gureba Teaching and Research Hospital were included. All patients were evaluated for UAT manifestations by endoscopic examination, and 22 of 37 patients were investigated for UGIT involvement by gastrointestinal endoscopy. Mucosal biopsies were obtained by UGIT endoscopy for direct immunofluorescence (DIF) examination, and a histopathological examination was conducted in patients with active UGIT mucosal lesions. Thirty-five of 37 patients (94.6%) had active pharyngeal, laryngeal, or nasal PV lesions on endoscopic evaluation. Oral symptoms (83.8%) and active oral PV lesions were the most frequent findings (100%). Pharyngeal lesions (64.9%) were the most commonly present lesions on UAT examination. The frequency for laryngeal and nasal lesions was 51.4% and 21.6%, respectively. Five of 22 patients (22.7%) presented with active laryngeal and esophageal lesions. Twenty-one of 22 (95.4%) patients had positive DIF results. We believe that UAT and UGIT endoscopies are useful and necessary diagnostic methods in patients with PV with or without UAT and UGIT symptoms. UAT and UGIT endoscopies should be performed as standard diagnostic procedures in all patients with PV. PMID- 20959279 TI - Squamous cell carcinoma arising in lichen simplex chronicus. PMID- 20959280 TI - Long-term remission of primary erythermalgia with R1150W polymorphism in SCN9A after chemical lumbar sympathectomy. AB - Primary erythermalgia (PEM) is recalcitrant and long-term remission is difficult to achieve. Favorable results of treatment using carbamazepine or mexiletine have been identified in some PEM patients with SCN9A gene mutations. However, no therapeutic studies regarding patients without pathogenic SCN9A gene mutation have been reported. Here we present a PEM case with R1150W polymorphism in SCN9A and a five-year remission was achieved by chemical lumbar sympathectomy (CLS). A 15-year-old girl with severe PEM attacks in both feet and lower legs was treated with CLS and followed up for five years. The encoding exons and their flanking sequences in the SCN9A gene were amplified and sequenced. A 50% immediate pain reduction was achieved after CLS. Burning pain, erythema and swelling in the lower legs disappeared in four days, and all ulceration healed in a month. The patient resumed normal exercise five months after CLS. There were no relapses in the following five years. R1150W polymorphism in SCN9A was detected in the patient and her healthy father. Long-term remission was achieved after CLS in this PEM case with R1150W polymorphism in SCN9A. The effectiveness of CLS and phenotype/genotype of PEM should be further studied in larger samples. PMID- 20959281 TI - Presumed consent: a distraction in the quest for increasing rates of organ donation. PMID- 20959282 TI - Interventions to promote cycling: systematic review. AB - OBJECTIVES: To determine what interventions are effective in promoting cycling, the size of the effects of interventions, and evidence of any associated benefits on overall physical activity or anthropometric measures. DESIGN: Systematic review. DATA SOURCES: Published and unpublished reports in any language identified by searching 13 electronic databases, websites, reference lists, and existing systematic reviews, and papers identified by experts in the field. Review methods Controlled "before and after" experimental or observational studies of the effect of any type of intervention on cycling behaviour measured at either individual or population level. RESULTS: Twenty five studies (of which two were randomised controlled trials) from seven countries were included. Six studies examined interventions aimed specifically at promoting cycling, of which four (an intensive individual intervention in obese women, high quality improvements to a cycle route network, and two multifaceted cycle promotion initiatives at town or city level) were found to be associated with increases in cycling. Those studies that evaluated interventions at population level reported net increases of up to 3.4 percentage points in the population prevalence of cycling or the proportion of trips made by bicycle. Sixteen studies assessing individualised marketing of "environmentally friendly" modes of transport to interested households reported modest but consistent net effects equating to an average of eight additional cycling trips per person per year in the local population. Other interventions that targeted travel behaviour in general were not associated with a clear increase in cycling. Only two studies assessed effects of interventions on physical activity; one reported a positive shift in the population distribution of overall physical activity during the intervention. CONCLUSIONS: Community-wide promotional activities and improving infrastructure for cycling have the potential to increase cycling by modest amounts, but further controlled evaluative studies incorporating more precise measures are required, particularly in areas without an established cycling culture. Studies of individualised marketing report consistent positive effects of interventions on cycling behaviour, but these findings should be confirmed using more robust study designs. Future research should also examine how best to promote cycling in children and adolescents and through workplaces. Whether interventions to promote cycling result in an increase in overall physical activity or changes in anthropometric measures is unclear. PMID- 20959283 TI - Promotion of cycling and health. PMID- 20959284 TI - Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients in prehospital setting: randomised controlled trial. AB - OBJECTIVES: To compare standard high flow oxygen treatment with titrated oxygen treatment for patients with an acute exacerbation of chronic obstructive pulmonary disease in the prehospital setting. DESIGN: Cluster randomised controlled parallel group trial. SETTING: Ambulance service in Hobart, Tasmania, Australia. PARTICIPANTS: 405 patients with a presumed acute exacerbation of chronic obstructive pulmonary disease who were treated by paramedics, transported, and admitted to the Royal Hobart Hospital during the trial period; 214 had a diagnosis of chronic obstructive pulmonary disease confirmed by lung function tests in the previous five years. INTERVENTIONS: High flow oxygen treatment compared with titrated oxygen treatment in the prehospital (ambulance/paramedic) setting. MAIN OUTCOME MEASURE: Prehospital or in-hospital mortality. RESULTS: In an intention to treat analysis, the risk of death was significantly lower in the titrated oxygen arm compared with the high flow oxygen arm for all patients (high flow oxygen n=226; titrated oxygen n=179) and for the subgroup of patients with confirmed chronic obstructive pulmonary disease (high flow n=117; titrated n=97). Overall mortality was 9% (21 deaths) in the high flow oxygen arm compared with 4% (7 deaths) in the titrated oxygen arm; mortality in the subgroup with confirmed chronic obstructive pulmonary disease was 9% (11 deaths) in the high flow arm compared with 2% (2 deaths) in the titrated oxygen arm. Titrated oxygen treatment reduced mortality compared with high flow oxygen by 58% for all patients (relative risk 0.42, 95% confidence interval 0.20 to 0.89; P=0.02) and by 78% for the patients with confirmed chronic obstructive pulmonary disease (0.22, 0.05 to 0.91; P=0.04). Patients with chronic obstructive pulmonary disease who received titrated oxygen according to the protocol were significantly less likely to have respiratory acidosis (mean difference in pH 0.12 (SE 0.05); P=0.01; n=28) or hypercapnia (mean difference in arterial carbon dioxide pressure -33.6 (16.3) mm Hg; P=0.02; n=29) than were patients who received high flow oxygen. CONCLUSIONS: Titrated oxygen treatment significantly reduced mortality, hypercapnia, and respiratory acidosis compared with high flow oxygen in acute exacerbations of chronic obstructive pulmonary disease. These results provide strong evidence to recommend the routine use of titrated oxygen treatment in patients with breathlessness and a history or clinical likelihood of chronic obstructive pulmonary disease in the prehospital setting. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Register ACTRN12609000236291. PMID- 20959285 TI - Avoidance of high concentration oxygen in chronic obstructive pulmonary disease. PMID- 20959286 TI - Patients seeking treatment abroad. PMID- 20959288 TI - Olig2 regulates Sox10 expression in oligodendrocyte precursors through an evolutionary conserved distal enhancer. AB - The HMG-domain transcription factor Sox10 is expressed throughout oligodendrocyte development and is an important component of the transcriptional regulatory network in these myelin-forming CNS glia. Of the known Sox10 regulatory regions, only the evolutionary conserved U2 enhancer in the distal 5'-flank of the Sox10 gene exhibits oligodendroglial activity. We found that U2 was active in oligodendrocyte precursors, but not in mature oligodendrocytes. U2 activity also did not mediate the initial Sox10 induction after specification arguing that Sox10 expression during oligodendroglial development depends on the activity of multiple regulatory regions. The oligodendroglial bHLH transcription factor Olig2, but not the closely related Olig1 efficiently activated the U2 enhancer. Olig2 bound U2 directly at several sites including a highly conserved one in the U2 core. Inactivation of this site abolished the oligodendroglial activity of U2 in vivo. In contrast to Olig2, the homeodomain transcription factor Nkx6.2 repressed U2 activity. Repression may involve recruitment of Nkx6.2 to U2 and inactivation of Olig2 and other activators by protein-protein interactions. Considering the selective expression of Nkx6.2 at the time of specification and in differentiated oligodendrocytes, Nkx6.2 may be involved in limiting U2 activity to the precursor stage during oligodendrocyte development. PMID- 20959287 TI - MethylViewer: computational analysis and editing for bisulfite sequencing and methyltransferase accessibility protocol for individual templates (MAPit) projects. AB - Bisulfite sequencing is a widely-used technique for examining cytosine DNA methylation at nucleotide resolution along single DNA strands. Probing with cytosine DNA methyltransferases followed by bisulfite sequencing (MAPit) is an effective technique for mapping protein-DNA interactions. Here, MAPit methylation footprinting with M.CviPI, a GC methyltransferase we previously cloned and characterized, was used to probe hMLH1 chromatin in HCT116 and RKO colorectal cancer cells. Because M.CviPI-probed samples contain both CG and GC methylation, we developed a versatile, visually-intuitive program, called MethylViewer, for evaluating the bisulfite sequencing results. Uniquely, MethylViewer can simultaneously query cytosine methylation status in bisulfite-converted sequences at as many as four different user-defined motifs, e.g. CG, GC, etc., including motifs with degenerate bases. Data can also be exported for statistical analysis and as publication-quality images. Analysis of hMLH1 MAPit data with MethylViewer showed that endogenous CG methylation and accessible GC sites were both mapped on single molecules at high resolution. Disruption of positioned nucleosomes on single molecules of the PHO5 promoter was detected in budding yeast using M.CviPII, increasing the number of enzymes available for probing protein-DNA interactions. MethylViewer provides an integrated solution for primer design and rapid, accurate and detailed analysis of bisulfite sequencing or MAPit datasets from virtually any biological or biochemical system. PMID- 20959289 TI - Protegen: a web-based protective antigen database and analysis system. AB - Protective antigens are specifically targeted by the acquired immune response of the host and are able to induce protection in the host against infectious and non infectious diseases. Protective antigens play important roles in vaccine development, as biological markers for disease diagnosis, and for analysis of fundamental host immunity against diseases. Protegen is a web-based central database and analysis system that curates, stores and analyzes protective antigens. Basic antigen information and experimental evidence are curated from peer-reviewed articles. More detailed gene/protein information (e.g. DNA and protein sequences, and COG classification) are automatically extracted from existing databases using internally developed scripts. Bioinformatics programs are also applied to compute different antigen features, such as protein weight and pI, and subcellular localizations of bacterial proteins. Presently, 590 protective antigens have been curated against over 100 infectious diseases caused by pathogens and non-infectious diseases (including cancers and allergies). A user-friendly web query and visualization interface is developed for interactive protective antigen search. A customized BLAST sequence similarity search is also developed for analysis of new sequences provided by the users. To support data exchange, the information of protective antigens is stored in the Vaccine Ontology (VO) in OWL format and can also be exported to FASTA and Excel files. Protegen is publically available at http://www.violinet.org/protegen. PMID- 20959290 TI - Regulation of the androgen receptor by SET9-mediated methylation. AB - The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors that plays a critical role in regulating expression of genes involved in prostate development and transformation. Upon hormone binding, the AR associates with numerous co-regulator proteins that regulate the activation status of target genes via flux to the post-translational modification status of histones and the receptor. Here we show that the AR interacts with and is directly methylated by the histone methyltransferase enzyme SET9. Methylation of the AR on lysine 632 is necessary for enhancing transcriptional activity of the receptor by facilitating both inter-domain communication between the N- and C termini and recruitment to androgen-target genes. We also show that SET9 is pro proliferative and anti-apoptotic in prostate cancer cells and demonstrates up regulated nuclear expression in prostate cancer tissue. In all, our date indicate a new mechanism of AR regulation that may be therapeutically exploitable for prostate cancer treatment. PMID- 20959291 TI - Identification of RNA recognition elements in the Saccharomyces cerevisiae transcriptome. AB - Post-transcriptional regulation of gene expression, including mRNA localization, translation and decay, is ubiquitous yet still largely unexplored. How is the post-transcriptional regulatory program of each mRNA encoded in its sequence? Hundreds of specific RNA-binding proteins (RBPs) appear to play roles in mediating the post-transcriptional regulatory program, akin to the roles of specific DNA-binding proteins in transcription. As a step toward decoding the regulatory programs encoded in each mRNA, we focused on specific mRNA-protein interactions. We computationally analyzed the sequences of Saccharomyces cerevisiae mRNAs bound in vivo by 29 specific RBPs, identifying eight novel candidate motifs and confirming or extending six earlier reported recognition elements. Biochemical selections for RNA sequences selectively recognized by 12 yeast RBPs yielded novel motifs bound by Pin4, Nsr1, Hrb1, Gbp2, Sgn1 and Mrn1, and recovered the known recognition elements for Puf3, She2, Vts1 and Whi3. Most of the RNA elements we uncovered were associated with coherent mRNA expression changes and were significantly conserved in related yeasts, supporting their functional importance and suggesting that the corresponding RNA-protein interactions are evolutionarily conserved. PMID- 20959292 TI - The Pancreatic Expression database: 2011 update. AB - The Pancreatic Expression database (PED, http://www.pancreasexpression.org) has established itself as the main repository for pancreatic-derived -omics data. For the past 3 years, its data content and access have increased substantially. Here we describe several of its new and improved features, such as data content, which now includes over 60,000 measurements derived from transcriptomics, proteomics, genomics and miRNA profiles from various pancreas-centred reports on a broad range of specimen and experimental types. We also illustrate the capabilities of its interface, which allows integrative queries that can combine PED data with a growing number of biological resources such as NCBI, Ensembl, UniProt and Reactome. Thus, PED is capable of retrieving and integrating different types of omics, annotations and clinical data. We also focus on the importance of data sharing and interoperability in the cancer field, and the integration of PED into the International Cancer Genome Consortium (ICGC) data portal. PMID- 20959293 TI - Evidence of the formation of G-quadruplex structures in the promoter region of the human vascular endothelial growth factor gene. AB - The polypurine/polypyrimidine (pPu/pPy) tract of the human vascular endothelial growth factor (VEGF) gene is proposed to be structurally dynamic and to have potential to adopt non-B DNA structures. In the present study, we further provide evidence for the existence of the G-quadruplex structure within this tract both in vitro and in vivo using the dimethyl sulfate (DMS) footprinting technique and nucleolin as a structural probe specifically recognizing G-quadruplex structures. We observed that the overall reactivity of the guanine residues within this tract toward DMS was significantly reduced compared with other guanine residues of the flanking regions in both in vitro and in vivo footprinting experiments. We also demonstrated that nucleolin, which is known to bind to G-quadruplex structures, is able to bind specifically to the G-rich sequence of this region in negatively supercoiled DNA. Our chromatin immunoprecipitation analysis further revealed binding of nucleolin to the promoter region of the VEGF gene in vivo. Taken together, our results are in agreement with our hypothesis that secondary DNA structures, such as G-quadruplexes, can be formed in supercoiled duplex DNA and DNA in chromatin in vivo under physiological conditions similar to those formed in single-stranded DNA templates. PMID- 20959294 TI - Interaction of Rep and DnaB on DNA. AB - Genome duplication requires not only unwinding of the template but also the displacement of proteins bound to the template, a function performed by replicative helicases located at the fork. However, accessory helicases are also needed since the replicative helicase stalls occasionally at nucleoprotein complexes. In Escherichia coli, the primary and accessory helicases DnaB and Rep translocate along the lagging and leading strand templates, respectively, interact physically and also display cooperativity in the unwinding of model forked DNA substrates. We demonstrate here that this cooperativity is displayed only by Rep and not by other tested helicases. ssDNA must be exposed on the leading strand template to elicit this cooperativity, indicating that forks blocked at protein-DNA complexes contain ssDNA ahead of the leading strand polymerase. However, stable Rep-DnaB complexes can form on linear as well as branched DNA, indicating that Rep has the capacity to interact with ssDNA on either the leading or the lagging strand template at forks. Inhibition of Rep binding to the lagging strand template by competition with SSB might therefore be critical in targeting accessory helicases to the leading strand template, indicating an important role for replisome architecture in promoting accessory helicase function at blocked replisomes. PMID- 20959295 TI - The UCSC Genome Browser database: update 2011. AB - The University of California, Santa Cruz Genome Browser (http://genome.ucsc.edu) offers online access to a database of genomic sequence and annotation data for a wide variety of organisms. The Browser also has many tools for visualizing, comparing and analyzing both publicly available and user-generated genomic data sets, aligning sequences and uploading user data. Among the features released this year are a gene search tool and annotation track drag-reorder functionality as well as support for BAM and BigWig/BigBed file formats. New display enhancements include overlay of multiple wiggle tracks through use of transparent coloring, options for displaying transformed wiggle data, a 'mean+whiskers' windowing function for display of wiggle data at high zoom levels, and more color schemes for microarray data. New data highlights include seven new genome assemblies, a Neandertal genome data portal, phenotype and disease association data, a human RNA editing track, and a zebrafish Conservation track. We also describe updates to existing tracks. PMID- 20959296 TI - Allele dynamics plots for the study of evolutionary dynamics in viral populations. AB - Phylodynamic techniques combine epidemiological and genetic information to analyze the evolutionary and spatiotemporal dynamics of rapidly evolving pathogens, such as influenza A or human immunodeficiency viruses. We introduce 'allele dynamics plots' (AD plots) as a method for visualizing the evolutionary dynamics of a gene in a population. Using AD plots, we propose how to identify the alleles that are likely to be subject to directional selection. We analyze the method's merits with a detailed study of the evolutionary dynamics of seasonal influenza A viruses. AD plots for the major surface protein of seasonal influenza A (H3N2) and the 2009 swine-origin influenza A (H1N1) viruses show the succession of substitutions that became fixed in the evolution of the two viral populations. They also allow the early identification of those viral strains that later rise to predominance, which is important for the problem of vaccine strain selection. In summary, we describe a technique that reveals the evolutionary dynamics of a rapidly evolving population and allows us to identify alleles and associated genetic changes that might be under directional selection. The method can be applied for the study of influenza A viruses and other rapidly evolving species or viruses. PMID- 20959297 TI - Palliative care beyond cancer. Death plans reduce death taboo. PMID- 20959298 TI - Palliative care beyond cancer. Spirituality is a weasel word. PMID- 20959299 TI - Obsolete clinical signs. Time to update. PMID- 20959300 TI - Palliative care beyond cancer. Good death for all remains distant goal. PMID- 20959301 TI - Self management of diabetes. Fallacy in intervention model. PMID- 20959302 TI - From trial to practice. Let's collaborate. PMID- 20959303 TI - Views on lipid lowering. JUPITER seems to be bypassed. PMID- 20959304 TI - Media and suicide. Papageno v Werther effect. PMID- 20959305 TI - Palliative care beyond cancer. Irish Hospice Friendly Hospitals programme. PMID- 20959306 TI - European Medicines Agency tightens rules on conflict of interest. PMID- 20959307 TI - Characteristics of fasciculations in amyotrophic lateral sclerosis and the benign fasciculation syndrome. AB - The aim of this study was to determine first, if benign fasciculations and those in amyotrophic lateral sclerosis can de distinguished on the basis of their waveforms or firing characteristics, and second to determine how fasciculation parameters evolved with progression of amyotrophic lateral sclerosis. Fasciculation potentials recorded from 63 muscles of 28 patients with definite amyotrophic lateral sclerosis were compared with those from 21 muscles of 11 patients with the benign fasciculation syndrome. In each muscle, at a single site, up to 15 identifiable fasciculation potentials could be recognized. Thus the characteristics of 430 fasciculations from patients with amyotrophic lateral sclerosis and 191 benign fasciculations were analysed. Fasciculation potential amplitude, area, turns, duration, firing interval, indices of waveform variability, evidence of axonal conduction block, evidence of axonal conduction variability and propensity to produce double fasciculations were measured. The waveforms of fasciculations in amyotrophic lateral sclerosis were on average of shorter duration and had a greater number of turns than benign fasciculations, but, although irregular in both conditions, the firing rate in amyotrophic lateral sclerosis was significantly higher. In both conditions, there was evidence of multifocal distal generation of fasciculations, axonal conduction block in the motor unit arborization and of variable axonal conduction. When severe weakness and marked chronic neurogenic change were present on electromyography, the firing rate of fasciculations in amyotrophic lateral sclerosis was higher but fasciculation potential amplitude, area and indices of waveform variability were little changed. Double fasciculations in which the waveforms of the two potentials were the same occurred in both conditions. The intervals were in two bands: an early band with 4-10 ms intervals showed identical waveforms of the two potentials, indicating the region of generation was the same. A second band of double fasciculation occurred in the tibialis anterior at an interval of 30-50 ms. Here, the first fasciculation waveform was variable in shape but the second fasciculation was the same on each occasion, suggesting reactivation of the fasciculation via the F-wave route. Double fasciculations in which the second discharge was different from the first had flat time-interval histograms, indicating no interaction between different fasciculations. In conclusion, benign and malignant fasciculations are not distinguishable on the basis of waveform; highly complex fasciculation potentials can be seen in both conditions. Fasciculation firing rate and the frequency of double fasciculations increases in amyotrophic lateral sclerosis when there is a marked lower motor neuron abnormality. PMID- 20959308 TI - The decrease of beta-synuclein in cortical brain areas defines a molecular subgroup of dementia with Lewy bodies. AB - Lewy body diseases include dementia with Lewy bodies and Parkinson's disease. Whereas dementia with Lewy bodies and Parkinson's disease can be distinguished as separate clinical entities, the pathological picture is very often identical. alpha-synuclein aggregation is a key event in the pathogenesis of Lewy body diseases and beta-synuclein inhibits alpha-synuclein aggregation in vitro and in vivo. Recently, beta-synuclein has been shown to interact directly with alpha synuclein, regulating its functionality and preventing its oligomerization. In this study, we analysed the expression of two beta-synuclein transcript variants and the main alpha-synuclein transcript SNCA140, in frozen samples of three areas from brains of patients with (i) pure diffuse Lewy body pathology; (ii) pure Alzheimer's disease pathology; (iii) diffuse Lewy body pathology and concomitant Alzheimer's disease pathology and (iv) controls. Relative messenger RNA expression was determined by real-time polymerase chain reaction, expression changes were evaluated by the DeltaDeltaC(t) method and messenger RNA expression data were confirmed at the protein level. A drastic diminution of beta-synuclein expression was observed in cortical areas of all samples that presented neuropathological features corresponding to pure diffuse Lewy body pathology and the clinical phenotype of dementia with Lewy bodies, but not in those with neuropathological features corresponding to diffuse Lewy body pathology and concomitant Alzheimer's disease pathology or the clinical phenotype of Parkinson's disease with dementia. The correlation of expression data with the clinical phenotype and neuropathological diagnosis of the patients suggested the existence of a specific molecular subtype of dementia with Lewy bodies, characterized by a strong decrease of beta-synuclein in the frontal and temporal cortices. Furthermore, our findings provide new insights into the pathogenesis of Lewy body diseases that may be important for the understanding of molecular mechanisms involved in these complex diseases. PMID- 20959309 TI - Distinct structural changes underpin clinical phenotypes in patients with Gilles de la Tourette syndrome. AB - Gilles de la Tourette syndrome is a childhood-onset neurodevelopmental disorder characterized by tics that are often associated with psychiatric co-morbidities. The clinical heterogeneity of Gilles de la Tourette syndrome has been attributed to the disturbance of functionally distinct cortico-striato-thalamo-cortical circuits, but this remains to be demonstrated. The aim of this study was to determine the structural correlates of the diversity of symptoms observed in Gilles de la Tourette syndrome. We examined 60 adult patients and 30 age- and gender-matched control subjects using cortical thickness measurement and 3 T high resolution T(1)-weighted images. Patients were divided into three clinical subgroups: (i) simple tics; (ii) simple and complex tics and (iii) tics with associated obsessive-compulsive disorders. Patients with Gilles de la Tourette syndrome had reduced cortical thickness in motor, premotor, prefrontal and lateral orbito-frontal cortical areas. The severity of tics was assessed using the Yale Global Tic Severity Scale and correlated negatively with cortical thinning in these regions, as well as in parietal and temporal cortices. The pattern of cortical thinning differed among the clinical subgroups of patients. In patients with simple tics, cortical thinning was mostly found in primary motor regions. In patients with simple and complex tics, thinning extended into larger premotor, prefrontal and parietal regions. In patients with associated obsessive compulsive disorders, there was a trend for reduced cortical thickness in the anterior cingulate cortex and hippocampal morphology was altered. In this clinical subgroup, scores on the Yale-Brown Obsessive-Compulsive Scale correlated negatively with cortical thickness in the anterior cingulate cortex and positively in medial premotor regions. These data support the hypothesis that different symptom dimensions in Gilles de la Tourette syndrome are associated with dysfunction of distinct cortical areas and have clear implications for the current neuroanatomical model of this syndrome. PMID- 20959310 TI - What is the role of the uncinate fasciculus? Surgical removal and proper name retrieval. AB - The functional role of the uncinate fasciculus is still a matter of debate. We examined 44 patients submitted to awake surgery for removal of a left frontal or temporal glioma. In 18 patients, the removal included the uncinate fasciculus. We compared patients with or without removal on a series of neuropsychological tasks, performed at different time intervals: pre-surgery, in the first week after surgery and 3 months after surgery. Functional magnetic resonance and diffusion tensor imaging, fibre-tracking techniques were performed before surgery. At the last examination, patients with uncinate removal were significantly impaired in naming of famous faces and objects as compared with patients without removal. We further divided patients according to the site of the tumour (either frontal or temporal). At the follow-up, patients with a temporal glioma who underwent uncinate removal had the worst loss of performance in famous face naming. In addition, on the same task, the group with a frontal glioma that underwent resection of the frontal part of the uncinate performed significantly worse than the group with a frontal glioma but without uncinate removal. In conclusion, the resection of the uncinate fasciculus, in its frontal or temporal part, has long-lasting consequences for famous face naming. We suggest that this fibre tract is part of a circuitry involved in the retrieval of word form for proper names. Retrieval of conceptual knowledge was intact. PMID- 20959311 TI - Effect of acupuncture on assisted reproduction treatment outcomes. AB - BACKGROUND: Acupuncture has recently been used as a complementary technique in the management of infertility. It has physiological and psychological effects and may be considered an alternative for stress reduction in women undergoing infertility treatments. OBJECTIVE: To examine the hypothesis that acupuncture treatment may increase the pregnancy rate in patients undergoing intracytoplasmic sperm injection cycles. METHODS: Patients enrolled in the study were stratified according to age and randomised to either a control group (n=208) or acupuncture group, (n=208). The pregnancy, implantation and abortion rates of the two groups were compared. RESULTS: No influence of acupuncture treatment on clinical outcomes was seen; however, when cycles in which the causes of infertility were exclusively tubal-uterine or idiopathic were evaluated separately, a positive influence of acupuncture on pregnancy (OR=5.15, 95% CI 1.03 to 34.5; p=0.048) was noted. Moreover, trends toward an increase in implantation were seen when acupuncture was performed (regression coefficient: 0.645; p=0.092). CONCLUSION: The results suggest that acupuncture treatment had no influence when performed immediately before and immediately after embryo transfer, on clinical outcomes overall. In a subgroup analysis, when the embryo was not affected by an ovarian or seminal influence, a benefit was noted. PMID- 20959313 TI - Towards a safer healthcare system. Introduction. PMID- 20959312 TI - Acupuncture reduces crying in infants with infantile colic: a randomised, controlled, blind clinical study. AB - OBJECTIVE: To investigate whether acupuncture reduces the duration and intensity of crying in infants with colic. Patients and methods 90 otherwise healthy infants, 2-8 weeks old, with infantile colic were randomised in this controlled blind study. 81 completed a structured programme consisting of six visits during 3 weeks to an acupuncture clinic in Sweden. Parents blinded to the allocation of their children met a blinded nurse. The infant was subsequently given to another nurse in a separate room, who handled all infants similarly except that infants allocated to receive acupuncture were given minimal, standardised acupuncture for 2 s in LI4. RESULTS: There was a difference (p=0.034) favouring the acupuncture group in the time which passed from inclusion until the infant no longer met the criteria for colic. The duration of fussing was lower in the acupuncture group the first (74 vs 129 min; p=0.029) and second week (71 vs 102 min; p=0.047) as well as the duration of colicky crying in the second intervention week (9 vs 13 min; p=0.046) was lower in the acupuncture group. The total duration of fussing, crying and colicky crying (TC) was lower in the acupuncture group during the first (193 vs 225 min; p=0.025) and the second intervention week (164 vs 188 min; p=0.016). The relative difference from baseline throughout the intervention weeks showed differences between groups for fussing in the first week (22 vs 6 min; p=0.028), for colicky crying in the second week (92 vs 73 min; p=0.041) and for TC in the second week (44 vs 29 min; p=0.024), demonstrating favour towards the acupuncture group. CONCLUSIONS: Minimal acupuncture shortened the duration and reduced the intensity of crying in infants with colic. Further research using different acupuncture points, needle techniques and intervals between treatments is required. PMID- 20959314 TI - Transitions from neonatal intensive care unit to ambulatory care: description and evaluation of the proactive risk assessment process. AB - OBJECTIVE: Over 20,000 US neonates annually make the potentially risky transition from the neonatal intensive care unit (NICU) to the care of primary care physicians whom they have never met. The authors describe the use of Health Care Failure Modes and Effects Analysis (HFMEA) to proactively assess the risks of this transition, and present a qualitative evaluation of the HFMEA process. METHODS: The HFMEA team, led by a patient safety specialist, included neonatologists, general paediatricians, nurses, a social worker and a parent of a premature infant. The authors conducted a facilitated debriefing session with the team, interviews of key informants, and a content analysis of documentation generated throughout the project. RESULTS: The authors identified 40 high-risk failure modes and 75 associated high-risk causes. Clear thematic categories included poor communication among care providers in the hospital, between care providers and parents/care givers, or between the hospital-based and ambulatory care providers, as well as a lack of knowledge and skills among community-based providers to care for fragile infants. Evaluation of the HFMEA process revealed a high level of involvement, with over 250 h of professional time devoted to the process, agreement that the interaction itself was valuable and concerns about the limitations of the HFMEA method in capturing the complexity of the transition from NICU to ambulatory care. CONCLUSION: While HFMEA holds promise for improving the safety of care transitions, the full effort required to realise the potential benefit requires additional evaluation to confirm its value over less intensive means of achieving safer care transitions. PMID- 20959315 TI - Partial truths in the pursuit of patient safety. AB - The paper explores several issues in the form of partial truths that dominate current thinking as investigators continue their pursuit of patient safety. Among the partial truths examined-cast as bipolar orientations-are evidence-based medicine versus quality improvement, 'knowledge in the head' versus 'knowledge in the world', sharp end versus blunt end, reporting systems versus local knowledge, changing beliefs versus changing behaviour and system components versus system interdependencies. The paper provides a cautionary note regarding the downside of creating dichotomies that tend to assert too much. An enhanced understanding of patient safety will likely result from rising above bipolar orientations and valuing them as partial approaches to a complex and dynamic problem space. PMID- 20959316 TI - Discrepancies between medication orders and infusion pump programming in a paediatric intensive care unit. AB - BACKGROUND: Errors and the incorrect use of medications are significant sources of risk and harm to children in US hospitals. The risk associated with medication infusions has led to recommendations for the adoption of technologies including computer order physician entry (CPOE) and 'smart' infusion pumps despite a paucity of evidence demonstrating the ability of these technologies to reduce harm to paediatric inpatients. OBJECTIVE: To measure discrepancies between medication orders for infusions entered into a CPOE system and the medication being infused as measured by the programmed settings of the smart infusion pump within a paediatric intensive care unit. METHODS: This study used a prospective, observational design in a 30-bed paediatric intensive care unit. Data were simultaneously collected from the medication orders in the CPOE system and the bedside smart infusion pumps by trained observers. Analysis consisted of a line by-line comparison of order observation data with the pump observation data. CONCLUSIONS: Of 296 observations of medication infusions and 231 observations of intravenous fluid infusions, the frequency of discrepancies between orders entered and pumps programming ranged from 24.3% for observed medications to 42.4% for observed fluids. Anti-infectives (100%), concentrated electrolytes (46.7%) and anticoagulants (46.2%) were associated with greatest discrepancy between orders and programmed doses. PMID- 20959317 TI - Coping with different roles in intensive care nursing: design implications for digital support. AB - OBJECTIVES: The aim of this study is to arrive at design implications for the digital support of intensive care nurses, with a focus on supporting them in their roles as practitioners, as scholars and in their human response to their work. METHODS: Seventeen nurses from six different Dutch hospitals were interviewed using a newly developed digital prototype designed around these roles. The nurses were questioned about the suitability of four functions: two supporting the practitioner role ('web of actors' and 'timeline and notes'); one supporting the scholar role ('assessment of the patient'); and one supporting the role of human ('perception of the shift'). The remarks of the nurses about these functions were grouped by their relevance to design (ie, the perceived added value of the function, suggestions for other uses, and the perceived negative impact of the function) and by topic. RESULTS: A total of 23 topics emerged: nine topics described the added values of the functions, nine were suggestions for other uses, and five concerned the negative impact of the functions as perceived by the participants. The main points of each topic were summarised, resulting in 23 design implications for digital role-based support. PMID- 20959318 TI - Simulation and patient safety: evaluative checklists for central venous catheter insertion. AB - In the advent of concerns for patient safety, simulation training is emerging as a method to train healthcare providers to perform invasive procedures such as central venous catheter (CVC) insertion while minimising harmful complications to the patient. New technologies in medical simulation have begun to shift research attention to the performance component of clinical competency. Accurate assessment of healthcare provider competence is a major priority in medical education necessitating the development of valid and reliable assessment tools. In the past year alone, nine evaluative tools, both global rating scales and procedural checklists, have been published in the research literature to evaluate the insertion of CVCs. A review of the advantages of published evaluation tools helps inform users with regard to the critical components necessary for a checklist. Ease of use, ability to be completed by a non-expert, categorical breakdown of critical actions involved in CVC insertion and the need for a comprehensive stepwise procedural checklist are discussed. The development of an ideal checklist may improve future competency-based training and performance evaluation in the clinical setting. A more thorough understanding of the status of checklists as evaluation tools in assessing performance of invasive procedures will lead to better training protocols and ultimately to improved patient safety. PMID- 20959319 TI - Simulation, safety and surgery. AB - OBJECTIVES: This paper explores the place of simulation in contemporary healthcare education and training, highlighting the challenges of recreating complex clinical settings which can support the development of competent, rounded and caring practitioners, and address issues around human factors as well as technical skill. It frames the relationship between clinical and simulation-based practice as a mutually dependent, two-way process. DISCUSSION: According to this view, simulation is less like a photograph of clinical care than a painting of it a process that requires selection and interpretation. The paper presents simulation as a canvas on which to paint this picture. To be effective, simulation must mirror the essentials of a clinical setting without reproducing every detail. After highlighting key issues with current approaches to simulation, the paper considers how authenticity and perceived realism can be heightened through innovative uses of technology and design, putting forward a conceptual framework based on the notion of 'circles of focus.' The paper then outlines the concept of Distributed Simulation, using low-cost, portable yet immersive environments to address limitations of access to dedicated facilities. CONCLUSION: The paper concludes by considering theoretical and practical implications of these innovations, focussing especially on surgery and other craft specialties. PMID- 20959320 TI - A new way of relating: perceptions associated with a team-based error disclosure simulation intervention. AB - BACKGROUND: Despite the call for open and team-based approaches to error disclosure, the participation beyond physicians and managers is not a common practice in health care settings. Moreover, within the growing literature base on error disclosure, team-based error disclosure is an emerging concept. To address this knowledge gap, a study was undertaken to explore the perceptions associated with an educational simulation intervention for team-based error disclosure. METHODS: A qualitative study that involved analysis of data obtained from semi structured interviews with a sample of 6 physicians, 6 surgeons, and 12 nurses recruited from the three participating hospitals. RESULTS: Perceptions from study participants elucidated a tension between team-based error disclosure as an unrealistic, forced practice and as a realistic, beneficial practice. This tension was highly contextual and differentiated by study participants' perceptions of the nature of the error; patient's preferences; and prevailing cultural and professional norms. Regardless of the view, study participants described the simulation experience as a new way of relating that departed from existing practice. CONCLUSIONS: Study findings revealed that a team-based approach to disclosure is not realistic or necessary for all error situations, such as when the error involves a single discipline. However, when the error involves a variety of health care professionals interacting with the patient, a team-based approach is beneficial to them and the patient. Further work is required by researchers and administrators to develop and test out interventions that enable health care professionals to practice team-based error disclosure in a safe and supported environment. PMID- 20959321 TI - Considerations for the design of safe and effective consumer health IT applications in the home. AB - INTRODUCTION: Consumer health IT applications have the potential to improve quality, safety and efficiency of consumers' interactions with the healthcare system. Yet little attention has been paid to human factors and ergonomics in the design of consumer health IT, potentially limiting the ability of health IT to achieve these goals. This paper presents the results of an analysis of human factors and ergonomics issues encountered by five projects during the design and implementation of home-based consumer health IT applications. METHODS: Agency for Healthcare Research and Quality-funded consumer health IT research projects, where patients used the IT applications in their homes, were reviewed. Project documents and discussions with project teams were analysed to identify human factors and ergonomic issues considered or addressed by project teams. The analysis focused on system design and design processes used as well as training, implementation and use of the IT intervention. RESULTS: A broad range of consumer health IT applications and diverse set of human factors and ergonomics issues were identified. The design and implementation processes used resulted in poor fit with some patients' healthcare tasks and the home environment and, in some cases, resulted in lack of use. Clinician interaction with patients and the information provided through health IT applications appeared to positively influence adoption and use. CONCLUSIONS: Consumer health IT application design would benefit from the use of human factors and ergonomics design and evaluation methods. Considering the context in which home-based consumer health IT applications are used will likely affect the ability of these applications to positively impact the quality, safety and efficiency of patient care. PMID- 20959322 TI - A new sociotechnical model for studying health information technology in complex adaptive healthcare systems. AB - BACKGROUND: Conceptual models have been developed to address challenges inherent in studying health information technology (HIT). METHOD: This manuscript introduces an eight-dimensional model specifically designed to address the sociotechnical challenges involved in design, development, implementation, use and evaluation of HIT within complex adaptive healthcare systems. DISCUSSION: The eight dimensions are not independent, sequential or hierarchical, but rather are interdependent and inter-related concepts similar to compositions of other complex adaptive systems. Hardware and software computing infrastructure refers to equipment and software used to power, support and operate clinical applications and devices. Clinical content refers to textual or numeric data and images that constitute the 'language' of clinical applications. The human- computer interface includes all aspects of the computer that users can see, touch or hear as they interact with it. People refers to everyone who interacts in some way with the system, from developer to end user, including potential patient users. Workflow and communication are the processes or steps involved in ensuring that patient care tasks are carried out effectively. Two additional dimensions of the model are internal organisational features (eg, policies, procedures and culture) and external rules and regulations, both of which may facilitate or constrain many aspects of the preceding dimensions. The final dimension is measurement and monitoring, which refers to the process of measuring and evaluating both intended and unintended consequences of HIT implementation and use. We illustrate how our model has been successfully applied in real-world complex adaptive settings to understand and improve HIT applications at various stages of development and implementation. PMID- 20959323 TI - A comparative study of safety climate differences in healthcare and the petroleum industry. AB - AIM: The aim of this article is to compare safety climate in healthcare and the petroleum industry by collecting empirical evidence of differences between the two sectors. METHODS: The Hospital Survey on Patient Safety Culture (HSOPSC) is used to measure the safety climate in two organisations operating in the two different sectors: (1) a large Norwegian university hospital offering a wide range of hospital services and (2) a large Norwegian petroleum company producing oil and gas worldwide. RESULTS AND DISCUSSION: Statistical analyses supported the expected hypotheses that safety climate is positively related to outcome measures and that the level on safety climate and outcome measures are generally higher in the petroleum sector. Empirical findings indicate that healthcare should learn from the petroleum industry regarding safety improvement efforts, and the implication of this is discussed in the paper. PMID- 20959324 TI - Patient safety and incident reporting: survey of Italian healthcare workers. AB - BACKGROUND: Incident-reporting systems (IRS) are tools that allow front-line healthcare workers to voluntary report adverse events and near misses. The WHO has released guidelines that outline the basic principles on how to design and implement successful IRS in healthcare organisations. METHODS: A written survey was administered with an assisted self-assessment technique to a representative sample of healthcare workers in Italian hospitals with and without IRS. Data were collected using two different 16-item questionnaires. The questionnaires targeted two issues: (1) workers' experience of patient safety incidents and (2) their expectations on incident reporting. RESULTS: 70% of respondents confirmed involvement in a patient safety incident, but only 40% utilised an IRS to formally report the event. The data indicate that information regarding patient safety incidents is not communicated throughout the entire organisation. CONCLUSIONS: Research findings are consistent with the available evidence on healthcare workers' experience of patient safety incidents. PMID- 20959325 TI - Gadolinium and systemic fibrosis: guilt by association. PMID- 20959326 TI - State-of-the-art: rheumatoid arthritis. AB - The understanding of the pathogenesis and optimal therapeutics for rheumatoid arthritis (RA) has advanced remarkably over the last decade. This review highlights these key advances, particularly the outcomes of genome-wide scans which have provided an increasingly robust appraisal of the complex genetics that underpin RA. Such observations are placed in pathogenetic context, particularly concerning the breach of tolerance that presages synovitis and the mechanisms that subserve chronicity. The key therapeutic strategies and treatment agents, both conventional and biological, now available to effectively manage the disease are described. Throughout the review, emphasis is placed on unanswered questions and challenges in this exciting field. PMID- 20959327 TI - NFkappaB activation and stimulation of chemokine production in normal human macrophages by the gadolinium-based magnetic resonance contrast agent Omniscan: possible role in the pathogenesis of nephrogenic systemic fibrosis. AB - OBJECTIVE: Nephrogenic systemic fibrosis (NSF) is a generalised fibrotic disorder occurring in certain individuals with renal insufficiency exposed to gadolinium based contrast agents (GdBCA) for MRI. Histopathological examination of affected tissues shows increased numbers of activated macrophages. To elucidate the mechanisms responsible for macrophage activation, the effects of the GdBCA Omniscan on normal human macrophage global gene expression, chemokine production and nuclear factor kappaB (NFkappaB) activation was examined. METHODS: Normal human monocyte-derived macrophages were incubated with Omniscan (50 mM) and their gene expression analysed by microarrays and real-time PCR. Macrophage chemokine production was assayed by multiplex ELISA. NFkappaB activation was assessed by NFkappaB nuclear localisation and quantitation of intracellular levels of inducible nitric oxide synthase (iNOS) protein. A specific cell-permeable NFkappaB peptide inhibitor was used to abrogate NFkappaB stimulation of chemokine and iNOS protein levels. CCL8/MCP-2 in affected skin of patients with NSF was examined by indirect immunofluorescence. RESULTS: Omniscan caused a profound change in the transcriptome of differentiated human normal macrophages in vitro, including a large increase in the expression of genes encoding CC and CXC chemokines. It induced rapid nuclear localisation of NFkappaB and stimulation of iNOS protein levels and chemokine production which were blocked by an NFkappaB inhibitory peptide. CCL8/MCP-2, the most upregulated chemokine following in vitro macrophage exposure to Omniscan, was strongly increased in NSF-affected skin. CONCLUSION: The GdBCA Omniscan induces potent stimulation of macrophage gene expression, NFkappaB activation and increased NFkappaB-mediated production of CC and CXC chemokines and iNOS. These alterations may play a crucial role in the pathogenesis of NSF. PMID- 20959328 TI - Differences in disability as measured by the Health Assessment Questionnaire between patients with and without digital ulcers in systemic sclerosis: a post hoc analysis of pooled data from two randomised controlled trials in digital ulcers using bosentan. PMID- 20959329 TI - Obstructive sleep apnoea and perioperative complications in bariatric patients. AB - BACKGROUND: The objective of this study was to determine the relationship between perioperative complications and the severity of obstructive sleep apnoea (OSA) in patients undergoing bariatric surgery who had undergone preoperative polysomnography (PSG). METHODS: The records of 797 patients, age >18 yr, who underwent bariatric operations (442 open and 355 laparoscopic procedures) at Mayo Clinic and were assessed before operation by PSG, were reviewed retrospectively. OSA was quantified using the apnoea-hypopnoea index (AHI) as none (<= 4), mild (5 15), moderate (16-30), and severe (>= 31). Pulmonary, surgical, and 'other' complications within the first 30 postoperative days were analysed according to OSA severity. Logistic regression was used to assess the multivariable association of OSA, age, sex, BMI, and surgical approach with postoperative complications. RESULTS: Most patients with OSA (93%) received perioperative positive airway pressure therapy, and all patients were closely monitored after operation with pulse oximetry on either regular nursing floors or in intensive or intermediate care units. At least one postoperative complication occurred in 259 patients (33%). In a multivariable model, the overall complication rate was increased with open procedures compared with laparoscopic. In addition, increased BMI and age were associated with increased likelihood of pulmonary and other complications. Complication rates were not associated with OSA severity. CONCLUSIONS: In obese patients evaluated before operation by PSG before bariatric surgery and managed accordingly, the severity of OSA, as assessed by the AHI, was not associated with the rate of perioperative complications. These results cannot determine whether unrecognized and untreated OSA increases risk. PMID- 20959330 TI - Assessment of severity of pulmonary regurgitation. PMID- 20959331 TI - Evidence of children's vulnerability to radiation in the context of radiological/nuclear events and considerations for emergency response. AB - International organisations, such as International Atomic Energy Agency, United Nations Scientific Committee on the Effects of Atomic Radiation and World Health Organisation, together with committees of experts such as Biological Effects of Ionising Radiation and Committee on Medical Aspects of Radiation in the Environment, have assessed the effects of radiation on large exposed populations (Chernobyl accident, and Hiroshima/Nagasaki atomic bombings) and on nuclear energy workers and people living near nuclear facilities. Childhood and in utero exposure to moderate and high levels of ionizing radiation, such as those experienced during the atomic bombings of Japan, or from radiotherapy, is an established cause of leukaemia and solid cancer. There is no evidence of increase in solid cancers (excluding thyroid cancer) or leukaemia in the children from Chernobyl, and no evident link between worker's exposure to radiation and leukaemia in their offspring or with the presence of leukaemia clusters around nuclear power plants. It has also not been possible to demonstrate the evidence of radiation hereditary effects in human populations. In accordance with international guidance, Canadian Nuclear Safety Commission recommends optimisation of protection strategies to reduce doses to children. The development of credible radiological/nuclear event scenarios would assist in identifying probable sources of radioactivity and pathways of exposure for children. Such scenarios should then be used to identify protection strategies appropriate for children. PMID- 20959332 TI - Monitoring on board spacecraft by means of passive detectors. AB - To estimate the radiation risk of astronauts during space missions, it is necessary to measure dose characteristics in various compartments of the spacecraft; this knowledge can be further used for estimating the health hazard in planned missions. This contribution presents results obtained during several missions on board the International Space Station (ISS) during 2005-09. A combination of thermoluminescent and plastic nuclear track detectors was used to measure the absorbed dose and dose equivalent. These passive detectors have several advantages, especially small dimensions, which enabled their placement at various locations in different compartments inside the ISS or inside the phantom. Variation of dosimetric quantities with the phase of the solar cycle and the position inside the ISS is discussed. PMID- 20959333 TI - Variability of radioiodine measurements in the thyroid. AB - Monte Carlo simulations were carried out to study the response of a thyroid monitor for measuring intake activities of (125)I and (131)I. The aim of the study was 3-fold: to cross-validate the Monte Carlo simulation programs, to study the response of the detector using different phantoms and to study the effects of anatomical variations. Simulations were performed using the Swiss reference phantom and several voxelised phantoms. Determining the position of the thyroid is crucial for an accurate determination of radiological risks. The detector response using the Swiss reference phantom was in fairly good agreement with the response obtained using adult voxelised phantoms for (131)I, but should be revised for a better calibration for (125)I and for any measurements taken on paediatric patients. PMID- 20959334 TI - Neutron response characterisation of an OSL neutron dosemeter. AB - The neutron response was characterised for Al(2)O(3):C material coated with (6)Li(2)CO(3). Al(2)O(3):C material, an optically stimulated luminescent (OSL) dosemeter, which is sensitive to both photons and beta radiation but is mostly insensitive to neutron radiation. The Al(2)O(3):C material was coated with (6)Li(2)CO(3) to create a material sensitive to neutrons, beta and photon radiation. In this paper, the neutron response of this new OSL material (OSLN) will be compared with various other neutron measurement technologies in laboratory and field environments. PMID- 20959335 TI - IAEA regional intercomparison of in vivo measurements of 131I in the thyroid: the Latin American and Caribbean experience. AB - An in vivo intercomparison exercise, organised in the scope of the IAEA Regional Latin American (RLA) Project 9066, was carried out in 2009 aimed to harmonise measurement procedures on the measurement of (131)I in the thyroid among Latin American and Caribbean countries. The exercise consisted in the measurement of an anthropomorphic thyroid phantom spiked with a certified source of (133)Ba. The phantom was supplied by the In Vivo Monitoring Laboratory of Institute for Radiation Protection and Dosimetry (IRD) to 17 Institutions from 12 countries of the regions. Among these, 13 Institutions from 10 countries returned their measurement results as well as a standard report form containing detailed information about their respective counting facilities. All participants reported activities within an acceptable range, considering American National Standard Institute (ANSI) limits. Uncertainties varied from 0.04 to 12.9 %. Although results show that the general performance was acceptable in terms of accuracy, the need for additional action towards the standardisation of uncertainty estimation in this type of measurement in the region should be highlighted. PMID- 20959336 TI - Exposure of workers in Tusnica coal mine. AB - The aim of this paper is to identify potential exposure of the workers in the coal mine Tusnica. The results of the investigation showed increased activity of brown coal up to 1060 +/- 88 Bq kg(-1) for (238)U, 976 +/- 30 Bq kg(-1) for (226)Ra and 118 +/- 31 Bq kg(-1) for (232)Th. Dose rate measurements ranged from 0.07 to 0.25 uSv h(-1). The annual effective dose, taking into account external exposure to ambient gamma radiation and internal exposure due to inhalation of the resuspended dust, would be 1.6 mSv a(-1). The results presented lead to the conclusion that Tusnica coal mine contains brown coal with significant radioactivity, indicating that the working hours in the area should be regulated and the use of respiratory protective equipment is obligatory. PMID- 20959337 TI - Practical low dose limits for passive personal dosemeters and the implications for uncertainties close to the limit of detection. AB - Recent years have seen the increasing use of passive dosemeters that have high sensitivities and, in laboratory conditions, detection limits of <10 uSv. However, in real operational use the detection limits will be markedly higher, because a large fraction of the accrued dose will be due to natural background, and this must be subtracted in order to obtain the desired occupational dose. No matter how well known the natural background is, the measurement uncertainty on doses of a few tens of microsieverts will be large. Individual monitoring services need to recognise this and manage the expectations of their clients by providing sufficient information. PMID- 20959338 TI - The new EC technical recommendations for monitoring individuals occupationally exposed to external radiation. AB - The purpose of the European Commission technical recommendations (TR) for monitoring individuals occupationally exposed to external radiation is to provide guidance on those aspects of the implementation of the European Union Parliament and Council Directives directly related to individual monitoring of external radiation, and to encourage harmonisation thereof. They are mainly aimed at the management and staff of IM services but also at manufacturers, laboratories supplying type-testing services, national authorities trying to harmonise approval procedures, and government bodies to harmonise regulations and guidance. The TR main topics are: objectives and aims of IM for external radiation; dosimetry concepts; accuracy requirements; calibration, type testing and performance testing; approval procedures; quality assurance and quality control; and dose record keeping. Attention is paid to particular aspects, such as wide energy ranges for the use of personal dosemeters, pulsed fields and non-charged particle equilibrium; and use of active personal dosemeters. The TR give proposals towards achieving harmonisation in IM and the eventual mutual recognition of services and of dose results. PMID- 20959339 TI - Design and testing of a new stand for the BOMAB family of phantoms. AB - A new stand has been designed to support the Bottle Manikin Absorber Phantoms when the phantoms are counted in the vertical position in a whole-body counter. The stand previously used by the Human Monitoring Laboratory was constructed from metal and was heavy to transport and making height adjustments to accommodate different phantom sizes was very time consuming. The new stand is constructed from lightweight plastic materials and allows easy height adjustments to accommodate different phantom sizes while supporting the weight of the phantoms. The stand was evaluated inside a whole-body counter at a nuclear-generating station and met all operational requirements for accessibility and ease of use. PMID- 20959340 TI - Dosimetry on sub-cellular level for intracellular incorporated auger-electron emitting radionuclides: a comparison of Monte Carlo simulations and analytic calculations. AB - A quantitative dosimetric comparison was performed between Monte Carlo (MC) simulations and analytic calculations at the (sub) cellular level (V79 cells) for four nucleus-incorporated radiochemicals ((125)I/(123)I/(77)Br-UdR and A (125)IP) and two radiochemicals that localised mainly in the cytoplasm of cells ((125)I dihydrorhodamine and Na(2)(51)CrO(4)). A microscopic investigation around the decay site of the three DNA-incorporated radionuclides ((125)I/(123)I/(77)Br-UdR) was also carried out. On the whole, deviations between MC and analytic calculations for the absorbed dose and dose rate to the cell nucleus were within ~10%. The dose rate to the nucleus for the radiochemicals that mainly localised in the cytoplasm was greater than that for the nucleus-incorporated ones. Also evident was that the dose rate to the nucleus was approximately the same for the three DNA-incorporated radiochemicals. In contrast to the small differences found between MC and analytic calculations for the (average) absorbed dose to the nucleus, the dosimetric analysis at the microscopic level for the three DNA incorporated radionuclides showed that the two computational approaches lead to a completely different energy deposition pattern around the decay site. PMID- 20959341 TI - A method to characterise site, urban and regional ambient background radiation. AB - Control dosemeters are routinely provided to customers to monitor the background radiation so that it can be subtracted from the gross response of the dosemeter to arrive at the occupational dose. Landauer, the largest dosimetry processor in the world with subsidiaries in Australia, Brazil, China, France, Japan, Mexico and the UK, has clients in approximately 130 countries. The Glenwood facility processes over 1.1 million controls per year. This network of clients around the world provides a unique ability to monitor the world's ambient background radiation. Control data can be mined to provide useful historical information regarding ambient background rates and provide a historical baseline for geographical areas. Historical baseline can be used to provide site or region specific background subtraction values, document the variation in ambient background radiation around a client's site or provide a baseline for measuring the efficiency of clean-up efforts in urban areas after a dirty bomb detonation. PMID- 20959342 TI - Revision of the Euratom Basic Safety Standards Directive--current status. AB - The European Commission is currently developing a revised Euratom Basic Safety Standards (BSS) Directive covering two major objectives: the consolidation of existing Euratom Radiation Protection legislation and the revision of the Euratom BSS. The consolidation will merge the following five Directives into one single Directive: the BSS Directive, the Medical Exposures Directive, the Public Information Directive, the Outside Workers Directive and the Directive on the Control of high-activity sealed radioactive sources and orphan sources. The revision of the Euratom BSS will take account of the latest recommendations by the International Commission on Radiological Protection and shall improve clarity of the requirements where appropriate. It is planned to introduce more binding requirements on natural radiation sources, on criteria for exemption and clearance, and on the cooperation between Member States for emergency planning and response. The provisions for regulatory control of planned exposure situations foresee a graded approach commensurate to the magnitude and likelihood of exposures from a practice. Finally, the new BSS shall take account of recent scientific developments. One additional goal is to achieve greater harmonisation between the Euratom BSS and the international BSS. While the requirements on the protection of workers, apprentices and students remain nearly unchanged, the revised BSS will clarify the roles and responsibilities of services and experts involved in technical and practical aspects of radiation protection, such as the occupational health services, the dosimetry services, the radiation protection expert and the medical physics expert. The requirements in the BSS on individual monitoring of category A workers remain unchanged, but the existing guidance on individual monitoring was revised and updated--the technical recommendations for monitoring individuals occupationally exposed to external radiation are published by the European Commission. This paper summarises the current status of the revision of the Euratom BSS Directive. PMID- 20959343 TI - Trends in heart failure care: has the incident diagnosis of heart failure shifted from the hospital to the emergency department and outpatient clinics? AB - AIMS: Studies of heart failure (HF) incidence and prevalence frequently rely on hospitalization to identify patients. Our objective was to describe the incidence, prevalence, or outcomes for HF patients diagnosed in the outpatient or emergency department (ED) setting. METHODS AND RESULTS: In a population-based study of 82,323 HF patients in a single-payer health-care system in Alberta, Canada from 1999 to 2007, we examined trends over time and clinical outcomes. Heart failure patients were first diagnosed in a general outpatient clinic (45.7%), a specialty outpatient clinic (4.0%), the ED (13.7%), or in hospital (36.6%). From years 2000 to 2006, the age-standardized incidence (per 100 000 population) decreased from 538 to 403, whereas the overall prevalence increased from 1585 to 2510. One-year mortality was significantly different among patients first diagnosed in a general outpatient clinic (6.6%), a specialty outpatient clinic (7.5%), ED (19.1%), and hospital (29.8%). Patients initially diagnosed at the time of hospitalization had the fewest median days alive and out of hospital [347, inter-quartile range (IQR): 136-363] over the next year compared with patients in the ED (354, IQR 313-365), specialty outpatient clinic (365, IQR 355 365), and general outpatient clinics (365, IQR: 359-365, P < 0.0001). Patients in the ED had the highest rate of subsequent ED visits, and all-cause, cardiovascular, or HF hospitalization. CONCLUSIONS: Over time, more patients were diagnosed as outpatients compared with a hospital setting. The trends observed in incidence, prevalence, and outcomes for patients with HF differ substantially depending on the location of initial diagnosis. Additionally, efforts to study patients with HF in the ED should be a priority. PMID- 20959344 TI - The effect of diabetes on incidence and mortality in end-stage renal disease in Germany. AB - BACKGROUND: We aimed to examine the epidemiology and mortality risk of patients with incident end-stage renal disease (ESRD) in diabetic and non-diabetic individuals and to determine differences between sexes. METHODS: We used the claims data of a statutory health insurance company. Patients aged 30 years and older who started dialysis or had pre-emptive kidney transplantation between 1 April 2006 and 7 October 2008 were included. We estimated incidence rates of ESRD according to diabetes status, sex and age as well as relative and attributable risks due to diabetes. Using Cox regression, we studied survival and estimated time-dependent hazard ratios (HR). RESULTS: We included 623 patients with incident ESRD (n = 254 had diabetes); 477 (76.6%) were male, and the mean age was 66.5 years. Standardized to the German population, incidences of ESRD in patients with and without diabetes were 157.9 and 25.6 per 100,000 person-years respectively (6.2-fold increased risk). The impact of diabetes on mortality was time-dependent. Diabetics had an increased mortality risk after the first year. An interaction of diabetes with time (per additional year of follow-up) was found in the whole population (HR 2.01, 95% CI 1.21-3.33) and in females (HR 3.27, 95% CI 1.03-10.39); however, males did not reach statistical significance (HR 1.78, 95% CI 0.99-3.18). The fixed baseline effect of diabetes in these models was non significant (HR ~ 0.7-0.8). CONCLUSIONS: Diabetes is an important risk factor for ESRD. We provide further evidence that the impact of diabetes on survival after ESRD is time-dependent and that differences between sexes might exist. PMID- 20959345 TI - Perceived barriers to guidelines in peritoneal dialysis. AB - BACKGROUND: Little is known regarding barriers to guideline adherence in the nephrology community. We set out to identify perceived barriers to evidence-based medicine (EBM) and measurement of continuous quality indicators (CQI) in an international cohort of peritoneal dialysis (PD) practitioners. METHODS: Subscribers to an online nephrology education site (Nephrology Now) were invited to participate in an online survey. Nephrology Now is a non-profit, monthly mailing list that highlights clinically relevant articles in nephrology. Four hundred and seventy-five physicians supplying PD care participated in an online survey assessing their use of EBM and CQI in their PD practice. Ordinal logistic regression was utilized to determine relationships between baseline characteristics and EBM and CQI practices. RESULTS: The majority of physicians were nephrologists (89.7%), and 50.4% worked in an academic centre. Respondents were from the following geographic regions: 13.5% Canadian, 24% American, 23.8% European, 4.4% Australian, 5.3% South American, 10.7% African and 12.2% Asian. Adherence to PD clinical practice guidelines were generally strong; however, lower adherence was associated with countries with lower healthcare expenditure, not using personal digital assistant (PDA), the longer the physician had been practising and smaller (< 20 patients per centre) PD practice. CONCLUSIONS: International variation in guideline adherence may be influenced by a country's healthcare expenditure, physician's PDA use and experience, and size of PD practice which may impact future guideline development and implementation. PMID- 20959346 TI - Focal segmental glomerulosclerosis as a complication of hepatitis B virus infection. AB - Human hepatitis B virus (HBV) is well known as a cause of membranous nephropathy (MN). While the association of HBV infection with MN is strong, data regarding its association with other glomerular diseases are conflicting. Here, we report a case of focal segmental glomerulosclerosis (FSGS) with HBV infection. In this case, we have found HBV-DNA in urinary podocytes by real-time PCR methods. After the administration of anti-viral therapy, FSGS improved, paralleling the decreased level of HBV-DNA in podocytes. The refractory FSGS induced by HBV could be effectively treated with appropriate anti-viral agents. PMID- 20959347 TI - Role of Sema4C in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. AB - BACKGROUND: The p38 mitogen-activated protein kinase (p38 MAPK) is an important intracellular signal transduction pathway involved in TGF-beta1-induced epithelial-mesenchymal transition (EMT). Sema4C, a member of the semaphorin family, was found to be essential for the activation of p38 MAPK. However, the role of Sema4C in promoting TGF-beta1-induced EMT is unclear. METHODS: Renal fibrosis was induced by 5/6 subtotal nephrectomy rat model. In vitro, Sema4C was induced in human proximal tubular epithelial cells (HKC) by treatment with TGF beta1, or was inhibited by siRNA or was over-expressed by Sema4C transfection. The selective p38 MAPK inhibitor, SB203580, was administered to inhibit the p38 pathway. The expression of Sema4C, the markers of EMT, p38 phosphorylation and fibronectin secretion were measured by western blotting, immunohistochemistry, immunocytochemistry or enzyme-linked immunosorbent assay. RESULTS: The expression of Sema4C increased in HKC cells that were treated with TGF-beta1. Knockdown of Sema4C potently inhibited phosphorylation of p38 MAPK and reversed TGF-beta1 induced EMT. Over-expression of Sema4C via Sema4C transfection elicited p38 MAPK phosphorylation and promoted EMT. The effects of Sema4C during EMT were blocked by a p38-specific inhibitor. In vivo, the expression of Sema4C increased in the tubular epithelia of 5/6-nephrectomized rats and human fibrotic renal tissue, and similar localization of phosphorylated p38 and Sema4C was demonstrated by immunohistochemistry on serial sections. CONCLUSIONS: Our findings suggest that Sema4C plays an important role in TGF-beta1-induced EMT through activation of p38 MAPK in proximal tubular epithelial cells. PMID- 20959348 TI - What about gr/gr deletions and male infertility? Systematic review and meta analysis. AB - BACKGROUND: The impact of gr/gr deletions on male fertility is unclear. These partial deletions of the AZFc region of the Y chromosome have been detected more frequently in infertile patients. However, few individual studies have demonstrated a statistically significant association. This study aims to quantify the strength of association between gr/gr deletions and male infertility, and to explore potential sources of heterogeneity, including ethnicity and geographical location. METHODS: Medline was searched up to 31 December 2009 for full articles investigating the prevalence of gr/gr deletions in infertile and control men. A pooled odds ratio (OR) was estimated by a random-effects model. Heterogeneity was assessed by the Cochran's Q test, and quantified by I(2) statistic. RESULTS: A total of 18 case-control studies, including 6388 cases and 6011 controls, met our inclusion criteria and showed that gr/gr deletions were present in 6.86% of cases and 4.69% of controls. The association between gr/gr deletions and infertility was significant (P < 0.001), with a pooled random-effects OR of 1.76 (1.21-2.66) for infertile men versus normozoospermic controls (13 studies). The test for heterogeneity among studies yielded a Q test P = 0.089 with I(2) value of 37%, indicating moderate heterogeneity. The association between gr/gr deletions and infertility was dependent on ethnicity and geographic region. CONCLUSIONS: Our meta-analysis comprising >12 000 men demonstrates that gr/gr deletions occur more frequently in infertile than control men. The association between gr/gr deletions and infertility varies according to ethnicity and geographic region, with an association reaching significance among Caucasian men, in Europe and the Western Pacific region. PMID- 20959349 TI - Epigenetics and the placenta. AB - BACKGROUND: The placenta is of utmost importance for intrauterine fetal development and growth. Deregulation of placentation can lead to adverse outcomes for both mother and fetus, e.g. gestational trophoblastic disease (GTD), pre eclampsia and fetal growth retardation. A significant factor in placental development and function is epigenetic regulation. METHODS: This review summarizes the current knowledge in the field of epigenetics in relation to placental development and function. Relevant studies were identified by searching PubMed, Medline and reference sections of all relevant studies and reviews. RESULTS: Epigenetic regulation of the placenta evolves during preimplantation development and further gestation. Epigenetic marks, like DNA methylation, histone modifications and non-coding RNAs, affect gene expression patterns. These expression patterns, including the important parent-of-origin-dependent gene expression resulting from genomic imprinting, play a pivotal role in proper fetal and placental development. Disturbed placental epigenetics has been demonstrated in cases of intrauterine growth retardation and small for gestational age, and also appears to be involved in the pathogenesis of pre-eclampsia and GTD. Several environmental effects have been investigated so far, e.g. ethanol, oxygen tension as well as the effect of several aspects of assisted reproduction technologies on placental epigenetics. CONCLUSIONS: Studies in both animals and humans have made it increasingly clear that proper epigenetic regulation of both imprinted and non imprinted genes is important in placental development. Its disturbance, which can be caused by various environmental factors, can lead to abnormal placental development and function with possible consequences for maternal morbidity, fetal development and disease susceptibility in later life. PMID- 20959350 TI - The role of mast cells and their mediators in reproduction, pregnancy and labour. AB - BACKGROUND: Mast cells (MCs) are the classical mediators of allergy, however, their importance in the development of innate and adaptive immune responses is increasingly being recognized. Herein, the present MC literature is summarized, with particular focus on studies of MCs in the endometrium and myometrium, and their involvement in fertility, implantation, pregnancy and labour. METHODS: Recent developments in MC biology were identified by systematic searches of PubMed, Medline and Google Scholar from 2000 to November 2009. To specifically examine the role of MCs in fertility and pregnancy, we then performed a systematic review of English literature cited in the PubMed, Medline and Google Scholar databases, but extended the search period, from 1980 to January 2010 RESULTS: MCs can respond to immunoglobulin E-independent innate immune stimuli and are present within the endometrium, with activation and release of mediators occurring prior to menstruation and in association with endometriosis. With respect to pregnancy, MCs are redundant during blastocyst implantation and although their mediators can induce myometrial contractility, there is no epidemiological link of preterm birth with allergy, suggesting a non-essential role or robust regulation. In males, MCs are present in the testes and are increased in oligo- and azoospermia, with MC mediators directly suppressing sperm motility in a potentially reversible manner. CONCLUSIONS: MCs are prevalent in the female and male reproductive tract. However, whether MCs are absolutely required for a successful pregnancy or are fundamental to reproductive pathology, and thereby a therapeutic target, remains to be determined. PMID- 20959351 TI - The telecardiology revolution: improving the management of cardiac disease in primary care. AB - Telecardiology allows for the remote specialist interpretation of electrocardiographic recordings via telephone transmission. It has the potential to change the way cardiac care is being delivered in the primary care setting. This review discusses the current status of cardiac care in the community, and highlights how telecardiology can help support general practitioners in the diagnosis and management of acute and chronic cardiac disease, as well as provide the potential for screening opportunities in particular patients at risk. Also reviewed is the success of recent trials of a telecardiology service in the north west of England. Thanks to developments in technology and ever decreasing costs, telecardiology has the potential to save time, money and lives. Telecardiology, it would seem, is set to revolutionize cardiac care in the community, making savings and bridging the gap between primary and secondary care. PMID- 20959352 TI - TARDBP gene mutations in south Italian patients with amyotrophic lateral sclerosis. PMID- 20959353 TI - Commentary: All is not what it seems: a systematic review and meta-analysis of quantitative interviewing tools to investigate self-reported HIV and STI associated behaviours in low- and middle-income countries. PMID- 20959354 TI - Fatherhood and incident prostate cancer in a prospective US cohort. AB - BACKGROUND: Fatherhood status has been hypothesized to affect prostate cancer risk but the current evidence is limited and contradictory. METHODS: We prospectively evaluated the relationship between offspring number and the risk of prostate cancer in 161,823 men enrolled in the National Institues of Health - American Association of Retired Persons Diet and Health Study. Participants were aged 50-71 years without a cancer diagnosis at baseline in 1995. Analysing 8134 cases of prostate cancer, Cox regression was used to estimate the association between offspring number and prostate cancer incidence while accounting for socio demographic and lifestyle characteristics. RESULTS: When examining the entire cohort, there was no relationship between fatherhood and incident prostate cancer [hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.86-1.02]. However, after stratifying for prostate cancer screening, prostate-specific antigen (PSA) unscreened childless men had a lower risk of prostate cancer (HR 0.73, 95% CI 0.58-0.91) compared with fathers due to the interaction between PSA screening and fatherhood (P for interaction < 0.01). A trend for the lower risk of prostate cancer among unscreened fathers compared with childless men was seen for low grade prostate cancer (HR 0.78, 95% CI 0.61-1.01), high-grade prostate cancer (HR 0.62, 95% CI 0.37-1.04) and even fatal prostate cancer (HR 0.28, 95% CI 0.07 1.12). The number of children fathered was not related to prostate cancer (P(trend) = 0.17). In addition, men's inability to sire female offspring showed a weak positive association with prostate cancer in the PSA unscreened study subjects. CONCLUSIONS: Our findings suggest fatherhood status and offspring gender is associated with a man's prostate cancer risk. PMID- 20959355 TI - Obesity in rheumatoid arthritis. AB - Obesity is a major threat for public health and its study has attracted significant attention in the general population, predominantly due to its association with significant metabolic and cardiovascular complications. In RA research, BMI is frequently reported as a demographical variable, but obesity, as such, has received little interest. This is surprising, in view of the clear associations of obesity with other arthritides, particularly OA, but also in view of the now-clear association of RA with increased cardiovascular morbidity and mortality. In this review, we summarize the studies that have looked into obesity in the RA population, evaluate their findings, identify knowledge gaps and propose directions for future research. We also pose a question of high clinical and research significance: is the use of BMI still a valid way of assessing obesity in RA? PMID- 20959356 TI - Rapidly progressive primary central nervous system vasculitis. AB - OBJECTIVE: To describe a subset of cases in a large cohort of patients with primary CNS vasculitis (PCNSV) who appear to have a rapidly progressive clinical course. METHOD: In the present study, we use our updated cohort of 131 consecutive patients with PCNSV seen over the 25-year period of 1983-2007 at Mayo Clinic, Rochester, MN, USA. The diagnosis of PCNSV was based on brain/spinal cord biopsy or cerebral angiography. The modified Rankin scale was used to identify rapidly progressive disease and included patients with Rankin scores indicating severe disability or death at diagnosis or within 6 months after the diagnosis. We compared patients with rapidly progressive disease to those without. RESULTS: Compared with the 120 patients without rapidly progressive vasculitis, the 11 patients with rapidly progressive vasculitis more frequently had paraparesis/quadriparesis at presentation, angiographic presence of bilateral, large-vessel vasculitis and MRI evidence of cerebral infarctions; those infarctions were more frequently multiple and bilateral, and more frequently involved both the cortex and subcortical regions on initial MRI. Granulomatous and/or necrotizing histopathological patterns of vasculitis were observed in patients with positive biopsies. CONCLUSION: Rapidly progressive PCNSV appears to form a subset of PCNSV at the worst end of the clinical spectrum of this vasculitis, characterized by bilateral, multiple, large cerebral vessel lesions and multiple CNS infarctions. PMID- 20959357 TI - Vacuum-assisted closure therapy: a novel treatment for wound healing in systemic sclerosis. PMID- 20959358 TI - Congenital hypothyroidism: managing the hinterland between fact and theory. PMID- 20959359 TI - Limbic encephalitis in children and adolescents. AB - OBJECTIVE: Limbic encephalitis is rare in people <18 years of age and rarely given a formal diagnosis. DESIGN: Retrospective study on presentation and outcome of children and adolescents with the clinico-radiological syndrome of limbic encephalitis tested for specific neuronal autoantibodies (Abs) over 3.5 years. SETTING: Assessment, diagnosis, treatment and follow-up at 12 neuropaediatric and neurological departments in Europe, with Abs determined in Bonn, Germany and Oxford, UK. PATIENTS: Ten patients <18 years of age who presented with a disorder mainly affecting the limbic areas of <5 years' duration with MRI evidence of mediotemporal encephalitis (hyperintense T2/FLAIR signal, resolving over time). RESULTS: Median age at disease onset was 14 years (range 3-17). Eight patients had defined Abs: one each with Hu or Ma1/2 Abs, four with high titre glutamic acid decarboxylase (GAD) Abs, two of whom had low voltage-gated potassium channel (VGKC) Abs and two with only low titre VGKC Abs. A tumour was only found in the patient with Hu Abs (a neuroblastoma). After a median follow-up of 15 months with corticosteroid or intravenous immunoglobulin treatment, starting after a median of 4 months, two patients recovered, eight remained impaired and one died. CONCLUSIONS: Limbic encephalitis is a disease that can occur in childhood or adolescence with many of the hallmarks of the adult disorder, suggesting that both result from similar pathogenic processes. Since most of the cases were non paraneoplastic, as now also recognised in adults, more systematic and aggressive immunotherapies should be evaluated in order to improve outcomes. PMID- 20959360 TI - Prospective assessment of short-term propylene glycol tolerance in neonates. AB - INTRODUCTION: Propylene glycol (PG) is an unintentional frequently administered solvent in neonates despite the fact that PG accumulation potentially results in hyperosmolarity, lactic acidosis and renal/hepatic toxicity. METHODS: Prospective evaluation of renal (diuresis, creatinaemia, sodium), metabolic (base excess, anion gap, lactate, bicarbonate) and hepatic (alanine transaminase, aspartate aminotransferase, direct bilirubinaemia) tolerance to PG in (pre)term neonates following intravenous administration of formulations (paracetamol, phenobarbital, digoxin) that contain PG. Observations from 48 h before up to 48 after the last PG administration were described and compared (paired analysis). Clinical characteristics and observations collected following intravenous PG-paracetamol administration were compared with a historical cohort of neonates in whom similar (renal, hepatic) observations during exposure to a mannitol-containing paracetamol formulation were collected. RESULTS: 5566 observations were collected in 69 neonates before, during and following median PG exposure of 34 mg/kg/24 h (range 14-252). Progressive postnatal adaptation in renal, metabolic and hepatic function was documented, unrelated to the PG exposure. In the subgroup of 40 cases treated with intravenous PG-paracetamol, observations on renal and hepatic function were similar to a historical cohort of published observations following exposure to intravenous mannitol-paracetamol. CONCLUSIONS: Unintended PG administration (34 mg/kg/24 h) for a maximum of 48 h seems to be tolerated in (pre)term neonates and does not affect short-term postnatal adaptations. Further studies on PG disposition and the level of safe exposure to PG, including long term safety data in neonates are needed. PMID- 20959361 TI - Curcumin dually inhibits both mammalian target of rapamycin and nuclear factor kappaB pathways through a crossed phosphatidylinositol 3-kinase/Akt/IkappaB kinase complex signaling axis in adenoid cystic carcinoma. AB - Adenoid cystic carcinoma (ACC) is a highly malignant tumor that is generally unresponsive or only weakly responsive to the currently available antineoplastic agents. Thus, novel therapeutic strategies and agents are urgently needed to treat this aggressive neoplasm. Curcumin, a component of turmeric (Curcuma longa), has been shown to have a diversity of antitumor activities. We show here that curcumin is a potent inhibitor of ACC progression in vitro and in vivo. Curcumin concentration-dependently inhibited the growth of ACC cells via induction of apoptosis. The ability of ACC cells to migrate/invade and induce angiogenesis was also significantly attenuated by curcumin, accompanied by the down-regulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 and -9. Moreover, our data also demonstrated that the inhibitory effects of curcumin on ACC cells were due to its dual inhibition of both mammalian target of rapamycin (mTOR) and nuclear factor-kappaB (NF-kappaB) pathways through a crossed phosphatidylinositol 3-kinase/Akt/IkappaBalpha kinase signaling axis. Most importantly, curcumin effectively prevented the in vivo growth and angiogenesis of ACC xenografts in nude mice, as revealed by the induction of cell apoptosis and reduction of microvessel density in tumor tissues. In addition, we further assessed the nature activation status of both mTOR and NF-kappaB pathways in ACC tissues and confirmed the concurrent high activation of these two pathways in ACC for the first time. Taken together, our findings suggest that further clinical investigation is warranted to apply curcumin as a novel chemotherapeutic regimen for ACC because of its dual suppression of both mTOR and NF-kappaB pathways. PMID- 20959362 TI - Histone deacetylase inhibitors stimulate histone H3 lysine 4 methylation in part via transcriptional repression of histone H3 lysine 4 demethylases. AB - This study investigates the mechanism by which histone deacetylase (HDAC) inhibitors up-regulate histone H3 lysine 4 (H3K4) methylation. Exposure of LNCaP prostate cancer cells and the prostate tissue of transgenic adenocarcinoma of the mouse prostate mice to the pan- and class I HDAC inhibitors (S)-(+)-N-hydroxy-4 (3-methyl-2-phenyl-butyrylamino)-benzamide (AR42), N-(2-aminophenyl)-4-[N (pyridine-3-yl-methoxycarbonyl)-aminomethyl]-benzamide (MS-275), and vorinostat led to differential increases in H3K4 methylation. Chromatin immunoprecipitation shows that this accumulation of methylated H3K4 occurred in conjunction with decreases in the amount of the H3K4 demethylase RBP2 at the promoter of genes associated with tumor suppression and differentiation, including KLF4 and E cadherin. This finding, together with the HDAC inhibitor-induced up-regulation of KLF4 and E-cadherin, suggests that HDAC inhibitors could activate the expression of these genes through changes in histone methylation status. Evidence indicates that this up-regulation of H3K4 methylation was attributable to the suppressive effect of these HDAC inhibitors on the expression of RBP2 and other JARID1 family histone demethylases, including PLU-1, SMCX, and LSD1, via the down-regulation of Sp1 expression. Moreover, shRNA-mediated silencing of the class I HDAC isozymes 1, 2, 3, and 8, but not that of the class II isozyme HDAC6, mimicked the drug effects on H3K4 methylation and H3K4 demethylases, which could be reversed by ectopic Sp1 expression. These data suggest a cross-talk mechanism between HDACs and H3K4 demethylases via Sp1-mediated transcriptional regulation, which underlies the complexity of the functional role of HDACs in the regulation of histone modifications. PMID- 20959363 TI - MT2 receptors mediate the inhibitory effects of melatonin on nitric oxide-induced relaxation of porcine isolated coronary arteries. AB - Previous studies from our laboratory demonstrated that melatonin inhibits nitric oxide (NO)-induced relaxation in porcine coronary arteries. The present study was designed to further characterize the mechanisms underlying this inhibitory effect of melatonin. Western immunoblot studies identified the presence of melatonin type 2 (MT(2)) receptors, but not MT(1) or MT(3) receptors, in porcine coronary arteries. Immunohistochemical analysis revealed that MT(2) receptors colocalized with alpha-actin in the smooth muscle cell layer. In coronary arterial rings suspended in organ chambers for isometric tension recording, melatonin (10(-7) M) inhibited relaxations induced by the exogenous NO donor sodium nitroprusside (SNP; 10(-9) to 10(-5) M) and by the alpha(2)-adrenoceptor agonist 5-bromo-6-[2 imidazolin-2-yl-amino]-quinoxaline (UK14,304; 10(-9) to 10(-5) M), an endothelium dependent vasodilator. The inhibitory effect of melatonin on SNP- and UK14,304 induced relaxations was abolished in the presence of the selective MT(2) receptor antagonists 4-phenyl-2-propionamidotetralin (4P-PDOT; 10(-7) M) and luzindole (10(-7) M). In contrast to melatonin, the selective MT(3) receptor agonist 5 methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT; 10(-7) M) had no effect on the concentration-response curves to either SNP or UK14,304. Melatonin (10(-7) M) had no effect on coronary artery relaxation induced by 8-bromoguanosine 3',5' cyclic monophosphate, but it significantly attenuated the increase in intracellular cyclic GMP levels in response to SNP (10(-5) M). This effect of melatonin was abolished in the presence of 4P-PDOT (10(-7) M). Taken together, these data support the view that melatonin acts on MT(2) receptors in coronary vascular smooth muscle cells to inhibit NO-induced increases in cyclic GMP and coronary arterial relaxation, thus demonstrating a novel function for MT(2) receptors in the vasculature. PMID- 20959364 TI - RG3487, a novel nicotinic alpha7 receptor partial agonist, improves cognition and sensorimotor gating in rodents. AB - Neuronal nicotinic alpha7 acetylcholine receptors (alpha7nAChRs) are expressed primarily in the brain and are implicated in modulating many cognitive functions (e.g., attention, working and episodic memory). Not surprisingly, much effort has been committed to the development of molecules acting at alpha7nAChRs as potential therapies for a variety of central nervous system diseases (e.g., Alzheimer's). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride (RG3487) binds potently to the human alpha7nAChR (K(i) = 6 nM), in which it acts as a partial agonist (63-69% of acetylcholine) as assessed by whole cell patch-clamp recordings in both oocytes and QM7 cell lines. RG3487 activates human alpha7nAChRs with an EC(50) of 0.8 MUM (oocytes) and 7.7 MUM (QM7 cells). RG3487 also exhibits antagonist properties at the serotonin 3 receptor [IC(50) = 2.8 nM (oocytes), 32.7 nM (N1E-115 cells)]. In vivo, RG3487 improved object recognition memory in rats after acute [minimally effective dose (MED) 1.0 mg/kg p.o.] or repeated (10 day) administration at brain and plasma concentrations in the low-nanomolar range. Spatial learning deficits in age-impaired rats were reversed after RG3487 administration (MED: 0.03 mg/kg i.p.) as evaluated in the Morris water maze task. In the prepulse inhibition (PPI) of startle model of sensorimotor gating, RG3487 improved apomorphine-induced deficits in PPI performance (MED: 0.03 mg/kg i.p.) and reversed phencyclidine-induced impairments in an attentional set-shifting model of executive function (MED: <=0.03 mg/kg i.p.). Cumulative evidence from these studies indicates RG3487 is a novel and potent alpha7nAChR partial agonist that improves cognitive performance and sensorimotor gating. PMID- 20959365 TI - Neutral vs positive oral contrast in diagnosing acute appendicitis with contrast enhanced CT: sensitivity, specificity, reader confidence and interpretation time. AB - OBJECTIVE: The study compared the sensitivity, specificity, confidence and interpretation time of readers of differing experience in diagnosing acute appendicitis with contrast-enhanced CT using neutral vs positive oral contrast agents. METHODS: Contrast-enhanced CT for right lower quadrant or right flank pain was performed in 200 patients with neutral and 200 with positive oral contrast including 199 with proven acute appendicitis and 201 with other diagnoses. Test set disease prevalence was 50%. Two experienced gastrointestinal radiologists, one fellow and two first-year residents blindly assessed all studies for appendicitis (2000 readings) and assigned confidence scores (1=poor to 4=excellent). Receiver operating characteristic (ROC) curves were generated. Total interpretation time was recorded. Each reader's interpretation with the two agents was compared using standard statistical methods. RESULTS: Average reader sensitivity was found to be 96% (range 91-99%) with positive and 95% (89-98%) with neutral oral contrast; specificity was 96% (92-98%) and 94% (90-97%). For each reader, no statistically significant difference was found between the two agents (sensitivities p-values >0.6; specificities p-values>0.08), in the area under the ROC curve (range 0.95-0.99) or in average interpretation times. In cases without appendicitis, positive oral contrast demonstrated improved appendix identification (average 90% vs 78%) and higher confidence scores for three readers. Average interpretation times showed no statistically significant differences between the agents. CONCLUSION: Neutral vs positive oral contrast does not affect the accuracy of contrast-enhanced CT for diagnosing acute appendicitis. Although positive oral contrast might help to identify normal appendices, we continue to use neutral oral contrast given its other potential benefits. PMID- 20959366 TI - Evaluation of flow measurement from the first pass bolus T1 weighted images using inversion recovery sequence. AB - OBJECTIVE: Previous studies have shown that the organ blood flows (OBFs) calculated using the T(1) weighted MRI technique were lower than the expected values. The aim of this study was a flow measurement comparison between the theoretical and experimental flows based on the technique before and after corrections (coil non-uniformity and inflow) using a flow phantom at two different concentrations (0.8 and 1.2 mmol l(-1)). METHODS: A flow phantom was designed to produce three different flow rates at the same time. Theoretical flow was calculated by measuring the volumes of the phantom and dividing them by the time taken to fill these volumes. T(1) weighted turbo fast low-angle shot images were used to measure signal intensity (SI) change during the first bolus passage of the contrast medium through the phantom using linear phase-encoding acquisition. RESULTS: The corrected experimental flow based on the technique shows a good agreement with the theoretical flow, where the flow rate is low at the two concentrations. CONCLUSION: The T(1) weighted MRI technique after the two correction factors can be used to measure the absolute flow where the flow rate is low, such as in the capillaries. For measuring high flow rate (e.g. artery), additional correction factors should be considered. PMID- 20959367 TI - Interventional management for complications following caesarean section. AB - OBJECTIVES: This study aimed to evaluate the efficacy and safety of interventional management for various intractable complications following caesarean section. METHODS: Between August 2005 and September 2009, 18 consecutive women were referred to interventional radiology for treatment of complications developing after caesarean section. Complications included vaginal bleeding (n = 14), haemoperitoneum with abdominal wall haematoma (n = 2), caesarean scar pregnancy (CSP) (n = 1) and post-caesarean fluid collection (n = 1). RESULTS: 17 women underwent transcatheter arterial embolisation (TAE) with a variety of embolic materials, and two women underwent percutaneous drainage (PCD) for fluid collection and haemoperitoneum. 5 of the 14 women with vaginal bleeding had extravasation of contrast media on angiography; the other 9 had no visible bleeding foci. The two women with haemoperitoneum with abdominal wall haematoma had injury to the inferior epigastric artery from angiography. TAE and PCD were successfully performed in both women. The CSP was successfully managed and the serum beta-human chorionic gonadotropin (beta-hCG) level finally normalised. Hysterectomy or dilatation and curretage was required in women with placenta accrete and undetectable bleeding foci. CONCLUSION: Interventional management including TAE and PCD is effective and safe in controlling complications following caesarean section. Use of these procedures can help avoid high-risk surgery, but subsequent procedures including hysterectomy may be required in cases of placental abnormalities and undetectable bleeding foci. PMID- 20959368 TI - Sensitivity and specificity: imperfect predictors of guideline utility in radiology. AB - OBJECTIVE: Many "guideline-development studies" have presented the sensitivity (SN) and specificity (SP) of a new decision tool to describe the potential improvements in utilisation of imaging techniques as a result of adopting the new guideline. However, SN and SP are measures designed to assess how well a new guideline compares with a gold standard. These measures do not evaluate how many patients with a positive test actually have the disease; nor do they evaluate how many patients with a negative test do not have the disease. To evaluate these characteristics of a decision tool, other measures, namely the positive predictive value (PPV) and negative predictive value (NPV), should be calculated. This report highlights some of the main methodological challenges in interpretation of the studies that attempt to evaluate the development of an imaging guideline and the effectiveness of an imaging guideline in real world practice. METHODS: We define four key measures of a decision tool: SN, SP, PPV and NPV. Using data from two hypothetical populations, we explain how these measures can be calculated and interpreted. We place special emphasis on the purpose of and differences between the SN-SP and PPV-NPV. RESULTS: Borrowing information from two studies, we demonstrate how these measures should be used in the radiology healthcare services research to evaluate decision guidelines. CONCLUSION: The use of appropriate measures for the specific question at hand will ensure the guidelines are useful, safe, cost reducing and effective clinical tools. PMID- 20959369 TI - Anti-tumour effects of transcatheter arterial embolisation administered in combination with thalidomide in a rabbit VX2 liver tumour model. AB - OBJECTIVE: Using a liver tumour model we investigated whether thalidomide enhances the anti-tumour effect of transcatheter arterial embolisation (TAE). METHOD: First, the viability of VX2 tumour cells co-cultured with thalidomide in a 21% and 1% O(2) atmosphere was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Second, we randomly assigned 20 rabbits bearing VX2 liver tumours to 4 groups: Group 1 (thalidomide plus TAE), Group 2 (TAE only), Group 3 (thalidomide only) and Group 4 (control). Thalidomide was orally administered for 5 days. The anti-tumour effects were assessed by the tumour proliferation rate using MRI and by immunohistochemical analysis of the area of intratumoural vessels. Analysis of variance and Tukey's honestly significant difference test were used for statistical analysis. RESULTS: The viability of cells grown under hypoxic and normal conditions was not significantly different, nor was there a difference among the four groups. The tumour size increased by 55.9+/-29.3% in Group 1, 250.6+/-73.3% in Group 2, 355.2+/-51.7% in Group 3 and 424.7+/-110.7% in Group 4; the difference between Group 1 and the other three groups was significant. The area of intratumour vessels in specimens was 0.22+/-0.28% in Group 1, 0.42+/-0.29% in Group 2, 1.44+/ 1.00% in Group 3 and 6.00+/-2.17% in Group 4; the difference between Group 1 and the other groups was statistically significant, as was the difference between Groups 3 and 4. CONCLUSION: Thalidomide used in combination with TAE enhanced anti-tumour effects in rabbits bearing VX2 liver tumours. PMID- 20959370 TI - Prognostic significance of parameters derived from co-registered 18F fluorodeoxyglucose PET and contrast-enhanced MRI in patients with high-grade glioma. AB - OBJECTIVE: The aim of this study was to determine the prognostic significance of the volume and intensity of abnormal (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) accumulation within areas of contrast enhancement on post therapeutic volumetric MRI. METHODS: A total of 10 patients with Grade III or IV glioma were treated with resection followed by intracavitary radiation therapy with (131)I-labelled antitenascin monoclonal antibody. Patients underwent serial FDG-PET and 1.5 T MR imaging. For each patient, MR and FDG-PET image volumes at each time point were aligned using a rigid-body normalised mutual information algorithm. Contrast-enhancing regions of interest (ROIs) were defined using a semi-automated k-means clustering technique. Activity within the ROI on the co registered PET scan was calculated as a ratio (mean activity ratio; MAR) to activity in contralateral normal-appearing white matter (NAWM). The PET lesion was defined as the portion of the ROI associated with activity greater than two standard deviations above the mean in NAWM. Survival was assessed using the logrank test. RESULTS: Larger contrast-enhancing ROIs were strongly associated with an increased MAR (r = 0.51; p<0.002). Enhancing lesions with an MAR >1.2 were associated with decreased survival (p<0.016). In nine patients who died, the MAR on PET correlated inversely with survival duration (r = -0.43; p<0.01), whereas PET lesion volume did not. CONCLUSION: Following intracavitary radiation therapy, the development of contrast-enhancing lesions that are associated with high mean FDG-PET accumulation suggests poor prognosis. PMID- 20959371 TI - The detection and discrimination of malignant and benign focal hepatic lesions: T2 weighted vs diffusion-weighted MRI. AB - OBJECTIVE: The purpose of this study was to evaluate the use of diffusion weighted imaging (DWI) for the detection and characterisation of focal hepatic lesions compared with the use of T(2) weighted imaging. METHOD: 45 patients with 97 hepatic lesions (51 malignant lesions and 46 benign lesions) were included in this retrospective study. Malignant hepatic lesions included 12 hepatocellular carcinomas, 26 metastases and 13 intrahepatic cholangiocarcinomas. Benign hepatic lesions included 19 haemangiomas and 27 cysts. The MRI protocol for the upper abdomen included T(2) weighted images, in- and opposed-phase T(1) weighted images and dynamic T(1) weighted images. Breath-hold fat-suppressed single-shot echo planar DWI was performed with the following parameters: 1338/66; b factors, 0, 50 and 800 s mm(-2). Two independent observers reviewed the T(2) weighted images and the DWI to detect and to characterise the hepatic lesions. RESULTS: For detection of malignant hepatic lesions, the use of DWI showed a significantly higher detection rate than the use of T(2) weighted images (p<0.05). However, there was no significant difference between the use of DWI and T(2) weighted images for benign hepatic lesions. For the differentiation between malignant and benign hepatic lesions, there was no significant difference in sensitivity, specificity and accuracy between the use of T(2) weighted images and the use of DWI. CONCLUSION: The use of DWI was better for the detection of malignant hepatic lesions than the use of T(2) weighted images. However, for detection of benign hepatic lesions and characterisation of hepatic lesions, the use of DWI was equivalent to the use of T(2) weighted images. PMID- 20959372 TI - Factors associated with nodal metastasis in nasopharyngeal cancer: an approach to reduce the radiation field in selected patients. AB - OBJECTIVES: The purpose of this study was to investigate factors associated with lymph node (LN) metastasis to identify which nasopharyngeal cancer (NPC) patients can undergo a reduction in the prophylactic radiation field. MRI of biopsy-proven NPC patients was evaluated to determine primary tumour extension and the existence of LN metastasis. METHODS: Sex, age, pathological type, T stage, primary tumour size, existence beyond the midline of the nasopharynx at the primary site and parapharyngeal extension of the primary tumour were assessed regarding their impact on the laterality of LN metastasis using the chi(2) test. RESULTS: Of the 167 patients, 149 (89%) showed nodal involvement. The existence beyond the midline of the nasopharynx was significantly associated with the laterality of LN metastasis (p<0.0001). Most patients (82%) with primary tumour presence within the midline showed only ipsilateral LN metastasis or no LN metastasis. In addition, contralateral LN metastases were seen only at Level II and the retropharyngeal LN among most of other patients. CONCLUSION: These results suggest that LN areas other than Level II and the retropharyngeal LN on the contralateral side could be omitted in patients with primary tumour presence within the midline and without the contralateral Level II or the retropharyngeal LN. Whether disease control is compromised by reducing the radiation field for subclinical diseases is a problem that should be solved in the future by prospective study. PMID- 20959373 TI - Assessment of hepatocellular carcinoma by contrast-enhanced ultrasound with perfluorobutane microbubbles: comparison with dynamic CT. AB - OBJECTIVE: The aim of this study was to evaluate tumour vascularity and Kupffer cell imaging in hepatocellular carcinoma (HCC) using contrast-enhanced ultrasonography (CEUS) with Sonazoid (perfluorobutane) and to compare performance with dynamic CT. METHODS: We studied 118 nodules in 88 patients with HCC. HCC was diagnosed as a hyperenhancement lesion in the arterial phase with washout in the portal phase on dynamic CT or by percutaneous biopsy. We observed tumour vascularity at the early vascular phase (10-30 s after contrast injection) and Kupffer imaging at the post-vascular phase (after 10 min). RESULTS: Detection of vascularity at the early vascular phase was 88% in nodules that were found to be hypervascular on dynamic CT and 28% in hypo-/isovascular nodules; the detection of local recurrence nodules was 92%. The detection of vascularity was significantly lower in nodules >9 cm deep than in those <=9 cm deep, but was not affected by tumour size. The detection of tumours at the post-vascular phase on CEUS was 83% in nodules with low density in the portal phase on dynamic CT and 82% in nodules with isodensity. The rate did not depend on the severity of underlying liver disease; rates decreased in nodules deeper than 9 cm, those smaller than 2 cm in diameter and in iso-enhancing nodules at the early vascular phase of CEUS. CONCLUSION: CEUS with Sonazoid is a useful tool for assessing the vascularity of HCC and is equal to that of dynamic CT; however, the detectability of HCC vascularity is affected by location. PMID- 20959374 TI - Non-laxative CT colonography with barium-based faecal tagging: is additional phosphate enema beneficial and well tolerated? AB - OBJECTIVE: The purpose of this study was to investigate the efficacy and tolerance of an additional phosphate enema prior to non-laxative CT colonography (CTC). METHODS: 71 patients (mean age 80 years, 28 male, 43 female) underwent non laxative CTC following 4 oral doses of diluted 2% w/w barium sulphate. Patients were invited to self-administer a phosphate enema 2 h before CTC. An experienced observer graded the volume of retained stool (1 (nil) to 4 (>75% bowel circumference coated)), retained fluid ((1 (nil) to 4 (>50% circumference obscured)), retained stool tagging quality (1 (untagged) to 5 (>=75% to 100%) tagged) and confidence a polyp >=6 mm could be excluded (yes/no) for each of six colonic segments. Tolerance of the enema was assessed via questionnaire. Data were analysed between those using and not using the enema by Mann-Whitney and Fisher's exact test. 18/71 patients declined the enema. RESULTS: There was no reduction in residual stool volume with enema use compared with non-use either overall (mean score 2.6 vs 2.7, p = 0.76) or in the left colon (mean 2.3 vs 2.4, p = 0.47). Overall tagging quality was no different (mean score 4.4 vs 4.3, p = 0.43). There was significantly more retained left colonic fluid post enema (mean score 1.9 vs 1.1, p<0.0001), and diagnostic confidence in excluding polyps was significantly reduced (exclusion not possible in 35% segments vs 21% without enema, p = 0.006). Of 53 patients, 30 (56%) found the enema straightforward to use, but 4 (8%) found it unpleasant. CONCLUSION: Phosphate enema use prior to non laxative CTC leads to greater retained fluid, reducing diagnostic confidence, and is not recommended. PMID- 20959375 TI - Diagnostic accuracy of fused positron emission tomography/magnetic resonance mammography: initial results. AB - OBJECTIVES: The aim of this study was to evaluate the diagnostic accuracy of fused fluoro-deoxy-D-glucose positron emission tomography/magnetic resonance mammography (FDG-PET/MRM) in breast cancer patients and to compare FDG-PET/MRM with MRM. METHODS: 27 breast cancer patients (mean age 58.9+/-9.9 years) underwent MRM and prone FDG-PET. Images were fused software-based to FDG-PET/MRM images. Histopathology served as the reference standard to define the following parameters for both MRM and FDG-PET/MRM: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for the detection of breast cancer lesions. Furthermore, the number of patients with correctly determined lesion focality was assessed. Differences between both modalities were assessed by McNemars test (p<0.05). The number of patients in whom FDG-PET/MRM would have changed the surgical approach was determined. RESULTS: 58 breast lesions were evaluated. The sensitivity, specificity, PPV, NPV and accuracy were 93%, 60%, 87%, 75% and 85% for MRM, respectively. For FDG PET/MRM they were 88%, 73%, 90%, 69% and 92%, respectively. FDG-PET/MRM was as accurate for lesion detection (p = 1) and determination of the lesions' focality (p = 0.7722) as MRM. In only 1 patient FDG-PET/MRM would have changed the surgical treatment. CONCLUSION: FDG-PET/MRM is as accurate as MRM for the evaluation of local breast cancer. FDG-PET/MRM defines the tumours' focality as accurately as MRM and may have an impact on the surgical treatment in only a small portion of patients. Based on these results, FDG-PET/MRM cannot be recommended as an adjunct or alternative to MRM. PMID- 20959376 TI - Dobutamine stress tagging and gradient-echo imaging for detection of coronary heart disease at 3 T. AB - OBJECTIVE: The purpose of this study was to evaluate the feasibility and diagnostic accuracy of a combined spoiled gradient-echo (sGRE) and tagged gradient-echo (SPAMM-GRE) protocol for detection of coronary artery disease (CAD) during high-dose dobutamine stress at 3 T. METHOD: The study protocol was approved by the local ethics committee. For stress testing, a standard high-dose dobutamine protocol was employed. Image quality at the highest stress level and diagnostic accuracy of the sGRE and SPAMM-GRE sequences were compared. The final study population consisted of 37 patients. RESULTS: The mean image quality score was 2.6+/-0.6 for the sGRE sequence and 2.4+/-0.6 for the SPAMM-GRE sequence (p>0.05). Sensitivity, specificity and diagnostic accuracy were 0.81, 0.86, 0.84 and 0.88, 0.86, 0.86 for the sGRE and SPAMM-GRE, respectively. In three cases with new wall motion abnormalities (WMAs), detected by sGRE and SPAMM-GRE, WMAs were detected at a lower stress level by tagging. CONCLUSION: The combined sGRE and SPAMM-GRE high-dose dobutamine protocol at 3 T is feasible and delivers good diagnostic accuracy. Tagging increases the sensitivity of high-dose dobutamine stress testing for detection of CAD and may allow for detection of new WMAs at lower stress levels compared with sGRE alone. PMID- 20959377 TI - CT enterography with polyethylene glycol solution vs CT enteroclysis in small bowel disease. AB - OBJECTIVE: The aim of the study is to compare CT enterography with polyethylene glycol solution (PEG-CT) with CT enteroclysis (CT-E) in patients with suspected small bowel disease. METHODS: 145 patients underwent abdominal contrast-enhanced 16-row multidetector CT after administration of 2000 ml of PEG by mouth (n = 75) or after administration of 2000 ml of methylcellulose by nasojejunal tube (n = 70). Small bowel distension, luminal and extraluminal findings were evaluated and compared with small bowel follow-through examination in 60 patients, double contrast enema in 50, surgery in 25 and endoscopy in 35. Statistical evaluation was carried out by chi2 testing. For both techniques we have also calculated the effective dose and the equivalent dose in a standard patient. RESULTS: Crohn's disease was diagnosed in 64 patients, neoplasms in 16, adhesions in 6. Distension of the jejunum was better with CT-E than PEG-CT (p<0.05: statistically significant difference). No significant difference was present for others sites (p>0.05). Evaluation of pathological ileal loops was good with both techniques. The values of sensitivity, specificity and diagnostic accuracy were respectively 94%, 100% and 96% with CT-E, and 93%, 94% and 93% with PEG-CT. The effective dose for PEG-CT was less than the dose for the CT-E (34.7 mSv vs 39.91 mSv). CONCLUSION: PEG-CT shows findings of Crohn's disease as well as CT-E does, although CT-E gives better bowel distension, especially in the jejunum, and has higher specificity than PEG-CT. PMID- 20959378 TI - Comprehensive hormone profiling in developing Arabidopsis seeds: examination of the site of ABA biosynthesis, ABA transport and hormone interactions. AB - ABA plays important roles in many aspects of seed development, including accumulation of storage compounds, acquisition of desiccation tolerance, induction of seed dormancy and suppression of precocious germination. Quantification of ABA in the F(1) and F(2) populations originated from crosses between the wild type and an ABA-deficient mutant aba2-2 demonstrated that ABA was synthesized in both maternal and zygotic tissues during seed development. In the absence of zygotic ABA, ABA synthesized in maternal tissues was translocated into the embryos and partially induced seed dormancy. We also analyzed the levels of ABA metabolites, gibberellins, IAA, cytokinins, jasmonates and salicylic acid (SA) in the developing seeds of the wild type and aba2-2. ABA metabolites accumulated differentially in the silique and seed tissues during development. Endogenous levels of SA were elevated in aba2-2 in the later developmental stages, whereas that of IAA was reduced compared with the wild type. These data suggest that ABA metabolism depends on developmental stages and tissues, and that ABA interacts with other hormones to regulate seed developmental processes. PMID- 20959379 TI - Model-free unsupervised gene set screening based on information enrichment in expression profiles. AB - MOTIVATION: A number of unsupervised gene set screening methods have recently been developed for search of putative functional gene sets based on their expression profiles. Most of the methods statistically evaluate whether the expression profiles of each gene set are fit to assumed models: e.g. co expression across all samples or a subgroup of samples. However, it is possible that they fail to capture informative gene sets whose expression profiles are not fit to the assumed models. RESULTS: To overcome this limitation, we propose a model-free unsupervised gene set screening method, Matrix Information Enrichment Analysis (MIEA). Without assuming any specific models, MIEA screens gene sets based on information richness of their expression profiles. We extensively compared the performance of MIEA to those of other unsupervised gene set screening methods, using various types of simulated and real data. The benchmark tests demonstrated that MIEA can detect singular expression profiles that the other methods fail to find, and performs broadly well for various types of input data. Taken together, this study introduces MIEA as a broadly applicable gene set screening tool for mining regulatory programs from transcriptome data. PMID- 20959380 TI - VEGA: variational segmentation for copy number detection. AB - MOTIVATION: Genomic copy number (CN) information is useful to study genetic traits of many diseases. Using array comparative genomic hybridization (aCGH), researchers are able to measure the copy number of thousands of DNA loci at the same time. Therefore, a current challenge in bioinformatics is the development of efficient algorithms to detect the map of aberrant chromosomal regions. METHODS: We describe an approach for the segmentation of copy number aCGH data. Variational estimator for genomic aberrations (VEGA) adopt a variational model used in image segmentation. The optimal segmentation is modeled as the minimum of an energy functional encompassing both the quality of interpolation of the data and the complexity of the solution measured by the length of the boundaries between segmented regions. This solution is obtained by a region growing process where the stop condition is completely data driven. RESULTS: VEGA is compared with three algorithms that represent the state of the art in CN segmentation. Performance assessment is made both on synthetic and real data. Synthetic data simulate different noise conditions. Results on these data show the robustness with respect to noise of variational models and the accuracy of VEGA in terms of recall and precision. Eight mantle cell lymphoma cell lines and two samples of glioblastoma multiforme are used to evaluate the behavior of VEGA on real biological data. Comparison between results and current biological knowledge shows the ability of the proposed method in detecting known chromosomal aberrations. AVAILABILITY: VEGA has been implemented in R and is available at the address http://www.dsba.unisannio.it/Members/ceccarelli/vega in the section Download. PMID- 20959381 TI - SmashCommunity: a metagenomic annotation and analysis tool. AB - SUMMARY: SmashCommunity is a stand-alone metagenomic annotation and analysis pipeline suitable for data from Sanger and 454 sequencing technologies. It supports state-of-the-art software for essential metagenomic tasks such as assembly and gene prediction. It provides tools to estimate the quantitative phylogenetic and functional compositions of metagenomes, to compare compositions of multiple metagenomes and to produce intuitive visual representations of such analyses. AVAILABILITY: SmashCommunity source code and documentation are available at http://www.bork.embl.de/software/smash CONTACT: bork@embl.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 20959383 TI - Interactional and functional centrality in transcriptional co-expression networks. AB - MOTIVATION: The noisy nature of transcriptomic data hinders the biological relevance of conventional network centrality measures, often used to select gene candidates in co-expression networks. Therefore, new tools and methods are required to improve the prediction of mechanistically important transcriptional targets. RESULTS: We propose an original network centrality measure, called annotation transcriptional centrality (ATC) computed by integrating gene expression profiles from microarray experiments with biological knowledge extracted from public genomic databases. ATC computation algorithm delimits representative functional domains in the co-expression network and then relies on this information to find key nodes that modulate propagation of functional influences within the network. We demonstrate ATC ability to predict important genes in several experimental models and provide improved biological relevance over conventional topological network centrality measures. AVAILABILITY: ATC computational routine is implemented in a publicly available tool named FunNet (www.funnet.info). PMID- 20959382 TI - MiRonTop: mining microRNAs targets across large scale gene expression studies. AB - SUMMARY: Current challenges in microRNA (miRNA) research are to improve the identification of in vivo mRNA targets and clarify the complex interplay existing between a specific miRNA and multiple biological networks. MiRonTop is an online java web tool that integrates DNA microarrays or high-throughput sequencing data to identify the potential implication of miRNAs on a specific biological system. It allows a rapid characterization of the most pertinent mRNA targets according to several existing miRNA target prediction approaches. It also provides useful representations of the enrichment scores according to the position of the target site along the 3'-UTR, where the contribution of the sites located in the vicinity of the stop codon and of the polyA tail can be clearly highlighted. It provides different graphs of miRNA enrichment associated with up- or down regulated transcripts and different summary tables about selections of mRNA targets and their functional annotations by Gene Ontology. AVAILABILITY: http://www.microarray.fr:8080/miRonTop/index. PMID- 20959384 TI - A prospective study assessing anxiety, depression and maternal-fetal attachment in women using PGD. AB - BACKGROUND: PGD has been described in previous cross-sectional and retrospective studies as a stressful experience. No prospective studies of the psychological impact of PGD are currently available. METHODS: Using a prospective study design, validated measures exploring anxiety and depression were used to assess women using PGD prior to treatment, following embryo transfer, following the pregnancy test result and at 24 weeks of pregnancy. Maternal-fetal attachment was also assessed during pregnancy. RESULTS: The prospective design revealed the cyclical pathway through PGD for many women, often comprising repeated cycles of ovarian stimulations and IVF and frozen embryo transfers. As predicted, there were significant fluctuations in women's anxiety scores, with increases observed following embryo transfer and pregnancy testing. Women's anxiety scores returned to baseline levels during pregnancy as assessed at 24 weeks gestation. Depression scores did not significantly fluctuate during PGD. Maternal-fetal attachment scores in this sample did not differ from the normative Australian data. CONCLUSIONS: For some women, the PGD pathway is convoluted and requires multiple IVF cycles and embryo transfers to achieve pregnancy. A subset of women experience significant emotional burden during PGD treatment, and it is these women who require closer attention and support. In this sample, emotional adjustment in pregnancy following PGD appears to be sound. PMID- 20959385 TI - Psychometric evaluation of the primary health-care satisfaction scale in Turkish women. AB - OBJECTIVE: This paper reports an adaptation of the English version of the primary health-care satisfaction scale for use with Turkish women and an evaluation of its psychometric properties. DESIGN: A psychometric study. SETTING AND PARTICIPANTS: A convenience sample of 381 women at a primary health-care centre completed a structured questionnaire including demographic characteristics and the primary health-care satisfaction scale for women in 2008. Item analysis, principal components analysis, internal consistency reliability and Cronbach's alpha were used to measure the psychometric properties of the items of the scale. RESULTS: In the assessment of construct validity, three factors were identified with a: (1) administration and office procedures, (2) communication, (3) care coordination and comprehensiveness. These factors together explained 54.8% of the total variance. Internal reliability coefficients of these three factor-based scales were 0.80 and 0.93, respectively. CONCLUSIONS: The present study provides evidence of the primary health-care satisfaction scale's validity, reliability and acceptability. This scale should be further evaluated with a larger representative sample of women seeking primary care in Turkey and diverse populations of the world. The scale has potential applications for use in research. The scale may be used both in studies to evaluative alternative models of primary care delivery for women and in quality improvement programs in women's primary care. PMID- 20959386 TI - Season of the first trimester of pregnancy predicts sensitisation to food allergens in childhood: a population-based cohort study from Finland. AB - OBJECTIVE: To examine whether the season of birth or season of the early phase of gestation is associated with sensitisation to food allergens in children, with special reference to mothers' pollen exposure in spring. DESIGN: A population based cohort study linking information from a questionnaire survey to allergy tests performed on the target population and regional pollen counts. POPULATION: Children born in 2001-6 who were resident in the province of South Karelia, Finland, at the time of the survey (N=5920). MAIN OUTCOME MEASURES: A positive result in any food allergy test or food-specific immunoglobulin E test (sIgE). RESULTS: The cumulative incidence of a positive food allergy test up to the age of 4 years was highest among children born in October-November (10%) and lowest among those born in June-July (5%), and correspondingly highest among children who were in their 11th gestational week in April-May (11%), the season of high concentrations of birch and alder pollen, and lowest among those reaching that stage in December-January (6%). The amplitude of seasonal variation in any test, estimated as the relative ratio between the peak and trough of the smoothed incidence curve over the year, was 2.03 (95% CI 1.52 to 2.76). The amplitudes of positive sIgE were especially pronounced for milk (3.07; 95% CI 1.81 to 5.50) and egg (3.03; 95% CI 1.86 to 5.18). CONCLUSIONS: Children having their early gestational period in the pollen season for broad-leafed trees are more prone to sensitisation to food allergens than other children. PMID- 20959387 TI - Association of rs10830963 and rs10830962 SNPs in the melatonin receptor (MTNR1B) gene among Han Chinese women with polycystic ovary syndrome. AB - The aim of the present study was to determine whether or not the 'melatonin receptor (MTNR1B)' gene polymorphisms are associated with a predisposition for polycystic ovary syndrome (PCOS). The single-nucleotide polymorphisms (SNPs), rs10830963 and rs10830962, in the MTNR1B gene were detected in 526 patients with PCOS and 547 healthy Chinese Han women. The association between MTNR1B gene variants and plasma glucose and insulin levels during the oral glucose tolerance test (OGTT) and hormone levels was investigated. The frequencies of three genotypes and two allelotypes of the SNP, rs10830963, differed significantly between women with PCOS and healthy controls (P < 0.001 and P < 0.001, respectively). The SNP, rs10830963, was significantly associated with higher fasting plasma glucose concentrations (P < 0.001) and increased the area under the curve of plasma glucose levels during the OGTT (P < 0.001), as well as increased homeostasis model assessment of insulin resistance (HOMA-IR; P = 0.027). No significant differences were observed in the genotypes and allele distributions of rs10830962 polymorphisms between the PCOS and the control groups (P = 0.311 and P = 0.178, respectively). There was no significant difference in the clinical and the metabolic characteristics in women with PCOS with different genotypes in the SNP, rs10830962 (all P > 0.005). The present study suggest that the SNP, rs10830963, in the MTNR1B gene is not only associated with susceptibility to PCOS, but also contributes to the PCOS phenotype. PMID- 20959388 TI - Prevention of childhood obesity: issues on the evaluation of interventions. PMID- 20959389 TI - Thermal perception of ventilation changes in full-face motorcycle helmets: subject and manikin study. AB - We report the effects of full-face motorcycle helmet ventilation systems on heat, airflow, noise, and comfort perception for ventilation changes on the scalp. Eight subjects (aged 28.0 +/- 5.4 years) underwent two experimental trials at ambient temperatures of 23.7 +/- 0.4 degrees C or 27.5 +/- 0.3 degrees C. In each trial, the thermally equilibrated subjects underwent two examination phases, during which four different helmets were assessed at wind speeds of 39.2 +/- 1.9 km h(-1) and 59.3 +/- 1.4 km h(-1). Vent-induced heat loss in the scalp ranged from -6.1 to 6.1 W, corresponding to vents being closed or opened, respectively. Perception of vent-induced changes was assessed immediately after the change. We find that the vent-induced heat loss, the subject, and the helmet are the most important response factors. In addition, comparison of two helmets with similar vent-induced heat loss suggests that internal airflow patterns may be important in explaining the observed perception differences. PMID- 20959390 TI - Nucleotide-induced conformational transitions in the CBS domain protein MJ0729 of Methanocaldococcus jannaschii. AB - Nucleotide-binding cystathionine beta-synthase (CBS) domains function as regulatory motifs in several proteins distributed through all kingdoms of life. This function has been proposed based on their affinity for adenosyl-derivatives, although the exact binding mechanisms remain largely unknown. The question of how CBS domains exactly work is relevant because in humans, several genetic diseases have been associated with mutations in those motifs. In this work, we describe the adenosyl-ligand (AMP, ATP, NADP and SAM) properties of the wild-type CBS domain protein MJ0729 from Methanocaldococcus jannaschii by using a combination of spectroscopic techniques (fluorescence, FTIR and FRET). The fluorescence results show that binding to AMP and ATP occurs with an apparent dissociation constant of ~10 uM, and interestingly enough, binding induces protein conformational changes, as shown by FTIR. On the other hand, fluorescence spectra (FRET and steady-state) did not change upon addition of NADP and SAM to MJ0729, suggesting that tryptophan and/or tyrosine residues were not involved in the recognition of those ligands; however, there were changes in the secondary structure of the protein upon addition of NADP and SAM, as shown by FTIR (thus, indicating binding to the nucleotide). Taken together, these results suggest that: (i) the adenosyl ligands bind to MJ0729 in different ways, and (ii) there are changes in the protein secondary structure upon binding of the nucleotides. PMID- 20959391 TI - Distinct expression profiles of UDP-galactose: beta-D-galactoside alpha1,4 galactosyltransferase and UDP-galactose: beta-D-galactoside beta1,4 galactosyltransferase in pigeon, ostrich and chicken. AB - We previously identified two novel enzymes in pigeon, alpha1,4- and beta1,4 galactosyltransferases (GalTs), which are responsible for the biosynthesis of the Galalpha1-4Gal and Galbeta1-4Gal sequences on glycoproteins, respectively. No such glycan structures and/or enzymes have been found in mammals, suggesting that the expression of these enzymes diverged during the course of vertebrate evolution. To compare their expression profiles among avian species, we first established a method for detecting the activities of these two GalTs based on the two-dimensional high pressure liquid chromatography mapping technique, using 2 aminopyridine-derivatized asialo-biantennary N-glycans as an acceptor substrate. When we analyzed the activities of GalTs in pigeon liver extracts in the presence of UDP-Gal, 13 different products containing Galalpha1-4Galbeta1-4GlcNAc, Galbeta1-4Galbeta1-4GlcNAc and/or Galalpha1-4Galbeta1-4Galbeta1-4GlcNAc branches were identified. The newly formed glycosidic linkages of the enzymatic products were determined by nuclear magnetic resonance and methylation analysis, as well as by galactosidase digestions. The activities of both alpha1,4- and beta1,4 GalTs were detected in various tissues in pigeon, although their relative activities were different in each tissue. In contrast, ostrich expressed beta1,4 GalT, but not alpha1,4-GalT, in all tissues analyzed, whereas neither alpha1,4- nor beta1,4-GalT activity was detected in chicken. These results indicate that alpha1,4- and beta1,4-GalTs are expressed in a species-specific manner and are distributed throughout the entire body of pigeon or ostrich when the enzymes are present. PMID- 20959392 TI - A novel fluorescent assay for T-synthase activity. AB - Loss of T-synthase (uridine diphosphate galactose:N-acetylgalactosaminyl-alpha1 Ser/Thr beta3galactosyltransferase), a key enzyme required for the formation of mucin-type core 1 O-glycans, is observed in several human diseases, including cancer, Tn syndrome and IgA nephropathy, but current methods to assay the enzyme use radioactive substrates and complicated isolation of the product. Here we report the development of a novel fluorescent assay to measure its activity in a variety of tumor cell lines. Deficiencies in T-synthase activity correlate with mutations in the gene encoding the molecular chaperone Cosmc that is required for folding the T-synthase. This new high-throughput assay allows for facile screening of tumor specimens and other biological material for T-synthase activity and could be used diagnostically. PMID- 20959393 TI - Tailored mobile phone text messages as an adjunct to obesity treatment for adolescents. AB - We examined the use of tailored messages sent to the mobile phones of obese adolescents enrolled in a weight-management programme, as a means of increasing adherence. The feasibility study was conducted in three phases: (1) a library of 90 messages was developed about five weight-related behaviours; (2) a computer application was developed to tailor these messages to participants' characteristics; the SMS messages (text and images) were sent to mobile phones daily; (3) a three-month trial of the intervention was performed with 20 adolescents. Semi-structured interviews were conducted to assess the participants' perceptions of the intervention and the participants', providers' and computer consultants' reports about technology performance. These interviews revealed that participants were enthusiastic about the intervention and most found the messages to be personally relevant. The favourite messages were meal suggestions and recipe ideas. The computer tailoring application performed faultlessly and messages were delivered on schedule and in the desired sequence. Computerized tailored text messaging is a feasible adjunct to multidisciplinary obesity treatment and is acceptable to adolescents as an enjoyable means of improving their adherence to healthy lifestyle practices. PMID- 20959394 TI - Using telemonitoring to construct knowledge about homebound patient populations: vital-signs alert rates. AB - Three home health agencies conducted daily telemonitoring of patients in western Montana. The agencies all used monitoring equipment of the same type, which provided up to six vital-signs measurements (heart rate, oxygen saturation, systolic blood pressure, diastolic blood pressure, glucose and bodyweight). There were 337 patients in all, two-thirds of whom were female. These patients were monitored for a total of 16,999 person-days. The rate of occurrence of any vital sign measurement falling outside acceptable ranges was 33.8 per patient per 60 day period. The highest alert rate for a specific vital sign was for decreased SpO(2) (6.4 per patient per 60-day period). The central station nurse took follow up action at a rate of 26.0 per patient per 60-day period; case manager nurses took follow-up action at a rate of 8.2 per patient per 60-day period. There were some differences between male and female patients in the alert rates, and between the agencies. The alert rates measured in the present study are expected to be useful to home care administrators in estimating the staffing requirements for telemonitoring. PMID- 20959395 TI - Sensitivity and specificity of telemedicine-based long-term pulse-oximetry in comparison with cardiorespiratory polygraphy and polysomnography in patients with obstructive sleep apnoea syndrome. AB - We investigated the feasibility of night-time pulse-oximetry telemedicine. We compared polysomnography (PSG) as the gold standard with simultaneously recorded pulse-oximetry from a wrist pulse-oximeter. The results were evaluated by a sleep specialist and compared with outpatient polygraphy. A total of 135 consecutive patients (mean age 55 years, mean body mass index 31.6 kg/m(2)) were studied. Patients with minor, moderate and severe PSG findings were grouped together and compared to those without PSG findings; the resulting sensitivity was 1 and specificity 0.35. In addition, patients with and without minor PSG findings were grouped together and compared to those with moderate and severe PSG findings; the resulting sensitivity was 0.66 and the specificity was 0.98. The receiver operating characteristic (ROC) of telemedically-evaluated oximetry was superior to that of outpatient polygraphy. In contrast, the automatic assessment of severity based on the Oxygen Desaturation Index was unsatisfactory. For patients suspected of sleep related breathing disorders (SRBD), telemedically-evaluated pulse-oximetry is able to identify those who should be referred to a sleep laboratory for definitive diagnosis and treatment. The technique appears to be suitable for first screening in all patients at risk for SRBD. PMID- 20959396 TI - Non-occupational exposure to asbestos and malignant mesothelioma in the Italian National Registry of Mesotheliomas. AB - BACKGROUND: Malignant mesotheliomas are strictly related to asbestos, but in a proportion of cases no exposure can be recalled. Published estimates of this proportion have important variations. Historical and geographical differences in the fraction of cancer due to any given exposure are to be expected, but incomplete identification of non-occupational exposures may have played a role. METHODS: To assess the role of non-occupational exposures in causing malignant mesotheliomas in Italy, the exposures of cases registered by the national mesothelioma registry (ReNaM) were examined. ReNaM started in 1993 in five regions and currently covers 98% of the Italian population. Information on occupational and non-occupational exposures of cases is collected whenever possible. RESULTS: From 1993 to 2001 ReNaM registered 5173 malignant mesothelioma cases, and exposures were assessed in 3552 of them. 144 and 150 cases with exposures limited to environmental (living in the neighbourhood of an industrial or natural source of asbestos) or familial (living with a person occupationally exposed to asbestos) circumstances, respectively, were identified, accounting for 8.3% of all cases. CONCLUSIONS: Geographical variations in the proportion of cases due to non-occupational exposures may be explained by the past distribution of asbestos-using industries. PMID- 20959397 TI - Exercises for prevention of recurrences of low-back pain. PMID- 20959398 TI - Occupational allergic rhinoconjunctivitis and bronchial asthma induced by Plukenetia volubilis seeds. PMID- 20959399 TI - High carbon dioxide concentrations in the classroom: the need for research on the effects of children's exposure to poor indoor air quality at school. PMID- 20959400 TI - Cancer epigenetics. AB - Epigenetics refers to stable alterations in gene expression with no underlying modifications in the genetic sequence and is best exemplified by differentiation, in which multiple cell types diverge physiologically despite a common genetic code. Interest in this area of science has grown over the past decades, especially since it was found to play a major role in physiologic phenomena such as embryogenesis, imprinting, and X chromosome inactivation, and in disease states such as cancer. The latter had been previously thought of as a disease with an exclusive genetic etiology. However, recent data have demonstrated that the complexity of human carcinogenesis cannot be accounted for by genetic alterations alone, but also involves epigenetic changes in processes such as DNA methylation, histone modifications, and microRNA expression. In turn, these molecular alterations lead to permanent changes in the expression of genes that regulate the neoplastic phenotype, such as cellular growth and invasiveness. Targeting epigenetic modifiers has been referred to as epigenetic therapy. The success of this approach in hematopoietic malignancies validates the importance of epigenetic alterations in cancer, not only at the therapeutic level but also with regard to prevention, diagnosis, risk stratification, and prognosis. PMID- 20959401 TI - Inflammatory breast cancer: the disease, the biology, the treatment. AB - Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 2.5% of all breast cancer cases. It is characterized by rapid progression, local and distant metastases, younger age of onset, and lower overall survival compared with other breast cancers. Historically, IBC is a lethal disease with less than a 5% survival rate beyond 5 years when treated with surgery or radiation therapy. Because of its rarity, IBC is often misdiagnosed as mastitis or generalized dermatitis. This review examines IBC's unique clinical presentation, pathology, epidemiology, imaging, and biology and details current multidisciplinary management of the disease, which comprises systemic therapy, surgery, and radiation therapy. PMID- 20959402 TI - Oral bisphosphonate use associated with a decreased risk of breast cancer. PMID- 20959403 TI - No gene-environment interactions found in Million Women Study of breast cancer. PMID- 20959404 TI - cIAP2 upregulated by E6 oncoprotein via epidermal growth factor receptor/phosphatidylinositol 3-kinase/AKT pathway confers resistance to cisplatin in human papillomavirus 16/18-infected lung cancer. AB - PURPOSE: Inhibitors of antiapoptosis protein (IAP) have been implicated in the resistance to cisplatin. Therefore, verifying which pathway is involved in cIAP2 upregulation may be helpful in finding a feasible pathway inhibitor to increase the chemotherapeutic efficacy in human papillomavirus (HPV)-infected lung cancer. EXPERIMENTAL DESIGN: Specific inhibitors of different pathways were used to verify which pathway is involved in cIAP2 transcription. cIAP2 promoter fragments with various deletions and/or mutations were constructed by site-directed mutagenesis. cIAP2, epidermal growth factor receptor (EGFR), and phospho-AKT (p AKT) expressions in 136 lung tumors were evaluated by immunohistochemistry. RESULTS: Our data show that two NF-kappaB (-209 to -200 and -146 to -137) and one CREB (cyclic AMP-responsive element binding protein; -52 to -42) binding sites in cIAP2 promoter region were responsible for cIAP2 upregulated by E6 in TL-1 cells. Moreover, CREB was phosphorylated by EGFR/phosphatidylinositol 3-kinase (PI3K) pathway. To test the involvement of cIAP2 on cisplatin resistance, IC(50) was lowered to 8.6 MUmol/L in TL-1 cells with cIAP2 short hairpin RNA (shRNA) transfection and compared with 39.7 MUmol/L in TL-1 cells with nonspecific shRNA. Pretreatment with EGFR or PI3K inhibitor in TL-1 cells diminished the resistance to cisplatin. Among the tumor groups, cIAP2 expression correlated significantly with HPV16/18 E6, EGFR, and p-AKT. We followed up 46 of 136 patients who had tumor recurrence and/or metastasis and underwent chemotherapy. Tumors with cIAP2 positive immunostaining were associated with a poorer tumor response to chemotherapy compared with those with negative immunostaining. CONCLUSIONS: cIAP2 upregulated by E6 via EGFR/PI3K/AKT cascades may contribute to cisplatin resistance, revealing that the EGFR or PI3K inhibitor combined with cisplatin may improve the chemotherapeutic efficacy in HPV-infected lung cancer. PMID- 20959405 TI - The IFNG (IFN-gamma) genotype predicts cytogenetic and molecular response to imatinib therapy in chronic myeloid leukemia. AB - PURPOSE: The present study analyzed treatment outcomes of imatinib therapy by interindividual genetic variants in candidate biological pathways of chronic myeloid leukemia (CML) such as apoptosis, angiogenesis, IFN-gamma signaling pathways, or drug transport/metabolism of imatinib. EXPERIMENTAL DESIGN: Peripheral blood DNAs were genotyped for 79 single nucleotide polymorphism markers involved in the pathways of apoptosis, angiogenesis, myeloid cell growth, xenobiotic metabolism, WT1 signaling, IFN signaling, and others in CML patients who were included in discovery (n = 229, Canada) and validation cohorts (n = 187, Korea). RESULTS: We found several genotypes associated with complete cytogenetic response: IFNG (rs1861494, rs2069705), FASL (rs763110), FAS (rs2234767, rs2234978), VEGFR2 (rs1531289), and WT1 (rs2234590); with major molecular response: IFNG (rs1861494, rs2069705), BIRC5 (rs9904341), FAS (rs2234978), and ABCG2 (rs2231142); with loss of response: IFNG (rs2069705), IFNGR2 (rs9808753), BIRC5 (rs9904341), and ORM (rs3182041); and with treatment failure: IFNG (rs2069705), JAK3 (rs3212713), and ORM (rs3182041). External validation for the above significant genotypes confirmed that the IFNG genotype (rs2069705) was predictive of complete cytogenetic response (hazard ratio, 2.17; P < 0.001) and major molecular response (hazard ratio, 1.96; P = 0.0001) in validation cohorts of Korean ethnicity. CONCLUSIONS: The IFNG genotype was predictive for response to imatinib therapy, suggesting potential involvement of the IFN-gamma signaling pathway in the mechanism of action of imatinib in CML. PMID- 20959406 TI - Psychologic intervention and survival: wishing does not make it so--letter. PMID- 20959407 TI - Safety and clinical effect of subcutaneous human interleukin-21 in patients with metastatic melanoma or renal cell carcinoma: a phase I trial. AB - PURPOSE: This phase I study in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of s.c. treatment of human recombinant interleukin 21 (IL-21). EXPERIMENTAL DESIGN: Phase I dose-escalation trial with treatment of three to six patients at each dose level, escalating from 3 to 300 MUg/kg. Treatment was administered s.c. on an outpatient basis 3 days per week for 8 or 16 weeks. RESULTS: Twenty-six patients entered the study. Recombinant IL-21 was generally well tolerated, and dose limiting toxicities (DLT) were first seen at dose levels of 200 and 300 MUg/kg. The following four DLTs were observed in three patients: increased transaminases, increased hyperbilirubinemia, hypersensitivity reaction, and lethargy. The MTD was declared to be 200 MUg/kg, although five of seven patients at the 300 MUg/kg dose level experienced no DLTs. A treatment-related effect on soluble CD25 was observed at all dose levels and increased with dose level. Furthermore, higher doses induced interferon-gamma, perforin, and granzyme B mRNA expression in peripheral blood, and granzyme B protein expression in both CD8(+) T cells and natural killer cells, consistent with the activation of cytotoxic lymphocytes. Three patients, one patient with MM and two with RCC, obtained a partial response. CONCLUSION: Outpatient treatment with s.c. administered IL-21 was tolerated and had dose-dependent pharmacodynamics. rIL-21 showed antitumor activity in patients with MM and RCC. PMID- 20959409 TI - Varying opinions on the authenticity of a human midgut carcinoid cell line- letter. PMID- 20959410 TI - IQGAP1 plays an important role in the invasiveness of thyroid cancer. AB - PURPOSE: This study was designed to explore the role of IQGAP1 in the invasiveness of thyroid cancer and its potential as a novel prognostic marker and therapeutic target in this cancer. EXPERIMENTAL DESIGN: We examined IQGAP1 copy gain and its relationship with clinicopathologic outcomes of thyroid cancer and investigated its role in cell invasion and molecules involved in the process. RESULTS: We found IQGAP1 copy number (CN) gain >= 3 in 1 of 30 (3%), 24 of 74 (32%), 44 of 107 (41%), 8 of 16 (50%), and 27 of 41 (66%) of benign thyroid tumor, follicular variant papillary thyroid cancer (FVPTC), follicular thyroid cancer (FTC), tall cell papillary thyroid cancer (PTC), and anaplastic thyroid cancer, respectively, in the increasing order of invasiveness of these tumors. A similar tumor distribution trend of CN >= 4 was also seen. IQGAP1 copy gain was positively correlated with IQGAP1 protein expression. It was significantly associated with extrathyroidal and vascular invasion of FVPTC and FTC and, remarkably, a 50%-60% rate of multifocality and recurrence of BRAF mutation positive PTC (P = 0.01 and 0.02, respectively). The siRNA knockdown of IQGAP1 dramatically inhibited thyroid cancer cell invasion and colony formation. Coimmunoprecipitation assay showed direct interaction of IQGAP1 with E-cadherin, a known invasion-suppressing molecule, which was upregulated when IQGAP1 was knocked down. This provided a mechanism for the invasive role of IQGAP1 in thyroid cancer. In contrast, IQGAP3 lacked all these functions. CONCLUSIONS: IQGAP1, through genetic copy gain, plays an important role in the invasiveness of thyroid cancer and may represent a novel prognostic marker and therapeutic target for this cancer. PMID- 20959411 TI - The level of glycolytic metabolism in acute myeloid leukemia blasts at diagnosis is prognostic for clinical outcome. AB - This research investigated the level of glycolytic metabolism in leukemic blasts as a prognostic marker in AML. Using an in vitro dye-reduction assay, we determined the level of glycolytic metabolism in 26 BM samples taken from 23 adult patients with newly diagnosed (n=19) or relapsed (n=4) AML, and AML blasts stratified into two distinct cohorts of moderate (<70%) or high (>80%) levels of glycolytic metabolism. All samples taken at relapse were moderately glycolytic. However, nine of the 19 samples taken at diagnosis were highly glycolytic, and 10 were moderately glycolytic. Three patients had paired samples taken at diagnosis and relapse, and the glycolytic metabolism of these samples did not alter between the two time-points. The level of glycolytic metabolism did not correlate with the percentage of marrow blasts, patient age, or CG/molecular risk group. Highly glycolytic AML blasts were more resistant to apoptosis induced by ATRA and/or ATO in vitro, suggesting potential resistance to induction chemotherapy, as has been observed in solid tumors. Despite this, high levels of glycolytic metabolism at diagnosis were predictive of a significantly improved duration of CR1 and OS following AML remission induction chemotherapy. In conclusion, we found that the extent of myeloblast glycolysis may be an effective and easily applied method to determine the pretreatment prognosis of AML. PMID- 20959412 TI - Adenosine deaminase potentiates the generation of effector, memory, and regulatory CD4+ T cells. AB - By interacting with CD26 on the CD4+ T cell surface and with the AdoR A(2B) on the DC surface, ADA triggers a costimulatory signal for human T cells. The aim of this study was to know whether ADA-mediated costimulation plays a role in the differentiation of T cells. The results show that irrespective of its enzymatic activity and dependent on TNF-alpha, IFN-gamma, and IL-6 action, ADA enhanced the differentiation of CD4+CD45RA+CD45RO- naive T cells toward CD4+CD25+CD45RO+ Teffs and CD4+CD45RA-CD45RO+ memory T cells. Furthermore, ADA potentiated generation of CD4+CD25(high)Foxp3+ Tregs by a mechanism that seems to be mainly dependent on the enzymatic activity of ADA. Interestingly, an ADA-mediated increase on Teff, memory T cell, and Treg generation occurred, not only in cocultures from healthy individuals but also from HIV-infected patients. These data suggest that ADA is a relevant modulator of CD4+ T cell differentiation, even in cells from immunologically compromised individuals. PMID- 20959413 TI - A caveat for T cell transfer studies: generation of cytotoxic anti-Thy1.2 antibodies in Thy1.1 congenic mice given Thy1.2+ tumors or T cells. AB - Thy1.1 congenic B6.PL mice were used to simultaneously monitor Thy1.2+ E.G7-OVA tumors transplanted in the a.c. of the eye and i.v.-transferred tumor-specific Thy1.2+ CTLs to determine mechanisms that inhibit the tumoricidal activity of CTL responses in mice with established ocular tumors. Transferred CTLs were systemically deleted in mice with established ocular tumors. However, this deletion was not a unique mechanism of immune evasion by ocular tumors. Rather, development of Thy1.2+ tumors in the eye or skin of B6.PL mice generated cytotoxic anti-Thy1.2 antibodies that eliminated a subsequent Thy1.2+ T cell transfer. Anti-Thy1.2 immune responses in B6.PL mice were influenced by the route of antigen administration, as the serum concentration of cytotoxic anti-Thy1.2 antibodies was 92-fold greater in mice with eye tumors in comparison with mice with skin tumors. In addition, anti-Thy1.2 immune responses were detected in B6.PL mice given naive Thy1.2+ T cells i.p. but not i.v. Anti-Thy1.2 responses were augmented in B6.PL mice with ocular Thy1.2+ EL-4 tumors that did not express OVA, suggesting immunodominance of OVA antigen over Thy1.2. Thy1.1+ T cells given i.p. was not immunogenic in Thy1.2 congenic mice. These data reaffirm that the introduction of antigens in the a.c. induces robust antibody responses. Experimentation using allotypic differences in Thy1 between donor cells and recipient mice must consider cytotoxic anti-Thy1 antibody generation in the interpretation of results. PMID- 20959414 TI - Evidence for a bimodal distribution in human communication. AB - Interacting human activities underlie the patterns of many social, technological, and economic phenomena. Here we present clear empirical evidence from Short Message correspondence that observed human actions are the result of the interplay of three basic ingredients: Poisson initiation of tasks and decision making for task execution in individual humans as well as interaction among individuals. This interplay leads to new types of interevent time distribution, neither completely Poisson nor power-law, but a bimodal combination of them. We show that the events can be separated into independent bursts which are generated by frequent mutual interactions in short times following random initiations of communications in longer times by the individuals. We introduce a minimal model of two interacting priority queues incorporating the three basic ingredients which fits well the distributions using the parameters extracted from the empirical data. The model can also embrace a range of realistic social interacting systems such as e-mail and letter communications when taking the time scale of processing into account. Our findings provide insight into various human activities both at the individual and network level. Our analysis and modeling of bimodal activity in human communication from the viewpoint of the interplay between processes of different time scales is likely to shed light on bimodal phenomena in other complex systems, such as interevent times in earthquakes, rainfall, forest fire, and economic systems, etc. PMID- 20959415 TI - Thromboxane A2 receptor and MaxiK-channel intimate interaction supports channel trans-inhibition independent of G-protein activation. AB - Large conductance voltage- and calcium-activated potassium channels (MaxiK, BK(Ca)) are well known for sustaining cerebral and coronary arterial tone and for their linkage to vasodilator beta-adrenergic receptors. However, how MaxiK channels are linked to counterbalancing vasoconstrictor receptors is unknown. Here, we show that vasopressive thromboxane A2 receptors (TP) can intimately couple with and inhibit MaxiK channels. Activation of the receptor with its agonist trans-inhibits MaxiK independently of G-protein activation. This unconventional mechanism is supported by independent lines of evidence: (i) inhibition of MaxiK current by thromboxane A2 mimetic, U46619, occurs even when G protein activity is suppressed; (ii) MaxiK and TP physically associate and display a high degree of proximity; and (iii) Forster resonance energy transfer occurs between fluorescently labeled MaxiK and TP, supporting a direct interaction. The molecular mechanism of MaxiK-TP intimate interaction involves the receptor's first intracellular loop and C terminus, and it entails the voltage-sensing conduction cassette of MaxiK channel. Further, physiological evidence of MaxiK-TP physical interaction is given in human coronaries and rat aorta, and by confirming TP role (with antagonist SQ29,548) in the U46619-induced MaxiK inhibition in human coronaries. We propose that vasoconstrictor TP receptor and MaxiK-channel direct interaction facilitates G-protein-independent TP to MaxiK trans-inhibition, which would promote vasoconstriction. PMID- 20959416 TI - microRNAs reveal the interrelationships of hagfish, lampreys, and gnathostomes and the nature of the ancestral vertebrate. AB - Hagfish and lampreys are the only living representatives of the jawless vertebrates (agnathans), and compared with jawed vertebrates (gnathostomes), they provide insight into the embryology, genomics, and body plan of the ancestral vertebrate. However, this insight has been obscured by controversy over their interrelationships. Morphological cladistic analyses have identified lampreys and gnathostomes as closest relatives, whereas molecular phylogenetic studies recover a monophyletic Cyclostomata (hagfish and lampreys as closest relatives). Here, we show through deep sequencing of small RNA libraries, coupled with genomic surveys, that Cyclostomata is monophyletic: hagfish and lampreys share 4 unique microRNA families, 15 unique paralogues of more primitive microRNA families, and 22 unique substitutions to the mature gene products. Reanalysis of morphological data reveals that support for cyclostome paraphyly was based largely on incorrect character coding, and a revised dataset is not decisive on the mono- vs. paraphyly of cyclostomes. Furthermore, we show fundamental conservation of microRNA expression patterns among lamprey, hagfish, and gnathostome organs, implying that the role of microRNAs within specific organs is coincident with their appearance within the genome and is conserved through time. Together, these data support the monophyly of cyclostomes and suggest that the last common ancestor of all living vertebrates was a more complex organism than conventionally accepted by comparative morphologists and developmental biologists. PMID- 20959417 TI - Pins and rubber band traction system and osteosynthesis with a hook plate for the treatment of old fracture-dislocation of a toe: application of hand operative techniques in a foot operation. AB - The treatment of old fracture-dislocation of a toe is usually difficult. The authors used 2 techniques that are commonly used in finger operations: One is the pins and rubber band traction system, and the other is the hook plate osteosynthesis. They treated a 56-year-old woman using these methods, and obtained a good result. PMID- 20959418 TI - Monolysocardiolipin: improved preparation with high yield. AB - A simple, high-yielding preparation of monolysocardiolipin (MLCL) by phospholipase A2 hydrolysis of cardiolipin (CL) in methanol on a semi-preparative scale is described. In methanol, phospholipase A2 preferentially hydrolyzes CL to MLCL. This selectivity results in ~80% yield of MLCL. The synthesized MLCL and dilysocardiolipin were characterized by NMR and ESI-MS/MS. Only the sn-2 position of CL was hydrolyzed by phospholipase A2 in methanol. PMID- 20959419 TI - Linking the salt transcriptome with physiological responses of a salt-resistant Populus species as a strategy to identify genes important for stress acclimation. AB - To investigate early salt acclimation mechanisms in a salt-tolerant poplar species (Populus euphratica), the kinetics of molecular, metabolic, and physiological changes during a 24-h salt exposure were measured. Three distinct phases of salt stress were identified by analyses of the osmotic pressure and the shoot water potential: dehydration, salt accumulation, and osmotic restoration associated with ionic stress. The duration and intensity of these phases differed between leaves and roots. Transcriptome analysis using P. euphratica-specific microarrays revealed clusters of coexpressed genes in these phases, with only 3% overlapping salt-responsive genes in leaves and roots. Acclimation of cellular metabolism to high salt concentrations involved remodeling of amino acid and protein biosynthesis and increased expression of molecular chaperones (dehydrins, osmotin). Leaves suffered initially from dehydration, which resulted in changes in transcript levels of mitochondrial and photosynthetic genes, indicating adjustment of energy metabolism. Initially, decreases in stress-related genes were found, whereas increases occurred only when leaves had restored the osmotic balance by salt accumulation. Comparative in silico analysis of the poplar stress regulon with Arabidopsis (Arabidopsis thaliana) orthologs was used as a strategy to reduce the number of candidate genes for functional analysis. Analysis of Arabidopsis knockout lines identified a lipocalin-like gene (AtTIL) and a gene encoding a protein with previously unknown functions (AtSIS) to play roles in salt tolerance. In conclusion, by dissecting the stress transcriptome of tolerant species, novel genes important for salt endurance can be identified. PMID- 20959420 TI - Global gene profiling of laser-captured pollen mother cells indicates molecular pathways and gene subfamilies involved in rice meiosis. AB - Pollen mother cells (PMCs) represent a critical early stage in plant sexual reproduction in which the stage is set for male gamete formation. Understanding the global molecular genetics of this early meiotic stage has so far been limited to whole stamen or floret transcriptome studies, but since PMCs are a discrete population of cells in developmental synchrony, they provide the potential for precise transcriptome analysis and for enhancing our understanding of the transition to meiosis. As a step toward identifying the premeiotic transcriptome, we performed microarray analysis on a homogenous population of rice (Oryza sativa) PMCs isolated by laser microdissection and compared them with those of tricellular pollen and seedling. Known meiotic genes, including OsSPO11-1, PAIR1, PAIR2, PAIR3, OsDMC1, OsMEL1, OsRAD21-4, OsSDS, and ZEP1, all showed preferential expression in PMCs. The Kyoto Encyclopedia of Genes and Genomes pathways significantly enriched in PMC-preferential genes are DNA replication and repair pathways. Our genome-wide survey showed that, in the buildup to meiosis, PMCs accumulate the molecular machinery for meiosis at the mRNA level. We identified 1,158 PMC-preferential genes and suggested candidate genes and pathways involved in meiotic recombination and meiotic cell cycle control. Regarding the developmental context for meiosis, the DEF-like, AGL2-like, and AGL6-like subclades of MADS box transcription factors are PMC-preferentially expressed, the trans-zeatin type of cytokinin might be preferentially synthesized, and the gibberellin signaling pathway is likely active in PMCs. The ubiquitin-mediated proteolysis pathway is enriched in the 127 genes that are expressed in PMCs but not in tricellular pollen or seedling. PMID- 20959421 TI - Loss of cytosolic phosphoglucomutase compromises gametophyte development in Arabidopsis. AB - Cytosolic phosphoglucomutase (cPGM) interconverts glucose-6-phosphate and glucose 1-phosphate and is a key enzyme of central metabolism. In this study, we show that Arabidopsis (Arabidopsis thaliana) has two cPGM genes (PGM2 and PGM3) encoding proteins with high sequence similarity and redundant functions. Whereas pgm2 and pgm3 single mutants were undistinguishable from the wild type, loss of both PGM2 and PGM3 severely impaired male and female gametophyte function. Double mutant pollen completed development but failed to germinate. Double mutant ovules also developed normally, but approximately half remained unfertilized 2 d after pollination. We attribute these phenotypes to an inability to effectively distribute carbohydrate from imported or stored substrates (e.g. sucrose) into the major biosynthetic (e.g. cell wall biosynthesis) and respiratory pathways (e.g. glycolysis and the oxidative pentose phosphate pathway). Disturbing these pathways is expected to have dramatic consequences for germinating pollen grains, which have high metabolic and biosynthetic activities. We propose that residual cPGM mRNA or protein derived from the diploid mother plant is sufficient to enable double mutant female gametophytes to attain maturity and for some to be fertilized. Mature plants possessing a single cPGM allele had a major reduction in cPGM activity. However, photosynthetic metabolism and growth were normal, suggesting that under standard laboratory conditions cPGM activity provided from one wild-type allele is sufficient to mediate the photosynthetic and respiratory fluxes in leaves. PMID- 20959422 TI - Characterization of delta-guaiene synthases from cultured cells of Aquilaria, responsible for the formation of the sesquiterpenes in agarwood. AB - The resinous portions of Aquilaria plants, called agarwood, have been used as medicines and incenses. Agarwood contains a great variety of sesquiterpenes, and a study using cultured cells of Aquilaria showed the production of sesquiterpenes (alpha-guaiene, alpha-humulene, and delta-guaiene) to be induced by treatment with methyl jasmonate (MJ). In this study, the accumulation and production of sesquiterpenes were quantified. The amounts accumulated and produced reached a maximum at 12 h, and the most abundant product was alpha-humulene at 6 h and delta-guaiene after 12 h. However, a headspace analysis of the cells revealed that alpha-humulene is likely to be volatilized; so overall, the most abundant sesquiterpene in the cells was delta-guaiene. A cDNA library from RNA isolated from MJ-treated cells was screened using PCR methodologies to isolate five clones with very similar amino acid sequences. These clones were expressed in Escherichia coli, and enzymatic reactions using farnesyl pyrophosphate revealed that three of the clones yielded the same compounds as extracted from MJ-treated cells, the major product being delta-guaiene. These genes and their encoded enzymes are the first sesquiterpene synthases yielding guaiane-type sesquiterpenes as their major products to be reported. Expression of a fourth terpene synthase gene in bacteria resulted in the accumulation of the protein in insoluble forms. Site-directed mutagenesis of the inactive clone and three dimensional homology modeling suggested that the structure of the N-terminal domain was important in facilitating proper folding of the protein to form a catalytically active structure. PMID- 20959423 TI - Photosynthesis, grain yield, and nitrogen utilization in rice and wheat. PMID- 20959424 TI - Factors predicting the probability of relapse after discontinuation of migraine preventive treatment with topiramate. AB - INTRODUCTION: Demographic and clinical variables were examined in a post hoc analysis of the PROlonged Migraine Prevention with Topiramate (PROMPT) study to determine potential contribution to relapse. METHODS: After a six-month open label (OL) topiramate phase, patients were randomised to continue topiramate or switch to placebo in a six-month double-blind (DB) phase. 'Relapse' was investigated in terms of change in monthly migraine days after randomisation compared with the month before randomisation, and was analysed during the first ('initial relapse') and last month ('sustained relapse') of the DB phase. More than 40 potential predicting factors were entered into analyses of variance and covariance. RESULTS: For initial relapse, variable-by-treatment interactions were significant for the Headache Impact Test (HIT-6) at DB baseline, and decline in acute medication intake or reporting of 'anxiety' in the OL phase. For sustained relapse, no statistically significant interactions were observed. CONCLUSION: Relapse after topiramate discontinuation in migraine prophylaxis appears to be unaffected by patient characteristics or baseline migraine frequency. PMID- 20959425 TI - 5-HTTLPR polymorphism in the serotonin transporter gene and migraine: a systematic review and meta-analysis. AB - BACKGROUND AND METHODS: Data on the association between the SLC6A4 5-HTTLPR polymorphism and migraine are conflicting. We performed a systematic review and meta-analysis among studies published up to September 2009. For each study with genotype information, we calculated odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs. RESULTS: Among the ten studies identified there was no overall association between the polymorphism and any migraine for Europeans or Asians. However, European women carrying the S allele had an increased risk for any migraine (dominant model: pooled OR=2.02; 95% CI 1.24 3.28). Results among Europeans further suggested an increased risk for migraine with aura among carriers of the S/S genotype (recessive model: pooled OR=1.41; 95% CI 0.83-2.40). CONCLUSIONS: While our results indicate no overall association between the SLC6A4 5-HTTLPR polymorphism and migraine among Europeans and Asians, gender and migraine aura status may have modifying roles among Europeans. PMID- 20959426 TI - Sex hormone receptor gene polymorphisms and migraine: a systematic review and meta-analysis. AB - BACKGROUND: Data on the association between sex hormone receptor polymorphisms and migraine are conflicting. METHODS: We performed a systematic review and meta analysis on this topic searching for studies published until August 2009. For each study, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs. RESULTS AND CONCLUSION: Among the seven genes targeted, four variants were investigated in multiple studies. Effect estimates from an additive model suggest that the ESR-1 594 G>A (pooled OR 1.37; 95% CI 1.02-1.83) and ESR-1 325 C>G (pooled OR 1.16; 95% CI 1.03-1.32) variants are associated with any migraine. This pattern does not differ between migraine with and without aura. In contrast, the ESR-1 Pvu II C>T and PGR PROGINS insert polymorphism do not appear to be associated with migraine. Results were driven by studies among Caucasians and may differ in other ethnic groups. PMID- 20959427 TI - Clinical features, imaging findings and outcomes of headache associated with sexual activity. AB - OBJECTIVES: To study the clinical profiles, imaging findings and outcomes and field test the diagnostic criteria proposed by the International Classification of Headache Disorders, 2nd edition (ICHD-II) in patients with headache associated with sexual activity (HSA). METHODS: We recruited 30 patients (16 men, 14 women, mean age at onset 40.2+/-10.0 years) with headache associated with sexual activity at a headache clinic from 2004 to 2009. None of the patients had neurological deficits at onset. RESULTS: Twenty patients (67%) had secondary causes, including one subarachnoid hemorrhage, one basilar artery dissection, and 18 cases reversible cerebral vasoconstriction syndrome (RCVS). Ten patients (33%) had primary HSA. The demographics, headache profiles, drug response and clinical course were similar between primary and secondary HSA. Compared to prior studies done in Western societies, our patients had similar clinical features but with a higher ratio of females (50%) and a higher frequency of chronic course (39%). DISCUSSION: Sixty-seven percent of patients with RCVS could not fulfill the criteria of reversible angiopathy of the central nervous system (Code 6.7.3) proposed by the ICHD-II. The most common reason was headache resolution in more than two months. In addition, 40% of patients with primary HSA could not fulfill the ICHD-II criteria for primary HSA (Code 4.4). CONCLUSIONS: Our study found that intracranial vascular disorders were very common in patients with HSA. Thorough neurovascular imaging is required for all patients with HSA. PMID- 20959428 TI - Efficacy and tolerability of a new powdered formulation of diclofenac potassium for oral solution for the acute treatment of migraine: results from the International Migraine Pain Assessment Clinical Trial (IMPACT). AB - OBJECTIVE: This study assessed the efficacy of diclofenac potassium for oral solution, a novel water-soluble buffered powder formulation, versus placebo for the acute treatment of migraine. Diclofenac potassium for oral solution has a time to maximum plasma concentration (Tmax) of 15 minutes, suggesting the potential for a rapid onset of therapeutic effects. METHODS: This was a randomized, double-blind, parallel-group, placebo-controlled study conducted in 23 US centers. Adult sufferers with an established migraine diagnosis according to the International Classification of Headache Disorders, second edition (ICHD II), treated one moderate or severe attack with 50 mg diclofenac potassium for oral solution (dissolved in approximately 2 ounces of water; N=343) or matching placebo (N=347). Four co-primary endpoints included the percentage of subjects who at two hours post-treatment reported no headache pain, no nausea, no photophobia and/or no phonophobia. RESULTS: Significantly more subjects treated with diclofenac potassium for oral solution (N=343) achieved a two-hour pain-free response (25% vs. 10%, p<.001), no nausea (65% vs. 53%; p=.002), no photophobia (41% vs. 27%; p<.001) and no phonophobia (44% vs. 27%; p<.001) compared to placebo. Pain intensity differences between treatments were significantly lower in the diclofenac potassium oral solution group, starting at 30 minutes post treatment (p=.013) with significant differences at all time points thereafter (p<.001). Twenty-four-hour sustained pain-free response favored diclofenac potassium oral solution treatment versus placebo (19% vs. 7%, p<.0001). The most common adverse event considered to be treatment related was nausea (diclofenac potassium for oral solution [4.6%]; placebo [4.3%]). CONCLUSIONS: This study shows that this formulation of diclofenac potassium for oral solution is effective in reducing pain intensity within 30 minutes, which may be related to the 15-minute T(max) associated with this formulation. The rapid-onset benefits were sustained through 24 hours post-treatment. PMID- 20959429 TI - CGRP receptor antagonist olcegepant (BIBN4096BS) does not prevent glyceryl trinitrate-induced migraine. AB - There is a striking similarity between the migraine-provoking effect of the nitric oxide (NO) donor glyceryl trinitrate (GTN) and that of calcitonin gene related peptide (CGRP). We tested the hypothesis that NO releases CGRP to cause the delayed migraine attack after GTN. METHODS: In a double-blind-cross-over study, 13 migraine without aura (MO) patients were administered GTN 0.5 ug/kg/minute for 20 minutes and subsequently BIBN4096BS (olcegepant) 10 mg or placebo. Headache scores and development of MO were followed for 24 hours. RESULTS: MO developed in seven of 13 with olcegepant and in nine of 13 with placebo (p=0.68). The headache scores were similar after the two treatments (p=0.58). Thus CGRP receptor blockade did not prevent GTN-induced migraine. CONCLUSIONS: The present study indicates that NO does not induce migraine by liberating CGRP. The most likely explanation for our findings is that CGRP has its effect higher than NO in the cascade of events leading to MO attacks. PMID- 20959430 TI - No arguments for increased endothelial nitric oxide synthase activity in migraine based on peripheral biomarkers. AB - OBJECTIVES: To assess whether migraine patients display a chronic nitric oxide synthase (NOS) hyperactivity by comparing the nitric oxide (NO) production before and following a loading dose of L-arginine between migraine patients (interictally) and matched healthy control subjects. In addition, we evaluated whether a loading dose of L-arginine triggers an acute migraine headache in migraineurs. SUBJECTS AND METHODS: Twenty healthy subjects and 20 migraine patients participated in a 2-period, randomised, double-blind, placebo-controlled study. Each subject received a 30-min infusion, by peripheral vein, of 30 g L arginine hydrochloride or placebo (i.e. an equal volume of 0.9% saline solution). Meanwhile, biomarkers associated with the L-arginine-NO pathway (i.e. exhaled NO/nasal NO), plasma citrulline and urinary excretion of nitrite/nitrate and cGMP were assessed before and for 6 h following the start of the infusion. RESULTS: At baseline, exhaled NO and nasal NO were higher in migraineurs compared to healthy subjects (mean+/-95% confidence interval): 15.9 (8.8, 23.0) parts per billion (ppb) versus 10.8 (7.0, 14.5) ppb for exhaled NO (P=0.04) and 76.3 (61.2, 91.4) versus 61.6 (51.2, 72.0) ppb for nasal NO (P=0.03), respectively. The AUC0-6 in ppb for exhaled NO and nasal NO following L-arginine or saline infusion did not differ between both groups. The increase in L-citrulline, following L-arginine infusion, was smaller in migraine patients (15 (13, 18) umol/l) compared to healthy volunteers (19 (16, 23) umol/l; P=0.046). In healthy subjects, both nitrate and cGMP excretion were higher following L-arginine compared to placebo infusion: 132.63 (100.24, 165.02) versus 92.07 (66.33, 117.82) umol/mmol creatinine for nitrate (P=0.014) and 50.53 (42.19, 58.87) versus 39.64 (33.94, 45.34) nmol/mmol creatinine for cGMP (P=0.0003), respectively. In migraineurs, excretion of these biomarkers was comparable following L-arginine or saline infusion. CONCLUSIONS: The results of the present study do not support the idea of a generalised increase in NO synthase activity in migraine patients outside of a migraine attack. The smaller increase in plasma L-citrulline, urinary nitrate and cGMP excretion following L-arginine infusion in migraine patients might indicate dysfunction of endothelial NO synthase. PMID- 20959431 TI - GLP-2 and leptin are associated with hyperinsulinemia in non-obese female migraineurs. AB - OBJECTIVE: Impaired insulin metabolism has been implicated in migraine. However, to date only some putative effects, especially regarding the involvement of adipocytokines and glucagon-like peptides (GLPs), have been described. The aim of the present study was to investigate adipocytokines and GLPs in non-obese female migraineurs. METHODS: Various parameters of the insulin metabolism and body measurements were determined in 84 non-obese female subjects. RESULTS: We found highly significantly increased insulin levels with an odds ratio of 10.62 for migraine. Leptin and GLP-2 levels were also increased and correlated with insulin. Logistic regression analysis of leptin and GLP-2 revealed odds ratios of 3.79 and 4.26 for migraine, respectively, when comparing the lowest with the highest quartile of the test variable in the complete study cohort. DISCUSSION: We show that non-obese female migraineurs suffer from hyperinsulinemia, which is associated with elevated leptin and GLP-2 levels. Increased leptin and GLP-2 are risk factors for migraine. Our data suggest that migraine is associated with a higher risk for insulin resistance and its clinical consequences. PMID- 20959432 TI - BDNF and CGRP interaction: implications in migraine susceptibility. AB - OBJECTIVES: Migraine pathophysiology involves several pathways. Our aims were to explore a possible role of the brain-derived neurotrophic factor gene (BDNF) in migraine susceptibility; to study, for the first time, the calcitonin gene related peptide gene (CGRP); and a possible interaction between the two. METHODS: Using a case-control approach, four tagging single nucleotide polymorphisms (SNPs) (rs7124442, rs6265, rs11030107, and rs2049046) of BDNF and one tagging SNP rs1553005-of CGRP were analyzed in 188 cases and 287 controls. A multivariable logistic regression was performed, adjusting for gender. Allelic and haplotypic frequencies were estimated. Interaction was assessed by a stepwise multivariable logistic regression and confirmed by a multifactor dimensionality reduction analysis. RESULTS: No significant main effects were found; however, a significant interaction was found between BDNF and CGRP, showing an increased risk for the AT genotype of rs2049046 and the GC-genotype of rs1553005 (odds ratio=1.88, 95% confidence interval: 1.20-2.93) for migraineurs. CONCLUSION: Our data support the hypothesis of an interaction between BDNF and CGRP in migraine susceptibility that should be further explored. PMID- 20959433 TI - Central nervous system dysregulation extends beyond the pain-matrix network in cluster headache. AB - INTRODUCTION: In this study, we investigated whether abnormalities of the brain resting-state networks (RSNs) occur in patients with episodic cluster headache (CH), outside the attacks of the disease. PATIENTS AND METHODS: RS fMRI scans were acquired from 13 CH patients and 15 healthy controls. RS fMRI data were analyzed using both independent component analysis (ICA) and a seed correlation analysis, starting from the hypothalamus and the thalamus. RESULTS: The seed correlation analysis revealed increased functional connectivity within the networks identified starting from the hypothalami and thalami in CH patients versus controls. ICA analysis detected 11 RSNs with potential functional relevance. Among these networks, CH patients had decreased fluctuations within the sensorimotor and the primary visual network compared to controls (P-values 0.03-0.007). RSN abnormalities were significantly correlated with disease duration. CONCLUSIONS: In CH patients a diffuse abnormality of brain functional connectivity is present, which extends beyond the antinoceptive system. PMID- 20959434 TI - An early 18th-century case description of cluster headache. AB - We present a previously unreported early 18th-century description of cluster headache by the English antiquary Abraham de la Pryme (1671-1704) initially attributed to hydrophobia (rabies). We will also give a short overview of other descriptions of cluster and cluster-like headache in historical literature. PMID- 20959435 TI - Nummular headache associated with focal hair heterochromia in a child. AB - Nummular headache (NH) is a recently described headache syndrome where continuous or intermittent pain is localised to a coin-shaped region of the skull. NH can be a primary headache disorder or secondary to intracranial or extracranial pathology. We report a four-year-old boy who presented with nummular headache co localised with a patch of discoloured hair and propose a common aetiology. PMID- 20959436 TI - Hypothermia during migraine attacks. AB - Episodic spontaneous hypothermia is an infrequent disorder. Here, the case of a patient with migraine who experienced hypothermia during her migraine attacks is presented. The authors propose that larger clinical series should be studied to evaluate the occurrence of hypothermia in migraine, as well as the possible influence of some preventive regimens in this setting. PMID- 20959437 TI - Low-level laser therapy for neck pain. PMID- 20959438 TI - Medication overuse headache--comments on the current International Headache Society classification criteria. PMID- 20959439 TI - Expression of connective tissue growth factor and IGF1 in normal and neoplastic gastrointestinal neuroendocrine cells and their clinico-pathological significance. AB - Connective tissue growth factor (CTGF) and IGF1 are both expressed in a variety of tumours and are involved in tumourigenesis. However, information about their expression in the gastrointestinal (GI) neuroendocrine (NE) cells and tumours is mainly limited, with the exception of midgut carcinoids where abundant CTGF expression has been demonstrated. Normal mucosa specimens from stomach and ileum, as well as tumour tissue specimens from gastric NE tumours (GNETs; n=58) and midgut NETs (n=38) were included. Immunohistochemical techniques were used to investigate the possible expression of CTGF and IGF1 in GI NE cells and tumours. The latter results were correlated with various clinico-biochemical and histopathological variables. CTGF was expressed in a proportion of NE cells of the normal GI mucosa but not in enterochromaffin-like (ECL) cells, whereas IGF1 was undetectable. CTGF was absent in the foci of ECL cell hyperplasia, and in most of the poorly differentiated carcinomas, but present in some GNETs (mainly in type III ECL cell carcinoids (ECL-CCs)) and in all but one midgut NETs. CTGF correlated with tumour stage in well-differentiated GNETs and with size larger than 1 cm but only in the subgroup of type I ECL-CCs. IGF1 was detected in the foci of ECL cell hyperplasia and in all GI NETs. These findings suggest that both CTGF and IGF1 may be involved in the neoplastic transformation of GI NE cells, whereas IGF1 may play an important role even at early stage. PMID- 20959440 TI - Ki-67 index, tumor differentiation, and extent of liver involvement are independent prognostic factors in patients with liver metastases of digestive endocrine carcinomas. AB - The prognosis remains ill-defined in patients with liver metastases of well differentiated (WD) digestive endocrine carcinomas (DEC) with high Ki-67 index. The objectives of this study were to determine whether Ki-67 index, tumor differentiation, and extent of liver involvement are independent prognostic factors in patients with DEC, and whether chemotherapy commonly used in patients with poorly differentiated (PD) carcinomas might be applied to those with high Ki 67 index but well-differentiated DEC. Sixty-three patients with DEC metastatic to the liver were retrospectively studied and divided into three prognostic groups. Group 1 comprised patients with well-differentiated carcinomas and Ki-67 index<15% (n=28), group 2 comprised those with well-differentiated carcinomas and Ki-67 index>=15% (n=17), and group 3 comprised those with poorly differentiated carcinomas (n=18). Therapeutic strategy was decided in accordance to guidelines, and tumoral response rate was assessed by computed tomography scan (RECIST). Prognostic factors were determined by uni/multivariate analysis. The 5-year survival rates were 89, 36, and 6% in groups 1, 2, and 3 respectively (P<0.001). Multivariate analysis showed that Ki-67 index>=15%, poor tumor differentiation, and large liver tumor burden were independent predictors of poorer survival. Disease control rates after etoposide-cisplatin were 50 and 53% in groups 2 and 3 respectively (NS). In conclusion, Ki-67 index, tumor differentiation, and extent of liver involvement are independent prognostic factors in patients with liver metastases of DEC. Patients with well-differentiated carcinomas with high Ki-67 index (>=15%) have intermediate prognosis and a similar response rate to the etoposide-cisplatin combination as those with poorly differentiated carcinomas. PMID- 20959441 TI - Expression of neuregulin 4 splice variants in normal human tissues and prostate cancer and their effects on cell motility. AB - The neuregulin 4 gene encodes at least five different variants (designated A1, A2, B1, B2 and B3) produced as a result of alternative splicing. We have determined their sites of expression in normal human adult tissues using isoform specific antibodies. Their expression is cell type specific and differs in subcellular location suggesting that they may have varied functions in these contexts. We have shown in a panel of prostate cancers that each form is present to differing degrees, and that principal component analysis indicates that there are three patterns of expression. Some isoforms were positively correlated with high prostate-specific antigen levels and others were inversely associated with Gleason score. Synthetic, refolded A forms promoted lamellipodia and filopodia formation in cells expressing the ErbB4 (CTa) receptor and stimulated cell motility in wound healing assays. The data suggest that the different forms have varied sites of expression and function, and this includes effects on cell architecture and motility. PMID- 20959442 TI - Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility. AB - Germline mutations in the von Hippel-Lindau disease (VHL) and succinate dehydrogenase subunit B (SDHB) genes can cause inherited phaeochromocytoma and/or renal cell carcinoma (RCC). Dysregulation of the hypoxia-inducible factor (HIF) transcription factors has been linked to VHL and SDHB-related RCC; both HIF dysregulation and disordered function of a prolyl hydroxylase domain isoform 3 (PHD3/EGLN3)-related pathway of neuronal apoptosis have been linked to the development of phaeochromocytoma. The 2-oxoglutarate-dependent prolyl hydroxylase enzymes PHD1 (EGLN2), PHD2 (EGLN1) and PHD3 (EGLN3) have a key role in regulating the stability of HIF-alpha subunits (and hence expression of the HIF-alpha transcription factors). A germline PHD2 mutation has been reported in association with congenital erythrocytosis and recurrent extra-adrenal phaeochromocytoma. We undertook mutation analysis of PHD1, PHD2 and PHD3 in two cohorts of patients with features of inherited phaeochromocytoma (n=82) and inherited RCC (n=64) and no evidence of germline mutations in known susceptibility genes. No confirmed pathogenic mutations were detected suggesting that mutations in these genes are not a frequent cause of inherited phaeochromocytoma or RCC. PMID- 20959443 TI - Ectosomes released by polymorphonuclear neutrophils induce a MerTK-dependent anti inflammatory pathway in macrophages. AB - At the earliest stage of activation, human polymorphonuclear neutrophils release vesicles derived directly from the cell surface. These vesicles, called ectosomes (PMN-Ect), expose phosphatidylserine in the outer membrane leaflet. They inhibit the inflammatory response of human monocyte-derived macrophages and dendritic cells to zymosan A (ZymA) and LPS and induce TGF-beta1 release, suggesting a reprogramming toward a tolerogenic phenotype. The receptors and signaling pathways involved have not yet been defined. Here, we demonstrate that PMN-Ect interfered with ZymA activation of macrophages via inhibition of NFkappaB p65 phosphorylation and NFkappaB translocation. The MerTK (Mer receptor tyrosine kinase) and PI3K/Akt pathways played a key role in this immunomodulatory effect as shown using specific MerTK-blocking antibodies and PI3K inhibitors LY294002 and wortmannin. As a result, PMN-Ect reduced the transcription of many proinflammatory genes in ZymA-activated macrophages. In sum, PMN-Ect interacted with the macrophages by activation of the MerTK pathway responsible for down modulation of the proinflammatory signals generated by ZymA. PMID- 20959444 TI - Ergosterol regulates sterol regulatory element binding protein (SREBP) cleavage in fission yeast. AB - In fission yeast, the endoplasmic reticulum membrane-bound proteins Sre1 and Scp1, orthologs of mammalian sterol regulatory element binding protein (SREBP) and Scap, monitor sterol synthesis as an indirect measure of oxygen supply. When cellular oxygen levels are low, sterol synthesis is inhibited, and the Sre1-Scp1 complex responds by increasing transcription of genes required for adaptation to hypoxia. Sre1 and Scp1 are believed to detect a blockage in sterol synthesis by monitoring levels of particular sterols, but the evidence concerning which sterol signals this condition is unclear. Here, we demonstrate that Sre1-Scp1 senses ergosterol. Processing experimental data with a mathematical model of Sre1 and Scp1 function reveals a clear quantitative relationship between ergosterol concentration in the endoplasmic reticulum and Sre1 activation. Based on this relationship, we predict that the Sre1-Scp1 complex exists under "active" and "inactive" states and that the transition between these states is cooperatively mediated by ergosterol. PMID- 20959445 TI - Thematic minireview series on nuclear receptors in biology and diseases. PMID- 20959446 TI - CD300 heterocomplexes, a new and family-restricted mechanism for myeloid cell signaling regulation. AB - The CD300 family of myeloid immunoglobulin receptors includes activating (CD300b, CD300e) and inhibitory members (CD300a, CD300f), as well as molecules of uncertain function presenting a negative charge within their transmembrane domain (CD300c, CD300d). In this paper, we establish that CD300c is a functional immune receptor able to deliver activating signals upon ligation in RBL-2H3 mast cells. CD300c signaling is partially mediated by a direct association with the immune receptor tyrosine-based activation motif-bearing adaptor FcepsilonRgamma. The existence of complementary transmembrane-charged residues in certain CD300 receptors suggested the formation of heterodimers within this family. Indeed, we proved the interaction between CD300b and CD300c in transfected COS-7 cells and demonstrated that it has important functional consequences. Unexpectedly, dimmer formation was dependent on the immunoglobulin domains rather than the charged transmembrane residues. Concordantly, all CD300 members were found to interact with each other, even with themselves, forming both homo- and heterodimers. We found that the combination of CD300 receptors in a complex differentially modulates the signaling outcome, strongly suggesting a new mechanism by which CD300 complexes could regulate the activation of myeloid cells upon interaction with their natural ligands. PMID- 20959447 TI - Protein kinase C {delta}-specific activity reporter reveals agonist-evoked nuclear activity controlled by Src family of kinases. AB - Conventional and novel protein kinase C (PKC) isozymes transduce the abundance of signals mediated by phospholipid hydrolysis; however redundancy in regulatory mechanisms confounds dissecting the unique signaling properties of each of the eight isozymes constituting these two subgroups. Previously, we created a genetically encoded reporter (C kinase activity reporter (CKAR)) to visualize the rate, amplitude, and duration of agonist-evoked PKC signaling at specific locations within the cell. Here we designed a reporter, deltaCKAR, that specifically measures the activation signature of one PKC isozyme, PKC delta, in cells, revealing unique spatial and regulatory properties of this isozyme. Specifically, we show two mechanisms of activation: 1) agonist-stimulated activation at the plasma membrane (the site of most robust PKC delta signaling), Golgi, and mitochondria that is independent of Src and can be triggered by phorbol esters and 2) agonist-stimulated activation in the nucleus that requires Src kinase activation and cannot be triggered by phorbol esters. Translocation studies reveal that the G-protein-coupled receptor agonist UTP induces the translocation of PKC delta into the nucleus by a mechanism that depends on the C2 domain and requires Src kinase activity. However, translocation from the cytosol into the nucleus is not required for the Src-dependent regulation of nuclear activity; a construct of PKC delta prelocalized to the nucleus continues to be activated by UTP by a mechanism dependent on Src kinase activity. These data identify the nucleus as a signaling hub for PKC delta that is driven by receptor mediated signaling pathways (but not phorbol esters) and differs from signaling at plasma membrane and Golgi in that it is controlled by Src family kinases. PMID- 20959448 TI - Uncoupling substrate transport from ATP hydrolysis in the Escherichia coli maltose transporter. AB - Members of the ATP-binding cassette superfamily couple the energy from ATP hydrolysis to the active transport of substrates across the membrane. The maltose transporter, a well characterized model system, consists of a periplasmic maltose binding protein (MBP) and a multisubunit membrane transporter, MalFGK(2). On the basis of the structure of the MBP-MalFGK(2) complex in an outward-facing conformation (Oldham, M. L., Khare, D., Quiocho, F. A., Davidson, A. L., and Chen, J. (2007) Nature 450, 515-521), we identified two mutants in transmembrane domains MalF and MalG that generated futile cycling; although interaction with MBP stimulated the ATPase activity of the transporter, maltose was not transported. Both mutants appeared to disrupt the normal transfer of maltose from MBP to MalFGK(2). In the first case, substitution of aspartate for glycine in the maltose-binding site of MalF likely generated a futile cycle by preventing maltose from binding to MalFGK(2) during the catalytic cycle. In the second case, a four-residue deletion of a periplasmic loop of MalG limited its reach into the maltose-binding pocket of MBP, allowing maltose to remain associated with MBP during the catalytic cycle. Retention of maltose in the MBP binding site in the deletion mutant, as well as insertion of this loop into the binding site in the wild type, was detected by EPR as a change in mobility of a nitroxide spin label positioned near the maltose-binding pocket of MBP. PMID- 20959449 TI - Spidroin N-terminal domain promotes a pH-dependent association of silk proteins during self-assembly. AB - Spider silks are spun from concentrated solutions of spidroin proteins. The appropriate timing of spidroin assembly into organized fibers must be highly regulated to avoid premature fiber formation. Chemical and physical signals presented to the silk proteins as they pass from the ampulle and through the tapered duct include changes in ionic environment and pH as well as the introduction of shear forces. Here, we show that the N-terminal domain of spidroins from the major ampullate gland (MaSp-NTDs) for both Nephila and Latrodectus spiders associate noncovalently as homodimers. The MaSp-NTDs are highly pH-responsive and undergo a structural transition in the physiological pH range of the spider duct. Tryptophan fluorescence of the MaSp-NTDs reveals a change in conformation when pH is decreased, and the pH at which the transition occurs is determined by the amount and type of salt present. Size exclusion chromatography and pulldown assays both indicate that the lower pH conformation is associated with a significantly increased MaSp-NTD homodimer stability. By transducing the duct pH signal into specific protein-protein interactions, this conserved spidroin domain likely contributes significantly to the silk-spinning process. Based on these results, we propose a model of spider silk assembly dynamics as mediated through the MaSp-NTD. PMID- 20959450 TI - YidC is involved in the biogenesis of the secreted autotransporter hemoglobin protease. AB - Autotransporters (ATs) constitute an important family of virulence factors secreted by Gram-negative bacteria. Following their translocation across the inner membrane (IM), ATs temporarily reside in the periplasmic space after which they are secreted into the extracellular environment. Previous studies have shown that the AT hemoglobin protease (Hbp) of Escherichia coli requires a functional signal recognition particle pathway and Sec translocon for optimal targeting to and translocation across the IM. Here, we analyzed the mode of IM translocation of Hbp in more detail. Using site-directed photocross-linking, we found that the Hbp signal peptide is adjacent to YidC early during biogenesis. Notably, YidC is in part associated with the Sec translocon but has until now primarily been implicated in the biogenesis of IM proteins. In vivo, YidC appeared critical for the biogenesis of the ATs Hbp and EspC. For Hbp, depletion of YidC resulted in the formation of secretion-incompetent intermediates that were sensitive to degradation by the periplasmic protease DegP, indicating that YidC activity affects Hbp biogenesis at a late stage, after translocation across the IM. This is the first demonstration of a role for YidC in the biogenesis of an extracellular protein. We propose that YidC is required for maintenance of the translocation-competent state of certain ATs in the periplasm. The large periplasmic domain of YidC is not critical for this novel functionality as it can be deleted without affecting Hbp biogenesis. PMID- 20959451 TI - Neuropeptide Y modulation of interleukin-1{beta} (IL-1{beta})-induced nitric oxide production in microglia. AB - Given the modulatory role of neuropeptide Y (NPY) in the immune system, we investigated the effect of NPY on the production of NO and IL-1beta in microglia. Upon LPS stimulation, NPY treatment inhibited NO production as well as the expression of inducible nitric-oxide synthase (iNOS). Pharmacological studies with a selective Y(1) receptor agonist and selective antagonists for Y(1), Y(2), and Y(5) receptors demonstrated that inhibition of NO production and iNOS expression was mediated exclusively through Y(1) receptor activation. Microglial cells stimulated with LPS and ATP responded with a massive release of IL-1beta, as measured by ELISA. NPY inhibited this effect, suggesting that it can strongly impair the release of IL-1beta. Furthermore, we observed that IL-1beta stimulation induced NO production and that the use of a selective IL-1 receptor antagonist prevented NO production upon LPS stimulation. Moreover, NPY acting through Y(1) receptor inhibited LPS-stimulated release of IL-1beta, inhibiting NO synthesis. IL-1beta activation of NF-kappaB was inhibited by NPY treatment, as observed by confocal microscopy and Western blotting analysis of nuclear translocation of NF-kappaB p65 subunit, leading to the decrease of NO synthesis. Our results showed that upon LPS challenge, microglial cells release IL-1beta, promoting the production of NO through a NF-kappaB-dependent pathway. Also, NPY was able to strongly inhibit NO synthesis through Y(1) receptor activation, which prevents IL-1beta release and thus inhibits nuclear translocation of NF-kappaB. The role of NPY in key inflammatory events may contribute to unravel novel gateways to modulate inflammation associated with brain pathology. PMID- 20959452 TI - Enhancement of reactive oxygen species production and chlamydial infection by the mitochondrial Nod-like family member NLRX1. AB - Chlamydia trachomatis infections cause severe and irreversible damage that can lead to infertility and blindness in both males and females. Following infection of epithelial cells, Chlamydia induces production of reactive oxygen species (ROS). Unconventionally, Chlamydiae use ROS to their advantage by activating caspase-1, which contributes to chlamydial growth. NLRX1, a member of the Nod like receptor family that translocates to the mitochondria, can augment ROS production from the mitochondria following Shigella flexneri infections. However, in general, ROS can also be produced by membrane-bound NADPH oxidases. Given the importance of ROS-induced caspase-1 activation in growth of the chlamydial vacuole, we investigated the sources of ROS production in epithelial cells following infection with C. trachomatis. In this study, we provide evidence that basal levels of ROS are generated during chlamydial infection by NADPH oxidase, but ROS levels, regardless of their source, are enhanced by an NLRX1-dependent mechanism. Significantly, the presence of NLRX1 is required for optimal chlamydial growth. PMID- 20959453 TI - CHIP promotes human telomerase reverse transcriptase degradation and negatively regulates telomerase activity. AB - The maintenance of eukaryotic telomeres requires telomerase, which is minimally composed of a telomerase reverse transcriptase (TERT) and an associated RNA component. Telomerase activity is tightly regulated by expression of human (h) TERT at both the transcriptional and post-translational levels. The Hsp90 and p23 molecular chaperones have been shown to associate with hTERT for the assembly of active telomerase. Here, we show that CHIP (C terminus of Hsc70-interacting protein) physically associates with hTERT in the cytoplasm and regulates the cellular abundance of hTERT through a ubiquitin-mediated degradation. Overexpression of CHIP prevents nuclear translocation of hTERT and promotes hTERT degradation in the cytoplasm, thereby inhibiting telomerase activity. In contrast, knockdown of endogenous CHIP results in the stabilization of cytoplasmic hTERT. However, it does not affect the level of nuclear hTERT and has no effect on telomerase activity and telomere length. We further show that the binding of CHIP and Hsp70 to hTERT inhibits nuclear translocation of hTERT by dissociating p23. However, Hsp90 binding to hTERT was not affected by CHIP overexpression. These results suggest that CHIP can remodel the hTERT-chaperone complexes. Finally, the amount of hTERT associated with CHIP peaks in G(2)/M phases but decreases during S phase, suggesting a cell cycle-dependent regulation of hTERT. Our data suggest that CHIP represents a new pathway for modulating telomerase activity in cancer. PMID- 20959454 TI - An alternative pathway for Okazaki fragment processing: resolution of fold-back flaps by Pif1 helicase. AB - Two pathways have been proposed for eukaryotic Okazaki fragment RNA primer removal. Results presented here provide evidence for an alternative pathway. Primer extension by DNA polymerase delta (pol delta) displaces the downstream fragment into an RNA-initiated flap. Most flaps are cleaved by flap endonuclease 1 (FEN1) while short, and the remaining nicks joined in the first pathway. A small fraction escapes immediate FEN1 cleavage and is further lengthened by Pif1 helicase. Long flaps are bound by replication protein A (RPA), which inhibits FEN1. In the second pathway, Dna2 nuclease cleaves an RPA-bound flap and displaces RPA, leaving a short flap for FEN1. Pif1 flap lengthening creates a requirement for Dna2. This relationship should not have evolved unless Pif1 had an important role in fragment processing. In this study, biochemical reconstitution experiments were used to gain insight into this role. Pif1 did not promote synthesis through GC-rich sequences, which impede strand displacement. Pif1 was also unable to open fold-back flaps that are immune to cleavage by either FEN1 or Dna2 and cannot be bound by RPA. However, Pif1 working with pol delta readily unwound a full-length Okazaki fragment initiated by a fold-back flap. Additionally, a fold-back in the template slowed pol delta synthesis, so that the fragment could be removed before ligation to the lagging strand. These results suggest an alternative pathway in which Pif1 removes Okazaki fragments initiated by fold-back flaps in vivo. PMID- 20959455 TI - Phosphorylated TP63 induces transcription of RPN13, leading to NOS2 protein degradation. AB - Head and neck squamous cell carcinoma cells exposed to cisplatin display ATM dependent phosphorylation of the most predominant TP63 isoform (DeltaNp63alpha), leading to its activation as a transcription factor. Here, we found that the phospho-DeltaNp63alpha protein binds to the genomic promoter of RPN13 through the TP63-responsive element. We further found that the phospho-DeltaNp63alpha protein associates with other transcription factors (DDIT3 (also known as CHOP), NF-Y, and NF-kappaB), activating RPN13 gene transcription. Furthermore, cisplatin induced and phospho-DeltaNp63alpha-dependent RPN13 gene transcription leads to NOS2 degradation. Finally, we show that RPN13 knockdown by siRNA essentially rescues NOS2 from cisplatin-dependent inactivation. These data provide a novel mechanism for the phospho-DeltaNp63alpha-dependent regulation of NOS2 function in cells upon cisplatin treatment, contributing to the cell death pathway of tumor cells. PMID- 20959456 TI - Phosphorylated alpha-synuclein at Ser-129 is targeted to the proteasome pathway in a ubiquitin-independent manner. AB - alpha-Synuclein (a-Syn) is a major component of fibrillar aggregates in Lewy bodies (LBs), a characteristic hallmark of Parkinson disease. Almost 90% of a-Syn deposited in LBs is phosphorylated at Ser-129. However, the role of Ser-129 phosphorylated a-Syn in the biogenesis of LBs remains unclear. Here, we investigated the metabolism of Ser-129-phosphorylated a-Syn. In SH-SY5Y cells, inhibition of protein phosphatase 2A/1 by okadaic acid, and inhibition of the proteasome pathway by MG132 or lactacystin accumulated Ser-129-phosphorylated a Syn. However, these inhibitions did not alter the amounts of total a-Syn within the observation time. Inhibition of the autophagy-lysosome pathway by 3 methyladenine or chloroquine accumulated Ser-129-phosphorylated a-Syn in parallel to total a-Syn during longer incubations. Experiments using cycloheximide showed that Ser-129-phosphorylated a-Syn diminished rapidly (t(½) = 54.9 +/- 6.4 min), in contrast to the stably expressed total a-Syn. The short half-life of Ser 129-phosphorylated a-Syn was blocked by MG132 to a greater extent than okadaic acid. In rat primary cortical neurons, either MG132, lactacystin, or okadaic acid accumulated Ser-129-phosphorylated a-Syn. Additionally, we did not find that phosphorylated a-Syn was ubiquitinated in the presence of proteasome inhibitors. These data show that Ser-129-phosphorylated a-Syn is targeted to the proteasome pathway in a ubiquitin-independent manner, in addition to undergoing dephosphorylation. The proteasome pathway may play a role in the biogenesis of Ser-129-phosphorylated a-Syn-rich LBs. PMID- 20959457 TI - HLA-DP, HLA-DQ, and HLA-DR have different requirements for invariant chain and HLA-DM. AB - The MHC is central to the adaptive immune response. The human MHC class II is encoded by three different isotypes, HLA-DR, -DQ, and -DP, each being highly polymorphic. In contrast to HLA-DR, the intracellular assembly and trafficking of HLA-DP molecules have not been studied extensively. However, different HLA-DP variants can be either protective or risk factors for infectious diseases (e.g. hepatitis B), immune dysfunction (e.g. berylliosis), and autoimmunity (e.g. myasthenia gravis). Here, we establish a system to analyze the chaperone requirements for HLA-DP and to compare the assembly and trafficking of HLA-DP, DQ, and -DR directly. Unlike HLA-DR1, HLA-DQ5 and HLA-DP4 can form SDS-stable dimers supported by invariant chain (Ii) in the absence of HLA-DM. Uniquely, HLA DP also forms dimers in the presence of HLA-DM alone. In model antigen-presenting cells, SDS-stable HLA-DP complexes are resistant to treatments that prevent formation of SDS-stable HLA-DR complexes. The unexpected properties of HLA-DP molecules may help explain why they bind to a more restricted range of peptides than other human MHC class II proteins and frequently present viral peptides. PMID- 20959458 TI - A conserved protein interaction interface on the type 5 G protein beta subunit controls proteolytic stability and activity of R7 family regulator of G protein signaling proteins. AB - Regulators of G protein signaling (RGS) proteins of the R7 subfamily limit signaling by neurotransmitters in the brain and by light in the retina. They form obligate complexes with the Gbeta5 protein that are subject to proteolysis to control their abundance and alter signaling. The mechanisms that regulate this proteolysis, however, remain unclear. We used genetic screens to find mutations in Gbeta5 that selectively destabilize one of the R7 RGS proteins in Caenorhabditis elegans. These mutations cluster at the binding interface between Gbeta5 and the N terminus of R7 RGS proteins. Equivalent mutations within mammalian Gbeta5 allowed the interface to still bind the N-terminal DEP domain of R7 RGS proteins, and mutant Gbeta5-R7 RGS complexes initially formed in cells but were then rapidly degraded by proteolysis. Molecular dynamics simulations suggest the mutations weaken the Gbeta5-DEP interface, thus promoting dynamic opening of the complex to expose determinants of proteolysis known to exist on the DEP domain. We propose that conformational rearrangements at the Gbeta5-DEP interface are key to controlling the stability of R7 RGS protein complexes. PMID- 20959459 TI - TLR4 recognizes Pseudallescheria boydii conidia and purified rhamnomannans. AB - Pseudallescheria boydii (Scedosporium apiospermum) is a saprophytic fungus widespread in the environment, and has recently emerged as an agent of localized as well as disseminated infections, particularly mycetoma, in immunocompromised and immunocompetent hosts. We have previously shown that highly purified alpha glucan from P. boydii activates macrophages through Toll-like receptor TLR2, however, the mechanism of P. boydii recognition by macrophage is largely unknown. In this work, we investigated the role of innate immune receptors in the recognition of P. boydii. Macrophages responded to P. boydii conidia and hyphae with secretion of proinflammatory cytokines. The activation of macrophages by P. boydii conidia required functional MyD88, TLR4, and CD14, whereas stimulation by hyphae was independent of TLR4 and TLR2 signaling. Removal of peptidorhamnomannans from P. boydii conidia abolished induction of cytokines by macrophages. A fraction highly enriched in rhamnomannans was obtained and characterized by NMR, high performance TLC, and GC-MS. Preparation of rhamnomannans derived from P. boydii triggered cytokine release by macrophages, as well as MAPKs phosphorylation and IkappaBalpha degradation. Cytokine release induced by P. boydii-derived rhamnomannans was dependent on TLR4 recognition and required the presence of non-reducing end units of rhamnose of the rhamnomannan, but not O-linked oligosaccharides from the peptidorhamnomannan. These results imply that TLR4 recognizes P. boydii conidia and this recognition is at least in part due to rhamnomannans expressed on the surface of P. boydii. PMID- 20959460 TI - Leukotriene B4 augments and restores Fc gammaRs-dependent phagocytosis in macrophages. AB - Phagocytosis by macrophages is essential for host defense, i.e. preventing invasion of pathogens and foreign materials. Macrophages engulf immunoglobulin G (IgG)-opsonized particles through the action of the receptors for the Fc of IgG (FcgammaRs). Leukotriene B(4) (LTB(4)) is a classical lipid chemoattractant derived from arachidonic acid. Leukotriene B(4) receptor 1 (BLT1), a high affinity LTB(4) receptor, is expressed in a variety of immune cells such as neutrophils, macrophages, and dendritic cells. Although LTB(4) has been shown to enhance macrophage phagocytosis, few studies have investigated the intracellular mechanisms involved in this in detail. Furthermore, there have been no reports of the direct cross-talk between LTB(4)-BLT1 and IgG-FcgammaRs signaling. Here, we show that FcgammaRs-dependent phagocytosis was attenuated in BLT1-deficient macrophages as compared with wild-type (WT) cells. Moreover, cross-talk between LTB(4)-BLT1 and IgG-FcgammaRs signaling was identified at the level of phosphatidylinositol 3-OH kinase (PI3K) and Rac, downstream of Syk. In addition, the trimeric G(i) protein (G(i)) was found to be essential for BLT1-dependent phagocytosis. Surprisingly, we found that LTB(4)-BLT1 signaling restores phagocytosis in the absence of FcgammaRs signaling. These data indicate that LTB(4)-BLT1 signaling plays a pivotal role in macrophage phagocytosis and innate immunity. PMID- 20959461 TI - ANKRD13C acts as a molecular chaperone for G protein-coupled receptors. AB - Although the mechanisms that regulate folding and maturation of newly synthesized G protein-coupled receptors are crucial for their function, they remain poorly characterized. By yeast two-hybrid screening, we have isolated ANKRD13C, a protein of unknown function, as an interacting partner for the DP receptor for prostaglandin D(2). In the present study we report the characterization of this novel protein as a regulator of DP biogenesis and trafficking in the biosynthetic pathway. Co-localization by confocal microscopy with an endoplasmic reticulum (ER) marker, subcellular fractionation experiments, and demonstration of the interaction between ANKRD13C and the cytoplasmic C terminus of DP suggest that ANKRD13C is a protein associated with the cytosolic side of ER membranes. Co expression of ANKRD13C with DP initially increased receptor protein levels, whereas siRNA-mediated knockdown of endogenous ANKRD13C decreased them. Pulse chase experiments indicated that ANKRD13C can promote the biogenesis of DP by inhibiting the degradation of newly synthesized receptors. However, a prolonged interaction between ANKRD13C and DP resulted in ER retention of misfolded/unassembled forms of the receptor and to their proteasome-mediated degradation. ANKRD13C also regulated the expression of other GPCRs tested (CRTH2, thromboxane A(2) (TPalpha), and beta2-adrenergic receptor), whereas it did not affect the expression of green fluorescent protein, GRK2 (G protein-coupled receptor kinase 2), and VSVG (vesicular stomatitis virus glycoprotein), showing specificity toward G protein-coupled receptors. Altogether, these results suggest that ANKRD13C acts as a molecular chaperone for G protein-coupled receptors, regulating their biogenesis and exit from the ER. PMID- 20959462 TI - Aurora B interacts with NIR-p53, leading to p53 phosphorylation in its DNA binding domain and subsequent functional suppression. AB - NIR (novel INHAT repressor) is a transcriptional co-repressor with inhibitor of histone acetyltransferase (INHAT) activity and has previously been shown to physically interact with and suppress p53 transcriptional activity and function. However, the mechanism by which NIR suppresses p53 is not completely understood. Using a proteomic approach, we have identified the Aurora kinase B as a novel binding partner of NIR. We show that Aurora B, NIR and p53 exist in a protein complex in which Aurora B binds to NIR, thus also indirectly associates with p53. Functionally, overexpression of Aurora B or NIR suppresses p53 transcriptional activity, and depletion of Aurora B or NIR causes p53-dependent apoptosis and cell growth arrest, due to the up-regulation of p21 and Bax. We then demonstrate that Aurora B phosphorylates multiple sites in the p53 DNA-binding domain in vitro, and this phosphorylation probably also occurs in cells. Importantly, the Aurora B-mediated phosphorylation on Ser(269) or Thr(284) significantly compromises p53 transcriptional activity. Taken together, these results provide novel insight into NIR-mediated p53 suppression and also suggest an additional way for p53 regulation. PMID- 20959463 TI - Three enzymatic steps required for the galactosamine incorporation into core lipopolysaccharide. AB - The core lipopolysaccharides (LPS) of Proteus mirabilis as well as those of Klebsiella pneumoniae and Serratia marcescens are characterized by the presence of a hexosamine-galacturonic acid disaccharide (alphaHexN-(1,4)-alphaGalA) attached by an alpha1,3 linkage to L-glycero-D-manno-heptopyranose II (L-glycero alpha-D-manno-heptosepyranose II). In K. pneumoniae, S. marcescens, and some P. mirabilis strains, HexN is D-glucosamine, whereas in other P. mirabilis strains, it corresponds to D-galactosamine. Previously, we have shown that two enzymes are required for the incorporation of D-glucosamine into the core LPS of K. pneumoniae; the WabH enzyme catalyzes the incorporation of GlcNAc from UDP-GlcNAc to outer core LPS, and WabN catalyzes the deacetylation of the incorporated GlcNAc. Here we report the presence of two different HexNAc transferases depending on the nature of the HexN in P. mirabilis core LPS. In vivo and in vitro assays using LPS truncated at the level of galacturonic acid as acceptor show that these two enzymes differ in their specificity for the transfer of GlcNAc or GalNAc. By contrast, only one WabN homologue was found in the studied P. mirabilis strains. Similar assays suggest that the P. mirabilis WabN homologue is able to deacetylate both GlcNAc and GalNAc. We conclude that incorporation of d-galactosamine requires three enzymes: Gne epimerase for the generation of UDP GalNAc from UDP-GlcNAc, N-acetylgalactosaminyltransferase (WabP), and LPS:HexNAc deacetylase. PMID- 20959464 TI - Altered chaperone-like activity of alpha-crystallins promotes cataractogenesis. AB - Despite the enormous number of studies demonstrating changes in the chaperone like activity of alpha-crystallins in vitro, little is known about how these changes influence life-long lens transparency in vivo. Using the gammaB crystallin I4F mutant protein as a target for alphaA-crystallins, we examined how cataract phenotypes are modulated by interactions between alpha-crystallins with altered chaperone-like activities and gammaB-I4F proteins in vivo. Double heterozygous alpha-crystallin knock-out alphaA(+/-) alphaB(+/-) mice with a decreased amount of alpha-crystallins were used to simulate reduced total alpha crystallin chaperone-like activity in vivo. We found that triple heterozygous alphaA(+/-) alphaB(+/-) gammaB(I4F/+) mice developed more severe whole cataracts than heterozygous gammaB(I4F/+) mice. Thus, total chaperone-like activity of alpha-crystallins is important for maintaining lens transparency. We further tested whether mutant alphaA-crystallin Y118D proteins with increased chaperone like activity influenced the whole cataract caused by the gammaB-I4F mutation. Unexpectedly, compound alphaA(Y118D/+) gammaB(I4F/+) mutant lenses displayed severe nuclear cataracts, whereas the lens cortex remained unaffected. Thus, the synergistic effect of alphaA-Y118D and gammaB-I4F mutant proteins is detrimental to the transparency only in the lens core. alpha-Crystallins with different chaperone-like activities are likely required in the lens cortex and nucleus for maintaining transparency. PMID- 20959465 TI - The prostaglandin E2 receptor, EP2, stimulates keratinocyte proliferation in mouse skin by G protein-dependent and {beta}-arrestin1-dependent signaling pathways. AB - The prostaglandin E(2) (PGE(2)) G protein-coupled receptor (GPCR), EP2, plays important roles in mouse skin tumor development (Chun, K. S., Lao, H. C., Trempus, C. S., Okada, M., and Langenbach, R. (2009) Carcinogenesis 30, 1620 1627). Because keratinocyte proliferation is essential for skin tumor development, EP2-mediated signaling pathways that contribute to keratinocyte proliferation were investigated. A single topical application of the EP2 agonist, butaprost, dose-dependently increased keratinocyte replication via activation of epidermal growth factor receptor (EGFR) and PKA signaling. Because GPCR-mediated activation of EGFR can involve the formation of a GPCR-beta-arrestin-Src signaling complex, the possibility of a beta-arrestin1-Src complex contributing to EP2-mediated signaling in keratinocytes was investigated. Butaprost induced beta-arrestin1-Src complex formation and increased both Src and EGFR activation. A role for beta-arrestin1 in EP2-mediated Src and EGFR activation was demonstrated by the observation that beta-arrestin1 deficiency significantly reduced Src and EGFR activation. In agreement with a beta-arrestin1-Src complex contributing to EGFR activation, Src and EGFR inhibition (PP2 and AG1478, respectively) indicated that Src was upstream of EGFR. Butaprost also induced the activation of Akt, ERK1/2, and STAT3, and both beta-arrestin1 deficiency and EGFR inhibition (AG1478 or gefitinib) decreased their activation. In addition to beta arrestin1-dependent EGFR activation, butaprost increased PKA activation, as measured by phospho-GSK3beta (p-GSK3beta) and p-cAMP-response element-binding protein formation. PKA inhibition (H89 or R(P)-adenosine-3',5'-cyclic monophosphorothioate (R(P)-cAMPS)) decreased butaprost-induced cAMP-response element-binding protein and ERK activation but did not affect EGFR activation, whereas beta-arrestin1 deficiency decreased EGFR activation but did not affect butaprost-induced PKA activation, thus indicating that they were independent EP2 mediated pathways. Therefore, the results indicate that EP2 contributed to mouse keratinocyte proliferation by G protein-independent, beta-arrestin1-dependent activation of EGFR and G protein-dependent activation of PKA. PMID- 20959466 TI - Feed-forward signaling by membrane-bound ligand receptor circuit: the case of NOTCH DELTA-like 4 ligand in endothelial cells. AB - The DELTA like-4 ligand (DLL4) belongs to the highly conserved NOTCH family and is specifically expressed in the endothelium. DLL4 regulates crucial processes in vascular growth, including endothelial cell (EC) sprouting and arterial specification. Its expression is increased by VEGF-A. In the present study, we show that VEGF-induced DLL4 expression depends on NOTCH activation. VEGF-induced DLL4 expression was prevented by the blockage of NOTCH signaling with gamma secretase or ADAM inhibitors in human cardiac microvascular ECs. Similar to VEGF A, recombinant DLL4 itself stimulated NOTCH signaling and resulted in up regulation of DLL4, suggesting a positive feed-forward mechanism. These effects were abrogated by NOTCH inhibitors but not by inhibition of VEGF signaling. NOTCH activation alone suffices to induce DLL4 expression as illustrated by the positive effect of NOTCH intracellular domain (NICD)-1 or -4 overexpression. To discriminate between NICD/RBP-Jkappa and FOXC2-regulated DLL4 expression, DLL4 promoter activity was assessed in promoter deletion experiments. NICD induced promoter activity was dependent on RBP-Jkappa site but independent of the FOXC2 binding site. Accordingly, constitutively active FOXC2 did not affect DLL4 expression. The notion that the positive feed-forward mechanism might propagate NOTCH activation to neighboring ECs was supported by our observation that DLL4 eGFP-transfected ECs induced DLL4 expression in nontransfected cells in their vicinity. In summary, our data provide evidence for a mechanism by which VEGF or ligand-induced NOTCH signaling up-regulates DLL4 through a positive feed-forward mechanism. By this mechanism, DLL4 could propagate its own expression and enable synchronization of NOTCH expression and signaling between ECs. PMID- 20959467 TI - Ligand-induced internalization and recycling of the human neuropeptide Y2 receptor is regulated by its carboxyl-terminal tail. AB - Agonist-induced internalization of G protein-coupled receptors plays an important role in signal regulation. The underlying mechanisms of the internalization of the human neuropeptide Y(2) receptor (hY(2)R), as well as its desensitization, endocytosis, and resensitization are mainly unknown. In the present study we have investigated the role of carboxyl-terminal (C-terminal) Ser/Thr residues and acidic amino acids in regulating receptor internalization, arrestin interaction, and recycling by fluorescence microscopy, cell surface enzyme-linked immunosorbent assay, and bioluminescence resonance energy transfer in several cell lines. Strikingly, C-terminal truncation mutants revealed two different internalization motifs. Whereas a distal motif (373)DSXTEXT(379) was found to be the primary regulatory internalization sequence acting in concert with arrestin 3, the proximal motif (347)DXXXSEXSXT(356) promoted ligand-induced internalization in an arrestin-3-independent manner. Moreover, we identified a regulatory sequence located between these internalization motifs ((357)FKAKKNLEVRKN(368)), which serves as an inhibitory element. We found that hY(2)R recycling is also governed by structural determinants within the proximal internalization motif. In conclusion, these results indicate that the hY(2)R C terminus is involved in multiple molecular events that regulate internalization, interaction with arrestin-3, and receptor resensitization. Our findings provide novel insights into complex mechanisms of controlled internalization of hY(2)R, which is likely applicable to other GPCRs. PMID- 20959468 TI - FTY720 (fingolimod) sensitizes prostate cancer cells to radiotherapy by inhibition of sphingosine kinase-1. AB - Radiotherapy is widely used as a radical treatment for prostate cancer, but curative treatments are elusive for poorly differentiated tumors where survival is just 15% at 15 years. Dose escalation improves local response rates but is limited by tolerance in normal tissues. A sphingosine analogue, FTY720 (fingolimod), a drug currently in phase III studies for treatment of multiple sclerosis, has been found to be a potent apoptosis inducer in prostate cancer cells. Using in vitro and in vivo approaches, we analyzed the impact of FTY720 on sphingolipid metabolism in hormone-refractory metastatic prostate cancer cells and evaluated its potential as a radiosensitizer on cell lines and prostate tumor xenografts. In prostate cancer cell lines, FTY720 acted as a sphingosine kinase 1 (SphK1) inhibitor that induced prostate cancer cell apoptosis in a manner independent of sphingosine-1-phosphate receptors. In contrast, gamma irradiation did not affect SphK1 activity in prostate cancer cells yet synergized with FTY720 to inhibit SphK1. In mice bearing orthotopic or s.c. prostate cancer tumors, we show that FTY720 dramatically increased radiotherapeutic sensitivity, reducing tumor growth and metastasis without toxic side effects. Our findings suggest that low, well-tolerated doses of FTY720 could offer significant improvement to the clinical treatment of prostate cancer. PMID- 20959469 TI - Tumorigenic and metastatic activity of human thyroid cancer stem cells. AB - Thyroid carcinoma is the most common endocrine malignancy and the first cause of death among endocrine cancers. We show that the tumorigenic capacity in thyroid cancer is confined in a small subpopulation of stem-like cells with high aldehyde dehydrogenase (ALDH(high)) activity and unlimited replication potential. ALDH(high) cells can be expanded indefinitely in vitro as tumor spheres, which retain the tumorigenic potential upon delivery in immunocompromised mice. Orthotopic injection of minute numbers of thyroid cancer stem cells recapitulates the behavior of the parental tumor, including the aggressive metastatic features of undifferentiated thyroid carcinomas, which are sustained by constitutive activation of cMet and Akt in thyroid cancer stem cells. The identification of tumorigenic and metastagenic thyroid cancer cells may provide unprecedented preclinical tools for development and preclinical validation of novel targeted therapies. PMID- 20959470 TI - F3-targeted cisplatin-hydrogel nanoparticles as an effective therapeutic that targets both murine and human ovarian tumor endothelial cells in vivo. AB - Recent studies indicate that ovarian cancer may be highly responsive to antivascular therapeutics. We have developed an antivascular tumor therapeutic using the F3 peptide to target cisplatin-loaded nanoparticles (F3-Cis-Np) to tumor vessels. We show that although F3-Cis-Np bind with high specificity to both human ovarian tumor cells and tumor endothelial cells in vitro, they only show cytotoxic activity against the tumor endothelial cells. In vivo these nanoparticles bind primarily to tumor endothelial cells. Therapeutic studies in both flank and orthotopic i.p. murine ovarian tumor models, as well as human tumor xenograft models, show rapid tumor regression with treatment. Treatment was associated with significant vascular necrosis consistent with an antivascular effect. Furthermore, treatment was active in both platinum-sensitive and platinum resistant cell lines. Importantly, we show that F3-Cis-Np bind to human tumor endothelial cells in vitro and to human tumor vessels in vivo. Therapy targeting human vasculature in vivo with F3-Cis-Np led to near complete loss of all human tumor vessels in a murine model of human tumor vasculature. Our studies indicate that F3-targeted vascular therapeutics may be an effective treatment modality in human ovarian cancer. PMID- 20959471 TI - Danger signaling protein HMGB1 induces a distinct form of cell death accompanied by formation of giant mitochondria. AB - Cells dying by necrosis release the high-mobility group box 1 (HMGB1) protein, which has immunostimulatory effects. However, little is known about the direct actions of extracellular HMGB1 protein on cancer cells. Here, we show that recombinant human HMGB1 (rhHMGB1) exerts strong cytotoxic effects on malignant tumor cells. The rhHMGB1-induced cytotoxicity depends on the presence of mitochondria and leads to fast depletion of mitochondrial DNA, severe damage of the mitochondrial proteome by toxic malondialdehyde adducts, and formation of giant mitochondria. The formation of giant mitochondria is independent of direct nuclear signaling events, because giant mitochondria are also observed in cytoplasts lacking nuclei. Further, the reactive oxygen species scavenger N acetylcysteine as well as c-Jun NH(2)-terminal kinase blockade inhibited the cytotoxic effect of rhHMGB1. Importantly, glioblastoma cells, but not normal astrocytes, were highly susceptible to rhHMGB1-induced cell death. Systemic treatment with rhHMGB1 results in significant growth inhibition of xenografted tumors in vivo. In summary, rhHMGB1 induces a distinct form of cell death in cancer cells, which differs from the known forms of apoptosis, autophagy, and senescence, possibly representing an important novel mechanism of specialized necrosis. Further, our findings suggest that rhHMGB1 may offer therapeutic applications in treatment of patients with malignant brain tumors. PMID- 20959472 TI - Prognostic and therapeutic implications of distinct kinase expression patterns in different subtypes of breast cancer. AB - Different kinases are expressed in different clinical subsets of breast cancer. In this study, we assessed kinase expression patterns in different clinical subtypes of breast cancer, evaluated the prognostic and predictive values of kinase metagenes, and investigated their functions in vitro. Four hundred twenty eight protein kinases in gene expression data were examined from 684 cases of breast cancer and 51 breast cancer cell lines to identify kinase expression patterns. We tested the prognostic value of kinase metagenes in 684 node-negative patients who received no adjuvant therapy and the predictive value in 233 patients who received uniform neoadjuvant chemotherapy. Twelve kinases were overexpressed in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 7 in HER2(+), and 28 in ER(-)/HER2(-) cancers, respectively. We examined the functional role of 22 kinases overexpressed in ER( )/HER2(-) cancers using siRNA. Downregulation of these kinases caused significant subtype-specific inhibition of cell growth in vitro. Two robust kinase clusters, including an immune kinase cluster and a mitosis kinase cluster, were present in all clinical subgroups. High mitosis kinase score was associated with worse prognosis but higher pathologic complete response (pCR) in ER(+)/HER2(-) cancers, but not in ER(-)/HER2(-) or HER2(+) cancers, in univariate and multivariate analyses including other genomic predictors (MammaPrint, genomic grade index, and the 76-gene signature). Conversely, higher immune kinase score was associated with better survival in ER(+)/HER2(-) and HER2(+) tumors and also predicted higher probability of pCR in HER2(+) cancers. Taken together, our results indicate that kinases regulating mitosis and immune functions convey distinct prognostic information that varies by clinical subtype. PMID- 20959473 TI - The oncoprotein c-ski functions as a direct antagonist of the transforming growth factor-{beta} type I receptor. AB - The oncoprotein c-Ski has been implicated in the negative regulation of transforming growth factor-beta (TGF-beta) signaling owing to its ability to repress Smad transcriptional activity via recruitment of a transcriptional corepressor complex containing histone deacetylases. However, c-Ski has also been shown to localize to the cytoplasm, raising the interesting possibility that it might disable TGF-beta signaling through alternative mechanisms. Here, we provide evidence that c-Ski can restrict TGF-beta signaling by interacting directly with the activated TGF-beta type I receptor (TbetaRI). We explored the physiologic relevance of the c-Ski/TbetaRI interaction and found that it can culminate in a constitutive association of TbetaRI with a nonfunctional R-Smad/Smad4 complex. Based on these findings, we hypothesize that the interaction between c-Ski and TbetaRI might interfere with nuclear translocation of the R-Smad/Smad4 complex, thereby attenuating TGF-beta signaling. Such a mechanism may play a crucial role in tumor progression, because many tumors that express high levels of c-Ski also display impaired nuclear accumulation of Smads. PMID- 20959474 TI - Zoledronic acid reduces bone loss and tumor growth in an orthotopic xenograft model of osteolytic oral squamous cell carcinoma. AB - Squamous cell carcinoma (SCC) is the most common form of oral cancer. Destruction and invasion of mandibular and maxillary bone frequently occurs and contributes to morbidity and mortality. We hypothesized that the bisphosphonate drug zoledronic acid (ZOL) would inhibit tumor-induced osteolysis and reduce tumor growth and invasion in a murine xenograft model of bone-invasive oral SCC (OSCC) derived from an osteolytic feline OSCC. Luciferase-expressing OSCC cells (SCCF2Luc) were injected into the perimaxillary subgingiva of nude mice, which were then treated with 100 MUg/kg ZOL or vehicle. ZOL treatment reduced tumor growth and prevented loss of bone volume and surface area but had no effect on tumor invasion. Effects on bone were associated with reduced osteolysis and increased periosteal new bone formation. ZOL-mediated inhibition of tumor-induced osteolysis was characterized by reduced numbers of tartrate-resistant acid phosphatase-positive osteoclasts at the tumor-bone interface, where it was associated with osteoclast vacuolar degeneration. The ratio of eroded to total bone surface was not affected by treatment, arguing that ZOL-mediated inhibition of osteolysis was independent of effects on osteoclast activation or initiation of bone resorption. In summary, our results establish that ZOL can reduce OSCC induced osteolysis and may be valuable as an adjuvant therapy in OSCC to preserve mandibular and maxillary bone volume and function. PMID- 20959475 TI - Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence. AB - Oncogene-induced senescence (OIS) is a potent tumor-suppressive mechanism that is thought to come at the cost of aging. The Forkhead box O (FOXO) transcription factors are regulators of life span and tumor suppression. However, whether and how FOXOs function in OIS have been unclear. Here, we show a role for FOXO4 in mediating senescence by the human BRAF(V600E) oncogene, which arises commonly in melanoma. BRAF(V600E) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-Jun NH(2) terminal kinase-mediated activation of FOXO4 via its phosphorylation on Thr(223), Ser(226), Thr(447), and Thr(451). BRAF(V600E)-induced FOXO4 phosphorylation resulted in p21(cip1) mediated cell senescence independent of p16(ink4a) or p27(kip1). Importantly, melanocyte-specific activation of BRAF(V600E) in vivo resulted in the formation of skin nevi expressing Thr(223)/Ser(226)-phosphorylated FOXO4 and elevated p21(cip1). Together, these findings support a model in which FOXOs mediate a trade-off between cancer and aging. PMID- 20959476 TI - Detection of elevated plasma levels of epidermal growth factor receptor before breast cancer diagnosis among hormone therapy users. AB - Applying advanced proteomic technologies to prospectively collected specimens from large studies is one means of identifying preclinical changes in plasma proteins that are potentially relevant to the early detection of diseases such as breast cancer. We conducted 14 independent quantitative proteomics experiments comparing pooled plasma samples collected from 420 estrogen receptor-positive (ER(+)) breast cancer patients <=17 months before their diagnosis and matched controls. Based on the more than 3.4 million tandem mass spectra collected in the discovery set, 503 proteins were quantified, of which 57 differentiated cases from controls with a P value of <0.1. Seven of these proteins, for which quantitative ELISA assays were available, were assessed in an independent validation set. Of these candidates, epidermal growth factor receptor (EGFR) was validated as a predictor of breast cancer risk in an independent set of preclinical plasma samples for women overall [odds ratio (OR), 1.44; P = 0.0008] and particularly for current users of estrogen plus progestin (E + P) menopausal hormone therapy (OR, 2.49; P = 0.0001). Among current E + P users, the EGFR sensitivity for breast cancer risk was 31% with 90% specificity. Whereas the sensitivity and specificity of EGFR are insufficient for a clinically useful early detection biomarker, this study suggests that proteins that are elevated preclinically in women who go on to develop breast cancer can be discovered and validated using current proteomic technologies. Further studies are warranted to examine the role of EGFR and to discover and validate other proteins that could potentially be used for early detection of breast cancer. PMID- 20959477 TI - Tissue-specific pathways for estrogen regulation of ovarian cancer growth and metastasis. AB - Menopausal estrogen (E2) replacement therapy increases the risk of estrogen receptor (ER)-positive epithelial ovarian cancers (EOC). Whether E2 is tumorigenic or promotes expansion of undiagnosed preexisting disease is unknown. To determine E2 effects on tumor promotion, we developed an intraperitoneal mouse xenograft model using ZsGreen fluorescent ER(-) 2008 and ER(+) PEO4 human EOC cells. Tumor growth was quantified by in vivo fluorescent imaging. In ER(+) tumors, E2 significantly increased size, induced progesterone receptors, and promoted lymph node metastasis, confirming that ERs are functional and foster aggressiveness. Laser-captured human EOC cells from ER(-) and ER(+) xenografted tumors were profiled for expression of E2-regulated genes. Three classes of E2 regulated EOC genes were defined, but <10% were shared with E2-regulated breast cancer genes. Because breast cancer selective ER modulators (SERM) are therapeutically ineffective in EOC, we suggest that our EOC-specific E2-regulated genes can assist pharmacologic discovery of ovarian-targeted SERM. PMID- 20959478 TI - Antibodies to merkel cell polyomavirus T antigen oncoproteins reflect tumor burden in merkel cell carcinoma patients. AB - Merkel cell polyomavirus (MCPyV) is a common infectious agent that is likely involved in the etiology of most Merkel cell carcinomas (MCC). Serum antibodies recognizing the MCPyV capsid protein VP1 are detectable at high titer in nearly all MCC patients and remain stable over time. Although antibodies to the viral capsid indicate prior MCPyV infection, they provide limited clinical insight into MCC because they are also detected in more than half of the general population. We investigated whether antibodies recognizing MCPyV large and small tumor associated antigens (T-Ag) would be more specifically associated with MCC. Among 530 population control subjects, these antibodies were present in only 0.9% and were of low titer. In contrast, among 205 MCC cases, 40.5% had serum IgG antibodies that recognize a portion of T-Ag shared between small and large T-Ags. Among cases, titers of T-Ag antibodies fell rapidly (~8-fold per year) in patients whose cancer did not recur, whereas they rose rapidly in those with progressive disease. Importantly, in several patients who developed metastases, the rise in T-Ag titer preceded clinical detection of disease spread. These results suggest that antibodies recognizing T-Ag are relatively specifically associated with MCC, do not effectively protect against disease progression, and may serve as a clinically useful indicator of disease status. PMID- 20959479 TI - Identification of susceptibility loci in a mouse model of KRASG12D-driven pancreatic cancer. AB - Genetic background affects susceptibility to pancreatic ductal adenocarcinoma in the Ela-KRAS(G12D) mouse model. In this model, KRAS oncogene expression is driven by an elastase promoter in acinar cells of the pancreas on an FVB/NTac (FVB) background [FVB-Tg(Ela-KRAS(G12D))] with the transgene carried on the Y chromosome. Through linkage analysis of crosses between the C57BL/6J (B6), BALB/cJ (BALB), and DBA/2J (D2) inbred strains of mice and resistant FVB-Tg(Ela KRAS(G12D)), we have identified six susceptibility loci that affect mean preinvasive lesion multiplicity. Markers on chromosome 2 segregated with high tumor multiplicity in all three strains; these loci were designated Prsq1-3 (pancreatic ras susceptibility quantitative trait loci 1-3; combined F2 and N2 LOD(W), 6.0, 4.1, and 2.7, respectively). Susceptibility loci on chromosome 4, designated Prsq4 and Prsq5, were identified in crosses between FVB transgenic mice and B6 or BALB mice (combined F2 and N2 LOD(W), 3.6 and 2.9, respectively). A marker on chromosome 12 segregated with tumor multiplicity in a BALB * FVB Tg(Ela-KRAS(G12D)) cross and was designated Prsq6 (LOD(W), ~2.5). B6-Chr Y(FVB Tg(Ela-KRASG12D)) and BALB-Chr Y(FVB-Tg(Ela-KRASG12D)) consomics, which carry the KRAS transgene on the FVB Y chromosome on an otherwise inbred B6 or BALB background, developed ~4-fold (B6) and ~10-fold (BALB) more lesions than FVB Tg(Ela-KRAS(G12D)) mice. By 12 months of age, 10% of BALB-Chr Y(FVB-Tg(Ela KRASG12D)) mice developed invasive carcinomas. Our findings provide evidence that regions of chromosomes 2, 4, and 12 influence the development and progression of pancreatic neoplasms initiated by an oncogenic allele of KRAS in mice. PMID- 20959480 TI - Transcriptome analysis reveals that p53 and {beta}-catenin alterations occur in a group of aggressive adrenocortical cancers. AB - Adrenocortical carcinoma (ACC) is a rare disease with an overall poor but heterogeneous prognosis. This heterogeneity could reflect different mechanisms of tumor development. Gene expression profiling by transcriptome analysis led to ACC being divided into two groups of tumors with very different outcomes. Somatic inactivating mutations of the tumor suppressor gene TP53 and activating mutations of the proto-oncogene beta-catenin (CTNNB1) are the most frequent mutations identified in ACC. This study investigates the correlation between p53 and beta catenin alterations and the molecular classification of ACC by transcriptome analysis of 51 adult sporadic ACCs. All TP53 and CTNNB1 mutations seemed to be mutually exclusive and were observed only in the poor-outcome ACC group. Most of the abnormal p53 and beta-catenin immunostaining was also found in this group. Fifty-two percent of the poor-outcome ACC group had TP53 or CTNNB1 mutations and 60% had abnormal p53 or beta-catenin immunostaining. Unsupervised clustering transcriptome analysis of this poor-outcome group revealed three different subgroups, two of them being associated with p53 or beta-catenin alterations, respectively. Analysis of p53 and beta-catenin target gene expressions in each cluster confirmed a profound and anticipated effect on tumor biology, with distinct profiles logically associated with the respective pathway alterations. The third group had no p53 or beta-catenin alteration, suggesting other unidentified molecular defects. This study shows the important respective roles of p53 and beta-catenin in ACC development, delineating subgroups of ACC with different tumorigenesis and outcomes. PMID- 20959482 TI - Cancer stem cells in the central nervous system--a critical review. AB - The cancer stem cell hypothesis postulates that tumors arise from, and are maintained by, a small subpopulation of cancer stem cells. This concept has recently become increasingly controversial, following a series of conflicting results. The cell-surface epitope CD133 has been proposed as a brain cancer stem cell marker, whereas a growing number of studies clearly show a tumorigenic potential among CD133(-) cells as well. Diverging results suggest that assays for isolating cancer stem cells impose a selection bias on which cells are defined as cancer stem cells. Here, we highlight some recent developments, with an emphasis on reports that call for caution in the acceptance of the brain cancer stem cell hypothesis. PMID- 20959481 TI - Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells. AB - The majority of melanomas show constitutive activation of the RAS-RAF-MAP/ERK kinase (MEK)-mitogen-activated protein kinase (MAPK) pathway. AZD6244 is a selective MEK1/2 inhibitor that markedly reduces tumor P-MAPK levels, but it produces few clinical responses in melanoma patients. An improved understanding of the determinants of resistance to AZD6244 may lead to improved patient selection and effective combinatorial approaches. The effects of AZD6244 on cell growth and survival were tested in a total of 14 Braf-mutant and 3 wild-type human cutaneous melanoma cell lines. Quantitative assessment of phospho-protein levels in the Braf-mutant cell lines by reverse phase protein array (RPPA) analysis showed no significant association between P-MEK or P-MAPK levels and AZD6244 sensitivity, but activation-specific markers in the phosphoinositide 3 kinase (PI3K)-AKT pathway correlated with resistance. We also identified resistant cell lines without basal activation of the PI3K-AKT pathway. RPPA characterization of the time-dependent changes in signaling pathways revealed that AZD6244 produced durable and potent inhibition of P-MAPK in sensitive and resistant Braf-mutant cell lines, but several resistant lines showed AZD6244 induced activation of AKT. In contrast, sensitive cell lines showed AZD6244 treatment-induced upregulation of PTEN protein and mRNA expression. Inhibition of AKT, TORC1/2, or insulin-like growth factor I receptor blocked AZD6244-induced activation of AKT and resulted in synergistic cell killing with AZD6244. These findings identify basal and treatment-induced regulation of the PI3K-AKT pathway as a critical regulator of AZD6244 sensitivity in Braf-mutant cutaneous melanoma cells and the novel regulation of PTEN expression by AZD6244 in sensitive cells, and suggest new combinatorial approaches for patients. PMID- 20959483 TI - Early detection of recurrent breast cancer using metabolite profiling. AB - We report on the development of a monitoring test for recurrent breast cancer, using metabolite-profiling methods. Using a combination of nuclear magnetic resonance (NMR) and two-dimensional gas chromatography-mass spectrometry (GC*GC MS) methods, we analyzed the metabolite profiles of 257 retrospective serial serum samples from 56 previously diagnosed and surgically treated breast cancer patients. One hundred sixteen of the serial samples were from 20 patients with recurrent breast cancer, and 141 samples were from 36 patients with no clinical evidence of the disease during ~6 years of sample collection. NMR and GC*GC-MS data were analyzed by multivariate statistical methods to compare identified metabolite signals between the recurrence samples and those with no evidence of disease. Eleven metabolite markers (seven from NMR and four from GC*GC-MS) were shortlisted from an analysis of all patient samples by using logistic regression and 5-fold cross-validation. A partial least squares discriminant analysis model built using these markers with leave-one-out cross-validation provided a sensitivity of 86% and a specificity of 84% (area under the receiver operating characteristic curve = 0.88). Strikingly, 55% of the patients could be correctly predicted to have recurrence 13 months (on average) before the recurrence was clinically diagnosed, representing a large improvement over the current breast cancer-monitoring assay CA 27.29. To the best of our knowledge, this is the first study to develop and prevalidate a prediction model for early detection of recurrent breast cancer based on metabolic profiles. In particular, the combination of two advanced analytical methods, NMR and MS, provides a powerful approach for the early detection of recurrent breast cancer. PMID- 20959484 TI - Loss of PTEN expression by blocking nuclear translocation of EGR1 in gefitinib resistant lung cancer cells harboring epidermal growth factor receptor-activating mutations. AB - Gefitinib (Iressa) and erlotinib (Tarceva), which target the epidermal growth factor receptor (EGFR), are approved for treatment of patients with advanced non small cell lung cancer (NSCLC). Patients whose tumors harbor mutations in the EGFR gene, including delE746-A750 in exon 19 and L858R in exon 21, may benefit in particular from gefitinib treatment. However, acquired resistance to gefitinib has been a serious clinical problem, and further optimization is needed for application of EGFR-targeted drugs in lung cancer patients. In this study, we established gefitinib-resistant NSCLC cells from PC-9 cell line, which harbors the delE746-A750 mutation, by exposing the cell line to gefitinib for over 7 months. Gefitinib-resistant PC-9/GEFs cell lines showed a marked downregulation of PTEN expression and increased Akt phosphorylation. In revertant, gefitinib sensitive clones (PC-9/Rev) derived from PC-9/GEF1-1 and PC-9/GEF2-1, PTEN expression, as well as sensitivity to gefitinib and erlotinib, was restored. Knockdown of PTEN expression using small interfering RNA specific for PTEN in PC 9 cells resulted in drug resistance to gefitinib and erlotinib. Nuclear translocation of the EGR1 transcription factor, which regulates PTEN expression, was shown to be suppressed in resistant clones and restored in their revertant clones. Reduced PTEN expression was also seen in tumor samples from a patient with gefitinib-refractory NSCLC. This study thus strongly suggests that loss of PTEN expression contributes to gefitinib and erlotinib resistance in NSCLC. Our findings reinforce the therapeutic importance of PTEN expression in the treatment of NSCLC with EGFR-targeted drugs. PMID- 20959485 TI - Hierarchical clustering of human papilloma virus genotype patterns in the ASCUS LSIL triage study. AB - Anogenital cancers are associated with ~13 carcinogenic human papilloma virus (HPV) types in a broader group that cause cervical intraepithelial neoplasia (CIN). Multiple concurrent cervical HPV infections are common, which complicates the attribution of HPV types to different grades of CIN. Here we report the analysis of HPV genotype patterns in the atypical squamous cells of undetermined significance-low-grade squamous intraepithelial lesion triage study with the use of unsupervised hierarchical clustering. Women who underwent colposcopy at baseline (n = 2,780) were grouped into 20 disease categories based on histology and cytology. Disease groups and HPV genotypes were clustered with the use of complete linkage. Risk of 2-year cumulative CIN3+, viral load, colposcopic impression, and age were compared between disease groups and major clusters. Hierarchical clustering yielded four major disease clusters: cluster 1 included all CIN3 histology with abnormal cytology; cluster 2 included CIN3 histology with normal cytology and combinations with either CIN2 or high-grade squamous intraepithelial lesion cytology; cluster 3 included older women with normal or low-grade histology/cytology and low viral load; and cluster 4 included younger women with low-grade histology/cytology, multiple infections, and the highest viral load. Three major groups of HPV genotypes were identified: group 1 included only HPV16; group 2 included nine carcinogenic types, plus noncarcinogenic HPV53 and HPV66; and group 3 included noncarcinogenic types, plus carcinogenic HPV33 and HPV45. Clustering results suggested that colposcopy missed a prevalent precancer in many women with no biopsy/normal histology and high-grade squamous intraepithelial lesion. This result was confirmed by an elevated 2-year risk of CIN3+ in these groups. Our novel approach to study multiple genotype infections in cervical disease with the use of unsupervised hierarchical clustering can address complex genotype distributions on a population level. PMID- 20959486 TI - Cediranib/AZD2171 inhibits bone and brain metastasis in a preclinical model of advanced prostate cancer. AB - Late stage or aggressive cancers exhibit metastatic growth at multiple sites, and the characterization of treatment response in various organs to drugs with potentially wide-ranging efficacy is needed. Tumor cells that induce angiogenesis are a common characteristic of metastatic disease, and clinically, antiangiogenic therapies have shown value in the setting of advanced cancer. However, recent preclinical studies have suggested that exposure to antiangiogenic drugs can increase tumor invasiveness and metastasis, making it important to determine which contexts antiangiogenic therapy is most appropriate. We describe here the effects of cediranib, a receptor tyrosine kinase inhibitor, in a model of advanced prostate cancer metastatic to skeleton and brain. Treatment with cediranib decreased metastatic tumor burden in the brain and bone, decreased cerebral vasogenic edema, and improved survival, despite increasing the invasive histology of brain metastases. Short-duration cediranib treatment given at the time of tumor cell dissemination was sufficient to inhibit the establishment and subsequent growth of bone metastases, although brain metastases were subject to rebound growth after the discontinuation of cediranib. Distinct growth patterns at different organ sites in the same animal showed that certain tumor microenvironments such as bone may be most amenable to interventions by anti vascular endothelial growth factor (VEGF) therapies. In addition, anti-VEGF treatment may be of utility in decreasing the rapid growth of solid brain metastases and vasogenic edema in patients with advanced cancer, leading to reduced morbidity and associated clinical benefit. PMID- 20959487 TI - Overexpression of transcription factor sp2 inhibits epidermal differentiation and increases susceptibility to wound- and carcinogen-induced tumorigenesis. AB - Sp proteins are evolutionarily conserved transcription factors required for the expression of a wide variety of genes that are critical for development and cell cycle progression. Deregulated expression of certain Sp proteins is associated with the formation of a variety of human tumors; however, direct evidence that any given Sp protein is oncogenic has been lacking. Here, we report that Sp2 protein abundance in mice increases in concert with the progression of carcinogen induced murine squamous cell carcinomas. Transgenic mice specifically overexpressing murine Sp2 in epidermal basal keratinocytes were highly susceptible to wound- and carcinogen-induced papillomagenesis. Transgenic animals that were homozygous rather than hemizygous for the Sp2 transgene exhibited a striking arrest in the epidermal differentiation program, perishing within 2 weeks of birth. Our results directly support the likelihood that Sp2 overexpression occurring in various human cancers has significant functional effect. PMID- 20959488 TI - K-ras mutation targeted to gastric tissue progenitor cells results in chronic inflammation, an altered microenvironment, and progression to intraepithelial neoplasia. AB - Chronic infectious diseases, such as Helicobacter pylori infection, can promote cancer in a large part through induction of chronic inflammation. Oncogenic K-ras mutation in epithelial cells activates inflammatory pathways, which could compensate for a lack of infectious stimulus. Gastric histopathology and putative progenitor markers [doublecortin and calcium/calmodulin-dependent protein kinase like 1 (Dcamkl1) and keratin 19 (K19)] in K19-K-ras-V12 (K19-kras) transgenic mice were assessed at 3, 6, 12, and 18 months of age, in comparison with Helicobacter felis-infected wild-type littermates. Inflammation was evaluated by reverse transcription-PCR of proinflammatory cytokines, and K19-kras mice were transplanted with green fluorescent protein (GFP)-labeled bone marrow. Both H. felis infection and K-ras mutation induced upregulation of proinflammatory cytokines, expansion of Dcamkl1(+) cells, and progression to oxyntic atrophy, metaplasia, hyperplasia, and high-grade dysplasia. K19-kras transgenic mice uniquely displayed mucous metaplasia as early as 3 months and progressed to high grade dysplasia and invasive intramucosal carcinoma by 20 months. In bone marrow transplanted K19-kras mice that progressed to dysplasia, a large proportion of stromal cells were GFP(+) and bone marrow-derived, but only rare GFP(+) epithelial cells were observed. GFP(+) bone marrow-derived cells included leukocytes and CD45(-) stromal cells that expressed vimentin or alpha smooth muscle actin and were often found surrounding clusters of Dcamkl1(+) cells at the base of gastric glands. In conclusion, the expression of mutant K-ras in K19(+) gastric epithelial cells can induce chronic inflammation and promote the development of dysplasia. PMID- 20959489 TI - RAP80 acts independently of BRCA1 in repair of topoisomerase II poison-induced DNA damage. AB - The tumor suppressor BRCA1 functions in DNA homologous recombination, and mutations in BRCA1 increase the risk of breast and ovarian cancers. RAP80 is a component of BRCA1-containing complexes that is required for recruitment of BRCA1 to sites of DNA damage. To evaluate the role of RAP80 in DNA damage repair, we genetically disrupted both RAP80 alleles in the recombinogenic avian DT40 cell line. The resulting RAP80(-/-) cells were proficient at homologous recombination and nonhomologous end-joining (NHEJ), but were specifically sensitized to the topoisomerase II inhibitor etoposide. Notably, doubly mutant RAP80(-/-)BRCA1(-/-) cells were more sensitive to etoposide than were BRCA1(-/-) cells, revealing that RAP80 performs a BRCA1-independent repair function. Moreover, jointly impairing the function of CtIP, a distinct BRCA1 effector protein, rendered RAP80(-/-) cells more sensitive to etoposide compared with singly mutant cells, again illustrating a BRCA1-independent role of RAP80. Based on our findings, we propose that RAP80 exerts a specific function in repair of the topoisomerase-cleavage complex, such as the removal of covalently bound polypeptides from double-strand break ends independently of BRCA1. PMID- 20959490 TI - Gprc5a deletion enhances the transformed phenotype in normal and malignant lung epithelial cells by eliciting persistent Stat3 signaling induced by autocrine leukemia inhibitory factor. AB - Signal transducers and activators of transcription 3 (Stat3) is activated by cytokines and growth factors in lung cancers and regulates expression of genes implicated in cell growth, survival, and transformation. Previously, we found that mice with a deletion of the G protein-coupled receptor, family C, group 5, member a (Gprc5a) gene develop lung tumors, indicating that Gprc5a is a tumor suppressor. Herein, we show that epithelial cells from Gprc5a knockout mouse lung (Gprc5a(-/-) cells) survive better in vitro in medium deprived of exogenous growth factors and form more colonies in semisolid medium than their counterparts from wild-type mice (Gprc5a(+/+) cells). Stat3 tyrosine 705 phosphorylation and expression of several Stat3-regulated antiapoptotic genes were higher in Gprc5a( /-) than in Gprc5a(+/+) cells. Both cell types secreted leukemia inhibitory factor (Lif); however, whereas Stat3 activation was persistent in Gprc5a(-/-) cells, it was transient in Gprc5a(+/+) cells. Lung adenocarcinoma cells isolated from Gprc5a(-/-) mice also exhibited autocrine Lif-mediated Stat3 activation. The level of Socs3, the endogenous Stat3 inhibitory protein, was higher in Gprc5a(+/+) than in Gprc5a(-/-) cells, and expression of the tumor suppressor stabilized Socs3. Inhibition of Stat3 signaling in Gprc5a(-/-) normal and cancer cells by the Janus-activated kinase 2 inhibitor AG490 or by a dominant negative Stat3(Y705F) increased starvation-induced apoptosis and inhibited colony formation. These results show that persistent Stat3 activation is important for the survival and transformation of Gprc5a(-/-) lung cells and suggest that the tumor suppressive effects of Gprc5a are mediated, at least in part, by inhibition of Stat3 signaling through Socs3 stabilization. PMID- 20959491 TI - Definition of ubiquitination modulator COP1 as a novel therapeutic target in human hepatocellular carcinoma. AB - The development of targeted therapeutics for hepatocellular carcinoma (HCC) remains a major challenge. The ubiquitination modulator COP1 regulates p53 activity by ubiquitination and it is frequently overexpressed in human HCC. In this study, we tested the hypothesis that COP1 blockade by short interfering RNA (siRNA)-mediated inhibition could affect the course of HCC progression. The COP1 isoform COP1-1 was selected as the most effective target for siRNAs in terms of growth inhibition and apoptotic induction in several HCC cell lines. Growth inhibition occurred in HCC cells that retained wild-type p53 or expressed mutant p53 (Y220C or R249S), whereas p53-null Hep3B cells were resistant. Microarray expression analysis revealed that the antiproliferative effects of COP1 blockade were driven by a common subset of molecular alterations including a p53 associated functional network. In an orthotopic mouse xenograft model of HCC, systemic delivery of a modified COP1 siRNA by stable nucleic acid-lipid particles suppressed neoplastic growth in liver without unwanted immune responses. Our findings offer a first proof of principle that COP1 can be a promising target for systemic therapy of HCC. PMID- 20959492 TI - Ablation of TAK1 upregulates reactive oxygen species and selectively kills tumor cells. AB - TAK1 kinase activates multiple transcription factors and regulates the level of reactive oxygen species (ROS). We have previously reported that ablation of TAK1 in keratinocytes causes hypersensitivity to ROS-induced cell apoptosis. It is known that some tumor cells produce ROS at higher levels compared with normal cells. We used inducible epidermal-specific TAK1 knockout mice and examined whether ablation of TAK1 in preexisting skin tumors could cause an increase in ROS and result in tumor cell death. Deletion of tak1 gene in skin tumors caused the accumulation of ROS and increased apoptosis, and skin tumors totally regressed within 5 to 10 days. Normal skin did not exhibit any significant abnormality on tak1 gene deletion. Thus, TAK1 kinase could be a new and effective molecular target for ROS-based tumor killing. PMID- 20959493 TI - Synthetic lethality screens reveal RPS6 and MST1R as modifiers of insulin-like growth factor-1 receptor inhibitor activity in childhood sarcomas. AB - The insulin-like growth factor-1 receptor (IGF1R) is emerging as a promising therapeutic target in human cancers. In the high-risk childhood sarcomas Ewing family tumor and rhabdomyosarcoma, IGF1R-blocking antibodies show impressive antitumor activity in some but not all patients, and acquired resistance is observed. Because tumor IGF1R mutations are not described, the basis of IGF1R inhibitor resistance remains unknown. We hypothesized that compensatory signaling cascades bypassing targeted IGF1R inhibition might be involved. To test this systematically, we performed small interfering RNA (siRNA) screens in sarcoma cell lines to identify IGF1R pathway components or related protein tyrosine kinase (PTK) networks that modulate the antitumor efficacy of the BMS-536924 IGF1R kinase inhibitor. This strategy revealed (a) that sarcoma cells are exquisitely sensitive to loss of distal rather than proximal IGF1R signaling components, such as ribosomal protein S6 (RPS6); (b) that BMS-536924 fails to block RPS6 activation in resistant sarcoma cell lines; and (c) that siRNA knockdown of the macrophage-stimulating 1 receptor tyrosine kinase (MST1R; also known as RON) restores BMS-536924 efficacy, even in highly drug-resistant cell lines. We confirmed MST1R expression across a broad panel of childhood sarcomas, and found that loss of MST1R by RNA interference blocks downstream RPS6 activation when combined with BMS-536924 in vitro. These findings underscore the importance of fully understanding PTK networks for successful clinical implementation of kinase inhibitor strategies. PMID- 20959494 TI - Protein tyrosine phosphatase receptor type {gamma} is a functional tumor suppressor gene specifically downregulated in chronic myeloid leukemia. AB - Chronic myelogenous leukemia (CML) is the most common myeloproliferative disease. Protein tyrosine phosphatase receptor type gamma (PTPRG) is a tumor suppressor gene and a myeloid cell marker expressed by CD34(+) cells. Downregulation of PTPRG increases colony formation in the PTPRG-positive megakaryocytic cell lines MEG-01 and LAMA-84 but has no effect in the PTPRG-negative cell lines K562 and KYO-1. Its overexpression has an oncosuppressive effect in all these cell lines and is associated with myeloid differentiation and inhibition of BCR/ABL dependent signaling. The intracellular domain of PTPRG directly interacts with BCR/ABL and CRKL, but not with signal transducers and activators of transcription 5. PTPRG is downregulated at the mRNA and protein levels in leukocytes of CML patients in both peripheral blood and bone marrow, including CD34(+) cells, and is reexpressed following molecular remission of disease. Reexpression was associated with a loss of methylation of a CpG island of PTPRG promoter occurring in 55% of the patients analyzed. In K562 cell line, the DNA hypomethylating agent 5-aza-2'-deoxycytidine induced PTPRG expression and caused an inhibition of colony formation, partially reverted by downregulation of PTPRG expression. These findings establish, for the first time, PTPRG as a tumor suppressor gene involved in the pathogenesis of CML, suggesting its use as a potential diagnostic and therapeutic target. PMID- 20959496 TI - The role of microRNA in modulating myocardial ischemia-reperfusion injury. AB - MicroRNAs (miRNAs) are small (~22 nt) noncoding single-stranded RNA molecules that downregulate gene expression. Studies have shown that miRNAs control diverse aspects of heart disease, including hypertrophy, remodeling, heart failure, and arrhythmia. Recently, several studies have suggested that miRNAs contribute to ischemia-reperfusion injury by altering key signaling elements, thus making them potential therapeutic targets. By altering the expression of various key elements in cell survival and apoptosis [such as phosphoinositide 3-kinase (PI3K), phosphatase and tensin homolog deleted on chromosome 10 (PTEN), Bcl-2, Mcl-1, heat shock protein (HSP)60, HSP70, HSP20, programmed cell death 4 (Pdcd4), LRRFIP1, Fas ligand (FasL), Sirt-1, etc.], miRNAs alter the response to ischemia reperfusion injury. Studies using various in vivo, ex vivo, and in vitro models have suggested the possible involvement of miR-1, miR-21, miR-29, miR-92a, miR 133, miR-199a, and miR-320 in ischemia-reperfusion injury and/or remodeling after myocardial infarction. Thus miRNAs could be potential therapeutic targets for the treatment of heart disease. Inhibiting miRNAs by antisense strategies or pharmacological approaches is likely to emerge as an alternative and safe method for conferring short- and intermediate-term protection against ischemia reperfusion injury. PMID- 20959495 TI - MicroRNAs in skin and wound healing. AB - MicroRNAs (miRNAs) are small endogenous RNA molecules ~22 nt in length. miRNAs are capable of posttranscriptional gene regulation by binding to their target messenger RNAs (mRNAs), leading to mRNA degradation or suppression of translation. miRNAs have recently been shown to play pivotal roles in skin development and are linked to various skin pathologies, cancer, and wound healing. This review focuses on the role of miRNAs in cutaneous biology, the various methods of miRNA modulation, and the therapeutic opportunities in treatment of skin diseases and wound healing. PMID- 20959497 TI - Distinct genetic regions modify specific muscle groups in muscular dystrophy. AB - Phenotypic expression in the muscular dystrophies is variable, even with the identical mutation, providing strong evidence that genetic modifiers influence outcome. To identify genetic modifier loci, we used quantitative trait locus mapping in two differentially affected mouse strains with muscular dystrophy. Using the Sgcg model of limb girdle muscular dystrophy that lacks the dystrophin associated protein gamma-sarcoglycan, we evaluated chromosomal regions that segregated with two distinct quantifiable characteristics of muscular dystrophy, membrane permeability and fibrosis. We previously identified a single major locus on murine chromosome 7 that influences both traits of membrane permeability and fibrosis in the quadriceps muscle. Using a larger cohort, we now found that this same interval strongly associated with both traits in all limb skeletal muscle groups studied, including the gastrocnemius/soleus, gluteus/hamstring, and triceps muscles. In contrast, the muscles of the trunk were modified by distinct genetic loci, possibly reflecting the embryological origins and physiological stressors unique to these muscle groups. A locus on chromosome 18 was identified that modified membrane permeability of the abdominal muscles, and a locus on chromosome 3 was found that regulated diaphragm and abdominal muscle fibrosis. Fibrosis in the heart associated with a region on chromosome 9 and likely reflects differential function between cardiac and skeletal muscle. These data underscore the complexity of inheritance and penetrance of single-gene disorders. PMID- 20959498 TI - Comment: The relationship between inpatient fluoroquinolone use and Clostridium difficile-associated disease. PMID- 20959499 TI - Grading the severity of drug-drug interactions in the intensive care unit: a comparison between clinician assessment and proprietary database severity rankings. AB - BACKGROUND: Computerized provider order entry with decision support software offers an opportunity to identify and prevent medication-related errors, including drug-drug interactions (DDIs), through alerting mechanisms. However, the number of alerts generated can overwhelm and lead to "alert fatigue." A DDI alert system based on severity rankings has been shown to reduce alert fatigue; however, the best method to populate this type of database is unclear. OBJECTIVE: To compare the severity ranking of proprietary databases to clinician assessment for DDIs occurring in critically ill patients. METHODS: This observational, prospective study was conducted over 8 weeks in the cardiac and cardiothoracic intensive care unit. Medication profiles of patients were screened for the presence of DDIs and a severity evaluation was conducted using rankings of proprietary databases and clinician opinion using a DDI severity assessment tool. The primary outcome measure was the number of DDIs considered severe by both evaluation methods. RESULTS: A total of 1150 DDIs were identified after 400 patient medication profiles were evaluated. Of these, 458 were unique drug pairs. Overall, 7.4% (34/458) were considered a severe interaction based upon proprietary database ratings. The assessment by clinicians ranked 6.6% (30/458) of the unique DDIs as severe. Only 3 interactions, atazanavir-simvastatin, atazanavir-tenofovir, and aspirin-warfarin, were considered severe by both evaluation methods. CONCLUSIONS: Since proprietary databases and clinician assessment of severe DDIs do not agree, developing a knowledge base for a DDI alert system likely requires proprietary database information in conjunction with clinical opinion. PMID- 20959500 TI - Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2. AB - BACKGROUND: Several microtubule targeting agents are capable of inducing CYP3A4 via activation of the pregnane X receptor (PXR; NR1I2). OBJECTIVE: To evaluate the CYP3A4 induction potential of vinblastine both clinically and in vitro and determine the involvement of the nuclear receptors NR1I2 and the constitutive androstane receptor (NR1I3). METHODS: Midazolam pharmacokinetics were evaluated in 6 patients who were enrolled in a Phase 1/2 study of infusional vinblastine given in combination with the ABCB1 (P-glycoprotein) antagonist valspodar (PSC 833) and received the CYP3A4 phenotyping probe midazolam on more than 1 occasion. Genotyping was conducted in CYP3A4, CYP3A5, and ABCB1 to rule out potential pharmacogenetic influences. Clinical data were followed-up by Western blotting and reporter assays in HepG2 and NIH3T3 cells treated with vinblastine over a dose range of 150-4800 ng/mL for 48 hours. RESULTS: In 6 patients with cancer, vinblastine increased the median (95% CI) clearance of the CYP3A4 phenotyping probe midazolam from 21.7 L/h (12.6 to 28.1) to 32.3 L/h (17.3 to 53.9) (p = 0.0156, Wilcoxon signed-rank test). No obvious effect of polymorphisms in CYP3A4, CYP3A5, and ABCB1 on midazolam clearance was observed. In vitro, vinblastine induced CYP3A4 protein. Furthermore, cell-based reporter gene assays using transiently transfected HepG2 and NIH3T3 cells indicated that vinblastine (150 4800 ng/mL) weakly activated human and mouse full-length NR1I2, but had no influence on NR1I3. CONCLUSIONS: Collectively, these findings suggest that vinblastine is able to induce CYP3A4, at least in part, via an NR1I2-dependent mechanism, and thus has the potential to facilitate its own elimination and cause interactions with other CYP3A4 substrates. PMID- 20959501 TI - Effects of dietary fiber and low glycemic index diet on glucose control in subjects with type 2 diabetes mellitus. AB - OBJECTIVE: To review the effects of dietary fiber and a low glycemic index diet on glycemic risk factors in people with type 2 diabetes mellitus (T2DM) or T2DM and dyslipidemia. DATA SOURCES: Literature search was conducted using PubMed, Cochrane Library, The Natural Standard, and The Natural Medicines through July 2010 using the terms type 2 diabetes mellitus, dietary fiber, psyllium, and glycemic index. STUDY SELECTION AND DATA EXTRACTION: Articles included were randomized controlled studies or meta-analyses examining the effects of dietary interventions (dietary fiber, low glycemic index diet, or psyllium) on glycemic risk factors (glycosylated hemoglobin A1(c) [A1C] or postprandial plasma glucose [PPG] concentrations) in subjects with T2DM or T2DM and dyslipidemia. DATA SYNTHESIS: Both psyllium supplementation and low glycemic index diets have been studied as monotherapy in the treatment of T2DM. Seven studies were reviewed (3 randomized crossover studies, 1 randomized parallel study, 3 randomized blinded parallel studies). Individually, psyllium supplementation and a low glycemic index diet improved glycemic risk factors. PPG and A1C decreased with psyllium 10.2 g per day, while A1C decreased with a low glycemic index diet (average glycemic index 59). However, the results for the low glycemic index diet are controversial. One study was underpowered to detect changes in A1C, while another study had psyllium fiber as a confounding variable. CONCLUSIONS: Psyllium supplementation might be an additional therapeutic option for people with T2DM who are already receiving diabetes medication and who still experience elevated PPG concentrations. Further well-designed clinical trials and adjustment for confounding variables are needed to determine the role of a low glycemic index diet in the treatment of T2DM. PMID- 20959502 TI - Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. AB - OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 MUg/mL and 0.52 MUg/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. PMID- 20959503 TI - Nighttime and weekend medication error rates in an inpatient pediatric population. AB - BACKGROUND: Nighttime and weekend admission has been associated with increased morbidity and mortality and has been linked to a variety of factors. Medication errors in hospitalized patients occur frequently, but the association between error rates and time of day and day of week (weekday vs weekend) has not been extensively studied. OBJECTIVE: To compare reported medication error rates over a 1-year period between daytime versus nighttime shifts and weekday versus weekend in a children's hospital and to characterize the types of errors that occurred. METHODS: One hundred forty errors reported between January and December 2008 were retrospectively reviewed and classified by error type and severity according to established standards. Two investigators independently classified errors, and a third investigator with pediatric pharmacy expertise resolved discrepancies. Data on doses dispensed were collected from pharmacy records. RESULTS: Over the study period, the reported error rate during daytime nursing shifts was 1.17 errors per 1000 doses dispensed versus 2.12 errors per 1000 doses dispensed for nighttime nursing shifts (p = 0.005). The error rates during pharmacy shifts (1st, 2nd, and 3rd) were 1.01, 2.24, and 1.88 per 1000 doses dispensed, respectively (p = 0.0019). Reported errors for weekday versus weekend were 1.9 errors per 1000 weekday doses versus 2.55 errors per 1000 doses, respectively (p = 0.181), and error rate for weekend shifts relative to first shift on weekdays was greater (p = 0.0004). Errors in medication administration, followed by dispensing errors, occurred most frequently. CONCLUSIONS: There was an increase in medication error rate during evening and nighttime shifts relative to day shift and during weekends relative to weekdays at this institution. Additional studies to validate this finding are needed; however, error prevention efforts should be instituted now for evening, nighttime, and weekend medication dispensing and administration. PMID- 20959504 TI - Comment: a population study of the frequency of high-dose acetaminophen prescribing and dispensing. PMID- 20959505 TI - Metal emissions and urban incident Parkinson disease: a community health study of Medicare beneficiaries by using geographic information systems. AB - Parkinson disease associated with farming and exposure to agricultural chemicals has been reported in numerous studies; little is known about Parkinson disease risk factors for those living in urban areas. The authors investigated the relation between copper, lead, or manganese emissions and Parkinson disease incidence in the urban United States, studying 29 million Medicare beneficiaries in the year 2003. Parkinson disease incidence was determined by using beneficiaries who had not changed residence since 1995. Over 35,000 nonmobile incident Parkinson disease cases, diagnosed by a neurologist, were identified for analysis. Age-, race-, and sex-standardized Parkinson disease incidence was compared between counties with high cumulative industrial release of copper, manganese, or lead (as reported to the Environmental Protection Agency) and counties with no/low reported release of all 3 metals. Parkinson disease incidence (per 100,000) in counties with no/low copper/lead/manganese release was 274.0 (95% confidence interval (CI): 226.8, 353.5). Incidence was greater in counties with high manganese release: 489.4 (95% CI: 368.3, 689.5) (relative risk = 1.78, 95% CI: 1.54, 2.07) and counties with high copper release: 304.2 (95% CI: 276.0, 336.8) (relative risk = 1.1, 95% CI: 0.94, 1.31). Urban Parkinson disease incidence is greater in counties with high reported industrial release of copper or manganese. Environmental exposure to metals may be a risk factor for Parkinson disease in urban areas. PMID- 20959506 TI - Complexities in quality-of-care information. PMID- 20959507 TI - What is the best model for estimating joint health states utilities? Comparing the linear index model to the proportional decrement model. PMID- 20959508 TI - Can knowledge translation tools better inform consumers about review evidence? PMID- 20959509 TI - Individual differences in working memory moderate stereotype-threat effects. PMID- 20959510 TI - Dissociable neural systems support retrieval of how and why action knowledge. AB - In everyday discourse, people typically represent actions in one of two ways: how they are performed or why they are performed. In the present study, we determined the neural systems that support these natural modes of representing actions. Participants underwent functional magnetic resonance imaging while identifying how and why people perform various familiar actions. Identifying how actions are performed produced activity in premotor areas that support the execution of actions and in higher-order visual areas that support the perception of action related objects; this finding supports an embodied view of action knowledge. However, identifying why actions are performed preferentially engaged areas of the brain associated with representing and reasoning about mental states; these areas were right temporoparietal junction, precuneus, dorsomedial prefrontal cortex, and posterior superior temporal sulcus. Our results suggest that why action knowledge is not sufficiently constituted by information in motor and visual systems, but requires a system for representing states of mind, which do not have reliable motor correlates or visual appearance. PMID- 20959511 TI - Remembrances of times East: absolute spatial representations of time in an Australian aboriginal community. AB - How do people think about time? Here we describe representations of time in Pormpuraaw, a remote Australian Aboriginal community. Pormpuraawans' representations of time differ strikingly from all others documented to date. Previously, people have been shown to represent time spatially from left to right or right to left, or from front to back or back to front. All of these representations are with respect to the body. Pormpuraawans instead arrange time according to cardinal directions: east to west. That is, time flows from left to right when one is facing south, from right to left when one is facing north, toward the body when one is facing east, and away from the body when one is facing west. These findings reveal a qualitatively different set of representations of time, with time organized in a coordinate frame that is independent from others reported previously. The results demonstrate that conceptions of even such fundamental domains as time can differ dramatically across cultures. PMID- 20959512 TI - In search of the silver lining: the justice motive fosters perceptions of benefits in the later lives of tragedy victims. AB - Past research has demonstrated that people's need to perceive the world as fair and just leads them to blame and derogate victims of tragedy. The research reported here shows that a positive reaction--bestowing additional meaning on the lives of individuals who have suffered--can also serve people's need to believe that the world is just. In two studies, participants whose justice motive was temporarily heightened or who strongly endorsed the belief that reward and punishment are fairly distributed in the world perceived more meaning and enjoyment in the life of someone who had experienced a tragedy than in the life of someone who had not experienced tragedy, but this pattern was not found for participants whose justice motive was not heightened or who did not strongly endorse a justice belief. These results suggest that being motivated to see the world as just--a motivation traditionally associated with victim derogation--also leads people to perceive a "silver lining" to tragic events. PMID- 20959513 TI - A role for lipoxin A4 as anti-inflammatory and proresolution mediator in human parturition. AB - The purpose of this study was to investigate the role of lipoxin A(4), an anti inflammatory and proresolution modulator, during human parturition. We measured serum levels of lipoxin A(4) and myometrial protein release using ELISA, quantified lipoxin receptor (FPR2/ALX) mRNA expression using qRT-PCR, and localized protein expression using immunohistochemstry in myometrial biopsies from pregnant women. In addition, we compared the effects of lipoxin A(4) (100 nM) with vehicle on basal and LPS-stimulated expression of proinflammatory cytokines from samples of myometrium from pregnant women. Mean +/- SE circulating level of lipoxin A(4) was 5.89 +/- 0.63 nM at 24-wk gestation, with a further modest increase during pregnancy (P<0.05), but no differences in gestation matched women before and after labor (P>0.05). Levels of lipoxin A(4) in nonpregnant women were 0.48 +/- 0.04 nM, significantly lower than in pregnant women (P<0.001). FPR2/ALX localized to myocytes and neutrophils, with a 9-fold increase in mRNA expression in labor (P<0.001). Lipoxin A(4) significantly reduced LPS-induced but not basal expression of the proinflammatory cytokines IL 6 and IL-8 in cultured myometrium (P<0.05), compared to vehicle-treated controls. We demonstrate for the first time a potential role for lipoxin A(4) and its receptor in the resolution of the inflammatory events of both physiological and pathological labor. PMID- 20959515 TI - Eosinophils promote resolution of acute peritonitis by producing proresolving mediators in mice. AB - Acute inflammation in healthy individuals is self-limiting and has an active termination program. The mechanisms by which acute inflammation is resolved are of interest. In murine zymosan-induced peritonitis, we found that eosinophils are recruited to the inflamed loci during the resolution phase of acute inflammation. In vivo depletion of eosinophils caused a resolution deficit, namely impaired lymphatic drainage with reduced appearance of phagocytes carrying engulfed zymosan in the draining lymph node, and sustained numbers of polymorphonuclear leukocytes in inflamed tissues. Liquid chromatography-tandem mass spectrometry based lipidomics of the resolving exudates revealed that locally activated eosinophils in the resolution phase produced proresolving mediators, including protectin D1 (PD1) from docosahexaenoic acid. The resolution deficit caused by eosinophil depletion was rescued by eosinophil restoration or the administration of PD1. Eosinophils deficient in 12/15-lipoxygenase could not rescue the resolution phenotype. The present results indicate that mouse eosinophils and eosinophil-derived lipid mediators, including PD1, have a role in promoting the resolution of acute inflammation, expanding the roles of eosinophils in host defense and resolution. PMID- 20959514 TI - Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration. AB - The potent lipid mediator sphingosine-1-phosphate (S1P) regulates diverse physiological processes by binding to 5 specific GPCRs, although it also has intracellular targets. Here, we demonstrate that S1P, produced in the mitochondria mainly by sphingosine kinase 2 (SphK2), binds with high affinity and specificity to prohibitin 2 (PHB2), a highly conserved protein that regulates mitochondrial assembly and function. In contrast, S1P did not bind to the closely related protein PHB1, which forms large, multimeric complexes with PHB2. In mitochondria from SphK2-null mice, a new aberrant band of cytochrome-c oxidase was detected by blue native PAGE, and interaction between subunit IV of cytochrome-c oxidase and PHB2 was greatly reduced. Moreover, depletion of SphK2 or PHB2 led to a dysfunction in mitochondrial respiration through cytochrome-c oxidase. Our data point to a new action of S1P in mitochondria and suggest that interaction of S1P with homomeric PHB2 is important for cytochrome-c oxidase assembly and mitochondrial respiration. PMID- 20959516 TI - Dietary fat decreases intestinal levels of the anorectic lipids through a fat sensor. AB - This study was undertaken to investigate the link between dietary fat content and intestinal levels of anorectic N-acylethanolamines (NAEs), including oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and linoleoylethanolamide (LEA). Male rats were fed high-fat diets (HFDs) with variable percentages of fat [20-45% of total energy (E%)] for 1-7 d; afterward, the jejunums were isolated, and jejunal NAE levels were measured by liquid-chromatography mass spectrometry. Enzyme activities and mRNA expression levels were measured for two synthesizing enzymes, N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and glycerophosphodiesterase (GDE1), and one degrading enzyme, fatty acid amide hydrolase (FAAH). We found a dose-response relation between the quantity/percentage of dietary fat, irrespective of the energy density, and the reduction of intestinal levels of OEA, PEA, and LEA. The reductions were present after 1 d of 45E% HFD. LEA, the major NAE species, was shown to have an anorectic potency slightly less than that of OEA but higher than PEA. Regulation at the enzyme level seems not to explain the changes in NAE levels. The results suggest the presence of a fat sensor, mediating the reduced intestinal NAE levels. The intestinal NAE levels are reduced in a dose- and time-dependent manner in response to dietary fat intake, and this may contribute to the well-known hyperphagic effect of HFDs. PMID- 20959517 TI - Diallyl trisulfide inhibits activation of signal transducer and activator of transcription 3 in prostate cancer cells in culture and in vivo. AB - Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor implicated in prostate carcinogenesis. The present study shows that diallyl trisulfide (DATS), a promising cancer-chemopreventive constituent of processed garlic, inhibits phosphorylation of STAT3 in prostate cancer cells in culture and in vivo. Exposure of DU145 and LNCaP human prostate cancer cells to growth-suppressive and pharmacologically relevant concentrations of DATS (20 and 40 MUmol/L) resulted in suppression of constitutive (DU145) as well as interleukin-6 (IL-6)-induced (LNCaP) phosphorylation of STAT3 (Tyr(705)), which correlated with inhibition of Janus-activated kinase 2 phosphorylation. Constitutive and/or IL-6-induced nuclear translocation of pSTAT3 and STAT3 dimerization was also markedly inhibited on treatment with DATS in both cell lines. Inhibition of prostate cancer development in transgenic adenocarcinoma of mouse prostate mice by gavage of DATS correlated with a visible decrease in the levels of pSTAT3. Interestingly, the IL-6-mediated activation of STAT3 largely failed to confer protection against proapoptotic response to DATS in both cells. Likewise, DATS-mediated inhibition of cell migration was either not affected or minimally reversed by IL-6 treatment or ectopic expression of constitutively active STAT3. In conclusion, the present study indicates that DATS treatment suppresses STAT3 phosphorylation in prostate cancer cells in culture and in vivo, but activation of this oncogenic transcription factor is largely dispensable for cellular responses to DATS. Ability of DATS to overcome STAT3 activation is a therapeutic advantage for this chemopreventive agent. PMID- 20959518 TI - MicroRNA expression profiling of exfoliated colonocytes isolated from feces for colorectal cancer screening. AB - To reduce the colorectal cancer (CRC) mortality rate, we have reported several CRC screening methods using colonocytes isolated from feces. Expression analysis of oncogenic microRNA (miRNA) in peripheral blood was recently reported for CRC detection. In the present study, we conducted miRNA expression analysis of exfoliated colonocytes isolated from feces for CRC screening. Two hundred six CRC patients and 134 healthy volunteers were enrolled in the study. miRNA expression of the miR-17-92 cluster, miR-21, and miR-135 in colonocytes isolated from feces as well as frozen tissues was analyzed by quantitative real-time PCR. The expression of the miR-17-92 cluster, miR-21, and miR-135 was significantly higher in CRC tissues compared with normal tissues. The exfoliated colonocytes of 197 CRC patients and 119 healthy volunteers were analyzed because of the presence of sufficient miRNA concentration. miR-21 expression did not differ significantly between CRC patients and healthy volunteers (P = 0.6). The expression of miR-17 92 cluster and miR-135 was significantly higher in CRC patients than in healthy volunteers (P < 0.0001). The overall sensitivity and specificity by using miRNA expression was 74.1% (146/197; 95% confidence interval, 67.4-80.1) and 79.0% (94/119; 95% confidence interval, 70.6-85.9), respectively. Sensitivity was dependent only on tumor location (P = 0.0001). miRNA was relatively well conserved in exfoliated colonocytes from feces both of CRC patients and healthy volunteers. miRNA expression analysis of the isolated colonocytes may be a useful method for CRC screening. Furthermore, oncogenic miRNA highly expressed in CRC should be investigated for CRC screening tests in the future. PMID- 20959519 TI - The origins and implications of intratumor heterogeneity. AB - Human tumors often display startling intratumor heterogeneity in various features including histology, gene expression, genotype, and metastatic and proliferative potential. This phenotypic and genetic heterogeneity plays an important role in neoplasia, cancer progression, and therapeutic resistance. In this issue of the journal (beginning on page 1388), Merlo et al. report their use of molecular data from 239 patients with Barrett's esophagus to evaluate the propensity of major diversity indices for predicting progression to esophageal adenocarcinoma. This work helps elucidate the implications of molecular heterogeneity for the evolution of neoplasia. PMID- 20959520 TI - Synthetic triterpenoids prolong survival in a transgenic mouse model of pancreatic cancer. AB - Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and is nearly always fatal. Whereas early detection offers the most promising approach for reducing the mortality of this disease, there is still a need to develop effective drugs for the prevention and treatment of pancreatic cancer. We tested two promising classes of noncytotoxic drugs, synthetic oleanane triterpenoids and rexinoids, for the prevention of carcinogenesis in the highly relevant LSL-Kras(G12D/+);LSL-Trp53(R127H/+);Pdx-1-Cre (KPC) mouse model of pancreatic cancer. KPC transgenic mice closely recapitulate the genetic mutations, clinical symptoms, and histopathology found in human pancreatic cancer. Beginning at 4 weeks of age, mice were fed powdered control diet or a diet containing the triterpenoids CDDO-methyl ester (CDDO-Me) or CDDO-ethyl amide, the rexinoid LG100268 (LG268), or the combination, until the mice displayed overt symptoms of pancreatic cancer. CDDO-Me, LG268, the combination of CDDO-Me and LG268, and the combination of CDDO-ethyl amide and LG268, all significantly (P < 0.05) increased survival in the KPC mice by 3 to 4 weeks. Recent studies have shown that gemcitabine, the current standard of care for human pancreatic cancer, does not extend survival in KPC mice. In cell lines developed from the KPC mice, the triterpenoids directly interact with both signal transducer and activator of transcription 3 and IkappaB kinase (IKK) to decrease constitutive interleukin-6 secretion, inhibit constitutive signal transducer and activator of transcription 3 phosphorylation, and block the degradation of IkappaBalpha when challenged with tumor necrosis factor alpha. These results suggest that oleanane triterpenoids and rexinoids have the potential to prevent pancreatic cancer. PMID- 20959521 TI - Role of syntaxin 4 in activity-dependent exocytosis and synaptic plasticity in hippocampal neurons. AB - Activity-dependent exocytosis of recycling endosomes that contain AMPA receptors in postsynaptic regions of hippocampal neurons occurs at microdomains enriched in the target SNARE [soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor] syntaxin 4 (Stx4). These Stx4-enriched domains are located near the postsynaptic density, and disrupting SNARE interactions involving Stx4 prevents the fusion of recycling endosomes that contain AMPA receptors in dendritic spines. AMPA receptor trafficking is important for long-term potentiation; thus, Stx4 is an essential postsynaptic component for synaptic plasticity in hippocampal neurons. PMID- 20959522 TI - Nuclear emancipation: a platelet tour de force. AB - Mammalian platelets are anucleate cells produced by the polyploid megakaryocyte. Platelets are more than just key players in hemostasis (blood clotting in response to injury); they also have important roles in inflammation, immunity, tumor progression, and thrombosis. Complex systems of homeostasis have been described for platelets, including posttranscriptional and translational mechanisms to regulate platelet function. Platelets contain transcription factors, and these proteins have essential roles in regulating nongenomic processes. A study provides evidence for a previously unknown negative feedback pathway for limiting platelet activation that occurs through the nuclear factor kappaB transcription factor family. This pathway is mediated by an adenosine 3',5'-monophosphate-independent protein kinase A activity in response to platelet stimulation. Our appreciation of the role of transcription factors in mammalian platelet biology is nascent but holds great promise for both understanding platelet function and translation into clinical uses. PMID- 20959523 TI - Single-cell analysis reveals that insulation maintains signaling specificity between two yeast MAPK pathways with common components. AB - Eukaryotic cells use multiple mitogen-activated protein kinase (MAPK) cascades to evoke appropriate responses to external stimuli. In Saccharomyces cerevisiae, the MAPK Fus3 is activated by pheromone-binding heterotrimeric guanosine triphosphate binding protein (G protein)-coupled receptors to promote mating, whereas the MAPK Hog1 is activated by hyperosmotic stress to elicit the high-osmolarity glycerol (HOG) response. Although these MAPK pathways share several upstream components, exposure to either pheromone or osmolyte alone triggers only the appropriate response. We used fluorescence localization- and transcription-specific reporters to assess activation of these pathways in individual cells on the minute and hour time scale, respectively. Dual activation of these two MAPK pathways occurred over a broad range of stimulant concentrations and temporal regimes in wild-type cells subjected to costimulation. Thus, signaling specificity is achieved through an "insulation" mechanism, not a "cross-inhibition" mechanism. Furthermore, we showed that there was a critical period during which Hog1 activity had to occur for proper insulation of the HOG pathway. PMID- 20959524 TI - Safety, tolerability, and pharmacokinetics of KNS-760704 (dexpramipexole) in healthy adult subjects. AB - Dexpramipexole (KNS-760704; [6R]-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole diamine) is a novel synthetic amino-benzothiazole in development for the treatment of amyotrophic lateral sclerosis (ALS). Preclinical studies have shown that dexpramipexole is neuroprotective in vitro and in vivo, is highly orally bioavailable and water soluble, and rapidly achieves and maintains high central nervous system concentrations relative to plasma. Two phase 1 clinical studies were conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of dexpramipexole in 54 healthy male and female adults. The effect of food on the single-dose PK of dexpramipexole was also evaluated. Single doses (50 mg, 150 mg, or 300 mg) and multiple doses (50 mg twice daily, 100 mg twice daily, or 150 mg twice daily) of dexpramipexole over 4.5 days were safe and well tolerated. Dexpramipexole was rapidly absorbed, with time to maximum plasma concentration ranging from 1.8 to 2.6 hours and half-life ranging from 6.4 to 8.1 hours under fasted conditions, and was mostly eliminated in urine as unchanged parent drug (84%-90% of dose). Food had no effect on the single-dose PK of dexpramipexole. These findings support the ongoing development of dexpramipexole for the treatment of ALS and further evaluation of the compound's therapeutic potential in other neurodegenerative diseases. PMID- 20959525 TI - Aclidinium bromide, a long-acting antimuscarinic, does not affect QT interval in healthy subjects. AB - In this phase I trial, the effect of aclidinium, a novel, inhaled long-acting muscarinic antagonist, on QT interval was evaluated, and its cardiovascular safety was assessed in 272 healthy subjects. Aclidinium 200 ug, aclidinium 800 ug, matching placebo, or open-label moxifloxacin 400 mg was administered daily for 3 days. The primary outcome was mean change in individual heart rate corrected QT interval (QTcI). Secondary measures included Bazett-corrected QT interval (QTcB), Fridericia-corrected (QTcF) intervals, 12-lead electrocardiogram (ECG) readings, and 24-hour 12-lead Holter ECG parameters. Adverse events, vital signs, and laboratory and pharmacokinetic parameters were also assessed. Maximum mean QTcI change from time-matched baseline on day 3 was -1.0 milliseconds at 2 hours for aclidinium 200 ug, -1.8 milliseconds at 5 minutes for 800 ug, +11.0 milliseconds at 4 hours for moxifloxacin, and -1.2 milliseconds at 23.5 hours for placebo. Aclidinium had no significant effects on secondary ECG measures. Aclidinium plasma concentrations were generally below the lower limit of quantitation (0.05 ng/mL) after 200 ug and were detected only up to 1 hour after the 800-ug dose in the majority of cases. It is concluded that aclidinium bromide, at doses up to 800 ug, has a favorable cardiovascular safety profile with no effect on QT interval. PMID- 20959526 TI - Adrenal glands are essential for activation of glucogenesis during undernutrition in fetal sheep near term. AB - In adults, the adrenal glands are essential for the metabolic response to stress, but little is known about their role in fetal metabolism. This study examined the effects of adrenalectomizing fetal sheep on glucose and oxygen metabolism in utero in fed conditions and after maternal fasting for 48 h near term. Fetal adrenalectomy (AX) had little effect on the rates of glucose and oxygen metabolism by the fetus or uteroplacental tissues in fed conditions. Endogenous glucose production was negligible in both AX and intact, sham-operated fetuses in fed conditions. Maternal fasting reduced fetal glucose levels and umbilical glucose uptake in both groups of fetuses to a similar extent but activated glucose production only in the intact fetuses. The lack of fasting-induced glucogenesis in AX fetuses was accompanied by falls in fetal glucose utilization and oxygen consumption not seen in intact controls. The circulating concentrations of cortisol and total catecholamines, and the hepatic glycogen content and activities of key gluconeogenic enzymes, were also less in AX than intact fetuses in fasted animals. Insulin concentrations were also lower in AX than intact fetuses in both nutritional states. Maternal glucose utilization and its distribution between the fetal, uteroplacental, and nonuterine maternal tissues were unaffected by fetal AX in both nutritional states. Ovine fetal adrenal glands, therefore, have little effect on basal rates of fetal glucose and oxygen metabolism but are essential for activating fetal glucogenesis in response to maternal fasting. They may also be involved in regulating insulin sensitivity in utero. PMID- 20959527 TI - Long-term treatment with atrial natriuretic peptide inhibits ATP production and insulin secretion in rat pancreatic islets. AB - Atrial natriuretic peptide (ANP) levels correlate with hyperglycemia in diabetes mellitus, but ANP effects on pancreatic islet beta-cell insulin secretion are controversial. ANP was investigated for short- and long-term effects on insulin secretion and mechanisms regulating secretion in isolated rat pancreatic islets. A 3-h incubation with ANP did not affect basal or glucose-stimulated islet insulin secretion. However, 7-day culture of islets with 5.5 mM glucose and ANP (1 nM - 1 MUM) markedly inhibited subsequent glucose (11 mM)-stimulated insulin secretion; total islet insulin content was not affected. Following ANP removal for 24 h, the islet insulin-secretory response to glucose was restored. The insulin-secretory response to other insulin secretagogues, including alpha ketoisocaproic acid, forskolin, potassium chloride, and ionomycin were also markedly inhibited by chronic exposure to ANP. However, the combination of potassium chloride and alpha-ketoisocaproic acid was sufficient to overcome the inhibitory effects of ANP on insulin secretion. The glucose-stimulated increases in islet ATP levels and the ATP/ADP ratio were completely inhibited in ANP 7-day treated islets vs. control; removal of ANP for 24 h partially restored the glucose response. ANP did not affect islet glycolysis. ANP significantly increased levels of islet activated hormone-sensitive lipase and the expression of uncoupling protein-2 and peroxisome proliferator-activated receptor-delta and alpha. Although islet ANP-binding natriuretic peptide receptor-A levels were reduced to 60% of control after 7-day culture with ANP, the ANP-stimulated cGMP levels remained similar to control islet levels. Thus, long-term exposure to ANP inhibits glucose-stimulated insulin secretion and ATP generation in isolated islets. PMID- 20959528 TI - Sensitivity to stress-induced reproductive dysfunction is associated with a selective but not a generalized increase in activity of the adrenal axis. AB - Stress-induced reproductive dysfunction is a relatively common cause of infertility in women. In response to everyday life stress, some individuals readily develop reproductive dysfunction (i.e., they are stress sensitive), whereas others are more stress resilient. Female cynomolgus monkeys, when exposed to mild combined psychosocial and metabolic stress (change in social environment + 20% reduced calorie diet), can be categorized as stress sensitive (SS; they rapidly become anovulatory in response to stress), medium stress resilient (MSR; they slowly become anovulatory in response to prolonged stress), or highly stress resilient (HSR; they maintain normal menstrual cycles in response to stress). In this study, we examined whether increased sensitivity to stress-induced reproductive dysfunction is associated with elevated adrenal axis activity by measuring 1) the diurnal release of ACTH and cortisol, 2) ACTH and cortisol in response to an acute psychological stress, 3) the percent suppression of cortisol in response to dexamethasone negative feedback, 4) the diurnal release of ACTH and cortisol following exposure to mild psychosocial and metabolic stress, 5) the concentration of cortisol in hair, and 6) adrenal weight. SS monkeys (n = 5) did not differ from MSR (n = 5) or HSR (n = 7) monkeys in any measurement of baseline HPA axis activity or the integrated measurements of chronic HPA axis activity. However, MSR + SS monkeys (n = 10) did secrete more cortisol than HSR monkeys during the daytime hours (1000-1800) following exposure to a novel social environment and reduced diet. We conclude that increased activity of the HPA axis is unlikely to be the primary mechanism causing increased sensitivity to stress induced reproductive dysfunction. PMID- 20959529 TI - Regulation of tryptophan 2,3-dioxygenase by HOXA10 enhances embryo viability through serotonin signaling. AB - Tryptophan 2,3-dioxygenase (TDO) is expressed in endometrium and catabolizes tryptophan, a precursor in the biosynthesis of serotonin. Tryptophan metabolism is an important mechanism for regulation of serotonin levels. Preimplantation mouse embryos are known to express serotonin receptors, specifically the 5-HT1D and 5-HT7 serotonin receptor subtypes. Here we demonstrate that Hoxa10 regulates endometrial TDO expression and improves embryo viability through increased serotonin production. Transfection of pcDNA-Hoxa10 to the murine uterus increased total TDO expression. In vitro, epithelial cell TDO expression was decreased after transfection with Hoxa10. Decreased glandular TDO in response to HOXA10 may augment serotonin production by increasing tryptophan availability. Conversely, stromal TDO expression increased with constitutive Hoxa10 expression. In mice, epithelial serotonin was increased in response to constitutive expression of Hoxa10. Embryo quality was impaired after treatment with Hoxa10 antisense. Blockade of serotonin receptors 1D and 7 also resulted in impaired embryo development, indicating an essential role for Hoxa10 induction of TDO and subsequent serotonin production in embryo development. Transfection of pcDNA-TDO also decreased the number of T cells in the endometrial stroma. We have shown a novel mechanism by which HOXA10 regulates endometrial TDO expression. In the endometrial stroma, HOXA10 increases TDO mRNA, which may increase tryptophan catabolism, allowing for immune tolerance at the time of embryo implantation. In endometrial glands, HOXA10 decreases TDO mRNA leading to increased serotonin that in turn acts to promote normal embryo development. PMID- 20959530 TI - Exercise training augments the peripheral insulin-sensitizing effects of pioglitazone in HIV-infected adults with insulin resistance and central adiposity. AB - The prevalence and incidence of insulin resistance and type 2 diabetes mellitus (DM) are higher in people treated for human immunodeficiency virus-1 (HIV) infection than in the general population. Identifying safe and effective interventions is a high priority. We evaluated whether the peroxisome proliferator-activated receptor-gamma agonist pioglitazone with exercise training improves central and peripheral insulin sensitivity more than pioglitazone alone in HIV-infected adults with insulin resistance and central adiposity. Forty-four HIV-infected adults with baseline insulin resistance and central adiposity were randomly assigned to 4 mo of pioglitazone (30 mg/day) with or without supervised, progressive aerobic, and resistance exercise training (1.5-2 h/day, 3 days/wk). The hyperinsulinemic euglycemic clamp was used to evaluate alterations in central and peripheral insulin sensitivity. Thirty-nine participants completed the study. Hepatic insulin sensitivity improved similarly in both groups. Exercise training augmented the beneficial effects of pioglitazone on peripheral insulin sensitivity. Greater improvements in peripheral insulin sensitivity were associated with reductions in total body and limb adipose content rather than increases in limb adiposity or pioglitazone-induced increases in adiponectin concentration. We conclude that supplementing pioglitazone with increased physical activity improved insulin sensitivity more effectively than pioglitazone alone in HIV-infected adults with insulin resistance and central adiposity. Pioglitazone alone did not significantly increase limb adipose content. Potential cardiovascular benefits of these interventions in HIV need investigation. PMID- 20959531 TI - Rose hip exerts antidiabetic effects via a mechanism involving downregulation of the hepatic lipogenic program. AB - The aim of this study was to investigate the metabolic effects of a dietary supplement of powdered rose hip to C57BL/6J mice fed a high-fat diet (HFD). Two different study protocols were used; rose hip was fed together with HFD to lean mice for 20 wk (prevention study) and to obese mice for 10 wk (intervention study). Parameters related to obesity and glucose tolerance were monitored, and livers were examined for lipids and expression of genes and proteins related to lipid metabolism and gluconeogenesis. A supplement of rose hip was capable of both preventing and reversing the increase in body weight and body fat mass imposed by a HFD in the C57BL/6J mouse. Oral and intravenous glucose tolerance tests together with lower basal levels of insulin and glucose showed improved glucose tolerance in mice fed a supplement of rose hip compared with control mice. Hepatic lipid accumulation was reduced in mice fed rose hip compared with control, and the expression of lipogenic proteins was downregulated, whereas AMP activated protein kinase and other proteins involved in fatty acid oxidation were unaltered. Rose hip intake lowered total plasma cholesterol as well as the low density lipoprotein-to-high-density lipoprotein ratio via a mechanism not involving altered gene expression of sterol regulatory element-binding protein 2 or 3-hydroxymethylglutaryl-CoA reductase. Taken together, these data show that a dietary supplement of rose hip prevents the development of a diabetic state in the C57BL/6J mouse and that downregulation of the hepatic lipogenic program appears to be at least one mechanism underlying the antidiabetic effect of rose hip. PMID- 20959533 TI - Improved glucose control and reduced body fat mass in free fatty acid receptor 2 deficient mice fed a high-fat diet. AB - Free fatty acid receptor 2 (Ffar2), also known as GPR43, is activated by short chain fatty acids (SCFA) and expressed in intestine, adipocytes, and immune cells, suggesting involvement in lipid and immune regulation. In the present study, Ffar2-deficient mice (Ffar2-KO) were given a high-fat diet (HFD) or chow diet and studied with respect to lipid and energy metabolism. On a HFD, Ffar2-KO mice had lower body fat mass and increased lean body mass. The changed body composition was accompanied by improved glucose control and lower HOMA index, indicating improved insulin sensitivity in Ffar2-KO mice. Moreover, the Ffar2-KO mice had higher energy expenditure accompanied by higher core body temperature and increased food intake. The liver weight and content of triglycerides as well as plasma levels of cholesterol were lower in the Ffar2-KO mice fed a HFD. A histological examination unveiled decreased lipid interspersed in brown adipose tissue of the Ffar2-KO mice. Interestingly, no significant differences in white adipose tissue (WAT) cell size were observed, but significantly lower macrophage content was detected in WAT from HFD-fed Ffar2-KO compared with wild-type mice. In conclusion, Ffar2 deficiency protects from HFD-induced obesity and dyslipidemia at least partly via increased energy expenditure. PMID- 20959532 TI - Free fatty acids in the presence of high glucose amplify monocyte inflammation via Toll-like receptors. AB - Type 2 diabetes (T2DM) is characterized by hyperglycemia, dyslipidemia, and increased inflammation. Previously, we showed that high glucose (HG) induces Toll like receptor (TLR) expression, activity, and inflammation via NF-kappaB followed by cytokine release in vitro and in vivo. Here, we determined how HG-induced inflammation is affected by free fatty acids (FFA) in human monocytes. THP-1 monocytic cells, CD14(+) human monocytes, and transiently transfected HEK293 cells were exposed to various FFA (0-500 MUM) and glucose (5-20 mM) for evaluation of TLR2, TLR4, NF-kappaB, IL-1beta, monocyte chemoattractant protein-1 (MCP-1), and superoxide release. In THP-1 cells, palmitate increased cellular TLR2 and TLR4 expression, generated reactive oxygen species (ROS), and increased NF-kappaB activity, IL-1beta, and MCP-1 release in a dose- and time-dependent manner. Similar data were observed with stearate and FFA mixture but not with oleate. Conversely, NADPH oxidase inhibitor treatment repressed glucose- and palmitate-stimulated ROS generation and NF-kappaB activity and decreased IL-1beta and MCP-1 expression. Silencing TLR2, TLR4, and p47phox with small inhibitory RNAs (siRNAs) significantly reduced superoxide release, NF-kappaB activity, IL 1beta, and MCP-1 secretion in HG and palmitate-treated THP-1 cells. Moreover, data from transient transfection experiments suggest that TLR6 is required for TLR2 and MD2 for TLR4 to augment inflammation in FFA- and glucose-exposed cells. These findings were confirmed with human monocytes. We conclude that FFA exacerbates HG-induced TLR expression and activity in monocytic cells with excess superoxide release, enhanced NF-kappaB activity, and induced proinflammatory factor release. PMID- 20959534 TI - Proteomics analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes. AB - Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. To date, the molecular mechanisms of DN remain largely unclear. The present study aimed to identify and characterize novel proteins involved in the development of DN by a proteomic approach. Proteomic analysis revealed that 3-hydroxy-3 methylglutaryl-CoA (HMG-CoA) synthase 2 (HMGCS2), the key enzyme in ketogenesis, was increased fourfold in the kidneys of type 2 diabetic db/db mice. Consistently, the activity of HMGCS2 in kidneys and 24-h urinary excretion of the ketone body beta-hydroxybutyrate (beta-HB) were significantly increased in db/db mice. Immunohistochemistry, immunofluorescence, and real-time PCR studies further demonstrated that HMGCS2 was highly expressed in renal glomeruli of db/db mice, with weak expression in the kidneys of control mice. Because filtered ketone bodies are mainly reabsorbed in the proximal tubules, we used RPTC cells, a rat proximal tubule cell line, to examine the effect of the increased level of ketone bodies. Treating cultured RPTC cells with 1 mM beta-HB significantly induced transforming growth factor-beta1 expression, with a marked increase in collagen I expression. beta-HB treatment also resulted in a marked increase in vimentin protein expression and a significant reduction in E-cadherin protein levels, suggesting an enhanced epithelial-to-mesenchymal transition in RPTCs. Collectively, these findings demonstrate that diabetic kidneys exhibit excess ketogenic activity resulting from increased HMGCS2 expression. Enhanced ketone body production in the diabetic kidney may represent a novel mechanism involved in the pathogenesis of DN. PMID- 20959535 TI - Multi-tissue, selective PPARgamma modulation of insulin sensitivity and metabolic pathways in obese rats. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands, including the insulin-sensitizing thiazolidinedione drugs, transcriptionally regulate hundreds of genes. Little is known about the relationship between PPARgamma ligand-specific modulation of cellular mechanisms and insulin sensitization. We characterized the insulin sensitivity and multitissue gene expression profiles of lean and insulin-resistant, obese Zucker rats untreated or treated with one of four PPARgamma ligands (pioglitazone, rosiglitazone, troglitazone, and AG 035029). We analyzed the transcriptional profiles of adipose tissue, skeletal muscle, and liver from the rats and determined whether ligand treatment insulin sensitizing potency was related to ligand treatment-induced alteration of functional pathways. Ligand treatments improved insulin sensitivity in obese rats to varying degrees. Adipose tissue profiles revealed ligand treatment-selective modulation of inflammatory and branched-chain amino acid (BCAA) metabolic pathways, which correlated with ligand treatment-specific insulin-sensitizing potency. Skeletal muscle profiles showed that obese rats exhibited elevated expression of adipocyte and slow-twitch fiber markers, which further increased after ligand treatment, but the magnitude of the treatment-induced changes was not correlated with insulin sensitization. Although PPARgamma ligand treatments heterogeneously improved dysregulated expression of cholesterol and fatty acid biosynthetic pathways in obese rat liver, these alterations were not correlated with ligand insulin-sensitizing potency. PPARgamma ligand treatment-specific insulin-sensitizing potency correlated with modulation of adipose tissue inflammatory and BCAA metabolic pathways, suggesting a functional relationship between these pathways and whole body insulin sensitivity. Other PPARgamma ligand treatment-induced functional pathway changes were detected in adipose tissue, skeletal muscle, and liver profiles but were not related to degree of insulin sensitization. PMID- 20959536 TI - Hormonal regulation of energy-protein homeostasis in hemodialysis patients: an anorexigenic profile that may predispose to adverse cardiovascular outcomes. AB - To assess whether endocrine dysfunction may cause derangement in energy homeostasis in patients undergoing hemodialysis (HD), we profiled hormones, during a 3-day period, from the adipose tissue and the gut and the nervous system around the circadian clock in 10 otherwise healthy HD patients and 8 normal controls. The protocol included a 40-h fast. We also measured energy-protein intake and output and assessed appetite and body composition. We found many hormonal abnormalities in HD patients: 1) leptin levels were elevated, due, in part, to increased production, and nocturnal surge in response to daytime feeding, exaggerated. 2) Peptide YY (PYY), an anorexigenic gut hormone, was markedly elevated and displayed an augmented response to feeding. 3) Acylated ghrelin, an orexigenic gut hormone, was lower and did not exhibit the premeal spike as observed in the controls. 4) neuropeptide Y (NPY), a potent orexigenic peptide, was markedly elevated and did not display any circadian variation. 5) Norepinephrine, marginally elevated, did not exhibit the normal nocturnal dip. By contrast, alpha-melanocyte-stimulating hormone and glucagon-like peptide-1 were not different between the two groups. Despite these hormonal abnormalities, HD patients maintained a good appetite and had normal body lean and fat mass, and there was no evidence of increased energy expenditure or protein catabolism. We explain the hormonal abnormalities as well as the absence of anorexia on suppression of parasympathetic activity (vagus nerve dysfunction), a phenomenon well documented in dialysis patients. Unexpectedly, we noted that the combination of high leptin, PYY, and NPY with suppressed ghrelin may increase arterial blood pressure, impair vasodilatation, and induce cardiac hypertrophy, and thus could predispose to adverse cardiovascular events that are the major causes of morbidity and mortality in the HD population. This is the first report attempting to link hormonal abnormalities associated with energy homeostasis to adverse cardiovascular outcome in the HD patients. PMID- 20959537 TI - Reducing selenoprotein P expression suppresses adipocyte differentiation as a result of increased preadipocyte inflammation. AB - Oxidative stress and low-grade inflammation have been implicated in obesity and insulin resistance. As a selenium transporter, ubiquitously expressed selenoprotein P (SeP) is known to play a role in the regulation of antioxidant enzyme activity. However, SeP expression and regulation in adipose tissue in obesity and its role in inflammation and adipocyte biology remain unexplored. In this study, we examined Sepp1 gene expression and regulation in adipose tissue of obese rodents and characterized the role of Sepp1 in adipose inflammation and adipogenesis in 3T3-L1 adipocytes. We found that Sepp1 gene expression was significantly reduced in adipose tissue of ob/ob and high-fat diet-induced obese mice as well as in primary adipose cells isolated from Zucker obese rats. Rosiglitazone administration increased SeP protein expression in adipose tissue of obese mice. Treatment of either TNFalpha or H(2)O(2) significantly reduced Sepp1 gene expression in a time- and dose-dependent manner in 3T3-L1 adipocytes. Interestingly, Sepp1 gene silencing resulted in the reduction in glutathione peroxidase activity and the upregulation of inflammatory cytokines MCP-1 and IL-6 in preadipocytes, leading to the inhibition of adipogenesis and adipokine and lipogenic gene expression. Most strikingly, coculturing Sepp1 KD cells resulted in a marked inhibition of normal 3T3-L1 adipocyte differentiation. We conclude that SeP has an important role in adipocyte differentiation via modulating oxidative stress and inflammatory response. PMID- 20959538 TI - Caveolin-1 is required for vascular endothelial insulin uptake. AB - As insulin's movement from plasma to muscle interstitium is rate limiting for its metabolic action, defining the regulation of this movement is critical. Here, we address whether caveolin-1 is required for the first step of insulin's transendothelial transport, its uptake by vascular endothelial cells (ECs), and whether IL-6 and TNFalpha affect insulin uptake or caveolin-1 expression. Uptake of FITC-labeled insulin was measured using confocal microscopy in control bovine aortic ECs (bAECs), in bAECs in which caveolin-1 was either knocked down or overexpressed, in murine ECs from caveolin-1(-/-) mice and in bAECs exposed to inflammatory cytokines. Knockdown of caveolin-1 expression in bAECs using specific caveolin-1 siRNA reduced caveolin-1 mRNA and protein expression by ~ 70%, and reduced FITC-insulin uptake by 67% (P < 0.05 for each). Over-expression of caveolin-1 increased insulin uptake (P < 0.05). Caveolin-1-null mouse aortic ECs did not take up insulin and re-expression of caveolin-1 by transfecting these cells with FLAG-tagged caveolin-1 DNA rescued FITC-insulin uptake. Knockdown of caveolin-1 significantly reduced both insulin receptor protein level and insulin stimulated Akt1 phosphorylation. Knockdown of caveolin-1 also inhibited insulin induced caveolin-1 and IGF-1 receptor translocation to the plasma membrane. Compared with controls, IL-6 or TNFalpha (20 ng/ml for 24 h) inhibited FITC insulin uptake as well as the expression of caveolin-1 mRNA and protein (P < 0.05 for each). IL-6 or TNFalpha also significantly reduced plasma membrane-associated caveolin-1. Thus, we conclude that insulin uptake by ECs requires expression of caveolin-1 supporting a role for caveolae mediating insulin uptake. Proinflammatory cytokines may inhibit insulin uptake, at least in part, by inhibiting caveolin-1 expression. PMID- 20959539 TI - Peripheral arterial occlusive disease: evaluation of a high spatial and temporal resolution 3-T MR protocol with a low total dose of gadolinium versus conventional angiography. AB - PURPOSE: To evaluate a peripheral magnetic resonance (MR) angiographic protocol combining continuous table movement (CTM) MR angiography of the entire runoff vasculature with time-resolved (TWIST) 3-T MR angiography of the calves with a total gadolinium dose of 0.1 mmol per kilogram of body weight. MATERIALS AND METHODS: In this retrospective institutional review board-approved study, 31 consecutive patients (22 men, nine women; mean age, 65 years +/- 14 [standard deviation]) with peripheral arterial occlusive disease who had undergone a low dose MR angiographic protocol that consisted of CTM MR angiography (repetition time msec/echo time msec, 2.4/1.0; 21 degrees flip angle; voxel size, 1.2 mm(3); gadolinium dose, 0.07 mmol per kilogram of body weight) and TWIST MR angiography (2.8/1.1; 20 degrees flip angle; voxel size, 1.1 mm(3); temporal resolution, 4.8 5.5 sec, gadolinium dose, 0.03 mmol/kg), as well as digital subtraction angiography (DSA), were included. Two radiologists rated image quality and stenosis degree on four-point scales. The accuracy of stenosis gradation and, specifically, the detection of high-grade stenoses (stenosis of 70%-99%) with CTM MR angiography alone and with the combined protocol were compared with accuracy of stenosis gradation and detection of high-grade stenoses with DSA. Means and standard deviations were calculated for all data. Interobserver agreement was determined with kappa statistics. Positive and negative predictive values, sensitivity, specificity, and overall diagnostic accuracy were calculated for CTM MR angiography alone and for the combined protocol. RESULTS: For CTM MR angiography, image quality was good or excellent in 95.9% of vessel segments; for TWIST MR angiography, image quality was good or excellent in 94.3% and 97.8% of vessel segments for readers 1 and 2, respectively. The combined protocol resulted in high overall diagnostic accuracy of more than 80% for detection of stenosis and diagnostic accuracy of 93.5% for detection of high-grade vessel stenosis. Inclusion of TWIST MR angiography increased diagnostic value over that achieved with CTM MR angiography alone. CONCLUSION: A combined MR angiographic approach in which a low total gadolinium dose (0.1 mmol/kg) is used yields excellent image quality and is accurate in the diagnosis of peripheral arterial stenosis. PMID- 20959540 TI - Appropriate patient selection at abdominal dual-energy CT using 80 kV: relationship between patient size, image noise, and image quality. AB - PURPOSE: To determine the computed tomographic (CT) detector configuration, patient size, and image noise limitations that will result in acceptable image quality of 80-kV images obtained at abdominal dual-energy CT. MATERIALS AND METHODS: The Institutional Review Board approved this HIPAA-compliant retrospective study from archival material from patients consenting to the use of medical records for research purposes. A retrospective review of contrast material-enhanced abdominal dual-energy CT scans in 116 consecutive patients was performed. Three gastrointestinal radiologists noted detector configuration and graded image quality and artifacts at specified levels-midliver, midpancreas, midkidneys, and terminal ileum-by using two five-point scales. In addition, an organ-specific enhancement-to-noise ratio and background noise were measured in each patient. Patient size was measured by using the longest linear dimension at the level of interest, weight, lean body weight, body mass index, and body surface area. Detector configuration, patient sizes, and image noise levels that resulted in unacceptable image quality and artifact rankings (score of 4 or higher) were determined by using multivariate logistic regression. RESULTS: A 14 * 1.2-mm detector configuration resulted in fewer images with unacceptable quality than did the 64 * 0.6-mm configuration at all anatomic levels (P = .004, .01, and .02 for liver, pancreas, and kidneys, respectively). Image acceptability for the kidneys and ileum was significantly greater than that for the liver for all readers and detector configurations (P < .001). For the 14 * 1.2-mm detector configuration, patient longest linear dimensions yielding acceptable image quality across readers ranged from 34.9 to 35.8 cm at the four anatomic levels. CONCLUSION: An 80-kV abdominal CT can be performed with appropriate diagnostic quality in a substantial percentage of the population, but it is not recommended beyond the described patient size for each anatomic level. The 14 * 1.2-mm detector configuration should be preferred. PMID- 20959541 TI - Science to practice: blood-brain barrier leakage--one size does not fit all. PMID- 20959542 TI - Total body fat distribution as part of multiorgan MR imaging: new tool for risk assessment in the metabolic syndrome? PMID- 20959543 TI - Interventional oncology: perspectives on current scholarly productivity and potential for future growth. PMID- 20959546 TI - Effect of menopause on lumbar disk degeneration: potential etiology. AB - Lumbar spine disk degeneration is a common musculoskeletal condition, the prevalence of which increases with age (1-3). Disk degeneration can progress to disk herniation, spinal canal stenosis, and, in conjunction with facet joint arthrosis, degenerative spondylolisthesis. It remains not fully understood what factors initiate and influence the progression of disk degeneration. Nevertheless, there is general agreement that spinal mechanical stress accelerates the development of disk degeneration and increases the likelihood of disk herniation (4-6). Increasing evidence suggests that sex hormones also influence the severity of disk degeneration. PMID- 20959547 TI - Clinical radiation management for fluoroscopically guided interventional procedures. AB - The primary goal of radiation management in interventional radiology is to minimize the unnecessary use of radiation. Clinical radiation management minimizes radiation risk to the patient without increasing other risks, such as procedural risks. A number of factors are considered when estimating the likelihood and severity of patient radiation effects. These include demographic factors, medical history factors, and procedure factors. Important aspects of the patient's medical history include coexisting diseases and genetic factors, medication use, radiation history, and pregnancy. As appropriate, these are evaluated as part of the preprocedure patient evaluation; radiation risk to the patient is considered along with other procedural risks. Dose optimization is possible through appropriate use of the basic features of interventional fluoroscopic equipment and intelligent use of dose-reducing technology. For all fluoroscopically guided interventional procedures, it is good practice to monitor radiation dose throughout the procedure and record it in the patient's medical record. Patients who have received a clinically significant radiation dose should be followed up after the procedure for possible deterministic effects. The authors recommend including radiation management as part of the departmental quality assurance program. PMID- 20959544 TI - What we can and cannot see coming. PMID- 20959548 TI - Time-resolved vessel-selective digital subtraction MR angiography of the cerebral vasculature with arterial spin labeling. AB - PURPOSE: To demonstrate an arterial spin-labeling (ASL) magnetic resonance (MR) angiographic technique that covers the entire cerebral vasculature and yields transparent-background, time-resolved hemodynamic, and vessel-specific information similar to that obtained with x-ray digital subtraction angiography (DSA) without the use of exogenous contrast agents. MATERIALS AND METHODS: Prior institutional review board approval and written informed consent were obtained for this HIPAA-compliant study in which 12 healthy volunteers (five women, seven men; age range, 21-62 years; average age, 28 years) underwent imaging. An ASL technique in which variable labeling durations are used to acquire hemodynamic inflow information and a vessel-selective pulsed-continuous ASL technique were tested. Region-of-interest signal intensities in various vessel segments were averaged across subjects and used to quantitatively compare images. For comparison, a standard time of flight (TOF) acquisition was performed in the circle of Willis. RESULTS: Inflow temporal resolution of 200 msec was demonstrated, revealing arterial transit times of 750, 950, and 1100 msec to consecutive segments of the middle cerebral artery from distal to the circle of Willis to deep regions of the midbrain. Selective labeling resulted in an average of eightfold suppression of contralateral vessels relative to the labeled vessel. Signal-to-noise ratios and contrast-to-noise ratios on maximum intensity projection images obtained with 88-second volumetric acquisitions (60 +/- 15 [standard deviation] and 57 +/- 15, respectively) and 11-second single-projection acquisitions (19 +/- 5 and 17 +/- 5, respectively) were comparable with standard TOF acquisitions, in which a 2.7-fold longer imaging duration for a 2.6-fold lower pixel area was used. Normal variations of the vasculature were identified with ASL angiography. CONCLUSION: ASL angiography can be used to acquire hemodynamic vessel-specific information similar to that obtained with x-ray DSA. PMID- 20959550 TI - Case 163: solitary neurocysticercosis. PMID- 20959551 TI - Highlights on power Doppler US of thyroid malignancy. PMID- 20959552 TI - Renal oncocytoma: misleading diagnosis of benignancy by using angular interface sign at MR imaging. PMID- 20959553 TI - Late-phase contrast-enhanced US to assess unstable carotid atherosclerotic plaques. PMID- 20959554 TI - Gadoxetic acid-enhanced hepatobiliary phase MR imaging: cellular insight. PMID- 20959555 TI - Continuation of statin therapy in patients with presumed infection: a randomized controlled trial. AB - RATIONALE: In patients on prior statin therapy who are hospitalized for acute infections, current literature is unclear on whether statins should be continued during their hospitalization. OBJECTIVES: To test the hypothesis that continuation of therapy with statins influences the inflammatory response to infection and that cessation may cause an inflammatory rebound. METHODS: Prospective randomized double-blind placebo-controlled trial of atorvastatin (20 mg) or matched placebo in 150 patients on preexisting statin therapy requiring hospitalization for infection. MEASUREMENTS AND MAIN RESULTS: The primary end point was progression of sepsis during hospitalization. At baseline, the rate of severe sepsis was 32% in both groups. Compared with baseline, the odds ratio for severe sepsis declined in both groups: 0.43 placebo and 0.5 statins (Day 3) versus 0.14 placebo and 0.12 statins (Day 14). The rate of decline of severe sepsis was similar between the groups (odds ratio 1.17 [0.56-2.47], P = 0.7 Day 3; 0.85 [0.21-3.34], P = 0.8 Day 14). IL-6 and C-reactive protein declined in both groups with no statistically significant difference (P = 0.7 and P = 0.2, respectively). An increase in cholesterol occurred in the placebo group (P < 0.0001). Most patients were not critically ill. Hospital mortality was 6.6%, with no difference between the groups (6 [8%] of 75 statin group; 4 [5.3%] of 75 placebo group; P = 0.75). CONCLUSIONS: This study does not support a beneficial role of continuing preexisting statin therapy on sepsis and inflammatory parameters. Cessation of established statin therapy was not associated with an inflammatory rebound. Clinical trial registered at the Australian New Zealand Clinical Trials Registry (ACTRN 12605000756628). PMID- 20959556 TI - Loss of suppression of tumorigenicity 2 (ST2) gene reverses sepsis-induced inhibition of lung host defense in mice. AB - RATIONALE: After surviving the initial hyperinflammatory phase, patients with sepsis display features consistent with immunosuppression, which renders the host susceptible to nosocomial infections, in particular bacterial pneumonia. Suppression of tumorigenicity 2 (ST2) is a negative regulator of Toll-like receptor signaling implicated in endotoxin tolerance. OBJECTIVES: The present study sought to determine the role of ST2 in modulating host defense in the lung during sepsis, using a murine model of cecal ligation and puncture (CLP)-induced sepsis followed by a secondary infection with Pseudomonas aeruginosa via the airways. METHODS: CLP or sham surgery was performed on BALB/c wild-type (WT) and ST2 knockout (KO) mice, and 24 hours later animals were challenged with 10(8) live P. aeruginosa. MEASUREMENTS AND MAIN RESULTS: CLP mice demonstrated impaired clearance of Pseudomonas from their lungs and reduced pulmonary levels of tumor necrosis factor-alpha and IL-6 compared with sham mice. After CLP, ST2KO mice with secondary pneumonia displayed a strongly improved survival and a better bacterial clearance compared with WT mice, which was accompanied by enhanced lung inflammation. CLP did not influence the responsiveness of alveolar macrophages toward P. aeruginosa ex vivo irrespective of the st2 genotype. In contrast, CLP resulted in a reduced capacity of WT CD4(+) and CD8(+) T cells to produce IFN gamma and tumor necrosis factor-alpha, an immune suppressive effect that was not seen in ST2KO mice. CONCLUSIONS: These findings indicate that gene products of ST2 contribute to the immune-compromised state during sepsis and the ensuing disturbed homeostasis of lung host defense. PMID- 20959557 TI - Epithelial cell death is an important contributor to oxidant-mediated acute lung injury. AB - RATIONALE: Acute lung injury and the acute respiratory distress syndrome are characterized by increased lung oxidant stress and apoptotic cell death. The contribution of epithelial cell apoptosis to the development of lung injury is unknown. OBJECTIVES: To determine whether oxidant-mediated activation of the intrinsic or extrinsic apoptotic pathway contributes to the development of acute lung injury. METHODS: Exposure of tissue-specific or global knockout mice or cells lacking critical components of the apoptotic pathway to hyperoxia, a well established mouse model of oxidant-induced lung injury, for measurement of cell death, lung injury, and survival. MEASUREMENTS AND MAIN RESULTS: We found that the overexpression of SOD2 prevents hyperoxia-induced BAX activation and cell death in primary alveolar epithelial cells and prolongs the survival of mice exposed to hyperoxia. The conditional loss of BAX and BAK in the lung epithelium prevented hyperoxia-induced cell death in alveolar epithelial cells, ameliorated hyperoxia-induced lung injury, and prolonged survival in mice. By contrast, Cyclophilin D-deficient mice were not protected from hyperoxia, indicating that opening of the mitochondrial permeability transition pore is dispensable for hyperoxia-induced lung injury. Mice globally deficient in the BH3-only proteins BIM, BID, PUMA, or NOXA, which are proximal upstream regulators of BAX and BAK, were not protected against hyperoxia-induced lung injury suggesting redundancy of these proteins in the activation of BAX or BAK. CONCLUSIONS: Mitochondrial oxidant generation initiates BAX- or BAK-dependent alveolar epithelial cell death, which contributes to hyperoxia-induced lung injury. PMID- 20959558 TI - Clustered transcription factor genes regulate nicotine biosynthesis in tobacco. AB - Tobacco (Nicotiana tabacum) synthesizes nicotine and related pyridine alkaloids in the root, and their synthesis increases upon herbivory on the leaf via a jasmonate-mediated signaling cascade. Regulatory NIC loci that positively regulate nicotine biosynthesis have been genetically identified, and their mutant alleles have been used to breed low-nicotine tobacco varieties. Here, we report that the NIC2 locus, originally called locus B, comprises clustered transcription factor genes of an ethylene response factor (ERF) subfamily; in the nic2 mutant, at least seven ERF genes are deleted altogether. Overexpression, suppression, and dominant repression experiments using transgenic tobacco roots showed both functional redundancy and divergence among the NIC2-locus ERF genes. These transcription factors recognized a GCC-box element in the promoter of a nicotine pathway gene and specifically activated all known structural genes in the pathway. The NIC2-locus ERF genes are expressed in the root and upregulated by jasmonate with kinetics that are distinct among the members. Thus, gene duplication events generated a cluster of highly homologous transcription factor genes with transcriptional and functional diversity. The NIC2-locus ERFs are close homologs of ORCA3, a jasmonate-responsive transcriptional activator of indole alkaloid biosynthesis in Catharanthus roseus, indicating that the NIC2/ORCA3 ERF subfamily was recruited independently to regulate jasmonate inducible secondary metabolism in distinct plant lineages. PMID- 20959559 TI - Nonflowering plants possess a unique folate-dependent phenylalanine hydroxylase that is localized in chloroplasts. AB - Tetrahydropterin-dependent aromatic amino acid hydroxylases (AAHs) are known from animals and microbes but not plants. A survey of genomes and ESTs revealed AAH like sequences in gymnosperms, mosses, and algae. Analysis of full-length AAH cDNAs from Pinus taeda, Physcomitrella patens, and Chlamydomonas reinhardtii indicated that the encoded proteins form a distinct clade within the AAH family. These proteins were shown to have Phe hydroxylase activity by functional complementation of an Escherichia coli Tyr auxotroph and by enzyme assays. The P. taeda and P. patens AAHs were specific for Phe, required iron, showed Michaelian kinetics, and were active as monomers. Uniquely, they preferred 10 formyltetrahydrofolate to any physiological tetrahydropterin as cofactor and, consistent with preferring a folate cofactor, retained activity in complementation tests with tetrahydropterin-depleted E. coli host strains. Targeting assays in Arabidopsis thaliana mesophyll protoplasts using green fluorescent protein fusions, and import assays with purified Pisum sativum chloroplasts, indicated chloroplastic localization. Targeting assays further indicated that pterin-4a-carbinolamine dehydratase, which regenerates the AAH cofactor, is also chloroplastic. Ablating the single AAH gene in P. patens caused accumulation of Phe and caffeic acid esters. These data show that nonflowering plants have functional plastidial AAHs, establish an unprecedented electron donor role for a folate, and uncover a novel link between folate and aromatic metabolism. PMID- 20959560 TI - Introducing aromatic amino acid hydroxylases from plants. PMID- 20959561 TI - Cytokinin and compound leaf development. PMID- 20959562 TI - Cytokinin regulates compound leaf development in tomato. AB - Leaf shape diversity relies on transient morphogenetic activity in leaf margins. However, how this morphogenetic capacity is maintained is still poorly understood. Here, we uncover a role for the hormone cytokinin (CK) in the regulation of morphogenetic activity of compound leaves in tomato (Solanum lycopersicum). Manipulation of CK levels led to alterations in leaf complexity and revealed a unique potential for prolonged growth and morphogenesis in tomato leaves. We further demonstrate that the effect of CK on leaf complexity depends on proper localization of auxin signaling. Genetic analysis showed that reduction of CK levels suppresses the effect of Knotted1 like homeobox (KNOXI) proteins on leaf shape and that CK can substitute for KNOXI activity at the leaf margin, suggesting that CK mediates the activity of KNOXI proteins in the regulation of leaf shape. These results imply that CK regulates flexible leaf patterning by dynamic interaction with additional hormones and transcription factors. PMID- 20959563 TI - The Arabidopsis dynamin-related protein2 family is essential for gametophyte development. AB - Clathrin-mediated membrane trafficking is critical for multiple stages of plant growth and development. One key component of clathrin-mediated trafficking in animals is dynamin, a polymerizing GTPase that plays both regulatory and mechanical roles. Other eukaryotes use various dynamin-related proteins (DRP) in clathrin-mediated trafficking. Plants are unique in the apparent involvement of both a family of classical dynamins (DRP2) and a family of dynamin-related proteins (DRP1) in clathrin-mediated membrane trafficking. Our analysis of drp2 insertional mutants demonstrates that, similar to the DRP1 family, the DRP2 family is essential for Arabidopsis thaliana development. Gametophytes lacking both DRP2A and DRP2B were inviable, arresting prior to the first mitotic division in both male and female gametogenesis. Mutant pollen displayed a variety of defects, including branched or irregular cell plates, altered Golgi morphology and ectopic callose deposition. Ectopic callose deposition was also visible in the pollen-lethal drp1c-1 mutant and appears to be a specific feature of pollen defective mutants with impaired membrane trafficking. However, drp2ab pollen arrested at earlier stages in development than drp1c-1 pollen and did not accumulate excess plasma membrane or display other gross defects in plasma membrane morphology. Therefore, the DRP2 family, but not DRP1C, is necessary for cell cycle progression during early gametophyte development. This suggests a possible role for DRP2-dependent clathrin-mediated trafficking in the transduction of developmental signals in the gametophyte. PMID- 20959564 TI - Age and sex differences and 20-year trends (1986 to 2005) in prehospital delay in patients hospitalized with acute myocardial infarction. AB - BACKGROUND: The prompt administration of coronary reperfusion therapy for patients with an evolving acute myocardial infarction (AMI) is crucial in reducing mortality and the risk of serious clinical complications in these patients. However, long-term trends in extent of prehospital delay and factors affecting patient's care-seeking behavior remain relatively unexplored, especially in men and women of different ages. The objectives of this study were to examine the overall magnitude and 20-year trends (1986 to 2005) in duration of prehospital delay in middle-aged and elderly men and women hospitalized with AMI. METHODS AND RESULTS: The study sample consisted of 5967 residents of the Worcester, Mass, metropolitan area hospitalized at all greater Worcester medical centers for AMI between 1986 and 2005 who had information available about duration of prehospital delay. Compared with men <65 years, patients in other age sex strata exhibited longer prehospital delays over the 20-year period under study. The multivariable-adjusted medians of prehospital delay were 1.96, 2.07, and 2.57 hours for men <65 years, men 65 to 74 years, and men >=75 years and 2.08, 2.33, and 2.27 hours for women <65 years, women 65 to 74 years, and women >=75 years, respectively. These age and sex differences have narrowed over time, which has been largely explained by changes in patient's comorbidity profile and AMI-associated characteristics. CONCLUSIONS: Our results suggest that duration of prehospital delay in persons with symptoms of AMI has remained essentially unchanged during the 20-year period under study and elderly individuals are more likely to delay seeking timely medical care than younger persons. PMID- 20959565 TI - Warfarin discontinuation after starting warfarin for atrial fibrillation. AB - BACKGROUND: Although warfarin is widely recommended to prevent atrial fibrillation-related thromboembolism, many eligible patients do not take warfarin. The objective of this study was to describe factors associated with warfarin discontinuation in patients newly starting warfarin for atrial fibrillation. METHODS AND RESULTS: We identified 4188 subjects newly starting warfarin in the Anticoagulation and Risk Factors in Atrial Fibrillation Study and tracked longitudinal warfarin use through pharmacy and laboratory databases. Data on patient characteristics, international normalized ratio (INR) tests, and incident hospitalizations for hemorrhage were obtained from clinical and laboratory databases. Multivariable Cox regression analysis was used to identify independent predictors of prolonged warfarin discontinuation, defined as >=180 consecutive days off warfarin. Within 1 year after warfarin initiation, 26.3% of subjects discontinued therapy despite few hospitalizations for hemorrhage (2.3% of patients). The risk of discontinuation was higher in patients aged <65 years (adjusted hazard ratio [HR], 1.33 [95% CI, 1.03 to 1.72] compared to those aged >=85 years), patients with poorer anticoagulation control (HR, 1.46 [95% CI, 1.42 to 1.49] for every 10% decrease in time in therapeutic INR range), and patients with lower stroke risk (HR, 2.54 [95% CI, 1.86 to 3.47] for CHADS(2) stroke risk index of 0 compared to 4 to 6). CONCLUSIONS: More than 1 in 4 patients newly starting warfarin for atrial fibrillation discontinued therapy in the first year despite a low overall hemorrhage rate. Individuals deriving potentially less benefit from warfarin, including those with younger age, fewer stroke risk factors, and poorer INR control, were less likely to remain on warfarin. Maximizing the benefits of anticoagulation for atrial fibrillation depends on determining which patients are most appropriately initiated and maintained on therapy. PMID- 20959566 TI - The cover. The list. PMID- 20959567 TI - A piece of my mind. A room with a view. PMID- 20959568 TI - Study reignites debate about viral agent in patients with chronic fatigue syndrome. PMID- 20959569 TI - Disclosing medical errors does not mean greater liability costs, new study finds. PMID- 20959570 TI - Study probes increase in cesarean rate. PMID- 20959571 TI - Surgical care improvement project adherence and postoperative infections. PMID- 20959572 TI - Surgical care improvement project adherence and postoperative infections. PMID- 20959573 TI - Surgical care improvement project adherence and postoperative infections. PMID- 20959574 TI - Surgical care improvement project adherence and postoperative infections. PMID- 20959575 TI - Hypertension control and cardiovascular outcomes among patients with diabetes and coronary artery disease. PMID- 20959576 TI - Effect of oral glucosamine on pain-related disability in patients with chronic low back pain. PMID- 20959577 TI - Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: a randomized controlled trial. AB - CONTEXT: Uncertainty about the benefits of dietary docosahexaenoic acid (DHA) for pregnant women and their children exists, despite international recommendations that pregnant women increase their DHA intakes. OBJECTIVE: To determine whether increasing DHA during the last half of pregnancy will result in fewer women with high levels of depressive symptoms and enhance the neurodevelopmental outcome of their children. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, multicenter, randomized controlled trial (DHA to Optimize Mother Infant Outcome [DOMInO] trial) in 5 Australian maternity hospitals of 2399 women who were less than 21 weeks' gestation with singleton pregnancies and who were recruited between October 31, 2005, and January 11, 2008. Follow-up of children (n = 726) was completed December 16, 2009. INTERVENTION: Docosahexaenoic acid-rich fish oil capsules (providing 800 mg/d of DHA) or matched vegetable oil capsules without DHA from study entry to birth. MAIN OUTCOME MEASURES: High levels of depressive symptoms in mothers as indicated by a score of more than 12 on the Edinburgh Postnatal Depression Scale at 6 weeks or 6 months postpartum. Cognitive and language development in children as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition, at 18 months. RESULTS: Of 2399 women enrolled, 96.7% completed the trial. The percentage of women with high levels of depressive symptoms during the first 6 months postpartum did not differ between the DHA and control groups (9.67% vs 11.19%; adjusted relative risk, 0.85; 95% confidence interval [CI], 0.70-1.02; P = .09). Mean cognitive composite scores (adjusted mean difference, 0.01; 95% CI, -1.36 to 1.37; P = .99) and mean language composite scores (adjusted mean difference, -1.42; 95% CI, -3.07 to 0.22; P = .09) of children in the DHA group did not differ from children in the control group. CONCLUSION: The use of DHA-rich fish oil capsules compared with vegetable oil capsules during pregnancy did not result in lower levels of postpartum depression in mothers or improved cognitive and language development in their offspring during early childhood. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12605000569606. PMID- 20959579 TI - Association between implementation of a medical team training program and surgical mortality. AB - CONTEXT: There is insufficient information about the effectiveness of medical team training on surgical outcomes. The Veterans Health Administration (VHA) implemented a formalized medical team training program for operating room personnel on a national level. OBJECTIVE: To determine whether an association existed between the VHA Medical Team Training program and surgical outcomes. DESIGN, SETTING, AND PARTICIPANTS: A retrospective health services study with a contemporaneous control group was conducted. Outcome data were obtained from the VHA Surgical Quality Improvement Program (VASQIP) and from structured interviews in fiscal years 2006 to 2008. The analysis included 182,409 sampled procedures from 108 VHA facilities that provided care to veterans. The VHA's nationwide training program required briefings and debriefings in the operating room and included checklists as an integral part of this process. The training included 2 months of preparation, a 1-day conference, and 1 year of quarterly coaching interviews MAIN OUTCOME MEASURE: The rate of change in the mortality rate 1 year after facilities enrolled in the training program compared with the year before and with nontraining sites. RESULTS: The 74 facilities in the training program experienced an 18% reduction in annual mortality (rate ratio [RR], 0.82; 95% confidence interval [CI], 0.76-0.91; P = .01) compared with a 7% decrease among the 34 facilities that had not yet undergone training (RR, 0.93; 95% CI, 0.80 1.06; P = .59). The risk-adjusted mortality rates at baseline were 17 per 1000 procedures per year for the trained facilities and 15 per 1000 procedures per year for the nontrained facilities. At the end of the study, the rates were 14 per 1000 procedures per year for both groups. Propensity matching of the trained and nontrained groups demonstrated that the decline in the risk-adjusted surgical mortality rate was about 50% greater in the training group (RR,1.49; 95% CI, 1.10 2.07; P = .01) than in the nontraining group. A dose-response relationship for additional quarters of the training program was also demonstrated: for every quarter of the training program, a reduction of 0.5 deaths per 1000 procedures occurred (95% CI, 0.2-1.0; P = .001). CONCLUSION: Participation in the VHA Medical Team Training program was associated with lower surgical mortality. PMID- 20959580 TI - Newborn hearing screening vs later hearing screening and developmental outcomes in children with permanent childhood hearing impairment. AB - CONTEXT: Newborn hearing screening programs have been implemented in many countries because it was thought that the earlier permanent childhood hearing impairment is detected, the less developmentally disadvantaged children would become. To date, however, no strong evidence exists for universal introduction of newborn hearing screening. OBJECTIVE: To study the effect of newborn hearing screening vs distraction hearing screening, conducted at 9 months of age, on development, spoken communication, and quality of life. DESIGN, SETTING, AND PARTICIPANTS: Between 2002 and 2006, all 65 regions in The Netherlands replaced distraction hearing screening with newborn hearing screening. Consequently, the type of hearing screening offered was based on availability at the place and date of birth and was independent of developmental prognoses of individual children. All children born in The Netherlands between 2003 and 2005 were included. At the age of 3 to 5 years, all children with permanent childhood hearing impairment were identified. Evaluation ended December 2009. MAIN OUTCOME MEASURES: Performance (education and spoken and signed communication), development (general and language), and quality of life. RESULTS: During the study period, 335,560 children were born in a newborn hearing screening region and 234,826 children in a distraction hearing screening region. At follow-up, 263 children in newborn hearing screening regions (0.78 per 1000 children) and 171 children in distraction hearing screening regions (0.73 per 1000 children) had been diagnosed with permanent childhood hearing impairment. Three hundred one children (69.4%) participated in analysis of general performance measures. There was no difference between groups in the primary mode of communication or type of education. Analysis of extensive developmental outcomes included 80 children born in newborn hearing screening regions and 70 in distraction hearing screening regions. Multivariate analysis of variance showed that overall, children in newborn hearing screening regions had higher developmental outcome scores compared with children in distraction hearing screening regions (Wilks lambda = 0.79; F(12) = 2.705; P = .003). For social development, the mean between-group difference in quotient points was 8.8 (95% CI, 0.8 to 16.7) and for gross motor development, 9.1 (95% CI, 1.1 to 17.1). For quality of life, the mean between-group difference was 5.3 (95% CI, 1.7 to 8.9), also in favor of children in newborn hearing screening regions. CONCLUSION: Compared with distraction hearing screening, a newborn hearing screening program was associated with better developmental outcomes at age 3 to 5 years among children with permanent childhood hearing impairment. PMID- 20959581 TI - Meaningful use of electronic health records: the road ahead. PMID- 20959582 TI - Putting the public back in public reporting of health care quality. PMID- 20959583 TI - Making research consent transparent. PMID- 20959584 TI - Accountable care organizations: accountable for what, to whom, and how. PMID- 20959578 TI - Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. AB - CONTEXT: In the Women's Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported. OBJECTIVE: To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009. DESIGN, SETTING, AND PARTICIPANTS: A total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants. MAIN OUTCOME MEASURES: Invasive breast cancer incidence and breast cancer mortality. RESULTS: In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07 1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group. CONCLUSIONS: Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611. PMID- 20959585 TI - Fish, fish oil, and pregnancy. PMID- 20959586 TI - Postmenopausal hormone therapy and breast cancer: an uncertain trade-off. PMID- 20959587 TI - Improving teamwork to reduce surgical mortality. PMID- 20959588 TI - JAMA patient page . Postpartum depression. PMID- 20959589 TI - The 9p21.3 locus: platelets enter the fray. PMID- 20959590 TI - Large-scale genome-wide association studies consortia: blessing, burden, or necessity? PMID- 20959591 TI - Circulating microRNAs as biomarkers and potential paracrine mediators of cardiovascular disease. PMID- 20959592 TI - Thromboaspiration leading to complete coronary artery stripping in acute myocardial infarction after blast injury. PMID- 20959593 TI - Letter by Chalmers regarding article "Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery: twelve-month results from the RESILIENT randomized trial". PMID- 20959595 TI - Letter by Lozano et al regarding article, "Increased risk of bleeding in patients on clopidogrel therapy after drug-eluting stents implantation: insights from the HMO Research Network-Stent Registry (HMORN-stent)". PMID- 20959597 TI - Does cool reperfusion limit myocardial infarction injury? PMID- 20959598 TI - Surgical update: hybrid procedures, do they have a role? PMID- 20959599 TI - Intravascular ultrasound-documented healing of spontaneous coronary artery dissection. PMID- 20959600 TI - Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities. AB - Over the past 2 decades considerable evidence has accumulated on the association between hepatitis C virus (HCV) and hepatitis B virus (HBV) and several hematologic malignancies, most notably B-cell non-Hodgkin lymphoma (NHL). In this review we summarize this evidence, address possible mechanisms whereby hepatitis viruses may contribute to lymphomagenesis, and discuss the therapeutic fallouts from this knowledge. Most of this evidence is on HCV, and this is the main focus of the review. Moreover, we mainly address the association with NHL, the most prevalent hematologic malignancy, and the most extensively investigated with regard to an association with hepatitis viruses. Available evidence on the association with other hematologic malignancies is also addressed briefly. PMID- 20959601 TI - Platelet factor 4 binds to bacteria, [corrected] inducing antibodies cross reacting with the major antigen in heparin-induced thrombocytopenia. AB - A clinically important adverse drug reaction, heparin-induced thrombocytopenia (HIT), is induced by antibodies specific for complexes of the chemokine platelet factor 4 (PF4) and the polyanion heparin. Even heparin-naive patients can generate anti-PF4/heparin IgG as early as day 4 of heparin treatment, suggesting preimmunization by antigens mimicking PF4/heparin complexes. These antibodies probably result from bacterial infections, as (1) PF4 bound charge-dependently to various bacteria, (2) human heparin-induced anti-PF4/heparin antibodies cross reacted with PF4-coated Staphylococcus aureus and Escherichia coli, and (3) mice developed anti-PF4/heparin antibodies during polymicrobial sepsis without heparin application. Thus, after binding to bacteria, the endogenous protein PF4 induces antibodies with specificity for PF4/polyanion complexes. These can target a large variety of PF4-coated bacteria and enhance bacterial phagocytosis in vitro. The same antigenic epitopes are expressed when pharmacologic heparin binds to platelets augmenting formation of PF4 complexes. Boosting of preformed B cells by PF4/heparin complexes could explain the early occurrence of IgG antibodies in HIT. We also found a continuous, rather than dichotomous, distribution of anti PF4/heparin IgM and IgG serum concentrations in a cross-sectional population study (n = 4029), indicating frequent preimmunization to modified PF4. PF4 may have a role in bacterial defense, and HIT is probably a misdirected antibacterial host defense mechanism. PMID- 20959602 TI - Dynamic combinatorial interactions of RUNX1 and cooperating partners regulates megakaryocytic differentiation in cell line models. AB - Specific interactions of transcription factors (TFs) with their targets are crucial for specifying gene expression programs during cell differentiation. How specificity is maintained despite limited selectivity of individual TF-DNA interactions is not fully understood. RUNX1 TF is among the most frequently mutated genes in human leukemia and an important regulator of megakaryopoiesis. We used megakaryocytic cell lines to characterize the network of RUNX1 targets and cooperating TFs in differentiating megakaryocytes and demonstrated how dynamic partnerships between RUNX1 and cooperating TFs facilitated regulatory plasticity and specificity during this process. After differentiation onset, RUNX1 directly activated a large number of genes through interaction with preexisting and de novo binding sites. Recruitment of RUNX1 to de novo occupied sites occurred at H3K4me1-marked preprogrammed enhancers. A significant number of these de novo bound sites lacked RUNX motif but were occupied by AP-1 TFs. Reciprocally, AP-1 TFs were up-regulated by RUNX1 after 12-O-tetradecanoylphorbol 13-acetate induction and recruited to RUNX1-occupied sites lacking AP-1 motifs. At other differentiation stages, additional combinatorial interactions occurred between RUNX1 and its coregulators, GATA1 and ETS. The findings suggest that in differentiating megakaryocytic cell lines, RUNX1 cooperates with GATA1, AP-1, and ETS to orchestrate cell-specific transcription programs through dynamic TF partnerships. PMID- 20959604 TI - Ndfip1-deficient mice have impaired DMT1 regulation and iron homeostasis. AB - The divalent metal ion transporter DMT1 is critical for nonheme iron import. We have previously shown that DMT1 is regulated in vitro by ubiquitination that is facilitated by the adaptor proteins Ndfip1 and Ndfip2. Here we report that in Ndfip1(-/-) mice fed a low- iron diet, DMT1 expression and activity in duodenal enterocytes are significant higher than in the wild-type animals. This correlates with an increase in serum iron levels and transferrin saturation. Liver and spleen iron stores were also increased in Ndfip1(-/-) mice fed a normal diet. Counterintuitive to the increase in iron uptake, Ndfip1(-/-) mice fed a low iron diet develop severe microcytic, hypochromic anemia. We demonstrate that this is due to a combination of iron deficiency and inflammatory disease in Ndfip1(-/-) mice, because Ndfip1(-/-)/Rag1(-/-) immunodeficient mice fed a low iron diet did not develop anemia and showed an iron overload phenotype. These data demonstrate that Ndfip1 is a critical mediator of DMT1 regulation in vivo, particularly under iron restricted conditions. PMID- 20959603 TI - von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models. AB - Deep vein thrombosis (DVT) and its complication, pulmonary embolism, are frequent causes of disability and mortality. Although blood flow disturbance is considered an important triggering factor, the mechanism of DVT initiation remains elusive. Here we show that 48-hour flow restriction in the inferior vena cava (IVC) results in the development of thrombi structurally similar to human deep vein thrombi. von Willebrand factor (VWF)-deficient mice were protected from thrombosis induced by complete (stasis) or partial (stenosis) flow restriction in the IVC. Mice with half normal VWF levels were also protected in the stenosis model. Besides promoting platelet adhesion, VWF carries Factor VIII. Repeated infusions of recombinant Factor VIII did not rescue thrombosis in VWF(-/-) mice, indicating that impaired coagulation was not the primary reason for the absence of DVT in VWF(-/-) mice. Infusion of GPG-290, a mutant glycoprotein Ibalpha immunoglobulin chimera that specifically inhibits interaction of the VWF A1 domain with platelets, prevented thrombosis in wild-type mice. Intravital microscopy showed that platelet and leukocyte recruitment in the early stages of DVT was dramatically higher in wild-type than in VWF(-/-) IVC. Our results demonstrate a pathogenetic role for VWF-platelet interaction in flow disturbance induced venous thrombosis. PMID- 20959605 TI - Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche. AB - The physiologic roles of angiopoietin-like proteins (Angptls) in the hematopoietic system remain unknown. Here we show that hematopoietic stem cells (HSCs) in Angptl3-null mice are decreased in number and quiescence. HSCs transplanted into Angptl3-null recipient mice exhibited impaired repopulation. Bone marrow sinusoidal endothelial cells express high levels of Angptl3 and are adjacent to HSCs. Importantly, bone marrow stromal cells or endothelium deficient in Angptl3 have a significantly decreased ability to support the expansion of repopulating HSCs. Angptl3 represses the expression of the transcription factor Ikaros, whose unregulated overexpression diminishes the repopulation activity of HSCs. Angptl3, as an extrinsic factor, thus supports the stemness of HSCs in the bone marrow niche. PMID- 20959606 TI - CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. AB - Phosphatidylinositol-3-kinase p110delta serves as a central integration point for signaling from cell surface receptors known to promote malignant B-cell proliferation and survival. This provides a rationale for the development of small molecule inhibitors that selectively target p110delta as a treatment approach for patients with B-cell malignancies. We thus identified 5-fluoro-3 phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one (CAL-101), a highly selective and potent p110delta small molecule inhibitor (half-maximal effective concentration [EC(50)] = 8nM). Using tumor cell lines and primary patient samples representing multiple B-cell malignancies, we have demonstrated that constitutive phosphatidylinositol-3-kinase pathway activation is p110delta dependent. CAL-101 blocked constitutive phosphatidylinositol-3-kinase signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in poly(ADP-ribose) polymerase and caspase cleavage and an induction of apoptosis. These effects have been observed across a broad range of immature and mature B-cell malignancies, thereby providing a rationale for the ongoing clinical evaluation of CAL-101. PMID- 20959607 TI - Tax ubiquitylation and SUMOylation control the dynamic shuttling of Tax and NEMO between Ubc9 nuclear bodies and the centrosome. AB - The human T-lymphotropic virus type I oncoprotein Tax is critical for T-cell transformation, acting mainly through nuclear factor kappa B essential modulator (NEMO) binding and subsequent nuclear factor-kappaB activation. Tax localizes to Tax nuclear bodies and to the centrosome and is subjected to ubiquitylation and small ubiquitin-like modifier (SUMO)ylation, which are both necessary for complete transcriptional activation. Using the photoconvertible fluorophore Dendra-2 coupled with live video confocal microscopy, we show for the first time that the same Tax molecule shuttles among Tax nuclear bodies and between these nuclear bodies and the centrosome, depending on its posttranslational modifications. Ubiquitylation targets Tax to nuclear bodies to which NEMO is recruited and subsequently SUMOylated. We also demonstrate that Tax nuclear bodies contain the SUMOylation machinery including SUMO and the SUMO conjugating enzyme Ubc9, strongly suggesting that these nuclear bodies represent sites of active SUMOylation. Finally, both ubiquitylation and SUMOylation of Tax control NEMO targeting to the centrosome. Altogether, we are proposing a model where both ubiquitylation and SUMOylation of Tax control the shuttling of Tax and NEMO between the cytoplasmic and nuclear compartments. PMID- 20959608 TI - Should catheter ablation of atrial fibrillation be a first-line therapy in the young? PMID- 20959609 TI - Risk assessment for sudden cardiac death in dialysis patients. PMID- 20959610 TI - Use of a primary prevention totally subcutaneous defibrillator in hypertrophic cardiomyopathy. PMID- 20959611 TI - Archival fine-needle aspiration cytopathology (FNAC) samples: untapped resource for clinical molecular profiling. AB - Microarray technologies provide high-resolution maps of chromosome imbalances and epigenomic aberrations in the cancer cell genome. Such assays are often sensitive to sample DNA integrity, voiding the utility of many archival pathology specimens and necessitating the special handling of prospective clinical specimens. We have identified the remarkable preservation of higher-molecular weight DNA in archival fine-needle aspiration cytopathology specimens from patients greater than 10 years of age. We further demonstrate the outstanding technical performance of 57 fine-needle aspiration cytopathology samples for aberration detection on high resolution comparative genomic hybridization array, DNA methylation, and single nucleotide polymorphism genotyping platforms. Forty-four of 46 malignant aspirates in this study manifested unequivocal genomic aberrations. Importantly, matched Papanicolaou and Diff-Quik fine-needle aspiration cytopathology samples showed critical differences in DNA preservation and DNA integrity. Overall, this study identifies a largely untapped reserve of human pathology specimens for molecular profiling studies, with ramifications for the prospective collection of clinical biospecimens. PMID- 20959612 TI - Assay design affects the interpretation of T-cell receptor gamma gene rearrangements: comparison of the performance of a one-tube assay with the BIOMED 2-based TCRG gene clonality assay. AB - Interpretation of capillary electrophoresis results derived from multiplexed fluorochrome-labeled primer sets can be complicated by small peaks, which may be incorrectly interpreted as clonal T-cell receptor-gamma gene rearrangements. In this report, different assay designs were used to illustrate how design may adversely affect specificity. Ten clinical cases, with subclonal peaks containing one of the two infrequently used joining genes, were identified with a tri-color, one-tube assay. The DNA was amplified with the same NED fluorochrome on all three joining primers, first combined (one-color assay) and then amplified separately using a single NED-labeled joining primer. The single primer assay design shows how insignificant peaks could easily be wrongly interpreted as clonal T-cell receptor-gamma gene rearrangements. Next, the performance of the one-tube assay was compared with the two-tube BIOMED-2-based TCRG Gene Clonality Assay in a series of 44 cases. Whereas sensitivity was similar between the two methods (92.9% vs. 96.4%; P = 0.55), specificity was significantly less in the BIOMED-2 assay (87.5% vs. 56.3%; P = 0.049) when a 2* ratio was used to define clonality. Specificity was improved to 81.3% by the use of a 5* peak height ratio (P = 0.626). These findings illustrate how extra caution is needed in interpreting a design with multiple, separate distributions, which is more difficult to interpret than a single distribution assay. PMID- 20959613 TI - Tissue deposition of the insect repellent DEET and the sunscreen oxybenzone from repeated topical skin applications in rats. AB - Insect repellent N,N-diethyl-m-toluamide (DEET) and sunscreen oxybenzone are capable of enhancing skin permeation of each other when applied simultaneously. We carried out a cellular study in rat astrocytes and neurons to assess cell toxicity of DEET and oxybenzone and a 30-day study in Sprague-Dawley rats to characterize skin permeation and tissue disposition of the compounds. Cellular toxicity occurred at 1 ug/mL for neurons and 7-day treatment for astrocytes and neurons. DEET and oxybenzone permeated across the skin to accumulate in blood, liver, and brain after repeated topical applications. DEET disappeared from the application site faster than oxybenzone. Combined application enhanced the disposition of DEET in liver. No overt sign of behavioral toxicity was observed from several behavioral testing protocols. It was concluded that despite measurable disposition of the study compounds in vivo, there was no evidence of neurotoxicological deficits from repeated topical applications of DEET, oxybenzone, or both. PMID- 20959614 TI - Antimutagenic and antioxidant characteristics of Chukrasia tabularis A Juss extracts. AB - The current study aims to evaluate the antioxidative and antimutagenic activities of methanol extract and different fractions of Chukrasia tabularis leaves. The antioxidative potential was evaluated using 2,2'-azinobis (3-ethylbenzothiazoline 6-sulfonic acid) (ABTS) cation and superoxide anion radical-scavenging assay. The antimutagenic potential was evaluated against direct-acting mutagens, 4-nitro-o phenylenediamine and sodium azide; and S9-dependent mutagen, 2-aminofluorene in TA98 and TA100 strains of Salmonella typhimurium using Ames assay. It has been found that methanol extract and its fractions were more efficient against S9 dependent mutagen in pre-incubation mode of treatment as compared to direct acting mutagens in both the strains. Methanol extract and its fractions also exhibited strong radical-scavenging potential. High-performance liquid chromatography (HPLC) analysis of methanol extract showed the presence of gallic acid, epicatechin, 7-hydroxycoumarin, and rutin. From the study, it could be concluded that antioxidative and antimutagenic activity of methanol extract and its fractions was related to the synergistic interactions among different chemical compounds. PMID- 20959615 TI - Oral repeat dose and reproductive toxicity of the chlorinated flame retardant Dechlorane Plus. AB - This study consisted of a 28-day oral repeat dose (repeat dose toxicity [RDT]) phase and a developmental and reproductive (developmental and reproductive toxicity [DART]) phase with rats. Rats were treated with Dechlorane Plus at doses of 0, 750, 1500, or 5000 mg/kg by gavage. For the RDT phase, no effects were observed on in-life parameters or clinical or anatomic pathology. In the DART phase, no effects were observed on reproductive or fertility indices, or fetal development through lactation day (LD) 4. No effects were noted on gestation day (GD) 20 implantation data, fetal indices, or external and visceral examinations. Mortalities occurred across all dose groups, although these were gavage-related errors and not compound related. Microscopic evidence of gavage-related errors included adhesions, inflammation, and fibrosis in the thoracic and pleural cavities. These findings were not test article related as they were observed only in animals with evidence of gavage injury. The no-observable-effect level (NOEL) in both phases of study was 5000 mg/kg. PMID- 20959616 TI - Fluid transport across leaky epithelia: central role of the tight junction and supporting role of aquaporins. AB - The mechanism of epithelial fluid transport remains unsolved, which is partly due to inherent experimental difficulties. However, a preparation with which our laboratory works, the corneal endothelium, is a simple leaky secretory epithelium in which we have made some experimental and theoretical headway. As we have reported, transendothelial fluid movements can be generated by electrical currents as long as there is tight junction integrity. The direction of the fluid movement can be reversed by current reversal or by changing junctional electrical charges by polylysine. Residual endothelial fluid transport persists even when no anions (hence no salt) are being transported by the tissue and is only eliminated when all local recirculating electrical currents are. Aquaporin (AQP) 1 is the only AQP present in these cells, and its deletion in AQP1 null mice significantly affects cell osmotic permeability (by ~40%) but fluid transport much less (~20%), which militates against the presence of sizable water movements across the cell. In contrast, AQP1 null mice cells have reduced regulatory volume decrease (only 60% of control), which suggests a possible involvement of AQP1 in either the function or the expression of volume-sensitive membrane channels/transporters. A mathematical model of corneal endothelium we have developed correctly predicts experimental results only when paracellular electro-osmosis is assumed rather than transcellular local osmosis. Our evidence therefore suggests that the fluid is transported across this layer via the paracellular route by a mechanism that we attribute to electro-osmotic coupling at the junctions. From our findings we have developed a novel paradigm for this preparation that includes 1) paracellular fluid flow; 2) a crucial role for the junctions; 3) hypotonicity of the primary secretion; and 4) an AQP role in regulation rather than as a significant water pathway. These elements are remarkably similar to those proposed by the laboratory of Adrian Hill for fluid transport across other leaky epithelia. PMID- 20959617 TI - Regulation of the pulmonary circulation in the fetus and newborn. AB - During the development of the pulmonary vasculature in the fetus, many structural and functional changes occur to prepare the lung for the transition to air breathing. The development of the pulmonary circulation is genetically controlled by an array of mitogenic factors in a temporo-spatial order. With advancing gestation, pulmonary vessels acquire increased vasoreactivity. The fetal pulmonary vasculature is exposed to a low oxygen tension environment that promotes high intrinsic myogenic tone and high vasocontractility. At birth, a dramatic reduction in pulmonary arterial pressure and resistance occurs with an increase in oxygen tension and blood flow. The striking hemodynamic differences in the pulmonary circulation of the fetus and newborn are regulated by various factors and vasoactive agents. Among them, nitric oxide, endothelin-1, and prostaglandin I(2) are mainly derived from endothelial cells and exert their effects via cGMP, cAMP, and Rho kinase signaling pathways. Alterations in these signaling pathways may lead to vascular remodeling, high vasocontractility, and persistent pulmonary hypertension of the newborn. PMID- 20959619 TI - Regulation of mammalian autophagy in physiology and pathophysiology. AB - (Macro)autophagy is a bulk degradation process that mediates the clearance of long-lived proteins and organelles. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded. Although the term autophagy was first used in 1963, the field has witnessed dramatic growth in the last 5 years, partly as a consequence of the discovery of key components of its cellular machinery. In this review we focus on mammalian autophagy, and we give an overview of the understanding of its machinery and the signaling cascades that regulate it. As recent studies have also shown that autophagy is critical in a range of normal human physiological processes, and defective autophagy is associated with diverse diseases, including neurodegeneration, lysosomal storage diseases, cancers, and Crohn's disease, we discuss the roles of autophagy in health and disease, while trying to critically evaluate if the coincidence between autophagy and these conditions is causal or an epiphenomenon. Finally, we consider the possibility of autophagy upregulation as a therapeutic approach for various conditions. PMID- 20959620 TI - Ca2+-activated K+ channels: from protein complexes to function. AB - Molecular research on ion channels has demonstrated that many of these integral membrane proteins associate with partner proteins, often versatile in their function, or even assemble into stable macromolecular complexes that ensure specificity and proper rate of the channel-mediated signal transduction. Calcium activated potassium (K(Ca)) channels that link excitability and intracellular calcium concentration are responsible for a wide variety of cellular processes ranging from regulation of smooth muscle tone to modulation of neurotransmission and control of neuronal firing pattern. Most of these functions are brought about by interaction of the channels' pore-forming subunits with distinct partner proteins. In this review we summarize recent insights into protein complexes associated with K(Ca) channels as revealed by proteomic research and discuss the results available on structure and function of these complexes and on the underlying protein-protein interactions. Finally, the results are related to their significance for the function of K(Ca) channels under cellular conditions. PMID- 20959618 TI - Mammalian Kruppel-like factors in health and diseases. AB - The Kruppel-like factor (KLF) family of transcription factors regulates diverse biological processes that include proliferation, differentiation, growth, development, survival, and responses to external stress. Seventeen mammalian KLFs have been identified, and numerous studies have been published that describe their basic biology and contribution to human diseases. KLF proteins have received much attention because of their involvement in the development and homeostasis of numerous organ systems. KLFs are critical regulators of physiological systems that include the cardiovascular, digestive, respiratory, hematological, and immune systems and are involved in disorders such as obesity, cardiovascular disease, cancer, and inflammatory conditions. Furthermore, KLFs play an important role in reprogramming somatic cells into induced pluripotent stem (iPS) cells and maintaining the pluripotent state of embryonic stem cells. As research on KLF proteins progresses, additional KLF functions and associations with disease are likely to be discovered. Here, we review the current knowledge of KLF proteins and describe common attributes of their biochemical and physiological functions and their pathophysiological roles. PMID- 20959624 TI - Compensatory expression and substrate inducibility of gamma-glutamyl transferase GGT2 isoform in Arabidopsis thaliana. AB - gamma-Glutamyl transferases (GGT; EC 2.3.2.2) are glutathione-degrading enzymes that are represented in Arabidopsis thaliana by a small gene family of four members. Two isoforms, GGT1 and GGT2, are apoplastic, sharing broad similarities in their amino acid sequences, but they are differently expressed in the tissues: GGT1 is expressed in roots, leaves, and siliques, while GGT2 was thought to be expressed only in siliques. It is demonstrated here that GGT2 is also expressed in wild-type roots, albeit in very small amounts. GGT2 expression is enhanced in ggt1 knockout mutants, suggesting a compensatory effect to restore GGT activity in the root apoplast. Supplementation with 100 MUM glutathione (GSH) resulted in the up-regulation of GGT2 gene expression in wild-type and ggt1 knockout roots, and of GGT1 gene expression in wild-type roots. Glutathione recovery was hampered by the GGT inhibitor serine/borate, suggesting a major role for apoplastic GGTs in this process. These findings can explain the ability of ggt1 knockout mutants to retrieve exogenously added glutathione from the growth medium. PMID- 20959625 TI - In planta function of compatible solute transporters of the AtProT family. AB - The three proline transporters of Arabidopsis thaliana (AtProTs) transport the compatible solutes proline and glycine betaine and the stress-induced compound gamma-aminobutyric acid when expressed in heterologous systems. The aim of the present study was to show transport and physiological relevance of these three AtProTs in planta. Using single, double, and triple knockout mutants and AtProT overexpressing lines, proline content, growth on proline, transport of radiolabelled betaine, and expression of AtProT genes and enzymes of proline metabolism were analysed. AtProT2 was shown to facilitate uptake of L- and D proline as well as [(14)C]glycine betaine in planta, indicating a role in the import of compatible solutes into the root. Toxic concentrations of L- and D proline resulted in a drastic growth retardation of AtProT-overexpressing plants, demonstrating the need for a precise regulation of proline uptake and/or distribution. Furthermore evidence is provided that AtProT genes are highly expressed in tissues with elevated proline content--that is, pollen and leaf epidermis. PMID- 20959623 TI - Intrinsically photosensitive retinal ganglion cells. AB - Life on earth is subject to alternating cycles of day and night imposed by the rotation of the earth. Consequently, living things have evolved photodetective systems to synchronize their physiology and behavior with the external light-dark cycle. This form of photodetection is unlike the familiar "image vision," in that the basic information is light or darkness over time, independent of spatial patterns. "Nonimage" vision is probably far more ancient than image vision and is widespread in living species. For mammals, it has long been assumed that the photoreceptors for nonimage vision are also the textbook rods and cones. However, recent years have witnessed the discovery of a small population of retinal ganglion cells in the mammalian eye that express a unique visual pigment called melanopsin. These ganglion cells are intrinsically photosensitive and drive a variety of nonimage visual functions. In addition to being photoreceptors themselves, they also constitute the major conduit for rod and cone signals to the brain for nonimage visual functions such as circadian photoentrainment and the pupillary light reflex. Here we review what is known about these novel mammalian photoreceptors. PMID- 20959626 TI - Cloning, characterization, and expression of xyloglucan endotransglucosylase/hydrolase and expansin genes associated with petal growth and development during carnation flower opening. AB - Growth of petal cells is a basis for expansion and morphogenesis (outward bending) of petals during opening of carnation flowers (Dianthus caryophyllus L.). Petal growth progressed through elongation in the early stage, expansion with outward bending in the middle stage, and expansion of the whole area in the late stage of flower opening. In the present study, four cDNAs encoding xyloglucan endotransglucosylase/hydrolase (XTH) (DcXTH1-DcXTH4) and three cDNAs encoding expansin (DcEXPA1-DcEXPA3) were cloned from petals of opening carnation flowers and characterized. Real-time reverse transcription-PCR analyses showed that transcript levels of XTH and expansin genes accumulated differently in floral and vegetative tissues of carnation plants with opening flowers, indicating regulated expression of these genes. DcXTH2 and DcXTH3 transcripts were detected in large quantities in petals as compared with other tissues. DcEXPA1 and DcEXPA2 transcripts were markedly accumulated in petals of opening flowers. The action of XTH in growing petal tissues was confirmed by in situ staining of xyloglucan endotransglucosylase (XET) activity using a rhodamine labelled xyloglucan nonasaccharide as a substrate. Based on the present findings, it is suggested that two XTH genes (DcXTH2 and DcXTH3) and two expansin genes (DcEXPA1 and DcEXPA2) are associated with petal growth and development during carnation flower opening. PMID- 20959627 TI - The cytosolic glutamine synthetase GLN1;2 plays a role in the control of plant growth and ammonium homeostasis in Arabidopsis rosettes when nitrate supply is not limiting. AB - Glutamine synthetase (EC 6.3.1.2) is a key enzyme of ammonium assimilation and recycling in plants where it catalyses the synthesis of glutamine from ammonium and glutamate. In Arabidopsis, five GLN1 genes encode GS1 isoforms. GLN1;2 is the most highly expressed in leaves and is over-expressed in roots by ammonium supply and in rosettes by ample nitrate supply compared with limiting nitrate supply. It is shown here that the GLN1;2 promoter is mainly active in the minor veins of leaves and flowers and, to a lower extent, in the parenchyma of mature leaves. Cytoimmunochemistry reveals that the GLN1;2 protein is present in the companion cells. The role of GLN1;2 was determined by examining the physiology of gln1;2 knockout mutants. Mutants displayed lower glutamine synthetase activity, higher ammonium concentration, and reduced rosette biomass compared with the wild type (WT) under ample nitrate supply only. No difference between mutant and WT can be detected under limiting nitrate conditions. Despite total amino acid concentration was increased in the old leaves of mutants at high nitrate, no significant difference in nitrogen remobilization can be detected using (15)N tracing. Growing plants in vitro with ammonium or nitrate as the sole nitrogen source allowed us to confirm that GLN1;2 is induced by ammonium in roots and to observe that gln1;2 mutants displayed, under such conditions, longer root hair and smaller rosette phenotypes in ammonium. Altogether the results suggest that GLN1;2 is essential for nitrogen assimilation under ample nitrate supply and for ammonium detoxification. PMID- 20959621 TI - The beta subunit of voltage-gated Ca2+ channels. AB - Calcium regulates a wide spectrum of physiological processes such as heartbeat, muscle contraction, neuronal communication, hormone release, cell division, and gene transcription. Major entryways for Ca(2+) in excitable cells are high voltage activated (HVA) Ca(2+) channels. These are plasma membrane proteins composed of several subunits, including alpha(1), alpha(2)delta, beta, and gamma. Although the principal alpha(1) subunit (Ca(v)alpha(1)) contains the channel pore, gating machinery and most drug binding sites, the cytosolic auxiliary beta subunit (Ca(v)beta) plays an essential role in regulating the surface expression and gating properties of HVA Ca(2+) channels. Ca(v)beta is also crucial for the modulation of HVA Ca(2+) channels by G proteins, kinases, and the Ras-related RGK GTPases. New proteins have emerged in recent years that modulate HVA Ca(2+) channels by binding to Ca(v)beta. There are also indications that Ca(v)beta may carry out Ca(2+) channel-independent functions, including directly regulating gene transcription. All four subtypes of Ca(v)beta, encoded by different genes, have a modular organization, consisting of three variable regions, a conserved guanylate kinase (GK) domain, and a conserved Src-homology 3 (SH3) domain, placing them into the membrane-associated guanylate kinase (MAGUK) protein family. Crystal structures of Ca(v)betas reveal how they interact with Ca(v)alpha(1), open new research avenues, and prompt new inquiries. In this article, we review the structure and various biological functions of Ca(v)beta, with both a historical perspective as well as an emphasis on recent advances. PMID- 20959622 TI - Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. AB - Among the myriad of intracellular signaling networks that govern the cardiac development and pathogenesis, mitogen-activated protein kinases (MAPKs) are prominent players that have been the focus of extensive investigations in the past decades. The four best characterized MAPK subfamilies, ERK1/2, JNK, p38, and ERK5, are the targets of pharmacological and genetic manipulations to uncover their roles in cardiac development, function, and diseases. However, information reported in the literature from these efforts has not yet resulted in a clear view about the roles of specific MAPK pathways in heart. Rather, controversies from contradictive results have led to a perception that MAPKs are ambiguous characters in heart with both protective and detrimental effects. The primary object of this review is to provide a comprehensive overview of the current progress, in an effort to highlight the areas where consensus is established verses the ones where controversy remains. MAPKs in cardiac development, cardiac hypertrophy, ischemia/reperfusion injury, and pathological remodeling are the main focuses of this review as these represent the most critical issues for evaluating MAPKs as viable targets of therapeutic development. The studies presented in this review will help to reveal the major challenges in the field and the limitations of current approaches and point to a critical need in future studies to gain better understanding of the fundamental mechanisms of MAPK function and regulation in the heart. PMID- 20959628 TI - Root-synthesized cytokinins improve shoot growth and fruit yield in salinized tomato (Solanum lycopersicum L.) plants. AB - Salinity limits crop productivity, in part by decreasing shoot concentrations of the growth-promoting and senescence-delaying hormones cytokinins. Since constitutive cytokinin overproduction may have pleiotropic effects on plant development, two approaches assessed whether specific root-localized transgenic IPT (a key enzyme for cytokinin biosynthesis) gene expression could substantially improve tomato plant growth and yield under salinity: transient root IPT induction (HSP70::IPT) and grafting wild-type (WT) shoots onto a constitutive IPT expressing rootstock (WT/35S::IPT). Transient root IPT induction increased root, xylem sap, and leaf bioactive cytokinin concentrations 2- to 3-fold without shoot IPT gene expression. Although IPT induction reduced root biomass (by 15%) in control (non-salinized) plants, in salinized plants (100 mM NaCl for 22 d), increased cytokinin concentrations delayed stomatal closure and leaf senescence and almost doubled shoot growth (compared with WT plants), with concomitant increases in the essential nutrient K(+) (20%) and decreases in the toxic ion Na(+) (by 30%) and abscisic acid (by 20-40%) concentrations in transpiring mature leaves. Similarly, WT/35S::IPT plants (scion/rootstock) grown with 75 mM NaCl for 90 d had higher fruit trans-zeatin concentrations (1.5- to 2-fold) and yielded 30% more than WT/non-transformed plants. Enhancing root cytokinin synthesis modified both shoot hormonal and ionic status, thus ameliorating salinity-induced decreases in growth and yield. PMID- 20959629 TI - pH-dependent localization of Btn1p in the yeast model for Batten disease. AB - Btn1p the yeast homolog of human CLN3, which is associated with juvenile Batten disease has been implicated in several cellular pathways. Yeast cells lacking BTN1 are unable to couple ATP hydrolysis and proton pumping activities by the vacuolar ATPase (V-ATPase). In this work, we demonstrate that changes in extracellular pH result in altered transcription of BTN1, as well as a change in the glycosylation state and localization of Btn1p. At high pH, Btn1p expression was increased and the protein was mainly located in vacuolar membranes. However, low pH decreased Btn1p expression and changed its location to undefined punctate membranes. Moreover, our results suggest that differential Btn1p localization may be regulated by its glycosylation state. Underlying pathogenic implications for Batten disease of altered cellular distribution of CLN3 are discussed. PMID- 20959630 TI - Transmembrane potential of GlyCl-expressing instructor cells induces a neoplastic like conversion of melanocytes via a serotonergic pathway. AB - Understanding the mechanisms that coordinate stem cell behavior within the host is a high priority for developmental biology, regenerative medicine and oncology. Endogenous ion currents and voltage gradients function alongside biochemical cues during pattern formation and tumor suppression, but it is not known whether bioelectrical signals are involved in the control of stem cell progeny in vivo. We studied Xenopus laevis neural crest, an embryonic stem cell population that gives rise to many cell types, including melanocytes, and contributes to the morphogenesis of the face, heart and other complex structures. To investigate how depolarization of transmembrane potential of cells in the neural crest's environment influences its function in vivo, we manipulated the activity of the native glycine receptor chloride channel (GlyCl). Molecular-genetic depolarization of a sparse, widely distributed set of GlyCl-expressing cells non cell-autonomously induces a neoplastic-like phenotype in melanocytes: they overproliferate, acquire an arborized cell shape and migrate inappropriately, colonizing numerous tissues in a metalloprotease-dependent fashion. A similar effect was observed in human melanocytes in culture. Depolarization of GlyCl expressing cells induces these drastic changes in melanocyte behavior via a serotonin-transporter-dependent increase of extracellular serotonin (5-HT). These data reveal GlyCl as a molecular marker of a sparse and heretofore unknown cell population with the ability to specifically instruct neural crest derivatives, suggest transmembrane potential as a tractable signaling modality by which somatic cells can control stem cell behavior at considerable distance, identify a new biophysical aspect of the environment that confers a neoplastic-like phenotype upon stem cell progeny, reveal a pre-neural role for serotonin and its transporter, and suggest a novel strategy for manipulating stem cell behavior. PMID- 20959631 TI - How moderate changes in Akt T-loop phosphorylation impact on tumorigenesis and insulin resistance. AB - The Akt signalling pathway plays vital roles in controlling cellular responses to insulin as well as in proliferation and survival. Inhibition of Akt signalling leads to insulin resistance and type 2 diabetes, whereas hyperactivation of Akt promotes tumorigenesis. In this study, we investigate how modest changes in the activity of the Akt signalling pathway, to an extent that might be achieved by drug treatment, would impact on insulin resistance and tumorigenesis. Using insulin-resistant PDK1(K465E/K465E) PH domain knock-in mice, we found that introducing the PTEN(+/-) mutation to slightly stimulate Akt restored normal insulin sensitivity. Introducing the PDK1(K465E/K465E) PH domain knock-in mutation into cancer-prone PTEN(+/-) mice, lowered Akt activity only by about 50%, but led to a delay in tumour onset of ~4 months in a broad range of tumours. This was also accompanied by slower growth of B cell follicular lymphomas, as monitored by magnetic resonance imaging. Our findings imply that signal transduction inhibitors that lead to a modest reduction in Akt activity would not only delay onset of tumours possessing elevated phosphoinositide 3-kinase pathway activity but would also reduce the growth rate of developed tumours. PMID- 20959632 TI - A mouse model for an erythropoietin-deficiency anemia. AB - In mammals, the production of red blood cells is tightly regulated by the growth factor erythropoietin (EPO). Mice lacking a functional Epo gene are embryonic lethal, and studying erythropoiesis in EPO-deficient adult animals has therefore been limited. In order to obtain a preclinical model for an EPO-deficient anemia, we developed a mouse in which Epo can be silenced by Cre recombinase. After induction of Cre activity, Epo(KO/flox) mice experience a significant reduction of serum EPO levels and consequently develop a chronic, normocytic and normochromic anemia. Furthermore, compared with wild-type mice, Epo expression in Epo(KO/flox) mice is dramatically reduced in the kidney, and expression of a well known target gene of EPO signaling, Bcl2l1, is reduced in the bone marrow. These observations are similar to the clinical display of anemia in patients with chronic kidney disease. In addition, during stress-induced erythropoiesis these mice display the same recovery rate as their heterozygous counterparts. Taken together, these results demonstrate that this model can serve as a valuable preclinical model for the anemia of EPO deficiency, as well as a tool for the study of stress-induced erythropoiesis during limiting conditions of EPO. PMID- 20959633 TI - Zebrafish model of tuberous sclerosis complex reveals cell-autonomous and non cell-autonomous functions of mutant tuberin. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by mutations in either the TSC1 (encodes hamartin) or TSC2 (encodes tuberin) genes. Patients with TSC have hamartomas in various organs throughout the whole body, most notably in the brain, skin, eye, heart, kidney and lung. To study the development of hamartomas, we generated a zebrafish model of TSC featuring a nonsense mutation (vu242) in the tsc2 gene. This tsc2(vu242) allele encodes a truncated Tuberin protein lacking the GAP domain, which is required for inhibition of Rheb and of the TOR kinase within TORC1. We show that tsc2(vu242) is a recessive larval-lethal mutation that causes increased cell size in the brain and liver. Greatly elevated TORC1 signaling is observed in tsc2(vu242/vu242) homozygous zebrafish, and is moderately increased in tsc2(vu242/+) heterozygotes. Forebrain neurons are poorly organized in tsc2(vu242/vu242) homozygous mutants, which have extensive gray and white matter disorganization and ectopically positioned cells. Genetic mosaic analyses demonstrate that tsc2 limits TORC1 signaling in a cell-autonomous manner. However, in chimeric animals, tsc2(vu242/vu242) mutant cells also mislocalize wild-type host cells in the forebrain in a non-cell-autonomous manner. These results demonstrate a highly conserved role of tsc2 in zebrafish and establish a new animal model for studies of TSC. The finding of a non-cell-autonomous function of mutant cells might help explain the formation of brain hamartomas and cortical malformations in human TSC. PMID- 20959635 TI - Enterohemorrhagic Escherichia coli induce attaching and effacing lesions and hemorrhagic colitis in human and bovine intestinal xenograft models. AB - Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is an important cause of diarrhea, hemorrhagic colitis and hemolytic uremic syndrome in humans worldwide. The two major virulence determinants of EHEC are the Shiga toxins (Stx) and the type III secretion system (T3SS), including the injected effectors. Lack of a good model system hinders the study of EHEC virulence. Here, we investigated whether bovine and human intestinal xenografts in SCID mice can be useful for studying EHEC and host tissue interactions. Fully developed, germ-free human and bovine small intestine and colon were established by subcutaneous transplantation of human and bovine fetal gut into SCID mice. Xenografts were allowed to develop for 3-4 months and thereafter were infected by direct intraluminal inoculation of Stx-negative derivatives of EHEC O157:H7, strain EDL933. The small intestine and colon xenografts closely mimicked the respective native tissues. Upon infection, EHEC induced formation of typical attaching and effacing lesions and tissue damage that resembled hemorrhagic colitis in colon xenografts. By contrast, xenografts infected with an EHEC mutant deficient in T3SS remained undamaged. Furthermore, EHEC did not attach to or damage the epithelium of small intestinal tissue, and these xenografts remained intact. EHEC damaged the colon in a T3SS dependent manner, and this model is therefore useful for studying the molecular details of EHEC interactions with live human and bovine intestinal tissue. Furthermore, we demonstrate that Stx and gut microflora are not essential for EHEC virulence in the human gut. PMID- 20959636 TI - PEX13 deficiency in mouse brain as a model of Zellweger syndrome: abnormal cerebellum formation, reactive gliosis and oxidative stress. AB - Delayed cerebellar development is a hallmark of Zellweger syndrome (ZS), a severe neonatal neurodegenerative disorder. ZS is caused by mutations in PEX genes, such as PEX13, which encodes a protein required for import of proteins into the peroxisome. The molecular basis of ZS pathogenesis is not known. We have created a conditional mouse mutant with brain-restricted deficiency of PEX13 that exhibits cerebellar morphological defects. PEX13 brain mutants survive into the postnatal period, with the majority dying by 35 days, and with survival inversely related to litter size and weaning body weight. The impact on peroxisomal metabolism in the mutant brain is mixed: plasmalogen content is reduced, but very long-chain fatty acids are normal. PEX13 brain mutants exhibit defects in reflex and motor development that correlate with impaired cerebellar fissure and cortical layer formation, granule cell migration and Purkinje cell layer development. Astrogliosis and microgliosis are prominent features of the mutant cerebellum. At the molecular level, cultured cerebellar neurons from E19 PEX13 null mice exhibit elevated levels of reactive oxygen species and mitochondrial superoxide dismutase-2 (MnSOD), and show enhanced apoptosis together with mitochondrial dysfunction. PEX13 brain mutants show increased levels of MnSOD in cerebellum. Our findings suggest that PEX13 deficiency leads to mitochondria mediated oxidative stress, neuronal cell death and impairment of cerebellar development. Thus, PEX13-deficient mice provide a valuable animal model for investigating the molecular basis and treatment of ZS cerebellar pathology. PMID- 20959637 TI - Targeting ependymal stem cells in vivo as a non-invasive therapy for spinal cord injury. PMID- 20959638 TI - Ethanol-lock therapy for the prevention of central venous access device infections in pediatric patients with intestinal failure. AB - BACKGROUND: Central venous access device (CVAD) infections are a major complication in pediatric patients receiving long-term parenteral nutrition (PN) and are particularly prevalent in patients with intestinal failure. This study evaluated the outcomes of outpatient ethanol-lock therapy (ELT) for the prevention of CVAD infections in children with intestinal failure. METHODS: In this retrospective analysis, the primary outcome measure was the rate of bloodstream infection (BSI) due to CVAD infections per 1,000 catheter days, and secondary measures included type of organisms cultured and complications of ELT. RESULTS: Over the course of 2 years, 15 patients received outpatient ELT. Sixty seven percent were male; patients had a mean +/- standard deviation age at enrollment of 5.6 +/- 6.9 years and body weight of 19.9 +/- 15.4 kg. Mean duration of ELT was 263 +/- 190 days. Mean BSI rate per 1,000 catheter days significantly decreased from 8.0 before ELT to 1.3 after ELT (P < .01). Seventy three percent of patients remained infection free throughout the entire study period. Adverse events potentially related to ELT included thrombosis (n = 1), difficulty withdrawing blood from the CVAD, requiring thrombolytic administration (n = 3), and repair of the CVAD for leakage/tear (n = 20). The rate of CVAD repair for leakage/tear with ELT was compared to prior rates per 1,000 catheter days and was found to be elevated after initiation of ELT (6.4 +/- 10.0 vs 3.1 +/ 5.2; P = .20). No signs and symptoms of ethanol intoxication were observed. CONCLUSIONS: ELT for the prevention of CVAD infections in pediatric intestinal failure patients significantly decreased BSI rates and may be used for extended periods of time in an outpatient setting. PMID- 20959639 TI - Assessing appropriate parenteral nutrition ordering practices in tertiary care medical centers. AB - BACKGROUND: Parenteral nutrition (PN) is an essential feeding route for specific patient populations. Despite its utility, PN is invasive, costly, and associated with clinical complications. In most U.S. hospitals, PN is overprescribed. This study measured rates of inappropriate PN use in hospitalized adults, as determined by the 2002 American Society for Parenteral and Enteral Nutrition guidelines, at 4 tertiary care South Carolina hospitals (facilities A-D). Secondary aims were to identify indicators of inappropriate use and estimated preventable costs. METHODS: Over a 3-month period, trained registered dietitians at each site collected data retrospectively and prospectively to determine PN appropriateness and indicators of use in 278 randomly selected PN cases. RESULTS: PN therapy was inappropriately prescribed in 32% of cases, resulting in approximately 552 days and $138,000 in preventable hospital costs. Thirteen percent of patients who were prescribed inappropriate PN were discharged on home PN. Mean duration of PN therapy was higher in inappropriate cases vs appropriate cases (6 +/- 7 days [range, 1-78 days] vs 10 +/- 10.6 days [range, 1-51 days]; P < .004). Facility B had lower rates of inappropriately prescribed PN (23%) compared with facilities A (33%), C (35%), and D (38%). Dietitians recommended against PN in >70% of all inappropriate cases at facilities A and D compared with <45% at facilities B and D (P < .001). Facility B employed more certified nutrition support dietitians (68% of staff) and was among the 2 hospitals using a nutrition support team (NST). CONCLUSION: This study was novel by comparing PN practices in statewide hospitals. Results indicate that NSTs and certified nutrition support clinicians can curtail preventable spending from inappropriate PN use. Future studies should identify barriers in implementing evidence-based practice. PMID- 20959640 TI - Acetylcholine receptor agonist reduces brain damage induced by hypoxia-ischemia in newborn rats. AB - OBJECTIVE: The newborn rat model has been developed to elucidate the mechanism and management of perinatal brain damage. Our study hypothesis is that an acetylcholine receptor agonist (carbachol) reduces hypoxia-ischemia (HI)-induced brain damage in a well-established newborn rat model. STUDY DESIGN: 7-day-old Wistar rats were divided into 3 groups at random: carbachol preinjection and HI (Carb/HI), saline preinjection and HI (Saline/HI), and only HI (HI). Rats were subjected to left carotid artery ligation followed by 2 hours of hypoxia (8% oxygen). We injected carbachol or saline before hypoxic loading. After 7 days, we checked for brain damage. RESULTS: In the cerebral cortex, 25% of the Carb/HI group showed mild neural damage, and the remaining 75% showed no damage. In contrast, more than 80% of the Saline/HI and HI groups had severe neural damage. Similarly, neural damage significantly decreased in Carb/HI compared with Saline/HI and HI for CA1, CA2, CA3, and the dentate gyrus of hippocampal regions. CONCLUSION: Acetylcholine receptor agonist has a potent effect by reducing perinatal brain damage induced by HI in newborn rats. PMID- 20959641 TI - Factors derived from preeclamptic placentas perturb polarity protein PARD-3 expression and distribution in endothelial cells. AB - OBJECTIVE: This study aimed to examine (1) whether polarity protein partitioning defective-3 (PARD-3) was expressed in endothelial cells (ECs) and contributed to endothelial barrier integrity and (2) whether altered PARD-3 expression and distribution were associated with disturbed endothelial junction protein VE cadherin expression induced by factors derived from preeclamptic (PE) placentas. METHODS: PARD-3 and VE-cadherin expressions were examined by immunofluorescent staining and Western blot in confluent ECs and in ECs treated with normal and PE placental conditioned medium (CM). Protein-protein interactions between PARD-3/VE cadherin, PARD-3/ atypical protein kinase C (aPKClambda), and VE cadherin/aPKClambda were examined by immuno-precipitation and immunobloting. RESULTS: Similar to VE-cadherin, PARD-3 is localized at the cell contacts in control ECs. Both PARD-3 and VE-cadherin expressions were markedly reduced in cells treated with PE-CM for 2h, but not in cells treated with normal-CM compared to non-treated controls. Cytosol staining of VE-cadherin and PARD-3 was pronounced in cells after 24h treatment with PE-CM. PARD-3/VE-cadherin and PARD 3/aPKClambda complexes were detected in PE-CM treated cells, but not in untreated control cells and in cells after recovery. In contrast, VE-cadherin/aPKClambda complex was detected in control cells and in cells after recovery, but not in PE CM treated cells. CONCLUSIONS: Polarity protein PARD-3 is localized at cell contacts. Factors-derived from PE placentas not only interrupt junction protein VE-cadherin distribution, but also perturb polarity protein PARD-3 expression and distribution in ECs. The results of PARD-3/VE-cadherin and PARD-3/aPKClambda complexes formation in cells treated with placental CM suggest that factors derived from placenta could interfere both junction protein and polarity protein functions in ECs. PMID- 20959642 TI - Preantral follicle growth is regulated by c-Jun-N-terminal kinase (JNK) pathway. AB - c-Jun N-terminal kinase (JNK) pathway has been shown to be essential for cell cycle progression and mitosis. We previously showed that this pathway is activated in mitotic granulosa cells of follicles from transitional to antral stages. In this study, we, therefore, aimed to investigate whether this signaling pathway has any effect on in-vitro growth of murine preantral follicles and granulosa cell cycle control. Two structurally different pharmacologic JNK inhibitors, SP600125 and AS601245, were used in the experiments. First their inhibitory concentrations were determined in granulosa cells by Western blot analysis. Then preantral follicles isolated from immature and adult C57BL/6 mice were cultured in matrigel and standard culture plates for 6 days with these inhibitors. Spontaneously immortalized rat granulosa cells (SIGCs) were first synchronized at G1/S and G2/M stages of cell cycle and then treated with JNK inhibitors. Cell cycle progression was analyzed with Bromodeoxyuridine (BrdU) assay and flow cytometry analysis. Both inhibitors significantly inhibited phosphorylation of c-Jun in granulosa cells at 25, 50, and 100 MUmol/L concentrations. Isolated preantral follicles cultured with these inhibitors exhibited arrested growth in culture in a dose-dependent manner. Cell cycle analyses showed that both inhibitors impair the progression of cell cycle at S phase and G2/M transition of granulosa cells. These results suggest that JNK pathway is essential for in vitro growth of preantral follicle growth and regulates both S phase and G2/M stages of cell cycle in granulosa cells. PMID- 20959643 TI - Semen parameters are unrelated to BMI but vary with SSRI use and prior urological surgery. AB - BACKGROUND: Male infertility affects approximately 6% of reproductive-aged men. It has been suggested that overweight men or men with obese body mass index (BMI) experience prolonged time to pregnancy, though the influence of male BMI on fertility remains understudied. AIMS: We hypothesized that BMI is inversely correlated with fertility, manifested by reduced sperm concentration, motility, and morphology. METHODS: Males of age 18 to 50 with semen analyses and self reported BMI were included (n = 530). Patient parameters analyzed included age, BMI, smoking, urological, and fertility history. Leutinizing hormone (LH), Follicle-stimulating hormone, testosterone, steroid hormone-binding globulin (SHBG) and free androgen index (FAI) levels (n = 55), and selective serotonin reuptake inhibitor (SSRI) use (n = 12) were also measured. RESULTS: The men in this study had a mean BMI of 28.2 +/- 4.9 kg/m(2) (range = 15-60), which is considered overweight, and a mean semen concentration of 55.4 +/- 46.8 million/mL, which is in normal range, according to WHO standard. No consistent relationship was observed between increasing BMI and sperm concentration, motility, or morphology, although the testosterone levels trended downward with increasing BMI; there was a suggestion for decreased sperm concentration in current smokers. Men treated with combination SSRI and other psychotropic agent therapy (n = 12) had significantly reduced sperm motility (P = .009). Not unexpectedly, prior urological surgery (n = 77) was associated with lower sperm concentration (P = .0001) and morphology (P = .0008). When in vitro fertilization embryo transfer (IVF-ET) was used as a treatment modality (n = 121), male BMI was not a significant predictor of clinical pregnancy (P = .06). CONCLUSIONS: In our study, we did not observe a significant association between male BMI and sperm concentration, motility or morphology, or clinical pregnancy following IVF-ET. Significantly, SSRI use may affect sperm parameters negatively. PMID- 20959644 TI - Progesterone modulates integrin {alpha}2 (ITGA2) and {alpha}11 (ITGA11) in the pregnant cervix. AB - OBJECTIVE: Fibrillar collagen in the cervical extracellular matrix (ECM) is the predominant component providing mechanical support. Cellular integrins contribute to structural integrity by cross-linking ECM components. We investigated the expression of collagen-binding integrins in the normal rat gestation and after treatment with mifepristone to determine whether integrin modulation is involved in changes in tissue resistance. STUDY DESIGN: Cervical tissue was harvested from nonpregnant and timed pregnant Sprague-Dawley rats. Normal gestational expression was evaluated in nonpregnant and timed pregnant tissue on days 12, 16, 18, 20, 21 and 22. Progesterone inhibition was induced with 3 mg mifepristone administered on day 15. Primary rat cervical stromal (RCS) cell cultures were generated from nonpregnant rats using tissue explants. The effects of progesterone environment on RCS cells were evaluated in the presence and absence of various inhibitors. Protein expression and signaling pathways were evaluated by Western blot. RESULTS: Integrin alpha2 (ITGA2) expression increased over gestation, peaking at the end of gestation (analysis of variance [ANOVA] P < .01). Integrin alpha11 (ITGA11) expression increased through mid-gestation, peaking on day 18 and decreasing through day 22 (ANOVA P < .001). Progesterone increased the expression of ITGA11 and phosphorylated focal adhesion kinase ([pFAK] P < .002). Mifepristone blocked these effects in vitro. Mifepristone increased ITGA2 and phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) in vivo and in vitro. Mifepristone-induced upregulation of ITGA2 was abrogated by inhibition of ERK1/2. CONCLUSION: Progesterone/progesterone withdrawal is involved in regulating the expression of collagen-binding integrins. These changes differ among the collagen-binding integrins. Mitogen-activated protein kinase (MAPK) signaling is involved in regulating some of these integrins. PMID- 20959645 TI - Na+,K+-ATPase activity and subunit protein expression: ontogeny and effects of exogenous and endogenous steroids on the cerebral cortex and renal cortex of sheep. AB - We examined the effects of development, exogenous, and endogenous glucocorticoids on Na(+),K(+)-ATPase activity and subunit protein expression in ovine cerebral cortices and renal cortices. Ewes at 60%, 80%, and 90% gestation, newborns, and adults received 4 dexamethasone or placebo injections. Cerebral cortex Na(+),K(+) ATPase activity was higher (P < .05) in placebo-treated newborns than fetuses of placebo-treated ewes and adults, alpha(1)-expression was higher at 90% gestation than the other ages; alpha(2)-expression was higher in newborns than fetuses; alpha(3)-expression was higher in newborns than 60% gestation; beta(1)-expression was higher in newborns than the other ages, and beta(2)-expression higher at 60% than 80% and 90% gestation, and in adults. Renal cortex Na(+),K(+)-ATPase activity was higher in placebo-treated adults and newborns than fetuses. Cerebral cortex Na(+),K(+)-ATPase activity was higher in dexamethasone- than placebo treated adults, and alpha(1)-expression higher in fetuses of dexamethasone- than placebo-treated ewes at 60% and 80% gestation. Renal cortex Na(+),K(+)-ATPase activity and alpha(1)-expression were higher in fetuses of dexamethasone- than placebo-treated ewes at each gestational age, and beta(1)-expression was higher in fetuses of dexamethasone- than placebo-treated ewes at 90% gestation and in dexamethasone- than placebo-treated adults. Cerebral cortex Na(+),K(+)-ATPase activity, alpha(1)-expression, beta(1)-expression, and renal cortex alpha(1) expression correlated directly with increases in fetal cortisol. In conclusion, Na(+),K(+)-ATPase activity and subunit expression exhibit specific developmental patterns in brain and kidney; exogenous glucocorticoids regulate activity and subunit expression in brain and kidney at some ages; endogenous increases in fetal cortisol regulate cerebral Na(+),K(+)-ATPase, but exogenous glucocorticoids have a greater effect on renal than cerebral Na(+),K(+)-ATPase. PMID- 20959646 TI - Digibind reverses inhibition of cellular rb+ uptake caused by endogenous sodium pump inhibitors present in serum and placenta of women with preeclampsia. AB - INTRODUCTION: Mechanisms mediating preeclampsia (PE) are unclear. Endogenous digitalis-like factors (EDLFs) are sodium pump (SP) inhibitors implicated in essential hypertension, but not fully explored in PE. This study asks whether EDLFs are present and increased in PE and considers their source. METHODS: EDLF in sera and placentas from third trimester women with uncomplicated pregnancies or PE was assessed by a Rb(+) uptake assay. A digoxin antibody Fab fragment (Digibind) known to inactivate EDLFs was also used to assess EDLFs. RESULTS: PE serum caused significantly more SP inhibition than serum from uncomplicated pregnancies. This inhibition was concentration-dependent and reversed by Digibind. Serum from uncomplicated pregnancies showed no concentration-dependence or reversal with Digibind. Placental homogenates from control women showed little SP inhibition, but homogenates from PE women showed marked SP inhibition reversed by Digibind. CONCLUSION: These studies evidence EDLF in PE serum. Additionally, PE placentas have high EDLF and may represent a source. PMID- 20959647 TI - Expression of the vasoactive proteins AT1, AT2, and ANP by pregnancy-induced mouse uterine natural killer cells. AB - Angiotensin II receptor type 1 (AT1) activation leads to vasoconstriction and type 2 receptor (AT2) leads to vasodilation. Atrial natriuretic peptide (ANP) antagonizes the effects of AT1. In human and murine pregnancies, uterine natural killer (uNK) cells closely associate with decidual blood vessels. Protein localization of AT1, AT2, and ANP to mouse uNK cells was examined between gestation days (gds) 6 and 12, the interval of uNK cell expansion. Percentages of uNK cells expressing AT1 or AT2 changed between gd6 and gd10. Atrial natriuretic peptide did not localize to uNK cells at gd6 or 8, but did colocalize to uNK cells at gd10 and 12, times immediately after spiral arterial modification. This is the first report of AT1, AT2, and ANP expression in uterine immune cells. Expression of these molecules suggests that uNK cells have the potential to contribute to the changes in blood pressure that occur between days 5 and 12 of pregnancy in mice. PMID- 20959648 TI - Testosterone levels and cardiovascular disease. PMID- 20959649 TI - Low serum testosterone and increased mortality in men with coronary heart disease. AB - BACKGROUND: To examine the effect of serum testosterone levels on survival in a consecutive series of men with confirmed coronary disease and calculate the prevalence of testosterone deficiency. DESIGN: Longitudinal follow-up study. SETTING: Tertiary referral cardiothoracic centre. Patients 930 consecutive men with coronary disease referred for diagnostic angiography recruited between June 2000 and June 2002 and followed up for a mean of 6.9+/-2.1 years. OUTCOME: All cause mortality and vascular mortality. Prevalence of testosterone deficiency. RESULTS: The overall prevalence of biochemical testosterone deficiency in the coronary disease cohort using bio-available testosterone (bio-T) <2.6 nmol/l was 20.9%, using total testosterone <8.1 nmol/l was 16.9% and using either was 24%. Excess mortality was noted in the androgen-deficient group compared with normal (41 (21%) vs 88 (12%), p=0.002). The only parameters found to influence time to all-cause and vascular mortality (HR +/- 95% CI) in multivariate analyses were the presence of left ventricular dysfunction (3.85; 1.72 to 8.33), aspirin therapy (0.63; 0.38 to 1.0), beta-blocker therapy (0.45; 0.31 to 0.67) and low serum bio-T (2.27; 1.45 to 3.6). CONCLUSIONS: In patients with coronary disease testosterone deficiency is common and impacts significantly negatively on survival. Prospective trials of testosterone replacement are needed to assess the effect of treatment on survival. PMID- 20959650 TI - Anatomical and functional impairment of the retina and optic nerve in patients with anorexia nervosa without vision loss. AB - AIM: The aim of this cross-sectional study is to evaluate the macular and retinal nerve fibre layer (RNFL) thickness, as well as the electrical activity of the macula in female patients suffering from anorexia nervosa (AN) without visual failure. MATERIAL AND METHODS: 13 female patients (26 eyes) suffering from AN without visual failure and 20 age and sex-matched healthy female controls (40 eyes) were studied. For the measurement of the macula thickness and the electrical activity of the macula, the optical coherence tomography (OCT) and the multifocal electroretinogram were used respectively. RESULTS: The visual acuity, as well as the visual fields, the colour vision testing and the dark adaptation test of all patients were normal. However, the mean foveal thickness was 140.04 MUm (vs 150.85 in the control group, p=0.005), and the RNFL thickness was limited to 116.42 MUm in the superior area (vs 123.15 in the control group, p=0.372) and 121.08 MUm in the inferior area (vs 137.6 in the control group, p<0.001) around the optic nerve. Also, the mean P1 response density amplitude of the foveal area was 159.04 nV/deg(2) (vs 292.43 in the control group, p<0.0001), and the perifoveal area was 79.04 nV/deg(2) (vs 82.63 in the control group, p=0.118). CONCLUSION: The present study shows that in patients with AN, even without visual failure there is a decrease in macular and RNFL thickness, as well as a decrease in the electrical activity of the macula. PMID- 20959651 TI - Histopathologic prognosis of thymomas: another example of medical surrogacy. PMID- 20959652 TI - Professional quality assurance in laboratory medicine: what about the competency of laboratory directors? PMID- 20959653 TI - Oral and extraoral plasmablastic lymphoma: similarities and differences in clinicopathologic characteristics. AB - Plasmablastic lymphoma (PBL), initially characterized as an aggressive lymphoma arising in the jaw and oral mucosa in HIV-infected patients, was recently reported to occur with extraoral manifestations, heterogeneous histologic findings, and variable association with immunodeficiency states. We reviewed clinical, morphologic, and immunophenotypic features of 13 cases of PBL to determine whether these different subtypes represent distinct morphologic and clinical entities. Two distinct subtypes of PBL were identified and classified as oral and extraoral PBL. The oral PBLs were strongly associated with HIV infection and commonly demonstrated plasmablastic morphologic features without plasmacytic differentiation. Extraoral PBLs tended to occur in patients with underlying non HIV-related immunosuppression and universally demonstrated plasmacytic differentiation. The patients with oral PBL demonstrated better overall survival compared with patients with extraoral PBL (P = .02). Our findings suggest that PBL with oral and extraoral manifestation represent 2 distinct clinicopathologic entities. PMID- 20959654 TI - Validation and implementation of an algorithm for reporting the automated absolute neutrophil count from selected flagged specimens. AB - Samples that are flagged by automated cell counters and, therefore, require a time-consuming microscopic review cause unacceptable wait times for patients in hematology/oncology clinics. We used a set of 518 samples to validate that 5 flags on Sysmex XE/XT instruments (Sysmex, Kobe, Japan) could safely be ignored when the absolute neutrophil count (ANC) was the primary clinical question. The R(2) between automated and manual ANCs was 96.9% for samples triggering non-ANC flags, with 1 clinically significant discrepant sample out of 296 (0.3%). A new test code allowing clinicians to specify "ANC-only" was implemented, and these non-ANC specific flags were disregarded. The new order set was used in 16.3% of patients. Automated reporting of the ANC in selected flagged samples reduced the review rate by 60% and decreased the turnaround time by 100 minutes. This approach to automatically report the ANC in selected flagged specimens in which the ANC is the primary clinical interest safely decreases the turnaround time for many ANC samples. PMID- 20959655 TI - CD200 (OX-2 membrane glycoprotein) expression in b cell-derived neoplasms. AB - We studied the expression of CD200, an immunoglobulin superfamily membrane glycoprotein, in a wide range of B cell-derived neoplasms by immunohistochemical staining of paraffin-embedded tissue sections. In addition to chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), CD200 is expressed in other B cell lymphoproliferative disorders, including hairy cell leukemia. In addition, neoplastic cells in classical Hodgkin lymphoma are immunoreactive for CD200. CD200 was previously reported to be expressed in acute myeloid leukemia, and we find that it is also expressed in B-lymphoblastic leukemia/lymphoma. We conclude that CD200 may be a useful immunophenotypic marker in the evaluation of B cell derived neoplasms. Furthermore, since an anti-CD200 immunotherapeutic agent is in clinical trials, a number of B cell-derived neoplasms in addition to CLL/SLL may be suitable therapeutic targets. PMID- 20959656 TI - Automated cerebrospinal fluid cell counts using the Sysmex XE-5000: is it time for new reference ranges? AB - The main objectives of the study were to compare manual and automated WBC counts on clear cerebrospinal fluid (CSF) samples. Clear CSF samples from 200 adults and children were studied. Cell counts were performed manually using a hemocytometer and then analyzed on the Sysmex XE-5000. Descriptive statistics and Spearman correlation for nonparametric data were used for method comparison. Manual WBC counts ranged from 0 to 702 cells/MUL, and Sysmex counts ranged from 0 to 629 cells/MUL. The Spearman rank correlation coefficient for the entire range of data was 0.77 (P < .001); however, the correlation was weaker at the low end of the data spectrum. For manual WBC ranges of 0 to 5 cells/MUL and 0 to 10 cells/MUL, the corresponding Sysmex 0 to 95th percentile ranges were 0 to 23 cells/MUL and 0 to 27 cells/MUL, respectively. The results suggest that larger studies are necessary to determine new reference ranges for automated CSF WBC counts. PMID- 20959657 TI - Immunophenotypic correlation between skin biopsy and peripheral blood findings in mycosis fungoides. AB - In mycosis fungoides (MF) with blood involvement, T-cell immunophenotypes in skin and blood have not been compared. Our aim was to evaluate T-cell immunophenotypes in skin by immunohistochemical analysis and compare results with flow cytometric (FC) findings in blood. Of 20 patients with MF with blood involvement, the immunophenotype was discrepant in 11 (55%). Compared with FC findings in blood, immunohistochemical analysis of skin samples failed to detect partial deletion of CD2 (5/11 [45%]), CD3 (3/11 [27%]), and CD5 (3/11 [27%]) and overrepresented deletion of CD7 in 2 (18%) of 11 patients. In addition, CD8+ MF was missed by immunohistochemical analysis in 2 (18%) of 11 patients. Identical T-cell populations were demonstrated by T-cell gene polymerase chain reaction in skin and blood in 8 of the 11 patients who had a discrepant immunophenotype. Awareness of the limitations of immunohistochemical analysis of skin samples is of practical value for pathologists interpreting skin biopsies in MF patients. In addition, our findings suggest CD8+ MF to be more common than previously reported. PMID- 20959658 TI - The specificity of immunophenotypic alterations in blasts in nonacute myeloid disorders. AB - Data regarding flow cytometry (FC) in nonacute myeloid disorders is confounded by variable gating strategies and controls limited to normal bone marrow (BM) samples. Blasts in diagnostic BM samples of myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), and chronic myelomonocytic leukemias (CMMLs) were compared with 20 nonneoplastic cytopenias/cytoses (CCs) and negative staging BM samples using 4-color FC. Blasts in 10 of 20 CCs showed immunophenotypic differences vs control samples. Immunophenotypic alterations were identified in 18 of 21 MDSs, 11 of 14 MPNs, and 7 of 7 CMMLs vs control samples and 13 (62%) of 21 MDSs, 7 (50%) of 14 MPNs, and 3 (43%) of 7 CMMLs vs CCs. Neoplastic-specific blast immunophenotypic changes included expression of CD7, CD11b, CD15, CD36, and CD56; CD34 overexpression; HLA-DR variability; lack of CD13 and CD33; underexpression of CD13, CD33, CD45, and HLA-DR; and partial loss of CD13, CD33, CD38, and CD117. In all cases, blasts were CD34+. Several blast immunophenotypic alterations are shared in neoplastic and nonneoplastic BM samples. Approximately 40% to 60% of neoplastic BM samples exhibited aberrancies not seen in reactive BM samples. PMID- 20959659 TI - Lupus anticoagulant testing: performance and practices by north american clinical laboratories. AB - Lupus anticoagulant (LAC) testing is important for evaluating patients with antiphospholipid syndromes and hypercoagulable states. We reviewed results of proficiency testing challenges (n = 5) distributed by the North American Specialized Coagulation Laboratory Association to examine LAC testing performed by participating laboratories. The activated partial thromboplastin time (APTT) and dilute Russell viper venom time (dRVVT) constituted major testing methods. In screening studies, LAC-sensitive APTT methods were more sensitive to weak LAC than dRVVT-based methods but less specific. In confirmatory testing, dRVVT methods performed better, but performance was LAC-dependent. The highest false negative confirmatory test results were obtained for the platelet neutralization procedure. Noncompliance with recommendations for LAC testing by the International Society on Thrombosis and Haemostasis was high (8%-38%), with the majority of noncompliant laboratories failing to report results of mixing studies. These data provide new insights into LAC testing in North America and identify opportunities for standardization. PMID- 20959660 TI - Platelet factor 4/heparin antibodies in blood bank donors. AB - Platelet factor 4 (PF4)/heparin antibody, typically associated with heparin therapy, is reported in some heparin-naive people. Seroprevalence in the general population, however, remains unclear. We prospectively evaluated PF4/heparin antibody in approximately 4,000 blood bank donors using a commercial enzyme linked immunosorbent assay for initial and then repeated (confirmatory) testing. Antibody was detected initially in 249 (6.6%; 95% confidence interval [CI], 5.8% 7.4%) of 3,795 donors and repeatedly in 163 (4.3%; 95% CI, 3.7%-5.0%) of 3,789 evaluable donors. "Unconfirmed" positives were mostly (93%) low positives (optical density [OD] = 0.40-0.59). Of 163 repeatedly positive samples, 116 (71.2%) were low positives, and 124 (76.1%) exhibited heparin-dependent binding. Predominant isotypes of intermediate to high seropositive samples (OD >0.6) were IgG (20/39 [51%]), IgM (9/39 [23%]), and indeterminate (10/39 [26%]). The marked background seroprevalence of PF4/heparin antibody (4.3%-6.6%) with the preponderance of low (and frequently nonreproducible) positives in blood donors suggests the need for further assay calibration, categorization of antibody level, and studies evaluating clinical relevance of "naturally occurring" PF4/heparin antibodies. PMID- 20959661 TI - Intratumoral expression level of epidermal growth factor receptor and cytokeratin 5/6 is significantly associated with nodal and distant metastases in patients with basal-like triple-negative breast carcinoma. AB - Triple-negative (TN) breast carcinoma, characterized by estrogen receptor, progesterone receptor, and HER2 negativity, is a group of aggressive tumors that can be further classified into 2 subtypes: basal-like, defined as CK5/6 and/or epidermal growth factor receptor (EGFR) positive by immunohistochemistry; and non basal-like. Clinical characteristics and tumor profiles were analyzed in 105 cases of TN tumors. Among these cases, 35 had distant metastasis, 34 had axillary nodal metastasis only, and 36 were nodal negative. Our results indicate basal like TN breast tumors with nodal and distant metastases are significantly associated with a higher intratumoral expression of EGFR and CK5/6 compared to those in the nodal negative group. High level of intratumoral EGFR and CK5/6 expression may play a role in development of nodal or distant metastases in patients with basal-like TN tumors and may be predictive of metastatic disease. Furthermore, EGFR targeted therapy may be potentially useful in the treatment of basal-like TN breast cancer. PMID- 20959662 TI - Does a repeated benign aspirate change the risk of malignancy after an initial atypical thyroid fine-needle aspiration? AB - Repeated fine-needle aspiration of the thyroid is sometimes recommended after an atypical diagnosis. However, histologic follow-up for patients with a benign second aspirate is limited. I reviewed the results of all thyroid aspirations with repeated aspirations and surgical resection for the last 13 years at Baptist Hospital, Miami, FL, and Homestead Hospital, Homestead, FL, and combined these with the results of intraoperative cytology and the literature. During the period, a total of 7,089 cases were aspirated and 1,331 resections were performed. There were 6 (1.7%) of 361 false-negative cases. Relevant intraoperative cytology was available for 24 cases. The order of the diagnoses (benign then atypical, atypical then benign) did not significantly affect the risk of malignancy (15% and 9%; P = .30). Patients with an atypical and benign diagnosis had a risk of malignancy (15%) higher than a single negative aspirate (3%; P < .001) and lower than that of patients with a single atypical diagnosis (27%; P < .001). Repeated aspirates are not independent events. Patients with a benign diagnosis after an atypical diagnosis have a risk of malignancy between the risks of a single benign or atypical diagnosis. Cytologists should strive to better communicate this risk. PMID- 20959663 TI - Invasive spindle cell thymomas (WHO Type A): a clinicopathologic correlation of 41 cases. AB - We report 41 cases of invasive spindle cell thymomas (World Health Organization type A). The patients were 16 women and 25 men between the ages of 38 and 80 years. Clinically, the patients had diverse symptomatology, including chest pain, cough, and dyspnea. None of the patients had a history of myasthenia gravis. According to the Mazaoka surgical staging system, 34 patients had stage II disease, 6 had stage III, and 1 had stage IV. Follow-up information showed that 30 patients were alive after a period ranging from 12 to 96 months; for 8 patients who are alive, the follow-up was less than 12 months; 1 patient died 10 months after initial diagnosis. For 2 patients, no follow-up information was obtained. This study stresses the fact that histologic features do not correlate with invasion or encapsulation because all thymomas, regardless of their histologic type, are capable of invasion. PMID- 20959664 TI - Characteristics of hepatic igf-ii expression and monitored levels of circulating igf-ii mRNA in metastasis of hepatocellular carcinoma. AB - The prognosis of hepatocellular carcinoma (HCC) remains dismal. Insulin-like growth factor II (IGF-II), a fetal growth factor, is highly expressed during HCC development. We examined serum IGF-II levels and circulating IGF-II messenger RNA (mRNA) expression and analyzed the clinicopathologic characteristics in patients with liver diseases. The higher IGF-II level in the serum of patients with HCC could be correlated with hepatitis B virus infection but not with patient sex, age, tumor size, or alpha-fetoprotein (AFP) level. Total RNAs were extracted from liver tissues or peripheral blood mononuclear cells, and IGF-II complementary DNA (cDNA) and AFP cDNA were synthesized through random primers and reverse transcriptase; gene fragments were amplified by nested polymerase chain reaction and confirmed by sequencing. The incidence of the hepatic IGF-II gene was 100% in HCC, 54.3% in paracancerous tissues, and none in noncancerous tissues. The incidence rates for circulating IGF-II and AFP genes were 34.3% and 52.7%, respectively, and for both, 61.6% in patients with HCC. They were 100% in cases with extrahepatic metastasis. The IGF-II abnormality associates with HCC, and circulating IGF-II and IGF-II mRNA are useful molecular markers for HCC differential diagnosis and hematogenous metastasis. PMID- 20959665 TI - Renal cell carcinomas with intratumoral fat and concomitant angiomyolipoma: potential pitfalls in staging and diagnosis. AB - Intratumoral fat and angiomyolipomas (AMLs) occurring within renal cell carcinomas (RCCs) have rarely been reported but may be mistaken for tumor invasion into perinephric or renal sinus fat or misdiagnosed as tumor exhibiting sarcomatoid differentiation. We report 16 such cases. In 14 RCC cases, there was intratumoral fat, 9 of which had fat located peripherally near the capsule (n = 6), renal sinus (n = 1), or both (n = 2). Inflammatory infiltrates and osseous metaplasia were identified in the intratumoral fat in 7 and 8 cases, respectively. Two cases had intratumoral AML foci located at the periphery of RCC. Intratumoral fat or AML at the periphery of RCC simulated the invasion into the fat, while the smooth muscle component of AML resembled spindle cell, or sarcomatoid, differentiation. Our study highlights the potential pitfalls in staging and diagnosis when intratumoral fat or AML is found within RCC. PMID- 20959666 TI - Effect of delayed formalin fixation on estrogen and progesterone receptors in breast cancer: a study of three different clones. AB - We previously reported that delayed formalin fixation (DFF) has a negative effect on immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PR), and HER2. The primary aim of the study was to determine if DFF affected commonly used clones of the ER and PR differentially. The specific clones evaluated were ER clones 1D5, 6F11, and SP1 and PR clones 16, 1E2, and PgR636. Ten breast cancer cases were dissected and fixed at different times (0, 10, and 30 minutes; 1, 2, 4, and 8 hours; and overnight) and were then stained with anti ER and anti-PR antibodies. The mean Q score for ER started to decline at 2 to 4 hours for clones 1D5 and 6F11 and at 1 hour for SP1. SP1 was superior to 1D5 at the 8-hour mark (P = .03). The Q score for PR started to decline at 1 hour for clones PgR636 and 16 and 4 to 8 hours for 1E2 (P = .03). Based on our findings, it appears that regardless of the antibody clones evaluated, DFF has a negative effect on hormone receptors. PMID- 20959667 TI - Cytotechnology labor market: an update. AB - Based on historic data, we recently developed a model for the cytotechnology labor market that predicted shrinkage in the workforce secondary to a reduced demand for cytotechnologists that would offset any expected increase secondary to demographic changes in the number of women eligible for cervical cancer screening. In this report, we describe the comparison of our previous model with data that were available for the 2005-2009 period. As predicted, the cytotechnology workforce experienced significant shrinkage. The 2008 wage decreased when adjusted for inflation, demand shifted downward significantly, and supply shifted, in response, slightly downward. In 2009 supply (6,064 available staff) and demand (6,355 open and filled positions) were lower than those of the 2005 market. PMID- 20959668 TI - Overexpression of DNA methyltransferases 1, 3a, and 3b significantly correlates with retinoblastoma tumorigenesis. AB - DNA methyltransferases (DNMTs) 1, 3a, and 3b affect DNA promoter methylation; studies have suggested that they have important roles in the development of cancers. In this study, we analyzed the expression of DNMTs 1, 3a, and 3b; the MIB-1 labeling index; and their clinical significance in 6 normal retinas and 62 retinoblastomas using immunohistochemical analysis. We found that DNMT proteins were not expressed in normal retinas, whereas they were frequently expressed in retinoblastomas (DNMT1, 100%; DNMT3a, 98%; and DNMT3b, 92%). Compared with well differentiated retinoblastomas, the expression of DNMTs 1 and 3a significantly increased in poorly differentiated retinoblastomas (P = .002 and P = .003, respectively); in addition, the frequency of their increased expression was high. DNMT1 expression was significantly higher in invasive retinoblastoma. Furthermore, the expression of DNMTs was positively correlated with the MIB-1 labeling index in retinoblastoma. Our findings suggest that the overexpression of DNMTs 1, 3a, and 3b may be related to retinoblastoma tumorigenesis and progression and may represent a novel approach for retinoblastoma therapy. PMID- 20959669 TI - Nectin 4 overexpression in ovarian cancer tissues and serum: potential role as a serum biomarker. AB - Early detection of ovarian cancer is difficult owing to the lack of specific and sensitive tests available. Previously, we found expression of nectin 4 to be increased in ovarian cancer compared with normal ovaries. Reverse transcriptase polymerase chain reaction (RT-PCR) and quantitative RT-PCR validated the overexpression of nectin 4 messenger RNA in ovarian cancer compared with normal ovarian cell lines and tissues. Protein levels of nectin 4 were elevated in ovarian cancer cell lines and tissue compared with normal ovarian cell lines as demonstrated by Western immunoblotting, flow cytometry, and immunohistochemical staining of tissue microarray slides. Cleaved nectin 4 was detectable in a number of patient serum samples by enzyme-linked immunosorbent assay. In patients with benign gynecologic diseases with high serum CA125 levels, nectin 4 was not detected in the majority of cases, suggesting that nectin 4 may serve as a potential biomarker that helps discriminate benign gynecologic diseases from ovarian cancer in a panel with CA125. PMID- 20959671 TI - Laboratory medicine curriculum. PMID- 20959672 TI - More on occupational hazards for pathologists. PMID- 20959673 TI - Discard tubes are sometimes necessary when drawing samples for hemostasis. PMID- 20959674 TI - Immunohistochemical staining of inflammatory cells in liver biopsy specimens of patients with autoimmune hepatitis, primary biliary cirrhosis, and overlap syndromes. PMID- 20959675 TI - A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL receptor reduces LDL cholesterol in vivo. AB - Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) regulates LDL cholesterol levels by inhibiting LDL receptor (LDLr)-mediated cellular LDL uptake. We have identified a fragment antigen-binding (Fab) 1D05 which binds PCSK9 with nanomolar affinity. The fully human antibody 1D05-IgG2 completely blocks the inhibitory effects of wild-type PCSK9 and two gain-of-function human PCSK9 mutants, S127R and D374Y. The crystal structure of 1D05-Fab bound to PCSK9 reveals that 1D05-Fab binds to an epitope on the PCSK9 catalytic domain which includes the entire LDLr EGF(A) binding site. Notably, the 1D05-Fab CDR-H3 and CDR-H2 loops structurally mimic the EGF(A) domain of LDLr. In a transgenic mouse model (CETP/LDLr-hemi), in which plasma lipid and PCSK9 profiles are comparable to those of humans, 1D05-IgG2 reduces plasma LDL cholesterol to 40% and raises hepatic LDLr protein levels approximately fivefold. Similarly, in healthy rhesus monkeys, 1D05-IgG2 effectively reduced LDL cholesterol 20%-50% for over 2 weeks, despite its relatively short terminal half-life (t(1/2) = 3.2 days). Importantly, the decrease in circulating LDL cholesterol corresponds closely to the reduction in free PCSK9 levels. Together these results clearly demonstrate that the LDL lowering effect of the neutralizing anti-PCSK9 1D05-IgG2 antibody is mediated by reducing the amount of PCSK9 that can bind to the LDLr. PMID- 20959676 TI - [Future manpower in medicine]. PMID- 20959677 TI - [Centenary: University of Iceland, Faculty of Medicine]. PMID- 20959678 TI - [Education, working environment and future employment prospects of Icelandic surgeons]. AB - INTRODUCTION: Information about the education, training and future employment prospects of Icelandic surgeons has not been available. MATERIALS AND METHODS: The study included all Icelandic surgeons, in all subspecialties, educated at the Faculty of Medicine at the University of Iceland. Information on specialty training, higher academic degrees and in which country these were obtained was collected. Future employment prospects were analysed by calculating supply and demand until the year 2025. Approximations, such as sustained demand for surgeons per capita, were used. RESULTS: Out of 237 licensed surgeons, two thirds were living in Iceland and 36 were retired. Majority (69.2%) had been trained in Sweden and orthopaedic (26.9%) and general surgery (23.9%) were the most common subspecialties. The average age of surgeons in Iceland was 52 years and 44 years for surgeons abroad. Females were 8% of surgeons in Iceland while being 17.4% among 36 doctors in surgical training overseas. Over 19% had received a PhD degree. Predictions suggest that supply and demand for surgeons in Iceland will be equal in the year 2025, not taking into account the prospects for the working market outside Iceland. CONCLUSION: A third of Icelandic surgeons live outside Iceland. The proportion of female surgeons is low but it is increasing. Our predictions indicate a balanced work market for surgeons in Iceland for the next 15 years. However, there are many uncertainty factors in the calculations and they do not predict the prospects for individual subspecialties. PMID- 20959679 TI - [Inherited deficiency of the initiator molecules of the lectin-complement pathway]. AB - The complement system is an important immune system. Its activation results in membranolytic elimination of microbes and opsonization. The classical, alternative and lectin pathways (LP) activate complement. Either mannan-binding lectin (MBL), ficolin-1, ficolin-2 or ficolin-3 initiate the LP through associated serine protease (MASP-2) after binding to microorganisms'surface carbohydrate patterns. Genetic polymorphisms behind MBL deficiency are rather common. Numerous studies indicate that MBL deficiency is a risk factor for invasive and recurrent infections, especially when other immune systems are immature, deficient or compromised. Research in ficolins is limited but last year ficolin-3 deficiency was described. This review focuses on these recently WHO defined immunodeficiencies. PMID- 20959680 TI - [Case report: Seminal vesicle cyst with ipsilateral renal agenesis]. AB - We describe a case of right seminal vesicle cyst with ipsilateral renal agenesis in a 25 year old male. The cyst caused severe pain syndrome with progressive perineal pain and pain on defecation and ejaculation. The cyst was surgically removed and the patient became asymtomatic. PMID- 20959681 TI - [Case of the month. Unexpected ECG changes]. PMID- 20959682 TI - [Adulterated alcoholic beverages]. AB - Adulterated alcoholic beverages are legal alcoholic products that have been illicitly tampered with, for instance, by criminally diluting them with water, purposely putting them into new containers to conceal their true origin or adding toxic substances to manipulate the qualities of alcoholic beverages. The collection of cases at the Department of Pharmacology and Toxicology, University of Iceland, which contains examples of each category of adulteration, is the basis of the present article. Especially noteworthy are cases involving the toxic substances methanol and/or ethylene glycol. Methanol has been added to legally produced wines to increase their "bite" and ethylene glycol to increase their sweetness. Adding these substances to wine has resulted in poisoning or death in other countries, but not in Iceland as far as is known. PMID- 20959683 TI - Measuring flow-mediated dilation through transverse and longitudinal imaging: comparison and validation of methods. AB - Three-dimensional ultrasound images (3DUS), having two spatial and one temporal dimension, were taken of the brachial artery during baseline conditions, in the transverse and longitudinal planes. The transverse images were analyzed by three different techniques used to quantify flow-mediated dilation (FMD): (1) measuring vessel area manually (TIMA), (2) measuring vessel area semi-automatically (TISA) and (3) measuring vessel diameter (TID). The inter- and intra-observer variability and transducer repositioning variability of each method were compared to each other and to the variability of measurements taken using the traditional method of measuring vessel FMD through measuring vessel diameter on longitudinal images (LID). The percent coefficient-of-variation describing the inter-observer variability (COV(inter)) was similar for the methods, indicating that each method was equally reproducible by the different observers. The percent coefficient-of variation describing the intra-observer variability (COV(intra)) and the smallest detectable percent change in diameter (Deltad(intra)) for each method indicated that TID was the most precise at measuring vessel diameter, and could measure the smallest changes in diameter between successive measurements (COV(intra) = 0.31%, Deltad(intra) = 0.87%). LID performed the poorest (COV(intra) = 0.57%, Deltad(intra) = 1.59%). The percent coefficient-of-variation describing transducer repositioning (COV(rep)) and the smallest detectable percent change in FMD over time (DeltaFMD) for each method indicated that TIMA was the most reproducible method (COV(rep) = 2.35%, DeltaFMD = 6.52%) closely followed by TISA. TID performed the poorest (COV(rep) = 5.37%, DeltaFMD = 14.89%). TIMA and TISA were found not to be statistically different so we suggest TISA as the method of choice to maximize reproducibility between measurements over time, as it is faster and simpler to perform. In each experiment it was clear that transverse imaging introduced equal or less variability into diameter measurements as compared to longitudinal imaging and we suggest this imaging plane be used in all assessments of FMD. PMID- 20959684 TI - Applying gold nanoparticles as tumor-vascular disrupting agents during brachytherapy: estimation of endothelial dose enhancement. AB - Tumor vascular disrupting agents (VDAs) represent a promising approach to the treatment of cancer, in view of the tumor vasculature's pivotal role in tumor survival, growth and metastasis. VDAs targeting the tumor's dysmorphic endothelial cells can cause selective and rapid occlusion of the tumor vasculature, leading to tumor cell death from ischemia and extensive hemorrhagic necrosis. In this study, the potential for applying gold nanoparticles (AuNPs) as VDAs, during brachytherapy, is examined. Analytic calculations based on the electron energy loss formula of Cole were carried out to estimate the endothelial dose enhancement caused by radiation-induced photo/Auger electrons originating from AuNPs targeting the tumor endothelium. The endothelial dose enhancement factor (EDEF), representing the ratio of the dose to the endothelium with and without gold nanoparticles was calculated for different AuNP local concentrations, and endothelial cell thicknesses. Four brachytherapy sources were investigated, I-125, Pd-103, Yb-169, as well as 50 kVp x-rays. The results reveal that, even at relatively low intra-vascular AuNP concentrations, ablative dose enhancement to tumor endothelial cells due to photo/Auger electrons from the AuNPs can be achieved. Pd-103 registered the highest EDEF values of 7.4-271.5 for local AuNP concentrations ranging from 7 to 350 mg g-1, respectively. Over the same concentration range, I-125, 50 kVp and Yb-169 yielded values of 6.4-219.9, 6.3-214.5 and 4.0-99.7, respectively. Calculations of the EDEF as a function of endothelial cell thickness showed that lower energy sources like Pd-103 reach the maximum EDEF at smaller thicknesses. The results also reveal that the highest contribution to the EDEF comes from Auger electrons, apparently due to their shorter range. Overall, the data suggest that ablative dose enhancement to tumor endothelial cells can be achieved by applying tumor vasculature-targeted AuNPs as adjuvants to brachytherapy, with lower energy sources. Such ablative magnitude dose enhancement in a relatively small endothelial volume may rapidly disrupt or cause severe biological damage to tumor endothelial cells, without increased toxicity to healthy tissues not containing AuNPs. The findings provide significant impetus for considering the application of AuNPs as VDAs during brachytherapy. PMID- 20959685 TI - Human erythrocytes as nanoparticle carriers for magnetic particle imaging. AB - The potential of red blood cells (RBCs) loaded with iron oxide nanoparticles as a tracer material for magnetic particle imaging (MPI) has been investigated. MPI is an emerging, quantitative medical imaging modality which holds promise in terms of sensitivity in combination with spatial and temporal resolution. Steady-state and dynamic magnetization measurements, supported by semi-empirical modeling, were employed to analyze the MPI signal generation using RBCs as novel biomimetic constructs. Since the superparamagnetic iron oxide (SPIO) bulk material that is used in this study contains nanoparticles with different sizes, it is suggested that during the RBC loading procedure, a preferential entrapment of nanoparticles with hydrodynamic diameter <=60 nm occurs by size-selection through the erythrocyte membrane pores. This affects the MPI signal of an erythrocyte-based tracer, compared to bulk. The reduced signal is counterbalanced by a higher in vivo stability of the SPIO-loaded RBCs constructs for MPI applications. PMID- 20959686 TI - Nonlinear least-squares modeling of 3D interaction position in a monolithic scintillator block. AB - This paper presents a study of possible models to describe the relation between the scintillation light point-of-origin and the measured photo detector pixel signals in monolithic scintillation crystals. From these models the X, Y and depth of interaction (DOI) coordinates can be estimated simultaneously by nonlinear least-square fitting. The method depends only on the information embedded in the signals of individual events, and therefore does not need any prior position training or calibration. Three possible distributions of the light sources were evaluated: an exact solid-angle-based distribution, an approximate solid-angle distribution and an extended approximate solid-angle-based distribution which includes internal reflection at side and bottom surfaces. The performance of the general model using these three distributions was studied using Monte Carlo simulated data of a 20 x 20 x 10 mm lutetium oxyorthosilicate (Lu2SiO5 or LSO) block read out by 2 Hamamatsu S8550 avalanche photo diode arrays. The approximate solid-angle-based model had the best compromise between resolution and simplicity. This model was also evaluated using experimental data by positioning a narrow 1.2 mm full width at half maximum (FWHM) beam of 511 keV photons at known positions on the 20 x 20 x 10 mm LSO block. An average intrinsic resolution in the X-direction of 1.4 mm FWHM was obtained for positions covering the complete block. The intrinsic DOI resolution was estimated at 2.6 mm FWHM. PMID- 20959687 TI - Biomechanical-based image registration for head and neck radiation treatment. AB - Deformable image registration of four head and neck cancer patients has been conducted using a biomechanical-based model. Patient-specific 3D finite element models have been developed using CT and cone-beam CT image data of the planning and a radiation treatment session. The model consists of seven vertebrae (C1 to C7), mandible, larynx, left and right parotid glands, tumor and body. Different combinations of boundary conditions are applied in the model in order to find the configuration with a minimum registration error. Each vertebra in the planning session is individually aligned with its correspondence in the treatment session. Rigid alignment is used for each individual vertebra and the mandible since no deformation is expected in the bones. In addition, the effect of morphological differences in the external body between the two image sessions is investigated. The accuracy of the registration is evaluated using the tumor and both parotid glands by comparing the calculated Dice similarity index of these structures following deformation in relation to their true surface defined in the image of the second session. The registration is improved when the vertebrae and mandible are aligned in the two sessions with the highest average Dice index of 0.86 +/- 0.08, 0.84 +/- 0.11 and 0.89 +/- 0.04 for the tumor, left and right parotid glands, respectively. The accuracy of the center of mass location of tumor and parotid glands is also improved by deformable image registration where the errors in the tumor and parotid glands decrease from 4.0 +/- 1.1, 3.4 +/- 1.5 and 3.8 +/ 0.9 mm using rigid registration to 2.3 +/- 1.0, 2.5 +/- 0.8 and 2.0 +/- 0.9 mm in the deformable image registration when alignment of vertebrae and mandible is conducted in addition to the surface projection of the body. PMID- 20959688 TI - Comparison of anatomy-based, fluence-based and aperture-based treatment planning approaches for VMAT. AB - Volumetric modulated arc therapy (VMAT) has the potential to reduce treatment times while producing comparable or improved dose distributions relative to fixed field intensity-modulated radiation therapy. In order to take full advantage of the VMAT delivery technique, one must select a robust inverse planning tool. The purpose of this study was to evaluate the effectiveness and efficiency of VMAT planning techniques of three categories: anatomy-based, fluence-based and aperture-based inverse planning. We have compared these techniques in terms of the plan quality, planning efficiency and delivery efficiency. Fourteen patients were selected for this study including six head-and-neck (HN) cases, and two cases each of prostate, pancreas, lung and partial brain. For each case, three VMAT plans were created. The first VMAT plan was generated based on the anatomical geometry. In the Elekta ERGO++ treatment planning system (TPS), segments were generated based on the beam's eye view (BEV) of the target and the organs at risk. The segment shapes were then exported to Pinnacle TPS followed by segment weight optimization and final dose calculation. The second VMAT plan was generated by converting optimized fluence maps (calculated by the Pinnacle TPS) into deliverable arcs using an in-house arc sequencer. The third VMAT plan was generated using the Pinnacle SmartArc IMRT module which is an aperture-based optimization method. All VMAT plans were delivered using an Elekta Synergy linear accelerator and the plan comparisons were made in terms of plan quality and delivery efficiency. The results show that for cases of little or modest complexity such as prostate, pancreas, lung and brain, the anatomy-based approach provides similar target coverage and critical structure sparing, but less conformal dose distributions as compared to the other two approaches. For more complex HN cases, the anatomy-based approach is not able to provide clinically acceptable VMAT plans while highly conformal dose distributions were obtained using both aperture-based and fluence-based inverse planning techniques. The aperture-based approach provides improved dose conformity than the fluence-based technique in complex cases. PMID- 20959689 TI - Segmentation of mouse dynamic PET images using a multiphase level set method. AB - Image segmentation plays an important role in medical diagnosis. Here we propose an image segmentation method for four-dimensional mouse dynamic PET images. We consider that voxels inside each organ have similar time activity curves. The use of tracer dynamic information allows us to separate regions that have similar integrated activities in a static image but with different temporal responses. We develop a multiphase level set method that utilizes both the spatial and temporal information in a dynamic PET data set. Different weighting factors are assigned to each image frame based on the noise level and activity difference among organs of interest. We used a weighted absolute difference function in the data matching term to increase the robustness of the estimate and to avoid over-partition of regions with high contrast. We validated the proposed method using computer simulated dynamic PET data, as well as real mouse data from a microPET scanner, and compared the results with those of a dynamic clustering method. The results show that the proposed method results in smoother segments with the less number of misclassified voxels. PMID- 20959691 TI - Cardiometabolic health in the United States: what's the story? And how can you, the sports medicine practitioner, help rewrite the story? PMID- 20959692 TI - Boxing-related head injuries. AB - Fatalities in boxing are most often due to traumatic brain injury that occurs in the ring. In the past 30 years, significant improvements in ringside and medical equipment, safety, and regulations have resulted in a dramatic reduction in the fatality rate. Nonetheless, the rate of boxing-related head injuries, particularly concussions, remains unknown, due in large part to its variability in clinical presentation. Furthermore, the significance of repeat concussions sustained when boxing is just now being understood. In this article, we identify the clinical manifestations, pathophysiology, and management of boxing-related head injuries, and discuss preventive strategies to reduce head injuries sustained by boxers. PMID- 20959693 TI - Brain functions after sports-related concussion: insights from event-related potentials and functional MRI. AB - The high incidence of concussions in contact sports and their impact on brain functions are a major cause for concern. To improve our understanding of brain functioning after sports-related concussion, advanced functional assessment techniques, namely event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI), have been recently used in research studies. Contrary to neuropsychological tests that measure verbal and/or motor responses, ERPs and fMRI assess the neural activities associated with cognitive/behavioral demands, and thus provide access to better comprehension of brain functioning. In fact, ERPs have excellent temporal resolution, and fMRI identifies the involved structures during a task. This article describes ERP and fMRI techniques and reviews the results obtained with these tools in sports-related concussion. Although these techniques are not yet readily available, they offer a unique clinical approach, particularly for complex cases (ie, athletes with multiple concussions, chronic symptoms) and objective measures that provide valuable information to guide management and return-to-play decision making. PMID- 20959694 TI - Cryotherapy to treat persistent muscle weakness after joint injury. AB - Cryotherapy is a widely used modality following acute joint injury. It is considered helpful in reducing pain and swelling, and there is a growing body of evidence to suggest that it may have additional benefits in muscle function. Following joint injury, it is common for patients to experience persistent muscle weakness that is resistant to traditional strengthening exercises. This may be due to a reflex inhibition of musculature surrounding the injured joint. The underlying cause of this reflex inhibition may arise from aberrant sensory information from the joints' neural receptors, which result in a neural inhibition of motor neurons. This inhibition is beyond conscious control, is ongoing, and impedes normal joint function via a disruption of normal muscle function. Cryotherapy treatments targeted at peripheral joints have been shown to result in transient resolution of reflex inhibition, which thereby provide an environment where injured patients can benefit from a more thorough motorneuron pool during controlled rehabilitation exercises. This article presents current evidence-based recommendations regarding the use of joint cryotherapy for maximizing the effectiveness of commonly used rehabilitation exercises in patients recovering from joint injury. PMID- 20959695 TI - Stress fractures: classification and management. AB - Stress fractures occur as a result of microdamage secondary to repetitive strains. A mechanism for the development of stress fractures involves the accumulation of microdamage, which occurs with multiple subultimate failure loads applied to the bone. Stress fractures may be classified as high or low risk, depending on the grade of the injury. The most common site of injury is the lower extremity. In this article, we review the pathophysiology, etiology, diagnosis, and management of stress fractures, and present treatment guidelines for return to play. PMID- 20959696 TI - Management of shoulder instability in in-season athletes. AB - Although shoulder instability is common in young athletes, there are limited prospective data to guide treatment for competitive athletes who sustain a dislocation mid-season. The management of athletes during their competitive season requires an understanding of the natural history of shoulder instability, the specific needs of the injured athlete (eg, specific sport, player position), and the duration of treatment. Rehabilitation can enable an athlete with a shoulder dislocation to return to play within 3 weeks of injury. Bracing is an option, but it can result in restricted glenohumeral motion and thereby possibly affect performance. Surgical stabilization should be considered for the athlete with recurrent instability or inability to perform; however, this frequently results in the termination of the player's season. In this article, we review the available literature to help guide physicians treating athletes with shoulder instability. PMID- 20959697 TI - Current concepts in ACL Injuries. AB - Anterior cruciate ligament (ACL) injuries are common in athletic and physically active populations, and can result in significant functional disability. Female athletes in particular have been found to be at a relatively high risk for noncontact ACL injuries. Many risk factors, both intrinsic and extrinsic, have been identified. Although some individuals may be treated nonoperatively with an aggressive rehabilitation program, athletes desiring to return to physical activities that require use of the ACL need surgical reconstruction. Surgical techniques remain controversial in regard to tunnel placement and optimal graft choices. Recent literature advocates a more oblique ACL reconstruction to more closely recreate normal knee kinematics and eliminate pathologic rotational laxity. A supervised and intensive rehabilitation program is necessary to achieve desired results. Anatomic and neuromuscular risk factors, often gender related, are the focus of most ACL injury prevention programs. PMID- 20959698 TI - Return to sports activity after postoperative septic arthritis in ACL reconstruction. AB - BACKGROUND: Septic arthritis after arthroscopic anterior cruciate ligament (ACL) reconstruction is a rare but potentially serious complication. Several different options have been proposed to treat this condition. Our study aims to report the clinical, radiological, and sports activity results using our original protocol based on outpatient irrigation of the knee as well as parenteral and oral antibiotics. METHODS: From January 2001 to January 2009, 14 patients (all active in sports) were treated for postoperative septic arthritis of the knee after ACL reconstruction in our institute. The treatment protocol included outpatient irrigation of the knee and parenteral antibiotics, followed by oral antibiotics. Repetitive irrigation was performed if necessary. The average follow-up period for our series was 38 months (range, 8-54 months). Follow-up included International Knee Documentation Committee (IKDC) forms, radiographs, Tegner and Lysholm scores, and KT-1000TM arthrometric evaluation. RESULTS: Treatment of infection was successful in all cases. At final examination, pivot shift score was negative in 12 of 14 patients, and was > 1 in 2 of 14 patients, whereas the Lachman item score was negative in all cases. The mean postoperative Tegner score was 7, and 12 of 14 patients returned to the same sport at the same level after surgery. The mean Lysholm score was 96. Using the IKDC score, 12 of 14 patients were graded as group A, and 2 of 14 patients were graded as group B. The mean postoperative manual maximum KT-1000TM side-to-side difference was 2.5 mm. No significant bone tunnel enlargement was found when evaluating the patients' radiographs. CONCLUSION: The treatment regimen previously described provides reliable results for this complication. There were no recurrences of septic arthritis or bone infection, and no further surgeries were required. The graft could be retained during treatment of septic arthritis. Almost all patients returned to the preoperative and preinfection sport at the same level. PMID- 20959699 TI - Review of cardiometabolic risk factors among current professional football and professional baseball players. AB - Data on the development of cardiovascular disease in professional football players are conflicting. Studies have documented a higher prevalence of obesity, lower high-density lipoprotein cholesterol levels, increased left ventricular and left atrial size, and higher prevalence of metabolic syndrome in former professional football linemen compared with nonlinemen. It has been suggested that former National Football League players are at risk for early cardiovascular disease and premature death. A print media report in 2006 indicated an increased prevalence of cardiovascular disease and early mortality in professional football players compared with professional baseball players. However, there has been little scientific evaluation of cardiovascular risk factors in professional baseball players. Our data suggest that there is increased cardiovascular disease risk in football players, but this is limited to heavier linemen. In preliminary studies, baseball players do not appear to demonstrate the same increased risk. However, caution should be used in the interpretation of increased cardiovascular disease risk, as it does not necessarily translate into early increased mortality. PMID- 20959700 TI - Alcohol consumption and risk of heart failure: a meta-analysis. AB - BACKGROUND: Heart failure is highly prevalent among older adults and is associated with high treatment costs. Identifying modifiable determinants of heart failure may help in prevention. Alcohol consumption has emerged as a modifiable risk factor for cardiovascular diseases. Although many studies have suggested a positive association between heavy drinking and cardiomyopathy, the association between infrequent or light-to-moderate drinking and heart failure risk has been less conclusive. PURPOSE: To examine the relation between various levels of alcohol intake and incident heart failure. METHODS: We conducted a meta analysis of 6 studies obtained through a PubMed literature search. Alcohol drinkers were classified as never, former, and current drinkers of 0.1 to 0.9, 1 to 7, 8 to 14, and > 14 drinks per week. RESULTS: Compared with never drinkers, the pooled relative risks were 1.16 (95% confidence interval [CI], 0.90-1.51) for former drinkers, 0.90 (95% CI, 0.83-0.98), 0.80 (95% CI, 0.73-0.88), 0.78 (95% CI, 0.65-0.95), and 0.77 (95% CI, 0.63-0.95) for current drinkers of 0.1 to 0.9, 1 to 7, 8 to 14, and > 14 drinks per week, respectively, in a random effects model. CONCLUSION: These data suggest that infrequent and light-to-moderate drinking is associated with a lower risk of heart failure. PMID- 20959701 TI - The inter-rater reliability and diagnostic accuracy of patellar mobility tests in patients with anterior knee pain. AB - BACKGROUND: Patients with patellofemoral pain syndrome (PFPS) often have nonspecific findings on clinical examination. A tight knee and diminished patellar mobility in particular, may contribute to anterior knee pain. METHODS: Qualifying patients with anterior knee pain of > 4 weeks were sequentially examined by 2 physicians who used the patellar mobility tests. The tests evaluated for diminished patellar translation superior-inferiorly and medial laterally, diminished patellar tendon mobility, and absent inferior pole tilt. Each of the 4 tests was scored as 1 (diminished/absent) or 0 (nondiminished/normal), with the sum of the scores determining the patellar mobility scale. Inter-rater reliability and diagnostic accuracy were determined and analyzed. Receiver operating characteristic analysis was used to determine the capacity of the patellar mobility scale to predict PFPS. RESULTS: 98 patients participated in the study. The inter-rater reliability for the 4 individual patellar mobility tests was moderately strong, with diminished medial-lateral patellar mobility demonstrating the strongest reliability (Kappa value [K], 0.59; 95% confidence interval [CI], 0.42-0.72), followed by diminished superior inferior mobility (K), 0.55; 95% CI, -0.37 to 0.69), inferior pole tilt (K, 0.48; 95% CI, -0.28 to 0.61), and patellar tendon mobility (K, 0.45; 95% CI, -0.27 to 0.56). The diagnostic accuracy of the individual patellar mobility tests in diagnosing PFPS was fair to moderate, with the individual diminished patella tendon mobility test having the highest level of diagnostic accuracy (sensitivity, 49%; specificity, 83%; likelihood ratio [LR] +/- 2.8; 95% CI, 1.3 7.3) and also having the highest positive predictive value (0.88). Diminished medial-lateral mobility was second in diagnostic accuracy (sensitivity, 54%; specificity, 69%; LR +/- 1.8; 95% CI, 0.9-3.6). Receiver operating characteristic analysis showed only moderate levels of diagnostic capacity (area under the curve, 0.65) because combining all 4 patellar mobility tests to form the patellar mobility scale did not improve the diagnostic accuracy. CONCLUSION: The clinical importance of diminished patellar and/or patellar tendon mobility findings in the evaluation of patients with anterior knee pain remains unclear. We determined that individual patellar mobility tests had moderate levels of inter-rater reliability, the best agreement found with medial-lateral mobility. The accuracy of the patellar mobility scale for diagnosing PFPS was marginal. As a tool, this cluster of examination techniques may be used by physicians to better understand their patients' conditions and descriptively communicate their findings. However, the patellar mobility scale cannot be used alone for determining the diagnosis of PFPS, as defined in our study. Future studies aim to determine whether post treatment symptomatic improvements correlate with an improvement on the patellar mobility scale. PMID- 20959702 TI - Anabolic processes in human skeletal muscle: restoring the identities of growth hormone and testosterone. AB - Testosterone supplementation acts via numerous mechanisms as a highly potent anabolic agent to skeletal muscle. Although growth hormone (GH) strongly affects collagen synthesis and lipolysis, as well as increasing lean body mass, it is not anabolic toward the contractile (ie, myofibrillar) muscle tissue in healthy individuals. However, there is a persistent belief (both in scientific literature and among recreational weightlifters) that exercise-induced release of GH and testosterone underpins muscular hypertrophy with resistance training. This is a premature assumption because although pharmacological GH supplementation can increase muscle strength or size in individuals with clinical GH deficiency, there is no evidence that transient exercise-induced changes in GH have the same effects in individuals with normal GH levels. Exercise paradigms are designed based on the assumption (not necessarily evidenced-based mechanisms) that GH and testosterone facilitate anabolic processes that lead to skeletal muscle protein accretion and hypertrophy. Our recent work disputes this assumption. Instead, our data indicate that exercise-induced hormonal elevations do not enhance intracellular markers of anabolic signaling or the acute postexercise elevation of myofibrillar protein synthesis. Furthermore, data from our training study demonstrate that exercise-induced increases in GH and testosterone availability are not necessary for and do not enhance strength and hypertrophy adaptations. Instead, our data lead us to conclude that local mechanisms that are intrinsic to the skeletal muscle tissue performing the resistive contractions (ie, weightlifting) are predominant in stimulating anabolism. The purpose of this article is 1) to provide a brief overview of the mechanisms of action of testosterone and GH; 2) to discuss the inability of physiological exercise induced elevations in these hormones to have a measurable impact on skeletal muscle anabolism; and 3) to describe factors that we believe are more important for stimulating hypertrophy in human skeletal muscle. Clarifying both the role of hormones in regulating muscle mass as well as the underlying basis for adaptation of skeletal muscle to resistance exercise will hopefully enhance and support the prescription of resistance exercise as an integral component of a healthy lifestyle. PMID- 20959703 TI - Anabolic steroid use in adolescents: identification of those at risk and strategies for prevention. AB - Success in sports is often defined by winning, which drives athletes to use performance-enhancing drugs (PEDs) to gain an advantage over opponents. Over the past 20 years, use of PEDs by Olympic and professional athletes has led to public discussion regarding potential negative health effects and ethical implications of their use. Unfortunately, PEDs are not isolated to professional athletes, as PED use in adolescents has increased dramatically. Many professional organizations, including the American Academy of Orthopaedic Surgeons (AAOS), have taken a stance against PED use in sports. The AAOS believes neither anabolic steroids nor their precursors should be used to enhance performance or appearance, and that these substances should be banned in all sports programs. Pediatricians and orthopedists are often the first physicians to see these young athletes. It is critical for these physicians to recognize the significance of the problem, have the knowledge to inform adolescents, dissuade them from future use, and provide viable alternatives for meeting performance goals. PMID- 20959704 TI - Male athletic activities and their effects on semen and hormonal parameters. AB - Infertility is generally defined as the inability to conceive a pregnancy or the failure to do so within a reasonable period (typically 12 months). Approximately 85% of couples conceive a first pregnancy within 12 months. The prevalence of infertility has increased over the past 10 years, with approximately 10 million affected couples in the United States. Roughly 40% to 50% of infertility is either due to, or is contributed by, a male factor. Given how common the condition is, men and their partners are understandably concerned and interested in identifying and eliminating risk factors for male infertility. This article reviews the available literature on various aspects of male infertility related to athletic pursuits. These include the effects of exercise on semen parameters, hormonal axes, and testicular health. Due to the prevalence and particular relevance of anabolic steroid use by athletes and the impact of steroid use on fertility, this topic is also reviewed. PMID- 20959705 TI - Evidence on ergogenic action of glucocorticoids as a doping agent risk. AB - Systemic administration of glucocorticoids (GCs) is banned by the World Anti Doping Agency (WADA) during competition. Few studies have examined the effects of GCs on exercise performance, but increasing evidence has shown that short-term GC intake enhances performance in animals and humans. However, there are many health risks associated with GC use. Based on the available evidence, as presented in this article, I conclude that GCs are doping agents and should remain on the WADA's list of banned products. Because of the complexity of GCs, however, determining the boundaries between their medical use and abuse (eg, in sports) is a constant challenge for the WADA. PMID- 20959707 TI - Body weight at birth and at age three and respiratory illness in preschool children. AB - OBJECTIVES: The purpose of this study was to examine the associations of current body weight and body mass index (BMI) at age three and birth weight in developing chronic respiratory illness in childhood and identify possible interaction underlying its mechanism. METHODS: The study was carried out with 422 children who were enrolled in a hospital-based birth cohort. Birth related anthropometric data were collected at birth. At age 3 years, the presence of respiratory symptoms was evaluated by using the Korean version of core questionnaire for wheezing and asthma from the International Study of Asthma and Allergies in Childhood (ISAAC). Physical examination was carried out to measure the child's weight and height. RESULTS: Children in the lowest birth weight tertile (aOR = 3.97, 95% CI = 0.94-16.68) or highest BMI tertile (aOR = 3.68, 95% CI = 1.24 10.95) at three years of age were at an increased risk of chronic respiratory illness. Children who were initially in the lowest birth weight tertile but now belong in the highest weight tertile had higher risk of chronic respiratory illness compared to those who had remained in the middle tertile (OR=16.35, 95% CI=1.66-160.57). CONCLUSIONS: Children with lower birth weight or higher BMI were at an increased risk of chronic respiratory illness. In addition, children who were initially in the lowest birth weight tertile but are now in the highest weight tertile had higher risk of chronic respiratory illness compared to those who remained in the middle tertile. PMID- 20959708 TI - Blood mercury concentration and related factors in an urban coastal area in Korea. AB - OBJECTIVES: This study was carried out for the purpose of evaluating the blood mercury concentration of the residents of Busan, Korea, as well as the relationship between the mercury concentration and the pattern of fish consumption along with other epidemiological factors. METHODS: Two hundred ninety three subjects (147 men and 146 women), who were aged 40 years or more, were recruited into this study between June and October 2009. The mean age of the subjects was 54.3 years (with a range of 40-70 years). Mercury concentrations in blood samples were measured using a gold-amalgam collection method. RESULTS: The geometric mean concentration of mercury in the total subjects was 8.63 ug/L [range: 1.48~45.71 ug/L]. The blood mercury concentration of the men (9.55 ug/L) was significantly higher than that of the women (7.76 ug/L). The blood mercury concentration of those who eat fish more than 4 times per week was higher than others, and was statistically significant (male p = 0.0019, female p = 0.0002). According to the multiple analysis, the blood mercury concentration was significantly affected by the consumed fish but other epidemiological factors were not related. CONCLUSIONS: It was found that the subjects who have consumed a large amount of fish may have high blood mercury concentration. It appears that fish consumption can influence blood mercury concentration. Therefore, guidelines for fish consumption that will decrease blood mercury concentration might be necessary in Korea. PMID- 20959709 TI - Physical and mental health of disaster victims: a comparative study on typhoon and oil spill disasters. AB - OBJECTIVES: The purpose of this study was to compare the physical and mental health status of disaster victims according to disaster types, such as a typhoon disaster and an oil spill disaster, and to suggest adequate health care services for them. METHODS: A total of 484 people who suffered disasters were selected for this study, and data were collected from July to August, 2008. The data-set for this study included 286 victims of typhoon disasters in Jeju and Jeollanamdo district in South Korea, and 198 victims of the oil spill disaster in Taean. Physical health status was measured using revised Patient Health Questionnaire and mental health status was measured using the Korean version of 'Post-traumatic Diagnostic Scale'. RESULTS: According to the comparative analyses of typhoon disaster victims and oil spill disaster victims, poorer physical health outcomes were shown among the oil spill disaster victims when compared to the typhoon disaster victims. Also, the oil spill disaster victims showed symptoms of depression, anxiety, and post-traumatic stress disorder, at rates higher than those found among the typhoon disaster victims. CONCLUSIONS: These findings suggest that there is a need to provide adequate physical and mental health related care services for oil spill disaster victims. The seriousness of oil spill disaster should be realized and reconsidered in developing recovery strategies and disaster preparedness for physical and mental health services. PMID- 20959710 TI - Validity of self-reported height, weight, and body mass index of the Korea Youth Risk Behavior Web-based Survey questionnaire. AB - OBJECTIVES: Self-reported anthropometric values, such as height and weight, are used to calculate body mass index (BMI) and assess the prevalence of obesity among adolescents. The aim of this study was to evaluate the validity of self reported height, weight, and BMI of the Korea Youth Risk Behavior Web-based Survey questionnaire. METHODS: A convenience sample of 137 middle school students and 242 high school students completed a self-administered questionnaire in 2008. Body height and weight were directly measured after self-reported values were obtained from the questionnaire survey. Sensitivity, specificity, and kappa statistics were computed in order to evaluate the validity of the prevalence of obesity (BMI >= 95th percentile or >= 25 kg/m(2)) based on self-reported data. RESULTS: Self-reported weight and BMI tended to be underestimated. Self-reported height tended to be overestimated among middle school females and high school males. Obese adolescents tended to underestimate their weight and BMI and overestimate their height more than non-obese adolescents. The prevalence estimate of obesity based on self-reported data (10.6%) was lower than that based on directly measured data (15.3%). The estimated sensitivity of obesity based on self-reported data was 69.0% and the specificity was 100.0%. The value of kappa was 0.79 (95% confidence interval, 0.70-0.88). CONCLUSIONS: This study demonstrated that self-reported height and weight may lead to the underestimation of BMI and consequently the prevalence of obesity. These biases should be taken into account when self-reported data are used for monitoring the prevalence and trends of obesity among adolescents nationwide. PMID- 20959711 TI - Test-retest reliability of a questionnaire for the Korea Youth Risk Behavior Web based Survey. AB - OBJECTIVES: A web-based survey has been administered annually since 2005 throughout Korea to assess the prevalence of adolescent health risk behaviors among middle and high school students. The aim of this study was to evaluate the test-retest reliability of the Korea Youth Risk Behavior Web-based Survey (KYRBWS) questionnaire. METHODS: A convenience sample of 2298 middle and high school students participated in self-administered questionnaire surveys twice, approximately two weeks apart, in 2008. The percent agreement, kappa statistics, and prevalence rates at the first and second surveys were computed for the core subset of 39 self-reported health risk behavior indices of the KYRBWS. RESULTS: Among 39 indices, seven indices had kappas >= 0.81 and all of the indices had kappas >= 0.41. Based on non-overlapping 95% confidence intervals, three indices had significantly different prevalence rates between the first and second surveys. In the subgroup analyses by school grade and gender, two indices had significantly different reliability estimates between middle and high school students. There were no significantly different reliability estimates between male and female students, except for one index. CONCLUSIONS: This study demonstrated that the reliability estimates for the KYRBWS questionnaire are varied, but generally reliable over time. The indices with low reliability estimates need to be evaluated further in order to determine whether the indices should be modified or deleted from future versions of the KYRBWS. PMID- 20959712 TI - [A study of factors related to Korean physicians' trust in the government: on the target for board members of physicians' associations]. AB - OBJECTIVES: This study aims to investigate the factors related to Korean physicians' trust in the government. METHODS: We used structured questionnaires that were composed of multidimensional scales for each of the various categories. RESULTS: The recognition levels of trust of the government by Korean physicians were not high, and they ranged from 3.6 to 4.8 for ten scales. The factors related to trust in the government were categorized into seven factors on the basis of a factor analysis. On the regression analysis, a positive relationship was found between "the individual propensity to trust" and trust in the government, while a negative relationship was found between "the recognition level regarding the government as an authoritarian power" and trust in the government. "Confidence about participation in the policy process" as internal efficacy and "belief in governmental ability and motivation toward public demand" as external efficacy also showed a strong positive relationship with trust in the government. CONCLUSIONS: From these results, we can draw the conclusion that making efforts to improve the recognition level of trust in the government among physicians is an important policy task. To increase the trust level, participation of physicians in the policy process in various ways and open communication between the physicians'associations and the government should be facilitated. PMID- 20959713 TI - [The effect of catastrophic health expenditure on the transition to poverty and the persistence of poverty in South Korea]. AB - OBJECTIVES: The low benefit coverage rate of South Korea's health security system has been continually pointed out. A low benefit coverage rate inevitably causes catastrophic health expenditure, which can be the cause of the transition to poverty and the persistence of poverty. This study was conducted to ascertain the effect of catastrophic health expenditure on the transition to poverty and the persistence of poverty in South Korea. METHODS: To determine the degree of social mobility, this study was conducted among the 6311 households that participated in the South Korea Welfare Panel Study in both 2006 and 2008. The effect of catastrophic health expenditure on the transition to poverty and the persistence of poverty in South Korea was assessed via multiple logistic regression analysis. RESULTS: The poverty rate in South Korea was 21.6% in 2006 and 20.0% in 2008. 25.1 - 7.3% of the households are facing catastrophic health expenditure. Catastrophic health expenditure was found to affect the transition to poverty even after adjusting for the characteristics of the household and the head of the household, at the threshold of 28% or above. CONCLUSIONS: 25.1% of the households in this study were found to be currently facing catastrophic health expenditure, and it was determined that catastrophic health expenditure is a cause of transition to poverty. This result shows that South Korea's health security system is not an effective social safety net. As such, to prevent catastrophic health expenditure and transition to poverty, the benefit coverage of South Korea's health security system needs to the strengthened. PMID- 20959714 TI - [Correlations between climate change-related infectious diseases and meteorological factors in Korea]. AB - OBJECTIVES: Infectious diseases are known to be affected by climate change. We investigated if the infectious diseases were related to meteorological factors in Korea. METHODS: Scrub typhus, hemorrhagic fever with renal syndrome (HFRS), leptospirosis, malaria and Vibrio vulnificus sepsis among the National Notifiable Infectious Diseases were selected as the climate change-related infectious diseases. Temperature, relative humidity and precipitation were used as meteorological factors. The study period was from 2001 through 2008. We examined the seasonality of the diseases and those correlations with meteorological factors. We also analyzed the correlations between the incidences of the diseases during the outbreak periods and monthly meteorological factors in the hyper endemic regions. RESULTS: All of the investigated diseases showed strong seasonality; malaria and V. vulnificus sepsis were prevalent in summer and scrub typhus, HFRS and leptospirosis were prevalent in the autumn. There were significant correlations between the monthly numbers of cases and all the meteorological factors for malaria and V. vulnificus sepsis, but there were no correlation for the other diseases. However, the incidence of scrub typhus in hyper-endemic region during the outbreak period was positively correlated with temperature and humidity during the summer. The incidences of HFRS and leptospirosis had positive correlations with precipitation in November and temperature and humidity in February, respectively. V. vulnificus sepsis showed positive correlations with precipitation in April/May/July. CONCLUSIONS: In Korea, the incidences of the infectious diseases were correlated with meteorological factors, and this implies that the incidences could be influenced by climate change. PMID- 20959715 TI - [Mind-body approach in the area of preventive medicine: focusing on relaxation and meditation for stress management]. AB - OBJECTIVES: Emotional support and a stress management program should be simultaneously provided to clients as effective preventive services for healthy behavioral change. This study was conducted to review various relaxation and meditation intervention methods and their applicability for a preventive service program. METHODS AND RESULTS: The author of this paper tried to find various relaxation and meditation programs through a literature review and program searching and to introduce them. The 'Relaxation Response' and 'Mindfulness Based Stress Reduction (MBSR)' are the most the widely used meditative programs in mainstream medical systems. Abdominal breathing, Progressive Musclular Relaxation (PMR), Relaxative Imagery, Autogenic Training (AT) and Biofeedback are other well known techniques for relaxation and stress management. I have developed and implemented some programs using these methods. Relaxation and meditation classes for cancer patients and a meditation based stress coping workshop are examples of this program. CONCLUSIONS: Relaxation and meditation seem to be good and effective methods for primary, secondary and tertiary preventive service programs. Program development and standardization and further study are needed for more and wider use of the mind-body approach in the preventive service area of medicine. PMID- 20959716 TI - [A comparison of fasting glucose and HbA1c for the diagnosis of diabetes mellitus among Korean adults]. AB - OBJECTIVES: The American Diabetes Association (ADA) has recently recommended the HbA1c assay as one of four options for making the diagnosis of diabetes mellitus, with a cut-point of >= 6.5%. We compared the HbA1c assay and the fasting plasma glucose level for making the diagnosis of diabetes among Korean adults. METHODS: We analyzed 8710 adults (age 45-74 years), who were not diagnosed as having diabetes mellitus, from the Namwon study population. A fasting plasma glucose level of >= 126 mg/dL and an A1c of >= 6.5% were used for the diagnosis of diabetes. The kappa index of agreement was calculated to measure the agreement between the diagnosis based on the fasting plasma glucose level and the HbA1c. RESULTS: The kappa index of agreement between the fasting plasma glucose level and HbA1c was 0.50. CONCLUSIONS: The agreement between the fasting plasma glucose and HbA1c for the diagnosis of diabetes was moderate for Korean adults. PMID- 20959717 TI - Baicalein protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis through inhibition of reactive oxygen species production and CHOP induction. AB - Baicalein is one of the major flavonoids in Scutellaria baicalensis Georgi and possesses various effects, including cytoprotection and anti-inflammation. Because endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and cerebral ischemia, we investigated the effects of baicalein on apoptotic death of HT22 mouse hippocampal neuronal cells induced by thapsigargin (TG) and brefeldin A (BFA), two representative ER stress inducers. Apoptosis, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) were measured by flow cytometry. Expression level and phosphorylation status of ER stress-associated proteins and activation and cleavage of apoptosis-associated proteins were analyzed by Western blot. Baicalein reduced TG- and BFA-induced apoptosis of HT22 cells and activation and cleavage of apoptosis-associated proteins, such as caspase-12 and -3 and poly(ADP-ribose) polymerase. Baicalein also reduced the TG- and BFA-induced expression of ER stress-associated proteins, including C/EBP homologous protein (CHOP) and glucose-regulated protein 78, the cleavage of X-box binding protein-1 and activating transcription factor 6alpha, and the phosphorylation of eukaryotic initiation factor-2alpha and mitogen activated protein kinases, such as p38, JNK, and ERK. Knock-down of CHOP expression by siRNA transfection and specific inhibitors of p38 (SB203580), JNK (SP600125), and ERK (PD98059) as well as anti-oxidant (N-acetylcysteine) reduced TG- or BFA-induced cell death. Baicalein also reduced TG- and BFA-induced ROS accumulation and MMP reduction. Taken together, these results suggest that baicalein could protect HT22 neuronal cells against ER stress-induced apoptosis by reducing CHOP induction as well as ROS accumulation and mitochondrial damage. PMID- 20959718 TI - Assessing cardiovascular risk in Mediterranean women with polycystic ovary syndrome. AB - BACKGROUND: Although dyslipidemia is common in the polycystic ovary syndrome (PCOS), current diagnostic guidelines suggest to evaluate only plasma HDL cholesterol and triglyceride concentrations, assuming that, in this disorder, cardiovascular risk is mainly due to the presence of the metabolic syndrome (MS). In the US, MS has been found in up to 50% of PCOS, but in other countries its prevalence is lower. METHODS: We compared the prevalence of MS with that of increased LDL- and non-HDL-cholesterol levels in 350 Mediterranean PCOS women (244 anovulatory and 106 ovulatory), and 95 normo-weight and 90 body mass index (BMI)- matched controls. RESULTS: The prevalence of MS was 7.1% in PCOS, higher than normoweight and BMI-matched controls (2.4% and 3.5%, respectively, p < 0.05 for both). The prevalence of elevated LDL- and non-HDL-cholesterol levels in PCOS was respectively, 14.9% and 8.6%, higher than normoweight (2.1% and 1.0%, respectively, p < 0.01 for both) and BMI-matched controls (4.4% and 2.2%, respectively, p<0.05 for both). In PCOS, increased LDL-cholesterol was twice more prevalent than MS or non-HDL-cholesterol. Only a minority of PCOS with MS had increased LDL-cholesterol while increased non-HDL-cholesterol was generally associated to increased LDL-cholesterol. CONCLUSIONS: We have found that in Mediterranean PCOS the prevalence of MS is relatively low while elevated LDL cholesterol levels are more prevalent. Therefore, beyond MS, a more comprehensive lipid evaluation, including LDL-cholesterol, is needed for a more effective assessment of cardiovascular risk in PCOS. PMID- 20959719 TI - Neonatal thyroid status in an area of iodine sufficiency. AB - BACKGROUND: Iodine deficiency constitutes a public health problem in many countries worldwide. Fetal neurodevelopment is affected by maternal iodine intake. The aim of present study was to assess urinary iodine excretion (UIE) in the 3 trimesters of pregnancy and evaluate its association with newborn thyroid function in Tehran, an area of iodine sufficiency. METHODS: Based on median urinary iodine in 3 trimesters, 138 pregnant women were divided into 2 groups with UIE<150 (group I) and UIE >= 150 MUg/l (group II). Cord blood samples of their newborns were evaluated for serum concentrations of TSH, T3, T4, free T4 (FT4), and thyroglobolin. Quartiles of UIE were also determined. Correlations between mothers' UIE and newborns' thyroid function in both groups were investigated. RESULTS: Fifty-two pregnant women (38%) had median UIE<150 MUg/l and 86 had (62%) UIE >= 150 MUg/l. Median UIE in groups I and II in the 1st, 2nd, and 3rd trimesters were 125 and 212 MUg/l, 97 and 213 MUg/l, 93 and 227 MUg/l, respectively. No significant difference was seen in thyroid function of newborns in the 2 groups. Mean concentrations of T4, T3, FT4, and TSH of newborn did not show significant difference in median UIE of mothers in various quartiles. CONCLUSION: This study shows that newborns, irrespective of mothers' UIE, in an area with a sustained iodine supplementation program, may not be at risk of alterations in thyroid functions. PMID- 20959720 TI - Acute effects of acylated and unacylated ghrelin on total and high molecular weight adiponectin inmorbidly obese subjects. AB - BACKGROUND: Energy homeostasis and body weight are regulated by a highly complex network involving the brain, the digestive tract, and white adipose tissue (WAT). Knowledge about signaling pathways connecting digestive tract and WAT is limited. Gut hormone ghrelin and adipokine adiponectin are both decreased in obesity and they share a potent effect on insulin sensitivity: both adiponectin and the combination of acylated (AG) and unacylated ghrelin (UAG) improve insulin sensitivity. AIM: In the present study, we evaluated whether acute administration of UAG alone or combined with AG affects adiponectin concentrations. SUBJECTS AND METHODS: Eight morbidly obese non-diabetic subjects were treated with either UAG 200 MUg, UAG 100 MUg + AG 100 MUg (Comb), or placebo in 3 episodes in a double blind randomized cross-over design. Study medication was administered as single iv bolus injections at 09:00 h after an overnight fast. High molecular weight (HMW) and total adiponectin, glucose, insulin, and total ghrelin and AG were measured up to 1 h after administration. RESULTS: HMW and total adiponectin concentrations did not change after administration of either UAG or Comb, nor were they different from placebo. Insulin concentrations decreased significantly after acute administration of Comb, reaching a minimum at 20 min: 58.2 +/- 3.9% of baseline. CONCLUSIONS: Acute iv administration of UAG and the combination of UAG and AG in morbidly obese non-diabetic subjects without overt diabetes does not affect total or HMW adiponectin concentrations, neither directly nor indirectly by changing insulin concentrations. PMID- 20959721 TI - Binding, uptake, and degradation of internalized thyroglobulin in cultured thyroid and non-thyroid cells. AB - Thyroid hormone release requires degradation of thyroglobulin (Tg) by thyroid epithelial cells, which occurs mainly in the lysosomal pathway following Tg endocytosis. Non-specific fluid-phase endocytosis is thought to be the main route of Tg uptake leading to degradation, whereas receptor- mediated endocytosis is believed to lead to post-endocytic pathways other than degradation. To gain more insights into these issues, we investigated handling of Tg by various cell types. Tg bound similarly to thyroid (FRTL-5, FRT) and non-thyroid (COS-7, IRPT) cells, indicating the presence of membrane-binding sites, presumably receptors, in both cell types. Tg was internalized and degraded by all cells and degradation paralleled uptake, with the exception of FRTL- 5 cells, in which a lower proportion of Tg was degraded, suggesting that in FRTL-5 cells mechanisms that target Tg to the various post-endocytic pathways (either receptors or postreceptorial factors) are differently represented. Immunoelectronmicroscopy showed a common path of endocytosis in FRTL-5, COS-7, and IRPT cells, namely the formation of pseudopods engulfing Tg, followed by internalization and accumulation of Tg in cytoplasmic vesicles and lysosomes. The fastest rate was observed in COS-7 cells, probably reflecting a lower impact of endocytic receptors. Our findings suggest that Tg uptake and degradation are not thyroid specific, that Tg binding sites exist in different cell types, and that uptake and/or degradation are differently regulated in differentiated thyroid cells, presumably because of a different impact of endocytic receptors or post-endocytic mechanisms, which are probably responsible for the regulation of hormone release. PMID- 20959722 TI - Environmental car exhaust pollution damages human sperm chromatin and DNA. AB - OBJECTIVE: The adverse role of traffic pollutants on male fertility is well known. Aim of this study was to evaluate their effects on sperm chromatin/DNA integrity. METHODS: To accomplish this, 36 men working at motorway tollgates and 32 unexposed healthy men (controls) were enrolled. All of them were interviewed about their lifestyle. Hormone, semen samples, and environmental and biological markers of pollution were evaluated. Sperm chromatin and DNA integrity were evaluated by flow cytometry following propidium iodide staining and TUNEL assay, respectively. RESULTS: LH, FSH, and testosterone serum levels were within the normal range in tollgate workers. Sperm concentration, total sperm count, total and progressive motility, and normal forms were significantly lower in these men compared with controls. Motorway tollgate workers had a significantly higher percentage of spermatozoa with damaged chromatin and DNA fragmentation, a late sign of apoptosis, compared with controls. A significant direct correlation was found between spermatozoa with damaged chromatin or fragmented DNA and the length of occupational exposure, suggesting a time-dependent relationship. CONCLUSION: This study showed that car exhaust exposure has a genotoxic effect on human spermatozoa. This may be of relevant importance not only for the reproductive performance of the men exposed, but also for the offspring health. PMID- 20959723 TI - Investments in patient safety thus compete with other efforts to improve services and to maintain operations. PMID- 20959725 TI - Assessing and responding in real time to online anti-vaccine sentiment during a flu pandemic. AB - The perceived safety of vaccination is an important explanatory factor for vaccine uptake and, consequently, for rates of illness and death. The objectives of this study were (1) to evaluate Canadian attitudes around the safety of the H1N1 vaccine during the fall 2009 influenza pandemic and (2) to consider how public health communications can leverage the Internet to counteract, in real time, anti-vaccine sentiment. We surveyed a random sample of 175,257 Canadian web users from October 27 to November 19, 2009, about their perceptions of the safety of the HINI vaccine. In an independent analysis, we also assessed the popularity of online flu vaccine-related information using a tool developed for this purpose. A total of 27,382 unique online participants answered the survey (15.6% response rate). Of the respondents, 23.4% considered the vaccine safe, 41.4% thought it was unsafe and 35.2% reported ambivalence over its safety. Websites and blog posts with anti-vaccine sentiment remained popular during the course of the pandemic. Current public health communication and education strategies about the flu vaccine can be complemented by web analytics that identify, track and neutralize anti-vaccine sentiment on the Internet, thus increasing perceived vaccine safety. Counter-marketing strategies can be transparent and collaborative, engaging online "influencers" who spread misinformation. PMID- 20959726 TI - Community pharmacy incident reporting: a new tool for community pharmacies in Canada. AB - Incident reporting offers insight into a variety of intricate processes in healthcare. However, it has been found that medication incidents are under reported in the community pharmacy setting. The Community Pharmacy Incident Reporting (CPhIR) program was created by the Institute for Safe Medication Practices Canada specifically for incident reporting in the community pharmacy setting in Canada. The initial development of key elements for CPhIR included several focus-group teleconferences with pharmacists from Ontario and Nova Scotia. Throughout the development and release of the CPhIR pilot, feedback from pharmacists and pharmacy technicians was constantly incorporated into the reporting program. After several rounds of iterative feedback, testing and consultation with community pharmacy practitioners, a final version of the CPhIR program, together with self-directed training materials, is now ready to launch. The CPhIR program provides users with a one-stop platform to report and record medication incidents, export data for customized analysis and view comparisons of individual and aggregate data. These unique functions allow for a detailed analysis of underlying contributing factors in medication incidents. A communication piece for pharmacies to share their experiences is in the process of development. To ensure the success of the CPhIR program, a patient safety culture must be established. By gaining a deeper understanding of possible causes of medication incidents, community pharmacies can implement system-based strategies for quality improvement and to prevent potential errors from occurring again in the future. This article highlights key features of the CPhIR program that will assist community pharmacies to improve their drug distribution system and, ultimately, enhance patient safety. PMID- 20959727 TI - Identification of medication safety indicators in acute care settings for public reporting in Ontario. AB - In healthcare settings, indicators are useful tools to assess the structure, process and outcomes of care. Moreover, when used to report to the public, indicators ensure greater transparency for our healthcare system. The purpose of this study was to identify in acute care settings three medication safety indicators that are suitable for public reporting in Ontario. A multi-phase process was developed that included a literature review, compilation and evaluation of possible indicators and a consensus-generation process involving a focus group (modified nominal group technique) with Ontario healthcare experts from various disciplines. More than 300 potential medication safety indicators were identified through the literature review. Two analysts, working independently and using a defined set of selection criteria, narrowed the focus to 49 and subsequently 12 candidate indicators. A focus group of leading experts across the healthcare fields in Ontario was convened and reached consensus on three indicators. These three indicators focused on the areas of venous thromboembolism prevention, acute myocardial infarction discharge medications and medication reconciliation. This report describes a multi-phase process undertaken by the Institute for Safe Medication Practices Canada to identify in acute care settings three medication safety indicators suitable for public reporting in Ontario. These indicators point to important areas in medication safety at which deficiencies can result in significant patient harm. There is a potential for these indicators to provide hospitals and healthcare providers with tangible and realistic mechanisms for measuring performance and, ultimately, improving the quality of care. PMID- 20959728 TI - National analysis of sepsis hospitalizations and factors contributing to sepsis in-hospital mortality in Canada. AB - Sepsis is one of the leading causes of in-hospital mortality in Canada. Patient safety is an important component of sepsis prevention and control. The Canadian Institute for Health Information recently released a report that examines a national picture of sepsis hospitalizations and mortality. This article highlights and expands some of the key findings from this report. Specifically, we look here more closely at patients admitted through the emergency departments (ED) in order to determine if earlier recognition of sepsis in the ED would lead to improved patient outcomes. PMID- 20959729 TI - Skin and wound care excellence: integrating best-practice evidence. AB - North York General Hospital (NYGH), in collaboration with Nursing Practice Solutions, Smith & Nephew and the Central Community Care Access Centre, implemented a program in skin and wound care that has made best-practice, evidenced-based wound care management possible, affordable and sustainable. Focused action using advanced wound care products and proven clinical approaches has dramatically improved the identification, protection and support of skin integrity. Wound prevention and management are among the most direct and cost effective measures a healthcare organization can take to improve patient safety and quality of life, and they allow for the reduction of expenditures and re allocation of funds into other important areas. The Skin and Wound Care Program was designed to create and maintain resources within NYGH to ensure the delivery of consistent, best-practice wound prevention and management. The program has successfully sustained a significant reduction in the prevalence of pressure ulcers. Benefits of the program include improved patient safety, health and quality of life. The Skin and Wound Care Program has seen the transfer of knowledge and evidence-based best practices to both the bedside and the community. Extending the collaborative effort beyond the walls of NYGH has helped the hospital gain further insight into and experience with our community partners to spread skin and wound best practices across the healthcare continuum. Lessons learned have been shared with other healthcare organizations in forums such as the Congress of the World Union of Wound Healing Societies, thus contributing to the advancement of continuous improvement in healthcare. PMID- 20959730 TI - Methods to assess the safety of health information systems. AB - Research has shown that the introduction of health information systems (HISs) can reduce the likelihood of medical errors. However, there is a growing body of evidence that suggests that if it is not designed or implemented properly, a HIS can actually cause or induce health professionals to make medical errors (i.e., technology-induced errors). In order to maximize the benefits of HISs while decreasing the likelihood of such inadvertent technology-induced error, it is important that we understand the range of methods that can be used to ensure the safety of our systems. In this article, we report the results of a review of the literature related to the methods used in predicting, preventing and evaluating the potential for a HIS to cause technology-induced error. These methods can be classified in terms of their application, including before a HIS is implemented, after a HIS has been implemented and after a technology-induced error has occurred. PMID- 20959731 TI - Increasing the safety of healthcare information systems through improved procurement: toward a framework for selection of safe healthcare systems. AB - In this article, we describe a framework that we have developed for improving the effectiveness of critical decision-making in selecting information systems. In our framework, we consider system selection in terms of strength of evidence obtained from the testing of candidate systems in order to reduce risk and increase the likelihood of selection and implementation of an effective and safe system. Two case studies, one from a major North American hospital and one from a major European hospital, are presented to illustrate how methods such as usability testing can be applied to improve system selection as well as customization (through early identification of system-organization mismatches and error-prone system features). It is argued that technology-organization fit and consideration of the potential for technology-induced error should be important selection criteria in the procurement process. Here, implications are discussed for the development of improved procurement processes to lead to safer healthcare systems. PMID- 20959732 TI - Challenges of hand hygiene in healthcare: the development of a tool kit to create supportive processes and environments. AB - Hand hygiene compliance by healthcare providers has been difficult to achieve due to diverse environments, work culture, processes and task requirements. Because of this complexity, hand hygiene lends itself well to a human factors analysis in order to design a system that matches human cognitive and physical strengths and makes allowances for human limitations. PMID- 20959733 TI - Case study of physician leaders in quality and patient safety, and the development of a physician leadership network. AB - There is increasing recognition of the need for physician leadership in quality and patient safety, and emerging evidence that physician leadership contributes to improved care. Hospitals are beginning to establish physician leader positions; however, there is little guidance on how to define these roles and the strategies physician leaders can use toward improving care. This case study examines the roles of four physician leaders, describes their contribution to the design and implementation of hospital quality and patient safety agendas and discusses the creation of a physician network to support these activities. The positions were established between July 2006 and April 2009. All are corporate roles with varying reporting and accountability structures. The physician leads are involved in strategic planning, identifying and leading quality and safety initiatives, physician engagement and culture change. All have significantly contributed to the implementation of hospital improvement activities and are seen as influential among their peers as resources and mentors for local project success. Despite their accomplishments, these physician leads have been challenged by ambiguous role descriptions and difficulty identifying effective improvement strategies. As such, an expanding physician network was created with the goal of sharing approaches and tools and creating new strategies. Physician leaders are an important factor in the improvement of safety and quality within hospitals. This case study provides a template for the creation of such positions and highlights the importance of networking as an effective strategy for improving local care and advancing professional development of physician leaders in quality and patient safety. PMID- 20959734 TI - Building safer systems through critical occurrence reviews: nine years of learning. AB - At The Hospital for Sick Children (SickKids), the term critical occurrence was developed to describe any event that results in an actual or potential serious, undesirable and unexpected patient or staff outcome including death or major permanent loss of function, not related to the natural course of the patient's illness or underlying condition. It also includes a breach of legislation including the Personal Health Information Protection Act of Ontario. Although broader in its definition, the term aligns closely with critical incident as defined within the amendments to Regulation 965, under the Public Hospitals Act (Government of Ontario 1990). Critical occurrences may include (but are not limited to) potential or actual adverse outcomes (including death) associated with or resulting from medication errors; a wrong site, patient or procedure performed; contaminated drugs, devices or products; an equipment malfunction; an outbreak or unusual pattern/type of nosocomial infection; employee actual or potentially serious injuries. PMID- 20959735 TI - Aiming for zero preventable deaths: using death review to improve care and reduce harm. AB - In 2005, our organization set a goal of zero preventable deaths by 2010- notionally a sound goal but extremely challenging to measure, monitor and evaluate. The development of an interdisciplinary Death and Adverse Event Review process has provided a measure and framework for action to decrease adverse events (AEs) that cause harm. Death and Adverse Event Review is a formal process in which trained reviewers consider patient deaths using a modified Global Trigger Tool to establish the presence of AEs or quality of care issues that may have potentially led to death or harm. When identified, these charts go to second level review by a physician/interdisciplinary team to determine recommendations for actions to prevent future reoccurrences. Data have provided trending of system influences to patient safety. In 2008-2009, 1,817 deaths were reviewed and AE rates of 12.1% and 16.3% were identified. There were 422 AEs and 114 quality of care issues identified for follow-up. Of the 4.7% and 6.3% referred to the physician/interdisciplinary team for secondary review, 2.3% and 2.6% resulted in recommendations for improvement. In addition to local improvements, many system improvements have occurred as a result of the review, such as proposed minimum standards for physician documentation; a formal review of post-operative guidelines for patients with sleep apnea; and a working group to review nursing documentation, communication/follow-up of vital signs, fluid balance and pain management. The Death and Adverse Event Review process provides a new critical level of detail that supports continuous improvements to our care processes and ongoing progress toward our goal of zero preventable deaths. PMID- 20959736 TI - Enhancing patient safety through undergraduate inter-professional health education. PMID- 20959737 TI - Using SBAR to communicate falls risk and management in inter-professional rehabilitation teams. AB - This study implemented and evaluated the adapted Situation-Background-Assessment Recommendation (SBAR) tool for use on two inter-professional rehabilitation teams for the specific priority issue of falls prevention and management. SBAR has been widely studied in the literature, but rarely in the context of rehabilitation and beyond nurse-physician communication. In phase one, the adapted SBAR tool was implemented on two teams with a high falls incidence over a six-month period. In phase two, process and outcome evaluations were conducted in a pre-post design comparing the impact of the intervention with changes in the rest of the hospital, including the perceptions of safety culture (as measured by the Hospital Survey on Patient Safety Culture); effective team processes, using the Team Orientation Scale; and safety reporting, including falls incidence, severity and near misses. This study suggests that the adapted SBAR tool was widely and effectively used by inter-professional rehabilitation teams as part of a broader program of safety activities. Near-miss and severity of falls incidence trended downward but were inconclusive, likely due to a short time frame as well as the nature of rehabilitation, which pushes patients to the limit of their abilities. While SBAR was used in the context of falls prevention and management, it was also utilized it in a variety of other clinical and non-clinical situations such as transitions in care, as a debriefing tool and for conflict resolution. Staff found the tool useful in helping to communicate relevant and succinct information, and to "close the loop" by providing recommendations and accountabilities for action. Suggestions are provided to other organizations considering adopting the SBAR tool within their clinical settings, including the use of an implementation tool kit and video simulation for enhanced uptake. PMID- 20959738 TI - Optimizing physician handover through the creation of a comprehensive minimum data set. AB - Handover is defined as the communication of information between individuals and teams of healthcare providers to support the transfer of patient care and maintain professional responsibility and accountability. Poor handovers are increasingly recognized as potentially dangerous for patient safety and are associated with adverse events. One suggested method to improve the timely and efficient exchange of clinical information at handover and to reduce discontinuities in care is through the use of a minimum data set (MDS). The objective of this study was to describe the process of developing a single comprehensive hospital-wide MDS, created through an analysis of current handover processes and customary information tools used to support physician handover (MDHO) at a large quaternary care pediatric academic health sciences centre. A 20 item questionnaire was administered in person to a senior resident or fellow on each of 49 services identified to objectively assess MDHO processes, including frequency, consistency, format, participants and duration, for each service. The presence, type, location, responsibility for updating and security characteristics of MDHO tools used to support MDHO were also analyzed. The MDHO tools currently in use were collected and analyzed to create a comprehensive cross-institutional MDS. The analysis indicates that MDHO is highly consistent in terms of frequency, processes, participants, duration and the use of written tools to guide information exchange across departments. However, many best practice recommendations for MDHO are not being followed. Further, many of the existing MDHO tools in use have a similar content structure and already contain a majority of the components of a comprehensive MDS. Current local consistency in practice will allow for improved acceptance and adoption of an MDHO tool that continues to meet the clinical and administrative needs of physicians but also addresses needs for data accuracy and security. These additional specifications can be met through the use of information communication technologies. PMID- 20959739 TI - Assessment of safety culture maturity in a hospital setting. AB - The Manchester Patient Safety Culture Assessment Tool (MaPSCAT) was used to examine the levels of safety culture maturity in four programs across one large healthcare organization. The MaPSCAT is based on a theoretical framework that was developed in the United Kingdom through extensive literature reviews and expert input. It provides a view of safety culture on 10 dimensions (continuous improvement, priority given to safety, system errors and individual responsibility, recording incidents, evaluating incidents, learning and effecting change, communication, personnel management, staff education and teamwork) at five progressive levels of safety maturity. These levels are pathological ("Why waste our time on safety?"), reactive ("We do something when we have an incident"), bureaucratic ("We have systems in place to manage safety"), proactive ("We are always on alert for risks") and generative ("Risk management is an integral part of everything we do"). This article highlights the use of a new tool, the results of a study completed with this tool and how the results can be used to advance safety culture. PMID- 20959740 TI - Healthcare culture and the challenge of preventing healthcare-associated infections. AB - Consider the following story: A patient in a teaching hospital is about to be examined by a resident physician. When asked by the patient to wash his hands, the resident refuses, saying he has done so recently. The staff physician then enters the room and the patient speaks of his disappointment regarding the actions of the resident. The staff physician is displeased and states that the patient should not be mistrusting his physicians. Later, when booking his follow up appointment, the patient asks not to be seen by the resident. The staff physician overhears and, in front of other patients, angrily tells the patient not to return to his clinic because of his disruptive behaviour. PMID- 20959741 TI - Dimensions of patient safety culture in family practice. AB - Safety culture has been shown to affect patient safety in healthcare. While the United States and United Kingdom have studied the dimensions that reflect patient safety culture in family practice settings, to date, this has not been done in Canada. Differences in the healthcare systems between these countries and Canada may affect the dimensions found to be relevant here. Thus, it is important to identify and compare the dimensions from the United States and the United Kingdom in a Canadian context. The objectives of this study were to explore the dimensions of patient safety culture that relate to family practice in Canada and to determine if differences and similarities exist between dimensions found in Canada and those found in previous studies undertaken in the United States and the United Kingdom. A qualitative study was undertaken applying thematic analysis using focus groups with family practice offices and supplementary key stakeholders. Analysis of the data indicated that most of the dimensions from the United States and United Kingdom are appropriate in our Canadian context. Exceptions included owner/managing partner/leadership support for patient safety, job satisfaction and overall perceptions of patient safety and quality. Two unique dimensions were identified in the Canadian context: disclosure and accepting responsibility for errors. Based on this early work, it is important to consider differences in care settings when understanding dimensions of patient safety culture. We suggest that additional research in family practice settings is critical to further understand the influence of context on patient safety culture. PMID- 20959742 TI - Whether Canada is ready to move forward with their implementation is another matter. PMID- 20959743 TI - Why social determinants? AB - There is overwhelming evidence that social factors have profound influences on health. Children are particularly sensitive to social determinants, especially in the early years. Life course models view health as a developmental process, the product of multiple gene and environment interactions. Adverse early social exposures become programmed into biological systems, setting off chains of risk that can result in chronic illness in mid-life and beyond. Positive health promoting influences can set in motion a more virtuous and health-affirming cycle, leading to more optimal health trajectories. Mounting an effective response to social determinants will involve both direct social policy initiatives designed to eliminate poverty and inequality, and indirect approaches focused on disrupting pathways between social risks and poor health outcomes. To be effective, these indirect strategies will require nothing short of a transformation of existing child health systems. Parents and professionals must work together from the ground up, raising public awareness about social determinants of health and implementing cross-sector place-based initiatives designed to promote positive health in childhood. PMID- 20959744 TI - The link between social inequality and child health outcomes. AB - Despite the scientific and technological advances of recent decades and their potential impact on healthcare delivery, major disparities in child health exist both between and within countries. Across the globe, over 25,000 children under five years of age die every day, the majority, but by no means all, in developing countries. Infant mortality is 10 times higher in the world's least-developed countries than in the industrialized world, and under-five mortality is 25 times higher (United Nations Children's Fund 2008). Vast discrepancies in child health also exist within high- and low-income countries. PMID- 20959745 TI - Social geography of developmental health in the early years. AB - What happens to children in their earliest years is critical for their development throughout the life course. The years from zero to school age are foundational for brain and biological development. Attachment and face recognition; impulse control and regulation of physical aggression; executive function in the prefrontal cortex and focused attention; fine and gross motor functions and coordination; receptive and expressive language; and understandings of quantitative concepts are all established during this time and become embedded in the architecture and function of the brain (Doherty 1997; Kolb 2009; McCain and Mustard 1999). Brain and biological development are in turn expressed through three broad domains of development of the whole child: physical, social-emotional and language-cognitive, which together are the basis of "developmental health" (Keating and Hertzman 1999). Developmental health influences many aspects of well being, including obesity and stunting, mental health, heart disease, competence in literacy and numeracy, criminality and economic participation throughout life (Irwin et al. 2007). Accordingly, developmental health is the central concern of this article. PMID- 20959746 TI - Aboriginal child health and the social determinants: why are these children so disadvantaged? AB - Canada's original people consist of First Nations, Inuit and Metis peoples. Their estimated population is 1.17 million. The total fertility rate for the period 1996-2001 was 2.6 for Aboriginal women versus 1.5 for Canada (Statistics Canada 2006). Thus, a high proportion of this rapidly growing segment of the population are children. Numerous articles have reviewed the health status of Canada's Aboriginal children and shown comparatively high prevalence and incidence of most of the common diseases that affect children. This article highlights some of the more specific disparities, but also attempts to provide some historical context and a few composite case studies that illustrate how the social determinants, colonialism, jurisdictional issues, geography and healthcare can interact to amplify disproportionately the disadvantage these children have in so many ways. Much of the historical detail recounts the contact with First Nations people, the most numerous and the first group to have contact with European settlement. PMID- 20959747 TI - Immigrant health and the children and youth of Canada: are we doing enough? AB - Sitting across from me in the crowded examining room of an inner-city Toronto pediatric clinic is a mother, a child and their family friend. The mother and her three-year-old have been in Canada for almost a year, having emigrated from Vietnam (insert virtually any country of origin here) and are currently living in a multi-family dwelling in a well-known area of lower socio-economic status. The mother speaks very little English, and the family friend is attempting to act as interpreter and support person. No official interpreter services are available today, and after completing my consultation (to the best of my abilities) regarding the presenting problem of "language delay," I am faced with having to try to discuss the possibility of this child having a much broader communication disorder, autism. PMID- 20959748 TI - Family as a social determinant of health: implications for governments and institutions to promote the health and well-being of families. AB - A growing appreciation of the powerful impact of the social determinants of health, particularly the toxic effect of poverty on health, is driving the need for a re-evaluation of the role of governments and institutions such as hospitals in the lives of children and families. The well-being of families is the cornerstone on which society rests; yet evidence is growing that families are facing significant challenges beyond their control that adversely impact their ability to perform their essential role. With evidence of a growing divide in society--an expanding gap between the rich and the poor (Novak 2007)- contributing to a polarization of health and social outcomes along this continuum, there is an urgent need for revisioning priorities for health and social policies. Bold new ideas and leadership are needed to plan a future that encompasses social justice as a key value and operating assumption. PMID- 20959749 TI - Turning the social determinants of health to our advantage: policy fundamentals for a better approach to children's health. PMID- 20959750 TI - The challenge of child and youth mental health. Interview by Mary Jo Haddad. PMID- 20959752 TI - What is stopping us from early mobility in the intensive care unit? PMID- 20959753 TI - A pioneer approach to preventing central venous catheter infections. PMID- 20959754 TI - 'Rescue oxygenation therapies' for severe pH1N1-associated acute respiratory distress syndrome. PMID- 20959755 TI - Predictions and outcomes for the critically ill patient with cirrhosis: is it time to settle on the SOFA and let jaundiced views on outcome MELD away? PMID- 20959756 TI - Why do intensivists still use hydroxyethyl starch? PMID- 20959757 TI - New insights into symptoms experienced by high-acuity intensive care unit patients. PMID- 20959758 TI - Cardiovascular effects of therapeutic hypothermia after resuscitation from cardiac arrest? PMID- 20959759 TI - Methylene blue as the future protecting agent for ischemic brain injury? PMID- 20959761 TI - Intravenous high-dose aspirin in acute coronary syndromes? PMID- 20959762 TI - Partitioning effect in lipid resuscitation: further evidence for the lipid sink. PMID- 20959764 TI - Trauma patients with normal vital signs: is shock index a reflection of injury severity? PMID- 20959765 TI - RIFLE criteria in the pediatric intensive care unit. PMID- 20959767 TI - Postprandial lipemia: what is the impact of exercise outside of the laboratory? PMID- 20959769 TI - Do the adjacent level intervertebral discs degenerate after a lumbar spinal fusion? An experimental study using a rabbit model. AB - STUDY DESIGN: A rabbit model of disc degeneration adjacent to a lumbar spinal fusion. OBJECTIVE: To use a rabbit model to determine the long-term changes in the intervertebral discs at the levels above (cephalad) and below (caudad) 2 fused lumbar levels. SUMMARY OF BACKGROUND DATA: Lumbar spinal fusion is generally carried out to eliminate motion at a specific lumbar level. However, it is commonly thought that by eliminating motion at a level, one increases the motion at the adjacent levels cephalad and caudad the fused levels. There have been studies that have reported on degeneration occurring at the cephalad and caudad levels adjacent to the fused levels. METHODS: A total of 9 New Zealand white, female rabbits: 4 rabbits in the control group and 5 rabbits in the experimental group. The 5 rabbits in the experimental group underwent a posterolateral 2-level lumbar spinal fusion from L3 to L5. The changes in the lumbar discs were assessed using radiographs, magnetic resonance (MR) images, and histology at 6 months and 12 months. RESULTS: The results at 6 months are less clear than those at 12 months. The results at 12 months for the experimental group are (1) the intervertebral disc height decreased at the caudad adjacent level and to a lesser extent at the cephalad adjacent level; (2) the MRI scores for the discs at the caudad and cephalad adjacent levels showed severe loss of signal intensity as compared to the discs at the same levels in the control group. This loss was more pronounced at the caudad level where the loss of signal intensity was similar to that seen at the fused levels; (3) the histologic analysis showed severe degenerative changes with a lack of live cells in the nucleus pulposus and in the endplate at the caudad adjacent level. At the cephalad level, live cells were apparent (albeit few) in the nucleus pulposus, and there was a more normal looking endplate with live cells. CONCLUSION: The intervertebral discs at both the cephalad and the caudad levels adjacent to the 2 fused lumbar levels in this rabbit-model experiment carried out over 12 months after surgery showed degenerative changes asassessed using disc-height measurements, MR images, and histology, and the effect was more severe at the caudad adjacent level. PMID- 20959770 TI - The impact of cervical pedicle screws for primary stability in multilevel posterior cervical stabilizations. AB - STUDY DESIGN: A total of 12 human cervical spines were tested in vitro in a biomechanical nondestructive set-up to compare the primary stability of different posterior cervical instrumentations after a bilevel corpectomy. OBJECTIVE: To evaluate the primary 3-dimensional stability with special focus on the impact of cervical pedicle screws. SUMMARY OF BACKGROUND DATA: Cervical pedicle screw fixation gains popularity due to supposed higher stability. However, biomechanical studies are rare. Especially the impact of a combination of lateral mass and pedicle screws on stability in multilevel posterior stabilizations has not been evaluated until now. METHODS: A total of 12 human cervical specimens were loaded with pure moments and unconstrained motion between C4 and C7 was measured. The specimen were tested in the intact state, all lateral mass screws (all LMS) from C4-C7, cervical pedicle screws (CPS) C4 and C7 left, LMS C4-C7 right, C5+C6 left, CPS C4+C7 bilateral, LMS C5+C6, and a anterior-posterior instrumentation (360 degrees ). RESULTS: All instrumentations showed a higher stability compared with the intact state. No difference was found for uni- or bilateral applied CPS. The all LMS showed comparable stability than the CPS instrumentations. CONCLUSION: From a biomechanical primary stability point it seems unnecessary to add CPS in a bilevel corpectomy model. If CPS are added, the unilateral application seems sufficient. PMID- 20959771 TI - Does interruption of the artery of Adamkiewicz during total en bloc spondylectomy affect neurologic function? AB - STUDY DESIGN: A retrospective review of patients with interruption of the artery of Adamkiewicz during total en bloc spondylectomy (TES). OBJECTIVE: To assess neurologic function after interruption of the artery of Adamkiewicz in TES. SUMMARY OF BACKGROUND DATA: The most important feeding artery of the thoracolumbar spinal cord is the great anterior radiculomedullary artery, also called the artery of Adamkiewicz. The artery of Adamkiewicz supplies the lower two-thirds of the spinal cord via the anterior spinal artery. It is naturally believed among spine surgeons that interruption of the artery of Adamkiewicz during surgeries is absolutely contraindicated. However, it is necessary to sacrifice the artery of Adamkiewicz during TES, when the tumor, by chance, exists at the level of the artery of Adamkiewicz. METHODS: Between 1990 and 2009, we have performed 180 cases of TES. All cases except for few emergency cases received preoperative embolization. The artery of Adamkiewicz was verified by angiography of the segmental arteries. There were 15 patients in which the artery of Adamkiewicz was found at the levels of resected vertebrae. Interruption of the artery was performed during surgery in these 15 cases. Neurologic function was analyzed retrospectively. RESULTS: Of the 15 patients, the Frankel grade before surgery was C in 1, D in 5, and E in 9. At follow-up, the Frankel grade was D in 1 and E in 14. There were no cases of neurologic deterioration or paralysis after TES. CONCLUSION: On the basis of our results of TES on up to 3 vertebrae, interruption of the artery of Adamkiewicz for TES does not adversely affect neurologic function. We advocate strongly that our surgeons are allowed to sacrifice up to 3 pairs of segmental arteries, even including the artery of Adamkiewicz, if necessary. PMID- 20959772 TI - Sagittal parameters of global spinal balance: normative values from a prospective cohort of seven hundred nine Caucasian asymptomatic adults. AB - STUDY DESIGN: Prospective study of normal sagittal global spinal balance in the Caucasian adult population. OBJECTIVE: To document values for parameters of global spinal balance in 709 asymptomatic adults without spinal pathology. SUMMARY OF BACKGROUND DATA: Previous studies have investigated sagittal spinal balance in the normal population, but there is still a need for a large prospective database with normative values on the basis of gender and age. METHODS: Spinosacral angle (SSA), spinal tilt (ST), and C7 translation ratio were evaluated in 709 asymptomatic adults (354 males and 355 females). Position of C7 plumbline relative to sacrum and hip axis (HA) was also assessed. Comparisons on the basis of gender were performed using analyses of covariance with age as covariate. Relationships between parameters and age were assessed using Spearman's coefficients. RESULTS: Mean SSA, ST, and C7 translation ratio were respectively 130.4 degrees +/- 8.1 degrees , 90.8 degrees +/- 3.4 degrees , and 0.1 degrees +/- 1.9 degrees . Mean +/- 2 standard deviations were respectively 110 degrees to 150 degrees for SSA and 85 degrees to 100 degrees for ST. Mean SSA and ST were higher in females but by less than 2 degrees . C7 plumbline was behind the HA in 86% of subjects. Correlations between global balance and age were small (-0.1 <= r <= 0.1), with only 1 correlation reaching statistical significance (SSA vs. age; r = -0.1), reflecting a slight tendency for SSA to decrease with age. There was no relationship between ST and age. CONCLUSION: Asymptomatic adults tend to stand with a stable global balance and it is expected that 95% of normal adults have an SSA and ST between 110 degrees to 150 degrees and 85 degrees to 100 degrees , respectively. C7 plumbline in front of the HA is not necessarily associated with a spinal pathology. Results suggest that in adults, anterior displacement of C7 plumbline with respect to sacrum cannot be attributed solely to aging and should raise a suspicion for the risk of developing spinal pathology. PMID- 20959774 TI - Radiographic evaluation of monocortical versus tricortical purchase approaches in lumbosacral fixation with sacral pedicle screws: a prospective study of ninety consecutive patients. AB - STUDY DESIGN: Prospective radiographic outcome analysis. OBJECTIVE: Radiographic evaluation of the rigidity of monocortical and tricortical purchase in lumbosacral fixation. SUMMARY OF BACKGROUND DATA: The lumbosacral junction continues to be a difficult region to obtain a successful spinal arthrodesis and is one of the primary regions for construct failure. In inserting sacral screws, 3 types of purchase are known: monocortical, bicortical, and tricortical. Among them no clinical or basic studies have compared monocortical with tricortical purchase. METHODS: Ninety consecutive patients diagnosed with spondylolisthesis who underwent lumbosacral fixation were evaluated. Fifty-three patients were treated with a monocortical approach and the other 37 patients were treated with a tricortical approach. Patients underwent surgery for posterolateral fusion or transforaminal lumbar interbody fusion (TLIF) according to their diagnosis. Their radiologic findings, radiolucent zones around sacral screws, and lumbosacral instability of more than 2 degrees flexion just after the surgery and 1 year later were compared. The angulation and length of the inserted screw were also measured and evaluated. RESULTS: There were no significances in the distributions of gender, average age, proportion of fixation method, and fusion range between the monocortical and tricortical groups (P > 0.05). Radiolucent zones and lumbosacral instability were more prevalent in the monocortical group than were in the tricortical group. Smaller angulation also affected the outcome in the monocortical group while screw length did not. Multivariate logistic regression analysis of possible risk factors revealed that female gender (odds ratio [OR]: 3.56, 95% confidence interval [CI]: 1.18-10.8), TLIF operative method (OR: 5.54, 95% CI: 1.08-8.2), number of fusion levels (OR: 1.84, 95% CI: 1.05-3.18), and monocortical purchase (OR: 7.11, 95% CI: 1.58-31.9) were statistically significant. CONCLUSION: More loosening of sacral screws was radiographically observed in the monocortical purchase group than in the tricortical group 1 year after the lumbosacral fixation surgery. A statistical analysis indicated that the tricortical approach should be used for patients undergoing multilevel fusion including lumbosacral junction by TLIF. PMID- 20959776 TI - Adjacent segment degeneration after lumbar spinal fusion: the impact of anterior column support: a randomized clinical trial with an eight- to thirteen-year magnetic resonance imaging follow-up. AB - STUDY DESIGN: Randomized controlled trial. OBJECTIVE: To analyze long-term adjacent segment degeneration (ASD) after lumbar fusion on magnetic resonance imaging and compare randomization groups with and without anterior column support. SUMMARY OF BACKGROUND DATA: ASD can be a long-term complication after fusion. The prevalence and the cause of ASD are not well documented, but ASD are one of the main arguments for introducing the use of motion-preserving techniques as an alternative to fusion. Anterior lumbar interbody fusion combined with posterolateral lumbar fusion (ALIF+PLF) has been proved superior to posterolateral fusion alone regarding outcome and cost-effectiveness. METHODS: Between 1996 and 1999, 148 patients with severe chronic low back pain were randomly selected for ALIF+PLF or for PLF alone. Ninety-five patients participated. ASD was examined on magnetic resonance imaging with regard to disc degeneration, disc herniation, stenosis, and endplate changes. Disc heights on radiographs taken at index surgery and at long-term follow-up were compared. Outcome was assessed by validated questionnaires. RESULTS: The follow-up rate was 76%. ASD was similar between randomization groups. In the total cohort, endplate changes were seen in 26% of the participants and correlated significantly with the presence of disc degeneration and disc herniation. Disc degeneration and dorsal disc herniation were the parameters registered most frequently and were significantly more pronounced at the first adjacent level than at the second and the third adjacent levels. Patients without disc height reduction over time were significantly younger than patients with disc height reduction. Disc degeneration and stenosis correlated significantly with outcome at the first adjacent level. CONCLUSION: The cause of the superior outcome in the group with anterior support is still unclear. Compared with the findings reported in the literature, the prevalence of ASD is likely to be in concordance with the expected changes in a nonoperated symptomatic population and therefore not accelerated by fusion. PMID- 20959777 TI - A detailed microscopic examination of alterations in normal anular structure induced by mechanical destabilization in an ovine model of disc degeneration. AB - STUDY DESIGN: Microstructural investigation of anular structure. OBJECTIVE: To reveal the effect of mechanical destabilization on the anular architecture both locally and distantly. SUMMARY OF BACKGROUND DATA: Several longitudinal ovine induced disc degeneration studies have documented degenerative changes in disc components using histologic, biomechanical, and biochemical approaches; however, changes in intervertebral disc (IVD) microstructure have largely remained neglected. In recent years, the use of structurally relevant section planes has improved our understanding of disc microstructure, including the presence of significant bridging structures radially linking the lamellae. It has been suggested that the translamellar cross-bridges offer a mechanism by which the anular wall can adaptively remodel itself in response to a changing biomechanical microenvironment. METHODS: IVDs harvested from lesion and sham-operated groups of Merino wethers were subjected to en face oblique and vertical sectioning. The macrostructural effect of the destabilization was examined in the vertically sectioned group with conventional histologic techniques. The second group was serially sectioned into 30-MUm slices allowing a global examination of the anular microstructure in its fully hydrated state using a differential interference contrast microscope. RESULTS: The previously described induced disc degeneration in the mid-inner anulus fibrosus (AF) and a spontaneous repair process in the outer AF was confirmed. Increased translamellar bridging was observed contralaterally to the lesion in the mechanically destabilized IVD and development of atypical broad bridging elements in the outer lamellae. Structural alterations in the lamellar anchorages to the cartilaginous endplates in destabilized IVDs, including lamellar branching and discontinuities atypical of normal lamellar attachments were also observed. CONCLUSION: The present investigation has offered a glimpse of an anular wall apparently capable of remodeling in response to perturbations in its normal mechanical environment. The translamellar cross-bridges undergo adaptations in structure, in response to altered stresses locally at the anular defect site but also distantly in the contralateral AF in the destabilized disc. It is currently not known whether such changes in anular microarchitecture, however, predispose the anulus to further mechanical damage or have a stabilizing role to play in this structure. PMID- 20959778 TI - The effects of risedronate and exercise on osteoporotic lumbar rat vertebrae and their sensory innervation. AB - STUDY DESIGN: Investigation of sensory innervation of rat osteoporotic lumbar vertebrae using in vitro and in vivo models. OBJECTIVE: To investigate (1) sensory innervation of osteoporotic rat vertebrae, (2) effects of risedronate on sensory neurons, (3) effects of osteoporosis treatment on bone mineral densities (BMDs) and the sensory innervation. SUMMARY OF BACKGROUND DATA: Osteoporotic patients without fractures sometimes experience vague low back pain of unknown origin. The mechanisms of osteoporosis treatments against the pain are unclear. METHODS: (1) The expression of calcitonin gene-related peptide (CGRP) immunoreactive (-ir) or transient receptor potential vanilloid 1 (TRPV1)-ir nerve fibers in vertebrae and dorsal root ganglions (DRG) innervating L3 vertebrae of Sprague Dawley rats labeled with neurotracer were examined in control, sham, and ovariectomized (OVX) rats. (2) Cultured rat neonate DRG neurons in media containing different concentrations of risedronate were immunostained for CGRP, and we measured its activity using axonal length and proportion of CGRP-ir neurons. (3) BMDs and CGRP expression in DRG neurons innervating L3 vertebrae were examined in the following 5 groups: sham (treated with saline), OVX (saline), OVX+EXE (treadmill exercise), OVX+RIS (risedronate), and OVX+RIS+EXE (risedronate and exercise). RESULTS: (1) A few CGRP-ir or TRPV1-ir nerve fibers were observed in the bone marrow. CGRP or TRPV1 expression in DRG was elevated in the OVX group (P < 0.05). (2) The axonal length and proportion of CGRP-ir neurons were dose-dependently suppressed (P < 0.05). (3) BMDs improved and the CGRP expression decreased in the risedronate-treated groups (P < 0.05), especially in the OVX+RIS+EXE group. CONCLUSION: Sensory innervation of osteoporotic rat vertebrae showed increased expression of CGRP and TRPV1 in DRG neurons. Risedronate suppressed activity of CGRP-ir neurons in vitro, improved BMD, and decreased CGRP expression, especially together with exercise in vivo. PMID- 20959779 TI - Pathomechanisms of sciatica in lumbar disc herniation: effect of periradicular adhesive tissue on electrophysiological values by an intraoperative straight leg raising test. AB - STUDY DESIGN: This study is aimed to investigate the changes of nerve root functions during the straight leg raising (SLR) test in vivo. OBJECTIVE: To investigate the relationship between nerve root movement and the electrophysiological values during an intraoperative SLR test. SUMMARY OF BACKGROUND DATA: The SLR test is one of the most significant signs for making a clinical diagnosis of lumbar disc herniation. A recent study showed that intraradicular blood flow apparently decreased during the SLR test in patients with disc herniation. METHODS: The study included 32 patients who underwent microdiscectomy. During the surgery, the nerve root motion affected by the hernia was observed during the SLR test. The patients' legs were allowed to hang down to the angle at which sciatica had occurred and the change of nerve root action potentials was measured. After removal of the hernia, a similar procedure was repeated. The periradicular specimens collected during surgery were examined by light and electron microscope. RESULTS: In all patients intraoperative microscopy revealed that the hernia was adherent to the dura mater of the nerve roots. During the SLR test, the limitation of nerve root movement occurred by periradicular adhesive tissue and amplitude of action potential showed a sharp decrease at the angle that produced sciatica. After removal of the hernia, all the patients showed smooth gliding of the nerve roots during the test, and there was no marked decrease of amplitude. Our data suggest that temporary ischemic changes in the nerve root cause transient conduction disturbances. Pathologic examination showed that the periradicular tissue consisted of the granulation with vascularization and many inflammatory cell infiltrations. CONCLUSION: The presence of periradicular fibrosis will compound the nerve root pain by fixing the nerve in one position, thereby increasing the susceptibility of the nerve root to tension or compression. PMID- 20959780 TI - Different arm positions and the shape of the thoracic spine can explain contradictory results in the literature about spinal loads for sitting and standing. AB - STUDY DESIGN: Loads acting in vivo on a vertebral body replacement (VBR) and the shape of the back were measured. OBJECTIVE: To find an explanation for the contradictory results in literature regarding spinal loads for sitting and standing. SUMMARY OF BACKGROUND DATA: In several in vivo studies, the intradiscal pressure was shown to be higher for sitting than for standing. However, stadiometric measurements, load measurements on internal spinal fixators, and 1 study on intradiscal pressure have shown contradictory results. It therefore remains unknown whether sitting or standing causes greater loading on the spine. METHODS: Telemeterized VBR was implanted into 5 patients. Implant loads were measured in several sessions during standing and during relaxed sitting on a stool. In the sitting position, the subjects' arms were either hanging at their sides or placed on their thighs. The shape of the back during sitting and standing was additionally determined by rasterstereography. RESULTS: When sitting with their arms hanging, the loads for the 5 patients ranged from 107% to 228% of the values for standing. A relationship was found between this sit-to-stand load ratio and both the kyphosis angles, which increased from 41 degrees to 67 degrees , and the distance between vertebra prominens and lordosis apex related to the body height, which increased from 0.21 to 0.26. By placing the arms on the thighs, the force on the VBR was reduced by an average of 13% (2%-41%), when compared to sitting with the arms hanging at the sides. CONCLUSION: The spinal load differences between sitting and standing depend on several key factors, most notably arm position and individual spinal shape. These 2 parameters, however, varied between studies in the literature and may therefore account for the continued contradictory discussion. Patients can reduce their spinal load during sitting by supporting the upper body by the arms. PMID- 20959781 TI - Dexmedetomidine-related atrial standstill and loss of capture in a pediatric patient after congenital heart surgery. AB - OBJECTIVE: Dexmedetomidine (DEX; Precedex) is an alpha-2 adrenergic receptor agonist that produces anxiolysis and sleep-like sedation without narcosis or respiratory depression and has relatively few cardiovascular side effects. Given its favorable sedative properties combined with its limited effects on hemodynamic and respiratory function, it is widely used in pediatric intensive care and anesthesia settings. DESIGN: Case report. SETTING: Pediatric intensive care unit. PATIENT: A three-yr-old girl was admitted after mitral valve replacement for persistent severe mitral insufficiency. Her prior history was significant for tetralogy of Fallot which was repaired at nine months of age. A year later the patient developed mitral and tricuspid valve insufficiency and subsequently underwent mitral and tricuspid valve repair, pulmonary valve replacement, and a maze procedure (the latter was performed for persistent atrial flutter). Following that operation she developed sinus node dysfunction and had a permanent epicardial dual-chamber pacemaker implanted. Due to remaining severe mitral insufficiency the patient had increasing pulmonary symptoms, necessitating the most recent surgery to replace her mitral valve. INTERVENTIONS: On postoperative day two the patient was hemodynamically stable and weaning off mechanical ventilation. Tracheal extubation was anticipated to occur within the next 24 hrs. A DEX infusion of 0.6 mcg/kg/hr was initiated. A pacemaker interrogation performed on postoperative day three, 21 hrs after the initiation of DEX, revealed unsuccessful atrial capture. MEASUREMENTS AND MAIN RESULTS: Dexmedetomidine was subsequently discontinued and the patient's pacemaker was reinterrogated. The interrogation findings were similar to those seen prior to the initiation of DEX. CONCLUSION: As a result of these findings, caution is warranted in the administration of DEX to patients with predisposing conduction abnormalities and patients who are pacemaker-dependent. PMID- 20959782 TI - Performance of an automated electronic acute lung injury screening system in intensive care unit patients. AB - OBJECTIVE: Lung protective ventilation reduces mortality in patients with acute lung injury, but underrecognition of acute lung injury has limited its use. We recently validated an automated electronic acute lung injury surveillance system in patients with major trauma in a single intensive care unit. In this study, we assessed the system's performance as a prospective acute lung injury screening tool in a diverse population of intensive care unit patients. DESIGN: Patients were screened prospectively for acute lung injury over 21 wks by the automated system and by an experienced research coordinator who manually screened subjects for enrollment in Acute Respiratory Distress Syndrome Clinical Trials Network (ARDSNet) trials. Performance of the automated system was assessed by comparing its results with the manual screening process. Discordant results were adjudicated blindly by two physician reviewers. In addition, a sensitivity analysis using a range of assumptions was conducted to better estimate the system's performance. SETTING: The Hospital of the University of Pennsylvania, an academic medical center and ARDSNet center (1994-2006). PATIENTS: Intubated patients in medical and surgical intensive care units. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1270 patients screened, 84 were identified with acute lung injury (incidence of 6.6%). The automated screening system had a sensitivity of 97.6% (95% confidence interval, 96.8-98.4%) and a specificity of 97.6% (95% confidence interval, 96.8-98.4%). The manual screening algorithm had a sensitivity of 57.1% (95% confidence interval, 54.5-59.8%) and a specificity of 99.7% (95% confidence interval, 99.4-100%). Sensitivity analysis demonstrated a range for sensitivity of 75.0-97.6% of the automated system under varying assumptions. Under all assumptions, the automated system demonstrated higher sensitivity than and comparable specificity to the manual screening method. CONCLUSIONS: An automated electronic system identified patients with acute lung injury with high sensitivity and specificity in diverse intensive care units of a large academic medical center. Further studies are needed to evaluate the effect of automated prompts that such a system can initiate on the use of lung protective ventilation in patients with acute lung injury. PMID- 20959783 TI - Diagnosing delirium in critically ill children: Validity and reliability of the Pediatric Confusion Assessment Method for the Intensive Care Unit. AB - OBJECTIVE: To validate a diagnostic instrument for pediatric delirium in critically ill children, both ventilated and nonventilated, that uses standardized, developmentally appropriate measurements. DESIGN AND SETTING: A prospective observational cohort study investigating the Pediatric Confusion Assessment Method for Intensive Care Unit (pCAM-ICU) patients in the pediatric medical, surgical, and cardiac intensive care unit of a university-based medical center. PATIENTS: A total of 68 pediatric critically ill patients, at least 5 years of age, were enrolled from July 1, 2008, to March 30, 2009. INTERVENTIONS: None. MEASUREMENTS: Criterion validity including sensitivity and specificity and interrater reliability were determined using daily delirium assessments with the pCAM-ICU by two critical care clinicians compared with delirium diagnosis by pediatric psychiatrists using Diagnostic and Statistical Manual, 4th Edition, Text Revision criteria. RESULTS: A total of 146 paired assessments were completed among 68 enrolled patients with a mean age of 12.2 yrs. Compared with the reference standard for diagnosing delirium, the pCAM-ICU demonstrated a sensitivity of 83% (95% confidence interval, 66-93%), a specificity of 99% (95% confidence interval, 95-100%), and a high interrater reliability (kappa = 0.96; 95% confidence interval, 0.74-1.0). CONCLUSIONS: The pCAM-ICU is a highly valid reliable instrument for the diagnosis of pediatric delirium in critically ill children chronologically and developmentally at least 5 yrs of age. Use of the pCAM-ICU may expedite diagnosis and consultation with neuropsychiatry specialists for treatment of pediatric delirium. In addition, the pCAM-ICU may provide a means for delirium monitoring in future epidemiologic and interventional studies in critically ill children. PMID- 20959784 TI - Influence of mild therapeutic hypothermia after cardiac arrest on hospital mortality. AB - OBJECTIVE: Following two randomized controlled trials that demonstrated reduced mortality and better neurological outcome in cardiac arrest patients, mild therapeutic hypothermia was implemented in many intensive care units. Up to now, no large observational studies have confirmed the beneficial effects of mild therapeutic hypothermia. DESIGN: Internet-based survey combined with a retrospective, observational study. PATIENTS: All patients admitted to an intensive care unit in The Netherlands after cardiac arrest from January 1, 1999 until January 1, 2009. DATA SOURCE: Dutch National Intensive Care Evaluation database. METHODS: The moment of implementation of mild therapeutic hypothermia for each hospital participating in the Dutch National Intensive Care Evaluation database was determined with an Internet survey. To compare mortality before and after implementation of mild therapeutic hypothermia, the odds ratio adjusted for Simplified Acute Physiology Score II score, age, gender, propensity score, and in or out-of-hospital cardiac arrest was calculated. Patients were excluded if 1) they were admitted to an intensive care unit that did not respond to the survey, 2) they were admitted within 3 months after implementation of mild therapeutic hypothermia, 3) they had a Glasgow Coma Scale score of >8, or 4) they did not satisfy the Simplified Acute Physiology Score II inclusion criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 13,962 patients were admitted to an intensive care unit following cardiac arrest. In total 8,645 patients were excluded, 5,544 because of a Glasgow Coma Scale score of >8. Of the resultant 5,317 patients, 1,547 patients were treated before and 3,770 patients after implementation of mild therapeutic hypothermia. Patients admitted after implementation of mild therapeutic hypothermia had lower minimal and maximal temperatures (p < .0001) during the first 24 hrs on the intensive care unit compared to patients admitted before implementation of mild therapeutic hypothermia. The adjusted odds ratio of the hospital mortality of patients treated after implementation of mild therapeutic hypothermia was 0.80 (95% confidence interval of 0.65-0.98, p = .029). CONCLUSION: The results of this retrospective, observational survey suggest that implementation of mild therapeutic hypothermia in Dutch intensive care units is associated with a 20% relative reduction of hospital mortality in cardiac arrest patients. PMID- 20959785 TI - Antiarrhythmic drug therapy for sustained ventricular arrhythmias complicating acute myocardial infarction. AB - OBJECTIVE: Few data exist to guide antiarrhythmic drug therapy for sustained ventricular tachycardia/ventricular fibrillation after acute myocardial infarction. The objective of this analysis was to describe the survival of patients with sustained ventricular tachycardia/ventricular fibrillation after myocardial infarction according to antiarrhythmic drug treatment. DESIGN AND SETTING: We conducted a retrospective analysis of ST-segment elevation myocardial infarction patients with sustained ventricular tachycardia/ventricular fibrillation in Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO) IIB and GUSTO III and compared all-cause death in patients receiving amiodarone, lidocaine, or no antiarrhythmic. We used Cox proportional-hazards modeling and inverse weighted estimators to adjust for baseline characteristics, beta-blocker use, and propensity to receive antiarrhythmics. Due to nonproportional hazards for death in early follow-up (0-3 hrs after sustained ventricular tachycardia/ventricular fibrillation) compared with later follow-up (>3 hrs), we analyzed all-cause mortality using time specific hazards. PATIENTS AND INTERVENTIONS: Among 19,190 acute myocardial infarction patients, 1,126 (5.9%) developed sustained ventricular tachycardia/ventricular fibrillation and met the inclusion criteria. Patients received lidocaine (n = 664, 59.0%), amiodarone (n = 50, 4.4%), both (n = 110, 9.8%), or no antiarrhythmic (n = 302, 26.8%). RESULTS: In the first 3 hrs after ventricular tachycardia/ventricular fibrillation, amiodarone (adjusted hazard ratio 0.39, 95% confidence interval 0.21-0.71) and lidocaine (adjusted hazard ratio 0.72, 95% confidence interval 0.53-0.96) were associated with a lower hazard of death-likely evidence of survivor bias. Among patients who survived 3 hrs, amiodarone was associated with increased mortality at 30 days (adjusted hazard ratio 1.71, 95% confidence interval 1.02-2.86) and 6 months (adjusted hazard ratio 1.96, 95% confidence interval 1.21-3.16), but lidocaine was not at 30 days (adjusted hazard ratio 1.19, 95% confidence interval 0.77-1.82) or 6 months (adjusted hazard ratio 1.10, 95% confidence interval 0.73-1.66). CONCLUSION: Among patients with acute myocardial infarction complicated by sustained ventricular tachycardia/ventricular fibrillation who survive 3 hrs, amiodarone, but not lidocaine, is associated with an increased risk of death, reinforcing the need for randomized trials in this population. PMID- 20959786 TI - Long-term complications of critical care. AB - OBJECTIVES: As critical care advances and intensive care unit mortality declines, the number of survivors of critical illness is increasing. These survivors frequently experience long-lasting complications of critical care. As a result, it is important to understand these complications and implement evidence-based practices to minimize them. DATA SOURCES: Database searches and review of relevant medical literature. DATA SYNTHESIS: Critical illness and intensive care unit care influence a wide range of long-term patient outcomes, with some impairments persisting for 5-15 yrs. Impaired pulmonary function, greater healthcare utilization, and increased mortality are observed in intensive care survivors. Neuromuscular weakness and impairments in both physical function and related aspects of quality of life are common and may be long-lasting. These complications may be reduced by multidisciplinary physical rehabilitation initiated early and continued throughout the intensive care unit care stay and by providing patient education for self-rehabilitation after hospital discharge. Common neuropsychiatric complications, including cognitive impairment and symptoms of depression and posttraumatic stress disorder, are frequently associated with intensive care unit sedation, delirium or delusional memories, and long-term impairments in quality of life. CONCLUSIONS: Survivors of critical illness are frequently left with a legacy of long-term physical, neuropsychiatric, and quality of life impairments. Understanding patient and intensive care risk factors can help identify patients who are most at risk of these complications. Furthermore, modifiable risk factors and beneficial interventions are increasingly being identified to help inform practical management recommendations to reduce the prevalence and impact of these long-term complications. PMID- 20959787 TI - Extracorporeal membrane oxygenation for pediatric respiratory failure: Survival and predictors of mortality. AB - OBJECTIVE: The last multicentered analysis of extracorporeal membrane oxygenation in pediatric acute respiratory failure was completed in 1993. We reviewed recent international data to evaluate survival and predictors of mortality. DESIGN: Retrospective case series review. SETTING: The Extracorporeal Life Support Organization Registry, which includes data voluntarily submitted from over 115 centers worldwide, was queried. The work was completed at the Division of Pediatric Critical Care, Department of Pediatrics, Primary Children's Medical Center, University of Utah, Salt Lake City, UT. SUBJECTS: Patients aged 1 month to 18 yrs supported with extracorporeal membrane oxygenation for acute respiratory failure from 1993 to 2007. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 3,213 children studied. Overall survival remained relatively unchanged over time at 57%. Considerable variability in survival was found based on pulmonary diagnosis, ranging from 83% for status asthmaticus to 39% for pertussis. Comorbidities significantly decreased survival to 33% for those with renal failure (n = 329), 16% with liver failure (n = 51), and 5% with hematopoietic stem cell transplantation (n = 22). The proportion of patients with comorbidities increased from 19% during 1993 to 47% in 2007. Clinical factors associated with mortality included precannulation ventilatory support longer than 2 wks and lower precannulation blood pH. CONCLUSIONS: Although the survival of pediatric patients with acute respiratory failure treated with extracorporeal membrane oxygenation has not changed, this treatment is currently offered to increasingly medically complex patients. Mechanical ventilation in excess of 2 wks before the initiation of extracorporeal membrane oxygenation is associated with decreased survival. PMID- 20959788 TI - Limiting ventilator-induced lung injury through individual electronic medical record surveillance. AB - BACKGROUND: To improve the safety of ventilator care and decrease the risk of ventilator-induced lung injury, we designed and tested an electronic algorithm that incorporates patient characteristics and ventilator settings, allowing near real-time notification of bedside providers about potentially injurious ventilator settings. METHODS: Electronic medical records of consecutive patients who received invasive ventilation were screened in three Mayo Clinic Rochester intensive care units. The computer system alerted bedside providers via the text paging notification about potentially injurious ventilator settings. Alert criteria included a Pao2/Fio2 ratio of <300 mm Hg, free text search for the words "edema" or "bilateral + infiltrates" on the chest radiograph report, a tidal volume of >8 mL/kg predicted body weight (based on patient gender and height), a plateau pressure of >30 cm H2O, and a peak airway pressure of >35 cm H2O. Respiratory therapists answered a brief online satisfaction survey. Ventilator induced lung injury risk was compared before and after the introduction of ventilator-induced lung injury alert. FINDINGS: The prevalence of acute lung injury was 42% (n = 490) among 1,159 patients receiving >24 hrs of invasive ventilation. The system sent 111 alerts for 80 patients, with a positive predictive value of 59%. The exposure to potentially injurious ventilation decreased after the intervention from 40.6 +/- 74.6 hrs to 26.9 +/- 77.3 hrs (p = .004). INTERPRETATIONS: Electronic medical record surveillance of mechanically ventilated patients accurately detects potentially injurious ventilator settings and is able to influence bedside practice at moderate costs. Its implementation is associated with decreased patient exposure to potentially injurious mechanical ventilation settings. PMID- 20959789 TI - Adverse events and their relation to mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia. AB - OBJECTIVES: To investigate the association between adverse events recorded during critical care and mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia. DESIGN: Prospective, observational, registry-based study. SETTING: Twenty-two hospitals in Europe and the United States. PATIENTS: Between October 2004 and October 2008, 765 patients were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Arrhythmias (7%-14%), pneumonia (48%), metabolic and electrolyte disorders (5%-37%), and seizures (24%) were common adverse events in the critical care period in cardiac arrest patients treated with therapeutic hypothermia, whereas sepsis (4%) and bleeding (6%) were less frequent. Sustained hyperglycemia (blood glucose >8 mmol/L for >4 hrs; odds ratio 2.3, 95% confidence interval 1.6-3.6, p < .001) and seizures treated with anticonvulsants (odds ratio 4.8, 95% confidence interval 2.9-8.1, p < .001) were associated with increased mortality in a multivariate model. An increased frequency of bleeding and sepsis occurred after invasive procedures (coronary angiography, intravascular devices for cooling, intra-aortic balloon pump), but bleeding and sepsis were not associated with increased mortality (odds ratio 1.0, 95% confidence interval 0.46-2.2, p = .91, and odds ratio 0.30, 95% confidence interval 0.12-0.79, p = .01, respectively). CONCLUSIONS: Adverse events were common after out-of-hospital cardiac arrest. Sustained hyperglycemia and seizures treated with anticonvulsants were associated with increased mortality. Bleeding and infection were more common after invasive procedures, but these adverse events were not associated with increased mortality in our study. PMID- 20959795 TI - The beneficial effect of vanillic acid on ulcerative colitis. AB - Vanillic acid, an oxidized form of vanillin, is a benzoic acid derivative used as a flavoring agent. The objective of this study was to determine whether vanillic acid has beneficial effects against dextran sulfate sodium (DSS)-induced ulcerative colitis. Our results showed that vanillic acid reduced the severity of the clinical signs of DSS-induced colitis, including weight loss and shortening of colon length, and the disease activity index. The results of this study showed that vanillic acid significantly suppressed the expression of cyclooxygenase-2 and the activation of transcription nuclear factor-kappaB p65 in DSS-treated colon tissues. In addition, we observed that the plasma levels of interleukin (IL)-6 were higher in the DSS-treated group than in the control group, but these increased levels were reduced by the administration of vanillic acid. Taken together, these findings suggest that vanillic acid has a beneficial effect on DSS-induced ulcerative colitis, thereby indicating its usefulness in the regulation of chronic intestinal inflammation. PMID- 20959796 TI - Reduce, refine, replace. AB - The European Union has passed new laws for the protection of laboratory animals according to the 'three Rs' concept. PMID- 20959797 TI - IL-1 family nomenclature. PMID- 20959798 TI - A model for harmonizing flow cytometry in clinical trials. AB - Complexities in sample handling, instrument setup and data analysis are barriers to the effective use of flow cytometry to monitor immunological parameters in clinical trials. The novel use of a central laboratory may help mitigate these issues. PMID- 20959799 TI - Host DNase TREX1 hides HIV from DNA sensors. PMID- 20959800 TI - A novel axis of innate immunity in cancer. PMID- 20959801 TI - Outfoxing Foxo1 with miR-182. PMID- 20959802 TI - PYHIN proteins: center stage in DNA sensing. PMID- 20959804 TI - B cell follicles and antigen encounters of the third kind. AB - Defining where and in what form lymphocytes encounter antigen is fundamental to understanding how immune responses occur. Although knowledge of the recognition of antigen by CD4(+) and CD8(+) T cells has advanced greatly, understanding of the dynamics of B cell-antigen encounters has lagged. With the application of advanced imaging approaches, encounters of this third kind are now being brought into focus. Multiple processes facilitate these encounters, from the filtering functions of lymphoid tissues and migration paths of B cells to the antigen presenting properties of macrophages and follicular dendritic cells. This Review will discuss how these factors work together in the lymph node to ensure efficient and persistent exposure of B cells to diverse forms of antigen and thus effective triggering of the humoral response. PMID- 20959805 TI - Tyrosine dephosphorylation is required for Bak activation in apoptosis. AB - Activation of the cell-death mediator Bak commits a cell to mitochondrial apoptosis. The initial steps that govern Bak activation are poorly understood. To further clarify these pivotal events, we have investigated whether post translational modifications of Bak impinge on its activation potential. In this study, we report that on apoptotic stimulation Bak undergoes dephosphorylation at tyrosine residue 108 (Y108), a critical event that is necessary but not sufficient for Bak activation, but is required both for early exposure of the occluded N-terminal domain and multimerisation. RNA interference (RNAi) screening identified non-receptor tyrosine phosphatases (PTPNs) required for Bak dephosphorylation and apoptotic induction through chemotherapeutic agents. Specifically, modulation of PTPN5 protein expression by siRNA and overexpression directly affected both Bak-Y108 phosphorylation and the initiation of Bak activation. We further show that MEK/ERK signalling directly affects Bak phosphorylation through inhibition of PTPN5 to promote cell survival. We propose a model of Bak activation in which the regulation of Bak dephosphorylation constitutes the initial step in the activation process, which reveals a previously unsuspected mechanism controlling the initiation of mitochondrial apoptosis. PMID- 20959806 TI - Snail1 is stabilized by O-GlcNAc modification in hyperglycaemic condition. AB - Protein O-phosphorylation often occurs reciprocally with O-GlcNAc modification and represents a regulatory principle for proteins. O-phosphorylation of serine by glycogen synthase kinase-3beta on Snail1, a transcriptional repressor of E cadherin and a key regulator of the epithelial-mesenchymal transition (EMT) programme, results in its proteasomal degradation. We show that by suppressing O phosphorylation-mediated degradation, O-GlcNAc at serine112 stabilizes Snail1 and thus increases its repressor function, which in turn attenuates E-cadherin mRNA expression. Hyperglycaemic condition enhances O-GlcNAc modification and initiates EMT by transcriptional suppression of E-cadherin through Snail1. Thus, dynamic reciprocal O-phosphorylation and O-GlcNAc modification of Snail1 constitute a molecular link between cellular glucose metabolism and the control of EMT. PMID- 20959808 TI - Polypeptide in the chaperonin cage partly protrudes out and then folds inside or escapes outside. AB - The current mechanistic model of chaperonin-assisted protein folding assumes that the substrate protein in the cage, formed by GroEL central cavity capped with GroES, is isolated from outside and exists as a free polypeptide. However, using ATPase-deficient GroEL mutants that keep GroES bound, we found that, in the rate limiting intermediate of a chaperonin reaction, the unfolded polypeptide in the cage partly protrudes through a narrow space near the GroEL/GroES interface. Then, the entire polypeptide is released either into the cage or to the outside medium. The former adopts a native structure very rapidly and the latter undergoes spontaneous folding. Partition of the in-cage folding and the escape varies among substrate proteins and is affected by hydrophobic interaction between the polypeptide and GroEL cavity wall. The ATPase-active GroEL with decreased in-cage folding produced less of a native model substrate protein in Escherichia coli cells. Thus, the polypeptide in the critical GroEL-GroES complex is neither free nor completely confined in the cage, but it is interacting with GroEL's apical region, partly protruding to outside. PMID- 20959807 TI - Polymerization of MIP-1 chemokine (CCL3 and CCL4) and clearance of MIP-1 by insulin-degrading enzyme. AB - Macrophage inflammatory protein-1 (MIP-1), MIP-1alpha (CCL3) and MIP-1beta (CCL4) are chemokines crucial for immune responses towards infection and inflammation. Both MIP-1alpha and MIP-1beta form high-molecular-weight aggregates. Our crystal structures reveal that MIP-1 aggregation is a polymerization process and human MIP-1alpha and MIP-1beta form rod-shaped, double-helical polymers. Biophysical analyses and mathematical modelling show that MIP-1 reversibly forms a polydisperse distribution of rod-shaped polymers in solution. Polymerization buries receptor-binding sites of MIP-1alpha, thus depolymerization mutations enhance MIP-1alpha to arrest monocytes onto activated human endothelium. However, same depolymerization mutations render MIP-1alpha ineffective in mouse peritoneal cell recruitment. Mathematical modelling reveals that, for a long-range chemotaxis of MIP-1, polymerization could protect MIP-1 from proteases that selectively degrade monomeric MIP-1. Insulin-degrading enzyme (IDE) is identified as such a protease and decreased expression of IDE leads to elevated MIP-1 levels in microglial cells. Our structural and proteomic studies offer a molecular basis for selective degradation of MIP-1. The regulated MIP-1 polymerization and selective inactivation of MIP-1 monomers by IDE could aid in controlling the MIP 1 chemotactic gradient for immune surveillance. PMID- 20959809 TI - Nucleolin-mediated cellular trafficking of DNA nanoparticle is lipid raft and microtubule dependent and can be modulated by glucocorticoid. AB - DNA nanoparticles (DNPs) are nonviral gene transfer vectors with excellent in vivo potential. Previously, we reported that cell surface nucleolin directly binds DNPs, and functions as an important receptor for DNPs. However, the fate of the nucleolin-DNP complex following cellular uptake remains elusive. In this study, we examined the role of lipid rafts in the uptake of DNPs, and found that both nucleolin and DNPs are recovered from the low-density raft fractions of the sucrose gradient. Furthermore, nucleolin colocalizes with, and coimmunoprecipitates with a raft protein, flotillin. Disruption of lipid rafts by depleting membrane cholesterol significantly inhibited DNP transfection, while inhibition of other endocytic pathways had little effect. Following the uptake, the nuclear import of the DNPs required microtubules but not F-actin. By coimmunoprecipitation in conjunction with tandem mass spectrometry, we identified glucocorticoid receptor (GCR) as a nucleolin-associated protein, and confirmed this result by western blot. Cortisone or dexamethasone increased nucleolin's association with GCR, and transfection by DNPs. Finally, we detected the expression of nucleolin on the surface of airway epithelia in vivo. Taken together, our findings shed light on important determinants of DNP trafficking in cells and support the notion that nucleolin is a good target for nonviral gene delivery. PMID- 20959810 TI - VSV oncolytic virotherapy in the B16 model depends upon intact MyD88 signaling. AB - We show here, for the first time to our knowledge, that the antitumor therapy of oncolytic vesicular stomatitis virus (VSV) in the B16ova model depends upon signaling through myeloid differentiation primary response gene 88 (MyD88) in host cells. VSV-mediated therapy of B16ova tumors was abolished in MyD88(-/-) mice despite generation of antigen-specific T cell responses similar to those in immune-competent mice. Mice defective in only toll-like receptor 4 (TLR4), TLR7, or interleukin 1 (IL-1) signaling retained VSV-induced therapy, suggesting that multiple, redundant pathways of innate immune activation by the virus contribute to antitumor immune reactivity. Lack of MyD88 signaling was associated with decreased expression of proinflammatory cytokines and neutrophil infiltration in response to intratumoral virus, as well as decreased infiltration of draining lymph nodes (LN) with plasmacytoid dendritic cells (pDCs) (CD11b(-)GR1(+)B220(+)) and myeloid-derived suppressor cells (CD11b(+)GR1(+)F4/80(+)). MyD88 signaling in response to VSV was also closely associated with a type I interferon (IFN) response. This inhibited virus replication within the tumor but also protected the host from viral dissemination from the tumor. Therefore, the innate immune response to oncolytic viruses can be, simultaneously, protherapeutic, antioncolytic, and systemically protective. These paradoxically conflicting roles need to be carefully considered in future strategies designed to improve the efficacy of oncolytic virotherapy. PMID- 20959811 TI - Modifications of adenovirus hexon allow for either hepatocyte detargeting or targeting with potential evasion from Kupffer cells. AB - In vivo gene transfer with adenovirus vectors would significantly benefit from a tight control of the adenovirus-inherent liver tropism. For efficient hepatocyte transduction, adenovirus vectors need to evade from Kupffer cell scavenging while delivery to peripheral tissues or tumors could be improved if both scavenging by Kupffer cells and uptake by hepatocytes were blocked. Here, we provide evidence that a single point mutation in the hexon capsomere designed to enable defined chemical capsid modifications may permit both detargeting from and targeting to hepatocytes with evasion from Kupffer cell scavenging. Vector particles modified with small polyethylene glycol (PEG) moieties specifically on hexon exhibited decreased transduction of hepatocytes by shielding from blood coagulation factor binding. Vector particles modified with transferrin or, surprisingly, 5,000 Da PEG or dextran increased hepatocyte transduction up to 18-fold independent of the presence of Kupffer cells. We further show that our strategy can be used to target high-capacity adenovirus vectors to hepatocytes emphasizing the potential for therapeutic liver-directed gene transfer. Our approach may lead to a detailed understanding of the interactions between adenovirus vectors and Kupffer cells, one of the most important barriers for adenovirus-mediated gene delivery. PMID- 20959812 TI - Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder typified by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Recent evidence indicates that neuroinflammation may play a critical role in the pathogenesis of PD, particularly tumor necrosis factor (TNF). We have previously shown that soluble TNF (solTNF) is required to mediate robust degeneration induced by 6-hydroxydopamine (6-OHDA) or lipopolysaccharide. What remains unknown is whether TNF inhibition can attenuate the delayed and progressive phase of neurodegeneration. To test this, rats were injected in the SNpc with lentivirus encoding dominant-negative TNF (lenti-DN-TNF) 2 weeks after receiving a 6-OHDA lesion. Remarkably, when examined 5 weeks after the initial 6 OHDA lesion, no further loss of nigral DA neurons was observed. Lenti-DN-TNF also attenuated microglial activation. Together, these data suggest that TNF is likely a critical mediator of nigral DA neuron death during the delayed and progressive phase of neurodegeneration, and that microglia may be the principal cell type involved. These promising findings provide compelling reasons to perform DN-TNF gene transfer studies in nonhuman primates with the long-term goal of using it in the clinic to prevent the delayed and progressive degeneration of DA neurons that gives rise to motor symptoms in PD. PMID- 20959813 TI - Intranasal DNA vaccination induces potent mucosal and systemic immune responses and cross-protective immunity against influenza viruses. AB - The induction of potent virus-specific immune responses at mucosal surfaces where virus transmission occurs is a major challenge for vaccination strategies. In the case of influenza vaccination, this has been achieved only by intranasal delivery of live-attenuated vaccines that otherwise pose safety problems. Here, we demonstrate that potent mucosal and systemic immune responses, both cellular and humoral, are induced by intranasal immunization using formulated DNA. We show that formulation with the DNA carrier polyethylenimine (PEI) improved by a 1,000 fold the efficiency of gene transfer in the respiratory track following intranasal administration of luciferase-coding DNA. Using PEI formulation, intranasal vaccination with DNA-encoding hemagglutinin (HA) from influenza A H5N1 or (H1N1)2009 viruses induced high levels of HA-specific immunoglobulin A (IgA) antibodies that were detected in bronchoalveolar lavages (BALs) and the serum. No mucosal responses could be detected after parenteral or intranasal immunization with naked-DNA. Furthermore, intranasal DNA vaccination with HA from a given H5N1 virus elicited full protection against the parental strain and partial cross protection against a distinct highly pathogenic H5N1 strain that could be improved by adding neuraminidase (NA) DNA plasmids. Our observations warrant further investigation of intranasal DNA as an effective vaccination route. PMID- 20959814 TI - A Th1-inducing adenoviral vaccine for boosting adoptively transferred T cells. AB - Although the benefits of adoptive T-cell therapy can be increased by prior lymphodepletion of the recipient, this process usually requires chemotherapy or radiation. Vaccination with antigens to which the transferred T cells respond should be a less toxic means of enhancing their activity, but to date such vaccines have not been effective. We, therefore, determined which characteristics an adenoviral vaccine has to fulfill to optimally activate and expand adoptively transferred antigen-specific T cells in vivo. We evaluated (i) antigen, (ii) flagellin, a Toll-like receptor (TLR) 5 ligand, and (iii) an inhibitor of the antigen-presenting attenuator A20. Vaccination of mice before T-cell transfer with a vaccine that contained all three components dramatically enhanced the effector function of ovalbumin (OVA)-specific T cells as judged by the regression of established B16-OVA tumors compared to one- and two-component vaccines. Immunization with the three-component vaccine induced a strong Th1 environment, which was critical for the observed synergy and proved as effective as cytoxan induced lymphodepletion in enhancing in vivo T-cell expansion. Thus, the combination of our vaccine with T-cell therapy has the potential to enhance and broaden adoptive cellular immunotherapy. PMID- 20959815 TI - NOD2 gene polymorphism rs2066844 associates with need for combined liver intestine transplantation in children with short-gut syndrome. AB - OBJECTIVES: The nucleotide-binding oligomerization protein 2 (NOD2) gene single nucleotide polymorphisms (SNPs) associated with Crohn's disease were recently associated with severe rejection after small-bowel transplantation (SBTx). The purpose of this study was to re-test this association and explore whether deficient innate immunity suggested by the NOD2 SNPs predisposes to intestine failure requiring isolated SBTx or combined liver-intestine failure requiring combined liver-SBTx (LSBTx). METHODS: Archived DNA from 85 children with primary isolated SBTx or LSBTx was genotyped with Taqman biallelic discrimination assays. To minimize confounding effects of racial differences in minor allele frequencies (MAFs), allelic associations were tested in 60 Caucasian recipients (discovery cohort). Replication was sought in an independent cohort of 39 Caucasian pediatric and adult SBTx patients. RESULTS: MAF for rs2066845 and rs2066847 was similar to that seen in 538 healthy North American Caucasians. In the discovery cohort, MAF for rs2066844 was significantly higher in LSBTx (13.5 vs. 3.6%, P=0.0007, Fisher's exact test), but not in isolated SBTx recipients (2.2 vs. 3.6%, P=NS), when compared with 538 healthy Caucasians. In addition, among LSBTx recipients who received identical immunosuppression, the minor allele of rs2066844 associated with early rejection in linear regression analysis (P=0.028) (all but one of the risk alleles were found in rejectors), decreased survival (P=0.015, log-rank, Kaplan-Meier analysis), and a 20-fold greater hazard of septic death in proportional hazard analysis (P=0.030). Steroid-resistant (severe) rejection and graft loss were associated with isolated SBTx (P=0.036 and 0.082, respectively), but not with NOD2 SNPs. The association between rs2066844 and combined liver-intestine failure requiring LSBTx was significant in the replication cohort (P=0.014), and achieved greater significance in the combined cohort (P=0.00006). CONCLUSIONS: The NOD2 SNP rs2066844 associates with combined liver and intestinal failure in subjects with short-gut syndrome, who require combined liver-intestine transplantation, and secondarily with early rejection and septic deaths. PMID- 20959816 TI - Sensitivity estimates of blood-based tests for colorectal cancer detection: impact of overrepresentation of advanced stage disease. AB - A large number of blood-based markers have been proposed for early detection of colorectal cancer (CRC). Their sensitivity for detecting CRC has mostly been evaluated in clinical settings, and found to be higher in more advanced stages compared with earlier stages of the disease. The aim of this study is to estimate the overall sensitivity of blood-based markers expected in screening settings, where the proportion of advanced stages is typically lower than in clinical settings. A systematic literature review was performed on studies evaluating sensitivity and specificity of blood-based markers for early detection of CRC. For each study, overall sensitivity expected in screening settings was estimated by weighting stage-specific sensitivities according to the stage distribution of CRC expected in the screening setting. The latter was derived from 12,605 CRC cases diagnosed in the German screening colonoscopy program during 2003-2007. Overall, 73 studies evaluating 55 blood-based markers were identified. Adjusted sensitivity was lower than reported sensitivity in 120 (90%) evaluations of different markers. Median absolute reduction in sensitivity after adjustment was 9.0% (interquartile range: 4.0-13.0) units, whereas median relative reduction was 19.5% (interquartile range: 11.3-33.3%). Blood-based markers for CRC detection reported from clinical settings showed higher sensitivities than expected in the screening setting in most cases, mainly due to substantially higher proportions of advanced stage cancers. Adjustment of sensitivity to the stage distribution expected in the screening setting is crucial to obtain realistic and comparable estimates of sensitivities. PMID- 20959817 TI - Association between the various mutations in viral core promoter region to different stages of hepatitis B, ranging of asymptomatic carrier state to hepatocellular carcinoma. AB - OBJECTIVES: The objective of this study was to determine the association of 19 mutations with frequencies >= 10% in the core promoter region of hepatitis B virus (HBV) with chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma (HCC). METHODS: Eight hundred forty-six asymptomatic hepatitis B surface antigen carriers (ASCs), 235 CHB patients, 188 cirrhosis patients, and 190 HCC patients with intact data of HBV genotyping, DNA sequencing, and serological parameters were studied. Nucleotides with the highest frequencies in HBV genotypes B and C from all ASCs were treated as wild-type nucleotides. RESULTS: Mutations at nt.1674, nt.1719, nt.1762, nt.1764, nt.1846, nt.1896, and nt.1913 in genotype C were significantly associated with CHB, cirrhosis, and HCC, as compared with ASCs. C1673T, A1726C, A1727T, C1730G, C1766T, T1768A, C1773T, and C1799G in genotype C were significantly associated with cirrhosis compared with the CHB patients, whereas these mutations were inversely associated with HCC compared with the cirrhosis patients. Multivariate regression analyses showed that age, male, abnormal alanine aminotransferase (ALT), T1768A, A1762T/G1764A, and A1846T were independently associated with cirrhosis compared with ASCs and the patients with CHB. Age, abnormal ALT, HBV DNA (>=10(4) copies/ml), genotype C, C1653T, T1674C/G, T1753V, and A1762T/G1764A were independently associated with HCC compared with those without HCC. Haplotypic carriages with two or more HBV mutations were significantly associated with HCC. T1674C/G, C1653T, and T1753V were specific for HCC. A1762T/G1764A had a moderate sensitivity and specificity for HCC. CONCLUSIONS: C1673T, A1726C, A1727T, C1730G, C1766T, T1768A, C1773T, and C1799G in genotype C are specific for cirrhosis. A1846T and T1674C/G are novel factors independently associated with cirrhosis and HCC, respectively. PMID- 20959818 TI - Epistatic relationships reveal the functional organization of yeast transcription factors. AB - The regulation of gene expression is, in large part, mediated by interplay between the general transcription factors (GTFs) that function to bring about the expression of many genes and site-specific DNA-binding transcription factors (STFs). Here, quantitative genetic profiling using the epistatic miniarray profile (E-MAP) approach allowed us to measure 48 391 pairwise genetic interactions, both negative (aggravating) and positive (alleviating), between and among genes encoding STFs and GTFs in Saccharomyces cerevisiae. This allowed us to both reconstruct regulatory models for specific subsets of transcription factors and identify global epistatic patterns. Overall, there was a much stronger preference for negative relative to positive genetic interactions among STFs than there was among GTFs. Negative genetic interactions, which often identify factors working in non-essential, redundant pathways, were also enriched for pairs of STFs that co-regulate similar sets of genes. Microarray analysis demonstrated that pairs of STFs that display negative genetic interactions regulate gene expression in an independent rather than coordinated manner. Collectively, these data suggest that parallel/compensating relationships between regulators, rather than linear pathways, often characterize transcriptional circuits. PMID- 20959819 TI - Impact of translational error-induced and error-free misfolding on the rate of protein evolution. AB - What determines the rate of protein evolution is a fundamental question in biology. Recent genomic studies revealed a surprisingly strong anticorrelation between the expression level of a protein and its rate of sequence evolution. This observation is currently explained by the translational robustness hypothesis in which the toxicity of translational error-induced protein misfolding selects for higher translational robustness of more abundant proteins, which constrains sequence evolution. However, the impact of error-free protein misfolding has not been evaluated. We estimate that a non-negligible fraction of misfolded proteins are error free and demonstrate by a molecular-level evolutionary simulation that selection against protein misfolding results in a greater reduction of error-free misfolding than error-induced misfolding. Thus, an overarching protein-misfolding-avoidance hypothesis that includes both sources of misfolding is superior to the translational robustness hypothesis. We show that misfolding-minimizing amino acids are preferentially used in highly abundant yeast proteins and that these residues are evolutionarily more conserved than other residues of the same proteins. These findings provide unambiguous support to the role of protein-misfolding-avoidance in determining the rate of protein sequence evolution. PMID- 20959820 TI - Insight into human alveolar macrophage and M. tuberculosis interactions via metabolic reconstructions. AB - Metabolic coupling of Mycobacterium tuberculosis to its host is foundational to its pathogenesis. Computational genome-scale metabolic models have shown utility in integrating -omic as well as physiologic data for systemic, mechanistic analysis of metabolism. To date, integrative analysis of host-pathogen interactions using in silico mass-balanced, genome-scale models has not been performed. We, therefore, constructed a cell-specific alveolar macrophage model, iAB-AMO-1410, from the global human metabolic reconstruction, Recon 1. The model successfully predicted experimentally verified ATP and nitric oxide production rates in macrophages. This model was then integrated with an M. tuberculosis H37Rv model, iNJ661, to build an integrated host-pathogen genome-scale reconstruction, iAB-AMO-1410-Mt-661. The integrated host-pathogen network enables simulation of the metabolic changes during infection. The resulting reaction activity and gene essentiality targets of the integrated model represent an altered infectious state. High-throughput data from infected macrophages were mapped onto the host-pathogen network and were able to describe three distinct pathological states. Integrated host-pathogen reconstructions thus form a foundation upon which understanding the biology and pathophysiology of infections can be developed. PMID- 20959821 TI - Molecular characterization of the evolution of phagosomes. AB - Amoeba use phagocytosis to internalize bacteria as a source of nutrients, whereas multicellular organisms utilize this process as a defense mechanism to kill microbes and, in vertebrates, initiate a sustained immune response. By using a large-scale approach to identify and compare the proteome and phosphoproteome of phagosomes isolated from distant organisms, and by comparative analysis over 39 taxa, we identified an 'ancient' core of phagosomal proteins around which the immune functions of this organelle have likely organized. Our data indicate that a larger proportion of the phagosome proteome, compared with the whole cell proteome, has been acquired through gene duplication at a period coinciding with the emergence of innate and adaptive immunity. Our study also characterizes in detail the acquisition of novel proteins and the significant remodeling of the phagosome phosphoproteome that contributed to modify the core constituents of this organelle in evolution. Our work thus provides the first thorough analysis of the changes that enabled the transformation of the phagosome from a phagotrophic compartment into an organelle fully competent for antigen presentation. PMID- 20959822 TI - Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. AB - BACKGROUND: We assessed the effectiveness of cetuximab plus chronomodulated irinotecan, 5-fluorouracil (5-FU), leucovorin (FA) and oxaliplatin (L-OHP) (chrono-IFLO) administered as neoadjuvant chemotherapy to increase the resectability of colorectal liver metastases. METHODS: This was a phase II prospective trial with rate of liver metastases resection as primary end point. Forty-three patients with unresectable metastases were enroled: 9 with metastases >5 cm; 29 with multinodular (>4) disease; 1 with hilar location; 4 with extrahepatic lung disease. Treatment consisted of cetuximab at day 1 plus chronomodulated irinotecan 5-FU, FA and L-OHP for 2-6 days every 2 weeks. After the first 17 patients, doses were reduced for irinotecan to 110 mg m-2, 5-FU to 550 mg m-2 per day and L-OHP to 15 mg m-2 per day. RESULTS: Macroscopically complete resections were performed in 26 out of 43 patients (60%) after a median of 6 (range 3-15) cycles. Partial response was noticed in 34 patients (79%). Median overall survival was 37 months (95% CI: 21-53 months), with a 2-year survival of 68% in the entire population, 80.6% in resected patients and 47.1% in unresected patients (P=0.01). Grade 3/4 diarrhoea occurred in 93% and 36% of patients before and after dose reduction. CONCLUSION: Cetuximab plus chrono-IFLO achieved 60% complete resectability of colorectal liver metastases. PMID- 20959823 TI - Schwann cell autophagy induced by SAHA, 17-AAG, or clonazepam can reduce bortezomib-induced peripheral neuropathy. AB - BACKGROUND: The proteasome inhibitor bortezomib has improved the survival of patients with multiple myeloma but bortezomib-induced peripheral neuropathy (BiPN) has emerged as a serious potential complication of this therapy. Animal studies suggest that bortezomib predominantly causes pathological changes in Schwann cells. A tractable system to evaluate combination drugs for use with bortezomib is essential to enable continuing clinical benefit from this drug. METHODS: Rat schwannoma cells were pretreated with vincristine (VCR), histone deacetylase inhibitors, anticonvulsants, or a heat-shock protein 90 (HSP90) inhibitor. To then monitor aggresome formation as a result of proteasome inhibition and the activation of chaperone-mediated autophagy (CMA), we performed double-labelling immunofluorescent analyses of a cellular aggregation-prone protein marker. RESULTS: Aggresome formation was interrupted by VCR, whereas combination treatments with bortezomib involving suberoylanilide hydroxamic acid, 17-allylamino-17-demethoxy-geldanamycin, or clonazepam appear to facilitate the disposal of unfolded proteins via CMA, inducing HSP70 and lysosome-associated membrane protein type 2A (LAMP-2A). CONCLUSIONS: This schwannoma model can be used to test BiPN-reducing drugs. The present data suggest that aggresome formation in Schwann cells is a possible mechanism of BiPN, and drugs that induce HSP70 or LAMP-2A have the potential to alleviate this complication. Combination clinical trials are warranted to confirm the relevance of these observations. PMID- 20959824 TI - Molecular imaging of glioblastoma multiforme using anti-insulin-like growth factor-binding protein-7 single-domain antibodies. AB - BACKGROUND: Insulin-like growth factor-binding protein 7 (IGFBP7) is an abundant, selective and accessible biomarker of glioblastoma multiforme (GBM) tumour vessels. In this study, an anti-IGFBP7 single-domain antibody (sdAb) was developed to target GBM vessels for molecular imaging applications. METHODS: Human GBM was modelled in mice by intracranial implantation of U87MG.EGFRvIII cells. An anti-IGFBP7 sdAb, isolated from an immune llama library by panning, was assessed in vitro for its binding affinity using surface plasmon resonance and by ex vivo immunobinding on mouse and human GBM tissue. Tumour targeting by Cy5.5 labelled anti-IGFBP7 sdAb as well as by anti-IGFBP7 sdAb conjugated to PEGylated Fe3O4 nanoparticles (NPs)-Cy5.5 were assessed in U87MG.EGFRvIII tumour-bearing mice in vivo using optical imaging and in brain sections using fluorescent microscopy. RESULTS: Surface plasmon resonance analyses revealed a medium affinity (K(D)=40-50 nM) binding of the anti-IGFBP7 sdAb to the purified antigen. The anti-IGFBP7 sdAb also selectively bound to both mouse and human GBM vessels, but not normal brain vessels in tissue sections. In vivo, intravenously injected anti-IGFBP7 sdAb-Cy5.5 bound to GBM vessels creating high imaging signal in the intracranial tumour. Similarly, the anti-IGFBP7 sdAb-functionalised PEGylated Fe3O4 NP-Cy5.5 demonstrated enhanced tumour signal compared with non-targeted NPs. Fluorescent microscopy confirmed the presence of anti-IGFBP7 sdAb and anti IGFBP7 sdAb-PEGylated Fe3O4 NPs selectively in GBM vessels. CONCLUSIONS: Anti IGFBP7 sdAbs are novel GBM vessel-targeting moieties suitable for molecular imaging. PMID- 20959825 TI - Elastin-derived peptides enhance melanoma growth in vivo by upregulating the activation of Mcol-A (MMP-1) collagenase. AB - BACKGROUND: Elastin peptides possess several biological activities and in vitro data suggest they could be involved in the early phase of melanoma growth. METHODS: Using diverse in vitro and in vivo techniques (cell proliferation, invasion and migration assays, zymography, western blots, collagen degradation assay, reverse transcription PCR, melanoma allographs and immunohistochemistry), we analysed the effect of elastin-derived peptides (EDPs) on B16F1 melanoma growth and invasion, as well as on the proteolytic systems involved. RESULTS: We found that EDPs dramatically promote in vivo tumour development of B16F1 melanoma, as well as their in vitro migration and invasion. The inhibition of serine proteases and matrix metalloproteinases (MMPs) activities, by aprotinin and galardin, respectively, demonstrated that these enzymes were involved in these processes. However, we found that EDPs did not increase urokinase-type plasminogen activator, tissue-type plasminogen activator or MMP-2 expression and/or activation, neither in vitro nor in vivo. Nevertheless, we observed a strong increase of pro-MMP-9 secretion in EDPs-treated tumours and, more importantly, an increase in the expression and activation of the murine counterpart of MMP-1, named murine collagenase-A (Mcol-A). Moreover, we show that plasminogen system inhibition decreases collagen degradation by this enzyme. Finally, the use of a specific blocking antibody against Mcol-A abolished EDP induced B16F1 invasion in vitro, showing that this MMP was directly involved in this process. CONCLUSION: Our data show that in vivo, EDPs are involved in melanoma growth and invasion and reinforced the concept of elastin fragmentation as a predictive factor. PMID- 20959826 TI - KRAS mutation detection and prognostic potential in sporadic colorectal cancer using high-resolution melting analysis. AB - BACKGROUND: The development of targeted therapies has created a pressing clinical need for molecular characterisation of cancers. In this retrospective study, high resolution melting analysis (HRMA) was validated and implemented for screening of 164 colorectal cancer (CRC) patients to detect KRAS hot-spot mutations and to evaluate its prognostic value. Direct sequencing was used to confirm and characterise HRMA results. METHODS: After establishing its sensitivity, HRMA was validated on seven cell lines and inter- and intra-variation were analysed. The prognostic value of KRAS mutations in CRC was evaluated using survival analysis. RESULTS: HRMA revealed abnormal melting patterns in 34.1% CRC samples. Kaplan Meier survival curves revealed a significantly shorter overall (OS) and disease free survival (DFS) for CRC patients harbouring a KRAS mutation. In the Cox regression analysis, only when colon and rectal cancer were analysed separately, KRAS mutation was a negative predictor for OS in patients with rectal cancer and DFS in those with stage II colon cancer. CONCLUSIONS: HRMA was found to be a valid screening method for KRAS mutation detection. The KRAS mutation came forward as a negative predictive factor for OS in patients with rectal cancer and for DFS in stage II colon cancer patients. PMID- 20959827 TI - Socioeconomic position and participation in colorectal cancer screening. AB - BACKGROUND: Colorectal cancer (CRC) screening with faecal occult blood test (FOBT) has the potential to reduce the incidence and mortality of CRC. Screening uptake is known to be inferior in people with low socioeconomic position (SEP) when compared with those with high position; however, the results of most previous studies have limited value because they are based on recall or area based measures of socioeconomic position, and might thus be subject to selective participation and misclassification. In this study we investigated differences in CRC screening participation using register-based individual information on education, employment, and income to encompass different but related aspects of socioeconomic stratification. Also, the impact of ethnicity and cohabiting status was analysed. METHODS: A feasibility study on CRC screening was conducted in two Danish counties in 2005 and 2006. Screening consisted of a self-administered FOBT kit mailed to 177 114 inhabitants aged 50-74 years. Information on individual socioeconomic status was obtained from Statistics Denmark. RESULTS: A total of 85 374 (48%) of the invited returned the FOBT kits. Participation was significantly higher in women than in men (OR=1.58 (1.55-1.61)), when all socioeconomic and demographic variables were included in the statistical model. Participation also increased with increasing level of education, with OR=1.38 (1.33-1.43) in those with a higher education compared with short education. Also, participation increased with increasing income levels, with OR=1.94 (1.87-2.01) in the highest vs lowest quintile. Individuals with a disability pension, the unemployed and self-employed people were significantly less likely to participate (OR=0.77 (0.74 0.80), OR=0.83 (0.80-0.87), and OR=0.85 (0.81-0.89), respectively). Non-western immigrants were less likely to participate (OR=0.62 (0.59-0.66)) in a model controlling for age, sex, and county; however, this difference might be attributed to low SEP in these ethnic groups ((OR=0.93 (0.87-0.99), when adjusting for SEP indicators). CONCLUSION: This study based on individual information on several socioeconomic dimensions in a large, unselected population allowed for identification of several specific subgroups within the population with low CRC screening participation. Improved understanding is needed on the effect of targeted information and other strategies in order to reduce socioeconomic inequalities in screening. PMID- 20959828 TI - Human papillomavirus predicts outcome in oropharyngeal cancer in patients treated primarily with surgery or radiation therapy. AB - OBJECTIVE: This study examines the prognostic significance of human papillomavirus (HPV) in patients with locally advanced oropharyngeal squamous cell carcinoma (SCC) treated primarily with surgery or definitive radiotherapy. METHODS: One hundred and ninety-eight patients with Stage 3/4 SCC were followed up for recurrence in any form or death from any cause for between 1 and 235 months after diagnosis. HPV status was determined using HPV E6-targeted multiplex real-time PCR/p16 immunohistochemistry. Determinants of recurrence and mortality hazards were modelled using Cox's regression with censoring at follow-up dates. RESULTS: Forty-two per cent of cancers were HPV-positive (87% type 16). HPV predicted loco-regional control, event-free survival and overall survival in multivariable analysis. Within the surgery with adjuvant radiotherapy (n=110), definitive radiotherapy-alone (n=24) and definitive radiotherapy with chemotherapy (n=47) groups, patients with HPV-positive cancers were one-third or less as likely to have loco-regional recurrence, an event or to die of any cause as those with HPV-negative cancers after adjusting for age, gender, tumour grade, AJCC stage and primary site. The 14 patients treated with surgery alone were considered too few for multivariable analysis. CONCLUSION: HPV status predicts better outcome in oropharyngeal cancer treated with surgery plus adjuvant radiotherapy as well as with definitive radiation therapy+/-chemotherapy. PMID- 20959829 TI - Dietary acrylamide intake and risk of breast cancer in the UK women's cohort. AB - BACKGROUND: No studies to date have demonstrated a clear association with breast cancer risk and dietary exposure to acrylamide. METHODS: A 217-item food frequency questionnaire was used to estimate dietary acrylamide intake in 33,731 women aged 35-69 years from the UK Women's Cohort Study followed up for a median of 11 years. RESULTS: In all, 1084 incident breast cancers occurred during follow up. There was no evidence of an overall association between acrylamide intake and breast cancer (hazard ratio=1.08 per 10 MUg day(-1), 95% CI: 0.98-1.18, P(trend)=0.1). There was a suggestion of a possible weak positive association between dietary acrylamide intake and premenopausal breast cancer after adjustment for potential confounders (hazard ratio=1.2, 95% CI: 1.0-1.3, P(trend)=0.008). There was no suggestion of any association for postmenopausal breast cancer (hazard ratio=1.0, 95% CI: 0.9-1.1, P(trend)=0.99). CONCLUSIONS: There is no evidence of an association between dietary acrylamide intake and breast cancer. A weak association may exist with premenopausal breast cancer, but requires further investigation. PMID- 20959830 TI - Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor. AB - BACKGROUND: Tumoural interstitial hypertension, possibly modulated by platelet derived and vascular endothelial growth factor receptors (PDGFR and VEGFR), may mediate resistance to chemotherapy. METHODS: Forty-eight patients with advanced solid tumours received oral PDGFR inhibitor CP-868,596 (60-100 mg twice daily (BID)) and docetaxel (75-100 mg m-2), or CP-868,596 (60 mg BID), docetaxel (75 mg m-2), and VEGFR inhibitor axitinib (5 mg BID). RESULTS: The CP-868,596/docetaxel was escalated as above. The CP-868,596/docetaxel/axitinib was not dose escalated because of increased incidence of mucositis-like adverse events (AEs) with concurrent neutropenia relative to that expected for docetaxel. All tested regimens were tolerable, including 100 mg BID CP-868,596 (recommended phase II dose) plus 100 mg m-2 docetaxel (maximum approved dose). Most treatment-emergent AEs were mild-moderate and reversible, commonly including nausea, diarrhoea, vomiting, constipation, fatigue, and anaemia (CP-868,596/docetaxel), and hypertension, lethargy, diarrhoea, and fatigue (CP-868,596/docetaxel/axitnib). Pharmacokinetics were unaffected by co-administration. Twenty-one patients achieved stable disease, including all seven evaluable on CP 868,596/docetaxel/axitinib. All nine CP-868,596/docetaxel/axitinib patients received therapy for a median of six (range, 3-16) cycles. CONCLUSIONS: The CP 868,596/docetaxel was well tolerated, but increased efficacy was not observed. Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs. PMID- 20959831 TI - Anthrax: modern exposure science combats a deadly, ancient disease. PMID- 20959832 TI - Better radiation exposure estimation for the Japanese atomic-bomb survivors enables us to better protect people from radiation today. PMID- 20959833 TI - Getting the lead out: important exposure science contributions. PMID- 20959836 TI - Clinical pharmacology and viral infections. PMID- 20959840 TI - The value of vaccines: our nation's front line against infectious diseases. PMID- 20959841 TI - Clinical trials of drugs and vaccines among the desperately poor in poor nations: ethical challenges and ethical solutions. AB - Clinical research has been expanding into poor nations in recent years. In doing research in such settings, the response to challenges arising due to the vulnerability and resultant potential exploitation of very poor subject populations is heightened awareness of the need for adequate local oversight and regulation. More regulation, however, often is difficult to implement and may not be practical. The provision of benefit at the conclusion of clinical trials in poor nations or for poor people is a better response to the moral challenge of exploitation. PMID- 20959842 TI - Drug interactions should be evaluated in patients. AB - Drug development involves learning and confirming in healthy volunteers and ultimately in patients. This approach should apply to drug-drug interactions because requirements to extrapolate pharmacokinetic and pharmacodynamic findings from healthy volunteers to patients are not uniformly met, and the designs of interaction studies often have little relevance to actual clinical use. Guidance to health-care professionals on a safe and effective dose for individual patients should include information from drug-drug interaction studies in the intended patients. PMID- 20959843 TI - The role of clinical pharmacology in supporting the emergency use authorization of an unapproved anti-influenza drug, peramivir. AB - On 23 October 2009, the commissioner of the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for peramivir for intravenous injection, an unapproved neuraminidase inhibitor used for treating certain hospitalized adult and pediatric patients infected with 2009 H1N1 influenza. This was the first EUA of an unapproved drug product. This report summarizes the critical contributions of the clinical pharmacology review team in support of the peramivir EUA. PMID- 20959844 TI - Impact of the new US health-care-reform legislation on the pharmaceutical industry: who are the real winners? AB - Over the past two years, the US pharmaceutical and biotechnology industries were preparing themselves for passage of some type of health-reform legislation with a clear appreciation-and concern-about the enormous impact any law would be likely to have on the structure and viability of the research-based industry. Now, with final passage in March 2010 of the Patient Protection and Affordable Care Act and its companion "quick-fix" and budget bill, the Health Care and Education Reconciliation Act, it is a good time to take a look at how the industry fared and assess how the various provisions of the health-care reform bill might affect the industry's long-term prosperity and growth. PMID- 20959845 TI - The enrichment window approach as a means of dealing with placebo response in antidepressant clinical trials. AB - In this issue, Merlo-Pich et al. present an enrichment-window approach that identifies sites with aberrant mean placebo responses and excludes data from those sites so as to improve drug-placebo discrimination in antidepressant clinical trials. The method appears to increase the signal in situations in which the test drug is better than placebo. However, confirmation of its impact on the rate of false-positive results is needed before the method can be used prospectively. PMID- 20959847 TI - Hatomarubigin E, a biosynthetic intermediate of hatomarubigins C and a substrate of HrbU O-methyltransferase. PMID- 20959848 TI - Isolation of 2 new naphthablin analogs, JBIR-79 and JBIR-80, from Streptomyces sp. RI24. PMID- 20959849 TI - 2754A: a new inhibitor of VEGFR-2 isolated from the Streptomyces sp. 2754. PMID- 20959850 TI - External globus pallidus stimulation modulates brain connectivity in Huntington's disease. AB - Positron emission tomography with O-15-labeled water was used to study at rest the neurophysiological effects of bilateral external globus pallidus (GPe) deep brain stimulation in patients with Huntington's disease (HD). Five patients were compared with a control group in the on and off states of the stimulator. External globus pallidus stimulation decreased neuronal activity and modulated cerebral connectivity within the basal ganglia-thalamocortical circuitry, the sensorimotor, and the default-mode networks. These data indicate that GPe stimulation modulates functional integration in HD patients in accordance with the basal ganglia-thalamocortical circuit model. PMID- 20959851 TI - Platelet mitochondrial complex I and I+III activities do not correlate with cerebral mitochondrial oxidative metabolism. AB - Assays of mitochondrial electron transport system (ETS) activity in circulating blood platelets have been used to investigate the cause of neurodegenerative diseases. However, the correspondence between platelet ETS function and cerebral mitochondrial metabolism is not well characterized. To assess the validity of using platelet ETS activity to infer cerebral mitochondrial metabolism, we measured platelet ETS activity (complex I and complex I+III), cerebral metabolic rate of oxygen (CMRO(2)), and the CMRO(2)/cerebral metabolic rate for glucose ratio in 40 subjects: 7 with never-medicated Parkinson's disease, 13 with genetically proved Huntington's disease, and 20 normal controls. We found no correlation between in vivo measures of cerebral mitochondrial oxidative metabolism and ex vivo assays of platelet complex I and complex I+III activity performed on blood collected immediately before cerebral metabolism studies. We saw no evidence of a threshold effect when comparing platelet complex I and complex I+III activity with cerebral oxidative metabolism across a 4- to 10-fold range of platelet ETS activity. On the basis of these data, we conclude that measures of mitochondrial complex I and I+III activity in platelets within the ranges we have studied do not correlate with oxidative function of cerebral mitochondria. PMID- 20959852 TI - Functional white-laser imaging to study brain oxygen uncoupling/recoupling in songbirds. AB - Contrary to the intense debate about brain oxygen dynamics and its uncoupling in mammals, very little is known in birds. In zebra finches, picosecond optical tomography with a white laser and a streak camera can measure in vivo oxyhemoglobin (HbO(2)) and deoxyhemoglobin (Hb) concentration changes following physiologic stimulation (familiar calls and songs). Picosecond optical tomography showed sufficient submicromolar sensitivity to resolve the fast changes in the hippocampus and auditory forebrain areas with 250 MUm resolution. The time course is composed of (1) an early 2-second-long event with a significant decrease in Hb and HbO(2) levels of -0.7 and -0.9 MUmol/L, respectively, (2) a subsequent increase in blood oxygen availability with a plateau of HbO(2) (+0.3 MUmol/L), and (3) pronounced vasodilatation events immediately after the end of the stimulus. One of the findings of our study is the direct link between blood oxygen level-dependent signals previously published in birds and our results. Furthermore, the early vasoconstriction event and poststimulus ringing seem to be more pronounced in birds than in mammals. These results in birds, tachymetabolic vertebrates with a long lifespan, can potentially yield new insights, e.g., into brain aging. PMID- 20959853 TI - A new technique for functional imaging in songbirds and beyond. PMID- 20959854 TI - Multiple sites of vasopressin synthesis in the injured brain. AB - Previous studies have indicated that the primary targets for vasopressin actions on the injured brain are the cerebrovascular endothelium and astrocytes, and that vasopressin amplifies the posttraumatic production of proinflammatory mediators. Here, the controlled cortical impact model of traumatic brain injury in rats was used to identify the sources of vasopressin in the injured brain. Injury increased vasopressin synthesis in the hypothalamus and cerebral cortex adjacent to the posttraumatic lesion. In the cortex, vasopressin was predominantly produced by activated microglia/macrophages, and, to a lesser extent, by the cerebrovascular endothelium. These data further support the pathophysiological role of vasopressin in brain injury. PMID- 20959855 TI - The effect of basal vasodilation on hypercapnic and hypocapnic reactivity measured using magnetic resonance imaging. AB - Cerebrovascular reactivity to vasodilatory hypercapnic and vasoconstrictive hypocapnic challenges is known to be altered in several hemodynamic disorders, which is often attributable to changes in smooth muscle-mediated vascular compliance. Recently, attenuated reactivity to hypercapnia but enhanced reactivity to hypocapnia was observed in patients with chronic stroke. We hypothesize that the latter observation could be explained by a change in the basal vascular tone. In particular, reduced cerebral perfusion pressure, as is prevalent in these patients, may cause vasodilation through autoregulatory mechanisms, and this compensatory baseline condition may alter reactivity to vasoconstrictive hypocapnic challenges. To test this hypothesis, a predilated vascular condition was created in young, healthy subjects (n=11; age=23 to 36 years) using inhalation of 4% CO(2). Using blood oxygenation level-dependent functional magnetic resonance imaging at 3 T, breath holding and cued deep breathing respiratory challenges were administered to assess hypercapnia and hypocapnia reactivity, respectively. During the predilated condition, vasoconstrictive reactivity to hypocapnia was significantly (21.1%, P=0.016) enhanced throughout the gray matter, whereas there was no significant change (6.4%, P=0.459) in hypercapnic vasodilatory reactivity. This suggests that baseline vasodilation may explain the enhanced hypocapnia reactivity observed in some stroke patients, and that hypocapnia challenges may help identify the level of vascular compliance in patients with reduced cerebral perfusion pressure. PMID- 20959856 TI - Bioavailability of zinc from NutriSet zinc tablets compared with aqueous zinc sulfate. AB - BACKGROUND/OBJECTIVES: The apparent widespread extent of zinc (Zn) deficiency in developing countries and the efficacy of oral Zn supplements as an adjunct to oral rehydration therapy make oral Zn supplementation an increasingly important modality in clinical medicine and public health. In this study we aimed to compare the relative bioavailability of oral doses of 30 mg of Zn in two dosing forms. SUBJECTS/METHODS: In total, 10 healthy male volunteers ingested oral Zn doses with 200 ml plain water at about 0830 hours in the fasting state on two occasions, once as 30 mg of Zn in an aqueous solution of reagent grade zinc sulfate (ZnSO(4)) and another time as 1.5 NutriSet Zn tablets (Nutriset, Malaunay, France); on a third occasion, only plain water was consumed. Venous blood specimens were collected at baseline, 60, 120, 180 and 240 min after ingestion and the plasma Zn was measured for each sample. RESULTS: The relative bioavailability of oral Zn from a commonly used, tableted (NutriSet) form is only about half of that of a reference dose of aqueous ZnSO(4) as indicated by the area under the curve of serial plasma Zn excursion and maximal change in circulating Zn. CONCLUSIONS: Reduced or absent functional outcomes in Zn intervention trials may derive, in part, from a lower than anticipated intestinal uptake of the Zn in the tableted form. PMID- 20959857 TI - Oolong tea does not improve glucose metabolism in non-diabetic adults. AB - BACKGROUND: Studies of the influence of tea on glucose metabolism have produced inconsistent results, possibly because of the lack of dietary control and/or unclear characterization of tea products. METHODS: Therefore, a double-blind crossover study was conducted in which healthy males (n = 19) consumed each of three oolong tea products or a control beverage as part of a controlled diet. Treatment beverages (1.4 l/day) were consumed for 5 days, followed by assessment of fasting plasma glucose, fasting serum insulin and an oral glucose tolerance test. Tea products included oolong tea, oolong tea with added catechins and oolong tea with added oolong tea polyphenols, and control beverages included caffeinated water and unsupplemented water. On the fifth day of each treatment period, treatment beverages were consumed with a standardized meal, and glucose and insulin responses were assessed for 240 min. RESULTS: No significant differences were detected for fasting plasma glucose, fasting serum insulin, incremental plasma glucose area under the concentration time curve (AUC), total plasma glucose AUC or total serum insulin AUC. CONCLUSIONS: Neither oolong tea nor oolong tea supplemented with catechins or other polyphenols produced improved glucose metabolism in healthy adult volunteers on the basis of this highly controlled dietary intervention trial. PMID- 20959858 TI - Classifying chemoreceptors: quantity versus quality. PMID- 20959859 TI - Twitter evolution: converging mechanisms in birdsong and human speech. AB - Vocal imitation in human infants and in some orders of birds relies on auditory guided motor learning during a sensitive period of development. It proceeds from 'babbling' (in humans) and 'subsong' (in birds) through distinct phases towards the full-fledged communication system. Language development and birdsong learning have parallels at the behavioural, neural and genetic levels. Different orders of birds have evolved networks of brain regions for song learning and production that have a surprisingly similar gross anatomy, with analogies to human cortical regions and basal ganglia. Comparisons between different songbird species and humans point towards both general and species-specific principles of vocal learning and have identified common neural and molecular substrates, including the forkhead box P2 (FOXP2) gene. PMID- 20959860 TI - Emotion processing and the amygdala: from a 'low road' to 'many roads' of evaluating biological significance. AB - A subcortical pathway through the superior colliculus and pulvinar to the amygdala is commonly assumed to mediate the non-conscious processing of affective visual stimuli. We review anatomical and physiological data that argue against the notion that such a pathway plays a prominent part in processing affective visual stimuli in humans. Instead, we propose that the primary role of the amygdala in visual processing, like that of the pulvinar, is to coordinate the function of cortical networks during evaluation of the biological significance of affective visual stimuli. Under this revised framework, the cortex has a more important role in emotion processing than is traditionally assumed. PMID- 20959861 TI - A general method for controlling the genome-wide type I error rate in linkage and association mapping experiments in plants. AB - Control of the genome-wide type I error rate (GWER) is an important issue in association mapping and linkage mapping experiments. For the latter, different approaches, such as permutation procedures or Bonferroni correction, were proposed. The permutation test, however, cannot account for population structure present in most association mapping populations. This can lead to false positive associations. The Bonferroni correction is applicable, but usually on the conservative side, because correlation of tests cannot be exploited. Therefore, a new approach is proposed, which controls the genome-wide error rate, while accounting for population structure. This approach is based on a simulation procedure that is equally applicable in a linkage and an association-mapping context. Using the parameter settings of three real data sets, it is shown that the procedure provides control of the GWER and the generalized genome-wide type I error rate (GWER(k)). PMID- 20959862 TI - Temporal genetic homogeneity among shore crab (Carcinus maenas) larval events supplied to an estuarine system on the Portuguese northwest coast. AB - Despite the importance of larval biology in the life histories of many marine animals, relatively little information exists on the dynamics and genetic composition of larval cohorts. The supply of megalopae larvae of the shore crab, Carcinus maenas, was measured on a daily basis during 8 months spread along two larval periods (2006 and 2007) at the Ria de Aveiro estuary, on the Portuguese northwest coast. A total of 10 microsatellite DNA loci were employed to explore the genetic structure, variability and relatedness of temporally distinct megalopal events, selected from the major pulses of supply. Larval variation was also compared genetically with that of a previously studied adult crabs sample, at the same loci, collected in 2006 and 2007 along the Iberian Peninsula. Results revealed a lack of genetic differentiation and identical diversity levels among larval events over time. No evidence of reduced genetic diversity between megalopae relative to the diversity assessed from the pooled sample of adults was found. Moreover, there was no evidence of any family relatedness among larvae from temporal events. The results obtained for C. maenas contradict predictions made by the sweepstakes reproduction hypothesis, in which large variance in reproductive success is expected, which is presumably detectable as sharp genetic discontinuities among separate larval events. Data here indicate conversely a high degree of temporal genetic stability among larval supply to a given estuary under variable oceanographic conditions, consistent with the hypothesis that sampled larvae were drawn from a large number of adults that do not differ in reproductive success. PMID- 20959863 TI - Patterns of genetic variation and covariation in ejaculate traits reveal potential evolutionary constraints in guppies. AB - Ejaculates comprise multiple and potentially interacting traits that determine male fertility and sperm competitiveness. Consequently, selection on these traits is likely to be intense, but the efficacy of selection will depend critically on patterns of genetic variation and covariation underlying their expression. In this study, I provide a prospective quantitative genetic analysis of ejaculate traits in the guppy Poecilia reticulata, a highly promiscuous live-bearing fish. I used a standard paternal half-sibling breeding design to characterize patterns of genetic (co)variation in components of sperm length and in vitro sperm performance. All traits exhibited high levels of phenotypic and additive genetic variation, and in several cases, patterns of genetic variation was consistent with Y-linkage. There were also highly significant negative genetic correlations between the various measures of sperm length and sperm performance. In particular, the length of the sperm's midpiece was strongly, negatively and genetically correlated with sperm's swimming velocity-an important determinant of sperm competitiveness in this and other species. Other components of sperm length, including the flagellum and head, were independently and negatively genetically correlated with the proportion of live sperm in the ejaculate (sperm viability). Whether these relationships represent evolutionary trade-offs depends on the precise relationships between these traits and competitive fertilization rates, which have yet to be fully resolved in this (and indeed most) species. Nevertheless, these prospective analyses point to potential constraints on ejaculate evolution and may explain the high level of phenotypic variability in ejaculate traits in this species. PMID- 20959864 TI - Adaptive divergence and speciation among sexual and pseudoviviparous populations of Festuca. AB - Pseudovivipary is an environmentally induced flowering abnormality in which vegetative shoots replace seminiferous (sexual) inflorescences. Pseudovivipary is usually retained in transplantation experiments, indicating that the trait is not solely induced by the growing environment. Pseudovivipary is the defining characteristic of Festuca vivipara, and arguably the only feature separating this species from its closest seminiferous relative, Festuca ovina. We performed phylogenetic and population genetic analysis on sympatric F. ovina and F. vivipara samples to establish whether pseudovivipary is an adaptive trait that accurately defines the separation of genetically distinct Festuca species. Chloroplast and nuclear marker-based analyses revealed that variation at a geographical level can exceed that between F. vivipara and F. ovina. We deduced that F. vivipara is a recent species that frequently arises independently within F. ovina populations and has not accumulated significant genetic differentiation from its progenitor. We inferred local gene flow between the species. We identified one amplified fragment length polymorphism marker that may be linked to a pseudovivipary-related region of the genome, and several other markers provide evidence of regional local adaptation in Festuca populations. We conclude that F. vivipara can only be appropriately recognized as a morphologically and ecologically distinct species; it lacks genetic differentiation from its relatives. This is the first report of a 'failure in normal flowering development' that repeatedly appears to be adaptive, such that the trait responsible for species recognition constantly reappears on a local basis. PMID- 20959865 TI - Genome-wide association of breast cancer: composite likelihood with imputed genotypes. AB - We describe composite likelihood-based analysis of a genome-wide breast cancer case-control sample from the Cancer Genetic Markers of Susceptibility project. We determine 14 380 genome regions of fixed size on a linkage disequilibrium (LD) map, which delimit comparable levels of LD. Although the numbers of single nucleotide polymorphisms (SNPs) are highly variable, each region contains an average of ~35 SNPs and an average of ~69 after imputation of missing genotypes. Composite likelihood association mapping yields a single P-value for each region, established by a permutation test, along with a maximum likelihood disease location, SE and information weight. For single SNP analysis, the nominal P-value for the most significant SNP (msSNP) requires substantial correction given the number of SNPs in the region. Therefore, imputing genotypes may not always be advantageous for the msSNP test, in contrast to composite likelihood. For the region containing FGFR2 (a known breast cancer gene) the largest chi(2) is obtained under composite likelihood with imputed genotypes (chi(2)(2) increases from 20.6 to 22.7), and compares with a single SNP-based chi(2)(2) of 19.9 after correction. Imputation of additional genotypes in this region reduces the size of the 95% confidence interval for location of the disease gene by ~40%. Among the highest ranked regions, SNPs in the NTSR1 gene would be worthy of examination in additional samples. Meta-analysis, which combines weighted evidence from composite likelihood in different samples, and refines putative disease locations, is facilitated through defining fixed regions on an underlying LD map. PMID- 20959866 TI - Expanding the clinical spectrum of the 16p11.2 chromosomal rearrangements: three patients with syringomyelia. AB - 16p11.2 rearrangements are associated with developmental delay, cognitive impairment, autism spectrum disorder, behavioral problems (especially attention deficit hyperactivity disorder), seizures, obesity, dysmorphic features, and abnormal head size. In addition, congenital anomalies and abnormal brain findings were frequently observed in patients with these rearrangements. We identified and performed a detailed microarray, phenotypic, and radiological characterization of three new patients with 16p11.2 rearrangements: two deletion patients and one patient with the reciprocal duplication. All patients have a heterozygous loss (deletion) or gain (duplication) corresponding to chromosomal coordinates (chr16: 29 528 190-30 107 184) with a minimal size of 579 kb. The deletion patients had language delay and learning disabilities and one met criteria for pervasive developmental disorder not otherwise specified. The duplication patient received a diagnosis of autism and had academic deficits and behavioral problems. The patients with deletion had long cervicothoracic syringomyelia and the duplication patient had long thoracolumbar syringomyelia. The syringomyelia in one patient with deletion was associated with Chiari malformation. Our findings highlight the broad spectrum of clinical and neurological manifestations in patients with 16p11.2 rearrangements. Our observation suggests that genes (or a single gene) within the implicated interval have significant roles in the pathogenesis of syringomyelia. A more comprehensive and systematic research is warranted to study the frequency and spectrum of malformations in the central nervous system in these patients. PMID- 20959867 TI - A Clinical Trial Comparing Tapering Doses of Buprenorphine with Steady Doses for Chronic Pain and Co-existent Opioid Addiction. AB - OBJECTIVES: Effective strategies are needed to manage individuals with chronic non-cancer pain and coexistent opioid addiction. This study compared opioid discontinuation and opioid replacement protocols. METHODS: We planned to enroll 60 individuals into an open-label trial who had been treated with opioids for chronic non-cancer pain, and who also had opioid addiction. Participants were randomly assigned to one of two 6-month treatment protocols of buprenorphine/naloxone sublingual tablets: 1) tapering doses for opioid weaning or "detoxification" (active comparator group) or 2) steady doses for opioid replacement (experimental group). They were followed monthly for the study outcomes: completion of the 6-month treatment protocol and self-reported pain control, physical functioning, alcohol consumption and illicit drug use. RESULTS: Enrollment was terminated after enrolling 12 participants because none of the 6 assigned to receive tapering doses could successfully complete the protocol (5 were given steady doses and 1 was admitted to an inpatient chemical dependency treatment program); whereas, of the 6 assigned to receive steady doses, 5 completed the protocol (1 withdrew). This difference between the 2 treatment conditions was significant (P = 0.015). Of the 10 participants who completed the 6 month follow-up, 8 reported improved pain control and physical functioning and 5 used alcohol and/or illicit drugs. CONCLUSIONS: We conclude that over 6 months, these participants with chronic pain and co-existent opioid addiction were more likely to adhere to an opioid replacement protocol than an opioid weaning protocol and that opioid replacement therapy with steady doses of buprenorphine/naloxone is associated with improved pain control and physical functioning. PMID- 20959868 TI - Open education, open minds. PMID- 20959869 TI - Conjugated Polymers Atypically Prepared in Water. AB - Processability remains a fundamental issue for the implementation of conducting polymer technology. A simple synthetic route towards processable precursors to conducting polymers (main chain and side chain) was developed using commercially available materials. These soluble precursor systems were converted to conjugated polymers electrochemically in aqueous media, offering a cheaper and greener method of processing. Oxidative conversion in aqueous and organic media each produced equivalent electrochromics. The precursor method enhances the yield of the electrochromic polymer obtained over that of electrodeposition, and it relies on a less corruptible electrolyte bath. However, electrochemical conversion of the precursor polymers often relies on organic salts and solvents. The ability to achieve oxidative conversion in brine offers a less costly and a more environmentally friendly processing step. It is also beneficial for biological applications. The electrochromics obtained herein were evaluated for electronic, spectral, and morphological properties. PMID- 20959870 TI - Development and validation of an LC-MS/MS method for determination of phencyclidine in human serum and its application to human drug abuse cases. AB - A new analytical method was developed and validated for the rapid determination of phencyclidine (PCP) in human blood and serum. Rapid chromatographic separation decreased the analysis time relative to standard gas chromatography (GC)-based methodologies. The method involved the use of solid-phase extraction for sample preparation and cleanup followed by liquid chromatography tandem spectrometric (LC-MS/MS) analysis and an electrospray-ionization (ESI) interface. PCP was quantified using multiple-reaction-monitoring with deuterium labeled PCP (PCP d(5)) as an internal standard. The method was validated for accuracy, precision, linearity, and recovery. The method was accurate with error <14% and precision with coefficient of variation (CV) <5.0%. The assay was linear over the entire range of calibration standards (r(2) > 0.997). The recovery of PCP after solid phase extraction was greater than 90% with the lower limit of detection (LLOD) for PCP in 500 ul of human serum after solid-phase extraction at 0.06 ng ml(-1). This method was used to determine the levels of PCP in postmortem human blood samples. The LLOD in blood was 1 ng ml(-1). Blood PCP concentrations were also determined separately using GC and flame ionization detection (FID). Blood calibration standards and serum calibration standards yielded similar concentrations when used to quantitate authentic human blood samples that tested positive for PCP under the GC-FID method. Extraction of PCP from serum required fewer steps and therefore could be used as a calibration matrix in place of blood. The LC-MS/MS methodology shown here was higher throughput compared with GC based methods because of very short chromatographic run times. This was accomplished without sacrificing analytical sensitivity. PMID- 20959871 TI - Identification of a Natural Product Antagonist against the Botulinum Neurotoxin Light Chain Protease. AB - Botulinum neurotoxins (BoNTs) are the etiological agents responsible for botulism, a disease characterized by peripheral neuromuscular blockade and a characteristic flaccid paralysis of humans. BoNTs are the most lethal known poisons affecting humans and has been recognized as a potential bioterrorist threat. Current treatments for botulinum poisoning are predominately prophylactic in nature relying on passive immunization with antitoxins. Inhibition of the BoNT light chain metalloprotease (LC) has emerged as a new therapeutic strategy for the treatment of botulism that may provide an effective post-exposure remedy. A high-throughput screening effort against the light chain of BoNT serotype A (LC/A) was conducted with the John Hopkins Clinical Compound Library comprised of over 1,500 existing drugs. Lomofungin, a natural product first isolated in the late 1960's, was identified as an inhibitor of LC/A, displaying classical noncompetitive inhibition kinetics with a K(i) of 6.7 +/- 0.7 uM. Inhibitor combination studies reveal that lomofungin binding is nonmutually exclusive (synergistic). The inhibition profile of lomofungin has been delineated by the use of both an active site inhibitor, 2,4-dichlorocinnamic hydroxamate, and a noncompetitive inhibitor d-chicoric acid; the mechanistic implications of these observations are discussed. Lastly, cellular efficacy was investigated using a rat primary cell model which demonstrated that lomofungin can protect against SNAP-25 cleavage, the intracellular protein target of LC/A. PMID- 20959872 TI - Foreword: The INDEPTH WHO-SAGE collaboration - coming of age. PMID- 20959873 TI - The health and well-being of older people in Nairobi's slums. AB - BACKGROUND: Globally, it is estimated that people aged 60 and over constitute more than 11% of the population, with the corresponding proportion in developing countries being 8%. Rapid urbanisation in sub-Saharan Africa (SSA), fuelled in part by rural-urban migration and a devastating HIV/AIDS epidemic, has altered the status of older people in many SSA societies. Few studies have, however, looked at the health of older people in SSA. This study aims to describe the health and well-being of older people in two Nairobi slums. METHODS: Data were collected from residents of the areas covered by the Nairobi Urban Health and Demographic Surveillance System (NUHDSS) aged 50 years and over by 1 October 2006. Health status was assessed using the short SAGE (Study on Global AGEing and Adult Health) form. Mean WHO Quality of Life (WHOQoL) and a composite health score were computed and binary variables generated using the median as the cut off. Logistic regression was used to determine factors associated with poor quality of life (QoL) and poor health status. RESULTS: Out of 2,696 older people resident in the NUHDSS surveillance area during the study period, data were collected on 2,072. The majority of respondents were male, aged 50-60 years. The mean WHOQoL score was 71.3 (SD 6.7) and mean composite health score was 70.6 (SD 13.9). Males had significantly better QoL and health status than females and older respondents had worse outcomes than younger ones. Sex, age, education level and marital status were significantly associated with QoL, while slum of residence was significantly associated with health status. CONCLUSION: The study adds to the literature on health and well-being of older people in SSA, especially those in urban informal settlements. Further studies are needed to validate the methods used for assessing health status and to provide comparisons from other settings. Health and Demographic Surveillance Systems have the potential to conduct such studies and to evaluate health and well-being over time. PMID- 20959874 TI - Foreword: INDEPTH WHO-SAGE study. PMID- 20959875 TI - Health and quality of life among older rural people in Purworejo District, Indonesia. AB - INTRODUCTION: Increasing life expectancy and longevity for people in many highly populated low- and middle-income countries has led to an increase in the number of older people. The population aged 60 years and over in Indonesia is projected to increase from 8.4% in 2005 to 25% in 2050. Understanding the determinants of healthy ageing is essential in targeting health-promotion programmes for older people in Indonesia. OBJECTIVE: To describe patterns of socio-economic and demographic factors associated with health status, and to identify any spatial clustering of poor health among older people in Indonesia. METHODS: In 2007, the WHO Study on global AGEing and adult health (SAGE) was conducted among 14,958 people aged 50 years and over in Purworejo District, Central Java, Indonesia. Three outcome measures were used in this analysis: self-reported quality of life (QoL), self-reported functioning and disability, and overall health score calculated from self-reported health over eight health domains. The factors associated with each health outcome were identified using multivariable logistic regression. Purely spatial analysis using Poisson regression was conducted to identify clusters of households with poor health outcomes. RESULTS: Women, older age groups, people not in any marital relationship and low educational and socio economic levels were associated with poor health outcomes, regardless of the health indices used. Older people with low educational and socio-economic status (SES) had 3.4 times higher odds of being in the worst QoL quintile (OR = 3.35; 95% CI = 2.73-4.11) as compared to people with high education and high SES. This disadvantaged group also had higher odds of being in the worst functioning and most disabled quintile (OR = 1.67; 95% CI = 1.35-2.06) and the lowest overall health score quintile (OR = 1.66; 95% CI = 1.36-2.03). Poor health and QoL are not randomly distributed among the population over 50 years old in Purworejo District, Indonesia. Spatial analysis showed that clusters of households with at least one member being in the worst quintiles of QoL, functioning and health score intersected in the central part of Purworejo District, which is a semi urban area with more developed economic activities compared with other areas in the district. CONCLUSION: Being female, old, unmarried and having low educational and socio-economic levels were significantly associated with poor self-reported QoL, health status and disability among older people in Purworejo District. This study showed the existence of geographical pockets of vulnerable older people in Purworejo District, and emphasized the need to take immediate action to address issues of older people's health and QoL. PMID- 20959876 TI - Guest Editorial: The INDEPTH WHO-SAGE multicentre study on ageing, health and well-being among people aged 50 years and over in eight countries in Africa and Asia. PMID- 20959877 TI - Patterns of health status and quality of life among older people in rural Viet Nam. AB - BACKGROUND: To effectively and efficiently respond to the growing health needs of older people, it is critical to have an indepth understanding about their health status, quality of life (QoL) and related factors. This paper, taking advantage of the INDEPTH WHO-SAGE study on global ageing and adult health, aims to describe the pattern of health status and QoL among older adults in a rural community of Viet Nam, and examine their associations with some socio-economic factors. METHODS: The study was carried out in the Bavi District, a rural community located 60 km west of Hanoi, the capital, within the Epidemiological Field Laboratory of Bavi (FilaBavi). Face-to-face household interviews were conducted with people aged 50 years and over who lived in the FilaBavi area. The interviews were performed by trained surveyors from FilaBavi using a standard summary version SAGE questionnaire. Both descriptive and analytical statistics were used to examine the patterns of health status and QoL, and associations with socio economic factors. RESULTS: Higher proportions of women reported both poor health status and poor QoL compared to men. Age was shown to be a factor significantly associated with poor health status and poor QoL. Higher educational level was a significant positive predictor of both health status and QoL among the study subjects. Higher economic status was also associated with both health status and QoL. The respondents whose families included more older people were significantly less likely to have poor QoL. CONCLUSION: The findings reveal problems of inequality in health status and QoL among older adults in the study setting by sex, age, education and socio-economic status. Given the findings, actions targeted towards improving the health of disadvantaged people (women, older people and lower education and economic status) are needed in this setting. PMID- 20959878 TI - Ageing and adult health status in eight lower-income countries: the INDEPTH WHO SAGE collaboration. AB - BACKGROUND: Globally, ageing impacts all countries, with a majority of older persons residing in lower- and middle-income countries now and into the future. An understanding of the health and well-being of these ageing populations is important for policy and planning; however, research on ageing and adult health that informs policy predominantly comes from higher-income countries. A collaboration between the WHO Study on global AGEing and adult health (SAGE) and International Network for the Demographic Evaluation of Populations and Their Health in developing countries (INDEPTH), with support from the US National Institute on Aging (NIA) and the Swedish Council for Working Life and Social Research (FAS), has resulted in valuable health, disability and well-being information through a first wave of data collection in 2006-2007 from field sites in South Africa, Tanzania, Kenya, Ghana, Viet Nam, Bangladesh, Indonesia and India. OBJECTIVE: To provide an overview of the demographic and health characteristics of participating countries, describe the research collaboration and introduce the first dataset and outputs. METHODS: Data from two SAGE survey modules implemented in eight Health and Demographic Surveillance Systems (HDSS) were merged with core HDSS data to produce a summary dataset for the site specific and cross-site analyses described in this supplement. Each participating HDSS site used standardised training materials and survey instruments. Face-to face interviews were conducted. Ethical clearance was obtained from WHO and the local ethical authority for each participating HDSS site. RESULTS: People aged 50 years and over in the eight participating countries represent over 15% of the current global older population, and is projected to reach 23% by 2030. The Asian HDSS sites have a larger proportion of burden of disease from non-communicable diseases and injuries relative to their African counterparts. A pooled sample of over 46,000 persons aged 50 and over from these eight HDSS sites was produced. The SAGE modules resulted in self-reported health, health status, functioning (from the WHO Disability Assessment Scale (WHODAS-II)) and well-being (from the WHO Quality of Life instrument (WHOQoL) variables). The HDSS databases contributed age, sex, marital status, education, socio-economic status and household size variables. CONCLUSION: The INDEPTH WHO-SAGE collaboration demonstrates the value and future possibilities for this type of research in informing policy and planning for a number of countries. This INDEPTH WHO-SAGE dataset will be placed in the public domain together with this open-access supplement and will be available through the GHA website (www.globalhealthaction.net) and other repositories. An improved dataset is being developed containing supplementary HDSS variables and vignette-adjusted health variables. This living collaboration is now preparing for a next wave of data collection. PMID- 20959879 TI - Left atrial size and force in patients with systolic chronic heart failure: Comparison with healthy controls and different cardiac diseases. AB - BACKGROUND: Left atrial (LA) systolic force (LASF) is significantly increased in chronic heart failure (CHF), arterial hypertension (HT) and aortic stenosis (AS). The increase is proportional to the degree of left ventricular hypertrophy and diastolic dysfunction. OBJECTIVES: To assess the magnitude of changes in maximal LA volume (LAV(max)) and LASF in systolic CHF compared with other cardiac diseases, and to assess whether the left atrium remodels differently and works in response to specific conditions affecting diastolic function and to individual factors associated with LA alterations. METHODS: LAV(max) and LASF were measured and evaluated by two-dimensional Doppler echocardiography in 94 patients with systolic CHF and normal left ventricular filling pressure, 100 control patients, 181 patients with HT, 40 patients with idiopathic hypertrophic cardiomyopathy (HCMP) and 85 patients with AS. The prevalence of LA dilation and supernormal LASF (defined as values of LAV(max) and LASF exceeding two SDs of the mean of controls) was measured in all groups. RESULTS: LAV(max) and LASF were 7.1+/-2 mL/m(3) and 7.8+/-4 kdynes in controls, and 11.0+/-4 mL/m(3) and 19.7+/-11 kdynes in systolic CHF patients, respectively (both P<0.001). These values were significantly higher than in patients with HT, but similar to those with AS and HCMP. LA dilation and supernormal LASF were detected in 13% and 11% of patients with HT, 32% and 59% of patients with AS, 26% and 43% of patients with HCMP, and 41% and 56% of patients with systolic CHF, respectively (all P<0.01). In multiple logistic analysis, systolic CHF represented the strongest predictor of supernormal LASF. It was not independently associated with LA dilation, which was mainly related to indexes of volume load. CONCLUSIONS: LAV(max) and LASF were markedly increased in patients with systolic CHF, with a magnitude that was significantly higher than that of HT patients, but similar to that measured in HCMP and AS patients. In the present community population with various cardiac diseases, systolic CHF represented the most powerful stimulus for increasing LASF and was not related to LA dilation. PMID- 20959880 TI - Lack of an association between connexin-37, stromelysin-1, plasminogen activator inhibitor type 1 and lymphotoxin-alpha genes and acute coronary syndrome in Czech Caucasians. AB - BACKGROUND: The majority of acute coronary syndrome (ACS) cases cannot be explained by the analysis of commonly recognized risk factors; thus, the analysis of possible genetic predispositions is of interest. The genes for connexin-37, stromelysin-1, plasminogen activator-inhibitor type 1 (PAI-1) and lymphotoxin alpha are among many presently known candidate genes that are associated with risk factors for ACS. OBJECTIVE: To identify the potential impact of the functional variants of connexin-37, stromelysin-1, PAI-1 and lymphotoxin-alpha on ACS in a Caucasian Czech population. METHODS: A total of 1399 consecutive patients (1016 men and 383 women) with ACS from five coronary care units located in Prague (Czech Republic) were analyzed; a representative sample of 2559 healthy individuals (1191 men and 1368 women) were also genotyped and served as controls. RESULTS: The gene variants analyzed were not significantly associated with the prevalence of ACS or the classical risk factors of ACS development such as high plasma lipid levels, hypertension, diabetes, high body mass index or smoking. CONCLUSION: In a Caucasian Czech population sample, genetic variants of connexin 37, stromelysin-1, PAI-1 and lymphotoxin-alpha were not significantly associated with a predisposition toward ACS. PMID- 20959881 TI - Bleeding complications associated with glycoprotein IIb/IIIa inhibitors in patients 80 years of age and older undergoing percutaneous coronary intervention. AB - BACKGROUND: Treatment of symptomatic coronary artery disease with percutaneous intervention requires antithrombotic therapy. Patients with elevated thromboembolic risk benefit from therapy with glycoprotein IIb/IIIa inhibitors. The safety and effectiveness of glycoprotein IIb/IIIa inhibition have been well documented in clinical trials. Drug-induced bleeding complications in elderly patients have not been specifically addressed. METHODS: Between 2006 and 2009, a total of 439 unselected patients 80 years of age and older undergoing percutaneous intervention for symptomatic coronary artery disease were included in the present nonrandomized retrospective study. In one-half of the patients, glycoprotein IIb/IIIa inhibitors were administered peri-interventionally. The in hospital occurrence of bleeding complications (access site, gastrointestinal and cerebral) were analyzed in the groups with and without glycoprotein IIb/IIIa inhibitors. RESULTS: The mean age of the patients was 84 years. Nearly all patients (95%) received dual antiplatelet therapy. Patients treated with glycoprotein IIb/IIIa inhibitors had more complex coronary lesions and bypass graft interventions, and a tendency toward more access site bleeding complications than patients without inhibitors, which included femoral hematomas (4.6% versus 2.3%, respectively; P not significant) and femoral pseudoaneurysms (6% versus 3.2%, respectively; P not significant). The rate of blood transfusion was equal in both groups (0.9%). Major hemorrhagic events did not occur. Vessel closure devices were used more often in patients without glycoprotein inhibition. CONCLUSIONS: An increase in minor bleedings must be expected when using glycoprotein IIb/IIIa inhibitors in patients 80 years of age and older. However, this issue must not prevent this treatment option from being offered to elderly patients. There appears to be no elevated risk for major bleeding complications. Broadened use of vascular closure devices in this specific patient population may lower the rate of access site complications. PMID- 20959882 TI - Low noise level unmasks late potentials on signal-averaged electrocardiography. AB - INTRODUCTION: Identification of late potentials requires the reduction of random noise by signal averaging. The importance of using a very low noise level (NL) as the end point of the averaging process in patients with ventricular tachycardia, the variation of results when a lower than standard NL was used and the modification of the sensitivity of the test when a very low NL was reached were evaluated. METHODS AND RESULTS: Signal-averaged electrocardiograms were recorded in 36 patients with ischemic heart disease and spontaneous or induced sustained or nonsustained ventricular tachycardia. Thirteen patients showed negative or indeterminate results on recordings with an NL of 0.3 MUV. Eight patients (group 1) underwent a second recording with an NL of 0.1 MUV. Eight normal volunteers constituted the control group (group 2). The total duration of the filtered QRS vector magnitude (QRSd), the root mean square voltage of the terminal 40 ms of the vector magnitude (RMS(40)) and the low amplitude signal duration under 40 MUV in the terminal portion of the vector magnitude (LAS) modifications were evaluated. A significant difference (P<0.01) in these parameters was observed in group 1 (15.88%, 48.25% and 68.5%, respectively) when both recordings were compared. Tests were positive in all patients (100%) with NL reduction. In group 2, tests were negative in all patients (100%) at both NLs (0.3 MUV and 0.1 MUV). QRSd was 1.18% longer, RMS(40) was 1.38% lower and LAS was 3.55% longer with NL reduction. CONCLUSION: Late potentials in patients with ischemic heart disease, ventricular tachycardia, and a negative or indeterminate signal-averaged electrocardiogram may be detected if the NL is reduced to 0.1 MUV. Reduction of the NL increased the sensitivity of the test without modifying its specificity. PMID- 20959883 TI - Fractional excretion of sodium predicts worsening renal function in acute decompensated heart failure. AB - BACKGROUND: Renal impairment (RI), defined as an increase in creatinine level of greater than 26.5 mmol/L, develops in more than 30% of acute decompensated heart failure (ADHF) patients. Fractional excretion of sodium (FeNa) reflects sodium handling by the kidneys during diuresis. AIM: To study the relationship between FeNa and RI in patients admitted with ADHF. METHOD: The hospital course and renal function of all ADHF patients admitted to the hospital were prospectively observed. Patients were included if their admission creatinine level was 176 mmol/L or lower, they had been on a low-salt diet since admission, had urine sodium and creatinine samples collected more than 6 h after a furosemide dose in the first few days of admission, and they were on daily intravenous furosemide doses of 20 mg or more. RESULTS: Over six months, 51 patients met the inclusion criteria; the average daily dose of intravenous furosemide was 58.8 mg. RI developed in 39% of patients. A FeNa cut-off point of 0.4% was determined using ROC curve analysis; patients with a FeNa of greater than 0.4% (28 patients) were compared with patients with a lower FeNa (23 patients). Admission creatinine level and furosemide dose were higher in the first group (P=0.01 and P=0.06, respectively). The first group developed RI more frequently (OR=6.3; 95% CI 1.7 to 23.5; P=0.0047; adjusted OR for admission creatinine = 6.18; 95% CI 1.6 to 24.5; P=0.0096; and adjusted OR for furosemide dose = 4.7; 95% CI 1.3 to 16.7; P=0.016). They had a longer hospitalization course (median nine days [interquartile range 6.3 to 13.5 days] versus seven days [interquartile range 4.0 to 9.0 days]; P=0.036) and they were admitted to the cardiac care unit more frequently (OR=6.8; 95% CI 1.3 to 34.9; P=0.02). CONCLUSION: A FeNa of greater than 0.4% more than 6 h after a dose of diuretics predicts RI and a complicated hospital course in ADHF patients. PMID- 20959884 TI - Successful conservative treatment of an undeployed embolized intracoronary stent with dual antiplatelet and warfarin therapy. AB - Intracoronary undeployed stent embolization occurring during percutaneous coronary intervention is an infrequent complication. Published data indicate that without stent retrieval, the outcome is unfavourable. The present report describes a case in which failure to retrieve an undeployed embolized stent from the mid right coronary artery was managed conservatively with acetylsalicylic acid, clopidogrel and warfarin without any major adverse cardiac events during hospitalization or up to 12 months follow-up. This approach may be an alternative treatment of undeployed embolized intracoronary stent when retrieval or deployment is unsuccessful. PMID- 20959886 TI - Erratum. AB - [This corrects the article on p. e36 in vol. 15, PMID: 20631863.]. PMID- 20959885 TI - Safe retrieval of embolized patent ductus arteriosus coil via left thoracotomy. AB - During transcatheter occlusion of a patent ductus arteriosus, one potential complication is that the coil can embolize into one of the branch pulmonary arteries or the aorta. It is often possible to remove this coil percutaneously, but at times, surgical intervention is required. The present report describes a case in which the coil migrated to the left pulmonary artery and repeated attempts to retrieve the coil were unsuccessful. A left thoracotomy was performed, the coil was removed and the patent ductus arteriosus was ligated. PMID- 20959887 TI - Conduction disorder in takotsubo cardiomyopathy: a transient phenomenon or not? PMID- 20959888 TI - The influence of renal insufficiency on sleep-disordered breathing in patients with symptomatic chronic heart failure. AB - BACKGROUND: Renal insufficiency, a common condition among patients with chronic heart failure, complicates the management of heart failure. However, the influence of renal insufficiency on sleep-disordered breathing (SDB) - another important comorbidity of heart failure - has not been well studied. METHODS: Seventy-nine patients (60 men and 19 women) with stable, symptomatic heart failure caused by left ventricular systolic dysfunction (left ventricular ejection fraction of less than 45%) were studied. RESULTS: Thirty-nine patients (49%) had SDB as defined by an apnea-hypopnea index (AHI) of five or greater: 15 patients were classified as having mild SDB (AHI of five or greater and less than 15), 10 patients as having moderate SDB (AHI of 15 or greater and less than 30) and 14 patients as having severe SDB (AHI of 30 or greater). The etiology of SDB was predominantly central. Plasma brain natriuretic peptide concentration in the severe SDB group was 587+/-377 pg/mL, which was significantly higher than those of the remaining three groups (P<0.05). On the other hand, estimated glomerular filtration rate (eGFR) was comparable between non-SDB and SDB groups. There was no statistically significant correlation between eGFR and AHI, or between eGFR and the number of central sleep apneas in the study patients. CONCLUSION: Higher plasma brain natriuretic peptide concentrations were associated with more severe SDB, whereas the level of eGFR was not correlated with the severity of SDB. The results suggest that renal dysfunction plays a relatively minor role in determining breathing abnormalities in chronic heart failure. PMID- 20959889 TI - High red blood cell distribution width is closely associated with risk of carotid artery atherosclerosis in patients with hypertension. AB - BACKGROUND: A high red blood cell distribution width (RDW) may be associated with adverse outcomes in patients with heart failure and risk of death, and cardiovascular events in people with previous myocardial infarction. Ultrasound detection of carotid plaque helps to identify asymptomatic patients with advanced subclinical atherosclerosis, which can predict risk of cardiovascular death or myocardial infarction. However, the relationship of RDW and carotid artery atherosclerosis in hypertensive people is less certain. OBJECTIVE: To evaluate the association between RDW and carotid artery atherosclerosis in people with hypertension. METHODS: RDW was determined using a Coulter counter together with white blood cell count in 156 hypertensive inpatients 60 to 85 years of age. Carotid intimal-medial thickness (IMT) and carotid atherosclerotic plaques were identified by ultrasound imaging. Total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglyceride levels were determined using a multichannel analyzer. Systolic and diastolic blood pressures were measured manually. RESULTS: The number of patients with carotid artery atherosclerotic plaque, as well as the carotid IMT to inner diameter ratio, were significantly different among the different RDW groups of hypertensive inpatients (P<0.01). With linear regression analysis, increased carotid IMT and higher white blood cell count were identified to be significant and independent contributors to the RDW of hypertensive inpatients (P<0.05). CONCLUSIONS: A close relationship between high RDW and IMT, and the incidence of carotid plaque, was identified in 156 hypertensive inpatients. PMID- 20959890 TI - Antibiotics: MRSA prevention measures in German hospitals: results of a survey among hospitals, performed as part of the MRSA-KISS module. AB - BACKGROUND: In this study, we investigated the measures currently being taken in German hospitals to prevent infection with methicillin-resistant strains of Staphylococcus aureus (MRSA). To this end, we circulated a questionnaire among hospitals participating in the MRSA-KISS module. "KISS" in the name of this project stands for "hospital infection surveillance system" (in German, Krankenhaus-Infektions-Surveillance-System). METHODS: The questionnaire was sent to all MRSA-KISS participants. A study doctor visited a representative sample of hospitals to validate the responses. The study doctor checked the questionnaire responses with a systematic on-site interview of the contact person in each hospital, then evaluated the information contained in them by recording all of the MRSA patients who were present in the hospital on the day of the visit in a point-prevalence study (PPS). RESULTS: All 134 participants filled out the questionnaire. The screening of patients at risk on admission is an established part of the clinical routine in all of the surveyed hospitals, as are MRSA decolonization procedures. These preventive measures have been recommended for routine use in Germany by the Robert Koch Institute (RKI, the German counterpart of the Centers for Disease Control and Prevention). The surveyed hospitals also used further preventive strategies, including, for example, an alerting system for the identification, upon hospital admission, of patients with a known history of MRSA positivity (72%); pre-admission screening of all patients (13%); universal screening on admission in some hospital wards (19%); and the prophylactic isolation of patients suspected of having MRSA with pending microbiological test results (21%). 35 hospitals were visited for validation. Most of the responses in each hospital were internally consistent and adequately reflected the real situation on site. Less consistency was seen in responses regarding the detection of MRSA by clinical testing and the measures that were taken after MRSA was detected. CONCLUSION: The surveyed hospitals are, in fact, implementing many of the RKI's recommendations, as well as other preventive measures against MRSA. PMID- 20959891 TI - The role of vitamin D in cancer prevention: does UV protection conflict with the need to raise low levels of vitamin D? AB - BACKGROUND: Vitamin D is essential for life. Part of the body's supply of vitamin D is ingested in food, but UV induced vitamin D synthesis in the body plays an even more important role. UV irradiation is a cause for the currently rising incidence of skin cancer in many countries; on the other hand, Vitamin D might be protective against some cancers. In this paper we summarize the current data on vitamin D and cancer and on the vitamin D status of populations in Europe and discuss whether current recommendations on UV protection require changes. METHODS: In 2008, the International Agency for Research on Cancer (IARC) published a systematic review on vitamin D and cancer. We describe its main findings and review additional publications retrieved by a selective literature search on vitamin D, UV light, and skin cancer. In addition, we systematically review the current recommendations on vitamin D supplementation. RESULTS: Higher vitamin D levels are associated with a lower risk of colon cancer. For breast cancer, the situation is less clear. In general, higher vitamin D levels are associated with lower overall mortality. Concerning optimal Vitamin D levels, serum values >= 50 nmol/L (ie.. >= 20 ng/mL) are frequently discussed, and a few authors favor markedly higher values. Brief UV exposures are usually adequate for endogenous vitamin D synthesis. CONCLUSION: More research is needed into the possible protective effects of vitamin D against cancer. Brief, daily UV exposure stimulates vitamin D production and causes negligible skin damage. Raising the vitamin D level even further by extended solar UV exposure or irradiation in a solarium is inadvisable because of the risk of skin cancer. Oral vitamin D supplementation can be considered as an alternative, particularly for persons at high risk, such as the elderly and members of certain ethnic groups. PMID- 20959892 TI - Re: Deep brain stimulation for psychiatric disorders. Additional reference. PMID- 20959893 TI - Re: Deep brain stimulation for psychiatric disorders. Topic for ethics committee. PMID- 20959894 TI - Re: Deep brain stimulation for psychiatric disorders. A new opportunity. PMID- 20959896 TI - Drug therapy in patients with chronic renal failure. AB - BACKGROUND: Roughly 20% of patients in hospital have impaired kidney function. This is frequently overlooked because of the creatinine-blind range in which early stages of renal failure are often hidden. Chronic kidney disease is divided into 5 stages (CKD 1 to 5). METHODS: Selective literature search. RESULTS: Methotrexate, enoxaparin and metformin are examples of drugs that should no longer be prescribed if the glomerular filtration rate (GFR) is 60 mL/min or less. With antidiabetic (e.g. glibenclamide), cardiovascular (e.g. atenolol) or anticonvulsive (e.g. gabapentin) drugs, the advice is to use alternative preparations such as gliquidone, metoprolol or carbamazepine which are independent of kidney function. Drug dose adjustment should be considered with antimicrobial (e.g. ampicillin, cefazolin), antiviral (e.g. aciclovir, oseltamivir) and, most recently, also for half of all chemotherapeutic and cytotoxic drugs in patients with impaired kidney function (with e.g. cisplatin, for instance, but not with paclitaxel). CONCLUSION: Decisions concerning drug dose adjustment must be based on the pharmacokinetics but this is an adequate prerequisite only in conjunction with the pharmacodynamics. There are two different dose adjustment rules: proportional dose reduction according to Luzius Dettli, and the half dosage rule according to Calvin Kunin. The latter leads to higher trough concentrations but is probably more efficient for anti-infective therapy. PMID- 20959897 TI - Complete disassembly of carbon disulfide by a ditantalum complex. AB - The side-on end-on dinitrogen complex [PhP(CH(2)SiMe(2)NPh)(2)Ta](MU-H)(2)(MU eta(2):eta(1)-N(2)) reacts with CS(2) with complete cleavage of both C=S double bonds and the formation of [PhP(CH(2)SiMe(2)NPh)(2)Ta](MU-S)(2)(MU-CH(2)), which has two bridging sulfides and a bridging methylene unit. Further reaction with H(2) produces CH(4) and the disulfide complex. PMID- 20959898 TI - Synthesis and photophysical properties of kinetically stable complexes containing a lanthanide ion and a transition metal antenna group. AB - A series of bimetallic complexes has been prepared in which an octadentate DOTA monoamide pocket containing a bound lanthanide ion is linked covalently to a Re(I) or Ru(II) bipyridyl unit via an alkyl spacer group. The transition metal chromophores incorporated in this way act as effective sensitisers for lanthanide centred luminescence. The rate and efficiency of energy transfer are dependent upon the nature of the spacer group, and upon the nature of the lanthanide acceptor. For the RuNd diad, there is a long rise-time associated with the energy transfer step, such that energy transfer is rate determining in H(2)O, but not in D(2)O. The results also lead us to suggest that energy transfer may precede formation of the (3)M((Ru/Re))L((bpy))CT state and may be a competitive deactivation pathway for the precursor state ((1)M((Ru/Re))L((bpy))CT). PMID- 20959899 TI - An unexpected base-induced [1,4]-phospho-Fries rearrangement. AB - An unexpected [1,4]-phospho-Fries rearrangement that gives rise to the formation of a O,O,O,O-tetraethyl methylenebis(thiophosphonate) derivative is reported. The regioselectivity of the metallation with n-BuLi or t-BuLi is the key factor that explains either the [1,4] or [1,3] rearrangement observed. PMID- 20959900 TI - The influence of protonation on molecular structure and physico-chemical properties of gossypol Schiff bases. AB - Protonation of gossypol Schiff bases (S1 and S2), possessing different numbers of basic N-atoms, was studied using potentiometric, spectroscopic, ESI MS and PM5 methods. Titration of S1 and S2 with HClO(4), monitored by the FT-IR and (1)H NMR, indicated that the change from the enamine-enamine into the protonated imine imine tautomeric form occurs at different Schiff base-H(+) ratio. The FT-IR and PM5 results show that for S1 the first protonation step occurs at Schiff base moiety whereas for S2 it is realised at N-atom of the morpholine. The formation of N(+)-HO hydrogen bond between morpholine moieties within S2 contributes to high pK(a(ACN)) = 22.65. PMID- 20959901 TI - Comment on "NMR spectroscopic studies of cellobiose solvation in EmimAc aimed to understand the dissolution mechanism of cellulose in ionic liquids" by J. Zhang, H. Zhang, J. Wu, J. Zhang, J. He and J. Xiang, Phys. Chem. Chem. Phys., 2010, 12, 1941. PMID- 20959903 TI - Computational design of orthogonal nucleoside kinases. AB - We report the computational enzyme design of an orthogonal nucleoside analog kinase for 3'-deoxythymidine. The best kinase variant shows an 8500-fold change in substrate specificity, resulting from a 4.6-fold gain in catalytic efficiency for the nucleoside analog and a 2000-fold decline for the native substrate thymidine. PMID- 20959904 TI - Chiral magnetic metal-organic frameworks of Mn(II) with achiral tetrazolate-based ligands by spontaneous resolution. AB - The enantiomers of complex 1 (1a and 1b) have been obtained by spontaneous resolution upon crystallization in the absence of a chiral source. The enantiomeric nature of 1a and 1b was confirmed by circular dichroism (CD) spectra and theoretical investigation. PMID- 20959905 TI - Isomerical and structural determination of N-hydroxyurea: a matrix isolation and theoretical study. AB - The structure, isomerization pathways and vibrational spectra of the important N hydroxyurea (HU) molecule were studied by matrix isolation FT-IR spectroscopy and molecular orbital calculations undertaken at the MP2/6-311++G(2d,2p) level of theory. In agreement with theoretical predictions, 1Ea represents the most stable keto isomer in the gas-phase, being the dominant species trapped in argon matrices, while the 1Za isomer also contributes to the spectrum of isolated HU molecules. According to the calculated abundance values at the temperature of evaporation of the compound (393 K), the 1Ea and 1Za isomers together with a small contribution of 1Eb are expected to appear in the experimental spectra. Since the barrier for interconversion 1Ea<-> 1Eb is only ~2 kJ mol(-1), these two isomers are in equilibrium in the matrices and, at low temperature, the population of the less stable 1Eb form is too small to be observed. Full assignment of the observed spectra of N-hydroxyurea and its deuterium analogue was undertaken on the basis of comparison with theoretical data. PMID- 20959906 TI - Polycyclic aromatic hydrocarbons in surface sediments from drinking water sources of Taihu Lake, China: sources, partitioning and toxicological risk. AB - Sources, partitioning and toxicological risk of 15 priority polycyclic aromatic hydrocarbons (PAHs) in surface sediments from drinking water sources of Taihu Lake, with an area of 2428 km(2) located in the most developed and populated area of China, were studied, and the results were compared with those in other lakes of China and the USA. Concentrations of the 15 PAHs in sediments ranged from 436.6 to 1334.9 ng g(-1) (dw). Gasoline combustion, coal combustion, diesel combustion from shipping and spillage of petroleum were apportioned to be the main sources of PAHs in this area by principal component analysis, which contributed 35.19%, 26.43%, 25.41% and 12.97% to the PAH sources estimated by further multiple linear regression. Levels of PAHs in sediments were negatively correlated with contents of clay and fine silt (<16 MUm), while positively with contents of medium silt, coarse silt and sand (>16 MUm). Humin with size larger than 16 MUm contained the largest part of the burden of PAHs in sediments, but the specific partitioning domain (bound humic acid, lipid or insoluble residue) depended on properties of organic matter reflected by optical absorbance at 465 and 665 nm. Total toxic benzo[a]pyrene equivalent (TEQ(carc)) of the carcinogenic PAHs in sediments varied from 31.8 to 209.3 ngTEQ(carc) g(-1). Benzo[a]pyrene and dibenzo[a,h]anthracene contributed 45.36 and 25.31% to total TEQ(carc), posing high toxicological risk to this area. PMID- 20959907 TI - Immuno-pillar chip: a new platform for rapid and easy-to-use immunoassay. AB - We present a new rapid and easy-to-use immunoassay chip which we have named the immuno-pillar chip. It has hydrogel pillars, fabricated inside a microchannel, with many antibody molecules immobilized onto 1 um diameter polystyrene beads. To evaluate the chip performance, we applied it to the sandwich assay of C-reactive protein (CRP), alpha-fetoprotein (AFP) and prostate-specific antigen (PSA), a cardiac and inflammation marker, tumors and prostate cancer markers, respectively. For detection of disease markers, we confirmed the chip provides rapid analysis (total assay time of about 4 min) with high sensitivity, it is easy-to-use (no special skills are needed), and it uses small volumes of the sample and reagent (0.25 uL each). Moreover, multiplex assay for three biomarkers was also possible. Additionally, the immuno-pillar chip has a big advantage of having hardly any influence on the assay results even if the introduction quantities of the sample or reagents are different. PMID- 20959916 TI - Combining in situ characterization methods in one set-up: looking with more eyes into the intricate chemistry of the synthesis and working of heterogeneous catalysts. AB - Several in situ techniques are known which allow investigations of catalysts and catalytic reactions under real reaction conditions using different spectroscopic and X-ray methods. In recent years, specific set-ups have been established which combine two or more in situ methods in order to get a more detailed understanding of catalytic systems. This tutorial review will give a summary of currently available set-ups equipped with multiple techniques for in situ catalyst characterization, catalyst preparation, and reaction monitoring. Besides experimental and technical aspects of method coupling including X-ray techniques, spectroscopic methods (Raman, UV-vis, FTIR), and magnetic resonance spectroscopies (NMR, EPR), essential results will be presented to demonstrate the added value of multitechnique in situ approaches. A special section is focussed on selected examples of use which show new developments and application fields. PMID- 20959917 TI - Characterization of xenobiotic reductase A (XenA): study of active site residues, substrate spectrum and stability. AB - Xenobiotic reductase A (XenA) has broad catalytic activity and reduces various alpha,beta-unsaturated and nitro compounds with moderate to excellent stereoselectivity. Single mutants C25G and C25V are able to reduce nitrobenzene, a non-active substrate for the wild type, to produce aniline. Total turnover is dominated by chemical rather than thermal instability. PMID- 20959919 TI - Titanium isopropoxide complexes of a series of sterically demanding aryloxo based [N2O2]2- ligands as precatalysts for ethylene polymerization. AB - Several titanium isopropoxide complexes [N,N'-bis(2-oxo-3-R(1)-5-R(2) phenylmethyl)-N,N'-bis(methylene-p-R(3)-C(6)H(4))-ethylenediamine]Ti(O(i)Pr)(2) [R(1) = t-Bu, R(2) = Me, R(3) = H (1b); R(1) = R(2) = t-Bu, R(3) = H, (2b); R(1) = R(2) = Cl, R(3) = H, (3b), R(1) = t-Bu, R(2) = Me, R(3) = Cl (4b); R(1) = R(2) = t-Bu, R(3) = Cl, (5b); R(1) = R(2) = R(3) = Cl, (6b)] supported over sterically demanding aryloxy based [N(2)O(2)]H(2) ligands have been designed as precatalysts for the ethylene polymerization. Specifically, the 1b-6b complexes, when treated with methylaluminoxane (MAO) under 88 +/- 0.5 psi of ethylene at 30 degrees C for 3 h, produced polyethylene polymers of high molecular weight (M(w) = ca. 7.2 8.3 * 10(5) g mol(-1)) having broad molecular weight distribution (PDI = ca. 13.1 14.6). The 1b-6b complexes were conveniently synthesized from the direct reaction of the [N(2)O(2)]H(2) ligands, 1a-6a, with Ti(O(i)Pr)(4) in 69-86% yield. PMID- 20959918 TI - Bio-templated CdSe nanoparticle synthesis in a cage shaped protein, Listeria-Dps, and their two dimensional ordered array self-assembly. AB - We report here, for the first time, a biotemplated synthesis of uniform CdSe nanoparticle (4.1 +/- 0.5 nm) and a fabrication of two-dimensional CdSe nanoparticles (over one micrometre) with nanometric gaps by cage-like protein, Listeria-Dps. PMID- 20959920 TI - Incorporation of metallocenes into the channel structured Metal-Organic Frameworks MIL-53(Al) and MIL-47(V). AB - A selection of metallocene inclusion compounds with channel structured MOFs (MOF = Metal-Organic Framework) were obtained via solvent-fee adsorption of the metallocenes from the gas-phase. The adsorbate structures ferrocene(0.5)@MIL 53(Al) (MIL-53(Al) = [Al(OH)(bdc)](n) with bdc = 1,4-terephthalate), ferrocene(0.25)@MIL-47(V) (MIL-47(V) = [V(O)(bdc)](n)), cobaltocene(0.25)@MIL 53(Al), cobaltocene(0.5)@MIL-47(V), 1-formylferrocene(0.33)@MIL-53(Al), 1,1'dimethylferrocene(0.33)@MIL-53(Al), 1,1'-diformylferrocene(0.5)@MIL-53(Al) were determined from powder X-ray diffraction data and were analyzed concerning the packing and orientation of the guest species. The packing of the ferrocene guest molecules inside MIL-47(V) is significantly different compared to MIL 53(Al) due to the lower breathing effect and weaker hydrogen bonds between the guest molecules and the host network in the case of MIL-47(V). The orientation of the metallocene molecule is also influenced by the substituents (CH(3) and CHO) at the cyclopentadienyl ring and the interaction with the bridging OH group of MIL-53(Al). The inclusion of redox active cobaltocene into MIL-47(V) leads to the formation of a charge transfer compound with a negatively charged framework. The reduction of the vanadium centers is stoichiometric. The resulting material is a mixed valence compound with a V(3+)/V(4+) ratio of 1:1. The new compounds were characterized via thermal gravimetric analysis, infrared spectroscopy, solid state NMR, and differential pulse voltammetry. Both systems are 1D-channel pore structures. The metallocene adsorbate induced breathing effect of MIL-53(Al) is more pronounced compared to MIL-47(V), this can be explained by the different bridging groups between the MO(6) clusters. PMID- 20959921 TI - Size-controlled syntheses and hydrophilic surface modification of Fe3O4, Ag, and Fe3O4/Ag heterodimer nanocrystals. AB - High-quality, monodisperse, and size-controlled Fe(3)O(4), Ag, and bifunctional Fe(3)O(4)/Ag heterodimer nanocrystals (NCs) have been synthesized successfully. In the synthesis of Fe(3)O(4) NCs, dodecanol was chosen as the substitute of 1,2 hexadecanediol and "size control" was achieved by simply adjusting the proportion among the ligands instead of utilizing seed-mediated growth. In the synthesis of Ag NCs, organometallic silver acetylacetonate (Agacac) was used as precursors and tunable particle size could be easily obtained by adjusting the reaction temperatures. By using different sized Fe(3)O(4) NCs as seeds, Fe(3)O(4)/Ag heterodimer NCs with particle sizes tuned from 5 to 16 nm for Fe(3)O(4) and 4 to 8 nm for Ag were successfully synthesized and superparamagnetism were maintained. We found that the size of Ag attached on the Fe(3)O(4) NCs relied on the size of Fe(3)O(4) seed. UV-vis absorption spectra and TEM investigations revealed that the bigger the Fe(3)O(4) NCs seed used, the bigger the Ag NCs that were obtained from the heterodimer NCs. In addition, we demonstrated that all of these NCs were successfully transferred into water by surface modification with biocompatible carboxylic acid groups, which made them meet the basic requirement for biolabeling and biomedical applications. PMID- 20959922 TI - Detection of benzotriazole UV stabilizers in the blubber of marine mammals by gas chromatography-high resolution mass spectrometry (GC-HRMS). AB - Benzotriazole UV stabilizers (BUVSs), such as UV-328 and UV-327, were identified in the blubbers of finless porpoises (Neophocaena phocaenoides) collected from the Ariake Sea, western Japan, by gas chromatography-high resolution mass spectrometry (GC-HRMS). The mean concentrations and standard deviations of UV-328 and UV-327 in five blubber samples were 38 +/- 28 ng g(-1) (lipid wt) and 19 +/- 19 ng g(-1), respectively. The bioconcentration factor (BCF) of UV-327 between water and finless porpoises was estimated to be 33 300, which is approximately one order of magnitude higher than that found for small fish inhabiting the same regions. The BCF of UV-327 in finless porpoises was similar to that of persistent organochlorine pesticide, hexachlorocyclohexane (HCH: 37 000) in marine mammals from the western North Pacific Ocean. These results suggest that BUVSs appear to be persistent and bioaccumulative in the aquatic food chain. Further investigations on temporal trends, and regional and global monitoring of BUVSs are needed to understand their environmental profiles and potential risks to wildlife and human. PMID- 20959924 TI - Room temperature synthesis of highly hemocompatible hydroxyapatite, study of their physical properties and spectroscopic correlation of particle size. AB - Needle shaped nanoparticles of hydroxyapatite (HA) have been synthesized at room temperature using orthophosphoric acid as the source of (PO4)3- ions, while calcium chloride, the calcium source, is suitably complexed with citric acid/tartaric acid/acetic acid. The presence of ligands inhibits the growth along [001] and [100] directions of the crystal and thus, helps in formation of needle shaped nanoparticles. The chemical compositions of the samples have been established through AAS and FTIR spectroscopy, while the crystallinity has been assessed through XRD and by the spectral changes in the upsilon1 and upsilon3 frequencies of the phosphate group in the respective FTIR spectra. The particle sizes of the samples have been determined from line broadening studies and correlations have been established between the curve fitted percentage area of FTIR and full width half height (FWHH) of the XRD peaks. TEM studies revealed the particle to be needle-shaped with a length and diameter in the range of 20-65 nm and 4-11 nm respectively. Changes in the surface charge of the water dispersed HA samples have been determined at different pH and the isoelectric point for the samples have been found in the range of 3.1-3.4. Finally, the morphology, surface area and hemocompatibility characteristics of the HA samples, prepared by using different complexing agents, have been compared. PMID- 20959925 TI - Photochromism of diarylethene single molecules and single crystals. AB - Photochromism is characterized as a reversible colour change of a chemical species upon photoirradiation. Although vast numbers of photochromic molecules have been so far synthesized, molecules which exhibit thermally irreversible photochromic reactivity are limited within a few families of compounds. Among the thermally irreversible photochromic molecules, diarylethene derivatives are the most promising candidates for applications to opto-electronic devices because of their fatigue resistance, high sensitivity and rapid response. In this review, characteristic photochromic performances of the derivatives, detection and analysis of the photochromic reactions at a single-molecule level and application of the single-crystalline photochromism to molecular machinery will be described. PMID- 20959926 TI - Construction and performance characterization of screen printed and carbon paste ion selective electrodes for potentiometric determination of naphazoline hydrochloride in pharmaceutical preparations. AB - This paper describes the development of screen-printed (SPE) and carbon paste (CPE) sensors for the rapid and sensitive quantification of naphazoline hydrochloride (NPZ) in pharmaceutical formulations. This work compares the electroactivity of conventional carbon paste and screen-printed carbon paste electrodes towards potentiometric titration of NPZ. The repeatability and accuracy of measurements performed in the analysis of these pharmaceutical matrices using new screen printed sensors were evaluated. The influence of the electrode composition, conditioning time of the electrode and pH of the test solution, on the electrode performance were investigated. The drug electrode showed Nernstain responses in the concentration range from 1 * 10(-6) to 1 * 10( 2) mol L(-1) with slopes of 57.5 +/- 1.3 and 55.9 +/- 1.6 mV per decade for SPE and CPE, respectively, and was found to be very precise and usable within the pH range 3-8. These sensors exhibited a fast response time (about 3 s for both SPE and CPE, respectively), a low detection limit (3.5 * 10(-6) and 1.5 * 10(-6) M for SPE and CPE, respectively), a long lifetime (3 and 2 months for SPE and CPE, respectively) and good stability. The selectivity of the electrode toward a large number of inorganic cations, sugars and amino acids was tested. It was applied to potentiometric determination of NPZ in pure state and pharmaceutical preparation under batch conditions. The percentage recovery values for the assay of NPZ in tablets (relative standard deviations <=0.3% for n = 4) were compared well with those obtained by the official method. PMID- 20959927 TI - Dual templating synthesis of hierarchical porous silica materials with three orders of length scale. AB - Three-dimensionally interconnected, highly porous silica materials with ordering on three different scales, that is, macropores (10-30 MUm), interconnecting windows (3-5 MUm), and nanoporous walls (~80 nm), are prepared via a dual templating approach. PMID- 20959928 TI - Phenotypic profile linked to inhibition of the major Zn influx system in Salmonella enterica: proteomics and ionomics investigations. AB - Zinc is required for a wide variety of cellular functions and plays a key role in bacterial metabolism and virulence. However, Zn can also be toxic and, therefore, its influx is tightly regulated. The high affinity zinc uptake transporter ZnuABC is the main Zn influx system in Salmonella enterica under conditions of Zn starvation. It has been shown that deletion of the gene encoding for its periplasmic subunit ZnuA significantly affects S. Typhimurium growth rate and virulence, highlighting the importance of this system in the host-pathogen interaction. To gain further insight into the mechanisms involved in Zn influx regulation, we characterized the main alterations in the ionome and proteome of S. Typhimurium wild type and znuA mutant strains grown either under Zn starvation or under Zn-replete conditions. We found significant differences in the element profile and protein expression that were reversed by Zn supplementation. In particular, several of the differentially regulated proteins are predicted to be metal-binding proteins. Interestingly, their over-expression in the znuA mutant strain strictly depends on Zn starvation and correlates with the differences found at the ionome level. In conclusion, our data demonstrate that inhibition of Zn influx has relevant effects either on the bacterial ionome or proteome and shed new light on the role of the ZnuABC system and Zn influx in S. Typhimurium pathogenicity. PMID- 20959929 TI - Fungal cyclooligomer depsipeptides: from classical biochemistry to combinatorial biosynthesis. AB - This review surveys the biological activities and the iterative and recursive biosynthetic mechanisms of fungal cyclooligomer depsipeptides, and their structural diversification by various combinatorial biosynthetic methods. PMID- 20959930 TI - Construction of a functional IgG-binding luciferase fusion protein for the rapid detection of specific bacterial strains. AB - A fusion protein consisting of two IgG-binding domains of streptococcal protein G and firefly luciferase was constructed, and a simple and specific bioluminescent immunodetection system for bacterial strains was developed. PMID- 20959931 TI - A new method for municipal solid waste incinerator (MSWI) fly ash inertization, based on colloidal silica. AB - Municipal solid waste incineration (MSWI) is a straightforward way to manage waste, however the disposal of process byproducts, mainly bottom and fly ash, is still a problem, because of their hazardous contents. Fly ash is a byproduct of many other processes that involve combustion to produce energy. In this paper we present and discuss a new method for MSWI fly ash inertization, mainly based on the use of colloidal silica as a stabilization agent for metals. In the patented procedure, fly ash of different provenance can be used to produce an inert and non-hazardous material, that can be reused. In fact to make the recovery process more efficient, landfilling should be totally avoided. For this reason, to enhance the possibility of reuse, a washing process, for salts recovery, is proposed as a final step of the inertization procedure. The obtained inert material is called COSMOS (COlloidal Silica Medium to Obtain Safe inert), and it is composed of calcium carbonate, calcium sulfate, silicon oxide and a wide quantity of non-soluble amorphous compounds. COSMOS does not contain any corrosive salts. This makes it extremely interesting for cement industry applications with several other advantages, and environmental benefits. The new proposed inertization procedure appears very promising, because it allows MSWI fly ash to be considered a valuable resource. Thanks to the obtained results, a demonstration project, in the frame of LIFE+, has been funded by the European Commission (LIFE+ 2008 project ENV/IT/000434, ). PMID- 20959932 TI - Use of the parameterised finite element method to robustly and efficiently evolve the edge of a moving cell. AB - In this paper we present a computational tool that enables the simulation of mathematical models of cell migration and chemotaxis on an evolving cell membrane. Recent models require the numerical solution of systems of reaction diffusion equations on the evolving cell membrane and then the solution state is used to drive the evolution of the cell edge. Previous work involved moving the cell edge using a level set method (LSM). However, the LSM is computationally very expensive, which severely limits the practical usefulness of the algorithm. To address this issue, we have employed the parameterised finite element method (PFEM) as an alternative method for evolving a cell boundary. We show that the PFEM is far more efficient and robust than the LSM. We therefore suggest that the PFEM potentially has an essential role to play in computational modelling efforts towards the understanding of many of the complex issues related to chemotaxis. PMID- 20959933 TI - In situ growth of gold nanoparticles on latent fingerprints-from forensic applications to inkjet printed nanoparticle patterns. AB - Latent fingerprints are made visible in a single step by in situ growth of gold nanoparticles on ridge patterns. The chemicals, among the essential components of human sweat, found responsible for the formation and assembly of gold nanoparticles are screened and used as ink to write invisible patterns, using common ball pen and inkjet printer, which are then developed by selectively growing gold nanoparticles by soaking them in gold salt solution. PMID- 20959934 TI - Development of an online citrate/Ca2+ sensing system for dialysis. AB - An online citrate and Ca(2+) sensing system based on sequential injection analysis (SIA) is developed as a safety module for hemodialysis. Host 1 displays high affinity towards citrate, and was selected for this study owing to its unique structural features. The o-aminomethylphenylboronic moiety can effectively interact with the alpha-hydroxycarboxylate moiety of citrate and the remaining two guanidiniums may further stabilize the complex via hydrogen bonds. Fura-2 chelates to Ca(2+) with a high selectivity and affinity and was utilized in this study for Ca(2+) measurements. The citrate sensing chemistry via an indicator displacement assay is orthogonal to the Ca(2+) sensing chemistry, and the use of sophisticated chemometrics is not required for data analysis. The citrate and Ca(2+) concentrations in dialysate samples are measured with the developed SIA system. The obtained citrate concentrations were verified via a commercially available enzymatic assay and an NMR method, respectively, while the Ca(2+) concentrations were verified via atomic absorption. PMID- 20959935 TI - Synthesis and electron-transfer properties of benzimidazole-functionalized ruthenium complexes for highly efficient dye-sensitized solar cells. AB - Novel heteroleptic ruthenium complexes--RD1, RD5, RD10 and RD11--with ligands based on benzimidazole were synthesized and characterized for application to dye sensitized solar cells (DSSC); the remarkable performance of RD5-based DSSC is understood for its superior light-harvesting ability and slower charge recombination kinetics. PMID- 20959936 TI - Iridium- and ruthenium-catalysed synthesis of 2,3-disubstituted indoles from anilines and vicinal diols. AB - A straightforward and atom-economical method is described for the synthesis of 2,3-disubstituted indoles. Anilines and 1,2-diols are condensed under neat conditions with catalytic amounts of either [Cp*IrCl(2)](2)/MsOH or RuCl(3).xH(2)O/phosphine (phosphine = PPh(3) or xantphos). The reaction does not require any stoichiometric additives and only produces water and dihydrogen as byproducts. Anilines containing methyl, methoxy, chloro and fluoro substituents can participate in the cyclocondensation. Meta-substituted anilines give good regioselectivity for 6-substituted indoles, while unsymmetrical diols afford excellent regioselectivity for the indole isomer with an aryl or large alkyl group in the 2-position. The mechanism for the cyclocondensation presumably involves initial formation of the alpha-hydroxyketone from the diol. The ketone subsequently reacts with aniline to generate the alpha-hydroxyimine which rearranges to the corresponding alpha-aminoketone. Acid- or metal-catalysed electrophilic ring-closure with the release of water then furnishes the indole product. PMID- 20959937 TI - A two-component polymeric optode membrane based on a multifunctional ionic liquid. AB - This work details the use of a 2-component optode membrane which is capable of generating three distinct colours in the presence of Cu(2+) and Co(2+) ions. It has been found that the ionic liquid (IL) trihexyltetradecylphosphonium dicyanamide [P(6,6,6,14)][DCA] can act as plasticizer, ligand and transducer dye when used in poly(vinyl chloride) (PVC) membranes, which significantly simplifies the optode membrane cocktail. Upon exposure to an aqueous Cu(2+) solution, a yellow colour is generated within the membrane, while exposure to an aqueous Co(2+) solution generates a blue colour. Exposure to a solution containing both ions produces a green colour. Vibrational spectroscopy has been used to investigate the molecular basis of the IL-metal ion the binding mechanism. Analytical characteristics of the membranes including the effect of interfering ions, binding constants and the limit of detection for both ions have been estimated. Finally the case of simultaneous dual-analyte recognition is presented based on two distinct absorption maxima. PMID- 20959938 TI - A metering rotary nanopump for microfluidic systems. AB - We describe the design, fabrication, and testing of a microfabricated metering rotary nanopump for the purpose of driving fluid flow in microfluidic devices. The miniature peristaltic pump is composed of a set of microfluidic channels wrapped in a helix around a central camshaft in which a non-cylindrical cam rotates. The cam compresses the helical channels to induce peristaltic flow as it is rotated. The polydimethylsiloxane (PDMS) nanopump design is able to produce intermittent delivery or removal of several nanolitres of fluid per revolution as well as consistent continuous flow rates ranging from as low as 15 nL min(-1) to above 1.0 uL min(-1). At back pressures encountered in typical microfluidic devices, the pump acts as a high impedance flow source. The durability, biocompatibility, ease of integration with soft-lithographic fabrication, the use of a simple rotary motor instead of multiple synchronized pneumatic or mechanical actuators, and the absence of power consumption or fluidic conductance in the resting state all contribute to a compact pump with a low cost of fabrication and versatile implementation. This suggests that the pump design may be useful for a wide variety of biological experiments and point of care devices. PMID- 20959939 TI - Microfluidic fabrication of SERS-active microspheres for molecular detection. AB - In this paper, we demonstrated a microfluidic system for fabricating microspheres with hierarchical surface nanopatterns for molecular detection based on surface enhanced Raman scattering (SERS). Briefly, a photocurable silica suspension was emulsified into monodisperse droplets using a microfluidic device composed of two coaxial glass capillaries. The silica particles in each droplet protruded through the interface and spontaneously formed a hexagonal array. After polymerization of the droplets, we selectively decorated the exposed areas of the silica particles with silver nanoparticles through electroless deposition. The resulting hierarchically-structured microspheres showed high sensitivity and fast binding kinetics in molecular detection based on SERS, owing to the dense array of hot spots on each microsphere and high mobility of the microspheres, respectively. Notably, the SERS signals from molecules adsorbed on the microspheres could be detected in both the dried and suspension states. In addition, we demonstrated that the SERS-active microspheres can be functionalized into structural colored or magnetoresponsive microspheres for advanced applications. PMID- 20959941 TI - Editorial. PMID- 20959940 TI - Magnesium hydride-promoted dearomatisation of pyridine. AB - Reaction of pyridine with well defined magnesium hydride species results in heterocycle dearomatisation by a hydride transfer which occurs with the formation of magnesium compounds containing 1,2- and 1,4-dihydropyridide anions as the respective kinetic and thermodynamic products. PMID- 20959942 TI - Alternatives in polymerization contraction stress management. AB - Polymerization contraction stress of dental composites is often associated with marginal and interfacial failure of bonded restorations. The magnitude of the stress depends on the composite's composition (filler content and matrix composition) and its ability to flow before gelation, which is related to the cavity configuration and curing characteristics of the composite. This article reviews the variations found among studies regarding the contraction stress testing method, contraction stress values of current composites, and discusses the validity of contraction stress studies in relation to results from microleakage tests. The effect of lower curing rates and alternative curing routines on contraction stress values is also discussed, as well as the use of low elastic modulus liners. Moreover, studies with experimental Bis-GMA-based composites and recent developments in low-shrinkage monomers are described. PMID- 20959943 TI - Water movement across bonded dentin - too much of a good thing. AB - Over the last decade, the classic concept of 3-step bonding to dental tissues has developed rapidly to more user-friendly, simplified adhesive systems. These comprise the total-etch 2 step, self-etch 2step and the self-etch "all-in-one" adhesives. These adhesives carry along with simplicity some characteristics that are relevant to their efficacy in providing long-lasting bond stability. They share with the glass ionomer cements a class of materials that have high affinity for water. Such hydrophilicity renders such adhesives very permeable and denies their ability to hermetically seal dentin surfaces. Additionally, the water flux across simplified adhesives may compromise bonding in certain circumstances and their durability in the oral environment. This paper presents evidences of the water transport across simplified adhesive systems and glass ionomer cements and relates them with clinical implications of the phenomenon. PMID- 20959944 TI - Dental ceramics and the molar crown testing ground. AB - All ceramic crowns are highly esthetic restorations and their popularity has risen with the demand for life-like and cosmetic dentistry. Recent ceramic research has concentrated on developing a fundamental understanding of ceramic damage modes as influenced by microstructure. Dental investigations have elucidated three damage modes for ceramic layers in the 0.5-2 mm thickness using point contacts that duplicate tooth cuspal radii; classic Hertzian cone cracking, yield (pseudo-plastic behavior), and flexural cracking. Constitutive equations based upon materials properties have been developed that predict the damage modes operational for a given ceramic and thickness. Ceramic thickness or thickness of the stiff supporting core in layer crowns is critical in flexural cracking as well as the flaw state of the inner aspect of the crown. The elastic module of the supporting structure and of the luting cement and its thickness play a role in flexural fracture. Clinical studies of ceramics extending over 16 years are compared to the above relationships and predictions. Recommendations for clinical practice are made based upon the above. PMID- 20959945 TI - [Not Available]. PMID- 20959946 TI - Bilateral vertebral artery dissection after chiropractic maneuver. PMID- 20959947 TI - Primary intradural Hodgkin's lymphoma in lumbosacral spine: a rare location. PMID- 20959948 TI - [Master of business administration as panacea]. PMID- 20959949 TI - [Protective ileostoma versus protective transverse stoma. What evidence is available?]. AB - The clinical outcome of anastomotic leakage in colorectal and coloanal anastomoses necessitates a loop stoma for fecal diversion. Controversy remains of the most suitable position of the stoma. In this respect a loop ileostomy or loop colostomy can be performed. The aim of this study was to determine the advantages and disadvantages of both surgical strategies from the literature and to derive possible recommendations. Both methods provide a good operative outcome with low complication rates. Overall there is a trend towards ileostomy because of lower complication rates after stoma creation and the incidence of sepsis and stoma prolapse in particular is significantly reduced after ileostomy. Concerning stoma reversal both methods seem to be equivalent. As long as no large evidenced-based, randomized studies are available loop ileostomy seems to be the most appropriate surgical procedure. PMID- 20959950 TI - [Cutis verticis gyrata with a combined blue and congenital dermal nevus]. AB - Cutis verticis gyrata (CVG) describes a rare thickening and folding of the scalp resembling the outer surface of the brain. Secondary CVG is caused by a variety of diseases such as nevi. A 38-year-old woman presented with a long history of a deformed right parietofrontal scalp. Clinical and histopathologic criteria lead to the diagnosis of CVG secondary to a combined blue and congenital nevus. Reports of malignant melanoma developing in this clinical setting mean that each patient must be followed closely or considered for prophylactic excision. PMID- 20959951 TI - [Signal transduction in urothelial cancer: how exactly do we know the targets for targeted therapy?]. AB - Targeted therapies have helped to improve the quality of life and prolong the survival of many cancer patients. This progress is based on the growing understanding of cellular signal transduction pathways and regulatory systems in human cancers. In urothelial carcinoma, a number of specific alterations have been identified. These include mutations in FGFR3, HRAS, and PIK3CA leading to overactivity of MAPK and Akt signaling pathways especially in papillary tumors. In comparison, the RB1 and p53 regulatory systems that act more directly on cell cycle control are more commonly compromised in invasive carcinomas. Nevertheless, targeted therapies have shown little efficacy in the treatment of urothelial carcinoma so far, owing presumably to our incomplete knowledge of molecular changes affecting signal transduction pathways in this cancer type. Target genes of cancer pathways are regulated by epigenetic mechanisms, which determine their inducibility. Elucidating these control mechanisms could therefore prove important for developing targeted therapies for urothelial carcinoma. PMID- 20959952 TI - [Become a urologist / Urologist for a day: The German contribution to EAU Urology Week 2010.]. PMID- 20959953 TI - [Molecular markers in the diagnostics and therapy of urothelial cancer]. AB - Many clinical decisions in the management of bladder cancer would benefit from better and reliable knowledge of individual prognosis. Marker for urothelial cancer can principally be measured in blood, urine and transurethrally resected tissue. In recent years new markers have been identified by new technologies and this opens exiting avenues. Since no single marker gives a clear Yes-or-no prognostic answer but always only a measure of probability, the use of marker systems has so far not gained widespread clinical applications. This will likely change in future. PMID- 20959954 TI - [Early detection of prostate cancer: is serum PSA testing alone sufficient?]. AB - The euphoria over PSA as an optimal marker for prostate cancer is gone. Measuring PSA levels has several deficiencies in detecting prostate cancer. First results of the randomized studies ERSPC and PLCO were not able to conclusively prove the value of PSA-based screening. Many attempts have been made to optimize early detection of prostate cancer like using modern imaging techniques or new biomarkers. This review deals with PSA isoforms und emerging biomarkers for the diagnosis of prostate cancer. Despite the inadequacies of PSA it is still the most important marker for the early detection of prostate cancer. Modern biomarkers with the ability to reliably predict aggressive prostate cancer are still missing. PMID- 20959955 TI - Non-fasting lipids and risk of cardiovascular disease in patients with diabetes mellitus. AB - AIMS/HYPOTHESIS: The aim of this study was to examine the effect of postprandial time on the associations and predictive value of non-fasting lipid levels and cardiovascular disease risk in participants with diabetes. METHODS: This study was conducted among 1,337 participants with diabetes from the Dutch and German (Potsdam) contributions to the European Prospective Investigation into Cancer and Nutrition. At baseline, total cholesterol, LDL- and HDL-cholesterol and triacylglycerol concentrations were measured and the ratio of total cholesterol/HDL-cholesterol was calculated. Participants were followed for incidence of cardiovascular disease. RESULTS: Lipid concentrations changed minimally with increasing postprandial time, except for triacylglycerol which was elevated just after a meal and declined over time (1.86 at 0.1 h to 1.33 at >6 h, p for trend <0.001). During a mean follow-up of 8 years, 116 cardiovascular events were documented. After adjustment for potential confounders, triacylglycerol (HR for third tertile compared with first tertile (HR(t)3(to)1), 1.73 [95% CI 1.04, 2.87]), HDL-cholesterol (HR(t)3(to)1, 0.41 [95% CI 0.23, 0.72]) and total cholesterol/HDL-cholesterol ratio (HR(t)3(to)1, 1.65 [95% CI 0.95, 2.85]) were associated with cardiovascular disease, independent of postprandial time. Cardiovascular disease risk prediction using the UK Prospective Diabetes Study risk engine was not affected by postprandial time. CONCLUSIONS/INTERPRETATION: Postprandial time did not affect associations between lipid concentrations and cardiovascular disease risk in patients with diabetes, nor did it influence prediction of cardiovascular disease. Therefore, it may not be necessary to use fasting blood samples to determine lipid concentrations for cardiovascular disease risk prediction in patients with diabetes. PMID- 20959957 TI - Accuracy of automated continuous calculation of pulse pressure variation in critically ill patients. PMID- 20959956 TI - Intensive glycaemic control and cancer risk in type 2 diabetes: a meta-analysis of major trials. AB - AIMS/HYPOTHESIS: The purpose of this study was to explore the relationship between hyperglycaemia in type 2 diabetes and risk of cancer incidence or cancer mortality. We were interested to determine if data from major randomised controlled trials would support a hypothesis that improving glycaemic control may reduce the risk of cancer outcomes. METHODS: We included major randomised controlled trials conducted with an overall aim of intensified glycaemic control in type 2 diabetes. We abstracted data from published papers and supplemental material and conducted separate meta-analyses of cancer mortality and cancer incidence. RESULTS: Four trials reported cancer mortality for the intensive (222 events in 53,892 person-years) and standard control (155 events in 38,743 person years) arms (UK Prospective Diabetes Study [UKPDS] 33, UKPDS 34, Action to Control Cardiovascular Risk in Diabetes [ACCORD] and Veterans Affairs Diabetes Trial [VADT]); the summary risk ratio for cancer mortality was 1.00 (95% CI 0.81 1.24; I2 = 0%). Excluding the UKPDS metformin trial resulted in a pooled risk estimate of 1.03 (95% CI 0.83-1.29; I2 = 0%). Three trials reported cancer incidence for the study arms (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE], PROspective pioglitAzone Clinical Trial In macroVascular Events [PROactive], Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes [RECORD]) with 357 events in 47,974 person-years with improved glycaemic control and 380 events in 45,009 person-years in the control arms; the pooled risk ratio for cancer incidence was 0.91 (95% CI 0.79-1.05; I2 = 0%). CONCLUSIONS/INTERPRETATION: Data from large randomised controlled trials of intensified glycaemic control suggest that cancer risk is not reduced by improving glycaemic control in type 2 diabetes. These data therefore do not support the hypothesis that hyperglycaemia is causally linked to increased cancer risk. PMID- 20959958 TI - Endobronchial drainage in case of infected posttraumatic pulmonary pseudocyst: an alternative to surgery? PMID- 20959959 TI - Decision to forgo life-sustaining therapies for elderly critically ill patients is a multidisciplinary challenge. PMID- 20959961 TI - Spine-hip discordance and fracture risk assessment: a physician-friendly FRAX enhancement. AB - The FRAX(r) tool estimates a 10-year probability of fracture based upon multiple clinical risk factors and an optional bone mineral density (BMD) measurement obtained from the femoral neck. We describe a simple procedure for using lumbar spine BMD to enhance fracture risk assessment under the FRAX system. INTRODUCTION: Discordance between lumbar spine (LS) and femoral neck (FN) T scores is common and a source of clinical confusion since the LS measurement is not an input variable for the FRAX algorithm. The purpose of this study is to develop a procedure for adjusting FRAX probability based upon the T-score difference between the LS and FN (termed offset). METHODS: The Manitoba BMD database was used to identify baseline LS and FN dual-energy X-ray absorptiometry examinations (33,850 women and 2,518 men age 50 and older) with FRAX estimates for a major osteoporotic fracture categorized as low (<10%), moderate (10-20%), and high (>20%). Fracture outcomes were assessed from population-based administrative data. An approach was developed and internally validated using a split-cohort design. RESULTS: The offset was found to significantly affect fracture risk [HR, 1.12 (95% CI, 1.06-1.18) per SD LS below FN] independent of the FRAX probability. The following rule was formulated: "Increase/decrease FRAX estimate for a major fracture by one tenth for each rounded T-score difference between LS and FN." In the validation subgroup, there was a significant improvement in the fracture prediction using FRAX with the proposed offset adjustment for major osteoporotic (P = 0.007) and vertebral fracture prediction (P < 0.001). For those at moderate risk under FRAX, 12.6% showed reclassification using the offset to a risk level that more accurately reflected their observed risk (25.2% reclassification for moderate risk discordant cases). CONCLUSION: A simple procedure that incorporates the offset between the LS and FN T-scores can enhance fracture risk prediction under the FRAX system. PMID- 20959960 TI - Systemic bone effects of biologic therapies in rheumatoid arthritis and ankylosing spondylitis. AB - Inflammatory joint diseases are responsible of chronic systemic inflammation, joint degradations, deformities, and altered quality of life. Patients suffering from chronic rheumatic diseases also present increased bone fragility and increased fracture risk. Registration of biologic therapies has deeply modified care in rheumatic diseases, especially in rheumatoid arthritis and ankylosing spondylitis. The available biologics are the anti proinflammatory cytokine therapies (TNFalpha blockers, anakinra and tocilizumab) and the biologics active on T cell activation (abatacept and rituximab). These drugs succeeded in blocking disease activity and joint degradation. They are also able to stop systemic bone loss among patients with inflammatory rheumatic diseases. In this review, we present the current understanding of the inflammatory-induced bone loss and the skeletal effects of biologic therapies in inflammatory joint diseases. PMID- 20959962 TI - Changes in the contents of enzymatic immature, mature, and non-enzymatic senescent cross-links of collagen after once-weekly treatment with human parathyroid hormone (1-34) for 18 months contribute to improvement of bone strength in ovariectomized monkeys. AB - Improvements in total content of enzymatic cross-linking, the ratio of hydroxylysine-derived enzymatic cross-links, and non-enzymatic advanced glycation end product cross-link formation from once-weekly administration of hPTH(1-34) for 18 months in OVX cynomolgus monkeys contributed to the improvement of bone strength. INTRODUCTION: Parathyroid hormone (PTH) is used for the treatment of osteoporosis. To elucidate the contribution of material properties to bone strength after once-weekly treatment with hPTH(1-34) in an ovariectomized (OVX) primate model, the content of collagen and enzymatic immature, mature, and non enzymatic cross-links, collagen maturity, trabecular architecture, and mineralization in vertebrae were simultaneously estimated. METHODS: Adult female cynomolgus monkeys were divided into four groups (n = 18-20 each) as follows: SHAM group, OVX group, and OVX monkeys given once-weekly subcutaneous injections of hPTH(1-34) either at 1.2 or 6.0 MUg/kg (low- or high-PTH groups) for 18 months. The content of collagen, enzymatic and non-enzymatic cross-linking pentosidine, collagen maturity, trabecular architecture, mineralization, and cancellous bone strength of vertebrae were analyzed. RESULTS: Low-PTH and high hPTH treatments increased the content of enzymatic immature and mature cross links, bone volume (BV/TV), and trabecular thickness, and decreased pentosidine, compared with the OVX group. Stepwise logistic regression analysis revealed that BV/TV, the content of total enzymatic cross-links, and calcium content independently affected ultimate load (model R (2) = 0.748, p < 0.001) and breaking energy (model R (2) = 0.702, p < 0.001). BV/TV was the most powerful and enzymatic cross-link content was the second powerful determinant of both ultimate load and breaking energy. The most powerful determinant of stiffness was the enzymatic cross-link content (model R (2) = 0.270, p < 0.001). CONCLUSION: Once weekly preventive administration of hPTH(1-34) increased the total contents of immature and mature enzymatic cross-links, which contributed significantly to vertebral cancellous bone strength. PMID- 20959963 TI - Oral bisphosphonates are associated with reduced mortality in frail older people: a prospective five-year study. AB - In a study of 2005 institutionalized older people, use of oral bisphosphonates was associated with a 27% reduction in risk of death compared to non-users after adjusting for potential confounders. INTRODUCTION: This study investigated whether reductions in mortality reported in a trial of intravenous zoledronate after hip fracture could be seen in older people taking oral bisphosphonates. METHODS: Two thousand and five institutionalized older people (mean age 85.7 years) were assessed at baseline and followed up for hip fracture and death for at least 5 years. Cox proportional hazards regression was used to estimate effects of bisphosphonates on risk of death. RESULTS: At baseline, 78 subjects were taking oral bisphosphonates. Over 5 years of follow-up, 1,596 participants (80%) died. Use of bisphosphonates was associated with a 27% reduction in risk of death compared to non-users after adjusting for age, gender, type of institution, immobility, number of medications, weight, cognitive function, co-morbidities, and hip fracture incidence during the follow-up period (hazard ratio 0.73; 95% CI, 0.56 to 0.94; P = 0.02). CONCLUSION: Oral bisphosphonates are associated with a reduction in the risk of death in the elderly. The mechanism of effect requires further investigation. PMID- 20959964 TI - Low bone turnover and increase of bone mineral density in a premenopausal woman with postoperative hypoparathyroidism and thyroxine suppressive therapy. AB - We report the case of a 36-year-old woman who developed permanent hypoparathyroidism after thyroidectomy for differentiated thyroid carcinoma. A 6 year follow-up showed an increase of 11% in absolute bone mineral density at the spine and 6% at the hip accompanied by low bone turnover despite thyroid stimulating hormone suppressive thyroxine therapy. PMID- 20959965 TI - Multifactorial evaluation and treatment of persons with a high risk of recurrent falling was not cost-effective. AB - SUMMARY: This study evaluated the cost-effectiveness of multifactorial evaluation and treatment of fall risk factors in community-dwelling older persons at high risk of falling. The intervention and usual care groups did not differ in fall risk or costs. The multifactorial approach was not cost-effective compared to usual care in this group. INTRODUCTION: International guidelines recommend multifactorial evaluation and tailored treatment of risk factors to reduce falling in older persons. The cost-effectiveness may be enhanced in high-risk persons. Our study evaluates the cost-effectiveness of multifactorial evaluation and treatment of fall risk factors in community-dwelling older persons at high risk of recurrent falling. METHODS: An economic evaluation was conducted alongside a randomised controlled trial. Participants (>=65 years) with a high risk of recurrent falling were randomised into an intervention (n = 106) and usual care group (n = 111). The intervention consisted of multifactorial assessment and treatment of fall risk factors. Clinical outcomes were proportions of fallers and utility during 1 year. Costs were measured using questionnaires at 3, 6 and 12 months after baseline and valued using cost prices, if available, and guideline prices. Differences in costs and cost-effectiveness were analysed using bootstrapping. Cost-effectiveness planes and acceptability curves were presented. RESULTS: During 1 year, 52% and 56% of intervention and usual care participants reported at least one fall, respectively. The clinical outcome measures did not differ between the two groups. The mean costs were Euro 7,740 (SD 9,129) in the intervention group and Euro 6,838 (SD 8,623) in the usual care group (mean difference Euro 902, bootstrapped 95% CI: -1,534 to 3,357). Cost-effectiveness planes and acceptability curves indicated that multifactorial evaluation and treatment of fall risk factors was not cost-effective compared with usual care. CONCLUSIONS: Multifactorial evaluation and treatment of persons with a high risk of recurrent falling was not cost-effective compared to usual care. PMID- 20959966 TI - Spatial memory alterations by activation of septal 5HT 1A receptors: no implication of cholinergic septohippocampal neurons. AB - INTRODUCTION: In rats, activation of medial septum (MS) 5-HT(1A) receptors with the 5-HT(1A)/5-HT(7) receptor agonist 8-OH-DPAT disrupts encoding and consolidation, but not retrieval of a spatial memory in the water maze task. These findings might be explained by an action of 8-OH-DPAT on 5-HT(1A) receptors located on cholinergic neurons which the drug could transiently hyperpolarise. If so, selective damage of these neurons should mimic the effects of 8-OH-DPAT, or, at least, synergistically interfere with them. METHODS: To test this hypothesis, rats were subjected to intraseptal infusions of 8-OH-DPAT (or phosphate-buffered saline) during acquisition of a water maze task before and/or after 192 IgG saporin-induced MS cholinergic lesion (vs. sham-operated). RESULTS: We confirmed that only pre-acquisition intraseptal 8-OH-DPAT infusions prevented learning and subsequent drug-free retrieval of the platform location in intact rats and found that (1) the cholinergic lesion did not prevent recall of the platform location, and (2) the impairing effects of 8-OH-DPAT were similar in sham-operated and lesioned rats, whether naive or not, to the task before lesion surgery. CONCLUSIONS: An action of 8-OH-DPAT on only MS cholinergic neurons is not sufficient to account for the drug-induced memory impairments. A concomitant 8-OH DPAT-induced hyperpolarisation of cholinergic and/or GABAergic and/or glutamatergic neurons (intact rats), or of only GABAergic and/or glutamatergic ones after cholinergic lesion, might be necessary to obliterate task acquisition, confirming that, in the MS, (1) the three neuronal populations could cooperate to process hippocampal-dependent information, and (2) non-cholinergic septohippocampal neurons might be more important than cholinergic ones in serotonin-induced modulation of hippocampus-dependent memory processing. PMID- 20959967 TI - Hypocretin 1/orexin A in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration. AB - RATIONALE: Recent evidence indicates that the hypocretin/orexin system participates in the regulation of reinforcement and addiction processes. For example, manipulations that decrease hypocretin neurotransmission result in disruptions of neurochemical and behavioral responses to cocaine. OBJECTIVES: To further assess the relationship between the hypocretin system and cocaine reinforcement, the current studies used microdialysis and in vivo voltammetry to examine the effects of hypocretin 1 on cocaine-induced enhancement of dopamine signaling in the nucleus accumbens core. Fixed ratio, discrete trials, and progressive ratio self-administration procedures were also used to assess whether hypocretin 1 promotes cocaine self-administration behavior. RESULTS: Infusions of hypocretin 1 into the ventral tegmental area increased the effects of cocaine on tonic and phasic dopamine signaling and increased the motivation to self administer cocaine on the discrete trials and progressive ratio schedules. CONCLUSIONS: Together with previous observations demonstrating that a hypocretin 1 receptor antagonist disrupts dopamine signaling and reduces self-administration of cocaine, the current observations further indicate that the hypocretin system participates in reinforcement processes likely through modulation of the mesolimbic dopamine system. PMID- 20959968 TI - Nigrostriatal denervation changes the effect of cannabinoids on subthalamic neuronal activity in rats. AB - RATIONALE: It is known that dopaminergic cell loss leads to increased endogenous cannabinoid levels and CB1 receptor density. OBJECTIVE: The aim of this study was to evaluate the influence of dopaminergic cell loss, induced by injection of 6 hydroxydopamine, on the effects exerted by cannabinoid agonists on neuron activity in the subthalamic nucleus (STN) of anesthetized rats. RESULTS: We have previously shown that Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and anandamide induce both stimulation and inhibition of STN neuron activity and that endocannabinoids mediate tonic control of STN activity. Here, we show that in intact rats, the cannabinoid agonist WIN 55,212-2 stimulated all recorded STN neurons. Conversely, after dopaminergic depletion, WIN 55,212-2, Delta(9)-THC, or anandamide inhibited the STN firing rate without altering its discharge pattern, and stimulatory effects were not observed. Moreover, anandamide exerted a more intense inhibitory effect in lesioned rats in comparison to control rats. CONCLUSIONS: Cannabinoids induce different effects on the STN depending on the integrity of the nigrostriatal pathway. These findings advance our understanding of the role of cannabinoids in diseases involving dopamine deficits. PMID- 20959970 TI - Drug-to-drug interaction between sodium valproate and trihexyphenidyl in a child with extrapyramidal cerebral palsy and epilepsy. PMID- 20959969 TI - Behavioral characterization of adult male and female rhesus monkeys exposed to cocaine throughout gestation. AB - RATIONALE: In utero cocaine exposure has been associated with alterations in the dopamine (DA) system in monkeys. However, the behavioral outcomes of prenatal cocaine exposure in adulthood are poorly understood. OBJECTIVES: To assess several behavioral measures in 14-year-old rhesus monkeys exposed to cocaine in utero and controls (n = 10 per group). MATERIALS AND METHODS: For these studies, two unconditioned behavioral tasks, novel object reactivity and locomotor activity, and two conditioned behavioral tasks, response extinction and delay discounting, were examined. In addition, cerebrospinal fluid (CSF) samples were analyzed for concentrations of the monoamine metabolites homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA). RESULTS: No differences in CSF concentrations of 5-HIAA and HVA, latencies to touch a novel object or locomotor activity measures were observed between groups or sexes. However, prenatally cocaine-exposed monkeys required a significantly greater number of sessions to reach criteria for extinction of food-reinforced behavior than control monkeys. On the delay-discounting task, male prenatally cocaine-exposed monkeys switched preference from the larger reinforcer to the smaller one at shorter delay values than male control monkeys; no differences were observed in females. CONCLUSIONS: These findings suggest that prenatal cocaine exposure results in long-term neurobehavioral deficits that are influenced by sex of the individual. PMID- 20959971 TI - Appearance of hypoplastic cochleae in CT and MRI: a new subclassification. AB - INTRODUCTION: Hypoplastic cochleae are among the inner ear malformations more frequently encountered by radiologists; little detailed information is available on these, however. We present the first large series of hypoplastic cochleae and document imaging findings to better characterize this anomaly radiologically. METHODS: We used our electronic database to search for inner ear malformations described between 1995 and 2009 and extracted 81 ears (of 47 patients) with hypoplastic cochleae out of 289 patients with inner ear malformations. Two neuroradiologists evaluated the available CT and MRI data. Measurements of all inner ear structures were performed. Accompanying findings were listed. RESULTS: Cochlear hypoplasia (58 ears, 32 patients) often involves not only the apical turn being reduced in size but also the basal turn being smaller in length. Additionally, 11 ears (eight patients) of hypoplastic cochleae with only a basal turn and five ears (four patients) of cochleae with only a small bud were identified. Non-classifiable hypoplastic cochleae (seven ears, five patients) were those with either a rudimentary or an absent basal turn or a "dwarf appearance" with no further partition. CONCLUSIONS: The term "hypoplastic cochlea" is very general; a further division into severe and less severe forms based on the length and existence of cochlea turns is possible and can help enhance the comparison of CI outcome data. Measurements can help the less experienced radiologist to detect them more easily. PMID- 20959972 TI - Proton MR spectroscopic imaging of basal ganglia and thalamus in neurofibromatosis type 1: correlation with T2 hyperintensities. AB - INTRODUCTION: Neurofibromatosis type 1 (NF1) is frequently associated with hyperintense lesions on T2-weighted images called "unidentified bright objects" (UBO). To better characterize the functional significance of UBO, we investigate the basal ganglia and thalamus using spectroscopic imaging in children with NF1 and compare the results to anomalies observed on T2-weighted images. METHODS: Magnetic resonance (MR) data of 25 children with NF1 were analyzed. On the basis of T2-weighted images analysis, two groups were identified: one with normal MR imaging (UBO- group; n = 10) and one with UBO (UBO+ group; n = 15). Within the UBO+ group, a subpopulation of patients (n = 5) only had lesions of the basal ganglia. We analyzed herein seven regions of interest (ROIs) for each side: caudate nucleus, capsulo-lenticular region, lateral and posterior thalamus, thalamus (lateral and posterior voxels combined), putamen, and striatum. For each ROI, a spectrum of the metabolites and their ratio was obtained. RESULTS: Patients with abnormalities on T2-weighted images had significantly lower NAA/Cr, NAA/Cho, and NAA/mI ratios in the lateral right thalamus compared with patients with normal T2. These abnormal spectroscopic findings were not observed in capsulo-lenticular regions that had UBO but in the thalamus region that was devoid of UBO. CONCLUSION: Multivoxel spectroscopic imaging using short-time echo showed spectroscopic abnormalities in the right thalamus of NF1 patients harboring UBO, which were mainly located in the basal ganglia. This finding could reflect the anatomical and functional interactions of these regions. PMID- 20959973 TI - Evaluation of liver fibrosis with T2 relaxation time in infants with cholestasis: comparison with normal controls. AB - BACKGROUND: The degree of hepatic fibrosis in biliary atresia (BA) correlates with the prognosis of the disease and thus, early diagnosis of liver fibrosis is clinically important. Liver biopsy is the gold standard for the evaluation of liver fibrosis, but it is an invasive procedure requiring sedation in children. Therefore, it is desirable to identify a noninvasive method for diagnosis and follow-up of hepatic fibrosis. OBJECTIVE: The purpose of this study is to evaluate the possibility of quantifying liver fibrosis in infants by T2 relaxation time measurements. MATERIALS AND METHODS: The institutional review board approved this prospective study and parental informed consent was obtained. During MR cholangiopancreatography using a 1.5-T MR scanner in infants with neonatal cholestasis, T2 relaxation time of the liver was calculated with the mean signal intensities measured on images obtained using spin-echo sequences (TR/TE, 2,000/20, 40, 60, 80, 100, 120, 140, 160 ms). A normal control study was performed during spinal MRI in infants with anorectal malformation and normal liver enzyme profiles. A liver biopsy was obtained in the children with cholestasis. The correlation between histopathological fibrosis stage and T2 relaxation time was evaluated by Kendall's Tau-b test. RESULTS: Twenty-five infants (male: female, 12:13; age range 0-11 months, mean 3.2 months), 14 with neonatal cholestasis (9 BA and 5 non-BA) and 11 normal controls were included in this study. Relaxation times (mean +/- standard deviation [SD]) for the liver were 57.8 ms +/- 8.8 in the normal control group (n=11) and 56.8 ms +/- 9.6 in the BA group (n=9) without statistically significant differences (P=0.811). T2 relaxation times were not significantly different between the low stage (<= F1) and high stage (>= F2) fibrosis (mean 57.8 vs 56.8; P=0.934). CONCLUSION: T2 relaxation of a normal infant liver at 1.5-T had a mean value of 57.8 ms, which is comparable with adult data (46-57 ms). However, T2 relaxation time was not different in patients with BA and did not correlate with stage of fibrosis. PMID- 20959974 TI - Is metal artefact reduction mandatory in cardiac PET/CT imaging in the presence of pacemaker and implantable cardioverter defibrillator leads? AB - PURPOSE: Cardiac PET/CT imaging is often performed in patients with pacemakers and implantable cardioverter defibrillator (ICD) leads. However, metallic implants usually produce artefacts on CT images which might propagate to CT-based attenuation-corrected (CTAC) PET images. The impact of metal artefact reduction (MAR) for CTAC of cardiac PET/CT images in the presence of pacemaker, ICD and ECG leads was investigated using both qualitative and quantitative analysis in phantom and clinical studies. METHODS: The study included 14 patients with various leads undergoing perfusion and viability examinations using dedicated cardiac PET/CT protocols. The PET data were corrected for attenuation using both artefactual CT images and CT images corrected using the MAR algorithm. The severity and magnitude of metallic artefacts arising from these leads were assessed on both linear attenuation coefficient maps (MU-maps) and attenuation corrected PET images. CT and PET emission data were obtained using an anthropomorphic thorax phantom and a dedicated heart phantom made in-house incorporating pacemaker and ICD leads attached at the right ventricle of the heart. Volume of interest-based analysis and regression plots were performed for regions related to the lead locations. Bull's eye view analysis was also performed on PET images corrected for attenuation with and without the MAR algorithm. RESULTS: In clinical studies, the visual assessment of PET images by experienced physicians and quantitative analysis did not reveal erroneous interpretation of the tracer distribution or significant differences when PET images were corrected for attenuation with and without MAR. In phantom studies, the mean differences between tracer uptake obtained without and with MAR were 10.16+/-2.1% and 6.86+/-2.1% in the segments of the heart in the vicinity of metallic ICD or pacemaker leads, and were 4.43+/-0.5% and 2.98+/-0.5% in segments far from the leads. CONCLUSION: Although the MAR algorithm was able to effectively improve the quality of MU-maps, its clinical impact on the interpretation of PET images was not significant. Therefore cardiac PET images corrected for attenuation using CTAC in the presence of metallic leads can be interpreted without correction for metal artefacts. It should however be emphasized that in some special cases with multiple ICD leads attached to the myocardium wall, MAR might be useful for accurate attenuation correction. PMID- 20959975 TI - Primitive neuroectodermal tumor arising in the abdominopelvic region: CT features and pathology characteristics. AB - BACKGROUND: We analyze the computed tomography (CT) findings of a peripheral primitive neuroectodermal tumor (pPNET) arising in the abdominopelvic cavity and to improve understanding of the CT images of the tumor. MATERIALS AND METHODS: Twelve cases of pPNET confirmed by histopathology were analyzed retrospectively. Image characteristics of CT scanning were analyzed and compared with the pathology of the tumors. RESULTS: There were 8 males and 4 females with mean age of 34.5 years. Unenhanced CT images showed large heterogeneous and ill-defined or well-defined masses with multiple patchy hypodense areas. The average diameter was 9.8 cm (range 4.0-17.2 cm). Contrast-enhanced CT images showed variable heterogeneous contrast enhancement with multiple non-enhancement areas. 3 cases revealed metastasis and 4 cases invaded into adjacent organs. Pathology showed areas of degeneration and necrosis in all tumors. Cluster of differentiation 99 and neurone specific enolase were detected positive in 11 and 12 cases, respectively. CONCLUSIONS: In conclusion, pPNET in the abdominopelvic cavity likely affects young adults with a slight male preponderance and tend to be large and aggressive. Although CT findings are nonspecific and variable, a large ill defined or well-defined heterogeneous mass with multiple patchy hypodense areas reflecting their cystic degeneration and necrosis on pathology examination may suggest the diagnosis of pPNET. PMID- 20959976 TI - Peritoneal metastases: evaluation with contrast-enhanced ultrasound. AB - OBJECTIVES: The aim of this study is to evaluate the contrast-enhanced ultrasound (CEUS) features of peritoneal metastases. MATERIALS AND METHODS: Unenhanced ultrasound and CEUS were conducted in 25 patients who had confident diagnoses of peritoneal metastases after ultrasound-guided biopsies of peritoneum. B-mode sonograms, color Doppler, CEUS pattern and quantitative analysis of blood perfusion in peritoneal metastases were successively evaluated. RESULTS: Peritoneum became markedly thickened and was well seen as a heterogeneous omental cake at B-mode ultrasound. Color Doppler only detected dotted or strip-like blood flow scattered in the thickened peritoneum and no blood signal was found in any metastatic nodule. At CEUS, the thickened peritoneum enhanced diffusely and parameters of time-intensity curves did not show any significant difference among variant metastases groups. All the metastatic nodules in the peritoneum showed fast radial enhancement and became homogeneous with adjacent parenchyma. These nodules soon became hypoechoic and the contour of the nodule was clearly shown during the wash-out phase. In all the nodules, the time to peak was shorter and peak intensity was higher compared with the peripheral tissue. CONCLUSION: CEUS played a good role in the evaluation of microcirculation and angiogenesis of peritoneal metastases and metastatic nodules in thickened peritoneum. PMID- 20959977 TI - CT colonography: patient tolerance of laxative free fecal tagging regimen versus traditional cathartic cleansing. AB - PURPOSE: The aim of our prospective study was to compare patient tolerance of laxative free fecal tagging regimen (LFT) versus traditional cathartic cleansing (TC). MATERIALS AND METHODS: 264 patients, at average risk for development of colorectal cancer (105 men and 159 women; mean age 62 years +/- 5 SD), underwent 32 rows CT colonography. Patients were alternatively placed into 2 study groups: Group 1 (n = 132) followed TC and Group 2 (n = 132) LFT. TC protocol consisted of no fiber diet and Phospho-lax((r)) 80 mL in 2 L of water the day before imaging. LFT protocol consisted of no fiber diet and ingestion with meals of 30 mL of water-soluble iodinated contrast agent (Gastrografin((r))) for 2 days before imaging. No frank laxative drugs were administered. All studies were reviewed in a combined fashion, primary 2D followed by 3D endoluminal and dissected views. After the examination all patients were asked to provide a feedback about tolerance to the each bowel preparation. The first 30 patients of each group were also investigated with optical colonoscopy (OC) used as gold standard to confirm our diagnosis (Group 1* and Group 2*). CONCLUSIONS: LFT reduces discomfort and seems to improve diagnostic accuracy of CTC. PMID- 20959978 TI - Intraductal papillary mucininous neoplasm of the bile ducts: multimodality assessment with pathologic correlation. AB - Mucin-producing intraductal papillary neoplasm (adenocarcinoma/adenoma) in the bile duct is becoming recognized as a specific type of neoplasm. Since, it bears a striking similarity to intraductal papillary mucinous neoplasms of the pancreas with regard to its histopathologic features, the term "intraductal papillary mucinous neoplasms of the bile duct" (IPMN-B) is frequently used, although no definite terminology or definition has been decided by World Health Organization. This neoplasm lacks ovarian-like stroma and communicates with the bile ducts, unlike biliary mucinous cystic neoplasm (MCN). On the other hand, malignant IPMN B is categorized as an intraductal-growth type of intrahepatic cholangiocarcinoma (ICC). In comparison to other types of ICC, such as the mass-forming type and periductal-infiltrating type that have poor resectability and an unfavorable prognosis, malignant IPMN-B can be resected and demonstrates a more favorable prognosis. Meanwhile, unlike biliary MCN that is usually confined in a closed cyst, IPMN-B can spread along the mucosal surface of the bile ducts, and it should be widely resected. Therefore, multimodality assessment is needed to ensure the correct diagnosis of IPMN-B. We herein review the imaging findings of IPMN-B with pathologic correlation. PMID- 20959979 TI - Primary hepatic leiomyoma: case report. AB - The patient is a previously healthy 28-year-old woman with incidentally detected focal liver lesion. On CT, the tumor showed brisk arterial enhancement and persistent hyperenhancement on portal and delayed phases. Histological study showed spindle cells without atypia and immunohistochemical study was consistent with leiomyoma. PMID- 20959980 TI - Reply to: comments on Alentorn-Geli et al.: anteromedial portal (AMP) versus transtibial (TT) drilling techniques in ACL reconstruction: a blinded cross sectional study at two- to five-year follow-up. PMID- 20959982 TI - Anatomic relationship between the spinal accessory nerve and the jugular vein: a cadaveric study. AB - BACKGROUND/PURPOSE: Previous studies of the course of the Spinal Accessory Nerve (SAN) and its relationship to the Internal Jugular Vein (IJV) have yielded conflicting results because of the small number of anatomic specimens and anatomic variability. Classic teaching in Head and Neck Surgery is that the SAN almost always crosses the IJV anteriorly in the upper neck. However, because of the morbidity associated with the injury to the IJV during nerve dissection, it is imperative that the surgeon is wary of the posteriorly crossing nerve. In order to further elucidate the anatomy of the SAN in relation to its surrounding structures, we have studied its anatomy at various points. Specifically, we have aimed to: (1) characterize the anatomic relationship of the SAN to the IJV at three major points: (a) within jugular foramen (JF), (b) at base of skull (BoS), and (c) at the posterior belly of the digastric muscle, (2) record the distance travelled by the SAN from the BoS to its medial to lateral crossing of the IJV, and (3) characterize the anatomy of the JF by with respect to greatest length, width, and partitioning. METHODS: Sixty-one cadavers, 27 male, and 34 female (84 necks) were dissected and the course of the SAN was followed from the BoS to the crossing the IJV. Data recorded included the relationship of the SAN to the IJV (a) within the JF from an intracranial view, (b) exiting the JF at BoS, and (c) in the neck at the level of the posterior belly of the digastric muscle where anterior versus posterior positioning of the crossing nerve with respect to the IJV was noted. The distance travelled by the SAN from BoS until crossing the IJV, the length and width of the JF within the cranial fossa, and JF partitioning were also recorded. RESULTS: Within the JF, the SAN travelled anteromedial to the IJV in 73/84 (87%) necks. While exiting the JF, the SAN was found lateral to the IJV in 56/84 (67%) of necks. In the anterior triangle of the neck the SAN crossed the IJV anteriorly in 67/84 (80%) necks, posteriorly in 16/84 (19%) and in the one case of IJV bifurcation, the nerve pierced the vein. The average distance travelled by SAN from BoS to crossing the IJV was 2.38 cm. The average length and width of the JF were, respectively, 1.42 and 0.78 cm, and the IJV was partitioned in 36/84 necks, with 3 of the partitions being bony and the remainder fibrinous. No relationship was found between JF dimensions/partitioning and the anatomic relationship of the structures exiting it. DISCUSSION/CONCLUSION: In this study, the dimensions and relationship of the IJV and SAN are described in detail. This relationship is specifically noted at three major points, namely within the cranium, at the BoS, and in the anterior neck triangle. In its medial to lateral path in the anterior neck triangle, the SAN crossed the IJV anteriorly in a majority of the cases. However, a posteriorly crossing nerve was not uncommon. These findings support results in previous literature in that the SAN is located anterior to the IJV in the majority of the cases, however, it is imperative for the surgeon to be mindful to the anatomic variability and possible posterior crossing of the IJV by the SAN in the neck to avoid injury to the IJV during the dissection of the nerve. The distance travelled by the nerve prior to crossing the IJV was measured and can be used as a helpful tool for the surgeon in finding the nerve during dissections. We were not able to demonstrate a correlation between the relationship of the SAN and IJV at other recorded points and their crossing relationship. Similarly, no correlation was found between the anatomy of JF and the relationship of the SAN and IJV at any point. PMID- 20959981 TI - Failure following revision total knee arthroplasty: infection is the major cause. AB - The objective of this study was to evaluate the survivorship of revision TKA and determine the reasons and predictors for failure. Between January 1999 to December 2005, 499 total knee arthroplasty revisions were performed on 474 patients. There were 292 (61.6%) women and 182 (38.4%) men. The average age at the time of index revision was 63.9 years. Revision was defined as surgery in which at least one component (tibial, patellar, femoral, or polyethylene) required exchange. At an average follow-up of 64.8 months (range, 24.1-111.6), and considering reoperation or re-revision as failure, there were 102 failures (18.3%). Infection was the major cause of failure (44.1%) followed by stiffness (22.6%), patellar or extensor mechanism problems (12.8%), periprosthetic fracture (5.9%), loosening (4.9%), haematoma formation (3.9%), malalignment (2.9%), and instability (2.9%). A total of 83% of failures were early (less than two years). Infection was the most common mechanism of failure of revision TKA. The majority of TKA revision failures tend to occur in the first two years after revision. The mode of failure of revision TKA appears to differ from the failure of primary TKA to some extent. Better understanding of current modes by which TKA revisions fail may enable surgeons to prevent these problems and improve outcomes for revision TKA. PMID- 20959988 TI - Improved osmotic tolerance and ethanol production of ethanologenic Escherichia coli by IrrE, a global regulator of radiation-resistance of Deinococcus radiodurans. AB - Successful fermentations to produce ethanol using ethanologenic Escherichia coli require tolerance to high concentrations of sugars. Here we demonstrate that irrE, encoding a regulatory protein for radiation-resistance in Deinococcus radiodurans, conferred improved osmotic stress tolerance to E. coli. Expression of the gene protected E. coli cells against 25% glucose or xylose, acid shock. It also markedly improved cellular viability, the transcriptional levels of trehalose biosynthetic genes (otsBA) and trehalose content in the IrrE-expressing strain compared with the control strain. IrrE expression also enhanced the expression levels and enzymatic activities of PDC and ADHB as well as ethanol production. Our results suggest that IrrE could potentially be used to improve osmotic stress tolerance and ethanol production in ethanologenic strains. PMID- 20959989 TI - [Histological classification of soft tissue tumors and staging according to the TNM system]. AB - The classification of soft tissue tumors is based on their resemblance to normal non-neoplastic tissues and provides an indication of how the tumor will behave in the further disease course. The current article presents the principles to be considered when classifying tumors into categories and discusses additional findings to be taken into account in the diagnosis. The importance of considering combinations of findings when classifying a tumor is underscored; individual (in particular immunohistochemical) findings can be misleading. A statement on the grade of malignancy of a soft tissue tumor requires its identification as a known entity, otherwise incorrect prediction of its biological behaviour is possible. The category of "intermediate malignancy" has been added to the categories of "benign" and "malignant", whereby locally aggressive and incidentally metastasizing tumors have been included in this new category. The staging of soft tissue tumors according to the TNM system is explained, emphasizing that one important feature compared with carcinomas is the inclusion of depth localisation and grade of malignancy. PMID- 20959990 TI - Long-term urinary adverse effects of pelvic radiotherapy. AB - OBJECTIVE: Radiation for tumors arising in the pelvis has been utilized for over a 100 years. Adverse effects (AEs) of radiotherapy (RT) continue to accumulate with time and are reported to show decades after treatment. The benefit of RT for pelvic tumors is well described as is their acute AEs. Late AEs are less well described. The burden of treatment for the late AEs is large given the high utilization of RT. REVIEW: For prostate cancer, 37% of patients will receive radiation during the first 6 months after diagnosis. Low-and high-grade AEs are reported to occur in 20-43 and 5-13%, respectively, with a median follow-up of ~60 months. For bladder cancer, the grade 2 and grade 3 late AEs occur in 18-27 and 6-17% with a median follow-up of 29-76 months. For cervical cancer, the risk of low-grade AEs following radiation can be as high as 28%. High-grade AEs occur in about 8% at 3 years and 14.4% at 20 years or ~0.34% per year. Radiation AEs appear to be less common or at least less well studied after radiation for rectal and endometrial cancers. CONCLUSION: Properly delineating the rate of long-term AEs after pelvic RT is instrumental to counseling patients about their options for cancer treatment. Further studies are needed that are powered to specifically evaluate long-term AEs. PMID- 20959991 TI - Patient preferences and urologist recommendations among local-stage prostate cancer patients who present for initial consultation and second opinions. AB - OBJECTIVES: This study describes urologist recommendations for treatment among local-stage prostate cancer patients presenting for initial management consultations versus second opinions. We hypothesized that urologists present a wider range of management recommendations and are less likely to consider the patient preference during the initial consultation. METHODS: Newly diagnosed local-stage prostate cancer patients and their urologists participated in a survey at urology practices in three states. The urologist's survey included questions about the patient's clinical status, treatments discussed and recommended, and factors that influenced the urologist's recommendations. RESULTS: Of the 238 eligible patients, 95 men presented for an initial consultation, and 143 men presented for a second opinion. In multivariate analysis, urologists recommended 0.52 more treatments (standard error 0.19, P<0.001) during an initial consultation as opposed to a second opinion. The proportion recommending surgery increased from 71-91% (initial consultation versus second opinion setting). Among initial consultations, 59% had low-risk disease, and urologists' recommendations included surgery (80%), external radiation (38%), brachytherapy (seeds) (52%), and active surveillance (25%). Of the 54% with low-risk disease in a second opinion consultation, urologists' recommendations included surgery (90%), external radiation (16%), brachytherapy (14%), and active surveillance (16%). CONCLUSIONS: In second opinion settings urologists discussed fewer treatment options and recommended surgery more often. These findings also applied to men with low-risk prostate cancer. PMID- 20959992 TI - Nerve-sparing technique and urinary control after robot-assisted laparoscopic prostatectomy. AB - OBJECTIVES: To characterize determinants of 4-, 12-, and 24-month urinary control after robot-assisted laparoscopic prostatectomy (RALP). METHODS: Adjusted comparative study using prospectively collected, patient self-reported urinary control for 602 consecutive RALPs. Urinary control defined as: (1) EPIC urinary function (UF) scored from 0 to 100 and (2) continence (zero pads per day). RESULTS: Both UF (62.8 vs. 42.4, P<0.001) and continence rates (47.2 vs. 26.7%, P=0.043) were better for bilateral nerve-sparing (BNS) vs. non-nerve-sparing (NNS) at 4 months, but only UF scores were significantly better at 12- (80.9 vs. 70.7, P=0.014) and 24-month (89.2 vs. 77.4, P=0.024) post-RALP. No difference in positive margin rates was observed. In multivariate analysis, older age (parameter estimate -0.42, 95% CI -0.80 to -0.04) and increasing gland volume ( 0.13, CI -0.26 to -0.01) resulted in lower UF scores at 4 months, while higher pre-operative UF (0.25, CI 0.05-0.46), bladder neck-sparing technique (10.1, CI 3.79-16.35), BNS (19.1, CI 9.37-28.82), and unilateral nerve-sparing (19.00, CI 7.88-30.11) resulted in higher UF scores at 4 months. At 12 months, higher pre operative UF (0.24, CI 0.083-0.40) and BNS (9.54, CI 1.92-17.16) resulted in higher UF scores. At 24 months, higher pre-operative UF (0.20, CI 0.06-0.33), bladder neck-sparing technique (7.80, CI 3.48-12.10), and BNS (7.86, CI 1.04 14.68) resulted in higher UF scores. CONCLUSIONS: BNS, bladder neck-sparing technique, and higher pre-operative UF score result in improved 24-month urinary control after RALP. PMID- 20959993 TI - Treatment of moderate to severe female stress urinary incontinence with the adjustable continence therapy (ACT) device after failed surgical repair. AB - INTRODUCTION: Treatment of recurrent stress incontinence after a failed surgical procedure is more complicated, and repeat surgeries have higher rates of complications and limited efficacy. We determined the technical feasibility, efficacy, adjustability, and safety of adjustable continence therapy device for treatment of moderate to severe recurrent urinary incontinence after failed surgical procedure. MATERIALS AND METHODS: Female patients with moderate to severe recurrent stress urinary incontinence who had at least one prior surgical procedure for incontinence were enrolled. All patients underwent percutaneous placement of adjustable continence therapy (ACT) device (Uromedica, Plymouth, Minnesota). Baseline and regular follow-up tests to determine subjective and objective improvement were performed. RESULTS: A total of 89 patients have undergone implantation with 1-3 years of follow-up. Data are available on 77 patients at 1 year. Of the patients, 47% were dry at 1 year and 92% improved after 1-year follow-up. Stamey score improved from 2.25 to 0.94 at 1 year (P < 0.001). IQOL questionnaire scores improved from 33.9 to 71.6 at 1 year (P < 0.001). UDI scores reduced from 60.7 to 33.3 (P < 0.001) at 1 year. IIQ scores reduced from 57.0 to 21.6 (P < 0.001) at 1 year. Diary incontinence episodes per day improved from 8.1 to 3.9 (P < 0.001) at 1 year. Diary pads used per day improved from 4.3 to 1.9 (P < 0.001). Explantation was required in 21.7% of patients. CONCLUSION: The ACT device is an effective, simple, safe, and minimally invasive treatment for moderate to severe recurrent female stress urinary incontinence after failed surgical treatment. PMID- 20959994 TI - Hydrodynamic trail following in a California sea lion (Zalophus californianus). AB - The mystacial vibrissae of pinnipeds constitute a sensory system for active touch and detection of hydrodynamic events. Harbour seals (Phoca vitulina) and California sea lions (Zalophus californianus) can both detect hydrodynamic stimuli caused by a small sphere vibrating in the water (hydrodynamic dipole stimuli). Hydrodynamic trail following has only been shown in harbour seals. Hydrodynamical and biomechanical studies of single vibrissae of the two species showed that the specialized undulated structure of harbour seal vibrissae, as opposed to the smooth structure of sea lion vibrissae, suppresses self-generated noise in the actively moving animal. Here we tested whether also sea lions were able to perform hydrodynamic trail following in spite of their non-specialized hair structure. Hydrodynamic trails were generated by a remote-controlled miniature submarine. Linear trails could be followed with high accuracy, comparable to the performance of harbour seals, but in contrast, increasing delay resulted in a reduced performance as compared to harbour seals. The results of this study are consistent with the hypothesis that structural differences in the vibrissal hair types of otariid compared to phocid pinnipeds lead to different sensitivity of the vibrissae during forward swimming, but still reveal a good performance even in the species with non-specialized hair type. PMID- 20959995 TI - Intraventricular dysembryoplastic neuroepithelial tumor in a pediatric patient: is it the most common extracortical location for DNT? AB - Dysembryoplastic neuroepithelial tumor (DNT) is commonly located in the supratentorial cortex. Extracortical localization of DNT is extremely rare. A 15 year-old female presented with loss of consciousness after head trauma. MRI demonstrated hydrocephalus secondary to a small non-enhancing T1 hypointense and T2 hyperintense mass lesion in the foramen of Monro; with radiologic impression of low-grade astrocytoma or colloid cyst. Tumor was gross totally resected. Histologic examination showed partly microcystic architecture with oligodendroglia-like neurocytic cells, glioneuronal element, and floating neurons, with synaptophysin reactivity mainly in cell processes, consistent with DNT. Focal subependymoma-like pattern was noted. The low tumor cellularity and morphologic pattern did not support a central neurocytoma. Patient was asymptomatic and was radiologically stable 9 months post-surgery. Literature review of previously reported supratentorial extracortical DNT cases demonstrate that 24 of 25 cases involved the ventricular system (as in our case) of which eight additionally involved periventricular deep gray or white matter. None of the cases recurred following surgery. Clinico-pathologically, extracortical DNTs were similar to the cerebral cortical simple DNTs and differed only in their presentation related to their location. The novel aspects of this report are the radiologic resemblance of DNT to colloid cyst and focal subependymoma-like pattern on histology. Importantly, intra-/periventricular region appears to be the most common extracortical location of cerebral DNT with a 100% disease-free survival reported in the literature. PMID- 20959996 TI - Rotational vertebral artery occlusion in a child with multiple strokes: a case based update. AB - INTRODUCTION: Rotational vertebral artery occlusion (RVAO), sometimes known as "Bow hunter syndrome," is an important and diagnostically challenging cause of posterior circulation stroke in children. It is caused by impingement of osseous and/or ligamentous structures on the vertebral artery. DISCUSSION: We review the differential diagnosis and recommended workup for posterior circulation stroke in children. The anatomical cause for pediatric RVAO is most commonly an anomalous bone formation of the rostral vertebral column. Many bony anomalies have been associated with RVAO, including the "ponticulus posticus," a common anomaly of the C1 vertebrae. The definitive diagnosis of RVAO is made with dynamic angiography, and surgical decompression of the vertebral artery prevents recurrent strokes. ILLUSTRATIVE CASE: We report a 15-year-old boy with recurrent posterior circulation ischemic strokes caused by an anomalous ossification of the C1 vertebrae. Three-dimensional (3D) and multiplanar reconstructed CT images showed the anomalous C1 ossification, and cervicocerebral digital subtraction angiography (DSA) revealed an associated vertebral artery (VA) dissection. The patient was initially managed by head immobilization in a hard collar and anticoagulation for 3 months. After healing of the dissection that was confirmed angiographically, dynamic DSA demonstrated reversible occlusion of the VA during contralateral head turn. Surgical decompression of the VA was performed and confirmed by intra-operative DSA with head turning. CONCLUSIONS: RVAO is an important diagnosis in children with posterior circulation stroke. Our case demonstrates the need for high clinical suspicion and careful analysis of 3D cervical spine CT images in children with posterior circulation stroke. PMID- 20959997 TI - Galectin-3-independent prognosis in heart failure. PMID- 20959998 TI - Performance figures of invasive cardiology in Germany 2006 and 2007 focussing on coronary artery disease. PMID- 20959999 TI - First experience with transcatheter aortic valve implantation and concomitant percutaneous coronary intervention. AB - OBJECTIVES: We investigated our experience with combined transcatheter aortic valve implantation (TAVI) and percutaneous coronary intervention (PCI) as an alternative strategy in high-risk patients. BACKGROUND: Combined surgical aortic valve replacement and coronary artery bypass grafting are the gold standard treatment for patients with aortic stenosis and concomitant coronary artery disease. However, a substantial share of patients is unfit for surgery due to contraindications. METHODS: Twenty-eight patients (15 female) underwent combined TAVI and PCI after being refused for surgery. In 21 patients (group 1) a staged approach of PCI prior to subsequent TAVI was chosen. Seven patients (group 2) were treated in a single-stage procedure. RESULTS: Mean patient age was 80.1 +/- 6.9 years, pre-procedural risk assessment revealed a mean logEuroSCORE of 26.8 +/ 13.4%. Left ventricular ejection fraction was 45.6 +/- 11.1%. Baseline mean/peak transvalvular gradients were 40.2 +/- 16.8 and 65.6 +/- 26.6 mmHg, respectively, and decreased to mean/peak values of 9.3 +/- 4.2/15.2 +/- 8.4 mmHg (p < 0.0001), effective orifice area increased from 0.73 +/- 0.25 to 1.74 +/- 0.47 cm(2) (p < 0.0001). In group 2, fluoroscopy time and amount of contrast agent were significantly higher compared to group 1 (18.1 +/- 9.2 vs. 9.5 +/- 7.0 min; p = 0.03/292.3 +/- 117.5 vs. 171.9 +/- 68.4 ml; p = 0.006). In group 1, patients received PCI 14.3 +/- 9.6 days prior to TAVI. In group 2, PCI was performed immediately before TAVI. A mean of 1.6 +/- 1.0 stents was placed per patient. No periprocedural myocardial infarction or stroke occurred in any patient. Thirty day mortality was 7.1% (2/28). CONCLUSION: Our strategy of staged or single-stage TAVI and PCI proved feasible and safe in this high-risk patient population. Whether there is advantage of one approach over the other remains to be elucidated. PMID- 20960000 TI - Seasons but not ethnicity influence urinary iodine concentrations in Belgian adults. AB - BACKGROUND: Mild iodine deficiency (MID) is endemic in Belgium. Previous surveys, which assessed iodine nutrition in Belgium, focused on children. The iodine status of adults and the influence of ethnicity or seasonality on urinary iodine concentrations (UIC) have not been investigated. Since the nutritional profile of children differs from that of adults, we may anticipate similar differences in iodine status. Seasonal fluctuations in UIC have also been reported from other MID regions. AIM OF THE STUDY: We aimed at assessing iodine status and its association with ethnicity and seasonality in adults. METHODS: A stratified random sample of 401 healthy subjects aged between 40 and 60 years, of Belgian, Moroccan, Turkish and Congolese descent residing in Brussels was obtained. Iodine status and thyroid function were determined. RESULTS: Median UIC was 68 MUg/L. The frequency of UIC below 100 MUg/L was 73.3%, of which 41.9% fell between 50 and 99 MUg/L, and 29.8% between 49 and 20 MUg/L. There was no difference in UIC and thyroid function between subjects of different ethnic origins. The frequency of UIC below 50 MUg/L was higher in the fall-winter compared to spring-summer periods (P = 0.004). Serum FT3 concentrations, but not FT4 and TSH, were significantly greater in winter than in summer. CONCLUSION: Seasonal fluctuations in UIC suggest that the risk of iodine deficiency among adults living in Brussels is higher in fall-winter than in spring-summer. The prevalence of MID in Brussels is high among adults but ethnicity does not appear to influence iodine status. PMID- 20960001 TI - Psychiatric illness through the lifespan. PMID- 20960002 TI - Altered amygdala functional connectivity in adult Tourette's syndrome. AB - Tourette's syndrome (TS) is a developmental neuropsychiatric disorder characterized by motor and vocal tics as well as psychiatric comorbidities. Recently, differences in maturation of cortical networks using functional connectivity metrics have been described for this disorder. However, adult data on subcortical networks are scarce. In particular, the connectivity of the amygdala, for which a role in the pathophysiology of TS has been established, has not been examined so far. We studied 15 adult TS patients (11 male, aged 30.4 +/- 9.7y) and 15 age- and sex-matched controls (11 male, aged 32.0 +/- 9.3y) in a functional magnetic resonance imaging study at 1.5T using a simple motor task. We corrected for possible confounds introduced by tics, motion and brain-structural differences as well as age, sex, and medication. Task performance was monitored by simultaneous MR-compatible video-recording. Data were analyzed using an independent component approach sensitive to functional connectivity patterns. A stable component comprising both amygdalae could be identified across all subjects. Additionally, we observed a highly significant increase in coupling between/within amygdalae in the TS group when compared to controls, although behavioral data obtained during scanning did not show significant differences. These findings are expected to add to our understanding of the functional architecture of Tourette's syndrome. PMID- 20960003 TI - Cognitive performance and cholinergic transmission: influence of muscarinic and nicotinic receptor blockade. AB - The cholinergic system is essential in mediating cognitive processes. Although there has been extensive research regarding cholinergic receptor subsystems, the specific contribution of the muscarinic and nicotinic receptor system to cognitive processes still has not been sufficiently explored. In the present study, we examined the selective contribution of muscarinic and nicotinic antagonism to cognitive performance in healthy human subjects. A single-blind, double-dummy, time-elapsed, repeated measures cross-over design was used on 15 healthy males. Subjects completed a neuropsychological test battery assessing a wide range of cognitive domains after 0.4 mg scopolamine (intravenous), 0.2 mg/kg mecamylamine (max. 15 mg; oral) or placebo. Subjects were tested under three conditions: placebo/placebo (PP), scopolamine/placebo (SP) and mecamylamine/placebo (MP). Results show that scopolamine significantly impaired the free recall and recognition performance in the verbal learning test. No other cognitive domain was affected, neither by scopolamine nor by mecamylamine. In line with the existing literature, antagonism of muscarinic receptors resulted in specific cognitive impairments, predominantly memory performance. PMID- 20960004 TI - Ethics in psychiatry: the lessons we learn from Nazi psychiatry. AB - Under the Euthanasia Program of Nazi Germany, more than 200,000 psychiatric patients were killed by doctors in psychiatric institutions. After summarising the historical facts and the slow and still going-on process of illuminating and understanding what happened, some ethical consequences are drawn. What can we learn from history? The following aspects are addressed: the special situation of psychiatry in times of war, bioethics and biopolitics, the responsibility of the psychiatrist for the individual patient, the effects of hierarchy on personal conscience and responsibility, the unethical "curable-uncurable" distinction and the atrocious concept that persons differ in their value. PMID- 20960005 TI - Anticholinergic drug use and risk for dementia: target for dementia prevention. AB - An increasing number of longitudinal cohort studies have identified a risk increase for dementia by the chronic use of drugs with anticholinergic properties. The respective data from the German Study on Aging, Cognition and Dementia in Primary Care Patients (AgeCoDe) also showing risk increase (hazard ratio = 2.081) are reported here. The mechanisms by which the risk increase is transported are still unknown. Irritation of compensated alterations of cholinergic transmission at the pre-dementia stage of Alzheimer's disease (AD) or acceleration of neuroinflammation by disturbance of the anti-inflammatory effect of cholinergic innervation are discussed. In terms of dementia prevention, centrally acting anticholinergic drugs should be strictly avoided, because of long-term dementia risk increase in addition to acute negative effects on cognition. PMID- 20960006 TI - Identification of suitable reference genes for normalization of qPCR data in comparative transcriptomics analyses in the Triticeae. AB - Comparative transcriptomics are useful to determine the role of orthologous genes among Triticeae species. Thus they constitute an interesting tool to improve the use of wild relatives for crop breeding. Reverse transcription quantitative real time PCR (qPCR) is the most accurate measure of gene expression but efficient normalization is required. The choice and optimal number of reference genes must be experimentally determined and the primers optimized for cross-species amplification. Our goal was to test the utility of wheat-reference genes for qPCR normalization when species carrying the following genomes (A, B, D, R, H ( v ) and H ( ch )) are compared either simultaneously or in smaller subsets of samples. Wheat/barley/rye consensus primers outperformed wheat-specific ones which indicate that consensus primers should be considered for data normalization in comparative transcriptomics. All genes tested were stable but their ranking in terms of stability differed among subsets of samples. CDC (cell division control protein, AAA-superfamily of ATPases, Ta54227) and RLI (68 kDa protein HP68 similar to Arabidopsis thaliana RNase L inhibitor protein, Ta2776) were always among the three most stable genes. The optimal number of reference genes varied between 2 and 3 depending on the subset of samples and the method used (geNorm vs. coefficient of determination between sequential normalization factors). In any case a maximum number of three reference genes would provide adequate normalization independent of the subset of samples considered. This work constitutes a substantial advance towards comparative transcriptomics using qPCR since it provides useful primers/reference genes. PMID- 20960007 TI - Differential impact of impaired fasting glucose versus impaired glucose tolerance on cardiometabolic risk factors in multi-ethnic overweight/obese children. AB - We aimed to investigate the prevalence of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), and their associations with cardiometabolic risk factors, according to ethnicity in a large obese paediatric cohort. A 75-g oral glucose tolerance test was performed in 1,007 overweight/obese Dutch children of multi-ethnic origin, referred to the obesity outpatient clinics of two Dutch hospitals in Amsterdam (mean age, 11.4 +/- 3.2 years; 50.7% boys). Anthropometric parameters and blood samples were collected, and cardiometabolic risk factors were assessed. The cohort consisted of Dutch native (26.0%), Turkish (23.7%), Moroccan (18.8%) and children of 'other' (31.5%) ethnicity. The prevalence of IFG was significantly higher in Moroccan and Turkish children as compared to Dutch native children (25.4% and 19.7% vs. 11.8%, respectively, P < 0.05). IGT was most frequently present in Turkish and Dutch native children, relative to Moroccan children (6.3% and 5.3% vs. 1.6%, P < 0.05). Besides pubertal status and ethnicity, components of 'metabolic syndrome' (MetS) which were associated with IGT, independent of hyperinsulinaemia, were hypertension [odds ratio (OR), 2.3; 95% CI, 1.1-4.9] while a trend was seen for high triglycerides (OR, 2.0; 95% CI, 0.9-4.3). When analyzing components of MetS which were associated with IFG, only low high-density lipoprotein cholesterol was significantly associated (OR, 1.7; 95% CI, 1.2-2.5) independent of hyperinsulinaemia. In conclusion, in a Dutch multi-ethnic cohort of overweight/obese children, a high prevalence of IFG was found against a low prevalence of IGT, which differed in their associations with cardiometabolic risk factors. PMID- 20960008 TI - Over-the-counter drug use--estimations within the Swedish paediatric population. AB - We have used three different sources to estimate the use of drugs sold over the counter (OTC) by the Swedish paediatric population during 2007-2008 as part of a European evaluation initiated by the European Medicines Agency. An estimation of the paediatric use from the total numbers of over-the-counter drugs (OTCD) packages sold by Swedish pharmacies and analyses of two separate questionnaires directed towards a population of 11- to 14-year-old children and another towards visitors to one of the paediatric emergency wards in Stockholm County were included in the study. In Sweden, 1.25 OTC packages are sold quarterly per child (0-18 years), and the children in both questionnaire studies use, on average, 0.9 OTC substances. Sixty-five percent of the children visiting an emergency ward and 67% of the 13-year-old Stockholm inhabitants had used at least one OTCD. OTCD use among children is common. Interpretation of OTCD data must be done carefully since questions with regard to OTCD use is subject to recall bias and the number of packages sold to children is hypothesised through a conversion factor. PMID- 20960009 TI - Root traits explain different foraging strategies between resprouting life histories. AB - Drought and fire are prevalent disturbances in Mediterranean ecosystems. Plant species able to regrow after severe disturbances (i.e. resprouter life history) have higher allocation to roots and higher water potential during the dry season than coexisting non-resprouting species. However, seedlings of non-resprouters have a higher survival rate after summer drought. We predict that, to counteract their shallow-rooting systems and to maximize seedling survival, non-resprouters have root traits that confer higher efficiency in soil resource acquisition than resprouters. We tested this prediction in seedlings of less than 1.5 months old. We select 13 coexisting woody species (including both resprouters and non resprouters), grew them in a common garden and measured the following root traits: length, surface, average diameter, root tissue density (RTD), specific root length (SRL), surface:volume ratio (SVR), specific tip density (STD), tip distribution in depth, internal links ratio (ILR), and degree of branching. These root traits were compared between the two resprouting life histories using both standard cross-species and phylogenetic-informed analysis. Non-resprouters showed higher SRL and longer, thinner and more branched laterals, especially in the upper soil layers. The external links (i.e. the most absorptive root region) were also more abundant, longer, thinner and with higher SVR for non-resprouters. The results were supported by the phylogenetic-informed analysis for the root traits most strongly related to soil resource acquisition (SRL, SVR and branching pattern). The seedling root structure of non-resprouters species allows them to more efficiently explore the upper soil layer, whereas seedling roots of resprouters will permit both carbon storage and deep soil penetration. PMID- 20960010 TI - Differentiation and adaptation in Brassica nigra populations: interactions with related herbivores. AB - Local adaptation and population differentiation of plants are well documented, but studies on interactions with natural enemies are rare. In particular, evidence for plant adaptation to the local biotic environment, such as herbivores remains poor. We used the black mustard Brassica nigra, an annual species of river valley and coastal habitats to (1) analyse population differentiation in plant traits and herbivory in a common garden experiment, (2) examine home versus away differences in a reciprocal transplant experiment and (3) test whether plants are adapted to local herbivores or vice versa under standard greenhouse conditions. In the common garden experiment, we found significant differentiation in plant traits, leaf damage and herbivore number among seven populations of B. nigra from France and Germany (distance 15-1,000 km). Differences were particularly strong among coastal and river valley populations and did not necessarily increase with geographical distance. A herbivore removal treatment did not change population differentiation when compared with the control allowing natural colonisation. The reciprocal transplant experiment at a scale of 15-30 km did not reveal local plant adaptation, whilst one dominant herbivore species (Meligethes aeneus) occurred in significantly higher numbers on local plants. A greenhouse experiment combining three aphid (Brevicoryne brassicae) and plant populations of the same provenance indicated herbivore adaptation to their local plants rather than plant adaptation, but overall contrasts between local and non local combinations were not significant. The results suggest that herbivores may counteract local plant adaptation to other environmental factors. Our study has important implications for plant translocations in ecological restoration projects. PMID- 20960011 TI - Cloning and biochemical properties of a highly thermostable and enantioselective nitrilase from Alcaligenes sp. ECU0401 and its potential for (R)-(-)-mandelic acid production. AB - A nitrilase gene from Alcaligenes sp. ECU0401 was cloned and overexpressed in Escherichia coli BL21 (DE3) in a soluble form. The encoded protein with a His6 tag was purified to nearly homogeneity as revealed by SDS-PAGE with a molecular weight of approximately 38.5 kDa, and the holoenzyme was estimated to be composed of 10 subunits of identical size by size exclusion chromatography. The V(max) and K(m) parameters were determined to be 27.9 MUmol min-1 mg-1 protein and 21.8 mM, respectively, with mandelonitrile as the substrate. The purified enzyme was highly thermostable with a half life of 155 h at 30 degrees C and 94 h at 40 degrees C. Racemic mandelonitrile (50 mM) could be enantioselectively hydrolyzed to (R)-(-)-mandelic acid by the purified nitrilase with an enantiomeric excess of 97%. The extreme stability, high activity and enantioselectivity of this nitrilase provide a solid base for its practical application in the production of (R)-(-)-mandelic acid. PMID- 20960012 TI - Transoral reduction of irreducible posteriorly displaced odontoid fracture. AB - A case of type II odontoid fracture with irreducible posterior dislocation is presented. Cervical traction was employed but reduction could not be achieved with up to 15 kg of traction. The patient was treated with intraoperative transoral open reduction combined with anterior-posterior fixation. Rigid fixation and bone union were obtained without any complication in the 12-month follow-up. The patient has restricted C-spine rotation but no neck pain with movement. Transoral open reduction may be considered in patients with irreducible posteriorly displaced odontoid fracture. PMID- 20960013 TI - Should smoking habit dictate the fusion technique? AB - The aim of this study was to evaluate the influence of smoking on the outcome of patients undergoing surgery for degenerative spinal diseases, and to examine whether smoking had a differential impact on outcome, depending on the fusion technique used. The cohort included 120 patients treated with two different fusion techniques (translaminar screw fixation and TLIF). They were categorised with regard to their smoking habits at the time of surgery and completed the Core Outcome Measures Index at baseline and follow-up (FU) (3, 12 and 24 months FU); at FU they also rated the global outcome of surgery. The distribution of smokers was comparable in the two groups. For the TS group, the greater the number of cigarettes smoked, the less the reduction in pain intensity from pre-op to 24 months FU; the relationship was not significant for the TLIF group. The percentage of good global outcomes declined with time in the TS smokers such that by 24 months FU, there was a significant difference between TS smokers and TS-non smokers. No such difference between smokers and non-smokers was evident in the TLIF group at any FU time. In conclusion, the TS technique was more vulnerable to the effects of smoking than was TLIF: possibly the more extensive stabilisation of the 360 degrees fusion renders the environment less susceptible to the detrimental effects on bony fusion of cigarette smoking. PMID- 20960014 TI - Operative treatment of isthmic spondylolisthesis in children: a long-term, retrospective comparative study with matched cohorts. AB - The purpose of the present study was to compare the long-term clinical, functional and radiographic outcomes of young patients operated on before or at the onset of puberty (Children) and those operated on after that (Adolescents). The study group consisted of 298 patients operated on under the age of 20 years; 55 of them were operated on before or at the onset of growth spurt (29 females<12.5 years, 26 males<14.5 years). Preoperative data were retrieved from patients' records. After mean follow-up of 17 years (10.7-26.3), physical examination, radiographic measurements and functional testing were performed by independent observers. SRS-24, Oswestry Disability Index (ODI), and Visual Analogue Scale (VAS) were utilised to evaluate health-related quality of life. The data were compared between the two age groups in the whole study population and in 41 pairs of patients matched by gender, operative method, severity of preoperative slip, and age at follow-up. Preoperatively, one-third of children did not have significant pain symptoms. They were operated upon for resistant postural anomalies in combination with high risk of slip progression. All of the adolescents had low-back pain as the main clinical symptom. The outcomes were satisfactory in both groups in the whole population (children vs. adolescents; low-grade slip: SRS-24: 95.9 vs. 92.0, ODI: 5.2 vs. 7.5, VAS low-back pain: 18.9 vs. 21.2; high-grade slip: SRS-24: 95.6 vs. 90.6, ODI: 3.4 vs. 6.9, VAS low-back pain: 10.5 vs. 22.1). The differences were statistically significant for ODI and VAS in high-grade patients in favor of the children. The clinical relevance of these differences seems to be minimal. The results of the comparison of the matched cohorts were comparably good. One-fifth of the whole study group had a non-union which did not affect the final outcome. In the children with high-grade slips, there was a mean slip improvement of 14 percentage points due to remodelling. The overall complication rate in the whole population was 7.7%. In conclusion, spinal fusion can be carried out at an early age for low- and high grade spondylolisthesis with good long-term clinical, functional, radiographic and health-related quality-of-life outcomes when the indications are met. PMID- 20960015 TI - Hypertrophy of the lumbar ligamentum flavum is associated with inflammation related TGF-beta expression. AB - BACKGROUND: Despite the significance of hypertrophy of the ligamentum flavum (HLF) in the disease progress of neurogenic claudication, the cellular mechanisms underlying the gradual fibrotic thickening of the ligamentum flavum remain poorly understood. The aim of our study was to get insight into the contribution of inflammatory mechanisms to the development of hypertrophy. METHODS: Specimens of hypertrophied ligamenta flava were obtained at surgery from 20 patients with acquired lumbar osteoligamentous spinal canal stenosis from the central part of the ligament. Paraffin sections were stained with hematoxylin and eosin and Elastica van Gieson to evaluate extracellular matrix architecture, and immunohistochemistry was performed to characterize the inflammatory reaction and the sources of transforming growth factor beta (TGF-beta) expression. Sections of normal ligamenta flava obtained from corresponding anatomical sites and stained in parallel served as a control. RESULTS: HLF was characterized by a considerable distortion of the elastic matrix and fibrotic transformation by extracellular collagen deposition. All specimens showed highly inflammatory cellular infiltrates confined to regions exhibiting marked degeneration of the elastic matrix composed mainly of macrophages, scattered T lymphocytes, and neovascularization, thus representing a chronic inflammation. Surprisingly, macrophages as well as vascular endothelial cells but not fibroblasts showed a strong expression of TGF-beta, a strong inducer of extracellular collagen deposition. CONCLUSIONS: Macrophages were identified as a major cellular source of TGF-beta in advanced HLF and may perpetuate further hypertrophy. This finding suggests that modulating the immune response locally or systemically could prove to be effective for impeding the disease progress. PMID- 20960016 TI - Gating of aquaporins by heavy metals in Allium cepa L. epidermal cells. AB - Changes in the water permeability, aquaporin (AQP) activity, of leaf cells were investigated in response to different heavy metals (Zn(2+), Pb(2+), Cd(2+), Hg(2+)). The cell pressure probe experiments were performed on onion epidermal cells as a model system. Heavy metal solutions at different concentrations (0.05 MUM-2 mM) were used in our experiments. We showed that the investigated metal ions can be arranged in order of decreasing toxicity (expressed as a decrease in water permeability) as follows: Hg>Cd>Pb>Zn. Our results showed that beta mercaptoethanol treatment (10 mM solution) partially reverses the effect of AQP gating. The magnitude of this reverse differed depending on the metal and its concentration. The time course studies of the process showed that the gating of AQPs occurred within the first 10 min after the application of a metal. We also showed that after 20-40 min from the onset of metal treatment, the water flow through AQPs stabilized and remained constant. We observed that irrespective of the metal applied, the effect of AQP gating can be recorded within the first 10 min after the administration of metal ions. More generally, our results indicate that the toxic effects of investigated metal ions on the cellular level may involve AQP gating. PMID- 20960017 TI - Estimation of desvenlafaxine transfer into milk and infant exposure during its use in lactating women with postnatal depression. AB - This study characterises the extent of desvenlafaxine transfer into milk and provides data on infant exposure to desvenlafaxine via breast milk in ten women with postnatal depression and their breastfed infants. Desvenlafaxine concentration in milk and plasma was measured chromatographically in milk and in maternal and infant plasma collected at steady state. Theoretic and relative infant doses via milk were estimated and the per cent drug in infant versus mother's plasma was calculated. Theoretic infant dose via milk was 85 (53-117) MUg kg(-1) day(-1) (mean and 95% confidence interval) and relative infant dose was 6.8% (5.5-8.1%). The ratio of drug in infant/maternal plasma also gave an infant exposure estimate of 4.8% (3.5-6.2%) for all ten infants and 5.3% (4.2 5.7%) in the eight infants who were exclusively breastfed. No adverse effects were seen in the infants. The relative infant dose was similar to that for previous studies using venlafaxine and was supported by a separate exposure measure using the ratio of drug in the infant's plasma relative to that in the mother's plasma. The theoretic infant dose of desvenlafaxine was 41-45% of that for venlafaxine and its metabolite desvenlafaxine in previous studies, reflecting the lower recommended maternal dose for desvenlafaxine. Although our data for desvenlafaxine use in lactation are encouraging and there are supporting data from venlafaxine studies, more patients and their infants need to be studied before the safety of desvenlafaxine as a single therapeutic agent can be fully assessed. PMID- 20960019 TI - Bilateral inguinal hernia repair: laparoscopic or open approach? AB - BACKGROUND: The aim of this study was to investigate outcomes in the treatment of bilateral inguinal hernia, comparing the laparoscopic totally extraperitoneal (TEP) and open tension-free mesh repair (LICHT) approaches. METHODS: We performed a prospective controlled non randomized clinical study in 128 patients with bilateral inguinal hernia over a period of 3 years. LICHT was used in 106 cases (53 patients) while TEP was employed in 150 cases (75 patients). The main outcome measurements were: recurrence rate, operating time, hospital stay and postoperative complications. RESULTS: There were three recurrences (2.3%): two in the LICHT group (3.8%) and one (1.3%) in the TEP group P = NS. The TEP procedure was faster than LICHT repair (48.8 +/- 10.8 vs. 70.4 +/- 11.2 min) P < 0.01. Postoperative complications were more frequent in LICHT group (16%) than TEP group (5.3%) P < 0.01. Hospital stay was significantly shorter in the TEP group (0.6 +/- 0.8 vs. 1.3 +/- 1.2 days) P < 0.001. CONCLUSIONS: The TEP approach is an effective option for the treatment of bilateral inguinal hernia when performed by experienced surgeons. PMID- 20960020 TI - Gene networks in the synthesis and deposition of protein polymers during grain development of wheat. AB - As the amino acid storing organelle, the protein bodies provide nutrients for embryo development, seed germination and early seedling growth through storage proteolysis in cereal plants, such as wheat and rice. In protein bodies, the monomeric and polymeric prolamins, i.e. gliadins and glutenins, form gluten and play a key role in determining dough functionality and end-product quality of wheat. The formation of intra- and intermolecular bonds, including disulphide and tyrosine bonds, in and between prolamins confers cohesivity, viscosity, elasticity and extensibility to wheat dough during mixing and processing. In this review, we summarize recent progress in wheat gluten research with a focus on the fundamental molecular biological aspects, including transcriptional regulation on genes coding for prolamin components, biosynthesis, deposition and secretion of protein polymers, formation of protein bodies, genetic control of seed storage proteins, the transportation of the protein bodies and key enzymes for determining the formation of disulphide bonds of prolamin polymers. PMID- 20960021 TI - Augmented antihypertensive effect of a fixed combination formula of candesartan and hydrochlorothiazide combined with furosemide in a patient on peritoneal dialysis. AB - A 38-year-old female patient on peritoneal dialysis (PD) due to type 1 diabetic nephropathy with a well-preserved residual renal function did not respond well to the conventional antihypertensive therapy consisting of candesartan, furosemide, and bunazosin. Switching candesartan for a fixed combination formula of candesartan plus hydrochlorothiazide (HCTZ) while the rest of the other two agents remained unchanged led to the remarkable reduction in both systolic and diastolic blood pressure (BP) without significant changes in the cardiothoracic ratio (CTR), body weight (BW), and residual renal function. This case suggests that when used in combination, diuretics acting on different functional segment of the nephron hold greater potential for enhanced antihypertensive effect, especially in patients on PD whose residual renal function is well preserved. A small dose of HCTZ with an angiotensin II receptor blocker (ARB) may partially explain the therapeutic benefit of this combination therapy in terms of a reliable hypotensive effect, a better adherence, and fewer side effects. PMID- 20960022 TI - A suspected case of paradoxical renal embolism through the patent foramen ovale. AB - We experienced a case of cryptogenic renal infarction in a previously healthy 60 year-old man. He had no systemic atherosclerotic changes. Holter monitoring revealed no atrial fibrillation. Transthoracic echocardiography showed no thrombus. Because the onset occurred while he was swinging a golf club (a similar maneuver to holding the breath), further examination was performed with a view to detecting paradoxical embolism through the foramen ovale. A positive bubble test with the Valsalva maneuver during transesophageal echocardiography led to the diagnosis of patent foramen ovale (PFO). This was a suspected case of paradoxical embolism through a PFO leading to renal infarction. PMID- 20960023 TI - Structure of the gap junction channel and its implications for its biological functions. AB - Gap junctions consist of arrays of intercellular channels composed of integral membrane proteins called connexin in vertebrates. Gap junction channels regulate the passage of ions and biological molecules between adjacent cells and, therefore, are critically important in many biological activities, including development, differentiation, neural activity, and immune response. Mutations in connexin genes are associated with several human diseases, such as neurodegenerative disease, skin disease, deafness, and developmental abnormalities. The activity of gap junction channels is regulated by the membrane voltage, intracellular microenvironment, interaction with other proteins, and phosphorylation. Each connexin channel has its own property for conductance and molecular permeability. A number of studies have tried to reveal the molecular architecture of the channel pore that should confer the connexin-specific permeability/selectivity properties and molecular basis for the gating and regulation. In this review, we give an overview of structural studies and describe the structural and functional relationship of gap junction channels. PMID- 20960024 TI - POU homeodomain protein OCT1 modulates islet 1 expression during cardiac differentiation of P19CL6 cells. AB - Islet 1 (ISL1), a marker of cardiac progenitors, plays a crucial role in cardiogenesis. However, the precise mechanism underlying the activation of its expression is not fully understood. Using the cardiac differentiation model of P19CL6 cells, we show that POU homeodomain protein, OCT1, modulates Isl1 expression in the process of cardiac differentiation. Oct1 knock-down resulted in reduction of Isl1 expression and downregulated mesodermal, cardiac-specific, and signal pathway gene expression. Additionally, the octamer motif located in the proximal region of Isl1 promoter is essential to Isl1 transcriptional activation. Mutation of this motif remarkably decreased Isl1 transcription. Although both OCT1 and OCT4 bound to this motif, it was OCT1 rather than OCT4 that modulated Isl1 expression. Furthermore, the correlation of OCT1 in regulation of Isl1 was revealed by in situ hybridization in early embryos. Collectively, our data highlight a novel role of OCT1 in the regulation of Isl1 expression. PMID- 20960025 TI - Aging and TOR: interwoven in the fabric of life. AB - Longstanding results with calorie and growth factor restriction plus recent results with the first interventional drug suggest that retarding the pace of aging to improve the quality of life of older people is at hand. The biological system targeted by these approaches is the target of rapamycin (TOR), which is central for cellular responses to a variety of stimuli including stressors, growth factors, and nutrients and energy states. That the life-extending response to reducing its activity is highly conserved from yeast to mammals is consistent with the evolution of aging as a strategy to preserve reproductive potential of young cells and animals. PMID- 20960026 TI - Direct concentration and viability measurement of yeast in corn mash using a novel imaging cytometry method. AB - Worldwide awareness of fossil-fuel depletion and global warming has been increasing over the last 30 years. Numerous countries, including the USA and Brazil, have introduced large-scale industrial fermentation facilities for bioethanol, biobutanol, or biodiesel production. Most of these biofuel facilities perform fermentation using standard baker's yeasts that ferment sugar present in corn mash, sugar cane, or other glucose media. In research and development in the biofuel industry, selection of yeast strains (for higher ethanol tolerance) and fermentation conditions (yeast concentration, temperature, pH, nutrients, etc.) can be studied to optimize fermentation performance. Yeast viability measurement is needed to identify higher ethanol-tolerant yeast strains, which may prolong the fermentation cycle and increase biofuel output. In addition, yeast concentration may be optimized to improve fermentation performance. Therefore, it is important to develop a simple method for concentration and viability measurement of fermenting yeast. In this work, we demonstrate an imaging cytometry method for concentration and viability measurements of yeast in corn mash directly from operating fermenters. It employs an automated cell counter, a dilution buffer, and staining solution from Nexcelom Bioscience to perform enumeration. The proposed method enables specific fluorescence detection of viable and nonviable yeasts, which can generate precise results for concentration and viability of yeast in corn mash. This method can provide an essential tool for research and development in the biofuel industry and may be incorporated into manufacturing to monitor yeast concentration and viability efficiently during the fermentation process. PMID- 20960027 TI - Sensitivity of BRCA2 mutated human cell lines to Aurora kinase inhibition. AB - Aurora kinases play a vital part in successful mitosis and cell division. Aberrant Aurora-A and -B expression is commonly seen in various types of tumors. Small molecule Aurora inhibitors have already entered clinical trials. Aurora-A amplification has been shown to be associated with breast tumors from BRCA2 mutation carriers and such patients might therefore be candidates for treatment with Aurora kinase inhibitors. There is a need to identify markers that can predict sensitivity to Aurora inhibition. In this study sensitivity to the inhibitor ZM447439 was tested on a panel of 15 non-malignant and malignant epithelial cell lines that differed with respect to BRCA2 and p53 status and related to level of Aurora kinase expression. The IC(50) value for cell survival ranged from 1.9-8.1 MUM and was not related to presence or absence of BRCA2 mutation. The levels of Aurora-A and -B expression correlated with each other but sensitivity towards ZM447439 did not correlate with levels of Aurora-A and -B mRNA expression, alone. Cells treated with the Aurora kinase inhibitor completed mitosis but cytokinesis was inhibited resulting in polyploidy and multinucleation. Different levels of polyploidy could not be fully explained by defects in p53. Only cell lines with a combination of high Aurora-A and -B expression, BRCA2 mutation and p53 defects showed more sensitivity towards Aurora inhibition than other cell lines. In conclusion, BRCA2-mutated cells showed variable sensitivity towards Aurora kinase inhibition. The level of sensitivity could not be predicted by Aurora expression levels alone but BRCA2 mutated tumors with high Aurora expression and non-functional p53 are likely candidates for treatment with Aurora inhibitors. PMID- 20960028 TI - Feasibility study of two schedules of sunitinib in combination with pemetrexed in patients with advanced solid tumors. AB - BACKGROUND: Sunitinib is an oral multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, as well as of other receptor types. We have performed a feasibility study to investigate the safety of sunitinib in combination with pemetrexed for treatment of advanced refractory solid tumors. METHODS: Sunitinib was administered once daily on a continuous daily dosing (CDD) schedule (37.5 mg/day) or a 2-weeks-on, 1-week-off treatment schedule (50 mg/day, Schedule 2/1) in combination with pemetrexed at 500 mg/m(2) on day 1 of repeated 21-day cycles. RESULTS: Twelve patients were enrolled in the study: six on the CDD schedule and six on Schedule 2/1. None of the treated patients experienced a dose-limiting toxicity. Toxicities were manageable and similar in type to those observed in monotherapy studies of sunitinib and pemetrexed. Pharmacokinetic analysis did not reveal any substantial drug-drug interaction. One patient with squamous cell lung cancer showed a partial response and five patients had stable disease. CONCLUSIONS: Combination therapy with sunitinib administered on Schedule 2/1 (50 mg/day) or a CDD schedule (37.5 mg/day) together with standard-dose pemetrexed (500 mg/m(2)) was well tolerated in previously treated patients with advanced solid tumors. PMID- 20960029 TI - Trabectedin in pre-treated patients with advanced or metastatic soft tissue sarcoma: a phase II study evaluating co-treatment with dexamethasone. AB - PURPOSE: This study assesses the efficacy, toxicity and pharmacokinetic profile of trabectedin with or without prophylactic dexamethasone co-treatment in patients with recurrent advanced soft tissue sarcoma (STS). PATIENTS AND METHODS: Patients were randomized to receive trabectedin as a 3-h infusion every 3 weeks with dexamethasone or placebo in the first cycle, with the alternate in the second cycle and with the patient's choice subsequently. Due to toxicity, the randomized design was modified to open-label to make dexamethasone mandatory and the initial dose (1,650 MUg/m(2)) was reduced to 1,500 MUg/m(2) and then to 1,300 MUg/m(2). RESULTS: Forty-one patients were enrolled and 35 were evaluable for efficacy. One partial response and 18 disease stabilizations were found. The median PFS and OS were 2.1 and 10.2 months, respectively, with the 3- and 6-month PFS rates indicating activity in pretreated STS. Twenty-three and 27 patients developed transient asymptomatic grade 3/4 AST and ALT elevation, respectively, and 21 patients had grade 3/4 neutropenia. Dose reduction from 1,650 MUg/m(2) to 1,300 MUg/m(2) decreased the incidence of grade 3/4 thrombocytopenia (26% vs. 0%), neutropenia (51% vs. 25%) and AST increase (76% vs. 25% of patients). Four patients died due to drug-related toxicities (3 with placebo). The total body clearance of trabectedin was 28% higher and half-life was 21% lower with dexamethasone compared to placebo, with no differences in volume of distribution. CONCLUSIONS: Trabectedin has confirmed activity in patients with pretreated STS. This study shows that co-treatment with dexamethasone improves the safety of trabectedin by reducing drug-induced hepatotoxicity and myelosuppression. PMID- 20960030 TI - Schedule-dependent inhibition of T-cell lymphoma cells by cotreatment with the mTOR inhibitor everolimus and anticancer drugs. AB - OBJECTIVE: Everolimus (RAD001) is a novel mammalian target of rapamycin (mTOR) inhibitor, and anti-proliferative activity in various malignancies has been reported. This study evaluated the anti-tumor effects and schedule-dependent synergism of everolimus in combination with other chemotherapeutic agents in T cell lymphoma cell lines. MATERIALS AND METHODS: Human T-cell lymphoma cell lines Hut-78 and Jurkat were treated with increasing doses of everolimus, alone or in combination with doxorubicin, etoposide, vincristine, or bortezomib, using different dosing schedules. Anti-tumor effects were measured by assays for cell proliferation, apoptosis, and cell cycle distribution. Drug interactions were determined by median effect analysis. RESULTS: Exposure to everolimus alone induced G1 phase cell cycle arrest without significant apoptosis. With certain dosing schedules, everolimus showed synergism with doxorubicin, etoposide, and bortezomib, but antagonism with vincristine. Cytotoxic synergism was observed following cotreatment with doxorubicin and everolimus, bortezomib and everolimus, doxorubicin followed by everolimus, and bortezomib followed by everolimus. By contrast, cell exposure to everolimus followed by doxorubicin or followed by bortezomib resulted in antagonistic effects. Sequential exposure to doxorubicin or bortezomib followed by everolimus effectively prevented potential negative interactions, and resulted in drug synergism. Drug combination synergisms or antagonisms were associated with variable effects on the cell cycle distribution. CONCLUSIONS: Everolimus effectively inhibited the growth of T-cell lymphoma cells in vitro. Specific schedule-dependent combinations of everolimus with other anti tumor agents which avoid potential drug antagonism and produce effective synergism may lead to clinically effective treatments for T-cell lymphoma. PMID- 20960031 TI - Ligand-guided optimization of CXCR4 homology models for virtual screening using a multiple chemotype approach. AB - CXCR4 is a G-protein coupled receptor for CXCL12 that plays an important role in human immunodeficiency virus infection, cancer growth and metastasization, immune cell trafficking and WHIM syndrome. In the absence of an X-ray crystal structure, theoretical modeling of the CXCR4 receptor remains an important tool for structure-function analysis and to guide the discovery of new antagonists with potential clinical use. In this study, the combination of experimental data and molecular modeling approaches allowed the development of optimized ligand receptor models useful for elucidation of the molecular determinants of small molecule binding and functional antagonism. The ligand-guided homology modeling approach used in this study explicitly re-shaped the CXCR4 binding pocket in order to improve discrimination between known CXCR4 antagonists and random decoys. Refinement based on multiple test-sets with small compounds from single chemotypes provided the best early enrichment performance. These results provide an important tool for structure-based drug design and virtual ligand screening of new CXCR4 antagonists. PMID- 20960032 TI - 3D-QSAR studies and molecular docking on [5-(4-amino-1H-benzoimidazol-2-yl)-furan 2-yl]-phosphonic acid derivatives as fructose-1,6-biphophatase inhibitors. AB - Fructose-1,6-biphophatase has been regarded as a novel therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). 3D-QSAR and docking studies were performed on a series of [5-(4-amino-1H-benzoimidazol-2-yl)-furan-2-yl] phosphonic acid derivatives as fructose-1,6-biphophatase inhibitors. The CoMFA and CoMSIA models using thirty-seven molecules in the training set gave r (cv) (2) values of 0.614 and 0.598, r (2) values of 0.950 and 0.928, respectively. The external validation indicated that our CoMFA and CoMSIA models possessed high predictive powers with r (0) (2) values of 0.994 and 0.994, r (m) (2) values of 0.751 and 0.690, respectively. Molecular docking studies revealed that a phosphonic group was essential for binding to the receptor, and some key features were also identified. A set of forty new analogues were designed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models. The findings can be quite useful to aid the designing of new fructose-1,6-biphophatase inhibitors with improved biological response. PMID- 20960034 TI - Do split your epidemiological data. PMID- 20960033 TI - Quantification of protein backbone hydrogen-deuterium exchange rates by solid state NMR spectroscopy. AB - We present the quantification of backbone amide hydrogen-deuterium exchange rates (HDX) for immobilized proteins. The experiments make use of the deuterium isotope effect on the amide nitrogen chemical shift, as well as on proton dilution by deuteration. We find that backbone amides in the microcrystalline alpha-spectrin SH3 domain exchange rather slowly with the solvent (with exchange rates negligible within the individual (15)N-T (1) timescales). We observed chemical exchange for 6 residues with HDX exchange rates in the range from 0.2 to 5 s(-1). Backbone amide (15)N longitudinal relaxation times that we determined previously are not significantly affected for most residues, yielding no systematic artifacts upon quantification of backbone dynamics (Chevelkov et al. 2008b). Significant exchange was observed for the backbone amides of R21, S36 and K60, as well as for the sidechain amides of N38, N35 and for W41epsilon. These residues could not be fit in our previous motional analysis, demonstrating that amide proton chemical exchange needs to be considered in the analysis of protein dynamics in the solid-state, in case D(2)O is employed as a solvent for sample preparation. Due to the intrinsically long (15)N relaxation times in the solid state, the approach proposed here can expand the range of accessible HDX rates in the intermediate regime that is not accessible so far with exchange quench and MEXICO type experiments. PMID- 20960035 TI - Proteome analysis of human pancreatic cancer cell lines with highly liver metastatic potential by antibody microarray. AB - Antibody microarrays have been successfully used to determine relative abundance of key proteins in various cancers and other diseases. We have previously showed liver metastatic-related genes between the metastatic pancreatic cancer line (SW1990HM) and its parental line (SW1990). In this study, we searched for potential markers for metastatic progression using antibody microarrays. The SpringBio Antibody Microarrays were used to analysis the different proteomes between SW1990HM and SW1990 cells. A standard >=2.0-fold cutoff value was used to determine differentially expressed proteins and Western blotting analysis further confirmed the results. Antibody microarrays revealed that 40 proteins were reproducibly altered more than 2-fold between the selected variant and its parental counterpart; 14 of the proteins were up-regulated, and 26 were down regulated. Most of the up-regulated proteins (7/14) play a role in tumor signal transduction, while a number of down-regulated proteins (10/26) function in cell differentiation; this might be crucial for pancreatic cancer metastasis. Four dysregulated proteins were validated by western blotting in the cell lines. Interestingly, the up-regulation of Glucagon and down-regulation of Prolactin were further confirmed in the culture supernatants by western blotting. These proteomic data are valuable for understanding pancreatic cancer metastasis and searching for potential markers of metastatic progression. PMID- 20960036 TI - High glucose promotes cell proliferation and enhances GDNF and RET expression in pancreatic cancer cells. AB - Hyperglycemia promotes pancreatic cancer progression, while the underlying mechanism is uncertain. We investigated the cell proliferation, glial cell line derived neurotrophic factor (GDNF) and its tyrosine kinase receptor RET expression in BxPC-3 and MIA PaCa-2 cells when exposed to different concentrations of glucose. Proliferation of both cells was effected by glucose in a concentration-dependent manner. Definite expression of GDNF and RET was detected in both cells. Glucose concentrations could alter the expression of GDNF and RET in a concentration-dependent manner, correspondingly with the alterations of cell proliferation. Up-regulation of GDNF and RET ligand-receptor interaction might participate in the glucose-induced cancer progression. PMID- 20960037 TI - Processing of a porous titanium alloy from elemental powders using a solid state isothermal foaming technique. AB - The authors have conducted a preliminary investigation with regard to the potential to manufacture porous titanium alloys for biomedical applications using toxic-free elemental powders, i.e., Ti, Nb, Ta, Zr, in combination with the pressurised gas bubble entrapment method and in contrast to standard processing routes that generally utilise prealloyed powder containing potentially toxic elements. Elemental powder compacts were either hot isostatic pressed (HIP-ed) at 1000 degrees C and then foamed at 1150 degrees C or else HIP-ed at 1100 degrees C and foamed at 1350 degrees C. Porous alpha + beta alloys containing up to 45 vol% of porosity in the size range 20-200 MUm were successfully produced, thus highlighting the potential of this manufacturing route. It was expected that further optimisation of the processing route would allow full development of the preferred beta-Ti phase (from the point of view of elastic modulus compatibility between implant and bone) with this being the subject of future work by the authors. PMID- 20960038 TI - Protective effect of quercetin on liver damage induced by biliary obstruction in rats. AB - The aim of this study was to evaluate the possible protective effects of quercetin (QE) against cholestatic oxidative stress and liver damage in the common bile duct ligated rats. A total of 24 male Wistar albino rats were divided into three groups: control, bile duct ligation (BDL) and BDL + received QE; each group contain 8 animals. The rats in QE treated groups were given QE (15 mg/kg) once a day intraperitoneally for 4 weeks starting 3 days prior to BDL operation. The changes demonstrating the bile duct proliferation and fibrosis in expanded portal tracts include the extension of proliferated bile ducts into lobules, mononuclear cells, and neutrophil infiltration into the widened portal areas were observed in BDL group. Treatment of BDL with QE attenuated alterations in liver histology. The alpha smooth muscle actin (alpha-SMA), transforming growth factor beta (TGF-beta1) positive cells and the activity of TUNEL in the BDL were observed to be reduced with the QE treatment. The data indicate that QE attenuates BDL-induced cholestatic liver injury, bile duct proliferation, and fibrosis. The hepatoprotective effect of QE is associated with antioxidative potential. PMID- 20960040 TI - Slowing down the presentation of facial and body movements enhances imitation performance in children with severe autism. AB - Imitation deficits observed among individuals with autism could be partly explained by the excessive speed of biological movements to be perceived and then reproduced. Along with this assumption, slowing down the speed of presentation of these movements might improve their imitative performances. To test this hypothesis, 19 children with autism, 37 typically-developing children and 17 children with Down syndrome were asked to reproduce facial and body movements presented on a computer at a normal/ecological and two slowed down speeds. Our main result showed that a subgroup of individuals with severe autism better reproduced the movements when presented slowly than at the ecological speed. This finding opens a new window for comprehension and rehabilitation of perceptual and imitative deficits in autism. PMID- 20960039 TI - Early intervention of eating- and weight-related problems. AB - Obesity and other eating-related problems are widespread and are associated with harmful physical, psychological, and social problems. The dramatic increases in rates of pediatric obesity has created a mounting need for psychologists and other mental health care providers to play a significant role in the assessment and treatment of youth with eating- and weight-related problems. Therefore, it is imperative for providers to be aware of the causes and consequences of eating- and weight-related problems and to be familiar with evidence-based assessment and intervention approaches. Currently, the most well-established intervention approaches are family-based behavioral treatments, and weight loss maintenance treatments with a socio-ecological focus are promising. This paper provides a comprehensive review of these topics and highlights the important roles that mental health care providers can have. Medical settings are often the patient's first point of contact within the healthcare system, making mental health care providers in such settings uniquely suited to assess for a broad range of eating- and weight-related problems and associated comorbidities, to deliver relevant evidence-based interventions, and to make appropriate referrals. Moving forward, providers and researchers must work together to address key questions related to the nature of eating- and weight-related problems in youth and to achieve breakthroughs in the prevention and treatment of such problems in this vulnerable population. PMID- 20960041 TI - Aggression in children and adolescents with ASD: prevalence and risk factors. AB - The prevalence of and risk factors for aggression were examined in 1,380 children and adolescents with autism spectrum disorders (ASD). Prevalence was high, with parents reporting that 68% had demonstrated aggression to a caregiver and 49% to non-caregivers. Overall, aggression was not associated with clinician observed severity of ASD symptoms, intellectual functioning, gender, marital status, parental educational level, or aspects of communication. Individuals who are younger, come from a higher income family, have more parent reported social/communication problems, or engage in repetitive behaviors were more likely to demonstrate aggression. Given the significant impact of aggression on individual and family outcomes, it is hoped that this knowledge will inform more targeted intervention efforts. PMID- 20960042 TI - Effects of task organization on the independent play of students with autism spectrum disorders. AB - The purpose of the study was to examine the impact of task organization, a component of Structured Teaching developed by Division TEACCH, on the independent play of children with autism spectrum disorders (ASD). On-task behavior, task accuracy, task performance and teacher prompting were measured across independent play sessions in the classroom. An ABAB design was implemented to evaluate the effects of task organization on the independent play skills of two young children with ASD. Results regarding on-task behavior, task accuracy and independence were variable and are discussed. The implications of findings on the use of task organization for increasing independence in children with ASD are discussed. PMID- 20960043 TI - Molecular characterization and genetic organization of the BamHI-C fragment of Clostera anachoreta granulovirus. AB - The BamHI-C restriction fragment of ClanGV genome was cloned and sequenced. Sequence analysis indicated that this region contains five important baculovirus homologous genes (chitinase, cathepsin, gp37, p49 and odv-e18) and one ORF unique to ClanGV genome. The genes, located within this restriction fragment, were compared with homologues in other baculoviruses. Comparison results indicated that ClanGV, Cydia pomonella GV and Pieris rapae GV have similar arrangement and orientation of the homologous genes. The ORFs related to these five genes were analyzed. PMID- 20960044 TI - Genetic characterization of H1 avian influenza viruses isolated from migratory birds and domestic ducks in Korea. AB - H1 avian influenza viruses (AIVs) isolated from migratory birds and domestic ducks from 2003 to 2007 were analyzed to determine their genetic relationship. Phylogenic analysis with nucleotide sequences of all eight gene segments showed that 13 H1 AIVs from migratory birds and domestic ducks belonged to Eurasian avian lineages and were closely related to each other. Compared with H1 influenza viruses of swine or human origin in Korea, there was no evidence of reassortment among the human, swine, and avian hosts. Our results show that H1 AIVs isolated in Korea from 2003 to 2007 were genetically stable. However, continued surveillance is needed considering the role of migratory birds and domestic duck as a source of AIVs. PMID- 20960045 TI - A large Finnish echovirus 30 outbreak was preceded by silent circulation of the same genotype. AB - An outbreak of echovirus 30 (E-30) in 2009 was confirmed by both frequent isolation of the virus from sewage as well as from patient samples in Finland. Over the last 10 years E-30 had only been isolated sporadically in Finland. We here study the phylogenetic relationships of the strains from the outbreak in the context of E-30 circulation over the last 20 years. The analyzed region comprised 276 nucleotides in the 5' end of VP1 (nucleotides 132-407 in the VP1 of the E-30 Bastianni strain). The Finnish strains were clustered into at least four distinct genogroups, with seven clusters exceeding the genotype demarcation of 12% and the 2009 epidemic strains forming the largest genogroup VII. Moreover, we detected largely divergent genotypes in 2007 and 2009. Interestingly, close genetic relatives of the epidemic strains had already been isolated a few years before the outbreak. Phylodynamic analysis estimated 8.9 years (95% highest posterior density intervals 7.0-11.0) as the age of genogroup VII, indicating a probable origin and evolutionary history prior to its introduction and epidemic expansion in Finland. Finally, the most recent common ancestor for the current E-30 diversity dates back to 1939 (95% highest posterior density intervals 1913-1956). PMID- 20960046 TI - Comparison of the replication properties of murine and human calicivirus RNA dependent RNA polymerases. AB - The human caliciviruses (CV), norovirus (NoV) and sapovirus (SaV), are major causes of outbreak gastroenteritis worldwide. To date, the investigation of human NoV and SaV replication cycles has been impeded as neither is culturable. Consequently, the recently discovered murine NoV (MNV) has been adopted as a surrogate replication model for the human CVs. In this study, we sought to compare the biochemical properties of the MNV RNA-dependent RNA polymerase (RdRp) with related human NoV and SaV-RdRps to address the suitability of MNV as a model for the human CVs. Three human NoV-RdRps (GII.b, GII.4 and GII.7), an MNV-RdRp and two human SaV-RdRps (GI and GII) were overexpressed in Escherichia coli, purified and their enzymatic activity and fidelity compared. Despite ~70% amino acid variation between the RdRp from the two different CV genera, the majority of the physiological characteristics of the RdRps were similar. All RdRps exhibited co-operative dimerisation and had optimal activity at 25 degrees C, a pH range between 7 and 8, required 2-5 mM MnCl(2) and were inhibited with increasing NaCl concentrations. We observed RdRp activity at temperatures as low as 5 degrees C and as high as 65 degrees C. Using an in vitro fidelity assay, similar mutation rates were observed for the separate RdRps (1 * 10(-4)-1 * 10(-5)). This is the first report to compare the physiological, biochemical and mutational properties of the MNV-RdRp to those of the human CV-RdRps and it suggests that MNV may be directly applicable to the study of human NoV. PMID- 20960047 TI - Normative beliefs and sexual risk in China. AB - We examined normative beliefs about multiple sexual partners and social status in China and their association with risky sexual behaviors and sexually transmitted infections (STIs). Self-reported and biological markers of sexual risk were examined among 3,716 market vendors from a city in eastern China. Men who were older or with less education believed having multiple sexual partners was linked to higher social status. Adjusting for demographic characteristics, normative beliefs were significantly associated with having multiple sexual partners, while having multiple sexual partners was significantly associated with STIs. Normative beliefs regarding sexual behaviors may play an important role in individual risk behaviors. Future HIV/STI interventions must address community beliefs about the positive meaning of sexual risks, particularly among men with traditional beliefs about gender roles. PMID- 20960048 TI - Sensation seeking moderates the effects of alcohol and drug use prior to sex on sexual risk in young men who have sex with men. AB - Men who have sex with men (MSM) account for more than half of all new HIV/AIDS diagnoses in the United States each year, and young MSM (ages 13-24) have the highest increases in new infections. Identifying which young MSM engage in sexual risk-taking in which contexts is critical in developing effective behavioral intervention strategies for this population. While studies have consistently found positive associations between the use of certain drugs and sexual risk, research on alcohol use as a predictor of risk has been less consistent. Participants included 114 young MSM from a longitudinal study of LGBT youth (ages 16-20 at baseline). Participants reported number of unprotected sex acts with up to nine partners across three waves of data collection spanning a reporting window of 18 months, for a total of 406 sexual partners. Sensation seeking was evaluated as a moderator of the effects of both alcohol and drug use prior to sex on sexual risk. Higher levels of sensation seeking were found to significantly increase the positive associations between frequency of unprotected sex and frequency of both alcohol use and drug use with partners. Follow-up analysis found that average rates of alcohol use moderated the association between alcohol use prior to sex and sexual risk, such that decreases in average alcohol use increased the positive association between these variables. Results suggest that while drug use with partners increased sexual risk for all young MSM, the effects of alcohol use prior to sex were limited in low sensation-seeking young MSM as well as those who are high alcohol consumers on average. Implications for future research and behavioral interventions are discussed. PMID- 20960049 TI - Life after HIV: examination of HIV serodiscordant couples' desire to conceive through assisted reproduction. AB - The current study addresses fertility desires and considerations among 143 HIV serodiscordant, opposite-sex couples (in which only the male partner is HIV positive) in the Northeastern U.S. Couples responded to questionnaires during their initial consultation for assisted reproduction, and data were collected over 7 years and analyzed retrospectively. Results indicated that a majority of the male participants had HIV when they met their partner, and a majority also disclosed their HIV status upon meeting. Most couples reported that they had previously discussed or considered a host of fertility-related issues, including the potential risk of HIV infection to the mother and the fetus during the process of fertility treatment. The majority of couples had also discussed the possibility that the male partner could die prematurely due to HIV/AIDS and had considered making arrangements for third-party parenting in the event of the male partner's death. If their fertility treatment were to be successful in the future, most couples desired additional children, and most believed that their future child should be told of the male partner's HIV status. Predictors of the desire for additional children after successful fertility treatment included: younger age, shorter relationship duration, being childless currently, and beginning their relationship after the male partner had already been diagnosed as HIV positive. Future research on fertility desires should include perspectives of HIV positive men on fatherhood, as well as concerns and issues specific to HIV serodiscordant couples. PMID- 20960051 TI - Joint attention in parent-child dyads involving children with selective mutism: a comparison between anxious and typically developing children. AB - Although joint attention processes are known to play an important role in adaptive social behavior in typical development, we know little about these processes in clinical child populations. We compared early school age children with selective mutism (SM; n = 19) versus mixed anxiety (MA; n = 18) and community controls (CC; n = 26) on joint attention measures coded from direct observations with their parent during an unstructured free play task and two structured tasks. As predicted, the SM dyads established significantly fewer episodes of joint attention through parental initiation acts than the MA and CC dyads during the structured tasks. Findings suggest that children with SM may withdraw from their parents during stressful situations, thus missing out on opportunities for learning other coping skills. We discuss the implications of the present findings for understanding the maintenance and treatment of SM. PMID- 20960050 TI - Dietary methyl donors, methyl metabolizing enzymes, and epigenetic regulators: diet-gene interactions and promoter CpG island hypermethylation in colorectal cancer. AB - Dietary methyl donors might influence DNA methylation during carcinogenesis of colorectal cancer (CRC). Among 609 CRC cases and 1,663 subcohort members of the Netherlands Cohort Study on diet and cancer (n = 120,852), we estimated CRC risk according to methyl donor intake across genotypes of folate metabolizing enzymes and methyltransferases.Although diet-gene interactions were not statistically significant, methionine intake was inversely associated with CRC among subjects having both common rs2424913 and rs406193 DNMT3B C > T genotypes (highest versus lowest tertile: RR = 0.44; p (trend) = 0.05). Likewise, vitamin B2 was modestly inversely associated among individuals with the MTHFR c.665CC (rs1801133) genotype (RR = 0.66; p (trend) = 0.08), but with a significant reduced risk when <= 1 rare allele occurred in the combination of folate metabolizing enzymes MTHFR, MTRR and MTR (RR = 0.30; p (trend) = 0.005). Folate or vitamin B6 were neither inversely associated with CRC nor was methyl donor intake associated with the CpG island methylator phenotype (CIMP).Despite the absence of heterogeneity across genotypes, might an effect of methyl donors on CRC be more pronounced among individuals carrying common variants of folate metabolizing enzymes or DNA methyltransferases. Combining genotypes may assist to reveal diet associations with CRC, possibly because rare variants of related genes may collectively affect specific metabolic pathways or enzymatic functions. PMID- 20960052 TI - A new method of exercising pandemic preparedness through an interactive simulation and visualization. AB - As seen in the spring 2009 A/H1N1 influenza outbreak, influenza pandemics can have profound social, legal and economic effects. This experience has also made the importance of public health preparedness exercises more evident. Universities face unique challenges with respect to pandemic preparedness due to their dense student populations, location within the larger community and frequent student/faculty international travel. Depending on the social structure of the community, different mitigation strategies should be applied for decreasing the severity and transmissibility of the disease. To this end, Arizona State University has developed a simulation model and tabletop exercise that facilitates decision-maker interactions around emergency-response scenarios. This simulation gives policy makers the ability to see the real-time impact of their decisions. Therefore, tabletop exercises with computer simulations are developed to practice these decisions, which can possibly give opportunities for practicing better policy implementations. This paper introduces a new method of designing and performing table-top exercises for pandemic influenza via state-of-the-art technologies including system visualization and group decision making with a supporting simulation model. The presented exercise methodology can increase readiness for a pandemic through the support of computer and information technologies and the survey results that we include in this paper certainly support this result. The video scenarios and the computer simulation model make the exercise appear very compelling and real, which makes this presented method of exercising different than the other table-top exercises in the literature. Finally, designing a pandemic preparedness exercise with supporting technologies can help identifying the communication gaps between responsible authorities and advance the table-top exercising methodology. PMID- 20960053 TI - Haematopoiesis in the head kidney of common carp (Cyprinus carpio L.): a morphological study. AB - The morphogenesis of head kidney haematopoietic cells in common carp has been shown to be very similar to that of higher vertebrates. The erythropoietic series consisted of the erythroblasts (basophilic, polychromatic and orthochromic), young erythrocyte and erythrocyte. The morphological changes that occur during maturation process are reduction in size and further increase at mature stage, gradual chromatin condensation and the increase in haemoglobin content. Maturation stages of neutrophils and basophils encompassed the young progranulocyte, progranulocyte and metagranulocyte. The early blast cells, basophilic lineage and lymphocytes were regularly present in kidney. In the monocytoid series in kidneys, promonocytes and mature monocytes were observed. Precursor stages of the eosinophile and thrombocyte were not discernible (although mature cells were observed). Lymphoid cells were the most abundant, followed by granuloid, thrombocyte, erythroid, blast and monocytoid cells. The neutrophilic progranulocyte was the most frequent granuloid cell. The lymphocyte was the most frequent cell in the kidney and the most numerous of the lymphoid lineage. PMID- 20960054 TI - Calcitonin gene-related peptide (CGRP) stimulates purkinje cell dendrite growth in culture. AB - Previous reports described the transient expression during development of Calcitonin Gene-Related Peptide (CGRP) in rodent cerebellar climbing fibers and CGRP receptor in astrocytes. Here, mixed cerebellar cultures were used to analyze the effects of CGRP on Purkinje cells growth. Our results show that CGRP stimulated Purkinje cell dendrite growth under cell culture conditions mimicking Purkinje cell development in vivo. The stimulation was not blocked by CGRP8-37, a specific antagonist, suggesting the activation of other related receptors. CGRP did not affect survival of Purkinje cells, granule cells or astrocytes. The selective expression of Receptor Component Protein (RCP) (a component of CGRP receptor family) in astrocytes points to a role of these cells as mediators of CGRP effect. Finally, in pure cerebellar astrocyte cultures CGRP induced a transient morphological differentiation from flat, polygonal to stellate form. It is concluded that CGRP influences Purkinje cell dendrite growth in vitro, most likely through the involvement of astrocytes. PMID- 20960055 TI - CNS targets support and sustain differentiation of cultured neuronal and retinal progenitor cells. AB - Superior colliculus (SC) is the target of retinal neurons, allowing them to form connections. Cultured stem cells/progenitors can potentially be used as donor tissue to reconstruct degenerated retina including perhaps replacing lost ganglion cells in glaucoma. In which case, it will be essential for these cells to integrate with the central nervous system targets. Here, we have investigated if the mid-brain region containing superior colliculus (SC) provides a permissive environment for the survival and differentiation of neural progenitors, including retinal progenitor cells propagated in cultures. Neural (NPCs) and retinal progenitor cells (RPCs) from green fluorescent protein (GFP) transgenic mice were cultured. Passage two through four neural and retinal progenitor cells were subsequently cocultured with the SC organotypic slices and maintained in culture for 17 and eight days respectively. Differentiation of the neurons was studied by immunocytochemistry for retinotypic neuronal markers. Retinal progenitor cells cocultured with SC slices were able to differentiate into various neuronal morphologies. Some cocultured progenitor cells differentiated into neurons as suggested by class III beta tubulin immunoreactivity. In addition, specific retinotypic neuronal differentiation of RPC was detected by immunoreactivity for calbindin and PKC. SC provides a permissive environment that supports survival and differentiation of the progenitor cells. PMID- 20960056 TI - Investigation of serum concentrations and immunohistochemical localization of alpha1-acid glycoprotein in tumor dogs. AB - The purpose of this study was to measure the dynamics of serum alpha1-acid glycoprotein (AGP) concentration in dogs with various tumors, and to investigate the localization of AGP in some tissues using immunohistochemical staining. Sera were obtained from 171 dogs bearing tumors of various types. Serum AGP concentration was measured by single radial immunodiffusion. Tumors occurring in the liver and spleen were also investigated immunohistochemically using anti canine AGP antibody. Mean serum AGP levels were 749 +/- 602 mg/L in dogs with carcinoma (n = 39), 1,014 +/- 971 mg/L with sarcoma (n = 18), and 887 +/- 935 mg/L with round cell tumors (n = 46), all significantly higher than serum AGP level in healthy dogs (n = 137, 364 +/- 106 mg/L). Mean serum AGP levels were significantly higher than in healthy dogs in complex mammary gland carcinoma (n = 5, 876 +/- 721 mg/L), malignant melanoma (n = 7, 1,010 +/- 821 mg/L), and hepatocellular carcinoma (n = 5, 936 +/- 741 mg/L) among carcinomas, hemangiosarcoma (n = 5, 1,740 +/- 1,323 mg/L) among sarcomas, and lymphoma (n = 19, 1,072 +/- 965 mg/L) and histiocytic tumor (n = 6, 1,800 +/- 1,387 mg/L) among round cell tumors. In an immunohistochemical investigation of AGP localization, both weak and strong staining for anti-AGP antibody were seen in hepatic tissue in dogs with primary non-tumorous lesions originating in the spleen (hematoma) and elevated serum AGP, but all tumor tissue in the spleen was negative. Among dogs with primary tumor lesions of the spleen (hemangiosarcoma) and elevated serum AGP levels, both weak, moderate and strong staining for anti-AGP antibody were seen in hepatic tissue, while strong positive staining was apparent in all tumorous tissue from the spleen. In primary tumor lesions in the liver (hepatocellular carcinoma), both moderate and strong staining for anti-AGP antibody were seen in normal hepatic tissue, and both weak, moderate and strong staining were seen in tumor tissues of the liver. AGP levels thus appear to be elevated in dogs with carcinomas, sarcomas, and round cell tumors. With some of these malignant tumors, localization of AGP in tumor tissue was seen. PMID- 20960057 TI - Tobacco as biofactory for biologically active hPL production: a human hormone with potential applications in type-1 diabetes. AB - Human placental lactogen (hPL) is a peptidic hormone that belongs to the short list of growth factors that could treat type-1 diabetes through pancreatic islet transplantation. Placental lactogen has the capacity to improve islet survival and function before or after transplantation. In this study, transgenic tobacco plants were used as a novel expression system for the production of recombinant hPL protein (rhPL). The expression vector pNEKhPL2 containing hPL cDNA was introduced into tobacco plants; the transcriptional activity was confirmed by real-time PCR, and the rhPL levels reached 1% of the total soluble protein (TSP) content in plants cultivated in the greenhouse. In vitro bioassays using the rat insulinoma (INS-1) cell line showed that recombinant protein was able to induce cell proliferation and activate the JAK-2/STAT-5 signal transduction pathway, demonstrating that plant cells can produce the biologically active hPL protein. To further characterize the plant expression system for hPL production, we analyzed the stability of the protein during the life cycle of tobacco plants as well as the transmission of the transgenic trait to the progeny. The recombinant protein was stably accumulated in young leaves, reaching the maximum level in the first month (6.51 MUg/g of fresh weight), but showing a decreasing trend of 26% from the initial sampling time until the end of plant's life cycle. The progeny of the selected pNEKhPL2 plant showed in vitro expression levels of up to 1.1% of TSP. Our results therefore indicate that transgenic plants are a suitable expression system for hPL production. PMID- 20960058 TI - Upregulation of pyrophosphate: fructose 6-phosphate 1-phosphotransferase (PFP) activity in strawberry. AB - Pyrophosphate: fructose 6-phosphate 1-phosphotransferase (PFP) is a cytosolic enzyme catalyzing the first committed step in glycolysis by reversibly phosphorylating fructose-6-phosphate to fructose-1,6-bisphosphate. The position of PFP in glycolytic and gluconeogenic metabolism, as well as activity patterns in ripening strawberry, suggest that the enzyme may influence carbohydrate allocation to sugars and organic acids. Fructose-2,6-bisphosphate activates and tightly regulates PFP activity in plants and has hampered attempts to increase PFP activity through overexpression. Heterologous expression of a homodimeric isoform from Giardia lamblia, not regulated by fructose-2,6-bisphosphate, was therefore employed to ensure in vivo increases in PFP activity. The coding sequence was placed into a constitutive expression cassette under control of the cauliflower mosaic virus 35S promoter and introduced into strawberry by Agrobacterium tumefaciens-mediated transformation. Heterologous expression of PFP resulted in an up to eightfold increase in total activity in ripe berries collected over two consecutive growing seasons. Total sugar and organic acid content of transgenic berries harvested during the first season were not affected when compared to the wild type, however, fructose content increased at the expense of sucrose. In the second season, total sugar content and composition remained unchanged while the citrate content increased slightly. Considering that PFP catalyses a reversible reaction, PFP activity appears to shift between gluconeogenic and glycolytic metabolism, depending on the metabolic status of the cell. PMID- 20960059 TI - Seroprevalence of and risk factors for Mycoplasma mycoides subspecies capri infection in small ruminants in Northern Jordan. AB - During the period from January 2002 to December 2003, serum samples were collected from 104 small ruminant flocks consisting of 18 sheep flocks, 27 goat flocks, and 59 mixed flocks containing both sheep and goats in northern Jordan. Only female sheep and goats were sampled. At least five females aged over 2 years per flock per species were sampled and examined for Mycoplasma mycoides subspecies capri using the latex agglutination test. To increase the chances of detecting positive flocks, sick or older ewes were sampled. Specific information was obtained using a questionnaire to identify potential risk factors for M. mycoides subsp. capri seropositivity in small ruminants. The true flock-level seroprevalences of M. mycoides subsp. capri were 34%, 32%, and 38% in small ruminants (sheep and goats), sheep, and goats, respectively. Differences between flock-level seroprevalences in sheep and goats were not significant (p = 0.7). Multivariable logistic regression analysis of 21 production and health management practices showed four to be associated with M. mycoides subsp. capri seropositivity including flocks which were grazed and fed concentrate supplement (OR = 4.6), improper cleaning of milking utensils (OR = 4.7), buying new animals to replace culled ones (OR = 0.3), and treating against helminths when clinical signs of helminth infections appear (OR = 0.4). PMID- 20960060 TI - Bacterial community associated with the trunk latex of Hancornia speciosa Gomes (Apocynaceae) grown in the northeast of Brazil. AB - Prevention or cure of different illnesses through the use of plant latex is a worldwide known concept. The antifungal activity of Hancornia speciosa latex has been observed against Candida albicans. However, H. speciosa latex is not a sterile plant exudate and secondary metabolites produced by bacteria could be involved in fungal inhibition. In the present study, the bacterial communities of the latex from three H. speciosa trees were characterized using traditional plating and molecular methods. Twelve strains isolated from the latex samples were clustered into four groups by amplified ribosomal DNA restriction analysis (ARDRA). One representative of each group was sequenced and they were identified as belonging to the genera Bacillus, Klebsiella, Enterobacter and Escherichia. None of the 12 isolates showed antifungal activity against C. albicans. A lack of a microbial origin for the antifungal properties of latex was noted. DGGE profiles generated from each of the three latex samples showed unique patterns. Sequencing of the DGGE bands demonstrated the affiliation with the genera Klebsiella, Pantoea, Enterobacter and Burkholderia. In addition, clone libraries were generated and the phylogenetic distribution of the 50 analyzed clones was similar to that obtained using DGGE. The presence of some potential pathogens should be considered before using H. speciosa latex in folk medicine. PMID- 20960061 TI - Head and neck loading in everyday and vigorous activities. AB - The purpose of this study was to document head and neck loading in a group of ordinary people engaged in non-injurious everyday and more vigorous physical activities. Twenty (20) volunteers that were representative of the general population were subjected to seven test scenarios: a soccer ball impact to the forehead, a self-imposed hand strike to the forehead, vigorous head shaking, plopping down in a chair, jumping off a step, a seated drop onto the buttocks, and a vertical drop while seated supine in a chair. Some scenarios involved prescribed and well-controlled stimuli, while others allowed the volunteers to perform common activities at a self-selected level of intensity. Head accelerations up to 31 g and 2888 rad/s(2) and neck loads up to 268 N in posterior shear, 526 N in compression, and 36 Nm in extension were recorded. Most head and neck injury criteria predicted a low risk of injury in all activities. However, rotational head accelerations and Neck Injury Criterion (NIC) values were much higher than some proposed tolerance limits in a large number of tests, all of which were non-injurious. The data from this study help us to establish an envelope of head and neck loading that is commonly encountered and presents a minimal risk of injury. PMID- 20960062 TI - Drug salts and solubilization: modeling the influence of cyclodextrins on oral absorption. AB - Substantial effort and resources are spent for the oral delivery of low solubility compounds using drug delivery technologies. Complexation using cyclodextrins (CDs) is one popular strategy used to enhance drug dissolution kinetics and solubility. In addition to delivery technologies, another common method of improving dissolution kinetics of a low solubility compound is to dose it as a salt. It is not often possible to anticipate how effective a technology such as CD will be in a certain formulation in improving drug absorption, leading to a trial-and-error based formulation process; simultaneous use of salt and complexation technologies increases the complexity of the system. A simple dynamic, systems-based model was developed for predicting the influence of CDs on oral absorption of a salt form of low solubility drug administered as a physical mixture with CD, and validated by in vitro experiments. Model predictions indicate that while CD is generally considered a solubilization technology, CD can enhance overall absorption of salt form drug mainly by decreasing the driving force for precipitation through binding free drug in solution. Modeling enabled examination of which physical and chemical properties result in oral absorption enhancement or decrement for drug salt administered as a physical mixture with CD. PMID- 20960063 TI - Asymmetry of blood flow and cancer cell adhesion in a microchannel with symmetric bifurcation and confluence. AB - Bifurcations and confluences are very common geometries in biomedical microdevices. Blood flow at microchannel bifurcations has different characteristics from that at confluences because of the multiphase properties of blood. Using a confocal micro-PIV system, we investigated the behaviour of red blood cells (RBCs) and cancer cells in microchannels with geometrically symmetric bifurcations and confluences. The behaviour of RBCs and cancer cells was strongly asymmetric at bifurcations and confluences whilst the trajectories of tracer particles in pure water were almost symmetric. The cell-free layer disappeared on the inner wall of the bifurcation but increased in size on the inner wall of the confluence. Cancer cells frequently adhered to the inner wall of the bifurcation but rarely to other locations. Because the wall surface coating and the wall shear stress were almost symmetric for the bifurcation and the confluence, the result indicates that not only chemical mediation and wall shear stress but also microscale haemodynamics play important roles in the adhesion of cancer cells to the microchannel walls. These results provide the fundamental basis for a better understanding of blood flow and cell adhesion in biomedical microdevices. PMID- 20960064 TI - Treatment of experimental periodontal disease by a selective inhibitor of cyclooxygenase-2 with scaling and root planing (SRP). AB - Lumiracoxib is a selective inhibitor of cyclooxygenase-2 (COX-2) approved for the relief of symptoms of chronic inflammatory conditions. The aim of this study was to evaluate the effects of this specific inhibitor of COX-2 as adjunctive treatment on induced periodontitis in rats. Periodontal disease was induced at the first mandibular molar of 60 rats. After 7 days, the ligature was removed and all animals were submitted to scaling and root planing (SRP) along with local irrigation with saline solution and were divided into 2 groups: SRP (n = 30) received subcutaneous injections of 1 mg/kg of body weight/day of saline solution for 3 days and; SRP + L (n = 30)-received subcutaneous injections of 1 mg/kg of body weight/day of Lumiracoxib for 3 days. Ten animals in each group were killed at 7, 15, and 30 days. The histological description was performed and the histometric values were statistically analyzed. In Group SRP + L, the histometric analysis (0.58 +/- 0.08, 0.64 +/- 0.06, and 0.56 +/- 0.10 mm(2)) showed less bone loss (p < 0.05) than Group SRP (1.52 +/- 0.08, 1.55 +/- 0.09, and 1.49 +/- 0.24 mm(2)) at 7, 15, and 30 days, respectively. Within the limits of this study it can be concluded that subcutaneous application of specific inhibitor of COX-2 was a beneficial adjunctive treatment for periodontal diseases induced in rats. PMID- 20960065 TI - Radiation-induced bowel complications: laparoscopic versus open staging of gynecologic malignancy. AB - PURPOSE: To evaluate whether the type of surgical approach used to stage gynecologic malignancies influences the risk of developing nonrectal radiation induced intestinal injury (NRRIII) in patients who subsequently receive adjuvant radiotherapy. METHODS: A prospectively entered database was queried for all women with either primary or recurrent gynecologic malignancy who underwent external beam radiation therapy +/- brachytherapy and who had prior abdominopelvic surgery at our institution. Univariate and multivariate analysis of variables potentially affecting the risk of developing significant bowel toxicity (defined as grade 2 or more according to Radiation Therapy Oncology Group scoring) were performed. RESULTS: One hundred fifty-nine patients were identified. The site of primary tumor was the cervix in 61 (38%) patients and the corpus uteri in the remaining patients (98, 62%). Treatment was delivered with a combination of external-beam and intracavitary irradiation to 50 (31.4%) patients, and 109 (68.6%) patients received only external-beam irradiation. Staging procedures were performed by open surgery in 93 (58.5%) patients, whereas laparoscopy was the surgical approach of choice in 66 (41.5%) women. Fifteen patients (9.4%) developed grade 2 or greater NRRIII, at median latency of 10 months (range 3-64 months); six were diagnosed as grade 3 complications requiring surgery, and three developed grade 4 complication. Multiple regression revealed an independent protective effect of pretreatment laparoscopic staging against the risk of developing both grade >=2 and grade >=3 NRRIII. CONCLUSIONS: Notwithstanding potential limitations of nonrandomized study design, our findings suggest that the benefits of minimal access surgery used to perform staging procedures may translate into long-term reduction in radiation-induced bowel injury. PMID- 20960066 TI - Letter to the editor: 25-hydroxyvitamin D status does not affect intraoperative parathyroid hormone dynamics in patients with primary hyperparathyroidism. PMID- 20960067 TI - Increased respiratory effort during sleep is non-invasively detected with movement sensor. AB - INTRODUCTION: Measuring breathing effort during sleep with an oesophageal pressure sensor remains technically challenging and has not become routine practice. The aim of the present work was to investigate whether increased thoracic pressure during sleep can be detected with the Emfit movement sensor. Experimental data suggest that increased respiratory efforts with the intrathoracic pressure variation induce high-frequency spikes in the Emfit signal, but this has not been systematically examined. METHODS: Polysomnography, oesophageal pressure and Emfit signal were recorded in 32 patients with suspected sleep-disordered breathing. Increased respiratory effort was defined as oesophageal pressure below -8 cmH(2)O during inspiration. The epochs of normal breathing, periodic breathing patterns and sustained spiking labelled as increased respiratory resistance (IRR) were defined on the Emfit signal according to established rules. RESULTS: Compared to normal breathing, the proportion of increased respiratory effort was higher during all periodic breathing with spiking. The highest proportion (18-23%) occurred during IRR, which is characterised by sustained spiking. CONCLUSION: The Emfit movement sensor is a non-invasive alternative to the oesophageal pressure sensor in the assessment of the respiratory effort during sleep. In particular, the Emfit sensor enhances detection of non-apnoeic sleep-disordered breathing, the significance of which should not be ignored. PMID- 20960068 TI - N-acylated bacteriohopanehexol-mannosamides from the thermophilic bacterium Alicyclobacillus acidoterrestris. AB - Identification of molecular species of various N-acylated bacteriohopanehexol mannosamides from the thermophilic bacterium Alicyclobacillus acidoterrestris by semipreparative HPLC and by RP-HPLC with ESI is described. We used triple quadrupole type mass spectrometer, (1)H and (13)C NMR for analyzing this complex lipid. CD spectra of two compounds (model compound--7-deoxy-D: -glycero-D: -allo heptitol obtained by stereospecific synthesis, and an isolated derivative of hopane) were also measured and the absolute configuration of both compounds was determined. On the basis of all the above methods, we identified the full structure of a new class of bacteriohopanes, represented by various N-acylated bacteriohopanehexol-mannosamides. PMID- 20960069 TI - Dietary monounsaturated fatty acids but not saturated fatty acids preserve the insulin signaling pathway via IRS-1/PI3K in rat skeletal muscle. AB - Saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) show different effects on the development of insulin resistance. In this study, we compared the effect of dietary SFA and MUFA on the insulin signaling pathway in the skeletal muscle of a type 2 diabetic animal model. Twenty-nine-week-old male Otsuka Long Evans Tokushima fatty (OLETF) rats were randomly divided into three groups and fed one of the following diets for 3 weeks; a normal chow diet, an SFA (lard oil) enriched or a MUFA (olive oil) enriched high-fat diet. The vastus lateralis muscle was used for analyses. Insulin tolerance test showed improved insulin sensitivity in rats fed the MUFA diet, as compared to those fed the SFA diet (p < 0.001). The SFA diet reduced IRS-1 expression and phosphorylated PI3K levels in skeletal muscle, as compared with a chow diet (p < 0.001, respectively). On the contrary, muscle IRS-2 expression and phosphorylated ERK1/2 was significantly increased in rats fed the SFA diet (p < 0.001, respectively). Membrane translocation of glucose transporter type 4 decreased in the skeletal muscle of rats fed the SFA diet, as compared to those fed a chow diet (p < 0.001). These changes in insulin signaling pathway in skeletal muscle were not observed in rats fed the MUFA diet. In conclusion, the beneficial effect of dietary MUFA on insulin sensitivity is associated with a conserved IRS-1/PI3K insulin signaling pathway which was altered by dietary SFA. PMID- 20960070 TI - Editors' commentary. PMID- 20960071 TI - The Santoro III massive enterectomy: how can we justify the risks in obese adolescents? PMID- 20960072 TI - The redox status in rats treated with flaxseed oil and lead-induced hepatotoxicity. AB - Lead is a persistent environmental pollutant, and its toxicity continues to be a major health problem due to its interference with natural environment. In the present study, we have evaluated the effect of flaxseed oil on lead acetate mediated hepatic oxidative stress and toxicity in rats. Lead acetate enhanced lipid peroxidation and nitric oxide production in both serum and liver with concomitant reduction in glutathione, catalase, superoxide dismutase, glutathione reductase, glutathione-S-transferase, and glutathione peroxidase activities, these findings were associated with DNA fragmentation. In addition, lead acetate caused liver injury as indicated by histopathological changed of the liver with an elevation in total bilirubin, serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase. Treatment of rats with flaxseed oil resulted in marked improvement in most of the studied parameters as well as histopathological features. On the basis of the above results it can hypothesized that flaxseed oil is a natural product can be protect against lead acetate-mediated hepatic cytotoxicity. PMID- 20960073 TI - Identification of obstructive sleep apnea syndrome by ambulatory electrocardiography: clinical evaluation of time-domain and frequency-domain analyses of heart rate variability in Chinese patients. AB - The application of ambulatory electrocardiography to identify obstructive sleep apnea syndrome (OSAS) patients was evaluated using time-domain and frequency domain analyses of heart rate variability (HRV). For this, overnight sleep pattern was investigated in 95 individuals (48 OSAS(+) patients and 47 OSAS(-) controls) by polysomnography and 24-h ambulatory electrocardiography. Apnea scores were calculated using two different HRV analyses. Average age and body mass index, and percentages of men and of patients with history of hypertension and/or diabetes were higher in study group as compared with control group. PNN50(night), SDNNI(day-night) and SDNNI(day-night) in time-domain analysis were more sensitive than other indices. In frequency-domain analysis, mean night-time total power, night-time VLF power, night-time LF power, and the difference between these measures in day and night were significantly higher in study group. LF/HF ratio was also significantly higher in study group in day-time or night time with a significant difference (P < 0.05) between day and night. At sleep apnea risk score >4, sensitivity, specificity, and positive predictive value were, respectively, 81.25, 46.81, and 64.21%. At sleep apnea risk scores >5, 6, or 7, the specificity increased, while the sensitivity and positive predictive value decreased. In conclusion, time-domain and frequency-domain HRV analyses are useful methods for OSAS screening, and the frequency-domain analysis is more sensitive. PMID- 20960075 TI - Study of predictive value of pediatric risk of mortality (PRISM) score in children with end stage liver disease and fulminant hepatic failure. AB - OBJECTIVE: To evaluate the use of the PRISM score as a predictor of outcome in patients with end stage liver disease (ESLD) and fulminant hepatic failure (FHF). METHODS: The present study included 30 patients with ESLD and FHF, with ages ranging from 2 to 108 months, who were admitted to the Emergency room (ER) and the Pediatric Hepatology Unit at Cairo University Children's Hospital (tertiary referral hospital) over a six-month-period from May through October 2008. Survivors were followed up for 6 months. Two other scores were also calculated, the PELD score and the Child-Pugh score. The outcome was defined as survivors and deceased. RESULTS: Deceased patients as compared with survivors were significantly younger (median age 7 vs. 24 months, p=0.003). A ROC curve was constructed for the PRISM score, the predicted death rate (PDR) and the PELD score in the 30 patients. PRISM score was significantly associated with mortality (p=0.04). The best cut off value was 9.5 (70.6% sensitive and 61% specific). PDR was also significantly associated with mortality (p=0.011). The best cut off value for PDR was 5.95 (70.6% sensitive, 85% specific). On the other hand, the PELD score was not associated with mortality (p=0.202). CONCLUSIONS: PRISM score can be applied with an adequate degree of accuracy for severity assessment and mortality prediction to pediatric patients with ESLD or FHF. PMID- 20960074 TI - Antitumor efficacy of a photodynamic therapy-generated dendritic cell glioma vaccine. AB - The objective of this study is to generate dendritic cell (DC) vaccines by exposing DCs to C6 glioma cancer cell antigenic (tumor) peptides following the exposure of C6 cells to photodynamic therapy (PDT) and acid elution. Effects of these DCs on host immunity were assessed by measuring cytokine induction (following adaptive transfer into rats) and assessing DC-induced cytotoxic T lymphocyte (CTL)-mediated lysis of C6 target cells. Precursor dendritic cells were purified from rat bone marrow and matured in vitro. C6 cells were stimulated with PDT, and adherent cells were acid-eluted to obtain cell surface antigens, whole cell antigens were also isolated from supernatants. C6 cells not stimulated with PDT were also used to isolate antigens by acid elution or freeze-thaw methods for comparison purposes. The isolated antigens from the respective purification methods were used to sensitize DCs for the generation of DC vaccines subsequently transferred into SD rats. Following adoptive transfer, the changes in interleukin (IL)-12, IL-10, and TNF-alpha expression were measured in rat serum by ELISA. CTL-mediated lysis was assessed using the MTT assay. PDT generated antigens further purified by acid elution had the greatest stimulatory effect on DCs based on the elevated serum IL-12 and TNF-alpha levels and decreased serum IL-10 levels. CTL activity in this group was also highest (percent lysis 95.5% +/- 0.016) compared with that elicited by PDT-supernatants, acid elution, and freeze-thawing (or the control group), which had 90.2% +/- 0.024, 73.3% +/- 0.027, 63.6% +/- 0.049, or 0.4% +/- 0.063 lysis, respectively. PDT significantly enhanced tumor cell immunogenicity. These data suggested that DC vaccines prepared by treating tumor cells with PDT to generate antigen specific CTL responses can be developed as novel cancer immunotherapeutic strategies. PMID- 20960076 TI - Bullying among school children: prevalence and association with common symptoms in childhood. AB - OBJECTIVE: To estimate the prevalence of bullying among girls and boys in school and examine its association with psychological and psychosomatic symptoms. METHODS: 500 students aged between 8-14 yrs from 5 randomly selected schools as well as their parents and teachers were interviewed using a pretested questionnaire. RESULTS: Bullying was reported by 302(60.4%) of the 500 children interviewed. Bullying was seen to be more prevalent among boys than girls, the commonest forms being calling names and making fun of one's looks. Physical abuse was reported by 38 students. Only 65 (39%) parents knew that their children were being bullied. Bullied children were more likely to report symptoms such as headache, loose motions, fever and depression. Teachers were found to be ignorant of the whole issue. CONCLUSIONS: Bullying is a major problem among school children. Bullied children complained of psychosomatic symptoms which are potentially harmful for development. Teachers must be adequately trained to tackle this problem. Pediatricians should always consider bullying as a causative agent for illness and plan for appropriate interventions. PMID- 20960078 TI - 1H, 13C and 15N resonance assignments of the rhodanese domain of YgaP from Escherichia coli. AB - Rhodanese domain is a ubiquitous structural module commonly found in bacterial, archaeal and eukaryotic cells. Growing evidence indicates that rhodanese domains act as the carrier of reactive sulfur atoms by forming persulfide intermediates in distinct metabolic pathways. YgaP, a membrane protein consisting of a rhodanese domain and a C-terminal transmembrane segment, is the only membrane associated rhodanese in Escherichia coli. Herein, we report the resonance assignments of (1)H, (13)C and (15)N atoms of rhodanese domain of YgaP. Totally, chemical shifts of more than 95% of the atoms were assigned. PMID- 20960079 TI - 1H, 13C and 15N resonance assignments of rhodanese GlpE from Escherichia coli. AB - Rhodanese catalyzes the sulfur-transfer reaction in which a sulfur atom is transferred from thiosulfate to cyanide by a double-displacement mechanism. During the reaction, a persulfide-intermediate form of rhodanese is generated by the reaction of a conserved active cysteine residue with thiosulfate. Escherichia coli GlpE is a prototype for the single-domain rhodanese superfamily. Though there are some studies on rhodaneses, the molecular mechanism of the catalytic activity of rhodaneses is still unclear. Herein, we report the resonance assignments of (1)H, (13)C and (15)N atoms of E. coli GlpE, which provides the basis for further structural, dynamic and functional studies of rhodaneses using NMR technique. PMID- 20960080 TI - 1H, 13C and 15N resonance assignments of the arsenate reductase from Synechocystis sp. strain PCC 6803. AB - Arsenate reductases (ArsC) are a group of enzymes that play essential roles in biological arsenic detoxification pathways by catalyzing the intracellular reduction of arsenate to arsenite, which is subsequently extruded from the cells by specific transport systems. The ArsC protein from cyanobacterium Synechocystis sp. strain PCC 6803 (SynArsC) is related to the thioredoxin-dependent ArsC family, but uses the glutathione/glutaredoxin system for arsenate reduction. Therefore, it is classified to a novel thioredoxin/glutaredoxin hybrid arsenate reductase family. Herein we report the chemical shift assignments of (1)H, (13)C and (15)N atoms for the reduced form of SynArsC, which provides a starting point for further structural analysis and elucidation of its enzymatic mechanism. PMID- 20960081 TI - The genetics of scleroderma. AB - The importance of the genetic component in the pathogenesis of scleroderma, or systemic sclerosis, has been strengthened in the past 2 years with studies on genetic markers-either candidate gene or genome-wide association studies--in large case-control series. Multiple genes have been consistently associated with susceptibility to scleroderma, and interestingly, several of them are involved in immune regulation. Because many of these genes are shared with other autoimmune diseases, a common underlying autoimmune mechanism has been proposed. The challenge that lies ahead is to confirm these associations and to find markers or pathways that are unique to scleroderma and that may define its distinctive phenotype. PMID- 20960082 TI - From the front lines: a qualitative study of anesthesiologists' work and professional values. AB - PURPOSE: Despite significant contributions to medicine, anesthesiology is poorly recognized and faces the threat of "deprofessionalization". Clear articulation of its work and professional values plays an integral role in maintaining the viability of a profession. The purpose of this qualitative study is to explore anesthesiologists' perspectives in order to define the distinct elements of their work and their professional values. METHODS: A qualitative research approach was used for this study. Sixteen Canadian faculty anesthesiologists were interviewed regarding their choice of anesthesiology as a career, the characteristics of a good anesthesiologist and good anesthetic care, and the sources of work-related stress. The interviews were taped and transcribed. The qualitative analysis of the interviews included primary coding, which separated the data into units of meaning. Next, similar codes were clustered into pattern codes to identify common themes and subthemes. The relationships between the themes and subthemes were analyzed and interpreted to identify core values. RESULTS: The anesthesiologists were motivated to choose their career path by the academic, technical, and practice aspects of the profession, influential role models, and an interest in human consciousness. Five themes characterized a good anesthesiologist: clinical competence, personality traits, physician-patient relationship, approach to anesthetic care, and outcomes. The major sources of stress were: balancing clinical care and teaching, unexpected critical events, and administrative issues. Four core professional values were identified: goal-directed care, responsibility, control, and humility. CONCLUSIONS: Anesthesiology is characterized by its distinct work and core professional values. Under the threat of deprofessionalization, the practice of anesthesiology should be guided by its professional values in defining and envisioning its future. PMID- 20960083 TI - The value of ultrasound in detecting pneumothorax. PMID- 20960084 TI - Effects of immunomodulatory drugs on plasma inflammatory markers in a rabbit model of atherosclerosis. AB - Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immuno-inflammatory mechanisms are involved. Inflammatory cytokines are implicated in the development and progression of atherosclerotic lesions. Immunomodulatory therapies have been proposed for the treatment of atherosclerosis. Therefore, the aim of this study was to investigate the systemic anti-inflammatory and immunomodulatory effects of atorvastatin, cyclosporine A (CsA), and tacrolimus (FK506) on plasma inflammatory markers in atherosclerotic rabbits. Male New Zealand rabbits were randomized into five groups each of 12 animals. Standard diet-fed group served as control, and the cholesterol-fed group received a diet supplemented with 1% cholesterol alone, cholesterol + atorvastatin, cholesterol + FK506, and cholesterol + CsA. Serum levels of lipid profile parameters (triglycerides, cholesterol, and high-density lipoprotein) were measured using colorimetric methods. Serum levels of C-reactive protein (CRP), interleukin-6 (Il-6), and interferon-gamma (INF-gamma) were measured in all studied groups using ELISA techniques. Our results revealed a significant decrease (p < 0.001) in the serum levels of lipid profile parameters, CRP, Il-6, and INF-gamma in atorvastatin-treated group compared with the cholesterol-fed group. On the other hand, a non-significant difference was observed for the same parameters in either FK506- or CsA-treated groups compared with the cholesterol fed group. In conclusion, atorvastatin has a systemic anti-inflammatory role that far surpassed the cholesterol reduction effect alone. FK506 or CsA failed to suppress elevated plasma inflammatory markers. Thus, low doses of these two immunomodulating drugs could not have generalized systemic anti-inflammatory or immunosuppressive effects. PMID- 20960087 TI - Local intense and systemic reactions to Aedes albopictus (Diptera, Culicidae) bites: a clinical case report. AB - We present here our experience with a 34-year-old woman living in the province of Cuneo in northwest Italy. The patient had no prior allergic disease history and in the place of bite by Aedes albopictus, she sustained significant reactions (ecchymosis), along with fever and localized lymphadenopathy. Thirty days later, the bites were still visible, characterized by cutaneous thickening and localized paresthesia. This clinical case represents a hypersensitive reaction and can be considered the first documented case of Skeeter syndrome in Italy. PMID- 20960086 TI - Black and green tea improves lipid profile and lipid peroxidation parameters in Wistar rats fed a high-cholesterol diet. AB - In the present study, the efficacy of black tea (BT) and green tea (GT) was studied in relation to serum and hepatic oxidative abnormalities in hypercholesterolemic rats. Hypercholesterolemia was induced in male Wistar rats (8 week old) by feeding them with a high-cholesterol diet (HCD) for 35 days. The experimental rats were given BT and GT as a supplement (7 g/L) via drinking water. Increased hepatic and serum lipid profile along with abnormalities in oxidative marker, with a concomitant increase in the body weight, food intake, and food efficiency, were seen in hypercholesterolemic rats. Following the supplementation of BT and GT to rats fed with HCD, significantly lower levels of serum and hepatic cholesterol, triglycerides, serum low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol levels were observed, when compared with hypercholesterolemic group. Further, significantly lower levels in the serum and hepatic lipid peroxidation, body weight gain, and food efficiency were observed in BT and GT group when compared with control and HCD fed group. However, no such significant changes were observed in the food intake upon supplementation with BT and GT. These results suggest that supplementation of BT and GT may protect against the serum and hepatic abnormalities in hypercholesterolemic rats. PMID- 20960085 TI - Decreased glutamine synthetase, increased citrulline-nitric oxide cycle activities, and oxidative stress in different regions of brain in epilepsy rat model. AB - To understand their role in epilepsy, the nitric oxide synthetase (NOS), argininosuccinate synthetase (AS), argininosuccinate lyase (AL), glutamine synthetase (GS), and arginase activities, along with the concentration of nitrate/nitrite (NOx), thiobarbituric acid reactive substances (TBARS), and total antioxidant status (TAS), were estimated in different regions of brain in rats subjected to experimental epilepsy induced by subcutaneous administration of kainic acid (KA). The short-term (acute) group animals were killed after 2 h and the long term (chronic) group animals were killed after 5 days of single injection of KA (15 mg/kg body weight). After decapitation of rats, the brain regions were separated and in their homogenates, the concentration of NOx, TBARS and TAS and the activities of NOS, AS, AL, arginase and glutamine synthetase were assayed by colorimetric methods. The results of the study demonstrated the increased activity of NOS and formation of NO in acute and chronic groups epilepsy. The activities of AS and AL were increased and indicate the effective recycling of citrulline to arginine. The activity of glutamine synthetase was decreased in acute and chronic groups of epilepsy compared to control group and indicate the modulation of its activity by NO in epilepsy. The activity of arginase was not changed in acute group; however it was decreased in chronic group and may favor increased production of NO in this condition. The concentration TBARS were increased and TAS decreased in acute and chronic groups of epilepsy and supports the oxidative stress in epilepsy. PMID- 20960088 TI - Ultrastructure of the ovary of Amphilina japonica Goto & Ishii, 1936 (Cestoda) and its implications for phylogenetic studies. AB - The ultrastructure of the ovary of the amphilinidean cestode Amphilina japonica Goto & Ishii, 1936 from the body-cavity of the American sturgeon Acipenser transmontanus Richardson is described using transmission electron microscopy. The characters of the ovary of Amphilina japonica are different from those of all other cestodes. The most important difference is in the nature of the relationship between the germ and accessory cells within the ovary. In A. japonica the oocytes and accessory cells form numerous different intercellular contacts (desmosome-like junctions and zonulae adherentes). Gap junctions are present between the narrow cytoplasmic processes of the accessory cells. Numerous micropinocytotic vesicles and vacuoles from the accessory cells discharge their content into spaces between the oocytes and the accessory cells. The accessory cells are closely associated with the oocytes during the early and middle stages of oogenesis. As the volume of oocytes increases, the accessory cells gradually lose their association with the oocyte surfaces. Peripherally located individual accessory cells of A. japonica give rise to a cellular epithelial layer of irregular shape and thickness which breaks down via numerous invaginations of the basal membrane and underlying basal matrix. The different arrangements of the interconnection of cell components in the Amphilinidea compared with the Gyrocotylidea and Eucestoda (the absence of specialised cell contacts and the syncytial nature of the accessory 'interstitial' cells) are evidence suggesting the presence of unrelated groups within the Cestoda. The nature of the association of the accessory and germ cells in ovary of A. japonica more closely resembles the ovary of non-platyhelminth invertebrates rather than that of other neodermatans. PMID- 20960089 TI - Support for the 'out-of-Southeast Asia' hypothesis for the origin of Australian populations of Radopholus similis (Cobb, 1893) (Nematoda: Pratylenchidae). AB - Radopholus similis is one of the world's ten most economically important plant parasitic nematodes. It is especially a problem in banana cultivation, where the nematodes' feeding reduces yields and causes toppling disease. It has been suggested that the genus Radopholus Thorne, 1949 might have an Australian origin, but the native range of R. similis (Cobb, 1893) is not well known. Here we undertake a phylogeographical study of samples of R. similis from banana plantations down the eastern seaboard of Australia, with additional samples from Costa Rica and accessions from GenBank, to examine the origin of pest populations of R. similis. The lack of genetic diversity of R. similis within Australia, and its sharing of a worldwide pest haplotype, suggest that populations of R. similis in Australia were introduced from a single source population, most likely from the Southeast Asian region. This might not be the case in Africa, where extensive genetic diversity has been found. PMID- 20960090 TI - Cryptic species of Euryakaina n. g. (Digenea: Cryptogonimidae) from sympatric lutjanids in the Indo-West Pacific. AB - A survey of the endohelminth fauna of Indo-West Pacific Lutjanidae (Perciformes) revealed the presence of the species Siphoderina manilensis (Velasquez, 1961) Miller & Cribb, 2008 and S. marina (Hafeezullah & Siddiqi, 1970) Miller & Cribb, 2008 in seven Lutjanus spp. from sites off the Great Barrier Reef, the Maldives, New Caledonia and Ningaloo Reef, Western Australia. A combination of morphological and ribosomal DNA analyses of these cryptogonimids prompted the transfer of these taxa to a new genus, Euryakaina n. g., as E. manilensis n. comb. and E. marina n. comb., based on comparative analysis with other cryptogonimid taxa. Euryakaina n. g. is distinguished from all other cryptogonimid genera by the combination of a fusiform body, the few relatively small, widely spaced oral spines (sometimes absent), a highly lobed ovary, opposite to slightly oblique testes, vitelline follicles that extend from the anterior margin of the testes to slightly posterior to the intestinal bifurcation, and an excretory vesicle that bifurcates dorsal to the ovary and reunites briefly slightly posterior to the intestinal bifurcation. Morphometric analysis of these taxa alone suggests they should be reduced to synonymy, but DNA sequence analyses and ecological niche partitioning provide evidence that they form a cryptic species complex in sympatric lutjanids in the Indo-West Pacific. The secondary structure of the ITS2 rDNA for species of Euryakaina was also modelled and analysed for the presences of compensatory base changes (CBCs) or hemi-CBCs in order to explore the usefulness of these changes as a tool to help elucidate the taxonomy of this complex system. We also report what we interpret here as intraspecific variation in the ITS2 rDNA between individuals of E. manilensis from Lutjanus vitta recovered off the Great Barrier Reef and New Caledonia. PMID- 20960091 TI - A new species of Neoheterocotyle Hargis, 1955 (Monogenea: Monocotylidae) from the gills of Rhinobatos annulatus Muller & Henle (Rhinobatidae) off the southern tip of Africa. AB - Neoheterocotyle robii n. sp. is described from the gills of four female Rhinobatos annulatus Muller & Henle caught as bycatch during routine demersal research trawls off the Southern Cape coast of South Africa. The new species can be distinguished from all other members of Neoheterocotyle Hargis, 1955 by the morphology of the accessory piece associated with the male copulatory organ, the presence of a distinct horseshoe-shaped muscle associated with the male copulatory organ and the presence of a sclerotised structure in the proximal portion of the vagina. This is the first Neoheterocotyle species described from South African waters. PMID- 20960092 TI - Pseudohatschekiidae, a new family for Pseudohatschekia branchiostegi Yamaguti, 1939 (Crustacea: Copepoda: Siphonostomatoida) from Branchiostegus spp. (Teleostei: Perciformes: Malacanthidae) in Japanese waters, with descriptions of the early developmental stages of P. branchiostegi. AB - The siphonostomatoid copepod Pseudohatschekia branchiostegi Yamaguti, 1939 is redescribed in detail based on specimens of both sexes collected from the gill filaments of three species of Branchiostegus Rafinesque (Teleostei: Malacanthidae) captured in Japanese waters. Descriptions of two naupliar stages and the infective copepodid stage of P. branchiostegi are also provided for the first time, and P. mebaru Yamaguti, 1939 is recognised herein as a junior synonym of P. branchiostegi. The latter copepod species represents a new family, the Pseudohatschekiidae fam. nov., of the Siphonostomatoida characterised by the following apomorphies: (a) two free pedigerous somites present between the cephalothorax and the genital complex; (b) a chelate antenna bearing two digitate processes and a thin cuticular covering; (c) a unilobate maxillule, with the palp completely fused to the endite and represented by a surface seta; (d) a rounded process furnished with pectinate membranes on the apex of the maxillary basis; (e) 2-segmented rami on legs 1-3; and (f) the absence of leg 4. It is also now evident that P. branchiostegi is a relatively common and abundant parasite of Branchiostegus spp. in the Far East. PMID- 20960093 TI - Taxonomy and host-specificity of Gyrodactylus aideni n. sp. and G. pleuronecti (Monogenea: Gyrodactylidae) from Pseudopleuronectes americanus (Walbaum) in Passamaquoddy Bay, New Brunswick, Canada. AB - Wild and cultured winter flounder Pseudopleuronectes americanus (Walbaum) from Passamaquoddy Bay were surveyed for species of Gyrodactylus Nordmann, 1832. Two species were found: G. pleuronecti Cone, 1981 and G. aideni n. sp, both members of Malmberg's 'groenlandicus group'. Although the hard parts in the haptor are very similar in the two species, hamuli of G. aideni are consistently shorter than those of G. pleuronecti. The two species differed by 35 base pairs in the ITS 1, 5.8 and ITS 2 region. A BLAST search identified a variety of species of Gyrodactylus from marine fishes in the Atlantic Ocean as closest matches, indicating the 'groenlandicus group' is part of a major marine lineage within Gyrodactylus (sensu lato) that has successfully radiated among coastal percid, pleuronectid, cottid and anarhichadid fishes. Exposure experiments suggested that winter flounder is the primary host of both species of parasites and that three other pleuronectid species in the bay may potentially serve only as occasional transport hosts. PMID- 20960094 TI - A case of fugitive acromegaly, initially presented as invasive prolactinoma. AB - Fugitive acromegaly is most commonly caused by pituitary acidophil stem cell adenomas, and is characterized by a relatively short clinical history, a large and locally invasive tumor, and relatively low hormonal activity. Here, we report an unusual case of fugitive acromegaly that initially presented as invasive prolactinoma. A 48-year-old man with a huge pituitary mass extending to the suprasellar area was referred to our hospital in December 2007. He had undergone transsphenoidal surgery in November 1999 because of a large invasive prolactinoma. The tumor had grown progressively, despite therapy with dopamine agonists. Subtle features of acromegaly were noted and serum IGF-1 levels were high (733 ng/ml). An oral glucose tolerance test revealed that basal and nadir levels of growth hormone (GH) were 1.56 and 1 ng/ml, respectively. As a therapeutic trial, long-acting octreotide (20 mg IM, monthly) was added, and the tumor size markedly reduced within 6 months on magnetic resonance imaging examination. Immunohistochemical staining of the tumor tissue obtained at the surgery in 1999 showed positive staining for GH and prolactin (PRL). Double immunofluorescence staining showed a mixed positivity for GH and PRL in the majority of tumor cells; however, the two hormones colocalized in a minority of tumor cells, indicating that the tumor was composed of three different cell types (GH, PRL, and GH/PRL). The diagnosis of fugitive acromegaly was initially overlooked in this patient because of normal serum GH levels and a lack of acromegalic features, although histological evidence for GH production was present. IGF-1 determinations would be helpful for the diagnosis of fugitive acromegaly. PMID- 20960095 TI - A patient with concurrent primary aldosteronism and Page kidney. AB - The ratio of aldosterone-to-renin activity is currently recommended as a screening test for primary aldosteronism (PA). There are many factors interfering the interpretation of aldosterone-renin ratio (ARR) and could hamper in-time diagnosis of PA. Here, we first report a patient with underlying Page phenomenon and an accidentally disclosed adrenal incidentaloma. High renin secretion from Page phenomenon had masked higher ARR into normal ARR obscuring the diagnosis of PA. However, adrenal venous sampling (AVS) confirmed the autonomous aldosterone secretion with left adrenal vein plasma aldosterone concentration (PAC) 124.1 ng/dl and a lateralization ratio 3.3. AVS may discriminate masked PA due to high renin secretion from Page kidney. It is suggested that clinicians should cautiously interpret aldosterone-renin ratio and consider diagnostic AVS if hyperaldosteronism is highly suspected especially in the background of other secondary hypertension. PMID- 20960096 TI - Hypolipidemic activity of Semecarpus anacardium in Streptozotocin induced diabetic rats. AB - Alterations in lipid metabolism and lipoprotein disturbances have played an important role in increasing the risk of cardiovascular mortality and morbidity in diabetes. A drug that has hypoglycemic activity can be used for the treatment of hyperlipidemia also. The present study was carried out to evaluate the hypolipidemic activity of Semecarpus anacardium. Male Wister rats weighing 250 270 g were injected with Streptozotocin at a dose of 50 mg/kg body weight and administered with S. anacardium (300 mg/kg body weight) and Metformin (500 mg/kg body weight) for 21 days. Control and drug control groups were also included in the study. After the experimental duration, serum was collected, liver and kidney were excised and used for the analysis of lipid and lipid metabolizing enzymes. The results of the study revealed that S. anacardium administration was able to decrease the levels of LDL, cholesterol, VLDL, TG, phospholipid and free fatty acid and increase the HDL levels and favorably modulate the lipid metabolizing enzymes in the liver and kidney. These results show that S. anacardium exerts hypolipidemic activity in diabetic rats. PMID- 20960097 TI - L157X nonsense mutation of the succinate dehydrogenase subunit B gene in a Japanese patient with right paraaortic paraganglioma. AB - Nuclear genes succinate dehydrogenase B subunit and succinate dehydrogenase D subunit, which encode two mitochondrial complex II subunits, are associated with the development of familial paraganglioma (PGL). Succinate dehydrogenase B subunit gene mutation is highly associated with extraadrenal PGL and subsequent distant metastasis. We describe the case of a 29-year-old Japanese man with a 3 year history of hypertension, headache, and palpitation. Endocrinological examinations showed that the patient had elevated levels of catecholamines, and imaging studies revealed a right paraaortic PGL without distant metastases. The PGL was surgically removed. Genetic analysis of the patient showed a heterozygous thymine deletion at position 470 (c.470delT) in exon 5 of the succinate dehydrogenase B subunit gene complementary DNA. This thymine deletion changed TTG (leucine) to TGA (stop codon) at codon 157 (L157X). It remains unclear whether this mutation was associated with PGL malignancy because the patient has had no metastases for the past 3 years. It has been recently reported that L157X is associated with malignant paraaortic PGL. Thus, strict follow-up is required because this succinate dehydrogenase B subunit gene's nonsense mutation (L157X) may be related to the malignancy. PMID- 20960098 TI - Liver failure due to antithyroid drugs: report of a case and literature review. AB - Hyperthyroidism is a common endocrine disorder affecting 2% of females and 0.5% of males worldwide and antithyroid drugs constitute the first line of treatment in the majority of cases. These agents may cause severe adverse effects and among them liver failure, although rare, is a potential lethal one. This case illustrates the sudden and abrupt deterioration of hepatic function due to antithyroid drug administration. This case along with a concise literature review is presented aiming to increase the awareness of endocrinologists of possible fatal complications from the everyday use of common agents such as antithyroid drugs. PMID- 20960099 TI - G protein-coupled receptor 30 in tumor development. AB - Estrogen plays several important physiological and pathological functions in not only reproductive system but many other systems as well. Its transcriptional activation has been traditionally described as being mediated by classic nuclear estrogen receptors (ERs). It is however established recently that a novel functional estrogen transmembrane receptor, G protein-coupled receptor 30 (GPR30), modulates both rapid non-genomic events and genomic transcriptional events of estrogen. It has been demonstrated that GPR30 promotes the progress of estrogen-related tumors through mitogen-activated protein kinase (MAPK) signaling pathways. Effects mediated by GPR30 are maintained when classic ERs are absent or blocked. In addition, GPR30 is involved in drug resistance, which is often occurring during cancer treatments. All these new findings strongly imply that GPR30 may be an important therapeutic target for estrogen-related tumors. Simultaneously blocking both GPR30 and classic ERs may be a better strategy for the treatment of estrogen-related tumors. PMID- 20960100 TI - p21-activated kinase 3 is overexpressed in thymic neuroendocrine tumors (carcinoids) with ectopic ACTH syndrome and participates in cell migration. AB - Thymic carcinoid is an important component of the tumor spectrum causing Ectopic ACTH Syndrome (EAS) and usually carries a poor prognosis. Efforts have been focused on exploring the mechanism of the excessive ACTH production in non pituitary tumors, whereas few studies have reported the molecular events underlying the tumor progression. In this study, seven patients with ACTH producing thymic carcinoids were enrolled. Of note is that five of them showed either lymph node metastasis, local invasion or distant metastasis. By using cDNA profiling approach, we evaluated the expression of cell adhesion pathway genes and found a remarkable overexpression of p21-activated kinase 3 (PAK3) in all thymic carcinoids which was further confirmed at both transcriptional and translational level. RAC1, an upstream activator of PAK3, was also overexpressed in thymic carcinoids. Overexpression of PAK3 in NIH3T3 cell enhanced cell migration and invasion. Importantly, we observed c-Jun NH(2)-terminal kinase (JNK) was activated in PAK3 transfected cells, and inhibition of JNK activity by SP600125, a JNK pathway inhibitor, abolished PAK3 mediated cell migration. Activation of JNK pathway was also detected in thymic carcinoid with high level of PAK3 expression. Our findings suggested a potential role of PAK3 in the progression of ACTH-producing thymic carcinoid. PMID- 20960101 TI - Bioequivalence between two human insulin analogs in Chinese population: Glulisine and Lispro. AB - Intensive insulin therapy for diabetic patients has been demonstrated as an appropriate treatment. Regular fast-acting insulin can hardly mimic the efficiency of endogenous meal-activated insulin secretion. Glulisine is a new rapid-acting insulin analog for mealtime insulin supplementation. We compared the pharmacokinetics and pharmacodynamics end points between the two rapid-acting insulin analogs Glulisine and Lispro. Twenty healthy adult males age ranging from 22 to 32 years were included in a randomized, open-label, cross contrast research. Two long duration hyperinsulinemic euglycemic clamp tests, one with Glulisine and the other with Lispro, were conducted on two separate days for all the participants. The two rapid-acting insulin analogs were administrated randomly to each participant. Glucose infusion rate (GIR) began to increase 20 min after injection in both Glulisine and Lispro groups. GIR increased sharply during the first 150 min and reached a peak at 6.23 +/- 1.35 mg/(kg min) in the Glulisine group and 6.02 +/- 1.27 mg/(kg min) in the Lispro group. It returned to the initial level at hour 5. The Area Under Curve (AUC(0-clamp end)) in Glulisine and Lispro groups were 1455.04 +/- 381.88 mg/kg and 1356.25 +/- 287.30 mg/kg (P > 0.05), respectively. However, AUC(0-1h) between the two groups showed significant difference, with Glulisine showed greater AUC(0-1h) in the first hour after injection. Other parameters showed no significant difference between the two groups. Insulin analogs Glulisine and Lispro were proved to have equivalent pharmacokinetic and pharmacodynamic parameters when administered to healthy Chinese adults, but with Glulisine showing greater AUC(0-1h) after injection. PMID- 20960102 TI - The transcription factor prolactin regulatory element-binding protein mediates prolactin transcription induced by thyrotropin-releasing hormone in GH3 cells. AB - The prolactin regulatory element-binding protein (PREB) is a transcription factor that regulates prolactin (PRL) promoter activity in the rat anterior pituitary. PRL gene expression and secretion are regulated by various hormones and growth factors, including dopamine, epidermal growth factor, and thyrotropin-releasing hormone (TRH). We examined the effect of TRH on PREB expression in pituitary cells. Western blots probed with a PREB-specific antiserum showed that the relative abundance of PREB in GH3 cells increased on treatment with TRH in a dose dependent manner. The relative abundance of PREB mRNA also increased in a dose dependent manner after treatment with TRH. TRH induced the expression of the luciferase reporter protein under the PREB promoter control. We used inhibitors of certain signal transduction pathways to show that TRH-induced PREB induction is sensitive to the protein kinase A (PKA) inhibitor. TRH stimulated the activity of the wild-type PRL promoter, whereas mutation of the PREB core-binding element on the PRL promoter reduced this ability. In summary, we have shown that TRH stimulated PREB expression in GH3 cells via the PKA pathway. PREB can function as a transcriptional regulator of PRL promoter activity and might be involved in TRH induced PRL gene transcription. PMID- 20960103 TI - SRC-3 deficient mice developed fat redistribution under high-fat diet. AB - An emerging concept suggests that an aberrant distributed body fat is closely linked to the occurrence of metabolic abnormalities. Mice deficient in steroid receptor coactivator-3 (SRC-3) are shown to be protected against high-fat diet (HFD) induced obesity but little is known about whether visceral (VAT) and subcutaneous adipose tissue (SCAT) distribute differently in SRC-3(-/-) mice versus SRC-3(+/+) mice. Here we reported that under HFD, fat redistributed between VAT and subcutaneous area of SRC-3(-/-) mice. When VAT/SCAT weight ratio (VAT/SCAT ratio) was calculated, SRC-3(-/-) mice had significantly elevated VAT/SCAT ratio in HFD versus normal diet (ND), while VAT/SCAT ratio was similar in SRC-3(+/+) mice under ND and HFD. Serological changes in SRC-3(-/-) mice paralleled the altered fat distribution. In SRC-3(-/-) mice, assays on gene expression revealed an increase in adipogenesis in VAT versus SCAT and an elevation in thermogenesis and lipolysis in SCAT versus VAT, which could explain the preferential fat accumulation in SRC-3(-/-) VAT. Our results presented in vivo evidence that SRC-3 deficiency could lead to fat redistribution under HFD in mice and provided new clues to researches on the pathogenesis of fat redistribution. PMID- 20960104 TI - MicroRNA expression in ACTH-producing pituitary tumors: up-regulation of microRNA 122 and -493 in pituitary carcinomas. AB - MicroRNAs (miRNAs) are involved in cell proliferation, differentiation, and apoptosis, and can function as tumor suppressor genes or oncogenes. The expression of miRNAs in pituitary carcinomas has not been previously examined. We used miRNA profiling with 1,145 probes to study miRNA expression in normal anterior pituitary (6 cases), adrenocorticotropin (ACTH)-producing adenomas (8 cases), and ACTH-producing pituitary carcinomas (two cases). Real-time RT-PCR and in situ hybridization were used to confirm and independently validate miRNAs that were significantly up-regulated or down-regulated between the pituitary tissues. There were more miRNAs up- (188) or down-regulated (160) between adenomas and normal pituitaries compared to carcinomas and normal pituitaries (92 up- and 91 down-regulated) or between carcinomas and adenomas (46 up- and 52 down regulated). Both real-time RT-PCR and in situ hybridization showed significant up regulation of miRNA-122 between pituitary carcinomas and adenomas. MiRNA-493 was also up-regulated in carcinomas compared to ACTH adenomas. Analysis of genes that miRNA-493 interacts with included LGALS3 and RUNX2 ( http://microrna.sanger.ac.uk ) both of which have been shown to have roles in pituitary tumor cell growth. These results provide information about marker miRNAs that may lead to further insights into the regulation of pituitary tumor growth and development. PMID- 20960105 TI - Metabolic syndrome is associated with increased risk of acute exacerbation of COPD: a preliminary study. AB - Studies have confirmed correlation between metabolic syndrome (MetS) and chronic obstructive pulmonary disease (COPD). However, to date, no studies have analyzed correlation between exacerbations of COPD (ECOPD) and MetS. The aim of this preliminary study was to examine if presence of MetS increases the frequency and duration of ECOPD. Patients with COPD were prospectively enrolled and followed between March 2008 and September 2009. Medical records, pulmonary function tests, chest X-rays; laboratory test results were gathered to establish the presence of COPD and MetS. Patients were divided in two groups; with and without MetS. The ECOPD was defined as worsening of symptoms requiring increased use of rescue medications and/or need for either systemic steroids or antibiotics or that led to emergency room visit or hospitalizations during 12 months follow-up. A total of 106 patients were recruited, 29 with MetS and 77 without. The mean exacerbation of COPD frequency was 2.4 +/- 0.8 in MetS group versus 0.68 +/- 0.6 in the control group during the follow-up period (P < 0.001). Mean duration of each exacerbation was 7.5 +/- 1.5 days in patients with MetS versus 5 +/- 2.4 days in patients without. Serum C-reactive protein (r = 0.31, P = 0.001), fasting blood glucose (r = 0.55, P < 0.001), and triglycerides (r = 0.251, P = 0.01) were positively and significantly correlated with exacerbation frequency. This study demonstrates an association between ECOPD and its duration with the MetS. The systemic inflammation induced by common cytokines may explain the linkage between the two conditions. PMID- 20960106 TI - Genetic variant in the aquaporin 9 gene is associated with bone mineral density in postmenopausal women. AB - This study investigated whether single nucleotide polymorphisms (SNP) in the aquaporin 9 (AQP9) gene is associated with bone mineral density (BMD) in Thai postmenopausal women, after an initial genome-wide screening using high throughput SNP genotyping in pooled DNA samples. Subjects consisted of 516 postmenopausal women aged 50 or more. High-throughput SNP screening was performed by comparing the estimated allele frequency derived from hybridization signal intensities of pooled DNA samples on the Affymetrix 500 K SNP genotyping chip set. The SNP was then genotyped for each subject individually. Data were expressed as mean +/- SEM. Pooled DNA SNP screening revealed the allele frequency of an intronic A/T SNP rs2414539 in the AQP9 gene as being different between subjects with femoral neck BMD in tertiles 1 and 3. Individual genotyping in all subjects revealed that femoral neck BMD in subjects with TT, TA, and AA genotypes were 0.79 +/- 0.06 (n = 3), 0.75 +/- 0.01 (n = 98), and 0.71 +/- 0.01 g/cm(2) (n = 415), respectively. The presence of the T allele in rs2414539 was associated with femoral neck BMD (r = 0.11, P < 0.05) but not with lumbar spine BMD. The relationship was still significant after controlling for body weight and age (P < 0.05). Genetic variation in the AQP9 gene is associated with femoral neck BMD in postmenopausal women, and may represent one of the susceptibility genes for phenotypes related to bone mass. PMID- 20960107 TI - Change in amputation predictors in diabetic foot disease: effect of multidisciplinary approach. AB - Diabetic foot disease causes important morbidity in diabetic population, and amputation due to diabetic foot disease occurs more often than in general population. We have been evaluating patients with diabetic foot disease in a multidisciplinary approach since year 2000. In the current study, we sought to investigate the change in amputation rate and its predictors in diabetic foot with a multidisciplinary team approach. Seventy-four patients (52 male, 22 female) hospitalised between January 2002 and December 2007 were retrospectively analysed. Sixteen out of 74 have undergone amputation. We found overall amputation rate as 21.6%, which is lower than previously reported from our institution (36.7 and 39.4%, respectively). Major amputations (syme, below-knee, above-knee) were applied to 11 patients (14.9%). A logistic regression model including osteomyelitis, peripheral neuropathy, peripheral vascular disease, hypertension, gangrene and age revealed that gangrene is now the only significant predictor for amputation. Our observations confirm that amputation rate has declined after implementation of a multidisciplinary team work, and risk factors apart from presence of gangrene are no longer amputation predictors in our centre. PMID- 20960108 TI - Heparanase-1 and Cyclooxygenase-2: prognostic indicators of malignancy in pheochromocytomas. AB - The objective of this article is to evaluate Heparanase-1 and Cyclooxygenase-2 as tissue-based markers of pheochromocytoma prognosis. Ninety-two sporadic pheochromocytoma patients with a minimum of 8-year follow-up post-diagnosis were enrolled. Slides of normal adrenal glands in nephrectomy specimens from 20 patients with benign renal tumors were as control. Heparanase-1 and Cyclooxygenase-2 expression as well as microvessel density were examined using immunohistochemistry in tissues from these patients. Positive staining for Heparanase-1 was observed in 23.68% of the benign and 77.78% of the malignant cases, whereas none of the normal adrenal controls showed positive staining. Similarly, Cyclooxygenase-2 staining was seen in 23.68% of the benign versus 83.33% of the malignant cases, and none of the normal controls appeared positive for Cyclooxygenase-2. Using both HPA-1 and Cox-2 combined, the positive predictive value of malignancy was significantly increased to 0.72, compared to about 0.45 by their own. Malignant cases showed higher microvessel density compared to benign tumors and normal controls (36.41, 21.43, and 13.36%, respectively). Heparanase-1 and Cyclooxygenase-2 may contribute to the invasive characteristics of malignant pheochromocytomas. Heparanase-1 and Cyclooxygenase-2 combined is better than their own to be used as a marker to distinguish malignant from benign pheochromocytoma. PMID- 20960109 TI - Male pseudohermaphroditism as a cause of secondary hypertension: a case report. AB - Seventeen alpha-hydroxylase deficiency (17OHD) syndrome is a rare genetic disorder of steroid biosynthesis causing decreased production of glucocorticoids and sex steroids and increased synthesis of mineralocorticoid precursors. There are only 130 cases reported worldwide with documented severe 17OHD. Here, we describe the clinical, hormonal, and molecular genetic characteristics of a Turkish patient with 17OHD, who presented to our clinic due to high blood pressure. A 29-year-old girl with 46,XY genotype was admitted to our nephrology clinic due to uncontrolled hypertension and hypokalemia. The diagnosis was suspected because of primary amenorrhea, absence of sexual maturation, hypertension, and hypokalemia. Endocrine investigation revealed low basal levels of all steroid hormones which require 17-hydroxylation for biosynthesis. Plasma concentrations of ACTH, FSH, and LH were elevated. Imaging did not reveal uterus or adnexial structures. The patient's hypertension and hypokalemia resolved after glucocorticoid replacement and treatment with potassium-sparing diuretics. 17OHD is a rare form of congenital adrenal hyperplasia in which defects in the biosynthesis of cortisol and sex steroids result in mineralocorticoid excess, hypokalemic hypertension, and sexual abnormalities such as pseudohermaphroditism in males, and sexual infantilism in females. 17OHD should be suspected in patients with hypokalemic hypertension and lack of secondary sexual development so that appropriate therapy can be implemented. PMID- 20960110 TI - Diet-induced obesity, exogenous leptin-, and MADB106 tumor cell challenge affect tissue leukocyte distribution and serum levels of cytokines in F344 rats. AB - The adipocyte-derived catabolic protein leptin alters cell-mediated immunity and cytokine crosstalk. This may provide new insights into the altered immune response, seen in obese individuals. Therefore, we determined the tissue distribution of immune cells in diet-induced obese (dio) and normal weight F344 rats challenged with MADB106 tumor cells or leptin. Immune cell distribution in blood (by FACS analysis) and tissues (NK cells in spleen and liver, immunohistologically) as well as pro-inflammatory cytokines (IL-6, TNF-alpha; by flow cytometry) were investigated in 28 normal weight and 28 dio rats (n = 4 6/group). Pro-inflammatory cytokines were increased 3-fold for IL-6 and 7-fold for TNF-alpha in obese animals. Higher numbers of blood monocytes and NK cells were found in obese as compared to normal weight animals. In dio rats challenged with leptin and MADB106 tumor cells, monocyte numbers were decreased as compared to the obese control animals. Immunohistochemistry revealed an altered NK cell distribution in a compartment-, treatment-, and bodyweight-specific manner. In conclusion, our data reveal a distinct distribution pattern of monocytes and NK cells in dio rats as compared to normal weight littermates and an additional modulatory effect of a leptin- and MADB106 tumor cell challenge. PMID- 20960111 TI - Co-morbidities, management and clinical outcome of auto-immune Addison's disease. AB - There are no consensus guidelines on the optimum long-term care of patients with primary adrenal failure. Published data suggest increased morbidity and mortality in patients treated with current therapy. Investigations of bone mineral density (BMD) in adults with adrenal failure have reported conflicting results. The objectives of this study were to determine the prevalence of auto-immune and other co-morbidities, describe the treatment regimens and to assess the BMD of adults with auto-immune Addison's disease (AAD). A retrospective, cohort study of adults with primary adrenal failure was used. Electronic and paper records were used to collect demographic, biochemical, BMD data and details of other co morbidities. 48 patients (35% male; 65% female; 50 +/- 16, years, mean +/- SD) with primary adrenal failure were identified. There was high prevalence of other auto-immune co-morbidities (hypothyroidism 58%, vitamin B(12) deficiency 29%, type 1 diabetes 10%). The presence of cardiovascular risk factors including dyslipidaemia (65% had total cholesterol >5 mmol/l) and excess weight (65% had a BMI >25 kg/m(2)) were high. Using WHO criteria, 17.9 and 53.5% of patients had spinal osteoporosis and osteopenia, respectively, at the spine. This did not relate to the duration or dose of glucocorticoid replacement. Our data shows a high prevalence of both auto-immune and non-autoimmune co-morbidities in patients with AAD. In addition to common auto-immune diseases, patients should be screened for other cardiovascular risk factors. Further studies are needed to assess the cause of the observed increased prevalence of reduced BMD at the lumbar spine. There is a need for internationally agreed long-term management guidelines. PMID- 20960112 TI - Functional interactions between pancreatic beta cells and (pre)adipocytes. AB - Type 2 diabetes is causally related to obesity and characterized by dysfunctional pancreatic beta cells. It is so far unclear whether direct interactions exist between adipocytes and beta cells and possibly raise any pathogenic relevance. In this study, we examined whether 9-day co-cultured 3T3-F442A (pre)adipocytes and primary rat pancreatic beta cells exert an influence on each other's function. In the presence of beta cells, 3T3-F442A cells became lipid-storing cells expressing markers of differentiated adipocytes and releasing adiponectin. This effect was attributed to the medium insulin levels (around 0.1 MUM) and was associated with an elevated glucose consumption by the 3T3-F442A cells. The subsequent decrease in medium glucose concentration reduced the rate of insulin release by beta cells cultured at 10 mM glucose, and thus suppressed their degranulation during culture. These changes in beta cell function did not occur at 20 mM glucose and were reversible upon removal of the 3T3-F422A cells. They could not be reproduced by 3T3-F422A-conditioned medium containing varying adiponectin concentrations. These data indicate that insulin secreted by beta cells is sufficient to induce differentiation of preadipocytes without addition of exogenous adipogenic factors. Over 9 days culture, (pre)adipocytes did not directly and irreversibly affect beta cell functions. PMID- 20960113 TI - Methylenetetrahydrofolate reductase C677T gene polymorphism in Turkish patients with polycystic ovary syndrome. AB - Higher Levels of Hcy are associated with several clinical conditions, among them non-insulin-dependent diabetes mellitus, endometrial dysplasia and hypertension with insulin resistance, and polycystic ovary syndrome. The purpose of this study was to investigate the serum homocystein levels and other metabolic parameters in relationship with the MTHFR C677T gene polymorphism in patients with PCOS. Our study included 86 young women with PCOS constituting the study group and 70 healthy women constituting the control group. Homocystein levels, metabolic, and hormonal parameters were measured, and genetic analysis of the MTHFR C677T gene polymorphism was performed in all the subjects. A statistically significant difference was observed in mean homocystein levels between patients with PCOS when compared to the control group. The MTHFR 677 CC genotypes had significantly higher proportions in the control group compared to the PCOS patients (chi(2) = 21.381, P < 0.001). Our data show that homocystein levels were higher than normal subjects in patients with PCOS and that the MTHFR C677T gene polymorphism does not influence homocystein levels of patients with PCOS. PMID- 20960116 TI - Isolation of photosystem II-enriched membranes and the oxygen-evolving complex subunit proteins from higher plants. AB - We describe methods to isolate highly active oxygen-evolving photosystem II (PSII) membranes and core complexes from higher plants, and to purify subunits of the oxygen-evolving complex (OEC). The membrane samples used as the material for various in vitro studies of PSII are prepared by solubilizing thylakoid membranes with the nonionic detergent Triton X-100, and the core complexes are prepared by further solubilization of the PSII membranes with n-dodecyl-beta-D-maltoside (beta-DDM). The OEC subunit proteins are dissociated from the PSII-enriched membranes by alkaline or salt treatment, and are then purified by ion-exchange chromatography using an automated high performance liquid chromatography system. PMID- 20960114 TI - Asymmetric dimethylarginine concentrations are elevated in women with gestational diabetes. AB - As shown in the previous studies, asymmetric dimethylarginine (ADMA) is related to endothelial dysfunction, whereas high-sensitive C-reactive protein (hCRP) is the marker of inflammation. In our study, we investigated ADMA, hCRP, and homocysteine concentrations in women with gestational diabetes mellitus (GDM) and normal glucose tolerance (NGT) during late pregnancy. Fifty-four women with GDM and 69 women with NGT between 32 and 39 weeks of gestation were included in this study. ADMA, hCRP, homocysteine, lipid parameters, glycated hemoglobin (HbA1c) levels, insulin, and homeostasis model assessment for insulin resistance (HOMA IR) were measured. The plasma ADMA concentrations were significantly higher in GDM patients than in NGT subjects (P = 0.03) and the hCRP levels were also significantly increased in GDM group when compared with those in the NGT group (P = 0.008). However, plasma homocysteine levels did not differ between the groups (P = 0.4), while HOMA-IR, insulin, and triglyceride levels were higher in the GDM group than in the NGT group (P = 0.001, 0.002, and 0.02, respectively). The ADMA concentrations in the third trimester were positively correlated with the glucose levels the 50-g glucose challenge test (GCT) during 24-28 weeks in the whole group (r = 0.21, P = 0.02). Our results demonstrate that ADMA and hCRP are elevated in women with GDM during late pregnancy. Further studies are needed to clarify the significance and the underlying mechanisms of the elevated ADMA and hCRP levels in women with GDM. PMID- 20960117 TI - Isolation of photosystem I submembrane fractions. AB - In this chapter, we describe a method to prepare photosystem I (PSI) submembrane fractions derived from the chloroplast stroma lamellae of spinach chloroplasts. These preparations retain the cytochrome b6/f complex and a pool of about 11 plastoquinones per P700. The PSI submembrane fractions are thus able to perform both cyclic and linear electron transport reactions from various artificial electron donors to oxygen or methylviologen. They are useful to study both PSI and cytochrome b6/f complex activities in a nearly native form without interference from photosystem II. PMID- 20960118 TI - Isolation of photosystem II reaction center complexes from plants. AB - Methods to isolate and purify 6- and 5-Chl D1/D2/Cyt b559 photosystem II (PSII) reaction center (RC) complexes from plants are presented, and the advantages and disadvantages of each procedure are discussed. One of the simpler 6-Chl procedures and a procedure for isolating 5-Chl complexes are described in detail. Furthermore, a rapid procedure that produces relatively large amounts of less pure 6-Chl material (i.e., more nonpigmented protein) is also described. Criteria to assess the purity of PSII RC preparations are presented, and problems associated with each of the isolation procedures are discussed. PMID- 20960119 TI - Methods for the isolation of functional photosystem II core particles from the cyanobacterium Synechocystis sp. PCC 6803. AB - This chapter contains the description of several methods used for the isolation of functional photosystem II (PS II) core particles from wild type, photosystem I less, and CP47 histidine-tagged cells of the cyanobacterium Synechocystis sp. PCC 6803. The presented protocols cover cultivation of photosystem I-containing and photosystem I-less cells, isolation of thylakoid membranes, purification of PS II core particles using a weak cation exchange or metal affinity column chromatography, and characterization of the final preparation. These isolation procedures yield highly active oxygen-evolving PS II particles and can be easily adapted for obtaining preparations from Synechocystis mutants with genetically modified photosystem II. PMID- 20960120 TI - Purification and crystallization of oxygen-evolving photosystem II core complex from thermophilic cyanobacteria. AB - This chapter describes the purification and crystallization of oxygen-evolving photosystem II core dimer complex from a thermophilic cyanobacterium Thermosynechococcus vulcanus. Procedures used for purification of photosystem II from the cyanobacterium involves cultivation of cells, isolation of thylakoid membranes, purification of crude and pure photosystem II core complexes by detergent solubilization, followed by differential centrifugation and column chromatography. The purified core dimer particles were successfully used for crystallization, and the methods and conditions used for crystallization are presented. These purification and crystallization procedures can be applied for another thermophilic cyanobacterium T. elongatus. PMID- 20960121 TI - Isolation of cytochrome b6f complex from grana and stroma membranes from spinach chloroplasts. AB - The cytochrome b6f complex is located in the appressed granal membranes and nonappressed stroma thylakoids. The procedure presents isolation of the complex from both types of thylakoids by washing with NaBr, detergent treatment, ammonium sulfate fractionation, and sucrose gradient centrifugation. Optimal concentration of the detergent is lower for grana than for stroma vesicles. The cytochrome b6f complex from stroma lamellae locates at a higher density in the sucrose gradient than the granal complex. Electrophoretic analyses indicate that both complexes are dimeric and contain four large subunits and at least three small subunits with masses below 4 kDa. Plastocyanin and 15 kDa protein are also identified in the complexes but in variable amounts. PMID- 20960122 TI - Purification and crystallization of the cyanobacterial cytochrome b6f complex. AB - The cytochrome b6f complex from the filamentous cyanobacteria (Mastigocladus laminosus, Nostoc sp. PCC 7120) and spinach chloroplasts has been purified as a homo-dimer. Electrospray ionization mass spectroscopy showed the monomer to contain eight and nine subunits, respectively, and dimeric masses of 217.1, 214.2, and 286.5 kDa for M. laminosus, Nostoc, and the complex from spinach. The core subunits containing or interacting with redox-active prosthetic groups are petA (cytochrome f), B (cytochrome b6, C (Rieske iron-sulfur protein), D (subunit IV), with protein molecular weights of 31.8-32.3, 24.7-24.9, 18.9-19.3, and 17.3 17.5 kDa, and four small 3.2-4.2 kDa polypeptides petG, L, M, and N. A ninth polypeptide, the 35 kDa petH (FNR) polypeptide in the spinach complex, was identified as ferredoxin:NADP reductase (FNR), which binds to the complex tightly at a stoichiometry of approx 0.8/cytf. The spinach complex contains diaphorase activity diagnostic of FNR and is active in facilitating ferredoxin-dependent electron transfer from NADPH to the cytochrome b6f complex. The purified cytochrome b6f complex contains stoichiometrically bound chlorophyll a and beta carotene at a ratio of approximately one molecule of each per cytochrome f. It also contains bound lipid and detergent, indicating seven lipid-binding sites per monomer. Highly purified complexes are active for approximately 1 week after isolation, transferring 200-300 electrons/cytf s. The M. laminosus complex was shown to be subject to proteolysis and associated loss of activity if incubated for more than 1 week at room temperature. The Nostoc complex is more resistant to proteolysis. Addition of pure synthetic lipid to the cyanobacterial complex, which is mostly delipidated by the isolation procedure, allows rapid formation of large (>=0.2 mm) crystals suitable for X-ray diffraction analysis and structure determination. The crystals made from the cyanobacterial complex diffract to 3.0 A with R values of 0.222 and 0.230 for M. laminosus and Nostoc, respectively. It has not yet been possible to obtain crystals of the b6f complex from any plant source, specifically spinach or pea, perhaps because of incomplete binding of FNR or other peripheral polypeptides. Well diffracting crystals have been obtained from the green alga, Chlamydomonas reinhardtii (ref. 10). PMID- 20960123 TI - Purification of plastocyanin and cytochrome c6 from plants, green algae, and cyanobacteria. AB - Plastocyanin and cytochrome c6 are widely distributed over the oxygen-evolving photosynthetic organisms. The two proteins are functionally equivalent, but strongly differ in their global electrostatic charge. In fact, they are acidic in eukaryotes, but either neutral or basic in cyanobacteria. Such a difference in their electrostatic features is a critical factor in designing the purification procedure, which must thus be modified and adapted accordingly. This chapter reports the methods for producing (including cell cultures), isolating, and purifying plastocyanin and cytochrome c6--which greatly differ in their isoelectric point--from a number of eukaryotic and prokaryotic organisms. PMID- 20960124 TI - Isolation and identification of chloroplast lipids. AB - Glycerolipids of photosynthetic organisms are accounted for largely by thylakoid membrane lipids consisting of chloroplast-specific glycolipids such as monogalactosyl diacylglycerol, digalactosyl diacylglycerol, and sulfoquinovosyl diacylglycerol, and a sole phospholipid, phosphatidylglycerol. In this chapter, methods for characterization of lipids from plant cells are described. The methods include extraction of total lipids from the cells, separation of these lipids into individual lipid classes by thin-layer chromatography, and identification of respective lipid classes by their mobility. We also present methods for the determination of compositions of constituent fatty acids, distribution of fatty acids between sn-1 and sn-2 positions, and determination of contents of individual lipid classes by gas-liquid chromatography. These methods are applicable to isolated chloroplasts or some membrane fractions such as thylakoid membranes. PMID- 20960125 TI - Isolation and purification of CP43 and CP47 photosystem II proximal antenna complexes from plants. AB - A method to isolate and purify CP43 and CP47 pigment-protein complexes from Photosystem (PS) II of higher plants is presented. The method has been developed in spinach, but it may also be valid for other plant species, since there is high PSII core complex homology in all plants. Core complex, obtained from highly enriched PSII membrane fragments (the extrinsic proteins were previously removed by Tris treatment), is used as starting material. The core complex is first treated with the chaotropic agent, LiClO4, and the nonionic detergent, n-dodecyl beta-D-maltoside. After dialysis against buffer lacking detergent or chaotropic agent, the solubilized material is separated by anion-exchange chromatography using a TSK Toyopearl DEAE 650s column. CP43 complex does not bind to the column under these conditions and elutes along with free pigments and few other contaminants. When the eluate becomes colorless, the column is subjected to a 0 170-mM LiClO4 linear gradient. The main pigment elution band corresponds to the CP47 complex with some contaminants. To obtain pure preparations of CP43 and CP47 complexes, other chromatographic steps were developed. The CP43 material is passed through a S-Sepharose cation-exchange column at room temperature and then through a Q-Sepharose anion-exchange column. After dialysis, the solution is passed through a new Q-Sepharose anion-exchange column at a different pH. The bound material is eluted with a 10-70-mM MgSO4 linear gradient, and the fractions with a prominent peak at 670 nm and a clear shoulder at 683 nm are combined. This constitutes the pure CP43 complex. The CP47 material from the first column is dialyzed, loaded onto a new TSK Toyopearl DEAE 650s column, and eluted with a 0 175-mM LiClO4 linear gradient. The fractions with a peak at 674.8 nm are combined and constitute the pure CP47 complex. PMID- 20960126 TI - Preparation of native and recombinant light-harvesting chlorophyll-a/b complex. AB - Procedures to isolate native light-harvesting chlorophyll-a/b complex (LHCIIb) and to reconstitute recombinant LHCIIb are described. Separation of trimeric from monomeric forms and free pigment by sucrose density-gradient ultracentrifugation can be applied to both native and reconstituted complexes. The preparations are characterized by their pigment composition, protein pattern, and spectral properties. PMID- 20960127 TI - Isolation and characterization of lamellar aggregates of LHCII and LHCII-lipid macro-assemblies with light-inducible structural transitions. AB - We describe the method of isolation of loosely stacked lamellar aggregates of LHCII that are capable of undergoing light-induced reversible structural changes, similar to those in granal thylakoid membranes (LHCII, the main chlorophyll a/b light-harvesting antenna complex of photosystem II). This unexpected structural flexibility of the antenna complexes depends largely on the lipid content that is retained during the isolation. As revealed by circular dichroism, in lipid-LHCII aggregates, the pigment-pigment interactions are very similar to those in the thylakoid membranes, while they differ significantly from those in solubilized trimers. The essence of the procedure is to adjust--for the plant material used- the proper conditions of detergent solubilization and purification that are mild enough for the associated lipids but provide sufficient purity. Microcrystals and most other LHCII preparations, which are more delipidated, are not capable of similar changes. The light-induced structural reorganizations can be enhanced by the addition of different thylakoid lipids, which--depending on the lipid species -also lead to the transformation of the lamellar structure. The preparation of different LHCII-lipid macro-assemblies is also described. Both in structurally flexible LHCII preparations and in thylakoids, the changes originate from a thermo-optic effect: fast local thermal transients, T-jumps, due to the dissipation of the (excess) excitation energy, which lead to elementary structural transitions in the close vicinity of the dissipating centers. This can occur because thylakoids and structurally flexible LHCII assemblies, but, e.g., not the microcrystals, exhibit a thermal instability below the denaturation temperature, and thus (local) heating leads to reorganizations without the loss of the molecular architecture of the constituents. We also list the main biochemical and biophysical techniques that can be used for testing the structural flexibility of LHCII, and discuss the potential physiological significance of the structural changes in light adaptation and photoprotection of plants. PMID- 20960128 TI - Protein targeting across and into chloroplast membranes. AB - The protein complexes in the thylakoid membrane are composed of subunits derived from both the nuclear and chloroplast genomes. While less is known about the mechanisms of delivery of the plastid-encoded subunits, the targeting mechanisms of the nuclear-encoded subunits have been more experimentally tractable. We have described in this chapter the methods used in our laboratory for investigations of the import of nuclear-encoded proteins across the chloroplast envelope membranes, and for their further delivery into or across the thylakoid membrane by one of the four distinct pathways. PMID- 20960129 TI - Proteomic analysis of thylakoid membranes. AB - Chlamydomonas is a model organism to study photosynthesis. Thylakoid membranes comprise several proteins belonging to photosystems I and II. In this chapter, we show the accurate proteomic measurements in thylakoid membranes. The chlorophyll containing membrane protein complexes were precipitated using chloroform/methanol solution. These complexes were separated using two-dimensional gel electrophoresis, and the resolved spots were exercised from the gel matrix and digested with trypsin. These peptide fragments were separated by MALDI-TOF, and the isotopic masses were blasted to a MASCOT server to obtain the protein sequence. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF). The method discussed here would be a useful method for the separation and identification of thylakoid membrane proteins. PMID- 20960130 TI - Thylakoid phosphoproteins: identification of phosphorylation sites. AB - Redox-dependent thylakoid protein phosphorylation regulates both the short- and long-term acclimation of the photosynthetic apparatus to changes in environmental conditions. The major thylakoid phosphoproteins belong to photosystem II (D1, D2, CP43, PsbH) and its light-harvesting antenna (Lhcb1, Lhcb2, CP29), but a number of minor phosphoproteins have also been identified. The detection methods traditionally include the radiolabeling techniques, electrophoretic separation of the phosphorylated and unphosphorylated forms of the protein, and the use of phosphoamino acid antibodies or phosphoprotein-specific dyes. The recent progress in mass spectrometry techniques and methods of proteomics allow for the successful identification and analyses of protein phosphorylation. In mass spectrometry approaches no exogenous tracer is needed and natural phosphorylation of proteins can be characterized with high sensitivity yielding the mapping of exact phosphorylation sites in the proteins as well. Various methods for the detection of thylakoid phosphoproteins, including the preparation of phosphopeptides for mass spectrometric analyses and techniques for phosphopeptide identification by electrospray ionization mass spectrometry (ESI-MS) are described. The experimental protocols for simultaneous identification of multiple phosphopeptides in complex peptide mixtures, enrichment of phosphopeptides by immobilized metal affinity chromatography (IMAC), and for their sequencing by tandem spectrometry are outlined. PMID- 20960131 TI - Direct detection of free radicals and reactive oxygen species in thylakoids. AB - In plants, reactive oxygen species (ROS), also known as active oxygen species (AOS), are associated with normal, physiologic processes as well as with responses to adverse conditions. ROS are connected to stress in many ways: as primary elicitors, as products and propagators of oxidative damage, or as signal molecules initiating defense or adaptation. The photosynthetic electron transport is a major site of oxidative stress by visible or ultraviolet light, high or low temperature, pollutants or herbicides. ROS production can be presumed from detecting oxidatively damaged lipids, proteins, or pigments as well as from the alleviating effects of added antioxidants. On the contrary, measuring ROS by special sensor molecules provides more direct information. This chapter focuses on the application of spin trapping electron paramagnetic resonance (EPR) spectroscopy for detecting ROS: singlet oxygen and oxygen free radicals in thylakoid membrane preparations. PMID- 20960132 TI - Assay of photoinhibition and heat inhibition of photosystem II in higher plants. AB - When thylakoids of higher plant chloroplasts are exposed to excessive light or moderate heat stress, photosystem II reaction center-binding protein D1 is damaged. The photodamage of the D1 protein is caused by reactive oxygen species, mostly singlet oxygen, and also by endogenous cationic radicals generated by the photochemical reactions of photosystem II. Moreover, it was shown recently that the damage to the D1 protein by moderate heat stress is due to reactive oxygen species produced by lipid peroxidation near photosystem II. To maintain photosystem II activity, the oxidatively damaged D1 protein must be replaced by a newly synthesized copy, and thus degradation and removal of the photo- or heat damaged D1 protein are essential for maintaining the viability of photosystem II. In this chapter, we describe the methods for assaying photoinhibition and heat inhibition of photosystem II in higher plant materials. PMID- 20960134 TI - Physical and chemical immobilization methods of photosynthetic materials. AB - Isolated photosynthetic materials have a relatively short active life time that limits their effective use. To circumvent this limitation, various immobilization techniques have been designed to improve their stability both under storage and working conditions. The immobilization methods are identified either as chemical or physical procedures depending on whether covalent bonds are established or not. In this chapter, two immobilization methods frequently used are described: a physical one based on the entrapment of photosynthetic materials in photo crosslinkable poly(vinylalcohol) polymer bearing styrylpyridinium groups (PVA SbQ) and a chemical one where the photosynthetic materials are immobilized by coreticulation in an albumin-glutaraldehyde cross-linked matrix (BSA-Glu). Different immobilization procedures in relation with various photosynthetic materials are mentioned. PMID- 20960133 TI - Photosystem II reconstitution into proteoliposomes and methodologies for structure-function characterization. AB - This chapter discusses the photosystem II (PSII) reconstitution into proteoliposomes. In the first part of the chapter, protocols are outlined for the preparation of lipid bilayer vesicles (liposomes) constituted of individual thylakoid lipids or their mixtures, for the preparation of PSII particles, and for the incorporation of the PSII particles into the liposomes. In the second part of the chapter, methodologies are described for the structure-function characterization of the PSII-lipid complexes (proteoliposomes). This includes the sodium dodecylsulfate-polyacrylamide gel electrophoresis determination of the PSII proteins, the measurement of oxygen-evolving activity of PSII in the proteoliposomes, the study of structural changes of the PSII proteins upon their incorporation into the lipid bilayers by Fourier transform infrared (FT-IR) spectroscopy, and the characterization of the PSII activity by fluorescence induction. PMID- 20960135 TI - Identifying chloroplast biogenesis and signalling mutants in Arabidopsis thaliana. AB - The chloroplast is the largest and arguably the most complex of the three energy organelles in the plant cell. The biogenesis of the chloroplast requires a combination of thousands of proteins encoded by the chloroplastic and nuclear genomes. Chloroplast function is also subject to modifications to enable responses to changes in environmental and developmental stimuli. As a consequence, interorganelle signalling and coordination between the chloroplast and nucleus is critical for the biogenesis and function of the chloroplast. Coordination and signalling during biogenesis is referred to as biogenic control and during the function as operational control (1). In this article, we report on two different mutant screens as examples of strategies for identifying mutations that affect biogenic and operational control signalling pathways and processes. We also describe strategies for the analysis and genotyping of the mutants. PMID- 20960136 TI - Expression of genes in cyanobacteria: adaptation of endogenous plasmids as platforms for high-level gene expression in Synechococcus sp. PCC 7002. AB - Synechococcus sp. PCC 7002 is an ideal model cyanobacterium for functional genomics and biotechnological applications through metabolic engineering. A gene expression system that takes advantage of its multiple, endogenous plasmids has been constructed in this cyanobacterium. The method involves the integration of foreign DNA cassettes with selectable markers into neutral sites that can be located on any of the several endogenous plasmids of this organism. We have exploited the natural transformability and powerful homologous recombination capacity of this organism by using linear DNA fragments for transformation. This approach overcomes barriers that have made the introduction and expression of foreign genes problematic in the past. Foremost among these is the natural restriction endonuclease barrier that can cleave transforming circular plasmid DNAs before they can be replicated in the cell. We describe herein the general methodology for expressing foreign and homologous genes in Synechococcus sp. PCC 7002, a comparison of several commonly used promoters, and provide examples of how this approach has successfully been used in complementation analyses and overproduction of proteins with affinity tags. PMID- 20960137 TI - Construction of gene interruptions and gene deletions in the cyanobacterium Synechocystis sp. strain PCC 6803. AB - A series of protocols are presented for the storage, growth, transformation, and characterization of wild type and mutant strains of Synechocystis sp. strain PCC 6803. These protocols include the isolation of genomic DNA and the strategies required for the construction of specific gene interruptions or deletions in this organism. This cyanobacterium has been used widely as a model for photosynthesis research, and the sequence of its genome is available at CyanoBase (http://genome.kazusa.or.jp/cyanobase/). The details provided in this chapter do not assume any previous experience in working with cyanobacteria and are intended to enable new investigators to take advantage of a wide range of gene modification and mutation mapping techniques that have been adapted for use in this system. PMID- 20960138 TI - A simple method for chloroplast transformation in Chlamydomonas reinhardtii. AB - Photosystem I (PSI) is a multisubunit pigment-protein complex that uses light energy to transfer electrons from plastocyanin to ferredoxin. Application of genetic engineering to photosynthetic reaction center proteins has led to a significant advancement in our understanding of primary electron transfer events and the role of the protein environment in modulating these processes. Chlamydomonas reinhardtii provides a system particularly amenable to analyze the structure-function relationship of Photosystem I. C. reinhardtii is also a particularly favorable organism for chloroplast transformation because it contains only a single chloroplast and grows heterotrophically when supplemented with acetate. Chlamydomonas has, therefore, served as a model organism for the development of chloroplast transformation procedures and the study of photosynthetic mutants generated using this method. Exogenous cloned cpDNA can be introduced into the chloroplast by using this biolistic gene gun method. DNA coated tungsten or gold particles are bombarded onto cells. Upon its entry into chloroplasts, the transforming DNA is released from the particles and integrated into the chloroplast genome through homologous recombination. The most versatile chloroplast selectable marker is aminoglycoside adenyl transferase (aadA), which can be expressed in the chloroplast to confer resistance to spectinomycin or streptomycin. This article describes the procedures for chloroplast transformation. PMID- 20960139 TI - Rapid isolation of intact chloroplasts from spinach leaves. AB - In this chapter, a rapid method to isolate intact chloroplasts from spinach leaves is described. Intact chloroplasts are isolated using two short centrifugation steps and avoiding the use of percoll gradient. Intactness of chloroplast is evaluated by the inability of potassium ferricyanide to enter inside the chloroplasts and to act as an electron acceptor for photosystem II. PMID- 20960140 TI - Mechanical isolation of bundle sheath cell strands and thylakoids from leaves of C4 grasses. AB - Bundle sheath (BS) strand cells and BS thylakoids from C4 plants represent a unique system for various studies using a combination of physiological, biochemical, and molecular approaches. We have developed procedures for mechanical disruption of leaf tissues in order to isolate metabolically active bundle sheath strand cells and thylakoids practically free from cross contamination coming from mesophyll cells. The procedures are described in detail together with useful practical suggestions. Using mechanical disruption we have shown the supramolecular organization of the dimeric LHCII-PSII in BS thylakoids of maize. PMID- 20960141 TI - Isolation of ribulose-1,5-bisphosphate carboxylase/oxygenase from leaves. AB - Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is a multifunctional enzyme that catalyzes the fixation of CO2 and O2 in photosynthesis and photorespiration, respectively. As the rate-limiting step in photosynthesis, improving the catalytic properties of Rubisco has long been viewed as a viable strategy for increasing plant productivity. Advances in biotechnology have made this goal more attainable by making it possible to modify Rubisco in planta. To properly evaluate the properties of Rubisco, it is necessary to isolate the enzyme in pure form. This chapter describes procedures for rapid and efficient purification of Rubisco from leaves of several species. PMID- 20960142 TI - Quantifying the amount and activity of Rubisco in leaves. AB - The CO2-fixing enzyme Rubisco plays a crucial biological role as a primary determinant of both plant yield and the response of the biosphere to global change. Here, we describe techniques for measuring the amount and activity of Rubisco in higher plants. To accommodate a range of experimental capabilities, we describe basic radioisotopic methods as well as non-radioactive techniques. The required calculations are included. We discuss problems that commonly arise during the extraction and assay of Rubisco. PMID- 20960143 TI - Purification of Rubisco activase from leaves or after expression in Escherichia coli. AB - Rubisco activase is a molecular chaperone that modulates the activation state of Rubisco by catalyzing the ATP-dependent removal of tightly-bound inhibitory sugar phosphates from Rubisco's catalytic sites. This chapter reports methods developed for the purification of native and recombinant Rubisco activase from leaves and bacterial cells, respectively. PMID- 20960144 TI - Rubisco activase activity assays. AB - Ribulose-1,5-bisphosphate (RuBP) carboxylase/oxygenase (Rubisco) activase functions as a mechano-chemical motor protein using the energy from ATP hydrolysis to contort the structure of its target protein, Rubisco. This action modulates the activation state of Rubisco by removing tightly-bound inhibitory sugar-phosphates from Rubisco's catalytic sites, thereby restoring the sites to catalytic competence. This chapter reports methods developed for assaying the two activities of Rubisco activase: ATP hydrolysis and Rubisco activation. PMID- 20960145 TI - Quantification of Rubisco activase content in leaf extracts. AB - Rubisco activase functions to promote and maintain the catalytic activity of Rubisco. Studies with the activase-lacking Arabidopsis rca mutant (Salvucci et al. Photosynth Res 7:193-201, 1985; Salvucci et al. Plant Physiol 80:655-659, 1986), antisense activase tobacco, Arabidopsis and Flaveria bidentis plants (Mate et al. Plant Physiol 102:1119-1128, 1993; Eckardt et al. Plant Physiol 113:575 586, 1997; von Caemmerer et al. Plant Physiol 137:747-755, 2005) have shown that photosynthesis at atmospheric levels of CO2 is severely impaired when plants lack activase because Rubisco becomes sequestered in an inactive form. Activase protein has been detected in all plant species, including C3 and C4 plants and green algae (Salvucci et al. Plant Physiol 84:930-936, 1987). Rubisco activase is essential in all these photosynthetic organisms for photosynthesis and plant growth. The physiological importance of Rubisco activase is reinforced by recent studies indicating that it plays a role in the response of photosynthesis to temperature. In this chapter, we describe how to extract and quantify Rubisco activase content in leaf. PMID- 20960146 TI - [Comparison of early total care (ETC) and damage control orthopedics (DCO) in the treatment of multiple trauma with femoral shaft fractures: benefit and costs]. AB - INTRODUCTION: Femoral fractures are common injuries in multiple trauma patients. The treatment concept of damage control orthopedics (DCO) is in competition with the concept of early total care (ETC). PATIENTS AND METHODS: In a retrospective study (2003-2007) 73 multiple trauma patients with femoral shaft fractures were included. The cohort was subdivided according to the Injury Severity Score (ISS) (16-24, 25-39 and more than 40) and treatment strategy (ETC versus DCO). Patients were analyzed for outcome and cost aspects. RESULTS: In the patient group with an ISS 16-24 ventilation time and intensive care treatment were longer after DCO treatment, overall costs and deficient cost cover were higher in the DCO group. In the patient group with an ISS 25-39 cost aspects showed a higher cover deficient in the DCO group. CONCLUSION: From an economic point of view the cost deficits for the ETC group were lower than in the DCO group. The treatment strategy should be selected by the pattern of injuries. The costs should be addressed by the Institute for the Hospital Remuneration System (INEK). PMID- 20960147 TI - [Recommendations of the German Working Party for Arthroscopy (section of the German Society for Orthopedics and Trauma Surgery) on equipment of facilities, process quality and qualification of operators by arthroscopic interventions: special features from the perspective of trauma surgery]. PMID- 20960148 TI - Short-term natural history in women with symptoms indicative of pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: Information about the natural history of pelvic organ prolapse (POP) is scarce. METHODS: This was a prospective cohort study of 160 women (mean age 56 years), whose answers in a population-based survey investigation indicated presence of symptomatic prolapse (siPOP), and 120 women without siPOP (mean age 51 years). RESULTS: Follow-up questionnaire was completed by 87%, and 67% underwent re-examination according to pelvic organ prolapse quantification (POP-Q) system after 5 years. Among re-examining siPOP women, 47% had an unchanged POP-Q stage, 40% showed regression, and 13% showed progression. The key symptom "feeling of a vaginal bulge" remained unchanged in 30% of women with siPOP, 64% improved by at least one step on our four-step rating scale, and 6% deteriorated. Among control women, siPOP developed in 2%. No statistically significant relationship emerged between changes in anatomic status and changes in investigated symptoms. CONCLUSION: Only a small proportion of women with symptomatic POP get worse within 5 years. PMID- 20960149 TI - Postoperative catheterization after anterior colporrhaphy: 2 versus 5 days. A multicentre randomized controlled trial. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to compare the number of temporary catheter replacements and urinary tract infections after indwelling catheterization for 2 versus 5 days following an anterior colporrhaphy. METHODS: Two hundred forty-six patients were randomly assigned to 2 or 5 days of indwelling catheterization. Outcome measures were temporary catheter replacements because of post-voiding residual >200 mL after removal of the indwelling catheter, urinary tract infections, and hospital stay. All patients were analyzed according to the intention to treat principle. RESULTS: Compared to the 5-day protocol group, in the 2-day protocol group more patients needed temporary catheter replacement (9% versus 28%, odds ratio (OR) 4.0, confidence interval (CI) 1.9-8.3, p < 0.01), whereas less patients had a urinary tract infection (37% versus 22%, OR 0.5, CI 0.3-0.9, p = 0.02) and median hospital stay was lower. CONCLUSIONS: Removal of an indwelling catheter after 2 versus 5 days following anterior colporrhaphy is associated with more temporary catheter replacements, but less urinary tract infections and a shorter hospital stay. PMID- 20960150 TI - Laparoscopic sacral colpoperineopexy: abdominal versus abdominal-vaginal posterior graft attachment. AB - INTRODUCTION AND HYPOTHESIS: Laparoscopic sacral colpoperineopexy (LSCP) involves posterior graft extension to the perineum for improved posterior support. The objective of this study was to determine whether posterior measurements differed between those that had graft extension done abdominally (A-LSCP) or abdomino vaginally (AV-LSCP). METHODS: This was a retrospective cohort study of patients that underwent A-LSCP (n = 17) and AV-LSCP (n = 51). Pre-, peri-, and postoperative variables were compared using Student's t, Fisher's exact, and analysis of covariance tests. RESULTS: Follow-up was 6 to 12 months. There were no differences between A-LSCP and AV-LSCP for any vaginal measurements or stage of prolapse (P > 0.05). Although not statistically different, A-LSCP patients had lower rates of mesh erosion and dyspareunia (P > 0.05). AV-LSCP patients had fewer prolapse symptoms (P = 0.01), but both groups had similar surgical satisfaction (P= 0.8). CONCLUSIONS: A-LSCP and AV-LSCP had comparable effects on posterior vaginal measurements; however, mesh erosion and subjective outcomes differed between the two approaches. PMID- 20960151 TI - A novel approach to teaching the pelvic organ prolapse quantification (POP-Q) exam. AB - INTRODUCTION AND HYPOTHESIS: The purpose of this study is to develop an inexpensive, feasible, and useful 3-D model for teaching and performing the pelvic organ prolapse quantification (POP-Q) exam. METHODS: We constructed POP-Q models using socks and cardboard tubing. During lectures at two residency programs, residents completed a self-assessment before and after using the model. We dichotomized learners into "beginner learners" (PGY-1-2s) and "experienced learners" (PGY-3-4s). Change in understanding, comfort performing, and confidence in teaching the POP-Q and perceived usefulness of the model were then assessed based on learner experience. RESULTS: The models took 2 h to build and cost seven dollars. Ninety percent (26/29) of residents completed both questionnaires. Eighty-nine percent "agreed" or "strongly agreed" the model was useful. All self assessment questions regarding the POP-Q exam improved after training for both groups. CONCLUSIONS: The "sock-and-tube" model is an inexpensive, easily constructed model for teaching the POP-Q exam that residents found useful and with improved understanding of and comfort with the exam. PMID- 20960153 TI - Two class-modelling techniques that give families of class-models and their relation with the structure of the data. AB - In class-modelling problems, which are again becoming increasingly important, there are two parameters to value the quality of the class-model built for a category, namely sensitivity and specificity. Using them as criteria, in this paper, two different approaches to class-modelling problems are presented, approaches that differ from other usual methods in the fact that they provide not just one class-model per category but a set of different class-models that accounts for the possible pairs of sensitivity-specificity values attainable for a given data set. One of the proposals is partial least squares class-modelling (PLS-CM) that, by the joint use of PLS with binary responses and the posterior statistical modelling of the distribution of the computed responses, permits the estimation of the risks related to the decision of assigning a sample into a class, and thus, the values of sensitivity and specificity. The other proposed method, Pareto-optimal front in class-modelling, is an analytical approach posed in a multi-response optimization framework, the one that corresponds to trying to simultaneously maximise the sensitivity and specificity of a class-model. Additionally, the whole family of computed class-models is validated in prediction by using cross-validation, showing the stability of both methods for prediction. The case-studies show the complementariness of both approaches and, in particular, that the joint use of both techniques allows the user to detect possible structures in the data set especially inadequate for PLS. The results, i.e. the whole set of sensitivity-specificity values achievable for a given problem, are graphically represented to improve its study and make it easy to make a decision about the model. PMID- 20960152 TI - Solventless sample preparation techniques based on solid- and vapour-phase extraction. AB - The main objective of this review is to critically evaluate recent developments in solventless sample preparation techniques. The potential of a variety of sample preparation techniques based on solid- and vapour-phase extraction techniques is evaluated. Direct thermal extraction and derivatization processes to facilitate the extraction of analytes in different areas are included. The applicability, disadvantages and advantages of each sample preparation technique for the determination of environmental contaminants in different matrices are discussed. PMID- 20960154 TI - Recent developments and applications of hybrid surface plasmon resonance interfaces in optical sensing. AB - Nanostructured noble metals exhibit an intense optical near field due to surface plasmon resonance, therefore promising widespread applications and being of interest to a broad spectrum of scientists, ranging from physicists, chemists, and materials scientists to biologists. A wealth of research is available discussing the synthesis, characterization, and application of noble metal nanoparticles in optical sensing. However, with respect to the sensitivity of the frequency and width of these surface plasmon resonance modes to the particle's shape, size, and environment, in nearly every case, success strongly depends on the availability of highly stable, adhesive, and sensitive nanoparticles. This undoubtedly presents a challenging task to nanofabrication. The past decade has witnessed fascinating advances in this field, in particular, the construction of oxide-based hybrid plasmonic interfaces to overcome the problem addressed above by (1) coating the metallic nanostructures with thin overlayers to form sandwiched structures or (2) embedding metallic nanostructures in a dielectric matrix to obtain metal/dielectric matrix nanocomposite films. In this critical review, we focus on recent work related to this field, beginning with a presentation of hybrid films with enhanced structural and optical stability, readily and selectively designed using chemical and physical techniques. We then illustrate their interesting optical properties and demonstrate exciting evidence for the postulated application in surface plasmon sensing fields. Finally, we survey the work remaining to be done for that potential to be realized. PMID- 20960155 TI - Normative calcaneal quantitative ultrasound data as an estimation of skeletal development in Swedish children and adolescents. AB - We present age- and gender-specific normative bone status data evaluated by quantitative ultrasound (QUS) in the calcaneus with the Lunar Achilles device and compare these estimates with bone mineral content (BMC) and bone mineral density (BMD) estimated by dual X-ray absorptiometry (DXA). Included were a sample of 518 population-based collected Swedish girls and 558 boys aged 6-19 years. QUS measurements included speed of sound (SOS), broadband ultrasound attenuation (BUA), and stiffness index (SI) in the calcaneus. DXA measurements included BMC and BMD in the femoral neck (FN), lumbar spine (L2-L4), and total body (TB). Height and weight were measured with standard equipment. Age, height, and weight were significantly associated with SOS, BUA, and SI. Compared to SOS, in both girls and boys there was a higher correlation between BUA and FN BMC (r = 0.71 and r = 0.73, respectively), FN BMD (r = 0.68 and r = 0.67, respectively), L2-L4 BMC (r = 0.70 and r = 0.64, respectively), L2-L4 BMD (r = 0.69 and r = 0.64, respectively), TB BMC (r = 0.76 and r = 0.75, respectively), and TB BMD (r = 0.74 and r = 0.74, respectively). The correlations between SOS and FN BMC (r = 0.38 and r = 0.52, respectively), FN BMD (r = 0.41 and r = 0.52, respectively), L2-L4 BMC (r = 0.31 and r = 0.40, respectively), L2-L4 BMD (r = 0.32 and r = 0.41, respectively), TB BMC (r = 0.42 and r = 0.49, respectively), and TB BMD (r = 0.48 and r = 0.54, respectively) were lower, although still significant (all P < 0.001). BUA seems to be the QUS parameter that best resembles the changes in BMC during growth. PMID- 20960156 TI - A 47, XXY patient and Xq21.31 duplication with features of Prader-Willi syndrome: results of array-based comparative genomic hybridization. AB - A man diagnosed with 47, XXY during childhood presents an appearance similar to that of Prader-Willi syndrome with hypogonadism and gynecomastia, developmental delay, and short stature and obesity. Array-based comparative genomic hybridization revealed duplication at Xq21.31 in addition to his abnormal karyotype. This duplication was also found in his mother who appeared normal. We raise the possibility that the phenotype in this patient is a combination of both extra X chromosome and Xq21 duplication. PMID- 20960157 TI - A polymorphism near osteoprotegerin gene confer risk of obesity in Uyghurs. AB - To investigate the association of single nucleotide polymorphism (SNP) rs4355801 near osteoprotegerin (OPG) gene and rs3736228 in low-density lipoprotein receptor related protein 5 (LRP5) gene with metabolic phenotypes [body mass index (BMI), waist-hip ratio, glucose, total cholesterol (CHO), and triglyceride], we carried out a population-based association study in Uyghur population living in Xinjiang Uyghur Autonomous Region of China. We observed a significant higher level of BMI in AG/AA carriers than in GG carriers (P = 0.022) for rs4355801. Subjects with the AG/GG genotype significantly increased the risk of BMI related obesity than subjects with the AA genotype, with an odds ratio of 1.31 (95% CI 1.09-1.56, P = 0.005). The association remained significant after controlling for covariates of age and gender. In addition, we observed a significant higher level of CHO in CT/TT carriers than in CC carriers (P = 0.021) for rs3736228. Our observations provide the first evidence that rs4355801 near OPG gene may confer susceptibility to obesity. In addition, SNP rs3736228 in LPR5 gene may affects the level of CHO in Uyghur population. PMID- 20960158 TI - Analysis of thyroglobulin gene polymorphisms in patients with autoimmune thyroiditis. AB - The autoimmune thyroid disease is a complex disorder caused by a combination of genetic susceptibility and environmental factors, which are believed to initiate the autoimmune response to thyroid antigens. Identification of the susceptibility genes has found that unique and diverse genetic factors are in association with Graves' disease and autoimmune thyroiditis. The thyroglobulin gene is an identified thyroid-specific gene associated to autoimmune thyroid disease and, principally, with autoimmune thyroiditis. The aim of this work was to test for evidence of allelic association between autoimmune thyroiditis and thyroglobulin polymorphism markers. We studied six polymorphisms distributed throughout all the thyroglobulin gene: four microsatellites (Tgms1, Tgms2, TGrI29 and TGrI30), one insertion/deletion (Indel) polymorphism (IndelTG-IVS18) and one exonic single nucleotide polymorphism (SNP) (c.7589G>A) in 122 patients with autoimmune thyroiditis compared with 100 non-related normal subjects. No differences in allele and genotype distribution were observed between autoimmune thyroiditis cases and controls for Tgms1, Tgms2, TGrI30, IndelTG-IVS18 and c.7589G>A. However, when we analyzed the patients with the TGrI29 microsatellite we found a significant association between the 199-bp allele and AT (33.7% vs. 24.5% in control group) (P = 0.0372). In addition, a higher prevalence of the 201-bp allele has been observed in control subjects (47.5% vs. 38.1% in patients group), although not statistically significant (P = 0.0536). Our work shows the association between the thyroglobulin gene and autoimmune thyroiditis and reinforce that thyroglobulin is a thyroid-specific susceptibility gene for this disease. PMID- 20960159 TI - Effect of concomitant progesterone administration or the effect of removal of estrogen capsule on changes caused by long-term estrogen treatment in pituitary VIP immunoreactivities. AB - In the anterior pituitary besides the classical tropic hormones, peptides of a small molecular weight are also synthesized. One of them is the vasoactive intestinal polypeptide (VIP). VIP immunoreactivity is readily detected in human and monkey pituitaries; however, in the rat VIP immunoreactive cells were observed in about 50% of intact rats. In estrogen treated rats VIP immunoreactive cells were observed in the anterior pituitary of all animals. In this work, we have examined the effect of long-term sexual steroid treatments on the VIP immunoreactivity of the anterior pituitary using diethylstilbestrol (DES) or progesterone (P) filled capsules. The effectiveness of steroid treatments was tested by the measurement of plasma prolactin (PRL) level and by the appearance of prolactinoma. DES enhanced the plasma PRL level and 5 months later it induced prolactinomas, the concomitant P treatment prevented both the elevation of plasma PRL level and the formation of prolactinomas. These results indicated that there was enough steroid in the capsules. There was a positive correlation between the duration of DES influence and the number of VIP immunoreactive cells. Two months after the implantation of DES there was a considerable number of VIP cells in the anterior pituitary, and 5 months after implantation the number of VIP cells was greatly increased so as to form a VIP-oma. Concomitant implantation of P prevented the formation of VIP-oma. Two months after the implantation, the DES capsule was removed. Already 2 months after removal the number of VIP cells approximated to the control level. It has been concluded that P can prevent the undesired effect of DES not only on the PRL, but on the VIP immunoreactivity as well. PMID- 20960160 TI - Exercise-induced nausea and vomiting: another sign and symptom of pheochromocytoma and paraganglioma. AB - A cohort of nine patients, mostly young adults, presented with a new sign/symptom of pheochromocytoma/paraganglioma: exercise-induced nausea and vomiting. The aims of this article are to introduce this sign/symptom and offer a possible hypothesis for the observation. Following a 2000 report from a paraganglioma patient experiencing exercise-induced nausea and vomiting, we began asking patients about instances of nausea and vomiting with exercise. A total of nine patients, 4.4% of our pheochromocytoma/paraganglioma population, presented with reports of exercise-induced nausea and vomiting, initially with moderate-to intense levels of exercise, at the first presentation of their disease. All of these patients reported a cessation of exercise-induced nausea and vomiting following the removal of their primary tumor. Two patients with metastatic disease to the lungs reported a recurrence of exercise-induced nausea and vomiting. The majority of patients studied were young adults with mean onset age of 19.4 years (range of 9-51 years) and the mean age of diagnosis being 24.1 years (range of 11-53 years). Exercise-induced nausea and vomiting should be considered a sign/symptom of pheochromocytoma/paraganglioma and should be addressed in the clinical evaluation of these patients, especially in young adults. Whether exercise-induced elevated catecholamine levels could account for the induced nausea and vomiting via activation of adrenergic receptors in the area postrema remains to be established. PMID- 20960161 TI - Clinical and genetic characterization of Portuguese patients with pseudohypoparathyroidism type Ib. AB - Patients with pseudohypoparathyroidism type Ib (PHP-Ib) present hypocalcemia and hyperphosphatemia, as a consequence of a resistance to PTH action, through its G protein-coupled receptor, in the renal tubules. This resistance results from tissue-specific silencing of the G-protein alpha-subunit (G(s)alpha), due to imprinting disruption of its encoding locus--GNAS. In familial PHP-Ib, maternally inherited deletions at the STX16 gene are associated to a regional GNAS methylation defect. In sporadic PHP-Ib, broad methylation changes at GNAS arise from unknown genetic causes. In this study, we describe the clinical presentation of PHP-Ib in four Portuguese patients (two of whom were siblings), and provide further insight for the management of patients with this disease. The diagnosis of PHP-Ib was made after detection of GNAS imprinting defects in each of the cases. In the siblings, a regional GNAS methylation change resulted from a known 3.0 kb STX16 deletion. In the other two patients, the broad methylation defects at GNAS, which were absent in their relatives, resulted from genetic alterations that remain to be identified. We report the first clinical and genetic study of Portuguese patients with PHP-Ib. The genetic identification of a hereditary form of this rare disease allowed an early diagnosis, and may prevent hypocalcemia related complications. PMID- 20960162 TI - Identification of novel transcript variants of estrogen receptor alpha, beta and progesterone receptor gene in human endometrium. AB - The human progesterone receptor (PR) and estrogen receptor genes (ESR1 and ESR2) are known to code for a multitude of transcript variants resulting from alternative splicing. Many of them are translated into nuclear receptor proteins with altered structure and function. Expression of these alternative estrogen and progesterone receptors modulates the cellular response to sexual steroid hormones. Recent studies also suggested their significance in development of hormone-dependent diseases like gynecological cancers. We report identification of 12 new transcript variations of the PR, ESR1, and ESR2 gene in human endometrium which result from differential exon-skipping. We succeeded in cloning of four new double or triple exon-deletion transcript variants of ERalpha, four single, double or triple exon-skipped mRNA isoforms of ERbeta, and four new transcript variations of PR gene. Sequence analysis suggested that at least four of them, ERalphaDelta5/6, ERalphaDelta5/6/7, PRDelta7, and PRDelta6/7 are translated into receptor proteins which might exert ligand-independent effects on steroid hormone signalling. Comparison of pre- and post-menopausal endometrium revealed differential expression of PRDelta6/7, ERalphaDelta5/6/7, ERalphaDelta3/4/5, and ERbetaDelta1-0N. We also report differential expression of the exon-skipped isoforms in a panel of human cancer cell lines derived from the breast, ovary, and endometrium. Our identification of additional transcript variations further increases the complexity of steroid hormone receptor gene expression and signalling. PMID- 20960163 TI - Subsequent stress increases gene expression of catecholamine synthetic enzymes in cardiac ventricles of chronic-stressed rats. AB - Since previous experience of stressful situation profoundly affects response to a subsequent novel stressor, we examined changes in gene expression and protein levels of catecholamine biosynthetic enzymes in cardiac ventricles after exposure of chronic psychosocially isolated adult Wistar male rats to short-term immobilization stress. Chronic social isolation did not affect gene expression of tyrosine hydroxylase (TH) in either right or left ventricle. Subsequent immobilization of these animals produced an elevation of TH mRNA level in right and left ventricles. The levels of dopamine-beta-hydroxylase (DBH) mRNA were detectable only after immobilization both in right and left ventricles of control and chronically isolated rats. Chronic isolation stress increased phenylethanolamine N-methyltransferase (PNMT) mRNA levels in the right ventricle. Immobilization led to an elevated PNMT mRNA level in right and left ventricles of both control and chronically stressed animals. Protein levels of TH, DBH, and PNMT in right and left ventricles of socially isolated rats were increased after subsequent immobilization. Taking into consideration the role of cardiac catecholamines in physiological and pathophysiological processes, it could be hypothesized that increased catecholamine synthesis in the ventricles after novel immobilization stress could point to the susceptibility of the heart to subsequent stress. PMID- 20960164 TI - Anti-tumor effects of adenovirus containing human growth hormone sequences in a mouse model of human ovarian cancer. AB - Women with ovarian cancer have a low survival rate and develop resistance to chemotherapy, so new approaches to treatment are needed. We unexpectedly found administration of a replication-deficient adenovirus containing human growth hormone sequences (AdXGH) was beneficial in a mouse model of human ovarian cancer. Intraperitoneal injections of AdXGH prolonged median survival from a mean of 31 +/- 1.2 to 40 +/- 1.4 days in immunodeficient SCID mice given SKOV3.ip1 human ovarian cancer cells in the peritoneal cavity. Adenovirus containing human prolactin or del32-71growth hormone sequences had no effect. Repeated injection of growth hormone or implantation of tablets with sustained growth hormone release did not increase survival. Control mice had overlapping tumors throughout the peritoneal cavity and liver and frequent lung metastases 24 days after tumor cell injection. Mice that received two injections of AdXGH had no lung metastases. Mice that received four injections had no lung or liver metastases and peritoneal fibrosis. They did not survive longer than mice that received two injections, but they had enlarged livers with hepatocellular changes, indicating that a limitation of increasing the dose is liver toxicity. PMID- 20960165 TI - Subacute thyroiditis in the course of novel H1N1 influenza infection. AB - To describe the first documented case of subacute (De Quervain) thyroiditis in the course of novel H1N1 influenza infection. This is a case report of a patient diagnosed at the General Hospital "G. Hatzikosta" of Ioannina, Greece. A 55-year old previously healthy male developed an influenza-like syndrome that was accompanied by severe neck pain, palpitations, weight loss, and disproportionately increased erythrocyte sedimentation rate. Polymerase chain reaction assay of pharyngeal swabs confirmed the diagnosis of novel H1N1 influenza infection. Serum thyroid-stimulating hormone was suppressed to zero and levels of free thyroxine and particularly triiodothyronine were increased. Technetium-99m-pertechnetate scintigraphy showed diffuse and inhomogeneous very low technetium trapping. The patient was treated with non-steroidal anti inflammatory drugs and thyroid function gradually normalized without evolving to a hypothyroid phase. This is the first case of subacute thyroiditis associated with novel H1N1 influenza infection. Furthermore, this is the first case to definitely demonstrate active influenza infection of any type concurrent with thyroiditis, and one of the very rare similar cases for any active viral disease etiologically implicated in the pathogenesis of subacute thyroiditis. PMID- 20960166 TI - Preliminary biochemical characterization of the novel, non-AT1, non-AT2 angiotensin binding site from the rat brain. AB - A novel binding site for angiotensins II and III was recently discovered in brain membranes in the presence of the sulfhydryl reactive angiotensinase inhibitor parachloromercuribenzoate. This binding site is distinctly different from the other known receptors for angiotensins: AT1, AT2, AT4, and mas oncogene protein (Ang 1-7 receptor). Preliminary biochemical characterization studies have been done on this protein by crosslinking it with (125)I-labeled photoaffinity probes and solubilizing the radiolabeled binding site. Polyacrylamide gel electrophoresis studies and isoelectric focusing indicate that this membrane bound binding site is a protein with a molecular weight of 70-85 kDa and an isoelectric point of ~7. Cyanogen bromide hydrolysis of the protein yielded two radiolabeled fragments of 12.5 and 25 kDa. The protein does not appear to be N glycosylated based upon the failure of PNGaseF to alter its migration rate on a 7.5% polyacrylamide gel. The binding of angiotensin II to this protein is not affected by GTPgammaS or Gpp(NH)p, suggesting that it is not a G protein-coupled receptor. Further characterization studies are directed to identify this protein either as a novel angiotensin receptor, an angiotensin scavenger (clearance receptor) or an angiotensinase. PMID- 20960167 TI - Plasma thrombin-activatable fibrinolysis inhibitor (TAFI) antigen levels in diabetic foot ulcers. AB - Plasma TAFI may participate in arterial thrombosis in cardiovascular diseases (CVD) and may be involved in the mechanism of vascular endothelial damage in diabetic patients. The aim of this study was to investigate the association of plasma TAFI antigen level in the development of diabetic foot ulcer in Type 2 diabetes. The TAFI antigen levels were determined in 50 patients with diabetic foot ulcers and 34 patients without diabetic foot ulcers and 25 healthy individuals. We measured TAFIa/ai antigen in plasma samples with a commercially available ELISA Kit. Diabetic foot ulcer group and diabetic group were similar in terms of mean age and sex distribution. Diabetes duration, retinopathy, neuropathy, macrovascular disease and infection were related to diabetic foot ulcers. HbA1c, HDL-cholesterol and Folic Acid levels were decreased in the diabetic foot ulcer group. TAFI levels were 99.44 +/- 55.94% in control group, 135.21 +/- 61.05% in diabetic foot ulcer group, 136.75 +/- 59.38% in diabetic group and was statistically different (P < 0.05). But no difference was seen in TAFI levels between the diabetic foot ulcer group and diabetic group (P > 0.05). No significant difference in plasma TAFI levels were seen between diabetic foot ulcer stages. TAFI antigen levels are increased in Type 2 diabetic patients, but are not related to diabetic foot ulcer development. PMID- 20960168 TI - Chitotriosidase activity predicts endothelial dysfunction in type-2 diabetes mellitus. AB - The enzyme chitotriosidase (ChT) is secreted by activated macrophages and play active role in human immune response. ChT activity is increased in atherosclerosis in association to the extent of the disease. We investigated the relevance of ChT to endothelial functions and insulin resistance in patients with T2DM. Forty newly diagnosed and untreated patients with T2DM (male 17; age 47.0 +/- 6.2 years) and 50 healthy volunteers (male 21; age 50.2 +/- 8.8 years) were enrolled. Plasma asymmetric dimethyl arginine (ADMA) levels were determined by ELISA. ChT activity was measured by the fluorescence method. Insulin resistance was calculated by the HOMA-IR formula. The patients had higher systolic blood pressures, HOMA-IR, ADMA levels, and ChT activities (P < 0.001 for all) and lower HDL cholesterol levels (P = 0.03) than the control group. The ChT activities of the total group were significantly correlated to the age (r = 0.031, p = 0.003), ADMA (r = 0.22, p = 0.04), and plasma glucose levels (r = 0.27, p = 0.01). ChT was the independent determinant of the plasma ADMA levels (r = 0.26, p = 0.02). The results of this study show that serum ChT activity is increased in patients with newly diagnosed, untreated, and uncomplicated patients with T2DM. The results also imply that increased ChT activity may be a predictor of endothelial dysfunction. PMID- 20960169 TI - Maternal diabetes increases apoptosis in mice oocytes, not 2-cell embryos. AB - Apoptosis may be closely involved in diabetes-induced embryonic malformations. We aimed to investigate the occurrence of apoptosis at an early stage of development, in oocytes and 2-cell embryos of streptozotocin-induced diabetic mice and nondiabetic mice. Diabetic mouse ovarian sections stained with hematoxylin and eosin showed reduced number of growing follicles and delayed oocyte development. Annexin V-positive oocytes were higher in number in diabetic mice than in nondiabetic mice. Quantitative RT-PCR and immunofluorescence analysis revealed the expression of Bax and caspase-3 significantly higher in diabetic than nondiabetic oocytes. In contrast, 2-cell embryos of diabetic and nondiabetic mice showed no annexin V-positive staining. Bax expression was elevated in diabetic 2-cell embryos, but caspase-3 expression did not significantly differ between diabetic and nondiabetic 2-cell embryos. Electron microscopy revealed increased number of swollen mitochondria in diabetic 2-cell embryos. These results suggested that maternal diabetes might increase oocyte apoptosis by a Bax-caspase-3 pathway to play a role in embryonic malformations by delayed oocyte development. Development of 2-cell embryos might be adversely affected by maternal diabetes, but not through Bax-regulated caspase-3 apoptotic pathway. PMID- 20960170 TI - Bone mineral density and bone fracture in male patients receiving long-term suppressive levothyroxine treatment for differentiated thyroid carcinoma. AB - Studies on the effect of exogenous subclinical thyrotoxicosis on bone mineral density (BMD) in male patients treated with suppressive doses of levothyroxine for differentiated thyroid carcinoma (DTC) are not conclusive. In order to evaluate BMD (in femoral neck, lumbar spine, and distal radius) and bone fractures in men under long-term suppressive treatment with levothyroxine for DTC, we conducted a cross-sectional, retrospective study in 33 Caucasian men (mean +/- SD age: 56 +/- 14 years) under treatment for DTC. The control group comprised 33 healthy age- and body mass index-matched male volunteers. BMD was assessed by dual-energy X-ray absorptiometry (DXA). Bone turnover biomarkers (calcium, phosphate, alkaline phosphatase, PTH, vitamin D, urinary calcium, and N Telopeptide/creatinine index) and testosterone were determined. Previous bone fractures were evaluated with a questionnaire and X-ray images of thoracic and lumbar vertebrae. Patients were treated for a mean duration of 15 +/- 5 years. No differences were found between patients and controls in bone turnover biomarkers or areal BMD, T-scores or Z-scores in all sites evaluated. No earlier fractures or pain episodes were registered in either group and the incidence of asymptomatic vertebral fractures did not differ significantly between patient (18.8%) and control groups (16.7%), (P = 0.9). In conclusion, long-term suppressive treatment with levothyroxine in men with DTC does not appear to exert deleterious effects on bone mineral density or increase the prevalence of fracture. PMID- 20960171 TI - A novel SLC4A1 variant in an autosomal dominant distal renal tubular acidosis family with a severe phenotype. AB - Mutations in SLC4A1, encoding the chloride-bicarbonate exchanger AE1, cause distal renal tubular acidosis (dRTA), a disease of defective urinary acidification by the distal nephron. We searched for SLC4A1 gene mutations in six patients from a Chinese family with a severe phenotype of dRTA (growth impairment, severe metabolic acidosis, with/or without gross nephrocalcinosis and renal impairment). All coding regions of kidney isoform of AE1, including intron exon boundaries, were analyzed using PCR followed by direct sequence analysis. A novel 1-bp duplication at nucleotide 2713 (c.2713dupG, band 3 Qingdao) in exon 20 of SLC4A1 in this family was identified by direct sequencing analysis. This duplication alters the encoded protein through codon 905, and results in a reading frame for 15 extra condons (instead of 8) before the new stop condon at position 919 (p.Asp905Glyfs15). We suggest that RTA should be considered as a diagnostic possibility in adult subjects with nephrocalcinosis and chronic renal insufficiency, and family survey should be carefully performed. PMID- 20960172 TI - Effect of intra-testicular melatonin injection on testicular functions, local and general immunity of a tropical rodent Funambulus pennanti. AB - Local antigonadotrophic action of melatonin in testes has never been correlated with local and general immune status of any rodent. Intra-testicular injection of melatonin (2.5 MUg/50 MUl) for 10 days (MI-10D) and 20 days (MI-20D) was given to young adult male of Funambulus pennanti and testicular androgen receptor (AR), androgen binding protein (ABP) expression, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activity, and Mel1aR expression in thymus was checked along with general immune parameters. Further, immunohistochemical localization of Mel1aR in testes was done. Decreased AR, ABP expression, testes weight, 3beta-HSD activity, testosterone level, and spermatogenesis but increased Mel1aR expression in thymus, immunoreactivity in testes, and testicular macrophages following injection was noted. Lymphatic tissue weight, leukocyte, lymphocyte count, lymphocyte proliferation in spleen, thymus, plasma melatonin, and IL-2 level increased in a duration-dependent manner following intra-testicular injection. Intra-testicular injection of melatonin decreased steroidogenesis by enhancing the primary effect of melatonin on Leydig cell endocrine function. Along with reduced circulatory testosterone production, an increase in testicular as well as general immunity was observed in a duration-dependent manner. Therefore, a local participation of melatonin in testes of F. pennanti to control testicular androgen production is suggested. PMID- 20960173 TI - Hyperglycemia induced by tacrolimus and sirolimus is reversible in normal sprague dawley rats. AB - Post-transplant diabetes mellitus (PTDM) worsens outcomes after kidney transplantation, and immunosuppression agents contribute to PTDM. We have previously shown that tacrolimus (TAC) and sirolimus (SIR) cause hyperglycemia in normal rats. While there is little data on the mechanism for immunosuppressant induced hyperglycemia, we hypothesized that the TAC and SIR-induced changes are reversible. To study this possibility, we compared normal rats treated for 2 weeks with either TAC, SIR, or a combination of TAC and SIR prior to evaluating their response to glucose challenge, with parallel groups also treated for 2 weeks after which treatment was stopped for 4 weeks, prior to studying their response to glucose challenge. Mean daily glucose and growth velocity was decreased in SIR, and TAC+SIR-treated animals compared to controls (P < 0.05). TAC, SIR, and TAC+SIR treatment also resulted in increased glucose response to glucose challenge, compared to controls (P < 0.05). SIR-treated animals also had elevated insulin concentrations in response to glucose challenge, compared to controls (P < 0.05). Insulin content was decreased in TAC and TAC+SIR, and islet apoptosis was also increased after TAC+SIR treatment (P < 0.05). Four weeks after treatments were stopped, all differences resolved between groups. In conclusion, TAC, SIR, and the combination of TAC+SIR-induced changes in glucose and insulin responses to glucose challenge that were accompanied by changes in islet apoptosis and insulin content. These changes were no longer present 4 weeks after cessation of therapy suggesting immunosuppressant-induced changes in glucose metabolism are likely reversible. PMID- 20960175 TI - -607 C/A polymorphism in the promoter of IL-18 gene is associated with 2 h post loading plasma glucose level in Chinese. AB - The purpose of this study is to find out whether the -607 C/A polymorphism in IL 18 gene promoter will affect serum IL-18 concentrations and glucose metabolism in Chinese subjects. In 232 patients with impaired glucose regulation (IGR) or type 2 diabetes and 212 subjects of normal glucose regulation (NGR), -607 C/A polymorphism was analyzed by polymerase chain reaction with sequence specific primers. Serum IL-18 concentrations were determined by ELISA in 200 subjects. Compared with subjects with NGR, those with type 2 diabetes and IGR had significant higher IL-18 concentrations [114.4 (92.9-149.2) and 102.1 (67.5 138.2) vs. 77.3 (53.8-107.8) pg/ml, P = 0.0026 and P < 0.0001, respectively]. A significantly higher proportion of A/A genotype of -607 C/A polymorphism presented in patients with type 2 diabetes compared with subjects of NGR (23.8% vs. 10.9%, P = 0.005). Subjects with an A/A genotype also had higher 2 h post loading plasma glucose (2 h-PPG) compared with C/A and C/C genotypes even after adjustments of age, sex and BMI [8.94 (7.55-12.3) vs. 7.80 (6.00-9.87) and 7.23 (5.66-8.99) mmol/l, P both < 0.05]. Multiple linear regression revealed that BMI (P < 0.0001) and 2 h-PPG (P = 0.019) were independently associated with IL-18 concentrations. In conclusion, subjects with IGR or type 2 diabetes had significantly higher concentrations of IL-18 than those with NGR. Genotype A/A of IL-18 gene promoter -607 C/A polymorphism was associated with higher prevalence of type 2 diabetes and 2 h post-loading plasma glucose level. PMID- 20960174 TI - Analysis of angiotensin II- and ACTH-driven mineralocorticoid functions and omental adiposity in a non-genetic, hyperadipose female rat phenotype. AB - The hypothalamic damage induced by neonatal treatment with monosodium L glutamate (MSG) induces several metabolic abnormalities, resulting in a rat hyperleptinemic-hyperadipose phenotype. This study was conducted to explore the impact of the neonatal MSG treatment, in the adult (120 days old) female rat on: (a) the in vivo and in vitro mineralocorticoid responses to ACTH and angiotensin II (AII); (b) the effect of leptin on ACTH- and AII-stimulated mineralocorticoid secretions by isolated corticoadrenal cells; and (c) abdominal adiposity characteristics. Our data indicate that, compared with age-matched controls, MSG rats displayed: (1) enhanced and reduced mineralocorticoid responses to ACTH and AII treatments, respectively, effects observed in both in vivo and in vitro conditions; (2) adrenal refractoriness to the inhibitory effect of exogenous leptin on ACTH-stimulated aldosterone output by isolated adrenocortical cells; and (3) distorted omental adiposity morphology and function. This study supports that the adult hyperleptinemic MSG female rat is characterized by enhanced ACTH driven mineralocorticoid function, impaired adrenal leptin sensitivity, and disrupted abdominal adiposity function. MSG rats could counteract undesirable effects of glucocorticoid excess, by developing a reduced AII-driven mineralocorticoid function. Thus, chronic hyperleptinemia could play a protective role against ACTH-mediated allostatic loads in the adrenal leptin resistant, MSG female rat phenotype. PMID- 20960176 TI - Monocyte chemoattractant protein-1 (MCP-1) 2518G/A gene polymorphism in Turkish type 2 diabetes patients with nephropathy. AB - Tissue macrophage accumulation is thought to induce insulin resistance during obesity and stimulate the progression of diabetic nephropathy (DN). The objective of this study was to investigate genotypic and allelic frequencies of monocyte chemoattractant protein-1 (MCP-1) gene polymorphism in the healthy and patients with and without DN. The MCP-1 genotypes were determined in 43 patients with nephropathy and 43 without nephropathy and a control group of 105 healthy individuals. The genotype MCP-1 (-2518G/A) distribution did differ between the control group and the type 2 diabetic patients (P = 0.004). The frequency of the polymorphic G allele was also no similar for the group with type 2 diabetes as for the control group with 20.9 and 32.4%, respectively (P = 0.012). The AA genotype and A allele at MCP-1 -2518 was an independent risk factor for the progression of type 2 diabetes. In conclusion, MCP-1 AA genotype and A allele may play a specific role(s) in determining diabetic susceptibility, but do not seem to be important in the clinical manifestations of DN. PMID- 20960177 TI - Mechanisms of HIV envelope-induced T lymphocyte apoptosis. AB - Infection by the human immunodeficiency virus (HIV) is characterized by a progressive depletion of CD4 T lymphocytes, which leads to dysfunction of the immune system. Although a variety of mechanisms may contribute to the gradual T cell decline that occurs in HIV-infected patients, abnormal apoptosis of infected or bystander T lymphocytes is an important event leading to immunodeficiency. The HIV envelope glycoprotein plays a crucial role in HIV associated apoptosis through both death receptor-mediated and mitochondria-dependent pathways. This review summarizes current knowledge of Env-mediated T lymphocyte apoptosis. PMID- 20960178 TI - Indinavir resistance evolution in one human immunodeficiency virus type 1 infected patient revealed by single-genome amplification. AB - Human Immunodeficiency Virus Type 1 exists in vivo as quasispecies, and one of the genome's characteristics is its diversity. During the antiretroviral therapy, drug resistance is the main obstacle to effective viral prevention. Understanding the molecular evolution process is fundamental to analyze the mechanism of drug resistance and develop a strategy to minimize resistance. OBJECTIVE: The molecular evolution of drug resistance of one patient who had received reverse transcriptase inhibitors for a long time and had treatment which replaced Nevirapine with Indinavir was analyzed, with the aim of observing the drug resistance evolution pathway. METHODS: The patient, XLF, was followed-up for six successive times. The viral populations were amplified and sequenced by single genome amplification. All the sequences were submitted to the Stanford HIV Drug Resistance Database for the analysis of genotypic drug resistance. RESULTS: 149 entire protease and 171 entire reverse transcriptase sequences were obtained from these samples, and all sequences were identified as subtype B. Before the patient received Indinavir, the viral population only had some polymorphisms in the protease sequences. After the patient began Indinavir treatment, the variants carrying polymorphisms declined while variants carrying the secondary mutation G73S gained the advantage. As therapy was prolonged, G73S was combined with M46I/L90M to form a resistance pattern M46I/G73S/L90M, which then became the dominant population. 97.9% of variants had the M46I/G73S/L90M pattern at XLF6. During the emergence of protease inhibitors resistance, reverse transcriptase inhibitors resistance maintained high levels. CONCLUSION: Indinavir-resistance evolution was observed by single-genome amplification. During the course of changing the regimen to incorporate Indinavir, the G73S mutation occurred and was combined with M46I/L90M. PMID- 20960179 TI - Analysis of synonymous codon usage bias in 09H1N1. AB - A novel subtype of influenza A virus 09H1N1 has rapidly spread across the world. Evolutionary analyses of this virus have revealed that 09H1N1 is a triple reassortant of segments from swine, avian and human influenza viruses. In this study, we investigated factors shaping the codon usage bias of 09H1N1 and carried out cluster analysis of 60 strains of influenza A virus from different subtypes based on their codon usage bias. We discovered that more preferentially used codons of 09H1N1 are A-ended or U-ended, and the intra-genomic codon usage bias of 09H1N1 is quite low. Base composition constraint, dinucleotide biases and translational selection are the main factors influencing the codon usage bias of 09H1N1. At the genome level, we find that the codon usage bias of 09H1N1 is similar to H1N1 (A/swine/Kansas/77778/2007H1N1), H9N2 from Asia, H1N2 from Asia and North America and H3N2 from North America. Our results provide insight for understanding the processes governing evolution, regulation of gene expression, and revealing the evolution of 09H1N1. PMID- 20960180 TI - In vitro anti-influenza virus activities of sulfated polysaccharide fractions from Gracilaria lemaneiformis. AB - In this paper, in vitro anti-influenza virus activities of sulfated polysaccharide fractions from Gracilaria lemaneiformis were investigated. Cytotoxicities and antiviral activities of Gracilaria lemaneiformis polysaccharides (PGL), Gracilaria lemaneiformis polysaccharide fraction-1 (GL-1), Gracilaria lemaneiformis polysaccharide fraction-2 (GL-2) and Gracilaria lemaneiformis polysaccharide fraction-3 (GL-3) were studied by the Methyl thiazolyl tetrazolium (MTT) method, and the inhibitory effect against Human influenza virus H1-364 induced cytopathic effect (CPE) on MDCK cells were observed by the CPE method. In addition, the antiviral mechanism of PGL was explored by Plaque forming unit (PFU), MTT and CPE methods. The results showed: i) Cytotoxicities were not significantly revealed, and H1-364 induced CPE was also reduced treated with sulfated polysaccharide fractions from Gracilaria lemaneiformis; ii) Antiviral activities were associated with the mass percentage content of sulfate groups in polysaccharide fractions, which was about 13%, in polysaccharides (PGL and GL-2) both of which exhibited higher antiviral activity; iii) A potential antiviral mechanism to explain these observations is that viral adsorption and replication on host cells were inhibited by sulfated polysaccharides from Gracilaria lemaneiformis. In conclusion, Anti-influenza virus activities of sulfated polysaccharide fractions from Gracilaria lemaneiformis were revealed, and the antiviral activities were associated with content of sulfate groups in polysaccharide fractions. PMID- 20960181 TI - Development of a polyclonal antibody-based AC-ELISA and its comparison with PCR for diagnosis of canine parvovirus infection. AB - A polyclonal antibody-based antigen-capture ELISA (AC-ELISA) has been developed for detection of Canine parvovirus (CPV) antigens in faecal samples of dogs. The assay uses rabbit anti-CPV polyclonal antibody as the capture antibody, guinea pig anti-CPV polyclonal antibody as tracing antibody and anti-guinea pig HRPO conjugate as the detection system. The optimum dilution of the capture antibody and the tracing antibody capable of detecting the CPV-2 antigens was found to be 1:1 600 and 1:400, respectively, in the check-board titration. In this study, a total of 152 samples (129 faecal samples and 23 cell culture supernatant) were tested both by AC-ELISA and by polymerase chain reaction (PCR). Of the samples tested, 69 and 78 samples were found positive by AC-ELISA and PCR, respectively. The AC-ELISA had relative sensitivity, relative specificity and accuracy of 88.4%, 100.0% and 91.4% respectively. The analytical sensitivity of AC-ELISA was estimated to be 10(2.8) TCID(50)/mL whereas PCR sensitivity was 10(0.8) TCID(50)/mL. The AC-ELISA is a simple, quick and reliable method for screening large numbers of faecal samples of dogs suspected of CPV infection. PMID- 20960183 TI - Cxcl16 interact with SARS-CoV N protein in and out cell. AB - Our study investigated the host cell protein which can interact with SARS-CoV N protein, and explored the functional connections. The eukaryotic expression vectors pEGFP-N1/SARS-CoVN and pdsRed2-N1/CXCL16 were constructed and used to co transfect HEK293FT cells by the calcium phosphate method. The HIS-tagged fusion protein SARS-CoVN-GFP was then built and purified for the binding assay in vitro. The co-localization of SARS-CoVN and CXCL16 in the cytoplasm of HEK293FT cells was also shown using confocal laser scanning microscopy. It is suggested that their interaction might be through direct combination. Under a fluorescence microscope, it was observed that the purified fusion protein SARS-CoVN-GFP was attached to the cell membrane of CXCL16-transfected cells, indicating that SARS CoVN and CXCL16 can be mutually combined. PMID- 20960182 TI - Establishment of the eukaryotic cell lines for inducible control of SARS-CoV nucleocapsid gene expression. AB - In order to establish the eukaryotic cell lines for inducible control of SARS-CoV nucleocapsid gene expression. The recombinant plasmid of pTRE-Tight-SARS-N was constructed by using the plasmid p8S as the PCR template which contains a cDNA clone covering the nucleocapsid gene of SARS-CoV HKU-39449. Restriction enzymes digestion and sequence analysis indicated the recombinant plasmid of pTRE-Tight SARS-N contained the nucleocapsid gene with the optimized nucleotide sequence which will improve the translation efficiency. Positive cell clones were selected by cotransfecting pTRE-Tight-SARS-N with the linear marker pPUR to BHK-21 Tet-on cells in the presence of puromycin. A set of double-stable eukaryotic cell lines (BHK-Tet-SARS-N) with inducible control of the SARS-CoV neucleocapsid gene expression was identified by using SDS-PAGE and Western-blot analysis. The expression of SARS-CoV nucleocapsid protein was tightly regulated by the varying concentration of doxcycline in the constructed double-stable cell line. The constructed BHK-Tet-SARS-N cell strains will facilitate the rescue of SARS-CoV in vitro and the further reverse genetic research of SARS-CoV. PMID- 20960184 TI - Effects of 1,2,4,6-tetra-O-galloyl-beta-D-glucose from P. emblica on HBsAg and HBeAg secretion in HepG2.2.15 cell culture. AB - A polyphenolic compound, 1,2,4,6-tetra-O-galloyl-beta-D-glucose (1246TGG), was isolated from the traditional Chinese medicine Phyllanthus emblica L. (Euphorbiaceae) and assayed for its potential as an anti-hepatitis B virus (HBV) agent. The cytotoxicity of 1246TGG on HepG2.2.15 as well as HepG2 cells was determined by observing cytopathic effects, and the effects of 1246TGG on secretion of HBsAg and HBeAg in HepG2.2.15 cells were assayed by enzyme immunoassay. Results indicates that treatment with 1246TGG (6.25 MUg/mL, 3.13 MUg/mL), reduced both HBsAg and HBeAg levels in culture supernatant, yet the inhibitory effects tend to decline with the assay time. This study provides a basis for further investigation of the anti-HBV activity and possible mechanism of action of 1246TGG. PMID- 20960185 TI - Use of a cardioselective beta-blocker for pediatric patients with prolonged QT syndrome. AB - The data on the efficacy of atenolol for long-QT syndrome (LQTS) are controversial. This study aimed to evaluate the efficacy of atenolol for pediatric patients with LQTS. A retrospective observational study investigating all patients who had LQTS treated with atenolol at two institutions was performed. The study identified 57 patients (23 boys and 34 girls) with a mean QT corrected for heart rate (QTc) of 521 +/- 54 ms. The mean age of these patients at diagnosis was 9 +/- 6 years. Their clinical manifestations included no symptoms (n = 33, 58%), ventricular tachycardia (n = 10, 18%), syncope (n = 6, 10%), resuscitated sudden cardiac death (n = 4, 7%), atrioventricular block (n = 2, 4%), and bradycardia or presyncope (n = 2, 3%). Of the 57 patients, 13 (22%) had a family history of sudden death. The follow-up period was 5.4 +/- 4.5 years. Atenolol at a mean dose of 1.4 +/- 0.5 mg/kg/day was administered twice a day for all the patients. The mean maximum heart rate was 132 +/- 27 bpm on Holter monitors and 155 +/- 16 bpm on exercise treadmill tests, with medication doses titrated up to achieve a maximum heart rate lower than 150 bpm on both tests. During the follow-up period, one patient died (noncompliant with atenolol at the time of death), and the remaining patients had no sudden cardiac death events. Four patients (8%) had recurrent ventricular arrhythmias, three of whom received an implantable cardioverter defibrillator (all symptomatic at the time of diagnosis). For three patients (6%), it was necessary to rotate to a different beta-blocker because of side effects or inadequate heart rate control. Atenolol administered twice daily constitutes a valid and effective alternative for the treatment of pediatric patients with LQTS. PMID- 20960186 TI - Fontan "Ten Commandments" revisited and revised. AB - Choussat's "Ten Commandments," which describes the components of an ideal Fontan candidate, was first published in 1977. Despite the wisdom in these commandments, it is clear from a historic perspective that total compliance with all criteria does not necessarily portend excellent long-term survival. I believe the end point of the original commandments should be modified to include improvement in long-term survival. I suggest the following single commandment: "Thou Shalt Be Perfect." PMID- 20960187 TI - Resistance to the proapoptotic effects of interferon-gamma on melanoma cells used in patient-specific dendritic cell immunotherapy is associated with improved overall survival. AB - The use of whole cell tumor vaccines and various means of loading antigen onto dendritic cells have been under investigation for over a decade. Induction of apoptosis and the exposure of immune-stimulating proteins are thought to be beneficial for the use in immunotherapy protocols, but conclusive evidence in the clinical setting has been lacking. Incubation of melanoma cell lines with interferon-gamma (IFN-gamma) increased phosphatidylserine and calreticulin exposure, but not in the IFN-gamma-resistant cell line Lu-1205. Short-term autologous melanoma cell lines used for loading dendritic cells for immunotherapy showed differential response to the pro-apoptotic effects of IFN-gamma. These IFN gamma-treated tumor cells (TCs) were irradiated and used for loading antigen for dendritic cell therapy. A log-rank comparison of survival for patients whose TCs were found to be either sensitive (upregulated phosphatidylserine and calreticulin) or insensitive to IFN-gamma revealed a strongly significant correlation to progression-free (p = 0.003) and overall survival (p = 0.002) favorably in those patients whose cell lines were resistant to the proapoptotic effect of IFN-gamma. These results suggest that the use of IFN-gamma in anti melanoma dendritic cell-based immunotherapy may only be beneficial when the cells do not undergo apoptosis in response to IFN-gamma and support the contention that the use of some apoptotic cells in vaccines may be detrimental. PMID- 20960188 TI - Receptor desensitization and blockade of the suppressive effects of prostaglandin E(2) and adenosine on the cytotoxic activity of human melanoma-infiltrating T lymphocytes. AB - Previous studies document that PGE(2) and adenosine suppress production of inflammatory cytokines. The present study demonstrates for the first time that (1) PGE(2) and 2-chloroadenosine (CADO; a stable analog of adenosine) directly inhibit the cytolytic function of human tumor-infiltrating lymphocytes (TILs); (2) the combination PGE(2) and CADO have additive suppressive effects; and (3) the cooperative immunosuppressive actions of PGE(2) and CADO are mediated via EP2 receptors (EP2Rs) and A(2A) receptors (A(2A)Rs) and are due to amplification of cAMP production, activation of protein kinase A (PKA) and T cell receptor (TCR) inhibitor Csk leading to inhibition of Lck, ZAP-70 and Akt phosphorylation. (4) During ex vivo expansion, TILs undergo three stages of differentiation converting from TILs with high cytotoxic activity and relative resistance to combined EP2R/A(2A)R suppression (stage I) to TILs retaining high cytotoxicity and gaining sensitivity to combined suppression (stage II) and then to TILS that are less cytotoxic and very sensitive to combined suppression (stage III). (5) Finally, we find that pretreatment of TILs with non-inhibitory concentrations of EP2R agonists (such as PGE(2) or butaprost) or A(2A)R agonists (such as CADO or CGS21680) increases their cytotoxic activity and induces resistance to EP2R and A(2A)R inhibitory signaling (cross-resistance) due to homologous and heterologous desensitization and internalization of EP2Rs and A(2A)Rs, thus preventing their inhibitory signaling. We conclude that inducing resistance of TILs to the suppressive effects of PGE(2) and adenosine in the tumor microenvironment could represent a novel strategy for improving the efficacy of adoptive immunotherapy. PMID- 20960190 TI - Secondary central nervous system (CNS) involvement in patients with diffuse large B-cell lymphoma: a therapeutic dilemma. AB - Secondary central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL) includes an isolated CNS relapse or CNS involvement with systemic disease progression. This rare but fatal clinical problem still remains a therapeutic dilemma in the management of DLBCL. However, there are limited data about its treatment outcome. In this study, we gathered 73 cases with secondary CNS involvement of DLBCL from 11 hospitals in Korea. The data were retrospectively compared according to the status of systemic disease (isolated vs. combined CNS involvement) and the use of high-dose methotrexate treatment (HD MTX). Twenty-nine patients showed isolated CNS involvement while 44 had combined CNS involvement with systemic relapse or progression. Thirty-three cases (45.2%) occurred within 6 months from the initial diagnosis, and the majority of these were associated with systemic disease relapse or progression (n = 27). In isolated CNS involvement, HD MTX resulted in fewer treatment failures (3/11) than the other treatments such as other salvage chemotherapy and/or radiotherapy/intraventricular chemotherapy (14/15). However, neither HD MTX nor other treatments were effective at reducing the treatment failure rate in combined CNS involvement (8/10 and 23/30, respectively). Thus, isolated CNS involvement had a better survival than combined involvement (P = 0.008), but systemic disease progression was the main cause of death in combined as well as isolated CNS involvement. In conclusion, the prognosis of secondary CNS involvement was dismal even after intensive chemotherapy using HD MTX. Further research focusing on the development of an optimal treatment strategy is warranted. PMID- 20960191 TI - Meta-analysis of neutropenia or leukopenia as a prognostic factor in patients with malignant disease undergoing chemotherapy. AB - PURPOSE: We performed a systematic review and meta-analysis to determine the impact of neutropenia or leukopenia experienced during chemotherapy on survival. METHODS: Eligible studies included prospective or retrospective analyses that evaluated neutropenia or leukopenia as a prognostic factor for overall survival or disease-free survival. Statistical analyses were conducted to calculate a summary hazard ratio and 95% confidence interval (CI) using random-effects or fixed-effects models based on the heterogeneity of the included studies. RESULTS: Thirteen trials were selected for the meta-analysis, with a total of 9,528 patients. The hazard ratio of death was 0.69 (95% CI, 0.64-0.75) for patients with higher-grade neutropenia or leukopenia compared to patients with lower-grade or lack of cytopenia. Our analysis was also stratified by statistical method (any statistical method to decrease lead-time bias; time-varying analysis or landmark analysis), but no differences were observed. CONCLUSIONS: Our results indicate that neutropenia or leukopenia experienced during chemotherapy is associated with improved survival in patients with advanced cancer or hematological malignancies undergoing chemotherapy. Future prospective analyses designed to investigate the potential impact of chemotherapy dose adjustment coupled with monitoring of neutropenia or leukopenia on survival are warranted. PMID- 20960189 TI - Modified vaccinia Ankara expressing survivin combined with gemcitabine generates specific antitumor effects in a murine pancreatic carcinoma model. AB - Survivin is overexpressed by 70-80% of pancreatic cancers, and is associated with resistance to chemotherapy and a poor prognosis. Gemcitabine has been a standard treatment for patients with advanced pancreatic cancer for a decade. Recent reports have demonstrated that gemcitabine treatment attenuates the tumor suppressive environment by eliminating CD11b(+)/Gr-1(+) myeloid-derived suppressor cells (MDSCs). We hypothesize that a cancer vaccine targeting survivin can achieve enhanced efficacy when combined with gemcitabine. In this study, we tested this hypothesis using modified vaccinia Ankara (MVA) expressing full length murine survivin. The poorly immunogenic mouse pancreas adenocarcinoma cell line, Pan02, which expresses murine survivin and is syngeneic to C57BL/6, was used for this study. Immunization with MVA-survivin resulted in a modest therapeutic antitumor effect on established Pan02 tumors. When administered with gemcitabine, MVA-survivin immunization resulted in significant tumor regression and prolonged survival. The enhanced vaccine efficacy was associated with decreased CD11b(+)/Gr-1(+) MDSCs. To analyze the survivin-specific immune response to MVA-survivin immunization, we utilized a peptide library of 15mers with 11 residues overlapping from full-length murine survivin. Splenocytes from mice immunized with MVA-survivin produced intracellular gamma-interferon in response to in vitro stimulation with the overlapping peptide library. Increased survivin-specific CD8(+) T cells that specifically recognized the Pan02 tumor line were seen in mice treated with MVA-survivin and gemcitabine. These data suggest that vaccination with MVA-survivin in combination with gemcitabine represents an attractive strategy to overcome tumor-induced peripheral immune tolerance, and this effect has potential for clinical benefit in pancreatic cancer. PMID- 20960192 TI - A prospective phase II study of 2-methoxyestradiol administered in combination with bevacizumab in patients with metastatic carcinoid tumors. AB - PURPOSE: Angiogenesis inhibition has emerged as a potentially promising treatment strategy for neuroendocrine tumors. 2-Methoxyestradiol (2ME2; Panzem((r))) is a natural derivative of estradiol with demonstrated anti-angiogenic activity in animal models. We performed a prospective, phase II study of 2ME2, administered in combination with bevacizumab, in patients with advanced carcinoid tumors. METHODS: Thirty-one patients with advanced carcinoid tumors were treated with 2ME2, administered orally at a dose of 1,000 mg four times daily. Patients also received bevacizumab 5 mg/kg intravenously every 2 weeks. Patients were observed for evidence of toxicity, tumor response, and survival. RESULTS: The combination of 2ME2 and bevacizumab was relatively easily tolerated and was associated with anticipated toxicities for these two agents. No confirmed radiologic responses (by RECIST) were observed. However, 68% of the radiologically evaluable patients experienced at least some degree of tumor reduction, and the median progression free survival (PFS) time was 11.3 months. CONCLUSION: 2ME2 and bevacizumab can be safely administered to patients with advanced carcinoid tumors. While major tumor regression was not observed with this regimen, the encouraging median progression free survival time suggests that this regimen has some degree of antitumor activity and supports the further investigation of angiogenesis inhibitors in this disease. PMID- 20960193 TI - [On taking over editorship]. PMID- 20960194 TI - [Differential diagnostics of hereditary colorectal cancer syndromes. The role of pathology]. AB - One third of colorectal carcinomas (CRC) show familial clustering of which about 5% have a monogenetic trait. Distinction between disease with and without polyposis, tumor histology and tumor spectrum in a given patient are all of diagnostic relevance. Familial adenomatous polyposis (FAP) underlies approximately 1% of CRC characterized by rapidly forming (>100) adenomas. In contrast to these about 2%-3% of CRC have a hereditary background without polyposis (HNPCC). This is the only hereditary tumour syndrome to date for which a tissue-based molecular screening test is available. Accordingly, expression analysis of mismatch repair genes (MSH2, MSH6 and MLH1, PMS2) is performed first. In the case of an equivocal result with no complete loss of expression testing of microsatellite instability (MSI) is added. In contrast to the other diseases MYH associated polyposis (MAP) follows a recessive trait with polyp numbers usually between 15-30 adenomas and should be distinguished from attenuated forms of FAP with <100 polyps in the differential diagnosis. In the case of suspected familial cancer syndrome genetic counseling is warranted in order to decide ultimately whether there is an indication for genetic testing (evidence of a germ-line mutation). PMID- 20960195 TI - [Multiple endocrine neoplasia type I]. AB - Multiple endocrine neoplasia type I (MEN1) is a rare hereditary cancer syndrome, which is manifested as a variety of endocrine and non-endocrine tumours and lesions caused by specific germline mutations of the MEN1 gene, a tumour suppressor gene. The detection of these germline mutations allows the early identification of affected, possibly still asymptomatic patients. The combined use of genetic and clinical tools for the diagnosis of MEN1-associated tumours substantially improves both the course of the disease and the quality of life of affected patients. This review summarizes the relevant morphological and clinical features of MEN1-associated endocrine and non-endocrine neoplasms and lesions. PMID- 20960196 TI - [Multiple endocrine neoplasia type 2]. AB - Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited cancer syndrome with the major components medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. Due to the clinical course three distinct subtypes are distinguished, MEN 2A, MEN 2B and familial medullary thyroid carcinoma. The disease is caused by germ-line mutations of the RET proto oncogene and the localization of these mutations correlates with the onset of the development of medullary thyroid carcinoma, which is crucial for the clinical course and outcome of the disease. It therefore has a substantial influence on the clinical management of the affected patients and their relatives. This review summarizes the morphology and clinic of MEN 2-associated tumors and their respective precursor lesions. PMID- 20960197 TI - [Hereditary renal cell carcinomas]. AB - Renal cell carcinomas occur in several hereditary tumor syndromes. These renal tumors frequently have a specific histopathological appearance which can be a sign for a hereditary cause of the disease. The genetic alterations responsible for most of these tumor syndromes were identified in recent years. Interestingly, renal cell carcinomas show specific histopathological features in each of the hereditary renal cancer syndromes. Clear cell and often cystic renal cell carcinomas occur in von Hippel-Lindau syndrome (VHL), while oncocytomas and chromophobe renal cell carcinomas are found in the Birt-Hugg-Dube syndrome, often also as hybrid tumors. Well differentiated papillary carcinomas (Type 1 according to the WHO) are found in the hereditary papillary renal cell carcinoma (HPRC). In contrast, poorly diffentiated papillary renal cell carcinomas (Type 2 according to the WHO) occur in combination with leiomyomas and leiomyosarcomas of the skin and uterus in hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC). The various genetic causes for these hereditary tumor syndromes open up new therapeutic possibilities, some of which are already being investigated in clinical studies. PMID- 20960198 TI - [Hereditary bone tumors]. AB - Familial diseases leading to bone tumor formation are rare. They are mainly caused by genetic alterations of cell cycle constituent genes, such as retinoblastoma syndrome (RB1) and Li-Fraumeni syndrome (p53), of genes involved in growth-regulating transcriptional cascades, such as enchondromatosis (PTHR1) and multiple hereditary exostoses (EXT1, EXT2) or of genes maintaining chromosomal stability, such as Rothmund-Thomson (RECQL4), Werner (WRN) and Bloom syndromes (BLM). This leads to multiple benign bone tumors, which may undergo secondary malignant transformation (enchondromatosis: enchondromas, multiple hereditary exostoses: osteochondromas) or bone sarcomas, mainly osteosarcomas, such as primary (Li-Fraumeni, Rothmund-Thomson, Werner and Bloom syndromes) or secondary manifestations (retinoblastoma syndrome) of the underlying disease. Some of these lesions also carry an increased risk for developing additional malignant diseases. In contrast to sporadically occurring similar tumors, differences in manifestation in time, topography or histology may be present which can aid in the correct recognition of the underlying syndrome. PMID- 20960199 TI - [Skin tumors as marker lesions for tumor syndromes]. AB - A number of hereditary tumor syndromes are associated with characteristic dermal neoplasms and knowledge and early diagnosis of these lesions may facilitate the diagnostic of the underlying syndrome. These syndromes include Muir-Torre syndrome, associated with cystic sebaceomas, Cowden syndrome, associated with multiple tricholemmomas, Carney complex associated with multiple superficial angiomyxomas, Birt-Hogg-Dube syndrome associated with multiple fibrofolliculomas, tuberous sclerosis associated with multiple facial angiofibromas and so-called Koenen tumors, patients with renal cell cancer associated with pilar leiomyomatosis and uterine leiomyomas, Gardner syndrome associated with Gardner fibromas and nevoid basal cell carcinoma associated with multiple basal cell carcinomas in young patients. PMID- 20960201 TI - Simultaneous isolation of pure and intact chloroplasts and mitochondria from moss as the basis for sub-cellular proteomics. AB - The moss Physcomitrella patens is increasingly being used as a model for plant systems biology studies. While genomic and transcriptomic resources are in place, tools and experimental conditions for proteomic studies need to be developed. In the present study we describe a rapid and efficient protocol for the simultaneous isolation of chloroplasts and mitochondria from moss protonema. Routinely, 60-100 MUg mitochondrial and 3-5 mg chloroplast proteins, respectively, were obtained from 20 g fresh weight of green moss tissue. Using 14 plant compartment marker antibodies derived from seed plant and algal protein sequences, respectively, the evolutionary conservation of the compartment marker proteins in the moss was demonstrated and purity and intactness of the extracted organelles confirmed. This isolation protocol and these validated compartment markers may serve as basis for sub-cellular proteomics in P. patens and other mosses. PMID- 20960202 TI - Fertile plant regeneration from cryopreserved calli of Oryza rufipogon Griff. and assessment of variation in the progeny of regenerated plants. AB - A protocol was developed for preservation of calli of Oryza rufipogon Griff. in liquid nitrogen (-196 degrees C). Optimal conditions for cryoprotection, pre freezing and post-thaw recovery of calli were identified. Cryoprotectant treatment at low temperature, pre-freezing in isopropanol bath for 1 h at -70 degrees C, rapid thawing and proper removal of cryoprotectant were critical for post-thaw survival. Genetic fidelity of the R1 plants obtained from cryopreserved, cryoprotectant-treated and untreated calli was assessed by phenotypic and molecular characterization. Comparison of phenotypic characters with seed-derived control plants showed no significant variation in the agronomic characters, but seed physical characters showed significant reduction in all the in vitro generated plants. Molecular data generated using 26 rice simple sequence repeat markers showed 4.78-7.25% change from control. Results suggested that both callus induction and cryopreservation induced heritable variations in O. rufipogon. In addition, a combination of phenotypic and molecular characterization using an appropriate marker provided better insight into genetic fidelity of recovered plants. PMID- 20960204 TI - Transgenic tobacco plants expressing atzA exhibit resistance and strong ability to degrade atrazine. AB - Atrazine chlorohydrolase (AtzA) catalyzes hydrolytic dechlorination and can be used in detoxification of atrazine, a herbicide widely employed in the control of broadleaf weeds. In this study, to investigate the potential use of transgenic tobacco plants for phytoremediation of atrazine, atzA genes from Pseudomonas sp. strain ADP and Arthrobacter strain AD1 were transferred into tobacco. Three and four transgenic lines, expressing atzA-ADP and atzA-AD1, respectively, were produced by Agrobacterium-mediated transformation. Molecular characterization including PCR, RT-PCR and Southern blot revealed that atzA was inserted into the tobacco genome and stably inherited by and expressed in the progenies. Seeds of the T(1) transgenic lines had a higher germination percentage and longer roots than the untransformed plants in the presence of 40-150 mg/l atrazine. The T(2) transgenic lines grew taller, gained more dry biomass, and had higher total chlorophyll content than the untransformed plants after growing in soil containing 1 or 2 mg/kg atrazine for 90 days. No atrazine residue remained in the soil in which the T(2) transgenic lines were grown (except 401), while, in the case of the untransformed plants, 0.91 mg (81.3%) and 1.66 mg (74.1%) of the atrazine still remained in the soil containing 1 and 2 mg/kg of atrazine, respectively, indicating that the transgenic lines could degrade atrazine effectively. The transgenic tobacco lines developed could be useful for phytoremediation of atrazine-contaminated soil and water. PMID- 20960205 TI - C4 protein of Beet severe curly top virus is a pathomorphogenetic factor in Arabidopsis. AB - The Curtovirus C4 protein is required for symptom development during infection of Arabidopsis. Transgenic Arabidopsis plants expressing C4 from either Beet curly top virus or Beet severe curly top virus produced phenotypes that were similar to symptoms seen during infection with wild-type viruses. The pseudosymptoms caused by C4 protein alone were novel to transgenic Arabidopsis and included bumpy trichomes, severe enations, disorientation of vascular bundles and stomata, swelling, callus-like structure formation, and twisted siliques. C4 induced abnormal cell division and altered cell fate in a variety of tissues depending on the C4 expression level. C4 protein expression increased the expression levels of cell-cycle-related genes CYCs, CDKs and PCNA, and suppressed ICK1 and the retinoblastoma-related gene RBR1, resulting in activation of host cell division. These results suggest that the Curtovirus C4 proteins are involved actively in host cell-cycle regulation to recruit host factors for virus replication and symptom development. PMID- 20960203 TI - Nucleo-cytoplasmic transport of proteins and RNA in plants. AB - Transport of macromolecules between the nucleus and the cytoplasm is an essential necessity in eukaryotic cells, since the nuclear envelope separates transcription from translation. In the past few years, an increasing number of components of the plant nuclear transport machinery have been characterised. This progress, although far from being completed, confirmed that the general characteristics of nuclear transport are conserved between plants and other organisms. However, plant-specific components were also identified. Interestingly, several mutants in genes encoding components of the plant nuclear transport machinery were investigated, revealing differential sensitivity of plant-specific pathways to impaired nuclear transport. These findings attracted attention towards plant specific cargoes that are transported over the nuclear envelope, unravelling connections between nuclear transport and components of signalling and developmental pathways. The current state of research in plants is summarised in comparison to yeast and vertebrate systems, and special emphasis is given to plant nuclear transport mutants. PMID- 20960206 TI - Development, characterization, and cross-species/genera transferability of SSR markers for rubber tree (Hevea brasiliensis). AB - Genomic simple sequence repeat (SSR) markers are particularly valuable in studies of genetic diversity, evolution, genetic linkage map construction, quantitative trait loci tagging, and marker-assisted selection because of their multi-allelic nature, reproducibility, co-dominant inheritance, high abundance, and extensive genome coverage. The traditional methods of SSR marker development, such as genomic-SSR hybrid screening and microsatellite enrichment, have the disadvantages of high cost and complex operation. The selectively amplified microsatellite method is less costly and highly efficient as well as being simple and convenient. In this study, 252 sequences with SSRs were cloned from the rubber tree (Hevea brasiliensis) genome from which 258 SSR loci were obtained. The average repeat number was six. There were only 10 (3.9%) mononucleotide, trinucleotide, and pentanucleotide repeats, whereas the remaining 248 (96.1%) were dinucleotide repeats, including 128 (49.6%) GT/CA repeats, 118 (45.7%) GA/CT repeats, and 2 (0.8%) AT/TA repeats. A total of 126 primer pairs (see ESM) were successfully designed of which 36 primer pairs generated polymorphic products from 12 accessions of the cultivated species, 4 related species, and 3 species of the family Euphorbiaceae. In addition, investigations based on four genomic SSRs (GAR4, ACR22, CTR25, and GTR28) by cloning and sequencing provided evidence for cross-species/genera applicability, and homologous sequences were obtained from the rubber tree and Euphorbiaceae. Further analysis about the variation of the flanking regions of the four markers was carried out. PMID- 20960207 TI - Role of surgical resection in colorectal lung metastases: analysis of 137 patients. AB - PURPOSE: The aim of this study is to investigate clinicopathologic characteristics and to identify prognostic factors in patients undergoing pulmonary metastasectomy for colorectal carcinoma. METHODS: This study is a single-institution retrospective study of 137 consecutive patients who underwent 158 pulmonary resections for metastatic colorectal carcinoma between January 1989 and June 2008. RESULTS: Median disease-free interval between colorectal resection and pulmonary metastasectomy was 35.6 months (range, 0.6 to 154.3 months). No perioperative deaths occurred. Follow-up was 100% complete and mean follow-up was 41.6 +/- 27.6 months. Median survival was 36.2 months (range, 4.6 to 126 months). Overall 5- and 10-year survival rates were 55.4% and 30.8%, respectively, after pulmonary metastasectomy. At univariate analysis of patient survival, number of lung metastases (p = 0.002), disease-free interval of more than 24 month (p = 0.013), and absence of residual tumor (p = 0.024) were significant prognostic factors. At multivariate analysis, presence of solitary lung metastasis and disease-free interval of more than 24 months remained significant prognostic factors. There was no significant difference in the 5-year survival for 121 patients undergoing single thoracotomy compared with 16 patients undergoing repeated resection(s) for recurrent colorectal lung metastasis (55.1% vs 59.5%; p = 0.79). Nor was the presence of hepatic metastasis associated with lower outcome (p = 0.77). CONCLUSIONS: Disease-free interval and number of metastases are the most significant prognostic factors for survival after pulmonary metastasectomy for colorectal carcinoma. Recurrent pulmonary disease can benefit from repeated resection. Prior hepatectomy for liver involvement does not influence survival. PMID- 20960208 TI - Neoadjuvant chemotherapy affects staging of colorectal liver metastasis--a comparison of PET, CT and intraoperative ultrasound. AB - PURPOSE: Surgery for colorectal liver metastasis facilitates long-term survival, and neoadjuvant chemotherapy improves resectability but may also alter staging accuracy. The aim of this study was to evaluate the effects of neoadjuvant chemotherapy on the efficacy of positron emission tomography (PET), PET-computed tomography (CT), CT and intraoperative ultrasound (IUS) in the detection of liver metastasis. METHODS: Between January 2007 and January 2010, 34 patients with resectable colorectal liver metastasis were included in this retrospective analysis. Seventeen patients had received neoadjuvant chemotherapy. PET or PET CT, CT or magnetic resonance imaging (MRI) and IUS were performed in all patients. Sensitivity, specificity, positive predictive value and negative predictive value were analysed. Histopathological examination of the resected specimens served as standard reference. RESULTS: A total of 109 liver segments were resected, of which 50 showed no metastatic involvement (45.9%). For patients without systemic chemotherapy, sensitivities for PET, CT/MRI and IUS were 92%, 64% and 100% respectively as compared with 63%, 65% and 94% for patients after neoadjuvant chemotherapy in a segment-based analysis. For PET, standardised uptake values were decreased by 3.9 in 10 patients after chemotherapy whereas lesion diameters were similar (3.0 vs. 3.2 cm). Additional metastases were detected by IUS in seven patients resulting in a change of operative procedure in 20.6%. CONCLUSION: Staging accuracy of colorectal liver metastasis is influenced by neoadjuvant chemotherapy. For PET, decreased tumour metabolism rather than downsizing may account for a drop in sensitivity after neoadjuvant chemotherapy. IUS is critical to avoid incomplete resections. PMID- 20960209 TI - Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion. AB - The signal transducer and activator of transcription 3 (STAT3) contributes to cardioprotection by ischemic pre- and postconditioning. Mitochondria are central elements of cardioprotective signaling, most likely by delaying mitochondrial permeability transition pore (MPTP) opening, and STAT3 has recently been identified in mitochondria. We now characterized the mitochondrial localization of STAT3 and its impact on respiration and MPTP opening. STAT3 was mainly present in the matrix of subsarcolemmal and interfibrillar cardiomyocyte mitochondria. STAT1, but not STAT5 was also detected in mitochondria under physiological conditions. ADP-stimulated respiration was reduced in mitochondria from mice with a cardiomyocyte-specific deletion of STAT3 (STAT3-KO) versus wildtypes and in rat mitochondria treated with the STAT3 inhibitor Stattic (STAT3 inhibitory compound, 6-Nitrobenzo[b]thiophene 1,1-dioxide). Mitochondria from STAT3-KO mice and Stattic-treated rat mitochondria tolerated less calcium until MPTP opening occurred. STAT3 co-immunoprecipitated with cyclophilin D, the target of the cardioprotective agent and MPTP inhibitor cyclosporine A (CsA). However, CsA reduced infarct size to a similar extent in wildtype and STAT3-KO mice in vivo. Thus, STAT3 possibly contributes to cardioprotection by stimulation of respiration and inhibition of MPTP opening. PMID- 20960210 TI - 13915*G DNA polymorphism associated with lactase persistence in Africa interacts with Oct-1. AB - Lactase gene expression declines with aging (lactase non-persistence) in the majority of humans worldwide. Lactase persistence is a heritable autosomal dominant condition and has been strongly correlated with several single nucleotide polymorphisms (SNPs) located ~14-kb upstream (-13907, -13910 and 13915) of the lactase gene in different ethnic populations. In contrast to the 13907*G and -13910*T SNPs, the -13915*G SNP was previously believed not to interact with Oct-1. In the present study, however, Oct-1 is shown to interact with the -13915*G SNP region DNA sequence by EMSAs and gel supershift. In addition, Oct-1 is capable of enhancing promoter activity of a lactase promoter reporter construct harboring the 13915*G SNP sequence in cell culture. Oct-1 binding to the -13907 to -13915 SNP region therefore remains a candidate interaction involved in lactase persistence. PMID- 20960211 TI - The Balneology paradox. PMID- 20960213 TI - Rab32 and the remodeling of the imaginal midgut in Helicoverpa armigera. AB - Midgut remodeling is a complex physiological process in holometabolous insects. During midgut remodeling, the larval midgut is decomposed by apoptosis or autophagy during metamorphosis, and the degraded larval midgut is partially absorbed as nutrients by the imaginal midgut for its formation. The molecular mechanism involved in this process is not clear. Here, we found that a Rab protein, which we have named HaRab32, is related to the organogenesis of insect imaginal midgut. Results show that HaRab32 is up-regulated in epidermis and midgut during metamorphosis. Its expression could be up-regulated by 20E. Immunohistochemistry shows Rab32 is distributed in the epithelium of the imaginal midgut during metamorphosis. Knockdown of HaRab32 by RNA interference disturbs the formation of the imaginal midgut. These data imply HaRab32 plays important roles in midgut remodeling by participating in the imaginal midgut formation. PMID- 20960212 TI - Early- and advanced non-enzymatic glycation in diabetic vascular complications: the search for therapeutics. AB - Cardiovascular disease is a common complication of diabetes and the leading cause of death among people with diabetes. Because of the huge premature morbidity and mortality associated with diabetes, prevention of vascular complications is a key issue. Although the exact mechanism by which vascular damage occurs in diabetes in not fully understood, numerous studies support the hypothesis of a causal relationship of non-enzymatic glycation with vascular complications. In this review, data which point to an important role of Amadori-modified glycated proteins and advanced glycation endproducts in vascular disease are surveyed. Because of the potential role of early- and advanced non-enzymatic glycation in vascular complications, we also described recent developments of pharmacological inhibitors that inhibit the formation of these glycated products or the biological consequences of glycation and thereby retard the development of vascular complications in diabetes. PMID- 20960214 TI - Characteristics of scar margin dynamic with time based on multiphoton microscopy. AB - Scar margins dynamic with time were quantitatively characterized using multiphoton microscopy (MPM). 2D large-area and 3D focused images of elastin and collagen at scar margins were obtained to extract quantitative parameters. An obvious boundary was observed at the scar margin, showing altered morphological patterns of elastin and collagen on both sides. Content alteration of elastin and collagen between the two sides of boundary were defined to characterize scar margins from different individuals. The statistical results from 15 normal scar samples strongly demonstrated that content alteration degree of elastin and collagen had decreasing tendency with the increase of patient age or scar duration, consistent with the fact of normal scars regressing spontaneously over time. It indicated that alteration degree can potentially serve as quantitative indicators to examine wound healing and scar progression over time. With the advent of clinical portable multiphoton endoscopes, the MPM technique can be applied in tracking scar formation and progression in vivo by examination of scar margin. PMID- 20960215 TI - Effects of Er:YAG laser treatments on surface roughness of base metal alloys. AB - We investigated the effects of different Er:YAG laser treatments on the surface roughness of base metal alloys. A total of 36 specimens were prepared of two base metal alloys (Wiron 99, Bellabond plus). The surfaces of the specimens were standardized by gradual wet grinding with 320-, 600-, 800- and 1,000-grit silicon carbide paper for 10 s each on a grinding machine at 300 rpm. Specimens of each alloy were randomly divided into six groups (n = 6) comprising a control group (group C), a group sandblasted with Al(2)O(3) powder at 60 psi for 10 s through a nozzle at a distance of 10 mm (group S), and four Er:YAG laser (Fotona AT) treatment groups. The laser treatment groups were as follows: 500 mJ, 10 Hz, 100 MUs (group 500MSP); 500 mJ, 10 Hz, 300 MUs (group 500SP); 400 mJ, 10 Hz, 100 MUs (group 400MSP); and 400 mJ, 10 Hz, 300 MUs (group 400SP). Surface roughness measurements (Ra) were performed using a profilometer. The data were analysed by two-way ANOVA, and mean values were compared using Tukey's HSD test (alpha = 0.05). According to the two-way ANOVA results, the base metal alloys and interaction between base metal alloy and surface treatment were not statistically significant different (p > 0.05), the surface treatments were significantly different (p < 0.0001). For the two base metal alloy groups, no significant differences were observed among the control, 400MSP, and 400SP groups (p = 0.912), and these groups demonstrated the lowest Ra values. The highest Ra value was observed in group S (p < 0.05). Er:YAG laser treatment at 400 and 500 mJ/10 Hz is not an alternative method for surface roughening of base metal alloys. PMID- 20960216 TI - Expression and functions of myo-inositol monophosphatase family genes in seed development of Arabidopsis. AB - Myo-inositol monophosphatase (IMP) catalyzes the dephosphorylation of myo inositol 3-phosphate in the last step of myo-inositol biosynthesis. IMP is also important in phosphate metabolism and is required for the biosynthesis of cell wall polysaccharides, phytic acid, and phosphatidylinositol. In Arabidopsis, IMP is encoded by VTC4. There are, however, two additional IMP candidate genes, IMPL1 and IMPL2, which have not yet been elucidated. In our genetic studies of Arabidopsis IMP genes, only the loss-of-function mutant impl2 showed embryonic lethality at the globular stage. All IMP genes were expressed in a similar manner both in the vegetative and reproductive organs. In developing seeds, expression of IMP genes was not coupled with the expression of the genes encoding myo inositol phosphate synthases, which supply the substrate for IMPs in the de novo synthesis pathway. Instead, expression of IMP genes was correlated with expression of the gene for myo-inositol polyphosphate 1-phosphatase (SAL1), which is involved in the myo-inositol salvage pathway, suggesting a possible salvage pathway role in seed development. Moreover, the partial rescue of the impl2 phenotype by histidine application implies that IMPL2 is also involved in histidine biosynthesis during embryo development. PMID- 20960217 TI - IL-17A promotes transdifferentiation of mouse myoblast cells (C2C12) into adipocytes by increasing the expression of peroxisome proliferator-activated receptor gamma through CAAT/enhancer binding protein beta signaling. AB - PURPOSE OF WORK: helper 17 T (Th17) effector cells are a recently identified Th subset and possess a unique property that distinguishes them from Th1 and Th2 subsets. The functional role of Th17 effector cells involves inflammatory responses, including autoimmunity and infection of specific pathogens. Therefore, IL-17A and its receptors may play a key role in determining the progression of certain inflammatory reactions. However, the relationship between IL-17A and adipogenesis has not yet been examined. Therefore, in this study, the effect of IL-17A on the adipogenic transdifferentiation of mouse myoblast (C2C12) cells was examined. CAAT/enhancer binding-protein beta (C/EPBbeta) signaling through the IL 17A receptor promoted adipogenic transdifferentiation of myoblast cells by activating peroxisome proliferator-activated receptor gamma (PPARgamma). These results will advance our understanding of the physiological function of IL-17A in myoblasts during inflammation, as well as the relationship between adipogenesis and inflammation. PMID- 20960218 TI - H(2) synthesis from pentoses and biomass in Thermotoga spp. AB - We have investigated H(2) production on glucose, xylose, arabinose, and glycerol in Thermotoga maritima and T. neapolitana. Both species metabolised all sugars with hydrogen yields of 2.7-3.8 mol mol(-1) sugar. Both pentoses were at least comparable to glucose with respect to their qualities as substrates for hydrogen production, while glycerol was not metabolised by either species. Glycerol was also not metabolised by T. elfii. We also demonstrated that T. neapolitana can use wet oxidised wheat straws, in which most sugars are stored in glycoside polymers, for growth and efficient hydrogen production, while glucose, xylose and arabinose are consumed in parallel. PMID- 20960219 TI - Surfactant-free poly(lactide-co-glycolide) honeycomb films for tissue engineering: relating solvent, monomer ratio and humidity to scaffold structure. AB - One-step surfactant-free, water-droplet templating has been developed as a fabrication method for a poly(lactide-co-glycolide) (PLGA) film that can be used as a model to investigate the relationship between solvent, monomer ratio, polymer concentration and humidity on its structure. The resulting material is a honeycomb-structured film. Formation of this structure was highly sensitive to solvent, monomer ratio, polymer concentration and humidity. Surfactant-free, water-droplet templating thus allows investigation of fabrication parameters and that PLGA monomer ratio selection is important for scaffold structure but not for MG63 cell attachment and proliferation. PMID- 20960220 TI - Identification of glycolaldehyde as the key inhibitor of bioethanol fermentation by yeast and genome-wide analysis of its toxicity. AB - Degradation of lignocellulose with pressurised hot water is an efficient method of bioethanol production. However, the resultant solution inhibits ethanol fermentation by Saccharomyces cerevisiae. Here, we first report that glycolaldehyde, which is formed when lignocellulose is treated with pressurised hot water, inhibits ethanol fermentation. The final concentration of glycolaldehyde formed by the treatment of lignocellulose with pressurised hot water ranges from 1 to 24 M, and 1-10 mM glycolaldehyde was sufficient to inhibit fermentation. This result indicates that glycolaldehyde is one of the main substances responsible for inhibiting fermentation after pressurised hot water degradation of lignocellulose. Genome-wide screening of S. cerevisiae revealed that genes encoding alcohol dehydrogenase, methylglyoxal reductase, polysomes, and the ubiquitin ligase complex are required for glycolaldehyde tolerance. These novel findings will provide new perspectives on breeding yeast for bioethanol production from biomass treated with pressurised hot water. PMID- 20960221 TI - Over-expression of microRNA169 confers enhanced drought tolerance to tomato. AB - Plant miRNA regulates multiple developmental and physiological processes, including drought responses. We found that the accumulation of Sly-miR169 in tomato (Solanum lycopersicum) was induced by drought stress. Consequently, Sly miR169 targets, namely, three nuclear factor Y subunit genes (SlNF-YA1/2/3) and one multidrug resistance-associated protein gene (SlMRP1), were significantly down-regulated by drought stress. Constitutive over-expression of a miR169 family member, Sly-miR169c, in tomato plant can efficiently down-regulate the transcripts of the target genes. Compared with non-transgenic plants, transgenic plants over-expressing Sly-miR169c displayed reduced stomatal opening, decreased transpiration rate, lowered leaf water loss, and enhanced drought tolerance. Our study is the first to provide evidence that the Sly-miR169c negatively regulates stomatal movement in tomato drought responses. PMID- 20960222 TI - Synthesis and characterization of a novel chitosan based E. coli cytosine deaminase nanocomposite for potential application in prodrug enzyme therapy. AB - Cytosine deaminase is a non-mammalian enzyme of widespread interest for prodrug enzyme therapy due to its ability to convert prodrug 5-fluorocytosine into anticancer drug 5-fluorouracil. Cytosine deaminase enzyme has been purified to homogeneity from E. coli K-12 MTCC 1302 strain. K(m) values for cytosine and 5 fluorocytosine were found to be 0.26 mM and 1.82 mM, respectively. We developed a chitosan-entrapped cytosine deaminase nanocomposite. Atomic force microscopy and transmission electron microscopy images showed an elongated sphere shape nanocomposite with an average size of 80 nm diameter. Fourier transform infrared spectroscopy and X-ray diffraction results confirmed gel formation and entrapment of cytosine deaminase within the nanocomposite. Sustained release of cytosine deaminase from the nanocomposite up to one week depicted its potential implication in prodrug inducted enzyme therapy. PMID- 20960223 TI - Origins of functional nucleotide polymorphisms in a major quantitative trait locus, qLTG3-1, controlling low-temperature germinability in rice. AB - qLTG3-1 is a major quantitative trait locus (QTL) controlling tolerance to low temperature at the seed germination stage (termed low-temperature germinability) in rice using a population derived from the cross between Italica Livorno from Italy and Hayamasari from Japan. Map-based cloning identified that qLTG3-1 encodes a protein of unknown function. The molecular identification of this major QTL could make it possible to identify allelic variation and favorable alleles for rice breeding programs. The present study examined the identification of qLTG3-1 alleles and their distribution among 62 landraces of Asian cultivated rice (Oryza sativa L.) collected from 19 different countries, termed the rice core collection. In the coding region, a single non-synonymous substitution and 3 in-frame insertion/deletion polymorphisms (indels) were detected. The almost completely conserved protein alignment of qLTG3-1 was also identified among 5 Oryza species, suggesting that the function of qLTG3-1 is critical for seed germination or for rice growth by pleiotropic effects of the gene. The functional nucleotide polymorphisms (FNPs), a 71-bp deletion found in Hayamasari and an amino acid substitution found in Nipponbare, was identified in varieties from Japan. These alleles with FNPs might be adapted to rice cultivation in specific local conditions. The present results may contribute to the utilization of favorable alleles of qLTG3-1 for the improvement of low-temperature germinability in rice breeding programs. PMID- 20960224 TI - Cytotoxic effects of permethrin in oocytes of Rhipicephalus sanguineus (Acari: Ixodidae) fully engorged females: I. Direct or indirect action of the acaricide in germ cells? AB - Given the wide use of synthetic chemicals to control ticks, this study evaluated the effects of the permethrin pyrethroid on oocytes of Rhipicephalus sanguineus fully engorged females in order to examine whether this compound, in addition to the proven neurotoxic effect, also acts directly on germ cells. The results revealed that permethrin effectively inhibits and/or interrupts the reproductive process of R. sanguineus. Exposed oocytes exhibited prominent structural changes such as altered shape of cells and germ vesicle (oocyte nucleus), cytoplasmic vacuolation, and decrease of yolk granules. The composition of the latter, however, was not altered. These findings confirm those already reported by Roma et al. (Food Chem Toxicol 48:825-830, 2010) demonstrating that permethrin acts on germ cells of R. sanguineus via direct absorption from the hemolymph by pedicel cells, or by the oocyte plasmic membrane. On the other hand, these results contradict studies reporting that acaricides act exclusively on the nervous systems of ticks and that all the changes in other organs are a result from the indirect action of these chemical compounds, because blocking of the nervous system would compromise the normal metabolism of other organs (dependent on sensory information). PMID- 20960225 TI - Integration of MR images with electroanatomical maps: feasibility and utility in guiding left ventricular substrate mapping. AB - PURPOSE: The purpose of the study is to evaluate the feasibility and utility of magnetic resonance (MR) image and electroanatomic (EA) maps integration in guiding detailed left ventricle (LV) anatomical and substrate mapping, identifying the most accurate registration strategy. METHODS: Twenty-five patients with dilated ischemic or non-ischemic cardiomyopathy were enrolled. We first verified the feasibility and accuracy of EA mapping and MR image integration using four different strategies (15 patients). Different EA maps were performed according to the strategy in exam: aortic map, collected from the descending portion of the arch to the ascending one; partial or complete LV map, reconstructed with a minimum of 40 widely distributed points or 200 points, respectively. We then evaluated the utility in LV substrate mapping of the most accurate integration method identified (ten patients). RESULTS: Strategy III, based on aortic map and a partial LV map, allowed us to obtain an accurate integration with MR images of aorta and LV with a lower number of EA LV points; we therefore used this strategy during phase II of the study. Both mean LV end diastolic volume and long- and short-axis LV end diastolic diameters obtained by MR were not significantly different compared with Carto measurements. Eighty eight percent of the segments with transmural/subendocardial scar detected by delayed enhanced MR were localized on bipolar voltage maps projected on MR integrated images. CONCLUSION: This study shows that integration strategy III represents the optimal registration method. Its clinical utility consists on guiding the catheter roving inside the chamber, mapping all areas of the LV and optimizing scar reconstruction. PMID- 20960226 TI - Periodontal disease may associate with breast cancer. AB - The main purpose was to evaluate the association between periodontal disease and the incidence of breast cancer in a prospective study of 3273 randomly selected subjects aged 30-40 years at baseline. Breast cancer incidence was registered from 1985 to 2001 according to the WHO International Classification of Diseases criteria. At baseline, 1676 individuals also underwent a clinical oral examination (Group A) whereas 1597 subjects were not clinically examined but were registered (Group B). The associations between breast cancer, periodontal disease, and missing molars were determined using multiple logistic regression models with several background variables and known risk factors for cancer. In total 26 subjects in group A and 15 subjects in group B had breast cancer. The incidence of breast cancer was 1.75% in subjects who had periodontal disease and/or any missing molars, and 0 in subjects who had periodontal disease but had no missing molars. For periodontally healthy subjects with no missing teeth the breast cancer incidence was 1%. For group B the respective incidence was 0.94%. Female gender (odds ratio (OR) 13.08) and missing any molar in the mandible (OR 2.36) were explanatory variables for breast cancer. Of the subjects with periodontal disease and any missing molars in the mandible 5.5% had breast cancer in comparison to 0.5% of the subjects who had periodontal disease but no missing molars in the mandible (P < 0.02). Chronic periodontal disease indicated by missing molars seemed to associate statistically with breast cancer. PMID- 20960227 TI - Genetic variation in the androgen estrogen conversion pathway in relation to breast cancer prognosticators. AB - Genetic variation in the androgen-to-estrogen conversion pathway has been shown to be associated with risk of breast cancer and, in particular, with estrogen receptor (ER) positive tumours. We aimed at studying how the genetic alterations, which have been identified for risk, are associated with breast cancer prognosticators, with a prior hypothesis that, in general, hormone-related breast cancers have a better prognosis than non-hormone-related breast cancers. Association between tagging SNPs in genes involved in estrogen metabolism and patient's lymph node status, tumour size and histological grade were estimated in a sample of 1569 Swedish breast cancer patients. Polymorphisms in CYP19A1, which have previously been linked to breast cancer risk, are shown to be associated with breast cancer prognosticators. The strongest association was observed for rs4646, with histological grade. The common allele of rs4646, which has been associated with increased breast cancer risk, was associated with low histological grade and small tumour size (P = 0.001 and 0.015; 1-sided, respectively). We also found evidence that SNP rs7167936 is associated with histological grade and tumour size (P = 0.010 and 0.005; 1-sided, respectively). We show that rs4646 and rs7167936 are associated with histological grade even amongst only ER-positive tumours (P = 0.008 and 0.011; 1-sided, respectively). Our results provide new evidence that CYP19A1 is involved in both breast cancer risk and prognosis. PMID- 20960228 TI - Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. AB - Three mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT) predominate among high risk breast ovarian cancer Ashkenazi Jewish families, with few "private" mutations described. Additionally, the spectrum of BRCA1 and BRCA2 germline mutations among high risk Jewish non Ashkenazi and non Jewish Israelis is undetermined. Genotyping by exon-specific sequencing or heteroduplex analysis using enhanced mismatch mutation analysis was applied to 250 high risk, predominantly cancer affected, unrelated Israeli women of Ashkenazi (n = 72), non Ashkenazi (n = 90), Moslem (n = 45), Christian Arabs (n = 21), Druze (n = 17), and non Jewish Caucasians (n = 5). All Jewish women were prescreened and did not harbor any of the predominant BRCA1 or BRCA2 Jewish mutations. Age at diagnosis of breast cancer (median +/- SD) (n = 219) was 40.1 +/- 11.7, 45.6 +/- 10.7, 38.7 +/- 9.2, 45.5 +/- 11.4 +/- and 40.7 +/- 8.1 years for Ashkenazi, non Ashkenazi, Moslem, Christian, and Druze participants, respectively. For ovarian cancer (n = 19) the mean ages were 45.75 +/- 8.2, 57.9 +/- 10.1, 54 +/- 8, 70 +/- 0, and 72 +/- 0 for these origins, respectively. Overall, 22 (8.8%) participants carried 19 clearly pathogenic mutations-10 BRCA1 and 9 BRCA2 (3 novel): 3 in Ashkenazim, 6 in 8 non-Ashkenazim, 6 in 7 Moslems, 2 in Druze, and 2 in non Jewish Caucasians. Only three mutations (c.1991del4, C61G, A1708E) were detected in 2 seemingly unrelated families of Moslem and non- Ashkenazi origins. There were no inactivating mutations among 55 Ashkenazi high risk breast cancer only families. In conclusion, there are no predominant recurring germline mutations in BRCA1 or BRCA2 genes among ethnically diverse Jewish and non Jewish high risk families in Israel. PMID- 20960229 TI - Benefits of early and prolonged fulvestrant treatment in 848 postmenopausal advanced breast cancer patients. AB - Response to fulvestrant and survival in postmenopausal hormone-sensitive advanced breast cancer was investigated within a non-randomized, In-Practice Evaluation Program, with the aim of optimizing treatment decisions. 848 patients (median age 64 years; 52% co-morbidity; 78% prior palliative therapy; median 4 prior regimens) received monthly fulvestrant injections (250 mg/month) and were followed-up three-monthly for 9 months. Clinical benefit (PFS >= 24 weeks) occurred in 532/848 (62.7%); stable disease (SD) in 627/848 patients (74%), including 62 complete and 177 partial responses. Best response was delayed in 115 patients. Estimated 9-month overall survival (OS) was 89%; 9-month event-free survival (EFS) was 71%. Indicators of disease aggressiveness affected response and survival, but number of fulvestrant cycles was the key OS and EFS determinant. The patients with SD at 3 months benefitted from continued fulvestrant. Excluding deaths, 7 serious adverse events occurred (none attributable to fulvestrant). No new or unexpected safety issues arose; 90% of the patients and physicians rated fulvestrant tolerability as "very good" or "good". In the largest prospective, fulvestrant-treated cohort to date, advanced breast cancer patients achieving SD or better after 3 months of treatment gained survival benefit by prolonging fulvestrant therapy-independent of disease and treatment history. PMID- 20960230 TI - The flow synthesis of heterocycles for natural product and medicinal chemistry applications. AB - This article represents an overview of recent research from the Innovative Technology Centre in the field of flow chemistry which was presented at the FROST2 meeting in Budapest in October 2009. After a short introduction of this rapidly expanding field, we discuss some of our results with a main focus on the synthesis of heterocyclic compounds which we use in various natural product and medicinal chemistry programmes. PMID- 20960231 TI - Cardiovascular disease in end-stage renal disease: the challenge of assessing and managing cardiac disease in dialysis patients. AB - Cardiovascular disease (CVD) is the leading cause of mortality in end-stage renal disease (ESRD), approximating a 10- to 20-fold higher risk of death in dialysis patients than in the general population. Despite this, dialysis patients often undergo fewer investigations, receive less invasive procedures, and are prescribed fewer medications compared with age-matched non-ESRD patients. A lack of randomized control trials for evidence-based treatment strategies in this population may explain some of these discrepancies, but there is concern that an attitude of "therapeutic nihilism" may be impacting on the medical care of these patients. In this review, we will explore CVD in the ESRD population. Specifically, we will try to address the following issues in patients with ESRD: (1) mechanisms of CVD, (2) cardiac evaluation and the role of coronary revascularization with percutaneous or coronary artery bypass procedures, and (3) cardiac pharmacotherapy use. PMID- 20960232 TI - A comparison of different methods for the determination of glomerular filtration rate in elderly patients with chronic renal failure. AB - OBJECTIVE: The aim of the present study was to asses the accuracy of prediction equations in elderly patients with advanced renal disease (ARD). PATIENTS AND METHODS: Twenty-three elderly patients (>60 years) with chronic kidney disease (CKD) stages 3-5 underwent technetium-99 m-diethylenetriaminepentaacetic acid (Tc 99m-DTPA) radionuclide measurement of glomerular filtration rate (GFR). To predict GFR, estimation formulas [Cockcroft-Gault (CG), 6-variable Modification of Diet in Renal Disease (6-var-MDRD) and the corrected 24-hour creatinine clearance (24-h CCL) method] were used. Estimates of bias and precision were obtained to compare prediction equations of GFR with standard radionuclide measurement. RESULTS: In the present study, all the prediction equations overestimated the GFR measured with the radionuclide method. Six-var-MDRD and 24 h CCL methods correlated better with standard radionuclide measurements compared to the CG formula (Rc of 0.53 and 0.50 vs. 0.41, respectively) as for GFR prediction, but they were still insufficiently accurate. CONCLUSION: Glomerular filtration rate prediction equations correlate poorly with standard radionuclide measurements and their use may lead to late initialization of renal replacement therapy in elderly patients with ARD. Therefore, measurement by standard radionuclide method (Tc-99m-DTPA) is recommended to accurately assess GFR in elderly patients with ARD. PMID- 20960233 TI - Congenital rock and a hard place: unicuspid aortic valve with sinus of valsalva aneurysm. AB - Cardiac CT angiography (CTA) is an ideal tool to investigate possible cardiac malformations. In this case, careful planning of the CTA acquisition and reconstruction provided high resolution images of cardiac anatomy revealing 2 extremely rare coexisting congenital defects; a unicuspid aortic valve (UAV) and sinus of Valsalva aneurysm (SVA). Detailed planning of CTA acquisition reconstruction protocols is essential in obtaining necessary information for clinical decision-making strategies and interventions in the patients with suspected cardiac anomalies. PMID- 20960234 TI - Temporal variations of skin pigmentation in C57BL/6 mice affect optical bioluminescence quantitation. AB - PURPOSE: Depilation-induced skin pigmentation in C57Bl/6 mice is a known occurrence, and presents a unique problem for quantitative optical imaging of small animals, especially for bioluminescence. The work reported here quantitatively investigated the optical attenuation of bioluminescent light due to melanin pigmentation in the skin of transgenic C57Bl/6 mice, modified such that luciferase expression is under the transcription control of a physiologically and pharmacologically inducible gene. PROCEDURE: Both in vivo and ex vivo experiments were performed to track bioluminescence signal attenuation through different stages of the mouse hair growth cycle. Simultaneous reflectance measurements were collected in vivo to estimate melanin levels. RESULTS: Biological variability of skin pigmentation was found to dramatically affect collected bioluminescent signal emerging through the skin of the mice. When compared to signal through skin with no pigmentation, the signal through highly pigmented skin was attenuated an average of 90%. Positive correlation was found between reflectance measurements and bioluminescence signal loss. A correction scheme is proposed based on this correlation, but signal variation due to non melanin scattering and absorption sources introduce significant errors. Advanced spectral reflectance analysis will be necessary to develop a more reliable correction method in the future. CONCLUSION: Skin pigmentation is a significant variable in bioluminescent imaging, and should be considered in experimental design and implementation for longitudinal studies, and especially when sensitivity to small signal changes, or differences among animals, is required. PMID- 20960235 TI - A portable fluorescence camera for testing surgical specimens in the operating room: description and early evaluation. AB - PURPOSE: Clinical translation of novel optical probes requires testing of human specimens ex vivo to ensure efficacy. However, it may be difficult to remove human tissue from the operating room due to regulatory/privacy issues. Therefore, we designed a portable fluorescence camera to test targeted optical imaging probes on human specimens in the operating room. PROCEDURES: A compact benchtop fluorescence camera was designed and built in-house. A mouse xenograft model of ovarian cancer with an activatable imaging probe based on rhodamine green was used to test the device. Comparison was made to commercially available imaging systems. RESULTS: The prototype camera produced images comparable to images acquired with commercially available, non-portable imaging systems. CONCLUSION: We demonstrate the feasibility of a specimen-based portable fluorescence camera for use in the operating room. Its small size ensures that tissue excised from patients can be tested promptly for fluorescence within the operating room environment, thus expediting the testing of novel imaging probes. PMID- 20960236 TI - Where it's at really matters: in situ in vivo vascular endothelial growth factor spatially correlates with electron paramagnetic resonance pO2 images in tumors of living mice. AB - PURPOSE: Tumor microenvironments show remarkable tumor pO(2) heterogeneity, as seen in prior EPR pO(2) images (EPROI). pO(2) correlation with hypoxia response proteins is frustrated by large rapid pO(2) changes with position. PROCEDURES: To overcome this limitation, biopsies stereotactically located in the EPROI were used to explore the relationship between vascular endothelial growth factor A (VEGF) concentrations in living mouse tumors and the local EPROI pO(2). RESULTS: Quantitative ELISA VEGF concentrations correlated (p = 0.0068 to 0.019) with mean pO(2), median pO(2), and the fraction of voxels in the biopsy volume with pO(2) less than 3, 6, and 10 Torr. CONCLUSIONS: This validates EPROI hypoxic fractions at the molecular level and provides a new paradigm for the assessment of the relationship, in vivo, between hypoxia and hypoxia response proteins. When translated to human subjects, this will enhance understanding of human tumor pathophysiology and cancer response to therapy. PMID- 20960237 TI - Pandemic H1N1 (2009) and renal failure: the experience of the Irish national tertiary referral centre. AB - INTRODUCTION: H1N1 influenza A, was first described in April 2009. A significant cohort of patients from this outbreak developed acute respiratory distress syndrome or pneumonia. H1N1 has since been transmitted across the world. Little has been described on the renal complications of this illness. METHODS: A retrospective review of all patients admitted to our institution with H1N1 infection was carried out from July to November 2009. Renal biochemistry, need for renal replacement therapy and hospital outcome was recorded. RESULTS: Thirty four patients with H1N1 were admitted. Average length of admission was 10 days (3 84). Eleven patients (32%) developed acute kidney injury (AKI) as defined by the RIFLE criteria (creatinine range 120-610). Four patients required renal replacement therapy, for a range of 10-52 days. Seven patients developed AKI that responded to volume resuscitation. The commonest cause of AKI was sepsis with acute tubular necrosis. CONCLUSION: This study highlights the significance and frequency of renal complications associated with this illness. PMID- 20960238 TI - Aberrant protein structure and diseases of the brain. AB - Extracellular fibrous amyloid deposits or intracellular inclusion bodies containing abnormal protein aggregates are pathological hallmarks of several neurodegenerative disorders and it has been hotly debated whether these aberrant protein structures merely occur as a consequence of disease or actually participate in a pathogenic cascade which culminates in neural dysfunction and death. Here, we review the role of aberrant protein structure in the two most common neurodegenerative disorders: Alzheimer's disease and Parkinson's disease and in two rare familial dementias, familial British dementia and familial Danish dementia. We also discuss possible mechanisms by which aberrant protein structures may mediate disease and the therapeutic opportunities this knowledge offers. PMID- 20960239 TI - Novel Cellulase Screening and Optimal Production from the Wood Decaying Xylariaceae: Daldinia Species. AB - The highest cellulases production from Daldinia caldariorum 263 (D-263) was found among Daldinia eschscholzii and Daldinia childiae. Three cellulases, one xylanase and one beta-glucosidase of the molecular weights 55, 43, 34, 30, and 105 kDa, respectively, were determined by zymographic sodium dodecyl sulfate polyacrylamide gel electrophoresis. From the N-terminal sequencing, the major cellulase CelA belonging to glycosyl hydrolase family 5 was determined. By following an orthogonal experiment design (L9), factors affecting the cultivation of D. caldariorum 263 are ranked as medium composition > temperature > pH >= FP (%). The optimum cultivation conditions for obtaining the best FPase (600 mU/ml) at 72 h are 150 rpm, 35 degrees C, pH 7, 0.2% soy peptone and 0.5% alpha cellulose in minimal requirement medium. In comparison with Trichoderma reesei (ATCC26921) secreting 1,135 mU/ml of FPase after 6 days cultivation at pH 5, D. caldariorum 263 grew faster at 35 degrees C and produced the maximum FPase within 3 days at pH 7. PMID- 20960240 TI - Treatment of carotid artery disease: endarterectomy or angioplasty? AB - The management of carotid stenosis has enjoyed renewed interest in the neurological community in recent years due to the advent of endovascular approaches. In concert, progress in medical treatment of these patients has rekindled the debate regarding the best management of carotid stenosis overall, both for symptomatic and asymptomatic disease. For symptomatic carotid stenosis, the major decision required is choosing the type of intervention best suited for individual patients: carotid endarterectomy versus carotid artery stenting. For patients with asymptomatic carotid stenosis, intensive medical management has evolved significantly over the past decade to decrease the risk of ischemic stroke to match surgical intervention under most circumstances. This review will examine the supporting evidence for each intervention, and discuss the recent advances in medical and endovascular therapy that provide the data for a new era in clinical decision making. PMID- 20960241 TI - Meaning in life: is it a protective factor for adolescents' psychological health? AB - BACKGROUND: Searching for a coherent meaning in life has long been proposed to be a protective factor in adolescent development. PURPOSE: The present study aimed to examine meaning in life as a protective factor in a largely unstudied population: Romanian adolescents. Additionally, we sought to provide a novel, multidimensional assessment of several health-related variables (substance abuse, health risk behaviors, psychological health). Potential gender differences were explored regarding the role of life meaning in adolescent health. METHOD: Data were collected in 2006 from students enrolled in the secondary schools of the Middle Transylvanian Region, Romania (n = 1,977). Self-administered questionnaires were used as a method of data collection including items of life meaning and psychological health. RESULTS: Meaning in life played a protective role with regard to health risk behaviors except smoking and binge drinking. Among males, meaning in life was found to be correlated only to illicit drug and sedative use, whereas among females, meaning in life was associated with binge drinking, unsafe sex, and lack of exercise and diet control. Psychological health was strongly related to meaning in life. CONCLUSION: In Romanian adolescents, meaning in life is a protective factor against health risk behaviors and poor psychological health. PMID- 20960242 TI - Time course of ribosomal kinase activity during hindlimb unloading. PMID- 20960243 TI - Transcriptional factor ENY2 promotes recruitment of the THO complex to the hsp70 gene of Drosophila melanogaster. PMID- 20960244 TI - Theorem about electron energy in many-electron atoms in biological molecules. PMID- 20960245 TI - Different effects of alpha- and gamma-polymorphs of glycine on behavior of GC rats predisposed to catalepsy. PMID- 20960246 TI - Simulation of the PCR amplification as two-type-particle branching process. PMID- 20960247 TI - Mapping the interaction site between recombination proteins in yeast cells. PMID- 20960248 TI - Phosphonium reversible inhibitors of cholinesterases of different animals. PMID- 20960249 TI - Genotoxic effect of long-lived protein radicals in vivo generated by X-ray irradiation. PMID- 20960250 TI - Manganese as a potential marker of atherogenesis. PMID- 20960251 TI - Electrochemical shift of the carotenoid molecule absorption band as an indicator of processes of energy migration in the reaction center of Rhodobacter sphaeroides. PMID- 20960252 TI - Novel low-molecular-weight mimetics of the nerve growth factor. PMID- 20960253 TI - Study of functional interaction between GAGA-containing sites from promoter regions of heat shock genes hsp26 and hsp70 in the model system of Drosophila melanogaster white gene. PMID- 20960254 TI - Anti-EGFR-miniantibody-barnase immunoconjugate is highly toxic for human tumor cells. PMID- 20960255 TI - The choice of atomic charges calculation scheme in 3D-QSAR modelling of GSK-3beta inhibition by paullones. PMID- 20960256 TI - Application of induced double-stranded breaks for stabilization of transgenes in the genome. PMID- 20960257 TI - Steroids for the treatment of methimazole-induced severe cholestatic jaundice in a 74-year-old woman with type 2 diabetes. AB - Methimazole is a widely used antithyroid agent. Although methimazole is generally well tolerated, rare but severe cholestatic jaundice may occur. We described a 74 year-old woman who had a 10-year history of type 2 diabetes had developed severe jaundice and itching 1 month after receiving methimazole (10 mg tid) and propranolol (10 mg tid) for the treatment of hyperthyroidism. Clinical investigations revealed no evidence of any mechanical obstruction in the common bile duct or other obvious causes of hepatic injury, and the diagnosis methimazole-induced cholestasis was made on the basis of the temporal relationship between initiation of methimazole and onset of cholestasis. Methimazole was hence discontinued. However, the patient experienced a progressive worsening in cholestasis after receiving 2 weeks of ursodeoxycholic acid (UDCA) therapy. Prednisone therapy was then attempted. Liver function tests eventually improved with combination of glucocorticoids and ursodeoxycholic acid therapy. This case clearly showed that glucocorticoids could be a possible additional way of treatment for some cases of drug-induced cholestatic jaundice even in diabetic patients. PMID- 20960258 TI - Mutation analysis and serum FGF23 level in a patient with pulmonary alveolar microlithiasis. AB - Pulmonary alveolar microlithiasis (PAM) is a rare, hereditary disorder characterized by ectopic formation of calcium-phosphate microliths in the alveolar space. PAM has been reported to arise from inactivating mutations in SLC34A2, encoding a sodium-dependent phosphate co-transporter essential for phosphate transport in the lungs and small intestine. Serum levels of the phosphaturic hormone fibroblast growth factor-23 (FGF23) in PAM have not been determined. Our objectives were to investigate the genetic etiology and circulating level of FGF23 in a 50-year-old male with clinical characteristics of PAM and extra-pulmonary calcifications. The SLC34A2 and FGF23 genes were sequenced for mutations and serum FGF23 analyzed by ELISA. We found no disease causing mutations or single nucleotide polymorphisms in the genes investigated. Importantly, repeated measurements revealed undetectable or markedly low serum FGF23 (<3-11 RU/ml). Surprisingly, in the face of low serum FGF23, 1,25-dihydroxy vitamin D3 level was low-normal and parathyroid hormone mildly elevated. Total 24 h urinary excretion of phosphate and calcium were low, as was fractional urinary excretion of calcium. In contrast, fractional excretion of phosphate was above normal, likely due to elevated PTH. Collectively, PAM may be a polygenic disorder that arises from mutations other than in SLC34A2. The low FGF23 level in our PAM patient supports an intestinal-bone axis, leading to decreased FGF23 expression when intestinal phosphate absorption is compromised. PMID- 20960259 TI - Idiopathic unilateral adrenal hemorrhage in an elderly patient. AB - We report the case of an 85-year-old woman who has been undergoing treatment for hypertension but has not received anticoagulation therapy. The patient was admitted to our hospital for the evaluation of a right adrenal tumor (size, 10 * 9 cm2). Preoperative contrast-enhanced computed tomography and magnetic resonance imaging findings were indicative of adrenal hemorrhage (AH). Laboratory data revealed mild anemia but no adrenal dysfunction. The final pathological diagnosis was simply idiopathic adrenal hematoma. There is no case report of exactly idiopathic AH over 80 years old. We report an unusual case of idiopathic unilateral adrenal hematoma in an elderly patient. It is important to distinguish this benign lesion from a neoplasm and to consider idiopathic AH in an adrenal tumor during differential diagnosis in elderly patients who have not received anticoagulation therapy or suffered from trauma. PMID- 20960260 TI - Are endogenously lower serum thyroid hormones new predictors for thyroid malignancy in addition to higher serum thyrotropin? AB - It is well known that TSH plays a major role in the secretion of thyroid hormones, maintenance of thyroid specific gene expression, and gland growth. In this study, we aimed to evaluate association between tests of thyroid functions (fT3, fT4, TSH) and differentiated thyroid carcinoma. 441 patients operated for nodular goiter between 2005 and 2008 were analyzed. Thyroid functions were studied in the period of 1-30 days prior to surgery. In postoperative histopathological examination, differentiated thyroid carcinoma and benign thyroid disease were detected in 166 (37.6%) and 275 (62.4%) patients, respectively. Patients with thyroid malignancy had significantly lower serum fT3 (P = 0.001), lower fT4 (P = 0.022), and higher TSH levels (P < 0.001) compared to patients with benign disease, although all analytes were within the normal range. We subdivided by quartile serum fT3, fT4, and TSH in normal limits into three groups. The odds ratio (ORs) for the risk of thyroid cancer with a serum TSH between 0.63 and 1.67 MUIU/ml and 1.68-4.00 MUIU/ml, compared with a serum TSH between 0.40 and 0.62 MUIU/ml were calculated as 2.60 (95% CIs 1.49-4.54) and 6.50 (95% CIs 3.51-12.03), respectively. There was also a greater risk of thyroid cancer in patients with fT3 levels of 1.57-3.00 pg/ml, compared with patients with fT3 levels of 3.89-4.71 pg/ml (OR 2.95, 95% CIs 1.68-5.20). For fT4, OR for the risk of thyroid cancer between 0.85 and 1.17 ng/dl compared with 1.48-1.78 ng/dl was 2.14 (95% CIs 1.22-3.74). In conclusion, lower fT3, fT4, and higher TSH concentrations within normal limits were related with increased thyroid cancer independent from sex and nodule type. Particularly, the association between lower fT3, fT4 levels and a diagnosis of thyroid cancer is a novel finding. PMID- 20960261 TI - Concurrent bilateral pheochromocytoma and thoracic paraganglioma during pregnancy. AB - Although hypertension occurring during pregnancies is not uncommon and its prognosis is generally excellent, some of its unusual causes can lead to catastrophic consequences, especially in undiagnosed cases. Here, we report a pregnant woman who presented with hypertension in her early pregnancy. It was subsequently found to be caused by bilateral pheochromocytoma. After removal of both tumors, catecholamine levels unexpectedly and unexplainably remained elevated. At 23 weeks of gestation, the fetus was found dead in utero. After the fetal death, additional studies were performed and revealed a thoracic paraganglioma. To our knowledge, this is the first report of a case of three catecholamine-producing tumors occurring concurrently during a pregnancy. Genetic analysis helped identify this unprecedented condition; the patient harbored a heterozygous missense mutation c.482G>A in exon 3 of the VHL gene, indicating von Hippel-Lindau syndrome. Physicians who care for hypertensive pregnant patients should be aware of this condition as its diagnosis would probably lead to a better outcome. PMID- 20960262 TI - Proteasome activity correlates with male BMI and contributes to the differentiation of adipocyte in hADSC. AB - We have previously reported that 26S proteasome subunit mRNA expressions correlate with male body mass index (BMI). In this study, to investigate whether proteasome activities are correlated with BMI, we recruited 61 healthy young Japanese male subjects, measured proteasome activities in their plasma, and correlated them with their BMI and various metabolic factors. We found that among three different proteasome activities, chymotrypsin-like activity in plasma was positively correlated with BMI in healthy Japanese male subjects. Furthermore, we analyzed proteasome activity in vitro during the differentiation of human adipose derived stem cell (hADSC) into mature adipocytes. In the early stage of differentiation, proteasome activity was at its highest level, and proteasome inhibitor could inhibit hADSC adipocyte differentiation. Our findings suggest that proteasome is an important controlling factor for the development of obesity and adipogenesis. PMID- 20960263 TI - The relationship between aortic stiffness and left ventricular function in patients with Cushing's disease: aortic stiffness in Cushing's disease. AB - We aimed to investigate the aortic function and to evaluate the relationship between aortic stiffness and systolic and diastolic functions of the left ventricle in patients with Cushing's disease (CD). Fourteen women and one man with newly diagnosed CD, and 17 control cases were enrolled in this study. All subjects underwent echocardiography and systolic and diastolic aortic measurements were noted from M-mode aortic root. Aortic elastic parameters, aortic strain, and distensibility were calculated. Left ventricle functions were measured using echocardiography including, two-dimensional, M-mode, conventional Doppler, and tissue Doppler imaging. Aortic strain (7.4 +/- 1.9 vs. 12.3 +/- 2.4%; P < 0.001), and aortic distensibility (3.2 +/- 1.1 * 10-6 vs. 5.6 +/- 1.4 * 10-6 cm2 dyn-1; P < 0.001) were significantly decreased in patient group compared with control group. Mitral E velocity and the ratio of E/A were significantly lower and deceleration time of E was significantly prolonged in patients with CD. We also observed that patients with CD had markedly lower early diastolic myocardial peak velocity (Em) and Em/Am ratio and higher Tei index than in control group. Aortic elastic parameters are deranged in patients with CD and there is a significant correlation between left ventricular parameters determined by tissue Doppler echocardiography and aortic elastic parameters in these patients. We think that patients with CD should also be evaluated with aortic stiffness known to be an early marker for atherosclerosis. PMID- 20960264 TI - Japanese cases of acute onset diabetic ketosis without acidosis in the absence of glutamic acid decarboxylase autoantibody. AB - We report consecutive Japanese patients presented with acute onset diabetic ketosis who had negative glutamic acid decarboxylase autoantibody (GADAb) to clarify the clinical characteristics of them. A total of consecutive 1,296 in patients with newly diagnosed diabetes mellitus, who were admitted to our center from April 2003 to October 2008, were analyzed. Among them, 17 patients who presented with acute onset diabetic ketosis without acidosis, and found to be negative for GADAb, were included. They showed male preponderance (n = 15). Ten patients had history of excessive ingestion of sugar-containing soft drink. Patients who successfully withdrew insulin therapy by 6 months (n = 7) showed significantly higher insulin secretion capacity and higher body mass index at the time of diagnosis than those who continued insulin therapy at least for 6 months (n = 10). These findings suggest that some of Japanese patients who presented with acute onset diabetic ketosis and negative for GADAb share several clinical characteristics with atypical type 2 diabetes such as ketosis-prone diabetes and "soft-drink ketosis," but others do not. PMID- 20960265 TI - Testicular enlargement in a patient with a FSH-secreting pituitary adenoma. AB - Clinically non-functional pituitary adenomas are often derived from gonadotropin producing cells. However, gonadotropinomas causing elevated serum levels of follicle-stimulating hormone (FSH) and clinical signs of FSH hypersecretion are very rarely described. Our patient, a 56-year-old man, was referred to our clinic with signs of hypogonadism. Magnetic resonance imaging (MRI) and biochemical examinations showed a large pituitary adenoma and excessive levels of serum FSH. Clinical examination and ultrasound measurement revealed bilaterally enlarged testes. After pituitary surgery, serum FSH levels normalized and there was a decrease in testicular volume. This case suggests that supraphysiological levels of FSH from a gonadotropinoma can cause a clinically observable effect, i.e. testicular enlargement. This is in line with experimental studies showing biological effect of FSH from pituitary adenomas and previous occasional reports of ovarian hyperstimulation and testicular enlargement in patients with FSH secreting gonadotropinomas. PMID- 20960266 TI - Macroprolactinemia, like hyperprolactinemia, may promote platelet activation. AB - Insulin resistance, which provides a convenient milieu for platelet activation, has been closely associated with atherosclerotic disorders. Although it often accompanies hyperprolactinemia, findings conflict concerning its clinical impact in macroprolactinemia. In order to investigate the relationship between hyperprolactinemia and platelet activation evidenced by ADP-stimulated P-selectin expression on flow cytometry, we studied hyperprolactinemic, macroprolactinemic, and normoprolactinemic subjects. Thirty-four hyperprolactinemic and 44 age- and body mass index-matched euprolactinemic premenopausal women were included. They were matched regarding insulin sensitivity status, waist circumference, blood pressures, and plasma lipids. In order to detect macroprolactinemia among hyperprolactinemic cases, prolactin was measured before and after polyethylene glycol (PEG) precipitation in patients' sera. P-selectin expression was significantly higher in the hyperprolactinemic group (P =0.001), and 41.2% of them exhibited macroprolactinemia. Expression of P-selectin was comparable between the macroprolactin-negative (monomeric hyperprolactinemia; n = 20) and positive (n = 14) subgroups (P = 0.90). Both subgroups showed greater expression compared with normoprolactinemic controls (P = 0.014 and 0.005, respectively). Platelet activation accompanies the atherosclerotic disorders closely associated with insulin resistance. Among groups matched with regard to insulin-sensitivity markers, both monomeric hyperprolactinemia and macroprolactinemia appeared to promote platelet activation. PMID- 20960268 TI - Rosiglitazone improves pancreatic mitochondrial function in an animal model of dysglycemia: role of the insulin-like growth factor axis. AB - Thiazolidinediones (TZDs) improve insulin sensitivity and maintain beta cell mass. This study examined whether this effect is attributable to improved mitochondrial function in the pancreas and the potential involvement of the pancreatic insulin-like growth factor (IGF) axis in mediating this effect. Female Wistar rats were given either saline (vehicle) or nicotine (1 mg kg-1 day-1) during pregnancy and lactation. Following weaning, nicotine-exposed offspring were randomized to receive either vehicle or rosiglitazone (3 mg kg-1 day-1) until 26 weeks of age when serum and pancreas tissue were collected. The effect of rosiglitazone on nicotine-induced mitochondrial dysfunction was also examined in vitro. Fetal and neonatal nicotine exposure resulted in structural and functional mitochondrial deficits relative to saline controls. The nicotine induced mitochondrial defects were attenuated by postnatal rosiglitazone administration. A similar effect was observed in vitro; nicotine (25 ng/ml) inhibited beta cell mitochondrial function and co-treatment with rosiglitazone (1 MUM) restored enzyme activity to control levels. Fetal and neonatal nicotine exposure also altered key components of the adult pancreatic IGF axis, an effect that was not prevented by rosiglitazone treatment. Rosiglitazone treatment maintains mitochondrial structure and function in the pancreas of rats that are prone to diabetes, as well as mitochondrial function in beta cell culture. We propose that this may be an important part of the mechanism by which rosiglitazone improves beta cell mass and prevents diabetes in individuals with impaired glucose tolerance and/or impaired fasting glucose. The underlying mechanism through which rosiglitazone targets the mitochondria remains to be determined, but does not appear to involve the IGF axis. PMID- 20960269 TI - Epithelial progenitor 1, a novel factor associated with epithelial cell growth and differentiation. AB - The growth and renewal of epithelial tissue is a highly orchestrated and tightly regulated process occurring in different tissue types under a variety of circumstances. We have been studying the process of pancreatic regeneration in mice. We have identified a cell surface protein, named EP1, which is expressed on the duct epithelium during pancreatic regeneration. Whereas it is not detected in the pancreas of normal mice, it is found in the intestinal epithelium of normal adult mice, as well as during pancreatic repair following cerulein-induced destruction of the acinar tissue. The distinctive situations in which EP1 is expressed, all of which share in common epithelial cell growth in the gastrointestinal tract, suggest that EP1 is involved in the growth and renewal of epithelial tissues in both the intestine and the pancreas. PMID- 20960270 TI - The effect of the alendronate on OPG/RANKL system in differentiated primary human osteoblasts. AB - Alendronate is a well-established treatment for osteoporosis and suppresses bone resorption by a direct effect on osteoclasts and their precursors. The effect of alendronate on osteoclasts is produced, at least in part, by the receptor activator of nuclear factor kappaB ligand (RANKL) and the osteoprotegerin (OPG) synthesized by the osteoblasts. This study analyzes the effect of alendronate in cell viability, alkaline phosphatase (ALP) activity and RANKL and OPG expression in primary human osteoblasts (hOB). Alendronate at concentrations lower than 10-5 M did not have a toxic effect on hOB in vitro and did not modify the ALP activity at least for 72 h. Alendronate did not change OPG expression in basal, 10% fetal bovine serum (FBS), and vitamin D-treated cultures. Similar results were observed at the protein level. Unexpectedly, alendronate at 10-7 and 10-5 M concentrations increased the RANKL expression with the presence of vitamin D in differentiated hOB, and this induction of RANKL mRNA levels by alendronate was dose-dependent. However, this effect was not observed in basal and 10% FBS culture conditions. Thus, we conclude that alendronate does not affect the ALP activity and OPG gene expression in differentiated hOB, but may increase RANKL gene expression induced by vitamin D. PMID- 20960271 TI - Endogenous estrogen levels are associated with endothelial function in males independently of lipid levels. AB - Estrogens and androgens may play an important role in vascular health in both sexes. The aim of this study was to examine the relation of endogenous sex hormone levels with early markers of atherosclerosis in a cohort of apparently healthy males. 124 males (age 46.25 +/- 9.56) attending a preventive medicine program were examined for unrecognised features of the metabolic syndrome. Flow mediated dilatation (FMD) and intima-media thickness (IMT) of the common carotid artery were evaluated. Obesity parameters were recorded; estradiol, testosterone, SHBG, free testosterone, insulin, as well as glucose and lipid levels were measured. FMD was positively correlated with estradiol (r = 0.201, P = 0.041) and negatively with total cholesterol (r = -0.205, P = 0.022), low density lipoproteins (r = -0.232, P = 0.009), and triglyceride levels (r = -0.179, P = 0.046). In multivariate analysis, the association of FMD with estrogen was independent of BMI and lipid levels. No significant association between FMD and testosterone levels was found. Subjects with an increased mean IMT (> 0.73 mm, i.e., > 3rd tertile) had lower levels of free (P = 0.021) and bioavailable (P = 0.016) testosterone. In multivariate logistic regression analysis, this association was no longer significant when age or cholesterol levels were considered. Endogenous estrogen levels are associated with FMD, independently of age and lipid levels, showing a protective effect in middle-age male subjects. Circulating androgens are associated, although not independently, with structural changes such as the IMT of carotid artery; this effect is possibly influenced by lipid levels and age. PMID- 20960272 TI - Disease and gender-specific dysregulation of NGAL and MMP-9 in type 1 diabetes mellitus. AB - Neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of renal injury, can bind matrix metalloproteinase-9 (MMP-9) and inhibit its degradation, thereby sustaining MMP-9 proteolytic activity. MMP-9 is produced by renal podocytes, and podocyte MMP production can be modified by high ambient glucose levels. Moreover, dysregulation of MMP-9 activity, gene expression, or urine concentrations has been demonstrated in T2DM-associated nephropathy and in non-diabetic proteinuric renal diseases. Our objective was to determine whether NGAL/MMP-9 dysregulation might contribute to or serve as a biomarker of diabetic nephropathy in type 1 DM (T1DM). Plasma MMP-9, and urine NGAL and MMP-9 concentrations were measured in 121 T1DM and 55 control subjects and examined relative to indicators of glycemia, renal function, and degree of albuminuria. T1DM was associated with a significant increase in urinary excretion of both NGAL and MMP-9, and urine NGAL:Cr (NGAL corrected to urine creatinine) and urine MMP-9:Cr concentrations were highly correlated with each other. Both were also positively correlated with measurements of glycemic control and with albuminuria. Plasma MMP-9, urine MMP-9, and urine NGAL concentrations were significantly higher in females compared to males, and urine MMP-9:Cr concentrations displayed a menstrual cycle specific pattern. Increased urinary excretion of NGAL and MMP-9 supports a role for NGAL/MMP-9 dysregulation in renal dysfunction; moreover, gender-specific differences could support a gender contribution to pathological mechanisms or susceptibility for the development of renal complications in diabetes mellitus. PMID- 20960273 TI - Graves' disease and gene polymorphism of TNF-alpha, IL-2, IL-6, IL-12, and IFN gamma. AB - The role of genetic factors in the pathogenesis of Graves' disease (GD) is not clear. The purpose of this study was to investigate the association between single nucleotide polymorphisms in pro-inflammatory cytokine genes and GD in Iranian patients. A case-control hospital-based study was carried out on 107 GD patients and 140 healthy controls. Cytokine typing was performed by polymerase chain reaction with sequence-specific primers (PCR-SSP) assay. The allele and genotype frequencies of the following cytokine genes were determined: TNF-alpha ( 308A/G, -238A/G), IL-2 (-330T/G, +166G/T), IL-6 (-174C/G, A/G nt565), IL-12 ( 1188A/C), and IFN-gamma (UTR 5644A/T). The following alleles and genotypes were significantly overrepresented in patients: TNF-alpha -308A allele (P < 0.01) and AA genotype (P < 0.05), IL-2 -330G allele (P < 0.01) and GG genotype (P < 0.01), IL-6 -174C allele (P < 0.01) and CC genotype (P < 0.01), IL-12 -1188C allele (P < 0.01) and CC genotype (P < 0.01), IFN-gamma UTR5644T allele (P < 0.01) and TT genotype (P < 0.01). In conclusion, this is the first study to show a significant association between GD and IL-2 -330G, IL-12 -1188C, and IFN-gamma UTR 5644T alleles. Our results support the hypothesis that polymorphism in pro-inflammatory cytokines might be involved in predisposition to GD. PMID- 20960274 TI - Screening for associated autoimmune disorders in Polish patients with Addison's disease. AB - Autoimmune Addison's disease (AAD) is the main reason of primary adrenal failure. More than a half of patients display additional autoimmune conditions, which represent a considerable clinical concern. This study aimed to investigate the prevalence of concomitant autoimmune disorders in 85 Polish AAD patients (61 females, 24 males). Mean age at AAD onset was 34.6 +/- 12.6 years, significantly earlier in males (P < 0.001). Sixty-nine patients presented positive serum antibodies to 21-hydroxylase and shorter AAD duration than those with negative results (P = 0.027). Seventy-three subjects suffered from coexisting autoimmune disorders. Serum autoantibodies against thyreoperoxidase, thyroglobulin, TSH receptor, glutamic acid decarboxylase, insulin, tyrosine phosphatase-like protein IA2, parietal cell H(+)/K(+)-ATPase, intrinsic factor and tissue transglutaminase were detectable in 71.8, 41.2, 4.7, 21.0, 4.9, 2.5, 49.4, 12.0 and 3.5% of patients, respectively. Antinuclear antibodies were found in 12.5%. Thyroid autoimmunity was most common (46 subjects with lymphocytic thyroiditis, 19 with Graves' disease), followed by atrophic gastritis (29.4%), pernicious anaemia (11.8%), hypergonadotropic hypogonadism (8.2%), vitiligo (8.2%), type 1 diabetes (7.1%), celiac disease (3.5%) and alopecia (2.4%). Gender differences were observed only for thyroid autoimmunity. Current study confirms particular tendency of AAD patients to develop other autoimmune disorders. Active search for concomitant conditions is warranted to prevent serious complications. PMID- 20960275 TI - Does the dopamine transporter protein allele predict growth hormone testing results or response to growth hormone therapy? AB - Animal studies have shown dopamine transporter protein (DAT1) knock out mice are growth retarded and hyperactive. DAT1 has been researched in several human psychiatric studies with varying results regarding phenotype and DAT1 alleles. However, the relationship between DAT1 and short stature in humans has not been explored. Buccal swabs were collected from patients receiving growth hormone (GH) therapy and were genotyped for variable number tandem repeat (VNTR) by polymerase chain reaction. Forty subjects were included; twenty-three patients had the 10/10 DAT1 genotype and thirteen had the 9/10 genotype. Fifteen of the patients with the 10/10 genotype tested GH deficient. Seven patients with the 9/10 genotype tested GH sufficient. The linear growth rate during the first year of GH therapy was equivalent in both genotypes. In conclusion, polymorphisms in the DAT1 40 base pair (bp) VNTR genotype do not predict GH deficiency or response to GH therapy in short children. PMID- 20960276 TI - Effects of resveratrol on NO secretion stimulated by insulin and its dependence on SIRT1 in high glucose cultured endothelial cells. AB - To investigate the effects of resveratrol on the secretion of NO induced by insulin in high glucose cultured primary human umbilical vein endothelial cells (HUVEC). HUVEC were treated with 1 MUmol/l resveratrol for 24 h before cultured in high glucose medium for 48 h, then all cells were stimulated by 100 nmol/l insulin for 30 min. Method based on nitric acid reductase was used to analyze the NO contents in the supernatant. Cells were collected to analyze the expression of eNOS, endothelin-1, E-selectin, and SIRT1. In order to investigate the dependence of resveratrol on SIRT1, the effects of resveratrol on cells treated by SIRT1 siRNA were also examined. Compared with control cells, high glucose decreased the secretion of NO induced by insulin. Resveratrol treatment increased the expression of SIRT1 and the secretion of NO. After interfering the expression of SIRT1 using SIRT1 siRNA, the effects of resveratrol on the NO secretion induced by insulin was impaired. Resveratrol also counteracted other pro-atherosclerotic effects of high glucose, including the up-regulating roles of high glucose on the expression of endothelin-1 mRNA and E-selectin mRNA, and the down-regulating roles of high glucose on the expression of eNOS mRNA and the basal NO secretion without the stimulating of insulin. Resveratrol can improve the NO stimulating function of insulin in high glucose cultured HUVEC in SIRT1-dependent manner. Thus, our results imply that resveratrol may have the preventive roles of atherosclerosis in diabetic patients. PMID- 20960277 TI - Primary hyperparathyroidism in Taiwan: clinical features and prevalence in a single-center experience. AB - In Taiwan, urolithiasis remains a common manifestation of primary hyperparathyroidism (PHPT). We designed this study to estimate the prevalence of PHPT in asymptomatic adults and to assess the complications already present when the disease was diagnosed. In the first phase of the study, we retrospectively reviewed 50 patients diagnosed with surgically or biochemically proven PHPT between April 1995 and April 2007. In the second phase, we reviewed the records of 4,359 asymptomatic subjects who had undergone a health examination between August 2002 and January 2007. Of the 50 patients reviewed in the first phase, hypercalcemia was the presenting complication in 33 patients (64%) followed by symptomatic recurrent solitary urolithiasis in 10 patients (20%). Of the 43 patients who underwent urologic imaging, 29 (67%) had urolithiasis and 7 (16%) had nephrocalcinosis, indicating that urinary stone disease is common. In the second phase, 28 of the 4,359 asymptomatic adults (0.64%) were found to have hypercalcemia; of these 28, 4 (0.092%) were diagnosed with PHPT. In Taiwan, PHPT remains underdiagnosed, and complications manifest in most patients upon admission. Although still relatively uncommon, screening serum calcium levels helps diagnose PHPT at an asymptomatic stage. PMID- 20960278 TI - The herpes simplex virus type 1 infected cell protein 22. AB - As one of the immediate-early (IE) proteins of herpes simplex virus type 1 (HSV 1), ICP22 is a multifunctional viral regulator that localizes in the nucleus of infected cells. It is required in experimental animal systems and some nonhuman cell lines, but not in Vero or HEp-2 cells. ICP22 is extensively phosphorylated by viral and cellular kinases and nucleotidylylated by casein kinase II. It has been shown to be required for efficient expression of early (E) genes and a subset of late (L) genes. ICP22, in conjunction with the UL13 kinase, mediates the phosphorylation of RNA polymerase II. Both ICP22 and UL13 are required for the activation of cdc2, the degradation of cyclins A and B and the acquisition of a new cdc2 partner, the UL42 DNA polymerase processivity factor. The cdc2-UL42 complex mediates postranscriptional modification of topoisomerase IIalpha in an ICP22-dependent manner to promote L gene expression. In addition, ICP22 interacts with cdk9 in a Us3 kinase dependent fashion to phosphorylate RNA polymerase II. PMID- 20960279 TI - Detection of HPV types and neutralizing antibodies in women with genital warts in Tianjin City, China. AB - The serum samples and corresponding cervical swabs were collected from 50 women with genital warts from Tianjin city, China. The neutralizing antibodies against HPV-16, -18, -58, -45, -6 and -11 in serum samples were tested by using pseudovirus-based neutralization assays and HPV DNAs in cervical swabs were also tested by using a typing kit that can detect 21 types of HPV. The results revealed that 36% (18/50) of sera were positive for type-specific neutralizing antibodies with a titer range of 160-2560, of which 22%(11/50), 12%(6/50), 10%(5/50), 4%(2/50), 4%(2/50) and 2%(1/50) were against HPVs -6, -16, -18, -58, 45 and -11, respectively. Additionally, 60% (30/50) of samples were HPV DNA positive, in which the most common types detected were HPV-68(18%), HPV-16(14%), HPV-58(12%), HPV-33(8%) and HPV-6, HPV-11, HPV-18 and HPV-52 (6% each). The concordance between HPV DNA and corresponding neutralizing antibodies was 56% (28/50) with a significant difference (P<0.05). The full-length sequences of five HPV types (HPV -42, -52, -53, -58 and -68) were determined and exhibited 98%-100% identities with their reported genomes. The present data may have utility for investigating the natural history of HPV infection and promote the development of HPV vaccines. PMID- 20960280 TI - B cell epitopes within VP1 of type O foot-and-mouth disease virus for detection of viral antibodies. AB - In this study, the coding region of type O FMDV capsid protein VP1 and a series of codon optimized DNA sequences coding for VP1 amino acid residues 141-160 (epitope1), tandem repeat 200-213 (epitope2 (+2)) and the combination of two epitopes (epitope1-2) was genetically cloned into the prokaryotic expression vector pP(RO)ExHTb and pGEX4T-1, respectively. VP1 and the fused epitopes GST-E1, GST-E2 (+2) and GST-E1-2 were successfully solubly expressed in the cytoplasm of Escherichia coli and Western blot analysis demonstrated they retained antigenicity. Indirect VP1-ELISA and epitope ELISAs were subsequently developed to screen a panel of 80 field pig sera using LPB-ELISA as a standard test. For VP1-ELISA and all the epitope ELISAs, there were clear distinctions between the FMDV-positive and the FMDV-negative samples. Cross-reactions with pig sera positive to the viruses of swine vesicular disease virus that produce clinically indistinguishable syndromes in pigs or guinea pig antisera to FMDV strains of type A, C and Asia1 did not occur. The relative sensitivity and specificity for the GST-E1 ELISA, GST-E2 (+2), GST-E1-2 ELISA and VP1-ELISA in comparison with LPB-ELISA were 93.3% and 85.0%, 95.0% and 90%, 100% and 81.8%, 96.6% and 80.9% respectively. This study shows the potential use of the aforementioned epitopes as alternatives to the complex antigens used in current detection for antibody to FMDV structural proteins. PMID- 20960281 TI - Development of HBsAg-binding aptamers that bind HepG2.2.15 cells via HBV surface antigen. AB - Hepatitis B virus surface antigen (HBsAg), a specific antigen on the membrane of Hepatitis B virus (HBV)-infected cells, provides a perfect target for therapeutic drugs. The development of reagents with high affinity and specificity to the HBsAg is of great significance to the early-stage diagnosis and treatment of HBV infection. Herein, we report the selection of RNA aptamers that can specifically bind to HBsAg protein and HBsAg-positive hepatocytes. One high affinity aptamer, HBs-A22, was isolated from an initial 115 mer library of ~1.1 x 1015 random sequence RNA molecules using the SELEX procedure. The selected aptamer HBs-A22 bound specifically to hepatoma cell line HepG2.2.15 that expresses HBsAg but did not bind to HBsAg-devoid HepG2 cells. This is the first reported RNA aptamer which could bind to a HBV specific antigen. This newly isolated aptamer could be modified to deliver imaging, diagnostic, and therapeutic agents targeted at HBV infected cells. PMID- 20960282 TI - Immunogenicity of the spike glycoprotein of bat SARS-like coronavirus. AB - A group of SARS-like coronaviruses (SL-CoV) have been identified in horseshoe bats. Despite SL-CoVs and SARS-CoV share identical genome structure and high level sequence similarity, SL-CoV does not bind to the same cellular receptor as for SARS-CoV and the N-terminus of the S proteins only share 64% amino acid identity, suggesting there are fundamental differences between these two groups of coronaviruses. To gain insight into the basis of this difference, we established a recombinant adenovirus system expressing the S protein from SL-CoV (rAd-Rp3-S) to investigate its immune characterization. Our results showed that immunized mice generated strong humoral immune responses against the SL-CoV S protein. Moreover, a strong cellular immune response demonstrated by elevated IFN gamma and IL-6 levels was also observed in these mice. However, the induced antibody from these mice had weaker cross-reaction with the SARS-CoV S protein, and did not neutralize HIV pseudotyped with SARS-CoV S protein. These results demonstrated that the immunogenicity of the SL-CoV S protein is distinct from that of SARS-CoV, which may cause the immunological differences between human SARS-CoV and bat SL-CoV. Furthermore, the recombinant virus could serve as a potential vaccine candidate against bat SL-CoV infection. PMID- 20960283 TI - Serial expression of the truncated fragments of the nucleocapsid protein of CCHFV and identification of the epitope region. AB - The Crimean-congo hemorrhagic fever virus (CCHFV) is a geographically widespread fatal pathogen. Identification of the epitope regions of the virus is important for the diagnosis and epidemiological studies of CCHFV infections. In this study, expression vectors carrying series truncated fragments of the NP (nucleocapsid protein) gene from the S fragment of CCHFV strain YL04057 were constructed. The recombinant proteins were expressed in E.coli and purified for detection. The antigenic of the truncated fragments of NP was detected with a polyclonal serum (rabbit) and 2 monoclonal (mAbs) (14B7 and 43E5) against CCHFV by Western-blot analyses. The results showed that the three expressed constructs, which all contained the region 235AA to 305AA could be detected by mAbs polyclonal serum. The results suggest that region 235-305 aa of NP is a highly antigenic region and is highly conserved in the NP protein. PMID- 20960284 TI - Construction of mTNFR1shRNA plasmid and its biological effects on MHV-3 induced fulminant hepatitis in BALB/cJ mice. AB - Previous study on TNFR1-mediated hepatocyte apoptosis has been implicated in the development of fulminant viral hepatitis. To interfere with the potentially effective target, plasmid named p-mTNFR1shRNA complimentary to the sequence responsible for mTNFR1 was also constructed and further confirmed by sequence analysis. To investigate the effect of mTNFR1shRNA plasmid on mTNFR1 expression in vivo and the disease progress in MHV-3 induced fulminant hepatitis mice model. By hydrodynamic injection of mTNFR1shRNA plasmid, the survival rate of mice, hepatic pathological change were examined and compared between mice with/without mTNFR1shRNA plasmid intervention. The expression of mTNFR1 was detected by Real time PCR, immunohistochemistry staining. The mTNFR1shRNA plasmid significantly reduced mTNFR1 expression in vivo, markedly ameliorates inflammatory infiltration, prolonged the survival time period and elevated the survival rate from 0 up to 13.3% in Balb/cJ mice with MHV-3 induced fulminant hepatitis. This study was designed to explore the opportunity of RNA interference technique in inhibiting TNFR1 expression, which has been reported to be involved in the development of a variety of diseases including fulminant viral hepatitis and severe chronic hepatitis B. PMID- 20960285 TI - A novel RT-LAMP assay for rapid and simple detection of classical swine fever virus. AB - A simple and rapid assay for the detection of Classical swine fever virus (CSFV) was established using reverse transcription loop-mediated isothermal amplification (RT-LAMP). This study describes the amplification of the genomic RNA of CSFV under isothermal conditions (63 degrees C) within one hour, using a set of six primers (two outer primers, two inner primers and two loop primers). This RT-LAMP assay showed 100-fold higher sensitivity than the standard RT-PCR method and identified eighteen additional positive cases that were negative when tested by RT-PCR. This RT-LAMP was able to detect all the 13 strains of CSFV but not the BVDV. PRRSV. SIV. PRV-PCV, thus showed a good specificity. Products amplified by RT-LAMP can be visualized by agarose gel electrophoresis and in addition, either as a white precipitate at the bottom of the tube after a pulse spin or as a color change when dyed with SYBR Green I which are visible to the naked eye. Because RT-LAMP is low-cost and produces rapid results, it has the potential to be an excellent tool for CSFV surveillance in the field, especially in developing countries. PMID- 20960286 TI - Screening of a high growth influenza B virus strain in Vero cells. AB - Due to the insufficient supply of embryonated chicken eggs, the preparation of large quantities of inactivated influenza vaccines will require an alternative virus culture system after the emergence or reemergence of a pandemic influenza virus. The Vero cell is one of the ideal options since it was used for producing many kinds of human vaccines. However, most of the influenza viruses can not grow well in Vero cells. To develop a new influenza vaccine with Vero cells as a substrate, the virus needs to adapt to this cell substrate to maintain high growth characteristics. By serial passages in Vero cells, the B/Yunnan/2/2005va (B) strain was successfully adapted to Vero cells, with the hemagglutination titer (HAT) of the virus reaching 1:512. The high growth characteristic of this strain is stable up to 21 passages. The strain was identified by hemagglutination inhibition (HAI) test and sequencing respectively; the HA1 gene sequence of the virus was cloned and analyzed. The screening and establishment of high growth B virus provides an important tool for influenza vaccine production in Vero cells. PMID- 20960287 TI - An indirect ELISA of classical swine fever virus based on quadruple antigenic epitope peptide expressed in E.coli. AB - In this study, a synthesized quadruple antigenic epitope gene region of the classical swine fever virus (CSFV) E2 glycoprotein was expressed in E. coli to a obtain target protein. This target protein was used as a coating antigen to establish an indirect ELISA for specifically detecting anti-CSFV antibodies in serum samples from pigs. The P/N cut-off value of this assay was 1.92 by receiver operating characteristic curve (ROC) analysis based on 30 negative sera and 80 positive samples. The test gave 97.5% sensitivity and 96.7% specificity compared with the indirect hemagglutination (IHA) test. The inter-assay and intra-assay coefficients of variation (CVs) for 16 sera were both <=6.8%. No cross-reactivity between the coating antigen and anti-bovine viral diarrhoea virus (BVDV) antibodies was observed. PMID- 20960288 TI - The nucleolus and viral infection. AB - The nucleolus is a subnuclear structure of eukaryocytes. It was thought that nucleolus only participates in the biogenesis and processing of rRNA. However, more and more evidence shows that it has many other functions, such as tRNA precursor processing, stress sensing and it is also involved in gene silencing, senescence and cell cycle regulation. Here, we summarize the recent understandings about the nucleolar functions, the regulation of nucleolar localization of proteins and the role that the nucleolus plays in virus infection, in which some related studies of Herpes simplex virus type 1 (HSV-1) US11, UL24 and bovine herpesvirus-1 infected cell protein 27 (BICP27) carried out in our lab will also be included. PMID- 20960289 TI - Analysis of the cellular localization of herpes simplex virus 1 immediate-early protein ICP22. AB - Nuclear proteins often form punctiform structures, but the precise mechanism for this process is unknown. As a preliminary study, we investigated the aggregation of an HSV-1 immediate-early protein, infected-cell protein 22 (ICP22), in the nucleus by observing the localization of ICP22-EGFP fusion protein. Results showed that, in high-level expression conditions, ICP22-EGFP gradually concentrates in the nucleus, persists throughout the cell cycle without disaggregation even in the cell division phase, and is finally distributed to daughter cells. We subsequently constructed a mammalian cell expression system, which had tetracycline-dependent transcriptional regulators. Consequently, the location of ICP22-EGFP in the nucleus changed with distinct induction conditions. This suggests that the cellular location of ICP22 is also influenced by promoter regulation, in addition to its own structure. Our findings provide new clues for the investigation of transcriptional regulation of viral genes. In addition, the non-protease reporter system we constructed could be utilized to evaluate the role of internal ribosome entry sites (IRES) on transcriptional regulation. PMID- 20960290 TI - Establishment of an ELISA to detect Kaposi's sarcoma-associated herpesvirus using recombinant ORF73. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is causally related to Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and a proportion of cases of multicentric Castleman's disease (MCD). The ORF73 protein was cloned into pQE80L orf73 and expressed in E.coli and purified. The expressed recombinant ORF73 was identified by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS PAGE). A protein of about 27 kDa was expressed as expected. Western Blotting showed that the purified recombinant ORF73 reacted with KSHV positive serum. The immunogenicity of the recombinant ORF73 was further analysed by ELISA and the optimal conditions were determined. The ORF73 ELISA was used to compare the KSHV seroprevalence between Hubei and Xinjiang Han people. The Han people in Xinjiang have significantly higher KSHV seroprevalence than their counterparts in Hubei (6.7% vs 2.9%, P = 0.005). PMID- 20960291 TI - In vivo kinetics and biodistribution of a Hantaan virus DNA vaccine after intramuscular injection in mice. AB - To study the kinetics in vivo of a Hantaan virus DNA vaccine, we constructed a fusion DNA vaccine, pEGFP/S, by cloning the S segment of Hantavirus into the vector, pEGFP-C1, which encodes Green fluorescent protein EGFP. In this report, we provide evidence that pEGFP/S was distributed and persistently expressed for more than 60 days in several organs after inoculation. Our findings suggest that the persistent immune responses induced by a Hantaan virus DNA vaccine are likely due to the plasmid pEGFP/S deposited in vivo, which acts as a booster immunization. PMID- 20960292 TI - Localization and functional analysis of SeMNPV IE1 in mammalian cells. AB - In this paper, the function of the ie1 gene from baculovirus Spodoptera exigua multiple nucleopolyhedrovirus (SeMNPV), belonging to group II nucleopolyhedrovirus, was studied in mammalian cells. We amplified the SeMNPV ie1 gene and expressed it by fusing to the C terminal of enhanced GFP protein in HEK 293 cells. Confocal microscopy revealed that the IE1-GFP fusion protein was localized in the nucleus of the mammalian cells. The promoter sequences of AcMNPV gp64, SeMNPV F protein and Drosophila hsp70 were also analyzed, to further study the function of SeMNPV IE1. The results showed that, in the absence of the hr sequence, IE1 improved the expression of the F promoter but didn't influence the gp64 promoter significantly, but IE1 moderately stimulated the hsp70 promoter. PMID- 20960293 TI - An ELISA based on a truncated soluble ORF2 protein for the detection of PCV2 antibodies in domestic pigs. AB - Postweaning multisystemic wasting syndrome (PMWS) is an important swine disease that is closely associated with porcine circovirus type 2 (PCV2). The capsid protein (Cap protein) is a major structural protein that has at least three immunoreactive regions, and it can be a suitable candidate antigen for detecting the specific antibodies of a PCV2 infection. In the present study, an indirect enzyme-linked immunosorbent assay (TcELISA) based on a truncated soluble Cap protein produced in Escherichia coli (E.coli) was established and validated for the diagnostic PCV2 antibodies in swine. The TcELISA was validated by comparison with an indirect immunofluorescence assay (IIFA). The diagnostic sensitivity (DSN), specificity (DSP), and accuracy of the TcELISA were 88.6%, 90.7% and 89.4%, respectively. The agreement rate was 89.38% between results obtained with TcELISA and IIFA on 113 field sera. A cross-reactivity assay showed that the method was PCV2-specific by comparison with other sera of viral disease. Therefore,the TcELISA will be helpful for the development of a reliable serology diagnostic test for large scale detection of PCV2 antibodies and for the evaluation of vaccine against PCV2 in swine. PMID- 20960294 TI - Herpes simplex virus type 1 ICP27 protein: its expression, purification and specific antiserum production. AB - Herpes simplex virus type 1 (HSV-1) is the causative agent of cold sores and other more serious diseases. HSV-1 infected-cell protein 27 (ICP27) is an immediate-early regulatory phosphoprotein homologous to gene products identified in all classes of herpesviruses so far. To raise the antiserum to ICP27 for further characterization of its biological function, the ICP27 gene was cloned into the pET-28a (+) vector, then ICP27 protein was expressed in E. coli and purified by nickel-nitrilotriacetic acid (Ni(2+)-NTA) affinity resin column, finally the purified protein was used to raise antiserum. Western blot analysis demonstrated that the antiserum recognized the recombinant protein, and the antiserum was able to probe the ICP27 in HSV-1 infected cells with high specificity by immunofluorescence assay (IFA). Therefore, the specific antiserum will provide a valuable tool for further studies investigating ICP27's biological function during HSV-1 infection. PMID- 20960295 TI - Expression and immunological analysis of capsid protein precursor of swine vesicular disease virus HK/70. AB - VP1, a capsid protein of swine vesicular disease virus, was cloned from the SVDV HK/70 strain and inserted into retroviral vector pBABE puro, and expressed in PK15 cells by an retroviral expression system. The ability of the VP1 protein to induce an immune response was then evaluated in guinea pigs. Western blot and ELISA results indicated that the VP1 protein can be recognized by SVDV positive serum, Furthermore, anti-SVDV specific antibodies and lymphocyte proliferation were elicited and increased by VP1 protein after vaccination. These results encourage further work towards the development of a vaccine against SVDV infection. PMID- 20960296 TI - Complete genomic sequence of transmissible gastroenteritis virus TS and 3' end sequence characterization following cell culture. AB - The complete genome sequence of transmissible Gastroenteritis virus (TGEV) strain TS, previously isolated from Gansu province, was cloned and compared with published sequence data from other TGEV strains. Phylogenetic tree analysis based on the amino acid and nucleotide sequences of the S gene showed that the TGEV strains were divided into 3 clusters. TGEV TS showed a close evolutionary relationship to the American Miller cluster but had a 5' non-translated region (NTR) sequence closely related to the American Purdue cluster. Continued culture in different cell types indicated that TGEV TS virulence could be attenuated after fifty passages in Porcine kidney (PK-15) cells, and that the Porcine kidney cell line IB-RS-2 (IBRS) was not suitable for culture of the TGEV strain TS. PMID- 20960297 TI - Antiviral drug therapy. PMID- 20960299 TI - Development of novel antiviral therapies for hepatitis C virus. AB - Over 170 million people worldwide are infected with hepatitis C virus (HCV), a major cause of liver diseases. Current interferon-based therapy is of limited efficacy and has significant side effects and more effective and better tolerated therapies are urgently needed. HCV is a positive, single-stranded RNA virus with a 9.6 kb genome that encodes ten viral proteins. Among them, the NS3 protease and the NS5B polymerase are essential for viral replication and have been the main focus of drug discovery efforts. Aided by structure-based drug design, potent and specific inhibitors of NS3 and NS5B have been identified, some of which are in late stage clinical trials and may significantly improve current HCV treatment. Inhibitors of other viral targets such as NS5A are also being pursued. However, HCV is an RNA virus characterized by high replication and mutation rates and consequently, resistance emerges quickly in patients treated with specific antivirals as monotherapy. A complementary approach is to target host factors such as cyclophilins that are also essential for viral replication and may present a higher genetic barrier to resistance. Combinations of these inhibitors of different mechanism are likely to become the essential components of future HCV therapies in order to maximize antiviral efficacy and prevent the emergence of resistance. PMID- 20960298 TI - Hepatitis C virus experimental model systems and antiviral drug research. AB - An estimated 130 million people worldwide are chronically infected with hepatitis C virus (HCV) making it a leading cause of liver disease worldwide. Because the currently available therapy of pegylated interferon-alpha and ribavirin is only effective in a subset of patients, the development of new HCV antivirals is a healthcare imperative. This review discusses the experimental models available for HCV antiviral drug research, recent advances in HCV antiviral drug development, as well as active research being pursued to facilitate development of new HCV-specific therapeutics. PMID- 20960300 TI - Ion channels as antivirus targets. AB - Ion channels are membrane proteins that are found in a number of viruses and which are of crucial physiological importance in the viral life cycle. They have one common feature in that their action mode involves a change of electrochemical or proton gradient across the bilayer lipid membrane which modulates viral or cellular activity. We will discuss a group of viral channel proteins that belong to the viroproin family, and which participate in a number of viral functions including promoting the release of viral particles from cells. Blocking these channel-forming proteins may be "lethal", which can be a suitable and potential therapeutic strategy. In this review we discuss seven ion channels of viruses which can lead serious infections in human beings: M2 of influenza A, NB and BM2 of influenza B, CM2 of influenza C, Vpu of HIV-1, p7 of HCV and 2B of picornaviruses. PMID- 20960301 TI - Strategies for antiviral screening targeting early steps of virus infection. AB - Viral infection begins with the entry of the virus into the host target cell and initiates replication. For this reason, the virus entry machinery is an excellent target for antiviral therapeutics. In general, a virus life cycle includes several major steps: cell-surface attachment, entry, replication, assembly, and egress, while some viruses involve another stage called latency. The early steps of the virus life cycle include virus attachment, receptor binding, and entry. These steps involve the initial interactions between a virus and the host cell and thus are major determinants of the tropism of the virus infection, the nature of the virus replication, and the diseases resulting from the infection. Owing to the pathological importance of these early steps in the progress of viral infectious diseases, the development of inhibitors against these steps has been the focus of the pharmaceutical industry. In this review, Herpes Simplex Virus (HSV), Hepatitis C Virus (HCV), and Human Enterovirus 71 (EV71) were used as representatives of enveloped DNA, enveloped RNA, and non-enveloped viruses, respectively. The current mechanistic understanding of their attachment and entry, and the strategies for antagonist screenings are summarized herein. PMID- 20960302 TI - Development of novel therapeutics for chronic hepatitis B. AB - Chronic infection of hepatitis B virus (HBV) presents one of the serious public health challenges worldwide. Current treatment of chronic hepatitis B (CHB) is limited, and is composed of interferon and nucleoside/nucleotide reverse transcriptase inhibitors (NRTI). Interferon is poorly tolerated and is only responsive in a small fraction of CHB patients and NRTIs often face the problem of emergence of drug resistance during long-term treatment. The current treatment of CHB can be improved in several ways including genotyping mutations associated with drug resistance before treatment to guide the choice of NRTIs and suitable combinations among NRTIs and interferon. It is important to continue research in the identification of novel therapeutic targets in the life cycle of HBV or in the host immune system to stimulate the development of new antiviral agents and immunotherapies. Several antiviral agents targeting HBV entry, cccDNA, capsid formation, viral morphogenesis and virion secretion, as well as two therapeutic vaccines are currently being evaluated in preclinical studies or in clinical trials to assess their anti-HBV efficacy. PMID- 20960303 TI - A few specialized issues that should be focused on anti-HIV drug evaluation in vitro. AB - Since the introduction of antiretroviral therapy (ART), the lifespan and quality of life of patients infected with HIV have been significantly improved. But treatment efficacy was compromised eventually by the development of resistance to antiretroviral drugs, and more new anti-HIV drugs with lower toxicity and higher activity were needed. Based on the experience and lessons learned from the treatment in the developed countries, US FDA suggested that more pharmacodynamical researches should be considered ahead of the clinical trials. To facilitate the anti-HIV drug research and development, we reviewed a few specialized issues that should be focused on drug evaluations in vitro, including: 1) Mechanism of action studies, demonstrating the candidate drug's efficacy to specifically inhibit viral replication or a virus-specific function and confirm the drug target. 2) Drug resistance studies, selecting the drug resistant variants in vitro and determining the activities inhibiting HIV isolates resistant to approved antiretroviral drugs of the same class. 3) Antiviral activity in vitro in the presence of serum proteins, ascertaining whether an investigational product is significantly bound by serum proteins. 4) Combination activity analysis, evaluating in vitro antiviral activity of an investigational product in two-drug combinations with other drugs approved. PMID- 20960304 TI - The nucleocytoplasmic transport of viral proteins. AB - Molecules can enter the nucleus by passive diffusion or active transport mechanisms, depending on their size. Small molecules up to size of 50-60 kDa or less than 10 nm in diameter can diffuse passively through the nuclear pore complex (NPC), while most proteins are transported by energy driven transport mechanisms. Active transport of viral proteins is mediated by nuclear localization signals (NLS), which were first identified in Simian Virus 40 large T antigen and had subsequently been identified in a large number of viral proteins. Usually they contain short stretches of lysine or arginine residues. These signals are recognized by the importin super-family (importin alpha and beta) proteins that mediate the transport across the nuclear envelope through Ran GTP. In contrast, only one class of the leucine-rich nuclear export signal (NES) on viral proteins is known at present. Chromosome region maintenance 1 (CRM1) protein mediates nuclear export of hundreds of viral proteins through the recognition of the leucine-rich NES. PMID- 20960305 TI - Prokaryotic expression and potential application of the truncated PCV-2 capsid protein. AB - Three pairs of specific primers were designed to amplify the F2-1, F2-2 and XF2-2 truncated sequences of ORF2 which encodes the capsid protein of porcine circovirus type 2 (PCV-2). The F2-1 sequence had most of the NLS region of ORF2, but the F2-2 and XF2-2 genes had the NLS region deleted. Truncated genes were subcloned into pET-32a(+) vectors to construct recombinant fusion expression vectors. The vectors were then transformed into Rosetta(DE3) E. coli and expressed by induction of IPTG. Expressed proteins were detected by western blotting and ELISA. The protein with best immunoreactivity was confirmed and selected, then utilized to inoculate SPF rabbits to prepare polyclonal antibodies. The protein and prepared polyclonal antibody were utilized to detect sera samples against PCV-2 from Shandong province and PCV-2 particles in PK-15 cells. In our study, three recombinant fusion proteins were successfully obtained, and the molecular weights of fusion proteins were 35.9 kDa, 33.6 kDa and 38.6 kDa respectively detected by SDS-PAGE. All of the proteins showed positive reaction with anti-PCV-2 antisera, and His-XF2-2 showed better immunoreactivity than the others. The protein of His-XF2-2 was coated as antigen in ELISA to detect the seroprevalence of PCV-2 in certain districts of Shandong province, the seropositivity rate was 27.7 % (73/264). Specific fluorescence and positive signals for PCV-2 could be detected in PK-15 cells inoculated with PCV-2 with the participation of prepared antibodies against His-XF2-2 in IFA and IPMA. Experimental results indicated that the truncated PCV-2 ORF2 gene containing most of the NLS region was successfully expressed in E. coli, and His-XF2-2 was demonstrated to have better immunoreactivity with anti-PCV-2 antisera than the other two fusion proteins. His-XF2-2 and prepared polyclonal antibodies against it had a satisfactory capability in detecting PCV-2 infection. PMID- 20960306 TI - A comparison of the biological characteristics of EV71 C4 subtypes from different epidemic strains. AB - The comparative analysis of the biological characterization and the genetic background study of EV71 circulating strains is commonly recognized as basic work necessary for development of an effective EV71 vaccine. In this study, we sequenced five EV71 circulating strains, isolated from Fuyang, Hefei, Kunming and Shenzhen city of China and named them FY-23, FY-22, H44, K9 and S1 respectively. The sequence alignment demonstrated their genotypes be C4. The genetic distance of the VP1 gene from these isolates suggested that they were highly co-related with genetic identity similar to other previously reported EV71 strains in China. Additionally, these strains were identified to display some obvious proliferation dynamics and plaque morphology when propagated in Vero cells. However, a distinctive difference in pathogenic ability in neonatal mice was found. Some differences in cross neutralization test & immunogenic analysis were also found. All these results are related to the biological characterization of circulating EV71 strains in China and aid in the development of an EV71 vaccine in the future. PMID- 20960307 TI - In vitro anti-viral activity of the total alkaloids from Tripterygium hypoglaucum against herpes simplex virus type 1. AB - Herpes simplex virus type 1 (HSV-1) is a commonly occurring human pathogen worldwide. There is an urgent need to discover and develop new alternative agents for the management of HSV-1 infection. Tripterygium hypoglaucum (level) Hutch (Celastraceae) is a traditional Chinese medicine plant with many pharmacological activities such as anti-inflammation, anti-tumor and antifertility. The usual medicinal part is the roots which contain about a 1% yield of alkaloids. A crude total alkaloids extract was prepared from the roots of T. hypoglaucum amd its antiviral activity against HSV-1 in Vero cells was evaluated by cytopathic effect (CPE) assay, plaque reduction assay and by RT-PCR analysis. The alkaloids extract presented low cytotoxicity (CC(50) = 46.6 MUg/mL) and potent CPE inhibition activity, the 50% inhibitory concentration (IC(50)) was 6.5 MUg/mL, noticeably lower than that of Acyclovir (15.4 MUg /mL). Plaque formation was significantly reduced by the alkaloids extract at concentrations of 6.25 MUg/mL to 12.5 MUg/mL, the plaque reduction ratio reached 55% to 75 which was 35% higher than that of Acyclovir at the same concentration. RT-PCR analysis showed that, the transcription of two important delayed early genes UL30 and UL39, and a late gene US6 of HSV-1 genome all were suppressed by the alkaloids extract, the expression inhibiting efficacy compared to the control was 74.6% (UL30), 70.9% (UL39) and 62.6% (US6) respectively at the working concentration of 12.5 MUg/mL. The above results suggest a potent anti-HSV-1 activity of the alkaloids extract in vitro. PMID- 20960308 TI - Preparation of BFV Gag antiserum and preliminary study on cellular distribution of BFV. AB - Viruses (e.g. Human immunodeficiency virus, Human simplex virus and Prototype foamy virus) are obligate intracellular parasites and therefore depend on the cellular machinery for cellular trafficking. Bovine foamy virus (BFV) is a member of the Spumaretrovirinae subfamily of Retroviruses, however, details of its cellular trafficking remain unknown. In this study, we cloned the BFV gag gene into prokaryotic expression vector pET28a and purified the denaturalized Gag protein. The protein was used to immunize BALB/c mouse to produce antiserum, which could specifically recognize the BFV Gag protein in BFV-infected cells through western blot assay. Additionally, these results demonstrated that both the optimal and suboptimal cleavage of Gag protein occur in BFV-infected cells. Subsequently, the Gag antiserum was used to investigate subcellular localization of BFV. In immunofluorescence microscopy assays, colocalization microtubules (MTs) and assembling viral particles were clearly observed, which implied that BFV may transport along cellular MTs in host cells. Furthermore, MTs depolymerizing assay indicated MTs were required for the efficient replication of BFV. In conclusion, our study suggests that BFV has evolved the mechanism to hijack the cellular cytoskeleton for its replication. PMID- 20960309 TI - Molecular characterization of nonstructural protein NS38 of grass carp reovirus. AB - Viral nonstructural proteins in both enveloped and non-enveloped viruses play important roles in viral replication. Protein NS38 of Grass carp reovirus (GCRV), has been deduced to be a non-structural protein, and, consistent with other reoviruses, is considered to cooperate with the NS80 protein in viral particle assembly. To investigate the molecular basis of the role of NS38, a complete protein was expressed in E.coli for the first time. It was found that there is a better expression of NS38 induced with IPTG at 28 degrees C rather than 37 degrees C. In addition, the antiserum of NS38 prepared with purified fusion protein and injected into rabbit could be used for detecting NS38 protein expression in GCRV infected cell lysate, while there is not any reaction crossed with purified virus particle, confirming NS38 is not a component of the viral structural protein. The result reported in this study will provide evidence for further viral protein-protein and protein-RNA interaction in dsRNA viruses replication. PMID- 20960310 TI - Isolation and identification of a subgroup A avian leukosis virus from imported meat-type grand-parent chickens. AB - An exogenous avian leukosis virus (ALV) strain SDAU09C1 was isolated in DF-1 cells from one of 240 imported 1-day-old white meat-type grand parent breeder chicks. Inoculation of SDAU09C1 in ALV-free chickens induced antibody reactions specific to subgroup A or B. But gp85 amino acid sequence comparisons indicated that SDAU09C1 fell into subgroup A; it had homology of 88.8%-90.3% to 6 reference strains of subgroup A, much higher compared to other subgroups including subgroup B. This is the first report for ALV of subgroup A isolated from imported breeders. PMID- 20960311 TI - A quantitative assay for measuring of bovine immunodeficiency virus using a luciferase-based indicator cell line. AB - In order to quantitate the bovine immunodeficiency virus (BIV) infection in vitro, a BIV indicator cell line (BIVL) was established by transfecting baby hamster kidney cells with reporter plasmids containing the firefly luciferase gene driven by a BIV long terminal repeat promoter. The BIV activates promoter activity of the LTR to express luciferase upon infection. BIV infection could therefore by quantified by detection of luciferase activity. Compared to standard assays used to detect BIV infection, the BIVL-based assay is 10 times more sensitive than the the CPE-based assay, and has similar sensitivity with the viral capsid protein Western blot assay. BIV indicator cell line could detect BIV infection specifically. Luciferase activity of BIV infected BIVL cells showed a time dependent manner, and 60 h post infection is the optimal time to detect BIV infection. Luciferase activity of BIVL cells correlates with the BIV capsid protein expression. Moreover, a linear relationship was found between MOI and the activated intensity of luciferase expression. In brief, the BIV indicator cell line is an easy, robust and quantitive method for monitoring BIV infection. PMID- 20960312 TI - In vivo inhibition of NAS preparation on H9N2 subtype AIV. AB - NAS preparation, a kind of Chinese herbal medicine found by the Yunnan Eco agricultural Research Institute, has potential antiviral activity. In this paper, the inhibiting effect of NAS preparation on H9N2 subtype Avian influenza virus (AIV) was investigated in vivo. Chickens infected with H9N2 virus were treated with NAS preparation for 4 days. The virus was then detected by hemoagglutination (HA) test and reverse transcription polymerase chain reaction (RT-PCR). The results showed that no H9N2 virus could be detected at the 7th day when the chickens were treated with 0.2 g/kg/d or 0.1 g/kg/d of NAS preparation. However the virus could be detected in other chickens without NAS preparation treatment. This result suggested that NAS preparation may be a potential drug candidate to control infection of H9N2 subtype AIV in chickens. PMID- 20960313 TI - From vision to reality: the origins of intraoperative MR imaging. AB - Intraoperative MR imaging has become one of the most important concepts in present day neurosurgery. The brain shift problem with navigation, the need for assessment of the degree of resection and the need for detection of early postoperative complications were the three most important motives that drove the development of this technology. The GE Signa System with the "double doughnut" design was the world's first intraoperative MRI. From 1995 to 2007 more than 1,000 neurosurgical cases were performed with the system. The system was used by several different specialties and in neurosurgery it was most useful for complete resection of low-grade gliomas, identification and resection of small or deep metastases or cavernomas, recurrent pituitary adenomas, cystic tumors, biopsies in critical areas and surgery in recurrent GBM cases. Main superiorities of the system were the ability to scan without patient movement to get image updates, the ability to do posterior fossa cases and other difficult patient positioning, the easiness of operation using intravenous sedation anesthesia and the flexibility of the system to be used as platform for new diagnostic and therapeutic modalities. PMID- 20960314 TI - Development of intraoperative MRI: a personal journey. AB - The initial attempts at intraoperative image guidance and imaging dates back to early 1980s. Since then Neuronavigation and intraoperative imaging technologies were developed in parallel. This works aims at summarizing the developments and giving an insider's view into the beginning stage of these technologies. The successes and obstacles encountered in the first few decades are relayed from the angle of one of the initial developers. PMID- 20960315 TI - Lows and highs: 15 years of development in intraoperative magnetic resonance imaging. AB - Intraoperative magnetic resonance imaging (ioMRI) during neurosurgical procedures was first implemented in 1995. In the following decade ioMRI and image guided surgery has evolved from an experimental stage into a safe and routinely clinically applied technique. The development of ioMRI has led to a variety of differently designed systems which can be basically classified in one- or two room concepts and low- and high-field installations. Nowadays ioMRI allows neurosurgeons not only to increase the extent of tumor resection and to preserve eloquent areas or white matter tracts but it also provides physiological and biological data of the brain and tumor tissue. This article tries to give a comprehensive review of the milestones in the development of ioMRI and neuronavigation over the last 15 years and describes the personal experience in intraoperative low and high-field MRI. PMID- 20960317 TI - Development and design of low field compact intraoperative MRI for standard operating room. AB - OBJECTIVES: To present the development of a compact low field intraoperative MR image guidance system and its application in brain surgery. METHODS: The PoleStar ioMRI system (Odin Medical Technologies, Israel and Medtronic, Inc. USA) was developed for use in a standard operating room. Its primary physical fixed parameters are magnetic field of 0.15 T and field of view of 20 x 16 cm. The magnet is mounted on a transportable gantry and can be positioned under the surgical table when not in use for scanning. Additional functionality includes integrated navigation, and system operation by the surgeons. RESULTS: The PoleStar system integrates into existing operating rooms requiring only slight modification of the surgical environment. Standard instruments can be used. The system's imaging allows it to be used for the following indications: pituitary tumors, low grade gliomas (including awake surgery), high grade gliomas, intraventricular tumors, accurate navigation to small lesions such as cavernous angiomas or metastases, drainage of cysts and brain abscesses. The image quality, which is comparable to post operative diagnostic high field imaging, enables high quality resection control. More than 6,000 brain surgeries were done with the system in 50 centers in the US and Europe. CONCLUSION: The low field intraoperative MRI system is a valuable tool in the modern operating room. PMID- 20960316 TI - Intraoperative imaging in neurosurgery: where will the future take us? AB - Intraoperative MRI (ioMRI) dates back to the 1990s and since then has been successfully applied in neurosurgery for three primary reasons with the last one becoming the most significant today: (1) brain shift-corrected navigation, (2) monitoring/controlling thermal ablations, and (3) identifying residual tumor for resection. IoMRI, which today is moving into other applications, including treatment of vasculature and the spine, requires advanced 3T MRI platforms for faster and more flexible image acquisitions, higher image quality, and better spatial and temporal resolution; functional capabilities including fMRI and DTI; non-rigid registration algorithms to register pre- and intraoperative images; non MRI imaging improvements to continuously monitor brain shift to identify when a new 3D MRI data set is needed intraoperatively; more integration of imaging and MRI-compatible navigational and robot-assisted systems; and greater computational capabilities to handle the processing of data. The Brigham and Women's Hospital's "AMIGO" suite is described as a setting for progress to continue in ioMRI by incorporating other modalities including molecular imaging. A call to action is made to have other researchers and clinicians in the field of image guided therapy to work together to integrate imaging with therapy delivery systems (such as laser, MRgFUS, endoscopic, and robotic surgery devices). PMID- 20960318 TI - Low field intraoperative MRI in glioma surgery. AB - The extent of resection marks one prognostic factor for patients with malignant gliomas. Among the methods used for the intraoperative control of the extent of resection, intraoperative magnetic resonance imaging (ioMRI) has become a very attractive method. It was introduced in the in the final decade of the last century. The first available system was a low magnetic field strength unit employing 0.5 Tesla (T). While currently high-field systems (1.5 T and above) are being developed, different low-field ioMRI systems (0.5 T and below) have been used for brain tumor resection in far more centers than high-field ioMRI, corresponding to a greater number of publications. Undoubtedly, high-field ioMRI systems offer superior image quality and faster acquisition times. Yet, low-field ioMRI has influenced intraoperative decision-making and improved brain tumor resection. With this article, we review the use of low-field ioMRI in glioma surgery. PMID- 20960319 TI - Intraoperative MRI (ioMRI) in the setting of awake craniotomies for supratentorial glioma resection. AB - Both awake craniotomy under conscious sedation and use of intraoperative MRI can increase the efficiency and safety of glioma resections. In contrast to craniotomies under general anesthesia, neurosurgery under conscious sedation requires several changes to the routine operative setup when performed in the ioMRI environment. This work reports our experience with awake craniotomies under conscious sedation using ioMRI. Seven patients underwent awake-craniotomies for resection of supratentorial gliomas using ioMRI at the Ohio State University Medical Center and James Cancer Hospital by a single surgeon. ioMRI can be safely employed in patients who are undergoing craniotomies under conscious sedation. Particularly important is the evaluation by the anesthesiologist whether the patient is a good candidate to sustain a likely longer than average procedure in a setting where his active cooperation is not only required, but also the essential aspect of this procedure. PMID- 20960320 TI - Glioma extent of resection and ultra-low-field iMRI: interim analysis of a prospective randomized trial. AB - Aiming at providing high-class evidence regarding the use of intraoperative MRI (ioMRI), we are conducting a prospective randomized controlled trial. Adult patients with contrast enhancing lesions suspicious of malignant gliomas scheduled to undergo radiologically complete tumor resection are eligible to enter this trial. After giving their informed consent, patients are randomized to undergo either ioMRI-guided or conventional microneurosurgical tumor resection. To assess the extent of resection, pre- and early postoperative high-field MR images are obtained to perform volumetric analyses. Primary endpoint of the study is the rate of radiologically complete tumor resections. After the inclusion of 35 patients, we performed an interim analysis. In six patients, histopathological examination revealed metastases, so they were excluded from further analyses. Thus, data from 29 patients with gliomas could be analyzed. There were no significant differences in patient age (P=0.28) or preoperative tumor sizes (P=0.40) between the two treatment groups. We observed a trend towards a higher rate of complete tumor resections in the ioMRI-group compared to the control group (P=0.07). Postoperative tumor volumes were significantly lower in the ioMRI group than in the control group (P<0.05). The use of ioMRI appears to be associated with a higher rate of radiographically complete as well as near total tumor resections compared to conventional microneurosurgery. PMID- 20960321 TI - Impact of a low-field intraoperative MRI on the surgical results for high-grade gliomas. AB - In this study the authors retrospectively evaluated the results of the operated intracranial high grade gliomas using low field intraoperative MRI system Polestar N 20+Stealth Station (Medtronic, Co, USA) at German Hospital, Istanbul. Between November 2006 and October 2008, 11 patients underwent microsurgical tumor resection with the use of intraoperative MRI for WHO Grade III and IV gliomas. There were six males and five females, mean age was 53 (range 30-73), and mean follow-up duration was 19 months (range 4-31). Ten total, one subtotal resection was achieved, whereas intraoperative MRI assessment demonstrated five residual tumors. Histopathological examination revealed that eight tumors were glioblastomas and three were anaplastic oligodendroglioma, anaplastic oligoastrocytoma and anaplastic ependymoma respectively. No complications directly related to the intraoperative scanning were observed and there was no mortality, but one patient with an insular tumor developed hemiparesis after the operation. Mean hospital stay was 4.8 day. Ten patients received additional radiotherapy and chemotherapy, one patient refused further therapy. Mean survival was 18.8 months for the entire group and 15.6 months for glioblastoma patients. In this small series of patients with high grade gliomas we found that the use of intraoperative MRI helps complete tumor removal and hence improves survival. PMID- 20960322 TI - Intraoperative MRI and functional mapping. AB - The integration of functional and anatomical data into neuronavigation is an established standard of care in many neurosurgical departments. Yet, this method has limitations as in most cases the data are acquired prior to surgery. Due to brain-shift the accurate presentation of functional as well as anatomical structures declines in the course of surgery. In consequence, the acquisition of information during surgery about the brain's current functional state is of specific interest. The advancement of imaging technologies (e.g. fMRI, MEG, Intraoperative Optical Intrinsic Signal Imaging--IOIS) and neurophysiological techniques and the advent of intraoperative MRI all had a major impact on neurosurgery. The combination of modalities such as neurophysiology and intraoperative MRI (ioMRI), as well as the acquisition of functional MRI during surgery (ifMRI) are in the focus of this work. Especially the technical aspects and safety issues are elucidated. PMID- 20960323 TI - Information-guided surgical management of gliomas using low-field-strength intraoperative MRI. AB - BACKGROUND: Contemporary technological developments revolutionized management of brain tumors. The experience with information-guided surgery of gliomas, based on the integration of the various intraoperative anatomical, functional, and histological data, is reported. METHODS: From 2000 to 2009, 574 surgeries for intracranial gliomas were performed in our clinic with the use of intraoperative MRI (ioMRI) with magnetic field strength of 0.3T, updated neuronavigation, neurochemical navigation with 5-aminolevulinic acid, serial intraoperative histopathological investigations of the resected tissue, and comprehensive neurophysiological monitoring. Nearly half of patients (263 cases; 45.8%) were followed more than 2 years after surgery. FINDINGS: Maximal possible tumor resection, defined as radiologically complete tumor removal or subtotal removal leaving the residual neoplasm within the vital functionally-important brain areas, was attained in 569 cases (99.1%). The median resection rate constituted 95%, 95%, and 98%, for WHO grade II, III, and IV gliomas, respectively. Actuarial 5-year survival was significantly worse in WHO grade IV gliomas (19%), but did not differ significantly between WHO grade III and II tumors (69% vs. 87%). CONCLUSIONS: Information-guided management of gliomas using low-field-strength ioMRI provides a good opportunity for maximal possible tumor resection, and may result in survival advantage, particularly in patients with WHO grade III neoplasms. PMID- 20960324 TI - Implementation of the ultra low field intraoperative MRI PoleStar N20 during resection control of pituitary adenomas. AB - OBJECTIVE: To describe our experience with the application of an intraoperative ultra low field magnetic resonance imaging system (ioMRI) PoleStar N20, Medtronic Surgical Navigation Technologies, Louisville, USA during resection control of pituitary adenomas. METHODS: Forty-four patients were operated on a pituitary adenoma (1 microadenoma, 43 macroadenomas; mean size 26.0 +/- 9.7 mm). The ioMRI system was used for navigation and resection control after transseptal, transsphenoidal microsurgical tumour removal using standard instruments and standard microscope. If any accessible tumour remnant was suspected surgery was continued for navigation guided re-exploration and if necessary continued resection. RESULTS: The applications of the scanner integrated navigation system, with a 3-planar reconstruction of the coronal scan, enabled the surgeon to safely approach and remove the tumour. The quality of preoperative tumour visualization with the ultra low field ioMRI in patients with macroadenomas is very good and has a good congruency with the preoperative 1.5 T MRI. For microadenomas the preoperative visualization is poor and very difficult to interpret. In seven patients ioMRI resection control showed residual tumours leading to further resection. After final tumour resection the ioMRI scan documented adequate decompression of the optic pathway in all patients. However, the intraoperative image interpretation was equivocal in four patients in whom it was difficult to distinguish between small intrasellar tumour remnants and perioperative changes. CONCLUSIONS: The PoleStar N20 is a safe, helpful and feasible tool for navigation guided pituitary tumour approach. Image interpretation is requires some experience, but decompression of the optic system can be reliable shown in cases with pituitary macroadenomas. This system is of limited value for resection control of pituitary microadenomas. PMID- 20960325 TI - Intraoperative MRI for stereotactic biopsy. AB - This work aims at demonstrating the value of intraoperative magnetic resonance imaging (ioMRI) as a routine tool for stereotactic brain biopsy. Biopsies were done using the PoleStar N-20 ioMRI (Medtronic Navigation, Louisville, Colorado, USA) under general anesthesia. Images were acquired after patient positioning and after insertion of an MRI-compatible biopsy cannula. A Navigus guide (Medtronic Navigation) was used to align and direct the cannula. Retargeting was done as necessary, to improve placement within the target and to avoid critical structures, using the system's integrated infrared navigation tool. Cannula placement was tracked using serial images. ioMRI-guided biopsy was done in 39 patients, of whom 28 had neoplasms and 11 had non-neoplastic conditions. Additional OR time related to the use of ioMRI (including positioning of the patient and magnet, and imaging acquisition) averaged 1.1h. In 53% of the surgeries the biopsy cannula was repositioned based on intraoperative imaging. A histologic diagnosis was obtained in all but one patient, with ioMRI confirming proper cannula placement in all cases. There were no significant hemorrhages on clinical or imaging grounds nor any other complications. IoMRI can be routinely used for stereotactic biopsy in a regular neurosurgical operating environment. While general anesthesia is used and there is some additional time incurred from this technology the improved diagnostic yield and ability to avoid complications make ioMRI an ideal technical adjunct for brain biopsy. PMID- 20960326 TI - The evolution of iMRI utilization for pediatric neurosurgery: a single center experience. AB - From its inception intraoperative magnetic resonance imaging (ioMRI) was envisioned to have significant applications in neurosurgery in general and pediatrics specifically. Over the last 9 years we have noted a dramatic shift in our ioMRI usage from intracranial tumors to cerebrospinal fluid management and complex cysts. Here we present seven selected cases to illustrate lessons learned from our operative experience within the GE Signa SP/I open-configuration "double doughnut" MRI. These cases including a ganglioglioma, ependymoma, and pilocytic astrocytoma tumor resection, as well as arachnoid cysts, complex cyst, and microabscess drainage reflect our current use of ioMRI in pediatric neurosurgical cases. Namely that ioMRI is optimal for (1) resection of small tumors with poorly differentiated tumor margins, (2) large tumors with mass effect, and (3) shunt or catheter placement requiring either extreme accuracy or intraoperative confirmation of catheter placement. We also comment on the legitimate limitations of this technology in certain operations. Additionally emphasized are cases in which ioMRI imaging drives operative decision making, highlighting the unique and unequaled abilities of this technology for a subset of pediatric neurosurgical cases. PMID- 20960327 TI - Implementation and preliminary clinical experience with the use of ceiling mounted mobile high field intraoperative magnetic resonance imaging between two operating rooms. AB - OBJECTIVE: Intraoperative magnetic resonance imaging (ioMRI) provides immediate feedback and quality assurance enabling the neurosurgeon to improve the quality of a range of neurosurgical procedures. Implementation of ioMRI is a complex and costly process. We describe our preliminary 16 months experience with the integration of an IMRIS movable ceiling mounted high field (1.5 T) ioMRI setup with two operating rooms. METHODS: Aspects of implementation of our ioMRI and our initial 16 months of clinical experience in 180 consecutive patients were reviewed. RESULTS: The installation of a ceiling mounted movable ioMRI between two operating rooms was completed in April 2008 at Barnes-Jewish Hospital in St. Louis. Experience with 180 neurosurgical cases (M:F-100:80, age range 1-79 years, 71 gliomas, 57 pituitary adenomas, 9 metastases, 11 other tumor cases, 4 Chiari decompressions, 6 epilepsy resections and 22 other miscellaneous procedures) demonstrated that this device effectively provided high quality real-time intraoperative imaging. In 74 of all 180 cases (41%) and in 54% of glioma resections, the surgeon modified the procedure based upon the ioMRI. Ninety-three percent of ioMRI glioma cases achieved gross/near total resection compared to 65% of non ioMRI glioma cases in this time frame. CONCLUSION: A movable high field strength ioMRI can be safely integrated between two neurosurgical operating rooms. This strategy leads to modification of the surgical procedure in a significant number of cases, particularly for glioma surgery. Long-term follow up is needed to evaluate the clinical and financial impact of this technology in the field of neurosurgery. PMID- 20960328 TI - High-field iMRI in glioblastoma surgery: improvement of resection radicality and survival for the patient? AB - Since the first patients underwent intracranial tumor removal with the radicality control of intraoperative MRI (ioMRI) in September 2005 in our department, the majority of operations performed in the ioMRI room have been indicated for high grade gliomas. In order to elucidate the role of ioMRI scanning in patients harboring high-grade gliomas (HGG) on their survival, one hundred ninety three patients with gliomas WHO grades III and IV were operated either in a standard microsurgical neuronavigated fashion or using additionally ioMRI and were included in a follow-up study. The series started with surgeries from September 2005 until October 2007. Patient attribution to the two groups was based on the logistical availability of the ioMRI on a scheduled surgery day, and on the assumed "difficulty" of the surgery based on the location of the glioma in or near to an eloquent area. Surgery was intended to be as radical as possible without reduction of quality of life. First surgery was performed in 103 patients (75 WHO IV and 28 WHO III) and will be the main topic of this paper. In 60 patients, ioMRI was used, while in 43 patients standard microsurgical neuronavigated resection techniques were applied. Patients were followed in regular intervals mostly until death. Statistical analysis showed a median survival time for patients in whom ioMRI had been used of 20, 37 months compared to 10, 3 months in the cohort who had undergone conventional microsurgical removal. Major influencing concomitants were WHO grades and age which were balanced in both groups. PMID- 20960329 TI - Image guided aneurysm surgery in a Brainsuite(r) ioMRI Miyabi 1.5 T environment. AB - OBJECTIVE: Current literature only gives sparse account of aneurysm surgery in an intraoperative MRI environment. After installation of a BrainSuite((r)) ioMRI Miyabi 1.5 T at our institution the aim of the present preliminary study was to evaluate feasibility, pros and cons of aneurysm surgery in this special setting. MATERIAL AND METHODS: Since February 2009, during a 3 months period we performed elective image guided aneurysm surgery in 4 ACM and 1 ACOM aneurysm (four patients) in this ioMRI setting. The patients' heads were rigidly fixed in the Noras 8-Channel OR Head Coil. Our imaging protocol included MP-RAGE, T2-TSE axial, TOF-MRA and diffusion-/perfusion-imaging immediately before surgery and after clip application. Presurgical 3D-planning was performed using the iPlan(r) Software. RESULTS: All five aneurysms were operated without temporary clipping. There were no intra- or postoperative complications. Patient positioning and head fixation with the integrated Noras Head Clamp was feasible, but there were significant limitations particularly with regard to more complex approaches and patient physiognomy. Image quality especially TOF-MRA was good in 4, insufficient in 1 aneurysm. Presurgical planning especially vessel extraction from TOF-MRA was possible but certainly needs significant future improvement. Diffusion- and perfusion weighted examinations yielded good image quality. CONCLUSION: Our limited experience is encouraging so far. Further improvement particularly concerning flexibility of patient positioning and presurgical 3D-planning for vascular procedures is most necessary. As a future perspective image guided aneurysm surgery in an ioMRI-environment may be helpful especially in complex aneurysms and provide neurosurgeons and neuroanaesthesiologists with additional information about cerebral haemodynamics and perfusion pattern in the vascular territory distal to the target vessel. PMID- 20960330 TI - From intraoperative angiography to advanced intraoperative imaging: the geneva experience. AB - OBJECTIVE: We aimed at the integration of recent flat panel technology in a joint interventional suite for neurosurgeons and neuroradiologists. METHODS: A Flat Panel system, allowing for intraoperative performance of 2D and 3D DSA, for automated segmentation of vascular structures, and for performance of computed tomography, was connected with a surgical microscope and neuronavigation. All surgical and neurointerventional cases were monitored and stored in a prospective data base. RESULTS: N=99 patients were treated neurosurgically: N=63 aneurysm clippings in n=51 patients; n=12 resections of arteriovenous malformations (AVM); n=6 clippings/excisions of dural AV fistulae (dAVF); n=3 EC-IC bypass procedures; n=10 resections of skull base tumours; n=17 spine procedures. All patients had intraoperative imaging for angiographic control and/or for anatomical allocation. Intraoperative 3D-rotational angiography was performed n=54 times in n=42 patients in < 15 min each, with repositioning of aneurysm clips in n=9 patients. CONCLUSION: This hybrid neuro-interventional suite opens a new avenue for intraoperative imaging by the provision of highly resoluted angiographic or CT images, which may be co-registered with a navigation system. In addition, the workflow in treatment of aneurysmal SAH can be improved, as all diagnostic and therapeutic measures can be taken without having to move the patient to other facilities. PMID- 20960331 TI - Intraoperative magnetic resonance imaging. AB - Neurosurgeons have become reliant on image-guidance to perform safe and successful surgery both time-efficiently and cost-effectively. Neuronavigation typically involves either rigid (frame-based) or skull-mounted (frameless) stereotactic guidance derived from computed tomography (CT) or magnetic resonance imaging (MRI) that is obtained days or immediately before the planned surgical procedure. These systems do not accommodate for brain shift that is unavoidable once the cranium is opened and cerebrospinal fluid is lost. Intraoperative MRI (ioMRI) systems ranging in strength from 0.12 to 3 Tesla (T) have been developed in part because they afford neurosurgeons the opportunity to accommodate for brain shift during surgery. Other distinct advantages of ioMRI include the excellent soft tissue discrimination, the ability to view the surgical site in three dimensions, and the ability to "see" tumor beyond the surface visualization of the surgeon's eye, either with or without a surgical microscope. The enhanced ability to view the tumor being biopsied or resected allows the surgeon to choose a safe surgical corridor that avoids critical structures, maximizes the extent of the tumor resection, and confirms that an intraoperative hemorrhage has not resulted from surgery. Although all ioMRI systems allow for basic T1- and T2 weighted imaging, only high-field (>1.5 T) MRI systems are capable of MR spectroscopy (MRS), MR angiography (MRA), MR venography (MRV), diffusion-weighted imaging (DWI), and brain activation studies. By identifying vascular structures with MRA and MRV, it may be possible to prevent their inadvertent injury during surgery. Biopsying those areas of elevated phosphocholine on MRS may improve the diagnostic yield for brain biopsy. Mapping out eloquent brain function may influence the surgical path to a tumor being resected or biopsied. The optimal field strength for an ioMRI-guided surgical system and the best configuration for that system are as yet undecided. PMID- 20960332 TI - 3 T ioMRI: the Istanbul experience. AB - Intraoperative imaging technologies have improved surgical results in glioma and pituitary adenoma surgeries. With improvements and refinements 3T intraoperative MRI systems offer a potential of further improving these results. Hereby we describe the equipment and technique of a cost-effective shared-resource 3-T ultra-high field intraoperative magnetic resonance imaging system and report our continuing experience on surgical tumor resection. A description of the facility design and equipment are given along with examples from our experience on low grade gliomas and transsphenoidal surgeries. Our facility based on the twin room concept and uses a 3-T Siemens Trio (Siemens, Erlangen, Germany) scanner. The unit consists of adjacent but independent MRI and operative suites, which are connected by a wide door for ioMRI procedure but are used as conventional MRI and operative units. Rigid head fixation during neurosurgery is achieved with a custom designed 5 pin head-rest which also combines a 4+4 channel head coil. Operation is performed using regular non-MRI compatible equipment and the patient is transferred to the MRI during the procedure using a custom designed floating table. Advanced sequences such as diffusion weighted and diffusion tensor imaging, MR angiography, MR venography, MR spectroscopy can be performed with no changes in the setup and result in image quality comparable to outpatient scans. The intraoperative 3-T ultra high field MRI unit with the twin room concept permits both diagnostic outpatient imaging and image guided surgery in the same setting and is a cost effective solution to afford a highly capable ioMRI system. PMID- 20960333 TI - Intra-operative 3.0 T magnetic resonance imaging using a dual-independent room: long-term evaluation of time-cost, problems, and learning-curve effect. AB - We present a short and comprehensive report of our 39-month experience using a 3.0 T intra-operative magnetic resonance imaging (ioMRI) neurosurgical-MR twin room, including a description of the problems encountered and the associated time delays. Forty-seven problems were experienced during the 189 ioMRI procedures (two ioMRI were performed in five of the 184 surgical procedures) performed in the 39-month period, including a blocked transfer table, failure of anesthetic monitoring material, and specific MRI-related problems, such as head and coil positioning difficulties, artefacts, coil malfunctions and other technical difficulties. None of these problems prevented the ioMRI procedure from taking place or affected image interpretation, but they sometimes caused a significant delay. Fifteen (32%) of these problems occurred during the initial learning curve period. The mean duration of the ioMRI procedure was 75 min, which decreased slightly with experience, although an average waiting-for-access time of 24 min could not be avoided. These results illustrate that although performing ioMRI at 3.0 T with the dual room is a challenging procedure, it remains safe and feasible and associated with only minor dysfunctions while offering optimal image quality and standard surgical conditions. PMID- 20960334 TI - Multifunctional surgical suite (MFSS) with 3.0 T iMRI: 17 months of experience. AB - The 3T ioMRI in Prague is composed of two independent suites: the operating theatre and the 3T MR suite, both of which can and do work independently. They are connected by a double door and a special transportation system. The whole operating table is moved on rails to and from the MR gantry. Anaesthesiological equipment is built from paramagnetic material, which is also moved to and from the MR suite. The integral parts of the multifunctional surgical suite (MFSS) are the neuronavigation system, electrophysiological monitoring, surgical microscope with availability of indocyanin green angiography and fluorescence-guided glioma resection technique and endoscopy equipment. The operating theatre is equipped in a normal fashion with the exception of a head holder that is paramagnetic. MR radiologist and MR assistants are alerted approximately 30 min before the requested intraoperative and out-patient service is interrupted to clean the MR suite. The ioMRI takes 15-20 min and immediately after the door closes the out patient activity is resumed. Intraoperative MR was performed in 332 surgeries in the first 17 months of operation. The most frequent indications were pituitary adenomas, followed by gliomas. Other indications were less frequent and included meningiomas, cavernomas, aneurysms, epilepsy surgery, intramedullary lesions, non pituitary sellar lesions, metastases and various other surgeries. In 332 cases no technical or medical complication connected with ioMRI was encountered. PMID- 20960335 TI - Intra-operative MRI at 3.0 Tesla: a moveable magnet. AB - This paper presents the development and implementation of an intra-operative magnetic resonance imaging (ioMRI) program using a moveable 3.0 T magnet with a large working aperture. METHODS: A previously established prototype 1.5 T ioMRI program based on a ceiling-mounted moveable magnet was upgraded to 3.0 T. The upgrade included a short, 1.73 m, magnet with a large 70 cm working aperture (IMRIS, Winnipeg, Canada), whole-room radio-frequency shielding, and a fully functional MR-compatible operating room (OR) table. Between January and September 2009, 100 consecutive patients were evaluated at 3.0 T. RESULTS: The ioMRI upgrade maintained a patient-focused environment. When not needed for surgery, the magnet was moved to an adjacent room. A large aperture and streamlined OR table allowed freedom of patient positioning while maintaining access and visibility. Working at 3.0 T enabled application of advanced imaging sequences to the full spectrum of neurosurgical pathology in the ioMRI environment. The use of ioMRI continues to show unsuspected residual tumor in up to 20% of cases. There were no adverse events or technical system failures. CONCLUSION: An ioMRI program based a 3.0 T moveable magnet is feasible. By moving the magnet, the system maintains a patient-focused surgical environment and the ability to share the technology between medical disciplines. PMID- 20960336 TI - One year experience with 3.0 T intraoperative MRI in pituitary surgery. AB - A multifunctional surgical suite with intraoperative 3.0 T MRI (ioMRI) has been operating at the Central Military Hospital, Prague since April 2008. Our experiences over the past year and the effect of ioMRI on the extent of pituitary adenoma resection are evaluated. Eighty-six pituitary adenoma resections were performed in 85 patients with ioMRI in the first year of the ioMRI service. Pituitary adenoma suprasellar extension was present in 60 cases, invasion into cavernous sinus in 49 cases, and retrosellar growth in one case. The surgical goal was set before surgery: either a radical resection (49 cases) or a partial resection (37 cases). In the group of patients where a decision for a radical resection was taken the results are as follows: ioMRI confirmed radical resection in 69.4% of the cases; ioMRI disclosed unexpected adenoma residuum and further resection led to radical resection in 22.4%. In the group of patients where a decision for a partial resection was taken, the results are as follows: no further resection was perfomed after ioMRI in 51.3% of the cases and further resection was performed after ioMRI in 48.7% of the cases. ioMRI seems to be a valuable tool to increase the extent of pituitary adenoma resection. PMID- 20960337 TI - Intraoperative computed tomography. AB - Intraoperative computed tomography (iCT) has gained increasing impact among modern neurosurgical techniques. Multislice CT with a sliding gantry in the OR provides excellent diagnostic image quality in the visualization of vascular lesions as well as bony structures including skull base and spine. Due to short acquisition times and a high spatial and temporal resolution, various modalities such as iCT-angiography, iCT-cerebral perfusion and the integration of intraoperative navigation with automatic re-registration after scanning can be performed. This allows a variety of applications, e.g. intraoperative angiography, intraoperative cerebral perfusion studies, update of cerebral and spinal navigation, stereotactic procedures as well as resection control in tumour surgery. Its versatility promotes its use in a multidisciplinary setting. Radiation exposure is comparable to standard CT systems outside the OR. For neurosurgical purposes, however, new hardware components (e.g. a radiolucent headholder system) had to be developed. Having a different range of applications compared to intraoperative MRI, it is an attractive modality for intraoperative imaging being comparatively easy to install and cost efficient. PMID- 20960338 TI - Intraoperative CT in spine surgery. AB - BACKGROUND: In spinal instrumentation the misplacement of screws, cages and rods may cause neurovascular complications. Therefore a large variety of methods have been used in recent years to reduce such complications especially by navigation techniques and intraoperative three-dimensional fluoroscopy. The aim of this study is to answer the question: will intraoperative CT improve the efficiency of the treatment as well as the safety for the patient at the spinal instrumentation? Specific questions were: are the implants placed correctly and has decompression been performed sufficiently? METHODS: This is a prospective study in 100 patients mostly with degenerative diseases, tumours and trauma. 80 patients were treated by spinal instrumentation. A helical CT (Somatom Emotion 2003) was used, which is firmly bound to the OR table by a track system. RESULTS: 569 implants were used: 159 vertebra body screws and plates, 88 cages, 154 pedicle screws, 73 facet joint screws and 95 rods. There was malpositioning in seven patients (8.75%). 18 of 154 pedicle screws were misplaced, 2 of 88 cages, and 4 of 73 facet joint screws, for a total of 24 (7.6%). CONCLUSIONS: Intraoperative CT is a useful tool to check the correct position of the implants used, the extent of decompression and the realignment as early as possible. It therefore reduces second operations. A postoperative CT is no longer necessary. PMID- 20960339 TI - O-arm guided balloon kyphoplasty: preliminary experience of 16 consecutive patients. AB - Balloon kyphoplasty is now widely used for the treatment of vertebral compression fractures. Excellent pain relief is achieved with cement injection, but the safety of the procedure relays on excellent radiological exposure. The balloon kyphoplasty technique is usually performed using one or two C-Arm devices to allow correct antero-posterior (AP) and lateral view throughout the surgical procedure. By definition, this minimal invasive spine surgery is associated with radiation exposure for both the patient and the surgeon. In our center, we recently moved from this way of proceeding to the use of an O-Arm image guidance system to perform cement augmentation in vertebral fractures. To our knowledge, there is no clinical series describing the O-arm use in a balloon kyphoplasty procedure published in the scientific literature. We prospectively evaluate on 16 consecutive patients, the feasibility of the O-Arm guided kyphoplasty procedure with the original, usual tools, and we measured the fluoroscopy time and the X ray exposure. We didn't experience any device related problem and demonstrated a significant reduction of X-ray exposure and time of fluoroscopy. We believe that using this new intraoperative system, the overall time of surgery and fluoroscopy could still be reduced in a near future. PMID- 20960340 TI - Intra-operative imaging with 3D ultrasound in neurosurgery. AB - In recent years the quality of ultrasound (US) imaging has improved considerably. The integration of three dimensional (3D) US with neuronavigation technology has created an efficient and inexpensive tool for intra-operative imaging in neurosurgery. Our experience is based on more than 900 operations with the intra operative 3D ultrasound equipment SonoWand(r) and some operations with the research equipment Custux X. The technology has been applied to improve surgery of intraparencymal brain tumours, but has also been found to be useful in a wide range of other procedures, such as operations for cavernomas, skull base tumours, medulla lesions, arteriovenous malformations (AVMs) and for endoscopy guidance. Compared to intraoperative magnetic resonance imaging (ioMRI), 3D US technology is advantageous in different ways: it is flexible and can be used in any operation theatre. There is no need for special instruments, and no need for radiologists or technicians. It adds very little extra time to the operation, and the investment-costs are considerably lower than for ioMRI. PMID- 20960341 TI - Intraoperative 3-dimensional ultrasound for resection control during brain tumour removal: preliminary results of a prospective randomized study. AB - INTRODUCTION: The amount of resection is closely related to survival in brain tumours. To enhance resection, especially intraoperative magnetic resonance imaging (MRI) has been applied. The aim of this prospective, randomized study was to test if intraoperative 3-D ultrasound likewise can be used for resection control. METHODS: 16 patients, who underwent surgery for intraaxial tumours in non-eloquent brain areas, were initially included into this prospective study. In two patients, the small size of the craniotomy hindered intraoperative ultrasound imaging. In 14 patients, 3-D ultrasound images were obtained before and after opening of the dura, during tumour removal, prior to evaluation by a blinded investigator for identification of tumour remnants, and after dura closure. Seven patients were randomized to complete tumour removal according to the impression of the surgeon (group 1). Seven patients were randomized to incomplete tumour removal (tumour remnant <1cm) (group 2); in these patients, the neurosurgeon intentionally left a tumour remnant prior to evaluation by the blinded investigator. The tumour remnant was then removed. It was tested if 3-D ultrasound can correctly identify complete and incomplete tumour resection. All patients underwent early postoperative MRI. RESULTS: In two patients (one each of the two groups) the image quality was too poor for a meaningful intraoperative evaluation. In the six patients randomized for incomplete tumour removal, 3-D ultrasound correctly identified tumour remnants in four patients (67%). In six patients randomized for complete tumour removal, 3-D ultrasound confirmed complete tumour resection in three patients. In addition, 3-D ultrasound identified correctly one tumour remnant in a patient randomized for complete tumour removal. Thus, the sensitivity for tumour remnant detection increased to 71% (five of seven patients) and that of confirmation of complete tumour removal was 60 % (three of five patients). CONCLUSION: The number of investigated patients is still to low to allow definite conclusions. However, the study results suggest, that 3-D ultrasound is especially helpful for detection of overseen brain tumour tissue. PMID- 20960342 TI - Advantages and limitations of intraoperative 3D ultrasound in neurosurgery. Technical note. AB - Three-dimensional ultrasound (US) technology is supposed to help combat some of the orientation difficulties inherent to two-dimensional US. Contemporary navigation solutions combine reconstructed 3D US images with common navigation images and support orientation. New real-time 3D US (without neuronavigation) is more time effective, but whether it further assists in orientation remains to be determined. An integrated US system (IGSonic, VectorVision, BrainLAB, Munich Germany) and a non-integrated system with real-time 3D US (iU22, Philips, Bothell, USA) were recently compared in neurosurgical procedures in our group. The reconstructed navigation view was time-consuming, but images were displayed in familiar planes (e.g., axial, sagittal, coronal). Further potential applications of US angiography and pure US navigation are possible. Real-time 3D images were displayed without the need for an additional acquisition and reconstruction process, but spatial orientation remained challenging in this preliminary testing phase. Reconstructed 3D US navigation appears to be superior with respect to spatial orientation, and the technique can be combined with other imaging data. However, the potential of real-time 3D US imaging is promising. PMID- 20960343 TI - Integrated intra-operative room design. AB - The design of intraoperative suites require significant inputs from the neurosurgeons. Prior consideration of specific surgical objectives before investment of capital resources will enable to surgeon to yield maximum value from the project. We describe the setup of the integrated neurosurgical centre at our institution which comprises of a hybrid high field MRI suite, an OR's consisting of a multi-slice CT scanner and iso-C 3D respectively. The iCT and ioMRI OR's carry ICG angiography capabilities. These ORs are linked to also the Novalis radiosurgery suites and outpatient clinics and offices to facilitate pre surgical review, planning as well as treatment plans on a common interface via the BRAINSUITE net.Design considerations include right sit-ing of imaging equipment as well as a focus of ergonomics and design features to maximize workflow. Whenever possible, standard neurosurgical instrumentation is utilized. With widespread availability of technology, neuro-imaging in the operating room may become more prevalent. The surgeon is the lead individual in the team with regards to planning and designing the ORs to accommodate the new imaging equipment. PMID- 20960344 TI - Multimodal navigation integrated with imaging. AB - Intraoperative high-field MRI in combination and close integration with microscope-based navigation serving as a common interface for the presentation of multimodal data in the surgical field seems to be one of the most promising surgical setups allowing avoiding unwanted tumor remnants while preserving neurological function. Multimodal navigation integrates standard anatomical, structural, functional, and metabolic data. Navigation achieves visualizing the initial extent of a lesion with the concomitant identification of neighboring eloquent brain structures, as well as, providing a tool for a direct correlation of histology and multimodal data. With the help of intraoperative imaging navigation data can be updated, so that brain shift can be compensated for and initially missed tumor remnants can be localized reliably. PMID- 20960345 TI - Multimodality imaging suite: neo-futuristic diagnostic imaging operating suite marks a significant milestone for innovation in medical technology. AB - In February 2006, Tokai University Hospital officially opened the imaging operation suite, which is the first hybrid neurosurgical procedure suite to combine magnetic resonance imaging, computed tomography and angiography with a neurosurgical operating room. Here, we describe the concept of the imaging operation suite and the first 4 years' experience using this suite. PMID- 20960346 TI - Improving patient safety in the intra-operative MRI suite using an on-duty safety nurse, safety manual and checklist. AB - This paper describes the use of an on-duty safety nurse, a surgical safety manual and a checklist as an essential precursor to evaluating how these approaches affect surgical quality, communication in surgery crews and contribute to the safety of surgical care in the intra-operative magnetic resonance imaging (MRI) suite. PMID- 20960347 TI - Operating room integration and telehealth. AB - The increasing use of advanced automated and computer-controlled systems and devices in surgical procedures has resulted in problems arising from the crowding of the operating room with equipment and the incompatible control and communication standards associated with each system. This lack of compatibility between systems and centralized control means that the surgeon is frequently required to interact with multiple computer interfaces in order to obtain updates and exert control over the various devices at his disposal. To reduce this complexity and provide the surgeon with more complete and precise control of the operating room systems, a unified interface and communication network has been developed. In addition to improving efficiency, this network also allows the surgeon to grant remote access to consultants and observers at other institutions, enabling experts to participate in the procedure without having to travel to the site. PMID- 20960348 TI - Intra-operative robotics: NeuroArm. AB - This manuscript describes the development and ongoing integration of neuroArm, an image-guided MR-compatible robot. METHODS: A neurosurgical robotics platform was developed, including MR-compatible manipulators, or arms, with seven degrees of freedom, a main system controller, and a human-machine interface. This system was evaluated during pre-clinical trials and subsequent clinical application, combined with intra-operative MRI, at both 1.5 and 3.0 T. RESULTS: An MR compatible surgical robot was successfully developed and merged with ioMRI at both 1.5 or 3.0 T. Image-guidance accuracy and microsurgical capability were established in pre-clinical trials. Early clinical experience demonstrated feasibility and showed the importance of a master-slave configuration. Surgeon directed manipulator control improved performance and safety. CONCLUSION: NeuroArm successfully united the precision and accuracy of robotics with the executive decision-making capability of the surgeon. PMID- 20960349 TI - Clinical requirements and possible applications of robot assisted endoscopy in skull base and sinus surgery. AB - Functional Endoscopic Surgery of Paranasal sinuses (FESS) and Skull Base surgery is one of the most frequent surgeries performed at the ENT department of the Bonn University, Germany. Beside of surgical Navigation Robotic is one of the upcoming fields of Computer assisted Surgery developments. This work presents novel research and concepts for Robot Assisted Endoscopic Sinus Surgery (RASS) of the Paranasal sinuses and the anterior Skull Base containing the analysis of surgical workflows, the segmentation and modelling of the Paranasal sinuses and the anterior Skull Base and the development of the robotic path planning. An interdisciplinary group of software engineers and surgeons in Braunschweig and Bonn, Germany are approximate to solutions by a clinical and technical research program financed through the DFG (Deutsche Forschungsgemeinschaft, German research Community). PMID- 20960350 TI - Robotic technology in spine surgery: current applications and future developments. AB - Medical robotics incrementally appears compelling in nowadays surgical work. The research regarding an ideal interaction between physician and computer assistance has reached a first summit with the implementation of commercially available robots (Intuitive Surgical's(r) da Vinci(r)). Moreover, neurosurgery--and herein spine surgery--seems an ideal candidate for computer assisted surgery. After the adoption of pure navigational support from brain surgery to spine surgery a meanwhile commercially available miniature robot (Mazor Surgical Technologies' The Spine Assist(r)) assists in drilling thoracic and lumbar pedicle screws. Pilot studies on efficacy, implementation into neurosurgical operating room work flow proved the accuracy of the system and we shortly outline them. Current applications are promising, and future possible developments seem far beyond imagination. But still, medical robotics is in its infancy. Many of its advantages and disadvantages must be delicately sorted out as the patients safety is of highest priority. Medical robots may achieve a physician's supplement but not substitute. PMID- 20960351 TI - Microscope integrated indocyanine green video-angiography in cerebrovascular surgery. AB - Microscope integrated indocyanine green video-angiography (ICG-VA) is a new technique for intraoperative assessment of blood flow that has been recently applied to the field of Neurosurgery. ICG-VA is known as a simple and practical method of blood flow assessment with acceptable reliability. Real time information obtained under magnification of operating microscope has many potential applications in the microneurosurgical management of vascular lesions. This review is based on institutional experience with use of ICG-VA during surgery of intracranial aneurysms, AVMs and other vascular lesions at the Department of Neurosurgery at Helsinki University Central Hospital. PMID- 20960352 TI - Application of intraoperative indocyanine green angiography for CNS tumors: results on the first 100 cases. AB - PURPOSE: To investigate the application of indocyanine green (ICG) videoangiography during microsurgery for central nervous system (CNS) tumors. METHODS: One hundred patients with CNS tumors who underwent microsurgical resection from December 2006 to December 2008 were retrospectively analyzed. The diagnosis was high grade glioma in 54 cases, low grade in 17 cases, meningioma in 14 cases, metastasis in 12 cases and hemangioblastoma in 3 cases. Overall, ICG was injected intraoperatively 194 times. The standard dose of 25mg of dye was injected intravenously and intravascular fluorescence from within the blood vessels was imaged through an ad hoc microscope with dedicated software (Pentero, Carl Zeiss Co., Oberkochen, Germany). Pre-resection and post-resection arterial, capillary and venous ICG videoangiographic phases were intraoperatively observed and recorded. RESULTS: ICG videangiography allowed for a good evaluation of blood flow in the tumoral and peritumoral exposed vessels in all cases. No side effects due to ICG were observed. CONCLUSIONS: ICG video-angiography is a significant method for monitoring blood flow in the exposed vessels during microsurgical removal of CNS tumors. Pre-resection videoangiography provides useful information on the tumoral circulation and the pathology-induced alteration in surrounding brain circulation. Post-resection examination allows for an immediate check of patency of those vessels that are closely related to the tumor mass and that the surgeon does not want to damage. PMID- 20960353 TI - A technical description of the brain tumor window model: an in vivo model for the evaluation of intraoperative contrast agents. AB - The evaluation of candidate optical contrast agents for brain tumor delineation in ex vivo models may not accurately predict their activity in vivo. This study describes an in vivo model system designed to assess optical contrast agents for brain tumor delineation. The brain tumor window (BTW) model was created by performing biparietal craniectomies on 8-week-old Sprague-Dawley rats, injecting 9L glioma cells into the cortex and bonding a cover slip to the cranial defect with cyanoacrylate glue. Tumor growth was followed serially and occurred in an exponential fashion. Once tumors on the cortical surface achieved a 1mm radius, intravenous contrast agents were injected while the appearance of the cortical surface was recorded. Computerized image analysis was used to quantitatively evaluate visible differences between tumor and normal brain. Tumor margins became readily apparent following contrast administration in the BTW model. Based on red component intensity, tumor delineation improved fourfold at 50 min post-contrast administration in the BTW model (P<0.002). In summary, window placement overlying an implanted glioma is technically possible and well tolerated in the rat. The BTW model is a valid system for assessing the in vivo activity of optical contrast agents. PMID- 20960354 TI - Elongation of labia minora in Uganda: including Baganda men in a risk reduction education programme. AB - Okukyalira ensiko or 'visiting the bush' is how, in Uganda, the Baganda people name the practice of elongating the labia minora, which young girls start performing before menarche. As a mandatory rite of passage that identifies membership of the tribe, one of its main purposes is to enhance sexual pleasure for both male and female partners. The conditions in which it is practiced involve certain physical health risks. In this qualitative study carried out in Wakiso district, a semi-structured interview was conducted among 31 Baganda men, in order to understand their perceptions, attitudes and knowledge toward the way in which their daughters practise labia minora elongation. According to our results, men highly value this practice for its capacity to enhance sexual stimulation even though they are aware of its risks. Since genital stretching is likely to endure, the authors discuss the possibility of addressing Baganda men by health workers in an education programme aimed at minimising the risks attached to the procedure and, hence, improving the sexual and reproductive health of Baganda girls. PMID- 20960355 TI - Blockage and flow: intimate experiences of condoms and microbicides in a South African clinical trial. AB - Based on qualitative research undertaken during a phase-three microbicide gel trial, this paper explores female participants' experiences and perceptions of gel and condom use and the opinions of their male partners and community members. Participants were aware that condoms were effective in preventing HIV infection and that the efficacy of the microbicide was unproven. Yet, in narratives about gel and condom use, participants ascribed improvements to their reproductive health and intimate relationships with men to gel use. In contrast, condoms were believed to prevent disease, yet also embodied mistrust, were believed to contain dangerous substances and were felt to block the womb. These apparently contradictory views about condoms and gels are explored in the light of conceptions of flow and blockage. Health is achieved by maintaining a steady balance of substances within the body, while preventing fluid flow results in illness. We argue that women enrolled in the trial broadened the meaning of the gel beyond its primary intended effect of preventing HIV. Through their accounts of gel use, women 'reinvented' the gel as a substance that transformed their bodies and sexual relations. This has implications for understanding how local knowledge of health and illness intersects with biomedical knowledge. PMID- 20960356 TI - Through the lens of hetero-normative assumptions: re-thinking attitudes towards gay parenting. AB - In this study we explored the attitudes and beliefs of nine heterosexual adults towards gay male and female couples parenting children. We conceptualised participants' perceptions as one primary lens through which gay parenting is viewed. Based on the narratives provided, this lens comprised hetero-normative, homophobic or heterosexist assumptions and coloured the way in which participants perceived aspects of the concept of gay couples parenting children. At times, participants attempted to adjust their primary lens and adopt different views that initially suggested ambivalence and sometimes contradictory positions. Despite the range of attitudes and assumptions about same-sex parenting, consensus over the potential negative developmental impact on children raised by same-sex parents remained evident. Evidence suggests that same-sex parenting is already a reality in Westernised nations and has little or no bearing on the sexual orientation of children. However, concern that children be brought up with every opportunity to 'become' heterosexual, whether they are the product of same sex or opposite-sex parents, remains evident. PMID- 20960357 TI - Responsibility, risk and negotiation in the discourse of gay men's group sex. AB - Responsibility for the practise of (un)safe sex, for taking or not taking risks in relation to HIV transmission and for the negotiation of (safe) sex have been concerns in HIV-prevention research for a long time. This paper presents the findings of a discourse analysis of interview texts collected as part of the Three or More Study. We examine what, in the discourse examined, constrains and enables 'response-ability' - the capacity to respond to others and one's self in light of the complex contingencies that operate to enliven sexual contexts. We identify three key aspects of these sexual contexts that impact on response ability: that there is an absence of 'explicit' (verbally communicated) negotiation and the presence of action-perception links, which are understood as forms of negotiation; that some sexual contexts appear to involve the passivity of participants to the sexual event, interaction or to other men, but that there is agency in and as part of this passivity; and that there exists a social obligation to being individually responsible for sexual decision making, including the taking of risks. PMID- 20960358 TI - Analysis of isothiazolinone biocides in paper for food packaging by ultra-high performance liquid chromatography-tandem mass spectrometry. AB - A novel and simple method to detect isothiazolinone-type biocides (2-methyl-3 isothiazolinone (MI), 5-chloro-2-methyl-3-isothiazolinone (CMI), 1,2 benzisothiazolinone (BIT) and 2-octyl-3-isothiazolinone (OIT)) in paper used for food packaging by ultrasonic extraction coupled with UPLC-MS/MS was developed. Parameters affecting process efficiency such as extraction solvents, UPLC mobile phase, gradient elution procedure and MS/MS conditions were studied to optimise the operating conditions. Using the optimised gradient elution procedure, the retention time was less than 6 min. The limits of detection (LODs) were found to be between 0.001 and 0.010 mg kg-1, which was validated using actual concentrations. After diluting the standard solution with a blank matrix, the linear calibration curve ranges were 0.002-1.000 mg kg-1 for BIT and OIT, 0.005 1.000 mg kg-1 for MI, and 0.020-1.000 mg kg-1 for CMI, with correlation coefficients higher than 0.9985 (n = 6). A good level of precision with a mean recovery greater than 81.3% and a relative standard deviation (RSD) less than 6.2% were also obtained. A methodology has been proposed for the analysis of isothiazolinones in paper. PMID- 20960359 TI - Validation of the procedure for the simultaneous determination of aflatoxins ochratoxin A and zearalenone in cereals using HPLC-FLD. AB - Method validation for quantitative analysis of aflatoxins (AFs), ochratoxin A (OTA) and zearalenone (ZEA) in cereals using HPLC with fluorescence detector (FLD) is described. Mycotoxins were extracted with methanol : water (80 : 20) and purified with a multifunctional AOZ immunoaffinity column before HPLC analysis. The validation of the analytical method was performed to establish the following parameters: specificity, selectivity, linearity, limits of detection (LOD) and quantification (LOQ), accuracy, precision (within- and between-day variability), stability, robustness, measurement of performance, and measurement of uncertainty. Calibration curves were linear (r > 0.999) over the concentration range, from the LOQ to 26, 40 and 400 ng/g for AFs, OTA and ZEA, respectively. LOD and LOQ were 0.0125 and 0.05 ng/g for aflatoxin B1 (AFB1) and G1 (AFG1), 0.0037 and 0.015 ng/g for aflatoxin B2 (AFB2) and G2 (AFG2), as well as 0.05 and 0.2 ng/g for OTA and 0.5 and 2 ng/g for ZEA, respectively. The mean recovery values were 77-104% for different concentrations of AFs, OTA and ZEA in spiked cereal samples. Both intra- and inter-day accuracy and precision were within acceptable limits. This method was successfully applied for the simultaneous determination of mycotoxins for 60 cereal samples collected from Malaysian markets. Fifty per cent of the cereal samples were contaminated with at least one of these mycotoxins, at a level greater than the LOD. Only one wheat sample and two rice samples were contaminated with levels greater than the European Union regulatory limits for AFs and OTA (4 and 5 ng/g). The means and ranges of mycotoxins obtained for the cereal samples were 0.4 ng/g and 0.01-5.9 ng/g for total AFs; 0.18 ng/g and 0.03-5.3 ng/g for OTA; and 2.8 ng/g and 2.4-73.1 ng/g for ZEA, respectively. The results indicate that the method is suitable for the simultaneous determination of AFs, OTA and ZEA in cereals and is suitable for routine analysis. PMID- 20960360 TI - Factors influencing sexual initiation, multiple partners and condom use among male slum youth in Pune, India. AB - This study examines the factors that influence sexual behaviours among young unmarried males living in urban slums in India, a population characterised by high vulnerability to STI and HIV infections. Data were collected from 600 unmarried male slum youth to examine the relationships between three outcomes of heterosexual behaviour (age at sexual initiation, number of sexual partners and condom use at first intercourse) and factors within the family/household social environment, peer environment and individual level during the respondents' formative years. Regression analyses found factors within the family and peer level domains such as growing up in a two-parent household, having adequate levels of parental supervision, experiencing violence in the home and having peers who drank significantly impact the age of sexual debut and the subsequent number of lifetime partners. Condom use at first intercourse appears to be significantly influenced by age of sexual debut and type of sexual partner. These findings indicate that in low-resource urban settings, the influence of family and friends as role models can play an important role in determining the initiation of sexual behaviour among male youth and in making behaviour choices that result in favourable health outcomes. PMID- 20960362 TI - Identifying the causal pathways from religiosity to delayed adolescent sexual behavior. AB - This study used the Integrative Model as a framework to examine whether religiosity delays onset of coitus among a longitudinal sample of virgins, and investigated the causal pathways of this relationship. In addition, this study examined the behavioral beliefs about the consequences of engaging in sex, which distinguishes between youth who vary in level of religiosity. A further analysis was also conducted to examine whether religiosity offers protective effects in terms of progression toward sexual intercourse on a sexual behavior index. The sexual behavior index assumes a progressive nature of sexual behaviors, and includes the following seven behaviors: kissing, having breasts touched (touching for boys), genital touching, receiving oral sex, vaginal intercourse, giving oral sex, and receiving (or giving) anal sex. Religiosity at baseline was negatively associated with sexual debut one year later. This relationship was mediated through attitudes toward personally engaging in sexual intercourse. Religiosity at baseline was also negatively associated with scores on the sexual behavior index one year later. These results suggest that religiosity offers protective effects for both coital and noncoital sexual behaviors. PMID- 20960363 TI - Carbon outclasses wood in racket paddles: Ratings of expert and intermediate tennis players. AB - Wooden racket paddles were modified with rubber and carbon fibre laminates and their differences tested in terms of flexural, damping, and coefficient of restitution properties. Four rackets types were designed: a wood reference, wood with rubber, carbon fibre 0 degrees , and carbon fibre 90 degrees . Seven expert and eight intermediate tennis players tested the rackets. To determine which of the four rackets suited the players best, we asked the players to compare the rackets two by two. After each pair tested, participants had to fill out a 4-item questionnaire in which different aspects of the rackets' performance were judged. The most preferred racket was the 0 degrees carbon fibre racket, followed by the 90 degrees carbon fibre racket, the wood racket and, finally, the 1-mm rubber racket. Thus, rackets with the highest stiffness, least damping, and highest coefficient of restitution were the most preferred. Interestingly, although experts and intermediate players overall judged the rackets in very similar ways according to force, vibration, and control, they were sensitive to quite different physical characteristics of the rackets. PMID- 20960364 TI - Reliability and discriminative ability of a modified Wingate rowing test in 12- to 18-year-old rowers. AB - We evaluated (1) the test-retest reliability of the Wingate test conducted on a rowing ergometer, and (2) the sensitivity of this test in determining the differences in performance attained by 12- to 18-year-old rowers. Altogether, 297 male rowers aged 12.0-18.9 years (mean +/- s: 14.8 +/- 1.7) completed a maximal 30-s test on a rowing ergometer, and 80 rowers representing all age groups were retested after 5-7 days. No change was evident in participants' performance in terms of mean power output (P = 0.726; Cohen's d = 0.04), maximal power output (P = 0.567; Cohen's d = 0.06), and minimum power output (P = 0.318; Cohen's d = 0.11) in the second test. The intra-class correlation coefficients were high (>=0.973) and coefficients of variation were low (<=7.3%). A series of analyses of variance were used to compare the performances among 12- to 18-year-old rowers, and age-related increases in performance were evident (P < 0.001; Cohen's d = 1.91-1.96). The age-related increases in performance were similar, although reduced, when the effects of body mass were partitioned out when using analysis of covariance (P < 0.001; Cohen's d = 0.82-0.85). The results suggest that: (1) the described test is reliable and can be used for maximal-intensity exercise assessment in youth rowing, and (2) it discriminates performance among 12- to-18 year-old rowers. PMID- 20960365 TI - [Case-Report: Reversal of a deep neuromuscular block with sugammadex after rapid sequence induction with high-dose rocuronium bromide]. AB - Sugammadex can reverse rocuronium-induced muscular relaxation by encapsulation of steroidal muscle relaxants without muscarinergic side effects. Clinical studies show effective dose-dependent reversal of neuromuscular blockades after rocuronium and vecuronium. We report on a patient with deep neuromuscular block at the end of surgery following rapid sequence induction of anesthesia with high dose rocuronium, who could rapidly be reversed without side effects after adequate i.v. sugammadex application. PMID- 20960366 TI - [Anaesthesia for children with epidermolysis bullosa]. AB - Epidermolysis bullosa (EB) is a heterogeneous group of inherited rare diseases, which are characterized by trauma-induced blister formation of the skin and mucosa. The underlying cause is a functional deficiency of structural proteins of the epidermis or the dermis. Depending on the level of the blister formation, EB is divided into EB simplex (intra-epidermal), junctional EB (within the lamina lucida), dystrophic EB (below the lamina lucida) and Kindler syndrome (variable level of split formation). Besides different distinct blister formation and pain symptoms secondary problems like anaemia, oesophageal stenosis, cardiomyopathy or squamous cell carcinoma may occur. Since causal therapies are not available strict prevention of friction and trauma is essential to avoid blister formation. Anaesthesia challenges exist in the field of bedding procedures, care of the skin, monitoring, airway management und analgesia. This article gives a review over the EB and highlights in detail the corresponding anaesthesia characteristics. PMID- 20960367 TI - [Occupational stress in anesthesiology--why we should talk about it]. PMID- 20960368 TI - [Burden and health effects of shift work]. AB - In Germany aprox. 15% of all employees have irregular or flexible working hours. Disturbed sleep and/or hypersomnia are direct consequences of shift work and therefore described as shift work disorder. Beyond this, shift work can also be associated with specific pathological disorders. There are individual differences in tolerance to shift work. Optimization of both shift schedules and sleep to "non-physiological" times of the day are measures to counteract the negative effects of shift work. There is still not enough evidence to recommend drugs for routine use in shift workers. PMID- 20960369 TI - [Addicted anaesthetists]. AB - Drug dependence of anaesthetists occurs more often than in other physicians, especially the noxious usage of common substances in anaesthesiology and pain management like opioids and anaesthetics. Opioids are the most frequent abusively taken medication followed by benzodiazepines, illegal drugs, Propofol and Ketamine. Determining for the behavioral pattern is the easy access to the drugs. Especially as some of the addictive-drugs (e. g. Propofol, Ketamine) are not underlying any release-control. Recent German surveys confirm the American figures. For the development of drug dependence many factors like biographic, social and genetic aspects as well as the substances and their potential itself are significant. Furthermore, the presence of many stimuli encourages the relapse risk for addicted people despite earlier abstinence. At least 16% of all cases and 37% of the Propofol-addiction cases proceed deadly. American studies with structured therapy-, rehabilitation- and follow-up surveillance-programs show a positive prognosis for anaesthetists. In Germany it requires rethinking and the establishment of comparable therapy-offers and facilities. PMID- 20960370 TI - [Professional burden for anaesthesiologists: "life after death"]. AB - The confrontation with lethal courses, either due to fate or treatment errors, is an inevitable factor in the professional life of anaesthesiologists working in the fields of pain and palliative medicine as well as in emergency and intensive medicine. Even those active in the central service of anaesthesia in the operating room are not strangers to this topic. Thus it is even more surprising that neither during undergraduate studies nor during continuing medical education are systematic aids or guidelines provided on how to cope with such situations. Furthermore, there are no structured recommendations on how individual physicians, institutions or their superiors should behave in such circumstances. This is worrying as post-traumatic stress disorders can result from these experiences and can be detrimental to further professional and private lives ranging through to burn-out, substance abuse, or abandonment of the medical profession, etc. Lessons can be learnt from the German railways that have long offered a structured counselling concept for train drivers who have been involved in accidents with human injury. The present article is thus intended to promote a sensitisation for the topic and the resultant problems in individual cases as well to provide first considerations on the establishment of possible remedial structures. PMID- 20960371 TI - [Presence and future of emergency medicine in Germany]. AB - Health care policy has changed duties and responsibilities of hospitals in Germany. The transition zone of in- and outpatient care has been recognized as a critical gateway for the success of hospitals, subsequently leading to the appreciation of the value of professionalized emergency departments. Currently, hospital-based emergency medicine in Germany is organized in a very heterogeneous manner. Due to the key function of emergency departments for the medical and economic success of hospitals, professional expertise in clinical emergency medicine has to be strengthened: We discuss possible models of hospital-based emergency care and present first data that professionalisation of hospital-based emergency medicine in Germany improves treatment quality and outcome of patients presenting with chest-pain or community-acquired pneumonia to the emergency department. Furthermore, those strategies are accompanied with the improvement of economic characteristics. Summing up, professionalisation of hospital-based emergency medicine in Germany is urgently needed and may improve medical and economic success of hospital-based patient care. PMID- 20960373 TI - Hepatitis A and hepatitis C viruses: divergent infection outcomes marked by similarities in induction and evasion of interferon responses. AB - Hepatitis A and hepatitis C viruses (HAV and HCV) are both positive-strand ribonucleic acid (RNA) viruses with hepatotropic lifestyles. Despite several important differences, they share many biological and molecular features and similar genome replication schemes. Despite this, HAV infections are usually effectively controlled by the host with elimination of the virus, whereas HCV most often is able to establish lifelong persistent infection. The mechanisms underlying this difference are unknown. The cellular helicases RIG-I and MDA5, and Toll-like receptor 3, are pattern recognition receptors that sense virus derived RNAs within hepatocytes in the liver. Activation of these receptors leads to their interaction with specific adaptor proteins, mitochondrial antiviral signaling protein (MAVS) and TIR-domain-containing adapter-inducing interferon beta (TRIF), respectively, which engage downstream kinases to activate two crucial transcription factors, nuclear factor kappa B (NF-kappaB) and interferon regulatory factor 3 (IRF3). This results in the induction of interferons (IFNs) and IFN-stimulated genes that ultimately establish an antiviral state. These signaling pathways are central to host antiviral defense and thus frequent targets for viral interference. Both HAV and HCV express proteases that target signal transduction through these pathways and that block the induction of IFNs upon sensing of viral RNA by these receptors. An understanding of the differences and similarities in the early innate immune responses to these infections is likely to provide important insights into the mechanism underlying the long-term persistence of HCV. PMID- 20960374 TI - New insights into structure and replication of the hepatitis C virus and clinical implications. AB - With the advent of efficient systems to propagate the hepatitis C virus (HCV) in cultured cells important new discoveries have been made. For instance, several molecules required for HCV infection of hepatocytes have been identified and first insights into the entry pathway have been gained. Ribonucleic acid (RNA) replication and virion assembly were found to be tightly linked to lipid metabolism and numerous host factors contributing to viral replication have been identified. Some of them such as cyclophilin A or microRNA-122 are attractive targets for antiviral therapy as are the viral serine-type protease residing in nonstructural protein 3 (NS3) and the NS5B RNA-dependent RNA polymerase. More recently, the viral phosphoprotein NS5A emerged as an additional and very promising target for selective therapy. These results illustrate the great progress that has been made in the HCV field and how this knowledge can be used to devise innovative strategies to counteract this pathogen. PMID- 20960375 TI - Management of untreated and nonresponder patients with chronic hepatitis C. AB - Hepatitis C infection has evolved in the past quarter century from a newly recognized entity without a known pathogen (non-A, non-B hepatitis) to one of the world's most prevalent causes of liver disease, an important source for hepatocellular carcinoma, and the major indication for liver transplantation. It is caused by a virus with a complex replication cycle that occurs in multiple genotypes, of which the four most prevalent (1, 2, 3, and 4) exhibit differences in clinical behavior and responses to therapy. Chronic hepatitis C virus (HCV) in particular has evolved from a disease with no known treatment to one with several primary treatment options, none of which is uniformly effective, and a growing list of secondary treatment options for those who have failed to respond to, or relapsed after initial therapy. As treatment is often associated with significant side effects, it is now a disease that presents clinicians with multiple important decisions: whom to treat, when and with what to treat them initially, and how to manage patients who have failed during initial therapy to achieve a sustained virological response, the gold standard of effective therapy. This review examines each of these important decisions, presenting evidence to help guide clinicians in their choices. The decisions are addressed sequentially as they arise during the initial evaluation and subsequent treatment of a typical, newly recognized patient with chronic HCV, and the considerations facing the clinician when the patient has failed to achieve an SVR. PMID- 20960376 TI - Management of chronic hepatitis B: status and challenges beyond treatment guidelines. AB - Several national and international guidelines have been published in the last years focusing on the problem of how to best treat patients with chronic hepatitis B virus (HBV) infection. Therapy with interferon or nucleos(t)ide analogues has been shown to be most effective in suppressing HBV deoxyribonucleic acid (DNA) levels and preventing fibrosis progression herby also reducing the risk of hepatocellular carcinoma (HCC). However even suppression of viral replication below the limit of detection does not prevent HCC development although fibrosis can be stopped. Thus, improvement of therapeutic strategies and the establishment of more sensitive markers that may help to decide when therapy should be initiated and stopped remain important goals in hepatitis research. The present review discusses several major issues in this respect such as strategies to identify the optimal time point for treatment indication and end of therapy. It also concentrates on questions and queries that have to do with the interpretation of viral parameters like HBsAg quantification, HBV genotypes, and HBeAg, or the characterization of risk patients prone to develop fatal sequel of the HBV infection. PMID- 20960377 TI - The role of lipid metabolism in the pathogenesis of alcoholic and nonalcoholic hepatic steatosis. AB - Hepatic steatosis is now understood to play an important role in the development of advanced liver disease. Alcoholic and nonalcoholic fatty liver each begin with the accumulation of lipids in the liver. Lipid accumulation in the liver can occur through maladaptations of fatty acid uptake (either through dietary sources or from fat tissue), fatty acid synthesis, fatty acid oxidation, or export of lipids from the liver. Alterations in mechanisms of fatty acid uptake through both dietary uptake and lipolysis in adipose tissue can contribute to the pathogenesis of both disorders, as can effects on fatty acid transporters. Effects on lipid synthesis in alcoholic and nonalcoholic fatty liver involve the endoplasmic reticulum (ER) stress response, homocysteine metabolism pathway, and different transcription factors regulating genes in the lipid synthesis pathway. Fatty acid oxidation, through effects on AMP-activated protein kinase (AMPK), adiponectin, peroxisome proliferator-activated receptors (PPARs), and mitochondrial function is predominantly altered in alcoholic liver disease, although studies suggest that activation of this pathway may improve nonalcoholic fatty liver disease. Finally, changes in fatty acid export, through effects on apolipoprotein B and microsomal transport protein are seen in both diseases. Thus, the similarities and differences in the mechanism of fat accumulation in the liver in nonalcoholic and alcoholic liver disease are explored in detail. PMID- 20960378 TI - Novel insights into the pathophysiology of nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease affecting both adults and children in the United States and many other parts of the world. NAFLD encompasses a wide spectrum of conditions associated with overaccumulation of lipids in the liver. It is strongly associated with obesity and insulin resistance and has been growingly recognized as an independent risk factor for cardiovascular disease. In this review, recently uncovered novel aspects of the molecular events responsible for the development and progression of this highly prevalent and potentially serious disease are discussed. These studies bring new insights that may significantly impact the clinical approach to patients with NAFLD, from novel diagnostics to innovative therapeutic strategies. PMID- 20960380 TI - Current status and future of liver transplantation. AB - Liver transplantation has rapidly advanced from an experimental therapy to a mainstream treatment option for a wide range of acute and chronic liver diseases. Indications for liver transplant have evolved to include previously contraindicated conditions such as hepatocellular carcinoma and alcohol-related liver disease. Cirrhosis from chronic hepatitis C infection remains the most common indication today. Multidisciplinary evaluation for liver transplantation is intended to confirm the patient's suitability and identify the appropriate timing of transplant, although the latter is problematic as a result of the ongoing donor organ shortage. Deceased liver donors have been increasing in number, but increasing donor age has been associated with less satisfactory posttransplant results. Living donor liver transplant is a dramatic but very infrequent procedure; risk to the living donor is of paramount concern. The main focus of deceased donor allocation has transitioned from waiting time to estimation of the likelihood of death without transplant (medical urgency), and now relies upon a laboratory-based Model for End-Stage Liver Disease (MELD) score for candidates with chronic liver disease. Those with acute liver failure are prioritized ahead of those with chronic conditions. Although not used as a direct criterion for allocation, development of the concept of transplant survival benefit, i.e., the extra years of life attributable to transplant, has facilitated better ordering of those candidates likely to have the most benefit, while restricting access to those whose lives will be extended minimally or not at all. Overall posttransplant outcomes have steadily improved, with unadjusted 5 year patient survival rates of 77% among patients transplanted with MELD score between 15 and 20, and 72% for those with MELD scores between 21 and 30. PMID- 20960379 TI - Apoptosis as a mechanism for liver disease progression. AB - Hepatocyte injury is ubiquitous in clinical practice, and the mode of cell death associated with this injury is often apoptosis, especially by death receptors. Information from experimental systems demonstrates that hepatocyte apoptosis is sufficient to cause liver hepatic fibrogenesis. The mechanisms linking hepatocyte apoptosis to hepatic fibrosis remain incompletely understood, but likely relate to engulfment of apoptotic bodies by professional phagocytic cells and stellate cells, and release of mediators by cells undergoing apoptosis. Inhibition of apoptosis with caspase inhibitors has demonstrated beneficial effects in murine models of hepatic fibrosis. Recent studies implicating Toll-like receptor 9 in liver injury and fibrosis are also of particular interest. Engulfment of apoptotic bodies is one mechanism by which the TLR9 ligand (CpG DNA motifs) could be delivered to this intracellular receptor. These concepts suggest therapy focused on interrupting the cellular mechanisms linking apoptosis to fibrosis would be useful in human liver diseases. PMID- 20960381 TI - Primary hepatic signet ring cell neuroendocrine tumor: a case report with literature review. AB - Primary hepatic signet ring cell neuroendocrine tumor is extremely rare and is characterized by distinct intracytoplasmic hyaline vacuoles that are mucin negative and cytokeratin positive. The unique histological features may cause difficulty in diagnosis and delay patient care. Here the authors report a 49-year old man with an incidental finding of a 2.7 cm liver mass in the absence of chronic liver disease. The resected tumor was grossly unencapsulated but well demarcated with friable tissue texture. Microscopically, the entire tumor consisted of sheets of monotonous cells separated by delicate microvasculature. The tumor cells had granular chromatin, inconspicuous nucleoli, and eosinophilic cytoplasm. Many of the tumor cells had eccentric, pale intracytoplasmic vacuoles resembling signet ring cells in adenocarcinoma. Immunohistochemical studies showed that the tumor cells were positive for neuroendocrine markers and that the intracytoplasmic vacuoles were negative for mucin but strongly positive for cytokeratins. Careful systemic search including OctreoScan scintigraphy (Mallinckrodt Medical, Inc., St. Louis, MO) and capsule endoscopy failed to reveal any other tumors. A diagnosis of primary hepatic signet ring cell neuroendocrine tumor was established. Ten months after surgery, the patient is well without any other detectable tumor on radiology. Serological neuroendocrine markers are also within normal limits. PMID- 20960382 TI - [Deficits in adherence on all levels. Current need of interventions in primary, secondary, and tertiary prevention of cardiovascular diseases]. AB - BACKGROUND AND OBJECTIVE: Previous studies often lack any differentiation between target groups for primary, secondary and tertiary prevention of cardiovascular disease (CVD). The aim of this study was to investigate the target group-specific adherence with lifestyle recommendations in different risk groups. This information may be useful in identifying better starting points for future CVD interventions. METHODS: 2,002 men and women aged 50 to 70 years were selected by random and interviewed about their health status, health behavior and health locus of control. Adherence was defined as regular physical activity, healthy diet, non-smoking, and moderate alcohol consumption. Differences between risk groups were determined using Chi-square tests and stratified logistic regression. RESULTS: Health behavior only varied to a limited extent between the risk groups: physical activity (77.8%), healthy diet (62.2%), moderate alcohol consumption (74.4%), non-smoking (total: 75.7%; healthy respondents 70.9%; risk group 79.1%; CVD patients 74.7%). 29.6% were adherent to lifestyle recommendations. Women were more likely to be adherent than men (35.4% vs. 23.5%). In CVD patients, those living together with a partner were also more likely to have a healthy lifestyle (32.2% vs. 20.0%). Furthermore, health locus of control seems to be an important factor. CONCLUSION: In the age group 50-70 adherence with lifestyle recommendations of almost 30% is rather low and not optimal. Health locus of control as motivational barrier should be taken into account particularly in secondary prevention. There is a need of health behavior interventions not only for persons at increased risk and CVD patients, but also for the (still) healthy. Men, singles and persons with external health locus of control should be particularly addressed by these interventions. PMID- 20960383 TI - [Rupture of a superior mesenteric artery aneurysm]. AB - HISTORY AND ADMISSION FINDINGS: A 54-year-old patient presented with acute abdominal pain that had started after having a bowel movement. INVESTIGATIONS AND DIAGNOSIS: Ultrasound examination revealed free intraabdominal fluid with no signs of organ rupture. CT-scan showed a peripherally located ruptured aneurysm of a branch of the superior mesenteric artery. TREATMENT AND COURSE: Intraoperatively the aneurysm was then ligated. A vascular reconstruction or bowel resection was not necessary. After an uneventful postoperative course, the patient could be discharged from the hospital on postoperative day four. Two weeks later the patient was readmitted, with fever and dyspnea. Transesophageal echocardiogram suggested the presence of bacterial growth on the aortic and mitral valves. Blood cultures and valvular vegetations grew Streptococcus viridans. The diagnosed infective endocarditis was caused by a tooth-infection, that had been recurrent for one year. After treatment of the tooth infection, the mitral and aortic valves were replaced without any complications. CONCLUSION: Because of the high mortality associated with rupture, it is important that visceral aneurysms are taken into consideration in the differential diagnosis of unexplained abdominal pain. It should also be kept in mind that the aneurysm could be due to an infective endocarditis. Therefore, echography should be carried out in each case, to avoid further complications and to give optimal treatment. PMID- 20960384 TI - [Pathophysiology of sepsis and possible influence of statins]. AB - Severe sepsis and septic shock are common complications in the intensive care unit and associated with high mortality. Early antimicrobial therapies together with organ-supportive measures are the major therapeutic approaches. However in the last decades immunomodulatory therapies have been investigated due to the notion of a compromised inflammatory response in septic patients. In addition to lowering circulating cholesterol, statins (HMG-CoA-reductase-inhibitors) have also been shown to possess pleiotropic anti-inflammatory potential. Recent studies indicate that these anti-inflammatory effects also modulate acute inflammatory response and therefore may play a protective role in septic patients. In this review, the pathophysiological background and first clinical trials of statins as a new adjuvant therapy in sepsis are summarized. PMID- 20960385 TI - [82-year-old patient with chronic cough, pulmonary infiltrations and eosinophilia]. PMID- 20960386 TI - [Non-cardiac chest pain]. AB - Thoracic pain and discomfort are symptoms that lead many patients to the presentation in private practice or emergency admissions in hospitals. It is one of the most common complaints in the acute care setting. Attendant symptoms like agitation and fear are often signals of unstableness, but can also be alarming symptoms of an acute emergency. At first it is the main purpose to exclude an acute life-threatening event, such as acute coronary heart syndrome or pulmonary embolism. If a cardiac cause is excluded, the spectrum ranges from reflux disease and other oesophageal disorders to functional and vertebral thoracic pain. These other causes need an interdisciplinary assessment. The aim of this article is to summarize the differential diagnoses of non cardiac chest pain. The causes of non cardiac chest pain encompass a vast spectrum of various diseases with different needs of diagnosis and therapy. PMID- 20960387 TI - [The impact of a university ENT emergency centre for the ambulatory care of ENT emergency patients]. AB - BACKGROUND: The impact of a German University ENT emergency unit has not been investigated yet. The present study had the aim to define the role of such an ENT emergency unit for the medical supply of ENT emergency cases. Patients' characteristics, diagnostics and therapeutical processes have been analysed. METHODS: In a retrospective study 3 695 emergency cases of the year 2004 have been characterized. RESULTS: Patients referring to the ENT emergency unit are relative young with an average age of 36 years. 72% are coming from the urban area. Two thirds referred themselves without seeing another physician before. The spectrum of diagnoses was broad, mainly similar to the normal spectrum of diseases seen in daily outpatient practice. 17% were emergency cases in narrower sense needing direct help because of real threat. 25% of the patients needed more than a clinical ENT examination. 9% of the cases were admitted to the hospital. DISCUSSION: In a major city without specialised outpatient ENT emergency system patient are attracted regularly to present at the University ENT emergency unit. This means a significant work load for the resident on duty. Most of the patients have ENT diseases treatable with this one and last patient contact. On the other hand, the hospital recruits an important amount of patients for inpatient treatment through the emergency unit. PMID- 20960388 TI - [Detection of olfactory areas in functional MRI--how many repetitions are necessary?]. AB - BACKGROUND AND PURPOSE: A useful tool for the investigation of the human olfactory system is functional magnetic resonance tomography (fMRI). Since the length of the fMRI examination is a limiting factor for its usefulness in clinical routine in this study a fast, reliable paradigm should be found in order to reduce the overall examination time and the olfactory habituation. METHODS: A MRI-compatible constant flow olfactometer was developed. 9 healthy normosmic subjects were stimulated 16 times with the odorant phenyl-ethyl-alcohol (PEA) using an event-related design. The statistical evaluation of the data was performed by the MATLAB based SPM5 software package. RESULTS: The group analysis showed cerebral activations within the insula, the adjacent operculum and orbitofrontal cortex bilaterally. Furthermore, bilateral activations were measured in the cingulum, piriform cortex and the cerebellum. All mentioned areas could be already identified after 8 repetitions of odorant condition. Bilateral insular activations and activations in the left piriform cortex were even shown after 4 repetitions. In the single subject analysis, all 9 subjects exhibited insular activity and in 3 subjects showed activation of the piriform cortex after 4 repetitions. CONCLUSION: In olfactory fMRI, stimulus repetition more than 8 did not improve the quality and reliability of the results. Therefore, 4-8 stimuli are expected to be sufficient. PMID- 20960389 TI - Natural products published in 2009 from plants traditionally used to treat malaria. AB - Malaria is a major parasitic disease and is responsible for almost one million deaths each year in Africa. There is an urgent need to discover new active compounds. Nature and particularly plants are a potential source of new antimalarial drugs since they contain a quantity of metabolites with a great variety of structures and pharmacological activities. This review covers the compounds with antiplasmodial activity isolated from plants which have been published during 2009 organized according to their phytochemical classes. Details are given for substances with IC50 values <= 11 uM. Sixty-seven references are identified. PMID- 20960390 TI - Risk factors for advanced lesions undetected at prior colonoscopy: not always poor preparation. AB - BACKGROUND AND STUDY AIM: Colonoscopy is regarded as the gold standard for diagnosis of colonic lesions. However, adenoma miss rates in tandem colonoscopy studies vary from 2 % to 26 %. We aimed to investigate the rates of advanced neoplasia in patients with a prior normal colonoscopy in an outpatient endoscopy unit. METHODS: Review of reports for colonoscopies performed in our Endoscopy Unit from 2000 to 2005. Undetected lesions were defined as advanced adenoma or colorectal cancer (CRC) not reported in a colonoscopy performed in the previous 2 or 3 years, respectively. Patients with hereditary nonpolyposis CRC (HNPCC) and familial adenomatous polyposis (FAP) were excluded. RESULTS: Between 2002 and 2005, 795 patients were diagnosed with at least one advanced adenoma and 386 with CRC. Among these, 107/795 patients (13.5 %) had advanced adenoma that had been undetected in a previous colonoscopy (39 % [53/135 lesions] in the right colon); 92/107 (86 %) had an undetected advanced adenoma >= 10 mm. Previously undetected CRCs were found in 27/386 patients (6.7 %), located in the left colon in 21/27 (78 %); in 7 the area had not been reached in the previous colonoscopy. Risk factors for undetected advanced adenoma were advanced age, male gender, the presence of another advanced adenoma at first colonoscopy, and history of advanced neoplasia. CONCLUSIONS: Failure to detect advanced neoplasia is common in a community-based endoscopy facility. Previously undetected advanced lesions are more frequently found in the left colon and rectum. Risk factors for non detection of advanced adenoma are similar to those for advanced neoplasia recurrence. Lowering non-detection rates is crucial for correct follow-up recommendations. Patients should be aware of rates of detection of advanced neoplasia after previous normal colonoscopic findings. PMID- 20960391 TI - The role of a computed tomography-based image registered navigation system for natural orifice transluminal endoscopic surgery: a comparative study in a porcine model. AB - BACKGROUND AND STUDY AIMS: Most natural orifice transluminal endoscopic surgery (NOTES) procedures have been performed in animal models through the anterior stomach wall, but this approach does not provide efficient access to all anatomic areas of interest. Moreover, injury of the adjacent structures has been reported when using a blind access. The aim of the current study was to assess the utility of a CT-based (CT: computed tomography) image registered navigation system in identifying safe gastrointestinal access sites for NOTES and identifying intraperitoneal structures. METHODS: A total of 30 access procedures were performed in 30 pigs: anterior gastric wall (n = 10), posterior gastric wall (n = 10), and anterior rectal wall (n = 10). Of these, 15 procedures used image registered guidance (IR-NOTES) and 15 procedures used a blind access (NOTES only). Timed abdominal exploration was performed with identification of 11 organs. The location of the endoscopic tip was tracked using an electromagnetic tracking system and was recorded for each case. Necropsy was performed immediately after the procedure. The primary outcome was the rate of complications; secondary outcome variables were number of organs identified and kinematic measurements. RESULTS: A total of 30 animals weighting a mean (+/- SD) of 30.2 +/- 6.8 kg were included in the study. The incision point was correctly placed in 11 out of 15 animals in each group (73.3 %). The mean peritoneoscopy time and the number of properly identified organs were equivalent in the two groups. There were eight minor complications (26.7 %), two (13.3 %) in the IR NOTES group and six (40.0 %) in the NOTES only group ( P = n. s.). Characteristics of the endoscope tip path showed a statistically significant improvement in trajectory smoothness of motion for all organs in the IR-NOTES group. CONCLUSION: The image registered system appears to be feasible in NOTES procedures and results from this study suggest that image registered guidance might be useful for supporting navigation with an increased smoothness of motion. PMID- 20960392 TI - Risk of lymph node metastasis associated with deeper invasion by early adenocarcinoma of the esophagus and cardia: study based on endoscopic resection specimens. AB - BACKGROUND: Most risk estimations for lymph node metastasis in adenocarcinoma of the esophagus and cardia (AEC) with invasion into the muscularis mucosae (m3) or submucosa are based on surgical series. This study aimed to correlate the lymph node metastasis rate with m3 and submucosal infiltration depth of AEC in endoscopic resection specimens. METHODS: Patients undergoing endoscopic resection for AEC between January 2000 and March 2008 at two centers were included if the endoscopic resection specimen showed m3 or submucosal cancer. Infiltration into the muscularis mucosae was defined as m3. Submucosal invasion was classified as sm1 (<= 500 um) or sm2/3 (> 500 um). Exclusion criteria were chemotherapy or radiotherapy and nonradical endoscopic resection. RESULTS: 82 patients included 57 with m3, 12 with sm1, and 13 with sm2/3 cancers. Of the tumors, 13 were poorly differentiated and five showed lymphovascular invasion. After initial endoscopic resection, seven patients underwent surgery and 75 endoscopic therapy. No lymph node metastases were found in 158 lymph nodes of the esophagectomy specimens and none of the endoscopically treated patients were diagnosed with lymph node metastasis during a median follow-up of 26 months (interquartile range [IQR] 14 - 41). CONCLUSION: This study suggests that lymph node metastasis risk for m3 and submucosal AEC may be lower than has been assumed on the basis of surgical series, and that current guidelines are valid regarding suitability of m3 AECs for endoscopic therapy. It may also suggest that selected patients with submucosal cancers are also eligible for endoscopic management. Confirmation of these results is needed in larger series with longer follow-up. PMID- 20960393 TI - [Immunosuppression and infection prophylaxis after lung transplantation]. AB - Lung transplantation (LTX) is an established therapeutic option for end-stage lung diseases. The main reasons for limited long-term survival rates are infections and bronchiolitis obliterans syndrome (BOS). An optimal immunosuppressive regimen is of critical importance for the prevention of both complications. Induction therapy is used in approximately 60 % of recipients. However, there are no controlled trials demonstrating a significant long-term survival benefit. The vast majority of patients receive a triple maintenance immunosuppressive therapy consisting of a calcineurin-inhibitor, a cell cycle inhibitor and corticosteroids. So far, no specific immunosuppressive drug combination has proven superiority regarding long-term survival rates. The potential benefits of the proliferation signal inhibitors sirolimus and everolimus remain to be elucidated. Therapeutic options for BOS encompass a switch in maintenance therapy, renewed induction therapy, aerolised cyclosporine, azithromycine, extracorporeal photopheresis and total lymphoid irradiation. Infection prophylaxis after LTX plays a pivotal role to guard against acute complications and for the prevention of BOS. In particular, prophylaxis for pneumocystis and cytomegalovirus disease is very effective. Moreover, colonisation with Pseudomonas aeruginosa and Aspergillus spp. was identified as risk factor for BOS. Consequently, in most transplant centres prophylactic and pre-emptive therapeutic approaches are applied in varying degrees. PMID- 20960394 TI - [Dementia, 2: Therapy, course and prognosis]. PMID- 20960395 TI - [Liver damage in a patient treated with a vitamin K antagonist, a statin and an ACE inhibitor]. AB - We report the case of a 71-year-old male patient who presented at the emergency room with episodes of epistaxis and jaundice. The patient was on therapy with phenprocoumon, atorvastatin and perindopril. Findings on admission included prominent elevation of transaminases and bilirubin and a high INR due to impaired liver function and oral anticoagulation. After exclusion of other causes like viral or autoimmune hepatitis and after having obtained a liver biopsy, a diagnosis of drug induced liver damage (DILI) was made. Epidemiology, pathophysiology and clinical signs of DILI are discussed with a special focus on coumarines, statins and ACE-inhibitors. PMID- 20960396 TI - [Comment on rule of thumb 11. "Fever in over 65- to 70-year-old patients is almost never unimportant"]. PMID- 20960397 TI - [Chronic subdural hematoma - assessment and management]. AB - Subdural hematomas (SDH) are associated with an increased morbidity and mortality and generally occur as chronic SDH among older patients. The most frequent signs and symptoms - like headache, alteration of consciousness, gait impairment and hemiparesis - are also prevalent among other diseases, which has to be taken into account in the differential diagnosis. In the case of symptomatic patients with focal neurological deficits, a surgical intervention should be considered, whereas in case of asymptomatic patients or patients with only slight headaches, also a conservative treatment with a clinical and radiological follow-up might be a possibility. Also after surgical intervention, the recurrence rate is between 5 and 33%. Therefore, all patients with chronic SDH depict, irrespective of the indication for an oral anticoagulation, a challenge for the treating physicians. PMID- 20960399 TI - [Cardiac low-dose computed tomography]. AB - Cardiac CT has evolved to a robust and accurate imaging modality in the cardiac diagnostic armamentarium. However, technical developments had been accompanied with an overall increase in radiation exposure. In the last years, several technical developments and algorithms aimed at the reduction of radiation exposure in cardiac CT. The most relevant dose reduction strategies will be highlighted in this article including appropriate indications for cardiac CT, different ECG synchronization techniques, reduction of tube voltage, and high pitch CT studies. PMID- 20960398 TI - [Allergen specific immunotherapy: new approaches]. AB - Specific immunotherapy (SIT) is the only disease-modifying and causal treatment of IgE mediated allergic diseases. Soon this treatment will turn 100 years old. Subcutaneous immunotherapy is still considered to be the gold standard of SIT. With the intention to improve efficacy, safety and desirability for patients, new strategies such as epicutaneous immunotherapy, i.e. administration of allergens using a skin patch, are under investigation in clinical trials at the Zurich University Hospital. PMID- 20960400 TI - [Sexual health counseling for men who have sex with men]. PMID- 20960401 TI - [Acute neck pain in an elderly patient]. AB - Case report of an 85-year-old patient with acute neck pain and elevated parameters of inflammation in the blood. The symptoms and the MRI of the cervical spine were misleading and mimicked an infectious spondylitis with abscess formation in the prevertebral soft tissue and the dens. Lack of improvement following intravenous antibiotics led to an investigation of the spine by computed tomography showing typical calcifications of the transverse ligament around the odontoid process. Crowned dens syndrome, the cervical manifestation of calcium pyrophosphate dehydrate deposition disease, was diagnosed. After insufficient response to NSAIDs, oral glucocorticoids quickly resulted in complete relief of symptoms. PMID- 20960402 TI - [Simultaneous administration of clopidogrel and proton pump inhibitors increases the risk for myocardial infarction]. PMID- 20960403 TI - [Telemonitoring and self management of the treatment for patients with arterial hypertonia are effective]. PMID- 20960405 TI - [CME ultrasound diagnosis 36. Solution. Neuroendocrine pancreatic carcinoma]. PMID- 20960406 TI - [Physician art column. By no means popular]. PMID- 20960407 TI - [Physician picture and literature puzzle. Altitude sickness]. PMID- 20960408 TI - Management of extrahepatic biliary obstruction: a role for temporary percutaneous biliary drainage. AB - Extrahepatic biliary obstruction (EHBO) is a life-threatening condition with several etiologies that leads to numerous systemic physiologic derangements. It often presents as an emergency condition and causes significant morbidity and mortality in small animals. Conventional treatment consists of corrective surgical procedures, frequently on an emergency basis, which have been associated with mortality rates of 28% to 64% in dogs. Mortality is exacerbated by prolonged anesthetic times. Cats with EHBO are at a similarly high risk for anesthetic and surgical complications, and their prognosis is considered guarded. To decrease mortality, attention must be focused on presurgical patient stabilization and integrated postoperative medical management strategies. PMID- 20960409 TI - Patent ductus arteriosus in dogs. AB - Patent ductus arteriosus (PDA) is the most common congenital heart disease in dogs. It is due to the failure of the ductus arteriosus muscle to constrict, leaving a passageway for blood flow and resulting in eventual left-sided heart disease and/or generalized heart failure. It is hereditary in several breeds. The typical left-to-right PDA is amenable to minimally invasive procedures or open surgery. The ideal surgical candidate for PDA occlusion is immature and lightweight, with minimal heart changes. There is a wide variety of surgical techniques involving different methods of dissection and suture passage. Intraoperative hemorrhage during dissection is the most serious potential complication and can be life-threatening. Minimally invasive techniques such as thorascopic ligation and intravascular coiling have been claimed to have lower morbidity and mortality than open techniques. Once the PDA is occluded, most patients have remodeling of the myocardial tissues, resulting in an excellent long-term prognosis. Late complications such as residual flow and recanalization are rare but may be clinically significant. PMID- 20960410 TI - Oral products and dental disease. AB - Dental disease is a common problem in dogs and cats. A study of North American pets showed a 20% incidence of calculus and/or gingivitis in dogs of all ages, while 24% and 13% of cats of all ages had calculus and gingivitis, respectively.1 Dental disease in older pets is especially common, and as pets age, the incidence of dental disease increases. One study identified periodontitis in 82% of dogs aged 6 to 8 years and in 96% of dogs aged 12 to 14 years.2 Dietary strategies to promote dental health have been established and can be useful additions to a complete home oral care regimen. PMID- 20960411 TI - Pharmacokinetics of buprenorphine in a sodium carboxymethylcellulose gel after buccal transmucosal administration in dogs. AB - Alternatives to intravenous administration of opioids are needed in veterinary medicine. Previous research suggests that opioids can be administered through the buccal mucosa in dogs. This study reports the pharmacokinetics of buprenorphine HCl (0.05 mg/kg) administered transmucosally in six dogs compared with those of buprenorphine HCl (0.015 mg/kg) administered intravenously. The results suggest that the pharmacokinetics of buprenorphine HCl administered intravenously or transmucosally are similar and that transmucosal administration may be considered as a noninvasive alternative to intravenous administration. PMID- 20960412 TI - Efficacy of tylosin tartrate on canine Staphylococcus intermedius isolates in vitro. AB - In the past 5 years, the incidence of canine skin infections caused by resistant strains of Staphylococcus (pseud)intermedius has increased. Many older antibiotics are used to treat these infections because the sensitivity can be demonstrated in vitro. Additionally, many of these older drugs are efficacious and unlikely to induce multidrug resistance. More than a decade ago, the antibiotic tylosin tartrate was reported to be efficacious in vitro and in vivo against Staphylococcus intermedius. The purpose of this study was to determine whether S. (pseud)intermedius isolated from untreated pyoderma cases at veterinary referral centers across the United States are sensitive in vitro to this antibiotic. Minimum inhibitory concentrations for tylosin tartrate and other commonly used antibiotics were determined for 103 isolates. Most (82.61%) of the isolates not exposed to antibiotics in the 3 months before submission were sensitive to tylosin tartrate. These findings suggest that tylosin tartrate warrants further study as a first-line option for the treatment of dogs initially presenting with pyoderma. PMID- 20960413 TI - In vitro comparison of Staphylococcus pseudintermedius susceptibility to common cephalosporins used in dogs. AB - The in vitro activity of 10 cephalosporin antimicrobial agents against 75 isolates of methicillin-susceptible Staphylococcus pseudintermedius derived from dogs was assessed. The lowest minimal inhibitory concentration for 90% of strains (MIC90) values obtained were for cephalothin, cefovecin, and cefazolin (0.12 ug/mL), followed by ceftiofur and cefoxitin (0.25 ug/mL), cefpodoxime (0.5 ug/mL), and cefaclor and cefadroxil (1 ug/mL). The highest MIC90 values were found for cephalexin and cefixime (2 ug/mL). In this in vitro study, sensitivity to cephalothin was indicative of cephalexin susceptibility, although there were marked differences in MICs. Cephalothin susceptibility was not indicative of susceptibility to all tested cephalosporins, nor was there a clear trend in susceptibility based on cephalosporin generation. PMID- 20960414 TI - Seroprevalence of Borrelia burgdorferi-specific C6 antibody in dogs before and after implementation of a nonadjuvanted recombinant outer surface protein A vaccine in a Rhode Island small animal clinic. AB - A Borrelia burgdorferi antibody screening and vaccination program was established at a 2.5-doctor small animal hospital where no prior program had existed. A commercially available nonadjuvanted recombinant outer surface protein A vaccine was given at day 0, 3 weeks, and 6 months and then yearly based on recommendations by Topfer and Straubinger. Analysis of Lyme-specific serologic results in the hospital's canine patient population over a 33-month period showed that >99% of C6 Lyme antibody-positive dogs had not been immunized, were previously C6 antibody positive, or had not completed the hospital's recommended vaccine protocol. Additionally, the overall seroprevalence of B. burgdorferi C6 antibody decreased in the patient population during the postvaccination period. PMID- 20960415 TI - Safety and tolerance of dietary supplementation with a canine-derived probiotic (Bifidobacterium animalis strain AHC7) fed to growing dogs. AB - Although probiotics are generally considered to be safe, their increasingly widespread use warrants better understanding of their risks in companion animals. This study evaluated the safety and tolerance of dietary supplementation with a canine-derived probiotic, Bifidobacterium animalis strain AHC7 (Prostora, Procter & Gamble Pet Care), fed to growing beagles beginning at approximately 6 months of age (11 males; 9 females). Probiotic B. animalis AHC7 administered orally once per day at a dose of up to 5 x 1010 colony-forming units for at least 12 consecutive weeks was well tolerated with no safety concerns. PMID- 20960416 TI - Serum concentrations of methimazole in cats after a single oral dose of controlled-release carbimazole or sugar-coated methimazole (thiamazole). AB - Methimazole (thiamazole) is an antithyroid drug commonly used to treat feline hyperthyroidism. It is routinely given twice daily. Carbimazole is a methimazole derivative that is rapidly metabolized to methimazole in vivo. A controlled release tablet for once-daily carbimazole therapy has recently been developed in an attempt to improve compliance during medical management of feline hyperthyroidism. The results of a crossover study in six cats suggest that the pharmacokinetics of methimazole with a single dose of this controlled-release tablet may be similar to those with a single dose of a sugar-coated methimazole tablet when the two drugs are given at an equimolar dose. The mean half-lives were nearly identical (3.12 hours, sugar-coated methimazole tablets; 3.28 hours, controlled-release carbimazole tablets). The serum concentrations of methimazole at 24 hours were 21.7 +/- 28.9 ng/mL in the cats treated with 5-mg sugar-coated methimazole tablets and 28.7 +/- 37 ng/mL in the cats treated with 10-mg carbimazole tablets (which provide approximately 25% more methimazole after conversion to the active metabolite). PMID- 20960417 TI - Effects of topical 0.5% levobunolol alone or in association with 2% dorzolamide compared with a fixed combination of 0.5% timolol and 2% dorzolamide on intraocular pressure and heart rate in dogs without glaucoma. AB - The goal of glaucoma management is to reduce intraocular pressure (IOP) and maintain it at a level compatible with the health of the optic nerve. New therapies are constantly being sought. Topical instillation of levobunolol 0.5%, alone or with dorzolamide 2%, has a hypotensive effect on the IOP in healthy dogs, and levobunolol combined with dorzolamide produces a stronger hypotensive effect than the combination of timolol and dorzolamide. All animals tolerate these topical medications well with no signs of discomfort, and no ocular side effects have been observed. Levobunolol, alone or in combination with dorzolamide, induces bradycardia, as does timolol with dorzolamide. PMID- 20960418 TI - The effect of body weight on adolescent sexual activity. AB - Recent research suggests that overweight females suffer penalties in the labor and marriage markets, while overweight males do not. This study explores whether similar gender differences in the effect of body weight exist in what Cawley et al. (2006) labeled 'the adolescent sex market'. Drawing on data from the National Longitudinal Study of Adolescent Health, we use fixed effects and instrumental variables identification strategies to estimate the relationship between body weight and sexual activity. We find evidence that increased body weight lowers the probability that female adolescents become sexually active. In contrast, there is little evidence of a causal relationship between body weight and sexual activity for male adolescents. PMID- 20960419 TI - Long-term effects of health investments and parental favoritism: the case of breastfeeding. AB - This paper re-examines the effects of breastfeeding on long-term educational outcomes using longitudinal data on siblings. While family-fixed effects allow controls for all shared family factors, these estimators are sensitive to compensating or reinforcing behaviors by parents. These biases may be particularly important for estimating the effects of parental investment such as breast feeding, where sibling discordance may be difficult to treat as a random outcome and may result in persistence in differential investments between siblings. This paper uses a unique question asked to adolescent siblings about parental favoritism to adjust for potential reinforcing behavior by parents. Standard fixed effects estimates suggest important long-term educational effects of breastfeeding; however, these effects are uniformly eliminated after focusing on families who treat siblings equally. These findings shed light on the mechanisms linking associations between breastfeeding and longer term outcomes. PMID- 20960420 TI - Effects of different irrigation, drying and production scenarios on the productivity, postharvest quality and economic feasibility of Origanum syriacum, a species typically over-collected from the wild in Lebanon. AB - BACKGROUND: The potential of Origanum syriacum L. to become a cultivated crop in Lebanon rather than being harvested from the wild was investigated at the production, postharvest and economic levels. Three irrigation schemes were tested on growth parameters of cultivated oregano plants. In order to identify the most quality-preserving drying technique, air-, oven (30 degrees C)- and freeze-dried oregano samples were assessed through sensory analysis. Cost/benefit analysis was used to compare the economic potential of O. syriacum in four production scenarios. RESULTS: An irrigation scheme of 16 L per plant administered every 2 weeks (medium irrigation) during the dry period resulted in a doubling of the horticultural (56.34%) and hydro-distilled essential oil (55.22%) yields. Descriptive sensory analysis showed that air-dried material had the desired flavour, aroma and colour attributes. Net present values ranged from - 677 406.02 to 562 301.5 US$ and benefit/cost ratios from 0.5341 to 5.1993 for a 1 ha, 5 year life-cycle oregano farm. CONCLUSION: Irrigating plants once every 2 weeks during the dry season optimised herbage and essential oil yields of oregano, while air drying of plant material preserved its organoleptic attributes as a spice. Three of the four production scenarios, namely Zaatar production, herbal tea and Zaatar production and essential oil production, were economically feasible, with the last of these having the highest economic feasibility. PMID- 20960421 TI - Whey protein-okra polysaccharide fraction blend edible films: tensile properties, water vapor permeability and oxygen permeability. AB - BACKGROUND: A hot-buffer-soluble-solid fraction (HBSS) and an alkaline-soluble solid fraction (ASS) of okra polysaccharides (OKP) were obtained using sequential extraction. These fractions were combined with whey protein isolate (WPI) and glycerol (Gly) plasticizer to form blend edible films. Effects of OKP fraction and content on tensile properties, water vapor permeability (WVP) and oxygen permeability (OP) were determined. RESULTS: HBSS film had significantly higher percent elongation (%E) and lower elastic modulus (EM), WVP and OP than ASS film. Increasing HBSS or ASS content in blend films with WPI significantly reduced film tensile strength and EM and increased film %E and WVP. OP values for WPI-HBSS blend films were significantly lower than OP for WPI or HBSS film. WPI-HBSS and WPI-ASS blend films had lower WVP and OP than WPI films with equivalent tensile properties. CONCLUSIONS: WPI-HBSS blend films have higher WVP and lower OP than WPI film or HBSS film, indicating unique interactions between WPI and HBSS. Compared to WPI film, WPI-HBSS blend films have improved flexibility, stretchability and oxygen barrier. Different HBSS and ASS compositions and structures are responsible for property differences between HBSS and ASS films and between WPI-HBSS and WPI-ASS blend films. PMID- 20960422 TI - Application of single-cell microfluorimetry to neurotoxicology assays. AB - Intracellular signaling events play fundamental roles in regulating physiological function. In neurons, these include inducing growth and differentiation, secretion, gene expression, and controlling processes associated with learning and memory. All of these processes have in common the vital dependence on changes in intracellular Ca2(+) [Ca2(+)](i). Numerous toxicants, including metals, polychlorinated biphenyls, and biological neurotoxins, can disrupt [Ca2(+)](i). Understanding how toxicants disrupt Ca2(+)-dependent neuronal signaling, and thus induce neuronal death or dysfunction, requires the ability to monitor [Ca2(+)](i) at the level of individual cells. A series of fluorophores that can report on changes in [Ca2(+)](i) has been pivotal in this process. This section describes how to use these fluorophores to study effects of neurotoxicants on two types of processes: changes in [Ca2(+)](i) in individual cells and changes in mitochondrial membrane potential. Similar techniques using distinct fluorophores can be applied to other physiological processes. PMID- 20960423 TI - Neonatal rat primary microglia: isolation, culturing, and selected applications. AB - Microglial cells elaborate trophic factors and cytokines and remove toxins and debris from the extracellular space in the central nervous system, acting analogously to peripheral macrophages. Over the past two decades, increased attention has been directed at the role of microglia, not only in normal physiology, but also in mediating neurotoxicity. Activation of microglia is inherent to multiple neurodegenerative disorders and exposure to toxic compounds. In large measure, these revelations have come about as a result of technologies that enable researchers to obtain high yield and purity primary cultures of rodent microglia. The mechanical isolation protocol discussed in this unit offers an economical method to isolate large amounts of microglia in a short and not too labor-intensive manner. Most importantly, it ensures a high yield of cells with great reproducibility. Given the ever-increasing importance of microglia to the field of neurotoxicology research, the ability to isolate large quantities of primary microglia makes it possible to investigate the role and mechanisms associated with microglial modulation of neurotoxicity. We provide a detailed description on the methods that are routinely used in our laboratory for the isolation and culture of microglia, with emphasis on the steps that are deemed most critical for obtaining pure and healthy cultures. PMID- 20960424 TI - Overview of teratology. AB - Teratology is the study of developmental processes to understand the causes and mechanisms of abnormal developmental outcomes. This unit provides an explanation of the basic principles of the field as a context for the more specialized protocol units to follow in the chapter. PMID- 20960425 TI - Rat embryo cultures for in vitro teratology. AB - Mammalian embryos provide a particular challenge to those who wish to study developmental processes because development takes place inside the mother's body, thus limiting the investigator's ability to directly affect and observe the embryonic stages of development. Fortunately, as this unit illustrates, methods have been developed for in vitro culture of rodent embryos during early postimplantation (gestation days 9 to 11) and early fetal (gestation days 12 to 14) stages, which are the periods during which the major systems of the embryo are established. Embryos at these stages are particularly suitable for screening studies to determine the effects of teratological agents. PMID- 20960426 TI - Micromass cultures in teratology. AB - This unit describes methods for culture of undifferentiated midbrain (mesencephalon) and limb bud cells from gestation day 12 rat embryos. When grown over 5 days in vitro, these mixed cell populations express many morphological, biochemical, molecular, and immunophenotypic characteristics observed during in vivo differentiation. These cultures can be used in a wide variety of studies designed to investigate normal cellular ontogeny, the teratogenic potential of test agents, or the mechanisms underlying the cellular response to environmental stress. PMID- 20960427 TI - Using chicken embryos for teratology studies. AB - This unit describes methods for injecting, incubating, handling and analyzing domestic chicken embryos used in teratology studies. It also includes a discussion of caveats and special handling issues as well as some discussion of statistical analyses that differentiate working with chicken embryos from working with clutches of eggs or litters of pups. As an example of potential data, preliminary data from a study of abnormalities in early embryos and hatchling chicks exposed to chlordane are presented. PMID- 20960428 TI - In vivo assessment of prenatal developmental toxicity in rodents. AB - This unit presents two basic protocols for testing prenatal developmental toxicity in rodents. The standard protocol for assessing prenatal developmental toxicity, often referred to as a Segment II study, describes the methods used for performing cesarean sections and examining cesarean-delivered fetuses for external, skeletal, and visceral alterations. The protocol for the Chernoff/Kavlock assay, a developmental toxicity screen, describes methods for examining parturition, and postnatal growth and viability of prenatally exposed litters. PMID- 20960429 TI - Organ culture of midfacial tissue and secondary palate. AB - Palatal organ culture provides an in vitro model for the study of the formation of the secondary palate, which forms the roof of the mouth in the developing fetus. The protocol describes the steps for culture of the mid-facial region of the fetal mouse or rat. In culture the secondary palatal shelves proceed through stages of growth, elevation and fusion in a manner analogous to that occurring in utero. This model provides a tool for studies of mechanisms of normal and abnormal palatogenesis and has applications for developmental biology and toxicology. PMID- 20960431 TI - Chloroplast thylakoid membrane-stabilised emulsions. AB - BACKGROUND: Thylakoid-stabilised emulsions have been reported to possess satiety promoting effects and inhibit pancreatic lipase-colipase activity in vitro, which prompted the investigation of their interfacial properties. RESULTS: Thylakoid membranes isolated from spinach were used as an emulsifier/stabiliser in oil (triglyceride)-in-water emulsions. Emulsions were characterised with respect to droplet size, interfacial tension, creaming, surface load and electron microscopy. The effects of pH and thylakoid concentration were also considered. Droplet size decreased with increasing thylakoid concentration, reaching a plateau around 15 microm beyond concentrations of 2 mg protein mL(-1) oil. The resulting emulsions were stable against coalescence but were subject to creaming. The surface pressure (air/water interface) of the thylakoid isolate was 44 mN m( 1) and the surface load 13 mg m(-2) at 10 mg protein mL(-1) oil. Electron micrographs showed thylakoids adsorbed as bunched vesicles on the drop surfaces. The stabilisation mechanism can be described as a combined effect of surface active molecules, mainly membrane proteins but also membrane lipids, exposed on surfaces of thylakoid membrane vesicles adsorbed as particles. CONCLUSION: Thylakoid membranes effectively stabilise oil-in-water emulsions, which should facilitate their incorporation in food with satiety-promoting effects. To the authors' knowledge, this is the first study on the emulsifying properties of an isolated biological membrane as a functional ingredient. PMID- 20960433 TI - Annotation error of a common beta degrees -thalassemia mutation (619 bp-deletion) has implications for molecular diagnosis. PMID- 20960432 TI - Characterization of mitochondrial ferritin-deficient mice. PMID- 20960434 TI - Constitutional trisomy 8 mosaicism in a healthy bone marrow donor: confirmation of first reported donor origin trisomy 8. PMID- 20960435 TI - Breaking communication barriers for RA patients of South Asian origin: the use of a bilingual educational audio CD and linguistically appropriate peer support and education. AB - BACKGROUND: People from the Indian subcontinent represent one of the largest ethnic groups in the UK. Patient education resources are required to address language barriers, poor literacy and (potentially discordant) cultural beliefs. We have investigated a novel strategy to meet this need. METHODS: Rheumatoid arthritis (RA) patients of South Asian origin who prefer to communicate in a South Asian language were invited to a face-to-face interaction with a trained patient volunteer to provide linguistically appropriate peer support and education, and given a bilingual educational audio CD. Qualitative methods were used to assess this approach; three focus groups were held and 15 patients participated in total. RESULTS: Four important themes were identified: (1) The need for information about RA; all patients agreed that this was vital to learn how to live with their chronic disease. (2) Currently available approaches to education; particular concerns related to a lack of time in clinic, language barriers, difficulties in communicating via interpreters and that most written information was available only in English. (3) Support provided by a trained patient volunteer; patients appreciated that they were listened to, and were motivated by the volunteers' positive attitude. (4) The usefulness of the audio CD; patients appreciated that information was presented in a language they could understand, via a convenient medium and which offered a helpful perspective on their illness. CONCLUSIONS: This approach is a successful way of delivering information and encouraged patients from a difficult-to-reach community to become more involved in their disease management. PMID- 20960436 TI - Apomorphine effect on pain threshold in Parkinson's disease: a clinical and positron emission tomography study. AB - Patients with Parkinson's disease (PD) frequently experience pain that could be in part due to central modification of nociception. In this randomized controlled double blind study, we compared the effect of apomorphine versus placebo on pain thresholds and pain-induced cerebral activity in 25 patients with PD. Subjective pain threshold (using thermal stimulation, thermotest), objective pain threshold (nociceptive flexion reflex), and cerebral activity (H(2)(15)O PET) during noxious and innocuous stimulations were performed. Neither subjective nor objective pain thresholds nor pain activation profile were modified by apomorphine compared with placebo in 25 PD patients. Apomorphine has no effect on pain processing in PD. We suggest that other monoamine systems than dopaminergic system could be involved. PMID- 20960438 TI - Computerized evaluation of mean residence times in multicompartmental linear system and pharmacokinetics. AB - Deriving mean residence times (MRTs) is an important task both in pharmacokinetics and in multicompartmental linear systems. Taking as starting point the analysis of MRTs in open or closed (Garcia-Meseguer et al., Bull Math Biol 2003, 65, 279) multicompartmental linear systems, we implement a versatile software, using the Visual Basic 6.0 language for MS-Windows, that is easy to use and with a user-friendly format for the input of data and the output of results. For any multicompartmental linear system of up to 512 compartments, whether closed or open, with traps or without traps and with zero input in one or more of the compartments, this software allows the user to obtain the symbolic expressions, in the most simplified form, and/or the numerical values of the MRTs in any of its compartments, in the entire system or in a part of the system. As far as we known from the literature, such a software has not been implemented before. The advantage of the present software is that it reduces on the work time needed and minimizes the human errors that are frequent in compartmental systems even those that are relatively staightforward. The software bioCelTer, along with instructions, can be downloaded from http://oretano.iele ab.uclm.es/~fgarcia/bioCelTer/. PMID- 20960439 TI - Synthesis of Ag2O nanocrystals with systematic shape evolution from cubic to hexapod structures and their surface properties. AB - We report the development of a facile method for the synthesis of Ag(2)O crystals with systematic shape evolution from cubic to edge- and corner-truncated cubic, rhombicuboctahedral, edge- and corner-truncated octahedral, octahedral, and hexapod structures by mixing AgNO(3), NH(4)NO(3), and NaOH at molar ratios of 1:2:11.8. A sufficient volume of NaOH solution was first added to a mixture of AgNO(3) and NH(4)NO(3) solution to promote the formation of Ag(NH(3))(2)(+) complex ions and the growth of Ag(2)O nanocrystals with good morphological control. The crystals are mostly submicrometer-sized. X-ray diffraction, scanning electron microscopy, and transmission electron microscopy characterization has been performed to determine the crystalline surface facets. A band gap value of approximately 1.45 eV has been found for the octahedral Ag(2)O crystals. By changing the molar ratios of AgNO(3)/NH(4)NO(3)/NaOH to 1:2:41.8, corner depressed rhombicuboctahedra and elongated hexapods were obtained as a result of enhanced crystal growth along the [100] directions. Smaller nanocubes with average sizes of approximately 200 and 300 nm and octapods can also be prepared by adjusting the reagent molar ratios and their added volumes. Both the octahedra and hexapods with largely silver atom-terminated {111} surface facets responded repulsively and moved to the surface of the solution when dispersing in a solution of positively charged methylene blue, but can be suspended in a negatively charged methyl orange solution. The cubes and octapods, bounded by the {100} faces, were insensitive to the molecular charges in solution. The dramatic facet-dependent surface properties of Ag(2)O crystals have been demonstrated. PMID- 20960437 TI - Decreased striatal dopamine receptor binding in primary focal dystonia: a D2 or D3 defect? AB - Dystonia is an involuntary movement disorder characterized by repetitive patterned or sustained muscle contractions causing twisting or abnormal postures. Several lines of evidence suggest that abnormalities of dopaminergic pathways contribute to the pathophysiology of dystonia. In particular, dysfunction of D2 like receptors that mediate function of the indirect pathway in the basal ganglia may play a key role. We have demonstrated with positron emission tomography that patients with primary focal cranial or hand dystonia have reduced putamenal specific binding of [(18)F]spiperone, a nonselective D2-like radioligand with nearly equal affinity for serotonergic 5-HT(2A) sites. We then repeated the study with [(18)F]N-methyl-benperidol (NMB), a more selective D2-like receptor radioligand with minimal affinity for 5-HT(2A). Surprisingly, there was no decrease in NMB binding in the putamen of subjects with dystonia. Our findings excluded reductions of putamenal uptake greater than 20% with 95% confidence intervals. The analysis of the in vitro selectivity of NMB and spiperone demonstrated that NMB was highly selective for D2 receptors relative to D3 receptors (200-fold difference in affinity), whereas spiperone has similar affinity for all three of the D2-like receptor subtypes. These findings when coupled with other literature suggest that a defect in D3, rather than D2, receptor expression may be associated with primary focal dystonia. PMID- 20960440 TI - Structures and H2 adsorption properties of porous scandium metal-organic frameworks. AB - Two new three-dimensional Sc(III) metal-organic frameworks {[Sc(3)O(L(1))(3)(H(2)O)(3)].Cl(0.5)(OH)(0.5)(DMF)(4)(H(2)O)(3)}(infinity) (1) (H(2)L(1)=1,4-benzene-dicarboxylic acid) and {[Sc(3)O(L(2))(2)(H(2)O)(3)](OH)(H(2)O)(5)(DMF)}(infinity) (2) (H(3)L(2)=1,3,5 tris(4-carboxyphenyl)benzene) have been synthesised and characterised. The structures of both 1 and 2 incorporate the trinuclear trigonal planar [Sc(3)(O)(O(2)CR)(6)] building block featuring three Sc(III) centres joined by a central MU(3)-O(2-) donor. Each Sc(III) centre is further bound by four oxygen donors from four different bridging carboxylate anions, and a molecule of water located trans to the MU(3)-O(2-) donor completes the six coordination at the metal centre. Frameworks 1 and 2 show high thermal stability with retention of crystallinity up to 350 degrees C. The desolvated materials 1a and 2a, in which the solvent has been removed from the pores but with water or hydroxide remaining coordinated to Sc(III), show BET surface areas based upon N(2) uptake of 634 and 1233 m(2) g(-1), respectively, and pore volumes calculated from the maximum N(2) adsorption of 0.25 cm(3) g(-1) and 0.62 cm(3) g(-1), respectively. At 20 bar and 78 K, the H(2) isotherms for desolvated 1a and 2a confirm 2.48 and 1.99 wt% total H(2) uptake, respectively. The isosteric heats of adsorption were estimated to be 5.25 and 2.59 kJ mol(-1) at zero surface coverage for 1a and 2a, respectively. Treatment of 2 with acetone followed by thermal desolvation in vacuo generated free metal coordination sites in a new material 2b. Framework 2b shows an enhanced BET surface area of 1511 m(2) g(-1) and a pore volume of 0.76 cm(3) g( 1), with improved H(2) uptake capacity and a higher heat of H(2) adsorption. At 20 bar, H(2) capacity increases from 1.99 wt% in 2a to 2.64 wt% for 2b, and the H(2) adsorption enthalpy rises markedly from 2.59 to 6.90 kJ mol(-1). PMID- 20960441 TI - Neutral and cationic alkylmanganese(II) complexes containing 2,6-bisiminopyridine ligands. AB - Manganese alkyl complexes stabilised by 2,6-bis(N,N'-2,6-diisopropyl phenyl)acetaldiminopyridine ((iPr)BIP) have been selectively prepared by reacting suitable alkylmanganese(II) precursors, such as homoleptic dialkyls [(MnR(2))(n)] or the corresponding THF adducts [{MnR(2)(thf)}(2)] with the mentioned ligand. For R=CH(2)CMe(2)Ph or CH(2)Ph, formally Mn(I) derivatives are produced, in which one of the two R groups migrates to the 4-position of the central pyridine ring in the (iPr)BIP ligand. In contrast, a true dialkyl complex [MnR(2)((iPr)BIP)] can be isolated for R=CH(2)SiMe(3). In solution, this compound slowly evolves to the corresponding Mn(I) monoalkyl derivative. A detailed study of this reaction provides insights on its mechanism, showing that it proceeds through successive alkyl migrations, followed by spontaneous dehydrogenation. Protonation of [Mn(CH(2)SiMe(3))(2)((iPr)BIP)] with the pyridinium salt [H(Py)(2)][BAr'(4)] (Ar'=3,5-C(6)H(3)(CF(3))(2)) leads to the cationic species [Mn(CH(2)SiMe(3))(Py)((iPr)BIP)](+). Alternatively, the same complex can be produced by reaction of the pyridine complex [{Mn(CH(2)SiMe(3))(2)(Py)}(2)] with the protonated ligand salt [H(iPr)BIP](+)[BAr'(4)](-). This last reaction allows the synthesis of analogous cationic alkylmanganese(II) derivatives, when precursors of type [MnR(2)((iPr)BIP)] are not available. Treatment of these neutral and cationic (iPr)BIP alkylmanganese derivatives with a range of typical co-catalysts (modified methylaluminoxane (MMAO), B(C(6)F(5))(3), trimethyl or triisobutylaluminum) does not lead to active ethylene polymerisation catalysts. PMID- 20960442 TI - Synthesis, photophysical and electrophosphorescent properties of fluorene-based platinum(II) complexes. AB - A series of platinum(II) complexes bearing tridentate cyclometalated C^N^N (C^N^N=6-phenyl-2,2'-bipyridine and pi-extended R-C^N^N=3-[6'-(naphthalen-2'' yl)pyridin-2'-yl]isoquinoline) ligands with fluorene units have been synthesised and their photophysical properties have been studied. The fluorene units are incorporated into the cyclometalated ligands by a Suzuki coupling reaction. An increase in the pi-conjugation of the cyclometalated ligands confers favourable photophysical properties compared to the 6-phenyl-2,2'-bipyridine analogues. The fluorene-based platinum(II) complexes display vibronic-structured emission bands with lambda(max)=558-601 nm, and high emission quantum yields up to 0.76 in degassed dichloromethane. Their emissions are tentatively assigned to excited states with mixed (3)IL/(3)MLCT parentage (IL=intraligand, MLCT=metal-to-ligand charge transfer). The crystal structures of these platinum(II) complexes reveal extensive Pt(II)...pi and/or pi-pi interactions. The fluorene-based platinum(II) complexes are soluble in organic solvents, have high thermal stability with decomposition temperature >350 degrees C, and can be thermally vacuum-sublimed or solution-processed as phosphorescent dopants for the fabrication of organic light-emitting diodes (OLEDs). A monochromic OLED with 3d as dopant (2 wt%) fabricated by vacuum deposition gave a current efficiency of 14.7 cd A(-1) and maximum brightness of 27000 cd m(-2). A high current efficiency (9.2 cd A(-1)) has been achieved in a solution-processed OLED using complex 3f (5 wt%) doped in a PVK (poly(9-vinylcarbazole)) host. PMID- 20960443 TI - Controlling optical properties and function of BODIPY by using asymmetric substitution effects. AB - Asymmetrically substituted BODIPY analogues of the dye PM567 have been synthesised from 2-acylpyrroles and pyrroles that bear indene, fluorene or difluorene units. The type of linkage between the fluorene and the BODIPY core plays an important role in the photophysics of the BODIPY chromophore. Indeed, an aliphatic bridge gives rise to an energy-transfer process between the chromophores, whereas a vinyl spacer allows an electronic interaction between them, leading to a large red shift of the spectral bands. The laser action of the new dyes has been analysed under transversal pumping at 10 Hz repetition rate, in both liquid phase and incorporated into solid polymeric matrices. Lasing efficiencies of up to 40% were reached with high photostabilities with the laser output remaining at the initial level after 1*10(5) pump pulses in the same position of the sample. The laser action of the new dyes outperforms the laser behaviour of commercial dyes that emit in the same spectral region. The replacement of fluorene by indene quenches the fluorescence and laser emission, but allows the development of an iron cation fluorescent sensor. PMID- 20960444 TI - Light-Induced Bistability in Iron(III) Spin-Transition Compounds of 5 X Salicylaldehyde Thiosemicarbazone (X=H, Cl, Br). AB - The iron(III) spin-crossover compounds [Fe(Hthsa)(thsa)]?H2 O (1), [Fe(Hth5Clsa)(th5Clsa)2 ]?H2 O (2), and [Fe(Hth5Brsa)(th5Brsa)2 ]?H2 O (3) (H2 thsa=salicylaldehyde thiosemicarbazone, H2 th5Clsa=5-chlorosalicylaldehyde thiosemicarbazone, and H2 th5Brsa=5-bromosalicylaldehyde thiosemicarbazone) have been synthesized and their spin-transition properties investigated by magnetic susceptibility, Mossbauer spectroscopy, and differential scanning calorimetry measurements. The three compounds exhibit an abrupt spin transition with a thermal hysteresis effect. The more polarizable the substituent on the salicylaldehyde moiety, the more complete is the transition at room temperature with an increased degree of cooperativity. The molecular structures of 1 and 2 in the high-spin state are revealed. The occurrence of the light-induced excited spin-state trapping phenomenon appears to be dependent on the substituent incorporated into the 5-position of the salicylaldehyde subunit. Whereas the compounds with an electron-withdrawing group (-Br or -Cl) exhibit light-induced trapped excited high-spin states with great longevity of metastability, the halogen-free compound does not, even though strong intermolecular interactions (such as hydrogen-bonding networks and pi stacking) operate in the system. For compound 2, the surface level of photoconversion is less than 35 %. In contrast, compound 3 displays full photoexcitation. PMID- 20960445 TI - Metal-dependent coordination modes displayed by macrocyclic polycarbene ligands. PMID- 20960446 TI - Total syntheses of the thiopeptides amythiamicin C and D. AB - The thiopeptides amythiamicin C and D were synthesized by employing amide bond formation, a Stille cross-coupling reaction, and two Negishi cross-coupling reactions as key transformations. The central 2,3,6-trisubstituted pyridine ring of the target compounds was introduced as a 2,6-dibromo-3-iodopyridine, which was selectively metalated at the 3-position and connected to the complete Southern fragment of the amythiamicins by a Negishi cross-coupling. For the synthesis of amythiamicin C, this step was followed by a Negishi cross-coupling at C-6 of the pyridine core. Subsequent attachment of the Eastern fragment was achieved by amide bond formation and macrolactam ring closure by a Stille cross-coupling at C 2. The Eastern bithiazole fragment of the amythiamins was constructed also by regioselective metalation and cross-coupling reactions. The pivotal step involved the diastereoselective addition of 4-bromothiazole-2-magnesium bromide to a chiral sulfinyl imine. For the synthesis of amythiamicin D, the order of cross coupling at C-6, amide bond formation, and cross-coupling at C-2 was changed. The amide bond formation to the Eastern fragment was performed first and it was subsequently attempted to close the macrolactam by an intramolecular regioselective Stille cross-coupling at C-2. Despite the low regioselectivity of this reaction it paved the way to the immediate completion of the amythiamicin D synthesis when followed by a Negishi cross-coupling at C-6 with 2-zincated methyl thiazole-5-carboxylate. PMID- 20960447 TI - Examination of the surface heterogeneity of reversed-phase packing materials with solvent adsorption. AB - The adsorption isotherms of acetonitrile, ethanol, 2-propanol, and THF were measured using frontal analysis on six columns packed with octadecyl RP stationary phase. The effect of the bonding density of the end-capped octadecyl bonded phase on the adsorption properties was measured. Adsorption isotherm data were collected from aqueous solutions of the four organic modifiers. The isotherm model for solvent adsorption was selected using two independent parameter estimation methods, the regression analysis and adsorption energy distribution. The fitted isotherm parameters were tested by modeling of overloaded elution bands with the aid of the equilibrium-dispersive model of chromatography. The surface heterogeneity estimations and the effect of the silanol groups on the adsorption of solvents were based on those data. PMID- 20960448 TI - Characterization of branched polysaccharides using multiple-detection size separation techniques. AB - The structure of branched polysaccharides involves a hierarchy of levels, from the constituent sugars, then the branching pattern, up to the macromolecular architecture, and then supramolecular organization. Finding causal relations between this complex structure/architecture and both (bio)synthetic mechanisms and final properties is needed for understanding the functionality of branched polysaccharides, which is important in fields ranging from improved nutrition and health through to papermaking and pharmaceuticals. The structural complexity makes this task especially challenging. This review focuses on the best current means to obtain reliable branch chain and size distributions using size separation technologies coupled with number-, mass- and molecular-weight sensitive detectors. Problems with current technologies are also critically appraised. PMID- 20960449 TI - Temperature gradient interaction chromatography of polymers: A molecular statistical model. AB - A new model describing the retention in temperature gradient interaction chromatography of polymers is developed. The model predicts that polymers might elute in temperature gradient interaction chromatography in either an increasing or decreasing order or even nearly independent of molar mass, depending on the rate of the temperature increase relative to the flow rate. This is in contrast to solvent gradient elution, where polymers elute either in order of increasing molar mass or molar mass independent. The predictions of the newly developed model were verified with the literature data as well as new experimental data. PMID- 20960450 TI - Separation of linear and star-shaped polystyrenes by phase distribution chromatography. AB - The phase distribution chromatographic technique was optimized and applied for the separation of linear and star-shaped polystyrene (PS). For this purpose non crosslinked, ultra high molecular weight PS coated on different supporting materials was used. The stability of the coating under chromatographic conditions was tested by thermo gravimetric analysis and microscopic techniques. The modification of different column packing materials was tested. Separation according to branching was indicated for different molecular weights of linear and star-shaped PS. The resolution of the separation was improved by changing the density of the stationary phase and the temperature. The separation results were supported by cloud point measurements and the determination of the critical conditions for linear and star-polymers at the same molecular weight. PMID- 20960452 TI - Identification of Leishmania-specific protein phosphorylation sites by LC-ESI MS/MS and comparative genomics analyses. AB - Human pathogenic protozoa of the genus Leishmania undergo various developmental transitions during the infectious cycle that are triggered by changes in the host environment. How these parasites sense, transduce, and respond to these signals is only poorly understood. Here we used phosphoproteomic approaches to monitor signaling events in L. donovani axenic amastigotes, which may be important for intracellular parasite survival. LC-ESI-MS/MS analysis of IMAC-enriched phosphoprotein extracts identified 445 putative phosphoproteins in two independent biological experiments. Functional enrichment analysis allowed us to gain insight into parasite pathways that are regulated by protein phosphorylation and revealed significant enrichment in our data set of proteins whose biological functions are associated with protein turn-over, stress response, and signal transduction. LC-ESI-MS/MS analysis of TiO(2)-enriched phosphopeptides confirmed these results and identified 157 unique phosphopeptides covering 181 unique phosphorylation sites in 126 distinct proteins. Investigation of phosphorylation site conservation across related trypanosomatids and higher eukaryotes by multiple sequence alignment and cluster analysis revealed L. donovani-specific phosphoresidues in highly conserved proteins that share significant sequence homology to orthologs of the human host. These unique phosphorylation sites reveal important differences between host and parasite biology and post translational protein regulation, which may be exploited for the design of novel anti-parasitic interventions. PMID- 20960451 TI - Proteomic characterization of Her2/neu-overexpressing breast cancer cells. AB - The receptor tyrosine kinase HER2 is an oncogene amplified in invasive breast cancer and its overexpression in mammary epithelial cell lines is a strong determinant of a tumorigenic phenotype. Accordingly, HER2-overexpressing mammary tumors are commonly indicative of a poor prognosis in patients. Several quantitative proteomic studies have employed two-dimensional gel electrophoresis in combination with MS/MS, which provides only limited information about the molecular mechanisms underlying HER2/neu signaling. In the present study, we used a SILAC-based approach to compare the proteomic profile of normal breast epithelial cells with that of Her2/neu-overexpressing mammary epithelial cells, isolated from primary mammary tumors arising in mouse mammary tumor virus Her2/neu transgenic mice. We identified 23 proteins with relevant annotated functions in breast cancer, showing a substantial differential expression. This included overexpression of creatine kinase, retinol-binding protein 1, thymosin 4 and tumor protein D52, which correlated with the tumorigenic phenotype of Her2 overexpressing cells. The differential expression pattern of two genes, gelsolin and retinol binding protein 1, was further validated in normal and tumor tissues. Finally, an in silico analysis of published cancer microarray data sets revealed a 23-gene signature, which can be used to predict the probability of metastasis free survival in breast cancer patients. PMID- 20960454 TI - Characterization of multiple alternative forms of heterogeneous nuclear ribonucleoprotein K by phosphate-affinity electrophoresis. AB - The phosphorylation of heterogeneous nuclear ribonucleoprotein K (hnRNP K) is thought to play an important role in cell regulation and signal transduction. However, the relationship between hnRNP K phosphorylation and cellular events has only been indirectly examined, and the phosphorylated forms of endogenous hnRNP K have not been biochemically characterized in detail. In this study, we extensively examined the phosphorylated forms of endogenous hnRNP K by direct protein-chemical characterization using phosphate-affinity electrophoresis followed by immunoblotting and MS. Phosphate-affinity electrophoresis enabled us to sensitively detect and separate the phosphorylated forms of hnRNP K. When we used 2-DE with phosphate-affinity SDS-PAGE in the second dimension, the nuclear fraction contained more than 20 spots of endogenous hnRNP K on the 2-D map. We determined that the multiple forms of hnRNP K were produced mainly by alternative splicing of the single hnRNP K gene and phosphorylation of Ser116 and/or Ser284. Furthermore, the subcellular localization of these proteins revealed by the 2-D gel correlated with their phosphorylation states and alternative splicing patterns. The results also indicated that the multiple forms of hnRNP K were differentially modulated in response to external stimulation with bacterial lipopolysaccharide or serum. PMID- 20960453 TI - Proteome mining for novel IgE-binding proteins from the German cockroach (Blattella germanica) and allergen profiling of patients. AB - Although cockroaches are known to produce allergens that can cause IgE-mediated hypersensitivity reactions, including perennial rhinitis and asthma, the various cockroach allergens have not yet been fully studied. Many proteins from the German cockroach show high IgE reactivity, but have never been comprehensively characterized. To identify these potential allergens, proteins were separated by 2-DE and IgE-binding proteins were analyzed by nanoLC-MS/MS or N-terminal sequencing analysis. Using a combination of proteomic techniques and bioinformatic allergen database analysis, we identified a total of ten new B. germanica IgE-binding proteins. Of these, aldolase, arginine kinase, enolase, Hsp70, triosephosphate isomerase, and vitellogenin have been reported as allergens in species other than B. germanica. Analysis of the Food Allergy Research and Resource Program allergen database indicated that arginine kinase, enolase, and triosephosphate isomerase showed significant potential cross reactivity with other related allergens. This study revealed that vitellogenin is an important novel B. germanica allergen. Personalized profiling and reactivity of IgE Abs against the panel of IgE-binding proteins varied between cockroach allergic individuals. These findings make it possible to monitor the individual IgE reactivity profile of each patient and facilitate personalized immunotherapies for German cockroach allergy disorders. PMID- 20960455 TI - Factors effecting the morphology of Eudragit S-100 based microsponges bearing dicyclomine for colonic delivery. AB - The purpose of this study was to design microsponge-based novel colon-specific drug delivery system bearing dicyclomine. Eudragit S-100-based microsponges containing the drug in varying amount were prepared using quasi-emulsion solvent diffusion method. The microsponges were prepared by optimizing various process parameters. Differential scanning calorimetry and Fourier transform infrared studies indicated compatibility and stability of the drug in various formulations. Shape and surface morphology of the microsponges were examined using scanning electron microscopy. The formulations were subjected to in vitro release studies, and the results were evaluated kinetically and statistically. In vitro release data showed a biphasic pattern with an initial burst effect. In the first hour, drug release from microsponges was found to be between 17% and 31%. The cumulative percent release at the end of eighth hour was noted to be between 53% and 83%. The release kinetics showed that the data followed Higuchi model and the main mechanism of drug release was diffusion. The colon-specific tablets were prepared by compressing the microsponges followed by coating with pectin:hydroxypropylmethylcellulose mixture. In vitro release studies exhibited that compression-coated colon-specific formulations started releasing the drug at the sixth hour corresponding to the arrival time at colon. The study presents a new approach for colon-specific drug delivery. PMID- 20960456 TI - Impact of symptom-reflux association analysis on long-term outcome after Nissen fundoplication. AB - BACKGROUND: A positive symptom association probability (SAP) is regarded as an important selection criterion for antireflux surgery by many physicians. However, no data corroborate the relationship between symptom-reflux association and outcome, nor is it clear what impact a negative SAP has on the outcome of antireflux surgery in patients with abnormal oesophageal acid exposure. This study compared long-term outcomes of Nissen fundoplication in patients with a negative versus positive SAP. METHODS: Five-year outcome of Nissen fundoplication in patients with proton-pump inhibitor (PPI)-refractory reflux and pathological acid exposure was compared between those with (SAP+, 109) and without (SAP-, 29 patients) a positive symptom association. Symptoms, quality of life (QoL), PPI use, endoscopic findings, manometry and acid exposure were evaluated. RESULTS: At 5 years' follow-up, relief of reflux symptoms (95 versus 87 per cent), reduction in PPI use (80 to 25 per cent versus 85 to 14 per cent; P < 0.050) and improvement in QoL were similar in the SAP- and SAP+ groups. Reduction in acid exposure time (13.4 to 1.6 per cent versus 11.1 to 0.2 per cent of total time; P < 0.010), improvement in oesophagitis (44 to 6 per cent versus 61 to 13 per cent; P < 0.050) and increase in lower oesophageal sphincter pressure were also comparable. CONCLUSION: The subjective and objective outcomes of fundoplication in patients with pathological acid exposure are comparable among those with a positive and negative SAP. Patients with pathological acid exposure and a negative SAP can also benefit from antireflux surgery. PMID- 20960457 TI - Nutritional predictors of postoperative outcome in pancreatic cancer. AB - BACKGROUND: Nutritional status plays an important role in the incidence of postoperative complications and the prognosis of various tumours. The prognostic value of preoperative nutritional factors in patients with pancreatic cancer is not known. METHODS: This retrospective study included 268 patients who underwent resection for adenocarcinoma of the pancreas. The predictive value of preoperative nutritional status for postoperative outcome (survival, complications) was assessed. Nutritional factors included the three constitutional indices, serum albumin and Onodera's prognostic nutrition index (PNI), calculated as 10 * serum albumin (g/dl) + 0.005* total lymphocyte count (per mm(3)). RESULTS: In multivariable analysis preoperative low PNI (but not low albumin) was an independent prognostic factor for poor survival: hazard ratio (HR) 1.73 (95 per cent confidence interval (c.i.) 1.21 to 2.47). The accuracy of a PNI value of less than 45 as cut-off for clinically significant preoperative malnutrition in predicting 1- or 2-year survival after surgery was, however, limited (66.4 and 56.3 per cent respectively). Low preoperative albumin concentration and PNI were significantly associated with postoperative complications: odds ratio 1.98 (95 per cent c.i. 1.18 to 3.32) and 2.14 (1.23 to 3.73) respectively. Low PNI and low body mass index were independently associated with pancreatic fistula: HR 2.52 (1.37 to 4.63) and 0.40 (0.17 to 0.93) respectively. CONCLUSION: The PNI is associated with overall survival and postoperative complications, in particular pancreatic fistula, in patients with pancreatic cancer. The moderate accuracy of PNI as a predictor of survival limits its clinical use. PMID- 20960458 TI - Modelling the metabolic characteristics of proteins in dairy cattle from co products of bioethanol processing: comparison of the NRC 2001 model with the DVE/OEB system. AB - BACKGROUND: Co-products from bioethanol processing include wheat dried distillers grains with solubles (DDGS), corn DDGS, blend DDGS (e.g. wheat/corn at 70:30, 60:40 or 50:50 w/w), triticale DDGS, barley DDGS and pea DDGS. The objective of this study was to compare two systems, the DVE/OEB system versus the NRC 2001 model, in modelling the metabolic characteristics of proteins in dairy cattle from different types of co-products (DDGS) from different bioethanol processing plants. RESULTS: The predicted values from the NRC 2001 model were 10% higher (P < 0.05) in truly absorbable rumen-synthesised microbial protein in the small intestine, 10% lower (P < 0.05) in truly absorbed rumen-undegraded feed protein in the small intestine, 30% lower (P < 0.05) in endogenous protein and 2% lower (P < 0.05) in total truly absorbed protein in the small intestine than the predicted values from the DVE/OEB system. However, no significant difference was detected in terms of the degraded protein balance between the two models (P > 0.05). CONCLUSION: The sensitivity of the two models in detecting differences among DDGS types and between bioethanol plants was similar. The two models coincided in the superior protein value of blend DDGS as well as in the more optimal degraded protein balance (DPB) for corn DDGS. Although the differences between the DVE/OEB system and the NRC 2001 model were significant (P < 0.05) for most outputs owing to differences in some of the concepts and factors used in modelling, the correlations between total truly absorbed protein (DVE) and metabolisable protein (MP) values and between degraded protein balances (DPB(OEB) vs DPB(NRC) ) were also significant (P < 0.05). PMID- 20960459 TI - Corn salad (Valerianella locusta (L.) Laterr.) growth in a water-saving floating system as affected by iron and sulfate availability. AB - BACKGROUND: Unbalanced nutrient availability causes disequilibrated plant growth, which can result in a worsening of harvested product quality, such as high nitrate content in edible tissues. To cope with this problem, improved knowledge of the mechanisms involved in nutrient acquisition and regulation is necessary. For this purpose the responses of acquisition mechanisms of N, Fe and S were studied as a function of Fe and S availability using two corn salad cultivars grown hydroponically, considering also aspects related to N metabolism. RESULTS: The results showed that an increase in Fe or S availability enhanced nitrate uptake and assimilation, which in turn increased biomass production of leaves with lower nitrate content. In particular, high S availability exerted a positive effect (gene expression and functionality) both on the uptake and metabolism of N and on Fe acquisition mechanisms. CONCLUSION: The data presented here show close interactions between N, S and Fe, highlighting that relevant improvements in yield and quality from soilless culture might also be obtained through appropriate adjustments of nutrient availability. In this respect, concerning the role of S in the acquisition mechanisms of N and Fe and in N metabolism, its level of availability should be taken into high consideration for equilibrated plant growth. PMID- 20960460 TI - Azacytidine impairs NK cell reactivity while decitabine augments NK cell responsiveness toward stimulation. AB - Azacytidine and decitabine are approved for treatment of acute myeloid leukemias and myelodysplastic syndromes. While clinical responses are attributed to epigenetic effects and induction of apoptosis in malignant cells, these azanucleosides also affect antitumor immune responses. NK cells as components of innate immunity may confine development and progression of cancer. Numerous therapeutic strategies presently aim to reinforce NK reactivity against hematopoietic malignancies. We here comparatively analyzed the effect of the two clinically available azanucleosides and report that NK cytotoxicity and IFN-gamma production are significantly impaired by pharmacological concentrations of azacytidine but enhanced by decitabine. This was not due to alterations in the target cells but caused by direct effects on NK cells depending on the chemical modifications by which azanucleosides differ from their physiological analogues. Although azacytidine impaired mRNA synthesis and induced apoptosis in NK cells, decitabine did not per se alter NK cell viability or reactivity but enhanced responsiveness to activating stimuli by inducing transcription of genes involved in NK reactivity. Tantalizingly, these effects were independent of incorporation of the azanucleosides into DNA during cell division. While azacytidine impairs NK antitumor immunity, decitabine augments NK reactivity by yet unidentified mechanisms and may thus serve well in therapeutic strategies combining its effects on malignant cells with its ability to enhance NK functions. PMID- 20960461 TI - Effect of visible light treatments on postharvest senescence of broccoli (Brassica oleracea L.). AB - BACKGROUND: Broccoli (Brassica oleracea L.) is a rapidly perishable vegetable crop. Several postharvest treatments have been applied in order to delay de greening. Since light has been shown to have an effect on pigment accumulation during development and darkness is known to induce senescence, the effect of continuous and periodic exposure to low-intensity white light at 22 degrees C on postharvest senescence of broccoli heads was assayed. RESULTS: Exposure to a constant dose of 12 micromol m(-2) s(-1) was selected as the most suitable treatment and was employed for subsequent experiments. During the course of the treatments, hue and L* values as well as chlorophyll content and visual observation of florets indicated an evident delay in yellowing in treated samples compared with controls. No statistically significant differences in total protein content were found, but soluble protein content was higher in treated samples. Total and reducing sugar as well as starch levels decreased during postharvest senescence, with lower values in control samples. CONCLUSION: The results of this study indicate that storage under continuous low-intensity light is an efficient and low-cost treatment that delays postharvest senescence while maintaining the quality of harvested broccoli florets. PMID- 20960463 TI - Modeling the effects of cingula structure on strain patterns and potential fracture in tooth enamel. AB - The mammalian cingulum is a shelf of enamel, which rings the base of the molar crown (fully or partially). Certain nonmammalian cynodonts show precursors of this structure, indicating that it may be an important dental character in the origins of mammals. However, there is little consensus as to what drove the initial evolution of the cingulum. Recent work on physical modeling of fracture mechanics has shown that structures which approximate mammalian dentition (hard enamel shell surrounding a softer/tougher dentine interior) undergo specific fracture patterns dependent on the material properties of the food items. Soft materials result in fractures occurring at the base of the stiff shell away from the contact point due to heightened tensile strains. These tensile strains occur around the margin in the region where cingula develop. In this article, we test whether the presence of a cingulum structure will reduce the tensile strains seen in enamel using basic finite element models of bilayered cones. Finite element models of generic cone shaped "teeth" were created both with and without cingula of various shapes and sizes. Various forces were applied to the models to examine the relative magnitudes and directions of average maximum principal strain in the enamel. The addition of a cingulum greatly reduces tensile strains in the enamel caused by "soft-food" forces. The relative shape and size of the cingulum has a strong effect on strain magnitudes as well. Scaling issues between shapes are explored and show that the effectiveness of a given cingulum to reducing tensile strains is dependent on how the cingulum is created. Partial cingula, which only surround a portion of the tooth, are shown to be especially effective at reducing strain caused by asymmetrical loads, and shed new light on the potential early function and evolution of mammalian dentitions. PMID- 20960462 TI - PKA knockdown enhances cell killing in response to radiation and androgen deprivation. AB - The therapeutic efficacy of Gem(r)231, a second generation antisense molecule targeted to the RIalpha subunit of PKA(RIalpha) (AS-PKA), administered in combination with androgen deprivation (AD) and radiation therapy (RT), was examined in androgen sensitive (LNCaP) and insensitive (PC3) cell lines. Apoptosis was assayed by Caspase 3 + 7 activity and Annexin V binding. AS-PKA significantly increased apoptosis in vitro from RT (both lines), with further increases in LNCaP cells grown in AD medium. In LNCaP cells, AD increased phosphorylated mitogen activated protein-kinase (pMAPK), which was reduced by AS PKA relative to the mismatch (MM) controls. AS-PKA also reduced pMAPK levels in PC3 cells. Cell death was measured by clonogenic survival assays. In vivo, LNCaP cells were grown orthotopically in nude mice. Tumor kinetics were measured by magnetic resonance imaging and serum prostate-specific antigen. PC3 cells were grown subcutaneously and tumor volume assessed by caliper measurements. In PC3 xenografts, AS-PKA caused a significant increase in tumor doubling time relative to MM controls as a monotherapy or in combination with RT. In orthotopic LNCaP tumors, AS-PKA was ineffective as a monotherapy; however, it caused a statistically significant increase in tumor doubling time relative to MM controls when used in combination with AD, with or without RT. PKA(RIalpha) levels in tumors were quantified via immunohistochemical (IHC) staining and image analysis. IHC measurements in LNCaP cells exhibited that AS-PKA reduced PKA(RIalpha) levels in vivo. We demonstrate for the first time that AS-PKA enhances cell killing androgen sensitive prostate cancer cells to AD +/- RT and androgen insensitive cells to RT. PMID- 20960464 TI - Developmental expression of neuromodulators in the central complex of the grasshopper Schistocerca gregaria. AB - The central complex is a major integrative region within the insect brain with demonstrated roles in spatial orientation, the regulation of locomotor behavior, and sound production. In the hemimetabolous grasshopper, the central complex comprises the protocerebral bridge, central body (CB), ellipsoid body, noduli, and accessory lobes, and this modular organization develops entirely during embryogenesis. From a biochemical perspective, a range of neuroactive substances has been demonstrated in these modules of the adult central complex, but little is known about their developmental expression. In this study, we use matrix assisted laser desorption/ionization-imaging mass spectrometry on single brain slices to confirm the presence of several peptide families (tachykinin, allatostatin, periviscerokinin/pyrokinin, FLRFamide, and neuropeptide F) in the adult central complex and then use immunohistochemistry and histology to examine their developmental expression, together with that of the indolamin serotonin, and the endogenous messenger nitric oxide (NO; via its synthesizing enzyme). We find that each neuromodulator is expressed according to a unique, stereotypic, pattern within the various modules making up the central complex. Neuropeptides such as tachykinin (55%) and allatostatin (65%), and the NO-synthesizing enzyme diaphorase (70%), are expressed earlier during embryonic development than the biogenic amine serotonin (80%), whereas periviscerokinin-like peptides and FLRFamide-like peptides begin to be expressed only postembryonically. Within the CB, these neuroactive substances are present in tangential projection neurons before they appear in columnar neurons. There is also no colocalization of serotonin-positive and peptide-positive projections up to the third larval instar during development, consistent with the clear dorsoventral layering of the neuropil we observe. Our results provide the first neurochemical fingerprint of the developing central complex in an hemimetabolous insect. PMID- 20960465 TI - Effects of pymetrozine, an antifeedant of Hemiptera, on Asian citrus psyllid, Diaphorina citri, feeding behavior, survival and transmission of Candidatus Liberibacter asiaticus. AB - BACKGROUND: Vector-borne plant disease management can be enhanced by deployment of antifeedants in addition to the use of broad-spectrum neurotoxic insecticides. The effects of pymetrozine on Asian citrus psyllid (ACP), Diaphorina citri Kuwayama, feeding behaviour, survival and transmission of Candidatus Liberibacter asiaticus (Las), the presumed causal pathogen of huanglongbing, were investigated. RESULTS: Pymetrozine applied at 52 and 104 ug mL(-1) to citrus plants [Swingle citrumelo (X Citroncirus webberi Ingram and Moore)] modified the feeding behavior of ACP and increased the amount of time spent performing non penetration behaviors while decreasing the time spent performing ingestion behaviors compared with the controls 1 day after treatment. However, the antifeedant effect of pymetrozine subsided 5 days after application. Pymetrozine reduced the survival of both adults and nymphs on treated plants compared with the control. However, it had a greater impact on survival of nymphs than on survival of adults. Pymetrozine applied at 52 and 104 ug mL(-1) on Las-infected 'Valencia' sweet orange plants [Citrus sinensis L. (Osbeck)] reduced acquisition (12 and 21% respectively) and transmission (11 and 18% respectively) of Las by feeding ACP adults compared with the controls; however, these reductions were not statistically significant. CONCLUSIONS: Pymetrozine exhibited moderate antifeedant effects by modifying the feeding behavior of ACP adults with short residual activity. The impact of pymetrozine on survival of nymphs was greater than on adults at the higher concentrations tested. Pymetrozine also reduced the acquisition and transmission of Las by feeding ACP adults up to 21 and 18%, respectively, compared with untreated controls. PMID- 20960467 TI - HaploGrep: a fast and reliable algorithm for automatic classification of mitochondrial DNA haplogroups. AB - An ongoing source of controversy in mitochondrial DNA (mtDNA) research is based on the detection of numerous errors in mtDNA profiles that led to erroneous conclusions and false disease associations. Most of these controversies could be avoided if the samples' haplogroup status would be taken into consideration. Knowing the mtDNA haplogroup affiliation is a critical prerequisite for studying mechanisms of human evolution and discovering genes involved in complex diseases, and validating phylogenetic consistency using haplogroup classification is an important step in quality control. However, despite the availability of Phylotree, a regularly updated classification tree of global mtDNA variation, the process of haplogroup classification is still time-consuming and error-prone, as researchers have to manually compare the polymorphisms found in a population sample to those summarized in Phylotree, polymorphism by polymorphism, sample by sample. We present HaploGrep, a fast, reliable and straight-forward algorithm implemented in a Web application to determine the haplogroup affiliation of thousands of mtDNA profiles genotyped for the entire mtDNA or any part of it. HaploGrep uses the latest version of Phylotree and offers an all-in-one solution for quality assessment of mtDNA profiles in clinical genetics, population genetics and forensics. HaploGrep can be accessed freely at http://haplogrep.uibk.ac.at. PMID- 20960466 TI - The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update. AB - Diamond-Blackfan Anemia (DBA) is characterized by a defect of erythroid progenitors and, clinically, by anemia and malformations. DBA exhibits an autosomal dominant pattern of inheritance with incomplete penetrance. Currently nine genes, all encoding ribosomal proteins (RP), have been found mutated in approximately 50% of patients. Experimental evidence supports the hypothesis that DBA is primarily the result of defective ribosome synthesis. By means of a large collaboration among six centers, we report here a mutation update that includes nine genes and 220 distinct mutations, 56 of which are new. The DBA Mutation Database now includes data from 355 patients. Of those where inheritance has been examined, 125 patients carry a de novo mutation and 72 an inherited mutation. Mutagenesis may be ascribed to slippage in 65.5% of indels, whereas CpG dinucleotides are involved in 23% of transitions. Using bioinformatic tools we show that gene conversion mechanism is not common in RP genes mutagenesis, notwithstanding the abundance of RP pseudogenes. Genotype-phenotype analysis reveals that malformations are more frequently associated with mutations in RPL5 and RPL11 than in the other genes. All currently reported DBA mutations together with their functional and clinical data are included in the DBA Mutation Database. PMID- 20960468 TI - How to catch all those mutations--the report of the third Human Variome Project Meeting, UNESCO Paris, May 2010. AB - The third Human Variome Project (HVP) Meeting "Integration and Implementation" was held under UNESCO Patronage in Paris, France, at the UNESCO Headquarters May 10-14, 2010. The major aims of the HVP are the collection, curation, and distribution of all human genetic variation affecting health. The HVP has drawn together disparate groups, by country, gene of interest, and expertise, who are working for the common good with the shared goal of pushing the boundaries of the human variome and collaborating to avoid unnecessary duplication. The meeting addressed the 12 key areas that form the current framework of HVP activities: Ethics; Nomenclature and Standards; Publication, Credit and Incentives; Data Collection from Clinics; Overall Data Integration and Access-Peripheral Systems/Software; Data Collection from Laboratories; Assessment of Pathogenicity; Country Specific Collection; Translation to Healthcare and Personalized Medicine; Data Transfer, Databasing, and Curation; Overall Data Integration and Access Central Systems; and Funding Mechanisms and Sustainability. In addition, three societies that support the goals and the mission of HVP also held their own Workshops with the view to advance disease-specific variation data collection and utilization: the International Society for Gastrointestinal Hereditary Tumours, the Micronutrient Genomics Project, and the Neurogenetics Consortium. PMID- 20960469 TI - Mutations in SOX17 are associated with congenital anomalies of the kidney and the urinary tract. AB - Congenital anomalies of the kidney and the urinary tract (CAKUT) represent a major source of morbidity and mortality in children. Several factors (PAX, SOX,WNT, RET, GDFN, and others) play critical roles during the differentiation process that leads to the formation of nephron epithelia. We have identified mutations in SOX17, an HMG-box transcription factor and Wnt signaling antagonist, in eight patients with CAKUT (seven vesico-ureteric reflux, one pelvic obstruction). One mutation, c.775T>A (p.Y259N), recurred in six patients. Four cases derived from two small families; renal scars with urinary infection represented the main symptom at presentation in all but two patients. Transfection studies indicated a 5-10-fold increase in the levels of the mutant protein relative to wild-type SOX17 in transfected kidney cells. Moreover we observed a corresponding increase in the ability of SOX17 p.Y259N to inhibit Wnt/beta-catenin transcriptional activity, which is known to regulate multiple stages of kidney and urinary tract development. In conclusion, SOX17 p.Y259N mutation is recurrent in patients with CAKUT. Our data shows that this mutation correlates with an inappropriate accumulation of SOX17-p.Y259N protein and inhibition of the beta-catenin/Wnt signaling pathway. These data indicate a role of SOX17 in human kidney and urinary tract development and implicate the SOX17 p.Y259N mutation as a causative factor in CAKUT. PMID- 20960470 TI - Chemical control of herbicide-resistant Lolium rigidum Gaud. in north-eastern Spain. AB - BACKGROUND: Lolium rigidum Gaud. is one of the most common weed species in winter cereals in north-eastern Spain, with populations that have evolved resistance to herbicides becoming more widespread since the mid-1990s. Nine trials on commercial fields with herbicide-resistant L. rigidum were conducted during the cropping seasons 2001-2002 to 2003-2004, testing the efficacy of 20 herbicides and mixtures pre- and post-emergence and as sequential applications. Weed populations chosen had different resistance patterns to chlortoluron, chlorsulfuron, diclofop-methyl and tralkoxydim, representative of the resistance problems faced by farmers. RESULTS: In pre-emergence, prosulfocarb mixed with trifluralin, chlortoluron or triasulfuron was effective on six populations. In post-emergence, iodosulfuron alone or mixed with mesosulfuron gave the best results but did not control three resistant populations. At Ferran 1, none of the herbicide combinations reached 90% efficacy. CONCLUSIONS: The diverse efficacy patterns of the different populations demonstrate the need for detailed knowledge of the populations before using herbicides. Moreover, the unexpected insufficient efficacy of the new herbicide iodosulfuron prior to its field use shows the need to combine herbicides with other non-chemical weed control methods to control resistant L. rigidum in north-eastern Spain. PMID- 20960471 TI - Effect of Candidatus Liberibacter asiaticus infection on susceptibility of Asian citrus psyllid, Diaphorina citri, to selected insecticides. AB - BACKGROUND: In the present investigation, the effect of Candidatus Liberibacter asiaticus (Las), a bacterium considered to be responsible for causing huanglongbing (HLB) disease in citrus, on the physiology of its vector, the Asian citrus psyllid (ACP) Diaphorina citri Kuwayama, was determined. Specifically, the effects of Las infection on the susceptibility of ACP to selected insecticides were determined. Furthermore, total protein content and general esterase activity were quantified in Las-infected and uninfected ACP to gain insight into the possible mechanism(s) responsible for altered susceptibility to insecticides owing to Las infection. RESULTS: LC(50) values were significantly lower in Las infected than in uninfected ACP adults for chlorpyrifos and spinetoram. Furthermore, there was a general trend towards lower LC(50) values for three other insecticides for Las-infected ACP; however, the differences were not statistically significant. Total protein content (ug mL(-1)) was significantly lower in Las-infected (23.5 +/- 1.3 in head + thorax; 27.7 +/- 1.9 in abdomen) than in uninfected (29.7 +/- 2.1 in head + thorax; 35.0 +/- 2.3 in abdomen) ACP. Likewise, general esterase enzyme activity (nmol min(-1) mg(-1) protein) was significantly lower in Las-infected (111.6 +/- 4.5 in head + thorax; 109.5 +/- 3.7 in abdomen) than in uninfected (135.9 +/- 7.5 in head + thorax; 206.1 +/- 23.7 in abdomen) ACP. CONCLUSION: Susceptibility of ACP to selected insecticides from five major chemistries was greater in Las-infected than in uninfected ACP. The lower total protein content and reduced general esterase activity in Las infected than in uninfected ACP may partly explain the observed higher insecticide susceptibility of Las-infected ACP. PMID- 20960472 TI - Increase of core biopsies in visceral organs--experience at one institution. AB - All targeted core biopsies in the surgical pathology file and all cytology specimens from liver, lung, kidney, and pancreas accessioned in 1997, 2002, and 2007 in the Pathology Department at the Beth Israel Deaconess Medical Center, Boston, were culled. Cytology specimen type [touch imprint smear (TIS) from core only, fine-needle aspiration (FNA)-only, or both] was determined. Seven hundred and fifty-eight targeted core biopsies were identified from the years 1997 (162), 2002 (249), and 2007 (347). Eight hundred and seventy-eight cytology specimens from the years 1997 (127), 2002 (264), and 2007 (487) were included. The overall percentage of TIS-only of all cytology specimens increased from 5.5 to 31% in 10 years and most prominently in the liver (14% in 1997 to 87% in 2007). In spite of the increasing use of core biopsies, the volume of cytology specimens from these organs increased from 127 in 1997 to 487 in 2007. PMID- 20960473 TI - Impact of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in lymph nodal and mediastinal lesions: a multicenter experience. AB - Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is an established procedure in lung cancer (LC) staging and in the diagnosis of mediastinal masses. Most of the experiences reported refer to single specialized centers where dedicated teams of endoscopists and pathologists perform the procedure. We report the EUS-FNA experience of a cooperation group involving clinicians and cytopathologists from three hospitals. Fifty-seven consecutive EUS-FNA of mediastinal nodes in LC patients, eight mediastinal and two subdiaphragmatic masses were collected in 3 years. EUS-FNA was performed by two endoscopists and three experienced pathologists. On-site evaluation was performed in all cases by the three cytopathologists. Lymph node negative cases underwent surgery, which confirmed the cytological diagnoses but also detected two false negatives. Four of the 10 EUS cytological diagnoses of mediastinal and subdiaphragmatic masses were histologically confirmed. All EUS diagnoses were blindly reviewed by three pathologists to assess intra and interpersonal reproducibility. FNA-EUS diagnoses were: 10 inadequate (17%), 10 negative (17%), 4 suspicious (7%) and 33 positive (59%). Diagnoses of mediastinal and subdiaphragmatic masses were: relapse of lung carcinoma (3), mesenchimal tumor not otherwise specifiable (3), gastrointestinal stromal tumor (GIST) (1), esophageal carcinoma (2) and paraganglioma (1). The sensitivity attained was 85% and the specificity 100%; revision of the slides demonstrated a significant diagnostic reproducibility of the three cytopathologists (P < 0.5). The sensitivity and specificity attained were similar to those reported in the literature suggesting that experienced cytopathologists and endoscopists from different institutions can employ the same procedure reaching comparable results. PMID- 20960474 TI - Dose response with onabotulinumtoxinA for post-stroke spasticity: a pooled data analysis. AB - Clinical trials demonstrate that onabotulinumtoxinA reduces upper limb post stroke spasticity, with therapeutic response influenced by injected dose. Individual studies provide limited insight regarding muscle group-specific dose response relationships. Our objective was to characterize dose-response relationships between onabotulinumtoxinA and muscle tone in specific upper limb muscles. Individual patient data from seven multicenter, randomized, double blind, placebo-controlled trials were pooled. Of 544 post-stroke patients enrolled, 362 received onabotulinumtoxinA and 182 received placebo, injected into the flexor carpi radialis (FCR), flexor carpi ulnaris (FCU), flexor digitorum superficialis (FDS), flexor digitorum profundus (FDP), and/or biceps brachii (BB). Ashworth Scale score change at week 6 (AshworthCBL) was the primary outcome measure for muscle tone. For a broader analysis of response, AshworthCBL/onabotulinumtoxinA dosage relationships were characterized using three techniques: (1) AshworthCBL plotted as a function of onabotulinumtoxinA dose in Units (U) [dose-response curve]; (2) mean AshworthCBL per onabotulinumtoxinA dose depicting the responses seen with specific dose injection clusters/groups for each specific muscle group; and (3) onabotulinumtoxinA dose estimated to produce a mean 1-point decrease in AshworthCBL as an indicator of clinically meaningful benefit of treatment. Increasing onabotulinumtoxinA doses produced greater AshworthCBLs (muscle tone improvements). The maximal week 6 response (E(max)) model indicated a saturating dose-response relationship, with mean E(max) AshworthCBL values of -1.48, -1.48, -0.63, -0.77, and -0.61 in the FCR, FCU, FDS, FDP, and BB, respectively. OnabotulinumtoxinA doses estimated to produce a mean 1-point decrease in AshworthCBL were: 22.5U, 18.4U, 66.3U, 42.5U in the FCR, FCU, FDS, and FDP, respectively, and not determinable in the BB. These analyses demonstrate a saturating effect of greater muscle tone improvements with increasing onabotulinumtoxinA doses in post-stroke spasticity patients. These findings suggest potentially effective onabotulinumtoxinA doses in selected muscle groups in this study population. PMID- 20960475 TI - Loss of sensory function in patients with idiopathic hand dystonia. AB - Former studies suggest an additional involvement of the sensory nervous system, beside the involuntary contractions of antagonist muscles, in idiopathic hand dystonia. We studied contact heat-evoked potentials and quantitative sensory testing (QST) in 10 patients suffering from idiopathic hand dystonia and 10 age matched healthy controls. Cortical potentials recorded from the vertex (Pz) after contact heat stimulation of the volar forearm and the dorsum of the hand at a temperature of 51 degrees C showed significantly reduced A-delta-amplitudes. Numerical pain ratings on the affected side in comparison to the unaffected side and to healthy controls were significantly reduced. QST results showed an impairment of the thermal detection thresholds, the mechanical pain sensitivity and the mechanical pain threshold at the affected body side of the patients. Our results suggest a loss of distinct sensory functions of the affected hand in comparison with the contralateral hand and to matched healthy subjects in patients suffering from idiopathic hand dystonia. For the first time, an extended loss of sensory function could be shown in patients suffering from idiopathic hand dystonia. PMID- 20960476 TI - Subcutaneous insulin-like growth factor-1 treatment in spinocerebellar ataxias: an open label clinical trial. PMID- 20960477 TI - Vestibular evoked myogenic potentials are intact in cervical dystonia. AB - Vestibular dysfunction has been reported in patients with cervical dystonia (CD), but it is still unclear whether the abnormalities occur as part of the CD syndrome or whether they arise from the abnormal posture and movement of the head. We compared vestibular-evoked myogenic potentials (VEMPs) recorded from the affected neck muscles (i.e., cervical VEMPs) with those recorded from muscles unaffected by the dystonia, the extraocular muscles (i.e., ocular VEMPs). We compared 21 patients and age-matched normal controls to investigate whether these short-latency reflexes are altered in CD. We also measured subjective visual horizontal (SVH). Seven patients had not received botulinum toxin treatment (naive group), 10 were receiving regular injections (treatment group), and four had previously received treatment but had developed antibodies (antibody group). Both cervical and ocular VEMPs were present in the majority of patients and controls. For both reflexes, there were no significant differences between stimulation of the two sides of the head, between the treatment groups, or between the patients and controls. There was also no difference in degree of deviation of SVH between the groups. Our results showed that VEMPs can be reliably recorded from both the neck and extraocular muscles in patients with CD, even after long disease or treatment durations, and provide evidence for intact short-latency vestibular reflexes in CD. PMID- 20960478 TI - Fall risk assessment using the Tinetti mobility test in individuals with Huntington's disease. AB - The Tinetti Mobility Test (TMT) is a clinical balance and gait test that predicts fall risk in the elderly. This study examined the concurrent validity, usefulness of the TMT as a fall risk screening tool, and the potential ability of the TMT to predict falls in individuals with Huntington's disease (HD). Data from a retrospective review of 94 patient records were used. TMT scores were correlated with Unified Huntington Disease Rating Scale (UHDRS) motor scores. The ability of the TMT to accurately assess fall risk was determined using validity index measures. Logistic regression was used to assess the ability of the TMT to predict falls. TMT scores correlated with UHDRS motor scores (r(s) = -0.751, P < 0.0001). Using a cutoff value of 21, the TMT had a sensitivity of 74% and a specificity of 60% to identify fallers. Lower TMT scores and younger age were significant predictors of falls. The TMT is a valid tool for assessing balance and gait status and fall risk of individuals with HD. PMID- 20960479 TI - Dopamine boosts memory for angry faces in Parkinson's disease. AB - The influence of emotional context on cognitive operations is of fundamental importance for the evolution of higher cognitive functions and their disturbance in neuropsychiatric disorders. The dopamine pathways projecting to prefrontal cortex and the basal ganglia are assumed to play a major role in such emotion cognition interactions. Here we provide evidence for such a role by studying working memory for emotional faces in patients with Parkinson's Disease. We studied 25 patients with Parkinson's disease during their on and off medication states. Faces with emotional expressions (happy, angry, sad, neutral or fearful) were shown and the participants had to remember and later recall the identity of the faces ignoring the expressions. We found that dopaminergic medication enhances working memory for angry faces and suppresses it for sad faces. The results elucidate neurochemical mechanisms for the saliency of threatening information and support cognitive explanations of the antidepressant effects of dopamine. They also suggest a role for dopamine in changing emotional-cognitive biases rather than as a generic cognitive enhancer. PMID- 20960480 TI - Serum vitamin B(12) and folate levels in Parkinson's disease patients treated with duodenal levodopa infusion. PMID- 20960481 TI - Interhemispheric motor networks are abnormal in patients with Gilles de la Tourette syndrome. AB - Brain imaging has shown altered corpus callosum (CC) morphology in patients with Gilles de la Tourette syndrome (GTS). Yet it is unclear whether these morphological changes are associated with altered interhemispheric interactions. Here, we combined transcranial magnetic stimulation (TMS) with diffusion tensor magnetic resonance imaging (DTI) to explore functional and structural interhemispheric connections between the left and right motor hand areas. We studied 14 unmedicated GTS patients without psychiatric comorbidity (2 women, mean age 35.5 years) and 15 healthy volunteers (3 women, mean age 35 years). Left to-right and right-to-left interhemispheric inhibitions (IHIs) were measured in hand muscles with TMS. In 13 GTS patients and all healthy controls, we measured fractional anisotropy (FA) with DTI to examine the relation between functional measures of interhemispheric connectivity as derived by TMS and structural properties of the CC region that carries fibers interconnecting both motor cortices. In GTS patients, left-to-right IHI was weaker than right-to-left IHI. Left-to-right IHI in GTS patients was also reduced compared with healthy controls. Voxel-based morphometric analysis revealed that FA in the motor region of the CC did not differ between groups. However, there was a significant interaction between groups and the relation between regional FA and left-to-right IHI in the motor region of the CC. A negative linear relation between FA and left to-right IHI was present in control subjects but not in patients. Our combined TMS-DTI approach demonstrates abnormal functional interhemispheric connectivity in GTS accompanied by an altered structure-function relationship in the motor CC. PMID- 20960482 TI - Nonlinear decline of mini-mental state examination in Parkinson's disease. AB - The trajectory of cognitive functioning in patients with Parkinson's disease (PD) is not known. We used a random change point model to study the individual cognitive trajectory for up to 15 years in a prevalence sample of 238 PD patients, and used the mini-mental state examination (MMSE) to assess the longitudinal cognitive course. We observed that the rate of global cognitive decline was nonlinear. Following a relatively stable period, an inflection point was identified, after which the rate of decline gained momentum with an annual decline of 2.8 points on the MMSE. The course was similar in men and women. This inflection point was estimated to occur 13.3 years (95% credible interval 11.8, 13.6) after the diagnosis of PD; however, there were wide interindividual variations in the time from onset of PD to the inflection point. PMID- 20960483 TI - Neuropsychological correlates of mild to severe hallucinations in Parkinson's disease. AB - The development of visual hallucinations (VH) is a frequent complication of Parkinson's disease (PD). Presence of hallucinations is one of the main risk factors associated with dementia, and severity progression of VH mainly contributes to impaired quality of life in PD. The neuropsychological features associated with severity progression of VH are unknown and might help to detect patients at risk of a more severe outcome. We aimed to explore the neuropsychological deficits associated with the different types of VH observed in PD, from minor hallucinations to well-formed VH with loss of insight. Prospective study of 57 PD patients with (n = 29) and without VH (n = 28) matched for age, education, antiparkinsonian medications, and disease duration. Description of VH was assessed by the Hallucinations and Psychosis item of the MDS-UPDRS. Cognition was assessed with the Parkinson's Disease-Cognitive Rating Scale (PD-CRS) and the Mattis Dementia Rating Scale (MDRS). Patients with minor VH did not differ from patients without VH in any cognitive domain. PD patients with major VH and insight retained performed worse on the action verbal fluency task (P < 0.04), and patients with VH and loss of insight showed a greater impairment on the PD CRS posterior cortical score (P = 0.021) and the clock copying item (P = 0.01). A double dissociation was found in the neuropsychological profile of patients with VH with and without loss of insight. While the presence of major VH with insight retained appeared related to a predominant frontal-striatal impairment, loss of insight was characterized by further impairment of cognitive functions related to posterior cortical areas. A comprehensible continuum pattern of clinical relationships emerged among VH and cognitive functioning in PD. PMID- 20960484 TI - Reversible Parkinsonism after accidental oral intake of mancozeb. PMID- 20960485 TI - Subtle rapid eye movement sleep abnormalities in presymptomatic spinocerebellar ataxia type 2 gene carriers. AB - Rapid eye movement (REM) sleep disorders are commonly associated to patients with spinocerebellar ataxia type 2 (SCA2); however, these abnormalities have not been studied in presymptomatic gene carriers. To determine whether the REM sleep pathology is detectable before clinical manifestation of SCA2 and evaluate it as a preclinical biomarker, we studied 36 presymptomatic SCA2 individuals and 36 controls by video-polysomnography (VPSG) and sleep questionnaires. Presymptomatic subjects showed significant decrease of REM sleep percentage, REMs density, total sleep time, and sleep efficiency. Aging effect on REM sleep percentage was significant in both groups. There was no correlation between cytosine-adenine guanine (CAG) repeat length and REM sleep. Our findings identified the REM sleep pathology as a prominent herald sign of SCA2, conferring a special importance to VPSG as a sensitive neurophysiological tool to detect early changes associated with SCA2, which contributes to the understanding of disease pathophysiology and the development of therapeutic trials focused on the preclinical disease stage. PMID- 20960486 TI - Transcutaneous port for continuous duodenal levodopa/carbidopa administration in Parkinson's disease. AB - Motor fluctuations in Parkinson's disease (PD) can be reduced by intraduodenal infusion of levodopa-carbidopa (Duodopa(r)) via percutaneous endoscopic gastrojejunostomy (PEG). We applied the transcutaneous soft-tissue anchored titanium port (T-port) in 15 PD patients with motor fluctuations; 7 Duodopa-naive (non-PEG), and 8 previously receiving Duodopa (former-PEG). Motor scores (UPDRS III) and quality of life (QOL, PDQ-8) were assessed at baseline and 6 month follow-up. Six patients had local irritation shortly after implantation, persisting in one patient at 6 month follow-up, which led to explantation. After having finished the protocol, four T-ports were explanted in total. UPDRS-III and PDQ-8 scores improved moderately in the non-PEG patients, but remained similar in the former-PEG users. Two former-PEG users developed polyneuropathy. No obstructions, retractions, or leakages occurred. Technical and hygienic properties of the T-port were preferred by most patients. The T-port seems to be suitable for most PD patients qualifying for Duodopa therapy, although local infection may lead to explantation during longer-term follow-up. PMID- 20960487 TI - Exercise elevates dopamine D2 receptor in a mouse model of Parkinson's disease: in vivo imaging with [18F]fallypride. AB - The purpose of the current study was to examine changes in dopamine D2 receptor (DA-D2R) expression within the basal ganglia of MPTP mice subjected to intensive treadmill exercise. Using Western immunoblotting analysis of synaptoneurosomes and in vivo positron emission tomography (PET) imaging employing the DA-D2R specific ligand [18F]fallypride, we found that high intensity treadmill exercise led to an increase in striatal DA-D2R expression that was most pronounced in MPTP compared to saline treated mice. Exercise-induced changes in the DA-D2R in the dopamine-depleted basal ganglia are consistent with the potential role of this receptor in modulating medium spiny neurons (MSNs) function and behavioral recovery. Importantly, findings from this study support the rationale for using PET imaging with [18F]fallypride to examine DA-D2R changes in individuals with Parkinson's Disease (PD) undergoing high-intensity treadmill training. PMID- 20960488 TI - Oligoclonal bands in cerebrospinal fluid in patients with Tourette's syndrome. AB - Since a postinfectious or autoimmune etiology is suggested to be involved in the pathogenesis of Tourette's syndrome (TS), we investigated oligoclonal bands (OB) of immunoglobulin G (IgG) in cerebrospinal fluid (CSF), indicating a humoral immune response in the central nervous system. CSF examinations including isoelectric focusing to analyze the presence of OB were performed in 21 TS patients [17 men/4 women, mean age = 29 +/- 12 (SD) years]. Isoelectric focusing showed the presence of positive OB in 6, borderline bands in 2, and serum and CSF bands ("mirrored pattern") in another 2 patients. Clinical data did not correlate with CSF findings. Thus, 38% (8 of 21) of our patients exhibited pathological CSF bands. Since none of them suffered from another disease known to be associated with OB, our results suggest an association with the pathogenesis of TS itself and point to an involvement of immunological mechanisms in TS pathology. PMID- 20960489 TI - Conditional survival of extremity soft-tissue sarcoma: results beyond the staging system. AB - BACKGROUND: With increasing interest in adult cancer survivorship, currently available prognostic estimates for long-term survivors of extremity soft-tissue sarcoma (ESTS) are limited. We assessed determinants of survival in adults surgically treated for nonmetastatic ESTS, conditional on specific survival periods. METHODS: We identified 6215 persons aged >18 in the Surveillance Epidemiology and End Results program who were surgically treated for nonmetastatic ESTS from 1991 to 2006. We used Cox proportional hazards regression to assess demographic, tumor, and treatment factors associated with 10-year sarcoma-specific survival (SSS) at diagnosis and conditional on surviving 3 and 5 years postdiagnosis. RESULTS: At the time of diagnosis, age, tumor, and treatment factors predicted SSS. Although older age significantly predicted worse SSS for all age groups at diagnosis (HR 3.78 for age >81 vs 18-35; P < .05 for all), the effect of age became nonsignificant as survival time increased, except for the oldest group (>80 years). Tumor size, grade, and histologic subtypes continued to be important predictors of SSS for all periods of conditional survival. Persons who underwent limb amputation were at 3 times the risk of mortality for all conditional survival periods. CONCLUSIONS: In this large population-based experience of ESTS survivors, age >80, tumor, and treatment factors continued to affect long-term survival, whereas the effect of age dampened over time. These estimates provide important counseling information for changing risk factors as survival time increases, help to streamline future surveillance programs, and provide insights into the design of adult survivorship care. Cancer 2011. (c) 2010 American Cancer Society. PMID- 20960490 TI - Trends, patterns, and outcomes in the management of malignant colonic polyps in the general population of the United States. AB - BACKGROUND: Colonoscopic screening has increased detection of malignant colonic polyps (MPs). The goal of this study was to analyze trends and patterns in the surgical treatment of MPs and to assess outcomes as measured by lymph node retrieval and patient survival. METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry was queried to identify 19,743 patients with MPs from 1988 to 2003. RESULTS: The majority of MPs were present in the sigmoid and descending colon (54%), and 38% were tubular, 40% were tubulovillous, and 22% were villous. During the study period, the incidence of MPs increased from 29% to 42% and surgical resection (SR) was increasingly used for treatment, from 54% to 70%. Predictors of SR were aged <70 years (odds ratio [OR], 1.3; 95% confidence interval [95% CI], 1.2-1.4), high-grade tumors (OR, 1.5; 95% CI, 1.2-1.9), diagnosis in 1999 through 2003 (OR, 1.7; 95% CI, 1.5-1.9), villous subtype (OR, 2.3; 95% CI, 2.0-2.6), and right colon location (OR, 8.1; 95% CI, 7.0-9.4). In patients undergoing SR, the mean and median number of lymph nodes was only 4 and 1, respectively. A significant percentage of patients (49%) had no lymph nodes retrieved and a worse overall survival at 5 years compared with patients who had at least 1 lymph node examined (64% vs 74%; P <.001). CONCLUSIONS: MPs appear to be increasing in incidence, and there is a trend toward increased use of SR for treatment. However, patients undergoing SR for MPs undergo suboptimal assessment of lymph nodes, with a detrimental impact on survival. Adequate lymphadenectomy and lymph node evaluation are crucial to improve outcomes in patients with these potentially curable lesions. Cancer 2011. (c) 2010 American Cancer Society. PMID- 20960491 TI - Block copolymers comprising pi-conjugated and liquid crystalline subunits: induction of macroscopic nanodomain orientation. PMID- 20960492 TI - Temperature-dependent rate coefficients and theoretical calculations for the OH+Cl2O reaction. AB - Rate coefficients k for the OH+Cl(2)O reaction are measured as a function of temperature (230-370 K) and pressure by using pulsed laser photolysis to produce OH radicals and laser-induced fluorescence to monitor their loss under pseudo first-order conditions in OH. The reaction rate coefficient is found to be independent of pressure, within the precision of our measurements at 30-100 Torr (He) and 100 Torr (N(2)). The rate coefficients obtained at 100 Torr (He) showed a negative temperature dependence with a weak non-Arrhenius behavior. A room temperature rate coefficient of k(1)(297 K)=(7.5+/-1.1)*10(-12) cm(3) molecule( 1) s(-1) is obtained, where the quoted uncertainties are 2sigma and include estimated systematic errors. Theoretical methods are used to examine OH...OCl(2) and OH...ClOCl adduct formation and the potential-energy surfaces leading to the HOCl+ClO (1a) and Cl+HOOCl (1d) products in reaction (1) at the hybrid density functional UMPW1K/6-311++G(2df,p) level of theory. The OH...OCl(2) and OH...ClOCl adducts are found to have binding energies of about 0.2 kcal mol(-1). The reaction is calculated to proceed through weak pre-reactive complexes. Transition state energies for channels (1a) and (1d) are calculated to be about 1.4 and about 3.3 kcal mol(-1) above the energy of the reactants. The results from the present study are compared with previously reported rate coefficients, and the interpretation of the possible non-Arrhenius behavior is discussed. PMID- 20960493 TI - Uptake of formic acid on thin ice films and on ice doped with nitric acid between 195 and 211 K. AB - The adsorption of formic acid on thin ice films and on ice doped with nitric acid (1.96, 7.69 and 53.8 wt%) is studied as a function of temperature T=195-211 K and gas concentration (0.33-10.6)*10(11) molecule cm(-3). Experiments are performed in a Knudsen flow reactor coupled with a quadrupole mass spectrometer. The initial uptake coefficients gamma are strongly and inversely dependent on the ice temperature. Initial uptake is determined at low surface coverages and ranges from (0.65-3.78)*10(-3). The adsorption uptake of formic acid on pure ice films and on ice lightly doped with HNO(3) is a reversible process, and the adsorption isotherms exhibit Langmuir behaviour. N(max)(1) is (2.94+/-0.67)*10(14) molecule cm(-2), in good agreement with previous measurements. The temperature dependence of K(Lin) is very well represented by the expression: K(Lin)(1)=(1.43+/-0.32)*10( 8) exp[(4720+/-520)/T] cm(3) molecule(-1); the quoted uncertainty is at the 95% level of confidence and includes systematic uncertainties. Formic acid uptakes on ice films highly doped with HNO(3) (53.8 wt%) are two orders of magnitude higher than those measured on pure ice films and irreversible, thus indicating the formation of a supercooled liquid layer on the ice films upon which dissolution of formic acid occurs. Finally, the atmospheric lifetime of formic acid due to heterogeneous loss on cirrus cloud ice particles and the removal of formic acid by adsorption are estimated under conditions related to the upper troposphere. PMID- 20960494 TI - Spin-labeled heparins as polarizing agents for dynamic nuclear polarization. AB - A potentially biocompatible class of spin-labeled macromolecules, spin-labeled (SL) heparins, and their use as nuclear magnetic resonance (NMR) signal enhancers are introduced. The signal enhancement is achieved through Overhauser-type dynamic nuclear polarization (DNP). All presented SL-heparins show high (1)H DNP enhancement factors up to E=-110, which validates that effectively more than one hyperfine line can be saturated even for spin-labeled polarizing agents. The parameters for the Overhauser-type DNP are determined and discussed. A striking result is that for spin-labeled heparins, the off-resonant electron paramagnetic resonance (EPR) hyperfine lines contribute a non-negligible part to the total saturation, even in the absence of Heisenberg spin exchange (HSE) and electron spin-nuclear spin relaxation (T(1ne)). As a result, we conclude that one can optimize the use of, for example, biomacromolecules for DNP, for which only small sample amounts are available, by using heterogeneously distributed radicals attached to the molecule. PMID- 20960495 TI - Photoinduced electron transfer in a distyryl BODIPY-fullerene dyad. AB - A novel distyryl BODIPY-fullerene dyad is prepared. Upon excitation at the distyryl BODIPY moiety, the dyad undergoes photoinduced electron transfer to give a charge-separated state with lifetimes of 476 ps and 730 ps in polar (benzonitrile) and nonpolar (toluene) solvents, respectively. Transient absorption measurements show the formation of the triplet excited state of distyryl BODIPY in the dyad, which is populated from charge-recombination processes in both solvents. PMID- 20960496 TI - Seven new monoterpenoid indole alkaloids from Gelsemium elegans. AB - Seven new indole alkaloids were isolated from the roots of Gelsemium elegans Benth. and their structures were determined by spectroscopic analysis and chemical transformation from known alkaloids. Kounaminal (1) is a new koumine type alkaloid that contains an unusual aminal moiety. Humantenoxenine (2) and 15 hydroxyhumantenoxenine (3) are humantenine-type alkaloids that contain a novel beta-amino-alpha,beta-unsaturated ketone residue. The other four novel alkaloids are two gelsedilam-related and two gelsenicine-related alkaloids. PMID- 20960498 TI - Midtreatment 18F-fluorodeoxyglucose positron-emission tomography in aggressive non-Hodgkin lymphoma. AB - BACKGROUND: The use of (18) F-fluorodeoxyglucose positron-emission tomography (PET) scan has increased considerably in the clinical management of non-Hodgkin lymphoma patients, and its role as a prognostic factor during chemotherapy has been established recently. METHODS: Between May 2003 and May 2009, 91 newly diagnosed patients with primary mediastinal large B-cell lymphoma (PMLBCL) and diffuse large B-cell lymphoma (DLBCL) were treated with 12 weekly cycles of rituximab-MACOP-B (n = 12 patients with PMLBCL), 6 cycles of rituximab-CHOP21 (n = 65 patients with DLBCL, aged < 60 years and 1 patient with PMLBCL), or 8 weekly cycles of rituximab-VNCOP-B (n = 13 DLBCL patients, aged >= 60 years). All patients underwent a staging PET examination at baseline and a midtreatment (interim) PET examination after 6 weeks of rituximab-MACOP-B treatment, 3 cycles of rituximab-CHOP21 treatment, or 4 weeks of rituximab-VNCOP-B treatment and again at the end of the chemo-immunotherapy regimen. RESULTS: At midtreatment evaluation, 35 patients showed a persistently positive PET scan; only 6 (17%) of these patients achieved a continuous complete response (CCR). However, 56 patients presented with a negative interim PET, and 50 (89%) of these patients achieved and maintained a CCR. Comparison between the 2 PET groups indicated a statistically significant association between PET findings and event-free survival (P = .0001) and overall survival (P = .0001). CONCLUSIONS: The results of this study indicated that midtreatment PET may represent a significant step forward in helping physicians make crucial decisions on further treatment. Cancer 2011. (c) 2010 American Cancer Society. PMID- 20960497 TI - Combined modality therapy of cT2N0M0 esophageal cancer: the University of Texas M. D. Anderson Cancer Center experience. AB - BACKGROUND: Treatment strategy for patients with adequately staged cT2N0M0 carcinoma of the thoracic esophagus is currently a subject of debate. This study analyzed the largest series of consecutive cT2N0M0 esophageal cancer patients treated with preoperative chemoradiotherapy. METHODS: Data from all patients with cT2N0M0 (assessment included endoscopic ultrasonography and computed tomography of the chest and abdomen) thoracic esophageal cancer who were treated with preoperative chemoradiation between 1997 and 2009 were analyzed. The Cox regression model and Kaplan-Meier plots were used to analyze the data. RESULTS: Data from 49 patients were analyzed. The median follow-up was 28.46 months. Male sex and adenocarcinoma histology predominated. Pathologic complete response was observed 19 (39%) patients. The 10-year actuarial overall survival (OS) for adenocarcinoma patients was >60%. In the univariate analysis for OS, squamous histology (P = .006), smoking (P = .015), and alcohol consumption (P = .032) were found to be associated with poor OS. In the univariate analysis for disease-free survival (DFS), squamous histology (P = .009) and smoking (P = .014) were associated with poor DFS. In the multivariate analysis for OS, smoking was an independent prognosticator (P = .02). In the multivariate analysis for DFS, advanced pathologic stage (P = .05) and lymph node metastases (P = .006) were independent prognosticators. Patients with adenocarcinoma (P = .002) and those with pathologic N0 disease had better OS and DFS. Upward stage migration occurred in only 10% of patients. CONCLUSIONS: These data suggest that smoking and alcohol influence the long-term outcome of patients with cT2N0M0 disease. Adenocarcinoma patients treated with trimodality therapy had an excellent actuarial 10-year OS and a high rate of pathologic complete response. Trimodality therapy should be prospectively compared with primary surgery in these patients. PMID- 20960499 TI - A note from history: landmarks in history of cancer, part 1. AB - Review of the earliest written descriptions and reports of cancer show that ancient physicians and surgeons made gradual progress in understanding cancer. It became clear to most of them that early detection and complete removal, before the cancer became ulcerated, afforded the best outcome. PMID- 20960500 TI - Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer: findings on the basis of North Central Cancer Treatment Group trials. AB - BACKGROUND: The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression-free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS. METHODS: Individual patient data from 870 untreated extensive stage small-cell lung cancer patients participating in 6 single-arm (274 patients) and 3 randomized trials (596 patients) were pooled. Patient-level associations between putative surrogate endpoints and OS were assessed by Cox models using landmark analyses. Trial-level surrogacy of putative surrogate endpoints were assessed by the association of treatment effects on OS and individual putative surrogate endpoints. Trial-level surrogacy measures included: R(2) from weighted least squares regression model, Spearman correlation coefficient, and R(2) from bivariate survival model (Copula R(2) ). RESULTS: Median OS and PFS were 9.6 (95% confidence interval [CI], 9.1-10.0) and 5.5 (95% CI, 5.2-5.9) months, respectively; best response, CR, and confirmed response rates were 44%, 22%, and 34%, respectively. Patient-level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (hazard ratio [HR], 0.42; 95% CI, 0.35-0.51; concordance index 0.63; P < .01), with 6 month PFS being the strongest (HR, 0.41; 95% CI, 0.35-0.49; concordance index, 0.66, P < .01). At the trial level, PFS showed the highest level of surrogacy for OS (weighted least squares R(2) = 0.79; Copula R(2) = 0.80), explaining 79% of the variance in OS. Tumor response endpoints showed lower surrogacy levels (weighted least squares R(2) <=0.48). CONCLUSIONS: PFS was strongly associated with OS at both the patient and trial levels. PFS also shows promise as a potential surrogate for OS, but further validation is needed using data from a larger number of randomized phase 3 trials. PMID- 20960501 TI - Gemcitabine and radiotherapy plus cisplatin after transurethral resection as conservative treatment for infiltrating bladder cancer: Long-term cumulative results of 2 prospective single-institution studies. AB - BACKGROUND: Cystectomy is the standard treatment for patients with infiltrating bladder cancer, but conservative treatment with cystoscopic resection followed by radiochemotherapy may be an alternative for highly selected patients. The addition of gemcitabine to cisplatin and radiotherapy may enhance disease control. METHODS: The long-term clinical outcomes of 26 patients enrolled in a previously published dose-finding study and a prematurely discontinued phase 2 trial were evaluated. All the patients underwent transurethral tumor resection followed by a radical dose of external radiotherapy administered at the same time as cisplatin and weekly gemcitabine therapy. RESULTS: After a median follow-up of 74 months, the projected 5-year clinical outcomes were a 70.1% overall survival rate, a 78.9% disease-specific survival rate, and a 73.8% bladder-intact survival rate. CONCLUSIONS: The long-term follow-up data from the current study confirmed that the addition of gemcitabine to radiotherapy and cisplatin is safe and leads to good local and distant disease control. The concomitant administration of cisplatin may explain the good long-term organ preservation that was observed. Conducting confirmatory and comparative trials could satisfy an unmet need but requires the multidisciplinary cooperation of urologists in selecting the right patients for a bladder-sparing strategy. PMID- 20960502 TI - Long-term prognostic impact of the use of erythropoietic-stimulating agents in patients with chronic myeloid leukemia in chronic phase treated with imatinib. AB - BACKGROUND: Anemia is a frequent side effect of imatinib in patients with chronic myeloid leukemia (CML). Erythropoietic-stimulating agents have been used for treatment of imatinib-induced anemia. There are no data on long-term safety of erythropoietic-stimulating agents in CML patients. METHODS: The records of chronic phase CML patients who received treatment with imatinib were reviewed for use of erythropoietic-stimulating agents and occurrence of thrombotic events. Data on cytogenetic response and survival were analyzed by use of erythropoietic stimulating agent. RESULTS: A total of 608 patients were included, and 217 patients received erythropoietic-stimulating agents. There were 30 thrombotic episodes. Patients who received erythropoietic-stimulating agents had a higher rate of thrombosis (8.5% vs 2.6%, P = .0025). There was no difference in cytogenetic response rate and survival by use of erythropoietic-stimulating agent. Development of grade 3-4 anemia occurred in 62 (10%) patients and was associated with significantly worse response and survival in patients in late chronic phase. By multivariate analysis, use of erythropoietic-stimulating agents was not a risk factor for event-free survival. CONCLUSIONS: In our cohort of chronic phase CML patients, use of erythropoietic-stimulating agents did not impact survival or cytogenetic response rate, but was associated with a higher thrombosis rate. Severe anemia is associated with worse survival and response. PMID- 20960503 TI - The selective Trk inhibitor AZ623 inhibits brain-derived neurotrophic factor mediated neuroblastoma cell proliferation and signaling and is synergistic with topotecan. AB - BACKGROUND: TrkB expression is associated with poor prognosis for patients with neuroblastoma. AZ623 is a novel potent and selective inhibitor of the Trk family of tyrosine kinases. The authors hypothesized that AZ623 would inhibit TrkB mediated signaling in neuroblastoma tumor cells and would be synergistic when combined with chemotherapy. METHODS: Neuroblastoma cell lines were screened for TrkB receptor mRNA expression and for their proliferation rates in response to brain-derived neurotrophic factor (BDNF). The effects of AZ623 on Trk receptor phosphorylation, signaling, and cell growth were evaluated in BDNF-treated neuroblastoma cells. Mice with human neuroblastoma xenograft tumors were treated with AZ623 alone and in combination with topotecan, and tumor growth rates were determined during and after treatment. RESULTS: Neuroblastoma cell lines expressed various levels of the TrkB receptor and demonstrated increased proliferation in response to BDNF. BDNF treatment stimulated TrkB phosphorylation and downstream signaling that could be inhibited by AZ623. Neuroblastoma cells demonstrated in vitro sensitivity to AZ623, with concentration that inhibits 50% (IC50) values between 0.8 to 7 MUM. AZ623 treatment was found to inhibit BDNF mediated neuroblastoma cell proliferation. Mice with human neuroblastoma xenograft tumors demonstrated tumor growth inhibition when treated with AZ623 and with AZ623 combined with topotecan. Limited tumor regrowth was noted in mice with tumors treated with AZ623 combined with topotecan after treatment discontinuation. CONCLUSIONS: AZ623 is a novel selective Trk inhibitor that inhibits BDNF-mediated signaling and neuroblastoma cell proliferation. AZ623 treatment inhibits the growth of human neuroblastoma xenograft tumors, and treatment with AZ623 combined with topotecan results in the prolonged inhibition of tumor regrowth. On the basis of these results, further preclinical development is warranted. PMID- 20960504 TI - Cumulative incidence of cancer among individuals with acquired immunodeficiency syndrome in the United States. AB - BACKGROUND: The overall burden of cancer may increase as individuals with acquired immunodeficiency syndrome (AIDS) live longer because of highly active antiretroviral therapy (HAART), which has been widely available since 1996. METHODS: A population-based, record-linkage study identified cancers in 472,378 individuals with AIDS from 1980 to 2006. By using nonparametric competing-risk methods, the cumulative incidence of cancer was estimated across 3 calendar periods (AIDS onset in 1980-1989, 1990-1995, and 1996-2006). RESULTS: Measured at 5 years after AIDS onset, the cumulative incidence of AIDS-defining cancer (ADC) declined sharply across the 3 AIDS calendar periods (from 18% in 1980-1989, to 11% in 1990-1995, to 4.2% in 1996-2006 [ie, the HAART era]). The cumulative incidence of Kaposi sarcoma declined from 14.3% during 1980 to 1989, to 6.7% during 1990 to 1995, and to 1.8% during 1996 to 2006. The cumulative incidence of non-Hodgkin lymphoma (NHL) declined from 3.8% during 1990 through 1995 to 2.2% during 1996 through 2006; during the HAART era, NHL was the most common ADC (53%). The cumulative incidence of non-AIDS-defining cancer (NADC) increased from 1.1% to 1.5% with no change thereafter (1%; 1996-2006), in part because of declines in competing mortality. However, cumulative incidence increased steadily over time for specific NADCs (anal cancer, Hodgkin lymphoma, and liver cancer). The cumulative incidence of lung cancer increased from 0.14% during 1980 to 1989 to 0.32% during 1990 to 1995, and no change was observed thereafter. CONCLUSIONS: Dramatically declining cumulative incidence was noted in 2 major ADCs (Kaposi sarcoma and NHL), and increases were observed in some NADCs (specifically, cancers of the anus, liver, and lung and Hodgkin lymphoma). As HIV/AIDS is increasingly managed as a chronic disease, greater attention should be focused on cancer screening and prevention. PMID- 20960505 TI - Fluorescence cystoscopy for nonmuscle invasive bladder cancer: is the honeymoon over for the blue light special? PMID- 20960507 TI - Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. PMID- 20960509 TI - Association of hyaluronic acid family members (HAS1, HAS2, and HYAL-1) with bladder cancer diagnosis and prognosis. AB - BACKGROUND: Cancer biomarkers are the backbone for the implementation of individualized approaches to bladder cancer (BCa). Hyaluronic acid (HA) and all 7 members of the HA family, that is, HA synthases (HA1, HA2, HA3), HYAL-1 hyaluronidase, and HA receptors (CD44s, CD44v, and RHAMM), function in tumor growth and progression. However, the diagnostic and prognostic potential of these 7 HA family members has not been compared simultaneously in any cancer. We evaluated the diagnostic and prognostic potential of HA family members in BCa. METHODS: Using quantitative PCR and immunohistochemistry, expression of HA family members was evaluated in prospectively collected bladder tissues (n = 72); mean and median follow-up were 29.6 +/- 5.3 and 24 months, respectively. Transcript levels were also measured in exfoliated urothelial cells from urine specimens (n = 148). RESULTS: Among the HA family members, transcript levels of the HA synthases, HYAL-1, CD44v, and RHAMM were 4- to 16-fold higher in BCa tissues than in normal tissues (P < .0001); however, CD44s levels were lower. In univariate and multivariate analyses, tumor stage (P = .003), lymph node invasion (P = .033), HYAL-1 (P = .019), and HAS1 (P = .027) transcript levels, and HYAL-1 staining (P = .021) were independently associated with metastasis. Tumor stage (P = .019) and HYAL-1 (P = .046) transcript levels were also associated with disease specific mortality. Although HA synthase and HYAL-1 transcript levels were elevated in exfoliated urothelial cells from BCa patients, the combined HAS2-HYAL 1 expression detected BCa with an overall sensitivity of 85.4% and a specificity of 79.5% and predicted BCa recurrence within 6 months (P = .004; RR = 6.7). CONCLUSIONS: HYAL-1 and HAS1 expression predicted BCa metastasis, and HYAL-1 expression also predicted disease-specific survival. Furthermore, the combined HAS2-HYAL-1 biomarker detected BCa and significantly predicted its recurrence. PMID- 20960510 TI - Caregiver symptom burden: the risk of caring for an underserved patient with advanced cancer. AB - BACKGROUND: The growing diversity of the population of the United States and the high burden of cancer-related symptoms reflect the need for caregiver research within underserved groups. In this longitudinal study, the authors assessed changes in symptom severity in caregivers and underserved minority patients diagnosed with advanced solid tumors who were being treated at public hospitals. METHODS: A total of 85 matched patient-caregiver dyads completed the M. D. Anderson Symptom Inventory 3 times during 20 weeks of chemotherapy. At each time point, symptom severity and interference with daily activities were assessed. Group-based trajectory modeling was used to classify caregivers into high-symptom or low-symptom burden groups. RESULTS: Sadness and distress were more prevalent among caregivers (P = .005). Symptom burden remained stable among caregivers in the high-symptom group (40%), whereas the low-symptom group (60%) demonstrated a statistically significant decrease over time. Multivariate analysis found being a family-member caregiver (adjusted odds ratio [ADJ-OR], 4.1; 95% confidence interval [95% CI], 1.4-11.6) and caring for a highly symptomatic patient (ADJ-OR, 8.0; 95% CI, 1.5-41.4), rather than race, ethnicity, or sociodemographic characteristics, were significant predictors of the caregiver's membership in the high-symptom burden group. CONCLUSIONS: Approximately 40% of the caregivers in the current study were found to be at an increased risk for moderate to severe sadness and distress, which remained severe throughout the patient's treatment course at public hospitals. To the authors' knowledge, this study marks the first time that the concept of symptom burden has been used to measure caregiver burden, and the first time that symptom burden has been measured and documented in dyads of caregivers and underserved minority patients. Cancer 2011. (c) 2010 American Cancer Society. PMID- 20960511 TI - In vivo assessment of the electrophysiological integration and arrhythmogenic risk of myocardial cell transplantation strategies. AB - Cell replacement strategies are promising interventions aiming to improve myocardial performance. Yet, the electrophysiological impact of these approaches has not been elucidated. We assessed the electrophysiological consequences of grafting of two candidate cell types, that is, skeletal myoblasts and human embryonic stem cell-derived cardiomyocytes (hESC-CMs). The fluorescently labeled (DiO) candidate cells were grafted into the rat's left ventricular myocardium. Two weeks later, optical mapping was performed using the Langendorff-perfused rat heart preparation. Images were obtained with appropriate filters to delineate the heart's anatomy, to identify the DiO-labeled cells, and to associate this information with the voltage-mapping data (using the voltage-sensitive dye PGH I). Histological examination revealed the lack of gap junctions between grafted skeletal myotubes and host cardiomyocytes. In contrast, positive Cx43 immunostaining was observed between donor and host cardiomyocytes in the hESC-CMs transplanted hearts. Optical mapping demonstrated either normal conduction (four of six) or minimal conduction slowing (two of six) at the hESC-CMs engraftment sites. In contrast, marked slowing of conduction or conduction block was seen (seven of eight) at the myoblast transplantation sites. Ventricular arrhythmias could not be induced in the hESC-CM hearts following programmed electrical stimulation but were inducible in 50% of the myoblast-engrafted hearts. In summary, a unique method for assessment of the electrophysiological impact of myocardial cell therapy is presented. Our results demonstrate the ability of hESC CMs to functionally integrate with host tissue. In contrast, transplantation of cells that do not form gap junctions (skeletal myoblats) led to localized conduction disturbances and to the generation of a proarrhythmogenic substrate. PMID- 20960512 TI - Concise review: Insights from normal bone remodeling and stem cell-based therapies for bone repair. AB - There is growing interest in the use of mesenchymal stem cells for bone repair. As a major reason for normal bone remodeling is the removal of fatigue microcracks, advances in our understanding of this process may inform approaches to enhance fracture healing. Increasing evidence now indicates that physiological bone remodeling occurs in close proximity to blood vessels and that these vessels carry perivascular stem cells that differentiate into osteoblasts. Similarly, fracture healing is critically dependent on the ingrowth of blood vessels not only for a nutrient supply but also for the influx of osteoblasts. A number of animal and human studies have now shown the potential benefit of bone marrow derived mesenchymal stem cells in enhancing bone repair. However, as in other tissues, the question of whether these cells improve fracture healing directly by differentiating into osteoblasts or indirectly by secreting paracrine factors that recruit blood vessels and the accompanying perivascular stem cells remains a major unresolved issue. Moreover, CD34+ cells, which are enriched for endothelial/hematopoietic cells, have also shown efficacy in various bone repair models, at least in part due to the induction of angiogenesis and recruitment of host progenitor cells. Thus, mesenchymal and nonmesenchymal stem/progenitor cells are attractive options for bone repair. It is possible that they contribute directly to bone repair, but it is also likely that they express paracrine factors in the appropriate amounts and combinations that promote and sustain the healing process. PMID- 20960513 TI - Notch3 null mutation in mice causes muscle hyperplasia by repetitive muscle regeneration. AB - Satellite cells are skeletal muscle stem cells responsible for growth, maintenance, and repair of postnatal skeletal muscle. Although several studies have demonstrated that Notch signaling plays a critical role in muscle regeneration through promoting proliferation and self-renewal of satellite cells, the function of Notch3 is yet to be elucidated. We analyzed muscle regeneration in Notch3-deficient mutant mice. We found a remarkable overgrowth of muscle mass in the Notch3-deficient mice but only when they suffered repetitive muscle injuries. Immunochemical analysis found that Notch3 was expressed in Pax7(+)/MyoD(-) quiescent satellite cells and also in Pax7(+)/MyoD(+)-activated satellite cells, but the expression was restricted to around half the population of each cell type. In Notch3-deficient mice, the number of sublaminar quiescent satellite cells was significantly increased compared with those in control mice. We also found that primary cultured myoblasts isolated from the Notch3-deficient mice proliferated faster than those from control mice. Analysis of cultured myofibers revealed that the number of self-renewing Pax7-positive satellite cells attached to the myofiber was increased in the Notch3-deficient mice when compared with control mice. The data obtained in this study suggested that Notch3 pathway might be distinct from Notch1 in muscle regeneration. Because overexpression of Notch3 activated the expression of Nrarp, a negative feedback regulator of Notch signaling, Notch3 might act as a Notch1 repressor by activating Nrarp. PMID- 20960514 TI - Human embryonic stem cells suffer from centrosomal amplification. AB - Propagation of human embryonic stem cells (hESCs) in culture tends to alter karyotype, potentially limiting the prospective use of these cells in patients. The chromosomal instability of some malignancies is considered to be driven, at least in part, by centrosomal overamplification, perturbing balanced chromosome segregation. Here, we report, for the first time, that very high percentage of cultured hESCs has supernumerary centrosomes during mitosis. Supernumerary centrosomes were strictly associated with an undifferentiated hESC state and progressively disappeared on prolonged propagation in culture. Improved attachment to culture substratum and inhibition of CDK2 and Aurora A (key regulators of centrosomal metabolism) diminished the frequency of multicentrosomal mitoses. Thus, both attenuated cell attachment and deregulation of machinery controlling centrosome number contribute to centrosomal overamplification in hESCs. Linking the excessive number of centrosomes in mitoses to the ploidy indicated that both overduplication within a single cell cycle and mitotic failure contributed to generation of numerical centrosomal abnormalities in hESCs. Collectively, our data indicate that supernumerary centrosomes are a significant risk factor for chromosome instability in cultured hESCs and should be evaluated when new culture conditions are being implemented. PMID- 20960515 TI - FLOWERING LOCUS C influences the timing of shoot maturation in Arabidopsis thaliana. PMID- 20960516 TI - FGF receptor gene expression and its regulation by FGF signaling during early zebrafish development. AB - The expression of all four fgfr genes was extensively examined throughout early embryogenesis of the zebrafish (Danio rerio). fgfr1 alone was expressed maternally throughout the blastoderm, and then zygotically in the anterior neural plate and presomitic mesoderm. fgfr4 expression was first detected in late blastulae and was gradually restricted to the brain. fgfr2 and fgfr3 expression were initiated in early and late gastrulae, respectively; fgfr2 was expressed in the anterior neural plate and somitic mesoderm, whereas fgfr3 was activated in the axial mesoderm and then in the midbrain and somitic mesoderm. During somitogenesis, each of these fgfr genes was expressed in a characteristic manner in the brain. Using an FGF signal inhibitor, dominant-negative FGF receptors and fgf8.1/fgf8a mutants, we found that fgfr expression is directly or indirectly regulated by FGF signaling during epiboly and at the end of somitogenesis, revealing the presence of an autoregulatory mechanism. PMID- 20960517 TI - GSK-3beta inhibition promotes engraftment of ex vivo-expanded hematopoietic stem cells and modulates gene expression. AB - Glycogen synthase kinase-3beta (GSK-3beta) has been identified as an important regulator of stem cell function acting through activation of the wingless (Wnt) pathway. Here, we report that treatment with an inhibitor of GSK-3beta, 6 bromoindirubin 3'-oxime (BIO) delayed cell cycle progression by increasing cell cycle time. BIO treatment resulted in the accumulation of late dividing cells enriched with primitive progenitor cells retaining the ability for sustained proliferation. In vivo analysis using a Non-obese diabetic/severe combined immunodeficient (NOD/SCID) transplantation model has demonstrated that pretreatment with BIO promotes engraftment of ex vivo-expanded hematopoietic stem cells. BIO enhanced the engraftment of myeloid, lymphoid and primitive stem cell compartments. Limiting dilution analysis of SCID repopulating cells (SRC) revealed that BIO treatment increased human chimerism without increasing SRC frequency. Clonogenic analysis of human cells derived from the bone marrow of transplant recipient mice demonstrated that a higher level of human chimerism and cellularity was related to increased regeneration per SRC unit. Gene expression analysis showed that treatment with BIO did not modulate the expression of canonical Wnt target genes upregulated during cytokine-induced cell proliferation. BIO increased the expression of several genes regulating Notch and Tie2 signaling downregulated during ex vivo expansion, suggesting a role in improving stem cell engraftment. In addition, treatment with BIO upregulated CDK inhibitor p57 and downregulated cyclin D1, providing a possible mechanism for the delay seen in cell cycle progression. We conclude that transient, pharmacologic inhibition of GSK-3beta provides a novel approach to improve engraftment of expanded HSC after stem cell transplantation. PMID- 20960518 TI - Prospective evaluation of the reliability, validity, and minimally important difference of the functional assessment of cancer therapy-gastric (FACT-Ga) quality-of-life instrument. AB - BACKGROUND: Recently, the Functional Assessment of Cancer Therapy-Gastric (FACT Ga) was developed to measure the quality of life (QoL) of patients with gastric cancer. This newly developed instrument has not yet been validated. METHODS: Eighty-two patients with gastric adenocarcinoma completed questionnaires at baseline. The FACT-Ga scores were measured as a function of disease stage and performance status, and they were correlated with the Medical Outcomes Study 36 item short-form health survey (SF-36), the Beck Depression Inventory-II, the Marlow-Crowne Social Desirability Scale, the Paulhus Deception Scale, and the State-Trait Anxiety Inventory. Patients received a second questionnaire 2 weeks after baseline to evaluate test-retest reliability and again at 3 months to evaluate the sensitivity of the FACT-Ga to changes in performance status and to estimate the minimally important differences in scores that represented meaningful change. RESULTS: The internal and test-retest reliability of the FACT Ga instrument was adequate. With the exception of the social well being subscale, all FACT-Ga scores were correlated as hypothesized with other measures. Relevant components of the FACT-Ga were sensitive to changes in performance status. CONCLUSIONS: The current results indicated that the FACT-Ga provides a valid and reliable measurement of QoL in patients with gastric adenocarcinoma. It is a useful instrument for QoL assessment in clinical trials, and it also may be useful for the detection of significant changes in the QoL of individual patients. PMID- 20960519 TI - A phase 1-2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome. AB - BACKGROUND: The authors conducted a phase 1/2 study of tipifarnib in combination with idarubicin and cytarabine (IA) in 95 patients with previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome. METHODS: Induction consisted of idarubicin 12 mg/m(2) a day on days 1-3, cytarabine 1.5 g/m(2) intravenously continuously daily on days 1-4 (days 1-3 if age >=60 years), and tipifarnib, with the first cohort (n = 6) receiving 200 mg orally twice a day and all others receiving 300 mg twice a day for 21 days every 28 days. Consolidation consisted of 5 courses of idarubicin 8 mg/m(2) a day on days 1-2, cytarabine 0.75 g/m(2) a day on days 1-3, and tipifarnib 300 mg twice a day for 14 days every 4-6 weeks. Maintenance with tipifarnib 300 mg twice a day for 21 days every 4-6 weeks was continued for 6 months. RESULTS: With a median follow-up of 33 months, 61 patients achieved complete remission (CR) (64%), and 9 achieved complete remission with incomplete platelet recovery (CRp) (9%). The median duration of CR was not reached. Median overall survival was 17 months. The most common grade 3 adverse events were gastrointestinal toxicities, liver dysfunction, and skin rash. Compared with historical IA, IA and tipifarnib showed a better CR duration (P = .04) and a trend toward a higher CR rate in patients with chromosome 5/7 abnormalities. CONCLUSIONS: The combination of IA and tipifarnib is safe and active. Further studies exploring different dosages and schedules are warranted, particularly in patients with poor-risk AML. PMID- 20960520 TI - Prediction of significant prostate cancer diagnosed 20 to 30 years later with a single measure of prostate-specific antigen at or before age 50. AB - BACKGROUND: We previously reported that a single prostate-specific antigen (PSA) measured at ages 44-50 was highly predictive of subsequent prostate cancer diagnosis in an unscreened population. Here we report an additional 7 years of follow-up. This provides replication using an independent data set and allows estimates of the association between early PSA and subsequent advanced cancer (clinical stage >=T3 or metastases at diagnosis). METHODS: Blood was collected from 21,277 men in a Swedish city (74% participation rate) during 1974-1986 at ages 33-50. Through 2006, prostate cancer was diagnosed in 1408 participants; we measured PSA in archived plasma for 1312 of these cases (93%) and for 3728 controls. RESULTS: At a median follow-up of 23 years, baseline PSA was strongly associated with subsequent prostate cancer (area under the curve, 0.72; 95% CI, 0.70-0.74; for advanced cancer, 0.75; 95% CI, 0.72-0.78). Associations between PSA and prostate cancer were virtually identical for the initial and replication data sets, with 81% of advanced cases (95% CI, 77%-86%) found in men with PSA above the median (0.63 ng/mL at ages 44-50). CONCLUSIONS: A single PSA at or before age 50 predicts advanced prostate cancer diagnosed up to 30 years later. Use of early PSA to stratify risk would allow a large group of low-risk men to be screened less often but increase frequency of testing on a more limited number of high-risk men. This is likely to improve the ratio of benefit to harm for screening. PMID- 20960521 TI - A Phase 2 study of combination therapy with arsenic trioxide and gemtuzumab ozogamicin in patients with myelodysplastic syndromes or secondary acute myeloid leukemia. AB - BACKGROUND: Higher-risk myelodysplastic syndromes (MDS) are similar pathobiologically to acute myeloid leukemia (AML), particularly in older adults. AML therapies thus may have activity in MDS. In the current study, phase 2 study data of arsenic trioxide (ATO) and gemtuzumab ozogamicin (GO) in CD33-positive patients with MDS and secondary AML (sAML) were presented. METHODS: Between June 2004 and February 2006, 30 patients with higher-risk MDS or sAML received ATO (at a dose of 0.25 mg/kg intravenously for 5 days during Week 1, then twice weekly during Weeks 2-12) and GO (at a dose of 3 mg/m(2) on Day 8) for 1 or 2 cycles of 12 weeks each. The primary endpoint was response as per MDS or AML International Working Group (IWG) criteria. Adverse events were collected throughout treatment. Patients were followed for a minimum of 3 years for survival. RESULTS: The median patient age was 69 years. A total of 18 patients had MDS, 12 had sAML, and 19 had been previously treated. Seventeen patients (57%) completed >=1 cycle, and 7 patients (23%) completed 2 cycles. IWG responses occurred in 9 patients (30%) according to IWG MDS criteria (including 2 of 7 patients who failed hypomethylating agents) and 3 of 12 AML patients (25%) according to IWG AML criteria. Grade 3/4 (according to National Cancer Institute Common Toxicity Criteria [version 3.0]) thrombocytopenia occurred in 47% of patients, neutropenia in 63%, and anemia in 37% of patients. The median overall survival was 9.7 months (28.6 months in responders and 7.6 months in nonresponders; P <.001). Patients who completed 2 cycles of therapy spent a median of 13 days in the hospital. CONCLUSIONS: Combination therapy with ATO and GO was found to have acceptable response rates and toxicity, and may be a viable treatment option to standard induction therapy, particularly for patients who fail therapy with hypomethylating agents. PMID- 20960522 TI - Monitoring molecular response in chronic myeloid leukemia. AB - Before the advent of tyrosine kinase inhibitor (TKI) therapy, the evaluation of hematologic and cytogenetic responses was sufficient to gauge treatment efficacy in patients with chronic myeloid leukemia. However, with more potent TKI therapies, the majority of patients achieve complete cytogenetic response. Furthermore, deeper molecular responses are now commonly achieved, necessitating a reliance on molecular monitoring to assess residual leukemic disease. The prognostic significance between molecular responses and duration of complete cytogenetic response, progression-free survival, and event-free survival is described herein. A discussion of the concept of complete molecular response is also provided, and the potential for imatinib treatment discontinuation is evaluated. The implications of rising BCR-ABL1 transcript levels and caveats of molecular monitoring are also described. PMID- 20960523 TI - Screening, risk assessment, and the approach to therapy in patients with prostate cancer. AB - The major challenge in prostate cancer is to identify patients at higher risk of death and to distinguish them from those more likely to die from other causes. Stratification of patients into risk groups can be used to guide management decisions at each disease stage. This review discusses the measures, tools, and nomograms available for risk assessment in prostate cancer. For patients with localized hormone-sensitive disease, the choice is between active surveillance and radical treatment, with focal therapy an emerging option. Current guidelines recommend treatment of patients with a life expectancy >=10 years, although active surveillance is being used with increasing frequency for low-risk patients, even with a long life expectancy. A number of risk stratification methods have been devised to assess the risk of biochemical recurrence (BCR) after treatment, with prostate-specific antigen (PSA) level, Gleason score, clinical stage, and tumor mass/volume all shown to be predictive of BCR. Among men with BCR after treatment, PSA doubling time (PSADT) was the best predictor of further progression. Although studies in patients with castration-resistant prostate cancer have shown that PSA level and PSADT are associated with a risk of developing metastatic disease, there is currently no clear surrogate for disease progression or overall survival for this patient group and no standard second- or third-line therapy after progression on first-line chemotherapy. The use of newly developed risk-stratification models and markers of disease progression should assist in the earlier identification of disease progression, allowing the optimal treatment of such patients. PMID- 20960524 TI - Editorial for "Prediction of significant prostate cancer diagnosed 20 to 30 years later with a single measure of prostate-specific antigen at or before age 50". PMID- 20960525 TI - Prognostic factors for survival in melanoma patients with brain metastases. AB - BACKGROUND: One of the most common and deadly complications of melanoma is brain metastases. The outcomes of advanced melanoma patients who developed brain metastases were reviewed to identify significant prognostic factors for overall survival (OS). METHODS: An institutional database of advanced melanoma patients enrolled on clinical trials in the Department of Melanoma Medical Oncology from 1986 to 2004 was reviewed and patients who developed brain metastases were identified. Date of diagnosis, patient age, pattern of brain involvement, timing relative to extracranial metastases, prior response to systemic therapy, and treatments given for brain metastases were assessed as potential prognostic factors for OS. RESULTS: Among 743 melanoma patients enrolled in clinical trials for regional or systemic metastatic disease, 330 (44%) patients developed brain metastases. The median OS after the diagnosis of brain metastases was 4.7 months. Diagnosis before 1996, increased number of parenchymal brain metastases, leptomeningeal involvement, and development of brain metastases after receiving systemic therapy for extracranial metastases were found to be significant prognostic factors for OS. Among patients who received systemic therapy as the initial treatment of brain metastases, patients who previously responded to systemic therapies had longer survival than patients who had not responded. CONCLUSIONS: The era, pattern, and timing of melanoma brain metastases were found to be strongly associated with survival. Previous responsiveness to systemic therapies did not predict better outcomes overall, but it did correlate with improved survival for patients with brain metastases who were treated with systemic therapies. These factors may be used in guiding patient management and for stratifying patients in clinical trials. PMID- 20960526 TI - Recent trends and future directions in human immunodeficiency virus-associated cancer. PMID- 20960527 TI - The impact of tumor burden characteristics in patients with metastatic renal cell carcinoma treated with sunitinib. AB - BACKGROUND: An important goal of noncurative therapy for metastatic renal cell carcinoma (mRCC) is tumor burden (TB) control. However, to the authors' knowledge, the impact of TB characteristics on clinical outcome has not been studied in patients with mRCC who were treated with vascular endothelial growth factor-targeted therapy. METHODS: Patients with clear cell mRCC who were treated with sunitinib between June 2004 and October 2007 were retrospectively identified. Computed tomography scans were re-reviewed from baseline, at the time of maximal TB shrinkage (TS) while receiving sunitinib, and at the time of progressive disease (PD). Measurements were recorded as per Response Evaluation Criteria In Solid Tumors (RECIST). RESULTS: A total of 69 patients were identified. The majority (54%) were classified as being of favorable risk using Cleveland Clinic Foundation Tyrosine Kinase Inhibitor (CCF TKI) risk group criteria. All patients underwent prior nephrectomy and 77% received prior systemic therapy. There were a median of 8 metastatic deposits across all organs (range, 1-27 deposits). The median TB at the initiation of therapy was 14.0 cm (range, 3.0 cm-42.2 cm). On multivariable analysis, baseline characteristics of disease confined to above the diaphragm (P = .03) and a total TB <13 cm (P = .09) were found to be independent positive predictors of progression-free survival. A+ baseline, total number of metastases <10 (P < .001) and TB above the diaphragm <6.5 cm (P = .05) were found to be independent positive predictors of overall survival (OS). Increased TS while receiving sunitinib was found to be significantly associated with OS (P < .001). At the time of PD, tumor location and pattern of disease progression were not found to be associated with survival as measured from the date of PD. However, total TB (P = .003) and total number of metastatic deposits (<=12 vs >12; P < .001) were found to be significant predictors of survival after PD. CONCLUSIONS: The results of the current study indicate that TB characteristics are associated with clinical outcome in patients with mRCC who are treated with sunitinib. PMID- 20960528 TI - Activity and safety of dose-adjusted infusional cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with rituximab in very elderly patients with poor-prognostic untreated diffuse large B-cell non-Hodgkin lymphoma. AB - BACKGROUND: This study was designed to assess the activity and safety of dose adjusted infusional cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with rituximab (DA-POCH-R) in elderly patients with poor-prognostic untreated diffuse large B-cell non-Hodgkin lymphoma (DLBCL). METHODS: From April 2006 to November 2009, 23 patients, aged >=70 years, with an age-adjusted International Prognostic Index (IPI) of 2 or 3, were enrolled. Only patients with left ventricular ejection fraction (LVEF) >=50% were allowed. The DA-POCH-R regimen was administered every 3 weeks for a minimum of 6 and a maximum of 8 cycles. RESULTS: Median patient age was 77 years (range, 70-90 years); 83% of patients had Ann Arbor stage III to IV disease. Median LVEF at baseline was 62%. Four (17%) patients had a history of abnormal cardiovascular conditions. Twenty one (91%) patients were evaluable for response. The overall response rate was 90%, with a complete response rate of 57%. The 3-year overall survival and event free survival rates were 56% and 54%, respectively. Neutropenia (48%) was the most frequent grade 3 to 4 adverse event (AE); no grade 3 to 4 cardiac AEs were observed. CONCLUSIONS: DA-POCH-R was an active and safe combination therapy for patients aged >=70 years with poor-prognostic untreated DLBCL. This regimen was a reasonable alternative for elderly patients who were not considered to tolerate standard R-CHOP treatment. PMID- 20960529 TI - Intrabundle microtubule dynamics in the Arabidopsis cortical array. AB - We tested the general hypothesis that bundling stabilizes the dynamic properties of the constituent microtubules (MTs) in vivo. We quantified the assembly dynamics of bundled and unbundled MTs in the interphase cortical array of Arabidopsis hypocotyl cells using high dynamic range spinning disk confocal microscopy. We find no evidence that bundled MTs are stabilized against depolymerization through changes to their dynamic properties. Our observations of MT plus and minus ends indicate that both bundled and unbundled polymers undergo persistent treadmilling in this system. We conclude that the temporal persistence of MT subassemblies in the Arabidopsis cortical array is largely dependent upon recruitment or nucleation of new treadmilling MTs and not on polymer stabilization. Monte Carlo simulations suggest that small differences discovered in the dynamic properties between bundled and unbundled polymers would produce relatively small macroscopic effects on the larger MT array. PMID- 20960530 TI - CNBP: a multifunctional nucleic acid chaperone involved in cell death and proliferation control. AB - Cellular nucleic acid binding protein (CNBP) has been implicated in vertebrate craniofacial development and in myotonic dystrophy type 2 (DM2) and sporadic inclusion body myositis (sIBM) human diseases. In these seemingly unrelated biological processes, CNBP appears to be involved in controlling cell death and proliferation rates. Low levels of CNBP may reduce rate of global protein synthesis, thereby reducing proliferation and increasing apoptosis. Conversely, CNBP might affect transcription of genes required for cell proliferation. Experimental evidences gathered so far make it difficult to ascertain or rule out any of these possibilities. Moreover, both possibilities may not be mutually exclusive. CNBP is a small and strikingly conserved single-stranded nucleic acid binding protein that is able to bind DNA as well as RNA. CNBP has a broad spectrum of targets, ranging from regulatory sites in gene promoters to translational regulatory elements in mRNA untranslated regions. Biochemical experiments have recently shed light on the possible mechanism of action for CNBP, which may act as a nucleic acid chaperone catalyzing the rearrangement of G rich nucleic acid secondary structures likely relevant for transcriptional and/or translational gene regulation. This review focuses on the involvement of CNBP in vertebrate craniofacial development and human DM2 and sIBM diseases, as well as on the biochemical and structural features of CNBP and its cellular and molecular mechanism of action. PMID- 20960531 TI - Functional and structural aspects of Helicobacter pylori acidic stress response factors. AB - Helicobacter pylori is a striking example of adaptation of a bacterium to a very peculiar niche, the human stomach. Despite being a neutralophile, a sophisticated control of gene expression allows it to live and to proliferate in an environment that cycles from nearly neutral to very acidic. Despite the numerous studies performed on the mechanisms of acid adaptation, the physiological function of a large part of the genes products that are up-regulated or down-regulated is often not clear, in particular in the context of the response of the bacterium to an acidic stress. In this review, we discuss the molecular and functional aspects of some of the proteins that are commonly found overexpressed during the acid stress. PMID- 20960532 TI - A cardiac catheterization laboratory is not just an angiographic suite. AB - When I began my cardiology training in 1965, my instructors in the cardiac catheterization laboratory made it clear to me that many things other than anatomic assessment by angiography could be accomplished in the cardiac catheterization laboratory. For example, at that time cardiac output, pressure gradients, valvar insufficiency, shunts, assessment of contractility, assessment of myocardial blood flow using radioactive techniques, lactate metabolism, and assessment of ventricular function were the principal physiologic parameters measured. PMID- 20960533 TI - Why did you order that echocardiogram? PMID- 20960534 TI - Spironolactone use in heart failure patients with end-stage renal disease on hemodialysis: is it safe? AB - BACKGROUND: Spironolactone is used in the treatment of cardiovascular disease, but is contraindicated in renal dysfunction due to the risk of hyperkalemia. It is not known if patients with end-stage renal disease (ESRD) on hemodialysis are at the same risk for hyperkalemia. The objective of this study was to systematically review the evidence evaluating the incidence of hyperkalemia with spironolactone use in ESRD patients on hemodialysis. HYPOTHESIS: Spironolactone use in ESRD patients on hemodialysis may not lead to greater incidence of hyperkalemia. METHODS: We searched the MEDLINE, Embase, CINAHL, Cochrane, and PubMed databases up to January 2010 for English-language, human-subject clinical trials that evaluated the rate of hyperkalemia with spironolactone use in ESRD patients on hemodialysis. Search terms included were "spironolactone," "eplerenone," "aldosterone antagonist," "heart failure," "kidney failure," "hemodialysis," "dialysis," and "renal replacement therapy." RESULTS: Six prospective trials demonstrated that spironolactone use was safe in ESRD patients on hemodialysis. The incidence of hyperkalemia with spironolactone treatment in these studies was similar to control groups. The studies involved a small population of compliant subjects who were at low risk for hyperkalemia. CONCLUSIONS: Small pilot studies demonstrated that spironolactone treatment in ESRD patients on hemodialysis did not result in higher hyperkalemia rates. Larger studies are needed to confirm these preliminary results before spironolactone is routinely considered in hemodialysis patients. PMID- 20960535 TI - Combination rosuvastatin plus fenofibric acid in a cohort of patients 65 years or older with mixed dyslipidemia: subanalysis of two randomized, controlled studies. AB - BACKGROUND: Coronary heart disease risk increases with advancing age and is further increased in patients with mixed dyslipidemia, characterized by elevated low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), and high triglycerides (TG). Combination lipid therapy is an option; however, efficacy and safety data among elderly patients are lacking. HYPOTHESIS: The combination of rosuvastatin and fenofibric acid (R + FA) results in more comprehensive lipid improvements than corresponding-dose monotherapies, without additional safety concerns, in elderly patients with mixed dyslipidemia. METHODS: This post-hoc analysis evaluated data from patients age >= 65 years (n = 401) with mixed dyslipidemia (LDL-C >= 130 mg/dL, HDL-C < 40 mg/dL [men] or < 50 mg/dL [women], and TG >= 150 mg/dL) in 2 randomized studies. Patients included in this analysis received either monotherapy (as R 5, 10, or 20 mg or FA 135 mg), or combination therapy with R (5, 10, or 20 mg) + FA 135 mg, for 12 weeks. Data were pooled and analyzed, and mean/median percent changes in multiple lipid parameters and biomarkers were compared. RESULTS: Combination therapy decreased LDL-C by 31.8%-47.2% vs 10.6% with FA monotherapy (P < 0.001). Combination therapy also increased HDL-C by 21.9%-27.0% vs 5.9%-9.9% with R monotherapy (P < 0.001), and decreased TG by 48.3%-53.5% vs 20.7%-32.8% with R monotherapy (P < 0.001). In general, safety profiles were consistent between combination therapy and individual monotherapies. CONCLUSIONS: In these elderly patients with mixed dyslipidemia, R 5, 10, or 20 mg in combination with FA 135 mg improved the overall lipid profile, without new or unexpected safety issues. PMID- 20960536 TI - Two-year clinical outcomes after large coronary stent (4.0 mm) placement: comparison of bare-metal stent versus drug-eluting stent. AB - BACKGROUND: The absolute benefit of drug-eluting stents (DES) in low-risk patients and lesions is not well established. HYPOTHESIS: The long term clinical outcomes after percutaneous coronary intervention in a single coronary artery disease may not be affected by the type of stent. METHODS: This study assessed and compared 2-year clinical outcomes of 304 consecutive patients (147 BMS patients and 157 DES patients) treated with a single coronary stent (4.0 mm) for single de novo large coronary artery disease in 3 referral cardiac centers. The primary outcome was a composite of major adverse cardiac events at 2 years after the index procedure. RESULTS: The reference vessel diameter was similar in both groups (3.92 +/- 0.29 mm in BMS vs 3.95 +/- 0.24 mm in DES, P = 0.50). Late loss was larger in the BMS group (1.04 +/- 0.83 mm vs 0.73 +/- 0.91 mm in DES, P = 0.03). The incidence of major adverse cardiac events at the 2-year clinical follow-up was very low, 24 of 304 patients (7.9%), regardless of stent type deployed (7.5% in BMS vs 8.3% in DES, P = 0.83). The rate of target vessel revascularization was also similar in both groups (4.8% in BMS vs 5.7% in DES, P = 0.80). CONCLUSIONS: Two-year clinical outcomes after PCI with a single large coronary stent (4.0 mm) were excellent. The clinical outcomes were not affected by the type of stent used. PMID- 20960537 TI - Autonomic dysfunction presenting as orthostatic intolerance in patients suffering from mitochondrial cytopathy. AB - BACKGROUND: Disturbances in autonomic nervous system function have been reported to occur in patients suffering from mitochondrial cytopathies. However, there is paucity of literature on the occurrence of orthostatic intolerance (OI) in these patients. We report on a series of patients diagnosed with mitochondrial cytopathy who developed features of autonomic dysfunction in the form of OI. METHODS: This was a single-center report on a series of 6 patients who were followed in our clinic for orthostatic intolerance. All of these patients had a diagnosis of mitochondrial cytopathy on the basis of muscle biopsy and were being followed at a center specializing in the treatment of mitochondrial disorders. This study was approved by our local institutional review board. Each of the patients had suffered from symptoms of fatigue, palpitations, near syncope, and syncope. The diagnosis of OI was confirmed by head-up tilt test. Collected data included demographic information, presenting symptoms, laboratory data, tilt table response, and treatment outcomes. RESULTS: Six patients (3 females) were identified for inclusion in this report. The mean age of the group was 48 +/- 8 years (range, 40-60 years). All of these patients underwent head-up tilt table testing and all had a positive response that reproduced their clinical symptoms. Among those having an abnormal tilt-table pattern, 1 had a neurocardiogenic response, 1 had a dysautonomic response, and 4 had a postural orthostatic tachycardia response. All but 1 patient reported marked symptom relief with pharmacotherapy. The patient who failed pharmacotherapy received a dual-chamber closed-loop pacemaker and subsequently reported marked improvement in her symptoms with elimination of her syncope. CONCLUSIONS: Orthostatic intolerance might be a significant feature of autonomic nervous system dysfunction in patients suffering from mitochondrial cytopathy. PMID- 20960538 TI - Atrioventricular reverse remodeling after valve repair for chronic severe mitral regurgitation: 1-year follow-up. AB - BACKGROUND: Chronic severe mitral regurgitation is associated with poor clinical outcome because chronic volume overload leads to hemodynamic changes and left ventricular and left atrial remodeling. Few data are available regarding left atrial volume index regression (LAVIR) and left ventricular mass index regression (LVMIR) after valve surgery for mitral regurgitation. We aimed to identify predictive correlates of LAVIR and LVMIR and to assess the relationship between these regressions. HYPOTHESIS: Volume overload in chronic severe mitral regurgitation may influence left atrial and ventricular remodeling and reverse remodeling. METHODS: Eighty-five patients who underwent valve repair for severe chronic mitral regurgitation were consecutively enrolled. Plasma N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP) and echocardiographic measurements were performed before surgery, before discharge, and at 12 months after surgery. LAVIR and LVMIR were assessed using serial echocardiography. RESULTS: There were significant decreases in left ventricular mass index (LVMI; from 125.9 +/- 31.3 g/m2 to 94.8 +/- 28.6 g/m2, P = 0.001) and left atrial volume index (LAVI; from 75.3 +/- 33.5 mL/m2 to 41.7 +/- 16.0 mL/m2, P = 0.001) after surgery. Preoperative LAVI positively correlated with preoperative LVMI (r = 0.437, P = 0.001) and LAVIR positively correlated with LVMIR (r = 0.347, P = 0.001). In multivariate stepwise linear regression analysis, preoperative LAVI, age, hypertension, and atrial fibrillation were independently predictive of LAVIR, and preoperative LVMI, hypertension, and NT proBNP were independently predictive of LVMIR. CONCLUSIONS: Volume overload in chronic severe mitral regurgitation may influence left ventricular remodeling and reverse remodeling, as well as left atrial remodeling and reverse remodeling. Preoperative lower LAVI, younger age, absence of hypertension, and absence of atrial fibrillation may predict LAVIR, and preoperative lower LVMI, lower NT proBNP levels, and absence of hypertension may predict LVMIR after surgery for chronic severe mitral regurgitation. PMID- 20960539 TI - Positive vasodilator stress ECG with normal myocardial perfusion imaging and its correlation with coronary angiographic findings in African Americans and Hispanics. AB - BACKGROUND: Ischemic electrocardiographic (ECG) changes during vasodilator stress testing (VST) in the presence of abnormal myocardial perfusion imaging (MPI) are uncommon and are associated with presence of multivessel coronary artery disease (CAD). However, there is a paucity of data regarding the significance of ischemic ECG changes during VST with normal MPI in general, and especially among African Americans and Hispanics. HYPOTHESIS: Ischemic changes during VST with normal MPI are associated with significant CAD. METHODS: A retrospective review was done of 2945 patients undergoing VST. RESULTS: Only 20 patients (0.7%) had positive ECG changes with normal MPI. Their demographics were: 60% Hispanic, 40% African American; 85% female; mean age 63 +/- 11 years; history of hypertension 80%, diabetes 50%, and dyslipidemia 75%; smokers 30%; atypical chest pain 60%, and typical chest pain 40%. Of these 20 patients, 12 patients underwent coronary angiography. All 12 had significant CAD; nine (75%) had multivessel disease and 3 (25%) had single-vessel disease. Prevalence of clinical variables and risk factors for CAD were similar among both the groups who did and did not undergo coronary angiography. CONCLUSIONS: Among African Americans and Hispanics, ischemic ECG changes during VST with normal MPI are likely to be associated with significant CAD and may warrant coronary angiography to assess presence and extent of CAD. PMID- 20960540 TI - Association of left atrial myocardial function with left ventricular diastolic dysfunction in subjects with preserved systolic function: a strain rate imaging study. AB - BACKGROUND: The purpose of this study was to investigate the relationship between left atrial (LA) myocardial function and left ventricular (LV) diastolic dysfunction in subjects with preserved LV ejection fraction (LVEF). METHODS: The study included a group of 118 hypertensive patients and normal subjects. LV diastolic dysfunction was classified into 4 groups: none, mild, moderate, and severe. Peak strain rates in systole (S-Sr), early diastole (E-Sr), and late diastole (A-Sr) were obtained from Doppler-derived strain rate imaging to evaluate LA myocardial deformation. RESULTS: No significant difference in LA dimension was observed in subjects with different degrees of LV diastolic dysfunction, although LA myocardial strain rate parameters were all significantly different across the 4 groups (all with P < 0.001). Compared with patients of normal diastolic function, the mild diastolic dysfunction group had significantly lower E-Sr (0.62 +/- 0.18 s-1 vs 1.20 +/- 0.38 s-1, P < 0.001) and S-Sr (0.78 +/- 0.16 s-1 vs 0.94 +/- 0.22 s-1, P < 0.001) but increased A-Sr (1.14 +/- 0.29 s-1 vs 1.00 +/- 0.23 s-1, P = 0.05). CONCLUSIONS: By using strain rate imaging, significant changes of LA deformation in response to different stages of LV diastolic dysfunction were detected in subjects with preserved LVEF. Quantification of LA myocardial function rather than LA size may have the potential to predict early LV diastolic dysfunction in subjects with preserved LVEF. PMID- 20960541 TI - Comparison of immediate vs early invasive strategy in patients with first acute non-ST-elevation myocardial infarction. AB - BACKGROUND: The best timing for coronary angiography (immediate vs early) in patients with acute non-ST-elevation myocardial infarction (NSTEMI) is controversial. HYPOTHESIS: Evaluate in NSTEMI patients the effects of an immediate compared to an early invasive strategy on microvascular damage, myocardial perfusion, and infarct size. METHODS: We randomized 54 consecutive patients with first episode of NSTEMI: 27 patients (22 males, age 58.8 +/- 9.4 years, group A) underwent immediate (<=6 hours) percutaneous coronary intervention (PCI) with a double bolus of eptifibatide, and 27 patients (24 males, age 59.7 +/- 9.8 years, P = 0.72, group B) underwent early (7-72 hours) PCI with upstream eptifibatide. Microvascular damage was evaluated at predischarge by myocardial contrast echocardiography, and the contrast defect length was calculated. RESULTS: There were no significant differences in pre-PCI myocardial blush grade (MBG) (41% MBG 0 or 1 in group A vs 37% MBG 0 or 1 in group B, P = 0.78), in post-PCI MBG (7.4% MBG 0 or 1 in both groups, P = 1.00), and in contrast defect length (4.5% in group A vs 2.8% in group B, P = 0.56). However, group A showed a significant reduction in creatine kinase myocardial band isoenzyme peak (26 +/- 26 ng/mL in group A vs 69 +/- 79 ng/mL in group B, P = 0.01) and in troponin T peak (0.84 +/- 1.2 ng/mL in group A vs 1.8 +/- 2.1 ng/mL in group B, P = 0.048). CONCLUSIONS: In patients with NSTEMI treated with eptifibatide, immediate PCI is associated with less increase in myonecrosis markers compared with PCI within 72 hours. There were no significant differences in myocardial perfusion between the 2 strategies. PMID- 20960542 TI - Canonical Wnt/beta-catenin signaling is required for maintenance but not activation of Pitx2 expression in neural crest during eye development. AB - Pitx2 is a paired-like homeodomain gene that acts as a key regulator of eye development. Despite its significance, upstream regulation of Pitx2 expression during eye development remains incompletely understood. We use neural crest specific ablation of Ctnnb1 to demonstrate that canonical Wnt signaling is not required for initial activation of Pitx2 in neural crest. However, canonical Wnt signaling is subsequently required to maintain Pitx2 expression in the neural crest. Eye development in Ctnnb1-null mice appears grossly normal early but significant phenotypes emerge following loss of Pitx2 expression. LEF-1 and beta catenin bind Pitx2 promoter sequences in ocular neural crest, indicating a likely direct effect of canonical Wnt signaling on Pitx2 expression. Combining our data with previous reports, we propose a model wherein a sequential code of retinoic acid followed by canonical Wnt signaling are required for activation and maintenance of Pitx2 expression, respectively. Other key transcription factors in the neural crest, including Foxc1, do not require intact canonical Wnt signaling. PMID- 20960544 TI - The obesity pandemic: meeting the clinical challenges. PMID- 20960543 TI - Regulation of heart valve morphogenesis by Eph receptor ligand, ephrin-A1. AB - Disease or malformation of heart valves is one of the leading causes of morbidity and mortality in both children and adults. These congenital anomalies can remain undetected until cardiac function is compromised, making it important to understand the underlying nature of these disorders. Here we show that ephrin-A1, a ligand for class A Eph receptor tyrosine kinases, regulates cardiac valve formation. Exogenous ephrin-A1-Fc or overexpression of ephrin-A1 in the heart inhibits epithelial-to-mesenchymal transformation (EMT) in chick atrioventricular cushion explants. In contrast, overexpression of wild-type EphA3 receptor promotes EMT via a kinase-dependent mechanism. To analyze ephrin-A1 in vivo, we generated an ephrin-A1 knockout mouse through gene targeting. Ephrin-A1 null animals are viable but exhibit impaired cardiac function. Loss of ephrin-A1 results in thickened aortic and mitral valves in newborn and adult animals. Analysis of early embryonic hearts revealed increased cellularity in outflow tract endocardial cushions and elevated mesenchymal marker expression, suggesting that excessive numbers of cells undergo EMT. Taken together, these data indicate that ephrin-A1 regulates cardiac valve development, making ephrin-A1-deficient mice a novel model for congenital heart defects. PMID- 20960545 TI - Medical therapy for obesity. AB - Obesity results from a prolonged small positive energy imbalance, and treatment needs to reverse this imbalance. Many different diets have been tried to treat obesity, and weight loss occurs with all of them. There is currently no evidence that supports the superiority of one macronutrient composition for diets over any other. The principal effect seems to be the degree of adherence to the prescribed calorie reduction. Obesity drugs have been developed that tap brain mechanisms for controlling feeding and the gastrointestinal tract and its peptides. Orlistat blocks intestinal lipase and produces modest weight loss. Sibutramine is a serotonin-norepinephrine reuptake inhibitor that has a warning on its label from the US Food and Drug Administration because of cardiovascular risk. Its marketing has been suspended in Europe. Several drug combinations are on the horizon for treatment of obesity. PMID- 20960546 TI - Surgical therapy for diabesity. AB - Type 2 diabetes mellitus affects more than 170 million people worldwide. Because this disease is strongly linked to obesity, the term "diabesity" has been coined to describe the confluence of the 2 disease processes. Bariatric surgery has been performed for many years to achieve sustained weight loss in the morbidly obese population. As a secondary effect, a remarkable improvement in glycemic control is commonly achieved postoperatively. This has led to substantial interest in the use of bariatric procedures to treat type 2 diabetes mellitus. Surgical procedures in common use include the adjustable gastric band, the Roux-en-Y gastric bypass, the biliopancreatic diversion with duodenal switch, and the sleeve gastrectomy. Additionally, several investigational procedures including the ileal interposition and duodenal-jejunal bypass have been proposed as primary interventions for type 2 diabetes mellitus. These operations achieve their metabolic effects through a combination of volume restriction, intestinal bypass, and hormonal changes. As more data become available on the positive effect of bariatric procedures on type 2 diabetes mellitus, the use of such operations may grow. Bariatric surgery may ultimately become a major tool in the long-term treatment of type 2 diabetes mellitus. This manuscript presents an extensive review of the literature supporting these concepts. PMID- 20960547 TI - Metabolic management following bariatric surgery. AB - Bariatric surgery is an effective treatment option for obesity. Commonly utilized procedures are either restrictive, malabsorptive, or both. Substantial weight loss can be achieved. Postoperatively, patients experience nutritional, metabolic, and hormonal changes that have important clinical implications. The postoperative diet should be advanced carefully, according to protocol. Micronutrient deficiencies such as vitamin C, vitamin A, and zinc deficiencies are common, especially following malabsorptive procedures. Bone metabolism is greatly affected, in part due to vitamin D deficiency, decreased calcium absorption, and secondary hyperparathyroidism. Diabetes improves acutely in malabsorptive procedures and in sequence with weight loss in restrictive procedures. Polycystic ovarian syndrome improves in nearly all women with this condition who undergo bariatric surgery. Testosterone levels in men also improve after surgery. Consideration of these nutritional, metabolic, and hormonal changes allows for optimal medical management following bariatric surgery. PMID- 20960548 TI - Hormone changes affecting energy homeostasis after metabolic surgery. AB - Worldwide, there is an epidemic of obesity and its associated diseases. The past decade of research has brought about a paradigm shift in our understanding of both the mechanisms underlying energy homeostasis and the multiple factors contributing to the pathophysiology of obesity. Metabolic surgery is currently far more effective than diet and exercise or pharmacotherapy in achieving durable weight loss. Moreover, the remarkable results of surgery in achieving a rapid remission of type 2 diabetes mellitus has sparked tremendous excitement and research into the mechanisms through which metabolic surgery has its dramatic effect. As opposed to the traditional understanding of "restriction" and "malabsorption," current evidence suggests that metabolic surgery alters the expression of multiple hormones that affect both short-term and long-term signals of energy balance. We review the hormonal changes following the most common types of metabolic operations currently being performed. The profile of hormonal changes provides a guide to tailor the choice of operation for each individual patient toward achieving the desired metabolic result. In the future, individualized metabolic surgery alone or modulated by targeted pharmacological therapy may achieve the most reliable and effective results with the highest safety and lowest side effect profile. PMID- 20960549 TI - Office-based management of obesity. AB - Appropriate recognition and management of obesity is imperative given the fact that one-third of Americans are clinically obese. Up to 25% of patients with a body mass index >= 30 are not appropriately identified by primary care physicians as being obese. An even smaller portion of recognized patients is offered any form of weight-loss treatment. This may be the result of approximately 40% of physicians possessing negative attitudes toward such patients given the challenges in managing this population. In the near future, physicians will be empowered with further knowledge regarding metabolic and neurologic adaptations that make weight loss so difficult. Along with this new information will come novel treatment options. It is predicted that many of the barriers preventing appropriate management of obesity will diminish as further knowledge and treatment options become available. PMID- 20960550 TI - Psychological treatments for obesity in youth and adults. AB - Obesity has become a leading global health concern affecting both physical and mental quality of life. This article reviews the psychological interventions currently utilized in confronting the obesity epidemic. It examines obesity in both the pediatric and adult populations, specifically considering empirical evidence of weight loss interventions through randomized control trials. Behavioral weight loss intervention and family-based interventions emerged as 2 of the more frequently utilized and data-supported approaches. Empirically supported psychological treatments for subgroups of the obese population, such as individuals with binge eating disorder, are considered here as well. Limitations of the current interventions are discussed, including issues with generalizability across demographic variables such as age and severity of overweight status. Despite these limitations, overall, psychological interventions play an important role in achieving and maintaining weight loss. PMID- 20960551 TI - Dietary approaches to obesity. AB - The treatment of obesity demands a negative energy balance, which obviously necessitates reducing the quantity of food intake. Yet the optimal diet composition quality for weight loss is far from known. The major controversy seems to be between choosing low-fat or low-carbohydrate diets, with additional debates on the importance of the glycemic index and the amounts of dairy products and calcium. It is evident from many large, randomized trials that the "best diet" that can suit everyone has yet to be identified. The different options for low-calorie diets should be prescribed on an individual basis, in order to best fit each patient's personal preferences. All hypocaloric regimens are suitable, as long as they work, for any given subject. The problem, of course, is long-term maintenance and adherence to an altered lifestyle. PMID- 20960552 TI - A personalized approach to metabolic aspects of obesity. AB - Metabolic syndrome, which is entwined in semantic controversy as to its actual existence as a distinct entity, links several important health conditions with obesity, and more specifically, excessive visceral adiposity. The most common linked disease states include type 2 diabetes mellitus, hypertension, dyslipidemia, obstructive sleep apnea, and cardiovascular and coronary heart disease. Much of the controversy surrounding the metabolic syndrome case definition is the purported centrality of insulin resistance as root cause, there being no universally agreed-upon standard for measurement of insulin resistance. Over the past decade, the visceral adipocyte itself has emerged as a key contributor rather than passive bystander in the genesis of the metabolic syndrome. Rather than being a simple storage bin for excess triglyceride, the visceral adipocyte is an active endocrine cell secreting a variety of signal hormones known in the aggregate as adipokines. In optimal health, the predominant recognized adipokine is adiponectin, with downstream insulin-sensitizing, anti inflammatory, antithrombotic, provasodilatory effects systemically. By contrast, metabolic syndrome is characterized by reduced adiponectin and increased inflammatory adipokine secretion, with downstream effects of insulin resistance, heightened inflammation, prothrombosis, and vasoconstriction. These alternative metabolic states of the adipocyte are characterized in this review as metabolic "yin" and "yang." Lifestyle modifications and drug therapies that promote weight loss, increased physical exercise activity, and increased adiponectin production tend to modulate the system favorably toward metabolic "yin." PMID- 20960553 TI - Insulin resistance in obesity as the underlying cause for the metabolic syndrome. AB - The metabolic syndrome affects more than a third of the US population, predisposing to the development of type 2 diabetes and cardiovascular disease. The 2009 consensus statement from the International Diabetes Federation, American Heart Association, World Heart Federation, International Atherosclerosis Society, International Association for the Study of Obesity, and the National Heart, Lung, and Blood Institute defines the metabolic syndrome as 3 of the following elements: abdominal obesity, elevated blood pressure, elevated triglycerides, low high-density lipoprotein cholesterol, and hyperglycemia. Many factors contribute to this syndrome, including decreased physical activity, genetic predisposition, chronic inflammation, free fatty acids, and mitochondrial dysfunction. Insulin resistance appears to be the common link between these elements, obesity and the metabolic syndrome. In normal circumstances, insulin stimulates glucose uptake into skeletal muscle, inhibits hepatic gluconeogenesis, and decreases adipose tissue lipolysis and hepatic production of very-low-density lipoproteins. Insulin signaling in the brain decreases appetite and prevents glucose production by the liver through neuronal signals from the hypothalamus. Insulin resistance, in contrast, leads to the release of free fatty acids from adipose tissue, increased hepatic production of very-low-density lipoproteins and decreased high-density lipoproteins. Increased production of free fatty acids, inflammatory cytokines, and adipokines and mitochondrial dysfunction contribute to impaired insulin signaling, decreased skeletal muscle glucose uptake, increased hepatic gluconeogenesis, and beta cell dysfunction, leading to hyperglycemia. In addition, insulin resistance leads to the development of hypertension by impairing vasodilation induced by nitric oxide. In this review, we discuss normal insulin signaling and the mechanisms by which insulin resistance contributes to the development of the metabolic syndrome. PMID- 20960554 TI - Therapeutic options for the prevention of type 2 diabetes mellitus in the metabolic syndrome. AB - The increasing prevalence of metabolic syndrome has created an impetus to prevent complications such as diabetes. There are no defined treatments for metabolic syndrome apart from addressing each of its components such as obesity, hypertension, dyslipidemia, and hyperglycemia. To evaluate diabetes-prevention strategies, we performed a Medline search and identified evidence suggesting that lifestyle intervention and certain medications can prevent diabetes. In addition, there are several agents on the horizon that seem promising. The mechanism responsible for diabetes prevention relates to improved insulin resistance as a result of weight loss or other processes. Lifestyle interventions and medications such as metformin are effective and safe in long-term prevention studies. However, the safety and efficacy of newer agents need clarification. PMID- 20960555 TI - Weight management in type 2 diabetes mellitus. AB - Obesity is a well known risk factor for type 2 diabetes mellitus. Individuals with type 2 diabetes mellitus are at risk for weight gain as a result of multiple influences, including sedentary lifestyle, high-calorie diet, diabetes medications, sociocultural factors, chronic medical and psychiatric illnesses, and a dysregulated enteroendocrine axis. Because both diabetes mellitus and obesity predispose patients to abnormal cardiometabolic profiles and increased cardiovascular disease, management of diabetes mellitus should focus on weight management and optimizing cardiometabolic parameters, concomitant with glycemic control. Lifestyle modification incorporating healthy, calorie-appropriate diets and increased physical activity, in addition to metformin, are central components to diabetes management and weight management. These interventions have been shown to improve body weight, glycemic control, and overall cardiometabolic profile. The weight-neutral and weight-losing diabetes medications include metformin, alpha-glucosidase inhibitors, glucagon-like peptide-1 analogs, dipeptidyl peptidase-4 inhibitors, and amylin analogs. It is essential that providers understand the metabolic and weight effects of diabetes medications in order to develop strategies for managing diabetes mellitus while helping patients maintain or lose weight in order to improve their overall health outcomes. PMID- 20960556 TI - Usefulness of anti-infective lock solutions for catheter-related bloodstream infections. AB - Central venous catheters are commonly used for the administration of medications in both the inpatient and outpatient settings, but their use carries the risk of developing catheter-related bloodstream infections, increasing morbidity and mortality. Guidelines from the Infectious Diseases Society of America include use of antibiotic lock solutions as a therapeutic option for intraluminal infections when the device is difficult to remove, but these lock solutions are not indicated routinely for the prophylaxis of catheter-related bloodstream infections. Because catheter removal is not always possible in patients who require chronic catheterization or who have multiple catheters, antibiotic lock therapy can be utilized with the goal of sparing removal of the catheter while sterilizing the lumen. The use of an antibiotic lock solution is an appealing option for localized infections because it is easy to use, is associated with a low cost, and is usually without systemic side effects if the catheter remains closed. Patients with long-term or short-term catheters with no signs of exit site or tunnel infection for whom salvage is the goal may benefit from this technique when treated with systemic antibiotics. Consider antibiotic lock therapy only in uncomplicated infections, typically nontunneled catheter or port infections with coagulase-negative staphylococci or gram-negative bacilli. Generally, a short-term regimen of 7 to 14 days is recommended. Several studies have supported antimicrobial lock therapy with vancomycin, gentamicin, cefazolin, or ethanol. Antibiotic locks have the potential to positively impact mortality and cost savings. A protocol at the Mount Sinai Medical Center is in development. PMID- 20960557 TI - Mechanisms of yogic practices in health, aging, and disease. AB - Mechanisms underlying the modulating effects of yogic cognitive-behavioral practices (eg, meditation, yoga asanas, pranayama breathing, caloric restriction) on human physiology can be classified into 4 transduction pathways: humoral factors, nervous system activity, cell trafficking, and bioelectromagnetism. Here we give examples of these transduction pathways and how, through them, yogic practices might optimize health, delay aging, and ameliorate chronic illness and stress from disability. We also recognize that most studies of these mechanisms remain embedded in a reductionist paradigm, investigating small numbers of elements of only 1 or 2 pathways. Moreover, often, subjects are not long-term practitioners, but recently trained. The models generated from such data are, in turn, often limited, top-down, without the explanatory power to describe beneficial effects of long-term practice or to provide foundations for comparing one practice to another. More flexible and useful models require a systems biology approach to gathering and analysis of data. Such a paradigm is needed to fully appreciate the deeper mechanisms underlying the ability of yogic practice to optimize health, delay aging, and speed efficient recovery from injury or disease. In this regard, 3 different, not necessarily competing, hypotheses are presented to guide design of future investigations, namely, that yogic practices may: (1) promote restoration of physiologic setpoints to normal after derangements secondary to disease or injury, (2) promote homeostatic negative feedback loops over nonhomeostatic positive feedback loops in molecular and cellular interactions, and (3) quench abnormal "noise" in cellular and molecular signaling networks arising from environmental or internal stresses. PMID- 20960558 TI - Control of carbohydrate metabolism in an anoxia-tolerant nervous system. AB - Anoxia-tolerant animal models are crucial to understand protective mechanisms during low oxygen excursions. As glycogen is the main fermentable fuel supporting energy production during oxygen tension reduction, understanding glycogen metabolism can provide important insights about processes involved in anoxia survival. In this report we studied carbohydrate metabolism regulation in the central nervous system (CNS) of an anoxia-tolerant land snail during experimental anoxia exposure and subsequent reoxygenation. Glucose uptake, glycogen synthesis from glucose, and the key enzymes of glycogen metabolism, glycogen synthase (GS) and glycogen phosphorylase (GP), were analyzed. When exposed to anoxia, the nervous ganglia of the snail achieved a sustained glucose uptake and glycogen synthesis levels, which seems important to maintain neural homeostasis. However, the activities of GS and GP were reduced, indicating a possible metabolic depression in the CNS. During the aerobic recovery period, the enzyme activities returned to basal values. The possible strategies used by Megalobulimus abbreviatus CNS to survive anoxia are discussed. PMID- 20960560 TI - Highlighted article: "A novel null allele of mouse Dscam survives to adulthood on an inbred C3H background with reduced phenotypic variability" by Fuerst, Harris, Johnson and Burgess. PMID- 20960562 TI - Atypically low spontaneous sister chromatid exchange formation in uveal melanoma. AB - Uveal melanoma (UM) is the most common primary intraocular cancer of adults and is characterized by several well-established chromosomal changes. More recently, a specific mutation of guanine nucleotide binding protein Gq alpha subunit (GNAQ) has also been identified in a proportion of UM. Although some of these alterations have been suggested to be early changes, the genetic alterations responsible for the development of UM have yet to be clearly determined. Cancers are characterized by increased genetic instability, and analysis of established cancer cell lines and blood from cancer patients has universally been associated with an increased level of sister chromatid exchange (SCE). We have observed that the spontaneous frequency of SCE in primary cultures of UM and UM-derived cell lines is decreased below normal baseline levels, a phenomenon unique to UM when compared with multiple other cancers. This finding was specific to the tumor and not found in lymphocytes from the patients. Although we cannot exclude the possibility that low SCE (LSCE) is peculiar to the uveal melanocytes lineage, as it was consistently observed in all UM studied, regardless of other genetic defects, we propose that this phenomenon contributes to the molecular pathogenesis of UM. PMID- 20960561 TI - Lack of motor neuron differentiation is an intrinsic property of the mouse secondary neural tube. AB - The cranial part of the amniote neural tube is formed by folding and fusion of the ectoderm-derived neural plate (primary neurulation). After posterior neuropore closure, however, the caudal neural tube is formed by cavitation of tail bud mesenchyme (secondary neurulation). In mouse embryos, the secondary neural tube expresses several genes important in early patterning and induction, in restricted domains similar to the primary neural tube, yet it does not undergo neuronal differentiation, but subsequently degenerates. Although the secondary neural tube, isolated from surrounding tissues, is responsive to exogenous Sonic Hedgehog proteins in vitro, motor neuron differentiation is never observed. This cannot be attributed to the properties of the secondary notochord, since it is able to induce motor neuron differentiation in naive chick neural plate explants. Taken together, these results support that the lack of motor neuron differentiation is an intrinsic property of the mouse secondary neural tube. PMID- 20960563 TI - Several lymphoma-specific genetic events in parallel can be found in mature B cell neoplasms. AB - The mature B-cell neoplasms frequently result from translocations involving the IGH gene localized on 14q32. In rare instances, combinations of different IGH rearrangements were described, and even coincidence of three genetic lymphoma specific events has been rarely reported. We here present eight patients with triple hit lymphoma, and two with four different lymphoma specific events detected by chromosome banding analysis and interphase FISH (seven males, three females, 47-82 years). All showed bone marrow involvement (Burkitt's lymphoma: n = 5, diffuse large B-cell lymphoma: n = 2; features intermediate between BL/DLBCL: n = 1; secondary aggressive B-cell lymphoma: n = 1; follicular lymphoma: n = 1). Eight patients had triple hit lymphoma combining IGH BCL2/t(14;18)(q32;q21), MYC/8q24, and BCL6/3q27 rearrangements. Two showed an additional IGH-CCND1/t(11;14)(q13;q32) as fourth genetic event (according to research of the Mitelman database, the first reports on four genetic hits in lymphomas). All cases had complex aberrant karyotypes (median, 11 cytogenetic alterations per patient). Interphase FISH revealed a high rate of CDKN2A deletions (five of nine cases investigated; 56%), being homozygous in two of these cases. At the time of study, four of nine patients with follow-up data were alive (44%), one of these in remission. The two patients with four genetic hits died 6 and 9 days from diagnosis. Additional cases of lymphomas with three or four genetic hits should be collected to evaluate whether their clinical course differs from dual hit lymphomas. PMID- 20960564 TI - Neck treatment and shoulder morbidity: still a challenge. AB - Shoulder complaints and functional impairment are common sequelae of neck dissection. This is often attributed to injury of the spinal accessory nerve by dissection or direct trauma. Nevertheless, shoulder morbidity may also occur in cases in which the spinal accessory nerve has been preserved. In this article, the physiology and pathophysiology of the shoulder are discussed, followed by a consideration of the impact of neck dissection on shoulder complaints, functional impairment, and quality of life. Finally, rehabilitation will be considered. PMID- 20960565 TI - Association between expression of embryonic lethal abnormal vision-like protein HuR and cyclooxygenase-2 in oral squamous cell carcinoma. AB - BACKGROUND: Increased cytoplasmic HuR expression has been noted in several cancer types, where it may contribute to the increased cyclooxygenase-2 (COX-2) expression observed during tumorigenesis and metastasis. METHODS: To assess the correlation between COX-2 and HuR in oral squamous cell carcinoma (OSCC), the expression patterns of HuR and COX-2 were assessed via immunohistochemistry analyses of 103 OSCC samples. RESULTS: Cytoplasmic HuR expression was significantly associated with COX-2 expression (p < .025) and lymph node metastasis (p < .050) and distant metastasis (p < .025). In multivariate analysis, cytoplasmic HuR expression was identified as an independent prognostic parameter for reduced overall survival. The inhibition of HuR expression by siRNA or leptomycin B (LMB) caused a reduction in the inducibility of COX-2 in oral cancer cells. CONCLUSION: Our results indicate that the cytoplasmic expression of HuR is associated with COX-2 expression in OSCCs and HuR can regulate COX-2 expression in oral cancer cell lines. PMID- 20960566 TI - Outcomes after definitive treatment for cutaneous angiosarcoma of the face and scalp. AB - BACKGROUND: The aim of the present analysis was to retrospectively evaluate outcomes in patients with cutaneous angiosarcoma of the face/scalp treated curatively with surgery, radiation therapy (RT), or a combination of surgery and RT. METHODS: In all, 70 patients with nonmetastatic angiosarcoma underwent surgery, RT, or combined-modality therapy. Of these, 20 patients (29%) were treated with surgery alone, 27 patients (39%) with RT alone, and 23 patients (33%) with combined-modality therapy; 44 patients received chemotherapy, either neoadjuvantly or adjuvantly or both. RESULTS: Median follow-up was 2.1 years. The overall survival (OS) rate was 43% at 5 years, and disease-specific survival (DSS) was 46% at 5 years. Tumor size > 5 cm and satellitosis were prognostic for inferior OS and DSS. Combined-modality therapy (vs surgery alone or RT alone) was associated with improved OS, DSS, and local control. CONCLUSIONS: Primary local therapy with combined-modality therapy was associated with improved local control, OS, and DSS for patients with angiosarcoma of the face/scalp. PMID- 20960567 TI - CGG repeats associated with fragile X chromosome form left-handed Z-DNA structure. AB - This work is a continuation of our effort to determine the structure responsible for expansion of the (CGG)(n) motif that results in fragile X chromosome syndrome. In our previous report, we demonstrated that the structure adopted by an oligonucleotide with this repeat sequence is not a quadruplex as was suggested by others. Here we demonstrate that (CGG) runs adopt another anomalous arrangement-a left-handed Z-DNA structure. The Z-DNA formation was induced by high salt and millimolar concentrations of Ni(2+) ions and likelihood of its formation increased with increasing number of repeats. In an oligonucleotide in which the CGG runs were interrupted by AGG triplets, as is observed in genomes of healthy individuals, the hairpin conformation was stabilized and Z-DNA formation was hindered. We show here that methylation of the (CGG) runs markedly stabilized Z-DNA formation. We hypothesize that rather than in the expansion process the Z DNA may be formed by long, expanded (CGG) stretches that become hypermethylated; this would inhibit transcription resulting in disease. PMID- 20960568 TI - Formulation development of therapeutic monoclonal antibodies using high throughput fluorescence and static light scattering techniques: role of conformational and colloidal stability. AB - In this work, we describe the application of two different high-throughput screening (HTS) techniques that can be used to determine protein stability during early formulation development. Differential scanning fluorescence (DSF) and differential static light scattering (DSLS) are used to determine the conformational and colloidal stability of therapeutic monoclonal antibodies (mAbs) during thermal denaturation in a high-throughput fashion. DSF utilizes SYPRO Orange, a polarity-sensitive extrinsic fluorescent probe, to monitor protein unfolding. We found that melting temperatures determined by DSF have a linear correlation with melting temperatures of the first domain unfolding determined by differential scanning calorimetry, establishing DSF as a reliable method for measuring thermal stability. The DSLS method employs static light scattering to evaluate protein stability during thermal denaturation in a 384 well format. Overall comparison between mAb aggregation under typical accelerated stress conditions (40 degrees C) and the thermal stability obtained by DSF and DSLS is also presented. Both of these HTS methods are cost effective with high throughput capability and can be implemented in any laboratory. Combined with other emerging HTS techniques, DSF and DSLS could be powerful tools for mAb formulation optimization. PMID- 20960569 TI - PCPP-formulated H5N1 influenza vaccine displays improved stability and dose sparing effect in lethal challenge studies. AB - The potential impact of an influenza pandemic can be mitigated through the realization of a successful vaccination program. The implementation of antigen stabilization and dose-sparing technologies is an important step in improving availability of vaccines at the time of a pandemic outbreak. We investigated poly[di(carboxylatophenoxy)phosphazene] (PCPP) as a potential stabilizing and immunostimulating agent for H5N1 influenza vaccine. Physicochemical characterization of PCPP-formulated H5N1 influenza vaccine revealed macromolecular complexation in the system, whereas single radial immunodiffusion assay verified antigenicity of the formulation in vitro. PCPP-enhanced formulation displayed a fourfold increase in the half-life at 40 degrees C compared with a nonadjuvanted vaccine. Lethal challenge studies in ferrets demonstrated 100% protection for low-antigen dose PCPP-adjuvanted formulations (1 MUg of hemagglutinin) and at least a 10-fold antigen-sparing effect. Therefore, PCPP demonstrated an ability to improve thermal stability of H5N1 influenza vaccine in solutions and provide for a substantial dose-sparing effect in vivo. PMID- 20960570 TI - Oil-frozen W1/O/W2 double emulsions for dermal biomacromolecular delivery containing ethanol as chemical penetration enhancer. AB - Oil-frozen water-in-oil-in-water (W1/O/W2) double emulsions (DE) containing ethanol up to 40% (w/v) in the external aqueous W2 phase exhibited external coalescence upon thawing of the oil phase, releasing up to 85% of the encapsulated protein of the internal aqueous phase. These emulsions were studied in vitro as potential dermal macromolecular delivery formulations, achieving fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA) penetration of up to 86 MUm into porcine skin, reaching the viable epidermis where the immunocompetent Langerhans cells are located. Enzyme-linked immunosorbent assay was performed to observe the effect of the emulsification process and ethanol content on the ability of BSA to form antigen-antibody complexes; results indicated that ethanol content and the emulsification process did not diminish the BSA-antibody complex formation when compared with a BSA standard aqueous solution. Therefore, it is shown that oil-frozen W1/O/W2 DE, with penetration enhancing ethanol in the W2 phase, can potentially be used for cutaneous vaccine delivery formulations. PMID- 20960571 TI - In vivo evaluation of the release of zidovudine and polystyrene sulfonate from a dual intravaginal bioadhesive polymeric device in the pig model. AB - This study focused on determining the concentration of zidovudine (AZT) and polystyrene sulfonate (PSS) in the plasma and vaginal tissue of the large white pig from an intravaginal bioadhesive polymeric device (IBPD). Biocompatible polymers were compressed with AZT and PSS into caplet-shaped devices for insertion into the posterior fornix of the pig vagina. A total of 25 pigs were used in this study. Plasma was sampled from the jugular vein at various time points after insertion of the IBPD reaching 28 days. At day 28, the pigs were euthanized and vaginal tissue was removed and digested with subtilisin for AZT and PSS extraction. The mean concentration detected in vaginal tissue at day 28 was 1.214 +/- 0.062 mg/mL for AZT and 1.400 +/- 0.071 mg/mL for PSS. Plasma concentration was significantly lower for AZT (0.332 +/- 0.014 mg/mL) and PSS (0.256 +/- 0.013 mg/mL). This indicated higher retention of AZT and PSS within the vaginal tissue. Molecular mechanics simulations blueprinted polymer-drug mucin force-field interactions and energies that explicated the spatial preference of AZT and PSS for the vaginal tissue. Histopathotoxicity studies revealed negative-to-mild foreign body events and results strongly suggest that the IBPD may be suitable for prolonged intravaginal drug delivery in preventing the transmission of sexually transmitted infections and HIV/AIDS. PMID- 20960572 TI - Reduced somatosensory activations in swallowing with age. AB - Understanding the neural functional organization of swallowing in healthy elders is essential in diagnosing and treating older adults with swallowing difficulties. The primary aims of this investigation were to identify the neural activation sites of different components of deglutition in healthy elders using functional Magnetic Resonance Imaging (fMRI) and to investigate age differences in the neural control of swallowing. Ten young (age range 19-25 years of age) and nine older (age range 66-77 years of age) right-handed healthy individuals were scanned in a 3-Tesla MRI scanner. Subjects were visually cued for both a "Swallow" task and for component/control tasks ("Prepare to swallow," "Tap your tongue," and "Clear your throat"). Behavioral interleaved gradient (BIG) methodology was used to address movement related artifacts. Between-group comparisons revealed statistically stronger activations in the primary somatosensory cortex of young adults during the motor tasks examined. Both groups showed activations in the major motor areas involved in the initiation and execution of movement; however, areas involved in sensory processing, sensorimotor integration and/or motor coordination and control, showed reduced or limited activity in the elderly. Potential implications of these findings for clinical practice are discussed. PMID- 20960573 TI - The 'Gator' Mouse Suit for early bioluminescent metastatic breast cancer detection and nanomaterial signal enhancement during live animal imaging. AB - Optical imaging is a cornerstone of modern oncologic research. The aim of this study is to determine the value of a new tool to enhance bioluminescent and fluorescent sensitivity for facilitating very-low-level signal detection in vivo. EXPERIMENTAL: For bioluminescent imaging experiments, a luciferase expressing breast cancer cell line with metastatic phenotype was implanted orthotopically into the mammary fat pad of mice. For fluorescent imaging experiments, near infrared (NIR) nanoparticles were injected intratumorally and subcutaneously into mice. Images were compared in mice with and without application of the 'Gator' Mouse Suit (GMS). RESULTS: The GMS was associated with early detection and quantification of metastatic bioluminescent very-low-level signal not possible with conventional imaging strategies. Similarly, NIR nanoparticles that were undetectable in locations beyond the primary injection site could be visualized and their very-low-level signal quantifiable with the aid of the GMS. CONCLUSION: The GMS is a device which has tremendous potential for facilitating the development of bioluminescent models and fluorescent nanomaterials for translational oncologic applications. PMID- 20960574 TI - High-sensitivity spectrofluorimetric determination of tiopronin based on inhibition of hemoglobin. AB - A highly sensitive and simple spectrofluorimetric method for the determination of tiopronin based on its inhibitory effect on the hemoglobin-catalyzed reaction of H(2)O(2) and L-tyrosine was developed. The concentration of tiopronin is linear with decreased fluorescence (DeltaF) of the system under the optimal experimental conditions. The calibration graph is linear in the range 1.23 * 10(-8) to 3.06 * 10(-5) mol L(-1) with a detection limit of 6.13 * 10(-9) mol L(-1). The relative standard deviation was 4.38% for 11 determinations of 6.13 * 10(-6) mol L(-1). This method can be used for the determination of tiopronin in pharmaceuticals with satisfactory results. PMID- 20960575 TI - Spectrofluorimetric determination of aluminium using 2-hydroxy-1-naphthylidene-(8 aminoquinoline). AB - A sensitive and selective spectrofluorimetric method has been developed for the rapid determination of aluminium. This method is based on the complex formation between aluminium and 2-hydroxy-1-naphthylidene-(8-aminoquinoline) (HNAQ). The optimum conditions for the complex formation were a metal-to-ligand (M : L) stoichiometric ratio of 1:1, a pH of 5.5 and a 0.20 m acetate buffer. The fluorescence of the complex was monitored at an emission wavelength of 502 nm with excitation at 438 nm. Under these conditions, linear calibration curves were obtained in the ranges 0.05-1 and 1-5 ppm. The detection limit was 3.4 ppb for the former and 13.5 ppb for the latter. The maximum relative standard deviation of the method for an aluminium standard of 200 ppb was 1.5% (n = 5). This method was successfully applied for the determination of aluminium in drinking water, pharmaceutical antacid tablets and suspension samples. PMID- 20960576 TI - A fluorescent probe for biothiols based on the conjugate addition of thiols to alpha,beta-unsaturated ester. AB - A sensitive fluorogenic probe 1 for biothiols was developed based on the Michael addition reaction. The probe 1 was readily synthesized via the reaction of 2-(4' hydroxyphenyl) benzimidazole (HPBI) with acryloyl chloride and shows weak fluorescence emission. Upon mixing with biothiols, the fluorescence of 1 is significantly enhanced due to the conjugate addition of thiols to the alpha,beta unsaturated carbonyl moiety, thus eliminating the photoinduced electron transfer (PET) quenching of the fluorophore by the intramolecular carbon-carbon double bond. Cysteine (Cys) was selected as the representative thiol in the spectral experiment. A good linear relationship was obtained from 1.0 to 30.0 umol L(-1) for Cys and the detection limit was 0.17 umol L(-1). Furthermore, probe 1 was highly selective for biothiols without the interference of some biologically relevant analytes and has been applied to detecting biothiols in human urine samples. PMID- 20960577 TI - Uniform prostate imaging and spectroscopy at 7 T: comparison between a microstrip array and an endorectal coil. AB - An endorectal coil and an eight-element microstrip array were compared for prostate imaging at 7 T. An extensive radiofrequency safety assessment was performed with the use of finite difference time domain simulations to determine safe scan parameters. These simulations showed that the endorectal coil can deliver substantially more B(1)(+) to the prostate than can the microstrip array within the specific absorption rate safety guidelines. However, the B(1)(+) field of the endorectal coil is very inhomogeneous, which makes the use of adiabatic pulses compulsory for T(1) - or T(2) -weighted imaging. As a consequence, a full prostate examination is only possible in a feasible amount of time when the microstrip array is used for T(1) - and T(2) -weighted imaging, whereas the endorectal coil is required for spectroscopic imaging. The pulse parameters were optimised within the specific absorption rate guidelines and thereafter used to provide a good illustration of the possibilities of prostate imaging at 7 T. PMID- 20960578 TI - High-field MRI of single histological slices using an inductively coupled, self resonant microcoil: application to ex vivo samples of patients with Alzheimer's disease. AB - A simple inductively coupled microcoil has been designed to image tissue samples placed on a microscope slide, samples which can subsequently be stained histologically. As the exact same tissue is used for MRI and histology, the two data sets can be compared without the need for complicated image registration techniques. The design can be integrated into any MRI system using existing commercial hardware. Compared with a commercial 25-mm-diameter birdcage, the signal-to-noise ratio was increased by a factor of 3.8, corresponding to an approximate 15-fold reduction in the data acquisition time. An example is shown of ex vivo samples from patients with Alzheimer's disease, in which the coregistration of highly sensitive iron staining and amyloid-beta deposits is confirmed. PMID- 20960579 TI - Preliminary observations of increased diffusional kurtosis in human brain following recent cerebral infarction. AB - By application of the MRI method of diffusional kurtosis imaging, a substantially increased diffusional kurtosis was observed within the cerebral ischemic lesions of three stroke subjects, 13-26 h following the onset of symptoms. This increase is interpreted as probably reflecting a higher degree of diffusional heterogeneity in the lesions when compared with normal-appearing contralateral tissue. In addition, for two of the subjects with white matter infarcts, the increase had a strong fiber tract orientational dependence. It is proposed that this effect is consistent with a large drop in the intra-axonal diffusivity, possibly related to either axonal varicosities or alterations associated with the endoplasmic reticulum. PMID- 20960580 TI - Quantitative magnetisation transfer imaging in glioma: preliminary results. AB - Quantitative magnetisation transfer imaging (qMTI) is an extension of conventional MT techniques and allows the measurement of parameters that reflect tissue ultrastructure through the properties of macromolecule-bound protons; these include the bound proton fraction and the relaxation times of free and bound proton pools. It has been used in multiple sclerosis and Alzheimer's disease, and has shown changes in some of the parameters, particularly the bound proton fraction. The purpose of this pilot study was to assess whether qMTI could distinguish between gliomas and normal brain tissue, and provide proof of principle for its use in tumour characterisation. Eight subjects [three men, five women; mean age, 44 years; range, 27-66 years; seven World Health Organization (WHO) Grade II, one Grade III] with biopsy-proven glioma were imaged with a structural MRI protocol that included three-dimensional qMTI. qMTI parameters were extracted from regions of interest selected from different tumour components visible on conventional MR sequences, normal-appearing peritumoral tissue and distant normal-appearing white matter. All patients gave informed consent and the study was approved by the Local Research Ethics Committee. Almost all of the qMTI parameters detected abnormalities in both glioma and the peritumoral region relative to the distant white matter. In particular, the bound proton fraction was reduced significantly from 6.0 percentage units (pu) [standard deviation (SD), 0.5 pu] in normal-appearing white matter to 1.7 pu (SD = 0.5 pu) in solid tumour and 2.2 pu (SD = 0.5 pu) in peritumoral areas. This work shows that qMTI reveals abnormalities, not only in glioma, but also in the apparently normal tissue surrounding the conventionally defined tumour. Thus, qMTI shows promise for tumour characterisation and for studying tumour boundaries. These preliminary data justify larger studies in a range of different tumour types and grades. PMID- 20960581 TI - Retention study of some cation-type compounds using bile acid sodium salts as ion pairing agents in liquid chromatography. AB - The possibility of forming ion-pairs between bile acids (sodium taurocholate, sodium taurodeoxycholate and sodium taurochenodeoxycholate) and different compounds (pralidoxime, obidoxime and pyridostigmine) having a cationic character has been studied in reversed-phase liquid chromatography (RP-LC). This study can be useful in understanding the role of bile acids in the transport of ionic species through hydrophobic membrane. The present study focused on the influence of mobile phase composition on the retention parameters of chosen compounds (percentage of acetonitrile, pH of aqueous component or ionic strength). For constant concentration of bile acids in aqueous component of mobile phase the functional dependencies between the logarithm of the retention factor (k) and the methanol content in the mobile phase followed a binomial pattern (U-shaped), with a minimum positioned within the interval 70-85% methanol. PMID- 20960582 TI - A Bayesian proportional hazards regression model with non-ignorably missing time varying covariates. AB - Missing covariate data are common in observational studies of time to an event, especially when covariates are repeatedly measured over time. Failure to account for the missing data can lead to bias or loss of efficiency, especially when the data are non-ignorably missing. Previous work has focused on the case of fixed covariates rather than those that are repeatedly measured over the follow-up period, hence, here we present a selection model that allows for proportional hazards regression with time-varying covariates when some covariates may be non ignorably missing. We develop a fully Bayesian model and obtain posterior estimates of the parameters via the Gibbs sampler in WinBUGS. We illustrate our model with an analysis of post-diagnosis weight change and survival after breast cancer diagnosis in the Long Island Breast Cancer Study Project follow-up study. Our results indicate that post-diagnosis weight gain is associated with lower all cause and breast cancer-specific survival among women diagnosed with new primary breast cancer. Our sensitivity analysis showed only slight differences between models with different assumptions on the missing data mechanism yet the complete case analysis yielded markedly different results. PMID- 20960583 TI - Three-dimensional T1 mapping of the mouse heart using variable flip angle steady state MR imaging. AB - Cardiac MR T(1) mapping is a promising quantitative imaging tool for the diagnosis and evaluation of cardiomyopathy. Here, we present a new preclinical cardiac MRI method enabling three-dimensional T(1) mapping of the mouse heart. The method is based on a variable flip angle analysis of steady-state MR imaging data. A retrospectively triggered three-dimensional FLASH (fast low-angle shot) sequence (3D IntraGate) enables a constant repetition time and maintains steady state conditions. 3D T(1) mapping of the complete mouse heart could be achieved in 20 min. High-quality, bright-blood T(1) maps were obtained with homogeneous T(1) values (1764 +/- 172 ms) throughout the myocardium. The repeatability coefficient of R(1) (1/T(1) ) in a specific region of the mouse heart was between 0.14 and 0.20 s(-1) , depending on the number of flip angles. The feasibility for detecting regional differences in DeltaR(1) was shown with pre- and post-contrast T(1) mapping in mice with surgically induced myocardial infarction, for which DeltaR(1) values up to 0.83 s(-1) were found in the infarct zone. The sequence was also investigated in black-blood mode, which, interestingly, showed a strong decrease in the apparent mean T(1) of healthy myocardium (905 +/- 110 ms). This study shows that 3D T(1) mapping in the mouse heart is feasible and can be used to monitor regional changes in myocardial T(1), particularly in relation to pathology and in contrast-enhanced experiments to estimate local concentrations of (targeted) contrast agent. PMID- 20960584 TI - Delineation of substrate selection and anaplerosis in tricarboxylic acid cycle of the heart by 13C NMR spectroscopy and mass spectrometry. AB - (13)C NMR and mass spectrometry (MS) provide complementary information regarding the (13)C labeling of intermediary metabolites. Currently, these two techniques are rarely used together because of the complexity of modeling the distribution of both positional and mass isotopomers. In this study, we developed a matrix based model for the assessment of (13)C label distribution in the tricarboxylic acid cycle and related metabolites. The model was applied to the analysis of NMR- and MS-measured (13)C isotopomers for quantification of substrate utilization and anaplerotic fluxes in isolated perfused rat hearts. NMR and MS data were acquired from two groups of rat hearts perfused with substrates in complementary labeling patterns, i.e. the (13)C-PAL + GLC group (0.6 mM [(13) C(16) ]palmitate + 5.5 mM glucose) and the PAL + (13)C-GLC group (0.6 mM palmitate + 5.5 mM [(13)C(6) ]glucose). Relative flux parameters were obtained by fitting the model to the NMR data, MS data and their combination, respectively. Our results suggest that, although both NMR and MS can provide accurate quantification of substrate selection in oxidative metabolism, the accuracy of estimation of anaplerotic fluxes relies on the combination of these two experimental methods. PMID- 20960585 TI - Evaluation of a quantitative blood oxygenation level-dependent (qBOLD) approach to map local blood oxygen saturation. AB - Blood oxygen saturation (SO(2)) is a promising parameter for the assessment of brain tissue viability in numerous pathologies. Quantitative blood oxygenation level-dependent (qBOLD)-like approaches allow the estimation of SO(2) by modelling the contribution of deoxyhaemoglobin to the MR signal decay. These methods require a high signal-to-noise ratio to obtain accurate maps through fitting procedures. In this article, we present a version of the qBOLD method at long TE taking into account separate estimates of T(2), total blood volume fraction (BV(f)) and magnetic field inhomogeneities. Our approach was applied to the brains of 13 healthy rats under normoxia, hyperoxia and hypoxia. MR estimates of local SO(2) (MR_LSO(2)) were compared with measurements obtained from blood gas analysis. A very good correlation (R(2) = 0.89) was found between brain MR_LSO(2) and sagittal sinus SO(2). PMID- 20960586 TI - New paradigm in training of undergraduate clinical skills: the NEPTUNE-CS project at the Split University School of Medicine. AB - Clinical skills' training is arguably the weakest point in medical schools' curriculum. This study briefly describes how we at the Split University School of Medicine cope with this problem. We consider that, over the last decades, a considerable advancement in teaching methodologies, tools, and assessment of students has been made. However, there are many unresolved issues, most notably: (i) the institutional value system, impeding the motivation of the teaching staff; (ii) lack of a strong mentoring system; (iii) organization, timing, and placement of training in the curriculum; (iv) lack of publications pertinent to training; and (v) unwillingness of patients to participate in student training. To improve the existing training models we suggest increased institutional awareness of obstacles, as well as willingness to develop mechanisms for increasing the motivation of faculty. It is necessary to introduce changes in the structure and timing of training and to complement it with a catalog, practicum, and portfolio of clinical skills. At Split University School of Medicine, we developed a new paradigm aimed to improve the teaching of clinical skills called "Neptune-CSS," which stands for New Paradigm in Training of Undergraduate Clinical Skills in Split. PMID- 20960587 TI - The Singapore statement on research integrity. PMID- 20960588 TI - In search of a Croatian model of nursing education. AB - AIM: To analyze the present status and ongoing reforms of nursing education in Europe, to compare it with the situation in Croatia, and to propose a new educational model that corresponds to the needs of the Croatian health care system. METHODS: The literature on contemporary nursing education in Europe and North America was reviewed, together with European Commission directives and regulations, as well as pertinent World Health Organization documents. In addition, 20 recent annual reports from 2003-2009, submitted by national nursing associations to the Workgroup of European Nurse Researchers (WERN), were studied. RESULTS: After appraisal of current trends, the Working Group on Reform of Nursing Education drafted The Croatian Model for Education in Nursing and developed a three-cycle curriculum with syllabus. The proposed curriculum is radically different from traditional ones. Responding to modern demands, it focuses on outcomes (developing competencies) and is evidence-based. CONCLUSIONS: A new, Croatian concept of nursing education is presented that is concordant with reforms in nursing education in other European countries. It holds promise for making nursing education an integral part of a unified European system of higher education. PMID- 20960589 TI - Effectiveness of the UNICEF/WHO 20-hour course in improving health professionals' knowledge, practices, and attitudes to breastfeeding: before/after study of 5 maternity facilities in Croatia. AB - AIM: To evaluate knowledge, practices, and attitudes to breastfeeding among Croatian health professionals before and after the United Nations International Children's Emergency Fund/World Health Organization (UNICEF/WHO) 20-hour course. METHODS: Study included 5 of 9 maternity hospitals in southern Croatia, which had completed the UNICEF/WHO 20-hour breastfeeding training course between December 2007 and February 2009. An anonymous questionnaire testing knowledge and practices, and attitudes was distributed to 424 health professionals before training and to 308 health professionals afterwards. Health professionals' attitudes were assessed using the validated Iowa Infant Feeding Attitude Scale. RESULTS: The pre-training response rate was >90%, but only 53% of data were analyzed; the post-training response rate was 69%. Only one-fifth of health professionals prior to training knew that breast preparation in pregnancy was unnecessary, but this increased to 57% after training (P<0.001). The proportion of health professionals who recognized hospital practices that support breastfeeding and signs of poor positioning when breastfeeding nearly doubled after training (P<0.001). The proportion of health professionals correctly recommending immediate "skin-to-skin" contact post-Cesarean section under local anesthesia did not improve significantly, and stratification analyses showed that younger respondents (<36 years) were more likely to support this practice. Although the proportion of health professionals who correctly managed mastitis improved significantly as a result of the training, the proportion of those who after training inappropriately recommended partial or complete cessation of breastfeeding remained high at 47%. The number of staff with positive attitudes toward breastfeeding increased from 65% to 79%, whereas the number of staff with neutral attitudes dropped from 26.6% to 9.9% (P<0.001). Even after training, a substantial proportion of health professionals showed uncertainty in their attitude toward alcohol consumption and breastfeeding. CONCLUSION: The UNICEF/WHO 20-hour course appears to be an effective tool for improving health professionals' breastfeeding knowledge, attitudes, and practices. PMID- 20960590 TI - Multi-type childhood abuse, strategies of coping, and psychological adaptations in young adults. AB - AIM: To retrospectively analyze the rate of multi-type abuse in childhood and the effects of childhood abuse and type of coping strategies on the psychological adaptation of young adults in a sample form the student population of the University of Mostar. METHODS: The study was conducted on a convenience sample of 233 students from the University of Mostar (196 female and 37 male), with a median age of 20 (interquartile range, 2). Exposure to abuse was determined using the Child Maltreatment Scales for Adults, which assesses emotional, physical, and sexual abuse, neglect, and witnessing family violence. Psychological adaptation was explored by the Trauma Symptom Checklist, which assesses anxiety/depression, sexual problems, trauma symptoms, and somatic symptoms. Strategies of coping with stress were explored by the Coping Inventory for Stressful Situations. RESULTS: Multi-type abuse in childhood was experienced by 172 participants (74%) and all types of abuse by 11 (5%) participants. Emotional and physical maltreatment were the most frequent types of abuse and mostly occurred together with other types of abuse. Significant association was found between all types of abuse (r=0.436 0.778, P<0.050). Exposure to sexual abuse in childhood and coping strategies were significant predictors of anxiety/depression (R(2)=0.3553), traumatic symptoms (R(2)=0.2299), somatic symptoms (R(2)=0.2173), and sexual problems (R(2)=0.1550, P<0.001). CONCLUSION: Exposure to multi-type abuse in childhood is a traumatic experience with long-term negative effects. Problem-oriented coping strategies ensure a better psychosocial adaptation than emotion-oriented strategies. PMID- 20960591 TI - Influence of early feeding practices on celiac disease in infants. AB - AIM: To investigate whether duration of breastfeeding and timing of gluten introduction influence the age at diagnosis and severity of celiac disease. METHODS: Medical records of 89 infants (59 girls and 30 boys; mean age of 14.2 months, standard deviation 4.80) diagnosed with classic celiac disease at the University Children's Hospital in Belgrade from 2000 to 2008 were retrospectively analyzed to determine the duration of breastfeeding and timing of gluten introduction. The severity of celiac disease was assessed based on weight loss, longitudinal growth retardation, anemia, and secondary lactose intolerance. RESULTS: Longer breastfeeding significantly reduced the risk that celiac disease would manifest in the first year of life (odds ratio, 0.655; 95% confidence interval, 0.481-0.891; P=0.007), and duration of breastfeeding was the most significant predictor of developing celiac disease (B=0.49; 95% confidence interval, 0.131-0.768; P=0.007). There were no significant differences in age at diagnosis between infants who had started consuming gluten before the fourth month and those who had started between the fourth and sixth month. Neither breastfeeding nor timing of gluten introduction affected the severity of the disease. CONCLUSION: Longer breastfeeding and continuation of breastfeeding after gluten introduction delay the onset of classic celiac disease. On the other hand, neither breastfeeding nor the timing of gluten introduction affects the severity of celiac disease. PMID- 20960592 TI - Pain to hospital times after myocardial infarction in patients from Dalmatian mainland and islands, southern Croatia. AB - AIM: To analyze pre-hospital delay in patients with myocardial infarction from mainland and islands of Split-Dalmatian County, southern Croatia. METHODS: The study included all patients with myocardial infarction transported by ambulance to the University Hospital Split in 1999, 2003, and 2005. Pre-hospital delay was analyzed in the following intervals: pain-to-call, call-to-ambulance, ambulance to-door, and door-to-coronary care unit interval. Patients were categorized according to the location from which they were transported: Split, mainland >15 km from Split, and islands. RESULTS: There were 1314 patients (62.9% men) transported and hospitalized for myocardial infarction. Total pre-hospital delay (pain-to-hospital) was significantly reduced from 1999 to 2005 (5.2 hours vs 4.3 hours, P=0.011). Seventy-five patients (5.7%) were admitted to the coronary care unit within the recommended time-frame of less than 90 minutes, none of which was from the islands, while 248 patients (18.9%) were admitted more than 12 hours from the onset of pain. CONCLUSION: Pre-hospital delay in patients with myocardial infarction in southern Croatia is still too long, especially in patients coming from outside of Split. Prognosis and survival of such patients may be improved by introducing changes to the health care system in remote areas, such as out-of-hospital thrombolysis, greater use of telemedicine, training of lay persons and paramedics in defibrillation, introduction of quality assessment mechanisms, and improved patient transport. PMID- 20960593 TI - Emotion work and burnout: cross-sectional study of nurses and physicians in Hungary. AB - AIM: To investigate predictors of occupational burnout, such as emotion work, among health care workers and compare the frequencies of burnout and emotion work in nurses and physicians. METHOD: A cross-sectional survey was conducted in 2007 and 2008 among 80 physicians and 76 nurses working in a variety of health care settings in Hungary. The survey contained sociodemographic questions and work- and health-related questions from, respectively, the Maslach Burnout Inventory Human Services Survey and the Hungarian version of the Frankfurt Emotion Work Scale. To identify the dimensions of emotion work associated with burnout, linear regression analyses were carried out. To analyze differences in burnout and emotion work between nurses and physicians, independent t tests were used. RESULTS: Nurses reported significantly higher emotional dissonance and fewer regulation possibilities, such as interaction and emotion control, than physicians. However, no differences were found in the level or frequency of burnout. Nurses had fewer regulation requirements regarding sensitivity and sympathy. Linear regression analyses showed that emotional dissonance for emotional exhaustion (beta=0.401) and display of negative emotions for depersonalization (beta=0.332) were the strongest predictors of burnout. CONCLUSION: The factors that should be taken into account when developing prevention and intervention programs differ for nurses and physicians. In nurses, the focus should be on stressors and emotional dissonance, while in physicians it should be on work requirements and display and regulation of negative emotions. PMID- 20960594 TI - Oral health status of psychiatric in-patients in Serbia and implications for their dental care. AB - AIM: To determine oral health status and identify predictors of oral health in a representative sample of psychiatric in-patients in Serbia. METHODS: The study included 186 psychiatric in-patients and 186 control participants without psychiatric illness matched to the study group by age, sex, marital status, education level, employment, and monthly income. Dental examinations were done in both groups to measure the following indices of oral health: decayed, missing, and filled teeth (DMFT) index; community periodontal index; and plaque index. Participants were also interviewed about their dental health behavior and their medical records were examined. RESULTS: Psychiatric in-patients had higher caries prevalence, poorer periodontal health, and poorer oral hygiene than controls. The average DMFT score in the patient group was 24.4 and 16.1 in the control group (P<0.001). Periodontal diseases were significantly more prevalent among psychiatric in-patients than among controls (P<0.001). The average plaque index for patients was 2.78 and 1.40 for controls (P<0.001). Multiple regression analysis demonstrated that 1) DMFT index was associated with age, male sex, duration of mental illness, use of antidepressants, time since the last visit to the dentist, and snacking frequency; 2) community periodontal index was associated with male sex; and 3) plaque index was associated with age, male sex, education level, employment, monthly income, tooth brushing technique, and snacking frequency. CONCLUSION: Psychiatric in-patients in Serbia have poorer oral health than healthy controls. It is necessary to intensify preventive dental care in this vulnerable population. PMID- 20960595 TI - Cross-sectional biomonitoring of metals in adult populations in post-war eastern Croatia: differences between areas of moderate and heavy combat. AB - AIM: To determine differences in metal and metalloid exposure between residents of areas in eastern Croatia exposed to heavy fighting during the war in Croatia and residents of areas exposed to moderate fighting. METHODS: Concentrations of aluminum (Al), arsenic (As), barium (Ba), cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), nickel (Ni), lead (Pb), uranium (U), vanadium (V), and zinc (Zn), reported to be associated with military operations, were determined in hair, serum, and urine samples using inductively-coupled plasma mass spectroscopy. A total of 127 and 46 participants from areas of heavy and moderate fighting, respectively, were included. RESULTS: Compared with participants from areas exposed to moderate fighting, participants from areas exposed to heavy fighting had significantly higher serum concentrations of Al (87.61 vs 42.75 MUg/L, P=0.007), As (5.05 ? 1.79 vs 4.16 ? 1.55 MUg/L, P=0.003), Ba (7.12 vs 6.01 MUg/L, P=0.044), and V (17.98 vs 16.84 MUg/L, P=0.008); significantly higher urine concentrations of As (43.90 vs 11.51 MUg/L, P<0.001) and Cd (0.67 vs 0.50 MUg/L, P=0.031); and significantly higher hair concentrations of Al (12.61 vs 7.33 MUg/L, P<0.001), As (0.32 vs 0.05 MUg/L, P<0.001), Cd (0.03 vs 0.02 MUg/L, P=0.002), Fe (22.58 vs 12.68 MUg/L, P=0.001), Pb (1.04 vs 0.69 MUg/L, P=0.006), and V (0.07 vs 0.03 MUg/L, P<0.001). CONCLUSION: Differences between populations from eastern Croatian areas exposed to heavy and populations exposed to moderate fighting point to the need for extensive monitoring of metal and metalloid exposure, emphasizing the role of biomonitoring through ecologic and preventive activities. PMID- 20960596 TI - Diagnoses of personality disorders between 1879 and 1929 in the largest Croatian psychiatric hospital. AB - AIM: To study demographic characteristics, comorbidities, and diagnoses of patients admitted for personality disorders to Psychiatric Hospital Vrapce between 1879 and 1929. METHODS: Data were collected from the archives of Vrapce Psychiatric Hospital for a 50-year period from November 1879 to December 1929. The ratio between the number of patients with personality disorder and the number of all admitted patients was determined. We used 3 systems of definitions of personality disorder: for cases before 1923, we used Prichard's concept of moral insanity and unpublished definitions of one of the hospital managers at that time; for cases after 1923, we used Schneider's classification of psychopathic personalities and unpublished definitions of one of the hospital managers at that time. RESULTS: The total number of admissions during the study period was 18 960, 141 (0.74%) of which were for a personality disorder. Of the admitted patients, 85.8% were men and 59.7% were single. The average age was 29.7 } 9.5 years. Most of them (61.7%) were sent to the hospital by courts or police, and the median length of stay was 92 days (interquartile range, 92.0 - 127.5 days). The first patient with a personality disorder was admitted in 1889 with a diagnosis of moral insanity. Until 1920, only 3 terms were used for personality disorder: moral insanity, psychopathic inferiority, and psychopathy. The term was subdivided only after that year. Of the 141 patients admitted for personality disorder, 34 (24.1%) were discharged with comorbid disorders, mainly substance abuse. The most common single comorbid diagnosis was Ganser syndrome (prison psychosis). CONCLUSION: Archives of the Vrapce Psychiatric Hospital contain reliable data about the earliest nomenclature of personality disorders, the increase in the prevalence of personality disorders, and further subdivision of the term personality disorder. Nomenclature for these disorders used at the Vrapce Psychiatric Hospital was consistent with that used in clinical practice in other parts of the world at the time. PMID- 20960597 TI - "I can't use a condom, I am a Christian:" salvation, death, and... naivety in Africa. PMID- 20960598 TI - It is October again, one more. PMID- 20960599 TI - Health care and economic crisis: can it get worse? PMID- 20960600 TI - A call for prospective studies in early-stage ovarian cancer. PMID- 20960601 TI - Editor's commentary on 'A randomised controlled trial comparing TVT, Pelvicol and autologous fascial slings for the treatment of stress urinary incontinence in women'. PMID- 20960602 TI - Gene symbol: LAMP2. Disease: Danon disease. PMID- 20960603 TI - Gene symbol: MTM1. Disease: Myotubular myopathy. PMID- 20960604 TI - Gene symbol: GLA. Disease: Fabry disease. PMID- 20960605 TI - Gene symbol: UBE3A. Disease: Angelman syndrome. PMID- 20960606 TI - Gene symbol: TBX19. Disease: ACTH deficiency, isolated? PMID- 20960607 TI - Gene symbol: MTM1. Disease: Myotubular myopathy? PMID- 20960608 TI - Gene symbol: VWF. Disease: Von Willebrand disease? PMID- 20960609 TI - Gene symbol: MTM1. Disease: Myotubular myopathy. PMID- 20960610 TI - Gene symbol: COL1A2. Disease: Ehlers-Danlos syndrome type VIIB. PMID- 20960611 TI - Gene symbol: ROBO3. Disease: Gaze Palsy, horizontal, with progressive scoliosis. PMID- 20960612 TI - Assessment: symptomatic treatment for muscle cramps (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. PMID- 20960613 TI - Gene symbol: KCNH2. Disease: Long QT syndrome. PMID- 20960614 TI - Gene symbol: KCNQ1. Disease: Long QT syndrome. PMID- 20960615 TI - In memoriam: William Richard Green, MD (1934-2010). PMID- 20960616 TI - Gene symbol: KCNH2. Disease: Long QT syndrome. PMID- 20960617 TI - Gene symbol: SCN5A. Disease: Brugada syndrome. PMID- 20960618 TI - Gene symbol: SCN5A. Disease: Brugada syndrome. PMID- 20960619 TI - Gene symbol: KCNQ1. Disease: Long QT syndrome. PMID- 20960620 TI - Gene symbol: KCNH2. Disease: Long QT syndrome. PMID- 20960621 TI - Gene symbol: MAP2K2. Disease: Cardio-Facio-Cutaneous syndrome. PMID- 20960622 TI - Gene symbol: LAMC2. Disease: Epidermolysis Bullosa, Herlitz. PMID- 20960623 TI - Gene symbol: ABCA4. Disease: Macular dystrophy. PMID- 20960624 TI - Gene symbol: ABCA4. Disease: Macular dystrophy. PMID- 20960625 TI - Gene symbol: AVP. Disease: Diabetes Insipidus, neurohypophyseal. PMID- 20960627 TI - Gene symbol: IDS. Disease: Mucopolysaccharidosis II. PMID- 20960628 TI - Gene symbol: ABCA4. Disease: Macular dystrophy. PMID- 20960629 TI - Gene symbol: IDS. Disease: Hunter syndrome. PMID- 20960631 TI - Gene symbol: FECH. Disease: Porphyria, Erythropoietic. PMID- 20960632 TI - Gene symbol: ABCA4. Disease: Macular dystrophy. PMID- 20960633 TI - Gene symbol: ABCA4. Disease: Macular dystrophy. PMID- 20960634 TI - Gene symbol: EDA. Disease: Ectodermal dysplasia. PMID- 20960636 TI - Gene symbol: EDA. Disease: Ectodermal dysplasia. PMID- 20960637 TI - Gene symbol: EDA. Disease: Ectodermal dysplasia. PMID- 20960638 TI - Gene symbol: MEN1. Disease: Multiple endocrine neoplasia 1. PMID- 20960639 TI - Gene symbol: ARX. Disease: Mental retardation. PMID- 20960640 TI - Gene symbol: CHD7. Disease: CHARGE syndrome. PMID- 20960641 TI - Gene symbol: CYP21A2. Disease: Adrenal hyperplasia. PMID- 20960642 TI - Gene symbol: CYP21A2. Disease: Adrenal hyperplasia. PMID- 20960643 TI - Gene symbol: CYP21A2. Disease: Adrenal hyperplasia. PMID- 20960644 TI - Gene symbol: MAP2K1. Disease: Cardio-Facio-Cutaneous syndrome. PMID- 20960645 TI - First reduce harm: tackling HIV in Ukraine. PMID- 20960646 TI - Nuclear tests leave Kazakhstan still searching for answers. PMID- 20960647 TI - Gene symbol: RS1. Disease: Retinoschisis, X-Linked juvenile. PMID- 20960648 TI - Empowering brain science with neuroethics. PMID- 20960650 TI - Gene symbol: GCDH. Disease: Glutaricacidaemia I. PMID- 20960651 TI - Gene symbol: GNE. Disease: Inclusion body myopathy. PMID- 20960653 TI - The great brain drain. By Caveman. PMID- 20960652 TI - Gene symbol: CLN5. Disease: Neuronal Ceroid Lipofuscinosis, finnish variant. PMID- 20960654 TI - Posterior instrumentation, reduction and fusion in spondyloptosis. PMID- 20960655 TI - Gene symbol: TPP1. Disease: Neuronal Ceroid Lipofuscinosis, late infantile. PMID- 20960656 TI - Surgery for cervical stenosis: anterior cervical decompression, corpectomy, and fusion. PMID- 20960657 TI - Direct screw fixation of the spondylolysis without fusion. PMID- 20960658 TI - Gene symbol: MEN1. Disease: Multiple endocrine neoplasia type 1. PMID- 20960659 TI - Gene symbol: CYP21A2. Disease: Non-classic 21-Hydroxylase deficiency. PMID- 20960660 TI - Gene symbol: HBD. Disease: Thalassaemia delta. PMID- 20960661 TI - Gene symbol: CLN5. Disease: Neuronal Ceroid Lipofuscinosis, Finnish Variant. PMID- 20960662 TI - Gene symbol: NOTCH3. Disease: CADASIL. PMID- 20960663 TI - Gene symbol: NOTCH3. Disease: CADASIL. PMID- 20960664 TI - Gene symbol: MECP2. Disease: Rett syndrome. PMID- 20960665 TI - Gene symbol: ABCA4. Disease: Stargardt disease. PMID- 20960666 TI - Physical health and mental illness--taking action to bridge the gap. PMID- 20960667 TI - TN: RN testified re hospital nursing standards: judgment v. pt. who signed out AMA affirmed. Luna v. Deversa, E2009-01198-COZ-R3 TNCIV (6/17/2010)-TN. PMID- 20960668 TI - Assessment: symptomatic treatment for muscle cramps (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. PMID- 20960669 TI - [Do you really understand your patients?]. PMID- 20960670 TI - [Biologics in rheumatology. Targeted therapy--and what must be considered]. PMID- 20960671 TI - [Naturopathy consultation. Metabolic syndrome]. PMID- 20960672 TI - Depth charges. PMID- 20960673 TI - New insights into climate carbon. PMID- 20960674 TI - Beefing up biodiversity issues. PMID- 20960675 TI - Extreme insects. PMID- 20960676 TI - Diversity worries. PMID- 20960677 TI - Peter J. Hollenbeck. PMID- 20960678 TI - Pharmacokinetics of etravirine, raltegravir and darunavir/ritonavir in treatment experienced patients. AB - Etravirine is an enzyme inducer and could lower the concentration of combined drugs. Ten HIV-1-infected patients with multiple treatment failure received raltegravir (400 mg, twice daily) and darunavir/ritonavir (600/100 mg, twice daily). Addition of etravirine (200 mg, twice daily) leads to a significant increase in raltegravir and darunavir trough concentrations (405 vs. 118 and 3837 vs. 2241 ng/ml) and darunavir area under the curve (AUC(12h)) (50 083 vs. 36 277 ng h/ml). All pharmacokinetic parameters appeared to be highly variable regardless to the addition of etravirine. PMID- 20960679 TI - Interest of chest ultrasonography in the detection of exercise-induced pulmonary edema. PMID- 20960680 TI - Edema in athletes vs. interstitial edema in anyone. PMID- 20960681 TI - Pulmonary edema during breath-hold diving immersion. PMID- 20960682 TI - Pulmonary edema in athletes: methodology or meaningful physiology? PMID- 20960683 TI - Exercise-induced pulmonary edema in the athlete, or couch potato? PMID- 20960684 TI - Pulmonary edema following exercise: an individual response? PMID- 20960685 TI - The exercise-induced pulmonary edema story doesn't hold water. PMID- 20960686 TI - Interstitial edema does occur with limited adverse effect in the long term. PMID- 20960687 TI - Exercise-induced pulmonary edema-the debate continues. PMID- 20960688 TI - Technology trends.Study finds little progress in EHR implementation. PMID- 20960690 TI - Person-centered care: at the core of assisted living. PMID- 20960689 TI - Frailty: an indication for palliative care. AB - Chronological age alone does not determine the vulnerability or frailty of an older adult.Frailty can, however, profoundly affect the quality of an older adult's life. Frail adults could benefit from palliative care provided by an interdisciplinary team. The principles of palliative care apply to any population that could benefit from a comprehensive, person-centered plan of care from the time of diagnosis through the illness trajectory. This article presents a conceptual overview of frailty and describes its clinical presentation and treatment options, including palliative care, an intervention used by gerontological nurses to improve the quality of life for frail older adults. PMID- 20960691 TI - Surgical observation unit creates safer environment for older adult patients at NICHE-designated hospital. An Interview with Pamela E. Windle,by Scott Bugg. PMID- 20960692 TI - Cytochrome P450: drug metabolism--why it's so important to understand. PMID- 20960693 TI - Serotonin syndrome: what is it? causes, recognition, and management. PMID- 20960694 TI - More drugs equal more problems: polypharmacy in elders--more problems than benefits? PMID- 20960695 TI - Sensitivity versus specificity of PennHIP as a screening test for osteoarthritis. PMID- 20960696 TI - Prognostic factors after repair of open globe injuries. PMID- 20960697 TI - That's not self-contracting. PMID- 20960698 TI - Why GPOs matter more now. PMID- 20960700 TI - Abstracts of the Summer 2008, Winter 2008, Summer 2009 & Winter 2009 Scientific Meetings of the Faculty of Public Health Medicine of the Royal College of Physicians of Ireland. May 27-28, 2008, December 10, 2008, May 26-27, 2009, and December 9, 2009. Dublin, Ireland. PMID- 20960699 TI - Quality & safety. 'This is about changing the way we lead'. PMID- 20960701 TI - Direct-to-consumer genetic testing kits. You send in a sample and get your results online. But is it worth the price? PMID- 20960702 TI - Midurethral sling surgery for stress incontinence. A minimally invasive approach is now the norm for treating this common urinary problem. PMID- 20960703 TI - The antidepressant citalopram cuts hot flash severity and frequency. PMID- 20960704 TI - Indoor tanning is strongly linked to melanoma risk. PMID- 20960705 TI - By the way, doctor. I suffer from blepharitis and have tried many medications, but the condition always returns. How can I cure it? PMID- 20960706 TI - [Differences in cytoarchitecture of speech-motor areas of the cerebral cortex between men and women]. AB - Cerebral cortex cytoarchitecture of speech-motor areas 44 and 45 in the left and right hemispheres of brain of men and women has been studied. Series of frontal sections stained with cresyl violet using Nissl's method have been investigated. In layer III, the surface of profile area of neurons, its width and the width of the whole cortex diameter have been measured. No significant differences of these values between men and women were detected. However, there was a clear tendency of increased values of these parameters in the left hemisphere in men, as compared with women, while women had highest values in the right hemisphere. PMID- 20960707 TI - [Pathologic changes of neurons of mesocorticolimbic dopaminergic system in healthy humans and rats]. AB - The purpose of the present study was to demonstrate pathologically changed forms of neurons and intensity of the neuronoglial interactions which represented the normal standard for the interconnected parts of mesocorticolimbic dopaminergic system (MDS) in 6 intact adult female Wistar rats and in 5 healthy humans aged 24 45 years. The percentages of unchanged, hypochromic, pyknomorphic and ghost neurons in proportion to their total number were determined in the anteromedial part of paranigral nucleus of ventral tegmental region of midbrain tegmentum (TVR), compact part of black substance (BS), anteromedial part of accumbent nucleus (NA) close to anterior brain commissure and in middle of layer III of a pregenual part of field 24b (Cg3 in rats). The structures of the brain, unrelated to MDS--layers III and V of field 1--were investigated as the control. The data obtained indicate significant changes of MDS neurons in the healthy people as compared to those in the intact rats. The number of pathologically changed MDS neurons, as well as the number of fibers in medial forebrain bundle, were shown to decrease with the increase of distance from catecholaminergic nuclei of reticular formation, reaching the minimum in non-dopaminoceptive and low noradrenoceptive layer V of field 1. More than 25% of the neurons in TVR paranigral nucleus were ghost cells. Over 30% of NA neurons were hypochromic and ghost cells. About 25% of neurons in field 24b were ghost cells, hypochromic and pyknomorphic. The intensity of neuronoglial interaction in human and rat dopaminergic nuclei is significantly greater than in the projectional parts of MDS and in the layers of field 1, unrelated to it. Local changes of MDS neurons in man and high intensity of neuronoglial interactions in dopaminergic nuclei reflect the blurring of the boundaries between the normal state and pathology and lower durability of this system, as compared to that of the cortical fields remote from the source of catecholaminergic fibers. PMID- 20960708 TI - [Quantitative characteristic of primary structural modules in relay nuclei of thalamic sensory systems in man]. AB - The module organization of neurons was studied in ventral posterior medial (VPM) and ventral posterior lateral (VPL) relay nuclei of thalamic sensory systems in adult man. Material, obtained from individuals aged 48-70 years, was fixed in 4% paraformaldehyde, sectioned at 40 microm and stained using Kluver-Barrer's method. The following parameters were determined: the numbers of neurons forming group and chain modules, profile field areas (PFA) of cell bodies of neurons forming modules, total number of satellite gliocytes and identified gliocytes (oligodendrocytes and astrocytes) in the module. Neuronal PFA was measured using digitizer on exact drawings of the cells made with the drawing device (at magnification of 1025). The data obtained were fed into the computer and processed using the program of non-parametric data analysis. Neurons, forming group and chain modules, were of medium size (201 to 350 microm2) in both nuclei. Most of group and chain modules in human VPM and VPL thalamic nuclei consisted of 3-4 cells. In VPM nucleus, a single group module includes 8.4 satellite gliocytes, and a chain module - 8.6 gliocytes. In VPL nucleus these parameters are equal to 7.7 and 8.2, respectively. Oligodendrocyte number in the modules in VPM and VPL thalamic nuclei is 3 times greater than that of the astrocytes. PMID- 20960709 TI - [Cellular aspects of regulation of nuclear factor kappaB (NF-kappabeta) transcriptional activity in sensory neurons in vitro]. AB - Nuclear factor kappaB (NF-kappaB) controls the expression of multiple anti/proapoptotic genes, including those in the nervous cells. Intranuclear deacetylation and acetylation events are implicated in the regulation of NF kappaB transcriptional activity. The goal of the work was to demonstrate the transcriptional activity of NF-kappaB in the sensory neurons in vitro and to find out whether NF-kappaB activity could be controlled by modification of acetylation processes, using a transgenic line of NF-kappaB reporter mice in which activation of NF-kappaB drives the expression of the lac-z gene. We show that the expression of the reporter gene was absent in transgenic neurons cultured in normal growth medium or stimulated by TNF-alpha. However, NF-kappaB transcriptional activity in most neurons was induced by in vitro exposure to Trichostatin A, which is a specific inhibitor of histone deacetylases. Taken together our results show that the transcriptional activity of NF-kappaB is limited in sensory neurons due to a transcriptional repression mechanism mediated by histone deacetylases. PMID- 20960710 TI - [Variant anatomy of the anterior tibial veins and its clinical implications]. AB - Variant anatomy of the anterior tibial veins (ATV) was studied using 22 preparations of the lower extremities of men and. The great variability of the ATV anatomic patterns was established, which was characterized by the presence of numerous anastomoses between the main trunks and lengthy regions of duplication, creating an impression of a larger number of venous trunks. In most specimens, ATV were observed to originate as two main trunks. In 34% of cases veins had a scattered pattern. Perforating veins of the anterior musculofascial compartment penetrated the fascia in two main directions. Most frequently perforators appeared at the border between the lower and the middle thirds of the calf and between the upper and the middle thirds, their frequency amounting to 18.1% at both levels. In 45.5% of the samples, the tributaries were found that connected ATV with deep venous system of the back of the calf. The results obtained allow to plan the interventions on perforators of the anterior musculofascial compartment and ATV. PMID- 20960711 TI - [Echinocytosis and changes of medium weight molecules content in endo- and exogenous intoxications]. AB - The purpose of this study was to detect the interrelationship between the increased serum concentration of the medium weight molecules (MWM) and echinocytosis, to establish the rate of echinocyte appearance in blood in endogenous and exogenous intoxications and the dependence of echinocytosis on phosphacol and carbophos doses or the degree of endogenous intoxication. Two series of studies were conducted. In the 1st series, the experiments were conducted on outbred albino rats. Rats of the 1st group received phosphacol in doses equal to 0.5, 5.0 and 50 LD50, while the rats of the 2nd group were given carbophos in doses equal to 0.1 and 1.0 LD50. In the 2nd series, the blood of cats with chronic renal failure at uremic stage was studied (as an example of endogenous intoxication). In all the animals, serum MWM concentrations were measured together with the relative echinocyte content and echinocytes were examined with electrone microscope. The ability of MWM to influence erythrocyte deformation was evaluated. Increased MWM concentrations and echinocyte content was found in association with the increase of intoxication severity, while echinocyte percentage in cats' blood was augmented under the action of MWM. PMID- 20960712 TI - [Differentiation of calf skeletal muscles in the postnatal period of ontogenesis]. AB - The aim of the present investigation was to detect the regularities of postnatal development of "motor end-plate-muscle fiber (MF)-vascular network" system in different calf muscles of intact albino rats. Gastrocnemius, plantaris and soleus muscles were studied in 72 albino rats aged from 14 to 180 days. Identification of MF type was performed on the basis of succinate dehydrogenase and NADH diaphorase activity. Cholinesterase activity of the neuro-muscular synapse (NMS) and alkaline phosphatase activity in the vascular endothelium were demonstrated using a combined histochemical method. The diameter of vascular network and the number of enzyme-active zones (EAZ) per one MF were the earliest parameters to be stabilized (before day 30). Histochemical profile of skeletal muscle was stabilized by the end of day 60. Dynamics of MF diameter and EAZ in NMS, vessel diameter and numbers per one MF is characterized by the periods of active changes (days 14-30), decrease (days 30-60) and stabilization (after day 60) of variance rate. The association between the level of oxidative metabolism and MF diameter was demonstrated. PMID- 20960713 TI - [The peculiarities of esophageal epithelium of the vertebrates in phylogenesis and Barrett's esophagus]. AB - The esophageal epithelium of vertebrates was studied in phylogenetic aspect and in patients with Barrett's esophagus (BE). The comparative investigation was undertaken to detect phylogenetic recapitulations in the course of BE development. The complex of histochemical methods for selective demonstration of mucins and proteins was used. It was shown that in the phylogenetic series amphibians-reptiles-mammals, the formation of a protective barrier occurred in different ways. In BE, within the areas of metaplasia and dysplasia, partial recapitulation of a histochemical type of protective barrier, peculiar to the esophagus of amphibians and reptiles, seems to take place. PMID- 20960714 TI - [Histological and ultrastructural changes in the liver in experimental pulmonary trunk stenosis at the stage of decompensation]. AB - Pulmonary trunk stenosis was modeled in 25 dog puppies. Structural changes of liver were examined in 8 animals with circulatory decompensation and in 10 control dogs. Material was studied using histological, morphometric, stereometric and electron microscopical methods. Results showed that in decompensated pulmonary trunk stenosis with the hypoxia, the relaxation of the walls of both afferent and efferent hepatic vessels took place, the numbers and the degree of development of arterial adaptational structures (intimal musculature, muscular elastic sphincters, and polypoid cushions) was reduced, while muscular bolsters in large and medium-sized vessels belonging to hepatic veins system, became atrophic. The adaptational mechanisms failure resulted in the development of chronic hepatic venous plethora. PMID- 20960715 TI - [Cellular-differon organization of vaginal wall muscular tissues in mammals]. AB - Complex histological analysis of vaginal wall muscular tissues was carried out in several species of laboratory animals (mature rats, cats, dogs) and humans. The muscular tunic of vaginal wall was found to be represented by two types of tissue: striated and smooth muscle. Striated muscular tissue of vagina has specific features and consists of two cellular differons: myosymplasts and satellite cells. The smooth muscular tissue is formed by a single cellular differon, in which undifferentiated, differentiating and differentiated cells could be distinguished. Phenotypically, within vaginal smooth muscular tissue, contractile and contractile-secretory smooth myocytes were demonstrated. PMID- 20960716 TI - [Sex- and age-related peculiarities of the morphometric characteristics of the lower part of facial skull in the adult persons]. AB - Age-related changes and sexual differences of some of the morphometric characteristics of the lower part of facial skeleton were studied. It was shown that the height of the face lower part in the skulls with intact orthognathic occlusion remained unchanged during the age period from 22 to 70 years. In both men and women with full dentition and orthognathic occlusion aged from 22 to 35 years, the significant decrease was observed in the angle of the ramus of mandible due to the bone tissue formation in this region. The parameters of the height of the ramus of mandible, the projection height of the mandibular condylar process, and the least width of the mandibular ramus in men and women have significant age- and sex-related differences. PMID- 20960717 TI - [Anatomical peculiarities of transcranial approach to the orbital cavity]. AB - The purpose of this work was to study the anatomical features of transcranial approach to the cranioorbital area and the orbital cavity. The preparation of 32 orbits obtained from 16 human cadavers fixed in formalin, was performed. In the anatomical study, typical fronto-temporal extradural approach to the anterior cranial fossa was used, together with the micropreparation of the orbital structures from 3 intermuscular approaches. It was demonstrated that at different stages of transcranial approach, its parameters were mainly influenced by either craniometric indices, or anatomical peculiarities of orbital nerves and vessels position. The data obtained allow to plan the surgical intervention on the basis of results of radiological study and the data on frequency of various anatomical variants of an arrangement of ophthalmic artery branches. PMID- 20960718 TI - [Secular trend of bone mineral content decrease in human bone tissue: analysis of the data from Ural region]. AB - Bone mineral content in rib samples from Ural region residents was analyzed depending on donors' gender, age and year of birth. Bone mineral content, that reflects the mineral density, was estimated as gram of minerals per 1 kg of wet bone mass. The period of sampling and measurements covered 1958-1988, the age of donors ranged from newborn to 99 years, birth years varied from 1872 to 1984, and the total number of samples was equal to 4685. A decrease in bone mineral density during 1958-1988 period was found in groups of close ages but different years of birth indicating an existence of the secular trend. For people born before 1920, the trend was insignificant. For people born in later years, a continuous decrease in bone mineral content was observed in groups of the same ages with an average rate of 3 g/kg per year, which is about 1% per year. Longitudinal and cross-sectional studies of bone mineral density provide different estimates of age dependent rate of bone mineral loss, and these values may differ by a factor of two. Different generations, i.e. people born in different periods of the XX century, have age-dependent features of bone mineral density specific for their groups. PMID- 20960719 TI - [Application of semi-conducting nanocrystals (quantum dots) in immunocytochemistry]. AB - Semi-conducting nanocrystals represent a new class of fluorescent inorganic objects which have a promising perspective for the application in biology and medicine. The aim of the current work was a determination of advantages and shortcimingss of quantum dots (QD) application in immunocytochemistry. It was shown that streptavidin-QD conjugates have more advantages (i.e. high intensity of fluorescence, photostability, wide excitation range, short and symmetric emission range) as compared to streptavidin conjugates with organic fluorochromes. This allows to recommend the use of QD in immunocytochemical studies. However, there are several disadvantages (like lower stability during long-term storage as compared to that one of organic fluorochrome conjugates, poor safety of aliquots, impossibility of long-term preservation of fluorescence of stained sections during their storage, incompatibility with several commercial mounting media) that limit the widespread application of nanocrystals in immunocytochemical studies. PMID- 20960720 TI - [Contribution to the discussion on syncytial connections in the nervous system]. AB - The paper discusses data on the existence of the syncytial interneuronal connections. Firstly, the discovery of synapses in principle is not a proof of the absence of syncytial connections in the nervous system. Secondly, there is a light microscopical evidence of the existence of the syncytial connections. These are found in giant axons of crustaceans, polychaetes, and other invertebrates, as well as during similar fusion of 2-3 processes into one fiber covered with myelin sheath in vertebrate neurons. In tissue culture, after the destruction of the neuronal body, its process connected to another neuron does not die, as it has syncytial connection with the latter. Thirdly, under the electron microscope, interneuronal syncytial connections were demonstrated in piglet intramural nervous system, in cat caudal mesenteric ganglion, in rabbit and frog hippocampus and cerebellum, and in cat cerebral cortex. Structural regularities of such connections have been described. By observing changes of contacting membranes in pathology, it was established that the essence of the process consists in a modification of tight junctions which are not refuted by anyone. The syncytial pores and perforations are also observed in intact animals in neurons without obvious lesions. PMID- 20960721 TI - [Some aspects of educational process at the Department of Histology of the Medical University in association with the formation of students' contingent on the basis of the results of Uniform State Exam]. PMID- 20960722 TI - [Department of Histology of Military Medical Academy during the Great Patriotic War (the contribution to the doctrine on the development and regeneration of tissues)]. PMID- 20960723 TI - [The double taboo]. PMID- 20960724 TI - [Drum beat in Munster: social court declares nursing care grades unlawful: six! Sit down!]. PMID- 20960725 TI - [PDLer talks clear text about the upcoming end of civil service: "We are left alone with many questions"]. PMID- 20960726 TI - [Mind-body interaction in the aging process: living with autonomy and dignity]. PMID- 20960727 TI - [Incontinence taboo - an ethical observation: structural problems delegated to nurses]. PMID- 20960728 TI - [Home nursing care: growing gap between wish and reality]. PMID- 20960729 TI - [5 frequent misconceptions for incontinence management in nursing: the big incontinence mistakes]. PMID- 20960730 TI - [Incontinence in patients with dementia: "between shame, helplessness and anger"]. PMID- 20960731 TI - [Promoting continence in nursing with a new special formula: risk properly assessed]. PMID- 20960732 TI - [Acquiring knowledge: errors - keys to the treasure chest!]. PMID- 20960733 TI - [Operation and procedure key (OPS) in psychiatry: nursing assume input for hospital budget]. PMID- 20960734 TI - [Minor responsibility - mini-job: equal rights, equal responsibilities]. PMID- 20960735 TI - [About the turning point in a nurse's life when giving up the profession. A qualitative-empirical study on the willingness to continue to work and on the conditions for continuing to work in the post-professional phase of life]. AB - Due to the increasing life expectancy and population ageing, the post professional phase of life is becoming more and more important to the individual and to society as a whole. The perception of the potentials of elderly people and, hence, the call for self-directed and independent activities in the post professional phase are becoming more intense. The relation between retirement and work in nurses has not been of scientific importance so far. This is primarily due to the assumption that nurses cannot or do not stay in their profession until retirement. However, nurses do manage to pursue their profession continuously and permanently until they reach the age of retirement. The aim of this qualitative research study is to investigate the post-professional phase of life of former nurses within the context of the profession pursued. The guiding research questions in this regard were: How do former nurses spend their retirement period? How do nurses use their nursing-related abilities and experiences in their postprofessional phase of life? What do nurses associate with their former profession in the post-professional phase of life? In one-to-one interviews, these questions were posed to eight retired nurses who had pursued their profession for many years. The assessment instruments used were a socio demographic questionnaire, a guideline and a record from memory. All data were summarized and evaluated analytically with regard to their content according to Mayring (2008). The present article shows the partial results of the study on retirement and work in the post-professional life of nurses. The results indicate that the transition to retirement is often accompanied by problems, that retired nurses do not fundamentally refuse to continue to work and that the willingness to continue to work is subject to certain conditions. Reasons and conditions for and against profession-based post-professional activities were revealed. Consequentially, concepts for the systematic identification of potentials of nurses in their post-professional phase of life should be developed. PMID- 20960736 TI - [Reconsidering structures: faculty training in health care: single path versus versatility]. PMID- 20960737 TI - [Dealing with ethically complex topics in training - preimplantation diagnosis: communicating not only abstract but also emotional aspects]. PMID- 20960738 TI - [From case to case: proper management of urinary and fecal incontinence]. PMID- 20960739 TI - [Overview: cytokine groups and their functions--pathophysiological roles of cytokines in diseases]. PMID- 20960740 TI - [Prostaglandin D2 and related substances]. PMID- 20960741 TI - [Prostaglandin E1, E2 and their metabolites]. PMID- 20960742 TI - [Prostaglandin F2alpha]. PMID- 20960743 TI - [Prostaglandin I2 and its metabolites]. PMID- 20960745 TI - [MIP-1alpha, MIP-1beta]. PMID- 20960744 TI - [Leukotriene (B4, C4, D4, E4)]. PMID- 20960746 TI - [Macrophage chemotactic factor and macrophage migration inhibitory factor]. PMID- 20960748 TI - [Macrophage colony-stimulating factor]. PMID- 20960747 TI - [Granulocyte colony-stimulating factor (G-CSF)]. PMID- 20960749 TI - [SCF(stem cell factor)]. PMID- 20960750 TI - [Interleukin-1(IL-1) alpha, beta, IL-1 receptor (IL-1R), IL-1 receptor antagonist (IL-1ra)]. PMID- 20960751 TI - [Interleukin-2(IL-2) and its receptor]. PMID- 20960752 TI - [Interleukin-3(IL-3), IL-4, IL-5]. PMID- 20960753 TI - [Interleukin-6 (IL-6)/soluble IL-6 receptor(sIL-6R)]. PMID- 20960754 TI - [Interleukin-7, 8, 9, 10(IL-7, 8, 9, 10)]. PMID- 20960755 TI - [Lymphotoxin (TNF-beta)]. PMID- 20960756 TI - [Interferon (IFN)-alpha, beta, gamma]. PMID- 20960757 TI - [Vascular endothelial growth factor (VEGF)]. PMID- 20960758 TI - [Epidermal growth factor (EGF)]. PMID- 20960759 TI - [Basic fibroblast growth factor (FGF-2)]. PMID- 20960760 TI - [HGF levels in serum, cerebrospinal fluid, joint fluid, tissues and various diseases]. PMID- 20960761 TI - [Brain-derived neurotrophic factor (BDNF)]. PMID- 20960762 TI - [Leukemia inhibitory factor (LIF)]. PMID- 20960763 TI - [HMGB1]. PMID- 20960764 TI - [Chemokines]. PMID- 20960765 TI - [Galectin]. PMID- 20960766 TI - [Osteoprotegerin (OPG)]. PMID- 20960767 TI - [Immunoglobulin superfamily (ICAM, VCAM, NCAM, L1, nectin)]. PMID- 20960768 TI - [Integrin family]. PMID- 20960769 TI - [Selectin family (E-selectin, P-selectin, L-selectin)]. PMID- 20960770 TI - [Cadherin family]. PMID- 20960771 TI - [Desmoglein]. PMID- 20960772 TI - [Growth hormone-binding protein (GHBP)]. PMID- 20960773 TI - [Insulin-like growth factor binding protein-1, 2, 3 (IGFBP-1, 2, 3)]. PMID- 20960774 TI - [Pituitary glycoprotein hormone alpha subunit]. PMID- 20960775 TI - [Adrenocorticotropic hormone (ACTH)]. PMID- 20960776 TI - [Melanin-concentrating hormone]. PMID- 20960777 TI - [Prolactin]. PMID- 20960778 TI - [Prolactin-releasing peptide (PrRP)]. PMID- 20960779 TI - [Vasopressin (AVP)]. PMID- 20960780 TI - [Neurophysin]. PMID- 20960781 TI - [Neurotensin]. PMID- 20960782 TI - [Thyrostimulin]. PMID- 20960783 TI - [Total thyroxine (T4), free thyroxine (FT4)]. PMID- 20960784 TI - [Monoiodothyronine (T1), diiodothyronine (T2)]. PMID- 20960785 TI - [Thyroglobulin (Tg)]. PMID- 20960786 TI - [Anti-TSH receptor antibody(TRAb, TBII, TSAb)]. PMID- 20960787 TI - [Antithyroglobulin antibodies]. PMID- 20960788 TI - [Antimicrosomal antibodies and thyroid peroxidase antibodies (TPOAb)]. PMID- 20960789 TI - [Parathyroid hormone (PTH)]. PMID- 20960790 TI - [Parathyroid hormone-related protein (PTHrP)]. PMID- 20960791 TI - [Cortisol, cortisone, urinary free cortisol]. PMID- 20960792 TI - [Corticosterone, deoxycorticosterone]. PMID- 20960793 TI - [18-Hydroxycorticosterone (18-OH-B)]. PMID- 20960794 TI - [DHEA, DHEA-S]. PMID- 20960795 TI - [Pregnenolone, pregnenolone sulfate]. PMID- 20960796 TI - [17alpha-Hydroxyprogesterone]. PMID- 20960797 TI - [Androstenedione]. PMID- 20960798 TI - [Androsterone, etiocholanolone]. PMID- 20960799 TI - [11-Hydroxycorticoid, 17-hydroxycorticoid]. PMID- 20960800 TI - [Corticosteroid-binding globulin (CBG): measurement and its clinical implication]. PMID- 20960801 TI - [Urinary 17-ketosteroids(17-KS) and 17-KS fractions]. PMID- 20960802 TI - [Urinary 17-ketogenic steroids (17-KGS) and 17-KGS fractions]. PMID- 20960803 TI - [Urinary tetrahydro-11-deoxycortisol]. PMID- 20960804 TI - [Catecholamine, three fractions of catecholamines, three fractions of free catecholamines]. PMID- 20960805 TI - [3,4-Dihydroxyphenyl alanine (DOPA)]. PMID- 20960806 TI - [3,4-Dihydroxyphenylacetic acid (DOPAC)]. PMID- 20960807 TI - [Dopamine]. PMID- 20960808 TI - [Dopamine -beta-hydroxylase]. PMID- 20960809 TI - [3-Methoxy-4 -hydroxyphenylglycol (MHPG)]. PMID- 20960810 TI - [Chromogranin A, chromogranin B, chromogranin C]. PMID- 20960811 TI - [Serotonin (5-hydroxytriptamin, 5HT)]. PMID- 20960812 TI - [Estrogen: estrone (E1), estradiol (E2), estriol (E3) and estetrol (E4)]. PMID- 20960813 TI - [Pregnanediol (P2), pregnanetriol (P3)]. PMID- 20960814 TI - [Total testosterone, free testosterone]. PMID- 20960815 TI - [5alpha-Dihydrotestosterone (DHT)]. PMID- 20960816 TI - [Androstanediol, androstanediol glucuronide]. PMID- 20960817 TI - [Placental leucine aminopeptidase (P-LAP)]. PMID- 20960818 TI - [Inhibin.activin]. PMID- 20960819 TI - [Antimullerian hormone (AMH)]. PMID- 20960820 TI - [Androgen receptor]. PMID- 20960821 TI - [Normal and abnormal insulin]. PMID- 20960822 TI - [C-peptide]. PMID- 20960823 TI - [Insulin receptor substrate (IRS)]. PMID- 20960824 TI - [Ghrelin measurement]. PMID- 20960825 TI - [Pancreatic glucagon (IRG), enteroglucagon (EG)]. PMID- 20960826 TI - [Cholecystokinin-pancreozymin (CCK-PZ)]. PMID- 20960827 TI - [Substance P]. PMID- 20960828 TI - [Motilin]. PMID- 20960829 TI - [Pancreatic polypeptide (PP)]. PMID- 20960830 TI - [Enterostatin, galanin, and GRP]. PMID- 20960831 TI - [Gastric inhibitory polypeptide (GIP)]. PMID- 20960832 TI - [Insulin antibody]. PMID- 20960833 TI - [Insulin receptor antibody]. PMID- 20960834 TI - [Islet cell antibody (ICA), islet cell surface antibody (ICSA)]. PMID- 20960835 TI - [Zinc transporter 8 (ZnT8) antibody]. PMID- 20960836 TI - [Anti glutamic acid decarboxylase (GAD) antibody]. PMID- 20960837 TI - [Islet amyloid polypeptide]. PMID- 20960838 TI - [Plasma renin activity (PRA) and active renin concentration (ARC)]. PMID- 20960839 TI - [Erythropoietin]. PMID- 20960840 TI - [Atrial natriuretic peptide(ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP)]. PMID- 20960841 TI - [Endothelin]. PMID- 20960842 TI - [Melatonin]. PMID- 20960843 TI - [Adrenomedullin]. PMID- 20960844 TI - [Urotensin II]. PMID- 20960845 TI - [Thrombopoietin (TPO)]. PMID- 20960846 TI - [Salusin-alpha, -beta]. PMID- 20960847 TI - [Measurement of alpha-fetoprotein with L3 fraction in the early diagnosis of patients with hepatocellular carcinoma]. PMID- 20960848 TI - [Carcinoembryonic antigen (CEA)]. PMID- 20960849 TI - [CEA in nipple discharge]. PMID- 20960850 TI - [The characteristics of CA125/MUC16]. PMID- 20960851 TI - [CA19-9, CA242]. PMID- 20960852 TI - [CA546, CA602]. PMID- 20960853 TI - [STN (sialyl Tn antigen)]. PMID- 20960854 TI - [2 --> 6 sialyl Le(a) antigen]. PMID- 20960855 TI - [BCA225]. PMID- 20960856 TI - [SLX(sialyl SSEA-1, sialyl Le(x)-i)]. PMID- 20960857 TI - [NCC-ST-439]. PMID- 20960858 TI - [Squamous cell carcinoma antigen]. PMID- 20960859 TI - [DU-PAN-2, SPan-1]. PMID- 20960860 TI - [KMO1]. PMID- 20960861 TI - [Prostate-specific antigen(PSA), PSA-ACT, free PSA and F/T]. PMID- 20960862 TI - [Prostatic acid phosphatase (PAP)]. PMID- 20960863 TI - [Tissue polypeptide antigen]. PMID- 20960864 TI - [Nonspecific cross-reacting antigen (NCA)--carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6)]. PMID- 20960865 TI - [Immunosuppressive acidic protein (IAP)]. PMID- 20960866 TI - [Neuron specific enolase]. PMID- 20960867 TI - [Elastase-1]. PMID- 20960868 TI - [5'-nucleotide phosphodiesterase isozyme -V (5' -NPD-V)]. PMID- 20960869 TI - [GAT(galactosyltransferase associated with tumor)]. PMID- 20960870 TI - [Small intestinal mucin antigen (SIMA)]. PMID- 20960871 TI - [Pregnancy specific beta1 glycoprotein (SP-1)]. PMID- 20960872 TI - [Pepsinogen I and pepsinogen II, PG I/II ratio]. PMID- 20960873 TI - [Neopterin]. PMID- 20960874 TI - [Urinary diacetylspermine]. PMID- 20960875 TI - [Pro-gastrin-releasing peptide (ProGRP)]. PMID- 20960876 TI - [Estrogen and progesterone receptors]. PMID- 20960877 TI - [Human urinary trypsin inhibitor]. PMID- 20960878 TI - [Urinary free fucose (UFC) and urinary sulfated bile acids (USBA)]. PMID- 20960879 TI - [Urinary melanogen]. PMID- 20960880 TI - [Urinary BTA (bladder tumor antigen)]. PMID- 20960881 TI - [Serum p53 antibody--diagnosis and monitoring for cancer]. PMID- 20960882 TI - [Assessment of serum GPC3 as a tumor marker for hepatocellular carcinoma and malignant melanoma]. PMID- 20960883 TI - [Palmitoleic acid and oleic acid]. PMID- 20960884 TI - [Lysophospholipids]. PMID- 20960885 TI - [Fetuin-A, alpha2-Heremans-Schmid glycoprotein (AHSG)]. PMID- 20960886 TI - [SLOX-1 (soluble lectin-like oxidized low-density lipoprotein receptor-1)]. PMID- 20960887 TI - [A novel cardiovascular marker: pentraxin 3]. PMID- 20960888 TI - [Placental growth factor (PlGF)]. PMID- 20960890 TI - [Malposition of epidural catheter: an 8-year retrospective analysis on an incident reporting system at an urban university hospital]. AB - Epidural anesthesia is widely used in patients who undergo thoracic, abdominal or lower extremity surgeries and generally considered useful for perioperative analgesic management. Epidural catheterization is often associated with some complications including misplacement of the catheter. Epidural catheters are known to be misplaced or migrate into subarachnoidal space, subdural space, vessels and thoracic cavities ; however, frequency, predominant sites of misplacement, and the timing of detection are not fully understood regarding the misplacement of the catheters. In this retrospective study, our incident reporting system dealt with a period of 8 years (from 1999 to 2007) at our university hospital. Out of 8 patients who had misplacement of the catheter, 6 patients were male and 2 patients were female. Epidural catheters were misplaced to subarachnoid space in 6 cases and thoracic cavity in 2 cases. The misplacement of the catheters was found before the induction of general anesthesia in 2 patients, after induction of general anesthesia in 1 patient, during surgical procedure in 3 patients, and postoperatively in 2 patients. Since misplacement of epidural catheters can occur at any moment during perioperative period, continuous monitoring and observation of patients seem to be very important to prevent and minimize the adverse events related to the misplacement of epidural catheters. PMID- 20960889 TI - [Evaluation of standard regimen of single shot spinal anesthesia for cesarean section in Japanese parturients]. AB - BACKGROUND: Recently, single shot spinal anesthesia using local anesthetic and opiate has been thought to be an ideal anesthetic method for cesarean section. For single shot spinal anesthesia, it is important to administer appropriate dose of drugs. However, optimal regimen for cesarean section in Japanese parturients has not been well studied. METHODS: In the present study, the validity of standard regimen of single shot spinal anesthesia for cesarean section was evaluated retrospectively. In the reviewed five month period (from May 2007 to September 2007), there were 183 cases of cesarean section, and single shot spinal was adopted in 144 cases. RESULTS: All of them were treated by the standard regimen (hyperbalic 0.5% bupivacaine 10 mg, fentanyl 25 microg, and morphine hydrochloride 0.1 mg). Among 144 cases, 139 cases (96.6%) required no additional pain relief until the delivery, and no parturient experienced critical adverse effects such as total spinal anesthesia. CONCLUSIONS: It is suggested that the studied regimen was valid for most of Japanese parturients. PMID- 20960891 TI - [Comparison of levobupivacaine and ropivacaine for postoperative epidural analgesia]. AB - BACKGROUND: Levobupivacaine is a long acting local anesthetic with less cardiovascular toxicity. Recently we can use levobupivacaine for postoperative analgesia. We retrospectively compared levobupivacaine with ropivacaine for the postoperative epidural analgesia in patients undergoing gynecological abdominal surgery. METHODS: The patients who had received epidural and general anesthesia from October 2008 to April 2009 were allocated into two groups. Analgesia intensity, the time to receive the first analgesic, and the number of times to use the additional analgesics were observed for three postoperative days. RESULTS: There was no difference in demographic data between the levobupivacaine and ropivacaine groups. In the levobupivacaine group (n=23) the patient received epidural 0.24% levobupivacaine and fentanyl, while the patients in the ropivacaine group (n=43) epidural 0.19% ropivacaine and fentanyl, at the rate of 3.5 ml x hr(-1). The volume of epidural fentanyl was similar between the groups. The time from the end of surgery to receive the first analgesic was longer in the levobupivacaine group than in the ropivacaine group. The number of the patients who did not require additional analgesia was greater in the levobupivacaine group than in the ropivacaine group. The patients who received metocropramide to treat nausea were fewer in the levobupivacaine group, compared with the ropivacaine group. CONCLUSIONS: These results suggest that the use of epidural 0.24% levobupivacaine in the patients undergoing the gynecological surgery is superior to the use of 0.19% ropivacaine. PMID- 20960892 TI - [Comparison of thoracoscopic and open repair of esophageal atresia with tracheoesophageal fistula]. AB - BACKGROUND: With the increasing use of endoscopic surgery in children, several papers report the comparison between the thoracoscopic and open repair of the neonatal esophageal atresia with tracheoesophageal fistula (EA/TEF). Most of them focus on the duration and outcome of the surgery with few focusing on the neonatal tolerance to the thoracoscopic procedure and intraoperative anesthetic management. METHODS: We retrospectively reviewed the repair surgery of EA/TEF performed during 2001 and 2006 in our institution and compared thoracoscopic repair (thoracoscopy group, n=5) with open repair (open group, n=7). The right main bronchus was blocked with Fogarty catheter in thoracoscopic repair, but not in open repair. Thoracoscopic repair was performed with insufflation of carbon dioxide (3-5 mmHg). RESULTS: The thoracoscopy group had a higher incidence of intraoperative hypercapnia and acidosis and required higher inspired oxygen fraction. On admission to ICU Pa(CO2) was in the normal range in both groups and there was no difference in the duration of mechanical ventilation and ICU stay. CONCLUSIONS: Hypercapnia and acidosis were severer in thoracoscopy group. Careful perioperative adjustment of inspired oxygen fraction and ventilator setting is required. PMID- 20960893 TI - [Successful anesthetic management of three patients receiving pheochromocytoma resection using extremely high-dose remifentanil infusion]. AB - We describe three consecutive cases of successful anesthetic management for pheochromocytoma resection under balanced anesthesia with sevoflurane inhalation and extremely high-dose remifentanil infusion. This case series aimed to examine whether the aggressive dosing of remifentanil, exerting both depressor and bradycardic actions with short durations, is applicable for hemodynamic control during pheochromocytoma resection. The remifentanil infusion rate was set to maintain the systolic arterial pressure below 150 mmHg and heart rate below 100 beats x min(-1). In 2 of 3 cases, intraoperative hemodynamics were controlled by titrated remifentanil infusion with up to 2 and 3 microg x kg(-1) min(-1) in each case, without additional vasoactive agents. In another case, since adequate antihypertensive control was ineffective despite incremental remifentanil infusion to a maximum of 5 microg x kg(-1) x min(-1) supplemented with repeated boluses of 200 microg remifentanil, a total of 2.4 mg of nicardipine as a depressor was needed. Ephedrine 12 mg was employed following tumor removal. This anesthetic regimen thus allowed minimal or no concomitant use of depressors during tumor manipulation and vasopressors following tumor removal. In conclusion, the liberal use of remifentanil for the anesthetic management of pheochromocytoma resection appears to be simple, safe and effective. PMID- 20960894 TI - [Continuous peripheral nerve block with a catheter placed under ultrasound guidance for analgesia after major orthopedic surgery]. AB - BACKGROUND: This prospective study was conducted to investigate the effects and complications of continuous peripheral nerve blocks after major orthopedic surgery using a catheter placed under ultrasound guidance. METHODS: We studied 182 adult patients who underwent one of three types of major orthopedic surgery and received peripheral nerve blocks with one or two perineural catheters: continuous femoral nerve block after reconstruction of the anterior cruciate ligament, n=93; continuous femoral with or without sciatic nerve block after total knee arthroplasty, n=39; and continuous brachial plexus block after arthroscopic surgery of the shoulder, n=50. All the patients received additional single peripheral nerve block and/or general anesthesia for surgery. A continuous injection of 0.2-0.25% ropivacaine was started immediately after surgery at a rate of 4-6 ml x hr(-1), with a 3 ml patient-controlled bolus available every 30 min, and lasted for at least 48hr. Pain was evaluated at rest and during movement, RESULTS: Despite large inter-individual variation, continuous peripheral nerve block produced satisfactory postoperative analgesia without any apparent major complications. CONCLUSIONS: Peripheral nerve block and catheter placement under ultrasound guidance may help manage postoperative analgesia after orthopedic surgery easily, reliably and safely. PMID- 20960895 TI - [A case of post-spinal tinnitus which improved after undergoing epidural anesthesia]. AB - A 34-year-old woman suffering from post-spinal tinnitus for 8 years was scheduled for a cesarean section under epidural anesthesia selected to prevent a deterioration of this condition due to a possible decrease in the cerebrospinal fluid level. Unexpectedly, the tinnitus disappeared completely after the epidural injection of 2% lidocaine 27 ml and following continuous epidural infusion. It is conceivable that moderate quantities of local anesthetics into the epidural space might have acted as an effective method similar to that of epidural physiologic saline injection in order to improve the cerebrospinal pressure. PMID- 20960896 TI - [Bleeding from the optical module connection port of a pulmonary artery catheter]. AB - A 91-year-old man underwent aortic valve replacement using a pulmonary artery catheter (PAC). Intraoperative hemodynamic monitoring with the PAC showed no abnormality except for bleeding from optical module connection port. In the intensive care unit, difficulty in withdrawing the PAC was noted. Surgical removal of the PAC was performed, revealing the PAC sutured to the right atrium. When bleeding from the PAC connection ports is noted, it is advisable to suspect that the PAC might have been sutured. PMID- 20960897 TI - [Experience of ultrasound-guided popliteal sciatic nerve block and femoral nerve perineural catheter placement in a morbidly obese patient undergoing total knee arthroplasty]. AB - A 60-year-old morbidly obese woman (150 cm, 112 kg, BMI 49.8) underwent total knee replacement under general anesthesia combined with sciatic nerve block and continuous femoral nerve block. Following induction of general anesthesia and tracheal intubation, the sciatic nerve was blocked using the popliteal approach with the patient in the supine position. Then the femoral nerve block was performed, followed by perineural catheter placement for postoperative continuous local anesthetic infusion. For both procedures, real-time ultrasound imaging was used to facilitate needle placement and confirm the adequate local anesthetic deposition. Twenty-five and 30 ml of 0.375% ropivacaine was injected around the sciatic and femoral nerves, respectively. Postoperatively 0.15% ropivacaine was infused at the rate of 5 ml x hr(-1) for 60 hours through the femoral catheter, which provided satisfactory pain relief in combination with scheduled loxoprofen administration. No block-related complications were noted. Our experience suggests that the ultrasound-guided technique may prove useful to facilitate safe and accurate block when technical difficulties are anticipated with anatomic landmark-based approaches. PMID- 20960898 TI - [Successful internal jugular vein puncture with ultrasound guidance for a terminal life stage patient in sitting position]. AB - We experienced an internal jugular vein cannulation of a terminal life stage patient suffering from serious peritonitis carcinomatosa with severely edematous limbs. He could not lie down on a bed because of dyspnea due to high abdominal pressure caused by massive ascites. We examined his internal jugular vein with ultrasound device, and found that it kept high venous pressure even in his inspiratory phase, although in sitting position. Internal jugular vein cannulation was successfully performed at first attempt by using ultrasound guide with no complications including air embolism, pneumothorax and bleeding. We considered that positive pressure of jugular vein during a respiratory cycle of the patient was obtained from his unconscious Valsalva's maneuver by increasing intrathoracic pressure following high abdominal pressure. Ultrasound-guided vascular access technique is useful and safe even in terminal life stage patients under palliative care. PMID- 20960899 TI - [Successful use of intravenous amiodarone for refractory ventricular fibrillation just after releasing aortic cross-clamp]. AB - Amiodarone is widely used in Europe and the United States for refractory ventricular fibrillation (VF) in various situations, such as VF after myocardial infarction or out-of-hospital cardiac arrest. We report a case of successful treatment with amiodarone of refractory VF immediately after releasing aortic cross-clamp in cardiac surgery. A 66-year-old man suffering from severe aortic stenosis underwent aortic valve replacement (AVR). General anesthesia was induced with propofol and remifentanil, and subsequently AVR was performed under cardiopulmonary bypass. Just after releasing aortic cross-clamp, VF occurred, and it continued despite multiple trials of cardioversion with direct current (DC) shocks of 20 J or 30 J. Furthermore, some DC shocks of 30 J or 50 J after administering lidocaine 60 mg and 0.5 mol x l(-1) magnesium sulfate 20 ml were also ineffective. Then, nifekalant 20 mg was administered and DC shocks of 50 J were repeated intermittently, but VF still persisted. Eventually, VF disappeared after a final DC shock of 50 J with intravenous amiodarone 125 mg. Overall duration of VF was 60 minutes. The patient's trachea was extubated three days after the surgery without any complications. Intravenous amiodarone may be one of the most useful remedies for some types of arrhythmias including persistent VE. PMID- 20960900 TI - [Usefulness of helmet type mask in the treatment of postoperative atelectasis in a child: a case report]. AB - A 7-year-old autistic girl underwent an appendectomy under general anesthesia. Both intraoperative course and postoperative one following extubation were uneventful;however, she suddenly developed severe hypoxemia caused by massive atelectasis in the right and lower lobes 27 hours after the operation. With a helmet type mask on her face, she was successfully managed with continuous positive airway pressure (noninvasive positive pressure ventilation) mode, in which PEEP level was 5 cmH2O and FI(O2) was 0.38. Compared with the face mask type, the helmet type has the advantage of better stability on the face without losing sight, and less discomfort with fixation. In spite of a slight difficulty in setting up the device and noise to the patient, the helmet type mask seems to be more useful in the treatment of respiratory distress in pediatric patients. PMID- 20960901 TI - [Epidural blood patch for postdural puncture headache in a five-year-old child]. AB - A case was presented of a 5-year-old girl who suffered an accidental dural puncture during placement of an epidural catheter under general anesthesia for orthopedic surgery. She complained of headache 4 days after the operation, which was relieved on supine position but became worse on sitting position. Her symptoms failed to respond to conservative management. An epidural blood patch was performed under general anesthesia and completely resolved her symptoms. The reported incidence of epidural blood patch for post dural puncture headache following accidental dural puncture in children is low. We outline this case and the consideration for management for epidural blood patch in pediatric patients. PMID- 20960902 TI - [Anesthetic management of a low birth weight infant with giant sacrococcygeal teratoma]. AB - We report the anesthetic management of a low birth weight infant (1912 g including the tumor) with a giant sacrococcygeal teratoma (Altman type II). The diagnosis was prenatally made at 24 weeks of gestation. She was delivered by emergent cesarean section at 28 weeks gestation, because fetal heart failure was aggravated by arteriovenous shunting through the tumor. Total resection was planned on day 0. Her trachea was intubated via nasotracheal route to prevent accidental extubation during surgery, which was performed in supine and prone position. A central venous line (5 Fr. double lumen) was inserted via right internal jugular vein for monitoring central venous pressure (CVP) and for rapid volume infusion. We infused volume to keep CVP at 10 mmHg throughout the surgery. The resected tumor weighed 766 g, total blood loss was 770 ml and blood transfusion was 965 ml. Although transient acidosis and hyperkalemia occurred, the surgery was completed and she was transferred to a neonatal intensive care unit in stable condition. In this case, nasotracheal intubation and the insertion of a central venous line were necessary and useful for the anesthetic management of the resection of giant sacrococcygeal teratoma. PMID- 20960903 TI - [Anesthetic management of Menkes disease infant with difficult vascular access]. AB - We report anesthetic management of a 6-month-old boy with Menkes disease who underwent three surgeries for vesicoureteral reflux, rupture of the bladder diverticulum, inguinal hernia, and gastroesophageal reflux. Menkes disease is a rare sex-linked disorder of copper absorption and metabolism. Anesthetic management of such patients is rather challenging because of high incidence of seizures, gastroesophageal reflux with the risk of aspiration, hypothermia, airway and vascular complications. In our patient general anesthesia was uneventfully maintained by sevoflurane combined with intravenous remifentanil and fentanyl. We experienced no major complications except some difficulties with intravenous and arterial cannulation. It was especially difficult to establish intravenous and invasive blood pressure lines because of tortuous blood vessels in this patient. We conclude that in patients with Menkes disease scheduled for surgery intravenous access should be established before the induction of general anesthesia. The necessity of invasive blood pressure monitoring should be also carefully considered beforehand. PMID- 20960904 TI - [A case report of successful treatment of a child with respiratory distress using non-invasive continuous positive airway pressure via helmet]. AB - Helmet is a new device of non-invasive continuous positive airway pressure (CPAP). Few cases have been described about usage of the helmet in children. We describe successful treatment of a child with respiratory distress using the helmet-delivered non-invasive CPAP. A 2-month-old male infant (3.1 kg) with multiple anomalies (cardiovascular, facial, and vertebral) developed respiratory distress after extubation. The helmet was well tolerated regardless of facial anomaly. Helmet CPAP started at initial settings of CPAP 8 cm H2O and FI(O2) 0.7, improved oxygenation. Pa(O2)/FI(O2) ratio increased from 106 to 316, and chest X rays showed a marked improvement (15 hour after NPPV initiation). The helmet offers important advantage: the possibility of fitting to any children, regardless of any facial or external anomalies. PMID- 20960905 TI - [Anaphylactic reaction to epidural block in an outpatient]. AB - A healthy 29-year-old woman received epidural block for severe lumbago in an outpatient clinic. Fifteen minutes after injection of mepivacaine 0.5% with dexamethasone into the epidural space, the patient complained of itching of eyelids followed by generalized pruritus. Hypotension, erythema and generalized urticaria were observed. Initial treatment was with 100% oxygen through face mask, and additional intravenous fluids, followed by administration of adrenaline, chlorpheniramine and dopamine. Cardiac ultrasound examination showed mildly impaired movement of inferior to septal wall. Her plasma histamine level was transiently elevated during the anaphylactic event; however the serum tryptase level was not. Biological assays for confirming the causative agent and cutaneous test were all negative, but clinical symptoms positivity showed nonimmunological anaphylactic reaction to mepivacaine or dexamethasone. This case report confirms the need for systematic allergological investigation in a case of immediate hypersensitivity reaction occurring during nerve block in patients who had even received similar nerve blocks repeatedly. Pain clinician should be aware of the possibility of anaphylactic reactions involving any drug or substance used for an outpatient. PMID- 20960906 TI - [Combined epidural-spinal anesthesia for radical hysterectomy in a patient complicated with bronchiectasis diagnosed on preoperative anesthetic consultation]. AB - A radical hysterectomy was performed in a patient complicated with bronchiectasis, under combined spinal-epidural anesthesia. The patient was asymptomatic and preoperatively diagnosed with bronchiectasis on an anesthetic consultation with an anesthesiologist. An epidural catheter was inserted between T12 and L1, and spinal anesthesia was subsequently performed with 0.5% bupivacaine 2.8 ml and fentanyl 10 microg. It was necessary to administer a supplemental epidural dose of 0.375% ropivacaine fifty minutes after the start of the operation. Postoperative epidural analgesia was effective and no perioperative complications were observed. PMID- 20960907 TI - [A case of anaphylactic shock induced by latex during cesarean section]. AB - We report a 39-year-old woman who showed intraoperative anaphylactic shock during elective cesarean section in the 38th week of pregnancy. She underwent cesarean sections under general anesthesia at 33 years of age, and under spinal anesthesia at 37 years without any complication; other past history was unremarkable. Spinal anesthesia was performed with 0.5% hyperbaric bupivacaine 2.5 ml and analgesia level up to T2 was obtained 12 minutes later. The operation was uneventful at the birth of a neonate weighing 2700 g delivered with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. Drip infusion of oxytocin was started after the delivery and uterine contraction was good. Five minutes later, blood pressure decreased abruptly to 70/40 mmHg, heart rate increased to 130 beats min(-1) and the patient complained of chest discomfort. Bolus injections of ephedrine and phenylephrine were ineffective, and continuous infusion of adrenaline was started to maintain blood pressure. The operation was finished and the patient was intubated for artificial ventilation to prevent airway obstruction. The tracheal tube was removed the following day and the postoperative course was uneventful thereafter. Plasma tryptase levels at 1 and 6 hours after the episode of hypotension were 9.0 and 1.3 ng x ml(-1). Postoperative blood tests revealed an increase in latex-specific immunoglobulin E, suggesting that anaphylactic shock was induced by latex. PMID- 20960908 TI - [Inadvertent thoracic duct puncture during right axially central venous cannulation]. AB - A case of inadvertent thoracic duct puncture during right axially central venous cannulation is reported. The catheterization was performed under the real time ultrasound guidance technique and the coronal view image was continuously displayed. After confirming the feelings of venous puncture, clear yellow fluid was aspired into the connected syringe to the needle. Initially, an accidental thoracic puncture with subsequent pleural fluid aspiration was suspected;however, no finding of pleural effusion was observed with ultrasound imaging and computed tomography. Thus, an accidental thoracic duct puncture and the subsequent lymph fluid aspiration were suspected. Even in a right side approach for central venous catheterization, thoracic duct injury might ensure. PMID- 20960909 TI - [Anesthetic management of a patient with Swyer-James syndrome]. AB - Swyer-James syndrome (SJS) shows the constellation of radiographic findings of a small, hyper lucent lung, with an ipsilateral, diminished peripheral vasculature, air trapping, and a lack of peripheral fill on bronchography. We report a case of 70-year-old woman with SJS who underwent pulmonary resection of the normal side lung for lung tumor. Because of this syndrome, we could predict the hypoxia during one-lung ventilation. In fact, about ten minutes after beginning of one lung ventilation, Sp(O2) decreased from 100% to 90%. As we could not improve the hypoxia in spite of increasing FI(O2), O2 administration to the operating side lung was started. Sp(O2) recovered after O2 administration. For anesthetic management of a patient with SJS in the normal-side-lung, it is essential to prevent the hypoxia during one-lung ventilation. PMID- 20960910 TI - [Remifentanil is useful for cardiovascular stability during cesarean delivery in a parturient with Marfan's syndrome]. AB - A 25-year-old parturient with Marfan's syndrome was scheduled for cesarean delivery. She suffered with severe scoliosis and asymptomatic aortic root dilatation. To establish a cardiovascular stability and prevent aortic dissection perioperatively, we selected the use of remifentanil, an ultra-short acting opioid analgesic with general anesthesia. General anesthesia was induced with remifentanil (0.2 microg x kg(-1) x min(-1)), propofol (100 mg), and vecuronium bromide (10 mg). Anesthesia was maintained with 100% O2, sevoflurane (1-1.5%), and remifentanil (0.2-0.25 microg x kg(-1) x min(-1)). She remained hemodynamically stable during surgery. A lively infant was delivered and Apgar scores were 8 and 9 at 1 and 5 min, respectively. Their post-delivery courses were uneventful. Remifentanil was useful for anesthetic management in a pregnant patient with Marfan's syndrome undergoing cesarean delivery, although attention to infant's respiratory condition should be paid because remifentanil can cross the placenta. PMID- 20960911 TI - [Perioperative management for open balloon atrial septostomy immediately after caesarean section in a baby with hypoplastic left heart syndrome and intact atrial septum]. AB - Hypoplastic left heart syndrome (HLHS) with intact atrial septum (IAS) is an extreme type of single ventricle physiology among congenital heart diseases, in which a baby cannot supply oxygenated blood into systemic circulation without alternative pathway. We report the case of the neonate undergoing open balloon atrial septostomy (BAS) and bilateral pulmonary artery banding (PAB) soon after scheduled caesarean sections (C/S). A 35-year-old female was pregnant and fetal echocardiography at 32 weeks revealed one of the twins as HLHS/IAS. Severe hypoxia soon after birth was suspected. Thus, scheduled C/S followed by open BAS was planned. At 36 weeks of gestation, the mother was anesthetized with spinal bupivacaine and the female baby with HLHS/IAS was delivered. After diagnosed definitely by pediatric cardiologists, her trachea was intubated by anesthegiologists and umbilical catheters were placed by neonatologists. Then the baby was transferred to neighboring operating theater for BAS 68 minutes after the birth, while her Sp(O2) was maintained around 75-85% through serial procedures. Open BAS and PAB were performed under general anesthesia without any hemodynamic instability or severe hypoxia. Cooperation among anesthegiologists, neonatologists, pediatric cardiologists, and cardiac surgeons is mandatory in order to successfully complete such a rushed procedure. PMID- 20960912 TI - [A case of coronary stent thrombosis occurring repeatedly in the perioperative period]. AB - A 60-year-old man with angina was scheduled for total gastrectomy, splenectomy, and cholecystectomy. Bare-metal stents were implanted into his left anterior descending coronary artery four weeks before the operation. Aspirin and clopidogrel were administered until one week before the operation and then injection of to 15,000 units of heparin per day was given. Anesthesia was maintained with sevoflurane, remifentanil and fentanyl. At 330 minutes after starting the operation, 2-mm ST segment elevation was observed and it recovered immediately. After the operation, new 9-mm ST segment elevation in leads V2-V6 was observed. Emergent cardiac catheterization showed occlusion of the coronary artery with in-stent thrombosis. An additional stent was implanted and 10,000 units of heparin per day was injected. After five days, new stent thrombosis occurred and an additional stent was implanted. Administration of aspirin, clopidogrel and cilostazol was started immediately. Anesthesiologists should pay attention to the kind of coronary stent, consider the timing of the operation, and continue administration of aspirin. PMID- 20960913 TI - [A case of successful tracheal tube exchange with Airway Scope for tube damage during maxillo-mandibular osteotomy]. AB - We report a case of surgical vertical-section of the nasoendotracheal tube during operation, resulting in intra-operative ventilatory difficulties. The patient was a 32-year-old female, scheduled for Maxillo-Mandibular osteotomy under general anesthesia. She was intubated with I.D. 6.0 mm non-kinking tube via left nasal cavity. Forty minutes into a maxillar osteotomy, sudden tracheal tube leak sound was noticed by surgeon. Ten more minutes later, ventilation became difficult, and laryngeal packing was done temporarily. We tried to exchange the nasotracheal tube with Airway Scope, but not with endotracheal tube exchanger, because there was a possibility of complete tube section or difficult extubation from nasal cavity. We could examine the larynx whether it was with edema or not, and two tracheal tubes at the same time. Therefore, we performed tube exchange smoothly and safely. The extubated tracheal tube had serious cut on cuff inflation line made by surgical maneuver. In the case of suspected laryngeal edema or tracheal tube injury, use of Airway Scope for tube exchange may be a safe and reliable method. PMID- 20960914 TI - [Nasotracheal intubation using GlideScope videolaryngoscope or Macintosh laryngoscope by novice laryngoscopists]. AB - BACKGROUND: We compared the performance of GlideScope videolaryngoscope with that of the conventional Macintosh laryngoscope for nasotracheal intubation by non anesthesia residents. METHODS: Forty patients requiring nasal endotracheal intubation for surgical convenience were allocated to intubation with the GlideScope videolaryngoscope or Macintosh laryngoscope. Each intubation was performed by non-anesthesia residents. RESULTS: The time to secure the airway was shorter with GlideScope laryngoscopy than with the Macintosh laryngoscopy. Magill forceps were not needed for any patient during GlideScope videolaryngoscopy, while Macintosh laryngoscopy required Magill forceps utilization for 75% of the patients. CONCLUSIONS: The unobstructed view of the glottic opening on the video monitor helped the laryngoscopist performing the nasal endotracheal intubation while an assistant provided laryngeal manipulation to improve the coordinated effort. GlideScope seems to facilitate nasotracheal intubation for individuals training in airway management. PMID- 20960916 TI - [Comprehensive analysis of lipid modifications of proteins using cell-free protein synthesis system]. PMID- 20960915 TI - [Incorrect descriptions about Seicho Kamata in "Seishu Hanaoka and his surgery"]. AB - "Seishu Hanaoka and his surgery" by Shuzo Kure is one of the most important books for the study of Seishu Hanaoka. However, several incorrect descriptions have been pointed out in the book. Therefore, we checked the content about Seicho Kamata, a distinguished disciple of Seishu Hanaoka (p.154-163) in the book, and found three incorrect descriptions. The figure being described as that of Seicho Kamata is his father's. His graveyard being described as "Nyohoji" is truly "Daizenji". Seicho Kamata is also described as the second distinguished disciple of Seishu Hanaoka ; however, authors think that he was the first distinguished disciple from his career. Further investigation into the content of the book is necessary. PMID- 20960918 TI - [EF-G2mt is an exclusive recycling factor in mammalian mitochondrial protein synthesis]. PMID- 20960917 TI - [Role of zinc/zinc transporter in allergic response]. PMID- 20960919 TI - [In vivo imaging reveals chronic inflammation and abnormal local immunity in obese adipose tissue]. PMID- 20960920 TI - [Epithelial intrinsic tumor suppression by TNF-JNK signaling]. PMID- 20960921 TI - [Synapse-to-nucleus signaling and activity-dependent gene expression in neurons: mechanisms of synaptic activity-dependent regulation of the Arc/Arg3.1 gene]. PMID- 20960922 TI - [Advantages and applications of human artificial chromosome vector]. PMID- 20960923 TI - [Dual regulation of hepatic ABCA1 gene expression]. PMID- 20960924 TI - [Monitoring method for the alteration of phosphorylation status in a high molecular-mass protein using Phos-tag electrophoresis technology]. PMID- 20960925 TI - [Introduction of MOPAC simulation for experimental biochemists]. PMID- 20960926 TI - [Treatment and pathogenesis of Parkinson's disease]. AB - Parkinson's disease (PD) is one of the most common chronic neurodegenerative diseases. Levodopa provides the best symptomatic benefit with the fewest short term adverse effects, but its use is associated with the development of motor fluctuations and dyskinesias. The introduction of dopamine agonists early in the treatment of PD leads to a delay of these motor complications, but all available dopamine agonists may cause profound adverse effects in some patients. The objective of this manuscript is to review the initial treatment, the neurotoxicity of levodopa, the swallowing disturbance and QOL of PD. Levodopa still is the gold standard for PD. However, the treatment decisions should be based on considerations of risks versus benefits for individual patients. PMID- 20960927 TI - [Non-invasive investigation of human brain function]. AB - The idea that each brain function is undertaken by a small part of focal brain was established in 19th century. Since then, trials to reveal an individual function in each area have been continued. Although intraoperative electric stimulation/suppression has been considered to be the most secure way of exploration of brain function, this method has several limitations due to its invasive nature. On the other hand, recent advancement of explorative measure with high sensitivity has enabled measurement of physical phenomenon accompanied with change of brain function from outside of the skull. These methods can be applied to normal subjects using their capability of repetitive and multiple measurements and have provided new findings. Combination of several techniques knowing characteristics and limitation of each method will provide new insight into the brain. PMID- 20960928 TI - [A patient with myelitis of varicella-zoster without skin lesions--diagnostic value of virus antibody index in CSF]. AB - A previously healthy 55-year-old woman developed abnormal sensation on the right occipital region. It expanded for the following three weeks. On admission, examination revealed abnormal and decreased sensation in touch and pinprick at right C2 to C6 dermatome without skin lesion. There was no muscle weakness. Deep tendon reflexes were more active in the right than in the left. MRI demonstrated a lesion of isointensity on T1-weighted, hyperintensity on T2-weighted, which was enhanced with contrast material on gadolinium-enhanced T1-weighted image at the upper cervical spinal cord corresponding to C2. Laboratory studies showed no immunosuppression and autoantibodies. The antibody index to varicella-zoster virus (VZV) was elevated in the cerebrospinal fluid (CSF). This finding prompted us to a diagnosis of myelitis of zoster sine herpete. VZV is thought to be a causative agent in cases of CNS infections of unknown etiology such as myelitis, even in the absence of skin manifestations. Amplification of VZV DNA by PCR in the CSF and the detection of an intrathecal production of anti-VZV antibodies have important diagnostic value, although their presence depends on the timing of the CSF sampling. The percentage of PCR-positive cases drops after seven or ten days, whereas that of specific antibodies-positive cases elevates. Because VZV myelitis are usually protracted, PCR does not always provide an exquisite sensitivity. Thus, the evaluation of antibody index provides the evidence of intrathecal production of anti-VZV antibodies. That is expressed as CSF antibody titer/serum antibody titer/CSF IgG/serum IgG. This quotient superior to 1.5 or 2.0 suggests CNS synthesis. As the sample of our patient was taken relatively late, this value was diagnostic. We would like to emphasize the importance of making precise diagnosis and adequate initial treatment in patients with myelitis of unknown etiology even if there is no skin lesions. PMID- 20960929 TI - [A case of spinocerebellar ataxia type 2 presenting with a clinical course similar to spastic paraparesis]. AB - We report a 50-year-old woman with an unremarkable birth and developmental history, and with no family history of neurological disorders. The patient had a 6-year history of progressive cervical dystonia, oral dyskinesia, and hyperreflexia. She was initially considered to have spastic paraparesis of unknown cause. Because brain MRI showed mild atrophy of the cerebellar vermis, genetic analysis for spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 12, and 17, and dentatorubral-pallidoluysian atrophy was performed. The results revealed an abnormal expansion of CAG repeats (38 repeats) in one allele of ATXN2, and the patient was diagnosed with spinocerebellar ataxia type 2 (SCA2). She had no major clinical features of SCA2 such as cerebellar ataxia, slow saccade, or hyporeflexia. Recent reports have shown the CAG repeat expansion in ATXN2 to be detected in patients with familial L-dopa-responsive parkinsonism. The present case suggests that CAG repeat expansion in ATXN2 may be detected in some patients with spastic paraparesis, and that wide variations of clinical manifestations exist in SCA2. PMID- 20960930 TI - [A case of amyotrophic lateral sclerosis/frontotemporal lobar degeneration with apraxia of eyelid opening]. AB - We report the case of a 76-year-old man with apraxia of eyelid opening (AEO) and amyotrophic lateral sclerosis with dementia (ALS-D)/frontotemporal lobar degeneration with motor neuron disease (FTLD-MND). The initial symptom was AEO. Neurological examination revealed mainly bulbar symptoms with a neurogenic pattern on needle electromyograms of the tongue muscles and the biceps muscles. Furthermore, he developed severe dementia with frontal lobe dysfunction and progressive non-fluent aphasia. Brain magnetic resonance imaging revealed severe cerebral atrophy and leukoaraiosis in the bilateral frontal lobes and the anterior part of the bilateral temporal lobes; brain 99mTc ethyl cysteinate dimer single photon emission computed tomography (ECD SPECT) showed hypoperfusion in the same areas. The patient showed improvement in stereotyped behavior and AEO after treatment with 50 mg/day of fluvoxamine maleate (the initial dose was 25 mg/day). Because serotonin receptors are markedly reduced in the frontal and temporal cortexes of patients with FTLD, we considered that dysfunction of the serotonergic system in the frontotemporal lobe caused AEO. Considering the findings of this case along with those of previous reports, we propose that there is a relatively homogeneous development of ALS-D/FTLD-MND with AEO. PMID- 20960931 TI - [An autopsy case of senile dementia suspected to be influenced by cerebral amyloid angiopathy with multiple cortical microinfarcts]. AB - A Japanese male showed gradually progressing dementia with psychiatric symptoms including abnormal behavior, night and day reversal, nocturnal delirium, loud shouting, agitation, resistance to care, and loud soliloquy. The patient had a history of right cerebral embolism due to atrial fibrillation 1 month before the onset of dementia. Head CT revealed widespread cerebral infarction in the right cerebral hemisphere with bilateral lateral ventricular dilatation. The patient died at the age of 83, 10 months after the onset of cerebral embolism. The clinical diagnosis was mixed-type dementia. On autopsy the brain weighed 1,160 g. Widespread cerebral amyloid angiopathy (CAA) was observed, with distribution most severe in the cerebral cortical vessels and slightly milder in the leptomeningial and subarachnoid vessels. The artery, arteriole, and capillary walls were thickened by the deposition of amorphous, eosinophilic and beta-protein immunopositive amyloid. Abeta-deposition was more severe in capillaries and CAA tended to be more severe in the occipital regions. Multiple cortical microinfarcts were found, particularly in the crests of the cerebral gyri of watershed zones. Cerebral white matter, basal ganglia, thalamus, brainstem and spinal cord were relatively preserved from CAA. Infarction was not apparent, except for an embolic lesion in the right cerebral hemisphere and the cortical microinfarcts. We did not observe fibrinoid necrosis, granulomatous angiitis or giant cell reaction associated with CAA-vasculopathies. Rare instances were observed of neurofibrillary tangles and senile plaques corresponding to Braak stages II and A, respectively. We thought the multiple cortical microinfarcts occurred due to chronic hypoperfusion associated with CAA-associated vasculopathies of capillaries in the cerebral cortex. We suspected that the dementia was influenced by the CAA with multiple cortical microinfarcts. Pathologic findings of the patient suggest that CAA without AD-related Abeta deposition might exist and that capillary Abeta-deposition might be an important factor of hemodynamic perturbation. PMID- 20960932 TI - [Successful treatment of multiple sinus thromboses and meningitis due to aspergilli and alpha-streptococci with preemptive antimycotic therapy: a case report]. AB - A 62-year-old immunocompetent woman presented with 11 days of headache, 2 days of right eye ache and 1 day of fever and lethargy. Neurological examination revealed nuchal stiffness, right proptosis, bilateral ptosis, and right abducens palsy. Cerebrospinal fluid (CSF) examination revealed elevated white cell count (164 /microl) and protein level (115 mg/dl). Cranial MRI showed sphenoid sinusitis, thromboses of the right superior ophthalmic vein, bilateral cavernous sinuses, left sphenoparietal sinus and left sigmoid sinus, and enhanced meninges. Purulent meningitis and multiple mycotic cerebral venous sinus thromboses were diagnosed. After empirical therapy with meropenem, fever persisted and CSF cell count further elevated (668/microl on day 3). Additional treatment with liposomal amphotericin B (L-AMB) and low-dose heparin from day 3 ameliorated her symptoms and lowered her CSF cell count. Laboratory test on admission later revealed elevated serum aspergillus antigen (index = 3.6) and positive blood culture for streptococcus viridans. L-AMB was replaced by voriconazole due to skin rash, and the latter was changed to itraconazole due to drug-induced hepatitis. She was discharged without complication and has been free of recurrence for 7 months. Aspergillus has a propensity to invade cerebral vessels and meninges, causing local thrombosis and meningitis with high mortality and morbidity. Direct penetration from adjacent sphenoid sinus can be a cause of cavernous sinus thrombosis, due to extreme thinness of the wall of sphenoid sinus. Cerebral venous sinuses lack valves, and this may facilitate the spread of mycotic thrombus to the other sinuses. Early preemptive treatment with antimycotic agents brought a favorable outcome to our patient. PMID- 20960933 TI - [Limb-girdle muscular dystrophy type 2M with adult-onset loss of ambulation. A case report]. AB - We report a 29-year-old man with limb-girdle muscular dystrophy type 2M (LGMD2M) caused by a compound heterozygous mutation of 3-kb insertion in the 3' untranslated region and c.1073A > C (p.Q358P) mutation in exon 9 in FKTN. He had been diagnosed since childhood as having Becker muscular dystrophy based on limb girdle muscle weakness and calf muscle hypertrophy. Loss of ambulation occurred at age 26 years and cardiomyopathy was noted one year later. Muscle biopsy at age 29 revealed dystrophic changes with loss of immunoreactivity to alpha dystroglycan (alpha-DG), which prompted us to analyze FKTN and subsequent establishment of the diagnosis of LGMD2M. Brain MRI revealed hypoplasia of the right cerebellar hemisphere and tonsil. Dysplastic part was present in the lower medial part of the hypoplastic hemisphare, which was bordered by a deep cleft. Previously reported LGMD2M patients had mild or minimal muscle weakness in addition to dilated cardiomyopathy. In contrast, our patient had more severe skeletal muscle weakness and loss of ambulation. Treatment with 3-blockers or angiotensin II converting enzyme blockers has been reported to be efficacious for cardiomyopathy in patients with muscular dystrophy. The precise diagnosis should be established early in patients with muscular dystrophy complicated with cardiomyopathy. PMID- 20960934 TI - [Progressive cerebral infraction initially presenting with pseudo-ulnar nerve palsy in a patient with severe internal carotid artery stenosis]. AB - A 63-year-old man with hypercholesterolemia developed sensory and motor disturbances in the ulnar side of the right hand, and over three days the weakness evolved to entire right arm. Examination on the 6th day after onset showed mild lower facial palsy in addition to the upper limb weakness on the right. The weakness involved entire right arm sparing shoulder girdle muscles, which was worse in the 4th and 5th digits with claw hand deformity of the hand. Magnetic resonance imaging showed multiple small infracts in the centrum semiovale as well as in the medial side of the precentral knob on the left. Magnetic resonance angiography, ultrasonography, and 3D-CT angiography of the neck showed severe stenosis associated with unstable plaque of the left internal carotid artery. Hemodynamic mechanisms including microemboli and hypoperfusion associated with severe internal carotid artery stenosis are likely to cause stroke in evolution after initial presentation of pseudo-ulnar palsy in the present case. PMID- 20960935 TI - [Successful isolation of IMP-1 carbapenemase-producing, but not carbapenem resistant species in Enterobacteriaceae family]. AB - Carbapenemases including Klebsiella pneumoniae carbapenemases (KPC) are widespread among clinical isolates in the family Enterobacteriaceae. In 2008, we isolated 4 IMP-1 metallo-beta-lactamase (MBL) producers of this family having transferable carbapenem-resistance markers. When examined with MicroScan Neg Combo Panels, all 4 showed imipenem-MIC of either <1 microg/mL or 2 microg/mL, although they were highly resistant to ceftazidime (MIC: >16 microg/mL). When isolates were examined by Sensi-Disc, however, discrepancies were seen in susceptibility testing results against carbapenems, i.e., some strains were susceptible to imipenem but resistant to meropenem. MBL productivity of isolates could be ensured by both sodium mercaptoacetic acid (SMA) and modified Hodge testing. Noted that atypical carbapenemase-producers may be overlooked in routine clinical microbiology laboratory testing, and both SMA disks and modified Hodge tests proved appropriate for accurately detecting such carbapenemase-producers. PMID- 20960936 TI - [Epidemiological study of influenza-like illness under enhanced surveillance in Saku, Nagano Prefecture, outpatients during the 2008-09 influenza season]. AB - Many influenza-like illness (ILI) outpatients visit healthcare facilities such as internal medicine and pediatric clinics every year. In Japan, however, ILI is reported only by sentinel healthcare facilities. We studied the number of ILI subjects visiting sentinel and non-sentinel healthcare facilities during the 2008 09 season in Saku, Nagano prefecture, obtaining the numbers of cases from sentinel and non-sentinel facilities. Most ILI subjects visited internal and pediatric facilities, and some visited otorhinolaryngological clinics not included as sentinel sites. We also estimated the total number of influenza cases based on data from sentinel facilities and total surveyed facilities, including non-sentinel. We divided facilities into hospitals with pediatrics, pediatric clinics, internal medicine and pediatric clinics, hospitals and clinics with internal medicine but no pediatrics, and otorhinolaryngological clinics. Estimated sentinel-site ILI cases was 2862, including 1020 for hospitals with pediatrics and 1,674 for clinics with internal medicine and pediatrics. The estimated number of ILI cases from total facilities surveyed was significantly lower, at 503 for hospitals with pediatrics, and 741 for clinics with internal medicine and pediatrics. Estimated ILI cases from categories not including sentinel sites were 967 for hospitals and clinics with internal medicine but no pediatrics, and 71 for otorhinolaryngological clinics. The estimated number of total ILI cases differed by 18.5%, depending on facility categories. This indicates that more detailed analysis is needed to accurately estimate ILI cases. PMID- 20960937 TI - [Can industrial laundry remove Bacillus cereus from hospital linen?]. AB - Contaminated hospital linen has caused some cases of Bacillus cereus bacteremia in Japan. We analyzed the disinfection efficacy of industrial washing of hospital towels and sheets by counting the number of B. cereus on linen before and after washing. That before washing averaged 7.6 cells/cm2 on unwashed sheets, decreasing to 1.2 cells/cm2 after washing. That on unwashed towels, however, averaged 10(6) cells/cm2 before washing and 1096 cells/cm2 after washing, which was very high and suggested the possibility of causing nosocomial infection. PMID- 20960938 TI - [Two cases of bacteremic pneumonia caused by Pseudomonas aeruginosa in solid organ cancer patients]. AB - Pseudomonas aeruginosa, the leading nosocomial pneumonia pathogen in immunocompromised patients, has Recently become typically presented as slowly progressive ventilator-associated pneumonia. We report two cases of bacteremic pneumonia due to Pseudomonas aeruginosa in non-neutropenic solid-organ cancer. Both subjects had sudden sepsis or septic shock but few respiratory symptoms. Chest radiography showed a diffuse unilateral decrease in permeability, becoming necrotizing pneumonia and lung abscess in 7-10 days. Conventional literature describe fulminant pseudomonas bacteremic pneumonia in non-neutropenic immunocompromised hosts as the initial presentation with septic shock and interstitial lung opacity, leading lung abscess. PMID- 20960939 TI - [Infectious endocarditis due to Gemella morbillorum found by splenic infarction- a case report]. AB - A 64-year-old man with prostate cancer and bone metastasis admitted for nausea, left abdominal pain showed no abnormal, and fever, abdominal ultrasound or chest X-ray findings. Despite antibiotics, left abdominal pain persisted for several days. Abdominal computed tomography (CT), showed splenic infarction. Transesophageal echocardiography suggested infectious endocarditis (IE) as a possible infarction cause, and roth spots were found on the retina. Gemella morbillorum was detected from blood culture. IE commonly causes Fever of Unknown Origin found by infarction. G. morbillorum, an anaerobic gram-positive, viridans group streptococci, is indigenous to the oropharynx, upper respiratory, urogenital, and gastrointestinal tracts, and is thought to have weak toxicity and pathogenicity in the body. PMID- 20960940 TI - [Non disseminated pulmonary cryptococcosis with very marked eosinophilia in solid organ cancer]. AB - Cryptococcal lung disease is usually diagnosed by chest X-ray abnormalities. Although no treatment exists for asymptomatically immunocompetent patients, a case with central nervous system (CNS) involvement as cryptococcus dissemination had a new chest X-ray abnormality during marked eosinophilia diagnosed as pulmonary cryptococcosis by lung biopsy. Eosinophilia may thus be associated with pulmonary cryptococcosis. We had seen reports of disseminated cryptococcosis with eosinophilia, so we conducted lumbar puncture and blood culture, but found no disseminated lesion or CNS involvement. Eosinophilia association with disseminated cryptococcosis has been reported, but not pulmonary cryptococcosis with solitary localized lung lesion with marked eosinophilia, making our case the first, in so far as we know reported of pulmonary cryptococcosis with a solitary localized lung lesion with marked eosinophilia. PMID- 20960942 TI - [Health related items in environmental impact assessment and strategic environment assessment]. PMID- 20960941 TI - [Listeriosis in non-Hodgkin's lymphoma following outpatient R-CHOP therapy]. AB - Non-Hodgkin's lymphoma, a hematolymphoid malignancy, puts subjects at risk for complete infection. A 65-year-old man with non-Hodgkin's lymphoma Stage IV had undergone 5 R-CHOP courses in May 2008. Six days later, he was hospitalized for a high fever for which he was initially administered cefepime. When blood culture was positive for Listeria monocytogenes, he was administered ampicillin. His medical interview indicated that he had gone hunting and dressed wild animal meat at his mountain retreat, where he was exposed to wild animals and their excreta following R-CHOP course 5. CSF was not checked because his general condition was good. On hospital day 2, his fever dropped, and he was discharged following two weeks of ampicillin administration. Listeriosis cases reported in Japan number far fewer than in the United States, France or Germany. From January 1983 to February 2009, 153 cases were reported in Japan, 12 of whom were cancer patients. Despite the high incidence of meningitis with listeriosis, 7 of the 12 were not examined for CSF--an examination necessary in listeriosis, however well the subject appears. PMID- 20960943 TI - [Literature review on the association between inactivated influenza vaccines and the Guillain-Barre syndrome]. AB - PURPOSE: To summarize data on associations between inactivated influenza vaccines and the Guillain-Barre syndrome. METHODS: The association between inactivated influenza vaccines and the Guillain-Barre syndrome was described and discussed, mainly on the basis of previous studies cited in "Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices". RESULTS: The A/New Jersey/76 swine influenza vaccine has been reported to be associated with occurrence of the Guillain-Barre syndrome. However, it is unclear whether seasonal inactivated influenza vaccines are associated with the occurrence of the syndrome. According to a study from the United States, which reported a statistically significant association between seasonal inactivated influenza vaccines and Guillain-Barre syndrome, the best estimate of maximum attributable risk, after allowing for study limitations, is 1.6 cases per million vaccinations. DISCUSSION: We could not draw any definite conclusions about any causal relationship between seasonal influenza vaccination and the Guillain-Barre syndrome. Therefore we considering the estimated benefits of seasonal influenza vaccination to outweigh the reported risk of subsequent development of the Guillain-Barre syndrome. PMID- 20960944 TI - [Relationships between foot problems, fall experience and fear of falling among Japanese community-dwelling elderly]. AB - PURPOSE: Although a foot care program for long-term care prevention has been launched in Japan, few studies have examined its effectiveness. The purpose of the present investigation was to examine the association of foot problems with fall experience and fear of falling among Japanese community-dwelling elderly people. METHODS: The participants were 10,581 community-dwelling elderly people (75.2 +/- 5.6 years) and the study design was cross-sectional using a questionnaire. Self-reported tinea pedis, skin problems (inflammation, swelling, or discoloration), nail problems (thickening or deformities), impairment (in function or blood flow), regular foot care, and wearing of appropriate shoes were selected as parameters of foot problems and their care. Logistic regression analysis was conducted to examine whether these were related to fall experience (in the past 1 year) and fear of falling adjusted for age, the Tokyo Metropolitan institute of gerontology index of competence, medical conditions, and lower limb functions. RESULTS: Forty-six percents of males and 39.0% of females reported at least one foot problem. After adjusting for covariates, tinea pedis (male: adjusted odds ratio = 1.37[95% confidence interval= 1.15-1.63], female: 1.29[1.08 1.53]), skin problems (male: 1.66[1.32-2.101, female: 1.37[1.13-1.66]), nail problems (male: 1.72[1.45-2.051, female: 1.48[1.26-1.74]), and functional impairment (male: 2.42[1.91-3.05], female: 1.66[1.36-2.04]) were significantly associated with fall experience. Also, each problem was negatively associated with fear of falling (tinea pedis[male: 1.37 [1.15-1.62], female: 1.25[1.07 1.47]], skin problems[male: 1.42[1.13-1.801, female: 1.62[1.34-2.00]], nail problems[male: 1.41[1.19-1.68], female: 1.46[1.25-1.70]], functional impairment [male: 2.05[1.61-2.60], female: 2.10[1.69-2.60]]). In addition, regular foot care (0.81[0.71-0.921) was a significant correlate of fear of falling in females. CONCLUSIONS: These results imply that focusing on foot problems (i.e., tinea pedis, skin problems, nail problems, functional impairment) would be one of means for fall preventions. Well-designed prospective studies evaluating foot problems objectively are now needed to confirm the relationships indicated by this study. PMID- 20960946 TI - [Nation-wide survey of arrangements for food and nutrition assistance in emergencies]. PMID- 20960945 TI - [Implementation and evaluation of a childhood dental health program in a community: twenty-year observational data]. AB - PURPOSE To evaluate a long-term community-based childhood dental health program comprising of caries screenings of one- and two-year old kindergarten and pre school children as well as in groups aged 1.5- and 3-years. METHODS: Fluoride treatment was introduced to 1.5-year, 2-year, 3-year screening from 1995, 1-year screening from 1997, and kindergarten/pre-school children from 2002 in Kyowa town, Makabe, Ibaraki (Kyowa district of Chikusei city) . Tests for caries prediction and caries bacteria load were also introduced from 1990 and 1995, respectively. To evaluate improvement in the dental health program between 1984 and 2004, we compared the prevalence trend for dental caries in Kyowa town with that in 7 other adjacent communities within the same public health center area, the Ibaraki prefectural average and data for all Japan. RESULTS: Between 1984 and 2004, the prevalence of dental caries declined by 59% for 3-year children with a large decrease from 1995, and by 57% for 1.5-year children. Decline during the twenty years ranked first and second among the communities, respectively, and was also larger than the prefectural and national averages. For 3-year children, the reduced prevalence of dental caries may have been enhanced by the introduction of fluoride treatment in 1995. CONCLUSION: A community-based dental health program including fluoride treatment for 1- and 2-year old kindergarten/pre-school children as well as for those aged 3- and 1.5 years may have had a larger impact on reducing dental caries in Kyowa town than in other communities, Ibaraki prefecture and all Japan. PMID- 20960947 TI - [Development of oral function and eating habits of infants living in a city area of Japan: in relation to the results of dental health examinations of infants aged 14 months at public health centers]. AB - OBJECTIVE: The aim of this study was to investigate the relationships between eruption of deciduous teeth and eating habits determined by health examinations of infants. METHODS: We verified eruption of deciduous teeth based on observations of 455 fourteen-month-old infants at health examinations in a ward of Tokyo, and performed a questionnaire survey involving their mothers regarding the hardness of infants' meals and their eating habits. We examined 420 infants excluding 17 whose births were 'pre-term delivery (born at or before 36 weeks)' and 18 whose questionnaire had excessive omissions. RESULTS: The percentage of infants who began a weaning diet at 5 to 6 months of age was 81.4%, and 71.2% of mothers considered their infant's age in months before starting a weaning diet. We divided the children into three stages: those not showing full eruption of the eight front deciduous teeth (stage I, 27.4%); those with full eruptions of the eight front deciduous teeth excluding the first primary molars (stage II, 61.9%); those with full eruptions of the first primary molars (stage III, 10.7%). Most mothers cooked meals considering the hardness of the gingival gums (stage I; 53.5%, stage II; 54.4%, stage III; 40.0%). The percentage of mothers who cooked meals considering the hardness of the primary molars was 14.0 and 15.1% in stages I and II, respectively. In addition, the percentage who cooked meals while considering the hardness in relation to adult meals was 7.0, 9.7, and 24.4% in stages I, II, and III, respectively. Moreover, the percentage considering the salt-taste in relation to adult meals was 13.2, 17.3, and 22.2% in stages I, II, and III, respectively. CONCLUSION: In the present study, we obtained valuable data showing that the timing deciduous teeth eruption varies among individuals. These results suggested that nutritional education on the appropriate quality of meals for infants based on their state of deciduous teeth eruption is necessary. PMID- 20960948 TI - [The present situation of measures against tuberculosis in hemodialysis facilities in Chiba Prefecture]. AB - PURPOSE: To observe the current situation of tuberculosis and its control measures in hemodialysis facilities in Chiba Prefecture, Japan. METHOD: Questionnaires on medical dialysis and tuberculosis were sent to hemodialysis facilities in Chiba Prefecture. RESULTS: The questionnaires were answered by 55 of 127 facilities. Of the respondents, 46 (83.6%) were not aware of the recommendation of treatment for latent tuberculosis infections in Japanese patients. Moreover, 30 (54.5%) facilities did not examine patients for tuberculosis prior to the initiation of hemodialysis. Of the 21 facilities that did assess patients for tuberculosis infection, only 5 (23.8%) performed a tuberculin skin test or QuantiFERON TB-2G. Three of the five (60.0%) that were treating tuberculosis by themselves expressed fear or uncertainty about the diagnosis and treatment of latent tuberculosis infections. During January 2006 through December 2007, tuberculosis patients were detected in 11 facilities, and the proportion of extrapulmonary tuberculosis among these patients was 52.4%. Seven facilities reported that they took no control measures against tuberculosis. CONCLUSION: It is important to inform medical dialysis facilities about latent tuberculosis infections, the early diagnosis of tuberculosis, and the combination of nosocomial infection control. It is also important for experts in hemodialysis and tuberculosis to work closely together. PMID- 20960949 TI - [Trends in tuberculosis infection among foreigners in Japan according to work status]. AB - PURPOSE: TB among foreigners is presently a serious issue in some developed countries and could become so in Japan. The purpose of this report is to assess the epidemiological situation of TB among foreigners in Japan. MATERIALS AND METHODS: The trend of TB reporting among foreigners in Japan was examined with regard to work status. RESULTS: The number of reported TB cases among employees and students in Japan increased between 1998 and 2008, but that among housekeepers was level throughout the same period. The increase among employees and students might be due to the increased numbers of foreign employees and students. In the case of housekeepers, the increase in the number of permanent residents did not lead to an increase in TB among these housekeepers. Estimates of TB reporting rates decreased during the study period, so the changes in reporting rates would not have caused the increase in TB cases. This downward trend may have been caused by an increase in longer-term residents and a decrease in TB incidence in home countries. Even though the TB reporting rate is decreasing, the rates in those countries are much higher than in Japan in the same work categories. DISCUSSION: To control the spread of TB, it is important to identify high-risk individuals. The Japanese TB control program should further strengthen mass health examination programs for foreign housekeepers and employees (especially temporary and daily employees), case-finding based on individuals' access to hospitals or clinics when suffering from TB symptoms, and flexible and periodic adjustment of TB control activities for foreigners according to future changes in the number and distribution of foreigners in Japan. Furthermore, improving the TB epidemiological situation in home countries might contribute to the downward trend of TB reporting rates among foreigners in Japan. Therefore, Japanese assistance in TB control activities in surrounding countries such as China, South Korea, and the Philippines might contribute to TB control activities for foreigners in Japan. PMID- 20960950 TI - [Clinical application of line probe assay (LiPA) for rifampicin (RFP)-resistant gene examination in sputum from tuberculosis patients]. AB - INTRODUCTION: Preventing the spread of drug-resistant tuberculosis is a clinically important challenge. In this effort, rifampicin (RFP)-resistant gene examination by line probe assay (LiPA) was evaluated for its clinical application for rapid detection of tuberculosis. METHODS: The RFP-resistant gene was examined in a total of 110 samples of sputum obtained from patients that were definitively diagnosed with pulmonary tuberculosis by auto-LiPA. The difference in detection sensitivity between the results of the smear and culture examinations was evaluated. Culture-positive samples were compared with the results of the drug susceptibility test. RESULTS: Smear-positive samples were LiPA positive in 69 of 73 samples (sensitivity: 94.5%), and smear-negative samples were LiPA positive in 25 of 37 samples (67.6%). More than half of the samples were LiPA positive, even those that were culture-negative or contaminated. Comparison of the 76 culture positive samples with the results of the drug susceptibility test found that all samples were wild type among the RFP-sensitive strains. Among the 8 RFP-resistant strains, 6 were mutation type. All samples shown to be mutation type were obtained from patients with multi-drug resistant tuberculosis. DISCUSSION: Using LiPA, the amount of smear can be used as a factor for detection of RFP-resistant genes. Detection was possible even with culture-negative and contaminated samples, allowing more rapid diagnosis of patients with multi-drug resistant tuberculosis. PMID- 20960951 TI - [The pathogenesis of the bowel infection with the Mycobacterium tuberculosis]. AB - The prevalence of primary intestinal tuberculosis is increasing with social change and medical progress. However, it remains unknown whether or not primary intestinal tuberculosis exists without the involvement of other internal organs. This review verifies hypotheses about infectious courses of intestinal tuberculosis. We also evaluate the significance of bowel infection. As a result, we found some patients with intestinal tuberculosis who do not have tuberculosis lesions in other internal or external organs, and the tubercle bacillus, which is ordinarily transmitted with airborne droplet nuclei, might cause oral transmission by several factors. PMID- 20960952 TI - [Weigh the patients! Weight stability - better survival]. PMID- 20960953 TI - [Recurrent herpes simplex labialis infections. Possible prevention with a new therapeutic regimen]. PMID- 20960954 TI - [Von Willebrand disease--from biochemistry to clinical practice]. PMID- 20960955 TI - [Gender and medicine--an ambiguous and politically sensitive question. Experiences of gender education in Linkoping]. PMID- 20960956 TI - [European accreditation for safe and equal specialist care. Endocrinologic surgery one of the many disciplines]. PMID- 20960957 TI - [Internship supervisor--a task for the future]. PMID- 20960958 TI - [The internship supervisor's task...to make the impossible possible]. PMID- 20960959 TI - [How risky is being a consultant physician?]. PMID- 20960960 TI - [Organ donation after heart death: therapeutic interests touch each other]. PMID- 20960961 TI - [Ethics and transportation certificates 1: issuing certificates sets high demands on the physician's integrity and objectivity]. PMID- 20960962 TI - [Results, not profits, the most important in health care]. PMID- 20960963 TI - [Schumann's life was a fight against the demons of disease]. PMID- 20960965 TI - Bibliography. Transfusion medicine and immunohematology. Current world literature. PMID- 20960964 TI - [On the 65th birthday of the editor of Vnitrni lekarstvi, Petra Svaciny]. PMID- 20960966 TI - [NHLW guideline and its application to regional health care systems]. PMID- 20960967 TI - [Security measure in center hospitals]. PMID- 20960968 TI - [Security management in regional health information exchange (RHIE)]. PMID- 20960969 TI - Phylogeny of fungal hemoglobins and expression analysis of the Aspergillus oryzae flavohemoglobin gene fhbA during hyphal growth. AB - The fhbA genes encoding putative flavohemoglobins (FHb) from Aspergillus niger and Aspergillus oryzae were isolated. Comparison of the deduced amino acid sequence of the A. niger fhbA gene and other putative filamentous fungal FHb encoding genes to that of Ralstonia eutropha shows an overall conserved gene structure and completely conserved catalytic amino acids. Several yeasts and filamentous fungi, including both Aspergillus species have been found to contain a small FHb gene family mostly consisting of two family members. Based on these sequences the evolutionary history of the fungal FHb family was reconstructed. The isolated fhbA genes from A. oryzae and A. niger belong to a phylogenetic group, which exclusively contains Aspergillus genes. Different experimental approaches show that fhbA transcript levels appear during active hyphal growth. Moreover, in a pclA-disrupted strain with a hyperbranching growth phenotype, the transcript levels of the fhbA gene were 2-5 times higher compared to the wild type. These results suggest that FHb from filamentous fungi have a function that is correlated to the hyphal growth phenotype. PMID- 20960970 TI - Saccharomyces cerevisiae BY4741 and W303-1A laboratory strains differ in salt tolerance. AB - Saccharomyces cerevisiae yeast cells serve as a model to elucidate the bases of salt tolerance and potassium homeostasis regulation in eukaryotic cells. In this study, we show that two widely used laboratory strains, BY4741 and W303-1A, differ not only in cell size and volume but also in their relative plasma membrane potential (estimated with a potentiometric fluorescent dye diS-C3(3) and as Hygromycin B sensitivity) and tolerance to alkali-metal cations. W303-1A cells and their mutant derivatives lacking either uptake (trk1 trk2) or efflux (nha1) systems for alkali-metal cations are more tolerant to toxic sodium and lithium cations but also more sensitive to higher external concentrations of potassium than BY4741 cells and their mutants. Moreover, our results suggest that though the two strains do not differ in the total potassium content, the regulation of intracellular potassium homeostasis is probably not the same in BY4741 and W303 1A cells. PMID- 20960971 TI - Trypsin-like proteins of the fungi as possible markers of pathogenicity. AB - Sequences of peptidases with conserved motifs around the active site residues that are characteristic of trypsins (similar to trypsin peptidases, STP) were obtained from publicly-available fungal genomes and related databases. Among the 75 fungal genomes, 29 species of parasitic Ascomycota contained genes encoding STP and their homologs. Searches of non-redundant protein sequences, patented protein sequences, and expressed sequence tags resulted in another 18 STP sequences in 10 fungal species from Ascomycota, Basidiomycota, and Zygomycota. A comparison of fungi species containing STP sequences revealed that almost all are pathogens of plants, animals or fungi. A comparison of the primary structure of homologous proteins, including the residues responsible for substrate binding and specificity of the enzyme, revealed three groups of homologous sequences, all presumably from S1 family: trypsin-like peptidases, chymotrypsin-like peptidases and serine peptidases with unknown substrate specificity. Homologs that are presumably functionally inactive were predicted in all groups. The results in general support the hypothesis that the expression of trypsin-like peptidases in fungi represents a marker of fungal phytopathogenicity. A phylogenetic tree was constructed using peptidase and homolog amino acid sequences, demonstrating that all have noticeable differences and almost immediately deviate from the common root. Therefore, we conclude that the changes that occurred in STP of pathogenic fungi in the course of evolution represent specific adaptations to proteins of their respective hosts, and mutations in peptidase genes are important components of life-style changes and taxonomic divergence. PMID- 20960972 TI - Characterisation of Phytophthora capsici isolates from black pepper in Vietnam. AB - Phytophthora foot rot of black pepper caused by Phytophthora capsici is a major disease of black pepper (Piper nigrum) throughout Vietnam. To understand the population structure of P. capsici, a large collection of P. capsici isolates from black pepper was studied on the basis of mating type, random amplified microsatellites (RAMS) and repetitive extragenic palindromic (REP) fingerprinting. Two mating types A1 and A2 were detected in four provinces in two climatic regions, with A1:A2 ratios ranging from 1:3 to 1:5. In several instances A1 and A2 mating types were found to co-exist in the same farm or black pepper pole, suggesting the potential for sexual reproduction of P. capsici in the field in Vietnam although its contribution to disease epidemics is uncertain. RAMS and REP DNA fingerprinting analysis of 118 isolates of P. capsici from black pepper showed that the population was genetically more diverse where two mating types were found, although the overall genetic diversity was low with most of the isolates belonging to one clonal group. The implication of these findings is discussed. The low diversity among isolates suggests that the P. capsici population may have originated from a single source. There was no genetic differentiation of isolates from different climatic regions. In addition to the large clonal group, several isolates with unique RAMS/REP phenotypes were also detected. Most of these unique phenotypes belonged to the minority A1 mating type. This may have significant implications for a gradual increase in overall genetic diversity. PMID- 20960973 TI - Analysis and clinical relevance of microparticles from red blood cells. AB - PURPOSE OF REVIEW: The mechanisms involved in the formation of red blood cell (RBC) microparticles in vivo as well as during erythrocyte storage are reviewed, and the potential role of microparticles in transfusion medicine is described. RECENT FINDINGS: Microparticles release is an integral part of the erythrocyte ageing process, preventing early removal of RBCs. Proteomics analyses have outlined the key role of band 3-ankyrin anchoring complex and the occurrence of selective RBC membrane remodelling mechanisms in microparticles formation. The presence of several RBC antigens, expressed on microparticles, has been demonstrated. The potential deleterious effects of RBC microparticles in transfused recipients, including hypercoagulability, microcirculation impairment and immunosuppression, are discussed. SUMMARY: Formation and role of RBC microparticles are far from being completely understood. Combining various approaches to elucidate these mechanisms could improve blood product quality and transfusion safety. Implementation of RBC microparticles as biomarkers in the laboratory routine needs to overcome technical barriers involved in their analysis. PMID- 20960974 TI - Proceedings and abstracts of the International Workshop on Clinical and Molecular Aspects of Congenital Heart Block. Stockholm, Sweden. September 17-19, 2010. PMID- 20960975 TI - Civilian Health and Medical Program of the Uniformed Services (CHAMPUS)/TRICARE: inclusion of TRICARE Retail Pharmacy Program in federal procurement of pharmaceuticals. AB - Section 703 of the National Defense Authorization Act for Fiscal Year 2008 (NDAA 08) states with respect to any prescription filled on or after the date of enactment, the TRICARE Retail Pharmacy Program shall be treated as an element of the DoD for purposes of procurement of drugs by Federal agencies under section 8126 of title 38, United States Code (U.S.C.), to the extent necessary to ensure pharmaceuticals paid for by the DoD that are provided by network retail pharmacies under the program to eligible covered beneficiaries are subject to the pricing standards in such section 8126. DoD issued a final rule on March 17, 2009, implementing the law. On November 30, 2009, the U.S. District Court for the District of Columbia remanded the final rule to DoD (without vacating the rule) for DoD to consider in its discretion whether to readopt the current iteration of the rule or adopt another approach. This final rule is the product of that reconsideration. DoD is readopting the 2009 final rule, with some revision. PMID- 20960976 TI - Countermeasures Injury Compensation Program (CICP): administrative implementation, interim final rule. Interim final rule with request for comments. AB - The Public Readiness and Emergency Preparedness Act (PREP Act) authorizes the Secretary of Health and Human Services (the Secretary) to establish the Countermeasures Injury Compensation Program (CICP or Program). The Department of Health and Human Services (HHS) is issuing this interim final rule with request for comments in order to establish administrative policies, procedures, and requirements for the CICP. This Program is designed to provide benefits to certain persons who sustain serious physical injuries or death as a direct result of administration or use of covered countermeasures identified by the Secretary in declarations issued under the PREP Act. In addition, the Secretary may provide death benefits to certain survivors of individuals who died as the direct result of such covered injuries or their health complications. The Secretary is seeking public comments on this interim final rule. PMID- 20960977 TI - The elephant in the room: huge rates of nursing and healthcare worker injury. PMID- 20960979 TI - Nonverbal Communications. PMID- 20960978 TI - Science, healing, and courage: the legacy of Florence Nightingale. PMID- 20960981 TI - I love college! PMID- 20960980 TI - Mental health courts: an effective way for treating offenders with serious mental illness. PMID- 20960982 TI - To breastfeed or not to breastfeed: a review of the impact of lactational exposure to polychlorinated biphenyls (PCBs) on infants. AB - Researchers have long debated the adverse effects of exposure to polychlorinated biphenyls (PCBs) on children versus the benefits of breastfeeding. In this article, the authors provide an overview of the known health effects of PCBs in children and examine the level of evidence regarding the risk of postnatal exposure via breastfeeding. The major source of PCBs is environmental, with over 90% of human exposure through the food chain. PCB exposure in infants is predominantly via breast milk, but limited evidence exists of significant toxicity associated with this mode of transmission. Breastfeeding should, therefore, continue to be encouraged on the basis of evidence of the benefits derived from human milk coupled with inconclusive proof that lactational PCB exposure has major detrimental effects on the overall health and development of infants. PMID- 20960983 TI - Effectiveness, suitability, and performance testing of the SKC Deployable Particulate Sampler (DPS) as compared to the currently deployed Airmetrics MiniVol portable air sampler. AB - Epidemiological studies have linked particulate matter (PM) exposure to morbidity and mortality from cardiovascular and respiratory disease. In order to monitor and assess the potential PM health risk to deployed military personnel, the U.S. Army must field a portable sampler that can accurately sample particles with an aerodynamic diameter less than or equal to a nominal 2.5 mm (PM2.5). In the study described in this article, the SKC Deployable Particulate Sampler (DPS) was compared to the currently deployed Airmetrics MiniVol portable air sampler in the hot, dry environment of Yuma Proving Grounds, Arizona, and the cold, wet environment of Fort Drum, New York. For all measurements taken and averaged, the DPS and the MiniVol did not differ significantly for mean concentration collected; however, the DPS collected 4.0 times more mass than the MiniVol (p < .05). The DPS was shown to be an improvement over the MiniVol when evaluated for measures of effectiveness, suitability, and performance. PMID- 20960984 TI - Common regulatory practices in onsite wastewater programs: a willing suspension of disbelief. PMID- 20960985 TI - Global environmental health: sustainability. PMID- 20960986 TI - The quandary and the essence of leadership. PMID- 20960987 TI - Revitalizing school health programs worldwide. AB - Each year, the Shils Fund recognizes outstanding activities that help improve oral health. The program is named in memory of Dr. Edward B. Shils, who led the Dental Manufacturers of America and Dental Dealers of America for more than 50 years. A 2010 Shils Award will be given to an innovative school health initiative called Fit For Schools Program (FFSP) in the Philippines. Such recognition in the US indicates the lessons that can be learned from a program initially tailored for another country. Health in a highly industrialized nation can be enhanced by heeding the FFSP principles used to craft an effective health promotion initiative. This evidence-based intervention is not exclusively an oral health initiative; it is an integration with other evidence-based health interventions and models a sustainable public-private partnership to advance positive health outcomes in socially responsible entrepreneurial ways. As the editor of this column in Compendium, I wish to applaud both leaders of FFSP: Dr. Habib Benzian and Dr. Bella Monse. The following article was written by the senior advisor, Dr. Benzian, who modestly refers to the program's receipt of another award from the World Bank, the United Nations Development Program, and the World Health Organization in 2009. To my knowledge, the presentation of that award was the first time a health promotion project led by dentists has ever received such high level global recognition and was one of three projects so recognized for innovative solutions to global health in that year. PMID- 20960988 TI - Light-curing considerations for resin-based composite materials: a review. Part II. AB - As discussed in Part I, the type of curing light and curing mode impact the polymerization kinetics of resin-based composite (RBC) materials. Major changes in light-curing units and curing modes have occurred. The type of curing light and mode employed affects the polymerization shrinkage and associated stresses, microhardness, depth of cure, degree of conversion, and color change of RBCs. These factors also may influence the microleakage in an RBC restoration. Apart from the type of unit and mode used, the polymerization of RBCs is also affected by how a light-curing unit is used and handled, as well as the aspects associated with RBCs and the environment. Part II discusses the various clinical issues that should be considered while curing RBC restorations in order to achieve the best possible outcome. PMID- 20960989 TI - Analgesic update: tapentadol hydrochloride. AB - Tapentadol HCI is an opioid (narcotic) analgesic, which also inhibits norepinephrine reuptake. While it appears to display a somewhat lower incidence of nausea and constipation than oxycodone 10 mg to 15 mg, its analgesic efficacy in acute postsurgical dental pain is inferior to ibuprofen 400 mg. Like other single-entity opioids, tapentadol should not be used as a first-line agent for postsurgical dental pain but can be employed as an add-on drug for breakthrough pain in patients already using a regimen of a non-steroidal anti-inflammatory drug and/or acetaminophen. PMID- 20960990 TI - There is more to front teeth than looks alone: diagnosis and treatment planning. AB - When treating high-risk parafunctional cases, patient compliance and understanding of the disease is paramount in the success and longevity of the restorations. Controlling the patient's expectations for augmenting the length and blocking out the dark color was accomplished (Figure 15 through Figure 18). PMID- 20960991 TI - Regenerative strategies for anterior esthetic rehabilitation: a clinical and histologic case report. AB - In order to solve the substantial challenge of achieving natural esthetics in compromised situations, a number of techniques and materials have been developed to restore deficient alveolar bone and maintain existing bone and soft tissue. This article reviews developments in both areas and reports on a clinical treatment in which a new form of xenograft in conjunction with a cross-linked, cell-occlusive membrane was used in a severely compromised anterior maxilla in preparation for placement of platform-switched implants. PMID- 20960992 TI - Severity and prevalence of plaque-induced gingivitis in the Chinese population. AB - This study investigated the prevalence and severity of gingivitis and plaque in a representative Chinese population of adults. METHODS: Using the Loe-Silness gingivitis index (GI) and the modified Quigley-Hein plaque index (PULI), researchers examined 1143 patients from Guangzhou, Shenyang, and Nanjing for the presence of gingivitis and plaque. A two-tailed t-test was used to determine significant differences in the GI and PLI scores between gender and urban/rural areas. The data pertaining to study sites and age groups were compared using the Kruskal-Wallis one-way analysis of variances (ANOVA) by ranks. The correlation between GI/PLI and age was examined using the Pearson correlation coefficient. Age differences among three sites were analyzed with the one-way ANOVA. RESULTS: The age and urban/rural compositions (mean age 42.2 years) paralleled the 2008 China census. The overall average and standard deviation of GI and PLI were 1.101 +/- 0.239 and 3.394 +/- 0.578, respectively. Age significantly correlated with GI and PLI (P < .0001). The PLI in males was significantly higher (P < .0001) than in females; however, no significant difference was noted between GI in males compared to females. Patients in rural areas showed a significantly higher GI and PLI (t = 7.723, P < .0001; t = 7.072, P < .0001) than those in urban ones. CONCLUSIONS: Clinical trials evaluating a product's antigingivitis efficacy should recruit participants from a population that represents accurately the intended product users. Variables should include gender, race, age, and geography. PMID- 20960993 TI - A dental esthetic checklist for treatment planning in esthetic dentistry. AB - A dental esthetic checklist form has been introduced for use in the diagnostic work-up of a patient accepted for treatment in an Advanced Education in General Dentistry program. The checklist, divided into seven basic criteria, is not a complete list of all possible categories and nuances that an esthetic restorative assessment might include. The correct initial identification of these criteria does not limit the dentist from pursuing more detail; in fact, this checklist is an introductory organizer that invites further exploration. In the authors' experience, the use of this form prompts the student to broaden his or her vision from purely a dental/periodontal focus to one that encompasses lip, cheek, and tongue configurations; smile; facial features; and related planes of symmetry. This approach directs the dental treatment plan toward the important additional goal of dentofacial harmony. PMID- 20960994 TI - Creating well-fitting restorations with a digital impression system. AB - The introduction of digital impressioning devices is enabling the creation of better-fitting restorations via the improved data-capture capabilities of these devices. This case report explores the creation of a porcelain-fused-to-metal bridge for a patient, outlining the steps involved in capturing a digital impression and the subsequent changes these impressions enable in the laboratory. While still a relatively new technology, statistics show that restorations created with digital impressions result in better fit, faster seating, and fewer remakes. PMID- 20960995 TI - Multidimensional imaging: immediate and imminent issues. PMID- 20960996 TI - An ambitious agenda. PMID- 20960998 TI - Learning from each to improve dementia care. AB - Recognising that healthcare assistants play a vital role in caring for hospital patients with dementia, two nurses undertook a facilitators course. PMID- 20960997 TI - An opportunity to influence politicians in uncertain times. PMID- 20960999 TI - Power to the people. AB - Nurses have been elected to their NHS boards in a pilot scheme to encourage public participation in decision making. PMID- 20961000 TI - Fast, honest feed back. AB - One NHS has introduced a system allowing patients to record their experiences immediately after contact with services. PMID- 20961001 TI - Help at last for women who lose babies. AB - Women who repeatedly miscarry can find help and support in a nurse-led clinic where care and research have been combined. PMID- 20961002 TI - Teamwork can help new NHS prosper. PMID- 20961003 TI - Understanding the experience and physiology of pain. AB - This article, the third in a series of articles written by pain nurse specialists, explains the underlying physiology of pain. Nociceptive pain describes the normal physiological process relating to tissue damage, and neuropathic pain occurs when there is damage to or dysfunction of the nervous system. These two types of pain are analysed using a case study to provide insight into the multidimensional nature and unique experience of pain. PMID- 20961004 TI - Treatment of patients with urge or stress urinary incontinence. AB - This article outlines the nursing assessment of urinary incontinence, and describes both conservative management of individuals with incontinence and common pharmacological treatment options. The article focuses on therapeutic options for patients with urge or stress incontinence. PMID- 20961005 TI - Urinary dysfunction: assessment and management in stroke patients. AB - Continence care is a high priority during the rehabilitative process following stroke. Effective continence care can significantly improve the quality of life of patients and carers. A lack of knowledge and understanding of the likely causes of incontinence can lead to a failure to adopt the correct care strategies, which may in turn cause incontinence. Nurses are given little training and support in continence care, yet a basic level of training and the ability to assess potential problems may improve rehabilitation progress and outcomes. PMID- 20961006 TI - Gunshot wounds. PMID- 20961007 TI - Present and correct. PMID- 20961008 TI - Nurses as information scientists. PMID- 20961009 TI - Fishing for emerging talent. PMID- 20961010 TI - The case for electronic health records. PMID- 20961011 TI - Something old, something new, something borrowed...something blue. PMID- 20961013 TI - Can I charge more for copies of medical records? PMID- 20961012 TI - Joining a PSO maintains peer review protection. PMID- 20961014 TI - Recent court decisions impact current peer review activity. PMID- 20961015 TI - Complications with a domino effect. PMID- 20961016 TI - Breach notification regulation addresses PHI disclosure. PMID- 20961017 TI - Back pain and mental retardation. AB - A 25-year-old African-American male with mental retardation was brought to the hospital by his caregiver with a chief complaint of low back pain for four months, complicated by recent anorexia and weight loss. Lumbar spine x-ray showed spondylosis at L2-L3 with normal sacroiliac joints, hip and femur; MRI showed a fracture of the L2 vertebral body. Consequently he underwent L2 anterior corpectomy with bone graft replacement and fusion. Spinal surgical biopsy revealed large cell neuroendocrine carcinoma with immunostaining studies suggesting lung origin. A chest CT scan showed a large solid mass in the mediastinum. CONCLUSION: We are reporting a unique case of large cell neuroendocrine carcinoma (LCNEC) of the lung in a nonsmoking young male which presented as low back pain to emphasize the importance of taking symptoms of patients with mental retardation seriously to avoid diagnostic delay. PMID- 20961018 TI - Is the cosyntropin test redundant in the acutely ill patient suspected of adrenal insufficiency? A case report and literature review. AB - Relative adrenal insufficiency is an increasingly documented phenomenon in acute illness. Recognizing and treating such adrenal insufficiency has the potential to improve outcome. A post-cosyntropin cortisol value greater than 20 microg/dl has been recognized as consistent with normal adrenal function. While the cosyntropin test remains a superb test of primary adrenal failure, its utilityin the diagnosis of secondary adrenal failure is less clearly defined. In the setting of acute illness, a number of other criteria such as increment from basal serum cortisol have been used; however, the criteria for establishing adrenal insufficiency remains less clearly defined. We report a 44-year-old Caucasian female who presented with hypoglycemia and hypotension. The patient had a basal cortisol of 1.6 ug/dl and a peak serum cortisol of 23.3 ug/dl after 250 ug of cosyntropin. Despite this apparent normal response to cosyntropin, the patient responded to glucocorticoids with an improvement in her clinical status. Pituitary MRI revealed a 7-mm pituitary cyst. Pending the availability of free cortisol levels, it is prudent not to disregard low basal cortisol levels, even in the presence of a normal cosyntropin response. We recommend that clinicians managing acutely ill patients have a low threshold for initiating glucocorticoid replacement in the presence of hypoglycemia and shock regardless of the peak cortisol values. PMID- 20961019 TI - A rite of passage. PMID- 20961020 TI - Don't be sidetracked--follow the clues. PMID- 20961021 TI - Code: complex. The complex physician-insurance relationship. PMID- 20961022 TI - Pregnancy and tobacco use. PMID- 20961023 TI - Right coronary artery to coronary sinus and right atrium fistula. PMID- 20961024 TI - Giant gastric hyperplastic polyp: not always a benign lesion. AB - Giant gastric hyperplastic polyps constitute of around 76% of all gastric polyps found. They are often found incidentally on upper GI endoscopy. They often present with occult GI bleeding causing iron deficiency anemia or partial gastric outlet obstruction. Although mostly benign, they do have potential for malignant transformation and hence must be excised endoscopically or surgically, whichever may be feasible. We hereby present a couple of cases of gastric hyperplastic polyps in an attempt to add to the current literature on this rather rare entity. PMID- 20961026 TI - Off the page and into practice. PMID- 20961025 TI - Sometimes I feel really stupid. PMID- 20961027 TI - Legal issues of perinatal oral health. AB - Every dental health care provider will inevitably be faced with perinatal oral health issues involving patients or staff members. The legal issues involving perinatal dental care are reviewed including the laws of malpractice claims by patients, employment claims involving staff, and Dental Board of California investigations involving patient care, and the administration of the business of dentistry. Recommendations are made for record keeping. PMID- 20961028 TI - Oral health during pregnancy and early childhood: barriers to care and how to address them. AB - This brief supplements recommendations developed by the California Dental Association Foundation and the American College of Obstetricians and Gynecologists that recommended practice guidelines during the perinatal period. This brief addresses the importance and safety of oral health care during pregnancy and outlines some of the multiple system-level barriers that make it difficult for many women to access oral health services, as well as offers specific strategies for mitigating these barriers. PMID- 20961029 TI - Physiologic and pharmacologic factors related to the provision of dental care during pregnancy. AB - During pregnancy, numerous physiologic changes occur that allow the mother to accommodate the needs of the developing fetus. Oral health care professionals should be knowledgeable about these changes and the impact they have on the safe provision of prophylactic and therapeutic dental care to pregnant women. Herein, the authors describe maternal physiologic adaptations and discuss changes in drug processing and placental drug transfer in order to enhance the knowledge base of oral health care professionals. PMID- 20961030 TI - Application of the perinatal oral health guidelines in clinical practice. AB - While dental treatment during pregnancy is safe, pregnant women go to the dentist less frequently than women who are not pregnant. METHODS: Practical strategies to reduce barriers to care based on the guidelines are presented. RESULTS: Collaboration with perinatal providers is critical to refer pregnant women into dental care. Recommendations regarding timing of care, treatment sequence, and patient positioning will help providers deliver care. CONCLUSION: Practical implementation of the guidelines can increase access to dental care for pregnant women and improve the oral health of the pregnant woman and her child. PMID- 20961032 TI - Going viral: getting the bugs out of your travel plans. PMID- 20961031 TI - The oral health conditions of the homeless in downtown Los Angeles. AB - The aim of this study is to evaluate a community health project serving the homeless and to assess their oral health. Clinical charts of 1,088 patients were evaluated. The prevalence of untreated caries was 58 percent among adults with a mean of 6.3 decayed teeth. Homeless individuals are in great need of restorative, surgical, and periodontal dental procedures. Community health projects are important in assessing and improving the oral health of the underserved homeless population. PMID- 20961033 TI - A leadership for life. PMID- 20961034 TI - Mothers' feelings about breastfeeding their premature babies in a rooming-in facility. AB - This study aimed at learning about the feelings experienced by mothers while breastfeeding their premature babies in a rooming-in facility, by means of individual interviews with 33 mothers during the period of February to April 2006, at a maternity hospital in Natal/RN/Brazil. The main feelings referred by the mothers regarding their inability to breastfeed their premature babies immediately after delivery were: sorrow, guilt, disappointment, frustration, insecurity, and fear of touching, holding or harming the delicate babies while breastfeeding. However, the mother-child bond that was formed when the baby was discharged from the Neonatal Intensive Care Unit and taken to the rooming-in facility was reflected by feelings of fulfillment, pride, and satisfaction at experiencing the first breastfeeding. PMID- 20961035 TI - Adaptable synthesis of C-glycosidic multivalent carbohydrates and succinamide linked derivatization. AB - A modular approach to the synthesis of trivalent C-glycosidic carbohydrates is described. The approach is illustrated employing carboxylate-terminated C glycosidic d-mannose, d-glucose, and d-galactose derivatives with different length C1-linked spacer units and also core units with different length linker units attached. The central core scaffold is additionally functionalized via a succinamide-based, conjugatable linker unit, exemplified in an extended multivalent derivative [31] and a pyrene-bearing fluorsecent-labeled tris-C mannosyl conjugate [33]. PMID- 20961036 TI - Evaluation of the beta value of the phenylene unit by probing exchange interaction between two nitroxides. AB - Oligophenylene molecular rods with bicyclo[2.2.2]octane having two nitronyl nitroxide radicals were synthesized to investigate the decay constant of p phenylene. By the measurement and simulation of the ESR spectra of the biradicals with different rod length, it was found that the exchange interaction was decreased with the decay constant beta of 0.51 +/- 0.01 A(-1). This result indicates that the spin-spin exchange interaction between neutral radicals has a decay constant similar to the molecular conductance. PMID- 20961037 TI - Modular face-to-face assembly of multichromophore arrays that absorb across the complete UV-visible spectrum and into the near-IR. AB - Defined face-to-face structures of phthalocyanine and porphyrin chromophores can be prepared using a modular strategy that allows directional, stepwise construction. MU-Oxo linkage between the central group of 14 metalloid atoms Si and Ge ensures pi-overlap between the macrocycles, and exciton coupling effects further extend the absorption profile to provide arrays that absorb across the whole UV-visible spectrum and into the near-IR. The strategy is sufficiently versatile to be extended to synthesis of higher defined oligomers and subsequent functionalization or attachment at either or both ends of the stack. PMID- 20961038 TI - A comparison of methanobactins from Methylosinus trichosporium OB3b and Methylocystis strain Sb2 predicts methanobactins are synthesized from diverse peptide precursors modified to create a common core for binding and reducing copper ions. AB - Methanobactins (mb) are low-molecular mass, copper-binding molecules secreted by most methanotrophic bacteria. These molecules have been identified for a number of methanotrophs, but only the one produced by Methylosinus trichosporium OB3b (mb-OB3b) has to date been chemically characterized. Here we report the chemical characterization and copper binding properties of a second methanobactin, which is produced by Methylocystis strain SB2 (mb-SB2). mb-SB2 shows some significant similarities to mb-OB3b, including its spectral and metal binding properties, and its ability to bind and reduce Cu(II) to Cu(I). Like mb-OB3b, mb-SB2 contains two five-member heterocyclic rings with associated enethiol groups, which together form the copper ion binding site. mb-SB2 also displays some significant differences compared to mb-OB3b, including the number and types of amino acids used to complete the structure of the molecule, the presence of an imidazolone ring in place of one of the oxazolone rings found in mb-OB3b, and the presence of a sulfate group not found in mb-OB3b. The sulfate is bonded to a threonine-like side chain that is associated with one of the heterocyclic rings and may represent the first example of this type of sulfate group found in a bacterially derived peptide. Acid-catalyzed hydrolysis and decarboxylation of the oxazolone rings found in mb-OB3b and mb-SB2 produce pairs of amino acid residues and suggest that both mb-OB3b and mb-SB2 are derived from peptides. In support of this, the gene for a ribosomally produced peptide precursor for mb-OB3b has been identified in the genome of M. trichosporium OB3b. The gene sequence indicates that the oxazolone rings in mb-OB3b are derived from the combination of a cysteine residue and the carbonyl from the preceding residue in the peptide sequence. Taken together, the results suggest methanobactins make up a structurally diverse group of ribosomally produced, peptide-derived molecules, which share a common pair of five-member rings with associated enethiol groups that are able to bind, reduce, and stabilize copper ions in an aqueous environment. PMID- 20961039 TI - Evaluation of four genes in rice for their suitability as endogenous reference standards in quantitative PCR. AB - The genetically modified (GM) food/feed quantification depends on the reliable detection systems of endogenous reference genes. Currently, four endogenous reference genes including sucrose phosphate synthase (SPS), GOS9, phospholipase D (PLD), and ppi phosphofructokinase (ppi-PPF) of rice have been used in GM rice detection. To compare the applicability of these four rice reference genes in quantitative PCR systems, we analyzed the target nucleotide sequence variation in 58 conventional rice varieties from various geographic and phylogenic origins, also their quantification performances were evaluated using quantitative real time PCR and GeNorm analysis via a series of statistical calculation to get a "M value" which is negative correlation with the stability of genes. The sequencing analysis results showed that the reported GOS9 and PLD taqman probe regions had detectable single nucleotide polymorphisms (SNPs) among the tested rice cultivars, while no SNPs were observed for SPS and ppi-PPF amplicons. Also, poor quantitative performance was detectable in these cultivars with SNPs using GOS9 and PLD quantitative PCR systems. Even though the PCR efficiency of ppi-PPF system was slightly lower, the SPS and ppi-PPF quantitative PCR systems were shown to be applicable for rice endogenous reference assay with less variation among the C(t) values, good reproducibility in quantitative assays, and the low M values by the comprehensive quantitative PCR comparison and GeNorm analysis. PMID- 20961040 TI - Analysis of agricultural residues on tea using d-SPE sample preparation with GC NCI-MS and UHPLC-MS/MS. AB - This study presents new sample preparation and analytical procedures for the quantification of pesticides on processed tea leaves. The new method includes tea extraction and dispersive solid phase extraction (d-SPE) to prepare gas chromatography (GC) and ultrahigh-performance liquid chromatography (UHPLC)-ready samples, providing a fast and cost-effective solution for time-sensitive industrial analysis to fulfill regulatory requirements. Both GC-negative chemical ionization mass spectrometry (GC-NCI-MS) and UHPLC-tandem mass spectrometry (UHPLC-MS/MS) were employed to produce highly sensitive and reproducible data. Excellent limits of detection (typically below 1 MUg/kg for GC and 10 MUg/kg for UHPLC), wide linearity ranges, and good recoveries (mostly >70%) were achieved on the selected pesticides. Twenty-seven tea samples purchased from local grocery stores were analyzed using the newly developed methods. Among the pesticides analyzed, endosulfan sulfate and kelthane were the most frequently detected by GC NCI-MS and imidacloprid and acetamiprid by UHPLC-MS/MS in these teas. The samples were found to be relatively clean, with <1 mg/kg of total pesticide residues. The organic-labeled teas were significantly cleaner than nonorganic ones. The cost per gram of tea did not correlate with pesticide residue levels detected. PMID- 20961041 TI - Differential effect of elicitors on biphenyl and dibenzofuran formation in Sorbus aucuparia cell cultures. AB - The Rosaceous subtribe Pyrinae (formerly subfamily Maloideae) is well-known for its economically important fruit trees, such as apple and pear, and also includes Sorbus aucuparia. Elicitor-treated S. aucuparia cell cultures are used to study the biosynthesis of the Pyrinae-specific phytoalexins, biphenyls and dibenzofurans. Three biphenyls (aucuparin, noraucuparin, 2'-hydroxyaucuparin) and a dibenzofuran (eriobofuran) were isolated and structure elucidated using GC-MS and NMR. A second dibenzofuran of low abundance was tentatively assigned as noreriobofuran. Treatment of S. aucuparia cell cultures with yeast extract induced the formation of aucuparin as the major phytoalexin. In contrast, addition of preparations from the fire blight bacterium, Erwinia amylovora, and the scab-causing fungus, Venturia inaequalis, resulted in accumulation of eriobofuran as the major inducible constituent. Methyl jasmonate was a poor elicitor. The observations are suggestive of a biogenic relationship between biphenyls and dibenzofurans. Elicitor-treated S. aucuparia cell cultures provide an interesting in vitro system for studying biphenyl and dibenzofuran metabolism in the economically valuable Pyrinae. PMID- 20961042 TI - Cordycepin induces apoptosis of CGTH W-2 thyroid carcinoma cells through the calcium-calpain-caspase 7-PARP pathway. AB - Cordycepin, a nucleoside isolated from Cordyceps sinensis, is an inhibitor of polyadenylation and has an antitumor effect. We used CGTH W-2, a follicular thyroid carcinoma cell line, to study the mechanism of the anticancer effect of cordycepin. Cordycepin decreased cell viability and resulted in apoptosis but not necrosis. Cordycepin increased intracellular calcium levels triggering calpain activation, which led to apoptosis. BAPTA/AM and calpeptin inhibited the cordycepin-induced cleavage of caspase 7 and poly (ADP-ribose) polymerase (PARP), implying an upstream role of calcium and calpain. CGTH W-2 cells expressed four subtypes of adenosine receptors (AR), A1AR, A2AAR, A2BAR, and A3AR. Specific antagonists to AR subtypes all blocked cordycepin-induced apoptosis to different degrees. Small interfering RNA for A1AR and A3AR abrogated cordycepin-induced apoptosis. In conclusion, the cordycepin-induced apoptosis of CGTH W-2 cells is mediated by the calcium-calpain-caspase 7-PARP pathway, and ARs are involved in the apoptotic effect of cordycepin. PMID- 20961043 TI - Ergosterol profiles, fatty acid composition, and antioxidant activities of button mushrooms as affected by tissue part and developmental stage. AB - This article investigated the mycochemical profiles and the antioxidant activities of the lipophilic extracts of the white and brown button mushrooms. We found that only free ergosterols were present in both mushrooms at 2.04-4.82 mg/g dry matter (DM). Ergosterol concentration was higher in early growth stages but decreased as the mushrooms grew, and it distributed evenly between the caps and stems during early developmental stages but accumulated more in the caps after maturation. The photochemiluminescence (PCL) values of the two mushrooms were 5.49-10.48 nmol trolox equivalent/mg DM, and the EC50 values of 2,2-diphenyl-1 picrylhydrazyl (DPPH) assay ranged 20.19-41.49 mg DM/MUg DPPH. The ergosterol content positively correlated with the antioxidant activities (r2>0.89). The total fatty acid content was 8.7 mg/g DM in the white and 5.1 mg/g DM in the brown button mushroom and contained mainly linoleic, palmitic, and stearic acids. Our data provide guidance for optimized harvesting time of mushrooms and maximized health benefits. PMID- 20961044 TI - Comparative protein and metabolite profiling revealed a metabolic network in response to multiple environmental contaminants in Mycobacterium aromativorans JS19b1(T). AB - Mycobacterium aromativorans JS19b1(T) was isolated from a petroleum-contaminated site that was acclimated almost 100 years. In the present study, metabolism of several polycyclic aromatic hydrocarbons (PAHs) and structural analogues in JS19b1(T) was studied. The proteomic profiles were compared when JS19b1(T) was cultured in nutrient broth and glucose-, phenanthrene-, and phthalate supplemented mineral media. Proteomic analysis showed notable characteristics of this species, for instance, the existence of enzymes for degradation of multiple classes of chemicals including biphenyl, phenanthrene, dibenzothiophene, and organophosphorus pesticides. Phenanthrene degradation enzymes were detected only in phenanthrene-fed cells, suggesting a very tight regulation of the enzymes. Detection of the other enzymes under various treatment conditions indicated that their regulation may be through very complex mechanisms. In comparison with common major metabolites, PAH transformations produced various types of potentially toxic intermediates, including epoxide, quinone, phenols, aldehydes, and phthalates. In a bioenergy production aspect, PAH transformation does not seem to provide substrates for glycolysis and pentose phosphate pathways. This study signifies the potential of protein profiling for studies of relatively uncharacterized bacteria for biodegradation of environmental pollutants. PMID- 20961045 TI - tert-Butoxide-mediated arylation of benzene with aryl halides in the presence of a catalytic 1,10-phenanthroline derivative. AB - Sodium tert-butoxide mediates the coupling of aryl halides with benzene derivatives without the aid of transition metal catalysts but with a catalytic 1,10-phenanthroline derivative. PMID- 20961046 TI - Identification of protonation state by XPS, solid-state NMR, and DFT: characterization of the nature of a new theophylline complex by experimental and computational methods. AB - Recent studies suggested that X-ray photoelectron spectroscopy (XPS) sensitively determines the protonation state of nitrogen functional groups in the solid state, providing a means for distinguishing between co-crystals and salts of organic compounds. Here we describe how a new theophylline complex with 5 sulfosalicylic acid dihydrate was established as a salt by XPS prior to assignment with conventional methods. The presence of a C=NH(+) (N9) N1s peak in XPS allows assignment as a salt, while this peak is clearly absent for a theophylline co-crystal. The large low frequency shift for N9 observed by (15)N solid-state nuclear magnetic resonance spectroscopy (ssNMR) and corresponding density functional theory (DFT) calculations confirm that protonation has occurred. The crystal structure and further analytical studies confirm the conclusions reached with XPS and ssNMR. This study demonstrates XPS as an alternative technique for determining whether proton transfer has occurred in acid-base complexes. PMID- 20961047 TI - Circular logic: nonribosomal peptide-like macrocyclization with a ribosomal peptide catalyst. AB - A protease from ribosomal peptide biosynthesis macrocyclizes diverse substrates, including those resembling nonribosomal peptide and hybrid polyketide-peptide products. The proposed mechanism is analogous to thioesterase-catalyzed chemistry, but the substrates are amide bonds rather than thioesters. PMID- 20961048 TI - Assessing the purity of metal-organic frameworks using photoluminescence: MOF-5, ZnO quantum dots, and framework decomposition. AB - Photoluminescence (PL) spectroscopy was used to characterize nanoscale ZnO impurities, amine-donor charge-transfer exciplexes, and framework decomposition in samples of MOF-5 prepared by various methods. The combined results cast doubt on previous reports describing MOF-5 as a semiconductor and demonstrate that PL as a tool for characterizing MOF purity possesses advantages such as simplicity, speed, and sensitivity over currently employed powder XRD MOF characterization methods. PMID- 20961049 TI - Carboranylamidinates. AB - Carboranylamidinate anions are readily accessible via addition of N,N' dialkylcarbodiimides to lithio-ortho-carborane. They represent a novel difunctional boron-rich ligand system for main group and transition elements (Li, Sn, Cr). Initial structural investigations revealed an unexpected N,C coordination mode instead of N,N'-chelation. PMID- 20961050 TI - Cattle, clean water, and climate change: policy choices for the Brazilian Agricultural Frontier. AB - In the Amazonian agricultural frontier, pasture for cattle ranching is an important and potentially hazardous form of land use because of sediment erosion as pastures degrade. This relationship between ranching, sediment load, and water quality is likely to further exacerbate environmental impacts, particularly in the context of climate change. We examine the role that river basin councils (RBCs) - a water governance option of Brazil's 1997 National Water Act - might play in managing this nonpoint-source pollution in the Amazonian state of Rondonia. We implement a simple coupled rancher-water system model to compare two potential governance options: a bulk water cleanup charge (BWC) implemented by RBCs and a land-use fine (LUF) for failing to maintain riparian buffers. We find no significant advantage of BWC over LUF in reducing sediment loading while keeping ranching profitable, under a changing climate. We also fail to find in Rondonia the important stake in water issues that has driven water reform elsewhere in Brazil. Moreover, the comparative success of reforestation programs suggests these programs may, in fact, have the potential to manage nonpoint source agricultural pollution in the region. PMID- 20961051 TI - Bovine serum albumin unfolding at the air/water interface as studied by dilational surface rheology. AB - Measurements of the surface dilational elasticity close to equilibrium did not indicate significant distinctions in the surface conformation of different forms of bovine serum albumin (BSA) in a broad pH range. At the same time, the protein denaturation in the surface layer under the influence of guanidine hydrochloride led to strong changes in the kinetic dependencies of the dynamic surface elasticity if the denaturant concentration exceeded a critical value. It was shown that the BSA unfolding at the solution surface occurred at lower denaturant concentrations than in the bulk phase. In the former case, the unfolding resulted in the formation of loops and tails at surface pressures above 12 mN/m. The maximal values of the dynamic surface elasticity almost coincided with the corresponding data for the recently investigated solutions of beta-lactoglobulin, thereby indicating a similar unfolding mechanism. PMID- 20961052 TI - Real-time potentiometric detection of bacteria in complex samples. AB - Detecting and identifying pathogen bacteria is essential to ensure quality at all stages of the food chain and to diagnose and control microbial infections. Traditional detection methods, including those based on cell culturing, are tedious and time-consuming, and their further application in real samples generally implies more complex pretreatment steps. Even though state-of-the-art techniques for detecting microorganisms enable the quantification of very low concentrations of bacteria, to date it has been difficult to obtain successful results in real samples in a simple, reliable, and rapid manner. In this Article, we demonstrate that the label-free detection and identification of living bacteria in real samples can be carried out in a couple of minutes and in a direct, simple, and selective way at concentration levels as low as 6 colony forming units/mL (CFU) in complex matrices such as milk or 26 CFU/mL in apple juice where the pretreatment step of samples is extremely easy. We chose Escherichia coli ( E. coli ) CECT 675 cells as a model organism as a nonpathogenic surrogate for pathogenic E. coli O157:H7 to test the effectiveness of a potentiometric aptamer-based biosensor. This biosensor uses single-walled carbon nanotubes (SWCNT) as excellent ion-to-electron transducers and covalently immobilized aptamers as biorecognition elements. The selective aptamer-target interaction significantly changes the electrical potential, thus allowing for both interspecies and interstrain selectivity and enabling the direct detection of the target. This technique is therefore a powerful tool for the immediate identification and detection of microorganisms. We demonstrate the highly selective detection of living bacteria with an immediate linear response of up to 10(4) CFU/mL. The biosensor can be easily built and used, is regenerated without difficulty, and can be used at least five times with no loss in the minimum amount of detected bacteria. PMID- 20961053 TI - Fate of endocrine-active compounds during municipal biosolids treatment: a review. AB - For two decades, the fates of endocrine-disrupting compounds (EDCs) across various wastewater treatment processes have been studied using chemical and in vitro bioassay measurements. In comparison, little work has been conducted to track the fates of EDCs during municipal biosolids stabilization, particularly using bioassay approaches. This leads to knowledge gaps with respect to understanding which single or combined biosolid treatments facilitate EDC removal, and what the total endocrine-active potency of treated biosolids might be. These unknowns in turn heighten public opposition and distrust of biosolids reuse applications. This review aims to summarize what is currently known regarding EDC removal during commonly used full-scale biosolids treatment processes and highlights analytical challenges that are relevant when in vitro bioassays and chemical analyses are applied to biosolids samples. PMID- 20961054 TI - Palladium-catalyzed asymmetric benzylation of 3-aryl oxindoles. AB - Herein we report palladium-catalyzed asymmetric benzylic alkylation with 3-aryl oxindoles as prochiral nucleophiles. Proceeding analogously to asymmetric allylic alkylation, asymmetric benzylation occurs in high yield and enantioselectivity for a variety of unprotected 3-aryl oxindoles and benzylic methyl carbonates using chiral bisphosphine ligands. This methodology represents a novel asymmetric carbon-carbon bond formation between a benzyl group and a prochiral nucleophile to generate a quaternary center. PMID- 20961056 TI - Stamp wound assay for studying coupled cell migration and cell debris clearance. AB - A new method for studying wound healing under realistic conditions in vitro was developed. The method involves creating defined patterns of damaged cell debris with poly(dimethyl)siloxane (PDMS) stamping. This novel assay permitted the quantification of wound healing rates in the presence of cell debris. Experimental results with this assay suggest that cell migration in the presence of cell debris is a two step process requiring (1) non-muscle myosin II-dependent cell clearance followed by (2) cell migration into newly cleared wound areas. The novel stamp wound assay allows the study of coupled cell migration and debris clearance and is a more realistic wound healing assay in vitro. PMID- 20961057 TI - Quick synthesis of lipid-polymer hybrid nanoparticles with low polydispersity using a single-step sonication method. AB - Lipid-polymer hybrid nanoparticle, consisting of a hydrophobic polymeric core and a lipid monolayer shell, represents a new and promising drug delivery platform that has shown controllable particle size and surface functionality, high drug loading yield, sustained drug release profile, and excellent in vitro and in vivo stability. These lipid monolayer-coated polymeric nanoparticles are typically fabricated through a modified nanoprecipitation method, which involves sample heating, vortexing, and solvent evaporation. Herein we report a new and fast method to synthesize lipid-polymer hybrid nanoparticles with controllable and nearly uniform particle size. Using a bath sonication approach, we demonstrate that the whole hybrid nanoparticle synthesis process can be completed in about 5 min compared with a few hours for previous synthesis approaches. The size and polydispersity of the resulting nanoparticles can be readily controlled by tuning the relative concentrations of individual building components. Colloidal stability tests of the synthesized hybrid nanoparticles in PBS buffer and serum show no signs of aggregation over a period of 5 days. The present method improves the production rate of the hybrid nanoparticles by near 20-fold while not compromising the physicochemical properties of the particles. This work may facilitate the bench-to-bedside translation of lipid-polymer hybrid nanoparticles as a robust drug nanocarrier by allowing for fabricating a large amount of these nanoparticles at high production rate. PMID- 20961055 TI - Inhibition of short patch and long patch base excision repair by an oxidized abasic site. AB - 5'-(2-Phosphoryl-1,4-dioxobutane) (DOB) is an oxidized abasic lesion that is produced by a variety of DNA damaging agents, including several antitumor antibiotics. DOB efficiently and irreversibly inhibits DNA polymerase beta, an essential base excision repair enzyme in mammalian cells. The generality of this mode of inhibition by DOB is supported by the inactivation of DNA polymerase lambda, which may serve as a possible backup for DNA polymerase beta during abasic site repair. Protein digests suggest that Lys72 and Lys84, which are present in the lyase active site of DNA polymerase beta, are modified by DOB. Monoaldehyde analogues of DOB substantiate the importance of the 1,4-dicarbonyl component of DOB for efficient inactivation of Pol beta and the contribution of a freely diffusible electrophile liberated from the inhibitor by the enzyme. Inhibition of DNA polymerase beta's lyase function is accompanied by inactivation of its DNA polymerase activity as well, which prevents long patch base excision repair of DOB. Overall, DOB is highly refractory to short patch and long patch base excision repair. Its recalcitrance to succumb to repair suggests that DOB is a significant source of the cytotoxicity of DNA damaging agents that produce it. PMID- 20961058 TI - On the concept of critical surface excess of micellization. AB - The critical surface excess of micellization (CSEM) should be regarded as the critical condition for micellization of ionic surfactants instead of the critical micelle concentration (CMC). There is a correspondence between the surface excesses Gamma of anionic, cationic, and zwitterionic surfactants at their CMCs, which would be the CSEM values, and the critical association distance for ionic pair association calculated using Bjerrum's correlation. Further support to this concept is given by an accurate method for the prediction of the relative binding of alkali cations onto dodecylsulfate (NaDS) micelles. This method uses a relative binding strength parameter calculated from the values of surface excess Gamma at the CMC of the alkali dodecylsulfates. This links both the binding of a given cation onto micelles and the onset for micellization of its surfactant salt. The CSEM concept implies that micelles form at the air-water interface unless another surface with greater affinity for micelles exists. The process would start when surfactant monomers are close enough to each other for ionic pairing with counterions and the subsequent assembly of these pairs becomes unavoidable. This would explain why the surface excess Gamma values of different surfactants are more similar than their CMCs: the latter are just the bulk phase concentrations in equilibrium with chemicals with different hydrophobicity. An intriguing implication is that CSEM values may be used to calculate the actual critical distances of ionic pair formation for different cations, replacing Bjerrum's estimates, which only discriminate by the magnitude of the charge. PMID- 20961059 TI - Characterization of plasma polymerized C, H, and O containing compounds by MALDI mass spectrometry. AB - Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry is used for the first time to characterize radio frequency plasma-deposited polymers and for investigation of the plasma polymerization process. The MALDI mass spectra of the plasma polymers of allyl alcohol, di(ethylene glycol) vinyl ether and ethylene glycol butyl vinyl ether are all reported using solvent-based MALDI sample preparation approaches. The MALDI mass spectra of each of the three plasma polymers contain distinctive polymer series ion signals having molecular weight distributions below 2000 Da. Unexpectedly, however, the ion signals from each of the three plasma polymers show a common polymer repeat unit of 44 Da, for which the chemical formula is most likely -(C(2)H(4)O)-, and no evidence of the expected radical chain polymerization polymer is detected. These results are discussed in terms of the likely involvement of gas-phase radical species having different stabilities in the radio frequency plasma environment. PMID- 20961060 TI - Evaluation of the particle growth of amorphous calcium carbonate in water by means of the Porod invariant from SAXS. AB - A time-resolved SAXS study has been carried out on the formation of amorphous calcium carbonate from supersaturated aqueous solutions at an initial concentration of 5 mmol/L CaCO(3). Particle formation was induced by mixing equal volumes of equinormal CaCl(2) and Na(2)CO(3) solutions with a stopped-flow device installed at the SAXS beamline. The resulting scattering curves were analyzed without any model assumption with respect to the particle shape. The analysis is based on the intercept of the scattering curve, its initial slope, and the Porod invariant. These parameters give access to the average particle mass, the average particle size, and the mass concentration of the particles, respectively. The evolution of particle mass and concentration with time gives access to the trend in the particle number density. The size and mass values were found to be correlated by characteristic exponents. Two different mass values can be used for this correlation: direct use of the intercept of the scattering curve or alternatively a ratio of this intercept with the corresponding Porod invariant. The resulting exponents depend on the particle growth mechanism. These exponents, together with the evolution of the number density, are capable of discriminating between a monomer-addition mechanism and a particle-particle coagulation mechanism as two alternative building mechanisms for the resulting amorphous CaCO(3) nanoparticles. A detailed description of the data analysis and its merit in establishing a particle growth mechanism is presented. PMID- 20961061 TI - Monodisperse cobalt ferrite nanomagnets with uniform silica coatings. AB - Ferro- and ferrimagnetic nanoparticles are difficult to manipulate in solution as a consequence of the formation of magnetically induced nanoparticle aggregates, which hamper the utility of these particles for applications ranging from data storage to bionanotechnology. Nonmagnetic shells that encapsulate these magnetic particles can reduce the interparticle magnetic interactions and improve the dispersibility of the nanoparticles in solution. A route to create uniform silica shells around individual cobalt ferrite nanoparticles--which uses poly(acrylic acid) to bind to the nanoparticle surface and inhibit nanoparticle aggregation prior to the addition of a silica precursor--was developed. In the absence of the poly(acrylic acid) the cobalt ferrite nanoparticles irreversibly aggregated during the silica shell formation. The thickness of the silica shell around the core-shell nanoparticles could be controlled in order to tune the interparticle magnetic coupling as well as inhibit magnetically induced nanoparticle aggregation. These ferrimagnetic core-silica shell structures form stable dispersion in polar solvents such as EtOH and water, which is critical for enabling technologies that require the assembly or derivatization of ferrimagnetic particles in solution. PMID- 20961062 TI - Indazolylpyrazolopyrimidine as highly potent B-Raf inhibitors with in vivo activity. AB - Novel indazolylpyrazolo[1,5-a]pyrimidine analogues have been prepared and found to be extremely potent type I B-Raf inhibitors. The lead compound shows good selectivity against a panel of 60 kinases, possesses a desirable pharmacokinetic profile, and demonstrates excellent in vivo antitumor efficacy in B-Raf mutant xenograft models. PMID- 20961063 TI - Direct, catalytic synthesis of carbapenams via cycloaddition/rearrangement cascade reaction: unexpected acetylenes' structure effect. AB - Reactions of acetylenes derived from glyceraldehyde and propargyl aldehyde show remarkable reactivity in Kinugasa cycloaddition/rearrangement cascade process catalyzed by Cu(I) ion. Reactions proceed by formation of a rigid dinuclear copper(I) complex in which each copper ion is coordinated to one or both oxygen atoms in the acetylene molecule and to both triple bonds. It has been demonstrated that one oxygen atom can be replaced by the phenyl ring, which is able to coordinate the copper ion by the aromatic sextet. Kinugasa reactions that proceed in a high yield can also be performed in the presence of a catalytic amount of the copper salt to provide products in an acceptable yield without a decrease of diastereoselectivity. PMID- 20961064 TI - Self-assembled supramolecular array of polymeric phthalocyanine on gold for the determination of hydrogen peroxide. AB - This Article describes for the first time the formation of a supramolecular self assembled monolayer of polymeric phthalocyanine (poly(CuPc)) onto a gold substrate. The latter is established through the interaction of the cyano group, belonging to the poly(CuPc), with the metal substrate. The functionalized gold substrate was characterized using Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and electrochemical methods. Results clearly demonstrated the interaction between gold and the nitrogen atom of cyano group and showed at the same time the formation of a completely covered polymeric monolayer on the gold surface. In addition, the modified gold surface seems to exhibit a reversible redox behavior and is found to act as an electronic conductor, which allows rapid electron transfer. Electrochemical impedance spectroscopy (EIS) analyses in the presence of [Fe(CN)(6)](3-/4-) as a redox couple revealed that the modified electrode showed a much lower electron transfer resistance compared with bare gold. In addition, the modified electrode is found to catalyze the H(2)O(2) reduction very effectively, showing a catalytic current that varies linearly with the peroxide concentration in the range of 0.35 to 70 MUM with a detection limit of 0.25 MUM. PMID- 20961065 TI - Replacing 32 proline residues by a noncanonical amino acid results in a highly active DNA polymerase. AB - Protein engineering may be achieved by rational design, directed evolution-based methods, or computational protein design. Mostly these methods make recourse to the restricted pool of the 20 natural amino acids. With the ability to introduce different new kinds of functionalities into proteins, the use of noncanonical amino acids became a promising new method in protein engineering. Here, we report on the generation of a multifluorinated DNA polymerase. DNA polymerases are highly dynamic enzymes that catalyze DNA synthesis in a template-dependent manner, thereby passing several conformational states during the catalytic cycle. Here, we globally replaced 32 proline residues by the noncanonical imino acid (4R)-fluoroproline in a DNA polymerase of 540 amino acids (KlenTaq DNA polymerase). Interestingly, the substitution level of the proline residues was very efficient (92%). Nonetheless, the introduction of (4R)-fluoroproline into the DNA polymerase resulted in a highly active fluorinated enzyme, which was investigated in primer extension and PCR assays to analyze activity, selectivity, and stability in comparison to the parental enzyme. The DNA polymerase retained fidelity, activity, and sensitivity as the parental wild-type enzyme accompanied by some loss in thermostability. These results demonstrate that a noncanonical amino acid can be used for substitutions of natural counterparts in a highly dynamic enzyme with high molecular weight without effecting crucial enzyme properties. Furthermore, the employed DNA polymerase represents a promising starting point for directed DNA polymerase evolution with noncanonical amino acids. PMID- 20961066 TI - Proteomic and metabolic profiling of rice suspension culture cells as a model to study abscisic acid signaling response pathways in plants. AB - Rice (Oryza sativa cv Taipei 309) suspension culture cells (SCCs) were used as a simple, single cell model system to gain insights into the complex abscisic acid (ABA) signaling response pathways in plants. Following system establishment involving morphological observations and transcript profiling of genes known to be ABA responsive in planta, a comprehensive proteomic and metabolomic study was performed. A total of 759 buffer-soluble proteins that included 3284 peptides categorized into 656 protein families are reported. Using iTRAQ, only 36 of these proteins showed statistically significant changes in abundance in response to ABA. In addition, a GC-MS based metabolite profiling study allowed the identification of 148 metabolites that included 25 amino acids (AAs), 45 organic acids (OAs), 35 sugars, 19 fatty acids, 2 polyamines, 4 sterols, 5 sugar acids, 4 sugar alcohols, and 9 miscellaneous compounds. Of these, only 11 (8.8%) changed in a statistically significant manner in response to ABA treatment. These studies provide important insights into plant responses to ABA at the protein and metabolite level. PMID- 20961067 TI - Discrimination of polymers by using their characteristic collision energy in tandem mass spectrometry. AB - The characteristic collision energy to obtain 50% fragmentation, expressed as the characteristic collision voltage (CCV), was used as a tool to discriminate different classes of polymers. The CCV value of different polymers was determined in a quadrupole ion trap mass spectrometer. Good linear correlation (0.980 < R(2) < 0.999) between the CCV values and precursor ion mass was found for all polymers studied. The position of the various linear trend lines varied among the various polymers, which allowed their grouping based on the respective CCV values. The collision energy necessary to drive fragmentation was decreasing in the order of polyethers > polymethacrylates > polyesters > polysaccharides. This suggests that polysaccharides fragment most easily (low CCVs), while polyethers require the highest collision energy among the polymers studied. The effect of end group on the CCV was also studied, showing a minor influence in most cases. In addition, the applicability of CCV as discriminator was studied for a mixture of (1) polylactic acid (PLA), (2) poly(tetramethylene glycol) (PTMEG), and (3) PLA-block PTMEG-block-PLA block copolymer. Differences between the CCV values of four nominally isobaric polymers (of which two were copolymers and two were homopolymers) were observed. These results demonstrate that the insertion of a "weak" link into a polymer chain significantly affects the energy required for fragmentation. PMID- 20961068 TI - Synthesis of lakshminine and antiproliferative testing of related oxoisoaporphines. AB - Lakshminine (6-amino-1-aza-5-methoxy-7H-dibenzo[de,h]quinolin-7-one, 1) is a recent addition to the small family of oxoisoaporphine alkaloids and a member of an even smaller set bearing an amino group at C-6. This rare natural product has now been synthesized in order to have sufficient amounts for biological testing. Lakshminine, its 4-amino isomer (2), their 6- and 4-nitro precursors (8 and 10, respectively), the intermediate 5-methoxy-7H-dibenzo[de,h]quinolin-7-one (6), and the unsubstituted skeleton (11) were tested against normal human fibroblasts and three human solid tumor cell lines. Only compound 10 showed marginal antiproliferative activity. PMID- 20961069 TI - Tandem mass spectrometry for the direct assay of lysosomal enzymes in dried blood spots: application to screening newborns for mucopolysaccharidosis VI (Maroteaux Lamy syndrome). AB - We report a new assay of N-acetylgalactosamine-4-sulfatase (aryl sulfatase B) activity in dried blood spots (DBS) for the early detection of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) in newborn screening. The assay uses a synthetic substrate consisting of N-acetylgalactosamine-4-sulfate moiety glycosidically linked to a hydrophobic residue and furnished with a tert butyloxycarbamido group as a marker for specific mass spectrometric fragmentation. Incubation with aryl sulfatase B present in DBS converts the substrate to a desulfated product which is detected by electrospray tandem mass spectrometry and quantified using a homologous internal standard. Assay and workup procedures were optimized to be compatible with the work flow in newborn screening laboratories. Analysis of DBS from human newborns showed clear distinction of aryl sulfatase B activity from 89 healthy individuals where it ranged between 1.4 and 16.9 MUmol/(h L of blood), with an average activity of 7.4 MUmol/(h L of blood), and an MPS-VI patient that had an activity of 0.12 MUmol/(h L of blood). Results are also reported for the aryl sulfatase B assay in DBS from groups of normal felines and felines affected with MPS-VI. PMID- 20961070 TI - Preparative and mechanistic studies toward the rational development of catalytic, enantioselective selenoetherification reactions. AB - A systematic investigation into the Lewis base catalyzed, asymmetric, intramolecular selenoetherification of olefins is described. A critical challenge for the development of this process was the identification and suppression of racemization pathways available to arylseleniranium ion intermediates. This report details a thorough study of the influences of the steric and electronic modulation of the arylselenenyl group on the configurational stability of enantioenriched seleniranium ions. These studies show that the 2-nitrophenyl group attached to the selenium atom significantly attenuates the racemization of seleniranium ions. A variety of achiral Lewis bases catalyze the intramolecular selenoetherification of alkenes using N-(2-nitrophenylselenenyl)succinimide as the electrophile along with a Bronsted acid. Preliminary mechanistic studies suggest the intermediacy of ionic Lewis base-selenium(II) adducts. Most importantly, a broad survey of chiral Lewis bases revealed that 1,1' binaphthalene-2,2'-diamine (BINAM)-derived thiophosphoramides catalyze the cyclization of unsaturated alcohols in the presence of N-(2 nitrophenylselenenyl)succinimide and methanesulfonic acid. A variety of cyclic seleno ethers were produced in good chemical yields and in moderate to good enantioselectivities, which constitutes the first catalytic, enantioselective selenofunctionalization of unactivated olefins. PMID- 20961071 TI - Quantitative detection of trace systemins in Solanaceous plants by immunoaffinity purification combined with liquid chromatography/electrospray quadrupole time-of flight mass spectrometry. AB - Systemins are a class of systemic wound polypeptide hormones that play a central role in mediating defenses against pest attacks and other woundings. It has been desired to develop a sensitive and accurate determination method to monitor trace systemins in plants for the better understanding of molecular mechanisms of the polypeptide hormones. A superior method for accurate identification and quantitative determination of trace systemins in Solanaceous plants is described in this work, which is based on immunoaffinity column (IAC) purification and enrichment followed by liquid chromatography online coupled to electrospray quadrupole time-of-flight mass spectrometry (LC/ESI QTOF MS). The specific antitomato systemin polyclonal antibody had been produced and immobilized on a CNBr-activated Sepharose stationary phase. The prepared IAC was utilized for the extraction and enrichment of tomato systemin (TomSys), potato systemin (PotSys I and PotSys II), pepper systemin (PepSys), and nightshade systemin (NishSys) from Solanaceous plants. Subsequent identification and determination by LC/ESI QTOF MS revealed that the IAC enables efficient and specific enrichment of PotSys I, PotSys II, and especially TomSys. Under the optimized conditions, the developed method was successfully applied in the determination of TomSys in tomato leaves and PotSys I and PotSys II in potato leaves, and it offers detection limits (LODs, S/N =3) of 29, 72, and 135 pg/g and mean recoveries of 92.9%, 56.7%, and 34.8% at three concentrations (1.0, 2.0, and 4.0 ng/g) for TomSys, PotSys I, and PotSys II, respectively. PMID- 20961072 TI - Synthesis of functionalized pentacenes from isobenzofurans derived from C-H bond activation. AB - The synthesis of unsymmetric functionalized pentacenes from 1,4-anthraquinones and functionalized isobenzofurans, which were prepared by transformation via C-H bond activation, was successfully accomplished. Examples of the synthesis of pentacenes with functional groups at the 5-position are still rare. These obtained functionalized pentacenes are highly soluble in hexane, toluene, and THF. PMID- 20961073 TI - Stereoselective synthesis of spirooxindole amides through nitrile hydrozirconation. AB - Spirooxindole amides can be prepared by the intramolecular addition of functionalized indoles into acylimines that are accessed from nitriles by hydrozirconation and acylation. The stereochemical outcome at the quaternary center was controlled by the steric bulk of the substituent at the 2-position of the indole unit. The products are well-suited for diversification to prepare libraries. PMID- 20961074 TI - Light-induced alteration of low-temperature interprotein electron transfer between photosystem I and flavodoxin. AB - Electron paramagnetic resonance (EPR) was used to study light-induced electron transfer in Photosystem I-flavodoxin complexes. Deuteration of flavodoxin enables the signals of the reduced flavin acceptor and oxidized primary donor, P(700)(+), to be well-resolved at X- and D-band EPR. In dark-adapted samples, photoinitiated interprotein electron transfer does not occur at 5 K. However, for samples prepared in dim light, significant interprotein electron transfer occurs at 5 K and a concomitant loss of the spin-correlated radical pair P(+)A(1A)(-) signal is observed. These results indicate a light-induced reorientation of flavodoxin in the PSI docking site that allows a high quantum yield efficiency for the interprotein electron transfer reaction. PMID- 20961075 TI - Entropy, information, and the arrow of time. AB - We shall investigate the relationships between the thermodynamic entropy and information theory and the implications that can be drawn for the arrow of time. This demands a careful study of classical thermodynamics and a review of its fundamental concepts. The statistical mechanical properties of time-dependent systems will be carefully studied, and the point at which the arrow of time appears will be described. PMID- 20961076 TI - Persisting water droplets on water surfaces. AB - Droplets of various liquids may float on the respective surfaces for extended periods of time prior to coalescence. We explored the features of delayed coalescence in highly purified water. Droplets several millimeters in diameter were released from a nozzle onto a water surface. Results showed that droplets had float times up to hundreds of milliseconds. When the droplets did coalesce, they did so in stepwise fashion, with periods of quiescence interspersed between periods of coalescence. Up to six steps were noted before the droplet finally vanished. Droplets were released in a series, which allowed the detection of unexpected abrupt float-time changes throughout the duration of the series. Factors such as electrostatic charge, droplet size, and sideways motion had considerable effect on droplet lifetime, as did reduction of pressure, which also diminished the number of steps needed for coalescence. On the basis of present observations and recent reports, a possible mechanism for noncoalescence is considered. PMID- 20961077 TI - Spirooxazine to merooxazine interconversion in the presence and absence of zinc: approach to a bistable photochemical switch. AB - A spironaphthoxazine (SO) photoswitch was synthesized, and its photochromic behaviors were investigated. SO underwent reversible ring-opening/closure isomerization between a spirocyclic isomer (closed form) and a merocyanine (MO isomer, open form) upon ultraviolet light irradiation. For the model SO in this work, the thermal equilibrium is substantially shifted toward the spirocyclic isomer even at -30.0 degrees C. However, addition of zinc, as Zn(ClO(4))(2), exerted an important effect on the thermal reversion process from the open (MO) to the closed form (SO). Kinetic analysis showed that thermal reversion with zinc is retarded more than 13-fold, significantly improving bistability. Moreover, introduction of zinc to the spirooxazine-merooxazine (SO-MO) system resulted in a new absorption band readily distinguishable from the bands arising from spirooxazine and merooxazine. For the first time, to the best of our knowledge, the microscopic rate constants for: MO photogeneration from SO (k(1)), thermal reversion of MO to SO (k(2)), complexation of MO with zinc (k(3)) and for dissociation of the complex, MO-Zn (k(4)), as well as for the ionization equilibria of Zn(ClO(4))(2) have been evaluated. The preferred transoid structures of MO and those of MO-Zn derived from the preferred MO structures are considered. Although the kinetic study does not permit elucidation of the nature of zinc binding to MO to give MO-Zn, nor the precursor isomers of MO, a DFT calculational study in progress should shed light on the structure and relative stability of these essential intermediates. PMID- 20961078 TI - Desolvation penalty for burying hydrogen-bonded peptide groups in protein folding. AB - A novel analysis of the enthalpy of protein unfolding is proposed and used to test for a desolvation penalty when hydrogen-bonded peptide groups are desolvated via folding. The unfolding enthalpy has three components, (1) the change when peptide hydrogen bonds are broken and the exposed -CO and -NH groups are solvated, (2) the change when protein-protein van der Waals interactions are broken and replaced by protein-water van der Waals interactions, and (3) the change produced by the hydrophobic interaction when nonpolar groups in the protein interior (represented as a liquid hydrocarbon) are transferred to water. A key feature of the analysis is that the enthalpy change from the hydrophobic interaction goes through 0 at 22 degrees C according to the liquid hydrocarbon model. Protein unfolding enthalpies are smaller at 22 degrees C than the enthalpy change for unfolding an alanine peptide helix. Data in the literature indicate that the van der Waals contribution to the unfolding enthalpy is considerably larger than the unfolding enthalpy itself at 22 degrees C, and therefore, a sizable desolvation penalty is predicted. Such a desolvation penalty was predicted earlier from electrostatic calculations of a stabilizing interaction between water and the hydrogen-bonded peptide group. PMID- 20961079 TI - Structure and dynamics of tetrahalomethane adsorption on (001) surfaces of graphite and alpha-quartz. AB - Molecular dynamics (MD) simulations were used to study the structural and dynamic properties of multilayer adsorption of each of three halomethanes, CF(4), CF(3)Cl, and CF(3)Br, adsorbed onto the (001) surface of either of two atomically flat but chemically and structurally different substrates (graphite and hydroxylated alpha-quartz) at temperatures ranging from 60 to 300 K. Analysis of the data shows a strong influence on the adsorption characteristics of these halomethane films due to the surface characteristics of the chosen substrate. In particular, the nature of the hydroxylation of alpha-quartz shows a striking ability to alter the affinity with which species adsorb onto its surface. This effect appears to be at least partly responsible for the differences in the orientation and packing of molecules in the first film layer as well as differences in the effect of temperature variation on phase behavior and dynamics. PMID- 20961080 TI - Development of a partition-controlled dosing system for cell assays. AB - Hydrophobic and volatile chemicals have proven to be difficult to dose in cell assays. Cosolvents are often needed to dissolve these chemicals in cell culture medium. Moreover, the free concentration of these chemicals in culture medium may diminish over time due to metabolism, evaporation, and nonspecific binding to well plate surfaces and serum constituents. The aim of this study was to develop a partition-controlled dosing system to maintain constant concentrations of benzo(a)pyrene, 1,2-dichlorobenzene, and 1,2,4-trichlorobenzene in an ethoxyresorufin-O-deethylase (EROD) assay and a cytotoxicity assay with the rainbow trout (Oncorhynchus mykiss) cell lines RTL-W1 and RTgill-W1. Polydimethylsiloxane (PDMS) sheets were loaded with test chemicals in a spiked methanol/water solution and placed in the wells, filled with culture medium, of a 24-well culture plate. Cells were grown on inserts and were subsequently added to the wells with the PDMS sheets. The system reached equilibrium within 24 h, even for the very hydrophobic chemical benzo(a)pyrene. The reservoir of test chemical in PDMS was large enough to compensate for the loss of >95% of the test chemical from the culture medium. The PDMS sheets maintained medium concentrations constant for >72 h. Nominal median effect concentrations (EC(50)) were 1.3-7.0 times lower in the partition-controlled dosing systems than in conventional assays spiked using dimethyl sulfoxide (DMSO) as a carrier solvent, thus indicating that the apparent sensitivity of the bioassay increased when controlled and constant exposure conditions could be assured. The EC(50) values of the test chemicals based on free concentrations were estimated in the partition-controlled dosing systems using measured PDMS-bare culture medium partition coefficients. Results indicated that 61, 70, and 99.8% of 1,2 diclorobenzene, 1,2,4-trichlorobenzene, and benzo(a)pyrene were bound to serum constituents in the culture medium. PMID- 20961081 TI - Theoretical studies on photoisomerizations of (6-4) and Dewar photolesions in DNA. AB - The (6-4) photoproduct ((6-4) PP) is one of the main lesions in UV-induced DNA damage. The (6-4) PP and its valence isomer Dewar photoproduct (Dewar PP) can have a great threat of mutation and cancer but gained much less attention to date. In this study, with density functional theory (DFT) and the complete active space self-consistent field (CASSCF) methods, the photoisomerization processes between the (6-4) PP and the Dewar PP in the gas phase, the aqueous solution, and the photolyase have been carefully examined. Noticeably, the solvent effect is treated with the CASPT2//CASSCF/Amber (QM/MM) method. Our calculations show that the conical intersection (CI) points play a crucial role in the photoisomerization reaction between the (6-4) PP and the Dewar PP in the gas and the aqueous solution. The ultrafast internal conversion between the S(2) ((1)pipi*) and the S(0) states via a distorted intersection point is found to be responsible for the formation of the Dewar PP lesion at 313 nm, as observed experimentally. For the reversed isomeric process, two channels involving the "dark" excited states have been identified. In addition to the above passages, in the photolyase, a new electron-injection isomerization process as an efficient way for the photorepair of the Dewar PP is revealed. PMID- 20961083 TI - Single gold nanoparticles counter: an ultrasensitive detection platform for one step homogeneous immunoassays and DNA hybridization assays. PMID- 20961082 TI - Covalent modifications of hemoglobin by nitrite anion: formation kinetics and properties of nitrihemoglobin. AB - The green nitrihemoglobin (alpha(2)beta(2) tetramer, NHb) was prepared by the aerobic reaction of excess nitrite with human hemoglobin A(0) under mildly acidic conditions. A rate equation was determined and found to depend on nitrite, hydrogen ion, and oxygen concentrations: -d[HbNO(2)]/dt = [k(1) + k(2)(K(a)[HNO(2)])[O(2)](1/2)][HbNO(2)], where k(1) = (2.4 +/- 0.9) * 10(-4) s( 1), k(2) = (1 +/- 0.2) * 10(5) M(-5/2) s(-1), and K(a) is the acid dissociation constant for nitrous acid (4.5 * 10(-4) M). Also, the chemical properties of NHb are compared to those of the normal hemoglobin (including the addition products of common oxidation states with exogenous ligands, the alkaline transitions of the ferric forms, and the oxygen binding characteristics of the ferrous forms) and were found to be nearly indistinguishable. Therefore, the replacement of a single vinyl hydrogen with a nitro group on the periphery of each macrocycle in hemoglobin does not significantly perturb the interaction between the hemes and the heme pockets. Because nonphotochemical reaction chemistry must necessarily be most dependent on electronic ground states, it follows that the clearly visible difference in color between hemoglobin A(0) and NHb must be associated primarily with the respective electronic excited states. The possibility of NHb formation in vivo and its likely consequences are considered. PMID- 20961084 TI - Easy and selective method for the synthesis of various mono-O-functionalized calix[4]arenes: de-O-functionalization using TiCl4. AB - An efficient and selective method for the monofunctionalization of p-tert butylcalix[4]arene is described. A mono-de-O-functionalization of disubstituted p tert-butylcalix[4]arenes using titanium tetrachloride was developed to synthesize a series of monosubstituted p-tert-butylcalix[4]arenes with the pendant functions being ethoxycarbonylmethyloxy, 3-ethoxycarbonylpropyloxy, cyanomethyloxy, 3 cyanopropyloxy, 4-bromobutyloxy, 3-hydroxypropyloxy, propyloxy, 2 methylpropyloxy, 3-butynyloxy, and 3-cyanopropyloxy groups. The reaction mechanism of the formation of 5,11,17,23-tetra-tert-butyl-26,27,28-trihydroxy-25 (3-ethoxycarbonylpropyloxy) calix[4]arene was studied by (1)H NMR and GC/mass spectroscopy monitoring. Reaction of TiCl4 with the disubstituted p-tert butylcalix[4]arene produced the corresponding dioxocalix[4]arene titanium dichloride complex, which undergoes elimination of ethyl 4-chlorobutyrate, leading to a trioxocalix[4]arene titanium dichloride complex and to monosubstituted calix[4]arene after hydrolysis. These two complexes were also synthesized, isolated, and fully characterized. PMID- 20961085 TI - Fast preparation of hydroxyapatite/superhydrophilic vertically aligned multiwalled carbon nanotube composites for bioactive application. AB - A method for the electrodeposition of hydroxyapatite films on superhydrophilic vertically aligned multiwalled carbon nanotubes is presented. The formation of a thin homogeneous film with high crystallinity was observed without any thermal treatment and with bioactivity properties that accelerate the in vitro biomineralization process and osteoblast adhesion. PMID- 20961086 TI - Measurement of nanoparticle concentration using quartz crystal microgravimetry. AB - Various nanoscale items (e.g., nanoparticles and nanotubes) have been actively investigated due to their unique physicochemical properties. A common issue encountered in such studies is accurate expression of nanoparticle concentration. Given the critical importance of the dose-response relationship, we present the use of quartz crystal microgravimetry (QCM) to accurately measure nanoparticle concentration in a colloidal suspension. Application of a small drop of the nanoparticle suspension in a volatile solvent to the crystal surface leaves a dry nanoparticle residue after solvent evaporation after which the shift in the crystal resonant frequency is recorded. The instrument was calibrated using a set of serial dilutions of Si and Ag nanopowder in methanol, rhodamine B in methanol, and ferrocene in cyclohexane. Using QCM, a linear response for nanoparticle concentrations up to 1300 MUg/mL was determined. The developed method was used to determine the concentrations of size-selected, octyl-terminated Si nanocrystal samples with median diameters in the range 1.1-14.8 nm and also to calculate size dependent nanocrystal extinction coefficients. PMID- 20961087 TI - DNA binding to an anticancer organo-ruthenium complex. AB - Because many anticancer drugs interact with DNA, the determination of their association constants to DNA is essential for quantifying their mechanisms of action. The interactions between a new ruthenium-derived compound [ruthenium(phenanthroline)(kappa-C,N-(2-phenyl-pyridine)(NCMe)(2)]PF(6), called RDC11] and DNA are studied using different techniques. Fluorescent experiments are used to determine the association and dissociation constants under different salt concentrations. The binding is shown to be reversible and noncovalent. The association constants vary from 1.5 * 10(6) M(-1) to 2.9 * 10(3) M(-1) when increasing the sodium concentration from 0.1 to 200 mM. Single-molecule stretching methods are used to study the interaction of RDC with longer DNA strands (8.6 kbp home-built dimer of pBR322). The affinities of RDC with DNA under different loads are obtained using McGhee and von Hippel analysis. The affinity constant and thermodynamic parameters are in good agreement with the values found in the literature and lead to the conclusion that this molecule intercalates dsDNA. PMID- 20961088 TI - Enhancement of ultraviolet photodissociation efficiencies through attachment of aromatic chromophores. AB - Two N-terminal derivatization reagents containing aromatic chromophores, 4 sulfophenyl isothiocyanate (SPITC) and 4-methylphosphonophenyl isothiocyanate (PPITC), were used to increase the dissociation efficiencies of peptides upon ultraviolet photodissociation (UVPD) at 193 nm. The resulting UVPD spectra are dominated by C-terminal ions, including y, z, x, v, and w ions, and immonium ions. The attachment of the PPITC or SPITC groups leads to a reduction in the number and abundances of N-terminal ions because the added phosphonate or sulfonate functionalities result in neutralization of some of the N-terminal species, ones that might normally be singly protonated in the absence of the negatively charged sulfonate or phosphonate groups. In addition, the greater photoabsorptivities of the PPITC- and SPITC-derivatized N-terminal product ions enhanced their secondary photodissociation, leading to formation of immonium ions. PMID- 20961089 TI - A kinetic study of rearrangement and degradation reactions of tetrathionate and trithionate in near-neutral solutions. AB - The kinetics of reactions of trithionate and tetrathionate via different reaction pathways were studied in near-neutral solutions. In the case of trithionate, the predominant degradation reaction is hydrolysis to thiosulfate and sulfate. The pseudofirst-order rate constant is independent of pH and measured to be (6.2 +/- 0.2) * 10(-7) s(-1) for the pH range of 5.5-10.5. With tetrathionate, the reaction in both neutral and alkaline solutions occurs via a thiosulfate catalyzed rearrangement reaction to trithionate and pentathionate followed by their further reactions. The data suggest that when thiosulfate is completely absent, this first step will not occur, and in the presence of thiosulfate, the rate of the first step is independent of pH in the pH range 6-8. The secondary reactions include the hydrolysis of trithionate and the further rearrangement and degradation of pentathionate. This mechanism explains the dominant reaction products for both neutral and alkaline solutions. In the presence of thiosulfate and at near-neutral pH, the rearrangement reactions dominate over the degradation reactions and exhibit second-order kinetics, with the rate constants in the pH range of 6-8 determined to be (4.24 +/- 0.26) and (1.89 +/- 0.18) * 10(-4) M(-1) s(-1) for tetra- and pentathionates, respectively. At extremely low thiosulfate concentrations, the main secondary reaction is the hydrolysis of trithionate at pH < 7, and at pH > 7, the degradation of pentathionate. PMID- 20961090 TI - Ipomotaosides A-D, resin glycosides from the aerial parts of Ipomoea batatas and their inhibitory activity against COX-1 and COX-2. AB - Four new resin glycosides, namely, ipomotaosides A-D (1-4), were isolated from the dried aerial parts of Ipomoea batatas. The structures of 1-4 were elucidated by analysis of their spectroscopic data and by chemical derivatization and were tested for their anti-inflammatory activity against cyclooxygenase (COX)-1 and 2. PMID- 20961091 TI - Triterpenoids and steroids from the fruits of Melia toosendan and their cytotoxic effects on two human cancer cell lines. AB - Ten new triterpenoids, named meliasenins I-R (1-10), one new steroid (11), and 11 related known compounds (12-22) were isolated from fruits of Melia toosendan. The structures of the new compounds were established on the basis of spectroscopic methods, including 2D NMR techniques and mass spectrometry. The relative configuration of 1, (20R*,23E)-25-hydroperoxyeupha-7,23-diene-3beta,16beta-diol (meliasenin I), was confirmed by single-crystal X-ray diffraction analysis. All isolated triterpenoids (1-10, 12-15) and two steroids (11, 20) were tested for their cytotoxicity against U20S human osteosarcoma and MCF-7 human breast cancer cells using the MTT assay, and some of them were significantly cytotoxic (IC(50) <10 MUg/mL). The insecticidal properties of compounds 1-15 and 20 were also briefly evaluated. PMID- 20961092 TI - Microbial transformations of aryltetralone and aryltetralin lignans by Cunninghamella echinulata and Beauveria bassiana. AB - Microbiological transformation of the aryltetralone lignan (-)-8'-epi aristoligone (1) with Cunninghamella echinulata ATCC 10028B afforded two known natural lignans, (-)-holostyligone (3) and (-)-arisantetralone (4). Incubation of the aryltetralin lignan (-)-isogalbulin (2), obtained by chemical transformation of 1, with C. echinulata ATCC 10028B afforded the known lignan aryltetralol (5) and seven new metabolites, (-)-8-hydroxyisogalbulin (6), (-)-7-methoxyisogalbulin (7), (-)-4'-O-demethyl-8-hydroxyisogalbulin (8), (-)-7-methoxy-8 hydroxyisogalbulin (9), (-)-4'-O-demethyl-7-methoxyisogalbulin (10), (-)-4',5-O didemethylcyclogalgravin (11), and (-)-4'-O-demethylcyclogalgravin (12). When 2 was subjected to biotransformation with Beauveria bassiana ATCC 7159, (-)-8 hydroxyisogalbulin (6) was the only isolable product. The structures of all new compounds were established by detailed analysis of their spectroscopic data. PMID- 20961093 TI - Abietane and C20-norabietane diterpenes from the stem bark of Fraxinus sieboldiana and their biological activities. AB - Fourteen new abietane (1-14) and seven new C(20)-norabietane (15-21) diterpenes, together with five known analogues, have been isolated from the stem bark of Fraxinus sieboldiana. Their structures were elucidated by spectroscopic data analysis. In the in vitro assays, at 10(-5) M, compounds 8, 16, and 22 showed inhibitory activity against the release of beta-glucuronidase in rat polymorphonuclear leukocytes induced by platelet-activating factor, with 59.7 +/- 4.8%, 56.1 +/- 5.6%, and 65.9 +/- 3.1% inhibition, respectively. Compound 23 was active against H5N1 avian influenza virus with an IC(50) value of 4.8 MUM. Compounds 3 and 5 exhibited selective cytotoxic activities against A2780 (IC(50) 1.7 MUM) and A549 (IC(50) 6.0 MUM), respectively. PMID- 20961094 TI - QM/MD simulation of SWNT nucleation on transition-metal carbide nanoparticles. AB - The mechanism and kinetics of single-walled carbon nanotube (SWNT) nucleation from Fe- and Ni-carbide nanoparticle precursors have been investigated using quantum chemical molecular dynamics (QM/MD) methods. The dependence of the nucleation mechanism and its kinetics on environmental factors, including temperature and metal-carbide carbon concentration, has also been elucidated. It was observed that SWNT nucleation occurred via three distinct stages, viz. the precipitation of the carbon from the metal-carbide, the formation of a "surface/subsurface" carbide intermediate species, and finally the formation of a nascent sp(2)-hybidrized carbon structure supported by the metal catalyst. The SWNT cap nucleation mechanism itself was unaffected by carbon concentration and/or temperature. However, the kinetics of SWNT nucleation exhibited distinct dependences on these same factors. In particular, SWNT nucleation from Ni(x)C(y) nanoparticles proceeded more favorably compared to nucleation from Fe(x)C(y) nanoparticles. Although SWNT nucleation from Fe(x)C(y) and Ni(x)C(y) nanoparticle precursors occurred via an identical route, the ultimate outcomes of these processes also differed substantially. Explicitly, the Ni(x)-supported sp(2) hybridized carbon structures tended to encapsulate the catalyst particle itself, whereas the Fe(x)-supported structures tended to form isolated SWNT cap structures on the catalyst surface. These differences in SWNT nucleation kinetics were attributed directly to the relative strengths of the metal-carbon interaction, which also dictates the precipitation of carbon from the nanoparticle bulk and the longevity of the resultant surface/subsurface carbide species. The stability of the surface/subsurface carbide was also influenced by the phase of the nanoparticle itself. The observations agree well with experimentally available data for SWNT growth on iron and nickel catalyst particles. PMID- 20961095 TI - 1,4-addition of lithium diisopropylamide to unsaturated esters: role of rate limiting deaggregation, autocatalysis, lithium chloride catalysis, and other mixed aggregation effects. AB - Lithium diisopropylamide (LDA) in tetrahydrofuran at -78 degrees C undergoes 1,4 addition to an unsaturated ester via a rate-limiting deaggregation of LDA dimer followed by a post-rate-limiting reaction with the substrate. Muted autocatalysis is traced to a lithium enolate-mediated deaggregation of the LDA dimer and the intervention of LDA-lithium enolate mixed aggregates displaying higher reactivities than LDA. Striking accelerations are elicited by <1.0 mol % LiCl. Rate and mechanistic studies have revealed that the uncatalyzed and catalyzed pathways funnel through a common monosolvated-monomer-based intermediate. Four distinct classes of mixed aggregation effects are discussed. PMID- 20961096 TI - The origin of charge localization observed in organic photovoltaic materials. AB - Two of the primary hurdles facing organic electronics and photovoltaics are their low charge mobility and the inability to disentangle morphological and molecular effects on charge transport. Specific chemical groups such as alkyl side chains are often added to enable spin-casting and to improve overall power efficiency and morphologies, but their exact influence on mobility is poorly understood. Here, we use two-photon photoemission spectroscopy to study the charge transport properties of two organic semiconductors, one with and one without alkyl substituents (sexithiophene and dihexyl-sexithiophene). We show that the hydrocarbon side chains are responsible for charge localization within 230 fs. This implies that other chemical groups should be used instead of alkyl ligands to achieve the highest performance in organic photovoltaics and electronics. PMID- 20961097 TI - Rh(II) carbene-promoted activation of the anomeric C-H bond of carbohydrates: a stereospecific entry toward alpha- and beta-ketopyranosides. AB - In this communication we report a new strategy toward ketopyranosides based on a carbene-mediated activation of the anomeric C-H bond of carbohydrates. By forming a new carbon-carbon bond after a glycosylation step, this approach enables the preparation of both alpha- and beta-ketopyranosides from advanced precursors. PMID- 20961098 TI - Structure of the p53 transactivation domain in complex with the nuclear receptor coactivator binding domain of CREB binding protein. AB - The activity and stability of the tumor suppressor p53 are regulated by interactions with key cellular proteins such as MDM2 and CBP/p300. The transactivation domain (TAD) of p53 contains two subdomains (AD1 and AD2) and interacts directly with the N-terminal domain of MDM2 and with several domains of CBP/p300. Here we report the NMR structure of the full-length p53 TAD in complex with the nuclear coactivator binding domain (NCBD) of CBP. Both the p53 TAD and NCBD are intrinsically disordered and fold synergistically upon binding, as evidenced by the observed increase in helicity and increased level of dispersion of the amide proton resonances. The p53 TAD folds to form a pair of helices (denoted Palpha1 and Palpha2), which extend from Phe19 to Leu25 and from Pro47 to Trp53, respectively. In the complex, the NCBD forms a bundle of three helices (Calpha1, residues 2066-2075; Calpha2, residues 2081-2092; and Calpha3, residues 2095-2105) with a hydrophobic groove into which p53 helices Palpha1 and Palpha2 dock. The polypeptide chain between the p53 helices remains flexible and makes no detectable intermolecular contacts with the NCBD. Complex formation is driven largely by hydrophobic contacts that form a stable intermolecular hydrophobic core. A salt bridge between D49 of p53 and R2105 of NCBD may contribute to the binding specificity. The structure provides the first insights into simultaneous binding of the AD1 and AD2 motifs to a target protein. PMID- 20961099 TI - The membrane-bound structure and topology of a human alpha-defensin indicate a dimer pore mechanism for membrane disruption. AB - Defensins are cationic and disulfide-bonded host defense proteins of many animals that target microbial cell membranes. Elucidating the three-dimensional structure, dynamics, and topology of these proteins in phospholipid bilayers is important for understanding their mechanisms of action. Using solid-state nuclear magnetic resonance spectroscopy, we have now determined the conformation, dynamics, oligomeric state, and topology of a human alpha-defensin, HNP-1, in DMPC/DMPG bilayers. Two-dimensional correlation spectra show that membrane-bound HNP-1 exhibits a conformation similar to that of the water-soluble state, except for the turn connecting strands beta2 and beta3, whose side chains exhibit immobilization and conformational perturbation upon membrane binding. At high protein/lipid ratios, rapid (1)H spin diffusion from the lipid chains to the protein was observed, indicating that HNP-1 was well inserted into the hydrocarbon core of the bilayer. Arg Czeta-lipid (31)P distances indicate that only one of the four Arg residues forms tight hydrogen-bonded guanidinium phosphate complexes. The protein is predominantly dimerized at high protein/lipid molar ratios, as shown by (19)F spin diffusion experiments. The presence of a small fraction of monomers and the shallower insertion at lower protein concentrations suggest that HNP-1 adopts concentration-dependent oligomerization and membrane-bound structure. These data strongly support a "dimer pore" topology of HNP-1 in which the polar top of the dimer lines an aqueous pore while the hydrophobic bottom faces the lipid chains. In this structure, R25 lies closest to the membrane surface among the four Arg residues. The pore does not have a high degree of lipid disorder, in contrast to the toroidal pores formed by protegrin 1, a two-stranded beta-hairpin antimicrobial peptide. These results provide the first glimpse into the membrane-bound structure and mechanism of action of human alpha-defensins. PMID- 20961100 TI - Disparate impact of the S33V mutation on conformational stability in rat beta parvalbumin (oncomodulin) and chicken parvalbumin 3. AB - Rat beta-parvalbumin (beta-PV) and chicken parvalbumin 3 (CPV3) exhibit diminished Ca(2+) affinity. Their sequences, 70% identical, are unusual in that serine replaces the consensus residue, valine, at position 33. Reasoning that the substitution of a compact, polar hydroxymethyl moiety for a bulky, apolar isopropyl group might contribute to the attenuated Ca(2+) affinities, we have characterized the S33V variants of both proteins. The impact of the mutation in CPV3 differs decidedly from that in rat beta. Whereas replacement of S33 by valine in CPV3 causes a substantial increase in the solvent-accessible apolar surface in the Ca(2+)-free protein, the mutation evidently decreases the exposed apolar surface area in rat beta. Although the mutation has a minimal effect on divalent ion affinity in both proteins, the DeltaDeltaH and -TDeltaDeltaS changes for Ca(2+) binding in CPV3 S33V, but not rat beta S33V, are consistent with increased burial of the apolar surface. The influence of the S33V substitution on conformational stability likewise differs for rat beta-PV and CPV3. Whereas the stability of the former is virtually unperturbed by the sequence alteration, the latter is destabilized by 0.7 kcal/mol. Moreover, the mutation greatly exacerbates the tendency for CPV3 to aggregate. The concentration and scan rate dependence observed in DSC studies of CPV3 S33V denaturation suggest that unfolding proceeds through an intermediate state that is prone to aggregation. Consistent with this idea, reversible unfolding data, collected at very low protein concentration, likewise indicate that the thermal denaturation is not a two-state process. PMID- 20961101 TI - CdSe quantum-dot-sensitized solar cell with ~100% internal quantum efficiency. AB - We have constructed and studied photoelectrochemical solar cells (PECs) consisting of a photoanode prepared by direct deposition of independently synthesized CdSe nanocrystal quantum dots (NQDs) onto a nanocrystalline TiO(2) film (NQD/TiO(2)), aqueous Na(2)S or Li(2)S electrolyte, and a Pt counter electrode. We show that light harvesting efficiency (LHE) of the NQD/TiO(2) photoanode is significantly enhanced when the NQD surface passivation is changed from tri-n-octylphosphine oxide (TOPO) to 4-butylamine (BA). In the PEC the use of NQDs with a shorter passivating ligand, BA, leads to a significant enhancement in both the electron injection efficiency at the NQD/TiO(2) interface and charge collection efficiency at the NQD/electrolyte interface, with the latter attributed mostly to a more efficient diffusion of the electrolyte through the pores of the photoanode. We show that by utilizing BA-capped NQDs and aqueous Li(2)S as an electrolyte, it is possible to achieve ~100% internal quantum efficiency of photon-to-electron conversion, matching the performance of dye sensitized solar cells. PMID- 20961102 TI - Biocompatibility of calcined mesoporous silica particles with cellular bioenergetics in murine tissues. AB - A novel in vitro system was developed to investigate the effects of two forms of calcined mesoporous silica particles (MCM41-cal and SBA15-cal) on cellular respiration of mouse tissues. O(2) consumption by lung, liver, kidney, spleen, and pancreatic tissues was unaffected by exposure to 200 MUg/mL MCM41-cal or SBA15-cal for several hours. Normal tissue histology was confirmed by light microscopy. Intracellular accumulation of the particles in the studied tissues was evident by electron microscopy. The results show reasonable in vitro biocompatibility of the mesoporous silicas with murine tissue bioenergetics. PMID- 20961103 TI - Scanning electrochemical microscopy as a quantitative probe of acid-induced dissolution: theory and application to dental enamel. AB - This Article reports the use of scanning electrochemical microscopy (SECM) for the quantitative study of acid-induced dissolution. An ultramicroelectrode (UME) is used to generate a flux of protons galvanostatically just above a sample surface, creating controlled acid challenges relevant to acid erosion. The electrochemical technique produces etch features in the sample, which are characterized by white light interferometry (WLI). The technique has been applied to bovine enamel where understanding the kinetics of dissolution is important in the context of acid erosion. Dissolution has been observed as a fast process, but the high rates of mass transport in SECM allow the surface kinetics of dissolution to be evaluated. Key attributes of SECM for these studies are the ability to deliver high, controllable, and local acid challenges in a defined way and that multiple dissolution measurements can be performed on one sample, eliminating intersample variability effects. A novel moving boundary finite element model has been designed to describe the etching process, which allows the etch kinetics to be evaluated quantitatively, simply by measuring the size and shape of etch features over time. PMID- 20961104 TI - Biodegradation of poly(2-hydroxyethyl methacrylate) (PHEMA) and poly{(2 hydroxyethyl methacrylate)-co-[poly(ethylene glycol) methyl ether methacrylate]} hydrogels containing peptide-based cross-linking agents. AB - PHEMA-peptide and P[HEMA-co-(MeO-PEGMA)]-peptide conjugate hydrogels [where PHEMA = poly(2-hydroxyethyl methacrylate; PEGMA = poly(ethylene glycol) methacrylate] were readily prepared via photoinitiated free-radical polymerization in water. The PHEMA-peptide hydrogels were opaque and had a heterogeneous morphology of interconnected polymer droplets, characteristic of polymers that separate from the aqueous phase during the polymerization experiment. The P[HEMA-co-(MeO PEGMA)]-peptide conjugates were transparent gels with a homogeneous morphology when formed in water, but when formed in aqueous NaCl solutions the P[HEMA-co (MeO-PEGMA)]-peptide conjugates were also opaque and exhibited the heterogeneous morphology of interconnected polymer droplets. When incubated in solutions containing activated papain, P[HEMA-co-(MeO-PEGMA)]-peptide conjugates underwent degradation that was characterized by macroscopic changes to sample shape and size, sample weight, and microscopic structure. PHEMA-peptide conjugates did not undergo any significant degradation when incubated with papain, although ninhydrin-staining experiments suggested that some peptide cross-linker groups were cleaved during the incubation. The difference in degradation behavior of PHEMA-peptide and P[HEMA-co-(MeO-PEGMA)]-peptide conjugates is attributed to differences in aqueous solubility of PHEMA and P[HEMA-co-(MeO-PEGMA)]. PMID- 20961105 TI - Reductions of challenging organic substrates by a nickel complex of a noninnocent crown carbene ligand. AB - The first crown-tetracarbene complex of Ni(II) has been prepared, and its crystal structure determined. The complex can be reduced by Na/Hg, with an uptake of two electrons. The reduced complex reductively cleaves arenesulfonamides, including those derived from secondary aliphatic amines, and effects Birch reduction of anthracenes as well as reductive cleavage of stilbene oxides. Computational studies show that the orbital that receives electrons upon reduction of the complex 2 is predominantly based on the crown carbene ligand and also that the HOMO of the parent complex 2 is based on the ligand. PMID- 20961107 TI - Disparate effects of Cu and V on structures of exohedral transition metal-doped silicon clusters: a combined far-infrared spectroscopic and computational study. AB - The growth mechanisms of small cationic silicon clusters containing up to 11 Si atoms, exohedrally doped by V and Cu atoms, are described. We find that as dopants, V and Cu follow two different paths: while V prefers substitution of a silicon atom in a highly coordinated position of the cationic bare silicon clusters, Cu favors adsorption to the neutral or cationic bare clusters in a lower coordination site. The different behavior of the two transition metals becomes evident in the structures of Si(n)M(+) (n = 4-11 for M = V, and n = 6-11 for M = Cu), which are investigated by density functional theory and, for several sizes, confirmed by comparison with their experimental vibrational spectra. The spectra are measured on the corresponding Si(n)M(+).Ar complexes, which can be formed for the exohedrally doped silicon clusters. The comparison between experimental and calculated spectra indicates that the BP86 functional is suitable to predict far-infrared spectra of these clusters. In most cases, the calculated infrared spectrum of the lowest-lying isomer fits well with the experiment, even when various isomers and different electronic states are close in energy. However, in a few cases, namely Si(9)Cu(+), Si(11)Cu(+), and Si(10)V(+), the experimentally verified isomers are not the lowest in energy according to the density functional theory calculations, but their structures still follow the described growth mechanism. The different growth patterns of the two series of doped Si clusters reflect the role of the transition metal's 3d orbitals in the binding of the dopant atoms. PMID- 20961106 TI - Mechanistic studies of the biosynthesis of 2-thiosugar: evidence for the formation of an enzyme-bound 2-ketohexose intermediate in BexX-catalyzed reaction. AB - The first mechanistic insight into 2-thiosugar production in an angucycline-type antibiotic, BE-7585A, is reported. d-Glucose 6-phosphate was identified as the substrate for the putative thiosugar biosynthetic protein, BexX, by trapping the covalently bonded enzyme-substrate intermediate. The site-specific modification at K110 residue was determined by mutagenesis studies and LC-MS/MS analysis. A key intermediate carrying a keto functionality was confirmed to exist in the enzyme-substrate complex. These results suggest that the sulfur insertion mechanism in 2-thiosugar biosynthesis shares similarities with that for thiamin biosynthesis. PMID- 20961108 TI - Time course and specificity of lipolysis in Swiss cheese. AB - Controlling lipolysis in cheese is necessary to ensure the formation of desirable flavor. To get a better understanding of the mechanism of lipolysis in Swiss cheese, cheeses were manufactured with and without (control) the addition of Propionibacterium freudenreichii. Products of lipolysis were quantified throughout ripening. Half of the free fatty acids (FFA) released in milk (3.66 mg/g fat), in particular the short-chain FFA, were lost in the whey during curd drainage, whereas diglycerides and monoglycerides were retained within the curd. P. freudenreichii was responsible for the release of most FFA during ripening (10.84 and 0.39 mg/g fat in propionibacteria-containing and control cheeses, respectively). Indices of lipolysis displayed low specificity. All types of FFA were released, but butyric and palmitic acids more significantly, which could be due to a low sn-1,3 regioselectivity. All glycerides were hydrolyzed in the following order: monoglycerides>diglycerides>triglycerides. The results of this study show the quantitative and qualitative contributions of the different lipolytic agents to Swiss cheese lipolysis. PMID- 20961109 TI - [m * n] metal ion arrays templated by coordination cages. AB - Three-dimensional m * n arrays of metal ion clusters can be assembled as aromatic stacks of planar polynuclear metal complexes within columnar coordination cages. The polynuclear complexes and cage height program the final array structures of the metal ion clusters. Cyclic trinuclear Au(I) complexes (m = 3) assembled into trigonal prismatic arrays (n = 1-3) within the cages and the array structures were clearly shown by X-ray crystallographic analysis. A silver-sandwiched hetero Au(3)-Ag-Au(3) cluster was also prepared by treating a hexanuclear Au(3)-Au(3) cluster with Ag(I) ion. PMID- 20961110 TI - Synthetic lethal compound combinations reveal a fundamental connection between wall teichoic acid and peptidoglycan biosyntheses in Staphylococcus aureus. AB - Methicillin resistance in Staphylococcus aureus depends on the production of mecA, which encodes penicillin-binding protein 2A (PBP2A), an acquired peptidoglycan transpeptidase (TP) with reduced susceptibility to beta-lactam antibiotics. PBP2A cross-links nascent peptidoglycan when the native TPs are inhibited by beta-lactams. Although mecA expression is essential for beta-lactam resistance, it is not sufficient. Here we show that blocking the expression of wall teichoic acids (WTAs) by inhibiting the first enzyme in the pathway, TarO, sensitizes methicillin-resistant S. aureus (MRSA) strains to beta-lactams even though the beta-lactam-resistant transpeptidase, PBP2A, is still expressed. The dramatic synergy between TarO inhibitors and beta-lactams is noteworthy not simply because strategies to overcome MRSA are desperately needed but because neither TarO nor the activities of the native TPs are essential in MRSA strains. The "synthetic lethality" of inhibiting TarO and the native TPs suggests a functional connection between ongoing WTA expression and peptidoglycan assembly in S. aureus. Indeed, transmission electron microscopy shows that S. aureus cells blocked in WTA synthesis have extensive defects in septation and cell separation, indicating dysregulated cell wall assembly and degradation. Our studies imply that WTAs play a fundamental role in S. aureus cell division and raise the possibility that synthetic lethal compound combinations may have therapeutic utility for overcoming antibiotic-resistant bacterial infections. PMID- 20961111 TI - Total synthesis of (+)-roxaticin via C-C bond forming transfer hydrogenation: a departure from stoichiometric chiral reagents, auxiliaries, and premetalated nucleophiles in polyketide construction. AB - A total synthesis of the oxo-polyene macrolide (+)-roxaticin is achieved in 20 steps from 1,3-propanediol. In this approach, 9 of 10 C-C bonds formed in the longest linear sequence are made via metal catalysis, including 7 C-C bonds formed by iridium catalyzed alcohol C-C coupling. Notably, the present synthesis, which represents the most concise preparation of any oxo-polyene macrolide reported to date, is achieved in the absence of chiral reagents and chiral auxiliaries with minimal use of premetalated C-nucleophiles. PMID- 20961112 TI - Structures of the Michaelis complex (1.2 A) and the covalent acyl intermediate (2.0 A) of cefamandole bound in the active sites of the Mycobacterium tuberculosis beta-lactamase K73A and E166A mutants. AB - The genome of Mycobacterium tuberculosis (TB) contains a gene that encodes a highly active beta-lactamase, BlaC, that imparts TB with resistance to beta lactam chemotherapy. The structure of covalent BlaC-beta-lactam complexes suggests that active site residues K73 and E166 are essential for acylation and deacylation, respectively. We have prepared the K73A and E166A mutant forms of BlaC and have determined the structures of the Michaelis complex of cefamandole and the covalently bound acyl intermediate of cefamandole at resolutions of 1.2 and 2.0 A, respectively. These structures provide insight into the details of the catalytic mechanism. PMID- 20961113 TI - Controlled plasmon resonance properties of hollow gold nanosphere aggregates. AB - Hollow gold nanospheres (HGNs) ranging from 29.9 nm/8.5 nm (outer diameter/shell thickness) to 51.5 nm/4.5 nm and having aspect ratios spanning 3.5-11.7 were employed to investigate the ability to tailor charge oscillations of HGN aggregates by systematic variation of particle aspect ratio, interparticle gap, and nanosphere inner surface spatial separation. Altering these properties in aggregated HGNs led to control over the interparticle plasmon resonance. Thiol mediated aggregation was accomplished using either ethanedithiol or cysteine, resulting in dimeric structures in which monomer subunits were spatially separated by <3 A and 1.2 +/- 0.7 nm, respectively. Particle dimensions and separation distances were confirmed by transmission electron microscopy. Experimental absorption spectra obtained for high-aspect ratio nanospheres dimerized using ethanedithiol exhibited an obvious blue shift of the surface plasmon resonance (SPR) relative to that observed for the native, monomeric HGN. This spectral difference likely results from a charge-transfer plasmon resonance at the dimer interface. The extent of the blue shift was dependent upon shell thickness. Dimers comprised of thin-shelled HGNs exhibited the largest shift; aggregates containing HGNs with thick shells (>=7 nm) did not display a significant SPR shift when the individual particles were in contact. By comparison, all cysteine-induced aggregates examined in this study displayed large interparticle gaps (>1 nm) and a red-shifted SPR, regardless of particle dimensions. This effect can be described fully by a surface mode coupling model. All experimental measurements were verified by finite difference time domain calculations. In addition, simulated electric field maps highlighted the importance of the inner HGN surface in the interparticle coupling mechanism. These findings, which describe structure-dependent SPR properties, may be significant for applications derived from the plasmonic nanostructure platform. PMID- 20961115 TI - Identification of descriptors capturing compound class-specific features by mutual information analysis. AB - The identification of molecular descriptors that contain compound class-specific information is of high relevance in chemoinformatics. A generally applicable way to identify such descriptors is to determine and compare their information content in a given compound activity class and in large databases where the vast majority of compounds do not have the desired activity. For this purpose, the Shannon entropy concept from information theory can in principle be employed. However, previous adaptations of this concept for descriptor profiling are insufficient to select discriminatory descriptors for data sets that dramatically differ in size. Therefore, we introduce a methodology to reliably select such descriptors by transforming the previously introduced differential Shannon entropy formalism into mutual information analysis, another concept from information theory. The newly introduced approach is evaluated by descriptor ranking and correlation analysis on 168 compound activity classes. PMID- 20961117 TI - Evaluation of nanoparticle aggregation in human blood serum. AB - In a certain stage of development, the performance of nanoparticle- or polymer drug conjugates is tested "in vivo", that is, in mice or rats. Besides pharmaceutical and chemical characterization, the structural characterization of such drug carrier systems in terms of size, size distribution, and shape is typically performed in physiological salt solution prior to animal tests. The present work introduces a simple method based on dynamic light scattering to monitor the particle size in blood serum. Utilizing a model system of pegylated poly-l-lysines (PLL-g-PEOx) of various degrees of pegylation, x, it is demonstrated that large aggregates may form in human serum solution that are not observed in isotonic salt solution. Aggregates of a few hundred nanometers in size were found in mixtures of serum solution and PLL-g-PEOx with degrees of pegylation <10%, whereas no aggregates are being observed if the degree of pegylation exceeds 20%. The described method may have the potential to become an easy and routine test for drug carrier systems prior to animal applications. PMID- 20961116 TI - Microchannel-nanopore device for bacterial chemotaxis assays. AB - Motile bacteria bias the random walk of their motion in response to chemical gradients by the process termed chemotaxis, which allows cells to accumulate in favorable environments and disperse from less favorable ones. In this work, we describe a simple microchannel-nanopore device that establishes a stable chemical gradient for chemotaxis assays in <=1 min. Chemoattractant is dispensed by diffusion through 10 nm diameter pores at the intersection of two microchannels. This design requires no external pump and minimizes the effect of transmembrane pressure, resulting in a stable, reproducible gradient. The microfluidic platform facilitates microscopic observation of individual cell trajectories, and chemotaxis is quantified by monitoring changes in cell swimming behavior in the vicinity of the intersection. We validate this system by measuring the chemotactic response of an aquatic bacterium, Caulobacter crescentus, to xylose concentrations from 1.3 MUM to 1.3 M. Additionally, we make an unanticipated observation of increased turn frequency in a chemotaxis-impaired mutant which provides new insight into the chemotaxis pathway in C. crescentus. PMID- 20961118 TI - Versatile polymer microspheres for injection therapy: aspects of fluoroscopic traceability and biofunctionalization. AB - Synthesis and characterization of a series of novel microspheres featuring (i) radiopacity (i.e., clear fluoroscopic traceability) and (ii) an outer surface exposing aldehyde groups are reported. The aldehydes allowed us to tether proteins onto the particles' surface under mild conditions, under which the protein conformation and, hence, structural motifs for biorecognition are preserved. Essential monomer building blocks were (i) 4-iodobenzoyl-2-oxo ethylmethacrylate (4-IEMA) for radiopacity and (ii) propenal for surface tethering of proteins. The particles demonstrated good X-ray visibility and cytocompatibility. Procedures to couple proteins onto the surface were optimized using fluorescent bovine serum albumin (FITC-BSA) or collagen (FITC-collagen). Furthermore, radiopaque microparticles with unlabeled bovine collagen type I were produced. The presence of immobilized collagen was verified with narrow-scan X ray photoelectron spectroscopy. Fibroblasts readily adhere to and grow on the collagen-modified surfaces, whereas this was much less the case for the unmodified controls. The results led us to suggest that immobilized nondenatured collagen may transform filler particles from passive space-occupying objects to particles that cross-talk with surrounding tissues. PMID- 20961119 TI - In vivo and in vitro starch digestion: are current in vitro techniques adequate? AB - The time evolution of the size distributions of (fully branched and debranched) starch molecules during in vivo and in vitro digestion was analyzed using size exclusion chromatography (SEC) and compared. In vivo digesta were collected from the small intestine of pigs fed with raw normal maize starch; in vitro digestion was carried out on the same diet fed to the pigs using a method simulating digestion in the mouth, stomach, and small intestine. A qualitative difference was observed between the in vitro and the in vivo digestion. The former showed a degradation of starch molecules to a more uniform size, whereas the in vivo digestion preserved the size distribution of native starch before producing a multimodal distribution, the heterogeneous nature of which current in vitro methods do not reproduce. The use of in vitro digestion to infer in vivo digestion patterns and, hence, potential nutrition benefits need to take account of this phenomenon. PMID- 20961120 TI - Chain stiffness of elastin-like polypeptides. PMID- 20961121 TI - Eu3+/Tb3+-doped La2O2CO3/La2O3 nano/microcrystals with multiform morphologies: facile synthesis, growth mechanism, and luminescence properties. AB - LaCO(3)OH nano/microcrystals with a variety of morphologies/sizes including nanoflakes, microflowers, nano/microrhombuses, two-double microhexagrams sandwichlike microspindles, and peach-nucleus-shaped microcrystals have been synthesized via a facile homogeneous precipitation route under mild conditions. A series of controlled experiments indicate that the pH values in the initial reaction systems, carbon sources, and simple ions (NH(4)(+) and Na(+)) were responsible for the shape determination of the LaCO(3)OH products. A possible formation mechanism for these products with diverse architectures has been presented. After annealing at suitable temperatures, LaCO(3)OH was easily converted to La(2)O(2)CO(3) and La(2)O(3) with the initial morphologies. A systematic study on the photoluminescence and cathodoluminescence properties of Eu(3+)- or Tb(3+)-doped La(2)O(2)CO(3)/La(2)O(3) samples has been performed in detail. The excitation and site-selective emission spectra were recorded to investigate the microstructure, site symmetry, and difference in the (5)D(0) -> (7)F(2) transition of Eu(3+) ions in La(2)O(2)CO(3) and La(2)O(3) host lattices. In addition, the dependence of the luminescent intensity on the morphology for the as-prepared La(2)O(2)CO(3)/La(2)O(3):Ln(3+) (Ln = Eu, Tb) samples has been investigated. The ability of generating diverse morphologies and multiemitting colors for different rare-earth activator ion (Ln = Eu, Tb) doped La(2)O(2)CO(3)/La(2)O(3) nano/microstructures provides a great opportunity for the systematic evaluation of morphology-dependent luminescence properties, as well as the full exploration of their application in many types of color display fields. PMID- 20961122 TI - Surface enhanced Raman scattering spot tests: a new insight on Feigl's analysis using gold nanoparticles. AB - Traditional Feigl's spot tests can be greatly improved with the aid of gold nanoparticles and Raman probes, by monitoring the changes in the surface enhanced Raman scattering (SERS) of the analytes directly applied on a filter paper previously impregnated with the selective organic reagent. As a proof of concept, diphenylthiocarbazone (dithizone) was treated with citrate stabilized gold nanoparticles and employed in paper spot tests for a variety of transition and heavy metal ions. Below 10(-5) mol L(-1), only mercury(II) ions were able to displace the dithizone molecules from the "coordination shell" of the gold nanoparticles, leading to a systematic decay of the Raman signals. Because of the huge enhancement of the dithizone vibrational peaks, the SERS spot tests allowed the detection of picograms of Hg(2+) ions. PMID- 20961123 TI - Photocaged morpholino oligomers for the light-regulation of gene function in zebrafish and Xenopus embryos. AB - Morpholino oligonucleotides, or morpholinos, have emerged as powerful antisense reagents for evaluating gene function in both in vitro and in vivo contexts. However, the constitutive activity of these reagents limits their utility for applications that require spatiotemporal control, such as tissue-specific gene disruptions in embryos. Here we report a novel and efficient synthetic route for incorporating photocaged monomeric building blocks directly into morpholino oligomers and demonstrate the utility of these caged morpholinos in the light activated control of gene function in both cell culture and living embryos. We demonstrate that a caged morpholino that targets enhanced green fluorescent protein (EGFP) disrupts EGFP production only after exposure to UV light in both transfected cells and living zebrafish (Danio rerio) and Xenopus frog embryos. Finally, we show that a caged morpholino targeting chordin, a zebrafish gene that yields a distinct phenotype when functionally disrupted by conventional morpholinos, elicits a chordin phenotype in a UV-dependent manner. Our results suggest that photocaged morpholinos are readily synthesized and highly efficacious tools for light-activated spatiotemporal control of gene expression in multiple contexts. PMID- 20961124 TI - Optimized measurement temperature gives access to the solution structure of a 49 kDa homohexameric beta-propeller. AB - Ph1500 is a homohexameric, two-domain protein of unknown function from the hyperthermophilic archaeon Pyrococcus horikoshii. The C-terminal hexamerization domain (Ph1500C) is of particular interest, as it lacks sequence homology to proteins of known structure. However, it resisted crystallization for X-ray analysis, and proteins of this size (49 kDa) present a considerable challenge to NMR structure determination in solution. We solved the high-resolution structure of Ph1500C, exploiting the hyperthermophilic nature of the protein to minimize unfavorable relaxation properties by high-temperature measurement. Thus, the side chain assignment (97%) and structure determination became possible at full proton density. To our knowledge, Ph1500C is the largest protein for which this has been achieved. To minimize detrimental fast water exchange of amide protons at increased temperature, we employed a strategy where the temperature was optimized separately for backbone and side chain experiments. PMID- 20961125 TI - Steam-stable zeolitic imidazolate framework ZIF-90 membrane with hydrogen selectivity through covalent functionalization. AB - A novel covalent functionalization strategy was developed to prepare reproducible ZIF-90 molecular sieve membranes by using 3-aminopropyltriethoxysilane as a covalent linker between the ZIF-90 layer and Al(2)O(3) support via imines condensation. The ZIF-90 membranes show high thermal and hydrothermal stabilities, and they allow the separation of hydrogen from larger gases by molecular sieving. PMID- 20961126 TI - Investigation of thermally responsive block copolymer thin film morphologies using gradients. AB - We report the use of a gradient library approach to characterize the structure and behavior of thin films of a thermally responsive block copolymer (BCP), poly(styrene-b-tert-butyl acrylate) (PS-b-PtBA), which exhibits chemical deprotection and morphological changes above a thermal threshold. Continuous gradients in temperature and film thickness, as well as discrete substrate chemistry conditions, were used to examine trends in deprotection, nanoscale morphology, and chemical structure. Thermal gradient annealing permitted the extraction of transformation rate constants (k(t)) for the completion of thermal deprotection and rearrangement of the film morphology from a single BCP library on hydroxyl and alkyl surfaces, respectively. The transformation rate constants ranged from 1.45 * 10(-4) s(-1) to 5.02 * 10(-5) s(-1) for temperatures between 185 and 140 degrees C for hydroxyl surfaces. For the same temperature range, the alkyl surfaces yielded k(t) values ranging from 4.76 * 10(-5) s(-1) to 5.73 * 10( 6) s(-1), an order of magnitude slower compared to hydroxyl surfaces. Activation energies of the thermal deprotection and film transformation on these surfaces were also extrapolated from linear fits to Arrhenius behavior. Moreover, we noted a morphology shift and orientation transformation from parallel lamellae to perpendicular cylinders at the free surface because of changes in volume fraction and surface energetics of the initially symmetric BCP. Using gradient techniques, we are able to correlate morphological and chemical structure changes in a rapid fashion, determine kinetics of transitions, and demonstrate the effect of surface chemistry on the deprotection reaction in thermally responsive BCP thin films. PMID- 20961127 TI - Layered graphene oxide nanostructures with sandwiched conducting polymers as supercapacitor electrodes. AB - We demonstrate a general approach to the preparation of layered graphene oxide structures with sandwiched conducting polymers of different morphologies. The approach is conceptualized on the basis of the electrostatic interactions between negatively charged graphene oxide sheets and positively charged surfactant micelles. A graphene oxide-polypyrrole composite prepared from this approach exhibited an excellent electrocapacitive performance with a high specific capacitance over 500 F g(-1). Good rate performance and cycle ability were realized by the composite electrode. The simple method described here opens up a generalized route to making a wide range of graphene oxide-based and graphene based composite materials for applications beyond electrochemical energy storage. PMID- 20961128 TI - Platinum-nanoparticle-modified TiO2 nanowires with enhanced photocatalytic property. AB - Highly crystalline Pt nanoparticles with an average diameter of 5 nm were homogeneously modified on the surfaces of TiO(2) nanowires (Pt-TiO(2) NWs) by a simple hydrothermal and chemical reduction route. Photodegradation of methylene blue (MB) in the presence of Pt-TiO(2) NWs indicates that the photocatalytic activity of TiO(2) NWs can be greatly enhanced by Pt nanoparticle modification. The physical chemistry process and photocatalytic mechanism for Pt-TiO(2) NWs hybrids degrading MB were investigated and analyzed. The Pt attached on TiO(2) nanowires induces formation of a Schottky barrier between TiO(2) and Pt naonoparticles, leading to a fast transport of photogenerated electrons to Pt particles. Furthermore, Pt incoporation on TiO(2) surface can accelerate the transfer of electrons to dissolved oxygen molecules. Besides enhancing the electron-hole separation and charge transfer to dissolved oxygen, Pt may also serve as an effective catalyst in the oxidation of MB. However, a high Pt loading value does not mean a high photocatalytic activity. Higher content loaded Pt nanoparticles can absorb more incident photons which do not contribute to the photocatalytic efficiency. The highest photocatalytic activity for the Pt-TiO(2) nanohybrids on MB can be obtained at 1 at % Pt loading. PMID- 20961129 TI - Dynamics of the crystal to plastic crystal transition in the hydrogen bonded N isopropylpropionamide. AB - N-Isopropylpropionamide (NiPPA), which can self-associate via hydrogen bonds, was found to undergo a solid-solid transition as identified by DSC and X-ray diffraction. Below the melting temperature of 51 degrees C NIPPA adopts a plastic crystalline state with a tetragonal unit cell until it transforms into an ordered crystal with a monoclinic structure at temperatures <=10 degrees C. Dielectric spectroscopy was used to characterize the dynamics of the system, determining the activation parameters for the plastic to crystalline phase transition. The activation enthalpy is relatively high, as expected for a system that involves hydrogen bonds. However, most of the activation energy as the plastic phase assumes a more crystalline state is due to the activation entropy, suggesting that the increased cooperativity observed in the relaxation processes is due to a steric locking of the molecules. PMID- 20961130 TI - Divergent approach to flavones and aurones via dihaloacrylic acids. Unexpected dependence on the halogen atom. AB - The reaction of phenols with 7a led to the synthesis of aurones, while the reaction of phenols with 7b led to the synthesis of flavones. PMID- 20961131 TI - Improved density functional description of the electrochemistry and structure property descriptors of substituted flavins. AB - The energetics of electrochemical changes have been investigated for several substituted flavins with the M06-L density functional. The reduction potentials for one- and two-electron reductions of these molecules have been determined and the results are consistent with experimental findings with a mean unsigned error of only 42 mV. It is especially noteworthy that the M06-L density functional makes a significant difference in the computed free energy of the first reduction of lumiflavin, which produces a neutral semiquinone. We also investigate the effects of flavin ring substituents on the geometries, charge distributions, reduction potentials, pK(a)'s, ionization potentials, electron affinities, hardnesses, softnesses, electrophilic powers, and nucleophilicities. PMID- 20961133 TI - Conformational flexibility of chitosan: a molecular modeling study. AB - Chitin and chitosan are naturally occurring polysaccharides composed of beta (1,4) linked N-acetylglucosamine units (GlcNAc) and, for chitosan, also glucosamine units (GlcN). In recent years, chitosan has attracted much interest because of its special physical and chemical properties related to drug delivery, wound healing, and tissue engineering. However, limited structural knowledge is available for chitosan because of its composition of the randomly mixed building blocks, GlcNAc and GlcN. In this study, we present exhaustive combined molecular dynamics and Monte Carlo simulations that unravel the conformational flexibility of the beta-(1,4)-linkage in di-, tri-, and tetrasaccharide models of chitin and chitosan. The most flexible disaccharide unit was found to be GlcN-GlcNAc, populating four conformations. Furthermore, it is found that the conformational freedom of a glycosidic bond is independent of the flexibility of the neighboring linkages along the oligomer. The results are interpreted with respect to hydrogen bond formation and implications for polymer properties. PMID- 20961132 TI - Multicolor protein labeling in living cells using mutant beta-lactamase-tag technology. AB - Protein labeling techniques using small molecule probes have become important as practical alternatives to the use of fluorescent proteins (FPs) in live cell imaging. These labeling techniques can be applied to more sophisticated fluorescence imaging studies such as pulse-chase imaging. Previously, we reported a novel protein labeling system based on the combination of a mutant beta lactamase (BL-tag) with coumarin-derivatized probes and its application to specific protein labeling on cell membranes. In this paper, we demonstrated the broad applicability of our BL-tag technology to live cell imaging by the development of a series of fluorescence labeling probes for this technology, and the examination of the functions of target proteins. These new probes have a fluorescein or rhodamine chromophore, each of which provides enhanced photophysical properties relative to coumarins for the purpose of cellular imaging. These probes were used to specifically label the BL-tag protein and could be used with other small molecule fluorescent probes. Simultaneous labeling using our new probes with another protein labeling technology was found to be effective. In addition, it was also confirmed that this technology has a low interference with respect to the functions of target proteins in comparison to GFP. Highly specific and fast covalent labeling properties of this labeling technology is expected to provide robust tools for investigating protein functions in living cells, and future applications can be improved by combining the BL-tag technology with conventional imaging techniques. The combination of probe synthesis and molecular biology techniques provides the advantages of both techniques and can enable the design of experiments that cannot currently be performed using existing tools. PMID- 20961134 TI - New intermetallics YbAu2In4 and Yb2Au3In5. AB - The intermetallic compounds YbAu(2)In(4) and Yb(2)Au(3)In(5) were obtained as single crystals in high yield from reactions run in liquid indium. Single crystal X-ray diffraction data of YbAu(2)In(4) showed that it crystallizes as a new structure type in the monoclinic space group P2(1)/m and lattice constants a = 7.6536(19) A, b = 4.5424(11) A, c = 9.591(2) A and beta = 107.838(4) degrees . The YbAu(2)In(4) compound is composed of a complex [Au(2)In(4)](3-) polyanionic network in which the rare-earth ions are embedded. Yb(2)Au(3)In(5) crystallizes in the polar space group Cmc2(1) with the Y(2)Rh(3)Sn(5) type structure and lattice constants a = 4.5351(9) A, b = 26.824(5) A, and c = 7.4641(15) A. The gold and indium atoms define a complex three-dimensional [Au(3)In(5)] network with a broad range of Au-In (2.751(2) A-3.0518(16) A) and In-In (3.062(3) A 3.3024(19) A) distances. Magnetic susceptibility measurements of YbAu(2)In(4) revealed a transition at 25 K. Below the transition, the susceptibility of YbAu(2)In(4) follows Curie-Weiss behavior with an effective paramagnetic moment of 0.79 MU(B)/Yb. Magnetic susceptibility measurements on Yb(2)Au(3)In(5) show a mixed valent ytterbium and the magnetic moment within the linear region (<100 K) of 1.95 MU(B)/Yb. Heat capacity data for YbAu(2)In(4) and Yb(2)Au(3)In(5) give Debye temperatures of 185 and 153 K, respectively. PMID- 20961135 TI - Pentafluorophenoxy boron subphthalocyanine as a fluorescent dopant emitter in organic light emitting diodes. AB - A fluorinated phenoxy boron subphthalocyanine (BsubPc) is shown to function as a fluorescent dopant emitter in small molecule organic light emitting diodes (OLEDs). Narrow electroluminescence (EL) emission with a full width at half maximum of ~30 nm was observed regardless of the host used, indicating that this narrow EL is intrinsic to the BsubPc molecule. A bathochromic shift and the growth of a new EL peak at higher wavelengths with increasing doping concentration were found to be a result of molecular aggregation. Excitation of BsubPc by direct charge trapping as well as Forster resonant energy transfer were shown using different host molecules. A maximum efficiency of 1.5 cd/A was achieved for a 4,4'-N,N'-dicarbazole-biphenyl (CBP) host. PMID- 20961136 TI - Simulations of nanocylinders self-assembled from cyclic beta-tripeptides. AB - This paper examines the self-assembly of cyclic beta-tripeptides using density functional theory. On the basis of literature precedents, these cyclic peptides were expected to self-assemble into cylindrical structures by stacking through backbone-backbone hydrogen bonding. Our calculations show that such stacking is energetically favorable, that the association energy per cyclic peptide decreases (becomes more favorable), and that the overall macrodipole moment of the cylindrical assembly increases with the number of stacked rings, for up to eight rings. For a structure in which two peptide ring units are joined through a single side chain-side chain covalent linker, the association energy between the two rings is favorable, albeit less so than for the unlinked rings. Significantly, the association energy in the dimers is only weakly dependent on the length (above a certain minimum) and conformation of the covalent linkers. Finally, as a plausible route for controlling assembly/disassembly of nanocylinders, we show that, for a pair of rings, each bearing a single amino functionalized side chain, protonation of the amino group results in a strongly positive (unfavorable) association energy between the two rings. PMID- 20961137 TI - Two-dimensional, pyrazine-based nonlinear optical chromophores with ruthenium(II) ammine electron donors. AB - Six new nonlinear optical (NLO) chromophores with pyrazinyl-pyridinium electron acceptors have been synthesized by complexing a known pro-ligand with electron donating {Ru(II)(NH(3))(5)}(2+) or trans-{Ru(II)(NH(3))(4)(py)}(2+) (py = pyridine) centers. These cationic complexes have been characterized as their PF(6)(-) salts by using various techniques including electronic absorption spectroscopy and cyclic voltammetry. The visible d -> pi* metal-to-ligand charge transfer (MLCT) absorptions gain intensity on increasing the number of Ru(II) centers from one to two, but remain at constant energy. One or two Ru(III/II) redox processes are observed which are reversible, quasi-reversible, or irreversible, while all of the ligand-based reductions are irreversible. Molecular first hyperpolarizabilities beta have been determined by using hyper Rayleigh scattering (HRS) at 1064 nm, and depolarization studies show that the NLO responses of the symmetric species are strongly two-dimensional (2D) in character, with dominant "off-diagonal" beta(zyy) components. Stark (electroabsorption) spectroscopic measurements on the MLCT bands also allow the indirect determination of estimated static first hyperpolarizabilities beta(0). Both the HRS and the Stark-derived beta(0) values increase on moving from mono- to bimetallic complexes, and substantial enhancements in NLO response are achieved when compared with one-dimensional (1D) and 2D monometallic Ru(II) ammine complexes reported previously. PMID- 20961139 TI - Gas-phase nucleophilic and elimination reactions in simple alkyl nitrates. AB - There has been increasing interest in the gas-phase reactivity of alkyl nitrates because of their well-known applications as explosives and because of their role in atmospheric and in marine processes. This manuscript describes an experimental study by FT-ICR techniques of the gas-phase reactions of OH(-) and F(-) with methyl and ethyl nitrate. For methyl nitrate, the main reaction channel is found to be an elimination process promoted by abstraction of an alpha proton from the methyl group. Nucleophilic displacement of nitrate anion through an S(N)2 process at the carbon center is also found to be an important reaction channel with methyl nitrate. In ethyl nitrate, formation of NO(3)(-) is greatly enhanced and this is attributed to the ease of an E2-type elimination process promoted by proton abstraction at the beta position of the ethyl group. Theoretical calculations at the MP2/6-311+G(3df,2p)//MP2/6-31+G(d) level of theory are consistent with the relative importance of the reaction channels and suggest that these reactions proceed through a double well potential. The calculations also predict that nucleophilic attack by OH(-) at the nitrogen center (Sn2@N) is energetically the preferred pathway but experiments with (18)OH(-) showed no evidence for this channel. Single-point calculations reveal a strong preference for approach to the carbon center and may explain the lack of reactivity at the nitrogen center. Calculations were also carried out for NH(2)(-) and SH(-) to establish the reactivity pattern to provide a better understanding of environmentally relevant nitrate esters. PMID- 20961138 TI - Sesquiterpene coumarins from Ferula gumosa. AB - A new sesquiterpene coumarin, gumosin (1), two new sesquiterpene coumarin glycosides, gumosides A (2) and B (3), and 10 known compounds, namely, cauferoside (4), feselol (5), conferoside, ferilin, ferocaulidin, ligupersin A, conferol, and daucosterol, and the phenolic compounds acantrifoside E and 4 hydroxybenzoic acid 4-(6-O-sulfo)glucopyranoside, were isolated from a methanolic extract of Ferula gumosa roots. The structures of 1-3 were elucidated by spectroscopic data interpretation. The cytotoxic activity of the sesquiterpene coumarin derivatives was evaluated against a small panel of cancer cell lines. PMID- 20961140 TI - The resistance of polyelectrolyte multilayers in a free-hanging configuration. AB - The resistivity rho(PEM) of polyelectrolyte multilayers (PEMs), PEI(PSS/PAH)(24), PEI(PGA/PAH)(12), PEI(HA/PLL)(12) and PEI(PSS/PLL)(12), in a free-hanging configuration was estimated combining electrochemical impedance spectroscopy (EIS) and atomic force microscopic (AFM) images. Surprisingly, the obtained value of several kOmegacm is at least 6 orders of magnitude lower than that reported previously, where the resistivity was determined in the conventional PEM-on electrode system. The significant discrepancy indicates the unexpectedly low electrical PEM resistance in the absence of redox-active ions and the sensitivity limitation in the conventional system. PMID- 20961142 TI - Findings of Cp maximum at 233 K for the water within silica nanopores and very weak dependence of the Tmax on the pore size. AB - How low-temperature water develops the formation of strong hydrogen bonds with some network structure is still open to a question. Heat capacities of the water confined within silica MCM-41 nanopores with different diameters in the range 1.7 4.2 nm were measured by adiabatic calorimetry. They revealed a hump with its maximum at 233 and 240 K for ordinary and heavy water, respectively. The maximum temperatures were essentially independent of the pore diameter, whereas the maximum values increased only in proportion to the fraction of the internal water molecules within the pores. It was concluded that the manner in which the hydrogen-bond formation progresses in bulk water is essentially the same as that in nanopore water and that strong hydrogen bonds are formed on cooling by arranging the neighboring water molecules at tetrahedral positions but keeping their network structure irregular to make striking contrast with ice structure. PMID- 20961143 TI - Protein specificity of charged sequences in polyanions and heparins. AB - Long-range electrostatic interactions are generally assigned a subordinate role in the high-affinity binding of proteins by glycosaminoglycans, the most highly charged biopolyelectrolytes. The discovery of high and low sulfation domains in heparan sulfates, however, suggests selectivity via complementarity of their linear sulfation patterns with protein charge patterns. We examined how charge sequences in anionic/nonionic copolymers affect their binding to a protein with prominent charge anisotropy. Experiments and united-atom Monte Carlo simulations, together with Delphi electrostatic modeling for the protein, confirm strongest binding when polyanion sequences allow for optimization of repulsive and attractive electrostatics. Simulations also importantly identified retention of considerable polyion conformational freedom, even for strong binding. The selective affinity for heparins of high and low charge density found for this protein is consistent with nonspecific binding to distinctly different protein charge domains. These findings suggest a more nuanced view of specificity than previously proposed for heparinoid-binding proteins. PMID- 20961141 TI - Mechanically, magnetically, and "rotationally aligned" membrane proteins in phospholipid bilayers give equivalent angular constraints for NMR structure determination. AB - The native environment for membrane proteins is the highly asymmetric phospholipid bilayer, and this has a large effect on both their structure and dynamics. Reproducing this environment in samples suitable for spectroscopic and diffraction experiments is a key issue, and flexibility in sample preparation is essential to accommodate the diverse size, shape, and other physical properties of membrane proteins. In most cases, to ensure that the biological activities are maintained, this means reconstituting the proteins in fully hydrated planar phospholipid bilayers. The asymmetric character of protein-containing bilayers means that it is possible to prepare either oriented or unoriented (powder) samples. Here we demonstrate the equivalence of mechanical, magnetic, and what we refer to as "rotational alignment" of membrane proteins in phospholipid bilayer samples for solid-state NMR spectroscopy. The trans-membrane domain of virus protein "u" (Vpu) from human immunodeficiency virus (HIV-1) and the full-length membrane-bound form of fd bacteriophage coat protein in phospholipid bilayers are used as examples. The equivalence of structural constraints from oriented and unoriented (powder) samples of membrane proteins is based on two concepts: (1) their alignment is defined by the direction of the bilayer normal relative to the magnetic field and (2) they undergo rapid rotational diffusion about the same bilayer normal in liquid crystalline membranes. The measurement of angular constraints relative to a common external axis system defined by the bilayer normal for all sites in the protein is an essential element of oriented sample (OS) solid-state NMR. PMID- 20961144 TI - Synthesis and structures of Pb3O2(CH3COO)2.0.5H2O and Pb2O(HCOO)2: two corrosion products revisited. AB - Reactions of carboxylic acids with lead play an important role in the atmospheric corrosion of lead and lead-tin alloys. This is of particular concern for the preservation of lead-based cultural objects, including historic lead-tin alloy organ pipes. Two initial corrosion products, Pb(3)O(2)(CH(3)COO)(2).0.5H(2)O (1) and Pb(2)O(HCOO)(2) (2), had been identified through powder diffraction fingerprints in the Powder Diffraction File, but their structures had never been determined. We have crystallized both compounds using hydrothermal solution conditions, and structures were determined using laboratory and synchrotron single-crystal X-ray diffraction data. Compound 1 crystallizes in P1, and 2 in Cccm. These compounds may be viewed as inorganic-organic networks containing single and double chains of edge-sharing Pb(4)O tetrahedra and have structural similarities to inorganic basic lead compounds. Bond valence sum analysis has been applied to the hemidirected lead coordination environments in each compound. Atmospheric exposure experiments contribute to understanding of the potential for conversion of these short-term corrosion products to hydrocerussite, Pb(3)(CO(3))(2)(OH)(2), previously identified as a long-term corrosion product on lead-rich objects. Each compound was also characterized by elemental analysis, thermogravimetric analysis and differential scanning calorimetry (TGA-DSC), and Raman spectroscopy. PMID- 20961145 TI - Biotin synthase exhibits burst kinetics and multiple turnovers in the absence of inhibition by products and product-related biomolecules. AB - Biotin synthase (BS) is a member of the "SAM radical" superfamily of enzymes, which catalyze reactions in which the reversible or irreversible oxidation of various substrates is coupled to the reduction of the S-adenosyl-l-methionine (AdoMet) sulfonium to generate methionine and 5'-deoxyadenosine (dAH). Prior studies have demonstrated that these products are modest inhibitors of BS and other members of this enzyme family. In addition, the in vivo catalytic activity of Escherichia coli BS requires expression of 5'-methylthioadenosine/S-adenosyl-l homocysteine nucleosidase, which hydrolyzes 5'-methylthioadenosine (MTA), S adenosyl-l-homocysteine (AdoHcy), and dAH. In the present work, we confirm that dAH is a modest inhibitor of BS (K(i) = 20 MUM) and show that cooperative binding of dAH with excess methionine results in a 3-fold enhancement of this inhibition. However, with regard to the other substrates of MTA/AdoHcy nucleosidase, we demonstrate that AdoHcy is a potent inhibitor of BS (K(i) <= 650 nM) while MTA is not an inhibitor. Inhibition by both dAH and AdoHcy likely accounts for the in vivo requirement for MTA/AdoHcy nucleosidase and may help to explain some of the experimental disparities between various laboratories studying BS. In addition, we examine possible inhibition by other AdoMet-related biomolecules present as common contaminants in commercial AdoMet preparations and/or generated during an assay, as well as by sinefungin, a natural product that is a known inhibitor of several AdoMet-dependent enzymes. Finally, we examine the catalytic activity of BS with highly purified AdoMet in the presence of MTAN to relieve product inhibition and present evidence suggesting that the enzyme is half-site active and capable of undergoing multiple turnovers in vitro. PMID- 20961146 TI - Theoretical investigations on the chemical bonding, electronic structure, and optical properties of the metal-organic framework MOF-5. AB - The chemical bonding, electronic structure, and optical properties of metal organic framework-5 (MOF-5) were systematically investigated using ab initio density functional calculations. The unit cell volume and atomic positions were optimized with the Perdew-Burke-Ernzerhof (PBE) functional leading to a good agreement between the experimental and the theoretical equilibrium structural parameters. The calculated bulk modulus indicates that MOF-5 is a soft material. The estimated band gap from a density of state (DOS) calculation for MOF-5 is about 3.4 eV, indicating a nonmetallic character. As MOFs are considered as potential materials for photocatalysts, active components in hybrid solar cells, and electroluminescence cells, the optical properties of this material were investigated. The detailed analysis of chemical bonding in MOF-5 reveals the nature of the Zn-O, O-C, H-C, and C-C bonds, that is, Zn-O having mainly ionic interaction whereas O-C, H-C, and C-C exhibit mainly covalent interactions. The findings in this paper may contribute to a comprehensive understanding about this kind of material and shed insight into the synthesis and application of novel and stable MOFs. PMID- 20961147 TI - Mn8 and Mn16 clusters from the use of 2-(hydroxymethyl)pyridine, and comparison with the products from bulkier chelates: a new high nuclearity single-molecule magnet. AB - The synthesis, crystal structures, and magnetochemical characterization of two new Mn clusters [Mn(8)O(2)(O(2)CPh)(10)(hmp)(4)(MeOH)(2)] (1; 6Mn(II), 2Mn(III)) and [Mn(16)O(8)(OH)(2)(O(2)CPh)(12)(hmp)(10)(H(2)O)(2)](O(2)CPh)(2) (2; 6Mn(II), 10Mn(III)) are reported. They were obtained from the use of 2 (hydroxymethyl)pyridine (hmpH) under the same reaction conditions but differing in the presence or absence of added base. Thus, the reaction of hmpH with Mn(O(2)CPh)(2) in CH(2)Cl(2)/MeOH led to isolation of octanuclear complex 1, whereas the analogous reaction in the presence of NEt(3) gave hexadecanuclear complex 2. Complexes 1 and 2 possess either very rare or unprecedented core structures that are related to each other: that of 1 can be described as a linked pair of incomplete [Mn(4)O(3)] cubanes, while that of 2 consists of a linked pair of complete [Mn(4)O(4)] cubanes, on either side of which is attached a tetrahedral [Mn(4)(MU(4)-O)] unit. Solid-state direct current (dc) and alternating current (ac) magnetic susceptibility measurements on 1 and 2 establish that they possess S = 5 and 8 ground states, respectively. Complex 2 exhibits frequency-dependent out-of-phase (chi(M)") ac susceptibility signals at temperatures below 3 K suggestive of a single-molecule magnet (SMM). Magnetization versus applied dc field sweeps on single crystals of 2.10MeOH down to 0.04 K exhibited hysteresis, confirming 2 to be a new SMM. Comparison of the structure of 2 (Mn(16)) with Mn(12) or Mn(6) clusters previously obtained under the same reaction conditions but with two Me or two Ph groups, respectively, added next to the alkoxide O atom of hmp(-) indicate their influence on the nuclearity and structure of the products as being due to the overall bulk of the chelate plus the decreased ability of the O atom to bridge. PMID- 20961148 TI - Photoinduced charge carrier dynamics of Zn-porphyrin-TiO2 electrodes: the key role of charge recombination for solar cell performance. AB - Time resolved absorption spectroscopy has been used to study photoinduced electron injection and charge recombination in Zn-porphyrin sensitized nanostructured TiO(2) electrodes. The electron transfer dynamics is correlated to the performance of dye sensitized solar cells based on the same electrodes. We find that the dye/semiconductor binding can be described with a heterogeneous geometry where the Zn-porphyrin molecules are attached to the TiO(2) surface with a distribution of tilt angles. The binding angle determines the porphyrin semiconductor electron transfer distance and charge transfer occurs through space, rather than through the bridge connecting the porphyrin to the surface. For short sensitization times (1 h), there is a direct correlation between solar cell efficiency and amplitude of the kinetic component due to long-lived conduction band electrons, once variations in light harvesting (surface coverage) have been taken into account. Long sensitization time (12 h) results in decreased solar cell efficiency because of decreased efficiency of electron injection. PMID- 20961150 TI - Tribute to Klaus Muller-Dethlefs. PMID- 20961149 TI - Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: the role of side chain chirality and Michael acceptor group for maximal potency. AB - HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model. PMID- 20961155 TI - Ultraviolet photodepletion spectroscopy of dibenzo-18-crown-6-ether complexes with alkaline Earth metal divalent cations. AB - Ultraviolet photodepletion spectra of dibenzo-18-crown-6-ether complexes with alkaline earth metal divalent cations (A(2+)-DB18C6, A = Ba, Sr, Ca, and Mg) were obtained in the gas phase using electrospray ionization quadrupole ion-trap reflectron time-of-flight mass spectrometry. Each spectrum exhibits the lowest energy absorption band in the wavenumber region of 35 400-37 800 cm(-1), which is tentatively assigned as the origin of the S(0)-S(1) transition of A(2+)-DB18C6. This origin band shows a red shift as the size of the metal dication increases from Mg(2+) to Ba(2+). The binding energies of the metal dications to DB18C6 at the S(0) state were calculated at the lowest energy structures optimized by the density functional theory and employed with the experimental energies of the origin bands to estimate the binding energies at the S(1) state. We suggest that the red shifts of the origin bands arise from the decrease in the binding energies of the metal dications at the S(1) state by nearly constant ratios with respect to the binding energies at the S(0) state, which decrease with increasing size of the metal dication. This unique relationship of the binding energies between the S(0) and S(1) states gives rise to a linear correlation between the relative shift of the origin band of A(2+)-DB18C6 and the binding energy of the metal dication at the S(0) state. The size effects of the metal cations on the properties of metal-DB18C6 complex ions are also manifested in the linear plot of the relative shift of the origin band as a function of the size to charge ratio of the metal cations, where the shifts of the origin bands for all DB18C6 complexes with alkali and alkaline earth metal cations are fit to the same line. PMID- 20961156 TI - Supersonic beams at high particle densities: model description beyond the ideal gas approximation. AB - Supersonic molecular beams constitute a very powerful technique in modern chemical physics. They offer several unique features such as a directed, collision-free flow of particles, very high luminosity, and an unsurpassed strong adiabatic cooling during the jet expansion. While it is generally recognized that their maximum flow velocity depends on the molecular weight and the temperature of the working fluid in the stagnation reservoir, not a lot is known on the effects of elevated particle densities. Frequently, the characteristics of supersonic beams are treated in diverse approximations of an ideal gas expansion. In these simplified model descriptions, the real gas character of fluid systems is ignored, although particle associations are responsible for fundamental processes such as the formation of clusters, both in the reservoir at increased densities and during the jet expansion. In this contribution, the various assumptions of ideal gas treatments of supersonic beams and their shortcomings are reviewed. It is shown in detail that a straightforward thermodynamic approach considering the initial and final enthalpy is capable of characterizing the terminal mean beam velocity, even at the liquid-vapor phase boundary and the critical point. Fluid properties are obtained using the most accurate equations of state available at present. This procedure provides the opportunity to naturally include the dramatic effects of nonideal gas behavior for a large variety of fluid systems. Besides the prediction of the terminal flow velocity, thermodynamic models of isentropic jet expansions permit an estimate of the upper limit of the beam temperature and the amount of condensation in the beam. These descriptions can even be extended to include spinodal decomposition processes, thus providing a generally applicable tool for investigating the two-phase region of high supersaturations not easily accessible otherwise. PMID- 20961157 TI - Coherent correlation between nonadiabatic rotational excitation and angle dependent ionization of NO in intense laser fields. AB - We investigate coherent correlation between nonadiabatic rotational excitation and angle-dependent ionization of NO in intense laser fields in the state resolved manner. When neutral NO molecules are partly ionized in intense laser fields (I(0) > 35 TW/cm(2)), a hole in the rotational wave packet of the remaining neutral NO is created because of the ionization rate depending on the alignment angle of the molecular axis with respect to the laser polarization direction. Rotational state distributions of NO are experimentally observed, and then the characteristic feature that the population at higher J levels is increased by the ionization can be identified. Numerical calculation for solving time-dependent rotational Schrodinger equations including the effect of the ionization is carried out. The numerical results suggest that NO molecules aligned perpendicular to the laser polarization direction are dominantly ionized at the peak intensity of I(0) = 42 TW/cm(2), where the multiphoton ionization is preferred rather than the tunneling ionization. PMID- 20961158 TI - Ultrafast relaxation dynamics observed through time-resolved photoelectron angular distributions. AB - Time-resolved photoelectron imaging of the 7,7,8,8-tetracyanoquinodimethane (TCNQ) radical anion is presented. Photoelectron angular distributions (PADs) are qualitatively analyzed in terms of the simple s-p model that is based on symmetry arguments. The internal conversion dynamics from the first excited state (1(2)B(3u)) to the ground state ((2)B(2g)) may be observed through temporal changes in the PADs of the spectrally overlapping photoelectron features arising from photodetachment of the ground state and the excited state. A formulism for extracting the population dynamics from the beta(2) anisotropy parameter of overlapping spectroscopic features is presented. This is used to extract the lifetime of the first excited state, which is in good agreement with that observed in the time-resolved photoelectron spectra. PMID- 20961159 TI - Wavelength dependence of electronic relaxation in isolated adenine using UV femtosecond time-resolved photoelectron spectroscopy. AB - Electronic relaxation pathways in photoexcited nucleobases have received much theoretical and experimental attention due to their underlying importance to the UV photostability of these biomolecules. Multiple mechanisms with different energetic onsets have been proposed by ab initio calculations yet the majority of experiments to date have only probed the photophysics at a few selected excitation energies. We present femtosecond time-resolved photoelectron spectra (TRPES) of the DNA base adenine in a molecular beam at multiple excitation energies between 4.7-6.2 eV. The two-dimensional TRPES data is fit globally to extract lifetimes and decay associated spectra for unambiguous identification of states participating in the relaxation. Furthermore, the corresponding amplitude ratios are indicative of the relative importance of competing pathways. We adopt the following mechanism for the electronic relaxation of isolated adenine; initially the S(2)(pipi*) state is populated by all excitation wavelengths and decays quickly within 100 fs. For excitation energies below ~5.2 eV, the S(2)(pipi*)->S(1)(npi*)->S(0) pathway dominates the deactivation process. The S(1)(npi*)->S(0) lifetime (1032-700 fs) displays a trend toward shorter time constants with increasing excitation energy. On the basis of relative amplitude ratios, an additional relaxation channel is identified at excitation energies above 5.2 eV. PMID- 20961160 TI - From synchronous to sequential double proton transfer: quantum dynamics simulations for the model porphine. AB - Quantum dynamics simulations of double proton transfer (DPT) in the model porphine, starting from a nonequilibrium initial state, demonstrate that a switch from synchronous (or concerted) to sequential (or stepwise or successive) breaking and making of two bonds is possible. For this proof of principle, we employ the simple model of Smedarchina, Z.; Siebrand, W.; Fernandez-Ramos, A. J. Chem. Phys. 2007, 127, 174513, with reasonable definition for the domains D for the reactant R, the product P, the saddle point SP2 which is crossed during synchronous DPT, and two intermediates I = I(1) + I(2) for two alternative routes of sequential DPT. The wavepacket dynamics is analyzed in terms of various properties, from qualitative conclusions based on the patterns of the densities and flux densities, until quantitative results for the time evolutions of the populations or probabilities P(D)(t) of the domains D = R, P, SP2, and I, and the associated net fluxes F(D)(t) as well as the domain-to-domain (DTD) fluxes F(D1,D2) between neighboring domains D1 and D2. Accordingly, the initial synchronous mechanism of the first forward reaction is due to the directions of various momenta, which are imposed on the wavepacket by the L-shaped part of the steep repulsive wall of the potential energy surface (PES), close to the minimum for the reactant. At the same time, these momenta cause initial squeezing followed by rapid dispersion of the representative wavepacket. The switch from the synchronous to sequential mechanism is called indirect, because it is mediated by two effects: First, the wavepacket dispersion; second, relief reflections of the broadened wavepacket from wide regions of the inverse L-shaped steep repulsive wall of the PES close to the minimum for the product, preferably to the domains I = I(1) + I(2) for the sequential DPT during the first back reaction, and also during the second forward reaction, etc. Our analysis also discovers a variety of minor effects, such as direct switch of the mechanisms, as well as damped oscillations in the net fluxes and populations due to compensations of partially overlapping DTD fluxes. PMID- 20961161 TI - Conformational isomers and isomerization of group 6 (Cr, Mo, and W) metal bis(toluene) sandwich complexes probed by variable-temperature electron spectroscopy. AB - Group 6 metal (Cr, Mo, and W)-bis(toluene) sandwich complexes are synthesized in a laser-vaporization molecular beam source. Conformational isomers and isomerization of these complexes are studied by variable-temperature pulsed-field ionization zero-electron-kinetic-energy spectroscopy and density functional theory. For Cr-bis(toluene), four rotational conformers are identified with methyl-group dihedral angles of 0, 60, 120, and 180 degrees . The ground electronic states of these conformers are (1)A(1) (C(2v), 0 degrees ), (1)A (C(2), 60 and 120 degrees ), and (1)A(g) (C(2h), 180 degrees ) in the neutral form and (2)A(1) (C(2v), 0 degrees ), (2)A (C(2), 60 and 120 degrees ), and (2)A(g) (C(2h), 180 degrees ) in the singly charged cationic form. For Mo- and W bis(toluene), the four rotamers are resolved into three (0, 60/120, and 180 degrees ) and two (0 and 60/120/180 degrees ) groups, respectively. For all three metal sandwiches, the most stable conformer is in the complete eclipsed configuration (0 degrees ) and has the highest ionization energy. The conversion from 60/120/180 degrees to 0 degrees rotamer is observed from helium to argon supersonic expansions and is more efficient for the heavier Mo and W species. PMID- 20961162 TI - Particle capture via discrete binding elements: systematic variations in binding energy for randomly distributed nanoscale surface features. AB - This work examines how the binding strength of surface-immobilized "stickers" (representative of receptors or, in nonbiological systems, chemical heterogeneities) influences the adhesion between surfaces that are otherwise repulsive. The study focuses on a series of surfaces designed with fixed average adhesive energy per unit area and demonstrates quantitatively how a redistribution of the adhesive functionality into progressively larger clusters (stronger stickers) increases the probability of adhesive events. The work employs an electrostatic model system: relatively uniform, negative 1 MUm silica spheres flow gently over negative silica flats. The flats contain small amounts of randomly positioned nanoscale cationic patches. The silica-silica interaction is repulsive; however, the cationic patches (present at sufficiently low levels that the overall surface charge remains substantially negative) produce local attractions. In this study, the attractions are relatively weak so that multiple patches engage to capture flowing particles. Experiments reveal an adhesion signature characteristic of a renormalized random distribution when the sticker strength is increased at an overall fixed binding strength per unit area of surface. The form of the particle capture curves are in good quantitative agreement with a simple model that assumes only a fixed adhesion energy needed for particle capture. Aside from the quantitative details that provide a simple formalism for anticipating particle adhesion, this work demonstrates how increasing the heterogeneities in the surface functionality can cause a system to go from being nonadhesive to becoming strongly adhesive. Indeed, systems containing small amounts of discretized adhesive functionality are always more adhesive than systems in which the same functionality is distributed uniformly over the surface (the mean field scenario). PMID- 20961163 TI - Birefringence control of semicrystalline block copolymers by crystallization under confinement. AB - A series of semicrystalline block copolymers (BCPs), poly(4-vinylpyridine)-block poly(epsilon-caprolactone) (P4VP-PCL), with lamellar phases have been synthesized. P4VP-PCL BCP thin films with large-scale, oriented lamellar microdomains were obtained by rimming coating process followed by oscillated shearing using a homemade shear device. Owing to the vitrified P4VP microdomains and strongly segregated microphase separation, specific PCL crystalline chain orientation can be formed from the growth of anisotropic PCL crystallites under confinement so as to uniformly increase the birefringence of the BCP thin films. The enhanced birefringence corresponds well with the increase of PCL crystallinity. Consequently, the birefringence of the P4VP-PCL thin-films can be fine-tuned by PCL crystallization. The variation on the birefringence of the BCP thin films attributed to crystallization and melting is a reversible process with respect to temperature. The BCP thin films can thus be used as temperature stimulated materials with controllable birefringence via crystallization kinetics. PMID- 20961164 TI - An algorithm for integrating contraindications into electronic prescribing decision support. AB - BACKGROUND: Contraindications to medicines define circumstances in which the medicines must not be given. Computerized prescribing systems with decision support should display alerts to warn prescribers of contraindications. However, for such systems to be effective, alerts should only be displayed when relevant. OBJECTIVE: We set out to construct an algorithm that would classify contraindications according to the data available to a computerized system, and allow them to be displayed in context as far as possible. METHOD: We drafted an initial algorithm from first principles, refined it by classifying further datasets, and then tested it on a further set of 95 phrases for contraindications. RESULTS: We were able to classify 94 of the 95 phrases; 13 related to age or sex and four related to allergies, but the majority depended on co-morbid conditions. CONCLUSIONS: We have constructed a practicable algorithm for classifying alerts to contraindications. The classification used will allow alerts to be displayed when relevant. However, most contraindications relate to co-morbid conditions, and prescribing systems will only be able to display these in context if they have access to relevant clinical data. PMID- 20961165 TI - Assessing the temperature of thermally generated inhalation aerosols. AB - BACKGROUND: Condensation aerosols are produced when a drug is vaporized and then cools in the inhalation air. Because energy is applied to vaporize the drug, there is a potential concern that the air temperature might not be well tolerated. A literature review indicates that the proper metric for this is the wet-bulb temperature (T(wb)) of the inhaled air. T(wb) measures the total energy of the air, including moisture content, and reflects the potential impact on safety and tolerability. METHODS: The Staccato(r) system (Alexza Pharmaceuticals, Mountain View, CA) uses thermal vaporization for aerosol generation and was used in a series of studies to characterize the peak transient value (peak T(wb)) of the air coming out of the device. These studies evaluated peak T(wb) over a range of air flow rates (15-45 L/min), ambient conditions [15-30 degrees C and 15 to 90% relative humidity (RH)] and vaporization temperatures. RESULTS: Under nominal conditions (30 L/min air flow, 25 degrees C and 50% RH), peak T(wb) was 28.8 +/- 0.6 degrees C (mean +/- standard deviation). Over the range of operating conditions tested, mean values for peak T(wb) ranged from 26.2 to 33.3 degrees C with similarly low variances. When operated under a combination of extreme conditions, peak T(wb) was measured to be 39.9 +/- 0.1 degrees C (mean +/- standard deviation). CONCLUSIONS: Technical standards indicate that the upper limit on inhaled T(wb) for safety and tolerability is 50 degrees C, and inhalation at that temperature can be sustained for 1 h. Peak values of T(wb) from the Staccato system are well below that threshold, approximately 30 degrees C at nominal conditions and approximately 40 degrees C at a combination of extreme conditions. Moreover, the peak lasts for only a few seconds, well under the time limit of 1 h. These results suggest that aerosols generated with the Staccato system will be safe and well tolerated. PMID- 20961166 TI - Swellable hydrogel particles for controlled release pulmonary administration using propellant-driven metered dose inhalers. AB - BACKGROUND: Swellable hydrogel microparticle-based pressurized metered dose inhaler (pMDI) formulations allow delivery of small respirable sized particles (1 5 microns), which swell upon the deposition in the deep lung and therefore can elude alveolar macrophage uptake via their larger geometric sizes. In addition, optimized surface chemistry may allow for sustained release of drug for multiple days. METHODS: Drug-loaded PLGA nanoparticles encapsulated in PEG/chitosan (Cs) graft copolymer-based hydrogel microparticles were synthesized and characterized. Physical stability of dispersions within Hydrofluoroalkane propellant systems was assessed. The formulations were evaluated for aerosolization performance using a Next Generation Impactor. RESULTS: Low density PEG/chitosan (Cs) graft copolymer based hydrogel microparticles containing drug-loaded PLGA nanoparticles has an average diameter of 1-2 MUm. These dispersions showed good compatibility with HFA227ea. Suspension stability was found to vary with the concentration of hydrogel particles. It was typically between 1 to 5 min and was found to be easily redispersible. Aerosolization studies showed fine particle fraction as high as 65% could be achieved. CONCLUSIONS: These swellable hydrogel-based microparticle pMDI formulations could be used as potential delivery vehicles for nanoparticle therapeutics. PMID- 20961167 TI - Method to introduce mannitol powder to intubated patients to improve sputum clearance. AB - BACKGROUND: Poor sputum clearance is a common problem encountered in intubated patients, which may cause airway obstruction, hypoxaemia, and increased risk of lower respiratory tract infection. This may result in longer intensive care unit (ICU) stay or even death. Dry powder mannitol has been shown to improve sputum clearance, and thus we developed a system to deliver it to intubated patients. METHODS: This delivery system consists of a standard adult manual ventilation bag, a one-way duck-billed valve, and a dry powder inhaler (OsmohalerTM) contained within a delivery chamber to allow positive pressure ventilation, which in turn, is connected in series to an endotracheal or tracheostomy tube. The aerosol is delivered by compressing the ventilation bag in a reproducible manner to generate positive pressure airflow to disperse the powder into the tracheal tube. We tested the powder output and characteristics of the powder in vitro from two endotracheal tubes (7.0 and 8.5 mm in diameter, 300 mm in length), and two tracheostomy tubes (7.0 mm in diameter and 95 mm in length; 90 mm in diameter and 115 mm in length). RESULTS AND CONCLUSIONS: Approximately 50 to 60% of the loaded dose of dry powder mannitol is delivered to the distal end of the tracheal tubes for both 4 * 40-mg and 4 * 80-mg capsules. The fine particle fraction (particles smaller than 5 MUm) ranges from 20 to 31% of the loaded dose. Powder was emptied from each 40- and 80-mg capsule within 5 +/- 1 puffs and 6 +/- 1 puffs, respectively. This delivery system has been shown to consistently deliver a very high dose of powder with a favourable fine particle fraction to the distal end of a number of tracheal tubes. This has the potential for a number of clinical therapeutic applications in critically ill patients. PMID- 20961168 TI - The relationship between venue indoor air quality and urinary cotinine levels among semiopen-air cafe employees: what factors determine the level of exposure? AB - BACKGROUND: Exposure to second-hand smoke (SHS) is increasingly recognized as an occupational hazard to workers in the service industry. In areas of the world with moderate climates, open windows and doors are assumed to provide a work environment with only marginally increased exposures to SHS. METHODS: We measured indoor fine particulate matter (PM2.5) in 50 semiopen air venues in Greece during the summer. Cotinine levels from a nonsmoking employee of each of these venues were measured from a postshift urine sample. RESULTS: In these semiopen-air venues, the mean level of indoor PM 2.5 levels were 113.5 +/- 72.3 MUg/m(3). The mean postshift urinary cotinine levels of nonworking workers in these venues was 15 ng/mL. PM2.5 levels were strongly correlated with urinary cotinine concentrations (Spearman's r = 0.914). Linear regression analyses indicated that when taking into account the time of the measurement, the day of the week, for each 1 cigarette/100 m(3) the indoor PM2.5 concentrations increased by 26.6 MUg/m(3) [95% confidence interval (CI): 7.6-45.7 MUg/m(3), p = 0.007) and urinary cotinine levels of nonsmoking workers increased by 5.0 ng/mL (95% CI: 0.4 to 9.6, p = 0.034). CONCLUSIONS: In a sample of bars and restaurants with windows and doors open, indoor PM2.5 concentrations were elevated and increased proportionately to the density of smoking. Cotinine levels of nonsmoking employees increased with indoor PM2.5 concentrations, and also with the density of smoking. Open windows and doors do not protect workers from exposure to second hand smoke. PMID- 20961170 TI - Spatial attention determines the nature of nonverbal number representation. AB - Coordinated studies of adults, infants, and nonhuman animals provide evidence for two systems of nonverbal number representation: a "parallel individuation" system that represents individual items and a "numerical magnitude" system that represents the approximate cardinal value of a group. However, there is considerable debate about the nature and functions of these systems, due largely to the fact that some studies show a dissociation between small (1-3) and large (>3) number representation, whereas others do not. Using event-related potentials, we show that it is possible to determine which system will represent the numerical value of a small number set (1-3 items) by manipulating spatial attention. Specifically, when attention can select individual objects, an early brain response (N1) scales with the cardinal value of the display, the signature of parallel individuation. In contrast, when attention cannot select individual objects or is occupied by another task, a later brain response (P2p) scales with ratio, the signature of the approximate numerical magnitude system. These results provide neural evidence that small numbers can be represented as approximate numerical magnitudes. Further, they empirically demonstrate the importance of early attentional processes to number representation by showing that the way in which attention disperses across a scene determines which numerical system will deploy in a given context. PMID- 20961169 TI - Hebrew brain vs. English brain: language modulates the way it is processed. AB - Is language processing universal? How do the specific properties of each language influence the way it is processed? In this study, we compare the neural correlates of morphological processing in Hebrew--a Semitic language with a rich and systematic morphology, to those revealed in English--an Indo-European language with a linear morphology. Using fMRI, we show that while in the bilingual brain both languages involve a common neural circuitry in processing morphological structure, this activation is significantly modulated by the different aspects of language. Whereas in Hebrew, morphological processing is independent of semantics, in English, morphological activation is clearly modulated by semantic overlap. These findings suggest that the processes involved in reading words are not universal, and therefore impose important constraints on current models of visual word recognition. PMID- 20961171 TI - The role of prosodic breaks and pitch accents in grouping words during on-line sentence processing. AB - The present study addresses the question whether accentuation and prosodic phrasing can have a similar function, namely, to group words in a sentence together. Participants listened to locally ambiguous sentences containing object- and subject-control verbs while ERPs were measured. In Experiment 1, these sentences contained a prosodic break, which can create a certain syntactic grouping of words, or no prosodic break. At the disambiguation, an N400 effect occurred when the disambiguation was in conflict with the syntactic grouping created by the break. We found a similar N400 effect without the break, indicating that the break did not strengthen an already existing preference. This pattern held for both object- and subject-control items. In Experiment 2, the same sentences contained a break and a pitch accent on the noun following the break. We argue that the pitch accent indicates a broad focus covering two words [see Gussenhoven, C. On the limits of focus projection in English. In P. Bosch & R. van der Sandt (Eds.), Focus: Linguistic, cognitive, and computational perspectives. Cambridge: University Press, 1999], thus grouping these words together. For object-control items, this was semantically possible, which led to a "good-enough" interpretation of the sentence. Therefore, both sentences were interpreted equally well and the N400 effect found in Experiment 1 was absent. In contrast, for subject-control items, a corresponding grouping of the words was impossible, both semantically and syntactically, leading to processing difficulty in the form of an N400 effect and a late positivity. In conclusion, accentuation can group words together on the level of information structure, leading to either a semantically "good-enough" interpretation or a processing problem when such a semantic interpretation is not possible. PMID- 20961172 TI - Fatigue after traumatic brain injury: Association with neuroendocrine, sleep, depression and other factors. AB - OBJECTIVE: Define associations between post-traumatic brain injury (TBI) fatigue and abnormalities in neuroendocrine axes, sleep, mood, cognition and physical functioning. DESIGN: Survey. SETTING: Large community hospital-based rehabilitation centre. PARTICIPANTS: Convenience sample of 119 individuals at least 1 year post-TBI. OUTCOME MEASURES: Multidimensional Assessment of Fatigue (MAF); Fatigue Severity Scale (FSS); neuroendocrine assessments-growth hormone (GH) reserve, thyroid, cortisol and testosterone levels; visual analogue pain rating; Pittsburgh Sleep Quality Index; Beck Depression Inventory-II; Disability Rating Scale; Craig Handicap Assessment and Reporting Technique; Neurobehavioural Functioning Inventory. RESULTS: Fifty-three per cent reported fatigue on the MAF and one-third on the FSS; 65% were found to have moderate/severe GH deficiency; 64% had adrenal insufficiency (low fasting cortisol); 12% had central hypothyroidism; and 15% of men had testosterone deficiency. Pituitary dysfunction did not correlate with fatigue or other symptoms. Predictors of MAF total scores were female gender, depression, pain and self-assessed memory deficits. Predictors of FSS scores were depression, self-assessed motor deficits and anti depressant usage. CONCLUSIONS: Robust correlates of fatigue were gender, depression, pain and memory and motor dysfunction. Investigation of post-TBI fatigue should include screening for depression, pain and sleep disturbance. There was no correlation between pituitary dysfunction and fatigue; however, the relatively high prevalence of hypothyroidism and adrenal dysfunction suggests screening for these hormone deficiencies. PMID- 20961173 TI - Acceptance rates in state-federal vocational rehabilitation of clients with brain injury: Is racial disparity an issue? AB - PRIMARY OBJECTIVE: To utilize Aday and Andersen's Framework for the Study of Access to examine racial disparity within the State-Federal vocational rehabilitation system, among clients with brain injury. Research questions included: Do pre-disposing characteristics such as age, race, ethnicity, gender, marital status and education influence vocational rehabilitation acceptance rates in the US? Do enabling characteristics such as referral source, insurance coverage and primary source of support at application influence vocational rehabilitation acceptance rates in the US? Is there a difference, based on race, in the reason for case closure for vocational rehabilitation services? METHODS AND PROCEDURES: Exhaustive CHAID analysis was conducted with acceptance for rehabilitation as the criterion variable and pre-disposing characteristics as predictor variables. Chi-square analysis was calculated with regard to reason for closure. MAIN OUTCOMES AND RESULTS: Descriptive findings are presented. Of the pre-disposing factors, the most significant predictor of acceptance rate was education level. Pearson Chi-square analyses revealed significant differences between White and non-White clients with brain injury with regard to reason for closure. CONCLUSIONS: The data indicate that racial differences were only a small part of the overall equation and again that distinct disparity by race is not evidenced in the RSA-911 data for persons with a primary or secondary diagnosis of brain injury. PMID- 20961174 TI - APOE genetic associations with seizure development after severe traumatic brain injury. AB - PRIMARY OBJECTIVE: The purpose of the current study is to assess the role of the APOE genotype in post-traumatic seizure (PTS) development. RESEARCH DESIGN: A retrospective study of 322 adult Caucasians with a severe TBI and APOE genotype. METHODS AND PROCEDURES: Medical records were searched for PTS. Time to first seizure was categorized as early, late or delayed-onset PTS. Potential PTS associations by genotype, grouped genotype and allele were investigated. MAIN OUTCOME AND RESULTS: No statistically significant associations were found. However, two out of the four individuals (50%) with the E4/E4 genotype had late/delayed-onset PTS. Furthermore, none with a E2/E2 or E2/E4 genotype seized in the late periods. CONCLUSIONS: The results of this study may suggest 4/4 as a risk genotype for late/delayed onset PTS and a potential neuroprotective role of the E2 allele. However, this study did not definitively support a role for the APOE genotype in PTS susceptibility and indicates that larger populations are needed to fully evaluate the potential impact of APOE on PTS. PMID- 20961175 TI - Analysis of homing potential of marrow-derived mononuclear cells in an experimentally-induced brain stroke mouse model. AB - PRIMARY OBJECTIVE: To analyse the efficacy of bone marrow-derived mononuclear cells (MNCs) in traversing the blood-brain barrier (BBB) in an experimental model of stroke. METHODS AND PROCEDURES: The middle cerebral artery occlusion (MCAo) mouse model was established and behavioural and histological analysis was performed, subsequently the carboxyfluorescein diacetate (CFDA)-labelled MNCs were transplanted through the tail vein immediately after 23 hours of reperfusion. The fluorescence microscopic analysis of the brain sections was analysed in both acute and sub-acute phases of transplantation. RESULTS: The neurological deficit was confirmed by TTC staining and contra lateral turning behaviour. After 2 and 7 days of transplantation, the CFDA-labelled MNCs were observed in the infarcted regions along the line of cortex. CONCLUSION: The presence of the CFDA-labelled cells in the ischaemic injured brain lesions proved homing of the implanted MNCs in the infarcted regions of the brain. The successful homing of MNCs may pave way for future clinical trials using MNC in stroke. PMID- 20961176 TI - Functional analysis and treatment of self-injurious behaviour in a young child with traumatic brain injury. AB - PRIMARY OBJECTIVE: There has been no research evaluating the utility of functional analysis (FA) in identifying effective interventions for severe problem behaviour in very young children with traumatic brain injury (TBI). It was hypothesized that FA technology would be applicable for this population and facilitate effective intervention development. RESEARCH DESIGN: A within-subject A-B-A reversal design was used to evaluate a functional communication training (FCT) intervention. This design allows for a demonstration of experimental control of the intervention over behaviour in single-case research. METHODS AND PROCEDURE: The authors conducted an FA of self-injurious behaviour (SIB) in an 18 month old boy with TBI. Results of the FA suggested that SIB was maintained, at least in part, by contingent maternal attention. An FCT intervention was used to teach a request for attention using an alternative communication device. MAIN OUTCOMES AND RESULTS: The FCT intervention reduced SIB to near zero and resulted in consistent use of an alternative communication device, functionally replacing SIB with desirable behaviour. The child's mother was coached to conduct all treatment sessions and reported satisfaction with the process. CONCLUSION: Analysis of behavioural function may play an important role in developing effective interventions for very young TBI patients with behaviour problems. PMID- 20961177 TI - "Still there is beauty": one man's resilient adaptation to stroke. AB - The study was designed to generate understanding of the phenomenon of resiliency following stroke, its role in supporting continuity of identity and ways in which occupational therapists might foster resiliency. The authors used a qualitative case study design to collect data during two face-to-face interviews. These were transcribed verbatim and analyzed using thematic analysis, narrative analysis, narrative smoothing, and content analysis using resiliency theory. The participant's narrative revealed resilient characteristics throughout his adaptive process including drawing upon positive social support, accessing spirituality, having an internal locus of control, building on past successes and a commitment to succeed, and having an action-oriented approach and positive personal goals for the future. Occupational therapists frequently interact with people following disability and have the opportunity to promote adaptation by identifying and fostering clients' resilient characteristics through narrative reconfiguration and other intervention approaches. Further research is needed to study facilitation of resiliency as a part of intervention to promote occupational engagement. PMID- 20961178 TI - Clinical patterns and outcomes of ischaemic colitis: results of the Working Group for the Study of Ischaemic Colitis in Spain (CIE study). AB - BACKGROUND: There is a lack of prospective studies evaluating the natural history of colonic ischaemia (CI). We performed such a study to evaluate the clinical presentation, outcome, and mortality as well as clinical variables associated with poor prognosis. METHODS: An open, prospective, and multicentre study was conducted in 24 Spanish hospitals serving a population of 3.5 million people. The study included only patients who met criteria for definitive or probable CI. A website (www.colitisisquemica.org) provided logistical support. RESULTS: A total of 364 patients met criteria for inclusion. CI was suspected clinically in only 24.2% of cases. The distribution of clinical patterns was as follows: reversible colopathy (26.1%), transient colitis (43.7%), gangrenous colitis (9.9%), fulminant pancolitis (2.5%), and chronic segmental colitis (17.9%). A total of 47 patients (12.9%) had an unfavorable outcome as defined by mortality and/or the need for surgery. Multivariate analysis identified the following signs as independent risk factors for an unfavorable outcome: abdominal pain without rectal bleeding [odds ratio (OR) 3.9; 95% confidence interval (CI) = 1.6-9.3], non-bloody diarrhoea (OR 10; 95% CI = 3.7-27.4), and peritoneal signs (OR 7.3; 95% CI = 2.7-19.6). Unfavorable outcomes also were more frequent in isolated right colon ischaemia (IRCI) compared with non-IRCI (40.9 vs. 10.3%, respectively; p < 0.0001). The overall mortality rate was 7.7%. CONCLUSIONS: The clinical presentation of CI is very heterogeneous, perhaps explaining why clinical suspicion of this disease is so low. The presence of IRCI, and occurrence of peritoneal signs or onset of CI as severe abdominal pain without bleeding, should alert the physician to a potentially unfavorable course. PMID- 20961179 TI - Effect of loss of regional fat assessed by DXA on insulin resistance and dyslipidaemia in obese men. AB - OBJECTIVE: To investigate the impact of reduction in total fat mass (FM) and regional FMs on indices of insulin resistance and dyslipidaemia in obese men (BMI > 30 kg/m2) after a 1-year weight loss (WL), and secondly, to examine the potential predictive effect of baseline insulin resistance on reduction in total and regional FMs. MATERIAL AND METHODS: In nine men with WL > 4 kg, body composition by DXA (dual X-ray absorptiometry) and indices of insulin resistance were assessed: fasting insulin, C-Peptide and HOMA-IR. Insulin sensitivity (QUICKI) and serum lipids were also assessed. RESULTS: Mean WL was 10.8%; Delta trunk and Delta leg FM were reduced by 30.1% and 21.3%, respectively, increasing leg/trunk FM ratio by 13.2%. Improvement in HOMA-IR was 63.1%, insulin 59.1%, and in QUICKI 17.4%. Loss of total FM, trunk FM, and increase in leg/trunk FM ratio were correlated with improvement in HOMA-IR (p < 0.001-0.05). Linear regression analysis of ln-transformed improvements in HOMA-IR was non-significantly related with losses of trunk FM and increases in leg/trunk FM ratio (p = 0.06). Multivariate analysis suggested improvements in fasting insulin and C-Peptide could be explained by leg/trunk FM ratio (R2 = 0.60, p = 0.013, R2 = 0.37, p = 0.012, respectively) and in HOMA-IR by trunk FM (R2 = 0.42, p = 0.06). The loss of FM and change in FM distribution had no effect on serum lipids. CONCLUSION: Both loss of trunk FM and increase in leg/trunk FM ratio assessed by DXA contribute to the improvement in insulin resistance. PMID- 20961180 TI - Variations in alanine aminotransferase levels within the normal range predict metabolic and androgenic phenotypes in women of reproductive age. AB - BACKGROUND AND AIMS: Obesity plays pathogenetic roles in nonalcoholic fatty liver disease (NAFLD) and hyperandrogenic states like polycystic ovary syndrome (PCOS). We tested the hypothesis that alanine aminotransferase (ALT), a marker of NAFLD, is associated with endocrine and metabolic abnormalities in women with normal ALT. METHODS AND RESULTS: Fasting glucose, insulin, total testosterone, DHEA-S, 17-hydroxyprogesterone, prolactin, leptin, soluble leptin receptor, free leptin index (FLI), lipid profile, ALT, gonadotropins, and sex hormone binding globulin (SHBG) were measured in 200 women aged 18-48 years. Beta cell function (%B), insulin sensitivity (%S) and insulin resistance were calculated using the homeostasis model assessment (HOMA-IR). Ninety-two women had PCOS (Rotterdam criteria); 64 had idiopathic hyperandrogenism; 44 were normal controls. ALT showed significant positive correlations with waist circumference (WC), systolic blood pressure, glucose, leptin, FLI, triglycerides, HOMA-IR and androgens and significant inverse correlations with leptin receptor, HDL-C, %S and SHBG. Correcting for WC and fat% showed that the associations between ALT and glucose, HOMA-IR, testosterone and free androgen index are independent of obesity. Binary logistic regression analyses showed significant association of ALT with PCOS and hyperandrogenemia. ALT >= 18 IU/L showed significant association with PCOS with Odds Ratio = 2.28 (95% Confidence Interval = 1.03-5.08), p = 0.043. CONCLUSIONS: In women of reproductive age, normal levels of ALT are associated with metabolic and androgenic phenotypes. We suggest a paradigm shift and extension of the routine use of ALT beyond the diagnosis of liver disease. PMID- 20961181 TI - Glucose metabolism parameters during an oral glucose tolerance test in patients with autosomal dominant polycystic kidney disease. AB - OBJECTIVE: The aim of the study was to estimate the pancreatic beta cell function and insulin resistance indexes in a group of Autosomal Dominant Polycystic Kidney Disease (ADPKD) patients with normal kidney function and no previous diabetes mellitus diagnosis. METHODS: A total of 49 adult patients with ADPKD aged 36 +/- 11 years, and 50 healthy controls, all of Caucasian origin, were included in the study. Blood glucose, insulin and C-peptide concentrations were measured during an oral glucose tolerance test (OGTT with 75 g glucose) performed according to WHO recommendations in all subjects. RESULTS: The insulin/glucose ratio at the 30th and 120th minute of the OGTT and the insulinogenic index [(insulin at 30 min - insulin at 0 min)/glucose at 30 min] were significantly lower (p = 0.018, p = 0.031 and p = 0.013, respectively) in the ADPKD group. Four other indexes of beta cell function were lower with the borderline statistical significance (p = 0.054 0.076) than in controls. None of the calculated insulin sensitivity indexes differed between the study and control groups. CONCLUSIONS: Presence of ADPKD in patients with normal kidney function is associated with impaired beta cell function after an oral glucose load, without a significant decrease in insulin sensitivity. PMID- 20961183 TI - Load on osseointegrated fixation of a transfemoral amputee during a fall: Determination of the time and duration of descent. AB - Mitigation of fall-related injuries for populations of transfemoral amputees fitted with a socket or an osseointegrated fixation is challenging. Wearing a protective device fitted within the prosthesis might be a possible solution, provided that issues with automated fall detection and time of deployment of the protective mechanism are solved. The first objective of this study was to give some examples of the times and durations of descent during a real forward fall of a transfemoral amputee that occurred inadvertently while attending a gait measurement session to assess the load applied on the residuum. The second objective was to present five semi-automated methods of detection of the time of descent using the load data. The load was measured directly at 200 Hz using a six channel transducer. The average time and duration of descent were 242 +/- 42 ms (145-310 ms) and 619 +/- 42 ms (550-715 ms), respectively. This study demonstrated that the transition between walking and falling was characterized by times of descent that occurred sequentially. The sensitivity and specificity of an automated algorithm might be improved by combining several methods of detection based on the deviation of the loads measured from their own trends and from a template previously established. PMID- 20961184 TI - Retention force of secondary crowns to copings after temporary cementation: the effect of crown material and luting agent. AB - Tooth-implant supported restorations can be temporarily cemented if the natural abutments are protected by permanently cemented copings. This in vitro study investigated the retention forces of pure titanium crowns to milled titanium alloy copings and of cobalt-chromium crowns to copings made of electroplated gold after cementation with different luting agents. Five specimens per group were cemented with acrylic-urethane cement (inner crown surface preisolated with petroleum jelly) and provisional zinc oxide cement. The retention was measured using a universal testing machine and a dental device for crown removal. The differences between groups were compared using analysis of variance. The pull-off forces for the cobalt-chromium secondary crowns cemented on gold copings using zinc oxide cement were significantly higher (mean=144.5 N) than the other crown cement combinations (32.2-54.4 N), which showed no significant differences in the retention force. The impulse number and magnitude of the dental device was usually low and showed no substantial differences between the crown-cement combinations. It can be concluded that the results of the clinical removal method for prostheses differ from the results of the pull-off test. The question which luting agent is the better choice for retrievable restorations remains unanswered without further clinical and laboratory studies. PMID- 20961185 TI - Determination of daptomycin in human plasma by liquid chromatography-tandem mass spectrometry. Clinical application. AB - BACKGROUND: Daptomycin is a recently developed cyclic lipopeptide antibiotic active against most Gram-positive pathogens including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. To optimize treatment efficacy and safety, especially in patients undergoing multiple drug regimens and/or co-morbidities, a specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of daptomycin in plasma. METHODS: A C18 column was used for separation, with a mobile phase initially consisting of 0.1% formic acid, water, and acetonitrile (ACN) in a linear gradient from 20% to 70%. After protein precipitation with ACN, the clear upper layer was diluted in water:ACN (50:50, v/v) before injection. Detection was performed using an electrospray ionization technique. MS/MS transitions, monitored in the positive ion mode were m/z 811.1 -> m/z 313.1 for daptomycin, and m/z 609.4 -> m/z 194.9 for reserpine, used as internal standard. RESULTS: Elution of daptomycin and reserpine occurred at 4.5 and 3.9 min, respectively. The method was validated over a range of concentrations from 1 mg/L to 120 mg/L. The assay met recommended acceptance criteria: coefficients of variation were <6.3% and <7.4%, and accuracies were between -5.9% and +11.2% and between -3.5% and +3.7%, for intra- and inter-day validations, respectively. CONCLUSIONS: This method appears well-adapted to routine hospital practice for therapeutic drug monitoring of daptomycin considering its time of analysis, range of concentrations measured, precision and accuracy. PMID- 20961186 TI - Harmonization of free thyroid hormone tests: a mission impossible? AB - The aim of in vitro testing of thyroid function is to accurately reflect the in vivo activity of key analytes, such as thyroid stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4). For these key laboratory parameters, it is highly desirable that assay results are interpretable in relation to consensus reference intervals, which should not vary depending on the choice of method used for measurement. The IFCC Working Group for Standardization of Thyroid Function Tests has recently published three reports on standardization of thyroid function tests in order to resolve the issues concerning method performance and quality specifications, as well as to meet clinical requirements. The aim of the present article is to discuss the relevant contribution of the IFCC Working Group study towards the standardization of free triiodothyronine (FT3) and free thyroxine (FT4) assays. The most important result obtained by this study is the establishment of a reliable candidate reference procedure and some commutable reference materials. These reference materials, including sera collected from blood donors, were measured by the gold standard method, and by several immunoassay methods and two equilibrium dialysis procedures in order to obtain a recalibration of test results. The recalibration on average eliminated assay specific biases with respect to reference method values. However, sample-related effects remained among the immunoassay methods tested. Although these findings are clearly important, they should only be considered a start towards harmonization of patients test results. In conclusion, further studies are necessary to answer the question of whether standardization and harmonization of the FT3 and FT4 test is an impossible mission (or not). PMID- 20961187 TI - Serum paraoxonase 1 (PON1) lactonase activity is lower in end-stage renal disease patients than in healthy control subjects and increases after hemodialysis. AB - BACKGROUND: The mechanism of paraoxonase 1 (PON1) atheroprotective remains elusive. The lactonizing/lactonase activity of PON1 is gaining favor as the most significant in physiology. METHODS: We studied 42 end-stage renal disease (ESRD) patients undergoing hemodialysis (HD) and 49 control subjects. We measured PON1 lactonase, arylesterase and triesterase activities by kinetic methods. RESULTS: Serum lactonase activity was 11% lower in ESRD patients (p<0.0001) and did not correlate with high-density lipoprotein (HDL) cholesterol when controlling for confounders. Lactonase activity was significantly higher after dialysis. Using a repeated measure-ANOVA adjusted for the confounders (age, gender, total cholesterol, triglyceride and HDL cholesterol) we show that the changes in lactonase after dialysis were significant (p<0.0001). HD increases lactonase activity to levels indistinguishable from those of control subjects. In simple linear regression analyses we showed a significant inverse correlation between changes in lactonase and those of creatinine by dialysis (r=-0.339, p=0.028). CONCLUSIONS: ESRD patients maybe more susceptible to lipid peroxidation and to protein homocysteinylation than healthy subjects due to the decreased activity of lactonase. A lower serum lactonase activity would be coupled with delayed catabolism of oxidized phospholipids in low-density lipoprotein and oxidized macrophages, and with greater protein homocysteinylation, accelerating atherogenesis. One mechanism for lower lactonase activity in ESRD patients may be inhibition by uremic toxins and oxidative stress. The pathophysiology of reduced lactonase activity in uremia and the beneficial effects of HD need further investigation. PMID- 20961188 TI - Evaluation of ovarian cancer biomarkers in subjects with benign asbestos-related pleural diseases. AB - BACKGROUND: Mesothelioma and ovarian cancer have been reported to have a similar pathogenesis, and for this reason it was hypothesized that there may be biomarkers in common and possibly associated with benign pleural diseases caused by asbestos exposure. METHODS: Serum biomarkers including insulin-like growth factor-II (IGF-II), leptin, prolactin and vascular endothelial growth factor (VEGF) were measured in an observational study of subjects with benign asbestos related pleural diseases (BARPD) (n=24) and healthy subjects with an asbestos exposure history (n=12). RESULTS: Mean serum IGF-II and VEGF concentration in healthy subjects with a history of asbestos exposure were higher than those with BARPD. Mean serum concentrations of leptin and prolactin showed opposite trends when compared to IGF-II and VEGF concentrations among these groups. CONCLUSIONS: The results suggest that IGF-II and VEGF concentrations are lower in BARPD, similar to studies of ovarian cancer. This finding warrants further investigation with malignant asbestos-related diseases. PMID- 20961189 TI - Age- and gender-dependent changes in circulating concentrations of tumor necrosis factor-alpha, soluble tumor necrosis factor receptor-1 and sulfated glycosaminoglycan in healthy people. AB - BACKGROUND: In this study, the effect of gender and physiological ageing on circulating concentrations of plasma sulfated glycosaminoglycans (sGAG) as well as molecules involved in pro- (tumor necrosis factor-alpha; TNF-alpha) and anti inflammatory responses (soluble tumor necrosis factor receptor-1, sTNF-RI) were assessed. The relationships between sGAG and molecules involved in age-dependent extracellular matrix (ECM) remodeling during physiological ageing were also investigated. METHODS: Circulating TNF-alpha and sTNF-RI were measured in 91 healthy volunteers using enzyme-linked immunosorbent assays. sGAG were quantified using an Alcian blue-binding assay. RESULTS: A linear age-related decline in plasma sGAG was found during the first five decades of life (r=-0.61, p<0.05), followed by an increase occurring only in females (r=0.46, p<0.05). Circulating TNF-alpha concentrations were inversely correlated with age (r=-0.24, p<0.05) over the lifetime. For TNF-alpha, the observed changes were gender specific. Serum sTNF-RI concentrations were not affected by age in either men or women. A significant positive correlation was found between the concentrations of TNF alpha and both sGAG (r=0.22, p<0.05) and sTNF-RI (r=0.21, p<0.05). CONCLUSIONS: Our data demonstrate that physiological ageing is associated with ECM remodeling, reflected by plasma sGAGs concentrations. Changes in the ECM metabolism during the ageing process were influenced by circulating TNF-alpha. Furthermore, serum concentrations of biomolecules involved in pro- and anti-inflammatory responses are not increased in healthy elderly subjects. PMID- 20961190 TI - Testosterone is an independent determinant of bone mineral density in men with type 2 diabetes mellitus. AB - BACKGROUND: Although many reports have elucidated pathophysiological characteristics of abnormal bone metabolism in patients with type 2 diabetes mellitus (DT2), determinants of bone mineral density (BMD) in patients with DT2 are still controversial. METHODS: We examined 168 Belarussian men 45-60 years of age. Plasma total cholesterol (TC), high-density lipoprotein cholesterol, low density lipoprotein cholesterol, very low-density lipoprotein cholesterol, triglycerides, hemoglobin A(1c) (HbA(1c)), immunoreactive insulin, and C-reactive protein concentrations were assessed. BMD was measured using dual energy X-ray densitometry of the lumbar spine (L(1)-L(4)). Total testosterone (TT) and sex hormone-binding globulin were measured, and free testosterone (FT) was calculated. RESULTS: Using univariate linear regression analysis, BMD of the lumbar spine was significantly correlated with FT (r=0.32, p<0.01) and TT (r=0.36, p<0.01). Using multiple linear regression analysis adjusted for confounding factors, BMD was significantly correlated with TT (beta=0.23, p<0.001) and TC (beta=-0.029, p=0.005). Age (beta=0.005, p=0.071), body mass index (beta=0.005, p=0.053), HbA(1c) (beta=-0.002, p=0.72) and duration of diabetes (beta=0.001, p=0.62) were not significantly correlated with BMD. CONCLUSIONS: Our data indicate that androgens are independent determinants of BMD in male patients with DT2. PMID- 20961191 TI - Development of a fluorescent microsphere immunoassay for cystatin B (CSTB) in serum of patients with hepatocellular carcinoma. AB - BACKGROUND: Serum cystatin B (CSTB) concentrations have been reported to be increased in patients with hepatocellular carcinoma compared to concentrations seen in normal subjects. In this study, we developed a "fluorescent microsphere immunoassay" (FMI) capable of specifically detecting CSTB in serum. METHODS: The FMI used a microparticle conjugated polyclonal antibody to CSTB and biotinylated monoclonal antibody as capture protein and probe protein, respectively. The results were obtained using the Bio-Plex(200) system. RESULTS: The dose-response relationship between CSTB and fluorescent intensity showed linearity in the range 0-1000 pg/mL and 7 pg/mL, sensitivity lower than 11.2 pg/mL. This result revealed that the FMI system was more sensitive than enzyme-linked immunoassay (ELISA). Additionally, the FMI system used smaller sample volumes compared to ELISA. CONCLUSIONS: We measured CSTB with both the FMI and an ELISA procedure and compared the two methods. The CSTB concentrations in serum specimens as measured with the FMI assay system were similar to those measured with ELISA. Thus, the new FMI using the Bio-Plex system may be useful for detection of CSTB in human serum. PMID- 20961192 TI - Use of serum free light chain analysis and urine protein electrophoresis for detection of monoclonal gammopathies. AB - BACKGROUND: Serum free light chain (FLC) analysis is used in the prognostic assessment and monitoring of patients with monoclonal gammopathies (MG). Its use in detection of MG is less widespread despite good sensitivity for diseases poorly detected by serum protein electrophoresis (SPE), e.g., FLC disease and AL amyloidosis. FLC analysis may facilitate earlier diagnosis in these diseases. However, if replacing urine protein electrophoresis (UPE) in an initial screening algorithm, this must be balanced against any loss of detection of Bence Jones proteinuria (BJP). METHODS: We assessed the effect of replacing UPE with FLC. Sensitivity of FLC for BJP was assessed in 126 clinical cases where UPE and FLC analyses were performed. Impact on disease detection was assessed from 753 patient sera tested by SPE and FLC and 128 patients matched associated urine samples. RESULTS: Sensitivity of FLC for BJP was 98%. Use of FLC in routine testing increased the number of MG detected by 7%. CONCLUSIONS: Using FLC alongside or in place of UPE can give clinical benefit through earlier diagnosis and hence treatment earlier in the patients' disease. PMID- 20961194 TI - Factors reducing hemolysis rates in blood samples from the emergency department. PMID- 20961193 TI - Gender-specific association of serum uric acid with metabolic syndrome and its components in juvenile obesity. AB - BACKGROUND: Hyperuricemia has been implicated in the pathogenesis of obesity and related metabolic abnormalities. Studies on the association between serum uric acid (sUA) and metabolic syndrome (MetS) in juvenile obesity are scant. The effect of gender has not been evaluated. METHODS: sUA (uricase method), anthropometric and biochemical indices were measured in gender-stratified children/adolescents consisting of 113 overweight/obese and 71 lean individuals. RESULTS: In males, sUA was significantly elevated in overweight as well as obese patients. sUA was strongly associated with obesity indices and reflected sexual development, decreases in high density lipoprotein-cholesterol, and moderately, the number of MetS components. Waist circumference (WC) and Tanner stage explained 40% of sUA variability. Controlling for body mass index (BMI) and other MetS components, sUA was associated with abdominal obesity, explaining 30% of variability in WC. In females, sUA was significantly increased in obesity, high blood pressure (BP), and MetS and corresponded with the number of MetS components, indices of glucose metabolism, triglycerides (TG), and the atherogenecity index. Insulin-resistance (IR) (homeostasis model assessment; HOMA) and high BP explained 29% of sUA variability, whereas sUA, while controlling for BMI, age, and other MetS components, was associated with hypertriglyceridemia, hyperglycemia, high BP, and abdominal obesity. IR mediated the associations with high TG and glucose. CONCLUSIONS: The association between sUA and MetS components in juvenile obesity is gender-specific, with females being related more closely and to more metabolic abnormalities. It may explain why, despite its lower concentrations, sUA is an independent predictor of mortality from all causes and from vascular diseases exclusively in females. Our findings may help in identifying metabolic abnormalities which may possibly be targeted by reducing sUA in males and females. PMID- 20961195 TI - Prevalence and course of pseudothrombocytopenia in outpatients. AB - BACKGROUND: The prevalence and course of pseudothrombocytopenia in outpatients is uncertain. METHODS: In a cohort study of 687,955 members of a health maintenance organization, we extracted 36,780 consecutive automated complete blood count test results and determined the point prevalence of pseudothrombocytopenia during a one-month period. We also calculated a retrospective cumulative prevalence over the past 5 years. RESULTS: There were 1105 (2.7%) patients with platelet counts of 100-149*10(9)/L and 304 (0.8%) with counts <100*10(9)/L, of whom 12.8% (n=39) had pseudothrombocytopenia newly discovered or in the past. There were 40 additional patients with a history of pseudothrombocytopenia, but now showing platelet counts of 150*10(9)/L or more, and another 21 with platelet counts of 100-149*10(9)/L. The total cumulative prevalence of pseudothrombocytopenia was 0.27% (100/36,780), 2.5-fold higher than the point prevalence of 0.11% (39/36,780). Platelet counts were extremely variable in these patients during the 5-year follow-up period. CONCLUSIONS: Physicians should be aware of the variability of platelet counts in patients with pseudothrombocytopenia in order to reduce unnecessary retesting. Since pseudothrombocytopenia can result in platelet counts between 100 and 149*10(9)/L, peripheral smears should be done in all patients with such values, or the reference limit value should be lowered to 100*10(9)/L. PMID- 20961196 TI - Non-invasive assessment of liver fibrosis: it is time for laboratory medicine. AB - Chronic liver diseases (CLDs) represent a major cause of morbidity and mortality worldwide. In all etiologies of CLDs, staging of liver fibrosis is essential for both prognosis and management. Until a few years ago, liver biopsy was the only tool for the diagnosis of liver fibrosis in patients with CLDs. However, liver biopsy is an invasive and costly procedure. More recently, various serum biomarkers and laboratory tests have been proposed as surrogates of liver histology. Due to inadequate diagnostic accuracy or to lack of sufficient validation, guidelines still do not recommend them as a substitute for liver biopsy that is still considered the gold standard for the diagnosis of liver fibrosis. Notably, non-invasive serum biomarkers, when combined, may reduce by 50%-80% the number of liver biopsies needed for correctly classifying hepatic fibrosis. However, liver biopsy cannot be avoided completely, but should be used in those cases in which non-invasive methods show poor accuracy. In this view, serum biomarkers and liver biopsy represent a union between laboratory medicine and hepatology. PMID- 20961197 TI - Application of proteomics to prenatal screening and diagnosis for aneuploidies. AB - Current screening for fetal aneuploidies relies on biochemical and ultrasound measurements, and the sensitivity and specificity needs to be improved to reduce the number of pregnant women subjected to invasive diagnostic procedures, such as amniocentesis. Proteomic technologies enable new strategies for discovering biomarkers from complex biological fluids in a high-throughput and sensitive manner. Since mass spectrometry-based techniques allow for both qualitative and quantitative analysis of a given proteome, they have been widely used to resolve and compare the proteome of maternal plasma, serum, urine, cervical-vaginal fluid, and amniotic fluid. Comparisons of proteomes of normal fluids with those from aneuploidy pregnancies have revealed a host of candidate markers that still need to be verified. In parallel with proteomics, there is interest in other emerging techniques, such as RNA-SNP analysis or quantitation of fetal DNA by shotgun sequencing. Although these genomic techniques hold much promise, discovery of additional markers via quantitative proteomic comparisons could drastically improve current conventional screening at reasonable cost. Proteomics based biomarker discovery is applicable to detection of not just aneuploidies, but also other pregnancy-related diseases. PMID- 20961198 TI - IFCC Scientific Division. PMID- 20961199 TI - Helicobacter pylori infection and the severity of gastritis are not associated with iron deficiency in a group of Brazilian patients. AB - BACKGROUND: Helicobacter pylori (H. pylori) infection has been associated with iron deficiency anemia. However, results reported in the literature are contradictory. The goal of the present study was to study the possible association between H. pylori infection and iron deficiency in a sample of adults. METHODS: One hundred and fifty individuals were studied (H. pylori positive n=75; H. pylori-negative n=50). The presence of anemia was determined using red cell indices and reticulocyte hemoglobin content (CHr). Iron status was assessed based on serum iron and ferritin levels. Possible involvement of inflammatory activity in erythropoiesis was investigated by measuring the correlation between C-reactive protein (CRP) and red cell indices and iron status. RESULTS: There were no significant differences in the hematological or biochemical parameters for the two groups. Iron deficiency was diagnosed in six individuals, but no difference in prevalence was found between the H. pylori positive and H. pylori-negative groups. A weak but significant inverse correlation was observed between CRP and CHr concentrations and between serum gastrin and CHr in the H. pylori-positive group. These results suggest a reduction in iron availability for reticulocyte hemoglobinization, but insufficient to cause anemia. CONCLUSIONS: H. pylori infection was not a determining factor for development of iron deficiency in our study population. PMID- 20961200 TI - Investigation of the relationship between apolipoprotein E gene polymorphisms and hepatitis B virus infection in northern China. AB - BACKGROUND: Certain genetic polymorphisms can lead to differences in immunity function, resulting in different clinical outcomes for hepatitis B virus (HBV) patients. The aim of this study was to investigate the association between apolipoprotein E (ApoE) gene polymorphisms and HBV infection status in northern Chinese individuals. METHODS: Genomic DNA was extracted using an improved sodium iodide (NaI) method from the peripheral blood of 270 patients with hepatitis B and 112 healthy controls. Multiplex Amplification Refractory Mutation System (Multi-ARMS) was performed to analyze ApoE gene polymorphisms with three alleles (E2, E3, E4) in patients and controls. A chemiluminescence assay was used to detect serological markers for hepatitis B infection status. RESULTS: An improved PCR system for the detection of ApoE gene polymorphisms was established successfully. The frequency of the E2 allele in patients with HBV infection was higher than that of normal controls (p<0.05). The E2 allele, compared with the E3 and E4 alleles, showed positive correlation with the different HBV infection models [odds ratio (OR)=1.735, 95% confidence interval (CI): 1.509-1.999, p<0.01; OR=1.768, 95% CI: 1.554-2.011, p<0.01]. The OR for the ApoE E2 allele was 1.503 in a multivariate unconditional logistic regression model (OR=1.503, 95% CI: 1.212-1.754, p<0.01). CONCLUSIONS: Our results indicated that the ApoE gene polymorphism was associated with HBV infection, and the E2 allele showed positive correlation with HBV infection in northern China. PMID- 20961201 TI - Fatty acid composition of serum phospholipids in cystic fibrosis (CF) patients with or without CF related liver disease. AB - BACKGROUND: In cystic fibrosis (CF), changes in fatty acid (FA) composition of serum phospholipids (PL) and cell membranes can account, in part, for the inflammatory state of the disease. The severity of the genotype is known to correlate with the degree of FA changes. Liver diseases, such as cholestasis and cirrhosis are also known to influence FA status. Until now, there is no data on the influence of CF related liver disease (CFRLD) on the FA status of CF patients. The aim of this study was to evaluate, whether the presence of CFRLD influences FA status. METHODS: A fasting blood sample for the determination of serum vitamin E and PL-FA composition was collected from 79 CF patients with stable pulmonary disease and under good control in our CF centre. Patients with CFRLD (n=13) were compared to CF patients with the same severity of genotype (n=66) but without CFRLD. RESULTS: The CF patients with CFRLD had lower docosahexaenoic acid (DHA, 22:6n-3) and increased docosatetraenoic acid (22:4n 6). There were no significant differences in the precursors of these FAs. CONCLUSIONS: DHA concentration in patients with CFRLD is decreased more substantially compared with their genotype controls. The presence of CFRLD should be taken into account in future FA studies in CF patients. PMID- 20961202 TI - Thyroid hormones are stable even during prolonged frozen storage. PMID- 20961204 TI - Relationship of hepatic steatosis and alanine aminotransferase with coronary calcification. AB - BACKGROUND: It has been observed that hepatic steatosis is related to an increased risk of cardiovascular disease (CVD). Alanine aminotransferase (ALT), an indicator of the severity of hepatic steatosis is also associated with CVD. This study focused on the relationship between hepatic steatosis and ALT with coronary calcification. METHODS: We performed a cross-sectional study to examine the association between hepatic steatosis and serum ALT with coronary calcification in 1218 subjects (772 men, 446 women; ages 30-75 years). We evaluated hepatic steatosis and ALT as categorical variables, and constructed four groups (reference group; only with hepatic steatosis; only with ALT >30 U/L; with both hepatic steatosis and ALT >30 U/L), which did not overlap. Multi detected row computed tomography (MDCT) was used to measure coronary calcium score. RESULTS: The adjusted ORs (95% CIs) for coronary calcification in the four groups were 1.00 (reference), 1.24 (0.68-2.26), 1.82 (0.78-4.23), and 2.12 (1.08 4.20) after adjusting for confounding variables. In addition, an increase in serum ALT activity of 10 U/L was associated with an increased risk of coronary atherosclerosis. CONCLUSIONS: In summary, patients with both hepatic steatosis and increases in ALT are associated with coronary calcification as a marker of coronary atherosclerosis determined by MDCT. This finding suggested that subjects with both hepatic steatosis and increased ALT should be considered for further evaluation of coronary atherosclerosis. PMID- 20961205 TI - Standardizing plasma protein measurements worldwide: a challenging enterprise. AB - The need for harmonizing laboratory results is particularly intense in the field of quantitative protein assays in consideration of the clinical impact of specific protein measurements and their relevance in monitoring disease. We report the efforts made by the Committee on Plasma Proteins of the IFCC Scientific Division to achieve worldwide comparability in plasma protein results. We focus on the production of reference materials and the methods applied throughout their production process. Particularly, the recent characterization of ERM-DA470k/IFCC and ERM-DA472/IFCC has demonstrated that it is possible to reproduce the earlier established procedures and thereby maintain standardization. Plasma protein reference materials have had a substantial impact in improving the harmonization of patient protein results that should translate into better patient care. PMID- 20961206 TI - Topical delivery of antifungal agents. AB - IMPORTANCE OF THE FIELD: Superficial fungal infections of skin, hair, nails and the eye are among the most widespread diseases known to man. Topical therapy is the most favored form of treatment for these infections because it lends itself to self-administration, patient compliance, and absence of systemic adverse effects. AREAS COVERED IN THIS REVIEW: The clinical efficacy of antifungal drugs depends on the concentration achieved in cutaneous/ocular tissue, which in turn depends on the molecular mass, route of administration, duration of contact and ability of the compound to penetrate the tissue. Several of these agents have a high molecular mass > 500 Da (such as amphotericin B, natamycin, or ketoconazole), resulting in their poor penetration (even if they are lipophilic in nature). The latter causes relapse infections and requires frequent administration. Packaging these agents into suitable delivery systems can improve the effectiveness of these agents. The usefulness of liposomes/niosomes, lipid emulsions, nanoparticles including solid lipid nanoparticles and microemulsions for development of these agents is discussed. WHAT THE READER WILL GAIN: This article aims to discuss limitations to the topical therapy of antifungal agents, and delivery approaches used to enhance their effectiveness. TAKE HOME MESSAGE: A physicochemical and pharmacokinetic guided approach can help to tailor-make therapeutically effective systems for existing antifungal agents, thus doing away with the need for newer agents, which will save on time, money and manpower. PMID- 20961207 TI - In vivo evaluation of novel nanoparticles containing dexamethasone for ocular drug delivery on rabbit eye. AB - PURPOSE: The purpose of this study was to investigate the in vivo effects of a new smart polymer loaded with dexamethasone on inflamed rabbit eye. MATERIALS AND METHODS: Polymeric micelles were prepared using N-isopropylacrylamide (NIPAAM), vinyl pyrrolidone (VP), and methacrylate (MAA) as monomers in the presence of N,N methylene bis-acrylamide (MBA) and triethyleneglycol dimethacrylate (TEGDMA) as cross-linking agents. These micelles were characterized on their physicochemical properties using a particle size analyzer, FT-IR, and (1)H NMR. Dexamethasone containing nanosuspensions consisting of these temperature- and pH-sensitive micellar nanoparticles were prepared. To evaluate the efficacy of the novel ocular drug delivery using these novel micellar nanoparticles, uveitis was induced by intravitreal injection of the endotoxin within the rabbit eyes. Clinical distinctions for the inflammation within eyes were performed using Hogan's classification method and statistically analyzed using independent student t-tests and Mann-Whitney U-tests. RESULTS: Cross-linked copolymer of NIPAAM-VP-MAA was prepared by free radical copolymerization of the monomers in the presence of NIPAAM and TEGDMA as cross-linking agents and ammonium per sulfate (APS) as the initiator in high yields. The PSA data represented that the particles have mean sizes between 300-450 nm. Topical administration of prepared nanosuspensions clearly reduced uveitis symptoms, which were qualified with Hogan scoring. Statistical analysis represented that both of the nano formulations significantly reduced inflammation (p < 0.05) during 48 hr after LPS injection. CONCLUSION: Nanosuspension prepared with MBA showed rapid treatment in comparison with other nano formulations. The formulation also showed higher anti inflammatory activity for a longer duration compared to aqueous suspension of the drug, which is due to small particle size and mucoadhesiveness of polymeric micelles. PMID- 20961208 TI - Inhibitors of anaplastic lymphoma kinase: a patent review. AB - IMPORTANCE OF THE FIELD: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that belongs to the insulin receptor superfamily. Aberrant ALK activity has been implicated in the oncogenesis of human cancers as a fusion protein in anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, diffuse large B-cell lymphoma, systemic histiocytosis and NSCLC or through mutations in the full length protein in hereditary familial neuroblastoma. Thus, abrogation of ALK signaling through direct kinase inhibition has become an attractive therapeutic intervention point for a subset of genetically defined human cancers. AREAS COVERED IN THIS REVIEW: This manuscript provides a comprehensive review of the patent literature pertaining to ALK inhibitors and outlines their potential as anticancer therapeutic agents. WHAT THE READER WILL GAIN: The reader will gain an understanding of the major structural classes of ALK inhibitors and insights into the future of this class of drugs. TAKE HOME MESSAGE: Multiple small-molecule ALK inhibitors have been reported with diverse chemical architecture, potency, kinase selectivity profiles and activity against potential resistance. The breadth of inhibitors combined with the recent discoveries of the involvement of ALK in lung, breast and colorectal cancers has kept the field advancing at a rapid pace. PMID- 20961209 TI - Immunohistochemical comparison of whisker pad cutaneous innervation in Swiss Webster and hairless mice. AB - To establish the mouse mutant, hairless (Hr), as a useful model for future analyses of target-ending interactions, we assessed the cutaneous innervation in the whisker pad after loss of primary hair targets. Postnatal (P) development of fur in Hr begins similarly to that of "normal" Swiss Webster (SW) mice. Around P10, hairs are shed and the follicles rendered permanently incompetent. Hair loss progresses rostrocaudally until the entire skin is denuded. Substantial alterations in the distribution and density of sensory and autonomic endings in the mystacial pad vibrissal and intervibrissal fur innervation were discovered. Pilo-neural complexes innervating fur hairs were dismantled in Hr. Epidermal innervation in SW was rich; only a few endings expressed growth-associated protein-43 kdal (GAP), suggesting limited changes in axonal elongation. Innervation in Hr formed a dense layer passing upward through the thickened epidermis, with substantial increases among all types of endings. Vibrissal follicle-sinus complexes were also hyperinnervated. Endings in Hr vibrissae and fur were strongly GAP-positive, suggesting reorganization of innervation. Dermal and vascular autonomic innervation in both strains co-localized tyrosine hydroxylase and neuropeptide Y, but only in Hr did neuropeptide Y co-localize calcitonin gene-related peptide (CGRP) and express GAP immunolabeling. Stereological quantitation of trigeminal ganglia revealed no differences in neuron number between Hr and SW, although there were small increases in cell volume in Hr trigeminal ganglion cells. These results suggested that a form of collateral sprouting was active in Hr mystacial pads, not in response to local injury, but as a result of loss of primary target tissues. PMID- 20961210 TI - Correlation between severity of sleep apnea and upper airway morphology: Cephalometry and MD-CT study during awake and sleep states. AB - CONCLUSION: The data show that the evaluation of obstruction site in patients with obstructive sleep apnea (OSA) should be performed in the sleep state rather than in wakefulness. OBJECTIVE: The aim of this study was to identify correlation between severity of OSA as measured by the apnea-hypopnea index (AHI) and upper airway morphology examined by cephalometry and dynamic multidetector computed tomography (MD-CT) in awake and sleep states. METHODS: Polysomnography and cephalometry were performed in 94 patients with snoring or OSA. Among them, 64 patients underwent MD-CT study. Thirteen cephalometric variables were measured. We analyzed the correlations between AHI and MD-CT measurements - minimal cross sectional area (mCSA) and collapsibility index (CI) in high retropalate (HRP), low retropalate (LRP), high retroglossal (HRG), and low retroglossal (LRG) areas. RESULTS: Statistically significant correlations between the AHI and inferior displacement of the hyoid bone and pharyngeal length were identified in the cephalometric study. In wakefulness, AHI had a negative correlation with mCSA in the LRP area and a significant correlation with CI in LRP and HRG in MD-CT measurements. However, in the sleep state, the AHI had a negative correlation with mCSA in LRP, HRG, and LRG areas and a meaningful correlation with CI for the whole upper airway (HRP, LRP, HRG, and LRG). PMID- 20961211 TI - Sensitivity and specificity of cytodiagnosis of body fluids in a laboratory of urgencies. AB - The main purpose for studying cytological body fluids is confirmation of a benign or malignant effusion. Our cytology laboratory analyzes body fluids and results are requested urgently. The samples are stained by the Giemsa and Papanicolaou methods to give a preliminary report, then they are examined by other complementary techniques. Three hundred thirty samples of pleural and peritoneal fluids were studied to compare the sensitivity of Papanicolaou and Giemsa stains. AgNOR assay, immunocytochemistry and assessment of ploidy were used to improve the sensitivity of the cytodiagnosis. Two hundred one samples were positive, 84 negative and 45 inconclusive using the Papanicolaou stain, while 135 samples were positive, 72 negative and 123 inconclusive using Giemsa stain. The sensitivity was 79%, 53% and 83% for Papanicolaou, Giemsa, and both techniques together, respectively. Using complementary techniques, the sensitivity reached 95% for AgNOR, 87% for tumor markers (panel), and 92% for Ploidy. There were no false positive in our series; therefore specificity was 100%. The use of both Papanicolaou and Giemsa in conjunction increased the sensitivity of the cytodiagnosis in body fluids. The complementary methods, especially AgNOR assay and assessment of ploidy, diminished the number of inconclusive cases. PMID- 20961213 TI - The effects of sleep deprivation on oculomotor responses. AB - PURPOSE: Fatigue due to sleep deprivation is one of the main causes of accidents. An objective and efficient method for determining whether the person is tired could provide a valuable tool in accident prevention. In this study, we evaluated whether oculomotor responses related to pupillary light reflex and saccadic velocity can identify subjects with sleep deprivation and whether these objective values correlate with subjective feeling of sleepiness. METHODS: Thirteen normal subjects (5 male, 8 female) participated in a 4-day study. During the first two days following a full night's (8 hr in bed) sleep, they underwent baseline automated oculomotor testing using the FIT-2500-Fatigue-Analyzer. Following a third full night's sleep, participants were then sleep-deprived for 28 hr. Ten measurements of automated oculomotor tests were performed during the sleep deprivation period. Visually-guided saccadic velocity (SV), initial pupil diameter (PD), pupillary constriction latency (CL), and amplitude of pupil constriction (CA) were assessed using the FIT-2500-Fatigue-Analyzer. The FIT index, which expresses the deviation of the ocular parameters from the baseline measurements, was calculated. Correlation of oculomotor parameters with the subjective Stanford Sleepiness Scale (SSS) was performed. RESULTS: We found that oculomotor measures showed a significant increase in CL (298.6 to 308.4 msec, P < 0.05) and calculated FIT index (3.4 to 16.8, P < 0.05) and a significant decrease in SV (64.8 to 59.6 deg/sec) during sleep deprivation. The SSS was found to significantly increase over the sleep deprivation period (2.05 to 5.05, P < 0.05) and was significantly correlated with the FIT-index (r > 0.66, P < 0.02). CONCLUSION: Evaluation of oculomotor responses, particularly CL and SV together with the FIT-index, might have practical applications for the assessment of an individual's state of alertness or fatigue. Correlation of the FIT-index to the SSS provides evidence for the potential usefulness of oculomotor function measurements in the detection of subjective sleepiness. PMID- 20961212 TI - Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes. AB - Cerebral metabolite disturbances occur among human immunodeficiency virus (HIV) infected people, and are thought to reflect neuropathology, including proinflammatory processes, and neuronal loss. HIV-associated cortical atrophy continues to occur, though its basis is not well understood, and the relationship of cerebral metabolic disturbance to structural brain abnormalities in HIV has not been well delineated. We hypothesized that metabolite disturbances would be associated with reduced cortical and subcortical volumes. Cerebral volumes were measured in 67 HIV-infected people, including 10 people with mild dementia (acquired immunodeficiency syndrome [AIDS] dimentia complex [ADC] stage >1) via automated magnetic resonance imaging (MRI) segmentation. Magnetic resonance spectroscopy (MRS) was used to measure levels of cerebral metabolites N acetylaspartate (NAA), myo-inositol (MI), choline-containing compounds (Cho), glutamate/glutamine (Glx), and creatine (Cr) from three brain regions (frontal gray matter, frontal white matter, basal ganglia). Analyses were conducted to examine the associations between MRS and cerebral volumetric measures using both absolute and relative metabolite concentrations. NAA in the mid-frontal gray matter was most consistently associated with cortical (global, frontal, and parietal), ventricular, and caudate volumes based on analysis of absolute metabolite levels, whereas temporal lobe volume was associated with basal ganglia NAA and Glx, and Cho concentrations in the frontal cortex and basal ganglia. Hippocampal volume was associated with frontal white matter NAA, whereas thalamic volume was associated with both frontal white matter NAA and basal ganglia Glx. Analyses of relative metabolite concentrations (referenced to Cr) yielded weaker effects, although more metabolites were retained as significant predictors in the models than the analysis of absolute concentrations. These findings demonstrate that reduced cortical and subcortical volumes, which have been previously found to be linked to HIV status and history, are also strongly associated with the degree of cerebral metabolite disturbance observed via MRS. Reduced cortical and hippocampal volumes were most strongly associated with decreased NAA, though reduced Glx also tended to be associated with reduced cortical and subcortical volumes (caudate and thalamus) as well, suggesting both neuronal and glial disturbances. Interestingly, metabolite-volumetric relationships were not limited to the cortical region from which MRS was measured, possibly reflecting shared pathophysiological processes. The relationships between Cho and volumetric measures suggest a complicated relationship possibly related to the effects of inflammatory processes on brain volume. The findings demonstrate the relationship between MRI-derived measures of cerebral metabolite disturbances and structural brain integrity, which has implication in understanding HIV-associated neuropathological mechanisms. PMID- 20961214 TI - The induction of an angiogenic response in corneal myofibroblasts by platelet activating factor (PAF). AB - PURPOSE: Although the exact mechanisms underlying corneal neovascularization remain unclear, cytokines and growth factors play an important role in their development. We have shown previously that the inflammatory mediator platelet activating factor (PAF) is a potent inducer of corneal neovascularization in vivo. In this study, we investigate the role of stromal myofibroblasts in neovascularization and the effect of PAF on this process. METHODS: Myofibroblasts were obtained from rabbit corneal keratocytes and identified with anti-alpha-SMA antibody. Cells were treated with PAF (100 nM) for 24 hr. In some experiments, cells were pre-treated with the PAF antagonist LAU-0901 (150 nM). Expression of vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1) was examined by immunofluorescence and immunoblotting. To study the effect of myofibroblasts on vessel formation in vitro, Vybrant((r)) CM-DiI labeled human umbilical vein endothelial cells (HUVECs) were cultured on myofibroblasts in a thin layer of collagen gel. CD31 was used as the cell marker of HUVEC. RESULTS: VEGF and TSP-1 were not detectable in keratocytes, but they were positively stained in myofibroblasts. PAF induced a significant increase in VEGF expression and a decrease in TSP-1 expression. These changes were inhibited in the presence of LAU-0901. HUVECs co-cultured with corneal myofibroblasts formed a typical structure of vessel-like tubes within 1 week. The addition of PAF to the medium increased HUVEC-induced vessel-like tube formation, which was abolished by LAU 0901. Addition of anti-VEGF antibody to the medium completely prevented the formation of vessel-like tubes. CONCLUSION: We provide evidence for the role of stromal myofibroblasts in the corneal neovascularization process. By enhancing VEGF production and decreasing TSP-1 production in myofibroblasts, PAF augments the angiogenic response. The PAF antagonist LAU-0901 could represent a new therapeutic venue for inhibiting corneal neovascularization. PMID- 20961215 TI - Lack of association between the Thr431Asn and Arg83Lys polymorphisms of the ROCK2 gene and diabetic retinopathy. AB - PURPOSE: To analyze the genotype distributions and allele frequencies for ROCK2 Thr431Asn and Arg83Lys polymorphisms among the diabetic retinopathy patients in a Turkish population. METHODS: In this case-control study, 335 patients with diabetes mellitus were recruited and divided into three groups according to non proliferative (n = 127), proliferative (n = 85) diabetic retinopathy, and no retinopathy (n = 123, served as a diabetic control group). Genomic DNA from the patients, and the nondiabetic healthy control cases (n = 132) was analyzed by real-time PCR using a Light-Cycler. RESULTS: Neither genotype distributions nor the allele frequencies for the Thr431Asn or Arg83Lys polymorphisms showed a significant difference between the groups. The haplotypes were also not significantly associated with diabetic retinopathy. CONCLUSION: These results suggest that there were no evidence for an association of ROCK2 gene Thr431Asn and Arg83Lys polymorphisms with diabetes or diabetic retinopathy in the Turkish population. PMID- 20961216 TI - Comparative in vivo confocal microscopical study of the cornea anatomy of different laboratory animals. AB - PURPOSE: The aim of the present study was to analyze and compare in vivo morphology of healthy cornea of six different laboratory animals. MATERIALS AND METHODS: One Pomeranian Coarsewool sheep, 5 Beagle dogs, 1 Norwegian and 2 Domestic Short-haired cats, 20 New Zealand White rabbits, 6 Wistar rats, and 10 Balb/c mice were included. The examination was performed bilaterally, using Heidelberg Retina Tomograph equipped with Rostock Cornea Module. The morphology of living corneal layers was visualized and compared between species. The central corneal thickness, density of keratocytes, and endothelial cells were quantified. RESULTS: The epithelial multilayer showed a similarity in morphology between animal types, displaying three clearly distinguishable layers: superficial, intermediate, and basal. Subbasal nerve fibers were displayed as hyperreflective structures underneath basal cells. The subbasal fibers were confirmed in all species, however, the density varied between species. A pronounced Bowman's membrane was visualized in sheep. In all other species, however, a thin acellular layer with overlying nerve fibers could be seen between basal epithelial cells and anterior stroma. The keratocytes nuclei could be demonstrated in all species except for mice, where no nuclei but only reflective structures resembling keratocytes cell bodies were detected. Overall, the density of keratocytes nuclei was significantly higher in the anterior than in the posterior stroma. Besides endothelial cells density, the endothelial cells morphology was very similar among all species, except for sheep. The endothelial cells were displayed as polygonal structures with bright cytoplasm and dark borders. In sheep, the appearance of the endothelium was very poor because of a thick hyperreflective Descemet's membrane. CONCLUSIONS: The present study will help researchers consider appropriate models for animal experiments, depending on focus of investigation. In vivo CLSM can be used for the characterization of the living cornea over time, thus, reducing the number of animal experiments. PMID- 20961217 TI - Investigation of kinetics of methotrexate for therapeutic treatment of intraocular lymphoma. AB - PURPOSE: Primary intraocular lymphoma (PIOL) provides a therapeutic challenge because of its diverse clinical picture and variable clinical course. The main objective of this study was to evaluate the retinal permeability of methotrexate for rabbit and human eyes and then investigate its kinetics in a human eye following the standard induction-consolidation-maintenance (I-C-M) injection protocols for the treatment of PIOL. Additionally, the therapeutic release rate of a 90-day sustained-release methotrexate implant was also determined for the effective treatment of PIOL. METHODOLOGY: The 3-dimensional model of a rabbit eye was adapted from our previous studies and a human eye model was constructed based on its physiological dimensions. The retinal permeability of methotrexate was the only unknown parameter in the numerical calculations and was determined by comparing the model simulated vitreous concentrations for rabbit and human eyes with the available in vivo and clinical data, respectively. RESULTS: The retinal permeability values of methotrexate calculated for an albino rabbit and human eye were 1.1 * 10(-5) cm/s and 9.25 * 10(-6) cm/s, respectively. Given that the dosage above 0.1 uM is considered tumoricidal, the cytotoxic levels of methotrexate were consistently achieved only in the induction phase and the concentration levels dropped below the cytotoxic levels for part of the consolidation and maintenance phases of the treatment following the I-C-M protocols. A sustained-release implant with a mean release rate of 0.2 MUg/day-2 MUg/day should be designed in order to maintain tumoricidal levels of methotrexate inside the vitreous of the human eye for a period of 3 months. CONCLUSIONS: By making use of the results of this study, one could select a dosing interval for serial injections of methotrexate or establish a treatment schedule using a controlled release methotrexate implant for the treatment of PIOL. PMID- 20961218 TI - The effect of adjuvant dimethylenastron, a mitotic Kinesin Eg5 inhibitor, in experimental glaucoma filtration surgery. AB - BACKGROUND: The aim of the study was to analyze the effect of Dimethylenaston, a mitotic kinesin 5 (Eg5) inhibitor, in an experimental setting of glaucoma filtration surgery. METHODS: On 37 chinchilla rabbits (ChBBCH), glaucoma filtration surgery similar to clinical practice, was performed. The animals received either no adjuvant, one unilateral subconjunctival injection of Dimethylenastron (1.0 umol, 3.0 umol), or the vehicle alone at baseline and in two further groups additionally at days 3 and 7 thereafter (1.0 umol, 3.0 umol). The evaluation of antifibrotic efficacy was performed by clinical response, histological examination, and immunohistochemical staining for smooth muscle actin (SMA) and CD 31. The animals were sacrificed on day 14, and the eyes processed for histology. RESULTS: The vehicle was well tolerated. Except for two cases of transient fibrinous reaction after the injection of 3.0 umol Dimethylenastron, no adverse effects, such as inflammation or blurring of the optical media, were observed. A bleb scarring occurred in the group that received surgery only, adjuvant DMSO, or Dimethylenastron 3.0 umol. Dimethylenastron (1.0 umol) induced a milder scarring compared with the control group but the length of bleb survival was not significantly prolonged (p = 0.053, Kaplan-Meier log rank test). In all groups, the intraocular pressure correlated with the fibrotic process and reached normal levels within 14 days after surgery. Those groups injected with 1.0 umol Dimethylenastron revealed a significantly reduced ratio of intraocular pressure and a milder, but not sufficiently reduced, subconjunctival fibrotic reaction according to the histological and immunohistochemical analysis. CONCLUSIONS: The subconjunctival administration of Dimethylenastron 1.0 umol induced a milder conjunctival scarring. The applied concentrations of Dimethylenastron did not improve the surgical outcome of glaucoma filtration treatments in rabbits sufficiently. PMID- 20961219 TI - Elbow kinematics during overground manual wheelchair propulsion in individuals with tetraplegia. AB - PURPOSE: The purpose of this study was to describe horizontal and vertical translation of the elbow and elbow angle in two planes and three speeds during manual wheelchair overground propulsion in individuals with tetraplegia. METHODS: Seven individuals with tetraplegia who used manual wheelchairs wheeled overground at three different speeds were recruited for the study. Video motion capture methods quantified their movements. Video data were tracked and used to calculate variables describing three-dimensional elbow translation and angular orientation. Repeated measures ANOVA were used to determine effects of speed on elbow translation and elbow angle. Paired t-tests were used to evaluate left to right differences. RESULTS: Right elbow anterior-posterior translation was found to be significantly different during slow and fast and slow and normal speeds. Vertical and medial-lateral translation of the right elbow was significantly different between slow and fast speeds. No significant effects for speed during left elbow movement or side-to-side movement were found. No significant effects were found for elbow angle across speeds or from side-to-side. Three patterns of elbow movement emerged for anterior-posterior and medial-lateral translation and for elbow angle. CONCLUSIONS: Results indicated that elbow translation was related to propulsion speed. Work involving this population is needed for further understanding of upper extremity kinematic patterns. PMID- 20961220 TI - The wired generation: academic and social outcomes of electronic media use among university students. AB - Little is known about the influence of electronic media use on the academic and social lives of university students. Using time-diary and survey data, we explore the use of various types of electronic media among first-year students. Time diary results suggest that the majority of students use electronic media to multitask. Robust regression results indicate a negative relationship between the use of various types of electronic media and first-semester grades. In addition, we find a positive association between social-networking-site use, cellular-phone communication, and face-to-face social interaction. PMID- 20961222 TI - Correlations between sequential timing decisions do not necessarily indicate strategic behavior: a comment on Bety et al. AB - Using correlation analysis, Bety, Gauthier, and Giroux confirmed that individuals of the migrating snow geese (Chen caerulescens atlantica) arriving earlier on their breeding grounds experienced longer prelaying periods but laid earlier than late-arriving birds. They concluded that these birds strategically adjusted timing to optimize fitness. This test is, however, not sufficient to indicate strategic behavior. We show analytically that, without assuming strategic behavior, arrival date, prelaying period, and laying date are correlated with each other because of their sequential occurrence. We conclude that correlation tests on sequentially occurring variables are not sufficient to detect nonrandom relations. PMID- 20961223 TI - Fishing indirectly structures macroalgal assemblages by altering herbivore behavior. AB - Fishing has clear direct effects on harvested species, but its cascading, indirect effects are less well understood. Fishing disproportionately removes larger, predatory fishes from marine food webs. Most studies of the consequent indirect effects focus on density-mediated interactions where predator removal alternately drives increases and decreases in abundances of successively lower trophic-level species. While prey may increase in number with fewer predators, they may also alter their behavior. When such behavioral responses impact the food resources of prey species, behaviorally mediated trophic cascades can dramatically shape landscapes. It remains unclear whether this pathway of change is typically triggered by ocean fishing. By coupling a simple foraging model with empirical observations from coral reefs, we provide a mechanistic basis for understanding and predicting how predator harvest can alter the landscape of risk for herbivores and consequently drive dramatic changes in primary producer distributions. These results broaden trophic cascade predictions for fisheries to include behavioral changes. They also provide a framework for detecting the presence and magnitude of behaviorally mediated cascades. This knowledge will help to reconcile the disparity between expected and observed patterns of fishing induced cascades in the sea. PMID- 20961224 TI - Physiological responses of free-swimming adult coho salmon to simulated predator and fisheries encounters. AB - The responses of free-swimming adult coho salmon (Oncorhynchus kisutch) to simulated predator and fisheries encounters were assessed by monitoring heart rate (f(H)) with implanted data loggers and periodically taking caudal blood samples. A 10- or 30-min corralling treatment was conducted to simulate conspecifics being cornered by a predator or corralled by fisheries gear without physical contact. Corralling rapidly doubled f(H) from ~31 beats min(-1) to a maximum of ~60 beats min(-1), regardless of the duration of the corralling. However, recovery of f(H) to precorralling levels was significantly faster after the 10-min corralling (7.6 h) than after the 30-min corralling (11.5 h). An exhaustive-exercise treatment (chasing for 3 min, with physical contact) to simulate a predator chasing a fish to exhaustion or a fish becoming exhausted after encountering fisheries gear resulted in increased f(H) (to 60 beats min( 1)), plasma lactate, glucose, sodium, osmolality, and cortisol (males only) and a significant decrease in mean corpuscular hemoglobin concentration. Recovery of f(H) and most blood variables was complete about 16 h after exhaustive exercise and handling. The results illustrate a clear relationship between the intensity of exercise and the duration required for recovery of f(H). Changes in f(H) were significantly correlated with those in plasma lactate, chloride, and sodium at 1 h after the exercise treatment protocols. Thus, measurements of f(H) may provide an accurate indication of the general physiological response of salmonids to exhaustive exercise in the natural environment. PMID- 20961225 TI - Listeria monocytogenes induces T cell receptor unresponsiveness through pore forming toxin listeriolysin O. AB - BACKGROUND: The success of many pathogens relies on their ability to circumvent the innate and adaptive immune defenses. How bacterial pathogens subvert adaptive immune defenses is not clear. Cholesterol-dependent cytolysins (CDCs) represent an expansive family of homologous pore-forming toxins that are produced by more than 20 gram-positive bacterial species. Listeriolysin O (LLO), a prototype CDC, is the main virulence factor of Listeria monocytogenes. METHODS: We employed flow cytometric and microarray techniques to analyze the effect of LLO on T cell activation in vitro and in vivo. RESULTS: In vivo and in vitro proliferation of CD4(+) T cells upon T cell receptor (TCR) activation was highly diminished in the presence of LLO or wild-type L. monocytogenes but not in the presence of LLO deficient L. monocytogenes. This block in T cell proliferation was specific to T cell activation via the TCR and not by phorbol 12-myristate 13-acetate-ionomycin, which bypasses the proximal TCR signaling event. The results of microarray analysis suggest that LLO-induced T cell unresponsiveness is due to the induction of a calcium-nuclear factor of activated T cells-dependent transcriptional program that drives the expression of negative regulators of TCR signaling. CONCLUSION: These findings provide important insights into how bacterial toxins silence adaptive immune responses and thus enable prolonged survival of the pathogen in the host. PMID- 20961226 TI - Photodynamic therapy mediated by methylene blue dye in wound healing. AB - OBJECTIVE: We sought to investigate the wound-healing process after photodynamic therapy (PDT) mediated by methylene blue dye (MB). BACKGROUND DATA: Few scientific studies show the PDT roles in wound healing. MATERIALS AND METHODS: One hundred rats were given a circular wound on the back, inflicted with a 6-mm diameter punch. The animals were divided into four groups: control (no treatment); dye (topical application of MB); laser (InGaAlP, 117.85 J/cm(2), 100 mW, 660 nm, single point); and PDT (topical application of MB followed by laser irradiation). After 1, 3, 5, 7, and 14 days, the cutaneous wounds were photographed and assessed with histopathologic examination by using light microscope. Changes seen in edema, necrosis, inflammation, granulation tissue, re epithelialization, and number of young fibroblasts were semiquantitatively evaluated. The wound-area changes were measured with special software and submitted to statistical analysis. RESULTS: The laser group demonstrated the smallest wound area at 14 days after the surgical procedure (p < 0.01). Concerning complete re-epithelialization, the laser group showed it at 5-7 days after surgery, whereas the PDT and the other groups showed it at 14 days. CONCLUSIONS: Laser interaction with tissue is somehow changed when exposed to the MB. PDT mediated by MB was not prejudicial to wound healing, as no delay occurred compared with the control group. PMID- 20961227 TI - Comparative study of the effects of gallium-aluminum-arsenide laser photobiomodulation and healing oil on skin wounds in wistar rats: a histomorphometric study. AB - OBJECTIVE: The present study compared the effects of gallium-aluminum-arsenide diode laser and healing oil on fibroblasts, blood vessels, and collagen maturation of skin wounds in Wistar rats. MATERIALS AND METHODS: Twenty-four male rats weighing 325 +/- 27 g were used. Five wounds, 12 mm in diameter, were made on the animals' backs. The rats were randomly divided into four groups with six animals in each group. CONTROL GROUP: saline solution; L30 group: 30 J/cm(2) laser; L60 group: 60 J/cm(2) laser; Oil group: healing oil. Histomorphometric analysis was performed on the scar tissue removed from the different wounds every 4 d for 20 d. RESULTS: On day 4, there were significantly more fibroblasts in the wounds treated with the laser and the healing oil compared to the controls. On day 8, there were significantly more fibroblasts in the oil group compared to the L30 and L60 groups. On the same day, the quantity of vessels was significantly greater in the L60 group compared to the other groups. On day 16, there was a significant increase in the number of blood vessels in the wounds treated with the 60 J/cm(2) laser compared to the other groups. Analysis of the collagen maturation index throughout the experiment showed significantly higher values in the L60 group compared to the other groups at all time points. CONCLUSION: The healing oil exerted a greater effect on fibroblast proliferation, whereas the 60 J/cm(2) laser was more effective in stimulating angiogenesis and scar-tissue maturation. PMID- 20961228 TI - Polarized light (lambda400-2000 nm) on third-degree burns in diabetic rats: immunohistochemical study. AB - AIM: The aim of this study was to evaluate with light microscopy the healing process of third-degree burns on diabetic rats treated with polarized light (lambda400-2000 nm, 20 or 40 J/cm(2)/session, 40 mW/cm(2), 2.4 J/cm(2)/min, 5.5 cm beam diameter). BACKGROUND: Uncontrolled diabetes mellitus causes severe disruption of the body's metabolism, including healing. Polarized light sources have been shown to be effective in improving healing in many situations. ANIMALS AND METHODS: Diabetes mellitus was induced with streptozotocin (60 mg/kg) in 45 male Wistar albino rats, and a third-degree burn (1.5 by 1.5 cm) was created on the dorsum of each animal under general anesthesia. The animals were randomly distributed into three groups: control, 20 J/cm(2), and 40 J/cm(2). Each group was then divided into three subgroups based on time of death (7, 14, 21 d). Phototherapy (20 or 40 J/cm(2) per session) was carried out immediately after the burning and repeated daily until the day before death. Following animal death, specimens were removed, embedded in paraffin, sectioned, and stained with hematoxylin and eosin (HE) or Sirius Red or immunomarked with CK AE1/AE3 antibody. Qualitative and semiquantitative analyses were performed under light microscopy. The results were statistically analyzed. RESULTS: The animals treated with 20 J/cm(2) showed significant differences with regard to revascularization and re-epithelialization. Although the 40 J/cm(2) group showed stimulation of fibroblastic proliferation as an isolated feature, no other difference from the control was observed. CONCLUSION: Our results suggest that the use of polarized light at 20 J/cm(2) effectively improves the healing of third-degree burns on diabetic animals at both early and late stages of repair. PMID- 20961229 TI - A combination of 670 nm and 810 nm diode lasers for wound healing acceleration in diabetic rats. AB - OBJECTIVES: To study the effects of the combination of 670 nm and 810 nm diode lasers on diabetic wound healing parameters in rats. BACKGROUND: An alternative to traditional treatment modalities for diabetic ulcers is low-level laser therapy (LLLT). A number of published studies demonstrate the beneficial effects of LLLT, although several other studies also exist which indicate results to the contrary. METHODS: Four groups were present in our study: Diabetic-laser (n = 5), Diabetic-control (n = 4), Nondiabetic-laser (n = 5) and Nondiabetic-control (n = 5) groups. Two intervention (laser) groups underwent low level laser therapy using 670 nm diode laser (500 mW, 10 J, 48 s) in the wound context, and 810 nm diode laser (250 mW, 12 J, 50 s) to the wound margins. The wound area was measured using computer software after digital microscopic photography on days 0, 3, 6, 9, 12, 15, 20, and 24. RESULTS: There were no statistically significant differences between the diabetic and non-diabetic groups in the wound area, percentage of open wound area, and wound healing rate throughout the repeated measurements of the study. After seven days of low level laser therapy in the non diabetic group, urine excretion was significantly increased in comparison with the control group. CONCLUSION: Overall, our study showed results of measured wound healing parameters that were not significantly different in the LLLT group compared with the control group. The urine volume increase in non-diabetic rats after LLLT was an incidental observation that warrants future study. PMID- 20961230 TI - Evaluation of pain levels after Nd: YAG laser and scalpel incisions: an experimental study in rats. AB - BACKGROUND: Postoperative pain is a recognized sequel of periodontal surgery. The pain experience has been shown to peak in the first 24 hours following the procedure, and to decrease rapidly in subsequent days. The aim of the present study was to evaluate the pain levels following scalpel- and laser-incision of rat hind paws. METHODS: The study was carried out on 10 albino Wistar male rats. Rats were randomly assigned to two groups: Group I (n = 5, laser surgery), or Group II (n = 5, conventional surgery with scalpel). For measuring mechanical hyperalgesia, the nociceptive threshold of the hind paw after mechanical stimulation was quantified using a Basile algesimeter. The measurements were done before the surgery and on the postoperative 1(st), 2(nd), 3(rd), and 7(th) days. RESULTS: While the pain levels of the groups were similar before the surgical procedures, the laser-applied rats had significantly fewer nociceptive thresholds of the hind paw after mechanical stimulation compared with the scalpel-incised rats on the postoperative 1(st), 2(nd), 3(rd), and 7(th) days. Functional complications were not observed in the laser groups at three days after the surgery. CONCLUSION: The results suggested that, for soft tissue surgery, Nd: YAG lasers have often led to shorter operative times, less pain, and fewer postoperative adverse events. PMID- 20961231 TI - Effect of low-power gallium-aluminum-arsenium noncoherent light (640 nm) on muscle activity: a clinical study. AB - BACKGROUND DATA: Studies have shown the significant effects of electromagnetic irradiation in the visible region, with laser as an irradiation source. However, the effect of LEDs (light-emitting diodes) irradiation in similar wavelengths is not known. OBJECTIVE: The purpose of this clinical study was to verify the effects of the LED (640 nm with 40 nm full bandwidth at half maximum) on muscle activity. METHODS: The study was done with 30 test subjects, of both genders, aged 23 +/- 3 years, with a mean weight of 60 kg, divided into three groups (n = 10). Fatigue was induced through the maximum power of a bite, for 60 s in two overlaid occlusal platforms, coupled to a load cell and to a biologic signal acquisition device. LED irradiation of the right masseter muscle was applied to all subjects. The left muscle received placebo treatment. Irradiation was applied in eight points on the right masseter muscle (transcutaneous), 1.044 J per point, 2.088 J per point, or 3.132 J per point, 0.116 W, 0.522 cm(2) spot size, 0.816 cm spot O, continuous wave, perpendicular to the skin. RESULTS: An increase in muscle activity was observed after irradiation with 1.044 J per point (p < 0.05). A significant increase (p < 0.01) in the time before fatigue was observed in the irradiated muscle with 2.088 J per point, without a change in the force of contraction (p > 0.05). This change was not observed with 1.044 J per point and 3.132 J per point. The results suggest a dose-dependent relation with this kind of noncoherent irradiation in the red region of the electromagnetic spectrum in the muscle-fatigue process. CONCLUSION: It was concluded that LED can be used as a clinical tool to increase muscle activity (1.044 J per point) and to prevent fatigue (2.088 J per point), without change in the muscle force. PMID- 20961232 TI - Long-term safety of single and multiple infrared transcranial laser treatments in Sprague-Dawley rats. AB - BACKGROUND AND OBJECTIVE: Growing interest exists in the use of near-infrared laser therapies for the treatment of numerous neurologic conditions, including acute ischemic stroke, traumatic brain injury, Parkinson's disease, and Alzheimer's disease. In consideration of these trends, the objective of this study was to evaluate the long-term safety of transcranial laser therapy with continuous-wave (CW) near-infrared laser light (wavelength, 808 +/- 10 nm, 2-mm diameter) with a nominal radiant power of 70 mW; power density, 2,230 mW/cm(2), and energy density, 268 J/cm(2) at the scalp (10 mW/cm(2) and 1.2 J/cm(2) at the cerebral cortical surface) in healthy Sprague-Dawley rats. MATERIALS AND METHODS: In this study, 120 anesthetized rats received sequential transcranial laser treatments to the right and left parietal areas of the head on the same day (minimum of 5 min between irradiation of each side), on either Day 1 or on each of Days 1, 3, and 5. Sixty anesthetized rats served as sham controls. Rats were evaluated 1 year after treatment for abnormalities in clinical hematology and brain and pituitary gland histopathology. RESULTS: No toxicologically important differences were found in the clinical hematology results between sham-control and laser-treated rats for any hematologic parameters examined. All values fell within historic control reference ranges for aged Sprague-Dawley rats. Similarly, brain and pituitary gland histopathology showed no treatment-related abnormalities or induced neoplasia. CONCLUSIONS: Single and multiple applications of transcranial laser therapy with 808-nm CW laser light at a nominal power density of 10 mW/cm(2) at the surface of the cerebral cortex appears to be safe in Sprague-Dawley rats 1 year after treatment. PMID- 20961233 TI - Tetrahydrocurcuminoid cream plus targeted narrowband UVB phototherapy for vitiligo: a preliminary randomized controlled study. AB - OBJECTIVE: The aim of this study was to compare the efficacy of targeted narrowband UVB phototherapy plus topical tetrahydrocurcuminoid with that of targeted narrowband UVB monotherapy for induction of repigmentation in vitiligo. BACKGROUND DATA: The 308-nm excimer laser and targeted narrowband UVB phototherapy have recently been shown to be effective in repigmenting vitiligo. Studies have suggested that the combination of the 308-nm excimer laser and various topical treatments is more effective than UV monotherapy in the treatment of vitiligo. MATERIALS AND METHODS: Ten subjects with focal or generalized vitiligo were enrolled in this study. Two similar lesions were treated with either targeted narrowband UVB plus topical tetrahydrocurcuminoid cream or targeted UVB alone. The UV treatments were carried out twice a week for 12 weeks. The degree of repigmentation, documented by monthly digital photography, was assessed by a blinded dermatologist. RESULTS: On completion of the study, statistically significant repigmentation, compared with baseline, occurred in both treatment groups. The overall degree of repigmentation was slightly better in the combination group at 8 and 12 weeks (p = 0.078 and 0.158 respectively). Adverse effects were minor and well tolerated. CONCLUSION: Targeted narrowband UVB phototherapy plus topical tetrahydrocurcuminoid cream was slightly more effective than targeted narrowband UVB monotherapy for vitiligo located in UV sensitive areas. However, the differences in degrees of repigmentation did not reach statistically significant levels. PMID- 20961234 TI - Methylaminolevulinic acid-based photodynamic therapy: the patient's view. AB - Topical photodynamic therapy (PDT) with methylaminolevulinate (MAL) for nonmelanomatous skin cancers (NMSC) has proven efficient and safe. Because pain and a phototoxic reaction (PTR) are frequent side effects, the ability to predict discomfort may improve the management of patient care. During a 3-month period, we enrolled 46 patients with a total of 120 precancerous actinic skin lesions or NMSCs. Patients were treated with MAL-PDT, and follow-up continued for 8 wk. PDT had no lasting side effects in 65% of the lesions, and nearly 90% healed. The most frequent adverse cosmetic effect was skin discoloration (26.7%). Scarring was observed more often on the nose (21%, 3 of 14 lesions). Women experienced erythema more often than men (24% vs. 6%). With approximately 80% of the lesions, the patient reported light or no PTR. The average patient-reported pain during irradiation was moderate (4.92 on a scale of 0 to 10). Pain was persistent in 45% of the cases, but it decreased rapidly thereafter (on average 1 d). Risk factors for a greater severity of pain were lesions on the scalp (average pain score: 6.62) and on the forehead (average: 7.00) and treatment over an extended area (average: 7.32). Treatment on the nose (average: 3.29) or on the thorax (average: 3.00) was less painful. The final level of satisfaction reported was good or very good by 90% of the patients. Based on our results, eligible patients can be individually identified and informed in advance about the likelihood of side effects, thereby improving their satisfaction. PMID- 20961235 TI - Clearance of a thick invasive squamous cell carcinoma after multiple treatments with topical photodynamic therapy. AB - OBJECTIVE: Tumor depth is the limiting factor for topical photodynamic therapy (PDT) treating cutaneous invasive squamous cell carcinoma (SCC). The thickness of < 2-3 mm below the epidermis is the currently recommended effective response depth in nonmelanoma skin cancers. We report an unusual outgrowing SCC with a tumor depth of 5.5 mm, which was successfully treated with PDT. METHODS: Topical 20% (wt/wt) 5-aminolaevulinic acid emulsion was applied for 6 h before irradiation with 633-nm red light. The lesion was irradiated 7 times, 1 week apart, at a total dose of 791 J/cm(2). RESULTS: Twelve months later, histologic and clinical examination showed a complete remission and no local or systemic metastases. No serious side effects occurred, and the cosmetic outcome was excellent. CONCLUSION: PDT may offer a noninvasive, well-tolerated, and effective therapy for inoperable low-risk SCC with an outgrowing pattern. It suggests that tumor depth is not an absolute predictor, but only a suggested reference. PMID- 20961236 TI - Photomedicine and LLLT literature watch. PMID- 20961239 TI - Why health care is going home. PMID- 20961240 TI - Images in clinical medicine. Hemichorea-hemiballism after diabetic ketoacidosis. PMID- 20961241 TI - Public release of clinical outcomes data-online CABG report cards. PMID- 20961245 TI - Expression of follicle-stimulating hormone receptor in tumor blood vessels. AB - BACKGROUND: In adult humans, the follicle-stimulating hormone (FSH) receptor is expressed only in the granulosa cells of the ovary and the Sertoli cells of the testis. It is minimally expressed by the endothelial cells of gonadal blood vessels. METHODS: We used immunohistochemical and immunoblotting techniques involving four separate FSH-receptor-specific monoclonal antibodies that recognize different FSH receptor epitopes and in situ hybridization to detect FSH receptor in tissue samples from patients with a wide range of tumors. Immunoelectron microscopy was used to detect FSH receptor in mouse tumors. RESULTS: In all 1336 patients examined, FSH receptor was expressed by endothelial cells in tumors of all grades, including early T1 tumors. The tumors were located in the prostate, breast, colon, pancreas, urinary bladder, kidney, lung, liver, stomach, testis, and ovary. In specimens obtained during surgery performed to remove tumors, the FSH receptor was not expressed in the normal tissues located more than 10 mm from the tumors. The tumor lymphatic vessels did not express FSH receptor. The endothelial cells that expressed FSH receptor were located at the periphery of the tumors in a layer that was approximately 10 mm thick; this layer extended both into and outside of the tumor. Immunoelectron microscopy in mice with xenograft tumors, after perfusion with anti-FSH-receptor antibodies coupled to colloidal gold, showed that the FSH receptor is exposed on the luminal endothelial surface and can bind and internalize circulating ligands. CONCLUSIONS: FSH receptor is selectively expressed on the surface of the blood vessels of a wide range of tumors. (Funded by INSERM.). PMID- 20961246 TI - Mutant CHUK and severe fetal encasement malformation. AB - We report an autosomal recessive lethal syndrome characterized by multiple fetal malformations, the most obvious anomalies being the defective face and seemingly absent limbs, which are bound to the trunk and encased under the skin. We identified the molecular defect that causes this syndrome, using a combined strategy of gene-expression arrays, candidate-gene analysis, clinical studies, and genealogic investigations. A point mutation in two affected fetuses led to the loss of the conserved helix-loop-helix ubiquitous kinase (CHUK), also known as IkappaB kinase alpha. CHUK has an essential role in the development of skin epidermis and its derivatives, along with various other morphogenetic events. (Funded by the Academy of Finland and others.). PMID- 20961243 TI - Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. AB - BACKGROUND: Many patients with severe aortic stenosis and coexisting conditions are not candidates for surgical replacement of the aortic valve. Recently, transcatheter aortic-valve implantation (TAVI) has been suggested as a less invasive treatment for high-risk patients with aortic stenosis. METHODS: We randomly assigned patients with severe aortic stenosis, whom surgeons considered not to be suitable candidates for surgery, to standard therapy (including balloon aortic valvuloplasty) or transfemoral transcatheter implantation of a balloon expandable bovine pericardial valve. The primary end point was the rate of death from any cause. RESULTS: A total of 358 patients with aortic stenosis who were not considered to be suitable candidates for surgery underwent randomization at 21 centers (17 in the United States). At 1 year, the rate of death from any cause (Kaplan-Meier analysis) was 30.7% with TAVI, as compared with 50.7% with standard therapy (hazard ratio with TAVI, 0.55; 95% confidence interval [CI], 0.40 to 0.74; P<0.001). The rate of the composite end point of death from any cause or repeat hospitalization was 42.5% with TAVI as compared with 71.6% with standard therapy (hazard ratio, 0.46; 95% CI, 0.35 to 0.59; P<0.001). Among survivors at 1 year, the rate of cardiac symptoms (New York Heart Association class III or IV) was lower among patients who had undergone TAVI than among those who had received standard therapy (25.2% vs. 58.0%, P<0.001). At 30 days, TAVI, as compared with standard therapy, was associated with a higher incidence of major strokes (5.0% vs. 1.1%, P=0.06) and major vascular complications (16.2% vs. 1.1%, P<0.001). In the year after TAVI, there was no deterioration in the functioning of the bioprosthetic valve, as assessed by evidence of stenosis or regurgitation on an echocardiogram. CONCLUSIONS: In patients with severe aortic stenosis who were not suitable candidates for surgery, TAVI, as compared with standard therapy, significantly reduced the rates of death from any cause, the composite end point of death from any cause or repeat hospitalization, and cardiac symptoms, despite the higher incidence of major strokes and major vascular events. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.). PMID- 20961247 TI - Franklin H. Epstein Lecture. Cardiac development and implications for heart disease. PMID- 20961248 TI - Ranibizumab therapy for neovascular age-related macular degeneration. PMID- 20961249 TI - Images in clinical medicine. Agitation associated with acute bladder obstruction. PMID- 20961244 TI - Effect of home testing of international normalized ratio on clinical events. AB - BACKGROUND: Warfarin anticoagulation reduces thromboembolic complications in patients with atrial fibrillation or mechanical heart valves, but effective management is complex, and the international normalized ratio (INR) is often outside the target range. As compared with venous plasma testing, point-of-care INR measuring devices allow greater testing frequency and patient involvement and may improve clinical outcomes. METHODS: We randomly assigned 2922 patients who were taking warfarin because of mechanical heart valves or atrial fibrillation and who were competent in the use of point-of-care INR devices to either weekly self-testing at home or monthly high-quality testing in a clinic. The primary end point was the time to a first major event (stroke, major bleeding episode, or death). RESULTS: The patients were followed for 2.0 to 4.75 years, for a total of 8730 patient-years of follow-up. The time to the first primary event was not significantly longer in the self-testing group than in the clinic-testing group (hazard ratio, 0.88; 95% confidence interval, 0.75 to 1.04; P=0.14). The two groups had similar rates of clinical outcomes except that the self-testing group reported more minor bleeding episodes. Over the entire follow-up period, the self testing group had a small but significant improvement in the percentage of time during which the INR was within the target range (absolute difference between groups, 3.8 percentage points; P<0.001). At 2 years of follow-up, the self testing group also had a small but significant improvement in patient satisfaction with anticoagulation therapy (P=0.002) and quality of life (P<0.001). CONCLUSIONS: As compared with monthly high-quality clinic testing, weekly self-testing did not delay the time to a first stroke, major bleeding episode, or death to the extent suggested by prior studies. These results do not support the superiority of self-testing over clinic testing in reducing the risk of stroke, major bleeding episode, and death among patients taking warfarin therapy. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT00032591.). PMID- 20961250 TI - Case records of the Massachusetts General Hospital. Case 32-2010. A pregnant woman with abdominal pain and fluid in the peritoneal cavity. PMID- 20961251 TI - Transcatheter aortic valves-where do we go from here? PMID- 20961252 TI - Treatment possibilities for retinitis pigmentosa. PMID- 20961253 TI - Second-generation BCR-ABL kinase inhibitors in CML. PMID- 20961254 TI - CISH and susceptibility to infectious diseases. PMID- 20961255 TI - Geographic differences in Medicare spending. PMID- 20961256 TI - New recommendations on duty hours from the ACGME. PMID- 20961257 TI - Case 21-2010: anoxic brain injury and a request for oocyte retrieval. PMID- 20961258 TI - Aprepitant for erlotinib-induced pruritus. PMID- 20961259 TI - Transfusion for protocol eligibility. PMID- 20961263 TI - Mucoadhesive liposomal delivery systems: the choice of coating material. AB - OBJECTIVE: Development of liposomal mucoadhesive drug delivery system, which is able to improve the bioavailability of poorly absorbed oral drugs by prolonging their gastric and intestinal residence time, through facilitating the intimate contact of the delivery system with the absorption membrane. MATERIALS AND METHODS: Liposomes containing model drug atenolol were prepared by the modified ethanol injection method. Liposomes containing atenolol were coated by different mucoadhesive polymers, for example, chitosan, Carbopol 974P, Eudragit L100, and Eudragit S100, to optimize the choice of coating material. The delivery systems were tested for their in vitro mucoadhesiveness. RESULTS: Liposomes prepared by the ethanol injection method were of satisfactory size (around 100 nm, before coating). Through the coating of liposomes in the presence of unentrapped material, the entrapment efficiency for drug was increased. In vitro mucoadhesive test confirmed the mucoadhesive properties of the coated layer for all tested polymers; however, Eudragit S100-coated liposomes were superior to other coating materials. DISCUSSION: Eudragit coating appeared to be an optimal polymer choice. These preliminary data indicate that polymer-coated mucoadhesive liposomes are able to carry sufficient amount of drug and to remain attached to the intestinal mucosa for a sufficient period of time to enable prolonged absorption of entrapped drug. CONCLUSION: While keeping in mind that the in vivo conditions may vary with the in vitro ones, we may recommend the system described in our work for possible oral delivery of peptides and phytochemicals. PMID- 20961264 TI - Experiences of participation in occupations of women on long-term sick leave. AB - The majority of individuals on long-term sick leave experience negative effects in their lives associated with limitations on their participation, decreased income, and feelings of guilt. The aim was to describe the experiences that women on long-term sick leave have of participation in occupation. Unstructured interviews were used for the data collection, which involved eight women; a grounded theory approach was used. The results showed that the women's long-term sick leave changed their roles, daily habits, and routines, and their participation in occupations was negatively influenced. Their occupational performance also diminished, thereby having a negative influence on their social relationships. However, over time they came to find different strategies that contributed to a feeling of occupational competence and thence they started to rebuild their occupational identity. Through this began the process of occupational adaptation, which resulted in an increased experience of participating in occupation. As a conclusion, it should be noted that occupational therapy interventions should be directed at women on long-term sick leave at an early stage in the rehabilitation process to address the adaptation of their roles, habits, routines, and social environment. PMID- 20961265 TI - Measuring perceived meaningfulness in day centres for persons with mental illness. AB - RATIONALE: As support in leading a meaningful and active life, a person with mental illness is often given the opportunity to attend a day centre. However, few studies have investigated the meaningfulness perceived by the person visiting a day centre. For such a purpose, a self-report instrument was developed. AIMS: To explore whether perceived meaningfulness, as expressed in the recently developed instrument Evaluation of Perceived Meaning in Day Centers (EPM-DC), could be viewed as one dimension and also to investigate the psychometric properties of this instrument. METHODS: Persons with mental illness attending five day centres in Sweden participated and completed the questionnaire. The data were analysed by Rasch analysis. MAJOR FINDINGS: The study showed that the concept captured in the instrument could be viewed as unidimensional and the result gave preliminary evidence for sound psychometric properties. PRINCIPAL CONCLUSION: The results indicate promising signs of validity and reliability, but the suitability of self-reporting may be questioned. PMID- 20961266 TI - Relation between expression of alpha(1)-adrenoceptor mRNAs in bladder mucosa and urodynamic findings in men with lower urinary tract symptoms. AB - OBJECTIVE: To investigate the possible relationship between the bladder mucosal expression of alpha(1)-adrenoceptor (AR) mRNAs, storage symptoms and urodynamic findings in patients with lower urinary symptoms (LUTS) and benign prostatic obstruction (BPO). MATERIAL AND METHODS: Mucosa was obtained from the posterior bladder wall from 20 patients with a diagnosis of LUTS and BPO undergoing prostatectomy. alpha(1)-AR subtype mRNA was quantified using competitive real time reverse transcription-polymerase chain reaction. A preoperative video urodynamic study measured volumes for first desire to void (FDV) and strong desire to void (SDV). Patients were divided into group 1, with volumes for FDV <= 200 ml or SDV <= 300 ml, and group 2, with volumes FDV >= 201 ml and SDV >= 301 ml. Preoperative and postoperative international prostate symptom score (IPSS) and Overactive Bladder Symptom Score (OABSS) were evaluated. RESULTS: The group 1 FDV (141.0 +/- 13.5 ml) was significantly lower than that of group 2 (299.0 +/- 48.1 ml). Similarly, the SDV for group 1 (247.0 +/- 21.9 ml) was also significantly lower than for group 2 (444.0 +/- 32.5 ml). There were no significant differences between groups 1 and 2 with respect to mucosal alpha(1a)- and alpha(1b)-AR mRNA levels. However, group 1 patients had significantly more alpha(1d)-mRNA than those in group 2. No relationship between the expression of alpha(1)-AR mRNAs and preoperative or postoperative OABSS or IPSS was detected. CONCLUSION: There was a relationship between the expression of alpha(1d)-AR mRNA in the bladder mucosa and storage-phase urodynamics in LUTS/BPO patients, suggesting a role of alpha(1D)-ARs in bladder sensation. PMID- 20961267 TI - PCA3 as a diagnostic marker for prostate cancer: a validation study on a Swedish patient population. AB - OBJECTIVE: Prostate cancer antigen 3 in urine (uPCA3) has been shown to perform better than total prostate-specific antigen in serum (tPSA) to predict prostate cancer (PCa) detection. The aim of this study was to validate the diagnostic precision of uPCA3 in a mixed set of patients with no previous history of PCa, including patients with previous negative biopsies. MATERIAL AND METHODS: The study included 62 men scheduled for prostate biopsy at Skane University Hospital Malmo, Sweden. Urine samples were obtained according to the ProgensaTM uPCA3 assay. Logistic regression and receiver operating characteristic curves were used to test associations between levels of biomarkers and prostate cancer. RESULTS: According to pathological examination of core needle biopsies, PCa was found in 18 out of 62 patients. A one-step increase in uPCA3 was associated with an increase in the odds of cancer of 1.026 (p = 0.005). Differences in the odds ratio between uPCA3 and tPSA were not statistically significant. A model using both markers did not increase prediction of event. Areas under the curve for uPCA3, tPSA and a model combining uPCA3 and tPSA did not differ significantly. No significant correlation was found between uPCA3 and tPSA or prostate volume. CONCLUSION: In this small set of mixed patients uPCA3 alone and tPSA performed equally well as diagnostic markers for PCa. A combination of the two markers did not improve the diagnostic performance. This study does not support a role for the uPCA3 urine test to replace or be added to tPSA in PCa detection. PMID- 20961268 TI - Sacral neuromodulation in urological indications: the Finnish experience. AB - OBJECTIVE: Sacral neuromodulation is a treatment modality for voiding dysfunction that is resistant to conventional medical and surgical treatments. In Finland, sacral neuromodulation has been used for the treatment of urgency-frequency syndrome, non-obstructive urinary retention and painful bladder/interstitial cystitis since 1996. MATERIAL AND METHODS: The investigation retrospectively evaluated 180 tested patients, 74 of whom underwent permanent implantation of the InterStim device. RESULTS: A positive test result leading to implantation was significantly more frequent among females than males. Among urinary retention patients, the patients with a positive test leading to implantation were significantly younger than those without implantation. The implantation operation time was significantly shorter when using a tined lead device compared with open electrode insertion (76 vs 122 min). The mean follow-up time was 41 months (range 0-143). Significant improvement after implantation was noted in the mean urinated volumes and number of daily urinations, as well as in the number of catheterizations in urgency-frequency syndrome and urinary retention, respectively. The subjective long-term outcome was similar in these indications. Surgical revision was required for 15 patients (20.3% of implanted patients). CONCLUSIONS: The difference in gender distribution compared with earlier published series may be explained by a selection bias due to the limited referrals of female patients from gynaecologists. The results favour the use of a tined lead device because of the shorter operating room time. Furthermore, the outcome seems to be more favourable among patients with a staged implant procedure compared with a one-stage operation with a tined lead device. PMID- 20961269 TI - Raloxifene: is it really effective on mood changes in postmenopausal osteopenic women? AB - OBJECTIVE: To investigate the effect of raloxifene therapy on menopausal symptoms, depression and anxiety scores using Kupperman's Scale, Hamilton Depression Rating Scale (HDRS) and Beck Anxiety Rating Scale (BARS) in osteopenic postmenopausal women. METHODS: This was a prospective, randomised, parallel and open labeled clinical study. One-hundred thirty-two postmenopausal osteopenic women with natural menopause enrolled into the study. One-hundred twenty-four of them completed the study. Group I patients were treated with oral raloxifene (60 mg/day), Group II patients were treated with oral calcium supplementation (1000 mg/day) for 3 months. The patient's menopausal, depressive and anxiety symptoms were assessed by using Kupperman's Scale, HDRS and BARS, before and at the end of treatment. For statistical analysis unpaired t, ANOVA, RM-ANOVA, MANCOVA, Pearson correlation tests were used. Statistical significance level was established at p < 0.05. RESULTS: Baseline Kupperman's Scale, HDRS and BARS scores were not different among two groups. At the end of 3 months of therapy, there was improvement in menopausal symptoms, depression and anxiety scores within both groups. When we compared change of scores before and after the treatment; group I scores were better than group II scores. CONCLUSION: Our results suggest that raloxifene may have a positive effect on mood in osteopenic postmenopausal women. PMID- 20961270 TI - Daily exposure to inhomogeneous static magnetic field significantly reduces blood glucose level in diabetic mice. AB - PURPOSE: The present study was designed to reveal, whether the 30 min daily full body exposure of mice to an inhomogeneous static magnetic field (SMF) has a statistically significant effect on diabetic neuropathy. MATERIALS AND METHODS: Three different doses (100, 150, or 200 mg/kg) of streptozotocin (STZ) were administered intraperitoneally in groups of mice to induce diabetes. Body weight, blood glucose level and the nociceptive temperature threshold of mice were monitored for a period of 12 weeks. The group treated with 200 mg/kg i.p. STZ produced manifest diabetic neuropathy. Results were compared to non-treated (no SMF, no STZ) and SMF exposure without STZ-treatment group (SMF, no STZ) group. The inhomogeneous SMF was in the range of 2.8-476.7 mT peak-to-peak magnetic flux density. RESULTS: Whereas SMF exposure did not seem to affect body weight and nociceptive temperature threshold, it statistically significantly (p < 0.001) reduced blood glucose level in the 200 mg/kg STZ (n = 6) group. CONCLUSIONS: Daily SMF exposure repeated for several weeks is protective against the development of high blood glucose level in diabetic mice. PMID- 20961271 TI - Effect of the canalith repositioning procedure on subjective visual horizontal in patients with posterior canal benign paroxysmal positional vertigo. AB - CONCLUSION: Substantial numbers of patients with posterior canal benign paroxysmal positional vertigo (p-BPPV) have signs of utricular dysfunction at baseline. This improves after performing the canalith repositioning procedure. OBJECTIVE: To evaluate the changes of subjective visual horizontal (SVH) in patients with p-BPPV before and after treatment with the canalith repositioning procedure. METHODS: Twenty-six patients with p-BPPV were treated with the canalith repositioning procedure, Epley's maneuver, according to the affected side. Baseline SVH measurements were taken before performing the Dix-Hallpike maneuver and Epley's maneuver, for comparison with measurements taken just after Epley's maneuver, and 2 weeks after Epley's maneuver. RESULTS: Among 26 patients with p-BPPV, 11 (42%) showed abnormal deviation of SVH at baseline. Just after performing Epley's maneuver, the number of patients who showed an abnormal deviation of SVH decreased significantly to 15% (4 of 26 patients; p < 0.05). Two weeks after performing Epley's maneuver, only two patients (8%) showed an abnormal deviation of SVH (p < 0.001). PMID- 20961272 TI - Red cell distribution width as a novel predictor of mortality in ICU patients. AB - BACJGROUND: the red cell distribution width (RDW) in ICU patients has never been investigated. METHODS: a total of 602 consecutive patients were prospectively enrolled. We collected each patient's base-line characteristics including the Acute Physiology and Chronic Health Evaluation II (APACHE-II) score, RDW, and C reactive protein (CRP). The primary outcome for this analysis was ICU mortality, and secondary outcome was the total length of stay in hospital (TLSH). Potential predictors were analyzed for possible association with outcomes. RESULTS: there was a significantly graded increase in APACHE-II score (tertile I = 10.7 +/- 6.5 versus tertile II = 13.3 +/- 6.2 versus tertile III = 15.8 +/- 7.2; all P < 0.001) and ICU mortality rate (tertile I = 11.2% versus tertile II = 18.8% versus tertile III = 33.8%; all P < 0.001) across increasing of RDW tertile. As compared with APACHE-II score, combination of RDW and APACHE-II score increased the area under the curve (AUC) for predicting ICU mortality from 0.832 +/- 0.020 to 0.885 +/- 0.017 (P < 0.05). Multivariate analysis demonstrated that RDW, APACHE-II score, and CRP were independent predictors of ICU mortality (P < 0.05). RDW was also independently associated with TLSH in patients alive (P < 0.05). CONCLUSION: we found a graded independent relation between higher RDW and adverse outcomes in ICU patients. RDW has the potentially clinical utility to predict outcome in ICU patients. PMID- 20961273 TI - Mini-Mental State Examination score and B-type natriuretic peptide as predictors of cardiovascular and total mortality in an elderly general population. AB - INTRODUCTION. The aim of the present study was to examine the power of B-type natriuretic peptide (BNP) and mild cognitive impairment as independent predictors of total and cardiovascular mortality in combination with established cardiovascular risk markers in an elderly general population without severe cognitive impairment. METHODS. A total of 499 individuals, aged more than 75 years, were examined and followed up for a median of 7.9 years in a prospective population-based stratified cohort study carried out in eastern Finland. The Cox proportional hazards regression model was used to determine the impact of multiple factors on total and cardiovascular mortality. RESULTS. In a multivariable model including established cardiovascular risk factors and conditions, both continuous BNP (adjusted hazard ratio (HR) 1.44 for a 1-SD change; 95% confidence interval (CI) 1.22-1.77; P < 0.001) and continuous MMSE score (HR 0.81 for a 1-SD change; 95% CI 0.70-0.94; P = 0.007) were independently associated with all-cause mortality. In a multivariable model, BNP remained a significant predictor of cardiovascular mortality, while MMSE score lost its significance. CONCLUSIONS. BNP, a measure of cardiovascular burden, and MMSE score 18-23, an indicator of mild cognitive impairment, are both independent predictors of total mortality. BNP and MMSE score may potentially be useful in screening elderly patients for elevated risk of mortality. PMID- 20961274 TI - B-type natriuretic peptides: looking to the future. AB - Whereas the role of the cardiac natriuretic peptides, ANP and BNP, in some aspects of physiology and pathophysiology is clear, their potential in diagnosis, prognosis, and therapeutics in many clinical disorders remains uncertain. We predict that circulating levels of these peptides will find increasing diagnostic utility in patients presenting with dyspnoea, in guiding the complex pharmacotherapy in heart failure, and may likewise be useful in guiding the management of patients on chronic maintenance renal dialysis. We predict also that levels of these peptides will be of practical use as prognostic indicators in 'at-risk' populations (such as those with diabetes, coronary heart disease, hypertension, thalassaemia, etc.) but probably not in the general population. It appears likely that administration of these peptides will find a place in the therapeutics of acute myocardial infarction, but this is less clear for heart failure. We describe the presence of a segment of the signal peptide for BNP within the circulation and discuss its potential clinical utility. PMID- 20961275 TI - RecDraw: a software package for the representation of HIV-1 recombinant structures. AB - The crucial role of recombination in HIV-1 biology is being increasingly recognized. In vitro studies have shown that up to 30 strand-transfer events may occur per viral replication cycle. Thus, recombination may surpass mutation as a major mechanism driving HIV-1 evolution. Currently, recombinant strains comprise 37% of the full-genome HIV-1 sequence database, including sequences representing 47 Circulating Recombinant Forms (CRFs) and more than 250 different Unique Recombinant Forms (URFs). Mapping of recombination breakpoints helps establish relationships among strains that are related by descent, such as CRF07_BC and CRF08_BC in China, and sheds light on their origin and epidemic spread. Additionally, unrelated recombinants sharing common breakpoints may reflect recombination hotspots within the viral genome. Here we present a software tool, RecDraw, for the graphical representation and efficient comparison of recombinant HIV-1 structures and breakpoints. RecDraw is a platform-flexible, Java stand alone application available through http://www.hivresearch.org/research.php?ServiceID = 5&SubServiceID = 6 . PMID- 20961276 TI - Darunavir outcomes study: comparative effectiveness of virologic suppression, regimen durability, and discontinuation reasons for three-class experienced patients at 48 weeks. AB - Several new antiretroviral (ARV) agents for treatment experienced HIV-infected patients have been approved since June 2006, including darunavir (DRV) and raltegravir (RAL). While efficacious in clinical trials, the effectiveness, durability, and tolerability of these new ARVs remains understudied in the context of routine clinical care. The Darunavir Outcomes Study is a prospective cohort study of three-class ARV-experienced patients changing regimens at the 1917 Clinic after 1/7/2006. All treatment decisions were at the discretion of primary providers. Multivariate (MV) logistic regression for 48 week VL < 400c/ml and Cox models for regimen durability were completed. Propensity score methods controlled for sociodemographics. Among 108 patients, mean age of 46, 48% were white, 80% male, with prior exposure to a mean 10.5 ARVs. Overall, 64% of patients achieved 48-week VL < 400 c/ml. In MV modeling DRV/rll (OR = 5.77;95%CI = 1.62-20.58) and RAL (OR = 3.84;95%CI = 1.23-11.95) use increased odds of 48 week suppression. Use of these agents exhibited a trend towards prolonged regimen durability in Cox models. Among those highly ARV-experienced, regimens containing DRV/r and/or RAL were more likely to achieve 48-week VL < 400 c/ml and exhibited a trend towards prolonged durability. New agents have transformed the treatment landscape for ARV-experienced patients, with effectiveness in routine clinical care mirroring efficacy in clinical trials. PMID- 20961277 TI - Pulmonary vascular lesions are common in SIV- and SHIV-env-infected macaques. AB - The lack of animal models of HIV-related pulmonary arterial hypertension (HIV PAH) severely limits investigation of this serious disease. While histological evidence of HIV-PAH has been demonstrated in macaques infected with simian immunodeficiency virus (SIV) as well as with chimeric simian/human immunodeficiency virus (SHIV) containing HIV-1-derived Nef protein, other primate models have not been studied. The objective was to document and describe the development of pulmonary vascular changes in macaques infected with SIV or with SIV containing HIV-1-derived envelope protein (SHIV-env). Lung tissue was obtained at necropsy from 13 SHIV (89.6P)-env-infected macaques and 10 SIV (DeltaB670)-infected macaques. Pulmonary arterial pathology, including arterial hyperplasia and the presence of plexiform lesions, was compared to normal monkey lung. Pulmonary artery hyperplasia was present in 8 of 13 (62%) SHIV-env-infected macaques and 4/10 (36%) SIV-infected macaques. The most common histopathological lesions were intimal and medial hyperplasia of medium and large pulmonary arteries. Hyperplastic lesions were predominantly due to smooth muscle cell hyperplasia. This is the first report of pulmonary vascular lesions in SHIV-env infected macaques and confirms prior reports of pulmonary vasculopathy in SIV infected macaques. The finding of pulmonary arteriopathy in monkeys infected with SHIV not containing HIV-nef suggests that other factors might also be important in the development of HIV-PAH. This SHIV-env model provides a new means to investigate HIV-PAH. PMID- 20961278 TI - HIV-1 integrase sequence variability in antiretroviral naive patients and in triple-class experienced patients subsequently treated with raltegravir. AB - Viruses were sequenced from 75 antiretroviral therapy (ARV)-naive and from 75 ARV treated patients who subsequently received a raltegravir-containing regimen. No major integrase inhibitor (INI)-resistance mutations were present in the 150 integrase (IN) sequences. Four ARV-naive (5.3%) and two ARV-treated patients (2.7%) had one of the following minor INI-resistance mutations: L74M, E157Q, G163R, and R263K but there was no association between baseline raltegravir genotype and subsequent response to raltegravir treatment. We also combined our sequences with 4170 previously published group M IN sequences from INI-naive patients to assess IN sequence variability and compared our findings with those of a study we performed in 2008 using data from 1563 patients. The number of polymorphic IN positions increased from 40% to 41% between the two studies. However, none of the major INI-resistance mutations was found to be polymorphic in either study and there were no significant changes in the prevalence of any of the minor INI-resistance mutations. PMID- 20961280 TI - [Prevalence of chronic otitis media in the young male population in Turkey]. AB - OBJECTIVES: In this study, we investigate the prevalence of chronic otitis media (COM) in young men. PATIENTS AND METHODS: Twenty thousand consecutive young men (mean age 22 years) who were under election for high performance military positions were examined by two otolaryngologists in the Military Hospital, Izmir. The otologic examination findings were noted. We evaluated the patients who have tympanic membrane perforation, retraction, adhesion, myringosclerosis and the patients who had underwent surgery before. RESULTS: Three-hundred and fifty-five young men (1.77%) had COM. Other findings were retraction (n=66; 0.33%), adhesion (n=36; 0.18%), myringosclerosis (n=720; 3.6%) and cerumen (n=3200; 16%). We found out that five (0.025%) of the cases had radical mastoidectomy surgery and 16 (0.08%) of them had tympanoplasty. CONCLUSION: The prevalence of COM in young men is 1.77%. Although our study has a limitation because all of our samples are young men, the study is unique due to its large sample size. PMID- 20961279 TI - Age specific responses to acute inhalation of diffusion flame soot particles: cellular injury and the airway antioxidant response. AB - Current studies of particulate matter (PM) are confounded by the fact that PM is a complex mixture of primary (crustal material, soot, metals) and secondary (nitrates, sulfates, and organics formed in the atmosphere) compounds with considerable variance in composition by sources and location. We have developed a laboratory-based PM that is replicable, does not contain dust or metals and that can be used to study specific health effects of PM composition in animal models. We exposed both neonatal (7 days of age) and adult rats to a single 6-h exposure of laboratory generated fine diffusion flame particles (DFP; 170 ug/m(3)), or filtered air. Pulmonary gene and protein expression as well as indicators of cytotoxicity were evaluated 24 h after exposure. Although DFP exposure did not alter airway epithelial cell composition in either neonates or adults, increased lactate dehydrogenase activity was found in the bronchoalveolar lavage fluid of neonates indicating an age-specific increase in susceptibility. In adults, 16 genes were differentially expressed as a result of DFP exposure whereas only 6 genes were altered in the airways of neonates. Glutamate cysteine ligase protein was increased in abundance in both DFP exposed neonates and adults indicating an initiation of antioxidant responses involving the synthesis of glutathione. DFP significantly decreased catalase gene expression in adult airways, although catalase protein expression was increased by DFP in both neonates and adults. We conclude that key airway antioxidant enzymes undergo changes in expression in response to a moderate PM exposure that does not cause frank epithelial injury and that neonates have a different response pattern than adults. PMID- 20961281 TI - [Quality of life before and after surgery in patients with nasal polyposis]. AB - OBJECTIVES: The postoperative symptoms, paranasal computed tomography (CT) findings and quality of life of the patients who had undergone surgical treatment for nasal polyposis were evaluated. PATIENTS AND METHODS: This study included 32 patients (18 females, 14 males; mean age 43 years; range 14 to 64 years) who applied to our clinic between January 2008 and January 2009 and were operated on with diagnosis of pure nasal polyps. In addition, 36 healthy volunteers were randomized to the control group. The patients were evaluated before and after surgery, on the 3rd week and 3rd month with routine ear nose and throat physical examination and through the Short Form-36 (SF-36) questionnaire as the nasal symptom scores and quality of life. The SF-36 questionnaire was used in the control group as well. In this SF-36 questionnaire the patients were evaluated for eight domains. Control paranasal CT findings at 6th months after surgery were compared with the CT findings before surgery. RESULTS: We determined improvement of nasal symptoms in patients (nasal obstruction, headache, loss of sense of smell, rhinorrhea and posterior rhinorrhea) at the 3rd week and 3rd month after surgery compared to before surgery (p<0.05). We also determined improvement in the domains of SF-36 questionnaire (general healthy, physical functioning, problems of emotional role, social functioning, pain, vitality and mental health) at the 3rd week and 3rd month after surgery compared to before surgery (p<0.05). Control paranasal CT findings of patients at 6th months after surgery was also improved significantly compared to before (p<0.001). CONCLUSION: We determined improvement in all symptoms and quality of life for a short period of time after the surgical treatment performed on patients with nasal polyposis. The paranasal CT has an important place for diagnosis and treatment. PMID- 20961282 TI - Alterations of NIS expression in functioning thyroid nodules. AB - OBJECTIVES: This study aimed to analyze both the level and the cell site of the sodium-iodide symporter (NIS) protein expression in autonomously functioning thyroid nodules (AFTNs) and extranodular thyroid tissues. In addition, this study sought to compare the clinical results of patients with the levels of human NIS (hNIS) protein expression. PATIENTS AND METHODS: The histological slides consisted of 36 AFTNs and 31 extranodular thyroid tissues from 28 patients (5 males, 23 females; mean age 54.5+/-11.0 years; range 37 to 72 years) who underwent surgery for toxic multinodular goitre. The expression of NIS protein was investigated by immunohistochemistry in paraffin-embedded tissue sections using anti-hNIS monoclonal antibody by the labeled streptavidin-biotin method. RESULTS: The percentage of hNIS positive follicular cells was significantly higher in the AFTNs (13.33+/-12.09) than in the extranodular thyroid tissues (1.35+/-3.03). Staining for hNIS was mostly confined to the cell membrane in the AFTNs (88.9%) and in the extranodular thyroid tissues (54.5%). The clinical parameters and nodule volume did not establish any correlation with hNIS immunoreactivity. CONCLUSION: Our data indicate that functioning nodules express higher amounts of NIS protein than the extranodular thyroid tissue, but the level of hNIS immunoreactivity was lower than had been reported in the previous literature. This result may be due to interindividual variability between different populations, and iodine status. Furthermore, the localization of the NIS protein might not give an indication of its functional status. PMID- 20961283 TI - Reconstruction of large nasal septal perforations with a three layer galeal pericranial flap: an anatomical and technical study. AB - OBJECTIVES: In this study, a modified surgical method was carried out to repair large nasal septal perforations with a galeal pericranial flap using endoscopic technique. MATERIALS AND METHODS: Six adult human cadavers were dissected by applying the classic open rhinoplasty technique. Large perforations were created in the septal cartilages. To repair the perforations, we prepared galeal pericranial flaps with supraorbital neurovascular pedicles and calvarial bone grafts under endoscopic visualization. The flaps were inserted between the upper lateral cartilages and folded into three layers. The flaps were sutured to the nasal mucosa with absorbable sutures. The length, the width, the size of the flaps and the perforations were measured using an electronic caliper and a flexible ruler. RESULTS: The mean length and width of the flap pedicles were measured as 26.8+/-5.1 mm (range 20 to 32 mm) and 19.3+/-2.6 mm (range 15 to 23 mm), respectively. In addition, the mean length and the width of the flaps were 54.1+/-4.9 mm (range 50 to 60 mm) and 51.6+/-7.8 mm (range 45 to 63 mm), respectively. All of the nasal septal perforations were repaired with a galeal pericranial flap. CONCLUSION: The galeal-pericranial flap is well-vascularized and similar to the nasal mucosa for tissue thickness. Therefore, reconstruction with galeal-pericranial flaps can be an alternative surgical technique for repair of large nasal septal perforations. PMID- 20961284 TI - The effect of melatonin on experimentally-induced myringosclerosis in rats. AB - OBJECTIVES: This study determined the preventive effect of melatonin on the occurrence of experimentally-induced myringosclerosis of the tympanic membrane (TM). MATERIALS AND METHODS: Twenty Wistar albino-type rats weighing approximately 300 g each were randomly separated into two groups and myringotomized on the left TMs: group 1 rats (n=6) received intraperitoneal melatonin injections 10 mg/kg/day whereas group 2 rats (n=12) were treated with physiological serum only. The remaining two rats were served as the control group for histological comparison and standardization. After 15 days of treatment, myringotomized membranes were examined by otomicroscopy and harvested for histopathological evaluation. The functional effect of myringosclerotic plaques in the TMs of the two groups were compared with tympanometric measurements. RESULTS: Tympanic membranes in group 2 revealed extensive myringosclerotic plaques, on the other hand, TMs in group 1 showed faint or no existence of myringosclerosis. The mean magnitude of the maximum admittance from group 2 measured by tympanometry reduced to about 40% of the values obtained from group 1 (Z=-2,067, p=0.041). The mean magnitude of the maximum admittance from melatonin group was very close to the mean tympanometric value of non-myringotomized Wistar albino rats, demonstrating a functional outcome. CONCLUSION: The occurrence of myringosclerosis following experimental myringotomy can be hindered by systemic melatonin treatment. PMID- 20961285 TI - Laser excision of a typical carcinoid tumor of the larynx: a case report. AB - Neuroendocrine carcinomas of the larynx include a range of rare tumors which have variable biologic behavior, affecting treatment and prognosis. Among these, typical carcinoid tumors are the least common type. Prognosis of typical carcinoid tumor is better than atypical carcinoid tumor and small cell carcinoma of the larynx. Conservation surgery is the preferred treatment modality. Transoral CO2 laser surgery can be a good alternative for appropriate cases because of the functional results and less morbidity. In this article, a 71-year old female presented with complaints of feeling a mass during swallowing. Fiberoptic examination of the larynx revealed a mass located on the right aryepiglottic fold and biopsy revealed the tumor as a typical carcinoid tumor. We describe CO2 laser excision of a typical carcinoid tumor of the larynx in this case report. PMID- 20961286 TI - A rare cause of nasal obstruction: giant invasive nonfunctioning pituitary adenoma. AB - Nasal obstruction is a very rare symptom caused by a pituitary adenoma. A 57-year old man admitted to our clinic with bilateral nasal obstruction for the last six months. Endoscopic examination revealed soft pinkish pulsatile tissues in both nasal cavities. Radiologic investigation revealed a suprasellar mass extending to the frontal lobes, spheno-ethmoidal sinuses and nasal cavities. He had bitemporal superior quadrant hemianopsia. Pituitary hormone levels were normal. Biopsies were taken from the patient endonasally. Pathological evaluations and laboratory findings were compatible with nonfunctioning pituitary adenoma. PMID- 20961287 TI - [Management of laryngeal hemangioma in adults: a case report]. AB - Hemangiomas are the most common vascular tumors mostly (60%) seen in the head neck region. Head-neck hemangiomas are seen frequently in the oral cavity, rarely in the larynx. Adult laryngeal hemangiomas are rare and often seen in the supraglottic region, therefore causing dysphagia/dysphonia. We presented two cases with laryngeal hemangioma, discussed the diagnosis, treatment and follow-up of adult cavernous hemangiomas. A forty-one-year-old female patient applied to hospital with hoarseness and breathing difficulty lasting for three years. A cavernous hemangioma located on laryngeal surface of the epiglottis was excised through a transoral endoscopic approach. The patient had no symptoms after the operation but on the postoperative 34th month follow-up she was admitted to our clinic again because of difficulty during swallowing. Relapsed hemangioma was diagnosed and reoperated by open surgery (laryngofissure). After reoperation the patient had symptomatic relief in three months and videolaryngoscopic examination showed granulation tissue. The patient's regular follow-up was continued. A forty year-old female other patient was applied to hospital with hoarseness and swallowing difficulty worsening in three months. Hemangioma located in the postcricoid area with extensive to hypopharynx-esophagus junction was diagnosed. The location of the lesion in imaging techniques was evaluated with the thoracic surgery and gastroenterology department and we decided not to do any operation and follow-up patient by considering the severity of symptoms, location of lesion and complications of operation. PMID- 20961288 TI - Nerve sheath myxoma of the upper lip: a case report. AB - Nerve sheath myxoma is a benign tumor that rarely occurs in the lip area. In this article, a 28-year-old woman admitted with a complaint of painless swelling in the upper lip is presented. The lesion was excised, and histopathological and immunohistochemical examinations were performed. There are only five reported cases in the available literature. Although very rare, nerve sheath myxoma should be considered in the differential diagnosis of lip mass and widely excised to avoid local recurrence. The patient is under clinical control with no signs of recurrence after 16 months. PMID- 20961289 TI - Contrasting effects of ERK on tight junction integrity in differentiated and under-differentiated Caco-2 cell monolayers. AB - ERK (extracellular-signal-regulated kinase) activation leads to disruption of tight junctions in some epithelial monolayers, whereas it prevents disruption of tight junctions in other epithelia. The factors responsible for such contrasting influences of ERK on tight junction integrity are unknown. The present study investigated the effect of the state of cell differentiation on ERK-mediated regulation of tight junctions in Caco-2 cell monolayers. EGF (epidermal growth factor) potentiated H2O2-induced tight junction disruption in under differentiated cell monolayers, which was attenuated by the MEK [MAPK (mitogen activated protein kinase)/ERK kinase] inhibitor U0126. In contrast, EGF prevented H2O2-induced disruption of tight junctions in differentiated cell monolayers, which was also attenuated by U0126. Knockdown of ERK1/2 enhanced tight junction integrity and accelerated assembly of tight junctions in under-differentiated cell monolayers, whereas it had the opposite effect in differentiated cell monolayers. Regulated expression of wild-type and constitutively active MEK1 disrupted tight junctions, and the expression of dominant-negative MEK1 enhanced tight junction integrity in under-differentiated cells, whereas contrasting responses were recorded in differentiated cells. EGF prevented both H2O2-induced association of PP2A (protein phosphatase 2A), and loss of association of PKCzeta (protein kinase Czeta), with occludin by an ERK-dependent mechanism in differentiated cell monolayers, but not in under-differentiated cell monolayers. Active ERK was distributed in the intracellular compartment in under differentiated cell monolayers, whereas it was localized mainly in the perijunctional region in differentiated cell monolayers. Thus ERK may exhibit its contrasting influences on tight junction integrity in under-differentiated and differentiated epithelial cells by virtue of differences in its subcellular distribution and ability to regulate the association of PKCzeta and PP2A with tight junction proteins. PMID- 20961290 TI - A highly efficient and thermostable alpha-amylase from soya bean seeds. AB - The alpha-amylase from soya bean seeds was purified by affinity precipitation, resulting in approx. 20-fold purification with approx. 84% recovery. The purified alpha-amylase had an optimum pH of 5.5, optimum temperature of 75 degrees C, Arrhenius energy of activation of 6.03 kcal/mol (1 kcal~4.184 kJ) and a Km of 2.427 mg/ml (starch substrate). The enzyme had maximum substrate specificity for starch. Among the various metal ions tested, Co2+ and Mn2+ were found to be strong activators. The effect of thiol group modifying agents showed that the thiols of soya bean alpha-amylase are not directly involved in catalysis. The thermostability of the enzyme makes it suitable for starch liquefaction and the detergent industry respectively. PMID- 20961291 TI - bFGF and PDGF-BB have a synergistic effect on the proliferation, migration and VEGF release of endothelial progenitor cells. AB - We have investigated the synergistic effects of bFGF (basic fibroblast growth factor) and PDGF-BB (platelet-derived growth factor-BB) on the proliferation, migration and VEGF (vascular endothelial growth factor) release of EPCs (endothelial progenitor cells). The proliferation of EPCs was assayed by MTS [3 (4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium]. EPCs migration was detected using the Transwell system. Real-time PCR was used to assess the transcription of PDGFRbeta mRNA. PLC-gamma (phospholipase C gamma) expression and VEGF release were analysed by Western blot and ELISA. bFGF and PDGF-BB could, respectively, or synergistically, promote the proliferation and migration of EPCs, and these effects of bFGF and PDGF-BB were implemented by enhancing PDGFRbeta mRNA, PLC-gamma and VEGF expression, while inhibitor of PDGF receptor kinase (AG1296) and the selective PLC inhibitor (U73122) could block these effects of bFGF and PDGF-BB. In the meantime, we proved that the amplification by bFGF and PDGF-BB-stimulated PDGFRbeta mRNA, PLC gamma and VEGF expression was abrogated by anti-bFGF antibody, AG1296 and U73122. These results strongly suggest that the proliferation and migration of EPCs may depend on bFGF and/or PDGF-BB by PDGFRbeta/PLC-gamma signalling pathway, and bFGF and/or PDGF-BB stimulate VEGF release at a point downstream from PDGFRbeta/PLC gamma in EPCs. PMID- 20961292 TI - Characterization of C- and N-terminal domains of Aquifex aeolicus MutL endonuclease: N-terminal domain stimulates the endonuclease activity of C terminal domain in a zinc-dependent manner. AB - DNA MMR (mismatch repair) is an excision repair system that removes mismatched bases generated primarily by failure of the 3'-5' proofreading activity associated with replicative DNA polymerases. MutL proteins homologous to human PMS2 are the endonucleases that introduce the entry point of the excision reaction. Deficiency in PMS2 function is one of the major etiologies of hereditary non-polyposis colorectal cancers in humans. Although recent studies revealed that the CTD (C-terminal domain) of MutL harbours weak endonuclease activity, the regulatory mechanism of this activity remains unknown. In this paper, we characterize in detail the CTD and NTD (N-terminal domain) of aqMutL (Aquifex aeolicus MutL). On the one hand, CTD existed as a dimer in solution and showed weak DNA-binding and Mn2+-dependent endonuclease activities. On the other hand, NTD was monomeric and exhibited a relatively strong DNA-binding activity. It was also clarified that NTD promotes the endonuclease activity of CTD. NTD mediated activation of CTD was abolished by depletion of the zinc-ion from the reaction mixture or by the substitution of the zinc-binding cysteine residue in CTD with an alanine. On the basis of these results, we propose a model for the intramolecular regulatory mechanism of MutL endonuclease activity. PMID- 20961293 TI - Deep brain stimulation in the treatment of depression. AB - OBJECTIVE: To present the technique of deep brain stimulation (DBS) and to evaluate the studies conducted on DBS in the treatment of therapy-refractory major depressive disorder (MDD). METHOD: A review of the literature on DBS in the treatment of MDD was conducted. RESULTS: The results of DBS in MDD have been presented in 2 case reports and 3 studies of 47 patients operated upon in 5 different target areas. Positive effects have been presented in all studies and side effects have been minor. DBS in the nucleus accumbens resulted in a mean reduction of Hamilton depression rating scale (HDRS) of 36% after 1 year and 30% of the 10 patients achieved remission. DBS in the internal capsule/ventral striatum resulted in a reduction of 44% after 1 year, and at the last evaluation after in mean 2 years, 40% of the 15 patients were in remission. The 20 patients with subcallosal cingulated gyrus DBS had a reduction of HDRS of 52% after 1 year, and 35% were within 1 point from remission or in remission. CONCLUSION: DBS is a promising treatment for therapy-refractory MDD. The published experience is, however, limited, and the method is at present an experimental therapy. PMID- 20961294 TI - Isolation and characterization of MAT genes in the symbiotic ascomycete Tuber melanosporum. AB - * The genome of Tuber melanosporum has recently been sequenced. Here, we used this information to identify genes involved in the reproductive processes of this edible fungus. The sequenced strain (Mel28) possesses only one of the two master genes required for mating, that is, the gene that codes for the high mobility group (HMG) transcription factor (MAT1-2-1), whereas it lacks the gene that codes for the protein containing the alpha-box- domain (MAT1-1-1), suggesting that this fungus is heterothallic. * A PCR-based approach was initially employed to screen truffles for the presence of the MAT1-2-1 gene and amplify the conserved regions flanking the mating type (MAT) locus. The MAT1-1-1 gene was finally identified using primers designed from the conserved regions of strains that lack the MAT1-2 1 gene. * Mating type-specific primer pairs were developed to screen asci and gleba from truffles of different origins and to genotype single ascospores within the asci. These analyses provided definitive evidence that T. melanosporum is a heterothallic species with a MAT locus that is organized similarly to those of ancient fungal lineages. * A greater understanding of the reproductive mechanisms that exist in Tuber spp. allows for optimization of truffle plantation management strategies. PMID- 20961295 TI - Cephalic phase responses and appetite. AB - The current food supply in many parts of the world differs substantially from that which existed during most of human evolution. It is characterized by a high variety of palatable foods with high energy density and low fiber content. Many foods can be eaten very quickly, and there is not always congruency between the sensory properties of the food and the subsequent metabolic consequences of its ingestion, (e.g., as in the consumption of artificially sweetened foods). It is not presently known how the human body copes with this incongruent food environment in terms of short-term satiety responses and long(er)-term regulation of food intake. Cephalic phase responses (CPRs) are innate and learned physiological responses to sensory signals that prepare the gastrointestinal tract for the optimal processing of ingested foods. CPRs could be affected by inconsistencies in the associations between sensory signals and subsequent post ingestive consequences. Reviewed here are the available data on how CPRs affect the control of food intake. PMID- 20961296 TI - Biomedical effects of grape products. AB - Accumulating evidence suggests that consumption of grapes and grape products can positively influence risk factors associated with cardiovascular health, cancer, neurodegenerative disease, and age-related cognitive decline. These effects are often attributed to the antioxidant activity and function of flavonoid compounds found in grapes as well as other actions such as increasing nitric oxide production. The well-established health effects of grapes on cardiovascular disease risk, mainly on endothelial function, LDL oxidation, progression of atherosclerosis, and reduction in oxidative stress, have been clearly identified. Emerging research has also demonstrated that grapes have beneficial effects on other chronic-degenerative diseases such as cancer, Alzheimer's disease, age related cognitive decline, and diabetes. Further beneficial effects of grapes on oral health, immune function, and antiviral activity have also been reported. This review examines the published evidence on the human health benefits associated with grapes and grape products, with animal and cell studies included for areas in which human research is either limited or unavailable. PMID- 20961298 TI - Relationship of calcium absorption with 25(OH)D and calcium intake in children with rickets. AB - Nutritional rickets has long been considered a disease caused by vitamin D deficiency, but recent data indicate that inadequate dietary calcium intake is an important cause of rickets, particularly in tropical countries. Children with rickets due to calcium deficiency do not have very low 25(OH)D concentrations, and serum 1,25(OH)(2) D values are markedly elevated. Studies of Nigerian children with rickets demonstrated they have high fractional calcium absorption. A high-phytate diet was demonstrated to increase calcium absorption compared with the fasting state, and enzymatic dephytinization did not significantly improve calcium absorption. When given vitamin D, children with rickets have a marked increase in 1,25(OH)(2) D concentrations without any change in fractional calcium absorption. No positive relationship was found between fractional calcium absorption and serum 25(OH)D concentrations in children on low-calcium diets. More research is needed to understand the interaction between calcium and vitamin D and the role of vitamin D in calcium absorption. PMID- 20961297 TI - Role of selenium in HIV infection. AB - HIV infection is a global disease that disproportionately burdens populations with nutritional vulnerabilities. Laboratory experiments have shown that selenium has an inhibitory effect on HIV in vitro through antioxidant effects of glutathione peroxidase and other selenoproteins. Numerous studies have reported low selenium status in HIV-infected individuals, and serum selenium concentration declines with disease progression. Some cohort studies have shown an association between selenium deficiency and progression to AIDS or mortality. In several randomized controlled trials, selenium supplementation has reduced hospitalizations and diarrheal morbidity, and improved CD4(+) cell counts, but the evidence remains mixed. Additional trials are recommended to study the effect of selenium supplementation on opportunistic infections, and other HIV disease related comorbidities in the context of highly active antiretroviral therapy in both developing and developed countries. PMID- 20961299 TI - Tissue-specific increases in endogenous all-trans retinoic acid: possible contributing factor in ethanol toxicity. AB - All-trans retinoic acid (atRA) is required for neurogenesis and dendritic growth in the hippocampus. The toxic effects of ethanol include developmental defects, cognitive dysfunction, and increased risk of cancer and have some similarities to the detrimental effects of excess atRA, the active form of vitamin A. It is therefore possible that disruption of atRA homeostasis would contribute to the deleterious effects of ethanol. However, previous work, using very high exogenous doses of retinol, found that ethanol toxicity led to decreased formation of atRA, apparently due to competitive inhibition of alcohol dehydrogenase, which is purportedly involved in the conversion of retinol to retinal. A new study, using assays that are highly sensitive for endogenous atRA, has reported that ethanol toxicity in mice actually increased atRA concentration in certain tissues, including brain hippocampus, apparently due to a mobilization of hepatic retinyl esters that led to increased retinol and atRA in specific tissues. PMID- 20961300 TI - Gut lymph and lymphatics: a source of factors leading to organ injury and dysfunction. AB - Major trauma, shock, sepsis, and other conditions can lead to the acute respiratory distress syndrome (ARDS), which may progress to the highly lethal multiple organ dysfunction syndrome (MODS). Although a number of therapeutic strategies have been initiated, their success has been limited largely due to an incomplete understanding of the biology of MODS. However, recent studies indicate that the intestinal lymphatics serve as the primary route for nonbacterial, tissue injurious gut-derived factors, which can induce acute ARDS and MODS. The gut lymph hypothesis of ARDS and MODS thus helps clarify several important issues. First, because the lung is the first organ exposed to mesenteric lymph and not the liver (i.e., mesenteric lymph enters the subclavian vein via the thoracic duct, which, in turn, empties directly into the heart and lungs), it would explain the clinical observation that the lung is generally the first organ to fail. Second, this hypothesis provides new pathophysiologic information, thereby providing a basis for novel therapies. Finally, by studying the composition of lymph, MODS-inducing factors can be isolated and identified. PMID- 20961301 TI - Basic mechanisms controlling lymph transport in the mesenteric lymphatic net. AB - This minireview summarizes an oral presentation given at the National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health workshop "Lymphatics in the Digestive System: Physiology, Health, and Disease" in Bethesda, Maryland on November 3-4, 2009. The concepts of extrinsic and intrinsic pumps, as well as intrinsic and extrinsic flows, are discussed in relation to the lymph transport in mesenteric lymphatic vessels. Age-related alterations in the structure and regulatory mechanisms of lymph flow in mesenteric lymphatic vessels may provide the basis for their diminished ability to work during the periods of increased functional loads in them. The recent development of modern experimental tools provides the opportunity to extend the knowledge on lymph transport function of lymphatic vessels that is absolutely necessary to maintain fluid and macromolecular homeostasis and to provide a transportation route for lipids adsorbed in gut and to immune cells. PMID- 20961302 TI - Causes and consequences of lymphatic disease. AB - The visceral manifestations of lymphatic disorders (lymphangiomatosis and lymphangiectasia) are particularly severe. Any pathology of the lymphatic vasculature, whether superficial or internal, regional, or systemic, is predominated by the appearance of lymphedema, the characteristic form of tissue edema that occurs when lymphatic dysfunction supervenes. Disease manifestations may include dysregulation of body fluid homeostasis, immune traffic impairment, and disturbances of lipid and protein reabsorption from the gut lumen. The appearance of lymphatic edema invokes complex biological alterations. Many of these changes seem to relate uniquely to chronic lymphatic edema, including a profound stimulus to collagen and adipose deposition. Despite the recent advances in our understanding of these disorders, substantial knowledge gaps remain; these gaps inhibit our ability to accurately identify, categorize, treat, and prevent these diseases. Future diagnostic, therapeutic, and reproductive decisions for affected individuals require an accurate knowledge of the clinical and laboratory presentation, mode of inheritance, treatment response, outcomes, and prognosis. PMID- 20961303 TI - Microanatomy of the intestinal lymphatic system. AB - The intestinal lymphatic system comprises two noncommunicating lymphatic networks: one containing the lacteals draining the villi and the connecting submucosal lymphatic network and one containing the lymphatics that drain the intestine muscular layer. These systems deliver lymph into a common network of collecting lymphatics originating near the mesenteric border. The intestinal lymphatic system serves vital functions in the regulation of tissue fluid homeostasis, immune surveillance, and the transport of nutrients; conversely, this system is affected by, and directly contributes to, disease processes within the intestine. Recent discoveries of specific lymphatic markers, factors promoting lymphangiogenesis, and factors selectively affecting the development of intestinal lymphatics, hold promise for unlocking the role of lymphatics in the pathogenesis of diseases affecting the intestine and for intestinal lymphatic selective therapies. Vital to progress in understanding how the intestinal lymphatic system functions is the integration of recent advances identifying molecular pathways for lymphatic growth and remodeling with advanced imaging modalities to observe lymphatic function and dysfunction in vivo. PMID- 20961304 TI - Role of intestinal lymphatics in interstitial volume regulation and transmucosal water transport. AB - Two of the principal functions of intestinal lymphatics are to assist in the maintenance of interstitial volume within relatively normal limits during alterations in capillary filtration (e.g., acute portal hypertension) and the removal of absorbed water and chylomicrons. The contribution of lymphatics to the prevention of interstitial overhydration or dehydration during alterations in transcapillary filtration is similar in the small intestine and colon. While the lymphatics of the small intestine contribute substantially to the removal of absorbed water (particularly at low and moderate absorption rates), the contribution of colonic lymphatics to the removal of the fluid absorbate is negligible. This difference is attributed to the relative caliber and location of lymphatics in the mucosal layer of the small and large intestines. In the small intestine, large lacteals lie in close proximity to transporting epithelium, while colonic lymph vessels are rather sparse and confined to the basal portion of the mucosa. In the small intestine, the lymphatics assume a more important role in removing absorbed water during lipid absorption than during glucose absorption. PMID- 20961305 TI - Lymphatics in intestinal transport of nutrients and gastrointestinal hormones. AB - The lymph fistula rat has been used for studying intestinal absorption of nutrients, especially lipids. Lipid absorption begins with the digestion of triacylglycerol (TAG) to form 2-monoacylglycerol (2-MAG) and fatty acids (FA), which are then incorporated in bile salt-mixed micelles. The mixed micelles deliver these digestion products to enterocytes for uptake. There, 2-MAG and FA are re-esterified to form TAG, which is then incorporated into chylomicrons (CMs) to be carried by the lymphatic system. Coincident with CMs' secretion into lymph, the small intestine also secretes incretin hormones. Advantages of the lymph fistula model in studying CMs and incretin secretion include the following: (1) the animal being conscious, (2) much less dilution of CMs and incretins than in portal blood, and (3) fewer degrading enzymes than portal blood, e.g., dipeptidyl peptidase-IV. Examples of the lymph fistula model being used for studying CMs' transport in normal and pathophysiologic states are presented. Recently, the lymph fistula rat has also been used for studying the secretion of incretins by the small intestine. PMID- 20961306 TI - Mechanisms of chylomicron uptake into lacteals. AB - Right from birth, the lymphatics play a crucial role in dietary functions. A majority of the lipid absorbed from the newborn's lipid-rich diet enters the blood circulation through the lymphatic system, which transports triglyceride loaded particles known as chylomicrons from the villi of the small intestine to the venous circulation near the heart. In light of the significance of this role, as well as the fact that lipid transport from the gut was one of the earliest discovered functions of the lymphatic vasculature, it is surprising that so little is known about how chylomicrons initially gain access to the lymphatic vessel. This review will focus on the current mechanisms thought to be important in this process and highlight important questions that need to be answered in the future. PMID- 20961307 TI - A yeast-based recombinogenic targeting toolset for transgenic analysis of human disease genes. AB - Transgenic mouse models are valuable resources for analyzing functions of genes involved in human diseases. Mouse models provide critical insights into biological processes, including in vivo visualization of vasculature critical to our understanding of the immune system. Generating transgenic mice requires the capture and modification of large-insert DNAs representing genes of interest. We have developed a methodology using a yeast-bacterial shuttle vector, pClasper, that enables the capture and modification of bacterial artificial chromosomes (BAC)-sized DNA inserts. Numerous improvements and technical advances in the original pClasper vector have allowed greater flexibility and utility in this system. Examples of such pClasper mediated gene modifications include: Claspette mediated capture of large-insert genomic fragments from BACs-human polycystic kidney disease-1 (PKD1); modification of pClasperA clones by the RareGap method PKD1 mutations; Claspette-mediated modification of pClasper clones-mouse albumin 1 gene; and, of most relevance to our interest in lymph node vasculature Claspimer-mediated modification of pClasper clones-high endothelial venule and lymphatic vessel genes. Mice that have been generated with these methods include mice with fluorescent high endothelial venules. PMID- 20961308 TI - Lymphatic pump function in the inflamed gut. AB - The role of the lymphatic circulation to actively remove fluid, cells, proteins, and other particles from the interstitium to prevent mounting edema is well appreciated, but whether and how this function is compromised during inflammation has been scarcely investigated. We discuss here the mechanisms of lymphatic pumping and their modulation in inflammatory conditions or by inflammatory mediators in the context of inflammatory bowel disease (IBD), an ensemble of disorders typically described with abnormal or dysfunctional intestinal or mesenteric lymphatic vessels. We report our findings showing impaired mesenteric lymphatic contractile activity in an animal model of intestinal inflammation that recapitulates some features of IBD and suggests a role for prostanoids in this dysfunction. With the knowledge that prostaglandin E(2) and prostacyclin are implicated in IBD pathogenesis and induce a potent inhibition of lymphatic pumping, we established the pharmacological profile for these prostaglandin receptors in mesenteric lymphatic vessels and their respective role in pumping inhibition. Inhibition of mesenteric lymphatic pumping during inflammation may be a cause of edema, compromised immune response, and granuloma associated with IBD. PMID- 20961310 TI - Emerging roles of lymphatics in inflammatory bowel disease. AB - The mobilization and recruitment of blood and lymphatic vasculatures are widely described in inflammatory bowel diseases (IBDs). Although angiogenesis contributes to intense gut inflammation, it remains unclear whether and when lymphangiogenesis amplifies or protects in IBD. The prolonged maintenance of lymphatic (over blood vessels) in inflammation indicates that lymphatic-blood vessel interactions may regulate IBD pathogenesis and restitution. Although lymphatic expansion helps to restore fluid balance and clear cytokines and immune cells, lymphatic failure results in accumulation of these factors and exacerbates IBD. Lymphatic obstruction and remodeling may impair lymphatic pumping, leading to repeated rounds of lymphangiogenesis. Early descriptions of Crohn's disease and ulcerative colitis describe colon lymphatic congestion, remodeling, expansion, and many other features that are recapitulated in experimental IBD and also by intestinal lymphatic obstruction, supporting lymphangitis as a cause and consequence of IBD. Growth factors, cytokines, gut flora, Toll receptors, and leukocytes all regulate inflammation and gut lymphatic remodeling in IBD. This review summarizes the importance of lymphatics and lymphangiogenesis in IBD etiology that may be useful in diagnosis and therapy of gut inflammation. PMID- 20961309 TI - Soluble VEGFR-2: an antilymphangiogenic variant of VEGF receptors. AB - The vascular endothelial growth factor (VEGF) family of secreted proteins and their receptors are major regulators of blood vessel development (hemangiogenesis) and lymphatic vessel development (lymphangiogenesis). VEGF acts through a complex system of receptor tyrosine kinases, which can be membrane bound or soluble. New data concerning the receptor system are still emerging, thus contributing to the complexity of the system. Very recently a soluble form of VEGFR-2, termed sVEGFR-2, which is a result of alternative splicing, has been discovered. Earlier, it has been shown that a secreted/soluble form of VEGFR-1, termed sVEGFR-1, is produced by alternative splicing and exerts an antihemangiogenic effect by binding VEGF-A. The newly discovered spliced variant of sVEGFR-2 binds the lymphangiogenic growth factor VEGF-C and thus inhibits VEGF C-induced activation of VEGFR-3, consequently inhibiting lymphatic endothelial cell proliferation. Its inactivation in murine embryos permits hyperplasia of dermal lymphatics and invasion of lymphatics into the cornea. Tumor lymphangiogenesis seems to influence the metastatic behavior of malignant cells. A correlation has been found between the downregulation of sVEGFR-2 and the malignant progression of neuroblastoma, which is characterized by lymphogenic metastases in progressed stages. Data show that lymphangiogenesis is regulated by both activators and inhibitors, and its balance is crucial in health and disease. PMID- 20961311 TI - Gut-associated lymphoid tissue, T cell trafficking, and chronic intestinal inflammation. AB - The etiologies of the inflammatory bowel diseases (IBD; Crohn's disease, ulcerative colitis) have not been fully elucidated. However, there is very good evidence implicating T cell and T cell trafficking to the gut and its associated lymphoid tissue as important components in disease pathogenesis. The objective of this review is to provide an overview of the mechanisms involved in naive and effector T cell trafficking to the gut-associated lymphoid tissue (GALT; Peyer's patches, isolated lymphoid follicles), mesenteric lymph nodes and intestine in response to commensal enteric antigens under physiological conditions as well as during the induction of chronic gut inflammation. In addition, recent data suggests that the GALT may not be required for enteric antigen-driven intestinal inflammation in certain mouse models of IBD. These new data suggest a possible paradigm shift in our understanding of how and where naive T cells become activated to yield disease-producing effector cells. PMID- 20961313 TI - AVNRT ablation: aiming for 100/0, and for comfort! PMID- 20961314 TI - Two papers by Michael Fordham (d.1995). AB - The Journal has decided to publish a selection of previously unpublished papers from the Michael Fordham archives, which are being prepared for publication by James Astor and Elizabeth Urban, and of which the two papers published here are the first, both dating from the 1950s. 'Analyst and Priest' seems to be addressed to an audience of mainly religious people who are interested in the relation between psychology and religion and to whom Fordham is introducing some basic Jungian concepts and ways of thinking. The analyst in this lecture is the advocate of a new science, the priest an established figure with a role in society and rituals to perform. As the paper progresses he refines the differences between priest and analyst in terms of individual development versus a philosophy of life. The paper ends with a plea for co-operation between priest and analyst. 'Analyst and Scientist' was a radio talk given in 1956. In this paper Fordham makes the case for paying attention to the irrational. He draws support from Pauli and Polanyi. His theme is to show the scientific value of the subjective. From this he describes the scientific basis for Jung's comparative method and consequently of archetypal psychology. PMID- 20961312 TI - Lymphatic system: a vital link between metabolic syndrome and inflammation. AB - Metabolic syndrome is defined by a cluster of different metabolic risk factors that include overall and central obesity, elevated fasting glucose levels, dyslipidemia, hypertension, and intimal atherogenesis. Metabolic syndrome leads to increased risk for the development of type 2 diabetes and cardiovascular disease (e.g., heart disease and stroke). The exacerbated progression of metabolic syndrome to cardiovascular disease has lead to intense study of the physiological ramifications of metabolic syndrome on the blood vasculature. These studies have particularly focused on the signaling and architectural alterations that manifest in hypertension and atherosclerosis. However, despite the overlap of metabolic syndrome pathology with lymphatic function, tangent effects on the lymphatic system have not been extensively documented. In this review, we discuss the current status of metabolic syndrome and provide evidence for, and the remaining challenges in studying, the connections among the lymphatic system, lipid transport, obesity, insulin resistance, and general inflammation. PMID- 20961316 TI - 'Fascination', 'contagion' and naming what we do: rethinking the transcendent function. AB - Taking 'The psychology of the transference' (Jung 1946) and 'Problems of modern psychotherapy' (Jung 1931) as its text, this paper begins by challenging the usefulness of the term 'transcendent function' in contemporary debate about the nature of 'imagination and psychic transformation in analysis'. It argues that Jung's language in The Practice of Psychotherapy (CW 16)-fascination, suffering, infection, influence-is closer and truer to the experience it describes than the philosophically inspired terms transcendent function and conflict of opposites. His ideas in these writings anticipate later trends in psychoanalytic theory concerning countertransference and the effect of one mind on another, and constitute a theoretical basis for the concept of mutual transformation. Jung's radical insistence on an analytic relationship founded on mutual unconsciousness as the locus of transformation cannot, it is argued, be satisfactorily accounted for by the traditional terminology. PMID- 20961317 TI - A survivor's account of sexual exploitation by a Jungian analyst. AB - This essay explains the ramifications of sexual exploitation in the context of Jungian analysis. It argues that misuse of work specifically framed as Jungian can cause severe, deep, and long-lasting harm. It suggests that Jungian professionals strengthen and increase the scope of their actions to deter rogue colleagues from exploiting their analysands. PMID- 20961320 TI - Social dreaming: competition or complementation to individual dreaming? AB - Social dreaming is presented as a method to explore the unconscious dimension of the social world. The theoretical position of social dreaming and its historical development is described. Two examples are given for the practical application of social dreaming, a professional meeting of psychotherapists and an experiential workshop dealing with the aftermath of trauma. It is suggested that social dreaming is complementary to individual dreaming and offers insights and explanations, as well as guidance on various levels for applications in clinical, organizational, institutional and social settings. PMID- 20961321 TI - Constructing the collective unconscious. AB - Innovative attempts at collating Jungian analytical psychology with a range of 'post-modern' theories have yielded significant results. This paper adopts an alternative strategy: a Lacanian vantage point on Jungian theory that eschews an attempt at reconciling Jung with post-structuralism. A focused Lacanian gaze on Jung will establish an irreducible tension between Jung's view of archetypes as factors immanent to the psyche and a Lacanian critique that lays bare the contingent structures and mechanisms of their constitution, unveiling the supposed archetypes'a posteriori production through the efficacy of a discursive field. Theories of ideology developed in the wake of Lacan provide a powerful methodological tool allowing to bring this distinction into focus. An assembly of Lacan's fragmentary accounts of Jung will be supplemented with an approach to Jungian theory via Zizek's Lacan-oriented theory of the signifying mechanism underpinning 'ideology'. Accordingly, the Jungian archetype of the self, which is considered in some depth, can begin to be seen in a new light, namely as a 'master signifier', not only of Jung's academic edifice, but also -and initially of the discursive strategies that establish his own subjectivity. A discussion of Jung's approach to mythology reveals how the 'quilting point' of his discourse comes to be coupled with a correlate in the Real, a non-discursive 'sublime object' conferring upon archetypes their fascinating aura. PMID- 20961328 TI - A newborn with double-outlet right ventricle and aortopulmonary window associated with maternal phenylketonuria: a first case report. PMID- 20961329 TI - Association between paternal smoking and nutritional status of under-five children attending Diarrhoeal Hospital, Dhaka, Bangladesh. AB - AIM: The study aimed at determining whether there is an association between paternal smoking and nutritional status of children aged 0-59 months. Furthermore, the study looked at the presence of any nutritional differentials within different socio-economic groups. METHODS: Secondary analysis of data on children aged 0-59 months enrolled in the Hospital Surveillance System of International Centre for Diarrhoeal Disease Research, Dhaka Hospital, Bangladesh, during 1996-2006. RESULTS: Among 13,555 under-five children, fathers of 49% were smokers. In multivariate logistic regression models adjusting for potential confounders, fathers' smoking was significantly associated with increased risk of moderate underweight (OR 1.16, 95% CI 1.08-1.25), severe underweight (OR 1.15, 95% CI 1.06-1.26), moderate stunting (OR 1.15, 95% CI 1.06-1.23) and severe stunting (OR 1.13, 95% CI 1.03-1.25). In middle and lower socio-economic strata, risk of moderate and severe child malnutrition was found to be significantly increased in the group where the father was a smoker. CONCLUSION: Results indicate that there is an association between fathers' smoking and malnutrition of under-five children particularly in lower socio-economic group. A possible mechanism - if this association is causal - may be through a negative effect on family economy. PMID- 20961330 TI - Ecological connectivity for a changing climate. PMID- 20961331 TI - Combined effects of levels of protection and environmental variables at different spatial resolutions on fish assemblages in a marine protected area. AB - The links between species-environment relations and species' responses to protection are unclear, but the objectives of marine protected areas (MPAs) are most likely to be achieved when those relations are known and inform MPA design. The components of a species' habitat vary with the spatial resolution of the area considered. We characterized areas at two resolutions: 250 m(2) (transect) and approximately 30,000 m(2) (seascape). We considered three categories of environmental variables: substrate type, bottom complexity, and depth. We sought to determine at which resolution habitat characteristics were a better predictor of abundance and species composition of fishes and whether the relations with environmental variables at either resolution affected species' responses to protection. Habitat features accounted for a larger proportion of spatial variation in species composition and abundances than differences in protection status. This spatial variation was explained best by habitat characteristics at the seascape level than at the transect level. Species' responses to protected areas were specific to particular seascape characteristics, primarily depth, and bottom complexity. Our method may be useful for prioritizing marine areas for protection, designing MPAs, and monitoring their effectiveness. It identified areas that provided natural shelter, areas acting as buffer zones, and areas where fish species were most responsive to protection. The identification of such areas is necessary for cost-effective establishment and monitoring of MPAs. PMID- 20961332 TI - The capacity of Australia's protected-area system to represent threatened species. AB - The acquisition or designation of new protected areas is usually based on criteria for representation of different ecosystems or land-cover classes, and it is unclear how well-threatened species are conserved within protected-area networks. Here, we assessed how Australia's terrestrial protected-area system (89 million ha, 11.6% of the continent) overlaps with the geographic distributions of threatened species and compared this overlap against a model that randomly placed protected areas across the continent and a spatially efficient model that placed protected areas across the continent to maximize threatened species' representation within the protected-area estate. We defined the minimum area needed to conserve each species on the basis of the species' range size. We found that although the current configuration of protected areas met targets for representation of a given percentage of species' ranges better than a random selection of areas, 166 (12.6%) threatened species occurred entirely outside protected areas and target levels of protection were met for only 259 (19.6%) species. Critically endangered species were among those with the least protection; 12 (21.1%) species occurred entirely outside protected areas. Reptiles and plants were the most poorly represented taxonomic groups, and amphibians the best represented. Spatial prioritization analyses revealed that an efficient protected-area system of the same size as the current protected-area system (11.6% of the area of Australia) could meet representation targets for 1272 (93.3%) threatened species. Moreover, the results of these prioritization analyses showed that by protecting 17.8% of Australia, all threatened species could reach target levels of representation, assuming all current protected areas are retained. Although this amount of area theoretically could be protected, existing land uses and the finite resources available for conservation mean land acquisition may not be possible or even effective for the recovery of threatened species. The optimal use of resources must balance acquisition of new protected areas, where processes that threaten native species are mitigated by the change in ownership or on-ground management jurisdiction, and management of threatened species inside and outside the existing protected-area system. PMID- 20961333 TI - Change in bone mineral density at one year following glucocorticoid withdrawal in kidney transplant recipients. AB - Glucocorticoid (GC) therapy induces deleterious effects on the skeleton in kidney transplantation but studies of GC discontinuation in this population are limited. This study evaluated changes in areal bone mineral density (BMD) with GC withdrawal. Subjects were enrolled one yr after renal transplantation and randomized to continue or stop prednisone; all subjects continued cyclosporine and mycophenolate mofetil. BMD measured by dual-energy X-ray absorptiometry was performed at enrollment and repeated at one yr and values were standardized. Mean +/- standard deviation of annualized change in standardized BMD between GC withdrawal vs. continuation group at the lumbar spine was +4.7% +/- 5.5 vs. +0.9% +/- 5.3 (p = 0.0014); total hip +2.4% +/- 4.2 vs. -0.4% +/- 4.2 (p = 0.013), and femoral neck +2.1% +/- 4.6 vs. +1.0% +/- 6.0 (p = 0.37). There was no confounding by prednisone dose prior to enrollment, change in creatinine clearance, weight, or use of bone-active medications following study entry. Multivariate analysis determined that the change in BMD was positively associated with baseline alkaline phosphatase and creatinine clearance and negatively associated with baseline BMD. BMD improves with GC withdrawal after renal transplantation, and this gain in BMD is dependent on the baseline bone turnover, renal function, and BMD. PMID- 20961334 TI - A cross-sectional study of fatigue and sleep quality before and after kidney transplantation. AB - Fatigue and sleep disturbances are common problems for adults with chronic kidney disease or end-stage renal disease. However, these issues have not been examined much in the context of kidney transplantation (KTx). This study characterizes these outcomes in the KTx population and examines their association with psychological functioning and quality of life (QOL). A cross-sectional cohort of 100 wait-listed pre-KTx and 100 post-KTx patients at one transplant center in the United States completed validated fatigue, sleep, mood, and QOL questionnaires, and their medical records were reviewed. Pre-KTx patients had higher levels of fatigue frequency, fatigue severity, and fatigue disruptiveness than post-KTx patients. Also, pre-KTx patients had more difficulty with sleep quality, latency, duration, efficiency, and disturbance and were more likely to have "poor" sleep quality compared with post-KTx patients. Multivariate predictors of high fatigue severity for both pre- and post-KTx patients were high body mass index (BMI), poor sleep quality, and mood disturbance, while poor sleep quality was predicted by high BMI and mood disturbance. Most sociodemographic and clinical parameters were not associated with fatigue severity or sleep disturbance. Fatigue and sleep disturbances are common before and after KTx, and study findings have important implications for their assessment and management. PMID- 20961335 TI - Dietary intake in adolescents with asthma--potential for improvement. AB - Associations between an unhealthy diet and overweight and the presence of asthma are reported. The aims of this study were to assess whether the intake of nutrients and food items in adolescents with asthma differs from that of healthy adolescents, whether the intake was in accordance with the Nordic Nutrition Recommendations (NNR) or whether possible relationships were confounded by body composition. A four-day-validated 18-page pre-coded food diary was completed by 169 13- to 14-year-old adolescents, 93 with asthma and 76 healthy control subjects, in addition to clinical assessment, anthropometric measurements, lung function and skin prick tests. Neither intake of added sugar, snacks nor saturated fat was associated with asthma. All groups had an intake of saturated fat and added sugars exceeding the NNR, while the intake of fruits and vegetables, fibre and vitamin D was lower than recommended. The intake of folate, calcium, magnesium and iron was lower than recommended for girls with asthma and healthy girls. The intake of vitamin C was satisfactory for all groups. Body composition did not influence eating habits, and the prevalence of overweight was similar in the two groups. The dietary intake among Norwegian adolescents in general had a potential for improvement. As girls have a lower energy intake than boys, they have a larger demand of quality of the diet. Additional dietary research in adolescents with asthma is recommended. PMID- 20961336 TI - Haplotypes covering the TNFSF10 gene are associated with bronchial asthma. AB - Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is elevated in the airways of subjects with asthma and has been linked to the development of allergic airway disease by promoting STAT6-dependent T helper 2 cell (T(H) 2) effector functions. To determine whether single nucleotide polymorphisms (SNPs) in the TNFSF10 gene are associated with bronchial asthma we genotyped 498 Caucasian subjects living in Southern Germany for eight SNPs in the TNFSF10 by restriction fragment length polymorphism analysis. In contrast to single SNPs, haplotypes constructed from eight SNPs were robustly associated with asthma (p=0.00012). A small haplotype approach returned four alleles consisting of two (rs3136586/ rs3136598), three (rs12488654/rs3136586/rs3136598 and rs3136586/rs3136598/rs3136604), and four SNPs (rs12488654/ rs3136586/ rs3136598/ rs3136604) that were highly associated with asthma (p=0.00005, p=0.00008, p=0.00017 and p=0.00038). Combinations of SNPs in the TNFSF10 allele were strongly associated with asthma supporting the concept that TRAIL is important in the development of hallmark features of this disease. PMID- 20961337 TI - A decrease in the prevalence and improved control of allergic conditions in 13- to 15-yr-old Maltese children (ISAAC). AB - The International Study of Asthma and Allergies in Childhood (ISAAC) has produced a reliable global map of childhood allergies through the use of a validated standardized questionnaire. Phase 1 of the study was carried out in the Maltese Islands in 1995 and repeated in 2002 in phase 3. To investigate the trends in prevalence and severity of childhood allergies in Maltese schoolchildren, in this article, we compare the data obtained from 4184 children, 13- to 15-yr-olds (88.7% response rate) in phase 1, to that of phase 3 when 4139 (90% response rate) children participated. The cumulative (27.9% vs. 27.4%: p=0.6) and current (16% vs. 14.6% p=0.08) prevalence rates of wheezing remained quite static but wheezers were more likely to be diagnosed with asthma in 2002 (11.1% vs. 14.1% p<0.0001). Along the 7 yrs, these asthmatics were better controlled with less wheezing attacks (p<0.01), less disturbed nights (p<0.05) and less acute severe episodes (p<0.05). Nasal problems were present in 52.7% of participants in 1995 and in 50.4% in 2002 (p<0.05), and 47.4% vs. 42.8% (p<0.0001) persisted with these symptoms and associated itchy eyes (29% vs. 21.8%: p<000001). Though prevalence decreased, the children were labelled as hayfever sufferers more often (32.3 vs. 40.7%: p<0.00001). Rhinitis symptoms seemed to interfere less with daily activities (p<0.01). In 2002, an itchy rash suggestive of eczema was also less present 'ever' (12.8% vs. 11.2%: p<0.05) or currently (10.1% vs. 8.5%: p<0.05) but again more likely to be diagnosed as eczema (p<0.001). This rash caused less sleepless nights in phase 3 of the study (p<0.05). These results indicate that asthma prevalence has reached a plateau between 1995 and 2002 while rhinitis and eczema are less common. All these allergic conditions are better controlled and more likely to be diagnosed in these schoolchildren by Maltese doctors in 2002 than in 1995. PMID- 20961338 TI - Heredity of food allergies in an unselected child population: an epidemiological survey from Finland. AB - The heredity of food allergies (FA) has not previously been addressed in a large unselected child population. Our target population comprised all children born from April 2001 to March 2006 resident in one province of South-East Finland (n c. 6000), as identified from the national population register. In a questionnaire survey conducted in 2005-2006, data were obtained on allergic manifestations (FA symptoms, atopic rash, allergic asthma, hay fever/pollen allergy, or animal allergy) in the biologic parents of 3800 children (64% of the total). Concurrently with the survey but independently of it, results of specific immunoglobulin E antibodies (sIgE), skin prick tests (SPT), and open food challenges (OFC) in the offspring were collected from patient records throughout the province. Up to the age of 4 yr, the incidences of any positive FA test, a positive SPT or sIgE for food items, and a positive OFC in these children were threefold higher if both parents reported having an allergic manifestation and twofold higher if either mother or father had such a manifestation when compared with children whose parents did not report any of these conditions. The estimated risk of any positive FA test increased by a factor of 1.3 (95% CI 1.2-1.4) for each additional allergic manifestation in the parents. Positive FA tests in the offspring were relatively strongly associated with the reports of allergic phenotypes and the number of these phenotypes in their biologic parents. PMID- 20961339 TI - Serum immunoglobulin levels as a predictive factor for a better outcome of non atopic childhood asthma. AB - Childhood asthma is a heterogeneous condition with different phenotypes. Hereby, we aimed to study impact of serum immunoglobulin levels on clinical phenotypes and outcome of asthma. Seventy-eight children (M: 26, F: 52) aged less than 10 yrs (mean = 8.56 +/- 3.23 yrs) and diagnosed as mild-moderate persistent asthma, followed up for at least 1 yr were included into the study. Asthmatic children were divided into two groups based on serum immunoglobulin levels at admission and were evaluated with respect to demographic data, allergic sensitization, symptom scores, medication usage, pulmonary functions, and non-specific bronchial hyper-reactivity. The age at onset of symptoms (40.88 +/- 32.02 vs. 23.04 +/- 26.97 months) was significantly younger in children with hypogammaglobulinemia (n = 28) compared to normogammaglobulinemia group (n = 50) (p = 0.016). Mean follow up duration was 3.8 +/- 2.1 yrs. Atopic sensitization rate was higher in those with normal immunoglobulin levels (81.2% vs. 17.9%), (p < 0.0001). Normal serum immunoglobulin levels were associated with atopic asthma (OR, 4.5; 95% confidence interval (CI): 2.0-10.1). For the prediction of atopic asthma, having normal immunoglobulin levels yielded predictive values of: sensitivity = 88.6%, specificity = 71.8%, positive predictive value = 81.1%, negative predictive value = 82.1%. Furthermore, percentages of atopic dermatitis and allergic conjunctivitis, elevated serum total IgE levels, eosinophilia, and bronchial hyper-reactivity were more common in normogammaglobulinemia with asthma group (p = 0.040, p = 0.003, p = 0.024, p = 0.030, p = 0.040, respectively). Although marked reductions in asthma scores and inhaled corticosteroid usage were observed in both groups over time, the rate of decline was significantly higher and earlier in hypogammaglobulinemia group (p = 0.0001, p = 0.004, respectively). In conclusion, asthmatic children with hypogammaglobulinemia presented at an earlier age, with lower rates of atopy, and earlier clinical improvement accompanied with earlier discontinuation of inhaled corticosteroids than children with normal immunoglobulin levels. Our data demonstrated that in children currently named as early-onset non-atopic asthma, hypogammaglobulinemia might be accompanying, providing evidence for a different phenotype of childhood asthma. PMID- 20961340 TI - Pituitary network connectivity as a mechanism for the luteinising hormone surge. AB - Ovulation in vertebrates is caused by a surge of luteinising hormone (LH) from the pituitary. The LH surge is initiated by rising oestradiol concentration, although the precise mechanism of oestradiol action in humans and primates is not yet understood. Recent advances in labelling and three-dimensional imaging have revealed a rich pituitary structure of interwoven networks of different cell types. In the present study, we develop a mathematical model to test the hypothesis that oestradiol modulation of connectivity between pituitary cells can underlie the LH surge. In the model, gonadotrophin-releasing hormone (GnRH) pulses stimulate LH secretion by two independent mechanisms. The first mechanism corresponds to the well known direct action of GnRH on gonadotrophs, which is inhibited by the rising oestradiol concentration. The second mechanism of GnRH action is to stimulate a recurrent network of pituitary cells; in this case, the folliculostellate cells, which in turn stimulate LH secretion from the gonadotrophs. The network activity is modelled by a one-dimensional ordinary differential equation. The key to the LH surge in the model lies in the assumption that oestradiol modulates network connectivity. When the circulating oestradiol concentration is low, the network is barely connected, and cannot maintain a recurrent signal. When the oestradiol concentration is high, the network is highly connected, and maintains a high level of activity even after GnRH stimulation, thereby leading to a surge of LH secretion. PMID- 20961341 TI - Number, length and end-rounding quality of bristles in manual child and adult toothbrushes. AB - BACKGROUND: The design of the bristles of a toothbrush can affect the overall efficacy of toothbrushing. AIM: To evaluate and compare a number of selected features associated with the bristle (length, number and end-rounding quality) of manual child and adult toothbrushes. DESIGN: The bristle lengths of 11 child and 29 adult toothbrushes were measured on digital micrographs using open source image analysis software. Bristles of tufts from five regions were counted and classified as acceptable or non-acceptable on stereomicroscopic images according to the end-rounding morphology. The data was evaluated statistically. RESULTS: The number of bristles were similar in child and adult toothbrushes (P > 0.05). Despite significant differences in bristle end-rounding in some regions (P < 0.05), the overall quality of bristles were similar in child and adult toothbrushes (P > 0.05). CONCLUSIONS: The variations observed in the number, length and end-rounding quality of the bristles indicate inherent shortcomings of a majority of the tested toothbrushes in plaque removal efficacy, along with the potential for irritation on the gums. PMID- 20961342 TI - Clinicians' preventive strategies for children and adolescents identified as at high risk of developing caries. AB - BACKGROUND: Clinicians handle diagnosis and treatment planning of caries in different ways, and the underlying factors leading to management of risk and choice of treatment strategies are poorly understood. AIM: The aim of this study was to investigate dentists' and dental hygienists' choices of preventive strategies for children and adolescents identified as at high risk of developing caries. DESIGN: A sample of dental records from 432 of a total of 3372 children in a Swedish county identified as at high risk of developing caries, aged 3-19 years, was randomly selected for analysis in the study. Information of importance for the therapists' choice of caries management strategies were obtained from the dental records. RESULTS: The results showed that therapists considered tooth brushing instruction and fluoride treatment at the clinic to be of primary importance as treatment given in 60% of the cases, respectively. Fluoride treatment at home and diet counselling were both chosen in half of the cases. Fissure sealant therapy was used in 21% of the cases, and 15% of the patients did not receive any preventive treatment at all. The results also showed that girls more often received fluoride treatment, tooth brushing instruction and oral hygiene information than boys. CONCLUSIONS: In the majority of the children and adolescents, several preventive measures were given. The more background factors included in the risk assessment, the more preventive measures were given. The differences between the treatments given to girls and the boys need to be further investigated. PMID- 20961344 TI - Twelve-month space changes after premature loss of a primary maxillary first molar. AB - BACKGROUND: Many early investigations concerning space changes following premature extraction of primary molars had a cross-sectional design, a small sample size, and a somewhat crude methodology, which may have led to misunderstandings. AIM: The aim of this study was to use established longitudinal data to investigate ongoing (12-month) dental-arch space problems arising as a result of premature loss of a primary maxillary first molar. DESIGN: Thirteen children (mean +/- SD age at time of tooth extraction, 6.0 +/- 0.74 years) with unilateral premature loss of a primary maxillary first molar were selected for this study. Maxillary dental study casts were obtained from participants 2 or 3 days after the tooth was removed, as well as at a follow-up appointment 12 months later. Six reference lines were measured on the study cast: D + E space, arch width, arch length, intercanine width, intercanine length, and arch perimeter. For each participant, the D + E space of the contralateral intact primary molar served as a control. A paired t-test was used to compare the cast measurements between initial examination and 12-month follow-up. A t-test was used to compare D + E space changes with those of the control group. RESULTS: The D + E space of the extraction side after 12 months was significantly smaller than that of the control side (P < 0.05) and the initial D + E space (P < 0.05). A significantly greater arch perimeter, intercanine width, and intercanine length were found after 12 months compared with the initial parameters. No significant differences were found, however, in arch width or arch length between the initial examination and the 12-month follow-up examination (P > 0.05). CONCLUSIONS: The 12-month space changes in the maxillary dental arch after premature loss of a primary maxillary first molar consist mainly of distal drift of the primary canine toward the extraction site. Mesial movement of permanent molars or tilting of the primary molars did not occur. An increased arch dimension was found especially in the anterior segment (intercanine width and length). There is no need for the use of space maintainers from the results in this study in cases of premature loss of a primary first molar. PMID- 20961343 TI - In vitro alterations in dental enamel exposed to acidic medicines. AB - OBJECTIVE: To evaluate the effect of acidic medicines (Klaricid((r)), Claritin((r)), and Dimetapp((r))) on surface enamel in vitro. METHODS: Enamel blocks (n=104) were randomly distributed into two groups: G1 (pH-cycling simulating physiological oral conditions) and G2 (erosive conditions). Each group was divided into four subgroups, three to be immersed in the medicines and the control in deionized water. Specimen surfaces were evaluated for roughness and hardness at baseline and again after the in vitro experimental phase, which included 30 min immersions in the medicines twice daily for 12 days. Scanning electron microscopy (SEM) was also performed after the in vitro experimental phase. RESULTS: All medicines produced a significant reduction in hardness in G1 after 12 days (P<0.05). The three medicines promoted greater roughness after both pH-regimens - G1 and G2 (P<0.01), except for Claritin in G1. Scanning electron microscopy analysis showed erosive patterns in all subgroups. Dimetapp((r)) showed the most erosion and Klaricid((r)) the least, in both groups. CONCLUSION: Dimetapp((r)) (lowest pH and viscosity) and deionized water (control) showed the most pronounced erosive patterns. Klaricid((r)) (highest pH and viscosity) presented an in vitro protective effect against acid attacks perhaps due to its mineral content and viscosity. PMID- 20961345 TI - Enamel hypoplasia in the primary dentition of monozygotic and dizygotic twins compared with singleton controls. AB - BACKGROUND: The study of enamel hypoplasia (EH) and opacity in twins provides insights into the contribution of genetic and environmental factors in the expression of enamel defects. AIM: This study examined prevalence and site concordance of EH and opacity in the primary dentition of 2- to 4-year-old twins and singleton controls to assess the relative contribution of genetics and the environment to the aetiology of these defects. DESIGN: The study sample consisted of 88 twin children and 40 singletons aged 2-4 years of age. Medical histories were obtained and the children examined for enamel defects. RESULTS: The prevalence of EH by teeth was 21% in monozygotic twins (MZ), 22% in dizygotic twins (DZ), and 15% in singleton controls. Twins showed a higher prevalence of EH compared with singletons (P < 0.05). Factors contributing to increase EH in twins were neonatal complications including intubation. There were no significant differences in site concordance of EH within the MZ twin pairs compared with DZ twin pairs when only presence of EH was considered, whereas a greater concordance was noted between MZ twin pairs compared with DZ twin pairs when both presence and absence of EH were considered. CONCLUSIONS: The results suggest that both genetic and environmental factors contribute to observed variation of EH, although it is likely that environmental factors exert a greater influence. PMID- 20961346 TI - Adverse events of fractionated carbon dioxide laser: review of 373 treatments. AB - OBJECTIVE: To determine the frequency and classification of adverse events (AEs) associated with fractionated carbon dioxide (CO2) laser treatment. METHODS: A retrospective evaluation of 373 successive fractionated 10,600-nm CO2 laser treatments in 287 patients conducted in a single center. AEs of laser therapy, including onset, duration, and treatment, were identified and analyzed through chart review, telephone calls, and email. RESULTS: Three hundred seventy-three treatments resulted in 47 AEs (12.6%) in 40 patients (13.9%). The most frequent AEs were allergic or contact dermatitis (4.6%) acneiform breakout (3.5%), prolonged erythema (1.1%), and herpes simplex virus outbreaks (1.1%). AEs were distributed across different ages, skin types (95% Type II, III, 5% Type IV), and laser parameters. Three of 22 patients (13.6%) with two body areas treated simultaneously and six of 16 patients (37.5%) with three body areas treated simultaneously experienced AEs. Because of the multiple areas treated, some patients experienced multiple AEs. Six AEs were documented in the three patients who underwent two concurrent treatments, and a total of nine AEs were documented in six patients who underwent three concurrent treatments. The 24 patients who had subsequent additional treatments had three documented AEs (12.5%). CONCLUSION: CO2 fractionated laser skin treatment is associated with a relatively low complication rate when one body location is treated, but the complication rate increases with three concurrent treatments of multiple body locations. Subsequent treatments of the same body location after a healing period of 1 to 6 months resulted in no greater risk of AEs. PMID- 20961347 TI - Hot or not--evaluating the effect of artificial tanning on the public's perception of attractiveness. AB - BACKGROUND: Despite strong evidence that sun exposure causes skin cancer, a significant proportion of the population continues to purposefully tan. Many individuals deliberately tan because they believe a tanned complexion makes them appear more attractive. OBJECTIVE: To measure the effect that a tanned complexion has on the public's perception of attractiveness. MATERIALS AND METHODS: Forty five women aged 21 to 35 were recruited. A digital photograph was taken of each subject. Each image was uploaded onto a public website until it had been rated at least 100 times on a scale from 1 to 10. An average baseline, or untanned, rating of the image was calculated. The image was then given an artificial tan using a skin tanning protocol available for Adobe Photoshop. The tanned image was then re uploaded onto the website and another average rating was calculated using the same criteria. RESULTS: The mean score+/-standard deviation was 6.3+/-2.3 for the untanned images and 6.5+/-2.3 for the tanned images (p<.001). CONCLUSIONS: The population who logged onto the website considers tanned people to be more attractive. PMID- 20961348 TI - Hair removal with neodymium-doped yttrium aluminum garnet laser and pneumatic skin flattening in Asians. AB - BACKGROUND: Based on the "gate theory" of pain transmission, pneumatic skin flattening (PSF) may reduce pain during laser hair removal. OBJECTIVE: To compare the pain, efficacy, and adverse effects after laser hair reduction using PSF with that using a dynamic cooling device (DCD) in Asians. METHODS: Twelve participants (skin types III-IV) received laser hair removal with a PSF device on the right axilla and DCD on the other side. Pain was assessed based on a visual analogue scale. Hair regrowth was rated based on photographs taken before treatment and in follow-up visits at 8 and 36 weeks. RESULTS: Sixty-seven percent of participants felt less pain in the PSF side than the DCD side right after laser treatment. On a scale of 1 to 10, the immediate mean pain score was 5.7+/-2.0 for the PSF side and 6.5+/-1.5 for the DCD side (p=.09). Seventy-five percent of the participants preferred treatments with PSF. Efficacy of hair reduction was similar on both sides 8 and 36 weeks after treatment. CONCLUSION: PSF decreases pain sensation during laser hair removal while allowing higher energy densities in Asian patients. The equal efficacy and complication rate of PSF indicates that it is a feasible alternative to DCD at lower cost. PMID- 20961349 TI - Split-face comparison of long-pulse-duration neodymium-doped yttrium aluminum garnet (Nd:YAG) 1,064-nm laser alone and combination long-pulse and Q-switched Nd:YAG 1,064-nm laser with carbon photoenhancer lotion for the treatment of enlarged pores in Asian women. AB - BACKGROUND: Long-pulse and Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) 1,064-nm laser used for facial rejuvenation can improve pore size. Topical carbon has been used to enhance efficacy. OBJECTIVE: To compare the efficacy and safety of a 1,064-nm long-pulse Nd:YAG laser alone with that of a combination Q-switched Nd:YAG laser with topical carbon lotion followed by long pulse Nd:YAG to improve enlarged pores. METHODS: Twenty Thai women randomly received five treatments with a long-pulse Nd:YAG laser on one facial half (LP side) and long-pulse Nd:YAG after carbon-assisted Q-switched Nd:YAG laser on the contralateral side (carbon QS+LP side) at 2-week intervals. Participants were evaluated using digital photography, complexion analysis, and a chromometer. RESULTS: There was significant decrease in pore counts of 35.5% and 33% from baseline on the carbon QS+LP and LP sides, respectively. Physician-evaluated pore size improvement was 67% on the carbon QS+LP sides and 60% on the LP sides. Chromometer measurement showed an increase in skin lightness index. There was no significant difference between the two treatments, although there were more adverse effects on the carbon QS+LP side. CONCLUSION: Long-pulse Nd:YAG 1,064-nm laser improves the appearance of facial pores and skin color. Adding carbon assisted Q-switched Nd:YAG did not enhance the results but produced more side effects. PMID- 20961350 TI - Venoarterial flow index steadily improves after endovenous laser treatment of the great saphenous vein. AB - BACKGROUND: Endovenous laser treatment (EVLT) is a minimally invasive procedure to ablate varicose veins. The venous arterial flow index (VAFI) represents a quantitative duplex ultrasound parameter to characterize venous hemodynamics, which has not been investigated in EVLT so far. OBJECTIVE: To analyze the hemodynamic improvement of EVLT of the great saphenous vein (GSV) according to VAFI measurement. MATERIALS AND METHODS: One hundred thirty-three participants with complete GSV insufficiency were treated with 810-nm EVLT. VAFI as a ratio of venous and arterial flow volumes of the common femoral vessels and digital photoplethysmography (DPPG) were assessed before and 3 (n=129) and 12 months (n=71) after EVLT. RESULTS: EVLT was performed with an energy fluence of 22.5 J/cm2, resulting in an occlusion rate of 98.4%. Duplex recurrence rates were 9.4% at 3-month and 15.5% at 12-month follow-up. VAFI significantly improved from 1.395 to 1.242 and 1.167 (p<.001) 3 and 12 months after EVLT. Venous refilling time (DPPG) accordingly increased from 20.0 to 36.9 seconds (p<.001) 3 months postoperatively. CONCLUSION: EVLT improves hemodynamic alterations in people with incompetent GSVs as demonstrated using VAFI and DPPG. VAFI might be a suitable diagnostic tool to quantify venous hemodynamics in people with varicose veins. The authors have indicated no significant interest with commercial supporters. PMID- 20961351 TI - Use of physician assistants in Mohs micrographic surgery: a survey of fellowship trained Mohs micrographic surgeons. AB - BACKGROUND: An increasing number of dermatologists are using physician assistants (PAs) in their practices. A lack of information regarding the use of PAs in Mohs micrographic surgery (MMS) served as the driving force for this research. OBJECTIVES: To quantify the extent to which Mohs surgeons are using PAs in MMS. METHODS: Five hundred seventy-six fellows of the American College of Mohs Surgery were sent surveys in the mail in January 2009. The survey was focused on what percentage of Mohs surgeons are using PAs and how those PAs are being used. RESULTS: One hundred forty-three of the 576 surgeons surveyed (24.8%) responded; 43 of those (30.1%) currently employed one or more PAs; and of those 43, 15 (34.9%) reported that PAs in their practice perform preoperative consults, 25 (58.1%) reported that PAs perform postoperative follow-up, 18 (41.9%) reported that PAs were participating in some aspect of repairs, and 35 (81.4%) reported that PAs were seeing general dermatology patients. CONCLUSION: Mohs surgeons are using PAs for perioperative care, as well as seeing general dermatology patients. A smaller percentage of Mohs surgeons are using PAs to perform portions of MMS or the consequent repairs. PMID- 20961352 TI - Microcystic lymphatic malformation (lymphangioma circumscriptum) treated using a minimally invasive technique of radiofrequency ablation and sclerotherapy. AB - BACKGROUND: Therapeutic interventions for microcystic lymphatic malformation (MLM), including surgical resection, have historically been difficult and frustrating because of a high recurrence rate due to multifocal lesions and failure to address the deeper component and excessive morbidity associated with excision of extensive lesions. MATERIALS AND METHODS: This study represents a retrospective analysis of response to treatment of 14 consecutive patients with MLM. The first four patients were treated with sclerotherapy alone using 3% polidocanol. The next 10 patients were treated with the combination technique of radiofrequency ablation (RFA) and sclerotherapy. The sessions were repeated at monthly intervals until complete clearance. RESULTS: Nine of 10 patients who were treated with the combination technique achieved near-complete clearance. There were minimal intra- and postoperative sequelae. The patients treated with the combination technique also achieved faster results. CONCLUSION: RFA ablates the lesions and achieves hemostasis while the sclerosant injected in and around the lesion reaches the deeper vascular lesions, preventing recurrence. The minimally invasive combination technique of RFA with sclerotherapy is a modality that can be used in the treatment of extensive microcystic malformations where surgical excision would lead to extensive scarring. PMID- 20961353 TI - Squamous cell carcinoma developing in Jadassohn's sebaceous nevus: case report and review of the literature. PMID- 20961354 TI - Mixed cell granulomatous panniculitis on the cheek due to injection of a solution containing phosphatidylcholine and deoxycholate. PMID- 20961355 TI - Alopecia of the scalp after ineffective treatment of Bowen's disease using red light 5-aminolevulinic acid photodynamic therapy: two case reports. PMID- 20961356 TI - Punctate leucoderma after 1,064-nm Q-switched neodymium-doped yttrium aluminum garnet laser with low-fluence therapy: is it melanocytopenic or melanopenic? PMID- 20961357 TI - Simple onycholysis: an attempt at surgical intervention. PMID- 20961358 TI - Does laser history have to repeat itself? Laser resurfacing and the risk/recovery/result ratio. PMID- 20961359 TI - Additional commentary on "addition of lidocaine to fillers". PMID- 20961360 TI - The phenomenon of unexpected hair growth. PMID- 20961361 TI - Nationwide survey and establishment of a clinical database for gastrointestinal surgery in Japan: Targeting integration of a cancer registration system and improving the outcome of cancer treatment. AB - As there was no nationwide database for gastrointestinal surgery in Japan at the time, in 2006, a Clinical Database Committee was established in the Japanese Society of Gastrointestinal Surgery (JSGS) to create a clinical database in Japan. The Committee first organized preliminary nationwide Japanese surveys in gastrointestinal surgery in 2006 and 2007. Data from more than 770,000 patients were accumulated from these web-based surveys, including 333,627 patients in 1039 institutions in 2006 and 440,230 patients in 1464 institutions in 2007. The mortality rate was stratified by organ, surgical procedure and hospital volume without using risk-adjustment techniques. The overall mortality rate was 0.95% in the 2006 survey and 0.92% in the 2007 survey. The organ-based analysis found that the mortality rates were almost similar in 2006 and 2007. Hospital volume influenced the mortality rate in six major surgical procedures, namely esophagectomy, gastrectomy, total gastrectomy, low anterior rectal resection, hepatic resection and pancreaticoduodenectomy. A risk reduction of 30-80% was noted in each surgical procedure, at least in our non-risk-adjusted analysis, in hospitals with a high volume of operations. These preliminary surveys indicate that hospital volume might influence the mortality rate after major abdominal surgery. Further analysis using risk-adjustment techniques should be conducted to understand the specific contribution of hospital volume to surgical mortality. A nationwide database of patients who have undergone gastrointestinal surgery and risk-adjustment analysis of the data are currently planned in Japan. PMID- 20961362 TI - Evaluation of MSX2 mRNA in brush cytology specimens distinguished pancreatic carcinoma from chronic pancreatitis. AB - It is difficult to distinguish pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) when stricture is present in the pancreatic duct. Endoscopic brushing cytology is a convenient method for investigating strictures in the pancreatic duct, however, the diagnostic sensitivity of this method for PDAC is reported to be low (40-70%). Recently, we revealed that MSX2 is frequently expressed in PDAC cells but not in normal cultured pancreatic duct or stellate cells. Thus, we analyzed MSX2 expression levels in brushing samples to examine whether this would differentiate PDAC from CP. Cytologic brushing specimens were obtained from pancreatic duct strictures during endoscopic retrograde cholangiopancreaticography in 82 patients. The brushing fluid was subjected to cytological diagnosis and RNA extraction. The expression level of MSX2 was evaluated by one-step real-time RT-PCR. MSX2 expression levels were significantly higher in PDAC than in CP (P = 0.0000007), and the expression level was associated with positive cytology (P = 0.013). The sensitivity, specificity, and diagnostic accuracy for PDAC of cytology and MSX2 expression in ductal strictures were: 47.4%, 100%, and 63.4%, and 73.7%, 84.0%, and 79.3%, respectively. The sensitivity and accuracy of MSX2 expression levels for diagnosis were much higher than those of cytology. This suggests that the evaluation of MSX2 levels in endoscopic retrograde cholangiopancreaticography brushing samples would be useful for distinguishing PDAC from CP. PMID- 20961363 TI - Potential of ceragenin CSA-13 and its mixture with pluronic F-127 as treatment of topical bacterial infections. AB - AIMS: Ceragenin CSA-13 is a synthetic mimic of cationic antibacterial peptides, with facial amphiphilic morphology reproduced using a cholic acid scaffold. Previous data have shown that this molecule displays broad-spectrum antibacterial activity, which decreases in the presence of blood plasma. However, at higher concentrations, CSA-13 can cause lysis of erythrocytes. This study was designed to assess in vitro antibacterial and haemolytic activity of CSA-13 in the presence of pluronic F-127. METHODS AND RESULTS: CSA-13 bactericidal activity against clinical strains of bacteria associated with topical infections and in an experimental setting relevant to their pathophysiological environment, such as various epithelial tissue fluids and the airway sputum of patients suffering from cystic fibrosis (CF), was evaluated using minimum inhibitory and minimum bactericidal concentration (MIC/MBC) measurements and bacterial killing assays. We found that in the presence of pluronic F-127, CSA-13 antibacterial activity was only slightly decreased, but CSA-13 haemolytic activity was significantly inhibited. CSA-13 exhibits bacterial killing activity against clinical isolates of Staphylococcus aureus, including methicillin-resistant strains, Pseudomonas aeruginosa present in CF sputa, and biofilms formed by different Gram (+) and Gram (-) bacteria. CSA-13 bactericidal action is partially compromised in the presence of plasma, but is maintained in ascites, cerebrospinal fluid, saliva, and bronchoalveolar lavage fluid. The synergistic action of CSA-13, determined by the use of a standard checkerboard assay, reveals an increase in CSA-13 antibacterial activity in the presence of host defence molecules such as the cathelicidin LL-37 peptide, lysozyme, lactoferrin and secretory phospholipase A (sPLA). CONCLUSION: These results suggest that CSA-13 may be useful to prevent and treat topical infection. SIGNIFICANCE AND IMPACT OF THE STUDY: Combined application of CSA-13 with pluronic F-127 may be beneficial by reducing CSA-13 toxicity. PMID- 20961364 TI - Molecular characterization of erm(B)- and mef(E)-mediated erythromycin-resistant Streptococcus pneumoniae in China and complete DNA sequence of Tn2010. AB - AIMS: To characterize the erm(B)- and mef(E)-mediated erythromycin-resistant Streptococcus pneumoniae clinical isolates obtained from ten hospitals located different cities in China. METHODS AND RESULTS: Totally 83 S. pneumoniae were collected, and eighteen representative strains of 66 strains that exhibited erythromycin resistance were used for further characterization by antibiograms, serotyping, PFGE, MLST, DNA sequencing of the macrolide-resistance elements and mapping of the elements on the chromosome. Twelve isolates showed a high-level resistance to erythromycin, and six other isolates showed a low-level resistance to erythromycin. Thirteen isolates harboured a Tn2010 transposon (26.4 kbp) encoding the erm(B), tet(M) and mef(E) genes and were classified into three types by Tn2010 structures. The remaining five isolates harboured a Tn6002 transposon (20.9 kbp) encoding the erm(B) and tet(M) genes and were classified into three types by Tn6002 locations on the chromosome. Three of the Tn6002 elements were located within the Tn5252-like element, implying that these composed a large mobile element. The MLST analyses showed that several clones had been disseminated and that the CC271 strains carrying the Tn2010 element expressing the high-level resistance to erythromycin were predominant in China. Four new MLST strains, which were designated as ST3262, ST3263, ST3397 and ST3398 were also identified. CONCLUSIONS: The erythromycin resistance determinant of S.pneumoniae that had been isolated in China was located in Tn2010 or the Tn6002 element and several clones had been disseminated, and the CC271 strains carrying the Tn2010 element expressing the high-level resistance to erythromycin were predominant in China. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first molecular analysis of erythromycin-resistant Streptococcus pneumoniae clinical isolates in China, and the first report of the complete nucleotide sequence of Tn2010 (26,390 bp). PMID- 20961365 TI - Different mutations in the oafA gene lead to loss of O5-antigen expression in Salmonella enterica serovar Typhimurium. AB - AIMS: To analyse genetic changes in the oafA gene explaining the loss of O5 antigen expression in Salmonella Typhimurium and Salm. 4,[5],12:i:-. METHODS AND RESULTS: The oafA gene in 52 O5-antigen-negative and 77 O5-antigen-positive Salm. Typhimurium (N = 47) and Salm. 4,[5],12:i:- (monophasic Salm. Typhimurium strains, N = 82) was investigated by a combination of PCR screening and DNA sequencing to identify mutations leading to the suppression of the O5-antigen. Various DNA sequence changes within the open reading frame (ORF) of oafA in O5 antigen-negative strains could be identified. In 77% of the O5-antigen-negative strains, a 7-bp deletion of a duplicated sequence within the functional oafA gene led to a frameshift in the ORF. In four strains, an IS4 element and in two, an IS1 element was inserted at different positions. Four other strains carried at different positions single base pair substitutions causing a premature stop codon. Finally, in two strains, a deletion of the oafA 3'end of undetermined size was responsible for the lack of O5-antigen expression. In none of the strains investigated, the complete ORF of oafA was deleted. Primers were designed and used to detect the most prominent variants. CONCLUSIONS: O5-antigen-negative Salm. Typhimurium and Salm. 4,[5],12:i:- strains carry an oafA pseudogene caused by different genetic events indicating that there is a selection for oafA mutations leading to the loss of O5-antigen expression. SIGNIFICANCE AND IMPACT OF THE STUDY: The loss of O5-antigen expression may be an example of a common evolutionary mechanism to escape host defence or to adapt to environmental changes. The data are the basis for the development of diagnostic PCR assays for the differentiation of O5-antigen-positive and O5-antigen-negative Salm. Typhimurium and its monophasic (Salm. 4,[5],12:i-) strains. PMID- 20961366 TI - Liver resections in metastatic gastric cancer. AB - BACKGROUND: The 5-year survival of patients receiving standard-of-care chemotherapy for metastatic gastric cancer (MGC) to the liver is <2%. This review examines the published data on liver resections for MGC and analyses the rationale for potentially aggressive surgical management. METHODS: A search of the PubMed and Scopus databases was used to identify studies published in English from 1990 to 2009 that reported on 10 or more patients who underwent liver resections for MGC. All available clinicopathologic data were analysed. In particular, we examined longterm survival and the characteristics of individuals surviving for >5 years. RESULTS: Nineteen studies reported on 436 patients. Median 5-year survival was 26.5% (range: 0-60%). Overall, 13.4% (48/358) of patients were alive at 5 years and studies with extended follow-up reported that 4.0% (7/174) of patients survived for >10 years. Overall in-hospital mortality was 3.5% (12/340 patients); however, the median mortality rate across the studies was 0%. No prognostic factor was found to be consistently statistically significant across these small studies. CONCLUSIONS: Despite the limitations of any analysis of retrospective data for highly selected groups of patients, it would appear that liver resections combined with systemic therapy for MGC can result in prolonged survival. PMID- 20961368 TI - Utility of preoperative imaging in evaluating colorectal liver metastases declines over time. AB - OBJECTIVES: Reports on the sensitivity and accuracy of contrast-enhanced helical computed tomography (HCT) in the preoperative evaluation of colorectal liver metastases (CLM) have been conflicting. Few studies have controlled for and reported on the time interval between HCT and eventual surgery. METHODS: A multi institution, retrospective review of consecutive patients who underwent hepatic resection for CLM from January 1999 to September 2004 was conducted. Data regarding lesion characteristics and resectability were extracted from radiology reports, operative findings and histopathological records. Findings in HCT were evaluated according to their sensitivity for detecting CLM and ability to predict resectability. RESULTS: A total of 217 consecutive patients who underwent hepatic resection for CLM were identified. The overall sensitivity of HCT for detection of CLM was 83.2%. Prolonged time between imaging and surgery was a negative predictor for HCT sensitivity in univariate and multivariate analysis (P < 0.001). In predicting resectability, preoperative HCT was accurate 77.0% of the time. The time interval to surgery was negatively correlated with HCT prediction accuracy in univariate and multivariate analyses (P < 0.001). CONCLUSIONS: The utility of HCT as a preoperative tool to evaluate CLM is inversely proportional to the time interval between imaging and surgery. This may explain conflicting reports of the accuracy of HCT in the current literature. PMID- 20961367 TI - Surgical management of acute pancreatitis in Italy: lessons from a prospective multicentre study. AB - OBJECTIVE: This study aimed to evaluate the surgical treatment of acute pancreatitis in Italy and to assess compliance with international guidelines. METHODS: A series of 1173 patients in 56 hospitals were prospectively enrolled and their data analysed. RESULTS: Twenty-nine patients with severe pancreatitis underwent surgical intervention. Necrosectomy was performed in 26 patients, associated with postoperative lavage in 70% of cases. A feeding jejunostomy was added in 37% of cases. Mortality was 21%. Of the patients with mild pancreatitis, 714 patients with a biliary aetiology were evaluated. Prophylactic treatment of relapses was carried out in 212 patients (36%) by cholecystectomy and in 161 using a laparoscopic approach. Preoperative endoscopic retrograde cholangiopancreatography was associated with cholecystectomy in 83 patients (39%). Forty-seven patients (22%) were treated at a second admission, with a median delay of 31 days from the onset of pancreatitis. Eighteen patients with severe pancreatitis underwent cholecystectomy 37.9 days after the first admission. There were no deaths. DISCUSSION: The results indicate poor compliance with published guidelines. In severe pancreatitis, early surgical intervention is frequently performed and enteral feeding is seldom used. Only a small number of patients with mild biliary pancreatitis undergo definitive treatment (i.e. cholecystectomy) within 4 weeks of the onset of pancreatitis. PMID- 20961369 TI - Delayed gastric emptying after pylorus-preserving pancreaticoduodenectomy: validation of International Study Group of Pancreatic Surgery classification and analysis of risk factors. AB - OBJECTIVES: This study evaluates the incidence and clinical features and associated risk factors of delayed gastric emptying (DGE) after pancreaticoduodenectomy, employing the International Study Group of Pancreatic Surgery (ISGPS) consensus definition. METHODS: Demographic, pathological and surgical details for 260 consecutive patients who underwent pylorus-preserving pancreaticoduodenectomy at a single institution were analysed using univariate and multivariate models. RESULTS: Postoperative complications occurred in 108 (41.5%) and DGE was diagnosed in 36 (13.8%) of 260 patients. Among the 36 DGE patients, 16 had grade A, 18 grade B and two grade C DGE. Resumption of a solid diet (P < 0.001), time to passage of stool (P= 0.002) and hospital discharge (P < 0.001) occurred later in DGE patients. The need for total parenteral nutrition was significantly higher in DGE grade B/C patients (P < 0.001). In the univariate analysis, abdominal collections (P<= 0.001), pancreatic fistula (PF) grades B and C (P < 0.001), biliary fistula (P= 0.002), pulmonary complications (P < 0.001) and sepsis (P= 0.002) were associated with DGE. Only abdominal collections (P= 0.009), PF grade B/C (P < 0.001) and sepsis (P= 0.024) were associated with clinically relevant DGE. In the multivariate analysis, PF grade B/C (P= 0.004) and biliary fistula (P= 0.039) were independent risk factors for DGE. CONCLUSIONS: The ISGPS classification and grading systems correlate well with the clinical course of DGE and are feasible for patient management. The principal risk factors for DGE seem to be pancreatic and biliary fistulas. PMID- 20961370 TI - Morphometric analysis of caudate veins for advanced liver surgery. AB - BACKGROUND: Accurate knowledge of the surgical anatomy of the caudate lobe is indispensable in the performance of liver surgery. Although previous cast studies have provided much useful overall information about the locations of the caudate veins, little is known about how to establish the exact locations of the caudate and short hepatic veins prior to surgery. OBJECTIVES: This study was conducted as a practical morphometric analysis of the caudate veins using preoperative enhanced computed tomography (CT) and intraoperative ultrasound (IOUS). METHODS: From July 2003 to October 2005, 116 donor hepatectomies were performed for adult living donor liver transplantation. The numbers and locations of visible caudate veins were examined pre- and intraoperatively using CT and IOUS. RESULTS: In the 116 patients, a total of 152 caudate veins were detected, which were classified as being of either typical (n= 135) or non-typical (n= 17) type. One caudate vein was detectable in 83 patients (72%), two in 30 patients (26%) and three in three patients (3%). A total of 67% of caudate veins detected by IOUS and 70% detected by CT were located on the ventral 60 degrees of the inferior vena cava (IVC). The remaining veins were scattered on both lateral sides. CONCLUSIONS: Preoperative CT and IOUS were useful in providing morphometric information of sizable caudate veins. Precise information on these veins is essential for the safe dissection of the caudate lobe from the IVC in advanced liver surgery. PMID- 20961371 TI - Evidence of aberrant lipid metabolism in hepatitis C and hepatocellular carcinoma. AB - OBJECTIVES: Lipids are linked to many pathological processes including hepatic steatosis and liver malignancy. This study aimed to explore lipid metabolism in hepatitis C virus (HCV) and HCV-related hepatocellular carcinoma (HCC). METHODS: Serum lipids were measured in normal, HCV and HCV-HCC patients. Whole-genome microarray was performed to identify potential signature genes involved in lipid metabolism characterizing normal vs. HCV vs. HCV-HCC conditions. RESULTS: Serum cholesterol was significantly reduced in HCV and HCV-HCC patients compared with normal controls, whereas there was no difference in glucose and triglycerides. Microarray analysis identified 224 probe sets with known functional roles in lipid metabolism (anova, 1.5-fold, P <= 0.001). Gene-mediated fatty acid (FA) de novo synthesis and uptake were upregulated in HCV and this upregulation was further enhanced in HCC. Genes involved in FA oxidation were downregulated in both the HCV and HCC groups. The abnormality of cholesterol metabolism in HCV was associated with downregulation of genes involved in cholesterol biosynthesis, absorption and transportation and bile acid synthesis; this abnormality was further intensified in HCC. CONCLUSIONS: Our data support the notion that HCV related lipid metabolic abnormalities may contribute to hepatic steatosis and the development of cancer. Identification of these aberrations would stratify patients and improve treatment algorithms. PMID- 20961372 TI - Longterm follow-up after transarterial chemotherapy for hepatocellular carcinoma in a Scandinavian centre. AB - BACKGROUND: Transarterial chemotherapy infusion (TAI) with lipiodol is a palliative treatment for hepatocellular carcinoma. The aim of this study was to describe the outcomes of TAI from a single scandinavian centre between 1995 to 2008. METHODS: The study is a retrospective analyse of prospectively collected data. TAI (doxorubicin, 50 mg with lipiodol) was administrated every 6 weeks. After 5 treatments, a CT scan was performed, and if the disease was stable, (RECIST score) treatment was continued. RESULTS: 57 patients with HCC were treated with TAI. Median age; 72 years (52-84), 41 (71%) men. 52 (91%) had Child Pugh score A, and 5 (9%) had Child-Pugh B. Nine (16%) patients had a BCLC score A, 19 (33%) B, 29 (51%) C, while none was classified as BCLC D. Twenty nine (51%) patients had a tumour size >= 10 cm. In total 254 treatments were performed, a median of 4 (1-20) per patient. Treatment mortality was 0%. In 30 (53%) patients the treatment strategy was not completed due to deteriorating clinical conditions. Median survival was 17 months (2-108), 2, 3, and 5-years survival was 34%, 22%, and 13%, respectively. Patients that responded to treatment (n = 23) had a median survival of 26 (13-108) months compared to 8 (2-48) months for those not fulfilling the treatment plan, p < 0.05. Tumour size >= 10 cm, AFP >= 400 ug/l, and Child-Pugh class B or C were negative prognostic factors for survival, p < 0.05. CONCLUSIONS: The 5 year survival was 13%, and median survival 17 months. Treatment mortality was 0%. Patients that responded to treatment (40%) had a median survival of 26 months. TAI provides good palliation but selection of patients is crucial. PMID- 20961373 TI - Increasing time delay from presentation until surgical referral for hepatobiliary malignancies. AB - BACKGROUND: Studies have shown that delayed treatment of several non hepatobiliary (HB) malignancies is associated with adverse effects on disease progression and survival. Delayed treatment of HB malignancies has not been thoroughly investigated. METHODS: We performed a retrospective institutional review of patients referred to the Hepatobiliary Surgery Service at Beth Israel Deaconess Medical Center (BIDMC) for hepatobiliary malignancies from 2002 to 2008. Primary outcomes included the time delays (TD) in patient workup. Secondary outcomes were reasons for delay as well as disparities in TD based on demographic factors. RESULTS: Multivariate-adjusted linear regression showed a significant trend of increasing time from presentation until referral to a HB surgeon over the 7-year period (P= 0.001). There were no differences in TD by gender, age or education level. Multivariate-adjusted linear regression showed a significant trend of increasing number of imaging tests performed prior to referral [computerized tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and ultrasound and endoscopic ultrasound (US/EUS)] (P < 0.001). Multivariate-adjusted linear regression in resectable patients showed a significant difference in overall length of survival in those with a TD1 > 30 days compared with those with a TD1 (TD from presentation until referral) <30 days (P = 0.042). CONCLUSIONS: Delays were associated with an increase in imaging studies and delays adversely affect survival in resected patients. Referring physicians are encouraged to expedite the evaluation and early referral of all patients to an HB surgeon for evaluation and treatment. PMID- 20961374 TI - Resection margin in laparoscopic hepatectomy: a comparative study between wedge resection and anatomic left lateral sectionectomy. AB - BACKGROUND: Experience from open hepatectomy shows that anatomic liver resection achieves a better resection margin than wedge resection. In recent years, laparoscopic hepatectomy has increasingly been performed in patients with liver pathology including malignant lesions. Wedge resection (WR) and left lateral sectionectomy (LLS), which also represent non-anatomic and anatomic resection respectively, are the two most common types of laparoscopic hepatectomy performed. The aim of the present study was to compare the two types of laparoscopic hepatectomy with emphasis on resection margin. METHODS: Between November 2003 and July 2009, 44 consecutive patients who underwent laparoscopic hepatectomy were identified and retrospectively reviewed. The WR and LLS group of patients were compared in terms of operative outcomes, pathological findings, recurrence patterns and survival. RESULTS: Out of the 44 patients, 21 underwent LLS and 23 a WR. The two groups of patients were comparable in demographics. The two groups did not differ in conversion rate, blood loss, blood transfusion, mortality, morbidity and post-operative length of stay. The LLS group patients had significantly larger liver lesions, wider resection margin and less sub centimetre margins. In patients with malignant liver lesions, there was no difference between the two groups in incidence of intra-hepatic recurrence and 3 year overall and disease-free survival. CONCLUSION: Operative outcomes are similar between laparoscopic WR and LLS. However, WR is less reliable than LLS in achieving a resection margin of more than 1 cm. Larger studies involving more patients with longer follow-up are warranted to determine the impact of the resection margin on intra-hepatic recurrence and survival. PMID- 20961375 TI - Pre-sorting endosomal transport of the GPI-anchored protein, CD59, is regulated by EHD1. AB - EHD1 regulates the trafficking of multiple receptors from the endocytic recycling compartment (ERC) to the plasma membrane. However, the potential role of EHD1 in regulating the family of glycosylphosphatidylinositol-anchored proteins (GPI-APs) has not been determined. Here we demonstrate a novel role for EHD1 in regulating the trafficking of CD59, an endogenous GPI-AP, at early stages of trafficking through the endocytic pathway. EHD1 displays significant colocalization with newly internalized CD59. Upon EHD1 depletion, there is a rapid Rab5-independent coalescence of CD59 in the ERC region. However, expression of an active Arf6 mutant (Q67L), which traps internalized pre-sorting endosomal cargo in phosphatidylinositol(4,5)-bisphosphate enriched vacuoles, prevents this coalescence. It is of interest that sustained PKC activation leads to a similar coalescence of CD59 at the ERC, and treatment of EHD1-depleted cells with a PKC inhibitor (Go6976) blocked this rapid relocation of CD59. However, unlike sustained PKC activation, EHD1 depletion does not induce the translocation of PKCalpha to ERC. The results presented herein provide evidence that EHD1 is involved in the control of CD59 transport from pre-sorting endosomes to the ERC in a PKC-dependent manner. However, the mechanisms of EHD1-induced coalescence of CD59 at the ERC differ from those induced by sustained PKC activation. PMID- 20961376 TI - Sexually transmitted bacteria affect female cloacal assemblages in a wild bird. AB - Ecology Letters (2010) 13: 1515-1524 ABSTRACT: Sexual transmission is an important mode of disease propagation, yet its mechanisms remain largely unknown in wild populations. Birds comprise an important model for studying sexually transmitted microbes because their cloaca provides a potential for both gastrointestinal pathogens and endosymbionts to become incorporated into ejaculates. We experimentally demonstrate in a wild population of kittiwakes (Rissa tridactyla) that bacteria are transmitted during copulation and affect the composition and diversity of female bacterial communities. We used an anti insemination device attached to males in combination with a molecular technique (automated ribosomal intergenic spacer analysis) that describes bacterial communities. After inseminations were experimentally blocked, the cloacal communities of mates became increasingly dissimilar. Moreover, female cloacal diversity decreased and the extinction of mate-shared bacteria increased, indicating that female cloacal assemblages revert to their pre-copulatory state and that the cloaca comprises a resilient microbial ecosystem. PMID- 20961377 TI - British HIV Association guidelines for antiretroviral treatment of HIV-2-positive individuals 2010. PMID- 20961378 TI - Nuclear envelope alterations generate an aging-like epigenetic pattern in mice deficient in Zmpste24 metalloprotease. AB - Mutations in the nuclear envelope protein lamin A or in its processing protease ZMPSTE24 cause human accelerated aging syndromes, including Hutchinson-Gilford progeria syndrome. Similarly, Zmpste24-deficient mice accumulate unprocessed prelamin A and develop multiple progeroid symptoms, thus representing a valuable animal model for the study of these syndromes. Zmpste24-deficient mice also show marked transcriptional alterations associated with chromatin disorganization, but the molecular links between both processes are unknown. We report herein that Zmpste24-deficient mice show a hypermethylation of rDNA that reduces the transcription of ribosomal genes, being this reduction reversible upon treatment with DNA methyltransferase inhibitors. This alteration has been previously described during physiological aging in rodents, suggesting its potential role in the development of the progeroid phenotypes. We also show that Zmpste24-deficient mice present global hypoacetylation of histones H2B and H4. By using a combination of RNA sequencing and chromatin immunoprecipitation assays, we demonstrate that these histone modifications are associated with changes in the expression of several genes involved in the control of cell proliferation and metabolic processes, which may contribute to the plethora of progeroid symptoms exhibited by Zmpste24-deficient mice. The identification of these altered genes may help to clarify the molecular mechanisms underlying aging and progeroid syndromes as well as to define new targets for the treatment of these dramatic diseases. PMID- 20961381 TI - Effectiveness of mechanical tongue cleaning on breath odour and tongue coating: a systematic review. AB - BACKGROUND: The objective of this review was to summarize the available evidence regarding the effects of mechanical tongue cleaning compared with no mechanical tongue cleaning on breath odour and tongue coating (TC). METHODS: PubMed-MEDLINE, EMBASE and Cochrane-CENTRAL were searched to identify potentially relevant studies. The inclusion criteria included the following: randomized controlled clinical trials (RCTs) or controlled clinical trials (CCTs) conducted in humans in good general health (no systemic disorders) and a patient age of >=17 years. For the intervention, we considered tongue cleaning [the use of a tongue scraper (TS) or tongue brush (TB)] and for the control, brushing only (B) groups. Clinical parameters such as volatile sulphur compound concentration, organoleptic scores and TC were the outcome variables of interest. Study selection, quality assessment and data extraction were carried out by two independent reviewers. RESULTS: After screening of the titles and abstracts and subsequent full text reading of the potential papers, we identified five publications that met the eligibility criteria and provided seven experiments. The five studies consisted of three RCTs and two CCTs. All experiments show a positive effect of mechanical tongue cleaning in addition to toothbrushing on various parameters of oral malodour. CONCLUSIONS: This review demonstrated that mechanical approaches, such as tongue brushing or tongue scraping to clean the dorsum of the tongue, have the potential to successfully reduce breath odour and TC. However, data concerning the effect of mechanical tongue cleaning on chronic oral malodour (halitosis) are insufficient. PMID- 20961382 TI - The plaque inhibitory effect of a CPC mouthrinse in a 3-day plaque accumulation model - a cross-over study. AB - OBJECTIVE: To test the plaque inhibitory effect of an experimental 0.07% cetylpyridinium chloride (CPC) mouthrinse in a 3-day plaque accumulation model in a cross-over design. MATERIAL AND METHODS: A total of 30 subjects (non-dental students), >=18 years of age, were randomly assigned to use one of three different mouthrinses three times a day. After 3 days, the subjects returned for the clinical assessments and received a questionnaire to evaluate their attitude towards the product used by them. The cross-over procedure was repeated twice to have all subjects use all products. RESULTS: A total of 29 subjects completed the protocol and this resulted in a statistically significant difference between the three groups (P < 0.001) with regard to plaque scores. Over three sessions, the mean plaque scores were 2.17 for the control product, 1.14 for the CPC group and 1.12 for the 0.1% Hexetidine product (positive control). Results of the questionnaire show that, compared with hexetidine, the taste of the CPC was appreciated better, and less oral sensations were observed following rinsing. CONCLUSION: The CPC mouthrinse proved to be effective in inhibiting 'de novo' plaque formation to an extent similar to that of a 0.1% hexetidine product. Compared with hexetidine, the taste of the CPC was appreciated better and less oral sensations were observed following rinsing. PMID- 20961383 TI - Parotid gland swelling following mouthrinse use. AB - BACKGROUND: Unilateral or bilateral swelling of the parotid gland is a reported side effect of rinsing the mouth with chlorhexidine. Although the incidence rate is extremely low, there have been several case reports on this topic and the authors of these reports have suggested several explanations for the mechanism of this complication. METHODS: In this report, two cases of parotid gland swelling are discussed. Both patients developed unilateral parotid swelling following the use of a mouthwash, case 1 after using a chlorhexidine mouthwash following flap surgery and case 2 after using a hexetidine mouthwash in an approved clinical trial that was testing different mouthwashes. RESULTS: In both of the cases, differential diagnoses were made to explain the cause of the parotid swelling. However, discontinuing use of the product resulted in an eventual complete resolution of symptoms in both patients. CONCLUSIONS: Swelling of the parotid gland following use of a mouthwash has previously been reported, although previous reports found this side effect only in patients who used chlorhexidine mouthwashes. This complication has therefore been informally linked to chlorhexidine. The present case report questions this hypothesis and suggests that parotid gland swelling may not be related to the type of mouthwash used, but may instead be a consequence of the rinsing action itself. PMID- 20961379 TI - Comparing the yeast retrograde response and NF-kappaB stress responses: implications for aging. AB - The mitochondrial retrograde response has been extensively described in Saccharomyces cerevisiae, where it has been found to extend life span during times of mitochondrial dysfunction, damage or low nutrient levels. In yeast, the retrograde response genes (RTG) convey these stress responses to the nucleus to change the gene expression adaptively. Similarly, most classes of higher organisms have been shown to have some version of a central stress-mediating transcription factor, NF-kappaB. There have been several modifications along the phylogenetic tree as NF-kappaB has taken a larger role in managing cellular stresses. Here, we review similarities and differences in mechanisms and pathways between RTG genes in yeast and NF-kappaB as seen in more complex organisms. We perform a structural homology search and reveal similarities of Rtg proteins with eukaryotic transcription factors involved in development and metabolism. NF kappaB shows more sophisticated functions when compared to RTG genes including participation in immune responses and induction of apoptosis under high levels of ROS-induced mitochondrial and nuclear DNA damage. Involvement of NF-kappaB in chromosomal stability, coregulation of mitochondrial respiration, and cross talk with the TOR (target of rapamycin) pathway points to a conserved mechanism also found in yeast. PMID- 20961384 TI - Safety and efficacy of two manual toothbrushes. AB - OBJECTIVE: The purpose of this study was to test the efficacy and safety of a newly designed multi-level manual toothbrush (Profit-Haije-Brush) compared with a control flat-trimmed manual reference toothbrush from the American Dental Association (ADA). MATERIAL AND METHODS: For this study, 36 healthy subjects without previous experience in the use of the Profit-Haije-Brush (PHB) were selected. Subjects were given a period of 2 weeks to become familiar with both types of brushes and were instructed to use them on alternate days for 2 min twice daily. Prior to their visit, subjects refrained from all oral hygiene procedures for 48 h. Prebrushing plaque and gingival abrasion scores were assessed. Subsequently, two randomly chosen contra-lateral quadrants were brushed with one of both brushes and the other two quadrants with the alternate brush. Subjects were supervised during their 2-min brushing exercise. After brushing, plaque and gingival abrasion were re-assessed. A questionnaire was filled out to investigate the subjects' attitudes towards both brushes. RESULTS: The overall mean prebrushing PI was 2.47 for the PHB and 2.44 for the ADA. The reduction in PI was 1.32 and 1.23 respectively (P < 0.05). With regard to gingival abrasion the overall mean prebrushing scores were 4.57 (PHB) and 5.34 (ADA). Post-brushing scores were 13.49 and 13.77 for the PHB and ADA respectively. CONCLUSION: Statistically, the multi-level PHB was significantly more efficacious than the flat-trimmed ADA. However, the difference is clinically considered small and the amount of remaining plaque was not significantly different between brushes. No greater potential to cause gingival abrasion to the oral tissues was observed. PMID- 20961385 TI - Training rural women to improve access to oral health awareness programmes in remote villages in Nepal. AB - OBJECTIVES: Description of experiences and results of training rural women in Nepal to recognize basic oral health problems and to perform basic oral health promotion activities. METHODS: Rural women from different districts of Nepal were trained in a 1-day course in oral health promotion as part of a 4-month vocational skills programme targeted at them. Their knowledge about preventive oral care, their recognition of basic oral health problems and their ability to perform basic oral health education were assessed qualitatively and quantitatively before and after the course. RESULTS: From 2006 to 2009, 141 women from 30 mostly rural districts were trained. Following the educational intervention, an overall trend towards improvement of their oral health awareness and their knowledge was documented. They proved to be competent in oral health promotion activities, in demonstrating oral hygiene techniques and in recognizing basic oral health problems. They were able to organize oral health awareness programmes in their villages and acted as advocates for the benefits of fluoridated toothpaste. After 3 years, they educated 2100 other community members, with at least 4000 children participating in their oral health awareness programmes. CONCLUSION: A community-oriented educational intervention programme for rural women in basic oral health promotion activities could be a successful culturally sensitive means to support access to oral health awareness programmes for Nepalese people in remote areas. PMID- 20961387 TI - Changes in the professional domain of Dutch dental hygienists. AB - OBJECTIVE: This study's purpose was to compare the scope of practice of Dutch dental hygienists educated through a two- or three-year curriculum ('old curriculum dental hygienists' [OCDHs]) with that of hygienists educated through a new extended four-year curriculum leading to a bachelor's degree ('new curriculum dental hygienists' [NCDHs]). METHODS: In 2005 and 2007, we obtained surveys from 320 OCDHs and the first 67 NCDHs, respectively, in which respondents were asked to complete a questionnaire and score how often they performed certain dental tasks. By means of factor analysis, these tasks were grouped into nine activity groups and 5 remaining single activities. T-tests and Mann-Whitney U-tests were used to compare the scope of practice between OCDHs and NCDHs. RESULTS: NCDHs worked more often in dental offices (instead of being self-employed) and generally worked more hours per week than OCDHs. They performed more often tasks dealing with caries diagnosis and treatment and less often tasks dealing with prevention and periodontology. These differences were statistically significant. However, in dental offices the differences between OCDHs en NCDHs were far less pronounced. In those practices OCDHs performed dental sealants, small corrections of dentures and/or restoration and caries diagnosis during dental check-up no less frequently than NCDHs. CONCLUSIONS: Although prevention remains the core domain (or role) of all Dutch dental hygienists surveyed, the scope of practice substantially differed. This, however, depended not only on education, but also on type of practice. The new curriculum answers to and legitimates an already developed practice of task delegation. PMID- 20961386 TI - The effect of 1% chlorhexidine gel and 0.12% dentifrice gel on plaque accumulation: a 3-day non-brushing model. AB - AIM: The purpose of the study was to compare the effects of four treatments on 'de novo' plaque accumulation. Treatments included tray application of 1% chlorhexidine gel (CHX-Gel), 0.12% chlorhexidine dentifrice-gel (CHX-DFG), a regular dentifrice (RDF) tray application, or 0.2% chlorhexidine mouthwash (CHX MW) in a 3-day non-brushing model. MATERIAL AND METHODS: The study was designed as a single blind, randomized parallel clinical trial. After professional prophylaxis, subjects abstained from all other forms of oral hygiene during a 3 day non-brushing period. Subjects were randomly assigned to one of the four test groups (CHX-Gel, CHX-DFG, RDF applied in a fluoride gel tray or rinsing with a CHX-MW). After 3 days, the Quigley & Hein plaque index (PI) and Bleeding on Marginal Probing (BOMP) index was assessed. Subsequently, all subjects received a questionnaire to evaluate their attitude, appreciation and perception towards the products used employing a Visual Analogue Scale. RESULTS: After 3 days, the full mouth PI means were 0.88 for the CHX-gel regimen, 0.79 for CHX-MW, 1.16 for CHX DFG and 1.31 for the RDF regimen. The two dentifrices (CHX-DFG and RDF) were significantly less effective than the CHX-Gel or the CHX-MW. CONCLUSION: Within the limitations of the present 3-day non-brushing study design, it can be concluded that the effect of a 1% CHX-Gel application tray is significantly greater than that of 0.12% CHX-DFG or RDF in inhibiting plaque accumulation. The 1% CHX-Gel applied via a tray and 0.2% CHX-MW rinse were comparably effective. PMID- 20961388 TI - The erosive potential of jawbreakers, a type of hard candy. AB - OBJECTIVES: To explore the consumption pattern of a specific type of acidic solid candy, the so-called jawbreakers, by primary school children and determine the erosive potential of this type of candy in vivo. METHODS: A questionnaire about jawbreaker consumption was distributed among 10-12 year-old-children (n = 302). Subsequently, 19 healthy volunteers tested four different jawbreakers in vivo. Whole saliva was collected 5 min before, 3 min during and 11 min after consumption. Salivary flow rate and pH were determined. RESULTS: Two-thirds of the children reported a history of jawbreaker consumption, 18% during the last week. More than half of the children estimated their average time for consumption of one jawbreaker to be more than 15 min. In vivo, the jawbreakers induced 8.6 13.9-fold increase in salivary flow rate. Sucking on sour, jumbo and strawberry jawbreakers induced a drop in salivary pH to values below pH 5.5. During consumption of fireball jawbreakers, the intra-oral pH hardly changed. CONCLUSIONS: Jawbreakers are frequently used by children, who keep this candy in their mouth for a long time. Jawbreakers differ considerable in erosive potential, with sour and jumbo jawbreakers > strawberry jawbreaker >> fireball jawbreaker. This information is of use for dental hygienists counselling juvenile patients with dental erosion. PMID- 20961389 TI - The I4895T mutation in the type 1 ryanodine receptor induces fiber-type specific alterations in skeletal muscle that mimic premature aging. AB - The I4898T (IT) mutation in type 1 ryanodine receptor (RyR1), the Ca(2+) release channel of the sarcoplasmic reticulum (SR) is linked to a form of central core disease (CCD) in humans and results in a nonleaky channel and excitation contraction uncoupling. We characterized age-dependent and fiber-type-dependent alterations in muscle ultrastructure, as well as the magnitude and spatiotemporal properties of evoked Ca(2+) release in heterozygous Ryr1(I4895T/WT) (IT/+) knock in mice on a mixed genetic background. The results indicate a classical but mild CCD phenotype that includes muscle weakness and the presence of mitochondrial deficient areas in type I fibers. Electrically evoked Ca(2+) release is significantly reduced in single flexor digitorum brevis (FDB) fibers from young and old IT/+ mice. Structural changes are strongly fiber-type specific, affecting type I and IIB/IIX fibers in very distinct ways, and sparing type IIA fibers. Ultrastructural alterations in our IT/+ mice are also present in wild type, but at a lower frequency and older ages, suggesting that the disease mutation on the mixed background promotes an acceleration of normal age-dependent changes. The observed functional and structural alterations and their similarity to age associated changes are entirely consistent with the known properties of the mutated channel, which result in reduced calcium release as is also observed in normal aging muscle. In strong contrast to these observations, a subset of patients with the analogous human heterozygous mutation and IT/+ mice on an inbred 129S2/SvPasCrl background exhibit a more severe disease phenotype, which is not directly consistent with the mutated channel properties. PMID- 20961390 TI - Chromatin remodeling in the aging genome of Drosophila. AB - Chromatin structure affects the accessibility of DNA to transcription, repair, and replication. Changes in chromatin structure occur during development, but less is known about changes during aging. We examined the state of chromatin structure and its effect on gene expression during aging in Drosophila at the whole genome and cellular level using whole-genome tiling microarrays of activation and repressive chromatin marks, whole-genome transcriptional microarrays and single-cell immunohistochemistry. We found dramatic reorganization of chromosomal regions with age. Mapping of H3K9me3 and HP1 signals to fly chromosomes reveals in young flies the expected high enrichment in the pericentric regions, the 4th chromosome, and islands of facultative heterochromatin dispersed throughout the genome. With age, there is a striking reduction in this enrichment resulting in a nearly equivalent level of H3K9me3 and HP1 in the pericentric regions, the 4th chromosome, facultative heterochromatin, and euchromatin. These extensive changes in repressive chromatin marks are associated with alterations in age-related gene expression. Large-scale changes in repressive marks with age are further substantiated by single-cell immunohistochemistry that shows changes in nuclear distribution of H3K9me3 and HP1 marks with age. Such epigenetic changes are expected to directly or indirectly impinge upon important cellular functions such as gene expression, DNA repair, and DNA replication. The combination of genome-wide approaches such as whole-genome chromatin immunoprecipitation and transcriptional studies in conjunction with single-cell immunohistochemistry as shown here provide a first step toward defining how changes in chromatin may contribute to the process of aging in metazoans. PMID- 20961391 TI - Repeated oral administration of chitosan/DNA nanoparticles delivers functional FVIII with the absence of antibodies in hemophilia A mice. AB - BACKGROUND: Current treatment of hemophilia A is expensive and involves regular infusions of factor (F)VIII concentrates. The supply of functional FVIII is further compromised by the generation of neutralizing antibodies. Thus, the development of an alternative safe, cost effective, non-invasive treatment that circumvents immune response induction is desirable. OBJECTIVES: To evaluate the feasibility of oral administration of chitosan nanoparticles containing FVIII DNA to provide sustainable FVIII activity in hemophilia A mice. METHODS: Nanoparticles were characterized for morphology, DNA protection and transfection efficiency. Oral administration of nanoparticles containing canine FVIII in C57Bl/6 FVIII(-/-) hemophilia A mice was evaluated for biodistribution, plasma FVIII activity and phenotypic correction. Sustainable FVIII expression was elucidated after repeated nanoparticle administration. Immune responses to repeated oral nanoparticle administration were also investigated. RESULTS: Chitosan nanoparticles had a particle size range of 200-400 nm and protected DNA from endonuclease and pH degradation. In addition, nanoparticles transfected HEK 293 cells resulted in expression of eGFP, luciferase and FVIII. Hemophilia A mice that ingested chitosan nanoparticles demonstrated transient canine FVIII expression reaching > 100 mU 1 day after treatment, together with partial phenotypic correction. The delivered FVIII plasmid DNA was detected in the intestine and, to a lesser extent, in the liver. Importantly, repeated weekly administrations restored FVIII activity. Furthermore, inhibitors and non neutralizing FVIII antibodies were not detectable. CONCLUSIONS: Repeat oral administration of FVIII DNA formulated in chitosan nanoparticles resulted in sustained FVIII activity in hemophilic mice, and thus may provide a non-invasive alternative treatment for hemophilia A. PMID- 20961392 TI - Redox-generated isoprostanes are associated with residual platelet activity in aspirin-treated patients with stable coronary heart disease. AB - AIM: Insufficient platelet inhibition by low-dose aspirin is associated with poor prognosis in patients with coronary heart disease (CHD). We sought to investigate the prevalence of this phenomenon in patients with stable CHD and to study whether oxidative stress plays a role in its pathogenesis. METHODS AND RESULTS: We studied the platelet response to long-term (>= 6 months) low-dose (100 mg per day) aspirin in 130 consecutive patients with stable CHD (age 66 +/- 8 years, 83% male). Among a wide distribution of platelet responses to collagen, ADP, and arachidonic acid, the vast majority of patients in the highest tertile of residual platelet activity (defined as 'aspirin low-responders') were characterized by lack of platelet inhibition by aspirin in vitro, significantly although not completely suppressed platelet TXB2 production and COX-1 activity, and significantly higher urinary 8-iso-prostaglandin F(2alpha) excretion [186 (147-230) vs. 230 (188-318) pg per mg creatinine; median (IQR), P < 0.001; measured by GC-MS]. CONCLUSION: A relevant proportion of patients with CHD show insufficient platelet inhibition by low-dose aspirin. Oxidative stress and lipid peroxidation causing isoprostane formation may underlie inadequate platelet inhibition in an aspirin-insensitive manner in patients with cardiovascular disease. PMID- 20961393 TI - Flow rate and fibrin fiber alignment. PMID- 20961394 TI - CXCL4L1 inhibits angiogenesis and induces undirected endothelial cell migration without affecting endothelial cell proliferation and monocyte recruitment. AB - BACKGROUND AND OBJECTIVES: The non-allelic variant of CXCL4/PF4, CXCL4L1/PF4alt, differs from CXCL4 in three amino acids of the C-terminal alpha-helix and has been characterized as a potent anti-angiogenic regulator. Although CXCL4 structurally belongs to the chemokine family, it does not behave like a 'classical' chemokine, lacking significant chemotactic properties. Specific hallmarks are its angiostatic, anti-proliferative activities, and proinflammatory functions, which can be conferred by heteromer-formation with CCL5/RANTES enhancing monocyte recruitment. METHODS AND RESULTS: Here we show that tube formation of endothelial cells was inhibited by CXCL4L1 and CXCL4, while only CXCL4L1 triggered chemokinesis of endothelial cells. The chemotactic response towards VEGF and bFGF was attenuated by both variants and CXCL4L1-induced chemokinesis was blocked by bFGF or VEGF. Endothelial cell proliferation was inhibited by CXCL4 (IC(50) 6.9 MUg mL(-1)) but not by CXCL4L1, while both chemokines bound directly to VEGF and bFGF. Moreover, CXCL4 enhanced CCL5-induced monocyte arrest in flow adhesion experiments and monocyte recruitment into the mouse peritoneal cavity in vivo, whereas CXCL4L1 had no effect. CXCL4L1 revealed lower affinity to CCL5 than CXCL4, as quantified by isothermal fluorescence titration. As evidenced by the reduction of the activated partial thromboplastin time, CXCL4L1 showed a tendency towards less heparin-neutralizing activity than CXCL4 (IC(50) 2.45 vs 0.98 MUg mL(-1)). CONCLUSIONS: CXCL4L1 may act angiostatically by causing random endothelial cell locomotion, disturbing directed migration towards angiogenic chemokines, serving as a homeostatic chemokine with a moderate structural distinction yet different functional profile from CXCL4. PMID- 20961395 TI - The role of thrombin activatable fibrinolysis inhibitor and factor XI in platelet mediated fibrinolysis resistance: a thromboelastographic study in whole blood. AB - BACKGROUND: The resistance of platelet-rich thrombi to fibrinolysis is generally attributed to clot retraction and platelet PAI-1 release. The role of TAFI in platelet-mediated resistance to lysis is unclear. OBJECTIVE: We investigated the contribution of TAFI to the antifibrinolytic effect of platelets in whole blood by thromboelastography. METHODS: Platelet-poor (PP-WB, < 40 * 10(3) MUL(-1) ) and platelet-rich (PR-WB, > 400 * 10(3) MUL(-1) ) blood samples were obtained from normal human blood (N-WB, 150-220 * 10(3) MUL(-1) ). Clot lysis time was measured by thromboelastography in recalcified blood supplemented with t-PA (100 ng mL(-1) ) and tissue factor (1:1000 Recombiplastin). RESULTS: t-PA-induced lysis time increased in parallel with platelet concentration (up to 3-fold). Neutralization of TAFI, but not of PAI-1, shortened the lysis time by ~ 50% in PR-WB and by < 10% in PP-WB. Accordingly, prothrombin F1+2 and TAFIa accumulation was greater in PR-WB than in PP-WB. A similar TAFI-dependent inhibition of fibrinolysis was observed when clot retraction was prevented by cytochalasin D or abciximab, or when platelet membranes were tested. Moreover, in blood with an intact contact system, platelet-mediated fibrinolysis resistance was attenuated by an anti-FXI but not by an anti F-XII antibody. Finally, platelets made the clots resistant to the profibrinolytic effect of heparin concentrations displaying a strong anticoagulant activity. CONCLUSIONS: Our data indicate that TAFI activation is one major mechanism whereby platelets make clots resistant to fibrinolysis and underscore the importance of TAFI inhibitors as new antithrombotic agents. PMID- 20961396 TI - Clopidogrel discontinuation and platelet reactivity following coronary stenting. AB - AIMS: Antiplatelet therapy with aspirin and clopidogrel is recommended for 1 year after drug-eluting stent (DES) implantation or myocardial infarction. However, the discontinuation of antiplatelet therapy has become an important issue as recent studies have suggested a clustering of ischemic events within 90 days of clopidogrel withdrawal. The objective of this investigation was to explore the hypothesis that there is a transient 'rebound' increase in platelet reactivity within 3 months of clopidogrel discontinuation. METHODS AND RESULTS: In this prospective study, platelet function was assessed in patients taking aspirin and clopidogrel for at least 1 year following DES implantation. Platelet aggregation was measured using a modification of light transmission aggregometry in response to multiple concentrations of adenosine diphosphate (ADP), epinephrine, arachidonic acid, thrombin receptor activating peptide and collagen. Clopidogrel was stopped and platelet function was reassessed 1 week, 1 month and 3 months later. Thirty-two patients on dual antiplatelet therapy were recruited. Discontinuation of clopidogrel increased platelet aggregation to all agonists, except arachidonic acid. Platelet aggregation in response to ADP (2.5, 5, 10, and 20 MUm) and epinephrine (5 and 20 MUm) was significantly increased at 1 month compared with 3 months following clopidogrel withdrawal. Thus, a transient period of increased platelet reactivity to both ADP and epinephrine was observed 1 month after clopidogrel discontinuation. CONCLUSIONS: This study demonstrates a transient increase in platelet reactivity 1 month after clopidogrel withdrawal. This phenomenon may, in part, explain the known clustering of thrombotic events observed after clopidogrel discontinuation. This observation requires confirmation in larger populations. PMID- 20961397 TI - Platelet activation in hypertension associated with hypercholesterolemia: effects of irbesartan. AB - AIM: The aim of this study was to determine the effect of simultaneous hypertension and hypercholesterolemia on platelet activation, nitric oxide (NO) production and oxidative stress, and to evaluate the role of irbesartan, an angiotensin II type 1 receptor antagonist. METHODS: Golden Syrian hamsters were divided into three groups: controls, C (fed a standard diet); hypertensive hypercholesterolemic, HH (fed a diet enriched in 3% cholesterol, 15% butter and 8% NaCl, for 4 months); and hypertensive-hypercholesterolemic treated with irbesartan, HHI (fed as HH group, plus irbesartan 10 mg kg(-1) per day, for 4 months). RESULTS: Compared with the C group, platelets isolated from the HH group showed: morphological modifications; increased integrin beta3 exposure and protein expression of P-selectin, FAK, PI3K, Akt and Src; reduced eNOS protein expression and NO production; higher generation of ROS, mostly produced by NADPH oxidase, cyclooxygenase-1 (COX-1) and 12-lipoxygenase; and enhanced NAD(P)H oxidase activity and protein expression of gp91phox and p22phox subunits, 12 lipoxygenase, COX-1, cPLA(2) and PKC. Compared with the HH group, the treatment with irbesartan (HHI group) significantly attenuates the changes in all the molecules tested, reduces platelet aggregation, and improves intraplatelet redox balance. CONCLUSIONS: Experimental hypertension associated with hypercholesterolemia produces major changes in morphology, signaling mechanisms and oxidative stress in blood platelets. These changes were significantly diminished by irbesartan administration, which functions as an antioxidant on platelets. PMID- 20961398 TI - Validation of improved performance characteristics for the automated von Willebrand factor ristocetin cofactor activity assay. PMID- 20961399 TI - A novel phytochemical, digoxigenin-3-O-rutin in the amelioration of isoproterenol induced myocardial infarction in rat: a comparison with digoxin. AB - INTRODUCTION: The commonly used cardiac glycoside, digoxin (DIG), has a narrow therapeutic window. Although some investigations were made to counteract its toxic effects, no alternate phytochemical is available till date that is more potent and safer than DIG. AIMS: Our main aim was to isolate a novel cardenolide from the seeds of Trigonella foenum graceium and to evaluate its relative potential in comparison to that of DIG. EXPERIMENTAL DESIGN: In one experiment effects of the isolated compound at 2.5, 5.0, and 10 mg/kg (p.o.) were evaluated in isoproterenol (ISO)-induced cardiovascular problems in rats. As the test drug (TDR) reversed most of the ISO-induced changes, it was subjected to the phytochemical analyses and was identified as digoxigenin-3-O-rutin. In another experiment effects of DIG and rutin (Rtn) were compared with those of TDR or DIG alone. The hydroxyl radical scavenging activity was also measured by electron spin resonance (EPR). RESULTS: digoxigenin-3-O-rutin at 10 mg/kg markedly reduced the ISO-induced increase in cardiac lipid peroxidation and in the levels of serum creatinine phosphokinase-MB, glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, lactate dehydrogenase, and creatinine. It also reversed the ISO-induced changes in the cardiac histomorphology. Interestingly TDR appeared to be more effective than DIG alone or DIG and Rtn in combination. CONCLUSION: The newly isolated digoxigenin-3-O-rutin appears to be more potent and safe than digoxin. Its higher efficacy could be due to its structural specificity and might have been mediated through its better free radical scavenging action. PMID- 20961400 TI - Histone deacetylases and mood disorders: epigenetic programming in gene environment interactions. AB - Epigenetics involves molecular mechanisms related to gene expression independent of DNA sequence, mostly mediated by modification of chromatin histones. It has recently been suggested that these transcriptional changes may be implicated in the pathophysiology of mood disorders. In addition, histone deacetylase (HDAC) inhibitors have been shown to control epigenetic programming associated with the regulation of cognition and behavior, and may reverse dysfunctional epigenetic regulation associated with early life events in preclinical models. In this context, the active and continuous adaptation of chromatin, and the access of gene promoters to transcription factor mechanisms may represent a potential therapeutic target in the treatment of mood disorders such as bipolar disorder (BD) and major depressive disorder (MDD). Notably, the standard mood stabilizer valproate (VPA) has been shown to modulate the epigenome by inhibiting HDACs. However, several potential limitations are associated with this class of agents, including lack of selectivity for specific HDAC isoforms as well as risk of potentially serious side effects. Further studies regarding the potential role of chromatin remodeling in the mechanism of action of antidepressants and mood stabilizers are necessary to clarify the potential role of this class of agents as therapeutics for mood disorders. PMID- 20961401 TI - Genomic organization and gene expression of the multiple globins in Atlantic cod: conservation of globin-flanking genes in chordates infers the origin of the vertebrate globin clusters. AB - BACKGROUND: The vertebrate globin genes encoding the alpha- and beta-subunits of the tetrameric hemoglobins are clustered at two unlinked loci. The highly conserved linear order of the genes flanking the hemoglobins provides a strong anchor for inferring common ancestry of the globin clusters. In fish, the number of alpha-beta-linked globin genes varies considerably between different sublineages and seems to be related to prevailing physico-chemical conditions. Draft sequences of the Atlantic cod genome enabled us to determine the genomic organization of the globin repertoire in this marine species that copes with fluctuating environments of the temperate and Arctic regions. RESULTS: The Atlantic cod genome was shown to contain 14 globin genes, including nine hemoglobin genes organized in two unlinked clusters designated beta5-alpha1-beta1 alpha4 and beta3-beta4-alpha2-alpha3-beta2. The diverged cod hemoglobin genes displayed different expression levels in adult fish, and tetrameric hemoglobins with or without a Root effect were predicted. The novel finding of maternally inherited hemoglobin mRNAs is consistent with a potential role played by fish hemoglobins in the non-specific immune response. In silico analysis of the six teleost genomes available showed that the two alpha-beta globin clusters are flanked by paralogs of five duplicated genes, in agreement with the proposed teleost-specific duplication of the ancestral vertebrate globin cluster. Screening the genome of extant urochordate and cephalochordate species for conserved globin-flanking genes revealed linkage of RHBDF1, MPG and ARHGAP17 to globin genes in the tunicate Ciona intestinalis, while these genes together with LCMT are closely positioned in amphioxus (Branchiostoma floridae), but seem to be unlinked to the multiple globin genes identified in this species. CONCLUSION: The plasticity of Atlantic cod to variable environmental conditions probably involves the expression of multiple globins with potentially different properties. The interspecific difference in number of fish hemoglobin genes contrasts with the highly conserved synteny of the flanking genes. The proximity of globin-flanking genes in the tunicate and amphioxus genomes resembles the RHBDF1-MPG-alpha-globin ARHGAP17-LCMT linked genes in man and chicken. We hypothesize that the fusion of the three chordate linkage groups 3, 15 and 17 more than 800 MYA led to the ancestral vertebrate globin cluster during a geological period of increased atmospheric oxygen content. PMID- 20961402 TI - Identification and structural analysis of C-terminally truncated collapsin response mediator protein-2 in a murine model of prion diseases. AB - BACKGROUND: Prion diseases are fatal neurodegenerative disorders that accompany an accumulation of the disease-associated form(s) of prion protein (PrPSc) in the central nervous system. The neuropathological changes in the brain begin with focal deposits of PrPSc, followed by pathomorphological abnormalities of axon terminal degeneration, synaptic loss, atrophy of dendritic trees, and eventual neuronal cell death in the lesions. However, the underlying molecular basis for these neuropathogenic abnormalities is not fully understood. RESULTS: In a proteomic analysis of soluble proteins in the brains of mice challenged intracerebrally with scrapie prion (Obihiro I strain), we found that the amount of the full-length form of collapsin response mediator protein-2 (CRMP-2; 61 kDa) decreased in the late stages of the disease, while the amount of its truncated form (56 kDa) increased to comparable levels observed for the full-length form. Detailed analysis by liquid chromatography-electrospray ionization-tandem mass spectrometry showed that the 56-kDa form (named CRMP-2-DeltaC) lacked the sequence from serine518 to the C-terminus, including the C-terminal phosphorylation sites important for the regulation of axonal growth and axon dendrite specification in developing neurons. The invariable size of the mRNA transcript in Northern blot analysis suggested that the truncation was due to post-translational proteolysis. By overexpression of CRMP-2-DeltaC in primary cultured neurons, we observed the augmentation of the development of neurite branch tips to the same levels as for CRMP-2T514A/T555A, a non-phosphorylated mimic of the full-length protein. This suggests that the increased level of CRMP 2-DeltaC in the brain modulates the integrity of neurons, and may be involved in the pathogenesis of the neuronal abnormalities observed in the late stages of the disease. CONCLUSIONS: We identified the presence of CRMP-2-DeltaC in the brain of a murine model of prion disease. Of note, C-terminal truncations of CRMP-2 have been recently observed in models for neurodegenerative disorders such as ischemia, traumatic brain injury, and Wallerian degeneration. While the structural identity of CRMP-2-DeltaC in those models remains unknown, the present study should provide clues to the molecular pathology of degenerating neurons in prion diseases in connection with other neurodegenerative disorders. PMID- 20961403 TI - Distinct target cell-dependent forms of short-term plasticity of the central visceral afferent synapses of the rat. AB - BACKGROUND: The visceral afferents from various cervico-abdominal sensory receptors project to the dorsal vagal complex (DVC), which is composed of the nucleus of the solitary tract (NTS), the area postrema and the dorsal motor nucleus of the vagus nerve (DMX), via the vagus and glossopharyngeal nerves and then the solitary tract (TS) in the brainstem. While the excitatory transmission at the TS-NTS synapses shows strong frequency-dependent suppression in response to repeated stimulation of the afferents, the frequency dependence and short-term plasticity at the TS-DMX synapses, which also transmit monosynaptic information from the visceral afferents to the DVC neurons, remain largely unknown. RESULTS: Recording of the EPSCs activated by paired or repeated TS stimulation in the brainstem slices of rats revealed that, unlike NTS neurons whose paired-pulse ratio (PPR) is consistently below 0.6, the distribution of the PPR of DMX neurons shows bimodal peaks that are composed of type I (PPR, 0.6-1.5; 53% of 120 neurons recorded) and type II (PPR, < 0.6; 47%) neurons. Some of the type I DMX neurons showed paired-pulse potentiation. The distinction of these two types depended on the presynaptic release probability and the projection target of the postsynaptic cells; the distinction was not dependent on the location or soma size of the cell, intensity or site of the stimulation, the latency, standard deviation of latency or the quantal size. Repeated stimulation at 20 Hz resulted in gradual and potent decreases in EPSC amplitude in the NTS and type II DMX neurons, whereas type I DMX neurons displayed only slight decreases, which indicates that the DMX neurons of this type could be continuously activated by repeated firing of primary afferent fibers at a high (~10 Hz) frequency. CONCLUSIONS: These two general types of short-term plasticity might contribute to the differential activation of distinct vago-vagal reflex circuits, depending on the firing frequency and type of visceral afferents. PMID- 20961404 TI - Simulation studies of age-specific lifetime major depression prevalence. AB - BACKGROUND: The lifetime prevalence (LTP) of Major Depressive Disorder (MDD) is the proportion of a population having met criteria for MDD during their life up to the time of assessment. Expectation holds that LTP should increase with age, but this has not usually been observed. Instead, LTP typically increases in the teenage years and twenties, stabilizes in adulthood and then begins to decline in middle age. Proposed explanations for this pattern include: a cohort effect (increasing incidence in more recent birth cohorts), recall failure and/or differential mortality. Declining age-specific incidence may also play a role. METHODS: We used a simulation model to explore patterns of incidence, recall and mortality in relation to the observed pattern of LTP. Lifetime prevalence estimates from the 2002 Canadian Community Health Survey, Mental Health and Wellbeing (CCHS 1.2) were used for model validation and calibration. RESULTS: Incidence rates predicting realistic values for LTP in the 15-24 year age group (where mortality is unlikely to substantially influence prevalence) lead to excessive LTP later in life, given reasonable assumptions about mortality and recall failure. This suggests that (in the absence of cohort effects) incidence rates decline with age. Differential mortality may make a contribution to the prevalence pattern, but only in older age categories. Cohort effects can explain the observed pattern, but only if recent birth cohorts have a much higher (approximately 10-fold greater) risk and if incidence has increased with successive birth cohorts over the past 60-70 years. CONCLUSIONS: The pattern of lifetime prevalence observed in cross-sectional epidemiologic studies seems most plausibly explained by incidence that declines with age and where some respondents fail to recall past episodes. A cohort effect is not a necessary interpretation of the observed pattern of age-specific lifetime prevalence. PMID- 20961405 TI - DMF inhibits PDGF-BB induced airway smooth muscle cell proliferation through induction of heme-oxygenase-1. AB - BACKGROUND: Airway wall remodelling is an important pathology of asthma. Growth factor induced airway smooth muscle cell (ASMC) proliferation is thought to be the major cause of airway wall thickening in asthma. Earlier we reported that Dimethylfumarate (DMF) inhibits platelet-derived growth factor (PDGF)-BB induced mitogen and stress activated kinase (MSK)-1 and CREB activity as well as IL-6 secretion by ASMC. In addition, DMF altered intracellular glutathione levels and thereby reduced proliferation of other cell types. METHODS: We investigated the effect of DMF on PDGF-BB induced ASMC proliferation, on mitogen activated protein kinase (MAPK) activation; and on heme oxygenase (HO)-1 expression. ASMC were pre incubated for 1 hour with DMF and/or glutathione ethylester (GSH-OEt), SB203580, hemin, cobalt-protoporphyrin (CoPP), or siRNA specific to HO-1 before stimulation with PDGF-BB (10 ng/ml). RESULTS: PDGF-BB induced ASMC proliferation was inhibited in a dose-dependant manner by DMF. PDGF-BB induced the phosphorylation of ERK1/2 and p38 MAPK, but not of JNK. DMF enhanced the PDGF-BB induced phosphorylation of p38 MAPK and there by up-regulated the expression of HO-1. HO 1 induction inhibited the proliferative effect of PDGF-BB. HO-1 expression was reversed by GSH-OEt, or p38 MAPK inhibition, or HO-1 siRNA, which all reversed the anti-proliferative effect of DMF. CONCLUSION: Our data indicate that DMF inhibits ASMC proliferation by reducing the intracellular GSH level with subsequent activation of p38 MAPK and induction of HO-1. Thus, DMF might reduce ASMC and airway remodelling processes in asthma. PMID- 20961406 TI - A multidisciplinary cognitive behavioural programme for coping with chronic neuropathic pain following spinal cord injury: the protocol of the CONECSI trial. AB - BACKGROUND: Most people with a spinal cord injury rate neuropathic pain as one of the most difficult problems to manage and there are no medical treatments that provide satisfactory pain relief in most people. Furthermore, psychosocial factors have been considered in the maintenance and aggravation of neuropathic spinal cord injury pain. Psychological interventions to support people with spinal cord injury to deal with neuropathic pain, however, are sparse. The primary aim of the CONECSI (COping with NEuropathiC Spinal cord Injury pain) trial is to evaluate the effects of a multidisciplinary cognitive behavioural treatment programme on pain intensity and pain-related disability, and secondary on mood, participation in activities, and life satisfaction. METHODS/DESIGN: CONECSI is a multicentre randomised controlled trial. A sample of 60 persons with chronic neuropathic spinal cord injury pain will be recruited from four rehabilitation centres and randomised to an intervention group or a waiting list control group. The control group will be invited for the programme six months after the intervention group. Main inclusion criteria are: having chronic (> 6 months) neuropathic spinal cord injury pain as the worst pain complaint and rating the pain intensity in the last week as 40 or more on a 0-100 scale. The intervention consists of educational, cognitive, and behavioural elements and encompasses 11 sessions over a 3-month period. Each meeting will be supervised by a local psychologist and physical therapist. Measurements will be performed before starting the programme/entering the control group, and at 3, 6, 9, and 12 months. Primary outcomes are pain intensity and pain-related disability (Chronic Pain Grade questionnaire). Secondary outcomes are mood (Hospital Anxiety and Depression Scale), participation in activities (Utrecht Activities List), and life satisfaction (Life Satisfaction Questionnaire). Pain coping and pain cognitions will be assessed with three questionnaires (Coping Strategy Questionnaire, Pain Coping Inventory, and Pain Cognition List). DISCUSSION: The CONECSI trial will reveal the effects of a multidisciplinary cognitive behavioural programme for people with chronic neuropathic spinal cord injury pain. This intervention is expected to contribute to the rehabilitation treatment possibilities for this population. TRIAL REGISTRATION: Dutch Trial Register NTR1580. PMID- 20961407 TI - An atlas of bovine gene expression reveals novel distinctive tissue characteristics and evidence for improving genome annotation. AB - BACKGROUND: A comprehensive transcriptome survey, or gene atlas, provides information essential for a complete understanding of the genomic biology of an organism. We present an atlas of RNA abundance for 92 adult, juvenile and fetal cattle tissues and three cattle cell lines. RESULTS: The Bovine Gene Atlas was generated from 7.2 million unique digital gene expression tag sequences (300.2 million total raw tag sequences), from which 1.59 million unique tag sequences were identified that mapped to the draft bovine genome accounting for 85% of the total raw tag abundance. Filtering these tags yielded 87,764 unique tag sequences that unambiguously mapped to 16,517 annotated protein-coding loci in the draft genome accounting for 45% of the total raw tag abundance. Clustering of tissues based on tag abundance profiles generally confirmed ontology classification based on anatomy. There were 5,429 constitutively expressed loci and 3,445 constitutively expressed unique tag sequences mapping outside annotated gene boundaries that represent a resource for enhancing current gene models. Physical measures such as inferred transcript length or antisense tag abundance identified tissues with atypical transcriptional tag profiles. We report for the first time the tissue-specific variation in the proportion of mitochondrial transcriptional tag abundance. CONCLUSIONS: The Bovine Gene Atlas is the deepest and broadest transcriptome survey of any livestock genome to date. Commonalities and variation in sense and antisense transcript tag profiles identified in different tissues facilitate the examination of the relationship between gene expression, tissue, and gene function. PMID- 20961408 TI - Detecting sequence polymorphisms associated with meiotic recombination hotspots in the human genome. AB - BACKGROUND: Meiotic recombination events tend to cluster into narrow spans of a few kilobases long, called recombination hotspots. Such hotspots are not conserved between human and chimpanzee and vary between different human ethnic groups. At the same time, recombination hotspots are heritable. Previous studies showed instances where differences in recombination rate could be associated with sequence polymorphisms. RESULTS: In this work we developed a novel computational approach, LDsplit, to perform a large-scale association study of recombination hotspots with genetic polymorphisms. LDsplit was able to correctly predict the association between the FG11 SNP and the DNA2 hotspot observed by sperm typing. Extensive simulation demonstrated the accuracy of LDsplit under various conditions. Applying LDsplit to human chromosome 6, we found that for a significant fraction of hotspots, there is an association between variations in intensity of historical recombination and sequence polymorphisms. From flanking regions of the SNPs output by LDsplit we identified a conserved 11-mer motif GGNGGNAGGGG, whose complement partially matches 13-mer CCNCCNTNNCCNC, a critical motif for the regulation of recombination hotspots. CONCLUSIONS: Our result suggests that computational approaches based on historical recombination events are likely to be more powerful than previously anticipated. The putative associations we identified may be a promising step toward uncovering the mechanisms of recombination hotspots. PMID- 20961409 TI - Extraperitoneal urine leak after renal transplantation: the role of radionuclide imaging and the value of accompanying SPECT/CT - a case report. AB - BACKGROUND: The differentiation of the nature of a fluid collection as a complication of kidney transplantation is important for management and treatment planning. Early and delayed radionuclide renography can play an important role in the evaluation of a urine leak. However, it is sometimes limited in the evaluation of the exact location and extent of a urine leak. CASE PRESENTATION: A 71-year-old male who had sudden anuria, scrotal swelling and elevated creatinine level after cadaveric renal transplantation performed Tc-99 m MAG3 renography to evaluate the renal function, followed by an ultrasound which was unremarkable. An extensive urine leak was evident on the planar images. However, an exact location of the urine leak was unknown. Accompanying SPECT/CT images confirmed a urine leak extending from the lower aspect of the transplant kidney to the floor of the pelvic cavity, presacral region and the scrotum via right inguinal canal as well as to the right abdominal wall. CONCLUSIONS: Renal scintigraphy is very useful to detect a urine leak after renal transplantation. However, planar imaging is sometimes limited in evaluating the anatomical location and extent of a urine leak accurately. In that case accompanying SPECT/CT images are very helpful and valuable to evaluate the anatomical relationships exactly. PMID- 20961410 TI - Lessons from genome-wide studies: an integrated definition of the coactivator function of histone acetyl transferases. AB - Histone acetylation is one of the key regulatory mechanisms controlling transcriptional activity in eukaryotic cells. In higher eukaryotes, a number of nuclear histone acetyltransferase (HAT) enzymes have been identified, most of which are part of a large multisubunit complex. This diversity, combined with the large number of potentially acetylable lysines on histones, suggested the existence of a specific regulatory mechanism based on the substrate specificity of HATs. Over the past decade, intensive characterisations of the HAT complexes have been carried out. However, the precise mode of action of HATs, and particularly the functional differences amongst these complexes, remains elusive. Here we review current insights into the functional role of HATs, focusing on the specificity of their action. Studies based on biochemical as well as genetic approaches suggested that HATs exert a high degree of specificity in their acetylation spectra and in the cellular processes they regulate. However, a different view emerged recently from genomic approaches that provided genome-wide maps of HAT recruitments. The careful analysis of genomic data suggests that all HAT complexes would be simultaneously recruited to a similar set of loci in the genome, arguing for a low specificity in their function. In this review, we discuss the significance of these apparent contradictions and suggest a new model that integrates biochemical, genetic and genome-wide data to better describe the functional specificity of HAT complexes. PMID- 20961411 TI - Long term costs and effects of reducing the number of twin pregnancies in IVF by single embryo transfer: the TwinSing study. AB - BACKGROUND: Pregnancies induced by in vitro fertilisation (IVF) often result in twin gestations, which are associated with both maternal and perinatal complications. An effective way to reduce the number of IVF twin pregnancies is to decrease the number of embryos transferred from two to one. The interpretation of current studies is limited because they used live birth as outcome measure and because they applied limited time horizons. So far, research on long-term outcomes of IVF twins and singletons is scarce and inconclusive. The objective of this study is to investigate the short (1-year) and long-term (5 and 18-year) costs and health outcomes of IVF singleton and twin children and to consider these in estimating the cost-effectiveness of single embryo transfer compared with double embryo transfer, from a societal and a healthcare perspective. METHODS/DESIGN: A multi-centre cohort study will be performed, in which IVF singletons and IVF twin children born between 2003 and 2005 of whom parents received IVF treatment in one of the five participating Dutch IVF centres, will be compared. Data collection will focus on children at risk of health problems and children in whom health problems actually occurred. First year of life data will be collected in approximately 1,278 children (619 singletons and 659 twin children). Data up to the fifth year of life will be collected in approximately 488 children (200 singletons and 288 twin children). Outcome measures are health status, health-related quality of life and costs. Data will be obtained from hospital information systems, a parent questionnaire and existing registries. Furthermore, a prognostic model will be developed that reflects the short and long-term costs and health outcomes of IVF singleton and twin children. This model will be linked to a Markov model of the short-term cost-effectiveness of single embryo transfer strategies versus double embryo transfer strategies to enable the calculation of the long-term cost-effectiveness. DISCUSSION: This is, to our knowledge, the first study that investigates the long-term costs and health outcomes of IVF singleton and twin children and the long-term cost effectiveness of single embryo transfer strategies versus double embryo transfer strategies. PMID- 20961412 TI - Optimizing imaging in suspected appendicitis (OPTIMAP-study): a multicenter diagnostic accuracy study of MRI in patients with suspected acute appendicitis. Study Protocol. AB - BACKGROUND: In patients with clinically suspected appendicitis, imaging is needed to substantiate the clinical diagnosis. Imaging accuracy of ultrasonography (US) is suboptimal, while the most accurate technique (CT) is associated with cancer related deaths through exposure to ionizing radiation. MRI is a potential replacement, without associated ionizing radiation and no need for contrast medium administration. If MRI is proven to be sufficiently accurate, it could be introduced in the diagnostic pathway of patients with suspected appendicitis, increasing diagnostic accuracy and improving clinical outcomes, without the risk of radiation induced cancer or iodinated contrast medium-related drawbacks. The multicenter OPTIMAP study was designed to estimate the diagnostic accuracy of MRI in patients with suspected acute appendicitis in the general population. METHODS/DESIGN: Eligible for this study are consecutive patients presenting with clinically suspected appendicitis at the emergency department in six centers. All patients will undergo imaging according to the Dutch guideline for acute appendicitis: initial ultrasonography in all and subsequent CT whenever US does not confirm acute appendicitis. Then MRI is performed in all patients, but the results are not used for patient management. A final diagnosis assigned by an expert panel, based on all available information including 3-months follow-up, except MRI findings, is used as the reference standard in estimating accuracy. We will calculate the sensitivity, specificity, predictive values and inter-observer agreement of MRI, and aim to include 230 patients. Patient acceptance and total imaging costs will also be evaluated. DISCUSSION: If MRI is found to be sufficiently accurate, it could replace CT in some or all patients. This will limit or obviate the ionizing radiation exposure associated risk of cancer induction and contrast medium induced nephropathy with CT, preventing the burden and the direct and indirect costs associated with treatment. Based on the high intrinsic contrast resolution of MRI, one might envision higher accuracy rates for MRI than for CT. If so, MRI could further decrease the number of unnecessary appendectomies and the number of missed appendicitis cases. TRIAL REGISTRATION: NTR2148. PMID- 20961413 TI - Lung abscess predicts the surgical outcome in patients with pleural empyema. AB - OBJECTIVES: Most cases of pleural empyema are caused by pulmonary infections, which are usually combined with pneumonia or lung abscess. The mortality of patients with pleural empyema remains high (up to 20%). It also contributes to higher hospital costs and longer hospital stays. We studied pleural empyema with combined lung abscess to determine if abscess was associated with mortality. METHODS: From January 2004 to December 2006, we retrospectively reviewed 259 patients diagnosed with pleural empyema who received thoracscopic decortications of the pleura in a single medical center. We evaluated their clinical data and analyzed their chest computed tomography scans. Outcomes of pleural empyema were compared between groups with and without lung abscess. RESULTS: Twenty-two pleural empyema patients had lung abscesses. Clinical data showed significantly higher incidences in the lung abscess group of pre-operative leukocytosis, need for an intensive care unit stay and mortality. CONCLUSION: Patients with pleural empyema and lung abscess have higher intensive care unit admission rate, higher mortality during 30 days and overall mortality than patients with pleural empyema. The odds ratio of lung abscess is 4.685. Physician shall pay more attention on high risk patient of lung abscess for early detection and management. PMID- 20961414 TI - The course of untreated anxiety and depression, and determinants of poor one-year outcome: a one-year cohort study. AB - BACKGROUND: Little is known about the course and outcome of untreated anxiety and depression in patients with and without a self-perceived need for care. The aim of the present study was to examine the one-year course of untreated anxiety and depression, and to determine predictors of a poor outcome. METHOD: Baseline and one-year follow-up data were used of 594 primary care patients with current anxiety or depressive disorders at baseline (established by the Composite Interview Diagnostic Instrument (CIDI)), from the Netherlands Study of Depression and Anxiety (NESDA). Receipt of and need for care were assessed by the Perceived Need for Care Questionnaire (PNCQ). RESULTS: In depression, treated and untreated patients with a perceived treatment need showed more rapid symptom decline but greater symptom severity at follow-up than untreated patients without a self perceived mental problem or treatment need. A lower education level, lower income, unemployment, loneliness, less social support, perceived need for care, number of somatic disorders, a comorbid anxiety and depressive disorder and symptom severity at baseline predicted a poorer outcome in both anxiety and depression. When all variables were considered at the same time, only baseline symptom severity appeared to predict a poorer outcome in anxiety. In depression, a poorer outcome was also predicted by more loneliness and a comorbid anxiety and depressive disorder. CONCLUSION: In clinical practice, special attention should be paid to exploring the need for care among possible risk groups (e.g. low social economic status, low social support), and support them in making an informed decision on whether or not to seek treatment. PMID- 20961415 TI - Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA). METHODS: Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. RESULTS: VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL 1beta and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. CONCLUSIONS: VERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis. PMID- 20961416 TI - Age related changes in T cell mediated immune response and effector memory to Respiratory Syncytial Virus (RSV) in healthy subjects. AB - Respiratory syncytial virus (RSV) is the major pathogen causing respiratory disease in young infants and it is an important cause of serious illness in the elderly since the infection provides limited immune protection against reinfection. In order to explain this phenomenon, we investigated whether healthy adults of different age (20-40; 41-60 and > 60 years), have differences in central and effector memory, RSV-specific CD8+ T cell memory immune response and regulatory T cell expression status. In the peripheral blood of these donors, we were unable to detect any age related difference in term of central (CD45RA CCR7+) and effector (CD45RA-CCR7-) memory T cell frequency. On the contrary, we found a significant increase in immunosuppressive regulatory (CD4+25+FoxP3+) T cells (Treg) in the elderly. An immunocytofluorimetric RSV pentamer analysis performed on these donors' peripheral blood mononuclear cells (PBMCs), in vitro sensitized against RSV antigen, revealed a marked decline in long-lasting RSV specific CD8+ memory T cell precursors expressing interleukin 7 receptor alpha (IL-7Ralpha), in the elderly. This effect was paralleled by a progressive switch from a Th1 (IFN-gamma and TNF-alpha) to a Th2 (IL-10) functional phenotype. On the contrary, an increase in Treg was observed with aging. The finding of Treg over-expression status, a prominent Th2 response and an inefficient RSV-specific effector memory CD8+ T cell expansion in older donors could explain the poor protection against RSV reinfection and the increased risk to develop an RSV related severe illness in this population. Our finding also lays the basis for new therapeutic perspectives that could limit or prevent severe RSV infection in elderly. PMID- 20961417 TI - Identification of conformational B-cell Epitopes in an antigen from its primary sequence. AB - BACKGROUND: One of the major challenges in the field of vaccine design is to predict conformational B-cell epitopes in an antigen. In the past, several methods have been developed for predicting conformational B-cell epitopes in an antigen from its tertiary structure. This is the first attempt in this area to predict conformational B-cell epitope in an antigen from its amino acid sequence. RESULTS: All Support vector machine (SVM) models were trained and tested on 187 non-redundant protein chains consisting of 2261 antibody interacting residues of B-cell epitopes. Models have been developed using binary profile of pattern (BPP) and physiochemical profile of patterns (PPP) and achieved a maximum MCC of 0.22 and 0.17 respectively. In this study, for the first time SVM model has been developed using composition profile of patterns (CPP) and achieved a maximum MCC of 0.73 with accuracy 86.59%. We compare our CPP based model with existing structure based methods and observed that our sequence based model is as good as structure based methods. CONCLUSION: This study demonstrates that prediction of conformational B-cell epitope in an antigen is possible from is primary sequence. This study will be very useful in predicting conformational B-cell epitopes in antigens whose tertiary structures are not available. A web server CBTOPE has been developed for predicting B-cell epitope http://www.imtech.res.in/raghava/cbtope/. PMID- 20961418 TI - Structuring heterogeneous biological information using fuzzy clustering of k partite graphs. AB - BACKGROUND: Extensive and automated data integration in bioinformatics facilitates the construction of large, complex biological networks. However, the challenge lies in the interpretation of these networks. While most research focuses on the unipartite or bipartite case, we address the more general but common situation of k-partite graphs. These graphs contain k different node types and links are only allowed between nodes of different types. In order to reveal their structural organization and describe the contained information in a more coarse-grained fashion, we ask how to detect clusters within each node type. RESULTS: Since entities in biological networks regularly have more than one function and hence participate in more than one cluster, we developed a k-partite graph partitioning algorithm that allows for overlapping (fuzzy) clusters. It determines for each node a degree of membership to each cluster. Moreover, the algorithm estimates a weighted k-partite graph that connects the extracted clusters. Our method is fast and efficient, mimicking the multiplicative update rules commonly employed in algorithms for non-negative matrix factorization. It facilitates the decomposition of networks on a chosen scale and therefore allows for analysis and interpretation of structures on various resolution levels. Applying our algorithm to a tripartite disease-gene-protein complex network, we were able to structure this graph on a large scale into clusters that are functionally correlated and biologically meaningful. Locally, smaller clusters enabled reclassification or annotation of the clusters' elements. We exemplified this for the transcription factor MECP2. CONCLUSIONS: In order to cope with the overwhelming amount of information available from biomedical literature, we need to tackle the challenge of finding structures in large networks with nodes of multiple types. To this end, we presented a novel fuzzy k-partite graph partitioning algorithm that allows the decomposition of these objects in a comprehensive fashion. We validated our approach both on artificial and real world data. It is readily applicable to any further problem. PMID- 20961419 TI - Use of consensus sequences for the design of high density resequencing microarrays: the influenza virus paradigm. AB - BACKGROUND: A resequencing microarray called PathogenID v2.0 has been developed and used to explore various strategies of sequence selection for its design. The part dedicated to influenza viruses was based on consensus sequences specific for one gene generated from global alignments of a large number of influenza virus sequences available in databanks. RESULTS: For each HA (H1, H2, H3, H5, H7 and H9) and NA (N1, N2 and N7) molecular type chosen to be tested, 1 to 3 consensus sequences were computed and tiled on the microarray. A total of 12 influenza virus samples from different host origins (humans, pigs, horses and birds) and isolated over a period of about 50 years were used in this study. Influenza viruses were correctly identified, and in most cases with the accurate information of the time of their emergence. CONCLUSIONS: PathogenID v2.0 microarray demonstrated its ability to type and subtype influenza viruses, often to the level of viral variants, with a minimum number of tiled sequences. This validated the strategy of using consensus sequences, which do not exist in nature, for our microarray design. The versatility, rapidity and high discriminatory power of the PathogenID v2.0 microarray could prove critical to detect and identify viral genome reassortment events resulting in a novel virus with epidemic or pandemic potential and therefore assist health authorities to make efficient decisions about patient treatment and outbreak management. PMID- 20961420 TI - Class prediction for high-dimensional class-imbalanced data. AB - BACKGROUND: The goal of class prediction studies is to develop rules to accurately predict the class membership of new samples. The rules are derived using the values of the variables available for each subject: the main characteristic of high-dimensional data is that the number of variables greatly exceeds the number of samples. Frequently the classifiers are developed using class-imbalanced data, i.e., data sets where the number of samples in each class is not equal. Standard classification methods used on class-imbalanced data often produce classifiers that do not accurately predict the minority class; the prediction is biased towards the majority class. In this paper we investigate if the high-dimensionality poses additional challenges when dealing with class imbalanced prediction. We evaluate the performance of six types of classifiers on class-imbalanced data, using simulated data and a publicly available data set from a breast cancer gene-expression microarray study. We also investigate the effectiveness of some strategies that are available to overcome the effect of class imbalance. RESULTS: Our results show that the evaluated classifiers are highly sensitive to class imbalance and that variable selection introduces an additional bias towards classification into the majority class. Most new samples are assigned to the majority class from the training set, unless the difference between the classes is very large. As a consequence, the class-specific predictive accuracies differ considerably. When the class imbalance is not too severe, down-sizing and asymmetric bagging embedding variable selection work well, while over-sampling does not. Variable normalization can further worsen the performance of the classifiers. CONCLUSIONS: Our results show that matching the prevalence of the classes in training and test set does not guarantee good performance of classifiers and that the problems related to classification with class-imbalanced data are exacerbated when dealing with high-dimensional data. Researchers using class-imbalanced data should be careful in assessing the predictive accuracy of the classifiers and, unless the class imbalance is mild, they should always use an appropriate method for dealing with the class imbalance problem. PMID- 20961421 TI - Pancreatic cancer and depression: myth and truth. AB - BACKGROUND: Various studies reported remarkable high incidence rates of depression in cancer patients compared with the general population. Pancreatic cancer is still one of the malignancies with the worst prognosis and therefore it seems quite logical that it is one of the malignancies with the highest incidence rates of major depression.However, what about the scientific background of this relationship? Is depression in patients suffering from pancreatic cancer just due to the confrontation with a life threatening disease and its somatic symptoms or is depression in this particular group of patients a feature of pancreatic cancer per se? DISCUSSION: Several studies provide evidence of depression to precede the diagnosis of pancreatic cancer and some studies even blame it for its detrimental influence on survival. The immense impact of emotional distress on quality of life of cancer patients enhances the need for its early diagnosis and adequate treatment. Knowledge about underlying pathophysiological mechanisms is required to provide the optimal therapy. SUMMARY: A review of the literature on this issue should reveal which are the facts and what is myth. PMID- 20961422 TI - Comparison of the pharmacokinetics, safety and tolerability of two concentrations of a new liquid recombinant human growth hormone formulation versus the freeze dried formulation. AB - BACKGROUND: Somatropin is recombinant human growth hormone (GH) used for the treatment of growth failure in children and GH deficiency in adults. Two concentrations of a liquid formulation have been developed: 5.83 and 8.0 mg/mL. This trial compared the pharmacokinetics (PK), safety and tolerability of these two liquid concentrations against the freeze-dried (FD) formulation in healthy volunteers. METHODS: In an open-label, single-centre, three-way crossover study, volunteers (aged 18-45 years) were given subcutaneous injections of the reconstituted FD and two liquid formulations in random sequential order, each at 4 mg/dose, with a 1-week wash-out period between doses. To suppress endogenous GH secretion, intravenous somatostatin was infused continuously 1 hour before to 24 hours after each dose, achieving a cumulative dose of 3 mg. Primary PK endpoints were area under the serum concentration-time curve (AUC0-t) and maximum serum concentration (Cmax). For each of the two liquid formulations, bioequivalence with the FD formulation was concluded if the 95% confidence intervals (CIs) for the estimated test/reference ratios of geometric means of AUC0-t and Cmax were within the standard pre-specified acceptance range (0.80-1.25). RESULTS: Fifteen men and 15 women enrolled (safety population, n = 30; PK population, n = 28). Bioequivalence with the FD formulation could be shown for both liquid formulations. The ratios of geometric means (95% CI) were 1.046 (0.980, 1.117) and 0.991 (0.929, 1.058) for AUC0-t and 0.954 (0.875, 1.040) and 0.955 (0.876, 1.041) for Cmax for the 5.83 and 8.0 mg/mL formulations, respectively. No significant differences between the three treatments in half-lives, time to reach Cmax, clearance or volume of distribution were observed. After injection, the most common side-effects were pain or injection-site reactions (all of mild intensity). There were no clinically significant abnormal vital signs, ECG or laboratory findings. There were 56 treatment-related adverse events (AEs): 49 mild, 6 moderate and 1 severe (vomiting). No serious AEs occurred. The pattern of AEs was as expected and all resolved by study end. CONCLUSION: Both concentrations of a new liquid multi-dose formulation are bioequivalent to the FD reference formulation and all are well tolerated. TRIAL REGISTRATION NUMBER: NCT01034735. PMID- 20961423 TI - Modern geographical reconnaissance of target populations in malaria elimination zones. AB - BACKGROUND: Geographical Reconnaissance (GR) operations using Personal Digital Assistants (PDAs) and Global Positioning Systems (GPS) have been conducted in the elimination provinces of Temotu, Solomon Islands and Tafea, Republic of Vanuatu. These operations aimed to examine modern approaches to GR to define the spatial distribution of target populations to support contemporary malaria elimination interventions. METHODS: Three GR surveys were carried out covering the outer islands of Temotu Province (October - November, 2008); Santa Cruz Island, Temotu Province (February 2009) and Tanna Island, Tafea Province (July - September 2009). Integrated PDA/GPS handheld units were used in the field to rapidly map and enumerate households, and collect associated population and household structure data to support priority elimination interventions, including bed net distribution, indoor residual spraying (IRS) and malaria case surveillance. Data were uploaded and analysed in customized Geographic Information System (GIS) databases to produce household distribution maps and generate relevant summary information pertaining to the GR operations. Following completion of field operations, group discussions were also conducted to review GR approaches and technology implemented. RESULTS: 10,459 households were geo-referenced and mapped. A population of 43,497 and 30,663 household structures were recorded during the three GR surveys. The spatial distribution of the population was concentrated in coastal village clusters. Survey operations were completed over a combined total of 77 field days covering a total land mass area of approximately 1103.2 km2. An average of 45 households, 118 structures and a population of 184 people were recorded per handheld device per day. Geo-spatial household distribution maps were also produced immediately following the completion of GR fieldwork. An overall high acceptability of modern GR techniques and technology was observed by both field operations staff and communities. CONCLUSION: GR implemented using modern techniques has provided an effective and efficient operational tool for rapidly defining the spatial distribution of target populations in designated malaria elimination zones in Solomon Islands and Vanuatu. The data generated are being used for the strategic implementation and scaling-up of priority interventions, and will be essential for establishing future surveillance using spatial decision support systems. PMID- 20961424 TI - Controlled expression of functional miR-122 with a ligand inducible expression system. AB - BACKGROUND: To study the biological function of miRNAs, and to achieve sustained or conditional gene silencing with siRNAs, systems that allow controlled expression of these small RNAs are desirable. Methods for cell delivery of siRNAs include transient transfection of synthetic siRNAs and expression of siRNAs in the form of short hairpins using constitutive RNA polymerase III promoters. Systems employing constitutive RNA polymerase II promoters have been used to express miRNAs. However, for many experimental systems these methods do not offer sufficient control over expression. RESULTS: We present an inducible mammalian expression system that allows for the conditional expression of short hairpin RNAs that are processed in vivo to generate miRNAs or siRNAs. Using modified nuclear receptors in a two hybrid format and a synthetic ligand, the Rheoswitch system allows rapid and reversible induction of mRNA expression. We evaluated the system's properties using miR-122 as a model miRNA. A short hairpin encoding miR 122 cloned into the expression vector was correctly processed to yield mature miRNA upon induction with ligand and the amount of miRNA produced was commensurate with the concentration of ligand. miR-122 produced in this way was capable of silencing both endogenous target genes and appropriately designed reporter genes. Stable cell lines were obtained, resulting in heritable, consistent and reversible expression of miR-122, a significant advantage over transient transfection. Based on these results, obtained with a microRNA we adapted the method to produce a desired siRNA by designing short hairpins that can be accurately and efficiently processed. CONCLUSION: We established an Inducible expression system with a miR-122 backbone that can be used for functional studies of miRNAs and their targets, in heterologous cells that do not normally express the miRNA. Additionally we demonstrate the feasibility of using the miR-122 backbone to express shRNA with a desired siRNA guide strand for inducible RNAi silencing. PMID- 20961425 TI - Gene expression in Pseudomonas aeruginosa swarming motility. AB - BACKGROUND: The bacterium Pseudomonas aeruginosa is capable of three types of motilities: swimming, twitching and swarming. The latter is characterized by a fast and coordinated group movement over a semi-solid surface resulting from intercellular interactions and morphological differentiation. A striking feature of swarming motility is the complex fractal-like patterns displayed by migrating bacteria while they move away from their inoculation point. This type of group behaviour is still poorly understood and its characterization provides important information on bacterial structured communities such as biofilms. Using GeneChip(r) Affymetrix microarrays, we obtained the transcriptomic profiles of both bacterial populations located at the tip of migrating tendrils and swarm center of swarming colonies and compared these profiles to that of a bacterial control population grown on the same media but solidified to not allow swarming motility. RESULTS: Microarray raw data were corrected for background noise with the RMA algorithm and quantile normalized. Differentially expressed genes between the three conditions were selected using a threshold of 1.5 log2-fold, which gave a total of 378 selected genes (6.3% of the predicted open reading frames of strain PA14). Major shifts in gene expression patterns are observed in each growth conditions, highlighting the presence of distinct bacterial subpopulations within a swarming colony (tendril tips vs. swarm center). Unexpectedly, microarrays expression data reveal that a minority of genes are up-regulated in tendril tip populations. Among them, we found energy metabolism, ribosomal protein and transport of small molecules related genes. On the other hand, many well-known virulence factors genes were globally repressed in tendril tip cells. Swarm center cells are distinct and appear to be under oxidative and copper stress responses. CONCLUSIONS: Results reported in this study show that, as opposed to swarm center cells, tendril tip populations of a swarming colony displays general down-regulation of genes associated with virulence and up regulation of genes involved in energy metabolism. These results allow us to propose a model where tendril tip cells function as "scouts" whose main purpose is to rapidly spread on uncolonized surfaces while swarm center population are in a state allowing a permanent settlement of the colonized area (biofilm-like). PMID- 20961426 TI - Gene duplications in prokaryotes can be associated with environmental adaptation. AB - BACKGROUND: Gene duplication is a normal evolutionary process. If there is no selective advantage in keeping the duplicated gene, it is usually reduced to a pseudogene and disappears from the genome. However, some paralogs are retained. These gene products are likely to be beneficial to the organism, e.g. in adaptation to new environmental conditions. The aim of our analysis is to investigate the properties of paralog-forming genes in prokaryotes, and to analyse the role of these retained paralogs by relating gene properties to life style of the corresponding prokaryotes. RESULTS: Paralogs were identified in a number of prokaryotes, and these paralogs were compared to singletons of persistent orthologs based on functional classification. This showed that the paralogs were associated with for example energy production, cell motility, ion transport, and defence mechanisms. A statistical overrepresentation analysis of gene and protein annotations was based on paralogs of the 200 prokaryotes with the highest fraction of paralog-forming genes. Biclustering of overrepresented gene ontology terms versus species was used to identify clusters of properties associated with clusters of species. The clusters were classified using similarity scores on properties and species to identify interesting clusters, and a subset of clusters were analysed by comparison to literature data. This analysis showed that paralogs often are associated with properties that are important for survival and proliferation of the specific organisms. This includes processes like ion transport, locomotion, chemotaxis and photosynthesis. However, the analysis also showed that the gene ontology terms sometimes were too general, imprecise or even misleading for automatic analysis. CONCLUSIONS: Properties described by gene ontology terms identified in the overrepresentation analysis are often consistent with individual prokaryote lifestyles and are likely to give a competitive advantage to the organism. Paralogs and singletons dominate different categories of functional classification, where paralogs in particular seem to be associated with processes involving interaction with the environment. PMID- 20961427 TI - Analysis of binding properties and specificity through identification of the interface forming residues (IFR) for serine proteases in silico docked to different inhibitors. AB - BACKGROUND: Enzymes belonging to the same super family of proteins in general operate on variety of substrates and are inhibited by wide selection of inhibitors. In this work our main objective was to expand the scope of studies that consider only the catalytic and binding pocket amino acids while analyzing enzyme specificity and instead, include a wider category which we have named the Interface Forming Residues (IFR). We were motivated to identify those amino acids with decreased accessibility to solvent after docking of different types of inhibitors to sub classes of serine proteases and then create a table (matrix) of all amino acid positions at the interface as well as their respective occupancies. Our goal is to establish a platform for analysis of the relationship between IFR characteristics and binding properties/specificity for bi-molecular complexes. RESULTS: We propose a novel method for describing binding properties and delineating serine proteases specificity by compiling an exhaustive table of interface forming residues (IFR) for serine proteases and their inhibitors. Currently, the Protein Data Bank (PDB) does not contain all the data that our analysis would require. Therefore, an in silico approach was designed for building corresponding complexes. The IFRs are obtained by "rigid body docking" among 70 structurally aligned, sequence wise non-redundant, serine protease structures with 3 inhibitors: bovine pancreatic trypsin inhibitor (BPTI), ecotine and ovomucoid third domain inhibitor. The table (matrix) of all amino acid positions at the interface and their respective occupancy is created. We also developed a new computational protocol for predicting IFRs for those complexes which were not deciphered experimentally so far, achieving accuracy of at least 0.97. CONCLUSIONS: The serine proteases interfaces prefer polar (including glycine) residues (with some exceptions). Charged residues were found to be uniquely prevalent at the interfaces between the "miscellaneous-virus" subfamily and the three inhibitors. This prompts speculation about how important this difference in IFR characteristics is for maintaining virulence of those organisms.Our work here provides a unique tool for both structure/function relationship analysis as well as a compilation of indicators detailing how the specificity of various serine proteases may have been achieved and/or could be altered. It also indicates that the interface forming residues which also determine specificity of serine protease subfamily can not be presented in a canonical way but rather as a matrix of alternative populations of amino acids occupying variety of IFR positions. PMID- 20961428 TI - Is human blood a good surrogate for brain tissue in transcriptional studies? AB - BACKGROUND: Since human brain tissue is often unavailable for transcriptional profiling studies, blood expression data is frequently used as a substitute. The underlying hypothesis in such studies is that genes expressed in brain tissue leave a transcriptional footprint in blood. We tested this hypothesis by relating three human brain expression data sets (from cortex, cerebellum and caudate nucleus) to two large human blood expression data sets (comprised of 1463 individuals). RESULTS: We found mean expression levels were weakly correlated between the brain and blood data (r range: [0.24,0.32]). Further, we tested whether co-expression relationships were preserved between the three brain regions and blood. Only a handful of brain co-expression modules showed strong evidence of preservation and these modules could be combined into a single large blood module. We also identified highly connected intramodular "hub" genes inside preserved modules. These preserved intramodular hub genes had the following properties: first, their expression levels tended to be significantly more heritable than those from non-preserved intramodular hub genes (p < 10-90); second, they had highly significant positive correlations with the following cluster of differentiation genes: CD58, CD47, CD48, CD53 and CD164; third, a significant number of them were known to be involved in infection mechanisms, post-transcriptional and post-translational modification and other basic processes. CONCLUSIONS: Overall, we find transcriptome organization is poorly preserved between brain and blood. However, the subset of preserved co-expression relationships characterized here may aid future efforts to identify blood biomarkers for neurological and neuropsychiatric diseases when brain tissue samples are unavailable. PMID- 20961429 TI - Review for the generalist: The antinuclear antibody test in children - When to use it and what to do with a positive titer. AB - The antinuclear antibody test (ANA) is a much overused test in pediatrics. The ANA does have a role in serologic testing but it should be a very limited one. It is often ordered as a screening test for rheumatic illnesses in a primary care setting. However, since it has low specificity and sensitivity for most rheumatic and musculoskeletal illnesses in children, it should not be ordered as a screening test for non-specific complaints such as musculoskeletal pain. It should only be used as a diagnostic test for children with probable Systemic Lupus Erythematosus (SLE) or Mixed Connective Tissue Disease, (MCTD) and other possible overlap-like illnesses. Such children should have developed definite signs and symptoms of a disease before the ANA is ordered. This review presents data supporting these conclusions and a review of the ANA literature in adults and children.By limiting ANA testing, primary care providers can avoid needless venipuncture pain, unnecessary referrals, extra medical expenses, and most importantly, significant parental anxieties. It is best not to do the ANA test in most children but if it ordered and is positive in a low titer (<1:640), the results can be ignored if the child is otherwise well and does not have other features of a systemic illness. PMID- 20961430 TI - Abalone visceral extract inhibit tumor growth and metastasis by modulating Cox-2 levels and CD8+ T cell activity. AB - BACKGROUND: Abalone has long been used as a valuable food source in East Asian countries. Although the nutritional importance of abalone has been reported through in vitro and in vivo studies, there is little evidence about the potential anti-tumor effects of abalone visceral extract. The aim of the present study is to examine anti-tumor efficacy of abalone visceral extract and to elucidate its working mechanism. METHODS: In the present study, we used breast cancer model using BALB/c mouse-derived 4T1 mammary carcinoma and investigated the effect of abalone visceral extract on tumor development. Inhibitory effect against tumor metastasis was assessed by histopathology of lungs. Cox-2 productions by primary and secondary tumor were measured by real-time RT-PCR and immunoblotting (IB). Proliferation assay based on [3H]-thymidine incorporation and measurement of cytokines and effector molecules by RT-PCR were used to confirm tumor suppression efficacy of abalone visceral extract by modulating cytolytic CD8+ T cells. The cytotoxicity of CD8+ T cell was compared by JAM test. RESULTS: Oral administration of abalone visceral extract reduced tumor growth (tumor volume and weight) and showed reduced metastasis as confirmed by decreased level of splenomegaly (spleen size and weight) and histological analysis of the lung metastasis (gross analysis and histological staining). Reduced expression of Cox-2 (mRNA and protein) from primary tumor and metastasized lung was also detected. In addition, treatment of abalone visceral extract increased anti-tumor activities of CD8+ T cells by increasing the proliferation capacity and their cytolytic activity. CONCLUSIONS: Our results suggest that abalone visceral extract has anti-tumor effects by suppressing tumor growth and lung metastasis through decreasing Cox-2 expression level as well as promoting proliferation and cytolytic function of CD8+ T cells. PMID- 20961431 TI - ECMO-assisted carinal resection and reconstruction after left pneumonectomy. AB - Extracorporeal Membrane Oxygenation (ECMO) has become an increasingly important technique for patients with respiratory or cardiac failure for a variety of causes. In addition, there are many reports about the use of ECMO in surgical operation on neonates and children patients with tracheal obstruction. In this report we present a case about an adult patient who underwent a carinal resection and reconstruction after left pneumonectomy with ECMO assistance successfully. To our knowledge, this case is the first of its kind to use ECMO in adult carinal resection and reconstruction after pneumonectomy. In this report, we try to illustrate that ECMO is effective in operations of this kind. PMID- 20961432 TI - HPV - immune response to infection and vaccination. AB - HPV infection in the genital tract is common in young sexually active individuals, the majority of whom clear the infection without overt clinical disease. However most of those who develop benign lesions eventually mount an effective cell mediated immune (CMI) response and the lesions regress.Failure to develop effective CMI to clear or control infection results in persistent infection and, in the case of the oncogenic HPVs, an increased probability of progression to CIN3 and invasive carcinoma. The prolonged duration of infection associated with HPV seems to be associated with effective evasion of innate immunity thus delaying the activation of adaptive immunity.Natural infections in animals show that neutralising antibody to the virus coat protein L1 is protective suggesting that this would be an effective prophylactic vaccine strategy. The current prophylactic HPV VLP vaccines are delivered i.m. circumventing the intra-epithelial immune evasion strategies. These vaccines generate high levels of antibody and both serological and B cell memory as evidenced by persistence of antibody and robust recall responses. However there is no immune correlate - no antibody level that correlates with protection. Recent data on how HPV infects basal epithelial cells and how antibody can prevent this provides a mechanistic explanation for the effectiveness of HPV VLP vaccines. PMID- 20961433 TI - Lassa virus-like particles displaying all major immunological determinants as a vaccine candidate for Lassa hemorrhagic fever. AB - BACKGROUND: Lassa fever is a neglected tropical disease with significant impact on the health care system, society, and economy of Western and Central African nations where it is endemic. Treatment of acute Lassa fever infections has successfully utilized intravenous administration of ribavirin, a nucleotide analogue drug, but this is not an approved use; efficacy of oral administration has not been demonstrated. To date, several potential new vaccine platforms have been explored, but none have progressed toward clinical trials and commercialization. Therefore, the development of a robust vaccine platform that could be generated in sufficient quantities and at a low cost per dose could herald a subcontinent-wide vaccination program. This would move Lassa endemic areas toward the control and reduction of major outbreaks and endemic infections. To this end, we have employed efficient mammalian expression systems to generate a Lassa virus (LASV)-like particle (VLP)-based modular vaccine platform. RESULTS: A mammalian expression system that generated large quantities of LASV VLP in human cells at small scale settings was developed. These VLP contained the major immunological determinants of the virus: glycoprotein complex, nucleoprotein, and Z matrix protein, with known post-translational modifications. The viral proteins packaged into LASV VLP were characterized, including glycosylation profiles of glycoprotein subunits GP1 and GP2, and structural compartmentalization of each polypeptide. The host cell protein component of LASV VLP was also partially analyzed, namely glycoprotein incorporation, though the identity of these proteins remain unknown. All combinations of LASV Z, GPC, and NP proteins that generated VLP did not incorporate host cell ribosomes, a known component of native arenaviral particles, despite detection of small RNA species packaged into pseudoparticles. Although VLP did not contain the same host cell components as the native virion, electron microscopy analysis demonstrated that LASV VLP appeared structurally similar to native virions, with pleiomorphic distribution in size and shape. LASV VLP that displayed GPC or GPC+NP were immunogenic in mice, and generated a significant IgG response to individual viral proteins over the course of three immunizations, in the absence of adjuvants. Furthermore, sera from convalescent Lassa fever patients recognized VLP in ELISA format, thus affirming the presence of native epitopes displayed by the recombinant pseudoparticles. CONCLUSIONS: These results established that modular LASV VLP can be generated displaying high levels of immunogenic viral proteins, and that small laboratory scale mammalian expression systems are capable of producing multi milligram quantities of pseudoparticles. These VLP are structurally and morphologically similar to native LASV virions, but lack replicative functions, and thus can be safely generated in low biosafety level settings. LASV VLP were immunogenic in mice in the absence of adjuvants, with mature IgG responses developing within a few weeks after the first immunization. These studies highlight the relevance of a VLP platform for designing an optimal vaccine candidate against Lassa hemorrhagic fever, and warrant further investigation in lethal challenge animal models to establish their protective potential. PMID- 20961434 TI - Complete response in gallbladder cancer to erlotinib plus gemcitabine does not require mutation of the epidermal growth factor receptor gene: a case report. AB - BACKGROUND: Gallbladder cancer typically follows an aggressive course, with chemotherapy the standard of care for advanced disease; complete remissions are rarely encountered. The epidermal growth factor receptor (EGFR) is a promising therapeutic target but the activity of single agent oral EGFR tyrosine kinase inhibitors is low. There have been no previous reports of chemotherapy plus an EGFR-tyrosine kinase inhibitor (TKI) to treat gallbladder cancer or correlations of response with the mutation status of the tyrosine kinase domain of the EGFR gene. CASE PRESENTATION: A 67 year old man with metastatic gallbladder cancer involving the liver and abdominal lymph nodes was treated with gemcitabine (1000 mg/m2) on day 1 and 8 every 21 days as well as daily erlotinib (100 mg). After four cycles of therapy, the CA 19-9 normalized and a PET/CT showed a complete remission; this response was maintained by the end of 12 cycles of therapy. Gemcitabine was then discontinued and single agent erlotinib was continued as maintenance therapy. The disease remains in good control 18 months after initiation of therapy, including 6 months on maintenance erlotinib. The only grade 3 toxicity was a typical EGFR-related skin rash. Because of the remarkable response to erlotinib plus gemcitabine, we performed tumor genotyping of the EGFR gene for response predicting mutations in exons 18, 19 and 21. This disclosed the wild-type genotype with no mutations found. CONCLUSION: This case report demonstrates a patient with stage IV gallbladder cancer who experienced a rarely encountered complete, prolonged response after treatment with an oral EGFR-TKI plus chemotherapy. This response occurred in the absence of an EGFR gene mutation. These observations should inform the design of clinical trials using EGFR-TKIs to treat gallbladder and other biliary tract cancers; such trials should not select patients based on EGFR mutation status. PMID- 20961435 TI - The 6th Meeting of the Global Alliance to Eliminate Lymphatic Filariasis: A half time review of lymphatic filariasis elimination and its integration with the control of other neglected tropical diseases. AB - The 6th Meeting of the Global Alliance to Eliminate Lymphatic Filariasis (GAELF6) was held 1-3 June, 2010 in Seoul, Korea, with 150 participants from 38 countries. The year 2010 marks the midpoint between the first GAELF meeting, in 2000, and the World Health Organization (WHO) 2020 goal of global elimination of lymphatic filariasis (LF) as a public health problem. The theme of the meeting, "Half-time in LF Elimination: Teaming Up with Neglected Tropical Diseases (NTDs)," reflected significant integration of LF elimination programmes into a comprehensive initiative to control NTDs. Presentations on LF epidemiology, treatment, research, and programmes highlighted both accomplishments and remaining challenges.The WHO strategy to interrupt LF transmission is based on annual mass drug administration (MDA) using two-drug combinations. After mapping the geographic distribution of LF, MDA is implemented for >= 5 years, followed by a period of post-MDA surveillance, and, ultimately, verification of LF elimination. Morbidity management further reduces disease burden.Of 81 countries considered LF-endemic in 2000, 52 (64.2%) have begun MDA; 10 (12.3%) others with low-level transmission are unlikely to require MDA. In 2008, ~695 million people were offered treatment (51.7% of the at-risk population); ~496 million participated. Approximately 22 million people have been protected from LF infection and disease, with savings of ~US $24.2 billion. Morbidity management programmes have been implemented in 27 (33.3%) countries.Significant challenges to LF elimination remain. These include: initiating MDA in the remaining 19 countries that require it; achieving full geographic coverage in countries where MDA has started; finding alternative strategies to address the problem of Loa loa co-endemicity in Central Africa; developing strategies to treat urban populations; initiating and sustaining MDA in settings of armed conflict; developing refined guidelines and procedures for stopping MDA, for post-MDA surveillance, and for verifying the elimination of LF; and integrating morbidity management into all LF elimination programmes. Scientific research and enhanced advocacy for NTDs remain critical for addressing these challenges.GAELF6 was characterized by enthusiasm and recognition that "teaming up with NTDs" offers opportunities for new partnerships, fresh perspectives, enhanced advocacy, and greater programmatic integration in a rapidly changing global health environment. PMID- 20961436 TI - Domains of disgust sensitivity: revisited factor structure of the questionnaire for the assessment of disgust sensitivity (QADS) in a cross-sectional, representative German survey. AB - BACKGROUND: Disgust sensitivity is defined as a predisposition to experiencing disgust, which can be measured on the basis of the Disgust Scale and its German version, the Questionnaire for the Assessment of Disgust Sensitivity (QADS). In various studies, different factor structures were reported for either instrument. The differences may most likely be due to the selected factor analysis estimation methods and the small non-representative samples. Consequently, the aims of this study were to explore and confirm a theory-driven and statistically coherent QADS factor structure in a large representative sample and to present its standard values. METHODS: The QADS was answered by N = 2473 healthy subjects. The respective households and participants were selected using the random-route sampling method. Afterwards, the collected sample was compared to the information from the Federal Statistical Office to ensure that it was representative for the German residential population. With these data, an exploratory Promax-rotated Principal Axis Factor Analysis as well as comparative confirmatory factor analyses with robust Maximum Likelihood estimations were computed. Any possible socio-demographic influences were quantified as effect sizes. RESULTS: The data driven and theoretically sound solution with the three highly interrelated factors Animal Reminder Disgust, Core Disgust, and Contamination Disgust led to a moderate model fit. All QADS scales had very good reliabilities (Cronbach's alpha) from .90 to .95. There were no age-differences found among the participants, however, the female participants showed remarkably higher disgust ratings. CONCLUSIONS: Based on the representative sample, the QADS factor structure was revised. Gender-specific standard percentages permit a population based assessment of individual disgust sensitivity. The differences of the original QADS, the new solution, and the Disgust Scale - Revised will be discussed. PMID- 20961437 TI - Treatment of femoral neck fractures in elderly patients over 60 years of age - which is the ideal modality of primary joint replacement? AB - BACKGROUND: Femoral neck fractures in the elderly are frequent, represent a great health care problem, and have a significant impact on health insurance costs. Reconstruction options using hip arthroplasty include unipolar or bipolar hemiarthroplasty (HA), and total hip arthroplasty (THA). The purpose of this review is to discuss the indications, limitations, and pitfalls of each of these techniques. METHODS: The Pubmed database was searched for all articles on femoral neck fracture and for the reconstruction options presented in this review using the search terms "femoral neck fracture", "unipolar hemiarthroplasty", "bipolar hemiarthroplasty", and "total hip arthroplasty". In addition, cross-referencing was used to cover articles eventually undetected by the respective search strategies. The resulting articles were then reviewed with regard to the different techniques, outcome and complications of the distinct reconstruction options. RESULTS: THA yields the best functional results in patients with displaced femoral neck fractures with complication rates comparable to HA. THA is beneficially implanted using an anterior approach exploiting the internervous plane between the tensor fasciae latae and the sartorius muscles allowing for immediate full weight-bearing. Based on our findings, bipolar hemiarthroplasty, similar to unipolar hemiarthroplasty, cannot restorate neither anatomical nor biomechanical features of the hip joint. Therefore, it can only be recommended as a second line of defense-procedure for patients with low functional demands and limited live expectancy. CONCLUSIONS: THA is the treatment of choice for femoral neck fractures in patients older than 60 years. HA should only be implanted in patients with limited life expectancy. PMID- 20961438 TI - Using gene expression profiles from peripheral blood to identify asymptomatic responses to acute respiratory viral infections. AB - BACKGROUND: A recent study reported that gene expression profiles from peripheral blood samples of healthy subjects prior to viral inoculation were indistinguishable from profiles of subjects who received viral challenge but remained asymptomatic and uninfected. If true, this implies that the host immune response does not have a molecular signature. Given the high sensitivity of microarray technology, we were intrigued by this result and hypothesize that it was an artifact of data analysis. FINDINGS: Using acute respiratory viral challenge microarray data, we developed a molecular signature that for the first time allowed for an accurate differentiation between uninfected subjects prior to viral inoculation and subjects who remained asymptomatic after the viral challenge. CONCLUSIONS: Our findings suggest that molecular signatures can be used to characterize immune responses to viruses and may improve our understanding of susceptibility to viral infection with possible implications for vaccine development. PMID- 20961439 TI - Universal and specific quantitative detection of botulinum neurotoxin genes. AB - BACKGROUND: Clostridium botulinum, an obligate anaerobic spore-forming bacterium, produces seven antigenic variants of botulinum toxin that are distinguished serologically and termed "serotypes". Botulinum toxin blocks the release of acetylcholine at neuromuscular junctions resulting in flaccid paralysis. The potential lethality of the disease warrants a fast and accurate means of diagnosing suspected instances of food contamination or human intoxication. Currently, the Food and Drug Administration (FDA)-accepted assay to detect and type botulinum neurotoxins (BoNTs) is the mouse protection bioassay. While specific and sensitive, this assay requires the use of laboratory animals, may take up to four days to achieve a diagnosis, and is unsuitable for high throughput analysis. We report here a two-step PCR assay that identifies all toxin types, that achieves the specificity of the mouse bioassay while surpassing it in equivalent sensitivity, that has capability for high-throughput analysis, and that provides quantitative results within hours. The first step of our assay consists of a conventional PCR that detects the presence of C. botulinum regardless of the neurotoxin type. The second step uses quantitative PCR (qPCR) technology to determine the specific serotype of the neurotoxin. RESULTS: We assayed purified C. botulinum DNA and crude toxin preparations, as well as food and stool from healthy individuals spiked with purified BoNT DNA, and one stool sample from a case of infant botulism for the presence of the NTNH gene, which is part of the BoNT gene cluster, and for the presence of serotype-specific BoNT genes. The PCR surpassed the mouse bioassay both in specificity and sensitivity, detecting positive signals in BoNT preparations containing well below the 1 LD50 required for detection via the mouse bioassay. These results were type-specific and we were reliably able to quantify as few as 10 genomic copies. CONCLUSIONS: While other studies have reported conventional or quantitative PCR-based assays for the detection of C. botulinum genes, our procedure's high-throughput capability and its portability allows most laboratories to quickly assess the possible presence of BoNTs either in food processing samples or in suspected cases of botulism. Thus, this assay provides rapid and specific detection of BoNT and toxin complex genes and would enable the targeting of appropriate therapeutics to infected individuals in a timely manner. PMID- 20961440 TI - Life-threatening hypersplenism due to idiopathic portal hypertension in early childhood: case report and review of the literature. AB - BACKGROUND: Idiopathic portal hypertension (IPH) is a disorder of unknown etiology and is characterized clinically by portal hypertension, splenomegaly, and hypersplenism accompanied by pancytopenia. This study evaluates the pathogenic concept of the disease by a systematic review of the literature and illustrates novel pathologic and laboratory findings. CASE PRESENTATION: We report the first case of uncontrolled splenic hyperperfusion and enlargement with subsequent hypersplenism leading to life-threatening complications of IPH in infancy and emergent splenectomy. CONCLUSIONS: Our results suggest that splenic NO and VCAM-1, rather than ET-1, have a significant impact on the development of IPH, even at a very early stage of disease. The success of surgical interventions targeting the splenic hyperperfusion suggests that the primary defect in the regulation of splenic blood flow seems to be crucial for the development of IPH. Thus, beside other treatment options splenectomy needs to be considered as a prime therapeutic option for IPH. PMID- 20961441 TI - Surveys of current status in biomedical science grant review: funding organisations' and grant reviewers' perspectives. AB - BACKGROUND: The objectives of this research were (a) to describe the current status of grant review for biomedical projects and programmes from the perspectives of international funding organisations and grant reviewers, and (b) to explore funders' interest in developing uniform requirements for grant review aimed at making the processes and practices of grant review more consistent, transparent, and user friendly. METHODS: A survey to a convenience sample of 57 international public and private organisations that give grants for biomedical research was conducted. Nine participating organisations then emailed a random sample of their external reviewers an invitation to participate in a second electronic survey. RESULTS: A total of 28 of 57 (49%) organisations in 19 countries responded. Organisations reported these problems as frequent or very frequent: declined review requests (16), late reports (10), administrative burden (7), difficulty finding new reviewers (4), and reviewers not following guidelines (4). The administrative burden of the process was reported to have increased over the past 5 years. In all, 17 organisations supported the idea of uniform requirements for conducting grant review and for formatting grant proposals. A total of 258/418 (62%) reviewers responded from 22 countries. Of those, 48% (123/258) said their institutions encouraged grant review, yet only 7% (17/258) were given protected time and 74% (192/258) received no academic recognition for this. Reviewers rated these factors as extremely or very important in deciding to review proposals: 51% (131/258) desire to support external fairness, 47% (120/258) professional duty, 46% (118/258) relevance of the proposal's topic, 43% (110/258) wanting to keep up to date, 40% (104/258) desire to avoid suppression of innovation. Only 16% (42/258) reported that guidance from funders was very clear. In all, 85% (220/258) had not been trained in grant review and 64% (166/258) wanted this. CONCLUSIONS: Funders reported a growing workload of biomedical proposals that is getting harder to peer review. Just under half of grant reviewers take part for the good of science and professional development, but many report lack of academic and practical support and clear guidance. Around two-thirds of funders supported the development of uniform requirements for the format and peer review of proposals to help ease the current situation. PMID- 20961442 TI - Normalisation process theory: a framework for developing, evaluating and implementing complex interventions. AB - BACKGROUND: The past decade has seen considerable interest in the development and evaluation of complex interventions to improve health. Such interventions can only have a significant impact on health and health care if they are shown to be effective when tested, are capable of being widely implemented and can be normalised into routine practice. To date, there is still a problematic gap between research and implementation. The Normalisation Process Theory (NPT) addresses the factors needed for successful implementation and integration of interventions into routine work (normalisation). DISCUSSION: In this paper, we suggest that the NPT can act as a sensitising tool, enabling researchers to think through issues of implementation while designing a complex intervention and its evaluation. The need to ensure trial procedures that are feasible and compatible with clinical practice is not limited to trials of complex interventions, and NPT may improve trial design by highlighting potential problems with recruitment or data collection, as well as ensuring the intervention has good implementation potential. SUMMARY: The NPT is a new theory which offers trialists a consistent framework that can be used to describe, assess and enhance implementation potential. We encourage trialists to consider using it in their next trial. PMID- 20961443 TI - A colliding maxillary sinus cancer of adenosquamous carcinoma and small cell neuroendocrine carcinoma--a case report with EGFR copy number analysis. AB - BACKGROUND: Small cell neuroendocrine carcinoma (SNEC) of maxillary sinus is a rare and aggressive malignancy. A tumor with squamous cell carcinoma, adenocarcinoma and SNEC co-existence is extremely rare. CASE PRESENTATION: We present a colliding tumor of squamous cell, adenocarcinoma and SNEC in maxillary sinus. The clinical features, diagnosis and EGFR flourescence in situ hybridization (FISH) study are presented. A 52-year-old female had a 1-month history of progressing left cheek swelling and purulent rhinorrhea. Magnetic resonance imaging showed a tumor involving left maxilla and orbital floor. Excision of tumor was done and the defect was reconstructed with free flap. The pathology revealed a malignant tumor composed of squamous cell carcinoma, adenocarcinoma and SNEC components. EGFR FISH study showed no gene amplification in 3 components of this tumor. The tumor progressed rapidly and the patient expired at 8 months after surgery. CONCLUSION: A colliding tumor of squamous cell, adenocarcinoma and neuroendocrine carcinoma in maxillary sinus was aggressive in behavior and the treatment response was poor due to the complexity of tumor. PMID- 20961444 TI - Study protocol for a randomized controlled trial comparing mindfulness-based cognitive therapy with maintenance anti-depressant treatment in the prevention of depressive relapse/recurrence: the PREVENT trial. AB - BACKGROUND: Depression is a common and distressing mental health problem that is responsible for significant individual disability and cost to society. Medication and psychological therapies are effective for treating depression and maintenance anti-depressants (m-ADM) can prevent relapse. However, individuals with depression often express a wish for psychological help that can help them recover from depression in the long-term. We need to develop psychological therapies that prevent depressive relapse/recurrence. A recently developed treatment, Mindfulness-based Cognitive Therapy (MBCT, see http://www.mbct.co.uk) shows potential as a brief group programme for people with recurring depression. In two studies it has been shown to halve the rates of depression recurring compared to usual care.This trial asks the policy research question, is MBCT superior to m ADM in terms of: a primary outcome of preventing depressive relapse/recurrence over 24 months; and, secondary outcomes of (a) depression free days, (b) residual depressive symptoms, (c) antidepressant (ADM) usage, (d) psychiatric and medical co-morbidity, (e) quality of life, and (f) cost effectiveness? An explanatory research question asks is an increase in mindfulness skills the key mechanism of change? METHODS/DESIGN: The design is a single blind, parallel RCT examining MBCT vs. m-ADM with an embedded process study. To answer the main policy research question the proposed trial compares MBCT plus ADM-tapering with m-ADM for patients with recurrent depression. Four hundred and twenty patients with recurrent major depressive disorder in full or partial remission will be recruited through primary care. Depressive relapse/recurrence over two years is the primary outcome variable. The explanatory question will be addressed in two mutually informative ways: quantitative measurement of potential mediating variables pre/post-treatment and a qualitative study of service users' views and experiences. DISCUSSION: If the results of our exploratory trial are extended to this definitive trial, MBCT will be established as an alternative approach to maintenance anti-depressants for people with a history of recurrent depression. The process studies will provide evidence about the effective components which can be used to improve MBCT and inform theory as well as other therapeutic approaches. TRIAL REGISTRATION NUMBER: ISRCTN26666654. PMID- 20961445 TI - Conservation of resources theory and research use in health systems. AB - BACKGROUND: Health systems face challenges in using research evidence to improve policy and practice. These challenges are particularly evident in small and poorly resourced health systems, which are often in locations (in Canada and globally) with poorer health status. Although organizational resources have been acknowledged as important in understanding research use resource theories have not been a focus of knowledge translation (KT) research. What resources, broadly defined, are required for KT and how does their presence or absence influence research use?In this paper, we consider conservation of resources (COR) theory as a theoretical basis for understanding the capacity to use research evidence in health systems. Three components of COR theory are examined in the context of KT. First, resources are required for research uptake. Second, threat of resource loss fosters resistance to research use. Third, resources can be optimized, even in resource-challenged environments, to build capacity for KT. METHODS: A scan of the KT literature examined organizational resources needed for research use. A multiple case study approach examined the three components of COR theory outlined above. The multiple case study consisted of a document review and key informant interviews with research team members, including government decision-makers and health practitioners through a retrospective analysis of four previously conducted applied health research studies in a resource-challenged region. RESULTS: The literature scan identified organizational resources that influence research use. The multiple case study supported these findings, contributed to the development of a taxonomy of organizational resources, and revealed how fears concerning resource loss can affect research use. Some resources were found to compensate for other resource deficits. Resource needs differed at various stages in the research use process. CONCLUSIONS: COR theory contributes to understanding the role of resources in research use, resistance to research use, and potential strategies to enhance research use. Resources (and a lack of them) may account for the observed disparities in research uptake across health systems. This paper offers a theoretical foundation to guide further examination of the COR-KT ideas and necessary supports for research use in resource-challenged environments. PMID- 20961446 TI - A prospective study of weight development and behavior problems in toddlers: the Norwegian Mother and Child Cohort Study. AB - BACKGROUND: Previous research has suggested that overweight children have a higher risk of behavior problems, but the causal direction of this relationship remains unclear. In a large prospective population study, we investigated whether child behavior problems and body mass index are associated in toddlers and whether overweight is a risk for behavior problems or vice versa. METHODS: The study was part of the Norwegian Mother and Child Cohort Study. The sample consisted of 10 860 toddlers, followed up to age 36 months. We used data from maternal questionnaires from gestation week 17 and at child ages 18 and 36 months, and data from the Medical Birth Registry of Norway. Child height and weight were assessed at child health stations and recorded by mothers. Behavior problems were assessed using shortened subscales from the Child Behavior Checklist. Statistical analyses were conducted using structural equation modeling. RESULTS: Behavior problems in toddlers were not associated with higher body mass index cross-sectionally at either age 18 or 36 months, and there was no indication that behavior problems caused increasing body mass index over time or vice versa. CONCLUSIONS: The association between behavior problems and body mass index found in older children did not appear in toddlers up to age 36 months. Future studies should focus on the age span from 3 to 6 years, which includes the period of adiposity rebound. PMID- 20961447 TI - Riboswitches as hormone receptors: hypothetical cytokinin-binding riboswitches in Arabidopsis thaliana. AB - BACKGROUND: Riboswitches are mRNA elements that change conformation when bound to small molecules. They are known to be key regulators of biosynthetic pathways in both prokaryotes and eukaryotes. PRESENTATION OF THE HYPOTHESIS: The hypothesis presented here is that riboswitches function as receptors in hormone perception. We propose that riboswitches initiate or integrate signaling cascades upon binding to classic signaling molecules. The molecular interactions for ligand binding and gene expression control would be the same as for biosynthetic pathways, but the context and the cadre of ligands to consider is dramatically different. The hypothesis arose from the observation that a compound used to identify adenine binding RNA sequences is chemically similar to the classic plant hormone, or growth regulator, cytokinin. A general tenet of the hypothesis is that riboswitch-binding metabolites can be used to make predictions about chemically related signaling molecules. In fact, all cell permeable signaling compounds can be considered as potential riboswitch ligands. The hypothesis is plausible, as demonstrated by a cursory review of the transcriptome and genome of the model plant Arabidopsis thaliana for transcripts that i) contain an adenine aptamer motif, and ii) are also predicted to be cytokinin-regulated. Here, one gene, CRK10 (for Cysteine-rich Receptor-like Kinase 10, At4g23180), contains an adenine aptamer-related sequence and is down-regulated by cytokinin approximately three-fold in public gene expression data. To illustrate the hypothesis, implications of cytokinin-binding to the CRK10 mRNA are discussed. TESTING THE HYPOTHESIS: At the broadest level, screening various cell permeable signaling molecules against random RNA libraries and comparing hits to sequence and gene expression data bases could determine how broadly the hypothesis applies. Specific cases, such as CRK10 presented here, will require experimental validation of direct ligand binding, altered RNA conformation, and effect on gene expression. Each case will be different depending on the signaling pathway and the physiology involved. IMPLICATIONS OF THE HYPOTHESIS: This would be a very direct signal perception mechanism for regulating gene expression; rivaling animal steroid hormone receptors, which are frequently ligand dependent transcription initiation factors. Riboswitch-regulated responses could occur by modulating target RNA stability, translatability, and alternative splicing - all known expression platforms used in riboswitches. The specific illustration presented, CRK10, implies a new mechanism for the perception of cytokinin, a classic plant hormone. Experimental support for the hypothesis would add breadth to the growing list of important functions attributed to riboswitches. REVIEWERS: This article was reviewed by Anthony Poole, Rob Knight, Mikhail Gelfand. PMID- 20961448 TI - Human functional genetic studies are biased against the medically most relevant primate-specific genes. AB - BACKGROUND: Many functional, structural and evolutionary features of human genes have been observed to correlate with expression breadth and/or gene age. Here, we systematically explore these correlations. RESULTS: Gene age and expression breadth are strongly correlated, but contribute independently to the variation of functional, structural and evolutionary features, even when we take account of variation in mRNA expression level. Human genes without orthologs in distant species ('young' genes) tend to be tissue-specific in their expression. As computational inference of gene function often relies on the existence of homologs in other species, and experimental characterization is facilitated by broad and high expression, young, tissue-specific human genes are often the least characterized. At the same time, young genes are most likely to be medically relevant. CONCLUSIONS: Our results indicate that functional characterization of human genes is biased against young, tissue-specific genes that are mostly medically relevant. The biases should not be taken lightly because they may pose serious obstacles to our understanding of the molecular basis of human diseases. Future studies should thus be designed to specifically explore the properties of primate-specific genes. PMID- 20961449 TI - Imported malaria in an area in southern Madrid, 2005-2008. AB - BACKGROUND: In Spain, malaria cases are mostly due to migrants and travellers returning from endemic areas. The objective of this work was to describe the malaria cases diagnosed at the Severo Ochoa University Hospital (HUSO) in Leganes in the south of the Madrid Region from 2005 to 2008. METHODS: Descriptive retrospective study performed at HUSO. Data sources are registries from the Microbiology Department and malaria cases notified to the Preventive Medicine Department. Analysed parameters were: administrative, demographical, related to the stay at the endemic country, clinical, microbiological diagnosis method, pregnancy, treatment and prophylaxis, co-infections, and days of hospital stay. RESULTS: Fifty-seven patients diagnosed with malaria were studied. Case distribution per year was 13 in 2005, 15 in 2006, 15 in 2007 and 14 in 2008. Thirty-three patients were female (57.9%) and 24 male (42.1%). Mean age was 27.8 years. Most of the malaria cases were acquired in Nigeria (49.1%) and Equatorial Guinea (32.7%). 29.1% of the patients were immigrants who had arrived recently, and 61.8% acquired malaria when travelling to their countries of origin to visit friends and relatives (VFR). Majority of cases were diagnosed between June and September. Microscopy was positive in 39 cases (68.4%) immunochromatography in 42 (73.7%) and PCR in the 55 cases where performed. Plasmodium falciparum was responsible for 94.7% of the cases. The more frequent symptoms were fever (77.2%), followed by headache and gastrointestinal symptoms (33.3%). Nine cases needed hospital admittance, a pregnant woman, three children, four VFR and an African tourist, but all evolved favourably. Chemoprophylaxis data was known from 55 patients. It was taken correctly in one case (1.8%), in five (9.1%) the prophylaxis was improper while the others 49 (89.1%) cases had not followed any anti-malarial prophylaxis. CONCLUSIONS: Children, pregnant women and the VFR have the highest risk to present severe malaria and to need hospital admittance. Another important risk factor for acquiring malaria is incorrect prophylaxis. The first place for malaria acquisition was Nigeria and the main species causing malaria was P. falciparum. PMID- 20961450 TI - Domiciliary pulse-oximetry at exacerbation of chronic obstructive pulmonary disease: prospective pilot study. AB - BACKGROUND: The ability to objectively differentiate exacerbations of chronic obstructive pulmonary disease (COPD) from day-to-day symptom variations would be an important development in clinical practice and research. We assessed the ability of domiciliary pulse oximetry to achieve this. METHODS: 40 patients with moderate-severe COPD collected daily data on changes in symptoms, heart-rate (HR), oxygen saturation (SpO2) and peak-expiratory flow (PEF) over a total of 2705 days. 31 patients had data suitable for baseline analysis, and 13 patients experienced an exacerbation. Data were expressed as multiples of the standard deviation (SD) observed from each patient when stable. RESULTS: In stable COPD, the SD for HR, SpO2 and PEF were approximately 5 min(-1), 1% and 10l min(-1). There were detectable changes in all three variables just prior to exacerbation onset, greatest 2-3 days following symptom onset. A composite Oximetry Score (mean magnitude of SpO2 fall and HR rise) distinguished exacerbation onset from symptom variation (area under receiver-operating characteristic curve, AUC = 0.832, 95%CI 0.735-0.929, p = 0.003). In the presence of symptoms, a change in Score of >=1 (average of >=1SD change in both HR and SpO2) was 71% sensitive and 74% specific for exacerbation onset. CONCLUSION: We have defined normal variation of pulse oximetry variables in a small sample of patients with COPD. A composite HR and SpO2 score distinguished exacerbation onset from symptom variation, potentially facilitating prompt therapy and providing validation of such events in clinical trials. PMID- 20961451 TI - Maximizing the general success of cecal intubation during propofol sedation in a multi-endoscopist academic centre. AB - BACKGROUND: Achieving the target of 95% colonoscopy completion rate at centres conducting colorectal screening programs is an important issue. Large centres and teaching hospitals employing endoscopists with different levels of training and expertise risk achieving worse results. Deep sedation with propofol in routine colonoscopy could maximize the results of cecal intubation. METHODS: The present study on the experience of a single centre focused on estimating the overall completion rate of colonoscopies performed under routine propofol sedation at a large teaching hospital with many operators involved, and on assessing the factors that influence the success rate of the procedure and how to improve this performance, analyzing the aspects relating to using of deep sedation. Twenty-one endoscopists, classified by their level of specialization in colonoscopic practice, performed 1381 colonoscopies under deep sedation. All actions needed for the anaesthesiologist to restore adequate oxygenation or hemodynamics, even for transient changes, were recorded. RESULTS: The "crude" overall completion rate was 93.3%. This finding shows that with routine deep sedation, the colonoscopy completion rate nears, but still does not reach, the target performance for colonoscopic screening programs, at centers where colonoscopists of difference experience are employed in such programs.Factors interfering with cecal intubation were: inadequate colon cleansing, endoscopists' expertise in colonoscopic practice, patients' body weight under 60 kg or age over 71 years, and the need for active intervention by the anaesthesiologist. The most favourable situation--a patient less than 71 years old with a body weight over 60 kg, an adequate bowel preparation, a "highly experienced specialist" performing the test, and no need for active anaesthesiological intervention during the procedure--coincided with a 98.8% probability of the colonoscopy being completed. CONCLUSIONS: With routine deep sedation, the colonoscopy completion rate nears the target performance for colonoscopic screening programs, at centers where colonoscopists of difference experience are employed in such programs. Organizing the daily workload to prevent negative factors affecting the success rate from occurring in combination may enable up to 85% of incomplete procedures to be converted into successful colonoscopies. PMID- 20961452 TI - Antitumor activity against murine lymphoma L5178Y model of proteins from cacao (Theobroma cacao L.) seeds in relation with in vitro antioxidant activity. AB - BACKGROUND: Recently, proteins and peptides have become an added value to foodstuffs due to new knowledge about its structural analyses as related to antioxidant and anticancer activity. Our goal was to evaluate if protein fractions from cacao seeds show antitumor activity on lymphoma murine L5178Y model. The antioxidant activity of these fractions was also evaluated with the aim of finding a correlation with the antitumor activity. METHODS: Differential extraction of proteins from unfermented and semi-fermented-dry cacao seeds was performed and characterized by SDS-PAGE and FPLC size-exclusion chromatography. Antitumor activity was evaluated against murine lymphoma L5178Y in BALB/c mice (6 * 104 cells i.p.), with a treatment oral dose of 25 mg/kg/day of each protein fraction, over a period of 15 days. Antioxidant activity was evaluated by the ABTS+ and ORAC-FL assays. RESULTS: Albumin, globulin and glutelin fractions from both cacao seed type were obtained by differential solubility extraction. Glutelins were the predominant fraction. In the albumin fraction, polypeptides of 42.3 and 8.5 kDa were found in native conditions, presumably in the form of two peptide chains of 21.5 kDa each one. The globulin fraction presented polypeptides of 86 and 57 kDa in unfermented cacao seed that produced the specific-cacao aroma precursors, and after fermentation the polypeptides were of 45 and 39 kDa. The glutelin fraction presented proteins >200 kDa and globulins components <100 KDa in lesser proportion. Regarding the semifermented-dry cacao seed, it was observed that the albumin fraction showed antitumoral activity, since it caused significant decreases (p < 0.05) in the ascetic fluid volume and packed cell volume, inhibiting cell growth in 59.98 +/- 13.6% at 60% of the population; while the greatest antioxidant capacity due to free radical scavenging capacity was showed by the albumin and glutelin fraction in both methods assayed. CONCLUSION: This study is the first report on the biological activity of semifermented-dry cacao protein fractions with their identification, supporting the traditional use of the plant. The albumin fraction showed antitumor and free radical scavenging capacity, however both activities were not correlated. The protein fractions could be considered as source of potential antitumor peptides. PMID- 20961454 TI - Echoic memory of a single pure tone indexed by change-related brain activity. AB - BACKGROUND: The rapid detection of sensory change is important to survival. The process should relate closely to memory since it requires that the brain separate a new stimulus from an ongoing background or past event. Given that sensory memory monitors current sensory status and works to pick-up changes in real-time, any change detected by this system should evoke a change-related cortical response. To test this hypothesis, we examined whether the single presentation of a sound is enough to elicit a change-related cortical response, and therefore, shape a memory trace enough to separate a subsequent stimulus. RESULTS: Under a paradigm where two pure sounds 300 ms in duration and 800 or 840 Hz in frequency were presented in a specific order at an even probability, cortical responses to each sound were measured with magnetoencephalograms. Sounds were grouped to five events regardless of their frequency, 1D, 2D, and 3D (a sound preceded by one, two, or three different sounds), and 1S and 2S (a sound preceded by one or two same sounds). Whereas activation in the planum temporale did not differ among events, activation in the superior temporal gyrus (STG) was clearly greater for the different events (1D, 2D, 3D) than the same event (1S and 2S). CONCLUSIONS: One presentation of a sound is enough to shape a memory trace for comparison with a subsequent physically different sound and elicits change-related cortical responses in the STG. The STG works as a real-time sensory gate open to a new event. PMID- 20961455 TI - To what extent does recurrent government health expenditure in Uganda reflect its policy priorities? AB - BACKGROUND: The National Health Policy 2000 - 2009 and Health sector strategic plans I & II emphasized that Primary Health Care (PHC) would be the main strategy for national development and would be operationalized through provision of the minimum health care package. Commitment was to spend an increasing proportion of the health budget for the provision of the basic minimum package of health services which was interpreted to mean increasing spending at health centre level. This analysis was undertaken to gain a better understanding of changes in the way recurrent funding is allocated in the health sector in Uganda and to what extent it has been in line with agreed policy priorities. METHODS: Government recurrent wage and non-wage expenditures - based on annual releases by the Uganda Ministry of Finance, Planning and Economic Development were compiled for the period 1997/1998 to financial year 2007/2008. Additional data was obtained from a series of Ministry of Health annual health sector reports as well as other reports. Data was verified by key government officials in Ministry of Finance, Planning and Economic Development and Ministry of Health. Analysis of expenditures was done at sector level, by the different levels in the health care system and the different levels of care. RESULTS: There was a pronounced increase in the amount of funds released for recurrent expenditure over the review period fueled mainly by increases in the wage component. PHC services showed the greatest increase, increasing more than 70 times in ten years. At hospital level, expenditures remained fairly constant for the last 10 years with a slight reduction in the wage component. CONCLUSION: The policy aspiration of increasing spending on PHC was attained but key aspects that would facilitate its realization were not addressed. At any given level of funding for the health sector, there is need to work out an optimal balance in investment in the different inputs to ensure efficiency in health spending. Equally important is the balance in investment between hospitals and health centers. There is a need to look comprehensively at what it takes to provide PHC services and invest accordingly. PMID- 20961453 TI - Risk-reducing strategies for women carrying BRCA1/2 mutations with a focus on prophylactic surgery. AB - BACKGROUND: Women who have inherited mutations in the BRCA1 or BRCA2 genes have substantially elevated risks of breast and ovarian cancer. Mutation carriers have various options, including extensive and regular surveillance, chemoprevention and risk-reducing surgery. The aim of this review is to provide an up-to-date analysis and to subsequently summarise the available literature in relation to risk-reducing strategies, with a keen focus on prophylactic surgery. METHODS: The literature review is facilitated by Medline and PubMed databases. The cross referencing of the obtained articles was used to identify other relevant studies. RESULTS: Prophylactic surgery (bilateral mastectomy, bilateral salpingo oophorectomy or a combination of both procedures) has proved to be the most effective risk-reducing strategy. There are no randomised controlled trials able to demonstrate the potential benefits or harms of prophylactic surgery; therefore, the evidence has been derived from retrospective and short follow-up prospective studies, in addition to hypothetical mathematical models.Based on the current knowledge, it is reasonable to recommend prophylactic oophorectomy for BRCA1 or BRCA2 mutation carriers when childbearing is completed in order to reduce the risk of developing breast and ovarian cancer. In addition, women should be offered the options of rigorous breast surveillance, chemoprevention with anti-oestrogens--especially for carriers of BRCA2--or bilateral prophylactic mastectomy. CONCLUSION: The selection of the most appropriate risk-reducing strategy is not a straightforward task. The impact of risk-reducing strategies on cancer risk, survival, and overall quality of life are the key criteria considered for decision-making. Notably, various other factors should be taken into consideration when evaluating individual mutation carriers' individual circumstances, namely woman's age, morbidity, type of mutation, and individual preferences and expectations.Although prospective randomised controlled trials concerned with examining the various interventions in relation to the woman's age and type of mutation are needed, randomisation is extremely difficult and rather deemed unethical given the current available evidence from retrospective studies. PMID- 20961456 TI - Estimation of the burden of cardiovascular disease attributable to modifiable risk factors and cost-effectiveness analysis of preventative interventions to reduce this burden in Argentina. AB - BACKGROUND: Cardiovascular disease (CVD) is the primary cause of mortality and morbidity in Argentina representing 34.2% of deaths and 12.6% of potential years of life lost (PYLL). The aim of the study was to estimate the burden of acute coronary heart disease (CHD) and stroke and the cost-effectiveness of preventative population-based and clinical interventions. METHODS: An epidemiological model was built incorporating prevalence and distribution of high blood pressure, high cholesterol, hyperglycemia, overweight and obesity, smoking, and physical inactivity, obtained from the Argentine Survey of Risk Factors dataset. Population Attributable Fraction (PAF) of each risk factor was estimated using relative risks from international sources. Total fatal and non-fatal events, PYLL and Disability Adjusted Life Years (DALY) were estimated. Costs of event were calculated from local utilization databases and expressed in international dollars (I$). Incremental cost-effectiveness ratios (ICER) were estimated for six interventions: reducing salt in bread, mass media campaign to promote tobacco cessation, pharmacological therapy of high blood pressure, pharmacological therapy of high cholesterol, tobacco cessation therapy with bupropion, and a multidrug strategy for people with an estimated absolute risk > 20% in 10 years. RESULTS: An estimated total of 611,635 DALY was lost due to acute CHD and stroke for 2005. Modifiable risk factors explained 71.1% of DALY and more than 80% of events. Two interventions were cost-saving: lowering salt intake in the population through reducing salt in bread and multidrug therapy targeted to persons with an absolute risk above 20% in 10 years; three interventions had very acceptable ICERs: drug therapy for high blood pressure in hypertensive patients not yet undergoing treatment (I$ 2,908 per DALY saved), mass media campaign to promote tobacco cessation amongst smokers (I$ 3,186 per DALY saved), and lowering cholesterol with statin drug therapy (I$ 14,432 per DALY saved); and one intervention was not found to be cost-effective: tobacco cessation with bupropion (I$ 59,433 per DALY saved) CONCLUSIONS: Most of the interventions selected were cost-saving or very cost-effective. This study aims to inform policy makers on resource-allocation decisions to reduce the burden of CVD in Argentina. PMID- 20961457 TI - Polytomous diagnosis of ovarian tumors as benign, borderline, primary invasive or metastatic: development and validation of standard and kernel-based risk prediction models. AB - BACKGROUND: Hitherto, risk prediction models for preoperative ultrasound-based diagnosis of ovarian tumors were dichotomous (benign versus malignant). We develop and validate polytomous models (models that predict more than two events) to diagnose ovarian tumors as benign, borderline, primary invasive or metastatic invasive. The main focus is on how different types of models perform and compare. METHODS: A multi-center dataset containing 1066 women was used for model development and internal validation, whilst another multi-center dataset of 1938 women was used for temporal and external validation. Models were based on standard logistic regression and on penalized kernel-based algorithms (least squares support vector machines and kernel logistic regression). We used true polytomous models as well as combinations of dichotomous models based on the 'pairwise coupling' technique to produce polytomous risk estimates. Careful variable selection was performed, based largely on cross-validated c-index estimates. Model performance was assessed with the dichotomous c-index (i.e. the area under the ROC curve) and a polytomous extension, and with calibration graphs. RESULTS: For all models, between 9 and 11 predictors were selected. Internal validation was successful with polytomous c-indexes between 0.64 and 0.69. For the best model dichotomous c-indexes were between 0.73 (primary invasive vs metastatic) and 0.96 (borderline vs metastatic). On temporal and external validation, overall discrimination performance was good with polytomous c-indexes between 0.57 and 0.64. However, discrimination between primary and metastatic invasive tumors decreased to near random levels. Standard logistic regression performed well in comparison with advanced algorithms, and combining dichotomous models performed well in comparison with true polytomous models. The best model was a combination of dichotomous logistic regression models. This model is available online. CONCLUSIONS: We have developed models that successfully discriminate between benign, borderline, and invasive ovarian tumors. Methodologically, the combination of dichotomous models was an interesting approach to tackle the polytomous problem. Standard logistic regression models were not outperformed by regularized kernel-based alternatives, a finding to which the careful variable selection procedure will have contributed. The random discrimination between primary and metastatic invasive tumors on temporal/external validation demonstrated once more the necessity of validation studies. PMID- 20961458 TI - The p75 neurotrophin receptor is expressed by adult mouse dentate progenitor cells and regulates neuronal and non-neuronal cell genesis. AB - BACKGROUND: The ability to regulate neurogenesis in the adult dentate gyrus will require further identification and characterization of the receptors regulating this process. In vitro and in vivo studies have demonstrated that neurotrophins and the p75 neurotrophin receptor (p75NTR) can promote neurogenesis; therefore we tested the hypothesis that p75NTR is expressed by adult dentate gyrus progenitor cells and is required for their proliferation and differentiation. RESULTS: In a first series of studies focusing on proliferation, mice received a single BrdU injection and were sacrificed 2, 10 and 48 hours later. Proliferating, BrdU positive cells were found to express p75NTR. In a second series of studies, BrdU was administered by six daily injections and mice were sacrificed 1 day later. Dentate gyrus sections demonstrated a large proportion of BrdU/p75NTR co expressing cells expressing either the NeuN neuronal or GFAP glial marker, indicating that p75NTR expression persists at least until early stages of maturation. In p75NTR (-/-) mice, there was a 59% decrease in the number of BrdU positive cells, with decreases in the number of BrdU cells co-labeled with NeuN, GFAP or neither marker of 35%, 60% and 64%, respectively. CONCLUSIONS: These findings demonstrate that p75NTR is expressed by adult dentate progenitor cells and point to p75NTR as an important receptor promoting the proliferation and/or early maturation of not only neural, but also glial and other cell types. PMID- 20961459 TI - Intranasal vaccination with messenger RNA as a new approach in gene therapy: use against tuberculosis. AB - BACKGROUND: mRNAs are highly versatile, non-toxic molecules that are easy to produce and store, which can allow transient protein expression in all cell types. The safety aspects of mRNA-based treatments in gene therapy make this molecule one of the most promising active components of therapeutic or prophylactic methods. The use of mRNA as strategy for the stimulation of the immune system has been used mainly in current strategies for the cancer treatment but until now no one tested this molecule as vaccine for infectious disease. RESULTS: We produce messenger RNA of Hsp65 protein from Mycobacterium leprae and show that vaccination of mice with a single dose of 10 MUg of naked mRNA-Hsp65 through intranasal route was able to induce protection against subsequent challenge with virulent strain of Mycobacterium tuberculosis. Moreover it was shown that this immunization was associated with specific production of IL-10 and TNF-alpha in spleen. In order to determine if antigen presenting cells (APCs) present in the lung are capable of capture the mRNA, labeled mRNA-Hsp65 was administered by intranasal route and lung APCs were analyzed by flow cytometry. These experiments showed that after 30 minutes until 8 hours the populations of CD11c+, CD11b+ and CD19+ cells were able to capture the mRNA. We also demonstrated in vitro that mRNA-Hsp65 leads nitric oxide (NO) production through Toll-like receptor 7 (TLR7). CONCLUSIONS: Taken together, our results showed a novel and efficient strategy to control experimental tuberculosis, besides opening novel perspectives for the use of mRNA in vaccines against infectious diseases and clarifying the mechanisms involved in the disease protection we noticed as well. PMID- 20961460 TI - Diet-induced obesity in zebrafish shares common pathophysiological pathways with mammalian obesity. AB - BACKGROUND: Obesity is a multifactorial disorder influenced by genetic and environmental factors. Animal models of obesity are required to help us understand the signaling pathways underlying this condition. Zebrafish possess many structural and functional similarities with humans and have been used to model various human diseases, including a genetic model of obesity. The purpose of this study was to establish a zebrafish model of diet-induced obesity (DIO). RESULTS: Zebrafish were assigned into two dietary groups. One group of zebrafish was overfed with Artemia (60 mg dry weight/day/fish), a living prey consisting of a relatively high amount of fat. The other group of zebrafish was fed with Artemia sufficient to meet their energy requirements (5 mg dry weight/day/fish). Zebrafish were fed under these dietary protocols for 8 weeks. The zebrafish overfed with Artemia exhibited increased body mass index, which was calculated by dividing the body weight by the square of the body length, hypertriglyceridemia and hepatosteatosis, unlike the control zebrafish. Calorie restriction for 2 weeks was applied to zebrafish after the 8-week overfeeding period. The increased body weight and plasma triglyceride level were improved by calorie restriction. We also performed comparative transcriptome analysis of visceral adipose tissue from DIO zebrafish, DIO rats, DIO mice and obese humans. This analysis revealed that obese zebrafish and mammals share common pathophysiological pathways related to the coagulation cascade and lipid metabolism. Furthermore, several regulators were identified in zebrafish and mammals, including APOH, IL-6 and IL-1beta in the coagulation cascade, and SREBF1, PPARalpha/gamma, NR1H3 and LEP in lipid metabolism. CONCLUSION: We established a zebrafish model of DIO that shared common pathophysiological pathways with mammalian obesity. The DIO zebrafish can be used to identify putative pharmacological targets and to test novel drugs for the treatment of human obesity. PMID- 20961461 TI - Social sciences research in neglected tropical diseases 1: the ongoing neglect in the neglected tropical diseases. AB - Centuries of scientific advances and developments in biomedical sciences have brought us a long way to understanding and managing disease processes, by reducing them to simplified cause-effect models. For most of the infectious diseases known today, we have the methods and technology to identify the causative agent, understand the mechanism by which pathology is induced and develop the treatment (drugs, vaccines, medical or surgical procedures) to cure, manage or control.Disease, however, occurs within a context of lives fraught with complexity. For any given infectious disease, who gets it, when, why, the duration, the severity, the outcome, the sequelae, are bound by a complex interplay of factors related as much to the individual as it is to the physical, social, cultural, political and economic environments. Furthermore each of these factors is in a dynamic state of change, evolving over time as they interact with each other. Simple solutions to infectious diseases are therefore rarely sustainable solutions. Sustainability would require the development of interdisciplinary sciences that allow us to acknowledge, understand and address these complexities as they occur, rather than rely solely on a form of science based on reducing the management of disease to simple paradigms.In this review we examine the current global health responses to the 'neglected' tropical diseases, which have been prioritised on the basis of an acknowledgment of the complexity of the poverty-disease cycle. However research and interventions for neglected tropical diseases, largely neglect the social and ecological contextual, factors that make these diseases persist in the target populations, continuing instead to focus on the simple biomedical interventions. We highlight the gaps in the approaches and explore the potential of enhanced interdisciplinary work in the development of long term solutions to disease control. PMID- 20961462 TI - A genetic ensemble approach for gene-gene interaction identification. AB - BACKGROUND: It has now become clear that gene-gene interactions and gene environment interactions are ubiquitous and fundamental mechanisms for the development of complex diseases. Though a considerable effort has been put into developing statistical models and algorithmic strategies for identifying such interactions, the accurate identification of those genetic interactions has been proven to be very challenging. METHODS: In this paper, we propose a new approach for identifying such gene-gene and gene-environment interactions underlying complex diseases. This is a hybrid algorithm and it combines genetic algorithm (GA) and an ensemble of classifiers (called genetic ensemble). Using this approach, the original problem of SNP interaction identification is converted into a data mining problem of combinatorial feature selection. By collecting various single nucleotide polymorphisms (SNP) subsets as well as environmental factors generated in multiple GA runs, patterns of gene-gene and gene-environment interactions can be extracted using a simple combinatorial ranking method. Also considered in this study is the idea of combining identification results obtained from multiple algorithms. A novel formula based on pairwise double fault is designed to quantify the degree of complementarity. CONCLUSIONS: Our simulation study demonstrates that the proposed genetic ensemble algorithm has comparable identification power to Multifactor Dimensionality Reduction (MDR) and is slightly better than Polymorphism Interaction Analysis (PIA), which are the two most popular methods for gene-gene interaction identification. More importantly, the identification results generated by using our genetic ensemble algorithm are highly complementary to those obtained by PIA and MDR. Experimental results from our simulation studies and real world data application also confirm the effectiveness of the proposed genetic ensemble algorithm, as well as the potential benefits of combining identification results from different algorithms. PMID- 20961463 TI - Genetic predisposition for femoral neck stress fractures in military conscripts. AB - BACKGROUND: Stress fractures are a significant problem among athletes and soldiers and may result in devastating complications or even permanent handicap. Genetic factors may increase the risk, but no major susceptibility genes have been identified. The purpose of this study was to search for possible genetic factors predisposing military conscripts to femoral neck stress fractures. RESULTS: Eight genes involved in bone metabolism or pathology (COL1A1, COL1A2, OPG, ESR1, VDR, CTR, LRP5, IL-6) were examined in 72 military conscripts with a femoral neck stress fracture and 120 controls. The risk of femoral neck stress fracture was significantly higher in subjects with low weight and body mass index (BMI). An interaction between the CTR (rs1801197) minor allele C and the VDR C-A haplotype was observed, and subjects lacking the C allele in CTR and/or the C-A haplotype in VDR had a 3-fold higher risk of stress fracture than subjects carrying both (OR = 3.22, 95% CI 1.38-7.49, p = 0.007). In addition, the LRP5 haplotype A-G-G-C alone and in combination with the VDR haplotype C-A was associated with stress fractures through reduced body weight and BMI. CONCLUSIONS: Our findings suggest that genetic factors play a role in the development of stress fractures in individuals subjected to heavy exercise and mechanical loading. The present results can be applied to the design of future studies that will further elucidate the genetics of stress fractures. PMID- 20961465 TI - Flight of the Chinese white pine beetle (Coleoptera: Scolytidae) in relation to sex, body weight and energy reserve. AB - The flight distance, flight time and individual flight activities of males and females of Dendroctonus armandi were recorded during 96-h flight trials using a flight mill system. The body weight, glucose, glycogen and lipid content of four treatments (naturally emerged, starved, phloem-fed and water-fed) were compared among pre-flight, post-flight and unflown controls. There was no significant difference between males and females in total flight distance and flight time in a given 24-h period. The flight distance and flight time of females showed a significant linear decline as the tethered flying continued, but the sustained flight ability of females was better than that of males. The females had higher glycogen and lipid content than the males; however, there was no significant difference between both sexes in glucose content. Water-feeding and phloem feeding had significant effects on longevity, survival days and flight potential of D. armandi, which resulted in longer feeding days, poorer flight potential and lower energy substrate content. Our results demonstrate that flight distances in general do not differ between water-fed and starved individuals, whereas phloem fed females and males fly better than water-fed and starved individuals. PMID- 20961464 TI - The association of the Clock 3111 T/C SNP with lipids and lipoproteins including small dense low-density lipoprotein: results from the Mima study. AB - BACKGROUND: The clock molecule plays major roles in circadian rhythmicity and regulating lipid and glucose metabolism in peripheral organs. Disruption of the circadian rhythm can lead to cardiometabolic disorders. The existence of small dense low-density lipoprotein (sdLDL) in the circulation, an abnormality of lipid metabolism, in part associated with lifestyle, is also one of risk parameters for cardiometabolic disorders. The 3111 T/C single nucleotide polymorphism (SNP) of the Clock gene has been reported to be associated with lifestyle including morning/evening preference. We investigated whether the Clock 3111 T/C SNP may affect lipids and lipoproteins including sdLDL. METHODS: In 365 community dwelling subjects (170 men and 195 women, mean age 63 +/- 14 years), the 3111 T/C SNP was genotyped using a fluorescent allele-specific DNA primer assay system. The levels of sdLDL were measured with the electrophoretic separation of lipoproteins employing the Lipoprint system. RESULTS: The frequency of the Clock 3111 C allele was 0.14. The area of sdLDL did not differ between the subjects with obesity and those without. In carriers of T/T homozygotes, the area of sdLDL was significantly higher compared with carriers of the C allele (T/C or C/C) (1.7 +/- 3.4 vs. 0.8 +/- 1.9%; p < 0.05). A multiple regression analysis showed that the area of sdLDL was significantly and negatively correlated with the Clock 3111 T/C SNP (beta = -0.114, p < 0.05), independently of age, sex, body mass index, and exercise habits. CONCLUSION: Our findings indicated that the Clock 3111 T/C SNP might be associated with the existence of sdLDL. PMID- 20961466 TI - Polyphasic approach applying artificial neural networks, molecular analysis and postabdomen morphology to West Palaearctic Tachina spp. (Diptera, Tachinidae). AB - Artificial neural networks (ANN) methodology, molecular analyses and comparative morphology of the male postabdomen were used successfully in parallel for species identification and resolution of some taxonomic problems concerning West Palaearctic species of the genus Tachina Meigen, 1803. Supervised feed-forward ANN with back-propagation of errors was applied on morphometric and qualitative characters to solve known taxonomic discrepancies. Background molecular analyses based on mitochondrial markers CO I, Cyt b, 12S and 16S rDNA and study of male postabdominal structures were published separately. All three approaches resolved taxonomic doubts with identical results in the following five cases: case 1, the four presently recognized subgenera of the genus Tachina were confirmed and the description of a new subgenus was recommended; case 2, the validity of a new boreo-alpine species (sp.n.) was confirmed; case 3, the previously supposed presence of T. casta (Rondani, 1859) in central Europe was not supported; case 4, West Palaearctic T. nupta (Rondani, 1859) was contrasted with East Palaearctic specimens from Japan, which seem to represent a valid species not conspecific with central European specimens; T. nupta needs detailed further study; case 5, T. nigrohirta (Stein, 1924) resurrected recently from synonymy with T. ursina Meigen, 1824 was confirmed as a valid species. This parallel application of three alternative methods has enabled the principle of 'polyphasic taxonomy' to be tested and verified using these separate results. For the first time, the value of using the ANN approach in taxonomy was justified by two non-mathematical methods (molecular and morphological). PMID- 20961467 TI - Rice planting systems, global warming and outbreaks of Nilaparvata lugens (Stal). AB - Brown Planthopper (BPH, Nilaparvata lugens (Stal)) is one of the most serious pests of rice in both temperate and tropical regions of East and South Asia and has become especially problematic over the past few years. In order to analyze the effect of the change of rice cropping system on the population dynamics of BPH, field surveys of the occurrence and distribution of BPH were performed and other relevant data, including light trap data and ovary dissection data were collected in nearly 40 Chinese counties encompassing six provinces (or municipalities), including Hainan, Guangxi, Anhui, Shanghai, Fujian and Guangdong from April to October in 2007.The mixed planting areas of single- and double cropping rice in China include Hubei, South and Central Anhui, North Hunan, and North Jiangxi. In these areas, double-cropping rice has now been greatly reduced and single-cropping rice has been rapidly increasing since 1997. The surveys revealed that when the immigration peak of BPH occurred in June and July, the single-cropping rice was at the tillering to booting stage and fit for BPH, but early rice had already matured and most of late rice had not yet been transplanted. BPH immigrants from southern rice areas prefer to inhabit and breed in single-cropping rice paddies. Moreover, farming activities between early rice and late rice interrupted the continuous growth of BPH populations in double cropping rice paddies. As a result, in comparison with data collected 30 years ago, the spatiotemporal dynamics and migration patterns of BPH have dramatically changed in the lower-middle reaches of the Yangtze River. In the mixed planting areas, due to their high suitability, the BPH population in single-cropping rice grew so quickly that it caused serious local damage and there was mass emigration of macropterous progeny to the Yangtze River Delta in late August and early September.Global warming may also affect BPH populations, where results suggest steadily warmer autumns have occurred from the 1990s on, with such conditions gradually the norm. The combination of 'cooler summer' and 'warmer autumn' are conditions known to promote outbreaks of BPH in the lower-middle reaches of the Yangtze River. Immigrant BPH arrivals in late August and September now cause serious damage to late-maturing mid-season rice and late rice in the lower-middle reaches of the Yangtze River. PMID- 20961468 TI - A comparative assessment of the response of three fruit fly species (Diptera: Tephritidae) to a spinosad-based bait: effect of ammonium acetate, female age, and protein hunger. AB - Ammonia-releasing substances are known to play an important role in fruit fly (Diptera: Tephritidae) attraction to food sources, and this information has been exploited for the development of effective synthetic food-based lures and insecticidal baits. In field studies conducted in Hawaii, we examined the behavioural response of wild female oriental fruit fly (Bactrocera dorsalis (Hendel)), melon fly (B. cucurbitae (Coquillett)), and Mediterranean fruit fly (Ceratitis capitata (Wiedemann)) to spinosad-based GF-120 NF Naturalyte Fruit Fly Bait((c)) formulated to contain either 0, 1 or 2% ammonium acetate. Use of visually-attractive yellow bait stations for bait application in the field allowed for proper comparisons among bait formulations. Field cage tests were also conducted to investigate, using a comparative behavioural approach, the effects of female age and protein starvation on the subsequent response of F1 generation B. cucurbitae and B. dorsalis to the same three bait formulations that were evaluated in the field. Our field results indicate a significant positive effect of the presence, regardless of amount, of AA in GF-120 for B. dorsalis and B. cucurbitae. For C. capitata, there was a significant positive linear relationship between the relative amounts of AA in bait and female response. GF 120 with no AA was significantly more attractive to female C. capitata, but not to female B. dorsalis or B. cucurbitae, than the control treatment. Our field cage results indicate that the effects of varying amounts of AA present in GF-120 can be modulated by the physiological stage of the female flies and that the response of female B. cucurbitae to GF-120 was consistently greater than that of B. dorsalis over the various ages and levels of protein starvation regimes evaluated. Results are discussed in light of their applications for effective fruit fly suppression. PMID- 20961469 TI - Chemotherapy against human African trypanosomiasis: is there a road to success? AB - For over fifty years, human African trypanosomiasis (HAT, sleeping sickness) has been treated with suramin, pentamidine and the very toxic organo-arsenical melarsoprol that was the only drug available for effective treatment of the second stage of the disease. Recently there have been significant efforts using molecular and biochemical approaches to drug design, including high-throughput screening, but the number of lead compounds with promising activity against T. brucei spp. and an acceptable toxicity index has remained astonishingly small. Clinical research continues to be difficult due to the economic constraints and the complexity of trials on a low prevalence disease in remote and impoverished African regions. Despite those limitations the situation for the patients is improving thanks to the combination of a number of critical factors. By the late 1990s the disease had reached epidemic levels that triggered political support. WHO would sign a donation agreement with the manufacturers for all drugs to treat HAT. A result of this agreement was that eflornithine which is much safer than melarsoprol became available and widely used by non-governmental organizations. The Impamel I and II programmes demonstrated that against all odds the conduct of clinical trials on HAT was feasible. This allowed the initiation of trials on combination therapies which eventually resulted in the nifurtimox-eflornithine combination treatment (NECT). This combination is currently being introduced as first line treatment, and there is even the prospect of having a new compound, fexinidazole, in the development pipeline. This review summarizes the key information about the existing drugs and gives a comprehensive summary about the recent and currently ongoing efforts towards new drugs. PMID- 20961470 TI - Facial emotion recognition impairments in individuals with HIV. AB - Characterized by frontostriatal dysfunction, human immunodeficiency virus (HIV) is associated with cognitive and psychiatric abnormalities. Several studies have noted impaired facial emotion recognition abilities in patient populations that demonstrate frontostriatal dysfunction; however, facial emotion recognition abilities have not been systematically examined in HIV patients. The current study investigated facial emotion recognition in 50 nondemented HIV-seropositive adults and 50 control participants relative to their performance on a nonemotional landscape categorization control task. We examined the relation of HIV-disease factors (nadir and current CD4 levels) to emotion recognition abilities and assessed the psychosocial impact of emotion recognition abnormalities. Compared to control participants, HIV patients performed normally on the control task but demonstrated significant impairments in facial emotion recognition, specifically for fear. HIV patients reported greater psychosocial impairments, which correlated with increased emotion recognition difficulties. Lower current CD4 counts were associated with poorer anger recognition. In summary, our results indicate that chronic HIV infection may contribute to emotion processing problems among HIV patients. We suggest that disruptions of frontostriatal structures and their connections with cortico-limbic networks may contribute to emotion recognition abnormalities in HIV. Our findings also highlight the significant psychosocial impact that emotion recognition abnormalities have on individuals with HIV. PMID- 20961471 TI - Spontaneous confabulation, temporal context confusion and reality monitoring: a study of three patients with anterior communicating artery aneurysms. AB - Spontaneous confabulation involves the production of false or distorted memories, and is commonly associated with ventromedial prefrontal damage. One influential theory proposes that the critical deficit is a failure to suppress currently irrelevant memory traces that intrude into ongoing thinking (Schnider & Ptak, 1999). In this study, we report experimental investigations with three spontaneously confabulating patients aimed at exploring this account. Using Schnider and Ptak's (1999) continuous recognition paradigm, we replicated their experimental results with our patients. However, our data suggest that the critical impairment might be more generalized than a failure to suppress currently irrelevant memories. First, a temporal source monitoring task failed to show that previous memory traces intrude into the present. Second, a reality monitoring task revealed that confabulating patients had a tendency to misidentify imagined events as real, a result that cannot be explained in terms of temporal confusion. This error was specific to confabulating patients and was not shared by non-confabulating ACoA patients. Our data therefore suggest a more generalized impairment in source monitoring, not only on the basis of temporality or current relevance, but across a range of contextual domains, including information used to distinguish real memories from imaginings. PMID- 20961472 TI - Telling it like it isn't: the cognitive neuroscience of confabulation. PMID- 20961473 TI - Field survey for strongyloidiasis in eastern Uganda with observations on efficacy of preventive chemotherapy and co-occurrence of soil-transmitted helminthiasis/intestinal schistosomiasis. AB - Following our previous field surveys for strongyloidiasis in western Uganda, 120 mothers and 232 children from four villages in eastern Uganda were examined, with two subsequent investigative follow-ups. As before, a variety of diagnostic methods were used: Baermann concentration, Koga agar plate and strongyloidid enzyme-linked immunosorbent assay (ELISA), as well as Kato-Katz faecal smears for detection of eggs of other helminths. At baseline, the general prevalence of Strongyloides stercoralis was moderate: 5.4% as estimated by Baermann and Koga agar methods combined. A much higher estimate was found by ELISA (42.3%) which, in this eastern setting, appeared to be confounded by putative cross-reaction(s) with other nematode infections. Preventive chemotherapy using praziquantel and albendazole was offered to all participants at baseline. After 21 days the first follow-up was conducted and 'cure rates' were calculated for all parasites encountered. Eleven months later, the second follow-up assessed longer-term trends. Initial treatments had little, if any, effect on S. stercoralis, and did not alter local prevalence, unlike hookworm infections and intestinal schistosomiasis. We propose that geographical patterns of strongyloidiasis are likely not perturbed by ongoing praziquantel/albendazole campaigns. Antibody titres increased after the first follow-up then regressed towards baseline levels upon second inspection. To better define endemic areas for S. stercoralis, careful interpretation of the ELISA is warranted, especially where diagnosis is likely being confounded by polyparasitism and/or other treatment regimens; new molecular screening tools are clearly needed. PMID- 20961474 TI - A computer-assisted depression intervention in primary care. AB - BACKGROUND: The clinical benefit for depression of an interactive computer assisted cognitive-behavioral program on CD-ROM, the Wellness Workshop (WW), was evaluated in a randomized controlled trial. METHOD: A total of 191 individuals referred by primary-care physicians were randomly assigned to a control group, where physician-directed treatment as usual (TAU) was provided, or to a treatment group, where TAU was supplemented with the WW CD-ROM, delivered by mail (WW+TAU). Data were collected at baseline, at 6 weeks' post-intervention, and at a 6-month follow-up assessment. Participants were given a strong incentive by a reimbursement of $75 for completion of each assessment. Measures included symptom ratings obtained via structured clinical diagnostic interviews, as well as a battery of self-report questionnaires on symptoms specifically targeted by the intervention. RESULTS: Analysis of results demonstrated evidence for skill acquisition for improving dysfunctional thinking and reducing anxiety. Among those who met diagnostic criteria for depression, WW+TAU participants were three times more likely to remit at 6 weeks' post-test than TAU participants. CONCLUSIONS: The evidence supports the conclusion that the WW intervention added benefit to traditional care for depression. No placebo comparison group was included and the WW+TAU participants received slightly more attention (a supportive telephone contact, <= 5 min from a psychologist 2 weeks after receiving the program). Overall, the findings add support to the accumulating evidence for the potential clinical benefit of computer-assisted behavioral health interventions. PMID- 20961475 TI - Patients with schizophrenia show increased aversion to angry faces in an associative learning task. AB - BACKGROUND: We were interested in examining the relationship between socially relevant stimuli and decision processes in patients with schizophrenia. METHOD: We tested patients with schizophrenia and healthy controls on a stochastically rewarded associative learning task. Participants had to determine, through trial and error, which of two faces was associated with a higher chance of reward: one face was angry, the other happy. RESULTS: Both patients and healthy controls were able to perform the task at above-chance accuracy, and there was no significant difference in overall accuracy between the groups. Both groups also reliably preferred the happy face, such that they selected it more often than the angry face on the basis of the same amount of positive versus negative feedback. However, patients were significantly more averse to the angry face, such that they chose it less often than control participants when the reward feedback strongly supported the angry face as the best choice. CONCLUSIONS: Patients show an increased aversion to angry faces, in a task in which they must learn to associate rewards with expressions. PMID- 20961476 TI - Relationship between adiposity, emotional status and eating behaviour in obese women: role of inflammation. AB - BACKGROUND: Obesity is characterized by chronic low-grade inflammation that may lead to emotional distress and behavioural symptoms. This study assessed the relationship between adiposity, low-grade inflammation, eating behaviour and emotional status in obese women awaiting gastric surgery and investigated the effects of surgery-induced weight loss on this relationship. METHOD: A total of 101 women with severe or morbid obesity awaiting gastric surgery were recruited. Assessments were performed before and at 1 year post-surgery and included the measurement of neuroticism and extraversion using the revised Neuroticism Extraversion-Openness personality inventory (NEO-PI-R) and eating behaviour using the Three-Factor Eating Questionnaire (TFEQ). Blood samples were collected for the measurement of serum inflammatory markers [interleukin-6 (IL-6), high sensitive C-reactive protein (hsCRP)] and adipokines (leptin, adiponectin). RESULTS: At baseline, body mass index (BMI) was positively correlated with inflammatory markers and adipokines. Regression analyses adjusting for age and diabetes revealed that baseline concentrations of IL-6 and hsCRP were associated with the depression and anxiety facets of neuroticism, with higher inflammation predicting higher anxiety and depression. This association remained significant after adjusting for BMI. Gastric surgery induced significant weight loss, which correlated with reduced inflammation. After controlling for BMI variations, decreases in inflammatory markers, notably hsCRP, were associated with reduced anxiety and TFEQ-cognitive restraint scores. CONCLUSIONS: These findings indicate strong associations between adiposity, inflammation and affectivity in obese subjects and show that surgery-induced weight loss is associated concomitantly with reduced inflammation and adipokines and with significant improvement in emotional status and eating behaviour. Inflammatory status appears to represent an important mediator of emotional distress and psychological characteristics of obese individuals. PMID- 20961477 TI - P300 deficits in adults with attention deficit hyperactivity disorder: a meta analysis. AB - BACKGROUND: The P300 (P3) event-related potential (ERP) component, a possible endophenotype for attention deficit hyperactivity disorder (ADHD), has been widely examined in children, but received little attention in adults. Our objective was to conduct a meta-analysis of P3 studies in adults with ADHD. METHOD: We searched the Medline and PsycINFO databases for controlled studies examining both adult ADHD and matched healthy controls. Six relevant publications were identified for the meta-analysis, which had comparable data across studies with regard to the amplitude of ERP components related to target detection (P3, P3b). Pooled effect size (ES) for P3 amplitude as well as the association of the ES with age and gender were investigated using meta-regression. RESULTS: Comparing the ADHD group versus controls, the pooled effect size for a decrease in P3 amplitude was in the medium range (Cohen's d=-0.55, p=0.0006). Additionally, meta-regression revealed that decrease in P3 amplitude significantly varied with the mean age of ADHD patients (p=0.0087), with a gradual increasing of the difference at higher ages. Results also showed a significant association between the ES and gender, indicating a more pronounced reduction of P3 amplitude in the ADHD group versus controls when females were predominantly represented in the sample. CONCLUSIONS: To our knowledge, this is the first meta-analysis of P3 characteristics in adults with ADHD. It reveals a significantly decreased P3 amplitude during target detection. Our result that the reduction in P3 amplitude increases with age is interpreted in a neurodevelopmental context. PMID- 20961478 TI - Copycat effect after celebrity suicides: results from the French national death register. PMID- 20961479 TI - The different trajectories of antipsychotic response: antipsychotics versus placebo. AB - BACKGROUND: It is generally accepted that antipsychotics are more effective than placebo. However, it remains unclear whether antipsychotics induce a pattern or trajectory of response that is distinct from placebo. We used a data-driven technique, called growth mixture modelling (GMM), to identify the different patterns of response observed in antipsychotic trials and to determine whether drug-treated and placebo-treated subjects show similar or distinct patterns of response. METHOD: We examined data on 420 patients with schizophrenia treated for 6 weeks in two double-blind placebo-controlled trials using haloperidol and olanzapine. We used GMM to identify the optimal number of response trajectories; to compare the trajectories in drug-treated versus placebo-treated patients; and to determine whether the trajectories for the different dimensions (positive versus negative symptoms) were identical or different. RESULTS: Positive symptoms were found to respond along four distinct trajectories, with the two most common trajectories ('Partial responder' and 'Responder') accounting for 70% of the patients and seen proportionally in both drug- and placebo-treated. The most striking drug-placebo difference was in the 'Dramatic responders', seen only among the drug-treated. The response of negative symptoms was more modest and did not show such distinct trajectories. CONCLUSIONS: Trajectory models of response, rather than the simple responder/non-responder dichotomy, provide a better statistical account of how antipsychotics work. The 'Dramatic responders' (those showing >70% response) were seen only among the drug-treated and make a significant contribution to the overall drug-placebo difference. Identifying and studying this subset may provide specific insight into antipsychotic action. PMID- 20961480 TI - Effects of education, literacy, and dementia on the Clock Drawing Test performance. AB - The Clock Drawing Test (CDT) has been recognized as an effective tool for dementia detection. This study investigated the clock drawing performance of 240 non-demented elderly Korean people with a wide-range of educational levels and 28 patients with mild dementia of the Alzheimer's type (DAT). We examined the effects of demographic factors, including education, and established norms for the elderly population. We found that the educational attainment and literacy status of older people influenced performance on the CDT significantly (p < .001). Furthermore, qualitative error analysis revealed that normal participants with low educational background committed errors similar to errors of the DAT patients. The DAT patients performed significantly worse than the non-demented participants in the CDT Total score (p < .001). However, the CDT has better criterion validity in participants with more than 6 years of education. In conclusion, the CDT performance in older people who are either illiterate or with 6 or less years of education should be interpreted with caution. Conceptual errors in the CDT can be the result of not only dementia but also lack of education. PMID- 20961481 TI - Unraveling the role of the rssC gene of Serratia marcescens by atomic force microscopy. AB - The product and direct role of the rssC gene of Serratia marcescens is unknown. For unraveling the role of the rssC gene, atomic force microscopy has been used to identify the surfaces of intact S. marcescens wild-type CH-1 cells and rssC mutant CH-1DeltaC cells. The detailed surface topographies were directly visualized, and quantitative measurements of the physical properties of the membrane structures were provided. CH-1 and CH-1DeltaC cells were observed before and after treatment with lysozyme, and their topography-related parameters, e.g., a valley-to-peak distance, mean height, surface roughness, and surface root-mean square values, were defined and compared. The data obtained suggest that the cellular surface topography of mutant CH-1DeltaC becomes rougher and more precipitous than that of wild-type CH-1 cells. Moreover, it was found that, compared with native wild-type CH-1, the cellular surface topography of lysozyme treated CH-1 was not changed profoundly. The product of the rssC gene is thus predicted to be mainly responsible for fatty-acid biosynthesis of the S. marcescens outer membrane. This study represents the first direct observation of the structural changes in membranes of bacterial mutant cells and offers a new prospect for predicting gene expression in bacterial cells. PMID- 20961482 TI - Development of a new quantitative X-ray microanalysis method for electron microscopy. AB - Quantitative X-ray microanalysis of thick samples is usually performed by measuring the characteristic X-ray intensities of each element in a sample and in corresponding standards. The ratio of the measured intensities from the unknown material to that from the standard is related to the concentration using the ZAF or phi(rhoz) equations. Under optimal conditions, accuracies approaching 1% are possible. However, all the experimental conditions must remain the same during the sample and standard measurements. This is not possible with cold field emission scanning electron microscopes (FE-SEMs) where beam current can fluctuate around 5% in its stable regime. Very little work has been done on variable beam current conditions (Griffin, B.J. & Nockolds, C.E., Scanning 13, 307-312, 1991), and none relating to cold FE-SEM applications. To address this issue, a new method was developed using a single spectral measurement. It is similar in approach to the Cliff-Lorimer method developed for the analytical transmission electron microscope. However, corrections are made for X rays generated from thick specimens using the ratio of the characteristic X-ray intensities of two elements in the same material. The proposed method utilizes the ratio of the intensity of a characteristic X-ray normalized by the sum of X-ray intensities of all the elements measured for the sample, which should also reduce the amplitude of error propagation. Uncertainties in the physical parameters of X-ray generation are corrected using a calibration factor that must be previously acquired or calculated. As an example, when this method was applied to the calculation of the composition of Au-Cu National Institute of Standards and Technology standards measured with a cold field emission source SEM, relative accuracies better than 5% were obtained. PMID- 20961483 TI - Simulating STEM imaging of nanoparticles in micrometers-thick substrates. AB - Scanning transmission electron microscope (STEM) images of three-dimensional (3D) samples were simulated. The samples consisted of a micrometer(s)-thick substrate and gold nanoparticles at various vertical positions. The atomic number (Z) contrast as obtained via the annular dark-field detector was generated. The simulations were carried out using the Monte Carlo method in the CASINO software (freeware). The software was adapted to include the STEM imaging modality, including the noise characteristics of the electron source, the conical shape of the beam, and 3D scanning. Simulated STEM images of nanoparticles on a carbon substrate revealed the influence of the electron dose on the visibility of the nanoparticles. The 3D datasets obtained by simulating focal series showed the effect of beam broadening on the spatial resolution and on the signal-to-noise ratio. Monte Carlo simulations of STEM imaging of nanoparticles on a thick water layer were compared with experimental data by programming the exact sample geometry. The simulated image corresponded to the experimental image, and the signal-to-noise levels were similar. The Monte Carlo simulation strategy described here can be used to calculate STEM images of objects of an arbitrary geometry and amorphous sample composition. This information can then be used, for example, to optimize the microscope settings for imaging sessions where a low electron dose is crucial for the design of equipment, or for the analysis of the composition of a certain specimen. PMID- 20961485 TI - Potential benefits of pro- and prebiotics on intestinal mucosal immunity and intestinal barrier in short bowel syndrome. AB - The mechanism of impaired gut barrier function in patients with short bowel syndrome (SBS) is poorly understood and includes decreased intestinal motility leading to bacterial overgrowth, a reduction in gut-associated lymphoid tissue following the loss of intestinal length, inhibition of mucosal immunity of the small intestine by intravenous total parental nutrition, and changes in intestinal permeability to macromolecules. Novel therapeutic strategies (i.e. nutritive and surgical) have been introduced in order to prevent the establishment or improve the outcome of this prevalent disease. Pre- and probiotics as a nutritive supplement are already known to be very active in the intestinal tract (mainly in the colon) by maintaining a healthy gut microflora and influencing metabolic, trophic and protective mechanisms, such as the production of SCFA which influence epithelial cell metabolism, turnover and apoptosis. Probiotics have been recommended for patients suffering from SBS in order to decrease bacterial overgrowth and prevent bacterial translocation, two major mechanisms in the pathogenesis of SBS. The present review discusses the research available in the international literature, clinical and experimental, regarding probiotic supplementation for this complicated group of patients based on the clinical spectrum and pathophysiological aspects of the syndrome. The clinical data that were collected for the purposes of the present review suggest that it is difficult to correctly characterise probiotics as a preventive or therapeutic measure. It is very challenging after all to examine the relationship of the bacterial flora, the intestinal barrier and the probiotics as, according to the latest knowledge, demonstrate an interesting interaction. PMID- 20961484 TI - Streamlined embedding of cell monolayers on gridded glass-bottom imaging dishes for correlative light and electron microscopy. AB - Correlative light and electron microscopy (CLEM) has facilitated study of intracellular trafficking. Routine application of CLEM would be advantageous for many laboratories but previously described techniques are particularly demanding, even for those with access to laser scanning confocal microscopy (LSCM) and transmission electron microscopy (TEM). We describe streamlined methods for TEM of green fluorescent protein (GFP)-labeled organelles after imaging by LSCM using gridded glass bottom imaging dishes. GFP-MAP 1A/1B LC3 (GFP-LC3) transfected cells were treated with rapamycin, fixed and imaged by LSCM. Confocal image stacks were acquired enabling full visualization of each GFP-LC3 labeled organelle. After LSCM, cells were embedded for TEM using a simplified two step method that stabilizes the glass bottom such that the block can be separated from the glass by mild heating. All imaging and TEM processing are performed in the same dish. The LSCM imaged cells were relocated on the block and serial sectioned. Correlation of LSCM, DIC, and TEM images was facilitated by cellular landmarks. All GFP labeled structures were successfully reidentified and imaged by serial section TEM. This method could make CLEM more accessible to nonspecialized laboratories with basic electron microscopy expertise and could be used routinely to confirm organelle localization of fluorescent puncta. PMID- 20961491 TI - Sustained release of VEGF by coaxial electrospun dextran/PLGA fibrous membranes in vascular tissue engineering. AB - VEGF-loaded core/shell fibrous membranes were prepared by coaxial electrospinning with dextran (DEX) as the core component and poly(lactide-co-glycolide) (PLGA) as the shell polymer, respectively. The electrospun DEX/PLGA fibers were observed by scanning electron microscopy, transmission electron microscopy and confocal microscopy to identify the core/shell fiber structure and the protein distribution. The results of tensile tests showed that the DEX/PLGA membranes possessed lower tensile strength and higher Young's modulus than PLGA one. The release profiles demonstrated that vascular endothelial growth factor (VEGF) release sustained for more than 28 days. Studies on cell viability and spreading demonstrated that the DEX(VEGF)/PLGA membranes positively promoted cell proliferation and cell-membrane interaction, which further testified that the processed VEGF remained bioactivities. Furthermore, the detections for the up regulation of intercellular adhesion molecular-1 and the release of von Willebrand factor under pathological stimuli, which are related to inflammation process and thrombus formation, exhibited a normal immune response for the DEX(VEGF)/PLGA membrane. These data suggested that the VEGF-loaded fibers could be feasible in vascular tissue engineering. PMID- 20961492 TI - Functionalization of calcium carbonate microparticles as a combined sensor and transport system for active agents in cells. AB - In recent years colloidal particles and capsules, layer-by-layer (LbL) coated with biocompatible polyelectrolytes, have received much attention as drug delivery systems. In this study an LbL-assembled, biopolymer-based multilayer system was established as a combined transporter and sensor for monitoring intracellular degradation and processing. CaCO(3) cores were functionalized with fluorescein isothiocyanatelabelled poly(allylamine hydrochloride) (FITC-PAH). This pH-sensitive fluorescent dye allows identifying the location of these LbL coated particles in cell compartments of different pH, like the endo-lysosome and cytoplasm. The labelled core was then coated with consecutive layers of protamine (PRM) and dextran sulfate (DXS). Finally, plasmid DNA (pEGFP-C1) as a reporter agent for drug release in the cytoplasm was integrated into the biocompatible and degradable PRM/DXS multilayer. The system was tested regarding its long-term stability and interaction with HEK 293T/17 cells. These multifunctional microparticles allow the simultaneous investigation of particle localization and processing within cells, and should thus provide a valuable tool for studying and improving the controlled LbL-based release of active agents into cells. PMID- 20961493 TI - Fluorescent identification and detection of Staphylococcus aureus with carboxymethyl chitosan/CdS quantum dots bioconjugates. AB - A fast and sensitive method based on fluorescent carboxymethyl chitosan/CdS quantum dots (CMCS-CdS QDs) composites was developed for specific detection of Staphylococcus aureus in food and the environment. Fluorescent CMCS-CdS QDs were prepared in aqueous solution through a green method. A human immunoglobulin (IgG) antibody was then bioconjugated to the QDs in the presence of 1-ethyl-3-(3) dimethylaminopropyl carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) to make a novel type of mono-dispersed water-soluble fluorescent bioprobes. The fluorescent bioprobes were employed to identify S. aureus by incubating them with the bacteria for a certain time and observing the marked cells under fluorescence microscopy after removing free fluorescent QDs. Fluorescence microscopy images showed the S. aureus cells were successfully recognized by the bioprobes. Several other bacteria commonly found in environment such as Escherichia coli and Bacillus subtilis were also incubated with the bioprobes to test their specificity. It was found that the novel QDs-CMCS-IgG bioprobes had specific identification to S. aureus cells. Fluorescence measurement using a luminescence spectrometer could be applied to quantify S. aureus cells. The fluorescence intensity of the samples at 600 nm was proportional to the cell concentration in the range of 10(3)-10(7) cfu/ml, and the detection limit was as low as 900 cfu/ml. Considering the simplicity and cost-efficiency of this method, its application in the identification and quantification of bacteria in clinical, food and environmental samples is anticipated. PMID- 20961494 TI - Random co-polymers based on the poloxamer Bayfit(r) 10WF15 for biomedical applications. AB - Random co-polymers were prepared from the poloxamer Bayfit((r)) 10WF15 and their thermal and biological properties analyzed. The poloxamer was characterized, functionalized with methacrylate groups (Bayfit-MA) and further co-polymerized with 2-hydroxyethyl methacrylate (HEMA) with Bayfit-MA feed contents of 1, 5 and 10 wt%. Co-polymers were partially soluble in organic solvents and exhibited a single glass transition temperature indicative of a random monomer distribution in the macromolecular chains. In thermogravimetric studies the co-polymers showed two degradation stages, around 210 and 350 degrees C, respectively. The thermosensitive behaviour of the poloxamer was studied by turbidimetry. Cloud point temperatures of aqueous solutions of Bayfit((r)) 10WF15 (0.5-5 wt%) ranged from 15 to 18 degrees C and for Bayfit((r)) 10WF15 methacrylate (0.5-1 wt%) from 6 to 7 degrees C. DSC thermograms of hydrated co-polymers showed the typical endothermic peaks with phase transition temperatures close to that of physiological medium. The biocompatibility of initial poloxamer and derivatives was analyzed with human fibroblasts cultures. The IC(50) value of Bayfit((r)) 10WF15 was 1.4 mg/ml. Cellular extracts of the co-polymers were not cytotoxic and cellular proliferation and DNA content depended on co-polymer composition. PMID- 20961495 TI - Preparation and characterization of a porous scaffold based on poly(D,L-lactide) and N-hydroxyapatite by phase separation. AB - In this study, a series of porous scaffolds were prepared from poly(D,L-lactide) (PLA) and nanohydroxyapatite (HA) using the phase separation method. HA/PLA composite membranes and PLA membranes with a microporous structure (pore size around 10-20 MUm) were observed by scanning electron microscopy and these micropores were well distributed throughout the PLA membranes. The surface morphology of HA/PLA composite membranes was significantly improved compared to pure PLA membrane. Also, the mechanical property and contact angle of composite membranes were different from that of pure PLA films. The immortalized rat osteoblastic ROS 17/2.8 cell line was used in this research to study the cell adhesion and proliferation behavior, and the results indicated that composite membranes had great cell affinity and good biocompatibility. PMID- 20961496 TI - Electroactivity and stability of polylactide/polypyrrole composites. AB - Electrically conductive biodegradable composites are useful in biomedical engineering to mediate electrical interactions between cells and electrical components. Because conductive polymers are often subjected to progressive oxidative deterioration and dedoping, their electrical stability in aqueous environment is, therefore, critical. We used cyclic voltammetry (CV) to investigate the electroactivity and stability of conductive membranes made of only 5% conductive polypyrrole (PPy) particles blended with 95% insulating polylactide (PLLA). During 1000 CV scans, the electroactivity of the composite membranes revealed a period of initial activation, followed by a relatively stable period and subsequent slow deterioration process. PPy membranes doped with heparin, a cell-adhesive polysaccharide and polyanion, displayed electrical stability superior to that of PPy membranes doped with chlorine anions. The latter, however, recorded a higher initial electroactivity during the first ca. 150 scans. XPS analysis showed that the deterioration of the electroactivity was likely due to the oxidation of the PPy. ATR-FT-IR and SEM were also used to characterize the materials. The PLLA/PPy membranes were thus electroactive and maximum electroactivity was achieved through an activation process. The heparin doped PPy composite was electrically stable and may, thus, be used for multiple long-term electrical stimulations. PMID- 20961497 TI - Hydrogel nanocomposites: a potential UV/blue light filtering material for ophthalmic lenses. AB - Poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) (poly(HEMA-co-MMA)) and ZnS hydrogel nanocomposites were prepared and characterized. The chemical composition of the inorganic nanoparticles was confirmed by X-ray diffraction, and the homogeneity of their distribution within the hydrogel was assessed by transmission electron microscopy. The influence of the content of ZnS nanoparticles on the optical performances of the nanocomposites was investigated by UV-Vis spectroscopy. The ability of the hydrogel nanocomposites to filter the hazardous UV light and part of the blue light was reported, which makes them valuable candidates for ophthalmic lens application. In contrast to the optical properties, the thermo-mechanical properties of neat poly(HEMA-co-MMA) hydrogels were found to be largely independent of filling by ZnS nanoparticles (<=2 mg/ml co-monomer mixture). Finally, in vitro cell adhesion test with lens epithelial cells (LECs), extracted from porcine lens crystalline capsule, showed that ZnS had no deleterious effect on the biocompatibility of neat hydrogels, at least at low content. PMID- 20961498 TI - Engineering a collagen matrix that replicates the biological properties of native extracellular matrix. AB - In this study, we aimed to replicate the function of native tissues that can be used in tissue engineering and regenerative medicine. The key to such replication is the preparation of an artificial collagen matrix that possesses a structure resembling that of the extracellular matrix. We, therefore, prepared a collagen matrix by fibrillogenesis in a NaCl/Na(2)HPO(4) aqueous solution using a dialysis cassette and investigated its biological behavior in vitro and in vivo. The in vitro cell adhesion and proliferation did not show any significant differences. The degradation rate in the living body could be controlled according to the preparation condition, where the collagen matrix with high water content (F collagen matrix, >98%) showed fast degradation and collagen matrix with lower water content (T-collagen matrix, >80%) showed no degradation for 8 weeks. The degradation did not affect the inflammatory response at all and relatively faster wound healing response was observed. Comparing this result with that of collagen gel and decellularized cornea, it can be concluded that the structural factor is very important and no cell abnormal behavior would be observed for quaternary structured collagen matrix. PMID- 20961499 TI - Staphylococcus aureus increases cytokine and matrix metalloproteinase expression in nasal mucosae of patients with chronic rhinosinusitis and nasal polyps. AB - BACKGROUND: Staphylococcus aureus is a common bacterial pathogen associated with chronic rhinosinusitis with/without nasal polyps (CRSw/sNP). We investigated the effect of S. aureus on the secretion of eotaxin, interleukin (IL)-5, IL-8, IL-13, matrix metalloproteinase (MMP) 2, MMP-9, and tissue inhibitor of MMP (TIMP) 1 in nasal mucosae from CRSwNP patients to assess the roles of these materials in NP pathogenesis. METHODS: We infected organ cultures of NP and inferior turbinate (IT) mucosae taken from patients with CRSwNP with S. aureus ATCC 25923 for 24 hours and incubated the cultures for an additional 48 hours at 37 degrees C. S. aureus infection and staphylococcal enterotoxins were confirmed by real-time polymerase chain reaction. Eotaxin, IL-5, IL-8, IL-13, MMP-2, MMP-9, and TIMP-1 protein levels were measured by ELISA. RESULTS: S. aureus infection significantly increased the concentrations of eotaxin, IL-5, IL-8, and IL-13 in the IT and NP groups (p < 0.01 for all comparisons). S. aureus infection also significantly increased the concentrations of MMP-2, MMP-9, and TIMP-1 in both groups (p < 0.001 for all comparisons). After S. aureus infection, the relative increases in eotaxin (6.42 versus 3.56), IL-5 (15.29 versus 8.89), MMP-2 (1.95 versus 1.58), MMP-9 (2.34 versus 1.95), and TIMP-1 (1.45 versus 1.31) were greater in the NP group than in the IT group. CONCLUSION: S. aureus infection enhances the secretion of cytokines, MMP-2, MMP-9, and TIMP-1 by both NPs and IT mucosae from patients with CRSwNP. S. aureus may play an important role in the pathogenesis of NP via tissue remodeling as well as eosinophilic inflammation. PMID- 20961500 TI - [Cardiac effects of glucagon-like peptide 1]. PMID- 20961501 TI - [Glucagon-like peptide-1: a cardiological perspective]. AB - Increasing experimental evidence points to direct effects of glucagon-like peptide-1 (GLP-1) and its analogs on the heart and circulatory system, in addition to the well-established, antidiabetic actions of these agents on glucose and on the energy metabolism. These effects are primarily vasodilation, diminished heart muscle loss after myocardial infarction and a contractility increase of a weak left ventricle. A few, small patient trials appear to support the latter effect. Experimental results suggest the myocardium-saving effect following coronary occlusion and reperfusion as particularly suitable for clinical testing. PMID- 20961502 TI - [Symptom presentation in cancer patients in general practice]. AB - INTRODUCTION: For the majority of cancer patients, the diagnostic investigations begin in general practice. The aim of the study was to investigate for which symptoms cancer patients consulted their general practitioner (GP). MATERIAL AND METHODS: All newly diagnosed cancer patients and their GPs in the County of Aarhus, Denmark, participated in a 1-year questionnaire survey. The GPs answered questions about the patients' first presentation of cancer symptoms and the GPs' interpretation of these symptoms. RESULTS: A total of 2,212 (83%) questionnaires were answered. The total number of reported symptoms was 3,208 corresponding to 1.7 reported symptoms per patient. The majority (57.6%) of patients presented only one symptom. Symptoms varied with the type of cancer. Patients with breast cancer and malignant melanoma mainly presented with diagnosis-specific symptoms. Patients with colorectal, lung and prostate cancer presented diagnosis-specific symptoms (change in bowel habits, cough and bladder dysfunction) as well as more non-specific symptoms (pain, weight loss and fatigue). The GPs interpreted the symptoms as alarm symptoms in 49%, as general symptoms in 24% and as non-cancer specific symptoms in 27% of the patients. CONCLUSIONS: In general practice, incident cancer patients often present with few and non-cancer specific symptoms. The fact that only half of the patients presented with alarm symptoms complicates the GPs' diagnostic work-up and the use of fast track for suspected cancer. Therefore, there is a need for alternative referral pathways for cancer patients with non-cancer specific symptoms. PMID- 20961503 TI - [Quality indicators for type 2 diabetes at referral to diabetes centre]. AB - INTRODUCTION: The Danish National Board of Health recommends graduated care of type 2 diabetes patients based on risk stratification. This requires a systematic monitoring of indicators for the development of complications. MATERIAL AND METHODS: Retrospective evaluation of type 2 diabetes patients referred from general practice in the 2004-2007 period. INCLUSION CRITERIA: 1) Diabetes duration = two years, 2) Diabetes control exclusively handled in primary care in the previous two years, 3) Referred from general practice to outpatient assessment by the diabetes centre, 4) The physician used a laboratory affiliated to the Aarhus County laboratory database, 5) Written referral could be found. Data was gathered by reviewing records, searching the laboratory database and register of diabetic eye care service. RESULTS: A total of 97 patients were included. By the time at referral (mean): Age 61.5 years, diabetes duration 8.4 years, body mass index 31.7 kg/m2. In the last two years before referral, the following percentage had at least one p-lipid measurement: 85%, eye examination: 61% and measurement of microalbuminuria: 53%. HbA1c at referral was 9.0% (n = 97), 9.1% (n = 93) seven months before and 8.7% (n = 82) 20 months before referral. CONCLUSION: Glycaemic control was poor 20 months before referral. The prerequisites for the recommendation of The Danish National Board of Health was not present since eye examination was not performed in 39% and assessment of microalbuminuria was not performed in 47% of the patients in the previous two years before referral. PMID- 20961504 TI - [Breast cancer surgery in Denmark]. AB - INTRODUCTION: Surgical treatment for breast cancer is changing towards less extensive procedures and hence the need for hospitalisation is reduced. In order to investigate the organisation of such procedures, the choice of surgical procedures, length of hospitalisation, and mortality were evaluated using information from The National Board of Health. MATERIAL AND METHODS: Mandatory data reported to the Danish National Board of Health for 2008. RESULTS: A total of 19 units performed 4,000 surgical procedures. Three private care units performed 1.2% of all procedures. No postoperative mortality was registered. Mean length of stay was 2.5 days. CONCLUSION: The organisation of breast cancer treatment in public health care in Denmark is satisfactory with high volume units (> 100 women with primary breast cancer per year). It seems possible to aim at further reduction in the mean length of stay moving towards a fast track concept. PMID- 20961505 TI - [Detection of stenoses in the coronary arteries using 64-slice computed tomography]. AB - INTRODUCTION: The purpose of the present study was to assess the diagnostic value of 64-slice computed tomography of the coronary arteries (CTCA) with invasive coronary angiography (CA) as reference. MATERIAL AND METHODS: We studied 194 patients (mean age: 62.7 +/- 9.5 years, males: 97) with symptoms suggesting angina who had been referred for CA according to usual criteria. We excluded patients with known ischaemic heart disease and patients with an unstable heart rhythm. CTCA was analysed without knowledge of CA and vice versa. Stenoses > 50% were considered significant. The effective radiation (mSv) was measured with both methods. RESULTS: In 17 patients (8.8%), the CT-angiogram was not assessable. In 177 patients (91.2%) with assessable CT-angiogram, the sensitivity of CTCA was 97%, the specificity 63%, the predictive value of a positive test 58%, and the predictive value of a negative test 97%. In the 174 patients in whom CTCA was performed using retrospective technique, the effective radiation was 14.0 +/- 2.3, versus 4.9 +/- 2.6 at CA (p < 0.0005). In the 20 patients in whom CTCA was performed using prospective technique, the effective radiation was 5.4 +/- 1.2 versus 5.9 +/- 3.6 at CA (non-significant) CONCLUSION: CTCA with 64-slice scanner has a high sensitivity for demonstration coronary artery stenoses. PMID- 20961506 TI - [Inadvertent instillation of superglue in both eyes should not be treated conservatively]. AB - We describe a case of a 4-year-old boy who accidentally had both eyes glued together. The eyelashes were cut and the boy's eyelids were separated in general anaesthesia. When both eyes are glued together, we do not recommend expectancy, especially not in paediatric cases. For psychological reasons, the lids should be separated surgically. Furthermore, we suggest that similarities between ophthalmic bottles and superglue bottles are avoided so that future incidences may be avoided. PMID- 20961507 TI - [Stress fracture following femoral epiphysiodesis]. AB - Growth guiding is currently widely practiced for deformity correction in the growing child. Different methods have been developed. In 2007 Stevens described a tension band device (8-plates) as a simple growth control method. Since then it has been widely used, e.g. in hemiepiphysiodesis to correct varus or valgus deformities or extension defect in the knee. Temporary epiphysiodesis can also be used to correct leg length discrepancy more accurately. Complications after treatment with 8-plates are well-described. Stress fracture after the usage of this device has to our knowledge not yet been described. We present a case with a fracture in the distal femur through 8-plates screw holes. PMID- 20961508 TI - [Umbilical pilonidal sinus]. AB - In this case report we describe a case of umbilical pilonidal sinus in a 45-year old male. He was referred to hospital following umbilical pain and bloody discharge from the umbilicus. Abdominal ultrasound scan showed a 2 * 1 * 0.5 cm high-density structure. The clinical diagnosis was urachus cyst. The patient was operated and the cyst removed. The pathological examination reached the diagnosis umbilical pilonidal sinus. PMID- 20961509 TI - [Herpes zoster oticus with cranial nerve affection]. AB - Herpes zoster oticus (HZO) with cranial polyneuropathy is also known as Ramsay Hunt syndrome (RHS). After primary varicella infection, the varicella zoster virus (VZV) remains dormant in the nervous system and can reactivate later in life causing RHS. This case describes a 56-year-old man with HZO and palsy of N. V, VII, VIII, IX, X and XII. Anti-viral agents might be effective in patients with RHS, although the only randomized controlled clinical trial on this subject found no significant benefit. There are no randomized controlled trials to support the use of corticosteroid therapy. PMID- 20961512 TI - Letter to the editor. Spotlight on measles 2010: timely administration of the first dose of measles vaccine in the context of an ongoing measles outbreak in France. PMID- 20961514 TI - Letter to the editor. Spotlight on measles 2010: measles in healthcare workers - vaccination should be revisited. PMID- 20961515 TI - Methicillin-resistant Staphylococcus aureus (MRSA): burden of disease and control challenges in Europe. AB - Methicillin-resistant Staphylococcus aureus (MRSA) isa major cause of healthcare- and community-associated infections worldwide. Within the healthcare setting alone, MRSA infections are estimated to affect more than 150,000 patients annually in the European Union (EU), resulting in attributable extra in-hospital costs of EUR 380 million for EU healthcare systems. Pan-European surveillance data on bloodstream infections show marked variability among EU Member States in the proportion of S. aureus that are methicillin-resistant, ranging from less than 1% to more than 50%. In the past five years, the MRSA bacteraemia rates have decreased significantly in 10 EU countries with higher endemic rates of MRSA infections. In addition to healthcare-associated infections, new MRSA strains have recently emerged as community and livestock-associated human pathogens in most EU Member States. The prevention and control of MRSA have therefore been identified as public health priorities in the EU. In this review, we describe the current burden of MRSA infections in healthcare and community settings across Europe and outline the main threats caused by recent changes in the epidemiology of MRSA. Thereby, we aim at identifying unmet needs of surveillance, prevention and control of MRSA in Europe. PMID- 20961516 TI - Travel-associated Legionnaires disease in Europe in 2009. AB - A total of 818 cases of Legionnaires' disease with onset of illness in 2009 were reported from 22 European and two non-European countries to the European Surveillance Scheme for Travel-Associated Legionnaires' Disease (EWGLINET). This is a decrease of 52 cases compared with 2008 and 129 fewer than in 2007 - the peak year of reporting to date. A total of 794 (97.1%) cases were reported as confirmed and 24 as presumptive cases. Outcome of illness was reported for 561 (68.6%) cases. Of these cases 28 (5%) were reported to have died. More than half, of the cases in 2009 (n=469, 57.3%) were reported within 20 days of symptom onset. Cases visited 53 countries and were infected in all months of the year, with a peak in September (n=146). By country of residence of the cases, the United Kingdom (UK) reported the highest number of cases (n=173). Italy reported the second highest number of cases (n=169) and was also the country associated with the most cases by country of infection (n=209). A total of 88 new clusters (75 in Europe and 13 outside Europe) were detected in 2009 and were associated with 196 cases. The largest cluster occurred in Italy and involved seven cases. Without the scheme's international database, thirty three (37.5%) of the newly detected clusters would not have been identified. In 49 of the accommodation sites with clusters of cases, environmental samples were found to be positive for Legionella spp. Details of 10 sites were published on the European Working Group for Legionella Infections (EWGLI) website for failure to return information on the status of environmental investigations. PMID- 20961517 TI - First autochthonous malaria case due to Plasmodium vivax since eradication, Spain, October 2010. AB - In October 2010, one case of autochthonous malaria due to Plasmodium vivax was diagnosed in Spain. The case occurred in Aragon, north-eastern Spain, where the vector Anopheles atroparvus is present. Although the source of infection could not be identified, this event highlights that sporadic autochthonous transmission of vector-borne diseases in continental Europe is possible and calls for enhanced surveillance and vector control measures. PMID- 20961518 TI - Anticipatory baseline effects and information integration in visual world studies. AB - Researchers often conduct visual world studies to investigate how listeners integrate linguistic information with prior context. Such studies are likely to generate anticipatory baseline effects (ABEs), differences in listeners' expectations about what a speaker might mention that exist before a critical speech stimulus is presented. ABEs show that listeners have attended to and accessed prior contextual information in time to influence the processing of the critical speech stimulus. However, further evidence is required to show that the information actually did influence subsequent processing. ABEs can compromise the validity of inferences about information integration if they are not appropriately controlled. We discuss four solutions: statistical estimation, experimental control, elimination of "on-target" trials, and neutral gaze. An experiment compares the performance of these solutions, and suggests that the elimination of on-target trials introduces bias in the direction of ABEs, due to the statistical phenomenon of regression toward the mean. We conclude that statistical estimation, possibly coupled with experimental control, offers the most valid and least biased solution. PMID- 20961519 TI - On the temporal dynamics of language-mediated vision and vision-mediated language. AB - Recent converging evidence suggests that language and vision interact immediately in non-trivial ways, although the exact nature of this interaction is still unclear. Not only does linguistic information influence visual perception in real time, but visual information also influences language comprehension in real-time. For example, in visual search tasks, incremental spoken delivery of the target features (e.g., "Is there a red vertical?") can increase the efficiency of conjunction search because only one feature is heard at a time. Moreover, in spoken word recognition tasks, the visual presence of an object whose name is similar to the word being spoken (e.g., a candle present when instructed to "pick up the candy") can alter the process of comprehension. Dense sampling methods, such as eye-tracking and reach-tracking, richly illustrate the nature of this interaction, providing a semi-continuous measure of the temporal dynamics of individual behavioral responses. We review a variety of studies that demonstrate how these methods are particularly promising in further elucidating the dynamic competition that takes place between underlying linguistic and visual representations in multimodal contexts, and we conclude with a discussion of the consequences that these findings have for theories of embodied cognition. PMID- 20961520 TI - Routine screening for silent pulmonary embolism is harmful and unnecessary. PMID- 20961521 TI - Prevalence and correlates of skin cancer screening among middle-aged and older white adults in the United States. PMID- 20961522 TI - Ludwig's Angina. PMID- 20961523 TI - Patent foramen ovales and cryptogenic strokes: another look. PMID- 20961524 TI - Modest response in translation to home management of deep venous thrombosis. AB - BACKGROUND: years may elapse between the publication of results of rigorous randomized trials and changes in clinical practice. It is not often that a definitive time interval can be identified that shows the time taken for published clinical trials to affect clinical practice. In the present study, we track the timelines of evidence for home treatment of deep venous thrombosis and its eventual impact on hospitalizations and early discharge. METHODS: the number of patients discharged from short-stay hospitals throughout the United States between 1979 and 2006 with a principal diagnosis of deep venous thrombosis and the proportion discharged in <= 2 days was determined from The National Hospital Discharge Survey. We also attempted to identify all published articles that reported home treatment of deep venous thrombosis in unselected populations. RESULTS: eleven years after demonstration of the safety and efficacy of home treatment, there was only a 21% decrease in the population-based incidence of hospitalizations of patients with a principal diagnosis of deep venous thrombosis. The proportion of patients with a principal diagnosis of deep venous thrombosis who were discharged in <= 2 days began to increase prominently after the 1996 publication of trials showing the safety and efficacy of home treatment, and continued to increase through 2006. However, the proportion discharged early remained modest (21% to 25%). CONCLUSIONS: whether the slow implementation of home treatment reflects a cautious approach accompanied by a gradual testing of shortened hospitalization for deep venous thrombosis or other factors is uncertain. PMID- 20961525 TI - Ice cream urticaria. PMID- 20961526 TI - Re-visioning Flexner: educating physicians to be clinical scientists and humanists. PMID- 20961527 TI - Read between the lines. PMID- 20961528 TI - Antibiotic prophylaxis for dental procedures to prevent indwelling venous catheter-related infections. AB - BACKGROUND: chronic indwelling central venous catheters are used commonly for a variety of indications. A predominant limitation of their use is catheter-related infections. Some clinicians believe that bacteremia from an invasive dental procedure could cause catheter-related infections and that antibiotic prophylaxis may prevent this complication. The topic is controversial, in large part because of the lack of clinical trial data supporting this notion. METHODS: we performed a systematic review to determine the level of evidence to support this practice. We retrieved studies, guidelines, recommendations, case reports, and editorials on prescribing prophylactic antibiotic therapy for indwelling central venous catheters before oral/dental procedures, using a search of PubMed, National Guideline Clearinghouse, and textbooks. RESULTS: there were no clinical trials and no documented cases of a catheter-related infection associated with an invasive dental procedure. Despite the lack of evidence, there are numerous recommendations and guidelines available in the literature that support the administration of "dental" prophylaxis. CONCLUSION: there is no evidence to support the administration of prophylactic antibiotics to prevent catheter related infections associated with an invasive oral procedure in patients with chronic indwelling central venous catheters. PMID- 20961529 TI - Patterns of care and outcomes after computed tomography scans for headache. AB - BACKGROUND: concerns exist about potential overuse of computed tomography (CT) scans for headache in ambulatory care. METHODS: we sought to examine health services use, brain tumor diagnosis, and death during the year after CT scanning for headache by linking records of an audit of 3930 outpatient CT brain scans performed in 2005 in Ontario, Canada, to administrative databases. RESULTS: of 623 patients receiving CT scans for a sole indication of headache, few (2.1%) scans contained findings potentially causing their headache. For most patients, the index CT scan was the only one received over an 11-year period. However, 28.4% of patients received 1 or more CT brain scans during the preceding decade and 6.7% received 1 or more CT brain scans during the subsequent year. Of the 473 patients (75.9%) whose index scan was ordered by a primary care physician, most (80.3%) did not see a specialist during follow-up. One patient with an indeterminate finding on the index scan was diagnosed with a malignant brain tumor (0.2%), and 6 patients (1.0%) died during follow-up. Among the 4 deaths in which the cause could be determined, none were due to central nervous system causes. CONCLUSION: because of the potential risk of cancer from exposure to ionizing radiation, efforts should be made to avoid CT scanning for headache when the likelihood of serious illness is low. Evidence-based decision rules that identify which patients with headache do not require neuroimaging may decrease the use of CT scans in situations of little benefit. PMID- 20961530 TI - Familial pituitary adenomas. AB - Pituitary adenomas are benign intracranial neoplasms that present a major clinical concern because of hormonal overproduction or compression symptoms of adjacent structures. Most arise in a sporadic setting with a small percentage developing as a part of familial syndromes such as multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC), and the recently described familial isolated pituitary adenomas (FIPA) and MEN-4. While the genetic alterations responsible for the formation of sporadic adenomas remain largely unknown, considerable advances have been made in defining culprit genes in these familial syndromes. Mutations in MEN1 and PRKAR1A genes are found in the majority of MEN1 and CNC patients, respectively. About 15% of FIPA kindreds present with mutations of the aryl hydrocarbon receptor-interacting protein (AIP) gene. Mutations in the CDKN1B gene, encoding p27(Kip)1 were identified in MEN4 cases. Familial tumours appear to differ from their sporadic counterparts not only in genetic basis but also in clinical characteristics. Evidence suggests that, especially in MEN1 and FIPA, they are more aggressive and affect patients at younger age, therefore justifying the importance of early diagnosis. In this review, we summarize the genetic and clinical characteristics of these familial pituitary adenomas. PMID- 20961531 TI - Product design enhancement using apparent usability and affective quality. AB - In this study, apparent usability and affective quality were integrated in a design framework called the Usability Perception and Emotion Enhancement Model (UPEEM). The UPEEM was validated using structural equation modeling (SEM). The methodology consists of four phases namely product selection, attribute identification, design alternative generation, and design alternative evaluation. The first stage involved the selection of a product that highly involves the consumer. In the attribute identification stage, design elements of the product were identified. The possible values of these elements were also determined for use in the experimentation process. Design of experiments was used to identify how the attributes will be varied in the design alternative stage and which of the attributes significantly contribute to affective quality, apparent usability, and desirability in the design evaluation stage. Results suggest that product attributes related to form are relevant in eliciting intense affect and perception of usability in mobile phones especially those directly related to functionality and aesthetics. This study considered only four product attributes among so many due to the constraints of the research design employed. Attributes related to aesthetic perception of a product enhance apparent usability such as those related to dimensional ratios. PMID- 20961532 TI - Interaction of aromatic imino glycoconjugates with jacalin: experimental and computational docking studies. AB - Altering the lectin properties by chemically modified glycoconjugates can have profound effect on their biological applications. In the present case, jacalin has been chosen to study the binding aspects toward glycoconjugates modified by connecting aromatic moieties through imine conjugation at their C-1- or C-2 positions. Out of 10 glycoconjugates, the galactosyl-naphthyl imine (1c) was found to be most effective toward agglutination inhibition (260 times better than galactose), quenching fluorescence intensity, and exhibiting greater binding (K(a), 1.3 * 10(4)M(-1)) with jacalin. The specific binding of galactose conjugates and the nonspecific binding of other conjugates have been demonstrated based on ITC. Changes in the secondary structures have been addressed by far- and near-UV CD spectroscopy. The present studies demonstrated that galactose-based conjugates bind at carbohydrate recognition domain (CRD) mainly through polar interactions in addition to exhibiting some nonpolar/hydrophobic interactions, whereas the conjugates other than galactose primarily interact through hydrophobic interactions. Binding of galactosyl conjugates at CRD has been further demonstrated by rigid docking. PMID- 20961533 TI - Revisiting the aldol reaction of cis-alpha,beta-epoxyaldehyde promoted by BF(3).Et(2)O: direct access to 2-deoxy-2-fluoro heptulosonic ester analogues. AB - The aldol reaction between cis-3-((tert-butyldiphenylsilyloxy)methyl)oxirane-2 carbaldehyde and ethyl-2-(trimethylsilyloxy)-2-propenoate promoted by boron trifluoride diethyl etherate was reinvestigated. By varying the work-up conditions, a new 2-deoxy-2-fluoro heptulosonic ester analogue was synthesized. Derivatizations and detailed NMR analysis allowed the complete characterization of this fluoro analogue and its derivatives. PMID- 20961534 TI - The Adams family. AB - According to Adams's Thesis, the acceptability of an indicative conditional sentence goes by the conditional probability of its consequent given its antecedent. We test, for the first time, whether this thesis is descriptively correct and show that it is not; in particular, we show that it yields the wrong predictions for people's judgments of the acceptability of important subclasses of the class of inferential conditionals. Experimental results are presented that reveal an interaction effect between, on the one hand, the type of inferential connection between a conditional's antecedent and its consequent and, on the other, the judged acceptability of the conditional in relation to the conditional probability of its consequent given its antecedent. Specifically, these results suggest a family of theses, each pertaining to a different type of conditional, about how conditionals relate to the relevant conditional probabilities. PMID- 20961535 TI - An off-line gating method for suppressing motion artifacts in ICUS sequence. AB - Intracoronary ultrasound (ICUS) imaging, an invasive catheter-based imaging modality, has been widely used in clinical diagnosis of coronary artery diseases. Motion artifacts due to cyclic cardiac motion and pulsatile blood are the main factors that hinder the visualization of ICUS longitudinal cut and 3D vessel reconstruction from ICUS image sequence. The aim of this work is to propose an off-line gating method based on ICUS image properties to suppress motion artifacts for continuous pullback ICUS image sequences acquired in vivo covering several cardiac cycles without the help of ECG signals. Based on analysis of intensity features of each ICUS frame, a difference matrix is firstly constructed. Then, potential information about cardiac cycle is extracted from the matrix and the correspondence of each ICUS frame in successive cardiac cycles is obtained through finding a globally optimal path with the lowest cumulative difference value in the matrix. Finally, a subsequence of frames each acquired at the end-diastole of each cardiac cycle is selected to obtain the gated sequence. The main advantage of this method is that it is applicable to those ICUS sequences where the subject's heart rate may be irregular during image acquisition. Also, any high-level image analysis performed to ICUS images is not needed. Results are given for clinical image data of patients in order to validate the proposed method. PMID- 20961537 TI - [Antibiotic resistance in urinary tract infection and identification of associated risk factors]. PMID- 20961536 TI - Varying coefficient function models to explore interactions between maternal nutritional status and prenatal methylmercury toxicity in the Seychelles Child Development Nutrition Study. AB - Maternal consumption of fish during the gestational period exposes the fetus to both nutrients, especially the long-chain polyunsaturated fatty acids (LCPUFAs), believed to be beneficial for fetal brain development, as well as to the neurotoxicant methylmercury (MeHg). We recently reported that nutrients present in fish may modify MeHg neurotoxicity. Understanding the apparent interaction of MeHg exposure and nutrients present in fish is complicated by the limitations of modeling methods. In this study we fit varying coefficient function models to data from the Seychelles Child Development Nutrition Study (SCDNS) cohort to assess the association of dietary nutrients and children's development. This cohort of mother-child pairs in the Republic of Seychelles had fish consumption averaging 9 meals per week. Maternal nutritional status was assessed for five different nutritional components known to be present in fish (n-3 LCPUFA, n-6 LCPUFA, iron status, iodine status, and choline) and associated with children's neurological development. We also included prenatal MeHg exposure (measured in maternal hair). We examined two child neurodevelopmental outcomes (Bayley Scales Infant Development-II (BSID-II) Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI)), each administered at 9 and at 30 months. The varying coefficient models allow the possible interactions between each nutritional component and MeHg to be modeled as a smoothly varying function of MeHg as an effect modifier. Iron, iodine, choline, and n-6 LCPUFA had little or no observable modulation at different MeHg exposures. In contrast the n-3 LCPUFA docosahexaenoic acid (DHA) had beneficial effects on the BSID-II PDI that were reduced or absent at higher MeHg exposures. This study presents a useful modeling method that can be brought to bear on questions involving interactions between covariates, and illustrates the continuing importance of viewing fish consumption during pregnancy as a case of multiple exposures to nutrients and to MeHg. The results encourage more emphasis on a holistic view of the risks and benefits of fish consumption as it relates to infant development. PMID- 20961538 TI - [Cerebral infarctions in tuberculous meningitis]. PMID- 20961539 TI - Efficacy of induced luteinizing hormone surge after "trigger" with gonadotropin releasing hormone agonist. AB - The magnitude of the LH surge after GnRH agonist "trigger" was correlated with oocyte yield and maturity and was suboptimal in approximately half of the cycles. A modest reduction in oocyte yield and maturity was observed when the serum level of LH 12 hours after GnRH agonist trigger was less than the median value (52 IU/L), and a dramatic reduction in yield and maturity was observed when that level was less than 12 IU/L. PMID- 20961540 TI - Comparison of united and nonunited fractures of the ulnar styloid following volar plate fixation of distal radius fractures. AB - INTRODUCTION: The purpose of this study was to determine whether associated nonunion of ulnar styloid fracture following plate-and-screw fixation of a distal radius fracture (DRF) has any effect on wrist functional outcomes, ulnar-sided wrist pain or distal radioulnar joint (DRUJ) instability. MATERIALS AND METHODS: A total of 91 consecutive patients with a DRF and an accompanying ulnar styloid fracture treated by open reduction and volar locking plate fixation were included in this study. In the first part of the analysis, the 91 study subjects were subdivided according to the presence or not of ulnar styloid union (20 and 71, respectively) by radiography at final follow-up (average 23 months). These two cohorts were compared with respect to wrist functions at 3 months postoperatively and the final follow-up visit, and ulnar-sided wrist pain and DRUJ instability at the final follow-up visit and ulnar styloid length as determined radiographically at final follow-up. In the second part of the analysis, 49 of the 91 study subjects with an ulnar styloid base fracture were subdivided according to the presence or not of ulnar styloid base fracture union (12 and 37, respectively) at final follow-up by radiography. These two groups were also compared with respect to the above-mentioned parameters. RESULTS: Ulnar styloid fractures united in 20 (22%) of the 91 patients at final follow-up visit (average 23 months). No significant differences were found at any time during follow-up between patients who achieved or did not achieve ulnar styloid fracture union or ulnar styloid base fracture union. CONCLUSION: Ulnar styloid nonunion does not appear to affect wrist functional outcomes, ulnar-sided wrist pain or DRUJ stability, at least when a DRF is treated by open reduction and volar plate fixation. PMID- 20961541 TI - Predictors of premenstrual syndrome among Nigerian university students. PMID- 20961542 TI - Prevalence and risk factors for domestic violence against infertile women in an Iranian setting. AB - OBJECTIVE: To determine the prevalence of and risk factors for domestic violence against women with female factor infertility in an Iranian setting. METHODS: In this cross-sectional survey conducted from August 1, 2009 to January 31, 2010, 400 women with primary infertility attending Valiasr Reproductive Health Research Center in Tehran, Iran, were interviewed using the Revised Conflict Tactics Scales questionnaire (CTS(2)). This instrument was developed to investigate the presence domestic violence. RESULTS: A total of 247 women (61.8%) reported having experienced domestic violence because of their infertility. The most common type of violence was psychological (n=135 [33.8%]), followed by physical (n=56 [14%]) and sexual (n=32 [8%]), with 24 women (6%) reporting injuries. All women reported their husbands to be the perpetrators. CONCLUSION: Domestic violence against infertile women is a considerable yet unreported problem. Clinicians should identify the abused women and provide them with medical care and supportive counseling. PMID- 20961543 TI - Contraceptive practices of women visiting a gynecology clinic in Beijing, China. PMID- 20961544 TI - A Chinese version of Iowa Infant Feeding Attitude Scale: reliability and validity assessment. AB - BACKGROUND: To achieve the goal of increasing the proportion and duration of breastfeeding in Taiwan, it is essential to assess the role of attitudes in determining which method of infant feeding will be chosen. Understanding maternal attitudes toward infant feeding methods may have utility in the development and implementation of public health policy and interventions facilitating increasing breastfeeding rates. However, no validated instrument to assess breastfeeding attitudes is available in Chinese for use in Taiwan. OBJECTIVE: To translate the Iowa Infant Feeding Attitude Scale (IIFAS) into Chinese and assess its psychometric properties among Taiwanese breastfeeding women. DESIGN: Methodological study. SETTING: One public hospital in Taichung city, Taiwan. PARTICIPANTS: A convenience sample of 140 in-hospital breastfeeding women was recruited. METHODS: The IIFAS was translated into Chinese using forward translation, back-translation, semantic equivalence, and pilot testing. Predict validity and internal consistency was assessed. The final sample consisted of 120 women (14% attrition) that were interviewed by telephone at 6 weeks postpartum to record the breastfeeding duration and infant feeding method. RESULTS: One item was modified to better reflect the item content. In-hospital IIFAS scores significantly predicted breastfeeding duration as well as exclusive breastfeeding at 6 weeks postpartum. The Cronbach's alpha coefficient for internal consistency was 0.74. CONCLUSIONS: This study provides evidence that the Chinese version of the IIFAS can be considered valid and reliable scale for assessing attitudes toward breastfeeding among breastfeeding women in Taiwan. PMID- 20961545 TI - Commentary on Aitken et al.'s (2010) 'Comparison of 'think aloud' and observation as data collection methods in the study of decision making regarding sedation in intensive care patients'. PMID- 20961546 TI - Parametric uncertainties and influence of the dead volume representation in modelling simulated moving bed separation processes. AB - In this study, a systematic numerical procedure for identifying the model parameters of simulated moving bed (SMB) separation processes is developed. The parameters are first estimated by minimizing a weighted least-squares criterion using experimental data from batch experiments, e.g. the time evolution of the concentration of elution peaks. Then, a cross-validation is achieved using data from experiments in SMB operation. At this stage, the importance of a careful modelling of the dead volumes within the SMB process is highlighted. In addition, confidence intervals on the estimated parameters and on the predicted concentration profiles are evaluated. PMID- 20961547 TI - Chromatographic techniques for the determination of alkyl-phenols, tocopherols and other minor polar compounds in raw and roasted cold pressed cashew nut oils. AB - Anacardium occidentale belongs to the family Anacardiaceae and is principally grown in tropical America (Mexico, Peru, Brazil, etc.) and India. Cashew nuts contain low amounts of hydroxy alkyl phenols that come from an oily liquid present in their shell and that is known as cashew-nut shell liquid. This paper reports the alkyl phenols composition of cold pressed raw and roasted cashew nut oil. First of all, cashew nut shell liquid was used for a basic fractionation of the alkyl phenol classes by preparative TLC and definitively identified by GC-MS and GC-FID. Anacardic acids were the major alkylphenols contained in both oils followed by cardol, cardanol and 2-methylcardol compounds, respectively. Raw and roasted oils did not show different compositions except for cardanols. The oil produced from roasted cashew nut reported a higher concentration of cardanols. Furthermore, tocopherols and other minor polar compounds were determined by HPLC FLD and HPLC-DAD-MS, respectively. Tocopherol content varied in a range of 171.48 29.56mg/100g from raw to roasted cashew nut oil, being beta-tocopherol the one which presented a higher decrease (93.68%). Also minor polar compounds in cashew oil decreased after roasting from 346.52 to 262.83mg/kg. PMID- 20961548 TI - Novel reduced pressure-balance syringe for chromatographic analysis. AB - When withdrawing a fluid sample (for additional chromatographic analyses) from an apparatus operated at a reduced pressure, a typical syringe proves to be ineffective (even if it is equipped with a gas tight plunger). It simply does not create enough pressure differential to remove a fluid sample from a reduced pressure environment. We encountered such a situation as part of efforts to extend the operation of the advanced distillation curve protocol to reduced pressures. The problem was solved by the development of a pressure balance syringe that allows reliable and precise sampling from an apparatus operating at sub-ambient pressures. This new device uses an external vacuum source to evacuate a syringe barrel, allowing a user to withdraw fluid samples from environments with pressures as low as 0.5kPa. To demonstrate the operation of the newly developed device, distillate analyses were performed on two fluids at low pressure: a predefined validation mixture, and a commercial soy based biodiesel fuel. The pressure balance syringe was used successfully for sampling in both cases. The use of the pressure balance syringe is not limited to reduced pressure distillations; indeed it can be used for a variety of applications in which chemical/compositional analyses are desired on a fluid contained in a reduced pressure environment. PMID- 20961549 TI - Universal response model for a corona charged aerosol detector. AB - The universality of the response of the Corona Charged Aerosol Detector (CoronaCAD) has been investigated under flow-injection and gradient HPLC elution conditions. A three-dimensional model was developed which relates the CoronaCAD response to analyte concentration and the mobile phase composition used. The model was developed using the response of four probe analytes which displayed non volatile behavior in the CoronaCAD and were soluble over a broad range of mobile phase compositions. The analyte concentrations ranged from 1MUg/mL to 1mg/mL, and injection volumes corresponded to on-column amounts of 25ng to 25MUg. Mobile phases used in the model were composed of 0-80% acetonitrile, mixed with complementary proportions of aqueous formic acid (0.1%, pH 2.6). An analyte set of 23 compounds possessing a wide range of physicochemical properties was selected for the purpose of evaluating the model. The predicted response was compared to the actual analyte response displayed by the detector and the efficacy of the model under flow-injection and gradient HPLC elution conditions was determined. The average error of the four analytes used to develop the model was 9.2% (n=176), while the errors under flow-injection and gradient HPLC elution conditions for the evaluation set of analytes were found to be 12.5% and 12.8%, respectively. Some analytes were excluded from the evaluation set due to considerations of volatility (boiling point <400 degrees C), charge and excessive retention on the column leading to elution outside the eluent range covered by the model. The two-part response model can be used to describe the relationship between response and analyte concentration and also to offer a correction for the non-linear detector response obtained with gradient HPLC for analytes which conform to the model, to provide insight into the factors affecting the CoronaCAD response for different analytes, and also as a means for accurately determining the concentration of unknown compounds when individual standards are not available for calibration. PMID- 20961550 TI - Amphiphilic silica nanoparticles as pseudostationary phase for capillary electrophoresis separation. AB - Amphiphilic silica nanoparticles surface-functionalized by 3 aminopropyltriethoxysilane (APTES) and octyltriethoxylsilane (OTES) were successfully prepared and characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectrometry (FT-IR) and thermogravimetry (TG) techniques. The potential use of these bifunctionalized nanoparticles as pseudostationary phases (PSPs) in capillary electrophoresis (CE) for the separation of charged and neutral compounds was evaluated in terms of their suitability. As expected, fast separation of representative aromatic acids was fulfilled with high separation efficiency, because they migrate in the same direction with the electroosmotic flow (EOF) under optimum experimental conditions. Using a buffer solution of 30mmol/L phosphate (pH 3.0) in the presence of 0.5mg/mL of the synthesized bifunctionalized nanoparticles, the investigated basic compounds were baseline resolved with symmetrical peaks. Due to the existence of amino groups on the surface of nanoparticles, "silanol effect" that occurs between positively charged basic analytes and the silanols on the inner surface of capillary was greatly suppressed. Furthermore, the separation systems also exhibited reversed-phase (RP) behavior when neutral analytes were tested. PMID- 20961551 TI - A surprising method for green extraction of essential oil from dry spices: Microwave dry-diffusion and gravity. AB - Without adding any solvent or water, we proposed a novel and green approach for the extraction of secondary metabolites from dried plant materials. This "solvent, water and vapor free" approach based on a simple principle involves the application of microwave irradiation and earth gravity to extract the essential oil from dried caraway seeds. Microwave dry-diffusion and gravity (MDG) has been compared with a conventional technique, hydrodistillation (HD), for the extraction of essential oil from dried caraway seeds. Essential oils isolated by MDG were quantitatively (yield) and qualitatively (aromatic profile) similar to those obtained by HD, but MDG was better than HD in terms of rapidity (45min versus 300min), energy saving, and cleanliness. The present apparatus permits fast and efficient extraction, reduces waste, avoids water and solvent consumption, and allows substantial energy savings. PMID- 20961552 TI - Ferrofluid-based liquid-phase microextraction. AB - A new mode of liquid-phase microextraction based on a ferrofluid has been developed. The ferrofluid was composed of silica-coated magnetic particles and 1 octanol as the extractant solvent. The 1-octanol was firmly confined within the silica-coated particles, preventing it from being lost during extraction. Sixteen polycyclic aromatic hydrocarbons (PAHs) were used as model compounds in the development and evaluation of the extraction procedure in combination with gas chromatography-mass spectrometry. Parameters affecting the extraction efficiency were investigated in detail. The optimal conditions were as follows: 20mL sample volume, 10mg of the silica-coated magnetic particles (28mg of ferrofluid), agitation at 20Hz, 20min extraction time, and 2min by sonication with 100MUL acetonitrile as the final extraction solvent. Under optimal extraction conditions, enrichment factors ranging from 102- to 173-fold were obtained for the analytes. The limits of detection and the limits of quantification were in the range of 16.8 and 56.7pgmL(-1) and 0.06 and 0.19ngmL(-1), respectively. The linearities were between 0.5-100 and 1-100ngmL(-1) for different PAHs. As the ferrofluid can respond to and be attracted by a magnet, the extraction can be easily achieved by reciprocating movement of an external magnet that served to agitate the sample. No other devices were needed in this new approach of extraction. This new technique is affordable, efficient and convenient for microextraction, and offers portability for potential onsite extraction. PMID- 20961553 TI - Evaluation of comprehensive two-dimensional gas chromatography coupled to time-of flight mass spectrometry for the diagnosis of inherited metabolic disorders using an automated data processing strategy. AB - Organic acidurias are a large group of inherited metabolic disorders (IMDs), commonly diagnosed by GC-MS analysis of organic acids in urine after acidic extraction and trimethylsilylation. In this study, a GC*GC-ToF-MS method has been optimized for the analysis of pathological metabolites in urine. An automated data processing strategy based on the use of mass spectra and GC retention times for the target search and quantification of pathological metabolites has been developed. Using this procedure, each unknown sample is automatically examined for the presence of markers of several diseases at the same time. The method has been applied for the analysis of 6 challenging proficiency testing samples from patients with IMDs (thymidine phosphorylase deficiency, mevalonic aciduria, hawkinsinuria, aromatic l-amino acid decarboxylase deficiency, propionic acidemia and medium-chain acyl-CoA dehydrogenase deficiency). Using the GC*GC-ToF-MS method, we were able to determine complete sets of markers for all the IMDs. The quality of the mass spectral matches for the pathological markers was higher than 800 (out of 1000). PMID- 20961554 TI - In vivo NIR imaging with CdTe/CdSe quantum dots entrapped in PLGA nanospheres. AB - Luminescent near-infrared (NIR) CdTe/CdSe QDs were synthesized and encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanospheres to prepare stable and biocompatible QDs-loaded nanospheres for in vivo imaging. QDs were encapsulated with PLGA nanospheres by a solid dispersion method and optimized to have high fluorescence intensity for in vivo imaging detection. The resultant QDs-loaded PLGA nanospheres were characterized by various analytical techniques such as UV Vis measurement, dynamic light scattering (DLS), fluorescence spectroscopy, and transmission electron microscopy (TEM). Finally, we evaluated toxicity and body distribution of QDs loaded in PLGA nanospheres in vitro and in vivo, respectively. From the results, the QDs loaded in PLGA nanospheres were spherical and showed a diameter range of 135.0-162.3 nm in size. The QD nanospheres increased their stability against photooxidation and photobleaching, which have the high potential for applications in biomedical imaging. We have also attained non-invasive in vivo imaging with light photons, representing an intriguing avenue for obtaining biological information by the use of NIR light. PMID- 20961555 TI - Pineocytoma in a lowland anoa (Bubalus depressicornis). AB - This report describes the first case of a pineocytoma in an 18-year-old female lowland anoa (Bubalus depressicornis). The tumour grossly appeared as a focal, non-infiltrative, yellow-tan, encapsulated mass occupying the normal anatomical location of the pineal gland. Microscopical, immunohistochemical and electron microscopical findings were consistent with a diagnosis of pineocytoma an entity not previously described in this member of the buffalo subgenus species. PMID- 20961556 TI - Acral mutilation syndrome in a miniature pinscher. AB - Acral mutilation syndrome (AMS) is a rare canine hereditary sensory neuropathy that results in progressive mutilation of the distal extremities and which has been reported only in German short-haired pointers, English pointers, English springer spaniels and French spaniels. The present report describes a case of AMS in an 18-month-old female miniature pinscher with progressive self-mutilation of the hind feet. The dog did not respond to any treatment and was humanely destroyed at the age of 30 months. Microscopical findings post mortem were restricted to the nervous system and were compatible with AMS. This is the first case of AMS described in a miniature pinscher. It is not known if the disease was the result of a point mutation in this particular dog or if the miniature pinscher breed will evolve to become a breed predisposed to AMS. PMID- 20961557 TI - Canine invasive lobular carcinoma of the mammary gland: morphological and immunohistochemical characterizations of three cases. AB - Invasive lobular carcinoma (ILC) represents 15% of invasive human breast tumours. This report describes the morphological and immunohistochemical features of three canine mammary tumours comparable with human ILC. These tumours were composed of a non-delimited proliferation of discrete cells infiltrating fibrous connective tissue. Multifocal in-situ carcinoma associated with invasive lesions was present. Invasive tumour cells and in-situ lesions expressed cytokeratin and CK34betaE12, but not E-cadherin. Based on these morphological and immunohistochemical characteristics, the tumours were classified as canine ILC. PMID- 20961558 TI - Overexpression of vimentin in canine prostatic carcinoma. AB - Canine prostatic tumours exhibit similarities to those of man and may represent a useful model system to explore the mechanisms of cancer progression. Tumour progression to malignancy requires a change from an epithelial phenotype to a fibroblastic or mesenchymal phenotype. Vimentin expression is associated with the invasive phenotype of human prostate cancer cells. The aim of the present study was to characterize immunohistochemically the expression of vimentin by canine prostatic carcinomas. Primary carcinomas and metastatic tumour foci both showed vimentin expression. This finding suggests that the acquisition of the epithelial mesenchymal transition phenotype in canine prostatic carcinoma may be characterized by the presence of mesenchymal intermediate filament (vimentin) that could lead to a higher likelihood of metastasis. PMID- 20961559 TI - Disseminated paracoccidioidomycosis in a Southern two-toed sloth (Choloepus didactylus). AB - A Southern two-toed sloth (Choloepus didactylus), originally acquired from French Guiana, died while maintained in quarantine in a pet store in Monterrey, Mexico. Large yeast cells with multiple buds compatible with Paracoccidioides brasiliensis were observed in disseminated granulomatous lesions in the lungs, liver, spleen and kidney. Transmission electron microscopical examination supported the diagnosis. This is the first report of paracoccidioidomycosis in a two-toed sloth. PMID- 20961560 TI - The role of emotion expectancies in adolescents' moral decision making. AB - This study investigated the impact of emotion expectancies on adolescents' moral decision making in hypothetical situations. The sample consisted of 160 participants from three different grade levels (mean age=15.79 years, SD=2.96). Participants were confronted with a set of scenarios that described various emotional outcomes of (im)moral actions and needed to decide what they would do if they were in the protagonist's shoes. Findings demonstrate that emotion expectancies differentially influenced adolescents' hypothetical decision making in antisocial versus prosocial behavioral contexts. Whereas negatively charged self-evaluative emotions over failing to act morally (e.g., guilt) were the strongest predictor for moral choice in antisocial behavioral contexts, positively charged self-evaluative emotions over acting morally (e.g., pride) most strongly predicted moral choice in prosocial contexts. Older adolescents paid greater attention to outcome-oriented emotions that make the decision to act morally less attractive (e.g., regret). Overall, the study suggests that emotion expectancies influence moral decision making in unique and meaningful ways. PMID- 20961561 TI - Pubertal timing predicts leg length and childhood body mass index predicts sitting height in young adult men. AB - OBJECTIVE: To investigate the impact of pubertal timing and childhood body mass index (BMI), both within normal range, on adult anthropometrics. STUDY DESIGN: Detailed growth charts were retrieved for the men participating in the population based Gothenburg Osteoporosis and Obesity Determinants study. Age at peak height velocity and childhood BMI were calculated (n = 527), and anthropometric measurements were performed. RESULTS: Analysis of variance analysis of tertiles according to age at peak height velocity demonstrated that the early peak height velocity tertile had a lower adult height (180.9 +/- 6.8 cm) compared with the middle tertile group (182.7 +/- 6.9 cm, P < .05), and this difference was attributable to shorter leg length. No difference was seen for sitting height. In contrast, analysis of tertiles according to childhood BMI demonstrated low sitting height in the low BMI tertile (93.7 +/- 3.3 cm for low, 94.6 +/- 3.3, for middle, and 94.8 +/- 3.3 cm for high childhood BMI tertiles, P < .05 and P < .01, respectively), but childhood BMI did not affect adult height and leg length. CONCLUSION: We demonstrate that subjects with early pubertal timing have reduced adult height and leg length, and subjects with low childhood BMI have reduced adult sitting height. Thus childhood body composition and pubertal timing have different impact on trunk growth and growth of long bones. PMID- 20961562 TI - Differential effects of intraventricular hemorrhage and white matter injury on preterm cerebellar growth. AB - OBJECTIVE: To hypothesize that detailed examination of early cerebellar volumes in time would distinguish differences in cerebellar growth associated with intraventricular hemorrhage (IVH) and white matter injury in preterm infants. STUDY DESIGN: Preterm newborns at the University of California San Francisco (n = 57) and the University of British Columbia (n = 115) were studied with serial magnetic resonance imaging scans near birth and again at near term-equivalent age. Interactive semi-automated tools were used to determine volumes of the cerebellar hemispheres. RESULTS: Adjusting for supratentorial brain injury, cerebellar hemorrhage, and study site, cerebellar volume increased 1.7 cm(3)/week postmenstrual age (95% CI, 1.6-1.7; P < .001). More severe supratentorial IVH was associated with slower growth of cerebellar volumes (P < .001). Volumes by 40 weeks were 1.4 cm(3) lower in premature infants with grade 1 to 2 IVH and 5.4 cm(3) lower in infants with grade 3 to 4 IVH. The same magnitude of decrease was found between ipsilateral and contralateral IVH. No association was found with severity of white matter injury (P = .3). CONCLUSIONS: Early effects of decreased cerebellar volume associated with supratentorial IVH in either hemisphere may be a result of concurrent cerebellar injury or direct effects of subarachnoid blood on cerebellar development. PMID- 20961563 TI - Dynamics and clinical evolution of bacterial gut microflora in extremely premature patients. AB - OBJECTIVE: To determine baseline clinical characteristics that influence bacterial gut flora dynamics in very preterm infants and the relationship between gut flora dynamics and clinical evolution. STUDY DESIGN: Prospective, monocentric study enrolling 29 consecutive very preterm infants. We collected data about growth, digestive tolerance, nutrition, and antibiotic use. Microflora in stool samples, collected between 3 and 56 days of life, was identified with direct molecular fingerprinting. RESULTS: Median (interquartile range) body weight and gestational age at birth were 950 g (760-1060 g) and 27 weeks (27-29 weeks), respectively. The diversity score (number of operational taxonomic units) increased 0.45 units/week (P < .0001), with staphylococci as the major group. Bifidobacterium was poorly represented. Gestational age (>= 28 weeks) and caesarean delivery independently correlated with better diversity scores during follow-up (P < .05). The 6-week diversity score inversely correlated with the duration of antibiotherapy (P = .0184) and parenteral feeding (P = .013). The microflora dynamics was associated with the digestive tolerance profile. Weight gain increased with increasing diversity score (P = .0428). CONCLUSION: Microflora diversity settled progressively in very preterm infants. Staphylococci were the major group, and few infants were colonized with Bifidobacterium spp. Measures that may improve microflora could have beneficial effects on digestive tolerance and growth. PMID- 20961564 TI - Celiac disease in children, adolescents, and young adults with autoimmune thyroid disease. AB - OBJECTIVE: To determine the prevalence of antibodies associated with celiac disease and biopsy-proven celiac disease in children with autoimmune thyroid disease. STUDY DESIGN: A total of 302 patients with positive anti-thyroid antibodies were prospectively studied. Total immunoglobulin A (IgA) and tissue transglutaminase-IgA (tTG-IgA) levels were obtained. Those with a positive tTG IgA titer were offered biopsy for definitive diagnosis of celiac disease. RESULTS: A total of 4.6% of subjects with autoimmune thyroid disease had positive tTG-IgA titers. The prevalence of biopsy-confirmed celiac disease was 2.3%. Our population was enriched with patients with type 1 diabetes mellitus (4.3%) and Down syndrome (3.4%). Excluding individuals with these co-morbidities, the prevalence of celiac disease in autoimmune thyroid disease is 1.3%, similar to that of the general population. The positive predictive value of biopsy-proven celiac disease in patients with autoimmune thyroid disease and positive tTG-IgA titer was 54%. CONCLUSION: The increase in prevalence of celiac disease in autoimmune thyroid disease in our study was largely caused by enrichment with co morbidities. Without comorbidities or symptoms, screening for celiac disease may not be justified in this population. The specificity of tTG-IgA titer for the diagnosis of celiac disease was decreased in patients with autoimmune thyroid disease compared with the general population. PMID- 20961565 TI - Neonatal and neurodevelopmental outcomes of very low birth weight infants with histologic chorioamnionitis. AB - OBJECTIVE: To determine survival and neurodevelopmental outcomes at 18 months corrected age among very low birth weight infants <= 32 weeks gestation with histologic chorioamnionitis. STUDY DESIGN: Observational, regionalized, single center cohort study with prospective follow-up. RESULTS: Of the 628 infants meeting the selection criteria, 303 (48%) were born to mothers with evidence of histologic chorioamnonitis. Neonates with histologic chorioamnonitis were of lower gestational age and birth weight. On univariate analysis, they were more likely to have hypotension, bronchopulmonary dysplasia, severe intraventricular hemorrhage, severe retinopathy of prematurity, early-onset sepsis, and death. Infants with histologic chorioamnonitis were more likely to have any neurodevelopmental impairment, specifically, mental delay with a lower mental developmental index. When adjusting for perinatal variables, histologic chorioamnonitis had a protective effect on mortality rates (adjusted OR = 0.44, 95% CI: 0.24-0.8; P = .01; n = 619), had a nonsignificant effect on neurodevelopmental impairment (adjusted odds ratio = 1.33, 95% CI: 0.82-2.17; P = .25; n = 496), and was associated with a 4-point lower mental developmental index at 18-months follow-up (adjusted difference -3.93, 95% CI: -7.52 to -0.33; P = .03; n = 496). CONCLUSIONS: Although infants with histologic chorioamnonitis were at an increased risk for death and neurodevelopmental impairment, after multivariate analyses, histologic chorioamnonitis was not associated with adverse long-term outcomes. Results suggest fetal protection from treatment-responsive maternal infection and inflammation. PMID- 20961566 TI - Effects of growth hormone and nutritional therapy in boys with constitutional growth delay: a randomized controlled trial. AB - OBJECTIVE: To examine whether supplemental nutrition augments the anabolic actions of growth hormone (GH) in boys with constitutional delay of growth and maturation (CDGM). STUDY DESIGN: We conducted a randomized, controlled trial at an outpatient clinical research center. Subjects were 20 prepubertal boys (age, 9.3 +/- 1.3 years) with CDGM (height standard deviation score, -2.0 +/- 0.5; bone age delay, 1.8 +/- 0.8 years; body mass index standard deviation score, -1.2 +/- 1.0; peak stimulated GH, 15.7 +/- 7.7 ng/mL), who were randomized (n = 10/group) to 6 months observation or daily nutritional supplementation, followed by additional daily GH therapy in all for another 12 months. t tests and repeated measures analyses of variance compared energy intake, total energy expenditure (TEE), growth, hormones, and nutrition markers. RESULTS: Energy intake was increased at 6 months within the nutrition group (P = .04), but not the observation group, and TEE was not statistically different within either group at 6 months. Addition of 6 months GH resulted in higher energy intake and TEE in the GH/nutrition group at 12 months (P < .01), but not in the GH group versus baseline. Height, weight, lean body mass, hormones, and nutrition markers increased comparably in both groups throughout 18 months. CONCLUSION: Boys with CDGM use energy at an accelerated rate, an imbalance not overcome with added nutrition. GH therapy increases growth comparably with or without added nutrition in these patients. PMID- 20961567 TI - B12 deficient megaloblastic anemia in a toddler with a history of gastroschisis. PMID- 20961568 TI - Knowledge, awareness, and attitudes regarding methicillin-resistant Staphylococcus aureus among caregivers of hospitalized children. AB - OBJECTIVES: To explore knowledge, awareness, and attitudes among caregivers of hospitalized children with regard to methicillin-resistant Staphylococcus aureus (MRSA). STUDY DESIGN: We developed and administered a bedside questionnaire to caregivers of hospitalized children in contact isolation for MRSA colonization or infection. RESULTS: Of 104 caregivers approached, 100 (96%) consented to participate. The caregivers' children included 28 (28%) newly recognized as colonized or infected with MRSA during the hospitalization and 72 (72%) previously identified as colonized or infected with MRSA. Eighteen (18%) caregivers had no knowledge of MRSA. Twenty-nine (29%) were unaware that their child had MRSA, including caregivers of 9 newly identified patients with MRSA and 20 patients with previously identified MRSA. Of the 71 caregivers aware of their child's MRSA status, 89% had concerns; 77% worried about risks of future MRSA infection, 51% worried about spreading MRSA, and 16% described a feeling of stigma. Worries were more common among caregivers of children with newly identified MRSA (P < .05). CONCLUSION: Caregivers of children hospitalized with MRSA are frequently unaware that their child has MRSA. Among those aware of their child's MRSA status, many have concerns and worries. Caregivers of children with newly identified MRSA more often are worried and may need additional education and reassurance. PMID- 20961569 TI - Editorial comment. PMID- 20961570 TI - Oral mucosa graft for repair of hypospadias: outcomes at puberty. AB - PURPOSE: Oral mucosa graft has been used in the treatment of hypospadias for the last 15 years. We assessed the long-term outcome of oral mucosa grafts for urethral substitution in hypospadias surgery at our institution. MATERIALS AND METHODS: We retrospectively reviewed patients who underwent oral mucosa graft for hypospadias between 1994 and 2002. Data collected included indications, site of oral mucosa graft, complications and long-term outcomes. Followup information was obtained from the last clinical contact. RESULTS: A total of 37 patients underwent oral mucosa graft consisting of an onlay graft (30), urethral tube (5) or 2-stage Bracka type procedure (2). Of the patients 26 had undergone at least 1 previous operation for hypospadias. Following oral mucosa graft 10 patients had an early surgical complication requiring reoperation, including fistula (7), urethral stricture (2) and tortuous urethra (1). Three of the 5 patients (60%) with tubed grafts had complications. Long-term followup was available in 30 patients, of whom 28 are now postpubertal and 2 are peripubertal. One patient required redo urethroplasty for obstructive balanitis xerotica obliterans in the grafted urethra. Five patients have varying degrees of meatal stenosis, with only 2 requiring intervention to date. CONCLUSIONS: Oral mucosa graft has a significant associated early complication rate of fistula and stricture, with 27% of cases requiring further surgery. However, the majority of oral mucosa grafts have stable urethral outcomes at puberty. PMID- 20961571 TI - Editorial comment. PMID- 20961572 TI - Tubeless mini percutaneous nephrolithotomy in infants and preschool children: a preliminary report. AB - PURPOSE: We retrospectively analyzed the outcomes of tubeless mini percutaneous nephrolithotomy in infants and preschool children, and compared them with age matched controls who underwent nephrostomy drainage. MATERIALS AND METHODS: A total of 28 renal units in 26 children were operated on for stone disease using the mini percutaneous nephrolithotomy technique. Holmium laser and pneumatic lithotriptor were used for stone fragmentation. Children who underwent complete stone removal and had a clear nephrostomy tract only had a ureteral catheter placed. Those with residual stones or bleeding from the nephrostomy tract underwent nephrostomy drainage. We compared both groups with regard to patient and stone characteristics, and postoperative findings. RESULTS: A total of 12 renal units had only a ureteral catheter for diversion, while 16 had nephrostomy drainage. Mean respective ages of the stentless and nephrostomy groups were 3 (range 0.58 to 6) and 3.3 years (1.5 to 6). Mean respective stone burdens were 192 (range 100 to 400) and 416 (775 to 1,380) mm2. Surgery and fluoroscopy times were shorter in the tubeless group. Complication rates were higher (6 of 14 vs 0 of 12) and duration of hospitalization was longer (4.9 [range 3 to 14] vs 3.1 days [2 to 6]) in the nephrostomy group. Stone-free rates were 91.6% in the tubeless and 78.5% in the nephrostomy groups. CONCLUSIONS: Tubeless percutaneous nephrolithotomy was observed to be a safe option for selected children with stone disease. The success and safety of tubeless percutaneous nephrolithotomy depends on patient selection criteria, including low volume and infection-free stones that are removed completely without any bleeding from the access tract. PMID- 20961573 TI - Editorial comment. PMID- 20961574 TI - Efficacy of desmopressin and enuresis alarm as first and second line treatment for primary monosymptomatic nocturnal enuresis: prospective randomized crossover study. AB - PURPOSE: We compared the efficacy of desmopressin and enuresis alarm as first and second line treatment options for monosymptomatic nocturnal enuresis. MATERIALS AND METHODS: A total of 104 children with monosymptomatic nocturnal enuresis were randomly assigned to either desmopressin (54) or enuresis alarm (50) as first line treatment. Following 12 weeks of first line treatment children with a full response were evaluated for relapse 12 weeks after withdrawal of treatment. Children with partial or no response were switched to the alternative treatment and then evaluated after 12 weeks of crossover treatment. Relapse was defined as more than 1 episode of bedwetting monthly. RESULTS: Following first line treatment 77.8% of the desmopressin group and 82% of the enuresis alarm group achieved a successful result, including full response in 37% and 50% of the groups, respectively (p=0.433). Of the children with a full response 50% in the desmopressin group and 12% in the enuresis alarm group experienced a relapse when treatment stopped (p=0.005). Following second line crossover treatment 71.4% of the enuresis alarm-desmopressin group and 67.8% of the desmopressin-enuresis alarm group achieved a successful result, including full response in 47.6% and 45.2% of the groups, respectively (p=0.961). CONCLUSIONS: There was no difference between desmopressin and enuresis alarm during treatment for achieving dryness, but the chance of relapse after treatment stopped was higher following desmopressin. Switching to the alternative treatment following partial or no response provided an additional benefit. PMID- 20961575 TI - Editorial comment. PMID- 20961576 TI - Editorial comment. PMID- 20961577 TI - Augmentation cystoplasty and risk of neoplasia: fact, fiction and controversy. AB - PURPOSE: We determined if ileal/colonic bladder augmentation performed in patients with congenital bladder abnormalities is an independent risk factor for bladder malignancy. MATERIALS AND METHODS: We reviewed a registry of patients with bladder dysfunction due to neurological abnormalities, exstrophy and posterior urethral valves. Individuals treated with augmentation cystoplasty were matched (1:1) to a control group treated with intermittent catheterization based on etiology of bladder dysfunction, gender and age (+/-2 years). RESULTS: We evaluated 153 patients with an ileal/colonic cystoplasty and a matched control population. There was no difference (p=0.54) in the incidence of bladder cancer in patients with augmentation cystoplasty (7 patients [4.6%]) vs controls (4 [2.6%]). In addition, there was no difference between the 2 groups regarding age at diagnosis (51 vs 49.5 years, p>0.7), stage (3.4 vs 3.8, p>0.5), mortality rate (5 of 7 [71%] vs 4 of 4 [100%], p>0.4) or median survival (18 vs 17 months, p>0.8). Irrespective of augmentation status patients with a history of renal transplant on chronic immunosuppression had a significantly higher incidence of bladder cancer (3 of 20 [15%]), compared to patients who were not immunosuppressed (8 of 286 [2.8%], p=0.03). CONCLUSIONS: In patients with congenital bladder dysfunction ileal/colonic bladder augmentation does not appear to increase the risk of bladder malignancy over the inherent cancer risk associated with the underlying congenital abnormality. In addition, immunosuppression irrespective of bladder treatment is an independent risk factor for malignancy in this patient population. PMID- 20961578 TI - Editorial comment. PMID- 20961579 TI - Editorial comment. PMID- 20961581 TI - Editorial comment. PMID- 20961580 TI - Is statistical significance sufficient? Importance of interaction and confounding in hypospadias analysis. AB - PURPOSE: We hypothesized that a stratified analysis, where measures of association between dartos flap coverage and fistula formation were adjusted by segregation into 2 strata according to stent insertion, would help better define the dartos flap-urethrocutaneous fistula association. MATERIALS AND METHODS: We retrospectively reviewed 153 consecutive boys with distal hypospadias who underwent tubularized incised plate repair by a single pediatric urologist between 2000 and 2005. Fistula rate was analyzed separately according to patient age, stenting and dartos flap coverage using univariate and multivariable analyses, and checking for effect modification/interaction. RESULTS: Mean+/-SD age at surgery was 16.5+/-12.8 months and followup was 17.0+/-11.6 months. Nonstented tubularized incised plate repair was performed in 88 patients (58%) and dartos flap coverage in 118 (77%). Urethrocutaneous fistula developed in 19 patients (12%). Nonstented repair (p=0.003) and absence of dartos flap coverage (p<0.001) were significantly associated with higher fistula rates. In children without stent a significant increase in fistula rate was observed when dartos flap coverage was not used (9% vs 37%, p=0.002; OR 0.16, 95% CI 0.05-0.51). In boys who underwent stent placement the fistula rate also increased in the absence of dartos flaps, from 2% to 25% (p=0.12; OR 0.05, 95% CI 0.002-1.0). CONCLUSIONS: Dartos flap coverage emerges as an important, clinically identifiable and modifiable risk factor associated with fistula reduction following tubularized incised plate repair for distal hypospadias after adjusting for placement of a urethral stent. Furthermore, stenting is an effect modifier in the association between dartos flap coverage and urethrocutaneous fistula. PMID- 20961582 TI - Establishment of a urological surgery quality collaborative. AB - PURPOSE: We describe the establishment of the Urological Surgery Quality Collaborative including our pilot project to improve radiographic staging for men with prostate cancer. MATERIALS AND METHODS: The Urological Surgery Quality Collaborative comprises more than 60 urologists from 3 group practices. From May through September 2009 Urological Surgery Quality Collaborative surgeons collected a uniform set of data (eg prostate specific antigen, clinical stage) for men with newly diagnosed prostate cancer. After categorizing the cancer of each patient as low, intermediate or high risk, we analyzed baseline use of staging studies across prostate cancer risk strata and Urological Surgery Quality Collaborative practice locations. RESULTS: Of 215 men with prostate cancer 34%, 42% and 24% had low, intermediate and high risk cancer, respectively. Overall 44% and 43% of patients underwent staging with a bone scan or computerized tomography, respectively, and only 9% and 7% of these studies, respectively, were positive for metastases. Use of staging studies increased across risk strata as bone scans or computerized tomography were performed in 17% and 18%, 41% and 40%, and 88% and 86% of patients, respectively, with low, intermediate and high risk tumors (p<0.01). For men with low risk prostate cancer the use of bone scans and computerized tomography differed significantly across Urological Surgery Quality Collaborative practices (p<0.01) and for this group only 1 bone scan (and no computerized tomography) was positive for metastases. CONCLUSIONS: Use of staging evaluations varies by prostate cancer risk strata and across Urological Surgery Quality Collaborative practices. By feeding these data back to surgeons we may be able to improve practice patterns and avoid unnecessary studies in low risk patients. Attainment of this goal would establish the Urological Surgery Quality Collaborative as a viable infrastructure for collaborative quality improvement in urology. PMID- 20961583 TI - Are urodynamics needed before surgery for straightforward female stress incontinence? PMID- 20961584 TI - A critical view of the environmental condition of the Sognefjord. AB - The world oceans and seas are experiencing a dramatic decline in their health and viability. In the midst of this crisis, the Norwegian fjords represent under studied and highly vulnerable ecosystems. Fjord chemistry and fjord ecosystems are poorly studied given the current focus on polar ice melting, fish stock reductions and oil disasters. For this reason, this review sheds light on and aims to accumulate local and national findings concerning the current viability of the Sognefjord, the world's second longest fjord and Norway's longest and deepest fjord, stretching 205 km (127 miles) and reaching 1308 m below sea level as its deepest point. This review shows that there is a critical need to establish knowledge and parameters to better monitor and prevent an ecosystem catastrophe from developing in Norwegian fjords. The poor circulation in fjords compared to opens seas reduces their ability to circulate waste and transport fresh water from hydroelectricity plants. Because of fjord morphology, pollutants and heavy metals are potentially trapped within them at great depths for decades. The monitoring of Norwegian fjords is thus of fundamental importance. PMID- 20961585 TI - Degradation of plastic carrier bags in the marine environment. AB - There is considerable concern about the hazards that plastic debris presents to wildlife. Use of polymers that degrade more quickly than conventional plastics presents a possible solution to this problem. Here we investigate breakdown of two oxo-biodegradable plastics, compostable plastic and standard polyethylene in the marine environment. Tensile strength of all materials decreased during exposure, but at different rates. Compostable plastic disappeared from our test rig between 16 and 24 weeks whereas approximately 98% of the other plastics remained after 40 weeks. Some plastics require UV light to degrade. Transmittance of UV through oxo-biodegradable and standard polyethylene decreased as a consequence of fouling such that these materials received ~ 90% less UV light after 40 weeks. Our data indicate that compostable plastics may degrade relatively quickly compared to oxo-biodegradable and conventional plastics. While degradable polymers offer waste management solutions, there are limitations to their effectiveness in reducing hazards associated with plastic debris. PMID- 20961586 TI - [Inflammatory biomarkers in the acute coronary syndrome]. PMID- 20961587 TI - [Cocaine use in acute coronary syndrome]. PMID- 20961588 TI - [Cannabinoid hyperemesis]. PMID- 20961589 TI - Dream changes following initiation of efavirenz treatment. AB - BACKGROUND AND OBJECTIVE: The objective was to evaluate abnormalities in the quality of dreams after the use of efavirenz. PATIENTS AND METHOD: Ten HIV patients without neuropsychiatric diseases underwent a polisomnography (PSG) study before and after efavirenz treatment, [after 10.4 (SD 5.4) days]. Patients were awoke after REM phases to record their dreams. All patients had therapeutic efavirenz plasma levels. RESULTS: Dreams were recalled in 84% before efavirenz and 43% after efavirenz (p=0.024). There were no differences in the mean number of words per dream before and after efavirenz treatment (61.9 versus 47.5, p=0.115). The proportion of dreams with no neutral emotional content (either pleasant or unpleasant) was 37.5% in the first night and 66.7% in the second night (p=0.046). CONCLUSIONS: There were a higher proportion of dreams with no neutral emotional content after efavirenz treatment in this group of patients. However, no longer dreams and no more dreams with negative emotional content were noted. Dream recall was lower after efavirenz treatment. PMID- 20961590 TI - Species comparison of enantioselective oral bioavailability and pharmacokinetics of ketoprofen. AB - As a part of ongoing research to further elucidate frequent and species-specific causes of differences in oral bioavailability, a 3mg/kg dose of racemic ketoprofen, a high permeability/low solubility compound in the human biopharmaceutics classification system, was administered intravenously and orally to different species. Due to possible enantioselective disposition kinetics and inversion, enantiomers were quantitated separately using a stereospecific HPLC assay. The absolute bioavailability of R(-) and S(+) ketoprofen in chickens, turkeys, dogs and pigs was 31.5% and 52.6%, 42.6% and 32.5%, 33.6% and 89.1%, and 85.9% and 83.5% respectively. Incomplete bioavailability in poultry is probably due to incomplete absorption in addition to first-pass elimination. Low bioavailability of R(-) ketoprofen in dogs, strongly indicates first-pass metabolism. High bioavailability of S(+) ketoprofen in dogs and both enantiomers in pigs confirms that absorption of these substances is complete and controlled by gastric emptying rather than dissolution. PMID- 20961591 TI - The effect of sCD4 on the binding and accessibility of HIV-1 gp41 MPER epitopes to human monoclonal antibodies. AB - Two human monoclonal anti-HIV-1 antibodies, 2F5 and 4E10, were utilized to investigate the accessibility and conservation of gp41 MPER epitopes on five different clades of HIV-1 in the absence and presence of sCD4. The binding of human monoclonal antibodies (mAbs) to HIV-1 was dependent upon the virus clade. Soluble CD4 significantly increased the accessibility of gp41 MPER-binding epitopes on several isolates that previously showed little or no binding with 2F5 and 4E10 mAbs as determined by a modified ELISA-based virus capture assay and surface plasmon resonance. Studies on the relationship between virus binding and neutralization in a TZM-bl pseudovirus assay indicated that in most cases, mAbs that exhibited neutralization also bound the virus. However, neither binding per se nor the total envelope content per virion was a predictor of neutralization. The hidden or conformational gp41 MPER epitopes unmasked by sCD4 may provide additional targets for vaccine design. PMID- 20961592 TI - Identification of aromatic amino acid residues in conserved region VI of the large polymerase of vesicular stomatitis virus is essential for both guanine-N-7 and ribose 2'-O methyltransferases. AB - Non-segmented negative-sense RNA viruses possess a unique mechanism for mRNA cap methylation. For vesicular stomatitis virus, conserved region VI in the large (L) polymerase protein catalyzes both guanine-N-7 (G-N-7) and ribose 2'-O (2'-O) methyltransferases, and the two methylases share a binding site for the methyl donor S-adenosyl-l-methionine. Unlike conventional mRNA cap methylation, the 2'-O methylation of VSV precedes subsequent G-N-7 methylation. In this study, we found that individual alanine substitutions in two conserved aromatic residues (Y1650 and F1691) in region VI of L protein abolished both G-N-7 and 2'-O methylation. However, replacement of one aromatic residue with another aromatic residue did not significantly affect the methyltransferase activities. Our studies provide genetic and biochemical evidence that conserved aromatic residues in region VI of L protein essential for both G-N-7 and 2'-O methylations. In combination with the structural prediction, our results suggest that these aromatic residues may participate in RNA recognition. PMID- 20961594 TI - IKKepsilon modulates RSV-induced NF-kappaB-dependent gene transcription. AB - Respiratory syncytial virus (RSV), a negative-strand RNA virus, is the most common cause of epidemic respiratory disease in infants and young children. RSV infection of airway epithelial cells induces the expression of immune/inflammatory genes through the activation of a subset of transcription factors, including Nuclear Factor-kappaB (NF-kappaB). In this study we have investigated the role of the non canonical IkappaB kinase (IKK)epsilon in modulating RSV-induced NF-kappaB activation. Our results show that inhibition of IKKepsilon activation results in significant impairment of viral-induced NF kappaB-dependent gene expression, through a reduction in NF-kappaB transcriptional activity, without changes in nuclear translocation or DNA-binding activity. Absence of IKKepsilon results in a significant decrease of RSV-induced NF-kappaB phosphorylation on serine 536, a post-translational modification important for RSV-induced NF-kappaB-dependent gene expression, known to regulate NF-kappaB transcriptional activity without affecting nuclear translocation. This study identifies a novel mechanism by which IKKepsilon regulates viral-induced cellular signaling. PMID- 20961593 TI - The identification of HLA class II-restricted T cell epitopes to vaccinia virus membrane proteins. AB - Three decades after the eradication of smallpox, the threat of bioterrorism and outbreaks of emerging diseases such as monkeypox have renewed interest in the development of safe and effective next-generation poxvirus vaccines and biodefense research. Current smallpox vaccines contain live virus and are contraindicated for a large percentage of the population. Safer, yet still effective inactivated and subunit vaccines are needed, and epitope identification is an essential step in the development of these subunit vaccines. In this study we focused on 4 vaccinia membrane proteins known to be targeted by humoral responses in vaccinees. In spite of the narrow focus of the study we identified 36T cell epitopes, and provide additional support for the physical linkage between T and B epitopes. This information may prove useful in peptide and protein-based subunit vaccine development as well as in the study of CD4 responses to poxviruses. PMID- 20961595 TI - Screening of 47 organic microcontaminants in agricultural irrigation waters and their soil loading. AB - Reclaimed water usage for crop irrigation is viewed both as an excellent sustainable water source and as a potential entrance for emerging organics into the food chain. This concern is backed by the already documented pollutant crop uptake potential. In the present study, irrigation waters used in agricultural fields (Torroella de Montgri, NE Spain) were screened for 47 analytes in a two year study (2007-2008). A total of 26 contaminants belonging to different chemical classes namely, pesticides, pharmaceuticals, personal care products, phenolic estrogens, antioxidants and disinfection by-products, were detected. Marked differences in concentration trends for the different chemical classes were evidenced from 2007 to 2008, and attributed to a persistent drought endured by the region in 2008. Also, loading mass rates of chemical classes were estimated based on crop irrigation regimes and they ranged from 0.8 to 121.3 g ha(-1) per crop cycle. These values were contrasted with those obtained for other water sources from countries where crop irrigation is commonly practiced. Finally, crops grown under these irrigation regimes, namely alfalfa and apple, were analyzed and 5 anthropogenic compounds were identified and quantitated, whose concentrations ranged from 13.9 to 532 ng g(-1) (fresh weight). PMID- 20961596 TI - Phytoremediation of an aged petroleum contaminated soil using endophyte infected and non-infected grasses. AB - Phytoremediation is a promising technique for cleaning petroleum contaminated soils. In this study, the effects of two grass species (Festuca arundinacea Schreb. and Festuca pratensis Huds.), infected (E(+)) and non-infected (E(-)) by endophytic fungi (Neotyphodium coenophialum and Neotyphodium uncinatum, respectively) on the degradation of petroleum hydrocarbons in an aged petroleum contaminated soil was investigated. Plants were grown in the soil for 7 months and unplanted soil considered as control. At the end of the experiment, total and oil-degrading bacteria, dehydrogenase activity, water-soluble phenols, total petroleum hydrocarbons (TPH) and polycyclic aromatic hydrocarbons (PAHs) contents were measured in the soil. The results demonstrated that E(+) plants contained more root and shoot biomass than E(-) plants and created higher levels of water soluble phenols and dehydrogenase activity in the soil, while there was no significant difference in bacterial counts of planted soils. Planting stimulated total and oil-degrading bacterial numbers, dehydrogenase activity and the soil content of water-soluble phenols. Regardless of endophyte infection, PAH and TPH removal in the rhizosphere of plants were 80-84 and 64-72% respectively, whereas the removals in controls were 56 and 31%, respectively. It was revealed that TPHs in retention time range of n-alkanes with C(10)-C(25) chain lengths and TPH were more degraded in the rhizosphere of E(+) plants compared to E(-) ones. Thus, grasses infected with endophytic fungi could be more efficient for removal of TPH from oil-contaminated soils. PMID- 20961597 TI - A non-linear analysis to detect the origin of PM10 concentrations in Northern Italy. AB - This work presents the formalization and the application of the factor separation technique in order to investigate the impact of precursor emission and their nonlinear interaction (in particulate matter accumulation processes). By processing the simulations of a 3D multiphase modeling system, the factor separation methodology can support the Environmental Authority in quantifying the impact of precursor emissions on PM10 production and consequently in assessing the feasible efficiency of different emission control strategies over a considered domain. The case study proposed by this paper focuses on the Po Valley region (Northern Italy), characterized by critical PM10 levels claiming for sound emission reduction policies. The results show the heavy nonlinearities and the strong seasonal dependence in the formation of PM10, over the study domain. Furthermore the results highlight that peak PM10 concentrations are mainly related to primary PM emissions in urban areas, and gas emissions (mainly NOx and NH3) in rural areas. PMID- 20961598 TI - Environment and immune-mediated diseases in Sub-Saharan Africa. PMID- 20961599 TI - The effects of phytophagous insects on water and soil nutrient concentrations and fluxes through forest stands of the Level II monitoring network in the UK. AB - The effects of insect defoliators on throughfall and soil nutrient fluxes were studied in coniferous and deciduous stands at five UK intensive monitoring plots (1998 to 2008). Links were found between the dissolved organic carbon (DOC), nitrogen (N) and potassium (K) fluxes through the forest system to biological activity within the canopy. Underlying soil type determined the leaching or accumulation of these elements. Under oak, monitored at two sites, frass from caterpillars of Tortrix viridana and Operophtera brumata added direct deposition of ~16kgha(-1)extra N during defoliation. Peaks of nitrate (NO(3)-N) flux between 5 and 9kgha(-1) (*5 usual winter values) were recorded in consecutive years in shallow soil waters. Synchronous rises in deep soil NO(3)-N fluxes at the Grizedale sandy site indicate downward flushing, not seen at the clay site. Under three Sitka spruce stands, generation of honeydew (DOC) was attributed to two aphid species (Elatobium abietinum and Cinara pilicornis) with distinctive feeding strategies. Throughfall DOC showed mean annual fluxes (6 seasons) ~45 60kgha(-1) compared with rainfall values of 14-22kgha(-1). Increases of total N in throughfall and NO(3)-N fluxes in shallow soil solution were detected - soil water fluxes reached 8kgha(-1) in Llyn Brianne, ~25kgha(-1) in Tummel, and ~40kg NO(3)-Nha(-1) in Coalburn. At Tummel, on sandy soil, NO(3)-N leaching showed increased concentration at depth, attributed to microbiological activity within the soil. By contrast, at Coalburn and Llyn Brianne, sites on peaty gleys, soil water NO(3)-N was retained mostly within the humus layer. Soil type is thus key to predicting N movement and retention patterns. These long term analyses show important direct and indirect effects of phytophagous insects in forest ecosystems, on above and below ground processes affecting tree growth, soil condition, vegetation and water quality. PMID- 20961600 TI - Using rainfall radar data to improve interpolated maps of dose rate in the Netherlands. AB - The radiation monitoring network in the Netherlands is designed to detect and track increased radiation levels, dose rate more specifically, in 10-minute intervals. The network consists of 153 monitoring stations. Washout of radon progeny by rainfall is the most important cause of natural variations in dose rate. The increase in dose rate at a given time is a function of the amount of progeny decaying, which in turn is a balance between deposition of progeny by rainfall and radioactive decay. The increase in progeny is closely related to average rainfall intensity over the last 2.5h. We included decay of progeny by using weighted averaged rainfall intensity, where the weight decreases back in time. The decrease in weight is related to the half-life of radon progeny. In this paper we show for a rainstorm on the 20th of July 2007 that weighted averaged rainfall intensity estimated from rainfall radar images, collected every 5min, performs much better as a predictor of increases in dose rate than using the non-averaged rainfall intensity. In addition, we show through cross validation that including weighted averaged rainfall intensity in an interpolated map using universal kriging (UK) does not necessarily lead to a more accurate map. This might be attributed to the high density of monitoring stations in comparison to the spatial extent of a typical rain event. Reducing the network density improved the accuracy of the map when universal kriging was used instead of ordinary kriging (no trend). Consequently, in a less dense network the positive influence of including a trend is likely to increase. Furthermore, we suspect that UK better reproduces the sharp boundaries present in rainfall maps, but that the lack of short-distance monitoring station pairs prevents cross validation from revealing this effect. PMID- 20961601 TI - A selective serotonin reuptake inhibitor, citalopram, inhibits collagen-induced platelet aggregation and activation. AB - Clinical depression is a significant risk factor for cardiovascular diseases and confers an increased risk of mortality. Increased platelet reactivity may predispose depressed patients to cardiovascular diseases. The antidepressants selective serotonin reuptake inhibitors (SSRIs) have been found to have cardioprotective effects probably via the attenuation of platelet activation independently in addition to treatment of depression itself. However, the characters of the inhibitory effect of SSRIs on platelets remain largely unknown. Here we show that an SSRI, citalopram, specifically inhibited collagen-induced platelet aggregation. Citalopram, however, revealed only little inhibitory effect on platelet aggregation induced by thrombin, U46619, and ionomycin, and failed to inhibit reversible platelet aggregation induced by adenosine diphosphate with fibrinogen. Collagen-induced of alphaIIbbeta3 integrin activation in platelets under a static condition was not influenced by citalopram. Citalopram inhibited convulxin-induced platelet aggregation and alphaIIbbeta3 integrin activation. In the experiments with fibrinogen-induced aggregation in elastase-treated platelets, citalopram inhibited only collagen-induced alphaIIbbeta3 activation but not the binding activities between activated alphaIIbbeta3 integrin and fibrinogen. Moreover, citalopram inhibited alpha-granule and dense granule secretion from platelets in response to collagen, as determined by a reduced expression of P-selectin and adenosine triphosphate release, respectively. In addition, collagen-induced thromboxane A2 release in platelets was attenuated by citalopram pretreatment. These findings might specify the mechanisms of inhibitory effects of citalopram on collagen mediated platelet activation and aggregation, and further support the cardioprotective effect of SSRIs. PMID- 20961602 TI - Thrombophilic dimension of Budd chiari syndrome and portal venous thrombosis--a concise review. AB - Budd chiari syndrome (BCS) is characterized by venous outflow obstruction either at hepatic veins or inferior vena cava, while portal vein thrombosis (PVT) is the consequence of thrombotic occlusion in the extrahepatic venous system. The aetiology of both these disorders is complicated wherein genetic, acquired and local factors interact in the pathogenesis. Among the inherited thrombophilia, factor V Leiden mutation has shown stronger association with BCS than PVT while the converse is true for prothrombin G20210A mutation. Very few studies are available on the role of fibrinolytic potential or the single nucleotide polymorphisms (SNPs) of fibrinolysis proteins, in both BCS and PVT. Among the acquired thrombophilia, myeloproliferative disorders (MPD) are the most frequent cause, while antiphospholipid antibodies (APA) and hyperhomocysteinemia have not shown very strong association with BCS and PVT. Oral contraceptives, infection, chronic inflammatory diseases like Behcets syndrome, inflammatory bowel disease, tumors, paroxysmal nocturnal hemoglobinuria (PNH), pregnancy, puerperium, poor nutrition are some of the other acquired and local risk factors associated with both these disorders. There exists a clear geographical variation both in the clinical manifestation and the underlying aetiology. Almost all the studies have proved that a multifactorial aetiology is the requisite for the manifestation. Evaluation of an extensive thrombophilia profile is essential for optimal management of patients which is further justified with the availability of specific treatment options for at least some thrombophilia markers. PMID- 20961603 TI - Kinetics of gene expression and signaling in bovine cumulus cells throughout IVM in different mediums in relation to oocyte developmental competence, cumulus apoptosis and progesterone secretion. AB - In vitro maturation of oocytes is a crucial step in assisted reproductive technologies in cattle; however, the molecular mechanisms of cumulus contribution to oocyte developmental potential require more investigation. Based on transcriptomic data, we studied by using real-time RT-PCR and western blot in bovine cumulus cells, the kinetics of expression of several candidate genes involved in oxidative stress response, apoptosis, steroid metabolism and signal transmission throughout IVM. Phosphorylations of the components of the main signaling pathways were also analyzed. In addition, IVM was performed in different maturation mediums which influenced the cumulus apoptosis, progesterone secretion and oocyte developmental competence. Glutathione-S-transferase A1 (GSTA1) transcript and protein abundance significantly decreased throughout IVM progression. Similarly, transcript levels of FSH receptor and aromatase (CYP19A1) and protein levels of three steroidogenic enzymes (steroidogenic acute regulatory protein, cytochrome P450scc and 3-beta-hydroxysteroid dehydrogenase) decreased along with progression of maturation and especially since 10 hours of IVM. Expression of progesterone receptor (PGR) and clusterin (CLU) mRNA and phosphorylations of protein kinases AKT, MAPK P38 and SMAD2 were particularly increased at 10 hours of IVM. This expression pattern supposed the role of these factors during oocyte metaphase-I check point of meiosis. Levels of CLU, GSTA1 and FSHR transcripts were higher in 199 basic hormone-free medium as compared to the medium 199EM, enriched in gonadotropins and growth factors, in which we recorded the higher developmental rate and progesterone secretion. Higher phosphorylation levels of SMAD2, AKT and MAP kinase JNK1, but not of MAP kinases ERK1/ERK2 or P38, was positively correlated with oocyte developmental competence and progesterone secretion and negatively correlated with cumulus apoptosis rate. These factors and signaling pathways in cumulus cells are potentially involved in controlling different stages of oocyte nuclear maturation and acquirement of its developmental potential. PMID- 20961604 TI - Isolation of methicillin-resistant Staphylococcus pseudintermedius from breeding dogs. AB - The overuse of antimicrobials can select resistant bacteria strains; staphylococci have the ability to become resistant to all beta-lactam antimicrobials and are a significant concern in human medicine and a growing issue for veterinary medicine. Because antimicrobials are sometimes incorrectly used in breeding kennels, the objective of the work was to assess the occurrence of methicillin-resistant coagulase-positive staphylococci in breeding dogs. The research was carried out in 13 kennels that were allotted to three categories according to the intensity of antimicrobial use. Vaginal and milk swabs were taken from 87 healthy bitches around parturition and also from multiple organs of 27 of their pups that died within the first 2 weeks. Standard bacteriological examinations were carried out and coagulase-positive staphylococci were identified. All the coagulase-positive staphylococci resulted to be Staphylococcus pseudintermedius. Susceptibility to oxacillin and the presence of the mecA gene were tested. Nine out of 89 strains (six isolated from the bitches' milk and three from dead puppies, all belonging to kennels characterized by an excessive use of antimicrobials) were multidrug-resistant, methicillin-resistant and mecA positive. Our results confirm that excessive use of antimicrobials entails the risk of selecting resistant staphylococci strains. Our data also indicate that the bacterial flora of healthy dogs belonging to specific populations may act as a reservoir of resistance genes. PMID- 20961606 TI - The transition between preluteolysis and luteolysis in cattle. AB - Novel characterization of the transition between preluteolysis and luteolysis was done in seven heifers. Blood samples were collected hourly and assayed for progesterone (P4), 13-14-dihydro-15-keto-PGF2alpha (PGFM), and estradiol (E2). The peaks of P4 oscillations were used to designate the transitional hour in each heifer. The interval from the peak of the last PGFM pulse of preluteolysis to the peak of the first pulse during luteolysis (transitional period) was longer (P < 0.0001) than the interval between the first and second pulses during luteolysis (13.4 +/- 1.3 h vs. 7.0 +/- 0.9 h). The long intervals from the last PGFM pulse of preluteolysis to the transitional hour (4.0 +/- 0.9 h) and from the transitional hour to the first PGFM pulse of luteolysis (9.4 +/- 1.3 h) resulted in the illusion that the beginning of luteolysis was not associated temporally with a PGFM pulse. The E2 and PGFM concentrations were less (P < 0.05) during the last PGFM pulse of preluteolysis than during the first pulse of luteolysis. Concentration of P4 was suppressed at the peak of the last PGFM pulse of preluteolysis and consistently rebounded at the transitional hour to the concentrations before the PGFM pulse. In four of seven heifers, one or two P4 rebounds occurred between the peak of the PGFM pulse and the rebound at the transitional hour. Results indicated that the prolonged transitional period may be related, at least in part, to increasing concentration of E2, intervening P4 rebounds between the peak of the last PGFM pulse of preluteolysis and the transitional hour, and the complete P4 rebound at the transitional hour. PMID- 20961605 TI - Efficiency of osmotic and chemical treatments to improve the permeation of the cryoprotectant dimethyl sulfoxide to Japanese whiting (Sillago japonica) embryos. AB - Insufficient cryoprotectant permeation is one of the major obstacles for successful fish embryo cryopreservation. The purpose of this study was to test the effectiveness of osmotic and chemical treatments to enhance cryoprotectant uptake by fish embryos. Japanese whiting Sillago japonica embryos at the somites and tail elongation stages were treated with hyperosmotic sugar solutions (1 M trehalose and sucrose) for 2-6 min, or a permeating agent (2-6 mg/mL pronase) for 30-120 min, and then impregnated with 10-15% DMSO in artificial sea water or aqueous solutions containing inorganic salts (0.125-0.25 M MgCl(2) and CaCl(2)). The viability of the embryos after the treatments was estimated from hatching rates and the internal DMSO concentration was measured by HPLC. Treatment with trehalose for 3 min prior to impregnation with DMSO enhanced the uptake of the cryoprotectant by 45% without significantly affecting embryo viability, whereas pronase had no noticeable effect on cryoprotectant permeation. Incorporation of DMSO into the embryos was enhanced by 143-170% in the presence of 0.25 M MgCl(2) and 0.125 M CaCl(2) compared to sea water. A combination of treatments with trehalose and MgCl(2) was even more effective in promoting DMSO permeation (191% compared to untreated embryos). Tail elongation embryos were less tolerant of the treatments, but had higher DMSO impregnation. In conclusion, the use of trehalose (as dehydrating agent) and MgCl(2)/CaCl(2) (as a vehicle during impregnation) greatly promoted cryoprotectant uptake and may be a promising aid for the successful cryopreservation of fish embryos. PMID- 20961607 TI - Assessment of pubertal development of boars derived from ultrasonographic determination of testicular diameter. AB - At the onset of puberty, seminiferous tubules rapidly increase in diameter, thereby occupying a greater proportion of the testis, resulting in a rapid increase in testicular size. The objective of the current studies was to evaluate ultrasonography for assessing testicular diameter, as a basis for ranking boars relative to their extent of pubertal development. In the initial study, prior to castration at 4, 5, 6, or 7 mo of age, testicular length and diameter were assessed by ultrasonography in 160 anesthetized boars. After castration, testes were weighed. Mean diameter of seminiferous tubules and percentage of the testis occupied by tubules were determined by histological evaluations of all testes. Testicular volume was calculated from length and diameter and was correlated with testicular weight (P < 0.001; r ? 0.78) within each of the four age groups. At 4 and 5 mo of age, testicular diameter correlated positively (P < 0.001) with diameter of seminiferous tubules; this relationship was not significant at older ages. In two subsequent studies, testicular diameter determined ultrasonographically in conscious boars was highly correlated (r > 0.8) when assessed twice on the same day, or when diameter of the right was compared with diameter of the left testis. Similarly, testicular diameter obtained initially at 92 d of age correlated positively (P < 0.001) with the diameter observed at older ages, but the magnitude of the relationship decreased as time between evaluations increased. These findings supported ultrasonographic determination of testicular diameter during early pubertal development, as a means to rank boars of similar chronological age for extent of pubertal development. PMID- 20961608 TI - Fetal calf serum enhances in vitro production of Bos taurus indicus embryos. AB - The objective of this study was to determine the effect of fetal calf serum (FCS) on the quality of in vitro produced bovine embryos. Cumulus oocyte-complexes (COCs, n = 2 449) recovered by ovum pick-up from Bos taurus indicus donors were randomly assigned to experimental groups. Sperm selected by Percoll gradient was used for in vitro fertilization (insemination = Day 0). In Experiment 1 (n = 1 745 COCs), zygotes were cultured in vitro in Synthetic Oviduct Fluid + 4 mg/mL of bovine serum albumin (BSA), or BSA + 2% FCS (BSA+FCS). In Experiment 2 (n = 704 COCs), the COCs were cultured in SOF + BSA, BSA + 2% FCS, or BSA + 2% FCS on D4 (BSA + FCSD4). In Experiment 1, blastocyst yield (51%) and Quality I blastocysts (41%) at Day 7 were higher (P < 0.05) in the BSA + FCS treatment than in BSA (42 and 30%, respectively). In Experiment 2, blastocyst yield was higher (P < 0.05) in the BSA+FCS (47%) treatment. Quality I blastocyst yield was higher (P < 0.05) for BSA + FCS (34%) and BSA+FCSD4 (32%) compared to the BSA treatment (20%). A total of 820 embryos were transferred, with no significant differences among groups in pregnancy rates. In conclusion, in vitro culture in SOFaaci + BSA + FCS enhanced blastocyst yield and Quality I blastocysts; adding FCS to the culture medium increased the efficiency of IVP of bovine embryos. PMID- 20961609 TI - Sperm chromatin structural integrity in normospermic boars is not related to semen storage and fertility after routine AI. AB - Standard semen parameters are limited in their capacity to distinguish subfertile boars and to assess storage influences on liquid preserved boar semen. The evaluation of sperm chromatin structural integrity could have potential as a diagnostic tool in AI practice. This study assessed whether the determination of sperm DNA integrity adds a useful diagnostic tool for selection of boar ejaculates in routine AI procedure and assessment of storage effects in diluted semen. Special emphasis was laid on the standard spermatological characterization of semen samples in parallel with the determination of the DNA fragmentation index (DFI) through the sperm chromatin structure assay (SCSA). Six hundred ninety two (692) ejaculates from 79 Pietrain boars in an AI center were analyzed for motility, morphology and DFI over a period of 24 weeks. 95.5% of the semen samples had a DFI < 5% with low distribution of variation for DFI due to boar and ejaculate (< 5%). 61.3% of ejaculates with DFI > 5% showed values below thresholds for sperm motility or morphology. Based on field data from 13,239 inseminations, fertility of boars with temporarily elevated DFI was not impaired (P > 0.05). 24 randomly selected diluted semen samples did not show a significant increase of DFI during 168 h storage (P > 0.05). In a further experiment, 42 diluted semen samples from 14 normospermic boars were assessed for motility, membrane integrity (PI, FITC-PNA) and SCSA parameters. Three single ejaculates showed an increase of DFI at 120 and 168 h storage time. This was accompanied by a pronounced loss of both motility and membrane integrity. In conclusion, the evaluation of sperm chromatin structural integrity by the SCSA has only limited value for identifying sperm deficiencies in normospermic fresh or stored boar semen. Temporarily elevated DFIs seem not to be indicative of subfertility in normospermic boars. PMID- 20961610 TI - Effects of vascular endothelial growth factor on porcine preimplantation embryos produced by in vitro fertilization and somatic cell nuclear transfer. AB - This study examined the effects of vascular endothelial growth factor (VEGF) on porcine embryos produced by in vitro fertilization (IVF) and somatic cell nuclear transfer (SCNT) at different developmental stages. Four sets of experiments were performed. In the first, supplementation of the in vitro culture medium with 5 ng/mL VEGF was suitable for porcine IVF embryo development, and the blastocyst formation rate was significantly higher than the control and other groups (57.73 +/- 6.78% (5 ng/mL VEGF) vs. 43.21 +/- 10.22% (control), 42.16 +/- 10.24% (50 ng/mL VEGF) and 41.91 +/- 11.74% (500 ng/mL VEGF); P < 0.05). The total cell number after supplementation with 5 ng/mL VEGF was significantly higher than the control and other groups (151.85 +/- 39.77 (5 ng/mL VEGF) vs. 100.00 +/- 34.43 (control), 91.2 +/- 31.51 (50 ng/mL VEGF), and 112.53 +/- 47.66 (500 ng/mL VEGF); P < 0.05). In the second experiment, when VEGF was added at different developmental stages of IVF derived embryos (early stage, days 1-3, late stage, days 4-7), the blastocyst formation rate and total cell number were significantly higher at the late stage (47.71 +/- 9.13% and 131.5 +/- 20.70, respectively) than in the control (34.32 +/- 7.44% and 85.50 +/- 20.41, respectively) and at the early stage (33.60 +/- 5.78% and 86.75 +/- 25.10, respectively; P < 0.05). There was no significant difference in the blastocyst development rate or total cell number between the whole culture period (days 1-7) and the late stage culture period after supplementation with 5 ng/mL VEGF (P > 0.05). In the third experiment, the cleavage rate was significantly higher when SCNT embryos were cultured with VEGF during the whole culture period than in the late stage (63.56 +/- 15.52% vs. 39.72 +/- 4.94%; P < 0.05), but there was no significant difference between the control and the early stage culture period (P > 0.05). The blastocyst formation rate was significantly higher at the late stage culture period with VEGF than at the early stage culture period (34.40 +/- 15.06% vs. (16.07 +/- 5.01%; P < 0.05). There was no significant difference in the total cell number between the groups (P > 0.05). In experiment 4, using real-time PCR, VEGF mRNA expression was detected in all the developmental stages of IVF and SCNT embryos, but the expression level varied according to the developmental stage. VEGF receptor, KDR mRNA was detected in all stages IVF and SCNT embryos. However, flt-1 mRNA was not expressed in all embryonic stages of IVF and SCNT embryos. These data suggest that VEGF supplementation at the late embryonic developmental stage might improve the developmental potential of both IVF and SCNT preimplantation porcine embryos through its receptors. PMID- 20961611 TI - Sub-centimeter language organization in the human temporal lobe. AB - The human temporal lobe is well known to be critical for language comprehension. Previous physiological research has focused mainly on non-invasive neuroimaging and electrophysiological techniques with each approach requiring averaging across many trials and subjects. The results of these studies have implicated extended anatomical regions in peri-sylvian cortex in speech perception. These non invasive studies typically report a spatially homogenous functional pattern of activity across several centimeters of cortex. We examined the spatiotemporal dynamics of word processing using electrophysiological signals acquired from high density electrode arrays (4mm spacing) placed directly on the human temporal lobe. Electrocorticographic (ECoG) activity revealed a rich mosaic of language activity, which was functionally distinct at four mm separation. Cortical sites responding specifically to word and not phoneme stimuli were surrounded by sites that responded to both words and phonemes. Other sub-regions of the temporal lobe responded robustly to self-produced speech and minimally to external stimuli while surrounding sites at 4mm distance exhibited an inverse pattern of activation. These data provide evidence for temporal lobe specificity to words as well as self-produced speech. Furthermore, the results provide evidence that cortical processing in the temporal lobe is not spatially homogenous over centimeters of cortex. Rather, language processing is supported by independent and spatially distinct functional sub-regions of cortex at a resolution of at least 4mm. PMID- 20961613 TI - Identity, prosocial behavior, and generative concern in German and Cameroonian Nso adolescents. AB - Little is known about whether ego identity statuses have the same developmental concomitants in different cultural contexts. Thus, 159 German and 158 Cameroonian Nso adolescents aged 15-18 were recruited to test if associations between identity and generativity (i.e. the desire to create a positive legacy) and prosocial behavior (i.e. helpful and supportive behavior), respectively, are comparable. In both cultural samples, only identity achievement was positively linked with generative concern and prosocial tendencies. Integrating these and previous findings on the association between prosocial behavior and generativity, a partial mediation of the relation between identity achievement and generative concern through prosocial tendencies was hypothesized and confirmed for both cultural groups. Thus, there is an equivalent association between identity achievement, prosocial behavior, and generative concern in adolescents with widely different cultural background. PMID- 20961612 TI - Support for anterior temporal involvement in semantic error production in aphasia: new evidence from VLSM. AB - Semantic errors in aphasia (e.g., naming a horse as "dog") frequently arise from faulty mapping of concepts onto lexical items. A recent study by our group used voxel-based lesion-symptom mapping (VLSM) methods with 64 patients with chronic aphasia to identify voxels that carry an association with semantic errors. The strongest associations were found in the left anterior temporal lobe (L-ATL), in the mid- to anterior MTG region. The absence of findings in Wernicke's area was surprising, as were indications that ATL voxels made an essential contribution to the post-semantic stage of lexical access. In this follow-up study, we sought to validate these results by re-defining semantic errors in a manner that was less theory dependent and more consistent with prior lesion studies. As this change also increased the robustness of the dependent variable, it made it possible to perform additional statistical analyses that further refined the interpretation. The results strengthen the evidence for a causal relationship between ATL damage and lexically-based semantic errors in naming and lend confidence to the conclusion that chronic lesions in Wernicke's area are not causally implicated in semantic error production. PMID- 20961614 TI - Membership exams overseas in light of new global code of practice. PMID- 20961615 TI - Is imatinib-related cardiotoxicity still an open issue? PMID- 20961616 TI - In vitro cellular drug resistance adds prognostic information to other known risk factors in childhood acute lymphoblastic leukemia. AB - Leukemic cells from 230 children with newly diagnosed B-cell precursor ALL were tested for in vitro drug resistance to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. During follow-up, 24 relapses occurred in the 159 children with MRD <0.1% day 29. The risk of any relapse was correlated to vincristine and doxorubicin resistance, with a relative risk of 3.7 (95% CI 1.3-10.5; p=0.016) for patients resistant to both drugs. There was a significant correlation also for the subgroup with extra-medullary relapses. Our findings indicate that analysis of drug resistance can add prognostic information to other known risk-factors including MRD. PMID- 20961617 TI - Bioaccumulation of trace metals in farmed fish from South China and potential risk assessment. AB - Concentrations of trace metals were determined in water, sediment, fish feed and two species of farmed fish, pompano and snapper, collected from Daya Bay and Hailing Bay of South China in July 2007 and January 2008. Total average concentrations of Cu, Pb, Zn, Cd, Cr, Hg and As were 1.6, 2.7, 27.3, 0.025, 0.62, 0.18 and 0.59 MUg/g dry wt in pompano and 1.5, 2.6, 23.6, 0.020, 0.55, 0.22 and 0.53 MUg/g dry wt in snapper. In general, the concentrations of all target metals except Hg were positively correlated with lipid contents whereas negative correlations were observed between the metal concentrations and fish body weights. Model calculation indicated that dietary uptake of Zn and Cd predominate their accumulation in snapper, accounting for 99.9% and 98.2% of the total inputs. Risk assessments suggested that potential ecological and human health risk may be present due to elevated Pb concentrations in sediment and farmed fish. PMID- 20961618 TI - Enhanced MR angiography for depiction of spinal dural arteriovenous fistula in the craniocervical junction. PMID- 20961619 TI - The amino acid residue at position 95 and the third CDR region in the H chain determine the ceiling affinity and the maturation pathway of an anti-(4-hydroxy-3 nitrophenyl)acetyl antibody. AB - Two groups of anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) Abs each possessing a different amino acid, Tyr or Gly, at position 95, appeared respectively at early and late stages of immunization. The early Abs predominantly harbored Tyr95 and were referred to as the Tyr95 type. These had ~100-fold lower ceiling affinity than the late Abs harboring Gly95, which were referred to as the Gly95 type. We found that in order to raise affinity, the Tyr95 type utilized a mutation at position 33 in V(H), while the Gly95 type used multiple mutations in both V(H) and V(L), and that the effect of the mutations was reciprocal; the former mutation had a positive effect on Tyr95 type Abs but a negative effect on Gly95 type Abs, and vice versa. The reciprocal effect of these mutations on affinity enabled us to assess the type of Abs prepared by introducing 20 different amino acids at position 95. We found that Abs harboring Lys95, Arg95, Pro95, and Tyr95 belonged to the Tyr95 type and those with Ala95 and Gly95, to the Gly95 type. Since this dependency on the amino acid at position 95 was observed in H chains whose third CDR (CDR 3H) consisted of 9 amino acids and not 11, the CDR 3H region was also considered to play an important role in determining the maturation pathway and the magnitude of the ceiling affinity. PMID- 20961620 TI - Predictors of response to ultrabrief right unilateral electroconvulsive therapy. AB - BACKGROUND: Recent trials have demonstrated clinically meaningful efficacy and minimal cognitive side effects with ultrabrief pulsewidth right unilateral (RUL) ECT. In many countries it is gradually being adopted into clinical practice and further information on predictors of response is needed. METHODS: Data collected from 75 depressed patients who received ultrabrief RUL ECT in a prospective research trial were analysed for predictors of response. Mood improvement was assessed with the Montgomery-Asberg Depression Rating Scale. Improvement in unipolar versus bipolar depression was analysed. RESULTS: Sixty-one percent of patients met the criteria for response and 36% met the criteria for remission. Logistic regression identified index episode duration >=one year (OR=10.50, p=.006), fewer failed antidepressant treatments (OR=0.46, p=.003), previous ECT course (OR=7.33, p=.01), and absence of concurrent antidepressant (OR=0.09, p=.005) as predictors of response. Psychotic features (OR=7.18, p=.032) and baseline depression severity (OR=0.90, p=.017) were predictors of remission. There was a trend towards greater improvement in bipolar than unipolar depression in the first week of treatment (p=0.077). LIMITATIONS: Data were obtained from a prospective but non-randomised clinical trial which was designed to evaluate efficacy rather than to examine predictors of response. Treatment decisions (concurrent medication, switching to other types of ECT) were made on clinical grounds. CONCLUSIONS: This preliminary study suggests that predictors of response for ultrabrief RUL ECT are similar to those identified for other types of ECT previously studied. PMID- 20961621 TI - Within-woman change in regulatory T cells from pregnancy to the postpartum period. AB - Regulatory T cells (Treg cells) are an important area of investigation in human health and disease. In this study, the trajectory of percentage of Treg cells (defined as CD4+CD25+Foxp3+CD127--lymphocytes) was measured in the blood of 208 women during pregnancy and up to three additional times in the postpartum period (1, 6 and 12 months postpartum). Whether the trajectory was affected by gravidity, parity, neonatal sex, pet exposure, maternal atopic and asthma status, smoking, maternal race or other pregnancy factors was examined. Multilevel models were fit using full maximum likelihood methods and included both random and fixed effects. Overall, percentages of Treg cells increased from the prenatal to the postpartum period. Among women who were not atopic, nulliparous women had lower percentages of Treg cells over time compared with parous women. Atopic women with pets in the home during pregnancy had lower percentages of Treg cells than atopic women who did not have pets. The trajectory was not affected by the other factors investigated. We conclude that within-woman change in percentages of Treg cells may vary by time in relation to delivery, as well as by maternal atopic status and exposure to pets and number of prior births. The data did not indicate an overall decline in Treg cells in the postpartum period. Future work to better identify the role of Treg cells in successful pregnancy would ideally include a set of well characterized women sampled serially starting prior to pregnancy and throughout the postpartum period. PMID- 20961622 TI - Unraveling the role of perfectionism in chronic fatigue syndrome: is there a distinction between adaptive and maladaptive perfectionism? AB - In the current study, we investigated whether the distinction between adaptive (i.e. high personal standards) and maladaptive (i.e. concern over mistakes and doubt about actions) perfectionism that has been found in the literature, is also valid in patients with chronic fatigue syndrome (CFS). We hypothesized that maladaptive, but not adaptive, perfectionism would be significantly and positively related to severity of fatigue and depression in CFS. We examined this hypothesis in a sample of 192 CFS patients using structural equation modelling (SEM). Although the two perfectionism dimensions were related to each other, results supported a model in which only maladaptive perfectionism was positively related to severity of fatigue and depression. Further, we found that depression fully mediated the effect of maladaptive perfectionism on fatigue. The results suggest that adaptive and maladaptive perfectionism are two distinct, albeit related, dimensions in CFS. Findings of this study have important implications for theory and treatment of CFS, particularly for cognitive-behavioral treatment. PMID- 20961623 TI - Plasma cells in the central nervous system in the Theiler's virus model of multiple sclerosis. AB - BACKGROUND: Immunoglobulin production within the central nervous system (CNS) is a prominent feature of multiple sclerosis and its animal model induced by infection with Theiler's meningoencephalitis virus, as well as of other inflammatory and infectious neurological diseases. However, relatively little is known about the plasma cells (PCs) responsible for producing Ig within the CNS. METHODOLOGY: We induced Theiler's-induced demyelinating disease, characterized by disability, inflammation, and demyelination. We used immunofluorescence to localize and characterize IgG-producing cells, and correlated the morphology with results from CSF and tissue analysis. RESULTS: Confidence that IgG production occurred within the CNS was gained by demonstrating high levels of IgG in the cerebrospinal fluid in the absence of blood-CSF barrier or blood-brain barrier breakdown. CNS IgG-producing cells were CD138+, like IgG-producing cells elsewhere in the body. Less than 5% of IgG-positive cells were Ki67-positive, indicating that most were nonproliferative PCs. The PCs were present primarily in perivascular infiltrates and in the meninges. Isolated PCs could be found in the CNS parenchyma, and, when present, were largely in demyelinated regions of the cord. SIGNIFICANCE: These results demonstrate that PCs are a significant part of this chronic progressive disabling demyelinating disease, and suggest the possibility that these cells play a role in CNS injury by their secretion of immunoglobulin. PMID- 20961624 TI - Controversial role of MMP-9 gene in MS disease. PMID- 20961625 TI - GPCR ligand-dendrimer (GLiDe) conjugates: future smart drugs? AB - Unlike nanocarriers that are intended to release their drug cargo at the site of action, biocompatibile polyamidoamine (PAMAM) conjugates are designed to act at cell surface G protein-coupled receptors (GPCRs) without drug release. These multivalent GPCR ligand-dendrimer (GLiDe) conjugates display qualitatively different pharmacological properties in comparison with monomeric drugs. They might be useful as novel tools to study GPCR homodimers and heterodimers as well as higher aggregates. The structure of the conjugate determines the profile of biological activity, receptor selectivity, and physical properties such as water solubility. Prosthetic groups for characterization and imaging of receptors can be introduced without loss of affinity. The feasibility of targeting multiple adenosine and P2Y receptors for synergistic effects has been shown. Testing in vivo will be needed to explore the effects on pharmacokinetics and tissue targeting. PMID- 20961626 TI - alpha-Synuclein and dopamine at the crossroads of Parkinson's disease. AB - alpha-Synuclein is central to the Lewy body neuropathology of Parkinson's disease (PD), a devastating neurodegenerative disorder characterized by numerous motor and non-motor manifestations. The cardinal motor symptoms are linked to death of dopaminergic neurons in the nigrostriatal pathway. Here we ask why these neurons are preferentially susceptible to neurodegeneration in PD and how alpha-synuclein is involved. To address these questions we bring together recent findings from genome-wide association studies, which reveal the involvement of alpha-synuclein gene variants in sporadic PD, with recent studies highlighting important roles for alpha-synuclein in synaptic transmission and dopaminergic neuron physiology. These latest advances add to our understanding of PD etiology and provide a central link between the genetic findings and neurodegeneration observed in sporadic PD. PMID- 20961628 TI - Ecotoxicology, ecophysiology, and mechanistic studies with rotifers. AB - Invertebrates play an increasing role in assessing the impacts of environmental contaminants in aquatic ecosystems. Substantial efforts were made to identify suitable and environmentally relevant models for toxicity testing. Rotifers have a number of promising characteristics which make them candidates worth considering in such efforts. They are small, simple in their organization, genetically homozygous, easy to cultivate. Rotifers are further widely distributed and ecologically important in freshwaters, in estuaries and coast, and also play an important role in the transportation of aquatic pollutants across the food web. In the last decades there has been a substantial increase of contributions on rotifers, particularly in areas of their ecology, geophylogeny, genomics and their behavioral, physiological, biochemical and molecular responses, following exposure to environmental chemicals and other stressors. Gene expression analysis enables ecotoxicologists to study molecular mechanisms of toxicity. Rotifers also appear as useful tools in the risk assessment of pharmaceuticals and their metabolites that find their way into aquatic ecosystems because their sensitivity to some of these substances is higher than that of cladocerans and algae. In respect to endocrine disruptors, rotifers seem to be particularly sensitive to androgenic and anti-androgenic substances, whereas copepods and cladocerans are typically more affected by estrogens and juvenile hormone-like compounds. Generally, a combination of whole-animal bioassays and gene expression studies allow an understanding of toxicological mechanisms. The purpose of this review is to demarcate the potential of using rotifers as important invertebrate aquatic model organisms for ecophysiology, ecotoxicology and environmental genomics. This review does not claim to find reasons for a superior use of rotifers in these fields. But the different phylogenetic allocation of rotifers in the Platyzoa (formerly Nemathelminthes) justifies its consideration since there are evolutionary differences in biochemical and genetic performances that need to be considered. Problems, controversials and needs for further studies are discussed. We are providing a literature survey here for the last 15 years that shows a steady increase of ecotoxicological research on rotifers. PMID- 20961630 TI - Effects of intracoronary infusion of bone marrow-derived stem cells on pulmonary artery pressure and diastolic function after myocardial infarction. PMID- 20961629 TI - Comparison of once and twice weekly water exercise on various bodily functions in community-dwelling frail elderly requiring nursing care. AB - Previous research suggests that water exercise (WE) improves bodily functions of the frail elderly, but there is as yet no research on the effect of once weekly WE. This study aims to compare the effects of once and twice weekly WE on bodily functions of frail elderly requiring nursing care in six months. The design is a prospective cohort study. Participants were assigned to two different exercise groups (once weekly group or twice weekly group; n=35). Once weekly group participate in a 60-min exercise session once a week, for six months while twice weekly group attended the session twice a week. Exercise sessions were divided into a 10-min warm-up on land and 50 min of exercise in water. The 50-min WE program consisted of 20 min walking, 10 min activities of daily living (ADL) exercise, 10 min stretching and strength exercises, and 10 min relaxation in water. Muscle strength, flexibility, balance, mobility and ADL disability were measured before the beginning of intervention and three months and six months after the program had started. Significant differences between the once and twice weekly groups were found in flexibility and balance at 3-months and 6-months and lower muscle strength and ADL disability only at 3-months. These results from present study suggested that the effects of WE frequency in the fail elderly who require nursing care were different for each bodily function. PMID- 20961631 TI - Bidirectional fascicular tachycardia with alternating axis deviation following acute myocardial infarction. PMID- 20961627 TI - When neurogenesis encounters aging and disease. AB - In this review, we consider the evidence that a reduction in neurogenesis underlies aging-related cognitive deficits and impairments in disorders such as Alzheimer's disease (AD). The molecular and cellular alterations associated with impaired neurogenesis in the aging brain are discussed. Dysfunction of presenilin 1, misprocessing of amyloid precursor protein and toxic effects of hyperphosphorylated tau and beta-amyloid probably contribute to impaired neurogenesis in AD. Because factors such as exercise, environmental enrichment and dietary energy restriction enhance neurogenesis, and protect against age related cognitive decline and AD, knowledge of the underlying neurogenic signaling pathways could lead to novel therapeutic strategies for preserving brain function. In addition, manipulation of endogenous neural stem cells and stem cell transplantation, as stand-alone or adjunct treatments, seems promising. PMID- 20961632 TI - Right bundle branch block with changing axis at the end of atrial fibrillation. PMID- 20961634 TI - A 14-year follow-up study of chest pain patients including stress hormones and mental stress at index event. AB - BACKGROUND: Knowledge of long-term outcome in chest pain patients is limited. We reinvestigated patients who 14 years earlier had visited the emergency department due to chest pain, and were discharged without hospitalization. Extensive examinations were made at that time on 484 patients including full medical history, exercise test, a battery of stress questions and stress hormone sampling. METHODS: From a previously conducted chest pain study patients still alive after 14 years were approached. Hospitalization or deaths with a diagnosis of ischemic heart disease or cerebrovascular disease were used as end point. RESULTS: During the follow-up period 24 patients had died with a diagnosis of ischemic heart or cerebrovascular disease, and 50 patients had been given such a diagnosis at hospital discharge. Age (OR 1.12, CI 1.06-1.19), previous history of angina pectoris (OR 9.69, CI 2.06-71.61), pathological ECG at emergency department visit (OR 3.27, CI 1.23-8.67), hypertension (OR 5.03, CI 1.90-13.76), smoking (OR 3.04, CI 1.26-7.63) and lipid lowering medication (OR 14.9, CI 1.60 152.77) were all associated with future ischemic heart or cerebrovascular events. Noradrenalin levels were higher in the event group than in the non-event group, mean (SD) 2.44 (1.02) nmol/L versus 1.90 (0.75) nmol/L. When noradrenalin was included in the regression model high maximal exercise capacity was protective of an event (OR 0.986, CI 0.975-0.997). CONCLUSION: In chest pain patients previous history of angina pectoris, hypertension, smoking, pathological ECG at primary examination, and age were the main risk factors associated with future cardiovascular or cerebrovascular events. PMID- 20961635 TI - Simultaneous occlusion of two coronary arteries in a patient with acute myocardial infarction: a result of plaque rupture and plaque erosion. PMID- 20961633 TI - Timing of events in STEMI patients treated with immediate PCI or standard medical therapy: implications on optimisation of timing of treatment from the CARESS-in AMI trial. AB - OBJECTIVES: Early angioplasty after thrombolysis is now recommended for ST elevation myocardial infarction, but the current guidelines propose a wide time window ranging between 3 and 24h after lytic administration. To identify the optimal timing for PCI after thrombolysis, we analyzed frequency and time course of the adverse events in patients randomized in the multicenter CARESS-in-AMI trial. METHODS: 598 high-risk patients with STEMI recruited in the CARESS-in-AMI study, were divided into the Immediate PCI group (IMM, n=298), Rescue PCI group (RES, n=107) and Standard Treatment Arm without rescue PCI (STA, n=193). RESULTS: RES patients had worse pre-procedural TIMI flow and post-procedural blush grade. At 30 days, there were 23 deaths: 11 (10.3%) in RES, 9 (3%) in IMM and 3 (1.6%) in STA (p<0.001). There were 22 episodes of refractory ischemia or re-infarction: 17 (8.8%) in the STA group, 4 (1.6%) in IMM and 1 (0.9%) in RES (p<0.001). In the RES group 10/11 (90.9%) deaths occurred before day 5. In the STA group, all deaths and the majority of ischemic events occurred after day 3. A reduction of risk of death was observed if PCI after thrombolysis was performed within 3.35 h from initial hospitalization. CONCLUSIONS: The mortality benefit of immediate referral to PCI after pharmacological treatment for STEMI derives from a reduction in the time to reperfusion of patients with failed thrombolysis in need of rescue PCI. In patients with evidence of successful reperfusion, "elective" PCI within 3 days may be sufficient to reduce the recurrent ischemic events. PMID- 20961636 TI - Resection of a primary leiomyosarcoma of the superior vena cava and right atrium on a beating heart. PMID- 20961637 TI - Cardiovascular disease risk factors are highly prevalent in the office-working population of Nanjing in China. AB - OBJECTIVE: To establish a profile of the modifiable cardiovascular disease (CVD) risk factors in the office-working population of Nanjing, China. BACKGROUND: With increasing modernization in China, CVD is now common among Chinese. Relevant information on the prevalence of CVD risk factors in China is, however, limited. METHODS: We recruited 2648 office working people aged 23-79 years without history of CVD or diabetes from 7 work units of Nanjing during the years 2003 to 2005. Information from a self-reported questionnaire on lifestyle, physical examination, fasting blood for lipid profiles, and a 75-gram oral glucose tolerance test (OGTT) were obtained from each participant. We analyzed the following 7 CVD risk factors: smoking, inadequate physical activity, unhealthy dietary habit, obesity, hypertension, dyslipidemia, and hyperglycemia. RESULTS: The whole study population had an average of 2.8 risk factors, while 95.6%, 79.4% and 55.6% of them had respectively >= 1, >= 2 and >= 3 of the 7 CVD risk factors. Men had a higher proportion of smoking, hypertension, dyslipidemia, hyperglycemia, but lower in light physical activity compared with women. Number of CVD risk factors increased with age. Although risk factors in men were more common than women, they increased alarmingly in postmenopausal women. CONCLUSIONS: CVD risk factors are common in office-working people in Nanjing, China. Effective interventions and treatment against risk factors should be adopted in the high risk population, which may greatly reduce the future burden of CVD in the Chinese population. PMID- 20961638 TI - Ideal bladder length. PMID- 20961639 TI - Recurrence of fever-related Brugada pattern and right ventricular functional correlates. PMID- 20961641 TI - Bacterial population genomics and infectious disease diagnostics. AB - New sequencing technologies have made the production of bacterial genome sequences increasingly easy, and it can be confidently forecasted that vast genomic databases will be generated in the next few years. Here, we detail how collections of bacterial genomes from a particular species (population genomics libraries) have already been used to improve the design of several diagnostic assays for bacterial pathogens. Genome sequencing itself is also becoming more commonly used for epidemiological, forensic and clinical investigations. There is an opportunity for the further development of bioinformatic tools to bring even further value to bacterial diagnostic genomics. PMID- 20961640 TI - Twin pregnancy in a woman with pulmonary atresia, ventricular septal defect, and aortopulmonary collaterals complicated by Eisenmenger physiology. PMID- 20961642 TI - Development of multiplex real-time PCR with Internal amplification control for simultaneous detection of Salmonella and Cronobacter in powdered infant formula. AB - Contamination of powdered infant formula (PIF) by the bacteria Cronobacter spp. and Salmonella enterica was deemed a matter of great concern by the World Health Organization and the Food and Agriculture Organization of the United Nations in 2004. Therefore, we developed a rapid and sensitive multiplex real-time PCR assay for the simultaneous detection of Cronobacter and Salmonella in PIF. In addition, an internal amplification control (IAC) was also included for exclusion of false negative results in this study. The quantitative detection range for pure cultures in this optimized multiplex real-time PCR assay was 103 to 108 CFU/ml for both Salmonella and Cronobacter. When our established multiplex real-time PCR system was applied to artificially contaminated PIF, the detection limit was 103 CFU/ml for Salmonella and Cronobacter without enrichment. The commercial PIF was then inoculated with Salmonella and Cronobacter at 10, 1 and 0.1 CFU per gram of formula and the single enrichment broth samples were analyzed by multiplex real time PCR after enrichment for 9, 12, and 24 h. At 12 h post-enrichment, we could detect Salmonella and Cronobacter at initial inoculation levels of approximately 0.1 CFU/g in PIF. Additionally, stable fluorescent IAC signals could be assessed between 29 and 34 cycles of PCR amplification. Results from this study showed that the multiplex real-time PCR assay is an effective method for the rapid and simultaneous detection and quantification of Cronobacter and Salmonella in PIF. PMID- 20961643 TI - Effect of pharmacist intervention on glycemic control in diabetes. AB - AIM: To conduct a meta-analysis evaluating the effect of pharmacist intervention on glycemic control. METHODS: A systematic search of Medline and CENTRAL was conducted from the earliest possible date through June 2010. Trials were included if they were randomized controlled trials in a diabetic population, evaluated any form of pharmacist intervention and reported data on hemoglobin A1C (A1C). A random-effects model was used to calculate weighted mean differences (WMDs) and 95% confidence intervals. RESULTS: Fourteen trials (n = 2073) evaluating the effect of pharmacist intervention on glycemic control were identified. Pharmacist intervention significantly lowered A1C (n = 14 trials, WMD -0.76%, 95%CI -1.06 to -0.47) and fasting blood glucose (FBG) (n = 4 trials, WMD -29.32 mg/dL, 95%CI 39.54 to -19.10). A moderate to high degree of statistical heterogeneity was observed in these analyses (I(2) >= 44.1% for both). CONCLUSIONS: Our findings demonstrate statistically and clinically significant associations between pharmacist intervention and improvement in glycemic control. PMID- 20961644 TI - Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease. AB - BACKGROUND & AIMS: Chronic ethanol consumption in the Long-Evans (LE) rat has been associated with hepatic p53 activation, and inhibition of the insulin/PI3K/AKT signal transduction cascade due to increased expression of PTEN. We hypothesize that p53 activation and altered insulin signaling may influence the susceptibility of rats to ethanol-induced liver damage. Furthermore, p53 not only activates programmed cell death pathways and suppresses hepatocellular survival signals, but also promotes gluconeogenesis to increase systemic insulin resistance due to a novel metabolic function. METHODS: Fischer (F), Sprague Dawley (SD) and LE rats were fed ethanol-containing or control liquid diet for 8 weeks. Histopathological and biochemical changes were assessed. RESULTS: Here, we demonstrate that chronic ethanol feeding in rats promotes p53 activation, hepatic steatosis, oxidative stress, PUMA, and PTEN expression, which contribute to hepatocellular death and diminished insulin signaling in the liver. Such changes are pronounced in the LE, less prominent in SD, and virtually absent in the F rat strain. More importantly, there is activation of Tp53-induced glycolysis and apoptosis regulator (TIGAR) in the ethanol-fed LE rat. This event generates low hepatic fructose-2,6-bisphosphate (Fru-2,6-P2) levels, reduced lactate/pyruvate ratio and may contribute to increased basal glucose turnover and high residual hepatic glucose production during euglycemic hyperinsulinemic clamp. CONCLUSIONS: p53 activation correlates with the susceptibility to ethanol-induced liver damage in different rat strains. p53 not only orchestrates apoptosis and suppresses cell survival, but by activating TIGAR and decreasing hepatic Fru-2,6-P2) levels it promotes insulin resistance and therefore, contributes to the metabolic abnormalities associated with hepatic steatosis. PMID- 20961645 TI - AFP-specific immunotherapy impairs growth of autochthonous hepatocellular carcinoma in mice. AB - BACKGROUND AND AIMS: In this study, we have assessed the potential of antigen specific immunotherapy against hepatocellular carcinoma (HCC) in conditions of low tumour burden, in an autochthonous HCC model. METHODS: Diethylnitrosamine (DEN) injected into infant mice results in the development of multi-nodular HCC in which alpha-fetoprotein (AFP) is re-expressed. DEN-injected animals received an antigen-specific immunization with a synthetic vector consisting of a low dose of AFP-encoding plasmid formulated with the amphiphilic block copolymer 704 (DNAmAFP/704). Animals were treated at 4 and 5 months, before macroscopic nodules were detected, and were sacrificed at 8 months. The tumour burden, as well as liver histology, was assessed. AFP and MHC class I molecule expression in the nodules were monitored by qRT-PCR. RESULTS: The AFP-specific immunotherapy led to a significant (65%) reduction in tumour size. The reduced expression of AFP and MHC class I molecules was measured in the remaining nodules taken from the DNAmAFP/704-treated group. CONCLUSIONS: This is the first study demonstrating the relevance of antigen-specific immunotherapy in an autochthonous HCC model. In this context, we validated the use of an anti-tumour immunotherapy based on vaccination with nanoparticles consisting of low dose antigen-encoding DNA formulated with a block copolymer. Our results demonstrate the potential of this strategy as adjuvant immunotherapy to reduce the recurrence risk after local treatment of HCC patients. PMID- 20961646 TI - Considering consumer choice in the economic evaluation of mandatory health programmes: a review. AB - OBJECTIVE: Governments are increasing their focus on mandatory public health programmes following positive economic evaluations of their impact. This review aims to examine whether loss of consumer choice should be included in economic evaluations of mandatory health programmes (MHP). METHOD: A systematic literature review was conducted to identify economic evaluations of MHP, whether they discuss the impact on consumer choice and any methodological limitations. RESULTS: Overall 39 economic evaluations were identified, of which 10 discussed the loss of consumer choice and 6 attempted to place a value on the loss of consumer choice. Methodological limitations included: measuring the marginal cost of compliance, unavailability of price elasticity estimates, the impact of income effects, double counting health impacts, biased willingness-to-pay responses, and "protest" responses. Overall it was found that the inclusion of the loss of consumer choice rarely impacted on the final outcome of the study. CONCLUSION: The impact of MHP on the loss of consumer choice has largely been ignored in economic evaluations. Its importance remains uncertain due to its infrequent inclusion and significant methodological limitations. Further research regarding which methodology is best for valuing the loss of consumer choice and whether it is important to the final implementation decision is warranted. PMID- 20961647 TI - Priority setting for orphan drugs: an international comparison. AB - OBJECTIVES: To describe the process of priority setting for two orphan drugs - Cerezyme and Fabrazyme - in Canada, Australia and Israel, in order to understand and improve the process based on stakeholder perspectives. METHODS: We conducted qualitative case studies of how three independent drug advisory committees made decisions relating to the funding of Cerezyme and Fabrazyme. Interviews were conducted with 22 informants, including committee members, patient groups and industry representatives. RESULTS: (1) DESCRIPTION: Orphan drugs reimbursement recommendations by expert panels were based on clinical evidence, cost and cost effectiveness analysis. (2) EVALUATION: Committee members expressed an overall preference for the current drug review process used by their own committee, but were concerned with the fairness of the process particularly for orphan drugs. Other informants suggested the inclusion of other relevant values (e.g. lack of alternative treatments) in order to improve the priority setting process. Some patient groups suggested the use of an alternative funding mechanism for orphan drugs. CONCLUSIONS: Priority setting for drugs is not solely a technical process (involving cost-effective analysis, evidence-based medicine, etc.). Understanding the process by which reimbursement decisions are made for orphan drugs may help improve the system for future orphan drugs. PMID- 20961648 TI - Assessing rapid evolution in a changing environment. AB - Climate change poses a serious threat to species persistence. Effective modelling of evolutionary responses to rapid climate change is therefore essential. In this review we examine recent advances in phylogenetic comparative methods, techniques normally used to study adaptation over long periods, which allow them to be applied to the study of adaptation over shorter time scales. This increased applicability is largely due to the emergence of more flexible models of character evolution and the parallel development of molecular technologies that can be used to assess adaptive variation at loci scattered across the genome. The merging of phylogenetic and population genetic approaches to the study of adaptation has significant potential to advance our understanding of rapid responses to environmental change. PMID- 20961649 TI - Names are key to the big new biology. AB - Those who seek answers to big, broad questions about biology, especially questions emphasizing the organism (taxonomy, evolution and ecology), will soon benefit from an emerging names-based infrastructure. It will draw on the almost universal association of organism names with biological information to index and interconnect information distributed across the Internet. The result will be a virtual data commons, expanding as further data are shared, allowing biology to become more of a 'big science'. Informatics devices will exploit this 'big new biology', revitalizing comparative biology with a broad perspective to reveal previously inaccessible trends and discontinuities, so helping us to reveal unfamiliar biological truths. Here, we review the first components of this freely available, participatory and semantic Global Names Architecture. PMID- 20961650 TI - Making statistics biologically relevant in fragmented landscapes. AB - The biological impacts of habitat fragmentation are routinely assessed using standard statistical modelling techniques that are used across many ecological disciplines. However, to assess the biological relevance of fragmentation impacts, we must consider an extra, spatial dimension to the standard statistical model: the biological importance of a significant and well supported model with large effect sizes crucially depends on the configuration of habitat within the study area. We argue that mapping the outputs from statistical models across a study area generates biologically meaningful estimates of fragmentation impacts. Integrating traditional statistical approaches with geographic information systems will facilitate rigorous comparisons of fragmentation impacts between taxa, studies and ecosystems. PMID- 20961651 TI - The TGF-beta signaling modulators TRAP1/TGFBRAP1 and VPS39/Vam6/TLP are essential for early embryonic development. AB - The pleiotropic cytokine transforming growth factor-beta (TGF-beta) signals through different pathways among which the Smad- and the MAP-Kinase pathways are already well characterized. Both pathways utilize adaptor/chaperone molecules that facilitate or modulate the intracellular signaling events. Two of the proteins shown in vitro to play a role in Smad-dependent signaling are the TGF beta Receptor Associated Protein-1 (TRAP1, also TGFBRAP1) and its homologue VPS39, also known as Vam6 and TRAP1-Like-Protein (TLP). We generated mice deficient for TRAP1 and VPS39/TLP, respectively. Absence of TRAP1 protein results in death at either of two defined timepoints during embryogenesis, before the blastula stage or during gastrulation, whereas most of the VPS39 deficient mice die before E6.5. Heterozygous mice show no overt phenotype. In summary, our data indicate that TRAP1 and VPS39 are nonredundant and essentially required for early embryonic development. PMID- 20961652 TI - p130Cas promotes invasiveness of three-dimensional ErbB2-transformed mammary acinar structures by enhanced activation of mTOR/p70S6K and Rac1. AB - ErbB2 over-expression is detected in approximately 25% of invasive breast cancers and is strongly associated with poor patient survival. We have previously demonstrated that p130Cas adaptor is a crucial mediator of ErbB2 transformation. Here, we analysed the molecular mechanisms through which p130Cas controls ErbB2 dependent invasion in three-dimensional cultures of mammary epithelial cells. Concomitant p130Cas over-expression and ErbB2 activation enhance PI3K/Akt and Erk1/2 MAPK signalling pathways and promote invasion of mammary acini. By using pharmacological inhibitors, we demonstrate that both signalling cascades are required for the invasive behaviour of p130Cas over-expressing and ErbB2 activated acini. Erk1/2 MAPK and PI3K/Akt signalling triggers invasion through distinct downstream effectors involving mTOR/p70S6K and Rac1 activation, respectively. Moreover, in silico analyses indicate that p130Cas expression in ErbB2 positive human breast cancers significantly correlates with higher risk to develop distant metastasis, thus underlying the value of the p130Cas/ErbB2 synergism in regulating breast cancer invasion. In conclusion, high levels of p130Cas favour progression of ErbB2-transformed cells towards an invasive phenotype. PMID- 20961653 TI - New aspects of CLAVATA2, a versatile gene in the regulation of Arabidopsis development. AB - In order to unravel the functions of receptor-like proteins in Arabidopsis (AtRLPs), including the CLAVATA2 (CLV2) receptor, we employed a reverse genetics approach. In previous studies, we assembled a genome-wide collection of AtRLP gene T-DNA insertion mutants and reported on the biological roles of a few AtRLPs closely related to CLV2. In this study, we showed that over-expression of CLV2 in wild-type plants unexpectedly resulted in a multi-carpel phenotype, mimicking the clv2 mutant, which suggests a co-suppression effect on the endogenous CLV2. We also found evidence that the phenotypes of various clv2 alleles are significantly affected by the genetic background of Arabidopsis ecotypes, which, however, did not depend on the ER locus. PMID- 20961654 TI - [Inaugural bilateral panuveitis in relapsing polychondritis]. AB - We report a case of a 72-year-old man who presented with bilateral panuveitis in a context of unclassified arthritis. The recurrence of uveitis associated with ear chondritis led to the diagnosis of relapsing polychondritis. Ocular symptoms are frequent in the course of relapsing polychondritis, but uveitis is a rare symptom and could compromise the visual outcome. PMID- 20961655 TI - [Preretinal residual perfluorocarbon liquid imaging with spectral-domain OCT]. PMID- 20961656 TI - [Analysis and treatment of a patient with bilateral pthiriasis palpebrarum]. AB - OBSERVATION: a 41-year-old man presented to the ophthalmologic emergency department with ocular burns. The examination showed many parasites at several stages of the parasitic cycle. The parasitologic analysis found many Pthirus pubis in the eyelids. The dermatological consultation determined that other locations were affected and sought other sexually transmitted diseases and also detected other exposed patients. The detailed clinical examination determined the type of ectoparasite concerned and noted the various phases of its parasitic cycle. The differential diagnosis with Pthirus capitatis can be difficult and its treatment is different. Precise knowledge of the various ectoparasites provided the diagnosis. Screening for sexually transmitted diseases and investigations of the subjects' contacts were essential. CONCLUSION: the diagnosis of pthiriasis is easy at an advanced stage; however, it could be more difficult at earlier stages. Its treatment is not often familiar to the ophthalmologist. Eradicating pthiriasis without investigating other sexually transmitted infections as well as the subjects' contacts could have more serious consequences on public health. PMID- 20961657 TI - The economic costs to United States hospitals of invasive fungal infections in transplant patients. AB - BACKGROUND: Patients with a solid organ transplant (SOTs) and hematopoietic stem cell or bone marrow transplants (HSC/BMTs) are at risk of contracting invasive fungal infections (IFIs). Data on the economic burden of IFIs in the United States are sparse. METHODS: We conducted a retrospective matched cohort study using the 2004-2005 Healthcare Cost and Utilization Project Nationwide Inpatient Sample. The IFI cohort included patients with ICD-9-CM codes indicating a transplant procedure and an IFI. Matched controls (transplant recipients without an IFI) were chosen based on age (10 year categories), sex, region, hospital type, year, and transplant type. Mortality, length of stay, and costs were reported overall, by transplant type, and by type of mycosis. RESULTS: Nine thousand eight hundred ninety-six patients underwent SOT, and 4661 underwent HSC/BMT. Of these, 80 (0.8%) SOT and 111 (2.4%) HSC/BMT patients had an IFI. Mean age was 41.8 years (SOT) and 37.8 years (HSC/BMT). Aspergillosis was the most common infection. Patients with an IFI had a 5-fold increase in mortality, an additional 19.2 hospital days, and $55,400 in excess costs compared with patients without an IFI. Excess mortality, length of stay, and costs varied by type of transplant and mycosis. CONCLUSION: The clinical and economic burden of IFIs in transplant recipients may be high. PMID- 20961659 TI - Cleavage of Tau by calpain in Alzheimer's disease: the quest for the toxic 17 kD fragment. AB - The amyloid cascade hypothesis of Alzheimer's disease (AD) posits that the generation of beta-amyloid (Abeta) triggers Tau neurofibrillary pathology. Recently a "17 kD" calpain-induced Tau fragment, comprising residues 45-230 (molecular weight [MW], 18.7 kD), was proposed to mediate Abeta-induced toxicity. Here, we demonstrate that the "17 kD" fragment is actually much smaller, containing residues 125-230 (molecular weight, 10.7 kD). Inducing Tau phosphorylation by okadaic acid or mimicking phosphorylation by Glu mutations at the epitopes of Alzheimer-diagnostic antibodies AT100/AT8/PHF1 could not prevent the generation of this fragment. The fragment can be induced not only by Abeta oligomers, but also by other cell stressors, e.g., thapsigargin (a Ca(2+)-ATPase inhibitor) or glutamate (an excitatory neurotransmitter). However, overexpression of neither Tau(45-230) nor Tau(125-230) fragment is toxic to Chinese hamster ovary (CHO) cells, neuroblastoma cells (N2a) or primary hippocampal neurons. Finally, the calpain-induced fragment can be observed both in Alzheimer's disease brains and in control normal human brains. We conclude that the 17 kD Tau fragment is not a mediator of Abeta-induced toxicity, leaving open the possibility that upstream calpain activation might cause both Tau fragmentation and toxicity. PMID- 20961660 TI - Selective white matter pathology induces a specific impairment in spatial working memory. AB - The integrity of the white matter is critical in regulating efficient neuronal communication and maintaining cognitive function. Damage to brain white matter putatively contributes to age-related cognitive decline. There is a growing interest in animal models from which the mechanistic basis of white matter pathology in aging can be elucidated but to date there has been a lack of systematic behavior and pathology in the same mice. Anatomically widespread, diffuse white matter damage was induced, in 3 different cohorts of C57Bl/6J mice, by chronic hypoperfusion produced by bilateral carotid stenosis. A comprehensive assessment of spatial memory (spatial reference learning and memory; cohort 1) and serial spatial learning and memory (cohort 2) using the water maze, and spatial working memory (cohort 3) using the 8-arm radial arm maze, was conducted. In parallel, a systematic assessment of white matter components (myelin, axon, glia) was conducted using immunohistochemical markers (myelin-associated glycoprotein [MAG], degraded myelin basic protein [dMBP], anti-amyloid precursor protein [APP], anti-ionized calcium-binding adapter molecule [Iba-1]). Ischemic neuronal perikarya damage, assessed using histology (hematoxylin and eosin; H&E), was absent in all shams but was present in some hypoperfused mice (2/11 in cohort 1, 4/14 in cohort 2, and 17/24 in cohort 3). All animals with neuronal perikaryal damage were excluded from further study. Diffuse white matter damage occurred, throughout the brain, in all hypoperfused mice in each cohort and was essentially absent in sham-operated controls. There was a selective impairment in spatial working memory, with all other measures of spatial memory remaining intact, in hypoperfused mice with selective white matter damage. The results demonstrate that diffuse white matter pathology, in the absence of gray matter damage, induces a selective impairment of spatial working memory. This highlights the importance of assessing parallel pathology and behavior in the same mice. PMID- 20961658 TI - Age-related changes in processing faces from detection to identification: ERP evidence. AB - We examined the ability of people 70 to 90 years old to apply global, configural, and featural face-processing strategies. In addition we investigated age-related changes in the ability to categorize faces at basic, subordinate, and individual levels. Using the N170 potential as index of early face processing and the P300 component as index of categorical decision making and effort, we found significant age-related perceptual changes which slowed and somewhat impaired face processing. Specifically, older participants had problems integrating face features into global structures, demonstrating enhanced dependence on distal global information. They did not apply configural computations by default while processing faces which suggests that, unless identification is required, they process faces only at a basic level. These perceptual changes could be the cause for slower and less accurate subordinate categorization, particularly when it is based on details. At the neural levels face processing was not right-lateralized, reflecting excessive involvement of the left hemisphere in perception leading to a more general reduction of interhemispheric asymmetry. In addition we found excessive but nonselective activation of frontal regions adding support to the view that executive control and particularly inhibition of irrelevant input are reduced in the elderly. PMID- 20961661 TI - Interaction of caudate dopamine depletion and brain metabolic changes with cognitive dysfunction in early Parkinson's disease. AB - Damage to nonmotor dopamine (DA)-mediated frontostriatal circuits has been proposed as the main pathophysiological basis of cognitive dysfunction in Parkinson's disease (PD). In the present study, 18 early nondemented drug naive PD patients were investigated, by dual-tracer N-omega-fluoropropyl-2beta carbomethoxy-3beta-4-[123I]iodophenyl-nortropane ([123I]FP-CIT) single-photon emission computed tomography (SPECT)/[18F] fluoro-deoxyglucose (FDG) positron emission tomography (PET) imaging, to test whether an early and not yet treatment modulated relation exists between cognitive functions, caudate nucleus (CN) DA impairment and brain metabolism (CMRglc) in associative frontostriatal circuits. Verbal fluency performance correlated with DA impairment in CN, and with CMRglc in dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). Further, CMRglc in orbitofrontal cortex, DLPFC, and ACC was shown to be early modulated by the level of DA impairment in CN. The present study demonstrates in vivo the early functional disruption of nonmotor frontostriatal circuits in PD. The effect of CN DA impairment on DLPFC and ACC metabolism is proposed as a possible early pathophysiological and functional substrate for executive dysfunction in PD. PMID- 20961662 TI - Cholinergic system function and cognition in mild cognitive impairment. AB - Evidence for cholinergic dysfunction in very early stages of neurodegeneration like mild cognitive impairment (MCI) is inconclusive. Previous positron emission tomography (PET) studies based on small samples investigated if it is related to memory impairment. We examined whether cortical acetylcholine esterase (AChE) activity is reduced at this stage and correlated with cognitive function. N [(11)C]-methyl-4-piperidyl acetate ([11C]MP4A), a positron emission tomography tracer for measuring cerebral AChE activity in vivo, was applied in 21 controls and 17 MCI patients. Parametric images of AChE activity were analyzed using standard atlas regions. Principal components analysis (PCA) of regional values of AChE activity and correlation analysis with neuropsychological test results was performed. Cortical AChE activity showed a significant decline in MCI patients compared with controls which was most pronounced in temporal regions. They formed the main part of a principal component that was related significantly to verbal and nonverbal memory, language comprehension and executive function. Cholinergic dysfunction is an early hallmark even before onset of dementia at the clinical stage of MCI. Its impact especially on temporal neocortex is associated with impaired neuropsychological function. PMID- 20961663 TI - Characterization of 7- and 19-month-old Tg2576 mice using multimodal in vivo imaging: limitations as a translatable model of Alzheimer's disease. AB - With 90% of neuroscience clinical trials failing to see efficacy, there is a clear need for the development of disease biomarkers that can improve the ability to predict human Alzheimer's disease (AD) trial outcomes from animal studies. Several lines of evidence, including genetic susceptibility and disease studies, suggest the utility of fluorodeoxyglucose positron emission tomography (FDG-PET) as a potential biomarker with congruency between humans and animal models. For example, early in AD, patients present with decreased glucose metabolism in the entorhinal cortex and several regions of the brain associated with disease pathology and cognitive decline. While several of the commonly used AD mouse models fail to show all the hallmarks of the disease or the limbic to cortical trajectory, there has not been a systematic evaluation of imaging-derived biomarkers across animal models of AD, contrary to what has been achieved in recent years in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (Miller, 2009). If animal AD models were found to mimic endpoints that correlate with the disease onset, progression, and relapse, then the identification of such markers in animal models could afford the field a translational tool to help bridge the preclinical-clinical gap. Using a combination of FDG-PET and functional magnetic resonance imaging (fMRI), we examined the Tg2576 mouse for global and regional measures of brain glucose metabolism at 7 and 19 months of age. In experiment 1 we observed that at younger ages, when some plaque burden and cognitive deficits have been reported, Tg2576 mice showed hypermetabolism as assessed with FDG-PET. This hypermetabolism decreased with age to levels similar to wild type (WT) counterparts such that the 19-month-old transgenic (Tg) mice did not differ from age matched WTs. In experiment 2, using cerebral blood volume (CBV) fMRI, we demonstrated that the hypermetabolism observed in Tg mice at 7 months could not be explained by changes in hemodynamic parameters as no differences were observed when compared with WTs. Taken together, these data identify brain hypermetabolism in Tg2576 mice which cannot be accounted for by changes in vascular compliance. Instead, the hypermetabolism may reflect a neuronal compensatory mechanism. Our data are discussed in the context of disease biomarker identification and target validation, suggesting little or no utility for translational based studies using Tg2576 mice. PMID- 20961664 TI - Antemortem amyloid imaging and beta-amyloid pathology in a case with dementia with Lewy bodies. AB - The association between ante mortem [(11)C]-Pittsburgh Compound B (PiB) retention and beta-amyloid (Abeta) load, Lewy body (LB) and neurofibrillary tangle (NFT) densities were investigated in a pathologically confirmed case of dementia with Lewy bodies (DLB). A 76 year old man presenting with a clinical diagnosis of DLB had undergone PiB-positron emission tomography (PET), (18)F FDG-PET and magnetic resonance imaging (MRI) 18 months before death. The pathologic diagnosis was DLB neocortical-type with low-likelihood of Alzheimer's disease by NIA-Reagan criteria. Sections from regions of interest (ROI) on post-mortem examination were studied. A significant correlation was found between cortical Abeta density and PiB retention in the 17 corresponding ROIs (r = 0.899; p < 0.0001). Bielschowsky silver stain revealed mostly sparse neocortical neuritic plaques, whereas diffuse plaques were frequent. There was no correlation between LB density and PiB retention (r = 0.13; p = 0.66); nor between NFT density and PiB retention (r = 0.36; p = 0.17). The ROI-based analysis of imaging and histopathological data confirms that PiB uptake on PET is a specific marker for Abeta density, but cannot differentiate neuritic from diffuse amyloid plaques in this case with DLB. PMID- 20961665 TI - Prepulse inhibition in patients with fragile X-associated tremor ataxia syndrome. AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder that affects carriers of the fragile X premutation, typically after age 50. Common symptoms include intention tremor, ataxia, neuropathy, autonomic dysfunction, cognitive decline, and dementia. The objectives of this study were to determine if patients with FXTAS have altered prepulse inhibition (PPI; a measure of sensorimotor gating), and to study possible correlations between PPI, molecular status, and cognitive performance. A passive acoustic PPI paradigm was applied in 163 subjects; 121 carriers of the fragile X premutation, and 42 healthy controls. There were significant differences in PPI between premutation carriers with FXTAS and controls at PPI 60 ms, and at 120 ms. This effect was more prominent in the male FXTAS patients. There was a tendency to an impaired PPI in female premutation carriers at the 120 ms condition. There was a significant correlation between the PPI deficit and a higher CGG repeat number. The results show an impairment in sensorimotor gating processes in male carriers of the fragile X premutation, which is more prominent in patients with FXTAS. PMID- 20961666 TI - Role of neuroinflammation in hypertension-induced brain amyloid pathology. AB - Hypertension and sporadic Alzheimer's disease (AD) have been associated but clear pathophysiological links have not yet been demonstrated. Hypertension and AD share inflammation as a pathophysiological trait. Thus, we explored if modulating neuroinflammation could influence hypertension-induced beta-amyloid (Abeta) deposition. Possible interactions among hypertension, inflammation and Abeta deposition were studied in hypertensive mice with transverse aortic coarctation (TAC). Given that brain Abeta deposits are detectable as early as 4 weeks after TAC, brain pathology was analyzed in 3-week TAC mice, before Abeta deposition, and at a later time (8-week TAC mice). Microglial activation and interleukin (IL) 1beta upregulation were already found in 3-week TAC mice. At a later time, along with evident Abeta deposition, microglia was still activated. Finally, immune system stimulation (LPS) or inhibition (ibuprofen), strategies described to positively or negatively modulate neuroinflammation, differently affected Abeta deposition. We demonstrate that hypertension per se triggers neuroinflammation before Abeta deposition. The finding that only immune system activation, but not its inhibition, strongly reduced amyloid burden suggests that stimulating inflammation in the appropriate time window may represent a promising strategy to limit vascular-triggered AD-pathology. PMID- 20961668 TI - Functional effects of genetic polymorphism in inflammatory genes in subjective memory complainers. AB - A number of genetic risk factors have been identified for Alzheimer's disease (AD) including genes involved in the inflammatory response (interleukin 1A, [IL 1alpha (-889)], interleukin 1B (IL-1beta [+3953]), and tumor necrosis factor (TNF [-308 and -850]). We investigated the prevalence and functional consequences (baseline cognitive performance, plasma cytokine levels) of possession of these putative genetic risk factors within a group of subjective memory complainers (SMC, n = 226) and age and sex matched noncomplainers (NMC, n = 167). We observed no effect of any of the genetic factors investigated on cognitive performance. Further, there was no difference in the frequency of the disease-associated alleles, or cytokine levels between subjective memory complainers and noncomplainer participants. There was no relationship between TNF polymorphisms and TNF levels. There was a significant increase in plasma IL-1beta levels in those homozygous for the disease-associated allele (i.e., IL-1beta +3953 TT). Follow-up longitudinal assessments on this cohort will provide insight as to how these polymorphisms may affect the risk of cognitive decline over time. PMID- 20961667 TI - 11beta-hydroxysteroid dehydrogenase type 1, brain atrophy and cognitive decline. AB - Excess cortisol levels are linked with brain atrophy and cognitive decline in older people. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) potently amplifies intracellular glucocorticoid action by converting inert cortisone to active cortisol, but any causal importance in brain aging is unexplored. We tested the hypotheses that higher systemic 11beta-HSD1 activity predicts brain atrophy and cognitive decline in older men. In a longitudinal study of 41 men (65 70 years old at baseline) we measured baseline systemic 11beta-HSD1 activity, the urinary 5alpha- and 5beta-tetrahydrocortisol to tetrahydrocortisone ratio (ratio of tetrahydrometabolites of cortisol (THFs)/ratio of tetrahydrometabolites of cortisol (THE)), and assessed change in brain atrophy, white matter lesions and cognitive function over 6 years. Baseline THFs/THE correlated negatively with baseline hippocampal volumes (left: r = -0.37; right: r = -0.34; p < 0.05) and positively with ventricular volumes (r = 0.43, p = 0.006) and periventricular white matter lesions (rho = 0.31, p = 0.047). Importantly, baseline THFs/THE but not cortisol predicted increase in ventricular volumes (r = 0.33, p = 0.037) and decline in processing speed (r = -0.55, p = 0.0002) over 6 years. The predictive link between systemic 11beta-HSD1 activity and progressive brain atrophy and cognitive decline suggests 11beta-HSD1 inhibition as a plausible therapy for brain aging. PMID- 20961669 TI - [Serological markers in immigrant and Spanish pregnant women in Granada]. AB - INTRODUCTION: Female immigration from less developed countries into Spain has grown in number over the years, and could contribute to changing the prevalence of routine serological markers in pregnant women. MATERIAL AND METHODS: From April 2007 until May 2008 we studied the prevalence of serum antibodies against Treponema pallidum, Toxoplasma gondii, rubella virus, human immunodeficiency virus (HIV 1/2), and hepatitis B virus (HBV) in samples from 4,171 immigrant and Spanish pregnant women in Granada. RESULTS: The seroprevalence of toxoplasmosis in pregnant immigrants was higher than in non-immigrants (44% vs. 14.4%). The overall prevalence against rubella was 97.3%. Sub-Saharan and North African women showed the lowest prevalence (88% and 89%). The prevalence of HBsAg was higher in immigrants than in Spanish women (2.6% vs. 0.4%), and especially high among the Eastern European (6.9%) and Asian (8.1%) pregnant women. The seroprevalences of HIV (0.9% vs. 0.1%) and syphilis (TPHA) (3.5% vs. 0.07%), were higher in immigrants. Seroprevalence against T. pallidum was higher among Eastern European (11.5%) and Latin-American (3.5%) women, whereas sub-Saharan (11.8%) and North African (1%) women showed the highest anti-HIV prevalence. CONCLUSION: Hepatitis B, anti-HIV, syphilis, and antibodies against T. gondii are found more frequently in immigrants than in Spanish pregnant women, whereas rubella protection in Spanish women is higher than immigrant pregnant women. PMID- 20961670 TI - Synthesis, characterization, antiamoebic activity and cytotoxicity of novel 2 (quinolin-8-yloxy) acetohydrazones and their cyclized products (1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives). AB - A series of 1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives were synthesized by the cyclization of novel 2-(quinolin-8-yloxy) acetohydrazones. In vitro antiamoebic activity was performed against HM1: IMSS strain of Entamoeba histolytica. The results showed that all the 2-(quinolin-8-yloxy) acetohydrazones were more active than their cyclized products (1,2,3-thiadiazole and 1,2,3 selenadiazole derivatives). SAR showed that the compounds having quinoline ring and hydrazone linkage with free N-H group are responsible for higher antiamoebic activity. The cytotoxic studies of these compounds on human breast cancer MCF-7 cell line showed that all the compounds were nontoxic at the concentration range of 1.56-50 MUM. PMID- 20961671 TI - Synthesis, biological activity, and evaluation of the mode of action of novel antitubercular benzofurobenzopyrans substituted on A ring. AB - The 8-, 9-, 10-, and 11-halo, hydroxy, and methoxy derivatives of the antimycobacterial 3,3-dimethyl-3H-benzofuro[3,2-f][1]benzopyran were synthesized by condensation of the diazonium salts of 2-chloroanilines (13-17) with 1,4 benzoquinone (18), reduction of the intermediate phenylbenzoquinones 19-22 to dihydroxybiphenyls, cyclisation to halo-2-hydroxydibenzofurans 24-27, and construction of the pyran ring by thermal rearrangement of the corresponding dimethylpropargyl ethers 35-38. Palladium catalyzed nucleophilic aromatic substitution permitted conversion of the halo to the corresponding hydroxy derivatives which were methylated to methoxy-3,3-dimethyl-3H-benzofuro[3,2 f][1]benzopyran. All compounds substituted on the A ring were found more potent than the reference compound 1 against Mycobacterium bovis BCG and the virulent strain Mycobacterium tuberculosis H37Rv. The effect of the most active derivatives on mycolate synthesis was explored in order to confirm the preliminary hypothesis of an effect on mycobacterial cell wall biosynthesis. The linear 9-methoxy-2,2-dimethyl-2H-benzofuro[2,3-g][1]benzopyran (46) exhibiting a good antimycobacterial activity and devoid of cytotoxicity appeared to be the most promising compound. PMID- 20961672 TI - Improvement of the shear fixation stability of intramedullary nailing. AB - BACKGROUND: The healing outcome of long bone fractures is strongly influenced by the mechanical environment. High interfragmentary movement at the fracture site is detrimental to the fracture healing process. Long bone fractures stabilized with thin intramedullary nails commonly used for unreamed intramedullary nailing might be very flexible in shear direction and therefore critical for the fracture healing outcome. The aims of this study were to simulate the shear interfragmentary movement during gait for a human tibia treated with intramedullary nailing and to investigate if this movement could be lowered by implant design modifications. METHODS: The shear movement was calculated with a 3D finite element model based on computer tomograph images of a cadaver bone implant complex of a transverse tibia fracture treated with a Stryker T2 Standard Tibial Nail. This model was validated through in vitro test results under pure shear, axial, bending and torsional loading. FINDINGS: High shear movements of approximately 4mm were calculated during gait. These shear movements could be reduced by approximately 30% either by implant modifications or the use of a 1mm thicker nail. Combining the implant modifications with a 1mm thicker nail, the shear movements could be reduced by 54%. INTERPRETATION: The increase of the fixation stiffness by using an implant material with a high Young's modulus in combination with an angle-stable nail-screw fixation helps to reduce the shear movement during gait and possibly to lower the risk of a prolonged healing time with unreamed intramedullary nailing. PMID- 20961673 TI - Rapid repetitive passive movement improves knee proprioception. AB - BACKGROUND: Proprioception can be affected by many factors including exercise. Most exercises involve certain degrees of repeated passive movements, and different velocities of these movements might affect proprioception differently. The purpose of this study was to evaluate the influences of different angular velocities of repeated passive movement on knee proprioception via active repositioning and kinesthesia measurement. METHODS: A quasi-experimental design with repeated measure on movement velocity (0 degrees /s, 2 degrees /s, 90 degrees /s, and 150 degrees /s). Sixteen healthy young adults participated in the study. All of them received 30 times repeated passive knee movement intervention in four different knee angular velocities - 0 degrees /s, 2 degrees /s, 90 degrees /s, and 150 degrees /s - with counter-balanced sequence in four successive days. Knee active repositioning and kinesthesia were measured with error scores before and after the intervention. FINDINGS: The results revealed a decrease in error scores in both active repositioning and kinesthesia measurement with the velocities of 90 degrees /s and 150 degrees /s (p<0.05); however no significant change was seen with the static condition (0 degrees /s ) or with the velocity of 2 degrees /s. INTERPRETATION: We concluded that repeated passive movement with rapid angular velocities was capable of improving knee proprioception, specifically in active repositioning and kinesthesia measurements. These results would provide information on the effects of different movement velocities onto knee proprioception. Along with further investigations, the findings could potentially enhance our knowledge on knee injury prevention, treatment, and rehabilitation. PMID- 20961674 TI - Use of the MicroRespTM method to assess pollution-induced community tolerance to metals for lotic biofilms. AB - Understanding the ecological status of aquatic ecosystems and the impact of anthropogenic contamination requires correlating exposure to toxicants with impact on biological communities. Several tools exist for assessing the ecotoxicity of substances, but there is still a need for new tools that are ecologically relevant and easy to use. We have developed a protocol based on the substrate-induced respiration of a river biofilm community, using the MicroRespTM technique, in a pollution-induced community tolerance approach. The results show that MicroRespTM can be used in bioassays to assess the toxicity toward biofilm communities of a wide range of metals (Cu, Zn, Cd, Ag, Ni, Fe, Co, Al and As). Moreover, a community-level physiological profile based on the mineralization of different carbon substrates was established. Finally, the utility of MicroRespTM was confirmed in an in-situ study showing gradient of tolerance to copper correlated to a contamination gradient of this metal in a small river. PMID- 20961675 TI - Eighty-year sedimentary record of heavy metal inputs in the intertidal sediments from the Nanliu River estuary, Beibu Gulf of South China Sea. AB - 210Pb analysis in the sediment core C11 was used to reconstruct the historical fluxes of Hg, Cu, Pb, Zn, Cd, Cr and As in the Nanliu River estuary during the last ~81 year. The 210Pbxs-derived sedimentation rates, molar C/N ratios, enrichment factors and excess fluxes indicated that the natural inputs prevailed till the early 1990s. When the erosion related to land-use modifications enhanced, it promoted higher accumulation rates of the sedimentary material. In the recent sediments they were found a moderate enrichment of Cd and Hg (maximum 3.5- and 2.8-fold corresponding to the local background levels, respectively) and a slight enrichment of Cr, Zn, As and Pb (maximum 1.3-, 1.3-, 1.3- and 1.2-fold, respectively). The excess metal fluxes also showed a consistently increasing tread since the early 1990s, which could be associated with the intensive use of phosphate fertilizers and the combustion of fossil fuels derived from human activities. PMID- 20961676 TI - Hemodialysis vascular access training and practices are key to improved access outcomes. AB - Recognizing that autologous arteriovenous fistula use was associated with improved outcomes in hemodialysis patients, the 1997 Dialysis Outcomes Quality Initiative (DOQI) vascular access practice guidelines from the National Kidney Foundation stressed fistulas as the optimal means of dialysis vascular access. In the United States, this emphasis has continued with the Fistula First Breakthrough Initiative. Much of the data supporting fistulas for dialysis access are derived from longitudinal cohorts, including the Dialysis Outcomes and Practice Patterns Study (DOPPS), dialysis provider databases, and other sources. This article reviews major findings from these data sources, focusing on specific practices and characteristics associated with greater arteriovenous fistula use in dialysis facilities worldwide. Important and often overlooked characteristics that are discussed in detail include specific preferences of dialysis staff regarding access type and the emphasis placed on fistula primacy and the number of fistulas created during surgical training. For example, in the DOPPS, the risk of initial fistula failure was 34% lower when fistulas were placed by surgeons who had created at least 25 fistulas during training (P = 0.002). It is imperative that dialysis clinicians advocate actively for specific dialysis access types on behalf of individual patients. Vascular surgery teaching programs must supervise adequate numbers of fistula procedures for every trainee. PMID- 20961677 TI - Systolic blood pressure and mortality among older community-dwelling adults with CKD. AB - BACKGROUND: Chronic kidney disease (CKD) is an increasingly common condition, especially in older adults. CKD manifests differently in older versus younger patients, with a risk of death that far outweighs the risk of CKD progressing to the point that dialysis is required. Current CKD guidelines recommend a blood pressure target <130/80 mm Hg for all patients with CKD; however, it is unknown how lower versus higher baseline blood pressures may affect older adults with CKD. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Older patients (aged >= 75 years) with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m(2)) in a community-based health maintenance organization. PREDICTOR: Baseline systolic blood pressure (SBP) < 130, 130-160 (reference group), and > 160 mm Hg. OUTCOMES: Participants were followed up for 5 years to examine rates of mortality (primary outcome) and cardiovascular disease hospitalizations (secondary outcome). RESULTS: At baseline, 3,099 participants (38.5%) had SBP < 130 mm Hg, 3,772 (46.9%) had SBP of 131-160 mm Hg, and 1,171 (14.6%) had SBP >160 mm Hg. A total of 3,734 (46.4%) died and 2,881 (35.8%) were hospitalized. Adjusted HRs for mortality in the groups with SBP < 130 and > 160 mm Hg were 1.22 (95% CI, 1.11-1.34) and 1.06 (95% CI, 0.93-1.22), respectively. Adjusted HRs for cardiovascular hospitalization in these groups were 1.10 (95% CI, 0.99-1.23) and 1.26 (95% CI, 1.09-1.45), respectively. LIMITATIONS: Although causality should not be inferred from this retrospective analysis, results from this study can generate hypotheses for future randomized controlled trials to investigate the relationship between blood pressure and outcomes in older patients with CKD. CONCLUSIONS: Our study suggests that lower baseline SBP (<= 130 mm Hg) may predict poorer outcomes in terms of both mortality and cardiovascular hospitalizations in older adults with CKD. Conversely, higher baseline SBP (> 160 mm Hg) may predict increased risk of cardiovascular hospitalizations, but does not predict mortality. Clinical trials are required to test this hypothesis. PMID- 20961678 TI - The four-stage approach to teaching skills: the end of a dogma? PMID- 20961679 TI - Binding of glutamate to the umami receptor. AB - The umami taste receptor is a heterodimer composed of two members of the T1R taste receptor family: T1R1 and T1R3. It detects glutamate in humans, and is a more general amino acid detector in other species. We have constructed homology models of the ligand binding domains of the human umami receptor (based on crystallographic structures of the metabotropic glutamate receptor of the central nervous system). We have carried out molecular dynamics simulations of the ligand binding domains, and we find that the likely conformation is that T1R1 receptor protein exists in the closed conformation, and T1R3 receptor in the open conformation in the heterodimer. Further, we have identified the important binding interactions and have made an estimate of the relative free energies associated with the two glutamate binding sites. PMID- 20961680 TI - Statistical analysis of plasma thermograms measured by differential scanning calorimetry. AB - Melting curves of human plasma measured by differential scanning calorimetry (DSC), known as thermograms, have the potential to markedly impact diagnosis of human diseases. A general statistical methodology is developed to analyze and classify DSC thermograms to analyze and classify thermograms. Analysis of an acquired thermogram involves comparison with a database of empirical reference thermograms from clinically characterized diseases. Two parameters, a distance metric, P, and correlation coefficient, r, are combined to produce a 'similarity metric,' rho, which can be used to classify unknown thermograms into pre characterized categories. Simulated thermograms known to lie within or fall outside of the 90% quantile range around a median reference are also analyzed. Results verify the utility of the methods and establish the apparent dynamic range of the metric rho. Methods are then applied to data obtained from a collection of plasma samples from patients clinically diagnosed with SLE (lupus). High correspondence is found between curve shapes and values of the metric rho. In a final application, an elementary classification rule is implemented to successfully analyze and classify unlabeled thermograms. These methods constitute a set of powerful yet easy to implement tools for quantitative classification, analysis and interpretation of DSC plasma melting curves. PMID- 20961681 TI - Embracing panarchy, building resilience and integrating adaptive management through a rebirth of the National Environmental Policy Act. AB - Environmental law plays a key role in shaping policy for sustainability of social ecological systems. In particular, the types of legal instruments, institutions, and the response of law to the inherent variability in social-ecological systems are critical. Sustainability likely must occur via the institutions we have in place, combined with alterations in policy and regulation within the context of these institutions. This ecosystem management arrangement can be characterized as a panarchy, with research on sustainability specific to the scale of interest. In this manuscript we examine an opportunity for integrating these concepts through a regulatory rebirth of the National Environmental Policy Act (NEPA). NEPA currently requires federal agencies to take a "hard look" at the environmental consequences of proposed action. The original intent of NEPA, however, was more substantive and its provisions, while currently equilibrium based, may be reconfigured to embrace new understanding of the dynamics of social-ecological systems. PMID- 20961682 TI - Multimodel inference and adaptive management. AB - Ecology is an inherently complex science coping with correlated variables, nonlinear interactions and multiple scales of pattern and process, making it difficult for experiments to result in clear, strong inference. Natural resource managers, policy makers, and stakeholders rely on science to provide timely and accurate management recommendations. However, the time necessary to untangle the complexities of interactions within ecosystems is often far greater than the time available to make management decisions. One method of coping with this problem is multimodel inference. Multimodel inference assesses uncertainty by calculating likelihoods among multiple competing hypotheses, but multimodel inference results are often equivocal. Despite this, there may be pressure for ecologists to provide management recommendations regardless of the strength of their study's inference. We reviewed papers in the Journal of Wildlife Management (JWM) and the journal Conservation Biology (CB) to quantify the prevalence of multimodel inference approaches, the resulting inference (weak versus strong), and how authors dealt with the uncertainty. Thirty-eight percent and 14%, respectively, of articles in the JWM and CB used multimodel inference approaches. Strong inference was rarely observed, with only 7% of JWM and 20% of CB articles resulting in strong inference. We found the majority of weak inference papers in both journals (59%) gave specific management recommendations. Model selection uncertainty was ignored in most recommendations for management. We suggest that adaptive management is an ideal method to resolve uncertainty when research results in weak inference. PMID- 20961683 TI - Microbial community analysis of perchlorate-reducing cultures growing on zero valent iron. AB - Anaerobic microbial mixed cultures demonstrated its ability to completely remove perchlorate in the presence of zero-valent iron. In order to understand the major microbial reaction in the iron-supported culture, community analysis comprising of microbial fatty acids and polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) techniques was performed for perchlorate reducing cultures. Analysis of fatty acid methyl esters (FAMEs) and subsequent principal component analysis (PCA) showed clear distinctions not only between iron supported perchlorate reducing culture and seed bacteria, but also among perchlorate-reducing cultures receiving different electron donors. The DGGE pattern targeting the chlorite dismutase (cld) gene showed that iron-supported perchlorate reducing culture is similar to hydrogen-fed cultures as compared to acetate-fed culture. The phylogenetic tree suggested that the dominant microbial reaction may be a combination of the autotrophic and heterotrophic reduction of perchlorate. Both molecular and chemotaxonomic experimental results support further understanding in the function of zero-valent iron as an adequate electron source for enhancing the microbial perchlorate reduction in natural and engineered systems. PMID- 20961684 TI - Polybrominated diphenyl ethers (PBDEs) in indoor and outdoor window organic films in Izmir, Turkey. AB - Polybrominated diphenyl ether (PBDE) concentrations of outdoor and indoor organic films on window glasses were measured at different locations (offices, laboratories, and homes in urban, suburban, rural, and industrial sites) in Izmir, Turkey. ?(7)PBDE concentrations were dominated by technical penta and deca BDE mixture components. Average total outdoor PBDE (?(7)PBDE) concentrations for suburban, urban, and industrial sites were 43.5, 45.5, and 206 ng m(-2), respectively. This spatial gradient (industrial>urban>suburban concentrations) was similar to one observed for ambient air concentrations recently in Izmir, Turkey. The highest concentrations measured in the industrial area were attributed to the significant PBDE emissions from several steel plants located in the area. Air-organic film partitioning modeling results have suggested that organic films can be used in conjunction with the dynamic uptake model to approximate the gas-phase ambient air concentrations. Modeling results have also indicated that congeners in the gas-phase with very large octanol-air partition coefficients (i.e., BDE-154, -153, and -209) will require several months to approach equilibrium with the surface films. This finding may have important implications for gas-particle and gas-film partitioning, transport, and photolytic degradation of atmospheric PBDEs. PMID- 20961686 TI - A new target for radiofrequency neurotomy? PMID- 20961687 TI - The development of fibromyalgia--I: examination of rates and predictors in patients with rheumatoid arthritis (RA). AB - We determined rates and predictors of future development of fibromyalgia in patients with rheumatoid arthritis (RA). After excluding patients with fibromyalgia and those with high levels of fibromyalgia symptoms (fibromyalgianess score>10) at baseline, we studied fibromyalgia development in 9739 RA patients during 42,591 patient-years of follow-up. We defined fibromyalgia using a modification of the ACR 2010 fibromyalgia criteria. We used Cox regression to predict future fibromyalgia, and examined the accuracy of predictions using Harrell's C concordance coefficient. At the last observation, 7.4% of patients satisfied criteria, although 19.8% satisfied criteria at some point during follow-up, an incidence rate of 5.3 (95% CI 5.1, 5.6) per 100 patients years, and at rates that were similar in men (7.0%) and women (8.1%). Among those satisfying criteria, during 11,363 years of follow-up from the time of first fibromyalgia diagnosis, half of follow-up time was fibromyalgia+and was associated with markedly abnormal RA variable and FM variable scores. Demographic factors were weak predictors of fibromyalgia (C=0.604). Demographic plus RA variables (C=0.720) and demographic plus fibromyalgia variables (C=0.765), and all predictors (C=0.782) increased accuracy. Clinically important hazard ratios were noted for cognition, depression, comorbidity, and high levels of RA and FM continuous variables Overall, study results indicate that multiple, inter correlated factors that include social disadvantage, psychological distress, comorbidity, RA severity, and fibromyalgia variables predict future development of fibromyalgia, but there is little evidence of the effect of underlying causes. After diagnosis, patients move in both directions across the diagnostic criteria cut points. PMID- 20961685 TI - Central sensitization: implications for the diagnosis and treatment of pain. AB - Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity. PMID- 20961689 TI - Secondary sclerosing cholangitis following major burn injury-An underestimated issue in burn care? PMID- 20961688 TI - Parent perceptions of adolescent pain expression: the adolescent pain behavior questionnaire. AB - Pain behaviors provide meaningful information about adolescents in chronic pain, enhancing their verbal report of pain intensity with information about the global pain experience. Caregivers likely consider these expressions when making judgments about their adolescents' medical or emotional needs. Current validated measures of pain behavior target acute or procedural pain and young or non-verbal children, while observation systems may be too cumbersome for clinical practice. The objective of this research was to design and evaluate the Adolescent Pain Behavior Questionnaire (APBQ), a parent-report measure of adolescent (11-19 years) pain expressions. This paper provides preliminary results on reliability and validity of the APBQ. Parent-adolescent dyads (N=138) seen in a multidisciplinary pain management clinic completed the APBQ and questionnaires assessing pain characteristics, quality of life, functional disability, depressive symptoms, and pain catastrophizing. Principal components analysis of the APBQ supported a single component structure. The final APBQ scale contained 23 items with high internal consistency (alpha=0.93). No relationship was found between parent-reported pain behaviors and adolescent-reported pain intensity. However, significant correlations were found between parent-reported pain behaviors and parent- and adolescent-reported functional disability, pain catastrophizing, depressive symptoms, and poorer quality of life. The assessment of pain behaviors provides qualitatively different information than solely recording pain intensity and disability. It has clinical utility for use in behavioral treatments seeking to reduce disability, poor coping, and distress. PMID- 20961690 TI - Acticoat dressings and major burns: systemic silver absorption. AB - Despite widespread use of wound dressings containing silver, few studies have investigated patients' serum silver levels. An earlier study of Acticoat use in small burns showed transient elevations of serum silver. The aim of this study was to examine the serum silver profile when Acticoat is used in major burns. A prospective study of 6 patients with burns greater than 20% total body surface area (TBSA). All burn wounds, including grafted and non-grafted areas and skin graft donor sites, were dressed with Acticoat or Acticoat Absorbent. Patients' serum silver levels, biochemistry and haematology were examined before, during and after the application of the silver dressings. The median total wound size (including donor sites) was 46.1% TBSA. The median maximum serum silver level recorded, 200.3 MUg/L, reached at a median of 9.5 days following initial silver dressing application. This decreased to a median of 164.8 MUg/L at the end of the treatment period and to a median of 8.2 MUg/L at the end of follow-up. One adverse event, partial skin graft loss was thought to be dressing related. In this small study, serum silver levels were elevated but remained similar to that reported following the use of silver sulfadiazine. This study confirmed our view that Acticoat is safe to use on patients with burns, even when they are extensive. PMID- 20961691 TI - Potential exposure to anti-drug advertising and drug-related attitudes, beliefs, and behaviors among United States youth, 1995-2006. AB - Using nationally representative data from the Monitoring the Future Study on United States middle and high school students, we related exposure to anti-drug television advertising as measured by Nielsen Media Research ratings points to student self-reported drug-related outcomes from 1995 to 2006. Multivariate analyses controlling for key socio-demographics and accounting for the complex survey design included 337,918 cases. Results indicated that attitudes, beliefs, and behaviors regarding substance use were significantly related to such advertising exposure over the six months prior to the date the youth were surveyed. However, the observed relationships varied by grade level, over time and by advertising tagline and marijuana focus. Findings differed markedly between middle and high school students across the study interval. One factor that may partially explain observed differences may be variation in the degree to which the ads focused on marijuana. Putting a concerted effort into increasing anti-drug advertising will likely increase the exposure to and recall of such ads among youth. However, the likelihood that such advertising will result in youth being less likely to use drugs seems to depend heavily on the type of advertising utilized and how it relates to different ages and characteristics of targeted youth. PMID- 20961692 TI - Mesenchymal stem cell transplantation: a potential therapy for oral lichen planus. AB - Oral lichen planus is a type of T cell-mediated autoimmune disease. Satisfactory therapy results are not usually achieved with conventional treatment; however, a new therapy employing T cell immune modulation may treat this disease. Mesenchymal stem cells are multipotent nonhematopoietic progenitor cells that are capable of self-renewal and differentiation into various cell types, including osteocytes and adipocytes. Thus, mesenchymal stem cells are regarded as a promising cell population for tissue regeneration in the clinic. In the past several years, there has been a dramatic improvement in the understanding of immunosuppressive properties of mesenchymal stem cells on various immune cell types. We propose that mesenchymal stem cells can be utilized to treat oral lichen planus patients via systemic infusion or local application. PMID- 20961693 TI - Do vertebroplasty and kyphoplasty have an antitumoral effect? PMID- 20961694 TI - Inflammaging: the driving force in osteoporosis? AB - With advancing age, the balance between the amounts of old bone removed and new bone formed during the remodelling process becomes negative. In the past, it was commonly thought that skeletal involution was the result of age-related changes in other organs, and in particular from the decline in ovarian function in women at menopause. Nonetheless, with regard to emerging epidemiologic studies, the hypothesis suggesting that age-related changes such as inflammatory modifications importantly account for age-related bone loss is gaining increasing interest. Aging is indeed associated with immune dysfunction that coexists with a chronic subclinical inflammatory status. The latter is illustrated by a 2-4-fold increase in the levels C-reactive protein (CRP) or interleukin (IL)-6. This inflammatory status, which has been referred to by the neologism "inflammaging", is of sufficient magnitude to impact health and survival time, and correlates with age related diseases such as atherosclerosis, insulin resistance and Alzheimer's disease. In this article, we first present the factors that condition inflammaging, and propose the hypothesis that inflammaging may be the driving force in age-related bone loss and may even be responsible for osteoporosis due to estrogen deficiency. Finally, we discuss the possibility that pro-inflammatory biomarkers may be used to provide clinical information for identifying patients at risk for osteoporosis, and the possibility that inflammatory cytokines may be targeted to improve bone formation in aged patients undergoing orthopaedic surgery. PMID- 20961695 TI - Adoption of preoperative radiation therapy for rectal cancer from 2000 to 2006: a Surveillance, Epidemiology, and End Results Patterns-of-Care Study. AB - PURPOSE: The German rectal study determined that preoperative radiation therapy (RT) as a component of combined-modality therapy decreased local tumor recurrence, increased sphincter preservation, and decreased treatment toxicity compared with postoperative RT for rectal cancer. We evaluated the use of preoperative RT after the presentation of the landmark German rectal study results and examined the impact of tumor and sociodemographic factors on receiving preoperative RT. METHODS AND MATERIALS: In total, 20,982 patients who underwent surgical resection for T3-T4 and/or node-positive rectal adenocarcinoma diagnosed from 2000 through 2006 were identified from the Surveillance, Epidemiology, and End Results tumor registries. We analyzed trends in preoperative RT use before and after publication of the findings from the German rectal study. We also performed multivariate logistic regression to identify factors associated with receiving preoperative RT. RESULTS: Among those treated with RT, the proportion of patients treated with preoperative RT increased from 33.3% in 2000 to 63.8% in 2006. After adjustment for age; gender; race/ethnicity; marital status; Surveillance, Epidemiology, and End Results registry; county level education; T stage; N stage; tumor size; and tumor grade, there was a significant association between later year of diagnosis and an increase in preoperative RT use (adjusted odds ratio, 1.26/y increase; 95% confidence interval, 1.23-1.29). When we compared the years before and after publication of the German rectal study (2000-2003 vs. 2004-2006), patients were more likely to receive preoperative RT than postoperative RT in 2004-2006 (adjusted odds ratio, 2.35; 95% confidence interval, 2.13-2.59). On multivariate analysis, patients who were older, who were female, and who resided in counties with lower educational levels had significantly decreased odds of receiving preoperative RT. CONCLUSIONS: After the publication of the landmark German rectal study, there was widespread, rapid adoption of preoperative RT for locally advanced rectal cancer. However, preoperative RT may be underused in certain sociodemographic groups. PMID- 20961696 TI - Ten-year outcomes: the clinical utility of single photon emission computed tomography/computed tomography capromab pendetide (Prostascint) in a cohort diagnosed with localized prostate cancer. AB - PURPOSE: To evaluate the clinical utility of capromab pendetide imaging with single photon emission computed tomography coregistration with computed tomography (SPECT/CT) in primary prostate cancer (CaP) for pretreatment prognostic staging and localization of biologic target volumes (BTV) for individualized image-guided radiotherapy dose escalation (IGRT-DE). METHODS AND MATERIALS: Patients consecutively presenting for primary radiotherapy (February 1997 to December 2002), having a clinical diagnosis of localized CaP, were evaluated for tumor stage using conventional staging and SPECT/CT (N=239). Distant metastatic uptake (mets) were identified by SPECT/CT in 22 (9.2%). None of the suspected mets could be clinically confirmed. Thus, all subjects were followed without alteration in disease management. The SPECT/CT pelvic images defined BTV for IGRT-DE (+150% brachytherapy dose) without (n=150) or with (n=89) external radiation of 45 Gy. The National Comprehensive Cancer Network criteria defined risk groups (RG). The median survivor follow-up was 7 years. Biochemical disease-free survival (bDFS) was reported by clinical nadir +2 ng/mL (CN+2) criteria. Statistical analyses included Kaplan-Meier, multivariate analysis, and Concordance-index models. RESULTS: At 10-year analyses, overall survival was 84.8% and bDFS was 84.6%. With stratification by RG, CN+2 bDFS was 93.5% for the low-RG (n=116), 78.7% for the intermediate-RG (n=94), and 68.8% for the high-RG (n=29), p=0.0002. With stratification by pretreatment SPECT/CT findings, bDFS was 65.5% in patients with suspected mets (n=22) vs. 86.6% in patients with only localized uptake (n=217), p=0.0014. CaP disease-specific survival (DSS) was 97.7% for the cohort. With stratification by SPECT/CT findings, DSS was 86.4% (with suspected mets) vs. 99.0% (localized only), p=0.0001. Using multivariate analysis, the DSS hazard ratio for SPECT/CT findings (mets vs. localized) was 3.58 (p=0.0026). Concordance-index tests, based on all data, by CN+2 bDFS criteria were 0.710 for RG alone and 0.773 for SPECT/CT + RG. CONCLUSIONS: Through long-term outcomes we demonstrate statistically significant bDFS and DSS predictive value for pretreatment capromab pendetide SPECT/CT imaging in primary CaP. Dual clinical utility is demonstrated, using SPECT/CT to define BTV for individualized IGRT-DE. PMID- 20961697 TI - Proton beam therapy for unresectable malignancies of the nasal cavity and paranasal sinuses. AB - PURPOSE: The cure rate for unresectable malignancies of the nasal cavity and paranasal sinuses is low. Because irradiation with proton beams, which are characterized by their rapid fall-off at the distal end of the Bragg peak and sharp lateral penumbra, depending on energy, depth, and delivery, provide better dose distribution than X-ray irradiation, proton beam therapy (PBT) might improve treatment outcomes for conditions located in proximity to risk organs. We retrospectively analyzed the clinical profile of PBT for unresectable malignancies of the nasal cavity and paranasal sinuses. METHODS AND MATERIALS: We reviewed 39 patients in our database fulfilling the following criteria: unresectable malignant tumors of the nasal cavity, paranasal sinuses or skull base; N0M0 disease; and treatment with PBT (>60 GyE) from January 1999 to December 2006. RESULTS: Median patient age was 57 years (range, 22-84 years); 22 of the patients were men and 17 were women. The most frequent primary site was the nasal cavity (n=26, 67%). The local control rates at 6 months and 1 year were 84.6% and 77.0%, respectively. With a median active follow-up of 45.4 months, 3 year progression-free and overall survival were 49.1% and 59.3%, respectively. The most common acute toxicities were mild dermatitis (Grade 2, 33.3%), but no severe toxicity was observed (Grade 3 or greater, 0%). Five patients (12.8%) experienced Grade 3 to 5 late toxicities, and one treatment-related death was reported, caused by cerebrospinal fluid leakage Grade 5 (2.6%). CONCLUSION: These findings suggest that the clinical profile of PBT for unresectable malignancies of the nasal cavity and paranasal sinuses make it is a promising treatment option. PMID- 20961698 TI - Hook of hamate pull test. AB - Hook of hamate fractures are often missed despite a distinct history. The purpose of this report was to describe a specific physical examination test that is diagnostic for a hook of hamate fracture, the hook of hamate pull test. It is highly sensitive and was positive in a consecutive series of 5 patients treated for a hook of hamate fracture. These patients also had a distinctive history of playing racket- or club-type sports and presented with longstanding wrist or palm pain. PMID- 20961699 TI - Improved, atraumatic access to digits with severe flexor contractures: surgical tape and suture modification of the lead hand. AB - We present a modification to the widely used lead hand retraction system that allows for improved surgical access to a digit with a severe flexor contracture. A simple construct using surgical adhesive tape and a silk suture can be made and applied to the digit and lead hand. Our technique is simple and inexpensive to use, and we recommend its use to improve surgical access without causing unnecessary trauma to the digit. PMID- 20961700 TI - Benign bony and soft tissue tumors of the hand. AB - It is important to be familiar with the wide variety of benign tumors that may present in everyday hand surgery practice. The treatment of many of these tumors in the hand is based on studies with small numbers of patients or the treatment of similar lesions elsewhere in the body. The purpose of this review is to summarize the recent literature relevant to benign bony and soft tissue tumors in the hand. PMID- 20961701 TI - Evaluation of early postoperative pain and the effectiveness of perifracture site injections following volar plating for distal radius fractures. AB - PURPOSE: Few studies have investigated the effectiveness of early postoperative pain control regimens after volar plating for distal radius fractures. This study evaluated postoperative levels of pain after volar plating of distal radius fractures under axillary nerve block in patients with and without injections of local anesthetics, narcotics, and epinephrine around the fracture site. METHODS: Perioperative pain levels were prospectively assessed in 44 consecutive patients who had had volar plating for a distal radius fracture under axillary nerve block at a mean time of 2.8 days after trauma. Intravenous, patient-controlled analgesia and prescheduled analgesic medications were administered to all patients. In addition, patients were randomly allocated to 2 groups: perifracture site injection (PI; n = 22) and no perifracture site injection (no-PI; n = 22). At the end of surgery, PI group patients were administered perifracture site injections and blocks of the superficial radial and interosseous nerves with a local anesthetic mixture consisting of ropivacaine, morphine, and epinephrine. During the first 48 hours after surgery, pain visual analog scale (VAS) scores (0 to 100), total amount of narcotic consumption, incidences of additional narcotic requirement, and opioid-related side effects were assessed. RESULTS: The overall mean pain VAS scores among all 44 study subjects were 29 before surgery, and 58, 47, 40, and 27 at 4, 8, 24, and 48 hours after surgery, respectively. Thirteen patients needed additional pain rescue despite the multimodal analgesic approach used. No intergroup differences were observed between the PI and no-PI groups in terms of VAS pain scores, total narcotic consumption, adjuvant pain rescue incidence, and opioid-related side effects. CONCLUSIONS: Postoperative mean pain VAS scores after volar plating of distal radius fractures were found to be 58 at 4 hours and 47 at 8 hours. Perifracture site injections were not found to provide any additional pain control benefit. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 20961702 TI - Repair of symptomatic forearm hernias using acellular dermal matrix--two case reports. AB - Symptomatic forearm hernias are troublesome conditions infrequently presented in the literature. We describe a novel approach using cadaveric acellular dermal matrix in an inlay technique to restore fascia integrity. In 2 patients who perform heavy labor, this technique resolved their hernia-related symptoms and allowed them to resume work activities. PMID- 20961703 TI - Incidence and risk factors for the development of radiographic arthrosis after traumatic elbow injuries. AB - PURPOSE: Radiographic arthrosis is a common sequela of elbow trauma. Few studies have addressed risk factors for radiographic arthrosis after elbow injury, especially in the long term. Data from multiple long-term follow-up studies of patients with surgically treated elbow fractures provided us with an opportunity to assess risk factors for long-term radiographic arthrosis after elbow injury. METHODS: During a 5-year period, we obtained radiographs during a research specific evaluation of 139 patients (81 men and 58 women) 10 or more years (median, 19.5 y; range, 10-34 y) after surgical treatment of an elbow fracture as part of multiple retrospective studies. Radiographic arthrosis was graded according to the system of Broberg and Morrey. Bivariate and multivariable analyses evaluated risk factors for radiographic arthrosis. RESULTS: Of 139 patients, 75 had radiographic evidence of arthrosis at final evaluation and 32 had moderate or severe radiographic arthrosis. Mechanism of injury, age, gender, follow-up time, occupation, and limb dominance were not associated with radiographic arthrosis. Multiple logistic regression analysis identified the type of injury as the only independent predictor of moderate to severe radiographic arthrosis. Patients with a bicolumnar fracture of the distal humerus, a capitellum/trochlear fracture, or an elbow fracture-dislocation were 8.0, 7.3, and 5.2 times more likely (odds ratio), respectively, to develop radiographic evidence of moderate or severe radiographic arthrosis than the average patient in this cohort. CONCLUSIONS: Distal humerus fractures (both columnar and capitellum/trochlea) and elbow fracture-dislocations are more likely than fractures of the olecranon and radial head to develop moderate or severe radiographic arthrosis in the long term. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 20961704 TI - Proximal interphalangeal joint arthritis. AB - Proximal interphalangeal joint function is critical for proper finger and hand function and arthritis of this joint can lead to considerable hand impairment. Proximal interphalangeal joint arthritides are broadly categorized into nonerosive and erosive osteoarthritis (OA), posttraumatic arthritis, and inflammatory arthritis. The nonerosive type is considered idiopathic or primary OA, whereas the erosive form exhibits an inflammatory component. Idiopathic or primary OA occurs as a consequence of abnormal mechanical stress that leads to damage of cartilage and subchondral bone, with subsequent cytokine and growth factor activation. Individual genetics then mediate the cellular responses. Although erosive OA is described as a separate entity, this remains controversial, with many suggesting that it is merely a more aggressive form of nonerosive, primary OA. Inflammatory OA occurs when connective tissues are diseased, allowing for normal use to incite arthritic damage. Treatment modalities for proximal interphalangeal joint arthritis are currently limited. PMID- 20961705 TI - Complications of radiation therapy to the hand after soft tissue sarcoma surgery. AB - PURPOSE: Radiation has been shown to improve local control after resection of soft tissue sarcomas. However, it may also result in major complications in the hand, given the compact nature of functional tissues and limited tissue volumes in the hand. The purpose of this investigation was to describe the hand-specific complications of radiation therapy for patients with soft tissue sarcoma of the hand (STSH). METHODS: We performed a retrospective chart review of 55 consecutive patients with STSH treated by a single surgeon between 1993 and 2006. We identified 26 patients who were treated with external beam radiation, brachytherapy, or both, either preoperatively or postoperatively, and reviewed their clinical course. RESULTS: After a median follow-up of 7 years, 29 treatment related complications occurred in 19 patients who had received radiation, whereas 3 of the 29 patients treated with surgery alone developed complications. All patients who received brachytherapy and 14 of the 21 treated with external beam radiation alone developed complications. There were 5 early minor, 2 early major, 3 late minor, and 19 late major complications. CONCLUSIONS: Patients with STSH who underwent radiation therapy had a high rate of complications. The complication rate in our series was higher in patients who had brachytherapy catheters placed adjacent to finger joints. A better understanding of predictors of complications will help to determine the optimal timing and type of radiation therapy to treat patients with STSH. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 20961706 TI - Anterior interosseous nerve syndrome. PMID- 20961707 TI - Pull-out wire fixation for acute mallet finger fractures with k-wire stabilization of the distal interphalangeal joint. AB - PURPOSE: The aim of this study was to describe and assess a surgical technique for the treatment of mallet finger fractures using a pull-out wire with K-wire stabilization of the distal interphalangeal (DIP) joint in extension. METHODS: From May 2003 to January 2008, we performed pull-out wire fixation of the fracture fragment with stabilization of the DIP joint using a K-wire in 65 closed mallet finger fractures in 65 patients with a mean age of 32 years (range, 18 48). The mean time between the injury and surgery was 8 days (range, 0-19 d). In this cohort, the mean joint surface involvement was 39% (range, 30% to 49%) and all injuries were associated with DIP joint subluxation. Fifteen days after surgery, the digits were assessed for skin necrosis, skin breakdown, and wound and wire track infection. Patient follow-up lasted 24 to 27 months, with a mean period of 25.5 months. The fingers were assessed for loss of extension and flexion of the DIP joints. We graded the results using Crawford's criteria. RESULTS: Fracture reduction was maintained and all fractures united. We found no skin necrosis, skin breakdown, infection, or nail deformities. At the final follow-up, the mean extensor loss of the DIP joints was 7 degrees (range, 0 degrees to 37 degrees ). The mean flexion loss of the DIP joints was 1 degrees (range, 0 degrees to 15 degrees ). We noted extensor loss of the joint less than 10 degrees in 57 digits and 10 degrees to 15 degrees (mean, 13 degrees ) in 8 digits. Based on Crawford's criteria, 52 digits were excellent, 8 were good, 4 were fair, and one was poor. CONCLUSIONS: Pull-out wire fixation of the reduced fracture fragment and K-wire stabilization of the DIP joint is a useful technique for the treatment of mallet finger fractures. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 20961708 TI - Epidemiology of congenital upper limb anomalies in 562 children born in 1997 to 2007: a total population study from stockholm, sweden. AB - PURPOSE: There are few true epidemiological studies of congenital anomalies of the upper limb (CULA) on total populations in the literature, and most incidence studies are hospital based. The purposes of this study were to describe the epidemiology and classify all CULA in a region of Sweden during an 11-year period. METHODS: Between 1997 and 2007, there were 261,914 live births in the Stockholm region. A total of 562 children born during this period were found to have CULA. From medical records and available radiographs, all cases were analyzed regarding the type of congenital anomaly, gender, laterality, occurrence among relatives, associated non-hand anomalies, and syndromes. All 585 main anomalies were classified according to the International Federation of Societies for Surgery of the Hand classification. Individuals with right- and left-side main anomalies belonging to different categories were counted as having 2 anomalies. RESULTS: The recorded incidence of CULA was 21.5 per 10,000 live births. Of the 562 children, 304 were boys. The anomalies affected the right side only in 169 children, the left side only in 186, and both sides in 207. Non-hand anomalies were recorded in 129 children, most commonly in the lower limbs. In 99 children, there was a known occurrence among relatives. Failure of differentiation was the most common category (276 of 585) followed by duplication (155 of 585), failure of formation (103 of 585), undergrowth (18 of 585), generalized abnormalities and syndromes (14 of 585), overgrowth (10 of 585), and constriction ring syndrome (9 of 585). CONCLUSIONS: The incidence of CULA in our region was similar to the only previously comparable total population study from Western Australia. The minor differences in incidences between the categories according to the International Federation of Surgical Societies of the Hand may be due to variations in classification strategy. The results of the present study can be used as a reference of CULA in a total population. PMID- 20961709 TI - Corrective osteotomy for isolated malunion of the palmar lunate facet in distal radius fractures. AB - PURPOSE: Malunion of the palmar lunate facet fragment of distal radius fractures is associated with both early functional impairment and late degenerative changes. The goal of this study was to describe the clinical and radiographic outcomes after corrective osteotomy for isolated malunion of the palmar lunate facet. METHODS: Between 1995 and 2000, a retrospective review identified 13 patients with an average age of 44 years who had undergone corrective intra articular osteotomy for isolated malunion of the palmar lunate facet. The average interval from the initial injury to the osteotomy was 5.4 months. Final evaluation was performed at 1 year. We performed statistical analysis using the Wilcoxon signed rank test. RESULTS: Wrist extension improved from an average of 53 degrees to 84 degrees (p = .002), flexion from 46 degrees to 61 degrees (p < .002), supination from 38 degrees to 87 degrees (p = .002), and pronation from 79 degrees to 87 degrees (p < .001). Grip strength improved from 30% to 73% of the contralateral side (p < .002). Disabilities of the Arm, Shoulder, and Hand scores improved from an average of 50.7 to 9.7 (p < .002). Palmar tilt improved from an average of 23 degrees to 11 degrees (p < .002). Radial inclination improved from an average of 29 degrees to 22 degrees (p < .002), ulnar variance decreased from +3.9 to -0.9 mm (p = .004), and intra-articular gap decreased from 3.6 to 0.9 mm (p < .002). All patients had excellent or good results according to both the Gartland and Werley and the Fernandez scoring systems. CONCLUSIONS: Early intra-articular osteotomy significantly improved wrist range of motion, grip strength, Disabilities of the Arm, Shoulder, and Hand scores, and radiographic parameters. Patients reported mostly positive outcomes. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 20961710 TI - Retrospective study of pestivirus infection in Pyrenean chamois (Rupicapra pyrenaica) and other ungulates in the Pyrenees (NE Spain). AB - In 2001 a new Pestivirus (Family Flaviviridae) was associated with an outbreak of a previously unreported disease in Pyrenean chamois (Rupicapra pyrenaica) in the Pyrenees (NE Spain). Molecular characterization assigned this virus to the Border Disease Virus (BDV) cluster, BDV-4 genotype. A retrospective study was performed in archived sera and spleen of 74 Pyrenean chamois and in archived sera of 28 mouflon (Ovis ammon), 56 red deer (Cervus elaphus), 43 roe deer (Capreolus capreolus) and 29 fallow deer (Dama dama) from the Pyrenees between the years 1990 and 2000. Thirty six of 74 (48.6%) sera of Pyrenean chamois, one of mouflon and one of red deer were positive by an ELISA antibody test. Comparative virus neutralization tests were performed on 26 seropositive chamois, one mouflon and one red deer, using five pestivirus strains. An ELISA antigen test was performed on 37 seronegative chamois and yielded positive results in one chamois and inconclusive result in two. RT-PCR and virus isolation performed on spleen samples from these three animals gave positive results in the positive and one inconclusive animal. Sequence analysis in the 5' unstranslated region revealed that they were grouped into the BDV-4 genotype. Virological and serological data of the present study indicate that BDV infection has been present in the chamois population since at least 1990, 11 years before the first outbreak of disease. Therefore, the emergence of the disease in 2001 is apparently due to other factors rather than the introduction of a new virus in the chamois population. PMID- 20961711 TI - Isolation of Bartonella capreoli from elk. AB - The aim of the present study was to investigate the presence of Bartonella infections in elk populations. We report the isolation of four Bartonella strains from 55 elk blood samples. Sequencing analysis demonstrated that all four strains belong to Bartonella capreoli, a bacterium that was originally described in the wild roe deer of Europe. Our finding first time demonstrated that B. capreoli has a wide geographic range, and that elk may be another host for this bacterium. Further investigations are needed to determine the impact of this bacterium on wildlife. PMID- 20961712 TI - Comparative analysis of the frequency, distribution and population sizes of yeasts associated with canine seborrheic dermatitis and healthy skin. AB - The purpose of this study was to investigate the diversity of yeast associated with the degree of canine seborrheic dermatitis (SD) by anatomical sites. Fifty seven samples were divided as 17 healthy skin, 20 with primary seborrheic dermatitis (PSD), and 20 with secondary seborrheic dermatitis (SSD). Yeast isolation and characterization were carried out based on microscopical features and biochemical properties. DNA analysis at the internal transcribed spacer I of 26S rDNA region was utilized for species confirmation. Four species of yeast consisting Malassezia pachydermatis, Malassezia furfur, Candida parapsilosis and Candida tropicalis recovered from examined dogs. M. pachydermatis and C. parapsilosis were isolated from all dogs, but C. tropicalis and M. furfur were recovered from 3 healthy dogs and one diseased dog, respectively. The number of M. pachydermatis and C. parapsilosis in diseased dogs was higher than that of healthy specimens (P<0.01). High frequency and population size of C. parapsilosis were closely associated to PSD, while those of M. pachydermatis were associated with both PSD and SSD (P<0.01). C. parapsilosis were predominant at the perianal area. This study demonstrated the co-colonization of M. pachydermatis and C. parapsilosis in large amounts and frequency associated with stage of disease and anatomical site. PMID- 20961713 TI - Molecular characterization of Malassezia nana isolates from cats. AB - Malassezia nana (M. nana) is a lipid-dependent yeast that has been isolated from cats and cows. Some sequence variability has been observed in the large subunit (LSU) and internal transcribed spacer (ITS) regions between strains isolated from cats and cows though these regions in M. nana isolates from cats alone have proven to be relatively conserved. In the present study, microsatellite PCR fingerprinting and beta-tubulin gene sequence analysis were carried out on M. nana isolates from cats to investigate the genetic diversity of this species. Although a relatively small number of isolates were available, the similarity in the sequences of the beta-tubulin and the microsatellite profiles indicate that a particular M. nana genotype colonizes cats. Moreover, all isolates obtained from animals with otitis externa had the same microsatellite fingerprinting pattern. Further studies of a wider population of M. nana isolates from other hosts and status disease are needed to establish that M. nana is a genetically homogeneous species. This is the first report of the characterization of the beta-tubulin gene in Malassezia spp. PMID- 20961714 TI - Identification of a conformational epitope on the VP1 G-H Loop of type Asia1 foot and-mouth disease virus defined by a protective monoclonal antibody. AB - Although neutralizing antigenic sites of foot-and-mouth disease virus (FMDV) can be defined by selection of monoclonal antibody (MAb) escape mutants, no conformational neutralizing epitope on the major antigenic site located on the G H loop of type Asia1 FMDV has been precisely mapped. In this study, we generated a potent neutralizing MAb 3E11, which recognized a conformation-dependent epitope and neutralized FMDV Asia1/YS/CHA/05 in vitro. Importantly, a dose of 5.5 NT(50) of the MAb 3E11 completely protected suckling mice from a dose of 10 LD(50) of homologous virus challenge in vivo. Through a 12-mer random peptide phage display, synthetic peptide analysis and constructing a series of FMDV Asia1/YS/CHA/05 mutants using reverse genetic system, we finely mapped the neutralizing epitope as the 12-amino acid peptide (141)SXRGXLXXLXRR(152). These results provide additional insights into the virus-MAb interaction at the amino acid level and may help in the development of an epitope-based Asia1 FMDV vaccine. PMID- 20961715 TI - Nutritional and socioeconomic factors in motor development of Santal children of the Purulia district, India. AB - AIMS: The aim of this study was to characterize the motor development of 5-12 year-old Santal children of the Purulia district of West Bengal, India. The effect of socioeconomic and nutritional status on motor development was also examined. STUDY DESIGN: 841 (427 boys and 414 girls) Santal children were examined in this cross-sectional study. The nutritional status of each child was assessed by height-for-age z-score based on WHO reference data. Socioeconomic status (SES) was measured by the updated Kuppusswami scale. Motor development was measured using the Bruininks-Oseretsky Test of Motor Proficiency-Second Edition, Short Form (BOT-2). RESULTS: Sex had a significant (p<0.05) effect on children's score of running speed and agility, upper-limb coordination and strength with higher scores for boys than girls. Children with a height-for-age z-score of -2 or less were significantly more likely to have a total BOT-2 z-score of -2 or less compared with children at a healthier height-for-age range (Chi(2)=271.136, p<0.0001). Well-nourished children scored significantly higher (p<0.05) than undernourished children in total BOT-2 score and in all individual motor subtests. Regression analysis showed that nutritional status, socioeconomic status and height have a significant impact on total BOT-2 score (p<0.001). Age and sex were found to be influencing factors in motor development. CONCLUSION: Santal children's motor proficiency is around the 1st percentile when compared with normative BOT-2 data. This may be, in part, a result of nutritional and economic disparities between children on who the BOT-2 was normed and Santal children, supporting the role of nutrition in motor development. Additionally, Santal children with lower SES and poorer nutritional status have lower motor proficiency compared with Santal children with comparatively higher SES and nutritional status. PMID- 20961716 TI - Nuchal translucency thickness and crown rump length discordance for the prediction of outcome in monochorionic diamniotic pregnancies. AB - BACKGROUND: Ultrasonographic features of the underlying hemodynamic changes in twin-twin transfusion syndrome (TTTS) may be present at the first trimester scan. AIMS: To investigate the value of intertwin discordance in nuchal translucency (NT) thickness and crown-rump length (CRL) to predict TTTS and other adverse outcomes. STUDY DESIGN: Cohort study. SUBJECTS: One hundred and thirty-five unselected consecutive monochorionic diamniotic twin pregnancies. OUTCOME MEASURES: NT and CRL discordance were assessed at 11 to 13(+6) weeks' gestation. Receiver-operating characteristics (ROC) curves were used to determine their predictive ability for the subsequent development of TTTS. RESULTS: TTTS complicated 16/135 (12%) pregnancies. Four other pregnancies were complicated by selective intrauterine growth restriction (sIUGR) and 3 by miscarriage <24 weeks gestation. The median NT discordance was 15% (range 0-37%) in TTTS pregnancies, 13% (12-19%) in those with miscarriage <24 weeks' gestation, 47% (30-50%) in those with sIUGR, and 14% (0-86%) in those without complications. Prediction for subsequent development of TTTS provided by the discordance in CRL, expressed as the area under ROC curve, was 0.52 (95% confidence interval 0.38-0.67), while it was 0.50 for NT discordance (95% confidence interval 0.35-0.64). NT discordance was significantly higher in sIUGR compared to both uncomplicated and TTTS pregnancies (p=0.004 and p=0.003, respectively). CONCLUSION: In an unselected population of monochorionic twin pregnancies, discordance in CRL and NT measured during first trimester scan is not a clinically useful predictor of the subsequent development of TTTS. Therefore, strict ultrasound follow up is recommended for the timely diagnosis of TTTS. PMID- 20961717 TI - Intermittent nutritional stimulus by short-term treatment of high-energy diet promotes ovarian performance together with increases in blood levels of glucose and insulin in cycling goats. AB - The aim of this study was to determine if short-term intermittent treatments of high-energy diet have any stimulatory effects on ovarian function and metabolic status in goat. Cycling Shiba goats were divided into treatment (TG; n=6) and control (CG; n=6) groups. After the detection of ovulation (1st ovulation, Day 0) by ultrasonography, a high-energy diet (250% of maintenance) was fed to the TG from Day 12 to Day 15 (4 days) and from Day 18 to Day 21 (4 days). The high energy diet comprised 1000 g hay-cubes and 300 g of concentrated feed/head/day (approximately 15 MJ of digestible energy/day). The CG was offered maintenance diet throughout the experiment. Transrectal ultrasound examinations were conducted every other day during the luteal phase and were conducted daily during the follicular phase. Blood samples were collected daily from Day -2 to 7 days after ovulation (2nd ovulation) following the nutritional treatment for analysis of follicle stimulating hormone (FSH), progesterone, oestradiol, glucose and insulin in plasma. Two wave-like rises in the concentrations of glucose and insulin appeared in response to the intermittent nutritional stimulus. Mean plasma concentrations of glucose and insulin were significantly (P<0.05) higher in the TG than in the CG on almost all days during each treatment period. For ovarian performance, the total number of follicles that developed on the day prior to the 2nd ovulation in the TG (7.5 +/- 2.7) was significantly higher than that of the CG (4.5 +/- 2.6). Ovulation rate of the 2nd ovulation (4.5 +/- 1.0) in the TG was significantly higher than that of the 1st ovulation (3.0 +/- 0.6) of the TG and than both 1st (2.5 +/- 0.5) and 2nd (2.7 +/- 0.5) ovulations of the CG. No significant difference was detected in the concentrations of FSH, progesterone and oestradiol throughout the experiment between TG and CG. The present experiment demonstrated that short-term intermittent nutritional stimulus from the luteal phase increased the total number of ovulatory follicles and the ovulation rate in association with increasing plasma concentrations of glucose and insulin in goats. PMID- 20961718 TI - In vivo fertility of bull semen following cryopreservation with an LDL (low density lipoprotein) extender: preliminary results of artificial inseminations. AB - A semen extender made with low density lipoproteins (LDL) has been used instead of a standard extender that is already available on the market for the cryopreservation of bovine semen. However, in order to extend its use to artificial insemination centres, in vivo fertility studies were required. Semen was taken from three bulls and frozen-thawed in two extenders: the LDL extender and a standard Tris-egg-yolk (20%) extender used by AI centres. The quality of the semen was assessed prior to artificial insemination: motility was assessed using an image analyser (Computer Assisted Semen Analysis (Hamilton Thorne)), and the integrity of the plasma membrane was assessed using the hypo-osmotic test (HOS test). For the first time, gestations were obtained following the artificial insemination of cows in the field (n=193) with semen that had been frozen-thawed in the LDL extender. No significant difference (p>0.05) was detected between the success rates of AI between the semen that had been frozen-thawed in the LDL extender (59.2%) and the control extender, Tris-20% egg yolk (65.3%). In conclusion, the in vivo fertility of semen that has been frozen-thawed in the LDL extender is maintained since gestations are obtained following AI. PMID- 20961719 TI - Death caused by cardioinhibitory reflex cardiac arrest--a systematic review of cases. AB - Forensic pathologists often refer to the cardioinhibitory reflex cardiac arrest (CiRCA) following short neck trauma as a mechanism of death. We sought via a systematic review of the literature to identify circumstances under which carotid bifurcation stimulation could lead to death. Two independent reviewers selected case studies or reports from Medline, ISI Web of Knowledge, and Embase. Circumstances and contributory factors were extracted for each case. From the available data, authors independently assessed whether CiRCA was highly probable (no alternative explanation possible), probable (alternative explanation possible), or unlikely (alternative explanation highly probable). A narrative approach was used to define circumstances in which CiRCA remained possible. From the 48 published cases evoking CiRCA as a possible cause of death between 1881 and 2009, 28 were most likely to result of other mechanism of death (i.e., cerebral hypoxia due to carotid compression, mechanical asphyxia, myocardial infarction). CiRCA remained possible for 20 cases (including five based on anecdotal evidence only) with only one case with no alternative explanation other than CiRCA. Our findings support the presumption that reflex cardiac arrhythmia due to carotid bifurcation stimulation cannot provoke death alone. Actual state of knowledge suggests CiRCA might be contributory to death in the presence of drug abuse and/or cardiac pathology, often associated with physical and/or mental excitation. PMID- 20961720 TI - Nerve stimulator-assisted sciatic nerve block for painful procedures in the ED. AB - OBJECTIVE: Emergency physicians must frequently perform painful procedures on an urgent basis. These are most commonly performed using procedural sedation techniques involving parenteral sedatives and/or analgesics. Popliteal block of the sciatic nerve is a proven and safe technique used extensively in anesthesiology practice for distal lower extremity analgesia. This technique offers the advantage of relative cardiopulmonary safety, dense and prolonged analgesia, and maintenance of normal airway reflexes in patients with increased aspiration risks. The objective of this study was to explore the usefulness of sciatic nerve block in the popliteal fossa in the emergency department (ED) setting. METHODS: We performed a retrospective analysis of all ED popliteal nerve block cases at our institution from April 2009 to April 2010. Sixteen cases were found where popliteal block was used for pain management during procedures of the leg, ankle, and foot, including fracture reduction, splinting, irrigation, and debridement. Procedural success was defined as successful completion of the technique without the need for additional procedural sedatives, patient satisfaction, and adequate postprocedural analgesia. RESULTS: A high degree of satisfaction was seen in our patient population, and all procedures were successfully completed. Tibial nerve rather than common peroneal nerve stimulation correlated with success of the block. Postprocedural analgesia was excellent in all cases and predictably lasted 90 to 120 minutes. CONCLUSIONS: Although limited by small numbers and its retrospective nature, this review of popliteal nerve block for painful lower extremity procedures in the ED suggests that this technique may be an attractive alternative in selected cases to parenteral procedural sedation. PMID- 20961721 TI - Nitric oxide stimulates progesterone and prostaglandin E2 secretion as well as angiogenic activity in the equine corpus luteum. AB - Cytokines and nitric oxide (NO) are potential mediators of luteal development and maintenance, angiogenesis, and blood flow. The aim of this study was to evaluate (i) the localization and protein expression of endothelial and inducible nitric oxide synthases (eNOS and iNOS) in equine corpora lutea (CL) throughout the luteal phase and (ii) the effect of a nitric oxide donor (spermine NONOate, NONOate) on the production of progesterone (P4) and prostaglandin (PG) E(2) and factor(s) that stimulate endothelial cell proliferation using equine luteal explants. Luteal tissue was classified as corpora hemorrhagica (CH; n = 5), midluteal phase CL (mid-CL; n = 5) or late luteal phase CL (late CL; n = 5). Both eNOS and iNOS were localized in large luteal cells and endothelial cells throughout the luteal phase. The expression of eNOS was the lowest in mid-CL (P < 0.05) and the highest in late CL (P < 0.05). However, no change was found for iNOS expression. Luteal explants were cultured with no hormone added or with NONOate (10(-5) M), tumor necrosis factor-alpha (TNFalpha; 10 ng/mL; positive control), or equine LH (100 ng/mL; positive control). Conditioned media by luteal tissues were assayed for P4 and PGE(2) and for their ability to stimulate proliferation of bovine aortic endothelial cells (BAEC). All treatments stimulated release of P4 in CH, but not in mid-CL. TNFalpha and NONOate treatments also increased PGE(2) levels and BAEC proliferation in CH (P < 0.05). However, in mid-CL, no changes were observed, regardless of the treatments used. These data suggest that NO and TNFalpha stimulate equine CH secretory functions and the production of angiogenic factor(s). Furthermore, in mares, NO may play a role in CL growth during early luteal development, when vascular development is more intense. PMID- 20961722 TI - Prenatal and neonatal exposure to the antiandrogen flutamide alters connexin 43 gene expression in adult porcine ovary. AB - Connexin 43 (Cx43) is the predominant gap junction protein within porcine ovary and is required for proper follicle and corpus luteum (CL) development. Recent research suggests maternally or neonatally mediated effects of antiandrogens on reproductive function during adulthood, notably those dependent on gap junctional communication. The current study was conducted to determine whether late gestational or neonatal exposure to the antiandrogen flutamide influences Cx43 gene expression in the adult porcine ovary. Flutamide was injected into pregnant gilts between days 80 and 88 of gestation and into female piglets between days 2 and 10 posnatally. After animals reached sexual maturity, the ovaries were collected from treated and nontreated (control) pigs. Expression of Cx43 mRNA and protein was determined for preantral and antral follicles and for CLs. In addition, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) expression and progesterone concentration were determined for luteal tissues. In preantral follicles, Cx43 mRNA was down-regulated (P < 0.01) following maternal and neonatal flutamide exposure. In large antral follicles, Cx43 mRNA was up regulated (P < 0.01) after neonatal flutamide administration. Immunofluorescence showed that Cx43 expression decreased (P < 0.001) in preantral follicles and increased (P < 0.001) in large antral follicles following flutamide exposure. In luteal tissues, Cx43 and 3beta-HSD expression and progesterone concentration decreased (P < 0.01) after postnatal flutamide treatment. Overall, these results suggest the involvement of androgens in the regulation of Cx43 expression in pig ovary. Moreover, alteration of Cx43 expression by the administration of flutamide during particular prenatal and neonatal time periods may affect porcine follicle development, as well as CL formation and function. PMID- 20961723 TI - Effect of trenbolone acetate on protein synthesis and degradation rates in fused bovine satellite cell cultures. AB - Although androgenic and estrogenic steroids are widely used to enhance muscle growth and increase feed efficiency in feedlot cattle, their mechanism of action is not well understood. Although in vivo studies have indicated that androgens affect protein synthesis and protein degradation rate in muscle, results from in vitro studies have been inconsistent. We have examined the effects of trenbolone acetate (TBA), a synthetic androgen, on protein synthesis and degradation rates in fused bovine satellite cell (BSC) cultures. Additionally, we have examined the effects of compounds that interfere with binding of TBA or insulin-like growth factor-1 (IGF-1) to their respective receptors on TBA-induced alterations in protein synthesis and degradation rates in BSC cultures. Treatment of fused BSC cultures with TBA results in a concentration-dependent increase (P < 0.05) in protein synthesis rate and a decrease (P < 0.05) in degradation rate, establishing that TBA directly affects these parameters. Flutamide, a compound that prevents androgen binding to the androgen receptor, suppresses (P < 0.05) TBA-induced alterations in protein synthesis and degradation in fused BSC cultures, indicating the androgen receptor is involved. JB1, a competitive inhibitor of IGF-1 binding to the type 1 IGF receptor (IGF1R), suppresses (P < 0.05) TBA-induced alterations in protein synthesis and degradation, indicating that this receptor also is involved in the actions of TBA on both synthesis and degradation. In summary, our data show that TBA acts directly to alter both protein synthesis and degradation rates in fused BSC cultures via mechanisms involving both the androgen receptor and IGF1R. PMID- 20961724 TI - In vitro effects of gonadotropin-releasing hormone (GnRH) on Leydig cells of adult alpaca (Lama pacos) testis: GnRH receptor immunolocalization, testosterone and prostaglandin synthesis, and cyclooxygenase activities. AB - The main objective of this study was to examine the modulatory in vitro effects of gonadotropin-releasing hormone (GnRH) on isolated Leydig cells of adult alpaca (Lama pacos) testis. We first evaluated the presence of GnRH receptor (GnRHR) and cyclooxygenase (COX) 1 and COX2 in alpaca testis. We then studied the in vitro effects of buserelin (GnRH analogue), antide (GnRH antagonist), and buserelin plus antide or inhibitor of phospholipase C (compound 48/80) and COXs (acetylsalicylic acid) on the production of testosterone, PGE(2), and PGF(2alpha) and on the enzymatic activities of COX1 and COX2. Immunoreactivity for GnRHR was detected in the cytoplasm of Leydig cells and in the acrosomal region of spermatids. COX1 and COX2 immunosignals were noted in the cytoplasm of spermatogonia, spermatocytes, spermatids, Leydig cells, and Sertoli cells. Western blot analysis confirmed the GnRHR and COX1 presence in alpaca testis. The in vitro experiments showed that buserelin alone increased (P < 0.01) and antide and buserelin plus acetylsalicylic acid decreased (P < 0.01) testosterone and PGF(2alpha) production and COX1 activity, whereas antide and compound 48/80 counteracted buserelin effects. Prostaglandin E(2) production and COX2 activity were not affected by buserelin or antide. These data suggest that GnRH directly up-regulates testosterone production in Leydig cells of adult alpaca testis with a postreceptorial mechanism that involves PLC, COX1, and PGF(2alpha). PMID- 20961727 TI - Effects of statins on early and late results of carotid stenting. AB - OBJECTIVES: Increasing data suggest that statins can significantly decrease cardiovascular and cerebrovascular events due to a plaque stabilization effect. However, the benefit of statins in patients undergoing carotid angioplasty and stenting (CAS) for carotid stenosis is not well defined. The aim of this study was to investigate whether statins use was associated with decreased perioperative and late risks of stroke, mortality, and restenosis in patients undergoing CAS. METHODS: All patients undergoing CAS for primary carotid stenosis from 2004 to 2009 were reviewed. The independent association of statins and perioperative morbidity was assessed using multivariable analysis. Survival curves and Cox regression models were used to assess late morbidity and restenosis. Propensity score adjustment was employed. RESULTS: A total of 1083 consecutive CAS were performed (29% females, mean age 71.5 years; 24.7% symptomatic); 465 (43%) were on statins medication before treatment that was not discontinued at discharge. Statins use was associated with a reduction of perioperative stroke and death (odds ratio [OR] 0.327, 95% confidence interval [CI] 0.13-0.80, P = .016) according to multivariable analysis. Statins effect was more significant in reducing stroke and death in symptomatic patients (OR 0.13; P = .032) and in males (OR 0.27, P = .01). At 5 years, survival (87.2% vs 78.3%; P = .009) and ischemic stroke-free interval (88.9% vs 99.7%; P = .02) rates were higher in the statins group of patients. Adjusting for propensity score and covariates in Cox regression analyses, statins use was independently associated with reduced long-term mortality risk (HR 0.56, 95% CI 0.32-0.97; P = .039) and borderline associated with decreased late ischemic stroke risk (HR 0.14; 95% CI 0.018-1.08, P = .059). There was no effect on restenosis rates. CONCLUSIONS: These data suggest that statins use is associated with decreased perioperative and late ischemic strokes risk and reduced mortality rates in patients undergoing CAS. Statins therapy should be considered part of the best medical treatment in current CAS practice. PMID- 20961728 TI - The advent of thoracic endovascular aortic repair is associated with broadened treatment eligibility and decreased overall mortality in traumatic thoracic aortic injury. AB - BACKGROUND: Aortic injury is the second leading cause of death in trauma. Thoracic endovascular aortic repair (TEVAR) has recently been applied to traumatic thoracic aortic injuries (TTAIs) as a minimally invasive alternative to open surgery. We sought to determine the impact of TEVAR on national trends in the management of TTAI. METHODS: We queried the Nationwide Inpatient Sample from the years 2001 to 2007 to select patients diagnosed with TTAI (International Classification of Disease-9 code 901.0). Patients were evaluated based on open surgical repair, TEVAR, or nonoperative management, before and after widespread adoption of TEVAR (2001-2005 and 2006-2007). Outcomes of interest were inpatient mortality, length of stay (LOS), and major complications. RESULTS: An estimated 1180 annual admissions occurred for TTAI in the United States. Comparing the two time periods, there was an increase in TEVAR (P < .001) with a simultaneous decrease in open repair (P < .001) in 2006 to 2007. The overall number of interventions also increased (P < .001). Overall mortality decreased (25.0% vs 19.0%;P < .001), corresponding to improved survival in the nonoperative group (28.0% vs 23.2%; P < .001). There was no improvement in open repair mortality rates between the two time periods. Comparing intervention types, the TEVAR group had a higher percentage of patients with brain injury (26.1% vs 20.6%; P = .008), lung injury (25.0% vs 17.7%; P < .001), and hemothorax (32.5% vs 21.7%; P < .001) than the open surgery group. There were no differences in the number of intra abdominal injuries or major orthopedic fractures. The open surgery group had more respiratory complications (43.9% vs 54.2%; P < .001), whereas TEVAR had a higher stroke rate (1.9% vs 0.7%; P = .021). There were no differences in paraplegia or renal failure. Overall in-hospital mortality was 23.2% (nonoperative group 26.7%, open repair 12.4%, and TEVAR 10.6%). Mortality between open repair and TEVAR groups were not significantly different. LOS was shorter among the TEVAR group vs open (15.7 vs 22.9 days; P < .001). CONCLUSION: TEVAR has replaced open repair as the primary operative treatment for TTAI and has extended operative treatment to those patients not previously considered candidates for repair. Increased utilization of TEVAR is associated with improved overall mortality. There is no difference in mortality between TEVAR and open repair groups in our study, which likely reflects the multisystem nature of injury and greater preoperative risk in the TEVAR group. PMID- 20961729 TI - Surgical treatment of primary melanoma of the umbilicus with sentinel lymph node biopsy and plastic reconstruction: case report and review of the literature. AB - AIMS, PATIENTS AND METHODS: The umbilical melanoma is rare, and the surgical treatment can create difficulties for both radical excision and plastic reconstruction. Our aims are to present a case of primary melanoma of the umbilicus and to discuss the best surgical treatment, as well as review the relevant literature. RESULTS: Surgical excision of primary melanoma of the umbilicus must be carried out to reach the peritoneum. Sentinel lymph node biopsy must be carried as well as plastic reconstruction. CONCLUSION: Despite the progress in new medical therapy for melanoma, suitable surgical excision is, at present, the only treatment able to improve patient prognosis. In this report we describe the surgical treatment and plastic reconstruction of a case of umbilical melanoma. PMID- 20961730 TI - The complete preventive effect of homologous tumor vaccines--based on a 5-year experimental study in mice. AB - By using a frozen-thaw method, we developed homologous and heterologous cell based tumor vaccines, which were derived from mouse H22 hepatoma, S180 sarcoma and human A549 lung carcinoma, SK-OV-3 ovarian, and SMMC-7721 hepatoma cell lines. The prophylactic and therapeutic effects of those vaccines were evaluated in mice challenged with live H22 or S180 cells. The result demonstrated that homologous vaccines and heterologous vaccines had no therapeutic effect on tumor growth. However, homologous vaccines showed a complete prevention against live H22 and S180 cell challenge and they could stimulate cross-immune response of anti-tumor in mice. Furthermore, these tumor-free mice immunized with homologous vaccines showed full protection against the repeat challenge every 3 months for 5 years. The study also revealed that tumor-free female, not male, mice transferred anti-tumor ability to some of their offsprings. Heterologous vaccines exhibited no protective effect on tumor development. Immunological analysis discovered that activities of CTLs and NK were enhanced and the levels of IL-2, IL-12 and IFN gamma were significantly increased. Our results demonstrated that homologous tumor vaccines could elicit complete cross-protection against the lethal challenge of tumor cells through enhancing cell-mediated immune response, which lasted for 5 years in mice. These observations may provide a new vaccine strategy for tumor prevention. PMID- 20961731 TI - Abnormal processing of emotional prosody in Williams syndrome: an event-related potentials study. AB - Williams syndrome (WS), a neurodevelopmental genetic disorder due to a microdeletion in chromosome 7, is described as displaying an intriguing socio cognitive phenotype. Deficits in prosody production and comprehension have been consistently reported in behavioral studies. It remains, however, to be clarified the neurobiological processes underlying prosody processing in WS. This study aimed at characterizing the electrophysiological response to neutral, happy, and angry prosody in WS, and examining if this response was dependent on the semantic content of the utterance. A group of 12 participants (5 female and 7 male), diagnosed with WS, with age range between 9 and 31 years, was compared with a group of typically developing participants, individually matched for chronological age, gender and laterality. After inspection of EEG artifacts, data from 9 participants with WS and 10 controls were included in ERP analyses. Participants were presented with neutral, positive and negative sentences, in two conditions: (1) with intelligible semantic and syntactic information; (2) with unintelligible semantic and syntactic information ('pure prosody' condition). They were asked to decide which emotion was underlying the auditory sentence. Atypical event-related potentials (ERP) components were related with prosodic processing (N100, P200, N300) in WS. In particular, reduced N100 was observed for prosody sentences with semantic content; more positive P200 for sentences with semantic content, in particular for happy and angry intonations; and reduced N300 for both types of sentence conditions. These findings suggest abnormalities in early auditory processing, indicating a bottom-up contribution to the impairment in emotional prosody processing and comprehension. Also, at least for N100 and P200, they suggest the top-down contributions of semantic processes in the sensory processing of speech. This study showed, for the first time, that abnormalities in ERP measures of early auditory processing in WS are also present during the processing of emotional vocal information. This may represent a physiological signature of underlying impaired on-line language and socio emotional processing. PMID- 20961732 TI - Using relative improvement over chance (RIOC) to examine agreement between tests: three case examples using studies of developmental coordination disorder (DCD) in children. AB - Although statistics such as kappa and phi are commonly used to assess agreement between tests, in situations where the base rate of a disorder in a population is low or high, these statistics tend to underestimate actual agreement. This can occur even if the tests are good and the classification of subjects is adequate. Relative improvement over chance or RIOC is a statistic that can correct for this bias; however, it is not yet commonly used in the health sciences or disability fields. In this paper, we introduce RIOC and demonstrate its application using the results from 3 previously published studies, all of which assessed the agreement between tests commonly used to identify children with a neurodevelopmental disorder known as developmental coordination disorder (or DCD). The results illustrate the differences between kappa and RIOC under conditions where the distribution of scores in a 2 * 2 table is unbalanced. The introduction of this statistic in the area of developmental disabilities research is encouraged. PMID- 20961733 TI - Improved tensor scale computation with application to medical image interpolation. AB - Tensor scale (t-scale) is a parametric representation of local structure morphology that simultaneously describes its orientation, shape and isotropic scale. At any image location, t-scale represents the largest ellipse (an ellipsoid in three dimensions) centered at that location and contained in the same homogeneous region. Here, we present an improved algorithm for t-scale computation and study its application to image interpolation. Specifically, the t scale computation algorithm is improved by: (1) enhancing the accuracy of identifying local structure boundary and (2) combining both algebraic and geometric approaches in ellipse fitting. In the context of interpolation, a closed form solution is presented to determine the interpolation line at each image location in a gray level image using t-scale information of adjacent slices. At each location on an image slice, the method derives normal vector from its t-scale that yields trans-orientation of the local structure and points to the closest edge point. Normal vectors at the matching two-dimensional locations on two adjacent slices are used to compute the interpolation line using a closed form equation. The method has been applied to BrainWeb data sets and to several other images from clinical applications and its accuracy and response to noise and other image-degrading factors have been examined and compared with those of current state-of-the-art interpolation methods. Experimental results have established the superiority of the new t-scale based interpolation method as compared to existing interpolation algorithms. Also, a quantitative analysis based on the paired t-test of residual errors has ascertained that the improvements observed using the t-scale based interpolation are statistically significant. PMID- 20961734 TI - Nutrient intake in Italian obese patients: relationships with insulin resistance and markers of non-alcoholic fatty liver disease. AB - OBJECTIVE: We investigated the prevalence of insulin resistance, elevated liver enzymes, and Non-Alcoholic Fatty Liver Disease Fibrosis Score (NFS) in obese and severely obese patients. Relations between inadequate nutrient intakes and the markers of metabolic and hepatic disorders were evaluated. METHODS: From January to September 2009, 63 consecutive obese patients (21 men and 42 women, 19-68 y old) were admitted to the study. According to the World Health Organization obesity classification, patients were categorized into three subgroups (classes I, II, and III). NFS scores lower than -1.455 were defined as NFS(-); higher scores were positive (NFS(+)). Insulin resistance (IR) was assessed by the homeostasis model assessment. Nutrient intakes and their potential role as risk factors for IR and liver damage were determined. RESULTS: Body mass index ranged from 30.9 to 73.7 kg/m(2) and most patients (54%) were in class III (body mass index >=40 kg/m(2)). Homeostasis model assessment of IR (>2.5) was recorded in 63.5%. The prevalence of NFS(+) was significantly higher in class III than in classes II and I. Excessive nutrient and energy intake prevalence showed significant differences for protein, fat, and carbohydrate among the obesity classes. Animal protein (odds ratio 3.43, 95% confidence interval 1.15-10.20) and carbohydrate (odds ratio 3.83, 95% confidence interval 1.33-10.94) intakes were the risk factors for IR and NFS(+). CONCLUSION: Non-normal alanine aminotransferase and gamma-glutamyltranspeptidase values were observed in less than one-third of patients, whereas NFS(+) and IR were significantly prevalent, suggesting a close relation between the progression of liver fibrosis and metabolic derangement. An excessive intake of animal protein is associated with an increased risk of IR. Carbohydrate intake, albeit at the highest limit of the recommended dietary allowance range, is associated with an increased risk of liver fibrosis. PMID- 20961735 TI - Functional outcomes following surgical treatment of bilateral mandibular condylar fractures. AB - Debate continues regarding unilateral or bilateral treatment for mandibular condylar fractures. This retrospective study evaluates the functional outcomes of bilateral condylar process fractures after surgical intervention. From May 1994 to December 2004, 51 adult patients with bilateral mandibular condylar process fractures were studied. There were 33 cases of bilateral condylar fractures (type I); 12 cases of condylar-subcondylar fractures (type II); and six cases of bilateral subcondylar fractures (type III). All patients underwent open reduction and internal fixation. Four patients had chin deviation, six had malocclusion, three had poor chewing function and eight had limited mouth opening. Type I patients had a significantly higher incidence of limited mouth opening (P=0.039) and associated maxillary fractures (n=12) and psychiatric disease (n=6) which yielded significantly poor functional outcomes. Complications included transient facial paresis (n=4), fracture and loosening of postoperative plates (n=3) and surgical wound infections (n=2). Open reduction with rigid fixation for bilateral condylar fractures provided satisfactory functional outcomes in this study. Concomitant maxillary fractures and underlying psychiatric problems are poor outcome factors. Aggressive rehabilitation in the first 9 months is important for early functional recovery. PMID- 20961736 TI - Arthroscopic management of intra-articular pigmented villonodular synovitis of temporomandibular joint. AB - This retrospective study reports on four patients with intra-articular pigmented villonodular synovitis (PVNS) of the temporomandibular joint (TMJ) who were managed with arthroscopy between 2002 and 2009. There were three females and one male, with a mean age of 46 years at diagnosis. The common symptoms were trismus and pain. No pre-auricular swelling or mass was detected. Magnetic resonance imaging (MRI) and arthrography showed an anteriorly displaced disc, disc perforation, osteophyte of the condyle, or increased joint effusion. No neoplasm was suspected radiologically. Under arthroscopy, a yellow nodule and loose bodies were found in one patient, and a yellow or brown hyperplasia of the synovial membrane was noted in the other three patients. Degeneration of the articular cartilage was detected in two patients. The arthroscopic procedures used for every patient were partial synovectomy and debridement of articular surfaces with electric shaving and coblation. Arthroscopic disc repositioning was performed for the two young patients. Postoperative histological examination verified the diagnosis of PVNS of the TMJ. The average follow-up period was 57.4 months, and no recurrence was found. Arthroscopy has proved to be a useful method for the management of intra-articular PVNS of the TMJ. PMID- 20961737 TI - High resolution ultrasound investigation of the temporomandibular joint in patients with chronic polyarthritis. AB - 40 patients with chronic polyarthritis were investigated prospectively. The TMJ was investigated to detect clicking, crepitation, and pain. High resolution ultrasound (HR-US) assessed destructive changes, effusion, and disc dislocation. The results of the clinical investigation and the HR-US investigation were compared using the chi(2) test. The statistical calculation of the correlation between the HR-US results and the clinical TMJ investigation by the chi(2) test showed a significant correlation between TMJ sounds, destructive changes and disc dislocation. A significant correlation between TMJ joint effusion, TMJ pathology and TMJ pain was detected using the chi(2) test. Pain on palpation of the masseter and temporal muscle correlated significantly with TMJ effusion. There was significant correlation between TMD and the HR-US diagnosis of destructive changes and effusion. The significant correlation between TMJ effusion and actual TMJ pain and TMJ pain on palpation shows the ability of HR-US to detect acute TMJ affection with high significance. There was a significant correlation between effusion and pain on palpation of the masticatory muscles, which could be interpreted as the ability of HR-US to determine acute TMD. That any TMD correlated significantly with destructive changes and TMJ effusion suggests that HR-US could detect chronic and acute TMD. PMID- 20961738 TI - Effect of induced hypotensive anaesthesia vs isovolaemic haemodilution on blood loss and transfusion requirements in orthognathic surgery: a prospective, single blinded, randomized, controlled clinical study. AB - Induced hypotensive anaesthesia and isovolaemic haemodilution are well established blood-sparing techniques in major surgery. This prospective study compared them for blood loss, transfusion requirements, and surgical field quality during standardized orthognathic operations. In a surgeon-blinded trial, 60 healthy patients requiring either Le Fort I osteotomy or bimaxillary surgery were randomly allocated to receive normotensive anaesthesia, induced hypotensive anaesthesia, or induced hypotensive anaesthesia combined with isovolaemic haemodilution. Blood loss and haemoglobin level were measured intraoperatively and calculated on postoperative day 3. The surgeons rated surgical field quality. Mean blood loss was 1021.63, 392.38 (p<0.05) and 1191.65ml in the normotensive, hypotensive and haemodilution groups, respectively. Mean haemoglobin level immediately after surgery was 9.3, 10.3, and 7.4g/dl (p<0.05), respectively. No hypotensive group patients received transfusions; four normotensive group patients required allogenic transfusions; seven haemodilution group patients needed autogenous retransfusions (p<0.05). Surgical field quality was significantly better in the hypotensive than in the normotensive (p<0.05) or haemodilution (p<0.05) groups. In orthognathic surgery, hypotensive anaesthesia significantly reduces blood loss and transfusion requirements and minimizes allogenic transfusions risks. Induced hypotensive anaesthesia combined with isovolaemic haemodilution has no additional blood-sparing effects but impairs surgical field quality. PMID- 20961739 TI - Adaptive clinical trials for new drug applications in Japan. AB - Adaptive design is regarded as an efficient method for clinical trials in order to increase the success rate of a new drug in development, and recently has been actively discussed among regulatory agencies, industry and academia. Since adaptive design involves interim analyses and is more complex than traditional fixed design, some points such as possibility of introducing statistical and operational bias should be considered when planning and implementing such trials. In this article, we share our perspectives in the consideration of adaptive design clinical trials based on our experiences discussing adaptive design in clinical trial consultation meetings in Japan. PMID- 20961740 TI - Effect of chronic mild stress on hippocampal transcriptome in mice selected for high and low stress-induced analgesia and displaying different emotional behaviors. AB - There is increasing evidence that mood disorders may derive from the impact of environmental pressure on genetically susceptible individuals. Stress-induced hippocampal plasticity has been implicated in depression. We studied hippocampal transcriptomes in strains of mice that display high (HA) and low (LA) swim stress induced analgesia and that differ in emotional behaviors and responses to different classes of antidepressants. Chronic mild stress (CMS) affected expression of a number of genes common for both strains. CMS also produced strain specific changes in expression suggesting that hippocampal responses to stress depend on genotype. Considerably larger number of genes, biological processes, molecular functions, biochemical pathways, and gene networks were affected by CMS in LA than in HA mice. The results suggest that potential drug targets against detrimental effects of stress include glutamate transporters, and cholinergic, cholecystokinin (CCK), glucocorticoids, and thyroid hormones receptors. Furthermore, some biological processes evoked by stress and different between the strains, such as apoptosis, neurogenesis and chromatin modifications, may be responsible for the long-term, irreversible effects of stress and suggest a role for epigenetic regulation of mood related stress responses. PMID- 20961741 TI - Updated hypothesis on the evolution of oligotrichid ciliates (Ciliophora, Spirotricha, Oligotrichida) based on somatic ciliary patterns and ontogenetic data. AB - The two recently established genera Apostrombidium Xu et al., 2009 and Varistrombidium Xu et al., 2009 and the analysis of ontogenetic data in Strombidium constrictum, S. montagnesi, S. wilberti, Omegastrombidium elegans, and Paratontonia gracillima necessitated a revision of the hypothesis about the somatic ciliary pattern evolution in oligotrichid ciliates. As a consequence, the species-rich genus Strombidium was split, establishing two genera for species with a horizontal girdle kinety posterior to the oral primordium: Opisthostrombidium nov. gen. with the extrusome attachment sites along the anterior margin of the girdle kinety and posterior to the oral primordium and Foissneridium nov. gen. with the extrusome attachment sites distinctly apart from the girdle kinety and anterior to the oral primordium. The ontogenetic data revealed that the Omega-shaped girdle kinety pattern evolved convergently from the Pseudotontonia pattern with its horizontal girdle kinety in the tailed genus Paratontonia and from the Novistrombidium pattern with its dextrally spiralled girdle kinety in the tailless genus Omegastrombidium. The somatic ciliary pattern of the latter genus probably gave rise to the patterns of Apostrombidium and Varistrombidium. PMID- 20961744 TI - Up-regulation of the novel proinflammatory adipokines lipocalin-2, chitinase-3 like-1 and osteopontin as well as angiogenic-related factors in visceral adipose tissue of patients with colon cancer. AB - BACKGROUND: Obesity is widely recognised as an important risk factor for colorectal cancer (CC). AIM: The study aimed to evaluate the effect of CC on circulating concentrations and gene expression levels of inflammatory and angiogenesis-related factors in human visceral adipose tissue (VAT). METHODS: VAT biopsies were obtained from 18 healthy individuals and 11 patients with CC. Real time polymerase chain reactions were performed to quantify gene expression levels and zymographic analyses were used to determine the activity of matrix metalloproteinases (MMPs). RESULTS: Patients with CC exhibited increased mRNA expression levels of lipocalin-2 (P=.014), osteopontin (P=.027), tumor necrosis factor-alpha (TNF-alpha) (P=.016) and chitinase-3 like-1 (P=.006) compared to control subjects in VAT. Gene expression levels of hypoxia-inducible factor-1 alpha, vascular endothelial growth factor and MMP-2 were significantly higher (P<.05) in VAT of patients with CC. The expression of insulin-like growth factor I, insulin growth factor binding protein 3 and MMP-9 followed the same trend, although no significant differences were reached. The enzymatic activity of MMP-9 was increased (P<.001) in patients with CC. Furthermore, individuals with CC showed increased (P<.05) circulating concentrations of the inflammatory markers interleukin-6, tumour necrosis factor alpha and hepatocyte growth factor, whereas levels of the anti-inflammatory adipokine adiponectin were decreased (P<.01). CONCLUSION: These findings represent the first observation that mRNA levels of the novel inflammatory factors lipocalin-2, chitinase-3 like-1 and osteopontin are increased in human VAT of subjects with CC. This observation together with the up-regulation of angiogenic factors suggests that adipokines secreted by VAT may be involved in the development of colon cancer. PMID- 20961745 TI - ZnO quantum dot labeled immunosensor for carbohydrate antigen 19-9. AB - Using ZnO quantum dots as electrochemical and fluorescent labels, a sandwich-type sensitive immunoassay was developed to detect carbohydrate antigen 19-9 (CA 19-9) which is a preferred label for pancreatic cancer. The immobilization process was mainly carried out through the electrostatic adsorption based on the high isoelectric point of ZnO, and the sandwich structure was built through the immunoreaction of CA 19-9 antibodies and antigens. The immunological recognition of CA 19-9 was converted into detection of the amplified signals of the square wave stripping voltammetry (SWV) and intrinsic photoluminescence of the labeled quantum dots. The electrochemical assay demonstrated a dynamic range of 0.1-180 U/ml with detection limit of 0.04 U/ml, while the optical spectral detection revealed 1-180 U/ml with detection limit of 0.25 U/ml. PMID- 20961746 TI - On chip real time monitoring of B-cells hybridoma secretion of immunoglobulin. AB - The secretions of molecules by cells are of tremendous interest for both fundamental insights studies and medical purposes. In this study, we propose a new biochip-based approach for the instantaneous monitoring of protein secretions, using antibody production by B lymphocytes cultured in vitro. This was possible thanks to the Surface Plasmon Resonance imaging (SPRi) of a protein biochip where antigen proteins (Hen Egg Lysozyme, HEL) were micro-arrayed along with series of control proteins. B cell hybridomas were cultured on the chip and the secretion of immunoglobulins (antibody) specific to HEL was monitored in real time and detected within only few minutes rather than after a 30-60 min incubation with standard ELISA experiments. This fast and sensitive detection was possible thanks to the sedimentation of the cells on the biochip sensitive surface, where local antibody concentrations are much higher before dilution in the bulk medium. An other interesting feature of this approach for the secretion monitoring was the independence of the SPR response--after normalization- regarding to the density of the surface-immobilized probes. Such biosensor might thus pave the way to new tools capable of both qualitative and semi-quantitative analysis of proteins secreted by other immune cells. PMID- 20961747 TI - Electrochemical sensing telomere-bending motions caused by hTRF1. AB - It has been reported that human telomeric repeat binding factor 1 (hTRF1) may cause telomeric DNA bent; however there is no direct evidence, thus controversy still exists. In this work, the interaction between hTRF1 and a simulated telomeric DNA was investigated by using electrochemical method. While the telomeric DNA was immobilized on a gold electrode surface, a guanine-quadruplex hemin complex was linked at the end of the DNA to serve as an electrochemical signal reporter. If hTRF1 made the telomeric tracts bent, electrochemical response from "off" to "on" could be observed. Therefore, this electrochemical method could give direct evidence whether hTRF1 binding to telomeric DNA would induce a shallow distortion of the DNA molecules, and a new way to explore the structural information of telomere was also proposed in this paper. PMID- 20961748 TI - The effectiveness of therapeutic ultrasound for musculoskeletal conditions of the lower limb: A literature review. AB - BACKGROUND: Ultrasound is suggested as one of the treatment options available for soft tissue musculoskeletal conditions of the lower limb and to this end, the objective was to review the literature and evaluate the effectiveness of therapeutic ultrasound for musculoskeletal conditions of the lower limb. METHODS: A search of the literature published between 1975 and February 2009 was carried out. All studies that fulfilled the inclusion criteria were quality assessed and scored using the Critical Appraisal Skills Programme (CASP) appraisal tool [1] for randomised controlled trials. RESULTS: Ten studies out of a possible fifteen were included in the review. Only one trial was considered to be high quality (score 16+), three medium quality trials (score 11-15) were identified and six trials were considered to be low or poor quality (score<=10). None of the six placebo-controlled trials found any statistically significant differences between true and sham ultrasound therapy. CONCLUSION: This literature review found that there is currently no high quality evidence available to suggest that therapeutic ultrasound is effective for musculoskeletal conditions of the lower limb. PMID- 20961749 TI - Algorithm for the management of antibiotic prophylaxis in onychocryptosis surgery. AB - BACKGROUND: Antibiotic prophylaxis in nail surgery is not clearly established, and there is scant scientific evidence regarding the need for its use in preventing surgical site infection, hematogenous total joint infection, and infective endocarditis. OBJECTIVES: To propose an algorithm based on the evidence for the management of antibiotic prophylaxis in onychocryptosis surgery. METHODS: A literature review was performed in Medline, Pubmed, Cochrane database and Scopus and recent prospective studies were examined. The most-current authoritative guidelines together with new classification system of the pathology have been taken into account. RESULTS: In non-risk patients with onychocryptosis stage II or III phenol technique can be used without the need for antibiotics. In stages IV and V, specific antibiotic treatment should be administered before surgery together with partial ablation of nail until the infection is resolved and the process remits to stage II or III. In the case of long-developing onychocryptosis, osteomyelitis should be ruled out, and specific antibiotic treatment besides the preoperative dose should be administered. In high-risk cardiac patients with infective onychocryptosis, the need for prophylaxis for bacterial endocarditis should be considered. CONCLUSION: Current evidence does not support the use of preoperative antibiotic prophylaxis in onychocrytosis surgery except in special patients with infective onychocryptosis. PMID- 20961750 TI - Logical and symbolic analysis of robust biological dynamics. AB - Logical models provide insight about key control elements of biological networks. Based solely on the logical structure, we can determine state transition diagrams that give the allowed possible transitions in a coarse grained phase space. Attracting pathways and stable nodes in the state transition diagram correspond to robust attractors that would be found in several different types of dynamical systems that have the same logical structure. Attracting nodes in the state transition diagram correspond to stable steady states. Furthermore, the sequence of logical states appearing in biological networks with robust attracting pathways would be expected to appear also in Boolean networks, asynchronous switching networks, and differential equations having the same underlying structure. This provides a basis for investigating naturally occurring and synthetic systems, both to predict the dynamics if the structure is known, and to determine the structure if the transitions are known. PMID- 20961751 TI - Preparation of PEI-coated bacterial biosorbent in water solution: optimization of manufacturing conditions using response surface methodology. AB - The aim of this study is to optimize preparation method of polyethyleneimine (PEI)-coated bacterial biosorbent in water as reaction media using fermentation waste biomass of Corynebacterium glutamicum as a raw material. The fermentation waste biomass of C. glutamicum and Reactive Red 4 were used as model raw bacterium and pollutant. Major factors affecting the performance of PEI-coated biosorbent were the amounts of polymer (PEI) and cross-linker glutaraldehyde (GA). These factors were optimized through response surface methodology (RSM) with two-level-two-factor (2(2)) full factorial central composite design. As a result, the optimum conditions were found to be 4.29 g of PEI and 0.15 mL of GA, with 10 g of the biomass, where the sorption capacity was enhanced 4.52-fold compared to that of the raw biomass. Therefore, this simple, cost-effective, and water-based method could be a useful modification tool for the development of a high performance biosorbent for removing anionic pollutants. PMID- 20961752 TI - Enhancement of photohydrogen production using phbC deficient mutant Rhodopseudomonas palustris strain M23. AB - This study used a DNA recombination method to knock out the poly-beta hydroxybutyrate (PHB) synthesis gene phbC in the photosynthetic bacterium Rhodopseudomonas palustris WP3-5. The experimental results indicated that the mutant strain Rps. palustris M23 could be successfully screened. Fluorescent observation with Nile blue staining showed no significant PHB granule accumulation in the mutant cells. Batch mode experiments using acetic acid as a carbon source revealed a 29.1% and 25.9% hydrogen gas content from M23 and WP3-5, respectively. However, this trend did not appear when using propionic acid as carbon source. Under continuous operation, the hydrogen gas content from M23 could be maintained above 72%. The average hydrogen production rates of the WP3-5 and M23 strains were 264 mL-H(2)/L/day and 457 mL-H(2)/L/day, respectively. The total biogas volume collected from M23 was 1.7 times higher than that from the wild type. PMID- 20961753 TI - Dynamic model-based evaluation of process configurations for integrated operation of hydrolysis and co-fermentation for bioethanol production from lignocellulose. AB - In this study a number of different process flowsheets were generated and their feasibility evaluated using simulations of dynamic models. A dynamic modeling framework was used for the assessment of operational scenarios such as, fed batch, continuous and continuous with recycle configurations. Each configuration was evaluated against the following benchmark criteria, yield (kg ethanol/kg dry biomass), final product concentration and number of unit operations required in the different process configurations. The results show that simultaneous saccharification and co-fermentation (SSCF) operating in continuous mode with a recycle of the SSCF reactor effluent, results in the best productivity of bioethanol among the proposed process configurations, with a yield of 0.18 kg ethanol/kgdry-biomass. PMID- 20961754 TI - 3D-QSAR, homology modeling, and molecular docking studies on spiropiperidines analogues as agonists of nociceptin/orphanin FQ receptor. AB - The nociceptin/orphanin FQ receptor (NOP) has been implicated in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have a great potential to be developed into anxiolytics. However, the crystal structure of NOP is still not available. In the present work, both structure-based and ligand-based modeling methods have been used to achieve a comprehensive understanding on 67N-substituted spiropiperidine analogues as NOP agonists. The comparative molecular-field analysis method was performed to formulate a reasonable 3D-QSAR model (cross-validated coefficient q(2)=0.819 and conventional r(2)=0.950), whose robustness and predictability were further verified by leave-eight-out, Y-randomization, and external test-set validations. The excellent performance of CoMFA to the affinity differences among these compounds was attributed to the contributions of electrostatic/hydrogen bonding and steric/hydrophobic interactions, which was supported by the Surflex Dock and CDOCKER molecular-docking simulations based on the 3D model of NOP built by the homology modeling method. The CoMFA contour maps and the molecular docking simulations were integrated to propose a binding mode for the spiropiperidine analogues at the binding site of NOP. PMID- 20961755 TI - Highly brominated metabolites from marine red alga Laurencia similis inhibit protein tyrosine phosphatase 1B. AB - Five new highly brominated metabolites, 3',5',6',6-tetrabromo-2,4 dimethyldiphenyl ether (1), 1,2,5-tribromo-3-bromoamino-7-bromomethylnaphthalene (2), 2,5,8-tribromo-3-bromoamino-7-bromomethylnaphthalene (3), 2,5,6-tribromo-3 bromoamino-7-bromomethylnaphthalene (4) and 2',5',6',5,6-pentabromo-3',4',3,4 tetramethoxybenzo-phenone (5) were isolated from the red alga Laurencia similis. Their structures were elucidated by spectroscopic methods including one- and two- dimensional NMR as well as HREIMS analysis. Compounds 1 and 5 showed strong inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) with IC(50) of 2.97 and 2.66 MUM, respectively. PMID- 20961756 TI - 5-(pyridinon-1-yl)indazoles and 5-(furopyridinon-5-yl)indazoles as MCH-1 antagonists. AB - A new series of 5-(pyridinon-1-yl)indazoles with MCH-1 antagonist activity were synthesized. Potential cardiovascular risk for these compounds was assessed based upon their interaction with the hERG potassium channel in a mini-patch clamp assay. Selected compounds were studied in a 5-day diet-induced obese mouse model to evaluate their potential use as weight loss agents. Structural modification of the 5-(pyridinon-1-yl)indazoles to give 5-(furopyridinon-5-yl)indazoles provided compounds with enhanced pharmacokinetic properties and improved efficacy. PMID- 20961757 TI - Sunnier days. PMID- 20961758 TI - Fukutin mutations in non-Japanese patients with congenital muscular dystrophy: less severe mutations predominate in patients with a non-Walker-Warburg phenotype. AB - Six genes including POMT1, POMT2, POMGNT1, FKRP, Fukutin (FKTN) and LARGE encode proteins involved in the glycosylation of alpha-dystroglycan (alpha-DG). Abnormal glycosylation of alpha-DG is a common finding in Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB), Fukuyama congenital muscular dystrophy (FCMD), congenital muscular dystrophy types 1C and 1D and some forms of autosomal recessive limb-girdle muscular dystrophy (LGMD2I, LGMD2K, LGMD2M), and is associated with mutations in the above genes. FCMD, caused by mutations in Fukutin (FKTN), is most frequent in Japan, but an increasing number of FKTN mutations are being reported outside of Japan. We describe four new patients with FKTN mutations and phenotypes ranging from: severe WWS in a Greek-Croatian patient, to congenital muscular dystrophy and cobblestone lissencephaly resembling MEB-FCMD in two Turkish patients, and limb-girdle muscular dystrophy and no mental retardation in a German patient. Four of the five different FKTN mutations have not been previously described. PMID- 20961759 TI - Prevalence, mutation spectrum and phenotypic variability in Norwegian patients with Limb Girdle Muscular Dystrophy 2I. AB - Mutations in the FKRP (Fukutin Related Protein) gene produce a range of phenotypes including Limb Girdle Muscular Dystrophy Type 2I (LGMD2I). In order to investigate the prevalence, the mutation spectrum and possible genotype-phenotype correlation, we studied a cohort of Norwegian patients with LGMD2I, ascertained in a 4-year period. In this retrospective study of genetically tested patients, we identified 88 patients from 69 families, who were either homozygous or compound heterozygous for FKRP mutations. This gives a minimum prevalence of 1/54,000 and a corresponding carrier frequency of 1/116 in the Norwegian population. Seven different FKRP mutations, including three novel changes, were detected. Seventy-six patients were homozygous for the common c.826C>A mutation. These patients had later disease onset than patients who were compound heterozygous - 14.0 vs. 6.1 years. We detected substantial variability in disease severity among homozygous patients. PMID- 20961760 TI - pH regulation and beyond: unanticipated functions for the voltage-gated proton channel, HVCN1. AB - Electrophysiological studies have implicated voltage-gated proton channels in several specific cellular contexts. In neutrophils, they mediate charge compensation that is associated with the oxidative burst of phagocytosis. Molecular characterization of the hydrogen voltage-gated channel 1 (HVCN1) has enabled identification of unanticipated and diverse functions: HVCN1 not only modulates signaling from the B-cell receptor following B-cell activation and histamine release from basophils, but also mediates pH-dependent activation of spermatozoa, as well as acid secretion by tracheal epithelium. The importance of HVCN1 in pH regulation during phagocytosis was established by surprising evidence that indicated its first-responder role. In this review, we discuss recent findings from a functional perspective, and the potential of HVCN1 as a therapeutic target for autoimmune and other diseases. PMID- 20961761 TI - Common themes in centriole and centrosome movements. AB - Centrioles are found in nearly all eukaryotic cells and are required for growth and maintenance of the radial array of microtubules, the mitotic spindle, and cilia and flagella. Different types of microtubule structures are often required at different places in a given cell; centrioles must move around to nucleate these varied structures. Here, we draw together recent data on diverse centriole movements to decipher common themes in how centrioles move. Par proteins establish and maintain the required cellular asymmetry. The actin cytoskeleton facilitates movement of multiple basal bodies. Microtubule forces acting on the cell cortex, and nuclear-cytoskeletal links, are important for positioning individual centrosomes, and during cell division. Knowledge of these common mechanisms can inform the study of centriole movements across biology. PMID- 20961762 TI - Autophagy: a broad role in unconventional protein secretion? AB - Autophagy, a cellular 'self-eating' process in eukaryotic cells, exists in both a basal and in an activated state that is induced in response to starvation. Basal and induced autophagy are associated with the packaging of cellular components, including damaged and/or redundant organelles, into double-membrane vesicles called autophagosomes, followed by autophagosome fusion with lysosomes, in which their contents are degraded and recycled. Recent results highlight a novel role for autophagy that does not involve lysosomal degradation of autophagosomal contents, but instead involves their redirection towards the extracellular delivery of an unconventionally secreted protein. Here, we discuss these findings, evaluate the strength of evidence, consider their implications for the field of protein trafficking, and suggest the next steps required to probe this interesting pathway. PMID- 20961763 TI - Effects of the Twin Shoe (Darco) to compensate height differences in normal gait. AB - BACKGROUND: After foot surgery or in diseases such as diabetes, orthopaedic shoes with an elevated sole construction are used to off-load the affected foot. The height difference between the shoes results in a leg length discrepancy and an abnormal gait pattern arises which can cause long-term discomfort in the joints of the lower extremity and the lower back. To compensate for this discrepancy and to ensure a symmetrical gait pattern a Twin Shoe (Darco) has been designed. AIM: To investigate the effect of wearing orthopaedic shoes in combination with the Twin Shoe on normal gait biomechanics. STUDY DESIGN: Cross-sectional study in a laboratory setting. METHODS: Normal gait was recorded in 15 healthy subjects with a gait analysis system. Four different shoe conditions were measured. Selected biomechanical parameters were calculated and compared between the shoe conditions. RESULTS: Walking in orthopaedic shoes with an elevated sole without compensation on the contralateral side leads to significant asymmetrical joint movements and higher loads in feet, knees, hips and the lower back during gait. By using the Twin Shoe these abnormal patterns were improved but not entirely compensated. CONCLUSIONS: Using the Twin Shoe as a partner to orthopaedic shoes with an elevated sole construction improves gait asymmetry and increased loading of joints induced by functional leg length discrepancy. PMID- 20961765 TI - Early surgical intervention in adult patients with ganglioglioma is associated with improved clinical seizure outcomes. AB - Gangliogliomas are rare central nervous system tumors, most commonly affecting children and young adults. Chronic seizure and epilepsy are the most frequent presentation of patients with gangliogliomas. In this report, we review the modern literature regarding the effects of early surgical intervention on the clinical outcome of patients with ganglioglioma. A boolean search of PubMed using key words "ganglioglioma", "adult", "seizure control", "treatment", "surgical intervention", and "observation", alone and in combination was performed. The inclusion criteria for articles were that: (i) clinical outcomes were reported specifically for gangliogliomas; (ii) data were reported for adult patients older than the age of 18 years; (iii) treatment data were included for the treatment of gangliogliomas; and (iv) ganglioglioma was the only pathological diagnosis for the evaluation of the tumor. Data were analyzed as a whole then stratified into two groups: early and late treatment intervention. The query identified a total of 99 articles including 1,089 cases of ganglioglioma meeting our inclusion and exclusion criteria. There was a 55% prevalence of males, representing a statistically significant predilection (51-59%, 95% confidence interval). Seizure control was significantly improved when surgical intervention occurred less than 3 years after symptom onset (78% versus 48%; p = 0.0001). Ganglioglioma in adults represents a rare group of tumors, and our systematic analysis suggests a higher prevalence in males. Our findings also support that an early surgical intervention is significantly associated with improved clinical seizure control. PMID- 20961764 TI - What is type VI secretion doing in all those bugs? AB - The identification of bacterial secretion systems capable of translocating substrates into eukaryotic cells via needle-like appendages has opened fruitful and exciting areas of microbial pathogenesis research. The recent discovery of the type VI secretion system (T6SS) was met with early speculation that it too acts as a 'needle' that pathogens aim at host cells. New reports demonstrate that certain T6SSs are potent mediators of interbacterial interactions. In light of these findings, we examined earlier data indicating its role in pathogenesis. We conclude that although T6S can, in rare instances, directly influence interactions with higher organisms, the broader physiological significance of the system is likely to provide defense against simple eukaryotic cells and other bacteria in the environment. The crucial role of T6S in bacterial interactions, along with its presence in many organisms relevant to disease, suggests that it might be a key determinant in the progression and outcome of certain human polymicrobial infections. PMID- 20961766 TI - Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents. AB - In previous studies, we identified promising anti-Trypanosoma cruzi cruzain inhibitors based on thiazolylhydrazones. To optimize this series, a number of medicinal chemistry directions were explored and new thiazolylhydrazones and thiosemicarbazones were thus synthesized. Potent cruzain inhibitors were identified, such as thiazolylhydrazones 3b and 3j, which exhibited IC(50) of 200 400nM. Furthermore, molecular docking studies showed concordance with experimentally derived structure-activity relationships (SAR) data. In the course of this work, lead compounds exhibiting in vitro activity against both the epimastigote and trypomastigote forms of T. cruzi were identified and in vivo general toxicity analysis was subsequently performed. Novel SAR were documented, including the importance of the thiocarbonyl carbon attached to the thiazolyl ring and the direct comparison between thiosemicarbazones and thiazolylhydrazones. PMID- 20961768 TI - Migration of strontium, cesium, and europium from poly(butyl acrylate)/phosphate/composites prepared using gamma radiation. AB - Composites based on natural phosphate powder and the monomer N-butyl acrylate have been prepared by means of gamma irradiation. The conversion of polymerization was followed up with respect to the irradiation dose using thermogravimetric analyzer (TGA). A total polymerization conversion was achieved by exposure of the samples to a dose of 10 kGy. A thermomechanical analyzer (TMA) was used to locate the region of the glass transition temperatures (T(g)) using the mode with alternative variable force; the mode with constant force was used to determine the T(g) of the pure polymer and the composite prepared at the same irradiation dose. The T(g) of the pure poly(butyl acrylate) is -51.41 degrees C, and the T(g) of poly(butyl acrylate)/phosphate/composites is -46.54 degrees C. The distribution of (137)Cs, (152)Eu, and (85)Sr in a solid-aqueous system, a composite of phosphate-polybutyl acrylate in contact with groundwater, was investigated using gamma-spectrometry. The effect of contact time, pH, and the concentration of concurrent elements (Na, Ca, and La) were studied. The results were compared with earlier results with phosphate alone in the solid phase. The ability of the produced composites to keep the studied radioisotopes in the solid phase is much higher than mineral phosphate. This improvement is more remarkable by strontium and cesium than europium, due to its high element ratio in the solid phase in phosphate experiments. PMID- 20961767 TI - Indeno[1,2-c]isoquinolin-5,11-diones conjugated to amino acids: Synthesis, cytotoxicity, DNA interaction, and topoisomerase II inhibition properties. AB - Three series of indeno[1,2-c]isoquinolin-5,11-dione-amino acid conjugates were designed and synthesized. Amino acids were connected to the tetracycle through linkers with lengths of n=2 and 3 atoms using ester (series I), amide (series II), and secondary amine (series III) functions. DNA binding was evaluated by thermal denaturation and fluorescence measurements. Lysine and arginine substituted derivatives with n=3 provided the highest DNA binding. Arginine derivative 32 (n=2, series II) and glycine derivative 34 (n=2, series III) displayed high topoisomerase II inhibition. Incrementing the length of the N-6 side chain from two to three methylene units provided a significant increase in DNA affinity but a substantial loss in topoisomerase II inhibition. The most cytotoxic compounds toward HL60 leukemia cells were 19, 33, and 34 displaying micromolar IC(50) values. When tested with the topoisomerase II-mutated HL60/MX2 cell line, little variation of IC(50) values was found, suggesting that topoisomerase II might not be the main target of these compounds and that additional targets could be involved. PMID- 20961769 TI - Abnormal chordae causing aortic and mitral regurgitation. PMID- 20961770 TI - Intraspinal K-wire migration after humeral fracture fixation. PMID- 20961771 TI - The efficacy of bipolar and multipolar radiofrequency ablation of lung neoplasms results of an ablate and resect study. AB - OBJECTIVE: Radiofrequency ablation (RFA) has obtained increasing attention as an interventional approach for the local treatment of primary and secondary lung neoplasms. The local effect of the procedure is usually controlled by radiologic means. The objectives of this 'ablate and resect' study were to investigate the efficacy of bipolar and multipolar RFA by histologic evaluation and to compare the two techniques. METHODS: In a total of 32 subjects with histologically proven non-small-cell lung cancer or pulmonary metastases from an extrathoracic primary tumor, bipolar, or multipolar RFA was performed during open thoracotomy. Curative resection (lobectomy or wedge resection including mediastinal lymph node dissection) was performed subsequently. The extent of cell death and early histologic findings following RFA were determined by histology and immunohistochemistry (nicotinamide adenine dinucleotide (NADH) and monoclonal anti-mitochondrial antibodies MAB 1273). RESULTS: Intra-operative bipolar and multipolar RFA is a safe procedure, and there was no bleeding or thermal damage of the lung tissue. Routine histologic staining could not identify tumor cell death. However, immunohistochemistry was able to verify cell death in the ablated tumor tissue. Complete tumor cell necrosis was determined in 12 tumors (37.5%); and scattered vital tumor tissue was detected in 16 tumors (50%). Incomplete ablation with a ratio of >20% vital tumor tissue was found in four tumors (12.5%), particularly surrounding vascular structures within the tumor tissue or in marginal zones of the tumor tissue. The local efficacy of bipolar and multipolar RFA was comparable, and incomplete ablations were found only in adenocarcinoma. CONCLUSIONS: Bipolar and multipolar RFA in an open thoracotomy setting is a technically feasible and safe procedure. Early immunohistochemical findings after RFA showed complete tumor cell necrosis in 38% of cases. The high rate of viable tumor cells remaining after ablation casts doubt on RFA as a curative concept. This approach should be reserved for palliative indications. Patients fulfilling the criteria for curative resection should not be denied surgery. PMID- 20961772 TI - Local iodine pleurodesis versus thoracoscopic talc insufflation in recurrent malignant pleural effusion: a prospective randomized control trial. AB - OBJECTIVE: To compare the efficacy, safety, and outcome of thoracoscopic talc poudrage (TTP) versus povidone-iodine pleurodesis (PIP) through a thoracostomy tube as a palliative treatment of pleural effusion due to metastatic breast carcinoma (MBC). METHODS: A total of 42 MBC patients were prospectively enrolled in a randomized controlled trial. Twenty-two patients received TTP (group A), whereas 20 patients (group B) underwent pleurodesis by instilling povidone-iodine through a thoracostomy tube, as a bedside procedure. RESULTS: The mean age was 48.2 +/- 9.9 (range: 29-64) years and 50.2 +/- 7 (range: 32-62) years for groups A and B, respectively (p=ns). At presentation, all patients had moderate to severe dyspnea, New York Heart Association (NYHA)>II and Medical Research Council (MRC) dyspnea scale 3-5. Morbidity in both groups was low. Post-procedure analgesic requirements due to severe pleuritic chest pain were higher in group A (18% vs 0%, p=0.2). Four patients in group A (18%) and one in group B (5%) were febrile (>38 degrees C) within 48 h of the procedure. Both groups achieved good symptom control, with improvement in MRC dyspnea scale (1-3). There were no in hospital deaths. Post-procedure hospital stay was lower in group B (p=0.009). The mean progression-free interval was 6.6 (range 3-15) months. At follow-up (mean: 22.6 (range: 8-48) months), recurrence of significant pleural effusion requiring intervention was noted in two and three patients in group A and group B, respectively (p=ns). CONCLUSION: Povidone-iodine can be considered as a good alternative to TTP to ensure effective pleurodesis for patients with malignant pleural effusion due to MBC. The drug is available, cost effective and safe, can be given through a thoracostomy tube and can be repeated if necessary. PMID- 20961773 TI - Muscle activation changes during body weight support treadmill training after focal cortical ischemia: A rat hindlimb model. AB - The study used a focal ischemia rat hindlimb model to investigate muscle activity changes during a 10-day body weight support (BWS) treadmill training program. The changes being studied included fatigue effects, EMG burst duration in the gait cycle, and the symmetry of muscle activation between affected and unaffected sides. Intramuscular EMG of medial gastrocnemius (MG) and tibialis anterior (TA) muscles in male Sprague Dawley rats at affected side (n=10) and unaffected side (n=10) were recorded during the treadmill running before a middle cerebral artery occlusion/reperfusion (MCAo/r) surgery and poststroke recovery stage. Behavioral test score and bodyweight were recorded at a daily basis after stroke. The mean power frequency (MPF) of the EMG, EMG burst duration in the gait cycle, and symmetry index between two sides were used for analysis. The drop rate of MPF of MG at the unaffected side increased (P<0.05) at poststroke day 2 and it generally decreased along the poststroke training days and almost returned to baseline value at poststroke day 6. Symmetry index of MG and TA showed a large imbalance right after stroke and tended to return to normal. Our findings of the MPF drop after stroke might indicate fatigue effects due to the compensation loading share of the ipsilateral side muscle and the increase of the symmetry index reflects abnormal gait pattern after the onset of stroke. The recovery rate after stroke could be investigated with EMG parameters together with the behavioral score, and both were improved during and after the BWS treadmill training. PMID- 20961774 TI - Drug-eluting tibial stents: objective patency determination. AB - PURPOSE: Endovascular management of limb-threatening ischemia often requires treatment of tibial occlusive disease. This study was preformed to examine the patency of drug-eluting tibial stents. MATERIALS AND METHODS: The medical records of all patients undergoing drug-eluting tibial stent placement for limb threatening ischemia from June 2004 to June 2008 were retrospectively reviewed. Postprocedural antiplatelet therapy included clopidogrel and aspirin. Patients were followed with serial arterial duplex ultrasonography and had selective subsequent angiographic evaluation based on noninvasive findings. Primary patency of the target lesion, limb salvage, and survival rates were reported. RESULTS: A total of 240 patients underwent 283 tibial angioplasty procedures to treat limb threatening ischemia during the 4-year period. Fifty-two patients (22%) had a suboptimal balloon result and were treated with a drug-eluting tibial stent. Balloon-expandable paclitaxel-eluting stents were used in all patients (1.2 stents per patient; range, 1-3; median diameter, 2.75 mm; range, 2.5-3.5 mm; median length, 24 mm; range, 20-32 mm). Forty-eight of those 52 patients (92%) had simultaneous endovascular treatment of proximal lesions. Mean follow-up was 14.3 months (range, 1-48 months). Target lesion patency of the drug-eluting tibial stent was 73% at 24 months (SE < 10%). Limb salvage rate in patients treated with drug-eluting tibial stents was 86% at 26 months (SE < 10%), and the survival rate was 65% at 24 months (SE < 10%). CONCLUSIONS: Drug-eluting tibial stents are a viable option for the endovascular management of limb-threatening ischemia and have acceptable patency rates. The majority of patients require multilevel endovascular treatment, and close surveillance is required for limb salvage. PMID- 20961775 TI - Urgent endovascular treatment of thoraco-abdominal aneurysms using a sandwich technique and chimney grafts--a technical description. AB - INTRODUCTION: So far the only endovascular option to treat patients with thoraco abdominal aortic aneurysms is the deployment of branched grafts. We describe a technique consisting of the deployment of standard off-the- shelf grafts to treat urgent cases. MATERIAL AND METHODS: The sandwich technique consists of the deployment of ViaBahn chimney grafts in combination with standard thoracic and abdominal aortic stent grafts. The chimney grafts are deployed using a transbrachial and transaxillary access. These coaxial grafts are placed inside the thoracic tube graft. After deployment of the infrarenal bifurcated abdominal graft a bridging stent-a short tube graft is positioned inside the thoracic graft further stabilizing the chimney grafts. RESULTS: 5 patients with symptomatic thoraco abdominal aneurysms were treated. There was one Type I endoleak that resolved after 2 months. In all patients 3 stentgrafts had to be used When possible all visceral and renal branches were revascularized. A total number of 17 arteries were reconnected with covered branches. During follow up we lost one target vessel the right renal artery. CONCLUSION: The sandwich technique in combination with chimney grafts permits a total endovascular exclusion of thoraco abdominal aortic aneurysms. In all cases off-the shelf products and grafts could be used. The number of patients treated so far is still too small to draw further more robust conclusions with regard to long term performance and durability. PMID- 20961776 TI - Selective arterial embolization for renal angiomyolipoma treating: the role of pain. PMID- 20961777 TI - Comments regarding 'A randomised placebo-controlled double-blind trial to evaluate lipid-lowering pharmacotherapy on proteolysis and inflammation in abdominal aortic aneurysms'. PMID- 20961778 TI - Recovery of Mycoplasma agalactiae from the ears of goats experimentally infected by the intramammary route. AB - The role of inapparent carriers of Mycoplasma agalactiae and the strategies used to colonise the external ear canal in goats remain unclear. This study examined the ability of M. agalactiae to colonise the ears of goats infected experimentally by the intramammary route. The right mammary glands of 15 lactating goats were inoculated with 10(10) colony forming units (cfu) of M. agalactiae. The goats were randomly assigned to three groups of five animals each and sampled at slaughter at 5, 15 or 45 days post-infection (dpi). A further four goats served as uninfected controls. Right and left ear swabs were collected for detection of M. agalactiae by culture before and after sacrifice. M. agalactiae was detected in 19/20 (95%) ear swabs from goats sampled at 15 and 45dpi, whereas all ear swabs collected before inoculation, ear swabs collected from the group sampled at 5dpi and ear swabs from control goats at the time of sacrifice were negative for M. agalactiae. Blood samples collected at 6, 12, 24, 48 and 72h post infection for detection of M. agalactiae by culture were also negative. There were differences in the antigenic profiles of isolates recovered from the ears compared to the 7MAG strain used to inoculate the animals and most isolates from the mammary gland, milk and supramammary lymph nodes. PMID- 20961779 TI - Hydration water dynamics in biopolymers from NMR relaxation in the rotating frame. AB - Assuming dipole-dipole interaction as the dominant relaxation mechanism of protons of water molecules adsorbed onto macromolecule (biopolymer) surfaces we have been able to model the dependences of relaxation rates on temperature and frequency. For adsorbed water molecules the correlation times are of the order of 10(-5)s, for which the dispersion region of spin-lattice relaxation rates in the rotating frame R(1)(rho)=1/T(1)(rho) appears over a range of easily accessible B(1) values. Measurements of T(1)(rho) at constant temperature and different B(1) values then give the "dispersion profiles" for biopolymers. Fitting a theoretical relaxation model to these profiles allows for the estimation of correlation times. This way of obtaining the correlation time is easier and faster than approaches involving measurements of the temperature dependence of R(1)=1/T(1). The T(1)(rho) dispersion approach, as a tool for molecular dynamics study, has been demonstrated for several hydrated biopolymer systems including crystalline cellulose, starch of different origins (potato, corn, oat, wheat), paper (modern, old) and lyophilized proteins (albumin, lysozyme). PMID- 20961780 TI - The effects of hyperglycemia on adrenal cortex function and steroidogenesis in the zebrafish. AB - Since the 1950s, scientists have attempted to characterize the relationship between diabetes mellitus (DM) and the hypothalamic-pituitary-adrenal (HPA) axis. Similar complications are seen in patients with diabetes and Cushing's syndrome, leading some to suggest that an underlying abnormality in the HPA axis may be responsible among those with DM. By inducing hyperglycemia in a zebrafish animal model, we show a direct correlation between glucose and cortisol levels. PMID- 20961781 TI - [What does it mean to be a development worker?]. PMID- 20961782 TI - [Need to approach the obesity in Asturias. Proposal of nursing actions in primary care]. AB - The number of people suffering from overweight and obesity has grown in Spain in recent years and the number of specialists warning us of an epidemic continues to rise. In 2006, the World Health Organization (WHO) raised the alarm in the European Charter on counteracting obesity. Two years later, a number of scientific societies and health organizations at international level agreed that obesity should be treated as a disease and vigorously approached. Asturias is not the exception; for instance between 2002 and 2008 the prevalence of morbid obesity increased from 0.4% to 5.1% in the community. In view of this data it seems essential to launch specific programmes to reverse this trend. In this work we will propose some measures that can be carried out at the primary care level in the public health service in order to offer quality and individualized care plans both to adult and children. First, the need of an exhaustive questionnaire on diet and physical activity to be included in the program of obesity of the clinical computerized history is suggested. Secondly, the Health Administration should promote specific courses on obesity, before the new obesity program was released. Thirdly, institutional publicising of Clinical Guidelines on obesity based on the scientific evidence is recommended so that health professionals are made aware of the importance of this disease. PMID- 20961783 TI - [Use of a faecal shunt system in an orthopaedic surgery unit in a patient with a necrotizing fasciitis of the perineal region]. AB - Necrotizing fasciitis is a severe infection of the subcutaneous tissue, with a higher mortality if treatment is not adequate. Nursing care can be fundamental in obtaining a good outcome of the healing process. We present a case of an 80 year old diabetic patient admitted to our orthopaedic surgery unit as consequence of a screw displacement in her hip. She was operated on and had to be immobilized during the postsurgical period. Measures were applied to prevent bed sores in the sacral region. Despite these measures the patient developed a pressure sore that became infected, progressing to a necrotizing fasciitis of perineal and bulbar region, which required surgical curettage. Due to contact and exposure to faecal material it was decided to use a faecal shunt system. The number and difficulty of the wound treatments decreased using this system, which had significant advantages for the patient and nurses and for a favourable outcome of the wound. Employing faecal shunt systems could be useful when they are used earlier in patients immobilized due to orthopaedic surgery, with bowel movement changes and bed sore wounds. PMID- 20961785 TI - [Appearance of anti-red blood cell antibodies in 80 years old and over transfused patients: result of 3 years haemovigilance survey]. AB - PURPOSE: Today most transfusions are given to people over 70. In order to evaluate the production and the circumstances of the appearance of red blood cells (RBC) allo-antibodies (Ab), a three-year study was performed in transfused patients aged 80 and over. MATERIAL AND METHODS: Based on the Adverse Event Reports (AER) on RBC Ab from 2007 to 2009 in the Rhone-Alpes area, the prevalence and specificity of the RBC Ab, the type of blood component involved, the imputability and the previous transfusion and obstetrical history were studied. RESULTS: Of 2,169 AER, 240 (11.1%) related to the appearance of RBC Ab; they included 150 females (F) patients (62.5%) and 90 males (M) (37.5%). The Rhesus (RH) blood group was most involved (75 AER) and anti-E was the most frequent Ab (52 cases; 69.3%). Packed RBC were predominantly involved (233 cases; 97,1%). Absolute imputability could be established in 120 cases only (50.0%). Previous transfusion history was observed in 85 F patients (56.7%) and 52M (57.8%). Pretransfusion Ab was noted in 18 F patients (12.0%) and five M (5.6%). Seventy three F patients (48.7%) had had a pregnancy but the number of unknown data was high (71 F patients; 47.3%). CONCLUSION: In the transfused patient population aged 80 and over, RBC Ab are common and in most cases are due to RBC transfusions. On the contrary, pretransfusion RBC Ab are not frequent. PMID- 20961784 TI - Comparisons of anemia, thrombocytopenia, and neutropenia at initiation of HIV antiretroviral therapy in Africa, Asia, and the Americas. AB - BACKGROUND: Hematological abnormalities are common manifestations of advanced HIV 1 infection that could affect the outcomes of highly-active antiretroviral therapy (HAART). Although most HIV-1-infected individuals live in resource constrained countries, there is little information about the frequency of hematological abnormalities such as anemia, neutropenia, and thrombocytopenia among individuals with advanced HIV-1 disease. METHODS: This study compared the prevalence of pre-antiretroviral therapy hematological abnormalities among 1571 participants in a randomized trial of antiretroviral efficacy in Africa, Asia, South America, the Caribbean, and the USA. Potential covariates for anemia, neutropenia, and thrombocytopenia were identified in univariate analyses and evaluated in separate multivariable models for each hematological condition. RESULTS: The frequencies of neutropenia (absolute neutrophil count <=1.3*109/l), anemia (hemoglobin <=10g/dl), and thrombocytopenia (platelets <=125*109/l) at initiation of antiretroviral therapy were 14%, 12%, and 7%, respectively, and varied by country (p<0.0001 for each). In multivariable models, anemia was associated with gender, platelet count, and country; neutropenia was associated with CD4+ lymphocyte and platelet counts; and thrombocytopenia was associated with country, gender, and chronic hepatitis B infection. CONCLUSIONS: Differences in the frequency of pretreatment hematological abnormalities could have important implications for the choice of antiretroviral regimen in resource-constrained settings. PMID- 20961786 TI - Antenatal Rh prophylaxis is unnecessary for "Asia type" DEL women. AB - BACKGROUND: Generally Rh-negative patients need to be transfused with Rh-negative red blood cells. For pregnant women carrying Rh-positive fetus, the antenatal anti-D detection and Rh immunoglobulin prophylaxis are required worldwide. In East Asia, a RhD variant, termed "Asia type" DEL, was found in approximately 30% of apparent Rh-negative individuals. The antigenic and molecular properties of the DEL were previously defined. Few data discuss whether DEL could be immunized by D antigen clinically although DEL was reported arousing alloimmunization to true Rh-negative patients. STUDY DESIGN AND METHODS: To determine whether the DEL variant can be immunized to the D antigen, we retrospectively evaluated 104 Rh negative pregnancies with allo-anti-D antibodies, and we also tracked 199 consecutive apparent Rh-negative pregnant women, with a history of gestations or parturitions but not subject to anti-D gamma-globulin prophylaxis, for evidence of allo-anti-D. The DEL variant was first excluded by ccee phenotypes and then identified through PCR analysis or sequencing. RESULTS: In the retrospective study, we expected to find 30 DEL variants, yet none of the anti-D alloimmunized women were DEL-positive. And in the second group, none of 44 DEL-positive women versus 38 of 155 (24.5%) true Rh-negative women (those excluding DEL) formed allo anti-D. CONCLUSION: The data indicate that the "Asia type" DEL variant does not appear at risk of alloimmunization to the D antigen. It strongly suggests that the antenatal Rh immune globulin prophylaxis is unnecessary for DEL women. Furthermore, it implicates that the "Asia type" DEL may be deemed Rh-positive safely for clinical transfusion therapy. PMID- 20961787 TI - [Occurrence of severe, persistent thrombocytopenia following allogeneic bone marrow transplantation, attributable to anti-HPA-1 allo-immunisation of the host]. AB - A 56 year-old, multiparous woman suffering from a myeloproliferative syndrome, who had received multiple red blood cell and platelet transfusions, was the recipient of an allograft of peripheral blood stem cells derived from her HLA-A, B, DR, DQ and DP and ABO identical sister, following myeloablative conditioning. The persistence of severe, isolated thrombopenia resistant to platelet transfusions led to the discovery of anti-HLA class I allo-immunisation. As HLA compatible platelet transfusions did not result in satisfactory platelet increments, we then discovered the simultaneous presence of anti-HPA-1a allo immunisation. Genotyping of the HPA-1 systems of the patient (HPA-1B/B) and her sister (HPA-1A/B) enabled us to elucidate the mechanism underlying the persistent thrombopenia and the inefficacy of transfusion. In fact, only transfusion of HPA 1B/B platelets (HLA compatible or incompatible) proved to be efficacious. To reduce the level of anti-HPA-1a antibodies, we performed plasmapheresis sessions and used an anti-CD20 monoclonal antibody. It was only on achieving total haematopoietic chimerism, through rapid interruption of the immunosuppression, that we obtained spontaneous normalisation of the platelet count. The present case emphasises the necessity, before undertaking any allograft of haematopoietic stem cells - even if the latter come from a strictly HLA identical member of the family - of performing a search for eventual anti-HPA allo-immunisation. PMID- 20961788 TI - Multiple transfusions for sickle cell disease in the Democratic Republic of Congo: the importance of the hepatitis C virus. AB - BACKGROUND AND OBJECTIVES: Improvement of transfusion security in sub-Saharan countries requires the determination of priorities taking into account the specific context. PATIENTS AND METHODS: One hundred and forty patients with sickle cell disease (SCD) from one clinical centre for SCD in Kisangani, DRC were tested for HBsAg, anti-HIV antibodies, anti-HCV antibodies and for alloantibodies against red blood cells and human leucocyte antigens (HLA). RESULTS: Thirteen patients had not been transfused and were free of HBV, HIV or HCV infection. HBV, HIV and HCV infections were detected in 2/127 (1.6%), 1/127 (0.9%) and 10/127 (7.9%) transfused patients, respectively. All ten cases of HCV infection were associated with patients who had transfusions prior to the introduction of HCV testing in 2004 (P=0.043). Red blood cells and HLA alloantibodies were detected in 13/127 (10%) and 2/127 (1.6%), respectively. CONCLUSION: HCV testing should be a priority. The rhesus (Rh) phenotype, mainly the RhD antigen and the Kell antigen should be assessed in SCD patients. Further extended phenotyping and deleucocytation should not be considered as priorities. PMID- 20961789 TI - [Frequency of red blood cell alloimmunization in polytransfused patients at the university teaching hospital of Point G, Bamako, Mali]. AB - This prospective study conducted within 9 months period aimed to determine the frequency of red cell alloimmunization among polytransfused patients of the medical Hematology and oncology ward, and the unit of hemodialysis of the Nephrology ward at the Point-G hospital. Irregular red blood cell antibody screening and identification were performed by gel-filtration method using indirect antiglobulin test and enzymatic treated cells. We did not use saline medium. A total of 78 patients were included in this study. The mean age of the patients was 36.78+/-14.73 years (range: 11 and 77 years). The sex ratio was of 1.11 in favour of the women. The mean blood units transfused were 12.21+/-9.99 units (range: 4 and 45 units). The Rhesus phenotypes Dccee, DccEe and DCcee were most predominant, with the respective frequencies of 67.9, 15.4 and 10.3%. Kell antigen was found at a frequency of 1.28%. The total rate of red cell alloimmunization was 10.3%. There was no significant difference between the two wards. All the screened agglutinins were warm antibodies belonging to the Rhesus system: anti-E (7.7%), anti-C (1.3%) and anti-D (1.3%). Only Anti-E was present among hematologic patients. We did not find a significant link between the sex, the age, the number of blood units transfused and the positivity of the antibody screening. We conclude that the frequency of post-transfusional alloimmunization is high among polytransfused patients in Mali. A systematic antibody screening among these patients and the selection of red cells with known Rhesus/Kell phenotypes would allow an optimal blood transfusion safety. PMID- 20961790 TI - Current treatments for juvenile idiopathic arthritis. AB - Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, most of which differ from the main adult-onset inflammatory joint diseases. Nonsystemic forms of JIA (oligoarthritis, polyarthritis with or without rheumatoid factors, and spondyloarthropathies) are managed similarly to adult-onset rheumatoid arthritis or spondylarthritis, with a few differences. More specifically, JIA associated chronic uveitis may require the use of biotherapies that remain experimental in JIA, such as monoclonal antibodies to TNFalpha or abatacept. International networks have enabled therapeutic trials of medications targeting TNFalpha alpha, interleukin (IL)-1, IL-6, or T-cell co-stimulation (abatacept). Systemic-onset JIA (also called childhood-onset Still's disease) raises specific treatment challenges and may require treatment with IL-1 antagonists, tocilizumab, or even thalidomide; as a very last resort, intensive immunosuppressant therapy with autologous hematopoietic stem-cell transplantation may be considered. Close monitoring of growth velocity and bone mass accrual is in order, and some patients require additional medications such as growth hormone. Patients with JIA should be managed in specialized centers that have coordinated chains of care for the entire pediatric period and into adulthood. In addition, the use in pediatric patients of recently introduced treatments requires close monitoring for long-term side effects. PMID- 20961791 TI - Cell and cytokine imbalances in rheumatoid synovitis. AB - Rheumatoid synovitis is a complex process in which systemic and local homeostatic dysregulation is expressed in the joint. The main genetic susceptibility factors are HLA-DRB1 alleles containing the shared epitope. Environmental factors predominate over genetic factors in the pathogenesis of rheumatoid arthritis (RA), and among them smoking is the most powerful. In RA, disruptions in self tolerance lead to abnormalities such as recognition of citrullinated antigens by B and T cells. The balance of lymphocyte differentiation in RA is skewed toward the Th1 phenotype, to the detriment of the Th2, Th17, and T regulator (Treg) phenotypes. Imbalances occur in the main cytokine systems including IL-1, TNF, IL 6, IL-18, IL-15, IL-33, IL-22, and IL-13. The joint destruction seen in RA is caused not only by these cytokine imbalances, but also by specific effects of the Wnt system and osteoprotegerin on osteoclasts and by matrix production dysregulation responsible for cartilage damage. PMID- 20961792 TI - Rheumatology drugs and pregnancy. AB - Medication exposure during pregnancy, especially in the first trimester, is a common event that causes considerable concern among patients and healthcare professionals alike. Once the pregnancy is known, the response often consists in stopping or substantially diminishing the use of medications. Some medications are teratogenic and/or fetotoxic, requiring effective birth control and prior information of women of childbearing potential. Nevertheless, limiting the use of medications out of a sense of caution is warranted only if no major adverse impact on the mother is expected throughout the 9 months of the pregnancy. Treatment decisions during pregnancy should rest on a careful reappraisal of treatment practices and on an in-depth evaluation of the risk/benefit ratio of each medication. Here, we will discuss the main rheumatology drug classes whose use during pregnancy is most likely to cause concern. PMID- 20961793 TI - Shoulder arthroplasty: evolving techniques and indications. AB - The development of modern shoulder replacement surgery started over half a century ago with the pioneering work done by CS Neer. Several designs for shoulder prostheses are now available, allowing surgeons to select the best design for each situation. When the rotator cuff is intact, unconstrained prostheses produce reliable and reproducible results, with prosthesis survival rates of 97% after 10 years and 84% after 20 years. In patients with three- or four-part fractures of the proximal humerus, the outcome of shoulder arthroplasty depends largely on healing of the greater tuberosity, which is therefore a major treatment objective. Factors crucial to greater tuberosity union include selection of the optimal prosthesis design, flawless fixation of the tuberosities, and appropriate postoperative immobilization. The reverse shoulder prosthesis developed by Grammont has been recognized since 1991 as a valid option for patients with glenohumeral osteoarthritis. Ten-year prosthesis survival rates are 91% overall (including trauma and revisions) and 94% for glenohumeral osteoarthritis with head migration. These good results are generating interest in the reverse shoulder prosthesis as a treatment option in situations where unconstrained prostheses are unsatisfactory (primary glenohumeral osteoarthritis with marked glenoid cavity erosion; comminuted fractures in patients older than 75 years; post-traumatic osteoarthritis with severe tuberosity malunion or nonunion; massive irreparable rotator cuff tears with pseudoparalysis; failed rotator cuff repair; and proximal humerus tumor requiring resection of the rotator cuff insertions). PMID- 20961794 TI - Role for toll-like receptors in autoimmune disease: the example of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a multisystem disease characterized by an autoimmune response to nuclear antigens. Although the pathophysiology of SLE remains incompletely understood, many recent studies indicate a major role for innate immunity. The toll-like receptors (TLRs), which play a key role in innate responses to infections, are also involved in acute and chronic inflammatory processes induced by endogenous ligands. Numerous in vitro studies have established that TLR7 and TLR9 are involved in immune complex recognition. Activation of these receptors leads to activation of immune cells, most notably B cells and dendritic cells, and to the inappropriate production of many cytokines known to be directly involved in the pathogenesis of SLE. These data prompted studies in several murine models of SLE to assess the impact of inactivation or overexpression of genes encoding TLRs or molecules involved in TLR signaling pathways. The results confirmed the major role for TLR7 and suggested involvement of TLR4 in the induction of an aggressive autoimmune response. However, in vivo data suggest a protective effect of TLR9, thus contradicting the in vitro results. In humans, genetic studies have identified polymorphisms associated with increased susceptibility to SLE. PMID- 20961795 TI - Chronic ankle instability and common fibular nerve injury. AB - The lateral collateral ligaments of the ankle are often damaged in ankle inversion injuries. Ankle inversion may also cause injury to other structures located around the ankle or further away, such as the common fibular nerve. Few descriptions exist of common fibular nerve injury associated with ankle sprains and chronic ankle instability. We describe the case of a patient who sustained common fibular nerve injury during each of two ankle sprain recurrences involving the lateral collateral ligaments. Our objectives are to illustrate the links between common fibular nerve and lateral collateral ligament injuries and to emphasize the importance of the neurological evaluation in patients seen for ankle sprains or chronic ankle instability. PMID- 20961796 TI - Simulation of abdominal aortic aneurysm growth with updating hemodynamic loads using a realistic geometry. AB - Advances in modeling vascular tissue growth and remodeling (G&R) as well as medical imaging usher in a great potential for integrative computational mechanics to revolutionize the clinical treatment of cardiovascular diseases. A computational model of abdominal aortic aneurysm (AAA) enlargement has been previously developed based on realistic geometric models. In this work, we couple the computational simulation of AAA growth with the hemodynamics simulation in a stepwise, iterative manner and study the interrelation between the changes in wall shear stress (WSS) and arterial wall evolution. The G&R simulation computes a long-term vascular adaptation with constant hemodynamic loads, derived from the previous hemodynamics simulation, while the subsequent hemodynamics simulation computes hemodynamic loads on the vessel wall during the cardiac cycle using the evolved geometry. We hypothesize that low WSS promotes degradation of elastin during the progression of an AAA. It is shown that shear stress-induced degradation of elastin elevates wall stress and accelerates AAA enlargement. Regions of higher expansion correlate with regions of low WSS. Our results show that despite the crucial role of stress-mediated collagen turnover in compensating the loss of elastin, AAA enlargement can be accelerated through the effect of WSS. The present study is able to account for computational models of image-based AAA growth as well as important hemodynamic parameters with relatively low computational expense. We suggest that the present computational framework, in spite of its limitations, provides a useful foundation for future studies which may yield new insight into how aneurysms grow and rupture. PMID- 20961797 TI - Differences in neighborhood accessibility to health-related resources: a nationwide comparison between deprived and affluent neighborhoods in Sweden. AB - This nationwide Swedish study used geocoded data from all businesses in Sweden to examine the distribution of 12 main categories of goods, services, and resources in 6986 neighborhoods, categorized as low, moderate, and high neighborhood deprivation. The main findings were that high- and moderate-deprivation neighborhoods had a significantly higher prevalence of all types of goods, services, and resources than low-deprivation neighborhoods. These findings do not support previous research that hypothesizes that poorer health among people in deprived neighborhoods is explained by a lack of health-promoting resources, although a higher presence of health-damaging resources may play a role. PMID- 20961798 TI - Space, structure and social dynamics within the clinical setting: two case studies of assisted reproduction in Mexico City. AB - Drawing on the concept of therapeutic environments and comparing two case studies, this paper explores the interaction between the spatial factors of the clinical setting, the structural elements of the health system, and the specific treatment requirements of assisted reproduction in order to see the type and degree of privacy and accessibility, as well as the particular social dynamics (i.e. patient-physician and among patients) fostered in two Mexico City fertility clinics. Both cases suggest that certain types of therapeutic environments encourage the formation of spontaneous support groups while others favour the patient-physician relationship. PMID- 20961799 TI - Patatin-related phospholipase A: nomenclature, subfamilies and functions in plants. AB - The release of fatty acids from membrane glycerolipids has been implicated in a variety of cellular processes, but the enzymes involved and their regulation are poorly understood in plants. One large group of acyl-hydrolyzing enzymes is structurally related to patatins. Patatins are potato tuber proteins with acyl hydrolyzing activity, and the patatin catalytic domain is widely spread in bacterial, yeast, plant and animal enzymes. Recent results have indicated that patatin-related enzymes are involved in different cellular functions, including plant responses to auxin, elicitors or pathogens, and abiotic stresses and lipid mobilization during seed germination. In this review, we highlight recent developments regarding these enzymes and propose the nomenclature pPLA for the patatin-related phospholipase A enzyme. PMID- 20961800 TI - Defining the boundaries: structure and function of LOB domain proteins. AB - The plant-specific LBD (Lateral Organ Boundaries Domain) gene family is essential in the regulation of plant lateral organ development and is involved in the regulation of anthocyanin and nitrogen metabolism. LBD proteins contain a characteristic LOB domain composed of a C-motif required for DNA-binding, a conserved glycine residue, and a leucine-zipper-like sequence required for protein-protein interactions. Recently, several LBD genes associated with mutant phenotypes related to almost all aspects of plant development, including embryo, root, leaf, and inflorescence development have been functionally characterized. These novel insights contribute to a better understanding of the molecular definition of boundaries between organs or boundaries between organs and meristems and the regulation of these processes by environmental cues and phytohormones. PMID- 20961801 TI - The effect of Cu2+ or Fe3+ on the noncovalent binding of rutin with bovine serum albumin by spectroscopic analysis. AB - The interaction of rutin to bovine serum albumin (BSA) in aqueous solution was investigated by fluorescence spectra and ultraviolet-visible (UV-vis) spectra at pH 7.40. There are also some metal ions present in blood plasma, thus the research about the effect of metal ions on the interaction of drugs with proteins is crucial. Therefore, we have studied the effect of Cu2+ or Fe3+ on the interaction between rutin and BSA by using spectroscopic technique at pH 7.40, for the first time. The results of fluorescence titration indicated that rutin could quench the intrinsic fluorescence of BSA in a static quenching way. The binding sites number (n), the binding constant (K) and the spatial-distance (r) of rutin with BSA without or with Cu2+ or Fe3+ at 310 K were calculated. The result showed that the presence of Cu2+ or Fe3+ increased the binding constant and changed the binding distance between the acceptor and the donor, which possibly results from the formation of metal ions-BSA complex. The effect of rutin on the conformation of BSA was also analyzed using UV under experimental conditions. Furthermore, the fluorescence displacement experiments indicated that rutin is situated within subdomain IIA of BSA. PMID- 20961802 TI - FT NIR Raman studies of alginic acid-benzimidazole polymer composite. AB - New bio-inspired polymer composites of alginic acid and benzimidazole were created and characterized by FT NIR Raman spectroscopy. The obtained films with 1:0.5, 1:1 and 1:1.5 molar ratio are homogeneous, with good mechanical properties. Raman spectra recorded at room temperature revealed that the obtained films are a new compound with a different molecular structure and physical properties compared with pure substrates: alginic acid and benzimidazole. Raman band related to vibration of COOH entity at 1740 cm(-1) of alginic acid disappears in the alginic acid:benzimidazole composites, in which new Raman band related to COO(-) was found. Additionally, characteristic lines observed in polymer composites which may be associated with vibrations of NH groups, can be attributed to the linking of proton to deprotonated N atom in benzimidazole group. Possibility of such proton exchange is a promising property which might facilitate the application of obtained composites to anhydrous proton conducting electrolytes in fuel cells. PMID- 20961803 TI - Perceived efficiency impacts following electronic health record implementation: an exploratory study of an urban community health center network. AB - PURPOSE: Faced with an increasingly complex patient population and growing demand for services, community health centers (CHCs) are recognizing that electronic health records (EHRs) may help their efforts to improve efficiency in care delivery. Yet little is known about the benefits, challenges, and specific impacts of EHR implementation in the often resource-constrained CHC environment, especially from users' perspectives. The objective of this study was to explore EHR users' perspectives about the EHR implementation process and impact in a CHC network. METHODS: We performed an exploratory case study following EHR implementation in a multi-site, urban CHC network. Data were collected through semi-structured interviews with 39 key informants across four sites. Key informants included physicians, clinical staff and administrators. We used both deductive and inductive approaches to code the transcribed interview data and to identify themes in our analyses. RESULTS: A key theme that emerged involved perceptions of efficiency related to the EHR implementation. While the EHR was widely credited with improving the efficiency of several clinical processes (e.g., lab ordering), it also created new challenges. Some of the early efficiency challenges we identified were common to EHR implementation in general (e.g., system interface issues), but others were unique to the CHC context (e.g., issues related to compliance with complex regulatory and reporting requirements). Further, constrained organizational resources for training and ongoing IT support were widely noted as challenges that may have exacerbated, or precluded early resolution of, efficiency issues. While limited to a single CHC network, our findings highlight important issues for CHCs to consider about EHRs. CONCLUSIONS: These findings suggest that CHCs face difficult and often unique barriers related to EHR implementation and use, and the resultant efficiency impacts should not be overlooked. PMID- 20961804 TI - Do the early attentional components of ERPs reflect attentional bias in depression? It depends on the stimulus presentation time. AB - OBJECTIVE: The study aimed to utilize behavioral and electrophysiological data to investigate whether depressed patients show an attentional bias in a task that allows for explicit insight into the time course of selective attention processes. METHODS: Event-related potentials (ERPs) were collected from 24 patients with major depressive disorder (MDD) and 25 never-depressed individuals (ND) during a dot-probe task, using pairs of affectively valenced pictures as cues. Cue presentation time was either 100 ms or 500 ms. RESULTS: When the cue presentation time was 500 ms, bias scores for positive-neutral picture pairs (POS NEU) were negative for the MDD group and positive for the ND group which means ND individuals were able to successfully select positive information. These behavioral effects were supported by ERP results. In the ND group, at the right parietal-occipital region, P1 amplitude during valid POS-NEU pairs was significantly larger than that during invalid POS-NEU pairs; this pattern did not appear in the MDD group. CONCLUSIONS: These results suggest that MDD patients are characterized by a deficit in protection bias, meaning that these participants cannot avoid attending to negative information in their environment, but only when negative stimuli are presented for a sufficient period of time. SIGNIFICANCE: Attentional bias is modulated by duration of emotional pictures presentation in depression. PMID- 20961805 TI - Somatosensory evoked fields by tactile-off stimulation. PMID- 20961806 TI - Quantitative EEG in ischemic stroke: correlation with functional status after 6 months. AB - OBJECTIVE: Stroke is a major cause of adult-onset disability and dependency. We investigated whether EEG parameters are of prognostic value for functional outcome 6 months after ischemic stroke. METHODS: One-hundred and ten patients presenting with acute ischemic stroke and persistent neurological deficits at EEG recording were incrementally included. Clinical characteristics, volume of ischemia and EEG parameters were correlated with functional outcome assessed with the modified Rankin Scale (mRS) score. Predictive values for disability, dependency and death were calculated using receiver operating characteristic (ROC) curves and logistic regression modeling. RESULTS: The EEG pairwise derived Brain Symmetry Index (pdBSI) and (delta+theta)/(alpha+beta) ratio (DTABR) were significantly correlated with the modified Rankin Scale (mRS) score at month 6 (Spearman rho=0.46 and rho=0.47, respectively, p<0.0005 for both). NIHSS (OR 1.15, 95% CI 1.04-1.27, p=0.005) and pdBSI (OR 4.07, 95% CI 1.32-12.58, p=0.015) were independently associated with disability 6 months after stroke. Dependency was independently indicated by NIHSS (OR 1.22, 95% CI 1.09-1.37, p<0.0005) and DTABR (OR 2.25, 95% CI 1.16-4.37, p=0.016). Six month mortality was independently indicated by age at stroke onset (OR 1.18, 95% CI 1.05-1.32, p=0.007), NIHSS (OR 1.11, 95% CI 1.03-1.21, p=0.009) and DTABR (OR 2.04, 95% CI 1.08-3.85, p=0.028). CONCLUSIONS: EEG in the subacute setting of ischemic stroke may be of prognostic value for disability, dependency and death after 6 months. SIGNIFICANCE: Early prognostication of functional outcome after stroke is relevant to efficient rehabilitation management to enhance recovery and minimize long-term disability. PMID- 20961808 TI - Prevalence of restless legs syndrome among adults in Iceland and Sweden: Lung function, comorbidity, ferritin, biomarkers and quality of life. AB - OBJECTIVE: This study investigates the prevalence and the association between restless legs syndrome (RLS) and a large variety of health variables in two well characterized random samples from the general population in Reykjavik, Iceland, and Uppsala, Sweden. METHODS: Using the national registries of inhabitants, a random sample from adults aged 40 and over living in Reykjavik, Iceland (n=939), and Uppsala, Sweden (n=998), were invited to participate in a study on the prevalence of COPD (response rate 81.1% and 62.2%). In addition, the participants were asked to answer the following questionnaires: International RLS Rating Scale, Short Form-12, the Epworth Sleepiness Scale, and questions about sleep, gastroeosophageal reflux, diabetes and hypertension, as well as pharmacological treatment. Interleukin-6 (IL-6), C-reactive protein (CRP) and ferritin were measured in serum. RESULTS: RLS was more commonly reported in Reykjavik (18.3%) than in Uppsala (11.5%). Icelandic women reported RLS almost twice as often as Swedish women (24.4 vs. 13.9% p=0.001), but there was no difference in prevalence of RLS between Icelandic and Swedish men. RLS was strongly associated with sleep disturbances and excessive daytime sleepiness. Subjects with RLS were more likely to be ex- and current smokers than subjects without RLS (p<0.001). Respiratory symptoms and airway obstruction were more prevalent among those reporting RLS and they also estimated their physical quality of life lower than those without RLS (p<0.001). RLS was not associated with symptoms of the metabolic syndrome like hypertension, obesity, markers of systemic inflammation (IL-6 and CRP) or cardiovascular diseases. Ferritin levels were significantly lower in RLS participants (p=0.0002), but not (p=0.07) after adjustment for center, age, sex and smoking history. CONCLUSION: Restless legs syndrome was twice as common among Icelandic women compared to Swedish women. No such difference was seen for men. RLS was strongly associated with smoking and respiratory symptoms, decreased lung function, sleep disturbances, excessive daytime sleepiness, and physical aspects of life quality. RLS was not associated with markers of the metabolic syndrome like hypertension, obesity, cardiovascular diseases or biomarkers of systemic inflammation. PMID- 20961809 TI - Sleep disorders and accidental risk in a large group of regular registered highway drivers. AB - OBJECTIVE: Despite convincing evidence regarding the risk of highway accidents due to sleepiness at the wheel, highway drivers still drive while sleepy. Sleep disorders can affect driving skills, but the relative impact of sleep complaints among a large population of highway drivers is still unknown. METHODS: Out of 37,648 questionnaires completed by frequent highway users (registered in an electronic payment system), we ran our analyses on 35,004 drivers who responded to all items. The questionnaire previously used in a telephone survey included socio-demographics, driving and sleep disorders items (Basic Nordic Sleep Questionnaire) and the Epworth Sleepiness Scale. RESULTS: Of all drivers, 16.9% complained of at least one sleep disorder, 5.2% reported obstructive sleep apnea syndrome, 9.3% insomnia, and 0.1% narcolepsy and hypersomnia; 8.9% of drivers reported experiencing at least once each month an episode of sleepiness at the wheel so severe they had to stop driving. One-third of the drivers (31.1%) reported near-miss accidents (50% being sleep-related), 2520 drivers (7.2%) reported a driving accident in the past year, and 146 (5.8%) of these driving accidents were sleep-related. The highest risk of accidents concerned patients suffering from narcolepsy and hypersomnia (odds ratio 3.16, p<.01) or multiple sleep disorders (odds ratio 1.46, p<.001). Other major risk factors were age [18 30 years (OR 1.42, p<.001)] and being unmarried (OR 1.21-fold, p<.01). CONCLUSIONS: In regular highway drivers, sleepiness at the wheel or sleep disorders such as hypersomnia and narcolepsy are responsible for traffic accidents independent of age, sex, marital status or socio-professional categories. PMID- 20961810 TI - Production of various disinfection byproducts in indoor swimming pool waters treated with different disinfection methods. AB - In this study, the concentrations of disinfection byproducts (DBPs), including trihalomethanes (THMs; chloroform, bromodichloromethane, dibromochloromethane, and bromoform), haloacetic acids (HAAs; dichloroacetic acid and trichloroacetic acid), haloacetonitriles (HANs; dichloroacetonitrile, trichloroacetonitrile, bromochloroacetonitrile, and dibromoacetonitrile), and chloral hydrate (CH) were measured in 86 indoor swimming pools in Seoul, Korea, treated using different disinfection methods, such as chlorine, ozone and chlorine, and a technique that uses electrochemically generated mixed oxidants (EGMOs). The correlations between DBPs and other environmental factors such as with total organic carbon (TOC), KMnO(4) consumption, free residual chlorine, pH, and nitrate (NO(3)(-)) in the pools were examined. The geometric mean concentrations of total DBPs in swimming pool waters were 183.1+/-2.5MUg/L, 32.6+/-2.1MUg/L, and 139.9+/-2.4MUg/L in pools disinfected with chlorine, ozone/chlorine, and EGMO, respectively. The mean concentrations of total THMs (TTHMs), total HAAs (THAAs), total HANs (THANs), and CH differed significantly depending on the disinfection method used (P<0.01). Interestingly, THAAs concentrations were the highest, followed by TTHMs, CH, and THANs in all swimming pools regardless of disinfection method. TOC showed a good correlation with the concentrations of DBPs in all swimming pools (chlorine; r=0.82, P<0.01; ozone/chlorine; r=0.52, P<0.01, EGMO; r=0.39, P<0.05). In addition, nitrate was positively correlated with the concentrations of total DBPs in swimming pools disinfected with chlorine and ozone/chlorine (chlorine; r=0.58; ozone/chlorine; r=0.60, P<0.01), whereas was negative correlated with the concentrations of total DBPs (r=-0.53, P<0.01) in the EGMO-treated pools. PMID- 20961811 TI - Symptom management in oncology care - where are we? PMID- 20961812 TI - Clinical application of therapeutic plasma exchange in the Three Gorges Area. AB - OBJECTIVE: To analyze the clinical effect of therapeutic plasma exchange (TPE) on 43 patients in the Three Gorges Area. METHODS: Plasma was collected by machine and combined with low-molecular-weight dextran and albumin for use as a replacement fluid for TPE treatment of 43 patients suffering from various blood disorders, diseases of the nervous system, ABO incompatible allogeneic hematopoietic stem cell transplantation and kidney disease. RESULTS: The volume of a single TPE was 1.6-2.0l, performed on average 2.3 times/case, and effective in 88.4% (38/43) of cases. CONCLUSION: TPE through the plasma collection machine is a well tolerated, economic and effective treatment. PMID- 20961813 TI - Virology, epidemiology, pathogenesis, and control of enterovirus 71. AB - First isolated in California, USA, in 1969, enterovirus 71 (EV71) is a major public health issue across the Asia-Pacific region and beyond. The virus, which is closely related to polioviruses, mostly affects children and causes hand, foot, and mouth disease with neurological and systemic complications. Specific receptors for this virus are found on white blood cells, cells in the respiratory and gastrointestinal tract, and dendritic cells. Being an RNA virus, EV71 lacks a proofreading mechanism and is evolving rapidly, with new outbreaks occurring across Asia in regular cycles, and virus gene subgroups seem to differ in clinical epidemiological properties. The pathogenesis of the severe cardiopulmonary manifestations and the relative contributions of neurogenic pulmonary oedema, cardiac dysfunction, increased vascular permeability, and cytokine storm are controversial. Public health interventions to control outbreaks involve social distancing measures, but their effectiveness has not been fully assessed. Vaccines being developed include inactivated whole-virus, live attenuated, subviral particle, and DNA vaccines. PMID- 20961814 TI - Prevalence of epilepsy and alcohol-related risk in Zayul County, Tibet Autonomous Region in China: an initial survey. AB - OBJECTIVE: The goal of this study was to establish the prevalence rates of epilepsy and alcohol-related risk and the treatment gap in Zayul County, Tibet Autonomous Region, to evaluate the diagnosis and treatment status of these patients. METHODS: A door-to-door epidemiological survey was conducted among all the people living in the towns of Shang Zayul and Xia Zayul. A screening questionnaire for epilepsy was used. Clinical and sociodemographic data were collected from patients confirmed to have epilepsy. An audit was used for patients with epilepsy who had a definite history of alcohol consumption and drinking habit change. RESULTS: A total of 7669 people were investigated. Of these, 180 were confirmed to have epilepsy, which was active in 175. Lifetime prevalence was estimated to be 23.5 per 1000 in this population. None of the patients with active epilepsy had received any reasonable antiepileptic therapy in the week before the survey (treatment gap). Ninety-six percent of patients with epilepsy aged between 20 and 60 drank alcoholic beverages. However, in only 25 (13.9%) patients with epilepsy was the epilepsy related to alcohol; most patients (80.6%) had no definite causes. There were no local health workers who received any formal training on epilepsy before, nor did the local health agencies provide any conventional antiepileptic drugs. CONCLUSION: The prevalence rates of epilepsy in the towns of Shang Zayul and Xia Zayul of the Tibet Autonomous Region were relatively higher than in other areas. The alcohol-related health problems cannot be ignored. This serious situation and the large treatment gap indicate a pressing need for medical, financial and social support in this population. PMID- 20961815 TI - Questioning the role of abuse in behavioral spells and epilepsy. AB - Past sexual trauma is frequently linked to the development of behavioral spells, present among 30% of patients admitted for video/EEG monitoring. Current attempts to verify and explore mechanisms in this reported association revealed that patients with epilepsy (n=58) and those with behavioral spells (n=38) did not differ in their self-report of past sexual trauma (among approximately 38% in each group). Ninety percent (90%) of men with behavioral spells endorsed past physical abuse, however, compared with 45% of men with epilepsy, and 40% of men with spells likely met current criteria for posttraumatic stress disorder. Among all patients, the presence of past physical, but not sexual, abuse positively predicted the diagnosis of spells rather than epilepsy. Current findings do not support a preponderance of sexual trauma in behavioral spells, yet within the subset of men with spells, greater exposure to physical abuse and current symptoms of posttraumatic stress disorder may be important etiological and sustaining factors. PMID- 20961816 TI - Quality of life in young people with treatment-responsive epilepsy: A controlled study. AB - OBJECTIVE: Quality of life (QoL) has been shown to be lower in individuals with epilepsy than the general public. However, few studies have investigated the QoL of individuals with well-controlled epilepsy. This study investigated the effects of epilepsy on QoL in persons with treatment-responsive seizures, beyond factors directly related to the presence of seizures. METHODS: Fifty young patients with controlled epilepsy and 102 healthy controls completed a generic, multidimensional, self-report QoL instrument, along with standardized scales assessing anxiety, depression, and other emotional or behavioral difficulties. RESULTS: Young people with epilepsy reported increased anxiety (P=0.037) and more emotional and behavioral difficulties (P<0.001). Though there were was no difference between the groups in Total QoL score, treatment-responsive epilepsy was associated with lower QoL within the Self domain (P=0.016). CONCLUSIONS: Epilepsy may exert a negative influence on QoL in relation to thoughts and feelings about the self in the context of complete seizure remission. Future research should investigate the therapeutic value of interventions targeting detrimental changes to self-perception in young people living with controlled epilepsy. PMID- 20961817 TI - Efficiency and fidelity of human DNA polymerases lambda and beta during gap filling DNA synthesis. AB - The base excision repair (BER) pathway coordinates the replacement of 1-10 nucleotides at sites of single-base lesions. This process generates DNA substrates with various gap sizes which can alter the catalytic efficiency and fidelity of a DNA polymerase during gap-filling DNA synthesis. Here, we quantitatively determined the substrate specificity and base substitution fidelity of human DNA polymerase lambda (Pol lambda), an enzyme proposed to support the known BER DNA polymerase beta (Pol beta), as it filled 1-10 nucleotide gaps at 1-nucleotide intervals. Pol lambda incorporated a correct nucleotide with relatively high efficiency until the gap size exceeded 9 nucleotides. Unlike Pol lambda, Pol beta did not have an absolute threshold on gap size as the catalytic efficiency for a correct dNTP gradually decreased as the gap size increased from 2 to 10 nucleotides and then recovered for non-gapped DNA. Surprisingly, an increase in gap size resulted in lower polymerase fidelity for Pol lambda, and this downregulation of fidelity was controlled by its non enzymatic N-terminal domains. Overall, Pol lambda was up to 160-fold more error prone than Pol beta, thereby suggesting Pol lambda would be more mutagenic during long gap-filling DNA synthesis. In addition, dCTP was the preferred misincorporation for Pol lambda and its N-terminal domain truncation mutants. This nucleotide preference was shown to be dependent upon the identity of the adjacent 5'-template base. Our results suggested that both Pol lambda and Pol beta would catalyze nucleotide incorporation with the highest combination of efficiency and accuracy when the DNA substrate contains a single-nucleotide gap. Thus, Pol lambda, like Pol beta, is better suited to catalyze gap-filling DNA synthesis during short-patch BER in vivo, although, Pol lambda may play a role in long-patch BER. PMID- 20961818 TI - Effect of an antioxidant-rich multivitamin supplement in cystic fibrosis. AB - BACKGROUND: Despite supplementation with standard multivitamins and pancreatic enzymes, deficiencies of vitamins D and K and antioxidants are common in cystic fibrosis (CF). METHODS: In this non-randomized, open-label study, AquADEKs(r) softgels were given daily over 12 weeks to 14 CF subjects (mean age 15 years, range 10-23) without a preceding wash-out period. Both pancreatic sufficient and insufficient subjects were enrolled. Plasma vitamin and antioxidant levels, urine 8-isoprostane levels, anthropometric measures, and pulmonary function were determined at baseline, 6 and 12 weeks. RESULTS: Daily supplementation significantly increased plasma beta(beta)-carotene, coenzyme Q10, and gamma tocopherol concentrations, decreased proteins induced in vitamin K absence (PIVKA II) levels, but did not normalize vitamin D and K status in all subjects. Vitamin A levels did not exceed the normal range for any subject during the entire study period. Modest improvements in weight percentile and pulmonary function were observed. Change in plasma beta-carotene concentrations weakly correlated with changes in weight and body mass index percentiles. CONCLUSIONS: In this study, AquADEKs(r) increased systemic antioxidant levels, while maintaining vitamin A levels in the normal range, and improved but did not completely normalize vitamin D and K status. Increased beta-carotene levels were associated with improved growth parameters. These results warrant further clinical evaluation in CF. PMID- 20961819 TI - Irreversible thermodynamics and the structure of life and the planet: comment on "Life, hierarchy, and the thermodynamic machinery of planet Earth" by A. Kleidon. PMID- 20961820 TI - Spreading the power: comment on "Life, hierarchy, and the thermodynamic machinery of planet Earth" by A. Kleidon. PMID- 20961821 TI - [Panhypopituitarism and cranial nerve IV palsy: pituitary macroadenoma?]. PMID- 20961822 TI - Comparative genomics in teleost species: Knowledge transfer by linking the genomes of model and non-model fish species. AB - Comparative genomics is a powerful tool to transfer knowledge coming from model fish species to non-model fish species of economic or/and evolutionary interest. Such transfer is of importance as functional studies either are difficult to perform with most non-model species. The first comparative map constructed using the human and the chimpanzee genome allowed the identification of putative orthologues. Although comparative mapping in teleosts is still in its infancy, five model teleost genomes from different orders have been fully sequenced to date and the sequencing of several commercially important species are also underway or near completion. The accessibility of these whole genome sequences and rapid developments in genomics of fish species are paving the way towards new and valuable research in comparative genetics and genomics. With the accumulation of information in model species, the genetic and genomic characterization of non model, but economically, physiologically or evolutionary important species is now feasible. Furthermore, comparison of low coverage gene maps of non-model fish species against fully sequenced fish species will enhance the efficiency of candidate gene identification projected for quantitative trait loci (QTL) scans for traits of special interest. PMID- 20961823 TI - Bariatric surgery in 2010: Towards a metabolic surgery. PMID- 20961825 TI - Recombinant activated factor VII for postoperative hemorrhage following repair of acute type A aortic dissection. AB - BACKGROUND: Perioperative hemorrhage in the repair of acute type A aortic dissection increases morbidity, mortality, and costs of treatment. Recombinant activated factor VII (rFVIIa) mitigates intractable blood loss in surgery. By enhancing thrombin generation on activated platelet surfaces and activating thrombin-activatable fibrinolysis inhibitor and factor XIII, rFVIIa promotes platelet aggregation and fibrin plug formation at the site of endothelial injury. We report outcomes for type A aortic dissection patients treated postoperatively with rFVIIa for life-threatening hemorrhage. METHODS: Patients' charts were reviewed to gather demographic, procedural, and laboratory data as well as information regarding clinical outcomes and blood product use. RESULTS: Nine patients with acute type A aortic dissection received rFVIIa in the perioperative period. In the 6 hour period after rFVIIa treatment, transfusion of blood products was reduced. The international normalized ratio decreased after treatment (1.6 versus 0.9, P < .01). One patient experienced perioperative stroke. CONCLUSIONS: In patients with acute type A aortic dissections who have life-threatening bleeding, early administration of rFVIIa may safely normalize coagulation variables, decrease transfusion requirements, and enhance hemostasis. PMID- 20961824 TI - Particulate matter-induced health effects: who is susceptible? AB - BACKGROUND: Epidemiological, controlled human exposure, and toxicological studies have demonstrated a variety of health effects in response to particulate matter (PM) exposure with some of these studies indicating that populations with certain characteristics may be disproportionately affected. OBJECTIVE: To identify populations potentially at greatest risk for PM-related health effects, we evaluated epidemiological studies that examined various characteristics that may influence susceptibility, while using results from controlled human exposure and toxicological studies as supporting evidence. Additionally, we formulated a definition of susceptibility, building from the varied and inconsistent definitions of susceptibility and vulnerability used throughout the literature. DATA SYNTHESIS: We evaluated recent epidemiological studies to identify characteristics of populations potentially susceptible to PM-related health effects. Additionally, we evaluated controlled human exposure and toxicological studies to provide supporting evidence. We conducted a comprehensive review of epidemiological studies that presented stratified results (e.g., < 65 vs. >= 65 years of age), controlled human exposure studies that examined individuals with underlying disease, and toxicological studies that used animal models of disease. We evaluated results for consistency across studies, coherence across disciplines, and biological plausibility to assess the potential for increased susceptibility to PM-related health effects in a specific population or life stage. CONCLUSIONS: We identified a diverse group of characteristics that can lead to increased risk of PM-related health effects, including life stage (i.e., children and older adults), preexisting cardiovascular or respiratory diseases, genetic polymorphisms, and low-socioeconomic status. In addition, we crafted a comprehensive definition of susceptibility that can be used to encompass all populations potentially at increased risk of adverse health effects as a consequence of exposure to an air pollutant. PMID- 20961826 TI - Bilateral versus single internal thoracic artery grafting in dialysis patients with multivessel disease. AB - BACKGROUND: The purpose of our study was to compare mortality in dialysis patients undergoing bilateral internal thoracic artery (BITA) or single internal thoracic artery (SITA) grafting and to quantify the magnitude of the BITA grafting benefit for survival. METHODS: Between January 2002 and December 2008, 656 consecutive patients underwent isolated coronary artery bypass grafting (99.1% by an off-pump technique). Fifty-six of these patients with chronic dialysis and multivessel disease were retrospectively compared with respect to surgical technique: BITA (n = 32) or SITA (n = 23) grafting. End points were all cause and cardiovascular mortality (mean follow-up duration, 2.5 years). In an attempt to minimize the selection bias, we created propensity scores based on 13 preoperative factors that would affect the surgeon's decision about operative strategy; these factors were used for regression adjustment (C statistic, 0.914). RESULTS: There were no significant differences between the 2 groups with respect to age, sex, left ventricular ejection fraction, prevalence of diabetes mellitus and peripheral arterial disease, and logistic EuroSCORE. All patients under-went revascularization with the off-pump technique, with no conversion to cardiopulmonary bypass. All arterial conduits were harvested with a skeletonization technique in all cases. Except for 1 patient who received a SITA, internal thoracic arteries were used as in situ grafts in both groups. Complete revascularization was achieved in all patients. The 1-, 3-, and 5-year survival rates free from all-cause mortality for BITA grafting versus SITA grafting were 94% versus 73%, 72% versus 42%, and 52% versus 28%, respectively (P = .01, logrank test). For survival free from cardiovascular mortality, the respective rates were 100% versus 90%, 80% versus 77%, and 80% versus 58% (P = .06). After propensity score adjustment, BITA grafting was significantly associated with lower risks for all-cause mortality (hazard ratio, 0.27; 95% confidence interval, 0.09-0.81; P = .02) and cardiovascular mortality (hazard ratio, 0.20; 95% confidence interval, 0.04-0.93; P = .04). CONCLUSION: In situ skeletonized BITA grafting provides better long-term survival in dialysis patients with multivessel disease. PMID- 20961827 TI - Outcome evaluation of coronary artery bypass grafting surgery applying the EuroSCORE in a Caribbean developing country. AB - BACKGROUND: The risk-adjusted outcome of coronary artery bypass grafting (CABG) in Trinidad and Tobago was evaluated by applying the EuroSCORE scoring system. METHODS: A retrospective study was undertaken by reviewing the case notes of patients who underwent CABG from 2003 to 2008 under Caribbean Heart Care. Data collected included age, sex, smoking status, comorbidities, chronic pulmonary disease, extracardiac arteriopathy, neurologic disease, previous cardiac surgery, serum creatinine, active endocarditis, critical preoperative state, and mode of surgery. Predicted mortality was calculated with the EuroSCORE, the model was calibrated by Hosmer-Lemeshow analysis, and the discriminant function was analyzed by using the receiver operating characteristic (ROC) curve. RESULTS: We studied 1082 patients who underwent CABG, 75.6% of whom were of Asian Indian ethnicity. The overall mean (+/-SD) EuroSCORE was 2.87 +/- 2.1. The predicted perioperative mortality rate was 2.3%, and the observed mortality rate was 1.2%. The overall standardized mortality ratio was 0.52. Eighty-six percent of the patients underwent off-pump CABG. Hosmer-Lemeshow analysis showed that the system calibrated well to our case mix (Hosmer-Lemeshow value, 6.87; degrees of freedom, 8; P = .551). The EuroSCORE discriminated patient outcomes well, as shown by the area under the ROC curve (0.78). Age and ethnicity did not influence the outcome. CONCLUSIONS: The outcomes of CABG surgery patients are good in Trinidad and Tobago and are comparable to standards in developed countries when evaluated with the EuroSCORE. The proportion of patients undergoing off-pump CABG is high. PMID- 20961828 TI - Impacts of intensive insulin therapy in patients undergoing heart valve replacement. AB - BACKGROUND AND AIMS: Cardiac surgery with cardioplegic cardiac arrest and cardiopulmonary bypass (CPB) is associated with severe stress response, systemic inflammatory response, and injury. This study was designed to investigate the effects of intensive insulin therapy on patients undergoing valve replacement with CPB. METHODS: One hundred nondiabetic inpatients undergoing valve replacement were randomly assigned to a control group or an intensive insulin therapy (IT) group. Plasma cytokine and cardiac troponin I (cTnI) levels were monitored perioperatively. RESULTS: Compared with the control group, the IT group had smaller increases in plasma concentrations of tumor necrosis factor alpha, interleukin 1beta (IL-1beta), IL-6, and cTnI, and had a more pronounced increase in IL-10 levels after the initiation of CPB. After surgery, the required inotropes were reduced in the IT group. In the IT group, the time of artificial ventilation and the postoperative length of stay in the hospital were markedly shortened; however, there were no significant differences between the IT and control groups in mortality and the rate of nosocomial infections of deep sternal wounds. CONCLUSIONS: IT can significantly attenuate the systemic inflammatory response and improve a damaged cardiac function, but it does not reduce the in hospital mortality rate. PMID- 20961829 TI - Modification of a hybrid technique for closure of muscular ventricular septal defects in a pig model. AB - OBJECTIVE: Closure of muscular ventricular septal defects (mVSDs) beyond the moderator band is still a challenge for both surgeons and interventional cardiologists. We evaluated a new technique in a pig model for hybrid patch closure of mVSDs via 2 stab wound incisions in the left ventricle (LV) without cardiopulmonary bypass. METHODS: Ten pigs underwent left anterolateral thoracotomy to expose the LV. mVSDs were created via a stab wound incision of the lateral wall of the LV under epicardial echocardiographic control. The patch system was forwarded through a second puncture of the LV apex and positioned in front of the mVSD. The stapler for fixation of the patch was introduced through the same incision as used for VSD creation. Finally, the patch was attached to the septum with nitinol anchors under epicardial echocardiographic and fluoroscopic guidance. Finally, detailed echocardiographic evaluation was done. All hearts were explanted, and macroscopic evaluation was done, either immediately after patch implantation (n = 4) or after 90 days (n = 6). RESULTS: mVSD creation was successful in all pigs. Closure of mVSDs was successful in 8 of 10 pigs, as confirmed by echocardiography, hemodynamic measurements, and macroscopic examination. One patch embolized through the mVSD into the pulmonary artery because of insecure fixation, and 1 animal died during the procedure because of ventricular fibrillation. The final echocardiographic evaluation revealed good LV function and no damage to the valves. CONCLUSIONS: Closure of mVSDs can be successfully performed in a hybrid technique on the beating heart with 2 stab wound incisions; however, further modifications need to be developed before clinical application. PMID- 20961830 TI - Ischemic postconditioning inhibits apoptosis after acute myocardial infarction in pigs. AB - OBJECTIVES: Recent studies have shown that ischemic postconditioning reduces myocardial ischemia-reperfusion (I/R) injury; however, the effects of inhibiting apoptosis on cardioprotection induced by ischemic postconditioning remain to be determined. The objective of this study was to investigate whether ischemic postconditioning attenuates myocardial I/R injury by reduced apoptosis in a closed-chest pig model of acute myocardial infarction. METHODS: Diannan small-ear pigs were randomly divided into 3 groups (5/group): (1) The sham group underwent a sham operation without ischemia; (2) the I/R group received 60 minutes of ischemia and 72 hours of reperfusion; and (3) the ischemic postconditioning (Postcond) group was treated the same as the I/R group except that the pigs received 8 cycles of 30 seconds of reperfusion and 30 seconds of ischemia at the onset of reperfusion. After 72 hours of reperfusion, infarct size was measured by 2,3,5-triphenyltetrazolium chloride staining. Apoptotic cells in the peri-infarct myocardium were evaluated with the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method, and apoptosis-related molecules were studied with western blotting analysis. RESULTS: After 72 hours of reperfusion, mean (+/-SEM) infarct size was significantly smaller in the Postcond group than in the I/R group (23.26% +/- 3.13% versus 10.89% +/- 2.02%, P < .05). Apoptotic myocytes in the peri-infarct region were lower in the Postcond group than in the I/R group (15.31% +/- 4.58% versus 33.83% +/- 4.44%, P < .05). This decrease in the extent of apoptosis was accompanied by a significant decrease in Bax expression (0.306 +/- 0.075 versus 0.433 +/- 0.102 for the I/R group; P < .05) and a significant increase in Bcl-2 expression (1.801 +/- 0.227 versus 1.267 +/- 0.308 for the I/R group; P < .05). CONCLUSIONS: In a clinically relevant closed chest pig model of myocardial infarction, these data suggest the following: (1) Ischemic postconditioning reduces infarct size following prolonged reperfusion, and (2) this cardioprotective effect is likely achieved via antiapoptotic mechanisms. PMID- 20961831 TI - Pericardial reconstruction using an extracellular matrix implant correlates with reduced risk of postoperative atrial fibrillation in coronary artery bypass surgery patients. AB - BACKGROUND: Postoperative atrial fibrillation (AF) is a significant complication following open heart surgery, with potentially serious clinical and economic implications. To assess the effect of a novel procedure, pericardial reconstruction using a porcine-derived extracellular matrix (ECM) implant, on the risk of postoperative AF after primary isolated coronary artery bypass grafting (CABG), we performed a retrospective comparison of the incidence of postoperative AF in patients who underwent this procedure versus an untreated control group. METHODS: We performed a retrospective comparison of the incidence of postoperative AF in 111 patients who underwent a pericardial reconstruction procedure with the CorMatrix ECM for Pericardial Closure (CorMatrix Cardiovascular, Atlanta, GA, USA) following primary isolated CABG, versus a control group of 111 patients who did not undergo pericardial reconstruction. RESULTS: Postoperative AF occurred in 43 of 111 control patients (39%; lower control limit [LCL], 30%; upper control limit [UCL], 49%) but in only 20 of 111 treated patients (18%; LCL, 11%; UCL, 27%). This result represents a 54% reduction in relative risk in the treatment group (P < .001). There was a small but statistically insignificant decrease in the hospital length of stay for the treated patients. The 2 treatment groups exhibited similar postoperative complication profiles. CONCLUSIONS: In this retrospective study, pericardial reconstruction with the ECM implant contributed directly to a statistically significant and clinically meaningful reduction in the rate of postoperative AF in patients undergoing primary isolated CABG. A prospective multicenter randomized trial has been planned to further test this approach. PMID- 20961832 TI - The convergent procedure: a multidisciplinary atrial fibrillation treatment. AB - BACKGROUND: Persistent atrial fibrillation (AF) and long-standing persistent AF (LSPAF) are difficult to treat. Epicardial surgical and percutaneous catheter ablations have lower success rates in these patients. The convergent procedure, an endoscopic transdiaphragmatic ablation procedure with conventional percutaneous endocardial ablation, is examined. METHODS: Twenty-eight patients with persistent AF or LSPAF underwent the convergent procedure. All underwent combined surgical epicardial radiofrequency ablation and electrophysiological transseptal endocardial ablation to electrically isolate the 4 pulmonary veins, to exclude the posterior left atrium, to ablate the coronary sinus, and to confirm block at the cavotricuspid isthmus. Follow-up was with 24-hour Holter monitoring at 3 months, and 24-hour or 7-day monitoring at 6 and 12 months. RESULTS: The mean duration of the procedure was 187 minutes (102 surgical ablation minutes; 85 endocardial ablation minutes). The mean total fluoroscopy time was 35.1 minutes. Two patients developed symptomatic pericardial effusions requiring percutaneous drainage, and 1 patient has demonstrated phrenic nerve paresis. There were no deaths. At 3 months, 87% were in sinus rhythm, and 43% were free of AF and antiarrhythmic medications (AADs). At 6 months, 76% were free from AF and AADs. CONCLUSION: The convergent procedure effectively combines surgical and electrophysiological AF expertise to provide a viable treatment option to patients with persistent AF or LSPAF. Long-term follow-up is under way. PMID- 20961833 TI - Surgical treatment of early acute thrombosis of mechanical mitral prosthesis. AB - Prosthetic valve thrombosis is a rare but life threatening complication of mechanical heart valve prosthesis. A 44-year-old woman diagnosed with rheumatic heart disease with severe mitral valve stenosis, moderate tricuspid valve insufficiency, and atrial fibrillation underwent transseptal mitral valve replacement and tricuspid valvuloplasty in our department. Heparin and warfarin were routinely used postoperatively. Although the international normalized ratio (INR), activated partial thromboplastin time ratio, and platelet count were satisfactory, the patient presented with severe dyspnea suddenly 10 days after discharge; echocardiogram showed that the prosthetic posterior leaflet was immobile. The patient suffered cardiac arrest suddenly during the examination and cardiopulmonary resuscitation was carried out successfully. Emergent surgery was performed, confirming the prosthetic valve thrombosis. The prosthetic valve was replaced with another mechanical prosthesis. The patient recovered smoothly and was discharged 14 days later with atrial fibrillation. During the 12-months follow-up period, her prosthetic valve and heart function were normal with INR around 3.0. This case highlights the need for awareness among clinicians for the possibility of valve thrombosis in the early postoperative period. PMID- 20961834 TI - Echocardiographic detection of cardiac ectopy: a possible alternative to electrophysiological mapping? AB - PURPOSE: Three-dimensional (3-D) visualization of ventricular activation sequence is imperative for the diagnosis and treatment of malignant cardiac arrhythmias. Modern mapping systems that serve as the gold standard for detection and localization of the focus are costly and require an invasive approach into the cavity of the ventricles. The aim of our study was the development of a noninvasive and 3-D mapping system based upon echocardiography. METHODS: In a porcine model, animals underwent ablation of the atrioventricular node (AV-node). 3-D electrophysiological cardiac mapping was performed using the ENSITETM electro anatomical system (St. Jude Medical, Minneapolis, MN, USA). Simultaneously, transesophageal echocardiography (TEE) including pulse wave (Pw) tissue Doppler was performed, and time to peak early diastolic velocity (PEDV) was measured. Both ENSITE-mapping and tissue Pw-Doppler were compared as to their ability to pinpoint the origin of ventricular ectopic focus. RESULTS: PEDV corresponded well with the results as determined by noncontact mapping with ENSITE. CONCLUSIONS: Tissue Doppler is a reliable method to deliver information about the topography of first onset of myocardial excitation. Further development of this method with a higher regional resolution and integration of color Doppler as well as 3-D echocardiography may eventually lead to the development of a completely noninvasive and echo-based electromechanical mapping system. PMID- 20961835 TI - Mitral regurgitation secondary to anterior leaflet rupture during percutaneous balloon valvuloplasty: case report. AB - Rheumatoid heart disease and the mitral stenosis secondary to it in the long term are still important cardiovascular problems in developing countries. Percutaneous balloon mitral valvuloplasty is a valid treatment option with low complication rates for relieving the signs and symptoms of selected patients with mitral valve stenosis. In this report, we describe subacute mitral regurgitation secondary to anterior leaflet rupture following percutaneous balloon mitral valvuloplasty and the management strategy in a 54-year-old female patient. Such a complication is rare in experienced hands in the current era. PMID- 20961836 TI - Papillary fibroelastoma of the right coronary cusp. AB - Cardiac papillary fibroelastoma (CPF) is a pathologically benign cardiac tumor. This tumor usually arises from cardiac valves, and it is the most common cardiac valvular tumor. This usually single and pedunculated tumor should be surgically treated when the mass is mobile and the patient has experienced a prior stroke, even if the stroke has manifested as a transient ischemic attack. Surgical treatment is definitive, and no recurrences have been reported in the literature. We describe a patient who had a diagnosis of CPF while undergoing investigation for a cryptogenic stroke. PMID- 20961837 TI - Recurrent cardiac metastasis of primary femoral osteosarcoma: a case report. AB - A 17-year-old female patient with a history of surgery for primary femoral and metastatic lung osteosarcoma was admitted to our clinic with palpitations. Upon evaluation, a metastatic osteosarcoma in the left ventricle was diagnosed. Based on the collaborative decision of the oncology and cardiovascular surgery clinics, surgery was performed and the patient was discharged without any problems. According to the recommendation of the oncology clinic, chemotherapy was postponed for 6 months after surgery. Five months postoperatively, however, she had a recurrence with 2 tumors. Based on the collaborative decision, chemotherapy was initiated and in 2 months the size of the recurrent tumors had diminished. The patient is still under the care of the oncology and cardiovascular surgery clinics and continuing her chemotherapy regimen. Osteosarcomas have a high mortality. Metastatic tumors of the heart are not common. The location of the metastasis and the characteristics of the primary tumor determine the treatment modality. In some previously published reports, various treatment choices have been described. In the present case report, we present a rare case with metastatic cardiac osteosarcoma. PMID- 20961838 TI - Mitral valve repair in a patient with thrombocytopenia-absent radius syndrome: case report. AB - Thrombocyte level and functions are vital factors during cardiac surgery. Thrombocytopenia-absent radius syndrome (TAR) is a rare genetic disorder consisting of skeletal abnormalities and thrombocytopenia. In this report, we present the management strategy for a 23-year-old female patient with TAR syndrome who underwent mitral valve repair. PMID- 20961839 TI - Repair of anomalous origin of right pulmonary artery from ascending aorta without cardiopulmonary bypass. AB - Anomalous origin of a pulmonary artery from the ascending aorta (AORPA) is a rare congenital cardiac malformation that needs prompt surgical repair; otherwise it is associated with poor prognosis. We describe 3 cases of AORPA that successfully underwent complete surgical correction without extracorporeal circulation. PMID- 20961840 TI - Preoperative optimization of multi-organ failure following acute myocardial infarction and ischemic mitral regurgitation by placement of a transthoracic intra-aortic balloon pump. AB - BACKGROUND: The management of acute myocardial infarction with resultant acute ischemic mitral regurgitation and acute multi-organ failure can prove to be a very challenging scenario. The presence of concomitant vascular disease can only serve to further compromise the complexity of the situation. We demonstrate a new indication for the transthoracic intra-aortic balloon pump as a preoperative means of unloading the heart and improving clinical outcome in such high-risk patients with severe vascular disease. METHODS: We present the case of a 75-year old man with a history of severe vascular disease who was transferred emergently to Vanderbilt University Medical Center with an acute inferolateral wall myocardial infarction resulting in severe acute ischemic mitral regurgitation and acute multi-organ failure. He presented with shock liver (serum glutamic oxaloacetic transaminase [SGOT] of 958), renal failure (creatinine of 3.0), and respiratory failure with a pH of 7.18. Emergent cardiac catheterization revealed 100% occlusion of the left circumflex artery as well as severe ileofemoral disease. The advanced nature of his ileofemoral disease was such that the arterial access catheter occluded the right femoral artery. The duration of time that the catheter was in the artery led to transient limb ischemia with an elevation of his creatine phosphokinase (CPK) to 10,809. Balloon angioplasty followed by stent placement was successfully performed, which restored flow to the coronary vessel. Given the grave nature of the patient's condition, we were very concerned that immediate operative intervention for his condition would entail prohibitively high risk. In fact, the Society of Thoracic Surgeons predicted risk adjusted mortality was calculated to be 56%. In order to minimize patient mortality and morbidity, it was critical to help restore perfusion and organ recovery. Therefore, we decided that the chances for this patient's survival would improve if his condition could be optimized by placement of an intra-aortic balloon pump before undergoing surgery. Given the limb ischemia following arterial sheath insertion, femoral placement of an intra-aortic balloon pump was not an option. Placement of the intra-aortic balloon pump was attempted via a left subclavian artery cutdown, but was not successful. Therefore, a sternotomy was performed, and we placed a transthoracic intra-aortic balloon pump in order to stabilize the patient's hemodynamics and allow for organ recovery. RESULTS: The patient showed immediate improvement, and 4 days later, the multi organ failure resolved and he successfully underwent mitral valve replacement. The patient was ultimately discharged to a local rehabilitation facility in satisfactory condition. CONCLUSION: This case demonstrates the utility of a transthoracic intra-aortic balloon pump as a preoperative means of stabilization in very high risk patients with severe peripheral vascular disease in whom the conventional approaches are not possible. PMID- 20961841 TI - Detection of human herpesvirus 6 DNA but not human herpesvirus 7 or 8 DNA in atherosclerotic and nonatherosclerotic vascular tissues. AB - INTRODUCTION: Various viral infections are thought to play a role in the development of atherosclerosis. A number of studies suggest that certain viruses from the Herpesviridae family in particular may lead to atherosclerosis. METHODS: We investigated the presence of human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), and human herpesvirus 8 (HHV-8) DNA in carotid, iliac, and coronary artery specimens obtained from a group of adult autopsy cases by means of polymerase chain reaction (PCR) analysis and nested PCR techniques. A 28-subject study group with at least type IV atherosclerosis and a 25-subject control group with no visible atherosclerosis were enrolled. RESULTS: HHV-6 DNA was found in the carotid artery specimen of 1 subject with atherosclerosis, in an iliac artery specimen of another subject, and in the iliac artery specimen of one of the control subjects. HHV-7 or HHV-8 DNA was not found in either the atherosclerosis or control cases. CONCLUSIONS: This study is the first to demonstrate the presence of HHV-6 in atherosclerotic vascular tissues. HHV-7 and HHV-8 were not found in atherosclerotic tissues; however, further research on broader study groups and with different protocols is needed to determine whether these viruses play a role in the formation of atherosclerosis. PMID- 20961842 TI - [An old "new" disease: body dysmorphic disorder (dysmorphophobia)]. AB - Body dysmorphic disorder causes significant suffering and serious impairment in psychosocial functions. However, this disease with dangerous risks is scarcely mentioned in the Hungarian medical literature. The objective of the author is to give a detailed review about this almost unknown, but relatively common disorder. The serious disorder of body perception is in the centre of symptoms, leading to social isolation, anxiety, depression and obsessive-compulsive phenomena. The disorder often remains unrecognized because of the lack of insight of disease. Comorbidity with affective disorders, anxiety disorders, personality disorders, eating disorders, alcoholism and substance use disorders is common. The life quality of affected patients is bad, the risk of suicide or violence is high. Biological, psychological and sociocultural factors play an important role in the etiopathogenesis of the disorder. Imaging techniques and neuropsychological measures revealed changes characteristic for the disease. Childhood abuse and neglect, appearance-related critical remarks, stressors and the impact of media are also supposed to have role in the development of the disorder. The point prevalence is 0.7-2.5% in the general population, however, in special groups such as in tertiary students, psychiatric, dermatological and cosmetic surgery patients the prevalence rates may be much higher. Typically, the disease begins in early adolescence, and it persists and deteriorates without treatment, showing a chronic course. By means of pharmacotherapy and/or psychotherapy long-during improvement or full recovery can be achieved within a relatively short period of time. PMID- 20961843 TI - [The epidemiology of pancreatic cancer]. AB - Pancreatic cancer is a relatively uncommon tumor, but even with early diagnosis, mortality rates are high, explaining why this form of cancer has now become a common cause of cancer mortality. There are no screening tests for early detection of pancreatic cancer. It is more common in men than women and is predominantly a disease of elderly people. There is wide variation in the incidence of pancreatic cancer around the world, suggesting that environmental factors are important in the pathogenesis. Smoking is the major known risk factor for pancreatic cancer, while dietary factors seem to be less important. Other possible risk factors include chronic pancreatitis, obesity and type 2 diabetes. Numerous inherited germ line mutations are associated with pancreatic cancer. Of these, hereditary pancreatitis confers the greatest risk, while BRCA2 mutations are the commonest inherited disorder. Polymorphisms in genes that control detoxification of environmental carcinogens and metabolic pathways may alter the risk of pancreatic cancer. PMID- 20961844 TI - [Ambulatory blood pressure monitoring]. AB - During the last decades non-invasive 24-hour ambulatory blood pressure monitoring has evolved from a research tool of limited clinical use into an important method for stratifying cardiovascular risk and guiding therapeutic decisions. Until recently, clinical use of ambulatory blood pressure monitoring focused on identifying patients with white-coat hypertension, but accumulated evidence now points to its greater prognostic significance in determining risk for target organ damage compared with that of office blood pressure measurements. Ambulatory measurement of blood pressure using automated devices has also demonstrated benefit in other indications, such as treatment resistance and borderline hypertension, or in hypertension during pregnancy. Future directions for hypertension research and treatment will need to consider the circadian cycle of blood pressure, the effect of treatment on blood pressure variability, and the magnitude of blood pressure changes in daily life. PMID- 20961845 TI - [Robert Schumann was born 200 years ago (1810-1856)]. PMID- 20961847 TI - Novel fold and carbohydrate specificity of the potent anti-HIV cyanobacterial lectin from Oscillatoria agardhii. AB - Oscillatoria agardhii agglutinin (OAA) is a recently discovered cyanobacterial lectin that exhibits potent anti-HIV activity. Up to now, only its primary structure and carbohydrate binding data have been available. To elucidate the structural basis for the antiviral mechanism of OAA, we determined the structure of this lectin by x-ray crystallography at 1.2 A resolution and mapped the specific carbohydrate recognition sites of OAA by NMR spectroscopy. The overall architecture of OAA comprises 10 beta-strands that fold into a single, compact, beta-barrel-like domain, creating a unique topology compared with all known protein structures in the Protein Data Bank. OAA sugar binding was tested against Man-9 and various disaccharide components of Man-9. Two symmetric carbohydrate binding sites were located on the protein, and a preference for Manalpha(1-6)Man linked sugars was found. Altogether, our structural results explain the antiviral activity OAA and add to the growing body of knowledge about antiviral lectins. PMID- 20961848 TI - Clustering of the neural cell adhesion molecule (NCAM) at the neuronal cell surface induces caspase-8- and -3-dependent changes of the spectrin meshwork required for NCAM-mediated neurite outgrowth. AB - Changes in neuronal morphology underlying neuronal differentiation depend on rapid and sustained cytoskeleton rearrangements in the growing neurites. Whereas cell adhesion molecules are well established as regulators of neuronal differentiation, less is known about the signaling mechanisms by which they influence the cytoskeleton. Here we show that the neural cell adhesion molecule (NCAM) associates with the active form of caspase-8 and that clustering of NCAM at the neuronal cell surface leads to activation of caspase-8 and -3 followed by the cleavage of the sub-membranous brain spectrin meshwork, but not of the actin or tubulin cytoskeleton. Inhibitors of caspase-8 and -3 specifically block the NCAM-dependent spectrin cleavage and abolish NCAM-dependent neurite outgrowth. NCAM-dependent rearrangements of the membrane associated spectrin meshwork via caspase-8 dependent caspase-3 activation are thus indispensable for NCAM-mediated neurite outgrowth. PMID- 20961849 TI - Basic tetrapeptides as potent intracellular inhibitors of type A botulinum neurotoxin protease activity. AB - Botulinum neurotoxins (BoNT) are the most potent of all toxins that cause flaccid muscle paralysis leading to death. They are also potential biothreat agents. A systematic investigation of various short peptide inhibitors of the BoNT protease domain with a 17-residue peptide substrate led to arginine-arginine-glycine cysteine having a basic tetrapeptide structure as the most potent inhibitor. When assayed in the presence of dithiothreitol (DTT), the inhibitory effect was drastically reduced. Replacing the terminal cysteine with one hydrophobic residue eliminated the DTT effect but with two hydrophobic residues made the pentapeptide a poor inhibitor. Replacing the first arginine with cysteine or adding an additional cysteine at the N terminus did not improve inhibition. When assessed using mouse brain lysates, the tetrapeptides also inhibited BoNT/A cleavage of the endogenous SNAP-25. The peptides penetrated the neuronal cell lines, N2A and BE(2)-M17, without adversely affecting metabolic functions as measured by ATP production and P-38 phosphorylation. Biological activity of the peptides persisted within cultured chick motor neurons and rat and mouse cerebellar neurons for more than 40 h and inhibited BoNT/A protease action inside the neurons in a dose- and time-dependent fashion. Our results define a tetrapeptide as the smallest peptide inhibitor in the backdrop of a large substrate protein of 200+ amino acids having multiple interaction regions with its cognate enzyme. The inhibitors should also be valuable candidates for drug development. PMID- 20961850 TI - CDC50 proteins are critical components of the human class-1 P4-ATPase transport machinery. AB - Members of the P(4) subfamily of P-type ATPases catalyze phospholipid transport and create membrane lipid asymmetry in late secretory and endocytic compartments. P-type ATPases usually pump small cations and the transport mechanism involved appears conserved throughout the family. How this mechanism is adapted to flip phospholipids remains to be established. P(4)-ATPases form heteromeric complexes with CDC50 proteins. Dissociation of the yeast P(4)-ATPase Drs2p from its binding partner Cdc50p disrupts catalytic activity (Lenoir, G., Williamson, P., Puts, C. F., and Holthuis, J. C. (2009) J. Biol. Chem. 284, 17956-17967), suggesting that CDC50 subunits play an intimate role in the mechanism of transport by P(4) ATPases. The human genome encodes 14 P(4)-ATPases while only three human CDC50 homologues have been identified. This implies that each human CDC50 protein interacts with multiple P(4)-ATPases or, alternatively, that some human P(4) ATPases function without a CDC50 binding partner. Here we show that human CDC50 proteins each bind multiple class-1 P(4)-ATPases, and that in all cases examined, association with a CDC50 subunit is required for P(4)-ATPase export from the ER. Moreover, we find that phosphorylation of the catalytically important Asp residue in human P(4)-ATPases ATP8B1 and ATP8B2 is critically dependent on their CDC50 subunit. These results indicate that CDC50 proteins are integral part of the P(4) ATPase flippase machinery. PMID- 20961851 TI - Protein kinase C-dependent phosphorylation of transient receptor potential canonical 6 (TRPC6) on serine 448 causes channel inhibition. AB - TRPC6 is a cation channel in the plasma membrane that plays a role in Ca(2+) entry following the stimulation of a G(q)-protein coupled or tyrosine kinase receptor. A dysregulation of TRPC6 activity causes abnormal proliferation of smooth muscle cells and glomerulosclerosis. In the present study, we investigated the regulation of TRPC6 activity by protein kinase C (PKC). We showed that inhibiting PKC with GF1 or activating it with phorbol 12-myristate 13-acetate potentiated and inhibited agonist-induced Ca(2+) entry, respectively, into cells expressing TRPC6. Similar results were obtained when TRPC6 was directly activated with 1-oleyl-2-acetyl-sn-glycerol. Activation of the cells with carbachol increased the phosphorylation of TRPC6, an effect that was prevented by the inhibition of PKC. The target residue of PKC was identified by an alanine screen of all canonical PKC sites on TRPC6. Unexpectedly, all the mutants, including TRPC6(S768A) (a residue previously proposed to be a target for PKC), displayed PKC-dependent inhibition of channel activity. Phosphorylation prediction software suggested that Ser(448), in a non-canonical PKC consensus sequence, was a potential target for PKCdelta. Ba(2+) and Ca(2+) entry experiments revealed that GF1 did not potentiate TRPC6(S448A) activity. Moreover, activation of PKC did not enhance the phosphorylation state of TRPC6(S448A). Using A7r5 vascular smooth muscle cells, which endogenously express TRPC6, we observed that a novel PKC isoform is involved in the inhibition of the vasopressin-induced Ca(2+) entry. Furthermore, knocking down PKCdelta in A7r5 cells potentiated vasopressin-induced Ca(2+) entry. In summary, we provide evidence that PKCdelta exerts a negative feedback effect on TRPC6 through the phosphorylation of Ser(448). PMID- 20961852 TI - Resting state Orai1 diffuses as homotetramer in the plasma membrane of live mammalian cells. AB - Store-operated calcium entry is essential for many signaling processes in nonexcitable cells. The best studied store-operated calcium current is the calcium release-activated calcium (CRAC) current in T-cells and mast cells, with Orai1 representing the essential pore forming subunit. Although it is known that functional CRAC channels in store-depleted cells are composed of four Orai1 subunits, the stoichiometric composition in quiescent cells is still discussed controversially: both a tetrameric and a dimeric stoichiometry of resting state Orai1 have been reported. We obtained here robust and similar FRET values on labeled tandem repeat constructs of Orai1 before and after store depletion, suggesting an unchanged tetrameric stoichiometry. Moreover, we directly visualized the stoichiometry of mobile Orai1 channels in live cells using a new single molecule recording modality that combines single molecule tracking and brightness analysis. By alternating imaging and photobleaching pulses, we recorded trajectories of single, fluorescently labeled Orai1 channels, with each trajectory consisting of bright and dim segments, corresponding to higher and lower numbers of colocalized active GFP label. The according brightness values were used for global fitting and statistical analysis, yielding a tetrameric subunit composition of mobile Orai1 channels in resting cells. PMID- 20961853 TI - The oligopeptidase B of Leishmania regulates parasite enolase and immune evasion. AB - Proteases are a ubiquitous group of enzymes that play key roles in the life cycle of parasites, in the host-parasite relationship, and in the pathogenesis of parasitic diseases. Furthermore, proteases are targets for the development of new anti-parasitic therapy. Protozoan parasites like Leishmania predominantly express Clan CA cysteine proteases for key life cycle functions. It was therefore unexpected to find a high level of serine protease activity expressed by Leishmania donovani. Purification of this activity followed by mass spectrometry identified oligopeptidase B (OPB; Clan SC, family S9A) as the responsible enzyme. This was confirmed by gene knock-out of OPB, which resulted in the disappearance of the detected serine protease activity of Leishmania extracts. To delineate the specific role of OPB in parasite physiology, proteomic analysis was carried out on OPB(-/-) versus wild type parasites. Four protein species were significantly elevated in OPB(-/-) parasites, and all four were identified by mass spectrometry as enolase. This increased enolase was enzymatically inactive and associated with the parasite membrane. Aside from its classic role in carbohydrate metabolism, enolase was recently found to localize to membranes, where it binds host plasminogen and functions as a virulence factor for several pathogens. As expected, there was a striking alteration in macrophage responses to Leishmania when OPB was deleted. Whereas wild type parasites elicited little, if any, response from infected macrophages, OPB(-/-) parasites induced a massive up regulation in gene transcription. Additionally, these OPB(-/-) parasites displayed decreased virulence in the murine footpad infection model. PMID- 20961854 TI - Molecular basis of the mixed lineage leukemia-menin interaction: implications for targeting mixed lineage leukemias. AB - Chromosomal translocations targeting the mixed lineage leukemia (MLL) gene result in MLL fusion proteins that are found in aggressive human acute leukemias. Disruption of MLL by such translocations leads to overexpression of Hox genes, resulting in a blockage of hematopoietic differentiation that ultimately leads to leukemia. Menin, which directly binds MLL, has been identified as an essential oncogenic co-factor required for the leukemogenic activity of MLL fusion proteins. Here, we characterize the molecular basis of the MLL-menin interaction. Using (13)C-detected NMR experiments, we have mapped the residues within the intrinsically unstructured fragment of MLL that are required for binding to menin. Interestingly, we found that MLL interacts with menin with a nanomolar affinity (K(d) ~ 10 nM) through two motifs, MBM1 and MBM2 (menin binding motifs 1 and 2). These motifs are located within the N-terminal 43-amino acid fragment of MLL, and the MBM1 represents a high affinity binding motif. Using alanine scanning mutagenesis of MBM1, we found that the hydrophobic residues Phe(9), Pro(10), and Pro(13) are most critical for binding. Furthermore, based on exchange-transferred nuclear Overhauser effect measurements, we established that MBM1 binds to menin in an extended conformation. In a series of competition experiments we showed that a peptide corresponding to MBM1 efficiently dissociates the menin-MLL complex. Altogether, our work establishes the molecular basis of the menin interaction with MLL and MLL fusion proteins and provides the necessary foundation for development of small molecule inhibitors targeting this interaction in leukemias with MLL translocations. PMID- 20961855 TI - Progranulin A-mediated MET signaling is essential for liver morphogenesis in zebrafish. AB - The mechanism that regulates embryonic liver morphogenesis remains elusive. Progranulin (PGRN) is postulated to play a critical role in regulating pathological liver growth. Nevertheless, the exact regulatory mechanism of PGRN in relation to its functional role in embryonic liver development remains to be elucidated. In our study, the knockdown of progranulin A (GrnA), an orthologue of mammalian PGRN, using antisense morpholinos resulted in impaired liver morphogenesis in zebrafish (Danio rerio). The vital role of GrnA in hepatic outgrowth and not in liver bud formation was further confirmed using whole-mount in situ hybridization markers. In addition, a GrnA deficiency was also found to be associated with the deregulation of MET-related genes in the neonatal liver using a microarray analysis. In contrast, the decrease in liver size that was observed in grnA morphants was avoided when ectopic MET expression was produced by co-injecting met mRNA and grnA morpholinos. This phenomenon suggests that GrnA might play a role in liver growth regulation via MET signaling. Furthermore, our study has shown that GrnA positively modulates hepatic MET expression both in vivo and in vitro. Therefore, our data have indicated that GrnA plays a vital role in embryonic liver morphogenesis in zebrafish. As a result, a novel link between PGRN and MET signaling is proposed. PMID- 20961856 TI - The transcriptionally active amyloid precursor protein (APP) intracellular domain is preferentially produced from the 695 isoform of APP in a {beta}-secretase dependent pathway. AB - Amyloidogenic processing of the amyloid precursor protein (APP) by beta- and gamma-secretases generates several biologically active products, including amyloid-beta (Abeta) and the APP intracellular domain (AICD). AICD regulates transcription of several neuronal genes, especially the Abeta-degrading enzyme, neprilysin (NEP). APP exists in several alternatively spliced isoforms, APP(695), APP(751), and APP(770). We have examined whether each isoform can contribute to AICD generation and hence up-regulation of NEP expression. Using SH-SY5Y neuronal cells stably expressing each of the APP isoforms, we observed that only APP(695) up-regulated nuclear AICD levels (9-fold) and NEP expression (6-fold). Increased NEP expression was abolished by a beta- or gamma-secretase inhibitor but not an alpha-secretase inhibitor. This correlated with a marked increase in both Abeta(1 40) and Abeta(1-42) in APP(695) cells as compared with APP(751) or APP(770) cells. Similar phenomena were observed in Neuro2a but not HEK293 cells. SH-SY5Y cells expressing the Swedish mutant of APP(695) also showed an increase in Abeta levels and NEP expression as compared with wild-type APP(695) cells. Chromatin immunoprecipitation revealed that AICD was associated with the NEP promoter in APP(695), Neuro2a, and APP(Swe) cells but not APP(751) nor APP(770) cells where AICD was replaced by histone deacetylase 1 (HDAC1). AICD occupancy of the NEP promoter was replaced by HDAC1 after treatment of the APP(695) cells with a beta- but not an alpha-secretase inhibitor. The increased AICD and NEP levels were significantly reduced in cholesterol-depleted APP(695) cells. In conclusion, Abeta and functional AICD appear to be preferentially synthesized through beta secretase action on APP(695). PMID- 20961857 TI - Cholesterol and lipid phases influence the interactions between serotonin receptor agonists and lipid bilayers. AB - Solid state NMR techniques have been used to investigate the effect that two serotonin receptor 1a agonists (quipazine and LY-165,163) have on the phase behavior of, and interactions within, cholesterol/phosphocholine lipid bilayers. The presence of agonist, and particularly LY-165,163, appears to widen the phase transitions, an effect that is much more pronounced in the presence of cholesterol. It was found that both agonists locate close to the cholesterol, and their interactions with the lipids are modulated by the lipid phases. As the membrane condenses into mixed liquid-ordered/disordered phases, quipazine is pushed up toward the surface of the bilayer, whereas LY-165,163 moves deeper into the lipid chain region. In light of our results, we discuss the role of lipid/drug interactions on drug efficacy. PMID- 20961858 TI - Cyclooxygenase-2 deficiency attenuates adipose tissue differentiation and inflammation in mice. AB - Obesity is associated with a variety of disorders and is a significant health problem in developed countries. One factor controlling the level of adiposity is the differentiation of cells into adipocytes. Adipocyte differentiation requires expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which is activated by ligands to regulate expression of genes involved in adipocyte differentiation. Although 15-deoxy-Delta(12,14)-prostaglandin (PG) J(2) (15d PGJ(2)) has long been known to be a potent activator of PPARgamma, the importance of its synthesis in adipose tissue in vivo is not clear. The current study utilized mice deficient in cyclooxygenase-2 (COX-2) to examine the role of COX-2 derived PGs as in vivo modulators of adiposity. As compared with strain- and age matched wild-type controls, the genetic deficiency of COX-2 resulted in a significant reduction in total body weight and percent body fat. Although there were no significant differences in food consumption between groups, COX-2 deficient mice showed increased metabolic activity. Epididymal adipose tissue from wild-type mice produced a significantly greater level of 15d-PGJ(2), as compared with adipose tissue isolated from mice deficient in COX-2. Furthermore, production of the precursor required for 15d-PGJ(2) formation, PGD(2), was also significantly reduced in COX-2-deficient adipose tissue. The expression of markers for differentiated adipocytes was significantly reduced in adipose tissue from COX-2-deficient mice, whereas preadipocyte marker expression was increased. Macrophage-dependent inflammation was also significantly reduced in adipose tissue of COX-2-deficient mice. These findings suggest that reduced adiposity in COX-2-deficient mice results from attenuated PPARgamma ligand production and adipocyte differentiation. PMID- 20961859 TI - Insights into radicicol biosynthesis via heterologous synthesis of intermediates and analogs. AB - Resorcylic acid lactones are fungal polyketides that display diverse biological activities, with the potent Hsp90 inhibitor radicicol being an important representative member. Two fungal iterative polyketide synthases (IPKSs), Rdc5, the highly reducing IPKS, and Rdc1, the nonreducing IPKS, are required for the biosynthesis of radicicol in Pochonia chlamydosporia. In this study, the complete reconstitution of Rdc5 and Rdc1 activities both in vitro and in Saccharomyces cerevisiae uncovered the earliest resorcylic acid lactone intermediate of the radicicol biosynthetic pathway, (R)-monocillin II. The enzymatic synthesis of (R) monocillin II confirmed the exquisite timing of the Rdc5 enoyl reductase domain. Using precursor-directed biosynthesis, the chemical modularity of the dual IPKS system was determined. Rdc1 readily accepted an N-acetylcysteamine thioester mimic of the reduced pentaketide product of Rdc5 to synthesize (R)-monocillin II with four additional iterations of polyketide elongation, indicating the C2' ketone group found in (R)-monocillin II is incorporated via the functions of Rdc1 instead of Rdc5. The involvement of the thioesterase domain in Rdc1 in macrolactonization was confirmed through both site-directed mutagenesis and domain deletion. The Rdc1 thioesterase domain was also shown to be tolerant of the opposite stereochemistry of the terminal hydroxyl nucleophile, demonstrated in the precursor-directed synthesis of the enantiomeric (S)-monocillin II. Finally, reconstitution of the halogenase Rdc2 was demonstrated both in vivo and in vitro in the synthesis of pochonin D and a new halogenated analog 6-chloro, 7',8'-dehydrozearalenol. PMID- 20961860 TI - Structural basis for proficient incorporation of dTTP opposite O6-methylguanine by human DNA polymerase iota. AB - O(6)-methylguanine (O(6)-methylG) is highly mutagenic and is commonly found in DNA exposed to methylating agents, even physiological ones (e.g. S adenosylmethionine). The efficiency of a truncated, catalytic DNA polymerase iota core enzyme was determined for nucleoside triphosphate incorporation opposite O(6)-methylG, using steady-state kinetic analyses. The results presented here corroborate previous work from this laboratory using full-length pol iota, which showed that dTTP incorporation occurs with high efficiency opposite O(6)-methylG. Misincorporation of dTTP opposite O(6)-methylG occurred with ~6-fold higher efficiency than incorporation of dCTP. Crystal structures of the truncated form of pol iota with O(6)-methylG as the template base and incoming dCTP or dTTP were solved and showed that O(6)-methylG is rotated into the syn conformation in the pol iota active site and that dTTP misincorporation by pol iota is the result of Hoogsteen base pairing with the adduct. Both dCTP and dTTP base paired with the Hoogsteen edge of O(6)-methylG. A single, short hydrogen bond formed between the N3 atom of dTTP and the N7 atom of O(6)-methylG. Protonation of the N3 atom of dCTP and bifurcation of the N3 hydrogen between the N7 and O(6) atoms of O(6) methylG allow base pairing of the lesion with dCTP. We conclude that differences in the Hoogsteen hydrogen bonding between nucleotides is the main factor in the preferential selectivity of dTTP opposite O(6)-methylG by human pol iota, in contrast to the mispairing modes observed previously for O(6)-methylG in the structures of the model DNA polymerases Sulfolobus solfataricus Dpo4 and Bacillus stearothermophilus DNA polymerase I. PMID- 20961861 TI - Polyetheylenimine-polyplexes of Spiegelmer NOX-A50 directed against intracellular high mobility group protein A1 (HMGA1) reduce tumor growth in vivo. AB - High mobility group A1 (HMGA1) proteins belong to a group of architectural transcription factors that are overexpressed in a range of human malignancies, including pancreatic adenocarcinoma. They promote anchorage-independent growth and epithelial-mesenchymal transition and are therefore suggested as potential therapeutic targets. Employing in vitro selection techniques against a chosen fragment of HMGA1, we have generated biostable l-RNA oligonucleotides, so-called Spiegelmers, that specifically bind HMGA1b with low nanomolar affinity. We demonstrate that the best binding Spiegelmers, NOX-A50 and NOX-f33, compete HMGA1b from binding to its natural binding partner, AT-rich double-stranded DNA. We describe a formulation method based on polyplex formation with branched polyethylenimine for efficient delivery of polyethylene glycol-modified Spiegelmers and show improved tissue distribution and persistence in mice. In a xenograft mouse study using the pancreatic cancer cell line PSN-1, subcutaneous administration of 2 mg/kg per day NOX-A50 formulated in polyplexes showed an enhanced delivery of NOX-A50 to the tumor and a significant reduction of tumor volume. Our results demonstrate that intracellular targets can be successfully addressed with a Spiegelmer using polyethylenimine-based delivery and underline the importance of HMGA1 as a therapeutic target in pancreatic cancer. PMID- 20961862 TI - Derivatization of haemoglobin with periodate-generated reticulation agents: evaluation of oxidative reactivity for potential blood substitutes. AB - Periodate modification of the sugar moiety in sugars, including adenosine triphosphate (ATP), has previously been employed in order to prepare dialdehyde type reagents, which were then utilized in crosslinking reactions on haemoglobin, yielding polymerized material with useful dioxygen-binding properties and hence proposed as possible artificial oxygen carriers ('blood substitutes'). Here, the periodate protocol is shown to be applicable to a wider range of oxygen containing compounds, illustrated by starch and polyethylene glycol. Derivatization protocols are described for haemoglobin with such periodate treated crosslinking agents, and the dioxygen-binding properties and redox reactivities are investigated for the derivatized haemoglobins, with emphasis on pro-oxidative properties. There is a general tendency of the derivatization to result in higher autooxidation rates. The peroxide reactivity of the met (ferric) form is also affected by derivatization, as witnessed, among others, by varying yields of ferryl [Fe (IV)-oxo] and free radical generated. In cell, culture tests (human umbilical vein epithelial cells, HUVEC), the derivatization protocols show no toxic effect. PMID- 20961863 TI - Increased globotriaosylceramide levels in a transgenic mouse expressing human alpha1,4-galactosyltransferase and a mouse model for treating Fabry disease. AB - Fabry disease is a lysosomal storage disorder caused by an alpha-galactosidase A (alpha-Gal A) deficiency and resulting in the accumulation of glycosphingolipids, predominantly globotriaosylceramide (Gb3). A transgenic mouse expressing the human alpha-Gal A R301Q mutant in an alpha-Gal A-knockout background (TgM/KO) should be useful for studying active-site-specific chaperone (ASSC) therapy for Fabry disease. However, the Gb3 content in the heart tissue of this mouse was too low to detect an ASSC-induced effect. To increase the Gb3 levels in mouse organs, we created transgenic mice (TgG3S) expressing human alpha1,4 galactosyltransferase (Gb3 synthase). High levels of Gb3 were observed in all major organs of the TgG3S mouse. A TgG3S (+/-)M(+/-)/KO mouse was prepared by cross-breeding the TgG3S and TgM/KO mice and the Gb3 content in the heart of the TgG3S(+/-)M(+/-)/KO mouse was 1.4 ug/mg protein, higher than in the TgM(+/-)/KO (<0.1 ug/mg protein). Treatment with an ASSC, 1-deoxygalactonojirimycin, caused a marked induction of alpha-Gal A activity and a concomitant reduction of the Gb3 content in the TgG3S(+/-) M(+/-)/KO mouse organs. These data indicated that the TgG3S(+/-) M(+/-)/KO mouse was suitable for studying ASSC therapy for Fabry disease, and that the TgG3S mouse would be useful for studying the effect of high Gb3 levels in mouse organs. PMID- 20961864 TI - Quinolone compounds enhance delta-aminolevulinic acid-induced accumulation of protoporphyrin IX and photosensitivity of tumour cells. AB - Exogenous delta-aminolevulinic acid (ALA)-induced photodynamic therapy (PDT) has been used in the treatment of cancer. To obtain a high efficacy of ALA-PDT, we have screened various chemicals affecting ALA-induced accumulation of protoporphyrin in cancerous cells. When HeLa cells were treated with quinolone chemicals including enoxacin, ciprofloxacin or norfloxacin, the ALA-induced photodamage accompanied by the accumulation of protoporphyrin was stronger than that with ALA alone. Thus, quinolone compounds such as enoxacin, ciprofloxacin and norfloxacin enhanced ALA-induced photodamage. The increased ALA-induced photodamage in enoxacin-treated HeLa cells was decreased by haemin or ferric nitrilotriacetate (Fe-NTA), suggesting that an increase in iron supply cancels the accumulation of protoporphyrin. On the other hand, the treatment of the cells with ALA plus an inhibitor of haem oxygenase, Sn-protoporphyrin, led to an increase in the photodamage and the accumulation of protoporphyrin compared with those upon treatment with ALA alone, indicating that the cessation of recycling of iron from haem augments the accumulation. The use of quinolones plus Sn protoporphyrin strongly enhances ALA-induced photodamage. To examine the mechanisms involved in the increased accumulation of protoporphyrin, we incubated ferric chloride with an equivalent amount of quinolones. Iron-quinolone complexes with visible colours with a maximum at 450 nm were formed. The levels of iron metabolizing proteins in enoxacin- or ciprofloxacin-treated cells changed, indicating that quinolones decrease iron utilization for haem biosynthesis. Hence, we now propose that the use of quinolones in combination with ALA may be an extremely effective approach for the treatment modalities for PDT of various tumour tissues in clinical practice. PMID- 20961865 TI - Two high pressure conundrums and a possible congenital link. PMID- 20961866 TI - Conventional cardiopulmonary resuscitation by bystanders improved outcomes in children with out-of-hospital cardiac arrest. PMID- 20961867 TI - Lactobacillus GG prevented nosocomial gastrointestinal and respiratory tract infections. PMID- 20961868 TI - School grades, parental education and suicide--a national register-based cohort study. AB - BACKGROUND: To investigate whether school performance is a risk factor for suicide death later in life and, if so, to what extent this is explained by intergenerational effects of parental education. METHODS: This population-based cohort study comprises national birth cohorts between 1972 and 1981 in Sweden. We followed 898,342 students, graduating between 1988 and 1997 from the 9 years of compulsory school, equivalent to junior high school, until 31 December 2006, generating 11,148,758 person-years and 1490 suicides. Final school grades, in six categories, and risk of suicide were analysed with Poisson regression. RESULTS: The incidence rate ratio (RR) for suicide death for students with the lowest grades was 4.57 (95% CI 2.82 to 7.40) for men and 2.67 (1.42 to 5.01) for women compared to those with highest grades after adjustment for a number of sociodemographic and parental morbidity variables, such as year of graduation, parental education, lone parenthood, household receiving social welfare or disability pension, place of schooling, adoption, maternal age and parent's mental illness. Students with grades in the middle categories had RRs in between. These relationships were not modified by parental education. CONCLUSIONS: The strong association between low school grades and suicide in youth and young adulthood emphasises the importance of both primary and secondary prevention in schools. PMID- 20961870 TI - Hospital discharge data for assessing myocardial infarction events and trends, and effects of diagnosis validation according to MONICA and AHA criteria. AB - BACKGROUND: Acute myocardial infarction (AMI; ICD9-CM 410*) is a leading cause of morbidity and mortality all over the world, and its community surveillance is essential to monitor variation in the occurrence of the disease. Between the late 1990s and the early 2000s more sensitive and specific biomarkers of myocardial necrosis (ie, troponins) were introduced and new diagnostic criteria, emphasising the role of biomarkers, have been developed for clinical and epidemiological purposes. METHODS: Tosc-AMI is a population-based registry based on the record linkage between hospital and mortality databases; it provides trends of coronary events in Tuscany, Italy. Two random samples of patients admitted to hospital in 2003 were validated according to the American Heart Association (AHA; 2003) and the Multinational MONItoring of trends and determinants in CArdiovascular disease (MONICA) (1983) criteria. Sample 1 (380 cases) was represented by patients admitted to hospital for AMI and sample 2 (380 cases) for other coronary diagnosis. RESULTS: Tosc-AMI attack rates increased from the period 1997 to 2005 (men: +17%; women: +30%) and then they decreased in the following 2 years (men: 8%; women: -13%). The rise of AMI hospital admissions was due to cases with ICD9 CM code 410.7 (largely representing non-ST elevation MI). According to the AHA criteria, 94.6% events of sample 1 and 29.8% events of sample 2 fulfilled the most extensive criteria for definite, probable or possible AMI. As expected, the more updated AHA definition identified as definite AMI an additional 33.3% when compared to the MONICA criteria (86.0% vs 52.7%). CONCLUSIONS: The study suggests an influence of the new diagnostic criteria on the rising AMI trend observed in the early 2000s, an increase of less severe cases and a decreasing trend of forms with a more extended myocardial damage. PMID- 20961871 TI - The impact of monetary incentives on general fertility rates in Western Australia. AB - BACKGROUND: There has been widespread international concern about declining fertility rates and the long-term negative consequences particularly for industrialised countries with ageing populations. In an attempt to boost fertility rates, the Australian Government introduced a maternity payment known as the Baby Bonus. However, major concerns have been raised that such monetary incentives would attract teenagers and socially disadvantaged groups. METHODS: Population-level data and generalised linear models were used to examine general fertility rates between 1995 and 2006 by socioeconomic group, maternal age group, Aboriginality and location in Western Australia prior to and following the introduction of the Baby Bonus in July 2004. RESULTS: After a steady decline in general fertility rates between 1995 and 2004, rates increased significantly from 52.2 births per 1000 women, aged between 15 and 49 years, in 2004 to 58.6 births per 1000 women in 2006. While there was an overall increase in general fertility rates after adjusting for maternal socio-demographic characteristics, there were no significant differences among maternal age groups (p=0.98), between Aboriginal and non-Aboriginal women(p=0.80), maternal residential locations (p=0.98) or socioeconomic groups (p=0.68). The greatest increase in births were among women residing in the highest socioeconomic areas who had the lowest general fertility rate in 2004 (21.5 births per 1000 women) but the highest in 2006 (38.1 births per 1000 women). CONCLUSIONS: Findings suggest that for countries with similar social, economic and political climates to Australia, a monetary incentive may provide a satisfactory solution to declining general fertility rates. PMID- 20961872 TI - Evaluating the impact of non-response bias in the Behavioral Risk Factor Surveillance System (BRFSS). AB - BACKGROUND: Response rates of national health surveys are decreasing, which potentially can bias obtained prevalence estimates. The purpose of this study is to evaluate the extent to which non-response impacts the representativeness of the 2000 Behavioral Risk Factor Surveillance System (BRFSS) sample compared to the 2000 Decennial Census. METHODS: The 2000 BRFSS had a median response rate of 48%, while the 2000 Decennial Census had a response rate of 67%. Representativeness of the BRFSS sample was evaluated on gender, race, ethnicity, age, household income and marital status. Prevalence of each factor in the BRFSS was compared to the prevalence found in the US Census on both the state and county levels. Prevalence differences between the BRFSS and Census were calculated and their association with response rates was evaluated using robust OLS regression and polytomous logistic regression. The relationship between prevalence differences and other survey design elements, such as data collection procedure and sampling fraction, was also explored. RESULTS: The BRFSS prevalence estimates diverged from the Census estimates on several sociodemographic factors even after adjustment for non-response/non-coverage. This was found on both the state and county levels; however, smaller absolute differences between the BRFSS and Census prevalence estimates were found for factors included in the non response/non-coverage adjustment weight. Lower response rates (<40%) were associated with the under-representation of racial/ethnic minorities, women and younger individuals in the BRFSS survey. CONCLUSION: Future research should examine alternative approaches to increase response rate (eg, mixed mode) and to adjust for non-response (eg, multiple imputation). PMID- 20961873 TI - Increasing railway suicide acts after media coverage of a fatal railway accident? An ecological study of 747 suicidal acts. AB - BACKGROUND: While coverage of a celebrity suicide in the mass media may trigger copycat suicides, evidence for the effect of media reports of non-prominent suicides is moderate. Diversification of current media may raise further doubts as to whether their influence on suicidal acts is still present. We examined whether widespread media coverage of a railway accident, in which several people were killed while investigating a presumed railway suicide, subsequently increased the number of railway suicides. METHODS: The daily incidence of railway suicides was derived from the national accident registry on the German railway net. We estimated incidence ratios by Poisson regression, adjusting for relevant confounders (eg, outdoor temperature, unemployment rate), for the 2 months following the accident (predefined index period) and predefined control periods (preceding 2 years of the same period and 1 month before/after the index period). RESULTS: The mean number of railway suicides per day in the index period increased significantly to 2.66 (95% CI 2.19 to 3.13) compared to 1.94 (95% CI 1.78 to 2.10) during both control periods. Fully adjusted Poisson regression showed a 44% daily increase in railway suicides in the index period compared to the control periods (incidence ratio 1.44, 95% CI 1.02 to 2.03). A maximum of eight suicides per day was reached about 1 week after the accident. CONCLUSIONS: Non-fictional media coverage of a fatal accident appears to affect subsequent railway suicide numbers. Supposedly, media reports drew attention to railways as a means of suicide. PMID- 20961874 TI - Socioeconomic inequality profiles in physical and developmental health from 0-7 years: Australian National Study. AB - BACKGROUND: Early and persistent exposure to socioeconomic disadvantage impairs children's health and wellbeing. However, it is unclear at what age health inequalities emerge or whether these relationships vary across ages and outcomes. We address these issues using cross-sectional Australian population data on the physical and developmental health of children at ages 0-1, 2-3, 4-5 and 6-7 years. METHODS: 10 physical and developmental health outcomes were assessed in 2004 and 2006 for two cohorts each comprising around 5000 children. Socioeconomic position was measured as a composite of parental education, occupation and household income. RESULTS: Lower socioeconomic position was associated with increased odds for poor outcomes. For physical health outcomes and socio emotional competence, associations were similar across age groups and were consistent with either threshold effects (for poor general health, special healthcare needs and socio-emotional competence) or gradient effects (for illness with wheeze, sleep problems and injury). For socio-emotional difficulties, communication, vocabulary and emergent literacy, stronger socioeconomic associations were observed. The patterns were linear or accelerated and varied across ages. CONCLUSIONS: From very early childhood, social disadvantage was associated with poorer outcomes across most measures of physical and developmental health and showed no evidence of either strengthening or attenuating at older compared to younger ages. Findings confirm the importance of early childhood as a key focus for health promotion and prevention efforts. PMID- 20961875 TI - Seasonal patterns of mortality in relation to social factors. AB - BACKGROUND: New Zealand is a temperate country with substantial excess winter mortality. We investigated whether this excess winter mortality varies with social factors. METHODS: Records from New Zealand censuses in 1981, 1986, 1991, 1996 and 2001 were each anonymously and probabilistically linked to 3 years of subsequent mortality data creating five cohort studies of the New Zealand adult population (age 30-74 years at census) each with 3 years' follow-up. Logistic regression analysis was used to model the risk of dying in winter compared to summer with winter deaths classified '1' and summer deaths '0'. There were 75,138 eligible mortality records with complete data on social variables recorded for 58,683 (78%). RESULTS: Adjusting for age, sex, census year, ethnicity and tenure, those in the lowest tertile of income were at increased risk of winter death compared to those in the highest tertile: OR 1.13 (95% CI 1.08 to 1.19). Compared to home owners, people living in rented accommodation were at greater risk of winter death: OR 1.05 (95% CI 1.01 to 1.10). Urban dwellers were also at significantly increased risk. The strongest associations were seen for infectious diseases. CONCLUSIONS: There was an increased risk of dying in winter for most New Zealanders, but more so among low-income people, those living in rented accommodation and those living in cities. Exact causal mechanisms are not known but possibly include correlated poorer health status, low indoor temperatures and household crowding. PMID- 20961876 TI - The impact of community-based outreach immunisation services on immunisation coverage with GIS network accessibility analysis in peri-urban areas, Zambia. AB - BACKGROUND: Accessibility to health services is a critical determinant for health outcome. OBJECTIVES: To examine the association between immunisation coverage and distance to an immunisation service as well as socio-demographic and economic factors before and after the introduction of outreach immunisation services, and to identify optimal locations for outreach immunisation service points in a peri urban area in Zambia. METHODS: Repeated cross-sectional surveys were conducted for two groups of children born between 1999 and 2001, and between 2003 and 2005.The association between immunisation coverage for DPT3 and measles, and access distance, child sex, female headed households, and monthly household income were assessed using logistic regression analysis. Optimal locations for outreach service points were identified using GIS network analysis and genetic algorithms. RESULTS: Before the introduction of outreach services, longer distances to the service points were associated with lower DPT3 and measles immunisation coverage (OR=0.24, 95% CI 0.10 to 0.56, p<0.01 for DPT3; and OR=0.38, 95% CI 0.17 to 0.83, p<0.05 for measles). However, access distances were not an impediment to immunisation coverage once the outreach services were introduced. The average distance to immunisation services could be decreased from 232.3 to 168.4 metres if the current 12 outreach service points were repositioned at optimal locations. CONCLUSION: Access distance to immunisation services was a critical determinant of immunisation coverage in a peri-urban area. Intervention via outreach services played an important role in averting the risk of missing out on immunisation. Optimal location analysis has the potential to contribute to efficient decision making regarding the delivery of immunisation services. PMID- 20961877 TI - Contribution of income-related inequality and healthcare utilisation to survival in cancers of the lung, liver, stomach and colon. AB - OBJECTIVES: To examine differences in the survival rates of cancer patients according to socioeconomic status, focusing on the role of the degree of healthcare utilisation by the patient. METHODS: An observational follow-up study was done for 261 lung cancer, 259 liver cancer, 268 stomach cancer and 270 colon cancer patients, diagnosed during 1999-2002. Income status and healthcare utilisation were assessed with National Health Insurance (NHI) data; survival during 1999-2002 was identified by death certificate. HRs and 95% CI were derived from Cox proportional hazards regression. RESULTS AND CONCLUSIONS: The HRs for low income status are larger for colon cancer (2.37, 95% CI 1.17 to 4.80), followed by stomach (1.67, 95% CI 1.01 to 2.78), liver (1.57, 95% CI 1.03 to 2.39) and lung cancers (1.46, 95% CI 0.99 to 2.14). In the model including the variable of healthcare utilisation, colon and stomach cancers exhibited a lower HR in the moderate healthcare utilisation groups (0.40, 95% CI 0.21 to 0.76 in colon; 0.59, 95% CI 0.37 to 0.96 in stomach), whereas for liver cancer, the high utilisation group exhibited a higher hazard (1.72, 95% CI 1.07 to 2.75). A lower income status is independently related to a shorter survival time in cancer patients, especially in less fatal cancers. Healthcare utilisation independently affects the likelihood of survival from colon and stomach cancers, implying that a moderate degree of healthcare utilisation contributes to a longer survival time. PMID- 20961878 TI - Erratum re: Prevalence of overweight and obesity in East and West German children in the decade after reunification: population-based series of cross-sectional studies. PMID- 20961879 TI - Patterning of a compound eye on an extinct dipteran wing. AB - We have discovered unexpected similarities between a novel and characteristic wing organ in an extinct biting midge from Baltic amber, Eohelea petrunkevitchi, and the surface of a dipteran's compound eye. Scanning electron microscope images now reveal vestigial mechanoreceptors between the facets of the organ. We interpret Eohelea's wing organ as the blending of these two developmental systems: the formation and patterning of the cuticle in the eye and of the wing. Typically, only females in the genus carry this distinctive, highly organized structure. Two species were studied (E. petrunkevitchi and E. sinuosa), and the structure differs in form between them. We examine Eohelea's wing structures for modes of fabrication, material properties and biological functions, and the effective ecological environment in which these midges lived. We argue that the current view of the wing organ's function in stridulation has been misconstrued since it was described half a century ago. PMID- 20961880 TI - Trematode parasites infect or die in snail hosts. AB - The Red Queen hypothesis is based on the assumption that parasites must genetically match their hosts to infect them successfully. If the parasites fail, they are assumed to be killed by the host's immune system. Here, we tested this using sympatric (mostly susceptible) and allopatric (mostly resistant) populations of a freshwater snail and its trematode parasite. We determined whether parasites which do not infect are either killed or passed through the host's digestive tract and remain infectious. Our results show that parasites do not get a second chance: they either infect or are killed by the host. The results suggest strong selection against parasites that are not adapted to local host genotypes. PMID- 20961881 TI - Decomposing phylogenetic entropy into alpha, beta and gamma components. AB - Measuring the phylogenetic diversity of communities has become a key issue for biogeography and conservation. However, most diversity indices that rely on interspecies phylogenetic distances may increase with species loss and thus violate the principle of weak monotonicity. Moreover, most published phylogenetic diversity indices ignore the abundance distribution along phylogenetic trees, even though lineage abundances are crucial components of biodiversity. The recently introduced concept of phylogenetic entropy overcomes these limitations, but has not been decomposed across scales, i.e. into alpha, beta and gamma components. A full understanding of mechanisms sustaining biological diversity within and between communities needs such decomposition. Here, we propose an additive decomposition framework for estimating alpha, beta and gamma components of phylogenetic entropy. Based on simulated trees, we demonstrate its robustness to phylogenetic tree shape and species richness. Our decomposition fulfils the requirements of both independence between components and weak monotonicity. Finally, our decomposition can also be adapted to the partitioning of functional diversity across different scales with the same desirable properties. PMID- 20961882 TI - Mushroom's spore size and time of fruiting are strongly related: is moisture important? AB - Most basidiomycete fungi produce annual short-lived sexual fruit bodies from which billions of microscopic spores are spread into the air during a short time period. However, little is known about the selective forces that have resulted in some species fruiting early and others later in the fruiting season. This study of relationships between morphological and ecological characteristics, climate factors and time of fruiting are based upon thorough statistical analyses of 66 520 mapped records from Norway, representing 271 species of autumnal fruiting mushroom species. We found a strong relationship between spore size and time of fruiting; on average, a doubling of spore size (volume) corresponded to 3 days earlier fruiting. Small-spored species dominate in the oceanic parts of Norway, whereas large-spored species are typical of more continental parts. In separate analyses, significant relationships were observed between spore size and climate factors. We hypothesize that these relationships are owing to water balance optimization, driven by water storage in spores as a critical factor for successful germination of primary mycelia in the drier micro-environments found earlier in the fruiting season and/or in continental climates. PMID- 20961883 TI - Intraspecific queen parasitism in a highly eusocial bee. AB - Insect societies are well-known for their advanced cooperation, but their colonies are also vulnerable to reproductive parasitism. Here, we present a novel example of an intraspecific social parasitism in a highly eusocial bee, the stingless bee Melipona scutellaris. In particular, we provide genetic evidence which shows that, upon loss of the mother queen, many colonies are invaded by unrelated queens that fly in from unrelated hives nearby. The reasons for the occurrence of this surprising form of social parasitism may be linked to the fact that unlike honeybees, Melipona bees produce new queens in great excess of colony needs, and that this exerts much greater selection on queens to seek alternative reproductive options, such as by taking over other nests. Overall, our results are the first to demonstrate that queens in highly eusocial bees can found colonies not only via supersedure or swarming, but also by infiltrating and taking over other unrelated nests. PMID- 20961884 TI - Eating the competition speeds up invasions. AB - Many introduced species engage in intraguild predation (IGP), the consumption of species with which they compete for shared resources. While the factors influencing local persistence of IG predator and prey species are well understood, using these factors to predict the invasion speed of an introduced IG predator has received less attention. Existing theory predicts that native competitors slow invasions via depletion of shared resources, but this fails to account for additional resources acquired when an invader consumes competitors. Here, I outline a general framework for understanding the effect of IGP on invasion speeds. I find that invaders that consume native competitors may be able to spread where invasion by pure competitors would fail, and that invasion speed increases with increasing levels of IGP. Notably, if the benefit from consuming competitors outweighs the loss of shared resources to competitors, invasion proceeds faster than invasion in the absence of competitors. This may explain empirical observations of rapid spread rates of invaders that feed at multiple trophic levels. PMID- 20961885 TI - Parasitic infection reduces dispersal of ciliate host. AB - Parasitic infection can modify host mobility and consequently their dispersal capacity. We experimentally investigated this idea using the ciliate Paramecium caudatum and its bacterial parasite Holospora undulata. We compared the short distance dispersal of infected and uninfected populations in interconnected microcosms. Infection reduced the proportion of hosts dispersing, with levels differing among host clones. Host populations with higher densities showed lower dispersal, possibly owing to social aggregation behaviour. Parasite isolates that depleted host populations most had the lowest impact on host dispersal. Parasite induced modification of dispersal may have consequences for the spatial distribution of disease, host and parasite genetic population structure, and coevolution. PMID- 20961886 TI - Resource availability affects the structure of a natural bacteria-bacteriophage community. AB - Antagonistic networks are known to be structured in the wild, but knowledge on how this structure may change as a response to environmental perturbations is scarce. We describe a natural bipartite network between bacteria and lytic bacteriophages, and investigate how it is affected by environmental productivity in the form of different resource levels for the bacteria. We report that low amounts of resource decrease phage generality and lead to less robust and less stable communities. We discuss how resource levels in nature may alter the structure of complex communities. PMID- 20961887 TI - Evaluation of sphingolipid metabolism in renal cortex of rats with streptozotocin induced diabetes and the effects of rapamycin. AB - BACKGROUND: Abnormal lipid metabolism contributes to the pathogenesis of diabetes, but it is uncertain whether it plays a role in the development of diabetic nephropathy (DN). While rapamycin was shown to prevent DN development in streptozotocin (STZ)-induced diabetic rats in our previous studies, it is unknown if it intervenes with lipid metabolism. METHODS: We divided the rats into four groups: normal control rats, rapamycin-treated normal rats, diabetic rats and rapamycin-treated DN rats. The apoptosis was evaluated by immunohistochemistry. The crude lipid and sphingolipid were extracted from rat renal cortex and analysed by matrix-assisted laser desorption ionization-time of flight mass spectrometry. The expression of the three key enzymes in sphingolipid metabolism including serine palmitoyltransferase, acid sphingomyelinase and sphingomyelin synthase was measured by western blot and immunohistochemistry in rat renal cortex. RESULTS: The level of apoptosis was increased in diabetic rats, and rapamycin treatment reduced apoptosis. STZ treatment significantly increased formation of many sphingolipids species through elevated de novo synthesis. These changes were inhibited by treatment with rapamycin. CONCLUSIONS: Accumulation of sphingolipids contributes to STZ-induced diabetes, and the therapeutic effect of rapamycin on diabetic nephropathy is partly through suppression of sphingolipid abnormality. PMID- 20961888 TI - The role of graft-versus-host disease in haematopoietic cell transplantation associated glomerular disease. AB - BACKGROUND: Glomerular disease among haematopoietic cell transplantation recipients has been attributed to chronic graft-versus-host disease. Clinical outcomes of this population may be influenced by the haematopoietic cell transplantation conditioning regimen, donor factors and chronic graft-versus-host disease. METHODS: In this review, 95 cases of haematopoietic cell transplantation associated glomerular disease were identified from literature review for analysis. Patient characteristics, the association of chronic graft-versus-host disease with glomerular diseases, and the impact of host and haematopoietic cell transplantation regimen on outcomes were evaluated. RESULTS: The median onset of glomerular disease from haematopoietic cell transplantation and from cessation of immunosuppressive agents was 15.5 and 1 month, respectively. Although chronic graft-versus-host disease was common among haematopoietic cell transplant recipients with glomerulonephritis (72%), this was no different from that observed in the overall haematopoietic cell transplantation population. Membranous nephropathy and minimal change disease are the most prevalent glomerular diseases among haematopoietic cell transplantation recipients. Chronic graft-versus-host disease, donor factors and haematopoietic cell transplant regimen did not significantly impact outcomes in this study population. CONCLUSIONS: Pathogenic mechanisms in addition to (or other than) chronic graft versus-host disease are likely contribute to haematopoietic cell transplantation associated glomerular disease. Further investigation will be required to delineate clearly the pathogenesis. PMID- 20961889 TI - Screening for renal cancer in recipients of kidney transplants. AB - BACKGROUND: Renal cancer is the most common solid organ cancer in the kidney transplant population with an excess risk ~ 5-fold greater than the general population. It is uncertain whether routine screening for renal cancer is cost effective. The aim of our study is to estimate the costs and health benefits of ultrasonographic (US) screening for renal cancer in the kidney transplant population. METHODS: A Markov model was developed to compare the costs and benefits in a cohort of kidney transplant recipients (n = 1000, aged 18-69 years), who underwent annual and biennial US screening for renal cancer, compared with a cohort that did not. RESULTS: For recipients of kidney transplants aged 18 69 years, the incremental cost-effectiveness ratio (ICER) for routine US screening ranged from $252,100/LYS for biennial screening to $320,988/LYS for annual screening. A total of two and one cancer deaths were averted in the annually and biennially screened population, with a relative cancer-specific mortality reduction by 25% and 12.5%, respectively. Using a series of sensitivity analyses, the ICER was most sensitive to the costs and test specificity of ultrasonography, prevalence of disease, and the risk of graft failure in the screened population. CONCLUSIONS: Routine screening for renal cancer may reduce the risk of cancer-related deaths in recipients of kidney transplants. Uncertainties, however, exist in the model's influential variables including the risk of graft failure among those who received contrast-enhanced diagnostic computer tomography. Given the available evidence, routine screening for renal cancers may not be cost-effective for recipients of kidney transplants. PMID- 20961890 TI - Cystatin C, mortality risk and clinical triage in US adults: threshold values and hierarchical importance. AB - BACKGROUND: It has been suggested that cystatin C may be a superior measure of estimated glomerular filtration rate (eGFR) than creatinine-based methods. We aimed to assess the utility of cystatin C for clinical triage in community-based settings. METHODS: We identified cystatin C thresholds that maximize sensitivity and specificity (Max(Sn + Sp)) for predicting death and subsequently applied classification tree methodology considering serum creatinine, creatinine-based eGFR, urinary albumin-creatinine ratio and conventional modifiable risk factors to define subgroups, interactions and hierarchical ranks in fasting US adults (National Health and Nutrition Examination Survey 1988-94, followed through 2006). RESULTS: A threshold cystatin C value of 0.94 mg/L exhibited the best maximum combined value of sensitivity and specificity for predicting death (Max(Sn + Sp), Sn 0.64/Sp 0.78). When all variables were considered jointly in a classification tree, cystatin C and albumin-creatinine ratio were the primary mortality discriminators in subgroups that added up to 41 and 14% of the study population, respectively; serum creatinine and creatinine-based eGFR were non discriminatory. CONCLUSION: Cystatin C may be useful for risk-based clinical triage in public health settings. PMID- 20961891 TI - Organ donation, transplantation and religion. AB - Religious concerns may be an important reason why patients decline listing for a renal transplant. These issues may be equally, or even more, important when live donation is discussed. There is good reason to believe that religious concerns play a significant role much more often than clinicians and transplant teams believe. The issue is certainly further compounded by the fact that a few, if any, patients come forward with their religious concerns, not least because issue of transplantation is new to them anyway and because they meet with transplant teams whom they do not know. Health professionals, on the other hand, may wish to avoid this sensitive issue altogether or may lack knowledge on religious issues pertaining to transplantation. Some may be entirely unaware. We encountered a case in clinic that revealed our remarkable lack of knowledge in this regard. Here, we aim to provide an overview on how the different religions view transplantation and organ donation, with an emphasis on practical points for health care professionals who are involved in transplant listing, organ donation and retrieval, and transplantation itself. Knowledge of these facts may provide a background to deal with these issues professionally and appropriately and to increase transplant numbers. PMID- 20961892 TI - A comparison of cystatin C- and creatinine-based prediction equations for the estimation of glomerular filtration rate in black South Africans. AB - BACKGROUND: Serum creatinine (S-Cr)-based prediction equations are commonly used for estimating glomerular filtration rate (GFR). However, S-Cr concentration is also affected by other factors such as tubular secretion, muscle mass, diet, gender and age. Serum cystatin C (S-Cys C)-based prediction equations have been proposed as an improved potential alternative as S-Cys C levels are not influenced by many of the factors that affect creatinine concentration other than GFR. This may be of great benefit to patients with low muscle mass such as those infected with human immunodeficiency virus who are at increased risk for the development of renal impairment. The aim of this study was to develop and evaluate a S-Cys C-based prediction equation for different stages of renal disease in black South Africans. METHODS: One hundred patients with varying degrees of renal function were enrolled in the study. The plasma clearance of (51)Cr-EDTA, a gold standard method, was used to measure GFR (mGFR). In addition, serum was analysed for S-Cr and S-Cys C on each participant. This dataset was split into a development dataset (n = 50) and a test dataset (n = 50). The development dataset was used to formulate a S-Cys C- and S-Cr-based prediction equation using multiple linear regression analysis. These equations together with the four-variable MDRD and CKD-EPI equation were then tested on the test dataset. RESULTS: In the test dataset, accuracy within 15% of measured GFR was 68% for the S-Cys C equation and 48% for the S-Cr equation. Root mean square error for S-Cr eGFR was 10.7 mL/min/1.73 m(2) for those patients with mGFR < 60 mL/min/1.73 m(2) and 25.5 mL/min/1.73 m(2) for those patients with mGFR > 60 mL/min/1.73 m(2). Root mean square error for S-Cys C eGFR was 10.2 mL/min/1.73 m(2) for those patients with mGFR < 60 mL/min/1.73 m(2) and 11.9 mL/min/1.73 m(2) for those patients with mGFR > 60 mL/min/1.73 m(2). CONCLUSIONS: In this study, S-Cys C based prediction equations appear to be more precise than those of S-Cr for those patients with mGFR > 60 mL/min/1.73 m(2) and may therefore be of benefit in the earlier detection of renal impairment. PMID- 20961894 TI - Strong seasonality produces spatial asynchrony in the outbreak of infectious diseases. AB - Models for infectious diseases usually assume a fixed demographic structure. Yet, a disease can spread over a region encountering different local demographic variations that may significantly alter local dynamics. Spatial heterogeneity in the resulting dynamics can lead to important differences in the design of surveillance and control strategies. We illustrate this by exploring the north south gradient in the seasonal demography of raccoon rabies over the eastern USA. We find that the greater variance in the timing of spring births characteristic of southern populations can lead to the spatial synchronization of southern epidemics, while the narrow birth-pulse associated with northern populations can lead to an irregular patchwork of epidemics. These results indicate that surveillance in the southern states can be reduced relative to northern locations without loss of detection ability. This approach could yield significant savings in vaccination programmes. The importance of seasonality in many widely distributed diseases indicates that our findings will find applications beyond raccoon rabies. PMID- 20961895 TI - Nano-mechanical properties of individual mineralized collagen fibrils from bone tissue. AB - Mineralized collagen fibrils (MCFs) are distinct building blocks for bone material and perform an important mechanical function. A novel experimental technique using combined atomic force microscopy and scanning electron microscopy is used to manipulate and measure the mechanical properties of individual MCFs from antler, which is a representative bone tissue. The recorded stress-strain response of individual MCFs under tension shows an initial linear deformation region for all fibrils, followed by inhomogeneous deformation above a critical strain. This inhomogeneous deformation is indicative of fibrils exhibiting either yield or strain hardening and suggests possible mineral compositional changes within each fibril. A phenomenological model is used to describe the fibril nano mechanical behaviour. PMID- 20961896 TI - The mixed mating system of the sea palm kelp Postelsia palmaeformis: few costs to selfing. AB - Naturally isolated populations have conflicting selection pressures for successful reproduction and inbreeding avoidance. These species with limited seasonal reproductive opportunities may use selfing as a means of reproductive assurance. We quantified the frequency of selfing and the fitness consequences for inbred versus outcrossed progeny of an annual kelp, the sea palm (Postelsia palmaeformis). Using experimentally established populations and microsatellite markers to assess the extent of selfing in progeny from six founding parents, we found the frequency of selfing was higher than expected in every population, and few fitness costs were detected in selfed offspring. Despite a decline in heterozygosity of 30 per cent in the first generation of selfing, self fertilization did not affect individual size or reproduction, and correlated only with a marginally significant decline in survival. Our results suggest both that purging of deleterious recessive alleles may have already occurred and that selfing may be key to reproductive assurance in this species with limited dispersal. Postelsia has an alteration of a free-living diploid and haploid stage, where the haploid stage may provide increased efficiency for purging the genetic load. This life history is shared by many seaweeds and may thus be an important component of mating system evolution in the sea. PMID- 20961897 TI - Helper effects on pup lifetime fitness in the cooperatively breeding red wolf (Canis rufus). AB - The evolutionary maintenance of cooperative breeding systems is thought to be a function of relative costs and benefits to breeders, helpers and juveniles. Beneficial effects of helpers on early-life survivorship and performance have been established in several species, but lifetime fitness benefits and/or costs of being helped remain unclear, particularly for long-lived species. We tested for effects of helpers on early- and late-life traits in a population of reintroduced red wolves (Canis rufus), while controlling for ecological variables such as home-range size and population density. We found that the presence of helpers in family groups was positively correlated with pup mass and survival at low population density, but negatively correlated with mass/size at high density, with no relation to survival. Interestingly, mass/size differences persisted into adulthood for both sexes. While the presence of helpers did not advance age at first reproduction for pups of either sex, females appeared to garner long-term fitness benefits from helpers through later age at last reproduction, longer reproductive lifespan and a greater number of lifetime reproductive events, which translated to higher lifetime reproductive success. In contrast, males with helpers exhibited diminished lifetime reproductive performance. Our findings suggest that while helper presence may have beneficial short-term effects in some ecological contexts, it may also incur long-term sex-dependent costs with critical ramifications for lifetime fitness. PMID- 20961898 TI - Salticid predation as one potential driving force of ant mimicry in jumping spiders. AB - Many spiders possess myrmecomorphy, and species of the jumping spider genus Myrmarachne exhibit nearly perfect ant mimicry. Most salticids are diurnal predators with unusually high visual acuity that prey on various arthropods, including conspecifics. In this study, we tested whether predation pressure from large jumping spiders is one possible driving force of perfect ant mimicry in jumping spiders. The results showed that small non-ant-mimicking jumping spiders were readily treated as prey by large ones (no matter whether heterospecific or conspecific) and suffered high attack and mortality rates. The size difference between small and large jumping spiders significantly affected the outcomes of predatory interactions between them: the smaller the juvenile jumping spiders, the higher the predation risk from large ones. The attack and mortality rates of ant-mimicking jumping spiders were significantly lower than those of non-ant mimicking jumping spiders, indicating that a resemblance to ants could provide protection against salticid predation. However, results of multivariate behavioural analyses showed that the responses of large jumping spiders to ants and ant-mimicking salticids differed significantly. Results of this study indicate that predation pressure from large jumping spiders might be one selection force driving the evolution of nearly perfect myrmecomorphy in spiders and other arthropods. PMID- 20961899 TI - Why the leopard got its spots: relating pattern development to ecology in felids. AB - A complete explanation of the diversity of animal colour patterns requires an understanding of both the developmental mechanisms generating them and their adaptive value. However, only two previous studies, which involved computer generated evolving prey, have attempted to make this link. This study examines variation in the camouflage patterns displayed on the flanks of many felids. After controlling for the effects of shared ancestry using a fully resolved molecular phylogeny, this study shows how phenotypes from plausible felid coat pattern generation mechanisms relate to ecology. We found that likelihood of patterning and pattern attributes, such as complexity and irregularity, were related to felids' habitats, arboreality and nocturnality. Our analysis also indicates that disruptive selection is a likely explanation for the prevalence of melanistic forms in Felidae. Furthermore, we show that there is little phylogenetic signal in the visual appearance of felid patterning, indicating that camouflage adapts to ecology over relatively short time scales. Our method could be applied to any taxon with colour patterns that can reasonably be matched to reaction-diffusion and similar models, where the kinetics of the reaction between two or more initially randomly dispersed morphogens determines the outcome of pattern development. PMID- 20961900 TI - The shape of things to come: woodland herb niche contraction begins during recruitment in mesic forest microhabitat. AB - Natural abundance is shaped by the abiotic requirements and biotic interactions that shape a species' niche, yet these influences are rarely decoupled. Moreover, most plant mortality occurs during early life stages, making seed recruitment critical in structuring plant populations. We find that natural abundance of two woodland herbs, Hexastylis arifolia and Hepatica nobilis, peaks at intermediate resource levels, a pattern probably formed by concurrent abiotic and biotic interactions. To determine how this abundance patterning reflects intrinsic physiological optima and extrinsic biotic interactions, we translocate adults and seeds to novel locations across experimentally extended abiotic gradients. These experiments indicate that the plant distributions probably reflect biotic interactions as much as physiological requirements, and that adult abundance provides a poor indication of the underlying niche requirements. The positive response exhibited by adult transplants in the wettest conditions is offset by increased fungal attack on buried seeds consistent with peak natural abundance where soil moisture is intermediate. This contraction of niche space is best described by Connell's model--species are limited by physiological tolerances where resources are low and biotic interactions where resources are high. PMID- 20961901 TI - Availability of new Bayesian-delimited gecko names and the importance of character-based species descriptions. PMID- 20961902 TI - A general rule for sensory cue summation: evidence from photographic, musical, phonetic and cross-modal stimuli. AB - The Euclidean and MAX metrics have been widely used to model cue summation psychophysically and computationally. Both rules happen to be special cases of a more general Minkowski summation rule , where m = 2 and infinity, respectively. In vision research, Minkowski summation with power m = 3-4 has been shown to be a superior model of how subthreshold components sum to give an overall detection threshold. Recently, we have previously reported that Minkowski summation with power m = 2.84 accurately models summation of suprathreshold visual cues in photographs. In four suprathreshold discrimination experiments, we confirm the previous findings with new visual stimuli and extend the applicability of this rule to cue combination in auditory stimuli (musical sequences and phonetic utterances, where m = 2.95 and 2.54, respectively) and cross-modal stimuli (m = 2.56). In all cases, Minkowski summation with power m = 2.5-3 outperforms the Euclidean and MAX operator models. We propose that this reflects the summation of neuronal responses that are not entirely independent but which show some correlation in their magnitudes. Our findings are consistent with electrophysiological research that demonstrates signal correlations (r = 0.1-0.2) between sensory neurons when these are presented with natural stimuli. PMID- 20961903 TI - Social complexity and linguistic diversity in the Austronesian and Bantu population expansions. AB - Reconstructing the rise and fall of social complexity in human societies through time is fundamental for understanding some of the most important transformations in human history. Phylogenetic methods based on language diversity provide a means to reconstruct pre-historic events and model the transition rates of cultural change through time. We model and compare the evolution of social complexity in Austronesian (n = 88) and Bantu (n = 89) societies, two of the world's largest language families with societies representing a wide spectrum of social complexity. Our results show that in both language families, social complexity tends to build and decline in an incremental fashion, while the Austronesian phylogeny provides evidence for additional severe demographic bottlenecks. We suggest that the greater linguistic diversity of the Austronesian language family than Bantu likely follows the different biogeographic structure of the two regions. Cultural evolution in both the Bantu and Austronesian cases was not a simple linear process, but more of a wave-like process closely tied to the demography of expanding populations and the spatial structure of the colonized regions. PMID- 20961904 TI - Azooxanthellate? Most Hawaiian black corals contain Symbiodinium. AB - The ecological success of shallow-water reef-building corals (Hexacorallia: Scleractinia) is framed by their intimate endosymbiosis with photosynthetic dinoflagellates in the genus Symbiodinium (zooxanthellae). In contrast, the closely related black corals (Hexacorallia: Anthipatharia) are described as azooxanthellate (lacking Symbiodinium), a trait thought to reflect their preference for low-light environments that do not support photosynthesis. We examined 14 antipatharian species collected between 10 and 396 m from Hawai'i and Johnston Atoll for the presence of Symbiodinium using molecular typing and histology. Symbiodinium internal transcribed spacer-2 (ITS-2) region sequences were retrieved from 43 per cent of the antipatharian samples and 71 per cent of the examined species, and across the entire depth range. The ITS-2 sequences were identical or very similar to those commonly found in shallow-water scleractinian corals throughout the Pacific. Histological analyses revealed low densities of Symbiodinium cells inside antipatharian gastrodermal tissues (0-92 cells mm(-3)), suggesting that the Symbiodinium are endosymbiotic. These findings confirm that the capacity to engage in endosymbiosis with Symbiodinium is evolutionarily conserved across the cnidarian subclass Hexacorallia, and that antipatharians associate with Symbiodinium types found in shallow-water scleractinians. This study represents the deepest record for Symbiodinium to date, and suggests that some members of this dinoflagellate genus have extremely diverse habitat preferences and broad environmental ranges. PMID- 20961905 TI - Asynchrony adaptation reveals neural population code for audio-visual timing. AB - The relative timing of auditory and visual stimuli is a critical cue for determining whether sensory signals relate to a common source and for making inferences about causality. However, the way in which the brain represents temporal relationships remains poorly understood. Recent studies indicate that our perception of multisensory timing is flexible--adaptation to a regular inter modal delay alters the point at which subsequent stimuli are judged to be simultaneous. Here, we measure the effect of audio-visual asynchrony adaptation on the perception of a wide range of sub-second temporal relationships. We find distinctive patterns of induced biases that are inconsistent with the previous explanations based on changes in perceptual latency. Instead, our results can be well accounted for by a neural population coding model in which: (i) relative audio-visual timing is represented by the distributed activity across a relatively small number of neurons tuned to different delays; (ii) the algorithm for reading out this population code is efficient, but subject to biases owing to under-sampling; and (iii) the effect of adaptation is to modify neuronal response gain. These results suggest that multisensory timing information is represented by a dedicated population code and that shifts in perceived simultaneity following asynchrony adaptation arise from analogous neural processes to well known perceptual after-effects. PMID- 20961906 TI - Plasma RANTES: a molecular fingerprint of the unstable carotid plaque? PMID- 20961908 TI - Treatment of progressive multifocal leukoencephalopathy and idiopathic CD4+ lymphocytopenia. AB - Progressive multifocal leukoencephalopathy is a neurological disease caused by the human polyoma virus JC virus and can present in patients with known immunodeficiencies. However, when associated with idiopathic CD4+ lymphocytopenia, management of patients can be quite challenging as these are two rare diseases with limited effective treatment options. In conjunction with the case report of a patient diagnosed with both conditions presented within this issue, a discussion of available treatment strategies is detailed. PMID- 20961907 TI - Drug-resistant cytomegalovirus in transplant recipients: a French cohort study. AB - OBJECTIVES: Cytomegalovirus (CMV) drug resistance is a therapeutic challenge in the transplant setting. No longitudinal cohort studies of CMV resistance in a real-life setting have been published in the valganciclovir era. We report findings for a French multicentre prospective cohort of 346 patients enrolled at initial diagnosis of CMV infection (clinical trial registered at clinicaltrials.gov: NCT01008540). PATIENTS AND METHODS: Patients were monitored for detection of CMV infection for >=2 years. Real-time detection of resistance by UL97 and UL54 gene sequencing and antiviral phenotyping was performed if viral replication persisted for >21 days of appropriate antiviral treatment. Plasma ganciclovir assays were performed when resistance was suspected. RESULTS: Resistance was suspected in 37 (10.7%) patients; 18/37 (5.2% of the cohort) had virological resistance, associated with poorer outcome. Most cases involved single UL97 mutations, but four cases of multidrug resistance were due to UL54 mutations. In solid organ transplant recipients, resistance occurred mainly during primary CMV infection (odds ratio 8.78), but also in two CMV-seropositive kidney recipients. Neither CMV prophylaxis nor antilymphocyte antibody administration was associated with virological resistance. CONCLUSIONS: These data show the feasibility of surveying resistance. Virological resistance was frequent in patients failing antiviral therapy. More than 1/5 resistant isolates harboured UL54 mutations alone or combined with UL97 mutations, which conferred a high level of resistance and sometimes were responsible for cross-resistance, leading to therapeutic failure. PMID- 20961909 TI - Comment on: role of changes in the L3 loop of the active site in the evolution of enzymatic activity of VIM-type metallo-beta-lactamases. PMID- 20961910 TI - Posaconazole cerebrospinal concentrations in an HIV-infected patient with brain mucormycosis. PMID- 20961911 TI - Polymyxin B versus other antimicrobials for the treatment of pseudomonas aeruginosa bacteraemia. AB - OBJECTIVES: to compare the efficacy of intravenous polymyxin B with other antimicrobials in the treatment of nosocomial Pseudomonas aeruginosa bacteraemia, assessing many potential confounding factors, including optimal dosage regimens of drugs. METHODS: a retrospective cohort study was performed. Patients >= 18 years of age and who received appropriate therapy for >= 48 h for P. aeruginosa bacteraemia were analysed. Clinical covariates were assessed and compared between patients treated with polymyxin B and other drugs (comparators). Data were retrieved from medical records. Renal toxicity was also assessed. A Cox regression model was performed including variables with a P <= 0.20 in the comparison between both groups. RESULTS: a total of 133 patients were included: 45 (33.8%) treated with polymyxin B and 88 (66.2%) with comparators. Most comparators (83.0%) were beta-lactams. The overall in-hospital mortality was 41.4% (55/133): 66.7% (30/45) and 28.4% (25/88) in polymyxin B and comparator groups, respectively (P <= 0.001). The final multivariate model showed that treatment with polymyxin B was independently associated with in-hospital mortality (adjusted hazard ratio 1.91, 95% confidence interval 1.05-3.45), after adjustment for Pitt bacteraemia score, and the presence of mechanical ventilation and primary bloodstream infection. Patients treated with polymyxin B presented a higher rate of >= 100% increase in creatinine level from baseline than comparators [11/45 (24.4%) versus 4/88 (4.5%); P = 0.002], although this was not subjected to multivariate analysis. CONCLUSIONS: intravenous polymyxin B therapy was inferior to other drugs in the treatment of P. aeruginosa bacteraemia, as indicated by the higher rate of in-hospital mortality. PMID- 20961912 TI - pUO-SeVR1 is an emergent virulence-resistance complex plasmid of Salmonella enterica serovar Enteritidis. PMID- 20961913 TI - Prognostic impact of sleep disordered breathing and its treatment in heart failure: an observational study. AB - AIMS: Sleep disordered breathing (SDB) may contribute to disease progression in patients with chronic heart failure (CHF). The objective of this observational study was to evaluate whether SDB is a risk factor for mortality in CHF patients and whether this risk can be attenuated by treatment with positive airway pressure (PAP). METHODS AND RESULTS: We studied 296 CHF patients (median left ventricular ejection fraction 33%) who underwent in-lab polysomnography between January 2002 and December 2009. We compared (i) mortality between patients with severe SDB [apnoea-hypopnoea index (AHI) >= 22.5 h(-1)] vs. those without severe SDB (AHI < 22.5 h(-1)) and (ii) evaluated the impact of PAP treatment on mortality in those with severe SDB. After accounting for significant confounding factors (age, NYHA class, cause of CHF, diabetes, and PAP treatment), patients with severe SDB (n= 176) had a 2.0-fold increased hazard ratio for death compared with those without severe SDB [95% confidence interval (CI) 1.1-3.5, P= 0.023]. In an adjusted on-treatment analysis of the group with severe SDB, mortality was significantly less in patients using PAP (18%) compared with those with untreated SDB (52%; hazard ratio 0.4, 95% CI 0.2-0.6, P= 0.001). Mortality in the PAP treated group was lower compared with the untreated group at any time-point of the follow-up period. CONCLUSION: The presence of severe SDB in CHF patients constitutes a significantly increased risk for death, independent of established risk factors. In CHF patients with SDB, use of PAP therapy was associated with a decreased mortality rate at any time point of the follow-up, suggesting that PAP can be safely used in such patients. PMID- 20961914 TI - Phases of school health promotion implementation through the lens of complexity theory: lessons learnt from an Austrian case study. AB - The implementation of health promotion concepts in (school) settings is a complex undertaking on which little scientific knowledge exists. The purpose of this study was to better understand organizational influences on the implementation of school health promotion. An extended case study design that incorporated important insights from complexity science was used. This design influenced the focus of analysis and led to the use of multiple methods of data collection and analysis. A primary school in Vienna served as a case for observing and analysing the first year of implementing the health-promoting school concept. The study provided detailed insights into the implementation process. Results showed four chronologically overlapping implementation phases (starting health promotion, deciding what to do, planning health promotion projects, doing health promotion) on different system levels. In each phase, the original health-promoting school concept was adapted to the necessities and characteristics of each level and, therefore, changed considerably. Implications for possible adaptations of the health-promoting school concept to better fit the situation in schools are discussed. PMID- 20961915 TI - Field-based fitness assessment in young people: the ALPHA health-related fitness test battery for children and adolescents. AB - The present study summarises the work developed by the ALPHA (Assessing Levels of Physical Activity) study and describes the procedures followed to select the tests included in the ALPHA health-related fitness test battery for children and adolescents. The authors reviewed physical fitness and health in youth findings from cross-sectional studies. The authors also performed three systematic reviews dealing with (1) the predictive validity of health-related fitness, (2) the criterion validity of field-based fitness tests and (3) the reliability of field based fitness tests in youth. The authors also carried out 11-methodological studies to determine the criterion validity and the reliability of several field based fitness tests for youth. Finally, the authors performed a study in the school setting to examine the reliability, feasibility and safety of the selected tests. The selected fitness tests were (1) the 20 m shuttle run test to assess cardiorespiratory fitness; (2) the handgrip strength and (3) standing broad jump to assess musculoskeletal fitness, and (4) body mass index, (5) skinfold thickness and (5) waist circumference to assess body composition. When there are time limits, the authors propose the high-priority ALPHA health-related fitness test battery, which comprises all the evidence-based fitness tests except the measurement of the skinfold thickness. The time required to administer this battery to a group of 20 youth by one physical education teacher is less than 2 h. In conclusion, the ALPHA fitness tests battery is valid, reliable, feasible and safe for the assessment of health-related physical fitness in children and adolescents to be used for health monitoring purposes at population level. PMID- 20961916 TI - Passive flooding of paranasal sinuses and middle ears as a method of equalisation in extreme breath-hold diving. AB - Breath-hold diving is both a recreational activity, performed by thousands of enthusiasts in Europe, and a high-performance competitive sport. Several 'disciplines' exist, of which the 'no-limits' category is the most spectacular: using a specially designed heavy 'sled,' divers descend to extreme depths on a cable, and then reascend using an inflatable balloon, on a single breath. The current world record for un-assisted descent stands at more than 200 m of depth. Equalising air pressure in the paranasal sinuses and middle-ear cavities is a necessity during descent to avoid barotraumas. However, this requires active insufflations of precious air, which is thus unavailable in the pulmonary system. The authors describe a diver who, by training, is capable of allowing passive flooding of the sinuses and middle ear with (sea) water during descent, by suppressing protective (parasympathetic) reflexes during this process. Using this technique, he performed a series of extreme-depth breath-hold dives in June 2005, descending to 209 m of sea water on one breath of air. PMID- 20961917 TI - Injury in elite county-level hurling: a prospective study. AB - OBJECTIVE: To determine the incidence, prevalence and nature of sports injuries in elite male hurling players. DESIGN: Prospective study of county-grade hurling teams. Incidence, prevalence and descriptions of injuries were collated. SETTING: Four county teams during the 2007 season; January to September inclusive. PARTICIPANTS: A total of 127 male players were followed over 34 weeks. Data were collected on a median (IQR) of 31 (30-32) players per team per week. The mean age was 23.3+/-2.5 years. RESULTS: There were 204 injuries to 104 players (82%, 95% CI (74 to 88)). Injury incidence rate during match-play (102.5 (84.4 to 123.2)) was 19 times higher than for training (5.3 (4.2 to 6.5)) (RR=19.5 (14.8 to 25.6)). The mean weekly prevalence of injury was 13.9% (12.5 to 14.8). Most injuries were new (n=170, 83.3%, (77.6 to 87.8)) and acute (n=165, 80.9% (74.9 to 85.7)). Muscle strain (n=86) accounted for 42.2% (35.6 to 49) of the total. 71% of injuries were to the lower limb (n=143, (63.5 to 76.0)) with hamstring strain (n=33, 16.5% (11.8 to 21.8)) predominating. Fractures constituted 7.4% injuries (n=15, 95% CI (4.5 to 11.8)), 12 of which were to the upper limb. There were three (1.5% (0.5 to 4.2)) eye injuries and one concussion injury (0.5% (0.1 to 2.7)). CONCLUSIONS: These results provide data on hurling injuries using definitions that reflect international consensus statements. Injury incidence from match-play in particular is high compared with other sports. These findings have relevance for clinicians and coaches. PMID- 20961918 TI - Injury risk of playing football in Futsal World Cups. AB - BACKGROUND: While injuries in football (soccer) have been the subject of numerous publications, little information is available about the injury risk in futsal. OBJECTIVE: Analysis of the incidence and characteristics of injury in futsal players during top-level international tournaments. DESIGN: Prospective survey. METHODS: Player injuries during three consecutive Futsal World Cups were analysed using an established injury report system. The physicians of all participating teams reported all injuries after each match on a standardised injury report form. The average response rate was 93%. RESULTS: A total of 165 injuries were reported from 127 matches, which is equivalent to an incidence of 195.6 injuries per 1000 player hours (95% CI 165.8 to 225.6) or 130.4 injuries per 1000 player matches (95% CI 110.5 to 150.3). The majority of injuries were caused by contact with another player, and 36% of the injuries occurred during non-contact activities. Most injuries affected the lower extremity (70%), followed by head and neck (13%), upper extremity (10%) and trunk (7%). The most frequent diagnoses were contusion of the lower leg (11%), ankle sprain (10%) and groin strain (8%). On average, one time-loss injury in every two matches was reported. CONCLUSION: While the location and diagnosis of injuries were similar in the two types of football, fewer injuries in futsal than in football were caused by contact with another player and by foul play. More information on injury mechanisms in futsal is needed to develop specific injury preventive interventions. PMID- 20961919 TI - Referrals from a primary care-based sports medicine department to an orthopaedic department: a retrospective cohort study. AB - OBJECTIVE: To describe the impact of an expanded primary care-based sports medicine clinic on referrals to an orthopaedics clinic and to describe the patients seen and procedures performed. DESIGN: Retrospective cohort study. SETTING: Primary care-based sports medicine clinic and orthopaedics clinic at a tax-supported American safety net healthcare system. PARTICIPANTS: All patients referred to the sports medicine clinic by other primary care physicians over a 1 year time period of July 2006-June 2007. MAIN OUTCOME MEASURES: The referral rate from sports medicine clinic to orthopaedics clinic, the percentage of referred patients who were recommended surgery by the orthopaedists, the change in average waiting time to be seen in orthopaedics clinic and the most common conditions and procedures. RESULTS: 4925 patients were seen by the sports medicine department; 118 (2.4%) of those patients were referred to the orthopaedic department. Of the referred patients, surgery was offered by orthopaedists to 80 (68%) patients. The average wait for initial consultation by the orthopaedic spine clinic decreased from 199 to 70 days; the wait for general orthopaedic clinic decreased from 97 to 19 days. No single patient complaint or musculoskeletal pathology predominated: knee degenerative joint disease (25.3%), mechanical low back pain (21.6%) and lumbar disc disease (19.9%). Knee injections and epidural steroid injections were the most common procedures performed. CONCLUSIONS: Very few patients with musculoskeletal pathology were referred by a primary care-based sports medicine clinic to an orthopaedics clinic. Of the referred patients, sports medicine physicians and orthopaedists frequently agreed on the need for surgery. Expansion of a primary care-based sports medicine service could help relieve overburdened orthopaedics departments of patients with conditions not requiring surgery. PMID- 20961920 TI - Clustered metabolic risk and leisure-time physical activity in adolescents: effect of dose? AB - OBJECTIVES: The authors studied the association of leisure-time physical activity (LTPA) with clustered and individual metabolic risk factors in adolescents taking into account diet and pubertal status. The authors also studied whether screen time was associated with clustered risk. METHODS: Self-reported LTPA and screen time, lipids, lipoproteins, apolipoproteins, high-sensitivity C reactive protein, blood pressure, body mass index (BMI), pubertal status and diet were assessed in 13-year-old adolescents (n=542) participating in an atherosclerosis prevention study (Special Turku Coronary Risk Factor Intervention Project for Children). Activity groups were formed according to sex-specific LTPA index tertile cut-off points. BMI, high-density lipoprotein cholesterol (HDL-C), triglycerides and blood pressure comprised the cluster. RESULTS: An increase in LTPA was associated with a decreased risk for clustered metabolic risk in girls. When sedentary and highly active adolescents were compared, an increase in LTPA decreased clustering of risk factors in boys as well. Little extra benefit on clustered risk was obtained by increasing LTPA from 30 MET h/week (eg, 4-5 h/week bicycling or playing soccer) to 50 MET h/week (eg, 7-8 h/week bicycling or playing soccer). LTPA was beneficially associated with BMI, HDL-C, systolic blood pressure and HDL C/total cholesterol in girls and HDL-C in boys. Diet and pubertal status were similar in all activity groups. In girls, screen time >2 h/day was associated with an increased risk for clustered risk, independent of LTPA. CONCLUSION: Sedentary adolescents had an increased risk for clustered metabolic risk compared with physically more active peers. Only minor extra benefit was obtained when LTPA increased over 30 MET h/week. Focus in the prevention of clustered risk should especially be on avoiding sedentary lifestyle. PMID- 20961921 TI - The epidemiology of injuries in English youth community rugby union. AB - INTRODUCTION: Recent studies report the incidence and epidemiology of injury in professional rugby union; however, there is limited research in amateur and youth rugby. Injuries in youth rugby may have consequences for sports participation and physical development. The authors performed a prospective cohort study of injuries during youth community rugby. METHODS: An injury surveillance programme was established for the 2008-2009 season (9 months, 1636 player-hours) of an English community rugby club. The study included 210 players, all males, in Under 9 to Under 17 (U9-U17) age groups. These were categorised into mini, junior, pubertal and school participation age groupings. Injuries were defined according to the International Rugby Board consensus statements. RESULTS: There were 39 injuries reported (overall injury rate 24/1000 player-hours). Injury rates ranged from 0 to 49.3/1000 player-hours. More injuries occurred in junior (34.2/1000 player-hours) than in minis (11.9/1000 player-hours) (p<0.025). Higher numbers of moderate (20.6/1000 player-hours, p<0.005) and severe (9.5/1000 player-hours, p<0.05) injuries occurred in the U16-U17 age groups compared with younger age groups (U9-U10) where only minor injuries were reported. Most injuries occurred in the tackle (59%). The knee (4.9/1000 player-hours), shoulder (4.9/1000 player hours) and head (4.3/1000 player-hours) were the most commonly affected areas. Concussion (1.8/1000 player-hours) affected half of the head injuries. CONCLUSIONS: Injuries in youth rugby occur infrequently and are lower than in adult series. The risk of injury and severity of injury increases with age. This study highlights the need for further research into injury risk factors around puberty and the need for first aid provision. PMID- 20961922 TI - Reproduction in females: the role of the early life environment. AB - BACKGROUND: There is now compelling evidence that long-term health and physiological function are modified by events that occur early in life and involve interactions between the genome and the developmental environment. That reproductive function may similarly be influenced by early life events has been established in selected human populations, and investigations into underlying mechanisms are the subject of current animal studies. METHODS: No systematic literature search was conducted. This review highlights early life influences on reproduction with a particular focus on nutritional impacts, and provides a brief overview with reference to some key studies in both the human and animal literature. We highlight the controversies, current unanswered questions and mechanisms underlying the association between the early life environment and long term reproductive function. RESULTS AND CONCLUSIONS: Currently, the impact of early life events on reproductive health and disease risk is poorly understood. It is clear, however, that nutrition spanning the entire developmental lifespan plays an integral role. Improved insight into the underlying mechanisms is likely to have significant implications for our current understanding of reproductive disorders, and therefore for the health and reproductive potential of future generations. PMID- 20961924 TI - Global economics. PMID- 20961923 TI - Reproductive isolation and pollination success of rewarding Galearis diantha and non-rewarding Ponerorchis chusua (Orchidaceae). AB - BACKGROUND AND AIMS: Increasing evidence challenges the conventional perception that orchids are the most distinct example of floral diversification due to floral or prezygotic isolation. Regarding the relationship between co-flowering plants, rewarding and non-rewarding orchids in particular, few studies have investigated whether non-rewarding plants affect the pollination success of rewarding plants. Here, floral isolation and mutual effects between the rewarding orchid Galearis diantha and the non-rewarding orchid Ponerorchis chusua were investigated. METHODS: Flowering phenological traits were monitored by noting the opening and wilting dates of the chosen individual plants. The pollinator pool and pollinator behaviour were assessed from field observations. Key morphological traits of the flowers and pollinators were measured directly in the field. Pollinator limitation and interspecific compatibility were evaluated by hand pollination experiments. Fruit set was surveyed in monospecific and heterospecific plots. KEY RESULTS: The species had overlapping peak flowering periods. Pollinators of both species displayed a certain degree of constancy in visiting each species, but they also visited other flowers before landing on the focal orchids. A substantial difference in spur size between the species resulted in the deposition of pollen on different regions of the body of the shared pollinator. Hand-pollination experiments revealed that fruit set was strongly pollinator-limited in both species. No significant difference in fruit set was found between monospecific plots and heterospecific plots. CONCLUSIONS: A combination of mechanical isolation and incomplete ethological isolation eliminates the possibility of pollen transfer between the species. These results do not support either the facilitation or competition hypothesis regarding the effect of nearby rewarding flowers on non-rewarding plants. The absence of a significant effect of non-rewarding P. chusua on rewarding G. diantha can be ascribed to low levels of overlap between the pollinator pools of two species. PMID- 20961925 TI - Rare epiphysiolysis of the radius in a 9-year-old boy. PMID- 20961926 TI - Harness suspension and first aid management: development of an evidence-based guideline. AB - The possibility of a fall into rope protection and subsequent suspension exists in some industrial situations. The action to take for the first aid management of rescued victims has not been clear, with some authors advising against standard first aid practices. To clarify the medical evidence relating to harness suspension the UK Health and Safety Executive commissioned an evidence-based review and guideline. Four key questions were posed relating to the incidence, circumstances, recognition and first aid management of the medical effects of harness suspension. A comprehensive literature search returned 60 potential papers with 29 papers being reviewed. The Scottish Intercollegiate Guideline Network (SIGN) methodology was used to critically review the selected papers and develop a guideline. A stakeholders' workshop was held to review the evidence and draft recommendations. Nine papers formed the basis of the guideline recommendations. No data on the incidence of harness suspension syncope were found. Presyncopal symptoms or syncope are thought to occur with motionless suspension as a consequence of orthostasis leading to hypotension. There was no evidence of any other pathology, despite this being hypothesised by others. No evidence was found that showed the efficacy or safety of positioning a victim in a semirecumbent position. In any case of harness suspension, the standard UK first aid guidance for recovery of a semiconscious or unconscious person in a horizontal position should be followed. Other recommendations included areas for further research and proposals for standard data collection on falls into rope protection. PMID- 20961927 TI - Which improvements could prevent the departure of the left-without-being-seen patients? AB - OBJECTIVES: To determine which measures, other than a reduction in waiting time, could prevent the departure of the left-without-being-seen (LWBS) patients in an emergency department. Secondary objectives were description of the characteristics of LWBS patients, analysis of their reasons for leaving and assessment of their medical outcome. METHODS: A feasibility study was used to establish a telephone survey form. A prospective study of 421 patients was then carried out between 23 November 2006 and 12 February 2007 in the Poissy emergency department. Every LWBS patient whose telephone number was available in the administrative file was included. Patients who could not be contacted within 7 days after their departure were excluded. Statistical analyses were performed using STATA 8.0 software. RESULTS: 12,702 patients were admitted to the emergency department, of whom 421 (3.3%) (95% CI 0.030 to 0.036) left without being seen by a physician. 229 patients (54%) agreed to respond to the survey. 56% of the LWBS patients informed the medical team that they were leaving the emergency department. 74% of the surveyed participants suggested measures that could have helped them wait longer. These measures can be separated into two main categories: an improvement in communication and an improvement in the comfort of the emergency department waiting room. CONCLUSION: The 'quality' of the waiting time appears to be important in the decision to leave. If this aspect was taken into account, a reduction in the number of LWBS patients and improved quality of care could be achieved in emergency departments. PMID- 20961928 TI - Can emergency department nurses performing triage predict the need for admission? AB - OBJECTIVE: To investigate whether nurses performing triage are able to predict the need for admission of patients attending the emergency department (ED) with sufficient accuracy to facilitate hospital bed management. METHODS: A prospective observational study was performed in which nurses performing triage, in a large urban UK hospital, were asked to predict whether patients would ultimately be admitted or discharged from the ED. RESULTS: 3144 patients attended the ED during the trial period, of which 296 were excluded from the study. The positive predictive value of the nurse performing triage's prediction for the whole study cohort was 54.23. CONCLUSION: Predicting admission at triage is not sufficiently accurate to inform hospital in-patient bed management systems. The decision to admit can only be determined after a comprehensive clinical work up and patients cannot be accurately 'signposted' during the triage process. PMID- 20961930 TI - Can S-100B serum protein help to save cranial CT resources in a peripheral trauma centre? A study and consensus paper. AB - BACKGROUND: Cranial CT (CCT) is the gold standard to rule out traumatic brain injury. The serum level of the protein S-100B has recently been proposed as promising marker of traumatic brain injury. We prospectively investigated whether it might be a reliable tool for CCT triage in mild brain injury at a peripheral trauma centre with limited CT resources. METHODS: Patients with mild head injury and a Glasgow Coma Score of 13-15 admitted to the emergency department of a peripheral trauma centre were enrolled. Blood samples for S-100B analysis were obtained after clinical evaluation. The cut-off level for positive S-100B was 0.105 MUg/l. All patients underwent CCT. The relationship between clinical findings, CCT results and S-100B levels was evaluated. RESULTS: 233 patients were enrolled. Median time between injury and sampling was 137 min. CCT was positive in 22 (9%) patients. Of these, 19 (8%) had positive serum S-100B levels. Overall, S-100B had a specificity of 12.2% and a sensitivity of 86.4%, with a positive predictive value of 12.8% and a negative predictive value of 85.7% as a selection tool for CCT triage in patients with mild head injury. CONCLUSION: The S-100B serum level showed a high sensitivity and negative predictive value in the screening of patients with mild head injury. The use of serum S-100B as a biomarker for CCT triage may improve patient screening and decrease the number of CCT scans performed. This would reduce unnecessary radiation exposure and free up capacity in the emergency rooms of peripheral hospitals to enable them to cope better with multiple admissions. PMID- 20961931 TI - Over-bedding or de-bunking. PMID- 20961932 TI - Acute coronary syndromes can be a headache. AB - Ischaemic heart disease is a common cause of morbidity and mortality worldwide. Patients typically present with chest pain and breathlessness either on exertion or at rest. Cardiac ischaemia can also lead to headache, although this is very rarely its only manifestation. Headache is mostly associated with migraine, cluster and tension headache disorders. More sinister causes include subarachnoid haemorrhage, temporal arteritis, meningitis, venous sinus thrombosis as well as vertebral and carotid artery dissection. A case of headache is presented where the underlying cause was cardiac ischaemia, itself the result of triple vessel coronary artery disease. This, also referred to as cardiac cephalgia, should be suspected in the older patient with risk factors for atherosclerotic disease presenting with recent-onset headache. Diagnosis of this requires high clinical suspicion and is essential for correct patient management. PMID- 20961933 TI - Precocious subdural haematoma. PMID- 20961934 TI - Body temperature of trauma patients on admission to hospital: a comparison of anaesthetised and non-anaesthetised patients. AB - BACKGROUND: Hypothermia at hospital admission has been found to independently predict increased mortality in trauma patients. Objectives To establish if patients anaesthetised in the prehospital phase of care had a higher rate of hypothermia than non-anaesthetised patients on admission to hospital. METHODS: Retrospective review of admission body temperature in 1292 consecutive prehospital trauma patients attended by a physician-led prehospital trauma service admitted to The Royal London Hospital between 1 July 2005 and 31 December 2008. RESULTS: 38% had a temperature recorded on admission. There was a significant difference in body temperature between the anaesthetised group (N=207) and the non-anaesthetised group (N=287): mean (SD) 35.0 (2.1) vs 36.2 (1.0) degrees C, respectively (p<0.001). No significant seasonal body temperature variation was demonstrated. CONCLUSION: This study confirmed that patients anaesthetised in the prehospital phase of care had a significantly lower admission body temperature. This has led to a change in the author's prehospital practice. Anaesthetised patients are now actively surface heated and have whole body insulation to prevent further heat loss in an attempt to conserve body temperature and improve outcome. This is an example of best in-hospital anaesthetic practice being carried out in the prehospital phase. PMID- 20961935 TI - Validation of a triage flowchart to rule out acute coronary syndrome. AB - OBJECTIVE: To validate a triage flowchart to rule out acute coronary syndrome (ACS) in chest pain patients attending the emergency department (ED). METHODS: An observational cohort study of consecutive patients. In all cases, a previously derived five-step triage flowchart (age <= 40 years, absence of diabetes, not previously known coronary artery disease, non-oppressive and non-retrosternal pain) was applied. Patients meeting all five discriminators were grouped as 'five step triage non-ACS', the rest as 'five-step triage ACS'. The same strategy was used with a four-step model (without age <= 40 years). After ED study and 1-month follow-up, patients were definitively classified as 'true ACS' or 'true non-ACS'. Validity indexes and receiver operating characteristics curves were calculated. RESULTS: 4231 patients were included: 918 (21.7%) were 'true ACS', 3303 (78.1%) 'true non-ACS'; 10 (0.2%) were lost to follow-up. The five-step triage flowchart classified 4000 (94.8%) as 'triage ACS' and 221 (5.2%) as 'triage non-ACS'; none of the latter was 'true ACS'. The four-step model classified 3194 (75.6%) as 'triage ACS' and 1027 (24.4%) as 'triage non-ACS'. A 'true ACS' was seen in 26 patients from the latter group. Accordingly, five-step triage flowchart specificity and positive predictive value (PPV) to rule out ACS were 100% (95% CI 100% to 100%). For the four-step model specificity and PPV were 97% (95% CI 96% to 98%). CONCLUSION: The five-step triage flowchart identifies chest pain patients without an ACS. However, only 5% of these patients meet these five criteria. A simpler model allows greater patient inclusion but a higher risk of misclassification of true ACS. PMID- 20961936 TI - Systematic review of trends in emergency department attendances: an Australian perspective. AB - Emergency departments (EDs) in many developed countries are experiencing increasing pressure due to rising numbers of patient presentations and emergency admissions. Reported increases range up to 7% annually. Together with limited inpatient bed capacity, this contributes to prolonged lengths of stay in the ED; disrupting timely access to urgent care, posing a threat to patient safety. The aim of this review is to summarise the findings of studies that have investigated the extent of and the reasons for increasing emergency presentations. To do this, a systematic review and synthesis of published and unpublished reports describing trends and underlying drivers associated with the increase in ED presentations in developed countries was conducted. Most published studies provided evidence of increasing ED attendances within developed countries. A series of inter-related factors have been proposed to explain the increase in emergency demand. These include changes in demography and in the organisation and delivery of healthcare services, as well as improved health awareness and community expectations arising from health promotion campaigns. The factors associated with increasing ED presentations are complex and inter-related and include rising community expectations regarding access to emergency care in acute hospitals. A systematic investigation of the demographic, socioeconomic and health-related factors highlighted by this review is recommended. This would facilitate untangling the dynamics of the increase in emergency demand. PMID- 20961937 TI - Management of acute allergic reactions by dispatching physicians in a Medical Emergency Dispatch Centre. AB - BACKGROUND: Acute allergic reactions often occur in out-of-hospital settings, and some of these reactions may cause death in the short term. However, initial diagnosis, management and processing of acute allergic reactions by Medical Emergency Dispatch Centres are not documented. The aim of the present study was to describe acute allergic reactions and their management by a Medical Emergency Dispatch Centre. METHODS: A prospective study was conducted from 20 August 2006 to 5 November 2006 on incoming calls for acute allergic reactions to the Medical Emergency Dispatch Centre for the Hauts de Seine (Paris West suburb, France). The agreement between initial diagnosis (made by dispatching physician) and final diagnosis (made by the physician who later examined the patient), and between initial and final severity, were evaluated using Cohen's weighted kappa coefficient. RESULTS: 210 calls were included. The diagnoses made by the dispatching physician were: in 58.1% of cases urticaria, in 23.8% angioedema, in 13.3% laryngeal oedema, and in 1.9% anaphylactic shock. The agreement between initial and final diagnoses was evaluated by a kappa coefficient at 0.44 (95% CI 0.26 to 0.61) and the agreement between initial and final severity was evaluated using a kappa coefficient at 0.37 (95% CI 0.24 to 0.50). CONCLUSIONS: Only moderate agreement is highlighted between the initial severity assessed by the dispatching physician and the final severity assessed by the physician later examining the patient. This demonstrates the need to develop a tool for assessing severity of acute allergic reactions for dispatching physicians in Medical Emergency Dispatch Centres. PMID- 20961938 TI - Posterior myocardial infarction: are we failing to diagnose this? AB - INTRODUCTION: Isolated posterior ST-elevation myocardial infarction (STEMI) accounts for up to 7% of STEMIs. The diagnosis is suggested by indirect anterior lead ECG changes. Confirmation requires presence of ST-elevation in posterior leads (V7-V9). We investigated the ability of hospital doctors and paramedics to diagnose posterior STEMI (PMI). METHODS: Doctors in the emergency department and acute medical unit at two teaching hospitals and West Midlands Ambulance Service Paramedics were asked to interpret a 12-lead ECG illustrating ST-depression and dominant R-wave in V1-V2 in the context of cardiac chest pain, and identify PMI as a potential diagnosis. Their ability to identify PMI was compared with their ability to diagnose anterolateral STEMI on a 12-lead ECG. We assessed whether doctors knew that posterior-leads were required to confirm PMI and whether doctors and nurses could position posterior-leads. RESULTS: 44 of the 117 doctors (38%) identified PMI as a potential diagnosis. PMI was identified by 73% of registrars, 30% of senior house-officers and 18% of house-officers. 50% of doctors who identified potential PMI knew that posterior-leads were required to confirm the diagnosis. 20% of doctors correctly positioned these and 19% knew the diagnostic criteria for PMI (ST-elevation >=1 mm in V7-V9). 13 of the 60 nurses (22%) in the emergency department and acute medical unit correctly positioned posterior-leads. Five of the 50 (10%) paramedics identified PMI as a potential diagnosis. Doctors and paramedics were significantly better at diagnosing anterolateral STEMI than PMI. CONCLUSIONS: A significant proportion of doctors and paramedics were unable to diagnose PMI. Hence, the majority of PMIs may be being missed. Routine use of posterior-leads in the standard assessment of patients with chest pain may identify up to an additional 7% of STEMIs, allowing prompt reperfusion therapy, which would reduce morbidity and mortality. PMID- 20961939 TI - Is computer-assisted telephone triage safe? A prospective surveillance study in walk-in patients with non-life-threatening medical conditions. AB - BACKGROUND: Patients often establish initial contact with healthcare institutions by telephone. During this process they are frequently medically triaged. PURPOSE: To investigate the safety of computer-assisted telephone triage for walk-in patients with non-life-threatening medical conditions at an emergency unit of a Swiss university hospital. METHODS: This prospective surveillance study compared the urgency assessments of three different types of personnel (call centre nurses, hospital physicians, primary care physicians) who were involved in the patients' care process. Based on the urgency recommendations of the hospital and primary care physicians, cases which could potentially have resulted in an avoidable hazardous situation (AHS) were identified. Subsequently, the records of patients with a potential AHS were assessed for risk to health or life by an expert panel. RESULTS: 208 patients were enrolled in the study, of whom 153 were assessed by all three types of personnel. Congruence between the three assessments was low. The weighted kappa values were 0.115 (95% CI 0.038 to 0.192) (hospital physicians vs call centre), 0.159 (95% CI 0.073 to 0.242) (primary care physicians vs call centre) and 0.377 (95% CI 0.279 to 0.480) (hospital vs primary care physicians). Seven of 153 cases (4.57%; 95% CI 1.85% to 9.20%) were classified as a potentially AHS. A risk to health or life was adjudged in one case (0.65%; 95% CI 0.02% to 3.58%). CONCLUSION: Medical telephone counselling is a demanding task requiring competent specialists with dedicated training in communication supported by suitable computer technology. Provided these conditions are in place, computer-assisted telephone triage can be considered to be a safe method of assessing the potential clinical risks of patients' medical conditions. PMID- 20961940 TI - Early goal-directed therapy for all UK emergency departments? PMID- 20961941 TI - In vitro maturation of human germinal vesicle-stage oocytes: role of epidermal growth factor-like growth factors in the culture medium. AB - BACKGROUND: In vitro maturation (IVM) of oocytes is a promising technique to reduce the costs and avert the side effects of gonadotrophin stimulation for IVF. The pregnancy rates from oocytes matured in vitro are still lower than those of in vivo stimulation cycles, indicating that optimization of IVM remains a challenge. Recently, it was demonstrated that LH exerts its action on ovulation, at least in part, through stimulation of the production of the epidermal growth factor family members amphiregulin (Areg) and epiregulin (Ereg) in pre-ovulatory follicles, and they, in turn, serve as paracrine mediators of LH. We aimed to investigate the effect of supplementation of the medium with Areg and Ereg on the maturation rate of immature oocytes. METHODS: A total of 105 sibling human germinal vesicle (GV) oocytes obtained after gonadotrophin stimulation were cultured in a complex defined medium either with or without supplemented recombinant human Areg (75 ng/ml) and Ereg (75 ng/ml) for 24 h. RESULTS: Significantly more oocytes reached the metaphase II stage at 24 h in media supplemented with Areg and Ereg (75.5 versus 36.5%, P < 0.001). In vitro matured oocytes retrieved from the two subgroups had no statistically significant difference in fertilization and cleavage rates or morphology scores. Overall, a significantly higher number of Day 2 (52.8 versus 26.9% P < 0.01) and Day 3 (45.2 versus 23%, P < 0.05) embryos originated from GV oocytes cultured in the Areg- and Ereg-enriched medium. CONCLUSIONS: Supplementation of the maturation medium with Areg and Ereg improves the maturation of human GV oocytes in vitro. PMID- 20961942 TI - Factors influencing physicians' advice about female sterilization in USA: a national survey. AB - BACKGROUND: Tubal ligation can be a controversial method of birth control, depending on the patient's circumstances and the physician's beliefs. METHODS: In a national survey of 1800 US obstetrician-gynecologist (Ob/Gyn) physicians, we examined how patients' and physicians' characteristics influence Ob/Gyns' advice about, and provision of, tubal ligation. Physicians were presented with a vignette in which a patient requests tubal ligation. The patient's age, gravida/parity and her husband's agreement/disagreement were varied in a factorial experiment. Criterion variables were whether physicians would discourage tubal ligation, and whether physicians would provide the surgery. RESULTS: The response rate was 66% (1154/1760). Most Ob/Gyns (98%) would help the patient to obtain tubal ligation, although 9-70% would attempt to dissuade her, depending on her characteristics. Forty-five percent of physicians would discourage a G2P1 (gravida/parity) woman, while 29% would discourage a G4P3 woman. Most physicians (59%) would discourage a 26-year-old whose husband disagreed, while 32% would discourage a 26-year-old whose husband agreed. For a 36-year-old patient, 47% would discourage her if her husband disagreed, while only 10% would discourage her if her husband agreed. Physicians' sex had no significant effect on advice about tubal ligation. CONCLUSIONS: Regarding patients who seek surgical sterilization, physicians' advice varies based on patient age, parity and spousal agreement but almost all Ob/Gyns are willing to provide or help patients obtain surgical sterilization if asked. An important limitation of the study is that a brief vignette, while useful for statistical analysis, is a rough approximation of an actual clinical encounter. PMID- 20961943 TI - Condom avoidance and determinants of demand for male circumcision in Johannesburg, South Africa. AB - BACKGROUND Circumcision is efficacious in reducing HIV acquisition in heterosexual males. The South Africa government has been reluctant to adopt a national circumcision programme, possibly due to concerns that circumcision may result in decreased condom use. OBJECTIVE To identify the determinants of demand for male circumcision, to examine variations by ethnicity, and to determine whether it is demanded to avoid condom use. METHODS 403 parents and 237 sons in Johannesburg, South Africa, were recruited through a randomized household survey, with oversampling to balance between blacks (n = 220), 'coloured' (mixed ethnicity) (n = 202) and whites (n = 218). The demand for male circumcision was estimated using a conjoint analysis, with each respondent randomly receiving four tasks comparing seven possible benefits-six identified through key informant interviews and one for condom avoidance. Respondents' choices were analysed using logistic regression, including stratified analyses to test for homogeneity. RESULTS Overall, circumcision's beneficial effects on HIV transmission (P < 0.001), sexually transmitted infection (STI) transmission (P < 0.001), hygiene (P < 0.05) and sex (P < 0.05) were identified as determinants of demand, but the condom avoidance hypothesis was rejected as it was 'repulsive' to respondents (P < 0.001). Consistent results were found for blacks (P < 0.001) and coloured (P < 0.001), but not for whites who found condom avoidance attractive (P < 0.04), a result not explained by variations in wealth, age or paternal circumcision status. CONCLUSIONS Male circumcision programmes should be tailored to accommodate variations in the determinants of demand across the target population. We find that circumcision's protective effect against HIV acquisition in men is the only determinant to be found consistently across all ethnic groups in Johannesburg. We also find that concerns over condom avoidance may have been overstated. This said, male circumcision strategies should reinforce a range of HIV prevention strategies, including condom use, as we find evidence that whites may view circumcision as a means to avoid condom use. PMID- 20961944 TI - The other crisis: the economics and financing of maternal, newborn and child health in Asia. AB - The Global Financial Crisis (GFC) of 2008/2009 was the largest economic slowdown since the Great Depression. It undermined the growth and development prospects of developing countries. Several recent studies estimate the impact of economic shocks on the poor and vulnerable, especially women and children. Infant and child mortality rates are still likely to continue to decline, but at lower rates than would have been the case in the absence of the GFC. Asia faces special challenges. Despite having been the fastest growing region in the world for decades, and even before the current crisis, this region accounted for nearly 34% of global deaths of children under 5, more than 40% of maternal deaths and 60% of newborn deaths. Global development goals cannot be achieved without much faster and deeper progress in Asia. Current health financing systems in much of Asia are not well placed to respond to the needs of women and their children, or the recent global financial and economic slowdown. Public expenditure is often already too low, and high levels of out-of-pocket health expenditure are an independent cause of inequity and impoverishment for women and their children. The GFC highlights the need for reforms that will improve health outcomes for the poor, protect the vulnerable from financial distress, improve public expenditure patterns and resource allocation decisions, and so strengthen health systems. This paper aims to highlight the most recent assessments of how economic shocks, including the GFC, affect the poor in developing countries, especially vulnerable women and children in Asia. It concludes that conditional cash transfers, increasing taxation on tobacco and increasing the level, and quality, of public expenditure through well-designed investment programmes are particularly relevant in the context of an economic shock. That is because these initiatives simultaneously improve health outcomes for the poor and vulnerable, protect them from further financial distress, improve public financing and/or provide a much needed counter-cyclical stimulus at times of economic slowdown. PMID- 20961945 TI - How is health a security issue? Politics, responses and issues. AB - In the closing decade of the 20th century the myriad challenges posed by infectious disease in a globalized environment began to be re-conceptualized as threats to national and human security. The most widely applied model for identifying and responding to such threats is securitization theory, as proposed by the Copenhagen School. Although its analytical framework is generally accepted, its utility remains contested; especially in non-European and non-state settings. The papers in this special edition have several aims: (1) to analyse ways by which Asian states and international organizations have identified health challenges as security threats, (2) to draw upon the securitization model as a way of understanding the full extent to which these states and international organizations have responded to the health threat, and (3) to identify areas where the theory might be strengthened so as to provide greater analytical clarity in areas of health security. This paper acts as a broad introduction to a set of papers on 'Unhealthy governance' and explores some of the key findings from the subsequent papers. PMID- 20961946 TI - Dilemmas of securitization and health risk management in the People's Republic of China: the cases of SARS and avian influenza. AB - Since the SARS epidemic in 2003, the international community has urged Chinese leaders to do more to address infectious diseases. This paper looks at two cases in which the Chinese government securitized infectious disease (SARS and avian influenza) and examines the pros and cons of securitization. It is argued that the reactive mobilization involved in a securitizing move runs counter to the preventive risk management strategy needed to address infectious diseases. Although the Copenhagen School favours desecuritization as a return to normal practices, in the Chinese cases desecuritizing moves proved detrimental, involving cover-ups and restrictions on activists pressing for greater information. The article begins by examining the contributions of the Copenhagen School and sociological theories of risk to conceptualizing the security challenges that pandemics pose. Although analysis of the cases of SARS and avian influenza gives credence to criticisms of this approach, securitization theory proves useful in outlining the different stages in China's reaction to epidemics involving reactive mobilization and subsequent efforts to return to politics as usual. The second section examines securitizing and desecuritizing moves in Chinese responses to SARS and avian influenza. Each case study concludes with an assessment of the consequences for health risk management in China. The reactive mobilization implicit in Chinese securitization moves in the two cases is contrasted with the preventive logic of risk management. A third section draws out the implications of these cases for theories of securitization and risk. It is argued here that when securitization has occurred, risk management has failed. Although Copenhagen School theorists see the return to politics as usual-what they call 'desecuritization'-as optimal, this turns out to be far from the case in China during SARS and avian influenza, where the process involved retribution against whistleblowers and new restrictions on health information. In conclusion, the article argues that alternatives to securitization, such as viewing health as a global public good, would require a prior commitment to risk management within affected states. PMID- 20961947 TI - Securitization of infectious diseases in Vietnam: the cases of HIV and avian influenza. AB - The frequent and swift emergence of new and devastating infectious diseases has brought renewed attention to health as an issue of international importance. Some states and regional organizations, including in Asia, have begun to regard infectious disease as a national and international security issue. This article seeks to examine the Vietnamese government's response to the epidemics of avian influenza and Human immunodeficiency virus. Both diseases have been recognized at different times as threats to international security and both are serious infectious disease problems in Vietnam. Yet, the character of the central government's response to these two epidemics has been starkly different. How and why this disparity in policy approaches occurs depends largely on the epidemiological, economic and political context in which they occur. Although epidemiological factors are frequently explored when discussing disease as a security issue, seldom are the political, social and economic characteristics of the state invoked. These dimensions, and their interaction with the epidemiology of the disease, are central to understanding which diseases are ultimately treated by states as security issues. In particular, the role of economic security as a powerful motivator for resistance to control measures and the role that local implementation of policies can have in disrupting the effect of central government policy are explored. In exploring both the outcomes of securitization, and its facilitating conditions, I suggest some preliminary observations on the potential costs and benefits of securitizing infectious disease and its utility as a mechanism for protecting health in Asia. PMID- 20961948 TI - Haggling over viruses: the downside risks of securitizing infectious disease. AB - This article analyses how the 'securitization' of highly pathogenic avian influenza (H5N1) contributed to the rise of a protracted international virus sharing dispute between developing and developed countries. As fear about the threat of a possible human H5N1 pandemic spread across the world, many governments scrambled to stockpile anti-viral medications and vaccines, albeit in a context where there was insufficient global supply to meet such a rapid surge in demand. Realizing that they were the likely 'losers' in this international race, some developing countries began to openly question the benefits of maintaining existing forms of international health cooperation, especially the common practice of sharing national virus samples with the rest of the international community. Given that such virus samples were also crucial to the high-level pandemic preparedness efforts of the West, the Indonesian government in particular felt emboldened to use international access to its H5N1 virus samples as a diplomatic 'bargaining chip' for negotiating better access to vaccines and other benefits for developing countries. The securitized global response to H5N1 thus ended up unexpectedly entangling the long-standing international virus-sharing mechanism within a wider set of political disputes, as well as prompting governments to subject existing virus-sharing arrangements to much narrower calculations of national interest. In the years ahead, those risks to international health cooperation must be balanced with the policy attractions of the global health security agenda. PMID- 20961949 TI - The role of the Biological Weapons Convention in disease surveillance and response. AB - This article assesses the role and significance of the Biological Weapons Convention (BWC) with respect to infectious disease surveillance and response to outbreaks. Increasingly, the BWC is being used as a platform for addressing infectious disease threats arising naturally as well as traditional concerns about malicious dissemination of pathogenic microorganisms. The latter have long had a place on the security agenda, but natural disease outbreaks too are now being partially 'securitized' through the use of the BWC as a forum for exchanging information and ideas on disease surveillance and response. The article focuses on two prominent issues discussed at recent meetings of BWC member states: enhancing capacity for disease surveillance and response; and responding to allegations of biological weapons use and investigating outbreaks deemed suspicious. It concludes, firstly, that the BWC supports the efforts of international health organizations to enhance disease surveillance and response capacity worldwide. And secondly, that the BWC, rather than the World Health Organization (WHO), is the appropriate institution to deal with biological weapons allegations and investigations of suspicious outbreaks. The overall message is that securitization in the health sphere cuts both ways. Adding a security dimension (BW) alongside the task of detecting and responding to naturally occurring disease outbreaks is beneficial, but requiring a non-security organization (the WHO) to assume a security role would be counterproductive. PMID- 20961950 TI - AIDS and international security in the United Nations System. AB - Two assumptions underpin much of the literature that has examined the links between HIV/AIDS and security: (1) that HIV/AIDS is now firmly established as an international security issue; and (2) that Resolution 1308, adopted by the UN Security Council in July 2000, was the decisive moment in the securitization process. This article questions both of those assumptions. It argues that even within the Security Council, HIV/AIDS' status as a bona fide threat to international peace and security is not entirely secure. Despite the fact that the Resolution was adopted unanimously, there is considerable doubt over the extent to which the Council members were persuaded that HIV/AIDS is genuinely a threat to international peace and security. Furthermore, the Council's subsequent actions suggest a retreat from the issue. The article moves on to examine statements made in and by some of the other key UN System bodies grappling with HIV/AIDS. Focusing in particular on the General Assembly, the Economic and Social Council and UNAIDS, it is argued that the international security framing of HIV/AIDS has not generally achieved a great deal of traction within these bodies. Alternative framings, in particular international development and human rights, occur far more frequently. This raises issues for our understanding of both securitization theory and the global governance of HIV/AIDS. PMID- 20961951 TI - Congenital toxoplasmosis: evaluation of molecular and serological methods for achieving economic and early diagnosis among Egyptian preterm infants. AB - BACKGROUND: Early diagnosis of congenital toxoplasmosis (CT) is difficult when specific immunoglobulin M (IgM) antibodies are absent, or if persist for months, in the newborn infant's blood. OBJECTIVES: To study the risk factors of neonatal toxoplasmosis and to compare different immunologic profiles (Toxoplasma-specific IgM, IgA antibodies and the avidity of IgG antibodies) with polymerase chain reaction (PCR) for reaching economic and early postnatal diagnosis. MATERIALS AND METHODS: We prospectively studied 80 preterm neonates, recruited from neonatal intensive care units (NICUs) of Cairo University hospitals. Whose gestational age <= 34 weeks with (n = 60) or without (n = 20) CT risk. Serum samples for specific IgA, IgM antibodies and avidity of IgG toxoplasma antibodies were measured by ELISA then compared to PCR. RESULTS: Of the 60 studied cases, 16 (26.7%) were positive for toxoplasmosis by PCR, of which 15 (25%) had low avidity of IgG antibodies (positive), 14 (23.3%) were positive for IgA and 10 (16.7%) were positive for IgM, with sensitivity for avidity of IgG, IgA and IgM: 93.2%, 87.5% and 62.5%, respectively. CONCLUSION: Determination of avidity of IgG toxoplasma antibodies and/or serological detection of specific IgA for toxoplasmosis offer, simple tests for diagnosis of congenital toxoplasmosis with (better sensitivity) than IgM. PMID- 20961952 TI - Evaluation of benzo(a)pyrene-induced gene mutations in male germ cells. AB - Polycyclic aromatic hydrocarbons (PAHs) are mutagenic in somatic cells, whereas it remains unclear whether PAHs induce mutations in male germ cells, subsequently increasing health risks in offspring. Although results from the classical specific locus test are negative or inconclusive, recent studies with environmentally exposed animals suggest that PAHs are mutagenic in sperm cells. Therefore, we studied whether benzo(a)pyrene (B[a]P) was able to induce gene mutations in testis and sperm cells of wild-type (Wt) and Xpc(-/-) mice containing the pUR288 lacZ reporter gene. Mice were exposed to B[a]P (13 mg/kg body weight, three times per week) during 1, 4, or 6 weeks and sacrificed 6 weeks after the final exposure to obtain mutations in sperm derived from B[a]P-exposed spermatogonial stem cells. The lacZ gene mutation assay was used to assess mutant frequencies in spleen, testis, and mature sperm, and (32)P-postlabeling was used for the detection of DNA adducts in testis. Successful exposure was confirmed by a dose-related higher mutant frequency in spleen of Xpc(-/-) mice as compared with Wt mice. Mutant frequencies were also increased in all ethyl nitrosourea exposed samples, which were used as positive control. Although B[a]P-related DNA adducts were detected in testis, mutant frequencies were not increased. On the other hand, B[a]P increased mutant frequencies in sperm of Wt mice, but not in Xpc(-/-) mice, after 6 weeks exposure. Therefore, we conclude that B[a]P can induce gene mutations in spermatogonial cells of mice, but it remains to be elucidated whether these mutations can be transmitted to offspring. PMID- 20961953 TI - In utero and lactational exposure to a complex mixture of polychlorinated biphenyls: toxicity in pups dependent on the Cyp1a2 and Ahr genotypes. AB - Polychlorinated biphenyls (PCBs) are persistent toxic pollutants occurring as complex mixtures in the environment. Humans are known genetically to have > 60 fold differences in hepatic cytochrome P450 1A2 (CYP1A2) levels and > 12-fold differences in aryl hydrocarbon receptor (AHR) affinity, both of which could affect PCB pharmacokinetics. Thus, we compared Ahr(b1)_Cyp1a2(+/+) high-affinity AHR wild-type, Ahr(d)_Cyp1a2(+/+) poor affinity AHR wild-type, Ahr(b1)_Cyp1a2(-/ ) knockout, and Ahr(d)_Cyp1a2(-/-) knockout mouse lines. We chose a mixture of three coplanar and five noncoplanar PCBs to reproduce that seen in human tissues, breast milk, and the food supply. The mixture was given by gavage to the mother on gestational day 10.5 (GD10.5) and postnatal day 5 (PND5); tissues were collected from pups and mothers at GD11.5, GD18.5, PND6, PND13, and PND28. Ahr(b1)_Cyp1a2(-/-) pups showed lower weight at birth and slower rate of growth postnatally. Absence of CYP1A2 resulted in significant splenic atrophy at PND13 and PND28. Presence of high-affinity AHR enhanced thymic atrophy and liver hypertrophy in the pups. Concentrations of each congener were analyzed at all time points: maximal noncoplanar congener levels in maternal tissues were observed from GD18 until PND6, whereas the highest levels in pups were found between PND6 and PND28. Coplanar PCB concentrations were generally higher in Ahr(d)-containing pup tissues; these findings are consistent with earlier studies demonstrating the crucial importance of AHR-mediated inducible CYP1 in the gastrointestinal tract as a means of detoxication of oral planar polycyclic aromatic hydrocarbons. PMID- 20961954 TI - Regulation and characterization of the ATP-binding cassette transporter-B1 in the epididymis and epididymal spermatozoa of the rat. AB - It has been reported that following administration, alkylphenols, such as octylphenol, reach the testis and epididymis but fail to accumulate in these tissues, suggesting the rapid expulsion of these chemicals by transporters. Specialized transporters that function to restrict compounds that enter target cells have been identified. ABCB1 is a member of the ATP-binding cassette family of proteins capable of transporting a broad range of drugs and xenobiotics out of tissues. The objective of this study was to characterize the expression profile and functional role of ABCB1a and ABCB1b along the different regions (initial segment, caput, corpus [CS], and cauda [CA]) of the adult rat epididymis. ABCB1a and ABCB1b transcripts were detected in all four regions of the epididymis. Immunolocalization revealed minimal ABCB1 staining in epithelial cells or spermatozoa of proximal regions of the epididymis; however, this progressively increased in the CS and CA epididymis. This expression gradient was confirmed by Western blot, suggesting that spermatozoa acquire ABCB1 during epididymal maturation. Multidrug resistance (MDR) assays revealed that rat epididymal cells and epididymal spermatozoa display an MDR phenotype that can be inhibited under control conditions. To assess whether or not the system was inducible by alkylphenols, cells from an immortalized epididymal cell line (RCE) were exposed to different concentrations of nonylphenol. Results revealed a significant induction of both ABCB1a and ABCB1b messenger RNA and ABCB1 protein in RCE cells. Our findings demonstrate a role for ABCB1 in protecting both epididymal principal cells and spermatozoa from xenobiotics. PMID- 20961955 TI - Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools. AB - The mechanisms by which imbalanced dNTPs induce mutations have been well characterized within a test tube, but not in vivo. We have examined mechanisms by which dNTP imbalances induce genome instability in strains of Saccharomyces cerevisiae with different amino acid substitutions in Rnr1, the large subunit of ribonucleotide reductase. These strains have different dNTP imbalances that correlate with elevated CAN1 mutation rates, with both substitution and insertion deletion rates increasing by 10- to 300-fold. The locations of the mutations in a strain with elevated dTTP and dCTP are completely different from those in a strain with elevated dATP and dGTP. Thus, imbalanced dNTPs reduce genome stability in a manner that is highly dependent on the nature and degree of the imbalance. Mutagenesis is enhanced despite the availability of proofreading and mismatch repair. The mutations can be explained by imbalanced dNTP-induced increases in misinsertion, strand misalignment and mismatch extension at the expense of proofreading. This implies that the relative dNTP concentrations measured in extracts are truly available to a replication fork in vivo. An interesting mutational strand bias is observed in one rnr1 strain, suggesting that the S-phase checkpoint selectively prevents replication errors during leading strand replication. PMID- 20961956 TI - Crystal structure of RIG-I C-terminal domain bound to blunt-ended double-strand RNA without 5' triphosphate. AB - RIG-I recognizes molecular patterns in viral RNA to regulate the induction of type I interferons. The C-terminal domain (CTD) of RIG-I exhibits high affinity for 5' triphosphate (ppp) dsRNA as well as blunt-ended dsRNA. Structures of RIG-I CTD bound to 5'-ppp dsRNA showed that RIG-I recognizes the termini of dsRNA and interacts with the ppp through electrostatic interactions. However, the structural basis for the recognition of non-phosphorylated dsRNA by RIG-I is not fully understood. Here, we show that RIG-I CTD binds blunt-ended dsRNA in a different orientation compared to 5' ppp dsRNA and interacts with both strands of the dsRNA. Overlapping sets of residues are involved in the recognition of blunt ended dsRNA and 5' ppp dsRNA. Mutations at the RNA-binding surface affect RNA binding and signaling by RIG-I. These results provide the mechanistic basis for how RIG-I recognizes different RNA ligands. PMID- 20961957 TI - TOPSAN: a dynamic web database for structural genomics. AB - The Open Protein Structure Annotation Network (TOPSAN) is a web-based collaboration platform for exploring and annotating structures determined by structural genomics efforts. Characterization of those structures presents a challenge since the majority of the proteins themselves have not yet been characterized. Responding to this challenge, the TOPSAN platform facilitates collaborative annotation and investigation via a user-friendly web-based interface pre-populated with automatically generated information. Semantic web technologies expand and enrich TOPSAN's content through links to larger sets of related databases, and thus, enable data integration from disparate sources and data mining via conventional query languages. TOPSAN can be found at http://www.topsan.org. PMID- 20961958 TI - Identification of new homologs of PD-(D/E)XK nucleases by support vector machines trained on data derived from profile-profile alignments. AB - PD-(D/E)XK nucleases, initially represented by only Type II restriction enzymes, now comprise a large and extremely diverse superfamily of proteins. They participate in many different nucleic acids transactions including DNA degradation, recombination, repair and RNA processing. Different PD-(D/E)XK families, although sharing a structurally conserved core, typically display little or no detectable sequence similarity except for the active site motifs. This makes the identification of new superfamily members using standard homology search techniques challenging. To tackle this problem, we developed a method for the detection of PD-(D/E)XK families based on the binary classification of profile-profile alignments using support vector machines (SVMs). Using a number of both superfamily-specific and general features, SVMs were trained to identify true positive alignments of PD-(D/E)XK representatives. With this method we identified several PFAM families of uncharacterized proteins as putative new members of the PD-(D/E)XK superfamily. In addition, we assigned several unclassified restriction enzymes to the PD-(D/E)XK type. Results show that the new method is able to make confident assignments even for alignments that have statistically insignificant scores. We also implemented the method as a freely accessible web server at http://www.ibt.lt/bioinformatics/software/pdexk/. PMID- 20961959 TI - A likelihood method for detecting trait-dependent shifts in the rate of molecular evolution. AB - Rate heterogeneity within groups of organisms is known to exist even when closely related taxa are examined. A wide variety of phylogenetic and dating methods have been developed that aim either to test for the existence of rate variation or to correct for its bias. However, none of the existing methods track the evolution of features that account for observed rate heterogeneity. Here, we present a likelihood model that assumes that rate variation is caused, in part, by species' intrinsic characteristics, such as a particular life-history trait, morphological feature, or habitat association. The model combines models of sequence and character state evolution such that rates of sequence change depend on the character state of a lineage at each point in time. We test, using simulations, the power and accuracy of the model to determine whether rates of molecular evolution depend on a particular character state and demonstrate its utility using an empirical example with halophilic and freshwater daphniids. PMID- 20961960 TI - A genome-wide search for signals of high-altitude adaptation in Tibetans. AB - Genetic studies of Tibetans, an ethnic group with a long-lasting presence on the Tibetan Plateau which is known as the highest plateau in the world, may offer a unique opportunity to understand the biological adaptations of human beings to high-altitude environments. We conducted a genome-wide study of 1,000,000 genetic variants in 46 Tibetans (TBN) and 92 Han Chinese (HAN) for identifying the signals of high-altitude adaptations (HAAs) in Tibetan genomes. We discovered the most differentiated variants between TBN and HAN at chromosome 1q42.2 and 2p21. EGLN1 (or HIFPH2, MIM 606425) and EPAS1 (or HIF2A, MIM 603349), both related to hypoxia-inducible factor, were found most differentiated in the two regions, respectively. Strong positive correlations were also observed between the frequency of TBN-dominant haplotypes in the two gene regions and altitude in East Asian populations. Linkage disequilibrium and further haplotype network analyses of world-wide populations suggested the antiquity of the TBN-dominant haplotypes and long-term persistence of the natural selection. Finally, a "dominant haplotype carrier" hypothesis could describe the role of the two genes in HAA. All of our population genomic and statistical analyses indicate that EPAS1 and EGLN1 are most likely responsible for HAA of Tibetans. Interestingly, one each but not both of the two genes were also identified by three recent studies. We reanalyzed the available data and found the escaped top signal (EPAS1) could be recaptured with data quality control and our approaches. Based on this experience, we call for more attention to be paid to controlling data quality and batch effects introduced in public data integration. Our results also suggest limitations of extended haplotype homozygosity-based method due to its compromised power in case the natural selection initiated long time ago and particularly in genomic regions with recombination hotspots. PMID- 20961961 TI - Diversification of bitter taste receptor gene family in western chimpanzees. AB - In mammals, bitter taste is mediated by T2R genes, which belong to the large family of seven transmembrane G protein-coupled receptors. Because T2Rs are directly involved in the interaction between mammals and their dietary sources, it is likely that these genes evolved to reflect species' specific diets during mammalian evolution. Here, we investigated the sequences of all 28 putative functional chimpanzee T2R genes (cT2Rs) in 46 western chimpanzees to compare the intraspecies variations in chimpanzees to those already known for all 25 human functional T2R genes (hT2Rs). The numbers of functional genes varied among individuals in western chimpanzees, and most chimpanzees had two or three more functional genes than humans. Similarly to hT2Rs, cT2Rs showed high nucleotide diversity along with a large number of amino acid substitutions. Comparison of the nucleotide substitution patterns in cT2Rs with those in five cT2R pseudogenes and 14 autosomal intergenic noncoding regions among the same individuals revealed that the evolution of cT2R genes was almost identical to that of putative neutral regions with slight but significantly positive Tajima's D values, suggesting that selective constraint on these genes was relaxed with weak balancing selection. These trends have resulted in the occurrence of various divergent alleles of T2Rs within the western chimpanzee populations and in heterozygous individuals who might have the ability to taste a broader range of substances. PMID- 20961962 TI - Quantifying nonvertical inheritance in the evolution of Legionella pneumophila. AB - The exchange of genetic material among bacterial strains and species is recognized as an important factor determining their evolutionary, population genetic, and epidemiological features. We present a detailed analysis of nonvertical inheritance in Legionella pneumophila, a human pathogen and facultative intracellular parasite of amoebas. We have analyzed the exchange of L. pneumophila genetic material with other bacteria at three different levels: population genetics, population genomics, and phylogenomics. At the population genetics level, we have analyzed 89 clinical and environmental isolates after sequencing six coding loci and three intergenic regions for a total of 3,923 bp. In the population genomics analysis, we have studied the roles of recombination and mutation in the common portion of the genome sequence of four L. pneumophila strains. In the phylogenomic analysis, we have studied the phylogenetic origin of 1,700 genes in the L. pneumophila pangenome. For this, we have considered 12 possible phylogenetic alternatives, derived from a reference tree obtained from 104 genes from 41 species, which have been tested under a rigorous statistical framework. The results obtained agree in assigning an important role to nonvertical inheritance in shaping the composition of the L. pneumophila genome and of the genetic variation in its populations. We have found a negative correlation between phylogenetic distance and likelihood of horizontal gene transfer. Phylogenetic proximity and increased chances resulting from sharing the ecological niche provided by the amoeba host have likely had a major influence on the rate of gene exchange in Legionella. PMID- 20961963 TI - Adaptive evolution of four microcephaly genes and the evolution of brain size in anthropoid primates. AB - The anatomical basis and adaptive function of the expansion in primate brain size have long been studied; however, we are only beginning to understand the genetic basis of these evolutionary changes. Genes linked to human primary microcephaly have received much attention as they have accelerated evolutionary rates along lineages leading to humans. However, these studies focus narrowly on apes, and the link between microcephaly gene evolution and brain evolution is disputed. We analyzed the molecular evolution of four genes associated with microcephaly (ASPM, CDK5RAP2, CENPJ, MCPH1) across 21 species representing all major clades of anthropoid primates. Contrary to prevailing assumptions, positive selection was not limited to or intensified along the lineage leading to humans. In fact we show that all four loci were subject to positive selection across the anthropoid primate phylogeny. We developed clearly defined hypotheses to explicitly test if selection on these loci was associated with the evolution of brain size. We found positive relationships between both CDK5RAP2 and ASPM and neonatal brain mass and somewhat weaker relationships between these genes and adult brain size. In contrast, there is no evidence linking CENPJ and MCPH1 to brain size evolution. The stronger association of ASPM and CDK5RAP2 evolution with neonatal brain size than with adult brain size is consistent with these loci having a direct effect on prenatal neuronal proliferation. These results suggest that primate brain size may have at least a partially conserved genetic basis. Our results contradict a previous study that linked adaptive evolution of ASPM to changes in relative cortex size; however, our analysis indicates that this conclusion is not robust. Our finding that the coding regions of two widely expressed loci has experienced pervasive positive selection in relation to a complex, quantitative developmental phenotype provides a notable counterexample to the commonly asserted hypothesis that cis-regulatory regions play a dominant role in phenotypic evolution. PMID- 20961964 TI - Interspersed DNA repeats bcr1-bcr18 of Bacillus cereus group bacteria form three distinct groups with different evolutionary and functional patterns. AB - Many short (<400 bp) interspersed sequence repeats exist in bacteria, yet little is known about their origins, mode of generation, or possible function. Here, we present a comprehensive analysis of 18 different previously identified repeated DNA elements, bcr1-bcr18 (Okstad OA, Hegna I, Lindback T, Rishovd AL, Kolsto AB. 1999. Genome organization is not conserved between Bacillus cereus and Bacillus subtilis. Microbiology. 145:621-631.; Tourasse NJ, Helgason E, Okstad OA, Hegna IK, Kolsto AB. 2006. The Bacillus cereus group: novel aspects of population structure and genome dynamics. J Appl Microbiol. 101:579-593.), in 36 sequenced genomes from the Bacillus cereus group of bacteria. This group consists of genetically closely related species with variable pathogenic specificity toward different hosts and includes among others B. anthracis, B. cereus, and B. thuringiensis. The B. cereus group repeat elements could be classified into three categories with different properties: Group A elements (bcr1-bcr3) exhibited highly variable copy numbers ranging from 4 to 116 copies per strain, showed a nonconserved chromosomal distribution pattern between strains, and displayed several features characteristic of mobile elements. Group B repeats (bcr4-bcr6) were present in 0-10 copies per strain and were associated with strain-specific genes and disruptions of genome synteny, implying a possible contribution to genome rearrangements and/or horizontal gene transfer events. bcr5, in particular, was associated with large gene clusters showing resemblance to integrons. In agreement with their potentially mobile nature or involvement in horizontal transfers, the sequences of the repeats from Groups A and B (bcr1 bcr6) followed a phylogeny different from that of the host strains. Conversely, repeats from Group C (bcr7-bcr18) had a conserved chromosomal location and orthologous gene neighbors in the investigated B. cereus group genomes, and their phylogeny matched that of the host chromosome. Several of the group C repeats exhibited a conserved secondary structure or had parts of the structure conserved, possibly indicating functional RNAs. Accordingly, five of the repeats in group C overlapped regions encoding previously characterized riboswitches. Similarly, other group C repeats could represent novel riboswitches, encode small RNAs, and/or constitute other types of regulatory elements with specific biological functions. The current analysis suggests that the multitude of repeat elements identified in the B. cereus group promote genome dynamics and plasticity and could contribute to the flexible and adaptive life style of these bacteria. PMID- 20961965 TI - Differential association of juvenile and adult systemic lupus erythematosus with genetic variants of oestrogen receptors alpha and beta. AB - Oestrogens acting via nuclear receptors (encoded by ESR1 or ESR2) are important for pathogenesis of systemic lupus erythematosus (SLE). rs2234693 and rs4986938 are two single nucleotide polymorphisms (SNPs) whose C and A variants increase transcription of ESR1 and ESR2, respectively. The T allele of rs2234693 was associated with early onset SLE, whereas the role of rs4986938 in SLE was not reported. Our aim was to examine the role of rs2234693 and rs4986938 in conferring susceptibility to juvenile and adult SLE (jSLE and aSLE). Genotype distribution of both SNPs was analysed in 84 jSLE, 112 aSLE patients and 1001 controls. Allele C of rs2234693 was associated with jSLE (OR = 1.87, p = 0.006, p(corrected) = 0.02), whereas allele A of rs4986938 showed an association with aSLE (OR = 1.46, p = 0.008, p(corrected) = 0.03). In jSLE, rs2234693 C had lower frequency in patients with central nervous system involvement (OR = 0.39, p = 0.005, p(corrected) = 0.04) and showed a trend for increase among males, patients with renal involvement and those without DR2/3 (p < 0.05, p(corrected) > 0.05). Whereas our results are consistent with a role of ESR1 variation in jSLE, more studies are needed since the direction of association was the opposite of that reported previously. The association between rs4986938 (ESR2) and aSLE is a novel finding, consistent with our recent report associating this variant with Graves' disease. PMID- 20961966 TI - Professional experience guides opioid prescribing for chronic joint pain in primary care. AB - BACKGROUND: Chronic joint pain is common and is a leading cause of disability. Most chronic joint pain is managed in primary care. Opioid pain medication is one option for pain management, but research suggests that its use by general practitioners (GPs) may be suboptimal. There is a widespread perception that doctors' concerns about misuse and addiction limit use of opioids. OBJECTIVES: To explore GPs' opinions about opioids and decision-making processes when prescribing 'strong' opioids for chronic joint pain. METHODS: Qualitative semi structured interviews were conducted with 27 GPs. Using thematic analysis methods, the data were coded and grouped into themes. RESULTS: GPs described a variety of prescribing habits for chronic joint pain. Opioids engendered strong opinions. GPs said that decisions about prescribing were based on careful assessment of patients' needs and their personal views about the management of adverse effects. Although addiction and misuse were discussed, there was limited concern about these issues. The overarching influence on prescribing decisions was GPs' previous experience, including previous outcomes and exposure to palliative care settings. CONCLUSIONS: GPs' prescribing decisions are primarily influenced by previous professional experience of opioids. Much existing literature stresses that opioids are not prescribed due to concerns about addiction or misuse, but our study indicates otherwise. Augmenting GPs' exposure to and experience of opioids may be key to providing better pain management for patients. PMID- 20961967 TI - Effect of pioglitazone on serum concentrations of osteoprotegerin in patients with type 2 diabetes mellitus. AB - OBJECTIVE: Osteoprotegerin (OPG) acts as an important regulatory molecule in atherosclerosis. Recent studies report that thiazolidinediones could affect OPG expression. We investigated the relationship between OPG and inflammatory cytokines and the effects of pioglitazone (a PPARgamma (PPARG) agonist) versus metformin on serum OPG levels in type 2 diabetic patients. DESIGN AND METHODS: Sixty-seven type 2 diabetic patients were included in this study. They were assigned to pioglitazone (15 mg/day, n=34) or metformin (1000 mg/day, n=33) during 24 weeks. Various anthropometric and metabolic parameters, OPG, interleukin 6 (IL6), C-reactive protein (CRP), adiponectin, and homeostasis model assessment of insulin resistance (HOMA-IR), were measured at baseline and at 6 months of treatment. RESULTS: Serum OPG levels correlated significantly with fasting plasma glucose (FPG), HbAlc, HOMA-IR, IL6, and CRP, and inversely correlated with adiponectin after adjusting for age (P<0.05). Multiple regression analysis showed that FPG, HbAlc, and adioponectin were independently correlated with OPG level. After 6 months of treatment, the reduction in FPG and HbAlc levels was similar between the two groups. Pioglitazone treatment significantly increased body mass index (P<0.05) and waist circumference (P<0.05) and decreased triglycerides (P<0.05) and HOMA-IR (P<0.01). The adiponectin concentration was increased (P<0.05), and OPG and CRP levels were decreased in the pioglitazone group (P<0.05), but were unchanged in the metformin group. The changes in serum OPG in the pioglitazone group showed significant correlation with changes in FPG, HbAlc, and adiponectin. CONCLUSIONS: In type 2 diabetic patients, pioglitazone decreases OPG levels, and this decrease in OPG levels might be associated with the increase in adiponectin. PMID- 20961968 TI - 'Empty sella syndrome': a case of a patient with sodium succinate hydrocortisone allergy. AB - OBJECTIVE: We present the case of a woman with 'empty sella syndrome' who experienced generalized urticaria after the administration of sodium succinate hydrocortisone in two episodes. METHODS: The patient underwent an allergological evaluation (prick, intradermal, and patch tests) with hydrocortisone sodium succinate, hydrocortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, methylprednisolone hemisuccinate, methylprednisolone, and preservatives held in the formulation of sodium succinate hydrocortisone (sodium phosphate and methyl-p-oxybenzoate). The basophil activation test (BAT) was also performed with hydrocortisone. The single-blind i.m. challenge test was performed with hydrocortisone sodium phosphate in 4 days. RESULTS: Skin test with hydrocortisone sodium succinate and methylprednisolone hemisuccinate was positive. On the contrary, allergological tests performed with other formulations of the same steroids and preservatives were negative. These results showed an immediate-type allergy to succinate ester. BAT was not helpful to improve our diagnostic work-up because our patient was a 'nonresponder.' Therefore, the patient underwent successfully to a challenge test with hydrocortisone sodium phosphate. CONCLUSIONS: Patients with succinate ester allergy can tolerate alternative corticosteroids without ester. PMID- 20961969 TI - Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation Into Cancer and Nutrition. AB - Estrogen-only menopausal hormone therapy (HT) increases the risk of endometrial cancer, but less is known about the association with other types of HT. Using Cox proportional hazards regression, the authors examined the association of various types of HT with the risk of endometrial cancer among 115,474 postmenopausal women recruited into the European Prospective Investigation into Cancer and Nutrition between 1992 and 2000. After a mean follow-up period of 9 years, 601 incident cases of endometrial cancer were identified. In comparison with never users of HT, risk of endometrial cancer was increased among current users of estrogen-only HT (hazard ratio (HR) = 2.52, 95% confidence interval (CI): 1.77, 3.57), tibolone (HR = 2.96, 95% CI: 1.67, 5.26), and, to a lesser extent, estrogen-plus-progestin HT (HR = 1.41, 95% CI: 1.08, 1.83), although risks differed according to regimen and type of progestin constituent. The association of HT use with risk was stronger among women who were older, leaner, or had ever smoked cigarettes. The finding of a strong increased risk of endometrial cancer with estrogen-only HT and a weaker association with combined HT supports the hypothesis that progestins have an attenuating effect on endometrial cancer risk. The increased risk associated with tibolone use requires further investigation. PMID- 20961970 TI - Validation of 3 food outlet databases: completeness and geospatial accuracy in rural and urban food environments. AB - Despite interest in the built food environment, little is known about the validity of commonly used secondary data. The authors conducted a comprehensive field census identifying the locations of all food outlets using a handheld global positioning system in 8 counties in South Carolina (2008-2009). Secondary data were obtained from 2 commercial companies, Dun & Bradstreet, Inc. (D&B) (Short Hills, New Jersey) and InfoUSA, Inc. (Omaha, Nebraska), and the South Carolina Department of Health and Environmental Control (DHEC). Sensitivity, positive predictive value, and geospatial accuracy were compared. The field census identified 2,208 food outlets, significantly more than the DHEC (n = 1,694), InfoUSA (n = 1,657), or D&B (n = 1,573). Sensitivities were moderate for DHEC (68%) and InfoUSA (65%) and fair for D&B (55%). Combining InfoUSA and D&B data would have increased sensitivity to 78%. Positive predictive values were very good for DHEC (89%) and InfoUSA (86%) and good for D&B (78%). Geospatial accuracy varied, depending on the scale: More than 80% of outlets were geocoded to the correct US Census tract, but only 29%-39% were correctly allocated within 100 m. This study suggests that the validity of common data sources used to characterize the food environment is limited. The marked undercount of food outlets and the geospatial inaccuracies observed have the potential to introduce bias into studies evaluating the impact of the built food environment. PMID- 20961971 TI - Why does lung function predict mortality? Results from the Whitehall II Cohort Study. AB - The authors examined the extent to which socioeconomic position, behavior-related factors, cardiovascular risk factors, inflammatory markers, and chronic diseases explain the association between poor lung function and mortality in 4,817 participants (68.9% men) from the Whitehall II Study aged 60.8 years (standard deviation, 5.9), on average. Forced expiratory volume in 1 second (FEV(1)) was used to measure lung function in 2002-2004. A total of 139 participants died during a mean follow-up period of 6.4 years (standard deviation, 0.8). In a model adjusted for age and sex, being in the lowest tertile of FEV(1)/height(2) was associated with a 1.92-fold (95% confidence interval: 1.35, 2.73) increased risk of mortality compared with being in the top 2 tertiles. Once age, sex, and smoking history were taken into account, the most important explanatory factors for this association were inflammatory markers (21.3% reduction in the FEV(1)/height(2)-mortality association), coronary heart disease, stroke, and diabetes (11.7% reduction), and alcohol consumption, diet, physical activity, and body mass index (9.8% reduction). The contribution of socioeconomic position and cardiovascular risk factors was small (<= 3.5% reduction). Taken together, these factors explained 32.5% of the association. Multiple pathways link lung function to mortality; these results show inflammatory markers to be particularly important. PMID- 20961972 TI - Glucose, insulin, and incident hypertension in the multi-ethnic study of atherosclerosis. AB - Diabetes mellitus and hypertension commonly coexist, but the nature of this link is not well understood. The authors tested whether diabetes and higher concentrations of fasting serum glucose and insulin are associated with increased risk of developing incident hypertension in the community-based Multi-Ethnic Study of Atherosclerosis. At baseline, 3,513 participants were free of hypertension, defined as systolic blood pressure >=140 mm Hg, diastolic blood pressure >=90 mm Hg, or use of antihypertensive medications to treat high blood pressure. Of these, 965 participants (27%) developed incident hypertension over 4.7 years' median follow-up between 2002 and 2007. Compared with participants with normal baseline fasting glucose, those with impaired fasting glucose and diabetes had adjusted relative risks of hypertension of 1.16 (95% confidence interval (CI): 0.96, 1.40) and 1.41 (95% CI: 1.17, 1.71), respectively (P = 0.0015). The adjusted relative risk of incident hypertension was 1.08 (95% CI: 1.04, 1.13) for each mmol/L higher glucose (P < 0.0001) and 1.15 (95% CI: 1.05, 1.25) for each doubling of insulin (P = 0.0016). Further adjustment for serum cystatin C, urinary albumin/creatinine ratio, and arterial elasticity measured by tonometry substantially reduced the magnitudes of these associations. In conclusion, diabetes and higher concentrations of glucose and insulin may contribute to the development of hypertension, in part through kidney disease and arterial stiffness. PMID- 20961973 TI - The relationship of gamma oscillations and face-specific ERPs recorded subdurally from occipitotemporal cortex. AB - The perception of faces evokes characteristic electrophysiological responses at discrete loci in human fusiform gyrus and adjacent ventral occipitotemporal cortical sites. Prominent among these responses are a surface-negative potential at ~200-ms postonset (face-N200) and face-induced spectral perturbations in the gamma band (face-gammaERSP). The degree to which these responses represent activity in the same cortical loci and the degree to which they are influenced by the same perceptual and task variables are unknown. We evaluated this anatomical colocalization and functional correlation in 2 experiments in which the electrocorticogram was recorded from subdural electrodes in 51 participants. Experiment 1 investigated the category specificity of the gammaERSP and its colocalization with the face-N200. Experiment 2 examined differences in face-N200 and face-gammaERSP to face stimuli that varied in featural complexity. We found that gammaERSP is a category-specific phenomenon with separate, though overlapping, category sensitivities as the N200. Further, the presence of face gammaERSP at an electrode site significantly predicted the presence and amplitude of face-N200 at that site. However, the converse was not true in that face-N200 was evoked by impoverished face stimuli that did not induce face-gammaERSP. These results demonstrate that these electrophysiological responses reflect separate components of the brain's face processing system. PMID- 20961974 TI - Attentional bias and craving in smokers: the impact of a single attentional training session. AB - INTRODUCTION: Investigations in both alcohol and smoking have provided preliminary evidence for the use of attentional training interventions to reduce vigilance toward salient drug cues. The current study evaluated the efficacy of an attentional training intervention for reducing attentional bias toward smoking cues and craving among cigarette smokers. METHODS: Participants were randomized to receive an attentional training intervention or a control training. Sixty-four regular cigarette smokers (individuals smoking at least 10 cigarettes/day for at least 1 year) provided informed consent and were enrolled in the study. The dot probe paradigm was used both to measure attentional bias and for the training intervention. Attentional bias and craving were measured prior to and following training. RESULTS: Results indicated that the randomized groups did not differ significantly in attentional bias as measured by novel stimuli and, correspondingly, in craving response to relevant cues following the training intervention. CONCLUSIONS: These results for a single-session training suggest that this "dose" is insufficient for reducing attentional bias. Given the success of this intervention in other applications, research on the efficacy of multiple session trainings is an important area for further study. PMID- 20961975 TI - A compendium of the mouse mammary tumor biologist: from the initial observations in the house mouse to the development of genetically engineered mice. AB - For over a century, mouse mammary tumor biology and the associated mouse mammary tumor virus (MMTV) have served as the foundation for experimental cancer research, in general, and, in particular, experimental breast cancer research. Spontaneous mouse mammary tumors were the basis for studies of the natural history of neoplasia, oncogenic viruses, host responses, endocrinology and neoplastic progression. However, lacking formal proof of a human mammary tumor virus, the preeminence of the mouse model faded in the 1980s. Since the late 1980s, genetically engineered mice (GEM) have proven extremely useful for studying breast cancer and have become the animal model for human breast cancer. Hundreds of mouse models of human breast cancer have been developed since the first demonstration in 1984. The GEM have attracted a new generation of molecular and cellular biologists eager to apply their skill sets to these surrogates of the human disease. Newcomers often enter the field without an appreciation of the origins of mouse mammary tumor biology and the basis for many of the prevailing concepts. Our purpose in writing this compendium is to extend an "olive branch" while simultaneously deepen the knowledge of the novice mouse mammary tumor biologist as they journey into a field rich in pathology and genetics spanning several centuries. PMID- 20961979 TI - Recurrent episodes of hemiparesis and aphasia. PMID- 20961980 TI - Starting Out. Why patients should complain. PMID- 20961976 TI - Ryanodine receptors: structure, expression, molecular details, and function in calcium release. AB - Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca(2+) from intracellular stores during excitation-contraction coupling in both cardiac and skeletal muscle. RyRs are the largest known ion channels (> 2MDa) and exist as three mammalian isoforms (RyR 1-3), all of which are homotetrameric proteins that interact with and are regulated by phosphorylation, redox modifications, and a variety of small proteins and ions. Most RyR channel modulators interact with the large cytoplasmic domain whereas the carboxy-terminal portion of the protein forms the ion-conducting pore. Mutations in RyR2 are associated with human disorders such as catecholaminergic polymorphic ventricular tachycardia whereas mutations in RyR1 underlie diseases such as central core disease and malignant hyperthermia. This chapter examines the current concepts of the structure, function and regulation of RyRs and assesses the current state of understanding of their roles in associated disorders. PMID- 20961981 TI - Personal View. An unfortunate way to die. PMID- 20961978 TI - RNA processing and export. AB - Messenger RNAs undergo 5' capping, splicing, 3'-end processing, and export before translation in the cytoplasm. It has become clear that these mRNA processing events are tightly coupled and have a profound effect on the fate of the resulting transcript. This processing is represented by modifications of the pre mRNA and loading of various protein factors. The sum of protein factors that stay with the mRNA as a result of processing is modified over the life of the transcript, conferring significant regulation to its expression. PMID- 20961982 TI - US Justice Department brings charges in massive Medicare fraud scheme. PMID- 20961983 TI - Commonly used, easily confused: let's eliminate hyper and hypo. PMID- 20961984 TI - Handling complaints poorly makes problems worse, says NHS ombudsman. PMID- 20961989 TI - Tricyclic antidepressants for migraine and tension-type headaches. PMID- 20961988 TI - Tricyclic antidepressants and headaches: systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the efficacy and relative adverse effects of tricyclic antidepressants in the treatment of migraine, tension-type, and mixed headaches. DESIGN: Meta-analysis. DATA SOURCES: Medline, Embase, the Cochrane Trials Registry, and PsycLIT. Studies reviewed Randomised trials of adults receiving tricyclics as only treatment for a minimum of four weeks. DATA EXTRACTION: Frequency of headaches (number of headache attacks for migraine and number of days with headache for tension-type headaches), intensity of headache, and headache index. RESULTS: 37 studies met the inclusion criteria. Tricyclics significantly reduced the number of days with tension-type headache and number of headache attacks from migraine than placebo (average standardised mean difference -1.29, 95% confidence interval -2.18 to -0.39 and -0.70, -0.93 to -0.48) but not compared with selective serotonin reuptake inhibitors (-0.80, -2.63 to 0.02 and 0.20, -0.60 to 0.19). The effect of tricyclics increased with longer duration of treatment (beta=-0.11, 95% confidence interval -0.63 to -0.15; P<0.0005). Tricyclics were also more likely to reduce the intensity of headaches by at least 50% than either placebo (tension-type: relative risk 1.41, 95% confidence interval 1.02 to 1.89; migraine: 1.80, 1.24 to 2.62) or selective serotonin reuptake inhibitors (1.73, 1.34 to 2.22 and 1.72, 1.15 to 2.55). Tricyclics were more likely to cause adverse effects than placebo (1.53, 95% confidence interval 1.11 to 2.12) and selective serotonin reuptake inhibitors (2.22, 1.52 to 3.32), including dry mouth (P<0.0005 for both), drowsiness (P<0.0005 for both), and weight gain (P<0.001 for both), but did not increase dropout rates (placebo: 1.22, 0.83 to 1.80, selective serotonin reuptake inhibitors: 1.16, 0.81 to 2.97). CONCLUSIONS: Tricyclic antidepressants are effective in preventing migraine and tension-type headaches and are more effective than selective serotonin reuptake inhibitors, although with greater adverse effects. The effectiveness of tricyclics seems to increase over time. PMID- 20961990 TI - Former BMA chairman fails to have most charges against him dropped. PMID- 20961992 TI - Differential adipogenic and inflammatory properties of small adipocytes in Zucker Obese and Lean rats. AB - We recently reported that a preponderance of small adipose cells, decreased expression of cell differentiation markers, and enhanced inflammatory activity in human subcutaneous whole adipose tissue were associated with insulin resistance. To test the hypothesis that small adipocytes exhibited these differential properties, we characterised small adipocytes from epididymal adipose tissue of Zucker Obese (ZO) and Lean (ZL) rats. Rat epididymal fat pads were removed and adipocytes isolated by collagenase digestion. Small adipocytes were separated by sequential filtration through nylon meshes. Adipocytes were fixed in osmium tetroxide for cell size distribution analysis via Beckman Coulter Multisizer. Quantitative real-time PCR for cell differentiation and inflammatory genes was performed. Small adipocytes represented a markedly greater percentage of the total adipocyte population in ZO than ZL rats (58+/-4% vs. 12+/-3%, p<0.001). In ZO rats, small as compared with total adipocytes had 4-fold decreased adiponectin, and 4-fold increased visfatin and IL-6 levels. Comparison of small adipocytes in ZO versus ZL rats revealed 3-fold decreased adiponectin and PPARgamma levels, and 2.5-fold increased IL-6. In conclusion, ZO rat adipose tissue harbours a large proportion of small adipocytes that manifest impaired cell differentiation and pro-inflammatory activity, two mechanisms by which small adipocytes may contribute to insulin resistance. PMID- 20961993 TI - What drives thrombogenesis despite antiplatelet therapy in diabetes mellitus? PMID- 20961994 TI - Subjectivity and severe psychiatric disorders. AB - To have a complete human science in the mental health field it is essential to give adequate attention to both the objective and the subjective data related to people with psychiatric disorders. The tendency in the past has been to ignore or discount one or the other of these data sources. Subjective data are particularly neglected, sometimes considered (only) part of the "art" of medicine since the usual methodologies of the physical sciences in themselves are not adequate to reflect the nature, elusiveness, and complexity of human subjective experience. The complete experience of hallucinated voices, for instance, often includes not only the voices themselves but also terrible anguish and terrifying inability to concentrate. But even such descriptors fall unnecessarily short of reflecting the data of the experience, thus leaving research, theory, and treatment with incomplete information. To represent adequately the subjective data it is essential to recognize that besides the usual discursive knowledge and methods of traditional physical science, a second kind of knowledge and method is required to reflect the depth of human experience. To accomplish this, we must employ approaches to narrative and the arts that are uniquely capable of capturing the nature of these experiences. Only by attending seriously in our research, training, theory, and practice to the unique nature of subjective data is it possible to have a true human science for our field. PMID- 20961995 TI - Transcriptional control of the ERBB2 amplicon by ERRalpha and PGC-1beta promotes mammary gland tumorigenesis. AB - Overexpression of ERBB2 and its neighboring genes on chromosome 17 occurs in approximately 25% of breast tumors and is associated with poor prognosis. While amplification of the 17q12-21 chromosomal region often correlates with an increase in the transcriptional rates of the locus, the molecular mechanisms and the factors involved in the coordinated expression of genes residing within the ERBB2 amplicon remain largely unknown. Here we demonstrate that estrogen-related receptor alpha (ERRalpha, NR3B1) and its coregulator PGC-1beta are key effectors in this process. Using a mouse model of ERBB2-initiated mammary tumorigenesis, we first show that ablation of ERRalpha significantly delays ERBB2-induced tumor development and lowers the levels of amplicon transcripts. Chromosome 17q-wide binding site location analyses in human breast cancer cells show preferential recruitment of ERRalpha to DNA segments associated with the ERBB2 amplicon. Furthermore, ERRalpha directs the co-recruitment of the coactivator PGC-1beta to segments in the 17q12 region and the recruitment of RNA polymerase II to the promoters of the ERBB2 and coamplified genes. ERRalpha and PGC-1beta also participate in the de-repression of ERBB2 expression through competitive genomic cross-talk with estrogen receptor alpha (ERalpha) and, as a consequence, influence tamoxifen sensitivity in breast cancer cells. Taken together, our results suggest that ERRalpha and PGC-1beta are key players in the etiology of malignant breast cancer by coordinating the transcriptional regulation of genes located in the 17q12 region, a process that also involves interference with the repressive function of ERalpha on ERBB2 expression. PMID- 20961996 TI - Combinatorial regulation of neuroblastoma tumor progression by N-Myc and hypoxia inducible factor HIF-1alpha. AB - In human neuroblastoma, amplification of the MYCN gene predicts poor prognosis and resistance to therapy. Because hypoxia contributes to aggressive tumor phenotypes, predominantly via two structurally related hypoxia inducible factors, HIF-1alpha and HIF-2alpha, we examined hypoxia responses in MYCN-amplified neuroblastoma cells. We demonstrate here that HIF-1alpha, but not HIF-2alpha, is preferentially expressed in both MYCN-amplified neuroblastoma cells and primary tumors in comparison to samples without MYCN amplification. Our results showed that interplay between N-Myc and HIF-1alpha plays critical roles in neuroblastoma. For example, high levels of N-Myc override HIF-1alpha inhibition of cell cycle progression, enabling continued proliferation under hypoxia. Furthermore, both HIF-1alpha and N-Myc are essential for the Warburg effect (aerobic glycolysis) in neuroblastomas by activating the transcription of multiple glycolytic genes. Of note, expressions of Phosphoglycerate Kinase 1 (PGK1), Hexokinase 2 (HK2), and Lactate Dehydrogenase A (LDHA) were each significantly higher in MYCN-amplified neuroblastomas than in tumors without MYCN amplification. Interestingly, MYCN-amplified neuroblastoma cells are "addicted" to LDHA enzymatic activity, as its depletion completely inhibits tumorigenesis in vivo. Thus, our results provide mechanistic insights explaining how MYCN amplified neuroblastoma cells contend with hypoxic stress and paradoxically how hypoxia contributes to neuroblastoma aggressiveness through combinatorial effects of N-Myc and HIF-1alpha. These results also suggest that LDHA represents a novel, pharmacologically tractable target for neuroblastoma therapeutics. PMID- 20961997 TI - Protecting privacy of health information for those who serve and protect us. PMID- 20961998 TI - Structure to function: muscle failure in critically ill patients. AB - Impaired physical function and reduced physical activity are common findings in intensive care unit (ICU) survivors. More importantly, reduced muscle strength during critical illness is an independent predictor of survival. Skeletal muscle wasting as a direct consequence of critical illness has been suggested as the cause. However, data on the physiological processes regulating muscle mass, and function, in these critically ill patients are limited as this is not only a technically challenging research area, but also the heterogeneity of the patient group adds complexity to the interpretation of results. Despite this, clinical and research interest in this area is growing. This article highlights the issues involved in measurement of muscle function and mass in critically ill patients and the physiological complexities involved in studying these patients. Although the data are limited, this article reviews the animal and healthy human data providing a rational approach to the potential pathophysiological mechanisms involved in muscle mass regulation in critically ill patients, including the established muscle wasting 'risk factors' such as ageing, immobility and systemic inflammation, all of which are common findings in the general critical care population. PMID- 20961999 TI - Metaplasticity of horizontal connections in the vicinity of focal laser lesions in rat visual cortex. AB - Focal cortical injuries are accompanied by a reorganization of the adjacent neuronal networks. An increased synaptic plasticity has been suggested to mediate, at least in part, this functional reorganization. Previous studies showed an increased long-term potentiation (LTP) at synapses formed by ascending fibres projecting onto layers 2/3 pyramidal cells following lesions in rat visual cortex. This could be important to establish new functional connections within a vertical cortical column. Importantly, horizontal intracortical connections constitute an optimal substrate to mediate the functional reorganization across different cortical columns. However, so far little is known about their potential implication in the functional rewiring post-lesion. Here, we investigated possible alterations of synaptic plasticity of horizontal connections in layers 2/3 in an 'ex vivo-in vitro' model of focal laser lesion in rat visual cortex. LTP at these synapses was found to be enhanced post-lesion, whereas long-term depression (LTD) was impaired, revealing a metaplastic shift toward strengthening of these synapses. Furthermore, we disclosed a prolonged decay-time constant of NMDAR-dependent currents, which can contribute to the enhanced LTP. Taken together these data revealed that a laser lesion-induced focal damage of the visual cortex is accompanied by a facilitated potentiation of horizontal synaptic connections in the vicinity of the focal injury. This specific strengthening of synaptic plasticity at horizontal connections in layers 2/3 might be one important cellular mechanism to compensate focal injury-mediated dysfunction in the cerebral cortex. PMID- 20962000 TI - Hydrogen ion dynamics in human red blood cells. AB - Our understanding of pH regulation within red blood cells (RBCs) has been inferred mainly from indirect experiments rather than from in situ measurements of intracellular pH (pH(i)). The present work shows that carboxy-SNARF-1, a pH fluorophore, when used with confocal imaging or flow cytometry, reliably reports pH(i) in individual, human RBCs, provided intracellular fluorescence is calibrated using a 'null-point' procedure. Mean pH(i) was 7.25 in CO(2)/HCO(3)(-) buffered medium and 7.15 in Hepes-buffered medium, and varied linearly with extracellular pH (slope of 0.77). Intrinsic (non-CO(2)/HCO(3)(-)-dependent) buffering power, estimated in the intact cell (85 mmol (l cell)(-1) (pH unit)(-1) at resting pH(i)), was somewhat higher than previous estimates from cell lysates (50-70 mmol (l cell)(-1) (pH unit)(-1)). Acute displacement of pH(i) (superfusion of weak acids/bases) triggered rapid pH(i) recovery. This was mediated via membrane Cl(-)/HCO(3)(-) exchange (the AE1 gene product), irrespective of whether recovery was from an intracellular acid or base load, and with no evident contribution from other transporters such as Na(+)/H(+) exchange. H(+)-equivalent flux through AE1 was a linear function of [H(+)](i) and reversed at resting pH(i), indicating that its activity is not allosterically regulated by pH(i), in contrast to other AE isoforms. By simultaneously monitoring pH(i) and markers of cell volume, a functional link between membrane ion transport, volume and pH(i) was demonstrated. RBC pH(i) is therefore tightly regulated via AE1 activity, but modulated during changes of cell volume. A comparable volume-pH(i) link may also be important in other cell types expressing anion exchangers. Direct measurement of pH(i) should be useful in future investigations of RBC physiology and pathology. PMID- 20962001 TI - Effects of inactivity on human muscle glutathione synthesis by a double-tracer and single-biopsy approach. AB - Oxidative stress is often associated to inactivity-mediated skeletal muscle atrophy. Glutathione is one of the major antioxidant systems stimulated, both at muscular and systemic level, by activation of oxidative processes. We measured changes in glutathione availability, oxidative stress induction and the extent of atrophy mediated by 35 days of experimental bed rest in vastus lateralis muscle of healthy human volunteers. To assess muscle glutathione synthesis, we applied a novel single-biopsy and double-tracer ([(2)H(2)]glycine and [(15)N]glycine) approach based on evaluation of steady-state precursor incorporation in product. The correlations between the traditional (multiple-samples, one-tracer) and new (one-sample, double-tracer infusion) methods were analysed in erythrocytes by Passing-Bablok and Altman-Bland tests. Muscle glutathione absolute synthesis rate increased following bed rest from 5.5 +/- 1.1 to 11.0 +/- 1.5 mmol (kg wet tissue)(-1) day(-1) (mean +/- S.E.M.; n = 9; P = 0.02) while glutathione concentration failed to change significantly. Bed rest induced vastus lateralis muscle atrophy, as assessed by pennation angle changes measured by ultrasonography (from 18.6 +/- 1.0 to 15.3 +/- 0.9 deg; P = 0.01) and thickness changes (from 2.3 +/- 0.2 to 1.9 +/- 0.1 cm; P < 0.001). Moreover, bed rest increased protein oxidative stress, as measured by muscle protein carbonylation changes (from 0.6 +/- 0.1 to 1.00 +/- 0.1 Oxydized-to-total protein ratio; P < 0.04). In conclusion, we developed in erythrocytes a new minimally invasive method to determine peptide synthesis rate in human tissues. Application of the new method to skeletal muscle suggests that disuse atrophy is associated to oxidative stress induction as well as to compensatory activation of the glutathione system. PMID- 20962002 TI - Loss of PDZ-adaptor protein NHERF2 affects membrane localization and cGMP- and [Ca2+]- but not cAMP-dependent regulation of Na+/H+ exchanger 3 in murine intestine. AB - Trafficking and regulation of the epithelial brush border membrane (BBM) Na+/H+ exchanger 3 (NHE3) in the intestine involves interaction with four different members of the NHERF family in a signal-dependent and possibly segment-specific fashion. The aim of this research was to study the role of NHERF2 (E3KARP) in intestinal NHE3 BBM localization and second messenger-mediated and receptor mediated inhibition of NHE3. Immunolocalization of NHE3 in WT mice revealed predominant microvillar localization in jejunum and colon, a mixed distribution in the proximal ileum but localization near the terminal web in the distal ileum. The terminal web localization of NHE3 in the distal ileum correlated with reduced acid-activated NHE3 activity (fluorometrically assessed). NHERF2 ablation resulted in a shift of NHE3 to the microvilli and higher basal fluid absorption rates in the ileum, but no change in overall NHE3 protein or mRNA expression. Forskolin-induced NHE3 inhibition was preserved in the absence of NHERF2, whereas Ca2+ ionophore- or carbachol-mediated inhibition was abolished. Likewise, Escherichia coli heat stable enterotoxin peptide (STp) lost its inhibitory effect on intestinal NHE3. It is concluded that in native murine intestine, the NHE3 adaptor protein NHERF2 plays important roles in tethering NHE3 to a position near the terminal web and in second messenger inhibition of NHE3 in a signal- and segment-specific fashion, and is therefore an important regulator of intestinal fluid transport. PMID- 20962003 TI - Ca2+ spark-dependent and -independent sarcoplasmic reticulum Ca2+ leak in normal and failing rabbit ventricular myocytes. AB - Sarcoplasmic reticulum (SR) Ca2(+) leak is an important component of cardiac Ca2(+) signalling. Together with the SR Ca2(+)-ATPase (SERCA)-mediated Ca2(+) uptake, diastolic Ca2(+) leak determines SR Ca2(+) load and, therefore, the amplitude of Ca2(+) transients that initiate contraction. Spontaneous Ca2(+) sparks are thought to play a major role in SR Ca2(+) leak. In this study, we determined the quantitative contribution of sparks to SR Ca2(+) leak and tested the hypothesis that non-spark mediated Ca2(+) release also contributes to SR Ca2(+) leak. We simultaneously measured spark properties and intra-SR free Ca2(+) ([Ca2(+)](SR)) after complete inhibition of SERCA with thapsigargin in permeabilized rabbit ventricular myocytes. When [Ca2(+)](SR) declined to 279 +/- 10 MUm, spark activity ceased completely; however SR Ca2(+) leak continued, albeit at a slower rate. Analysis of sparks and [Ca2(+)](SR) revealed, that SR Ca2(+) leak increased as a function of [Ca2(+)](SR), with a particularly steep increase at higher [Ca2(+)](SR) ( >600 MUm) where sparks become a major pathway of SR Ca2(+) leak. At low [Ca2(+)](SR) (< 300 MUm), however, Ca2(+) leak occurred mostly as non-spark-mediated leak. Sensitization of ryanodine receptors (RyRs) with low doses of caffeine increased spark frequency and SR Ca2(+) leak. Complete inhibition of RyR abolished sparks and significantly decreased SR Ca2(+) leak, but did not prevent it entirely, suggesting the existence of RyR-independent Ca2(+) leak. Finally, we found that RyR-mediated Ca2(+) leak was enhanced in myocytes from failing rabbit hearts. These results show that RyRs are the main, but not sole contributor to SR Ca2(+) leak. RyR-mediated leak occurs in part as Ca2(+) sparks, but there is clearly RyR-mediated but Ca2(+) sparks independent leak. PMID- 20962004 TI - Critical speed in the rat: implications for hindlimb muscle blood flow distribution and fibre recruitment. AB - Critical speed (CS) constitutes an important metabolic and performance demarcator. However, active skeletal muscle blood flow distribution specifically surrounding CS remains unknown. We tested the hypotheses that CS could be accurately determined in the running rat and that measurement of hindlimb inter- and intramuscular blood flow below and above CS would support that the greatest muscle fibre recruitment above, relative to below, CS occurs in the predominantly glycolytic muscles. Seven male Sprague-Dawley rats performed five constant-speed tests to exhaustion at speeds between 95 and 115% of the speed that elicited to determine CS. Subsequent constant-speed tests were performed at speeds incrementally surrounding CS to determine time to exhaustion, V(O2), and hindlimb muscle blood flow distribution. Speed and time to exhaustion conformed to a hyperbolic relationship (r(2) = 0.92 +/- 0.03) which corresponded to a linear 1/time function (r(2) = 0.93 +/- 0.02) with a CS of 48.6 +/- 1.0 m min(-1). Time to exhaustion below CS was ~ 5* greater (P < 0.01) than that above. Below CS V(O2) stabilized at a submaximal value (58.5 +/- 2.5 ml kg(-1) min(-1)) whereas above CS (81.7 +/- 2.5 ml kg(-1) min(-1)) increased to (84.0 +/- 1.8 ml kg(-1) min(-1), P > 0.05 vs. above CS). The 11 individual muscles or muscle parts that evidenced the greatest blood flow increases above, relative to below, CS were composed of >= 69% Type IIb/d/x muscle fibres. Moreover, there was a significant correlation (P < 0.05, r = 0.42) between the increased blood flow above expressed relative to below CS and the percentage Type IIb/d/x fibres found in the individual muscles or muscle parts. These data validate the powerful CS construct in the rat and identify that running above CS, relative to below CS, incurs disproportionate blood flow increases (indicative of recruitment) in predominantly highly glycolytic muscle fibres. PMID- 20962005 TI - Regulation of exocytic mode in hippocampal neurons by intra-bouton calcium concentration. AB - Release of neurotransmitters from synaptic vesicles is a central event in synaptic transmission. Recent evidence suggests that synaptic vesicles fuse with the plasma membrane by multiple routes during exocytosis, but the regulation and physiological implications of this choice are unclear. At hippocampal synapses in culture, two modes of synaptic vesicle exocytosis can be distinguished by virtue of the rate and extent of loss of a fluorescent lipid marker (FM1-43). Here we investigate these two modes of exocytosis using fluorescence imaging of FM1-43, combined with quantitative Ca(2+) imaging using Oregon green BAPTA-1 (OGB1), to examine how the balance of exocytic mode changes during a stimulus train. Our findings are twofold: that the full fusion mode becomes progressively favoured through the course of a 5 or 10 Hz stimulus train, and that this occurs in parallel with presynaptic accumulation of calcium. Blockade of calcium accumulation with AM-EGTA also prevents the conversion of exocytic mode. This conversion of exocytic mode may provide insight as to the mechanisms underpinning short term plasticity. PMID- 20962006 TI - Effects of maternal hypoxia on muscle vasodilatation evoked by acute systemic hypoxia in adult rat offspring: changed roles of adenosine and A1 receptors. AB - Suboptimal conditions in utero can have long-lasting effects including increased risk of cardiovascular disease in adult life. Such programming effects may be induced by chronic systemic hypoxia in utero (CHU). We have investigated how CHU affects cardiovascular responses evoked by acute systemic hypoxia in adult male offspring, recognising that adenosine contributes to hypoxia-induced muscle vasodilatation and bradycardia by acting on A(1) receptors in normal (N) rats. In the present study, dams were housed in a hypoxic chamber at 12% O(2) for the second half of gestation; offspring were born and reared in air until 9-10 weeks of age. Under anaesthesia, acute systemic hypoxia (breathing 8% O(2) for 5 min) evoked similar biphasic tachycardia/bradycardia, fall in arterial pressure and increase in femoral vascular conductance (FVC) in N and CHU rats (+2.0 vs. +2.7 conductance units respectively). However, in CHU rats, neither the non-selective adenosine receptor antagonist 8-sulphophenyltheopylline (8-SPT), nor the A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) affected the increase in FVC, but DPCPX attenuated the hypoxia-induced bradycardia. Further, in N and CHU rats, 5 min infusion of adenosine induced similar increases in FVC; in CHU rats, DPCPX reduced the adenosine-induced increase in FVC (by >50%) and accentuated the concomitant tachycardia. These results suggest that CHU rats have functional A(1) receptors in heart and vasculature, but the release and/or vasodilator influence of adenosine on the endothelium in acute hypoxia is attenuated and replaced by other dilator factors. Such changes from normal endothelial function may have implications for general cardiovascular regulation. PMID- 20962007 TI - Segmental patterns of vestibular-mediated synaptic inputs to axial and limb motoneurons in the neonatal mouse assessed by optical recording. AB - Proper control of movement and posture occurs partly via descending projections from the vestibular nuclei to spinal motor circuits. Days before birth in rodents, vestibulospinal neurons develop axonal projections that extend to the spinal cord. How functional these projections are just after birth is unknown. Our goal was to assess the overall functional organization of vestibulospinal inputs to spinal motoneurons in a brainstem-spinal cord preparation of the neonatal mouse (postnatal day (P) 0-5). Using calcium imaging, we recorded responses evoked by electrical stimulation of the VIIIth nerve, in many motoneurons simultaneously throughout the spinal cord (C2, C6, T7, L2 and L5 segments), in the medial and lateral motor columns. Selective lesions in the brainstem and/or spinal cord distinguished which tracts contributed to the responses: those in the cervical cord originated primarily from the medial vestibulospinal tracts but with a substantial contribution from the lateral vestibulospinal tract; those in the thoracolumbar cord originated exclusively from the lateral vestibulospinal tract. In the thoracolumbar but not the cervical cord, excitatory commissural connections mediated vestibular responses in contralateral motoneurons. Pharmacological blockade of GABA(A) receptors showed that responses involved a convergence of excitatory and inhibitory inputs which in combination produced temporal response patterns specific for different segmental levels. Our results show that by birth vestibulospinal projections in rodents have already established functional synapses and are organized to differentially regulate activity in neck and limb motoneurons in a tract- and segment-specific pattern similar to that in adult mammals. Thus, this particular set of descending projections develops several key features of connectivity appropriately at prenatal stages. We also present novel information about vestibulospinal inputs to axial motoneurons in mammals, providing a more comprehensive platform for future studies into the overall organization of vestibulospinal inputs and their role in regulating postural stability. PMID- 20962008 TI - Boosting brain excitability by transcranial high frequency stimulation in the ripple range. AB - Alleviating the symptoms of neurological diseases by increasing cortical excitability through transcranial stimulation is an ongoing scientific challenge. Here, we tackle this issue by interfering with high frequency oscillations (80 250 Hz) via external application of transcranial alternating current stimulation (tACS) over the human motor cortex (M1). Twenty-one subjects participated in three different experimental studies and they received on separate days tACS at three frequencies (80 Hz, 140 Hz and 250 Hz) and sham stimulation in a randomized order. tACS with 140 Hz frequency increased M1 excitability as measured by transcranial magnetic stimulation-generated motor evoked potentials (MEPs) during and for up to 1 h after stimulation. Control experiments with sham and 80 Hz stimulation were without any effect, and 250 Hz stimulation was less efficient with a delayed excitability induction and reduced duration. After-effects elicited by 140 Hz stimulation were robust against inversion of test MEP amplitudes seen normally under activation. Stimulation at 140 Hz reduced short interval intracortical inhibition, but left intracortical facilitation, long interval cortical inhibition and cortical silent period unchanged. Implicit motor learning was not facilitated by 140 Hz stimulation. High frequency stimulation in the ripple range is a new promising non-invasive brain stimulation protocol to increase human cortical excitability during and after the end of stimulation. PMID- 20962009 TI - The C-terminal domain of betaIV-spectrin is crucial for KCNQ2 aggregation and excitability at nodes of Ranvier. AB - The spectrin cytoskeleton has an important function in the targeting of proteins to excitable membrane domains. In axons, betaIV-spectrin stabilizes voltage-gated sodium (Nav) channel clusters at nodes of Ranvier and axon initial segments, two regions crucial for the generation and conduction of action potentials. Here, I investigated the physiology of the neuromuscular junction and peripheral nerves in quivering-3J mice, which show a frame-shift base insertion in the Spnb4 gene and lack the C-terminus of betaIV-spectrin. The quivering-3J mice show prominent spontaneous and evoked hyperactivities at diaphragm neuromuscular junctions. These neuromyotonic and myokymic discharges were more prominent in adult animals when tremors and ataxia were pronounced. Recordings of sciatic and phrenic nerves showed that the hyperactivities originate in myelinated axons distally from nerve terminals. Axon and myelin structure in the PNS were unaffected in quivering-3J mice. Of interest, KCNQ2 subunit aggregates were undetectable at PNS and CNS nodes, whereas Nav and Kv1.1/Kv1.2 channels were properly concentrated at nodal and juxtaparanodal regions, respectively. The protein level of KCNQ2 subunits was normal in mutant animals, suggesting that KCNQ2 subunit absence stems from clustering or trafficking defects in axons. The quivering-3J nodes also presented high densities of ankyrin-G and CK2alpha, two cytosolic molecules involved with aggregating Nav and KCNQ2/3 channels in axons. Because betaIV-spectrin does not interact with KCNQ2/3 subunits, it is suspected that betaIV-spectrin regulates the distribution of KCNQ2/3 subunits in axonal subdomains via regulatory partners. Retigabine, an activator of KCNQ2/3 channels, attenuated the repetitive activities in quivering-3J mice, suggesting that depletion of KCNQ2 subunits at nodes initiates neuromyotonic/myokymic discharges. These findings demonstrate that spectrin cytoskeleton finely regulates ion channel distribution and implicates KCNQ2/3 subunits in axonal excitability and in myokymia aetiology. PMID- 20962010 TI - Effects of acidification and increased extracellular potassium on dynamic muscle contractions in isolated rat muscles. AB - Since accumulation of both H(+) and extracellular K(+) have been implicated in the reduction in dynamic contractile function during intense exercise, we investigated the effects of acidification and high K(+) on muscle power and the force-velocity relation in non-fatigued rat soleus muscles. Contractions were elicited by supramaximal electrical stimulation at 60 Hz. Force-velocity (FV) curves were obtained by fitting data on force and shortening velocity at different loads to the Hill equation. Acidification of the muscles by incubation with up to 24 mm lactic acid produced no significant changes in maximal power (P(max)) at 30 degrees C. More pronounced acidification, obtained by increasing CO(2) levels in the equilibration gas from 5% to 53%, markedly decreased P(max) and maximal isometric force (F(max)), increased the curvature of the FV relation, but left maximal shortening velocity (V(max)) unchanged. Increase of extracellular K(+) from 4 to 10 mm caused a depression of 58% in P(max) and 52% in F(max), but had no significant effect on V(max) or curvature of the FV curve. When muscles at 10 mM K(+) were acidified by 20 mm lactic acid, P(max) and F(max) recovered completely to the initial control level at 4 mm K(+). CO(2) acidification also induced significant recovery of dynamic contractions, but not entirely to control levels. These results demonstrate that in non-fatigued muscles severe acidification can be detrimental to dynamic contractile function, but in muscles depolarised by exposure to high extracellular [K(+)], approaching the [K(+)] level seen during intense fatiguing exercise, acidification can have positive protective effects on dynamic muscle function. PMID- 20962011 TI - Voltage-dependent block by internal spermine of the murine inwardly rectifying K+ channel, Kir2.1, with asymmetrical K+ concentrations. AB - Effects of internal spermine on outward single-channel currents through a strongly inwardly rectifying K(+) channel (Kir2.1) were studied at asymmetrical K(+) concentrations (30 mm external and 150 mm internal K(+)). The current voltage (I-V) relation for the single channel was almost linear and reversed at 37 +/- 3 mV (V(R); n = 19). The channel conductance was 26.3 +/- 1.3 pS (n = 24). The open-time and closed-time histograms were fitted with a single exponential function. Internal spermine at a concentration of 1-100 nm reduced the open time of the outward currents in a concentration-dependent manner and produced a blocked state. The steady-state open probability of the outward current decreased with larger depolarizations in both the absence and presence of internal spermine. The steady-state open probability with asymmetrical K(+) and symmetrical (150 mm external and internal K(+)) concentrations plotted against driving force (V - V(R)) coincided with smaller depolarizations in the absence of spermine and larger depolarizations and higher spermine concentrations in the presence of spermine. The blocking rate constants and unblock rates with 30 mm and 150 mm external K(+) were similar at the same driving force. The dissociation constant-membrane potential relation for 30 mm external K(+) was shifted in the negative direction from that for 150 mm external K(+) by 36 mV. These results suggested that the blocking kinetics depends on driving force to produce driving force-dependent inward rectification when the equilibrium potential for K(+) is altered by changing external K(+) and that the energy barriers and wells for blocking ions from passing or lodging are not stable but affected by external K(+) ions. PMID- 20962012 TI - The influence of leptin on trabecular architecture and marrow adiposity in GH deficient rats. AB - The relationship between the degree of GH deficiency and impaired bone integrity is not simple and may be influenced by related endocrine variables. To test the hypothesis that elevated adiposity and hyperleptinaemia are contributory factors, we quantified femoral trabecular organisation in two models of GH deficiency with divergent degrees of adiposity - the moderately GH-deficient/hyperleptinaemic transgenic growth retarded (Tgr) rat and the profoundly GH deficient/hypoleptinaemic dw/dw rat. Trabecular density (bone volume/total volume) and surface were reduced by 16% in dw/dw males, with a more fragmented trabecular lattice. This impairment was more pronounced in Tgr rats, with trabecular number and density further reduced (by an additional 21%) and relative surface (bone surface/bone volume), trabecular convexity (structural modal index) and fragmentation (pattern factor) increased. To establish whether the presence of obesity/hyperleptinaemia exacerbates bone impairment in GH deficiency, trabecular structure was assessed in dw/dw rats following diet-induced obesity (DIO). DIO had minimal effect on trabecular architecture, the increased concavity of trabecular surfaces being the only observable effect. Similarly, infusion of leptin into the tibial bone marrow cavity had no effect on trabecular organisation or tibial growth in wild-type rats. However, while this procedure also failed to affect trabecular architecture or osteoclast number in dw/dw rats, distal osteoblast surface was increased by 23%, marrow adipocyte number and epiphyseal plate width being reduced (by 40 and 5% respectively), without increasing caspase-3 immunoreactivity. These findings suggest that while leptin may directly inhibit adipocyte differentiation and favour osteoblast production, hyperleptinaemia makes only a minimal contribution to the impairment of bone structure in GH deficiency. PMID- 20962013 TI - Seasonal effects of central leptin infusion and prolactin treatment on pituitary SOCS-3 gene expression in ewes. AB - Suppressors of cytokine signalling (SOCS) negatively regulate cytokine-induced signalling pathways and may be involved in leptin and prolactin (PRL) interactions. Herein, we examined the effect of PRL on SOCS-3 mRNA expression in pituitary explants and investigated whether leptin could modify the expression of SOCS-3 mRNA in pituitary explants. In the first experiment, we used pituitaries isolated from 16 ewes decapitated in March, May, July and October (four per month). Tissues were cut into 50 mg explants, which were treated with control or medium containing PRL (100 or 300 ng/ml). Incubation was maintained for different time intervals: 0, 60, 120, 180, 240 or 300 min. Real-time PCR was used to measure SOCS-3 mRNA levels. In the second study, we used 24 ewes surgically fitted with third ventricle cannulas (12 were used during the long-day period, and 12 were used during the short-day (SD) period). Each ewe was administered an i.c.v. injection of Ringer-Locke buffer or leptin (0.5 or 1.0 MUg/kg body weight). Explants of anterior pituitaries were collected and snap frozen 1 h after injection. Semi-quantitative expression of SOCS-3 mRNA was performed using reverse transcription-PCR. PRL stimulated SOCS-3 expression in the pituitaries collected in March (P<0.05) and May (P<0.01 and P<0.05 for lower and higher doses respectively), inhibited SOCS-3 expression in pituitaries collected in July (P<0.01) and had no effect in pituitaries collected in October. Treatment with leptin increased SOCS-3 expression during the SDs in a dose-dependent manner (P<0.01). The results demonstrated that photoperiod may be involved in leptin and PRL effects on SOCS-3 expression in sheep. PMID- 20962014 TI - Isolation and characterization of the antibreast carcinoma cell growth components of Vernonia amygdalina extracts. AB - Vernonia amygdalina (VA) is widely used for medicinal and food purposes in tropical Africa. Many health benefits (antioxidant, antimicrobial, anticancer activities and more) of VA extracts have been reported. The mechanisms of actions have also been described. We have previously reported that VA extracts elicited growth inhibitory activities in human estrogen receptor-positive (ER(+)) cells (MCF-7 cells) and ductal carcinoma cells (BT-549) in vitro. The active components in the organic solvent (chloroform)-extracted VA have been previously determined. However, the active components in the ethanolic extracts of VA have not been previously studied. Hence, the objectives of this study are to isolate and characterize the active components of the ethanolic extracts of VA using liquid liquid extraction, thin layer chromatography and column techniques. Fractionation of the ethanolic extracts of VA yielded three fractions named A1, A2 and A3, and A2 retained the DNA synthesis-inhibitory activity of the extracts. Subsequent fractionation of A2 yielded fraction A2B whose activity was 16 and three times more potent than the ethanolic fraction and fraction A2, respectively. The treatment of cells with 100 MUg/mL of either the ethanolic VA extracts, fraction A2 or fraction A2B resulted in a 23% (P < 0.01), 86% (P < 0.0001) and 97% (P < 0.0001) inhibition of DNA synthesis compared with vehicle-treated controls, respectively. Further purification of A2B by high-speed countercurrent chromatography and confirmed by spectroscopic analysis revealed that the major active components of A2B (65% by weight) were steroid glucosides. PMID- 20962015 TI - Inhibition of adipocyte differentiation and adipogenesis by the traditional Chinese herb Sibiraea angustata. AB - Obesity has become a major health concern due to its strong association with the metabolic syndrome. Inhibition of adipocyte differentiation represents a key strategy to inhibit obesity. Sibiraea angustata (SA), a traditional Chinese herb, has a wide range of pharmacological effects, such as improving digestive functions. Here, we report a novel antiadipogenic effect of SA. By using the SA water extract (SAW), SA acetic ether extract (SAA) and the 3T3-L1 model of adipocyte differentiation and adipogenesis, we showed that both SAW and SAA impaired the proliferation and adipo-differentiation of 3T3-L1 in a dose- and time-dependent manner. At the molecular level, treatment of 3T3-L1 cells with SAW or SAA inhibited the expression of the key adipocyte differentiation regulator CCAAT enhancer binding protein beta (C/EBPbeta), as well as peroxisome proliferator activated receptor gamma, adipocyte protein-2, lipoprotein lipase and glucose transporter 4. Cell cycle analysis showed that both SAW and SAA blocked cell cycle at the G1-S transition phase, causing cells to remain in the preadipocyte state. The expression of CyclinA and cyclin-dependent kinase 2 was also inhibited by SAW and SAA. Treatment with SAW also prevented the localization of C/EBPbeta to the centromeres. Taken together, our results show that SA has a potent antiadipogenic effect in 3T3-L1 cells due to the inhibition of adipocyte differentiation and adipogenesis. We propose that SA may be used as a safe and effective neutraceutical to manage obesity. PMID- 20962016 TI - Extracellular signal-regulated kinases 1/2 suppression aggravates transforming growth factor-beta1 hepatotoxicity: a potential mechanism for liver injury in methionine-choline deficient-diet-fed mice. AB - Hepatocyte cell death is a characteristic indication in the development of non alcoholic steatohepatitis (NASH); however, the underlying mechanism is still unclear. In this study, we examined the potential mechanism(s) involved in the development of liver injury using a methionine-choline deficient (MCD) diet feeding NASH model. Male C57BL6/J mice were fed MCD and methionine-choline sufficient (MCS) diet for two weeks before being killed. Our results showed that MCD diet feeding resulted in fatty liver and liver injury, evidenced by increased hepatic triglyceride (TG), plasma alanine aminotransferases and hepatic thiobarbituric acid reactive substances levels in MCD-fed mice. Furthermore, we found that MCD diet feeding caused remarkable suppression of hepatic extracellular signal-regulated kinases (ERK) 1/2 activation and increased transforming growth factor (TGF)-beta1 levels in plasma and the liver tissue. In vitro investigations showed that intracellular MEK/ERK1/2 activation status played a critical role in the determination of sensitivity of hepatocytes to TGF beta1-induced cell death. HepG2 cells, otherwise resistant to TGF-beta1 killing due to high level of ERK1/2 activation, was sensitized by U0126, a specific MEK/ERK1/2 inhibitor, to TGF-beta1 cytotoxicity. H4IIEC3 cells, which have lower level of constitutive ERK1/2 activity, are sensitive to TGF-beta1-induced cell death. Lastly, we demonstrated that administration of epidermal growth factor, a strong ERK1/2 activator, to MCD-fed mice attenuated liver injury without affecting hepatic TG accumulation. Our findings demonstrated that hepatic ERK1/2 inactivation aggravates TGF-beta1-induced hepatotoxicity, which may contribute, at least in part, to the initiation of liver injury in NASH. PMID- 20962017 TI - Clinical and functional characteristics of a novel heterozygous mutation of the IGF1R gene and IGF1R haploinsufficiency due to terminal 15q26.2->qter deletion in patients with intrauterine growth retardation and postnatal catch-up growth failure. AB - CONTEXT: Mutations in the IGF1R gene result in intrauterine growth retardation and postnatal growth failure. OBJECTIVE: The objective of this study was to describe the clinical features of subjects with a mutation in the IGF1R gene and to evaluate the molecular and functional characteristics of a novel IGF1R mutation. SUBJECTS: Three children with unexplained intrauterine growth retardation (birth weight <-1.5 SD score) and persistent short stature (<-2.0 SD score) were included in the study. METHODS: Auxological and endocrinological profiles were measured. All coding regions, including the intron-exon boundaries of the IGF1R gene, were amplified via PCR and directly sequenced. To study the functional effect of the IGF1R gene mutation on IGF-I signaling, total IGF1R protein expression, and IGF-I-dependent Akt and ERK phosphorylation were assessed by Western blotting. RESULTS: Two children and their father possessed a novel c.420del (p.A110fsX20) mutation in exon 2 of the IGF1R gene. After recombinant human GH therapy, the growth deficit decreased in these two children. Our data show that IGF-I-induced autophosphorylation of the phosphorylated tyrosine and phosphorylated Akt of IGF1R increased in a dose-dependent manner but did so less efficiently in patients. Array comparative genomic hybridization of chromosome 15 identified a heterozygous deletion of 15q26.2 to 15qter in subject 3. CONCLUSIONS: The novel heterozygous mutation described in this study reduced IGF1R expression and represents haploinsufficiency of the IGF1R gene. Our results indicate that this mutation in the IGF1R gene leads to abnormalities in the function of IGF1R and also retards intrauterine and subsequent growth in humans. PMID- 20962018 TI - The metabolic phenotype of Prader-Willi syndrome (PWS) in childhood: heightened insulin sensitivity relative to body mass index. AB - CONTEXT: Insulin sensitivity is higher in patients with Prader-Willi syndrome (PWS) than in body mass index-matched obese controls (OCs). Factors contributing to the heightened insulin sensitivity of PWS remain obscure. We compared the fasting levels of various hormones, cytokines, lipids, and liver function tests in 14 PWS patients and 14 OCs with those in 14 age- and gender-matched lean children (LC). We hypothesized that metabolic profiles of children with PWS are comparable with those of LC, but different from those of OCs. RESULTS: Leptin levels were comparable in PWS patients and OCs, suggesting comparable degrees of adiposity. Glucose levels were comparable among groups. However, fasting insulin concentrations and homeostasis model assessment insulin resistance index were lower in PWS patients than in OCs (P < 0.05) and similar to LC. Moreover, high density lipoprotein levels were lower and triglycerides higher in OCs (P < 0.05) but not PWS patients. Total adiponectin, high-molecular-weight (HMW) adiponectin and the HMW to total adiponectin ratio were higher in PWS patients (P < 0.05) than in OCs and similar to LC. High-sensitivity C-reactive protein and IL-6 levels were higher in OCs than in PWS patients or LC (P < 0.05). Nevertheless, PAI-1 levels were elevated in both OC and PWS patients. There were no group differences in glucagon-like peptide-1, macrophage chemoattractant protein-1, TNFalpha, IL-2, IL-8, IL-10, IL-12p40, IL-18, resistin, total or low-density lipoprotein cholesterol, aspartate aminotransferase, or alanine aminotransferase. CONCLUSIONS: The heightened insulin sensitivity of PWS patients relative to OCs is associated with higher levels of adiponectin and lower levels of high sensitivity C-reactive protein and IL-6. Future studies will determine whether PWS children are protected from obesity comorbidities such as type 2 diabetes, hyperlipidemia, and nonalcoholic fatty liver disease. PMID- 20962019 TI - Are women more at risk of false-positive primary aldosteronism screening and unnecessary suppression testing than men? AB - BACKGROUND: Because primary aldosteronism is not uncommon, specifically treatable and in some cases curable, and carries higher risks for cardiovascular morbidity and mortality than essential hypertension, screening hypertensive patients for its presence by measuring aldosterone to renin ratio (ARR) is increasingly common. A significantly higher false-positive ARR rate for women than men, resulting in unnecessary suppression tests has previously been reported. METHODS: Using a new, highly accurate aldosterone assay and both of the currently widely used renin assays, ARR was measured in 19 normal, ovulating women at three time points in the menstrual cycle and compared with single measurements in 21 normal males of similar age. RESULTS: ARRs in males were possibly too well down in the current normal range. Although normotensive and normokalemic, two women had raised ARRs in the luteal phase but only when direct renin concentration (DRC) was used. Their DRC levels were low at all sampling times [despite midrange plasma renin activity levels], whereas their progesterone and aldosterone levels were highest for the group. Saline suppression testing, performed in one of them, showed normal aldosterone suppressibility. CONCLUSION: False-positive ARRs in normal women during the luteal phase only when DRC is used may explain the higher incidence of false-positive ARRs in hypertensive women than men and suggest the following: 1) plasma renin activity is preferable to DRC in determination of ARR and 2) new reference ranges for ARR that take into account gender and sex hormone levels are required. PMID- 20962020 TI - Methylation allelic polymorphism (MAP) in chorionic gonadotropin beta5 (CGB5) and its association with pregnancy success. AB - CONTEXT: Increased epigenetic variability in the placenta may have evolved in response to its role in mediating the conflicting demands of the mother and fetus. One essential guardian of early pregnancy maintenance is the placental hormone human chorionic gonadotropin (HCG). OBJECTIVE: Among the four primate specific duplicate HCGbeta-coding genes, chorionic gonadotropin-beta8 (CGB8) and chorionic gonadotropin-beta5 (CGB5) jointly contribute 62-82% of the total HCGbeta transcript pool. Because these genes share common features with known imprinted placenta-expressed loci, we addressed the role of epigenetic mechanisms affecting their action. DESIGN AND SUBJECTS: Parental origin of CGB5 and CGB8 transcripts and promoter methylation patterns were addressed in trophoblastic tissues from 23 mother-offspring duos and nine mother-father-offspring trios including the following: 1) third-trimester normal delivery at term (n = 14), 2) first-trimester elective termination of uncomplicated pregnancy (n = 10), and 3) first-trimester recurrent (>=3) miscarriage (n = 8). RESULTS: A normal uncomplicated pregnancy was characterized by balanced, biallelic expression of CGB5 and CGB8. However, in three (two recurrent miscarriage and one early elective termination of uncomplicated pregnancy) of nine genetically informative cases of CGB5, monoallelic expression of maternal alleles and hemimethylated gene promoters were identified. CONCLUSION: Our finding may represent a novel methylation allelic polymorphism or gain of imprinting in CGB5 promoter leading to expressional silencing of paternal alleles and increasing susceptibility to pregnancy loss. Aberrant methylation patterns in placenta may result from random reprogramming defects affecting normal implantation process. Alternatively, methylation allelic polymorphism in the placenta favoring the failure of pregnancy may arise as a response to cellular stress caused by, in general, aneuploidy or conditions in placental-maternal interface. PMID- 20962022 TI - Thyroid nodules and cancer in children with PTEN hamartoma tumor syndrome. AB - CONTEXT: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a complex disorder caused by germline-inactivating mutations of the PTEN tumor suppressor gene. Carriers develop benign and malignant tumors of multiple tissues, including the breast, thyroid, intestine, and skin. Surveillance to facilitate the early detection and treatment of malignancies is recommended but, because thyroid cancers have been reported almost exclusively in adults, childhood risk is considered to be low, and consensus guidelines recommend that surveillance imaging begin at 18 yr of age. OBJECTIVE/PATIENTS: Seven children with PHTS referred to two thyroidologists form the basis of this report. Medical records, operative histology, and PTEN mutational analysis were reviewed to evaluate the pediatric presentation of PHTS-associated thyroid neoplasia. RESULTS: Five of the seven children presented with thyroid nodules or thyroid cancer between the ages of 6 and 12 yr, often as the initially identified component of their PHTS. Two others were diagnosed with PHTS on the basis of extrathyroidal features but had markedly abnormal screening ultrasounds with solid thyroid nodule(s) of at least 2 cm, despite the documentation of normal physical examinations. Five of the seven children in this cohort developed thyroid cancer. CONCLUSIONS: Patients with PHTS can develop thyroid nodules and thyroid cancer in early childhood. This argues both for a high index of suspicion for PHTS in children diagnosed with multiple thyroid nodules and for careful thyroid surveillance in children diagnosed with PHTS. Because early detection improves the outcome of thyroid cancer, we recommend ultrasound surveillance for all patients upon the confirmation of a germline PTEN mutation, regardless of their age. PMID- 20962023 TI - GH response to oral glucose tolerance test: a comparison between patients with acromegaly and other pituitary disorders. AB - CONTEXT: The cutoff value of nadir GH after an oral glucose tolerance test (OGTT) used to define disease remission in acromegaly is higher than that observed in healthy subjects. However, it is uncertain whether the impaired GH inhibition might be related to subtle abnormalities of GH secretion or to functional and/or anatomical hypothalamic-pituitary disconnection due to tumor per se or treatments. OBJECTIVE: The objective of the study was to evaluate the impact of pituitary disorders other than acromegaly on GH response to OGTT. DESIGN, SUBJECTS, AND METHODS: Thirty-three patients (24 females and nine males, aged 50.1 +/- 12.3 yr, 13 operated and two irradiated) with various hypothalamic pituitary disorders (HPDs), 45 healthy subjects (controls), and 42 cured acromegalic patients matched for sex, age. and body mass index were investigated. All subjects were studied for IGF-I levels and GH levels before and during the OGTT. RESULTS: In HPD patients mean postglucose nadir GH levels were 0.11 +/- 0.08 MUg/liter without any difference between patients treated with neurosurgery and/or radiotherapy and untreated and between patients with and without pituitary stalk alterations and/or hyperprolactinemia. Mean nadir GH values were similar in HPD patients and controls (0.11 +/- 0.08 vs. 0.08 +/- 0.08 MUg/liter, P = 0.23) and lower than those found in cured acromegalic patients (0.18 +/- 0.13 MUg/liter, P = 0.02), although there was an overlapping in about half of patients. CONCLUSIONS: Hypothalamic control of glucose-mediated GH suppression is not perturbed in patients with HPD. These data indicate that defective GH suppression to glucose that is found in acromegaly is unlikely to reflect a lack of integrity of hypothalamic function. PMID- 20962021 TI - Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. AB - CONTEXT: The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort represents the largest and best-characterized national sample of American youth with recent-onset type 2 diabetes. OBJECTIVE: The objective of the study was to describe the baseline characteristics of participants in the TODAY randomized clinical trial. DESIGN: Participants were recruited over 4 yr at 15 clinical centers in the United States (n = 704) and enrolled, randomized, treated, and followed up 2-6 yr. SETTING: The study was conducted at pediatric diabetes care clinics and practices. PARTICIPANTS: Eligible participants were aged 10-17 yr inclusive, diagnosed with type 2 diabetes for less than 2 yr and had a body mass index at the 85th percentile or greater. INTERVENTIONS: After baseline data collection, participants were randomized to one of the following groups: 1) metformin alone, 2) metformin plus rosiglitazone, or 3) metformin plus a lifestyle program of weight management. MAIN OUTCOME MEASURES: Baseline data presented include demographics, clinical/medical history, biochemical measurements, and clinical and biochemical abnormalities. RESULTS: At baseline the cohort included the following: 64.9% were female; mean age was 14.0 yr; mean diabetes duration was 7.8 months; mean body mass index Z-score was 2.15; 89.4% had a family history of diabetes; 41.1% were Hispanic, 31.5% were non-Hispanic black; 38.8% were living with both biological parents; 41.5% had a household annual income of less than $25,000; 26.3% had a highest education level of parent/guardian less than a high school degree; 26.3% had a blood pressure at the 90th percentile or greater; 13.6% had a blood pressure at the 95th percentile or greater; 13.0% had microalbuminuria; 79.8% had a low high-density lipoprotein level; and 10.2% had high triglycerides. CONCLUSIONS: The TODAY cohort is predominantly from racial/ethnic minority groups, with low socioeconomic status and a family history of diabetes. Clinical and biochemical abnormalities and comorbidities are prevalent within 2 yr of diagnosis. These findings contribute greatly to our understanding of American youth with type 2 diabetes. PMID- 20962024 TI - Loss of the C terminus of melanocortin receptor 2 (MC2R) results in impaired cell surface expression and ACTH insensitivity. AB - OBJECTIVE: Mutations in melanocortin receptor 2 (MC2R) and its related melanocortin receptor accessory protein (MRAP) cause familial glucocorticoid deficiency. We identified a novel MC2R mutation, K289fs. This unique mutation in the C terminus of MC2R is located in the intracellular part of the protein for which the exact function is unknown. SETTING: A 6-wk-old boy presented with severe hypoglycemia, unmeasurable cortisol, and grossly elevated ACTH but normal electrolytes. Genetic analysis revealed homozygote K289fs mutation in MC2R. His parents and siblings were heterozygous but phenotypically normal. INTERVENTION AND RESULTS: The role of the C terminus of MC2R was studied in two cell systems. Because the K289fs mutant changes the last eight amino acids of the protein and leads to protein elongation, wild-type MC2R and C-terminally mutated constructs were tested for activity to respond to ACTH in an OS3 cell-based reporter assay. Wild-type and alanine-substituted constructs responded normally to ACTH. By contrast K289fs and M290X had a total loss of activity. Cell surface assays and confocal localization studies revealed that K289fs and M290X receptors were not found at the cell surface, indicating that their transport from the endoplasmic reticulum to the cell membrane is disrupted. Interestingly, coimmunoprecipitation experiments showed no alteration in the interaction of mutant MC2R with MRAP, suggesting that interaction between these two proteins does not guarantee normal localization. CONCLUSIONS: Loss of the C terminus of MC2R impairs cell surface expression and ACTH sensitivity but does not disrupt interaction of MC2R with MRAP. These findings highlight the extreme sensitivity of MC2R to structural disruption. PMID- 20962025 TI - Estrogen receptor-alpha but not -beta or GPER inhibits high glucose-induced human VSMC proliferation: potential role of ROS and ERK. AB - CONTEXT: The decreased incidence of cardiovascular disease in premenopausal women has been attributed, at least partially, to protective effects of estrogens. However, premenopausal women with diabetes mellitus are no longer selectively protected. High-glucose (HG) conditions have previously been shown to abolish the antimitogenic effects of 17beta-estradiol (E(2)) in vascular smooth muscle cells (VSMCs). OBJECTIVE: Because E(2) mediates its action via different estrogen receptor (ER) subtypes, we hypothesized that different subtypes may have different, if not opposing, effects on HG-induced VSMC proliferation. METHODS AND RESULTS: Treatment of human aortic VSMCs isolated from premenopausal women with the selective ERalpha agonist, 4,4',4'-(4-propyl-[1H]-pyrazole-1,3,5 triyl)trisphenol, but not with E(2), the selective ERbeta agonist 2,3-bis(4 hydroxyphenyl)-propionitrile, or the selective G protein-coupled ER agonist G-1 completely prevented increased HG-induced VSMC proliferation. Under these conditions, ERalpha activation selectively prevented increased hydrogen peroxide (H(2)O(2)) and total intracellular reactive oxygen species (ROS) production, caused up-regulation of manganese superoxide dismutase protein and activity, and inhibited prolonged ERK phosphorylation. The latter was mediated by ROS, and ROS inhibition reversed HG-induced ERK-dependent VSMC proliferation. The selective coactivation of ERbeta reversed the antimitogenic and antioxidative effects of ERalpha as well as the up-regulation of manganese superoxide dismutase protein expression. CONCLUSION: Selective activation of ERalpha is required for reducing oxidative stress and the consequent hyperproliferation of VSMCs under HG. Our results may further suggest that ERalpha activation inhibits HG-induced proliferation by down-regulating ROS-mediated ERK activation and may explain why antimitogenic effects of E(2) are abolished under HG. Pharmacological activation of ERalpha may thus have therapeutic potential for treating cardiovascular dysregulation associated with diabetes. PMID- 20962026 TI - Associations between the pubertal timing-related variant in LIN28B and BMI vary across the life course. AB - CONTEXT: The common C allele of rs314276 in LIN28B has been robustly associated with earlier age at menarche in girls and associated with earlier timing of other pubertal traits in both sexes. OBJECTIVE: Our objective was to explore the associations between rs314276, as a marker of earlier pubertal timing, and body mass index (BMI), weight, and height across the life course. METHODS: The rs314276 in LIN28B was genotyped in 1242 men and 1209 women born in 1946 and participating in the Medical Research Council National Survey of Health and Development. Birth weight was recorded, and height and weight were measured or self-reported repeatedly at 11 time points between ages 2 and 53 yr. Polynomial mixed models were used to test whether additive genetic associations with sd scores (SDS) for BMI and height changed with age between 0 and 53 yr. RESULTS: Longitudinal analyses revealed age-dependent associations between rs314276 genotype and BMI (P < 0.001 for genotype-by-age(2) interaction) and body weight (P < 0.001 for genotype-by-age(2) interaction) in women, but not in men. In women only, the C allele at rs314276 was associated with higher BMI SDS from ages 15-43 yr. In contrast, C allele associations with shorter height SDS were apparent in both men and women and did not vary with age. CONCLUSION: A common genetic variant in LIN28B that confers earlier puberty was associated with a prolonged increase in BMI during adolescence and early to mid-adulthood in women only. Such genetic associations may provide insights into the direct effects of pubertal timing on obesity risk. PMID- 20962027 TI - 25-hydroxyvitamin D, insulin-like growth factor-I, and bone mineral accrual during growth. AB - CONTEXT: The extent to which 25-hydroxyvitamin D [25(OH)D] and IGF-I influence bone mineral content (BMC) accrual from early to mid-puberty is unclear. OBJECTIVE, SETTING, AND PARTICIPANTS: This study sought to determine relationships among 25(OH)D, IGF-I, and BMC in community-dwelling prepubertal females (n = 76; aged 4-8 yr at baseline) over a period of up to 9 yr. DESIGN: The hypothesis that changes in IGF-I vs. 25(OH)D are more strongly associated with BMC accrual was formulated after data collection. 25(OH)D and IGF-I were log transformed and further adjusted using two-way ANOVA for differences in season and race. Linear mixed modeling (including a random subject-specific intercept and a random subject-specific slope on age) was employed to analyze the proportion of variance the transformed 25(OH)D and IGF-I variables explained for the bone outcomes. RESULTS: IGF-I was more strongly associated with BMC accrual than 25(OH)D at the total body (R(2) = 0.874 vs. 0.809), proximal femur (R(2) = 0.847 vs. 0.771), radius (R(2) = 0.812 vs. 0.759), and lumbar spine (R(2) = 0.759 vs. 0.698). The rate of BMC accrual was positively associated with changes in IGF I but negatively associated with 25(OH)D. When IGF-I and 25(OH)D were included in the same regression equation, 25(OH)D did not have a significant predictive effect on BMC accrual above and beyond that of IGF-I. CONCLUSIONS: These prospective data in early adolescent females indicate that both 25(OH)D and IGF-I have a significant impact on bone mineral accrual; however, the positive association of IGF-I and BMC accrual is greater than the negative association of 25(OH)D and BMC accrual. PMID- 20962029 TI - The GluK1 (GluR5) Kainate/{alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist LY293558 reduces soman-induced seizures and neuropathology. AB - The possibility of mass exposure to nerve agents by a terrorist attack necessitates the availability of antidotes that can be effective against nerve agent toxicity even when administered at a relatively long latency after exposure, because medical assistance may not be immediately available. Nerve agents induce status epilepticus (SE), which can cause brain damage or death. Antagonists of kainate receptors that contain the GluK1 (formerly known as GluR5) subunit (GluK1Rs) are emerging as a new potential treatment for SE and epilepsy from animal research, whereas clinical trials to treat pain have shown that the GluK1/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5 yl)ethyl]decahydroisoquinoline-3-carboxylic acid] is safe and well tolerated. Therefore, we tested whether LY293558 is effective against soman-induced seizures and neuropathology, when administered 1 h after soman exposure, in rats. LY293558 stopped seizures induced by soman and reduced the total duration of SE, monitored by electroencephalographic recordings within a 24 h-period after exposure. In addition, LY293558 prevented neuronal loss in the basolateral amygdala (BLA) and the CA1 hippocampal area on both days 1 and 7 after soman exposure and reduced neuronal degeneration in the CA1, CA3, and hilar hippocampal regions, entorhinal cortex, amygdala, and neocortex on day 1 after exposure and in the CA1, CA3, amygdala, and neocortex on day 7 after exposure. It also prevented the delayed loss of glutamic acid decarboxylase-67 immuno-stained BLA interneurons on day 7 after exposure. LY293558 is a potential new emergency treatment for nerve agent exposure that can be expected to be effective against seizures and brain damage even with late administration. PMID- 20962028 TI - Hypoxia and hypoxia-inducible factors: master regulators of metastasis. AB - Hypoxia is a common condition found in a wide range of solid tumors and is often associated with poor prognosis. Hypoxia increases tumor glycolysis, angiogenesis, and other survival responses, as well as invasion and metastasis by activating relevant gene expressions through hypoxia-inducible factors (HIF). HIF-1alpha and HIF-2alpha undergo oxygen-dependent regulation, and their overexpression is frequently associated with metastasis and poor clinical outcomes. Recent studies show that each step of the metastasis process, from the initial epithelial mesenchymal transition to the ultimate organotropic colonization, can potentially be regulated by hypoxia, suggesting a master regulator role of hypoxia and HIFs in metastasis. Furthermore, modulation of cancer stem cell self-renewal by HIFs may also contribute to the hypoxia-regulated metastasis program. The hypoxia induced metastatic phenotype may be one of the reasons for the modest efficacy of antiangiogenic therapies and may well explain the recent provocative findings that antiangiogenic therapy increased metastasis in preclinical models. Multiple approaches to targeting hypoxia and HIFs, including HIF inhibitors, hypoxia activated bioreductive prodrugs, and gene therapies may become effective treatments to prevent or reduce metastasis. PMID- 20962030 TI - The fate and function of therapeutic antiaddiction monoclonal antibodies across the reproductive cycle of rats. AB - During preclinical development of neuroprotective antiaddiction therapeutic monoclonal antibodies (mAbs) against phencyclidine (PCP) and (+)-methamphetamine, we discovered novel, gestation stage-specific changes in mAb disposition spanning the entire reproductive cycle of female rats. Each pharmacological change was independent of mAb dose and antigen target but was precisely coincident with transitions between the gestational trimesters, parturition, and lactation periods of the female reproductive cycle. Whereas anti-PCP mAb6B5 terminal elimination half-life (t(1/2lambdaz)) in nonpregnant females was 6.6 +/- 1.6 days, the mAb6B5 t(1/2lambdaz) significantly changed to 3.7 +/- 0.4 days, then 1.4 +/- 0.1 days, then 3.0 +/- 0.4 days in the second trimester, third trimester, and postpartum periods, respectively (p < 0.05 for each change). Initially, these evolving changes in mAb6B5 clearance (3.3-fold), distribution volume (1.8-fold), and elimination half-life (4.7-fold) affected our ability to sustain sufficient mAb6B5 levels to sequester PCP in the bloodstream. However, understanding the mechanisms underlying each transition allowed development of an adaptive mAb dosing paradigm, which substantially reduced PCP levels in dam brains and fetuses throughout pregnancy. These mAb functional studies also revealed that antidrug mAbs readily cross the placenta before syncytiotrophoblast barrier maturation, demonstrating the dynamic nature of mAb pharmacokinetics in pregnancy and the importance of maintaining maternal mAb levels. These studies provide the first preclinical pregnancy model in any species for chronic mAb dosing and could have important implications for the use of antibody therapies involving blood organ barriers (such as addiction) or other chronic diseases in women of childbearing age (e.g., irritable bowel diseases, multiple sclerosis, breast cancer, rheumatoid arthritis). PMID- 20962031 TI - The nitric oxide prodrug JS-K is effective against non-small-cell lung cancer cells in vitro and in vivo: involvement of reactive oxygen species. AB - Non-small-cell lung cancer is among the most common and deadly forms of human malignancies. Early detection is unusual, and there are no curative therapies in most cases. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Here, we show that O(2)-(2,4 dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS K) is a potent cytotoxic agent against a subset of human non-small-cell lung cancer cell lines both in vitro and as xenografts in mice. JS-K treatment led to 75% reduction in the growth of H1703 lung adenocarcinoma cells in vivo. Differences in sensitivity to JS-K in different lung cancer cell lines seem to be related to their endogenous levels of reactive oxygen species (ROS)/reactive nitrogen species (RNS). Other related factors, levels of peroxiredoxin 1 (PRX1) and 8-oxo-deoxyguanosine glycosylase (OGG1), also correlated with drug sensitivity. Treatment of the lung adenocarcinoma cells with JS-K resulted in oxidative/nitrosative stress in cells with high basal levels of ROS/RNS, which, combined with the arylating properties of the compound, was reflected in glutathione depletion and alteration in cellular redox potential, mitochondrial membrane permeabilization, and cytochrome c release. Inactivation of manganese superoxide dismutase by nitration was associated with increased superoxide and significant DNA damage. Apoptosis followed these events. Taken together, the data suggest that diazeniumdiolate-based NO-releasing prodrugs may have application as a personalized therapy for lung cancers characterized by high levels of ROS/RNS. PRX1 and OGG1 proteins, which can be easily measured, could function as biomarkers for identifying tumors sensitive to the therapy. PMID- 20962032 TI - Bis-halogen-anthraniloyl-substituted nucleoside 5'-triphosphates as potent and selective inhibitors of Bordetella pertussis adenylyl cyclase toxin. AB - Whooping cough is caused by Bordetella pertussis and still constitutes one of the top five causes of death in young children, particularly in developing countries. The calmodulin-activated adenylyl cyclase (AC) toxin CyaA substantially contributes to disease development. Thus, potent and selective CyaA inhibitors would be valuable drugs for the treatment of whooping cough. However, it has been difficult to obtain potent CyaA inhibitors with selectivity relative to mammalian ACs. Selectivity is important for reducing potential toxic effects. In a previous study we serendipitously found that bis-methylanthraniloyl (bis-MANT)-IMP is a more potent CyaA inhibitor than MANT-IMP (Mol Pharmacol 72:526-535, 2007). These data prompted us to study the effects of a series of 32 bulky mono- and bis anthraniloyl (ANT)-substituted nucleotides on CyaA and mammalian ACs. The novel nucleotides differentially inhibited CyaA and ACs 1, 2, and 5. Bis-ANT nucleotides inhibited CyaA competitively. Most strikingly, bis-Cl-ANT-ATP inhibited CyaA with a potency >=100-fold higher than ACs 1, 2, and 5. In contrast to MANT-ATP, bis-MANT-ATP exhibited low intrinsic fluorescence, thereby substantially enhancing the signal-to noise ratio for the analysis of nucleotide binding to CyaA. The high sensitivity of the fluorescence assay revealed that bis MANT-ATP binds to CyaA already in the absence of calmodulin. Molecular modeling showed that the catalytic site of CyaA is sufficiently spacious to accommodate both MANT substituents. Collectively, we have identified the first potent CyaA inhibitor with high selectivity relative to mammalian ACs. The fluorescence properties of bis-ANT nucleotides facilitate development of a high-throughput screening assay. PMID- 20962033 TI - Considerations of circadian impact for defining 'shift work' in cancer studies: IARC Working Group Report. AB - Based on the idea that electric light at night might account for a portion of the high and rising risk of breast cancer worldwide, it was predicted long ago that women working a non-day shift would be at higher risk compared with day-working women. This hypothesis has been extended more recently to prostate cancer. On the basis of limited human evidence and sufficient evidence in experimental animals, in 2007 the International Agency for Research on Cancer (IARC) classified 'shift work that involves circadian disruption' as a probable human carcinogen, group 2A. A limitation of the epidemiological studies carried out to date is in the definition of 'shift work.' IARC convened a workshop in April 2009 to consider how 'shift work' should be assessed and what domains of occupational history need to be quantified for more valid studies of shift work and cancer in the future. The working group identified several major domains of non-day shifts and shift schedules that should be captured in future studies: (1) shift system (start time of shift, number of hours per day, rotating or permanent, speed and direction of a rotating system, regular or irregular); (2) years on a particular non-day shift schedule (and cumulative exposure to the shift system over the subject's working life); and (3) shift intensity (time off between successive work days on the shift schedule). The group also recognised that for further domains to be identified, more research needs to be conducted on the impact of various shift schedules and routines on physiological and circadian rhythms of workers in real world environments. PMID- 20962034 TI - Mortality related to temperature and persistent extreme temperatures: a study of cause-specific and age-stratified mortality. AB - OBJECTIVES: High and low ambient temperatures are associated with large numbers of deaths annually. Many studies show higher mortalities during heatwaves. However, such effects are rarely explicitly incorporated in models of temperature and mortality, although dehydration followed by cardiovascular stress is more likely to occur. The authors aim to establish time-series models in which the effects of persistent extreme temperature and temperature in general can be disentangled. METHODS: The authors established time-series Poisson regression models based on cause-specific mortality and age-stratified mortality in Stockholm County (Sweden), 1990-2002, adjusting for time trends and potential confounders, and studied the effects of temperature and persistence of extreme temperature. RESULTS: Persistent extremely high temperature was associated with additional deaths, and the risk of death increased significantly per day of extended heat exposure. Extreme exposure to heat was associated with higher death rates in adults and for cardiovascular causes of death, compared with a rise in temperature. Warmer temperatures increase daily mortality from natural causes, while decreasing colder temperatures increase the risk of cardiovascular deaths. Furthermore, the impact of warm and cold temperatures decreases within the season, while the impact of persistent extremely high temperatures remains similar throughout the summer. CONCLUSIONS: The authors found the mortality impact of persistence of extreme high temperatures to increase proportionally to the length of the heat episode in addition to the effects of temperature based on the temperature-mortality relationship. Thus, the additional effect of persistent extreme heat was found to be important to incorporate for models of mortality related to ambient temperatures to avoid negatively biased attributed risks, especially for cardiovascular mortality. Moreover, the effects associated with non-extreme temperatures may decline as the pool of fragile individuals shrink as well as due to acclimatisation/adaptation. However, a similar decline was not observed for the effects associated with extreme heat episodes. PMID- 20962036 TI - A novel Caenorhabditis elegans allele, smn-1(cb131), mimicking a mild form of spinal muscular atrophy, provides a convenient drug screening platform highlighting new and pre-approved compounds. AB - Spinal muscular atrophy (SMA), an autosomal recessive genetic disorder, is characterized by the selective degeneration of lower motor neurons, leading to muscle atrophy and, in the most severe cases, paralysis and death. Deletions and point mutations cause reduced levels of the widely expressed survival motor neuron (SMN) protein, which has been implicated in a range of cellular processes. The mechanisms underlying disease pathogenesis are unclear, and there is no effective treatment. Several animal models have been developed to study SMN function including the nematode, Caenorhabditis elegans, in which a large deletion in the gene homologous to SMN, smn-1, results in neuromuscular dysfunction and larval lethality. Although useful, this null mutant, smn 1(ok355), is not well suited to drug screening. We report the isolation and characterization of smn-1(cb131), a novel allele encoding a substitution in a highly conserved residue of exon 2, resembling a point mutation found in a patient with type IIIb SMA. The smn-1(cb131) animals display milder yet similar defects when compared with the smn-1 null mutant. Using an automated phenotyping system, mutants were shown to swim slower than wild-type animals. This phenotype was used to screen a library of 1040 chemical compounds for drugs that ameliorate the defect, highlighting six for subsequent testing. 4-aminopyridine, gaboxadol hydrochloride and N-acetylneuraminic acid all rescued at least one aspect of smn 1 phenotypic dysfunction. These findings may assist in accelerating the development of drugs for the treatment of SMA. PMID- 20962035 TI - Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B. AB - Brachydactyly type B (BDB1) and Robinow syndrome (RRS) are two skeletal disorders caused by mutations in ROR2, a co-receptor of Wnt5a. Wnt5a/Ror2 can activate multiple branches of non-canonical Wnt signaling, but it is unclear which branch(es) mediates Wnt5a/Ror2 function in limb skeletal development. Here, we provide evidence implicating the planar cell polarity (PCP) pathway as the downstream component of Wnt5a in the limb. We show that a mutation in the mouse PCP gene Vangl2 causes digit defects resembling the clinical phenotypes in BDB1, including loss of phalanges. Halving the dosage of Wnt5a in Vangl2 mutants enhances the severity and penetrance of the digit defects and causes long bone defects reminiscent of RRS, suggesting that Wnt5a and Vangl2 function in the same pathway and disruption of PCP signaling may underlie both BDB1 and RRS. Consistent with a role for PCP signaling in tissue morphogenesis, mutation of Vangl2 alters the shape and dimensions of early limb buds: the width and thickness are increased, whereas the length is decreased. The digit pre chondrogenic condensates also become wider, thicker and shorter. Interestingly, altered limb bud dimensions in Vangl2 mutants also affect limb growth by perturbing the signaling network that regulates the balance between Fgf and Bmp signaling. Halving the dosage of Bmp4 partially suppresses the loss of phalanges in Vangl2 mutants, supporting the hypothesis that an aberrant increase in Bmp signaling is the cause of the brachydactyly defect. These findings provide novel insight into the signaling mechanisms of Wnt5a/Ror2 and the pathogenesis in BDB1 and RRS. PMID- 20962037 TI - Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice. AB - Approximately 10% of patients with amyotrophic lateral sclerosis (ALS) have familial ALS (FALS), and 20% of FALS are caused by mutations of superoxide dismutase type 1 (MTSOD1). The fact that some MTSOD1s that cause FALS have full dismutase activity (e.g. G37R) and others no dismutase activity (e.g. G85R) suggests that MTSOD1 causes FALS due to toxicity of the protein rather than a loss in enzymatic function. Compelling data have demonstrated that motor neuron (MN) degeneration can result from a non-cell autonomous effect of the MTSOD1. In order to clarify the role of astrocytes in FALS, we deleted MTSOD1 in astrocytes of G85R transgenic mice. In contrast to a similar study using G37R mice in which astrocyte MTSOD1 loss affected only the late phase of ALS disease, we found that astrocyte MTSOD1 loss in G85R mice delayed disease onset and prolonged the early phase of disease progression, without affecting the late phase. In addition, astrocyte G85R knockdown resulted in decreased microgliosis, decreased SOD1 immunoreactive inclusions and preservation of GLT-1 transporter expression. The differential effects of astrocyte G85R versus G37R knockdown on MN death demonstrate SOD1 mutation-specific effects on ALS pathogenesis; these differences may be a result of the different dismutase activities of the two mutants. The effect of the knockdown of G85R expression in astrocytes on onset as well as disease duration highlights the importance of this cell type in FALS. PMID- 20962038 TI - Modification of 16S ribosomal RNA by the KsgA methyltransferase restructures the 30S subunit to optimize ribosome function. AB - All organisms incorporate post-transcriptional modifications into ribosomal RNA, influencing ribosome assembly and function in ways that are poorly understood. The most highly conserved modification is the dimethylation of two adenosines near the 3' end of the small subunit rRNA. Lack of these methylations due to deficiency in the KsgA methyltransferase stimulates translational errors during both the initiation and elongation phases of protein synthesis and confers resistance to the antibiotic kasugamycin. Here, we present the X-ray crystal structure of the Thermus thermophilus 30S ribosomal subunit lacking these dimethylations. Our data indicate that the KsgA-directed methylations facilitate structural rearrangements in order to establish a functionally optimum subunit conformation during the final stages of ribosome assembly. PMID- 20962039 TI - A novel Nop5-sRNA interaction that is required for efficient archaeal box C/D sRNP formation. AB - Archaeal and eukaryotic box C/D RNPs catalyze the 2'-O-methylation of ribosomal RNA, a modification that is essential for the correct folding and function of the ribosome. Each archaeal RNP contains three core proteins--L7Ae, Nop5, and fibrillarin (methyltransferase)--and a box C/D sRNA. Base-pairing between the sRNA guide region and the rRNA directs target site selection with the C/D and related C'/D' motifs functioning as protein binding sites. Recent structural analysis of in vitro assembled archaeal complexes has produced two divergent models of box C/D sRNP structure. In one model, the complex is proposed to be monomeric, while the other suggests a dimeric sRNP. The position of the RNA in the RNP is significantly different in each model. We have used UV-cross-linking to characterize protein-RNA contacts in the in vitro assembled Pyrococcus furiosus box C/D sRNP. The P. furiosus sRNP components assemble into complexes that are the expected size of di-sRNPs. Analysis of UV-induced protein-RNA cross links revealed a novel interaction between the ALFR motif, in the Nop domain of Nop5, and the guide/spacer regions of the sRNA. We show that the ALFR motif and the spacer sequence adjacent to box C or C' are important for box C/D sRNP assembly in vitro. These data therefore reveal new RNA-protein contacts in the box C/D sRNP and suggest a role for Nop5 in substrate binding and/or release. PMID- 20962040 TI - Loop and stem dynamics during RNA hairpin folding and unfolding. AB - 2-Aminopurine (2AP) is a fluorescent adenine analog that probes mainly base stacking in nucleic acids. We labeled the loop or the stem of the RNA hairpin gacUACGguc with 2AP to study folding thermodynamics and kinetics at both loci. Thermal melts and fast laser temperature jumps detected by 2AP fluorescence monitored the stability and folding/unfolding kinetics. The observed thermodynamic and kinetic traces of the stem and loop mutants, though strikingly different at a first glance, can be fitted to the same free-energy landscape. The differences between the two probe locations arise because base stacking decreases upon unfolding in the stem, whereas it increases in the loop. We conclude that 2AP is a conservative adenine substitution for mapping out the contributions of different RNA structural elements to the overall folding process. Molecular dynamics (MD) totaling 0.6 MUsec were performed to look at the conformations populated by the RNA at different temperatures. The combined experimental data, and MD simulations lead us to propose a minimal four-state free-energy landscape for the RNA hairpin. Analysis of this landscape shows that a sequential folding model is a good approximation for the full folding dynamics. The frayed state formed initially from the native state is a heterogeneous ensemble of structures whose stem is frayed either from the end or from the loop. PMID- 20962041 TI - Serum-stable RNA aptamers to urokinase-type plasminogen activator blocking receptor binding. AB - The serine proteinase urokinase-type plasminogen activator (uPA) is widely recognized as a potential target for anticancer therapy. Its association with cell surfaces through the uPA receptor (uPAR) is central to its function and plays an important role in cancer invasion and metastasis. In the current study, we used systematic evolution of ligands by exponential enrichment (SELEX) to select serum-stable 2'-fluoro-pyrimidine-modified RNA aptamers specifically targeting human uPA and blocking the interaction to its receptor at low nanomolar concentrations. In agreement with the inhibitory function of the aptamers, binding was found to be dependent on the presence of the growth factor domain of uPA, which mediates uPAR binding. One of the most potent uPA aptamers, upanap-12, was analyzed in more detail and could be reduced significantly in size without severe loss of its inhibitory activity. Finally, we show that the uPA-scavenging effect of the aptamers can reduce uPAR-dependent endocytosis of the uPA-PAI-1 complex and cell-surface associated plasminogen activation in cell culture experiments. uPA-scavenging 2'-fluoro-pyrimidine-modified RNA aptamers represent a novel promising principle for interfering with the pathological functions of the uPA system. PMID- 20962042 TI - Prolactin inhibits activity of pyruvate kinase M2 to stimulate cell proliferation. AB - Mitogenic and prosurvival effects underlie the tumorigenic roles of prolactin (PRL) in the pathogenesis of breast cancer. PRL signaling is mediated through its receptor (PRLr). A proteomics screen identified the pyruvate kinase M2 (PKM2), a glycolytic enzyme known to play an important role in tumorigenesis, as a protein that constitutively interacts with PRLr. Treatment of cells with PRL inhibited pyruvate kinase activity and increased the lactate content in human cells in a manner that was dependent on the abundance of PRLr, activation of Janus kinase 2, and tyrosine phosphorylation of the intracellular domain of PRLr. Knockdown of PKM2 attenuated PRL-stimulated cell proliferation. The extent of this proliferation was rescued by the knock-in of the wild-type PKM2 but not of its mutant insensitive to PRL-mediated inhibition. We discuss a hypothesis that the inhibition of PKM2 by PRL contributes to the PRL-stimulated cell proliferation. PMID- 20962043 TI - Interferon tau regulates PGF2alpha release from the ovine endometrial epithelial cells via activation of novel JAK/EGFR/ERK/EGR-1 pathways. AB - In ruminants, pulsatile release of prostaglandin F2alpha (PGF(2alpha)) from the endometrium is transported to the ovary and induces luteolysis thereby allowing new estrous cycle. Interferon tau (IFNT), a type 1 IFN secreted by the trophoblast cells of the developing conceptus, acts on endometrial luminal epithelial (LE) cells and inhibits pulsatile release of PGF(2alpha) and establishes pregnancy. One of the unknown mechanisms is that endometrial pulsatile release of PGF(2alpha) is inhibited whereas basal release of PGF(2alpha) is increased in pregnant compared with nonpregnant sheep. We have recently found that pulsatile release of PGF(2alpha) from the endometrium is regulated by prostaglandin transporter (PGT)-mediated mechanisms. We hypothesize that modulation in the endometrial pulsatile vs. basal release of PGF(2alpha) likely requires PGT-mediated selective transport, and IFNT interacts with PGT protein and modulates pulsatile vs. basal release of PGF(2alpha). The new findings of the present study are: 1) IFNT activates novel JAK-SRC kinase-EGFR RAS-RAF-ERK1/2-early growth response (EGR)-1 signaling module in LE cells; 2) IFNT increases interactions between PGT and ERK1/2 or EGR-1 proteins and alters phosphorylation of PGT protein; 3) IFNT precludes action of protein kinase C and Ca(2+) on PGT function; and 4) IFNT inhibits 80% PGT-mediated but not 20% simple diffusion-mediated release of PGF(2alpha) from the endometrial LE cells through this novel signaling module. The results of the present study provide important new insights on IFNT signaling and molecular control of PGT-mediated release of PGF(2alpha) and unravel the underlying mechanisms responsible for the increased basal release of PGF(2alpha) at the time of establishment of pregnancy in ruminants. PMID- 20962044 TI - Cytokine and progesterone receptor interplay in the regulation of MUC1 gene expression. AB - Mucin 1 (MUC1), a transmembrane mucin expressed at the apical surface of uterine epithelia, is a barrier to microbial infection and enzymatic attack. MUC1 loss at implantation sites appears to be required to permit embryo attachment and implantation in most species. MUC1 expression is regulated by progesterone (P) and proinflammatory cytokines, including TNFalpha and interferon gamma (IFNgamma). TNFalpha and IFNgamma are highly expressed in uterine tissues under conditions where MUC1 expression is also high and activate MUC1 expression via their downstream transcription factors, nuclear factor (NF) kappaB and signal transducers and activators of transcription. P receptor (PR) regulates MUC1 gene expression in a PR isoform-specific fashion. Here we demonstrate that interactions among PR isoforms and cytokine-activated transcription factors cooperatively regulate MUC1 expression in a human uterine epithelial cell line, HES. Low doses of IFNgamma and TNFalpha synergistically stimulate MUC1 promoter activity, enhance PRB stimulation of MUC1 promoter activity and cooperate with PRA to stimulate MUC1 promoter activity. Cooperative stimulation of MUC1 promoter activity requires the DNA-binding domain of the PR isoforms. MUC1 mRNA and protein expression is increased by cytokine and P treatment in HES cells stably expressing PRB. Using chromatin immunoprecipitation assays, we demonstrate efficient recruitment of NFkappaB, p300, SRC3 (steroid receptor coactivator 3), and PR to the MUC1 promoter. Collectively, our studies indicate a dynamic interplay among cytokine-activated transcription factors, PR isoforms and transcriptional coregulators in modulating MUC1 expression. This interplay may have important consequences in both normal and pathological contexts, e.g. implantation failure and recurrent miscarriages. PMID- 20962045 TI - Function of a transcription factor CDX2 beyond its trophectoderm lineage specification. AB - The transcription factor caudal-related homeobox 2 (CDX2) regulates trophectoderm differentiation, but its function beyond trophectoderm differentiation is not well characterized. CDX2 was shown to regulate a trophoblast-specific gene, interferon tau (IFNT), in the ruminants. However, its regulatory mechanism has not been determined. Here, we report a new role of CDX2 in histone modifications of the IFNT gene. Chromatin immunoprecipitation assays using ovine conceptuses obtained from d 14, 16, 16.5, or 20 of pregnancy (d 0, day of mating) revealed that H3K18 acetylation was highly detectable at the upstream and open reading frame regions of the IFNT gene on d 14 and 16, when CDX2 reached its peak expression. From d 16.5, when the conceptus initiates attachment to uterine epithelial cells, histone acetylation along with CDX2 expression declines. Two candidate CDX2 binding sites (-300 to -294 bp and -293 to -287 bp) of the bovine IFNT gene promoter region were detected from chromatin immunoprecipitation and luciferase assay. When Cdx2 constructs were transfected into bovine ear-derived fibroblast cells, histone acetylation was increased, concurrent with the recruitment of cAMP response element binding protein-binding protein, which has histone acetyltransferase activity. H3K18 acetylation was seen in the proximity of the CDX2 binding region located at the IFNT gene's upstream region in CT-1 cells, but when these cells were treated with specific CDX2 small interfering RNA, H3K18 acetylation was decreased. These findings suggest that CDX2 regulates its targeted gene through cAMP response element binding protein-binding protein recruitment, which correlates with greater histone acetylation. PMID- 20962046 TI - Abnormal epithelial cell polarity and ectopic epidermal growth factor receptor (EGFR) expression induced in Emx2 KO embryonic gonads. AB - The gonadal primordium first emerges as a thickening of the embryonic coelomic epithelium, which has been thought to migrate mediodorsally to form the primitive gonad. However, the early gonadal development remains poorly understood. Mice lacking the paired-like homeobox gene Emx2 display gonadal dysgenesis. Interestingly, the knockout (KO) embryonic gonads develop an unusual surface accompanied by aberrant tight junction assembly. Morphological and in vitro cell fate mapping studies showed an apparent decrease in the number of the gonadal epithelial cells migrated to mesenchymal compartment in the KO, suggesting that polarized cell division and subsequent cell migration are affected. Microarray analyses of the epithelial cells revealed significant up-regulation of Egfr in the KO, indicating that Emx2 suppresses Egfr gene expression. This genetic correlation between the two genes was reproduced with cultured M15 cells derived from mesonephric epithelial cells. Epidermal growth factor receptor signaling was recently shown to regulate tight junction assembly through sarcoma viral oncogene homolog tyrosine phosphorylation. We show through Emx2 KO analyses that sarcoma viral oncogene homolog tyrosine phosphorylation, epidermal growth factor receptor tyrosine phosphorylation, and Egfr expression are up-regulated in the embryonic gonad. Our results strongly suggest that Emx2 is required for regulation of tight junction assembly and allowing migration of the gonadal epithelia to the mesenchyme, which are possibly mediated by suppression of Egfr expression. PMID- 20962047 TI - Pregnane X receptor as a therapeutic target to inhibit androgen activity. AB - The androgen-androgen receptor signaling pathway plays an important role in the pathogenesis of prostate cancer. Accordingly, androgen deprivation has been the most effective endocrine therapy for hormone-dependent prostate cancer. Here, we report a novel pregnane X receptor (PXR)-mediated and metabolism-based mechanism to reduce androgenic tone. PXR is a nuclear receptor previously known as a xenobiotic receptor regulating the expression of drug metabolizing enzymes and transporters. We showed that genetic (using a PXR transgene) or pharmacological (using a PXR agonist) activation of PXR lowered androgenic activity and inhibited androgen-dependent prostate regeneration in castrated male mice that received daily injections of testosterone propionate by inducing the expression of cytochrome P450 (CYP)3As and hydroxysteroid sulfotransferase (SULT)2A1, which are enzymes important for the metabolic deactivation of androgens. In human prostate cancer cells, treatment with the PXR agonist rifampicin (RIF) inhibited androgen dependent proliferation of LAPC-4 cells but had little effect on the growth of the androgen-independent isogenic LA99 cells. Down-regulation of PXR or SULT2A1 in LAPC-4 cells by short hairpin RNA or small interfering RNA abolished the RIF effect, indicating that the inhibitory effect of RIF on androgens was PXR and SULT2A1 dependent. In summary, we have uncovered a novel function of PXR in androgen homeostasis. PXR may represent a novel therapeutic target to lower androgen activity and may aid in the treatment and prevention of hormone dependent prostate cancer. PMID- 20962048 TI - Generation of transgenic mice overexpressing a ghrelin analog. AB - After the discovery of ghrelin, we attempted to generate ghrelin gene transgenic (Tg) mice. These animals, however, produced only des-acyl ghrelin, which lacked the n-octanoyl modification at Ser(3) necessary to manifest ghrelin activity. Because the mechanism for acyl-modification of ghrelin had been unclear until the recent identification of GOAT (ghrelin O-acyltransferase), it had been difficult to generate Tg mice overexpressing ghrelin using standard procedures. Therefore, we planned to generate Tg mice overexpressing a ghrelin analog, which possessed ghrelin-like activity in the absence of acylation at Ser(3) and could be synthesized in vivo. As the replacement of Ser(3) of ghrelin with Trp(3) (Trp(3) ghrelin) preserves a low level of ghrelin activity and Trp(3)-ghrelin can be synthesized in vivo, we generated mice overexpressing Trp(3)-ghrelin by using the hSAP (human serum-amyloid-P) promoter. Plasma Trp(3)-ghrelin concentrations in the Tg mice were approximately 85-fold higher than plasma ghrelin concentrations in non-Tg littermates. Because Trp(3)-ghrelin is approximately 1/10-1/20 less potent than ghrelin in vivo, plasma Trp(3)-ghrelin concentrations in Tg mice were calculated to have an activity approximately 6-fold greater than that of acylated ghrelin seen in non-Tg mice (85-fold x 1/10-1/20). Tg mice exhibited a normal growth and glucose metabolism in their early life stage. However, 1-yr-old Tg mice demonstrated impaired glucose tolerance and reduced insulin sensitivity. This model will be useful to evaluate the long-term effects of ghrelin or ghrelin analogs. In addition, this technique may be a useful method to generate gain-of activity models for hormones that require posttranscriptional modifications. PMID- 20962049 TI - Enhanced amylin-mediated body weight loss in estradiol-deficient diet-induced obese rats. AB - In rodents, ovariectomy (OVX) elicits weight gain and diminished responsiveness to homeostatic signals. Here we characterized the response of obese OVX rats to peripheral amylin. Rats received sham surgery (SHAM), OVX, or OVX with hormonal replacement (17beta-estradiol, 2 MUg per 4 d; OVX+E) and were infused with vehicle or amylin (50 MUg/kg . d) for 28 d. Amylin reduced body weight (5.1 +/- 1.1%) and food intake (10.9 +/- 3.4%) in SHAM rats but was twice as efficacious in OVX rats in reducing weight (11.2 +/- 1.9%) and food intake (23.0 +/- 2.0%). There were no differences between amylin-treated SHAM and OVX+E rats. OVX decreased metabolic rate (~24%) and increased respiratory exchange ratio relative to SHAM. Amylin partially normalized metabolic rate (13% increase) in OVX rats and decreased respiratory exchange ratio in OVX and SHAM rats. Regarding central mechanisms, amylin infusion corrected the OVX-induced decrease in hippocampal neurogenesis and increased immobility in the forced swim test. Additionally, amylin increased neurogenesis (~2-fold) within the area postrema of OVX rats. To assess the contribution of endogenous leptin to amylin-mediated weight loss in OVX rats, amylin was administered to SHAM or OVX Zucker diabetic fatty rats. In SHAM rats, amylin infusion reduced food intake but not body weight, whereas in OVX Zucker diabetic fatty rats, food intake, body weight, and insulin were reduced. Overall, amylin induced greater body weight loss in the absence of estradiol via central and peripheral actions that did not require leptin. These findings support the clinical investigation of amylin in low estradiol (e.g. postmenopausal) states. PMID- 20962050 TI - Energetic metabolism and human sperm motility: impact of CB1 receptor activation. AB - It has been reported that the endocannabinoid anandamide (AEA) exerts an adverse effect on human sperm motility, which has been ascribed to inhibition of mitochondrial activity. This seems to be at variance with evidence suggesting a major role of glycolysis in supplying ATP for sperm motility; furthermore, the role of AEA-binding receptors in mediating mitochondrial inhibition has not yet been explored. In this study, human sperm exposure to Met-AEA (methanandamide, nonhydrolyzable analog of AEA) in the micromolar range significantly decreased mitochondrial transmembrane potential (DeltaPsim), similarly to rotenone, mitochondrial complex I inhibitor. The effect of Met-AEA (1 MUm) was prevented by SR141716, CB(1) cannabinoid receptor antagonist, but not by SR144528, CB(2) antagonist, nor by iodoresiniferatoxin, vanilloid receptor antagonist. The effect of Met-AEA did not involve activation of caspase-9 or caspase-3 and was reverted by washing. In the presence of glucose, sperm exposure either to Met-AEA up to 1 MUm or to rotenone for up to 18 h did not affect sperm motility. At higher doses Met-AEA produced a CB(1)-independent poisoning of spermatozoa, reducing their viability. Under glycolysis blockage, 1 MUm Met-AEA, similarly to rotenone, dramatically abolished sperm motility, an effect that was prevented by SR1 and reverted by washing. In conclusion, CB(1) activation induced a nonapoptotic decrease of DeltaPsim, the detrimental reflection on sperm motility of which could be revealed only under glycolysis blockage, unless very high doses of Met AEA, producing CB(1)-independent sperm toxicity, were used. The effects of CB(1) activation reported here contribute to elucidate the relationship between energetic metabolism and human sperm motility. PMID- 20962051 TI - Progestin signaling through mPRalpha in Atlantic croaker granulosa/theca cell cocultures and its involvement in progestin inhibition of apoptosis. AB - Although there is substantial evidence that membrane progestin receptors (mPRs) perform a critical physiological role in meiotic maturation of fish oocytes, it is unknown whether they are also intermediaries in progestin signaling in the surrounding follicular cells. Here, we show that mPRalpha protein is located on the plasma membranes of both granulosa and theca cells (G/T cells) isolated from Atlantic croaker ovaries and is associated with the presence of a single high affinity, limited capacity, pertussis toxin-sensitive, specific progestin [17,20beta,21-trihydroxy-4-pregnen-3-one (20beta-S)] membrane binding site with the characteristics of mPRalpha. Treatment of G/T cells with 20beta-S caused rapid G protein activation and a transient, pertussis toxin-sensitive, decrease in cAMP levels, whereas the selective nuclear progesterone receptor agonist, R5020, did not cause G protein activation, consistent with previous reports on mPRalpha signaling. 20beta-S treatment decreased serum starvation-induced cell death in both G/T cells and in seatrout mPRalpha-transfected MDA-MB-231 cells, whereas R5020 was ineffective. Moreover, a selective mPRalpha agonist, 10-ethenyl 19-norprogesterone, mimicked the protective action of 20beta-S against cell death, which was lost upon knockdown of mPRalpha protein but not after progesterone receptor knockdown, further demonstrating an involvement of mPRalpha. Signaling molecules involved in inhibition of apoptosis, Erk and serine threonine kinase, were activated in G/T cells by 20beta-S, which suggests a potential mechanism for mPRalpha inhibition of apoptosis. This is the first study to demonstrate endogenous mPR signaling in the ovarian follicle and to suggest a novel physiological role for mPRalpha in mediating the antiapoptotic actions of progestins in ovarian follicle cells. PMID- 20962052 TI - An elastic Van Gieson stain is unnecessary for the histological diagnosis of giant cell temporal arteritis. AB - BACKGROUND: Elastic Van Gieson (EVG) stain is used routinely to identify the internal elastic lamina in biopsy specimens from clinically suspected cases of giant cell arteritis (GCA). It is widely recognised, however, that disruption of the internal elastic lamina is not specific for GCA. Evidence suggests that routine use of special stains in temporal artery biopsies does not increase diagnostic sensitivity and current American College of Rheumatology guidelines do not include structural changes to the vessel wall in their recommended diagnostic criteria. Objective To assess whether use of EVG stain contributes to the diagnosis of GCA, compared with standard H&E stained sections alone. METHODS: A retrospective case series of 105 temporal artery biopsies positive for GCA between 1999 and 2009 were retrieved and reviewed histologically. Comparable diagnostic information was extracted from reports for 406 negative biopsies over the same period. RESULTS: Review of H&E stained sections showed diagnostic features of GCA in 97.2% (n=102) of positive cases. Disruption or reduplication of the internal elastic lamina was apparent in 96.1% (n=101) of EVG stained sections, but was also reported as present in nearly two-thirds of negative biopsies. CONCLUSIONS: An EVG stain does not contribute to recognition of diagnostic features in a majority of cases and should therefore be reserved for use as a supplementary investigation. Inclusion of pre-biopsy treatment on histology request forms would assist in the interpretation of equivocal biopsies. PMID- 20962053 TI - Array-based comparative genomic hybridisation analysis reveals recurrent chromosomal alterations in primary diffuse large B cell lymphoma of bone. AB - AIMS: Primary non-Hodgkin's lymphoma of bone (PLB) is a rare subtype of primary extranodal diffuse large B cell lymphoma. PLB has morphological homogeneity and a relatively favourable clinical behaviour. Recent studies report that array-based comparative genomic hybridisation (array-CGH) analysis can be used to classify lymphomas into clinically and biologically relevant phenotypes and possibly reveal differences in oncogenic mechanisms. Here the authors performed the first array-CGH study to detect illness related genomic alterations in nine, clinically well-staged primary lymphoma of bone cases. METHODS: Nine frozen samples from primary lymphoma of bone patients were immunophenotyped and subsequently investigated using a well-established array-CGH platform. The array-CGH results were confirmed by fluorescence in situ hybridisation. Clinical data and follow-up were obtained for all nine patients. RESULTS: Of the nine patients, eight reached complete remission, and one had progressive disease and died of primary lymphoma of bone. Frequent aberrations were: loss of 14q32 (n=7), trisomy 7 (n=6), gain of the long arm of chromosome 1 (n=5) and amplification of 2p16.1 (n=4). No statistically significant correlation between genetic abnormalities and clinical outcome was found. CONCLUSIONS: The authors found several recurrent genomic aberrations, including five cases with gain of 1q and four cases with 2p16.1 amplification. These findings are associated with a germinal centre-like phenotype and favourable treatment outcome, and differ from chromosomal aberrations found in other extranodal lymphomas. These findings further substantiate the notion that primary lymphoma of bone should be considered as a distinct entity not only on clinic-pathological grounds but also on the genomic level as well. PMID- 20962055 TI - Clinicopathological evaluation of 100 cases of mucinous carcinoma of breast with emphasis on axillary staging and special reference to a micropapillary pattern. AB - BACKGROUND: Pure mucinous breast carcinoma (PMBC) is uncommon and associated with better prognosis than mixed mucinous breast carcinoma (MMBC). A micropapillary pattern in PMBC has been identified although its prognostic significance is questionable. METHODS: A retrospective review of 100 cases of mucinous carcinoma diagnosed between 2000 and 2009 was conducted. Two broad categories were studied: PMBC (more than 90% mucinous component; n=45) and MMBC (less than 90% mucinous component; n=55). PMBC was further subclassified as hypocellular/type A (n=37) and cellular/type B (n=8). Receptor status, clinicomorphological and prognostic features were compared without patient follow-up. RESULTS: Mean age at diagnosis in PMBC and MMBC was 60 and 63 years, while mean tumour size was 1.65 and 2.5 cm, respectively. Mean age in type A and type B PMBC patients was 75 and 55 years, respectively. The majority of PMBCs were well differentiated, with two poorly differentiated cases as well. The majority of MMBCs were moderately differentiated. A micropapillary pattern was seen in 20% of PMBCs. Sentinel lymph nodes were positive in 18.5% of PMBCs and 16% of MMBCs. Non-sentinel lymph nodes were positive in 14% of PMBCs and 39% of MMBCs. A micropapillary pattern was seen in 60% of LN positive PMBCs and 14% of LN negative PMBCs. Furthermore, 95% of PMBCs were ER(+), 84% were PR(+) and 9% were Her-2(+); 91% of MMBCs were ER(+), 87% were PR(+) and 33% were Her-2(+). CONCLUSIONS: PMBCs with a micropapillary pattern were more frequently associated with nodal disease. PMBCs with axillary disease had one or more of the following: micropapillary pattern, high nuclear grade, Her-2 positivity, smaller tumour size or younger age. Hence, axillary staging by sentinel lymph node biopsy is recommended in PMBCs. PMID- 20962056 TI - New insights into thyroid hormone action in the developing brain: the importance of T3 degradation. PMID- 20962057 TI - Maintaining mesenchymal properties of ovarian surface epithelial cells: a potential early protective role for TGF-beta in ovarian carcinogenesis. PMID- 20962058 TI - CTRP-3: blocking a toll booth to obesity-related inflammation. PMID- 20962060 TI - Generation of human chiral metabolites of simvastatin and lovastatin by bacterial CYP102A1 mutants. AB - Recently, the wild-type and mutant forms of cytochrome P450 BM3 (CYP102A1) from Bacillus megaterium were found to oxidize various xenobiotic substrates, including pharmaceuticals, of human P450 enzymes. Simvastatin and lovastatin, which are used to treat hyperlipidemia and hypercholesterolemia, are oxidized by human CYP3A4/5 to produce several metabolites, including 6'beta-hydroxy (OH), 3" OH, and exomethylene products. In this report, we show that the oxidation of simvastatin and lovastatin was catalyzed by wild-type CYP102A1 and a set of its mutants, which were generated by site-directed and random mutagenesis. One major hydroxylated product (6'beta-OH) and one minor product (6'-exomethylene), but not other products, were produced by CYP102A1 mutants. Formation of the metabolites was confirmed by high-performance liquid chromatography, liquid chromatography mass spectroscopy, and NMR. Chemical methods to synthesize the metabolites of simvastatin and lovastatin have not been reported. These results demonstrate that CYP102A1 mutants can be used to produce human metabolites, especially chiral metabolites, of simvastatin and lovastatin. Our computational findings suggest that a conformational change in the cavity of the mutant active sites is related to the activity change. The modeling results also suggest that the activity change results from the movement of several specific residues in the active sites of the mutants. Furthermore, our computational findings suggest a correlation between the stabilization of the binding site and the catalytic efficiency of CYP102A1 mutants toward simvastatin and lovastatin. PMID- 20962061 TI - Organic cation transporter-mediated renal secretion of ipratropium and tiotropium in rats and humans. AB - Ipratropium bromide (ipratropium) and tiotropium bromide (tiotropium), anticholinergic agents with bronchodilating properties, are used to treat patients with chronic obstructive pulmonary disease. Because they are actively secreted into urine, the interaction of these agents with organic cation transporters (OCTs/Octs) was examined in rat kidney slices and in cultured cells expressing rat Oct (rOct) or human OCT (hOCT). Uptake of radiolabeled ipratropium in rat kidney slices was significantly inhibited by OCT/Oct substrates including cimetidine, imipramine, and quinidine, but not by organic anion transporter substrates (e.g., p-aminohippuric acid and estrone-3-sulfate). [(3)H]Tiotropium uptake showed similar characteristics. Reverse transcription-polymerase chain reaction showed that, in rat kidney, mRNA expression of rOct2 was the highest, followed by rOct1, but little rOct3 was detected. In vitro, rOct1 and rOct2 transported both anticholinergics, but rOct3 accepted only ipratropium. Ipratropium uptake by rat kidney slices consisted of two components with K(m) values of 0.114 +/- 0.06 and 24.5 +/- 2.21 MUM. The K(m) value of rOct2-mediated ipratropium uptake (0.143 +/- 0.03 MUM) was consistent with that of the high affinity component. The OCT/Oct inhibitor corticosterone, at a concentration of 1 MUM (IC(50), 1.11 +/- 0.20 MUM for rOct2-mediated ipratropium transport), inhibited ipratropium by 18.4%, suggesting that rOct2 is involved in renal secretion of ipratropium. In a similar manner, ipratropium and tiotropium were taken up by cultured cells expressing hOCT1 and hOCT2 but not hOCT3. We conclude that OCT2/Oct2 plays a role in renal secretion of both anticholinergics in these species. Coadministration of these anticholinergics with cationic drugs recognized by OCT2/Oct2 may decrease renal clearance, resulting in increased systemic exposure. PMID- 20962062 TI - Quantitative investigation of the impact of P-glycoprotein inhibition on drug transport across blood-brain barrier in rats. AB - The magnitude of P-glycoprotein [(P-gp)/multidrug resistance protein 1 (MDR1)] mediated drug-drug interaction (DDI) at the blood-brain barrier (BBB) in rats was estimated by in vitro-in vivo correlation (IVIVC). In in vitro studies, rat Mdr1a expressing LLC-PK1 cells were examined for the evaluation of P-gp inhibitory activity using digoxin as a P-gp probe substrate. The in vitro K(i) value was calculated using a modified corrected flux ratio that reflects the P-gp function. In in vivo studies, digoxin with or without P-gp inhibitors was administered to rats by constant intravenous infusion to evaluate the effect of P-gp inhibition on digoxin transport to the brain under steady-state conditions. In the presence of elacridar, the brain-to-plasma concentration ratio (K(p,brain)) of digoxin was approximately 14 times the control value. However, no significant change in the K(p,brain) was observed in the presence of clinically used P-gp inhibitors, with the exception of cyclosporine A. A positive correlation was found between the in vivo K(p,brain) of digoxin and [I(,unbound)/K(i)] (where I(,unbound) is the unbound plasma concentration of P-gp inhibitors). Compounds with [I(,unbound)/K(i)] values of >1 increased K(p,brain) of digoxin in rats. In summary, we used a quantitative approach to evaluate the impact of P-gp-mediated DDI at the rat BBB. We successfully established the IVIVC, which indicated the potential DDI in the presence of potent P-gp inhibitors. On the basis of the IVIVC in rats and K(i) values in human MDR1, we speculated that clinically used P gp inhibitors do not cause DDI at the human BBB, because none of the compounds studied showed [I(,unbound)/K(i)] values of >1 at therapeutic doses. PMID- 20962063 TI - When choosing the traits of children is hurtful to others. AB - Some commentators object to the use of embryonic and fetal diagnostic technologies by parents who wish to avoid disabilities in their children. In particular, they say this use is hurtful in the meaning it expresses, namely that the lives of people with disabilities are not valuable or are less valuable than the lives of others. Other commentators have tried to show that this meaning does not necessarily belong to parents' choices and is not therefore credible as a general moral objection. However, this analysis overlooks the way in which the use of these technologies can be legitimately interpreted as hurtful. Once we admit to these hurtful effects felt by people with disabilities and those who hold them dear, it becomes important to ask whether that hurt can justify limits on parents' choices. Because the use of these technologies does not hurt people with disabilities directly and because there is no requirement that people having children work to ensure the continued existence of people with disabilities, no justification for limiting parents' choices is to be found in the hurt some people experience in steps taken to avoid disabilities in children. PMID- 20962064 TI - Case-based seminars in medical ethics education: how medical students define and discuss moral problems. AB - Discussion of real cases encountered by medical students has been advocated as a component of medical ethics education. Suggested benefits include: a focus on the actual problems that medical students confront; active learner involvement; and facilitation of an exploration of the meaning of their own values in relation to professional behaviour. However, the approach may also carry risks: students may focus too narrowly on particular clinical topics or show a preference for discussing legal problems that may appear to have clearer solutions. Teaching may therefore omit areas generally considered to be important components of the curriculum. In this paper, the authors present an analysis of the moral problems raised by medical students in response to a request to describe ethically problematic cases they had encountered during two clinical attachments, for the purpose of educational discussion at case-based seminars. We discuss the problems raised and compare the content of the cases to the UK Consensus Statement on core content of learning. The authors also describe the approaches that the students used to undertake an initial analysis of the problems raised, and consider possible implications for the development of medical ethics education. PMID- 20962065 TI - If I were a rich man could I sell a pancreas? A study in the locus of oppression. AB - Dan Brock argues that since the unexploitable rich could sell their kidneys too, exploitation could not be an essential feature of organ vending. This paper takes his claim as the point of departure for a discussion on the locus of organ vending-associated oppression. While it accepts Brock's conclusion, it explores the possibility that such oppression is invariably found rather outside the sphere of exchange. It then analyses the implications of this possibility for the discourse surrounding the ethics of organ vending. PMID- 20962066 TI - Deception as treatment: the case of depression. AB - Is it ever right to prescribe placebos to patients in clinical practice? The General Medical Council is ambivalent about the issue; the American Medical Association asserts that placebos can be administered only if the patient is (somehow) 'informed'. The potential problem with placebos is that they may involve deception: indeed, if this is the case, an ethical tension arises over the patient's autonomy and the physician's requirement to be open and honest, and the notion that medical care should be the primary concern. This paper examines the case of depression as an entry point for understanding the complexities of the prescription of placebos. Recent important meta-analyses of antidepressants claim that they are not significantly more effective in a clinical setting than placebos. Given that antidepressants have numerous adverse side effects and are hugely expensive, this provocative research has serious potential ethical and practical implications for patients and medical providers. Should placebos be prescribed in place of antidepressants? The case of depression highlights another important issue which medical ethical codes have hitherto overlooked: well-being is not synonymous with being realistic about oneself, one's circumstances and the future. While severely depressed individuals are unduly pessimistic about themselves and the world around them, treatment of depressed individuals can be deemed successful when patients have successfully attained those positive illusions that are indicative of psychological health. This is exactly what successful psychological treatments of depression seem to achieve. It is therefore possible that there may be a limited unavoidable role for deception in medicine. PMID- 20962067 TI - Oscillatory entrainment of thalamic neurons by theta rhythm in freely moving rats. AB - The anterior thalamic nuclei are assumed to support episodic memory with anterior thalamic dysfunction a core feature of diencephalic amnesia. To date, the electrophysiological characterization of this region in behaving rodents has been restricted to the anterodorsal nucleus. Here we compared single-unit spikes with population activity in the anteroventral nucleus (AV) of freely moving rats during foraging and during naturally occurring sleep. We identified AV units that synchronize their bursting activity in the 6-11 Hz range. We show for the first time in freely moving rats that a subgroup of AV neurons is strongly entrained by theta oscillations. This feature together with their firing properties and spike shape suggests they be classified as "theta" units. To prove the selectivity of AV theta cells for theta rhythm, we compared the relation of spiking rhythmicity to local field potentials during theta and non-theta periods. The most distinguishable non-theta oscillations in rodent anterior thalamus are sleep spindles. We therefore compared the firing properties of AV units during theta and spindle periods. We found that theta and spindle oscillations differ in their spatial distribution within AV, suggesting separate cellular sources for these oscillations. While theta-bursting neurons were related to the distribution of local field theta power, spindle amplitude was independent of the theta units' position. Slow- and fast-spiking bursting units that are selectively entrained to theta rhythm comprise 23.7% of AV neurons. Our results provide a framework for electrophysiological classification of AV neurons as part of theta limbic circuitry. PMID- 20962068 TI - Conditional perception under stimulus ambiguity: polarization- and azimuth sensitive neurons in the locust brain are inhibited by low degrees of polarization. AB - Sensory perception often relies on the integration and matching of multisensory inputs. In the brain of desert locusts, identified neurons that signal the sun's direction relative to the animal's head integrate information about the polarization pattern of the sky with information on the color and intensity contrast of the sky. The cloudless blue sky exhibits a gradient from unpolarized sunlight to strongly polarized light at 90 degrees from the sun. Therefore the percentage of polarized light in the sky is highest at dusk and dawn and lowest when the sun is in the zenith. We investigated the effect of different degrees of polarization on neurons of the anterior optic tubercle of the desert locust through intracellular recordings. Whereas dorsal presentation of strongly polarized light largely excited the neurons, weakly polarized light, i.e., a blend of polarized light of many orientations, led to inhibition. The data suggest that the polarization input to these neurons is inhibited within a radius of 50 degrees around the sun, thereby avoiding conflicting input from the polarization and direct sunlight channels. These properties can be regarded as sensory filters to avoid ambiguous signaling during sky compass orientation. PMID- 20962069 TI - Behavior of the oculomotor vermis for five different types of saccade. AB - Single unit and lesion studies have implicated the oculomotor vermis of the cerebellum in the control of targeting saccades to jumping visual targets. However, saccades can be made in a variety of other target situations where they can occur with different reaction times (express or delayed saccades) in response to a remembered target location (memory-guided saccades) or between several targets that are always visible (scanning saccades). Here we ask whether the oculomotor vermis contributes to generating all these types of saccades by examining the simple spike discharge of its Purkinje cells. Twenty-six of 32 P cells (81%) exhibited qualitatively similar phasic firing patterns for targeting, express, scanning, delayed, and memory-guided saccades. The remaining six exhibited a different pattern for just scanning saccades. Although a sensitive test of discharge patterns revealed significant differences for some pairs of saccade types in ~29% of P-cells, there was no cell-to-cell consistency as to which pairs were associated with different patterns. Also, a less sensitive comparison identified substantially fewer cells (~15%) with different patterns. Thus the lack of any consistent difference in firing for different saccade types leads us to conclude that the oculomotor vermis is not likely to contribute differently to targeting, express, scanning, delayed, or memory-guided saccades. PMID- 20962070 TI - Identification and modulation of voltage-gated Ca2+ currents in zebrafish Rohon Beard neurons. AB - Electrically excitable cells have voltage-dependent ion channels on the plasma membrane that regulate membrane permeability to specific ions. Voltage-gated Ca(2+) channels (VGCCs) are especially important as Ca(2+) serves as both a charge carrier and second messenger. Zebrafish (Danio rerio) are an important model vertebrate for studies of neuronal excitability, circuits, and behavior. However, electrophysiological properties of zebrafish VGCCs remain largely unexplored because a suitable preparation for whole cell voltage-clamp studies is lacking. Rohon-Beard (R-B) sensory neurons represent an attractive candidate for this purpose because of their relatively large somata and functional homology to mammalian dorsal root ganglia (DRG) neurons. Transgenic zebrafish expressing green fluorescent protein in R-B neurons, (Isl2b:EGFP)(ZC7), were used to identify dissociated neurons suitable for whole cell patch-clamp experiments. Based on biophysical and pharmacological properties, zebrafish R-B neurons express both high- and low-voltage-gated Ca(2+) current (HVA- and LVA-I(Ca), respectively). Ni(+)-sensitive LVA-I(Ca) occur in the minority of R-B neurons (30%) and omega-conotoxin GVIA-sensitive Ca(V)2.2 (N-type) Ca(2+) channels underlie the vast majority (90%) of HVA-I(Ca). To identify G protein coupled receptors (GPCRs) that modulate HVA-I(Ca), a panel of neurotransmitters was screened. Application of GABA/baclofen or serotonin produced a voltage-dependent inhibition while application of the mu-opioid agonist DAMGO resulted in a voltage independent inhibition. Unlike in mammalian neurons, GPCR-mediated voltage dependent modulation of I(Ca) appears to be transduced primarily via a cholera toxin-sensitive Galpha subunit. These results provide the basis for using the zebrafish model system to understanding Ca(2+) channel function, and in turn, how Ca(2+) channels contribute to mechanosensory function. PMID- 20962071 TI - Neuromodulatory effect of GnRH on the synaptic transmission of the olfactory bulbar neural circuit in goldfish, Carassius auratus. AB - Gonadotropin-releasing hormone (GnRH) is well known as a hypophysiotropic hormone that is produced in the hypothalamus and facilitates the release of gonadotropins from the pituitary gonadotropes. On the other hand, the functions of extrahypothalamic GnRH systems still remain elusive. Here we examined whether the activity of the olfactory bulbar neural circuits is modulated by GnRH that originates mainly from the terminal nerve (TN) GnRH system in goldfish (Carassius auratus). As the morphological basis, we first observed that goldfish TNs mainly express salmon GnRH (sGnRH) mRNA and that sGnRH-immunoreactive fibers are distributed in both the mitral and the granule cell layers. We then examined by extracellular recordings the effect of GnRH on the electrically evoked in vitro field potentials that arise from synaptic activities from mitral to granule cells. We found that GnRH enhances the amplitude of the field potentials. Furthermore, these effects were observed in both cases when the field potentials were evoked by stimulating either the lateral or the medial olfactory tract, conveying functionally different sensory information, separately, and suggesting that GnRH may modulate the responsiveness to wide categories of odorants in the olfactory bulb. Because GnRH also changed the paired-pulse ratio, it is suggested that the increased amplitude of the field potential results from changes in the presynaptic glutamate release of mitral cells rather than the increase in the glutamate receptor sensitivity of granule cells. These results suggest that TN regulates the olfactory responsiveness of animals appropriately by releasing sGnRH peptides in the olfactory bulbar neural circuits. PMID- 20962072 TI - Contributions of altered stretch reflex coordination to arm impairments following stroke. AB - Patterns of stereotyped muscle coactivation, clinically referred to as synergies, emerge following stroke and impair arm function. Although researchers have focused on cortical contributions, there is growing evidence that altered stretch reflex pathways may also contribute to impairment. However, most previous reflex studies have focused on passive, single-joint movements without regard to their coordination during volitional actions. The purpose of this study was to examine the effects of stroke on coordinated activity of stretch reflexes elicited in multiple arm muscles following multijoint perturbations. We hypothesized that cortical injury results in increased stretch reflexes of muscles characteristic of the abnormal flexor synergy during active arm conditions. To test this hypothesis, we used a robot to apply position perturbations to impaired arms of 10 stroke survivors and dominant arms of 8 healthy age-matched controls. Corresponding reflexes were assessed during volitional contractions simulating different levels of gravitational support, as well as during voluntary flexion and extension of the elbow and shoulder. Reflexes were quantified by average rectified surface electromyogram, recorded from eight muscles spanning the elbow and shoulder. Reflex coordination was quantified using an independent components analysis. We found stretch reflexes elicited in the stroke group were significantly less sensitive to changes in background muscle activation compared with those in the control group (P < 0.05). We also observed significantly increased reflex coupling between elbow flexor and shoulder abductor-extensor muscles in stroke subjects relative to that in control subjects. This increased coupling was present only during volitional tasks that required elbow flexion (P < 0.001), shoulder extension (P < 0.01), and gravity opposition (P < 0.01), but not during the "no load" condition. During volitional contractions, reflex amplitudes scaled with the level of impairment, as assessed by Fugl-Meyer scores (r(2) = 0.63; P < 0.05). We conclude that altered reflex coordination is indicative of motor impairment level and may contribute to impaired arm function following stroke. PMID- 20962073 TI - A within-trial measure of the stop signal reaction time in a head-unrestrained oculomotor countermanding task. AB - The countermanding (or stop-signal) task, which requires the cancellation of an impending response on the infrequent presentation of a stop signal, enables study of the contextual control of movement generation and suppression. Here we present a novel and empirical measure of the time needed to cancel an impending gaze shift by recording neck muscle activity during a head-unrestrained oculomotor countermanding paradigm. On a subset of stop signal trials, subjects generated small head movements toward a target even though gaze remained stable due to a compensatory vestibular-ocular reflex. On such trials, we observed a burst of antagonist neck muscle activity during the small head-only error. Such antagonist neck muscle activity served as an active braking pulse as its magnitude scaled with the kinematics of the head-only error. This activity was selective for trials in which the head was arrested in mid-flight and did not appear on trials without a stop signal, on noncancelled stop signal trials when the gaze shift was completed, or on stop signal trials without head motion. Importantly, the timing of this antagonist activity related best to the onset of the stop signal (lagging it by ~180 ms), and strongly correlated with behavioral estimates of the time needed to cancel a movement (the stop signal reaction time). These results are consistent with the notion that such selective antagonist neck muscle activity arises as a peripheral expression of the oculomotor stop process that successfully cancelled the gaze shift. Studying movement cancellation within nested systems like the head-unrestrained gaze shifting system offers a unique opportunity for investigating underlying neural mechanisms as the overall goal (i.e., to cancel a gaze shift) can be achieved despite motion of other components; on such individual trials, the oculomotor stop process is expressed as an active braking pulse. PMID- 20962074 TI - Electrophysiological analysis of the inhibitory effects of FMRFamide-like peptides on the pacemaker activity of gonadotropin-releasing hormone neurons. AB - Gonadotropin-releasing hormone (GnRH) neurons in the terminal nerve (TN) show endogenous pacemaker activity, which is suggested to be dependent on the physiological conditions of the animal. The TN-GnRH neurons have been suggested to function as a neuromodulatory neuron that regulates long-lasting changes in the animal behavior. It has been reported that the TN-GnRH neurons are immunoreactive to FMRFamide. Here, we find that the pacemaker activity of TN-GnRH neuron is inhibited by FMRFamide: bath application of FMRFamide decreased the frequency of pacemaker activity of TN-GnRH neurons in a dose-dependent manner. This decrease was suppressed by a blockage of G protein-coupled receptor pathway by GDP-beta-S. In addition, FMRFamide induced an increase in the membrane conductance, and the reversal potential for the FMRFamide-induced current changed according to the changes in [K(+)](out) as predicted from the Nernst equation for K(+). We performed cloning and sequence analysis of the PQRFamide (NPFF/NPAF) gene in the dwarf gourami and found evidence to suggest that FMRFamide-like peptide in TN-GnRH neurons of the dwarf gourami is NPFF. NPFF actually inhibited the pacemaker activity of TN-GnRH neurons, and this inhibition was blocked by RF9, a potent and selective antagonist for mammalian NPFF receptors. These results suggest that the activation of K(+) conductance by FMRFamide-like peptide (~NPFF) released from TN-GnRH neurons themselves causes the hyperpolarization and then inhibition of pacemaker activity in TN-GnRH neurons. Because TN-GnRH neurons make tight cell clusters in the brain, it is possible that FMRFamide-like peptides released from TN-GnRH neurons negatively regulates the activities of their own (autocrine) and/or neighboring neurons (paracrine). PMID- 20962075 TI - Inhibition dominates the early phase of up-states in the basolateral amygdala. AB - Slow oscillations (<1 Hz) in neural activity occur during sleep and quiet wakefulness in both animals and humans. Single-cell recordings in cortical neurons have shown that these oscillations are driven by a combination of excitatory and inhibitory synaptic inputs. During up-states, although the ratio between them varies between cells, excitation and inhibition follow similar time courses. Neurons in the basolateral amygdala (BLA) also show slow oscillations between the resting membrane potential (down-state) and depolarized potentials (up-states). Delivery of footshock during the down-state fully reproduces up states in these cells. Here we report that up-states in BLA principal neurons up states begin with an excitatory drive that is rapidly (within ~50 ms) overwhelmed by inhibitory input. This excess of inhibitory drive is short lasting (300-400 ms), after which up-states are maintained by a tight balance between excitation and inhibition. This initial large inhibitory input restricts action potential generation and reduces the firing frequency of these cells. These results indicate that, in contrast to cortical neurons, up-states in BLA neurons show an initial period of strong cortically driven feed-forward inhibition. For the remainder of the up-state, feedback inhibition then acts to balance excitatory input. PMID- 20962076 TI - Neutralizing antibody-resistant hepatitis C virus cell-to-cell transmission. AB - Hepatitis C virus (HCV) can initiate infection by cell-free particle and cell cell contact-dependent transmission. In this study we use a novel infectious coculture system to examine these alternative modes of infection. Cell-to-cell transmission is relatively resistant to anti-HCV glycoprotein monoclonal antibodies and polyclonal immunoglobulin isolated from infected individuals, providing an effective strategy for escaping host humoral immune responses. Chimeric viruses expressing the structural proteins representing the seven major HCV genotypes demonstrate neutralizing antibody-resistant cell-to-cell transmission. HCV entry is a multistep process involving numerous receptors. In this study we demonstrate that, in contrast to earlier reports, CD81 and the tight-junction components claudin-1 and occludin are all essential for both cell free and cell-to-cell viral transmission. However, scavenger receptor BI (SR-BI) has a more prominent role in cell-to-cell transmission of the virus, with SR-BI specific antibodies and small-molecule inhibitors showing preferential inhibition of this infection route. These observations highlight the importance of targeting host cell receptors, in particular SR-BI, to control viral infection and spread in the liver. PMID- 20962077 TI - Simian immunodeficiency virus from the sooty mangabey and rhesus macaque is modified with O-linked carbohydrate. AB - Although stretches of serine and threonine are sometimes sites for O-linked carbohydrate attachment, specific sequence and structural determinants for O linked attachment remain ill defined. The gp120 envelope protein of SIVmac239 contains a serine-threonine-rich stretch of amino acids at positions 128 to 139. Here we show that lectin protein from jackfruit seed (jacalin), which binds to non- and monosialylated core 1 O-linked carbohydrate, potently inhibited the replication of SIVmac239. Selection of a jacalin-resistant SIVmac239 variant population resulted in virus with specific substitutions within amino acids 128 to 139. Cloned simian immunodeficiency virus (SIV) variants with substitutions in the 128-to-139 region had infectivities equivalent to, or within 1 log unit of, that of SIVmac239 and were resistant to the inhibitory effects of jacalin. Characterization of the SIVmac239 gp120 O-linked glycome showed the presence of core 1 and core 2 O-linked carbohydrate; a 128-to-139-substituted variant gp120 from jacalin-resistant SIV lacked O-linked carbohydrate. Unlike that of SIVmac239, the replication of HIV-1 strain NL4-3 was resistant to inhibition by jacalin. Purified gp120s from four SIVmac and SIVsm strains bound jacalin strongly in an enzyme-linked immunosorbent assay, while nine different HIV-1 gp120s, two SIVcpz gp120s, and 128-to-139-substituted SIVmac239 gp120 did not bind jacalin. The ability or inability to bind jacalin thus correlated with the presence of the serine-threonine-rich stretch in the SIVmac and SIVsm gp120s and the absence of such stretches in the SIVcpz and HIV-1 gp120s. Consistent with sequence predictions, two HIV-2 gp120s bound jacalin, while one did not. These data demonstrate the presence of non- and monosialylated core 1 O-linked carbohydrate on the gp120s of SIVmac and SIVsm and the lack of these modifications on HIV-1 and SIVcpz gp120s. PMID- 20962078 TI - Chikungunya virus induces IPS-1-dependent innate immune activation and protein kinase R-independent translational shutoff. AB - Chikungunya virus (CHIKV) is an arthritogenic mosquito-transmitted alphavirus that is undergoing reemergence in areas around the Indian Ocean. Despite the current and potential danger posed by this virus, we know surprisingly little about the induction and evasion of CHIKV-associated antiviral immune responses. With this in mind we investigated innate immune reactions to CHIKV in human fibroblasts, a demonstrable in vivo target of virus replication and spread. We show that CHIKV infection leads to activation of the transcription factor interferon regulatory factor 3 (IRF3) and subsequent transcription of IRF3 dependent antiviral genes, including beta interferon (IFN-beta). IRF3 activation occurs by way of a virus-induced innate immune signaling pathway that includes the adaptor molecule interferon promoter stimulator 1 (IPS-1). Despite strong transcriptional upregulation of these genes, however, translation of the corresponding proteins is not observed. We further demonstrate that translation of cellular (but not viral) genes is blocked during infection and that although CHIKV is found to trigger inactivation of the translational molecule eukaryotic initiation factor subunit 2alpha by way of the double-stranded RNA sensor protein kinase R, this response is not required for the block to protein synthesis. Furthermore, overall diminution of cellular RNA synthesis is also observed in the presence of CHIKV and transcription of IRF3-dependent antiviral genes appears specifically blocked late in infection. We hypothesize that the observed absence of IFN-beta and antiviral proteins during infection results from an evasion mechanism exhibited by CHIKV that is dependent on widespread shutoff of cellular protein synthesis and a targeted block to late synthesis of antiviral mRNA transcripts. PMID- 20962079 TI - Blood myeloid dendritic cells from HIV-1-infected individuals display a proapoptotic profile characterized by decreased Bcl-2 levels and by caspase-3+ frequencies that are associated with levels of plasma viremia and T cell activation in an exploratory study. AB - Reduced frequencies of myeloid and plasmacytoid dendritic cell (DC) subsets (mDCs and pDCs, respectively) have been observed in the peripheral blood of HIV-1 infected individuals throughout the course of disease. Accumulation of DCs in lymph nodes (LNs) may partly account for the decreased numbers observed in blood, but increased DC death may also be a contributing factor. We used multiparameter flow cytometry to evaluate pro- and antiapoptotic markers in blood mDCs and pDCs from untreated HIV-1-infected donors, from a subset of infected donors before and after receiving antiretroviral therapy (ART), and from uninfected control donors. Blood mDCs, but not pDCs, from untreated HIV-1-infected donors expressed lower levels of antiapoptotic Bcl-2 than DCs from uninfected donors. A subset of HIV-1 infected donors had elevated frequencies of proapoptotic caspase-3(+) blood mDCs, and positive correlations were observed between caspase-3(+) mDC frequencies and plasma viral load and CD8(+) T-cell activation levels. Caspase-3(+) mDC frequencies, but not mDC Bcl-2 expression, were reduced with viral suppression on ART. Apoptosis markers on DCs in blood and LN samples from a cohort of untreated, HIV-1-infected donors with chronic disease were also evaluated. LN mDCs displayed higher levels of Bcl-2 and lower caspase-3(+) frequencies than did matched blood mDCs. Conversely, LN pDCs expressed lower Bcl-2 levels than their blood counterparts. In summary, blood mDCs from untreated HIV-1-infected subjects displayed a proapoptotic profile that was partially reversed with viral suppression, suggesting that DC death may be a factor contributing to blood DC depletion in the setting of chronic, untreated HIV disease. PMID- 20962080 TI - Identification of binary interactions between human cytomegalovirus virion proteins. AB - Human cytomegalovirus (HCMV) virions are composed of a DNA-containing nucleocapsid surrounded by a tegument layer and host-derived lipid envelope studded with virally encoded glycoproteins. These complex virions are estimated to be composed of more than 50 viral proteins. Assembly of HCMV virions is poorly understood, especially with respect to acquisition of the tegument; however, it is thought to involve the stepwise addition of virion components through protein protein interactions. We sought to identify interactions among HCMV virion proteins using yeast two-hybrid analysis. Using 33 known capsid and tegument proteins, we tested 1,089 pairwise combinations for binary interaction in the two hybrid assay. We identified 24 interactions among HCMV virion proteins, including 13 novel interactions among tegument proteins and one novel interaction between capsid proteins. Several of these novel interactions were confirmed by coimmunoprecipitation of protein complexes from transfected cells. In addition, we demonstrate three of these interactions in the context of HCMV infection. This study reveals several new protein-protein interactions among HCMV tegument proteins, some of which are likely important for HCMV replication and pathogenesis. PMID- 20962081 TI - Varicella-zoster virus glycoprotein E is a critical determinant of virulence in the SCID mouse-human model of neuropathogenesis. AB - Varicella-zoster virus (VZV) is a neurotropic alphaherpesvirus. VZV infection of human dorsal root ganglion (DRG) xenografts in immunodeficient mice models the infection of sensory ganglia. We examined DRG infection with recombinant VZV (recombinant Oka [rOka]) and the following gE mutants: gEDelta27-90, gEDeltaCys, gE-AYRV, and gE-SSTT. gEDelta27-90, which lacks the gE domain that interacts with a putative receptor insulin-degrading enzyme (IDE), replicated as extensively as rOka, producing infectious virions and significant cytopathic effects within 14 days of inoculation. Since neural cells express IDE, the gE/IDE interaction was dispensable for VZV neurotropism. In contrast, gEDeltaCys, which lacks gE/gI heterodimer formation, was significantly impaired at early times postinfection; viral genome copy numbers increased slowly, and infectious virus production was not detected until day 28. Delayed replication was associated with impaired cell cell spread in ganglia, similar to the phenotype of a gI deletion mutant (rOkaDeltagI). However, at later time points, infection of satellite cells and other supportive nonneuronal cells resulted in extensive DRG tissue damage and cell loss such that cytopathic changes observed at day 70 were more severe than those for rOka-infected DRG. The replication of gE-AYRV, which is impaired for trans-Golgi network (TGN) localization, and the replication of gE-SSTT, which contains mutations in an acidic cluster, were equivalent to that of rOka, causing significant cytopathic effects and infectious virus production by day 14; genome copy numbers were equivalent to those of rOka. These experiments suggest that the gE interaction with cellular IDE, gE targeting to TGN sites of virion envelopment, and phosphorylation at SSTT are dispensable for VZV DRG infection, whereas the gE/gI interaction is critical for VZV neurovirulence. PMID- 20962082 TI - The alphaherpesvirus US3/ORF66 protein kinases direct phosphorylation of the nuclear matrix protein matrin 3. AB - The protein kinase found in the short region of alphaherpesviruses, termed US3 in herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PRV) and ORF66 in varicella-zoster virus (VZV), affects several viral and host cell processes, and its specific targets remain an area of active investigation. Reports suggesting that HSV-1 US3 substrates overlap with those of cellular protein kinase A (PKA) prompted the use of an antibody specific for phosphorylated PKA substrates to identify US3/ORF66 targets. HSV-1, VZV, and PRV induced very different substrate profiles that were US3/ORF66 kinase dependent. The predominant VZV-phosphorylated 125-kDa species was identified as matrin 3, one of the major nuclear matrix proteins. Matrin 3 was also phosphorylated by HSV-1 and PRV in a US3 kinase dependent manner and by VZV ORF66 kinase at a novel residue (KRRRT150EE). Since VZV-directed T150 phosphorylation was not blocked by PKA inhibitors and was not induced by PKA activation, and since PKA predominantly targeted matrin 3 S188, it was concluded that phosphorylation by VZV was PKA independent. However, purified VZV ORF66 kinase did not phosphorylate matrin 3 in vitro, suggesting that additional cellular factors were required. In VZV-infected cells in the absence of the ORF66 kinase, matrin 3 displayed intranuclear changes, while matrin 3 showed a pronounced cytoplasmic distribution in late-stage cells infected with US3-negative HSV-1 or PRV. This work identifies phosphorylation of the nuclear matrix protein matrin 3 as a new conserved target of this kinase group. PMID- 20962083 TI - Small-molecule inhibition of human immunodeficiency virus type 1 infection by virus capsid destabilization. AB - Human immunodeficiency virus type 1 (HIV-1) infection is dependent on the proper disassembly of the viral capsid, or "uncoating," in target cells. The HIV-1 capsid consists of a conical multimeric complex of the viral capsid protein (CA) arranged in a hexagonal lattice. Mutations in CA that destabilize the viral capsid result in impaired infection owing to defects in reverse transcription in target cells. We describe here the mechanism of action of a small molecule HIV-1 inhibitor, PF-3450074 (PF74), which targets CA. PF74 acts at an early stage of HIV-1 infection and inhibits reverse transcription in target cells. We show that PF74 binds specifically to HIV-1 particles, and substitutions in CA that confer resistance to the compound prevent binding. A single point mutation in CA that stabilizes the HIV-1 core also conferred strong resistance to the virus without inhibiting compound binding. Treatment of HIV-1 particles or purified cores with PF74 destabilized the viral capsid in vitro. Furthermore, the compound induced the rapid dissolution of the HIV-1 capsid in target cells. PF74 antiviral activity was promoted by binding of the host protein cyclophilin A to the HIV-1 capsid, and PF74 and cyclosporine exhibited mutual antagonism. Our data suggest that PF74 triggers premature HIV-1 uncoating in target cells, thereby mimicking the activity of the retrovirus restriction factor TRIM5alpha. This study highlights uncoating as a step in the HIV-1 life cycle that is susceptible to small molecule intervention. PMID- 20962084 TI - Modifications in the polymerase genes of a swine-like triple-reassortant influenza virus to generate live attenuated vaccines against 2009 pandemic H1N1 viruses. AB - On 11 June 2009, the World Health Organization (WHO) declared that the outbreaks caused by novel swine-origin influenza A (H1N1) virus had reached pandemic proportions. The pandemic H1N1 (H1N1pdm) virus is the predominant influenza virus strain in the human population. It has also crossed the species barriers and infected turkeys and swine in several countries. Thus, the development of a vaccine that is effective in multiple animal species is urgently needed. We have previously demonstrated that the introduction of temperature-sensitive mutations into the PB2 and PB1 genes of an avian H9N2 virus, combined with the insertion of a hemagglutinin (HA) tag in PB1, resulted in an attenuated (att) vaccine backbone for both chickens and mice. Because the new pandemic strain is a triple reassortant (TR) virus, we chose to introduce the double attenuating modifications into a swine-like TR virus isolate, A/turkey/OH/313053/04 (H3N2) (ty/04), with the goal of producing live attenuated influenza vaccines (LAIV). This genetically modified backbone had impaired polymerase activity and restricted virus growth at elevated temperatures. In vivo characterization of two H1N1 vaccine candidates generated using the ty/04 att backbone demonstrated that this vaccine is highly attenuated in mice, as indicated by the absence of signs of disease, limited replication, and minimum histopathological alterations in the respiratory tract. A single immunization with the ty/04 att-based vaccines conferred complete protection against a lethal H1N1pdm virus infection in mice. More importantly, vaccination of pigs with a ty/04 att-H1N1 vaccine candidate resulted in sterilizing immunity upon an aggressive intratracheal challenge with the 2009 H1N1 pandemic virus. Our studies highlight the safety of the ty/04 att vaccine platform and its potential as a master donor strain for the generation of live attenuated vaccines for humans and livestock. PMID- 20962085 TI - Novel F141L pre-S2 mutation in hepatitis B virus increases the risk of hepatocellular carcinoma in patients with chronic genotype C infections. AB - Several lines of evidence have suggested that some naturally occurring mutations of hepatitis B virus (HBV) play a critical role in hepatocellular carcinoma (HCC). Here, we describe a novel HCC-related pre-S2 mutation, F141L. To prove the relationship between the F141L mutation and HCC, molecular epidemiology studies using MboII PCR restriction analysis (PRA) were performed, and the molecular mechanism was investigated through construction of a stable hepatocyte cell line expressing the large surface HB protein (LHB) with the F141L mutation (F141L LHB). Application of MboII PRA to samples from 241 Korean patients with chronic liver diseases of different clinical stages confirmed that F141L mutants were significantly related to HCC, even in comparison to liver cirrhosis (HCC, 26.3% of patients, or 26/99; liver cirrhosis, 3.8% of patients, or 2/52; P = 0.001). By studying stable cell lines, we found that F141L-LHBs could induce cell cycle progression by downregulating the p53 and p21 pathways and upregulating CDK4 and cyclin A. Furthermore, we found that in a colony-forming assay, the colony forming rates in cell lines expressing F141L-LHBs were about twice as high as those of the wild type. In conclusion, our results suggest that F141L-LHBs may contribute importantly to the pathogenesis of HCC by inducing cell proliferation and transformation. So, the F141L mutation examined in this study could serve as a diagnostic marker for the prognosis of HCC. PMID- 20962086 TI - Poliovirus-mediated disruption of cytoplasmic processing bodies. AB - Metazoan cells form cytoplasmic mRNA granules such as stress granules (SG) and processing bodies (P bodies) that are proposed to be sites of aggregated, translationally silenced mRNAs and mRNA degradation. Poliovirus (PV) is a plus strand RNA virus containing a genome that is a functional mRNA; thus, we investigated if PV antagonizes the processes that lead to formation of these structures. We have previously shown that PV infection inhibits the ability of cells to form stress granules by cleaving RasGAP-SH3-binding protein (G3BP). Here, we show that P bodies are also disrupted during PV infection in cells by 4 h postinfection. The disruption of P bodies is more rapid and more complete than disruption of stress granules. The kinetics of P body disruption correlated with production of viral proteinases and required substantial viral gene product expression. The organizing mechanism that forms P body foci in cells is unknown; however, potential scaffolding, aggregating, or other regulatory proteins found in P bodies were investigated for degradation. Two factors involved in 5'-end mRNA decapping and degradation, Xrn1 and Dcp1a, and the 3' deadenylase complex component Pan3 underwent accelerated degradation during infection, and Dcp1a may be a direct substrate of PV 3C proteinase. Several other key factors proposed to be essential for P body formation, GW182, Edc3, and Edc4, were unaffected by poliovirus infection. Since deadenylation has been reported to be required for P body formation, viral inhibition of deadenylation, through Pan3 degradation, is a potential mechanism of P body disruption. PMID- 20962087 TI - The magnitude of local immunity in the lungs of mice induced by live attenuated influenza vaccines is determined by local viral replication and induction of cytokines. AB - While live attenuated influenza vaccines (LAIVs) have been shown to be efficacious and have been licensed for human use, the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) have to be updated for optimal protective efficacy. Little is known about the effect of different HA and NA proteins on the immunogenicity of LAIVs developed using the same backbone. A panel of LAIVs that share the internal protein genes, with unique HA and NA gene segments from different influenza subtypes, was rescued by reverse genetics, and a comparative study of immune responses induced by these vaccines was conducted in mice. The results suggest that the magnitude of lung immunity, including pulmonary IgA antibody and memory CD8(+) T lymphocytes, induced by the vaccines depends on the replication efficiency of the LAIVs, as well as the induction of cytokines/chemokines in the lungs. However, these factors are not important in determining systemic immunity such as serum antibody titers and memory CD8(+) T cells in the spleen. A qualitative analysis of immune responses induced by a single dose of an H5N1 LAIV revealed that the vaccine induced robust systemic and mucosal immunity in mice. In addition, antibodies and memory lymphocytes established in the lungs following vaccination were required for protection against lethal challenge with homologous and heterologous H5N1 viruses. Our results highlight the different requirements for inducing systemic and lung immunity that can be explored for the development of pulmonary immunity for protection against respiratory pathogens. PMID- 20962088 TI - Multiple innate immune pathways contribute to the immunogenicity of recombinant adenovirus vaccine vectors. AB - The innate immune pathways that contribute to the potent immunogenicity of recombinant adenovirus (rAd) vaccine vectors remain largely undefined. Previous studies assessing innate immunity triggered by vaccine vectors have largely focused on in vitro studies involving antigen-presenting cells and on early in vivo inflammatory responses. Here, we systematically explore the Toll-like receptor (TLR) signaling requirements for the generation of cellular immune responses by intramuscular immunization with common and alternative serotype rAd vectors in mice. Antigen-specific CD8(+) T-lymphocyte responses elicited by these rAd vectors were significantly diminished in MyD88(-/-) mice but not in TRIF(-/-) or TLR3(-/-) mice, suggesting the importance of MyD88-dependent TLR signaling. However, the absence of each individual TLR resulted in minimal to no effect on vaccine-elicited cellular immune responses. Moreover, responses were not diminished in IL-1R(-/-) or IL-18R(-/-) mice. These data suggest that rAd vectors engage multiple MyD88-dependent signaling pathways, none of which are individually critical; rather, they are integrated to contribute to the potent immunogenicity of rAd vectors. Stimulation of multiple innate immune mechanisms may prove a generalizable property of potent vaccines, and this strategy could be harnessed in the development of next-generation vaccine vectors and adjuvants. PMID- 20962089 TI - Antiviral effects of a transgenic RNA-dependent RNA polymerase. AB - Transgenic expression of the RNA-dependent RNA polymerase 3D(pol) inhibited infection of Theiler's murine encephalitis virus (TMEV), a picornavirus from which it was derived. Here, we infected 3D(pol) transgenic mice with another picornavirus, as well as an alphaherpesvirus and a rhabdovirus. 3D(pol) transgenic FVB mice had significantly lower viral loads and survived longer after infection with all three types of viruses than nontransgenic FVB mice. Viral inhibition among three different types of virus by transgenic 3D(pol) suggests that the mechanism of action is not the direct interference with picornaviral 3D(pol) but instead may be the changing of host cells to an antiviral state before or after viral infection occurs, as basal interferon levels were higher in 3D(pol) transgenic mice before infection. Further study of this mechanism may open new possibilities for future antiviral therapy. PMID- 20962090 TI - Marek's disease virus type 1 microRNA miR-M3 suppresses cisplatin-induced apoptosis by targeting Smad2 of the transforming growth factor beta signal pathway. AB - Viruses cause about 15% of the cancers that are still the leading causes of human mortality. The discovery of viral oncogenes has enhanced our understanding of viral oncogenesis. However, the underlying molecular mechanisms of virus-induced cancers are complex and require further investigation. The present study has attempted to investigate the effects of the microRNAs (miRNAs) encoded by Marek's disease virus 1 (MDV1), a chicken herpesvirus causing acute T-cell lymphomas and solid visceral tumors in chickens, on anti-cancer drug-induced apoptosis and identify the targets of the miRNAs. The results showed that of the total 14 miRNAs encoded by MDV1, MDV1-miR-M3 significantly promoted cell survival under treatment with cisplatin, a widely used chemotherapy drug. MDV1-miR-M3 suppressed cisplatin-induced apoptosis by directly downregulating expression at the protein but not the mRNA level of Smad2, a critical component in the transforming growth factor beta signal pathway. Our data suggest that latent/oncogenic viruses may encode miRNAs to directly target cellular factors involved in antiviral processes including apoptosis, thus proactively creating a cellular environment beneficial to viral latency and oncogenesis. Furthermore, the knowledge of the apoptosis resistance conferred by viral miRNAs has great practical implications for improving the efficacy of chemotherapies for treating cancers, especially those induced by oncogenic viruses. PMID- 20962091 TI - Macaque long-term nonprogressors resist superinfection with multiple CD8+ T cell escape variants of simian immunodeficiency virus. AB - Human immunodeficiency virus (HIV)-positive individuals can be superinfected with different virus strains. Individuals who control an initial HIV infection are therefore still at risk for subsequent infection with divergent viruses, but the barriers to such superinfection remain unclear. Here we tested long-term nonprogressors' (LTNPs') susceptibility to superinfection using Indian rhesus macaques that express the major histocompatibility complex class I (MHC-I) allele Mamu-B 17, which is associated with control of the pathogenic AIDS virus SIVmac239. The Mamu-B 17-restricted CD8(+) T cell repertoire is focused almost entirely on 5 epitopes. We engineered a series of SIVmac239 variants bearing mutations in 3, 4, or all 5 of these epitopes and used them to serially challenge 2 Mamu-B 17-positive LTNPs. None of the escape variants caused breakthrough replication in LTNPs, although they readily infected Mamu-B 17-negative naive macaques. In vitro competing coculture assays and examination of viral evolution in hosts lacking Mamu-B 17 suggested that the mutant viruses had negligible defects in replicative fitness. Both LTNPs maintained robust immune responses, including simian immunodeficiency virus (SIV)-specific CD8(+) and CD4(+) T cells and neutralizing antibodies. Our results suggest that escape mutations in epitopes bound by "protective" MHC-I molecules may not be sufficient to establish superinfection in LTNPs. PMID- 20962092 TI - Induction of type I interferon secretion through recombinant Newcastle disease virus expressing measles virus hemagglutinin stimulates antibody secretion in the presence of maternal antibodies. AB - Measles virus (MV) vaccine effectively protects seronegative individuals against infection. However, inhibition of vaccine-induced seroconversion by maternal antibodies after vaccination remains a problem, as it leaves infants susceptible to MV infection. In cotton rats, passive transfer of MV-specific IgG mimics maternal antibodies and inhibits vaccine-induced seroconversion. Here, we report that immunization in the presence of passively transferred IgG inhibits the secretion of neutralizing antibodies but not the generation of MV-specific B cells. This finding suggested that MV-specific B cells require an additional stimulus to mature into antibody-secreting plasma cells. In order to provide such a stimulus, we generated a recombinant Newcastle disease virus (NDV) expressing the MV hemagglutinin (NDV-H). In contrast to MV, NDV-H induced high levels of type I interferon in plasmacytoid dendritic cells and in lung tissue. In cotton rats immunized with NDV-H, neutralizing antibodies were also generated in the presence of passively transferred antibodies. In the latter case, however, the level and kinetics of antibody generation were reduced. In vitro, alpha interferon stimulated the activation of MV-specific B cells from MV-immune spleen cells. NDV infection (which induces alpha interferon) had the same effect, and stimulation could be abrogated by antibodies neutralizing alpha interferon, but not interleukin 6 (IL-6). In vivo, coapplication of UV-inactivated MV with NDV led to increased MV-specific antibody production in the presence and absence of passively transferred antibodies. These data indicate that MV-specific B cells are being generated after immunization in the presence of maternal antibodies and that the provision of alpha interferon as an additional signal leads to antibody secretion. PMID- 20962093 TI - Human pluripotent stem cells produce natural killer cells that mediate anti-HIV-1 activity by utilizing diverse cellular mechanisms. AB - Cell-based therapies against HIV/AIDS have been gaining increased interest. Natural killer (NK) cells are a key component of the innate immune system with the ability to kill diverse tumor cells and virus-infected cells. While NK cells have been shown to play an important role in the control of HIV-1 replication, their functional activities are often compromised in HIV-1-infected individuals. We have previously demonstrated the derivation of NK cells from human embryonic stem cells (hESCs) with the ability to potently kill multiple types of tumor cells both in vitro and in vivo. We now demonstrate the derivation of functional NK cells from human induced pluripotent stem cells (iPSCs). More importantly, both hESC- and iPSC-derived NK cells are able to inhibit HIV-1 NL4-3 infection of CEM-GFP cells. Additional studies using HIV-1-infected human primary CD4(+) T cells illustrated that hESC- and iPSC-derived NK cells suppress HIV-1 infection by at least three distinct cellular mechanisms: killing of infected targets through direct lysis, antibody-dependent cellular cytotoxicity, and production of chemokines and cytokines. Our results establish the potential to utilize hESC- and iPSC-derived NK cells to better understand anti-HIV-1 immunity and provide a novel cellular immunotherapeutic approach to treat HIV/AIDS. PMID- 20962094 TI - Yeast-elicited cross-reactive antibodies to HIV Env glycans efficiently neutralize virions expressing exclusively high-mannose N-linked glycans. AB - The HIV envelope (Env) protein uses a dense coat of glycans to mask conserved domains and evade host humoral immune responses. The broadly neutralizing antibody 2G12, which binds a specific cluster of high-mannose glycans on HIV Env, shows that the glycan shield can also serve as a target for neutralizing antibodies. We have described a triple mutant Saccharomyces cerevisiae strain that expresses high-mannose glycoproteins that bind to 2G12. When used to immunize rabbits, this yeast elicits antibodies that bind to gp120-associated glycans but fail to neutralize virus. Here we sought to determine the reason for these discordant results. Affinity purification of sera over columns conjugated with three 2G12-reactive yeast glycoproteins showed that these proteins could adsorb 80% of the antibodies that bind to gp120 glycans. Despite binding to monomeric gp120, these mannose-specific antibodies failed to bind cell surface expressed trimeric Env. However, when Env was expressed in the presence of the mannosidase inhibitor kifunensine to force retention of high-mannose glycans at all sites, the purified antibodies gained the abilities to bind trimeric Env and to strongly and broadly neutralize viruses produced under these conditions. Combined, these data show that the triple mutant yeast strain elicits antibodies that bind to high-mannose glycans presented on the HIV envelope, but only when they are displayed in a manner not found on native Env trimers. This implies that the underlying structure of the protein scaffold used to present the high-mannose glycans may be critical to allow elicitation of antibodies that recognize trimeric Env and neutralize virus. PMID- 20962095 TI - Role of RNase MRP in viral RNA degradation and RNA recombination. AB - RNA degradation, together with RNA synthesis, controls the steady-state level of viral RNAs in infected cells. The endoribonucleolytic cleavage of viral RNA is important not only for viral RNA degradation but for RNA recombination as well, due to the participation of some RNA degradation products in the RNA recombination process. To identify host endoribonucleases involved in degradation of Tomato bushy stunt virus (TBSV) in a Saccharomyces cerevisiae model host, we tested eight known endoribonucleases. Here we report that downregulation of SNM1, encoding a component of the RNase MRP, and a temperature-sensitive mutation in the NME1 gene, coding for the RNA component of RNase MRP, lead to reduced production of the endoribonucleolytically cleaved TBSV RNA in yeast. We also show that the highly purified yeast RNase MRP cleaves the TBSV RNA in vitro, resulting in TBSV RNA degradation products similar in size to those observed in yeast cells. Knocking down the NME1 homolog in Nicotiana benthamiana also led to decreased production of the cleaved TBSV RNA, suggesting that in plants, RNase MRP is involved in TBSV RNA degradation. Altogether, this work suggests a role for the host endoribonuclease RNase MRP in viral RNA degradation and recombination. PMID- 20962096 TI - Identification and structural characterization of the ALIX-binding late domains of simian immunodeficiency virus SIVmac239 and SIVagmTan-1. AB - Retroviral Gag proteins contain short late-domain motifs that recruit cellular ESCRT pathway proteins to facilitate virus budding. ALIX-binding late domains often contain the core consensus sequence YPX(n)L (where X(n) can vary in sequence and length). However, some simian immunodeficiency virus (SIV) Gag proteins lack this consensus sequence, yet still bind ALIX. We mapped divergent, ALIX-binding late domains within the p6(Gag) proteins of SIV(mac239) ((40)SREKPYKEVTEDLLHLNSLF(59)) and SIV(agmTan-1) ((24)AAGAYDPARKLLEQYAKK(41)). Crystal structures revealed that anchoring tyrosines (in lightface) and nearby hydrophobic residues (underlined) contact the ALIX V domain, revealing how lentiviruses employ a diverse family of late-domain sequences to bind ALIX and promote virus budding. PMID- 20962097 TI - Variola and monkeypox viruses utilize conserved mechanisms of virion motility and release that depend on abl and SRC family tyrosine kinases. AB - Vaccinia virus (VacV) enters mammalian cells, replicates extranuclearly, and produces virions that move to the cell surface along microtubules, fuse with the plasma membrane, and move from infected cells toward apposing cells on actin filled membranous protrusions or actin tails. To form actin tails, cell associated enveloped virions (CEV) require Abl and Src family tyrosine kinases. Furthermore, release of CEV from the cell requires Abl but not Src family tyrosine kinases and is blocked by imatinib mesylate (STI-571; Gleevec), an Abl family kinase inhibitor used to treat chronic myelogenous leukemia in humans. Here we demonstrate that the Poxviridae family members monkeypox virus (MPX) and variola virus (VarV) use conserved mechanisms for actin motility and extracellular enveloped virion (EEV) release. Furthermore, we show that imatinib mesylate is effective in a mouse model of infection with VacV, whether delivered prophylactically or postinfection, and restricts spread of virions from the site of inoculation. While inhibitors of both Src and Abl family kinases, such as dasatinib (BMS-354825; Sprycel), are effective in limiting dissemination of VacV, VarV, and MPX in vitro, members of this class of drugs appear to have immunosuppressive effects in vivo that preclude their use as anti-infectives. Together, these data suggest a possible utility for imatinib mesylate in treating smallpox or MPX infections or complications associated with vaccination. PMID- 20962098 TI - PB2 residue 158 is a pathogenic determinant of pandemic H1N1 and H5 influenza a viruses in mice. AB - Influenza A viruses are human and animal pathogens that cause morbidity and mortality, which range from mild to severe. The 2009 H1N1 pandemic was caused by the emergence of a reassortant H1N1 subtype (H1N1pdm) influenza A virus containing gene segments that originally circulated in human, avian, and swine virus reservoirs. The molecular determinants of replication and pathogenesis of H1N1pdm viruses in humans and other mammals are poorly understood. Therefore, we set out to elucidate viral determinants critical to the pathogenesis of this novel reassortant using a mouse model. We found that a glutamate-to-glycine substitution at residue 158 of the PB2 gene (PB2-E158G) increased the morbidity and mortality of the parental H1N1pdm virus. Results from mini-genome replication assays in human cells and virus titration in mouse tissues demonstrated that PB2 E158G is a pathogenic determinant, because it significantly increases viral replication rates. The virus load in PB2-E158G-infected mouse lungs was 1,300 fold higher than that of the wild-type virus. Our data also show that PB2-E158G had a much stronger influence on the RNA replication and pathogenesis of H1N1pdm viruses than PB2-E627K, which is a known pathogenic determinant. Remarkably, PB2 E158G substitutions also altered the pathotypes of two avian H5 viruses in mice, indicating that this residue impacts genetically divergent influenza A viruses and suggesting that this region of PB2 could be a new antiviral target. Collectively, the data presented in this study demonstrate that PB2-E158G is a novel pathogenic determinant of influenza A viruses in the mouse model. We speculate that PB2-E158G may be important in the adaptation of avian PB2 genes to other mammals, and BLAST sequence analysis identified a naturally occurring human H1N1pdm isolate that has this substitution. Therefore, future surveillance efforts should include scrutiny of this region of PB2 because of its potential impact on pathogenesis. PMID- 20962099 TI - Replicative and transcriptional activities of hepatitis B virus in patients coinfected with hepatitis B and hepatitis delta viruses. AB - Hepatitis B virus (HBV) and hepatitis delta virus (HDV) interplay was investigated by examining liver and serum samples from 21 coinfected and 22 HBV monoinfected patients with chronic liver disease. Different real-time PCR assays were applied to evaluate intrahepatic amounts of HBV DNA, covalently closed circular DNA (cccDNA), pregenomic RNA (pgRNA), pre-S/S RNAs, and HDV RNA. Besides HBV DNA and HDV RNA levels, HBsAg concentrations in the sera were also determined. HDV-coinfected cases showed significantly lower median levels of serum HBV DNA (-5 log), intrahepatic relaxed-circular DNA (-2 log), and cccDNA ( 2 log) than those of HBV-monoinfected cases. Interestingly, pgRNA and pre-S/S RNA amounts were significantly lower (both -1 log) in HDV-positive patients, whereas serum HBsAg concentrations were comparable between the two patient groups. Pre S/S RNA and HBsAg amounts per cccDNA molecule were higher in HDV-positive patients (3-fold and 1 log, respectively), showing that HBV replication was reduced, whereas synthesis of envelope proteins was not specifically decreased. The ratios of cccDNA to intracellular total HBV DNA showed a larger proportion of cccDNA molecules in HDV-positive cases. For these patients, both intrahepatic and serum HDV RNA amounts were associated with cccDNA but not with HBsAg or HBV DNA levels. Finally, HBV genomes with large deletions in the basal core promoter/precore region were detected in 5/21 HDV-positive patients but in no HDV negative patients and were associated with lower viremia levels. These findings provide significant information about the interference exerted by HDV on HBV replication and transcription activities in the human liver. PMID- 20962100 TI - Dynamics of two separate but linked HIV-1 CRF01_AE outbreaks among injection drug users in Stockholm, Sweden, and Helsinki, Finland. AB - Detailed phylogenetic analyses were performed to characterize an HIV-1 outbreak among injection drug users (IDUs) in Stockholm, Sweden, in 2006. This study investigated the source and dynamics of HIV-1 spread during the outbreak as well as associated demographic and clinical factors. Seventy Swedish IDUs diagnosed during 2004 to 2007 were studied. Demographic, clinical, and laboratory data were collected, and the V3 region of the HIV-1 envelope gene was sequenced to allow detailed phylogenetic analyses. The results showed that the Stockholm outbreak was caused by a CRF01_AE variant imported from Helsinki, Finland, around 2003, which was quiescent until the outbreak started in 2006. Local Swedish subtype B variants continued to spread at a lower rate. The number of new CRF01_AE cases over a rooted phylogenetic tree accurately reflected the transmission dynamics and showed a temporary increase, by a factor of 12, in HIV incidence during the outbreak. Virus levels were similar in CRF01_AE and subtype B infections, arguing against differences in contagiousness. Similarly, there were no major differences in other baseline characteristics. Instead, the outbreak in Stockholm (and Helsinki) was best explained by an introduction of HIV into a standing network of previously uninfected IDUs. The combination of phylogenetics and epidemiological data creates a powerful tool for investigating outbreaks of HIV and other infectious diseases that could improve surveillance and prevention. PMID- 20962101 TI - Hepatitis C virus NS2 protein serves as a scaffold for virus assembly by interacting with both structural and nonstructural proteins. AB - Many aspects of the assembly of hepatitis C virus (HCV) remain incompletely understood. To characterize the role of NS2 in the production of infectious virus, we determined NS2 interaction partners among other HCV proteins during productive infection. Pulldown assays showed that NS2 forms complexes with both structural and nonstructural proteins, including E1, E2, p7, NS3, and NS5A. Confocal microscopy also demonstrated that NS2 colocalizes with E1, E2, and NS5A in dot-like structures near lipid droplets. However, NS5A did not coprecipitate with E2 and interacted only weakly with NS3 in pulldown assays. Also, there was no demonstrable interaction between p7 and E2 or NS3 in such assays. Therefore, NS2 is uniquely capable of interacting with both structural and nonstructural proteins. Among mutations in p7, NS2, and NS3 that prevent production of infectious virus, only p7 mutations significantly reduced NS2-mediated protein interactions. These p7 mutations altered the intracellular distribution of NS2 and E2 and appeared to modulate the membrane topology of the C-terminal domain of NS2. These results suggest that NS2 acts to coordinate virus assembly by mediating interactions between envelope proteins and NS3 and NS5A within replication complexes adjacent to lipid droplets, where virus particle assembly is thought to occur. p7 may play an accessory role by regulating NS2 membrane topology, which is important for NS2-mediated protein interactions and therefore NS2 function. PMID- 20962102 TI - The role of pulmonary veins vs. autonomic ganglia in different experimental substrates of canine atrial fibrillation. AB - AIMS: Pulmonary vein (PV)-encircling ablation, which is effective in suppressing atrial fibrillation (AF), damages autonomic ganglia near the PV ostia. This study examined the effects of PV isolation (PVI) vs. peri-PV ganglionic plexus ablation (GPA) in two discrete canine AF models: ventricular tachypacing (240 bpm, 2 weeks)-induced congestive heart failure (CHF), and atrial tachypacing (400 bpm, 1 week)-induced atrial tachycardia remodeling (ATR). METHODS AND RESULTS: All PVs were isolated with an epicardial radiofrequency clamp in nine CHF and eight ATR dogs. Peri-PV ganglionic plexi (identified by bradycardic responses to high frequency stimulation) were ablated in six CHF and five ATR dogs with an epicardial radiofrequency-ablation pen. Electrophysiologic measurements, including 240-electrode AF mapping, were obtained and dominant frequencies (DFs) determined. Atrial growth associated protein-43 (GAP-43) and neurofilament-M (NF M) expression were determined immunohistologically. In CHF, neither PVI nor GPA affected AF duration, DF or the already low AF vulnerability. In ATR, PVI reduced AF vulnerability (75 +/- 6% to 55 +/- 11%, P< 0.05) but did not alter AF duration or DF. In contrast, GPA prolonged atrial refractory period and decreased AF vulnerability (75 +/- 8 to 30 +/- 10%, P< 0.05), AF duration (617 +/- 246 to 39 +/- 23 s, **P< 0.01), and DF (11.4 +/- 0.6 to 8.6 +/- 0.3** Hz, left atrium) in ATR dogs. Both GAP-43 and NF-M expression were decreased in CHF (by 63.1** and 60.0%**) and increased in ATR (by 65.5** and 92.1%, P< 0.001) compared with control. CONCLUSIONS: PVs play a minor role in experimental AF due to CHF or ATR, but autonomic ganglia are important in AF related to ATR. Differential neural remodelling may contribute to varying effects of GPA in discrete AF substrates. PMID- 20962104 TI - SLC4A7 sodium bicarbonate co-transporter controls mitochondrial apoptosis in ischaemic coronary endothelial cells. AB - AIMS: Bicarbonate transport has been shown to participate in apoptosis under ischaemic stress. However, the precise transporting mechanisms involved in ischaemic apoptosis are unknown and were thus the aim of the present study. METHODS AND RESULTS: Rat coronary endothelial cells (EC) were exposed to simulated in vitro ischaemia for 2 h, and apoptosis was subsequently determined by chromatin staining and caspase-3 activity analysis. By examining the expression of bicarbonate transporters (BT) in EC by reverse transcriptase polymerase chain reaction and western blotting, a marked expression of the electroneutral sodium bicarbonate co-transporter (SLC4A7) was defined. To analyse the potential role of this transporter during apoptosis, a selective inhibitor (S0859, Sanofi-Aventis) was applied. Treatment with S0859 significantly increased caspase-3 activity and elevated the number of apoptotic EC. These results were comparable with an unselective inhibition of all BT due to withdrawal of bicarbonate in the anoxic medium. Knockdown of SLC4A7 in EC by transfecting appropriate siRNA similarly increased apoptosis of EC under simulated ischaemia. The initial characterization of the participating mechanisms of SLC4A7-dependent apoptosis revealed an activation of the mitochondrial pathway of apoptosis, i.e. cleavage of caspase-9 and binding of Bax to mitochondria. In contrast, no activation of the endoplasmic reticulum-dependent pathway (caspase-12 cleavage) or the extrinsic apoptotic pathway (caspase-8 cleavage) was found. Finally, a mitochondrial localization of SLC4A7 was demonstrated. CONCLUSION: The electroneutral sodium bicarbonate co-transporter SLC4A7 localizes in mitochondria and suppresses the ischaemia-induced activation of the mitochondrial pathway of apoptosis in coronary EC. PMID- 20962103 TI - Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation. AB - Cardiac fibroblasts account for about 75% of all cardiac cells, but because of their small size contribute only ~10-15% of total cardiac cell volume. They play a crucial role in cardiac pathophysiology. For a long time, it has been recognized that fibroblasts and related cell types are the principal sources of extracellular matrix (ECM) proteins, which organize cardiac cellular architecture. In disease states, fibroblast production of increased quantities of ECM proteins leads to tissue fibrosis, which can impair both mechanical and electrical function of the heart, contributing to heart failure and arrhythmogenesis. Atrial fibrosis is known to play a particularly important role in atrial fibrillation (AF). This review article focuses on recent advances in understanding the molecular electrophysiology of cardiac fibroblasts. Cardiac fibroblasts express a variety of ion channels, in particular voltage-gated K(+) channels and non-selective cation channels of the transient receptor potential (TRP) family. Both K(+) and TRP channels are important determinants of fibroblast function, with TRP channels acting as Ca(2+)-entry pathways that stimulate fibroblast differentiation into secretory myofibroblast phenotypes producing ECM proteins. Fibroblasts can couple to cardiomyocytes and substantially affect their cellular electrical properties, including conduction, resting potential, repolarization, and excitability. Co-cultured preparations of cardiomyocytes and fibroblasts generate arrhythmias by a variety of mechanisms, including spontaneous impulse formation and rotor-driven reentry. In addition, the excess ECM proteins produced by fibroblasts can interrupt cardiomyocyte-bundle continuity, leading to local conduction disturbances and reentrant arrhythmias. A better understanding of the electrical properties of fibroblasts should lead to an improved comprehension of AF pathophysiology and a variety of novel targets for antiarrhythmic intervention. PMID- 20962105 TI - Mechanisms involved in increased plasma brain natriuretic peptide after heart transplantation. AB - Increased brain natriuretic peptide (BNP), reflecting increased ventricular wall stress and pressure, is a well-known diagnostic and prognostic marker in patients with chronic heart failure. Heart transplantation (HT), the process of replacing the failing heart and restoring haemodynamics, should normalize cardiac endocrine function. Nevertheless, BNP levels remain raised after HT, likely because of increased secretion and/or decreased clearance of the cardiac hormone. Thus, BNP increases in proportion to the extent of left and right ventricular dysfunction after HT. Clinically complicated cardiac transplantation (cardiac systolic dysfunction, renal failure) is associated with the higher level of circulating BNP, and clinically successful cardiac transplantation (mild cardiac diastolic dysfunction) is associated with moderately increased BNP values. Surprisingly, however, increased BNP has also been found after HT in the absence of haemodynamic perturbations or allograft rejection, raising the hypothesis that even subtle modification in the immune system might influence BNP expression. In view of the potential interest in the cardiac hormone for subjects' risk stratification and therapy, a better knowledge of the mechanisms involved in the BNP increase after HT might be helpful for HT recipients' follow-up. PMID- 20962106 TI - In courtroom 7--the Children's Koori Court at work: findings from an evaluation. AB - This article reports some of the findings of an evaluation of the Children's Koori Court (CKC)--the first legislated effort in Australia to involve the Indigenous community in the sentencing of young Aboriginal offenders as a strategy for reducing their overrepresentation in the juvenile justice system. A prominent feature of this court of summary jurisdiction is that the presiding magistrate, while remaining the sentencing authority, is assisted by Aboriginal Elders. This article focuses on the evaluation findings that were derived from observations of the CKC in action. They indicate that the operational objective of cultural responsiveness was realized. They also point to realization of the community-building goal-fostering Indigenous ownership of the administration of the law. Little slippage was found between the CKC's design and operation, although some areas of improvement were identified. Nevertheless, the scope for the CKC by itself to significantly reduce overrepresentation is limited. PMID- 20962107 TI - Toxicopathology of the developing immune system: investigative and development strategies. AB - Developmental immunotoxicity (DIT) has gained attention with the recognition that environmental chemicals can potentially affect the developing immune system and the incidence of childhood allergic diseases. Preclinical safety assessment of pharmaceuticals for men and women of childbearing potential as well as for pediatric and juvenile indications may require DIT assessments. Draft documents from environmental and chemical regulatory agencies propose strategies that use the rat as a test species and incorporate histopathology and functional testing as endpoints. While there are no guidelines for DIT assessment of pharmaceuticals, current discussions suggest that combining immunotoxicity and developmental and reproductive toxicology studies may serve this purpose. Knowledge of the principles and applications of DIT will facilitate participation in strategy development and effective conduct of relevant studies. PMID- 20962111 TI - Galectin-3 preserves renal tubules and modulates extracellular matrix remodeling in progressive fibrosis. AB - Renal tubular cell apoptosis is a critical detrimental event that leads to chronic kidney injury in association with renal fibrosis. The present study was designed to investigate the role of galectin-3 (Gal-3), an important regulator of multiple apoptotic pathways, in chronic kidney disease induced by unilateral ureteral obstruction (UUO). After UUO, Gal-3 expression significantly increased compared with basal levels reaching a peak increase of 95-fold by day 7. Upregulated Gal-3 is predominantly tubular at early time points after UUO but shifts to interstitial cells as the injury progresses. On day 14, there was a significant increase in TdT-mediated dUTP nick end labeling-positive cells (129%) and cytochrome c release (29%), and a decrease in BrdU-positive cells (62%) in Gal-3-deficient compared with wild-type mice. The degree of renal damage was more extensive in Gal-3-deficient mice at days 14 and 21, 35 and 21% increase in total collagen, respectively. Despite more severe fibrosis, myofibroblasts were significantly decreased by 58% on day 14 in the Gal-3-deficient compared with wild-type mice. There was also a corresponding 80% decrease in extracellular matrix synthesis in Gal-3-deficient compared with wild-type mice. Endo180 is a recently recognized receptor for intracellular collagen degradation that is expressed by interstitial cells during renal fibrogenesis. Endo180 expression was significantly decreased by greater than 50% in Gal-3-deficient compared with wild type mice. Taken together, these results suggested that Gal-3 not only protects renal tubules from chronic injury by limiting apoptosis but that it may lead to enhanced matrix remodeling and fibrosis attenuation. PMID- 20962112 TI - Renal denervation modulates angiotensin receptor expression in the renal cortex of rabbits with chronic heart failure. AB - Excessive sympathetic drive is a hallmark of chronic heart failure (HF). Disease progression can be correlated with plasma norepinephrine concentration. Renal function is also correlated with disease progression and prognosis. Because both the renal nerves and renin-angiotensin II system are activated in chronic HF we hypothesized that excessive renal sympathetic nerve activity decreases renal blood flow in HF and is associated with changes in angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) expression. The present study was carried out in conscious, chronically instrumented rabbits with pacing induced HF. We found that rabbits with HF showed a decrease in mean renal blood flow (19.8+/-1.6 in HF vs. 32.0+/-2.5 ml/min from prepace levels; P<0.05) and an increase in renal vascular resistance (3.26+/-0.29 in HF vs. 2.21+/-0.13 mmHg.ml( 1).min in prepace normal rabbits; P<0.05) while the blood flow and resistance was not changed in HF rabbits with the surgical renal denervation. Renal AT1R expression was increased by ~67% and AT2R expression was decreased by ~87% in rabbits with HF; however, kidneys from denervated rabbits with HF showed a near normalization in the expression of these receptors. These results suggest renal sympathetic nerve activity elicits a detrimental effect on renal blood flow and may be associated with alterations in the expression of angiotensin II receptors. PMID- 20962113 TI - ROK controls urethral tone, but by what mechanism? PMID- 20962115 TI - Proinflammatory gene expression and renal lipogenesis are modulated by dietary protein content in obese Zucker fa/fa rats. AB - Obesity is a risk factor for the development of chronic kidney disease (CKD) and end-stage renal disease. It is not clear whether the adoption of a high-protein diet in obese patients affects renal lipid metabolism or kidney function. Thus the aims of this study were to assess in obese Zuckerfa/fa rats the effects of different types and amounts of dietary protein on the expression of lipogenic and inflammatory genes, as well as renal lipid concentration and biochemical parameters of kidney function. Rats were fed different concentrations of soy protein or casein (20, 30, 45%) for 2 mo. Independent of the type of protein ingested, higher dietary protein intake led to higher serum triglycerides (TG) than rats fed adequate concentrations of protein. Additionally, the soy protein diet significantly increased serum TG compared with the casein diet. However, rats fed soy protein had significantly decreased serum cholesterol concentrations compared with those fed a casein diet. No significant differences in renal TG and cholesterol concentrations were observed between rats fed with either protein diets. Renal expression of sterol-regulatory element binding protein 2 (SREBP-2) and its target gene HMG-CoA reductase was significantly increased as the concentration of dietary protein increased. The highest protein diets were associated with greater expression of proinflammatory cytokines in the kidney, independent of the type of dietary protein. These results indicate that high soy or casein protein diets upregulate the expression of lipogenic and proinflammatory genes in the kidney. PMID- 20962114 TI - Isoflurane activates intestinal sphingosine kinase to protect against bilateral nephrectomy-induced liver and intestine dysfunction. AB - Acute kidney injury (AKI) frequently leads to systemic inflammation and extrarenal organ dysfunction. Volatile anesthetics are potent anti-inflammatory agents and protect against renal ischemia-reperfusion injury. Here, we sought to determine whether isoflurane, a commonly used volatile anesthetic, protects against AKI-induced liver and intestinal injury, the mechanisms involved in this protection, and whether this protection was independent of the degree of renal injury. Bilateral nephrectomy-induced AKI under pentobarbital sodium anesthesia led to severe hepatic and intestinal injury with periportal hepatocyte vacuolization, small intestinal necrosis, apoptosis, and proinflammatory mRNA upregulation. In contrast, isoflurane anesthesia reduced hepatic and intestinal injury after bilateral nephrectomy. Mechanistically, isoflurane anesthesia upregulated and induced small intestinal crypt sphingosine kinase-1 (SK1) as SK1 mRNA, protein, and enzyme activity increased with isoflurane treatment. Furthermore, isoflurane failed to protect mice treated with a selective SK inhibitor (SKI-II) or mice deficient in the SK1 enzyme against hepatic and intestinal dysfunction after bilateral nephrectomy, demonstrating the key role of SK1. Therefore, in addition to its potent anesthetic properties, isoflurane protects against AKI-induced liver and intestine injury via activation of small intestinal SK1 independently of the effects on the kidney. These findings may help to elucidate the cellular signaling pathways underlying volatile anesthetic mediated hepatic and intestinal protection and result in novel clinical applications of volatile anesthetics to attenuate perioperative complications arising from AKI. PMID- 20962116 TI - Sympathetic blockade prevents the decrease in cardiac VEGF expression and capillary supply in experimental renal failure. AB - Uremic cardiomyopathy of men and rodents is characterized by lower myocardial capillary supply that in rats could be prevented by central and peripheral blockade of the sympathetic nervous system. The underlying pathomechanisms remain largely unknown. We investigated whether alterations of cardiac vascular endothelial growth factor (VEGF) gene and protein expression were involved. In our long-term experiment, we analyzed whether VEGF gene and protein expression was altered in the heart of male Sprague-Dawley rats with either sham operation (sham, n=10) or subtotal nephrectomy (SNX, n=10). In our short-term experiment (17 sham, 24 SNX), the effect of a putative downregulation of sympathetic nervous activity by surgical renal denervation (interruption of renal afferent pathways) on cardiac gene expression of VEGF, flt-1, and flk-1 and on myocardial capillary supply was analyzed. In the long-term study, cardiac capillary supply and vascular endothelial growth factor gene and protein expression were significantly lower in SNX than in sham. In the short-term experiment, cardiac VEGF mRNA expression was significantly lower in untreated SNX (4,258+/-2,078 units) than in both sham groups (11,709+/-4,169 and 8,998+/-4,823 units); this decrease was significantly prevented by renal denervation (8,190+/-3,889, P<0.05). We conclude that cardiac VEGF gene and protein expression is reduced in experimental renal failure, and this may be considered as one potential reason for impaired myocardial adaptation under the situation of cardiac hypertrophy. The beneficial effect of sympathetic downregulation on cardiac structure and function in renal failure may be at least in part explained by increased cardiac VEGF gene expression. PMID- 20962117 TI - High glucose promotes nascent nephron apoptosis via NF-kappaB and p53 pathways. AB - A hyperglycemic environment in utero reduces kidney size and nephron number due to nascent nephron apoptosis. However, the underlying mechanisms are incompletely understood. The present study investigated whether the nascent nephron apoptosis promoted by high glucose is mediated via the transcription factor NF-kappaB and p53 signaling pathways. Neonatal mouse kidneys from the offspring of nondiabetic, diabetic, and insulin-treated diabetic dams were used for in vivo studies, and MK4 cells, an embryonic metanephric mesenchymal (MM) cell line, were used for in vitro studies. Neonatal kidneys of the offspring of diabetic mothers exhibited an increased number of apoptotic cells and reactive oxygen species (ROS) generation, enhanced NF-kappaB activation, and nuclear translocation of its subunits (p50 and p65 subunits) as well as phosphorylation (Ser 15) of p53 compared with kidneys of offspring of nondiabetic mothers. Insulin treatment of diabetic dams normalized these parameters in the offspring. In vitro, high-glucose (25 mM) induced ROS generation and significantly increased MK4 cell apoptosis and caspase-3 activity via activation of NF-kappaB pathway, with p53 phosphorylation and nuclear translocation compared with normal glucose (5 mM). These changes in a high glucose milieu were prevented by transient transfection of small interfering RNAs for dominant negative IkappaBalpha or IKK or p53. Our data demonstrate that high glucose-induced nascent nephron apoptosis is mediated, at least in part, via ROS generation and the activation of NF-kappaB and p53 pathways. PMID- 20962118 TI - Angiotensin-(1-7) reduces proteinuria and diminishes structural damage in renal tissue of stroke-prone spontaneously hypertensive rats. AB - Angiotensin (ANG)-(1-7) constitutes an important functional end-product of the renin-angiotensin-aldosterone system that acts to balance the physiological actions of ANG II. In the kidney, ANG-(1-7) exerts beneficial effects by inhibiting growth-promoting pathways and reducing proteinuria. We examined whether a 2-wk treatment with a daily dose of ANG-(1-7) (0.6 mg.kg(-1).day(-1)) exerts renoprotective effects in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). Body weight, glycemia, triglyceridemia, cholesterolemia, as well as plasma levels of Na+ and K+ were determined both at the beginning and at the end of the treatment. Also, the weekly evolution of arterial blood pressure, proteinuria, and creatinine clearance was evaluated. Renal fibrosis was determined by Masson's trichrome staining. Interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and nuclear factor-kappaB (NF-kappaB) levels were determined by immunohistochemistry and confirmed by Western blotting analysis. The levels of glomerular nephrin were assessed by immunofluorescence. Chronic administration of ANG-(1-7) normalized arterial pressure, reduced glycemia and triglyceridemia, improved proteinuria, and ameliorated structural alterations in the kidney of SHRSP as shown by a restoration of glomerular nephrin levels as detected by immunofluorescence. These results were accompanied with a decrease in both the immunostaining and abundance of IL-6, TNF-alpha, and NF-kappaB. In this context, the current study provides strong evidence for a protective role of ANG-(1-7) in the kidney. PMID- 20962119 TI - ATP as a death factor: purinergic signaling in renal epithelial-fibroblast cross talk. PMID- 20962120 TI - Foundational biomedical informatics research in the clinical and translational science era: a call to action. AB - Advances in clinical and translational science, along with related national-scale policy and funding mechanisms, have provided significant opportunities for the advancement of applied clinical research informatics (CRI) and translational bioinformatics (TBI). Such efforts are primarily oriented to application and infrastructure development and are critical to the conduct of clinical and translational research. However, they often come at the expense of the foundational CRI and TBI research needed to grow these important biomedical informatics subdisciplines and ensure future innovations. In light of this challenge, it is critical that a number of steps be taken, including the conduct of targeted advocacy campaigns, the development of community-accepted research agendas, and the continued creation of forums for collaboration and knowledge exchange. Such efforts are needed to ensure that the biomedical informatics community is able to advance CRI and TBI science in the context of the modern clinical and translational science era. PMID- 20962122 TI - All's well that ends well for JAMIA editors. AB - Dr Randolph A Miller begins a self-imposed JAMIA retirement on January 1, 2011 after serving as Editor-in-Chief for eight and a half years. He lauds the selection of Lucia Ohno-Machado as an energetic, innovative, and highly qualified successor. PMID- 20962121 TI - Health information technology: fallacies and sober realities. AB - Current research suggests that the rate of adoption of health information technology (HIT) is low, and that HIT may not have the touted beneficial effects on quality of care or costs. The twin issues of the failure of HIT adoption and of HIT efficacy stem primarily from a series of fallacies about HIT. We discuss 12 HIT fallacies and their implications for design and implementation. These fallacies must be understood and addressed for HIT to yield better results. Foundational cognitive and human factors engineering research and development are essential to better inform HIT development, deployment, and use. PMID- 20962123 TI - Application of information technology within a field hospital deployment following the January 2010 Haiti earthquake disaster. AB - Following the January 2010 earthquake in Haiti, the Israel Defense Force Medical Corps dispatched a field hospital unit. A specially tailored information technology solution was deployed within the hospital. The solution included a hospital administration system as well as a complete electronic medical record. A light-weight picture archiving and communication system was also deployed. During 10 days of operation, the system registered 1111 patients. The network and system up times were more than 99.9%. Patient movements within the hospital were noted, and an online command dashboard screen was generated. Patient care was delivered using the electronic medical record. Digital radiographs were acquired and transmitted to stations throughout the hospital. The system helped to introduce order in an otherwise chaotic situation and enabled adequate utilization of scarce medical resources by continually gathering information, analyzing it, and presenting it to the decision-making command level. The establishment of electronic medical records promoted the adequacy of medical treatment and facilitated continuity of care. This experience in Haiti supports the feasibility of deploying information technologies within a field hospital operation. Disaster response teams and agencies are encouraged to consider the use of information technology as part of their contingency plans. PMID- 20962124 TI - Impact of health information technology interventions to improve medication laboratory monitoring for ambulatory patients: a systematic review. AB - Medication errors are a major source of morbidity and mortality. Inadequate laboratory monitoring of high-risk medications after initial prescription is a medical error that contributes to preventable adverse drug events. Health information technology (HIT)-based clinical decision support may improve patient safety by improving the laboratory monitoring of high-risk medications, but the effectiveness of such interventions is unclear. Therefore, the authors conducted a systematic review to identify studies that evaluate the independent effect of HIT interventions on improving laboratory monitoring for high-risk medications in the ambulatory setting using a Medline search from January 1, 1980 through January 1, 2009 and a manual review of relevant bibliographies. All anticoagulation monitoring studies were excluded. Eight articles met the inclusion criteria, including six randomized controlled trials and two pre-post intervention studies. Six of the studies were conducted in two large, integrated healthcare delivery systems in the USA. Overall, five of the eight studies reported statistically significant, but small, improvements in laboratory monitoring; only half of the randomized controlled trials reported statistically significant improvements. Studies that found no improvement were more likely to have used analytic strategies that addressed clustering and confounding. Whether HIT improves laboratory monitoring of certain high-risk medications for ambulatory patients remains unclear, and further research is needed to clarify this important question. PMID- 20962125 TI - A review on systematic reviews of health information system studies. AB - The purpose of this review is to consolidate existing evidence from published systematic reviews on health information system (HIS) evaluation studies to inform HIS practice and research. Fifty reviews published during 1994-2008 were selected for meta-level synthesis. These reviews covered five areas: medication management, preventive care, health conditions, data quality, and care process/outcome. After reconciliation for duplicates, 1276 HIS studies were arrived at as the non-overlapping corpus. On the basis of a subset of 287 controlled HIS studies, there is some evidence for improved quality of care, but in varying degrees across topic areas. For instance, 31/43 (72%) controlled HIS studies had positive results using preventive care reminders, mostly through guideline adherence such as immunization and health screening. Key factors that influence HIS success included having in-house systems, developers as users, integrated decision support and benchmark practices, and addressing such contextual issues as provider knowledge and perception, incentives, and legislation/policy. PMID- 20962126 TI - A systematic literature review of automated clinical coding and classification systems. AB - Clinical coding and classification processes transform natural language descriptions in clinical text into data that can subsequently be used for clinical care, research, and other purposes. This systematic literature review examined studies that evaluated all types of automated coding and classification systems to determine the performance of such systems. Studies indexed in Medline or other relevant databases prior to March 2009 were considered. The 113 studies included in this review show that automated tools exist for a variety of coding and classification purposes, focus on various healthcare specialties, and handle a wide variety of clinical document types. Automated coding and classification systems themselves are not generalizable, nor are the results of the studies evaluating them. Published research shows these systems hold promise, but these data must be considered in context, with performance relative to the complexity of the task and the desired outcome. PMID- 20962127 TI - Development and evaluation of a common data model enabling active drug safety surveillance using disparate healthcare databases. AB - OBJECTIVE: Active drug safety surveillance may be enhanced by analysis of multiple observational healthcare databases, including administrative claims and electronic health records. The objective of this study was to develop and evaluate a common data model (CDM) enabling rapid, comparable, systematic analyses across disparate observational data sources to identify and evaluate the effects of medicines. DESIGN: The CDM uses a person-centric design, with attributes for demographics, drug exposures, and condition occurrence. Drug eras, constructed to represent periods of persistent drug use, are derived from available elements from pharmacy dispensings, prescriptions written, and other medication history. Condition eras aggregate diagnoses that occur within a single episode of care. Drugs and conditions from source data are mapped to biomedical ontologies to standardize terminologies and enable analyses of higher-order effects. MEASUREMENTS: The CDM was applied to two source types: an administrative claims and an electronic medical record database. Descriptive statistics were used to evaluate transformation rules. Two case studies demonstrate the ability of the CDM to enable standard analyses across disparate sources: analyses of persons exposed to rofecoxib and persons with an acute myocardial infarction. RESULTS: Over 43 million persons, with nearly 1 billion drug exposures and 3.7 billion condition occurrences from both databases were successfully transformed into the CDM. An analysis routine applied to transformed data from each database produced consistent, comparable results. CONCLUSION: A CDM can normalize the structure and content of disparate observational data, enabling standardized analyses that are meaningfully comparable when assessing the effects of medicines. PMID- 20962128 TI - An analysis of computer-related patient safety incidents to inform the development of a classification. AB - OBJECTIVE: To analyze patient safety incidents associated with computer use to develop the basis for a classification of problems reported by health professionals. DESIGN: Incidents submitted to a voluntary incident reporting database across one Australian state were retrieved and a subset (25%) was analyzed to identify 'natural categories' for classification. Two coders independently classified the remaining incidents into one or more categories. Free text descriptions were analyzed to identify contributing factors. Where available medical specialty, time of day and consequences were examined. MEASUREMENTS: Descriptive statistics; inter-rater reliability. RESULTS: A search of 42,616 incidents from 2003 to 2005 yielded 123 computer related incidents. After removing duplicate and unrelated incidents, 99 incidents describing 117 problems remained. A classification with 32 types of computer use problems was developed. Problems were grouped into information input (31%), transfer (20%), output (20%) and general technical (24%). Overall, 55% of problems were machine related and 45% were attributed to human-computer interaction. Delays in initiating and completing clinical tasks were a major consequence of machine related problems (70%) whereas rework was a major consequence of human-computer interaction problems (78%). While 38% (n=26) of the incidents were reported to have a noticeable consequence but no harm, 34% (n=23) had no noticeable consequence. CONCLUSION: Only 0.2% of all incidents reported were computer related. Further work is required to expand our classification using incident reports and other sources of information about healthcare IT problems. Evidence based user interface design must focus on the safe entry and retrieval of clinical information and support users in detecting and correcting errors and malfunctions. PMID- 20962129 TI - Drug safety surveillance using de-identified EMR and claims data: issues and challenges. AB - The author discusses the challenges of pharmacovigilance using electronic medical record and claims data. Use of ICD-9 encoded data has low sensitivity for detection of adverse drug events (ADEs), because it requires that an ADE escalate to major-complaint level before it can be identified, and because clinical symptomatology is relatively under-represented in ICD-9. A more appropriate vocabulary for ADE identification, SNOMED CT, awaits wider deployment. The narrative-text record of progress notes can potentially be used for more sensitive ADE detection. More effective surveillance will require the ability to grade ADEs by severity. Finally, access to online drug information that includes both a reliable hierarchy of drug families as well as structured information on existing ADEs can improve the focus and predictive ability of surveillance efforts. PMID- 20962130 TI - The UMLS-CORE project: a study of the problem list terminologies used in large healthcare institutions. AB - OBJECTIVE: To study existing problem list terminologies (PLTs), and to identify a subset of concepts based on standard terminologies that occur frequently in problem list data. DESIGN: Problem list terms and their usage frequencies were collected from large healthcare institutions. MEASUREMENT: The pattern of usage of the terms was analyzed. The local terms were mapped to the Unified Medical Language System (UMLS). Based on the mapped UMLS concepts, the degree of overlap between the PLTs was analyzed. RESULTS: Six institutions submitted 76,237 terms and their usage frequencies in 14 million patients. The distribution of usage was highly skewed. On average, 21% of unique terms already covered 95% of usage. The most frequently used 14,395 terms, representing the union of terms that covered 95% of usage in each institution, were exhaustively mapped to the UMLS. 13,261 terms were successfully mapped to 6776 UMLS concepts. Less frequently used terms were generally less 'mappable' to the UMLS. The mean pairwise overlap of the PLTs was only 21% (median 19%). Concepts that were shared among institutions were used eight times more often than concepts unique to one institution. A SNOMED Problem List Subset of frequently used problem list concepts was identified. CONCLUSIONS: Most of the frequently used problem list terms could be found in standard terminologies. The overlap between existing PLTs was low. The use of the SNOMED Problem List Subset will save developmental effort, reduce variability of PLTs, and enhance interoperability of problem list data. PMID- 20962131 TI - Impact of generic substitution decision support on electronic prescribing behavior. AB - OBJECTIVE: To evaluate the impact of generic substitution decision support on electronic (e-) prescribing of generic medications. DESIGN: The authors analyzed retrospective outpatient e-prescribing data from an academic medical center and affiliated network for July 1, 2005-September 30, 2008 using an interrupted time series design to assess the rate of generic prescribing before and after implementing generic substitution decision support. To assess background secular trends, e-prescribing was compared with a concurrent random sample of hand generated prescriptions. MEASUREMENTS: Proportion of generic medications prescribed before and after the intervention, evaluated over time, and compared with a sample of prescriptions generated without e-prescribing. RESULTS: The proportion of generic medication prescriptions increased from 32.1% to 54.2% after the intervention (22.1% increase, 95% CI 21.9% to 22.3%), with no diminution in magnitude of improvement post-intervention. In the concurrent control group, increases in proportion of generic prescriptions (29.3% to 31.4% to 37.4% in the pre-intervention, post-intervention, and end-of-study periods, respectively) were not commensurate with the intervention. There was a larger change in generic prescribing rates among authorized prescribers (24.6%) than nurses (18.5%; adjusted OR 1.38, 95% CI 1.17 to 1.63). Two years after the intervention, the proportion of generic prescribing remained significantly higher for e-prescriptions (58.1%; 95% CI 57.5% to 58.7%) than for hand-generated prescriptions ordered at the same time (37.4%; 95% CI 34.9% to 39.9%) (p<0.0001). Generic prescribing increased significantly in every specialty. CONCLUSION: Implementation of generic substitution decision support was associated with dramatic and sustained improvements in the rate of outpatient generic e prescribing across all specialties. PMID- 20962132 TI - Using global unique identifiers to link autism collections. AB - OBJECTIVE: To propose a centralized method for generating global unique identifiers to link collections of research data and specimens. DESIGN: The work is a collaboration between the Simons Foundation Autism Research Initiative and the National Database for Autism Research. The system is implemented as a web service: an investigator inputs identifying information about a participant into a client application and sends encrypted information to a server application, which returns a generated global unique identifier. The authors evaluated the system using a volume test of one million simulated individuals and a field test on 2000 families (over 8000 individual participants) in an autism study. MEASUREMENTS: Inverse probability of hash codes; rate of false identity of two individuals; rate of false split of single individual; percentage of subjects for which identifying information could be collected; percentage of hash codes generated successfully. RESULTS: Large-volume simulation generated no false splits or false identity. Field testing in the Simons Foundation Autism Research Initiative Simplex Collection produced identifiers for 96% of children in the study and 77% of parents. On average, four out of five hash codes per subject were generated perfectly (only one perfect hash is required for subsequent matching). DISCUSSION: The system must achieve balance among the competing goals of distinguishing individuals, collecting accurate information for matching, and protecting confidentiality. Considerable effort is required to obtain approval from institutional review boards, obtain consent from participants, and to achieve compliance from sites during a multicenter study. CONCLUSION: Generic unique identifiers have the potential to link collections of research data, augment the amount and types of data available for individuals, support detection of overlap between collections, and facilitate replication of research findings. PMID- 20962133 TI - Biomedical negation scope detection with conditional random fields. AB - OBJECTIVE: Negation is a linguistic phenomenon that marks the absence of an entity or event. Negated events are frequently reported in both biological literature and clinical notes. Text mining applications benefit from the detection of negation and its scope. However, due to the complexity of language, identifying the scope of negation in a sentence is not a trivial task. DESIGN: Conditional random fields (CRF), a supervised machine-learning algorithm, were used to train models to detect negation cue phrases and their scope in both biological literature and clinical notes. The models were trained on the publicly available BioScope corpus. MEASUREMENT: The performance of the CRF models was evaluated on identifying the negation cue phrases and their scope by calculating recall, precision and F1-score. The models were compared with four competitive baseline systems. RESULTS: The best CRF-based model performed statistically better than all baseline systems and NegEx, achieving an F1-score of 98% and 95% on detecting negation cue phrases and their scope in clinical notes, and an F1 score of 97% and 85% on detecting negation cue phrases and their scope in biological literature. CONCLUSIONS: This approach is robust, as it can identify negation scope in both biological and clinical text. To benefit text mining applications, the system is publicly available as a Java API and as an online application at http://negscope.askhermes.org. PMID- 20962134 TI - Assessment of email communication skills of rheumatology fellows: a pilot study. AB - Physician-patient email communication is gaining popularity. However, a formal assessment of physicians' email communication skills has not been described. We hypothesized that the email communication skills of rheumatology fellows can be measured in an objective structured clinical examination (OSCE) setting using a novel email content analysis instrument which has 18 items. During an OSCE, we asked 50 rheumatology fellows to respond to a simulated patient email. The content of the responses was assessed using our instrument. The majority of rheumatology fellows wrote appropriate responses scoring a mean (+/-SD) of 10.6 (+/-2.6) points (maximum score 18), with high inter-rater reliability (0.86). Most fellows were concise (74%) and courteous (68%) but not formal (22%). Ninety two percent of fellows acknowledged that the patient's condition required urgent medical attention, but only 30% took active measures to contact the patient. No one encrypted their messages. The objective assessment of email communication skills is possible using simulated emails in an OSCE setting. The variable email communication scores and incidental patient safety gaps identified, suggest a need for further training and defined proficiency standards for physicians' email communication skills. PMID- 20962135 TI - Developing and validating a model to predict the success of an IHCS implementation: the Readiness for Implementation Model. AB - OBJECTIVE: To develop and validate the Readiness for Implementation Model (RIM). This model predicts a healthcare organization's potential for success in implementing an interactive health communication system (IHCS). The model consists of seven weighted factors, with each factor containing five to seven elements. DESIGN: Two decision-analytic approaches, self-explicated and conjoint analysis, were used to measure the weights of the RIM with a sample of 410 experts. The RIM model with weights was then validated in a prospective study of 25 IHCS implementation cases. MEASUREMENTS: Orthogonal main effects design was used to develop 700 conjoint-analysis profiles, which varied on seven factors. Each of the 410 experts rated the importance and desirability of the factors and their levels, as well as a set of 10 different profiles. For the prospective 25 case validation, three time-repeated measures of the RIM scores were collected for comparison with the implementation outcomes. RESULTS: Two of the seven factors, 'organizational motivation' and 'meeting user needs,' were found to be most important in predicting implementation readiness. No statistically significant difference was found in the predictive validity of the two approaches (self-explicated and conjoint analysis). The RIM was a better predictor for the 1 year implementation outcome than the half-year outcome. LIMITATIONS: The expert sample, the order of the survey tasks, the additive model, and basing the RIM cut off score on experience are possible limitations of the study. CONCLUSION: The RIM needs to be empirically evaluated in institutions adopting IHCS and sustaining the system in the long term. PMID- 20962136 TI - Comparing and evaluating terminology services application programming interfaces: RxNav, UMLSKS and LexBIG. AB - To facilitate the integration of terminologies into applications, various terminology services application programming interfaces (API) have been developed in the recent past. In this study, three publicly available terminology services API, RxNav, UMLSKS and LexBIG, are compared and functionally evaluated with respect to the retrieval of information from one biomedical terminology, RxNorm, to which all three services provide access. A list of queries is established covering a wide spectrum of terminology services functionalities such as finding RxNorm concepts by their name, or navigating different types of relationships. Test data were generated from the RxNorm dataset to evaluate the implementation of the functionalities in the three API. The results revealed issues with various aspects of the API implementation (eg, handling of obsolete terms by LexBIG) and documentation (eg, navigational paths used in RxNav) that were subsequently addressed by the development teams of the three API investigated. Knowledge about such discrepancies helps inform the choice of an API for a given use case. PMID- 20962137 TI - Development of a combined system for identification and classification of adverse drug reactions: Alerts Based on ADR Causality and Severity (ABACUS). AB - Currently, adverse drug reaction (ADR) causality and severity are assessed using different systems but there is no standard method to combine the results. In this work, a combined ADR causality and severity assessment system, including an online version, was developed. Logical rules were defined to translate the score obtained from the system into three alert zones: green, amber, and red. The alert zones are useful for triaging ADR cases as they help define the seriousness of the ADR and the urgency of the responses required. This new scoring system may be useful for clinicians, investigators, and regulators seeking information on the likelihood of a drug causing an adverse reaction, and whether an adverse reaction is sufficiently dangerous for the drug to be withheld or undergo further investigation. PMID- 20962138 TI - Molecular detection of mixed infections of Mycobacterium tuberculosis strains in sputum samples from patients in Karonga District, Malawi. AB - The occurrence of mixed infections of Mycobacterium tuberculosis is no longer disputed. However, their frequency, and the impact they may have on our understanding of tuberculosis (TB) pathogenesis and epidemiology, remains undetermined. Most previous studies of frequency applied genotyping techniques to cultured M. tuberculosis isolates and found mixed infections to be rare. PCR based techniques may be more sensitive for detecting multiple M. tuberculosis strains and can be applied to sputum. To date, one study in South Africa has used a PCR approach and suggested that mixed infection could be common. We investigated mixed infections in northern Malawi using two lineage-specific PCR assays targeting the Latin American-Mediterranean (LAM) and Beijing lineages. Compared with spoligotyping, the specificity and sensitivity of both assays was 100%. From 160 culture-positive sputa, mixed LAM and non-LAM strains were detected in 4 sputa belonging to 2 (2.8%) patients. Both patients were HIV positive, with no history of TB. Cultured isolates from both patients showed only LAM by PCR and spoligotyping. In a set of 377 cultured isolates, 4 were mixed LAM and non-LAM. Only one showed evidence of more than one M. tuberculosis strain using IS6110-based restriction fragment length polymorphism (IS6110-RFLP) and spoligotyping analyses. Corresponding sputa for the 4 isolates were unavailable. Mixed Beijing and non-Beijing strains were not detected in this study. Mixed infections appear to be rare in our setting and are unlikely to affect findings based on DNA fingerprinting data. Molecular methods, which avoid the selective nature of culture and target distinct strains, are well suited to detection of mixed infections. PMID- 20962139 TI - Molecular probes for diagnosis of clinically relevant bacterial infections in blood cultures. AB - Broad-range real-time PCR and sequencing of the 16S rRNA gene region is a widely known method for the detection and identification of bacteria in clinical samples. However, because of the need for sequencing, such identification of bacteria is time-consuming. The aim of our study was to develop a more rapid 16S real-time PCR-based identification assay using species- or genus-specific probes. The Gram-negative bacteria were divided into Pseudomonas species, Pseudomonas aeruginosa, Escherichia coli, and other Gram-negative species. Within the Gram positive species, probes were designed for Staphylococcus species, Staphylococcus aureus, Enterococcus species, Streptococcus species, and Streptococcus pneumoniae. The assay also included a universal probe within the 16S rRNA gene region for the detection of all bacterial DNA. The assay was evaluated with a collection of 248 blood cultures. In this study, the universal probe and the probes targeting Pseudomonas spp., P. aeruginosa, E. coli, Streptococcus spp., S. pneumoniae, Enterococcus spp., and Staphylococcus spp. all had a sensitivity and specificity of 100%. The probe specific for S. aureus showed eight discrepancies, resulting in a sensitivity of 100% and a specificity of 93%. These data showed high agreement between conventional testing and our novel real-time PCR assay. Furthermore, this assay significantly reduced the time needed for identification. In conclusion, using pathogen-specific probes offers a faster alternative for pathogen detection and could improve the diagnosis of bloodstream infections. PMID- 20962140 TI - Fast detection of volatile organic compounds from bacterial cultures by secondary electrospray ionization-mass spectrometry. AB - We propose a novel application of secondary electrospray ionization-mass spectrometry (SESI-MS) as a real-time clinical diagnostic tool for bacterial infection. It is known that volatile organic compounds (VOCs), produced in different combinations and quantities by bacteria as metabolites, generate characteristic odors for certain bacteria. These VOCs comprise a specific metabolic profile that can be used for species or serovar identification, but rapid and sensitive analytical methods are required for broad utility. In this study, the VOC profiles of five bacterial groups from four genera, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Salmonella enterica serovar Typhimurium, and Salmonella enterica serovar Pullorum, were characterized by SESI MS. Thirteen compounds were identified from these bacterial cultures, and the combination of these VOCs creates a unique pattern for each genus. In addition, principal component analysis (PCA) was applied for the purpose of species or serovar discrimination. The first three principal components exhibit a clear separation between the metabolic volatile profiles of these five bacterial groups that is independent of the growth medium. As a first step toward addressing the complexity of clinical application, in vitro tests for mixed cultures were conducted. The results show that individual species or serovars in a mixed culture are identifiable among a biological VOC background, and the ratios of the detected volatiles reflect the proportion of each bacterium in the mixture. Our data confirm the utility of SESI-MS in real-time identification of bacterial species or serovars in vitro, which, in the future, may play a promising clinical role in diagnosing infections. PMID- 20962141 TI - Comparison of GeneXpert FluA PCR to direct fluorescent antibody and respiratory viral panel PCR assays for detection of 2009 novel H1N1 influenza virus. PMID- 20962142 TI - The liposome PCR assay is more sensitive than the Vibrio cholerae enterotoxin and Escherichia coli heat-labile enterotoxin reversed passive latex agglutination test at detecting cholera toxin in feces and water. AB - Practical detection of cholera toxin (CT) by a liposome PCR (LPCR) immunoassay was compared to that of an established V. cholerae enterotoxin and Escherichia coli heat-labile enterotoxin reversed passive latex agglutination (VET-RPLA) assay. LPCR detected CT in the range of 10 pg/ml to 100 ng/ml in simulated feces and environmental water. Detection by VET-RPLA required at least 4 to 19 ng/ml CT. PMID- 20962143 TI - False-negative PCR result due to gene polymorphism: the example of Neisseria meningitidis. AB - Early treatment of meningococcal meningitis is mandatory but may negate the cerebrospinal fluid culture. Etiological diagnosis then mainly relies on PCR. Here, we report a case of false-negative results for real-time PCR for a Neisseria meningitidis serogroup B isolate with a polymorphism in the ctrA gene. PMID- 20962144 TI - Evaluation of a new chromogenic medium (StrepB select) for detection of group B Streptococcus from vaginal-rectal specimens. AB - We compared StrepB Select medium (Select) after enrichment with conventional culture for the detection of Group B Streptococcus (GBS). Postenrichment sensitivities of Select and conventional culture were 98.8% and 92.2%, respectively (P<0.05). Select was superior for detection of GBS from vaginal rectal specimens. Growth of non-GBS colonies required additional work to exclude the presence of GBS, especially after 48 h of incubation. Incubation of Select beyond 24 h did not significantly increase the yield of GBS. PMID- 20962145 TI - Contamination of commercial PCR master mix with DNA from Coxiella burnetii. AB - Contamination of an in-house diagnostic real-time PCR for Q fever was traced back to a commercially obtained PCR Master Mix. It was established that this Master Mix contained DNA from Coxiella burnetii, probably as a result of the use of compounds of animal origin such as bovine serum albumin. PMID- 20962146 TI - Evaluation of the BD GeneOhm assay using the rotor-gene 6000 platform for rapid detection of methicillin-resistant Staphylococcus aureus from pooled screening swabs. AB - As health services move toward universal methicillin-resistant Staphylococcus aureus (MRSA) screening for hospital admissions, the most cost-effective approach is yet to be defined. In this study, one of the largest to date, we evaluated the performance of the BD GeneOhm MRSA assay on the Rotor-Gene 6000 thermal cycler, using samples taken directly from pooled MRSA screens. Results were compared with the same assay performed on the Smart-Cycler II platform and overnight broth culture. Samples yielding discrepant results were subjected to detailed analysis with an in-house PCR and patient note review. A total of 1,428 pooled MRSA screens were tested. Sensitivities and specificities of 85.3% and 95.8% for the Rotor-Gene and 81% and 95.7% for the Smart-Cycler were obtained, compared with broth enrichment. The sensitivity of the BD GeneOhm assay was increased to 100% when the results of in-house PCR and patient note review were taken into account. This study demonstrates that the Rotor-Gene 6000 thermal cycler is a reliable platform for use with the BD GeneOhm assay. It also proves that commercial PCR can be performed direct on pooled samples in selective broth, without the need for overnight incubation. PMID- 20962147 TI - Vancomycin susceptibility trends and prevalence of heterogeneous vancomycin intermediate Staphylococcus aureus in clinical methicillin-resistant S. aureus isolates. AB - Due to the rise in methicillin-resistant Staphylococcus aureus (MRSA) infections and widespread use of vancomycin, MRSA isolates with reduced susceptibility to vancomycin are emerging (i.e., MIC creep). However, the prevalence of heterogeneous vancomycin-intermediate S. aureus (hVISA) is unknown due to the difficulty in detecting this phenotype. Recently, Etest glycopeptide resistance detection (GRD) strips have been developed to detect hVISA. This study assessed vancomycin susceptibility in MRSA isolates and determined the prevalence of hVISA by Etest GRD and population analysis profile-area under the curve ratio (PAP AUC). The genetic backgrounds of 167 MRSA isolates collected from 2000 to 2008 were identified by pulsed-field gel electrophoresis. Vancomycin MICs were determined using Etest and two broth microdilution assays, MicroScan and Sensititre. Etest GRD was performed on all isolates, and those exhibiting a hVISA phenotype were further tested by PAP-AUC. The vancomycin MIC modes remained consistent at 1 MUg/ml, as assessed by Sensititre and MicroScan. Etest reported a significant increase (mode MIC = 1.5 MUg/ml) in the MIC between 2000 and 2008 (P < 0.01); however, this increase did not reflect a >= 2-fold change. In addition, the slight MIC increase did not increase linearly from 2000 to 2008, suggesting biological fluctuation, and is inconsistent with the concept of MIC creep. Etest GRD identified six hVISA isolates, two of which were confirmed to be hVISA by PAP AUC. In conclusion, reduced vancomycin susceptibility was not detected in our hospital over a 9-year period using three different MIC methodologies, and the hVISA incidence was 1.2%, as determined by Etest GRD and PAP-AUC. PMID- 20962148 TI - Daily supplementation with 25 MUg cholecalciferol does not increase calcium absorption or skeletal retention in adolescent girls with low serum 25 hydroxyvitamin D. AB - In healthy adolescents, cross-sectional studies show either no or negative relationships between serum 25-hydroxyvitamin D [25(OH)D] and calcium (Ca) absorption. Using a 2-period metabolic balance study, the effect of vitamin D supplementation on Ca absorption and retention in adolescent girls was investigated. Eleven girls aged 12-14 y with a mean entry serum 25(OH)D of 35.1 nmol/L consumed a controlled intake (providing 5 MUg vitamin D and 1117 mg Ca/d) for two 3-wk metabolic balance periods separated by a 1-wk washout period. Sunlight exposure was minimized by sunscreen with a sun protection factor >= 15. After the first metabolic balance period, participants received 25 MUg/d cholecalciferol supplementation for 4 wk. Fractional Ca absorption was measured in each metabolic balance period using a stable Ca isotope method. All urine and fecal samples were collected and analyzed to measure net Ca absorption and Ca retention. Paired t tests and correlations were used to analyze the data. Daily supplementation with 25 MUg vitamin D resulted in a mean increase in serum 25(OH)D of 13.3 nmol/L (P < 0.01) but a decrease in fractional Ca absorption of 8.3% (P < 0.05) and no significant change in fasting serum 1,25-dihydroxyvitamin D, parathyroid hormone, net Ca absorption, or Ca skeletal retention. In pubertal girls with vitamin D status considered insufficient in adults, vitamin D supplementation of 25 MUg/d for 4 wk did not improve fractional Ca absorption, net Ca absorption, or Ca retention. PMID- 20962150 TI - It's the right time for Advances in Nutrition. PMID- 20962149 TI - Damage to the intestinal epithelial barrier by antibiotic pretreatment of salmonella-infected rats is lessened by dietary calcium or tannic acid. AB - Perturbation of the intestinal microbiota by antibiotics predisposes the host to food-borne pathogens like Salmonella. The effects of antibiotic treatment on intestinal permeability during infection and the efficacy of dietary components to improve resistance to infection have not been studied. Therefore, we investigated the effect of clindamycin on intestinal barrier function in Salmonella-infected rats. We also studied the ability of dietary calcium and tannic acid to protect against infection and concomitant diarrhea and we assessed intestinal barrier function. Rats were fed a purified control diet including the permeability marker chromium EDTA (CrEDTA) (2 g/kg) or the same diet supplemented with calcium (4.8 g/kg) or tannic acid (3.75 g/kg). After adaptation, rats were orally treated with clindamycin for 4 d followed by oral infection with Salmonella enteritidis. Two additional control groups were not treated with antibiotics and received either saline or Salmonella. Urine and feces were collected to quantify intestinal permeability, diarrhea, cytotoxicity of fecal water, and Salmonella excretion. In addition, Salmonella translocation was determined. Diarrhea, CrEDTA excretion, and cytotoxicity of fecal water were higher in the clindamycin-treated infected rats than in the non-clindamycin treated infected control group. Intestinal barrier function was less in the Salmonella-infected rats pretreated with antibiotics compared with the non clindamycin- treated rats. Both calcium and tannic acid reduced infection associated diarrhea and inhibited the adverse intestinal permeability changes but did not decrease Salmonella colonization and translocation. Our results indicate that calcium protects against intestinal changes due to Salmonella infection by reducing luminal cytotoxicity, whereas tannic acid offers protection by improving the mucosal resistance. PMID- 20962151 TI - Latent class analysis is useful to classify pregnant women into dietary patterns. AB - Empirical dietary patterns are derived predominantly using principal components, exploratory factor analysis (EFA), or cluster analysis. Interestingly, latent variable models are less used despite their being more flexible to accommodate important characteristics of dietary data and despite dietary patterns being recognized as latent variables. Latent class analysis (LCA) has been shown empirically to be more appropriate to derive dietary patterns than k-means clustering but has not been compared yet to confirmatory factor analysis (CFA). In this article, we derived dietary patterns using EFA, CFA, and LCA on food items, tested how well the classes from LCA were characterized by the factors from CFA, and compared participants' direct classification from LCA on food items compared with 2 a posteriori classifications from factor scores. Methods were illustrated with the Pregnancy, Infection and Nutrition Study, North Carolina, 2000-2005 (n = 1285 women). From EFA and CFA, we found that food items were grouped into 4 factors: Prudent, Prudent with coffee and alcohol, Western, and Southern. From LCA, pregnant women were classified into 3 classes: Prudent, Hard core Western, and Health-conscious Western. There was high agreement between the direct classification from LCA on food items and the classification from the 2 step LCA on factor scores [kappa=0.70 (95% CI = 0.66, 0.73)] despite factors explaining only 25% of the total variance. We suggest LCA on food items to study the effect for mutually exclusive classes and CFA to understand which foods are eaten in combination. When interested in both benefits, the 2-step classification using LCA on previously derived factor scores seems promising. PMID- 20962153 TI - Loss of carotene-9',10'-monooxygenase expression increases serum and tissue lycopene concentrations in lycopene-fed mice. AB - Two enzymes have been identified for the oxidative metabolism of carotenoids in mammals. Carotene-15,15'-monooxygenase (CMO-I) primarily centrally cleaves beta,beta-carotene to form vitamin A. We hypothesize that carotene-9',10' monooxygenase (CMO-II) plays a key role in metabolism of acyclic nonprovitamin A carotenoids such as lycopene. We investigated carotenoid bioaccumulation in young adult, male, wild-type (WT) mice or mice lacking CMO-II (CMO-II KO). Mice were fed an AIN-93G diet or identical diets supplemented with 10% tomato powder, 130 mg lycopene/kg diet (10% lycopene beadlets), or placebo beadlets for 4 or 30 d. Lycopene preferentially accumulated in CMO-II KO mouse tissues and serum compared with WT mouse tissues. beta-Carotene preferentially accumulated in some CMO-II KO mouse tissues compared with WT mouse tissues. Relative tissue mRNA expression of CMO-I and CMO-II was differentially expressed in mouse tissues, and CMO-II, but not CMO-I, was expressed in mouse prostate. In conclusion, the loss of CMO-II expression leads to increased serum and tissue concentrations of lycopene in tomato-fed mice. PMID- 20962154 TI - The household food insecurity access scale and an index-member dietary diversity score contribute valid and complementary information on household food insecurity in an urban West-African setting. AB - The number of urban poor is increasing quickly in West Africa, yet food security early warning systems still do not include urban areas. One reason is the lack of appropriate and internationally agreed-upon indicators to measure urban household food insecurity. Our objective was to assess the performance of the household food insecurity access scale (HFIAS) and an index-member's dietary diversity score (IDDS) to approximate the adequacy of urban households' diets. A survey was performed on a random cluster sample of 1056 households in Ouagadougou, Burkina Faso. Data on HFIAS and IDDS and 2 nonconsecutive household quantitative 24-h recalls were collected twice, in June-July and in November-December 2007. Diet adequacy was assessed through the household's mean adequacy ratio (MAR) using energy and 11 micronutrients. Structural equation modeling was used to quantify the association of each candidate indicator with the MAR and receiver-operating characteristic (ROC) analyses were performed to assess their targeting performance in predicting low or high MAR. HFIAS was negatively associated with the MAR [path coefficient (P) = -7.95 * 10(-3) +/- 1.45 * 10(-3); P < 0.001], whereas IDDS was positively associated with it (P = 5.19 * 10(-2) +/- 1.27 * 10( 2); P < 0.001). Areas under the ROC curves ranged from 0.585 to 0.661 for HFIAS and from 0.536 to 0.629 for IDDS. In conclusion, HFIAS and IDDS performed well in approximating adequacy of urban households' diets. They are informative indicators about urban food insecurity, promising for evaluation and monitoring but not for household targeting given their insufficient predictive power. PMID- 20962152 TI - Leucine supplementation of a low-protein meal increases skeletal muscle and visceral tissue protein synthesis in neonatal pigs by stimulating mTOR-dependent translation initiation. AB - Protein synthesis and eukaryotic initiation factor (eIF) activation are increased in skeletal muscle of neonatal pigs parenterally infused with amino acids. Leucine appears to be the most effective single amino acid to trigger these effects. To examine the response to enteral leucine supplementation, overnight food-deprived 5-d-old pigs were gavage fed at 0 and 60 min a: 1) low-protein diet (LP); 2) LP supplemented with leucine (LP+L) to equal leucine in the high-protein diet (HP); or 3) HP diet. Diets were isocaloric and equal in lactose. Fractional protein synthesis rates and translation initiation control mechanisms were examined in skeletal muscles and visceral tissues 90 min after feeding. Protein synthesis rates in longissimus dorsi, gastrocnemius, and masseter muscles, heart, jejunum, kidney, and pancreas, but not liver, were greater in the LP+L group compared with the LP group and did not differ from the HP group. Feeding LP+L and HP diets compared with the LP diet increased phosphorylation of mammalian target of rapamycin (mTOR), 4E-binding protein 1, ribosomal protein S6 kinase-1, and eIF4G and formation of the active eIF4E.eIF4G complex in longissimus dorsi muscle. In all tissues except liver, activation of mTOR effectors increased in pigs fed LP+L and HP vs. LP diets. Our results suggest that leucine supplementation of a low-protein meal stimulates protein synthesis in muscle and most visceral tissues to a rate similar to that achieved by feeding a high protein meal and this stimulation involves activation of mTOR downstream effectors. PMID- 20962155 TI - Specific metabolic rates of major organs and tissues across adulthood: evaluation by mechanistic model of resting energy expenditure. AB - BACKGROUND: The specific resting metabolic rates (K(i); in kcal . kg(-1 ). d(-1)) of major organs and tissues in adults were suggested by Elia (in Energy metabolism: tissue determinants and cellular corollaries. New York, NY: Raven Press, 1992) to be as follows: 200 for liver, 240 for brain, 440 for heart and kidneys, 13 for skeletal muscle, 4.5 for adipose tissue, and 12 for residual organs and tissues. However, Elia's K(i) values have never been fully evaluated. OBJECTIVES: The objectives of the present study were to evaluate the applicability of Elia's K(i) values across adulthood and to explore the potential influence of age on the K(i) values. DESIGN: A new approach was developed to evaluate the K(i) values of major organs and tissues on the basis of a mechanistic model: REE = Sigma(K(i) * T(i)), where REE is whole-body resting energy expenditure measured by indirect calorimetry, and T(i) is the mass of individual organs and tissues measured by magnetic resonance imaging. With measured REE and T(i), marginal 95% CIs for K(i) values were calculated by stepwise univariate regression analysis. An existing database of nonobese, healthy adults [n = 131; body mass index (in kg/m2) <30] was divided into 3 age groups: 21-30 y (young, n = 43), 31-50 y (middle-age, n = 51), and > 50 y (n = 37). RESULTS: Elia's K(i) values were within the range of 95% CIs in the young and middle-age groups. However, Elia's K(i) values were outside the right boundaries of 95% CIs in the >50-y group, which indicated that Elia's study overestimated K(i) values by 3% in this group. Age-adjusted K(i) values for adults aged >50 y were 194 for liver, 233 for brain, 426 for heart and kidneys, 12.6 for skeletal muscle, 4.4 for adipose tissue, and 11.6 for residuals. CONCLUSION: The general applicability of Elia's K(i) values was validated across adulthood, although age adjustment is appropriate for specific applications. PMID- 20962156 TI - Dietary glycemic load and risk of colorectal cancer in Chinese women. AB - BACKGROUND: Mixed results have been reported in recent epidemiologic studies in Western populations that have investigated the hypothesis that high glycemic load may increase the risk of colorectal cancer. This association has not been prospectively evaluated in other populations. OBJECTIVE: We examined the association of overall glycemic index and glycemic load with colorectal cancer risk in a prospective cohort of Chinese women. DESIGN: A total of 73,061 women aged 40-70 y and free of cancer at enrollment were included in this analysis. Usual dietary intake was assessed at baseline (1997-2000) and reassessed during the first follow-up (2000-2002) through in-person interviews by using a validated food-frequency questionnaire. RESULTS: During an average follow-up of 9.1 y, 475 incident colorectal cancer cases were identified. Glycemic load was not associated with colorectal cancer risk (P for trend = 0.84). The multivariable hazard ratio for the highest compared with the lowest quintile of glycemic load was 0.94 (95% CI: 0.71, 1.24). Similar results were also observed for associations with dietary glycemic index and total carbohydrate intake, and results did not vary by excluding individuals with a history of diabetes from the analysis. CONCLUSION: This prospective study, conducted in a population with a high intake of carbohydrates, provides no evidence that a high-glycemic index diet or high glycemic load is associated with an increased risk of colorectal cancer. PMID- 20962157 TI - Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption. AB - BACKGROUND: Recently, a genetic variant (rs738409; C->G) of the PNPLA3 gene was identified to be associated with increased hepatic fat deposition, and the effect was more pronounced in Hispanics. Animal models have also shown that PNPLA3 expression can be regulated by dietary carbohydrate. OBJECTIVE: The aim of this study was to examine whether the influence of PNPLA3 genotype on hepatic fat is modulated by dietary factors in Hispanic children. DESIGN: PNPLA3 was genotyped in 153 Hispanic children (75% female, ages 8-18 y) by using the TaqMan method. Dietary intake was assessed by using three 24-h dietary recalls or diet records. Visceral adipose tissue (VAT), subcutaneous abdominal adipose tissue (SAAT), and hepatic fat fraction (HFF) were assessed in multiple abdominal slices by magnetic resonance imaging. Analysis of covariance was used to assess the diet * genotype interaction in liver fat, with the following a priori covariates: sex, age, energy, VAT, and SAAT. RESULTS: HFF was influenced by a significant interaction between genotype and diet (genotype * carbohydrate, P = 0.04; genotype * total sugar, P = 0.01). HFF was positively related to carbohydrate (r = 0.31, P = 0.04) and total sugar (r = 0.34, P = 0.02) intakes but only in the GG group, independent of covariates. Dietary variables were not related to HFF in the CC or CG group or to other fat depots in all genotype groups. CONCLUSIONS: These findings suggest that Hispanic children carrying the GG genotype are susceptible to increased hepatic fat when dietary carbohydrate intake, specifically sugar, is high. Specific dietary interventions based on genetic predisposition in this population may lead to more effective therapeutic outcomes for fatty liver. This trial was registered at clinicaltrials.gov as NCT00697580, 195-1642394A1, and NCT00693511. PMID- 20962158 TI - Intakes of dietary iron and heme-iron and risk of postmenopausal breast cancer in the National Institutes of Health-AARP Diet and Health Study. AB - BACKGROUND: Intakes of dietary iron and, in particular, heme iron may increase breast cancer risk because of the prooxidant properties of iron. However, few studies have examined the association of iron and heme-iron intakes with breast cancer risk. OBJECTIVE: We assessed the association of intakes of dietary iron and heme iron with risk of postmenopausal breast cancer. DESIGN: We used data from the National Institutes of Health-AARP Diet and Health Study to assess intakes of total dietary iron, iron from meat, iron from red meat, and heme iron in relation to breast cancer risk in 116,674 postmenopausal women who completed a detailed questionnaire regarding meat preparation methods and degrees of doneness. During 6.5 y of follow-up, 3396 cases of invasive breast cancer were identified. Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% CIs. RESULTS: After adjustment for covariates, HRs for the highest compared with the lowest quintiles of intakes of total iron, iron from meat, iron from red meat, and heme iron were all close to unity, and there were no increasing trends with increasing intakes. The multivariable-adjusted HR for the highest compared with the lowest quintile of heme-iron intake was 1.01 (95% CI: 0.89, 1.14; P for trend = 0.97). In addition, no associations were seen when iron variables were stratified by possible effect modifiers or hormone receptor status. CONCLUSION: The results of this large cohort study do not support an association between iron or heme-iron intakes and postmenopausal breast cancer. PMID- 20962159 TI - A computational model to determine energy intake during weight loss. AB - BACKGROUND: Energy intake (EI) during weight loss is difficult and costly to measure accurately. OBJECTIVE: The objective was to develop and validate a computational energy balance differential equation model to determine individual EI during weight loss. DESIGN: An algorithm was developed to quantify EI during weight loss based on a validated one-dimensional model for weight change. By using data from a 24-wk calorie-restriction study, we tested the validity of the EI model against 2 criterion measures: 1) EI quantified through food provision from weeks 0-4 and 4-12 and 2) EI quantified through changes in body energy stores [measured with dual-energy X-ray absorptiometry (DXA)] and energy expenditure [measured with doubly labeled water (DLW)] from weeks 4-12 and 12-24. RESULTS: Compared with food provision, the mean (+/-SD) model errors were 41 +/- 118 kcal/d and -22 +/- 230 kcal/d from weeks 0-4 and 4-12, respectively. Compared with EI measured with DXA and DLW, the model errors were -71 +/- 272 kcal/d and 48 +/- 226 kcal/d from weeks 4-12 and 12-24, respectively. In every comparison, the mean error was never significantly different from zero (P values > 0.10). Furthermore, Bland and Altman analysis indicated that error variance did not differ significantly over amounts of EI (P values > 0.26). Almost all individual participants' values were within CI limits. CONCLUSION: The validity of the newly developed EI model was supported by experimental observations and can be used to determine an individual participant's EI during weight loss. PMID- 20962161 TI - Adherence to the Mediterranean diet, long-term weight change, and incident overweight or obesity: the Seguimiento Universidad de Navarra (SUN) cohort. AB - BACKGROUND: The Mediterranean dietary pattern might be a potential tool for the prevention of obesity. OBJECTIVES: We studied the association between adherence to 6 previously published scores used to assess the adherence to the Mediterranean diet and weight change. We also assessed the risk of relevant weight gain (>= 5 kg) or the risk of developing overweight or obesity. DESIGN: The study population included 10,376 Spanish men and women who were university graduates (mean age = 38 y) and were followed up for a mean (+/- SD) of 5.7 +/- 2.2 y. Diet was assessed at baseline with a 136-item, previously validated food frequency questionnaire. Weight was assessed at baseline and biennially during follow-up. RESULTS: Participants with the lowest adherence (<= 3 points) to the Mediterranean dietary score (MDS) proposed by Trichopoulou et al (range: 0-9; N Engl J Med 2003;348:2599-608) exhibited the highest average yearly weight gain, whereas participants with the highest (>= 6 points) adherence exhibited the lowest weight gain (adjusted difference: -0.059 kg/y; 95% CI: -0.111, -0.008 kg/y; P for trend = 0.02). This inverse association was extended to other a priori-defined MDSs. The group with the highest adherence to the MDS also showed the lowest risk of relevant weight gain (>= 5 kg) during the first 4 y of follow up (odds ratio: 0.76; 95% CI: 0.64, 0.90). CONCLUSIONS: Adherence to the Mediterranean dietary pattern is significantly associated with reduced weight gain. This dietary pattern can be recommended to slow down age-related weight gain. PMID- 20962160 TI - The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Cote d'Ivoire. AB - BACKGROUND: Iron is essential for the growth and virulence of many pathogenic enterobacteria, whereas beneficial barrier bacteria, such as lactobacilli, do not require iron. Thus, increasing colonic iron could select gut microbiota for humans that are unfavorable to the host. OBJECTIVE: The objective was to determine the effect of iron fortification on gut microbiota and gut inflammation in African children. DESIGN: In a 6-mo, randomized, double-blind, controlled trial, 6-14-y-old Ivorian children (n = 139) received iron-fortified biscuits, which contained 20 mg Fe/d, 4 times/wk as electrolytic iron or nonfortifoed biscuits. We measured changes in hemoglobin concentrations, inflammation, iron status, helminths, diarrhea, fecal calprotectin concentrations, and microbiota diversity and composition (n = 60) and the prevalence of selected enteropathogens. RESULTS: At baseline, there were greater numbers of fecal enterobacteria than of lactobacilli and bifidobacteria (P < 0.02). Iron fortification was ineffective; there were no differences in iron status, anemia, or hookworm prevalence at 6 mo. The fecal microbiota was modified by iron fortification as shown by a significant increase in profile dissimilarity (P < 0.0001) in the iron group as compared with the control group. There was a significant increase in the number of enterobacteria (P < 0.005) and a decrease in lactobacilli (P < 0.0001) in the iron group after 6 mo. In the iron group, there was an increase in the mean fecal calprotectin concentration (P < 0.01), which is a marker of gut inflammation, that correlated with the increase in fecal enterobacteria (P < 0.05). CONCLUSIONS: Anemic African children carry an unfavorable ratio of fecal enterobacteria to bifidobacteria and lactobacilli, which is increased by iron fortification. Thus, iron fortification in this population produces a potentially more pathogenic gut microbiota profile, and this profile is associated with increased gut inflammation. This trial was registered at controlled-trials.com as ISRCTN21782274. PMID- 20962162 TI - Effects of a low-glycemic load diet in overweight and obese pregnant women: a pilot randomized controlled trial. AB - BACKGROUND: The optimal diet for pregnancy that is complicated by excessive weight is unknown. OBJECTIVE: We aimed to examine the effects of a low-glycemic load (low-GL) diet in overweight and obese pregnant women. DESIGN: We randomly assigned 46 overweight or obese pregnant women to receive a low-GL or a low-fat diet. Participants received carbohydrate-rich foods, fats, and snack foods through home delivery or study visits. The primary outcome was birth weight z score. Other endpoints included infant anthropometric measurements, gestational duration, maternal weight gain, and maternal metabolic parameters. RESULTS: There were no significant differences in birth weight z score or other measures of infant adiposity between groups. However, in the low-GL compared with the low-fat group, gestational duration was longer (mean +/- SD: 39.3 +/- 1.1 compared with 37.9 +/- 3.1 wk; P = 0.05) and fewer deliveries occurred at <= 38.0 wk (13% compared with 48%, P = 0.02; with exclusion of planned cesarean deliveries: 5% compared with 53%; P = 0.002). Adjusted head circumference was greater in the low GL group (35.0 +/- 0.8 compared with 34.2 +/- 1.3 cm, P = 0.01). Women in the low GL group had smaller increases in triglycerides [median (interquartile range): 49 (19, 70) compared with 93 (34, 129) mg/dL; P = 0.03] and total cholesterol [13 (0, 36) compared with 33 (22, 56) mg/dL, P = 0.04] and a greater decrease in C reactive protein [-2.5 (-5.5, -0.7) compared with -0.4 (-1.4, 1.5) mg/dL, P = 0.007]. CONCLUSIONS: A low-GL diet resulted in longer pregnancy duration, greater infant head circumference, and improved maternal cardiovascular risk factors. Large-scale studies are warranted to evaluate whether dietary intervention during pregnancy aimed at lowering GL may be useful in the prevention of prematurity and other adverse maternal and infant outcomes. This trial is registered at clinicaltrials.gov as NCT00364403. PMID- 20962163 TI - Reinforcing the proximal anastomosis in Bentall's procedure: before or after unclamping the aorta? PMID- 20962164 TI - Could effect of smoking guide us to a new treatment option for atrial fibrillation? PMID- 20962165 TI - One-stage hybrid approach for type A acute aortic dissection repair: just because we can, should we do it? PMID- 20962166 TI - Re: Is an involved circumferential resection margin following oesphagectomy for cancer an important prognostic indicator? PMID- 20962167 TI - Aortic pseudoaneurysm: clinical suspicion is life-saving. PMID- 20962168 TI - Papillary fibroelastoma of the left heart with multiple origins? PMID- 20962169 TI - Pulmonary embolectomy in heparin-induced thrombocytopenia and thrombosis? Safety of heparin use. PMID- 20962170 TI - Prognosis of Fontan procedure outcome: are all selection criteria known? PMID- 20962171 TI - Diagnostics and intramural hematoma treatment. PMID- 20962172 TI - Management of type A aortic dissection complicated by coronary ischemia. PMID- 20962173 TI - Incarcerated maternal diaphragmatic hernia mimics hyperemesis gravidarum. A difficult differential diagnosis. PMID- 20962175 TI - Occam's razor... blunted. AB - Occam's razor, [When there are two competing theories making the same prediction, the simpler one is chosen], is a popular method in making clinical diagnosis. This theory gets 'blunted' in our case report, as our immunocompromised patient was found to have multiple non-related aetiologies for a single pathological event. PMID- 20962176 TI - Study of pain management in advanced cancer patients in a tertiary care hospital in India. AB - This observational study was carried out to investigate the pain management of 100 advanced cancer patients in a multidisciplinary academic centre. Ninety-five percent of patients reported substantial pain, 66% of patients received inadequate analgesics and only 6.32% received strong opioids. This study revealed that pain management was insufficient at the investigated institute, which could be attributed to the restricted use of strong opioids. PMID- 20962177 TI - The effects of introducing artemether-lumefantrine malaria treatment and insecticide-impregnated bed nets to an elective surgical hospital. AB - Malaria and anaemia in patients admitted for elective orthopaedic operations commonly cause delays to surgery. Our hospital has introduced artemether lumefantrine as the standard treatment for malaria in accordance with the national policy, replacing sulphadoxine-pyrimethamine. Insecticide-impregnated bed nets were also introduced throughout our wards. A retrospective audit of all new elective surgical admissions over a 12-month period was performed in order to assess the effect of these changes. The study was designed to follow an identical audit performed before their introduction. Of the 435 patients admitted, 75 (17.2%) had malaria parasites present on blood film. In these patients, surgery was significantly delayed, by a mean of 9.9 days more than the group without malaria (P < 0.001). Before the changes to malaria treatment, the mean delay was 2.2 days (P < 0.05). Six patients (1.7%) developed malaria during admission, significantly fewer than the 16 (4.3%) before the introduction of bed nets (P = 0.036). The average haemoglobin level on admission in patients with malaria parasites was 11.8 g/dL (95% confidence interval [CI] 11.4-12.2) and in those without 13.1 g/dL (95% CI: 12.9-13.3). Seventeen patients (3.9%) were admitted with a haemoglobin concentration of <10 g/dL and two (0.5%) of <8 g/dL. There were no significant delays to surgery in these patients compared to those without anaemia. The adoption of artemether-lumefantrine by our hospital significantly increased delays to surgery. The introduction of insecticide-impregnated bed nets significantly reduced the number of patients developing malaria during their hospital stay. PMID- 20962186 TI - Commentary on an article by David D. Greenberg, MD, et al.: "Allograft compared with autograft infection rates in primary anterior cruciate ligament reconstruction". PMID- 20962187 TI - Commentary on an article by B.H. Currier, MChE, et al.: "In vivo oxidation in remelted highly cross-linked retrievals". PMID- 20962188 TI - Lateral ligament repair and reconstruction restore neither contact mechanics of the ankle joint nor motion patterns of the hindfoot. AB - BACKGROUND: Ankle sprains may damage both the lateral ligaments of the hindfoot and the osteochondral tissue of the ankle joint. When nonoperative treatment fails, operative approaches are indicated to restore both native motion patterns at the hindfoot and ankle joint contact mechanics. The goal of the present study was to determine the effect of lateral ligament injury, repair, and reconstruction on ankle joint contact mechanics and hindfoot motion patterns. METHODS: Eight cadaveric specimens were tested with use of robotic technology to apply combined compressive (200-N) and inversion (4.5-Nm) loads to the hindfoot at 0 degrees and 20 degrees of plantar flexion. Contact mechanics at the ankle joint were simultaneously measured. A repeated-measures experiment was designed with use of the intact condition as control, with the other conditions including sectioned anterior talofibular and calcaneofibular ligaments, the Brostrom and Brostrom-Gould repairs, and graft reconstruction. RESULTS: Ligament sectioning decreased contact area and caused a medial and anterior shift in the center of pressure with inversion loads relative to those with the intact condition. There were no significant differences in inversion or coupled axial rotation with inversion between the Brostrom repair and the intact condition; however, medial translation of the center of pressure remained elevated after the Brostrom repair relative to the intact condition. The Gould modification of the Brostrom procedure provided additional support to the hindfoot relative to the Brostrom repair, reducing inversion and axial rotation with inversion beyond that of intact ligaments. There were no significant differences in center-of-pressure excursion patterns between the Brostrom-Gould repair and the intact ligament condition, but this repair increased contact area beyond that with the ligaments intact. Graft reconstruction more closely restored inversion motion than did the Brostrom-Gould repair at 20 degrees of plantar flexion but limited coupled axial rotation. Graft reconstruction also increased contact areas beyond the lateral ligament-deficient conditions but altered center-of-pressure excursion patterns relative to the intact condition. CONCLUSIONS: No lateral ankle ligament reconstruction completely restored native contact mechanics of the ankle joint and hindfoot motion patterns. PMID- 20962189 TI - Effect of early and delayed mechanical loading on tendon-to-bone healing after anterior cruciate ligament reconstruction. AB - BACKGROUND: Modulation of the mechanical environment may profoundly affect the healing tendon graft-bone interface. The purpose of this study was to determine how controlled axial loading after anterior cruciate ligament reconstruction affects tendon-to-bone healing. Our hypothesis was that controlled cyclic axial loading after a period of immobilization would improve tendon-to-bone healing compared with that associated with immediate axial loading or prolonged immobilization. METHODS: One hundred and fifty-six male Sprague-Dawley rats underwent anterior cruciate ligament reconstruction with use of a flexor digitorum longus autograft. A custom-designed fixture was used to apply an external fixator across the knee parallel to the anterior cruciate ligament graft. Animals were randomly assigned to be treated with immobilization (n = 36) or controlled knee distraction along the long axis of the graft to achieve approximately 2% axial strain beginning (1) immediately postoperatively (n = 36), (2) on postoperative day 4 ("early delayed loading," n = 42), or (3) on postoperative day 10 ("late delayed loading," n = 42). The animals were killed at fourteen or twenty-eight days postoperatively for biomechanical testing, micro computed tomography, and histomorphometric analysis of the bone-tendon-bone complex. Data were analyzed with use of a two-way analysis of variance followed by a post hoc Tukey test with p < 0.05 defined as significant. RESULTS: Delayed initiation of cyclic axial loading on postoperative day 10 resulted in a load to failure of the femur-anterior cruciate ligament-tibia complex at two weeks that was significantly greater than that resulting from immediate loading or prolonged immobilization of the knee (mean and standard deviation, 9.6 +/- 3.3 N versus 4.4 +/- 2.3 N and 4.4 +/- 1.5 N, respectively; p < 0.01). The new-bone formation observed in the tibial tunnels of the delayed-loading groups was significantly increased compared with that in the immediate-loading and immobilization groups at both two and four weeks postoperatively (1.47 +/- 0.11 mm(3) [postoperative day-10 group] versus 0.89 +/- 0.30 mm(3) and 0.85 +/- 0.19 mm(3), respectively, at two weeks; p < 0.003). There were significantly fewer ED1+ inflammatory macrophages and significantly more ED2+ resident macrophages at the healing tendon-bone interface in both delayed-loading groups compared with the counts in the immediate-loading and immobilization groups at two and four weeks (2.97 +/- 0.7 [postoperative day 10] versus 1.14 +/- 0.47 and 1.71 +/- 1.5 ED2+ cells, respectively, per high-power field at two weeks; p < 0.02). The numbers of osteoclasts in the delayed-loading groups were significantly lower than those in the immediate-loading and immobilization groups at two and four weeks postoperatively (0.35 +/- 0.15 [postoperative-day-10 group] versus 1.02 +/- 0.08 and 1.44 +/- 0.2 cells, respectively, per high-power field at two weeks; p < 0.01), and the delayed-loading groups also had significantly reduced interface tissue vascularity compared with the other groups (p < 0.003). CONCLUSIONS: Delayed application of cyclic axial load after anterior cruciate ligament reconstruction resulted in improved mechanical and biological parameters of tendon-to-bone healing compared with those associated with immediate loading or prolonged postoperative immobilization of the knee. PMID- 20962190 TI - Allograft compared with autograft infection rates in primary anterior cruciate ligament reconstruction. AB - BACKGROUND: Injuries to the anterior cruciate ligament are the most common surgically treated knee ligament injury. There is no consensus regarding the optimal graft choice between allograft and autograft tissue. Postoperative septic arthritis is an uncommon complication after anterior cruciate ligament reconstruction. The purpose of this study was to compare infection rates between procedures with use of allograft and autograft tissue in primary anterior cruciate ligament reconstruction. METHODS: A combined prospective and retrospective multicenter cohort study was performed over a three-year period. Graft selection was determined by the individual surgeon. Inclusion and exclusion criteria were equivalent for the two groups (allograft and autograft tissue). Data collected included demographic characteristics, clinical information, and graft details. Patients were followed for a minimum of 5.5 months postoperatively. Our primary outcome was intra-articular infection following anterior cruciate ligament reconstruction. RESULTS: Of the 1298 patients who had anterior cruciate ligament reconstruction during the study period, 861 met the criteria for inclusion and formed the final study group. Two hundred and twenty one patients (25.6%) received an autograft, and 640 (74.3%) received an allograft. There were no cases of septic arthritis in either group. The 95% confidence interval was 0% to 0.57% for the allograft group and 0% to 1.66% for the autograft group. The rate of superficial infections in the entire study group was 2.32%. We did not identify a significant difference in the rate of superficial infections between autograft and allograft reconstruction in our study group. CONCLUSIONS: While the theoretical risk of disease transmission inherent with allograft tissue cannot be eliminated, we found no increased clinical risk of infection with the use of allograft tissue compared with autologous tissue for primary anterior cruciate ligament reconstruction. PMID- 20962191 TI - In vivo oxidation in remelted highly cross-linked retrievals. AB - BACKGROUND: Elimination of free radicals to prevent oxidation has played a major role in the development and product differentiation of the latest generation of highly cross-linked ultra-high molecular weight polyethylene bearing materials. In the current study, we (1) examined oxidation in a series of retrieved remelted highly cross-linked ultra-high molecular weight polyethylene bearings from a number of device manufacturers and (2) compared the retrieval results with findings for shelf-stored control specimens. The hypothesis was that radiation cross-linked remelted ultra-high molecular weight polyethylene would maintain oxidative stability in vivo comparable with the stability during shelf storage and in published laboratory aging tests. METHODS: Fifty remelted highly cross linked ultra-high molecular weight polyethylene acetabular liners and nineteen remelted highly cross-linked ultra-high molecular weight polyethylene tibial inserts were received after retrieval from twenty-one surgeons from across the U.S. Thirty-two of the retrievals had been in vivo for two years or more. Each was measured for oxidation with use of Fourier transform infrared spectroscopy. A control series of remelted highly cross-linked ultra-high molecular weight polyethylene acetabular liners from three manufacturers was analyzed with electron paramagnetic resonance spectroscopy to measure free radical content and with Fourier transform infrared spectroscopy to measure oxidation initially and after eight to nine years of shelf storage in air. RESULTS: The never-implanted, shelf-aged controls had no measurable free-radical content initially or after eight to nine years of shelf storage. The never-implanted controls showed no increase in oxidation during shelf storage. Oxidation measurements showed measurable oxidation in 22% of the retrieved remelted highly cross-linked liners and inserts after an average of two years in vivo. CONCLUSIONS: Because never implanted remelted highly cross-linked ultra-high molecular weight polyethylene materials had no measurable free-radical concentration and no increase in oxidation during shelf storage, these materials were expected to be oxidation resistant in vivo. However, some remelted highly cross-linked ultra-high molecular weight polyethylene retrievals showed measurable oxidation after an average of more than two years in vivo. This apparent departure from widely expected behavior requires continued study of the process of in vivo oxidation of ultra-high molecular weight polyethylene materials. PMID- 20962192 TI - Metal-on-metal hip arthroplasty in patients thirty years of age or younger. AB - BACKGROUND: Total hip arthroplasty in patients younger than thirty years of age represents a long-term challenge. As polyethylene wear secondary to a high activity level could be problematic, hard-on-hard bearings have been proposed to reduce wear. The aim of this retrospective case series was to assess the clinical and radiographic results of primary metal-on-metal total hip arthroplasty in patients thirty years of age or younger. METHODS: We retrospectively studied thirty-four patients (forty-seven hips) who had undergone metal-on-metal total hip arthroplasty and analyzed the radiographic and clinical measurements after a mean duration of follow-up of 108 months (range, 62.4 to 153.6 months). The mean age of the patients at the time of surgery was twenty-five years (range, fifteen to thirty years). The diameter of the head of the femoral component was 28 mm in all hips except five, in which it was 32 mm. The metal-on-metal bearing was the same in all patients. RESULTS: The mean Merle d'Aubigne score increased from 10.6 (range, 1 to 14) to 17.1 (range, 12 to 18). No wear was found on the latest radiograph, but osteolysis was noted in three femora and two acetabula. Two revisions were performed, one because of impingement secondary to cup malorientation and the other because of acetabular loosening with osteolysis. Kaplan-Meier analysis with revision of either component as the end point revealed a ten-year survival rate of 94.5% (95% confidence interval, 80% to 98.6%). The survival rate of the femoral stem was 100%. CONCLUSIONS: These encouraging intermediate-term results indicate that hip arthroplasty with metal-on-metal bearing components may be a suitable solution for young and active patients with hip osteoarthritis or osteonecrosis of the femoral head. PMID- 20962193 TI - Interobserver reliability of radiographic measurements of contralateral feet of pediatric patients with unilateral clubfoot. AB - BACKGROUND: Radiographs have traditionally been used to describe and quantify foot deformities in infants and children. We hypothesized that the interobserver reliability of measurements obtained from radiographs of pediatric feet would be low, especially with regard to the infant foot, and that normal ranges and standard deviations would decrease in association with increasing patient age. METHODS: We retrospectively reviewed 494 radiographs of 121 patients treated for unilateral clubfoot at our institution and studied the contralateral normal foot. All anteroposterior radiographs, lateral radiographs, and lateral radiographs made with the foot in maximum dorsiflexion were analyzed by three observers, and the values were recorded. The databases created by the three observers were statistically analyzed according to five predefined age groups (birth to less than three months, three months to less than twelve months, twelve months to less than three years, three years to less than seven years, and seven years to less than fourteen years). RESULTS: The anteroposterior talocalcaneal angle was rated as having good interobserver reliability (i.e., an intraclass correlation coefficient of 0.61 to 0.80) for all patients in each age group. Other angles that were associated with good interobserver reliability were the anteroposterior calcaneus-fifth metatarsal angle in the twelve months to less than three-year age group, the three-year to less than seven-year age group, and the seven-year to less than fourteen-year age group; the lateral talocalcaneal angle in the three year to less than seven-year age group; the lateral tibiotalar angle in the three year to less than seven-year age group; and the lateral talus-first metatarsal angle in the seven-year to less than fourteen-year age group. All other angles were rated as having very good interobserver reliability (i.e., an intraclass correlation coefficient of 0.81 to 1). The mean difference and the maximum difference among the observers decreased for all angles in nearly all age groups. CONCLUSIONS: Interobserver reliability with regard to the radiographic measurement of pediatric feet was higher than expected, although measurement discrepancies can be as great as 30 degrees with the infant foot. Interobserver reliability tended to improve with increasing patient age. The standard deviation showed a trend toward a decrease as patient age increased, although the trend was less notable than expected. PMID- 20962194 TI - Prevalence of cam-type femoroacetabular impingement morphology in asymptomatic volunteers. AB - BACKGROUND: Femoroacetabular impingement is a cause of hip pain in adults and is a possible precursor of osteoarthritis, with the cam type of impingement being the most common. The purpose of this study was to determine the prevalence of cam type morphology of the hip in asymptomatic patients. METHODS: Two hundred asymptomatic volunteers with no prior hip surgery or childhood hip problems underwent magnetic resonance imaging targeted to both hips. The subjects were examined at the time of magnetic resonance imaging for internal rotation of the hips at 90 degrees of hip flexion and for a positive impingement sign. The contour of the femoral head-neck junction was quantified with use of the alpha angle. A value of >50.5 degrees was considered positive for cam morphology. Measurements were performed independently by two musculoskeletal radiologists. RESULTS: The mean age of the individuals was 29.4 years (range, 21.4 to 50.6 years); 79% were white, and 55.5% were women. The mean alpha angle anteriorly at the three o'clock position was 40.9 degrees +/- 7.0 degrees on the right and 40.6 degrees +/- 7.1 degrees on the left, whereas the mean alpha angle anterosuperiorly at the 1:30 position was 50.2 degrees +/- 8.0 degrees on the right and 50.1 degrees +/- 8.3 degrees on the left. Fourteen percent of the volunteers had at least one hip with cam morphology: 10.5% had an elevated alpha angle on either the right or the left side, and 3.5% had the deformity in both hips. Seventy-nine percent (twenty-two) of twenty-eight individuals who had an elevated alpha angle were men, and 21% (six) were women. Individuals with an elevated alpha angle on at least one side tended to be male (p < 0.001), with 24.7% (twenty-two) of eighty-nine men having cam morphology compared with only 5.4% (six) of 111 women. CONCLUSIONS: The prevalence of cam-type femoroacetabular impingement deformity is higher in men as well as in individuals with decreased internal rotation. Defining what represents a normal head-neck contour is important for establishing treatment strategies in patients presenting with prearthritic hip pain. PMID- 20962195 TI - Limitations of the Knee Society Score in evaluating outcomes following revision total knee arthroplasty. AB - BACKGROUND: Traditionally, the results of revision total knee arthroplasty have been determined with use of surgeon-based measures such as the Knee Society rating system. Recently, outcome and quality-of-life measures have shifted toward a greater emphasis on patient-based evaluation. The aim of our study was to determine the validity and responsiveness of the Knee Society rating system compared with the Short Form-36 health survey (SF-36), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and a four-question 4-point Likert scale satisfaction questionnaire following revision total knee arthroplasty. METHODS: A total of 152 patients underwent revision total knee arthroplasty at our institution, between August 2003 and January 2007, and had a two-year follow-up evaluation after revision surgery. The SF-36, WOMAC, Knee Society rating system, and satisfaction scores were completed preoperatively and postoperatively. Spearman correlation coefficients were calculated to determine the degree of correlation for each outcome scale. The SF-36, WOMAC, and patient satisfaction were correlated with the Knee Society rating system. RESULTS: Both before and after surgery, the correlation among items of the Knee Society rating system displayed low to negligible levels of association. The Knee Society rating system pain score showed modest levels of convergent construct validity with the WOMAC and SF-36. However, the Knee Society functional score displayed negligible to low correlation with its WOMAC functional counterpart preoperatively. The Knee Society pain and functional scores, respectively, showed marked and moderate association with satisfaction. The change in the Knee Society pain and functional scores had moderate association with the SF-36 and WOMAC counterparts, except low correlation was displayed between the pain scores for the Knee Society rating system and the SF-36. The Knee Society rating system pain score was found to be the most responsive of the measures with a standardized response mean of 1.6, whereas the Knee Society rating system functional score was found to be the least responsive at 0.7. CONCLUSIONS: Currently, there is no so-called gold standard that optimally reflects the status of the knee, as well as the patient, prior to and following revision total knee arthroplasty. Ideally, numerous assessment scales should be administered to the patient in order to accurately reflect the patient characteristics for the purpose of academic study, but from a practical standpoint, this may not be feasible. We encourage further research and development of a simple and concise standardized questionnaire for use before and after revision total knee arthroplasty. PMID- 20962196 TI - Effect of insurance status on the rate of surgery following a meniscal tear. AB - BACKGROUND: Uninsured and underinsured Americans face barriers to access to medical care. The objective of this study was to characterize the effect of insurance status on whether patients with a torn meniscus proceed to elective arthroscopic knee surgery. METHODS: The records from January 2003 through April 2006 at a single academic orthopaedic surgery institution in Massachusetts were retrospectively reviewed to identify patients diagnosed with a meniscal tear and to determine whether surgery had been performed within six months after the diagnosis. Six categories of insurance were identified: private insurance, Workers' Compensation, Medicare, Medicaid, Uncompensated Care Pool, and self pay. A comparison of the proportions of insured and uninsured patients who underwent surgery was the primary outcome measure. RESULTS: A total of 1127 patients were identified, and 446 (40%) of them underwent surgery within six months after an office visit. The patients with and without surgery had similar age and sex distributions. When patients were divided, according to their insurance status, into insured and uninsured groups, no significant difference was found in the rate of surgery (p = 0.23). However, subgroup analysis revealed significant differences among the six insurance categories. Logistic regression analysis showed that patients in the self-pay group had a lower rate of surgery than those with private insurance (odds ratio, 0.33; 95% confidence interval, 0.14 to 0.75; p = 0.008), whereas patients receiving Workers' Compensation (odds ratio, 1.93; 95% confidence interval, 1.05 to 3.55; p = 0.034) and those receiving Medicaid (odds ratio, 1.63; 95% confidence interval, 1.09 to 2.42; p = 0.016) had higher surgical rates than those with private insurance. CONCLUSIONS: The rate of elective arthroscopic knee surgery for meniscal tears varied significantly for some insurance categories at this single academic institution in Massachusetts. Further work is necessary to clarify the patient and surgeon factors influencing these disparities in clinical decision-making. PMID- 20962197 TI - Proximal patellar quadricepsplasty realignment during total knee arthroplasty for irreducible congenital dislocation of the patella: a report of two cases. PMID- 20962198 TI - Pirogoff amputation for foot trauma: an unusual amputation level: a case report. PMID- 20962199 TI - American Academy of Orthopaedic Surgeons clinical practice guideline on treatment of Achilles tendon rupture. PMID- 20962200 TI - Surgical management of articular cartilage defects of the knee. PMID- 20962201 TI - What's new in orthopaedic research. PMID- 20962202 TI - Chronic hypoxia increases insulin-stimulated glucose uptake in mouse soleus muscle. AB - People living at high altitude appear to have lower blood glucose levels and decreased incidence of diabetes. Faster glucose uptake and increased insulin sensitivity are likely explanations for these findings: skeletal muscle is the largest glucose sink in the body, and its adaptation to the hypoxia of altitude may influence glucose uptake and insulin sensitivity. This study tested the hypothesis that chronic normobaric hypoxia increases insulin-stimulated glucose uptake in soleus muscles and decreases plasma glucose levels. Adult male C57BL/6J mice were kept in normoxia [fraction of inspired O2 = 21% (Control)] or normobaric hypoxia [fraction of inspired O2 = 10% (Hypoxia)] for 4 wk. Then blood glucose and insulin levels, in vitro muscle glucose uptake, and indexes of insulin signaling were measured. Chronic hypoxia lowered blood glucose and plasma insulin [glucose: 14.3 +/- 0.65 mM in Control vs. 9.9 +/- 0.83 mM in Hypoxia (P < 0.001); insulin: 1.2 +/- 0.2 ng/ml in Control vs. 0.7 +/- 0.1 ng/ml in Hypoxia (P < 0.05)] and increased insulin sensitivity determined by homeostatic model assessment 2 [21.5 +/- 3.8 in Control vs. 39.3 +/- 5.7 in Hypoxia (P < 0.03)]. There was no significant difference in basal glucose uptake in vitro in soleus muscle (1.59 +/- 0.24 and 1.71 +/- 0.15 MUmol.g-1.h-1 in Control and Hypoxia, respectively). However, insulin-stimulated glucose uptake was 30% higher in the soleus after 4 wk of hypoxia than Control (6.24 +/- 0.23 vs. 4.87 +/- 0.37 MUmol.g-1.h-1, P < 0.02). Muscle glycogen content was not significantly different between the two groups. Levels of glucose transporters 4 and 1, phosphoinositide 3-kinase, glycogen synthase kinase 3, protein kinase B/Akt, and AMP-activated protein kinase were not affected by chronic hypoxia. Akt phosphorylation following insulin stimulation in soleus muscle was significantly (25%) higher in Hypoxia than Control (P < 0.05). Neither glycogen synthase kinase 3 nor AMP activated protein kinase phosphorylation changed after 4 wk of hypoxia. These results demonstrate that the adaptation of skeletal muscles to chronic hypoxia includes increased insulin-stimulated glucose uptake. PMID- 20962203 TI - Allosteric modulation by S-nitrosation in the low-O2 affinity myoglobin from rainbow trout. AB - Myoglobin (Mb) serves in the facilitated diffusion and storage of O2 in heart and skeletal muscle, where it also regulates O2 consumption via nitric oxide (NO) scavenging or generation. S-nitrosation at reactive cysteines may generate S nitroso Mb (Mb-SNO) and contribute further to NO homeostasis. In being a monomer, Mb is commonly believed to lack allosteric control of heme reactivity. Here, we test whether in rainbow trout, a fast swimmer living in well-aerated water, the Mb-O2 affinity is regulated by ionic cofactors and S-nitrosation. O2 equilibria showed the lowest O2 affinity ever reported among vertebrate Mbs (P50 = 4.92 +/- 0.29 mmHg, 25 degrees C), a small overall heat of oxygenation (DeltaH = -12.03 kcal/mol O2), and no effect of chloride, pH, or lactate. Although the reaction with 4,4'-dithiodipyridine (4-PDS) showed 1.3-1.9 accessible thiols per heme, the reaction of Mb with S-nitroso cysteine (Cys-NO) and S-nitrosoglutathione (GSNO) to generate Mb-SNO yielded ~0.3-0.6 and ~0.1 SNO/heme, respectively, suggesting S nitrosation at only one cysteine (likely Cys10). At ~60% S-nitrosation, trout Mb SNO showed a higher O2 affinity (P50 = 2.23 +/- 0.19 mmHg, 20 degrees C) than unmodified Mb (3.36 +/- 0.11 mmHg, 20 degrees C). Total SNO levels measured by chemiluminescence in trout myocardial preparations decreased after hypoxia, but not significantly, indicating that transnitrosation reactions between thiols may occur in vivo. Our data reveal a novel, S-nitrosation-dependent allosteric mechanism in this low-affinity Mb that may contribute to targeted O2-linked SNO release in the hypoxic fish heart and be of importance in preserving cardiac function during intense exercise. PMID- 20962204 TI - Regulation of sFlt-1 and VEGF secretion by adenosine under hypoxic conditions in rat placental villous explants. AB - The role of adenosine in the regulation of cardiovascular function has long been acknowledged, but only recently has its importance in angiogenesis been appreciated, most notably, through its direct regulation of the proangiogenic growth factor, VEGF. Recent work has established that proangiogenic and antiangiogenic factors, specifically VEGF and and the soluble VEGF receptor fms like tyrosine kinase-1 (sFlt-1), are directly influenced by hypoxia in placental ischemia. While adenosine has been reported to be an important regulator of VEGF in vascular tissue, the importance of adenosine in regulating VEGF and sFlt-1 in placental tissue is unclear. Here, we have investigated the role of adenosine in the secretion of VEGF and the antiangiogenic protein sFlt-1 in placental villous explants. Under normoxic conditions (6% oxygen), the nonspecific adenosine receptor antagonist, 8-sulphophenyltheophylline (8-SPT) had no effect on either VEGF (P = 0.38) or sFlt-1 (P = 0.56) secretion. However, under hypoxic conditions (1% oxygen), 8-SPT attenuated the increase in the secretion of both VEGF and sFlt 1 (P < 0.05 and P < 0.005, respectively). Exogenous and the adenosine transporter inhibitor dipyridamole (which increases extracellular levels of adenosine) showed differential effects under normoxic conditions: sFlt-1 levels in media increased significantly (P < 0.05), whereas VEGF was unaffected (P = 0.67 and P = 0.19, respectively). These data indicate that extracellular adenosine can regulate VEGF and sFlt-1 secretion in the hypoxic placenta and could, therefore, control the balance of these competing angiogenic factors in diseases characterized by placental ischemia. PMID- 20962205 TI - Acute in vitro hypoxia and high-altitude (4,559 m) exposure decreases leukocyte oxygen consumption. AB - Hypoxia impairs metabolic functions by decreasing activity and expression of ATP consuming processes. To separate hypoxia from systemic effects, we tested whether hypoxia at high altitude affects basal and PMA-stimulated leukocyte metabolism and how this compares to acute (15 min) and 24 h of in vitro hypoxia. Leukocytes were prepared at low altitude and ~24 h after arrival at 4559 m. Mitochondrial oxygen consumption (JO2) was measured by respirometry, oxygen radicals by electron spin resonance spectroscopy, both at a Po2 = 100 mmHg (JO2,100) and 20 mmHg (JO2,20). Acute hypoxia of leukocytes decreased JO2 at low altitude. Exposure to high altitude decreased JO2,100, whereas JO2,20 was not affected. Acute hypoxia of low-altitude samples decreased the activity of complexes I, II, and III. At high altitude, activity of complexes I and III were decreased when measured in normoxia. Stimulation of leukocytes with PMA increased JO2,100 at low (twofold) and high altitude (five-fold). At both locations, PMA-stimulated JO2 was decreased by acute hypoxia. Basal and PMA-stimulated reactive oxygen species (ROS) production were unchanged at high altitude. Separate in vitro experiments performed at low altitude show that ~75% of PMA-induced increase in JO2 was due to increased extra-mitochondrial JO2 (JO2(,res); in the presence of rotenone and antimycin A). JO2(,res) was doubled by PMA. Acute hypoxia decreased basal JO2(,res) by ~70% and PMA-stimulated JO2(,res) by about 50% in cells cultured in normoxia and hypoxia (1.5% O2; 24 h). Conversely, 24 h in vitro hypoxia decreased mitochondrial JO2,100 and JO2,20, extra-mitochondrial, basal, and PMA-stimulated JO2 were not affected. These results show that 24 h of high altitude but not 24 h in vitro hypoxia decreased basal leukocyte metabolism, whereas PMA-induced JO2 and ROS formation were not affected, indicating that prolonged high-altitude hypoxia impairs mitochondrial metabolism but does not impair respiratory burst. In contrast, acute hypoxia impairs respiratory burst at either altitude. PMID- 20962206 TI - CX43 expression, phosphorylation, and distribution in the normal and autoimmune orchitic testis with a look at gap junctions joining germ cell to germ cell. AB - Spermatogenesis requires connexin 43 (Cx43).This study examines normal gene transcription, translation, and phosphorylation of Cx43 to define its role on germ cell growth and Sertoli cell's differentiation, and identifies abnormalities arising from spontaneous autoimmune orchitis (AIO) in mink, a seasonal breeder and a natural model for autoimmunity. Northern blot analysis detected 2.8- and a 3.7-kb Cx43 mRNA bands in seminiferous tubule-enriched fractions. Cx43 mRNA increased in seminiferous tubule-enriched fractions throughout development and then seasonally with the completion of spermatogenesis. Cx43 protein levels increased transiently during the colonization of the tubules by the early-stage spermatocytes. Cx43 phosphorylated (PCx43) and nonphosphorylated (NPCx43) in Ser368 decreased during the periods of completion of meiosis and Sertoli cell differentiation, while Cx43 mRNA remained elevated throughout. PCx43 labeled chiefly the plasma membrane except by stage VII when vesicles were also labeled in Sertoli cells. Vesicles and lysosomes in Sertoli cells and the Golgi apparatus in the round spermatids were NPCx43 positive. A decrease in Cx43 gene expression was matched by a Cx43 protein increase in the early, not the late, phase of AIO. Total Cx43 and PCx43 decreased with the advance of orchitis. The study makes a novel finding of gap junctions connecting germ cells. The data indicate that Cx43 protein expression and phosphorylation in Ser368 are stage-specific events that may locally influence the acquisition of meiotic competence and the Sertoli cell differentiation in normal testis. AIO modifies Cx43 levels, suggesting changes in Cx43-mediated intercommunication and spermatogenic activity in response to cytokines imbalances in Sertoli cells. PMID- 20962207 TI - Causal relationships between heart period and systolic arterial pressure during graded head-up tilt. AB - In physiological conditions, heart period (HP) affects systolic arterial pressure (SAP) through diastolic runoff and Starling's law, but, the reverse relation also holds as a result of the continuous action of baroreflex control. The prevailing mechanism sets the dominant temporal direction in the HP-SAP interactions (i.e., causality). We exploited cross-conditional entropy to assess HP-SAP causality. A traditional approach based on phases was applied for comparison. The ability of the approach to detect the lack of causal link from SAP to HP was assessed on 8 short-term (STHT) and 11 long-term heart transplant (LTHT) recipients (i.e., less than and more than 2 yr after transplantation, respectively). In addition, spontaneous HP and SAP variabilities were extracted from 17 healthy humans (ages 21-36 yr, median age 29 yr; 9 females) at rest and during graded head-up tilt. The tilt table inclinations ranged from 15 to 75 degrees and were changed in steps of 15 degrees . All subjects underwent recordings at every step in random order. The approach detected the lack of causal relation from SAP to HP in STHT recipients and the gradual restoration of the causal link from SAP to HP with time after transplantation in the LTHT recipients. The head-up tilt protocol induced the progressive shift from the prevalent causal direction from HP to SAP to the reverse causality (i.e., from SAP to HP) with tilt table inclination in healthy subjects. Transformation of phases into time shifts and comparison with baroreflex latency supported this conclusion. The proposed approach is highly efficient because it does not require the knowledge of baroreflex latency. The dependence of causality on tilt table inclination suggests that "spontaneous" baroreflex sensitivity estimated using noncausal methods (e.g., spectral and cross-spectral approaches) is more reliable at the highest tilt table inclinations. PMID- 20962209 TI - Assessment of the IgA immunoassay diagnostic potential of the Mycobacterium tuberculosis MT10.3-MPT64 fusion protein in tuberculous pleural fluid. AB - Pleural tuberculosis (PL-TB) remains difficult to diagnose. An enzyme-linked immunosorbent assay (ELISA) was developed based on a construction containing the fusion of the Rv3019c (MT10.3) and Rv1980c (MPT64) gene sequences, and its performance was evaluated in an area where TB is endemic. A total of 92 pleural fluid (PF) samples at serial dilutions of 1:50 to 1:800 were included in the ELISA IgA MT10.3-MPT64 evaluation: 70 from TB patients and 22 from patients with other pleurisies. Confirmation of the expression and subsequent purification of the protein was made by SDS-PAGE and Western blot assays, resulting in a 36-kDa protein. ELISA IgA MT10.3-MPT64 showed sensitivities of 61.4%, 58.6%, 62.9%, 67.1%, and 70% at each PF dilution, respectively. The cumulative results of all dilutions increased sensitivity to 81.4% without jeopardizing specificity. Similar results were also obtained at the combined dilutions of 1:50, 1:200, and 1:800 or 1:50 plus 1:800 dilutions (80%). The overall sensitivity of the reference test, i.e., histopathological examination, was 74%. But, via the ELISA IgA MT10.3-MPT64 test, sensitivity was high for specimens with a negative culture (23/27; 85.2%) or nonspecific histopathology (17/18; 94.4%). Our findings demonstrated the promising use of this test as an adjunct in PL-TB diagnoses, particularly in cases with lower bacterial loads and false-negative results in the reference tests, since the new test includes such important features as quick and easy application, high sensitivity and, perhaps most importantly, affordability, which is so crucial for its widespread use in developing countries. PMID- 20962210 TI - Contemporary seasonal influenza A (H1N1) virus infection primes for a more robust response to split inactivated pandemic influenza A (H1N1) Virus vaccination in ferrets. AB - Human influenza pandemics occur when influenza viruses to which the population has little or no immunity emerge and acquire the ability to achieve human-to human transmission. In April 2009, cases of a novel H1N1 influenza virus in children in the southwestern United States were reported. It was retrospectively shown that these cases represented the spread of this virus from an ongoing outbreak in Mexico. The emergence of the pandemic led to a number of national vaccination programs. Surprisingly, early human clinical trial data have shown that a single dose of nonadjuvanted pandemic influenza A (H1N1) 2009 monovalent inactivated vaccine (pMIV) has led to a seroprotective response in a majority of individuals, despite earlier studies showing a lack of cross-reactivity between seasonal and pandemic H1N1 viruses. Here we show that previous exposure to a contemporary seasonal H1N1 influenza virus and to a lesser degree a seasonal influenza virus trivalent inactivated vaccine is able to prime for a higher antibody response after a subsequent dose of pMIV in ferrets. The more protective response was partially dependent on the presence of CD8(+) cells. Two doses of pMIV were also able to induce a detectable antibody response that provided protection from subsequent challenge. These data show that previous infection with seasonal H1N1 influenza viruses likely explains the requirement for only a single dose of pMIV in adults and that vaccination campaigns with the current pandemic influenza vaccines should reduce viral burden and disease severity in humans. PMID- 20962211 TI - An intranasally delivered Toll-like receptor 7 agonist elicits robust systemic and mucosal responses to Norwalk virus-like particles. AB - Norwalk virus (NV) is an enteric pathogen from the genus Norovirus and a major cause of nonbacterial gastroenteritis in humans. NV virus-like particles (VLPs) are known to elicit systemic and mucosal immune responses when delivered nasally; however, the correlates of immune protection are unknown, and codelivery with a safe and immunogenic mucosal adjuvant may enhance protective anti-NV immune responses. Resiquimod (R848), an imidazoquinoline-based Toll-like receptor 7 and/or 8 (TLR7/8) agonist, is being evaluated as an adjuvant in FDA-approved clinical vaccine trials. As such, we evaluated the adjuvant activity of two imidazoquinoline-based TLR7 and TLR7/8 agonists when codelivered intranasally with plant-derived NV VLPs. We also compared the activity of these agonists to the gold standard mucosal adjuvant, cholera toxin (CT). Our results indicate that codelivery with the TLR7 agonist, gardiquimod (GARD), induces NV VLP-specific serum IgG and IgG isotype responses and mucosal IgA responses in the gastrointestinal, respiratory, and reproductive tracts that are superior to those induced by R848 and comparable to those induced by the mucosal adjuvant CT. This study supports the continued investigation of GARD as a mucosal adjuvant for NV VLPs and possible use for other VLP-based vaccines for which immune responses at distal mucosal sites (e.g., respiratory and reproductive tracts) are desired. PMID- 20962212 TI - Influenza and meningococcal vaccinations are effective in healthy subjects treated with the interleukin-1 beta-blocking antibody canakinumab: results of an open-label, parallel group, randomized, single-center study. AB - The objective of this study was to evaluate the efficacy of influenza and meningococcal vaccines in healthy subjects exposed to the anti-interleukin-1beta (anti-IL-1beta) monoclonal antibody canakinumab. This was an open-label, parallel group, randomized, single-center study of healthy subjects (aged 18 to 45 years). At baseline, antibody (Ab) titers were measured and subjects were randomized (1:1) to a single 300-mg canakinumab dose administered subcutaneously (s.c.) or received no treatment (control group). After 2 weeks, subjects were treated with inactivated, unadjuvanted influenza and conjugated group C meningococcal (MenC) vaccines, administered intramuscularly (i.m.). The primary efficacy variable was the response (>= 2-fold increase in Ab titer in >= 2 of 3 influenza virus strains) after 4 weeks in subjects treated with canakinumab compared to the control group. Secondary efficacy variables were the antibody response to vaccines at different thresholds and time points. Fifty-one of 112 subjects screened were randomized to canakinumab (n = 25) or the control group (n = 26). Antibody responses to vaccinations measured against different influenza virus strains and one MenC strain at 4 weeks were comparable in the canakinumab and control groups. The primary efficacy variable, the response to influenza vaccination (>= 2-fold increase in Ab titer in >= 2 of 3 serotypes) at 4 weeks, was shown in 24/25 subjects in the canakinumab group compared to 25/25 subjects in the control group. Antibody responses remained comparable in the two groups at the different time points assessed. Headache was the most frequently reported adverse event. No deaths or serious adverse events were reported during the study. We concluded that a single dose of 300 mg canakinumab s.c. does not affect the induction or persistence of antibody responses after vaccination with unadjuvanted influenza or alum-adjuvanted MenC vaccines in healthy subjects. PMID- 20962213 TI - Occipital-parietal network prepares reflexive saccades. PMID- 20962208 TI - Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine, cognitive, and behavioral functions. AB - Central noradrenergic (NA) signaling is broadly implicated in behavioral and physiological processes related to attention, arousal, motivation, learning and memory, and homeostasis. This review focuses on the A2 cell group of NA neurons, located within the hindbrain dorsal vagal complex (DVC). The intra-DVC location of A2 neurons supports their role in vagal sensory-motor reflex arcs and visceral motor outflow. A2 neurons also are reciprocally connected with multiple brain stem, hypothalamic, and limbic forebrain regions. The extra-DVC connections of A2 neurons provide a route through which emotional and cognitive events can modulate visceral motor outflow and also a route through which interoceptive feedback from the body can impact hypothalamic functions as well as emotional and cognitive processing. This review considers some of the hallmark anatomical and chemical features of A2 neurons, followed by presentation of evidence supporting a role for A2 neurons in modulating food intake, affective behavior, behavioral and physiological stress responses, emotional learning, and drug dependence. Increased knowledge about the organization and function of the A2 cell group and the neural circuits in which A2 neurons participate should contribute to a better understanding of how the brain orchestrates adaptive responses to the various threats and opportunities of life and should further reveal the central underpinnings of stress-related physiological and emotional dysregulation. PMID- 20962214 TI - The influence of natural scene dynamics on auditory cortical activity. AB - The efficient cortical encoding of natural scenes is essential for guiding adaptive behavior. Because natural scenes and network activity in cortical circuits share similar temporal scales, it is necessary to understand how the temporal structure of natural scenes influences network dynamics in cortical circuits and spiking output. We examined the relationship between the structure of natural acoustic scenes and its impact on network activity [as indexed by local field potentials (LFPs)] and spiking responses in macaque primary auditory cortex. Natural auditory scenes led to a change in the power of the LFP in the 2 9 and 16-30 Hz frequency ranges relative to the ongoing activity. In contrast, ongoing rhythmic activity in the 9-16 Hz range was essentially unaffected by the natural scene. Phase coherence analysis showed that scene-related changes in LFP power were at least partially attributable to the locking of the LFP and spiking activity to the temporal structure in the scene, with locking extending up to 25 Hz for some scenes and cortical sites. Consistent with distributed place and temporal coding schemes, a key predictor of phase locking and power changes was the overlap between the spectral selectivity of a cortical site and the spectral structure of the scene. Finally, during the processing of natural acoustic scenes, spikes were locked to LFP phase at frequencies up to 30 Hz. These results are consistent with an idea that the cortical representation of natural scenes emerges from an interaction between network activity and stimulus dynamics. PMID- 20962215 TI - A dominant mutation in a neuronal acetylcholine receptor subunit leads to motor neuron degeneration in Caenorhabditis elegans. AB - Inappropriate or excessive activation of ionotropic receptors can have dramatic consequences for neuronal function and, in many instances, leads to cell death. In Caenorhabditis elegans, nicotinic acetylcholine receptor (nAChR) subunits are highly expressed in a neural circuit that controls movement. Here, we show that heteromeric nAChRs containing the acr-2 subunit are diffusely localized in the processes of excitatory motor neurons and act to modulate motor neuron activity. Excessive signaling through these receptors leads to cell-autonomous degeneration of cholinergic motor neurons and paralysis. C. elegans double mutants lacking calreticulin and calnexin-two genes previously implicated in the cellular events leading to necrotic-like cell death (Xu et al. 2001)-are resistant to nAChR mediated toxicity and possess normal numbers of motor neuron cell bodies. Nonetheless, excess nAChR activation leads to progressive destabilization of the motor neuron processes and, ultimately, paralysis in these animals. Our results provide new evidence that chronic activation of ionotropic receptors can have devastating degenerative effects in neurons and reveal that ion channel-mediated toxicity may have distinct consequences in neuronal cell bodies and processes. PMID- 20962216 TI - The expression of TAG-1 in glial cells is sufficient for the formation of the juxtaparanodal complex and the phenotypic rescue of tag-1 homozygous mutants in the CNS. AB - Myelinated fibers are organized into specialized domains that ensure the rapid propagation of action potentials and are characterized by protein complexes underlying axoglial interactions. TAG-1 (Transient Axonal Glycoprotein-1), a cell adhesion molecule of the Ig superfamily, is expressed by neurons as well as by myelinating glia. It is essential for the molecular organization of myelinated fibers as it maintains the integrity of the juxtaparanodal region through its interactions with Caspr2 and the voltage-gated potassium channels (VGKCs) on the axolemma. Since TAG-1 is the only known component of the juxtaparanodal complex expressed by the glial cell, it is important to clarify its role in the molecular organization of juxtaparanodes. For this purpose, we generated transgenic mice that exclusively express TAG-1 in oligodendrocytes and lack endogenous gene expression (Tag-1(-/-);plp(Tg(rTag-1))). Phenotypic analysis clearly demonstrates that glial TAG-1 is sufficient for the proper organization and maintenance of the juxtaparanodal domain in the CNS. Biochemical analysis shows that glial TAG-1 physically interacts with Caspr2 and VGKCs. Ultrastructural and behavioral analysis of Tag-1(-/-);plp(Tg(rTag-1)) mice shows that the expression of glial TAG-1 is sufficient to restore the axonal and myelin deficits as well as the behavioral defects observed in Tag-1(-/-) animals. Together, these data highlight the pivotal role of myelinating glia on axonal domain differentiation and organization. PMID- 20962217 TI - GABAA receptor trafficking is regulated by protein kinase C(epsilon) and the N ethylmaleimide-sensitive factor. AB - Disturbances in GABA(A) receptor trafficking contribute to several neurological and psychiatric disorders by altering inhibitory neurotransmission. Identifying mechanisms that regulate GABA(A) receptor trafficking could lead to better understanding of disease pathogenesis and treatment. Here, we show that protein kinase Cepsilon (PKCepsilon) regulates the N-ethylmaleimide-sensitive factor (NSF), an ATPase critical for membrane fusion events, and thereby promotes the trafficking of GABA(A) receptors. Activation of PKCepsilon decreased cell surface expression of GABA(A) receptors and attenuated GABA(A) currents. Activated PKCepsilon associated with NSF, phosphorylated NSF at serine 460 and threonine 461, and increased NSF ATPase activity, which was required for GABA(A) receptor downregulation. These findings identify new roles for NSF and PKCepsilon in regulating synaptic inhibition through downregulation of GABA(A) receptors. Reducing NSF activity by inhibiting PKCepsilon could help restore synaptic inhibition in disease states in which it is impaired. PMID- 20962218 TI - Silencing of CDK5 reduces neurofibrillary tangles in transgenic alzheimer's mice. AB - Alzheimer's disease is a major cause of dementia for which treatments remain unsatisfactory. Cyclin-dependent kinase 5 (CDK5) is a relevant kinase that has been hypothesized to contribute to the tau pathology. Several classes of chemical inhibitors for CDK5 have been developed, but they generally lack the specificity to distinguish among various ATP-dependent kinases. Therefore, the efficacy of these compounds when tested in animal models cannot definitively be attributed to an effect on CDK5. However, RNA interference (RNAi) targeting of CDK5 is specific and can be used to validate CDK5 as a possible treatment target. We delivered a CDK5 RNAi by lentiviral or adenoassociated viral vectors and analyzed the results in vitro and in vivo. Silencing of CDK5 reduces the phosphorylation of tau in primary neuronal cultures and in the brain of wild-type C57BL/6 mice. Furthermore, the knockdown of CDK5 strongly decreased the number of neurofibrillary tangles in the hippocampi of triple-transgenic mice (3*Tg-AD mice). Our data suggest that this downregulation may be attributable to the reduction of the CDK5 availability in the tissue, without affecting the CDK5 kinase activity. In summary, our findings validate CDK5 as a reasonable therapeutic target for ameliorating tau pathology. PMID- 20962219 TI - Consolidating the effects of waking and sleep on motor-sequence learning. AB - Sleep is widely believed to play a critical role in memory consolidation. Sleep dependent consolidation has been studied extensively in humans using an explicit motor-sequence learning paradigm. In this task, performance has been reported to remain stable across wakefulness and improve significantly after sleep, making motor-sequence learning the definitive example of sleep-dependent enhancement. Recent work, however, has shown that enhancement disappears when the task is modified to reduce task-related inhibition that develops over a training session, thus questioning whether sleep actively consolidates motor learning. Here we use the same motor-sequence task to demonstrate sleep-dependent consolidation for motor-sequence learning and explain the discrepancies in results across studies. We show that when training begins in the morning, motor-sequence performance deteriorates across wakefulness and recovers after sleep, whereas performance remains stable across both sleep and subsequent waking with evening training. This pattern of results challenges an influential model of memory consolidation defined by a time-dependent stabilization phase and a sleep-dependent enhancement phase. Moreover, the present results support a new account of the behavioral effects of waking and sleep on explicit motor-sequence learning that is consistent across a wide range of tasks. These observations indicate that current theories of memory consolidation that have been formulated to explain sleep dependent performance enhancements are insufficient to explain the range of behavioral changes associated with sleep. PMID- 20962220 TI - The contribution of blood lactate to brain energy metabolism in humans measured by dynamic 13C nuclear magnetic resonance spectroscopy. AB - To determine whether plasma lactate can be a significant fuel for human brain energy metabolism, infusions of [3-(13)C]lactate and (1)H-(13)C polarization transfer spectroscopy were used to detect the entry and utilization of lactate. During the 2 h infusion study, (13)C incorporation in the amino acid pools of glutamate and glutamine were measured with a 5 min time resolution. With a plasma concentration ([Lac](P)) being in the 0.8-2.8 mmol/L range, the tissue lactate concentration ([Lac](B)) was assessed as well as the fractional contribution of lactate to brain energy metabolism (CMRlac). From the measured relationship between unidirectional lactate influx (V(in)) and plasma and brain lactate concentrations, lactate transport constants were calculated using a reversible Michaelis-Menten model. The results show that (1) in the physiological range, plasma lactate unidirectional transport (V(in)) and concentration in tissue increase close to linearly with the lactate concentration in plasma; (2) the maximum potential contribution of plasma lactate to brain metabolism is 10% under basal plasma lactate conditions of ~1.0 mmol/L and as much as 60% at supraphysiological plasma lactate concentrations when the transporters are saturated; (3) the half-saturation constant K(T) is 5.1 +/- 2.7 mmol/L and V(MAX) is 0.40 +/- 0.13 MUmol . g(-1) . min(-1) (68% confidence interval); and (4) the majority of plasma lactate is metabolized in neurons similar to glucose. PMID- 20962221 TI - Differential subcellular recruitment of monoacylglycerol lipase generates spatial specificity of 2-arachidonoyl glycerol signaling during axonal pathfinding. AB - Endocannabinoids, particularly 2-arachidonoyl glycerol (2-AG), impact the directional turning and motility of a developing axon by activating CB(1) cannabinoid receptors (CB(1)Rs) in its growth cone. Recent findings posit that sn 1-diacylglycerol lipases (DAGLalpha/beta) synthesize 2-AG in the motile axon segment of developing pyramidal cells. Coincident axonal targeting of CB(1)Rs and DAGLs prompts the hypothesis that autocrine 2-AG signaling facilitates axonal outgrowth. However, DAGLs alone are insufficient to account for the spatial specificity and dynamics of 2-AG signaling. Therefore, we hypothesized that local 2-AG degradation by monoacylglycerol lipase (MGL) must play a role. We determined how subcellular recruitment of MGL is temporally and spatially restricted to establish the signaling competence of 2-AG during axonal growth. MGL is expressed in central and peripheral axons of the fetal nervous system by embryonic day 12.5. MGL coexists with DAGLalpha and CB(1)Rs in corticofugal axons of pyramidal cells. Here, MGL and DAGLalpha undergo differential axonal targeting with MGL being excluded from the motile neurite tip. Thus, spatially confined MGL activity generates a 2-AG-sensing microdomain and configures 2-AG signaling to promote axonal growth. Once synaptogenesis commences, MGL disperses in stationary growth cones. The axonal polarity of MGL is maintained by differential proteasomal degradation because inhibiting the ubiquitin proteasome system also induces axonal MGL redistribution. Because MGL inactivation drives a CB(1)R-dependent axonal growth response, we conclude that 2-AG may act as a focal protrusive signal for developing neurons and whose regulated metabolism is critical for attaining correct axonal complexity. PMID- 20962223 TI - The neural fate of task-irrelevant features in object-based processing. AB - Objects are one of the most fundamental units in visual attentional selection and information processing. Studies have shown that, during object-based processing, all features of an attended object may be encoded together, even when these features are task irrelevant. Some recent studies, however, have failed to find this effect. What determines when object-based processing may or may not occur? In three experiments, observers were asked to encode object colors and the processing of task-irrelevant object shapes was evaluated by measuring functional magnetic resonance imaging responses from a brain area involved in shape representation. Whereas object-based task-irrelevant shape processing was present at low color-encoding load, it was attenuated or even suppressed at high color encoding load. Moreover, such object-based processing was short-lived and was not sustained over a long delay period. Object-based processing for task-irrelevant features of attended objects thus does exist, as reported previously; but it is transient and its magnitude is determined by the encoding demand of the task relevant feature. PMID- 20962222 TI - Structural remodeling of fibrous astrocytes after axonal injury. AB - Reactive astrocytes are a pathological hallmark of many CNS injuries and neurodegenerations. They are characterized by hypertrophy of the soma and processes and an increase in the expression of glial fibrillary acidic protein. Because the cells obscure each other in immunostaining, little is known about the behavior of a single reactive astrocyte, nor how single astrocytes combine to form the glial scar. We have investigated the reaction of fibrous astrocytes to axonal degeneration using a transgenic mouse strain expressing enhanced green fluorescent protein in small subsets of astrocytes. Fibrous astrocytes in the optic nerve and corpus callosum initially react to injury by hypertrophy of the soma and processes. They retract their primary processes, simplifying their shape and dramatically reducing their spatial coverage. At 3 d after crush, quantitative analysis revealed nearly a twofold increase in the thickness of the primary processes, a halving of the number of primary processes leaving the soma and an eightfold reduction in the spatial coverage. In the subsequent week, they partially reextend long processes, returning to a near-normal morphology and an extensive spatial overlap. The resulting glial scar consists of an irregular array of astrocyte processes, contrasting with their original orderly arrangement. These changes are in distinct contrast to those reported for reactive protoplasmic astrocytes of the gray matter, in which the number of processes and branchings increase, but the cells continue to maintain nonoverlapping individual territories throughout their response to injury. PMID- 20962224 TI - Opioid-Induced GABA potentiation after chronic morphine attenuates the rewarding effects of opioids in the ventral tegmental area. AB - GABA transmission in the ventral tegmental area (VTA) is critical for fine tuning the activity of dopamine neurons in response to opioids. However, the precise mechanism by which GABA input shapes opioid reward is poorly understood. We observed a reduction of conditioned place preference for low doses of the opioid [d-Ala2, N-MePhe4, Gly5-ol]-enkephalin (DAMGO) and a switch in the functional effects of MU-opioid receptor modulation of GABA postsynaptic currents in the mouse VTA 1 d after chronic morphine treatment. Specifically, whereas in naive mice DAMGO inhibits GABA postsynaptic currents, GABAergic currents are potentiated by DAMGO after chronic morphine treatment. Importantly, pretreatment with the cAMP signaling inhibitor (R)-adenosine, cyclic 3',5' (hydrogenphosphorothioate) triethylammonium both restored DAMGO reward and reversed the DAMGO-mediated potentiation, thereby reestablishing the inhibitory effects of opioids on GABA currents. Thus, a paradoxical bidirectionality in MU receptor-mediated control of GABA transmission following chronic morphine treatment is a critical mechanism that determines the expression of opioid reward in the VTA. PMID- 20962225 TI - Timescales of sensory- and decision-related activity in the middle temporal and medial superior temporal areas. AB - The contribution of sensory neurons to perceptual decisions about external stimulus events has received much attention, but it is less clear how sensory responses are integrated over time to produce decisions that are both rapid and reliable. To address this issue, we recorded from middle temporal area and medial superior temporal area neurons in rhesus macaques performing a task requiring the detection and discrimination of unpredictable speed changes. We examined how neuronal activity encoded the sign of the speed change and predicted the animals' behavioral judgments and reaction times, with a focus on the timescales over which neuronal activity is informative. False detection trials, on which animals reported a speed change even though none had occurred, were grouped according to the animals' discrimination judgment. By comparing the neuronal responses between the two groups of false detection trials, we were able to predict the animals' choices from the sensory activity of single neurons at levels significantly better than chance. These choice probability measurements were strongest using spike counts in an 80 ms window ending 150 ms before a choice saccade began, but significant choice probabilities were observed in windows as short as 10 ms. While the maximum deviation in spiking rate following a speed change is evident in the transient response, averaging neuronal activity in longer time windows can be more informative about both the stimulus and the animals' behavioral judgments. Thus the timescales found in this study represent a trade-off between producing rapid reactions and overcoming the noise inherent in short time windows. PMID- 20962226 TI - Endogenous dopamine regulates the rhythm of expression of the clock protein PER2 in the rat dorsal striatum via daily activation of D2 dopamine receptors. AB - A role for dopamine (DA) in the regulation of clock genes in the mammalian brain is suggested by evidence that manipulations of DA receptors can alter the expression of some clock genes outside the suprachiasmatic nucleus (SCN), the master circadian clock. The role of endogenous DA in the regulation of clock gene expression is unknown. Here, we demonstrate a direct relationship between extracellular DA levels and the rhythm of expression of the clock protein PERIOD2 (PER2) in the dorsal striatum of the male Wistar rat. Specifically, we show that the peak of the daily rhythm of extracellular DA in the dorsal striatum precedes the peak of PER2 by ~6 h and that depletion of striatal DA by 6-hydroxydopamine or alpha-methyl-para-tyrosine or blockade of D(2) DA receptors by raclopride blunts the rhythm of striatal PER2. Furthermore, timed daily activation of D(2) DA receptors, but not D(1) DA receptors, restores and entrains the PER2 rhythm in the DA-depleted striatum. None of these manipulations had any effect on the PER2 rhythm in the SCN. Our findings are consistent with the idea that the rhythm of expression of PER2 in the dorsal striatum depends on daily dopaminergic activation of D(2) DA receptors. These observations may have implications for circadian abnormalities seen in Parkinson's disease. PMID- 20962227 TI - 14-3-3 proteins regulate protein kinase a activity to modulate growth cone turning responses. AB - Growth cones regulate the speed and direction of neuronal outgrowth during development and regeneration. How the growth cone spatially and temporally regulates signals from guidance cues is poorly understood. Through a proteomic analysis of purified growth cones we identified isoforms of the 14-3-3 family of adaptor proteins as major constituents of the growth cone. Disruption of 14-3-3 via the R18 antagonist or knockdown of individual 14-3-3 isoforms switches nerve growth factor- and myelin-associated glycoprotein-dependent repulsion to attraction in embryonic day 13 chick and postnatal day 5 rat DRG neurons. These effects are reminiscent of switching responses observed in response to elevated cAMP. Intriguingly, R18-dependent switching is blocked by inhibitors of protein kinase A (PKA), suggesting that 14-3-3 proteins regulate PKA. Consistently, 14-3 3 proteins interact with PKA and R18 activates PKA by dissociating its regulatory and catalytic subunits. Thus, 14-3-3 heterodimers regulate the PKA holoenzyme and this activity plays a critical role in modulating neuronal responses to repellent cues. PMID- 20962228 TI - Neural coding of interaural time differences with bilateral cochlear implants: effects of congenital deafness. AB - Human bilateral cochlear implant users do poorly on tasks involving interaural time differences (ITD), a cue that provides important benefits to the normal hearing, especially in challenging acoustic environments, yet the precision of neural ITD coding in acutely deafened, bilaterally implanted cats is essentially normal (Smith and Delgutte, 2007a). One explanation for this discrepancy is that the extended periods of binaural deprivation typically experienced by cochlear implant users degrades neural ITD sensitivity, by either impeding normal maturation of the neural circuitry or altering it later in life. To test this hypothesis, we recorded from single units in inferior colliculus of two groups of bilaterally implanted, anesthetized cats that contrast maximally in binaural experience: acutely deafened cats, which had normal binaural hearing until experimentation, and congenitally deaf white cats, which received no auditory inputs until the experiment. Rate responses of only half as many neurons showed significant ITD sensitivity to low-rate pulse trains in congenitally deaf cats compared with acutely deafened cats. For neurons that were ITD sensitive, ITD tuning was broader and best ITDs were more variable in congenitally deaf cats, leading to poorer ITD coding within the naturally occurring range. A signal detection model constrained by the observed physiology supports the idea that the degraded neural ITD coding resulting from deprivation of binaural experience contributes to poor ITD discrimination by human implantees. PMID- 20962229 TI - Separate valuation subsystems for delay and effort decision costs. AB - Decision making consists of choosing among available options on the basis of a valuation of their potential costs and benefits. Most theoretical models of decision making in behavioral economics, psychology, and computer science propose that the desirability of outcomes expected from alternative options can be quantified by utility functions. These utility functions allow a decision maker to assign subjective values to each option under consideration by weighting the likely benefits and costs resulting from an action and to select the one with the highest subjective value. Here, we used model-based neuroimaging to test whether the human brain uses separate valuation systems for rewards (erotic stimuli) associated with different types of costs, namely, delay and effort. We show that humans devalue rewards associated with physical effort in a strikingly similar fashion to those they devalue that are associated with delays, and that a single computational model derived from economics theory can account for the behavior observed in both delay discounting and effort discounting. However, our neuroimaging data reveal that the human brain uses distinct valuation subsystems for different types of costs, reflecting in opposite fashion delayed reward and future energetic expenses. The ventral striatum and the ventromedial prefrontal cortex represent the increasing subjective value of delayed rewards, whereas a distinct network, composed of the anterior cingulate cortex and the anterior insula, represent the decreasing value of the effortful option, coding the expected expense of energy. Together, these data demonstrate that the valuation processes underlying different types of costs can be fractionated at the cerebral level. PMID- 20962230 TI - Drosophila PQBP1 regulates learning acquisition at projection neurons in aversive olfactory conditioning. AB - Polyglutamine tract-binding protein-1 (PQBP1) is involved in the transcription splicing coupling, and its mutations cause a group of human mental retardation syndromes. We generated a fly model in which the Drosophila homolog of PQBP1 (dPQBP1) is repressed by insertion of piggyBac. In classical odor conditioning, learning acquisition was significantly impaired in homozygous piggyBac-inserted flies, whereas the following memory retention was completely normal. Mushroom bodies (MBs) and antennal lobes were morphologically normal in dPQBP1-mutant flies. Projection neurons (PNs) were not reduced in number and their fiber connections were not changed, whereas gene expressions including NMDA receptor subunit 1 (NR1) were decreased in PNs. Targeted double-stranded RNA-mediated silencing of dPQBP1 in PNs, but not in MBs, similarly disrupted learning acquisition. NR1 overexpression in PNs rescued the learning disturbance of dPQBP1 mutants. HDAC (histone deacetylase) inhibitors, SAHA (suberoylanilide hydroxamic acid) and PBA (phenylbutyrate), that upregulated NR1 partially rescued the learning disturbance. Collectively, these findings identify dPQBP1 as a novel gene regulating learning acquisition at PNs. PMID- 20962231 TI - Medial dorsal hypothalamus mediates the inhibition of reward seeking after extinction. AB - Extinction promotes abstinence from drug seeking. Extinction expression is an active process, dependent on infralimbic prefrontal cortex (ilPFC). However, the neurocircuitry mediating extinction expression is unknown. Here we studied the neural mechanisms for expression of extinction of alcoholic beer seeking in rats. We first examined the pattern of activation in prefrontal cortex projections to medial dorsal hypothalamus (MDH) (i.e., perifornical and dorsomedial nuclei) during extinction expression. Double labeling for retrograde tracer cholera toxin B subunit (CTb) and the neuronal activity marker c-Fos revealed significant recruitment of MDH projecting ilPFC neurons during extinction expression. We then studied the causal role of MDH in inhibiting alcoholic beer seeking during extinction expression. MDH infusion of the inhibitory neuropeptide cocaine- and amphetamine-regulated transcript prevented extinction expression, showing that MDH is necessary for extinction expression. Next we examined the pattern of activation in MDH projections to paraventricular thalamus (PVT) during extinction expression. Double labeling for CTb and c-Fos revealed significant recruitment of PVT projecting MDH neurons during extinction expression. We also showed, using triple-label immunofluorescence, that the majority of PVT projecting extinction neurons express prodynorphin, suggesting that actions at kappa opioid receptors (KORs) in PVT may be critical for inhibiting alcoholic beer seeking. Consistent with this, infusions of a KOR agonist into PVT prevented reinstatement of alcoholic beer seeking showing that PVT KOR activation is sufficient to inhibit alcoholic beer seeking. Together, these findings identify a role for MDH and its ilPFC afferents and PVT efferents in inhibiting alcoholic beer seeking during extinction expression. PMID- 20962232 TI - Local hemodynamics dictate long-term dendritic plasticity in peri-infarct cortex. AB - Changes in dendritic spine turnover are a major mechanism of experience-dependent plasticity in the adult neocortex. Dendritic spine plasticity may also contribute to functional recovery after stroke, but in that setting its expression may be complicated by alterations in local tissue perfusion, especially around the infarct. Using adult Thy-1 GFP-M mice, we simultaneously recorded long-term spine dynamics in apical dendrites from layer 5 pyramidal cells and blood flow from surrounding capillaries with in vivo two-photon microscopy in peri-infarct cortex before and after unilateral middle cerebral artery occlusion. Blood flow in peri infarct cortex decreased significantly immediately after stroke and improved gradually over time, in a distance-dependent manner from the epicenter of the infarct. However, local tissue perfusion was never fully restored even after a 3 month recovery period. On average, surviving layer 5 pyramidal neurons experienced a ~20% decrease in spine density acutely after stroke but eventually recovered. The dynamics of this improvement were different depending on the degree of tissue perfusion acutely after arterial occlusion. Cells in ischemic areas closer to the infarct returned to normal spine density levels slowly by retaining spines, while cells in more remote regions with preserved blood flow recovered faster by adding more spines, eventually surpassing baseline spine density by 15%. Our data suggest that maintaining tissue perfusion in the area surrounding the infarct could hasten or augment synaptic plasticity and functional recovery after stroke. PMID- 20962233 TI - Learning alters the tuning of functional magnetic resonance imaging patterns for visual forms. AB - Learning is thought to facilitate the recognition of objects by optimizing the tuning of visual neurons to behaviorally relevant features. However, the learning mechanisms that shape neural selectivity for visual forms in the human brain remain essentially unknown. Here, we combine behavioral and functional magnetic resonance imaging (fMRI) measurements to test the mechanisms that mediate enhanced behavioral sensitivity in the discrimination of visual forms after training. In particular, we used high-resolution fMRI and multivoxel pattern classification methods to investigate fine learning-dependent changes in neural preference for global forms. We measured the observers' choices when discriminating between concentric and radial patterns presented in noise before and after training. Similarly, we measured the choices of a pattern classifier when predicting each stimulus from fMRI activity. Comparing the performance of human observers and classifiers demonstrated that learning alters the observers' sensitivity to visual forms and the tuning of fMRI activation patterns in visual areas selective for task-relevant features. In particular, training on low-signal stimuli enhanced the amplitude but reduced the width of pattern-based tuning functions in higher dorsal and ventral visual areas. Thus, our findings suggest that learning of visual patterns is implemented by enhancing the response to the preferred stimulus category and reducing the response to nonpreferred stimuli in higher extrastriate visual cortex. PMID- 20962234 TI - Regulation of synaptic Rac1 activity, long-term potentiation maintenance, and learning and memory by BCR and ABR Rac GTPase-activating proteins. AB - Rho family small GTPases are important regulators of neuronal development. Defective Rho regulation causes nervous system dysfunctions including mental retardation and Alzheimer's disease. Rac1, a member of the Rho family, regulates dendritic spines and excitatory synapses, but relatively little is known about how synaptic Rac1 is negatively regulated. Breakpoint cluster region (BCR) is a Rac GTPase-activating protein known to form a fusion protein with the c-Abl tyrosine kinase in Philadelphia chromosome-positive chronic myelogenous leukemia. Despite the fact that BCR mRNAs are abundantly expressed in the brain, the neural functions of BCR protein have remained obscure. We report here that BCR and its close relative active BCR-related (ABR) localize at excitatory synapses and directly interact with PSD-95, an abundant postsynaptic scaffolding protein. Mice deficient for BCR or ABR show enhanced basal Rac1 activity but only a small increase in spine density. Importantly, mice lacking BCR or ABR exhibit a marked decrease in the maintenance, but not induction, of long-term potentiation, and show impaired spatial and object recognition memory. These results suggest that BCR and ABR have novel roles in the regulation of synaptic Rac1 signaling, synaptic plasticity, and learning and memory, and that excessive Rac1 activity negatively affects synaptic and cognitive functions. PMID- 20962235 TI - Eyelid conditioning to a target amplitude: adding how much to whether and when. AB - Conceptual and practical advantages of pavlovian eyelid conditioning facilitate analysis of cerebellar computation and learning. Even so, eyelid conditioning procedures are unrealistic in an important way. The error signal to the olivocerebellar system does not decrease as learning adapts response amplitude or gain. This inherently limits the utility of eyelid conditioning for studies investigating how cerebellar learning mechanisms acquire and store an adaptive response amplitude. We report the development and characterization of a training procedure in which conditioned response amplitude is brought under experimental control with contingencies that more closely parallel natural conditions. In this procedure, the delivery of the unconditioned stimulus (US) is made contingent on conditioned response amplitude: the US is delivered for responses that fail to reach a specified target amplitude and is omitted for responses that meet or exceed the target. We find that rabbits trained with either a tone or with mossy fiber stimulation as the conditioned stimulus learn responses that approach target amplitudes ranging from 2 to 5 mm. Inactivating the interpositus nucleus with muscimol infusions abolished these conditioned responses, indicating that cerebellar involvement in eyelid conditioning is not tied explicitly to the use of pavlovian procedures. Together with previous studies, these data suggest that response amplitude is learned and encoded in the cerebellum during eyelid conditioning. As such, these results provide a foundation for systematic and controlled investigations of the cerebellar mechanisms that learn and encode the proper amplitude of adaptive movements. PMID- 20962237 TI - PKA-induced internalization of slack KNa channels produces dorsal root ganglion neuron hyperexcitability. AB - Inflammatory mediators through the activation of the protein kinase A (PKA) pathway sensitize primary afferent nociceptors to mechanical, thermal, and osmotic stimuli. However, it is unclear which ion conductances are responsible for PKA-induced nociceptor hyperexcitability. We have previously shown the abundant expression of Slack sodium-activated potassium (K(Na)) channels in nociceptive dorsal root ganglion (DRG) neurons. Here we show using cultured DRG neurons, that of the total potassium current, I(K), the K(Na) current is predominantly inhibited by PKA. We demonstrate that PKA modulation of K(Na) channels does not happen at the level of channel gating but arises from the internal trafficking of Slack channels from DRG membranes. Furthermore, we found that knocking down the Slack subunit by RNA interference causes a loss of firing accommodation analogous to that observed during PKA activation. Our data suggest that the change in nociceptive firing occurring during inflammation is the result of PKA-induced Slack channel trafficking. PMID- 20962236 TI - Human immunodeficiency virus-1 Tat activates calpain proteases via the ryanodine receptor to enhance surface dopamine transporter levels and increase transporter specific uptake and Vmax. AB - Human immunodeficiency virus-associated neurological disease (HAND) still causes significant morbidity, despite success reducing viral loads with combination antiretroviral therapy. The dopamine (DA) system is particularly vulnerable in HAND. We hypothesize that early, "reversible" DAergic synaptic dysfunction occurs long before DAergic neuron loss. As such, aging human immunodeficiency virus (HIV)-infected individuals may be vulnerable to other age-related neurodegenerative diseases like Parkinson's disease (PD), underscoring the need to understand shared molecular targets in HAND and PD. Previously, we reported that the neurotoxic HIV-1 transactivating factor (Tat) acutely disrupts mitochondrial and endoplasmic reticulum calcium homeostasis via ryanodine receptor (RyR) activation. Here, we further report that Tat disrupts DA transporter (DAT) activity and function, resulting in increased plasma membrane (PM) DAT and increased DAT V(max), without changes in K(m) or total DAT protein. Tat also increases calpain protease activity at the PM, demonstrated by total internal reflection fluorescence microscopy of a cleavable fluorescent calpain substrate. Tat-increased PM DAT and calpain activity are blocked by the RyR antagonists ryanodine and dantrolene, the calpain inhibitor calpastatin, and by a specific inhibitor of GSK-3beta. We conclude that Tat activates RyRs via a calcium- and calpain-mediated mechanism that upregulates DAT trafficking to the PM, and is independent of DAT protein synthesis, reinforcing the feasibility of RyR and GSK-3beta inhibition as clinical therapeutic approaches for HAND. Finally, we provide key translational relevance for these findings by highlighting published human data of increased DAT levels in striata of HAND patients and by demonstrating similar findings in Tat-expressing transgenic mice. PMID- 20962238 TI - Decision time, slow inhibition, and theta rhythm. AB - In this paper, we examine decision making in a spiking neuronal network and show that longer time constants for the inhibitory neurons can decrease the reaction times and produce theta rhythm. We analyze the mechanism and find that the spontaneous firing rate before the decision cues are applied can drift, and thereby influence the speed of the reaction time when the decision cues are applied. The drift of the firing rate in the population that will win the competition is larger if the time constant of the inhibitory interneurons is increased from 10 to 33 ms, and even larger if there are two populations of inhibitory neurons with time constants of 10 and 100 ms. Of considerable interest is that the decision that will be made can be influenced by the noise-influenced drift of the spontaneous firing rate over many seconds before the decision cues are applied. The theta rhythm associated with the longer time constant networks mirrors the greater integration in the firing rate drift produced by the recurrent connections over long time periods in the networks with slow inhibition. The mechanism for the effect of slow waves in the theta and delta range on decision times is suggested to be increased neuronal spiking produced by depolarization of the membrane potential on the positive part of the slow waves when the neuron's membrane potential is close to the firing threshold. PMID- 20962239 TI - Distinct levels of dopamine denervation differentially alter striatal synaptic plasticity and NMDA receptor subunit composition. AB - A correct interplay between dopamine (DA) and glutamate is essential for corticostriatal synaptic plasticity and motor activity. In an experimental model of Parkinson's disease (PD) obtained in rats, the complete depletion of striatal DA, mimicking advanced stages of the disease, results in the loss of both forms of striatal plasticity: long-term potentiation (LTP) and long-term depression (LTD). However, early PD stages are characterized by an incomplete reduction in striatal DA levels. The mechanism by which this incomplete reduction in DA level affects striatal synaptic plasticity and glutamatergic synapses is unknown. Here we present a model of early PD in which a partial denervation, causing mild motor deficits, selectively affects NMDA-dependent LTP but not LTD and dramatically alters NMDA receptor composition in the postsynaptic density. Our findings show that DA decrease influences corticostriatal synaptic plasticity depending on the level of depletion. The use of the TAT2A cell-permeable peptide, as an innovative therapeutic strategy in early PD, rescues physiological NMDA receptor composition, synaptic plasticity, and motor behavior. PMID- 20962240 TI - Differential effects of GABAB receptor subtypes, {gamma}-hydroxybutyric Acid, and Baclofen on EEG activity and sleep regulation. AB - The role of GABA(B) receptors in sleep is still poorly understood. GHB (gamma hydroxybutyric acid) targets these receptors and is the only drug approved to treat the sleep disorder narcolepsy. GABA(B) receptors are obligate dimers comprised of the GABA(B2) subunit and either one of the two GABA(B1) subunit isoforms, GABA(B1a) and GABA(B1b). To better understand the role of GABA(B) receptors in sleep regulation, we performed electroencephalogram (EEG) recordings in mice devoid of functional GABA(B) receptors (1(-/-) and 2(-/-)) or lacking one of the subunit 1 isoforms (1a(-/-) and 1b(-/-)). The distribution of sleep over the day was profoundly altered in 1(-/-) and 2(-/-) mice, suggesting a role for GABA(B) receptors in the circadian organization of sleep. Several other sleep and EEG phenotypes pointed to a more prominent role for GABA(B1a) compared with the GABA(B1b) isoform. Moreover, we found that GABA(B1a) protects against the spontaneous seizure activity observed in 1(-/-) and 2(-/-) mice. We also evaluated the effects of the GHB-prodrug GBL (gamma-butyrolactone) and of baclofen (BAC), a high-affinity GABA(B) receptor agonist. Both drugs induced a state distinct from physiological sleep that was not observed in 1(-/-) and 2(-/ ) mice. Subsequent sleep was not affected by GBL whereas BAC was followed by a delayed hypersomnia even in 1(-/-) and 2(-/-) mice. The differential effects of GBL and BAC might be attributed to differences in GABA(B)-receptor affinity. These results also indicate that all GBL effects are mediated through GABA(B) receptors, although these receptors do not seem to be involved in mediating the BAC-induced hypersomnia. PMID- 20962241 TI - Frontostriatal involvement in task switching depends on genetic differences in d2 receptor density. AB - Recent studies suggest an association of dopamine D2 receptor (DRD2) availability with flexibility in reward-based learning. We extend these results by demonstrating an association of genetically based differences in DRD2 density with the ability to intentionally switch between nonrewarded tasks: noncarriers of the A1 allele of the DRD2/ANKK1-TaqIa polymorphism, associated with higher DRD2 density, show increased task-switching costs, increased prefrontal switching activity in the inferior frontal junction area, and increased functional connectivity in dorsal frontostriatal circuits, relative to A1 allele carriers. A DRD2 haplotype analysis in the same sample confirmed these results, indicating an association between high D2 density and increased task-switching effort. Our results provide evidence that converges with that from association studies relating increased D2 density to deficits in cognitive flexibility in schizophrenia. We suggest that individual differences in striatal D2 signaling in healthy humans modulate goal-directed gating to prefrontal cortex, thus leading to individual differences in switching intentionally to newly relevant behaviors. PMID- 20962242 TI - Experimental characterization and mathematical modeling of P2X7 receptor channel gating. AB - The P2X7 receptor is a trimeric channel with three binding sites for ATP, but how the occupancy of these sites affects gating is still not understood. Here we show that naive receptors activated and deactivated monophasically at low and biphasically at higher agonist concentrations. Both phases of response were abolished by application of Az10606120, a P2X7R-specific antagonist. The slow secondary growth of current in the biphasic response coincided temporally with pore dilation. Repetitive stimulation with the same agonist concentration caused sensitization of receptors, which manifested as a progressive increase in the current amplitude, accompanied by a slower deactivation rate. Once a steady level of the secondary current was reached, responses at high agonist concentrations were no longer biphasic but monophasic. Sensitization of receptors was independent of Na(+) and Ca(2+) influx and ~30 min washout was needed to reestablish the initial gating properties. T15E- and T15K-P2X7 mutants showed increased sensitivity for agonists, responded with monophasic currents at all agonist concentrations, activated immediately with dilated pores, and deactivated slowly. The complex pattern of gating exhibited by wild-type channels can be accounted for by a Markov state model that includes negative cooperativity of agonist binding to unsensitized receptors caused by the occupancy of one or two binding sites, opening of the channel pore to a low conductance state when two sites are bound, and sensitization with pore dilation to a high conductance state when three sites are occupied. PMID- 20962243 TI - Evidence for cortical automaticity in rule-based categorization. AB - There is evidence that rule-based category learning is supported by a broad neural network that includes the prefrontal cortex, the anterior cingulate cortex, the head of the caudate nucleus, and medial temporal lobe structures. Although thousands of studies have examined rule-based category learning, only a few have studied the development of automaticity in rule-based tasks. Categorizing by a newly learned rule makes heavy demands on declarative memory, but after thousands of repetitions rule-based categorizations are made with no apparent effort. Thus, it seems likely that the neural systems that mediate automatic rule-based categorization are substantially different from the systems that mediate initial learning. This research aims at identifying the neural systems responsible for early and late rule-based categorization performances. Toward this end, this article reports the results of an experiment in which human participants each practiced a rule-based categorization task for >10,000 trials distributed over 20 separate sessions. Sessions 1, 4, 10, and 20 were performed inside a magnetic resonance imaging scanner. The main findings are as follows: (1) cortical activation remained approximately constant throughout training, (2) subcortical activation increased with practice (i.e., there were more activated voxels in the striatum), and (3) only cortical activation was correlated with accuracy after extensive training. The results suggest an initial subcortical neural system centered around the head of the caudate that is gradually replaced by a cortical system centered around the ventrolateral prefrontal cortex. With extensive practice, the cortical system progressively becomes more caudal and dorsal, and is eventually centered around the premotor cortex. PMID- 20962244 TI - The locus of motor activity in the superior colliculus of the rhesus monkey is unaltered during saccadic adaptation. AB - The location of motor-related activity in the deeper layers of the superior colliculus (SC) is thought to generate a desired displacement command specifying the amplitude and direction of saccadic eye movements. However, the amplitude of saccadic eye movements made to visual targets can be systematically altered by surreptitiously moving the target location after the saccade has been initiated. Depending on whether the target is moved closer to or further from the fixation location, adaptation of saccade amplitude results in movements that are either smaller or larger than control movements. It remains an open question whether the SC specifies the desired movement to the original target location or whether SC activity specifies the vector of the amplitude-altered movement that is observed as adaptation progresses. We investigated this question by recording the activity of saccade-related burst neurons in the SC of head-restrained rhesus monkeys during both backward and forward saccadic adaptation. During adaptation in each direction, we find no evidence that is consistent with a change in the locus of SC activity despite changes in saccade amplitude; the location of SC motor related activity does not appear to be remapped during either forward or backward saccadic adaptation. These data are inconsistent with hypotheses that propose a key role for the SC in mediating the changes in saccade amplitude observed during adaptation. PMID- 20962245 TI - Prefrontal dynamics underlying rapid instructed task learning reverse with practice. AB - The ability to rapidly reconfigure our minds to perform novel tasks is important for adapting to an ever-changing world, yet little is understood about its basis in the brain. Furthermore, it is unclear how this kind of task preparation changes with practice. Previous research suggests that prefrontal cortex (PFC) is essential when preparing to perform either novel or practiced tasks. Building upon recent evidence that PFC is organized in an anterior-to-posterior hierarchy, we postulated that novel and practiced task preparation would differentiate hierarchically distinct regions within PFC across time. Specifically, we hypothesized and confirmed using functional magnetic resonance imaging and magnetoencephalography with humans that novel task preparation is a bottom-up process that involves lower-level rule representations in dorsolateral PFC (DLPFC) before a higher-level rule-integrating task representation in anterior PFC (aPFC). In contrast, we identified a complete reversal of this activity pattern during practiced task preparation. Specifically, we found that practiced task preparation is a top-down process that involves a higher-level rule integrating task representation (recalled from long-term memory) in aPFC before lower-level rule representations in DLPFC. These findings reveal two distinct yet highly inter-related mechanisms for task preparation, one involving task set formation from instructions during rapid instructed task learning and the other involving task set retrieval from long-term memory to facilitate familiar task performance. These two mechanisms demonstrate the exceptional flexibility of human PFC as it rapidly reconfigures cognitive brain networks to implement a wide variety of possible tasks. PMID- 20962246 TI - Pyramidal cells in piriform cortex receive convergent input from distinct olfactory bulb glomeruli. AB - Pyramidal cells in piriform cortex integrate sensory information from multiple olfactory bulb mitral and tufted (M/T) cells. However, whether M/T cells belonging to different olfactory bulb glomeruli converge onto individual cortical cells is unclear. Here we use calcium imaging in an olfactory bulb-cortex slice preparation to provide direct evidence that neurons in piriform cortex receive convergent synaptic input from different glomeruli. We show that the combined activity of distinct glomerular pathways recruits ensembles of pyramidal cells that are not activated by the individual pathways alone. This cooperative recruitment of cortical neurons only occurs over a narrow time window and is a feature intrinsic to the olfactory cortex that can be explained by the integration of converging, subthreshold synaptic input. Cooperative recruitment enhances the differences between cortical representations of partially overlapping input patterns and may contribute to the initial steps of olfactory discrimination. PMID- 20962247 TI - Laminar-specific maturation of GABAergic transmission and susceptibility to visual deprivation are related to endocannabinoid sensitivity in mouse visual cortex. AB - The developmental period when neuronal responses are modified by visual experience is reported to start and end earlier in layer 4 than in layer 2/3 of the visual cortex, and the maturation of GABAergic inhibitory circuits is suggested to determine the timing of this period. Here, we examine whether the laminar difference in such timing corresponds to a difference in the time course of the functional maturation of GABAergic synaptic transmission to star pyramidal and pyramidal cells in layers 4 and 2/3, respectively, of the mouse visual cortex and whether the development of the strength of GABAergic transmission is affected by visual deprivation in a laminar-specific manner. Our analysis of developmental changes in inhibitory postsynaptic currents of star pyramidal and pyramidal cells evoked by electrical stimulation of afferents or action potentials of fast spiking GABAergic neurons revealed that there was a sequential maturation of GABAergic function from layers 4 to 2/3. The maturation of inhibition in layer 4 occurred at postnatal week 3, which preceded by 1 week that of layer 2/3. Visual deprivation by dark rearing arrested the functional development of GABAergic transmission in layer 2/3, whereas dark rearing was not so effective in layer 4. GABAergic synapses in layer 2/3 were sensitive to an agonist for cannabinoid type 1 receptors and not normally matured in receptor knock-out mice, whereas those in layer 4 were not so. These results suggest laminar-specific maturation of inhibition and susceptibility to visual deprivation, which may be related to the laminar difference in sensitivity to endocannabinoids. PMID- 20962248 TI - Influence of phasic and tonic dopamine release on receptor activation. AB - Tonic and phasic dopamine release is implicated in learning, motivation, and motor functions. However, the relationship between spike patterns in dopaminergic neurons, the extracellular concentration of dopamine, and activation of dopamine receptors remains unresolved. In the present study, we develop a computational model of dopamine signaling that give insight into the relationship between the dynamics of release and occupancy of D(1) and D(2) receptors. The model is derived from first principles using experimental data. It has no free parameters and offers unbiased estimation of the boundaries of dopaminergic volume transmission. Bursts primarily increase occupancy of D(1) receptors, whereas pauses translate into low occupancy of D(1) and D(2) receptors. Phasic firing patterns, composed of bursts and pauses, reduce the average D(2) receptor occupancy and increase average D(1) receptor occupancy compared with equivalent tonic firing. Receptor occupancy is crucially dependent on synchrony and the balance between tonic and phasic firing modes. Our results provide quantitative insight in the dynamics of volume transmission and complement experimental data obtained with electrophysiology, positron emission tomography, microdialysis, amperometry, and voltammetry. PMID- 20962249 TI - Two regions within the proximal steroidogenic factor 1 promoter drive somatic cell-specific activity in developing gonads of the female mouse. AB - Targets of steroidogenic factor 1 (SF1; also known as NR5A1 and AD4BP) have been identified within cells at every level of the hypothalamic-pituitary-gonadal and adrenal axes, revealing SF1 to be a master regulator of major endocrine systems. Mouse embryos express SF1 in the genital ridge until Embryonic Day 13.5 (E13.5). Thereafter, expression persists in the male and is substantially lower in the female gonad until birth. We hypothesize that the sexually dimorphic expression of Sf1 during gonadogenesis is mediated by sex-specific regulation of its promoter. To investigate dimorphic regulation within the fetal gonad, we developed an experimental strategy using transient transfection of E13.5 gonad explant cultures and evaluated various Sf1 promoter constructs for sexually dimorphic DNA elements. The proximal Sf1 promoter correctly targeted reporter activity to SF1-expressing cells in both XY and XX gonads. Stepwise deletion of sequences from the Sf1 promoter revealed two regions that affected regulation within female gonads. Mutation of both sequences together did not cause further disruption of reporter activity, suggesting the two sites might work in concert to promote activity in female somatic cells. Results from gel mobility shift assays and fetal gonad-chromatin immunoprecipitation showed that TCFAP2 binds to one of the two female-specific sites within the proximal promoter of Sf1. Together, we show that transient transfection experiments performed within developing testes and ovaries are a powerful tool to uncover elements within the Sf1 promoter that contribute to sex-specific expression. PMID- 20962250 TI - The "Glow"rious Sertoli and germ cells: mouse testis development visualized in multi-colors. PMID- 20962252 TI - The role of luteinizing hormone in regulating gene expression during selection of a dominant follicle in cattle. AB - At approximately 8.5 mm in diameter, the future dominant follicle is "selected" for continued growth in cattle. In the present study, cows were treated with a gonadotropin-releasing hormone receptor antagonist, acyline, just before follicle selection (near 7.8 mm) to investigate the role of LH in changing mRNA concentrations during selection of a dominant follicle. The ovaries containing the expected dominant follicle (EDF; first largest follicle) and expected largest subordinate follicle (ESF) were removed after 12 or 24 h of treatment. Real-time PCR was used to determine mRNA concentrations. ELISA was used to measure testosterone and 17beta-estradiol (E(2)) and radioimmunoassay to measure androstenedione (A(4)) in follicular fluid. Concentrations of E(2) were greater in EDF than in ESF of untreated cows near the time of follicle selection (12 h) or at 12 h after selection (24 h). Testosterone, E(2), and A(4) were all dramatically decreased by acyline treatment at both times. In theca cells, acyline treatment reduced CYP17A1 (P450 17alpha) in EDF and STAR (steroidogenic acute regulatory protein) in both EDF and ESF but did not alter CYP11A1 (P450scc). In granulosa cells (GCs), LHCGR (luteinizing hormone [LH] receptor) was much greater in EDF than in ESF at both time of selection (739% greater) and 12 h after selection (2837% greater) and was decreased by acyline in EDF (87% decrease). The mRNA for CYP19A1 (cytochrome P450 aromatase) and PAPPA (pregnancy associated plasma protein-A) tended to be greater in EDF than in ESF at follicle selection, and both mRNAs were much greater at 12 h after selection, with acyline significantly decreasing PAPPA mRNA after 24 h of treatment. The mRNA for FSHR (follicle-stimulating hormone receptor) was not different in EDF versus ESF and was not altered by acyline. Thus, induction of LHCGR mRNA in GCs is an early event during the follicle selection process, and surprisingly, expression of LHCGR mRNA is dependent on circulating LH. Production of follicular A(4), testosterone, and E(2) are also acutely related to LH but due to changes in expression of STAR and CYP17A1 in TC. PMID- 20962251 TI - WNTs in the neonatal mouse uterus: potential regulation of endometrial gland development. AB - The WNTs are secreted proteins that control essential developmental processes, such as embryonic patterning, cell growth, migration, and differentiation. In mice, three members of the Wnt gene family (Wnt4, Wnt5a, and Wnt7a) have been studied extensively in the female reproductive tract. The present study determined effects of postnatal day and exposure to diethylstilbestrol (DES) on Wnt and Fzd gene expression in the mouse uterus as well as the biological role of Wnt11 in postnatal mouse uterine development and function. Wnt4, Wnt5a, Wnt7a, Wnt7b, Wnt11, Wnt16, Fzd6, and Fzd10 were detected by in situ hybridization in the neonatal mouse uterus. In situ hybridization analyses revealed that Wnt4, Wnt5a, and Wnt16 were localized in the endometrial stroma, whereas Wnt7a, Wnt7b, Wnt11, Fzd6, and Fzd10 were in the uterine epithelia of neonatal mice. Exposure of mice to estrogen or estrogen receptor agonists during critical development periods inhibits endometrial adenogenesis. In the present study, DES-induced disruption of endometrial gland development was associated with reduction or suppression of Wnt4, Wnt5a, Wnt7a, Wnt11, Wnt16, and Fzd10. Ablation of Wnt11, an epithelial-expressed, DES-regulated gene, in the neonatal uterus did not affect endometrial adenogenesis or expression of other Wnt genes. Interestingly, Wnt11 deleted uteri had more endometrial glands on Postnatal Day 10. Although CTNNB1 expression was not affected by ablation of Wnt11, Vangl2 was inhibited in the uteri of Wnt11(d/d) mice. These results support the idea that a number of different Wnt genes are potential regulators for uterine morphogenesis; however, Wnt11 does not have a direct effect on uterine development. PMID- 20962253 TI - Use of minimal enteral nutrition to prevent necrotizing enterocolitis: got milk? PMID- 20962254 TI - Peritonitis after gastrostomy tube replacement: a case series and review of literature. AB - BACKGROUND: The placement of feeding gastrostomy (G) tubes through a percutaneous endoscopic gastrostomy (PEG) technique has become common because of its simplicity and safety. The majority of the serious complications are reported to occur within a few days of initial tube placement and happen in fewer than 3% of cases. Long-term reported complications of this procedure include occlusion or breakage of the G-tube, requiring reinsertion. This report describes the complication of intraperitoneal placement and the development of peritonitis after replacement of an established PEG tube and reviews the pertinent world literature. METHODS: A retrospective review of cases of intraperitoneal insertion of replacement G-tubes was done as well as a Medline search for cases of intraperitoneal insertion of replacement G-tube or development of peritonitis after replacement tube insertion. RESULTS: Three new cases of inadvertent intraperitoneal insertion of a replacement G-tube in adult patients with mature tracts are reported. An additional 5 cases have been previously described in adults. Significant morbidity was associated with this complication, and 4 deaths were related to it. Methods used to determine whether the replacement G-tube was intragastric were not uniform. CONCLUSIONS: There have been few reports of intraperitoneal insertion of replacement G-tubes in patients with mature (>30 days) stoma sites. The cases presented in this report highlight for the clinician the importance of considering this complication, particularly if there are any difficulties with the reinsertion. Prospective studies are needed to determine the frequency of this complication and the optimal protocol for PEG replacement. PMID- 20962255 TI - Evidence that the erythrocyte invasion ligand PfRh2 is a target of protective immunity against Plasmodium falciparum malaria. AB - Abs targeting blood-stage Ags of Plasmodium falciparum are important in acquired immunity to malaria, but major targets remain unclear. The P. falciparum reticulocyte-binding homologs (PfRh) are key ligands used by merozoites during invasion of erythrocytes. PfRh2a and PfRh2b are functionally important members of this family and may be targets of protective immunity, but their potential role in human immunity has not been examined. We expressed eight recombinant proteins covering the entire PfRh2 common region, as well as PfRh2a- and PfRh2b-specific regions. Abs were measured among a cohort of 206 Papua New Guinean children who were followed prospectively for 6 mo for reinfection and malaria. At baseline, Abs were associated with increasing age and active infection. High levels of IgG to all PfRh2 protein constructs were strongly associated with protection from symptomatic malaria and high-density parasitemia. The predominant IgG subclasses were IgG1 and IgG3, with little IgG2 and IgG4 detected. To further understand the significance of PfRh2 as an immune target, we analyzed PfRh2 sequences and found that polymorphisms are concentrated in an N-terminal region of the protein and seem to be under diversifying selection, suggesting immune pressure. Cluster analysis arranged the sequences into two main groups, suggesting that many of the haplotypes identified may be antigenically similar. These findings provide evidence suggesting that PfRh2 is an important target of protective immunity in humans and that Abs act by controlling blood-stage parasitemia and support its potential for vaccine development. PMID- 20962256 TI - Targeted complement inhibitors protect against posttransplant cardiac ischemia and reperfusion injury and reveal an important role for the alternative pathway of complement activation. AB - Ischemia reperfusion injury (IRI) is an unavoidable event during solid organ transplantation and is a major contributor to early graft dysfunction and subsequent graft immunogenicity. In a therapeutic paradigm using targeted complement inhibitors, we investigated the role of complement, and specifically the alternative pathway of complement, in IRI to heart isografts. Mouse heterotopic isograft heart transplants were performed in C57BL/6 mice treated with a single injection of either CR2-Crry (inhibits all complement pathways) or CR2-fH (inhibits alternative complement pathway) immediately posttransplantation. Transplanted hearts were harvested at 12 and 48 h for analysis. Both inhibitors resulted in a significant reduction in myocardial IRI, as measured by histology and serum cardiac troponin I levels. Furthermore, compared with untreated controls, both inhibitors reduced graft complement deposition, neutrophil and macrophage infiltration, adhesion molecule expression (P-selectin, E-selectin, and I-CAM-1), and proinflammatory cytokine expression (TNF-alpha, IL-1beta, KC, and MCP-1). The reduction in myocardial damage and cellular infiltration was not significantly different between CR2-Crry- and CR2-fH-treated mice, although adhesion molecule and cytokine levels were significantly lower in CR2-Crry treated mice compared with CR2-fH-treated mice. In conclusion, the alternative complement pathway plays a major contributing role in myocardial IRI after heart transplantation, and local (targeted) complement inhibition has the potential to provide an effective and safe therapeutic strategy to reduce graft injury. Although total complement blockade may be somewhat more efficacious in terms of reducing inflammation, specific blockade of the alternative pathway is likely to be less immunosuppressive in an already immunocompromised recipient. PMID- 20962257 TI - Platelets contribute to allograft rejection through glutamate receptor signaling. AB - Platelets recruit leukocytes and mediate interactions between leukocytes and endothelial cells. Platelets have been long described as markers of transplant rejection, but the contribution of platelets to transplant rejection has not been critically examined. We demonstrate in this study that following T cell initiation of allograft rejection, platelets contribute to T cell recruitment and increased plasma inflammatory mediators and accelerate T cell-meditated skin graft rejection. Prior work from our laboratory has shown that platelets secrete glutamate when activated, which then induces platelet thromboxane production by signaling through platelet-expressed ionotropic glutamate receptors. Glutamate receptor antagonists therefore represent, to our knowledge, novel inhibitors of platelet-accelerated inflammation. We have found that plasma glutamate is increased in mice that receive skin grafts and that mice treated with glutamate receptor antagonists have improved graft survival and decreased plasma thromboxane, platelet factor 4 (CXCL4), and IFN-gamma. Taken together, our work now demonstrates that subsequent to T cell initiation of skin graft rejection, platelets contribute to further T cell recruitment and that by blunting glutamate mediated platelet activation, graft survival is improved. PMID- 20962258 TI - An inflammasome-independent role for epithelial-expressed Nlrp3 in renal ischemia reperfusion injury. AB - Cytoplasmic innate immune receptors are important therapeutic targets for diseases associated with overproduction of proinflammatory cytokines. One cytoplasmic receptor complex, the Nlrp3 inflammasome, responds to an extensive array of molecules associated with cellular stress. Under normal conditions, Nlrp3 is autorepressed, but in the presence of its ligands, it oligomerizes, recruits apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc), and triggers caspase 1 activation and the maturation of proinflammatory cytokines such as IL-1beta and IL-18. Because ischemic tissue injury provides a potential source for Nlrp3 ligands, our study compared and contrasted the effects of renal ischemia in wild-type mice and mice deficient in components of the Nlrp3 inflammasome (Nlrp3(-/-) and Asc(-/-) mice). To examine the role of the inflammasome in renal ischemia-reperfusion injury (IRI) we also tested its downstream targets caspase 1, IL-1beta, and IL-18. Both Nlrp3 and Asc were highly expressed in renal tubular epithelium of humans and mice, and the absence of Nlrp3, but not Asc or the downstream inflammasome targets, dramatically protected from kidney IRI. We conclude that Nlrp3 contributes to renal IRI by a direct effect on renal tubular epithelium and that this effect is independent of inflammasome-induced proinflammatory cytokine production. PMID- 20962259 TI - Cutting edge: The adapters EAT-2A and -2B are positive regulators of CD244- and CD84-dependent NK cell functions in the C57BL/6 mouse. AB - EWS/FLI1-activated transcript 2 (EAT-2)A and EAT-2B are single SH2-domain proteins, which bind to phosphorylated tyrosines of signaling lymphocyte activation molecule family receptors in murine NK cells. While EAT-2 is a positive regulator in human cells, a negative regulatory role was attributed to the adapter in NK cells derived from EAT-2A-deficient 129Sv mice. To evaluate whether the genetic background or the presence of a selection marker in the mutant mice could influence the regulatory mode of these adapters, we generated EAT-2A-, EAT-2B-, and EAT-2A/B-deficient mice using C57BL/6 embryonic stem cells. We found that NK cells from EAT-2A- and EAT-2A/B-deficient mice were unable to kill tumor cells in a CD244- or CD84-dependent manner. Furthermore, EAT-2A/B positively regulate phosphorylation of Vav-1, which is known to be implicated in NK cell killing. Thus, as in humans, the EAT-2 adapters act as positive regulators of signaling lymphocyte activation molecule family receptor-specific NK cell functions in C57BL/6 mice. PMID- 20962260 TI - On how monospecific memory-like autoregulatory CD8+ T cells can blunt diabetogenic autoimmunity: a computational approach. AB - We have recently shown that during progression to autoimmune diabetes in NOD mice, memory autoreactive regulatory CD8(+) T cells arising from low-avidity precursors can be expanded to therapeutic levels using nanoparticles coated with disease-relevant peptide-major histocompatibility complexes (pMHCs). Here we examine the dynamics of memory autoregulatory CD8(+) T cells specific for islet specific glucose-6-phosphatase catalytic subunit-related protein(206-214), a prevalent beta cell autoantigen; their high-avidity counterparts (dominant effectors); and all other autoreactive non-islet-specific glucose-6-phosphatase catalytic subunit-related protein(206-214)-specific CD8(+) T cell specificities (subdominant effectors) in response to pMHC-coated nanoparticle (pMHC nanoparticle) therapy. We combine experimental data with mathematical modeling to investigate the clonal competition dynamics of these T cell pools. To mimic the response diversity observed in NOD mice, we simulated many individual mice, using a wide range of parameters, and averaged the results as done experimentally. We find that under certain circumstances, pMHC-nanoparticle-induced expansion of autoregulatory CD8(+) T cells can effectively suppress the expansion of dominant and subdominant effectors simultaneously but, in some few cases, can lead to the substitution (or switching) of one effector population by another. The model supports the idea that disease suppression is based on the elimination of autoantigen-loaded APCs by the expanded autoregulatory CD8(+) T cells. The model also predicts that treatment strategies that operate by selectively inhibiting autoantigen-loaded APCs, such as the pMHC-nanoparticle approach, have the highest promise to blunt polyclonal, multiantigen-specific autoimmune responses in vivo without impairing systemic immunity. PMID- 20962262 TI - Comment on "Cutting edge: FcR-like 6 is an MHC class II receptor". PMID- 20962261 TI - Annexin A1: a central player in the anti-inflammatory and neuroprotective role of microglia. AB - The brain microenvironment is continuously monitored by microglia with the detection of apoptotic cells or pathogens being rapidly followed by their phagocytosis to prevent inflammatory responses. The protein annexin A1 (ANXA1) is key to the phagocytosis of apoptotic leukocytes during peripheral inflammatory resolution, but the pathophysiological significance of its expression in the CNS that is restricted almost exclusively to microglia is unclear. In this study, we test the hypothesis that ANXA1 is important in the microglial clearance of apoptotic neurons in both noninflammatory and inflammatory conditions. We have identified ANXA1 to be sparingly expressed in microglia of normally aged human brains and to be more strongly expressed in Alzheimer's disease. Using an in vitro model comprising microglial and neuronal cell lines, as well as primary microglia from wild-type and ANXA1 null mice, we have identified two distinct roles for microglial ANXA1: 1) controlling the noninflammatory phagocytosis of apoptotic neurons and 2) promoting resolution of inflammatory microglial activation. In particular, we showed that microglial-derived ANXA1 targets apoptotic neurons, serving as both an "eat me" signal and a bridge between phosphatidylserine on the dying cell and formyl peptide receptor 2 on the phagocytosing microglia. Moreover, inflammatory activation of microglia impairs their ability to discriminate between apoptotic and nonapoptotic cells, an ability restored by exogenous ANXA1. We thus show that ANXA1 is fundamental for brain homeostasis, and we suggest that ANXA1 and its peptidomimetics can be novel therapeutic targets in neuroinflammation. PMID- 20962263 TI - Comment on "Paroxetine prevents loss of nigrostriatal dopaminergic neurons by inhibiting brain inflammation and oxidative stress in an experimental model of Parkinson's disease". PMID- 20962264 TI - CRACking the code without Rosetta: molecular regulation of calcium-stimulated gene transcription after T cell activation. PMID- 20962265 TI - Identification of a putative regulator of early T cell activation genes. Science. 1988. 241: 202-205. PMID- 20962266 TI - CD20+ B cells: the other tumor-infiltrating lymphocytes. AB - Tumor-infiltrating CD8(+) T cells are strongly associated with patient survival in a wide variety of human cancers. Less is known about tumor-infiltrating CD20(+) B cells, which often colocalize with T cells, sometimes forming organized lymphoid structures. In autoimmunity and organ transplantation, T cells and B cells collaborate to generate potent, unrelenting immune responses that can result in extensive tissue damage and organ rejection. In these settings, B cells enhance T cell responses by producing Abs, stimulatory cytokines, and chemokines, serving as local APCs, and organizing the formation of tertiary lymphoid structures that sustain long-term immunity. Thus, B cells are an important component of immunological circuits associated with persistent, rampant tissue destruction. Engagement of tumor-reactive B cells may be an important condition for generating potent, long-term T cell responses against cancer. PMID- 20962267 TI - Podoplanin associates with CD44 to promote directional cell migration. AB - Podoplanin is a transmembrane glycoprotein up-regulated in different human tumors, especially those derived from squamous stratified epithelia (SCCs). Its expression in tumor cells is linked to increased cell migration and invasiveness; however, the mechanisms underlying this process remain poorly understood. Here we report that CD44, the major hyaluronan (HA) receptor, is a novel partner for podoplanin. Expression of the CD44 standard isoform (CD44s) is coordinately up regulated together with that of podoplanin during progression to highly aggressive SCCs in a mouse skin model of carcinogenesis, and during epithelial mesenchymal transition (EMT). In carcinoma cells, CD44 and podoplanin colocalize at cell surface protrusions. Moreover, CD44 recruitment promoted by HA-coated beads or cross-linking with a specific CD44 antibody induced corecruitment of podoplanin. Podoplanin-CD44s interaction was demonstrated both by coimmunoprecipitation experiments and, in vivo, by fluorescence resonance energy transfer/fluorescence lifetime imaging microscopy (FRET/FLIM), the later confirming its association on the plasma membrane of cells with a migratory phenotype. Importantly, we also show that podoplanin promotes directional persistence of motility in epithelial cells, a feature that requires CD44, and that both molecules cooperate to promote directional migration in SCC cells. Our results support a role for CD44-podoplanin interaction in driving tumor cell migration during malignancy. PMID- 20962268 TI - Dephosphorylation of nucleophosmin by PP1beta facilitates pRB binding and consequent E2F1-dependent DNA repair. AB - Nucleophosmin (NPM) is an important phosphoprotein with pleiotropic functions in various cellular processes. Although phosphorylation has been postulated as an important functional determinant, possible regulatory roles of this modification on NPM are not fully characterized. Here, we find that NPM is dephosphorylated on various threonine residues (Thr199 and Thr234/237) in response to UV-induced DNA damage. Further experiments indicate that the serine/threonine protein phosphatase PP1beta is a physiological NPM phosphatase under both the genotoxic stress and growth conditions. As a consequence, NPM in its hypophosphorylated state facilitates DNA repair. Finally, our results suggest that one possible mechanism of this protective response lies in enhanced NPM-retinoblastoma tumor suppressor protein (pRB) interaction, leading to the relief of the repressive pRB E2F1 circuitry and the consequent transcriptional activation of E2F1 and several downstream DNA repair genes. Thus, this study unveils a key phosphatase of NPM and highlights a novel mechanism by which the PP1beta-NPM pathway contributes to cellular DNA damage response. PMID- 20962269 TI - P2Y1 and P2Y13 purinergic receptors mediate Ca2+ signaling and proliferative responses in pulmonary artery vasa vasorum endothelial cells. AB - Extracellular ATP and ADP have been shown to exhibit potent angiogenic effects on pulmonary artery adventitial vasa vasorum endothelial cells (VVEC). However, the molecular signaling mechanisms of extracellular nucleotide-mediated angiogenesis remain not fully elucidated. Since elevation of intracellular Ca(2+) concentration ([Ca(2+)](i)) is required for cell proliferation and occurs in response to extracellular nucleotides, this study was undertaken to delineate the purinergic receptor subtypes involved in Ca(2+) signaling and extracellular nucleotide-mediated mitogenic responses in VVEC. Our data indicate that stimulation of VVEC with extracellular ATP resulted in the elevation of [Ca(2+)](i) via Ca(2+) influx through plasma membrane channels as well as Ca(2+) mobilization from intracellular stores. Moreover, extracellular ATP induced simultaneous Ca(2+) responses in both cytosolic and nuclear compartments. An increase in [Ca(2+)](i) was observed in response to a wide range of purinergic receptor agonists, including ATP, ADP, ATPgammaS, ADPbetaS, UTP, UDP, 2 methylthio-ATP (MeSATP), 2-methylthio-ADP (MeSADP), and BzATP, but not adenosine, AMP, diadenosine tetraphosphate, alphabetaMeATP, and betagammaMeATP. Using RT PCR, we identified mRNA for the P2Y1, P2Y2, P2Y4, P2Y13, P2Y14, P2X2, P2X5, P2X7, A1, A2b, and A3 purinergic receptors in VVEC. Preincubation of VVEC with the P2Y1 selective antagonist MRS2179 and the P2Y13 selective antagonist MRS2211, as well as with pertussis toxin, attenuated at varying degrees agonist-induced intracellular Ca(2+) responses and activation of ERK1/2, Akt, and S6 ribosomal protein, indicating that P2Y1 and P2Y13 receptors play a major role in VVEC growth responses. Considering the broad physiological implications of purinergic signaling in the regulation of angiogenesis and vascular homeostasis, our findings suggest that P2Y1 and P2Y13 receptors may represent novel and specific targets for treatment of pathological vascular remodeling involving vasa vasorum expansion. PMID- 20962270 TI - Structure-function activity of the human sodium-dependent multivitamin transporter: role of His¹¹⁵ and His254. AB - Intestinal absorption of biotin occurs via a Na(+)-dependent carrier-mediated process that involves the sodium-dependent multivitamin transporter (SMVT; product of the Slc5a6 gene). The SMVT system is exclusively expressed at the apical membrane domain of the polarized intestinal epithelial cells. Whereas previous studies from our laboratory and others have characterized different physiological and biological aspects of SMVT, little is currently known about its structure-function activity relationship. Using site-directed mutagenesis approach, we examined the role of the positively charged histidine (His) residues of the human SMVT (hSMVT) in transporting the negatively charged biotin. Of the seven conserved (across species) His residues in the hSMVT polypeptide, only His115 and His254 were found to be important for the function of hSMVT as their mutation led to a significant reduction in carrier-mediated biotin uptake. This inhibition was mediated via a significant reduction in the maximal velocity (V(max)), but not the apparent Michaelis constant (K(m)), of the biotin uptake process and was not related to the charge of the His residue. The inhibition was also not due to changes in transcriptional or translational efficiency of the mutated hSMVT compared with wild-type carrier. However, surface biotinylation assay showed a significant reduction in the level of expression of the mutated hSMVT at the cell surface, a finding that was further confirmed by confocal imaging. Our results show important role for His115 and His254 residues in hSMVT function, which is most probably mediated via an effect on level of hSMVT expression at the cell membrane. PMID- 20962271 TI - High-throughput injection with microfluidics using picoinjectors. AB - Adding reagents to drops is one of the most important functions in droplet-based microfluidic systems; however, a robust technique to accomplish this does not exist. Here, we introduce the picoinjector, a robust device to add controlled volumes of reagent using electro-microfluidics at kilohertz rates. It can also perform multiple injections for serial and combinatorial additions. PMID- 20962272 TI - Graded enhancement of p53 binding to CREB-binding protein (CBP) by multisite phosphorylation. AB - The transcriptional activity of p53 is regulated by a cascade of posttranslational modifications. Although acetylation of p53 by CREB-binding protein (CBP)/p300 is known to be indispensable for p53 activation, the role of phosphorylation, and in particular multisite phosphorylation, in activation of CBP/p300-dependent p53 transcriptional pathways remains unclear. We investigated the role of single site and multiple site phosphorylation of the p53 transactivation domain in mediating its interaction with CBP and with the ubiquitin ligase HDM2. Phosphorylation at Thr18 functions as an on/off switch to regulate binding to the N-terminal domain of HDM2. In contrast, binding to CBP is modulated by the extent of p53 phosphorylation; addition of successive phosphoryl groups enhances the affinity for the TAZ1, TAZ2, and KIX domains of CBP in an additive manner. Activation of p53-dependent transcriptional pathways requires that p53 compete with numerous cellular transcription factors for binding to limiting amounts of CBP/p300. Multisite phosphorylation represents a mechanism for a graded p53 response, with each successive phosphorylation event resulting in increasingly efficient recruitment of CBP/p300 to p53-regulated transcriptional programs, in the face of competition from cellular transcription factors. Multisite phosphorylation thus acts as a rheostat to enhance binding to CBP/p300 and provides a plausible mechanistic explanation for the gradually increasing p53 response observed following prolonged or severe genotoxic stress. PMID- 20962273 TI - Stoichiometry of the KCNQ1 - KCNE1 ion channel complex. AB - The KCNQ1 voltage-gated potassium channel and its auxiliary subunit KCNE1 play a crucial role in the regulation of the heartbeat. The stoichiometry of KCNQ1 and KCNE1 complex has been debated, with some results suggesting that the four KCNQ1 subunits that form the channel associate with two KCNE1 subunits (a 42 stoichiometry), while others have suggested that the stoichiometry may not be fixed. We applied a single molecule fluorescence bleaching method to count subunits in many individual complexes and found that the stoichiometry of the KCNQ1 - KCNE1 complex is flexible, with up to four KCNE1 subunits associating with the four KCNQ1 subunits of the channel (a 44 stoichiometry). The proportion of the various stoichiometries was found to depend on the relative expression densities of KCNQ1 and KCNE1. Strikingly, both the voltage-dependence and kinetics of gating were found to depend on the relative densities of KCNQ1 and KCNE1, suggesting the heart rhythm may be regulated by the relative expression of the auxiliary subunit and the resulting stoichiometry of the channel complex. PMID- 20962274 TI - Phosphorylation of Ser312 contributes to tumor suppression by p53 in vivo. AB - The tumor suppressor p53 is a master sensor of stress, and posttranslational modifications are key in controlling its stability and transcriptional activities. p53 can be phosphorylated on at least 23 Ser/Thr residues, the majority of which are phosphorylated by stress-related kinases. An exception is Ser315 in human p53 (Ser312 in mouse), which is predominantly phosphorylated by cell cycle-related kinases. To understand the biological importance of Ser312 phosphorylation in vivo, we generated p53Ser312Ala knock-in mice. We show here that, although Ser312 is not essential for mouse life span under normal physiological conditions, Ser312Ala mutation dampens p53's activity during embryonic development. This is evident from its partial rescue of embryonic lethality caused by Mdm4 deletion. In agreement with the notion that Ser312 mutation weakens p53 function, Ser312Ala mice are also more susceptible to tumorigenesis following a sublethal ionizing radiation dose. Importantly, in the cohort studied, Ser312 mutation predisposes mice to develop thymic lymphomas and liver tumors, partly due to p53Ser312Ala's inability to fully induce a set of p53 target genes including p21 and cyclin G1. Thus, we demonstrate that phosphorylation of Ser312 is required for p53 to function fully as a tumor suppressor in vivo. PMID- 20962275 TI - How to separate entangled sisters: interplay between condensin and decatenase. PMID- 20962276 TI - Is bioenergy for the birds? An evaluation of alternative future bioenergy landscapes. PMID- 20962277 TI - Distinct functions of antigen-specific CD4 T cells during murine Mycobacterium tuberculosis infection. AB - The immune response elicited after Mycobacterium tuberculosis (Mtb) infection is critically dependent on CD4 T cells during both acute and chronic infection. How CD4 T-cell responses are maintained throughout infection is not well understood, and evidence from other infection models has suggested that, under conditions of chronic antigen stimulation, T cells can undergo replicative exhaustion. These findings led us to determine whether subpopulations of CD4 T cells existed that displayed markers of terminal differentiation or exhaustion during murine Mtb infection. Analysis of antigen-specific effector CD4 T cells revealed that programmed death-1 (PD-1) and the killer cell lectin-like receptor G1 (KLRG1) delineated subpopulations of T cells. PD-1-expressing CD4 T cells were highly proliferative, whereas KLRG1 cells exhibited a short lifespan and secreted the cytokines IFNgamma and TNFalpha. Adoptive transfer studies demonstrated that proliferating PD-1-positive CD4 T cells differentiated into cytokine-secreting KLRG1-positive T cells, but not vice versa. Thus, proliferating PD-1-positive cells are not exhausted, but appear to be central to maintaining antigen-specific effector T cells during chronic Mtb infection. Our findings suggest that antigen specific T-cell responses are maintained during chronic mycobacterial infection through the continual production of terminal effector cells from a proliferating precursor population. PMID- 20962278 TI - Acetylation modulates prolactin receptor dimerization. AB - Cytokine-activated receptors undergo extracellular domain dimerization, which is necessary to activate intracellular signaling pathways. Here, we report that in prolactin (PRL)-treated cells, PRL receptor (PRLR) undergoes cytoplasmic loop dimerization that is acetylation-dependent. PRLR-recruited CREB-binding protein (CBP) acetylates multiple lysine sites randomly distributed along the cytoplasmic loop of PRLR. Two PRLR monomers appear to interact with each other at multiple parts from the membrane-proximal region to the membrane-distal region, relying on the coordination among multiple lysine sites neutralized via acetylation. Cytoplasmic loop-dimerized PRLR activates STAT5, which is also acetylated by CBP and undergoes acetylation-dependent dimerization. PRLR dimerization and subsequent signaling are enhanced by treating the cells with deacetylase sirtuin (SIRT) inhibitor nicotinamide or histone deacetylase (HDAC) inhibitor trichostatin A but inhibited by expressing exogenous deacetylase SIRT2 or HDAC6. Our results suggest that acetylation and deacetylation provide the rheostat-like regulation for the cytokine receptor PRLR in its cytoplasmic loop dimerization and subsequent STAT5 activation. PMID- 20962279 TI - Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage. AB - In nonneuronopathic type 1 Gaucher disease (GD1), mutations in the glucocerebrosidase gene (GBA1) gene result in glucocerebrosidase deficiency and the accumulation of its substrate, glucocerebroside (GL-1), in the lysosomes of mononuclear phagocytes. This prevailing macrophage-centric view, however, does not explain emerging aspects of the disease, including malignancy, autoimmune disease, Parkinson disease, and osteoporosis. We conditionally deleted the GBA1 gene in hematopoietic and mesenchymal cell lineages using an Mx1 promoter. Although this mouse fully recapitulated human GD1, cytokine measurements, microarray analysis, and cellular immunophenotyping together revealed widespread dysfunction not only of macrophages, but also of thymic T cells, dendritic cells, and osteoblasts. The severe osteoporosis was caused by a defect in osteoblastic bone formation arising from an inhibitory effect of the accumulated lipids LysoGL 1 and GL-1 on protein kinase C. This study provides direct evidence for the involvement in GD1 of multiple cell lineages, suggesting that cells other than macrophages may be worthwhile therapeutic targets. PMID- 20962280 TI - Qualitative and quantitative assessment of meningococcal antigens to evaluate the potential strain coverage of protein-based vaccines. AB - A unique multicomponent vaccine against serogroup B meningococci incorporates the novel genome-derived proteins fHbp, NHBA, and NadA that may vary in sequence and level of expression. Measuring the effectiveness of such vaccines, using the accepted correlate of protection against invasive meningococcal disease, could require performing the serum bactericidal assay (SBA) against many diverse strains for each geographic region. This approach is impractical, especially for infants, where serum volumes are very limited. To address this, we developed the meningococcal antigen typing system (MATS) by combining a unique vaccine antigen specific ELISA, which detects qualitative and quantitative differences in antigens, with PorA genotyping information. The ELISA correlates with killing of strains by SBA and measures both immunologic cross-reactivity and quantity of the antigens NHBA, NadA, and fHbp. We found that strains exceeding a threshold value in the ELISA for any of the three vaccine antigens had >=80% probability of being killed by immune serum in the SBA. Strains positive for two or more antigens had a 96% probability of being killed. Inclusion of multiple different antigens in the vaccine improves breadth of coverage and prevents loss of coverage if one antigen mutates or is lost. The finding that a simple and high-throughput assay correlates with bactericidal activity is a milestone in meningococcal vaccine development. This assay allows typing of large panels of strains and prediction of coverage of protein-based meningococcal vaccines. Similar assays may be used for protein-based vaccines against other bacteria. PMID- 20962281 TI - Human RORgammat+ TH17 cells preferentially differentiate from naive FOXP3+Treg in the presence of lineage-specific polarizing factors. AB - RORgammat(+) T(H)17 cells are a proinflammatory CD4(+) T-cell population associated with autoimmune tissue injury. In mice, priming of T(H)17 requires TGF beta, which alone directs the priming of FOXP3(+) regulatory T cells (Treg), in association with inflammatory cytokines. Priming of human T(H)17 cells from conventional naive CD4(+) T cells under similar conditions, however, has proved difficult to achieve. Here, we report that differentiation of human T(H)17 cells preferentially occurs from FOXP3(+) naive Treg (NTreg) in the presence of IL-2 and IL-1beta and is increased by IL-23 and TGF-beta. IL-1beta-mediated differentiation correlated with IL-1RI expression in stimulated NTreg and was accompanied by induction of RORgammat along with down-regulation of FOXP3. IL-17 secreting cells in NTreg cultures cosecreted TNF-alpha and IL-2 and contained distinct subpopulations cosecreting or not cosecreting IFN-gamma and other T(H)17 associated cytokines. Polarized NTreg contained significant subpopulations of CCR6-expressing cells that were highly enriched in IL-17-secreting cells. Finally, analysis of CCR6 expression with respect to that of IL-1RI identified distinct IL-17-secreting subpopulations that had maintained or lost their suppressive functions. Together our results support the concept that priming of human T(H)17 from naive CD4(+) T cells preferentially takes place from FOXP3(+) Treg precursors in the presence of lineage-specific polarizing factors. PMID- 20962282 TI - Relevance of synaptic tagging and capture to the persistence of long-term potentiation and everyday spatial memory. AB - Memory for inconsequential events fades, unless these happen before or after other novel or surprising events. However, our understanding of the neurobiological mechanisms of novelty-enhanced memory persistence is mainly restricted to aversive or fear-associated memories. We now outline an "everyday appetitive" behavioral model to examine whether and how unrelated novelty facilitates the persistence of spatial memory coupled to parallel electrophysiological studies of the persistence of long-term potentiation (LTP). Across successive days, rats were given one trial per day to find food in different places and later had to recall that day's location. This task is both hippocampus and NMDA receptor dependent. First, encoding with low reward induced place memory that decayed over 24 h; in parallel, weak tetanization of CA1 synapses in brain slices induced early-LTP fading to baseline. Second, novelty exploration scheduled 30 min after this weak encoding resulted in persistent place memory; similarly, strong tetanization--analogous to novelty--both induced late-LTP and rescued early- into late-LTP on an independent but convergent pathway. Third, hippocampal dopamine D1/D5 receptor blockade or protein synthesis inhibition within 15 min of exploration prevented persistent place memory and blocked late-LTP. Fourth, symmetrically, when spatial memory was encoded using strong reward, this memory persisted for 24 h unless encoding occurred under hippocampal D1/D5 receptor blockade. Novelty exploration before this encoding rescued the drug-induced memory impairment. Parallel effects were observed in LTP. These findings can be explained by the synaptic tagging and capture hypothesis. PMID- 20962283 TI - Organization of deutocerebral neuropils and olfactory behavior in the centipede Scutigera coleoptrata (Linnaeus, 1758) (Myriapoda: Chilopoda). AB - Myriapods represent an arthropod lineage, that originating from a marine arthropod ancestor most likely conquered land independently from hexapods and crustaceans. Establishing aerial olfaction during a transition from the ocean to land requires molecules to be detected in gas phase instead of in water solution. Considering that the olfactory sense of myriapods has evolved independently from that in hexapods and crustaceans, the question arises if and how myriapods have solved the tasks of odor detection and odor information processing in air. Comparative studies between arthropod taxa that independently have established a terrestrial life style provide a powerful means of investigating the evolution of chemosensory adaptations in this environment and to understand how the arthropod nervous system evolved in response to new environmental and ecological challenges. In general, the neuroethology of myriapods and the architecture of their central nervous systems are insufficiently understood. In a set of experiments with the centipede Scutigera coleoptrata, we analyzed the central olfactory pathway with serial semi-thin sectioning combined with 3-dimensional reconstruction, antennal backfilling with neuronal tracers, and immunofluorescence combined with confocal laser-scanning microscopy. Furthermore, we conducted behavioral experiments to find out if these animals react to airborne stimuli. Our results show that the primary olfactory and mechanosensory centers are well developed in these organisms but that the shape of the olfactory neuropils in S. coleoptrata is strikingly different when compared with those of hexapods and malacostracan crustaceans. Nevertheless, the presence of distinct neuropils for chemosensory and mechanosensory qualities in S. coleoptrata, malacostracan Crustacea, and Hexapoda could indicate a common architectural principle within the Mandibulata. Furthermore, behavioral experiments indicate that S. coleoptrata is able to perceive airborne stimuli, both from live prey and from a chemical extract of the prey. These results are in line with the morphological findings concerning the well-developed olfactory centers in the deutocerebrum of this species. PMID- 20962284 TI - Cataract surgery in posterior polymorphous corneal dystrophy. PMID- 20962285 TI - Allergic contact dermatitis: a case series and review for the ophthalmologist. AB - Eyelid dermatitis is most commonly caused by an allergenic response, potentially from exposure at another site, rather than from local toxicity. Yet allergic contact dermatitis is a diagnosis often missed by ophthalmologists. The authors review the literature and detail their experience relating to the causes, clinical features and management of this condition. 14 patients over a 2-year period that were referred to the oculoplastic service for a further opinion were reviewed in a retrospective, non-comparative study. All patients underwent patch testing for diagnosis. 8 of the 14 patients had delays of more than 6 months from symptoms to diagnosis. In six of these, this was greater than 1 year. Similar delays are reported in the literature. 79% of the cases were referred by ophthalmologists. Although two of the patients were biopsied, this did not help in making the diagnosis. 13 patients had disease restricted to the eyelids, though only five of these had direct contact of the allergen with the eyelids. Two patients were also sensitised to topical steroid creams prescribed for their treatment. All patients improved after removal of the allergen. Further clinical features and management options from the literature are reviewed and discussed. PMID- 20962286 TI - Neurosonographic monitoring of 105 spontaneous cervical artery dissections: a prospective study. AB - OBJECTIVE: To monitor the sonographic course of spontaneous cervical artery dissections (sCADs) and investigate their recanalization and recurrence rates. METHODS: All consecutive patients with an MRI-proven sCAD were prospectively evaluated by neurovascular ultrasound (nUS) daily while in hospital, then monthly for the first 6 months after discharge and every 6 months thereafter, for a mean follow-up period of 58 months (range, 28-96 months). RESULTS: A total of 105 sCADs were detected in 76 patients: 61 (58.1%) involved the internal carotid artery and 44 (41.9%) the vertebral artery, while multiple sCADs were found in 4 patients (5.3%). Follow-up was obtained in 74 patients (97.3%, 103 vessels). The complete and hemodynamically significant (<50% stenosis) recanalization rates were 51.4% (53/103) and 20.4% (21/103). All but one complete recanalization occurred within the first 9 months. There were early recurrences (while in hospital) in 20 previously unaffected arteries (26.3%) and late recurrences in 2 arteries (2.7%), site of a previous sCAD. All patients (n = 6) with a family history of arterial dissection had a sCAD recurrence (4 early and 2 late) as opposed to 16 (22.8%) among those with no known familial disease (p < 0.001). CONCLUSIONS: These results suggest that most lumen changes occur within the first few months after the initial event, but recanalization may occur even after 1 year. Early recurrence is not uncommon and usually involves arteries previously unaffected by dissection, while the risk of late recurrence is low. A family history of arterial dissection is strongly associated with sCAD recurrence. PMID- 20962287 TI - Hallucinations and sleep disorders in PD: ten-year prospective longitudinal study. AB - OBJECTIVE: To assess prospectively progression and relationship of hallucinations and sleep disorders over a 10-year longitudinal study of patients with Parkinson disease (PD). METHODS: Eighty-nine patients with PD were recruited to fill cells of normal sleep without hallucinations (n = 20), sleep fragmentation only (n = 20), vivid dreams/nightmares (n = 20), hallucinations with insight (n = 20), and hallucinations without insight (n = 9). At baseline, 0.5, 1.5, 4, 6, and 10 years, sleep disorders and hallucinations were assessed by standardized scales with the longitudinal data analyzed by generalized estimating equations with assumptions of linearity in time. RESULTS: At 10 years, we could account for all subjects (27 interviewed, 61 deceased, and 1 too ill for interview). Hallucination prevalence and severity increased over time (p < 0.0001, p = 0.0001). Acting out dreams also increased over time (p = 0.001). In contrast, presence of vivid dreams/nightmares or sleep fragmentation did not increase over time. For all visits, the prevalence of sleep fragmentation did not differ between subjects with vs without hallucinations (odds ratio [OR] = 1.50, p = 0.09). However, severe sleep fragmentation was associated with concurrent hallucinations (OR 2.01, p = 0.006). The presence of hallucinations was also highly associated with concurrent vivid dreams/nightmares (OR = 2.60, p < 0.0001) and with concurrent acting out dreams (OR = 2.38, p = 0.0004). Among the baseline nonhallucinators, no sleep abnormalities at study entry predicted future development of hallucinations. CONCLUSIONS: Hallucinations and sleep abnormalities follow very different patterns of progression in PD over 10 years. Whereas patients with hallucinations often have concurrent sleep aberrations, no sleep problem is predictive of future hallucinations. PMID- 20962288 TI - CSF alpha-synuclein as a diagnostic biomarker for Parkinson disease and related dementias. PMID- 20962289 TI - Are anti-ganglioside antibodies of clinical value in multifocal motor neuropathy? PMID- 20962290 TI - Detection of elevated levels of alpha-synuclein oligomers in CSF from patients with Parkinson disease. AB - BACKGROUND: To date, there is no accepted clinical diagnostic test for Parkinson disease (PD) that is based on biochemical analysis of blood or CSF. The discovery of mutations in the SNCA gene encoding alpha-synuclein in familial parkinsonism and the accumulation of alpha-synuclein in the PD brain suggested a critical role for this protein in PD etiology. METHODS: We investigated total and alpha synuclein oligomers levels in CSF from patients clinically diagnosed with PD, progressive supranuclear palsy (PSP), or Alzheimer disease (AD), and age-matched controls, using ELISA developed in our laboratory. RESULTS: The levels of alpha synuclein oligomers and oligomers/total-alpha-synuclein ratio in CSF were higher in the PD group (n = 32; p < 0.0001, Mann-Whitney U test) compared to the control group (n = 28). The area under the receiver operating characteristic curve (AUC) indicated a sensitivity of 75.0% and a specificity of 87.5%, with an AUC of 0.859 for increased CSF alpha-synuclein oligomers in clinically diagnosed PD cases. However, when the CSF oligomers/total-alpha-synuclein ratio was analyzed, it provided an even greater sensitivity of 89.3% and specificity of 90.6%, with an AUC of 0.948. In another cross-sectional pilot study, we confirmed that the levels of CSF alpha-synuclein oligomers were higher in patients with PD (n = 25) compared to patients with PSP (n = 18; p < 0.05) or AD (n = 35; p < 0.001) or control subjects (n = 43; p < 0.05). CONCLUSION: Our results demonstrate that levels of alpha-synuclein oligomers in CSF and the oligomers/total-alpha synuclein ratio can be useful biomarkers for diagnosis and early detection of PD. PMID- 20962291 TI - Multifocal motor neuropathy: association of anti-GM1 IgM antibodies with clinical features. AB - OBJECTIVE: To determine the prevalence and specificity of antibodies against single gangliosides and ganglioside complexes in serum from 88 patients with multifocal motor neuropathy (MMN) and to study the association with clinical features. METHODS: ELISA was used to detect immunoglobulin (Ig)M, IgG, and IgA antibodies against GM1, GM2, GD1a, GD1b, GM1b, GT1a, GT1b, GQ1b, GalNAc-GD1a, and the glycolipid SGPG; absorption studies were performed to study cross-reactivity. Presence of antibodies against ganglioside complexes consisting of any of combinations of GM1, GM2, GD1a, GD1b, GT1b, and GQ1b was also tested. RESULTS: Anti-GM1 IgM, IgG, and IgA antibodies were detected in serum from 43%, 1%, and 5% of patients with MMN. Anti-GM2 IgM antibodies were detected in 6% and anti-GD1b IgM antibodies in 9% of patients. Patients with MMN with anti-GM1 IgM antibodies had more severe weakness (p < 0.01), more disability (p < 0.01), and more axon loss (p = 0.05) than patients without anti-GM1 IgM antibodies. Anti-GM1 IgM antibody titers correlated with Medical Research Council scores (correlation coefficient = 0.43; p < 0.0001). Anti-GD1b IgM antibody activity was associated with reduced vibration sense (p < 0.01). Absorption studies showed that anti-GD1b and anti-GM2 IgM antibodies cross-reacted with GM1. Antibodies against ganglioside complexes were not detected. Complexes containing GD1a, GD1b, GT1b, or GQ1b with GM1 lowered antibody activity against GM1. CONCLUSION: Anti ganglioside IgM antibodies in MMN display limited specificity and are associated with severity and clinical characteristics. Results of this study suggest that anti-GM1 IgM antibodies may play a role in MMN pathogenesis. PMID- 20962292 TI - The importance of longitudinal data on PD, hallucinations, and dream-enacting behaviors. PMID- 20962293 TI - Is frequent ultrasound monitoring of spontaneous cervical artery dissection clinically useful? PMID- 20962294 TI - Could direct inhibition of inflammation be the "next big thing" in treating atherosclerosis? PMID- 20962295 TI - Genome-wide association studies of plasma lipids: have we reached the limit? PMID- 20962296 TI - ADAM-mediated shedding, a new flavor in angiogenesis regulation. PMID- 20962297 TI - Urine menthol as a biomarker of mentholated cigarette smoking. AB - OBJECTIVES: Menthol cigarettes are smoked by 27% of U.S. smokers, and there are concerns that menthol might enhance toxicity of cigarette smoking by increasing systemic absorption of smoke toxins. We measured urine menthol concentrations in relation to biomarkers of exposure to nicotine and tobacco carcinogens. METHODS: Concentrations of menthol glucuronide (using a novel analytical method), nicotine plus metabolites (nicotine equivalents, NE), 4-(methylnitrosamino)-1-(3-pyridyl) 1-butanol (NNAL), and polycyclic aromatic hydrocarbon (PAH) metabolites were measured in the urine of 60 menthol and 67 regular cigarette smokers. RESULTS: Urine menthol was measurable in 82% of menthol and 54% in regular cigarette smokers. Among menthol smokers, urine menthol was highly correlated with NE, NNAL, and PAHs. In a multiple regression model NE but not menthol was significantly associated with NNAL and PAHs. CONCLUSIONS: Urine menthol concentration is a novel biomarker of exposure in menthol cigarette smokers, and is highly correlated with exposure to nicotine and carcinogens. Menthol is not independently associated with carcinogen exposure when nicotine intake is considered. PMID- 20962298 TI - Dietary benzo[a]pyrene intake from meat and the risk of colorectal cancer. AB - INTRODUCTION: One possible mechanism for the postulated link between high consumption of meat and colorectal cancer (CRC) is the content of benzo[a]pyrene (BaP) in meat. METHODS: We investigated this association in a population-based case-control study in Western Australia (567 cases and 713 controls). Participants' self-report of meat consumption and lifestyle was used in conjunction with the CHARRED carcinogen database to estimate their BaP intake. RESULTS: Dietary exposure to BaP from meat consumption was not associated with the risk of CRC. CONCLUSIONS: Our findings do not support the hypothesis that BaP exposure from meat consumption is a risk factor for CRC. IMPACT STATEMENT: This large-scale case-control study used a detailed meat questionnaire in conjunction with the CHARRED database in a large population with high meat intake but was unable to find any association between intake of BaP and colorectal cancer. PMID- 20962299 TI - The road from discovery to clinical diagnostics: lessons learned from the first FDA-cleared in vitro diagnostic multivariate index assay of proteomic biomarkers. AB - BACKGROUND: After more than a decade of biomarker discovery research using advanced genomic and proteomic technologies, very few biomarkers have been translated into clinical diagnostics for patient care. This has become an urgent issue to be addressed because the continuing funding from both the public and private sources are called into question. METHODS: We use as an example, OVA1, the first in vitro diagnostic multivariate index assay (IVDMIA) of proteomic biomarkers recently cleared by the US FDA (Food and Drug Administration) to describe our experience through the long road from biomarker discovery, to validation, and finally to multi-institutional trial for regulatory approval by the FDA. RESULTS: We discuss 3 issues that are key bridges in the path of biomarker development to actual clinical diagnostics: 1) to generate sufficient and "portable" evidence in preliminary validation studies to support investment for large-scale validation trials; 2) to carefully and clearly define clinical utility that balances desire for broad applicability and feasibility for completing clinical trials for regulatory approval; and 3) to select/develop assays with analytical performance suitable for clinical deployment. CONCLUSIONS: We learned that the road from biomarker discovery, validation, to clinical diagnostics could be long and winding, and often frustrating. However, we also know that, with the right approaches, at the end of the road, there is a rainbow waiting for us. IMPACT: Provide insights and recommendations for the translation of proteomic biomarkers into clinical diagnostics. PMID- 20962302 TI - Editor's note. Nutrition education. PMID- 20962300 TI - Targeting peptide termini, a novel immunoaffinity approach to reduce complexity in mass spectrometric protein identification. AB - Mass spectrometry and peptide-centric approaches are powerful techniques for the identification of differentially expressed proteins. Despite enormous improvements in MS technologies, sample preparation and efficient fractionation of target analytes are still major bottlenecks in MS-based protein analysis. The complexity of tryptically digested whole proteomes needs to be considerably reduced before low abundance proteins can be effectively analyzed using MS/MS. Sample preparation strategies that use peptide-specific antibodies are able to reduce the complexity of tryptic digests and lead to a substantial increase in throughput and sensitivity; however, the number of peptide-specific capture reagents is low, and consequently immunoaffinity-based approaches are only capable of detecting small sets of protein-derived peptides. In this proof-of principle study, special anti-peptide antibodies were used to enrich peptides from a complex mixture. These antibodies recognize short amino acid sequences that are found directly at the termini of the peptides. The recognized epitopes consist of three or four amino acids only and include the terminally charged group of the peptide. Because of its limited length, antibodies recognizing the epitope will enrich not only one peptide but a whole class of peptides that share this terminal epitope. In this study, beta-catenin-derived peptides were used to demonstrate that it is possible (i) to effectively generate antibodies that recognize short C-terminal peptide epitopes and (ii) to enrich and identify peptide classes from a complex mixture using these antibodies in an immunoaffinity MS approach. The expected beta-catenin peptides and a set of 38 epitope-containing peptides were identified from trypsin-digested cell lysates. This might be a first step in the development of proteomics applications that are based on the use of peptide class-specific antibodies. PMID- 20962303 TI - Strategies for selecting effective patient nutrition education materials. AB - Nutrition and diet therapy are at the center of health promotion activities and self-management of chronic diseases. To assist an individual in making informed decisions regarding his or her diet and increase adherence to dietary recommendations or treatments, healthcare professionals must select health information that is appropriate to the client's level of understanding. A systematic approach in the evaluation of patient education material, whether in print or on the World Wide Web, must focus on the information's content, literacy level, graphical displays, layout and typography, motivating principles, cultural relevance, and feasibility. Additional criteria should be evaluated when accessing Web sites and include source, site credibility, conflict of interest, disclaimer, disclosure, navigation, and interactivity information. PMID- 20962304 TI - Education methods and techniques for training home parenteral nutrition patients. AB - The goal of home infusion therapy education is to teach patients and their caregivers all aspects of home infusion to ensure independence in therapy administration and to decrease vascular access device complications and long-term parenteral nutrition (PN) complications. When patients receive home PN (HPN), the education is generally more complicated and requires a focus different from routine intravenous medication infusion. In addition, the management of an HPN patient is different from a hospitalized PN patient because needs and goals of HPN patients vary from those of hospitalized patients. Educating HPN patients so that goals and outcomes can be achieved effectively while allowing the patient to maintain as independent as possible and reduce PN complications is a challenge. This article reviews the methods of education currently available to HPN patients. The education provided to HPN patients also is reviewed, with an emphasis on achieving independence and reducing PN complications. PMID- 20962305 TI - Education materials for home nutrition support consumers. AB - Parenteral and enteral nutrition (PEN) are life-sustaining therapies that can be administered in the home. They are also complex therapies, with many facets about which patients and caregivers must learn. Once home on PEN, the patient assumes much of the responsibility for day-to-day care. Although patients are trained in many aspects of home PEN management before they leave the hospital and often again upon arrival home, there is much to retain and put into practice. Many health care facilities, companies, and nonprofit organizations create home PEN patient education materials. In 1993 and 1995, directories were created to list the home nutrition support materials that were available. The 1995 directory has been updated and appended to this article. This directory was created in the spirit of the original: to encourage communication and the exchange of information between individuals and institutions. PMID- 20962306 TI - Nutrition in medicine: nutrition education for medical students and residents. AB - Proper nutrition plays a key role in disease prevention and treatment. Many patients understand this link and look to physicians for guidance diet and physical activity. Actual physician practice, however, is often inadequate in addressing the nutrition aspects of diseases such as cancer, obesity, and diabetes. Physicians do not feel comfortable, confident, or adequately prepared to provide nutrition counseling, which may be related to suboptimal knowledge of basic nutrition science facts and understanding of potential nutrition interventions. Historically, nutrition education has been underrepresented at many medical schools and residency programs. Our surveys over a decade show that most medical schools in the United States are still not ensuring adequate nutrition education, and they are not producing graduates with the nutrition competencies required in medical practice. Physicians, residents, and medical students clearly need more training in nutrition assessment and intervention. The Nutrition in Medicine (NIM) project, established to develop and distribute a core nutrition curriculum for medical students, offers a comprehensive online set of courses free of charge to medical schools. The NIM medical school curriculum is widely used in the United States and abroad. A new initiative, Nutrition Education for Practicing Physicians, offers an innovative online medical nutrition education program for residents and other physicians-in-training, but with targeted, practice-based educational units designed to be completed in 15 minutes or less. The NIM project is strengthening medical nutrition practice by providing a free, comprehensive, online nutrition curriculum with clinically relevant, evidence-based medical education for undergraduate and postgraduate learners. PMID- 20962307 TI - Developing an education program for nutrition support teams. AB - Focused training and continuing medical education are necessary for nutrition support clinicians to acquire new skills, maintain competence, and keep abreast of advancements in the field. Unfortunately, there is a lack of physician nutrition specialists to act as teachers and role models. One solution is to have members of a multidisciplinary nutrition support team, regardless of discipline, share their expertise with others. This is best accomplished within the framework of a formal education program that can accommodate the knowledge and skill level of each instructor and educational goals of each student. Developing an education program should include the following steps: formulate general goals of the program, specify learning objectives, assess each student's current level of knowledge and educational goals, determine educational strategies and learning activities that will best meet the goals of each student and the program, and devise a method to evaluate the performance of each student and the program as a whole. PMID- 20962308 TI - Use of a standardized progress note and assessment form for performance evaluation and quality improvement. AB - In addition to filling patient care-related duties, the Nutrition Support Service also serves as a platform for experiential education and training of pharmacy residents, surgical interns, doctor of pharmacy students, and graduate dietetic students. Because of the diversity in experience and training among members of the team and their trainees, a standardized progress note form with a subsequent progress note assessment form was developed to maintain consistency and to ensure a certain level of quality in the daily progress notes written by the trainees. The instructor randomly chose one of the trainee's patient progress notes for verbal and written evaluation weekly. Twelve trainees from July 2009 to January 2010 were evaluated. A significant improvement in weekly performance scores (from an average score of 74% +/- 12% to 91% +/- 7% to 96% +/- 6%) was noted by the second and third weeks compared with the first week, respectively (P < .001). Trainees were unanimous that this tool facilitated improvement of their clinical skills and ability to write effective daily progress notes. PMID- 20962309 TI - Professional outcomes of completing a clinical nutrition fellowship: Cleveland Clinic's 16-year experience. AB - BACKGROUND: Cleveland Clinic has trained 17 physician nutrition specialists since the establishment of its clinical nutrition fellowship (CNF) in 1994. The paths taken by the graduates and whether they continue to practice clinical nutrition are largely unknown. METHODS: To investigate the professional outcomes of completing a CNF, a survey of graduates was conducted. RESULTS: Fifty-seven percent of respondents (n = 8) applied to another fellowship prior to applying to a CNF. The 2 most common reasons for applying to a CNF were to increase knowledge of clinical nutrition and increase the chance of acquiring a gastroenterology fellowship. Eighty-five percent (n = 10) of graduates found the CNF to be valuable. Eighty-six percent (n = 12) went on to complete a gastroenterology fellowship, and 67% (n = 8) of graduates believed that completing a CNF increased their chances of gaining acceptance to a gastroenterology fellowship. Only 42% (n = 6) of the graduates currently hold professions that specifically dictate the use of clinical nutrition, but 61% (n = 8) reported using clinical nutrition in their daily or weekly practice. Fifty percent (n = 7) of graduates believed that completing a CNF made them more competitive job candidates, but only 21% (n = 3) said that their extra training is reflected in their current salary. CONCLUSIONS: It appears that CNFs are being used as a method of subsequently acquiring a gastroenterology or other medical fellowships. Although not working in defined clinical nutrition professions, >50% of graduates continue to apply their CNF skills after completing their training. A small percentage have found dedicated nutrition-based clinical professions. PMID- 20962310 TI - Barriers to providing nutrition counseling cited by physicians: a survey of primary care practitioners. AB - In a 1995 pivotal study, Kushner described the attitudes, practice behaviors, and barriers to the delivery of nutrition counseling by primary care physicians. This article recognized nutrition and dietary counseling as key components in the delivery of preventive services by primary care physicians. Kushner called for a multifaceted approach to change physicians' counseling practices. The prevailing belief today is that little has changed. Healthy People 2010 and the U.S. Preventive Task Force identify the need for physicians to address nutrition with patients. The 2010 objective was to increase to 75% the proportion of office visits that included ordering or providing diet counseling for patients with a diagnosis of cardiovascular disease, diabetes, or hypertension. At the midcourse review, the proportion actually declined from 42% to 40%. Primary care physicians continue to believe that providing nutrition counseling is within their realm of responsibility. Yet the gap remains between the proportion of patients who physicians believe would benefit from nutrition counseling and those who receive it from their primary care physician or are referred to dietitians and other healthcare professionals. The barriers cited in recent years continue to be those listed by Kushner: lack of time and compensation and, to a lesser extent, lack of knowledge and resources. The 2010 Surgeon General's Vision for a Healthy and Fit Nation and First Lady Obama's "Let's Move Campaign" spotlight the need for counseling adults and children on diet and physical activity. PMID- 20962311 TI - Loss of protein, immunoglobulins, and electrolytes in exudates from negative pressure wound therapy. AB - BACKGROUND: A relatively new technology in wound care, negative pressure wound therapy (NPWT), has become widely used for the management of open abdomens and soft tissue wounds and provides a means to collect wound exudate to quantify protein loss. METHODS: A prospective observational study was conducted in surgical, trauma, or burn patients (8 patients with open abdomens and 9 patients with acute soft tissue wounds on NPWT). NPWT exudate was collected and assayed to characterize loss of protein, electrolyte, and immunoglobulins over multiple days of NPWT. RESULTS: Total protein was present in open abdomen NPWT exudate, 2.9 +/- 0.9 g/dL. In the soft tissue wound exudate, a similar mean concentration was found, 2.59 +/- 0.6 g/dL (P = .34). Exudate concentrations of albumin, urea nitrogen, immunoglobulins, and electrolytes between wound types were also not significantly different. There were significant (P = .03) differences in the median volume of exudate, 1031 mL/d for open abdomens in contrast to 245 mL/d soft tissue wounds. Therefore, 24-hour losses of proteins and electrolytes were greater in patients with open abdomens than soft tissue wounds. Mean total protein loss was 25 +/- 17 g/d for open abdomens and 8 +/- 5 g/d for soft tissue wounds. CONCLUSION: There are significant losses of proteins in wound exudate. As there is no significant difference in the concentration of total protein between wound type, the rate of loss may be calculated as 2.9 g/dL times the volume of wound exudate. The rate of protein loss from wounds is similar to the presently assumed insensible loss rate of 12-25 g/d. PMID- 20962312 TI - Effect of a fish oil-containing beverage on changes in plasma lipid fatty acids in patients with malabsorption. AB - BACKGROUND: The aim of this pilot study was to assess tolerance of a beverage containing omega-3 fatty acids (fish oil) in patients with malabsorption receiving chronic parenteral nutrition (PN). The authors wanted to determine whether fish oil could be absorbed and incorporated into plasma fatty acids and reduce markers of inflammation. METHODS: This was a small intervention study in home-dwelling PN-dependent patients with chronic malabsorption. Ten patients were provided a drink containing 1.5 g of fish oil per day for 12 weeks. Baseline and post-supplement serum fatty acid profiles were compared. RESULTS: Five of 10 patients withdrew from the study because of GI side effects, principally worsened diarrhea, associated with the supplement. Modest increases were found in 20:5omega-3, 22:5omega-3, and 22:6omega-3 levels in both phospholipids and triglycerides in plasma (all P < .05). In phospholipids, a reduced arachidonic acid level was seen (P = .02). These changes were not sufficient to effect improvements in serum tumor necrosis factor-alpha (TNFalpha), soluble TNF receptor, C-reactive protein, or interleukin-6. CONCLUSIONS: Some patients with severe malabsorption can absorb oral omega-3 fatty acid supplements and incorporate these fatty acids into serum phospholipids and triglycerides. However, side effects are very common, and no anti-inflammatory effect was found, presumably related to the modest level of fatty acid change. PMID- 20962313 TI - Maternal vitamin D status in gestational diabetes mellitus. AB - BACKGROUND: Vitamin D deficiency has long been suspected as a risk factor for glucose intolerance. This study compared serum levels of 25-hydroxy vitamin D(3) in pregnant women with gestational diabetes mellitus (GDM), impaired glucose tolerance (IGT), and non-GDM control subjects. METHODS: In this case-control study, 54 women with diagnosed GDM and 39 women with IGT (1 abnormal oral glucose tolerance test) were compared with 111 non-GDM control women in whom GDM were excluded by glucose challenge test. Controls were matched in gestational age, age, and body mass index with IGT and GDM groups. RESULTS: Maternal serum 25 hydroxy vitamin D(3) concentration in GDM and IGT groups at 24-28 weeks of gestation were significantly lower than non-GDM controls (P = .001). A total of 83.3% of GDM compared with 71.2% of the control group had plasma 25-hydroxy vitamin D(3) concentrations consistent with a diagnosis of vitamin D deficiency (<20 ng/mL; P = .03). Women with GDM had a 2.66-fold increased risk of deficient status (25-hydroxy vitamin D(3) <15 ng/mL) compared with control group. CONCLUSIONS: These results suggested that rates of vitamin D deficiency are higher among women with IGT/GDM, and the relationship between vitamin D status and glucose tolerance in pregnancy needs further study. PMID- 20962314 TI - Low-fat versus low-carbohydrate diets, weight loss, vascular health, and prevention of coronary artery disease: the evidence, the reality, the challenge, and the hope. PMID- 20962315 TI - Carbohydrate- vs fat-controlled diet effect on weight loss and coronary artery disease risk: a pilot feeding study. AB - This pilot study compared weight loss and serum indicators of coronary artery disease (CAD) risk between 2 weight loss (energy-deficit) diets, one controlled for carbohydrate as a percentage of total calories and the other controlled for fat as percentage of total calories. Participants were randomized to 1 of 2 diets and fed on an outpatient basis for 70 days, after which they followed their diets using their own resources for an additional 70 days. Energy deficit for the diets was determined by indirect calorimetry with a 500- to 750-calorie per day adjustment. Weight and CAD risk indicators and serum lipid and C-reactive protein levels were measured at baseline, day 70, and day 140. The study was completed by 16 of 20 participants who were able to comply with the feeding portion of the study as well as with follow-up appointments during the second (self-management) period of the study. Participants lost weight in both diet groups (24.4 lbs, carbohydrate controlled; 18.5 lbs, fat controlled), and serum CAD risk factors decreased in both groups. There were no significant differences in CAD risk factors between diet groups, although there was a trend toward lighter low density lipoprotein (LDL) size in the carbohydrate-controlled group. During the self-management portion of the study, weight loss stalled or regained from loss during the previous feeding period. The results, although underpowered, are consistent with recent studies in which macronutrient ratio of total calories in diet did not affect degree of weight loss and in which carbohydrate-controlled diets produced a predominance of lighter LDLs. PMID- 20962316 TI - Patient education: the value of support groups. PMID- 20962318 TI - Commentary 1: The importance of expertise. PMID- 20962317 TI - Evaluation of extended-release pancreatic enzyme to dissolve a clog. PMID- 20962319 TI - Commentary 2: The perils of "success": maintaining the richness and diversity of qualitative scholarship. PMID- 20962320 TI - Commentary 3: The disciplinary divide. PMID- 20962322 TI - MicroRNAs 15a/16-1 function as tumor suppressor genes in multiple myeloma. AB - Multiple myeloma is characterized by frequent chromosomal alterations. Deletion of chr 13, especially band 13q14, is commonly observed in early stages of MM, suggesting the presence of tumor suppressor genes within this region. Here, we functionally validate the role of the microRNAs-15a/16-1 cluster, centered at the deleted region, as TSGs and delineate their downstream target genes in MM. Using "sponge" lentiviral vectors to competitive stably inhibit mature microRNAs in vitro and in vivo, we have documented enhanced proliferative and invasive capacity of cells with stably inhibition of miR-16. Importantly, miR-16 inhibition decreased animal survival in a xenograft model of MM by increasing tumor load and host angiogenesis. Expression profiling analysis of miR-16 deficient cells identified a large number of downstream target genes including FGFR1, PI3KCa, MDM4, VEGFa, as well as secondary affected genes such as JUN and Jag1. We validated designated genes showing binding sites within the conserved 3' UTR and also within the mRNA coding region as direct miR-16 targets, thus indicating that the miRNAs may have many more targets than anticipated by conventional prediction methods. This loss-of-function system, which mimics the 13q chromosomal deletion, provides a valuable tool to investigate their function in MM pathogenesis and their potential use as therapeutic targets. PMID- 20962323 TI - Translocation t(14;16) and multiple myeloma: is it really an independent prognostic factor? AB - Many trials in myeloma are stratified on cytogenetic abnormalities. Among them, the most commonly chosen are the t(4;14), the del(17p), and the t(14;16). If data are well established for t(4;14) and del(17p), very few data support the use of t(14;16). To address this issue, we retrospectively analyzed 1003 patients with newly diagnosed myeloma for this abnormality. We identified 32 patients with the t(14;16). Compared with patients lacking the t(14;16), we did not observe any difference in overall survival (P = .28). Moreover, in multivariate analyses, the t(14;16) was not prognostic (P = .39). In conclusion, our data do not support the use of t(14;16)-specific probes in the diagnostic panels of multiple myeloma. PMID- 20962325 TI - Visualization of lymphatic vessels by Prox1-promoter directed GFP reporter in a bacterial artificial chromosome-based transgenic mouse. AB - Although the blood vessel-specific fluorescent transgenic mouse has been an excellent tool to study vasculogenesis and angiogenesis, a lymphatic-specific fluorescent mouse model has not been established to date. Here we report a transgenic animal model that expresses the green fluorescent protein under the promoter of Prox1, a master control gene in lymphatic development. Generated using an approximately 200-kb-long bacterial artificial chromosome harboring the entire Prox1 gene, this Prox1-green fluorescent protein mouse was found to faithfully recapitulate the expression pattern of the Prox1 gene in lymphatic endothelial cells and other Prox1-expressing organs, and enabled us to conveniently visualize detailed structure and morphology of lymphatic vessels and networks throughout development. Our data demonstrate that this novel transgenic mouse can be extremely useful for detection, imaging, and isolation of lymphatic vessels and monitoring wound-associated lymphangiogenesis. Together, this Prox1 green fluorescent protein transgenic mouse will be a great tool for the lymphatic research. PMID- 20962324 TI - Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. AB - Regulatory B cells control inflammation and autoimmunity in mice, including the recently identified IL-10-competent B10 cell subset that represents 1% to 3% of spleen B cells. In this study, a comparable IL-10-competent B10 cell subset was characterized in human blood. B10 cells were functionally identified by their ability to express cytoplasmic IL-10 after 5 hours of ex vivo stimulation, whereas progenitor B10 (B10pro) cells required 48 hours of in vitro stimulation before they acquired the ability to express IL-10. B10 and B10pro cells represented 0.6% and approximately 5% of blood B cells, respectively. Ex vivo B10 and B10pro cells were predominantly found within the CD24(hi)CD27(+) B-cell subpopulation that was able to negatively regulate monocyte cytokine production through IL-10-dependent pathways during in vitro functional assays. Blood B10 cells were present in 91 patients with rheumatoid arthritis, systemic lupus erythematosus, primary Sjogren syndrome, autoimmune vesiculobullous skin disease, or multiple sclerosis, and were expanded in some cases as occurs in mice with autoimmune disease. Mean B10 + B10pro-cell frequencies were also significantly higher in patients with autoimmune disease compared with healthy controls. The characterization of human B10 cells will facilitate their identification and the study of their regulatory activities during human disease. PMID- 20962326 TI - Genome-wide identification of human microRNAs located in leukemia-associated genomic alterations. AB - Cytogenetic alterations, such as amplifications, deletions, or translocations, contribute to myeloid malignancies. MicroRNAs (miRNAs) have emerged as critical regulators of hematopoiesis, and their aberrant expression has been associated with leukemia. Genomic regions containing sequence alterations and fragile sites in cancers are enriched with miRNAs; however, the relevant miRNAs within these regions have not been evaluated on a global basis. Here, we investigated miRNAs relevant to acute myeloid leukemia (AML) by (1) mapping miRNAs within leukemia associated genomic alterations in human AML cell lines by high-resolution genome arrays and (2) evaluating absolute expression of these miRNAs by massively parallel small RNA sequencing. Seventy-seven percent (542 of 706) of miRNAs mapped to leukemia-associated copy-number alterations in the cell lines; however, only 18% (99 of 542) of these miRNAs are expressed above background levels. As evidence that this subset of miRNAs is relevant to leukemia, we show that loss of 2 miRNAs identified in our analysis, miR-145 and miR-146a, results in leukemia in a mouse model. Small RNA sequencing identified 28 putative novel miRNAs, 18 of which map to leukemia-associated copy-number alterations. This detailed genomic and small RNA analysis points to a subset of miRNAs that may play a role in myeloid malignancies. PMID- 20962327 TI - Deciphering the human platelet sheddome. AB - Activated platelets shed surface proteins, potentially modifying platelet function as well as providing a source of bioactive fragments. Previous studies have identified several constituents of the platelet sheddome, but the full extent of shedding is unknown. Here we have taken a global approach, analyzing protein fragments in the supernate of activated platelets using mass spectroscopy and looking for proteins originating from platelet membranes. After removing plasma proteins and microparticles, 1048 proteins were identified, including 69 membrane proteins. Nearly all of the membrane proteins had been detected previously, but only 10 had been shown to be shed in platelets. The remaining 59 are candidates subject to confirmation. Based on spectral counts, protein representation in the sheddome varies considerably. As proof of principle, we validated one of the less frequently detected proteins, semaphorin 7A, which had not previously been identified in platelets. Surface expression, cleavage, and shedding of semaphorin 7A were demonstrated, as was its association with alpha granules. Finally, cleavage of semaphorin 7A and 12 other proteins was substantially reduced by an inhibitor of ADAM17, a known sheddase. These results define a subset of membrane proteins as sheddome candidates, forming the basis for further studies examining the impact of ectodomain shedding on platelet function. PMID- 20962328 TI - Metabolic syndromes and malignant transformation: where the twain shall meet. AB - Recurrent somatic mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes that result in the accumulation of D-2-hydroxyglutarate (D-2-HG) have been identified in malignant gliomas and in acute myeloid leukemia (AML). However, the function of this metabolite in normal and malignant tissues remains uncertain. A report in the current issue of Science describes a germline IDH2 mutation in a subset of patients with a rare metabolic disorder--D-2-hydroxyglutaric aciduria that is similar to mutations seen in cancer patients. These observations further elucidate the effects of IDH mutations on normal and malignant cells. PMID- 20962329 TI - p11 and gene therapy for severe psychiatric disorders: a practical goal? AB - In this issue of Science Translational Medicine, Alexander and colleagues describe coherent evidence drawn from humans and from modeled animals that supports a brain region-specific gene therapy for depression: adeno-associated virus (AAV)-mediated transfer of the gene encoding p11 to the nucleus accumbens (NAcc). The investigators found that focal NAcc knockdown of p11 expression in mice resulted in behavioral deficits related to depression and that AAV-mediated p11 gene transfer to the NAcc rescued the depression-related behavioral deficits of mice in which endogenous p11 had been genetically knocked out. They also found that p11 levels were lower in the NAcc of patients with depression than in the NAcc of matched controls. Taken together, the data suggest that gene therapies aimed at enhancing p11 in the NAcc may represent promising new approaches for treating depression; however, a large number of clinical and regulatory issues must be overcome before such therapies can be implemented. PMID- 20962330 TI - Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens. AB - The etiology of major depression remains unknown, but dysfunction of serotonergic signaling has long been implicated in the pathophysiology of this disorder. p11 is an S100 family member recently identified as a serotonin 1B [5 hydroxytryptamine 1B (5-HT(1B))] and serotonin 4 (5-HT(4)) receptor-binding protein. Mutant mice in which p11 is deleted show depression-like behaviors, suggesting that p11 may be a mediator of affective disorder pathophysiology. Using somatic gene transfer, we have now identified the nucleus accumbens as a key site of p11 action. Reduction of p11 with adeno-associated virus (AAV) mediated RNA interference in the nucleus accumbens, but not in the anterior cingulate, of normal adult mice resulted in depression-like behaviors nearly identical to those seen in p11 knockout mice. Restoration of p11 expression specifically in the nucleus accumbens of p11 knockout mice normalized depression like behaviors. Human nucleus accumbens tissue shows a significant reduction of p11 protein in depressed patients when compared to matched healthy controls. These results suggest that p11 loss in rodent and human nucleus accumbens may contribute to the pathophysiology of depression. Normalization of p11 expression within this brain region with AAV-mediated gene therapy may be of therapeutic value. PMID- 20962331 TI - An integrated genomic and epigenomic approach predicts therapeutic response to zebularine in human liver cancer. AB - Epigenomic changes such as aberrant hypermethylation and subsequent atypical gene silencing are characteristic features of human cancer. Here, we report a comprehensive characterization of epigenomic modulation caused by zebularine, an effective DNA methylation inhibitor, in human liver cancer. Using transcriptomic and epigenomic profiling, we identified a zebularine response signature that classified liver cancer cell lines into two major subtypes with different drug responses. In drug-sensitive cell lines, zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines showed up-regulation of oncogenic networks (for example, E2F1, MYC, and TNF) that drive liver cancer growth in vitro and in preclinical mouse models. Assessment of zebularine-based therapy in xenograft mouse models demonstrated potent therapeutic effects against tumors established from zebularine-sensitive but not zebularine-resistant liver cancer cells, leading to increased survival and decreased pulmonary metastasis. Integration of the zebularine gene expression and demethylation response signatures allowed differentiation of patients with hepatocellular carcinoma according to their survival and disease recurrence. This integrated signature identified a subclass of patients within the poor-survivor group that is likely to benefit from therapeutic agents that target the cancer epigenome. PMID- 20962332 TI - Enhanced angiogenic capacity of human umbilical vein endothelial cells from women with preeclampsia. AB - Maternal and placental angiogenic abnormalities are a common feature of preeclampsia. The aim of this study was to determine if endothelial cells from women with preeclampsia exhibit different angiogenic responses compared to healthy cells. Using the endothelial tube formation assay, we have shown that primary human umbilical vein endothelial cells (HUVECs) isolated from women with preeclampsia display greater levels of in vitro angiogenic branching compared to cells from healthy women. A comparable increase in tube formation was observed in healthy cells cultured at 0.5% O(2). Vascular endothelial growth factor (VEGF) receptor inhibition resulted in a decrease in angiogenesis in both healthy hypoxic cells and cells from women with preeclampsia. These findings demonstrate that HUVECs from women with preeclampsia exhibit inherent differences in their angiogenic capacity which are apparent in the absence of placental or maternal factors. PMID- 20962333 TI - Designing a measure of Complexity Compression in registered nurses. AB - Researchers in Minnesota have described and validated the phenomenon of Complexity Compression in qualitative studies of registered nurses. Analysis of themes from this research led to the design of a survey to assess nurses' agreement with variables that contribute to their experience of Complexity Compression. The survey was administered to a random sample of 199 registered nurses in Minnesota. Exploratory factor analysis was used to evaluate the attributes of Complexity Compression and its underlying structure. Three factors emerged that explained 51.4% of the variance in responses: work of nursing, systems, and personal factors. Internal consistency of the factors ranged from .79 to .89. Validity of the survey for assessment of Complexity Compression in hospital-based nurses was supported. The construct of Complexity Compression and its contributing factors will be tested in future studies with nurses in a variety of health care settings. PMID- 20962334 TI - Molecular rearrangements involved in the capsid shell maturation of bacteriophage T7. AB - Maturation of dsDNA bacteriophages involves assembling the virus prohead from a limited set of structural components followed by rearrangements required for the stability that is necessary for infecting a host under challenging environmental conditions. Here, we determine the mature capsid structure of T7 at 1 nm resolution by cryo-electron microscopy and compare it with the prohead to reveal the molecular basis of T7 shell maturation. The mature capsid presents an expanded and thinner shell, with a drastic rearrangement of the major protein monomers that increases in their interacting surfaces, in turn resulting in a new bonding lattice. The rearrangements include tilting, in-plane rotation, and radial expansion of the subunits, as well as a relative bending of the A- and P domains of each subunit. The unique features of this shell transformation, which does not employ the accessory proteins, inserted domains, or molecular interactions observed in other phages, suggest a simple capsid assembling strategy that may have appeared early in the evolution of these viruses. PMID- 20962335 TI - Differences in patellar cartilage thickness, transverse relaxation time, and deformational behavior: a comparison of young women with and without patellofemoral pain. AB - BACKGROUND: The origin of patellofemoral pain (PFP) may be associated with the inability of the patellofemoral joint cartilage to absorb and distribute patellofemoral joint forces. HYPOTHESIS: When compared with a pain-free control group, young active women with PFP will demonstrate differences in their baseline patellar cartilage thickness and transverse (T2) relaxation time, as well as a less adaptive response to an acute bout of joint loading. STUDY DESIGN: Controlled laboratory study; Level of evidence, 3. METHODS: Ten women between the ages of 23 to 37 years with PFP and 10 sex-, age-, and activity-matched pain-free controls participated. Quantitative magnetic resonance imaging of the patellofemoral joint was performed at baseline and after participants performed 50 deep knee bends. Differences in baseline cartilage thickness and T2 relaxation time, as well as the postexercise change in patellar cartilage thickness and T2 relaxation time, were compared between groups. RESULTS: Individuals with PFP demonstrated reductions in baseline cartilage thickness of 14.0% and 14.1% for the lateral patellar facet and total patellar cartilage, respectively. Similarly, individuals with PFP exhibited significantly lower postexercise cartilage thickness change for the lateral patellar facet (2.1% vs 8.9%) and the total patellar cartilage (4.4% vs 10.0%) when compared with the control group. No group differences in baseline or postexercise change in T2 relaxation time were found. CONCLUSION: The findings suggest that a baseline reduction in patellar cartilage thickness and a reduced deformational behavior of patellar cartilage following an acute bout of loading are associated with presence of PFP symptoms. PMID- 20962336 TI - Fifteen-year outcome of endoscopic anterior cruciate ligament reconstruction with patellar tendon autograft for "isolated" anterior cruciate ligament tear. AB - BACKGROUND: Few studies report the long-term results of anterior cruciate ligament rupture and single-incision endoscopic reconstructive surgery. Outcomes are often clouded by concomitant meniscal, chondral, or ligament injuries. PURPOSE: To determine the 15-year outcomes of anterior cruciate ligament ruptures treated with endoscopic anterior cruciate ligament reconstruction using middle third patellar tendon autograft. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between January 1993 and April 1994, 333 consecutive patients underwent anterior cruciate ligament reconstruction. Patients with associated ligamentous injury requiring surgery, previous meniscectomy, or meniscal injury requiring more than one-third meniscectomy; chondral injury diagnosed at arthroscopy; and an abnormal contralateral knee were excluded. Ninety patients met the inclusion criteria. Outcomes included range of motion, Lachman and pivot-shift tests, instrumented ligament testing, single-legged hop test, Lysholm Knee Score, the International Knee Documentation Committee evaluation, and radiographic assessment. RESULTS: Thirty percent of patients had further anterior cruciate ligament injury. Twenty-four percent of patients (n = 22) sustained contralateral anterior cruciate ligament ruptures, and 8% (n = 7) ruptured the graft (P = .009). Graft rupture was associated with a graft inclination angle <17 degrees (P = .02). Contralateral anterior cruciate ligament rupture was associated with age <18 years at time of primary injury (P = .001). All patients had normal or nearly normal (International Knee Documentation Committee evaluation) Lachman and instrumented testing, and 91% had a negative pivot-shift result. Seventy percent of patients had kneeling pain. Median subjective International Knee Documentation Committee evaluation was 91 of 100. Fifty-one percent of patients had radiographic evidence of osteoarthritis (41% grade B; 10% grade C). CONCLUSION: Good results are maintained at 15 years after surgery with respect to ligamentous stability, subjective outcomes, and range of motion. Kneeling pain remains a significant problem. Concern remains regarding the incidence of further anterior cruciate ligament injury and the increasing number of patients with radiographic and clinical signs of osteoarthritis despite surgical stabilization. PMID- 20962337 TI - Cardiogenic shock in the setting of severe aortic stenosis: role of intra-aortic balloon pump support. AB - OBJECTIVE: To investigate the haemodynamic effects of intra-aortic balloon pump (IABP) support in patients with severe aortic stenosis (AS) presenting in cardiogenic shock (CS). DESIGN: Observational cohort study. Setting Tertiary academic centre coronary intensive care unit (CICU). Patients Patients presenting to the CICU in CS with an established diagnosis of AS (n=25 with mean age (+/- SD) of 73.5 +/- 9.5 years). The peak and mean Doppler AV gradients were 67 +/- 26.8 mm Hg and 39.8 +/- 16.8 mm Hg, respectively, with a mean baseline cardiac index of 1.77 +/- 0.38 l/min/m2). Interventions Utilisation of IABP. Main outcome measures Haemodynamic impact of IABP over time. RESULTS: With the insertion of an IABP, patients' cardiac index improved from 1.77 l/min/m2 to 2.18 and 2.36 l/min/m2 at 6 and 24 h, respectively (p<0.001 for both times points). Systemic vascular resistance was reduced from 1331 dyn/s/cm5 to 1265 and 1051 dyn/s/cm5 at 6 and 24 h, respectively (p=0.66 and p=0.005, respectively). The central venous pressure was reduced from 14.8 mm Hg to 13.2 and 10.9 mm Hg at 6 and 24 h, respectively (p=0.12 and p=0.03, respectively). IABP insertion was associated with a complication in 3 of the 25 cases, including a deep vein thrombosis, thrombocytopenia, limb ischaemia, and technical malfunctioning of the device. CONCLUSIONS: IABP support improves the haemodynamic profile in patients with severe AS who present in CS. IABP utilisation in this critically ill population should be strongly considered as patients are being evaluated for candidacy for advanced interventions. PMID- 20962338 TI - High-dose tirofiban pretreatment reduces the need for bail-out study medication in patients with ST-segment elevation myocardial infarction: results of a subgroup analysis of the On-TIME 2 trial. AB - OBJECTIVE: This study investigated the outcome of patients who received bail-out study medication and evaluated whether high-dose tirofiban (HDT) pretreatment may reduce the need for bail-out study medication. DESIGN: A prespecified analysis of the multicentre, double-blind, placebo controlled, randomised On-TIME 2 trial. Bail-out use of study medication was predefined and part of the combined clinical end point. PATIENTS: 984 patients excluded from many coronary intervention hospitals in different countries were randomly assigned to HDT or placebo. In the subgroup who received blinded bail-out treatment, patients pretreated with placebo who received bail-out HDT were compared with those pretreated with HDT who received bail-out placebo. Interventions Routine prehospital initiation of HDT versus bail-out use of HDT. MAIN OUTCOME MEASURES: Electrocardiographic and clinical outcome. RESULTS: Blinded bail-out study medication was used in 24% (237/980) of patients, with a higher rate in patients pretreated with placebo: 29% (140/492) versus 20% (97/488), p=0.002. Bail-out versus no bail-out use of study medication was associated with more residual ST deviation (5.5+/-7.2 vs 3.7+/-4.8 mm, p=0.005), and worse clinical outcome (major adverse cardiac events (MACE) at 30 days 12.2% vs 5.6%, p<0.001), mainly due to poor outcome in patients who received HDT bail-out. In patients pretreated with HDT who received placebo bail-out study medication, residual ST deviation and clinical outcome did not differ significantly compared with patients who did not receive bail-out medication (4.0+/-4.6 vs 3.7+/- 4.8 mm, p=0.703, MACE 7.2% vs 5.6%, p=0.535). CONCLUSIONS: Routine prehospital treatment with HDT significantly reduced the use of blinded bail-out study medication. The need for bail-out therapy was associated with a less favourable outcome. This analysis suggests that routine pretreatment is superior to provisional use of HDT in patients with ST-segment elevation myocardial infarction. PMID- 20962339 TI - Control of free fatty acids during acute myocardial ischaemia. AB - During the onset of an acute coronary syndrome, an immediate increase in plasma free fatty acid (FFA) concentrations presents the ischaemic underperfused myocardium with a metabolic challenge to its survival. For the maintenance of contraction and to counter ventricular arrhythmias, parenteral treatment to reduce FFA availability should be available for paramedics when the patient is first seen. The best treatment options are insulin which partly inhibits FFA release from adipose tissue, immediate reduction of adipose tissue lipolysis, perhaps by new analogues of nicotinic acid, or measures to decrease the FFA/molar binding ratio with albumin. None has yet been tested in appropriate clinical trials. PMID- 20962340 TI - Cardiac memory in Ebstein anomaly. PMID- 20962341 TI - Short-term effects of transcatheter aortic valve implantation. PMID- 20962342 TI - Diesel exhaust inhalation does not affect heart rhythm or heart rate variability. AB - OBJECTIVE: Exposure to air pollution is associated with increases in cardiovascular morbidity and mortality. This study was undertaken to determine the effect of diesel exhaust inhalation on heart rhythm and heart rate variability in healthy volunteers and patients with coronary heart disease. DESIGN AND SETTING: Double-blind randomised crossover studies in a university teaching hospital. PATIENTS: 32 healthy non-smoking volunteers and 20 patients with prior myocardial infarction. INTERVENTIONS: All 52 subjects were exposed for 1 h to dilute diesel exhaust (particle concentration 300 MUg/m3) or filtered air. MAIN OUTCOME MEASURES: Heart rhythm and heart rate variability were monitored during and for 24 h after the exposure using continuous ambulatory electrocardiography and assessed using standard time and frequency domain analysis. RESULTS: No significant arrhythmias occurred during or following exposures. Patients with coronary heart disease had reduced autonomic function in comparison to healthy volunteers, with reduced standard deviations of the NN interval (SDNN, p < 0.001) and triangular index (p < 0.001). Diesel exhaust did not affect heart rate variability compared with filtered air (p > 0.05 for all) in healthy volunteers (SDNN 101 +/- 6 vs 91 +/- 6, triangular index 20 +/- 1 vs 21 +/- 1) or patients with coronary heart disease (SDNN 47 +/- 5 vs 38 +/- 4, triangular index 8 +/- 1 vs 7 +/- 1). CONCLUSIONS: Brief exposure to dilute diesel exhaust does not alter heart rhythm or heart rate variability in healthy volunteers or well-treated patients with stable coronary heart disease. Autonomic dysfunction does not appear to be a dominant mechanism that can explain the observed excess in cardiovascular events following exposure to combustion-derived air pollution. PMID- 20962343 TI - Utility of high and standard right precordial leads during ajmaline testing for the diagnosis of Brugada syndrome. AB - AIMS: The authors sought to assess the value of the high right precordial leads (RPL) to detect the Type I Brugada ECG pattern in patients suspected of carrying Brugada syndrome (BrS). METHODS: Ajmaline testing using 15-lead ECGs was performed in 183 patients suspected of carrying BrS. Standard 12-lead ECG with V1 V3 recorded from the fourth intercostal space and an additional three leads placed over V1-V3 recorded from the third intercostal space were analysed. ECGs were analysed for a Type I ECG pattern in either the standard or high RPLs. RESULTS: Of the 183 tests, 31 (17%) were positive, and 152 were negative. In all positive studies, at least one high RPL became positive. In 13/31 (42%) cases, the Type I ECG pattern could be observed only in the high RPLs. Standard or high V3 were never positive before standard or high V1-V2. In seven patients, a Type I pattern was seen in one standard and one high RPL (vertical relationship). CONCLUSIONS: The high RPLs are more sensitive than the conventional 12-lead ECG alone and initial observations suggest that they remain specific for BrS, while standard and high lead V3 offer redundant data. A vertical relationship of type 1 patterns may have a similar diagnostic value to that of a horizontal pair. PMID- 20962345 TI - Long-term prognostic value of left ventricular dyssynchrony assessment by phase analysis from myocardial perfusion imaging. AB - OBJECTIVE: To assess the value of left ventricular (LV) dyssynchrony, using phase analysis of nuclear single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) as independent predictor of cardiac events. METHODS: Phase analysis using Emory Cardiac Toolbox was applied on gated rest MPI scans to assess LV dyssynchrony in a total of 202 patients. Follow-up was obtained in 197 patients (97.5%). Major adverse cardiac events (MACE) (cardiac death and hospitalisation for any cardiac reasons, including worsening of heart failure, non-fatal myocardial infarction, unstable angina and coronary revascularisation) were determined using the Kaplan-Meier method. Cox proportional hazard regression was used to identify independent predictors of cardiac events. RESULTS: At a median follow-up of 3.2 +/- 1.2 years, 41 patients had at least one event, including 5 cardiac deaths. LV dyssynchrony (n = 35) was associated with a significantly higher incidence of MACE (p<0.001) and proved to be an independent predictor of cardiac events. CONCLUSION: LV dyssynchrony assessed by phase analysis of gated SPECT-MPI is a strong predictor of MACE independent of other known predictors such as perfusion defects or decreased LV ejection fraction. PMID- 20962344 TI - Family history of premature coronary heart disease and risk prediction in the EPIC-Norfolk prospective population study. AB - OBJECTIVE: The value of a family history for coronary heart disease (CHD) in addition to established cardiovascular risk factors in predicting an individual's risk of CHD is unclear. In the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort, the authors tested whether adding family history of premature CHD in first-degree relatives improves risk prediction compared with the Framingham risk score (FRS) alone. METHODS AND RESULTS: This study comprised 10,288 men and 12,553 women aged 40-79 years participating in the EPIC-Norfolk cohort who were followed for a mean of 10.9+/-2.1 years (mean+/-SD). The authors computed the FRS as well as a modified score taking into account family history of premature CHD. A family history of CHD was indeed associated with an increased risk of future CHD, independent of established risk factors (FRS-adjusted HR of 1.74 (95% CI 1.56 to 1.95) for family history of premature CHD). However, adding family history of CHD to the FRS resulted in a negative net reclassification of 2%. In the subgroup of individuals estimated to be at intermediate risk, family history of premature CHD resulted in an increase in net reclassification of 2%. The sensitivity increased with 0.4%, and the specificity decreased 0.8%. CONCLUSION: Although family history of CHD was an independent risk factor of future CHD, its use did not improve classification of individuals into clinically relevant risk categories based on the FRS. Among study participants at intermediate risk of CHD, adding family history of premature CHD resulted in, at best, a modest improvement in reclassification of individuals into a more accurate risk category. PMID- 20962346 TI - An unusual connection of the right and left inferior pulmonary veins in the left atrium via a common ostium. PMID- 20962347 TI - The cost-effectiveness of primary angioplasty. PMID- 20962348 TI - Probing the active site of the deoxynucleotide N-hydrolase Rcl encoded by the rat gene c6orf108. AB - Rcl is a potential anti-angiogenic therapeutic target that hydrolyzes the N glycosidic bond of 2'-deoxyribonucleoside 5'-monophosphate, yielding 2 deoxyribose 5-phosphate and the corresponding base. Its recently elucidated solution structure provided the first insight into the molecular basis for the substrate recognition. To facilitate the development of potent and specific inhibitors of Rcl, the active site was probed by site-directed mutagenesis and by the use of substrate analogs. The nucleobase shows weak interactions with the protein, and the deoxyribose binding pocket includes the catalytic triad Tyr-13, Asp-69, and Glu-93 and the phosphate binding site Ser-87 and Ser-117. The phosphomimetic mutation of Ser-17 to Glu prevents substrate binding and, thus, abolishes the activity of Rcl. The synthetic ligand-based analysis of the Rcl binding site shows that substitutions at positions 2 and 6 of the nucleobase as well as large heterocycles are well tolerated. The phosphate group at position 5 of the (deoxy)ribose moiety is the critical binding determinant. This study provides the roadmap for the design of small molecules inhibitors with pharmacological properties. PMID- 20962350 TI - Relicensing of transcriptionally inactivated replication origins in budding yeast. AB - DNA replication origins are licensed in early G(1) phase of the cell cycle where the origin recognition complex (ORC) recruits the minichromosome maintenance (MCM) helicase to origins. These pre-replicative complexes (pre-RCs) remain inactive until replication is initiated in the S phase. However, transcriptional activity in the regions of origins can eliminate their functionality by displacing the components of pre-RC from DNA. We analyzed genome-wide data of mRNA and cryptic unstable transcripts in the context of locations of replication origins in yeast genome and found that at least one-third of the origins are transcribed and therefore might be inactivated by transcription. When investigating the fate of transcriptionally inactivated origins, we found that replication origins were repetitively licensed in G(1) to reestablish their functionality after transcription. We propose that reloading of pre-RC components in G(1) might be utilized for the maintenance of sufficient number of competent origins for efficient initiation of DNA replication in S phase. PMID- 20962349 TI - Prospecting metagenomic enzyme subfamily genes for DNA family shuffling by a novel PCR-based approach. AB - DNA family shuffling is a powerful method for enzyme engineering, which utilizes recombination of naturally occurring functional diversity to accelerate laboratory-directed evolution. However, the use of this technique has been hindered by the scarcity of family genes with the required level of sequence identity in the genome database. We describe here a strategy for collecting metagenomic homologous genes for DNA shuffling from environmental samples by truncated metagenomic gene-specific PCR (TMGS-PCR). Using identified metagenomic gene-specific primers, twenty-three 921-bp truncated lipase gene fragments, which shared 64-99% identity with each other and formed a distinct subfamily of lipases, were retrieved from 60 metagenomic samples. These lipase genes were shuffled, and selected active clones were characterized. The chimeric clones show extensive functional and genetic diversity, as demonstrated by functional characterization and sequence analysis. Our results indicate that homologous sequences of genes captured by TMGS-PCR can be used as suitable genetic material for DNA family shuffling with broad applications in enzyme engineering. PMID- 20962351 TI - Progress towards understanding the functioning of the trabecular meshwork based on lessons from studies of laser trabeculoplasty. PMID- 20962352 TI - Canaloplasty for primary open-angle glaucoma: long-term outcome. AB - BACKGROUND/AIMS: To study the safety and effectiveness of 360 degrees viscodilation and tensioning of Schlemm canal (canaloplasty) in black African patients with primary open-angle glaucoma (POAG). METHODS: Sixty randomly selected eyes of 60 consecutive patients with POAG were included in this prospective study. Canaloplasty comprised 360 degrees catheterisation of Schlemm's canal by means of a flexible microcatheter with distension of the canal by a tensioning 10-0 polypropylene suture. RESULTS: The mean preoperative intraocular pressure pressure (IOP) was 45.0 +/- 12.1 mm Hg. The mean follow-up time was 30.6 +/- 8.4 months. The mean IOP at 12 months was 15.4 +/- 5.2 mm Hg (n=54), at 24 months 16.3 +/- 4.2 mm Hg (n = 51) and at 36 months 13.3 +/- 1.7 mm Hg (n=49). For IOP <= 21 mm Hg, complete success rate was 77.5% and qualified success rate was 81.6% at 36 months. Cox regression analysis showed that preoperative IOP (HR = 1.003, 95% CI = 0.927 to 1.085; p = 0.94), age (HR = 1.000, CI = 0.938 to 1.067; p = 0.98) and sex (HR = 3.005, CI=0.329 to 27.448; p=0.33) were all not significant predictors of IOP reduction to <= 21 mm Hg. Complication rate was low (Descemet's detachment n=2, elevated IOP n = 1, false passage of the catheter n = 2). CONCLUSION: Canaloplasty produced a sustained long-term reduction of IOP in black Africans with POAG independent of preoperative IOP. As a bleb-independent procedure, canaloplasty may be a true alternative to classic filtering surgery, in particular in patients with enhanced wound healing and scar formation. PMID- 20962353 TI - Lesions mimicking lacrimal gland pleomorphic adenoma. AB - AIM: To report a series of patients with lacrimal gland lesions simulating the clinicoradiological features of lacrimal gland pleomorphic adenoma (LGPA). METHODS: Multicentre retrospective, interventional case series. Clinical records of all patients with lesions mimicking LGPA seen in five orbital units were reviewed. RESULTS: The study included 14 patients (seven men and seven women) with a mean age of 50.9 years. The diagnosis of LGPA was made in all cases by experienced orbital surgeons, based on clinicoradiological features, and lacrimal gland excision was performed. Postoperative histology revealed lymphoma (four patients), chronic dacryoadenitis (three patients), adenoid cystic carcinoma (two patients), Sjogren's syndrome (two patients), cavernous haemangioma (one patient), benign lymphoid hyperplasia (one patient) and granulomatous dacryoadenitis (one patient). Comparison with the total number of histologically confirmed LGPA cases seen during the study period revealed that 22.6% of cases of suspected LGPA were misdiagnosed based on clinicoradiological criteria. CONCLUSIONS: Many different lesions may mimic the clinicoradiological features of LGPA. The accepted clinicoradiological criteria used for the diagnosis of LGPA have a high false-positive rate, even in experienced hands. Based on this study, the authors believe that fine-needle aspiration biopsy or intraoperative biopsy and frozen section diagnosis may help reduce unnecessary lacrimal gland excision. PMID- 20962354 TI - Sorafenib prevents human retinal pigment epithelium cells from light-induced overexpression of VEGF, PDGF and PlGF. AB - BACKGROUND: Cumulative light exposure is significantly associated with progression of age-related macular degeneration (AMD). Inhibition of vascular endothelial growth factor is the main target of current antiangiogenic treatment strategies in AMD. However, other growth factors, such as platelet-derived growth factor (PDGF) and placenta growth factor (PlGF), have a substantial impact on development of AMD. Previous reports indicate that sorafenib, an oral multikinase inhibitor, might have beneficial effects on exudative AMD. This study investigates the effects of sorafenib on light-induced overexpression of growth factors in human retinal pigment epithelial (RPE) cells. METHODS: Primary human RPE cells were exposed to white light and incubated with sorafenib. Viability, expression, and secretion of VEGF-A, PDGF-BB, and PlGF and their mRNA were determined by reverse transcription-polymerase chain reactions, immunohistochemistry and enzyme-linked immunosorbent assays. RESULTS: Light exposure decreased cell viability and increased expression and secretion of VEGF A, PDGF-BB and PlGF. These light-induced effects were significantly reduced when cells were treated with sorafenib at a dose of 1 MUg/ml. CONCLUSION: The results show that sorafenib has promising properties as a potential antiangiogenic treatment for AMD. PMID- 20962355 TI - Management of epithelial hyperplasia after photorefractive keratectomy on a cornea with intrastromal corneal ring segments. PMID- 20962356 TI - Were the groups in the trabeculectomy versus Ahmed valve study really comparable? PMID- 20962357 TI - Incomplete blinking and dysfunctional tear syndromes. PMID- 20962358 TI - Investigating the effects of low to moderate levels of prenatal alcohol exposure on child behaviour: a critical review. AB - Conflicting findings exist regarding the risks of low to moderate levels of alcohol use during pregnancy. A recent study from Australia has suggested that mild gestational drinking is not associated with adverse fetal effects, and may even be associated with favorable outcomes as compared to "no drinking".The study may lead women to continue consuming alcohol throughout pregnancy, despite methodological limitations that render its conclusions uncertain. This review discusses the challenges of assessing long-term effects of moderate drinking during pregnancy. Recommendations are provided for researchers investigating the effects of prenatal alcohol consumption on subsequent developmental outcomes in children. PMID- 20962359 TI - [The feasibility of synthetic enhancer substances for preventive nanotherapy]. AB - Nanotechnology, the great promise of the 21st century, may revolutionize also the art of healing. Previously unexpected broadening of diagnostic procedures and methods to deliver specific drugs acting in lower than nanomolecular concentrations right to the target cells may play a crucial role in the rapid development of preventive medicine. In this context, (-)-deprenyl/selegiline, a drug developed 40 years ago and still world-wide used to treat Parkinson's disease, Alzheimer's disease and depression, by enhancing the activity of catecholaminergic neurons in the brain stem via a previously unknown mechanism [catecholaminergic activity enhancer (CAE) effect], is a highly promising experimental tool for further research in this direction. The same fits for (-) BPAP, the newly developed enhancer substance, 100 times more potent than (-) deprenyl, which in contrast to the latter is not only an enhancer of the catecholaminergic neurons but also of the serotonergic neurons in the brain stem. Tiny amounts of enhancer substances are closed in liposomes and marked with a specific signal to help identify the exact location of the target cells, through the activation of which the drug exerts its specific enhancer effect. The method also offers an approach to better understand the up-to-the-present unknown mechanism of the enhancer effect. PMID- 20962360 TI - [The dopamin D3 receptor--the gray eminence of pharmacotherapy?]. AB - The dopamine system plays a crucial role in the pathophysiology of many neuropsychiatric disorders. Altough there is sufficient information and knowledge about several dopamine receptor subtypes and their functions, until the last decade the role of the D3 receptor was almost unclear. Recent research data proved that the D3 receptor might have a significant role in fine tuning the modulation of dopaminergic neurotransmission. Cariprazine is a novel agent developed in Hungary, its activity on the dopamine D3 receptor might open up new dimensions in the pharmacotherapy of schizophrenia and affective disorders. PMID- 20962361 TI - Long-term neuronal damage and recovery after a single dose of MDMA: expression and distribution of serotonin transporter in the rat brain. AB - "Ecstasy", 3,4-methylenedioxymethamphetamine (MDMA), an amphetamine analogue is one of the most widely used recreational drugs. In spite of the fact that neurotoxic effects of MDMA has been found in several species from rodents to non human primates, and results increasingly point to damage also in human MDMA users, data about the sensitivity of different brain areas and the recovery after neuronal damage are scarce. Serotonin transporter (5-HTT) mRNA in the raphe nuclei also has not been examined. Humans with genetic predisposition for the slow metabolism of MDMA, the so-called "poor metabolizers" of debrisoquin are at higher risk. Five- 9% of the Caucasian population is considered to carry this phenotype. These studies were carried out in Dark Agouti rats, a special strain that show decreased microsomal CYP2D1 isoenzyme activity, and thus may serve as a model of vulnerable human users. These works were designed to characterize MDMA induced damage and recovery of the serotonergic system including sleep and morphological changes within 180 days. In our experiments we investigated the 5 HTT mRNA expression in the brainstem and medullary raphe nuclei, 5-HTT immunoreactive (IR) fibre densities in several brain areas, and 16 functional measures of sleep in response to a single dose of +/- MDMA (15mg?kg). Furthermore, behavioural experiments were performed 21 days after MDMA treatment. We found similar changes in 5-HTT mRNA expression in the examined raphe nuclei, namely transient increases 7 days after MDMA treatment followed by transient decreases at 21 days. Significant (20-40%), widespread reductions in 5-HTT-IR fibre density were detected in most brain areas at 7 and 21 days after MDMA administration. All cortical, but only some brainstem areas were damaged. Parallel to the neuronal damage we observed significant reductions in rapid eye movement (REM) sleep latency, increased fragmentation of sleep and increases in delta power spectra in non-REM sleep. At 180 days almost all functional changes in sleep were normalized together with 5-HTT mRNA expression in the examined raphe nuclei and the recovery of 5-HTT-IR fibre density in most brain areas. Our results also suggest that the acute MDMA administration abolished aggressive behaviour but MDMA pretreatment and the consequent depletion of serotonergic terminals did not affect aggression. Our findings concerning the changes detected in 5-HTT mRNA expression and fibre density indicate lasting impairment of the serotonergic system and suggest that a single use of MDMA may be associated with long-lasting cognitive, learning, memory and mood deficits and sleep disturbances particularly when a constellation of genetic vulnerability and certain environmental factors are present. Our data provide further evidence for the connection between altered serotonergic functions and sleep disturbance. PMID- 20962362 TI - [9-hydroxy-risperidone (9OHRIS) prevents stress-induced beta-actin overexpression in rat hippocampus]. AB - Alzheimer's disease (AD) is the most frequent form of neurodegenerative dementias. The aetiology and the exact pathomechanism of AD is not known, but stress has been considered recently in the aetiology. Beside the abnormal metabolism of the amyloid protein precursor (APP), the hyperactivity of the mitogen-activated protein kinase 1 (MAPK1) involved in the hyperphosphorylation of the tau proteins, which are considered the major component of neurofibrillary tangles, in addition to beta-actin, being involved in synaptogenesis and neuronal plasticity, are all considered important contributors to the development of AD specific neuropathological changes. The chief aim of our present investigation was to examine the effect of stress on the expression of APP, MAPK1 and beta actin mRNAs in the rat hippocampus and cortex. The effect of 9-hydroxy risperidone (9OHRIS) on the transcription of these genes was also examined. Adult, male Wistar rats were exposed to chronic immobilization stress for 3 weeks. The 9OHRIS (4 mg/bwkg) was administred by gastric tube. Four groups were formed depending on the treatment: (1) control, (2) stress, (3) 9OHRIS, (4) stress and parallel 9OHRIS treatment (n=5-6). The expression of APP, MAPK1, beta actin mRNAs from the perfused brain samples was measured with real-time PCR technique. The beta-actin mRNA was significantly overexpressed in the hippocampus after 3 weeks of stress treatment. On the other hand, the stress induced hippocampal beta-actin mRNA overexpression was repressed by the 9OHRIS treatment. There were no changes in the cortical or hippocampal expression of APP and MAPK1 mRNAs after neither the stress nor the 9OHRIS treatments. These results emphasize the importance of the stress induced beta-actin expression in rat hippocampus. The stress induced alterations in the beta-actin RNA expression could be associated with neuronal plasticity and adaptional processes, which could be modified by the 9OHRIS treatment. Our findings indicate that a second generation antipsychotic drug could have a beneficial effect in the pathomechanism of stress and this may have relevance in the treatment of such devastating conditions like AD and psychotic disorders. PMID- 20962363 TI - [Application of lamotrigine in bipolar disorder--3T MR spectroscopy follow up (part 1)]. AB - MR spectroscopy (MRS) is a widely used and useful additional tool in the diagnostic process of several neuropsychiatric disorders. Despite several MRS studies in bipolar spectrum research, establishing a clean image about special metabolite alterations in the disorder still needs further investigation. The first part of this case study presents a bipolar II patient and her first 3T MR spectroscopy in drug-naive conditions, comparing to a healthy subject. Having finished the first MRS investigation, we applied lamotrigine medication. The ongoing second part of the study will show the data of the second MRS scan, after 5 month of lamotrigine therapy. PMID- 20962364 TI - Reduction of the effect of non-uniform backscatter from an E-type support arm of a Varian a-Si EPID used for dosimetry. AB - Backscatter from the metallic components in the support arm is one of the sources of inaccuracy in dosimetry with Varian amorphous silicon electronic portal imaging devices (a-Si EPIDs). In this study, the non-uniform arm backscatter is blocked by adding lead sheets between the EPID and an E-type support arm. By comparing the EPID responses on and off the arm, with and without lead and considering the extra weight on the imager, 2 mm of lead was determined as the optimum thickness for both 6 and 18 MV beam energies. The arm backscatter at the central axis with the 2 mm lead in place decreased to 0.1% and 0.2% for the largest field size of 30 * 30 cm(2) using 6 and 18 MV beams, from 2.3% and 1.3% without lead. Changes in the source-to-detector distance (SDD) did not affect the backscatter component more than 1%. The symmetry of the in-plane profiles improved for all field sizes for both beam energies. The addition of lead decreased the contrast-to-noise ratio and resolution by 1.3% and 0.84% for images taken in 6 MV and by 0.5% and 0.38% for those in 18 MV beams. The displacement of the EPID central pixel was measured during a 360 degrees gantry rotation with and without lead which was 1 pixel different. While the backscatter reduces with increasing lead thickness, a 2 mm lead sheet seems sufficient for acceptable dosimetry results without any major degradation to the routine performance of the imager. No increase in patient skin dose was detected. PMID- 20962365 TI - Development of a geometrically accurate imaging protocol at 3 Tesla MRI for stereotactic radiosurgery treatment planning. AB - The purpose of this study is to develop a geometrically accurate imaging protocol at 3 T magnetic resonance imaging (MRI) for stereotactic radiosurgery (SRS) treatment planning. In order to achieve this purpose, a methodology is developed to investigate the geometric accuracy and stability of 3 T MRI for SRS in phantom and patient evaluations. Forty patients were enrolled on a prospective clinical trial. After frame placement prior to SRS, each patient underwent 3 T MRI after 1.5 T MRI and CT. MR imaging protocols included a T1-weighted gradient echo sequence and a T2-weighted spin echo sequence. Phantom imaging was performed on 3 T prior to patient imaging using the same set-up and imaging protocols. Geometric accuracy in patients and phantoms yielded comparable results for external fiducial reference deviations and internal landmarks between 3 T and 1.5 T MRI (mean <= 0.6 mm; standard deviation <= 0.3 mm). Mean stereotactic reference deviations between phantoms and patients correlated well (T1: R = 0.79; T2: R = 0.84). Statistical process control analysis on phantom QA data demonstrated the stability of our SRS imaging protocols, where the geometric accuracy of the 3 T SRS imaging protocol is operating within the appropriate tolerance. Our data provide evidence supporting the spatial validity of 3 T MRI for targeting SRS under imaging conditions investigated. We have developed a systematic approach to achieve confidence on the geometric integrity of a given imaging system/technique for clinical integration in SRS application. PMID- 20962366 TI - Secondary absorbed doses from light ion irradiation in anthropomorphic phantoms representing an adult male and a 10 year old child. AB - Secondary organ absorbed doses were calculated by Monte Carlo simulations with the SHIELD-HIT07 code coupled with the mathematical anthropomorphic phantoms CHILD-HIT and ADAM-HIT. The simulated irradiations were performed with primary (1)H, (4)He, (7)Li, (12)C and (16)O ion beams in the energy range 100-400 MeV/u which were directly impinging on the phantoms, i.e. approximating scanned beams, and with a simplified beamline for (12)C irradiation. The evaluated absorbed doses to the out-of-field organs were in the range 10(-6) to 10(-1) mGy per target Gy and with standard deviations 0.5-20%. While the contribution to the organ absorbed doses from secondary neutrons dominated in the ion beams of low atomic number Z, the produced charged fragments and their subsequent charged secondaries of higher generations became increasingly important for the secondary dose delivery as Z of the primary ions increased. As compared to the simulated scanned (12)C ion beam, the implementation of a simplified beamline for prostate irradiation with (12)C ions resulted in an increase of 2-50 times in the organ absorbed doses depending on the distance from the target volume. Comparison of secondary organ absorbed doses delivered by (1)H and (12)C beams showed smaller differences when the RBE for local tumor control of the ions was considered and normalization to the RBE-weighted dose to the target was performed. PMID- 20962367 TI - Development and validation of a variance model for dynamic PET: uses in fitting kinetic data and optimizing the injected activity. AB - The precision of biological parameter estimates derived from dynamic PET data can be limited by the number of acquired coincidence events (prompts and randoms). These numbers are affected by the injected activity (A(0)). The benefits of optimizing A(0) were assessed using a new model of data variance which is formulated as a function of A(0). Seven cancer patients underwent dynamic [(15)O]H(2)O PET scans (32 scans) using a Biograph PET-CT scanner (Siemens), with A(0) varied (142-839 MBq). These data were combined with simulations to (1) determine the accuracy of the new variance model, (2) estimate the improvements in parameter estimate precision gained by optimizing A(0), and (3) examine changes in precision for different size regions of interest (ROIs). The new variance model provided a good estimate of the relative variance in dynamic PET data across a wide range of A(0)s and time frames for FBP reconstruction. Patient data showed that relative changes in estimate precision with A(0) were in reasonable agreement with the changes predicted by the model: Pearson's correlation coefficients were 0.73 and 0.62 for perfusion (F) and the volume of distribution (V(T)), respectively. The between-scan variability in the parameter estimates agreed with the estimated precision for small ROIs (<5 mL). An A(0) of 500-700 MBq was near optimal for estimating F and V(T) from abdominal [(15)O]H(2)O scans on this scanner. This optimization improved the precision of parameter estimates for small ROIs (<5 mL), with an injection of 600 MBq reducing the standard error on F by a factor of 1.13 as compared to the injection of 250 MBq, but by the more modest factor of 1.03 as compared to A(0) = 400 MBq. PMID- 20962369 TI - SHELX makes an impact. PMID- 20962368 TI - Evaluation of sparse-view reconstruction from flat-panel-detector cone-beam CT. AB - Flat-panel-detector x-ray cone-beam computed tomography (CBCT) is used in a rapidly increasing host of imaging applications, including image-guided surgery and radiotherapy. The purpose of the work is to investigate and evaluate image reconstruction from data collected at projection views significantly fewer than what is used in current CBCT imaging. Specifically, we carried out imaging experiments using a bench-top CBCT system that was designed to mimic imaging conditions in image-guided surgery and radiotherapy; we applied an image reconstruction algorithm based on constrained total-variation (TV)-minimization to data acquired with sparsely sampled view-angles and conducted extensive evaluation of algorithm performance. Results of the evaluation studies demonstrate that, depending upon scanning conditions and imaging tasks, algorithms based on constrained TV-minimization can reconstruct images of potential utility from a small fraction of the data used in typical, current CBCT applications. A practical implication of the study is that the optimization of algorithm design and implementation can be exploited for considerably reducing imaging effort and radiation dose in CBCT. PMID- 20962370 TI - Data scaling and temperature calibration in time-resolved photocrystallographic experiments. AB - Experiments in which structural changes in crystals are induced by pulsed-laser exposure involve an increase in sample temperature due to the dissipation of the deposited excess energy. The heat increase is especially pronounced when a large number of pulses is needed, as in pseudo-steady-state experiments conducted at conventional sources, but not negligible in synchrotron studies in which very short laser exposures may be adequate. The relative scaling of the light-ON and light-OFF data and the correction for temperature differences between the two sets are discussed. PMID- 20962371 TI - Simple tilings by polyhedra with five- and six-sided faces. AB - Thirteen tilings of space by simple polyhedra with five- and six-sided faces ('fullerenes') are reported in which there are up to 11 kinds of vertex (vertex 11-transitive). All tilings contain dodecahedra and one or more of nine other kinds of tile. The duals are tilings by tetrahedra and include the four simplest of the known Frank-Kasper intermetallic structure phases. A fifth structure involving just the Frank-Kasper coordination polyhedra has a higher average coordination number than any known or postulated Frank-Kasper phase. PMID- 20962372 TI - X-ray specular scattering from statistically rough surfaces: a novel theoretical approach based on the Green function formalism. AB - The Green function formalism is applied to the problem of grazing-incidence small angle X-ray scattering from statistically rough surfaces. Kirchhoff's integral equation is used to describe the X-ray wavefield propagation through a single rough surface separating vacuum and medium. Taking into account multiple diffuse X-ray scattering effects, the reflection R(coh)(theta) and transmission T(coh)(theta) coefficients of the specular wave are obtained using the Gaussian statistical model of rough surfaces in terms of the two-point height-height correlation function. In the limiting cases when the correlation length xi is equal to zero or infinity, analytical formulae for the reflection R(coh)(theta) and transmission T(coh)(theta) coefficients of the specular wave are obtained. It is important that in the case xi --> infinity they coincide with the corresponding reflection R(DW)(theta) and transmission T(DW)(theta) coefficients related to the conventional Debye-Waller approximation for describing the grazing X-ray scattering from a rough surface. In the case of finite values of correlation length ?xi the reflection |R(coh)(theta)|(2) and transmission |T(coh)(theta)|(2) scans are numerically calculated. PMID- 20962373 TI - Magnetic space and superspace groups, representation analysis: competing or friendly concepts? AB - Although encoded in theoretical works, relationships between the diffraction symmetry of magnetic structures and magnetic space/superspace groups are often ignored in practical applications. It is shown that magnetic symmetry operations have a direct impact through the rotation parts in the diffraction symmetry of the crystal and can be used to simplify calculations of magnetic structure factors. Besides, the translation parts can introduce specific systematic extinctions of magnetic reflections. Another point is that the efficiency and stability of refinement of magnetic crystal structures, in analogy with the refinement of nuclear structures, depend on direct application of the magnetic symmetry in the structure-factor formula. Magnetic symmetry also allows diffractionally independent magnetic domains and their mutual spatial orientations to be recognized. The selection of one irreducible representation can provide extra relationships between magnetic moments which do not directly affect diffraction symmetry. Thus the combination of both methods seems to be the most effective way to analyze and refine magnetic structures. PMID- 20962374 TI - The influence of different Student's T mosaic distributions on the extinction factor in mosaic crystals. AB - During the preparation of versatile tables for the secondary extinction factor Y(MU) of cylindrical and spherical mosaic crystals expressed as functions of the Bragg angle theta, absorption coefficient times radius MUrho and reduced radius tau(0) = sigma(0)rho [sigma(0) = (2pi)(1/2)Q/eta], or of theta, tau(0) and xi(0) = MU/sigma(0), five kinds of Student's Tn probability functions T1, T2, T3, T4, Tinfinity for describing the mosaic distribution of crystals have been tested. T1 is Lorentzian (L) and Tinfinity is close to Gaussian (G). The influence of these different mosaic distributions upon the reflection power ratio, the integrated reflection power ratio (the area under the rocking curve) and the extinction factor Y(MU) in cylindrical crystals has been thoroughly investigated. For a weakly absorbing cylindrical crystal with tau(0) = 30, the value of Y(MU) for the T2 distribution turns out to be nearly two times the value for G, but the difference between these distributions becomes small when xi(0) > 1. The L distribution has been found to be unsuitable for describing the mosaic distribution. The determination of different types of mosaic distribution from the rocking curves is discussed based on these results. Finally T2, T4 and the G distribution have been found to be acceptable for the calculation of secondary extinction factor tables for cylindrical and spherical crystals. PMID- 20962375 TI - Double-slit dynamical diffraction of X-rays in ideal crystals (Laue case). AB - The theoretical investigation of double-slit dynamical X-ray diffraction in ideal crystals shows that, on the exit surface of crystals, interference fringes similar to Young's fringes are formed. An expression for the period of the fringes was obtained. The visibility of the fringes depending on temporal and spatial coherent properties of the incident beam is studied. The polarization state of the incident beam also affects the visibility of the fringes, which in turn depends on the size of the slits. The deviation from Bragg's exact angle causes a shift of the fringes and can also affect the amplitude of the intensity. One of the parameters on which the visibility of the fringes depends is the source-crystal distance. The proposed scheme can be used as a Rayleigh X-ray interferometer. Use of the scheme as a Michelson X-ray stellar interferometer is also possible. PMID- 20962376 TI - Probability density functions of the average and difference intensities of Friedel opposites. AB - Trigonometric series for the average (A) and difference (D) intensities of Friedel opposites were carefully rederived and were normalized to minimize their dependence on sin(theta)/lambda. Probability density functions (hereafter p.d.f.s) of these series were then derived by the Fourier method [Shmueli, Weiss, Kiefer & Wilson (1984). Acta Cryst. A40, 651-660] and their expressions, which admit any chemical composition of the unit-cell contents, were obtained for the space group P1. Histograms of A and D were then calculated for an assumed random structure model and for 3135 Friedel pairs of a published solved crystal structure, and were compared with the p.d.f.s after the latter were scaled up to the histograms. Good agreement was obtained for the random-structure model and a qualitative one for the published solved structure. The results indicate that the residual discrepancy is mainly due to the presumed statistical independence of the p.d.f.'s characteristic function on the contributions of the interatomic vectors. PMID- 20962377 TI - Is there a fundamental upper limit for the significance I/sigma(I) of observations from X-ray and neutron diffraction experiments? AB - The answer is yes. A fundamental limit exists, which is not strongly applicable to individual reflections but to a sufficiently large set of reflections such as any set for structure determination. The limit originates from Poisson statistics which gives a minimum (average) error. The proposed limit of significance and a proposed decrease in significance due to data processing are also tested by monitoring W = / for raw and for Bragg data. Since Poisson statistics are the lower limit for the experimental standard uncertainties, it is expected that W < 1 for raw and Bragg data, and that W decreases upon data processing. W also gives a measure of systematic errors in the experimental data as W ~ 1 characterizes pure Poisson data, W >> 1 is physically impossible for sufficiently large data sets of unmerged reflections and W < 1 describes the contamination with systematic errors. Systematic differences depending on the software used to process the data were found. Also, the frequency distributions in particular of sigma(I) values change considerably depending on the data-processing software used. We have no explanation for these differences in the distributions of sigma(I), which lead to distinct changes in the frequency distribution of the significances I/sigma(I) compared with the raw data. Another consequence of Poisson statistics is that lower limits also exist for the agreement factors, the internal agreement factor and the goodness of fit. These limits depend on the moments <1/I(o)>, , and of the observed set of intensities I(o) about the origin. These agreement factors are theoretically attainable when no systematic sources of error apply. They may be used in future to construct further measures of systematic error in experimental data. PMID- 20962378 TI - Determination of Debye-Waller factor and structure factors for Si by quantitative convergent-beam electron diffraction using off-axis multi-beam orientations. AB - Debye-Waller (DW) factors and structure factors have been measured for Si using convergent-beam electron diffraction (CBED) experiments with a transmission electron microscope equipped with a field-emission gun and a post-column energy filtering device. Si has been used here to evaluate the accuracy of multi-beam near-zone-axis orientations for the simultaneous refinement of DW factors and multiple structure factors. Strong dynamic interactions among different beams are obtained by tilting the crystal to specific four- or six-beam orientations near major zone axes, which provide sufficient sensitivity to determine accurate DW factors and structure factors. The DW factors of Si were measured using four-beam conditions near the [001] zone axis for temperatures ranging from 96 to 300 K. A comparison of the multi-beam near-zone-axis orientations with other CBED methods for DW and structure factor F(g) refinement is presented. PMID- 20962379 TI - Simultaneous determination of highly precise Debye-Waller factors and structure factors for chemically ordered NiAl. AB - Accurate Debye-Waller (DW) factors and several low-index structure factors of chemically ordered beta-NiAl at different temperatures have been measured using an off-zone-axis multi-beam convergent-beam electron diffraction method. The temperature dependences of DW factors of Ni and Al atoms are compared with previous experimental measurements and theoretical calculations. The temperature below which the DW factor of Ni becomes smaller than that of Al was found to be lower than previously reported. Structure factors are determined with an accuracy of 0.05% and compared with prior reports. PMID- 20962380 TI - X-ray diffraction peaks from correlated dislocations: Monte Carlo study of dislocation screening. AB - X-ray diffraction peak profiles are calculated by the Monte Carlo method for arbitrarily correlated dislocations without making any approximations or simplifications. The arrangement of dislocations in pairs with opposite Burgers vectors provides screening of the long-range strains. Moreover, any screening can be modeled by appropriate distribution of the dislocation pairs. Analytical description of the peak profiles is compared with the Monte Carlo results. Symmetric peaks due to screw dislocations and asymmetric peaks due to edge dislocations are simulated and analyzed. PMID- 20962381 TI - Volume of intersection of two balls in orientation space. AB - Orientations deviating from an ideal orientation by angles not exceeding a given limit constitute a ball in the metric space of orientations. Such balls arise in crystallographic computations, and in some cases intersections of the balls are of interest. This paper provides an analytical formula for calculation of the volume of the intersection of two balls from their radii and the distance between their centers. The formula is used to determine the volumes of the intersections of balls corresponding to misorientations of coincident lattices. PMID- 20962382 TI - David H. Templeton (1920-2010). PMID- 20962384 TI - Surface properties and adsorption characteristics to methylene blue and iodine of adsorbents from sludge. AB - Adsorbent materials created from wastewater sludge have unique surface characteristics and could be effective in adsorption applications. In this research, the sludge-adsorbents were generated by pyrolyzing mixtures of sewage sludge and H(2)SO(4). Scanning electron microscope (SEM), thermal analysis, X-ray diffraction (XRD) and X-ray photoelectron spectroscope (XPS) were used to analyze the properties of sludge-adsorbent. XPS results show that the adsorbent surface functional groups with high contents of oxygen-containing groups serve as active sites for the adsorption and affect the surface characteristics; the adsorption mechanism of methylene blue (MB) is mainly Bronsted acid-base reaction between the adsorbent surface and MB; and iodine atoms are bonded to the surface of the adsorbent mainly by dispersive interactions rather than by electrostatic interactions. The results also show that H(2)SO(4) level, pyrolysis temperature and sulfuric acid/sludge weight ratio actually affected the adsorption characteristics. Using the conditions (H(2)SO(4) level of 1-18 M, pyrolysis temperature of 650 degrees C, and weight ratio of 0.8), the adsorption capacities for MB and iodine were 74.7-62.3 mg g(-1) and 169.5-209.3 mg g(-1), respectively. PMID- 20962385 TI - Active slag filters-simple and sustainable phosphorus removal from wastewater using steel industry byproduct. AB - Active filtration, where effluent is passed through a reactive substrate such as steel slag, offers a simple and cost-effective option for removing phosphorus (P) from effluent. This work summarises a series of studies that focused on the world's only full-scale active slag filter operated through to exhaustion. The filter achieved 75% P-removal during its first 5 years, reaching a retention capacity of 1.23 g P/kg slag but then its performance sharply declined. Scanning electron microscopy, X-ray diffraction, X-ray fluorescence, and chemical extractions revealed that P sequestration was primarily achieved via adsorption onto iron (Fe) oxyhydroxides on the slag's surface. It was concluded that batch equilibrium tests, whose use has been repeatedly proposed in the literature, cannot be used as an accurate predictor of filter adsorption capacity because Fe oxyhydroxides form via chemical weathering in the field, and laboratory tests don't account for this. Research into how chemical conditions affect slag's P retention capacity demonstrated that near-neutral pH and high redox are optimal for Fe oxyhydroxide stability and overall filter performance. However, as Fe oxyhydroxide sites fill up, removal capacity becomes exhausted. Attempts to regenerate P removal efficiency using physical techniques proved ineffective contrary to dogma in the literature. Based on the newly-developed understanding of the mechanisms of P removal, chemical regeneration techniques were investigated and were shown to strip large quantities of P from filter adsorption sites leading to a regenerated P removal efficiency. This raises the prospect of developing a breakthrough technology that can repeatedly remove and recover P from effluent. PMID- 20962386 TI - Removal of manganese ions from synthetic groundwater by oxidation using KMnO(4) and the characterization of produced MnO(2) particles. AB - The aim of this study is to investigate the conditions for the removal of manganese ions from synthetic groundwater by oxidation using KMnO(4) to keep the concentration below the allowed level (0.05 mg/L). The process includes low-level aeration and addition of KMnO(4) in a Jar test system with Mn(2 + ) concentration of 0.50 mg/L, similar to that of natural groundwater in Taiwan. Different parameters such us aeration-pH, oxidant dose, and stirring speed were studied. Aeration alone was not sufficient to remove Mn(2 + ) ions completely even when the pH was increased. When a stoichiometric amount of KMnO(4) (0.96 mg/L) was used, a complete Mn(2 + ) removal was achieved within 15 min at an optimum pH of 8.0. As the amount of KMnO(4) was doubled, lower removal efficiency was obtained because the oxidant also generated manganese ions. The removal of Mn(2 + ) ions could be completed at pH 9.0 using an oxidant dose of 0.48 mg/L because Mn(2 + ) could be sorbed onto the MnO(2) particles. Finally, The MnO(2) particles were characterized using scanning electron microscopy (SEM) and energy dispersive X ray analysis (EDX). PMID- 20962387 TI - Analysis of landfill components in estimating the percolated leachate to groundwater using the HELP model. AB - Landfills are one of the groundwater pollution sources in Gaza Strip. This study focuses on two landfills operating in Gaza Strip; the first is Dear Al Balah landfill which has a lining system and the second landfill is Gaza landfill which does not have a lining system. The main objective of the present study is to assess the effect of landfill components on percolated leachate to groundwater aquifer using the Hydrologic Evaluation of Landfill Performance (HELP) model. A comprehensive analysis of landfill components affecting the generated leachate was conducted. The results showed that the landfill components were ordered in priority according to their effects on percolated leachate through clay layer as follows: (1) existing of lining system enhances the percolation reduction up to 87%, (2) 30% reduction of rainfall level enhances the percolation reduction up to 50%, (3) 50% reduction of existing landfill area enhances the percolation reduction up to 50%, and (4) the absent of recirculation system slight enhances the percolation reduction up to 2.5% more than with the availability of recirculation system. The waste depth has no significant effect on the quantity of percolated leachate. Analysis suggested that changes in lining system type, rainfall level, landfill area, and recirculation ratio have the most significant impact on model outputs indicating that these parameters should be carefully selected when similar modeling studies are performed. PMID- 20962388 TI - The adoption of the Australian Water Recycling Guidelines by regulators with specific reference to treatment validation requirements. AB - Australian Guidelines for Water Recycling: Managing Health and Environmental Risks (Phase 1) (AGWR) were published in 2006 and present a risk management framework. A major component is the validation of a treatment process for log removal of microorganisms. A National Water Commission (NWC) Fellowship looked at the adoption of the AGRW and the validation requirements of the individual jurisdictions within Australia. To enhance the uptake of recycled water, reduce the technical burden on jurisdictions and promote consistence between jurisdictions, three recommendations were proposed: 1. Agree that treatment systems for low exposure schemes be exempt from individual validation; 2. Develop a national database for log removal values for use with low exposure schemes; and 3. Develop a national approach to the validation of treatment processes. A process for achieving these goals is outlined in the paper. PMID- 20962389 TI - Evaluation of a novel oxidation ditch system for biological nitrogen and phosphorus removal from domestic sewage. AB - A novel oxidation ditch system using anaerobic tanks and innovative dual dissolved oxygen (DO) control technology is proposed for biological nitrogen and phosphorus removal from domestic sewage. A continuous bench-scale experiment running for more than 300 days was performed to evaluate the system. Monitoring and controlling the airflow and recirculation flow rate independently using DO values at two points along the ditch permitted maintenance of aerobic and anoxic zone ratios of around 0.30 and 0.50, respectively. The ability to optimize aerobic and anoxic zone ratios using the dual DO control technology meant that a total nitrogen removal efficiency of 83.2-92.9% could be maintained. This remarkable nitrogen removal performance minimized the nitrate recycle to anaerobic tanks inhibiting the phosphorus release. Hence, the total phosphorus removal efficiency was also improved and ranged within 72.6-88.0%. These results demonstrated that stabilization of the aerobic and anoxic zone ratio by dual DO control technology not only resulted in a marked improvement of nitrogen removal, but it also enhanced phosphorus removal. PMID- 20962390 TI - Investigation of surfactant-modified activated carbon for recycled water disinfection. AB - This study investigated the effectiveness of surfactant-loaded granular activated carbon (GAC) to deactivate total coliform, E. coli, and enterococci found in tertiary effluent under various experimental conditions, i.e. varying surfactant dose, GAC dose, and contact time. The results indicate that GAC loaded with 100 mg/g of hexadecyltrimethylammonium bromide (CTAB) and didodecyldimethylammonium bromide (DDAB), achieved log reductions as high as 1.02 and 1.86 of total coliform, respectively. At varying GAC doses and contact times, 200 mg/g of DDAB dose achieved 99.9 to 100% reduction in total coliform at initial concentrations as high as 38,000 MPN/100 mL. Complete deactivation of E. coli and enterococci were observed for CTAB and DDAB at 200 mg/g dose for varying GAC doses and contact times used in this study. DDAB was more effective than CTAB at deactivating total coliform and E. coli, both Gram-negative bacteria, while both surfactants were shown to have similar disinfection capabilities against enterococci. Surfactant dose and GAC dose were shown to enhance bacteria deactivation; however, surfactant dose was found to be the most important parameter. For contact times evaluated in this research, bacterial deactivation remained the same or slightly decreased with contact time. In conclusion, surfactant-modified GAC can be used as an effective disinfection technique for recycled water. PMID- 20962391 TI - Simultaneous and sequential adsorption of crystal violet and 2-naphthol onto montmorillonite: a microstructural and thermodynamic study. AB - Thermodynamic analysis of simultaneous and sequential adsorption of crystal violet (CV) and 2-naphthol adsorption on montmorillonite has been conducted, and the changes of microstructure of the clay after adsorption were investigated using X-ray diffraction (XRD). The basal spacing and structural order of CV and 2 naphthol adsorbed montmorillonites varied with different CV loadings. In principle, larger basal spacing was resulted from a higher loading of CV in montmorillonites. The excellent structural order of the resultant hybrids is achieved in samples with 0.50-0.75 CEC (cation exchange capacity) loadings of CV. The effects of temperature and ionic strength on the adsorption of CV and 2 naphthol on montmorillonite were also investigated. The Freundlich isotherm model was applied for curve-fitting of the equilibrium isotherm data. The resulting thermodynamics parameters suggested that the sorption process was a spontaneous exothermic process in the case of low CV concentrations. The negative values of Gibbs free energy in all of the adsorption processes indicated that these processes are spontaneous processes. With the increase of CV concentration, the sequential adsorption of 2-naphthol onto montmorillonite proved to be an endothermic process. PMID- 20962392 TI - Photoinactivation of Staphylococcus aureus and Vibrio parahaemolyticus in the model aquatic microcosm: effect of light intensity and dissolved biodegradable organic compound. AB - The impact of light (1,000 * 100,000 lx) on the inactivation of S. aureus and V. parahaemolyticus has been assessed under different concentrations of dissolved biodegradable organic compound (BOC) at pH 7.0. First, a gradual decrease in the number of cultivable cells was observed. Secondly, a cell reactivation was observed and it was marked in the absence of BOC. In the absence of BOC, the lowest value of cell inhibition rate (CIR) during the first 3 h was 0.138 h(-1) for S. aureus and 0.218 h(-1) for V. parahaemolyticus. In the presence of 10,100 and 1,000 mg/l of BOC, it was 0.196 h(-1), 0.243 h(-1) and 0.257 h(-1) for S. aureus respectively, and 0.285 h(-1), 0.306 h(-1) and 0.409 h(-1) for V. parahaemolyticus respectively. The CIRs values of each bacterial species significantly varied (P<0.001) with the changes in BOC concentration. In most cases, no significant difference was noted in the CIRs of both species when they were under the same light intensity and BOC. Nevertheless, it seems important to consider the impact of dissolved BOC during the treatment of bacterial polluted water. PMID- 20962393 TI - Biodegradation of organic compounds from coking wastewater with UASB reactor. AB - The UASB reactor was applied for biodegradation of organic compounds in coking wastewater. The influent pH ranged between 6.8 and 7.2, and stirring speed and temperature were controlled at 2 r/min and 30+/-1 degrees C, respectively. The reactor was successfully started up in 133 days. When the influent COD was 2,600 mg/L (VLR was 2.6 kg/m(3) d), the removal rate of COD was about 54% and the effluent VFA was below 400 mg/L. GC/MS analysis indicated that the coking wastewater mainly contained aniline, phenol, o-phenol, p-cresol, benzoic acid, indole, quinoline etc. Twenty four kinds of organic compounds were detected in the influent, and 20 kinds of organic compounds were completely removed in the UASB reactor. The biodegradation of organic compounds followed Grau second-order kinetics. It was proved to be an effective and feasible method for coking wastewater anaerobic treatment. PMID- 20962394 TI - Methanization and mineralization of 2-chlorophenol by anaerobic digestion. AB - The aim of this study is to contribute to the knowledge about 2-Chlorophenol (2CP) mineralization and methanization in batch culture. This work was focused on evaluating the effect of: (i) the use of sludge with different periods of previous contact to 2CP, (ii) the electron donor addition in stoichiometric relation with 2CP and (iii) the presence of different initial oxygen concentrations. When compared with the control, 50 and 80 days of previous contact to 2CP resulted in a lag phase reduction of 57% and an increase in 2CP specific consumption rate (q(2CP)) of 114%. These results were obtained with no addition of an external electron donor. When acetate was used as an electron donor its consumption resulted independently of 2CP consumption. No lag phase and increase of 46% in q(2CP) was observed when phenol was used as an electron donor. In the third part when sludge without previous contact to 2CP was used, it was found that consumption efficiency (E(2CP)) and q(2CP) values did not increase in the presence of different oxygen concentrations. However, at the highest oxygen concentration, CH(4) yield (Y(CH(4))(-C/2CP-C)) and phenol yield (Y(phenol-C/2CP C)) values decreased, while CO(2) yield value (Y(CO(2))(-C/2CP-C)) increased with regard to the methanogenic control. The use of sludge previously exposed to both 2CP and O(2) resulted in an increase in q(2CP) of 73%. However, among the different oxygen concentrations, no significant difference in E(2CP) or q(2CP) values was observed when compared to the control without oxygen. Therefore, previous contact to 2CP resulted in being a key factor for improving 2CP mineralization and methanization in batch culture. PMID- 20962395 TI - Influence of cyanide on the anaerobic degradation of glucose. AB - Bacteria in the anaerobic degradation process convert the substrate to the final products methane and carbon dioxide. Toxic substances can change the process substantially. The purpose of this study was to investigate the influence of toxic cyanide on biogas production in anaerobic degradation of glucose at 40 degrees C. The OxiTop respirometric system offers a quick and simple method for measurement of the biogas formed. Concentrations of cyanide (CN(-)) added to 640 mg COD/L of glucose varied from 0.325 up to 31.000 mg/L. The inhibition of anaerobic degradation of glucose was evaluated from the lag phase, the coefficient of anaerobic degradation (D(h)), the volume and composition of the biogas and degradation of COD in the liquid phase. If the concentration of cyanide was above 2.600 mg/L inhibition of the anaerobic process was substantial. PMID- 20962396 TI - Evacuation of aged persons from inundated underground space. AB - Underground is an important space that supports function of cities, such as subways, shopping malls and basement parking. However in consequence a new type of disaster, the "urban flood" menaces these spaces. In the last decade, urban floods struck Tokyo, Nagoya and Fukuoka. When underground inundation occurs, people must evacuate to the ground as soon as possible. But, when such an inundation situation happens, aged persons may not be able to evacuate quickly to ground level. In this paper, the method of safety assessment for aged persons is discussed on the experimental results and flood simulation data in an underground space. As a criterion of the safety evacuation, the specific force per unit width is used in this study. From the result of experiments, it is difficult to implement safety evacuation when the specific force per unit width is over 0.100 m(2) for the aged male. PMID- 20962397 TI - Reuse and recycling of secondary effluents in refineries employing advanced multi barrier systems. AB - In this paper the reclamation and reuse of municipal secondary effluents, as well as the reclamation and recycling of refinery secondary effluents, are technically and economically evaluated. It is shown that both practices are feasible and sustainable, and that the reclamation costs depend largely on specific circumstances such as legal requirements, price policy, reuse application, raw water composition, etc. The reclaimed water is reused, or respectively recycled, as boiler make-up. Therefore both reclamation plants employ advanced multi barrier systems including ultra-filtration and reverse osmosis. The employed processes have shown excellent performance with regard to the removal of critical parameters such as silica. For example, this parameter was reduced from 13 mg/l in the raw water to 7 MUg/l in the boiler make-up. PMID- 20962398 TI - Mathematical modelling of biofilms and biofilm reactors for engineering design. AB - Mathematical models are critical to modern environmental biotechnology-both in research and in the engineering practice. Wastewater treatment plant (WWTP) simulators are used by consulting engineers and WWTP operators when planning, designing, optimizing, and evaluating the unit processes that comprise municipal and industrial WWTPs. Many WWTP simulators have been expanded to include a submerged completely-mixed biofilm reactor module that is based on the mathematical description of a one-dimensional biofilm. Leading consultants, equipment manufacturers, and WWTP modelling software developers have made meaningful contributions to advancing the use of biofilm models in engineering practice, but the bulk of the engineering community either does not use the now readily available biofilm reactor modules or utilizes them as 'black-box' design tools. The latter approach results in the mathematical biofilm models being no more useful than the empirical design criteria and formulations that have been historically applied to biofilm reactor design. The present work provides a consensus report on the state-of-the art, areas of uncertainty, and future needs for advancing the use of biofilm models in engineering design. PMID- 20962399 TI - Estimation of total nitrogen transport and retention during flow in a catchment using a mass balance model incorporating the effects of land cover distribution and human activity information. AB - The load of total nitrogen (TN) in stream water was surveyed in the Nagara River Basin (2,000 km(2)), central Japan. Multivariate analysis placed the TN data in an environmental and social context, relating TN to land use conditions such as geologic features, population density, and percentage of the population using the sewer system. Multivariate analysis was used to examine relationships among the land use distribution with and without human activity and the amount of pollution effluent from waste water treatment plants (WWTP). The pollution load in stream water is related to characteristics of the land cover in the river basin, so the influence of land use on the pollutant load was investigated. However, key factors affecting the pollutant load are human activities associated with the land use. In this study, a relationship between pollutant load, land use, and human activity is developed. Land use was estimated from Landsat data using ISODATA clustering. The distribution of the land cover factors was related to human activities, i.e. population density, agricultural production, industrial wastewater discharge, percentage of sewered population, and stock breeding in the catchment. Multivariate analysis related the TN data to land use and human activities. However, the types of land use were found to be insufficient to evaluate the TN, which appeared to be largely governed by other human-related factors such as industrial wastewater discharge, agricultural production, population density, and livestock density. Socioeconomic data, were obtained from government agencies. The results indicate that the TN load outflow characteristics of the study catchment were affected not only by outside human activity, but also largely by the various human activities in the small drainage basin. Industrial waste water contributed as much to the pollution load outflow as did human activity. This is shown quantitatively in that land use information collected at the same time as that collected on human activities provides effective baseline data. The model proposed here is suitable for evaluating best management practices. PMID- 20962400 TI - Ability of Preissmann slot scheme to simulate smooth pressurisation transient in sewers. AB - Urban drainage networks are generally designed to operate in a free-surface flow condition. However, as a consequence of heavy rainfall events or network malfunctions, the filling of sewers (pressurisation) and network overflow may occur. Several modelling software products are commonly used to simulate floods in drainage networks, and their results are usually thought to be reliable and robust. However, no specific studies have been carried out on the behaviour of these modelling products during the pressurisation transition. Mathematical models often use the Preissmann slot concept to handle pressurisation. In this paper, on the basis of laboratory pipe tests, the reliability of such a scheme is studied by means of a popular and open-source software product: SWMM (Storm Water Management Model). Many numerical tests were carried out with SWMM, varying the spatial and time steps and the Preissmann slot width, in order to examine the performance of the modelling software over intervals of these parameters even wider than what is usual in practical applications. The comparison between simulated and experimental surges allows one to draw interesting conclusions regarding the effectiveness of software products analogous to SWMM in simulating pressurisation, as well as the choice of the parameters themselves. PMID- 20962401 TI - Large-scale flooding analysis in the suburbs of Tokyo Metropolis caused by levee breach of the Tone River using a 2D hydrodynamic model. AB - In order to assess the effects of climate change on flood disasters in urban areas, we applied a two dimensional finite element hydrodynamic model (2D-FEM) to simulate flood processes for the case analysis of levee breach caused by Kathleen Typhoon on 16 September 1947 in Kurihashi reach of Tone River, upstream of Tokyo area. The purpose is to use the model to simulate flood inundation processes under the present topography and land-use conditions with impending extreme flood scenarios due to climate change for mega-urban areas like Tokyo. Simulation used 100 m resolution topographic data (in PWRI), which was derived from original LiDAR (Light Detection and Ranging) data, and levee breach hydrographic data in 1947. In this paper, we will describe the application of the model with calibration approach and techniques when applying for such fine spatial resolution in urban environments. The fine unstructured triangular FEM mesh of the model appeared to be the most capable of introducing of constructions like roads/levees in simulations. Model results can be used to generate flood mapping, subsequently uploaded to Google Earth interface, making the modeling and presentation process much comprehensible to the general public. PMID- 20962402 TI - Effects of intermittent loading on nitrogen removal in horizontal subsurface flow wetlands. AB - Removal of CBOD(5) and nitrogen from septic tank effluent was evaluated in four horizontal subsurface flow (HSSF) wetlands. An intermittently loaded cell was compared to a continuously loaded control cell, with both treatments receiving the same weekly volume. The intermittent cell was rapidly drained and "rested" for 24-hr, then refilled in steps, twice weekly. Two media with different particle sizes but similar porosities were also compared. The two media, light weight expanded shale and gravel, were both continuously loaded. As hypothesized, the wetland cell that was intermittently loaded had higher dissolved oxygen, greater ammonia removal, and greater nitrate production than the continuously loaded cells. Areal NH(3)-N removal for the intermittently loaded cell was 0.90 g m(-2) d(-1) compared to 0.47 g m(-2) d(-1) for the control. Ammonia removal was also higher in continuously loaded gravel cells than in cells with expanded shale. Ammonia-N removal was an order of magnitude lower in a similar SSF wetland that had been in operation for 3 years. However, CBOD(5), total suspended solids, and total nitrogen did not vary substantially among the treatments. PMID- 20962403 TI - Computational modeling of ultraviolet disinfection. AB - The efficient design of ultraviolet light (UV) systems for water and wastewater treatment requires detailed knowledge of the patterns of fluid motion that occur in the disinfection channel. This knowledge is increasingly being obtained using Computational Fluid Dynamics (CFD) software packages that solve the equations governing turbulent fluid-flow motion. In this work, we present predictions of the patterns of flow and the extent of disinfection in a conventional reactor consisting of an open channel with an array of UV lamps placed with their axes perpendicular to the direction of flow. It is shown that the resulting flow is inherently unsteady due to the regular shedding of vortices from the submerged lamps. It is also shown that the accurate prediction of the hydraulic residence time and, consequently, the extent of disinfection is strongly dependent on the ability of the CFD method to capture the occurrence and strength of the vortex shedding, and its effects on the turbulent mixing processes. PMID- 20962404 TI - Catalytic wet peroxide oxidation of p-nitrophenol by Fe (III) supported on resin. AB - Fe(III) supported on resin (Fe(III)-resin) as an effective catalyst for peroxide oxidation was prepared and applied for the degradation of p-nitrophenol (PNP). Catalytic wet peroxide oxidation (CWPO) experiments with hydrogen peroxide as oxidant were performed in a batch rector with p-nitrophenol as the model pollutant. Under given conditions (PNP concentration 500 mg/L, H(2)O(2) 0.1 M, 80 degrees C, resin dosage 0.6% g/mL), p-nitrophenol was almost completely removed, corresponding to an 84% of COD removal. It was found that the reaction temperature, oxidant concentration. and initial pH of solution significantly affected both p-nitrophenol conversion and COD removal by oxidation. It can be inferred from the experiments that Fe(III) supported on resin was an effective catalyst in the mineralization of p-nitrophenol. In an acidic environment of oxidation, the leaching test showed that there was only a slight leaching effect on the activity of catalytic oxidation. It was also confirmed by the aging test of catalysts in the oxidation. PMID- 20962405 TI - Removal of fluoride from aqueous solution by adsorption onto Kanuma mud. AB - Kanuma mud, a geomaterial, is used as an adsorbent for the removal of fluoride from water. The influences of contact time, solution pH, adsorbent dosage, initial fluoride concentration and co-existing ions were investigated by batch equilibration studies. The rate of adsorption was rapid with equilibrium being attained after about 2 h, and the maximum removal of fluoride was obtained at pH 5.0-8.0. The Freundlich isotherm model was found to represent the measured adsorption data well. The negative value of the thermodynamic parameter DeltaG suggests the adsorption of fluoride by Kanuma mud was spontaneous, the endothermic nature of adsorption was confirmed by the positive DeltaH value. The negative DeltaS value for adsorbent denoted decreased randomness at the solid/liquid interface. The adsorption process using Kanuma mud followed the pseudo-second-order kinetic model. Fluoride uptake by the Kanuma mud was a complex process and intra-particle diffusion played a major role in the adsorption process. It was found that adsorbed fluoride could be easily desorbed by washing the adsorbent with a solution of pH 12. This indicates the material could be easily recycled. PMID- 20962406 TI - The spectral absorption coefficient at 254 nm as a real-time early warning proxy for detecting faecal pollution events at alpine karst water resources. AB - Because spring water quality from alpine karst aquifers can change very rapidly during event situations, water abstraction management has to be performed in near real-time. Four summer events (2005-2008) at alpine karst springs were investigated in detail in order to evaluate the spectral absorption coefficient at 254 nm (SAC254) as a real-time early warning proxy for faecal pollution. For the investigation Low-Earth-Orbit (LEO) Satellite-based data communication between portable hydrometeorological measuring stations and an automated microbiological sampling device was used. The method for event triggered microbial sampling and analyzing was already established and described in a previous paper. Data analysis including on-line event characterisation (i.e. precipitation, discharge, turbidity, SAC254) and comprehensive E. coli determination (n>800) indicated that SAC254 is a useful early warning proxy. Irrespective of the studied event situations SAC254 always increased 3 to 6 hours earlier than the onset of faecal pollution, featuring different correlation phases. Furthermore, it seems also possible to use SAC254 as a real-time proxy parameter for estimating the extent of faecal pollution after establishing specific spring and event-type calibrations that take into consideration the variability of the occurrence and the transferability of faecal material It should be highlighted that diffuse faecal pollution from wildlife and live stock sources was responsible for spring water contamination at the investigated catchments. In this respect, the SAC254 can also provide useful information to support microbial source tracking efforts where different situations of infiltration have to be investigated. PMID- 20962407 TI - Flocculation properties of a bioflocculant produced by Bacillus licheniformis. AB - Studies of the flocculation properties of bioflocculant combined with its structure characterization are helpful to develop more effective bioflocculant. This paper reports findings of our research on the flocculation properties of the bioflocculant ZS-7 in the kaolin suspension based on its structure characterization. With the addition of 2 mg/L ZS-7 and 9 mM CaCl(2), the optimum temperature for flocculation performance of ZS-7 in the kaolin suspension is about 30 degrees C, giving the highest flocculating activity 99.2%. Studies of the flocculation properties revealed that it was stable at 60-100 degrees C and pH 4-10. Moreover, it could flocculate a kaolin suspension over a wide range of pH (2-12) and temperatures (4-95 degrees C) in the presence of CaCl(2). PMID- 20962408 TI - Identification of key water quality characteristics affecting the filterability of biologically treated effluent in low-pressure membrane filtration. AB - There are many water quality characteristics which could influence the filterability of biologically treated effluent from Melbourne's Western Treatment Plant (WTP). Statistical correlation was used to identify the key water characteristics affecting the microfiltration (MF) and ultrafiltration (UF) filterability in terms of permeate volume of the treated effluent. The models developed showed that turbidity, dissolved organic carbon (DOC) and total suspended solids (TSS) were the key factors which influenced the MF and UF filterability. Turbidity was the dominant factor affecting the accuracy of the model for MF filterability while DOC was the major factor affecting the accuracy of the model for UF filterability. A prediction accuracy of 85% was obtained for MF and 86% for UF filterability of the WTP effluent. The characteristics of the organic components of the wastewater were demonstrated by EEM spectra to have seasonal variation which would have reduced the prediction accuracy. As turbidity, DOC and TSS can be determined on-line, the models would be useful for rapid prediction of the filterability of WTP effluent and this may assist the control of low-pressure membrane filtration processes. PMID- 20962409 TI - Modelling of wet deposition of atmospheric polycyclic aromatic hydrocarbons by the consecutive measurements in an urban area, Japan. AB - The wet deposition for particulate matter (PM) and polycyclic aromatic hydrocarbons (PAHs) was modelled from the consecutive measurements of atmospheric concentration and wet deposition for particulate matter and PAHs in Higashi Hiroshima city, Japan. In order to estimate the model in detail, the wet deposition was classified with that from gaseous and PM phase. The gaseous PAHs assumed to be dissolved into raindrops according to Henry's constant, and the PAHs attached on atmospheric PM were assumed to be trapped with PM. The PM was classified with coarse (>7 MUm) and fine (0.6-7 MUm) PM for the calculation of trap. PM and PAHs depositions estimated with the wet deposition model were compared with measured data. The ratios of the measured to the estimated values of PM and PAHs gave close agreement with measurements (0.41-4.29 (1.35: average) for PM and (0.32-3.83 (1.42)) for PAHs) regardless of precipitation. The depositions of PAHs of liquid and particulate phase were on the other hand significantly different from those from gaseous and PM phases respectively. From those differences, the transfer from particulate to liquid phase was suggested to occur during the precipitation. PMID- 20962410 TI - Water balance: case study of a constructed wetland as part of the bio-ecological drainage system (BIOECODS). AB - The Bio-ecological Drainage System, or BIOECODS, is an urban drainage system located at the Engineering Campus, Universiti Sains Malaysia. It consists of a constructed wetland as a part of the urban drainage system to carry storm water in a closed system. In this closed system, the constructed wetland was designed particularly for further treatment of storm water. For the purpose of studying the water balance of the constructed wetland, data collection was carried out for two years (2007 and 2009). The results show that the constructed wetland has a consistent volume of water storage compared to the outflow for both years with correlation coefficients (R(2)) of 0.99 in 2007 and 0.86 in 2009. PMID- 20962411 TI - Hydraulic residence time and iron removal in a wetland receiving ferruginous mine water over a 4 year period from commissioning. AB - Analysis of residence time distribution (RTD) has been conducted for the UK Coal Authority's mine water treatment wetland at Lambley, Northumberland, to determine the hydraulic performance of the wetland over a period of approximately 4 years since site commissioning. The wetland RTD was evaluated in accordance with moment analysis and modelled based on a tanks-in-series (TIS) model to yield the hydraulic characteristics of system performance. Greater hydraulic performance was seen during the second site monitoring after 21 months of site operation i.e. longer hydraulic residence time to reflect overall system hydraulic efficiency, compared to wetland performance during its early operation. Further monitoring of residence time during the third year of wetland operation indicated a slight reduction in hydraulic residence time, thus a lower system hydraulic efficiency. In contrast, performance during the fourth year of wetland operation exhibited an improved overall system hydraulic efficiency, suggesting the influence of reed growth over the lifetime of such systems on hydraulic performance. Interestingly, the same pattern was found for iron (which is the primary pollutant of concern in ferruginous mine waters) removal efficiency of the wetland system from the second to fourth year of wetland operation. This may therefore, reflect the maturity of reeds for maintaining efficient flow distribution across the wetland to retain a longer residence time and significant fractions of water involved to enhance the extent of treatment received for iron attenuation. Further monitoring will be conducted to establish whether such performance is maintained, or whether efficiency decreases over time due to accumulation of dead plant material within the wetland cells. PMID- 20962412 TI - An electrostatic shielding-based coupled electrodialysis/electrodeionization process for removal of cobalt ions from aqueous solutions. AB - Electrode graphite powder beds were interposed between anode and cathode as intermediate electrodes inside an electrolytic setup. Due to electrostatic shielding they eliminate the applied electric field and therefore stop the electromigration of ions within their mass. It was found that the intermediate electrodes can act as ionic current sinks-ion concentrating compartments and therefore cause a new type of a membrane-less electrodialysis/electrodeionization process. The proposed electrostatic shielding based coupled electrodialysis/electrodeionization treatment of synthetic cobalt plating rinse water containing 300 mg L(-1) Co(2 + ) ions produced a low-volume Co(2 + ) concentrate which could be recycled to the electroplating bath for reuse and a diluate containing 43.8 mg L(-1) Co(2 + ) ions. The diluate was then used as feed in the subsequent electrostatic shielding electrodeionization process which produced pure water with a cobalt ion concentration less than 0.1 mg L(-1). The current efficiency was 22-29%, the enrichment factor 13.5-26.1, the current density 20-40 A m(-2) and the flow rate 1.54 * 10(-4)-4.06 * 10(-4) dm(3) s(-1). The proposed membrane free electrostatic shielding electrodialysis/electrodeionization process could be developed into a new alternative electrochemical method of cobalt or other heavy metal removal and water purification and recycling from industrial effluents laden with heavy metals. PMID- 20962413 TI - Cyanobacteria and bacteria co-occurrence in a wastewater treatment plant: absence of allelopathic effects. AB - Fifty-one cyanobacteria strains, belonging to Phormidium autumnale, Planktothrix mougeotii, Limnotrix sp. and Synechocystis sp. species, were isolated during a twelve months period, from a Wastewater Treatment Plant (WWTP) located in the north of Portugal. Isolated strains and environmental samples were analyzed by Polymerase Chain Reaction (PCR) technique to evaluate the presence of the genes linked to the biosynthesis of the cyanotoxins, microcystin (MC), nodularin (NOD) and cylindrospermopsin (CYN). Even though none of the isolated strains contained the genes responsible for these toxins production, the use of PCR in the water samples detected the mcyE gene, in the biological treatment tank, and the result of its sequence revealed 92% of maximum identity with the microcystin gene. ELISA assay confirmed the presence of the toxin with values of 0.60 MUg MC-LR eq/l. The effects of extracts of the cyanobacteria strains on bacteria isolated from the WWTP, revealed that none of the tested strains inhibited or reduced the bacterial growth. This may indicate that those prokaryote communities may have co-evolved in a way that success of both cyanobacteria and bacteria was achieved. PMID- 20962417 TI - Excessive apoptosis as a downstream molecular event during the development of congenital heart diseases. PMID- 20962418 TI - Reduced ACTC1 expression might play a role in the onset of congenital heart disease by inducing cardiomyocyte apoptosis. AB - BACKGROUND: The Cardiac alpha actin 1 gene (ACTC1) has been related to familial atrial septal defects. This study was set to explore a potential role of this gene in the formation of sporadic congenital heart disease (CHD). METHODS AND RESULTS: Assessment of cardiac tissue samples from 33 patients with sporadic CHD (gestational age (GA) 18 weeks-49 months) with real-time RT-PCR, Western blotting and immunohistochemistry has revealed a markedly decreased ACTC1 expression in the majority of samples (78.8%) compared with autopsied normal heart tissue from aged-matched subjects (GA 17 weeks-36 months). Also, as shown by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay, the proportion of apoptotic cardiomyocytes in samples featuring down-regulated ACTC1 expression (Group 1) was significantly greater than those with normal expression (Group 2) and the controls (P<0.01). The proportion of apoptotic cells strongly correlated with the expression of ACTC1 (r=-0.918, P<0.01). A study of 2 essential genes involved in apoptosis, Caspase-3 and Bcl-2, confirmed that the former has significantly increased expression, whilst the latter has decreased expression in Group 1 than in the other groups (P<0.01). Transfection of a small interfering RNA targeting, Actc1 (Actc1-siRNA), to a cardiomyocyte cell line, H9C2, also detected more apoptotic cells. CONCLUSIONS: Reduced ACTC1 expression might play a role in the onset of CHD through induction of cardiomyocyte apoptosis. PMID- 20962419 TI - Guidelines for pharmacotherapy of atrial fibrillation (JCS 2008): digest version. PMID- 20962420 TI - Still searching for a new therapeutic strategy for acute myocardial infarction. PMID- 20962421 TI - Nifekalant hydrochloride for patients with cardiac arrest caused by shockable rhythm. PMID- 20962422 TI - Cytoskeletal proteins: hidden targets of cytoprotective signaling? PMID- 20962423 TI - Risk stratification and role of implantable defibrillators for prevention of sudden death in patients with hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death (SCD) in young people, including trained athletes. It is now 30 years since the introduction of implantable cardioverter-defibrillators (ICDs) to clinical cardiovascular practice and coronary artery disease, and now device therapy represents the most significant therapeutic innovation and the only definitive strategy for prolonging the life of HCM patients. ICDs have proved effective in preventing SCD in young HCM patients with appropriate intervention rates of 11% for secondary and 4% for primary prevention, despite massive left ventricular (LV) hypertrophy, LV outflow obstruction, diastolic dysfunction or microvascular ischemia. Targeting candidates for prophylactic ICD therapy can be complex, compounded by the unpredictability of the arrhythmogenic substrate, the absence of a dominant risk factor, and difficulty in assembling randomized trials. However, a single major risk factor is often sufficient to justify an ICD, although additional markers and other disease features can resolve ambiguous decision-making. Nevertheless, the absence of all risk factors does not convey absolute immunity to SCD. The current risk factor algorithm, when combined with a measure of individual physician judgment (and patient autonomy considerations), is an effective guide to identifying high-risk HCM patients. ICDs have altered the natural history of HCM for many patients and provided an opportunity to achieve many decades of productive life, and the potential for normal or near normal longevity. Indeed, prevention of SCD has now become a new paradigm in the management of HCM. PMID- 20962424 TI - Resume driving after a refueling pit stop. PMID- 20962425 TI - Impaired coronary vasomotion after coronary intervention with drug-eluting stents. PMID- 20962426 TI - Combined renin-angiotensin system-inhibition therapy: what really accounts for the additive benefits? PMID- 20962427 TI - Developmental origins of cardiovascular disease: cholesterol metabolism and higher carotid artery intima-media thickness in young adults born small for gestational age. PMID- 20962428 TI - Update on the role of endothelial lipase in high-density lipoprotein metabolism, reverse cholesterol transport, and atherosclerosis. AB - Endothelial lipase (EL) is a phospholipase that belongs to the lipoprotein lipase (LPL) family, which includes LPL and hepatic lipase (HL). Similar to LPL and HL, EL regulates lipoprotein metabolism, mainly high-density lipoprotein (HDL) metabolism and HDL cholesterol (HDL-C) levels in humans and mice. Existing data strongly suggest that inhibition of EL in humans would be expected to increase the HDL-C level. However, it has not been definitively established whether the effect of EL activity on HDL-C levels translates into effects on reverse cholesterol transport or atherosclerosis. The available data regarding the impact of EL expression and activity on HDL metabolism, reverse cholesterol transport, and atherosclerosis are reviewed. PMID- 20962429 TI - Aging and arterial stiffness. AB - Arterial walls stiffen with age. The most consistent and well-reported changes are luminal enlargement with wall thickening and a reduction of elastic properties at the level of large elastic arteries. Longstanding arterial pulsation in the central artery causes elastin fiber fatigue and fracture. Increased vascular calcification and endothelial dysfunction are also characteristic of arterial aging. These changes lead to increased pulse wave velocity, especially along central elastic arteries, and increases in systolic blood pressure and pulse pressure. Vascular aging is accelerated by coexisting cardiovascular risk factors, such as hypertension, metabolic syndrome and diabetes. Vascular aging is an independent risk factor for cardiovascular disease, from atherosclerosis to target organ damage, including coronary artery disease, stroke and heart failure. Various strategies, especially controlling hypertension, show benefit in preventing, delaying or attenuating vascular aging. PMID- 20962430 TI - Cyclophilin A: promising new target in cardiovascular therapy. AB - Cyclophilin A (CyPA) has been studied as a multifunctional protein that is upregulated in a variety of inflammatory conditions, such as rheumatoid arthritis, autoimmune disease, and cancer. CyPA has been classified as an immunophilin and has a variety of intracellular functions, including intracellular signaling, protein trafficking, and the regulation of other proteins activity. Besides its intracellular functions, CyPA is a secreted molecule that has a physiological and pathological role in cardiovascular diseases, making it a potential biomarker and mediator in cardiovascular diseases, such as vascular stenosis, atherosclerosis, and abdominal aortic aneurysms. PMID- 20962431 TI - Low risk for arrhythmic events in asymptomatic patients with drug-induced type 1 ECG. Do patients with drug-induced Brugada type ECG have poor prognosis? (Con). AB - The type 1 ST-segment elevation is diagnostic for Brugada syndrome (BS) and its presence may sometimes be associated with a high risk of arrhythmic events. The type 1 ECG is also known to be unmasked by administration of sodium-channel blockers in equivocal or suspected cases of BS, and the drug-challenge test is frequently used in the diagnostic approach. In large cohort studies the spontaneous appearance of the type 1 ECG with symptoms of aborted sudden death or unexplained syncope are indicative of a poor prognosis for patients with BS compared with not having clinical symptoms. Therefore, the spontaneous type 1 ECG appears to represent an important predictive sign for cardiac events. It is unknown, however, whether or not the drug-induced type 1 ECG is as useful as the spontaneous type 1 for predicting cardiac events in asymptomatic subjects showing non-type 1 ECG. Review of the literature for large cohort studies indicates that there is a low incidence of arrhythmic events in asymptomatic patients with either the spontaneous or drug-induced type 1 ECG compared with symptomatic subjects, and the drug-induced type 1 ECG in asymptomatic patients does not add to an increase in arrhythmic risk. Therefore, drug testing to unmask the type 1 ECG in asymptomatic patients with a non-type 1 BS ECG does not have an additional value for risk stratification of cardiac events, although it might be useful in symptomatic patients showing only the non-type 1 ECG. PMID- 20962432 TI - Is this a philosophic issue? Do patients with drug-induced Brugada type ECG have poor prognosis? (Pro). AB - Brugada syndrome (BS) has an intermittent or concealed type, which can be unmasked by the sodium (Na(+))-channel-blocker challenge test. The appropriate risk stratification of patients with a drug-induced Brugada-type electrocardiographic (ECG), especially those without a history of syncope or aborted sudden cardiac death, remains unclear. The prognosis of patients with BS depends on the clinical type, cardiac arrest, syncope or if asymptomatic. The ratio of the asymptomatic group varies from 56.9% to 63.6% and, furthermore, their annual cardiac event rate is relatively lower at 0.24-3.6% compared with the cardiac arrest group. Patients with a drug-induced Brugada-type ECG have a poor prognosis if they had a history of ventricular fibrillation (VF) or aborted sudden cardiac death, because their risk becomes similar to that of patients with spontaneous Brugada-type ECG. They have the disturbance of the Na(+)-channel and the electrophysiologic substrate of VF, proven by the high inducibility of VF by stimulation test even in patients without spontaneous VF. Spontaneous VF will never occur if there is no VF substrate. Implantable cardioverter-defibrillators will certainly protect them, so patients with a drug-induced Brugada-type ECG, even without a history of VF or aborted sudden cardiac death, should be considered to have a poor prognosis. PMID- 20962433 TI - Benzbromarone pharmacokinetics and pharmacodynamics in different cytochrome P450 2C9 genotypes. AB - Benzbromarone is a uricosuric drug and has been shown to be metabolized predominantly by cytochrome P450(CYP)2C9 in vitro findings. This study aims to investigate the influence of the CYP2C9 genotype on plasma levels of benzbromarone and 6-hydroxybenzbromarone, as well as uric acid lowering effects. A single oral dose pharmacokinetic and pharmacodynamic trial of benzbromarone (100 mg) was performed in 20 healthy volunteers, which included 15 with CYP2C9*1/*1, 4 with CYP2C9*1/*3, and 1 with CYP2C9*3/*3. The oral clearance of benzbromarone in the CYP2C9*1/*1 genotype and CYP2C9*1/*3 genotype was 58.8+/ 25.2 L/hr/kg (mean+/-SD) and 51.3+/-7.9 L/hr/kg, respectively, whereas 8.58 L/hr/kg in the CYP2C9*3/*3 genotype. The metabolic ratio (6 hydroxybenzbromarone/benzbromarone) in urine was 38.6+/-10.7 in the CYP2C9*1/*1 genotype, 35.4+/-12.4 in the CYP2C9*1/*3 genotype and 12.9 in the CYP2C9*3/*3 genotype. Although benzbromarone significantly increased the urinary excretion and reduced the plasma concentration of uric acid, there were no significant differences in its effects for different CYP2C9 genotypes. These results suggest a critical role for CYP2C9 in the metabolism of benzbromarone in humans and a possible risk of toxicity in the CYP2C9*3 homozygote by lowering clearance of the drug. Further studies are required to assess the clinical impact of CYP2C9 on the metabolism of benzbromarone. PMID- 20962434 TI - A population approach to eplerenone pharmacokinetics and saturable protein binding. AB - Eplerenone deviates from linear pharmacokinetics at doses above the therapeutic dose range. In addition, saturable protein binding of eplerenone is observed in in vitro plasma protein binding studies. The purpose of the present study was to clarify the factors contributing to the nonlinear pharmacokinetics of eplerenone. Plasma concentration data for eplerenone and its metabolite SC-70303, to which eplerenone is reversibly converted, obtained from four phase I studies were analyzed using NONMEM. A population pharmacokinetic model incorporating protein binding and the reversible relationship between eplerenone and SC-70303 was developed. Models with linear and nonlinear protein binding were fitted to the observed concentration data. The observed concentration data of eplerenone and SC 70303 were best described by a model with nonlinear protein binding. The area under the plasma concentration-time curve of eplerenone simulated by the model increased less than proportionally with increasing dose, whereas that of SC-70303 increased proportionally with increasing dose, consistent with observations from the non-compartmental analysis. In conclusion, the nonlinear pharmacokinetics of eplerenone and the apparently linear pharmacokinetics of SC-70303 were described by applying a model with nonlinear protein binding to observed plasma eplerenone and SC-70303 concentrations, suggesting that nonlinear protein binding plays a role in the nonlinear kinetics. PMID- 20962436 TI - Erythrocyte zinc concentration as an indicator to distinguish painless thyroiditis-associated transient hypothyroidism from permanent hypothyroidism. AB - Red blood cell (RBC) zinc (Zn) concentration reflects a patient's mean thyroid hormone level over the preceding several months. The aim of this study was to examine whether RBC Zn level can be used as an indicator to distinguish painless thyroiditis-associated transient hypothyroidism (TH) from permanent hypothyroidism (PH). RBC Zn level was measured in 30 untreated PH patients with Hashimoto's thyroiditis and 7 untreated TH patients with painless thyroiditis in whom preceding transient thyrotoxicosis had been confirmed. RBC Zn concentration was significantly lower in TH patients than that in PH patients. There was a positive correlation between RBC Zn and serum TSH, and the latter was clearly lower in TH patients than that in PH patients. However, RBC Zn level was again significantly lower in TH patients than PH patients despite of the comparable serum TSH levels in both groups when RBC Zn was evaluated in patients with serum TSH levels of less than 50 mU/L. Thus TH patients could be identified with RBC Zn measurement, allowing us avoidance of unnecessarily prolonged T4 administration to them. PMID- 20962435 TI - Persistent high TRAb values during pregnancy predict increased risk of neonatal hyperthyroidism following radioiodine therapy for refractory hyperthyroidism. AB - Serum levels of TSH receptor antibody (TRAb) often increase after radioiodine treatment for Graves' disease, and high-serum levels of maternal TRAb in late pregnancy indicate a risk of neonatal hyperthyroidism. The aim of this retrospective study is to investigate the characteristics of Graves' women who had a history of radioiodine treatment for intractable Graves' disease, and whose neonates suffered from hyperthyroidism. The subjects of this study were 45 patients with Graves' disease who became pregnant during the period from 1988 to 1998 after receiving radioiodine treatment at Ito Hospital. 25 of the 45 subjects had had a relapse of hyperthyroidism after surgical treatment for Graves' disease. 19 pregnancies were excluded because of artificial or spontaneous abortion. In the remaining 44 pregnancies of 35 patients, neonatal hyperthyroidism developed in 5 (11.3%) pregnancies of 4 patients. Serum levels of TRAb at delivery were higher in patients whose neonates suffered from hyperthyroidism (NH mother) than those of patients who delivered normal infants (N mother). Furthermore, serum levels of TRAb in NH mother did not change during pregnancy, although those of 4 patients of N mother, in which serum levels of TRAb before radioiodine treatment were as high as in NH mother, decreased significantly during pregnancy. In conclusion, women who delivered neonates with hyperthyroidism following radioiodine treatment seem to have very severe and intractable Graves' disease. Persistent high TRAb values during pregnancy observed in those patients may be a cause of neonatal hyperthyroidism. PMID- 20962437 TI - Efficacy of Rikkunshito, a traditional Japanese medicine (Kampo), in treating functional dyspepsia. AB - BACKGROUND: Rikkunshito, a traditional Japanese (Kampo) medicine, is widely prescribed as an oral preparation for the treatment of functional dyspepsia (FD). In our previous study, we reported that extracorporeal ultrasonography (US) is a useful technique for the assessment of the gastric accommodation reflex (AR) and duodenogastric motility. In this study, we examined the effects of Rikkunshito on the gastroduodenal function in patients with FD. METHODS: Sixteen FD patients (median age, 45 y) underwent US, before and after 14 days of treatment with Rikkunshito (7.5 g b.d.). For assessment of the AR, a cross-sectional area of the proximal stomach was measured after incremental ingestion of a liquid meal up to 400-mL. The expansion rate was used as the parameter to determine the AR. Then, the gastric emptying rate (GER), motility index (MI), and reflux index (RI) were evaluated using previously reported methods. RESULTS: Although no significant changes were observed in the total score of the Gastrointestinal Symptom Rating Scale (GSRS), the scores of 3 of the 15 symptoms of GSRS decreased significantly after treatment with Rikkunshito. The expansion rate of the proximal stomach was significantly greater after treatment with Rikkunshito than before the treatment. Although the GER and MI increased significantly, no significant differences in the RI were observed after treatment with Rikkunshito. CONCLUSION: These observations suggested that Rikkunshito may be beneficial for the treatment of FD patients with impaired AR and gastric motility. These results also suggested that Rikkunshito has a therapeutic potential for FD and GERD. PMID- 20962438 TI - Analysis of factors associated with renal function in Chinese adults with congenital solitary kidney. AB - BACKGROUND: Patients with congenital solitary kidney have an increased risk of developing hypertension, proteinuria and renal insufficiency. However, the specific factors associated with the progression of renal function in adults with congenital solitary kidney remain still unclear. The purpose of this study was to identify factors that are independently associated with renal function progression in patients with congenital solitary kidney. METHODS: Sixty-five Chinese adults with congenital solitary kidney (48 patients with unilateral renal agenesis and 17 with severe unilateral renal dysplasia) were recruited into our study retrospectively. Clinical data were analyzed. RESULTS: Of sixty-five patients with congenital solitary kidney, the prevalence of hypertension, proteinuria and renal insufficiency was 36.9%, 35.4% and 38.5%, respectively. There was no significant difference in the glomerular filtration rate (GFR) between patients with and without hypertension, whereas GFR in patients with proteinuria was significantly lower than in those without proteinuria (p<0.05). While there was no statistically significant difference in prevalence of hypertension between patients with and without renal insufficiency, the prevalence of proteinuria in patients with renal insufficiency was significantly higher than in those without renal insufficiency (p<0.05). Logistic regression analysis revealed that kidney length and proteinuria were independently associated with the progression of renal function (OR=0.20, 95%CI 0.05-0.79, and OR=8.30, 95%CI 2.30-29.96, respectively). CONCLUSION: Hypertension, proteinuria or renal insufficiency was present in approximately one-third of adults with congenital solitary kidney. Those with a kidney length of less than 120 mm or proteinuria had a much higher risk of renal insufficiency. PMID- 20962440 TI - Japanese lung cancer research trends and performance in Science Citation Index. AB - OBJECTIVE: This study was undertaken to explore a bibliometric approach to quantitatively assess current research trends in lung cancer in Japan, using the related literature in the Science Citation Index (SCI) database from 1991 to 2008. MATERIALS AND METHODS: Articles were analyzed by the scientific output and research performances of individuals, institutes, and collaborative countries with Japan. Distribution of words in the article title, author keywords, and KeyWords Plus in different periods was applied to evaluate research trends by the frequency of keywords used. RESULTS: Keyword analysis indicated that there has been a strategy to connect molecular biology with clinical practice. Researchers in Japan have published high impact articles related to non-small cell and small cell lung cancer. CONCLUSION: Finally, this study highlights the topics in lung cancer research that are becoming popular in Japan. PMID- 20962439 TI - Efficacy and safety of mizoribine by one single dose administration for patients with rheumatoid arthritis. AB - OBJECTIVE: Mizoribine (MZR) is an immunosuppressant that inhibits nucleic acid metabolism and is a relatively safe disease-modifying anti-rheumatic drug (DMARD). We evaluated the efficacy and safety of one single dose per day for patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: In this study 32 patients with RA received MZR therapy. We evaluated the average dose of MZR and prednisolone, response to treatment and peak plasma level of MZR. RESULTS: The average dose of MZR was 146.1+/-31.2 (range: 50-200) mg/day. The average dose of prednisolone was 4.63+/-3.59 (range: 0-14) mg/day. The average plasma level of MZR, measured after 3 hours, was 2.20+/-0.49 ug/mL in the responder group and 1.59+/-0.82 ug/mL in the non-responder group (p=0.020). The treatment with MZR for 24 weeks was completed by 71.9% of patients and the proportion of patients who achieved a good and moderate response rate according to the European League Against Rheumatism (EULAR) criteria was 56.3% at 24 weeks. The plasma level of MZR which was greater than or equal to 2.12 ug/mL was significantly correlated with the clinical response (p<0.01). Only one of thirty-two cases discontinued the treatment, because of skin eruption. CONCLUSION: This study included patients that could not be treated with other DMARDs and/or biologic agents because of age, interstitial pneumonia and other complications. We show that MZR may be a useful and relatively safe therapy for patients in this group. PMID- 20962441 TI - Acquired factor V inhibitor in a patient with a mechanical aortic valve under warfarin therapy. AB - An 84-year-old woman under warfarin therapy, who had undergone mechanical valve replacement 29 months previously, developed coagulation abnormalities after antibiotic treatment for pyelonephritis. Laboratory findings included PT at 47.6 sec, activated thromboplastin time (APTT) at 147 sec, factor V (FV) activity of 4% and FV inhibitor of 8 BU. Although overt bleeding was not observed, administration of prednisolone was started. Her coagulation abnormalities were rapidly normalized. It was later determined that the patient had received bovine thrombin at surgery. The presence of a FV inhibitor should be considered in the differential diagnosis in patients demonstrating an unexpected prolongation of PT under warfarin therapy following surgery. PMID- 20962442 TI - Resistant hypertension in an aged woman presenting with clinical features simulating ectopic ACTH syndrome--response to spironolactone--. AB - A 91-year-old depressed woman had resistant hypertension despite a triple combination of anti-hypertensives, including a Ca-antagonist, an angiotensin receptor blocker, and a thiazide diuretic at optimal doses. She had hypokalemic metabolic alkalosis, elevated plasma cortisol and ACTH, and elevated urinary cortisol. The high-dose dexamethasone did not suppress the elevated ACTH and cortisol. The addition of spironolactone to her previous medications controlled and normalized hypertension, hypokalemia, and hormonal abnormalities within 4 months. Her blood pressure, serum electrolytes, and the hormonal states remained normalized for more than a year thereafter. Her depressed mental state also improved after spironolactone. PMID- 20962443 TI - Primary bilateral adrenal diffuse large B-cell lymphoma demonstrating adrenal failure. AB - Primary adrenal lymphoma (PAL) is extremely rare although involvement of malignant lymphoma into adrenals is common. We report a case of a 58-year-old man with bilateral PAL who demonstrated adrenal insufficiency. Primary large B-cell lymphoma was proven by a computed tomography-guided needle biopsy of the adrenal tumor. Although a complete remission was once achieved by combination chemotherapy plus rituximab, a recurrence occurred with brain metastasis leading to his death. We concluded that PAL should be considered as a possible cause of bilateral adrenal incidentalomas with progressive adrenal insufficiency. PMID- 20962444 TI - Fabry disease exhibiting recurrent stroke and persistent inflammation. AB - We describe two cases of Fabry disease in non-blood-related Japanese men, manifesting recurrent stroke even after the start of enzyme replacement therapy. Both exhibited chronic inflammation and ocular involvement with elevated levels of serum C reactive protein prior to the onset of stroke. We, therefore, suggest the association among persistent inflammation, ocular involvement and recurrent stroke in a certain subset of Fabry disease patients. Both cases received enzyme replacement therapy with no improvement in inflammatory signs or laboratory data. These cases suggest that Fabry disease should be considered in young patients with cryptogenic stroke or CNS manifestations and fever of unknown origin. PMID- 20962445 TI - Long-term survival of a patient with splenic angiosarcoma after resection, high dose chemotherapy, and autologous peripheral blood stem cell transplantation. AB - A 48-year-old woman was admitted to our hospital in 2003, complaining of weight loss. Complete blood cell count revealed thrombocytopenia. Abdominal CT demonstrated marked splenomegaly. FDG-PET revealed a hot spot in the whole spleen. A splenectomy was performed. Histological examination was typical for angiosarcoma. Adjuvant chemotherapy was given, and high-dose chemotherapy with autologous peripheral blood stem cell transplantation was performed. Thrombocytopenia developed again in 2008. CT scan showed a hepatic tumor. A fine needle biopsy of the liver revealed the first relapse. Despite hepatic lobectomy, radiofrequency ablations and administration of recombinant interleukin-2, she died from respiratory failure in 2009. PMID- 20962446 TI - Periodic peritonitis due to familial Mediterranean fever in a patient with systemic lupus erythematosus. AB - We report a patient with systemic lupus erythematosus (SLE) who showed periodic peritonitis with spontaneous remission. She showed compound heterozygous mutations in the MEFV gene, leading to the diagnosis of familial Mediterranean fever (FMF). Oral colchicine successfully reduced the severity and frequency of her peritonitis. SLE occasionally manifests abdominal symptoms, but in cases with periodic peritonitis, associated FMF should be considered as a possible cause. PMID- 20962447 TI - Aortic aneurysm with severe aortic regurgitation in a patient with systemic lupus erythematosus. AB - A 37-year-old man was admitted to our hospital for precordial chest pain. He had taken prednisolone (5 mg/day) for systemic lupus erythematosus (SLE) and had been symptom free for the past 12 years. Echocardiography and contrast-enhanced CT of chest showed an enlarged ascending aortic aneurysm, which is rarely seen in SLE. Severe aortic regurgitation was also present, and surgical replacement of the ascending aorta and aortic valve was successfully accomplished by the Bentall procedure. Medial cystic necrosis in the ascending aorta, which is rarely seen in SLE angiopathy, was confirmed by histology. There were no significant histopathological findings in the aortic valve. PMID- 20962448 TI - Treatment of histiocytic necrotizing lymphadenitis (Kikuchi's disease) with prolonged fever by a single course of methylprednisolone pulse therapy without maintenance therapy: experience with 13 cases. AB - A 26-year-old man was hospitalized with a 1-month history of fever. Cervical lymph node biopsy showed necrosis in the paracortical area with abundant nuclear debris and proliferation of histiocytes. A diagnosis of histiocytic necrotizing lymphadenitis (HNL) (Kikuchi's disease) was made. He received methylprednisolone pulse therapy (MPT) (0.5 g/day for 3 days) without maintenance therapy and experienced dramatic improvement. We also used MPT for another 12 cases of HNL. All patients became afebrile within 1 day without adverse events. Four patients relapsed after the initial MPT, but only 1 patient relapsed during the following year. Our results suggest that MPT is warranted in HNL patients with prolonged fever. PMID- 20962449 TI - Spontaneous pancreaticorenal fistula. PMID- 20962450 TI - Colonoscopy in acute appendicitis. PMID- 20962451 TI - A rare image of a pulmonary nodule revealed on FDG-PET scans. PMID- 20962452 TI - An 11-year-old boy with familial hypercholesterolemia showing multiple xanthomas and advanced atherosclerosis, who responded to lipid-lowering therapy using statin. PMID- 20962453 TI - Interactions of 5'-UTR thymidylate synthase polymorphism with 677C -> T methylene tetrahydrofolate reductase and 66A -> G methyltetrahydrofolate homocysteine methyl-transferase reductase polymorphisms determine susceptibility to coronary artery disease. AB - AIM: The current study aimed to address the inconsistencies in association studies, specifically with reference to methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism in the light of gene-gene and gene-nutrient interactions. METHODS: A case-control study was conducted to analyze four genetic polymorphisms i.e. thymidylate synthase (TYMS) 5'-UTR 28 bp tandem repeat, MTHFR C677T, methyltetrahydrofolate homocysteine methyltransferase (MTR) A2756G, methyltetrahydrofolate homocysteine methyltransferase reductase (MTRR) A66G using PCR-AFLP and PCR-RFLP methods; plasma folate and B12 using AxSYM kits; plasma homocysteine by reverse phase HPLC and nitric oxide using Griess reaction. Fisher's exact test, logistic regression analysis and multifactor dimensionality reduction analysis were used for statistical analysis of genetic parameters. Student's t-test was used for biochemical parameters. RESULTS: MTHFR C677T and MTRR A66G were found to increase the risk for CAD by 1.61-fold (95% CI: 1.04 2.50) and 1.92-fold (95% CI: 1.29-2.87) whereas TYMS 2R allele was found to reduce the risk for CAD (OR: 0.66, 95% CI: 0.49-0.88) by counteracting MTHFR and MTRR variant alleles. Significant gene-gene interactions were observed among TYMS/MTRR (P < 0.0001), MTR/TYMS/MTRR (P < 0.0001), and MTHFR/MTR/TYMS/MTRR (P < 0.0001). MTHFR was found to increase the risk (OR: 2.36, 95% CI: 1.28-4.37) only in the absence of the TYMS 2R allele, with marked impairment of the remethylation process (P = 0.007). This impairment was predominant when the dietary folate was in the lowest tertile. In subjects with dietary folate intake in the highest tertile, no such impairment was observed. CONCLUSION: Dietary folate status and TYMS 5'-UTR 28bp tandem repeat polymorphism are important effect modifiers of CAD risk associated with genetic variants in remethylating genes. PMID- 20962454 TI - Neuroprotective effects of genistein in Mongolian gerbils: estrogen receptor-beta involvement. AB - Genistein is a naturally occurring plant-derived phytoestrogen, present in the human diet, known to possess some beneficial effects. The present study investigated the effect of genistein on neuroprotection evaluated through electroencephalographic and behavioural correlates in a model of global cerebral ischemia in gerbils. Over the dose range tested, genistein (3 and 10 mg/kg), given 5 min after recirculation antagonized the ischemia-induced electroencephalographic total spectral power decrease 7 days after ischemia; fully prevented ischemia-induced hyperlocomotion evaluated 1 day after ischemia; reversed ischemia-induced memory impairment evaluated through both nest building behaviour and object recognition test; decreased malondialdehyde overproduction in the brain, evaluated 7 days after reperfusion; and fully promoted the survival of pyramidal cells in the CA(1) hippocampal subfield. The selective antagonist for estrogen receptor-beta (ERbeta), 4-[2-phenyl-5,7-bis(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) given 30 min before carotid occlusion, fully prevented the neuroprotective effect of genistein at the dose of 3 mg/kg. These results demonstrate the neuroprotective effect of genistein through the activation of ERbeta and provide further grounds for the growing interest concerning the true potential of phytoestrogens as compounds to beneficially affect brain injury without having the disadvantages of estrogens. PMID- 20962455 TI - Antipsychotic potential of quinazoline ErbB1 inhibitors in a schizophrenia model established with neonatal hippocampal lesioning. AB - Hyper-signaling of the epidermal growth factor receptor family (ErbB) is implicated in the pathophysiology of schizophrenia. Various quinazoline inhibitors targeting ErbB1 or ErbB2 - 4 have been developed as anti-cancer agents and might be useful for antipsychotic treatment. In the present study, we used an animal model of schizophrenia established by neonatal hippocampal lesioning and evaluated the neurobehavioral consequences of ErbB1-inhibitor treatment. Subchronic administration of the ErbB1 inhibitor ZD1839 to the cerebroventricle of rats receiving neonatal hippocampal lesioning ameliorated deficits in prepulse inhibition as well as those in the latent inhibition of tone-dependent fear learning. There were no apparent adverse effects on basal learning scores or locomotor activity, however. The administration of other ErbB1 inhibitors, PD153035 and OSI-774, similarly attenuated the prepulse inhibition impairment of this animal model. In parallel, there were decreases in ErbB1 phosphorylation in animals treated with ErbB1 inhibitors. These results indicate an antipsychotic potential of quinazoline ErbB1 inhibitors. ErbB receptor tyrosine kinases may be novel therapeutic targets for schizophrenia or its related psychotic symptoms. PMID- 20962456 TI - Age-dependent changes in progranulin expression in the mouse brain. AB - The progranulin (PGRN) gene is involved in sexual differentiation of the brain during the perinatal period and estrogen-induced adult neurogenesis in the hippocampus. Mutations in the PGRN gene are also implicated in human frontotemporal lobar degeneration. Thus, while PGRN appears to play important roles as a growth factor in the brain, the localization of PGRN-expressing cells throughout the brain has not been fully established. In the present study, we examined the localization of PGRN proteins in the brain using adult male wild type mice and PGRN-deficient mice we had generated previously. We also evaluated age-dependent changes in PGRN expression at the mRNA and protein levels. As expected, no immunoreactivity was observed in the brains of the PGRN-deficient mice. In the wild-type mice, intense immunoreactivity was observed in several brain regions including the cingulate and piriform cortices, the pyramidal cell layer and dentate gyrus of the hippocampus, the amygdala, the ventromedial and arcuate nuclei of the hypothalamus and the Purkinje cell layer in the cerebellum. Moreover, PGRN mRNA and protein expression decreased in the cortex, hippocampus and hypothalamus in an age-dependent manner. Since many of these brain regions are involved in emotion, memory and recognition, PGRN may play roles as a growth factor in these brain functions that decline with age. PMID- 20962457 TI - Treatment with a histone deacetylase inhibitor after nuclear transfer improves the preimplantation development of cloned bovine embryos. AB - We examined the effects of treatment with histone deacetylase inhibitors (HDACi), trichostatin A (TSA) and scriptaid (SCR), on the blastocyst formation rate in bovine somatic cell nuclear transferred (SCNT) embryos derived from fibroblast cells. Three fibroblast cell lines (L1, L2 and L3) were used as somatic cell donors to produce SCNT embryos (L1, L2 and L3 embryos, respectively). In Experiment 1, we compared the in vitro developmental competence of L1 embryos treated with various concentrations of TSA for different time periods following chemical activation. Embryos treated with 5 nM TSA for 20 h showed a significantly increased blastocyst formation rate compared with untreated controls. In Experiment 2, we examined the effect of TSA (5 nM) treatment of L1, L2 and L3 embryos as well as the effect of treatment of L1, L2 and L3 embryos with various concentrations of SCR on in vitro developmental competence. It was found that 5 nM TSA treatment significantly increased the blastocyst formation rate in L1 and L3 embryos but did not have an influence on the development of L2 embryos. On the other hand, 5 nM SCR treatment significantly increased the blastocyst formation rates of L1 and L2 embryos compared with controls. However, there was no significant increase in the blastocyst formation rate of L3 embryos when they were treated with SCR. In Experiment 3, acetylation of H4K12 was examined in donor cells and pronuclear-stage L1, L2 and L3 embryos treated with 5 nM TSA or 5 nM SCR by immunostaining. The level of H4K12 acetylation was different among donor cells. The staining intensities in the TSA-treated L1 and L3 embryos and SCR-treated L2 embryos were significantly higher than those of untreated embryos. These results suggest that HDACi treatment of bovine SCNT embryos improves the blastocyst formation rate; however, the optimal treatment conditions may differ among donor cell lines. PMID- 20962458 TI - Bovine oocytes in secondary follicles grow in medium containing bovine plasma after vitrification. AB - There has been no culture system that supports the growth of bovine oocytes for more than 2 weeks. In the present study, bovine secondary follicles were cultured for 4 weeks, and the effects of supplemented protein components and FSH in the culture medium on the growth of the oocytes were examined. The effect of vitrification of secondary follicles on the subsequent oocyte growth was also examined. Secondary follicles (150 to 200 um in diameter) containing growing oocytes (approximately 60 um in diameter) were dissected from ovaries and cultured in a medium supplemented with FSH (0, 25 or 50 ng/ml) and one of the following four kinds of protein components: bovine serum albumin (BSA), bovine plasma (BPL), fetal calf serum (FCS) and bovine follicular fluid (BFF). In BSA- and BPL-supplemented media with 0 or 25 ng/ml FSH, more than 50% of follicles showed no degenerative signs during culture, and oocytes significantly increased in size after 4 weeks (P<0.05). Higher percentages of granulosa cell-enclosed oocytes were recovered from the follicles cultured in BPL-supplemented media with 0 and 25 ng/ml FSH, and the oocytes grew to 90 um or more in diameter. In FCS- and BFF-supplemented media, FSH increased the numbers of degenerating follicles. Next, vitrified-warmed secondary follicles were cultured in BPL-supplemented medium. One third of the follicles showed no degenerative signs, and the oocytes increased in diameter to 88.8 +/- 3.1 um after 4 weeks of culture. These results suggest that a BPL-supplemented medium supports oocyte growth in bovine secondary follicles for 4 weeks, even after vitrification and warming of the follicles. PMID- 20962459 TI - Relationship between the peripheral concentrations of estradiol-17beta (E2) and preovulatory characteristics of cumulus-oocyte complexes (COCs) during superovulation treatment in Japanese Black cows. AB - The relationship between the peripheral concentrations of estradiol-17beta (E(2)) and the preovulatory characteristics of cumulus oocyte complexes (COCs) during superovulation treatment was investigated in Japanese Black cows. A superovulation regimen with FSH treatment in a descending manner was commenced on day 7 (n=3) or day 10 (n=2) of the estrous cycle (day 0=estrus). Peripheral blood was collected to measure E(2) concentrations twice a day throughout the treatment. Ovariectomies were performed at 100 h after the initial FSH treatment in five cows. Every follicle more than 8 mm in diameter was isolated from the ovaries, and cumulus-oocyte complexes (COCs) were gently aspirated. The COCs were then separated into three groups based on the characteristics of the cumulus (compact, expanded and denuded) and subgrouped based on the stage of the nucleus in the oocytes (GV, GVBD). Plasma E(2) concentrations tended to increase gradually and reached the peak level at around 84 h (E(2)-84: n=3) or 96 h (E(2) 96: n=2) after the initial FSH treatment. The ratio of COCs with expanded cumulus was significantly higher in E(2)-84 than in E(2)-96 (P<0.01). However, there was no difference in the ratio of oocytes showing GVBD between E(2)-84 and E(2)-96 (P=0.73), and the characteristics of the cumulus did not affect the stage of the nucleus in the oocytes in either groups (compact, expanded and nude; P=0.61, 0.81 and 1.00). It was possible that the time until the peak plasma E(2) concentrations after the FSH treatment could become an indicator for the maturation of follicles and oocytes in preovulatory follicles during superovulation treatment in Japanese Black cows. PMID- 20962460 TI - Mycoplasma ovis detected in free-living Japanese serows, Capricornis crispus. AB - Nineteen blood samples collected from free-ranging wild Japanese serows, Capricornis crispus, between 2006 and 2008 in Iwate prefecture were examined for the hemoplasma infection by real-time PCR targeting the 16S rRNA gene. Five (26.3%) out of the 19 samples were positive in real-time PCR with an average melting temperature at 85.18 degrees C. The positive samples in the real-time PCR were reconfirmed by conventional PCR, and one of them was successful for direct DNA sequencing. The nucleotide sequence of the 16S rRNA gene of the representative stain was identical to that of Mycoplasma ovis. This was the first demonstration of hemotropic mycoplasma infections among the free-living Japanese serows in Japan. PMID- 20962461 TI - Microcystic meningioma of the fourth ventricle in a dog. AB - A 5-year-old female cross-breed dog was presented with a 1-month history of progressive changes in the posture of the head and in the gait. At neurological examination the dog showed a central vestibular syndrome lateralized to the left. MRI showed a space occupying lesion within the fourth ventricle, characterized by iso- to hypointensity in T1 and hyperintensity in T2 with a heterogeneous contrast uptake. Histologically, a neoplasia composed of meningothelial cells forming compact whorls with slight atypia, and stellate cells delimitating microcysts containing eosinophilic fluid was observed. Neoplastic cells were positive for vimentin and negative for GFAP and FVIII. A diagnosis of intraventricular microcystic meningioma was achieved. Intraventricular meningiomas in dogs are rarely encountered and reports of meningiomas within the fourth ventricle have not yet been described. Although choroid plexus tumor is the most frequent neoplasia localized in the fourth ventricle, intraventricular meningioma should be included in the differential diagnoses. PMID- 20962462 TI - Ribosomal protein s3 immunoreactivity in the young, adult and aged gerbil hippocampus. AB - Ribosomal protein S3 (rpS3) is well known to participate in DNA repair mechanisms. In the present study, we compared rpS3 immunoreactivity and its protein levels in the hippocampus among young, adult and aged gerbils. In the postnatal month (PM) 3 group as the young, rpS3 immunoreaction was observed in pyramidal and non-pyramidal cells of the hippocampus proper and in granule and polymorphic cells of the dentate gyrus. In the PM 12 group as adult and 24 group as the aged, rpS immunoreactivity in the hippocampus was decreased compared to the PM 3 group. Western blot analysis showed that rpS3 levels were decreased with time; lowest at PM 24. These results indicate that rpS3 immunoreactivity and protein levels were markedly decreased in the aged gerbil hippocampus. PMID- 20962463 TI - 18F-FDG and 11C-MET positron emission tomography findings of cutaneous mast cell tumor in a dog. AB - A 12-year-old intact male Maltese dog presented with an inguinal mass. Histopathology revealed a grade III mast cell tumor. Computed tomography demonstrated pulmonary and inguinal nodules and masses. Chemotherapy was performed using a vinblastine/prednisone protocol, and the inguinal mass disappeared 5 weeks later. Use of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) and (L)-[methyl- 11C]methionine (11C-MET)-positron emission tomography (PET) demonstrated hypermetabolic areas in the lungs and inguinal region one week after initial chemotherapy. The standardized uptake values of 18F-FDG were not different between lung and inguinal lesions; however, the inguinal lesion had a higher 11C-MET standardized uptake value than the lung lesions. The hypermetabolic area was still visible on the second 18F-FDG-PET scan despite the disappearance of the mass. This is the first report of 11C-MET-PET findings associated with a cutaneous mast cell tumor in a dog. PMID- 20962465 TI - [The state-of-the-art chemotherapy for AML]. PMID- 20962464 TI - [Molecular pathogenesis of AML]. PMID- 20962466 TI - [Hematopoietic stem cell transplantation for acute myeloid leukemia]. PMID- 20962467 TI - [Current topics on the pathophysiology of follicular lymphoma]. PMID- 20962468 TI - [Treatment strategies for follicular lymphoma]. PMID- 20962469 TI - [CML stem cell biology]. PMID- 20962470 TI - [Management of chronic myeloid leukemia by imatinib]. PMID- 20962471 TI - [The 2nd generation of TKIs for chronic myeloid leukemia]. PMID- 20962472 TI - [Treatment for localized diffuse large B-cell lymphoma]. PMID- 20962473 TI - [Treatment for diffuse large B cell lymphoma, advanced stage or/and low risk]. PMID- 20962474 TI - [Standard or up-to-date treatment for high risk, relapsed and refractory DLBCL]. PMID- 20962475 TI - [Molecular biology of myeloproliferative neoplasms]. PMID- 20962476 TI - [Treatment of myeloproliferative neoplasms]. PMID- 20962477 TI - [Target therapy for myeloproliferative neoplasms]. PMID- 20962478 TI - [Diagnosis and treatment of aplastic anemia]. PMID- 20962479 TI - [Recent advances in the understanding and management of paroxysmal nocturnal hemoglobinuria]. PMID- 20962480 TI - [Cytogenetic features of myelodysplastic syndrome]. PMID- 20962481 TI - [Diagnosis of myelodysplastic syndrome]. PMID- 20962482 TI - [Treatment strategy for myelodysplastic syndromes (MDS)]. PMID- 20962483 TI - [Progress in the management of multiple myeloma introduced by serum free light chain measurement]. PMID- 20962484 TI - [Treatment of newly diagnosed myeloma: summary of overseas reports and current status in Japan]. PMID- 20962485 TI - [Treatment strategy against relapsed and refractory myeloma and further development of novel agents]. PMID- 20962486 TI - [Platelet transfusion for patients with haematological diseases--indications and transfusion triggers]. PMID- 20962487 TI - [Diagnosis and treatment of acquired hemophilia]. PMID- 20962488 TI - [Inherited coagulation disorders: rare inherited bleeding disorders]. PMID- 20962489 TI - [Current chemotherapy of adult acute lymphoblastic leukemia]. PMID- 20962490 TI - [Recent progress in acute lymphoblastic leukemia in childhood]. PMID- 20962491 TI - [Hematopoietic stem cell transplantation for adult acute lymphoblastic leukemia]. PMID- 20962492 TI - [Age-related EBV-associated B-cell lymphoproliferative disorders]. PMID- 20962494 TI - [New treatment strategies for NK/T-cell lymphoma]. PMID- 20962493 TI - [New agent development for T-cell non-Hodgkin lymphoma: current status and future directions]. PMID- 20962495 TI - [ATL]. PMID- 20962496 TI - [Erythropoietin producing cells]. PMID- 20962497 TI - [Current status and future prospects of immune gene and cell therapy in malignancies]. PMID- 20962499 TI - [Blood transfusion in Japan: a "white paper"]. PMID- 20962498 TI - [Standards for hemopoietic stem cell processing in clinical use]. PMID- 20962501 TI - Vitamin B12 supplement exerts a beneficial effect on the seminiferous epithelium of cimetidine-treated rats. AB - Treatment of gastric ulcer with cimetidine reduces acid secretion and interferes in the vitamin B(12) absorption. Regarding the harmful effect of cimetidine on the seminiferous tubules, the aim of the present study was to verify if prolonged treatment with cimetidine causes vitamin B(12) deficiency and whether the testicular damages are attenuated by vitamin B(12) supplementation. Adult male rats received, for 50 days, cimetidine (CMTG), cimetidine and vitamin B(12) (CMT/B(12)G), vitamin B(12) (B(12)G) and saline solution (CG). Vitamin B(12) and homocysteine plasma levels were evaluated and the testes were embedded in glycol methacrylate for the morphometric analyses of total, epithelial and luminal areas of the seminiferous tubules, number of Sertoli cells and frequencies of tubules according to stages and containing Sertoli and germ cells in the lumen. Terminal deoxynucleotidyl-transferase mediated dUTP nick end labeling (TUNEL) method and proliferating cell nuclear antigen (PCNA) immunohistochemistry were carried out. CMTG showed TUNEL-positive Sertoli cells and significant reductions in the epithelial and total tubular areas, number of Sertoli cells and frequency of tubules VII-VIII. In the CMT/B(12)G, the number of Sertoli cells and the epithelial and total tubular areas were similar to CG. The number of Sertoli cells (in B(12)G) and the frequency of tubules at stages VII-VIII (in B(12)G and CMT/B(12)G) increased significantly; PCNA-positive Sertoli cells were found in these groups. Although cimetidine was not able to induce vitamin B(12) deficiency, this drug causes tubular atrophy due to Sertoli cell damage and loss of germ cells. However, vitamin B(12) supplement is able to stimulate spermatogenesis and restore the number of Sertoli cells, softening the harmful effect of cimetidine on spermatogenesis. PMID- 20962502 TI - Oral appliance therapy versus nasal continuous positive airway pressure in obstructive sleep apnea: a randomized, placebo-controlled trial. AB - BACKGROUND: Previous randomized controlled trials have addressed the efficacy of mandibular advancement devices (MADs) in the treatment of obstructive sleep apnea (OSA). Their common control condition, nasal continuous positive airway pressure (nCPAP), was frequently found to be superior to MAD therapy. However, in most of these studies, only nCPAP was titrated objectively but not MAD. To enable an unbiased comparison between both treatment modalities, the MAD should be titrated objectively as well. OBJECTIVE: The aim of the present study was to compare the treatment effects of a titrated MAD with those of nCPAP and an intra-oral placebo device. METHODS: Sixty-four mild/moderate patients with obstructive sleep apnea (OSA; 52.0 +/- 9.6 years) were randomly assigned to three parallel groups: MAD, nCPAP and placebo device. From all patients, two polysomnographic recordings were obtained at the hospital: one before treatment and one after approximately 6 months of treatment. RESULTS: The change in the apnea-hypopnea index (DeltaAHI) between baseline and therapy evaluation differed significantly between the three therapy groups (ANCOVA; p = 0.000). No differences in the DeltaAHI were found between the MAD and nCPAP therapy (p = 0.092), whereas the changes in AHI in these groups were significantly larger than those in the placebo group (p = 0.000 and 0.002, respectively). CONCLUSION: There is no clinically relevant difference between MAD and nCPAP in the treatment of mild/moderate OSA when both treatment modalities are titrated objectively. PMID- 20962500 TI - E-cadherin and transglutaminase-1 epithelial barrier restoration precedes type IV collagen basement membrane reconstruction following vocal fold mucosal injury. AB - The vocal fold epithelium is critical to upper airway immunologic defense and water/ion transport; therefore, any form of physical trauma or insult increases the vulnerability of this structure to functional impairment and pathogen invasion/infection. In this study, we examined the reestablishment of epithelial and basement membrane barrier structures in a well-established rat model of vocal fold mucosal injury. We observed active cell recruitment culminating in peak hyperplasia at 3 days postinjury, the establishment of robust E-cadherin+ and transglutaminase-1+ biochemical barrier signals along the epithelial surface by 3 days postinjury, and the persistent absence of a type IV collagen+ basement membrane at 7 days postinjury. The distinct spatial and temporal immunoactivity of these molecules is consistent with a programmed repair process driving the restoration of vocal fold mucosal integrity and permeability. These data may inform future efforts to optimize functional mucosal recovery postinjury and avoid undesirable events such as barrier compromise or epithelial metaplasia. PMID- 20962503 TI - Bone marrow-derived endothelial progenitor cells: a promising therapeutic alternative for corneal endothelial dysfunction. AB - BACKGROUND: The global shortage of donor corneas has motivated the development of bioengineered corneas. Although corneal endothelium has been reconstituted using corneal endothelial cells (CEC) and precursor cells with various carrier materials, all of the current options require corneal tissue and are also limited by the scarcity of donor corneas. Here, we explored the feasibility of inducing bone marrow-derived endothelial progenitor cells (BEPC) to differentiate into CEC for the repair of corneal endothelial defects. MATERIALS AND METHODS: BEPC were isolated from human fetal bone marrow, and identified using several antigen markers. BEPC were cocultured with CEC for 10 days in a transwell system with conditioned medium from CEC, and cell transdifferentiation was then examined. With a porcine corneal acellular matrix (PCACM) as the carrier, the induced BEPC were transplanted onto a cat's cornea from which Descemet's membrane and the endothelium had been stripped. RESULTS: The induced BEPC resembled CEC in polygonal shape, expressing aquaporin-1, tightly opposed cell junctions, and neurone-specific enolase. Twenty-eight days after surgery, the transparency gradually returned to the corneas transplanted with the induced BEPC on PCACM. CONCLUSIONS: Human fetal BEPC transdifferentiate into corneal endothelial-like cells in vitro. Features of the induced BEPC indicated that they may be useful for the repair of corneal endothelial dysfunction. PMID- 20962505 TI - Could prostate biopsies be avoided in men older than 75 years with raised PSA? AB - OBJECTIVES: Our purpose was to review current practice regarding the use of prostate biopsies in men older than 75 years with raised PSA by presenting the results of a retrospective audit and to identify these older men who really benefit from prostate biopsies. METHODS: A high-volume tertiary center's prospectively maintained prostate biopsy database of contemporary biopsies was reviewed. Men were stratified by age and PSA. Logistic regression analysis, Mantel-Haenszel and Fisher's exact tests were used for statistical analysis. RESULTS: Overall, 1,593 men underwent prostate biopsies between April 2004 and August 2006. Of these, 293 patients (18.4%) with a mean age of 82.62 years and mean PSA of 30.37 ng/ml were eligible for the study with an overall incidence of prostate cancer of 73.7%. Elderly men with PSA >20 ng/ml had a prostate cancer detection rate of 91%. They were more likely to have-high grade disease (OR = 5.4, 95% CI = 2.8-10.8, p < 0.0001) and receive hormone deprivation therapy (RR = 3.0, 95% CI = 2.1-4.3, p < 0.0001). Elderly men with PSA <20 ng/ml had a 3-fold risk of being placed on active monitoring. Almost 20% of them had 1 complication following biopsy, of whom 12 (4.1%) needed hospitalization. CONCLUSIONS: Given the high probability of detecting prostate cancer and receiving conservative treatment, prostate biopsies can be omitted in men >75 years with PSA >20 ng/ml. However, they are still useful in fit men >75 and <80 years with PSA <20 ng/ml who can be the potential candidates for treatment with curative intent. PMID- 20962504 TI - Examining the relationship between the lung-to-head ratio measured on ultrasound and lung volumetry by magnetic resonance in fetuses with isolated congenital diaphragmatic hernia. AB - PURPOSE: In fetuses with isolated congenital diaphragmatic hernia (CDH), lung development can be measured by the lung-to-head ratio (LHR) using ultrasound as well as by lung volumetry determined by fetal magnetic resonance imaging (MRI). We aimed to investigate their relationship as well as to analyze the factors that may have an impact on it. MATERIAL AND METHODS: In 153 consecutive fetuses with isolated CDH, both the LHR and total fetal lung volume (TFLV) were measured. The observed LHR was calculated by dividing the lung area by the head circumference. On MRI, planimetric measurements of ipsilateral, contralateral and TFLV were performed on T(2)-HASTE (half-Fourier acquisition single-shot turbo spin echo) sequences in transverse as well as coronal or sagittal planes. All values were expressed as a ratio of what was observed over what is expected in a gestational age-matched normal fetus. Secondary analyses were performed for right- versus left-sided hernia and for measurements made prior to 25 weeks' gestation. A multivariate linear regression approach was used to determine the influence of the independent variables such as observed/expected (O/E) LHR, gestational age, liver position and CDH side on the dependent variables O/E TFLV and O/E contralateral FLV, and to determine the optimal formulas for calculation of the O/E TFLV as well as contralateral FLV. RESULTS: In total, 200 pairs of measurements were obtained between 20 and 37 weeks' gestation (median 26+6). There was a significant association between the O/E contralateral FLV and O/E LHR (R(2) = 0.44; p < 0.001) as well as between the O/E TFLV and the O/E LHR (R(2) = 0.37; p < 0.001). After adding the independent variables that were first shown to be significant on univariate analysis, the multiple regression analysis demonstrated that gestational age (p = 0.017) and side of the defect (p < 0.001) were predictive of O/E LHR (p < 0.001) and strongly improved the estimation of O/E TFLV (R(2) = 0.43 instead of 0.37 when using O/E LHR only). In terms of estimating O/E contralateral FLV, only the O/E LHR was a significant (p < 0.001) independent predictor (R(2) = 0.44). These correlations also applied when considering only left-sided CDH cases. For measurements done prior to the third trimester, the O/E LHR (p = 0.034), gestational age (p = 0.035) as well as liver herniation (p = 0.029) were significantly correlated to the O/E TFLV (R(2) = 0.33). In terms of predicting the O/E contralateral FLV (R(2) = 0.25), only O/E LHR (p = 0.008) and gestational age (p = 0.037) were useful predictors. CONCLUSION: Measurement of the O/E LHR on ultrasound allows a good estimation of the O/E contralateral FLV as well as TFLV as measured by MRI. Whereas the additional parameters such as gestational age, liver position and side of the defect did not improve the estimation of the contralateral FLV, they did so for estimating the TFLV. PMID- 20962506 TI - A novel Y332C missense mutation in the intracellular domain of the human growth hormone receptor does not alter STAT5b signaling: redundancy of GHR intracellular tyrosines involved in STAT5b signaling. AB - BACKGROUND: The growth hormone receptor (GHR), upon binding with GH, induces JAK2 mediated phosphorylation of GHR intracellular tyrosines, which then recruit STAT5b. Aberrancies in STAT5b signaling, due to mutations in GHR or STAT5b genes, result in poor responses to GH and severe short stature. OBJECTIVE: To evaluate and compare the role of a novel Y332C GHR variant identified in a patient with short stature to the other GHR intracellular tyrosines in the GHR-STAT5b signaling process. RESULTS: Recombinant human GHR constructs carrying Y332C or single Y to F changes for each of the 7 intracellular tyrosines did not alter GH induced GHR-STAT5b signaling in reconstitution studies. However, GH-induced STAT5b activation was specifically abrogated in an hGHR variant in which all 7 tyrosines were inactivated (MYF). When hGHR variants carrying single intracellular tyrosines were evaluated, STAT5b activation was comparable to that of wild-type hGHR only with variants carrying Y534, Y566 or Y627. CONCLUSION: We provide evidence that in human GHR, 3 intracellular tyrosines are critical and redundant in the GH-induced STAT5b signaling process. This redundancy may explain why an Y332C variant did not alter STAT5b signaling. Identification of missense variants in human GHR intracellular domain should be interpreted with caution and rigorously analyzed. PMID- 20962508 TI - Citrobacter rodentium infection induces MyD88-dependent formation of ubiquitinated protein aggregates in the intestinal epithelium. AB - Citrobacter rodentium utilizes a type 3 secretion system (T3SS) to inject effector proteins into host intestinal epithelial cells, causing structural and functional changes in these cells during infection. Here, we examined the effects of C. rodentium infection on host cell protein ubiquitination in vivo. We observed the appearance of ubiquitinated protein (Ub(+)) aggregates in intestinal epithelial cells near the site of bacterial attachment. Formation of aggregates was dependent on T3SS activity and the effector translocated intimin receptor (Tir). Aggregates formed at 6 days after infection, when bacterial loads were maximal, but were absent at 12 days. Aggregates were not observed in MyD88(-/-) mice. Aggregate formation correlated with MyD88-dependent induction of NADPH oxidase 1, implicating reactive oxygen species in their formation. Aggregates were also observed in gastric tissues of mice infected with Helicobacter pylori. This is the first report describing the formation of Ub(+) aggregates in vivo during enteric infection, and reveals that this phenotype is dependent on both bacterial and host factors. Our experiments extend previous in vitro studies suggesting that Ub(+) aggregates play an important role in the initiation of immune responses to infection. Ub(+) aggregates are a novel marker of the cellular response to enteric pathogens and will be useful for studies of host pathogen interactions in vivo. PMID- 20962507 TI - Placental IGF-I, estrogen receptor, and progesterone receptor expression, and maternal anthropometry in growth-restricted pregnancies in the Swedish population. AB - BACKGROUND/AIMS: Fetal growth restriction is a complex problem of pregnancy arising from multiple etiologies. Key regulatory elements of growth are the insulin-like growth factor (IGF) axis, and estrogen and progesterone receptors. The aims were to determine the relations of expression of IGF-I, estrogen receptors alpha and beta (ERalpha and ERbeta, respectively), and progesterone receptor (PR), with maternal anthropometry, focusing on birth weight outcomes. METHODS: Placental samples were obtained from 33 patients following delivery. mRNA expression was determined by a solution hybridization technique. Samples were divided into normal control (NC) and growth-restricted (GR) groups. RESULTS: IGF-I expression was lower in the GR as compared to the NC group. PR levels correlated positively with IGF-I expression, infant anthropometry, and gestational age (GR). ERalpha correlated positively with PR expression (NC), and maternal BMI at delivery (GR). ERbeta correlated positively with maternal delivery weight and gestational age (NC). CONCLUSION: The differences in placental expression of IGF-I emphasize its key role in birth weight outcomes. We further suggest the importance of PR expression in the pathogenesis of intrauterine growth restriction, as there were direct correlations of PR expression with both IGF-I expression and infant anthropometric parameters, as well as gestational age. PMID- 20962509 TI - Gender dichotomy in long term growth trajectories of children with 21-hydroxylase deficiency congenital adrenal hyperplasia. AB - AIM: To evaluate longitudinal growth in 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH), factors contributing to this and outcome for BMI, weight (Wt) and height (Ht) in adolescence. METHODS: Multi-level longitudinal models were used to evaluate growth patterns of 45 salt wasters (SW) and 12 non SW with CAH. RESULTS: Ht, Wt and BMI growth curves differed between SW and non SW, and by gender. In contrast to SW and males, non-SW females showed a markedly different pattern with a progressive increase in Wt and BMI SDS over childhood and adolescence and only a slight gain in Ht SDS. BMI SDS remained above 0 after early childhood. Over the 15 years, the growth variables were negatively associated with fludrocortisone (FC) (shorter children were receiving larger doses) but not hydrocortisone (HC) doses nor FC and HC doses in the first year. CONCLUSION: The growth patterns in these children with CAH were influenced by age, gender, phenotype and FC treatment. There was a trend to increasing BMI from an early age, greater adiposity during childhood and females had disproportionately greater adiposity but shorter stature during adolescence. These patients therefore have a predisposition to obesity in childhood and later life independent of early corticosteroid treatment. PMID- 20962510 TI - Does intervention in utero preserve the obstructed kidneys of fetal lambs? A radiological and pathological study. AB - OBJECTIVE: Ureteropelvic junction obstruction is a common cause of end-stage pediatric nephropathy. Our aim was to investigate whether in utero decompression can influence its development. METHODS: A silastic tube was tied around the superior segment of the left ureter to cause partial unilateral obstruction in 22 fetal lambs at 75-85 days of gestation. Three weeks later, tubes were removed in 10 of the fetuses. A single sham procedure was performed on 4 control fetuses. Intravenous pyelography (IVP) and pathological evaluations were conducted in obstructed, decompressed and control subjects. RESULTS: IVP revealed damaged renal function in obstructed subjects. Macroscopically, obstructed kidneys were larger but weighed less and had thinned parenchyma. Microscopy revealed cortical cysts of various sizes and interstitial fibrosis. The number of glomeruli was markedly decreased. In contrast, decompressed kidneys were visualized during IVP, and pathological changes were greatly ameliorated. CONCLUSIONS: Relief of obstruction in utero seems to prevent or attenuate development of nephropathy in lambs. Clinical application of this procedure should proceed with caution until further data are obtained. PMID- 20962511 TI - Impact of overactive bladder symptoms on sexuality in both sexes. AB - OBJECTIVES: To define the epidemiological impact of the overactive bladder syndrome (OAB) on sexual life. We therefore analyzed this issue in a large cohort of individuals participating in a health screening project. PATIENTS AND METHODS: A total of 2,365 men and women completed the Bristol Female Lower Urinary Tract Symptoms Questionnaire (BFLUTS). OAB was defined according to the International Continence Society (ICS). The impact of OAB on sexual life was assessed by a single question: 'In general, how do your micturition problems affect your sexual life'. RESULTS: A total of 1.199 men and 1.166 women with were analyzed. The overall prevalence of OAB was 13.9% (n = 329): 9.7% had OAB(dry) and 4.2% OAB(wet). A total of 17.6% (n = 58) of individuals with OAB reported a negative impact of OAB on sexual life as compared to 4.7% of those without OAB (p < 0.001). One of 4 with OAB(wet) reported a negative impact on sexual life (25%) as compared to 14.4% in those with OAB(dry) (p < 0.005). CONCLUSION: Sexual dysfunction is frequently reported in individuals with OAB. Individuals with OAB(wet) are experiencing a more profound impact on sexuality. Therefore, patients with OAB should be assessed regarding sexual dysfunction by the urologist. PMID- 20962512 TI - Pediatric idiopathic intracranial hypertension (pseudotumor cerebri). AB - Idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, is a condition of elevated intracranial pressure in the absence of clinical, laboratory or radiological evidence of an intracranial space occupying lesion that can occur in the pediatric population. While IIH is more commonly recognized as a disorder of adults, it affects children of all ages and can have distinctive characteristics when presenting in the prepubertal age group. This review discusses the demographics, clinical presentation, diagnosis, neuroimaging, and management of pediatric IIH. Common etiologies of IIH in children, with particular focus on endocrine abnormalities, are highlighted. PMID- 20962514 TI - Large fetal goiter due to placental passage of maternal antithyroperoxidase antibodies. AB - We report a case of fetal goiter in a pregnant woman with Graves-Basedow disease. It was diagnosed in the third trimester by a routine ultrasound, and the cordocentesis verified increased levels of thyroxine (T4) and increased autoantibodies (antithyroperoxidase antibodies) that were also increased in maternal blood. Fetal goiter got smaller on the follow-up scans, and the newborn presented hypothyroidism. Current notions on the diagnosis and management of fetal goiter are briefly discussed. PMID- 20962513 TI - Imaging in bladder cancer: present role and future perspectives. AB - Advances in imaging have an increasingly significant role in the diagnosis, staging and restaging of patients with bladder cancer. This paper reviews the current use of imaging in bladder neoplasms, comparing the different radiologic investigations, and discusses the potential applications of novel imaging techniques in the management of patients with bladder cancer. PMID- 20962515 TI - Reactive metabolites and AGE/RAGE-mediated cellular dysfunction affect the aging process: a mini-review. AB - Aging is a dynamic process in which its rate and subsequent longevity of an organism are dependent upon the balance between the reactive intermediates of normal cellular metabolism and the ability of the body to reduce these by products through a multifaceted antioxidant defence system. Every disturbance of this balance constitutes a clear and present danger to the macromolecular integrity of the body. When defence mechanisms become diminished or impaired, the resulting imbalance results in accumulation of endogenous agents, such as reactive oxygen and carbonyl species, and a state of increased cellular stress, which can accelerate the rate of aging. Glycation is the non-enzymatic glycosylation of proteins, nucleotides and lipids by saccharide derivatives. Glucose and other reducing sugars are important glycating agents, but the most reactive physiological relevant glycating agents, are the dicarbonyls, in particular methylglyoxal. Endogenously formed dicarbonyl compounds can react with proteins to form advanced glycation endproducts (AGEs). Experimental models have recently provided evidence that reduced detoxification of AGE precursors by the glyoxalase system, engagement of the cellular receptor RAGE and RAGE-dependent sustained activation of the pro-inflammatory transcription factor nuclear factor kappaB might significantly contribute to the rate of aging and the onset of age related neurodegenerative, musculoskeletal and vascular diseases. PMID- 20962516 TI - Science in time of crisis. AB - A crisis usually poses novel challenges that cannot be met with existing knowledge. To confront the unexpected, we need scientific inquisitiveness and long-term basic research. Narrowly focused research programs cater to short-term thinking and are rarely an effective way to spend precious public funds. PMID- 20962517 TI - Development and validation of a patient safety culture questionnaire in acute geriatric units. AB - BACKGROUND: Older patients (>=65 years) are exposed to more harm resulting from adverse events in hospitals than younger patients. Theoretical considerations and empirical findings suggest that safety culture is the key to improving the quality of health care. OBJECTIVE: To describe the development of a German language instrument for assessing patient safety culture (PSC) and its reliability and validity; to verify criterion validity by means of a cross sectional analysis of the impact of PSC on clinical quality that compares acute geriatric units with a sample from intensive care, surgery and trauma surgery departments, and to report variations in the PSC profile between these groups. METHODOLOGY: Using a review of existing safety culture surveys, multidimensional scaling procedures and expert interviews, we tested the content and convergent validity of a 158-item questionnaire completed by 508 physicians and nurses from 31 acute geriatric units and 7 comparison departments. Criterion validity was verified by various regression models with a self-reported measure of adverse events. Differences in PSC profiles were analyzed using a one-factorial ANOVA and regression models. RESULTS: We identified 7 constructs of PSC and demonstrated substantial convergent and criterion validity. In the acute geriatric units, higher levels of 'management commitment to patient safety' and lower levels of 'error fatalism' were associated with a reduced incidence of medical errors. In the comparison group, only the variable 'active learning from mistakes' was relevant for safety performance. Our results also indicate that acute geriatric units display higher standards than the comparison group in all the aspects of patient safety examined. CONCLUSION: It is possible to measure salient features of PSC using a valid and reliable survey. Some aspects of PSC are more closely related to safety events than others. In acute geriatric units, patient safety appears to be influenced mainly by management's determination of how things are done whereas improvement of the system itself in a more incremental manner is required in the other high-risk ward types. PMID- 20962518 TI - Leukocyte alkaline phosphatase score correlation with bone marrow blast percentage in myelodysplastic syndrome. PMID- 20962519 TI - Increased risk for acute lymphoblastic leukemia in children with cytochrome P450A1 (CYP1A1)- and NAD(P)H:quinone oxidoreductase 1 (NQO1)-inherited gene variants. PMID- 20962521 TI - der(14)t(6;14)(p21;q32) detected in a phytohemagglutinin-stimulated culture from an asymptomatic woman with CD5- monoclonal B-cell lymphocytosis. PMID- 20962520 TI - Reversible painful oral mucosal hyperpigmentation following palifermin administration. PMID- 20962522 TI - Genetic polymorphisms in nitric oxide synthase 3 gene and implications for kidney disease: a meta-analysis. AB - BACKGROUND/AIMS: The NOS3 gene is a biological and positional candidate for diabetic nephropathy. However, the relationship between NOS3 polymorphisms and renal disease is inconclusive. This study aimed to clarify the association of NOS3 variants with nephropathy in individuals with type 1 diabetes. METHODS: We conducted a case-control study examining all common SNPs in the NOS3 gene by a tag SNP approach. Individuals with type 1 diabetes and persistent proteinuria (cases, n = 718) were compared with individuals with type 1 diabetes but no evidence of renal disease (controls, n = 749). Our replication collection comprised 1,105 individuals with type 1 diabetes recruited to a nephropathy case group and 862 control individuals with normal urinary albumin excretion rates. Meta-analysis was conducted for SNPs where more than three genotype datasets were available. RESULTS: A novel association was identified in the discovery collection (rs1800783, p(genotype) = 0.006, p(allele) = 0.002, OR = 1.26, 95% CI: 1.08-1.47) and supported by independent replication using a tag SNP (rs4496877, pairwise r2 = 0.96 with rs1800783) in the replication collection (p(genotype) = 0.002, p(allele) = 0.0006, OR = 1.27, 95% CI: 1.10-1.45). CONCLUSION: The A allele of rs1800783 is a significant risk factor for nephropathy in individuals with type 1 diabetes, and further comprehensive studies are warranted to confirm the definitive functional variant in the NOS3 gene. PMID- 20962523 TI - Advances in the genetics of anti-glomerular basement membrane disease. AB - Anti-glomerular basement membrane (GBM) disease is a rare but lethal autoimmune disorder. Over the past few years, the nature of the autoantigen and its epitopes has been defined, as well as the possible pathogenic role played by environmental factors, and by cellular and humoral immunity. However, the majority of data on anti-GBM disease comes from studies conducted on animal models, since human studies are relatively scarce. Genetic studies have highlighted strong positive associations of anti-GBM disease with the HLA-DRB1*1501 allele. In addition, the disease has been associated with genes of the FCGR and KLK families. Important as they are, these findings have to be considered preliminary, if not contentious. Here, we provide an overview of recent discoveries in the genetics of anti-GBM disease that may help elucidate the disease pathogenesis while improving therapeutic approaches. We also discuss the limitations of such discoveries. Finally, we suggest that extensive collaboration between investigators and novel integrative approaches are essential to the progress of our understanding of the anti-GBM disease. We attempted to summarize the current knowledge on the pathogenesis of anti-GBM disease by providing different but complementary perspectives from previous reviews. PMID- 20962524 TI - Daily short-term intratympanic dexamethasone treatment alone as an initial or salvage treatment for idiopathic sudden sensorineural hearing loss. AB - OBJECTIVE: Intratympanic (IT) steroid therapy has been proposed as an alternative treatment option for patients with idiopathic sudden sensorineural hearing loss (ISSNHL). However, the number and frequency of IT treatments and drug delivery methods remain to be determined. The purpose of this study was to evaluate the efficacy of daily short-term IT dexamethasone (DEX) treatment alone in ISSNHL patients using laser-assisted myringotomy (LAM) for the drug delivery route as an initial and/or salvage treatment. STUDY DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: Seventy-six ISSNHL patients receiving IT DEX. Patients with low-tone hearing loss, unilateral or bilateral fluctuating hearing loss or contralateral hearing loss were excluded. INTERVENTION: DEX (4 mg/ml) was injected through a perforation made by LAM. IT DEX administration was performed on 8 sequential days. MAIN OUTCOME MEASURES: Pre- and postprocedure hearing levels. The average hearing level was determined by 5 frequencies (250, 500, 1000, 2000 and 4000 Hz). RESULTS: Nineteen out of 76 patients fit the criteria for initial treatment in the study (group I), while 24 patients, who had failed systemic therapy, received salvage treatment (group S). The mean age of the patients in groups I and S was 56.2 years with a range from 31 to 73 years of age and 46.0 years with a range from 11 to 76 years of age, respectively. The mean number of days from onset of symptoms to IT therapy in groups I and S was 4.8 days with a range of 1-23 days and 15.3 days with a range of 6-28 days, respectively. In group I, 18 of the 19 patients (95%) showed improvement of more than 10 dB in the pure-tone audiogram, with a mean improvement of 40 dB. Twelve patients (63%) recovered completely and 16 patients (84%) demonstrated successful results with an improvement of more than 30 dB. In group S, 14 of the 24 patients (58%) showed improvement of more than 10 dB with a mean improvement of 16 dB. Two (8%) of the 7 patients (29%) with successful results recovered completely. CONCLUSIONS: Daily short-term IT DEX administration using LAM for ISSNHL patients without concurrent therapy showed a high response rate and high cure rate and proved to be an alternative therapeutic option to high-dose systemic steroids as a first- and/or second-line treatment. PMID- 20962525 TI - Viral load and CD4+ cell count as risk factors for prolonged QT interval in HIV infected subjects: a cohort-nested case-control study in an outpatient population. AB - BACKGROUND: QTc interval prolongation is a serious ECG finding which has frequently been reported in HIV-infected patients, but associated risk factors have not been determined in this population. METHODS: Data were collected from the charts of a cohort of 135 consecutive HIV-infected patients from our HIV outpatient clinic. The cohort was divided into two groups, patients with prolonged QTc and those with normal QTc interval. Multiple variables and potential risk factors were analyzed, including the CD4+ cell count and viral load (VL), which were assessed on the same day or within several days of the initial ECG. RESULTS: 23 patients were found to have prolonged QTc (17%). No significant difference in baseline characteristics was observed between the groups; however, statistically significant differences were observed with regard to the CD4+ cell count and VL. CONCLUSION: A low CD4 cell count and a high VL may be risk factors potentially related to QT prolongation in HIV patients in the outpatient setting. PMID- 20962527 TI - Left ventricular hypercontractility immediately after tilting triggers a disregulated cardioinhibitory reaction in vasovagal syncope: echocardiographic evaluation during the head-up tilt test. AB - OBJECTIVES: Vasovagal syncope (VVS) has been believed to occur when mechanoreceptors are discharged by vigorous ventricular contraction. However, previous investigators have reported divergent observations regarding the presence of left ventricular (LV) hypercontractility in VVS. Because the autonomic nervous system can be promptly activated after certain stimuli, we postulated that instantaneously increased LV contractility at the time of venous pooling may trigger the disregulated vasovagal reaction in VVS. METHODS: Forty seven patients (31 males, mean age 41 +/- 18 years) with unexplained syncope were enrolled. Echocardiography was performed during the head-up tilt test (HUTT) as follows: baseline, passive tilting (0 and 20 min), and tilting with isoproterenol administration (5 and 10 min). Patients were divided into 2 groups according to the results of the HUTT; group 1 (n = 12) had a positive result and group 2 had a negative response. RESULTS: LV ejection fraction (LVEF), determined immediately after tilting, increased in group 1, whereas LVEF decreased in group 2 (p = 0.032). Although left atrial and LV volumes decreased similarly during the test, group 1 showed a progressive reduction in LVEF, while LVEF progressively increased in group 2 (p = 0.007). CONCLUSION: Patients with HUTT-induced VVS presented LV hypercontractions immediately after tilting and a subsequent decrease in LV contractility. An instantaneous activation of the sympathetic nervous system at the time of venous pooling may trigger an early disregulated vasovagal reflex via an increase in LV contractility in VVS. PMID- 20962528 TI - Sudden cardiac arrest during acute coronary occlusion - who is at risk? AB - Many people with acute myocardial infarction die from sudden cardiac arrest before reaching the hospital. The current clinical understanding of the mechanisms and risk factors surrounding sudden cardiac death is limited. However, 2 factors related to sudden death, namely the occluded coronary vessel (right coronary, left circumflex, or left anterior descending artery) and the extent of collateral circulation, are of potential relevance. Recent data suggest that the risk differs between the different coronary arteries and that coronary collateral circulation seems to have an important protective 'antiarrhythmic' effect. This editorial will address possible mechanisms and potential implications in clinical practice. PMID- 20962526 TI - Relation of diastolic and systolic function, exercise capacity and brain natriuretic peptide in adults after Mustard procedure for transposition of the great arteries. AB - OBJECTIVES: To evaluate the relation of echocardiographic parameters of diastolic function, exercise capacity (expressed as peakVO(2)) and NT-proBNP in patients with transposition of the great arteries (TGA) and Mustard procedure. METHODS: Diastolic function was determined by measuring tricuspid flow velocities (Ea/Aa ratio), isovolumic relaxation time (IVRT), and deceleration time (DT). E/Ea ratios were calculated. For assessment of systolic function, CMR was applied. RESULTS: E/A (r = 0.07, p = 0.66), E/Ea medial (r = 0.03, p = 0.84), E/Ea lateral (r = -0.01, p = 0.92), IVRT (r = -0.13, p = 0.44), and DT (r = -0.05, p = 0.76) were not correlated with peakVO(2). NT-proBNP showed a significant correlation with IVRT (r = 0.44, p = 0.004) and Ea/Aa medial (r = -0.34, p = 0.025). No correlation was found between RV systolic function and peakVO(2) (r = 0.07, p = 0.63). CONCLUSIONS: Exercise capacity in patients with TGA and Mustard procedure is not related to echocardiographic parameters of diastolic function. NT-proBNP is associated with selected echocardiographic parameters of diastolic function. PMID- 20962529 TI - Microvascular determinants of cognitive decline and brain volume change in elderly patients with type 2 diabetes. AB - BACKGROUND/AIMS: The present study examined the relationship between microvascular complications and cognitive decline and the development of structural brain abnormalities over a period of 4 years in patients with type 2 diabetes mellitus (T2DM). METHODS: Sixty-eight elderly patients with T2DM had 2 cognitive assessments with a 4-year interval. Two MRI scans, performed at the same time as the cognitive assessments, were available from 55 patients. Changes in cognitive performance over time were expressed as a regression-based index (RBI). Automated volumetric measurements of total brain, lateral ventricles and white matter hyperintensities were performed. The relationship between baseline microvascular complications [diabetic retinopathy, peripheral neuropathy or albuminuria (micro- or macroalbuminuria)] and cognition and brain volumes was examined with linear regression analyses adjusted for age and sex (for cognition also for IQ). RESULTS: At baseline, diabetic retinopathy was present in 18% of patients, peripheral neuropathy in 36%, albuminuria in 15%. Retinopathy or neuropathy were not significantly associated with baseline cognition or brain volumes, or changes in these measures over time. Albuminuria was associated with a lower composite RBI score, indicating accelerated cognitive decline (adjusted mean difference between patients with or without albuminuria: -0.58, 95% CI -0.85 to -0.31, p < 0.001). CONCLUSION: Albuminuria predicted accelerated cognitive decline in patients with T2DM, but other microvascular complications were unrelated to accelerated cognitive decline or brain MRI abnormalities. PMID- 20962530 TI - Effects of parents' education and occupation on adolescent smoking and the mediating role of smoking-specific parenting and parent smoking. AB - The current study examined the independent effects of parents' educational attainment and occupational status on adolescent smoking and mediation of smoking specific communication and parents' smoking behaviours on this link. Data were collected in a multi-informant, full-family design in two sampling waves separated by 3 years (n = 358). Education, occupational status, communication, and smoking were assessed via parent and child report. Different effects were found for the indicators of father and mother's socioeconomic status (education and occupation) for three study outcomes (adolescent lifetime smoking, smoking onset, and smoking continuation). Bootstrapping procedures revealed no mediation in any of the socioeconomic status adolescent smoking associations. Study limitations and implications are discussed. PMID- 20962531 TI - The prevention pendulum: avoidance or introduction. PMID- 20962532 TI - Detection of Bet v1, Bet v2 and Bet v4 specific IgE antibodies in the sera of children and adult patients allergic to birch pollen: evaluation of different IgE reactivity profiles depending on age and local sensitization. AB - BACKGROUND: Birch pollen belongs to the major allergen triggers in the spring season in Europe. Our rapidly expanding knowledge of the allergenic molecules enables us to better recognize the individual differences between the reactivity of specific IgE antibodies of individual patients and allergic populations living in various regions of the world. METHOD: In a group of birch pollen-allergic patients living in the Czech Republic (107 children, 71 adults) we detected the presence of Bet v1, Bet v2 and Bet v4 specific IgE antibodies. RESULTS: Bet v1 specific IgE antibodies were identified in most patients without any significant differences between children and adults. Bet v2 positivity was found more frequently in the group of children than in adults (p = 0.02). In most adult patients Bet v1 monospecificity was more expressed as compared to the pediatric group. More allergic subjects reacted against minor birch allergens in the pediatric group (p = 0.02). Specific IgE antibodies against Bet v1 were not detected in 10% of the tested patients. In this group, 5% of birch pollen allergic patients were found to not have specific IgE antibodies against any of the tested recombinant allergens. CONCLUSION: The investigation of specific IgE antibodies against Bet v1, Bet v2 and Bet v4 demonstrated that the specificity of allergen-induced IgE antibodies in birch pollen-allergic individuals is dependent not only on the region in which a patient lives but also on age. Especially in children, there is an increase in the number of allergic subjects who do not react exclusively against the major allergen. The question is whether some allergen-specific IgE antibodies will disappear depending on age or on the contrary whether their synthesis will be increased. PMID- 20962534 TI - Purification of the major group 1 allergen from Bahia grass pollen, Pas n 1. AB - BACKGROUND: Group 1 grass pollen allergens are glycoproteins of the beta-expansin family. They are a predominant component of pollen and are potent allergens with a high frequency of serum IgE reactivity in grass pollen-allergic patients. Bahia grass is distinct from temperate grasses and has a prolonged pollination period and wide distribution in warmer climates. Here we describe the purification of the group 1 pollen allergen, Pas n 1, from Bahia grass (Paspalum notatum), an important subtropical aeroallergen source. METHODS: Pas n 1 was purified from an aqueous Bahia grass pollen extract by ammonium sulphate precipitation, hydrophobic interaction and size exclusion chromatography, and assessed by one- and two-dimensional gel electrophoresis, immunoblotting and ELISA. RESULTS: Pas n 1 was purified to a single 29-kDa protein band containing two dominant isoforms detected by an allergen-specific monoclonal antibody and serum IgE of a Bahia grass pollen-allergic donor. The frequency of serum IgE reactivity with purified Pas n 1 in 51 Bahia grass pollen-allergic patients was 90.6%. Serum IgE reactivity with purified Pas n 1 was highly correlated with serum IgE reactivity with Bahia grass pollen extract and recombinant Pas n 1 (r = 0.821 and 0.913, respectively). CONCLUSIONS: Pas n 1 is a major allergen reactive at high frequency with serum IgE of Bahia grass pollen-allergic patients. Purified natural Pas n 1 has utility for improved specific diagnosis and immunotherapy for Bahia grass pollen allergy. PMID- 20962533 TI - Isomaltitol exacerbates neutrophilia but reduces eosinophilia: new insights into the sephadex model of lung inflammation. AB - BACKGROUND: We have previously examined isomaltitol in an in vitro static adhesion assay and were interested in investigating whether the potentially anti inflammatory effects observed there could be relevant in vivo. The Sephadex induced lung inflammation model was considered a suitablemodel due to the significant changes in global inflammatory endpoints seen upon provocation with Sephadex. METHODS: Male Sprague-Dawley rats were instilled intratracheally with Sephadex (5 mg/ml), vehicle (0.9% NaCl), isomaltitol (50 mg/ml) or a combination of isomaltitol and Sephadex. After 24 h, the lungs were weighed to measure edema and preserved for histology. Bronchoalveolar lavage fluid was used for analysis of tumor necrosis factor, cysteinyl leukotrienes, and differential and total leukocyte counts. RESULTS: Differential counts showed that isomaltitol increased the neutrophil component while decreasing the eosinophilia, thus asserting a modulatory role on the usually eosinophil-dominated Sephadex-induced cell profile. Isomaltitol alone also increased edema and cysteinyl leukotrienes, and generally aggravated total inflammation in combination with Sephadex. The mechanisms were not investigated in this study, but effects could relate to a combination of isomaltitol's osmotic and structure-specific properties. CONCLUSION: Our results show that isomaltitol can modulate the inflammatory response induced by Sephadex instillation in addition to having proinflammatory effects on its own, and may therefore provide new insights into the mechanisms of this widely used animal model. Sugar alcohols similar to isomaltitol have already been used to aid mucus clearance in cystic fibrosis patients, and it is possible that isomaltitol could also be used for this purpose. PMID- 20962535 TI - Epicutaneous immunotherapy using a new epicutaneous delivery system in mice sensitized to peanuts. AB - BACKGROUND: Peanut allergy is a life-threatening condition for which new efficient and safe treatment is expected. We evaluated epicutaneous immunotherapy (EPIT) as a new alternative treatment for peanut allergy in sensitized mice. METHODS: Sixty BALB/c mice were sensitized by gavages with peanut protein extract (PPE) mixed with cholera toxin. An epicutaneous delivery system, coated with 100 MUg PPE (Viaskin(r), DBV Technologies, Paris, France), was applied to intact skin every week during 48 h (EPIT; n = 20). This group was compared with sensitized mice treated with subcutaneous immunotherapy (SCIT; n = 20), untreated sensitized mice (sham, n = 20), and naive mice (naive; n = 20). After the 8-week treatment, a histamine release test, airway hyperreactivity measurement by plethysmography, and a resistance-compliance measurement after the challenge were performed. Blood and bronchoalveolar lavage were sampled for serology, cytokines, and cytology. RESULTS: Specific IgE (sIgE) increased after sensitization in the EPIT (0.26 MUg/ml) and SCIT (0.21 MUg/ml) groups and decreased after treatment (0.09 MUg/ml, p < 0.001 and 0.06 MUg/ml, p < 0.001, respectively). The IgG1/IgG2a ratio decreased in the EPIT and SCIT groups versus the sham group (3.7; p < 0.001 and 2.7; p < 0.01 and 15.1, respectively). At the higher metacholine concentration, enhanced pause values were lower in the EPIT and SCIT groups than in the sham group (7.29, 6.74, and 10.99, p < 0.01, respectively), and did not differ from that of the naive group (5.06). Resistance-compliance was reversed in the treated groups versus the sham group (p < 0.001). IL-4, IL-5, IL-13, eotaxin, and eosinophils were reduced in the BAL of the EPIT and SCIT groups versus the sham group (p < 0.001). CONCLUSION: In peanut-sensitized mice, based on biological and physiological responses, EPIT is as efficient as subcutaneous treatment which is the reference method in immunotherapy. PMID- 20962536 TI - Evidence of hepatitis E virus exposure among seronegative healthy residents of an endemic area. AB - OBJECTIVE: Hepatitis E virus (HEV) infection is endemic in the Indian subcontinent. Detection of serum anti-HEV IgG has traditionally been used to determine prior exposure to this virus. We studied HEV-specific recall immune responses in healthy subjects with and without detectable anti-HEV IgG. METHODS: Memory B and T cells specific for HEV recombinant proteins pORF2 and pORF3 were estimated among healthy subjects residing in an HEV-endemic region using enzyme linked immunospot (ELISPOT) assays. RESULTS: Anti-HEV IgG-negative and anti-HEV IgG-positive healthy subjects had a similar median (range) number of IgG secreting memory B cells specific for HEV pORF2 [percent of total IgG-producing cells: 0.39 (0-13.63) vs. 0.83 (0-12.78)] and HEV pORF3 [0.33 (0.05-12.35) vs. 1.01 (0.08-9.48)], and of IFN-gamma-secreting memory T cells specific for HEV pORF2 [per one million PBMCs: 16 (0-220) vs. 36.5 (0-474)] and HEV pORF3 [166 (0 957) vs. 70.5 (0-533)]. Eight healthy volunteers residing in the USA and studied as controls lacked detectable T cells specific for HEV pORF2. CONCLUSION: ELISPOT assays may detect evidence of prior HEV infection in persons residing in areas endemic for this infection and lacking detectable anti-HEV IgG. Seroepidemiological studies that use the serum anti-HEV IgG test may underestimate the frequency of exposure to HEV. PMID- 20962537 TI - The p-type ATPase superfamily. AB - P-type ATPases function to provide homeostasis in higher eukaryotes, but they are essentially ubiquitous, being found in all domains of life. Thever and Saier [J Memb Biol 2009;229:115-130] recently reported analyses of eukaryotic P-type ATPases, dividing them into nine functionally characterized and 13 functionally uncharacterized (FUPA) families. In this report, we analyze P-type ATPases in all major prokaryotic phyla for which complete genome sequence data are available, and we compare the results with those for eukaryotic P-type ATPases. Topological type I (heavy metal) P-type ATPases predominate in prokaryotes (approx. tenfold) while type II ATPases (specific for Na(+),K(+), H(+) Ca(2+), Mg(2+) and phospholipids) predominate in eukaryotes (approx. twofold). Many P-type ATPase families are found exclusively in prokaryotes (e.g. Kdp-type K(+) uptake ATPases (type III) and all ten prokaryotic FUPA familes), while others are restricted to eukaryotes (e.g. phospholipid flippases and all 13 eukaryotic FUPA families). Horizontal gene transfer has occurred frequently among bacteria and archaea, which have similar distributions of these enzymes, but rarely between most eukaryotic kingdoms, and even more rarely between eukaryotes and prokaryotes. In some bacterial phyla (e.g. Bacteroidetes, Flavobacteria and Fusobacteria), ATPase gene gain and loss as well as horizontal transfer occurred seldom in contrast to most other bacterial phyla. Some families (i.e. Kdp-type ATPases) underwent far less horizontal gene transfer than other prokaryotic families, possibly due to their multisubunit characteristics. Functional motifs are better conserved across family lines than across organismal lines, and these motifs can be family specific, facilitating functional predictions. In some cases, gene fusion events created P-type ATPases covalently linked to regulatory catalytic enzymes. In one family (FUPA Family 24), a type I ATPase gene (N-terminal) is fused to a type II ATPase gene (C-terminal) with retention of function only for the latter. Several pseudogene-encoded nonfunctional ATPases were identified. Genome minimalization led to preferential loss of P-type ATPase genes. We suggest that in prokaryotes and some unicellular eukaryotes, the primary function of P-type ATPases is protection from extreme environmental stress conditions. The classification of P type ATPases of unknown function into phylogenetic families provides guides for future molecular biological studies. PMID- 20962538 TI - Telephone administration of the Mental Alternation Test: sensitivity to cognitive decline and practice effects across midlife and late life. AB - BACKGROUND: We evaluated the utility of the telephone-administered Mental Alternation Test (MAT, an oral variant of the Trail-Making Test) for remote assessment of cognitive functioning in older adults. We examined (1) the sensitivity of MAT scores to cognitive change across 4 age groups, (2) practice effects associated with repeat administration, and (3) the uniformity of practice effects across age groups. METHODS: Community-dwelling volunteers were recruited randomly and categorized as young-middle-aged (45-54 years; n = 51), middle-aged (55-64 years; n = 58), young-old (65-74 years; n = 43) or old-old (75-85 years; n = 43). The participants completed the MAT twice within 2 weeks. The data were analyzed using mixed ANOVA. RESULTS: We found an effect of age on MAT performance [F(3, 191) = 11.37; p < 0.001], with planned comparisons revealing significantly lower scores in the old-old (p < 0.05). The scores on the second MAT administration were significantly higher than on the first administration [F(1, 191) = 12.82; p < 0.001], but this practice effect did not differ across age groups. CONCLUSIONS: The MAT was sensitive to cognitive decline in older adulthood. Practice effects were measurable but uniform across the observed age cohorts. As a brief telephone-administered test, the MAT represents a promising measure of cognitive functioning in older adults that is feasible for use in large-scale epidemiological studies. PMID- 20962539 TI - No role for melanoma treatment in the association between melanoma and amyotrophic lateral sclerosis or Parkinson's disease. PMID- 20962540 TI - The nuclear localization of CAPON in hippocampus and cerebral cortex neurons after lipopolysaccharide stimulation. AB - OBJECTIVE: In the brain, nitric oxide (NO) is a retrograde signalling molecule that transfers information from post- to pre-synaptic nerve endings. NO has been shown to be an important inflammatory mediator responding to lipopolysaccharide (LPS). It has been stated that the constitutive NO synthase isoforms (nNOS and eNOS) may also contribute to the inflammation. CAPON, a nNOS regulator, helps regulate nNOS stability, localization and possibly expression during synapse formation as well as muscle re-innervation. Recently, it has been reported that CAPON is associated with psychiatric illness. So we speculated that the CAPON expression-induced physiological changes may be mediated by modifications of NOS NO signalling pathways. But little is known about the role of CAPON during the inflammation in the central nervous system, so we investigated the expression of CAPON in the brain treated with LPS. METHODS AND RESULTS: Real-time PCR and Western blot showed that the expression of CAPON increased at mRNA and protein levels in the brain after LPS stimulation. Immunocytochemistry staining revealed that CAPON localized in the nuclei of neurons in the brain after peritoneal injection with LPS in vivo. The same phenomenon was also shown in primary cultured neurons in vitro incubated with LPS for 36 h. In addition, we found that CAPON had a colocalization with phosphorylated nNOS Ser847 but not with nNOS in hippocampus and cerebral cortex by double immunofluorescence. CONCLUSION: CAPON localized in the nuclei of neurons in hippocampus and cerebral cortex after LPS treatment. Because CAPON competed with PSD-95 for binding nNOS in neurons and nNOS was activated to produce NO through the NMDA- NMDAR pathway, we hypothesized that CAPON might play a proactive role in the process of inflammation by transferring from cytoplasm to the nucleus and through the NMDA-nNOS signal pathway. Further studies are required to clarify the mechanism of the nuclear localization of CAPON and the possible relationship with nNOS/NO signalling. PMID- 20962541 TI - Novel antidepressants and panic disorder: evidence beyond current guidelines. AB - AIM: The aim of the present review is to summarize available evidence about the efficacy and side effects of novel antidepressants for the treatment of panic disorder. METHODS: A literature search was undertaken using MEDLINE, ISI web of knowledge and references of retrieved articles. The search included articles published in English up to September 2009. Both controlled and uncontrolled trials were included. The quality of the reviewed articles was also assessed. RESULTS: Fourteen mainly poor-quality studies were included. Mirtazapine showed some efficacy in reducing the number and the severity of panic symptoms in many uncontrolled studies and was comparable to selective serotonin reputake inhibitors (SSRIs) in direct-comparison studies. Reboxetine was significantly more efficacious than placebo but less effective than SSRIs. Further uncontrolled studies suggested preliminary evidence for the use of milnacipran and duloxetine as well. All drugs were usually well tolerated. DISCUSSION: Current studies do not yet provide convincing evidence supporting the efficacy of mirtazapine, reboxetine, milnacipran and duloxetine for the treatment of panic disorder patients. However, on account of positive preliminary results, further research is warranted. PMID- 20962542 TI - Levels of tumour necrosis factor-alpha and interleukin-6 in severely ill patients with eating disorders. AB - BACKGROUND: The underlying pathophysiology of eating disorders (ED) is dependent on complex interactions between psychological, biological and social factors. The purpose of the present study was to examine a possible increase in cytokines indicating inflammation, as measured by tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in ED patients, and to explore possible relationships between cytokines and self-reported personality traits. METHODS: Female patients with severe ED (n = 26) were recruited consecutively from an inpatient clinic and were compared to age-matched healthy females (n = 12). Commercial ELISA tests developed for the measurement of serum levels of TNF-alpha and IL-6 were employed. Personality traits were measured using Karolinska Scales of Personality. RESULTS: The patient group displayed increased levels of the cytokine TNF-alpha and a tendency towards increased IL-6 levels. Spearman's rank correlation coefficient was used to examine possible relationships between levels of cytokines and personality traits. The results showed that IL-6 levels were positively related to both somatic and psychic anxiety and to aggression scales, such as irritability and suspicion. Increased levels of TNF-alpha, in turn, were significantly correlated with high scores on the depression-related anxiety scale Inhibition of Aggression. However, increased levels of cytokines in the ED group did not seem to be mainly associated with symptoms of depression. CONCLUSION: We cannot rule out the possibility that comorbid conditions in the group contribute to the higher cytokine values. Further studies need to explore the possible influence of cytokines on the severity of ED and whether this might be mediated or moderated by specific personality traits. PMID- 20962543 TI - Hair MDMA samples are consistent with reported ecstasy use: findings from a study investigating effects of ecstasy on mood and memory. AB - AIMS: Our group has conducted several Internet investigations into the biobehavioural effects of self-reported recreational use of MDMA (3,4 methylenedioxymethamphetamine or Ecstasy) and other psychosocial drugs. Here we report a new study examining the relationship between self-reported Ecstasy use and traces of MDMA found in hair samples. METHODS: In a laboratory setting, 49 undergraduate volunteers performed an Internet-based assessment which included mood scales and the University of East London Drug Use Questionnaire, which asks for history and current drug use. They also provided a hair sample for determination of exposure to MDMA over the previous month. RESULTS: Self-report of Ecstasy use and presence in hair samples were consistent (p < 0.00001). Both subjective and objective measures predicted lower self-reported ratings of happiness and higher self-reported stress. Self-reported Ecstasy use, but not presence in hair, was also associated with decreased tension. CONCLUSION: Different psychoactive drugs can influence long-term mood and cognition in complex and dynamically interactive ways. Here we have shown a good correspondence between self-report and objective assessment of exposure to MDMA. These data suggest that the Internet has potentially high utility as a useful medium to complement traditional laboratory studies into the sequelae of recreational drug use. PMID- 20962544 TI - Smaller hippocampus volume is associated with short variant of 5-HTTLPR polymorphism in medication-free major depressive disorder patients. AB - AIM: Serotonin is known for its importance in the pathophysiology of major depressive disorder. Although the hippocampus is one of the key regions in which neurogenesis occurs, and serotonin plays an important role in neurogenesis, results of studies that investigate effect of the 5-HTTLPR polymorphism on hippocampal volumes in major depressive disorder are inconclusive. METHOD: We looked for a relationship between the 5-HTTLPR polymorphism and hippocampal volumes in 44 depressed patients (mean age +/- SD 33.6 +/- 9.5 years) and 43 healthy controls (30.4 +/- 6.7 years). Region of interest analysis was conducted on the images acquired via MRI. RESULTS: Although hippocampal volumes were similar in healthy and patient groups, there was a significant interaction between genotype and diagnosis on hippocampus volumes. Post-hoc ANCOVA showed that hippocampal volumes of S/S homozygous depressed patients were smaller compared to healthy controls in both hemispheres. CONCLUSION: The 5-HTTLPR polymorphism has an effect on hippocampal volumes of depressed patients, which is apparent only in S/S genotype. It seems that decreased neurogenesis by effects of reduced serotoninergic transmission may be responsible for smaller hippocampal volumes observed in S/S homozygous depressed patients. PMID- 20962545 TI - Inotropic effects of ivabradine in the mammalian heart. AB - Ivabradine represents a novel heart-rate-lowering agent that acts on the sino atrial node supposedly by selectively inhibiting the 'funny' current (I(f) current). In clinical studies, it was reported that ivabradine effectively reduced resting heart rate and was well tolerated. The aim of this study was to evaluate potential effects of ivabradine on cardiac contractility. Contractile effects of ivabradine were studied in isolated electrically driven atrial preparations from patients undergoing cardiac bypass surgery and for comparison in isolated spontaneously beating right atria and electrically driven left atria from mice. In human trabeculae, a concentration-dependent negative inotropic effect was noted in 7 from 10 patients. However, in 3 patients from 10, a pronounced positive inotropic effect of ivabradine was noted. As expected, in spontaneously beating mouse right atria ivabradine exerted a concentration dependent negative chronotropic effect. Unexpectedly, contractile effects in mouse and man seem to disagree. In mouse left atria, ivabradine and cilobradine, another hyperpolarization-activated cyclic-nucleotide-gated blocker, always exerted a pronounced positive inotropic effect. These positive inotropic effects were converted to negative inotropic effects in the additional presence of the L type Ca2+ channel blocker verapamil. The present study demonstrates that ivabradine at high concentrations can affect the force of contraction in atrial preparations from the human heart. PMID- 20962546 TI - Prof. Ismail Lotfy El-Shafei (1928-2009). PMID- 20962547 TI - The retrograde ventriculovenous shunts: the El-Shafei retrograde ventriculojugular and ventriculosinus shunts. AB - Retrograde ventriculovenous (RVV) shunts utilize the impact pressure of the venous bloodstream to maintain the intraventricular pressure more than the pressure in the draining venous channel and to maintain a continuous flow of cerebrospinal fluid (CSF) to the venous circulation at a rate equal to and dependent upon the rate of its formation regardless of changes in posture or intrathoracic pressure, create impact zones which discourage stagnation and clotting of blood at the venous end of the connection and utilize collapse of the internal jugular vein in the erect posture to prevent siphonage. During the past 40 years, 229 RVV shunts were implanted; 219 of the patients (95.63%) benefited from the shunt, and only 2 of them needed a single shunt revision. The manifestations of increased intracranial pressure disappeared, different degrees of regression of the ventriculomegaly occurred in patients with closed craniums but not in infants and young children with open craniums, and there were no problems related to improper CSF drainage or venous thrombosis. The follow-up period is up to 40 years (mean 9 years 8 months). PMID- 20962548 TI - Removal of ventricular shunts. AB - BACKGROUND: Although most patients with an implanted ventriculoperitoneal shunt device will require cerebrospinal fluid diversion over the course of their lifetime, there appears to be a small number of patients that are shunt independent and may benefit from shunt removal. METHODS: We retrospectively analyzed 661 patients with hydrocephalus treated over a 10-year period at a single institution. In 10 patients, a systematic shunt weaning protocol was attempted before removal of the cerebrospinal fluid shunt. RESULTS: Ten patients underwent an attempt at shunt removal. Seven of these patients were successfully weaned and 3 were not. The indications to attempt shunt removal for the 7 patients that were successfully weaned were recurrent complications and infections requiring multiple shunt externalizations and revisions in 4 patients, asymptomatic shunt disconnection in 2 patients, and symptomatic overdrainage in 1 patient. None of the patients that were successfully weaned had a history of shunt failure resulting in ventriculomegaly. Two of the 3 patients who failed shunt weaning attempts had a history of shunt failure that resulted in ventriculomegaly. CONCLUSION: A small number of patients with shunted hydrocephalus may benefit from removal of their shunt. PMID- 20962549 TI - The impact of a 'resident replacement' nurse practitioner on an Academic Pediatric Neurosurgical service. AB - INTRODUCTION: The introduction of 80-hour workweek limitations has challenged resident training programs with creative scheduling while maintaining comprehensive training experiences. The work hour restrictions may be more adaptable to a medical service, but have been very challenging to an academic surgical program. The particular challenges include maximizing academic learning opportunities, operating room experiences and direct bedside patient care while adhering to the 80-hour restriction. This paper examines the addition of a pediatric nurse practitioner (NP) to a pediatric neurosurgical academic program in response to the resident work hour restrictions. METHOD: A survey questionnaire asking for responses to questions on a 1-10 rating scale was distributed to physicians, nurses and allied care providers approximately 1 year after addition of the NP. Participants were asked to rate satisfaction with the service's availability, responsiveness and assessment of patient clinical satisfaction prior to the addition of the NP and at the time of questionnaire distribution. In addition, the hospital paging log was reviewed over a several month epoch before and after addition of the NP. Finally, the number of quality assurance sentinel events was reviewed for the year prior to and the year after the initiation of the NP program. RESULTS: The satisfaction scores in all categories, including overall satisfaction, significantly improved (p < 0.001) after the addition of the NP to the neurosurgery service. Also, during the NP on duty coverage hours, the number of paging calls received by the residents was reduced commensurate to the large number of calls received by the NP. This change was presumed to be due to the confidence of other services in obtaining a timely and appropriate response. Finally, the number of sentinel event reports remained stable. DISCUSSION: The addition of an NP in response to resident training changes has been a positive influence on satisfaction with the pediatric neurosurgical service while reducing the reliance on residents for bedside clinical care. Patient safety appears not to have been affected. Presumably, this response to resident work hour limitations will provide the needed time to enhance resident didactic and intraoperative training experiences. PMID- 20962550 TI - Electroencephalography features of primary epileptogenic regions in surgically treated MRI-negative infantile spasms. AB - OBJECTIVE: To evaluate the surgical outcome for intractable, MRI-negative infantile spasms (IS), and to identify diagnostic targets in the focal epileptogenic area by methods other than MRI. METHODS: We retrospectively studied 9 patients who had had surgery for intractable IS, and whose lesions did not appear on MRI. We analyzed video/electroencephalography (EEG), single photon emission computed tomography (SPECT) and positron emission tomography (PET) findings and their surgical outcomes. In 7 patients who were seizure free after surgery, we analyzed the EEG parameters for characteristics expected in the primary epileptogenic region. RESULTS: All patients underwent resective surgery including frontal lobectomy and multilobar resection. Seven patients showed an Engel class I outcome, and 2 patients showed a class III outcome. Interictal SPECT results showed 66.7% concordance for the hemisphere affected (lateralization), and 55.6% for lesion location (localization). Ictal SPECT showed 71.4% concordance for lateralization and localization. PET showed 66.7% concordance for lateralization, and 55.6% for localization. EEG parameters, including localized paroxysmal fast activities, spindle-shaped fast activities, repetitive or rhythmic sharp/spike wave discharges, and subclinical seizures showed highly localized specificity, and may serve to identify the epileptogenic lesion. CONCLUSION: Surgical treatment of MRI-negative IS should be justified using a combination of diagnostic methods. PMID- 20962551 TI - Expression of epidermal growth factor receptor and HER-2 in pediatric embryonal brain tumors. AB - BACKGROUND/AIMS: Medulloblastomas (MBs), atypical teratoid rhabdoid tumors (AT/RTs) and central nervous system primitive neuroectodermal tumors (PNETs) are aggressive embryonal brain neoplasms in children with overlapping histological features but with different pathogenetic pathways. We set out to evaluate the role of epidermal growth factor receptor (EGFR), HER-2, Ki-67 and p53 in embryonal tumors. MATERIAL AND METHODS: We retrospectively evaluated 36 children with embryonic tumors (27 MBs, 7 AT/RTs and 2 supratentorial PNETs). The immunohistochemical expression of EGFR and HER-2 was correlated to histology, expression of the Ki-67/MIB-1 proliferative index, p53 tumor suppressor oncoprotein and prognosis. RESULTS: High expression of Ki-67 was observed in all MBs being particularly increased (> 50%) in 8 cases, while p53 protein was detected in 25/27 MBs showing a high expression in 16 cases. EGFR and HER-2 expression was observed in 10/27 and 17/27 MBs, respectively. High Ki-67/MIB-1 and p53 expression was revealed in all AT/RTs and PNETs, while EGFR and HER-2 were detected in 3/7 and 6/7 AT/RTs, respectively. The 5-year progression-free survival and overall survival were 55.5 and 69.2%, respectively. In MBs, the univariate analysis revealed that the Ki-67 index and male gender were both at a significant level related to the survival of the patient. In multivariate analysis, the Ki-67 index was the only independent predictive variable. CONCLUSIONS: The Ki-67 index was identified as a factor with independent prognostic power. EGFR and HER-2 expression is variable in embryonal tumors. HER 2 expression, in a considerable number of MBs and AT/RTs, suggests that HER-2 may be implicated in their pathogenesis representing a potential target for novel therapies. PMID- 20962552 TI - The risk of growing skull fractures in craniofacial patients. AB - BACKGROUND/AIMS: Growing skull fractures (GSFs) are unusual sequelae of head injury in young children which have also been reported to occur after craniofacial procedures complicated by inadvertent durotomy. We reviewed the craniofacial experience in a single institution, detailing 180 cases of craniofacial surgery and suspected dural tears and their relationship to the subsequent development of GSFs. This experience was then compared to that of the pertinent published literature. METHODS: A retrospective review of the senior authors' craniofacial surgical experience from 2000 to 2007 was performed. This was compared to an English-language literature review of GSFs after craniofacial surgery. RESULTS: In our institution, 180 cases of craniofacial surgery (83 open, 97 endoscopic) were performed, with an average follow-up of 23.5 months. Twenty five patients (15 open, 10 endoscopic surgeries) had operative dural compromise. One of these patients developed a persistent pseudomeningocele requiring reoperation. Twelve cases of GSF after craniofacial surgery were identified in a review of the English-language literature, of which 7 (58%) had coronal suture fusion. CONCLUSIONS: While durotomy may occur during craniofacial surgery, the subsequent development of a GSF appears to be an unlikely event with an aggressive intraoperative approach of identification and repair. Coronal craniosynostosis may confer an increased risk for this complication. PMID- 20962553 TI - Clinical characteristics of neonatal meningomyelocele cases and effect of operation time on mortality and morbidity. AB - OBJECTIVE: We aimed to evaluate the clinical features, short-term prognosis, and effect of operation time on mortality and morbidity in neonates with meningomyelocele. METHODS: This prospective study was conducted between January 2006 and December 2008. Clinical features, defective area, existence of additional anomalies, operation time, and morbidity and mortality data were recorded. The effect of operation time on mortality and morbidity was evaluated. RESULTS: Patients (n = 28) were assessed during the study period. Mean birth weight, height, and head circumference were found to be 3,160 +/- 582 g, 46.2 +/- 3.3 cm, and 36.7 +/- 4.1 cm, respectively. None of the mothers received folate supplementation. Hydrocephaly (n = 13), pes equinovarus (n = 4), pelvicalyceal ectasia (n = 4), acetabular dysplasia (n = 2), Chiari II malformation (n = 2), and hydronephrosis (n = 2) accounted for additional anomalies. The mean postnatal age for surgical operation was 3.2 +/- 2.8 days; mean length of hospital stay was 10.2 +/- 9.7 days. The cases operated after 72 h were hospitalized longer, received antibiotherapies for a longer duration and had higher total complication rates (p = 0.04, 0.02, and 0.01, respectively). CONCLUSION: Surgical operation of patients with meningomyelocele within 72 h after delivery significantly reduces not only the duration of hospitalization and antibiotic usage, but also complication rates. PMID- 20962554 TI - Endocrinological outcomes of pediatric craniopharyngiomas with anatomical pituitary stalk preservation: preliminary study. AB - OBJECTIVE: We reviewed 17 pediatric craniopharyngioma patients, with a special focus on endocrinological outcomes and tumor recurrence with pituitary stalk preservation. METHODS: From 1992 to February 2008, 17 patients underwent 27 surgical procedures. The male-female patient ratio was 12:5 and median patient age was 12 years (range, 4-18 years). The median follow-up period was 4.97 years (range, 1.16-15.08 years). The most frequent major presenting symptom was increased intracranial pressure (in 76.5%), followed by visual disturbance (in 23.5%). Tumors were totally removed in 70.6% of patients, subtotally removed in 23.5% and partially removed in 5.9%. RESULTS: The postoperative visual improvement rate was 47.6% and the postoperative visual deterioration rate was 33.3%. In 7 patients with stalk preservation, 1 received partial hormone replacement and 6 received total hormone replacement. The overall tumor recurrence and re-growth rate were 52.9%. In patients who did not receive radiotherapy immediately after their first operation, the recurrence-free survival rate differed between those with pituitary stalk preservation and those with stalk section (p = 0.04). The recurrence rate was 60% (3 of 5) in the former and 33.3% (3 of 9) in the latter. Two patients who had undergone a second operation for recurrences died. The operative morbidity rate was 23.5%. CONCLUSIONS: Pediatric craniopharyngiomas had high recurrence rates and low pituitary functional preservation despite anatomical stalk preservation. Therefore, maximal tumor resection might be more important than anatomical stalk preservation in pediatric craniopharyngiomas. PMID- 20962555 TI - [A case of clonorchiasis presenting as common bile duct mass]. PMID- 20962556 TI - [Pathology of endoscopic submucosal dissection; how do we interpret?]. AB - It is widely accepted that endoscopic submucosal dissection (ESD) is an important treatment option for cases of early gastric carcinoma where the probability of lymph node metastasis is very low. The resected ESD specimens are carefully examined by serial sections at 2 mm intervals, and if pathology reveals submucosal invasion more than 500 MUm and/or lymphovascular invasion, or if the resection margin is involved by the tumor, surgery is recommended. In this point of view, thorough pathologic examination and reporting the accurate pathologic diagnosis of ESD specimen is very important. The diagnostic approach and pitfalls in the diagnosis of ESD specimen are reviewed. PMID- 20962558 TI - [Antibiotics-associated diarrhea and other gastrointestinal abnormal responses regarding Helicobacter pylori eradication]. AB - BACKGROUND/AIMS: Helicobacter pylori (H. pylori) is closely related with a wide range of gastrointestinal disease. One-week triple therapy is currently considered as the golden standard for the treatment of H. pylori infection. However, gastrointestinal abnormal responses are major pitfalls in such regimen. The aim of this study was to identify symptoms, frequency and severity of antibiotics-associated gastrointestinal abnormal responses during H. pylori eradication therapy. METHODS: Sixty-seven patients with H. pylori infection between September 2005 and March 2006 were included. After 1 week of H. pylori eradication triple therapy (rabeprazol 10 mg, clarithromycin 500 mg, amoxicillin 1 g bid), we evaluated gastrointestinal abnormal responses (diarrhea, bloating, constipation, abdominal pain, borborygmus, flatulence, stool frequency, belching, and nausea) and severities every week for 4 weeks. RESULTS: The incidence of diarrhea was the highest in week 1, which was 41.28% (n=28) and the lowest in week 4, which was 9.52% (n=6) and decreased from week 1 to week 4 with statistical significance (p<0.0001). The most common gastrointestinal abnormal responses were associated with flatulence in week 1 (n=21, 31.34%), week 2 (n=21, 33.33%) and abdominal distention in week 3 (n=16, 25.40%), week 4 (n=15, 23.81%). Most of gastrointestinal abnormal responses were mild, and the most common symptom with higher than moderate grade was abdominal pain (n=4, 40.00%) in week 1. Alcohol consumption and coexisting medical illness were not associated with diarrhea (p=0.0852, 0.9009 respectively). CONCLUSIONS: H. pylori eradication therapy is commonly associated with antibiotics-associated gastrointestinal abnormal responses, which may result in antibiotics intolerance and H. pylori eradication failure. Even though those symptoms are not so severe, we have to consider the gastrointestinal abnormal responses associated with H. pylori eradication, especially diarrhea. PMID- 20962557 TI - [Risk factors for development and recurrence of peptic ulcer disease]. AB - BACKGROUND/AIMS: Peptic ulcer disease (PUD) is one of the common gastrointestinal diseases, and its medical management has been developed so much that the incidence of its serious complications, such as bleeding and perforation, are declining significantly. Its prevalence in Korea is not definitely decreased, probably due to increasing proportion of elderly patients and their rising usage of non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin. This study was conducted to identify the risk factors for development and recurrence of peptic ulcer disease in Korea. METHODS: From 2003 to 2008, upper gastrointestinal endoscopy and detailed personal questionnaires were performed for patients who visited Department of Gastroenterology at Seoul National University Bundang Hospital. In total, 475 PUD patients and 335 non-ulcer dyspepsia patients were included. The results of questionnaires and repeated upper gastrointestinal endoscopy at initial diagnosis time and follow-up periods were analyzed. RESULTS: Multivariable analysis showed that male, H. pylori infection, NSAIDs use and smoking were risk factors for the development of PUD. The use of proton pump inhibitors (PPIs) and H2 receptor antagonists has significantly reduced the risk of PUD in patients who had taken NSAIDs and/or aspirin. H. pylori infection was found as the only risk factor for the recurrence of PUD. CONCLUSIONS: For the old patients who are taking drugs, such as NSAIDs and aspirin, concomitant use of PPIs or H2 receptor antagonists should be considered to protect from the development of PUD. H. pylori eradication has been confirmed again to be essential for the treatment of PUD patients infected with H. pylori. PMID- 20962560 TI - [Usefulness of lactulose breath test for the prediction of small intestinal bacterial overgrowth in irritable bowel syndrome]. AB - BACKGROUND/AIMS: Lactulose breath test (LBT) has been used as a presumptive surrogate marker for small intestinal bacterial overgrowth (SIBO). However, recent reports suggest that abnormal LBT cannot discriminate patients with irritable bowel syndrome (IBS) from the control. Thus, the aim of this study was to evaluate the usefulness of LBT in IBS. METHODS: LBT from 76 IBS patients, 70 functional bowel disorders (FBD), and 40 controls were examined. LBT was considered positive if (1) baseline breath hydrogen (H2) >20 parts per million (ppm) or rise of breath H2 >20 ppm above the baseline in <90 mins, or (2) baseline breath methane (CH4) >10 ppm or rise of breath CH4 >10 ppm above the baseline in <90 mins. The subjects were categorized into predominant hydrogen producers (PHP), predominant methane producers (PMP), combined producer, and both negative group based on LBT. RESULTS: The rate of abnormal LBT in the IBS, FBD, and control group were 44.7%, 41.4%, and 40.0% respectively without significant differences. The rate of PHP or PMP was not significantly different among the IBS, FBD, and control group. When clinical characteristics were analyzed in IBS and FBD according to LBT types, IBS subtypes and symptoms were not significantly different. CONCLUSIONS: LBT was not useful to discriminate IBS/FBD patients from the control. The assessment of SIBO by LBT in IBS should be revalidated in the future. PMID- 20962559 TI - Rates of early surgery and associated risk factors in Crohn's disease. AB - BACKGROUND/AIMS: The individual course of Crohn's disease is diverse, and some patients may require bowel resection. The aims of this study were to determine the early surgery rate of Crohn's disease and to identify risk factors associated with early surgery in Korea. METHODS: Ninety six patients with Crohn's disease (68 men; median age at the time of diagnosis: 25 years), who had been followed up more than a year, were retrospectively analyzed. Early surgery was defined as a bowel operation for Crohn's disease or its complications occurring within 3 years from diagnosis. Early surgery rate and risk factors for early surgery were identified. RESULTS: Fifteen patients (15.6%) underwent early surgery. The cumulative surgery rate was 8.6% after 6 months, 11.9% after 12 months, 14.1% after 18 months, and 16.7% after 24 to 36 months. Multivariate analysis revealed penetrating or stricturing behavior to be an independent risk factor for early surgery (p<0.001, Exp (B)=2.97 CI 1.39-6.37). CONCLUSIONS: The cumulative early surgery rate in Korean patients seems to be lower than Western patients. Penetrating or stricturing behavior is significantly associated with early surgery, requiring early aggressive medical treatments. PMID- 20962561 TI - [A case of acute myocardial infarction occurred immediately after endoscopic submucosal dissection]. AB - Endoscopic methods such as endoscopic mucosal resection or endoscopic submucosal dissection (ESD) have been increasingly used for the treatment of gastric adenoma and early gastric cancer. Especially, ESD is very useful since it allows en bloc resection of large lesions. Bleeding and perforation are well known as common complications after ESD. However, there is no report of acute myocardial infarction associated with ESD. We report a case of acute myocardial infarction which was detected immediately after ESD. PMID- 20962562 TI - [A case of inferior vena cava thrombosis and acute pancreatitis in a patient with ulcerative colitis]. AB - A 21-year-old man admitted complaining of sudden severe epigastric pain for 1 day. He had been diagnosed as ulcerative colitis (UC) and taking mesalazine for two months. UC was in nearly complete remission at admission. He never drank an alcohol, and serum amylase was 377 IU/L. CT scan showed inferior vena cava (IVC) thrombosis in addition to mild acute pancreatitis. To evaluate the cause of acute pancreatitis and IVC thrombosis, magnetic resonance cholangiopancreatogram (MRCP), endoscopic ultrasonogram (EUS), lower extremity Doppler ultrasonogram (US) and blood test of hypercoagulability including factor V, cardiolipin Ab, protein C, protein S1, antithrombin III, and anti phospholipids antibody were performed. There was no abnormality except mild acute pancreatitis and IVC thrombosis in all the tests. He was recommended to stop taking mesalazine and start having anticoagulation therapy. After all symptoms disappeared and amylase returned normal, rechallenge test with mesalazine was done. Flare-up of abdominal pain occurred and the elevation of serum amylase was observed. Ulcerative colitis came to complete remission with short-term steroid monotherapy. Acute pancreatitis and IVC thrombosis were completely resolved after 3-month anticoagulation therapy with no more mesalazine. We postulated that IVC thrombosis occurred due to hypercoagulable status of UC and intra-abdominal inflammation caused by mesalazine-induced pancreatitis. PMID- 20962563 TI - [A case of spontaneous hemorrhagic cholecystitis without gallstone]. AB - Hemorrhagic acalculous cholecystitis is an extremely rare but potentially fatal disease if detection is delayed. Its risk factors include critical illness, diabetes, malignant disease, uremia, and bleeding diathesis. This is the first case report in which hemorrhagic acalculous cholecystitis not accompanied by any risk factor. We herein present a case of hemorrhagic acalculous cholecystitis in a previously healthy patient who suffered from acute abdomen. PMID- 20962565 TI - [Risk factors of peptic ulcer disease in Korea]. PMID- 20962564 TI - [A case of hepatic congestion due to right heart failure mimicking liver tumor]. AB - This report describes a patient with hepatic congestion due to right heart failure mimicking liver tumor. The patient had a history of breast cancer and left total mastectomy 30 years ago, tricuspid valve regurgitation and tricuspid valve replacement 4 years ago. Three years ago, abdominal contrast-enhanced computed tomography (CT) was performed to evaluate inguinal hernia, which revealed multiple small hepatic nodules. After 1 year, the number and size of liver nodules were increased in CT scan. The patient underwent gun biopsy and histopathology revealed sinusoid enlargement. The patient recently had jaundice, abdominal distension, and peripheral edema. Liver dynamic CT scan was done to evaluate the palpable liver. The number and size of liver nodules were more increased in CT than 2 years ago. In magnetic resonance imaging (MRI), numerous variable sized ill-defined nodules replacing entire liver with progressing centripetal enhancement, which were suggestive of malignancy such as angiosarcoma, were noted. MRI finding suspects malignancy or hemangiosarcoma. Finally, the patient received repeated gun biopsy, and histopathology revealed findings compatible with hepatic congestion. PMID- 20962567 TI - Genetic markers and danger signals in stevens-johnson syndrome and toxic epidermal necrolysis. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life threatening adverse reactions, which could be induced by a variety of drugs. It was proposed that human leukocyte antigen (HLA)-restricted presentation of antigens (drugs or their metabolites) to T lymphocytes initiates the immune reactions of SJS/TEN. However, the genetic susceptibility and the exact pathogenesis were not clear until the recent studies. We first identified that HLA-B*1502 is strongly associated with carbamazepine (CBZ)-induced SJS/TEN and HLA-B*5801 with allopurinol-SJS/TEN in Han Chinese. The same associations had been validated across different human populations. For the downstream danger signals, Fas-Fas ligand (FasL) and perforin/granzyme B had been advocated as cytotoxic mediators for keratinocyte death in SJS/TEN. However, expression levels of these cytotoxic proteins from the skin lesions were too low to explain the distinct and extensive epidermal necrosis. Our recent study identified that the granulysin, a cytotoxic protein released from cytotoxic T cells or natural killer (NK) cells, is a key mediator for disseminated keratinocyte death in SJS/TEN. This article aims to provide an overview of both of the genomic and immunologic perspectives of SJS/TEN. These studies give us a better understanding of the immune mechanisms, biomarkers for disease prevention and early diagnosis, as well as providing the therapeutic targets for the treatments of SJS/TEN. PMID- 20962568 TI - Recognition of immune reconstitution syndrome necessary for better management of patients with severe drug eruptions and those under immunosuppressive therapy. AB - The immune reconstitution syndrome (IRS) is an increasingly recognized disease concept and is observed with a broad-spectrum of immunosuppressive therapy related opportunistic infectious diseases and severe drug eruptions complicated by viral reactivations. Clinical illness consistent with IRS includes tuberculosis, herpes zoster, herpes simples, cytomegalovirus infections and sarcoidosis: thus, the manifestations of this syndrome and diverse and depend on the tissue burden of the preexisting infectious agents during the immunosuppressive state, the nature of the immune system being restored, and underlying diseases of the hosts. Although IRS has originally been reported to occur in the setting of HIV infection, it has become clear that the development of IRS can also be in HIV-negative hosts receiving immunosuppressive agents, such as prednisolone and tumor necrosis factor alpha inhibitors, upon their reduction and withdrawal. Drug-induced hypersensitivity syndrome, a life-threatening multiorgan system reaction, is another manifestation of the newly observed IRS. Clinical recognition of the IRS is especially important in improving the outcome for diseases with an otherwise life-threatening progenosis. Clinicians should be aware of the implications of IRS and recognize that relieving the symptoms and signs of immune recovery by anti-inflammatory therapies needs to be balanced with anti-microbial therapies aiming at reducing the amplitude and duration of tissue burden of preexisting microbes. PMID- 20962566 TI - Systemic LPS administration induces brain inflammation but not dopaminergic neuronal death in the substantia nigra. AB - It has been suggested that brain inflammation is important in aggravation of brain damage and/or that inflammation causes neurodegenerative diseases including Parkinson's disease (PD). Recently, systemic inflammation has also emerged as a risk factor for PD. In the present study, we evaluated how systemic inflammation induced by intravenous (iv) lipopolysaccharides (LPS) injection affected brain inflammation and neuronal damage in the rat. Interestingly, almost all brain inflammatory responses, including morphological activation of microglia, neutrophil infiltration, and mRNA/protein expression of inflammatory mediators, appeared within 4-8 h, and subsided within 1-3 days, in the substantia nigra (SN), where dopaminergic neurons are located. More importantly, however, dopaminergic neuronal loss was not detectable for up to 8 d after iv LPS injection. Together, these results indicate that acute induction of systemic inflammation causes brain inflammation, but this is not sufficiently toxic to induce neuronal injury. PMID- 20962569 TI - Proteome analysis of bronchoalveolar lavage fluid in lung fibrosis associated with systemic sclerosis. AB - BACKGROUND: Interstitial lung disease (ILD) is the major cause of mortality in collagen vascular diseases. However, its pathogenesis still needs to be elucidated. METHODS: To evaluate the alteration of certain proteins in bronchoalveolar lavage fluid (BALF) and clarify the causative role in the processes of ILD in systemic sclerosis (SSc), we compared a BALF protein profile between 5 patients with systemic sclerosis with pulmonary fibrosis (SSc-fib+) and 4 patients with systemic sclerosis without pulmonary fibrosis (SSc-fib-) using two-dimensional gel electrophoresis (2-DE), and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). RESULTS: We analyzed spots over the range of 10.1kDa to 207.4kDa. SSc-fib+ patients showed increased 3 proteins compared to SSc-fib- including alpha2-macroglobulin, alpha1 antitrypsin, and pulmonary surfactant protein A and decreased 2 proteins including alpha2 heat shock protein (HSP) and glutathione S-transferase (GST) compared to SSc-fib- patients. CONCLUSIONS: In conclusion, we identified several interesting proteins that might have roles in ILD of SSc patients. Further studies are warranted to clarify the role of these proteins in the processes of pulmonary fibrosis in SSc. PMID- 20962570 TI - A case of juvenile dermatomyositis manifesting inflammatory epidermal nevus-like skin lesions: unrecognized cutaneous manifestation of blaschkitis? AB - BACKGROUND: Juvenile dermatomyositis is potentially life threatening rare autoimmune illness that mainly affects muscle and skin. Cutaneous features are useful in establishing the diagnosis of this disease. CASE SUMMARY: We report an 8-year-old male juvenile dermatomyositis who presented epidermal nevus like lesions on the back of the right thigh. Characteristic cutaneous changes such as Gottron's papules of the hand, heliotrope rash of the eyelids, and poikiloderma like lesions on the back were observed. Diagnosis of juvenile dermatomyositis was made by positive muscle biopsy and magnetic resonance imaging findings and typical cutaneous manifestations. However, epidermal nevus-like skin lesions, an acquired inflammatory dermatosis that follows Blaschko lines, seen in this case have been rarely reported in the literatures. DISCUSSION: We would like to report this case and discuss about the significance and pathogenesis of this rare cutaneous manifestation like Blaschkitis in juvenile dermatomyositis. PMID- 20962571 TI - A case of acute eosinophilic pneumonia following short-term passive smoking: an evidence of very high level of urinary cotinine. AB - Acute eosinophilic pneumonia (AEP) is characterized by febrile illness, diffuse pulmonary infiltrates with eosinophilia. The pathogenesis is not well understood. We report a case of 22-year-old men who never smoke presented with AEP 2 days after acute passive smoke exposure. He developed acute respiratory failure despite having no history of the disease. Computed tomography of the lung revealed diffuse bilateral pulmonary infiltrates. Lung biopsy specimens revealed marked eosinophil infiltration in the alveolar septa without signs of vasculitis. Two days prior to the disease, he was exposed to cigarette smoke for 2 hours in a closed area. In the absence of other causes, passive smoking may cause lung inflammatory responses. The level of urinary cotinine, which is a biomarker of smoke exposure, was considerably higher (0.198 MUg/ml [201 ng/mg Creatinine]) than that in nonsmokers, but never detected following period. This case suggests that short-term passive smoking may cause AEP. PMID- 20962572 TI - Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. Drug treatments for HCC have been largely unsuccessful. Histone deacetylase inhibitors can reactivate tumor suppressor genes in cancer cells and serve as potential anti-cancer drugs. Two potent HDAC inhibitors OSU-HDAC42 and SAHA induced autophagy in HCC cells as revealed by transmission electron microscopy, immunofluorescence and LC3-II accumulation. We found that SAHA and OSU-HDAC42 induced autophagy through downregulation of Akt/mTOR signaling and induction of ER stress response. Inhibition of autophagy by 3-MA or Atg5 knockout reduced SAHA-induced cytotoxicity, indicating that SAHA-induced autophagy led to cell death. Our results show that the combination of autophagy inducers with SAHA might be attractive for the treatment of HCC and pharmacological targeting of autophagy provides promise for the management of cancer therapy. PMID- 20962573 TI - Atg9 reservoirs, a new organelle of the yeast endomembrane system? AB - Despite all the advances in understanding the roles and the regulation of autophagy in health and disease realized during the past decade, the key question about the origin of the initial autophagosomal membranes remains largely unknown. Among the 16 autophagy-related (Atg) proteins composing the conserved machinery required for autophagy, Atg9 is the only integral membrane component and it is one of the first Atg proteins to be recruited to the phagophore assembly site (PAS) emphasizing its relevance in the early stages of autophagosome biogenesis. Because it is: intrinsically associated with lipid bilayers, Atg9 has all the prerequisites to be a major factor in regulating the supply of at least part of the membranes necessary for the formation and expansion of nascent autophagosomes. PMID- 20962574 TI - Fibronectin-mediated upregulation of alpha5beta1 integrin and cell adhesion during differentiation of mouse embryonic stem cells. AB - Embryonic stem (ES) cells have a broad potential application in regenerative medicine and can be differentiated into cells of all three germ layers. Adhesion of ES cells to extracellular matrix (ECM) proteins is essential for the differentiation pathway; Cell-ECM adhesion is mediated by integrins that have the ability to activate many intracellular signaling pathways. Therefore, we hypothesize that the expression and function of integrin receptors is a critical step in ES differentiation. Using functional cell adhesion assays, our study demonstrates that alpha5beta1 is a major functional integrin receptor expressed on the cell surface of undifferentiated mouse ES-D3 cells, which showed significantly higher binding to fibronectin as compared to collagens. This adhesion was specific mediated by integrin alpha5beta1 as evident from the inhibition with a disintegrin selective for this particular integrin. Differentiation of ES-D3 cells on fibronectin or on a collagen type1/fibronectin matrix, caused further selective up-regulation of the alpha5beta1 integrin. Differentiation of the cells, as evaluated by immunofluorescence, FACS analysis and quantitative RT-PCR, was accompanied by the upregulation of mesenchymal (Flk1, isolectin B4, alpha-SMA, vimentin) and endodermal markers (FoxA2, SOX 17, cytokeratin) in parallel to increased expression of alpha5beta1 integrin. Taken together, the data indicate that fibronectin-mediated, upregulation of alpha5beta1 integrin and adhesion of ES-D3 cells to specific ECM molecules are linked to early stages of mouse embryonic stem cells commitment to meso endodermal differentiation. PMID- 20962575 TI - Notch-1 signaling facilitates survivin expression in human non-small cell lung cancer cells. AB - The oncogenic potential of Notch activation is observed in many instances including lung tumorigenesis, but the associated molecular regulatory mechanism has not been thoroughly defined. It has been demonstrated that hypoxia can act as one of the major stimuli in the progression of many types of tumorigenesis. This study was designed to examine the activation of Notch-1 signaling by hypoxia and its contribution to survivin expression in human lung carcinomas. Western-blot and PCR analysis showed that Notch-1 signaling is activated by hypoxia in the human non-small cell lung cancer (NSCLC) cell line, A549, through the upregulation of Notch-1, along with its intracellular domain (N1ICD). The activity of Hes-1, a crucial target molecule of N1ICD, was also increased under hypoxia. Interestingly, blockade of the Notch-1 pathway by a gamma-secretase inhibitor or small interfering RNA (siRNA) inhibited survivin expression. Conversely, activation of Notch-1 signaling by N1ICD or stimulation with the Jagged1 ligand enhanced survivin levels in A549 cells. Notably, HIF-1alpha cooperated with Notch-1 signaling to increase survivin expression through its direct association with N1ICD, consequently accelerating survivin transcription. Overall, our findings suggest that Notch-1 signaling is involved in the upregulation of survivin expression in lung cancer cells, which is synergized by HIF-1alpha. PMID- 20962577 TI - Growth hormone-releasing hormone: extrapituitary effects in physiology and pathology. AB - Growth Hormone-Releasing Hormone (GHRH) is secreted by the hypothalamus and regulates the release of growth hormone from the anterior pituitary gland. In addition to its endocrine role, this peptide has been shown to act as a growth factor in diverse malignancies. Recent studies indicate that GHRH is also a regulator of several important physiological processes. These processes which include the regulation of the metabolism of the reactive oxygen and nitrogen species are similarly enhanced by GHRH agonists. In contrast, GHRH antagonists can counteract the growth factor effects of GHRH. GHRH and its agonists have been shown to contribute to the recovery of heart tissue after myocardial infarction and can promote the survival and proliferation of pancreatic islets after transplantation into diabetic animals. PMID- 20962579 TI - Combination of promoter hypomethylation and PDX1 overexpression leads to TBX15 decrease in vascular IUGR placentas. AB - Preeclampsia (PE) and vascular intra-uterine growth restriction (vIUGR) are two pathological obstetrical conditions originating from placental dysfunction. Recently, methylation changes at the placental level have been shown to be indicative of these diseases. The alteration of such epigenetic marks is therefore a novel pathway that might be critical for these pathologies. Here, we identified a region located in the distal promoter of the T-box-containing transcription factor TBX15 that is differentially methylated in pathological placentas. The level of methylation correlated significantly with the weight and stature of the newborn. The promoter was found to be hypomethylated in vIUGR coinciding with the down-regulation of its expression. PDX1, a transcription factor important for the regulation of insulin metabolism regulation was able to repress the TBX15 promoter in a methylation-dependent manner, which might, at least partially, explain the specific mRNA decrease of TBX15 observed in vIUGR placentas. Overall, the data presented herein suggest that TBX15 might be involved in the pathophysiology of placental diseases. PMID- 20962580 TI - Courtship, aggression and avoidance: pheromones, receptors and neurons for social behaviors in Drosophila. AB - Chemical communication between individual Drosophila is extremely important for social behaviors required for survival and reproduction, such as con-specific recognition, courtship, aggression and avoidance of odor from "stressed" flies. Characterization of the receptors and neural circuits that detect pheromone cues and an understanding of how these circuits are modulated by the social interactions are fundamental questions about the neurobiology of social behaviors. Recent years have seen important advances in the identification of chemoreceptors and sensory neurons that are involved in sensing pheromones. Here we present a brief review of the current understanding of the peripheral chemosensory systems that are involved in social behaviors. PMID- 20962578 TI - A LIF/Nanog axis is revealed in T lymphocytes that lack MARCH-7, a RINGv E3 ligase that regulates the LIF-receptor. AB - Nanog is a stem cell transcription factor required for self-renewal and for maintaining pluripotency, and Nanog itself is regulated at least in part by leukaemia inhibitory factor (LIF)--a pluripotent cytokine of the IL6 family. MARCH-7 is an E-3 ligase linked to regulation of the LIF-receptor in T lymphocytes and T cells from mice that lack expression of MARCH-7 are hyper responsive to activation signals and show a five-fold increase in LIF activity. Here we ask, does MARCH-7 influence the expression profile of Nanog during the synchronized entry of T cells into the cell cycle? We discovered that lack of MARCH-7 was permissive for Nanog expression at both transcript and protein levels during G1/S: moreover, addition of exogenous LIF to the MARCH-7 null cells caused a further 13-fold induction of Nanog; other measured transcripts including TGFbeta, p53 and STAT3 were relatively unchanged. Since lack of MARCH-7 altered responsiveness to activation signals we sought evidence for pre-existing regulatory miR's that might correlate with MARCH-7 gene dose using head-to-head comparisons between MARCH-7 null, heterozygous and wt spleen cells. 34 miRs were found including miR-346 that is known to target LIF transcripts and miR-346 is one of 16 miRs differentially expressed between hESCs and induced hiPSCs. Of the 34 miRs, 12 were known to be temporally regulated in embryonic nerve cells. In summary, in the absence of MARCH-7 a new signaling pathway is unmasked that involves Nanog expression in the T cell lineage. This is the first demonstration that T cells retain responsiveness to a LIF/Nanog axis and that this axis is linked to MARCH-7. PMID- 20962581 TI - Detailed specificity analysis of antibodies binding to modified histone tails with peptide arrays. AB - Chromatin structure is greatly influenced by histone tail post-translational modifications (PTM), which also play a central role in epigenetic processes. Antibodies against modified histone tails are central research reagents in chromatin biology and molecular epigenetics. We applied Celluspots peptide arrays for the specificity analysis of 36 commercial antibodies from different suppliers which are directed towards modified histone tails. The arrays contained 384 peptides from 8 different regions of the N-terminal tails of histones, viz. H3 1 19, 7-26, 16-35 and 26-45, H4 1-19 and 11-30, H2A 1-19 and H2B 1-19, featuring 59 post-translational modifications in many different combinations. Using various controls we document the reliability of the method. Our analysis revealed previously undocumented details in the specificity profile. Most of the antibodies bound well to the PTM they have been raised for, but some failed. In addition some antibodies showed high cross-reactivity and most antibodies were inhibited by specific additional PTMs close to the primary one. Furthermore, specificity profiles for antibodies directed towards the same modification sometimes were very different. The specificity of antibodies used in epigenetic research is an important issue. We provide a catalog of antibody specificity profiles for 36 widely used commercial histone tail PTM antibodies. Better knowledge about the specificity profiles of antibodies will enable researchers to implement necessary control experiments in biological studies and allow more reliable interpretation of biological experiments using these antibodies. PMID- 20962582 TI - Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: what have we learned? AB - The pharmacokinetics (PK) of therapeutic antibodies is determined by target and non-target mediated mechanisms. These antibody-specific factors need to be considered during prediction of human PK based upon preclinical information. Principles of allometric scaling established for small molecules using data from multiple animal species cannot be directly applied to antibodies. Here, different methods for projecting human clearance (CL) from animal PK data for 13 therapeutic monoclonal antibodies (mAbs) exhibiting linear PK over the tested dose ranges were examined: simple allometric scaling (CL versus body weight), allometric scaling with correction factors, allometric scaling based on rule of exponent and scaling from only cynomolgus monkey PK data. A better correlation was obtained between the observed human CL and the estimated human CL based on cynomolgus monkey PK data and an allometric scaling exponent of 0.85 for CL than other scaling approaches. Human concentration-time profiles were also reasonably predicted from the cynomolgus monkey data using species-invariant time method with a fixed exponent of 0.85 for CL and 1.0 for volume of distribution. In conclusion, we expanded our previous work and others and further confirmed that PK from cynomolgus monkey alone can be successfully scaled to project human PK profiles within linear range using simplify allometry and Dedrick plots with fixed exponent. PMID- 20962586 TI - BAG3 expression is sustained by FGF2 in neural progenitor cells and impacts cell proliferation. PMID- 20962587 TI - Reduced spermatogonial proliferation and decreased fertility in mice overexpressing cyclin E in spermatogonia. AB - Cyclin E is a key component of the cell cycle regulatory machinery, contributing to the activation of Cdk2 and the control of cell cycle progression at several stages. Cyclin E expression is tightly regulated, by periodic transcription and ubiquitin-mediated degradation. Overexpression of cyclin E has been associated with tumor development and poor prognosis in several tumor types, including germ cell tumors and both cyclin E and its partner Cdk2 are required for normal spermatogenesis. Here we have generated and characterized transgenic mice overexpressing a cyclin E mutant protein, resistant to ubiquitin-mediated proteolysis, in testicular germ cells, under the control of the human EF-1alpha promoter. The transgenic mice develop normally and live a normal life span, with no signs of testicular tumor development. The transgenic mice display however reduced fertility and testicular atrophy, due to reduced spermatogonial proliferation as a consequence of deregulated cyclin E levels. Overall our results show that deregulation of cyclin E expression contribute to infertility, due to inability of the spermatogonial cells to start the mitotic cycles prior to entering meiosis. PMID- 20962583 TI - Autophagy in protists. AB - Autophagy is the degradative process by which eukaryotic cells digest their own components using acid hydrolases within the lysosome. Originally thought to function almost exclusively in providing starving cells with nutrients taken from their own cellular constituents, autophagy is in fact involved in numerous cellular events including differentiation, turnover of macromolecules and organelles, and defense against parasitic invaders. During the last 10-20 years, molecular components of the autophagic machinery have been discovered, revealing a complex interactome of proteins and lipids, which, in a concerted way, induce membrane formation to engulf cellular material and target it for lysosomal degradation. Here, our emphasis is autophagy in protists. We discuss experimental and genomic data indicating that the canonical autophagy machinery characterized in animals and fungi appeared prior to the radiation of major eukaryotic lineages. Moreover, we describe how comparative bioinformatics revealed that this canonical machinery has been subject to moderation, outright loss or elaboration on multiple occasions in protist lineages, most probably as a consequence of diverse lifestyle adaptations. We also review experimental studies illustrating how several pathogenic protists either utilize autophagy mechanisms or manipulate host-cell autophagy in order to establish or maintain infection within a host. The essentiality of autophagy for the pathogenicity of many parasites, and the unique features of some of the autophagy-related proteins involved, suggest possible new targets for drug discovery. Further studies of the molecular details of autophagy in protists will undoubtedly enhance our understanding of the diversity and complexity of this cellular phenomenon and the opportunities it offers as a drug target. PMID- 20962588 TI - Cdc5 blocks in vivo Rad53 activity, but not in situ activity (ISA). AB - DNA damage promotes the activation of a signal transduction cascade referred to as the DNA damage checkpoint. This pathway initiates with the Mec1/ATR kinase, which then phosphorylates the Rad53/Chk2 kinase. Mec1 phosphorylation of Rad53 is then thought to promote Rad53 autophosphorylation, ultimately leading to a fully active Rad53 molecule that can go on to phosphorylate substrates important for DNA damage resistance. In the absence of DNA repair, this checkpoint is eventually downregulated in a Cdc5-dependent process referred to as checkpoint adaptation. Recently, we showed that overexpression of Cdc5 leads to checkpoint inactivation and loss of the strong electrophoretic shift associated with Rad53 inactivation. Interestingly, this same overexpression did not strongly inhibit Rad53 autophosphorylation activity as measured by the in situ assay (ISA). The ISA involves incubating the re-natured Rad53 protein with gamma 32P labeled ATP after electrophoresis and western blotting. Using a newly identified Rad53 target, we show that despite strong ISA activity, Rad53 does not maintain phosphorylation of this substrate. We hypothesize that, during adaptation, Rad53 may be in a unique state in which it maintains some Mec1 phosphorylation, but does not have the auto-phosphorylations required for full activity towards exogenous substrates. PMID- 20962584 TI - Mechanisms driving neural crest induction and migration in the zebrafish and Xenopus laevis. AB - The neural crest is an evolutionary adaptation, with roots in the formation of mesoderm. Modification of neural crest behavior has been is critical for the evolutionary diversification of the vertebrates and defects in neural crest underlie a range of human birth defects. There has been a tremendous increase in our knowledge of the molecular, cellular, and inductive interactions that converge on defining the neural crest and determining its behavior. While there is a temptation to look for simple models to explain neural crest behavior, the reality is that the system is complex in its circuitry. In this review, our goal is to identify the broad features of neural crest origins (developmentally) and migration (cellularly) using data from the zebrafish (teleost) and Xenopus laevis (tetrapod amphibian) in order to illuminate where general mechanisms appear to be in play, and equally importantly, where disparities in experimental results suggest areas of profitable study. PMID- 20962585 TI - Regional differences in neural crest morphogenesis. AB - Neural crest cells are pluripotent cells that emerge from the neural epithelium, migrate extensively, and differentiate into numerous derivatives, including neurons, glial cells, pigment cells and connective tissue. Major questions concerning their morphogenesis include: 1) what establishes the pathways of migration and 2) what controls the final destination and differentiation of various neural crest subpopulations. These questions will be addressed in this review. Neural crest cells from the trunk level have been explored most extensively. Studies show that melanoblasts are specified shortly after they depart from the neural tube, and this specification directs their migration into the dorsolateral pathway. We also consider other reports that present strong evidence for ventrally migrating neural crest cells being similarly fate restricted. Cranial neural crest cells have been less analyzed in this regard but the preponderance of evidence indicates that either the cranial neural crest cells are not fate-restricted, or are extremely plastic in their developmental capability and that specification does not control pathfinding. Thus, the guidance mechanisms that control cranial neural crest migration and their behavior vary significantly from the trunk. The vagal neural crest arises at the axial level between the cranial and trunk neural crest and represents a transitional cell population between the head and trunk neural crest. We summarize new data to support this claim. In particular, we show that: 1) the vagal-level neural crest cells exhibit modest developmental bias; 2) there are differences in the migratory behavior between the anterior and the posterior vagal neural crest cells reminiscent of the cranial and the trunk neural crest, respectively; 3) the vagal neural crest cells take the dorsolateral pathway to the pharyngeal arches and the heart, but the ventral pathway to the peripheral nervous system and the gut. However, these pathways are not rigidly specified because of prior fate restriction. Understanding the molecular, cellular and behavioral differences between these three populations of neural crest cells will be of enormous assistance when trying to understand the evolution of the neck. PMID- 20962589 TI - p53-dependent repression of polo-like kinase-1 (PLK1). AB - PLK1 is a critical mediator of G2/M cell cycle transition that is inactivated and depleted as part of the DNA damage-induced G2/M checkpoint. Here we show that downregulation of PLK1 expression occurs through a transcriptional repression mechanism and that p53 is both necessary and sufficient to mediate this effect. Repression of PLK1 by p53 occurs independently of p21 and of arrest at G1/S where PLK1 levels are normally repressed in a cell cycle-dependent manner through a CDE/CHR element. Chromatin immunoprecipitation analysis indicates that p53 is present on the PLK1 promoter at two distinct sites termed p53RE1 and p53RE2. Recruitment of p53 to p53RE2, but not to p53RE1, is stimulated in response to DNA damage and/or p53 activation and is coincident with repression-associated changes in the chromatin. Downregulation of PLK1 expression by p53 is relieved by the histone deacetylase inhibitor, trichostatin A, and involves recruitment of histone deacetylase to the vicinity of p53RE2, further supporting a transcriptional repression mechanism. Additionally, wild type, but not mutant, p53 represses expression of the PLK1 promoter when fused upstream of a reporter gene. Silencing of PLK1 expression by RNAi interferes with cell cycle progression consistent with a role in the p53-mediated checkpoint. These data establish PLK1 as a direct transcriptional target of p53, independently of p21, that is required for efficient G2/M arrest. PMID- 20962590 TI - Role of a novel coiled-coil domain-containing protein CCDC69 in regulating central spindle assembly. AB - The formation of the central spindle (or the spindle midzone) is essential for cytokinesis in animal cells. In this study, we report that coiled-coil domain containing protein 69 (CCDC69) is implicated in controlling the assembly of central spindles and the recruitment of midzone components. Exogenous expression of CCDC69 in HeLa cells interfered with microtubule polymerization and disrupted the formation of bipolar mitotic spindles. Endogenous CCDC69 proteins were localized to the central spindle during anaphase. RNA interference (RNAi) mediated knockdown of CCDC69 led to the formation of aberrant central spindles and disrupted the localization of midzone components such as aurora B kinase, protein regulator of cytokinesis 1 (PRC1), MgcRacGAP/HsCYK-4, and polo-like kinase 1 (Plk1) at the central spindle. Aurora B kinase was found to bind to CCDC69 and this binding depended on the coiled-coil domains at the C-terminus of CCDC69. Further, disruption of aurora B function in HeLa cells by treatment with a small chemical inhibitor led to the mislocalization of CCDC69 at the central spindle. Our results indicate that CCDC69 acts as a scaffold to regulate the recruitment of midzone components and the assembly of central spindles. PMID- 20962591 TI - Epigenetic quantification of tumor-infiltrating T-lymphocytes. AB - The immune system plays a pivotal role in tumor establishment. However, the role of T-lymphocytes within the tumor microenvironment as major cellular component of the adaptive effector immune response and their counterpart, regulatory T-cells (Treg), responsible for suppressive immune modulation, is not completely understood. This is partly due to the lack of reliable technical solutions for specific cell quantification in solid tissues. Previous reports indicated that epigenetic marks of immune cells, such as the Treg specifically demethylated region (TSDR) within the FOXP3 gene, may be exploited as robust analytical tool for Treg-quantification. Here, we expand the concept of epigenetic immunophenotyping to overall T-lymphocytes (oTL). This tool allows cell quantification with at least equivalent precision to FACS and is adoptable for analysis of blood and solid tissues. Based on this method, we analyse the frequency of Treg, oTL and their ratio in independent cohorts of healthy and tumorous ovarian, colorectal and bronchial tissues with 616 partly donor-matched samples. We find a shift of the median ratio of Treg-to-oTL from 3-8% in healthy tissue to 18-25% in all tumor entities. Epigenetically determined oTL frequencies correlate with the outcome of colorectal and ovarian cancers. Together, our data show that the composition of immune cells in tumor microenvironments can be quantitatively assessed by epigenetic measurements. This composition is disturbed in solid tumors, indicating a fundamental mechanism of tumor immune evasion. Epigenetic quantification of T-lymphocytes serves as independent clinical parameter for outcome prognosis. PMID- 20962592 TI - Could STAT3 provide a link between respiration and cell cycle progression? AB - Maintaining the intracellular environment is important for the survival and proliferation of eukaryotic cells. How a cell regulates its redox potential during fluctuations in the generation of intracellular reactive oxygen species and exposure to extracellular oxidants is unclear. The recent findings that Signal Transducer and Activator of Transcription 3 (STAT3) regulates mitochondrial respiration and can be oxidised directly by peroxide to form multimers may have revealed features of a homeostatic mechanism coupling cell cycle progression to the intracellular redox potential. PMID- 20962593 TI - Conservation and divergence of DNA methylation in eukaryotes: new insights from single base-resolution DNA methylomes. AB - DNA methylation is one of the most important heritable epigenetic modifications of the genome and is involved in the regulation of many cellular processes. Aberrant DNA methylation has been frequently reported to influence gene expression and subsequently cause various human diseases, including cancer. Recent rapid advances in next-generation sequencing technologies have enabled investigators to profile genome methylation patterns at single-base resolution. Remarkably, more than 20 eukaryotic methylomes have been generated thus far, with a majority published since November 2009. Analysis of this vast amount of data has dramatically enriched our knowledge of biological function, conservation and divergence of DNA methylation in eukaryotes. Even so, many specific functions of DNA methylation and their underlying regulatory systems still remain unknown to us. Here, we briefly introduce current approaches for DNA methylation profiling and then systematically review the features of whole genome DNA methylation patterns in eight animals, six plants and five fungi. Our systematic comparison provides new insights into the conservation and divergence of DNA methylation in eukaryotes and their regulation of gene expression. This work aims to summarize the current state of available methylome data and features informatively. PMID- 20962596 TI - Decrease in natural killer cell associated gene expression as a major characteristic of the immune status in the bloodstream of colorectal cancer patients. AB - Early detection and stratification of patients with colorectal cancer (CRC) are major challenges, particularly in the context of the development of new therapies. Several screening strategies are already in place in various countries, but compliance remains a major issue, mainly due to logistics or discomfort for the patients. In this study, we hypothesized that transcriptional signatures associated with leukocytes in peripheral blood can be informative to the identification of CRC patients. Gene expression was studied using RNA extracted from whole blood samples collected in PAXgene tubes and DNA microarrays. Analyzing 119 CRC patients and 101 colonoscopy-negative control (CNC) samples, we observed 327 differentially expressed genes (DEG), mostly associated with immune cell activation and trafficking. Natural Killer (NK) cell signaling and cytotoxicity associated genes appeared to undergo major changes in CRC peripheral blood samples. These changes were more pronounced in the advanced stages of the disease. A summarizing score of the expression of 10 genes related to NK cells interestingly revealed a marked heterogeneity within the CRC Stage IV group, suggesting possible further stratification of the patients. This study shows the potential of transcriptomics in peripheral blood to discover biomarkers and provides new insight on the immune response in colorectal cancer. In addition to preparing a possible alternative to current screening modalities, these results also show that the expression analysis of genes like those related to NK cells should allow the stratification of patients with colorectal cancer, opening the door to personalized medicine. PMID- 20962594 TI - HP1alpha is not necessary for the structural maintenance of centromeric heterochromatin. AB - Heterochromatin protein 1 (HP1) was discovered as a protein essential for maintaining the silent transcriptional status of genes located within or close to centromeric regions of Drosophila chromosomes. Mammals express three variants of HP1; of these, HP1alpha is a direct homolog of Drosophila HP1. The prevailing view states that HP1 is a structural component of heterochromatin and is essential for compact DNA packaging. HP1 contains a chromodomain that binds to di and- tri-methylated lysine 9 of histone H3. Additionally, it contains a chromoshadow domain that allows HP1 to dimerize and interact with other proteins. HP1 is thought to form "bridges" between neighboring rows of nucleosomes in heterochromatin. In mammalian cells, a significant portion of HP1alpha is located in the centromeric regions of chromosomes. In this study, we show that the majority of HP1alpha is removed from centromeres upon heat shock. This occurs without a loss of H3K9 trimethylation and does not correlate with a decompaction of centromeres. Furthermore, HP1alpha is not degraded and remains bound to chromatin. Therefore, it is likely that HP1alpha is simply redistributed to euchromatic regions. We propose that this redistribution is essential for reversal of the transcriptional status of euchromatic and heterochromatic compartments. PMID- 20962597 TI - Upper back pain: an unusual presentation of non-Hodgkin's lymphoma. PMID- 20962595 TI - Novel insights into the molecular origins and treatment of lung cancer. AB - Lung cancer is the most common and most deadly cancer worldwide. Because of the aggressive and metastatic nature of many forms of the disease, it is frequently diagnosed late and responds poorly to the therapies currently available. Although our understanding of the molecular origins and evolution of lung cancer is still incomplete, recent research has yielded several developments that may offer opportunities for new, targeted and effective therapy. In this review we first discuss the prevalence and origins of lung cancer, with emphasis on non-small cell lung cancer and adenocarcinoma, together with current treatments and their efficacy. We then look at a selection of recent papers which between them shed new light on possible therapeutic opportunities, including a novel synthetic interaction with the Kras gene and genomic or proteomic profiling studies that may pave the way for personalized treatment for lung cancer based on specific "signatures" of protein and gene expression. Lung cancer remains the foremost cause of cancer deaths worldwide. Despite advances in both detection and treatment, diagnosis is often late and the prognosis for patients poor. Our understanding of the molecular basis and progression of lung cancer remains incomplete, hampering the design and development of more effective diagnostic tools and therapies for this devastating disease. However, the last twelve months have witnessed the publication of several studies that represent significant advances in our knowledge of lung cancer, and may represent important steps on the road to effective new therapies. In this review we aim to summarize these recent developments, and give our perspectives on the therapeutic possibilities they may offer in the future. PMID- 20962598 TI - Effect of transcranial direct current stimulation on motor recovery in patients with subacute stroke. AB - OBJECTIVE: To test the hypothesis that 10 sessions of transcranial direct current stimulation combined with occupational therapy elicit more improvement in motor function of the paretic upper limb than sham stimulation in patients with subacute stroke. DESIGN: Eighteen patients with subacute stroke with hand motor impairment were randomly assigned to one of the three 10-day sessions of (a) anodal transcranial direct current stimulation over the affected motor cortex, (b) cathodal transcranial direct current stimulation over the unaffected motor cortex, or (c) sham stimulation. Blinded evaluators assessed upper limb motor impairment and global functional state with the Fugl-Meyer Assessment score and the Modified Barthel Index at baseline, 1 day after stimulation, and 6 mos after stimulation. RESULTS: Baseline scores for Fugl-Meyer Assessment and Modified Barthel Index were comparable in all groups (P > 0.05). At 6-mo follow-up, cathodal transcranial direct current stimulation led to a greater improvement in Fugl-Meyer Assessment than the sham procedure (P < 0.05). There was a significant inverse correlation between baseline Fugl-Meyer Assessment and Fugl-Meyer Assessment increase at 6 mos (r = -0.846; P < 0.01). CONCLUSIONS: Our results suggest a potentially beneficial effect of noninvasive cortical stimulation during rehabilitative motor training of patients who have suffered from subacute strokes. PMID- 20962599 TI - Physical and occupational therapy in inpatient stroke rehabilitation: the contribution of therapy extenders. AB - OBJECTIVE: To understand the use of therapy extenders in stroke rehabilitation. DESIGN: Descriptive analysis of a prospective observational cohort study. RESULTS: Two hundred ninety-eight patients with moderate stroke and 284 with severe stroke from 5 inpatient rehabilitation facilities with complete physical and occupational therapy data are included in the study. Overall, occupational therapists and assistants contributed ~70% and 21% of all occupational therapy hours, respectively. For physical therapy, these percentages in moderate group (60% vs. 31%) differ from those in severe group (65% vs. 23%). Some variations in the use of therapy extenders are noted in both disciplines across sites. Physical and occupational therapists spend more time in delivering advanced activities that include ongoing integrated evaluation and treatment planning or modification. Their assistants spend more time in delivering lower-level activities, such as bed mobility, transfers, dressing, or nonfunctional activities. Also, therapists are more likely to assign responsibility to assistants to treat moderate motor impairment among patients with stroke. CONCLUSIONS: Characterizing therapy practice in stroke rehabilitation is not straightforward. It is multifactorial and takes into account the (1) type of therapy, (2) therapy activity, (3) therapy provider including extender personnel, (4) specific training in stroke, and (5) years of experience. Future research to examine the association between use of therapy extenders and outcomes is recommended. PMID- 20962600 TI - Prevalence of 25-hydroxyvitamin D deficiency in the outpatient rehabilitation population. AB - OBJECTIVE: To assess the prevalence of 25-hydroxyvitamin D insufficiency and deficiency in the outpatient rehabilitation setting and to identify patient characteristics associated with low serum 25-hydroxyvitamin D levels. DESIGN: 25 Hydroxyvitamin D levels from 136 rehabilitation outpatients at an academic rehabilitation facility obtained from April 2007 to December 2008 for patient care purposes were captured via retrospective electronic medical record review. RESULTS: Considering only those subjects not receiving 25-hydroxyvitamin D supplementation at time of evaluation, 33.0% were 25-hydroxyvitamin D Sufficient while 53.2% were Insufficient and 13.8% Deficient. Those outpatient subjects receiving supplementation at time of evaluation had significantly higher 25 hydroxyvitamin D levels compared with those not receiving supplementation (34.1 +/- 14.2 ng/ml vs. 25.9 +/- 15.2 ng/ml; P = 0.005). Blacks had significantly lower 25-hydroxyvitamin D levels compared with whites (18.0 +/- 10.6 ng/ml vs. 31.3 +/- 14.3 ng/ml; P < 0.001). Subjects not on vitamin D supplementation assigned to diagnostic groups, Spinal Cord Injury, Brain Injury, and Hereditary Musculoskeletal, all had average 25-hydroxyvitamin D levels well below the lower limit of Sufficiency. CONCLUSIONS: Sixty-seven percent of rehabilitation outpatients are 25-hydroxyvitamin D Insufficient or Deficient. Supplementation significantly affects 25-hydroxyvitamin D levels in the outpatient rehabilitation population. Non-white race and history of Spinal Cord Injury, Brain Injury, or Hereditary Musculoskeletal diagnosis seem to be associated with lower 25 hydroxyvitamin D levels. PMID- 20962601 TI - Patterns of rehabilitation after hip arthroplasty and the association with outcomes: an episode of care view. AB - OBJECTIVES: To examine the patterns of rehabilitation after elective and nonelective hip arthroplasty and its association with outcomes over an episode of postacute care. DESIGN: Data were obtained from a multisite prospective observational cohort study and its companion follow-up study. Patterns of care were measured by the combination of settings of care where hip arthroplasty patients received rehabilitation therapy. Main outcome measure was motor portion of the functional independence measure. RESULTS: Approximately 90% of hip arthroplasty patients received rehabilitation care from more than one setting. Eight patterns of care were identified in the follow-up period. Patterns of subsequent care were driven more by initial setting than by etiology. Nonelective hip arthroplasty patients had lower motor functional independence measure scores and used more rehabilitation services than did elective hip arthroplasty patients. Patterns of care were modest factors (accounted for only 7% of variance) in predicting patient motor functional independence measure over an episode of postacute care. CONCLUSIONS: Etiology of hip arthroplasty is associated with amounts of rehabilitation care used and outcomes. After the initial postacute rehabilitation setting, patients continued to receive considerable amounts of therapy in various settings. It is important to look beyond a single setting of care to an entire episode of care when examining clinical outcomes. PMID- 20962603 TI - Paucity of muscle metastasis in otherwise widely disseminated cancer: a conundrum. AB - Despite widespread dissemination of cancer to multiple organs, muscle metastasis remains a rare occurrence. Limiting factors in this regard include, among others, repetitive muscle contraction, increased lactic acid, and decreased pH as well as protease metabolism. With the approval of hospital's research committee, a 10-yr review of histopathologic and imaging studies of patients diagnosed as having muscle metastasis was attempted. A review of the literature dealing with this phenomenon was also initiated. The review of the literature with reference to muscle metastasis highlighted its rare occurrence, which in turn correlated with our own 40-yr clinical experience (M.M.L.). As a potential target, muscle tissue remains an "infrequent soil" for metastasis because of its unique mechanical and metabolic qualities. PMID- 20962604 TI - Ultrasound evaluation of a spontaneous plantar fascia rupture. AB - Plantar fascia rupture is an occasional complication in patients with chronic plantar fasciitis or in patients with plantar fasciitis treated with steroid injection. Very few cases of spontaneous plantar fascia rupture have been reported in the literature (Herrick and Herrick, Am J Sports Med 1983;11:95; Lun et al, Clin J Sports Med 1999;9:48-9; Rolf et al, J Foot Ankle Surg 1997;36:112 4; Saxena and Fullem, Am J Sports Med 2004;32:662-5). Spontaneous medial plantar fascia rupture in a 37-yr-old man with no preceding symptoms or steroid injections was confirmed with diagnostic ultrasound, which revealed severe fasciitis at the calcaneal insertion with partial tearing. After conservative treatment, the patient returned to full activities. We discuss the anatomy, risk factors, examination findings, and treatment for this condition, as well as the unique benefits that ultrasound offers over magnetic resonance imaging. It is important to consider plantar fascia rupture in patients with hindfoot pain and medioplantar ecchymosis, particularly if an injury occurred during acceleration maneuvers. Ultrasound in these cases can be used to diagnose a plantar fascia tear quickly, accurately, and cost-effectively. PMID- 20962606 TI - Medical educators and physiatrists: venturing into the new world of "reformed" health care. PMID- 20962608 TI - Stem-cell "hype" in tracheal transplantation? PMID- 20962610 TI - Short-term follow-up of radioembolization with yttrium-90 microspheres before liver transplantation: new perspectives in advanced hepatocellular carcinoma. PMID- 20962612 TI - Use of intravenous immune globulin and rituximab for desensitization of highly human leukocyte antigen-sensitized patients awaiting kidney transplantation. PMID- 20962613 TI - Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication. AB - OBJECTIVES: Sustained suppression of plasma viremia in HIV-infected individuals is attainable with antiretroviral therapy (ART); however, eradication of virus that would allow discontinuation of ART has been hampered by the persistence of HIV reservoirs. It is of great interest to identify individuals who had received ART for prolonged periods of time with extremely low or undetectable HIV reservoirs and monitor plasma viremia following discontinuation of therapy. METHODS: We measured the size of HIV reservoirs in CD4(+) T cells of individuals on long-term ART and monitored plasma viremia following cessation of ART in one individual with an exceptionally low viral burden after a decade of therapy. RESULTS: We demonstrated undetectable levels of HIV DNA in the blood of eight of 45 infected individuals on long-term ART. Among those eight individuals, the frequency of cells carrying infectious virus was significantly lower in those who initiated ART during the early versus the chronic phase of infection. One individual with undetectable HIV DNA in both blood and tissue and a profoundly low level of infectious virus experienced plasma viral rebound 50 days following discontinuation of ART. CONCLUSIONS: Our data suggest that a significant reduction in the size of viral reservoirs may be achievable in selected individuals who initiate standard ART early in infection. However, given re emergence of plasma viremia in an individual with an extraordinarily low viral burden, therapeutic strategies aimed at specifically targeting these extremely rare HIV-infected cells with novel interventions may be necessary in order to achieve eradication of virus. PMID- 20962614 TI - Alpha interferon administration during structured interruptions of combination antiretroviral therapy in patients with chronic HIV-1 infection: INTERVAC ANRS 105 trial. AB - Interferon-alpha administration during structured treatment interruptions (STIs) was studied in a phase III trial. We randomized 168 chronically infected HIV undetectable under combined antiretroviral therapy patients to have three STIs with or without alpha-interferon. The number of patients who had to resume treatment during post-STI follow-up was not significantly different between the two arms. Patients with a low CD4 nadir and a high baseline HIV-DNA had a higher risk of treatment resumption in the interferon arm. PMID- 20962615 TI - Remedicalizing an epidemic: from HIV treatment as prevention to HIV treatment is prevention. PMID- 20962616 TI - Maraviroc does not affect humoral response to the pandemic influenza A-H1N1v 2009 adjuvanted vaccine in HIV-1-infected patients. AB - Immune changes induced by the CCR5 antagonist maraviroc raise the question of an impairment of responses to vaccines. We evaluated the immunogenicity of the adjuvanted pandemic influenza A-H1N1v 2009 vaccine in HIV-1-infected patients with suppressed HIV viremia with or without a maraviroc-containing regimen. Seroprotection, seroconversion, and geometric mean titer ratio of specific antibody titers did not differ between groups. These results suggest that maraviroc does not significantly affect the immune response to this adjuvanted vaccine. PMID- 20962617 TI - Insights into the rise in HIV infections, 2001 to 2008: a Bayesian synthesis of prevalence evidence. AB - OBJECTIVE: To estimate trends in prevalence of HIV infection, undiagnosed and total, among adults aged 15-44 years in England and Wales since 2001. DESIGN: Multiple surveillance systems and survey data are available to inform different aspects of the HIV epidemic in England and Wales. To coherently and consistently combine this information to estimate trends in HIV prevalence, we apply a multiparameter evidence synthesis in a Bayesian statistical framework. METHODS: The study population is stratified by exposure group and region of residence. We synthesize data from behavioural and community surveys, unlinked anonymous seroprevalence surveys, and an annual survey of individuals with diagnosed HIV infection. Prevalence estimates are given with 95% credible intervals. RESULTS: The estimated number of prevalent HIV infections in 15-44-year-olds has increased from 32,400 (29,600-35,900) in 2001 to 54,500 (50,500-59,100) in 2008, corresponding to an estimated prevalence of 1.5 per 1000 (1.4-1.7) rising to 2.4 per 1000 (2.3-2.6) in 2008. A rise in prevalence of diagnosed infection contributes substantially to the increase. There is no evidence of a statistically significant decrease in the prevalence of undiagnosed infection. The proportion of infections that are diagnosed has therefore also increased. CONCLUSION: Although the increase in the proportion of infections that are diagnosed is encouraging, the rise in HIV prevalence and lack of evidence of a decrease in prevalence of undiagnosed infection suggest that diagnosis rates are not high enough to reduce the pool of individuals unaware of their infection and that new infections must be occurring. PMID- 20962618 TI - Benign serrated colorectal fibroblastic polyps/intramucosal perineuriomas are true mixed epithelial-stromal polyps (hybrid hyperplastic polyp/mucosal perineurioma) with frequent BRAF mutations. AB - Colorectal fibroblastic polyp and intramucosal perineurioma are 2 synonyms for a recently described benign mucosal lesion with a predilection for the rectosigmoid colon. These lesions are characterized by aggregates of bland spindled cells separating and distorting mucosal crypts. The latter frequently showed a serrated architecture. The pathogenesis of fibroblastic polyp/intramucosal perineurioma and the nature of serrated crypts observed in them are poorly understood. We analyzed the clinicopathological features of 29 fibroblastic polyps and investigated them for the first time for mutations known to be involved in serrated colorectal epithelial polyps (BRAF, KRAS, and PIK3CA). Patients were 23 women and 6 men with a mean age of 64 years (range: 47 to 84 y). All lesions represented asymptomatic solitary polyps (mean size 3.5 mm) localized predominantly in the rectosigmoid colon (81%). Hyperplastic polyps, classical adenoma, and sessile serrated adenoma/lesion coexisted in 12 (44%), 12 (44%), and 5 (17%) patients, respectively. All lesions showed irregular aggregates of bland spindled cells separating and distorting mucosal crypts. Serrated (hyperplastic) crypts were observed on the top or contiguous with the lesion in all cases. Immunohistochemistry revealed expression of at least one perineurial cell marker (epithelial membrane antigen, claudin-1, and glucose transporter-1) in 26 out of 27 lesions (96%), but expression of CD34 was less common (8 of 27; 30%). Immunostaining for hMLH1 showed a normal nuclear expression. Molecular analysis in 22 cases showed V600E BRAF mutation in 14 cases (63%) and KRAS mutation in 1 (4%). The remainder were wild-type for all 3 genes. Our results indicate that serrated fibroblastic polyps/intramucosal perineuriomas represent a unique type of mixed epithelial-stromal polyps (hybrid hyperplastic polyp/mucosal perineurioma). The perineurial stromal component might be derived from modified pericryptic fibroblasts as a consequence of a yet poorly understood epithelial stromal interaction. PMID- 20962619 TI - Encapsulated well-differentiated follicular thyroid adenocarcinomas. PMID- 20962620 TI - IG/MYC rearrangements are the main cytogenetic alteration in plasmablastic lymphomas. AB - Plasmablastic lymphoma (PBL) is an aggressive lymphoma characterized by a terminally differentiated B-cell phenotype that usually occurs in the immunocompromised or elderly patients. Although the clinical and pathologic characteristics of these tumors have been defined, the genetic alterations involved in their pathogenesis are not well known. In this study, we have investigated the chromosomal alterations of MYC, BCL2, BCL6, MALT1, PAX5, and IGH loci using fluorescence in situ hybridization in 42 PBL and 3 extracavitary primary effusion lymphomas. MYC rearrangements were identified in 20 of 41 (49%) PBL and the immunoglobulin (IG) genes were the partners in most tumors. MYC rearrangements were more common in Epstein-Barr virus (EBV)-positive (14 of 19, 74%) than EBV-negative (9 of 21, 43%) tumors (P<0.05). No rearrangements of BCL2, BCL6, MALT1, or PAX5 were detected in any PBL but gains of these loci were observed in 31% to 41% of the cases examined. Twelve of the 40 PBL in which 3 or more loci could be investigated had multiple simultaneous gains in 3 or more loci. No differences in the survival of the patients according to MYC were observed but the 4 patients with the longest survival (>50 mo) had no or low number of gains (<3). No rearrangements of any of these loci were seen in the primary effusion lymphomas. In conclusion, PBL are genetically characterized by frequent IG/MYC translocations and gains in multiple chromosomal loci. The oncogenic activation of MYC in these lymphomas may be an important pathogenetic element associated with EBV infection. PMID- 20962621 TI - Morphologic findings in upper gastrointestinal biopsies of patients with ulcerative colitis: a controlled study. AB - INTRODUCTION: Upper gastrointestinal involvement, both gastric and duodenal, is known to occur in both Crohn disease and ulcerative colitis (UC). However, the frequency and types of inflammation in upper gastrointestinal biopsies in patients with UC has not been well studied, especially in a controlled study. METHODS: Twenty-four esophageal, 59 gastric, and 40 duodenal biopsies from 69 UC patients were reviewed. These were compared with 35 esophageal, 66 gastric, and 46 duodenal biopsies from a control group of 97 consecutive patients of similar age and sex distribution. The pattern and extent of inflammation were noted in each biopsy. RESULTS: There were 3 types of gastric inflammation that occurred more in UC patients than in controls, and the differences were statistically significant. The most common was an intense focal gastritis, present in 29% of UC gastric biospies, compared with 9% of controls. Twenty-two percent of UC patients had a basal mixed inflammation compared with 8% of controls, and 20% of the UC patients had superficial plasmacytosis compared with 6% of controls. There were no esophageal inflammations that occurred more commonly in UC than controls. Four UC patients and no controls had diffuse chronic duodenitis, also a statistically significant difference. All 4 UC-duodenitis patients were among the 10 with previous colectomies, and all 4 patients had pouchitis. Only 1 of the 4 UC colectomy patients without duodenitis developed pouchitis. CONCLUSIONS: Most UC patients have no upper gastrointestinal inflammation in biopsies, and most of the inflammations they have are not unique. The most common upper gastrointestinal inflammatory pattern in patients with UC is focal gastritis, followed by gastric basal mixed inflammation and superficial plasmacytosis. The one unique upper gastrointestinal inflammation in UC patients is diffuse chronic duodenitis, present in 10% of patients who had duodenal biopsies, and in 40% of UC patients who had colectomy and all of these patients had pouchitis. This association strongly suggests that diffuse chronic duodenitis in UC patients who have colectomy is a strong predictor of pouchitis. PMID- 20962622 TI - Myometrial invasion and lymph node metastasis in endometrioid carcinomas: tumor associated macrophages, microvessel density, and HIF1A have a crucial role. AB - Myometrial invasion is an independent prognostic parameter of the endometrioid carcinomas which correlates with the risk of metastasis to pelvic and/or paraaortic lymph nodes. Recognition of myometrial invasion is sometimes difficult. In fact, myoinvasion is overdiagnosed in routine practice in as many as 25% of the cases. Recently, it has been observed that tumor-associated macrophages stimulate angiogenesis and promote cancer dissemination. Tumor macrophages (CD163), microvessel density (CD31), and hypoxia inducible factor 1 alpha subunit (HIF1A) were investigated in 64 primary endometrioid carcinomas with (50 cases) and without (14 cases) myometrial invasion as well as in the corresponding regional lymph nodes metastases of 20 of the myoinvasive tumors. Endometrioid carcinomas with myometrial invasion showed higher number of CD163 tumor macrophages and greater microvessel density than endometrioid carcinomas without myometrial invasion (P=0.000 and P=0.000, respectively). In carcinomas confined to the corpus uteri (stage I), expression of HIF1A was associated with deep myoinvasion (stage IC) (P=0.006). There was a significant relationship between microvessel density and CD163-macrophages both in the myoinvasive and nonmyoinvasive tumors. On the other hand, high-grade endometrioid carcinomas had more macrophage infiltrates and microvessels than low-grade tumors (P=0.03 and P=0.07). Also, there was a positive correlation between CD163-macrophages and microvessel density in the primary tumors and their corresponding regional lymph node metastases. These findings link increased microvessel proliferation to stromal macrophage infiltrate and suggest that enhanced tumor angiogenesis, triggered by stromal macrophages, regulates the progression of endometrioid carcinomas. The identical stroma microenvironment found in the primary and the corresponding metastatic tumor suggests that tumor stroma response is determined by the intrinsic biology of the tumor. PMID- 20962623 TI - Prevention of contrast-induced impairment of renal function by short-term or long term statin therapy in patients undergoing elective coronary angiography. AB - A decline in kidney function after contrast exposure is associated with a high risk of morbidity and mortality during hospitalization and over long-term periods. Several retrospective and recent prospective clinical trials have shown that statin therapy might prevent contrast-induced nephropathy in patients undergoing percutaneous coronary intervention. In this study, we aimed to assess the effects of statin therapies on renal function parameters in patients undergoing elective coronary angiography. One hundred and sixty patients undergoing elective coronary angiography were randomized equally into two groups: atorvastatin 40 mg/day group (statin started 3 days before coronary angiography) and an untreated control group. An additional 80 patients were included as a chronic statin therapy group. Serum creatinine, serum cystatin C, and glomerular filtration rate (GFR) were measured before and 48 h after coronary angiography. Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) equations were used to determine GFR. After coronary angiography, serum creatinine and GFR determined by MDRD were significantly better in patients using atorvastatin than those in controls (P = 0.002 and P = 0.004, respectively). Postprocedure serum creatinine, cystatin C, and GFR determined by MDRD were also significantly better in chronic statin therapy group than those in controls (P = 0.006, P = 0.003, and P = 0.004, respectively). There were no differences in renal function parameters between the short-term atorvastatin group and the chronic statin therapy group. Our data demonstrate that the use of short-term atorvastatin and chronic statin therapy may have a role in protecting renal function after elective coronary angiography. PMID- 20962624 TI - The efficacy of different dose intravenous immunoglobulin in treating acute idiopathic thrombocytopenic purpura: a meta-analysis of 13 randomized controlled trials. AB - The purpose of this study was to compare the effects of different dose intravenous immunoglobulin for treatment of acute idiopathic thrombocytopenic purpura. Randomized controlled trials (RCTs) comparing high-dose intravenous immunoglobulin (HD-IVIG) with low-dose intravenous immunoglobulin (low-IVIG) for acute idiopathic thrombocytopenic purpura (ITP) were identified using a predefined search strategy. Effective rate, time of cessation of bleeding, time of platelet count beginning to rise, platelet count by the first week of treatment, the number of platelets after 2 weeks of treatment, time of platelet count to reach peak, peak value of platelet count after treatment, side-effects and rate of developing into chronic ITP were extracted and compared by RevMan 4.2.8 (The Cochrane Collaboration, Oxford, UK). Thirteen RCTs (646 patients) were identified. Meta-analysis showed that effective rate, time of cessation of bleeding, time of platelet count beginning to rise, platelet count by the first week of treatment, the number of platelets after 2 weeks of treatment, time of platelet count to reach peak, peak value of platelet count after treatment and rate of developing into chronic ITP were not statistically different between the two different treatment administrations. However, low-IVIG was associated with a significantly reduced risk of side-effects {odds ratio (OR) 0.39 [95% confidence interval (CI) 0.18-0.83]; P = 0.01]. In conclusion, low-IVIG can be performed as effectively as HD-IVIG without increasing the rate of developing into chronic ITP. Furthermore, the low-IVIG regimen can have fewer side-effects than HD-IVIG administration in patients with acute ITP. PMID- 20962625 TI - Reviewed diagnosis of primary and secondary immune thrombocytopenic purpura in 79 adult patients hospitalized in 2000-2002. AB - Despite the accepted distinction between primary and secondary immune thrombocytopenic purpura (ITP), a systematic analysis of the incidence of secondary ITP is not available. The present study was aimed at verifying the frequency and, consequently, the approximate rates of prevalence and incidence of secondary ITP and analysing its clinical and laboratory characteristics in patients needing ordinary hospital treatment for ITP. The study was based on 79 consecutive, adult ITP patients admitted to three Italian hospitals in 2000-2002. Using data collected in a previous study on the appropriateness of hospital management of ITP, we evaluated the frequency of secondary ITP, with the diagnosis formulated on the basis of new acquisitions, derived its rates of prevalence and incidence, and examined the available clinical and laboratory parameters. At our case review, a diagnosis of secondary ITP could be formulated in 38% of the 79 patients. This frequency was significantly higher than that determined at the time the patients were discharged from hospital (13.9%) (P = 0.000). The derived rates of prevalence and incidence of secondary ITP in the general population were, respectively, 2.3 and 1.23 per 100 000 inhabitants per year. In comparison with patients with primary ITP, those with a secondary form more frequently had spleen enlargement (P = 0.000), hepatomegaly (P = 0.001) and lower haemoglobin values (P = 0.005). The high frequency of secondary ITP must be mainly attributed to the currently available knowledge about the nature of some forms of ITP. Particular contributors to the high frequency were cases secondary to infections and those observed in patients who had undergone bone marrow or solid organ transplantation. Some clinical and laboratory alterations appear to be more frequent in secondary ITP than in primary ITP. However, the importance that the identification of particular forms of ITP, such as those secondary to Helicobacter pylori or hepatitis C virus infections, has on the choice of treatment suggests that these conditions must be ascertained independently of the presence or absence of clinical and laboratory alterations. PMID- 20962626 TI - Association between the monocyte chemoattractant protein-1 -2518G/A gene polymorphism and acute myocardial infarction patients among Egyptian population. AB - The aim of the present study was to investigate the possible association between the -2518G/A polymorphism of the monocyte chemoattractant protein-1 (MCP-1) gene and acute myocardial infarction (MI) in a sample of the Egyptian population. A total of 30 Egyptian patients with coronary artery disease (CAD) manifested as acute myocardial infarction (MI) for the first time and 25 unrelated healthy control individuals were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The proportion of G/A and G/G genotypes were significantly higher in the acute MI group than the control group (P < 0.05). The acute MI patients group showed a significant higher frequency of the G allele compared to the controls (P < 0.05). Analysis of the relationship between the G/A, G/G genotypes and A/A genotype acute MI group regarding the conventional risk factors showed statistical significant difference regarding age, total cholesterol, low-density lipoprotein and high-density lipoprotein (P < 0.05), but there was no significant relationship regarding sex, smoking, history of diabetes mellitus, hypertension, obesity, body mass index (BMI) and triglyceride, but we observed that the percentage of men was higher than the percentage of women in both G/A, G/G genotypes and A/A genotype acute MI patients. Also, among our patients, the percentage of smokers, diabetics, hypertensive, and obesity and the mean of BMI and triglyceride were higher in the G/A, G/G genotypes acute MI patients than that in A/A genotype acute MI patients. In conclusion, our study indicated that there was a significant association between the MCP-1 -2518G/A polymorphism and acute MI in the Egyptian population, but this significant association is dependent on the presence of MI risk factors. PMID- 20962627 TI - Endothelial cell survival after descemet stripping with automated endothelial keratoplasty with retained anterior chamber intraocular lens. AB - PURPOSE: To evaluate the donor endothelial cell loss in the first year after Descemet stripping endothelial keratoplasy (DSAEK) for the treatment of endothelial dysfunction in the presence of an anterior chamber (AC) intraocular lens (IOL). METHODS: We performed a retrospective study of a surgical case series of 25 patients who underwent DSAEK in the presence of an AC IOL. The donor central endothelial cell density (ECD) was recorded at 6 months and 1 year postoperatively and then compared with the preoperative eye bank values. RESULTS: The average and SD ECD at 6 months was 1876 +/- 286 cells per square millimeters representing a mean cell loss from preoperative ECD measurement of 37% +/- 13%. At 1 year postoperatively, ECD was 1793 +/- 311 cells per square millimeters that correspond to a 40% +/- 11% cell loss from preoperative ECD measurement. The increased cell loss between 6 months and 1 year was not significant statistically (P = 0.365). CONCLUSIONS: DSAEK in the presence of a well-centered AC IOL and an AC depth greater than 3 mm has a mean donor endothelial cell loss of 37% at 6 months and 40% at 12 months postoperatively. We found no difference in cell loss in our series compared with previous ECD loss in DSAEK surgery alone. Emphasis in a surgical technique that minimizes tissue manipulation and reduces the risk of graft-AC IOL touch should be considered to maximize the endothelial graft survival in these cases. PMID- 20962628 TI - Association of Helicobacter pylori infection with acute myocardial infarction. AB - OBJECTIVES: Helicobacter pylori infection has been linked to cardiovascular diseases (CVD) and several studies have reported its positive association with inflammatory response after acute myocardial infarction (AMI). On account of the importance of the inflammatory process in the development of CVD, we decided to examine the seroprevalence of H. pylori, the prevalence of CVD risk in the more virulent strains bearing the cytotoxin-associated protein (CagA), and the changes in C-reactive protein (CRP) as an inflammatory marker in Iranian patients with AMI. METHODS: A case-control study was designed to determine the seropositivity status of H. pylori and CagA in blood samples obtained from 500 patients with AMI and 500 control individuals without any evidence of clinical CVD. Serum and peripheral blood mononuclear cells were analyzed using the enzyme-linked immunosorbent assay and western blotting methods, respectively. CRP levels were also measured in all individuals. RESULTS: The prevalence of H. pylori infection and CagA status were significantly higher among the patients with AMI than the controls (66 vs. 20% and 75.7 vs. 30%, respectively); the odds ratio was 2.57 (95% confidence interval 1.89-3.49). CRP levels were significantly different in the patients compared with the controls (5.02+/-1.04 mg/l vs. 2.41+/-0.9 mg/l, respectively). CONCLUSION: Our results confirmed that the patients with AMI had a significantly higher prevalence of H. pylori infection and CagA seropositivity than the control population. Infection with H. pylori may influence AMI, which in our findings shows an association between H. pylori seropositivity and AMI through an inflammatory process. PMID- 20962629 TI - Display of information in the operating room. AB - PURPOSE OF REVIEW: The ongoing development of new sensors and parameters for intraoperative monitoring has outpaced the development of display design, leading to a gap between the load of information and the quality of its delivery. This is not a circumstantial problem, as a large portion of critical incidents is attributable to inadequate situation awareness and the failure to recognize readily monitored data. This review also addresses improvements of current threshold alarms. RECENT FINDINGS: Research has focused on advanced integrated displays, drawing on the findings of human factor science and on the exploitation of alternative sensory pathways. Integrated displays, as well as auditory, vibrotactile and head-mounted displays have been shown to promote situation awareness and reduce cognitive workload. Intelligent alarm design can successfully reduce the number of false alarms. SUMMARY: Improvement of the display of information in the operating room is warranted, and recent developments are promising. However, their introduction into mass market is not yet on the horizon, although the shortcomings of the traditional single-sensor single-indicator principle are known for a long time. If manufacturers are reluctant to implement new techniques into their devices, they should at least facilitate access to monitoring raw data in order to allow independent development of displays. PMID- 20962630 TI - Shaping the operating room and perioperative systems of the future: innovating for improved competitiveness. AB - PURPOSE OF REVIEW: To review the current state of anesthesiology for operative and invasive procedures, with an eye toward possible future states. RECENT FINDINGS: Anesthesiology is at once a mature specialty and in a crisis--requiring breakthrough to move forward. The cost of care now approaches reimbursement, and outcomes as commonly measured approach perfection. Thus, the cost of further improvements seems ready to topple the field, just as the specialty is realizing that seemingly innocuous anesthetic choices have long-term consequences, and better practice is required. SUMMARY: Anesthesiologists must create more headroom between costs and revenues in order to sustain the academic vigor and creativity required to create better clinical practice. We outline three areas in which technological and organizational innovation in anesthesiology can improve competitiveness and become a driving force in collaborative efforts to develop the operating rooms and perioperative systems of the future: increasing the profitability of operating rooms; increasing the efficiency of anesthesia; and technological and organizational innovation to foster improved patient flow, communication, coordination, and organizational learning. PMID- 20962632 TI - Skeletal manifestations of systemic autoimmune diseases. AB - PURPOSE OF REVIEW: There is an increased risk of osteoporotic fractures and osteonecrosis often at a young age among patients with certain systemic autoimmune diseases. The loss of bone mineral density and bone integrity seen with these diseases often cannot be explained by traditional risk factors alone. In this review, we focus on rheumatoid arthritis and systemic lupus erythematosus, two systemic autoimmune diseases in which skeletal manifestations have been well described. RECENT FINDINGS: There is recent evidence that autoimmunity and its associated inflammation and vitamin D deficiency play key roles in the pathogenesis of adverse skeletal effects. SUMMARY: Understanding these processes carries implications for the prevention and treatment of osteoporosis and osteonecrosis among patients with autoimmune diseases. PMID- 20962633 TI - Epigenetic regulation of reprogramming factors towards pluripotency in mouse preimplantation development. AB - PURPOSE OF REVIEW: Pluripotency is the ability of a cell to give rise to all the tissues of the adult body. During development, both genetic and epigenetic mechanisms are proposed to be involved in the establishment of the pluripotent state in the cells of the epiblast. Here, we review recent findings on the biological function and epigenetic regulation of reprogramming factors with a particular focus on the early mouse embryo. RECENT FINDINGS: A number of functional studies have identified a group of transcription factors required for reprogramming during mouse preimplantation development. Among these transcription factors, Oct4, Sox2, and Nanog are also crucial for establishment and/or maintenance of pluripotency in vivo. Genome-wide studies with ES cells have highlighted the colocalization of these factors onto ES cell chromatin and the existence of a transcriptional network that might direct pluripotency. Furthermore, recent studies on transcription factor-mediated induced reprogramming to induced pluripotent stem cells have revealed roles of these transcription factors on reprogramming. SUMMARY: Oct4, Sox2, and Nanog seem to work at different times of the reprogramming process in vivo. Elucidating the regulatory mechanisms of these factors provides not only insights into the reprogramming mechanisms but also in the regulation of mouse preimplantation development. PMID- 20962631 TI - Prenatal stress and developmental programming of human health and disease risk: concepts and integration of empirical findings. AB - PURPOSE OF REVIEW: The concept of the developmental origins of health and disease susceptibility is rapidly attracting interest and gaining prominence as a complementary approach to understanding the causation of many complex common disorders that confer a major burden of disease; however several important issues and questions remain to be addressed, particularly in the context of humans. RECENT FINDINGS: In this review we enunciate some of these questions and issues, review empirical evidence primarily from our own recent studies on prenatal stress and stress biology, and discuss putative maternal-placental-fetal endocrine and immune/inflammatory candidate mechanisms that may underlie and mediate short-term and long-term effects of prenatal stress on the developing human embryo and fetus, with a specific focus on body composition, metabolic function, and obesity risk. SUMMARY: The implications for research and clinical practice are discussed with a summary of recent advances in noninvasive methods to characterize fetal, newborn, infant, and child developmental and health related processes that, when coupled with available state-of-the-art statistical modeling approaches for longitudinal, repeated measures time series analysis, now afford unprecedented opportunities to explore and uncover the developmental origins of human health and disease. PMID- 20962634 TI - Epigenetics in humans: an overview. AB - PURPOSE OF REVIEW: The purpose of review is to describe the recent advances in the field of human epigenetics. RECENT FINDINGS: With the completion of the genome project in 2003, high expectations existed for the DNA sequence information to provide answers about the causative mutations for common diseases. However, this was not completely the case. Another interesting finding that resulted from the genome project was that the perceived level of complexity of humans was not accompanied with a relative increase in the number of genes when compared to 'lower species'. Epigenetics is able to provide answers to previously unanswered health-related questions and can explain differences in level of complexity between organisms. Epigenetic studies accomplished in the last few years have exposed a very complex multilayered regulatory mechanism that is able to answer previously puzzling questions in biology. SUMMARY: Understanding and interpretation of the role for epigenetic modifications in the human genome has progressed rapidly over the past decade with the advancement of microarray-based and sequence-based technologies. The complex interaction between DNA methylation, histone modifications, protein complexes and microRNAs has become better appreciated in the context of both local and long range epigenetic control of transcription in both normal cellular differentiation and tumorigenesis. PMID- 20962635 TI - Disorders of phosphorus homeostasis. AB - PURPOSE OF REVIEW: The study of phosphorus physiology and investigations into clinical disorders of phosphorus metabolism has blossomed over the past decade. Recent work has confirmed and further extended our knowledge of basic mechanisms of phosphorus metabolism. RECENT FINDINGS: This review will focus on FGF-23 and Klotho, and on the recent further dissection of their roles in phosphorus and skeletal metabolism. Additionally, this review will detail recent studies that implicate a role for these phosphaturic and vitamin D regulating factors in extraskeletal calcification, including that occurring in soft tissue and vascular beds. SUMMARY: These findings in total provide fertile ground for investigations into the cause and treatment of abnormal skeletal and extraskeletal calcification in patients with inherited hypophosphatemic disorders. More importantly, and certainly with wider potential clinical application, these studies likewise imply a role for these factors in the pathogenesis of accelerated cardiovascular disease that occurs in patients with the most common hyperphosphatemic disorder, chronic kidney disease. Future studies are needed to confirm a harmful or possibly even beneficial role for FGF-23 and other factors in these disease states, and to determine whether therapeutic manipulation of these factors does truly affect clinical outcomes in patients with hypophosphatemia and hyperphosphatemia. PMID- 20962637 TI - Nonprogressive behavioural frontotemporal dementia: recent developments and clinical implications of the 'bvFTD phenocopy syndrome'. AB - PURPOSE OF REVIEW: The clinical features of behavioural variant frontotemporal dementia (bvFTD) are well established; however, recent work has identified patients fulfilling diagnostic criteria for the disease who do not appear to progress clinically. This review describes means of distinguishing this group at an early stage from patients who are likely to deteriorate. RECENT FINDINGS: Despite indistinguishable clinical profiles, studies in a cohort of bvFTD patients showed a particularly good prognosis in a subgroup of predominantly male patients in whom initial structural imaging was normal. This could not be explained by differences in disease duration, and was confirmed by subsequent PET studies. Retrospective review of clinical data in these groups verified that the current clinical diagnostic criteria are both insensitive to true progressive bvFTD, particularly in the early stages, and also poorly specific. In contrast, measures of activity of daily living performance, executive function and tests of social cognition appear to have better discriminatory value for patients who show clear clinical progression, with many individual diagnoses verified by post mortem examination in this group. SUMMARY: It remains doubtful that the nonprogressive group have a neurodegenerative disease. The implication for the current clinical diagnostic criteria and their proposed revision is discussed. PMID- 20962636 TI - Imprinting disorders and assisted reproductive technology. AB - PURPOSE OF REVIEW: To summarize current evidence in the association of imprinting disorders and assisted reproductive technology. RECENT FINDINGS: The worldwide usage of assisted reproductive technology (ART) has continued to increase since the first successful birth of a human after IVF. Since 2002, several reports have raised concerns that children conceived by ART are at increased risk of having imprinting disorders. The majority of published studies have examined DNA methylation in children conceived by ART, but results are conflicting. Beckwith Wiedemann syndrome and Angelman syndrome are the most extensively studied imprinting disorders and multiple case series and reports have been published on ART-conceived children with these syndromes. Overall the majority of reports suggest that ART might be associated with Beckwith-Wiedermann syndrome and Angelman syndrome, but larger collaborative studies need to be performed. SUMMARY: The current data suggest an association between imprinting disorders and ART although the absolute risk appears to be low. However, animal studies have established biologic plausibility and there is continuing concern about the possibility of epigenetic changes resulting from ART. PMID- 20962638 TI - Community integration after severe traumatic brain injury in adults. AB - PURPOSE OF REVIEW: Despite being the main cause of death and disability in young adults, traumatic brain injury (TBI) is a rather neglected epidemic. Community integration of persons with TBI was, until recently, insufficiently informed by clinical research. RECENT FINDINGS: To bridge the gap between rehabilitation and community re-entry, the first task is to assess the person, using TBI-specific outcome measures. The second task is to provide re-entry programs, the effectiveness of which is assessed by those measures, using well designed studies. There are very few such studies. However, there are some effective comprehensive programs and others which are specifically targeted dealing mainly with return to work, behavior, and family issues. The complex psychological and environmental components of the disability require individualized and often long term care. SUMMARY: For persons with severe TBI trying to achieve the best possible community integration a new semiology is required, not just limited to medical care, but also involving social and psychological care that is tailored to the needs of each individual and family, living within his/her environment. Currently, only a minority benefit from well validated programs. PMID- 20962639 TI - Potential for new technologies in clinical practice. AB - PURPOSE OF REVIEW: Cost-effective neurorehabilitation is essential owing to financial constraints on healthcare resources. Technologies have the potential to contribute but without strong clinical evidence are unlikely to be widely reimbursed. This review presents evidence of new technologies since 2008 and identifies barriers to translation of technologies into clinical practice. RECENT FINDINGS: Technology has not been shown to be superior to intensively matched existing therapies. Research has been undertaken into the development and preliminary clinical testing of novel technologies including robotics, electrical stimulation, constraint-induced movement therapy, assistive orthoses, noninvasive brain stimulation, virtual reality and gaming devices. Translation of the research into clinical practice has been impeded by a lack of robust evidence of clinical effectiveness and usability. Underlying mechanisms associated with recovery are beginning to be explored, which may lead to more targeted interventions. Improvements in function have been demonstrated beyond the normal recovery period, but few trials demonstrate lasting effects. SUMMARY: Technologies, alone or combined, may offer a cost-effective way to deliver intensive neurorehabilitation therapy in clinical and community environments, and have the potential to empower patients to take more responsibility for their rehabilitation and continue with long-term exercise. PMID- 20962640 TI - Community integration following severe childhood traumatic brain injury. AB - PURPOSE OF REVIEW: Severe childhood traumatic brain injury (TBI) is the leading cause of death and acquired disability in children, causing impairments in children's sensory-motor, cognitive and behavioural functioning, with devastating consequences on community integration. Community integration is the ultimate goal of rehabilitation; it is a complex outcome, with many variables contributing to it. RECENT FINDINGS: Community integration and quality of life (QOL) are lower in children who sustained severe TBI at a younger age. Further, a wide range of injury-related, demographic and postinjury factors influence outcomes, and should serve as targets for specific interventions. An increasing number of interventions targeting cognitive, behavioural or family-related issues have been developed, with promising results. SUMMARY: Children should benefit from early integrated patient and family-centred specific care, and receive long-term follow up until early adulthood, with regular assessments, enabling detection and treatment of any emerging problem, and to ensure the acquisition of independent living skills and stable vocational outcome when this is possible. So far, few well conducted intervention studies are available, but their number is increasing with positive results on the trained skills. Well designed studies using large samples and looking at generalization of the skills in everyday life are needed. PMID- 20962641 TI - Cognition and behaviour in motor neurone disease. AB - PURPOSE OF REVIEW: Motor neurone disease has traditionally been considered a pure motor syndrome which spares aspects of cognition and behaviour, although in recent years it has been suggested that up to 50% of patients with motor neurone disease may develop frontal dysfunction which, in some cases, is severe enough to reach criteria for frontotemporal dementia. We review the cognitive and behavioural changes in motor neurone disease emphasizing the recent advances. RECENT FINDINGS: A major advance in pathology has been the recent discovery of TDP-43 and FUS inclusions as the key components in cases of motor neurone disease, frontotemporal dementia-motor neurone disease and some cases with pure frontotemporal dementia. In addition, mutations in TARDBP and FUS genes have been reported in recent years. Longitudinal studies showed that progression of cognitive impairment over the course of motor neurone disease appears to be mild and occurs only in a proportion of motor neurone disease patients. The presence of cognitive impairment seems to be related to a faster disease and a shorter survival. SUMMARY: Motor neurone disease is a multi-system disorder which overlaps with frontotemporal dementia. Behavioural and cognitive changes appear to occur in a subset of patients with motor neurone disease, but the cause of this variability remains unclear. PMID- 20962642 TI - Steroids in neurooncology: actions, indications, side-effects. AB - PURPOSE OF REVIEW: Glucocorticoids are frequently used in the treatment of patients with neurooncological disorders. This review addresses different clinical indications and provides information on beneficial and undesired effects exerted by these drugs. The most important cellular mechanisms of action of glucocorticoids under different conditions are highlighted. RECENT FINDINGS: Glucocorticoids have been used for the treatment of lymphoid neoplasms for decades. In addition to proapoptotic effects, recent studies have delineated the induction of autophagy in lymphoma cells as an important alternative mode of cell death. In contrast, glucocorticoids may reduce the sensitivity of tumor cells, including glioma cells, other than lymphoma cells to chemotherapeutic agents. Corticosteroids also provide transient relief from neurological symptoms caused by increased intracranial pressure and edema associated with primary and secondary brain tumors. However, treatment with glucocorticoids is also commonly associated with considerable side-effects including hyperglycemia, myopathy, osteoporosis, lymphopenia and others. SUMMARY: Although in clinical use for more than 40 years in the field of neurooncology, steroids remain a central and essential part in the treatment of brain tumor patients. Along with improved therapeutic options and prolonged life expectancy of many of these patients, careful administration is required and long-term side-effects must be considered. PMID- 20962643 TI - Characterization of vocal fold scar formation, prophylaxis, and treatment using animal models. AB - PURPOSE OF REVIEW: To review recent literature on animal models used to study the pathogenesis, detection, prevention, and treatment of vocal fold scarring. Animal work is critical to studying vocal fold scarring because it is the only way to conduct systematic research on the biomechanical properties of the layered structure of the vocal fold lamina propria, and therefore develop reliable prevention and treatment strategies for this complex clinical problem. RECENT FINDINGS: During the period of review, critical anatomic, physiologic, and wound healing characteristics, which may serve as the bases for selection of a certain species to help answer a specific question, have been described in mouse, rat, rabbit, ferret, and canine models. A number of different strategies for prophylaxis and chronic scar treatment in animals show promise for clinical application. The pathways of scar formation and methods for quantifying treatment induced change have become better defined. SUMMARY: Recent animal vocal fold scarring studies have enriched and confirmed earlier work indicating that restoring pliability to the scarred vocal fold mucosa is challenging but achievable. Differences between animal models and differences in outcome measurements across studies necessitate considering each study individually to obtain guidance for future research. With increased standardization of measurement techniques it may be possible to make more inter-study comparisons. PMID- 20962644 TI - Laryngomalacia: factors that influence disease severity and outcomes of management. AB - PURPOSE OF REVIEW: Laryngomalacia is a well described cause of newborn stridor. The spectrum of disease presentation, progression, and outcomes is varied. Some infants will have inconsequential stridor where others will develop feeding symptoms or even severe or life-threatening complications of airway obstruction. The purpose of this review is to identify factors that influence disease severity and outcomes. RECENT FINDINGS: Review of the current literature and a prospectively collected database shows that patient factors that influence disease severity include APGAR scores, resting SAO2 level at time of presentation, and the presence of a secondary airway lesion. Gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) contribute to feeding symptoms. Medical co-morbidities of GERD/LPR, neurologic disease, congenital heart disease, a genetic syndrome, or anomaly also contribute to disease severity and additively affect surgical outcomes. Those with severe disease requiring surgery who have GERD/LPR and one additional co-morbidity are more likely to require revision supraglottoplasty. Those with three medical co-morbidities are more likely to require tracheostomy. SUMMARY: Most with laryngomalacia will have mild to moderate symptoms and not require surgical intervention. Those with GERD/LPR have symptoms improvement from acid suppression therapy. Those with severe enough disease to require supraglottoplasty will have minimal complications and good outcomes if multiple medical co-morbidities are not present. Those with multiple medical co-morbidities could be offered supraglottoplasty as the first intervention but counseled that tracheostomy may be required. PMID- 20962645 TI - Rhinoplasty for cleft and hemangioma-related nasal deformities. AB - PURPOSE OF REVIEW: To provide a concise review of recent articles on rhinoplasty approaches for cleft nasal deformity and nasal hemangiomas published in 2008 2010. RECENT FINDINGS: Cleft nasal deformity rhinoplasty approaches have undergone further refinements as well as new development in techniques and surgical principles to minimize recurrent cleft nasal deformities. There is a paucity of studies addressing cleft septal deformity although there appears to be a greater emphasis on functional outcome in cleft rhinoplasty. Complications from primary cleft rhinoplasty and presurgical nasoalveolar molding were also reported. Similarly, nasal hemangioma rhinoplasty approaches have undergone further modifications with open rhinoplasty and subunit approaches gaining wider acceptance. SUMMARY: There are several new studies that compare different rhinoplasty techniques to determine which approaches offer superior surgical outcomes; however, there needs to be a greater acceptance of objective measurements when assessing surgical results to identify a uniform surgical protocol and technique for both cleft rhinoplasty and nasal hemangiomas. PMID- 20962646 TI - Pediatric endoscopic skull base surgery. AB - PURPOSE OF REVIEW: Pediatric endoscopic skull base surgery (ESBS) has changed the current management of pediatric sinonasal and skull base disorders. This review focuses on the recent literature exploring pediatric ESBS, including its utility and limitations. RECENT FINDINGS: Pediatric ESBS has been established as a safe and feasible technique for a variety of disease states. Special considerations in the pediatric populations include the use of image guidance technology, potential anatomic access limitations, and skull base reconstruction with vascularized flaps to prevent cerebrospinal fluid leak. The indications for endoscopic skull base surgery continue to expand as experience and technology evolve. SUMMARY: Pediatric endoscopic skull base surgery is a proven technique established upon adult skull base experience. Despite certain limitations, the current literature would recommend consideration for this approach for many sinonasal and skull base lesions. Further research is required to determine long-term patient outcomes. PMID- 20962647 TI - Role of robotic surgery in urogynecologic surgery and radical hysterectomy: how far can we go? AB - PURPOSE OF REVIEW: The purpose is to review the current literature regarding robotic assistance in urogynecologic surgery and radical pelvic surgery and to discuss the future of robotics in these two areas of gynecology. RECENT FINDINGS: When the first and only Food and Drug Administration-approved robot-assisted device, the daVinci surgical system, was approved for use in gynecology in April 2005, many procedures were translated to a robotic approach. In the field of urogynecology, much attention was given to the use of robotic assistance for sacrocolpopexy. In oncology, there was an attraction to the use of robotics for radical hysterectomies. There are a number of published observational studies comparing the outcomes of both robot-assisted laparoscopic sacrocolpopexy (RALS) and robot-assisted radical hysterectomy (RRH) to their conventional laparoscopic and open versions. Overall, the literature suggests that the use of robotics for these procedures increases operative time and cost, but decreases estimated blood loss and length of stay. The complication rates appear to be similar. Recurrence of apical prolapse after RALS appears to be similar to that in conventional laparoscopic or open sacrocolpopexy. The number of lymph nodes harvested is the same or increases with RRH, whereas the disease-free progression and overall survival are similar for all the methods of radical hysterectomy. SUMMARY: Literature suggests that RALS and RRH have equivalent outcomes when compared to conventional laparoscopic and open techniques. The question is whether the use of robotics that combines the outcomes of an open procedure, the benefits of minimally invasive surgery, and easy adoptability will outweigh the increased cost and time associated with robotic surgery. PMID- 20962648 TI - Robotic partial nephrectomy: the real benefit. AB - PURPOSE OF REVIEW: Robot-assisted partial nephrectomy (RPN) is an option for patients desiring minimally invasive nephron-sparing surgery. RPN outcomes, including safety, functional results, and oncological control, continue to be reported as the technique emerges. In the current review, we chronicle the development, recent advances, and current status of RPN. RECENT FINDINGS: RPN appears to have a shorter learning curve when compared to alternative minimally invasive techniques. Outcomes from recent series have confirmed the safety and feasibility of RPN in the management of small renal masses, many of them in complex locations. Recent comparative studies have demonstrated favorable-to equivalent outcomes for RPN when compared to laparoscopic partial nephrectomy (LPN), particularly in regards to decreased warm ischemia time. Novel technical developments include use of TilePro, the fourth robotic arm, sliding-clip renorrhaphy, and selective clamping techniques. SUMMARY: RPN appears to have favorable early-to-intermediate stage outcomes. RPN helps with the technical challenges of LPN, potentially extending the benefits of minimally invasive nephron-sparing surgery to a wider audience of patients and surgeons. PMID- 20962649 TI - Robotic natural orifice translumenal endoscopic surgery and laparoendoscopic single-site surgery: current status. AB - PURPOSE OF REVIEW: To analyse the evidence supporting current and future application of robotic technology in natural orifice translumenal endoscopic surgery (NOTES) and laparoendoscopic single-site surgery (LESS). RECENT FINDINGS: Early clinical experience with the application of currently available da Vinci robotic system to LESS has been encouraging, as some of the constraints encountered during conventional LESS can be overcome. Robotic devices that are currently being developed for NOTES and LESS focus on improving either tissue manipulation capabilities for externally actuated robotic and flexible endoscopy systems or visualization for robots that are inserted completely into the peritoneal cavity. SUMMARY: Robotic technology is rapidly evolving and is expected to drive several aspects of minimally invasive surgery forward in the near future with the ultimate goal of minimizing complications and improving outcomes. PMID- 20962650 TI - Level of agreement between heart rate variability and pulse rate variability in healthy individuals. AB - BACKGROUND AND OBJECTIVE: According to international standards, autonomic function is assessed by heart rate variability (HRV) calculated from R-R intervals obtained with an electrocardiogram (ECG). However, intra-operative movement artefacts and electrical interference may complicate R-wave detection. Pulse rate variability (PRV) derived from continuous blood pressure measurements may provide a feasible alternative for HRV. We aimed to investigate the level of agreement between PRV and traditional HRV using a novel beat-to-beat non-invasive blood pressure monitoring device. METHODS: In this prospective observational study, R-R intervals and non-invasive blood pressure waveforms were recorded simultaneously from 20 healthy male individuals at rest. HRV and PRV were analysed offline by spectral analysis, which divides the signal into its composing frequencies. Spearman's correlation coefficient, intra-class correlation coefficients and Bland-Altman analysis were used to study the level of agreement between HRV and PRV. RESULTS: The correlation coefficient between HRV and PRV was 0.99 (P < 0.001). Level of agreement was excellent with a mean difference of 1% in the very low frequency and low-frequency band and 14% in the high-frequency band. Reliability of both HRV and PRV was moderate to high. CONCLUSION: Our data show that PRV derived from non-invasive blood pressure waveforms corresponds well with traditional HRV derived from ECG. These results indicate that under standard conditions, blood pressure waveforms may replace HRV in healthy individuals and that the use of PRV in the peri-operative setting should be further evaluated. PMID- 20962651 TI - Closed claims from Switzerland: an important contribution to improving patient safety in anaesthesia. PMID- 20962652 TI - Sevoflurane impairs post-operative olfactory memory but preserves olfactory function. AB - BACKGROUND AND OBJECTIVE: The effect of anaesthesia on olfaction has not been systematically studied. Our aim is to compare the effects of general and regional anaesthesia on olfactory acuity and memory in the immediate post-operative period. METHODS: Sixty adult patients with the American Society of Anesthesiologists I and II status scheduled for elective minor surgery were included. Exclusion criteria were smoking, alcoholism, psychiatric disease and recent or past airway infection with resulting hyposmia. Patients were randomly allocated to one of three groups (in the analysis, n = 16 in each group): epidural anaesthesia (group E), general anaesthesia with propofol (group P) and general anaesthesia with sevoflurane (group S) of 40-120 min duration. The evening before surgery, at 0.5 and at 3 h post-operatively olfactory acuity and memory were tested, along with blood sampling to measure plasma melatonin and oxytocin levels. Olfactory acuity was tested with successive dilutions of n-butyl alcohol, and olfactory memory (interpretation of odours) with the University of Pennsylvania Smell Identification Test. RESULTS: Patient characteristics did not differ between groups. Olfactory acuity was intact in all patients, before and after anaesthesia. Olfactory memory deteriorated in group S compared to groups P and E at both post-operative time-points. This was accompanied by a significant post-operative reduction of plasma melatonin levels in group S. Oxytocin levels remained constant in all groups. CONCLUSION: Our results manifest a specific effect of sevoflurane on olfactory memory, not observed with neuraxial or total intravenous anaesthesia. The misinterpretation of odours in the immediate post operative period by sevoflurane could be mediated by the decreased levels of melatonin. PMID- 20962653 TI - Anaesthetic management of a patient with limb-girdle muscular dystrophy for laparoscopic cholecystectomy. PMID- 20962654 TI - Sevoflurane in anaesthetic management of a patient with methylmalonic acidaemia. PMID- 20962655 TI - Tranexamic acid partially improves platelet function in patients treated with dual antiplatelet therapy. AB - BACKGROUND: Although the impact of tranexamic acid on platelet function remains controversial, tranexamic acid is part of clinical algorithms for the management of platelet dysfunction. The goal of our prospective, observational study was to examine the effects of tranexamic acid on platelet function in patients treated with dual antiplatelet therapy compared to those who ceased antiplatelet therapy for at least 7 days. METHODS: Forty patients scheduled for cardiac surgery were enrolled in this study. Group 1 consisted of 20 patients who ceased antiplatelet therapy with aspirin and clopidogrel at least 7 days before surgery. Group 2 consisted of 20 patients who were treated with aspirin and clopidogrel until the day before surgery. Using the Multiplate device (Dynabyte, Munich, Germany), multiple electrode aggregometry (MEA) was performed following platelet stimulation with thrombin receptor activating peptide-6 (TRAP-6), arachidonic acid or ADP on blood collected 20 min before and after application of 2 g tranexamic acid. RESULTS: Compared with group 1, platelet aggregation was statistically significantly reduced in ASPItest and ADPtest in group 2, whereas there were no significant differences in the TRAPtest. In group 1, platelet aggregation did not differ significantly before and after tranexamic acid treatment. In contrast, in group 2, we observed a significant increase in arachidonic acid-induced [295 (280/470) arbitrary aggregation units * min [AU*min; median (25th/75th percentile) vs. 214 (83/409) AU*min, P = 0.01] and ADP induced platelet aggregation [560 AU*min (400/760 AU*min) vs. 470 AU*min (282/550 AU*min), P = 0.013], whereas platelet aggregation following stimulation with TRAP 6 did not change significantly [980 (877/1009) AU*min, median (25th/75th percentile) after tranexamic acid vs. 867 (835/961) AU*min before tranexamic acid, P = 0.464]. CONCLUSION: The results of this study indicate that tranexamic acid potentially corrects defects in arachidonic acid-induced and ADP-induced platelet aggregation imposed by dual antiplatelet therapy. However, platelet aggregation in response to arachidonic acid or ADP in the blood of patients who have not received aspirin and clopidogrel is unaffected by tranexamic acid. These results support the use of tranexamic acid to partially reverse platelet aggregation dysfunction due to antiplatelet therapy. PMID- 20962656 TI - Transcutaneous electrical nerve stimulation on ST36 and SP6 acupoints prevents hyperglycaemic response during anaesthesia: a randomised controlled trial. AB - BACKGROUND AND OBJECTIVE: Hyperglycaemia is a common result of stress signals caused by pain and surgical procedure. Volatile anaesthetics also directly manipulate glucose homeostasis by affecting pancreatic insulin release and induce hyperglycaemia without surgical stress. We determined the preoperative application of transcutaneous electrical nerve stimulation (TENS) to the Chinese acupoints ST36 (Zusanli) and SP6 (Sanyinjiao) as a complementary therapy for controlling plasma glucose and improving insulin resistance during anaesthesia. METHODS: We designed a single-blind, randomised controlled clinical study of female patients, scheduled for elective hysterectomy. The 52 patients consented to enrolment and were assigned to receive either TENS (n = 26) on bilateral ST36 and SP6 acupoints with continuous mode at a frequency of 15 Hz and the intensity of 10 mA synchronously for 30 min or non-stimulation (placebo group, n = 26) preoperatively. Haemodynamics, blood glucose and plasma insulin were measured during general anaesthesia. RESULTS: At baseline, there was no significant difference between the TENS group and the placebo group in plasma glucose and insulin levels as well as homeostasis model assessment (HOMA) index. In the placebo group, plasma glucose, insulin and HOMA index increased during induction of general anaesthesia, surgical incision, and throughout the operation. Plasma glucose and insulin levels as well as HOMA index were significantly lower in the TENS group as compared to the placebo group at different time points after discontinuation of TENS application. These results indicate the positive effect of prevention of hyperglycaemia and the increased sensitivity of plasma insulin in the TENS group. CONCLUSION: We found TENS at bilateral ST36 and SP6 acupoints to be an alternative means of managing the plasma glucose level and improving insulin resistance perioperatively. PMID- 20962657 TI - Efficacy of the Airway Scope on tracheal intubation in the lateral position: comparison with the Macintosh laryngoscope. AB - BACKGROUND: The Airway Scope (AWS) may become a rescue airway device to secure the airway in the lateral position. We evaluated the efficacy of the AWS on tracheal intubation in patients in this position in comparison with the Macintosh laryngoscope. METHODS: Seventy patients scheduled for surgery in the lateral position under general anaesthesia with tracheal intubation were randomised into two groups: intubation with the Macintosh laryngoscope and that with the AWS. After general anaesthesia and muscle relaxation, experienced anaesthetists performed laryngoscopy and intubation using either laryngoscope in the right or left lateral position. Laryngoscopic view, intubation time, intubation difficulty scale score and success rate of tracheal intubation (within 60 s) were recorded and compared between intubation with the Macintosh laryngoscope and that with the AWS. RESULTS: In the lateral position, the laryngoscopic view with the AWS was significantly better than that with the Macintosh laryngoscope (P < 0.01). Tracheal intubation was successful at the first attempt with the AWS in all patients and with the Macintosh laryngoscope in 85.3% of patients (P < 0.05). The median times to intubation with the AWS and with the Macintosh laryngoscope were 14 (interquartile range, 9-19) s and 29 (20-31) s, respectively (P < 0.01). Also, the AWS significantly reduced the intubation difficulty scale score compared with the Macintosh laryngoscope (P < 0.01). CONCLUSION: In the situation in which securing the airway in the lateral position is required, the AWS is more effective than the Macintosh laryngoscope. PMID- 20962658 TI - Post-operative nausea and vomiting prevention with perphenazine: long overdue. PMID- 20962659 TI - The use of sugammadex in a patient with myotonic dystrophy. PMID- 20962660 TI - Esophago-gastro-duodenoscopy is not indicated in patients with positive immunochemical test and nonexplanatory colonoscopy. AB - OBJECTIVES: Patients with positive fecal occult blood test and unrevealing colonoscopy are often advised to undergo esophago-gastro-duodenoscopy (EGD) to exclude a bleeding source in the upper gastrointestinal tract. In this study, we evaluated EGD findings in patients with positive immunochemical fecal occult blood test (I-FOBT) not explained by colonoscopy. METHODS: Out of 1221 consecutive patients having total colonoscopy after preparing I-FOBT (OC-MICRO, with threshold of 75 or 100 ngHb/ml), we included only patients without colorectal cancer or advanced adenomatous polyp on colonoscopy, who also underwent EGD within 4 months of the fecal blood testing. Findings on EGD were classified as those lesions which are likely or unlikely to bleed. RESULTS: EGD was performed in 160 patients after a negative colonoscopy. The procedure was performed 1.6 +/- 1.4 months after the I-FOBT. Lesion with a bleeding potential was found in 24 patients (15%). In three (12.5%) and two (8.3%) of these patients I-FOBT was positive at the 75 and 100 ngHb/ml threshold, respectively. In 136 patients EGD was normal, and I-FOBT was similarly positive in 16 (11.7%) and 13 patients (9.5%), respectively. The mean fecal hemoglobin was also similar between the groups. CONCLUSION: Immunological FOBT positivity was not correlated with the finding of lesions, which are likely to bleed on EGD. Thus, EGD is probably not indicated in patients with positive I-FOBT and unrevealing colonoscopy. PMID- 20962661 TI - Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. AB - Laboratory evaluation of patients with developmental delay/intellectual disability, congenital anomalies, and dysmorphic features has changed significantly in the last several years with the introduction of microarray technologies. Using these techniques, a patient's genome can be examined for gains or losses of genetic material too small to be detected by standard G-banded chromosome studies. This increased resolution of microarray technology over conventional cytogenetic analysis allows for identification of chromosomal imbalances with greater precision, accuracy, and technical sensitivity. A variety of array-based platforms are now available for use in clinical practice, and utilization strategies are evolving. Thus, a review of the utility and limitations of these techniques and recommendations regarding present and future application in the clinical setting are presented in this study. PMID- 20962662 TI - Effects of enzyme replacement therapy in Fabry disease--a comprehensive review of the medical literature. AB - Enzyme replacement therapy with alpha-galactosidase A has been used to treat Fabry disease since 2001. This article reviews the published evidence for clinical efficacy of the two available enzyme preparations. We focused on heart, kidney, and nervous system manifestations, which impact both quality of life and overall prognosis. A literature search was undertaken to identify prospective open or randomized controlled trials of enzyme replacement therapy in patients with Fabry disease published since 2001. To date, no definitive conclusion can be drawn from studies that have directly compared therapeutic responses between the two commercially available enzyme preparations. Significant clinical benefits of enzyme replacement therapy have been demonstrated, mainly in patients at an early phase of the disease, with beneficial effects on heart, kidneys, pain, and quality of life in treated patients. Incidence of antibodies against agalsidase alfa and agalsidase beta observed during major clinical studies suggests a greater antigenic response to agalsidase beta. Further studies are required to confirm the long-term clinical benefits of enzyme replacement therapy. More studies with female patients are needed as are investigations of early initiation of enzyme replacement therapy to determine the optimal time to start treatment to prevent irreversible organ damage. The value of adjunctive and supportive therapies should also be rigorously analyzed. PMID- 20962663 TI - Antidepressants for major depressive disorder in patients with a co-morbid axis III disorder: a meta-analysis of patient characteristics and placebo response rates in randomized controlled trials. AB - The objective of this study is to assess whether the antidepressants are effective in treating major depressive disorder (MDD) in patients with a co morbid axis-III disorder, and to compare the relative efficacy (vs. placebo) of antidepressants between these patients and those enrolled in general MDD trials. Medline/Pubmed publication databases were searched. We selected for randomized, double-blind, placebo-controlled trials of antidepressants for MDD, whether conducted in a general population, or in populations with an axis-III disorder. Antidepressants were more effective than placebo in patients with axis-III disorders overall [risk ratio for response (RR)=1.42, P<0.0001], as well as specifically for post-stroke (RR=1.43, P=0.04), human-immunodeficiency virus positive or acquired immunodeficiency syndrome (RR=1.66, P=0.005), but not cancer patients (RR=1.26, P=0.19). There was a trend for higher placebo response rates in studies, which did (41.2%) versus those which did not (37.7%) select for axis III disorders (P=0.06), and significantly higher antidepressant response rates in studies which did (57.4%) versus those which did not (53.5%) select for axis-III disorders (P=0.01). Antidepressants are effective for MDD in patients who present with co-morbid axis-III disorders and as effective (vs. placebo) in this population as they are in the general MDD population. Higher general response rates observed in the co-morbid MDD population are intriguing, and require replication. PMID- 20962664 TI - Head-to-head comparison of early vessel healing by optical coherence tomography after implantation of different stents in the same patient. AB - OBJECTIVES: Strut coverage represents the most powerful morphometric predictor of stent thrombosis and the best surrogate indicator of endothelization. The aim of this study was to get new insights on temporal patterns of vessel healing after stenting with different types of stent. METHODS: Optical coherence tomography (OCT) was used to investigate the early strut coverage of lesions treated with CATANIA (CAT) stent, drug-eluting stent (DES) or cobalt-chromium bare metal stent (BMS). Two cohorts of 10 and 24 patients underwent OCT follow-up at 7-10 and 28 32 days after stenting, respectively. In each cohort, patients were randomly assigned to receive a CAT stent in one lesion and a BMS or a DES in a separate lesion. RESULTS: A total of 7975 and 8406 struts were analyzed for the comparisons of CAT stent vs. DES and CAT stent vs. BMS at 7-10 days, respectively. A total of 21 123 and 25 069 struts were analyzed for the comparisons of CAT stent vs. DES and CAT stent vs. BMS at 28-32 days, respectively. At 7-10 days, the CAT stent showed higher coverage rates compared with DES (90.0 vs. 85.9%, P < 0.0001) and BMS (90.2 vs. 83.6%, P < 0.0001). Similarly, at 28-32 days, the coverage rate was higher with CAT stent compared with DES (97.7 vs. 90.5%, P < 0.0001) and BMS (97.2 vs. 96.5%, P < 0.0001). CONCLUSION: The CAT stent yields quicker and more complete strut coverage than DES and BMS in the early phases of vessel healing following stent implantation. PMID- 20962665 TI - Preinfarction angina entailing precordial ST segment depression with positive T wave. PMID- 20962666 TI - Cardiovascular and noncardiovascular comorbidities in patients with chronic heart failure. AB - A broad spectrum of concomitant disorders may complicate heart failure adding further morbidity and mortality risk. Comorbidities may be subdivided into cardiovascular and noncardiovascular. The first group includes hypertension, coronary artery disease, peripheral artery disease, cerebrovascular disease, arrhythmias and valvular heart disease. Noncardiovascular comorbidities include respiratory, endocrine, metabolic, nutritional, renal, hematopoietic, neurological as well as musculoskeletal conditions. In recent years, advances in the treatment of heart failure have not been attended by important changes in management of its comorbidities. They now seem to be major causes of the poor prognosis of heart failure patients. In this review we provide an updated summary of the epidemiological, pathophysiological and clinical characteristics of comorbidities as well as their potential impact for heart failure treatment. PMID- 20962668 TI - Laparoscopic liver resection for hepatic adenoma in pregnancy. AB - INTRODUCTION: Liver cell adenomas (LCA) can present during pregnancy with abdominal pain and bleeding. Assessment and management at this time are complicated by concerns over fetal well-being. METHODS: We reviewed cases from our own institution, including the only laparoscopic liver resection reported in pregnancy, and systematically reviewed the literature to identify successful management strategies for this clinical dilemma. RESULTS: Two cases of surgery for bleeding liver adenoma were identified in our own institution. One case was managed with an elective laparoscopic segmental resection at 16 weeks and 1 with open surgery and successful fetal delivery at 32 weeks gestation. In the second case hepatic rupture of a 3.5-cm lesion was precipitated by diagnostic biopsy. In the world literature, spontaneous rupture of an LCA during pregnancy has been reported in 19 cases and is associated with maternal mortality and fetal loss approaching 50%. CONCLUSIONS: We advocate an aggressive approach to management of LCA in pregnancy owing to the high mortality associated with rupture. Biopsy of LCA in pregnancy is unsafe and can be complicated by rupture. Hence, patients presenting de novo with clinical or radiologic signs of bleeding or large (>5 cm) undiagnosed lesions should be offered laparoscopic resection if feasible. PMID- 20962667 TI - The role of cytology and HPV typing as a screening tool in patients with intraanal warts. AB - BACKGROUND AND AIM: Given that anorectal human papillomavirus (HPV) infection has been related to anal intraepithelial neoplasia (AIN) and rectal cancer, we conducted this study to evaluate the role of cytology of anal smears in the diagnosis of intraanal disease and related AIN and to correlate it to HPV genotypes. METHOD: A total of 72 patients (58 males and 14 females) with perianal warts underwent anoscopy with biopsies and anal cytologic examination. Cytology was carried out for the identification of any dysplasia according to the Bethesda system. All specimens were examined with polymerase chain reaction (PCR) for HPV DNA identification. Exclusion criteria included immunosuppression and high-grade squamous intraepitheliel lesion (HGSIL) or SCC in anal specimens. RESULTS: Seven patients were excluded from the study. Intraanal warts were detected with anoscopy in 57 out of 65 patients, whereas histology showed HPV infection in 56 out of 65 patients and cytology was positive in 52 out of 65 low-grade squamous intraepitheliel lesion (LGSIL) patients. In 43 out of 52 positive patients, simple HPV infection was detected whereas in 9 out of 52 positive patients AIN I. HPV DNA was detected in 51 out of 65 patients, whereas 3 specimens were characterized as invalids. In the majority, HPV 6 could be identified (39/48, 81%), whereas HPV 16 was detected in 4 patients (4/48, 8.3%). One fourth of the positive patients had been infected with more than 1 HPV types (13/48, 27%). Cytology presented a sensitivity 87.5% and specificity 67% in comparison with the histology. CONCLUSIONS: Cytology is highly sensitive in the diagnosis of intraanal warts comparable with histopathology. The combination of the 3 examinations (anoscopy, cytology, and PCR HPV typing) improves diagnostic accuracy and offers a global picture of the anorectal HPV disease. PMID- 20962669 TI - Clinical profile of calcific and noncalcific chronic pancreatitis in north India. AB - GOALS: To compare the clinical profile of calcific and noncalcific chronic pancreatitis (CP) in north India. BACKGROUND: The profile of calcific CP has not been adequately studied. STUDY: Detailed demographic data were recorded; hematologic, biochemical, and radiologic investigations were carried out on 225 patients with CP. The patients were divided into calcific and noncalcific groups based on the presence of pancreatic calcification, which was detected on computed tomography. RESULTS: Calcific CP was reported in 46.7% of the patients and noncalcific CP in 53.3%. The mean age, duration of symptoms before presentation, sex ratio, body mass index, and frequency of various symptoms and complications including abdominal pain, ascites, pleural effusion, and segmental portal hypertension was not statistically different between the 2 groups. However, pseudocysts occurred more frequently in noncalcific CP, whereas jaundice because of bile duct stricture, diabetes mellitus, and steatorrhea occurred more frequently in patients with calcific CP (P<0.05). On comparing calcific and noncalcific alcoholic pancreatitis, only steatorrhea was reported more frequently in patients with calcific alcoholic CP. However, pseudocysts and segmental portal hypertension occurred more frequently in noncalcific idiopathic CP, whereas diabetes mellitus occurred more frequently in patients with calcific idiopathic CP (P<0.05). On comparing calcific alcoholic CP with calcific idiopathic CP, we found significantly lower mean age in patients with idiopathic CP and a higher frequency of male patients and pseudocysts in alcoholic CP (P<0.05). CONCLUSION: Calcific CP has a higher frequency of bile duct stricture, diabetes mellitus, and steatorrhea, whereas noncalcific CP has higher frequency of pseudocysts and segmental portal hypertension. PMID- 20962670 TI - Drug-induced QT prolongation in cirrhotic patients with transjugular intrahepatic portosystemic shunt. AB - GOALS AND BACKGROUND: Nearly 40% of cytochrome P450 3A (CYP3A) activity is located in the small intestine. An earlier study has shown that cirrhotics with transjugular intrahepatic portosystemic shunts (TIPS) have diminished intestinal CYP3A activity. We hypothesized that oral CYP3A substrates known to prolong QT interval may cause further prolongation of the QT interval in cirrhotic patients with TIPS. STUDY: A total of 23 patients (9 healthy controls, 6 cirrhotics without and 8 cirrhotics with TIPS) participated in a study that tested this hypothesis using erythromycin as the probe drug. Participants with cirrhosis with and without TIPS were matched for age, sex, race, BMI and etiology of liver disease. Serial electrocardiograms were obtained at baseline, after single dose of erythromycin 500 milligrams, and after 7 days of erythromycin (500 milligrams orally twice daily). QT intervals were measured in 3 consecutive beats in 3 leads and corrected QT intervals (QTc) were obtained using various correction formulae. The maximal QTc change (DeltaQTc Max) after single and multiple dose administration was the primary outcome. RESULTS: At baseline, the QTc intervals (mean+/-S.E) in cirrhotics with TIPS (418+/-6 msec) and cirrhosis (431+/-6 msec) were significantly higher compared with controls (388+/-9 msec, P=0.021). After a single dose of erythromycin, there was no significant difference among the 3 groups in DeltaQTc Max (P=0.7). However, after a 7 day course, cirrhotics with TIPS developed significantly greater DeltaQTc Max (179.5+/-67.8 msec) compared with cirrhotics (31.2+/-9.5 msec) and healthy controls (38.3+/-3.3 msec) (P=0.03). CONCLUSION: This study suggests that patients with TIPS are potentially at increased risk for abnormal QT prolongation when exposed to oral CYP 3A substrates with QT prolonging effect. PMID- 20962671 TI - Analysis of survival in very early hepatocellular carcinoma after resection. AB - GOALS, BACKGROUND: The Barcelona-Clinic-Liver-Cancer staging system recommended liver resection only for patients with "very early stage HCC." Liver transplantation was suggested for patients with "early stage HCC" without associated diseases when liver transplantation is always associated with organ shortage. We hypothesized that patients with early hepatocellular carcinoma (HCC) might have comparable survival rate as that with the very early HCC after the surgical treatment if they were spared from early recurrence (ER) defined as tumor recurrence within 1 year after the curative resection. The aim of this study was to validate this hypothesis and to identify preoperative risk factors for ER in early HCC patients after the surgical resection. METHOD: The medical records of 194 patients, who underwent surgical resection of HCC, were retrospectively reviewed. One hundred eighty-two patients with either very early or early HCC were included in the final analysis. RESULTS: The overall survival (OS) rate of very early HCC was significantly longer than that of early HCC after the surgery. However, if the patients with ER were removed, there was no statistically significant difference in OS rate between very early and early HCC where the 3 years OS rates were 91.3 and 86.1%, respectively (P=0.451). Cox proportional hazard model showed that HCC nodule with hyperattenuation in arterial phase, and which lack encapsulation had a risk of ER. CONCLUSION: Early HCC without hyperattenuation on arterial phase and with tumor encapsulation might be expected to have comparable outcome with very early HCC after the surgical resection. PMID- 20962673 TI - Establishment, characterization, and drug sensitivity of a new Ewing sarcoma cell line (SS-ES-1). AB - Ewing sarcoma (ES) is one of the most malignant tumors in children and young adults. We present here a new ES cell line, SS-ES-1, established from the left thoracic tumor of a 16-year-old female patient. The SS-ES-1 cells retained genotype, morphology, and growth rate for over 150 passages. Immunocytochemical staining showed the strong immunoreactivity for cytokeratin, epithelial membrane antigen, neurofilament, CD99, P53, Ki-67, platelet-derived growth factor receptor beta, estrogen receptor-alpha (ER-alpha), and Bcl-2, but no reactivity for glial fibrillary acidic protein, epidermal growth factor receptor, and HER-2/neu. The presence of the type 1 EWS/FLI-1 fusion transcripts was confirmed by reverse transcriptase-polymerase chain reaction. On the basis of the MTT assay results, GW2974, a dual inhibitor of epidermal growth factor receptor and HER-2/neu, exhibited only a weak cytotoxic response in SS-ES-1 cells. In contrast, tyrphostin A9, a specific inhibitor of platelet-derived growth factor receptor, had a high cytotoxic effect against these cells. Surprisingly, it was found that SS-ES-1 cells displayed a high sensitivity to 4OH-tamoxifen. In conclusion, the SS-ES-1 cell line shows unique cellular properties, which makes it a useful model for studying various aspects of the biology of ES. In addition, the results suggest that ER can be a good therapeutic target for ER + ES. PMID- 20962674 TI - Treatment of Gorham-Stout disease with zoledronic acid and interferon-alpha: a case report and literature review. AB - Gorham-Stout disease is a rare disease characterized by osteolysis, angiomatosis, and soft-tissue swelling. It is a diagnosis of exclusion and has an unknown etiology. Chylothorax is a common complication of the disease that is associated with a high mortality rate. There is no standard of treatment. We report a case of a 16-year-old female with Gorham-Stout disease and recurrent pleural effusions who was successfully treated with concurrent zoledronic acid and peg-interferon alpha-2b. PMID- 20962675 TI - Intrathecal liposomal cytarabine in relapsed or refractory infant and pediatric leukemias: the Children's Hospital of Philadelphia experience and review of the literature. AB - Intrathecal chemotherapy is integral to curing childhood leukemia; however, bioavailability is limited by the blood-brain barrier. Recently FDA-approved, intrathecal liposomal cytarabine (ITlipAC) increases drug concentration over time with fewer invasive procedures. We present a series of 4 children, including 2 infants, with relapsed central nervous system leukemia who went into remission using ITlipAC, with a review of the literature reporting ITlipAC use in children with relapsed leukemia. Drug-attributable side effects were observed more frequently in children with preexisting neurologic conditions and with adult dosing. Combined with other pediatric reports, our experience supports the efficacy of ITlipAC in pediatric and infant leukemic meningitis. PMID- 20962676 TI - Nutritional status at diagnosis in children with cancer I. An assessment by dietary recall--compared with body mass index and body composition measured by dual energy X-ray absorptiometry. AB - The nutritional status of children with cancer is clinically important. In an effort to separate the influences of disease and treatment, we studied children at the time of diagnosis. A total of 99 children underwent assessment by 24 hours dietary recall, measurement of body mass index (BMI), and analysis of body composition by dual energy x-ray absorptiometry (DXA scan). The group averages for calorie intake and BMI were close to the median population norms but ranged widely among individuals. As a group the study participants exceeded the Dietary Reference Intake for protein. Nine children (9%) had a BMI 7%. Women gaining >7% FFM had greater increases in total IGF-I, maintained bioavailable IGF I concentrations and experienced greater decreases in IGFBP-2 and increases in IGFBP-6 than those women gaining <7% FFM. CONCLUSIONS: Circulating bioavailable IGF-I has a moderate association with physical activity-induced increases in FFM accretion in young, healthy women, and this association is greater than observed for total IGF-I. PMID- 20962686 TI - Does controlling for biological maturity improve physical activity tracking? AB - Tracking of physical activity through childhood and adolescence tends to be low. Variation in the timing of biological maturation within youth of the same chronological age (CA) might affect participation in physical activity and may partially explain the low tracking. PURPOSE: To examine the stability of physical activity over time from childhood to late adolescence when aligned on CA and biological age (BA). METHODS: A total of 91 males and 96 females aged 8-15 yr from the Saskatchewan Pediatric Bone Mineral Accrual Study (PBMAS) were assessed annually for 8 yr. BA was calculated as years from age at peak height velocity. Physical activity was assessed using the Physical Activity Questionnaire for Children/Adolescents. Tracking was analyzed using intraclass correlations for both CA and BA (2-yr groupings). To be included in the analysis, an individual required a measure at both time points within an interval; however, not all individuals were present at all tracking intervals. RESULTS: Physical activity tracking by CA 2-yr intervals were, in general, moderate in males (r=0.42-0.59) and females (r=0.43-0.44). However, the 9- to 11-yr CA interval was low and nonsignificant (r=0.23-0.30). Likewise, tracking of physical activity by BA 2-yr intervals was moderate to high in males (r=0.44-0.60) and females (r=0.39-0.62). CONCLUSIONS: Accounting for differences in the timing of biological maturity had little effect on tracking physical activity. However, point estimates for tracking are higher in early adolescence in males and to a greater extent in females when aligned by BA versus CA. This suggests that maturity may be more important in physical activity participation in females than males. PMID- 20962687 TI - Temporal ordering of motivational quality and athlete burnout in elite sport. AB - INTRODUCTION: Using self-determination theory as the theoretical framework, we conducted a longitudinal investigation of the relationships between motivation and athlete burnout. We tested four hypotheses: H0: low self-determination (SD) does not precede burnout, and burnout does not precede low SD; H1: low SD precedes burnout; H2: burnout precedes low SD; and H3: burnout and motivation have a reciprocal relationship. METHODS: We used a two-wave design, with the follow-up assessment 4 months after baseline. Elite New Zealand athletes (n=119, mean age=24.74 yr (standard deviation=8.54 yr); 57.14% of whom were females) completed the Athlete Burnout Questionnaire and the Behavioral Regulation in Sport Questionnaire. Structural equation modeling of cross-lagged panel models was used to test the hypotheses. RESULTS: The relationship between motivation and burnout varied depending on the type of motivation assessed. Analyses related to overall levels of self-determined motivation, amotivation, and controlled forms of extrinsic motivation provided support for H1: low SD precedes burnout. When compared with external regulation, introjected regulation seemed to be a clearer antecedent of athlete burnout. Analyses related to the self-determined forms of extrinsic motivation provided support for H2: burnout precedes low SD. The only analyses in which the null hypothesis could not be rejected were those relating to intrinsic motivation. Finally, there was little support for a reciprocal effects model. CONCLUSIONS: Low levels of self-determination may lead to increases in athlete burnout, whereas athlete burnout may precede decrements in self-determined extrinsic motivation. Particular efforts could be made to help support the basic psychological needs of athletes with controlled forms of motivation, thereby leading to an internalization of motivation and decreased risk of burnout. PMID- 20962688 TI - Effects of exercise on bone mass in young women with anorexia nervosa. AB - PURPOSE: The response of bone to exercise in women with anorexia nervosa (AN) is unclear. We investigated the associations between bone mineral density (BMD) and exercise performed while ill and while recovered in women with a history of AN. METHODS: A cross-sectional study was conducted with 141 women with AN (85 ill; 56 recovered), aged 17-40 yr. BMD at the lumbar spine (LS), femoral neck (FN), and total body (TB) was measured by dual-energy x-ray absorptiometry. Life History Calendar and Minnesota Leisure Time Physical Activity interviews were used to collect lifetime illness and exercise histories (amount and bone loading type). Average hours per week of each of moderate (MOD) and high (HI) bone loading exercise were determined for three illness phases: "before ill," "while ill," and "while recovered." Participants were categorized into four exercise groups for each phase: MOD-ONLY, HI-ONLY, BOTH, and NEITHER (reference group). Weight adjusted BMD z-scores were compared in the exercise groups by multivariable linear regression, adjusting for illness duration and severity, and exercise during the other illness phases. RESULTS: In ill participants, MOD-ONLY "while ill" had lower BMD at LS (beta = -0.69, 95% confidence interval (CI) = -1.02 to 0.05) and TB (beta = -0.73, 95% CI = -1.31 to -0.15) than the NEITHER group. In recovered participants, HI-ONLY "while recovered" had higher BMD at FN (beta = 0.95, 95% CI = 0.15-1.75) and TB (beta = 0.79, 95% CI = 0.07-1.51) than the NEITHER group. CONCLUSIONS: The effect of exercise on bone in AN patients is dependent on both the type of mechanical loading and the phase of illness during which it was performed. Excessive moderate loading exercise while ill may put patients at higher risk of low bone mass, but high bone loading activities may provoke bone accrual during recovery. PMID- 20962689 TI - Effects of body mass index and tilt angle on output of two wearable activity monitors. AB - Accelerometer-based activity monitors have been used to provide objective measures of physical activity and energy expenditure (EE) in free-living individuals. However, output from these devices has not been compared among normal, overweight, and obese individuals. PURPOSE: The purpose of this study was to examine the effects of body mass index (BMI) and device tilt angle on activity counts recorded by wearable monitors in a controlled laboratory setting. A secondary aim was to examine the effects of these variables on estimated EE. METHODS: Seventy-one healthy adults wore an Actical and an ActiGraph GT1M on the right and left hip, respectively, while walking at 40, 67, and 94 m.min. EE was measured by indirect calorimetry and compared with estimated values using published equations. Three-way repeated-measures ANOVA were used to examine differences in outcome variables (activity counts and EE) between speeds, BMI, and tilt angle for each device. RESULTS: No significant differences in activity counts were observed among BMI categories for either the Actical or ActiGraph (P>0.05). For the Actical, however, among those with an absolute tilt angle <10 degrees , the obese group recorded higher activity counts than the normal weight group (P=0.01). Using the Heil two-regression model, the Actical overestimated EE by up to 35% at the intermediate speed and up to 12% at the fastest speed (P<0.001). The Freedson METs regression equation yielded closer estimates of EE than the Freedson kilocalorie regression equation. CONCLUSIONS: Our findings indicate that the Actical has limitations when comparing individuals with varying BMI and tilt angles in a controlled laboratory environment. The ActiGraph seems to be a more suitable device for making these comparisons. PMID- 20962690 TI - Changes in running kinematics, kinetics, and spring-mass behavior over a 24-h run. AB - PURPOSE: This study investigated the changes in running mechanics and spring-mass behavior over a 24-h treadmill run (24TR). METHODS: Kinematics, kinetics, and spring-mass characteristics of the running step were assessed in 10 experienced ultralong-distance runners before, every 2 h, and after a 24TR using an instrumented treadmill dynamometer. These measurements were performed at 10 km.h, and mechanical parameters were sampled at 1000 Hz for 10 consecutive steps. Contact and aerial times were determined from ground reaction force (GRF) signals and used to compute step frequency. Maximal GRF, loading rate, downward displacement of the center of mass, and leg length change during the support phase were determined and used to compute both vertical and leg stiffness. RESULTS: Subjects' running pattern and spring-mass behavior significantly changed over the 24TR with a 4.9% higher step frequency on average (because of a significantly 4.5% shorter contact time), a lower maximal GRF (by 4.4% on average), a 13.0% lower leg length change during contact, and an increase in both leg and vertical stiffness (+9.9% and +8.6% on average, respectively). Most of these changes were significant from the early phase of the 24TR (fourth to sixth hour of running) and could be speculated as contributing to an overall limitation of the potentially harmful consequences of such a long-duration run on subjects' musculoskeletal system. CONCLUSIONS: During a 24TR, the changes in running mechanics and spring-mass behavior show a clear shift toward a higher oscillating frequency and stiffness, along with lower GRF and leg length change (hence a reduced overall eccentric load) during the support phase of running. PMID- 20962691 TI - Physiology, power output, and racing strategy of a Race Across America finisher. AB - The Race Across America, a 4800-km nonstop cycle race, is one of the most demanding endurance sports events. We display the racing strategy, power output, HR, hormonal levels, and inflammatory markers of an athlete before and during the race, which he completed in 10 d 23 h.The athlete showed physiological characteristics of a well-trained (nonelite) cyclist (VO2peak=63 mL.min.kg, heart volume=11.3 mL.kg). The race was mainly performed at low intensities (mean +/- SD: power output=141 +/- 76 W, HR=117 +/- 14 bpm). During the race, testosterone levels dropped initially by 30-40% and returned to baseline toward the end. Cortisol remained elevated throughout (+75%-90% compared with baseline). Markers of inflammation (C-reactive protein), dehydration, and protein catabolism (albumin) were not affected. The athlete used a race strategy with regular sleeping breaks (total rest=91 h, 45 h of sleep).Contrasting conventional racing strategies for the Race Across America, which aim at minimizing sleep and maximizing ride time, our case demonstrates that by emphasizing regular recovery and sleep, such alternative strategy might lead an equally successful race result. PMID- 20962692 TI - Energetics of best performances in elite kayakers and canoeists. AB - PURPOSE: The objectives of this study were 1) to validate a new test to determine maximal oxygen uptake (VO2max) in kayakers, 2) to calculate the energy cost (Ck) of high-level kayakers and canoeists at submaximal and race speeds, and 3) to correlate individual best performances achieved in practice with those theoretically calculated. These were obtained from the individual relationships Er=f(t) and Emax=f(t), where Er is the metabolic power required to cover the distance in question and Emax is the maximal metabolic power. The time yielding Er=Emax was assumed to yield the best performance time. METHODS: Seventy-four male and female athletes from the Italian national canoe kayak teams participated in this study. A portable metabolic unit was used to determine VO2max during an incremental exercise test on the boat. Peak oxygen uptake (VO2peak) was also measured in a 2-min test at 100% race speed over 1000 m. Individual Ck values were evaluated in tests of 6, 5, and 2 min at average speeds of 84%, 90%, and 100% of the 1000-m race speed. RESULTS: The VO2max values determined during the incremental or the 2-min test were not significantly different (4613 +/- 619 vs 4582 +/- 598 mL.min). The Ck (J.kg.m) of male kayakers increased from approximately 4 (at 3.23 m.s) to approximately 6 (at 4.63 m.s) and was approximately 30.7% smaller than that of male canoeists (P<0.001). Over the same speed range, male kayakers were approximately 14.2% more economical than female kayakers (P=0.044). CONCLUSIONS: Individual theoretical best times and speeds were essentially equal to those measured during actual competitions. PMID- 20962693 TI - Self-reported and objectively measured activity related to biomarkers using NHANES. AB - PURPOSE: The purpose of this study was to examine the independent associations of self-reported and objectively measured (using accelerometers) moderate to vigorous physical activity (MVPA) with physiological and anthropometric biomarkers in a nationally representative sample of U.S. adults. METHODS: Data from the cross-sectional National Health and Nutrition Examination Survey 2003 2006 data were analyzed. Adults 20 yr and older (N=5797) with self-reported PA and 4 d or more of accelerometer data were included in the analyses. Pregnant or lactating women were excluded. Outcomes were blood pressure, body mass index, waist circumference, triceps and subscapular skinfolds, cholesterol, triglyceride, C-reactive protein, homocysteine, and insulin resistance and hyperinsulinemia indices. RESULTS: Objectively measured MVPA displayed stronger independent associations with the biomarkers than did self-reported MVPA, even after adjusting for sociodemographic and health factors (adjusted Wald F values=3.9-85.6, P<0.05-0.0001). Self-reported and objectively measured MVPA were independently associated with skinfold measures, HDL, and C-reactive protein when both were included in the model. CONCLUSIONS: Objectively measured MVPA displayed stronger associations with physiological and anthropometric biomarkers than self reported MVPA. However, self-reported and objectively measured MVPA appear to capture distinct aspects of PA that are independently associated with certain biomarkers. Further understanding of the distinct contributions of self-reported and objectively measured PA to health outcomes could help to better identify optimal activity level and pattern. PMID- 20962694 TI - A reverse pathway? Actual and perceived skill proficiency and physical activity. AB - PURPOSE: Motor skills are considered a prerequisite to physical activity, yet the relationship may be reciprocal and perceived sports competence might mediate associations. METHODS: In 2006/2007, 215 adolescents completed motor skill proficiency (Get Skilled Get Active), perceived sport competence (Physical Self Perception Profile) and physical activity assessments (Adolescent Physical Activity Recall Questionnaire) as part of the Physical Activity and Skills Study. Using AMOS (Version 7.0), reciprocal relationships were examined between motor skill (object control and locomotor) and moderate to vigorous physical activity (MVPA). Both models were then run in different versions to understand the role of perceived sports competence as a potential mediator. RESULTS: Mean age was 16.4 yr (SD=0.6), 51.6% (111/215) were females. A reciprocal relationship between object control and MVPA and a one-way relationship from MVPA to locomotor skill was found. When perceived sports competence was examined as a mediator, the best fitting model versions explained 16% (R=0.16) MVPA variation, and 30% object control (R=0.30), and 12% locomotor skill variation (R=0.12) (reverse relationship). Perceived sports competence partially mediates the relationship between object control proficiency and physical activity for both directions and fully mediates the relationship between physical activity and locomotor skill; but only when locomotor skill is the outcome. CONCLUSIONS: If the relationship between object control skill and physical activity is viewed as a "positive feedback loop," skill development and increasing physical activity should simultaneously be targeted in physical activity interventions. Increasing perceived sport competence should also be an intervention focus. PMID- 20962695 TI - Identifying group-sensitive physical activities: a differential item functioning analysis of NHANES data. AB - PURPOSE: The purpose of this study was to identify subgroup-sensitive physical activities (PA) using differential item functioning (DIF) analysis. METHODS: A sub-unweighted sample of 1857 (men=923 and women=934) from the 2003-2004 National Health and Nutrition Examination Survey PA questionnaire data was used for the analyses. Using the Mantel-Haenszel, the simultaneous item bias test, and the ANOVA DIF methods, 33 specific leisure-time moderate and/or vigorous PA (MVPA) items were analyzed for DIF across race/ethnicity, gender, education, income, and age groups. RESULTS: Many leisure-time MVPA items were identified as large DIF items. When participating in the same amount of leisure-time MVPA, non-Hispanic blacks were more likely to participate in basketball and dance activities than non-Hispanic whites (NHW); NHW were more likely to participated in golf and hiking than non-Hispanic blacks; Hispanics were more likely to participate in dancing, hiking, and soccer than NHW, whereas NHW were more likely to engage in bicycling, golf, swimming, and walking than Hispanics; women were more likely to participate in aerobics, dancing, stretching, and walking than men, whereas men were more likely to engage in basketball, fishing, golf, running, soccer, weightlifting, and hunting than women; educated persons were more likely to participate in jogging and treadmill exercise than less educated persons; persons with higher incomes were more likely to engage in golf than those with lower incomes; and adults (20-59 yr) were more likely to participate in basketball, dancing, jogging, running, and weightlifting than older adults (60+ yr), whereas older adults were more likely to participate in walking and golf than younger adults. CONCLUSIONS: DIF methods are able to identify subgroup-sensitive PA and thus provide useful information to help design group-sensitive, targeted interventions for disadvantaged PA subgroups. PMID- 20962696 TI - Dyspareunia is associated with decreased frequency of intercourse in the menopausal transition. AB - OBJECTIVE: The frequency of sexual intercourse declines as women enter midlife. Whereas partner availability and function probably play a role, menopausal symptoms, such as vaginal dryness, are also present. We examine the associations among vaginal dryness, dyspareunia, and frequency of sexual intercourse. METHODS: In the second year of a longitudinal study, women completed questionnaires that included menopause status and symptoms, participation in sexual activities, dyspareunia, marital status, and race. We used univariable and multivariable ordered logistic regression models to examine the associations among the frequency of sexual intercourse, vaginal dryness, use of lubrication during sex, and dyspareunia. RESULTS: In multivariable analyses of the 363 sexually active women with complete data, women reporting more frequent dyspareunia, but not vaginal dryness, also reported less frequent intercourse. Advancing menopause status was associated with lower frequency of intercourse, whereas age was not. Dyspareunia and vaginal dryness were only moderately correlated (r = 0.4). CONCLUSIONS: Women continue to participate in sexual intercourse through midlife. Women who report dyspareunia, but not vaginal dryness, report less frequent intercourse. Relief of dyspareunia should be addressed to maintain sexual functioning during midlife. PMID- 20962697 TI - Making sure: registered nurses watching over their patients. AB - BACKGROUND: Surveillance has been identified as an important patient quality and safety intervention, but the process used by registered nurses as they perform this function with their hospitalized patients on a single work shift has not been conceptualized or studied. OBJECTIVE: The purpose of this study was to generate a substantive theory of the process used by hospital registered nurses as they watch over their assigned patients during a work shift. METHODS: Classical grounded theory was used to generate the substantive theory. Fifteen registered nurses from a variety of hospital patient care settings were interviewed to determine the process they used to watch over their assigned patients during a work shift and the conditions that facilitated or hindered their abilities to watch over their patients. RESULTS: Making Sure emerged as the basic social process used by registered nurses as they watch over their assigned patients during a single work shift. Making Sure was conceptualized as a process involving six categories: (a) knowing what's going on and (b) being close set conditions for (c) watching in which the nurse is (d) not taking anything for granted. As necessary, (e) taking action occurs to achieve the outcome of this process, (f) protecting patients from harm and negative events to the extent possible. As more information about the patient is obtained through the process, this information is incorporated into the knowing what's going on category. CONCLUSIONS: The results of this study provide the theoretical basis for the process used by registered nurses as they watch over their patients on a work shift and provide insight into one of the key nursing care processes that may impact patient outcomes. Measures should be developed to operationalize the concepts of the theory and to conduct quantitative testing of the theory. PMID- 20962699 TI - Contralateral suppression of otoacoustic emissions in tinnitus patients. AB - OBJECTIVE: To compare the functioning of the medial olivocochlear efferent system between tinnitus patients and control subjects. STUDY DESIGN: Prospective, nonrandomized controlled analysis of suppression of otoacoustic emissions with contralateral acoustic stimulation. SETTING: Tertiary referral center. PATIENTS: Initial analysis of 97 tinnitus patients and 44 control subjects with click evoked otoacoustic emission measurement. If subjects had reproducible otoacoustic emissions at 80 dB SPL, suppression of otoacoustic emission with contralateral acoustic stimulation was measured with a 65-dB click stimulus. This resulted in inclusion of 44 ears of tinnitus patients and 57 ears of control subjects. INTERVENTION: Suppression of the otoacoustic emissions generated by the 65-dB click stimulus was tested using contralateral broadband noise at 70 dB SPL. Suppression was calculated in half-octave frequency bands centered at 1.0, 1.4, 2.0, 2.8, and 4.0 kHz. MAIN OUTCOME MEASURE: The amount of suppression of the OAE, calculated in half-octave frequency bands. RESULTS: Otoacoustic emission amplitudes were equal in both groups. Contralateral suppression of the signal was found in both patients and controls. The amount of suppression was equal, except for the 2.0- and 2.8-kHz frequency bands in the right ear (p value of 0.03, 0.008, respectively), for which the patients had less suppression. CONCLUSION: The suppression of otoacoustic emissions with CAS seems equally effective in tinnitus patients and healthy controls. The minor differences between both groups suggest subtle differences in the function of the medial olivocochlear efferent system. PMID- 20962698 TI - Factors explaining children's responses to intravenous needle insertions. AB - BACKGROUND: Previous research shows that numerous child, parent, and procedural variables affect children's distress responses to procedures. Cognitive behavioral interventions such as distraction are effective in reducing pain and distress for many children undergoing these procedures. OBJECTIVES: The purpose of this report was to examine child, parent, and procedural variables that explain child distress during a scheduled intravenous insertion when parents are distraction coaches for their children. METHODS: A total of 542 children, between 4 and 10 years of age, and their parents participated. Child age, gender, diagnosis, and ethnicity were measured by questions developed for this study. Standardized instruments were used to measure child experience with procedures, temperament, ability to attend, anxiety, coping style, and pain sensitivity. Questions were developed to measure parent variables, including ethnicity, gender, previous experiences, and expectations, and procedural variables, including use of topical anesthetics and difficulty of procedure. Standardized instruments were used to measure parenting style and parent anxiety, whereas a new instrument was developed to measure parent performance of distraction. Children's distress responses were measured with the Observation Scale of Behavioral Distress-Revised (behavioral), salivary cortisol (biological), Oucher Pain Scale (self-report), and parent report of child distress (parent report). Regression methods were used for data analyses. RESULTS: Variables explaining behavioral, child-report and parent-report measures include child age, typical coping response, and parent expectation of distress (p < .01). Level of parents' distraction coaching explained a significant portion of behavioral, biological, and parent-report distress measures (p < .05). Child impulsivity and special assistance at school also significantly explained child self-report of pain (p < .05). Additional variables explaining cortisol response were child's distress in the morning before clinic, diagnoses of attention deficit hyperactivity disorder or anxiety disorder, and timing of preparation for the clinic visit. DISCUSSION: The findings can be used to identify children at risk for high distress during procedures. This is the first study to find a relationship between child behavioral distress and level of parent distraction coaching. PMID- 20962700 TI - Intraoperative monitoring of active middle ear implant function in patients with normal and pathologic middle ears. AB - OBJECTIVE: To describe a technique enabling the intraoperative assessment of the mechanical coupling of active middle ear implants in patients with normal or dysfunctional middle ears. PATIENTS: Patients with sensorineural or mixed hearing loss subjected to revision surgery of an active middle ear implant. INTERVENTION: Recording of compound action potentials (CAPs) of the auditory nerve in response to stimulation via an active middle ear implant during revision surgery. MAIN OUTCOME MEASURES: CAP thresholds as a measure of mechanical coupling and system integrity. CONCLUSION: Determining CAP thresholds may be suitable for identifying a proper mechanical coupling of active middle ear implants in patients with a dysfunctional middle ear, even if the ossicular chain is disrupted. PMID- 20962701 TI - In vivo measurements of the insertion depth of cochlear implant arrays using flat panel volume computed tomography. AB - OBJECTIVE: The development of a procedure for the measurement of insertion depth angles of cochlear implant electrode arrays based on flat-panel computed tomography (FPCT) and the application of this technique to in vivo postoperative images. BACKGROUND: The knowledge of the insertion depth angle of electrode arrays is relevant for the preservation of low-frequency residual hearing and for optimizing speech coding strategies. Until now, the angular position of electrodes was derived from 2-dimensional radiographs. METHOD: In the present study, 3-dimensional (3D) radiographs provided by FPCT were used to determine the insertion depth according to angular electrode positions with higher accuracy. For this purpose, a new evaluation procedure was designed and applied to radiographs of 15 cochlear implant patients. RESULTS: In contrast to 2 dimensional radiographs, the obtained 3D images show all 3 semicircular channels and therefore allow the determination of a clear reference, which is required for precise insertion angle measurements. Furthermore, the presented FPCT radiographs visualize distinct electrodes. Despite the constant length of the implanted electrode arrays, we have found a considerable variation of measured insertion depth angles, which is consistent with published observations on the variability and the gender dependence of the size of human cochleae. CONCLUSION: FPCT provides 3D high-resolution radiographic data that enable the determination of the insertion depth angle with high accuracy and, potentially, an angle determination of individual electrodes. Therefore, this low-dose technique is especially appropriate for postoperative investigations after cochlea implantation. PMID- 20962702 TI - Histopathology of cochlear otosclerosis: implications for cochlear implantation. PMID- 20962703 TI - Conversion disorder: a missed diagnosis leading to cochlear reimplantation. AB - OBJECTIVE: To report a case of a patient presenting with presumed cochlear implant (CI) device failure that underwent revision surgery and was ultimately diagnosed with conversion disorder. STUDY DESIGN: Clinical capsule report. SETTING: Tertiary academic referral center. PATIENT: A pediatric patient with Waardenburg syndrome underwent unilateral CI at the age of 6 years for bilateral profound sensorineural hearing loss. During the following 2 years, the patient experienced subjective symptoms of device malfunction including abnormal sounds and intermittent loss of signal despite external component exchange. The patient subsequently underwent revision surgery only to have persistent intermittent complaints. Given the severity of the symptoms, the patient underwent a second reimplantation procedure. Extensive device testing by our institutional implant program and the manufacturer failed to reveal any causal device defects. INTERVENTIONS AND RESULTS: Given the ongoing but inconsistent subjective complaints and normal device testing, the patient was referred for psychiatric consultation to evaluate for a nonorganic underlying cause. The patient was subsequently diagnosed with conversion disorder and successfully managed with ongoing psychiatric counseling and close follow-up with our CI program. CONCLUSION: This represents the first report of a patient presenting with symptoms of device failure, who underwent revision surgery and was ultimately found to have conversion disorder. Although rare, conversion disorder should be considered in the differential diagnosis of patients presenting with symptoms of device malfunction and normal integrity testing particularly among those with significant psychosocial stressors or a history of psychiatric illness. Thorough device testing and in-depth psychological evaluation is required for diagnosis, and close multidisciplinary follow-up with the CI team and psychiatrist is crucial. PMID- 20962704 TI - Stapes displacement in chronic otitis media. PMID- 20962705 TI - The clinical spectrum of patients with deficiency of Signal Transducer and Activator of Transcription-1. AB - STAT-1 (Signal Transducer and Activator of Transcription-1) is a key signaling component of interferon gamma responses. We present long-term manifestations in siblings with a mutation in the STAT1 gene, which include invasive salmonellosis, recurrent severe respiratory syncytial virus pneumonitis, and hepatosplenic mycobacterial disease, and we summarize all other reported cases with STAT-1 deficiency. PMID- 20962706 TI - Sudden-onset tachypnea and confusion in a previously healthy teenager. AB - Acute intoxication with acetylsalicylic acid is a severe event commonly seen in children resulting from wide availability of this drug without prescription. Cases of self-poisoning resulting from overdose continue to occur and, although far less common, they are often severe and life-threatening. We report a 14-year old girl who presented to the emergency department with tachypnea and altered mental status as a result of acetylsalicylic acid overdose in a suicide attempt. We discuss her presentation and the pathophysiological considerations leading to the management decisions taken during her emergency department stay, highlighting the role of the clinician and therapeutic drug monitoring consultant. The use of rapid decontamination with multiple doses of charcoal, even when more than 4 hours have passed since ingestion, and the use of urinary alkalinization are stressed. Timely management can obviate the need for dialysis. Published cases of acetylsalicylic acid intoxication are reviewed. PMID- 20962707 TI - Approaches to clear residual chemotherapeutics from indwelling catheters in children with cancer. AB - OBJECTIVES: To develop a method for drug dosing and pharmacokinetic (PK) sampling in children with cancer from a single indwelling central venous catheter that minimized drug contamination. METHODS: A benchtop system was designed to simulate dosing and clearing actinomycin-D (AMD) and vincristine (VCR) from central venous catheters. The authors evaluated the effects of flush volume, composition and pH, timed drug instillation, and number of blood-draw return cycles on residual drug concentrations. A proof-of-principle study was conducted in three pediatric patients with cancer with paired PK samples obtained by both central and peripheral catheters. RESULTS: Nearly complete removal of drug from the catheter was obtained after five blood-draw return cycles consisting of 5 mL of whole blood. Residual concentration of AMD was 0.18 +/- 0.02 ng/mL or 0.16% of the initial infusion concentration. VCR exhibited lower propensity for catheter adsorption than AMD with residual concentrations undetectable after three blood draw return cycles. In patients in which the clearance procedure was used, higher drug concentrations were generally observed from centrally cleared samples at most time points, but differences relative to peripherally obtained samples were not statistically significant for either AMD or VCR. Two of three patients had higher exposure for AMD based on PK samples obtained from central catheters, whereas exposure for VCR was similar for both sampling catheters in all patients. CONCLUSIONS: A reliable procedure to efficiently reduce AMD and VCR contamination during PK sampling has been established and is currently being used in a PK study being conducted by the Children's Oncology Group. PMID- 20962708 TI - Population pharmacokinetic modeling and optimal sampling strategy for Bayesian estimation of amikacin exposure in critically ill septic patients. AB - Because the sepsis-induced pharmacokinetic (PK) modifications need to be considered in aminoglycoside dosing, the present study aimed to develop a population PK model for amikacin (AMK) in severe sepsis and to subsequently propose an optimal sampling strategy suitable for Bayesian estimation of the drug PK parameters. Concentration-time profiles for AMK were obtained from 88 critically ill septic patients during the first 24 hours of antibiotic treatment. The population PK model was developed using a nonlinear mixed effects modeling approach. Covariate analysis included demographic data, pathophysiological characteristics, and comedication. Optimal sampling times were selected based on a robust Bayesian design criterion. Taking into account clinical constraints, a two-point sampling approach was investigated. A two-compartment model with first order elimination best fitted the AMK concentrations. Population PK estimates were 19.2 and 9.34 L for the central and peripheral volume of distribution and 4.31 and 2.21 L/h for the intercompartmental and total body clearance. Creatinine clearance estimated using the Cockcroft-Gault equation was retained in the final model. The two optimal sampling times were 1 hour and 6 hours after onset of the drug infusion. Predictive performance of individual Bayes estimates computed using the proposed optimal sampling strategy was reported: mean prediction errors were less than 5% and root mean square errors were less than 30%. The present study confirmed the significant influence of the creatinine clearance on the PK disposition of AMK during the first hours of treatment in critically ill septic patients. Based on the population estimates, an optimal sampling strategy suitable for Bayesian estimation of the drug PK parameters was developed, meeting the need of clinical practice. PMID- 20962709 TI - Longitudinal comparison of thyroxine pharmacokinetics between pregnant and nonpregnant women: a stable isotope study. AB - The treatment of maternal hypothyroidism presents clinicians with a unique challenge, because dosing regimens previously developed and validated for nonpregnant women cannot be easily extrapolated to dosing in pregnancy. Thyroid hormone requirement increases by 20% to 40% early during pregnancy, persisting throughout gestation. Accordingly, women with treated hypothyroidism need to increase their levothyroxine dose to prevent maternal hypothyroidism and the associated impaired cognitive development and increased fetal mortality. We investigated the pharmacokinetic properties of levothyroxine during pregnancy through the use of a novel, traceable form of levothyroxine. The objective was to conduct a longitudinal study to determine whether levothyroxine pharmacokinetics differ in the pregnant versus nonpregnant state. We used a unique C-levothyroxine tracer method to distinguish between endogenous and exogenous levothyroxine and studied the pharmacokinetics of a single oral dose of levothyroxine using tandem mass spectrometry. Moreover, we were able to detect single dose amounts of the drug, in picogram/mL concentrations. The area under the curve was 23.0 ng*h/mL in pregnancy and 14.8 ng*h/mL in nonpregnant women (P < 0.03) with median serum half lives of 32.1 hours and 24.1 hours, respectively (P < 0.04). Further research involves the measurement of free thyroxine on these samples using tandem mass spectrometry. Future work should focus on the mechanisms responsible for the gestational differences in pharmacokinetics and whether these should necessitate dose schedule changes in pregnancy. PMID- 20962710 TI - Studies on effects of indigenous plant extracts on malarial vector, Anopheles subpictus Grassi (Diptera:Culicidae). AB - Mosquitoes transmit serious human diseases, causing millions of deaths every year. Use of synthetic insecticides to control vector mosquitoes has caused physiological resistance and adverse environmental effects in addition to high operational cost. Insecticides of botanical origin may serve as suitable alternative biocontrol techniques in the future. The present investigations were made to evaluate the repellent, ovicidal and oviposition-deterrent potential of leaf hexane and chloroform extracts of Aegle marmelos, Andrographis lineata, Andrographis paniculata, Cocculus hirsutus, Eclipta prostrata and Tagetes erecta against Anopheles subpictus Grassi (Diptera:Culicidae). The hexane extract of A. lineata was more effective in exhibiting the repellent action against the mosquito as compared with A. marmelos extract. Complete protections for 150 min were found in hexane extract of A. lineata at 500 ppm against An. subpictus bites. Mean percent hatchability of the ovicidal activity was observed 24 h after treatment. The percent hatchability was inversely proportional to the concentration of extract and directly proportional to the eggs. No hatchability was observed with hexane and chloroform extracts of A. lineata, A. paniculata and hexane extract of T. erecta were exerted at 1,000 ppm. The percentage of effective oviposition repellency of 93.07, 93.95, 98.03, 90.43, 92.63, 81.53, 94.81, 97.50, 97.26, 92.22, 82.85 and 72.77 at 500 ppm and the lowest repellency of 62.03, 53.64, 73.47, 59.05, 57.95, 48.17, 62.22, 72.99, 75.48, 67.77, 40.57 and 52.11 at 31.25 ppm in hexane and chloroform extracts of A. marmelos, A. lineata, A. paniculata, C. hirsutus, E. prostrata and T. erecta, respectively. The oviposition activity index (OAI) values revealed that the solvent plant extracts have deterrent effect, and they caused a remarkable negative response resulting in oviposition of very few eggs. These results clearly reveal that the hexane extract of A. lineata, served as a potential repellent, ovicidal and oviposition- deterrent against An. subpictus. PMID- 20962711 TI - The availability of 16S rRNA for the identification of forensically important flies (Diptera: Muscidae) in China. AB - Many species of Muscidae are cosmopolitan synanthropic insects. It is frequently found on dead bodies after death, so an accurate identification of each species is necessary for the correct estimation of the postmortem interval (PMI). Identification species of Muscidae is traditionally performed through their morphological features. However, the morphological similarity of Muscidae in the level of species usually poses a challenge for forensic entomologists. Therefore a molecular method used 16S rRNA sequence on mitochondrial DNA was established for species identification. In this study, a 289 base pair region of mitochondrial DNA (mtDNA) coding for 16S rRNA was investigated for identification of the following forensically important species of Muscidae. The specimens were from four genera, including 18 Musca domestica (Linnaeus, 1758), 2 Ophyra spinigera (Stein, 1910), 2 Ophyra chalcogaster (Wiedemann, 1824), 1 Morellia hortorum (Fallen, 1817), and 1 Fannia canicularis (Linnaeus, 1761). 16S rDNA region allowed the identification of these species of Muscidae, indicating the possibility of separation congeneric species with molecular method. PMID- 20962712 TI - Entire genome characterization of Chikungunya virus from the 2008-2009 outbreaks in Thailand. AB - The resurgence of Chikungunya virus (CHIKV) in the southern, northeastern and northern parts of Thailand, inflicting approximately 46,000 reported cases since October 2008 until December 2009, has raised public health concerns. In the present study, we characterized nearly complete genome sequences of four CHIKV isolates obtained from 2008 to 2009 outbreaks in Thailand. Phylogenetic analysis was performed to determine the relationships of the study viruses with previously reported isolates. Results showed that 2008-2009 Thailand isolates belonged to the East, Central and South African genotype and were most closely related to isolates detected in Malaysia and Singapore in 2008. This was in contrast to isolates from all previous outbreaks in Thailand which were caused by an Asian genotype. We describe several novel mutations in Thailand isolates that warrants further investigation on characterization of CHIKV from different parts of the country to better understand the molecular epidemiology of Chikungunya fever outbreaks in Thailand. PMID- 20962713 TI - Evaluation and modification of the formalin-ether sedimentation technique. AB - Formalin-ether sedimentation (MGL) is a well-known technique for the examination of faeces for parasites, but some recent reports have indicated that its efficiency is not as high as originally thought. We reevaluated the recovery efficiency of the original MGL (O-MGL) technique to modify it. We subsequently adopted the following modified MGL technique (M-MGL): filtration by three layers of gauze and washing, adjustment to pH 3, retreatment of plug, and use of 1.5 g of faeces. We also compared five faecal examination techniques (including the O MGL and the M-MGL) for three parameters: recovery efficiency, sensitivity, and mean number of eggs detected. The highest sensitivity was obtained by the M-MGL (95%), followed by the commercially available kit (Kit; 90%), O-MGL (76%), Kato Katz (KK; 57%), and direct smear (DS; 50%). The mean numbers of Ascaris lumbricoides eggs recovered by the techniques were in order M-MGL (148 eggs), Kit (97), O-MGL (41), KK (11), and DS (6). This M-MGL technique has the advantage not only of the above-mentioned three parameters, but also the ease of microscopic observation and the concentration index. The parameters of the O-MGL technique were not necessarily sufficient compared with the other techniques. It seems that the improved M-MGL technique in the present study is applicable for field surveys, particularly when the survey is done in areas of low parasite endemicity. PMID- 20962714 TI - Dengue vector surveillance in insular settlements of Pulau Ketam, Selangor, Malaysia. AB - A year-long ovitrap surveillance was conducted between November 2007 and October 2008 in two insular settlements (Kampung Pulau Ketam and Kampung Sungai Lima) within the Malaysian island of Pulau Ketam. Eighty standard ovitraps were placed indoors and outdoors of randomly selected houses/locations. Results demonstrated an endemic baseline Aedes population throughout the year without weekly large fluctuations. Kampung Pulau Ketam has high Aedes aegypti and Aedes albopictus population, but only Ae. aegypti was found in Kampung Sungai Lima. Aedes aegypti showed no preference for ovitraps placed indoor versus outdoor. However, as expected, significantly more outdoor ovitraps were positive for Ae. albopictus (p<0.05). Trends in Ae. albopictus and Ae. aegypti populations mirrored each other suggesting that common factors influenced these two populations. PMID- 20962715 TI - CD 28 gene polymorphism and plasma concentration of soluble CD 28 in Iranian patients with visceral leishmaniasis. AB - In visceral leishmaniasis (VL), the development of protective immunity is associated with expansion of leishmania-specific T-cell responses. Because of the essential role of CD28 in the effectiveness of T-cell activation, this study was carried out to investigate the CD28 gene polymorphism and plasma levels of soluble (s) CD28 molecule in Iranian patients with VL. Plasma concentrations of CD28 in 88 patients with VL, 132 individual with subclinical leishmaniasis, and 100 seronegative healthy controls were measured by enzyme-linked immunosorbent assay. Genotyping of CD28 gene polymorphism was performed by polymerase chain reaction based allotyping method using allele-specific primers for C or T at intron 3 position +17 in three groups. The frequency of CC genotype was significantly higher in subclinical VL patients (42.4%) than active VL group (27.3%) and healthy controls (16%) (P<0.001). Also, the frequency of allele C among subclinical VL group (57.6%) was significantly higher than active VL (40.9%) and control groups (34%) (p=0.003). No significant differences were observed between the plasma levels of sCD28 in three groups. Our findings suggest that the CD28 gene may have significant role in the protection of active VL in the Iranian population. PMID- 20962716 TI - In vitro activity of fluconazole and voriconazole against clinical isolates of Candida spp. by E-test method. AB - The in vitro susceptibility of clinical Candida isolates towards fluconazole and voriconazole was determined using the E-test method. A total of 41 clinical isolates recovered from patients since 2004 until 2009 from two local hospitals in Kuala Lumpur, Malaysia were used. These comprised Candida tropicalis, Candida albicans, Candida krusei, Candida parapsilosis, Candida rugosa, Candida dubliniensis and Candida glabrata. Strains from American Type Culture Collection were used as quality control. Lawn cultures of the isolates on RPMI-1640 agar medium supplemented with 2% glucose were incubated with the E-test strips at 35oC for 48 h. Our results show that 71% were susceptible to fluconazole and 90% were susceptible to voriconazole. All strains of C. krusei were resistant to fluconazole and 50% were susceptible in a dose-dependent manner to voriconazole. There were 66% and 33% of C. glabrata that were resistant to fluconazole and voriconazole. Our study revealed that majority of the clinical Candida isolates was susceptible to fluconazole and voriconazole with a small percentage being resistant to both the drugs. PMID- 20962717 TI - An unusual cause of hemoptysis in a child: live leech in the posterior pharynx. AB - An 8-year-old girl was admitted to the emergency department with hemoptysis. Her history revealed that she had been drinking unfiltered tap water several days before. Physical examination revealed a black live foreign object in the pharynx with local posterior pharyngeal oozing. Pharyngeal leech was suspected and removed immediately using forceps. After removal of the leech, the bleeding stopped immediately and the patient felt comfortable. The leech was identified as belonging to the species Limnatis nilotica. Pharyngeal leeches should be included in the differential diagnosis of patients with hemoptysis, especially in patients with a history of drinking unfiltered water from sources where aquatic leeches are commonly found. Cases such as this should be considered as emergencies, and all measures should be taken to avoid hemoptysis and death. PMID- 20962718 TI - Larvicidal efficacy of medicinal plant extracts against Anopheles stephensi and Culex quinquefasciatus (Diptera: Culicidae). AB - Mosquitoes transmit serious human diseases, causing millions of deaths every year. Natural products of plant origin with insecticidal properties have been used in recent years for control of a variety of pest insects and vectors. The present study was based on assessments of the larvicidal activity to determine the efficacies of hexane, chloroform, ethyl acetate, acetone and methanol extracts of ten medicinal plants tested against fourth instar larvae of malaria vector, Anopheles stephensi Liston and lymphatic filariasis vector, Culex quinquefasciatus Say (Diptera: Culicidae). The larvicidal activity was assessed by the procedure of WHO with some modification. The highest larval mortality was found in leaf acetone of Adhatoda vasica, bark ethyl acetate of Annona squamosa, methanol leaf and flower of Cassia auriculata, leaf ethyl acetate of Hydrocotyle javanica, methanol leaf and seed of Solanum torvum and leaf hexane extracts of Vitex negundo against the fourth instar larvae of An. stephensi and Cx. quinquefasciatus. The calculated LC90 for acetone, ethyl acetate, methanol and hexane extracts of dried leaf and bark of A. vasica, A. squamosa, S. torvum, and V. negundo were in the range of 70.38-210.68 ppm. Our results suggest that the leaf methanol extract of S.torvum and bark ethyl acetate extract of A. squamosa from Southern India have the potential for use to control mosquitoes. Therefore, this study provides the larvicidal activity against An. stephensi and Cx. quinquefasciatus of plant extracts. PMID- 20962719 TI - A seroepidemiological survey for toxoplasmosis among schoolchildren of Sari, Northern Iran. AB - A seroepidemiological survey for toxoplasmosis among schoolchildren of public schools of the urban areas of the Sari, Mazandaran province, Iran, was carried out from September 2006 to March 2007. A total of 1209 serum samples (686 males, 523 females) were examined for IgG antibodies by ELISA. Questionnaires were completed for all participants. In regard to criteria>10 IU/mL as positive, the infection coefficient (IC) was 266 (22%), of which 161 were males (IC=23.5) and 105 females (IC=20.1) (P=0.15). No age-antibody association was detected, although an increase in positivity with increasing age was observed, reaching 23.1% in the oldest group (P=0.84). A significant association was observed with the presence of cat, contact with soil, washing hands before meals and eating raw or undercooked meat. An improvement in personal hygienic conditions and behavioral characteristics such as eating cooked meat is important in reducing the rate of Toxoplasma infection. PMID- 20962720 TI - Biorational control programme for the German cockroach (Blattaria: Blattellidae) in selected urban communities. AB - This study assessed the effectiveness of a biorational control approach using 2% hydramethylnon gel bait on German cockroaches, Blattella germanica (L.) in some residential and hospital buildings in South Western Iran. In total, three buildings consisting of 150 apartment units and 101 hospital units were monitored weekly via sticky trap for German cockroach infestations over a period of eight months. These infested units were randomly subjected to intervention and control treatments. Pamphlets and posters were provided and lectures were given to support the educational programmes as a tactic of the biorational system. Survey on cockroach index for intervention units showed 67-94% recovery to achieve clean level of infestation for intervention units of the residential buildings and 83% for the hospital. Mean percentage reductions for treatment groups throughout the 15-week treatment period were 76.8% for the residential buildings and 88.1% for the hospital, showing significant differences compared to the control groups. Linear regression of infestation rates were recorded weekly after treatment and their negative slope for treatment groups substantiated significant reductions for interventions. The results of this study showed that biorational control method, using gel bait, educational programmes and sanitation, is an effective way to manage German cockroach infestation. PMID- 20962721 TI - Lungworm of cattle in Malaysia. AB - Bovine lungworm Dictyocaulus viviparus is highly endemic in temperate regions. However, the occurrence of the lungworm has not been reported in any South East Asian country. The main aim of the present study was to detect the presence of lungworm in cattle in peninsular Malaysia and to examine the morphology of the parasite. A cross-sectional study was carried out in which 602 animals from four large scale government cattle farms and one dairy smallholder farm were sampled. In addition, 283 lungs from 11 abattoirs around the country were examined. Faecal samples were examined using the Baermann technique while post-mortem examination was performed on the lungs. Approximately 5% of faecal samples and 1% of lungs were positive for lungworm. Based on the morphology of adult lungworm, eggs and first stage larvae, Malaysian bovine lungworms were D. viviparus. PMID- 20962723 TI - A novel alternative method for 3D visualisation in Parasitology: the construction of a 3D model of a parasite from 2D illustrations. AB - Three-dimensional (3D) models of the marginal hooks, dorsal and ventral anchors, bars and haptoral reservoirs of a parasite, Sundatrema langkawiense Lim & Gibson, 2009 (Monogenea) were developed using the polygonal modelling method in Autodesk 3ds Max (Version 9) based on two-dimensional (2D) illustrations. Maxscripts were written to rotate the modelled 3D structures. Appropriately orientated 3D haptoral hard-parts were then selected and positioned within the transparent 3D outline of the haptor and grouped together to form a complete 3D haptoral entity. This technique is an inexpensive tool for constructing 3D models from 2D illustrations for 3D visualisation of the spatial relationships between the different structural parts within organisms. PMID- 20962722 TI - A low molecular weight lipopolysaccharide antigen preparation reactive to acute leptospirosis heterologous sera. AB - There is a need for identification of new infection markers against common Leptospira isolates in Malaysia. To achieve this goal, seven-day-old cultures of Leptospira interrogans serogroup Icterohemorrhagiae (L44) and Leptospira interrogans serogroup Javanica (L55) were used for antigen preparation by sequential extraction method using 40 mM Tris, 8M Urea and 2M thiourea. Immunoblot analysis of the antigens were performed using serum samples from 46 local patients with confirmed acute leptospirosis, 28 patients with other infections and 14 healthy controls. The patients serum samples used in this study contained heterologous antibody against a number of different leptospira serovars. A strong IgM reactivity to a broad diffuse band of 10-15 kDa was observed. Combining results using L44 and L55 antigens showed sensitivity of 80.4% and specificity of 95.2% for detection of leptospirosis. Proteinase K and periodate treatment indicated that the band is likely to be lipopolysaccharide (LPS) in nature. This study showed that the 10-15 kDa antigen could potentially be useful for serodiagnosis of acute leptospirosis in Malaysia. PMID- 20962724 TI - An acute gastroenteritis outbreak of Vibrio parahaemolyticus O4:K55 in Nursing College, Thailand. AB - A cluster of acute gastroenteritis among nursing students was noticed on 13th September 2005. Between 13th and 17th September 2005, a retrospective cohort study was then conducted to identify the most likely cause of gastroenteritis at a nursing college in Bangkok, Thailand. Self-administered questionnaires, interviews, environmental investigations, and rectal swabs from all participants were carried out. In the investigation, 98.9% female nursing students were investigated and had completed the questionnaire, 49.4% of the participants were diagnosed to have acute gastroenteritis. The predominant symptoms were watery diarrhoea (90.8%) and abdominal cramps (71.3%). Of 28.9% of rectal swab isolates were identified as Vibrio parahaemolyticus O4:K55 (40.4%), Salmonella spp. (19.2%), Vibrio cholerae non O1/non O139/non O141 (11.5%), Aeromonas trota (3.9%), Vibrio alginolyticus (1.9%) and other co-infections (23.1%). The tdh gene was identified from all V. parahaemolyticus using multiplex PCR. The implicated food risk factor for gastroenteritis was boiled egg (adjusted prevalence rate ratio; PR=1.9, 95% CI, 1.04-3.79). However the bitter melon soup was not significantly associated for gastroenteritis (adjusted PR=1.3, 95% CI, 0.98 1.82). The population attributable fraction analysis indicated that boiled eggs item was an implicated food risk for this outbreak (PAF=45.8%). Vibrio parahaemolyticus O4:K55 was identified as a major causative agent for gastroenteritis in which the contaminated boiled eggs was a vehicle in this outbreak. Cross-contamination control should be emphasized in food operation plans among institutes. PMID- 20962725 TI - Seroprevalence of Toxoplasma gondii in water buffaloes (Bubalus bubalis) in South West of Iran. AB - The prevalence of antibodies to Toxoplasma gondii was conducted in 300 buffaloes from Ahvaz, Kouzestan province, southwest of Iran. Blood sera were screened using a Modified agglutination test (MAT) incorporating 2-mercaptoethanol. Positive reactions in sera dilutions above 1:25 were considered as indicative for the presence of T. gondii antibodies. The overall prevalence of infection in the animals was 14.33% with titers of 1:25 in 21, 1:50 in 12, 1:100 in 6, 1:200 in 2 and 1:400 in 2. The prevalence was different in relation to the sex with buffaloes with 19.7% and 7% in females and males respectively. These results indicate that T. gondii infection in water buffaloes of Khouzestan is relatively high and consumption of buffalo meat may be a risk factor for humans in Ahvaz, southwest of Iran. PMID- 20962726 TI - Potential influence of climate variability on dengue incidence registered in a western pediatric Hospital of Venezuela. AB - Climate change and variability is affecting human health and disease direct or indirectly through many mechanisms. Dengue is one those diseases that is strongly influenced by climate variability. In this study we assess potential associations between macroclimatic variation and dengue cases in a western pediatric hospital of Venezuela in an eight-year period. Between 2001 and 2008, 7,523 cases of dengue were reported in the Hospital Agustin Zubillaga, Barquisimeto, Venezuela. Climatic periods marked a difference of 23.15% in the mean incidence of cases, from El Nino weeks (-14.16% of cases below the mean incidence) to La Nina months (+8.99% of cases above it) (p=0.0001). Linear regression showed significantly higher dengue incidence with lower values of Oceanic Nino Index (ONI) (El Nino periods) and lower dengue incidence with higher values of ONI (La Nina periods) (p=0.0002). As has been shown herein, climate variability is an important element influencing the dengue epidemiology in Venezuela. However, it is necessary to extend these studies in this and other countries in the region, because these models can be applied for surveillance as well for prediction of dengue. PMID- 20962727 TI - A new record of Iranihindia martellata (Senior-White,1924) (Diptera: Sarcophagidae) from peninsular Malaysia and female identification using both morphology and DNA-based approaches. AB - Iranihindia martellata (Senior-White, 1924) is recorded from peninsular Malaysia for the first time. Male and female specimens in the recent collections of forensically important sarcophagid flies were examined and identified based on morphology and DNA sequencing analysis. Male genitalia offer unambiguous species identification characteristics in the traditional taxonomy of flesh flies but the female flies are very similar to one another in general morphology. Female of I. martellata was determined by DNA sequencing (COI and COII) and PCR-RFLP (COI) analysis. Identified females were carefully examined and compared with the morphologically similar species, Liopygia ruficornis (Fabricius, 1794). Female genitalia are re-described and illustrated in this paper. PMID- 20962728 TI - The association between pre-morbid conditions and respiratory tract manifestations amongst Malaysian Hajj pilgrims. AB - In a very closed and overcrowding environment, influenza transmission during Hajj season is almost inevitable. The aim of this study was to determine the association between pre-morbid conditions and influenza-like illness (ILI) amongst Hajj pilgrims. A cross-sectional study was conducted amongst Malaysian Hajj pilgrims in year 2007. Survey forms were distributed at Madinatul-Hujjaj, Jeddah and Tabung Haji Clinic, Medina, Saudi Arabia where pilgrims stay on transit before returning to Malaysia. Allergic rhinitis was significantly associated with sore throat (p=0.047), longer duration of cough (p=0.017) and runny nose (p=0.016). Pilgrims who suffered from chronic obstructive pulmonary diseases (COPD) had significant association with longer duration of cough (p=0.041) and those with diabetes mellitus had significant association with longer duration of sore throat (p=0.048). Underlying asthma was significantly associated with severe influenza like illness requiring admission to hospital for further treatment of respiratory symptoms (p=0.016). Based on these findings, we suggest those with underlying asthma should be discouraged from participating in the hajj and they should seek early treatment if they develop respiratory symptoms. PMID- 20962729 TI - The seroprevalence of bovine babesiosis in Malaysia. AB - One hundred sera of Malaysian cattle were used in this seroprevalence study for bovine babesiosis. All sera were obtained from the Serological Unit of the Veterinary Research Institute (VRI), Ipoh, Perak. The sera were tested using a Veterinary Medical Research & Development (VMRD) commercial Indirect Immunofluourescent Antibody Test (IFAT) kit. The results showed that 17.0% were found to be positive for Babesia bovis, 16.0% for Babesia bigemina, and 9.0% for both B. bovis and B. bigemina infections. PMID- 20962730 TI - Prospective surveillance of nosocomial device-associated bacteremia in three adult intensive units in Malaysia. AB - Nosocomial blood stream infection (or nosocomial bacteremia) is a common problem in hospitals worldwide, including Malaysia. A three-year prospective cohort study (October 2003-March 2007) of the incidences, risk factors, and patterns of the microorganisms causing bacteremia was conducted using a validated surveillance form in three intensive care units (ICUs) in Malaysia. Center for Disease Control criteria were used to diagnose bacteremia. Patients were monitored from admission until the end point of study, which was the first detection of bacteremia in the blood in each patient. The frequency of occurrence of bacteremia with clinical symptoms was 10.7% (n=23). Bacteremia was observed to occur within a mean length of stay of 10 days in ICU. The rate of device-related infection was 10.4% per device utilization days with a device utilization rate of 95.9%/1000 patient days. The total number of patient days was 2309 and the period of device utilization was 2211 days. The common bacteria detected were extended-spectrum beta-lactamases (ESBLs) Klebsiella pneumoniae (n=6); Pseudomonas aeruginosa (n=6); Acinetobacter species (n=5); Methicillin-resistant Staphylococcus aureus (MRSA)(n=3); and (non- ESBL) Klebsiella pneumoniae (n=2). Multivariable analysis using Cox Proportional Hazard Model showed that the predictors for developing bacteremia were cancer, MRSA carriage, duration of central venous catheter (CVC) infusion, frequency change of CVC, and the administration of hydrocortisone drugs. These results indicate that a combination of nursing and medical interventions as well as patients' severity of illness could lead to bacteremia in ICU. Strategic implementation of quality assurance measures in ICUs could help to control this problem. PMID- 20962731 TI - Temporal fluctuations of insecticides resistance in Musca domestica Linn (Diptera: Muscidae) in Malaysia. AB - House flies were collected from April 2007-April 2008 from two poultry farms (Balik Pulau and Juru) in the state of Penang. The resistance level of the first generation offspring was evaluated against DDT, malathion, propoxur, and permethrin using the topical application method. The resistance ratio (RR) of the Balik Pulau strain house flies for propoxur, malathion and DDT ranged from 10.28 to 99.00, 7.83 to 47.01 and 6.05 to 31.10, respectively. Resistance to propoxur and malathion in house fly was attributed to cross resistance to organophosphate insecticides used in the farm. Increased metabolic detoxification might be the mechanism involved in DDT resistance due to excessive application of cypermethrin formulation. The RR of the Juru strain for propoxur, malathion and DDT was in a decreasing pattern throughout the study period, ranging from 5.58 to 83.38, 15.19 to 27.82, and 10.04 to 22.69, respectively. Permethrin appeared to be the most potent insecticide in controlling house fly in both the Balik Pulau (RR=0.50 to 1.96) and Juru poultry farms (RR=0.64 to 2.40). The fluctuations of insecticides resistance in house fly was also found to correlate with climatic factors due to its rapid breeding. Relative humidity exhibited positive correlation indices with the changes in the resistance level for DDT (r=0.481, p<0.05), malathion (r=0.698, p<0.01), and permethrin (r=0.580, p<0.05) in Balik Pulau. Similarly, relative humidity in Juru also showed strong correlation with the RR for DDT (r=0.900, p<0.01), malathion (r=0.762, p<0.05), permethrin (r=0.760, p<0.05), and propoxur (r=0.897, p<0.01). PMID- 20962732 TI - Congenital malaria--a case report from a non-endemic area. AB - Eighteen day old neonate presented with features of early neonatal sepsis. History of mother revealed a travel from non-endemic area of malaria to endemic area, and on the 7th gestational age mother detected as having malaria. She was treated with quinine and cured. Baby was also evaluated for congenital malaria in first few neonatal days and discharged. Now the baby on evaluation shows anemia, hepatosplenomegaly and diagnosed with a Plasmodium vivax infection on peripheral smear. The quinine failed to prevent transplacental transmission. Prolonged interval between birth and onset of symptoms may be explained by transmission late in pregnancy or during delivery or by presence of transplacentally acquired maternal antibody (IgG). Mother acquired malarial infection after travel to an endemic area and transmitted to the baby. A high level of suspicion is warranted in babies of malaria infected mothers even when the neonate peripheral smear shows no evidence of infection. PMID- 20962733 TI - Studies on community knowledge and behavior following a dengue epidemic in Chennai city, Tamil Nadu, India. AB - In 2001, a major dengue outbreak was recorded in Chennai city, with 737 cases (90%) out of a total of 861 cases recorded from Tamil Nadu state. A KAP survey was carried out to assess the community knowledge, attitude and practice on dengue fever (DF), following the major dengue outbreak in 2001. A pre- tested, structured questionnaire was used for data collection. The multistage cluster sampling method was employed and 640 households (HHs) were surveyed. Among the total HHs surveyed, 34.5% of HHs were aware of dengue and only 3.3% of HHs knew that virus is the causative agent for DF. Majority of the HHs (86.5%) practiced water storage and only 3% of them stored water more than 5 days. No control measures were followed to avoid mosquito breeding in the water holding containers by majority of HHs (65%). Sixty percent of HHs did not know the biting behaviour of dengue vector mosquitoes. The survey results indicate that the community knowledge was very poor on dengue, its transmission, vector breeding sources, biting behavior and preventive measures. The lack of basic knowledge of the community on dengue epidemiology and vector bionomics would be also a major cause of increasing trend of dengue in this highly populated urban environment. There is an inevitable need to organize health education programmes about dengue disease to increase community knowledge and also to sensitize the community to participate in integrated vector control programme to resolve the dengue problem. PMID- 20962734 TI - Prevalence of Schistosoma haematobium infection among inhabitants of Lowveld, Swaziland, an endemic area for the disease. AB - We carried out a parasitological survey of Schistosoma haematobium infection among the residents of Lowveld Siphofaneni, Swaziland, an area which is devoid of sanitation. Subjects with positive infection were confirmed by the detection of S. haematobium ova in their urine. The intensity of the infection was estimated by calculating the total number of S. haematobium ova present in 10 ml urine specimen (geometric mean intensity; GMI). Overall, the prevalence of S. haematobium infection was 6.1% (18/295) with a GMI of 20.7 (95% CI=9.1~32.2). Female (10.5%, 16/153) had significantly higher prevalence than that in male (1.4%, 2/142) (ORs=8.2, 95% CI=1.8- 36.2, P<0.01); conversely, male had higher GMI (60.0) than that (17.3) in female. The age group of <=5 yrs (15.3%, 9/59) had significantly higher prevalence than that in age group of >=19 yrs (2.6%, 3/115) (ORs=0.2, 95% CI=0.04-0.57, P<0.01). The highest GMI of 27.9 (95% CI=7.6~48.2) was also seen in age group of <=5 yrs. PMID- 20962735 TI - Chikungunya virus-associated death in Malaysia. AB - Chikungunya virus (CHIKV) is a mosquito-borne alphavirus which causes fever, rash, and arthralgia. In the past, life-threatening complications were very rarely reported. However, during the recent worldwide outbreaks, there have been several reports of unusually severe complications and deaths. Malaysia is experiencing a nationwide outbreak of CHIKV, with over 10 000 patients affected since April 2008. We report the first case of culture-confirmed CHIKV-associated death in Malaysia, in a patient with fever, rash, acute exacerbation of pre existing heart failure, rhabdomyolysis, and multiple organ failure. CHIKV infections may cause atypical, severe or fatal presentations. PMID- 20962736 TI - Gastrointestinal helminthiasis presenting with acute diarrhoea and constipation: report of two cases with a second pathology. AB - Gastrointestinal helminthiasis in developing countries contributes to malnutrition and anemia. Diagnosis and treatment of helminthiasis, especially with low worm load is an unmet public health need in such settings. The infection may sometimes become manifest when a second pathology leads to purgation of the gastrointestinal tract. Two cases of helminthiasis are presented in which the infections only became amenable to diagnosis due to acute diarrhoea caused by giardiasis and lactulose administration. In the first case, acute giardiasis revealed Ascaris lumbricoides infestation, and in the second case primary helminthiasis (strongyloidiasis) was revealed by lactulose, and also led to Vibrio cholera bacteremia. These cases highlight the need to diagnose helminth infestations especially with low worm burdens by means of public health surveillance programmes. These cases highlight the need to diagnose helminth infestations especially with low worm burdens by means of public health surveillance programmes. PMID- 20962737 TI - Modified gel preparation for distinct DNA fragment analysis in agarose gel electrophoresis. AB - Agarose gel electrophoresis is the standard method that is used to separate, identify, and purify DNA fragments. However, this method is time-consuming and capable of separating limited range of fragments. A new technique of gel preparation was developed to improve the DNA fragment analysis via electrophoresis. PMID- 20962738 TI - First report of the house fly larvae, Musca domestica (Linnaeus) (Diptera: Muscidae) associated with the monkey carcass in Malaysia. AB - A study on insect succession of monkey carcass in a forested area in Ulu Gombak, Selangor, Malaysia was conducted from 9 May to 18 June 2007. The third instar of the housefly, Musca domestica (Linnaeus) (Diptera: Muscidae) were only found on dry stage of a decomposed (Day-33) monkey carcass (Macaca fascicularis Raffles). This observation revealed that M. domestica maggots were found together with other muscid fly maggots, Hydrotaea (=Ophyra) spinigera (Stein) (Diptera: Muscidae) on dry stage of a carcass. However, the role of M. domestica on forensic entomological study remains unknown. This study recorded the first finding of M. domestica maggots on primate carcass in Malaysia. PMID- 20962740 TI - Changes in anemia management and hemoglobin levels following revision of a bundling policy to incorporate recombinant human erythropoietin. AB - In April 2006, Japan's health insurance system instituted a bundling policy that included recombinant human erythropoietin (rHuEPO) in outpatient hemodialysis therapy. To evaluate outcomes of this, we analyzed a prospective cohort of hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study, in 53 facilities using prevalent cross-sections of 1584 patients before and 1622 patients after the rHuEPO reimbursement change. Patient data included hemoglobin levels, iron management profiles, and anemia treatment with rHuEPO and intravenous iron. No significant differences were found in pre- or post-policy cross-sections for hemoglobin distributions or the percentage of patients prescribed rHuEPO. Among patients receiving rHuEPO, the mean dose significantly decreased by 11.8 percent. The percentage of patients prescribed intravenous iron over 4 months significantly increased; however, the mean dose of iron did not significantly change. Thus, this bundling policy was associated with reduced rHuEPO doses, increased intravenous iron use, and stable hemoglobin levels in Japanese patients receiving hemodialysis. PMID- 20962739 TI - Inhibition of 20-HETE synthesis and action protects the kidney from ischemia/reperfusion injury. AB - 20-Hydroxyeicosatetraenoic acid (20-HETE) production is increased in ischemic kidney tissue and may contribute to ischemia/reperfusion (I/R) injury by mediating vasoconstriction and inflammation. To test this hypothesis, uninephrectomized male Lewis rats were exposed to warm ischemia following pretreatment with either an inhibitor of 20-HETE synthesis (HET0016), an antagonist (20-hydroxyeicosa-6(Z),15(Z)-dienoic acid), an agonist (20 hydroxyeicosa-5(Z),14(Z)-dienoic acid), or vehicle via the renal artery and the kidneys were examined 2 days after reperfusion. Pretreatment with either the inhibitor or the antagonist attenuated I/R-induced renal dysfunction as shown by improved creatinine clearance and decreased plasma urea levels, compared to controls. The inhibitor and antagonist also markedly reduced tubular lesion scores, inflammatory cell infiltration, and tubular epithelial cell apoptosis. Administering the antagonist accelerated the recovery of medullary perfusion, as well as renal medullary and cortical re-oxygenation, during the early reperfusion phase. In contrast, the agonist did not improve renal injury and reversed the beneficial effect of the inhibitor. Thus, 20-HETE generation and its action mediated kidney injury due to I/R. Whether or not these effects are clinically important will need to be tested in appropriate human studies. PMID- 20962741 TI - Rho kinase inhibition protects kidneys from diabetic nephropathy without reducing blood pressure. AB - Rho-associated kinases (ROCK) are activated in the kidney as well as in cultured cells of diabetic models and have been implicated in renal pathophysiology. To explore whether inhibition of ROCK is protective, we studied its role in a model of accelerated diabetic nephropathy where uninephrectomized rats were made diabetic by streptozotocin. After establishing diabetes, rats were treated with the ROCK inhibitor fasudil continuously or for the final 6 weeks of an 18-week experimental period. The results were compared to similar rats given losartan, an established treatment of clinical and experimental diabetic nephropathy, or a combination of both agents. Vehicle-treated diabetic and non-diabetic uninephrectomized rats served as controls. Diabetes resulted in a rapid development of albuminuria, higher glomerulosclerosis and interstitial fibrosis scores, lower glomerular filtration rates, and increased expression of several molecular markers of diabetic nephropathy. Eighteen weeks of fasudil treatment reduced renal ROCK activity, and ameliorated diabetes-induced structural changes in the kidney and expression of the molecular markers in association with a modest anti-proteinuric effect but no change in blood pressure. Late intervention with fasudil reduced glomerulosclerosis, but did not influence proteinuria. Most effects of fasudil were comparable to those of losartan, although losartan lowered blood pressure and further lowered proteinuria. The combination of both treatments was no different than losartan alone. Thus, ROCK inhibition protected the kidney from diabetic nephropathy even though it did not reduce the blood pressure. PMID- 20962742 TI - Bacterial CpG-DNA accelerates Alport glomerulosclerosis by inducing an M1 macrophage phenotype and tumor necrosis factor-alpha-mediated podocyte loss. AB - Loss of function mutations in the alpha3 or alpha4 chain of type IV collagen cause Alport nephropathy, characterized by progressive glomerulosclerosis. While studying the mechanisms that determine disease progression, we found that the evolution of kidney disease in Col4a3-deficient mice was associated with an influx of immune cell subsets including nonactivated macrophages. This suggested that intrarenal inflammation might accelerate Alport nephropathy. A possible mechanism might be the well-known enhancement of immune recognition by bacterial products. We found that exposure to bacterial endotoxin from 4 to 6 weeks of age did not affect disease progression, whereas an equipotent dose of cytosine guanine (CpG)-DNA, a synthetic mimic of bacterial DNA, accelerated all aspects of Alport nephropathy and reduced the overall lifespan of Col4a3-deficient mice. This effect was associated with a significant increase of renal CD11b+/Ly6C(hi) macrophages, intrarenal production of inducible nitric oxide synthase, tumor necrosis factor (TNF)-alpha, interleukin-12, and CXCL10, and loss of podocytes. TNF-alpha was essential for acceleration of Alport nephropathy, as etanercept (a soluble TNF-alpha receptor) entirely abrogated the CpG-DNA effect. Thus, systemic exposure to CpG-DNA induces classically activated (M1) macrophages that enhance intrarenal inflammation and disease progression. Hence, factors that modulate the phenotype of renal macrophages can affect the progression of Alport nephropathy and, potentially, other types of chronic kidney diseases. PMID- 20962743 TI - Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans. AB - Recent studies suggest that correcting low serum bicarbonate levels may reduce the progression of kidney disease; however, few patients with chronic kidney disease have low serum bicarbonate. Therefore, we examined whether higher levels of serum bicarbonate within the normal range (20-30 mmol/l) were associated with better kidney outcomes in the African American Study of Kidney Disease and Hypertension (AASK) trial. At baseline and during follow-up of 1094 patients, the glomerular filtration rates (GFR) were measured by iothalamate clearances and events were adjudicated by the outcomes committee. Mean baseline serum bicarbonate, measured GFR, and proteinuria were 25.1 mmol/l, 46 ml/min per 1.73 m(2), and 326 mg/g of creatinine, respectively. Each 1 mmol/l increase in serum bicarbonate within the normal range was associated with reduced risk of death, dialysis, or GFR event and with dialysis or GFR event (hazard ratios of 0.942 and 0.932, respectively) in separate multivariable Cox regression models that included errors-in-variables calibration. Cubic spline regression showed that the lowest risk of GFR event or dialysis was found at serum bicarbonate levels near 28-30 mmol/l. Thus, our study suggests that serum bicarbonate is an independent predictor of CKD progression. Whether increasing serum bicarbonate into the high normal range will improve kidney outcomes during interventional studies will need to be considered. PMID- 20962744 TI - Cell division autoantigen 1 enhances signaling and the profibrotic effects of transforming growth factor-beta in diabetic nephropathy. AB - Cell division autoantigen 1 (CDA1) modulates cell proliferation and transforming growth factor-beta (TGF-beta) signaling in a number of cellular systems; here we found that its levels were elevated in the kidneys of two animal models of diabetic renal disease. The localization of CDA1 to tubular cells and podocytes in human kidney sections was similar to that seen in the rodent models. CDA1 small interfering RNA knockdown markedly attenuated, whereas its overexpression increased TGF-beta signaling, modulating the expression of TGF-beta, TGF-beta receptors, connective tissue growth factor, collagen types I, III, IV, and fibronectin genes in HK-2 cells. CDA1 and TGF-beta together were synergistic in stimulating TGF-beta signaling and target gene expression. CDA1 knockdown effectively blocked TGF-beta-stimulated expression of collagen genes. This was due to its ability to modulate the TGF-beta type I, but not the type II, receptor, leading to increased phosphorylation of Smad3 and extracellular signal regulated kinase mitogen-activated protein kinase. Furthermore, the Smad3 inhibitor, SIS3, markedly attenuated the activities of CDA1 in stimulating TGF beta signaling as well as gene expression of collagens I, III, and IV. Thus, our in vitro and in vivo findings show that CDA1 has a critical role in TGF-beta signaling in the kidney. PMID- 20962745 TI - Genetics and calcium nephrolithiasis. AB - Calcium nephrolithiasis is one of the most prevalent uronephrologic disorders in the western countries. Studies in families and twins evidenced a genetic predisposition to calcium nephrolithiasis. Family-based or case-control studies of single-candidate genes evidenced the possible involvement of calcium-sensing receptor (CASR), vitamin D receptor (VDR), and osteopontin (OPN) gene polymorphisms in stone formation. The only high-throughput genome-wide association study identified claudin 14 (CLDN14) gene as a possible major gene of nephrolithiasis. Specific phenotypes were related with these genes: CASR gene in normocitraturic patients, VDR gene in hypocitraturic patients with severe clinical course, and CLDN14 gene in hypercalciuric patients. The pathogenetic weight of these genes remains unclear, but an alteration of their expression may occur in stone formers. Technological skills, accurate clinical examination, and a detailed phenotype description are the basis to get new insight about the genetic basis of nephrolithiasis. PMID- 20962746 TI - The dualistic role of vitamin D in vascular calcifications. AB - Vitamin D is a multifunctional hormone that can affect many essential biological functions, ranging from the immune regulation to mineral ion metabolism. A close association between altered activity of vitamin D and vascular calcification has been reported in various human diseases, including in patients with atherosclerosis, osteoporosis, and chronic kidney disease (CKD). Vascular calcification is a progressive disorder and is a major determinant of morbidity and mortality of the affected patients. Experimental studies have shown that excessive vitamin D activities can induce vascular calcification, and such vascular pathology can be reversed by reducing vitamin D activities. The human relevance of these experimental studies is not clear, as vitamin D toxicity is relatively rare in the general population. Contrary to the relationship between vitamin D and vascular calcification, in experimental uremic models, low levels of vitamin D were shown to be associated with extensive vascular calcification, a phenomenon that is very similar to the vascular pathology seen in patients with CKD. The current treatment approach of providing vitamin D analogs to patients with CKD often poses a dilemma, as studies linked vitamin D treatment to subsequent vascular calcification. Recent genetic studies, however, have shown that vascular calcification can be prevented by reducing serum phosphate levels, even in the presence of extremely high serum 1,25-dihydroxyvitamin D and calcium levels. This article will briefly summarize the dual effects of vitamin D in vascular calcification and will provide evidence of vitamin D-dependent and independent vascular calcification. PMID- 20962747 TI - Testosterone and 17beta-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice. AB - Podocyte damage and apoptosis are thought to be important if not essential in the development of glomerulosclerosis. Female estrogen receptor knockout mice develop glomerulosclerosis at 9 months of age due to excessive ovarian testosterone production and secretion. Here, we studied the pathogenesis of glomerulosclerosis in this mouse model to determine whether testosterone and/or 17beta-estradiol directly affect the function and survival of podocytes. Glomerulosclerosis in these mice was associated with the expression of desmin and the loss of nephrin, markers of podocyte damage and apoptosis. Ovariectomy preserved the function and survival of podocytes by eliminating the source of endogenous testosterone production. In contrast, testosterone supplementation induced podocyte apoptosis in ovariectomized wild-type mice. Importantly, podocytes express functional androgen and estrogen receptors, which, upon stimulation by their respective ligands, have opposing effects. Testosterone induced podocyte apoptosis in vitro by androgen receptor activation, but independent of the TGF-beta1 signaling pathway. Pretreatment with 17beta-estradiol prevented testosterone-induced podocyte apoptosis, an estrogen receptor-dependent effect mediated by activation of the ERK signaling pathway, and protected podocytes from TGF-beta1- or TNF alpha-induced apoptosis. Thus, podocytes are target cells for testosterone and 17beta-estradiol. These hormones modulate podocyte damage and apoptosis. PMID- 20962748 TI - New vitamin D analogs and changing therapeutic paradigms. AB - Vitamin D compounds have been used successfully to treat secondary hyperparathyroidism for almost three decades. Side effects of increased levels of serum calcium and phosphate and potential complications have increasingly been recognized as problematic, and this has become an even more difficult clinical challenge with the desire to capitalize on some of the pleiotropic effects of vitamin D. Nonclassical nuclear vitamin D receptor (VDR) effects on the cardiovascular system, kidneys, and immune system, with the prospect of improved patient survival, have moved to center stage. Selective vitamin D compounds with minimal effects on mineral metabolism and with maximal cardiovascular and renal benefits are now needed. New vitamin D compounds already in clinical use, which have an improved side-effect profile and differential nonclassical effects compared with calcitriol, are limited to the three licensed pharmaceuticals- paricalcitol, 22-oxacalcitriol, and doxercalciferol. Other compounds are under early development and it is anticipated that these novel therapeutic concepts will result in new vitamin D therapies that will help to reduce the high mortality rate patients with kidney disease experience. PMID- 20962750 TI - Variation, selection and adaptation in fruit flies. PMID- 20962751 TI - Heart attacks and social isolation. PMID- 20962754 TI - Response to refusal to renew an expiring protocol: cruel to be kind. PMID- 20962755 TI - Refusal to renew an expiring protocol. PMID- 20962756 TI - Response to refusal to renew an expiring protocol: three strikes; PI's out! PMID- 20962757 TI - Response to refusal to renew an expiring protocol: IACUC acted appropriately, but... PMID- 20962758 TI - Response to refusal to renew an expiring protocol: a word from OLAW. PMID- 20962759 TI - Epidural anesthesia and analgesia in ferrets. AB - Anesthesia and analgesia should be provided to ferrets that are undergoing potentially painful surgical procedures. The epidural route of administration for anesthetic or analgesic drugs can be used. This column outlines the relevant ferret anatomy, indications and contraindications and technique of epidural administration of anesthesia and analgesia in ferrets. PMID- 20962760 TI - Evaluation of dosages and routes of administration of tramadol analgesia in rats using hot-plate and tail-flick tests. AB - Tramadol is an opioid-like analgesic with relatively mild side effects. Because it is inexpensive and is not classified as a controlled substance by the US federal government, the authors wanted to evaluate its applicability as a practical and effective analgesic in male Sprague Dawley rats. They measured the efficacy of four dosages (4, 12.5, 25 or 50 mg tramadol per kg body weight) and three routes of administration (per os (p.o.) in a flavored gelatin cube, subcutaneous (s.c.) or intraperitoneal (i.p.)) using the hot-plate test and the tail-flick test, which were carried out 1 week apart. Rats that were dosed p.o. were given flavored gelatin cubes without tramadol on the 2 d before testing to help them become acclimated to the gelatin, in an effort to increase the likelihood that they would consume the gelatin on the testing day. Results from the hot-plate and tail-flick tests for rats that were given tramadol p.o. were similar before and after administration, regardless of tramadol dosage, suggesting that this route of administration was not effective. The s.c. route of administration was effective at dosages of 25 mg and 50 mg tramadol per kg body weight, although these dosages also resulted in sedation and skin lesions. The i.p. route of administration was also effective at dosages of 12.5 mg, 25 mg and 50 mg tramadol per kg body weight, though sedation was observed at dosages of 25 mg and 50 mg per kg body weight. Intraperitoneal administration of 12.5 mg tramadol per kg body weight had no notable side effects, and the authors plan to further study this dosage and route of administration in a rodent surgical model of pain. PMID- 20962761 TI - Long-term subarachnoid catheter placement in the middle cranial fossa of the rat. AB - Research using rats sometimes requires long-term placement of catheters in the subarachnoid space, the cavity between the arachnoid mater and the pia mater in the brain. These catheters can be used to experimentally induce subarachnoid bleeding by injecting blood or to locally administer drugs or other substances. To date, published techniques for penetrating the subarachnoid space of small experimental animals require the use of inflexible or relatively inflexible catheters. These catheters typically consist of metal or stiff plastic and are used to access the occipital or frontal cranial cavity or to directly access the cisterna magna via the atlantooccipital membrane. However, inflexible catheters are not ideal for long-term placement in the subarachnoid space. In this paper, the authors describe a reliable procedure for long-term catheterization of the subarachnoid cavity of the rat. For this method, personnel insert the catheter and keep it in place in the rat's middle cranial cavity, in the vicinity of the cerebral arterial circle. This new approach allows personnel to repeatedly use the catheter for a period of at least 2 weeks. The catheter, which is well tolerated by rats, can be used for administering saline solutions and for injecting blood that has not been treated with heparin into the subarachnoid space. PMID- 20962762 TI - Designing a chamber for studies involving manipulation of light:dark cycles. AB - The authors designed and built a device that can house mice or rats and allow researchers to control the light:dark cycles inside. They developed this chamber for neuroscientists who are studying the condition-dependent plasticity of the mouse visual cortex. The chamber, which (when closed) completely blocks outside light, consists of two units. Each unit can hold eight small mouse cages or six rat cages. Each unit contains an optical sensor that triggers an audible and visual alarm when light is detected. Researchers can monitor the environmental conditions inside each unit using a control panel located outside the unit. Researchers have reported that this chamber is ideal for use in their work involving manipulations of light:dark cycles. PMID- 20962765 TI - Prolonged attenuation of the reinforcing strength of cocaine by chronic d amphetamine in rhesus monkeys. AB - Chronic treatment with the indirect dopamine agonist d-amphetamine can reduce cocaine use in clinical trials and, in preclinical studies in laboratory animals, attenuates daily cocaine self-administration. The present study extended previous results to conditions designed to reflect a more clinically relevant experience of cocaine exposure and d-amphetamine treatment. Each morning, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio schedule of reinforcement. After determining a dose-response curve for cocaine (0.003-0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule of reinforcement in the evening, cocaine self-administration sessions were suspended and d-amphetamine (0.01-0.056 mg/kg/h, i.v.) was administered continuously for at least 24 days, except during cocaine self-administration sessions, which were conducted using the PR schedule once every 8 days. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was redetermined. Cocaine- and food-maintained responding were also examined after discontinuation of d-amphetamine. Although individual differences in sensitivity were observed, d amphetamine produced selective, qualitatively similar decreases in the reinforcing strength of cocaine in all monkeys that persisted at least 4 weeks. Moreover, cocaine dose-effect curves were shifted downward and/or to the right. For 2 weeks following discontinuation of d-amphetamine treatment, the reinforcing strength of cocaine varied within and across individuals, however, on the whole no increased sensitivity was apparent. These data provide further support for the use of agonist medications for cocaine abuse, and extend the conditions under which such treatment is successful to those that incorporate clinically relevant patterns of cocaine use and drug treatment. PMID- 20962766 TI - Signs of preclinical Wernicke's encephalopathy and thiamine levels as predictors of neuropsychological deficits in alcoholism without Korsakoff's syndrome. AB - The purpose of this study was to determine whether meeting historical criteria for unsuspected Wernicke's encephalopathy (WE), largely under-diagnosed in vivo, explains why some alcoholics have severe neuropsychological deficits, whereas others, with a similar drinking history, exhibit preserved performance. Demographic, clinical, alcohol related, and neuropsychological measures were collected in 56 abstinent alcoholics and 38 non-alcohol-dependent volunteers. Alcoholics were classified using the clinical criteria established by Caine et al (1997) and validated in their neuropathological study of alcoholic cases. Our alcoholics who met a single criterion were considered 'at risk for WE' and those with two or more criteria with 'signs of WE'. Whole blood thiamine was also measured in 22 of the comparison group and 28 alcoholics. Of the alcoholics examined, 27% met no criteria, 57% were at risk for WE, and 16% had signs of WE. Neuropsychological performance of the alcoholic subgroups was graded, with those meeting zero criteria not differing from controls, those meeting one criterion presenting mild-to-moderate deficits on some of the functional domains, and those meeting two or more criteria having the most severe deficits on each of the domains examined. Thiamine levels were selectively related to memory performance in the alcoholics. Preclinical signs of WE can be diagnosed in vivo, enabling the identification of ostensibly 'uncomplicated' alcoholics who are at risk for neuropsychological complications. The graded effects in neuropsychological performance suggest that the presence of signs of WE explains, at least partially, the heterogeneity of alcoholism-related cognitive and motor deficits. PMID- 20962767 TI - Role of dorsal medial prefrontal cortex dopamine D1-family receptors in relapse to high-fat food seeking induced by the anxiogenic drug yohimbine. AB - In humans, relapse to maladaptive eating habits during dieting is often provoked by stress. In rats, the anxiogenic drug yohimbine, which causes stress-like responses in both humans and nonhumans, reinstates food seeking in a relapse model. In this study, we examined the role of medial prefrontal cortex (mPFC) dopamine D1-family receptors, previously implicated in stress-induced reinstatement of drug seeking, in yohimbine-induced reinstatement of food seeking. We trained food-restricted rats to lever press for 35% high-fat pellets every other day (9-15 sessions, 3 h each); pellet delivery was accompanied by a discrete tone-light cue. We then extinguished operant responding for 10-16 days by removing the pellets. Subsequently, we examined the effect of yohimbine (2 mg/kg, i.p.) on reinstatement of food seeking and Fos (a neuronal activity marker) induction in mPFC. We then examined the effect of systemic injections of the D1-family receptor antagonist SCH23390 (10 MUg/kg, s.c.) on yohimbine-induced reinstatement and Fos induction, and that of mPFC SCH23390 (0.5 and 1.0 MUg/side) injections on this reinstatement. Yohimbine-induced reinstatement was associated with strong Fos induction in the dorsal mPFC and with weaker Fos induction in the ventral mPFC. Systemic SCH23390 injections blocked both yohimbine-induced reinstatement and mPFC Fos induction. Dorsal, but not ventral, mPFC injections of SCH23390 decreased yohimbine-induced reinstatement of food seeking. In addition, dorsal mPFC SCH23390 injections decreased pellet-priming-induced reinstatement, but had no effect on ongoing high-fat pellet self-administration or discrete-cue induced reinstatement. Results indicate a critical role of dorsal mPFC dopamine D1-family receptors in stress-induced relapse to palatable food seeking, as well as relapse induced by acute re-exposure to food taste, texture, and smell. PMID- 20962768 TI - Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear. AB - Current models of conditioned fear expression and extinction involve the basolateral amygdala (BLA), ventral medial prefrontal cortex (vmPFC), and the hippocampus (HPC). There is some disagreement with respect to the specific roles of these structures, perhaps due to subregional differences within each area. For example, growing evidence suggests that infralimbic (IL) and prelimbic (PL) subregions of vmPFC have opposite influences on fear expression. Moreover, it is the ventral HPC (vHPC), rather than the dorsal HPC, that projects to vmPFC and BLA. To help determine regional specificity, we used small doses of the GABA(A) agonist muscimol to selectively inactivate IL, PL, BLA, or vHPC in an auditory fear conditioning and extinction paradigm. Infusions were performed prior to extinction training, allowing us to assess the effects on both fear expression and subsequent extinction memory. Inactivation of IL had no effect on fear expression, but impaired the within-session acquisition of extinction as well as extinction memory. In contrast, inactivation of PL impaired fear expression, but had no effect on extinction memory. Inactivation of the BLA or vHPC impaired both fear expression and extinction memory. Post-extinction inactivations had no effect in any structure. We suggest a model in which amygdala-dependent fear expression is modulated by inputs from PL and vHPC, whereas extinction memory requires extinction-induced plasticity in IL, BLA, and/or vHPC. PMID- 20962769 TI - NMDA receptor hypofunction phase couples independent gamma-oscillations in the rat visual cortex. AB - Hallucinations, a hallmark of psychosis, can be induced by the psychotomimetic N methyl-D-aspartic acid (NMDA) receptor antagonists, ketamine and phencyclidine (PCP), and are associated with hypersynchronization in the gamma-frequency band, but it is unknown how reduced interneuron activation associated with NMDA receptor hypofunction can cause hypersynchronization or distorted perception. Low frequency gamma-oscillations (LFgamma) and high-frequency gamma-oscillations (HFgamma) serve different aspects of perception. In this study, we test whether ketamine and PCP affect the interactions between HFgamma and LFgamma in the rat visual cortex in vitro. In slices of the rat visual cortex, kainate and carbachol induced LFgamma (~ 34 Hz at 32 degrees C) in layer V and HFgamma (~ 54 Hz) in layer III of the same cortical column. In controls, HFgamma and LFgamma were independent, and pyramidal neurons recorded in layer III were entrained by HFgamma, but not by LFgamma. Sub-anesthetic concentrations of ketamine selectively decelerated HFgamma by 22 Hz (EC(50)=2.7 MUM), to match the frequency of LFgamma in layer V. This caused phase coupling of the two gamma-oscillations, increased spatial coherence in layer III, and entrained the firing of layer III pyramidal neurons by LFgamma in layer V. PCP similarly decelerated HFgamma by 22 Hz (EC(50)=0.16 MUM), causing cross-layer phase coupling of gamma-oscillations. Selective NMDA receptor antagonism, selective NR2B subunit-containing receptor antagonism, and reduced D-serine levels caused a similar selective deceleration of HFgamma, whereas increasing NMDA receptor activation through exogenous NMDA, D serine, or mGluR group 1 agonism selectively accelerated HFgamma. The NMDA receptor hypofunction-induced phase coupling of the normally independent gamma generating networks is likely to cause abnormal cross-layer interactions, which may distort perceptions due to aberrant matching of top-down information with bottom-up information. If decelerated HFgamma and subsequent cross-layer synchronization also underlie pathological psychosis, acceleration of HFgamma could be the target for improved antipsychotic therapy. PMID- 20962770 TI - The ubiquitin ligase adaptor Ndfip1 regulates T cell-mediated gastrointestinal inflammation and inflammatory bowel disease susceptibility. AB - Nedd4 family interacting protein 1 (Ndfip1) is an adaptor protein that regulates Itch, an E3 ubiquitin ligase that ubiquitylates JunB, thereby preventing interleukin (IL)-4 and IL-5 production. Mice lacking Ndfip1 or Itch develop T helper type 2 (T(H)2)-mediated inflammation in the skin and lungs and die prematurely. In this study we show that Ndfip1-/- mice also develop inflammation in the gastrointestinal tract. Inflammation is characterized by infiltration of eosinophils and T cells and is accompanied by a failure to gain weight. T cells are both necessary and sufficient for eosinophil recruitment and inflammation. This is because Ndfip1-/- T cells become activated and produce IL-5. Itch mutant mice develop much less severe gastrointestinal inflammation, suggesting that Ndfip1 regulation of Itch cannot entirely account for this phenotype and that Ndfip1 has both Itch-dependent and Itch-independent roles. Ndfip1 may also regulate human disease. We found single-nucleotide polymorphisms in the Ndfip1 locus that associate with inflammatory bowel disease. Taken together, our data support a role for Ndfip1 in gastrointestinal inflammation in both mice and humans. PMID- 20962771 TI - Sustained TL1A expression modulates effector and regulatory T-cell responses and drives intestinal goblet cell hyperplasia. AB - The tumor necrosis factor (TNF) superfamily protein TNF-like 1A (TL1A) is the ligand for death receptor 3 (DR3). TL1A is induced on activated dendritic cells (DCs) and its expression has been linked to human inflammatory bowel disease. To address how TL1A might influence intestinal inflammation, we generated transgenic mice that constitutively express TL1A on DCs. TL1A transgenic mice developed striking goblet cell hyperplasia in the ileum that was associated with elevated interleukin (IL)-13 levels in the small intestine. IL-13- and IL-17-producing small intestinal lamina propria T cells were increased in TL1A transgenic mice. TL1A also enhanced regulatory T (Treg) cell turnover in vivo and directly stimulated Treg cell proliferation in vitro. The presence of TL1A attenuated the ability of Treg cells to suppress conventional T cells, an effect that required DR3 signaling in either conventional T cells or Treg cells. Our findings identify mechanisms by which chronic DR3 signaling could promote pathogenesis in inflammatory bowel disease. PMID- 20962774 TI - Conditional approval and approval under exceptional circumstances as regulatory instruments for stimulating responsible drug innovation in Europe. AB - The need for fast drug innovation and the public demand for risk-free drugs creates a dilemma for regulatory authorities: less restrictive procedures involve uncertainties about benefit/risk profiles of new drugs. The European Union has introduced two instruments that regulate early market access: conditional approvals (CAs) and approvals under exceptional circumstances (ECs). We have studied whether these instruments compromise the safety of new drugs and whether they lead to earlier access to innovative drugs. Our study shows that neither of these regulatory pathways accelerates the approval process for innovative drugs. However, the CA pathway shortens the clinical development period. Approvals under ECs are associated with longer clinical development periods, but this regulatory pathway may open up opportunities for specific drugs to be admitted into the market because less comprehensive data are required. Despite the fact that these advanced approvals are based on limited safety databases, there are no special safety issues associated with using these pathways. PMID- 20962773 TI - Reactive oxygen species mediate inflammatory cytokine release and EGFR-dependent mucin secretion in airway epithelial cells exposed to Pseudomonas pyocyanin. AB - Despite the long-appreciated in vivo role of the redox-active virulence factor pyocyanin in Pseudomonas airway infections and the importance of airway epithelial cells in combating bacterial pathogens, little is known about pyocyanin's effect on airway epithelial cells. We find that exposure of bronchiolar epithelial cells to pyocyanin results in MUC2/MUC5AC induction and mucin secretion through release of inflammatory cytokines and growth factors (interleukin (IL)-1beta, IL-6, heparin-bound epidermal growth factor, tissue growth factor-alpha, tumor necrosis factor-alpha) that activate the epidermal growth factor receptor pathway. These changes are mediated by reactive oxygen species produced by pyocyanin. Microarray analysis identified 286 pyocyanin induced genes in airway epithelial cells, including many inflammatory mediators elevated in cystic fibrosis (granulocyte colony-stimulating factor (G-CSF), granulocyte-monocyte CSF, chemokine (C-X-C motif) ligand 1 (CXCL1), serum amyloid, IL-23) and several novel pyocyanin-responsive genes of potential importance in the infection process (IL-24, CXCL2, CXCL3, CCL20, CXCR4). This comprehensive study uncovers numerous details of pyocyanin's proinflammatory action and establishes airway epithelial cells as key responders to this microbial toxin. PMID- 20962772 TI - Intestinal macrophages and response to microbial encroachment. AB - Macrophages in the gastrointestinal mucosa represent the largest pool of tissue macrophages in the body. In order to maintain mucosal homeostasis, resident intestinal macrophages uniquely do not express the lipopolysaccharide (LPS) co receptor CD14 or the IgA (CD89) and IgG (CD16, 32, and 64) receptors, yet prominently display Toll-like receptors (TLRs) 3-9. Remarkably, intestinal macrophages also do not produce proinflammatory cytokines in response to TLR ligands, likely because of extracellular matrix (stromal) transforming growth factor-beta (TGF-beta) dysregulation of nuclear factor (NF)-kappaB signal proteins and, via Smad signaling, expression of IkappaBalpha, thereby inhibiting NF-kappaB-mediated activities. Thus, in noninflamed mucosa, resident macrophages are inflammation anergic but retain avid scavenger and host defense function, an ideal profile for macrophages in close proximity to gut microbiota. In the event of impaired epithelial integrity during intestinal infection or inflammation, however, blood monocytes also accumulate in the lamina propria and actively pursue invading microorganisms through uptake and degradation of the organism and release of inflammatory mediators. Consequently, resident intestinal macrophages are inflammation adverse, but when the need arises, they receive assistance from newly recruited circulating monocytes. PMID- 20962775 TI - Pharmacy benefit managers: evaluating clinical utility in the real world. AB - Over the years, pharmacy benefit managers (PBMs) have conducted and published peer-reviewed research covering a broad spectrum of activities ranging from studying the impact of alternative-benefit designs on outcomes to identifying the epidemiology of treated disease to understanding the impact of medication use on overall health-care costs. It is the unique "wired" interactive role in the health-care system that enables PBMs to play an emerging role in evaluating the clinical utility of biomarkers. PMID- 20962776 TI - Maximizing the clinical utility of comparative effectiveness research. AB - Providers, consumers, payers, and policy makers are awash in choices when it comes to medical decision making and need better evidence to inform their decisions. Large federal investments in comparative effectiveness research (CER) aim to fill this need. But how do we ensure the clinical utility of CER? Here, I define comparative effectiveness and clinical utility, outline metrics to evaluate clinical utility, and suggest methods for maximizing the clinical utility of CER for the various stakeholders. PMID- 20962778 TI - Formation of the black-hole binary M33 X-7 through mass exchange in a tight massive system. AB - The X-ray source M33 X-7 in the nearby galaxy Messier 33 is among the most massive X-ray binary stellar systems known, hosting a rapidly spinning, 15.65M(?) black hole orbiting an underluminous, 70M(?) main-sequence companion in a slightly eccentric 3.45-day orbit (M(?), solar mass). Although post-main-sequence mass transfer explains the masses and tight orbit, it leaves unexplained the observed X-ray luminosity, the star's underluminosity, the black hole's spin and the orbital eccentricity. A common envelope phase, or rotational mixing, could explain the orbit, but the former would lead to a merger and the latter to an overluminous companion. A merger would also ensue if mass transfer to the black hole were invoked for its spin-up. Here we report simulations of evolutionary tracks which reveal that if M33 X-7 started as a primary body of 85M(?)-99M(?) and a secondary body of 28M(?)-32M(?), in a 2.8-3.1-d orbit, its observed properties can be consistently explained. In this model, the main-sequence primary transfers part of its envelope to the secondary and loses the rest in a wind; it ends its life as a ~16M(?) helium star with an iron-nickel core that collapses to a black hole (with or without an accompanying supernova). The release of binding energy, and possibly collapse asymmetries, 'kick' the nascent black hole into an eccentric orbit. Wind accretion explains the X-ray luminosity, and the black-hole spin can be natal. PMID- 20962777 TI - A methyl transferase links the circadian clock to the regulation of alternative splicing. AB - Circadian rhythms allow organisms to time biological processes to the most appropriate phases of the day-night cycle. Post-transcriptional regulation is emerging as an important component of circadian networks, but the molecular mechanisms linking the circadian clock to the control of RNA processing are largely unknown. Here we show that PROTEIN ARGININE METHYL TRANSFERASE 5 (PRMT5), which transfers methyl groups to arginine residues present in histones and Sm spliceosomal proteins, links the circadian clock to the control of alternative splicing in plants. Mutations in PRMT5 impair several circadian rhythms in Arabidopsis thaliana and this phenotype is caused, at least in part, by a strong alteration in alternative splicing of the core-clock gene PSEUDO RESPONSE REGULATOR 9 (PRR9). Furthermore, genome-wide studies show that PRMT5 contributes to the regulation of many pre-messenger-RNA splicing events, probably by modulating 5'-splice-site recognition. PRMT5 expression shows daily and circadian oscillations, and this contributes to the mediation of the circadian regulation of expression and alternative splicing of a subset of genes. Circadian rhythms in locomotor activity are also disrupted in dart5-1, a mutant affected in the Drosophila melanogaster PRMT5 homologue, and this is associated with alterations in splicing of the core-clock gene period and several clock-associated genes. Our results demonstrate a key role for PRMT5 in the regulation of alternative splicing and indicate that the interplay between the circadian clock and the regulation of alternative splicing by PRMT5 constitutes a common mechanism that helps organisms to synchronize physiological processes with daily changes in environmental conditions. PMID- 20962779 TI - Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. AB - Accumulation of amyloid fibrils in the viscera and connective tissues causes systemic amyloidosis, which is responsible for about one in a thousand deaths in developed countries. Localized amyloid can also have serious consequences; for example, cerebral amyloid angiopathy is an important cause of haemorrhagic stroke. The clinical presentations of amyloidosis are extremely diverse and the diagnosis is rarely made before significant organ damage is present. There is therefore a major unmet need for therapy that safely promotes the clearance of established amyloid deposits. Over 20 different amyloid fibril proteins are responsible for different forms of clinically significant amyloidosis and treatments that substantially reduce the abundance of the respective amyloid fibril precursor proteins can arrest amyloid accumulation. Unfortunately, control of fibril-protein production is not possible in some forms of amyloidosis and in others it is often slow and hazardous. There is no therapy that directly targets amyloid deposits for enhanced clearance. However, all amyloid deposits contain the normal, non-fibrillar plasma glycoprotein, serum amyloid P component (SAP). Here we show that administration of anti-human-SAP antibodies to mice with amyloid deposits containing human SAP triggers a potent, complement-dependent, macrophage-derived giant cell reaction that swiftly removes massive visceral amyloid deposits without adverse effects. Anti-SAP-antibody treatment is clinically feasible because circulating human SAP can be depleted in patients by the bis-d-proline compound CPHPC, thereby enabling injected anti-SAP antibodies to reach residual SAP in the amyloid deposits. The unprecedented capacity of this novel combined therapy to eliminate amyloid deposits should be applicable to all forms of systemic and local amyloidosis. PMID- 20962780 TI - Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. AB - Aneuploidy, referring here to genome contents characterized by abnormal numbers of chromosomes, has been associated with developmental defects, cancer and adaptive evolution in experimental organisms. However, it remains unresolved how aneuploidy impacts gene expression and whether aneuploidy could directly bring about phenotypic variation and improved fitness over that of euploid counterparts. Here we show, using quantitative mass spectrometry-based proteomics and phenotypic profiling, that levels of protein expression in aneuploid yeast strains largely scale with chromosome copy numbers, following the same trend as that observed for the transcriptome, and that aneuploidy confers diverse phenotypes. We designed a novel scheme to generate, through random meiotic segregation, 38 stable and fully isogenic aneuploid yeast strains with distinct karyotypes and genome contents between 1N and 3N without involving any genetic selection. Through quantitative growth assays under various conditions or in the presence of a panel of chemotherapeutic or antifungal drugs, we found that some aneuploid strains grew significantly better than euploid control strains under conditions suboptimal for the latter. These results provide strong evidence that aneuploidy directly affects gene expression at both the transcriptome and proteome levels and can generate significant phenotypic variation that could bring about fitness gains under diverse conditions. Our findings suggest that the fitness ranking between euploid and aneuploid cells is dependent on context and karyotype, providing the basis for the notion that aneuploidy can directly underlie phenotypic evolution and cellular adaptation. PMID- 20962781 TI - Relationship between ambulatory arterial stiffness index and subclinical target organ damage in hypertensive patients. AB - Increased arterial stiffness has been shown to predict cardiovascular risk in hypertensive patients. Our objective was to evaluate the relationship between the ambulatory arterial stiffness index (AASI) and subclinical organ damage (SOD). The design was a cross-sectional study. Subjects included 554 hypertensive patients with and without drug treatment (mean age 57+/-12 years, 60.6% men). The AASI was defined as 1 minus the regression slope of diastolic over systolic blood pressure (BP) readings obtained from 24-h recordings. Renal damage was evaluated on the basis of glomerular filtration rate (GFR) and microalbuminuria; vascular damage was measured by carotid intima-media thickness (IMT) and ankle/brachial index (ABI); and cardiac damage was evaluated on the basis of the Cornell voltage duration product (VDP) and left ventricular mass index. The mean AASI was 0.38+/ 0.07 (0.39+/-0.07 in treated patients and 0.37+/-0.06 in nontreated subjects). The AASI showed a positive correlation with IMT (r=0.417, P<0.001) and Cornell VDP (r=0.188, P<0.001), and a negative correlation with GFR (r=-0.205, P=0.001) and the ABI. The variables associated with the presence of SOD were AASI (odds ratio (OR)=3.89) and smoking (OR=1.55). The variables associated with IMT were smoking and waist circumference, whereas those associated with GFR were AASI, body mass index and waist circumference. In turn, smoking, total cholesterol and glycosylated hemoglobin A1c were associated with the ABI. Increased AASI implies a greater presence of SOD in primary hypertensive patients with or without BP lowering drug treatment. PMID- 20962782 TI - Association of nighttime hypertension with central arterial stiffness and urinary albumin excretion in dipper hypertensive subjects. AB - Both blood pressure (BP) non-dipping and nighttime hypertension have been associated with accelerated target-organ damage (TOD). However, increased nighttime BP in subjects with a dipping circadian BP profile has never been reported or associated with TOD. Here, we investigated the relationships of nighttime BP with indices of vascular and kidney damage in dipper hypertensive subjects. We studied 402 subjects with untreated stage I-II essential hypertension. According to ambulatory BP recordings, 127 dipper subjects were selected and subdivided into nighttime hypertensives (NH, n = 69) (nighttime BP >= 120/70) and nighttime normotensives (NN, n = 50) (nighttime BP <120/70 mm Hg). All participants underwent echocardiographic examination and assessments of carotid-to-femoral pulse wave velocity (c-f PWV), albumin-to-creatinine ratio (ACR), metabolic profile and high sensitivity C-reactive protein (hs-CRP) level. Compared with NN dippers, NH dippers had higher c-f PWV (P < 0.001), ACR values (P = 0.01) and hs-CRP levels (P < 0.001). Multiple regression analysis showed that nighttime BP was more correlated with c-f PWV and ACR than was daytime BP. Among dippers, nighttime BP is associated more closely with c-f PWV and ACR than is daytime BP. These findings imply that even in dippers, absolute nighttime BP values should be taken into account when predicting surrogate end points such as arterial stiffness and urinary albumin excretion. PMID- 20962783 TI - Can arterial stiffness parameters be measured in the sitting position? AB - Despite the introduction of arterial stiffness measurements in the European recommendation, pulse wave velocity (PWV) and augmentation index (AI) are still not used routinely in clinical practice. It would be of advantage if such measurements were done in the sitting position as is done for blood pressure. The aim of this study was to evaluate whether there is a difference in stiffness parameters in sitting vs. supine position. Arterial stiffness was measured in 24 healthy volunteers and 20 patients with cardiovascular disease using three different devices: SphygmoCor (Atcor Medical, Sydney, Australia), Arteriograph (TensioMed, Budapest, Hungary) and Vascular Explorer (Enverdis, Jena, Germany). Three measurements were performed in supine position followed by three measurements in sitting position. Methods were compared using correlation and Bland-Altman analysis. There was a significant correlation between PWV in supine and sitting position (Arteriograph: P<0.0001, r=0.93; Vascular Explorer; P<0.0001, r=0.87). There were significant correlations between AI sitting and AI supine using Arteriograph (P<0.0001, r=0.97), Vascular Explorer (P<0.0001, r=0.98) and SphygmoCor (P<0.0001, r=0.96). When analyzed by Bland-Altman, PWV and AI measurements in supine vs. sitting showed good agreement. There was no significant difference in PWV obtained with the three different devices (Arteriograph 7.5+/-1.6 m s(-1), Vascular Explorer 7.3+/-0.9 m s(-1), SphygmoCor 7.0+/-1.8 m s(-1)). AI was significantly higher using the Arteriograph (17.6+/ 15.0%) than Vascular Explorer and SphygmoCor (10.2+/-15.1% and 10.3+/-18.1%, respectively). The close agreement between sitting and supine measurements suggests that both PWV and AI can be reliably measured in the sitting position. PMID- 20962784 TI - Should primary aldosteronism be diagnosed among normotensive subjects during general health check-up and/or at general outpatient clinics? PMID- 20962785 TI - Does primary aldosteronism exist in normotensive and mildly hypertensive patients, and should we look for it? PMID- 20962786 TI - Does immunosuppressant medication lower blood pressure and arterial stiffness in patients with chronic kidney disease? An observational study. AB - Chronic kidney disease is a proinflammatory state associated with increased arterial stiffness. We hypothesized that chronic kidney disease patients on long term immunosuppression would have lower arterial stiffness and require treatment with less antihypertensive medication compared with non-immunosuppressed patients. A total of 254 patients (97 on immunosuppression) with chronic kidney disease were recruited from specialist renal clinics. Brachial blood pressure, central aortic pressure and waveform and pulse wave velocity were measured. Age, peripheral blood pressure and pulse wave velocity increased with worsening renal function but were not different between immunosuppressed and non-immunosuppressed patients. Central systolic (P < 0.001) and pulse pressure (P = 0.003) and the number of antihypertensive medications (P < 0.001) increased with worsening renal function and were higher in non-immunosuppressed patients (P = 0.02, P = 0.004 and P < 0.001, respectively). Age, mean arterial pressure, number of antihypertensive medications and a diagnosis of diabetes were found to be independent predictors of pulse wave velocity (R(2) = 0.375; P < 0.001). In a subgroup of 30 patient pairs without diabetes mellitus and cardiovascular disease and with a proven renal diagnosis, carefully matched for age, gender, renal function and systolic pressure, the prescribed antihypertensive medication remained lower in the immunosuppressed patients compared with non immunosuppressed patients (P = 0.04). Pulse wave velocity was lower in the immunosuppressed group (7.5 +/- 1.8 vs. 8.8 +/- 1.9 m s(-1); P = 0.02). This study suggests that immunosuppression might be a method of reducing blood pressure and arterial stiffness in patients with chronic kidney disease. PMID- 20962787 TI - Relationship between chronic kidney disease and sleep blood pressure in patients with sleep apnea syndrome. AB - Chronic kidney disease (CKD) is common disease in patients with sleep apnea syndrome (SAS), which is considered to be responsible for secondary and nocturnal hypertension. In this study, we assessed blood pressure (BP) changes in SAS patients with CKD. Of 460 Japanese outpatients with suspected SAS who underwent ambulatory BP monitoring within 3 months of overnight polysomnography, 198 patients (172 males and 26 females) who were not receiving treatment with antihypertensives or nitroglycerin were enrolled. The estimated glomerular filtration rate (eGFR) was calculated, and the patients were stratified into the high (H; eGFR>=60 ml min-1 per 1.73 m2) or the low (L; eGFR<60 ml min-1 per 1.73 m2) group. The patients in the L group were significantly older than those in the H group (P<0.001), and body mass index was significantly smaller in the L group than in the H group (P=0.025). The rate of patients treated with statin (P=0.030) and the levels of both triglyceride (P=0.006) and creatinine (P<0.001) differed significantly between the two groups. The sleep data, 24-h BP, awake BP and morning BP showed no significant differences between the two groups. However, sleep systolic and diastolic BPs were significantly higher in the L group (122.5+/-16.7 mm Hg and 81.1+/-12.2 mm Hg, respectively) than in the H group (117.1+/-11.8 mm Hg, P=0.033; and 76.1+/-9.5 mm Hg, P=0.012, respectively). SAS patients with CKD had elevated sleep BP. This result suggests that appropriate treatments for both SAS and CKD prevent sleep BP elevation, which is considered a risk factor for the onset risk of a cardiovascular event. PMID- 20962788 TI - Increased arterial stiffness in obstructive sleep apnea: a systematic review. AB - Obstructive sleep apnea is a prevalent disease that is associated with significant morbidity and mortality, particularly due to cardiovascular disease. An emerging cardiovascular risk factor, arterial stiffness, may also be involved in the cardiovascular complications of obstructive sleep apnea. The purpose of this review was to summarize the current literature regarding the effect of obstructive sleep apnea on arterial stiffness. We conducted a systematic literature review using PubMed, Embase and the Cochrane Library. We identified 24 studies that met search criteria investigating the effect of obstructive sleep apnea on arterial stiffness. Arterial stiffness was found to be increased in obstructive sleep apnea patients compared with controls or increased in severe compared with mild sleep apnea. In some studies, a positive correlation was identified between the degree of arterial stiffness and sleep apnea severity. In the two randomized, controlled trials and the two nonrandomized trials identified, treatment of obstructive sleep apnea with continuous positive airway pressure led to significant decreases in arterial stiffness. Obstructive sleep apnea appears to have an independent effect on arterial stiffness, which may be one of the mechanisms accounting for sleep apnea-associated cardiovascular risk. PMID- 20962789 TI - RGS2 determines the preventive effects of ARBs against vascular remodeling: toward personalized medicine of anti-hypertensive therapy with ARBs. PMID- 20962790 TI - How to evaluate real-world medicine in a Japanese population: important lessons from the JIKEI, CASE-J, KYOTO and VART studies. PMID- 20962791 TI - Methylenetetrahydrofolate reductase gene polymorphisms and cerebral palsy in Chinese infants. AB - Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) have been suggested as being associated with cerebral palsy (CP) but the evidence is uncertain. The purpose of this study was to investigate whether MTHFR gene polymorphisms contribute to the development of CP in Chinese infants. For this study, 169 health controls and 159 infants with CP including 43 cases also suffering from mental retardation (MR) were recruited. Genomic DNA was prepared from venous blood and all five single nucleotide polymorphisms in MTHFR (rs4846049, rs1476413, rs1801131, rs1801133 and rs9651118) were genotyped using TaqMan technology. There were no significant differences in allele or genotype frequencies between the CP patients and controls at any of the five genetic polymorphisms. Subgroup analysis found statistically significant difference in allele and genotype frequencies between cases with both CP and MR (CP + MR) compared with both CP-only cases and controls at rs4846049, rs1476413 and rs1801131. The frequencies of the T alleles of rs4846049, rs1476413 and the G allele of rs1801131 were greater in the CP + MR patients than in the CP-only patients and controls. This study provides the first evidence pointing to a MTHFR gene polymorphism as a potential risk factor for CP combined with MR. PMID- 20962795 TI - Save our cities. PMID- 20962793 TI - An investigation of sexual dysfunction in female partners of men with erectile dysfunction: how interviews expand on questionnaire responses. AB - Using the Female Sexual Function Index (FSFI) for investigating female sexual function has become widespread. A score of 26.5 has been suggested as delineating 'functional' from 'dysfunctional' women. This study aimed to understand in greater detail what contributes to changes in women's FSFI scores while their partners are taking oral erectile medications for erection problems. Couples randomized to receive two erectile medications for two 3-month phases, completed questionnaires. FSFI scores were augmented by individual interviews at baseline, 3 and 6 months, in order to better understand what the scores meant in the context of ED medication use. In all, 50% of the women scored <26.5 at baseline; of these 56% recovered by 6 months. A number of 'dysfunctional' women recorded low FSFI scores solely as a result of their partner's ED. Overall, 22% were still 'dysfunctional' at 6 months, but one third of these appeared 'functional' at 3 months. A further group of women continued to record low scores despite reporting much improved sexual satisfaction. The women's interviews elaborate on their FSFI results, with five themes emerging to provide more clarity about the relative changes seen in a prospective study situation, and potentially in clinical practise contexts. The increasing use of questionnaires to determine sexual function should be supplemented with good clinical interviewing. The interview details explain how FSFI fluctuations occurred and contain clinical implications for research and practise in the area of couple's sexuality. PMID- 20962796 TI - The balance of probabilities. PMID- 20962797 TI - A hammer blow to national ethics. PMID- 20962798 TI - Scientists vs engineers: this time it's financial. PMID- 20962810 TI - IPCC signs up for reform. PMID- 20962812 TI - Superlaser fires a blank. PMID- 20962811 TI - Elemental shift for kilo. PMID- 20962813 TI - UK science funds in limbo. PMID- 20962814 TI - Ireland defends research from cuts. PMID- 20962815 TI - Quango bonfire kindles advice fears. PMID- 20962816 TI - Paris plans science in the suburbs. PMID- 20962817 TI - Gene-synthesis rules favour convenience. PMID- 20962818 TI - Cities: The urban equation. PMID- 20962819 TI - Cities: The century of the city. PMID- 20962820 TI - Environment: Mexico's scientist in chief. PMID- 20962821 TI - Cities: Building the best cities for science. PMID- 20962822 TI - Cities lead the way in climate-change action. PMID- 20962823 TI - A unified theory of urban living. PMID- 20962824 TI - Vital statistics. PMID- 20962828 TI - Concrete evidence of confusion. PMID- 20962829 TI - Nature redesign: what's not to like? PMID- 20962830 TI - Let's keep the debate focused. PMID- 20962832 TI - Nature redesign: what is to dislike. PMID- 20962833 TI - Metabolic disorders: Fathers' nutritional legacy. PMID- 20962834 TI - Nanotechnology: Beyond the confines of templates. PMID- 20962835 TI - Astronomy: Galaxy sets distance mark. PMID- 20962836 TI - Structural biology: Last of the multidrug transporters. PMID- 20962837 TI - Atmospheric physics: Chorus keeps the diffuse aurora humming. PMID- 20962840 TI - Spectroscopic confirmation of a galaxy at redshift z = 8.6. AB - Galaxies had their most significant impact on the Universe when they assembled their first generations of stars. Energetic photons emitted by young, massive stars in primeval galaxies ionized the intergalactic medium surrounding their host galaxies, cleared sightlines along which the light of the young galaxies could escape, and fundamentally altered the physical state of the intergalactic gas in the Universe continuously until the present day. Observations of the cosmic microwave background, and of galaxies and quasars at the highest redshifts, suggest that the Universe was reionized through a complex process that was completed about a billion years after the Big Bang, by redshift z ~ 6. Detecting ionizing Lyman-alpha photons from increasingly distant galaxies places important constraints on the timing, location and nature of the sources responsible for reionization. Here we report the detection of Lyalpha photons emitted less than 600 million years after the Big Bang. UDFy-38135539 (ref. 5) is at a redshift of z = 8.5549 +/- 0.0002, which is greater than those of the previously known most distant objects, at z = 8.2 (refs 6 and 7) and z = 6.96 (ref. 8). We find that this single source is unlikely to provide enough photons to ionize the volume necessary for the emission line to escape, requiring a significant contribution from other, probably fainter galaxies nearby. PMID- 20962839 TI - The energetics of genome complexity. AB - All complex life is composed of eukaryotic (nucleated) cells. The eukaryotic cell arose from prokaryotes just once in four billion years, and otherwise prokaryotes show no tendency to evolve greater complexity. Why not? Prokaryotic genome size is constrained by bioenergetics. The endosymbiosis that gave rise to mitochondria restructured the distribution of DNA in relation to bioenergetic membranes, permitting a remarkable 200,000-fold expansion in the number of genes expressed. This vast leap in genomic capacity was strictly dependent on mitochondrial power, and prerequisite to eukaryote complexity: the key innovation en route to multicellular life. PMID- 20962841 TI - Scattering by chorus waves as the dominant cause of diffuse auroral precipitation. AB - Earth's diffuse aurora occurs over a broad latitude range and is primarily caused by the precipitation of low-energy (0.1-30-keV) electrons originating in the central plasma sheet, which is the source region for hot electrons in the nightside outer magnetosphere. Although generally not visible, the diffuse auroral precipitation provides the main source of energy for the high-latitude nightside upper atmosphere, leading to enhanced ionization and chemical changes. Previous theoretical studies have indicated that two distinct classes of magnetospheric plasma wave, electrostatic electron cyclotron harmonic waves and whistler-mode chorus waves, could be responsible for the electron scattering that leads to diffuse auroral precipitation, but it has hitherto not been possible to determine which is the more important. Here we report an analysis of satellite wave data and Fokker-Planck diffusion calculations which reveals that scattering by chorus is the dominant cause of the most intense diffuse auroral precipitation. This resolves a long-standing controversy. Furthermore, scattering by chorus can remove most electrons as they drift around Earth's magnetosphere, leading to the development of observed pancake distributions, and can account for the global morphology of the diffuse aurora. PMID- 20962842 TI - Nonlinear electrophoresis of dielectric and metal spheres in a nematic liquid crystal. AB - Electrophoresis is a motion of charged dispersed particles relative to a fluid in a uniform electric field. The effect is widely used to separate macromolecules, to assemble colloidal structures and to transport particles in nano- and microfluidic devices and displays. Typically, the fluid is isotropic (for example, water) and the electrophoretic velocity is linearly proportional to the electric field. In linear electrophoresis, only a direct-current (d.c.) field can drive the particles. An alternating-current (a.c.) field is more desirable because it makes it possible to overcome problems such as electrolysis and the absence of steady flows. Here we show that when the electrophoresis is performed in a liquid-crystalline nematic fluid, the effect becomes strongly nonlinear, with a velocity component that is quadratic in the applied voltage and has a direction that generally differs from the direction of linear velocity. The new phenomenon is caused by distortions of the liquid-crystal orientation around the particle that break the fore-aft (or left-right) symmetry. The effect makes it possible to transport both charged and neutral particles, even when the particles themselves are perfectly symmetric (spherical), thus allowing new approaches in display technologies, colloidal assembly and separation, microfluidic and micromotor applications. PMID- 20962843 TI - Continental warming preceding the Palaeocene-Eocene thermal maximum. AB - Marine and continental records show an abrupt negative shift in carbon isotope values at ~55.8 Myr ago. This carbon isotope excursion (CIE) is consistent with the release of a massive amount of isotopically light carbon into the atmosphere and was associated with a dramatic rise in global temperatures termed the Palaeocene-Eocene thermal maximum (PETM). Greenhouse gases released during the CIE, probably including methane, have often been considered the main cause of PETM warming. However, some evidence from the marine record suggests that warming directly preceded the CIE, raising the possibility that the CIE and PETM may have been linked to earlier warming with different origins. Yet pre-CIE warming is still uncertain. Disentangling the sequence of events before and during the CIE and PETM is important for understanding the causes of, and Earth system responses to, abrupt climate change. Here we show that continental warming of about 5 degrees C preceded the CIE in the Bighorn Basin, Wyoming. Our evidence, based on oxygen isotopes in mammal teeth (which reflect temperature-sensitive fractionation processes) and other proxies, reveals a marked temperature increase directly below the CIE, and again in the CIE. Pre-CIE warming is also supported by a negative amplification of delta(13)C values in soil carbonates below the CIE. Our results suggest that at least two sources of warming-the earlier of which is unlikely to have been methane-contributed to the PETM. PMID- 20962844 TI - Demographic compensation and tipping points in climate-induced range shifts. AB - To persist, species are expected to shift their geographical ranges polewards or to higher elevations as the Earth's climate warms. However, although many species' ranges have shifted in historical times, many others have not, or have shifted only at the high-latitude or high-elevation limits, leading to range expansions rather than contractions. Given these idiosyncratic responses to climate warming, and their varied implications for species' vulnerability to climate change, a critical task is to understand why some species have not shifted their ranges, particularly at the equatorial or low-elevation limits, and whether such resilience will last as warming continues. Here we show that compensatory changes in demographic rates are buffering southern populations of two North American tundra plants against the negative effects of a warming climate, slowing their northward range shifts, but that this buffering is unlikely to continue indefinitely. Southern populations of both species showed lower survival and recruitment but higher growth of individual plants, possibly owing to longer, warmer growing seasons. Because of these and other compensatory changes, the population growth rates of southern populations are not at present lower than those of northern ones. However, continued warming may yet prove detrimental, as most demographic rates that improved in moderately warmer years declined in the warmest years, with the potential to drive future population declines. Our results emphasize the need for long-term, range-wide measurement of all population processes to detect demographic compensation and to identify nonlinear responses that may lead to sudden range shifts as climatic tipping points are exceeded. PMID- 20962845 TI - Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. AB - The global prevalence of obesity is increasing across most ages in both sexes. This is contributing to the early emergence of type 2 diabetes and its related epidemic. Having either parent obese is an independent risk factor for childhood obesity. Although the detrimental impacts of diet-induced maternal obesity on adiposity and metabolism in offspring are well established, the extent of any contribution of obese fathers is unclear, particularly the role of non-genetic factors in the causal pathway. Here we show that paternal high-fat-diet (HFD) exposure programs beta-cell 'dysfunction' in rat F(1) female offspring. Chronic HFD consumption in Sprague-Dawley fathers induced increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had an early onset of impaired insulin secretion and glucose tolerance that worsened with time, and normal adiposity. Paternal HFD altered the expression of 642 pancreatic islet genes in adult female offspring (P < 0.01); genes belonged to 13 functional clusters, including cation and ATP binding, cytoskeleton and intracellular transport. Broader pathway analysis of 2,492 genes differentially expressed (P < 0.05) demonstrated involvement of calcium-, MAPK- and Wnt-signalling pathways, apoptosis and the cell cycle. Hypomethylation of the Il13ra2 gene, which showed the highest fold difference in expression (1.76-fold increase), was demonstrated. This is the first report in mammals of non-genetic, intergenerational transmission of metabolic sequelae of a HFD from father to offspring. PMID- 20962846 TI - Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. AB - CD4(+) T-helper cells that selectively produce interleukin (IL)-17 (T(H)17), are critical for host defence and autoimmunity. Although crucial for T(H)17 cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-beta1 have been proposed to be the factors responsible for initiating specification. Here we show that T(H)17 differentiation can occur in the absence of TGF-beta signalling. Neither IL-6 nor IL-23 alone efficiently generated T(H)17 cells; however, these cytokines in combination with IL-1beta effectively induced IL-17 production in naive precursors, independently of TGF-beta. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-beta1, allowing the generation of cells that co-expressed RORgammat (encoded by Rorc) and T-bet. T bet(+)RORgammat(+) T(H)17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred T(H)17 cells generated with IL-23 without TGF-beta1 were pathogenic in this disease model. These data indicate an alternative mode for T(H)17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications. PMID- 20962847 TI - Maternal Rnf12/RLIM is required for imprinted X-chromosome inactivation in mice. AB - Two forms of X-chromosome inactivation (XCI) ensure the selective silencing of female sex chromosomes during mouse embryogenesis. Imprinted XCI begins with the detection of Xist RNA expression on the paternal X chromosome (Xp) at about the four-cell stage of embryonic development. In the embryonic tissues of the inner cell mass, a random form of XCI occurs in blastocysts that inactivates either Xp or the maternal X chromosome (Xm). Both forms of XCI require the non-coding Xist RNA that coats the inactive X chromosome from which it is expressed. Xist has crucial functions in the silencing of X-linked genes, including Rnf12 (refs 3, 4) encoding the ubiquitin ligase RLIM (RING finger LIM-domain-interacting protein). Here we show, by targeting a conditional knockout of Rnf12 to oocytes where RLIM accumulates to high levels, that the maternal transmission of the mutant X chromosome (Deltam) leads to lethality in female embryos as a result of defective imprinted XCI. We provide evidence that in Deltam female embryos the initial formation of Xist clouds and Xp silencing are inhibited. In contrast, embryonic stem cells lacking RLIM are able to form Xist clouds and silence at least some X linked genes during random XCI. These results assign crucial functions to the maternal deposit of Rnf12/RLIM for the initiation of imprinted XCI. PMID- 20962848 TI - TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. AB - Aberrant expression of microRNAs (miRNAs) and the enzymes that control their processing have been reported in multiple biological processes including primary and metastatic tumours, but the mechanisms governing this are not clearly understood. Here we show that TAp63, a p53 family member, suppresses tumorigenesis and metastasis, and coordinately regulates Dicer and miR-130b to suppress metastasis. Metastatic mouse and human tumours deficient in TAp63 express Dicer at very low levels, and we found that modulation of expression of Dicer and miR-130b markedly affected the metastatic potential of cells lacking TAp63. TAp63 binds to and transactivates the Dicer promoter, demonstrating direct transcriptional regulation of Dicer by TAp63. These data provide a novel understanding of the roles of TAp63 in tumour and metastasis suppression through the coordinate transcriptional regulation of Dicer and miR-130b and may have implications for the many processes regulated by miRNAs. PMID- 20962850 TI - A targeted association study in systemic lupus erythematosus identifies multiple susceptibility alleles. AB - Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Multiple genetic and environmental factors contribute to the pathogenesis of this disease. Recent genome-wide association studies have added substantially to the number of genes associated with SLE. To replicate some of these susceptibility loci, single nucleotide polymorphisms reported to be associated to SLE were evaluated in a cohort of 245 well-phenotyped Canadian SLE trios. Our results replicate previously reported associations to alleles of interferon regulatory factor 5 (IRF5), major histocompatibility complex (MHC), tumor necrosis factor (ligand) superfamily member 4 (TNFSF4), Kell blood group complex subunit-related family member 6 (XKR6), B-cell scaffold protein with ankyrin repeats 1 (BANK1), protein tyrosine phosphatase non-receptor type 22 (PTPN22), ubiquitin-conjugating enzyme E2L 3 (UBE2L3) and islet cell autoantigen 1 (ICA1). We also identify putative associations to cytotoxic T-lymphocyte-associated protein 4 (CTLA4), a gene associated with several autoimmune disorders, and ERBB3, a locus on 12q13 that was previously reported to be associated with type 1 diabetes. This study confirms the existence of multiple genetic risk factors for SLE, and supports the notion that some risk factors for SLE are shared with other inflammatory disorders. PMID- 20962851 TI - Members 6B and 14 of the TNF receptor superfamily in multiple sclerosis predisposition. AB - TNFRSF6B and TNFRSF14 genes were recently associated with Crohn's disease and rheumatoid arthritis. TNFRSF14 is known as herpes virus entry mediator (HVEM), and herpes viruses have been involved in the aetiology of multiple sclerosis (MS). MS patients present human herpes virus 6 (HHV6) in active plaques and increased antibody responses to HHV6. We aimed to ascertain the role of these genes in MS susceptibility and to investigate the relationship of the gene encoding the widely expressed HVEM receptor with the active replication of HHV6 found in some MS patients. Genotyping of 1370 Spanish MS patients and 1715 ethnically matched controls was performed. HHV6A DNA levels (surrogate of active viral replication) were analysed in serum of MS patients during a 2-year follow up. Both polymorphisms were associated with MS predisposition, with stronger effect in patients with HHV6 active replication-TNFRSF6B-rs4809330(*)A: P=0.028, OR=1.13; TNFRSF14-rs6684865(*)A: overall P=0.0008, OR=1.2; and HHV6-positive patients vs controls: P=0.017, OR=1.69. PMID- 20962852 TI - Differential contribution of dermal resident and bone marrow-derived cells to collagen production during wound healing and fibrogenesis in mice. AB - Recent studies show that bone marrow (BM)-derived cells migrating into a dermal wound promote healing by producing collagen type I. However, their contribution to the repair process has not been fully verified yet. It is also unclear whether BM-derived cells participate in dermal fibrogenesis. We have addressed these issues using transgenic mice that harbor tissue-specific enhancer/promoter sequences of alpha2(I) collagen gene linked to either enhanced green fluorescent protein (COL/EGFP) or the luciferase (COL/LUC) reporter gene. Following dermal excision or subcutaneous bleomycin administration, a large number of EGFP positive collagen-producing cells appeared in the dermis of COL/EGFP reporter mice. When wild-type mice were transplanted with BM cells from transgenic COL/EGFP animals and subjected to dermal excision, no EGFP-positive BM-derived collagen-producing cells were detected throughout the repair process. Luciferase assays of dermal tissues from COL/LUC recipient mice also excluded collagen production by BM-derived cells during dermal excision healing. In contrast, a limited but significant number of CD45-positive collagen-producing cells migrated from BM following bleomycin injection. These results indicate that resident cells in the skin are the major source of de novo collagen deposition in both physiological and pathological conditions, whereas BM-derived cells participate, in part, in collagen production during dermal fibrogenesis. PMID- 20962854 TI - Skin barrier function in healthy subjects and patients with atopic dermatitis in relation to filaggrin loss-of-function mutations. PMID- 20962853 TI - EGFR and IL-1 signaling synergistically promote keratinocyte antimicrobial defenses in a differentiation-dependent manner. AB - Ligands of the EGF family regulate autocrine keratinocyte proliferation, and IL-1 family cytokines orchestrate epithelial defense responses. Although members of both families are overexpressed in wound healing and psoriasis, their roles in regulating the innate immune functions of keratinocytes remain incompletely explored. Using sensitive assays, we found significant increases of heparin binding EGF-like growth factor, transforming growth factor-alpha, and amphiregulin mRNA and protein in lesional psoriasis compared with uninvolved or control skin. In normal human keratinocyte (NHK) monolayers, EGFR ligands were ineffective in inducing DEFB4, S100A7, and CCL20 mRNAs and human beta-defensin (hBD)-2 peptide. Combined with IL-1alpha, however, EGFR ligands provoked 250 * more DEFB4 and CCL20 and a 9-fold rise in S100A7 mRNA relative to the EGFR ligand alone. This synergy was also reflected in secreted hBD-2 protein, both from NHK and reconstituted human epidermis. Keratinocyte differentiation was critical for these responses, as postconfluent NHK yielded mRNA and protein levels an order of magnitude greater than subconfluent cells. Differentiation also influenced signal transduction, with subconfluent cells using NF-kappaB and postconfluent cells using EGFR, MEK1/2, and p38. We propose that EGFR ligands are important modifiers of IL-1 activity, synergizing with IL-1 to stimulate epidermal production of hBD 2, S100A7, and CCL20, three of the most upregulated transcripts in psoriatic plaques. PMID- 20962855 TI - Fuz controls the morphogenesis and differentiation of hair follicles through the formation of primary cilia. AB - Planar cell polarity (PCP) signaling is essential in determining the polarity of cells within the plane of an epithelial sheet. Core PCP genes have been recently shown to control the global polarization of hair follicles in mice. Fuz, a homologue of the Drosophila PCP effector gene, fuzzy, is critical in ciliogenesis in vertebrates, and is required for the development of a wide range of organs in mice. Here, we report that disruption of the Fuz gene in mice severely blocked the development of hair follicles in the skin. In contrast to the loss of hair follicle polarization in mice deficient in core PCP genes, hair follicles in mice lacking the Fuz gene retained their typical anterior-posterior orientation. We show that disruption of Fuz impaired the formation of primary cilia and the hedgehog signaling pathway in the skin. In addition, using skin grafts and skin reconstitution assays we demonstrate that the expression of Fuz is required in both epidermal and dermal cells and that the formation of primary cilia is a cell autonomous process that does not require cross talk between the epithelia and mesenchymal compartments during hair follicle formation. PMID- 20962856 TI - A circadian clock in HaCaT keratinocytes. AB - To anticipate daily environmental changes, most organisms developed endogenous timing systems, the so-called circadian (~24 hours) clocks. Circadian clocks exist in most peripheral tissues and govern a huge variety of cellular, metabolic, and physiological processes. Recent studies have suggested daytime dependent variations in epidermal functions such as barrier recovery and pH homeostasis. However, a local circadian clock in epidermal keratinocytes has not been reported yet, and as such the molecular link between the circadian system and epidermal physiology remains elusive. In this study we describe a functional cell autonomous circadian clock in human adult low calcium temperature (HaCaT) keratinocytes. Using live-cell bioluminescence imaging and mRNA expression time series, we show robust circadian transcription of canonical clock genes in synchronized HaCaT keratinocytes. Genetic and pharmacological perturbation experiments as well as the phase relations between clock gene rhythms confirm that the molecular makeup of the HaCaT keratinocyte clock is very similar to that of other peripheral clocks. Furthermore, temperature was identified to be a potent time cue (Zeitgeber) for the epidermal oscillator. Temperature cycles entrain HaCaT keratinocytes, leading to the identification of rhythmic expression of several genes involved in epidermal physiology such as cholesterol homeostasis and differentiation. Thus, we present HaCaT keratinocytes as an excellent model to study the regulation of keratinocyte physiology by the circadian clock in a simple yet robust in vitro system. PMID- 20962857 TI - Spheres of influence in cancer stem cell biology. PMID- 20962858 TI - The diverse associations of uric acid with low-grade inflammation, adiponectin and arterial stiffness in never-treated hypertensives. AB - The data regarding the role of serum uric acid (SUA) along with subclinical inflammation in the context of hypertensive vascular damage are rather scarce and controversial. Towards this end, we assess the links between SUA, high sensitivity CRP (hs-CRP), adiponectin and carotid to femoral pulse wave velocity (c-f PWV) in 292 subjects with never-treated stage I-II essential hypertension. On the basis of the median SUA levels (0.31 mmol l(-1)), the study population was divided into subjects with low (n=149) and high (n=143) SUA values. By multiple regression analysis, it was revealed that SUA was independently associated with log hs-CRP (R(2)=0.098; P=0.02), log adiponectin (R(2)=0.102; P=0.03), waist circumference (R(2)=0.049; P=0.04), 24-h systolic blood pressure (SBP) (R(2)=0.179; P=0.001) and estimated glomerular filtration rate (R(2)=0.156; beta (s.e.)=-0.169 (0.023); P=0.02). In addition, c-f PWV was independently associated with age (R(2)=0.116; P<0.0001), waist circumference (R(2)=0.088; P<0.0001), 24-h SBP (R(2)=0.167; P=0.001), log adiponectin (R(2)=0.07; P=0.006) and log hs-CRP (R(2)=0.06; P=0.034). In conclusion, SUA levels are independently associated with hs-CRP and adiponectin levels but not with c-f PWV in essential hypertensive patients. Increased SUA levels are accompanied by a state of pronounced inflammatory activation and hypoadiponectinemia that significantly impairs the arterial stiffness accelerating the vascular ageing process in this setting. PMID- 20962859 TI - Association between ankle blood pressure and central arterial wave reflection. AB - There is an increasing recognition that central aortic pressure is more relevant than brachial measure for the prediction and pathophysiology of cardiovascular disease. Central pressure is influenced by the phenomenon of arterial wave reflections returning from the peripheral vasculature, which can be quantified by augmentation index. Accordingly, the primary aim of this study was to determine the association between central augmentation index and arterial blood pressures (BPs), recorded in both the upper and lower limbs. A total of 833 apparently healthy adults of varying ages were studied. All of the BP (brachial and ankle, systolic, mean, diastolic and pulse) measurements were significantly associated with carotid augmentation index. Among them, ankle mean arterial pressure was the strongest correlate of carotid augmentation index (r=0.51, P<0.0001). This relation remained highly significant even after the influence of potential confounders was accounted for by the partial correlation analyses. Stepwise regression analyses revealed that ankle mean arterial pressure was the strongest independent predictor of carotid augmentation index. Ankle BP is strongly associated with the augmentation of central BP, and this relation is independent of other BP measures (brachial BP). PMID- 20962860 TI - Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy. AB - Fludarabine combination chemotherapy achieves high response rates in chronic lymphocytic leukemia (CLL) and indolent lymphoma. The aim of this study was to investigate the incidence and characteristics of treatment-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) after treatment with fludarabine in combination for lymphoproliferative disorders and identify risk factors for its development. In all, 176 patients treated with fludarabine combination were followed for a median of 41 months (range 6-125 months). In all, 19 cases of t MDS/AML have been identified for an overall rate of 10.8%. Median overall survival post-t-MDS/AML diagnosis was 11 months. Patients developing t-MDS/AML included 11/54 with follicular lymphoma (FL) (crude rate 20.4%), 5/82 with CLL (6.1%) and 3/24 with Waldenstrom macroglobulinemia or marginal zone lymphoma (12.5%). Most patients had other cytotoxic treatments (median 4, range 0-7) but three with FL had fludarabine combination as their only line of treatment. Of the eleven patients (6.3%) who received mitoxantrone with their first fludarabine combination, four (36.4%) developed t-MDS/AML (P=0.007). There was a trend toward prior cytotoxic therapy increasing the risk for t-MDS/AML (P=0.067). Fludarabine combination chemotherapy is associated with a moderate risk of t-MDS/AML particularly when combined with mitoxantrone. This complication should be considered when evaluating the potential benefit of this treatment in lymphoproliferative disorders. PMID- 20962861 TI - A nonsense mutation of IDH1 in myelodysplastic syndromes and related disorders. PMID- 20962862 TI - IDH2 somatic mutations in chronic myeloid leukemia patients in blast crisis. PMID- 20962863 TI - Thyroid gland: Variation in 'normal' thyroid function--effect on bone health? PMID- 20962864 TI - Therapy: What evidence should guide the use of thiazolidinediones? PMID- 20962865 TI - Reproductive endocrinology: Late-onset hypogonadism: evidence for diagnostic criteria. PMID- 20962866 TI - Parathyroid gland: Hyperparathyroidism in MEN1 syndrome: time to operate? PMID- 20962867 TI - Adrenal function: A gold standard test for adrenal insufficiency in children? PMID- 20962868 TI - Surgery: Risks of pituitary surgery in the elderly. PMID- 20962869 TI - Prototype development and preclinical immunogenicity analysis of a novel minimally invasive electroporation device. AB - The magnitude of the immune response to a DNA vaccine depends on three criteria- the optimized vector design, the use of a suitable adjuvant and the successful delivery and subsequent expression of the plasmid in the target tissue. In vivo electroporation (EP) has proved to be particularly effective in efficiently delivering DNA immunogens to the muscle and the skin, and indeed several devices have entered into human clinical trials. Here, we report on a novel concept of DNA delivery to the dermal tissue using a minimally invasive EP device, which is powered using low-voltage parameters. We show that this prototype device containing a novel 4 * 4-electrode array results in robust and reproducible transfection of dermal tissue and subsequent antigen expression at the injection site. Using DNA encoding for NP and M2e influenza antigens, we further show induction of potent cellular responses in a mouse model as measured by antigen specific T-cell ELISpot assays. Importantly, 100% of the immunized animals were protected when challenged with VN/1203/04 (H5N1) strain of influenza. We have also extended our findings to a guinea-pig model and demonstrated induction of HI titers greater than 1:40 against a pandemic novel H1N1 virus showing proof of concept efficacy for DNA delivery with the prototype device in a broad spectrum of species and using multiple antigens. Finally, we were able to generate protective HI titers in macaques against the same novel H1N1 strain. Our results suggest that the minimally invasive dermal device may offer a safe, tolerable and efficient method to administer DNA vaccinations in a prophylactic setting, and thus potentially represents an important new option for improved DNA vaccine delivery in vivo. PMID- 20962870 TI - Validation of recombinant Sendai virus in a non-natural host model. AB - We have previously shown that recombinant Sendai virus (SeV) vector, derived from murine parainfluenza virus, is one of the most efficient vectors for airway gene transfer. We have also shown that SeV-mediated transfection on second administration, although reduced by 60% when compared with levels achieved after a single dose, is still high because of the efficient transfection achieved by SeV vector in murine airways. Here, we show that these levels further decrease on subsequent doses. In addition, we validated SeV vector repeat administration in a non-natural host model, the sheep. As part of these studies we first assessed viral stability in a Pari LC Plus nebuliser, a polyethylene catheter (PEC) and the Trudell AeroProbe. We also compared the distribution of gene expression after PEC and Trudell AeroProbe administration and quantified virus shedding after sheep transduction. In addition, we show that bronchial brushings and biopsies, collected in anaesthetized sheep, can be used to assess SeV-mediated gene expression over time. Similar to mice, gene expression in sheep was transient and had returned to baseline values by day 14. In conclusion, the SeV vector should be strongly considered for lung-related applications requiring a single administration of the vector even though it might not be suitable for diseases requiring repeat administration. PMID- 20962871 TI - Physiological and tissue-specific vectors for treatment of inherited diseases. AB - After more than 1500 gene therapy clinical trials in the past two decades, the overall conclusion is that for gene therapy (GT) to be successful, the vector systems must still be improved in terms of delivery, expression and safety. The recent development of more efficient and stable vector systems has created great expectations for the future of GT. Impressive results were obtained in three primary immunodeficiencies and other inherited diseases such as congenital blindness, adrenoleukodystrophy or junctional epidermolysis bullosa. However, the development of leukemia in five children included in the GT clinical trials for X linked severe combined immunodeficiency and the silencing of the therapeutic gene in the chronic granulomatous disease clearly showed the importance of improving safety and efficiency. In this review, we focus on the main strategies available to achieve physiological or tissue-specific expression of therapeutic transgenes and discuss the importance of controlling transgene expression to improve safety. We propose that tissue-specific and/or physiological viral vectors offer the best balance between efficiency and safety and will be the tools of choice for future clinical trials in GT of inherited diseases. PMID- 20962872 TI - Transfection of shRNA-encoding Minivector DNA of a few hundred base pairs to regulate gene expression in lymphoma cells. AB - This work illustrates the utility of Minivector DNA, a non-viral, supercoiled gene therapy vector incorporating short hairpin RNA from an H1 promoter. Minivector DNA is superior to both plasmid DNA and small interfering RNA (siRNA) in that it has improved biostability while maintaining high cell transfection efficiency and gene silencing capacity. Minivector DNAs were stable for over 48 h in human serum, as compared with only 0.5 and 2 h for siRNA and plasmid, respectively. Although all three nucleic acids exhibited similar transfection efficiencies in easily transfected adhesion fibroblasts cells, only Minivector DNAs and siRNA were capable of transfecting difficult-to-transfect suspension lymphoma cells. Minivector DNA and siRNA were capable of silencing the gene encoding anaplastic lymphoma kinase, a key pathogenic factor of human anaplastic large cell lymphoma, and this silencing caused inhibition of the lymphoma cells. Based on these results, Minivector DNAs are a promising new gene therapy tool. PMID- 20962873 TI - Microbial biodegradation of aromatic alkanoic naphthenic acids is affected by the degree of alkyl side chain branching. AB - Naphthenic acids (NAs) occur naturally in oil sands and enter the environment through natural and anthropogenic processes. NAs comprise toxic carboxylic acids that are difficult to degrade. Information on NA biodegradation mechanisms is limited, and there are no studies on alkyl branched aromatic alkanoic acid biodegradation, despite their contribution to NA toxicity and recalcitrance. Increased alkyl side chain branching has been proposed to explain NA recalcitrance. Using soil enrichments, we examined the biodegradation of four aromatic alkanoic acid isomers that differed in alkyl side chain branching: (4'-n butylphenyl)-4-butanoic acid (n-BPBA, least branched); (4'-iso-butylphenyl)-4 butanoic acid (iso-BPBA); (4'-sec-butylphenyl)-4-butanoic acid (sec-BPBA) and (4' tert-butylphenyl)-4-butanoic acid (tert-BPBA, most branched). n-BPBA was completely metabolized within 49 days. Mass spectral analysis confirmed that the more branched isomers iso-, sec- and tert-BPBA were transformed to their butylphenylethanoic acid (BPEA) counterparts at 14 days. The BPEA metabolites were generally less toxic than BPBAs as determined by Microtox assay. n-BPEA was further transformed to a diacid, showing that carboxylation of the alkyl side chain occurred. In each case, biodegradation of the carboxyl side chain proceeded through beta-oxidation, which depended on the degree of alkyl side chain branching, and a BPBA degradation pathway is proposed. Comparison of 16S rRNA gene sequences at days 0 and 49 showed an increase and high abundance at day 49 of Pseudomonas (sec-BPBA), Burkholderia (n-, iso-, tert-BPBA) and Sphingomonas (n , sec-BPBA). PMID- 20962874 TI - Phylogenetic and gene-centric metagenomics of the canine intestinal microbiome reveals similarities with humans and mice. AB - This study is the first to use a metagenomics approach to characterize the phylogeny and functional capacity of the canine gastrointestinal microbiome. Six healthy adult dogs were used in a crossover design and fed a low-fiber control diet (K9C) or one containing 7.5% beet pulp (K9BP). Pooled fecal DNA samples from each treatment were subjected to 454 pyrosequencing, generating 503,280 (K9C) and 505,061 (K9BP) sequences. Dominant bacterial phyla included the Bacteroidetes/Chlorobi group and Firmicutes, both of which comprised ~35% of all sequences, followed by Proteobacteria (13-15%) and Fusobacteria (7-8%). K9C had a greater percentage of Bacteroidetes, Fusobacteria and Proteobacteria, whereas K9BP had greater proportions of the Bacteroidetes/Chlorobi group and Firmicutes. Archaea were not altered by diet and represented ~1% of all sequences. All archaea were members of Crenarchaeota and Euryarchaeota, with methanogens being the most abundant and diverse. Three fungi phylotypes were present in K9C, but none in K9BP. Less than 0.4% of sequences were of viral origin, with >99% of them associated with bacteriophages. Primary functional categories were not significantly affected by diet and were associated with carbohydrates; protein metabolism; DNA metabolism; cofactors, vitamins, prosthetic groups and pigments; amino acids and derivatives; cell wall and capsule; and virulence. Hierarchical clustering of several gastrointestinal metagenomes demonstrated phylogenetic and metabolic similarity between dogs, humans and mice. More research is required to provide deeper coverage of the canine microbiome, evaluate effects of age, genetics or environment on its composition and activity, and identify its role in gastrointestinal disease. PMID- 20962875 TI - Capturing diversity of marine heterotrophic protists: one cell at a time. AB - Recent applications of culture-independent, molecular methods have revealed unexpectedly high diversity in a variety of functional and phylogenetic groups of microorganisms in the ocean. However, none of the existing research tools are free from significant limitations, such as PCR and cloning biases, low phylogenetic resolution and others. Here, we employed novel, single-cell sequencing techniques to assess the composition of small (<10 MUm diameter), heterotrophic protists from the Gulf of Maine. Single cells were isolated by flow cytometry, their genomes amplified, and 18S rRNA marker genes were amplified and sequenced. We compared the results to traditional environmental PCR cloning of sorted cells. The diversity of heterotrophic protists was significantly higher in the library of single amplified genomes (SAGs) than in environmental PCR clone libraries of the 18S rRNA gene, obtained from the same coastal sample. Libraries of SAGs, but not clones contained several recently discovered, uncultured groups, including picobiliphytes and novel marine stramenopiles. Clone, but not SAG, libraries contained several large clusters of identical and nearly identical sequences of Dinophyceae, Cercozoa and Stramenopiles. Similar results were obtained using two alternative primer sets, suggesting that PCR biases may not be the only explanation for the observed patterns. Instead, differences in the number of 18S rRNA gene copies among the various protist taxa probably had a significant role in determining the PCR clone composition. These results show that single-cell sequencing has the potential to more accurately assess protistan community composition than previously established methods. In addition, the creation of SAG libraries opens opportunities for the analysis of multiple genes or entire genomes of the uncultured protist groups. PMID- 20962876 TI - The dynamics of microbial partnerships in the coral Isopora palifera. AB - Both bacteria and algal symbionts (genus Symbiodinium), the two major microbial partners in the coral holobiont, respond to fluctuations in the environment, according to current reports; however, little evidence yet indicates that both populations have any direct interaction with each other in seasonal fluctuation. In this study, we present field observations of a compositional change in bacteria and Symbiodinium in the coral Isopora palifera in three separate coral colonies following monthly sampling from February to November in 2008. Using massively parallel pyrosequencing, over 200,000 bacterial V6 sequences were classified to build the bacterial community profile; in addition, the relative composition and quantity of Symbiodinium clades C and D were determined by real time PCR. The results showed that coral-associated bacterial and Symbiodinium communities were highly dynamic and dissimilar among the tagged coral colonies, suggesting that the effect of host specificity was insignificant. The coral associated bacterial community was more diverse (Shannon index up to 6.71) than previous estimates in other corals and showed rapid seasonal changes. The population ratios between clade C and D groups of Symbiodinium varied in the tagged coral colonies through the different seasons; clade D dominated in most of the samples. Although significant association between bacteria and symbiont was not detected, this study presents a more detailed picture of changes in these two major microbial associates of the coral at the same time, using the latest molecular approaches. PMID- 20962877 TI - BIPES, a cost-effective high-throughput method for assessing microbial diversity. AB - Pyrosequencing of 16S rRNA (16S) variable tags has become the most popular method for assessing microbial diversity, but the method remains costly for the evaluation of large numbers of environmental samples with high sequencing depths. We developed a barcoded Illumina paired-end (PE) sequencing (BIPES) method that sequences each 16S V6 tag from both ends on the Illumina HiSeq 2000, and the PE reads are then overlapped to obtain the V6 tag. The average accuracy of Illumina single-end (SE) reads was only 97.9%, which decreased from ~99.9% at the start of the read to less than 85% at the end of the read; nevertheless, overlapping of the PE reads significantly increased the sequencing accuracy to 99.65% by verifying the 3' end of each SE in which the sequencing quality was degraded. After the removal of tags with two or more mismatches within the medial 40-70 bases of the reads and of tags with any primer errors, the overall base sequencing accuracy of the BIPES reads was further increased to 99.93%. The BIPES reads reflected the amounts of the various tags in the initial template, but long tags and high GC tags were underestimated. The BIPES method yields 20-50 times more 16S V6 tags than does pyrosequencing in a single-flow cell run, and each of the BIPES reads costs less than 1/40 of a pyrosequencing read. As a laborsaving and cost-effective method, BIPES can be routinely used to analyze the microbial ecology of both environmental and human microbiomes. PMID- 20962878 TI - Phage-induced lysis enhances biofilm formation in Shewanella oneidensis MR-1. AB - Shewanella oneidensis MR-1 is capable of forming highly structured surface attached communities. By DNase I treatment, we demonstrated that extracellular DNA (eDNA) serves as a structural component in all stages of biofilm formation under static and hydrodynamic conditions. We determined whether eDNA is released through cell lysis mediated by the three prophages LambdaSo, MuSo1 and MuSo2 that are harbored in the genome of S. oneidensis MR-1. Mutant analyses and infection studies revealed that all three prophages may individually lead to cell lysis. However, only LambdaSo and MuSo2 form infectious phage particles. Phage release and cell lysis already occur during early stages of static incubation. A mutant devoid of the prophages was significantly less prone to lysis in pure culture. In addition, the phage-less mutant was severely impaired in biofilm formation through all stages of development, and three-dimensional growth occurred independently of eDNA as a structural component. Thus, we suggest that in S. oneidensis MR-1 prophage-mediated lysis results in the release of crucial biofilm promoting factors, in particular eDNA. PMID- 20962879 TI - Exposure of conjugative plasmid carrying Escherichia coli biofilms to male specific bacteriophages. AB - Escherichia coli carrying a natural conjugative F-plasmid generates F-pili mating pairs, which is important for early biofilm formation. In this study, we investigated the effect of male-specific filamentous single stranded DNA bacteriophage (f1) and RNA bacteriophage (MS2) on the formation of biofilms by E. coli carrying a natural conjugative F-plasmid. We showed that the early biofilm formation was completely inhibited by addition of the f1 phage, but not the MS2 phage. This suggests that the tip of F-pili is the specific attachment site for mating pairs formation and the side of F-pili has a non-obligatory role during biofilm formation. The inhibitory effect of the f1 phage was dependent on the time of addition during the biofilm formation. No inhibitory effect was observed when the f1 phages were added to the mature biofilms. This resistant mechanism of the mature biofilms could be attributed to the biofilm-specific phenotypes representing that the F-pili mating pairs were already formed and then the curli production commenced during the biofilm maturation. The pre-formed mating pairs seemed to resist the f1 phages. Altogether, our results indicate a close relationship between the presence of conjugative plasmid and male-specific bacteriophages within sessile biofilm communities, as well as the possibility of using the male-specific bacteriophages to control biofilm formation. PMID- 20962880 TI - Environmental modification and niche construction: developing O2 gradients drive the evolution of the Wrinkly Spreader. AB - The evolutionary success of the novel Wrinkly Spreader (WS) genotypes in diversifying Pseudomonas fluorescens SBW25 populations in static liquid microcosms has been attributed to the greater availability of O(2) at the air liquid (A-L) interface where the WS produces a physically cohesive-class biofilm. However, the importance of O(2) gradients in SBW25 adaptation has never been examined. We have explicitly tested the role of O(2) in evolving populations using microsensor profiling and experiments conducted under high and low O(2) conditions. Initial colonists of static microcosms were found to establish O(2) gradients before significant population growth had occurred, converting a previously homogenous environment into one containing a resource continuum with high and low O(2) regions. These gradients were found to persist for long periods by which time significant numbers of WS had appeared colonising the high O(2) niches. Growth was O(2) limited in static microcosms, but high O(2) conditions like those found near the A-L interface supported greater growth and favoured the emergence of WS-like genotypes. A fitness advantage to biofilm formation was seen under high but not low O(2) conditions, suggesting that the cost of biofilm production could only be offset when O(2) levels above the A-L interface were high. Profiling of mature WS biofilms showed that they also contained high and low O(2) regions. Niches within these may support further diversification and succession of the developing biofilm population. O(2) availability has been found to be a major factor underlying the evolutionary success of the WS genotype in static microcosms and illustrates the importance of this resource continuum in microbial diversification and adaptation. PMID- 20962881 TI - Low-complexity sequences and single amino acid repeats: not just "junk" peptide sequences. AB - For decades proteins were thought to interact in a "lock and key" system, which led to the definition of a paradigm linking stable three-dimensional structure to biological function. As a consequence, any non-structured peptide was considered to be nonfunctional and to evolve neutrally. Surprisingly, the most commonly shared peptides between eukaryotic proteomes are low-complexity sequences that in most conditions do not present a stable three-dimensional structure. However, because these sequences evolve rapidly and because the size variation of a few of them can have deleterious effects, low-complexity sequences have been suggested to be the target of selection. Here we review evidence that supports the idea that these simple sequences should not be considered just "junk" peptides and that selection drives the evolution of many of them. PMID- 20962882 TI - Genetic effects of major QTLs controlling low-temperature germinability in different genetic backgrounds in rice (Oryza sativa L.). AB - The effects of QTLs are demonstrated basically within the population used in the original QTL analysis as the difference between the alleles of the parental varieties. For the efficient use of QTLs in breeding programs, it is necessary to assess whether the QTL exhibits its genetic effect when it is introgressed into different genetic backgrounds. Extensive studies of tolerance to low temperature at the seed germination stage (called low-temperature germinability) in rice revealed that 2 major QTLs on chromosomes 3 and 11, qLTG3-1 and qLTG11, have large effects. This study assessed the effects of these 2 QTLs from an aus variety, Kasalath, in different genetic backgrounds of 3 japonica varieties, Hoshinoyume, Hayamasari, and Koshihikari. Backcrossed progenies and chromosome segment substitution lines showed that both qLTG3-1 and qLTG11 were effective in the Hoshinoyume and Koshihikari backgrounds, while only qLTG3-1 was effective in the Hayamasari background. The results in this study demonstrated that these 2 QTLs are useful for the improvement of low-temperature germinability in rice breeding programs. The results also indicated that low-temperature germinability in rice is governed by an epistatic interaction of qLTG11. PMID- 20962883 TI - Species-diagnostic and species-specific DNA sequences evenly distributed throughout pine and spruce chromosomes. AB - Genome organization in the family Pinaceae is complex and largely unknown. The main purpose of the present study was to develop and physically map species diagnostic and species-specific molecular markers in pine and spruce. Five RAPD (random amplified polymorphic DNA) and one ISSR (inter-simple sequence repeat) species-diagnostic or species-specific markers for Picea mariana, Picea rubens, Pinus strobus, or Pinus monticola were identified, cloned, and sequenced. In situ hybridization of these sequences to spruce and pine chromosomes showed the sequences to be present in high copy number and evenly distributed throughout the genome. The analysis of centromeric and telomeric regions revealed the absence of significant clustering of species-diagnostic and species-specific sequences in all the chromosomes of the four species studied. Both RAPD and ISSR markers showed similar patterns. PMID- 20962884 TI - Molecular genetic characterization of Drosophila ATM conserved functional domains. AB - ATM-related kinases promote repair of DNA double-strand breaks and maintenance of chromosome telomeres, functions that are essential for chromosome structural integrity in all eukaryotic organisms. In humans, loss of ATM function is associated with ataxia telangiectasia, a neurodegenerative disease characterized by extreme sensitivity to DNA damage. Drosophila melanogaster has recently emerged as a useful animal model for analyzing the molecular functions of specific domains of this large, multifunctional kinase. The gene encoding Drosophila ATM kinase (dATM) was originally designated tefu because of the telomere fusion defects observed in atm mutants. In this report, molecular characterization of eight atm (tefu) alleles identified nonsense mutations predicted to truncate conserved C-terminal domains of the dATM protein, as well as two interesting missense mutations. One of these missense mutations localized within a putative HEAT repeat in the poorly characterized N-terminal domain of dATM (atm4), whereas another associated with a temperature-sensitive allele (atm8) changed the last amino acid of the conserved FATC domain. Leveraging this molecular information with the powerful genetic tools available in Drosophila should facilitate future analysis of conserved ATM-mediated molecular mechanisms that are important for telomere maintenance, DNA repair, and neurodegeneration. PMID- 20962885 TI - Mechanisms of magnesium amelioration of aluminum toxicity in soybean at the gene expression level. AB - Micromolar concentration of magnesium (Mg) in culture solution is known to ameliorate aluminum (Al) toxicity in soybean and other leguminous species. To advance the understanding of this phenomenon at the level of gene expression in soybean, we undertook a comparative transcriptome analysis using DNA microarrays and Al-tolerant and Al-sensitive genotypes treated with Al ions alone or Al plus Mg ions. We observed a more rapid alteration of transcription for Al-tolerant than Al-sensitive soybean after introduction of Mg into Al-containing medium, but at 72 h, far more genes were altered (both upregulated and downregulated) in the Al-sensitive line, reflecting the known greater saving effect of Mg for Al sensitive than Al-tolerant lines. Mg appears to ameliorate Al toxicity in the sensitive genotype by the dual mechanisms of (i) specifically increasing the expression level of several genes that are upregulated in the Al-treated, Al tolerant genotype in the absence of Mg and (ii) possibly saving energy by decreasing expression of most genes relative to expression under Al stress. Mg mediated reduction in gene expression also appears to be an important mechanism of Mg protection of the Al-tolerant genotype. PMID- 20962886 TI - Fine mapping a domestication-related QTL for spike-related traits in a synthetic wheat. AB - QTL analysis using a BC5F2:3 mapping population derived from a cross between Am3, a synthetic hexaploid wheat as a donor parent, and Laizhou953, a Chinese winter wheat cultivar as a recurrent parent, showed that variation at the microsatellite locus Xgwm113 on chromosome 4B was associated with variation in grain number per spike (GN), spike length (SL), and spikelet number per spike (SPI). The Qgn.caas 4B, Qsl.caas-4B, and Qspi.caas-4B were responsible for 16.6%-35.6%, 18.0%-32.3%, and 23.7%-25.9% of the phenotypic variation present in two environments, respectively. Segregation for GN fit a Mendelian monogenic ratio. A subpopulation consisting of 497 plants was used to map the QTL to a 1.2 cM interval between Xgwm113 and Xgwm857. The three spike traits, GN, SL, and SPI, were correlated and were thus probably under the pleiotropic control of the QTL. The Am3 allele had a reduction effect on all three spike traits. Evidence for positive selective history on SSR locus Xgwm113 was supported using Ewens-Watterson's statistic test on a germplasm panel of wild and landrace entries, suggesting that this genomic region may contain genes under selection during wheat domestication. PMID- 20962887 TI - Segregation distortion and linkage analysis in eggplant (Solanum melongena L.). AB - An anther-derived doubled haploid (DH) population and an F2 mapping population were developed from an intraspecific hybrid between the eggplant breeding lines 305E40 and 67/3. The former incorporates an introgressed segment from Solanum aethiopicum Gilo Group carrying the gene Rfo-sa1, which confers resistance to Fusarium oxysporum; the latter is a selection from an intraspecific cross involving two conventional eggplant varieties and lacks Rfo-sa1. Initially, 28 AFLP primer combinations (PCs) were applied to a sample of 93 F2 individuals and 93 DH individuals, from which 170 polymorphic AFLP fragments were identified. In the DH population, the segregation of 117 of these AFLPs as well as markers closely linked to Rfo-sa1 was substantially distorted, while in the F2 population, segregation distortion was restricted to just 10 markers, and thus the latter was chosen for map development. A set of 141 F2 individuals was genotyped with 73 AFLP PCs (generating 406 informative markers), 32 SSRs, 4 tomato RFLPs, and 3 CAPS markers linked to Rfo-sa1. This resulted in the assignment of 348 markers to 12 major linkage groups. The framework map covered 718.7 cM, comprising 238 markers (212 AFLPs, 22 SSRs, 1 RFLP, and the Rfo-sa1 CAPS). Marker order and inter-marker distances in this eggplant map were largely consistent with those reported in a recently published SSR-based map. From an eggplant breeding perspective, DH populations produced by anther culture appear to be subject to massive segregation distortion and thus may not be very efficient in capturing the full range of genetic variation present in the parental lines. PMID- 20962888 TI - Characterization of three terpenoid glycosyltransferase genes in 'Valencia' sweet orange (Citrus sinensis L. Osbeck). AB - Three putative terpenoid UDP-glycosyltransferase (UGT) genes, designated CsUGT1, CsUGT2, and CsUGT3, were isolated and characterized in 'Valencia' sweet orange (Citrus sinensis L. Osbeck). CsUGT1 consisted of 1493 nucleotides with an open reading frame encoding 492 amino acids, CsUGT2 consisted of 1727 nucleotides encoding 504 amino acids, and CsUGT3 consisted of 1705 nucleotides encoding 468 amino acids. CsUGT3 had a 145 bp intron at 730-874, whereas CsUGT1 and CsUGT2 had none. The three deduced glycosyltransferase proteins had a highly conserved plant secondary product glycosyltransferase motif in the C terminus. Phylogenetic analysis showed that CsUGT1 and CsUGT3 were classified into group L of glycosyltransferase family 1, and CsUGT2 was classified into group D. Through Southern blotting analysis, CsUGT1 was found to have two copies in the sweet orange genome, whereas CsUGT2 and CsUGT3 had at least seven and nine copies, respectively. CsUGT1, CsUGT2, and CsUGT3 were constitutively expressed in leaf, flower, and fruit tissues. The results facilitate further investigation of the function of terpenoid glycosyltransferases in citrus and the biosynthesis of terpenoid glycosides in vitro. PMID- 20962889 TI - Genomic relationships among diploid and polyploid species of the genus Eryngium L. using genomic in situ hybridization. AB - Eryngium L. (Umbelliferae) is a large genus including more than 250 species worldwide. The large morphological variability in this genus makes it difficult to delimit the species or to establish phylogenetic relationships. The occurrence of different ploidy levels within the genus might indicate a hybrid origin of the polyploid species. In the present study, the chromosome number and karyotype of E. regnellii are reportedfor the first time and the ploidy level of a population of E. paniculatum is confirmed. We compare the genomes of the diploids E. horridum and E. eburneum, the tetraploids E. megapotamicum and E. regnellii, and the hexaploids E. pandanifolium (as a representative of the whole pandanifolium complex) and E. paniculatum using genomic in situ hybridization (GISH). Although it was not possible to identify the parental species of the polyploid taxa analyzed, the GISH technique allowed us to postulate some hypotheses about their origin. Eryngium horridum and E. eburneum do not seem to be the direct progenitors of the polyploids analyzed. On the other hand, it seems that other diploid species unrelated to E. horridum and E. eburneum are involved in their origin. Our results are consistent with morphological and phylogenetic studies, indicating a close relationship between the species of the series Latifolia. PMID- 20962890 TI - EST sequencing and gene expression profiling of cultivated peanut (Arachis hypogaea L.). AB - Peanut (Arachis hypogaea L.) is one of the most important oil crops in the world. However, biotechnological based improvement of peanut is far behind many other crops. It is critical and urgent to establish the biotechnological platform for peanut germplasm innovation. In this study, a peanut seed cDNA library was constructed to establish the biotechnological platform for peanut germplasm innovation. About 17,000 expressed sequence tags (ESTs) were sequenced and used for further investigation. Among which, 12.5% were annotated as metabolic related and 4.6% encoded transcription or post-transcription factors. ESTs encoding storage protein and enzymes related to protein degradation accounted for 28.8% and formed the largest group of the annotated ESTs. ESTs that encoded stress responsive proteins and pathogen-related proteins accounted for 5.6%. ESTs that encoded unknown proteins or showed no hit in the GenBank nr database accounted for 20.1% and 13.9%, respectively. A total number of 5066 EST sequences were selected to make a cDNA microarray. Expression analysis revealed that these sequences showed diverse expression patterns in peanut seeds, leaves, stems, roots, flowers, and gynophores. We also analyzed the gene expression pattern during seed development. Genes that were upregulated (>=twofold) at 15, 25, 35, and 45 days after pegging (DAP) were found and compared with 70 DAP. The potential value of these genes and their promoters in the peanut gene engineering study is discussed. PMID- 20962891 TI - Isolating promoters of multigene family members from the polyploid sugarcane genome by PCR-based walking in BAC DNA. AB - The availability of a wider range of promoters for regulated expression in valuable transgenic crops would benefit functional genomics studies and current biotechnology programs aimed at improved productivity. Polymerase chain reaction (PCR)-based genome walking techniques are commonly used to isolate promoters or 5' flanking genomic regions adjacent to known cDNA sequences in genomes that are not yet completely sequenced. However, these techniques are problematic when applied directly to DNA isolated from crops with highly complex and large genomes. An adaptor ligation-mediated PCR-based BAC genome walking method is described here for the efficient isolation of promoters of multigene family members, such as the putative defense and fiber biosynthesis DIRIGENT genes that are abundant in the stem of sugarcane, a species with a highly polyploid genome. The advantage of this method is the efficient and specific amplification of the target promoter using BAC genomic DNA as template for the adaptor ligation mediated PCR walking. PMID- 20962892 TI - Molecular, developmental, and evolutionary genetic studies highlight rapid evolution of genes and genetic systems. AB - The 53rd annual conference of the Genetics Society of Canada was held at McMaster University in Hamilton, Ontario, from 17 to 20 June 2010. About 100 geneticists from across Canada and the US attended the meeting, with a total of 27 posters and 55 oral presentations. The presentations highlighted the power of genetics for understanding a variety of biological issues from sex and recombination to alcoholism and cancer, from DNA replication to antimicrobial resistance, horizontal gene transfer, foraging, and courtship. Large-scale genomic and transcriptomic comparisons were included in many presentations to demonstrate the impact of genomics in biomedical research. The combined molecular, developmental, and evolutionary genetic investigations presented at the meeting, especially those on model organisms, highlighted that genes and genetic systems can evolve very rapidly. PMID- 20962893 TI - Calculation of muscle maximal shortening velocity by extrapolation of the force velocity relationship: afterloaded versus isotonic release contractions. AB - The maximal shortening velocity of a muscle (V(max)) provides a link between its macroscopic properties and the underlying biochemical reactions and is altered in some diseases. Two methods that are widely used for determining V(max) are afterloaded and isotonic release contractions. To determine whether these two methods give equivalent results, we calculated V(max) in 9 intact single fibres from the lumbrical muscles of the frog Xenopus laevis (9.5-15.5 degrees C, stimulation frequency 35-70 Hz). The data were modelled using a 3-state cross bridge model in which the states were inactive, detached, and attached. Afterloaded contractions gave lower predictions of Vmax than did isotonic release contractions in all 9 fibres (3.20 +/- 0.84 versus 4.11 +/- 1.08 lengths per second, respectively; means +/- SD, p = 0.001) and underestimated unloaded shortening velocity measured with the slack test by an average of 29% (p = 0.001, n = 6). Excellent model predictions could be obtained by assuming that activation is inhibited by shortening. We conclude that under the experimental conditions used in this study, afterloaded and isotonic release contractions do not give equivalent results. When a change in the V(max) measured with afterloaded contractions is observed in diseased muscle, it is important to consider that this may reflect differences in either activation kinetics or cross-bridge cycling rates. PMID- 20962894 TI - Reversal of isoprenaline-induced cardiac remodeling by rutaecarpine via stimulation of calcitonin gene-related peptide production. AB - Dysfunction of capsaicin-sensitive sensory nerves is involved in cardiac remodeling, and rutaecarpine has been shown to exert a beneficial effect on cardiac function through activating the sensory nerves. This study was conducted to explore the potential inhibitory effect of rutaecarpine on cardiac remodeling and the underlying mechanisms. A rat cardiac remodeling model was established by injection of isoprenaline (5 mg/kg per day, s.c.) for 10 days. Rutaecarpine (10 or 40 mg/kg, i.g.) was coadministrated with isoprenaline to evaluate the effect of rutaecarpine on cardiac remodeling. After echocardiographic analysis was performed, blood samples were collected to quantify calcitonin gene-related peptide (CGRP), dorsal root ganglia were isolated for examining CGRP mRNA expression, and the hearts were weighed and saved for evaluating the parameters related to apoptosis and hypertrophy. Isoprenaline significantly increased the ratio of left ventricle weight to body weight, the cross-sectional area of cardiomyocytes, cardiac apoptosis, and collagen deposition concomitantly with decreased CGRP production, which were reversed by rutaecarpine treatment. The beneficial effects of rutaecarpine were attenuated by pretreatment with capsaicin, which selectively depleted CGRP. These results suggest that rutaecarpine was able to reverse isoprenaline-induced cardiac remodeling through stimulating CGRP production. PMID- 20962895 TI - Influence of small doses of various drug vehicles on acetaminophen-induced liver injury. AB - The biological effects of drug vehicles are often overlooked, often leading to artifacts in acetaminophen-induced liver injury assessment. Therefore, we decided to investigate the effect of dimethylsulfoxide, dimethylformamide, propylene glycol, ethanol, and Tween 20 on acetaminophen-induced liver injury. C57BL/6 male mice received a particular drug vehicle (0.6 or 0.2 mL/kg, i.p.) 30 min before acetaminophen administration (300 mg/kg, i.p.). Control mice received vehicle alone. Liver injury was assessed by measuring the concentration of alanine aminotransferase in plasma and observing histopathological changes. The level of reduced glutathione (GSH) was assessed by measuring total nonprotein hepatic sulfhydrils. Dimethylsulfoxide and dimethylformamide (at both doses) almost completely abolished acetaminophen toxicity. The higher dose of propylene glycol (0.6 mL/kg) was markedly protective, but the lower dose (0.2 mL/kg) was only slightly protective. These solvents also reduced acetaminophen-induced GSH depletion. Dimethylformamide was protective when given 2 h before or 1 h after acetaminophen administration, but was ineffective if given 2.5 h after acetaminophen. Ethanol at the higher dose (0.6 mL/kg) was partially protective, whereas ethanol at the lower dose (0.2 mL/kg) as well as Tween 20 at any dose had no influence. None of the vehicles (0.6 mL/kg) was hepatotoxic per se, and none of them was protective in a model of liver injury caused by D-galactosamine and lipopolysaccharide. PMID- 20962896 TI - Identification of VEGF receptor-2 tyrosine phosphorylation sites involved in VEGF mediated endothelial platelet-activating factor synthesis. AB - Vascular endothelial growth factor (VEGF)-mediated inflammation requires the synthesis of acute platelet-activating factor (PAF) by endothelial cells (ECs). We previously reported that VEGF-mediated PAF synthesis involves the activation of the homodimeric tyrosine kinase receptor VEGFR-2/R-2, leading to the recruitment of p38 and p42/p44 mitogen-activated protein kinases (MAPKs) and activation of secreted group V phospholipase A2 (sPLA2-V). We have also reported that VEGF-A165-mediated prostacyclin (PGI2) synthesis requires VEGFR-1/R-2 heterodimeric receptor activation. Selective activation of VEGF receptors can coordinate the synthesis of pro-PAF and anti-PGI2 inflammatory factors. It is unknown which VEGFR-2 tyrosine phosphorylation site(s) contribute(s) to PAF synthesis. Bovine aortic endothelial cells (BAECs) were transfected with pcDNA vectors encoding for native VEGF receptor-2 (VEGFR-2) cDNA or VEGFR-2 cDNA containing tyrosine phosphorylation sites mutated into phenylalanine residues (Y801F, Y1059F, Y1175F, Y1214F); an empty pcDNA vector was used as a negative control. Treatment of pcDNA-transfected BAECs with VEGF (10-9 mol/L) for 15 min increased PAF synthesis by 180%. In BAECs transfected with pcDNA vectors encoding mutated Y801F, Y1059F, Y1175F, or Y1214F VEGFR-2 cDNA, we observed a marked reduction of VEGF-mediated PAF synthesis by 38%, 46%, 69%, and 31%, respectively, compared with BAECs transfected with pcDNA vector encoding VEGFR-2 cDNA. Our data provide a novel insight as to the mechanisms by which VEGF promotes PAF synthesis. PMID- 20962897 TI - Retinol-deficient rats can convert a pharmacological dose of astaxanthin to retinol: antioxidant potential of astaxanthin, lutein, and beta-carotene. AB - Retinol (ROH) and provitamin-A carotenoids are recommended to treat ROH deficiency. Xanthophyll carotenoids, being potent antioxidants, can modulate health disorders. We hypothesize that nonprovitamin-A carotenoids may yield ROH and suppress lipid peroxidation under ROH deficiency. This study aimed to (i) study the possible bioconversion of astaxanthin and lutein to ROH similar to beta carotene and (ii) determine the antioxidant potential of these carotenoids with reference to Na(+)/K(+)-ATPase, antioxidant molecules, and lipid peroxidation (Lpx) induced by ROH deficiency in rats. ROH deficiency was induced in rats (n = 5 per group) by feeding a diet devoid of ROH. Retinol-deficient (RD) rats were gavaged with astaxanthin, lutein, beta-carotene, or peanut oil alone (RD group) for 7 days. Results show that the RD group had lowered plasma ROH levels (0.3 umol/L), whereas ROH rose in astaxanthin and beta-carotene groups (4.9 and 5.7 umol/L, respectively), which was supported by enhanced (69% and 70%) intestinal beta-carotene 15,15'-monooxygenase activity. Astaxanthin, lutein, and beta carotene lowered Lpx by 45%, 41%, and 40% (plasma), respectively, and 59%, 64%, and 60% (liver), respectively, compared with the RD group. Lowered Na(+)/K(+) ATPase and enhanced superoxide dismutase, catalase, and glutathione-S-transferase activities support the lowered Lpx. To conclude, this report confirms that astaxanthin is converted into beta-carotene and ROH in ROH-deficient rats, and the antioxidant potential of carotenoids was in the order astaxanthin > lutein > beta-carotene. PMID- 20962898 TI - The activity of the thiazide-sensitive Na(+)-Cl(-) cotransporter is regulated by protein phosphatase PP4. AB - Cation transport in the distal mammalian nephron relies on the SLC12 family of membrane cotransporters that include the thiazide-sensitive Na(+)-Cl- cotransporter (NCC). NCC is regulated through a scaffold of interacting proteins, including the WNK kinases, WNK 1 and WNK 4, which are mutated in the hypertensive Gordon's syndrome. Dynamic regulation of NCC function by kinases must involve dephosphorylation by phosphatases, as illustrated by the role of PP1 and PP2B in the regulation of KCC members of the SLC12 family. There are 2 phosphorylation controlled regulatory pathways for NCC: type 1, mediated by WNK4 and affecting trafficking to the surface membrane, and type 2, affecting intrinsic transporter kinetics by phosphorylation of conserved N-terminal S/T amino acids. Using the Xenopus oocyte expression system, we show that PP4 inhibits NCC activity - but not trafficking to the surface membrane - by a mechanism that requires phosphatase activity and a conserved N-terminal amino acid of NCC, threonine 58. This action is distinct from WNK4 regulation of membrane trafficking. In the mouse kidney, PP4 is selectively expressed in the distal nephron, including cells of the distal convoluted tubule cells, suggesting that PP4 may have a physiological role in regulating NCC and hence NaCl reabsorption in vivo. PMID- 20962899 TI - The acute administration of either amiloride or captopril does not prevent endothelial dysfunction induced by ischemia and reperfusion in the human forearm vasculature. AB - Animal studies have demonstrated the ability of both sodium-hydrogen exchange inhibitors and angiotensin-converting enzyme inhibitors to reduce infarct size and preserve postischemic ventricular function following ischemia and reperfusion (IR) injury. Whether these interventions can also prevent IR-induced impairment of endothelial function in humans has not been investigated. We performed 2 separate double-blind, placebo-controlled, crossover studies. In the first study, 10 healthy volunteers were randomized to receive oral amiloride (10 mg) or a placebo. In a separate study, another group of volunteers (n = 10) was randomized to receive oral captopril (50 mg) or a placebo. At the time of the peak hemodynamic effect of the drug (3 and 1.5 h after administration of amiloride and captopril, respectively), endothelium-dependent, flow-mediated dilatation of the radial artery was measured before and after IR. IR significantly blunted flow mediated dilatation in all groups (placebo: pre-IR: 6.8% +/- 0.7%; post-IR: 2.9% +/- 0.9%; P < 0.01; amiloride: pre-IR: 5.9% +/- 0.6%; post-IR: 2.1% +/- 1.3%; P = 0.01; captopril: pre-IR: 6.0% +/- 0.5%; post-IR: 2.0% +/- 0.6%; P < 0.01). In humans, neither 10 mg of oral amiloride nor 50 mg of oral captopril was able to provide protection against IR-induced endothelial dysfunction in the peripheral vasculature. PMID- 20962900 TI - Restricted feeding improves postischemic recovery of Langendorff-perfused rat hearts. AB - The goal of the present study was to assess the effects of a restricted feeding schedule (RFS) on postischemic contractile recovery in relation to triacylglycerol (TAG), glycogen, and ATP content. Glucose-6-phosphate dehydrogenase (G6PDH) activity, reduced/oxidized glutathione ratio (GSH/GSSG), and thiobarbituric acid reactive substances (TBARS) levels were also determined. Isolated rat hearts entrained to daily RFS (2 h food access starting at 1200) or fed ad libitum (FED) for 3 weeks were Langendorff-perfused (25 min ischemia, 30 min reperfusion) with Krebs-Ringer bicarbonate solution (10 mmol/L glucose). RFS improved the recovery of contractility and reduced creatine kinase (CK) release upon reperfusion. Further, at the end of reperfusion, RFS hearts exhibited increased G6PDH activity and repletion of tissue glycogen, TAG, and ATP that was not observed in the FED hearts. GSH/GSSG at the end of reperfusion fell to the same value in both nutritional states, and TBARS levels were higher in the RFS hearts. In conclusion, RFS improved postischemic functional recovery, which was accompanied by a reduction in CK release and a striking energy recovery. Although enhanced G6PDH activity was displayed, RFS was unable to reduce lipid peroxidation, supporting a clear dissociation between protection against mechanical dysfunction and CK release on the one hand and oxidative damage on the other. PMID- 20962901 TI - Paeonol attenuates airway inflammation and hyperresponsiveness in a murine model of ovalbumin-induced asthma. AB - Paeonol, the main active component isolated from Moutan Cortex, possesses extensive pharmacological activities such as anti-inflammatory, anti-allergic, and immunoregulatory effects. In the present study, we examined the effects of paeonol on airway inflammation and hyperresponsiveness in a mouse model of allergic asthma. BALB/c mice sensitized and challenged with ovalbumin were administered paeonol intragastrically at a dose of 100 mg/kg daily. Paeonol significantly suppressed ovalbumin-induced airway hyperresponsiveness to acetylcholine chloride. Paeonol administration significantly inhibited the total inflammatory cell and eosinophil count in bronchoalveolar lavage fluid. Treatment with paeonol significantly enhanced IFN-gamma levels and decreased interleukin-4 and interleukin-13 levels in bronchoalveolar lavage fluid and total immunoglobulin E levels in serum. Histological examination of lung tissue demonstrated that paeonol significantly attenuated allergen-induced lung eosinophilic inflammation and mucus-producing goblet cells in the airway. These data suggest that paeonol exhibits anti-inflammatory activity in allergic mice and may possess new therapeutic potential for the treatment of allergic bronchial asthma. PMID- 20962902 TI - Ferrous iron oxidation in moderately thermophilic acidophile Sulfobacillus sibiricus N1(T). AB - The iron-oxidizing system of a moderately thermophilic, extremely acidophilic, gram-positive mixotroph, Sulfobacillus sibiricus N1(T), was studied by spectroscopic, high-performance liquid chromatography and inhibitory analyses. Hemes B, A, and O were detected in membranes of S. sibiricus N1(T). It is proposed that the electron transport chain from Fe2(+) to O2 is terminated by 2 physiological oxidases: aa3-type cytochrome, which dominates in the early exponential phase of growth, and bo3-type cytochrome, whose role in iron oxidation becomes more prominent upon growth of the culture. Both oxidases were sensitive to cyanide and azide. Cytochrome aa3 was more sensitive to cyanide and azide, with K(i) values of 4.1 and 2.5 umol.L-1, respectively, compared with K(i) values for cytochrome bo3, which were 9.5 umol.L-1 for cyanide and 7.0 umol.L-1 for azide. This is the first evidence for the participation of a bo3-type oxidase in ferrous iron oxidation. The respiratory chain of the mixotroph contains, in addition to the 2 terminal oxidases, a membrane-bound cytochrome b573. PMID- 20962903 TI - Effect of culture age, protectants, and initial cell concentration on viability of freeze-dried cells of Metschnikowia pulcherrima. AB - The effect of freeze-drying using different lyoprotectants at different concentrations on the viability and biocontrol efficacy of Metschnikowia pulcherrima was evaluated. The effects of initial yeast cell concentration and culture age on viability were also considered. Yeast cells grown for 36 h were more resistant to freeze-drying than were 48 h cells. An initial concentration of 108 cells.mL-1 favoured the highest survival after freeze-drying. When maltose (25%, m/v) was used as protectant, a high cell viability was obtained (64.2%). Cells maintained a high viability after 6 months of storage at 4 degrees C. The biocontrol efficacy of freeze-dried cells was similar to the activity of fresh cells on 'Gala' apples and was slightly lower on 'Golden Delicious' apples. After optimizing freeze-drying conditions, the viability of M. pulcherrima cells was similar to that obtained in other studies. The results constitute a first step towards the commercial development of M. pulcherrima as a biocontrol agent. PMID- 20962904 TI - Effect of diallyldisulphide on an antioxidant enzyme system in Candida species. AB - This study was carried out to show the effect of diallyldisulphide (DADS), an important organosulphur compound found in garlic (Allium sativum), on antioxidant systems in Candida species. Changes in antioxidant metabolites and antioxidant activity in the presence of DADS were found in Candida albicans and Candida tropicalis. Candida cells were treated with sublethal concentrations of DADS. DADS caused a decrease in the activity of all antioxidant enzymes except catalase, resulting in oxidative stress and damaged cells. The amount of oxidative stress generated by DADS was found to be a function of its concentration. A significant decrease in superoxide dismutase, glutathione-S transferase, and glutathione peroxidase activities but an increase in catalase activity were observed. Increased levels of lipid peroxidation and decreased levels of glutathione were observed in treated cells. Activity of glucose-6 phosphate dehydrogenase decreased significantly following DADS treatment and could be correlated with a decrease in glutathione concentration in both Candida species. These results indicate that diallyl disulphide acts as a pro-oxidant to Candida species and hence may act as a potent antifungal in the management of candidiasis. PMID- 20962905 TI - Survival of phosphate-solubilizing bacteria against DNA damaging agents. AB - Phosphate-solubilizing bacteria (PSBs) were isolated from different plant rhizosphere soils of various agroecological regions of India. These isolates showed synthesis of pyrroloquinoline quinone (PQQ), production of gluconic acid, and release of phosphorus from insoluble tricalcium phosphate. The bacterial isolates synthesizing PQQ also showed higher tolerance to ultraviolet C radiation and mitomycin C as compared to Escherichia coli but were less tolerant than Deinococcus radiodurans. Unlike E. coli, PSB isolates showed higher tolerance to DNA damage when grown in the absence of inorganic phosphate. Higher tolerance to ultraviolet C radiation and oxidative stress in these PSBs grown under PQQ synthesis inducible conditions, namely phosphate starvation, might suggest the possible additional role of this redox cofactor in the survival of these isolates under extreme abiotic stress conditions. PMID- 20962906 TI - Pectin lyase production by recombinant Penicillium griseoroseum strain 105. AB - Recombinant Penicillium griseoroseum strain 105 overproduces an extracellular pectin lyase (PL) under the transcriptional control of the strong gpdA promoter of Aspergillus nidulans. Our aim was to evaluate PL production by recombinant P. griseoroseum strain 105 in submerged fermentation system bioreactors BioFloIII and BioFloIV using 2 or 10 L working volumes under different growth conditions and to analyze the production of cellulase, polygalacturonase, pectin methylesterase, and protease. PL overproduction by recombinant P. griseoroseum strain 105 was 112 times higher than that of P. griseoroseum PG63 grown in sugarcane juice. Cellulases and proteases were not detected in the culture filtrate, and evaluation for extracellular proteins in the culture medium by SDS PAGE showed the presence of a 36 kDa predominant band, similar to the molecular mass estimated from the nucleotide sequence of plg1 gene for PL of P. griseoroseum strain 105. This recombinant strain provides the advantage of PL production, which predominates over other extracellular proteins usually present in most commercial pectinase preparations, using sugarcane juice as a substrate of low cost. PMID- 20962907 TI - Quantitative PCR assay of sewage-associated Bacteroides markers to assess sewage pollution in an urban lake in Dhaka, Bangladesh. AB - This paper aimed to assess the magnitude of sewage pollution in an urban lake in Dhaka, Bangladesh, by using quantitative PCR of sewage-associated Bacteroides HF183 markers. PCR was also used for the quantitative detection of ruminant wastewater-associated CF128 markers along with the enumeration of traditional fecal indicator bacteria, namely enterococci. The number of enterococci in lake water samples ranged from 1.1 * 104 to 1.9 * 105 colony-forming units/100 mL water. From the 20 water samples tested, 14 (70%) and 7 (35%) were PCR positive for HF183 and CF128 markers, respectively. The numbers of HF183 and CF128 markers in lake water samples were 3.9 * 104 to 6.3 * 107 and 9.3 * 103 to 6.3 * 105 genomic units/100 mL water, respectively. The high numbers of enterococci and HF183 markers are indicative of sewage pollution and potential health risks to those who use the lake water for nonpotable purposes such as bathing and washing clothes. This is the first study that investigated the presence of microbial source tracking markers in Dhaka, Bangladesh, where diarrhoeal disease is one of the major causes of childhood mortality. The molecular assay used in this study can provide valuable information on the extent of sewage pollution, thus facilitating the development of robust strategies to minimize potential health risks. PMID- 20962908 TI - Detection of WWE2-related Lentisphaerae by 16S rRNA gene sequencing and fluorescence in situ hybridization in landfill leachate. AB - We collected samples of anaerobic landfill leachate from municipal solid waste landfill (Vert-le-Grand, France) and constructed 16S rRNA clone libraries using primers targeting Planctomycetes and relatives (Pla46F and 1390R). Analyses of 16S rRNA gene sequences resulted in the abundant representation of WWE2-related Lentisphaerae, members of the phylum Lentisphaerae, in the clone library (98% of the retrieved sequences). Although the sequences that are phylogenetically affiliated with the cultured isolate Victivallis vadensis were identified (WWE2 subgroup II), the majority of the sequences were affiliated with an uncultured Lentisphaerae lineage (WWE2 subgroup I). We designed oligonucleotides probes targeting the specific 16S rRNA gene regions of those 2 subgroups. Fluorescence in situ hybridization confirmed the abundance of the uncultivated WWE2 subgroup I in our leachate samples. PMID- 20962909 TI - Molecular analyses of the diversity in marine bacterioplankton assemblages along the coastline of the northeastern Gulf of Mexico. AB - Bacterial community diversity in marine bacterioplankton assemblages were examined in 3 coastal locations along the northeastern Gulf of Mexico (GOM) using 16S rRNA gene libraries and fluorescence in situ hybridization approaches. The majority of the sequences (30%-60%) were similar to the 16S rRNA gene sequences of unknown bacteria; however, the operational taxonomic units from members of the Cyanobacteria, Proteobacteria, and Bacteroidetes were also present at the 3 GOM sites. Overall, sequence diversity was more similar between the Gulf sites of Carrabelle and Ochlockonee than between either of the Gulf sites and Apalachicola Bay. Fluorescence in situ hybridization analyses revealed the quantitative predominance of members of the Alphaproteobacteria subclass and the Cytophaga Flavobacterium cluster within the bacterioplankton assemblages. In general, the study further reveals the presence of many bacterial taxa that have been previously found to be dominant in coastal marine environments. Differences observed in the representation of the various bacterial phylogenetic groups among the GOM coastal sites could be partly attributed to dynamic variations in several site-specific conditions, including intermittent tidal events, nutrient availability, and anthropogenic influences. PMID- 20962910 TI - Selection of genetically diverse Trichoderma spp. isolates for suppression of Phytophthora capsici on bell pepper. AB - Environmentally compatible control measures are needed for suppression of Phytophthora capsici on pepper. Twenty-three isolates of Trichoderma were screened for suppression of a mixture of 4 genetically distinct isolates of this pathogen on bell pepper (Capsicum anuum) in greenhouse pot assays. Of these 23 isolates, GL12, GL13, and Th23 provided significant suppression of P. capsici in at least 2 assays. These isolates were then compared with Trichoderma virens isolates GL3 and GL21 for suppression of this disease in the presence and absence of the harpin-based natural product Messenger. Isolates GL3 and Th23 provided significant disease suppression (P <= 0.05) in 3 of 4 assays, while GL12, GL13, and GL21 provided significant suppression in 2 of 4 assays. There was no apparent benefit from the application of Messenger. Phylogenetic analysis of these 5 isolates (based on the ITS1 region of the nuclear rDNA cluster and tef1), and an additional 9 isolates that suppressed P. capsici in at least 1 assay, separated isolates into 2 clades, with 1 clade containing GL3, GL12, GL13, and GL21. There were also 2 more distantly related isolates, one of which was Th23. We report here the identification of genetically distinct Trichoderma isolates for potential use in disease management strategies employing isolate combinations directed at suppression of P. capsici on pepper. PMID- 20962911 TI - Influence of carbon source on growth and mycotoxin production by isolates of Pyrenophora tritici-repentis from wheat. AB - The fungus Pyrenophora tritici-repentis can infect wheat kernels, causing red smudge, and has been shown to produce the anthraquinone mycotoxins emodin, catenarin, and islandicin. The growth of 8 fungal isolates from diverse regions was evaluated on various culture media and was found to be generally slowest on the semisynthetic Fries medium. The choice of carbon source had a significant effect on mycotoxin production, as assessed by high-performance liquid chromatography. The highest emodin concentration (194.18 +/- 16.26 ug/g medium) was observed for isolate Alg 3-24 on Fries medium supplemented with fructose, while the highest catenarin concentration (302.54 +/-13.92 ug/g medium) was observed for TS93-71B on Fries medium supplemented with starch. Islandicin was not produced by any isolate under the conditions tested. Evaluation of the dynamics of mycotoxin production by isolate 331-2 on V8-potato dextrose agar medium revealed a rapid accumulation of emodin and catenarin during the first week of incubation, followed by a large decline by 14 days. Differences in the growth of and mycotoxin production by isolates of P. tritici-repentis likely resulted from the differential composition of the media and (or) intraspecies variability. Accordingly, the optimization of growth medium should be considered when evaluating the potential of specific isolates for mycotoxin production. PMID- 20962912 TI - Effects of exercise combined with caloric restriction on inflammatory cytokines. AB - Chronic inflammation has been implicated in the pathogenesis of several chronic diseases, such as atherosclerosis and diabetes, as well as certain types of cancers. It has been suggested that circulating biomarkers for inflammation may be modified by exercise; however, few laboratory-based studies have been conducted in nonobese premenopausal women. The purpose of this investigation was to determine the impact of a 4-month exercise training and caloric-restriction intervention with the goal of weight loss on circulating biomarkers of inflammation in sedentary premenopausal women aged 25- 40 years (weight, 57 +/- 2 kg). Subjects were studied for 6 consecutive menstrual cycles: 1 Screening, 1 Baseline, then 4 interventions (Interventions 1-4). Supervised aerobic training, consisting primarily of treadmill running and elliptical machine exercise, was performed 4 times per week for 40-90 min at 79% +/- 0.7% of maximal heart rate. Subjects also consumed 30% fewer calories vs. baseline (1863 +/- 58 to 1428 +/- 53 kcalday(-1) (1 kcal = 4.186 kJ), p < 0.0001). Circulating inflammatory biomarkers, including adiponectin, high-sensitivity (hs) C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interferon gamma (IFN-gamma), and leptin, as well as body composition, aerobic capacity, and energy balance, were measured before and after the intervention. Maximal aerobic capacity increased by 8.5 +/- 1.7 mL kg(-1)min-1 (p < 0.001) and body mass declined by an average of 3.7 +/- 0.5 kg (p < 0.001). Significant reductions in IL-6 (0.39 +/- 0.04 to 0.30 +/- 0.03 pgmL(-1), p = 0.025), IFN-gamma (0.58 +/- 0.83 to 0.42 +/- 0.64 pgmL-1, p = 0.030), and leptin (13.18 +/- 1.28 to 6.28 +/- 0.71 pgmL(-1), p < 0.001) were detected in response to the intervention. No significant changes in adiponectin, hs-CRP, or TNF-alpha were found. Weight loss in response to exercise training and caloric restriction is effective in reducing inflammatory markers, specifically IL-6 and leptin. PMID- 20962913 TI - Protein consumption following aerobic exercise increases whole-body protein turnover in older adults. AB - Research measuring whole-body protein turnover (WBPT) after both exercise and nutrition has generally focused on resistance exercise; however, there is a paucity of data regarding the effect of postaerobic exercise nutrition, especially in older adults. It is not known if postexercise protein feeding has a beneficial effect on protein turnover after low- to moderate-intensity exercise. We investigated whether consuming protein plus carbohydrate (PRO) immediately after an acute bout of aerobic exercise has an additive effect over carbohydrate alone (CHO) on WBPT in older individuals. Twelve healthy older adults (age, 59 +/ 4 years) were studied on 2 separate occasions after 1 h of exercise at approximately 50% of maximal rate of oxygen uptake, followed by 4 h of recovery. Immediately following exercise, subjects ingested a CHO (60 g) or an isocaloric PRO beverage (40 g carbohydrate, 20 g whey protein). Whole-body protein metabolism was determined using [1-13C]leucine infusion (60 mg prime; 75 mgh(-1) continuous), and sampling blood and expired breath. Rates of whole-body leucine appearance and oxidation, and nonoxidative leucine disposal during the third and fourth hours of postexercise recovery were higher in the PRO group (2.51 +/- 0.55, 0.78 +/- 0.37, and 1.71 +/- 0.44 micromol kg(-1).min(-1), respectively) than in the CHO group (1.81 +/- 0.27, 0.33 +/- 0.14, and 1.47 +/- 0.25 micromol kg(-1).min-1, respectively; p = 0.001). Our results indicate that consumption of a PRO beverage after aerobic exercise increased WBPT to a greater extent than a CHO beverage. PMID- 20962914 TI - Effects of a highly palatable diet on lipid and glucose parameters, nitric oxide, and ectonucleotidases activity. AB - Obesity has reached epidemic proportions worldwide and is stimulated by the ready availability of food rich in fat and sugar (highly palatable diet). This type of diet increases the risks of obesity-associated pathologies, such as insulin resistance and cardiovascular disease. Nitric oxide, a potent endogenous vasodilator, is decreased in these pathologies, mostly as a result of insulin resistance. Ectonucleotidases are ecto and soluble enzymes that regulate the availability of the nucleotides ATP, ADP, and AMP and the nucleoside adenosine in the vascular system, thereby affecting vasoconstriction, vasodilatation, and platelet aggregation homeostasis. The aim of this study was to evaluate the effects of a highly palatable diet on serum lipid and glucose parameters, nitric oxide, and ectonucleotidase activity. Forty male Wistar rats were fed 1 of 2 diets for either 45 days or 4 months: standard chow (SC, n = 10) or a highly palatable diet enriched with sucrose (HP, n = 10). Body mass, visceral fat mass, glucose tolerance, cholesterol (total, high-density lipoprotein (HDL) and non HDL), serum triacylglycerol, liver triacylglycerol, and free glycerol were increased in the HP group after 45 days and after 4 months, whereas insulin levels were not different between the groups at either time. Furthermore, levels of nitric oxide metabolites and ATP, ADP, and AMP hydrolysis were significantly lower in the HP group (p < 0.05) after 4 months. In conclusion, the consumption of the HP diet for 4 months induced overall corporal and metabolic changes, and decreased nitric oxide metabolites and ectonucleotidase activity, thereby promoting an appropriate environment for the development of cardiovascular diseases, without apparent changes in insulin levels. PMID- 20962915 TI - Influence of high-fat diet from differential dietary sources on bone mineral density, bone strength, and bone fatty acid composition in rats. AB - Previous studies have suggested that high-fat diets adversely affect bone development. However, these studies included other dietary manipulations, including low calcium, folic acid, and fibre, and (or) high sucrose or cholesterol, and did not directly compare several common sources of dietary fat. Thus, the overall objective of this study was to investigate the effect of high fat diets that differ in fat quality, representing diets high in saturated fatty acids (SFA), n-3 polyunsaturated fatty acids (PUFA), or n-6 PUFA, on femur bone mineral density (BMD), strength, and fatty acid composition. Forty-day-old male Sprague-Dawley rats were maintained for 65 days on high-fat diets (20% by weight), containing coconut oil (SFA; n = 10), flaxseed oil (n-3 PUFA; n = 10), or safflower oil (n-6 PUFA; n = 11). Chow-fed rats (n = 10), at 105 days of age, were included to represent animals on a control diet. Rats fed high-fat diets had higher body weights than the chow-fed rats (p < 0.001). Among all high-fat groups, there were no differences in femur BMD (p > 0.05) or biomechanical strength properties (p > 0.05). Femurs of groups fed either the high n-3 or high n-6 PUFA diets were stronger (as measured by peak load) than those of the chow fed group, after adjustment for significant differences in body weight (p = 0.001). As expected, the femur fatty acid profile reflected the fatty acid composition of the diet consumed. These results suggest that high-fat diets, containing high levels of PUFA in the form of flaxseed or safflower oil, have a positive effect on bone strength when fed to male rats 6 to 15 weeks of age. PMID- 20962916 TI - Physiological effects of caffeine, epigallocatechin-3-gallate, and exercise in overweight and obese women. AB - The aim of this study was to evaluate the combined effects of a 10-week exercise program with ingestion of caffeine and epigallocatechin-3-gallate (EGCG) on body composition, cardiovascular fitness, and strength in overweight and obese women. In a double-blind, placebo-controlled approach, overweight and obese women (n = 27) were randomly assigned to treatment groups with exercise (an active supplementing group with exercise (EX-Act) and a placebo group with exercise (EX PL)) or without exercise (an active-supplementing group without exercise (NEX Act) and a placebo group without exercise (NEX-PL)). All participants consumed 1 drink per day for 10 weeks; EX-Act and EX-PL participated in a concurrent endurance and resistance training program. Changes in body composition were assessed using a 4-compartment model. Changes in muscle mass (MM) were evaluated using a DXA-derived appendicular lean-soft tissue equation. There was a significant time * treatment interaction for MM (p = 0.026) and total cholesterol (TC) (p = 0.047), and a significant time * training interaction for peak oxygen consumption (p = 0.046) and upper-body and lower-body strength (p < 0.05). Significant differences between the EX groups and NEX groups for percentage change in MM and peak oxygen consumption, and upper-body and lower-body strength, were revealed. Clinical markers for hepatic and renal function revealed no adverse effects. TC significantly decreased for the active-supplementing groups (EX-Act, NEX-Act). The current study suggests that implementing a caffeine-EGCG containing drink prior to exercise may improve MM, fitness, and lipid profiles in overweight women. PMID- 20962917 TI - Local histamine H(1-) and H(2)-receptor blockade reduces postexercise skeletal muscle interstitial glucose concentrations in humans. AB - Elevated blood flow can potentially influence skeletal muscle glucose uptake, but the impact of postexercise hyperemia on glucose availability to skeletal muscle remains unknown. Because postexercise hyperemia is mediated by histamine H(1)- and H(2)-receptors, we tested the hypothesis that postexercise interstitial glucose concentrations would be lower in the presence of combined H1- and H2 receptor blockade. To this end, 4 microdialysis probes were inserted into the vastus lateralis muscle of 14 healthy subjects (21-27 years old) immediately after 60 min of either upright cycling at 60% peak oxygen uptake (exercise, n = 7) or quiet rest (sham, n = 7). Microdialysis probes were perfused with a modified Ringer's solution containing 3 mmol L(-1) glucose, 5 mmol L(-1) ethanol, and [6-3H] glucose (200 disintegrations.min-1 microL(-1)). Two sites (blockade) received both H1- and H2-receptor antagonists (1 mmol L(-1) pyrilamine and 3 mmol L-1 cimetidine) and 2 sites (control) did not receive antagonists. Ethanol outflow/inflow ratios (an inverse surrogate of local blood flow) were higher in blockade sites than in control sites following exercise (p < 0.05), whereas blockade had no effect on ethanol outflow/inflow ratios following sham (p = 0.80). Consistent with our hypothesis, during 3 of the 5 dialysate collection periods, interstitial glucose concentrations were lower in blockade sites vs. control sites following exercise (p < 0.05), whereas blockade had no effect on interstitial glucose concentrations following sham (p = 0.79). These findings indicate that local H1- and H2-receptor activation modulates skeletal muscle interstitial glucose levels during recovery from exercise in humans and suggest that the availability of glucose to skeletal muscle is enhanced by postexercise hyperemia. PMID- 20962918 TI - Core cooling and thermal responses during whole-head, facial, and dorsal immersion in 17 degrees C water. AB - This study isolated the effects of dorsal, facial, and whole-head immersion in 17 degrees C water on peripheral vasoconstriction and the rate of body core cooling. Seven male subjects were studied in thermoneutral air (approximately 28 degrees C). On 3 separate days, they lay prone or supine on a bed with their heads inserted through the side of an adjustable immersion tank. Following 10 min of baseline measurements, the water level was raised such that the water immersed the dorsum, face, or whole head, with the immersion period lasting 60 min. During the first 30 min, the core (esophageal) cooling rate increased from dorsum (0.29 +/- 0.2 degrees C h-1) to face (0.47 +/- 0.1 degrees C h-1) to whole head (0.69 +/- 0.2 degrees C h(-1)) (p < 0.001); cooling rates were similar during the final 30 min (mean, 0.16 +/- 0.1 degrees C h(-1)). During the first 30 min, fingertip blood flow (laser Doppler flux as percent of baseline) decreased faster in whole head immersion (114 +/- 52% h(-1)) than in either facial (51 +/- 47% h-1) or dorsal (41 +/- 55% h(-1)) immersion (p < 0.03); rates of flow decrease were similar during minutes 30 to 60 (mean, 22.5 +/- 19% h(-1)). Total head heat loss over 60 min was significantly different between whole-head (120.5 +/- 13 kJ), facial (86.8 +/- 17 kJ), and dorsal (46.0 +/- 11 kJ) immersion (p < 0.001). The rate of core cooling, relative to head heat loss, was similar in all conditions (mean, 0.0037 +/- 0.001 degree C kJ(-1)). Although the whole head elicited a higher rate of vasoconstriction, the face did not elicit more vasoconstriction than the dorsum. Rather, the progressive increase in core cooling from dorsal to facial to whole-head immersion simply correlates with increased heat loss. PMID- 20962919 TI - The Oslo health study: soft drink intake is associated with the metabolic syndrome. AB - It has been reported that the frequency of cola intake (COLA) is positively associated with serum triglycerides and negatively associated with high-density lioprotein (HDL) cholesterol, both components of the metabolic syndrome (MetS). The question now is whether noncola soft drink intake (NCOLA) is associated with MetS. Among the 18 770 participants in the Oslo Health Study, 5373 men and 6181 women had data on COLA and NCOLA and risk factors for MetS (except fasting glucose). Main MetS requirements are central obesity and 2 of the following: increased triglycerides, low HDL cholesterol, increased systolic or diastolic blood pressure, and elevated fasting blood glucose. The MetSRisk index was calculated to estimate many MetS components. Using regression analyses, the association between COLA (NCOLA) and MetS (MetSRisk) was studied. In young (aged 30 years), middle-aged (aged 40 and 45 years), and senior (aged 59 and 60 years) men and women, there was, in general, a positive correlation between COLA and MetSRisk, and between COLA and single MetS risk factors, except HDL cholesterol, which was negatively correlated. A less consistent picture was found for NCOLA. By regression analyses, after adjustment for sex, age, time since last meal, and use of sugar-sweetened soft drinks, a positive association between COLA (NCOLA) and MetSRisk (MetS) was still found. However, when also controlling for cheese, fatty fish, coffee, alcohol, smoking, physical activity, education, and birthplace, only the association with COLA remained significant, irrespective of the presence or absence of sugar. In conclusion, the self-reported intake frequency of soft drinks can be positively associated with MetS. PMID- 20962920 TI - Metabolic responses of upper-body accelerometer-controlled video games in adults. AB - Historically, video games required little physical exertion, but new systems utilize handheld accelerometers that require upper-body movement. It is not fully understood if the metabolic workload while playing these games is sufficient to replace routine physical activity. The purpose of this study was to quantify metabolic workloads and estimate caloric expenditure while playing upper-body accelerometer-controlled and classic seated video games. Nineteen adults completed a peak oxygen consumption treadmill test followed by an experimental session where exercising metabolism and ventilation were measured while playing 3 video games: control (CON), low activity (LOW) and high activity (HI). Resting metabolic measures (REST) were also acquired. Caloric expenditure was estimated using the Weir equation. Mean oxygen consumption normalized to body weight for HI condition was greater than LOW, CON, and REST. Mean oxygen consumption normalized to body weight for LOW condition was also greater than CON and REST. Mean exercise intensities of oxygen consumption reserve for HI, LOW, and CON were 25.8% +/- 5.1%, 6.4% +/- 4.8%, and 0.8% +/- 2.4%, respectively. Estimated caloric expenditure during the HI was significantly related to aerobic fitness, but not during other conditions. An active video game significantly elevated oxygen consumption and heart rate, but the increase was dependent on the type of game. The mean oxygen consumption reserve during the HI video game was below recommended international standards for moderate and vigorous activity. Although upper-body accelerometer-controlled video games provided a greater exercising stimulus than classic seated video games, these data suggest they should not replace routine moderate or vigorous exercise. PMID- 20962921 TI - Perceived exertion and heart rate models for estimating metabolic workload in elite British soldiers performing a backpack load-carriage task. AB - Identifying field measures to estimate backpack load-carriage work intensity in elite soldiers is of interest to the military. This study developed rating of perceived exertion (RPE) and heart rate models to define metabolic workload for a backpack load-carriage task valid for a population of elite soldiers using serial data. Male soldiers (n = 18) from the British Parachute or Special Air Service Regiment completed an incremental treadmill walking and (or) running protocol while carrying a 20-kg backpack. Heart rate, RPE, and oxygen uptake were recorded at each incremental stage of the protocol. Linear mixed models were used to model the RPE and heart rate data in the metric of measured peak oxygen uptake. Workload was accurately estimated using RPE alone (SE = 6.03), percentage of estimated maximum heart rate (%E-MHR) (SE = 6.9), and percentage of measured maximum heart rate (%M-MHR) (SE = 4.9). Combining RPE and %E-MHR resulted in a field measure with an accuracy (SE = 4.9) equivalent to the %M-MHR model. We conclude that RPE, %E-MHR, and %M-MHR provide accurate field-based proxy measures of metabolic workload in elite British soldiers performing a backpack load carriage task. The model is accurate for the metabolic range measured by these serial data for the backpack load-carriage task. PMID- 20962922 TI - Cellular responses in skeletal muscle to a season of ice hockey. AB - We hypothesized that a season of ice hockey would result in extensive remodeling of muscle. Tissue sampled from the vastus lateralis of 15 players (age = 20.6 +/- 0.4 years; mean +/- SE) prior to (PRE) and following (POST) a season was used to characterize specific adaptations. Measurement of representative metabolic pathway enzymes indicated higher maximal activities in POST than in PRE (p < 0.05) for succinic dehydrogenase (3.26 +/- 0.31 vs. 3.91 +/- 0.11 mol mg protein( 1) min(-1)), citrate synthase (7.26 +/- 0.70 vs. 8.70 +/- 0.55 mol mg protein(-1) min(-1)), and phosphofructokinase (12.8 +/- 1.3 vs. 14.4 +/- 0.96 mol mg protein( 1) min(-1)) only. The season resulted in an increase in Na+-K+-ATPase concentration (253 +/- 6.3 vs. 265 +/- 6.0 pmol g(-1) wet weight), a decrease (p < 0.05) in maximal activity of the sarcoplasmic reticulum Ca2+-ATPase (107 +/- 4.2 micromol g protein(-1) min(-1) vs. 92.0 +/- 4.6 micromol g protein(-1) min( 1)), and no change in the distribution (%) of fibre types. A smaller (p < 0.05) cross-sectional area (CSA) for both type I (-11.7%) and type IIA (-18.2%) fibres and a higher (p < 0.05) capillary count/CSA for type I (+17.9%) and type IIA (+17.2%) were also found over the season. No changes were found in peak oxygen consumption (51.4 +/- 1.2 mL kg(-1) min(-1) vs. 52.3 +/- 1.3 mL kg(-1) min(-1)). The results suggest, based on the alterations in oxidative and perfusion potentials and muscle mass, that the dominant adaptations are in support of oxidative metabolism, which occurs at the expense of fibre CSA and possibly force generating potential. PMID- 20962923 TI - Physiological responses and air consumption during simulated firefighting tasks in a subway system. AB - Professional firefighters (33 men, 3 women), ranging in age from 30 to 53 years, participated in a simulation of a subway system search and rescue while breathing from their self-contained breathing apparatus (SCBA). We tested the hypothesis that during this task, established by expert firefighters to be of moderate intensity, the rate of air consumption would exceed the capacity of a nominal 30 min cylinder. Oxygen uptake, carbon dioxide output, and air consumption were measured with a portable breath-by-breath gas exchange analysis system, which was fully integrated with the expired port of the SCBA. The task involved descending a flight of stairs, walking, performing a search and rescue, retreat walking, then ascending a single flight of stairs to a safe exit. This scenario required between 9:56 and 13:24 min:s (mean, 12:10 +/- 1:10 min:s) to complete, with an average oxygen uptake of 24.3 +/- 4.5 mL kg(-1) min(-1) (47 +/- 10 % peak oxygen uptake) and heart rate of 76% +/- 7% of maximum. The highest energy requirement was during the final single-flight stair climb (30.4 +/- 5.4 mL kg(-1) min(-1)). The average respiratory exchange ratio (carbon dioxide output/oxygen uptake) throughout the scenario was 0.95 +/- 0.08, indicating a high carbon dioxide output for a relatively moderate average energy requirement. Air consumption from the nominal "30-min" cylinder averaged 51% (range, 26%-68%); however, extrapolation of these rates of consumption suggested that the low-air alarm, signalling that only 25% of the air remains, would have occurred as early as 11 min for an individual with the highest rate of air consumption, and at 16 min for the group average. These data suggest that even the moderate physical demands of walking combined with search and rescue while wearing full protective gear and breathing through the SCBA impose considerable physiological strain on professional firefighters. As well, the rate of air consumption in these tasks classed as moderate, compared with high-rise firefighting, would have depleted the air supply well before the nominal time used to describe the cylinders. PMID- 20962924 TI - Aerobic activity before and following short-duration static stretching improves range of motion and performance vs. a traditional warm-up. AB - Many activities necessitate a high degree of static joint range of motion (ROM) for an extended duration. The objective of this study was to examine whether ROM could be improved with a short duration and volume of static stretching within a warm-up, without negatively impacting performance. Ten male recreationally active participants completed 2 separate protocols to examine changes in ROM and performance, respectively, with different warm-ups. The warm-up conditions for the ROM protocol were static stretching (SS), consisting of 6 repetitions of 6 s stretches; 10 min of running prior to the SS (AS); and 5 min of running before and after the SS (ASA). The performance protocol included a control condition of 10 min of running. Measures for the ROM protocol included hip flexion ROM, passive leg extensor tension, and hamstring electromyographic (EMG) activity at pre-warm-up, and at 1, 10, 20, and 30 min post-warm-up. Performance measures included countermovement jump (CMJ) height, reaction time (RT), movement time (MT), and balance at pre-warm-up and at 1 and 10 min post-warm-up. The ASA produced greater ROM overall than the SS and AS conditions (p < 0.0001), persisting for 30 min. There were no significant alterations in passive muscle tension or EMG. For the performance protocol, there were no main effects for condition, but there was a main effect for time, with CMJ height being greater at 1 and 10 min post-warm-up (p = 0.0004). Balance ratios and MT improved at 10 min post-warm-up (p < 0.0001). Results indicate that the ASA method can provide ROM improvements for 30 min with either facilitation or no impairment in performance. This may be especially important for athletes who substitute later into a game with minimal time for a full warm-up. PMID- 20962925 TI - Relationship of potassium ions and blood lactate to ventilation during exercise. AB - Ventilatory control during exercise is a complex network of neural and humoral signals. One humoral input that has received little recent attention in the exercise literature is potassium ions [K(+)]. The purpose of this study was to examine the relationship between [K(+)] and ventilation during an incremental cycle test and to determine if the relationship between [K(+)] and ventilation differs when blood lactate [lac-] is manipulated. Eight experienced triathletes (4 of each sex) completed 2 incremental, progressive (5-min stages) cycle tests to volitional fatigue: 1 with normal glycogen stores and 1 with reduced glycogen. Minute ventilation was measured during the final minute of each stage, and blood [lac(-)] and [K+] were measured at the end of each exercise stage. Minute ventilation and [K(+)] increased with exercise intensity and were similar between trials (p > 0.5), despite lower [lac-] during the reduced-glycogen trial. The concordance correlations (R(c)) between [lac(-)] and minute ventilation were stronger for both trials (R(c) = approximately 0.88-0.96), but the slopes of the relationships were different than the relationships between [K(+)] and minute ventilation (R(c) = approximately 0.76-0.89). The slope of the relationship between [lac-] and minute ventilation was not as steep during the reduced glycogen trial, compared with the normal trial (p = 0.002). Conversely, the slope of the relationships between [K(+)] and minute ventilation did not change between trials (p = 0.454). The consistent relationship of minute ventilation and blood [K(+)] during exercise suggests a role for this ion in the control of ventilation during exercise. Conversely, the inconsistent relationship between blood lactate and ventilation brings into question the importance of the relationship between lactate and ventilation during exercise. PMID- 20962926 TI - A decreased n-6/n-3 ratio in the fat-1 mouse is associated with improved glucose tolerance. AB - A reduction in skeletal muscle fatty acid oxidation (FAO), manifested as a reduction in mitochondrial content and (or) FAO within mitochondria, may contribute to the development of insulin resistance. n-3 polyunsaturated fatty acids (PUFA) have been observed to increase the capacity for FAO and improve insulin sensitivity. We used the fat-1 mouse model, a transgenic animal capable of synthesizing n-3 PUFA from n-6 PUFA, to examine this relationship. Fat-1 mice exhibited a approximately 20-fold decrease in the n-6/n-3 ratio in skeletal muscle, and plasma glucose and the area under the glucose curve were significantly (p < 0.05) lower in fat-1 mice during a glucose challenge test. The improvement in whole-body glucose tolerance in the fat-1 mouse was associated with a approximately 21% (p < 0.05) decrease in whole-muscle citrate synthase (CS) activity (in red muscle only), without alterations in CS activity of isolated mitochondria (either red or white muscle; p > 0.05). These data suggest that the fat-1 mouse has decreased skeletal muscle mitochondrial content. However, the intrinsic ability of mitochondria to oxidize fatty acids was not altered in the fat-1 mouse, as rates of palmitate oxidation in isolated mitochondria from both red and white muscle were unchanged. Overall, this study demonstrates that a decrease in the n-6/n-3 ratio can enhance glucose tolerance in healthy animals, independent of changes in mitochondrial content. PMID- 20962927 TI - Evolution of sarcopenia research. AB - The term "saropenia" was coined by Irwin Rosenberg in 1989 to refer to age related loss of skeletal muscle mass. The purpose of this current opinion is to provide an evolutionary overview of sarcopenia research since 1989. This includes the creation of an operational definition of sarcopenia; consideration of the impacts of sarcopenia on physical function, chronic disease, and mortality risk; the distinction between the process of sarcopenia and the process of age-related loss of muscle strength, a phenomenon that has recently been termed dynapenia; a comparison of the independent effects of sarcopenia and dynapenia on physical function, chronic disease, and mortality risk; and consideration of the combined influence of sarcopenia and dynapenia with obesity (i.e., sarcopenic-obesity and dynapenic-obesity) on physical function, chronic disease, and mortality risk. PMID- 20962928 TI - Paradoxical contractile properties in the knee extensors of HIV-infected men treated with antiretroviral therapy. AB - We assessed contractile properties in the knee extensors of 18 men with the human immunodeficiency virus (HIV+) being treated with antiretroviral therapy (ART), and 9 healthy controls matched for age and body mass index. We found significant, divergent differences between groups with regard to force relaxation. Half-times of twitch relaxation were shorter (62.6 +/- 5.4 ms vs. 48.9 +/- 3.0 ms; p = 0.045) and maximum rates of torque relaxation were slower (0.47% +/- 0.04%(s-)1 vs. 1.32% +/- 0.10%(s-)1; p < 0.001) in HIV+ individuals. These preliminary findings suggest potential intramuscular impairments in HIV+ individuals on ART, perhaps because of interactions between calcium handling and mitochondrial dysfunction. PMID- 20962929 TI - Vitamin D status and recommendations to improve vitamin D status in Canadian youth. AB - Little is known regarding the vitamin D status of Canadian youth. Our objectives were (i) to describe the vitamin D status of Quebec youth using a representative sample; (ii) to examine the relative contributions of diet, physical activity, and fat mass to the variance in plasma 25-hydroxyvitamin D(25(OH)D), the best biomarker of vitamin D status; and (iii) to examine the influence of household income and food insecurity on the intakes of dietary vitamin D, calcium, and dairy foods. To describe vitamin D status, we used data from the Quebec Child and Adolescent Health and Social Survey (QCAHS), which is a cross-sectional survey representative of Quebec youth aged 9, 13, and 16 years. For the second objective, 159 youth, aged 8 to 11 years, whose parents (at least one) were obese or had the metabolic syndrome, were used for cross-sectional analysis in the Quebec Adipose and Lifestyle InvesTigation in Youth (QUALITY). Fat mass was measured using dual X-ray absorptiometry (DXA), and physical activity was assessed by an accelerometer. Finally, we analyzed data from the Canadian Community Health Survey (CCHS), which collected data from 9 to 18 year olds (N = 8960), and was representative of Canadian youth. From this survey a single 24-h dietary recall, measured height and weight, sociodemographic, and food insecurity information were available. In both the QUALITY and QCAHS study, >90% of youth had suboptimal vitamin D levels (plasma 25(OH)D < 75 nmol L(-1)) at the end of winter and beginning of spring. In the QCAHS study, older youth had a higher prevalence of vitamin D deficiency (25(OH)D < 27.5 nmol L(-1)) (>10%) than younger youth, and girls from low-income households had lower plasma 25(OH)D concentrations. In the QUALITY study, milk consumption and physical activity had modest associations with plasma 25(OH)D, corresponding to 2.9 nmol L(-1) and 2.1 nmol L(-1) higher plasma 25(OH)D per standard deviation increase in these exposures, respectively. In the CCHS study, we found evidence that milk intake was being displaced by sweetened beverages among low-income boys and food insecure girls. We conclude that population-wide measures to increase dietary vitamin D intake should be examined in Canadian youth. PMID- 20962931 TI - In vivo rat brain measurements of changes in signal intensity depth profiles as a function of temperature using wide-field optical coherence tomography. AB - In our previous study, we used optical coherence tomography (OCT) and reported an increase in signal intensity of depth profiles between euthanasia injection and cardiac arrest (CA), demonstrating the potential as a tool for monitoring/diagnosing brain tissue viability [Appl. Opt.48, 4354 (2009)]. Here, for the first time to our knowledge, we measured three-dimensional (3D) OCT images through a thinned skull changing temperatures in the rat brain. The measurements were made at 10 min intervals for 210 min to evaluate correlations of temperature with heart rate and ratios of signal intensity (RSI). The 3D image area was 4 mm * 4 mm * 2.8 mm. When the temperature was decreased from 28 degrees C to 18 degrees C to reduce tissue viability, the heart rate was found to decrease with an increase in RSI. Negative correlation coefficients (CCs) between temperatures and RSIs, and between heart rate and RSIs, were obtained. This indicates that OCT signals increase with reductions of viability caused by decreases in heart rates and temperatures in tissues. These observations correspond to estimations obtained by multiwavelength diffuse reflectance spectroscopy [Appl. Opt.47, 4164 (2008)]. CCs and stationary RSIs would depend upon measured positions in tissues. Without injections for euthanasia, a similar rapid increase in RSI has also been measured before CA. PMID- 20962932 TI - Unified design of sinusoidal-groove fused-silica grating. AB - A general design rule of deep-etched subwavelength sinusoidal-groove fused-silica grating as a highly efficient polarization-independent or polarization-selective device is studied based on the simplified modal method, which shows that the device structure depends little on the incident wavelength, but mainly on the ratio of groove depth to incident wavelength and the ratio of wavelength to grating period. These two ratios could be used as the design guidelines for wavelength-independent structure from deep ultraviolet to far infrared. The optimized grating profile with a different function as a polarizing beam splitter, a polarization-independent two-port beam splitter, or a polarization independent grating with high efficiency of -1st order is obtained at a wavelength of 1064 nm, and verified by using the rigorous coupled-wave analysis. The performance of the sinusoidal grating is better than a conventional rectangular one, which could be useful for practical applications. PMID- 20962933 TI - All-spherical catadioptric telescope design for wide-field imaging. AB - The current trend in building medium-size telescopes for wide-field imaging is to use a Ritchey-Chretien (RC) design with a multilens corrector near the focus. Our goal is to find a cost-effective alternative design to the RC system for seeing limited observations. We present an f/4.5 all-spherical catadioptric system with a 1.5 degrees field of view. The system consists of a 0.8 m spherical primary and 0.4 m flat secondary mirror combined with a meniscus lens and followed by a three-lens field corrector. The optical performance is comparable to an equivalent f/4.5 RC system. We conclude that, for telescopes with apertures up to 2 m, the catadioptric design is a good alternative to the RC system. PMID- 20962934 TI - Image data compression based on non-negative incoherent imaging systems. AB - Channel and memory capacities are limited and expensive resources in optical communication. In this work we propose several approaches to reduce the required capacity by using the a priori knowledge about the optical system used to capture the spatial information. The a priori knowledge is related to the triangularlike shape of the optical transfer function and to its spectral symmetry. In our work we will demonstrate a reduction in memory capacity required for the same image quality or a resolution enhancement for the same physical memory capacity. We will also present a nearly all-optical implementation of these techniques. PMID- 20962935 TI - Multispectral quantitative photoacoustic imaging of osteoarthritis in finger joints. AB - We present in vivo experimental evidence that multispectral quantitative photoacoustic tomography (qPAT) has the potential to detect osteoarthritis (OA) in the finger joints. In this pilot study, two OA patients and three healthy volunteers were enrolled, and their distal interphalangeal (DIP) joints were examined photoacoustically by a multispectral PAT scanner. Images of tissue physiological/functional parameters including oxyhemoglobin, deoxyhemoglobin, oxygen saturation, and water content, along with the tissue acoustic velocity of all the examined joints, were simultaneously recovered using a finite element reconstruction algorithm for multispectral photoacoustic measurements. The recovered multispectral photoacoustic images show that the OA joints have significantly elevated water content, decreased oxygen saturation, and increased acoustic velocity compared to the normal joints. PMID- 20962936 TI - Enhanced three-dimensional discrete cosine transform based compression method for integral images by adaptive three-dimensional block construction. AB - In this paper, we propose an efficient compression method for integral images based on three-dimensional discrete cosine transform (3D-DCT). Even though the existing 3D-DCT based techniques are efficient, they may not be optimized to the characteristics of integral images, such as applying a fixed size block construction and a fixed scanning in placing 2D blocks to construct a 3D block. Therefore, we propose a variable size block construction and a scanning method adaptive to characteristics of integral images, which are realized by adaptive 3D block modes. Experimental results show that the proposed method gives significant improvement in coding efficiency. In particular, at the high bit rates, the proposed method is more improved, since overhead bits for signaling of the 3D block modes take a smaller part of the total bits. PMID- 20962937 TI - Loose abrasive slurries for optical glass lapping. AB - Loose abrasive lapping is widely used to prepare optical glass before its final polishing. We carried out a comparison of 20 different slurries from four different vendors. Slurry particle sizes and morphologies were measured. Fused silica samples were lapped with these different slurries on a single side polishing machine and characterized in terms of surface roughness and depth of subsurface damage (SSD). Effects of load, rotation speed, and slurry concentration during lapping on roughness, material removal rate, and SSD were investigated. PMID- 20962938 TI - Case study about the accuracy behavior of three different T-matrix methods. AB - In this paper we discuss the influence of two different sets of weighting functions on the accuracy behavior of T-matrix calculations for scalar scattering problems. The first set of weighting functions is related to one of Waterman's original approaches. The other set results into a least-squares scheme for the transmission problem. It is shown that both sets of weighting functions produce results with a converse accuracy behavior in the near and far fields. Additional information, such as reciprocity and the fulfillment of the boundary condition, are needed to choose the set of weighting functions that is most appropriate for a certain application. The obtained criteria are applied afterward to an iterative T-matrix approach we developed to analyze scattering on regular particle geometries with an impressed but slight surface irregularity. However, its usefulness is demonstrated in this paper by analyzing the far-field scattering behavior of Chebyshev particles of higher orders. PMID- 20962939 TI - Optimal noise suppression in Fresnel incoherent correlation holography (FINCH) configured for maximum imaging resolution. AB - An optimal setup in the sense of imaging resolution for the Fresnel incoherent correlation holography (FINCH) system is proposed and analyzed. Experimental results of the proposed setup in reflection mode suffer from low signal-to-noise ratio (SNR) due to a granular noise. SNR improvement is achieved by two methods that rely on increasing the initial amount of phase-shifted recorded holograms. In the first method, we average over several independent complex-valued digital holograms obtained by recording different sets of three digital phase-shifted holograms. In the second method, the least-squares solution for solving a system of an overdetermined set of linear equations is approximated by utilizing the Moore-Penrose pseudoinverse. These methods improve the resolution of the reconstructed image due to their ability to reveal fine and weak details of the observed object. PMID- 20962940 TI - Terahertz properties of liquid crystals with negative dielectric anisotropy. AB - We present what is believed to be the first terahertz time-domain study of a set of liquid crystals (LCs) with negative dielectric anisotropy. From the measured data, refractive indices, and absorption coefficients for ordinary and extraordinary polarization are extracted. We find that the investigated materials exhibit a much smaller absorption than LCs with positive dielectric anisotropy. Thus, these materials are more useful for switchable terahertz devices. Moreover, the LC 1808 shows what is to our knowledge the largest terahertz birefringence reported so far. PMID- 20962941 TI - Wavelet filter for improving detection performance of compression-based joint transform correlator. AB - A new method for improving fingerprint detections by a compression-based joint transform correlator (JTC) via wavelet filter is proposed. The simulation results show that the proposed method has advantages over the conventional compression based JTC in that detection performance can be maximized to be higher than a classical JTC by using a smaller file size for the compressed-reference images. PMID- 20962942 TI - Time average vibration fringe analysis using Hilbert transformation. AB - Quantitative phase information from a single interferogram can be obtained using the Hilbert transform (HT). We have applied the HT method for quantitative evaluation of Bessel fringes obtained in time average TV holography. The method requires only one fringe pattern for the extraction of vibration amplitude and reduces the complexity in quantifying the data experienced in the time average reference bias modulation method, which uses multiple fringe frames. The technique is demonstrated for the measurement of out-of-plane vibration amplitude on a small scale specimen using a time average microscopic TV holography system. PMID- 20962943 TI - Preferential-order waveguide grating couplers: a comparative rigorous analysis using the finite-difference time-domain method. AB - We rigorously analyze and compare preferential-order waveguide grating output couplers using the finite-difference time-domain method in the total field/scattered-field formulation for TE and TM polarizations. Four kinds of preferential-order grating couplers are studied: volume holographic grating couplers, slanted parallelogrammic surface-relief grating couplers, double corrugated surface-relief grating couplers, and reflecting-stack surface-relief grating couplers. The outcoupling efficiencies and branching ratios of the couplers, revealing their preferentiality, are calculated and compared with the rigorous coupled-wave analysis leaky-mode method. In addition, their performance is examined in terms of the main design parameters and the excitation wavelength. PMID- 20962944 TI - Refractive index change in ytterbium-doped fibers induced by photodarkening and thermal bleaching. AB - High-accuracy measurements and analysis of refractive index change induced by photodarkening and thermal bleaching in ytterbium-doped fibers are presented, based on a modal interference method. Photodarkening-induced refractive index change is positive at the ytterbium lasing wavelengths near 1080 nm, and it approaches a saturated level, which is in the order of 10(-6)~10(-5) for the tested fiber samples. It is found that the value of this refractive index change is linearly proportional to the photodarkening-induced excess loss at an arbitrary probe wavelength in the visible band. Thermal bleaching can only partially erase the photodarkening-induced refractive index change, leaving a residual index change of (0.2~0.3)*10(-5). The influence of the photodarkening induced refractive index change on fiber lasers is discussed. PMID- 20962945 TI - Image reconstruction using a photonic crystal based flat lens operating at 1.55 MUm. AB - We used an optimized photonic crystal based flat lens for target detection and image reconstruction of micrometer sized objects for an operating wavelength of 1.55 MUm. Using numerical retrieval procedures inspired from tomography, the ability to detect subwavelength sized targets and to image metallic objects of complex shapes is shown. The relation between the reconstructed image quality and lens resolution is investigated. PMID- 20962946 TI - Design of finite impulse response deconvolution filters. AB - This paper describes inverse filters that restore imagery with minimal artifacts. Deconvolution kernels are obtained by windowing Wiener-type inverse filters (WTIFs). Windowed WTIFs exhibit good restoration properties. Constraining the size of the WTIF kernel is necessary because of the edge effects associated with discrete convolutions. Spatial windowing is necessary even if processing is performed in the frequency domain. The kernel design procedure is described, and the theory is explained. The performance penalty associated with limiting kernel size is discussed and quantified. PMID- 20962947 TI - Actual focal length of a symmetric biconvex microlens and its application in determining the transmitted beam waist position. AB - The actual focal length of a three-dimensional continuous profile symmetric biconvex microlens with normal monochromatic plane wave illumination is theoretically determined using a full-field separation of variables method in the oblate spheroidal coordinate system. The investigations are performed for microlenses of 5, 10, and 20 wavelength diameters by calculating the electromagnetic field distributions inside of and adjacent to the microlenses. The importance and potential application of the microlens actual focal length in the design of microlens optical systems are demonstrated by showing that for normal monochromatic TEM00 mode Gaussian beam illumination, the transmitted beam waist position through a single microlens, calculated using Self's beam waist position transformation formula [Appl. Opt.22, 658 (1983)] with the microlens actual focal length, closely matches the exact value given by the separation of variables method. PMID- 20962948 TI - Precise measurement of optical phase retardation of a wave plate using modulated polarized light. AB - We propose a new method for precisely measuring the optical phase retardation of a wave plate using modulated-polarized light. Modulated-polarized light is used such that the zeros of the system can be accurately determined. A Babinet-Soleil compensator is employed to measure the optical phase retardation. A cross wavelength measurement is also proposed for determining the phase retardation at a wavelength, which is not the measuring wavelength. PMID- 20962949 TI - Optical zooming interferometer for subnanometer positioning using an optical frequency comb. AB - A high-precision positioning stage based on an optical zooming interferometer is proposed. Two external-cavity diode lasers, stabilized to a femtosecond optical frequency comb, are used as optical sources. The zooming principle is demonstrated, and the positioning resolution of 0.2 nm is achieved. The positioning accuracy was partly evaluated. PMID- 20962950 TI - Vision ray calibration for the quantitative geometric description of general imaging and projection optics in metrology. AB - Exact geometric calibration of optical devices like projectors or cameras is the basis for utilizing them in quantitative metrological applications. The common state-of-the-art photogrammetric pinhole-imaging-based models with supplemental polynomial corrections fail in the presence of nonsymmetric or high-spatial frequency distortions and in describing caustics efficiently. These problems are solved by our vision ray calibration (VRC), which is proposed in this paper. The VRC takes an optical mapping system modeled as a black box and directly delivers corresponding vision rays for each mapped pixel. The underlying model, the calibration process, and examples are visualized and reviewed, demonstrating the potential of the VRC. PMID- 20962951 TI - Diffraction-attenuation resistant beams: their higher-order versions and finite aperture generations. AB - Recently, a method for obtaining diffraction-attenuation resistant beams in absorbing media has been developed in terms of suitable superposition of ideal zero-order Bessel beams. In this work, we show that such beams keep their resistance to diffraction and absorption even when generated by finite apertures. Moreover, we shall extend the original method to allow a higher control over the transverse intensity profile of the beams. Although the method is developed for scalar fields, it can be applied to paraxial vector wave fields, as well. These new beams have many potential applications, such as in free-space optics, medical apparatus, remote sensing, and optical tweezers. PMID- 20962952 TI - Three-dimensional point spread function and generalized amplitude transfer function of near-field flat lenses. AB - We derive a nonsingular, polarization-dependent, 3D impulse response that provides unambiguously the wave field scattered by a negative-refractive-index layered lens and distributed in its image volume. By means of a 3D Fourier transform, we introduce the generalized amplitude transfer function in order to gain a deep insight into the resolution power of the optical element. In the near field regime, fine details containing some depth information may be transmitted through the lens. We show that metamaterials with moderate absorption are appropriate for subwavelength resolution keeping a limited degree of depth discrimination. PMID- 20962953 TI - Polarization-independent Fabry-Perot interferometer in a hole-type silicon photonic crystal. AB - We propose and numerically demonstrate a polarization-independent Fabry-Perot interferometer (PI-FPI) based on the self-collimation effect in a hole-type silicon photonic crystal (PhC). By use of the polarization peak matching method, a resonance frequency of the transverse-electric modes can equal that of the transverse-magnetic modes in the PI-FPI, although the transmission spectra are quite polarization dependent due to birefringence of the PhC. For the operating wavelength of 1550 nm, the PI free spectral range of the PI-FPI is up to 32.3 nm, which nearly covers the whole optical communication C-band window. With its small dimensions, simple structure, and silicon-based material, this PI-FPI may play an important role in photonic integrated circuits. PMID- 20962954 TI - Polarization conversion cube-corner retroreflector. AB - Polarization conversion cube-corner retroreflectors rotate the major axis of the incident electric field by 90 degrees . We show that polarization conversion cube corner retroreflectors cannot be created with isotropic reflecting surfaces, but can be created by incorporating nonisotropic reflecting surfaces. Two types are considered-cube corners with surfaces having elliptical eigenstates and cube corners having subwavelength gratings. Implementations that use subwavelength surface relief phase gratings are investigated, and three examples are shown. PMID- 20962955 TI - Online monitoring of a belt grinding process by using a light scattering method. AB - Industrially ground surfaces often have a characteristic surface topography known as chatter marks. The surface finishing is mainly monitored by optical measurement techniques. In this work, the monitoring of an industrial belt grinding process with a light scattering sensor is presented. Although this technique is primarily applied for parametric surface roughness analysis, here it is shown that it enables also the measurement of the surface topography, i.e., the chatter marks occurring during the belt grinding process. In particular, it is proven that the light scattering method is appropriate to measure online the topography of chatter marks. Furthermore, the frequency analysis of the data reveals that the wavelength of chatter marks strongly depends on process parameters, such as the grinding speed. PMID- 20962956 TI - Coherent incident field information through thick random scattering media from speckle correlations over source position. AB - With two nonoverlapping beams incident at different angles on a heavily scattering medium, the spatial correlation of speckle patterns over source position has a beat that is related to the incident angle difference. A model presented explains the measurement. The spatial correlation is shown to decorrelate faster than the beam intensity correlation function and to be sensitive to the incident field profile. Increased scatter results in more rapid decorrelation. This work suggests new opportunities for imaging through scattering media. PMID- 20962957 TI - Spherical aberration gauge for human vision. AB - Spherical aberration affects vision in varying degrees depending on pupil size, accommodation, individual eye characteristics, and interpretations by the brain. We developed a spherical aberration gauge to help evaluate the correction potential of spherical aberration in human vision. Variable aberration levels are achieved with laterally shifted polynomial plates from which a user selects a setting that provides the best vision. The aberration is mapped into the pupil of the eye using a simple telescope. Calibration data are given. PMID- 20962958 TI - Lens distortion models evaluation. AB - Many lens distortion models exist with several variations, and each distortion model is calibrated by using a different technique. If someone wants to correct lens distortion, choosing the right model could represent a very difficult task. Calibration depends on the chosen model, and some methods have unstable results. Normally, the distortion model containing radial, tangential, and prism distortion is used, but it does not represent high distortion accurately. The aim of this paper is to compare different lens distortion models to define the one that obtains better results under some conditions and to explore if some model can represent high and low distortion adequately. Also, we propose a calibration technique to calibrate several models under stable conditions. Since performance is hard conditioned with the calibration technique, the metric lens distortion calibration method is used to calibrate all the evaluated models. PMID- 20962959 TI - Extended phase modulation depth in twisted nematic liquid crystal displays. AB - We show how the phase modulation depth in twisted nematic liquid crystal displays (TNLCDs) can be increased dramatically by selecting a polarization configuration with a reduced mean intensity transmission. This phenomenon, which we have validated with various devices, is shown here for a device that presents a phase only modulation only slightly over pi radians in our classical rotated eigenvector configuration, but it is capable of producing close to a 2pi phase depth for a configuration with 5% mean intensity transmission. A quantitative explanation is presented by means of a phasor analysis of the TNLCD eigenvector projections over input and output polarization states. The proposed technique can be a very useful solution in modern TNLCDs that have a very thin liquid crystal layer and a reduced maximum achievable phase modulation. PMID- 20962960 TI - Optically switching parallel processors by means of Langmuir-Blodgett multilayer films. AB - The photoexcitation transport and the reversible photochemical reaction in Langmuir-Blodgett film is studied and shows its applicability to an optical parallel processor. The excitation transport is switched depending on UV or visible irradiation, which controls the photochromic reaction. The performance of this photochromic Langmuir-Blodgett multilayer is 10(12) NOT operations s(-1) and is comparable with other types of optical processors, such as a liquid-crystal light valve. PMID- 20962961 TI - Diffraction efficiency of random binary-amplitude diffracting screens. AB - The diffraction characteristics of random binary-amplitude diffracting screens are investigated. It is shown that, for such a random diffracting screen with complex amplitude transmittance t equal to either 0 or 1, the diffraction efficiency of the screen is maximized when 50% of the screen has transmittance t = 1, independent of other characteristics of the screen. The maximum diffraction efficiency equals 1/4. For this result to hold the screen must be adequately modeled by a stationary binary random process. PMID- 20962962 TI - Digital optical computing with magneto-optic spatial light modulators: a new and efficient multiplication algorithm. AB - Digital optical computing executed on arrays of binary data can offer parallel processing and multivalued output, which permits more flexibility in algorithm development. The hardware used consists of two computer-controlled magneto-optic spatial-light-modulator arrays in conjunction with a CCD detector array as the computational hardware. Algorithms for binary-processing tasks are presented. We used magneto-optic spatial light modulators for parallel processing in a way that exploits multivalued output. Also, in carrying this evaluation out, we developed a new and efficient multiplication algorithm. Multiplication is an important operation in many digital systems, and the design of fast multipliers is of great interest to computer scientists and engineers. The speed of this computing system is evaluated. PMID- 20962963 TI - Toward a free-space parallel optoelectronic computer: a 300-MHz optoelectronic counter using holographic interconnects. AB - We built and tested one of the key components of a free-space holographically interconnected stored-program optoelectronic computer: a counter. The counter is constructed with 1-ns-latency optoelectronic NOR gates and is interconnected with holographic optical elements. Two synchronization methods were also demonstrated: the gate-and-strobe method and the time-of-flight method. These counters represent prototypical optoelectronic finite-state controllers. They were developed to demonstrate the feasibility of providing optoelectronic controllers for optoelectronic processors. PMID- 20962964 TI - Scalable optical hypercube-based interconnection network for massively parallel computing. AB - Two important parameters of a network for massively parallel computers are scalability and modularity. Scalability has two aspects: size and time (or generation). Size scalability refers to the property that the size of the network can be increased with nominal effect on the existing configuration. Also, the increase in size is expected to result in a linear increase in performance. Time scalability implies that the communication capabilities of a network should be large enough to support the evolution of processing elements through generations. A modular network enables the construction of a large network out of many smaller ones. The lack of these two important parameters has limited the use of certain types of interconnection networks in the area of massively parallel computers. We present a new modular optical interconnection network, called an optical multimesh hypercube (OMMH), which is both size and time scalable. The OMMH combines positive features of both the hypercube (small diameter, high connectivity, symmetry, simple routing, and fault tolerance) and the torus (constant node degree and size scalability) networks. Also presented is a three dimensional optical implementation of the OMMH network. A basic building block of the OMMH network is a hypercube module that is constructed with free-space optics to provide compact and high-density localized hypercube connections. The OMMH network is then constructed by the connection of such basic building blocks with multiwavelength optical fibers to realize torus connections. The proposed implementation methodology is intended to exploit the advantages of both space invariant free-space and multiwavelength fiber-based optical interconnect technologies. The analysis of the proposed implementation shows that such a network is optically feasible in terms of the physical size and the optical power budget. PMID- 20962965 TI - Chirp filtering in the fractional Fourier domain. AB - In the Wigner domain of a one-dimensional function, a certain chirp term represents a rotated line delta function. On the other hand, a fractional Fourier transform (FRT) can be associated with a rotation of the Wigner-distribution function by an angle connected with the FRT order. Thus with the FRT tool a chirp and a delta function can be transformed one into the other. Taking the chirp as additive noise, the FRT is used for filtering the line delta function in the appropriate fractional Fourier domain. Experimental filtering results for a Gaussian input function, which is modulated by an additive chirp noise, are shown. Excellent agreement between experiments and computer simulations is achieved. PMID- 20962966 TI - Concentrators for focal-plane arrays. AB - It is generally assumed that lenslet arrays are needed to concentrate image light upon the relatively sparse detector areas in a focal-plane array. These have severe field-of-view difficulties and require considerable space to implement. We show how to manufacture optically parallel arrays of concentrators of controllable size and field of view with photorefractive crystals. PMID- 20962967 TI - Signal-to-noise ratio of nonlinearity recorded holograms of diffuse objects. AB - A nonlinear model for holographic recording materials is used to evaluate the signal-to-noise ratio in diffuse-object holograms. A comparison of this model with the linear model proposed by Upatnieks and Leonard [J. Opt. Soc. Am. 60, 297 (1970)] shows that our model justifies the experimental results obtained for dieletric holograms at high density before bleaching. PMID- 20962968 TI - Strehl ratio versus defocus for noncentrally obscured pupils. AB - We discuss from the viewpoint of the Strehl ratio versus defocus, or the normalized axial-irradiance distribution, the influence of decentering the dark mask of an annular pupil. Our treatment, which is valid for pupil apertures with any Fresnel number, permits us to infer that the axial behavior of a noncentrally obscured pupil is equivalent to that of an apodizer with continuous amplitude variations. Hence the Strehl ratio versus defocus of an optical system can be shaped by use of noncentered dark masks that act as continuous gray apodizers. Several numerically evaluated examples are presented. PMID- 20962969 TI - Detection accuracy in zero-crossing-based spectrum analysis and image reconstruction. AB - We examine how the accuracy in describing the exact location of a signal crossing affects the quality of the spectrum or the reconstructed two-dimensional image that is computed by a representation of sampled zero crossings. The position of a zero crossing within a Nyquist interval is described by the ratio between the number of clock pulses that have elapsed before the crossing occurred and the total number of clock pulses that could fit within the interval. The pulses scale the Nyquist interval, and the greater their total number, the more accurate the description of the crossing location. In a real zero-crossing detector the ability to increase the total number of square pulses contained within the Nyquist interval is limited by the finite response time of its circuit components [Opt. Lett. 18, 1468 (1993)]. PMID- 20962970 TI - Complementary-reference joint transform correlator. AB - We present a new input configuration for the joint transform correlator called a complementary-reference joint transform correlator (CRJTC). The difference between the CRJTC and the existingjoint transform correlator is that the CRJTC has an additional complementary reference in the input plane. We use a criterion defined as the ratio of the cross correlation between the target and the reference to the cross correlation between the target and the complementary reference to perform recognition. This ratio can attain its maximum if and only if the reference and the target are matched and if it is stable to the light source intensity fluctuations; therefore it is unnecessary to normalize the input images. The CRJTC is suitable for the recognition of a binary-amplitude image only. The experimental demonstration of a CRJTC is given. PMID- 20962971 TI - Holographic-recording improvement in a bismuth silicon oxide crystal by the moving-grating technique. AB - We investigate the enhancement of the diffraction efficiency of dynamic gratings recorded in a bismuth silicon oxide crystal at large modulation by the moving grating technique. The optimum fringe velocity for maximum diffraction efficiency and the degree of enhancement of the diffraction efficiency at optimum fringe velocity are experimentally found to be dependent on the fringe modulation. We apply this technique to real-time incoherent correlation using bismuth silicon oxide. There are two main advantages in using moving gratings: First, the signal to-noise ratio can be improved considerably because of the improved diffraction efficiency. Second, the resonant effect reduces the effect of environmental disturbances on the peak-correlation intensity, which is significant when the threshold detection level of the correlator is set. PMID- 20962972 TI - Real-time joint transform correlation with photoanisotropic dye-polymer films. AB - The results of joint transform correlation with photoanisotropic organic materials are presented. The materials' dynamic holographic recording capability and high resolution permit the operation of such a correlator in real time. Both theoretical and experimental results show that the photoanisotropic properties cause a dependence of the correlation output on the state of the polarization of the readout beam and can be used to produce an output polarization orthogonal to the input, which permits polarization filtering to be used, greatly increasing the signal-to-noise ratio. The effect of the saturation of the nonlinearity on correlation performance is investigated and is shown to be able to improve correlator recognition and discrimination. The correlation results of binary images and of a highresolution synthetic-aperture radar image are presented, demonstrating excellent optical quality, nonlinear edge enhancement, and real time operation. PMID- 20962973 TI - Modified filter synthetic discriminant functions for improved optical correlator performance. AB - By the filter modulation operator N, the modified filter synthetic discriminant function permits advantageous preprocessing of individual training-set images that are used in a linear combination to construct the filter synthetic discriminant function, which applies a modulation operator M to the synthetic discriminant function. A relaxation algorithm is used to satisfy the equal correlation peaks rule in the correlator output plane. As the filter modulation operators M and N can be given any functional form, the modified filter synthetic discriminant function design proposed is sufficiently general to be described as a unified filter modulation synthetic discriminant function design. PMID- 20962974 TI - Photorefractive phase-conjugate technique for measuring surface granularity. AB - A self-aligned photorefractive autocorrelator is implemented for the real-time use of second-order statistics for texture analysis. We demonstrate the measurement of the length scale of the granularity of a rough surface. PMID- 20962975 TI - Fractional fourier transform: photonic implementation. AB - The family of fractional Fourier transforms permits presentation of a temporal signal not only as a function of time or as a pure frequency function but also as a mixed time and frequency function with a continuous degree of emphasis on time or on frequency features. We show how it is possible to implement the fractional Fourier transform on time signals by using optoelectronic modulators and optical fibers with suitable dispersion. We also show how a fractional-Fourier-transform based photonic signal-processing system could be composed. PMID- 20962976 TI - High-capacity neural networks on nonideal hardware. AB - We present a new training-out algorithm for neural networks that permits good performance on nonideal hardware with limited analog neuron and weight accuracy. Optical neural networks are emphasized with the error sources including nonuniform beam illumination and nonlinear device characteristics. We compensate for processor nonidealities during gated learning (off-line training); thus our algorithm does not require real-time neural networks with adaptive weights. This permits use of high-accuracy nonadaptive weights and reduced hardware complexity. The specific neural network we consider is the Ho-Kashyap associative processor because it provides the largest storage capacity. Simulation results and optical laboratory data are provided. The storage measure we use is the ratio M/N of the number of vectors stored (M) to the dimensionality of the vectors stored (N). We show a storage capacity of M/N = 1.5 on our optical laboratory system with excellent recall accuracy, > 95%. The theoretical maximum storage is M/N = 2 (as N approaches infinity), and thus the storage and performance we demonstrate are impressive considering the processor nonidealities we present. Our techniques can be applied to other neural network algorithms and other nonideal processing hardware. PMID- 20962977 TI - Birefringence examination in a practical fiber-current-sensing system. AB - The output of a fiber-current sensor with a nonideal input (either misaligned linear or elliptical polarization) and moderate output misalignment in the setup (the fiber end versus the Wollaston prism) has been considered. Based on this, a novel method that uses a statistical approach, including a set of scanning elliptical polarization inputs and the corresponding curve-fitting outputs for a given current, is used to determine the birefringence of the fiber-current sensing system. The experimentally measured bend-induced birefringence agrees with the estimated value of the bend birefringence. PMID- 20962978 TI - Flow-graph approach for optical analysis of planar structures. AB - The flow-graph approach (FGA) is applied to optical analysis of isotropic stratified planar structures (ISPS's) at inclined light incidence. Conditions for the presence of coherent and noncoherent light interaction within ISPS's are determined. Examples of the use of FGA for calculation of the transmission and the reflection of two-layer ISPS's for different types of light interaction are given. The advantages of the use of FGA for optical analysis of ISPS's are discussed. PMID- 20962979 TI - High-precision direct measurements of (13)CH(4)/(12)CH(4) and (12)CH(3)D/(12)CH(4) ratios in atmospheric methane sources by means of a long path tunable diode laser absorption spectrometer. AB - Measurements of (13)CH(4)/(12)CH(4) and (12)CH(3)D/(12)CH(4) ratios in atmospheric methane (CH(4)) sources provide important information about the global CH(4) budget as well as about CH(4) production and consumption processes occurring within the various sources. As an alternative to the conventional mass spectrometer (MS) technique, which requires conversion of CH(4) to CO(2) and H(2), we have developed a tunable diode laser absorption spectrometer (TDLAS), which permits rapid direct measurements of the (13)CH(4)/(12)CH(4) and (12)CH(3)D/(12)CH(4) ratios. An intercomparison between TDLAS and MS techniques for samples from natural wetlands, landfills, and natural gas sources resulted in a mean deviation of Deltadelta(13)C = 0.440/00 and DeltadeltaD = 5.10/00. In the present system the minimum mixing ratios required are 50 parts in 10(6) by volume (ppmv) CH(4) (sample size 2 umol CH(4)) for direct delta(13)C measurements and 2000 ppmv (sample size 80 umol CH(4)) for direct deltaD measurements. These mixing-ratio limits are adequate for most CH(4) source characterization studies without requiring sample preconcentration. PMID- 20962980 TI - Polarizing rectangular prism used in laser techniques. AB - A polarizing rectangular prism is presented. The prism has the advantages of low loss and a high extinction ratio and can be used in laser oscillators to replace polarizers and reflecting prisms. PMID- 20962981 TI - Reflected optical harmonics from dielectric mirrors. AB - Optical second and third harmonics were generated in reflection from commercially available laser dielectric mirrors. Although most dielectric coatings on laser mirrors are centrosymmetric, the inversion symmetry is broken at the dielectric air interface. When intense femtosecond laser pulses are reflected off the dielectric mirrors, a second-order dipole contribution to surface second-harmonic generation can exist and is detected. More dramatically, at a laser fluence of ~10 GW/cm(2) the normally much weaker electric-dipole-allowed third-harmonic generation that originated in the bulk accentuates the second-harmonic generation. These reflected harmonics are, in some cases, nonnegligible in many sensitive experiments. PMID- 20962982 TI - Bending-loss studies of a single-mode triangular-index fiber with a depressed cladding ring with a vector-mode method. AB - Attention is directed to the bending-loss properties of a triangular-index fiber with a depressed cladding ring, which can be advantageously used to obtain either a dispersion-shifted or a dispersion-flattened feature. Both cases are studied to search for the set of ring parameters that yield the lowest bending loss while ensuring a low dispersion. Near-optimal designs are proposed and compared with other well-known dispersion-shifted and dispersion-flattened fiber designs. The numerical methods used in our computations are the vector-mode power-series expansion method for fields and dispersion calculations and the volume-current method for bending-loss predictions. PMID- 20962983 TI - Beam propagation in parabolically tapered graded-index waveguides. AB - To a good approximation, the electromagnetic-propagation characteristics of graded-index waveguides can be written in terms of polynomial-Gaussian modes. For uniform quadratic-index waveguides the behavior of these modes is well known. However, there are sometimes practical reasons for using tapered waveguides, but detailed propagation solutions are known for only a few specific taper functions. The parabolic taper is perhaps the most important special case, and the solution generating techniques that we generalize are used to obtain analytic solutions for this case. PMID- 20962984 TI - COP: a data library of optical properties of hexagonal ice crystals. AB - The data library of optical properties of hexagonal ice crystals for radiative modeling, Cirrus Optical Properties (COP), is introduced. It includes phase functions, asymmetry parameters, extinction cross sections, and single scattering albedos. Furthermore, lidar ratios and depolarization are given. The dependence of these parameters on wavelength, particle size, and shape is calculated, and different particle orientations are considered. In addition, a simple FORTRAN code is provided to calculate the corresponding properties of size distributions. Thus the data library is a very flexible tool for determining the optical parameters of ice clouds for climatological purposes and remote sensing. The data library and the FORTRAN code are distributed through electronic mail. PMID- 20962985 TI - Intrapulse temporal and wavelength shifts of a high-power 2.1-um Ho:YAG laser and their potential influence on atmospheric lidar measurements. AB - A high-power, flash-lamp-pumped, Q-switched Ho:YAG laser has been developed to produce up to 150 mJ in a 100-ns Q-switched pulse. The Ho laser was initially used in a direct detection lidar-differential absorption lidar (DIAL) system to measure vertical density profiles of aerosols and water vapor in the atmosphere. It was found, however, that the Ho laser operated simultaneously on two closely spaced spectral emission wavelengths (2.090 and 2.097 um) and that the distribution of energy between the two wavelengths could change significantly on time scales of several seconds to minutes. Such intrapulse temporal and wavelength shifts were found to alter the atmospheric lidar return significantly because one of the laser lines coincided with a water vapor absorption line in the atmosphere. This laser spectral output problem was overcome by the use of intracavity etalons that controlled the laser spectral-temporal characteristics but reduced the laser output energy to approximately 75 mJ/pulse in a 100-ns pulse length. These results are important as they serve to point out the difficulties of developing and using a high-power 2.1- um Ho laser for atmospheric lidar when high-resolution spectral and temporal characteristics can significantly influence the lidar return and be misinterpreted as resulting from atmospheric signals. PMID- 20962986 TI - Influence of oceanic whitecaps on atmospheric correction of ocean-color sensors. AB - The effects of oceanic whitecaps on ocean-color imagery are simulated and inserted into the proposed Sea-Viewing Wide-Field-of-View Sensor (SeaWiFS) atmospheric-correction algorithm to understand its tolerance to error in the estimated whitecap contribution. The results suggest that for wind speeds ? 10-12 m/s, present models that relate whitecap reflectance to wind speed are sufficiently accurate to meet the SeaWiFS accuracy goal for retrieval of the water-leaving radiance in the blue, when the aerosol scattering is weakly dependent on wavelength. In contrast, when the aerosol scattering has a strong spectral signature, the retrievals will meet the goal only when the whitecap reflectance is underestimated. PMID- 20962987 TI - Asymmetrical spectral curvature algorithms: oceanic-constituents sensitivities. AB - The asymmetrical spectral curvature algorithm for Morel case 1 waters has been characterized by application of the semianalytical radiance model of ocean color to post-Coastal Zone Color Scanner (CZCS) sensor bands. Results of the study suggest that the [L (490)/L (443)][L (490)/L (555)] asymmetrical spectral curvature algorithm has a higher pigment-retrieval sensitivity than does the [L (490)/L (443)][L (490)/L (510)] curvature algorithm that was initially identified for pigment recovery. When this [L (490)/L (443)][L (490)/L (555)] algorithm was highlighted for study, it was found to (a) xhibit pigment-retrieval sensitivity that is intermediate to the [L (443)/L (555)] and the [L (510)/L (555)] CZCS-type radiance-ratio algorithms, (b) have less sensitivity to nonabsorbing particulate backscatter (NAB) than the [L (443)/L (555)] radiance ratio, (c) display remarkable insensitivity to the absorption of dissolved organic material (DOM), and (d) possess a NAB invariance point at an algorithm value of ~1.8 (corresponding to a pigment concentration of ~0.35 mg/M(3)). At this invariance point the [L (490)/L (443)][L (490)/L (555)] algorithm is insensitive to a wide concentration range of coccolith-like backscatterers in addition to being insensitive to DOM. The dual DOM and NAB insensitivity of the algorithm at a specific curvature value and chlorophyllous-pigment concentration suggests that such invariance points should be further studied for possible use in (1) the validation of other chlorophyllouspigment algorithms or model inversions and (2) the computation of other inherent optical properties. PMID- 20962988 TI - Optical remote sensing of surface roughness through the turbulent atmosphere. AB - Using a CO(2), cw, coherent lidar, we have measured the surface roughness of diffuse targets through 1000 m of turbulent atmosphere. The technique measures the phase fluctuations of the speckle field at the receiver and relates the measured phase variance to the surface roughness. Measurements were made with aluminum targets that had been sandblasted with 8-, 16-, and 30-grit material and also with a flame-sprayed aluminum target. It was found that a linear relationship exists between the standard deviation (SD) of the unwrapped phase fluctuations and the SD of the target surface-height fluctuations. Good results were obtained with modest transmitter power and small receiver optics in just a few seconds of averaging time. PMID- 20962989 TI - Visualization of CN by the use of planar laser-induced fluorescence in a cross section of an unseeded turbulent CH(4)-air flame. AB - CN is known to be the important species in forming NO(x) in hydrocarbon-air flames, and we describe the qualitative mapping of the CN distribution of the order of less than 1 in 10(6) at atmospheric pressure in a cross section of an unseeded turbulent CH(4)-air flame by the use of a single-shot laser pulse with planar laser-induced fluorescence. We obtained the results by comparing the different excitation-detection schemes to find the most appropriate scheme for visualization. In addition, the images obtained have good spatial resolution of 200 um. Based on a laminar flame experiment with the same optical systems, it is observed that the CN distribution zone is located outside of the inner cone even at atmospheric pressure. PMID- 20962990 TI - Hydrocarbon-vapor measurements in pulsed fuel sprays. AB - The feasibility of the use of a nonintrusive, line-of-sight averaging, infrared extinction technique for the quantitative measurement of fuel-vapor concentration and flux in transient sprays has been examined. A collinear visible and infrared system with a compact sandwich detector design allows for the detection of radiation at both wavelengths simultaneously. With a controlled simulated fuel spray that consists of styrene spheres and methane vapor, vapor concentrations were measured within 10% of the known input value for a large range of particle loadings. Quantitative measurements were also made in a transient isooctane spray with an automotive-type injector. The time-resolved vapor mole fraction, velocity, and mass flux were compared with the transient liquid-phase characteristics obtained with a phase/Doppler anemometer system. The combined use of both instruments for discerning differences in liquid and vapor transport is discussed. PMID- 20962991 TI - Structural resonances in a coated sphere: investigation of the volume-averaged source function and resonance positions. AB - Morphology-dependent resonances in a coated sphere are investigated by computation of the volumeaveraged source function obtained from Lorenz-Mie theory. Analytic expressions for the source function in absorbing and nonabsorbing spheres are given in a suitable form for computations. An advantage of the investigation of the source function is that core and shell contributions can be computed and examined independently. Furthermore the influences of the refractive index and the thickness of the outer layer on resonance positions and height are studied in detail. These influences are presented for the alpha(104) partial-wave example. PMID- 20962992 TI - Quasi-stationary scattering of electromagnetic pulses by spherical particles. AB - The Lorentz-Mie theory is generalized for the case of a spherical particle irradiated by a pulse with a finite length L that is transferred by a carrier wavelength lambda(0). Two cases should be physically distinguished, depending on radiation-receiver properties: quasi-stationary scattering (a receiver integrates the entire signal over time) and nonstationary scattering, when a receiver is capable of recording scattered signal changes with time. General formulas that allow one to calculate optical characteristics for both scattering cases and for an arbitrary ratio L/lambda(0) are derived. Quasi-stationary-scattering peculiarities and limiting cases of small and large particles are studied in detail. The formulas are illustrated with calculations of spherical-particle optical characteristics for pulses of different lengths, for differently sized particles, and for a case in which a scattered pulse has a Gaussian form. The results obtained should be taken into account when one is studying the passage of a pulse through scattering media. PMID- 20962994 TI - Image rotation. AB - A simple equation is presented that describes the rotationof an image by a mirror or prism, and that can be used tocalculate the amount of image rotation in a complex opticalsystem. The equation also provides an intuitive understandingof heretofore mystical(1) optical devices such as derotationprisms (for example, the dove prism). PMID- 20962993 TI - Intercomparison of spectral-UV-radiation measurement systems. AB - The results of what is to our knowledge the first intercomparison of seven independent spectroradiometers measuring solar UV irradiances are presented. The intercomparison was carried out in the GSF-Forschungszentrum fur Umwelt und Gesundheit, Neuherberg (near Munich, Germany), on 13 July 1990. The spectroradiometric measurements were supplemented by other meteorological, optical, and chemical measurements at the same time. As this day was cloudless, the data can be compared with the measurements taken by Bener in Switzerland in the 1960's and with the results of radiative transfer models. The measured irradiances at noon differed by factors of up to 100. These large differences demonstrate the great difficulties with this type of measurement. Some instrument systems, however, ranged within tolerances of +/-10%, thus allowing us to make recommendations for the spectroradiometry of solar UV irradiances. PMID- 20962995 TI - Performance of a circle-to-line optical system for a Fabry-Perot interferometer: a laboratory study. AB - We describe the characterization and laboratory study of a new optical device, a circle-to-line interferometer optical (CLIO) system, for a Fabry-Perot interferometer. The CLIO system converts a circular Fabry-Perot interferometer fringe pattern into a linear fringe pattern that can be analyzed by a linear array detector or a charge-coupled device. One can achieve the circle-to-line conversion by the use of a mirrored kaleidoscope and a 90-deg segment of a 45-deg half-angle internally reflecting cone. Our laboratory results are in good agreement with theoretical predictions. The aberrations associated with this optical system are minor for large F-number optical systems, especially for the cone segment. The finesse degradation caused by this CLIO system is relatively small, which agrees with the results of a ray-trace study. PMID- 20962996 TI - Fourier-transform speckle profilometry: three-dimensional shape measurements of diffuse objects with large height steps and/or spatially isolated surfaces. AB - An interferometric technique for automated profilometry of diffuse objects has been proposed. It is based on the Fourier-fringe analysis of spatiotemporal specklegrams produced by a wavelength-shift interferometer with a laser diode as a frequency-tunable light source. Unlike conventional moire techniques the proposed technique permits the objects to have discontinuous height steps and/or surfaces spatially isolated from one another. Experimental results are presented that demonstrate the validity of the principle. PMID- 20962997 TI - Characterization of the basic statistical properties of very rough surfaces of transparent solids by immersion shearing interferometry. AB - A new shearing-interferometry method is used to characterize the basic statistical properties of very rough surfaces of transparent solids. The mean level of these rough surfaces can be curved or flat. Using this method, one evaluates the root-mean-square values (standard deviations) of the heights and slopes of the surface irregularities. Moreover the values of autocorrelation lengths, autocorrelation functions, and one-dimensional height-distribution functions are also determined. The method is applied to a statistical analysis of rough flat or curved glass surfaces. The results from this method agree very well with those obtained with a stylus-type surface instrument and speckle contrast method. PMID- 20962998 TI - Real-time digital control of optical interferometers by the mechanical-modulation technique. AB - We discuss the application of digital systems to the automatic control of dual wave optical interferometers. We show that, if the mechanical-modulation technique is used for error-signal extraction, digital techniques can be used both for error-signal extraction and for control-signal generation. Therefore, apart from two front/end amplifiers that are necessary to match the dynamics of the detectors and actuators to the dynamics of the analog-to-digital converters and digital-to-analog converters, no other analog devices are required. In particular, the mechanical-modulation technique requires the synchronous demodulation of the photodiode output signal. Hence we need to implement a digital lock-in amplifier whose algorithm is described here. Finally, we describe one of the possible applications of this digital control procedure, such as the control of a classic Mach-Zehnder interferometer in air. PMID- 20962999 TI - Double-pulse electronic speckle interferometry for vibration analysis. AB - We describe a double-pulse electronic-speckle-interferometry system. Two separate speckle patterns of an object being tested are recorded within a few microseconds with a CCD camera. Their two images are stored in a frame grabber. The fringes obtained from subtraction are quantitatively analyzed by the spatial-carrier phase-shift method. Using three directions of illumination and one direction of observation, one can record at the same time all the information necessary for the reconstruction of the three-dimensional deformation vector. Applications of this system for measuring the rotating objects are discussed for the case for which a derotator needs to be used. Experimental results are presented. PMID- 20963000 TI - Structure determination of weak phase objects from interferometric near-field measurements. AB - Amplitude and phase of diffraction near fields behind two-dimensional weak phase objects (n ? 1.02 + iO.0002) are measured with electromagnetic 3-cm waves in TM and TE polarization. Dielectric slabs and strips with a trapezoidal or rectangular cross section are considered (width 1.5lambda-36.0lambda; thickness 0.6lambda-2.4lambda; wedge angle 30 degrees -150 degrees ). For numerical simulation of the measured fields, a modification of the first Born approximation for weak scatterers is developed, which yields a remarkably better agreement with the measurements but requires no higher numerical efforts than the first Born approximation. Procedures for the determination of width, thickness, and wedge angle of the objects from measured diffraction fields are presented. PMID- 20963001 TI - Design of antireflection gratings with approximate and rigorous methods. AB - High-spatial-frequency gratings can be used as an alternative to thin-film antireflection coatings to reduce the reflectivity at the boundary between two different media. In the case of one-dimensional gratings, the conditions on the grating structure can be approximately determined by the effective medium theory (EMT) in combination with the thin-film theory. For two-dimensional gratings, which can be used to reduce the polarization sensitivity, a corresponding EMT does not exist. We present an estimation of the effective permittivity of two dimensional gratings. The range of validity of the antireflection grating design by the EMT is determined by the use of rigorous electromagnetic theory. Beyond the validity of EMT, rigorous theory is used to design antireflection gratings with a maximized feature size. PMID- 20963002 TI - Reflection and transmission properties of holographic mirrors and holographic Fabry-Perot filters. Ill. Holographic Fabry-Perot filters. AB - The reflection and transmission coefficients of holographic Fabry-Perot filters (HFPF's) are derived. Angular selectivities and wavelength sensitivities of the HFPF's on transmitted light are investigated. The effects of transmission by a HFPF on the spectrum and on the coherence properties of a partially coherent incident light are also analyzed. Numerical examples are presented for the case in which the incident light is generated by a Gaussian Schell-model source. PMID- 20963003 TI - Dichroism and birefringence in aperiodic coupled cavities and their influence on the polarization states of quasi-isotropic lasers. AB - We show that aperiodic coupled cavities may be designed to have a frequency dependent complex reflectance that is anisotropic in phase (birefringent) and in amplitude (dichroic). The complex mean or average reflectivity may also be frequency dependent. As an illustration we show how such multicavity effects influence the stability of the polarization of light in quasi-isotropic lasers. Possible applications of the properties of aperiodic coupled cavities are suggested. PMID- 20963004 TI - Comparative photothermal study of reactive low-voltage ion-plated andelectron beam-evaporated TiO(2) thin films. AB - The thickness-dependent optical and thermal properties and the corresponding damage thresholds have been investigated by means of various photothermal techniques on titanium dioxide thin films prepared by the conventional techniques of reactive electron-beam evaporation and reactive low-voltage ion plating (RLVIP). Compared with the reactive-electron-beam-evaporated samples, the RLVIP films exhibit a higher absorption, lower damage threshold, better thermal conductivity, lower defect density, and an almost perfect stability under Ar(+) laser irradiation. These results are correlated with data from a multimethod approach, and a mechanism is proposed to explain the low damage threshold for the RLVIP TiO(2) films. PMID- 20963005 TI - Diffuse reflectance and transmittance spectra of an interference layer: 1. Model formulation and properties. AB - A model for the calculation of the diffuse reflectance and transmittance of a single interference layer with rough interfaces on a transparent substrate is presented. The model is based on electric field calculations and scalar scattering theory, and it assumes that the interfaces of the layer are totally uncorrelated. Examples are given of calculated spectra in which the parameters of the model are varied systematically to show the influence from different interface roughness and refractive index combinations as well as absorption in the film. A wavelength-dependent effective root-mean-square roughness is introduced. This depends on the nature of the roughness, and the bandwidth limits are given by the experimental conditions. Finally, total integrated scattering spectra are calculated and the importance of taking multiple reflections in the substrate into account is shown. PMID- 20963006 TI - Diffuse reflectance and transmittance spectra of an interference layer. 2. Evaluation of tin oxide-coated glass. AB - A model for the calculation of diffuse reflectance and transmittance of a single interference layer on a transparent substrate is applied to pyrolytically deposited tin oxide films on glass. Total as well as diffuse reflectance and transmittance spectra were measured in an integrating sphere, and scattering levels between 0.002 and 0.1 were recorded. The optical constants and the thickness of the films were determined from the total reflectance and transmittance spectra. The wavelength-dependent effective root-mean-square roughness of aluminum-coated tin oxide front surfaces was determined by the application of the scalar scattering theory. Surface roughness values between 5 and 25 nm were obtained. The obtained effective rms roughness values of the air film interface were used together with the other film parameters to calculate the diffuse reflectance and transmittance spectra of the tin oxide-coated glass substrates. A comparison between calculated and experimental spectra showed good agreement for diffuse reflectance, diffuse transmittance, and total integrated scattering spectra. PMID- 20963007 TI - Scheme for x-ray tracing in capillary optics. AB - A set of trigonometric equations is derived for deterministic x-ray tracing in capillaries. A variety of capillary shapes is encompassed by this approach. The resulting reflectivity coefficients, gain factors, and angular beam divergence are determined. The results can also be applied to the case of neutron and proton guiding in narrow pipes. PMID- 20963008 TI - Procedures and standards for accurate spectrophotometric measurements of specular reflectance. AB - Procedures and standards that have been developed at the National Research Council of Canada for the accurate measurement of specular reflectance are discussed for both absolute and relative methods over the spectral range 250 to 2500 nm. There has been an increasing demand for these types of measurements, particularly for coated samples approaching the extremes of 0% reflectance and 100% reflectance. In some applications of these coatings, such as energy conservation and control, conventional methods of measuring specular reflectance give insufficient accuracies for the prediction of optical performance. Details of alignment procedures for both absolute and relative reflectance methods, the preparation and application of several candidate reflectance standards, and the compensation, attenuation, and verification procedures that have been developed to improve the precision and accuracy of specular reflectance measurements are described. Using these various techniques, one can routinely achieve accuracies of 0.3% reflectance at reflectance values as high as 97% and as low as 4%. PMID- 20963009 TI - Improved geometry of double-sided polished parallel wafers prepared for direct wafer bonding. AB - Optical technological applications have upgraded polishing, including flat surface polishing, to an extremely high level of geometrical precision. We deal with the application of this type of precision technology for the preparation of, e.g., silicon or fused-silica wafers that are thin compared to their diameter. To this end a standard optical polishing process using a double-sided polishing machine was modified by giving the polishing pad holder an adaptable curvature. By carefully choosing the process conditions 10-cm-diameter silicon and fused silica wafers (500-um thickness) were obtained with a very small deviation from parallelism in the 0.01-um range. The level of smoothness, surface and subsurface damage, was identical with that required for integrated-circuit processing. PMID- 20963010 TI - Profilometry by phase-shifted Talbot images. AB - We introduce a profilometry sensor that combines phase shifting with a Talbot self-image of a sinusoidal grating as the illumination part of the sensor. Contrast of the Talbot diffraction pattern produced with a sinusoidal grating in a diverging beam is theoretically discussed and verified experimentally. The mathematical relationship that is used to convert the phase measured with this sensor to the corresponding relief of an object is derived in the Appendix. A ceramic former used in the production of lenses was profiled with this sensor, and measurement results are presented. PMID- 20963011 TI - Effect of high pressure on the optical detection of gas by index-of-refraction methods. AB - An optical method for the detection of gas in high-pressure flow streams has been developed. One can detect gas by measuring the variation in intensity of reflected, p-polarized light at a sapphire-flow stream interface over a range of angles including the Brewster and critical angles for gas. The effects of high pressure and gas identity have been determined for this gas detection method. Pressure ranges to 20,000 psi of helium, nitrogen, argon, and methane along with a gas mixture were used in these experiments. Excellent agreement is obtained in the pressure- and gas-dependent shifts in critical angle between experimental observations and predictions based on literature values of gas densities and molar refractivities. Significant gas nonidealities are discussed in terms of the correspondence principle. PMID- 20963012 TI - Broadband alignment scheme for a stepper system using combinations of diffractive and refractive lenses. AB - By using broadband illumination, a stepper alignment system is less sensitive to asymmetric coverage of photoresist around alignment targets and realizes high accuracy. However, a projection lens causes chromatic aberrations at the wavelengths in the broadband light. To correct the chromatic aberrations, we employed a Schupmann system composed of a projection lens, an achromat lens, and a refractive-diffractive hybrid lens. With the proposed system the spread of image planes and the magnification difference in the spectral range from 550 to 650 nm can be reduced to 50 um and 0.05%, whereas without the correction system these values are 11.28 mm and 1.18%, respectively. PMID- 20963013 TI - Field cross correlator for analysis of ultrafast signals. AB - The cross-correlation function between two light fields is recorded with the help of a new device. The proposed correlator exhibits ultrashort time resolution. The optical path difference between the two interfering beams does not have to be known with interferometric precision. The experimental dynamic range proved to be as large as 10(5). The device features imaging capabilities that could be applied to the analysis of two-dimensional images with ultrashort time resolution. PMID- 20963014 TI - Ring-lens focusing and push-pull tracking scheme for optical disk systems. AB - An experimental comparison of the ring-lens and the astigmatic techniques of generating a focus-error signal (FES) in optical disk systems reveals that the ring lens generates a FES curve over two times steeper than that produced by the astigmat. Partly because of this large slope and partly because of its diffraction-limited behavior, the ring-lens scheme exhibits superior performance characteristics. In particular, the undesirable signal known as feedthrough (induced on the FES by track crossings during the seek operation) is substantially lower than that observed with the astigmatic method. The ring lens is easy to align and has reasonable tolerance for positioning errors. PMID- 20963015 TI - Direct measurement of standing evanescent waves with a photon-scanning tunneling microscope. AB - We present a detailed analysis of a standing evanescent wave that is caused by total internal reflection of an Ar-ion laser beam on a glass prism and investigate the coupling to a subwavelength dielectric tip of a photon-scanning tunneling microscope that is raster scanned at a close distance over the prism surface. The intensity of the evanescent field is spatially modulated with a period of 239.2 nm. It decays exponentially with a constant of 103.9 nm with increasing distance from the prism surface. Precise measurements of the standing evanescent wave can be used to calibrate the scanner and permit one to determine the spatial resolution and the coupling efficiency of the tip. PMID- 20963016 TI - Discomfort glare indices: a comparative study. AB - From the luminance distribution measured with a stereoluminancemeter we have studied the variation in the principal indices of discomfort glare while considering the orientation of the line of vision of the observer and the limiting luminance of the glare source. This method provides the ideal orientation for the observer in a lighted environment, minimizes the detrimental effects of glare, and determines the reliability of the indices calculated for discomfort glare. PMID- 20963017 TI - Multilens system design with an athermal chart. AB - We have introduced an athermal chart that plots chromatic dispersive power and thermal dispersive power on a Cartesian coordinate, and we give the design method of a multilens system in contact that satisfies achromatism and athermalization. The advantages of this chart are (1) that the condition of achromatism and athermalization is clear and (2) that the approximate power of the lenses that compose the multilens system is easily found on the chart. Design indices are given through a few design examples with an athermal chart. PMID- 20963018 TI - Slant-propagation characteristics in tapered optical waveguides: analysis. AB - Although several analysis methods for tapered waveguides have been proposed, they dealt with the problem of a light wave traveling parallel to the tapered direction of the waveguide. Light waves that propagate at a slant in the tapered direction are discussed as mode-coupling problems, including radiation modes that are made discrete by the hypothetical boundary method. We propose a method of determining the three-dimensional wave vectors of the discrete radiation modes in the slant propagation; the slant-propagation characteristics, such as the transmission efficiency of the tapered waveguide, are analyzed. PMID- 20963019 TI - Medical diagnostic system based on simultaneous multispectral fluorescence imaging. AB - A multicolor fluorescence imaging system applied to medical diagnostics is described. The system presented simultaneously records four fluorescence images in different wavelength bands, permitting low-resolution spectroscopy imaging. An arithmetic function image of the four spectral images is constructed by a pixel to-pixel calculation and is presented on a monitor in false-color coding. A sensitive detector is required for minimizing the excitation energy necessary to obtain an image and thus avoid side effects on the investigated tissue. Characteristics of the system of importance for the detector sensitivity as well as image quality are discussed. A high degree of suppression of ambient background light is reached with this system by the use of a pulsed laser as an excitation source together with gated detection. Examples of fluorescence images from tumors on the hind legs and in the brain of rats injected with Photofrin are given. PMID- 20963020 TI - Model for analyzing optical properties of silicate glasses. AB - A new model for analyzing optical properties of silicate glass materials including borosilicates has been developed. The model is based on computing refractive-index and density values of a given optical glass whose oxide composition is known in terms of weight fractions. The refractive-index variation with wavelength has also been used to predict the chromatic behavior of these glasses. The model has been compared with the existing chromatic model and was found to give more accurate values for borosilicates. PMID- 20963021 TI - Precise thickness and refractive index determination of polyimide films using attenuated total reflection. AB - Surface plasmons generated at a silver-polyimide interface and the guided modes coupled into planar films cause dips in the reflectivity curve of a transparent dielectric-silver-polyimide-air structure. These minima in the reflectivity curve were used to measure the polyimide thickness as well as the real and imaginary parts of the polymer refractive index (extinction). Precision within 1% of the polymer coat thickness was achieved through the use of this technique over the range 0.5-10 um. In some cases, this technique is capable of yielding a precision of ~ 10% on the imaginary part of the polymer refractive index and provides a useful method for determining the performance of a low-loss polymer waveguide. Techniques in fitting the experimental reflectivity data to obtain the optical constants are also described. PMID- 20963022 TI - Lambert absorption coefficients of water in the frequency range of 3000-934 cm( 1). AB - Accurate values for the Lambert absorption coefficients of water have been determined in the atmospherically important frequency region of 3000-934 cm(-1) (3.333-10.707 um). These values were calculated at every 2 wave numbers from linear regression of 13 spectra obtained by using both transmission and internal reflection techniques with varying sample thicknesses. Correlation coefficients (R(2)) varied from 0.998 to 0.826 and estimated errors in the measured values ranged from 1% to 10%. Results are compared with those reported earlier from single measurements. PMID- 20963023 TI - Infrared optical constants of polycrystalline boron nitride: comment. AB - In contrast to statements in a recent article by M. Khelkhal and F. Herlemont [Appl. Opt. 32, 57-59 (1993)], it is pointed out that well-documented IR data exist for boron nitride in both the cubic and hexagonal phases. Furthermore, the existence of a strong reststrahlen band causes a significant dispersion over the wavelength region of 1-10 um. PMID- 20963024 TI - Infrared optical constants of polycrystalline boron nitride: reply to comment. AB - This reply is to the comment by C. G. Ribbing [Appl. Opt. 33, 8055 (1994)] on our paper on IR optical constants of polycrystalline boron nitride. PMID- 20963025 TI - Hemispherical concentrators and spectral filters for planar sensors in diffuse radiation fields. AB - A dielectric hemisphere of refractive index N can act as an N(2) concentrator of isotropic diffuse radiation under appropriate conditions. We give an analytic expression for the gain of a concentrator of arbitrary radius, neglecting surface reflections, and numerical methods for calculating the gain when the surface transmissivity is an arbitrary function of incidence angle. The theory is applied to the design of multilayer spectral filters for hemispherical concentrators. When an appropriate wavelength shift is incorporated into the design process, an 11-layer, coupled-cavity spectral filter on the surface of a hemisphere of index 1.5 shows excellent bandpass performance with a concentrator radius as small as 3 times the sensor radius. This concentrator-filter combination shows a peak response of 97% of the ideal N(2) response at 950 nm, together with a FWHM of 55 nm. PMID- 20963026 TI - Orthogonal polarization fiber gyroscope with increased stability and resolution. AB - The orthogonal polarization fiber gyroscope (OPFG) is an interferometric fiber gyroscope design that requires no phase bias in the fiber ring and is insensitive to light-source intensity noise. However, in the original OPFG [Hitachi Rev. 33, 215 (1984)], environmental changes caused first-order false rotation signals. We propose and experimentally verify modifications that eliminate the first-order sensitivity to environmental changes and that improve the gyroscope's resolution as well. We believe that this modified OPFG is the first interferometric fiber gyroscope capable of stable, high-sensitivity measurement that contains only reciprocal optical elements. PMID- 20963027 TI - Uniformity of some recent color metrics tested with an accurate color-difference tolerance dataset. AB - The Rochester Institute of Technology-Dupont dataset [Color Res. Appl. 16, 297 316 (1991)] has been used to analyze the uniformity of seven color metrics, developed after CIELUV and CIELAB, with methods similar to those previously applied to several other classical datasets [J. Opt. Soc. Am. A 9, 1247-1253 (1992)]. Significant performance improvements over CIELAB were found with several CIELAB-based metrics, mainly with the model recently proposed by Commission Internationale de L'Eclairage Technical Committee 1-29 [Color Res. Appl. 18, 137 139 (1993)]. Several significant differences found between some pairs of metrics became insignificant when we selected from the Rochester Institute of Technology Dupont dataset pairs of samples with only chromaticity differences. PMID- 20963028 TI - Selective formation of gradient-index profiles inside a planar polymer substrate by a lithographic technique. AB - A fabricating technique that is capable of easy pattern formation for gradient index polymer optical devices is proposed. Monomers with low refractive indices are diffused into a gel that contains barium ion patterned by a lithographic technique, and then the diffusion profile is fixed by thermal polymerization. The gradient-index profiles can be selectively formed in the ultraviolet- (UV-) irradiated regions by utilizing the difference in diffusion rate of monomers between regions in the same substrate. The optical properties and shapes of the gradient-index profiles are determined by the diffusion behavior of the monomers into the UV-irradiated regions. A lens array, consisting of two equivalent gradient-index lenses distributed uniformly in the substrate, and a low-loss Y branched waveguide are fabricated by this technique, and their optical properties are demonstrated. PMID- 20963029 TI - Gradient-index rod lens with a high acceptance angle for color use by Na(+) for Li(+) exchange. AB - The relationship between the characteristics of gradient-index rod lenses obtained by ion exchange and their mother glass compositions is studied. It is observed that Li(2)O content, R(2)O (Li(2)O + Na(2)O) content, and the Li(2)O/Na(2)O ratio are important factors in attaining a high acceptance angle and a small field curvature. Thus the gradient-index lens array is fabricated by the use of a newly developed glass composition and its optical performance; the modulation transfer function, luminous intensity, and chromatic aberration are precisely evaluated. The array is found to have a sufficiently high performance to be applicable for color use. PMID- 20963030 TI - Practical design and performance of the stressed-lap polishing tool. AB - We present an overview of the engineering design and empirical performance of four stressed-lap polishing tools developed at the University of Arizona. Descriptions of the electromechanical actuators, servo systems, computer interfacing, and attachment of the lap to the polishing machine are provided. The empirical performance of a representative tool is discussed in terms of accuracy, repeatability, and hysteresis. Finally, we estimate the statistical likelihood of aluminum lap-plate failure through a metal-fatigue analysis for a worst-case stress-cycling situation. PMID- 20963031 TI - The precision polishing of bismuth silicate and bismuth germanate. AB - A recipe is given for the polishing of precise surfaces oncrystals of bismuth silicate (BSO) and bismuth germanate(BGO). Using this recipe, crystals having surface figure betterthan 1/10 wave, roughness of 20-50 A rms, and laserquality parallelism (10 arcsec or better) were obtained withabout 1-2 hours effort. PMID- 20963032 TI - Dynamic Recording Using a TDI Camera. AB - Dynamic recording of physical events is an interesting andchallenging problem for scientists and artists. Applicationof a digital camera for dynamic recording and analysis ispresented. Some experiments are described demonstratingthe working modes, advantages, and limitations of the device. PMID- 20963033 TI - Uses of microfiche viewers. PMID- 20963034 TI - Materials for birefringent coatings. AB - We discuss recent developments in methods for monitoring the anisotropic growth and properties of tilted columnar films and present results for the perpendicular incidence birefringence of aluminum oxide, Merck Substance Hi, silicon oxide, tantalum oxide, titanium oxide, and zirconium oxide. PMID- 20963035 TI - A versatile optical alignment tool. AB - An optical alignment tool is described, which acts like an optical tee to produce two collinear beams whose direction can be adjusted. The device can be used to align optica subsystems. PMID- 20963036 TI - A novel method for measuring the vertical birefringence of optical disk substrates. AB - We describe a simple method of measuring vertical birefringence over the entire surface of an optical disk substrate.Our design consists of a linearly polarized He-Ne laser (1-2 mW) and a CCD camera interfaced to a computer. The measurement is non-intrusive, easy to set up, and needs only a few seconds to collect the data and plot a map of vertical birefringence over the surface area of the disk. The system described here is potentially useful as a qualitycontrol tool in substrate manufacturing environments. PMID- 20963037 TI - Three-channel Homodyne Interferometer. AB - A three-channel homodyne interferometer based on a structured delay plate is described. Detection and data acquisition are performed with standard optoelectronics in a PC environment. The device, which is used as a displacement sensor, features sub-nanometric sensitivity. PMID- 20963039 TI - Room Illumination without Degrading Narrow-Band Detection. AB - A pair of complementary spectral filters can be used to block detector background illumination and provide bright illumination for an operator in a room. PMID- 20963038 TI - Polarimetric detection of land sediment runoff into the ocean using space shuttle imagery. AB - A new technique employing optical polarization is used to examine polarized radiation scattered by the sea in a region west of the Island of Hawaii. The technique is a very sensitive indicator of land sediment runoff following a storm.Polarization data acquisition details are described with an approach easily adapted to simplified instrumentation. PMID- 20963040 TI - Zernike circle polynomials and optical aberrations of systems with circular pupils. AB - Zernike circle polynomials, their numbering scheme, and relationship to balanced optical aberrations of systems with circular pupils are discussed. PMID- 20963041 TI - Specifying dispersion in the design of diffractive optics. AB - The chromatic aberration of a diffractive optical surface can be specified within a lens design program using the Sweatt model' by choosing the fictitious high refractive index equalto its corresponding wavelength in an appropriate unit. PMID- 20963042 TI - Zernike annular polynomials and optical aberrations of systems with annular pupils. AB - Zernike annular polynomials that represent orthogonal andbalanced aberrations suitable for systems with annular pupilsare described. Their numbering scheme is the same asfor Zernike circle polynomials. Expressions for standard deviationof primary and balanced primary aberrations are given. PMID- 20963043 TI - Integrated optics pockels cell-choice of crystal cut and waveguide orientation. AB - Several benefits are realized when one chooses az-propagating waveguide in a y cut substrate of lithiumniobate for use in an integrated optics Pockels cell: (1)waveguide can be biased by controlling its length; (2) polarizationstate is nearly uniform over the entire outputplane of the waveguide; (3) temperature change does notsignificantly affect the bias of the waveguide; (4) opticaldamage is negligible; and (5) waveguide fabrication is very simple. PMID- 20963044 TI - More on the accurate measurement of refractive indices. AB - Measurement of refractive indices using the normalincidenceprocedure and its relationship to the general andminimum deviation method are described. PMID- 20963045 TI - Folk wisdom in optical design. AB - Building optical systems that actually meet specificationsrequires more than a knowledge of optics and the use ofcontemporary design codes. Excellence also comes with akind of "street" knowledge, learned not from textbooks butfrom experience, mostly from failures. These hard-won lessons are colloquially described here as "folk wisdom." If considered during system conceptualization and design,these notes may improve efficiency, effectiveness, and uitimate performance. Costs, mechanical constraints, parts choice, specification and procurement, available adjustments,alignment sequence and retention, deterioration of performance with aging, and other topics are considered. PMID- 20963046 TI - Substrate-mode holographic polarization-division multi/demultiplexer for optical communications. AB - Based on the diffractive properties of a transmission-type phase volume hologram, a new type of polarization-division multi/demultiplexer for optical communications is presented. PMID- 20963047 TI - Multi-input optical parallel logic processing with the shadow-casting technique. AB - The lensless shadow-casting technique for coded pattern processing usually accommodates two inputs at a time to perform desired logical operations in parallel. A method of binary encoding is proposed that can accommodate multiple input patterns for simultaneous processing. With the proposed multiple-input encoding a carry-look-ahead technique of binary addition is developed that requires fewer processing steps than the conventional ripple-carry method. Experimental results for a few logic-processing operations are included to establish the validity of the proposed technique. PMID- 20963048 TI - Optical content-addressable parallel processor for high-speed database processing. AB - We extend the concept of optical content-addressable parallel processing [Appl. Opt. 31, 3241 (1992)] to a novel architecture designed specifically for the parallel and high-speed implementation of database operations called optical content-addressable parallel processor for relational database processing (OCAPPRP). An OCAPPRP combines a parallel model of computation, associative processing, with parallel and high-speed technology optics. The architecture is developed to provide optimal support for high-speed parallel equivalence (pattern matching) and relative-magnitude searches (greater than and lesser than). Distinctive features of the proposed architecture include (1) a two-dimensional match-compare unit for two-dimensional pattern matching, (2) constant-time retrieval of database entries, (3) an optical word and bit-parallel relative magnitude single-step algorithm, and (4) the capability of constanttime sorting. Since relational database operations rely heavily on parallel equivalence or relativemagnitue searches, database processing is an excellent candidate for implementation on an OCAPPRP. The architecture delivers a speedup factor of n over conventional optical database architectures, where n is the number of rows in a database table. We present an overview of the architecture followed by its optical implementation. The representative relational database operations, intersection, and selection are outlined to illustrate the architecture's potential for efficiently supporting high-speed database processing. PMID- 20963049 TI - Bitonic sorting using an optoelectronic recirculating architecture. AB - An optoelectronic bitonic sorter based on a recirculating architecture is presented. The data are input inword parallel-bit parallel fashion and processed by two smart pixel arrays made up of bitwise compare-and-exchange modules. Along with the logic design, the control and synchronization of the bitwise compare-and exchange modules are discussed. Finally, the capacity, hardware requirements, response time, and throughput of the recirculating bitonic sorter are compared with a pipeline implementation. The proposed recirculating architecture is shown to require less hardware than the pipelined systems. However, the decrease in hardware results in a decrease in system throughput. PMID- 20963050 TI - Development and field demonstration of a hardware-compressive fiber-optic true time-delay steering system for phased-array antennas. AB - We describe the design, fabrication, testing, and antenna-range demonstration of a photonic wavelengthmultiplexed true-time-delay steering system for use with broadband phased-array antennas. The prototype system is based on a unique hardware-compressive architecture and can drive 16 antenna elements over the 0.35 2.1-GHz band with 6-bit angular resolution over a +/-45 degrees scan angle. PMID- 20963051 TI - Estimation of point-spread functions and modulation-transfer functions of optical devices by statistical properties of randomly distributed surfaces. AB - The point-spread function a(PSF) and the modulation-transfer function (MTF) are important tools to characterize the information transfer through optical devices. They give useful information about the resolution. Several methods have already been achieved to calculate the PSF and the MTF from theoretical aspects of wave propagation or from experimental results. I present a novel way of estimating these two functions. It deals with statistical considerations for a randomly distributed surface involving a statistical determination of the PSF and the MTF. Indeed, in this case the theoretical shape of the autocorrelation function of such surface profiles is known. It is a decaying exponential function alpha[exp( beta|x|)]. Comparingthe theoretical autocorrelation-function profile with the experimental one and deconvolving in Fourier space leads to an estimation of the MTF of the imaging device. Applying the inverse Fourier transform to the MTF involves the computation of the PSF, assuming that the latter has no imaginary part and is symmetrical. The two-dimensional images are regarded as an iteration of one-dimensional ones according to the orthogonal direction. The MTF's and PSF's are therefore one-dimensional. Different results are presented. The first result proceeds from investigation with scanning near-field microscopy and illustrates the method step by step. The tunneling effect is detected assuming that the information transfer is linear. The last result concerns an optical profilometer, and the influence of the microscope objective is studied. PMID- 20963052 TI - Subharmonic focal-length intensities formed by Fresnel lenses. AB - Binary Fresnel lenses produce focused spots at subharmonics of the principal focal length of the lens. The intensities of these focal spots can be controlled by variation of the relative widths of the rings of the Fresnel lens compared with the spacings between the rings. Theory is presented and experimentalverification is provided with Fresnel lenses written onto the magneto optic spatial light modulator. PMID- 20963053 TI - Performance of minimum-mean-square-error filters for spatially nonoverlapping target and input-scene noise. AB - Using computer simulations, we investigate the performance of a minimum-mean square-error filter for input-scene noise that is spatially nonoverlapping (disjoint) with a target for a limited set of images. Different input-scene-noise statistics are used to test the filter performance. We show that in the presence of spatially nonoverlapping target and input-scene noise, the output of the minimummean- square-error filter has a well-defined correlation peak, small sidelobes, and a high peak-to-correlationenergy ratio compared with other widely used filters such as the classical matched filter, the phase-only filter, and the inverse filter. We also test the robustness of the minimum-mean-square-error filter to errors in noise statistics used in the filter design. We show that, for the images tested here, the performance of the minimum-mean-square-error filter is not sensitive to errors in noise statistics and the filter can detect the target even if a considerable error exists. The discrimination capability and the illumination sensitivity of the minimum-mean-square-error filter are also tested. PMID- 20963054 TI - Effect of the modulation transfer function of a digital image-acquisition device on phase-measuring profilometry. AB - Systematic errors in phase-measuring profilometry that are introduced by the modulation transfer function of a digital image-acquisition device are analyzed. New phase expressions and phase-deviation formulas are given. The results for simulations and experiments demonstrate that the algorithm of phase-measuring profilometry cannot be regarded as a point-to-point operation. To obtain precise results, an optimum scheme for setting the measurement system is also proposed. PMID- 20963055 TI - All-optical nonlinear joint Fourier transform correlator. AB - We present the first all-optical nonlinear joint transform correlator based on a square-law receiver in the Fourier plane. Our device uses a photorefractive limiting quadratic processor. The compressional nonlinearity associated with the transfer function of the limiting quadratic processor enables the correlator to detect signals embedded in Gaussian and non-Gaussian noise. In the limiting region this device correlates the phase-only information of the input. This is the first time to our knowledge that photorefractives or real-time holography has been used in the correlation of the phase-only information. We demonstrate the operation of this device experimentally, and we evaluate its performance throughcomputer simulation for various forms of noise. PMID- 20963056 TI - Morphological and wavelet transforms for object detection and image processing. AB - We consider the problem of detecting multiple distorted objects in an input scene with clutter. The input scenes contain different types of background clutter and multiple objects in different classes, with different object aspect views, different object representations, hot/cold/bimodal/partial object variations, and high/low contrast object variations. Several new optical morphological operations for use in the above detection problem and in other general low-level image processing applications are described, and several examples of their use are provided. For difficult detection problems in which high detection rates and low false-alarm rates are required we combine morphological operations and optical wavelet transforms to reduce clutter and improve object detection. The details of this set of filters and initial testresults are given. The most computationally demanding operations required in all cases are realizable on an optical correlator. PMID- 20963057 TI - Average speckle size as a function of intensity threshold level: comparisonof experimental measurements with theory. AB - Speckle phenomena result whenever spatially coherent radiation is reflected from a rough surface or propagated through a random medium such as atmospheric turbulence. Speckle characteristics are therefore a major concern in many laser imaging or wave-propagation applications. We present the results of experimental measurements of target-induced speckle patterns produced in the laboratory from a variety of targets and illumination conditions. We then compare these experimental measurements with a theoretical model for the average speckle size as a function of intensity threshold level. Excellent agreement is obtained for intensity threshold levels greater than approximately twice the mean intensity level. PMID- 20963058 TI - Real-time binary phase holograms on a reflective ferroelectric liquid-crystal spatial light modulator. AB - A ferroelectric liquid-crystal spatial light modulator with an active silicon backplane is used to implement reconfigurable reflective phase holograms. Optical results are presented for an optimized computergenerated Fourier hologram. PMID- 20963059 TI - Synthetic scanner arrays in tomographic reconstructionsfrom fan- and cone-beam projections. AB - A deterministic method for artifact-free reconstruction from truncated sets of fan-beam projections thatextends the artifact-free zone of fan-beam scanners is presented. Truncated partial sets of projectionsare merged into a complete virtual set of projections before reconstruction through synthetic scannerarrays. The reconstruction from the virtual set of projections yields the artifact-free representation ofthe whole object needed for evaluation of its global structure. The extent of the artifact-free zone in reconstructions from cone-beam projections is evaluated. The concept of synthetic linear and circular scanner arrays for reconstruction from truncated sets of projections is extended to cone beam geometry. It is shown that linear scanner arrays are not directly applicable to cone-beam geometry but yieldreasonable approximations if the partial sets of projections are resorted into a virtual set of wedge-beam projections before reconstruction. The presented solution constitutes a practical and exact det rministic method of horizontally extending the artifact-free zone in cone-beam geometry. The extension of the vertical limits of the artifact-free zone is discussed. The proposed methods provide a practical low-cost approach to artifact free reconstruction of large objects. Illustrative examples are provided. PMID- 20963060 TI - Optical implementation of a translation-invariant second-order neural network for multiple-pattern classification. AB - A novel approach to the optical implementation of second-order neural networks that can recognize multiple patterns is reported. The systems issues, especially the accuracy required for the weighted interconnections, are discussed for numeric character (0-9) recognition. It is shown that the accuracy of the weighted interconnections has a far greater influence on the network performance during training than on classification. To lessen the problem, we introduce an adaptive learning rule, whereby the optical power is adjusted during training. Finally, numeric character recognition using an experimental system with a liquid crystal display is demonstrated. PMID- 20963061 TI - Noise in single-shot broadband coherent anti-Stokes Raman spectroscopy that employs a modeless dye laser. AB - The noise in single-shot coherent anti-Stokes Raman (CARS) spectroscopy that employs a broadband modeless dye laser (MDL) is examined and the results are compared with those of a conventional dye laser. The noise of the dye-laser, the nonresonant CARS, and the resonant N(2) CARS signals are determined. The use of a MDL is shown to result in substantially reduced CARS noise when the CARS signal is generated with a single-mode pump laser, but only a marginal reduction of noise is observed with a multimode pump source The noise measurements are compared with theoretical predictions that are based on models that assume modes of random amplitudes and phases in the multimode laser sources. The combination of a MDL and a single-mode pump laser is shown to increase the precision of single-shot N(2) CARS temperature measurements. PMID- 20963062 TI - Relative phase control between two successive coherent anti-Stokes Raman scattering signals for the recovery of spectral lines. AB - We have controlled the relative phase between two successively generated coherent anti-Stokes Raman-scattering signals with a homemade phase-shifting unit, the thickness of which could be automatically adjusted as the wavelength of Stokes beam scanned in a wide spectral range. With this technique we have recovered the Q-branch spectrum of carbon monoxide distorted by a large nonresonant contribution from propane. Also, we have selectively recorded the spectrum of hydrogen chloride buried in the spectrum of propane. PMID- 20963063 TI - Optical constants of liquid and solid methane. AB - The optical constants n(r) + in(i) of liquid methane and phase I solid methane were determined over the entire spectral range by the use of various data sources published in the literature. Kramers-Kronig analyses were performed on the absorption spectra of liquid methane at the boiling point (111 K) and the melting point (90 K) and on the absorption spectra of phase I solid methane at the melting point and at 30 K. Measurements of the static dielectric constant at these temperatures and refractive indices determined over limited spectral ranges were used as constraints in the analyses. Applications of methane optical properties to studies of outer solar system bodies are described. PMID- 20963064 TI - Structure of a general pure Mueller matrix. AB - Changes in the radiance and state of polarization of a beam of radiation can often be described by means of a pure Mueller matrix. Such a 4 * 4 matrix transforms Stokes parameters and can be expressed in terms of the elements of a 2 * 2 Jones matrix. Relations between the two types of matrix are discussed. Explicit expressions are given for changes of a pure Mueller matrix that are caused by certain elementary changes of its Jones matrix, such as when its transpose, complex conjugate, or Hermitian conjugate are taken. It is shown that every pure Mueller matrix has a simple and elegant structure, which is embodied by interrelations that involve either only squares of the elements or only products of different elements. All possible interrelations for the elements of a general pure Mueller matrix are derived from this simple structure. PMID- 20963065 TI - Ultrahigh-efficiency, very narrowpassband, tunable optical filter. AB - Recently developed technologies have been uniquely integrated to produce optical filters with unprecedented performance. The precise design and fabrication of narrow-passband and high-efficiency optical filters with a central frequency of 532 nm are reported. Measurements with these filters demonstrate a performance that accurately mirrors the design specification, with one filter having a passband of 70 pm and an efficiency greater than 90% and the second filter having a passband of 7 pm and an efficiency greater than 80%. PMID- 20963066 TI - Dependence of laser intensity on cavity losses for a detuned, single-mode laser. AB - It is shown that for a detuned, single-mode, homogeneously broadened laser, semiclassical laser theory predicts a transition from a nonlasing state to a lasing state when cavity losses are increased for a range of cavity detunings when dispersion is large. A physical explanation for this behavior is presented in which the influence of dispersion on the cavity resonance frequencies is considered. PMID- 20963067 TI - Time-resolved xenon flash-lamp opacity measurements. AB - A laser-aided technique has been used for measuring time-resolved optical transmissions of xenon flash lamps at numerous visible and infrared wavelengths, flash-lamp current densities, lamp diameters, pulse durations, and xenon pressures. Long-pulse (~ 600-us) and short-pulse (~ 10-us) cases specific for optically pumping solid-state, dye, and atomic iodine lasers were studied. Opacity measurements were made for flash-lamp current densities up to 30 kA/cm(2) . Flash lamps having fused silica envelope diameters between 0.8 and 4.5 cm and xenon pressures between 2 and 450 Torr were investigated in these experiments. Xenon temperatures between 6000 and 25,000 K were estimated from the frequencies of observed arc-acoustic oscillations. Important applications for increasing the pumping efficiencies of large Nd:glass and photolytic iodine laser amplifiers are discussed. PMID- 20963068 TI - Optical imaging through turbid media with a degenerate four wave mixing correlation time gate. AB - A novel method for detection of ballistic light and rejection of unwanted diffusive light to image structures inside highly scattering media is demonstrated. Degenerate four wave mixing (DFWM) of a doubled YAG laser in Rhodamine 6G is used to provide an ultrafast correlation time gate to discriminate against light that has undergone multiple scattering and therefore lost memory of the structures inside the scattering medium. We present preliminary results that determine the nature of the DFWM grating, confirm the coherence time of the laser, prove the phase-conjugate nature of the signal beam, and determine the dependence of the signal (reflectivity) on dye concentration and laser intensity. Finally, we have obtained images of a test cross-hair pattern through highly turbid suspensions of whole milk in water that are opaque to the naked eye. These imaging experiments demonstrate the utility of DFWM for imagingthrough turbid media. Based on our results, the use of DFWM as an ultrafast time gate for the detectionof ballistic light in optical mammography appears to hold great promise for improving the current state of the art. PMID- 20963069 TI - Effect of dispersion on the operation of a KTP electro-optic Q switch. AB - The effect of dispersion on the operation of a KTP electro-optic Q switch was investigated. A KTP crystal in the normal orientation has been successfully operated as a Q switch. The experiment was performed with a laser resonator containing a Nd:YLF crystal end pumped with a cw diode-laser array. A pulse length of approximately 100 ns was obtained at a repetition rate of 1 KHz. Temperature tuning was used to eliminate static phase retardation. The effect of dispersion was found to affect Q switching. Wavelength stabilization was performed to counteract the effect of dispersion. These measures allowed us to achieve Q switching action. PMID- 20963070 TI - Modeling of symmetric 2 * 2 fused-fiber couplers. AB - A complete analysis of symmetric 2 * 2 fused-fiber couplers in terms of supermode beating is made. The tranverse and longitudinal geometry of the couplers has been carefully modeled to take into account the fabrication parameters. The first two scalar supermodes and their polarization corrections have then been calculated for each degree of fusion and taper ratio, resulting in powerful tools for the design of particular couplers. The good agreement between the observed and the predicted responses for slightly and strongly fused couplers confirms the validity of each step of this analysis. PMID- 20963071 TI - Simple high-precision method for measuring the specular reflectance of optical components. AB - We present a simple method to determine precisely the specular reflectance of optical components. The absence of transmissive elements in this method makes a wide spectral range available. High accuracy and precision are achieved with a fast, periodic change between the reference beam and the probe beam. Special efforts were made to eliminate inhomogeneities of beam intensity and detector sensitivity. With our experimental setup we obtain a precision of +/-3 * 10(-4) at the wavelength of 10.6 um and +/-3 * 10(-5) at 1.06 um for a single-bounce measuring setup. PMID- 20963072 TI - Properties of nonblocking single-substrate optical space switching networks constructed from directional couplers. AB - Some of the properties of single-substrate nonblocking optical space switching networks that are constructed from directional couplers, waveguide bends, and waveguide crossovers are considered. Expressions are given for the ratio of network output signal to cross talk, insertion loss, and total switch count for ten different structures. Based on these expressions, estimates of the maximum switch sizes attainable are made. Consideration is also given to the factors that govern the practical implementation of such structures, and this shows that rearrangeably nonblocking single-substrate switches of up to 128 * 128 should be possible if technologies other than Ti:LiNbO(3) are used. PMID- 20963073 TI - Angular distribution of fluorescence from dye-filled capillaries. AB - We studied the angular distribution of fluorescence from a small, lossy capillary filled with a laser-dye solution. We found that the fluorescence is isotropic for the liquid core and that, far from the liquid-solid phase transition, this isotropy shows no temperature dependence. This result, an extension of studies with solid cylinders, is at variance with theoretical expectations for solids as well as with previous reports by other investigators but is explained by the motion of the molecules in the liquid. Therefore the optimal viewing angle for capillary zone electrophoresis experiments is near 90 degrees because the elastic scattering of the incident laser light is at or near a minimum for these small capillaries. This reduces contamination of the fluorescence signal as a result of stray laser light in the optical system. PMID- 20963074 TI - Differential absorption lidar measurement of vertical ozone profiles in the troposphere that contains aerosol layers with strong backscattering gradients: a simplified version. AB - A technique for determining approximate ozone-concentration profiles from differential absorption lidar (DIAL) data obtained in the troposphere with large gradients of aerosol backscattering is presented. The atmospheric interferences are defined as errors of the off-on DIAL signal ratio; the interferences are separated and removed before the ratio is differentiated. To facilitate the separation of the regular (subjected to differentiation) component of the signal ratio from random noise, the ratio is transformed into an intermediate function, and the measurement error is minimized by fitting of an analytical function to the transformed function. Simple criteria are used to demarcate atmospheric layering, for which a strong aerosol-backscattering gradient can result in an unacceptably large error in the measured ozone concentration. PMID- 20963075 TI - Variations of refraction angles from observations of the Moon from space. AB - We present the results of measurements of optical refraction angles from photographs of the Moon taken from the orbital station Mir. We made estimations of rms fluctuations of refraction angles and of the characteristics of multipath propagation. PMID- 20963076 TI - Atmospheric inner-scale effects on normalized irradiance variance. AB - We have investigated five types of atmospheric optical-turbulence inner scales for their effects on normalized laser irradiance variance in the Rytov and early saturation regimes: (1) zero inner scale, (2) Gaussian inner scale, (3) Hill's viscous-convective enhancement inner scale, (4) Frehlich's parameterization of the viscous-convective enhancement, and (5) turbulence spectrum truncation because of the discrete grid representation. Wave-optics computer simulations yielded normalized irradiance variances within 2% of the results from numerical integrations of the Rytov-Tatarskii predictions. In the Rytov regime a Gaussian inner scale reduces the normalized irradiance variance compared with the zero innerscale case, and the viscous-convective inner scale first raises, then lowers the irradiance variance as the inner-scale size increases. In the saturation regime all inner-scale models increase the intensity variance for a spherical wave. PMID- 20963077 TI - Optical properties of interacting particles. AB - The radiative cross sections of random homogenous dense systems of interacting Rayleigh particles are studied analytically in terms of a proposed model for the radial distribution function. The model provides a closed-form expression for the radial distribution function that captures the essential features of the function's behavior as described by experimental results and numerical calculations. PMID- 20963078 TI - Shadow Doppler technique for sizing particles of arbitrary shape. AB - The output from a linear diode array is used in a modified laser Doppler velocimeter to measure the size and shape of irregular particles. The sizing accuracy for transparent and opaque particles between 30 and 140 um is better than 10%. The inaccuracy caused by trajectories that lay at angles of less than 24 degrees to the axis of the array was less than +5%, and a further inaccuracy of +5% was caused by defocusing of the particle from the center of the velocimeter measuring volume by up to +/-500 um. The advantages of the shadow Doppler technique over other techniques for sizing irregular particles, such as amplitude systems with pointer volumes, are that the shadow Doppler technique records shape, the optical arrangement is more robust, less precise alignment is required, and the equipment can be constructed at low cost. PMID- 20963079 TI - Fourier description of the propagation and focusing of an extraordinary beam in a planar uniaxial medium. AB - The scalar-angular-spectrum approach is used to examine a focused extraordinary wave propagating along an arbitrary direction in a homogeneous uniaxial planar medium, and the Fraunhofer diffraction formula is generalized for this case. The size of the focal spot is found to be inversely proportional to an effective index, depending on the refractive indices and the propagation direction. The validity of the paraxial model is checked by nonparaxial (but scalar) numerical calculations. They show that the paraxial formulas predict the spot size correctly, but if the beam propagates neither parallel with nor perpendicular to the optic axis, they do not reproduce the symmetries of the amplitude distribution in the focal line. PMID- 20963080 TI - Absorption spectroscopy in tissue-simulating materials: a theoretical and experimental study of photon paths. AB - A diffusion model of noninvasive absorption spectroscopy was used to determine how the change in signal resulting from a point absorber depends on the position of that absorber relative to the source and detector. This is equivalent to calculating the relative probability that a photon will visit a certain location in tissue before its detection. Experimental mapping of the point-target response in tissue-simulating materials confirmed the accuracy of the model. For steady state spectroscopy a simple relation was derived between the mean depth visited by detected photons, the source-detector separation, and the optical penetration depth. It was also demonstrated theoretically that combining a pulsed source with time-gated detection provides additional control over the spatial distribution of the photon-visit probability. PMID- 20963082 TI - Determination method of an initial damping factor in the damped-least-squares problem: errata. PMID- 20963081 TI - Retroreflecting ellipsometer for measuring the birefringence of optical disk substrates. AB - A retroreflecting ellipsometer has been constructed for measuring the birefringence of optical disk substrates. In contrast to conventional ellipsometers with two mechanical arms, this system has only one arm along which both the incident and reflected beams travel. This construction eliminates the mechanical limitations of conventional ellipsometers, thereby permitting normal incidence on the sample. In addition, the single arm is adjustable in two dimensions, with the polar incident angle, theta(inc), varying from 0 degrees to 70 degrees , and the azimuthal incident angle, Phi(inc), varying from 0 degrees to 360 degrees . The condition of normal incidence permits accurate measurement of in-plane birefringence. The adjustability of both theta(inc) and Phi(inc) is necessary for the measurement of possible tilts of the index ellipsoid, and also for the variation of birefringence through the substrate thickness. Measurement results showing the useful features of the equipment are presented. The optics of the hemispherical assembly used for retroreflection as well as for the elimination of undesirable refractions are also studied by use of the ZEMAX lens design program. PMID- 20963083 TI - Studies on the diffraction image of a thermal lens. AB - We calculated the intensity distribution behind a thermal lens by using a numerical quadrature of the Fresnel diffraction integral and compared it to several given approximate models for laser light detection in the center behind a thermal lens, which includes a new approximate solution of the diffraction integral with applicability to strong thermal lenses. Consideration of the aberrant nature of the thermal lens is crucial even if the thermal lens is weak. A simple approximate formula for the position of the most intense interference ring stating a linear dependence of the thermal lens strength is given. The transverse profile of a weak thermal lens is discussed. It is shown that spherical aberration modifies the central intensity even if a Gaussian profile is observed. PMID- 20963084 TI - Technique for obtaining visibility amplitudes from atmospherically disturbed interferograms. AB - We describe the general data-reduction techniques that we developed to deal with stellar interferograms. The techniques that we describe here were used to obtain the fundamental visibility data from raw Earth-scanned interferograms obtained with the infrared Michelson array stellar interferometer. The reduced visibility data have resulted in new direct angular diameter measurements and effective temperature determinations for alpha Her, alpha Ori, and Mira. These astrophysical results were previously published. We point out that the data reduction techniques described here are completely general in the sense that they can be used to reduce the data from any stellar interferometer that records the temporal data stream as the fringe packet is swept by the detectors. PMID- 20963085 TI - Line-shape studies for single- and triple-pass Fabry-Perot interferometer systems. AB - To test the model developed in the preceding paper [Appl. Opt. 34, this issue (1994)] regarding the line shape produced by a Fabry-Perot interferometer system in a multipass mode, we have used three Lorentzian line shapes formed in scattering processes and subjected them to single and triple passes with some variation in the pinhole diameter. In most cases we find good agreement with the calculations with the only adjustable parameter being the single-pass contrast C(1). Where differences occur, plausible explanations are offered. PMID- 20963086 TI - Closed-form expressions to fit data obtained with a multipass Fabry-Perot interferometer. AB - We have studied the effect of a multipass Fabry-Perot interferometer (FP) on a scattering line. Here we describe a method that we applied to derive a closed form expression for a line shape obtained with an ideal, multipass FP. The method reduces the convolution problem between the multipass function and the scattering line to the corresponding single-pass problem. We illustrate the method with a Lorentzian and a damped-harmonic-oscillator line passed through a single-, triple , and quintuple-pass FP. Furthermore we have applied the method to a study of the effect of the collecting pinhole on a sharp line obtained by multipassing. We show how we used these functions to fit the complete spectra obtained with a single- and triple-pass FP. PMID- 20963087 TI - Optimum determination of speckle size to be used in electronic speckle pattern interferometry. AB - Characteristics of the fringe pattern detected by an electronic speckle pattern interferometer, in conditions in which a test object deforms in an arbitrary direction and the speckle intensity is detected over a pixel area in the TV camera to be used, have been investigated from two aspects: speckle noise reduction and fringe contrast. The main result is that the fringes are obtained with high contrast and low speckle noise, if the speckle size is selected by the optical system so as to be smaller than the pixel size. This result is applicable to highly accurate measurements of the out-of-plane displacements of the test object, whose in-plane displacement is small. PMID- 20963088 TI - Design and performance of cryogenic, scanning Fabry-Perot interferometers for the Long-Wavelength Spectrometer on the Infrared Space Observatory. AB - The design of cryogenic, scanning Fabry-Perot interferometers for the Long Wavelength Spectrometer on the ESA Infrared Space Observatory is presented. The interferometers were designed to provide a spectral resolving power of 10(4) over the wavelength range 45-180 um, with the highest possible transmission efficiency consistent with this requirement. Metal meshes, custom designed with the aid of a theoretical model of metallic reflection, were used as the reflecting elements. The scanning mechanism featured a spring-suspended plate, which was servocontrolled by moving coil actuators and monitored by capacitance micrometers. The spectroscopic performance of the interferometers was measured in the laboratory and is compared with the model developed for the interferometer design. Although the measured resolving powers were somewhat lower than expected because of the laboratory measurement conditions, the transmission efficiencies were in approximate agreement with the design specification. PMID- 20963089 TI - Wave-front sensing by pseudo-phase-conjugate interferometry. AB - A wave-front sensor based on pseudo-phase-conjugate interferometry is presented. We show that a pseudo-phase-conjugate interferometer is suitable for the measurement of phase distribution on a propagating wave. This new method may be employed for optical workshop applications and wave-front sensing for adaptive optics. The theoretical sensitivity of the interferometer is twice that of the Hartmann-Shack wave-front sensor. Preliminary laboratory experiments demonstrate excellent performance and consistency with computer simulations. PMID- 20963090 TI - Fourth-order optical aberrations and phase-space transformation for reflection and diffraction optics. AB - One can derive fourth-order optical ray deviations for a mirror or grating from the optical path function by using the analytical code REDUCE. Some of the aberrations are discussed for normal-incidence and grazing-incidence monochromators. The nonlinear transformation of light from the source to the image plane of a mirror or grating is represented by a transformation matrix. The optical properties of a combination of several optical elements are given by the product of the matrices of the individual optical elements. The matrix elements can be interpreted as optical aberrations. A program has been written that optimizes a complete beam line with respect to various optical aberrations by minimizing an appropriate cost function that is built from a weighted sum of the matrix elements. PMID- 20963091 TI - Lens design for a white-light cosine-transform achromat. AB - We describe the lens design for a twin-imaging white-light interferometer in which the interference pattern at the exit-pupil plane is the cosine transform of the spatial-intensity distribution of the object. The achromatic condition in terms of optical power is derived. The analysis of the transform aberration shows that the even aberrations, e.g., spherical aberration and field curvature, do not degrade the cosine transform and need not be corrected. This significant simplification permits us to design systems with good performance and uncomplicated lens structures. We present a lens design with three elements and a length of 320 mm. The system is capable of resolving more than 10(6) pixels with an operating spectral bandwidth of 100 nm. The results of an experiment with an early four-element design are also presented. PMID- 20963092 TI - Photophysical properties and photoisomerization processes of Methyl Red embedded in rigid polymer. AB - The photophysical properties of Methyl Red molecules embedded in a poly(methyl methacrylate) (PMMA) matrix were investigated with photoinduced absorption, absorption kinetics, steady-state, and time-resolved luminescence spectroscopy. The excited singlet (S(1)) state lifetimes for trans and cis isomers of Methyl Red in PMMA at room temperature have been measured as 35 and 420 ps, respectively. The excited triplet (T(1)) state energy level and its lifetime at 77 K were also obtained. A slow trans-cis isomerization process having a time constant of a few hundred seconds was observed for the illuminated Methyl Red in rigid polymer. Based on measured photophysical properties and dynamic processes, an energy-level diagram for Methyl Red molecules in rigid polymer is introduced to explain these observations. PMID- 20963093 TI - Examination of scattering at 90 degrees from a cylindrical volume illuminated by polarized light. AB - A comparison is presented of the effects of particle size, concentration, and detector depth on side scattering for linearly and circularly polarized incident light. The scattering medium consists of various concentrations of particles, which are either 1.24, 0.494, 0.36, 0.123, or 0.065 um in diameter, and which were mixed into filtered, distilled water and serve as the scattering centers. The results indicate that when this scattering medium is irradiated with linearly polarized laser light whose beam has been put through a quarter-wave plate in an effort to produce circularly polarized light, then there are two components scattered 90 degrees , that is, circularly and linearly polarized light. The amount of each component and the ratio to total intensity of scattered light are analyzed for the different particles. PMID- 20963094 TI - Depolarization measurements of an integrating sphere. AB - Mueller-matrix polarimetry performed in the visible and near IR indicates that an integrating sphere acts as an ideal depolarizer to the 0.5% accuracy of the polarimeter. The integrating sphere emits unpolarized light regardless of the incident polarization state. PMID- 20963095 TI - ZrCo as a new H(2) storage and getter for Lyman-alpha radiation sources. AB - In the past, in sealed-off Lyman-alpha radiation sources (121.57 nm), uranium hydride was used as the hydrogen reservoir. We found that the zirconium-cobalt alloy ZrCo, which has similar thermodynamic properties, can also be used for hydrogen storage in such lamps. Like uranium, ZrCo acts as a getter for atmospheric contaminants. The advantage of the use of ZrCo lies in much easier and safer handling during production and disposal of the lamps. Using ZrCo, we succeeded in producing radiation sources with a large Lyman-alpha radiation output and high spectral purity, which were successfully applied in a Lyman-alpha fluorescence hygrometer for stratospheric observations. PMID- 20963096 TI - Determination method of optical properties. AB - A new parameter called the coefficient of reflectivity differentiated with respect to the wavelength of light (dR/dlambda) is introduced. This parameter is used to describe a new method of determining the optical properties, a refractive index, and the thickness of nonabsorbent thin films from reflectivity R and a differential coefficient (dR/dlambda) for either s-polarized light or p-polarized light. It is also shown that optical properties can be obtained from reflectivity R and a coefficient of reflectivity differentiated with respect to the incident angle of light (dR/dtheta). PMID- 20963097 TI - Scatter from tilted-columnar birefringent thin films: observation and measurement of anisotropic scatter distributions. AB -

We show that the angular distribution of scattered light (haze) from tilted columnar birefringent thin films is highly anisotropic. When a narrow laser beam is incident normally upon a substrate coated with a tilted-columnar film, such as titania deposited at 60 degrees to a thickness of ~2 um, the distribution of light scattered into the surrounding transmission and reflection air spaces has the form of one or more arcs. Scatter of light into the substrate is also highly anisotropic, and secondary scatter from the trapped substrate flux produces characteristic bright patterns that appear superposed on the coating.

When viewed in transmission the bright pattern typically consists of two strong lobes and in reflection four weaker lobes that make a cross. The various anisotropic distributions are shown to be consistent with interference of light from scattering centers that are correlated along the column direction and hence can be described as reflections from the tilted-columnar thin-film microstructure.

PMID- 20963098 TI - Optical properties of Langmuir-Blodgett films investigated by a photoacoustic technique. AB - A photoacoustic (PA) technique based on a four-layer prism configuration has been developed for nondestructive determination of the optical properties of Langmuir Blodgett (LB) films, in which the PA signal amplitudes are measured as functions of the incident angle of light. With this technique the experimental PA angular spectra of manganese stearate and cadmium stearate LB films were obtained. Based on the electromagnetic theory and taking into account the anisotropic properties of LB films, as well as use of the numerical optimization method, we have simultaneously determined the optical constants and thicknesses of films based on experimental PA angular spectra. PMID- 20963099 TI - High-speed framing camera with an ellipsoidal scanner. AB - A new type of rotating-mirror framing-camera optical system is proposed. A study is reported of the feasibility of the use of an aspherical mirror, with its surface in the shape of a prolate ellipsoid of revolution, in the scanning system of the camera. Starting from the aberration minimization conditions, the optimization of the parameters of the optical system is carried out. An aspherical mirror of this kind performs not only the scanning function, but also acts as a condenser, thus greatly simplifying construction of the camera. PMID- 20963100 TI - Optical measurements of the core radius of high-Delta fibers with 1-nm resolution. AB - An optical technique for measuring the core radius of high-Delta optical fibers is described. Variations in the core radius of step-index fibers can be measured down to a scale of 1 nm. PMID- 20963101 TI - Measured limits to contamination of optical surfaces by elastomers in vacuum. AB - We have monitored the reflectivity of mirrors that were exposed to a fluoroelastomer (3M-Fluorel 2176) and a room-temperature vulcanizing silicone rubber (RTV-615) in vacuum. The 95% confidence limit on the decrease of mirror reflectivities was less than 0.35 ppm/week for Fluorel and <0.29 ppm/week for RTV 615. PMID- 20963102 TI - Vibration transducer using an ultrashort Fabry-Perot cavity. AB - We report here on the development of an optical transducer for mechanical vibration, making use of an ultrashort Fabry-Perot cavity. The noise level measured by a cavity 150 um long is ~1.3 * 10(-16) m/?Hz at ~1 kHz, which was obtained without a frequency-stabilization system. It was, however, large compared with the shot noise. PMID- 20963103 TI - Very-large-scale-integration fabrication technique for binary-phase gratings on sapphire. AB - An efficient, high-yield process for the production of binary-phase holograms is presented by controlled deposition of silicon nitride over a sapphire substrate with the binary structure formed by plasma etch of the silicon nitride. Optical results are presented for a 16 * 16 transmission fanout element that shows near optimal performance. PMID- 20963104 TI - Particle image velocimetry: image labeling using encoding of the point-spread function by application of a polarization-sensitive pupil mask. PMID- 20963105 TI - Calculation of the power spectral density from surface profile data. AB - The power spectral density (PSD), in its two-dimensional form, has been designated as the preferred quantity for specifying surface roughness on a draft international drawing standard for surface texture. The correct calculation of the one-dimensional PSD from discrete surface profile data is given, and problems in using fast Fourier-transform routines that are given in some of the standard reference books are flagged. The method given here contains the correct normalizing factors. Two ways to reduce the variance of the PSD estimate are suggested. Examples are shown of the variance reduction possible in the PSD's. PMID- 20963106 TI - Topographic measurements of supersmooth dielectric films made with a mechanical profiler and a scanning force microscope. AB - The roughnesses of five supersmooth dielectric films of Si(3)N(4), TiO(2), HfO(2), Ta(2)O(5), and Al(2)O(3) prepared by an ion-beam-sputtering technique were measured with a commercial Talystep mechanical profiler and a sensitive Leica WYKO SPM30 scanning force microscope (SFM) to determine how much roughness the films added to the ~1-A-rms roughness fused-silica substrates on which they were deposited. In all cases the increase in roughness for the three-quarter-wave optical thickness films was a small fraction of an angstrom. SFM measurements showed that the topography of the Ta(2)O(5) and Al(2)O(3) films was less random than that of the other film materials and the substrates. PMID- 20963107 TI - Scanning force microscope as a tool for studying optical surfaces. AB - The scanning force microscope (SFM) is used to study the characteristics of optical surfaces, such as polished and precision-machined surfaces and thin-film structures. Previously unreported images of raised surface scratches and clumpiness on the surface of extremely smooth dielectric films are presented. The characteristics of SFM's that are important in studying optical surfaces are discussed. They include the effects of tip geometry, surface charging, particulate contamination, scanner artifacts, and instrument calibration. PMID- 20963108 TI - Spatial frequency filtering in holographic image reconstruction. AB - We show that reconstructing a hologram by its object beam leads to spatial filtering, namely, to the suppression of spatial frequency components that are perpendicular to the plane of the recording beams. We conduct experiments by rotating the transparencies of Ronchi gratings and crossed gratings and measuring the corresponding diffraction efficiencies. Good agreement is found with a theory based on image reconstruction with a beam that does not quite satisfy the Bragg condition. PMID- 20963109 TI - Two-dimensional wavelet transform and application to holographic particle velocimetry. AB -

The goal of holographic particle velocimetry is to infer fluid velocity patterns from images reconstructed from doubly exposed holograms of fluid volumes seeded with small particles. The advantages offered by in-line holography in this context usually make it the method of choice, but seeding densities sufficient to achieve high spatial resolution in the sampling of the velocity fields cause serious degradation, through speckle, of the signal-to-noise ratio in the reconstructed images. The in-line method also leads to a great depth of field in paraxial viewing of reconstructed images, making it essentially impossible to estimate particle depth with useful accuracy. We present here an analysis showing that these limitations can be circumvented by variably scaled correlation, or wavelet transformation. The shift variables of the wavelet transform are provided automatically by the optical correlation methodology. The variable scaling of the wavelet transform derives, in this case, directly from the need to accommodate varying particle depths. To provide such scaling, we use a special optical system incorporating prescribed variability in spacings and focal length of lenses to scan through the range of particle depths.

Calculation shows, among other benefits, improvement by approximately two orders of magnitude in depth resolution. A much higher signal-to-noise ratio together with faster data extraction and processing should be attainable.

PMID- 20963110 TI - Polarization-selective computer-generated holograms: design, fabrication, and applications. AB - We constructed polarization-selective computer-generated holograms that apply an independent phase profile during readout by horizontal and vertical light polarizations. These elements are composed of two surface-relief-etched birefringent substrates joined face to face. We describe the design methodology for arbitrary birefringent substrate and gap materials. We show how these holograms are fabricated with standard microelectronics technology and discuss the effects of etching and alignment errors on performance. We demonstrated a diffraction efficiency of 60% with a polarization contrast ratio of >100:1 using a multilevel phase hologram made from two birefringent lithium niobate substrates. We also showed that a single-layer SiO(2) thin-film antireflection coating on all surfaces can reduce reflections from the high-index substrates without significant effect on hologram performance. We also consider some possible applications of this technology and demonstrate experimentally a dual focal-length lens and a self-interconnecting binary 2 * 2 polarization switch. PMID- 20963111 TI - Rank-order and morphological enhancement of image details with an optoelectronic processor. AB - In all-optical processors, enhancement of image details is the result of high pass filtering. We describe an optoelectronic processor in which detail enhancement results from the digitally calculated difference between an original input image and its low-pass filtered version. The low-pass filtering is realized through the rank-order median and the morphological opening and closing operations calculated by use of the optical convolver. It is shown that the normalized difference between the morphological white and black top hats enhances bright and dark image details analogously to the rank-order unsharp masking. PMID- 20963112 TI - Incoherent optical image processing with acousto-optic pupil-plane filtering. AB - We describe an incoherent image processor that uses orthogonally oriented one dimensional acoustooptic cells to implement dynamic, arbitrary bipolar point spread functions (PSF's). Arbitrary PSF's are implemented as a linear superposition in time of separable PSF's. The use of incoherent illumination increases the input field of view over that provided by coherent illumination, and implementation of the PSF by a pupil-plane filter yields a simple, compact single-lens imaging system. The acousto-optic cells offer a faster PSF update rate than that of conventional spatial light modulators, which is a critical issue for the implementation of a bipolar PSF as a subtraction between its positive and rectified negative parts. Initial experimental results are presented that demonstrate the realization of an arbitrary nonseparable PSF, image convolution with a bipolar PSF, two-dimensional image correlation, and an increased processor field of view. PMID- 20963113 TI - Ternary phase and amplitude modulations using a twisted nematic liquid crystal spatial light modulator. AB - Ternary phase and amplitude modulations that use a reflective mode, 45 degrees twisted nematic liquid-crystal spatial-light modulator are demonstrated. This use offers a simple method for implementation of ternary phase-amplitude filters with high resolution, high optical efficiency, and fast response time. PMID- 20963114 TI - Two-dimensional operation of a scanning optical microscope by vibrating knife edge tomography. AB - We analyze and demonstrate a scanning optical imaging system that uses a vibrating knife edge to collect sets of tomographic projection data of two dimensional objects. Special concerns arising from nonuniform illumination and offset projection data are covered. A tomographic filtered backprojection algorithm is implemented to reconstruct an image from collected projections. Implications for near-field scanning optical microscopy and x-ray microscopy are discussed. PMID- 20963115 TI - Rotating-kernel min-max algorithms for straight-line feature enhancement. AB - The rotating-kernel min-max transformation is a nonlinear image-processing operation that can be applied to the enhancement of directional features in noisy images. Associated with a particular transformation are (a) a convolution kernel and (b) a function that maps to a final output value the maximum and minimum values measured at point (x, y) in the convolution output as the kernel rotates through 360 degrees . Frequently used kernels are narrow in one direction and broad in the other, typically with rectangular, triangular, or Gaussian profiles in the long direction. Simple but effective functional mappings include I(out)(x, y) = [Max(x, y) - Min(x, y)] and I(out)(x, y) = {1 -[Min(x, y)/Max(x, y)](m)}. Improved results are often obtained if successive rotating-kernel min-max transformation operations are performed in cascaded systems. Two binarization procedures based on the rotating-kernel min-max transformation can be used to extract straight-line features from noisy gray-scale images. The effects on the processed image of kernel type and size, mapping function, and binarization scheme are discussed. PMID- 20963116 TI - Multiple-image formation by Fresnel-Dirac sampling. AB - The theory of lensless formation of multiple images from a single object by Fresnel-Dirac sampling is reexamined. It is concluded that the multiple-image formation does not really occur in principle. However, reasonably good image arrays can be obtained if the sampling filter is properly designed. These image arrays appear when the reduced length Q satisfies the Montgomery zone-plate condition for self-imaging of a periodic grating. The explicit formula for the quasi multiple images is derived within the framework of the Fresnel diffraction. The results are to some extent different from those given previously in the literature. A simple interpretation of the results in terms of geometric optics confirms their acceptability. PMID- 20963117 TI - Fractional correlation. AB - Recently, optical interpretations of the fractional-Fourier-transform operator have been introduced. On the basis of this operator the fractional correlation operator is defined in two different ways that are both consistent with the definition of conventional correlation. Fractional correlation is not always a shift-invariant operation. This property leads to some new applications for fractional correlation as shift-variant image detection. A bulk-optics implementation of fractional correlation is suggested and demonstrated with computer simulations. PMID- 20963118 TI - Composite harmonic filters for scale-, projection-, and shift-invariant pattern recognition. AB - The Mellin radial harmonic filter and the logarithmic harmonic filter are useful for performing optical scale- and projection-invariant pattern recognition, respectively. To our knowledge, on the basis of the harmonic-function method, no one has been able to obtain more than one invariant property (in addition to the shift invariance) when using the matched-filter approach. A new method of combining the scale-, the projection-, and the shift-invariance properties is proposed, based on two decomposition stages of the input pattern. Computer simulations are presented as well as preliminary experimental results. PMID- 20963119 TI - Synthesis of analog apodizers with binary angular sectors. AB - We describe a new procedure for generating complex amplitude distributions along the optical axis of an optical processor by the use of binary masks in the form of binary angular sectors. This type of binary spatial filter acts as a gray level apodizer with rotational symmetry. Experimental verifications are included. PMID- 20963120 TI - Wavelength optimization of quantum-well modulators in smart pixels. AB - We extend our recent general discussion of electroabsorption and refraction in multiple-quantum-well modulators to determine the optimum modulator design for smart-pixel applications. In addition to the optimum operating wavelength shift, from that of the zero-voltage exciton, we determine the optimum number of quantum wells, and we calculate the reflectivity change and the contrast ratio obtainable. This analysis is undertaken for both simple detectors and modulators, meaning that they are antireflection coated, as well as for devices that include Fabry-Perot resonators. The optimization is performed on a figure of merit that is inversely proportional to the incident optical read energy required on a device to switch another, downstream device. We maximize the figure of merit to minimize the optical read energy. An interesting result is that there should be no significant improvement in our smart-pixel circuit figure of merit with the use of Fabry-Perot resonant modulators and detectors. Our results are, of course, material-system specific, but for the 850-nm AlGalAs/GaAs quantum-well system the optimum wavelength shift from the exciton location is approximately 6 nm. The general trends and approach are applicable to other material systems. PMID- 20963121 TI - Real-time image processing with a cat conjugator. AB - We demonstrate the real-time image-processing operations of edge enhancement, theta filtering, and pattern recognition with a self-pumped phase conjugator with an external erase beam to modify the index gratings formed inside the photorefractive BaTiO(3) crystal. PMID- 20963122 TI - Write compensation using the thermal transfer function in an optical disk. AB - The theoretical basis for a write-compensation scheme is developed with a simplified thermal transfer function in an optical disk. The thermal transfer function is analytically approximated to a first-order exponential filter similar to that of an integrating circuit. A write-compensation method is then given directly by the inverse function of the filter. A simplified form of the compensation is also derived, and this is verified by experiments. This method eliminates the thermal interference and shows how to form mark edges uniformly for an arbitrary optical disk. PMID- 20963123 TI - Photorefractive two-beam coupling optimal thresholding filter for additive signal dependent noise reduction. AB - Computer simulations of photorefractive thresholding filters for the reduction of artifact or dust noise demonstrate an increase in signal-to-noise ratio (SNR) of 70% to 95%, respectively, of that provided by the Wiener filter for inputs with a SNR of approximately 3. These simple, nearly optimal filters use a spectral thresholding profile that is proportional to the envelope of the noise spectrum. Alternative nonlinear filters with either 1/nu or constant thresholding profiles increase the SNR almost as much as the noise-envelope thresholding filter. PMID- 20963124 TI - Single-rail translation-invariant optical associative memory. AB - A single-rail optical memory is proposed. The associated memory is based on a double-correlator architecture coupled with an optoelectronic thresholding feedback module. The latter permits complete translation invariance of the neural network. The system requires only a single 35-mW He-Ne laser. The associative memory is recorded with the help of computer-generated holograms. The global iterative coding [Opt. Eng. 32, 2216 (1993)] technique provides good performance with high diffraction efficiency. PMID- 20963125 TI - Optical parallel-access shared memory system: analysis and experimental demonstration. AB - An optical implementation of a parallel-access shared memory uses a single photorefractive crystal and can realize the set of memory modules in a digital shared memory computer. This implementation uses two arrays of sources that are individually coherent but mutually incoherent from region to region across each array, and it permits incoherent/coherent double angular multiplexing of data in the crystal. A complete instruction set for its memory access consists of four operations, READ, WRITE, SELECTIVE ERASE, and REFRESH, which can be applied to any memory module independent of (and parallel with) instructions to the other memory modules. In addition, a memory module can execute a sequence of READ operations simultaneously with the execution of a WRITE operation to accommodate differences efficiently in optical recording and readout times common to optical volume storage media. An experimental shared memory system demonstrates two memory modules, each consisting of up to two 5-bit data blocks, implemented in a single Fe:LiNbO(3) crystal. The projected performance of the optical parallel access shared memory system is analyzed and compared with conventional page addressed volume holographic memories. PMID- 20963127 TI - Patents. AB - 5,150,956; 5,157,461; 5,187,757; 5,189,488; 5,245,407; 5,260,962; 5,272,717; 5,280,493; 5,283,795; 5,296,699; 5,298,748; 5,298,762; 5,304,805; 5,309,271; 5,311,019; 5,311,022; 5,315,125. PMID- 20963126 TI - Joint wavelet-transform correlator for image feature extraction. AB - We describe a joint wavelet-transform correlator in which the wavelet function is combined with the input image as the input joint image to realize the wavelet transform of the objective image. The Haar wavelet and the Roberts filter are chosen as the wavelet functions to extract the features of the objective image. The relationship of the Haar wavelet and the Roberts filter is analyzed mathematically based on admissible condition of the wavelet. Computer simulations are provided to verify the theory and to illustrate the performance of this correlator. PMID- 20963128 TI - Myocardial temperature distribution under cw Nd:YAG laser irradiation in in vitro and in vivo situations: theory and experiment. AB - Tissue samples ranging from 2 to 16 mm in thickness were irradiated at 1064 nm with energies ranging from 40 to 2400 J. Coagulation lesions of in vitro and in vivo experiments were subjected to temperature profiling and submitted for histology. Irreversible damage was calculated with the damage integral formalism, following the bioheat equation solved with Monte Carlo computer light distribution simulations. Numerical temperature rise and coagulation depth compared well with the in vitro results. The in vivo data required a change in the optical properties based on integrating sphere measurements for high irradiance to make the experimental and numerical data converge. The computer model has successfully solved several light-tissue interaction situations in which scattering dominates over absorption. PMID- 20963129 TI - Gauss-core resonator: a novel stable resonator with a large-diameter diffraction limited output beam. AB - A novel cavity design based on a stable resonator configuration is presented. The output coupler of the new stable resonator has a circular partial-reflection region in the center that is surrounded by an antireflection region. This resonator operates in a large-volume TEM(00) mode that is mainly determined by the partial-reflection region of the output coupler and is characterized by the use of an additional laser beam that is spread from the optical path in the cavity because of diffraction and is amplified by a laser medium. By combining part of a beam transmitted from the partial-reflection region with the amplified diffraction beam, a laser beam having a large diameter is obtained. A diffraction limited output beam with the M(2) factor of 1.3 is obtained, as predicted theoretically when the new stable resonator is applied to a high-power cw CO(2) laser. PMID- 20963130 TI - Digital divider circuit for a laser-beam-pointing stabilization system. AB - Adigital divider circuit is used in a feedback circuit that is designed to stabilize laser-beam pointing. PMID- 20963131 TI - Study of an injection-seeded supra-atmospheric CO(2) laser operated below emission threshold with a ring cavity. AB - The dynamics and tuning range of an injection-seeded supra-atmospheric CO(2) laser operated at a pressure of 10 atm with a ring cavity are studied theoretically and experimentally. When the losses of such a laser are sufficiently high, the short lifetime of the gain does not permit the buildup of intense pulses that start from spontaneous emission noise; the laser is then said to be operated below emission threshold. Under such circumstances, injection seeding with a few milliwatts of a single-mode signal permits nearly full extraction of the available power. The extraction efficiency is shown to depend in a sensitive manner on the frequencies of a cavity mode and of the injected signal. When these two frequencies are mismatched, a lower power is extracted, and two-mode emission takes place. The laser is shown to be tunable over 41 transition lines of the CO(2) spectrum. PMID- 20963132 TI - Mode and frequency control of compact CO(2) slab lasers through intracavity coherent imaging. AB - The modal properties of a compact, slab-waveguide CO(2) laser are presented. Laser operation without mode selection is observed to be in groups of well defined slab-waveguide modes that systematically change with mirror translation through a free spectral range and produce multiple homodyne beats. Single-mode operation, which is obtained through the addition of a wire-grid mode selector in combination with Talbot-effect imaging, is found to be stable over a significant range of resonator mirror tilt and optical cavity length translation. An output power of 65 W in a stable mode has been obtained from a compact laser head that is approximately 260 mm in overall length. PMID- 20963133 TI - Temporal variations in the spectral output of a xenon fluoride excimer laser. AB - The behavior of a xenon fluoride excimer laser's spectral output as a function of the gas fill's age has been measured, and significant variations have been found. The output was preferentially shifted from the 348-nm band into the 351-nm band. PMID- 20963134 TI - Perylene- and pyrromethene-doped xerogel for a pulsed laser. AB - Hydrophobic photostable dye molecules such as perylenes or pyrromethenes were trapped in xerogel matrices. Using these new materials as solid-state dye lasers, we have demonstrated efficient laser operation. Slope efficiencies of up to 30% were obtained in the millijoule output-energy range. Tunabilities of up to 60 nm were observed, and more than 150,000 pulses were emitted by the same spot of a given sample when the laser was pumped at millijoule energy levels. PMID- 20963135 TI - Dye-mixture laser tunable in three primary color regions with a linear variable filter. AB - The tuning characteristics of a Coumarine 460-Disodium Fluorescein-Rhodamine 640 dye-mixture laser in the blue, green, and yellow-orange regions are reported. A linear variable filter was inserted into the laser cavity as a tuning element. The tunable range was 439-485 nm in the blue region, 509-531 nm in the green region, and 592-601 nm in the yellow-orange region. Comparison of the characteristics of the one-wavelength tuning output with those of simultaneous broadband outputs in the three color regions showed that energy transfer was an important mechanism for the oscillations, especially in the longer-wavelength region, which was farthest away from a pumping wavelength. PMID- 20963136 TI - Tm:YVO(4) microchip laser. AB - When pumped with a 1-W laser diode, a Tm:YVO(4) microchip laser produced 150 mW of 1.92-um output in a near-diffraction-limited beam at room temperature. Using a Ti:Al(2)O(3) laser to pump the same device, we showed that reducing the temperature of the Tm:YVO(4) from 20 to -30 degrees C resulted in no measurable change in threshold and increased the slope efficiency by only 20%. PMID- 20963137 TI - Long-range tunable diode laser. AB - A novel, simple tuning mechanism for single-mode, pseudo-external-cavity diode lasers has been developed. The model calculations predict that the laser can be tuned continuously by as much as 300 GHz in the vicinity of the chosen frequency without locking it to an external cavity. Experimentally, the continuous tuning range is approximately 120 GHz at constant current and temperature for the 7-cm long pseudo-external cavity; this is several times more than previously reported. A turning wedge inside the laser cavity is used as the tuning element. The laser is based on a commercial laser diode chip, and a diffraction grating is used for feedback. The total tuning range depends on the laser diode type and can be up to 20 nm. PMID- 20963138 TI - Broadband, multiwavelength stimulated-emission source based on stimulated Kerr and Raman scattering in a liquid-core fiber system. AB - A novel broadband and multiwavelength stimulated-emission source that consists of a Kerr liquid-filled hollow-fiber system pumped with a monochromatic laser beam is described. The device operates by multiorder stimulated Raman scattering (SRS) and stimulated Kerr scattering (SKS) that result from the high local optical intensity and long gain length provided by the liquid-core hollow-fiber system. A number of transparent liquids have been investigated; CS(2) is identified as the medium that most efficiently generates SKS and SRS. The overall efficiency from the pump input to the coherent output of the system is measured as a function of the fiber parameters (internal diameter and length), inputcoupling focusing length, and pump conditions (pulse duration, spectral width, and wavelength). A number of other experimental results, such as optimized working conditions, output spectral structure, total spectral-covering range, pump-threshold requirements, and the maximum capacity for high pump operation are also presented and discussed. PMID- 20963139 TI - Determination of ion-exchanged channel waveguide profile parameters by mode-index measurements. AB - We report a method for characterizing ion-exchanged channel waveguides in terms of the diffusion depth, width, and surface-index change from mode-index measurements. The method is then used to study the effect of the diffusion time and the mask width on these parameters in K(+)-Na(+)-exchanged guides in BK7 glass. It is observed that the mask width affects the waveguide dimensions in ways not reported in earlier studies. Our results reveal that the diffusion depth depends on the mask opening and saturates with time to a maximum value for a given mask width. The lateral-diffusion rate and the side diffusion beneath the mask are independent of the mask width, which indicates that the lateral electric field associated with the metallic mask plays an important role in such diffusion. We discuss the implications of this behavior to modeling and fabricating integrated optical devices. PMID- 20963141 TI - Aerosol extinction and backscatter profiles by means of a multiwavelength Raman lidar: a new method without a priori assumptions. AB - The Raman wave-number shift for scattering at oxygen molecules is almost exactly 2/3 of the nitrogen Raman shift. This is used to build up a chain of three consecutive laser emission lines separated by 1/3 of the nitrogen Raman shift. It is shown that it is possible to determine aerosol extinction and backscatter coefficients without a priori assumptions from the received Rayleigh-Mie and Raman (oxygen and nitrogen) signals. PMID- 20963140 TI - Optical-activity measurements with bihelicoidal laser eigenstates. AB - A novel, doubly differential method for the measurement of optical activity that uses the so-called bihelicoidal eigenstates of a laser is demonstrated. An experimental realization is presented, and prospects are discussed. PMID- 20963142 TI - Remote sensing of trace gases in the midinfrared spectral region from a nadir view. AB - High-resolution IR remote-sensing measurements from space by means of a nadir viewing geometry are particularly suited to the detection of trace gases and yield high temporal and horizontal resolutions on a global scale. To identify the potential of such a technique, an extensive feasibility study has been performed. The column amount of some trace gases, namely H(2)O, CH(4), N(2)O, CO, and O(3), may be determined with accuracies of approximately 10%. In addition, some information on the vertical distribution of these species is also possible. Concerning CFC-12, an accuracy of 10%-20% may be expected. Furthermore, it is believed that column amounts can be derived with an accuracy of 20% for HNO(3), and 50% for species like NO(2), OCS, and CFC-11. PMID- 20963143 TI - Sensitivity analysis of Na narrowband wind-temperature lidar systems. AB - The performance and measurement accuracy of Na narrowband wind-temperature lidar systems are characterized. Error budgets are derived that include several effects not previously reported, such as power-dependent spectral characteristics in the frequency reference, magnetic-field-dependent oscillator line strengths (Hanle effect), saturation, and optical pumping. It is shown that the overall system uncertainty is dependent on the power, pulse temporal characteristics, and beam divergence of the laser transmitter. Results indicate that even systems with significant saturation can produce accurate measurements, which implies the prospect of continuous daytime wind and temperature measurements on semidiurnal and diurnal time periods. PMID- 20963144 TI - Simulation in the time domain for heterodyne coherent laser radar. AB - A feuillete model for assessment of the performance of heterodyne coherent laser radar (HCLR) under nonstationary atmospheric conditions such as wind shear and a fine layering of scattering properties is proposed. The model is an end-to-end signal simulation in the time domain at intermediate frequency from beam propagations to signal processing. The model takes into account the full transversedimension of the problem of laser-atmosphere interaction. The scatterers are grouped into slices, then an integration is performed over the slices that contribute to the HCLR signal. Two applications are presented: wind shear detection for 10-um HCLR and wind-vortex detection for 2-um HCLR. PMID- 20963145 TI - Treatment of the layer temperature-gradient problem in band-model emission codes. AB - An approximate method for rapid and reasonably accurate sublayer integration in band-model-based radiative transfer codes is described. The method is based on a five-parameter, second-order Pade approximation to the molecular equivalent width that is a function of a single variable, the molecular weak-line optical depth tau(m). Three of the parameters are determined by boundary conditions at tau(m) = 0 and tau(m) = infinity The other two parameters are obtained with an error minimization fit to the molecular equivalent width at two points along the curve of growth. This process can be applied sequentially to all adjacent pairs of points along the entire curve of growth to yield the total path radiance. Sample calculations are performed for representative curves of growth: exponential, Lorentz, and Doppler. It is shown that for atmospheric radiative flux and cooling rate calculations this approach will yield results to within approximately 0.2% of fully converged calculations. PMID- 20963146 TI - Maximum-likelihood criterion and single-molecule detection. AB - The maximum-likelihood criterion is shown to be a powerful method for analyzing fluorescence-detection data with small signal-to-noise ratios. A probability study of the maximum-likelihood criterion for a supposed single-molecule detection experiment is presented that takes into account the photokinetics of the molecule to be detected, its diffusion, and the laser-beam geometry. Furthermore, the efficiency of time-integrated and time-correlated single-photon counting methods are studied and compared. PMID- 20963147 TI - Degenerate four-wave mixing from laser-populated excited states. AB - Degenerate four-wave mixing (DFWM) from laser-populated excited states, i.e., two step DFWM (2S-DFWM), has been performed to investigate the possibility of increasing signal quality (i.e., strength or signal-to-noise ratio) when species with low transition probabilities or far-UV transitions are to be detected or when large beam areas are used. Gold atoms, aspirated into an air-acetylene flame, were chosen as a suitable species for this investigation. The 2S-DFWM signal strength was found to be comparable to the ordinary (one-step) DFWM signals for moderately high UV-light intensities but substantially better for low UV-light intensities. This finding implies that DFWM detection of species with lower transition probabilities in the first step as compared with gold (<10(-8) s(-1)) can benefit from the 2S-DFWM technique when moderate or low UV-light intensities are available. Additional possible advantages of using 2S-DFWM are also discussed. PMID- 20963148 TI - Three-dimensional flow visualization with picosecond Mie scattering and streak camera detection. AB - Two-dimensional images of Mie scattered light from a water aerosol have been recorded by a streak camera with a time resolution of a few picoseconds. The laser pulse, which is 35 ps long, is repeatedly reflected and refocused in the probe volume. On the output phosphor screen of the streak camera, the images of the scattering appear as adjacent, separated pictures on the temporal axis of the streak camera. Because the pictures obtained in this way are separated in time by less than 3 ns, which is much shorter than the typical time scales of the turbulent gas flow, and because they are separated in space by fixed intervals, the resulting images can be used to compose a three-dimensional picture of the aerosol distribution. PMID- 20963149 TI - Extinction efficiency in the infrared (2-18 um) of laboratory ice clouds: observations of scattering minima in the Christiansen bands of ice. AB - Extinction measurements with a laser diode (0.685 um) and a Fourier transform infrared spectrometer (2-18 um) were performed on laboratory ice clouds (5 um <= D <= 70 um) grown at a variety of temperatures, and thus at a variety of crystal habits and average projected crystal area. Ice clouds were grown by nucleation of a supercooled water droplet cloud with a rod cooled with liquid nitrogen. The ice crystals observed were mainly plates and dendrites at the coldest temperatures (~ 15 degrees C) and were mainly columns and needles at warmer temperatures (~-5 degrees C). The crystals were imaged with both a novel microscope equipped with a video camera and a heated glass slide and a continuously running Formvar replicator. The IR spectral optical-depth measurements reveal a narrow (0.5-um width) extinction minimum at 2.84 um and a wider (3-um-width) minimum at 10.5 um. These partial windows are associated with wavelengths where the real part of the index of refraction for bulk ice has a relative minimum so that extinction is primarily due to absorption rather than scattering (i.e., the Christiansen effect). Bulk ice has absorption maxima near the window wavelengths. IR extinction efficiency has a noticeable wavelength dependence on the average projected crystal area and therefore on the temperaturedependent crystal properties. The average-size parameters in the visible for different temperatures ranged from 64 to 128, and in the IR they ranged from 2.5 to 44. The extinction efficiency and the single-scatter albedo for ice spheres as computed from Mie scattering also show evidence of the Christiansen effect. PMID- 20963150 TI - Nonstationary scattering of electromagnetic pulses by spherical particles. AB - We have studied time variances of the shape of an electromagnetic pulse scattered by a spherical particle. General formulas are derived for a pulse with an arbitrary envelope, for momentary values of scattered-light fields and light intensity, and for efficiencies of extinction and scattering. It is possible, by the use of these formulas, to obtain by routine integration the sensitivity reaction of a receiver with any time dependence. The formulas are illustrated with examples of scattering of a Gaussian pulse with a carrier wave lambda(0) = 0.6328 um and of multisized water drops. Pulses of different durations are studied. However, only those pulses that have all significant values of the Fourier density in the domain of positive frequencies omega are considered. PMID- 20963151 TI - Improved Gaussian beam-scattering algorithm. AB - The localized model of the beam-shape coefficients for Gaussian beam-scattering theory by a spherical particle provides a great simplification in the numerical implementation of the theory. We derive an alternative form for the localized coefficients that is more convenient for computer computations and that provides physical insight into the details of the scattering process. We construct a FORTRAN program for Gaussian beam scattering with the localized model and compare its computer run time on a personal computer with that of a traditional Mie scattering program and with three other published methods for computing Gaussian beam scattering. We show that the analytical form of the beam-shape coefficients makes evident the fact that the excitation rate of morphology-dependent resonances is greatly enhanced for far off-axis incidence of the Gaussian beam. PMID- 20963152 TI - Application of dynamic light scattering to the study of small marine particles: errata. PMID- 20963153 TI - Multilayer optics provides laser-plasma-coupling insight. AB - The Herpin theorem permits the reflectance of an arbitrary medium to be reproduced with a substrate of one complex refractive index overlaid with a coating film of a second complex refractive index and an appropriate thickness. The reflectances of a variety of laser-plasma-coupling experiments can be matched with a simple and physically meaningful procedure for choosing the fitting parameters. For short-pulse experiments, s-light coupling is dominated by substrate interactions at electron densities above critical and p-light coupling is dominated by resonance at the critical density. The weak dependence of resonance absorption on damping is the result of the harmonic-oscillator resonance form. As the plasma scale length becomes vanishingly small, the reflectance is that of the Fresnel equations, but surprisingly small plasma scale lengths have dramatic effects on the p-light reflectance. Film-substrate and WKB models predict similar resonance absorption, where both models are valid approximations and both should agree with multilayer and Helmholtz wave-optics calculations. For plasma scale lengths well below a wavelength, the film substrate and the vacuum-heating models are closely related. PMID- 20963155 TI - Patents. AB - 5,278,691; 5,280,370; 5,319,188; 5,319,978; 5,326,956; 5,326,962; 5,329,397; 5,329,399. PMID- 20963154 TI - Excimer-laser surface treatment of metals for improved adhesion. AB - Excimer-laser-induced ablation has been used to produce surface structuring of various metals. Such structuring contributed to a 5-15% enhancement of the bonding strength of these metals when a commercial adhesive was used. PMID- 20963156 TI - Developed profile of holographically exposed photoresist gratings. AB - A simulation of the profile of holographically recorded structures in photoresists is performed. In addition to its simplicity this simulation can be used to take into account the effects that arise from exposure, photosensitization, development, and resolution of positive photoresists. We analyzed the effects of isotropy of wet development, nonlinearity of the photoresist response curve, background light, and standing waves produced by reflection at the film-substrate interface by using this simulation, and the results agree with the experimentally recorded profiles. PMID- 20963157 TI - High-efficiency input coupling into optical waveguides using gratings with double surface corrugation. AB - Waveguide grating couplers that have surface corrugation on both boundaries of the waveguide were fabricated by the deposition of waveguide material at high vacuum pressures onto a surface-relief grating etched into the substrate. A lateral shift between the two gratings along the direction of the common grating vector was created during the waveguide deposition when the substrate normal was tilted with respect to the direction of material deposition. A series of waveguide thicknesses having an identical angle of deposition were examined to observe the effect of the waveguide thickness, and corresponding lateral shift, on the branching ratio and input-coupling efficiency. Branching ratios of above 98% and input-coupling efficiencies near the theoretical limit for an incident Gaussian beam were obtained. PMID- 20963158 TI - Optical diffuse reflectance accessory for measurements of skin tissue by near infrared spectroscopy. AB - An optimized accessory for measuring the diffuse reflectance spectra of human skin tissue in the near-infrared spectral range is presented. The device includes an on-axis ellipsoidal collecting mirror with efficient illumination optics for small sampling areas of bulky body specimens. The optical design is supported by the results of a Monte Carlo simulation study of the reflectance characteristics of skin tissue. Because the results evolved from efforts to measure blood glucose noninvasively, the main emphasis is placed on the long-wavelength near-infrared range where sufficient penetration depth for radiation into tissue is still available. The accessory is applied for in vivo diffuse reflectance measurements. PMID- 20963159 TI - Dynamic fiber specklegram sensing. AB - We introduce a concept of dynamic sensing that uses fiber speckle fields. By autonomously updating the fiber speckle patterns (i.e., using a moving reference to perform frame-to-frame comparison) on an electronically addressable spatial light modulator, we can exploit the dynamic fiber status. In other words, by joint transforming the rapidly changing speckle patterns from a sensing fiber, we can determine the dynamic aspects of the fiber status. For demonstration, dynamic displacement sensing is illustrated in which we have observed that the rate change and the trend of the fiber perturbation can indeed be detected. We note that the dynamic sensing technique can be applied to a variety of sensing parameters, e.g., strain, stress, temperature, and possibly seismic monitoring. PMID- 20963160 TI - Fidelity of POSTSCRIPT-generated masks for diffractive optics fabrication. AB - A page description language such as POSTSCRIPT provides inexpensive and rapid output to high-resolution graphics engines for generating binary masks. However, the limitations of this technology have not been considered beyond a statement of the resolution of the output device. Measurements of three high-resolution laser image setters to quantify the limitations inherent to this type of mask fabrication show that the spot size and spot placement affect the performance of the final element. The expression of the graphics figure within the illustration program used to print the masks must also be considered. Strategies for compensating for print errors are described. PMID- 20963161 TI - Infrared emission from selected areas in ion-beam-irradiated diamond. AB - The infrared emission properties of an electrically heated single resistive element produced by ion implantation of diamond is reported. It is found that good contrast can be obtained between the implanted and unimplanted regions of the diamond mainly because of the increased emissivity following implantation. The infrared output is stronger if the diamond is viewed with the implanted surface facing away from the detector. The possible utilization of diamond-based pixels in infrared scene generation is discussed. PMID- 20963162 TI - Physically reasonable analytic expression for the single-scattering phase function: errata. PMID- 20963163 TI - Method for estimating numerical adequacy of derivative increments of variables in the damped least-squares automatic lens design problem. AB - It is shown that an analytical approach for setting an adequate initial value of a damping factor in the damped least-squares optimization process can also be used to estimate whether the given increments of variables are adequate together with some numerical experiments. It is clarified that the value of a damping factor should almost equal the median of a series of eigenvalues of a squared Jacobian matrix, which is evaluated by use of given increments. PMID- 20963164 TI - Extreme-ultraviolet polarization and filtering with gold transmission gratings. AB - The polarization and transmission characteristics of freestanding gold transmission gratings, with 200-nm periods, for extreme-ultraviolet (EUV) radiation (1 < 200 nm) have been measured. We find that EUV transmission through the gratings is dominated by the waveguide characteristics of the gratings and that polarization efficiencies of 90% for wavelengths of 121.6 nm are achievable. Both the EUV polarization and transmission properties are in good agreement with a complete vector, numerical solution of Maxwell's equations. The fraction of open area to total area of the grating has been measured using a 10-keV proton beam and was found to be in good agreement with the microscopic slit and wire dimensions that were obtained by scanning electron microscopy. The use of these gratings for particle measurements in the presence of intense EUV radiation is briefly discussed. PMID- 20963165 TI - Domain effects in Faraday effect sensors based on iron garnets. AB - Domain-induced diffraction effects produced by two iron garnet thick films and two bulk crystals are compared. The thick films, characterized by a serpentine magnetic domain structure, produced nonlinear response functions; this is in qualitative agreement with a one-dimensional diffraction model. Bulk iron garnet crystals, which exhibited a complex three-dimensional domain structure, produced qualitatively similar effects that diminished with increasing crystal length. Differential signal processing resulted in a linear signal for the thick films and a primarily sinusoidal response for the bulk crystals. PMID- 20963166 TI - Aberration-corrected concave grating for the mid-infrared spectrometer aboard the Infrared Telescope in Space. AB - A mechanically ruled aberration-corrected concave grating was developed for use in the low-resolution mid-infrared spectrometer aboard the cryogenically cooled Infrared Telescope in Space. The design and the performance testing of the grating are reported. The spectrometer requires a wide spectral range (4.5-11.7 um) and a wide field of view (8 * 8 arcmin) with a low wavelength resolution (Deltalambda <= 0.3 um). The aberration-corrected concave grating provides a flat focal plane with a small aberration in the spatial direction compared with those caused by the finite size of the entrance slit. It also permits a simple design for the spectrometer, which is advantageous for applications in space cryogenic instruments. The measurements of the wavelength resolution and the spatial resolution are shown to be in good agreement with the predicted performance. The diffraction efficiency of the grating is more than 80% at the blaze wavelength (6 um) and fairly high (>30%) over the entire wavelength range in question. The grating produces polarization of less than 10% for lambda < 6.4 um and of 10-20% for 6.7 um 18 years old) with diabetes living in the border region between the United States of America and Mexico, and to explore variation in those variables between all adults on the Mexican side of the border ("Mexicans") and three groups on the U.S. side of the border ("all U.S. adults," "U.S.-born Hispanics," and "Mexican immigrants"). METHODS: Using data from Phase I (February 2001-October 2002) of the U.S.-Mexico Border Diabetes Prevention and Control Project, a prevalence study of type 2 diabetes and its risk factors, age-adjusted prevalence of hypertension-related variables was calculated for the sample (n = 682) and differences between the border groups were examined through logistic regression. RESULTS: Less than one-third of the sample had controlled blood pressure (< 130/80 mm Hg), almost half had hypertension (>=140/90 mm Hg), and hypertension awareness and treatment were inadequate. After adjusting for demographics, body mass index, and access to health care, there were no differences in blood pressure control, hypertension, hypertension awareness, or treatment between Mexicans and both U.S. adults and Mexican immigrants. However, compared to Mexicans and Mexican immigrants, U.S.-born Hispanics, particularly younger individuals, had the lowest rates of blood pressure control (17.3%) and the highest rates of coexisting hypertension (54.8%). Compared to Mexicans, U.S.-born Hispanics had lower odds of controlled blood pressure (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.09-0.95) and greater odds of hypertension (OR 3.75, 95% CI 1.51-9.29) and hypertension awareness (OR 6.19, 95% CI 1.46-26.15). CONCLUSION: Co-occurrence of diabetes and hypertension is a major public health problem among U.S.-Mexico border residents. The low rate of blood pressure control among various border groups, especially younger U.S.-born Hispanics, suggests that initiatives should aggressively target blood pressure control. PMID- 20963264 TI - Prevalence of type 2 diabetes and impaired fasting glucose: cross-sectional study of multiethnic adult population at the United States-Mexico border. AB - OBJECTIVE: To estimate prevalence of type 2 diabetes (diabetes) and impaired fasting glucose (IFG) in the border region between the United States of America and Mexico, by ethnic origin and country of residence; identify risk factors associated with both conditions; and explore the extent to which these factors account for cross-border or ethnic disparities in prevalence. METHODS: From April 2001 to November 2002, Phase I of the U.S.-Mexico Border Diabetes Prevention and Control Project, a prevalence study of diabetes and its risk factors, was conducted at the U.S.-Mexico border using multistage cluster sampling. A questionnaire was administered on diabetes (self-reported) and lifestyle and a physical examination and blood sample were obtained. A total of 4,027 adults participated in the study: 2,120 Hispanics from the Mexican side of the border and 1,437 Hispanics and 470 non-Hispanics (of whom 385 were classified as "white") from the U.S. side of the border. RESULTS: The age-adjusted prevalence of self-reported and unrecognized diabetes in Hispanics was 15.4% (16.6% on the Mexican side of the border and 14.7% on the U.S. side). The age-adjusted prevalence of IFG was similar on both sides of the border (14.1% on the Mexican side and 13.6% on the U.S. side). CONCLUSIONS: Established risk factors for diabetes (e.g., age, obesity, and family history) were relevant and there was an inverse relationship between diabetes and education and socioeconomic level. While diabetes prevalence is high on both sides of the U.S.-Mexico border, one third of the cases remain undiagnosed, suggesting a need for development and implementation of a public health program for prevention, diagnosis, and control of diabetes in the region. PMID- 20963265 TI - Access to health care and undiagnosed diabetes along the United States-Mexico border. AB - OBJECTIVE: To examine the relationship between access to health care and undiagnosed diabetes among the high-risk, vulnerable population in the border region between the United States of America and Mexico. METHODS: Using survey and fasting plasma glucose data from Phase I of the U.S.-Mexico Border Diabetes Prevention and Control Project (February 2001 to October 2002), this epidemiological study identified 178 adults 18-64 years old with undiagnosed diabetes, 326 with diagnosed diabetes, and 2 966 without diabetes. Access to health care among that sample (n = 3,470), was assessed by type of health insurance coverage (including "none"), number of health care visits over the past year, routine pattern of health care utilization, and country of residence. RESULTS: People with diabetes who had no insurance and no place to go for routine health care were more likely to be undiagnosed than those with insurance and a place for routine health care (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.0-6.6, and OR 4.5, 95% CI 1.4-14.1, respectively). When stratified by country, the survey data showed that on the U.S. side of the border there were more people with undiagnosed diabetes if they were 1) uninsured versus the insured (28.9%, 95% CI 11.5%-46.3%, versus 9.1%, 95% CI 1.5%-16.7%, respectively) and if they 2) had made no visits or 1-3 visits to a health care facility in the past year versus had made >= 4 visits (40.8%, 95% CI 19.6%-62.0%, and 23.4%, 95% CI 9.9% 36.9%, respectively, versus 2.4%, 95% CI -0.9%-5.7%) (all, P < 0.05). No similar pattern was found in Mexico. CONCLUSIONS: Limited access to health care- especially not having health insurance and/or not having a place to receive routine health services--was significantly associated with undiagnosed diabetes in the U.S.-Mexico border region. PMID- 20963266 TI - Acculturation and healthy lifestyle habits among Hispanics in United States Mexico border communities. AB - OBJECTIVE: To explore the relationship between acculturation and healthy lifestyle habits in the largely Hispanic populations living in underserved communities in the United States of America along the U.S.-Mexico border. METHODS: A cross-sectional study was conducted from April 2006 to June 2008 using survey data from the Alliance for a Healthy Border, a program designed to reduce health disparities in the U.S.-Mexico border region by funding nutrition and physical activity education programs at 12 federally qualified community health centers in Arizona, California, New Mexico, and Texas. The survey included questions on acculturation, diet, exercise, and demographic factors and was completed by 2,381 Alliance program participants, of whom 95.3% were Hispanic and 45.4% were under the U.S. poverty level for 2007. Chi-square (chi2) and Student's t tests were used for bivariate comparisons between acculturation and dietary and physical activity measures. Linear regression and binary logistic regression were used to control for factors associated with nutrition and exercise. RESULTS: Based on univariate tests and confirmed by regression analysis controlling for sociodemographic and health variables, less acculturated survey respondents reported a significantly higher frequency of fruit and vegetable consumption and healthier dietary habits than those who were more acculturated. Adjusted binary logistic regression confirmed that individuals with low language acculturation were less likely to engage in physical activity than those with moderate to high acculturation (odds ratio 0.75, 95% confidence interval 0.59-0.95). CONCLUSIONS: Findings confirmed an association between acculturation and healthy lifestyle habits and supported the hypothesis that acculturation in border community populations tends to decrease the practice of some healthy dietary habits while increasing exposure to and awareness of the importance of other healthy behaviors. PMID- 20963267 TI - Disparities in undiagnosed diabetes among United States-Mexico border populations. AB - OBJECTIVE: To compare the prevalence of undiagnosed diabetes among populations with diabetes living on the United States (U.S.)-Mexico border, examine explanations for differences between groups, and investigate differences in metabolic outcomes by diagnosis status. METHODS: Data come from the U.S.-Mexico Border Diabetes Prevention and Control Project survey (2001-2002), which used a stratified, multistage design. The sample included 603 adults (18 years or older) with diabetes. Undiagnosed diabetes was defined as a fasting plasma glucose (FPG) value of >= 126 mg/dL and no report of diagnosis. Logistic regression was used to compare the odds of being undiagnosed among border populations with diabetes. Metabolic outcomes included FPG, glycosylated hemoglobin, and mean arterial blood pressure. RESULTS: One in four adults with diabetes (25.9%) living on the U.S. Mexico border was undiagnosed. Mexicans (43.8%) and Mexican immigrants (39.0%) with diabetes were significantly more likely to be undiagnosed than were U.S. born Hispanics (15.0%; P < 0.05 for either comparison) or non-Hispanic whites (6.6%; P < 0.001 for either comparison). Mexicans were more likely to be undiagnosed than were all U.S. adults (14.7%; P < 0.001) with diabetes. Significant differences in the likelihood of being undiagnosed remained between all groups with diabetes after adjustment for sociodemographic and healthcare related covariates, with the exception of that between Mexicans and U.S.-born Hispanics. Worse metabolic control and potentially greater benefits of diagnosis for control were observed for Mexicans in particular compared with U.S. groups with undiagnosed diabetes. CONCLUSIONS: Efforts to improve diabetes diagnosis should concentrate on Mexican and Mexican immigrant populations on the U.S. Mexico border. PMID- 20963268 TI - Quality of diabetes care: a cross-sectional study of adults of Hispanic origin across and along the United States-Mexico border. AB - OBJECTIVE: To assess and monitor the quality of care provided to Hispanics diagnosed with diabetes living in the border region between the United States of America and Mexico. METHODS: From April 2001 to November 2002, Phase I of the U.S.-Mexico Border Diabetes Prevention and Control Project, a prevalence study of type 2 diabetes and its risk factors, was conducted along the U.S.-Mexico border using two-stage cluster sampling of towns and households within towns. A questionnaire was administered on diabetes (self-reported) and lifestyle and a physical examination and blood sample were obtained. Of the 4 027 study participants, 521 (13.0%) reported receiving a pre-study diagnosis of diabetes. Of those, 466 were of Hispanic origin (226 on the Mexican side of the border and 240 on the U.S. side). RESULTS: Results indicated 42.1% of Hispanics on the U.S. side of the border (95% confidence interval [CI] 35.8%-48.6%) and 37.6% of Hispanics on the Mexican side (95% CI 31.3%-44.3%) had controlled diabetes (defined as glycosylated hemoglobin A1c < 7.0 %), and only one (on the Mexican side of the border) received optimal diabetes care, defined according to international criteria for systolic blood pressure and body mass index as well as health provider provision of yearly examinations of foot and eyes as preventive care measures for early detection of diabetes complications. CONCLUSIONS: Adult Hispanics diagnosed with diabetes and living on the U.S.-Mexico border region are not receiving adequate diabetes-related care, and health care professionals are not following international recommendations for providing that care. To improve diabetes control in the region, health care providers must become more aware of the effect of education and culture on diabetes self-care as well as the provision of preventative measures by health care professionals. PMID- 20963269 TI - Ethnic and health correlates of diabetes-related amputations at the Texas-Mexico border. AB - OBJECTIVE: To examine the association between diabetes-related lower-extremity amputation (LEA) and ethnicity, age, source of payment, geographic location, diabetes severity, and health condition in adults with diabetes mellitus type 2 living in border and non-border counties in Texas, United States of America, and to assess intra-border region geographic differences in post-LEA treatment. METHODS: This correlational study was based on secondary data from the 2003 Texas Inpatient Hospital Discharge Data. The sample consisted of individuals 45 years of age and older with type 2 diabetes who had undergone a nontraumatic LEA (n = 5,865). Descriptive statistics and logistic regression analyses were applied. RESULTS: The following characteristics were predictors of LEA: being Hispanic or African American, male, >= 55 years old, and a Medicare or Medicaid user, and living in a border county. Persons with moderate diabetes and those who suffered from cardiovascular disease or stroke also had higher odds of undergoing an LEA. Post-LEA occupational therapy was significantly less prevalent among border residents (9.5%) than non-border residents (15.3%) (P < 0.001). CONCLUSION: Understanding the factors that influence diabetes-related LEA may lead to early detection and effective treatment of this disabling consequence of diabetes along the U.S.-Mexico border. PMID- 20963270 TI - Smoking behavior among Hispanic adults with diabetes on the United States-Mexico border: a public health opportunity. AB - OBJECTIVE: To examine the prevalence of smoking behaviors among adults with diabetes on the United States-Mexico border, to compare these behaviors in U.S. Hispanics and Mexicans with diabetes, and to identify explanations for group differences. METHODS: Data came from the U.S.-Mexico Border Diabetes Prevention and Control Project survey (2001-2002), a stratified, multistage sample representative of the border population. The analytic sample included adults from all racial and ethnic backgrounds with diabetes (n = 665), including 333 Mexicans and 268 U.S. Hispanics. Smoking behaviors were based on self-reports. Age- and gender-specific prevalence of smoking behavior was estimated and logistic regression was used for mediation analysis of group differences. RESULTS: One in five adults with diabetes (20.1%) in the region was a current smoker. Prevalence was higher among Mexicans (26.2%) than U.S. Hispanics (10.1%, P = 0.003); differences were not explained by sociodemographic or healthcare-related characteristics (odds ratio [OR] 3.86, 95% confidence interval [CI] 1.50-9.91, P = 0.004). Younger Mexicans with diabetes (< 55 years) were four times more likely to smoke than younger U.S. Hispanics (32.1% versus 8.1%, P < 0.001) and Mexican men with diabetes were more than twice as likely to smoke as U.S. Hispanic men (38.9% versus 15.8%, P = 0.003). Among adults with diabetes with a smoking history, 52.5% were former smokers; U.S. Hispanics were more likely to be former smokers than Mexicans with diabetes (62.6% versus 27.5%, P = 0.001). A marginally significant difference remained after adjusting for potential mediators (OR 0.42, 95% CI 0.17-1.08, P = 0.074). CONCLUSIONS: Smoking interventions should focus on Mexicans with diabetes in the border region, especially younger adults and men. Identifying sources of differences in smoking behaviors among border groups with diabetes may further inform intervention. PMID- 20963271 TI - Support for disease management, depression, self-care, and clinical indicators among Hispanics with type 2 diabetes in San Diego County, United States of America. AB - This study used a social-ecological framework to examine predictors of depression, diabetes self-management, and clinical indicators of health risk among Hispanics with type 2 diabetes residing in the United States (U.S.)-Mexico border region in San Diego County, California, United States of America. Important links were observed between greater social-environmental support for disease management and less depression, better diabetes self-management, and lower body mass index and serum triglyceride concentrations. Less depressive symptomatology was also related to lower hemoglobin A1c levels. Findings suggest that programs aiming to improve diabetes self-management and health outcomes in Hispanics with type 2 diabetes should consider multilevel, social, and environmental influences on health, behavior, and emotional well-being. PMID- 20963272 TI - The impact of sociodemographic conditions on quality of life among adolescents in a Brazilian birth cohort: a longitudinal study. AB - OBJECTIVE: To examine associations between certain aspects of self-reported Quality of Life (QoL) in early adolescence, and gender, skin color, maternal education at birth, and changes in socioeconomic position (SEP) occurring from 0 11 years of age. METHODS: A longitudinal study of a birth cohort composed of 5 249 individuals born in 1993 in Pelotas, Brazil, who were followed periodically from birth to age 11. Socioeconomic variables were collected at birth in 1993, and again, in 2004. The following eight variables were analyzed: relationship with mother, relationship with father, family conflicts, physical punishment by parents, family relationship problems, discrimination, academic failure, and fear of neighborhood of residence. Adjustments were made using a hierarchical model. RESULTS: Skin color was related to all the variables (more so for nonwhites than for whites), except in family conflicts. Physical punishment and academic failure were more frequent in males. Discrimination and fear of neighborhood were more prevalent in females. Maternal education at birth was inversely associated, especially with failing/repeating a grade in school(19.5 times more frequent in the lower maternal education group than in the highest). A similar pattern was found with the SEP change: worse QoL in the group that was always poor (at birth and at 11 years of age) than in the group that was never poor. Fear of neighborhood was not related to maternal education or SEP change. CONCLUSIONS: Gender, skin color, maternal education, and SEP change were related to various measured aspects of QoL. These results should be considered in policymaking that seeks to minimize inequities at birth, across the life-course, and for future generations. PMID- 20963273 TI - Adding the Standard Days Method(r) to the contraceptive method mix in a high prevalence setting in Peru. AB - OBJECTIVE: To determine what contribution the Standard Days Method(r) (SDM) makes to the contraceptive mix offered by regular health services in areas of Peru where contraceptive prevalence rates (CPR) are already high. METHODS: SDM was added to the family planning methods offered by the Ministry of Health in two provinces in Peru in September 2002. Retrospective interviews were conducted in March-June 2004 with 1 200 women who had chosen SDM as their contraceptive method and had used it for 2-20 months. Data were also obtained from the databases of the participating health services. The evaluation covered SDM demand, whether or not clients were switching to SDM from other modern methods, and SDM continuation and effectiveness. RESULTS: Demand for SDM stabilized at 6% of all new family planning users. Most users had not been using any reliable contraception at the time they started using SDM. About 89% of those who began using SDM at least 6 months before the interview were still using it at 6 months. The 12-month typical use pregnancy rate was estimated to be around 10.0 per 100 women years. CONCLUSIONS: Adding SDM to a program's existing contraceptive method mix can increase coverage even in an already high-CPR setting. Most women who choose SDM do not switch from any other modern family planning method. Continuation compares well with other modern user-directed methods. SDM effectiveness, when offered in regular service delivery circumstances, compares well to efficacy trial findings. PMID- 20963274 TI - [Oral health in 12 year-old students from public and private schools in the city of Goiania, Brazil]. AB - OBJECTIVE: To compare 12-year-old students from public and private schools in the city of Goiania, Brazil, in terms of the prevalence of caries, periodontal conditions, dentofacial anomalies, and fluorosis. METHODS: In 2003, the 2002-2003 Oral Health Conditions in the Brazilian Population project (SB Brasil) was expanded to Goiania as a cross-sectional study, as described in the present article. The sample included 1 947 students from urban schools: 1 790 (91.9%) attended public schools and 157 (8.1%) attended private schools. Data on the following oral conditions were collected through clinical examination: dental caries (decayed, missing, or filled teeth index, DMFT), periodontal condition (Community Periodontal Index, CPI), dentofacial anomaly (Dental Aesthetics Index, DAI), and dental fluorosis (Dean index). The groups were compared using the chi square and Mann-Whitney U tests. RESULTS: There were differences between the public and private schools for all the variables. DMFT, CPI, and DAI indexes were higher in children from public schools (P < 0.05). Fluorosis was more prevalent in students from private schools (P < 0.05). CONCLUSIONS: The type of school was associated with the oral health condition of the children in this sample. Investments in actions and services to mitigate this inequality and its effects should be made as part of the policies to promote oral health. PMID- 20963275 TI - [Cost-effectiveness of universal pneumococcal vaccination in Uruguay]. AB - OBJECTIVE: Evaluate the cost-effectiveness ratio of the program for universal vaccination with heptavalent pneumococcal conjugate vaccine (PCV7) in children under 5 years of age in Uruguay. METHODS: A Markov model was developed that simulated a cohort of 48 000 children born in 2007 and their progress to age 76. The baseline case used a regimen of three doses with estimated protection for five years. The presumption of vaccine efficacy and effectiveness was based on studies conducted in the United States with adjustment for serotype prevalence incidence in Uruguay. The results were expressed as the incremental cost per life year gained (LYG) and quality-adjusted life year (QALY) [gained]. RESULTS: For the baseline case, the incremental cost was US $7334.60 for each LYG and US $4655.80 for each QALY. Eight deaths and 4 882 cases of otitis, 56 cases of bacteremia-sepsis, 429 cases of pneumonia, and 7 cases of meningitis were prevented. The model shows sensitivity to variations in vaccine cost, efficacy, and pneumonia-related mortality. CONCLUSIONS: The universal vaccination program with PCV7 in Uruguay is highly cost-effective. Therefore, it is recommended for other countries with burden of pneumococcal disease and serotype coverage similar to those of Uruguay. PMID- 20963276 TI - [Magnitude of mortality from cervical cancer in the Brazilian Northeast and socioeconomic factors]. AB - OBJECTIVE: To analyze the time trend of cervical cancer mortality based on adjusted or unadjusted mortality data and to investigate the association between these data and socioeconomic indicators in women aged 20 years or older in the Brazilian Northeast (in capitals and non-capital cities) during the period from 1996 to 2005. METHODS: All deaths from cervical cancer recorded in the Brazilian Health Ministry's Mortality Data System (SIM) were included in the study. Also included were the cervical cancer deaths identified after the adjustment process. Simple linear regression was used to analyze the time trends for mortality and their correlations (Pearson) with selected socioeconomic indicators. RESULTS: The highest mortality coefficients with unadjusted data were observed in capitals and the lowest were observed in non-capital cities. Conversely, the highest mortality coefficients with adjusted data were observed in non-capital cities. Similarly, the lowest unadjusted mortality rates were observed in the states with the most poverty, illiteracy, fertility, and child mortality, whereas the highest unadjusted mortality rates were observed in the regions with the best social indicators. Adjusted mortality rates showed a negative association with the indicators describing better living conditions, and a positive association with the indicators describing worse living conditions. CONCLUSIONS: The use of unadjusted mortality data may lead to underestimation of cervical cancer rates and compromise the interpretations of comparative analyses of the magnitude, distribution, and factors associated with this disease. The magnitude of cervical cancer should be reassessed at least in the Brazilian Northeast. However, the findings show that positive results have been obtained with early detection efforts in Brazil. PMID- 20963277 TI - Implementation of a standardized HIV patient monitoring system in Guyana. AB - OBJECTIVE: To describe the process used to implement a comprehensive, standardized, and reliable national system for data collection for HIV care and treatment in Guyana; to provide examples of the program-level data resulting from implementation; and to highlight the monitoring benefits for national programs. METHODS: In 2007, Guyana's Ministry of Health and other key stakeholders adapted the World Health Organization's generic HIV care and antiretroviral therapy (ART) patient monitoring guidelines to fit the Guyana context, which included modifying the patient chart, patient registers, and cross-sectional and cohort reports. Following initial training and feedback from clinical staff, a national patient monitoring system (PMS) was finalized, piloted, and implemented at all care and treatment sites. Thereafter, sites received monthly supportive supervisory visits to review data collection and validate reports. RESULTS: Implementation of the PMS enabled analysis of cohort data for patients on ART. After 12 months, 79% of a combined national cohort of all 50 patients who started ART in June 2007 were alive and on first-line ART regimens. After six years, 58% of the first (April 2002) cohort of ART patients in the country were alive and on ART, with only two (8%) patients on second-line regimens. CONCLUSIONS: Implementation of a national PMS for standardized data collection and reporting across multiple clinical sites ultimately provided important and reliable information on utilization of services, patient outcomes, and survival rates on treatment. These data are used at the national level to monitor the efficacy of the HIV care and treatment program. Successful implementation requires early inclusion of all committed stakeholders and a dedicated human resource team to ensure sustainability of the system. PMID- 20963278 TI - [Environmental sanitation and mortality associated with waterborne diseases in children under 5 years of age in Brazil]. AB - OBJECTIVE: Determine and evaluate the relationship between the variables for water conditions, environmental sanitation, and mortality in children under 5 years of age associated with a group of waterborne diseases. METHODS: An exploratory ecological study was conducted based on data obtained from the 2000 national demographic census and the Unified Health System for the 558 microregions of Brazil. The model used multiple linear regression analysis. Mortality associated with waterborne diseases in children under 5 years of age was considered to be the response variable. Water conditions, sanitation, and level of education were considered to be explanatory variables. RESULTS: A direct relationship was observed between inadequate sanitation in the dwelling (e.g., sewage disposal via rudimentary gutters and pits, the disposal of waste in uncultivated land or public areas) and mortality in children under 5 years of age associated with waterborne diseases. An inverse relationship was found between level of education and mortality associated with waterborne diseases in these children. CONCLUSIONS: The greatest health hazards related to poor sanitation were found in the microregions with a high concentration of low-income population with limited education. The general sanitation conditions and other factors related to dwelling quality and infrastructure are major determinants of mortality. Coverage of the water services, which reach 90% of households in Brazil, was not in itself found to be an important factor in the reduction of the mortality studied. PMID- 20963279 TI - Invasive pneumococcal diseases among hospitalized children in Lima, Peru. AB - OBJECTIVE: To determine the epidemiology of invasive pneumococcal disease (IPD) and the antibiotic susceptibility and serotype distribution of S. pneumoniae in pediatric patients in Lima, Peru. METHODS: A 2-year, multicenter, passive surveillance study conducted from May 2006- April 2008 in 11 public hospitals and five private laboratories in Lima, Peru, in patients less than 16 years of age with sterile site cultures yielding S. pneumoniae. Antibiotic susceptibility was performed by Etest(r) (AB Biodisk, Solna, Switzerland). Strains were serotyped by the Quellung reaction. RESULTS: In all, 101 IPD episodes were studied, 68.3% of which were among children less than 24 months of age. Diagnoses were: pneumonia (47.5%), meningitis (38.6%), and sepsis (7.9%). The overall case fatality rate was 22.0%; case fatality rate in meningitis was 32.4%. While 80.0% of fatal cases were in those less than 24 months of age, only 50.7% of non-fatal cases (P < 0.05) were in this age group. Resistance rates were high for trimethoprim/ sulfamethoxazole (76.2%), erythromycin (24.8%), and penicillin (22.8%). The most common serotypes were 14, 6B, 19F, 23F, and 5, which accounted for 69.7% of all strains and 87.0% of penicillin non-susceptible strains. CONCLUSIONS: IPD in hospitalized children in Lima is associated with high antimicrobial resistance levels and elevated case fatality rate, especially in young children. This baseline data will be useful for evaluating the effects of vaccine introduction. PMID- 20963280 TI - [Tourism and health: methodological approaches and courses of action]. AB - OBJECTIVE: To identify relationships between tourism and health as well as the methods employed in studies about this topic. METHODS: The PubMed and SciELO databases were searched in March of 2008 using the following strategy: traveler or traveller or tourism or tourist AND risk or hazard or vulnerability AND health or surveillance. The following were excluded: articles on animal health, conceptual and review articles, articles about non-tourist travel, and articles written in languages other than Portuguese, English, Italian, and Spanish. Of 153 articles identified, 112 were excluded, and 41 articles were examined. RESULTS: The number of articles on tourism and health increased from one in the 1970s to 34 in the 2000s. Most studies were carried out in Europe, followed by the Americas, and most covered insect-borne diseases, respiratory diseases transmitted from person to person, and gastrointestinal diseases. Mail, telephone, or face-to-face questionnaires were generally used for data collection. In terms of location, 21 studies were performed at the place of departure, 17 at the destination, and in 3 this information was not specified. Four studies were carried out before the trip, 9 during the trip, 24 after the trip, and 3 did not specify this information. Most studies focus on the tourist as a likely victim of health problems, unprepared to face situations of exposure during the trip. CONCLUSIONS: The need to implement health care policies aimed at the tourist population is evident, with emphasis on infectious diseases and emergency actions to detect outbreaks involving tourists. A tourist-specific surveillance and notification system is also necessary, together with measures to prepare health care institutions to meet the individual demands of this population. PMID- 20963281 TI - [The worrisome lack of disaster training in Latin American medical schools]. PMID- 20963283 TI - A new cohort every 11 years. PMID- 20963282 TI - Health in the transition from childhood to adolescence: the 11-year follow-up of the 1993 Pelotas (Brazil) birth cohort study. PMID- 20963284 TI - The 11-year follow-up of the 1993 Pelotas (Brazil) birth cohort study: methods. AB - The aim of this study is to describe the methodology of the 2004-2005 follow-up visit of the 1993 Pelotas (Brazil) birth cohort. All children born in Pelotas in 1993 and whose mothers lived in the city at that time were eligible to be enrolled in a longitudinal study. Between July 2004 and March 2005, all cohort participants were sought for a follow-up visit. Several strategies were used to help trace cohort members, including a census of the city's schools and a census of all households in the municipality. The Mortality Information System was monitored in order to identify deaths among cohort members. Of the 5,249 cohort members, 4,452 were interviewed in 2004-5. When added to the 141 deaths, these represent 87.5% of the original cohort. In spite of the logistic and financial difficulties, it is possible to carry out prospective studies with long-term follow-up in the Brazilian context. PMID- 20963285 TI - Well-being in adolescents: the 11-year follow-up of the 1993 Pelotas (Brazil) birth cohort study. AB - Studies on well-being and its possible determinants are rare in the international literature, and almost non-existent in Brazil, particularly among youth. The present study focused on the epidemiology of well-being among adolescents belonging to a birth cohort. Well-being was measured using face-to-face interviews, with a question whose answer was based on a graphic scale of faces. 4,452 adolescents were interviewed. Approximately half (49.4%) classified themselves as very happy (face 1); this proportion was higher among girls than boys. Poorer adolescents were more likely than their wealthier peers to identify with the happiest face (number 1), but were also more likely to report moderate to low levels of well-being (faces 3-7). Body mass index was inversely associated with well-being. Among girls, physical activity was directly associated with well being. PMID- 20963286 TI - Nutritional status of adolescents: the 11-year follow-up of the 1993 Pelotas (Brazil) birth cohort study. AB - We evaluate the influence of demographic, socioeconomic, and maternal variables on the nutritional status of adolescents aged 11 years. We conducted a prospective cohort study including 4,452 adolescents born in Pelotas, Southern Brazil, in 1993, accounting for 87.5% of the original cohort. Nutritional status was evaluated based on World Health Organization criteria. Subjects were classified according to nutritional status into thin, normal, overweight and obese. Independent variables analyzed included skin color, socioeconomic status, maternal schooling, and maternal body mass index (BMI). Analyses were stratified by sex, and multivariable regression was performed using the multinomial logistic approach. Overall, 7% of adolescents were classified as thin, 11.6% as overweight, and 11.6% as obese. Among boys, thinness was inversely associated with maternal schooling and maternal BMI. Among girls, thinness was directly associated with maternal BMI. Overweight and obesity were directly associated with socioeconomic status and maternal BMI, the former showing the strongest association with nutritional status among adolescents. PMID- 20963287 TI - Intake of fat and fiber-rich foods according to socioeconomic status: the 11-year follow-up of the 1993 Pelotas (Brazil) birth cohort study. AB - This study describes the food intake of adolescents participating in the 1993 birth cohort from Pelotas, Southern Brazil, according to socioeconomic position. We carried out a cross-sectional analysis of data collected in the 2004-2005 follow-up visit. Food intake in the previous year was evaluated using the Block questionnaire. Socioeconomic status was evaluated based on an assets index, divided into quintiles. Foods with the highest frequency of daily intake were white bread (83%), butter or margarine (74.6%), beans (66.4%) and milk (48.5%). Intake of butter or margarine, bread, and beans was more frequent among poorer adolescents, and the inverse was true for milk. Intake of fruits and vegetables was low in all socioeconomic strata, but particularly low among the poor. In early adolescence, all socioeconomic groups showed high consumption of foods rich in fat and low consumption of foods rich in fiber. PMID- 20963288 TI - Factors associated with weight loss dieting among adolescents: the 11-year follow up of the 1993 Pelotas (Brazil) birth cohort study. AB - Evidence has shown the negative effects of unsupervised diets and those with excessive calorie restriction. The aim of this study was to determine the proportion of adolescents engaging in weight loss dieting and associated factors. This was a cross-sectional study of 4,452 adolescents born in Pelotas, Rio Grande do Sul State, Brazil, in 1993. The outcome was defined as adolescents that reported having practiced some type of weight loss dieting in the previous 12 months. Prevalence of such dieting was 8.6% (95%CI: 7.7;9.4), and was higher in girls. Elevated maternal body mass index (BMI) was associated with dieting among girls. The adolescent's and parents' view of the adolescent's weight, excess weight, and consumption of diet or light soft drinks were associated with adolescent dieting. There was a positive association between dieting and socioeconomic status. The findings provide important backing for policies aimed at improving adolescents' diet, since they express a major concern over weight and thus a significant percentage of individuals with erroneous and unhealthy behaviors. PMID- 20963289 TI - Self-reporting versus parental reporting of physical activity in adolescents: the 11-year follow-up of the 1993 Pelotas (Brazil) birth cohort study. AB - The aim of this study was to verify the agreement between different approaches for estimating levels of physical activity in adolescents. One questionnaire was administered to parents and two were administered to the adolescents. This was a cross-sectional analysis of data collected in the 2004-2005 follow-up of the 1993 Pelotas (Brazil) birth cohort study. Parents or guardians answered the following question: "Compared to most children the same age, would you say that your child exercises more, less, or the same amount?" A similar question was addressed to adolescents, as was a detailed questionnaire on physical activity. Agreement between the questionnaires was measured by the weighted kappa statistic. A total of 4,254 adolescents and parents/guardians answered the questionnaires. Kappa values indicated low agreement for all comparisons (kappa < 0.33 for all analyses). Measurement of physical activity in adolescents is complex, and available instruments should be validated prior to their use. PMID- 20963290 TI - Sedentary behavior in adolescents: the 11-year follow-up of the 1993 Pelotas (Brazil) birth cohort study. AB - The aim of this study was to estimate the prevalence of sedentary behavior and investigate associated factors in adolescents 11 years of age from the 1993 birth cohort in Pelotas, Rio Grande do Sul State, Brazil. Sedentary behavior was investigated with a questionnaire, and was defined as spending more than two hours per day watching television, playing videogames, or using the computer. Of the 4,452 adolescents interviewed, 98% reported watching television, 44% playing videogames, and 22% using the computer. The average time spent on each of these electronic media was 197, 36, and 17 minutes per day, respectively. Prevalence of sedentary behavior was 79.7% (95%CI: 78.6; 80.9) and showed a positive association with socioeconomic level and nutritional status and a negative association with well-being. These 11-year-olds spent extensive time at TV viewing, videogames, and the computer. Special attention should be given to the most exposed groups of adolescents, including the more affluent, overweight, and those with limited schooling. PMID- 20963291 TI - Experimental use of alcohol in early adolescence: the 11-year follow-up of the 1993 Pelotas (Brazil) birth cohort study. AB - The aim of this study was to estimate the prevalence of experimental alcohol intake and associated factors in early adolescence. The overall sample consisted of 4,452 adolescents (mean age = 11.3 years; SD = 0.3) from the 1993 birth cohort in Pelotas, Rio Grande do Sul State, Brazil. Experimental use of alcohol was reported by 17.5% of the interviewees (95%CI: 16.3-18.6), and 5% reported having tried alcohol at nine years of age or younger. Prevalence of experimental alcohol use was higher among adolescents whose mothers had consumed alcohol during pregnancy, whose parents consumed alcohol, who worked outside the home themselves, and who had ever tried smoking. Family strife, parental alcohol intake, and adolescent smoking were strong predictors of experimental alcohol use in early adolescence. Special attention should be targeted to these groups in order to avoid heavy and premature alcohol use in early adolescence. PMID- 20963292 TI - Medicine use among adolescents: the 11-year follow-up of the 1993 Pelotas (Brazil) birth cohort study. AB - The aim of this study was to investigate medicine use and associated factors among adolescents. This was a prospective cohort study including 4,452 adolescents born in Pelotas, Rio Grande do Sul State, Brazil, in 1993. Information on medicine use in the 15 days prior to the interviews was collected from the mothers. Overall prevalence of medicine use was 30.9%, and 64.7% of the medicines had been prescribed by a physician. The most frequently used pharmacological groups were medicines for the nervous (35.9%) and respiratory systems (25.7%). Medicine use was directly associated with socioeconomic status, maternal schooling, complications during pregnancy or delivery, and neonatal problems resulting in the need for intensive care. Underweight and obese adolescents were more likely to use medicines as compared to those with normal body mass index. A direct association was observed between maternal use of hypnotic drugs and sedatives and adolescent medicine use. It is essential to implement educational policies aimed at promoting rational use of medicines by adolescents. PMID- 20963293 TI - Early determinants of attention and hyperactivity problems in adolescents: the 11 year follow-up of the 1993 Pelotas (Brazil) birth cohort study. AB - The aim of this study was to assess early determinants of attention and hyperactivity problems in adolescents. In 1993, all hospital births in the city of Pelotas, Rio Grande do Sul State, Brazil, were monitored and mothers were interviewed (N = 5,249). At 11 years of age, 4,423 mothers answered the Strengths and Difficulties Questionnaire (SDQ) in order to evaluate attention and hyperactivity problems in the adolescents. Crude and adjusted prevalence ratios were calculated using Poisson regression. Prevalence of attention and hyperactivity problems was 19.9%. Factors associated with the outcome in the adjusted analysis were: male gender, low family income, smoking during pregnancy, minor psychiatric disorders in the mother, and history of child's behavioral/emotional problems at four years of age. Early life events impacted attention and hyperactivity problems in adolescence. Risk factors for attention and hyperactivity problems found in this study were similar to those reported in other cultures. PMID- 20963294 TI - Resting pulse rate among adolescents: the 11-year follow-up of the 1993 Pelotas (Brazil) birth cohort study. AB - The aim of this study was to describe resting pulse rate and associated factors among adolescents. This was a cross-sectional analysis nested in a prospective cohort study, including 4,452 adolescents born in Pelotas, Rio Grande do Sul State, Brazil in 1993, representing 87.5% of the original cohort. Pulse rate was measured with an electronic device at the beginning and end of the interview, and the mean value was used in the analyses. Mean pulse rate was 78.4 bpm (SD = 11.0) in the total sample, 76.5 bpm (SD = 10.7) in boys, and 80.2 bpm (SD = 10.9; p < 0.001) in girls. Black adolescents showed lower mean pulse rates. There was a direct association between pulse rate and blood pressure. Physical activity was inversely associated with pulse rate in the crude analysis only. Elevated pulse rate is strongly associated with high blood pressure, and both variables are predictors of risk of chronic disease in adulthood. PMID- 20963295 TI - Concurrent determinants of blood pressure among adolescents: the 11-year follow up of the 1993 Pelotas (Brazil) birth cohort study. AB - The aim of this study was to evaluate concurrent risk factors for high blood pressure in adolescents. This is a prospective cohort study including 4,452 adolescents born in Pelotas, Rio Grande do Sul State, Brazil, in 1993. Blood pressure was measured before and after the interview, and the mean value was used in the analyses. Mean systolic blood pressure was 101.9mmHg (SD = 12.3) and mean diastolic pressure was 63.4mmHg (SD = 9.9). Adolescents with black skin had higher blood pressure than those with white skin. Mean systolic pressure among subjects in the top quartile of body mass index (BMI) was 11.6mmHg higher than among those in the lowest quartile. Mean systolic pressure among postmenarcheal girls was 5.4mmHg higher than among premenarcheal girls. Similar trends were found for diastolic arterial pressure. Our findings suggest that blood pressure control must begin already in childhood and adolescence. PMID- 20963296 TI - Hospital admissions from birth to early adolescence and early-life risk factors: the 11-year follow-up of the 1993 Pelotas (Brazil) birth cohort study. AB - The aim of this prospective analysis was to describe the cumulative incidence of hospital admissions in the first year of life and between 1 and 11 years of age and to explore associated factors. Hospital admissions were collected through regular monitoring in the first year of life, and through maternal report on admissions between 1 and 11 years. Analyses were stratified by sex and adjusted for confounding factors. 18.1% of children were hospitalized in the first year of life, and 30.7% between ages 1 and 11 years. Among boys, hospital admission in the first year was associated with low family income, paternal smoking during pregnancy, preterm delivery, and low birthweight. Among girls, in addition to the variables described for boys, black/mixed skin color was also a risk factor for hospital admission. For admissions between 1 and 11 years of age, low family income and gestational age > 37 weeks were found to be significant risk factors. PMID- 20963297 TI - Oral health follow-up studies in the 1993 Pelotas (Brazil) birth cohort study: methodology and principal results. AB - The aim of this study was to describe oral health follow-up studies nested in a birth cohort. A population-based birth cohort was launched in 1993 in Pelotas, Rio Grande do Sul State, Brazil. Two oral health follow-up studies were conducted at six (n = 359) and 12 (n = 339) years of age. A high response rate was observed at 12 years of age; 94.4% of the children examined at six years of age were restudied in 2005. The mean DMF-T index at age 12 was 1.2 (SD = 1.6) for the entire sample, ranging from 0.6 (SD = 1.1) for children that were caries-free at age six, 1.3 (SD = 1.5) for those with 1-3 carious teeth at six years, and 1.8 (SD = 1.8) for those with 4-19 carious teeth at six years (p < 0.01). The number of individuals with severe malocclusions at 12 years was proportional to the number of malocclusions at six years. Oral health problems in early adolescence were more prevalent in individuals with dental problems at six years of age. PMID- 20963298 TI - [Governance and health: contributions to innovation in health systems]. AB - The need to strengthen the field of health policy and systems research has been widely recognized among public health research organizations. This is especially so in the case of Latin America and the Caribbean. Moreover, there is also an increasing interest in the development of new research models with greater capacity to influence policy agendas and health reforms. This publication argues that in order to bridge research to policy, the design of technical solutions alone is largely not sufficient; it is essential to achieve a better understanding of the planning and implementation of health policies. Sound research can play a relevant role, but it has to include new analytical categories and generate appropriate interfaces between researchers and decision makers. This article introduces the Journal's special edition devoted to governance and health policies in the Americas.Its purpose is to present the advances achieved by Latin American researchers,in collaboration with Canadian scientists, in the conceptual and methodological development of governance in health, and to showcase different field projects in the region. The authors present complementary views, both analytical and normative,confirming the advantages and opportunities of developing a governance dimension in health systems research projects. This enables a better understanding of the policy process and consequently increases the potential to influence public policies. PMID- 20963299 TI - [Governance of primary health-care-based health-care organization]. AB - An analytical framework was developed for explaining the conditions for the effectiveness of different strategies promoting integrated primary health-care (PHC) service-based systems in Latin-America. Different modes of governance (clan, incentives and hierarchy) were characterised from a political economics viewpoint for representing alternative forms of regulation promoting innovation in health-service-providing organisations. The necessary conditions for guaranteeing the modes of governance's effectiveness are presented, as are their implications in terms of posts in play. The institutional construction of an integrated health system is interpreted as being a product of a social process in which different modes of governance are combined, operating with different ways of resolving normative aspects for regulating service provision (with the hierarchical mode), resource distribution (with the incentives mode) and on the social values legitimising such process (with the clan mode). PMID- 20963300 TI - [Ethical principles and approaches to health systems governance research: conceptual and methodological implications]. AB - Governance refers to decision-making processes in which power relationships and actors and institutions' particular interests converge. Situations of consensus and conflict are inherent to such processes. Furthermore, decision-making happens within a framework of ethical principles, motivations and incentives which could be explicit or implicit. Health systems in most Latin-American and Caribbean countries take the principles of equity, solidarity, social participation and the right to health as their guiding principles; such principles must thus rule governance processes. However, this is not always the case and this is where the importance of investigating governance in health systems lies. Making advances in investigating governance involves conceptual and methodological implications. Clarifying and integrating normative and analytical approaches is relevant at conceptual level as both are necessary for an approach seeking to investigate and understand social phenomena's complexity. In relation to methodological level, there is a need to expand the range of variables, sources of information and indicators for studying decision-making aimed to greater equity, health citizenship and public policy efficiency. PMID- 20963301 TI - [Governance in Public Health: towards an analytical framework]. AB - This paper argues that the governance analytical framework (GAF) is a methodology having strong potential for investigation in social policy, particularly in the case of public health. It defines the concept of governance in a pragmatic way as being the processes of interactions between the actors involved in a public affair leading to decision-making or to formulating social norms. It is postulated that any society has governance processes and, unlike other approaches, that these can be observed and be analysed from a non-normative perspective. A methodology for analysing governance processes based on five main analytical units is presented here: problems/stakes, actors, norms, processes and nodal points. These logically articulated analytical units make up a coherent methodology aimed at being used as a tool for social policy research. PMID- 20963302 TI - Health Systems Governance for health equity: critical reflections. AB - This article addresses several issues pertinent to health systems governance for health equity. It argues the importance of health systems using measures of positive health (well-being), discriminating in favour of historically less advantaged groups and weighing the costs of health care against investments in the social determinants of health. It cautions that the concept of governance could weaken the role of government, with disequalizing effects, while emphasizing the importance of two elements of good governance (transparency and participation) in health systems decision-making. It distinguishes between participation as volunteer labour and participation as exercising political rights, and questions the assumption that decentralization in health systems is necessarily empowering. It then identifies five health system roles to address issues of equity (educator/watchdog, resource broker, community developer, partnership developer and advocate/catalyst) and the implications of these roles for practice. Drawing on preliminary findings of a global research project on comprehensive primary health care, it discusses political aspects of progressive health system reform and the implications of equity-focused health system governance on health workers' roles, noting the importance of health workers claiming their identity as citizens. The article concludes with a commentary on the inherently political nature of health reforms based on equity; the necessary confrontation with power relations politics involves; and the health systems governance challenge of managing competing health discourses of efficiency and results-based financing, on the one hand, and equity and citizen empowerment, on the other. PMID- 20963303 TI - [Notes for studying primary care within the context of segmented health systems]. AB - This paper discusses the contribution of the concept of governance, combined with traditional approaches to primary health care (PHC) analysis, in a multicentre study covering Argentina, Brazil, Paraguay and Uruguay. Considering health systems? variety of configurations and their segmented context, it aims to compare PHC implementation and performance characteristics in each country so as to explain them according to different determinants and compare them to governance models. Each country?s segmented context is presented, identifying public, private and social insurance sub-sectors? arrangements. The PHC concept and its potential role in reorganizing equity- and access-based health systems are discussed. Five dimensions for PHC study are then defined: stewardship, financing, resources, comprehensiveness and intersectorality. Governance analysis revealed state-society relationships and is thus proposed as a tool for understanding such dimensions? dynamic relationships. PMID- 20963304 TI - [Governance of PHC development in Rosario, Argentina]. AB - OBJECTIVE: Describing the development of PHC policy as promoted by Rosario Municipality (Argentina). METHODS: A case-study was carried out during 2007 and 2008. Data was collected from secondary and primary sources (interviews, organisational census and observations). PHC development stages were identified by recognising the social norms which produced institutional change and transformation in municipal health services structure and health care and management models. The prevailing modes of governance in each stage were reconognised and characterised (clan, hierarchy and/or incentives). RESULTS: Four stages were identified between 1990 and 2008: 1990-1995/hierarchical mode: primary health care level organisation autonomied from hospitals. 1995-2000/ clan mode: developing of participatory managerial boards and community participation. 2000-2004/ clan mode: maturation of the "PHC movement" in competition with hospitals. 2004-2008/ clan-hierarchical mode: "movement's" crisis and constructions of norms tending towards enhancing an integrated network. DISCUSSION: Strengthening and empowering first-level health-care produced innovation favouring: the consolidation of a "PHC movement" having strong social commitment and improved services performance. The clan governance mode (regulating collective action via voluntary adhesion to shared values) was crucial for developing PHC between 1995 and 2004. Later on, the movement's fragmentation and the challenges of integrating the health system required developing hierarchical regulation mechanisms to complement the governance clan mode regulation. PMID- 20963305 TI - [Governance and health: the rise of the managerialism in public sector reform]. AB - The article examines various healthcare systems reform projects in Canada and some Canadian provinces and reveals some tendencies in governance renewal. The analisis is based on the hypothesis that reform is an exercise aiming at the renewal of governance conception and practices. In renewing governance, reform leaders hope to use adequate and effective levers to attain announced reform objectives. The article shows that the conceptions and operational modalities of governance have changed over time and that they reveal tensions inherent to the transformation and legitimation process of public healthcare systems. The first section discusses the relationships between reform and change. The second section defines the conception of gouvernance used for the analisis. Based on a content analisis of the various reform reports, the third section reveals the evolution of the conception of governance in healthcare systems in Canada. In order to expose the new tendencies, ideologies and operational principles at the heart of the reform projects are analysed. Five ideologies are identified: the democratic ideology, the "population health" ideology, the business ideology, the managerial ideology and the ideology of equity and humanism. This leads to a discussion on the dominant influence of the managerial ideology in the current reform projects. PMID- 20963306 TI - [A governance approach applied to analysing research into unemployed workers in the city of Medellin in Colombia]. AB - OBJECTIVE: Performing an academic exercise aimed at applying the analytical categories from the governance approach developed by Marc Hufty et al., to understand social actors? relationships in an investigation and intervention project studying so-cioeconomic conditions and seeking to guarantee health insurance continuity for those workers who had lost their work in the city of Medellin, Colombia, from 2004 to 2007. METHODOLOGY: A process of investigation and intervention was examined as a casestudy in which researchers were one of the actors so involved. Characterising stake-holders included: their level of inclusion/involvement in the problem; their power for influencing public policy proposals; their perceptions and proposals? characteristics, power and dynamics regarding the problem of unemployment and health insurance when someone has lost her/his work; and the characteristics of their interaction with other actors. RESULTS: The results showed that the four analytical dimensions proposed by Hufty (actors, social norms, nodal points and processes) were useful for describing and understanding the interaction of the actors involved in the research and intervention proposal being analysed here (i.e. the case-study). CONCLUSIONS: It was concluded that the analytical governance framework proposed by Hufty was useful for understanding how the social subjects interacted; these were the rules which were taken for describing their interaction, being the most important nodes for interaction and progresses achieved whilst implementing the intervention proposal. PMID- 20963307 TI - [Governance in Guatemalan municipal development councils: an analysis of actors and power relationships]. AB - OBJECTIVES: Decentralisation and other public policies have created public spaces for participation in most Latin-American countries where community representatives, together with municipal authorities and other public functionaries, decide on social investment plans, including health services and infrastructure. The municipal development council system constitutes such public space in Guatemala. METHODS: This study analysed such system's governance in a sample of 6 rural municipalities. A descriptive design was used, applying qualitative and quantitative techniques to study three central categories: the strategic actors, the rules of the game and power asymmetry levels amongst actors. RESULTS: The findings revealed inconsistencies amongst the actors who had to participate according to the legal framework and those actors who actually did so in practice. Divergent interests were also identified for participating which affected the possibility of reaching consensus during decision-making. Analysing the rules of the game led to identifying formal and non-formal mechanisms favouring some actors' ability to influence decisions. Analysing power asymmetry levels led to identifying that community representatives had fewer power resources than institutional representatives (local government and other government organisations). Community representatives also face different barriers blocking their participation and perceive a lesser capacity to influence decision making. CONCLUSIONS: Existing barriers and fewer power resources experienced by community representatives reduce their abilities to influence decision-making in municipal development councils. PMID- 20963308 TI - [Governance and health: meaning and implications in Latin America]. AB - The term governance is used more and more often in the formulation, implementation, and evaluation of public policies. The purpose of this paper is twofold: to shed light on its meaning, and to study its applicability for the study of recent public health policies in Latin America. After discussing the differences between governance and the close concepts of management, governability and government, we propose the adoption of the notion of Giddens' duality of social structure for better understanding of the governance processes. Then we use this theoretical framework for reviewing the conceptual and empirical implications of the set of papers about governance and health in Latin America included in the present special issue of the Journal of Public Health. Recognizing that the debate on governance is not closed, we end the paper highlighting the main contributions of the revised works, namely: the importance of equity in decision-making processes, the appreciation of the political nature of governance, and the advantages and limitations of the clan mechanism of governance for regulating interactions among actors involved in the health policy decision-making processes. PMID- 20963309 TI - Profile of patients with hypertension included in a cohort with HIV/AIDS in the state of Pernambuco, Brazil. AB - BACKGROUND: Hypertension (HBP) is modifiable risk factor, whose control may reduce cardiovascular disease in patients with human immunodeficiency virus (HIV). OBJECTIVE: To estimate the prevalence of hypertension and describe the characteristics of patients with hypertension infected by HIV/AIDS. METHODS: A cross-sectional study aligned to a cohort of patients with HIV/AIDS. The study considered hypertension at levels > 140/90 mmHg or use of antihypertensive drugs and pre-hypertension at levels > 120/80 mmHg. RESULTS: Out of 958 patients, 388 (40.5%) were normotensive, 325 (33.9%) were pre-hypertensive, and 245 (25.6%) were hypertensive. Out of these 245 patients, 172 (70.2%) were aware of the fact there they were hypertensive, and 36 (14.8%) had blood pressure controlled. Sixty two (62) patients (54.4%) were diagnosed with hypertension after HIV diagnosis. Lipodystrophy occurred in 95 (46.1%) patients; overweight/obesity in 129 (52.7%). Use of antiretrovirals occurred in 184 (85.9%), 89 (41.6%) with protease inhibitors (PI) and 95 (44.4%) without PI. Out of these patients, 74.7 used antivirals > 24 months. Age, family history of hypertension, waist circumference, body mass index and triglyceride levels were higher among hypertensive patients. Time of HIV infection, CD4 count, viral load, time and type of antiretroviral regimen were similar in hypertensive and prehypertensive patients. CONCLUSION: The high frequency of uncontrolled hypertensive patients and cardiovascular risks in HIV-infected patients point out to the need for preventive and therapeutic measures against hypertension in this group. PMID- 20963311 TI - [Guidelines of the Brazilian Society of Cardiology on unstable angina and myocardial infarction without ST segment elevation (second edition, 2007).]. PMID- 20963310 TI - Ministernotomy in myocardial revascularization preserves postoperative pulmonary function. AB - BACKGROUND: In coronary artery bypass graft (CABG) surgery, the need to perform a midsternotomy has been considered a factor for the decrease in postoperative pulmonary function. OBJECTIVE: To prospectively evaluate early postoperative (PO) pulmonary function in patients submitted to off-pump CABG, comparing the conventional midsternotomy with the ministernotomy approach. METHODS: A total of 18 patients were evaluated and assigned to the two groups: Group Conventional Midsternotomy (CMS, n=10) and Group Ministernotomy (MS, n=8). Spirometric results of the forced vital capacity (FVC) and the Forced Expiratory Volume in one second (FEV1) were obtained on the 1st, 3rd and 5th PO days and the arterial gasometry was obtained before and on the 1st PO day. The pulmonary shunt percentage and the pain score were also assessed. RESULTS: When compared in terms of percentage of the preoperative value, the FVC was higher in the MS group than in the CMS group on the 1st, 3rd and 5th PO days (p<0.001). Similar results were obtained for FEV1. The recovery of the FVC between the 1st and the 5th PO days was higher in the MS than in the CMS group (p=0,043). The PaO2 decreased on the 1st PO day in both groups (p<0.05), with a higher decrease in the CMS group (p=0.002). The shunt increased in the two groups on the 1st PO day (p<0.05); however, it was lower in the MS group (p=0.02). The reported pain score was lower and the duration of the hospital stay was shorter in the MS group. CONCLUSION: Patients submitted to CABG by MS present better preservation and recovery of pulmonary function than those submitted to CMS. PMID- 20963312 TI - [III Brazilian Guidelines on Chronic Heart Failure]. PMID- 20963314 TI - Primary anterior parietal wall abscess due to Salmonella Typhi. PMID- 20963313 TI - Overwhelming diffuse psoriasis during chronic HCV infection, after peginterferon ribavirin treatment, supported by frequent resort to filgrastim rescue. PMID- 20963315 TI - Long-term follow-up of patients with chronic hepatitis C with sustained virologic response to interferon. AB - BACKGROUND AND AIM: The durability of the sustained virologic response (SVR) in patients with chronic hepatitis C after treatment and the ideal follow-up time for these patients remains undefined. The objective of the study was to evaluate the durability of the virologic response in patients with chronic hepatitis C followed up for at least 12 months after SVR at HCFMRP-USP. METHODS: The study was conducted on 174 patients with chronic hepatitis C treated with different antiviral regimens who had achieved SVR. Qualitative serum HCV-RNA was determined by the commercial kit (COBAS AMPLICOR HCV, v2.0). RESULTS: There was predominance of male (73%) with a mean age of 45.6 +/- 10 years. Liver cirrhosis was present in 16.1% of the study subjects. Mean follow-up time after SVR was 47 months (12 156 months). Twenty-two patients received monotherapy with interferon; 94 received interferon plus ribavirin, and 58 received pegylated interferon plus ribavirin. A total of 134 patients (77.0%) received one treatment course, 29 (16.7%) received two courses, and 11 (6.3%) received three courses. The distribution of HCV genotypes was: genotype 1 (40.2%), genotype 3 (40.8%) and genotype 2 (10.3%). Genotype was undetermined in 8.7% of cases. None of the 174 patients had recurrence of HCV infection. Two cirrhotic patients developed hepatocellular carcinoma (HCC) during follow-up. CONCLUSIONS: Among patients with SVR there was no recurrence of HCV infection or evidence of liver disease progression in any patient followed up for a mean of 47 months after SVR, except for patients with advanced hepatic disease before treatment, who may develop HCC despite SVR. Therefore, one can assume that SVR is associated with long term good prognosis. PMID- 20963316 TI - Hyaluronic acid in the evaluation of liver fibrosis in patients with hepatitis C on haemodialysis. AB - BACKGROUND: This study evaluated the role of HA as a marker of liver fibrosis in patients with hepatitis C on haemodialysis. METHODS: This is a cross-sectional study in which 52 patients were divided into two groups: Group 1: patients with hepatitis C and end-stage renal disease (ESRD) undergoing haemodialysis (n = 23); and Group 2: patients with hepatitis C without ESRD (n = 29). Plasma levels of HA were associated with histological data of the samples obtained by liver biopsy and classified by METAVIR group scoring system. RESULTS: Higher plasma levels were significantly correlated to significant liver fibrosis (METAVIR > F2). In Group 1, the HA cutoff to discriminate significant fibrosis was 984.8 ng/mL, with accuracy, sensitivity and specificity of 80.8%, 83.0%, and 70.0%, respectively. In Group 2, the HA cutoff was 222.3 ng/mL, with accuracy, sensitivity and specificity of 74.5%, 70.0%, and 94.0%, respectively. CONCLUSION: HA was an accurate noninvasive marker in predicting significant fibrosis in patients with hepatitis C on haemodialysis. PMID- 20963317 TI - Epidemiological profile of leishmaniasis at a reference service in the state of Alagoas, Brazil, from January 2000 to September 2008. AB - Leishmaniasis is a parasitic disease found in the continents of Europe, Asia, Africa and the Americas. In Brazil, the disease is an important public health problem, occurring in most states, but mainly in the Northeast region of the country, with the state of Alagoas having a significant number of confirmed cases. The present study establishes and discusses the epidemiological profile of cases of leishmaniases treated at the Reference Center of Alagoas, Hospital Escola Helvio de Farias Auto, between January 2000 and October 2008. During this period, records of 2,104 patients notified to the hospital Epidemiological Surveillance Center were reviewed. The epidemiology of leishmaniasis, both visceral and tegumentary, has shown a profile that has changed over throughout the years, with a decrease in the number of notified cases. Disease occurrence was associated with lower social economic classes, and affected mainly rural workers in general, housewives and students. PMID- 20963318 TI - Molecular diagnosis of cerebral toxoplasmosis: comparing markers that determine Toxoplasma gondii by PCR in peripheral blood from HIV-infected patients. AB - As cerebral toxoplasmosis is the most common cerebral focal lesion in AIDS patients, this study evaluated three PCR markers for diagnosis, since some limitations remain present, such as low parasite levels in some clinical samples. The molecular markers were B22-B23 and Tg1-Tg2 (based on the B1 gene) and Tox4 Tox5 (non-coding fragment, repeated 200-300-fold). DNA samples from 102 AIDS patients with previously known diagnosis were analyzed. The cerebral toxoplasmosis group was constituted of DNA extracted from the blood of 66 AIDS patients, which was collected before or until the third day of the therapy for toxoplasmosis. DNA from the blood of 36 AIDS patients with other neurologic opportunistic infections was used as control group. Sensitivities of B22-B23, Tg1 Tg2, and Tox4-Tox5 markers were of 95.5%, 93.9%, and 89.3%, respectively. In the control group, the specificities were of 97.2% (B22-B23), 88.9% (Tg1-Tg2), and 91.7% (Tox4-Tox5). The association of at least two markers increased the PCR sensitivity and specificity. The concordance index between two markers varied from 83.3% to 93.1%. These data demonstrated that all markers evaluated here were highly sensitive for T. gondii determination, although B22-B23 has been shown to be the best. The association of two markers increases PCR sensitivity, but the procedure was more expensive and time-consuming. PMID- 20963319 TI - A single center 14 years study of infectious complications leading to hospitalization of patients with primary antibody deficiencies. AB - Primary antibody deficiencies (PADs) are a heterogeneous group of disorders, characterized by hypogammaglobulinemia and increased susceptibility to bacterial infections, leading to hospitalizations. This study was performed to determine the main infectious causes of hospital admissions in selective Iranian patients with PADs. Forty patients with PADs, who were admitted to the Infectious Ward of Children's Medical Center Hospital during a 14-year period, were reviewed in this study. There were 115 documented episodes of hospital admission during a 14-year period. The average length of hospital stay was 33.30 +/- 25.72 days. Pneumonia was the most prominent infection leading to hospitalization among these patients (n = 48), followed by gastroenteritis (n = 23). Other less frequent causes of hospitalization were fever and neutropenia, septic arthritis, encephalitis, orbital cellulitis, sepsis, urinary tract infection, meningitis, oral ulcer, and lung abscess. The most common causative organisms of diarrhea were: Giardia lamblia, followed by Candida albicans, and Salmonella sp. Many patients with PADs suffer from repeated infections leading to hospitalization, in spite of immunoglobulin replacement therapy. Respiratory tract infections were the prominent cause of hospitalization among studied patients, followed by gastrointestinal infections. PMID- 20963320 TI - Economic impact of treatment for surgical site infections in cases of total knee arthroplasty in a tertiary public hospital in Brazil. AB - The aim of this study was to estimate the additional cost of treatment of a group of nosocomial infections in a tertiary public hospital. A retrospective observational cohort study was conducted by means of analyzing the medical records of 34 patients with infection after total knee arthroplasty, diagnosed in 2006 and 2007, who met the criteria for nosocomial infection according to the Centers for Disease Control and Prevention. To estimate the direct costs of treatment for these patients, the following data were gathered: length of hospital stay, laboratory tests, imaging examinations, and surgical procedures performed. Their costs were estimated from the minimum values according to the Brazilian Medical Association. The estimated cost of the antibiotics used was also obtained. The total length of stay in the ward was 976 days, at a cost of US$ 18,994.63, and, in the intensive care unit, it was 34 days at a cost of US$ 5,031.37. Forty-two debridement procedures were performed, at a cost of US$ 5,798.06, and 1965 tests (laboratory and imaging) were also performed, at a cost of US$ 15,359.25. US$ 20,845.01 was spent on antibiotics and US$ 1,735.16 on vacuum assisted closure therapy, microsurgical flaps, implant removal, spacer use, and surgical revision. The total additional cost of these cases of hospital infection in 2006 and 2007 was of US$ 91,843.75. Based on that, we demonstrate that the high cost of treatment for hospital infections emphasizes the importance of taking measures to prevent and control hospital infection. PMID- 20963321 TI - HIV-1 genotypic resistance profile of patients failing antiretroviral therapy in Parana, Brazil. AB - Antiretroviral therapy (ART) has reduced morbidity and mortality related to human immunodeficiency virus (HIV) infection, but in spite of this advance, HIV mutations decrease antiretroviral susceptibility, thus contributing to treatment failure in patients. Genotyping HIV-1 allows the selection of new drugs after initial drug failure. This study evaluated the genotypic profile of HIV-1 isolates from treated (drug-experienced) patients in Parana, Brazil. The prevalence of mutations in reverse transcriptase (RT) and protease (PR) genes were assessed. We analyzed 467 genotypes of patients with HIV-1 viral loads above 1,000 copies/mL. Mutations at HIV-1 RT and PR genes and previously used ART regimens were recorded. The most prevalent RT mutations were: 184V (68.31%), 215YF (51.6%), 103NS (46%), 41L (39.4%), 67N (38.54%), 210W (23.5%), 190ASE (23.2%), and 181C (17.4%). PR mutations were 90M (33.33%), 82ATFS (29%), 46I (26.8%) and 54V (22.2%). The prevalence of mutations was in line with previous national and international reports, except to nonnucleoside analogue reverse transcriptase inhibitors related mutations, which were more prevalent in this study. Previous exposure to antiretroviral drugs was associated with genotypic resistance to specific drugs, leading to treatment failure in HIV patients. PMID- 20963322 TI - Hepato-pulmonary amebiasis: a case report. AB - Infections with Entamoeba histolytica are seen worldwide and are more prevalent in the tropics. About 90% of infections are asymptomatic, and the remaining 10% produce a spectrum of clinical syndromes, ranging from dysentery to abscesses of the liver or other organs. Extra-intestinal infection by E. histolytica most often involves liver. Pleuro-pulmonary involvement, seen as the second most common extra-intestinal pattern of infection, is frequently associated with amebic liver abscess. Pulmonary amebiasis occurs in about 2-3% of patients with invasive amebiasis. We report herein the case of a 45-year-old male presenting with hepato-pulmonary amebiasis. The diagnosis was established from direct examination of sputum, in which trophozoites of E. histolytica were detected, and by serology. Following treatment with metronidazole and chloroquine, the clinical evolution improved significantly. On regular follow-up visits, the patient was asymptomatic. This case report reiterates the need for collaboration between clinicians and microbiologists for timely diagnosis of such infections. PMID- 20963323 TI - Emphysematous and xanthogranulomatous pyelonephritis: rare diagnosis. AB - Pyelonephritis is a pyogenic infection of renal parenchyma that involves the renal pelvis. It is generally of easy diagnosis. The present case report aims to describe two different manifestations of this infection: xanthogranulomatous pyelonephritis and emphysematous pyelonephritis, which have poor prognosis and require a more effective treatment. The two cases were women in the fiftieth and sixtieth decade of life, with diabetes mellitus and history of weight loss. The diagnosis of the renal infection was established through computed tomography and the treatment was based in surgical procedure, with favorable outcome. PMID- 20963324 TI - Spondylodiscitis and endocarditis caused by S. vestibularis. AB - Streptococcus vestibularis is a recently described member of the viridans group that was first isolated from the vestibular mucosa of the human oral cavity and described as a new species in 1988. It has been rarely associated with human infections. In few papers, it has been reported as a causal agent of systemic infection in immunosupressed adults and in those with other severe underlying diseases, like coronary valve diseases. A 65-year-old woman was admitted to the hospital with complaints of fever for three months, general malaise, effort dyspnea, weight loss, back pain and myalgia. Both native aortic valve endocarditis and spondylodiscitis due to Streptococcus vestibularis were detected. The patient was successfully treated with intravenous potassium penicillin G and gentamicin for six weeks, followed by oral amoxicillin for three months, in addition to aortic valve replacement. In all patients with spondylodiscitis, infective endocarditis should be considered, particularly in patients with heart valve disease history, since spondylodiscitis may be the presenting sign of an infective endocarditis. Cardiac valve replacement surgery should be performed if the course of fever and inflammatory syndrome is unfavorable after appropriate antibiotic treatment. We report the first case with both native aortic valve endocarditis and spondylodiscitis due to Streptococcus vestibularis. PMID- 20963325 TI - Recommendations for hygiene of masks and circuits in mechanically home ventilated patients. AB - Home mechanical ventilation requires equipment, consisting of a generator of pressure, a tubing and an interface to deliver air to the patient. Instructions for equipment maintenance are generally not based on scientific evidence. Studies however have reported that tubing and masks used at home are the most commonly found as very dirty and contaminated. Dirtiness and contamination of equipment potentially expose patients to a higher risk of airway colonization, which, in turn, should cause respiratory infections. For this reason, published hygiene instructions include the use of disinfectant solution. Nevertheless, they generally fail to explain how basic maintenance may be achieved by simple cleaning with soap and water. The instructions for post-cleaning disinfection will depend upon the relative sensitivity of patients to respiratory tract infections and the related risks for bacterial colonization of the airways. Restrictive and obstructive disease patients are not equally sensitive to infections and, as a consequence, should not require similarly elaborate disinfection level. According with the restrictive or obstructive origin of respiratory insufficiency, the current educational review suggests simple and adequate rules for hygiene of tubing and masks in the home setting. Written instructions on how to clean the equipment for home ventilation are useful and sufficient in restrictive patients. In obstructive patients, cleaning always precedes disinfection. After cleaning, rinsing and drying are important. An effective weekly 20-minute disinfection may be achieved by using an hypochlorite solution of soaking in a concentration of 0.5%. PMID- 20963326 TI - Sampling studies to estimate the HIV prevalence rate in female commercial sex workers. AB - INTRODUCTION: We investigated sampling methods being used to estimate the HIV prevalence rate among female commercial sex workers. METHODS: The studies were classified according to the adequacy or not of the sample size to estimate HIV prevalence rate and according to the sampling method (probabilistic or convenience). RESULTS: We identified 75 studies that estimated the HIV prevalence rate among female sex workers. Most of the studies employed convenience samples. The sample size was not adequate to estimate HIV prevalence rate in 35 studies. DISCUSSION: The use of convenience sample limits statistical inference for the whole group. It was observed that there was an increase in the number of published studies since 2005, as well as in the number of studies that used probabilistic samples. This represents a large advance in the monitoring of risk behavior practices and HIV prevalence rate in this group. PMID- 20963327 TI - Interferon therapy shifts natural killer subsets among Egyptian patients with chronic hepatitis C. AB - Natural killer cells can be divided into five subpopulations based on the relative expression of CD16 and CD56 markers. The majority of natural killer cells are CD56(dim), which are considered to be the main cytotoxic effectors. A minority of the natural killer cells are CD56(bright), and function as an important source of immune-regulatory cytokines. Shifts of these subsets have been reported in patients with chronic hepatitis C virus infection. We sought to investigate the shift of natural killer subsets among Egyptian patients with chronic HCV and to analyze the influence of interferon therapy on this shift. We applied a flow cytometric analysis of peripheral blood natural killer subsets for 12 interferon-untreated and 12 interferon-treated patients with chronic HCV, in comparison to 10 control subjects. Among interferon-untreated patients, there was a significant reduction of CD56-16(+) (immature natural killer) cells. Among interferon-treated patients, the absolute count of natural killer cells was reduced, with expansion of the CD56(bright) subset and reduction of the CD56(dim)16(+) subset. Natural killer subset counts were not significantly correlated to HCV viral load and were not significantly different among interferon responders and non-responders. In conclusion, HCV infection in Egyptian patients has been observed to be statistically and significantly associated with reduction of the CD56-16(+)NK subset, while a statistically significant expansion of CD56(bright) and reduction of CD56(dim)16(+) subsets were observed after interferon therapy. Further studies are required to delineate the molecular basis of interferon-induced shift of natural killer subsets among patients with HCV. PMID- 20963328 TI - Prevalence and antimicrobial susceptibility of respiratory pathogens in patients with cystic fibrosis. AB - Respiratory infection is very common in patients suffering from cystic fibrosis (CF). However, the antimicrobial resistance rate of isolates from CF patients is not often documented. In this study, 279 respiratory specimens of 146 patients were prospectively collected from July to December 2006. Microbiological cultures and antimicrobial susceptibility tests of the most frequently isolated bacteria were performed. Sputum and oropharyngeal swabs were processed for culture. During the study period, 50% of the patients harbored Staphylococcus aureus, 35% Pseudomonas aeruginosa, 4.7% Haemophilus influenzae. Methicillin resistant S. aureus (MRSA) were detected in 8 (6%) patients; ESBL and MBL-producing P. aeruginosa were not identified in these patients. The detection of MRSA in CF patients confirms that antimicrobial resistance patterns should be always kept under surveillance. Moreover, hygiene regulations in CF clinics should prevent a further spread of resistant bacterial strains. PMID- 20963329 TI - Clinical aspects of hemolysis in patients with P. vivax malaria treated with primaquine, in the Brazilian Amazon. AB - This report describes the development of hemolysis in eighteen glucose-6 phosphate dehydrogenase deficient patients treated for Plasmodium vivax malaria with chloroquine and primaquine. The most frequent findings accompanying hemolysis were fever and leukocytosis, in addition to anemia requiring red blood cell transfusion, and development of acute renal failure. Hemolysis in patients using primaquine is not infrequent and contributes to the morbidity of infection caused by Plasmodium vivax. PMID- 20963330 TI - Osteoarthritis in the neonate: risk factors and outcome. AB - OBJECTIVES: The aim of this study was to identify the clinical, radiological, and bacteriological features, risk factors, and outcome of neonates with bone and joint infections. STUDY DESIGN: Observational, retrospective, and analytical study of 77 patients less than 2 months of age, admitted to a tertiary neonatal intensive care unit (NICU) with the diagnosis of bone or joint infection, based on clinical, radiological, and microbiological criteria. RESULTS: Seventy-seven patients with 99 acute osteoarthritis foci in a 16 year period were included in the study. Risk factors for infection could be identified in 69% of the patients. The hip was the most frequent. Staphylococcus aureus was the main isolated microorganism. Twenty-nine infants (38%) had sequelae. Hip involvement, culture positive, and Staphylococcus aureus isolation were risk factors associated with sequelae. CONCLUSION: Osteoarticular infection is unusual in the neonate; however it is associated with an elevated incidence of sequelae. This mandates for a high degree of suspicion to diagnose this potentially disabling entity. PMID- 20963331 TI - Changing patterns of AIDS: impact on the indications and diagnostic yield of bone marrow biopsies. AB - After the advent of HAART, the clinical course of HIV infection has dramatically improved. Therefore, it seems appropriate to reevaluate the performance of bone marrow biopsy (BMB) as a diagnostic tool. The aim of the present study was to compare the reasons for performing a BMB and its diagnostic yield in HIV-patients before and after HAART. A total of 165 BMB specimens obtained from HIV-infected patients receiving care at the Hospital of Universidade Federal do Rio de Janeiro in two different periods (1986-1994 and 1999-2004) were analysed. The main reason for BMB examination in the first period was fever (88%), which decreased in the second period (57%, p < 0.0001), when cytopenia (51%) was the leading reason for BMB, whereas in the first period it accounted for only 30% (p = 0.008). A definitive diagnosis (infection, granulomas or lymphomas) was obtained in 28% of patients in the first period and in 19% during the second period (p = 0.20). The diagnosis turned out as infections decreased from 16% in period 1 to 2% in period 2 (p = 0.003). Despite the the limitations in the evaluation of fever, the use of BMB must be considered on an individual basis, whenever less invasive alternatives have been exhausted, and should be complemented by a bone marrow aspiration for microbiological studies. PMID- 20963332 TI - Hepatitis C in hemodialysis: the contribution of injection drug use. AB - BACKGROUND: Hepatitis C virus (HCV) infection is the most common cause of acute or chronic hepatitis in patients on hemodialysis (HD). The purpose of this study was to describe the prevalence of positive HCV RNA and investigate injection drug use as an emerging risk factor in patients with chronic renal disease on HD. METHODS: This was a multicenter cross-sectional study with 325 patients with chronic renal disease on HD in the period between August 1, 2005 to August 30, 2006, receiving care at four institutions in the city of Porto Alegre, Southern Brazil. Epidemiological data were collected by means of a structured questionnaire. The following laboratory tests were performed: alanine aminotransferase (ALT), anti-hepatitis C virus antibodies (anti-HCV), and qualitative polymerase chain reaction (PCR). RESULTS: Of 325 patients, 68 had positive HCV RNA results. The comparison between patients with positive and negative PCR results revealed significant differences in duration of HD (mean = 71 versus 52.4 months; p = 0.02); previous blood transfusion (92% versus 72%; p < 0.01); injection drug use (13% versus 0.7%; p < 0.01); anti-HCV positivity at start of HD therapy (60% versus 4%; p < 0.01); and mean ALT value (39 versus 26.5; p < 0.01). Logistic regression analysis showed a positive HCV RNA independently associated to being on HD for more than five years [OR: 2.1 (95% CI 1.2 -3.8)]; previous blood transfusion [OR: 3.7 (95% CI 1.4 - 9.5)]; and injection drug use [OR: 22.6 (95% CI 4.2 - 119.6)]. CONCLUSION: Injection drug use was an independent risk factor for HCV infection among chronic renal disease patients on HD. PMID- 20963333 TI - Ethics in scientific publications: the double copyright problem. PMID- 20963334 TI - Maxillary sinuses microbiology from patients with chronic rhinosinusitis. AB - There isn't definitive and consistent data concerning the distribution of bacterial species in patients with Chronic Sinusitis (CS). The variability of the results from studies in CS may be due to the different techniques used as collection method, variations in culture methods, previous antibiotic use, and difficulty in distinguishing bacterial flora from pathogenic agents. STUDY DESIGN: Clinical prospective. AIM: To identify the incidence of microorganisms in patients with CRS by growing bacteria from the secretion of the maxillary sinus. PATIENTS AND METHODS: Cross-sectional study in 62 patients that had undergone FESS for treatment of chronic sinusitis; cultures from the maxillary sinus were obtained. RESULTS: 62 samples, 33 (53.2%) had no growth; 29 (45.2%) counts of aerobic bacteria; one case (1.6%) of fungus growth; we did not find anaerobic bacteria. Pseudomonas aeruginosa was the one more frequently found - 8 samples (27.6%), Staphylococcus aureus and Staphylococcus epidermidis in 4 samples each; Streptococcus pneumoniae in 3 samples (10.4%); other Gram negative agents in 17 samples (31%). CONCLUSION: In the present study we concluded that Pseudomonas aeruginosa, other Gram negatives bacteria and Staphylococcus spp were the representatives of the bacterial flora found in the paranasal sinuses of patients with CS. PMID- 20963335 TI - Obstructive sleep apnea syndrome (OSAS) in mouth breathing children. AB - It is well known that mouth breathing is associated with adenotonsillar hypertrophy - which is the main cause of obstructive sleep apnea among children. Despite the importance of this matter, there are only a handful of studies showing the relationship between OSAS and mouth breathing. AIM: to determine the prevalence of obstructive sleep disorders in mouth breathing children and study its correlation with otorhinolaryngological findings. STUDY DESIGN: Retrospective cohort study. METHOD: Data analysis from 248 medical charts of mouth breathing children seen at the Pediatric Otolaryngologic Division of a large medical institution between the years of 2000 and 2006. All patients had nasofibroscopy and or Cavum radiographs and polysomnographic exams. According to the Apnea index, patients were classified as primary snorers (AI<1); and as OSAS (>1). RESULTS: From 248 patients included in the study, 144 (58%) were primary snorers and 104 (42%) had OSAS. The most prevalent otorhinolaryngological findings were adenotonsillar hypertrophy (n=152; 61.2%), tonsilar hypertrophy (n=17; 6.8%), adenoid hypertrophy (n=37; 14.9%), rhinitis (n=155; 62.5%) and secretory otitis (n=36; 14.5%). CONCLUSIONS: primary snoring and OSAS are frequent findings in mouth breathing children. The most frequent otorhinolaryngological disorder in children with OSAS is adenotonsillar hypertrophy with or without rhinitis. PMID- 20963336 TI - Correlation between the Friedman classification and the Apnea-Hypopnea Index in a population with OSAHS. AB - OSAHS is an important disease in current medical settings because of its association with chronic cardiovascular diseases and socioeconomic impacts. AIMS: to establish the correlation between the Friedman Classification and the OSAHS severity through the Apnea-Hypopnea Index) in patients with OSAHS for assessment and surgery purposes. MATERIALS AND METHODS: Cross-sectional study. We evaluated and classified 143 patients, using the Epworth's and Friedman's scale and OSAHS severity according to the AHI. RESULTS: 112 patients were submitted to polysomnography. We compared the Friedman Score and the IAH. The variables were associated with p<0.05. We found that patients with light OSAHS, tended to have a lower Friedman classification (better surgical result). By the same token, patients with moderate to severe OSAHS had a greater prevalence of Friedman's score of III and IV; p< 0.05 (lower success rates from uvulopalatopharyngoplasty). CONCLUSION: We conclude that the Friedman's classification correlates with OSAHS severity - the higher the Friedman's score, the more severe is the OSAHS. PMID- 20963337 TI - Local anesthesia for cochlear implant surgery: a possible alternative. AB - The aim of this paper is to illustrate the possibility of performing a cochlear implant surgery with local anesthesia and sedation, the anesthetic technique and the advantages of that in comparison to a general anesthesia. AIMS: prospective study demonstrating the possibility of doing cochlear implant surgery under local anesthesia and sedation. MATERIALS AND METHODS: we describe three successful cases operated under local anesthesia, including neural telemetry and the conditions the patient presented after the surgery, with a very good recovery and no complications during and after the procedure. RESULTS: these three surgeries show the possibility of doing the cochlear implant surgery with this kind of anesthesia, with a fast recovery, no symptoms of dizziness and vomiting after the surgery, and very few complaints from the patient. CONCLUSION: local anesthesia with sedation for cochlear implant surgery in adults is a very good alternative for lowering the morbidity for the patient. It bears fewer risks, low costs for the hospital, with a very good procedure control, being very useful for older patients or the ones that have contraindications for general anesthesia. PMID- 20963338 TI - Six years of facial trauma care: an epidemiological analysis of 355 cases. AB - Facial traumas are frequent in emergencies, and they require the diagnosis of fractures and associated lesions. AIM: To analyze epidemiological data concerning facial trauma care. MATERIALS AND METHODS: Three hundred and fifty-five charts from patients with facial trauma treated by the Service of Otorhinolaryngology, from January 2002 to December 2008, were revised. The following data was collected: age, gender, etiology, anatomical localization of the fracture, associated injuries, alcohol consumption, treatment, and hospitalization. STUDY DESIGN: A retrospective historical longitudinal study. RESULTS: Most of the patients are young adult men (p<0.05) with a male:female ratio of 4:1(p<0.05). Interpersonal violence is the most prevalent cause of facial trauma (27.9%), followed by motor vehicle accidents (16.6%) (p<0.05). The mandible is the most prevalent facial bone fractured (44.2%), followed by nasal fracture (18.9%) (p<0.05). 41.1% of the patients consumed alcohol with a male:female ratio of 11.2:1 (p<0.05). Seventy-seven percent of the patients required surgical intervention (p<0.05) and 84.5% were hospitalized (p<0.05). CONCLUSION: Young male adults are the most prevalent victims of facial trauma, and interpersonal violence is responsible for the majority of the facial injuries. Most of the cases of facial trauma are associated with the consumption of alcohol. Further studies will be necessary to provide a clear understanding of the trends in the etiology of facial trauma. PMID- 20963339 TI - Surgical simulator for temporal bone dissection training. AB - Temporal bone dissection plays an important role in the training of surgeons; however, they are difficult to obtain. AIM: To develop a synthetic replica of the temporal bone for dissection training. STUDY DESIGN: Experimental. MATERIALS AND METHODS: An acrylic synthetic resin replica was obtained from a human temporal bone. For the evaluation of the method, we selected five ear surgeons to dissect the model in a laboratory of experimental surgery. A questionnaire was filled, assessing external appearance, the simulation of procedures (placement of ventilation tube, mastoidectomy, decompression of the facial nerve and translabyrinthine access to the internal auditory canal) and their final conclusion. RESULTS: The evaluation indicated satisfaction in using the model (80%), being more evident concerning the dissection of the mastoid segment of the facial nerve and translabyrinthine access to the internal auditory canal. The placement of a ventilation tube was reasonable for 60% and satisfactory for 40% of them. Mastoidectomy was satisfactory for 60% and fully satisfactory for 40%. CONCLUSION: Dissection in this simulator does not replace otologic training in cadaveric temporal bones. However, given the increasing difficulty in obtaining the latter, the development of new teaching tools should be encouraged to continuously improve surgeons. PMID- 20963340 TI - Nasal mucosa study of leprosy contacts with positive serology for the phenolic glycolipid 1 antigen. AB - Leprosy is a chronic infectious disease caused by Mycobacterium leprae. The disease more frequently affects the nasal mucosa and can occur independently of its clinical form or even before lesions on the skin or on other parts of the body. It is necessary to employ epidemiological surveillance of household contacts with new leprosy cases for early disease diagnosis. AIM: identify specific and early leprosy lesions through endoscopic, baciloscopy, histopathology exams, and real time polymerase chain reaction of the nasal cavity mucosa on household and peridomiciliary contacts with positive serology for the phenolic glycolipid 1 antigen. METHODOLOGY: Between 2003 at 2006 there was a prospective cross-sectional clinical study with 31 contacts with patients with leprosy with positive serology against PGL-1, 05 negative controls and 01 positive control. RESULTS: Between seropositive contacts, real-time PCR was positive for M. leprae DNA in 06 (19.35%) of them and the higher number of genome copies were found in contacts who became sick. CONCLUSION: Nasal mucosa tests alone did not enable the early diagnosis of Leprosy. However, through the combination of various methods, tests on the contacts can help identify subclinical infection and monitor the contacts that could be responsible for spreading the disease. PMID- 20963341 TI - Balloon sinuplasty, an initial assessment: 10 cases, results and follow-up. AB - INTRODUCTION AND AIMS: Balloon sinuplasty has been the object of recent discussions and papers. It is believed that the use of these tools can bring benefits, when compared with traditional endoscopic sinus surgery. Although there already are papers on the efficacy of this new instrument in the literature, there is no study in our country with a series of cases and follow-up of patients undergoing sinuplasty. Our study aims to review the information of 10 patients who underwent balloon sinuplasty, alone or in combination, discussing the indications, complementary therapy and follow up evaluation. METHOD: retrospective study. RESULTS: Of 10 patients, 6 were males and 4 females. Their ages ranged from 7 to 58 years. All patients had chronic rhinosinusitis without nasal polyps, of which 8 are associated with allergic disease. 3 patients underwent sinuplasty only, and 7 had other procedures done during the same procedure. Follow-up ranged from 2 to 7 months. Of the 10 patients, 9 showed symptoms improvement in imaging studies. CONCLUSION: sinuplasty was successfully performed in all patients, without major technical difficulties or complications. This instrument can become an alternative surgical treatment for some groups of patients. PMID- 20963342 TI - Nasal obstruction and high Mallampati score as risk factors for Obstructive Sleep Apnea. AB - Respiratory sleep disorders are strongly associated with upper airway patency. Nasal obstruction is associated with higher incidences of sleep apnea, primarily by increasing the negative pressure on the airway during inspiration. AIMS: To evaluate the influence of nasal obstruction in the worsening of sleep apnea in patients with OSA and a high score on the modified classification of Mallampati. MATERIALS AND METHODS: We evaluated and classified 206 patients complaining of snoring, and with a past suggestive of OSA through the Modified Mallampati score, Friedman, nasal obstruction and the severity of OSA by AHI. RESULTS: 168 patients who underwent polysomnography were included. Cross-plotting was made comparing the modified Mallampati score, nasal obstruction and AIH. The odds ratio between high Mallampati score and AHI was OR = 5.053, 95% CI = 1.458 to 7.517 (p = 0.0071). High Mallampati score associated with nasal obstruction was correlated with OSAS (p = 0.0227). However the influence of nasal obstruction on the relationship of high Mallampati score and OSA was not significant: OR = 2.850, 95% CI = 0.992 to 8.189. CONCLUSION: The combination of high Mallampati score and nasal obstruction represents a greater risk factor for worsening of OSA. PMID- 20963343 TI - Service profile of Orthognathic Surgery of a medical school. AB - Orthognathic surgeries are very important for both the correction of dentofacial deformities as well as for the treatment of obstructive sleep apnea/hypopnea syndrome. Nowadays, most of the population presents some type of morphological and/or functional disorder of the stomatognathic system. AIM: The present study aims at assessing the information from the individuals treated in the Orthognathic Surgical Service of a Medical School. METHODS: Search in medical records - 2004-2008, identification procedures, individual characteristics, malocclusion and surgery. RESULTS: The number of surgical treatments due to dentofacial deformities has been increasing. Maxillary advancement surgery alone comprised the highest number in the sample. CONCLUSION: Orthognathic surgery cases have been increasing in the last years and maxillary advancement alone comprised the highest number of surgical treatments. PMID- 20963344 TI - Newborn hearing screening in the Limiar Clinic in Porto Velho - Rondonia. AB - With the universal hearing screening we can prevent auditory disorders in children. AIM: To characterize the program of neonatal auditory screening into a population of neonates. MATERIALS AND METHODS: longitudinal cohort study. We surveyed the clinic's database on neonatal auditory screening in the city of Porto Velho, Rondonia. RESULTS: Among the 6,889 newborns in the database, 5,700 (82.7%) passed and 1,189 (17.3%) failed the first screening. Of the group which failed 900 (75.7 %) returned for retesting. Among these, 15 (0.22 %) newborns had hearing loss confirmed. The most prevalent was neural hearing loss with 46.7% confirmed cases; they had hyperbilirubinemia as the most prevalent risk factor. CONCLUSION: hyperbilirubinemia was the most prevalent risk factor found in the group of hearing impaired children. The prevalence of hearing loss was of 2 in 1,000 newborns. It is important to highlight the relevant association between neural hearing loss caused by hyperbilirubinemia and sensorineural hearing loss of unknown causes. PMID- 20963345 TI - Balance Rehabilitation Unit (BRU) posturography in Meniere's disease. AB - Posturography has been used in the evaluation of patients with vestibular disorders. AIM: To evaluate balance control with the Balance Rehabilitation Unit (BRU) posturography in patients with Meniere's disease. STUDY DESIGN: Prospective case-control. MATERIAL AND METHOD: 30 patients diagnosed with Meniere's disease and a control group consisting of 40 healthy matching individuals in relation to age and gender, were submitted to a balance function evaluation by means of a Balance Rehabilitation Unit (BRU) posturography. RESULTS: Comparing patients with Meniere's disease and the control group, we found significant differences between the values of the sway speed in the static force plate, down optokinetic stimulation (p=0.038) and horizontal visual vestibular interaction (p=0.049); and of the ellipse area in the static force plate, eyes closed (p=0.001); left optokinetic stimulation (p=0.007); down optokinetic stimulation (p=0.003); horizontal visual vestibular interaction (p=0.003); and vertical visual vestibular interaction (p=0.028). CONCLUSION: The postural control assessment with the Balance Rehabilitation Unit (BRU) posturography enables the identification of sway speed and ellipse area abnormalities in patients with Meniere's disease. PMID- 20963346 TI - Prognostic value of sinus CT scans in hematopoietic stem cell transplantation. AB - Hematopoietic Stem Cell Transplant (HSCT) causes immunosuppression and predisposition to sinusitis. CT scans are complementary exams used in the diagnosis of sinusitis; however, its use in every patient is questionable. AIM: to check the usefulness of ordering a CT scan prior to HSCT and to study the relationship between anatomical variations and sinusitis. METHOD: prospective study in which we performed paranasal CT scans before and after HSCT, using the Lund and Mackay score. RESULTS: 77.5% and 61% of CT scans showed no evidence of sinus disease before and after HSCT. CT staging was not associated with sinusitis after HSCT. Anatomical variations were related to radiographic disease severity, but not to development of sinusitis after HSCT. There was no relation between pre CT staging and sinusitis after BMT. CONCLUSION: CT scans are not useful for all patients before HSCT. Anatomical variation is not a predictive feature to sinusitis but it can determine its severity. PMID- 20963347 TI - Results from the balance rehabilitation unit in benign paroxysmal positional vertigo. AB - Posturography is a useful new tool to study the influence of vestibular diseases on balance. AIM: to compare the results from the Balance Rehabilitation Unit (BRU) static posturography in elderly patients with Benign Paroxysmal Positional Vertigo (BPPV), before and after Epley's maneuver. MATERIALS AND METHODS: a prospective study of 20 elderly patients with a diagnosis of BPPV. The patients underwent static posturography and the limit of stability (LE) and ellipse area were measured. We also applied the Dizziness Handicap Inventory (DHI) questionnaire to study treatment effectiveness. RESULTS: 80% were females, with a mean age of 68.15 years. After the maneuver, the LE increased significantly (p=0.001). The elliptical area of somatosensory, visual and vestibular conflicts (2,7,8,9 situations) in BRU and the DHI scores decreased significantly (p<0.05) after treatment. CONCLUSION: the study suggests that elderly patients with BPPV may present static postural control impairment and that the maneuver is effective for the remission of symptoms, to increase in the stability and improvement in postural control in situations of visual, somatosensory and vestibular conflicts. PMID- 20963348 TI - Directivity and noise reduction in hearing aids: speech perception and benefit. AB - Hearing aid. AIM: To compare the performance, benefit and satisfaction of users of ITE, CIC and BTE digital hearing aid with noise reduction and omnidirectional and directional microphones. METHOD: 34 users of hearing aid were evaluated by means of speech perception in noise tests and APHAB and IOI self assessment questionnaires. Prospective study. RESULTS: Better results were obtained by users of ITE, CIC and directional hearing aids, however, no statistical significance was found between the groups. CONCLUSION: Directivity improved speech perception in noise and benefit in daily life situations. PMID- 20963349 TI - Intratemporal facial nerve ultrastructure in patients with idiopathic facial paralysis: viral infection evidence study. AB - The etiology of idiopathic peripheral facial palsy (IPFP) is still uncertain; however, some authors suggest the possibility of a viral infection. AIM: to analyze the ultrastructure of the facial nerve seeking viral evidences that might provide etiological data. MATERIAL AND METHODS: We studied 20 patients with peripheral facial palsy (PFP), with moderate to severe FP, of both genders, between 18-60 years of age, from the Clinic of Facial Nerve Disorders. The patients were broken down into two groups - Study: eleven patients with IPFP and Control: nine patients with trauma or tumor-related PFP. The fragments were obtained from the facial nerve sheath or from fragments of its stumps - which would be discarded or sent to pathology exam during the facial nerve repair surgery. The removed tissue was fixed in 2% glutaraldehyde, and studied under Electronic Transmission Microscopy. RESULTS: In the study group we observed an intense repair cellular activity by increased collagen fibers, fibroblasts containing developed organelles, free of viral particles. In the control group this repair activity was not evident, but no viral particles were observed. CONCLUSION: There were no viral particles, and there were evidences of intense activity of repair or viral infection. PMID- 20963350 TI - New system of instrument stabilization in laryngeal microsurgery. AB - Laryngeal microsurgery is a kind of treatment for various laryngeal diseases. Because of the need of long instruments and delicate maneuvers, involuntary movements represent relevant difficulty and may be responsible for unintended post-operative results. AIM: This study proposes a new stabilization system, flexible and versatile, which can significantly reduce involuntary movements made by surgeons. METHODS: This experimental study compared the amplitude of surgeons' involuntary movements with and without the stabilization system. Ten surgeons performed a total of six movements mimicking movements used in laryngeal microsurgery, two of them without the stabilization system. The maneuvers were repeated with the stabilization system and the wire stretched, and after this, the wire was then expanded 3mm and the maneuvers were performed. The average values of the maximum instrument displacement were compared between the groups. RESULTS: The maximum displacement was higher during the maneuver with the still micro-scissors without the system, when compared with the stabilization system in three different situations. The average was also higher in the maneuver to open and close the micro scissors without the system and with it. CONCLUSION: The proposed stabilization system was effective in reducing surgeon shaking in the different situations tested. PMID- 20963351 TI - Cleft lip and palate: series of unusual clinical cases. AB - Cleft lip and/or palate (CL/P) represent the most common congenital anomalies of the face, corresponding to approximately 65% of all malformations of the craniofacial region. AIM: to describe unusual clinical cases of non-syndromic CL/P (CL/PNS), diagnosed in a reference service in Minas Gerais, Brazil, and correlate these alterations with possible risk factors. MATERIALS AND METHODS: we carried out a retrospective study, between the years of 1992 and the 1st half of 2009, from medical records. RESULTS: Among the 778 cases of CL/PNS diagnosed in the period of 17 years, 5 (0.64%) were unusual CL/PNS, and all patients were male. It was found that among the 5 patients, 2 had incomplete right cleft lip with incomplete cleft palate, 2 were affected by left incomplete cleft lip and incomplete cleft palate, and 1 had a cleft lip and palate associated with complete right cleft palate. Risk factors such as consanguinity, maternal smoking and alcohol consumption, medication usage during pregnancy, history of abortion and/or stillbirths and maternal diseases were not associated with unusual CL/PNS. CONCLUSIONS: This study described 5 unusual cases of CL/PNS in a Brazilian population; no associations with the risk factors analyzed were seen. It also confirmed the unusualness of the prevalence of such alterations. PMID- 20963352 TI - Acoustic radiation effects on bone conduction threshold measurement. AB - Acoustic radiation is the sound energy escape from a bone vibrator that may be detected by air conduction mechanisms. The presence of acoustic radiation may result in an unreal bone conduction threshold, promoting an unreal air/bone gap in the high frequencies. AIM: aim to analyze the acoustic radiation effect on the extension of air/bone gap at 2,000, 3,000 and 4,000 Hz. MATERIALS AND METHOD: our clinical and experimental study had a sample of 101 individuals, who matched inclusion criteria: to have an air/bone gap higher than 10 dB in the frequencies of 2,000; 3,000 and 4,000 Hz. All of them had their bone conduction threshold measured in two conditions: open ear canal and closed ear canal. RESULTS: we found that major differences between the two conditions evaluated occurred at the 4,000 Hz; data analysis showed significant difference in the extension for the air/bone gap; analysis of the number of cases of mixed hearing loss that changed to sensorineural was significant too. CONCLUSION: These studies concluded that when the MAE is occluded, the acoustic radiation phenomenon is controlled or avoided, enabling bone measures at the frequencies of 3,000 and 4,000Hz to be more accurate. PMID- 20963353 TI - Pilocarpine used to treat xerostomia in patients submitted to radioactive iodine therapy: a pilot study. AB - Xerostomia complaint is very commonly associated to radioactive iodine therapy. Alternatives to treat this morbidity can offer better quality of life to patients with thyroid cancer submitted to adjuvant iodine therapy. AIM: to report on the experience with pilocarpine on the treatment of xerostomia in thyroid cancer patients submitted to adjuvant radioactive iodine therapy (RIT). MATERIALS AND METHODS: The five patients who met the inclusion criteria received 5mg of pilocarpine, 3 tid for one week. Side effects of the drug and subjective response to xerostomia complaints after treatment were evaluated. DESIGN: it is a prospective, non-randomized study. RESULTS: Sudoresis was the most frequent side effect of pilocarpine use, followed by fatigue and headache. Two patients reported relief of xerostomia using pilocarpine, but only one patient was able to tolerate the side effects. CONCLUSIONS: Pilocarpine seems to relieve xerostomia complaints in thyroid cancer patients because it is able to stimulate salivary flow, but the observed side effects made the patients refuse long-term therapy continuation. PMID- 20963354 TI - Profile of audiometric thresholds and tympanometric curve of elderly patients. AB - AIM: to analyze the audiological profile of elderly patients seen in a clinic from an audiology school clinic in the city of Belo Horizonte. METHODS: we studied all the charts from the patients who underwent audiologic assessment from April of 2004 and August of 2007 in an audiology clinic in the city of Belo Horizonte. RESULTS: We studied the 313 audiological tests from patients 60 years of age or over. The results from the audiological evaluations as to the type of hearing loss were: auditory thresholds within normal standards - 22.28%; sensorineural hearing loss - 60.62%; mixed hearing loss - 14.70%, conductive hearing loss - 2.40%. The level varied between normal and profound. As to the tympanometry, 83.22% had the type A curve, and the other types of curves obtained made up a total of 16.3%. The percentage of individuals who did not undergo the test was 0.48%. 1.76% of the patients who had unilateral hearing loss and 98.24% had bilateral hearing loss. CONCLUSIONS: we found a greater prevalence of sensorineural hearing loss, and the degree of the loss varied from mild to profound, with a prevalence of the moderate degree. PMID- 20963355 TI - Hyperproliferation markers in ear canal epidermis. AB - Several studies involving immunohistochemical methods to assess external auditory canal epidermis have been performed with different objectives. With this method it is possible to assess the expression of various antigens such as cytokeratins, cytokines, and hyperproliferation markers among others. AIM: to revise, describe and analyze the knowledge generated by identifiable papers published on the worldwide literature about immunohistochemical hyperproliferation markers in normal external auditory canal epidermis. MATERIALS AND METHODS: systematic review of the papers published until 2009, in indexed international journals. RESULTS: Various antigens related to hyperproliferation were investigated by immunohistochemical methods among the included papers. The most studied ones were cytokeratin 16, Ki-67 and PCNA. CONCLUSIONS: most of the studies utilized external auditory canal epidermis as control sample to study external ear or middle ear cholesteatoma with immunohistochemical methods. There is a hyperproliferative antigen concentration, such as CK16, Ki-67 and PCNA, in the annulus tympanicus, adjacent meatus and tympanic regions, mainly in the lower areas. PMID- 20963356 TI - Evaluation of auditory processing before and after treatment in patients with speech disorders. PMID- 20963357 TI - Middle ear Schwannoma. PMID- 20963358 TI - Maxillomandibular myxoma in neonates. PMID- 20963359 TI - Angioleiomyoma of the nasal septum. PMID- 20963360 TI - Evidence-based assessment of new technologies: good for Barack Obama's healthcare plan and good for Brazil, and at everyone's reach through HTAi Rio 2011. PMID- 20963361 TI - Medical education beyond graduation: scientific initiation. PMID- 20963362 TI - Prognosis for patients diagnosed with pregnancy-associated breast cancer: a paired case-control study. AB - CONTEXT AND OBJECTIVE: Previous studies have suggested that the occurrence of pregnancy concomitantly with a diagnosis of breast cancer may affect the evolution of the neoplasia. The present study aimed to compare pregnancy associated breast cancer (PABC) patients with non-pregnant cancer patients (controls) in relation to the time taken to diagnose the disease, tumor characteristics and mortality. DESIGN AND SETTING: A retrospective, paired case control study was conducted at the Hospital da Santa Casa de Misericordia and Centro de Quimioterapia Antiblastica e Imunoterapia in Belo Horizonte, Brazil. METHODS: The study involved 87 PABC and 252 control patients. The influence of covariables (interval between first symptoms and diagnosis, tumor histology, size of primary tumor, distant metastasis, grade of malignancy, hormone receptor status and axillary lymph node involvement) and the pregnancy variable on overall survival was investigated using univariate and multivariate analyses. RESULTS: The median overall survival for PABC patients of 30.1 months (95% confidence interval, CI: 19.4-40.9 months) was significantly different (P = 0.005) from that of the control group (53.1 months; 95% CI: 35.1-71.0 months). The cumulative overall survivals after five and ten years were, respectively, 29.7 and 19.2% for PABC patients, and 47.3 and 34.8% for control patients (P = 0.005). Tumor size, grade of malignancy, distant metastasis and pregnancy were independent factors that significantly modified disease prognosis. CONCLUSIONS: Pregnancy was an independent prognostic factor. The overall survival of PABC patients was shorter than that of non-pregnant patients. PMID- 20963363 TI - A multivariate analysis on prognostic factors for lobular carcinoma of the breast. AB - CONTEXT AND OBJECTIVE: Lobular carcinoma is the second most common type of breast neoplasia and has unique clinical and pathological features. Our aim was to evaluate prognostic factors for this type of breast cancer. DESIGN AND SETTING: Retrospective study at a tertiary oncological institution. METHODS: 162 patients diagnosed and treated between January 1985 and January 2002 were included. The inclusion criteria were: absence of previous treatment, histological diagnosis of lobular carcinoma, no previous history of breast cancer and minimum follow-up of 36 months. RESULTS: In univariate analysis, the following factors were statistically significant: clinical stage T (P = 0.0005), clinical stage N (P = 0.0014), neoadjuvant chemotherapy (P = 0.0008), primary tumor size (P < 0.0001), vascular invasion (P < 0.0001), lymphatic invasion (P = 0.0004), neural invasion (P = 0.0004), skin invasion (P < 0.0001), capsular transposition (P = 0.0008), lymph node ratio (P < 0.0001), estrogen receptor expression (P = 0.0186), progesterone receptor expression (P = 0.0286), pathological stage T (P < 0.0001), pathological stage N (P < 0.0001), adjuvant chemotherapy (P < 0.0001) and postoperative hormone therapy (P = 0.0367). After grouping the variables, multivariate analysis was performed. Presence of lymph node metastases, capsular transposition, lymph node ratio and postoperative hormone therapy remained significant. CONCLUSION: In this series, the most important prognostic factors for lobular carcinoma of the breast seemed to relate to lymph node status and presence of capsular transposition. Factors relating to axillary involvement, capsular transposition and hormone therapy were significant for survival. PMID- 20963364 TI - Intra and interobserver reliability of the interpretation of high-resolution computed tomography on the lungs of premature infants. AB - CONTEXT AND OBJECTIVE: High-resolution computed tomography (HRCT) of the lungs is more sensitive than radiographs for evaluating pulmonary disease, but little has been described about HRCT interpretation during the neonatal period or shortly afterwards. The aim here was to evaluate the reliability of the interpretation of HRCT among very low birth weight premature infants (VLBWPI; < 1500 g). DESIGN AND SETTING: Cross-sectional study on intra and interobserver reliability of HRCT on VLBWPI. METHODS: 86 VLBWPI underwent HRCT. Two pediatric radiologists analyzed the HRCT images. The reliability was measured by the proportion of agreement, kappa coefficient (KC) and positive and negative agreement indices. RESULTS: For radiologist A, the intraobserver reliability KC was 0.79 (confidence interval, CI: 0.54-1.00) for normal/abnormal examinations; for each abnormality on CT, KC ranged from 0.05 to 1.00. For radiologist B, the intraobserver reliability KC was 0.79 (CI: 0.54-1.00) for normal/abnormal examinations; for each abnormality on CT, KC ranged from 0.37 to 0.83. The interobserver agreement was 88% for normal/abnormal examinations and KC was 0.71 (CI: 0.5- 0.93); for most abnormal findings, KC ranged from 0.51-0.67. CONCLUSION: For normal/abnormal examinations, the intra and interobserver agreements were substantial. For most of the imaging findings, the intraobserver agreement ranged from moderate to substantial. Our data demonstrate that in clinical practice, there is no reason for more than one tomographic image evaluator, provided that this person is well trained in VLBWPI HRCT interpretation. Analysis by different observers should be reserved for research and for difficult cases in clinical contexts. PMID- 20963365 TI - Cardiovascular and metabolic syndrome risk among men with and without erectile dysfunction: case-control study. AB - CONTEXT AND OBJECTIVE: Erectile dysfunction has been associated with cardiovascular diseases. The aim here was to evaluate cardiovascular risk through the Framingham Risk Score (FRS) criteria, C-reactive protein (CRP) assays and presence of metabolic syndrome (MS) in men with and without erectile dysfunction diagnosed within a healthcare program. DESIGN AND SETTING: A retrospective case control study was conducted. The patients were selected from a healthcare program at the Hospital Israelita Albert Einstein, between January and December 2007. METHODS: 222 men were retrospectively selected, and they were divided into two groups: men with erectile dysfunction (n = 111) and men without erectile dysfunction (n = 111). The patients were stratified according to the International Index of Erectile Function-Erectile Function domain (IIEF-EF domain). CRP and FRS were analyzed and the two groups were compared. RESULTS: The CRP levels were significantly higher among men with erectile dysfunction (P = 0.04). Patients with erectile dysfunction also had high FRS (P = 0.0015). CRP and FRS did not correlate with the severity of erectile dysfunction. The presence of metabolic syndrome was greater among men with erectile dysfunction (P < 0.05). The severity of erectile dysfunction was directly associated with metabolic syndrome. CONCLUSION: Men with erectile dysfunction presented higher cardiovascular risk according to the FRS criteria and CRP measurements. Severe erectile dysfunction seemed to have a correlation with metabolic syndrome. PMID- 20963366 TI - Efficacy and safety of atypical antipsychotic drugs (quetiapine, risperidone, aripiprazole and paliperidone) compared with placebo or typical antipsychotic drugs for treating refractory schizophrenia: overview of systematic reviews. AB - CONTEXT AND OBJECTIVE: According to some cohort studies, the prevalence of refractory schizophrenia (RS) is 20-40%. Our aim was to evaluate the effectiveness and safety of aripiprazole, paliperidone, quetiapine and risperidone for treating RS. METHODS: This was a critical appraisal of Cochrane reviews published in the Cochrane Library, supplemented with reference to more recent randomized controlled trials (RCTs) on RS. The following databases were searched: Medical Literature Analysis and Retrieval System Online (Medline) (1966 2009), Controlled Trials of the Cochrane Collaboration (2009, Issue 2), Embase (Excerpta Medica) (1980-2009), Literatura Latino-Americana e do Caribe em Ciencias da Saude (Lilacs) (1982-2009). There was no language restriction. Randomized controlled trials, systematic reviews and meta-analyses evaluating atypical antipsychotics for treating RS were included. RESULTS: Seven Cochrane systematic reviews and 10 additional RCTs were included in this review. The data generally showed minor differences between the atypical antipsychotics evaluated and typical antipsychotics, regarding improvement in disease symptoms, despite better adherence to treatment with atypical antipsychotics. Risperidone was specifically evaluated in patients with RS in one of the systematic reviews included, with favorable outcomes, but without definitive superiority compared with other drugs of proven efficacy, like amisulpride, clozapine and olanzapine. CONCLUSIONS: The findings underscore the difficulty in treating these patients, with high dropout rates and treatment patterns of modest improvement in assessments of effectiveness. Atypical antipsychotics have advantages over typical antipsychotics mainly through their better safety profile, which leads to better adherence to treatment. A combination of antipsychotics may also be an option for some refractory patients. PMID- 20963367 TI - Restless legs syndrome: literature review. AB - Restless legs syndrome is a distressing condition, with negative effects on sleep and daytime activities that affect personal, family and occupational life. The overall impact of restless legs syndrome on quality of life is comparable to that of chronic and frustrating conditions such as depression and diabetes. Misdiagnosis and inappropriate treatment may increase patients' suffering in terms of uncertainty, overuse or misuse of care services and lack of trust. Presenting a synthesis of the main topics in the literature on restless legs syndrome facilitates for a better understanding and its management in primary care settings. PMID- 20963368 TI - Avoiding pitfalls in diagnosing basilar artery occlusive disease: clinical and imaging clues - case report. AB - CONTEXT: The aim of this paper was to report on the characteristics that aid in establishing the diagnosis of basilar artery occlusive disease (BAOD) among patients with hemiparesis and few or minor symptoms of vertebrobasilar disease. CASE REPORT: This report describes two cases in a public university hospital in Sao Paulo, Brazil. We present clinical and imaging findings from two patients with hemiparesis and severe BAOD, but without clinically relevant carotid artery disease (CAD). One patient presented transient ischemic attacks consisting of spells of right hemiparesis that became progressively more frequent, up to twice a week. The neurological examination revealed slight right hemiparesis and right homonymous hemianopsia. Magnetic resonance imaging (MRI) revealed pontine and occipital infarcts. Magnetic resonance angiography and digital subtraction angiography revealed severe basilar artery stenosis. The other patient presented sudden left-side hemiparesis and hypoesthesia. One year earlier, she had reported sudden onset of vertigo that, at that time, was attributed to peripheral vestibulopathy and was not further investigated. MRI showed a right-side pontine infarct and an old infarct in the right cerebellar hemisphere. Basilar artery occlusion was diagnosed. Both patients presented their symptoms while receiving aspirin, and became asymptomatic after treatment with warfarin. CONCLUSIONS: Misdiagnosing asymptomatic CAD as the cause of symptoms in BAOD can have disastrous consequences, such as unnecessary carotid endarterectomy and exposure to this surgical risk while failing to offer the best available treatment for BAOD. Clinical and imaging features provided important clues for diagnosis in the cases presented. PMID- 20963369 TI - Urological complication following aortoiliac graft: case report and review of the literature. AB - CONTEXT: Ureteral stenosis and ureterohydronephrosis may be serious complications of aortoiliac or aortofemoral reconstructive surgery. CASE REPORT: A 62-year-old female patient presented with a six-month history of left lumbar pain. She was a smoker, and had mild chronic arterial hypertension and Takayasu arteritis. She had previously undergone three vascular interventions. In two procedures, Dacron prostheses were necessary. Excretory urography showed moderate left ureterohydronephrosis and revealed a filling defect in the ureter close to where the iliac vessels cross. This finding was compatible with ureteral stenosis, and the aortoiliac graft may have been the reason for this inflammatory process. The patient underwent laparotomy, which showed that there was a relationship between the ureteral stenosis and the vascular prosthesis. Segmental ureterectomy and end to-end ureteroplasty with the ureter crossing over the prosthesis anteriorly were performed. There were no complications. The early and late postoperative periods were uneventful. The patient evolved well and the results from a new excretory urogram were normal. We concluded that symptomatic ureterohydronephrosis following aortoiliac graft is a real complication and needs to be quickly diagnosed and treated by urologists. PMID- 20963373 TI - Investigating the role played by social support in the association between religiosity and mental health in low income older adults: results from the Sao Paulo Ageing & Health Study (SPAH). AB - OBJECTIVE: Religiosity has been associated with mental health, especially in the elderly. There is a shortage of studies on the factors that mediate this association, including social support. The aim of this study was to assess the association between the various dimensions of religiosity and the prevalence of common mental disorders among the elderly, and to verify whether social support can work as a mechanism that explains such mediation. METHOD: The sample consisted of an elderly population living in a low income region of the city of Sao Paulo (N = 1,980). Data on the socio-demographic profile of this population and on the prevalence of common mental disorders were collected, and indicators of religiosity and social support were identified. RESULTS: 90.7% of the sample considered themselves to be religious. In terms of denomination, 66.6% were Catholic. Forty-one per cent attended some kind of religious activity at least once or more times a week. The presence of common mental disorders was not associated with religious affiliation or subjective religiosity. The prevalence of common mental disorders in followers attending religious services was approximately half (OR between 0.43 and 0.55, p < 0.001) compared to those who never attend a religious service. Attending religious services was associated with higher levels of social support. The association between a higher attendance frequency and fewer common mental disorders did not change after the inclusion of relevant of social support variables. CONCLUSION: The study showed that subjects presented high levels of religiosity and that there is a strong association between religious attendance and the prevalence of common mental disorders, which could not be explained by social support. PMID- 20963377 TI - [Conventional reparation of parastomal hernia]. AB - The reparation of parastomal hernias and their recurrence remain problematic although the implementation of mesh techniques has lowered recurrences rates. Conventional surgical techniques include suture repair, relocation of the stoma as well as diverse hernia repair procedures with mesh implantation. Suture repair has been abandoned due to its high recurrence rate. Simple relocation is not recommended because of high rates of recurrent parastomal hernias. Conventional hernia repair using mesh implants is classified according to the mesh position into epifascial (onlay), retromuscular (sublay) and intraperitoneal (IPOM) techniques. Furthermore, a combination of relocation with additional mesh enforcement is also possible. The value of the different mesh techniques and of new biological mesh prostheses must be evaluated in randomized controlled studies. PMID- 20963378 TI - [Chronic Strongyloides stercoralis infection. Larva currens as skin manifestation]. AB - Strongyloidiasis is a nematode infection that can persist asymptomatically for years. Pathognomonic skin manifestation is the larva currens. A human immunodeficiency virus-infected patient native from an endemic area presented with pruritus, an urticarial serpiginous rash and eosinophilia. The histology was not helpful. Strongyloidiasis was confirmed on the basis of stool and serum examination. He was treated successfully with Ivermectin. PMID- 20963379 TI - [Inappropriate test methods in allergy]. AB - Inappropriate test methods are increasingly utilized to diagnose allergy. They fall into two categories: I. Tests with obscure theoretical basis, missing validity and lacking reproducibility, such as bioresonance, electroacupuncture, applied kinesiology and the ALCAT-test. These methods lack both the technical and clinical validation needed to justify their use. II. Tests with real data, but misleading interpretation: Detection of IgG or IgG4-antibodies or lymphocyte proliferation tests to foods do not allow to separate healthy from diseased subjects, neither in case of food intolerance, allergy or other diagnoses. The absence of diagnostic specificity induces many false positive findings in healthy subjects. As a result unjustified diets might limit quality of life and lead to malnutrition. Proliferation of lymphocytes in response to foods can show elevated rates in patients with allergies. These values do not allow individual diagnosis of hypersensitivity due to their broad variation. Successful internet marketing, infiltration of academic programs and superficial reporting by the media promote the popularity of unqualified diagnostic tests; also in allergy. Therefore, critical observation and quick analysis of and clear comments to unqualified methods by the scientific medical societies are more important than ever. PMID- 20963380 TI - [Tongue fixation in OSA]. PMID- 20963381 TI - [Ultrasound: an appraisal]. PMID- 20963382 TI - [Ultrasound of the larynx, hypopharynx and upper esophagus]. AB - Sonography is an integral part of the routine diagnosis of diseases of the head and neck area. Ultrasound plays an important role in particular in the diagnosis, treatment and follow-up of head and neck cancer. Sonographic imaging of the larynx, hypopharynx and upper esophagus is often difficult due to the anatomical conditions. Therefore, CT and MRI are performed as the imaging techniques of first choice for diseases of these organs. In addition to the well-established transcutaneous ultrasound, endoscopic endoluminal ultrasound has developed as a promising new technique in recent years. Hollow organs can be displayed in high resolution transcutaneously and endoluminally. Thus, the attending otolaryngologist can use endoscopy and ultrasonography for accurate surgical planning. The aim of the present paper is to present the possibilities and limitations of ultrasonography of the larynx, hypopharynx and upper esophagus. PMID- 20963383 TI - [The value of ultrasound examinations, including intraoperative sonography, in ENT practice]. AB - Sonography is an established part of routine ENT examinations. Due to the anatomy of the head neck region most organs and their diseases are easily accessible to sonography. Constant technical advances mean that ultrasound, due to its high resolution capabilities, represents an outstanding diagnostic alternative to magnetic resonance imaging and computer tomography. Sonography provides additional information of diagnostic value on various diseases occurring in the head and neck region. The use of sonography for diagnostic and follow-up examinations is integrated in daily clinical routine. Moreover, sonography is also a helpful intraoperative tool for both diagnostic and therapeutic reasons and offers new approaches for intraoperative navigation. PMID- 20963384 TI - [History of ultrasound diagnosis in the head and neck]. AB - The history of ultrasonography of the head and neck region begins in the 1970s, initially with one-dimensional A-scan examinations and later on with two dimensional imaging using linear and compound scanners. In the early 1980s dynamic developments took place, not only in terms of the technical possibilities presented by ultrasonography but also in terms of broadened medical applications in all specialties. Progressing from analog to digital image processing, colour coding and combining B-mode with Doppler technology provided for improved topographic, structural and functional analysis. All this highlights the importance of ultrasonography in the armamentarium of clinical and imaging diagnostics. PMID- 20963385 TI - [Hypopharyngeal carcinoma and red ear drum]. AB - A 46-year-old male patient with an unresectable hypopharyngeal carcinoma was treated with primary radio-chemotherapy. At follow-up, the patient presented with a red ear drum and combined hearing loss. Because of radiotherapy-induced tubal dysfunction, paracentesis was performed. Biopsy of the polypoid middle ear mucosa revealed petrous bone infiltration of hypopharyngeal carcinoma. MRI studies revealed paracarotideal tumor infiltration to the petrous bone and the middle ear arising from a cervical retropharyngeal lymph node metastasis. PMID- 20963386 TI - [Nuchal swelling]. AB - In the unusual case of a 68-year-old woman with one-sided painless lateral neck swelling, the ENT examination showed a firm nuchal mass (4 * 4 cm) on the right side with no other pathological findings. Angio-MRI confirmed a solid, sharply demarcated tumor with arterial hyperperfusion. Core needle aspiration biopsy was performed, revealing well-circumscribed tufts showing the typical "cannonball" aspect. After preoperative embolisation we performed extirpation of the mass. Histological examination showed an acquired tufted angioma. Clinical as well as radiological follow-up examination detected neither local relapse nor metastases. PMID- 20963387 TI - [Current therapy concepts in head and neck tumors. Post ASCO Congress]. PMID- 20963388 TI - [The current value of induction chemotherapy. ASCO Congress 2010]. AB - The aim of systemic induction chemotherapy is organ preservation and tumor downstaging to improve resectability and reduce surgical risk. Not only the prolongation of overall survival but also the entitlement to a better quality of life during the treatment of patients with head and neck squamous cell cancer (HNSCC) have made changes to current treatment regimes necessary. Disappointing results prevented the breakthrough of PF therapy (cisplatin and 5-fluorouracil, 5 FU). New approaches using docetaxel, cisplatin and 5-FU (TPF) as a triple combination as well as the additional extension of novel biological targets within study designs are cause for fresh hope. Thus, the TPF combination has been established as the standard induction chemotherapy regime. PMID- 20963389 TI - [HPV infection in head and neck squamous cell carcinoma (HNSCC). Highlights from ASCO 2010]. AB - The human papillomavirus (HPV) is now understood to be important in the development of oropharyngeal cancers, particularly when other risk factors typically associated with this disease, such as smoking and nicotine abuse, are less evident. Case series have suggested that HPV-positive status is associated with better outcomes than HPV-negative status. The HPV status of patients with oropharyngeal cancer should be established before treatment commences. The risks and potential benefits of individual treatment modalities for patients with HPV positive disease should be carefully considered with the aim of preserving quality of life, improving outcomes, and minimizing morbidity. The new data presented at ASCO will be discussed. PMID- 20963390 TI - [Radiation therapy in head and neck cancer. Highlights from ASCO 2010]. AB - In contrast to conventional radiotherapy, intensity modulated radiotherapy (IMRT) enables individually adjusted dose and intensity depending on tumor size and organs at risk, thus enabling radiotherapy of complex volumes in the head and neck area using high doses. Despite new data presented at the annual congress of the American Society of Clinical Oncology (ASCO), questions remain unanswered in two basic categories: (a) How do we use IMRT with other important advances in head and neck cancer treatment, such as altered fractionation, chemotherapy, and novel agents? (b) Does IMRT in its current form produce sufficient risk:benefit improvements in salivary gland sparing/less xerostomia, better targeting/local control and less late toxicity? Whether IMRT with its complex target volume definition and dose distribution leads to improved local control needs to be further investigated in relevant studies. PMID- 20963391 TI - [Dyspnea and chronic recurrent respiratory tract infections]. AB - A 48-year-old man presented with recurrent bronchopulmonary infections of many years' standing. The diagnosis of tracheobronchomegaly (Mounier-Kuhn syndrome) was based on CT examination and subsequent bronchoscopy. Since lung transplantation was not considered advisable, a biluminal stent was inserted to prevent bronchial collapse. PMID- 20963392 TI - [Conception, realization and analysis of a modern operating theatre workplace for ENT surgery]. AB - BACKGROUND: The requirements of ENT (ear, nose and throat) surgery, i. e. operating theatre, have changed dramatically in recent years, e. g. by high definition video endoscopy, navigation, neuromonitoring, intraoperative imaging, navigated and navigation-controlled instruments and intraoperative imaging and video documentation. For this reason a specialized operating theatre is necessary for ENT. The aim of this work was to compare this operating theatre with the previous standard. MATERIAL AND METHODS: The scientific basis of this work represents a surgical workflow analysis. Over 200 completely documented operations in conventional operating theatres were available for comparison. In addition the log files of the medical technical devices, software analysis modules of the clinical documentation and ergonomics questionnaires (NASA TLX standard) were available. In the period from 1(st) June 2009 to 31(st) September 2009 a total of 139 standard procedures (9 different ENT surgeons) were analyzed in the new ly integrated operating theatre system "Surgical Deck1-ENT". RESULTS: In the newly developed operating theatre system four work areas are specified: preparation area, technical cockpit, surgical cockpit and anesthesia cockpit. The medical technical components are permanently installed. The surgical cockpit incorporates five permanently arranged monitors, two main screens, two navigation screens and a surgical dashboard. A suitable high definition video routing system is installed and procedure-specific light profiles are developed. Documentation is automatically carried out in the picture archive and communication system (PACS). The comparison to the conventional operating theatre system the slot time was reduced from 73.8 min to 65.6 min (-11%), the preoperative time was reduced on average by 31% (8 min) per case and the documentation time was decreased on average by 6 min (67%). The interaction steps of the surgeon with the system were reduced by 70% (from 17 to 5 steps). No significant differences in complications could be observed. In the total evaluation of all 16 questions on the ergonomics there was a significant improvement of the workplace layout. DISCUSSION: The presented operation unit can significantly improve safety and efficiency as well as the ergonomics for ENT surgery and related procedures. PMID- 20963393 TI - [Acoustic neuroma (vestibular schwannoma). Treatment from a neurosurgical perspective]. AB - During the last century microsurgical approaches laid emphasis in descending order on preservation of life, total tumor excision and function. Today, the priority of microsurgery has changed to functional preservation. The management of vestibular schwannomas consists of observation, surgical resection, or radiation therapy. In recent years, there has been an increase in observation only management for small tumors, or radiotherapy in the case of tumor progression. The number of surgical procedures is in decline, with surgery being reserved mainly for large tumors. PMID- 20963395 TI - [Space-occupying lesion of the nasopharynx and skull base]. AB - We report the case of a 73-year-old female patient who presented with an asymptomatic tumor of the nasal cavity and nasopharynx as well as bilateral hydromyrinx. MRI scan showed a bilaterally symmetric liquor-intense mass of the skull base, which proved to be a transsphenoidal meningocele. Since the finding was incidental and symptoms were absent, high-risk surgical intervention was not recommended. PMID- 20963394 TI - [Recording cervical and ocular vestibular evoked myogenic potentials. Part 2: influencing factors, evaluation of findings and clinical significance]. AB - VEMP measurements are subject to various influencing factors: patient age, threshold, sound intensity and frequency. Using air (AC) and bone conduction (BC) the vestibular receptors and afferents of the otolith organs can be activated to varying degrees. Recordings of cervical (cVEMP) and ocular VEMP (oVEMP) are clinically possible. AC-cVEMP are primarily an indicator of the sacculocollic reflex pathway. Together with findings on the vestibuloocular reflex (VOR) and complimentary otolith tests, VEMP enable otolith function analysis of each side separately. In addition, the distinction between combined or isolated canal and otolith dysfunction in terms of subtyping and patterns of damage in mono- and bilateral disorders, such as vestibular neuritis or bilateral vestibulopathy, is possible. Moreover, VEMP is relevant in terms of prognostic and therapeutic considerations as well as expert assessments. PMID- 20963396 TI - [Karl Wilmanns' theoretical contributions and his clinical practice. What does it mean for contemporary psychiatry?]. AB - Karl Wilmanns (1873-1945) is widely known as the founder of the Heidelberg school of psychopathology. His important contributions to criminology and forensic psychiatry and his encouragement of psychoanalysis in the inpatient setting are less known today. During the First World War, he worked as director of the military hospitals in the German county of Baden and as director of the Reichenau Mental Hospital at Lake Constance. Thus, he was familiar with the needs of everyday psychiatric practice under difficult circumstances. In Heidelberg he dealt intensively with criminology, social psychiatry and psychoanalysis. Wilmanns remained sceptical towards deterministic positions including the biological psychiatry of his days, but he fought for psychiatry open to social and political questions and open to different scientific methods. In 1933, the Nazis expelled him from office. Wilmanns remained as a private practitioner in Germany and died shortly after the liberation in 1945. PMID- 20963397 TI - [Incidental findings in cardiac CT : the importance of a complete field of vision]. PMID- 20963398 TI - Glucose-responsive beta cells in islets isolated from a patient with long standing type 1 diabetes mellitus. PMID- 20963399 TI - Fall mechanisms, bone strength, and hip fractures in elderly men and women in Taiwan. AB - Three modifiable factors of fall direction, poor bone strength, and depression were associated with an increased risk of hip fractures for elderly men and women; fall direction was a much stronger predictor than the other two. When a fall occurs, changing fall direction may be most effective to prevent hip fractures. INTRODUCTION: A matched case-control study was conducted to identify risk factors for hip fractures in elderly men and women in Taiwan. METHODS: Cases were defined as persons who visited the emergency room due to a fall and were diagnosed with a first hip fracture. For each case, a control was matched by gender and time of falling, selected from persons who sought care at the same emergency room due to a fall resulting in injury other than a hip fracture. In total, 85 paired men and 221 paired women were included. RESULTS: For men, backward, straight-down, and sideways falls were associated with 10.8-, 13.6-, and 15.2-fold increased risks of hip fractures, respectively, compared with forward falls. Poor bone strength and depression were associated with 2.27- and 2.85-fold increased risks of hip fractures, respectively, while dependence in >=3 activities of daily living was associated with a fivefold lower risk. For women, compared with forward falls, backward, straight-down, and sideways falls were associated with 10.2-, 9.86-, and 12.8-fold increased risks of hip fractures, respectively. Living in a rented house, poor bone strength, depression, and use of antidiabetics were associated with 1.65-, 2.78-, 1.89-, and 1.92-fold increased risks of hip fractures, respectively. Hormone replacement therapy was associated with a fivefold lower risk of hip fractures. CONCLUSIONS: While bone strength and depression can be risk factors for hip fractures in elderly people, the direction of the fall was the strongest predictor. Some risk factors differed between elderly men and women. PMID- 20963400 TI - The relationship of fetuin-A and lactoferrin with bone mass in elderly women. AB - SUMMARY: The relationships of fetuin-A and lactoferrin to bone-related phenotypes were investigated in elderly women. Fetuin-A was associated not only with bone mineral density (BMD) but also with bone resorption marker suggesting an influence of fetuin-A on osteoclasts. INTRODUCTION: The aim of this study is to investigate the relationship of bone-related phenotypes in elderly women with circulating fetuin-A and lactoferrin. METHODS: Eighty-two elderly women were studied. Serum fetuin-A, lactoferrin, C-terminal telopeptide of type I collagen (CTx), total procollagen type 1 amino-terminal propeptide, and plasma intact parathyroid hormone (PTH) were analyzed. BMD of the lumbar spine at L2-4 and at the femoral neck was measured. RESULTS: Serum fetuin-A was significantly associated with L2-4 BMD (r = 0.23, P < 0.05). After controlling for age and body weight, the association remained statistically significant. There was a significant association between serum fetuin-A and serum CTx (r = -0.37, P < 0.001). The association between fetuin-A and L2-4 BMD no longer existed after controlling for serum CTx. There were positive associations of circulating lactoferrin with plasma PTH (r = 0.24, P < 0.05) and serum CTx (r = 0.26, P < 0.05). No association between serum lactoferrin and BMD at the lumbar spine or femoral neck was detected. CONCLUSIONS: Circulating fetuin-A is related to bone mass and bone resorption markers in elderly women. Lactoferrin, in contrast, is associated only with bone resorption markers. PMID- 20963401 TI - Identification of the finishing technique of an early eighteenth century musical instrument using FTIR spectromicroscopy. AB - The study of varnishes from musical instruments presents the difficulty of analysing very thin layers of heterogeneous materials on samples most of which are generally brittle and difficult to prepare. Such study is crucial to the understanding of historical musical instrument varnishing practices since written sources before 1800 are very rare and not precise. Fourier-transform infrared (FTIR) spectroscopy and imaging methods were applied to identify the major chemical components within the build-up of the varnish layers on a cello made by one of the most prominent French violin-makers of the eighteenth century (Jacques Boquay, ca. 1680-1730). Two types of FTIR imaging methods were used: scanning with a synchrotron-based microscope and full-field imaging using a 2D imager with a conventional source. An interpretation of the results obtained from these studies on the Boquay cello is that the maker first applied a proteinaceous layer, probably gelatine-based animal glue. He later applied a second layer based on a mixture of a drying oil and diterpenic resin from Pinaceae sp. From an historical perspective, the results complement previous studies by describing a second technique used for musical instrument finishes at the beginning of the eighteenth century in Europe. PMID- 20963402 TI - An implantable biochip to influence patient outcomes following trauma-induced hemorrhage. AB - Following hemorrhage-causing injury, lactate levels rise and correlate with the severity of injury and are a surrogate of oxygen debt. Posttraumatic injury also includes hyperglycemia, with continuously elevated glucose levels leading to extensive tissue damage, septicemia, and multiple organ dysfunction syndrome. A temporary, implantable, integrated glucose and lactate biosensor and communications biochip for physiological status monitoring during hemorrhage and for intensive care unit stays has been developed. The dual responsive, amperometric biotransducer uses the microdisc electrode array format upon which were separately immobilized glucose oxidase and lactate oxidase within biorecognition layers, 1.0-5.0 MUm thick, of 3 mol% tetraethyleneglycol diacrylate cross-linked p(HEMA-co-PEGMA-co-HMMA-co-SPA)-p(Py-co-PyBA) electroconductive hydrogels. The device was then coated with a bioactive hydrogel layer containing phosphoryl choline and polyethylene glycol pendant moieties [p(HEMA-co-PEGMA-co-HMMA-co-MPC)] for indwelling biocompatibility. In vitro cell proliferation and viability studies confirmed both polymers to be non-cytotoxic; however, PPy-based electroconductive hydrogels showed greater RMS 13 and PC12 proliferation compared to controls. The glucose and lactate biotransducers exhibited linear dynamic ranges of 0.10-13.0 mM glucose and 1.0-7.0 mM and response times (t(95)) of 50 and 35-40 s, respectively. Operational stability gave 80% of the initial biosensor response after 5 days of continuous operation at 37 degrees C. Preliminary in vivo studies in a Sprague-Dawley hemorrhage model showed tissue lactate levels to rise more rapidly than systematic lactate. The potential for an implantable biochip that supports telemetric reporting of intramuscular lactate and glucose levels allows the refinement of resuscitation approaches for civilian and combat trauma victims. PMID- 20963403 TI - Cephalosporin-induced recurrent aplastic anemia. PMID- 20963404 TI - Lack of a pharmacokinetic interaction between steady-state tipranavir/ritonavir and single-dose valacyclovir in healthy volunteers. AB - OBJECTIVE: This study assessed the single-dose pharmacokinetics of the herpes antiviral acyclovir (administered as the pro-drug valacyclovir) alone and in combination with twice-daily 200 mg ritonavir-boosted tipranavir (500 mg) at steady state. METHODS: The study was an open label, one-sequence cross-over pharmacokinetic study in HIV-negative adults. Plasma drug concentrations were measured by validated LC/MS/MS assays; pharmacokinetics (AUC, C(max)) were determined using noncompartmental methods. The geometric mean ratio and 90% confidence interval [GMR, 90% CI] were used to evaluate the drug interaction. RESULTS: Twenty-six of 29 subjects completed the trial. With steady-state tipranavir/ritonavir, acyclovir C(max) decreased 4.9% [0.95, 0.88-1.02] and AUC increased 6.6% [1.07, 1.04-1.09]. The majority of subjects experienced at least one adverse event, most of which were mild gastrointestinal disorders. Three subjects discontinued tipranavir/ritonavir treatment as a result of drug-related increases in ALT/AST, including one subject who experienced mild upper abdominal pain. All subjects recovered without sequelae. CONCLUSIONS: When administered as a single dose of valacyclovir with steady-state tipranavir/ritonavir, there were no clinically important changes in acyclovir pharmacokinetics. This result indicates that valacyclovir can be co-administered safely with no dose adjustments. PMID- 20963405 TI - The pharmacokinetics of Biolimus A9 after elution from the BioMatrix II stent in patients with coronary artery disease: the Stealth PK Study. AB - OBJECTIVES: This prospective, open-label multicenter study was conducted to assess the pharmacokinetics of Biolimus A9 after elution from BioMatrix II coronary stents. Recent clinical trials have demonstrated the efficacy and safety of Biolimus A9 eluted from different stent platforms. To date, the pharmacokinetics of Biolimus A9 in patients following the deployment of BioMatrix II stents has not yet been studied METHODS: BioMatrix II stents were implanted into 27 patients with coronary artery disease. The primary endpoints of the study were the systemic concentrations of Biolimus A9 after 28 days and 6 months as measured using a sensitive validated liquid chromatography-tandem mass spectrometry assay. RESULTS: The highest measured blood concentration at any time point was 394 pg/mL. At 28 days and 6 months following stent placement, 51.8 and 100% of patients, respectively, had Biolimus A9 concentrations <10 pg/mL. After 9 months, 100% of the patients were free of major cardiac adverse events (MACE). There was no Biolimus A9 toxicity, no cardiac or non-cardiac deaths, no myocardial infarctions, nor target vessel or target lesion revascularizations during the 9 months of follow-up. No case of acute, subacute, or late stent thrombosis was detected. CONCLUSIONS: Compared to other drug-eluting stents, such as Cypher, BioMatrix II results in relatively low systemic exposure, which may be explained by the ablominal coating of the Biomatrix II stent in combination with Biolimus A9's high lipophilicity. PMID- 20963406 TI - Dimethyl sulfoxide with lignocaine versus eutectic mixture of local anesthetics: prospective randomized study to compare the efficacy of cutaneous anesthesia in shock wave lithotripsy. AB - The objective of the study was to compare the efficacy of dimethyl sulfoxide (DMSO) mixed with lignocaine and eutectic mixture of local anesthetics (EMLA) cream as topically applied surface anesthetics in relieving pain during shock wave lithotripsy (SWL) in a prospective randomized study. Of the 160 patients, 80 patients received DMSO with lignocaine and 80 patients received EMLA cream, applied to the skin of the flank at the area of entry of shock waves. SWL was done with Seimens lithostar multiline lithotripter. The pain during the procedure was assessed using visual analog and verbal rating scores. The mean visual analog scale scores for the two groups were 3.03 for DMSO group and 4.43 for EMLA group. The difference of pain score on visual analog scale was statistically significant (p < 0.05). Similarly, the pain scores as rated on the verbal rating scale were also evaluated; the mean score on verbal rating scale were 2.34 for DMSO group and 3.00 for the EMLA group. The difference between the pain score on verbal rating scale was also found to be statistically significant (p < 0.05). Our study showed that DMSO with lignocaine is a better local anesthetic agent for SWL than EMLA cream. The stone fragmentation and clearance rates are also better in the DMSO group. PMID- 20963407 TI - Shock wave lithotripsy for distal ureteric stones: supine or prone. AB - Shock wave lithotripsy (SWL) has become the preferred first-line approach to most patients with symptomatic urolithiasis. The purpose of this study is to assess the ideal patient position during SWL for the treatment of distal ureter stones. A total of 342 patients included in this retrospective study. 148 (108 men, 40 women) patients were included in the first group and were treated in supine position. The remaining 194 (143 men, 51 women) patients were included to second group and were treated in prone position. This study designed retrospectively. The procedure was accepted as a success if the patient was stone free or had only clinically insignificant fragments (<=3 mm) for 3 months or more after the last SWL session. Before SWL, the mean is one area in the first group was 61.32 mm2 while the mean stone area in the second group was 59.04 mm2 (p = 0.208). Mean energy, Mean energy maximum and mean number of applied shock waves of the first group was 4.65, 3.19 and 3,960, respectively. The same parameters in second group were 4.26, 3.03 and 2,953, respectively. These results show that there are statistically significant differences between two groups with respect to mean energy, mean energy maximum and mean number of applied shock waves (p = 0.003, p = 0.010, p = 0.000, respectively). Success rate was 85.1% in group 1 and 72.7% in group 2 (p = 0.006). Our results suggest that supine position is effective and better than prone position for SWL in patients with distal ureteric stones. PMID- 20963408 TI - Outcome of acute graft rejection associated with hemodynamic compromise in pediatric heart transplant recipients. AB - We sought to analyze the outcome of hemodynamically significant acute graft rejection in pediatric heart transplant recipients from a single-center experience. Acute graft rejection remains a major cause of morbidity and mortality for patients who undergo orthotopic heart transplantation and has been associated with the severity of the rejection episode. A retrospective review of all children experiencing a hemodynamically significant rejection episode after orthotopic heart transplantation was performed. Fifty-three patients with 54 grafts had 70 rejection episodes requiring intravenous inotropic support. Forty one percent of these patients required high-dose inotropic support, with the remaining 59% of patients requiring less inotropic support. Overall graft survival to hospital discharge was 41% for patients in the high-dose group compared to 94% in the low-dose group. Six-month graft survival in patients who required high-dose inotropes remained at 41% compared to 44% in the low-dose group. Hemodynamically significant acute graft rejection in pediatric heart transplant recipients is a devastating problem with poor short- and long-term outcomes. Survival to hospital discharge is dismal in patients who require high dose inotropic support. In contrast, survival to discharge is quite good in patients who require only low-dose inotropic support; however, six-month graft survival in this group is low secondary to a high incidence of graft failure related to worsening or aggressive transplant coronary artery disease. PMID- 20963409 TI - Looping charged elastic rods: applications to protein-induced DNA loop formation. AB - We analyze looping of thin charged elastic filaments under applied torques and end forces, using the solution of linear elasticity theory equations. In application to DNA, we account for its polyelectrolyte character and charge renormalization, calculating electrostatic energies stored in the loops. We argue that the standard theory of electrostatic persistence is only valid when the loop's radius of curvature and close-contact distance are much larger than the Debye screening length. We predict that larger twist rates are required to trigger looping of charged rods as compared with neutral ones. We then analyze loop shapes formed on charged filaments of finite length, mimicking DNA looping by proteins with two DNA-binding domains. We find optimal loop shapes at different salt amounts, minimizing the sum of DNA elastic, DNA electrostatic, and protein elastic energies. We implement a simple model where intercharge repulsions do not affect the loop shape directly but can choose the energy optimized shape from the allowed loop types. At low salt concentrations more open loops are favored due to enhanced repulsion of DNA charges, consistent with the results of computer simulations on formation of DNA loops by lac repressor. Then, we model the precise geometry of DNA binding by the lac tetramer and explore loop shapes, varying the confined DNA length and protein opening angle. The characteristics of complexes obtained, such as the total loop energy, stretching forces required to maintain its shape, and the reduction of electrostatic energy with increment of salt, are in good agreement with the outcomes of more elaborate numerical calculations for lac-repressor-induced DNA looping. PMID- 20963410 TI - A bacterial laccase from marine microbial metagenome exhibiting chloride tolerance and dye decolorization ability. AB - Laccases are blue multicopper oxidases with potential applications in environmental and industrial biotechnology. In this study, a new bacterial laccase gene of 1.32 kb was obtained from a marine microbial metagenome of the South China Sea by using a sequence screening strategy. The protein (named as Lac15) of 439 amino acids encoded by the gene contains three conserved Cu(2+) binding domains, but shares less than 40% of sequence identities with all of the bacterial multicopper oxidases characterized. Lac15, recombinantly expressed in Escherichia coli, showed high activity towards syringaldazine at pH 6.5-9.0 with an optimum pH of 7.5 and with the highest activity occurring at 45 degrees C. Lac15 was stable at pH ranging from 5.5 to 9.0 and at temperatures from 15 to 45 degrees C. Distinguished from fungal laccases, the activity of Lac15 was enhanced twofold by chloride at concentrations lower than 700 mM, and kept the original level even at 1,000 mM chloride. Furthermore, Lac15 showed an ability to decolorize several industrial dyes of reactive azo class under alkalescent conditions. The properties of alkalescence-dependent activity, high chloride tolerance, and dye decolorization ability make the new laccase Lac15 an alternative for specific industrial applications. PMID- 20963411 TI - Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909. AB - T cells with specificity for antigens derived from Wilms Tumor gene (WT1), Proteinase3 (Pr3), and mucin1 (MUC1) have been demonstrated to lyse acute myeloid leukemia (AML) blasts and multiple-myeloma (MM) cells, and strategies to enhance or induce such tumor-specific T cells by vaccination are currently being explored in multiple clinical trials. To test safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted peptides and the pan HLA-DR T helper cell epitope (PADRE) or MUC1-helper epitopes in combination with CpG7909 and MontanideISA51, four patients with AML and five with MM were repetitively vaccinated. No clinical responses were observed. Neither pre existing nor naive WT1-/Pr3-/MUC1-specific CD8+ T cells expanded in vivo by vaccination. In contrast, a significant decline in vaccine-specific CD8+ T cells was observed. An increase in PADRE-specific CD4+ T helper cells was observed after vaccination but these appeared unable to produce IL2, and CD4+ T cells with a regulatory phenotype increased. Taken into considerations that multiple clinical trials with identical antigens but different adjuvants induced vaccine specific T cell responses, our data caution that a vaccination with leukemia associated antigens can be detrimental when combined with MontanideISA51 and CpG7909. Reflecting the time-consuming efforts of clinical trials and the fact that 1/3 of ongoing peptide vaccination trails use CpG and/or Montanide, our data need to be taken into consideration. PMID- 20963412 TI - CD4+ T cell response against a non-tumor antigen is unaffected in melanoma bearing mice. AB - The tumor microenvironment is complex and creates an immunosuppressive network to tolerize tumor-specific immune responses; however, little information is available regarding the response against non-tumor antigens in tumor-bearing individuals. The goal of the present study was to evaluate if tumor burden could influence a CD4(+) T cell response against a soluble protein, not expressed by the tumor, in the absence of in vitro stimulation. Using an experimental system in which we can compare CD4(+) T cell responses to the Ea antigen when it is either expressed by B16F10 melanoma cells (B16EaRFP cells) or is an exogenous, non-tumor antigen (soluble EaRFP protein), in immunizations of B16F10 tumor bearing mice, we observed that the tumor can modulate the CD4(+) T cell-specific response to the antigen when it is expressed by the tumor cells. TEa cells proliferated poorly and produced less IFN-gamma in mice bearing B16F10 melanoma expressing Ea peptide, and tumor growth was impervious to this response. However, in mice bearing 7 days B16F10 tumors, not expressing the Ea antigen, priming of TEa cells was similar to that observed in tumor-free mice, based on the total number of cells recovered and proliferation assessed by CFSE dilution after EaRFP immunization. We also investigated if tumor burden could influence recall responses of already differentiated effector cells. We immunized mice with EaRFP antigen and after a few days injected B16F10 cells. After 10 days of tumor growth, we challenged the mice with the non-tumor antigen. We found that the number of TEa cells producing IFN-gamma in tumor-bearing mice was not different compared to tumor-free mice. No differences in antigen presentation, assessed by YAe antibody staining, were verified in the draining lymph node of these two groups. Collectively, our data indicate that tumor burden does not affect immune responses to non-tumor antigens. These results have important implications in the design of anti-cancer therapy. PMID- 20963414 TI - Conservation, conflict and the governance of fisher wellbeing: analysis of the establishment of the Gulf of Mannar National Park and Biosphere Reserve. AB - This article examines one MPA--the Gulf of Mannar National Park and Biosphere Reserve--located in southern India, and four types of social conflict that have surrounded its establishment. Taking the strength of wellbeing aspirations as point of departure, we focus on two themes: the implications of MPA embeddedness in wider societal systems, and the consequences of natural and social variety for governance. We conclude first of all that conflict resolution depends on MPA authorities' willingness to engage with the interferences that emerge from outside the MPA area. Secondly, we point out the varying wellbeing aspirations of the population and the need to develop governance partnerships. The latter are argued to contribute to more balanced decision making, as well as to a greater appreciation among the target population of the 'fairness' of MPA policy. PMID- 20963415 TI - Squaring the circle? Combining models, indicators, experts and end-users in integrated land-use management support tools. AB - The most important challenges faced in the field of integrated land-use management are (i) harmonizing and integrating different datasets, (ii) selecting appropriate indicators, (iii) fitting suitable models to adequate scales, and finally (iv) integrating data, indicators and models into systems that allow both a high level of participation and flexibility with the adaptation to a variety of questions and applications. The articles of this special issue "Squaring the Circle? Combining Models, Indicators, Experts and End-Users in Integrated Land Use Management Support Tools" demonstrate the challenges that are related to this topic. The case studies present examples of such integrated systems in order to recommend best practices to support land-use management and to reveal existing shortcomings. As a conclusion, seven features of a successful applicable integrated land-use management support system are derived: (1) ability to deal with discontinuity in information and datasets, (2) contribution to solve the problem of indicator diversity, (3) structuring the decision-making process, (4) support of participation processes in generating decisions, (5) development, comparison and evaluation of land-use alternatives, (6) assessment of the efficiency and trade-offs of management options, and (7) assistance of stakeholders in group communication processes. PMID- 20963416 TI - Characterization of vegetative insecticidal protein vip genes of Bacillus thuringiensis from Sichuan Basin in China. AB - Vegetative insecticidal proteins (Vip), the second generation of insecticides, are produced during the vegetative growth stage of Bacillus thuringiensis (Bt). To perform a systematic study of vip genes in Bt strains from different ecological regions of Sichuan Basin, 1,789 soil samples were collected from this basin, which is situated in the western region of China. The basin has a complicated geomorphology and contains mountains, forests, highlands, hursts, and plains. A total of 2,134 Bt strains have been screened from the 1,789 soil samples. According to the results, three vip-type genes were found in this basin, namely the vip1, vip2, and vip3-type genes. Strains containing vip3-type genes were the most abundant in our collection (67.4%), followed by vip2-type genes (14.6%) and vip1-type genes (8.1%). The three types of vip genes were distributed in most of the regions, but E Mei Mountain and the Ba Lang Mountains only contained vip3 genes in environments with high elevation, low temperature, insufficient oxygen, and abundant snow. Moreover, five novel vip3 genes were found, and these Vip proteins were toxic for Chilo suppressalis. All the results mentioned above suggest that Sichuan Basin is a rich resource for vip genes. PMID- 20963417 TI - Nematicidal activity of a nonpathogenic biocontrol bacterium, Pseudomonas chlororaphis O6. AB - Bacterial culture filtrates of an aggressive rhizobacterium, Pseudomonas chlororaphis O6, displayed strong nematicidal activity. The nematicidal activity of P. chlororaphis O6 was markedly reduced in the gacS mutant of P. chlororaphis O6 grown in the presence of glycine, but no reduction of nematicidal activity in the gacS mutant was noted in the absence of glycine. The results of bioassay with P. chlororaphis O6 mutants showed that phenazine and pyrrolnitrin production was not a major factor, but the effects of glycine in the culture medium suggest that formation of hydrogen cyanide might be important. Assessments in greenhouse studies with tomatoes growing in nematode-infested soils confirmed that the application of P. chlororaphis O6 resulted in the control of the root-knot nematode. Our results demonstrated that P. chlororaphis O6 could be employed as a biocontrol agent for the control of the root-knot nematode, and the global regulator, GacS, functions as a positive regulator of the expression of nematicidal compounds and enzymes in P. chlororaphis O6. PMID- 20963418 TI - Chitosan-EDTA new combination is a promising candidate for treatment of bacterial and fungal infections. AB - Chitosan is an attractive preparation widely used as a pharmaceutical excipient. This study aimed to evaluate the antimicrobial activities of chitosan derivatives, EDTA, and the newly developed chitosan-EDTA combination against Gram negative and Gram-positive bacteria as well as Candida albicans. Antimicrobial activity was studied. Both minimal Inhibitory Concentrations (MIC) and minimal biocidal concentrations (MBC) were determined. Chitosan acetic acid recorded lower MIC values against Enterococcus faecalis, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans than those exhibited by EDTA. EDTA failed to have inhibitory activity against Enterococcus faecalis as well as MBC against any of the studied microorganisms. Chitosan acetic acid's MBC were recorded to all examined species. Checkerboard assay results indicated a synergistic antimicrobial activity of the new combination against Staphylococcus aureus and an additive effect against other microorganisms. Moreover, a short microbial exposure to chitosan-EDTA (20-30 min) caused complete eradication. Due to the continuous emergence of resistant strains, there is an urgent need to discover new antimicrobial agents. Our findings suggest the use of chitosan as an enhancing agent with antibacterial and antifungal properties in combination with EDTA in pharmaceutical preparations. PMID- 20963420 TI - Adult-onset Henoch-Schonlein purpura with positive c-ANCA (anti-proteinase 3): case report and review of literature. PMID- 20963419 TI - Elevated interleukin-18 and skewed Th1:Th2 immune response in lupus nephritis. AB - There is evidence that interleukin-18 plays a role in lupus nephritis (LN). Since interleukin -18 (IL-18) promotes polarization of the immune response toward Th1, we investigated level of IL-18 and assessed the phenotypic distribution of Th1 and Th2 type cells in LN. A predominance of Th1 type (IFN-gamma+) cells and significant correlations with serum IL-18 was seen in the patients with LN compared to healthy controls. Although most patients were treated with high dosage of glucocorticoid and other immunosuppressive agents, higher level of IL 18 was found in both serum and glomeruli. However, there was no paralleled upregulation of its gene expression in peripheral blood mononuclear cells. Our findings indicate that the elevated IL-18 should be a symbol of disease activity and play a major role in the pathogenesis of LN by promoting cytokine imbalance towards Th1 type immune response. We conclude that patients with LN would benefit from it while the bioactivity of this cytokine was effectively counteracted. PMID- 20963421 TI - Prevalence and factors associated with uncomplicated storage and voiding lower urinary tract symptoms in community-dwelling Australian men. AB - PURPOSE: To determine the prevalence of, and associated risk factors for, voiding and storage lower urinary tract symptoms (LUTS) in a population-based sample of Australian men. METHODS: Data were collected from 1,103 men randomly selected, community-dwelling men, as part of the Florey Adelaide Male Ageing Study, after exclusion of men with prostate or bladder cancer or prior surgery to either organ. The presence of LUTS was assessed using the International Prostate Symptom Score. Urine flow was measured via flow meter. Demographic, clinical, and bio psychosocial data were collected by questionnaire. RESULTS: The prevalence of total, storage, and voiding LUTS was 18.1, 28.0 and 12.6%, respectively. The most common storage symptoms were frequency (12.3%), nocturia (9.9%) and urgency (8.1%), and voiding symptoms were weak stream (8.5%), intermittency (5.4%), incomplete emptying (5.1%) and straining (2.4%). There were linear associations between storage LUTS and increased abdominal fat mass, plasma glucose and low HDL cholesterol (components of the metabolic syndrome), obstructive sleep apnoea (OSA) risk, and retirement. Voiding symptoms were associated with a previous diagnosis of benign prostatic enlargement (BPH), mean peak urine flow, total energy intake, elevated risk of OSA, erectile dysfunction, physician-diagnosed thyroid dysfunction and higher household income. CONCLUSIONS: The close association of storage LUTS with the metabolic syndrome, and of both storage and voiding LUTS with OSA, suggest that these conditions should be considered in men presenting with LUTS. PMID- 20963422 TI - Image guidance for focal therapy of prostate cancer. AB - Focal therapy is an appealing strategy for any tumor and in time may prove to be a valuable treatment option for low-risk, carefully selected prostate cancer (PCa) patients. In an era where active surveillance is now considered a viable option for low-risk PCa patients, it is conceivable that organ-sparing treatments could also become an established option. The aim of focal therapy is to achieve long-term cancer control with minimal morbidity yet without the side effects of radical therapy. Although lacking in evidence, it remains intuitive that if we treat the smallest possible region of the prostate where to ensure cancer control by ablation (laser, cryotherapy or another ablative source), then there is less potential for untoward side effects. Thus, we believe the ultimate goal in focal therapy is to target specifically the cancerous site while ablating it and the smallest zone of normal prostate tissue around it to obtain cancer control. To achieve this goal, one is dependent on high-quality imaging to: locate the cancerous lesion and have it assist in guiding the ablative modality toward the lesion; monitor the ablation in real time; accurately assess the extent and totality of the ablation post-treatment and finally be used to follow-up and monitor the prostate in search of a recurrence of cancer in the treated area or the development ion new zones. This review seeks to discuss such issues focusing on imaging modalities as they relate to focal therapy of PCa. PMID- 20963424 TI - Reply to the comment to the paper (CNS-09-0420) "The clinical spectrum of Blake's pouch cyst: report of 6 illustrative cases" by Professor Charles Raybaud. PMID- 20963423 TI - Changes of globin expression in the Japanese medaka (Oryzias latipes) in response to acute and chronic hypoxia. AB - Fishes live in an aquatic environment with low or temporally changing O(2) availability. Variations in O(2) levels require many anatomical, behavioral, physiological, and biochemical adaptations that ensure the uptake of an adequate amount of O(2). Some fish species are comparatively well adapted to tolerate low O(2) partial pressure (hypoxia). The Japanese ricefish medaka (Oryzias latipes) is an important model organism for biomedical research that shows remarkable tolerance towards hypoxia. We have investigated the regulation and role of globins under hypoxia. We applied four different regimes of chronic hypoxia (24 and 48 h at PO(2) = 2 or 4 kPa) as well as acute hypoxia (2 h at PO(2) = 0.5 kPa) to adult male medaka. Changes of mRNA levels of seven globin genes (adult hemoglobin alpha and beta, myoglobin, neuroglobin, cytoglobin 1 and 2, globin X), three hypoxia-response genes (lactate dehydrogenase b, phosphoglycerate kinase, adrenomedullin 1) and two putative reference genes (cyclophilin, acidic ribosomal phosphoprotein P0) were monitored by means of quantitative real-time reverse transcription PCR. We observed strong upregulation of myoglobin, which is also expressed in the medaka brain, as previously demonstrated for carp, goldfish and zebrafish. The hemoglobin chains were found upregulated, whereas earlier studies found down-regulation of hemoglobin in hypoxic zebrafish. By contrast, neuroglobin mRNA was not affected by hypoxia in medaka, but had been found upregulated in zebrafish. Globin X is induced in medaka brain, but down-regulated in zebrafish. Thus, the patterns of hypoxia response of globins are strikingly different in various fish species, which can be interpreted as indication for different roles of the various globins in hypoxia response and for alternative metabolic strategies of fish species in coping with O(2) deprivation. PMID- 20963425 TI - Apoptotic protein expression in favorable-histology Wilms tumor correlates with tumor recurrence. AB - PURPOSE: Outcome for patients with Wilms tumor (WT) with favorable histology is good. Deletions of chromosomes 1p and 16q impart a poorer outcome. Value of apoptotic protein expression is not clear. METHODS: Expression of four immunohistochemically detectable apoptosis-regulating proteins (bcl-2, bcl-x, bax and p53) were analyzed in 30 specimens of WT and compared to recurrence and recurrence-free survival (RFS). RESULTS: The 30 patients included ranged from 4 to 72 months in age (mean 31). The mean available follow-up was 35.3 months (range 1-54). Six patients developed recurrence. The 5-year RFS for blastema predominant tumors was 40% as compared to 91% for triphasic histology which was significant (p = 0.048). The 5-year RFS in patients with bcl-2 negative tumors was 63% as compared to 100% for bcl-2 positive tumors, the difference being significant (p = 0.019). The 5-year RFS in patients with p-53 positive tumors was 27% as compared to 91% for p-53 negative tumors; however, this difference in the RFS was not statistically significant (p = 0.143). bax and bcl-x expression were not related to the RFS. CONCLUSIONS: Tumors that are bcl-2 negative have a relatively higher recurrence rate and a poorer RFS. They may benefit from a more intensive follow-up regime for early detection of recurrence. PMID- 20963426 TI - Adenocarcinoma in the ileal pouch: early detection and potential role of fecal DNA methylated markers in surveillance. PMID- 20963427 TI - Focus on small lesion of alpha-fetoprotein producing gastric cancer. PMID- 20963428 TI - Mini hook plate fixation for palmar fracture-dislocation of the proximal interphalangeal joint. AB - Fracture-dislocations of the proximal interphalangeal joint are challenging to treat, since it is difficult to achieve both rigid fixation and early joint motion simultaneously. Palmar fracture-dislocations of the proximal interphalangeal joint are less frequent injuries and a small number of treatment methods have been reported. We describe here a patient with a chronic palmar fracture-dislocation of the proximal interphalangeal joint, who was treated with a new surgical technique. In the surgery, a mini hook plate that was made by adapting a 1.5 mm AO hand modular system straight plate was used. Despite the thinness of the fragment, rigid fixation was achieved, resulting in early active motion. At final follow up, the active ranges of motion were 0 degrees -100 degrees at the proximal and 0 degrees -80 degrees at the distal interphalangeal joint, and there were no complications. This technique may become a useful surgical method to treat palmar fracture-dislocations of the proximal interphalangeal joint. PMID- 20963429 TI - Management of proximal humeral fractures in elderly patients with uni- or polyaxial locking osteosynthesis system. AB - INTRODUCTION: To evaluate the clinical efficacy of uni- and polyaxial locking osteosynthesis systems in the management of proximal humeral fractures in elderly patients, totally 76 cases were reviewed including 18 cases of two-part (Neer classification), 36 cases of three-part, and 22 cases of four-part fractures. METHODS: All the patients received open reduction and internal fixation with proximal humerus internal locking osteosynthesis system (PHILOS) or Numelock systems designed for proximal humerus. RESULTS: Results showed no significant difference between groups considering the Constant-Murley scores assessed at 6 and 12 months, postoperatively. Satisfactory outcomes were achieved in 73.7 and 75.0% of the patients from the PHILOS and Numelock groups, respectively. Complications included four cases of varus malunion, one case of screw cut-out, and another case of avascular necrosis. CONCLUSION: Both of the PHILOS and Numelock systems showed equally good results considering fixation stability and functional outcomes of proximal humeral fractures in elderly patients. PMID- 20963430 TI - Initial promising results of the dynamic locking blade plate, a new implant for the fixation of intracapsular hip fractures: results of a pilot study. AB - INTRODUCTION: The osteosynthesis of intracapsular hip fractures results in a 19 48% failure rate. Only when the anatomical reduction is secured by stable fixation, revascularisation of the femoral head can take place and the fracture can heal by primary osteonal reconstruction. The common implants lack rotational and/or angular stability. Also the relative large volume of the implants within the femoral head compromises the (re)vascularisation. The combination of an anatomical reduction and a low volume, dynamic implant, providing angular and rotational stability seem to be crucial factors in the treatment of intracapsular hip fractures. This assumption formed the starting point for the development of the dynamic locking blade plate (DLBP), a new implant for the internal fixation of intracapsular hip fractures. This report describes the first clinical results of the new implant. PATIENTS AND METHODS: Internal fixation with the DLBP was performed in 25 consecutive patients with an intracapsular hip fracture within 24 h from admission. Failure of fixation, due to non-union, avascular necrosis, implant failure or secondary displacement of the fracture, was the primary outcome measurer. Functional outcome was assessed by the Harris Hip Score. RESULTS: Following internal fixation of intracapsular hip fractures with the DLBP, a failure rate of 2 out of 25 patients and excellent functional results were seen after a follow-up of more than 2 years. CONCLUSION: The initial clinical results of the DLBP are promising and justify the start of a randomised controlled trial. PMID- 20963431 TI - Pasteurized autograft-prosthesis composite for proximal femoral reconstruction: an alternative to allograft composite. AB - BACKGROUND: Allograft-prosthesis composite (APC) for proximal femur reconstruction have shown favorable longevity and functional outcome compared to endoprosthesis, owing to restoration of bone stock, load-sharing property, and biological attachment of abductors and iliopsoas tendons. QUESTIONS/PURPOSES: This study examined whether a pasteurized-prosthesis composite (PPC) is comparable to APC regarding implant survival, functional outcome, and complication rates. PATIENTS AND METHODS: We retrospectively reviewed 18 patients with proximal femur malignancy that underwent reconstruction with a cemented pasteurized autograft-prosthesis composite between 1993 and 2008. We evaluated implant survival (Kaplan-Meier), functional outcome (MSTS score), complications and secondary operations. RESULTS: The estimated survival rate of the 18 composites was 86% at 5 and 10 years. Within a mean follow-up of 93 months (median 113, range 14-163) two composites (11%) were removed due to un-resolving infection. The mean MSTS functional score of surviving 16 composites was 80% (range 70-95). Non-union and stem loosening in host bone were identified in a single patient, while infection developed in two patients. THA conversion occurred in three composites due to secondary osteoarthritis in two, and subluxation in one case. Two of the six cases, with greater trochanter (GT) reconstruction, showed GT avulsion. No autograft was fractured. CONCLUSIONS: Pasteurized autograft-prosthesis composite (PPC) of the proximal femur has comparable survival rate, functional outcome, and complication rates to allograft prosthesis composite (APC), thereby offering an alternative reconstructive option for proximal femoral reconstruction. PMID- 20963432 TI - Ten years experience in the management of borderline ovarian tumors at Tom Baker Cancer Centre. AB - OBJECTIVE: The aim of this study was to review the clinical outcomes of patients with borderline ovarian tumors (BOTs) at Tom Baker Cancer Centre (TBCC) and to assess the value of surgical staging. METHODS: This retrospective study included 138 patients treated for BOTs at TBCC between January 1994 and December 2005. Patients were divided into two groups: group I with complete surgical staging (n = 89) and group II with incomplete surgical staging (n = 49). This population based study identified patients using the Alberta Cancer Registry. Charts were reviewed by a single person. Data extracted included demographic information and prognostic factors such as age, histological type, laterality of the cyst, presence of microinvasion, and the type of surgical procedure. Data were extracted and entered into a study database for analysis. Overall survival and overall recurrence-free survival of both groups were calculated using the Kaplan Meier method. Risk factors for recurrence were analyzed using Cox regression analysis. RESULTS: A total of 138 patients were enrolled, with a mean age of 46 years. The median follow-up time was 37 months. The most common histological type of BOT was the serous type found in 70 (50.7%) patients. Microinvasion was identified in four (2.9%) patients. Twelve patients were found to have implants as result of the staging procedure; two of them were invasive implants and both required chemotherapy. Forty-three (31%) patients had conservative surgery and 95 (68.8%) patients had non-conservative surgery. Nine (6.5%) patients experienced recurrence: five (5.6%) patients in group I versus four (8.2%) patients in group II. The presence of microinvasion is the risk factor for recurrence (P = 0.013). CONCLUSIONS: The indications for restaging surgery remain controversial, as there was no difference in recurrence rates observed between the study groups. However, surgical staging is important for identifying invasive extraovarian implants that need to be treated with chemotherapy. For patients who have conservative surgery, close- and long-term follow-up is required. PMID- 20963435 TI - Bilateral central retinal artery occlusion in a patient with primary central nervous system lymphoma. PMID- 20963434 TI - BG-12 reduces evolution of new enhancing lesions to T1-hypointense lesions in patients with multiple sclerosis. AB - BG-12, an immunomodulatory agent, reduces frequency of new gadolinium-enhancing (Gd+) lesions in relapsing multiple sclerosis (MS). This study reports the effect of 240 mg BG-12 orally three times daily (tid) for 24 weeks on the evolution of new Gd+ lesions to T1-hypointense lesions. Brain magnetic resonance imaging (MRI) scans from patients in placebo and 240 mg BG-12 tid arms of a phase 2b study were examined retrospectively. Included patients had at least one new Gd+ lesion from weeks 4 to 12. Week 24 scans were analyzed for number and proportion of new Gd+ lesions that evolved to T1-hypointense lesions. Eighteen patients receiving BG-12 and 38 patients receiving placebo were included in the analysis. The analysis tracked 147 new Gd+ lesions in patients from the BG-12 group and 221 Gd+ lesions in patients from the placebo group. The percentage of Gd+ lesions that evolved to T1-hypointense lesions was 34% lower with BG-12 treatment versus placebo (29%, BG 12; 44%, placebo; odds ratio 0.51; 95% confidence interval 0.43, 0.61; p < 0.0001). In addition to reducing frequency of new Gd+ lesions, BG-12 significantly reduced probability of their evolution to T1-hypointense lesions in patients with MS compared with placebo. PMID- 20963433 TI - Gene therapy: a viable therapeutic strategy for Parkinson's disease? AB - Gene therapy represents a potentially useful additional technique to ameliorate the motor symptoms of Parkinson's disease (PD), and the motor complications of its treatment. The neurodegenerative process itself, as well as the non-motor symptoms of PD, both remain less amenable to most of the current gene therapy approaches. This review presents an overview of the four gene therapies in phase I/II clinical trials, outlines some of the challenges they face, and proposes additional alternative strategies that might improve the clinical prospects of gene therapy for PD. In so doing, we hope to highlight the issue of the current absence of effective treatment for non-motor symptoms of PD and the potential of further candidate targets for gene therapy intervention that might improve upon this, for both specific individuals with genetic forms of PD as well as "sporadic" PD patients. PMID- 20963436 TI - Decreased collagen types I and IV, laminin, CK-19 and alpha-SMA expression after bone marrow cell transplantation in rats with liver fibrosis. AB - Bone marrow cells have frequently been tested in animal models of liver fibrosis to assess their role in hepatic regeneration. The mononuclear fraction of bone marrow cells is of particular interest, as many studies show that these cells may be beneficial to treat hepatic fibrosis. In this study, we used the bile duct ligation model to induce hepatic fibrosis in an irreversible manner, and rats were treated with bone marrow mononuclear (BMMN) cells after fibrosis was established. Analysis of collagen types I and IV, laminin and alpha-SMA showed a decreased expression of these proteins in fibrotic livers after 7 days of BMMN cell injection. Moreover, cytokeratin-19 analysis showed a reduction in bile ducts in the BMMN cell-treated group. These results were accompanied by ameliorated levels of hepatic enzymes GPT (Glutamic-pyruvic transaminase), GOT (glutamic-oxaloacetic transaminase) and alkaline phosphatase (AP). Therefore, we showed that BMMN cells decrease hepatic fibrosis by significantly reducing myofibroblast numbers and through reduction of the collagen and laminin-rich extracellular matrix of fibrotic septa and hepatic sinusoids. PMID- 20963437 TI - Hormone responses to a continuous bout of rock climbing in men. AB - Rock climbing is rapidly increasing in popularity as a recreational activity and as a competitive sport. Few studies have tested acute physiological responses to climbing, and no studies to date have tested hormone responses to a climbing based workout. This study aimed to measure testosterone (T), growth hormone (GH), and cortisol (C) responses to continuous vertical climbing in young male rock climbers. Ten male rock climbers, aged between 21 and 30 years, climbed laps on a submaximal 55' climbing route for 30 min, or until exhaustion, whichever came first. Heart rate (HR) was recorded after every lap. Blood samples were collected by venipuncture before (Pre), immediately post (IP), and 15 min after the climbing exercise (P15) to assess blood lactate and plasma GH, T, and C. Subjects climbed 24.9 +/- 1.9 min and 507.5 +/- 82.5 feet. Peak HR was 182.1 +/- 2.3 bpm, and lactate (Pre: 2.9 +/- 0.6 mmol/dL, IP: 11.1 +/- 1.0 mmol/dL) significantly (P < 0.05) increased from Pre to IP. T concentrations significantly (P < 0.05) increased from Pre (6.04 +/- 0.31 ng/mL) to IP (7.39 +/- 0.40 ng/mL) and returned to baseline at P15 (6.23 +/- 0.33 ng/mL). Cortisol levels did not significantly change during the protocol. GH significantly (P < 0.01) increased from Pre (0.63 +/- 0.17 ng/mL) to IP (19.89 +/- 4.53 ng/mL) and remained elevated at P15 (15.03 +/- 3.89 ng/mL). An acute, short-term bout of high-intensity continuous climbing was an effective exercise stimulus for elevating plasma testosterone and growth hormone levels in young males. PMID- 20963438 TI - The development of physiological profiles and identification of training needs in NCAA female collegiate rowers using isoperformance curves. AB - The purpose of this study was to propose a systematic method for the identification of training strategies and team selection using isoperformance curves. Rowing is a sport that relies on both aerobic and anaerobic energy contributions during a standard 2,000 m competition. The critical velocity model combines both aerobic (critical velocity, CV) and anaerobic (anaerobic rowing capacity, ARC) parameters in a single two-dimensional graphic display. The concept of isoperformance curves, a series of linear equations corresponding to minimum performance standards, allows for an objective overview of a large group of athletes of varying talent. The purpose of this study was to develop physiological profiles from the CV test, and to evaluate results with isoperformance curves to identify training strategies for collegiate rowers. Thirty-five female collegiate rowers completed four time trials over various distances (400, 600, 800, and 1,000 m). CV and ARC were calculated and compared between novice and varsity athletes. CV values for the varsity group were significantly higher than the novice group (P = 0.016). No significant differences were found between groups for ARC (P = 0.068). Mean and individual CV and ARC values were plotted on the x- and y-axes, respectively, and junior, collegiate, and elite isoperformance curves were developed using 2,000 m times from recent indoor rowing competitions. Stratification of athletes through isoperformance curves was used to identify specific training interventions (anaerobic and/or aerobic) needed to improve their 2,000 m performance. The information drawn from isoperformance curves and the parameters of the CV test can be used to provide an objective view of physiological capabilities and training needs on both an individual and team basis. PMID- 20963439 TI - Risk-benefit assessment of closed intra-abdominal drains after pancreatic surgery: a systematic review and meta-analysis assessing the current state of evidence. AB - BACKGROUND: This systematic review aims to analyse the risk-benefit association of (1) prophylactic drains and/or (2) the time of their removal after pancreatic resection. MATERIALS AND METHODS: A systematic literature search (Medline, Embase, Biosis, and The Cochrane Library) was performed to identify all types of controlled trials comparing the role of drainage or the time of their removal on postoperative complications following pancreatic surgery. Meta-analysis was performed using a random-effects model. RESULTS: Four studies, two randomised trials and two prospective cohort studies, were included in the systematic review and meta-analysis. Removal of drains at day 5 or later did not show an influence on mortality, morbidity, re-intervention or hospital stay compared to no insertion of drains. Early (day 3-4) compared to late (>= day 5) drain removal significantly reduced pancreatic fistulas (odds ratio (OR) 0.13; 95% confidence interval (CI) 0.03-0.32; P = 0.0002), intra-abdominal collections (OR 0.08; 95% CI 0.01-0.67; P = 0.02) and abscesses (OR 0.26; 95% CI 0.07-1.00; P = 0.05). Moreover, hospital stay was significantly reduced after early drain removal (mean difference -2.60 days; 95% CI -4.74 to -0.46; P = 0.02) CONCLUSION: Further randomised controlled trials are warranted to clarify whether drains are of any use. In case of drain insertion, early removal seems to be superior to late removal. PMID- 20963440 TI - Alternative promoters in the pst operon of Escherichia coli. AB - The pst operon of Escherichia coli is composed of five genes pstS, pstC, pstA, pstB and phoU, that encode a high-affinity phosphate transport system and a negative regulator of the PHO regulon. Transcription of pst is induced under phosphate shortage and is initiated at the promoter located upstream of the first gene of the operon, pstS. Here, we show by four different technical approaches the existence of additional internal promoters upstream of pstC, pstB and phoU. These promoters are not induced by Pi-limitation and do not possess PHO-box sequences. Plasmids carrying the pst internal genes partially complement chromosomal mutations in their corresponding genes, indicating that they are translated into functional proteins. PMID- 20963441 TI - Genome-scan for IQ discrepancy in autism: evidence for loci on chromosomes 10 and 16. AB - Performance IQ (PIQ) greater than verbal IQ (VIQ) is often observed in studies of the cognitive abilities of autistic individuals. This characteristic is correlated with social and communication impairments, key parts of the autism diagnosis. We present the first genetic analyses of IQ discrepancy (PIQ-VIQ) as an autism-related phenotype. We performed genome-wide joint linkage and segregation analyses on 287 multiplex families, using a Markov chain Monte Carlo approach. Genetic data included a genome-scan of 387 micro-satellite markers in 210 families augmented with additional markers added in a subset of families. Empirical P values were calculated for five interesting regions. Linkage analysis identified five chromosomal regions with substantial regional evidence of linkage; 10p12 [P = 0.001; genome-wide (gw) P = 0.05], 16q23 (P = .015; gw P = 0.53), 2p21 (P = 0.03, gw P = 0.78), 6q25 (P = 0.047, gw P = 0.91) and 15q23-25 (P = 0.053, gw P = 0.93). The location of the chromosome 10 linkage signal coincides with a region noted in a much earlier genome-scan for autism, and the chromosome 16 signal coincides exactly with a linkage signal for non-word repetition in specific language impairment. This study provides strong evidence for a QTL influencing IQ discrepancy in families with autistic individuals on chromosome 10, and suggestive evidence for a QTL on chromosome 16. The location of the chromosome 16 signal suggests a candidate gene, CDH13, a T-cadherin expressed in the brain, which has been implicated in previous SNP studies of autism and ADHD. PMID- 20963442 TI - Silencing of Plum pox virus 5'UTR/P1 sequence confers resistance to a wide range of PPV strains. AB - An effective disease-control strategy should protect the host from the major economically important and geographically widespread variants of a pathogen. Plum pox virus (PPV) is the causal agent of sharka, the most devastating viral disease of Prunus species. We have shown previously that the hairpin RNA expression driven by h-UTR/P1, h-P1/HCPro, h-HCPro and h-HCPro/P3 constructs, derived from the PPV-M ISPaVe44 isolate, confers resistance to the homologous virus in Nicotiana benthamiana plants. Since the production of transgenic stone fruits and their evaluation for PPV resistance would take several years, the ISPaVe44 resistant plant lines were used to evaluate which construct would be the best candidate to be transferred to Prunus elite cultivars. To do that, nine PPV isolates of the D, M, Rec, EA and C strains originally collected from five Prunus species in different geographical areas, were typed by sequencing and used to challenge the transgenic N. benthamiana lines; 464 out of 464 virus-inoculated plants of lines h-UTR/P1, h-HCPro and h-HCPro/P3 showed complete and long-lasting resistance to the seven PPV isolates of D, M and Rec strains. Moreover, the h UTR/P1 plants were also fully resistant to PPV-C and -EA isolates. Our data suggest that the h-UTR/P1 construct is of particular practical interest to obtain stone fruit plants resistant to the sharka disease. PMID- 20963443 TI - Cardiac magnetic resonance imaging in dilated cardiomyopathy in adults--towards identification of myocardial inflammation. AB - OBJECTIVE: To assess active myocardial inflammation by cardiovascular magnetic resonance (CMR) and endomyocardial biopsy (EMB) amongst adult patients with dilated cardiomyopathy (DCM). METHODS: We evaluated 23 adults with chronic DCM, who had successfully undergone both CMR and EMB within 3.5 +/- 2.6 days. EMB was considered the gold standard. CMR assessment of myocardial inflammation used the following parameters as recommended by the recently published "Lake Louise Criteria": global myocardial oedema, global relative enhancement (RE), and late gadolinium enhancement (LGE). According to "Lake Louise Criteria", myocardial inflammation was diagnosed if two or more of the three above-mentioned parameters were positive. RESULTS: Myocardial inflammation was confirmed by immunohistology in 12 patients (52.2%). Sensitivity, specificity, and diagnostic accuracy of CMR to detect immunohistologically confirmed myocardial inflammation were 75.0%, 72.7%, and 73.9%, respectively. Sensitivity, specificity, and diagnostic accuracy of the individual CMR parameters to detect myocardial inflammation were as follows: global myocardial oedema, 91.7%, 81.8%, and 87.0%, respectively; global RE, 58.3%, 63.6%, and 60.9%, respectively; LGE, 58.3%, 45.4%, and 52.2%, respectively. CONCLUSION: Global myocardial oedema was identified as a promising CMR parameter for assessment of myocardial inflammation in patients with DCM. In these patients, global myocardial oedema yielded superior diagnostic performance compared to "Lake Louise Criteria". PMID- 20963444 TI - Non-emergency small bowel obstruction: assessment of CT findings that predict need for surgery. AB - OBJECTIVE: To identify CT findings predictive of surgical management in non emergency small bowel obstruction (SBO). METHODS: Contrast-enhanced abdominal CT of 129 patients with non-emergency SBO were evaluated for small bowel luminal diameter, wall thickness, presence of the small bowel faeces sign (intraluminal particulate matter in a dilated small bowel) and length, transition point, submucosal oedema, mesenteric stranding, ascites and degree of obstruction (low grade partial, high grade partial and complete obstruction). Medical records were reviewed for age, gender, management and history of abdominal surgery, abdominal malignancy, or SBO. Statistical analyses were performed with Stata Release 9.2. RESULTS: Degree of obstruction was the only predictor of need for surgery. Whereas 18.0% of patients with low-grade partial obstruction (n = 50) underwent surgery, 32.5% of patients with high-grade partial obstruction (n = 77) and 100% of patients with complete obstruction (n = 2) required surgery (P = 0.004). The small bowel faeces sign was inversely predictive of surgery (P = 0.018). CONCLUSION: In non-emergency SBO patients with contrast-enhanced CT imaging, grade of obstruction predicts surgery, while the small bowel faeces sign inversely predicts need for surgery. PMID- 20963445 TI - Enhanced pesticide sensitivity of novel housefly acetylcholinesterases: a new tool for the detection of residual pesticide contamination. AB - The full-length cDNA encoding an acetylcholinesterase (AChE) was cloned and sequenced from the housefly, Musca domestica, by reverse transcriptase-polymerase chain reaction (RT-PCR). Sequence analysis revealed that this 2,076 bp sequence encodes a mature protein of 612 amino acids (67 kDa) and a 79 residue signal peptide. The amino acid sequence shared 52.8-81.4% identity with the AChE proteins of other insects. The cDNA sequence, which lacked the signal peptide was inserted into the vector pPIC9K and then introduced into strain GS115 of the yeast Pichia pastoris. The recombinant AChE protein was then expressed in P. pastoris strain GS115 by methanol induction. Site-directed mutagenesis of the A262G, Y327F, Y327D and I374D residues, either singly or in combination, was performed by reverse PCR. These mutants improved the catalytic activity and sensitivity to the organophosphate and carbamate insecticides. Although the sensitivity of other mutants was slightly increased, the results still showed that the sensitivity of triple mutant, GDD (A262G/Y327D/I374D), enhanced remarkably as much as 16 times for methomyl, 14 times for both carbofuran and chlorpyrifos, and ten times for parathion-methyl, compared to that of the wild type. The results strongly suggested that these residues are the key structural elements controlling AChE enzyme catalytic activity and sensitivity to inhibition by insecticides. The AChE enzyme obtained by this method could be used to detect the organophosphate and carbamate insecticide residues in fruits and vegetables, a characteristic of great potential research and industrial application. PMID- 20963446 TI - A 25-year experience with pediatric anti-glomerular basement membrane disease. AB - Anti-glomerular basement membrane (anti-GBM) disease, which is extremely uncommon in children, is characterized by rapidly progressive glomerulonephritis (RPGN) and autoantibodies against GBM collagen. Pulmonary hemorrhage is the third component in Goodpasture Syndrome. Cigarette smoking and exposure to hydrocarbons have been linked to anti-GBM disease in adults, but such an association has not been established in children. We reviewed renal biopsy and autopsy specimens over 25 years from a major tertiary care U.S. children's hospital, diagnosing anti-GBM by clinical RPGN, crescentic glomerulonephritis, and linear immunofluorescence (IF) immunoglobulin G staining in patients under 18 years of age. We identified four patients, with and without pulmonary manifestations. The sole autopsy case showed diagnostic IF despite undetectable serum anti-GBM antibodies and positive testing for serum anti-neutrophil cytoplasmic antibodies (ANCA). Three patients have survived 1-18 years following diagnosis, one of whom is recovering renal function. One adolescent had a history of smoking cigarettes and one had a probable hydrocarbon exposure. Anti-GBM disease is unusual in children, and the relationship to inhaled agents is incompletely understood. Serum anti-GBM antibodies are typically present, but cases with undetectable levels can occur. Some patients are anti-GBM and ANCA positive, with a small subset ANCA-positive, anti-GBM-negative. Ours is the first such described pediatric case. PMID- 20963447 TI - Regional citrate anticoagulation--a safe and effective procedure in pediatric apheresis therapy. AB - Regional citrate anticoagulation (RCA) has been considered to be a standard component of pediatric apheresis therapy for more than a decade. However, data on dosing recommendations and evaluations of the effectiveness and safety of anticoagulation are rarely found in published reports. The aim of this retrospective analysis was to present our single-center experience with RCA in pediatric apheresis therapy with the aim of developing an operating procedure. Five children aged 7-14 years underwent a total of 72 (range 3-44) therapeutic apheresis sessions with RCA in the form of immunoadsorption therapy (2 patients), low-density lipoprotein (LDL)-apheresis (1 patient), and plasmapheresis (two patients). A 3% citrate solution was used. Citrate flow was started at 4.0% of the blood flow velocity and was adapted to match post-filter ionized calcium levels <= 0.30 mmol/l. Once the patient's ionized calcium fell to <1.05 mmol/l, an intravenous 10% calcium gluconate solution was administered. Twenty pediatric apheresis patients who received standard heparinization, matched for age, body surface area, processed plasma volume, and blood flow velocity, were enrolled in the study as a comparison group. No side effects were experienced in 72 apheresis session. The 3% citrate solution had to be reduced gradually during the apheresis session and was infused at a mean of 2.8-3.8% of the blood flow rate. Serum bicarbonate levels before and after the apheresis session with RCA [23.9 (range 18.9-30.1) vs. 26.3 (20.2-33.0) mmol/l, respectively] were significantly different (p=0.013). All patients required intravenous calcium substitution to maintain serum calcium levels within the physiological range. Due to the administration of the 3% citrate solution and calcium, all patients significantly gained weight during the procedure, with a median weight gain of 2.5% (p<0.001). The extra fluid load caused problems in patients with kidney failure. Our regimen with RCA is safe, feasible, and effective in pediatric therapeutic apheresis therapy. For RCA in apheresis, we recommend (1) a citrate (3%) flow of 3.3% of the blood flow, (2) prophylactic intravenous calcium substitution from the beginning, and (3) a more highly concentrated citrate solution in the case of oliguric patients. PMID- 20963448 TI - Generalized allergy due to zinc in insulin treated with zinc-free insulin. AB - Allergy to insulin became a rare complication due to the introduction of recombinant human insulin preparations. Nevertheless, allergic reactions to components of such preparations can occur. We report a case of a 61-year-old man with an atopic background and affected by diabetes mellitus type 2 since 27 years, who experienced generalized allergy to insulin at the moment of switching oral anti-diabetics to insulin. Prick tests revealed an allergy specifically to zinc, and the patient was treated with zinc-free glulisine insulin. After 8 months of such treatment, patient's glucose is stable and he never experienced allergic reactions to insulin injections. Even insulin allergy due specifically to zinc is rare, such complication must be assessed especially in a patient suffering from multiple allergies. PMID- 20963449 TI - Evaluation of the efficacy and tolerability of miglitol in Chinese patients with type 2 diabetes mellitus inadequately controlled by diet and sulfonylureas. AB - The objective of this study is to examine the efficacy and tolerability of miglitol with respect to improving glycemic control in Chinese patients with type 2 diabetes mellitus inadequately controlled by diet and sulfonylurea treatment. This was a randomized, double-blinded, placebo-controlled, multicenter study. A total of 105 patients were randomized to receive 24 weeks of treatment with miglitol (n = 52; titrated from 50 mg to 100 mg 3 times daily) or placebo (n = 53). Concomitant sulfonylurea treatment and diet remained unchanged. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline at 24 weeks. Secondary endpoints were changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and postprandial serum insulin (PSI). The miglitol treatment group showed significantly greater reductions in HbA1c and PPG levels compared with the placebo group. With respect to adverse events, abdominal discomfort, diarrhea, and hypoglycemia occurred with similar frequency in both groups. Results of this study indicate that miglitol significantly improves metabolic control in Chinese patients with type 2 diabetes mellitus. Miglitol is safe and well tolerated, with the exception of abdominal discomfort. Therefore, miglitol may be a useful adjuvant therapy for Chinese patients with type 2 diabetes mellitus inadequately controlled by diet and sulfonylurea treatment. PMID- 20963450 TI - What is the cause of post-traumatic stress disorder following subarachnoid haemorrhage? Post-ictal events are key. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is common after subarachnoid haemorrhage (SAH) and causes poor outcome. Knowing which SAH events cause the stress leading to PTSD development could allow for their severity, and so the chances of PTSD, to be reduced. The dramatic nature of SAH onset has meant ictal events have been the presumed cause. Frequent loss of consciousness (LOC) at ictus, and presumed resultant amnesia, however, means this might not be correct. We examined two hypotheses for how SAH patients develop PTSD despite frequent LOC. Firstly, has the frequency of amnesia for ictal events subsequent to LOC been overestimated? Secondly, is it the stress of post-ictal events, rather than ictal events, which causes PTSD? METHOD: Sixty SAH patients, 18 months post ictus, were assessed for PTSD, LOC at ictus, memory for ictal events, as well as which aspects of their SAH, ictal and post-ictal, were psychologically stressful. Patients also underwent neuropsychological examination. FINDINGS: Of patients, 36.7% had PTSD. Memory overall for ictal events was more common than expected: 50% reported LOC, and only 18% reported no memory. However, memory was not associated with PTSD development. Rather, the key predictor of PTSD was the stress of post-ictal events. The stress of ictal events, cognitive impairment and clinical characteristics were unrelated to PTSD development. Post-ictal events included realizing that their life could have/had changed, that they may have been left with long-term problems, that they could have died and that they had little memory for some SAH events and regaining consciousness. CONCLUSIONS: The traumatic quality of an SAH lies in post-ictal events, rather than ictal events. These events are related to the patients' adjustment to the experience of having had an SAH. Reducing the traumatic severity of these events could potentially reduce the likelihood of PTSD in SAH patients and so improve their outcome. PMID- 20963451 TI - Active cortical innervation protects striatal neurons from slow degeneration in culture. AB - Spiny striatal GABAergic neurons receive most of their excitatory input from the neocortex. In culture, striatal neurons form inhibitory connections, but the lack of intrinsic excitatory afferents prevents the development of spontaneous network activity. Addition of cortical neurons to the striatal culture provides the necessary excitatory input to the striatal neurons, and in the presence of these neurons, striatal cultures do express spontaneous network activity. We have confirmed that cortical neurons provide excitatory drive to striatal neurons in culture using paired recording from cortical and striatal neurons. In the presence of tetrodotoxin (TTX), which blocks action potential discharges, the connections between cortical and striatal neurons are still formed, and in fact synaptic currents generated between them when TTX is removed are far larger than in control, undrugged cultures. Interestingly, the continuous presence of TTX in the co-culture caused striatal cell death. These observations indicate that the mere presence of cortical neurons is not sufficient to preserve striatal neurons in culture, but their synchronous activity, triggered by cortical excitatory synapses, is critical for the maintenance of viability of striatal neurons. These results have important implications for understanding the role of activity in neurodegenerative diseases of the striatum. PMID- 20963452 TI - MicroPET imaging of ketamine-induced neuronal apoptosis with radiolabeled DFNSH. AB - Recent reports indicate that 6-12 h of ketamine anesthesia can trigger neuronal apoptosis in postnatal day (PND) 7 rats. In vitro, ex vivo, and confocal fluorescent imaging studies suggest that dansyl compounds can accumulate within the cytoplasm of the apoptotic cell. High-resolution positron emission tomography (microPET) imaging has been proposed as a minimally invasive method for detecting apoptosis in the rat brain. Compared with [(18)F]-labeled annexin V, which binds to externalized phosphatidylserine (PS) on the outer membrane of apoptotic cells, intracellular uptake of the dansylhydrazone of p-fluorobenzaldehyde (DFNSH) may lead to improved target-to-background contrast ratios. In this study, the effect of ketamine on the uptake and retention of [(18)F]-DFNSH in the rat brain was investigated using microPET imaging. On PND 7, rat pups in the experimental group were exposed, at 2-h intervals, to six subcutaneous injections of ketamine (20 mg/kg) and control rat pups received six injections of saline. On PND 35, [(18)F] DFNSH (37 MBq) was injected into the tail vein of rats and microPET images were obtained over 2 h following the injection. Radiolabeled tracer accumulation in the region of interest (ROI) in the frontal cortex was converted into standard uptake values (SUVs). The radiotracer was quickly distributed into the brains of both ketamine- and saline-treated rats. Compared with the control group, the uptake of [(18)F]-DFNSH was significantly increased in the ROI, frontal cortex area of ketamine-treated rats. In addition, the wash-out duration of the tracer was prolonged in the ketamine-treated animals. This study demonstrates that microPET imaging is capable of distinguishing differences in retention of [(18)F] DFNSH in ROI and suggests that this compound may serve as a minimally invasive biomarker of neuronal apoptosis in rodents. PMID- 20963454 TI - Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome. AB - Methylglyoxal (MG) is a potent protein glycating agent. Glycation is directed to guanidino groups of arginine residues forming mainly hydroimidazolone N (delta) (5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) residues. MG-H1 formation is damaging to the proteome as modification is often directed to functionally important arginine residues. MG-H1 content of proteins is quantified by stable isotopic dilution analysis tandem mass spectrometry and also by immunoblotting with specific monoclonal antibodies. MG-glycated proteins undergo cellular proteolysis and release MG-H1 free adduct for excretion. MG-H1 residues have been found in proteins of animals, plants, bacteria, fungi and protoctista. MG-H1 is often the major advanced glycation endproduct in proteins of tissues and body fluids, increasing in diabetes and associated vascular complications, renal failure, cirrhosis, Alzheimer's disease, arthritis, Parkinson's disease and ageing. Glyoxalase 1 and aldo-keto reductase 1B1 metabolise >99% MG to innocuous products and thereby protect the proteome, providing an enzymatic defence against MG-mediated glycation. Proteins susceptible to MG modification with related functional impairment are called the "dicarbonyl proteome" (DCP). DCP includes albumin, haemoglobin, transcription factors, mitochondrial proteins, extracellular matrix proteins, lens crystallins and other proteins. DCP component proteins are linked to mitochondrial dysfunction in diabetes and ageing, oxidative stress, dyslipidemia, cell detachment and anoikis and apoptosis. Biochemical and physiological susceptibility of a protein to modification by MG and sensitivity of biochemical pathways and physiological systems to related functional impairment under challenge of physiologically relevant increases in MG exposure are key concepts. Improved understanding of the DCP will likely have profound importance for human health, longevity and treatment of disease. PMID- 20963453 TI - Cardiac arrest-induced regional blood-brain barrier breakdown, edema formation and brain pathology: a light and electron microscopic study on a new model for neurodegeneration and neuroprotection in porcine brain. AB - Brief cardiac arrest and survival is often associated with marked neurological alterations related to cognitive and sensory motor functions. However, detail studies using selective vulnerability of brain after cardiac arrest in animal models are still lacking. We examined selective vulnerability of five brain regions in our well-established cardiac arrest model in pigs. Using light and electron microscopic techniques in combinations with immunohistochemistry, we observed that 5, 30, 60 and 180 min after cardiac arrest results in progressive neuronal damage that was most marked in the thalamus followed by cortex, hippocampus, hypothalamus and the brain stem. The neuronal damages are largely evident in the areas showing leakage of serum albumin in the neuropil. Furthermore, a tight correlation was seen between neuronal damage and increase in brain water content and Na(+) indicating vasogenic edema formation after cardiac arrest. Damage to myelinated fibers and loss of myelin as seen using Luxol fast blue and myelin basic protein (MBP) immunoreactivity is clearly evident in the brain areas exhibiting neuronal damage. Upregulation of GFAP positive astrocytes closely corresponds with neuronal damages in different brain areas after cardiac arrest. At the ultrastructural level, perivascular edema together with neuronal, glial and endothelia cell damages is frequent in the brain areas showing albumin leakage. Damage to both pre- and post-synaptic membrane is also common. Treatment with methylene blue, an antioxidant markedly reduced neuronal damage, leakage of albumin, overexpression of GFAP and damage to myelin following cardiac arrest. Taken together, these observations suggest that (a) cardiac arrest is capable to induce selective neuronal, glial and myelin damage in different parts of the pig brain, and (b) antioxidant methylene blue is capable to induce neuroprotection by reducing BBB disruption. These observations strongly suggest that the model could be used to explore new therapeutic agents to enhance neurorepair following cardiac arrest-induced brain damage for therapeutic purposes. PMID- 20963455 TI - The pathogenic role of Maillard reaction in the aging eye. AB - The proteins of the human eye are highly susceptible to the formation of advanced glycation end products (AGEs) from the reaction of sugars and carbonyl compounds. AGEs progressively accumulate in the aging lens and retina and accumulate at a higher rate in diseases that adversely affect vision such as, cataract, diabetic retinopathy and age-related macular degeneration. In the lens AGEs induce irreversible changes in structural proteins, which lead to lens protein aggregation and formation of high-molecular-weight aggregates that scatter light and impede vision. In the retina AGEs modify intra- and extracellular proteins that lead to an increase in oxidative stress and formation of pro-inflammatory cytokines, which promote vascular dysfunction. This review outlines recent advances in AGE research focusing on the mechanisms of their formation and their role in cataract and pathologies of the retina. The therapeutic action and pharmacological strategies of anti-AGE agents that can inhibit or prevent AGE formation in the eye are also discussed. PMID- 20963456 TI - Glycation in diabetic nephropathy. AB - The kidney is an extremely complex organ with broad ranging functions in the body, including but not restricted to waste excretion, ion and water balance, maintenance of blood pressure, glucose homeostasis, generation of erythropoietin and activation of vitamin D. With diabetes, many of these integral processes are interrupted via a combination of haemodynamic and metabolic changes including increases in the accumulation of proteins modified by advanced glycation, known as advanced glycation end products (AGEs). Indeed, hyperglycaemia and the redox imbalances seen with diabetes are each independent accelerants for the production of AGEs, which synergistically combine in this disorder. In addition, as kidney function declines, characterised by a loss of glomerular filtration, the excretion of AGEs is decreased, possibly exacerbating renal injury by further elevating the body's tissue and circulating AGE pool. Therefore, it has become apparent that decreasing the accumulation of AGEs or interrupting their downstream effects on the kidney, are desirable therapeutic targets for the treatment of diabetic renal disease. PMID- 20963457 TI - Effects of oral L-carnitine supplementation on insulin sensitivity indices in response to glucose feeding in lean and overweight/obese males. AB - Infusion of carnitine has been observed to increase non-oxidative glucose disposal in several studies, but the effect of oral carnitine on glucose disposal in non-diabetic lean versus overweight/obese humans has not been examined. This study examined the effects of 14 days of L-carnitine L-tartrate oral supplementation (LC) on blood glucose, insulin, NEFA and GLP-1 responses to an oral glucose tolerance test (OGTT). Sixteen male participants were recruited [lean (n = 8) and overweight/obese (n = 8)]. After completing a submaximal predictive exercise test, participants were asked to attend three experimental sessions. These three visits were conducted in the morning to obtain fasting blood samples and to conduct 2 h OGTTs. The first visit was a familiarisation trial and the final two visits were conducted 2 weeks apart following 14 days of ingestion of placebo (PL, 3 g glucose/day) and then LC (3 g LC/day) ingested as two capsules 3*/day with meals. On each visit, blood was drawn at rest, at intervals during the OGTT for analysis of glucose, insulin, non-esterified fatty acids (NEFA) and total glucagon-like peptide-1 (GLP-1). Data obtained were used for determination of usual insulin sensitivity indices (HOMA-IR, AUC glucose, AUC insulin, 1st phase and 2nd phase beta-cell function, estimated insulin sensitivity index and estimated metabolic clearance rate). Data were analysed using RMANOVA and post hoc comparisons where appropriate. There was a significant difference between groups for body mass, % fat and BMI with no significant difference in age and height. Mean (SEM) plasma glucose concentration at 30 min was significantly lower (p < 0.05) in the lean group on the LC trial compared with PL [8.71(0.70) PL; 7.32(0.36) LC; mmol/L]. Conversely, plasma glucose concentration was not different at 30 min, but was significantly higher at 90 min (p < 0.05) in the overweight/obese group on the LC trial [5.09(0.41) PL; 7.11(0.59) LC; mmol/L]. Estimated first phase and second phase beta-cell function both tended to be greater following LC in the lean group only. No effects of LC were observed on NEFA or total GLP-1 response to OGTT. It is concluded that LC supplementation induces changes in blood glucose handling/disposal during an OGTT, which is not influenced by GLP-1. The glucose handling/disposal response to oral LC is different between lean and overweight/obese suggesting that further investigation is required. LC effects on gastric emptying and/or direct 'insulin like' actions on tissues should be examined in larger samples of overweight/obese and lean participants, respectively. PMID- 20963458 TI - Bioconversion of L-tyrosine to L-DOPA by a novel bacterium Bacillus sp. JPJ. AB - L-DOPA is an amino acid derivative and most potent drug used against Parkinson's disease, generally obtained from Mucuna pruriens seeds. In present communication, we have studied the in vitro production of L-DOPA from L-tyrosine by novel bacterium Bacillus sp. JPJ. This bacterium produced 99.4% of L-DOPA from L tyrosine in buffer (pH 8) containing 1 mg ml(-1) cell mass incubated at 40 degrees C for 60 min. The combination of CuSO(4) and L-ascorbic acid showed the inducing effect at concentrations of 0.06 and 0.04 mg ml(-1), respectively. The activated charcoal 2 mg ml(-1) was essential for maximum bioconversion of L tyrosine to L-DOPA and the crude tyrosinase activity was 2.7 U mg(-1) of tyrosinase. Kinetic studies showed significant values of Y (p/s) (0.994), Q (s) (0.500) and q (s) (0.994) after optimization of the process. The production of L DOPA was confirmed by analytical techniques such as HPTLC, HPLC and GC-MS. This is the first report on rapid and efficient production of L-DOPA from L-tyrosine by bacterial source which is more effective than the plant, fungal and yeast systems. PMID- 20963459 TI - Bone geometry and strength adaptations to physical constraints inherent in different sports: comparison between elite female soccer players and swimmers. AB - Sports training characterized by impacts or weight-bearing activity is well known to induce osteogenic effects on the skeleton. Less is known about the potential effects on bone strength and geometry, especially in female adolescent athletes. The aim of this study was to investigate hip geometry in adolescent soccer players and swimmers compared to normal values that stemmed from a control group. This study included 26 swimmers (SWIM; 15.9 +/- 2 years) and 32 soccer players (SOC; 16.2 +/- 0.7 years), matched in body height and weight. A group of 15 age matched controls served for the calculation of hip parameter Z-scores. Body composition and bone mineral density (BMD) were assessed by dual-energy X-ray absorptiometry (DXA). DXA scans were analyzed at the femoral neck by the hip structure analysis (HSA) program to calculate the cross-sectional area (CSA), cortical dimensions (inner endocortical diameter, ED; outer width and thickness, ACT), the centroid (CMP), cross-sectional moment of inertia (CSMI), section modulus (Z), and buckling ratio (BR) at the narrow neck (NN), intertrochanteric (IT), and femoral shaft (FS) sites. Specific BMDs were significantly higher in soccer players compared with swimmers. At all bone sites, every parameter reflecting strength (CSMI, Z, BR) favored soccer players. In contrast, swimmers had hip structural analysis (HSA) Z-scores below the normal values of the controls, thus denoting weaker bone in swimmers. In conclusion, this study suggests an influence of training practice not only on BMD values but also on bone geometry parameters. Sports with high impacts are likely to improve bone strength and bone geometry. Moreover, this study does not support the argument that female swimmers can be considered sedentary subjects regarding bone characteristics. PMID- 20963460 TI - Voriconazole plasma levels in children are highly variable. PMID- 20963461 TI - Surfer's myelopathy--an unusual cause of acute spinal cord ischemia: a case report and review of the literature. AB - Surfer's myelopathy is an emergent medical condition, representing a rare type of nontraumatic injury of the spinal cord, triggered by continued hyperextension of the back in inexperienced surfers. Subsequent acute spinal cord ischemia is the main pathological "substrate" for extensive cord myelopathy, determining potential neurological damage and thus predicting a patient's outcome. Awareness of the regional vascular anatomy and correct interpretation of the radiological findings are essential in making a precise diagnosis. Magnetic resonance imaging is an accurate and sensitive modality to identify early ischemic changes, particularly if diffusion-weighted images are initially performed. We report a case of 23-year-old male in whom the diagnosis of surfer's myelopathy was made based on an appropriate clinical history and imaging findings compatible with acute spinal cord ischemia. We also discuss miscellaneous pathological conditions, causing acute myelopathy, which can mimic clinical signs or/and imaging appearance of this rare, but potentially disabling disorder. PMID- 20963462 TI - Pictorial review: computed tomography features of cardiovascular emergencies and associated imminent decompensation. AB - Multi-detector computed tomography (MDCT) scanner is available in most hospitals and is increasingly being used as the first line imaging in trauma and suspected cardiovascular emergencies, such as acute coronary syndrome, pulmonary artery thrombo-embolism, abdominal aortic aneurysm and acute haemorrhage (Ryan et al. Clin Radiol 60:599-607, 2005). A significant number of these patients are haemodynamically unstable and can rapidly progress into shock and death. Recognition of computed tomography (CT) signs of imminent cardiovascular decompensation will alert the clinical radiologist to the presence of shock. In this review, the imaging findings of cardiovascular emergencies in both acute traumatic and non-traumatic settings with associated signs of imminent decompensation will be described and illustrated. PMID- 20963463 TI - Trigeminal schwannomas: experience with 57 cases and a review of the literature. AB - Trigeminal schwannoma is a mostly benign tumor that can be cured by complete resection. Over the last few decades, several pioneers have developed surgical approaches enabling the total removal of such tumors. We analyzed 57 patients who underwent radical surgery, including 45 patients who underwent skull base surgery as their initial treatment, for removal of trigeminal schwannomas. Here, we report the surgical management of these cases. Since 1990, all such patients have been treated using three main types of middle fossa skull base approaches, which minimize the exposure of the brain: the anterior transpetrosal approach, subtemporal interdural approach (Dolenc), or a combination of these approaches. Before 1990, total tumor removal was achieved in only three of eight patients (38%). After 1990, the tumors were totally removed in 43 patients (90%) and were nearly completely removed in an additional three patients (6%). Among the patients who underwent skull base surgery as their initial treatment, a complete resection was achieved in 93% (42/45 patients) of the cases. However, total surgical removal after surgery and Gamma knife surgery was very difficult because of dense adhesions to the brain stem and cranial nerves. No surgery-related mortalities occurred in this series, and the individual KPS scores were more than 90% among the patients who underwent skull base surgery. No recurrences requiring additional surgery have occurred after an average follow-up period of 4.9 years. Most of the trigeminal schwannomas could be removed totally and safely during a single operation after the introduction of skull base surgery. Therefore, radiosurgery should not be applied as the treatment of first choice for younger patients. A correct anatomical knowledge is critical for minimizing brain exposure and avoiding surgical complications. PMID- 20963464 TI - Headache, epilepsy and photosensitivity: how are they connected? AB - Although headache and epilepsy have often been associated, the precise electroclinical and pathophysiological interaction between these disorders and in particular its relations with photosensitivity is as yet to be fully understood in adults or children. The association between headache and epilepsy commonly occurs in all types of epilepsy and not only in occipital epilepsy. Generally, peri-ictal headache is often neglected, regardless of its severity, because patients are more concerned about their seizures. Altered cerebral cortex excitability may be the link between these two conditions and photosensitivity shows this. The physician should bear this association in mind when dealing with epileptic and migraine patients so as to be able to offer such patients an accurate diagnosis and appropriate treatment; this should be borne in mind when declaring epileptic patients 'seizure free'. To date neither the International Headache Society nor the International League against Epilepsy mention that headache/migraine may, on occasion, be the sole ictal epileptic manifestation. Lastly, studies designed to investigate the triggering role of photosensitivity in both headache and epilepsy are warranted. PMID- 20963465 TI - Pes cavus and hereditary neuropathies: when a relationship should be suspected. AB - The hereditary peripheral neuropathies are a clinically and genetically heterogeneous group of diseases of the peripheral nervous system. Foot deformities, including the common pes cavus, but also hammer toes and twisting of the ankle, are frequently present in patients with hereditary peripheral neuropathy, and often represent one of the first signs of the disease. Pes cavus in hereditary peripheral neuropathies is caused by imbalance between the intrinsic muscles of the foot and the muscles of the leg. Accurate clinical evaluation in patients with pes cavus is necessary to exclude or confirm the presence of peripheral neuropathy. Hereditary peripheral neuropathies should be suspected in those cases with bilateral foot deformities, in the presence of family history for pes cavus and/or gait impairment, and in the presence of neurological symptoms or signs, such as distal muscle hypotrophy of limbs. Herein, we review the hereditary peripheral neuropathies in which pes cavus plays a key role as a "spy sign," discussing the clinical and molecular features of these disorders to highlight the importance of pes cavus as a helpful clinical sign in these rare diseases. PMID- 20963466 TI - Association of increased serum IL-33 levels with clinical and laboratory characteristics of systemic lupus erythematosus in Chinese population. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by abnormal production of autoantibodies and proinflammatory cytokines. Although interleukin-33 (IL-33), a novel number of the IL-1 family, has been reported to have proinflammatory effects, the association of IL-33 with SLE has remained unknown. The aim of this study was to examine whether the serum IL-33 level is associated with SLE. A total of 70 patients with SLE were recruited. Sera from these patients were obtained at their visit and were compared to sera from 40 healthy controls or 28 patients with rheumatoid arthritis (RA) for IL-33 level. Furthermore, blood samples from patients with SLE were determined for various SLE related laboratory variables, including blood routine, complements, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and some autoantibodies. Serum IL-33 level was significantly increased in patients with SLE, compared with healthy controls, but was lower than that with RA. In patients with SLE, most clinical and laboratory characteristics did not correlate with serum IL-33 levels, with exceptions of thrombocytopenia, erythrocytopenia, anti-SSB antibody, ESR, CRP and IgA. By Spearman's correlation coefficient, patients with SLE showed close correlation of IL-33 with ESR, CRP and IgA, and by multivariate logistic regressions, patients with SLE showed significantly independent association of IL 33 with thrombocytopenia, erythrocytopenia and anti-SSB antibody. Our results suggest that IL-33 may play a role in acute phase of SLE, but it was not associated with course of the disease. Moreover, IL-33 may exert biologic effects on erythrocytes and platelets or their precursors in SLE. PMID- 20963467 TI - Tako-tsubo cardiomyopathy in a patient with bilateral lesions in the dorsal medulla. AB - Tako-tsubo-like cardiomyopathy (TTC) is much more common than originally thought. The exact pathophysiology of TTC is unclear. The most accepted theory proposes myocardial stunning of neurogenic origin, supported by the frequent antecedent of emotional or physical stress, suggesting a catecholamine-mediated mechanism. We present a patient with this syndrome and bilateral damage of the dorsal medulla oblongata likely affecting both solitary tract nuclei. Our case points to a link between baroreflex failure and TTC, highlighting the important role of sympathetic discharge in the pathophysiology of TTC. PMID- 20963468 TI - Education and depressive symptoms in 22 European countries. AB - OBJECTIVES: Variations in the association between education and depressive symptoms in 22 European countries are investigated. METHODS: Analyses are based on the European Social Survey Round 3 (N = 34,443). Education was coded according to the International Standard Classification of Education. Depressive symptoms are measured by the shortened Center for Epidemiologic Studies Depression Scale (CES-D 8). RESULTS: The results of multiple logistic regressions show that people with low education have elevated risks of experiencing a high score of depressive symptoms. Relatively large inequalities were observed among both sexes for Hungary and Slovenia, small and non-significant inequalities for Austria, Denmark, and Estonia. CONCLUSION: The results indicate that educational inequalities in depressive symptoms are a generalized although not invariant phenomenon. PMID- 20963469 TI - The use of a surveillance system to measure changes in mental health in Australian adults during the global financial crisis. AB - OBJECTIVE: This study aimed to describe trends in a range of mental health indicators in South Australia where a surveillance system has been in operation since July 2002 and assess the impact of the global financial crisis (GFC). METHODS: Data were collected using a risk factor surveillance system. Participants, aged 16 years and above, were asked about doctor-diagnosed anxiety, stress or depression, suicidal ideation, psychological distress (PD), demographic and socioeconomic factors using Computer-Assisted Telephone Interviewing (CATI). RESULTS: Overall, there was a decreasing trend in the prevalence of PD between 2002 and 2009. Stress has decreased since 2004 although anxiety has increased. Comparing 2008 or 2009 (the economic crisis period) with 2005 or 2007, there was significant increase in anxiety for part-time workers but a decrease for full time workers. There were significant differences for stress by various demographic variables. CONCLUSION: The overall prevalence of mental health conditions has not increased during the GFC. Some subgroups in the population have been disproportionately impacted by changes in mental health status. The use of a surveillance system enables rapid and specifically targeted public health and policy responses to socioeconomic and environmental stressors, and the evaluation of outcomes. PMID- 20963470 TI - Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP. AB - PURPOSE: Erlotinib (Tarceva(r), OSI-774) is a small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. As high-grade gliomas frequently show amplification, overexpression and/or mutation of EGFR, this drug has been tested in several clinical trials with glioblastoma patients, but unfortunately, with little success. As erlotinib is a known substrate of P glycoprotein (P-gp) and breast cancer resistance protein (BCRP) we have investigated the effect of these ABC-transporters on the brain penetration of erlotinib. STUDY DESIGN: Erlotinib (50 mg/kg) was given by i.p. administration to wild-type (WT), Mdr1ab(-/-) (single P-gp knockout), Bcrp1(-/-) (single Bcrp1 knockout) and Mdr1ab(-/-)Bcrp1(-/-) (compound P-gp and Bcrp1 knockout) mice. Drug levels in plasma and tissues were determined by reversed-phase high-performance liquid chromatography. RESULTS: Relative to Mdr1ab(-/-)Bcrp1(-/-) mice that are deficient for both drug transporters, the area under the concentration time curve in brain tissue (AUC)(brain) of erlotinib decreased significantly by 1.6-fold in Mdr1ab(-/-) mice where Bcrp1 is present (49.6 +/- 3.95 versus 31.1 +/- 1.7, MUg/g*h; P < 0.01). In Bcrp1(-/-) mice, were P-gp is present, a more pronounced 3.8-fold decrease to 13.0 +/- 0.70, MUg/g*h (P < 0.01) was observed, which is close to the 4.5-fold decrease in the AUC(brain) of erlotinib found in WT mice where both drug transporters are present (11.0 +/- 1.35, P < 0.01). The plasma clearance of erlotinib was similar in mice deficient for P-gp and/or Bcrp1 compared with wild-type mice. In all other tissues the differences between the genotypes were negligible. CONCLUSIONS: Both P-gp and Bcrp1 reduce the brain penetration of erlotinib. Although P-gp appears to be the most effective factor limiting the brain penetration of erlotinib, the highest brain accumulation was observed when Bcrp1 was also absent. Strategies to inhibit P-gp/BCRP in patients to improve delivery of (novel molecular-targeted) substrate agents, such as erlotinib, to the brain may be required for treatment of intracranial malignancies. PMID- 20963471 TI - Evaluation of different lignocellulosic substrates for the production of cellulases and xylanases by the basidiomycete fungi Bjerkandera adusta and Pycnoporus sanguineus. AB - Agricultural waste products are potential resources for the production of a number of industrial compounds, including biofuels. Basidiomycete fungi display a battery of hydrolytic enzymes with prospective use in lignocellulosic biomass transformation, however little work has been done regarding the characterization of such activities. Growth in several lignocellulosic substrates (oak and cedar sawdust, rice husk, corn stubble, wheat straw and Jatropha seed husk) and the production of cellulases and xylanases by two basidiomycete fungi: Bjerkandera adusta and Pycnoporus sanguineus were analyzed. Growth for P. sanguineus was best in rice husk while corn stubble supported the highest growth rate for B. adusta. Among the substrates tested, cedar sawdust produced the highest cellulolytic activities in both fungal species, followed by oak sawdust and wheat straw. Xylanolytic activity was best in oak and cedar sawdust for both species. We found no correlation between growth and enzyme production. Zymogram analysis of xylanases and cellulases showed that growth in different substrates produced particular combinations of protein bands with hydrolytic activity. PMID- 20963472 TI - Tick infestation (Acari: Ixodidae) in roe deer (Capreolus capreolus) from northwestern Spain: population dynamics and risk stratification. AB - During the 2007 and 2008 hunting seasons (April-October) the skin of 367 roe deer (Capreolus capreolus L.), hunted in different preserves from Galicia (Northwestern Spain), were examined for ticks (Acari: Ixodidae). The overall prevalence of infestation by ticks was 83.1%. The predominant species was Ixodes ricinus (83.1%), whereas a single Dermacentor marginatus specimen appeared in one roe deer. All developmental stages of I. ricinus were found parasitizing roe deer, the adults being the most frequent (82.2%), followed by nymphs (45.6%) and larvae (27.2%). The mean intensity of infestation by I. ricinus was 43.2 +/- 49.85; most of them were adults (30.7 +/- 31.64) and in a lesser extend nymphs (16.9 +/- 24.74) and larvae (10.7 +/- 29.90). Ixodes ricinus was present all over the study with percentages that oscillated between 100% in spring and 57.4% in autumn. CHAID algorithm showed the sex of roe deer as the most influential factor in tick prevalence, followed by the climatic area. The different developmental stages of I. ricinus were more frequent in males than in females, and the prevalence of adults and larvae were higher in roe deer from coastal areas than in those from mountainous and central areas, whereas nymphs were more frequent in mountainous areas. Host age and density were not determinants for tick infestation. Our results confirm that roe deer are important hosts for I. ricinus in northwestern Spain, serving as a vehicle for the geographic distribution of these ticks. PMID- 20963474 TI - Fish oil, but not soy bean or olive oil enriched infusion decreases histopathological severity of acute pancreatitis in rats without affecting eicosanoid synthesis. AB - Different dietary fatty acids affect eicosanoid metabolism in different ways, thus influencing the pro- and anti-inflammatory balance of prostaglandins and leukotrienes. Therefore, we analyzed the impact of [n-3], [n-6], and [n-9] fatty acids on eicosanoid metabolism and histopathology in acute pancreatitis in rats. Seventy-five male Sprague-Dawley rats were randomized into five groups (n = 15). Group 1 underwent only laparotomy, while in groups, 2-5 pancreatitis was induced. Groups 1 and 2 were then given saline infusion, groups 3-5 received fat emulsion (group 3: rich in [n-6], group 4: rich in [n-9], group 5: rich in [n-3] fatty acids) for another 18 h. Infusion rich in [n-3] fatty acids significantly decreased histopathological severity of pancreatitis, compared to all other groups. There was no difference concerning the concentrations of prostaglandins and leukotrienes between all groups. Parenteral infusion rich in [n-3] fatty acids reduced histopathological severity of acute pancreatitis in rats without changing eicosanoid metabolism at the endpoint. PMID- 20963473 TI - Prognostic significance of claudin expression changes in breast cancer with regional lymph node metastasis. AB - Adherent and tight junction molecules have been described to contribute to carcinogenesis and tumor progression. Additionally, the group of claudin-low tumors have recently been identified as a molecular subgroup of breast carcinoma. In our study, we examined the expression pattern of claudins, beta-catenin and E cadherin in invasive ductal (IDCs) and lobular (ILCs) carcinomas and their corresponding lymph node metastases (LNMs). Tissue microarrays of 97 breast samples (60 invasive ductal carcinomas, 37 invasive lobular carcinomas) and their corresponding LNMs have been analyzed immunohistochemically for claudin-1, -2, 3, -4, -5, -7, beta-catenin and E-cadherin expression. The stained slides were digitalized with a slide scanner and the reactions were evaluated semiquantitatively. When compared to LNMs, in the IDC group beta-catenin and claudin-2, -3, -4 and -7 protein expression showed different pattern while claudin-1, -2, -3, -4 and -7 were differently expressed in the ILC group. Lymph node metastases developed a notable increase of claudin-5 expression in both groups. Decrease or loss of claudin-1 and expression of claudin-4 in lymph node metastases correlated with reduced disease-free survival in our patients. According to our observations, the expression of epithelial junctional molecules, especially claudins, is different in primary breast carcinomas compared to their lymph node metastases as demonstrated by immunohistochemistry. Loss of claudin junctional molecules might contribute to tumor progression, and certain claudin expression pattern might be of prognostic relevance. PMID- 20963475 TI - Genetic diversity of tomato-infecting Tomato yellow leaf curl virus (TYLCV) isolates in Korea. AB - Epidemic outbreaks of Tomato yellow leaf curl virus (TYLCV) diseases occurred in greenhouse grown tomato (Solanum lycopersicum) plants of Busan (TYLCV-Bus), Boseong (TYLCV-Bos), Hwaseong (TYLCV-Hwas), Jeju Island (TYLCV-Jeju), and Nonsan (TYLCV-Nons) in Korea during 2008-2009. Tomato disease by TYLCV has never occurred in Korea before. We synthesized the full-length genomes of each TYLCV isolate from the tomato plants collected at each area and determined their nucleotides (nt) sequences and deduced the amino acids of six open reading frames in the genomes. TYLCV-Bus and -Bos genomes shared higher nt identities with four Japanese isolates -Ng, -Omu, -Mis, and -Miy. On the other hand, TYLCV-Hwas, Jeju, and -Nons genomes shared higher nt identities with five Chinese isolates TYLCV-AH1, -ZJ3, -ZJHZ12, -SH2, -Sh10, and two Japanese isolates -Han and -Tosa. On the basis of a neighbor-joining tree, five Korean TYLCV isolates were separated into three clades. TYLCV-Bus and -Bos formed the first clade, clustering with four Japanese isolates TYLCV-Mis, -Omu, -Ng, and -Miy. TYLCV-Jeju and -Nons formed the second clade, clustering with two Chinese isolates -ZJHZ212 and -Sh10. TYLCV-Hwas was clustered with two Japanese isolates -Han and -Tosa and three Chinese isolates -AH1, -ZJ3, and -SH2. Two fragments that had a potentially recombinant origin were identified using the RDP, GENECONV, BootScan, MaxChi, Chimaera, SiScan, and 3Seq methods implemented in RDP3.41. On the basis of RDP analysis, all TYLCV isolates could originated from the interspecies recombination between TYLCV-Mld[PT] isolated from Portugal as a major parent and TYLCTHV-MM isolated from Myanmar as a minor parent. PMID- 20963476 TI - The insect repellent DEET (N,N-diethyl-3-methylbenzamide) increases the synthesis of glutathione S-transferase in cultured mosquito cells. AB - DEET (N,N-diethyl-3-methylbenzamide) is the active ingredient used in many commonly used insect repellents, but its mode of action remains poorly understood. Efforts to identify properties that could lead to the development of more effective active ingredients have distinguished among DEET's repellent, deterrent, and insecticidal activities. We used an Aedes albopictus mosquito cell line to evaluate DEET's toxicological properties in the absence of sensory input mediated by the olfactory system. When cells were treated with DEET and labeled with [(35)S]methionine/cysteine, a single 25-kDa protein was induced, relative to other proteins, on SDS-polyacrylamide gels. The 25-kDa band from DEET-treated cells was enriched in peptides corresponding to glutathione S-transferase D10 and/or theta in the Aedes aegypti genome. Consistent with the increased expression of the labeled protein, DEET-treated cells had increased glutathione S transferase activity, and the radiolabeled band bound to Sepharose 4B containing reduced glutathione. By analyzing partial tryptic digests, we established that DEET induces the homolog of A. aegypti glutathione S-transferase, class theta, corresponding to protein XP_001658009.1 in the NCBI database. This specific effect of DEET at the subcellular level suggests that DEET induces physiological responses that extend beyond recognition by the peripheral olfactory system. PMID- 20963477 TI - Revision of comprehensive cancer control plans: experiences shared by three states. AB - In the early 1990 s, a new movement emerged across the country to improve the way organizations coordinate and collaborate in the fight against cancer. Central to this movement is the development and implementation of a strategic plan, called a comprehensive cancer control (CCC) plan. Currently, sixty-nine plans exist among US states, tribes or tribal organizations, territories and Pacific Island Jurisdictions. The majority of CCC plans cover a five-year timeframe; typically in the fifth year, a plan update or plan revision process begins. Although many plans have common components, different processes have been utilized by various programs to update plans. This article describes the process used by Kentucky, Michigan and Wyoming to update and revise their CCC plans. Common key factors for successful cancer plan revision and implementation will be described based on experiences shared by the three states. PMID- 20963479 TI - Desistance from intimate partner violence: the role of legal cynicism, collective efficacy, and social disorganization in Chicago neighborhoods. AB - This paper examined the relationship between reported Intimate Partner Violence (IPV) desistance and neighborhood concentrated disadvantage, ethnic heterogeneity, residential instability, collective efficacy and legal cynicism. Data from the Project on Human Development in Chicago Neighborhoods (PHDCN) Longitudinal survey were used to identify 599 cases of IPV in Wave 1 eligible for reported desistance in Wave 2. A Generalized Boosting Model was used to determine the best proximal predictors of IPV desistance from the longitudinal data. Controlling for these predictors, logistic regression of neighborhood characteristics from the PHDCN community survey was used to predict reported IPV desistance in Wave 2. The paper finds that participants living in neighborhoods high in legal cynicism have lower odds of reporting IPV desistance, controlling for other variables in the logistic regression model. Analyses did not find that IPV desistance was related to neighborhood concentrated disadvantage, ethnic heterogeneity, residential instability and collective efficacy. PMID- 20963478 TI - Non-invasive prenatal detection of achondroplasia using circulating fetal DNA in maternal plasma. AB - PURPOSE: To perform a reliable non-invasive detection of the fetal achondroplasia using maternal plasma. METHODS: We developed a quantitative fluorescent polymerase chain reaction (QF-PCR) method suitable for detection of the FGFR3 mutation (G1138A) causing achondroplasia. This method was applied in a non invasive detection of the fetal achondroplasia using circulating fetal-DNA (cf DNA) in maternal plasma. Maternal plasmas were obtained at 27 weeks of gestational age from women carrying an achondroplasia fetus or a normal fetus. RESULTS: Two percent or less achondroplasia DNA was reliably detected by QF-PCR. In a woman carrying a normal fetus, analysis of cf-DNA showed only one peak of the wild-type G allele. In a woman expected an achondroplasia fetus, analysis of cf-DNA showed the two peaks of wild-type G allele and mutant-type A allele and accurately detected the fetal achondroplasia. CONCLUSIONS: The non-invasive method using maternal plasma and QF-PCR may be useful for diagnosis of the fetal achondroplasia. PMID- 20963480 TI - The role for public funding of faith-based organizations delivering behavioral health services: guideposts for monitoring and evaluation. AB - The paper reviews policies promoting faith-based organizations' (FBO) participation in publicly-funded programs since the Charitable Choice statute was enacted during the Clinton administration and then additional faith-based initiatives were implemented by the Bush administration. The paper focuses on research findings on FBO participation in publicly-funded human service programs under these policies. It then proposes a framework for evaluation to assess the appropriateness of public funding for behavioral health services delivered by FBOs, in order to address: (1) the programmatic and systemic effects resulting from the infusion of new players from the faith community, and the consequences to the profile of services and who gets served; and (2) the content and effectiveness of faith-infused services as a basis for identifying interventions appropriate for public funding. The analysis considers classification issues, theoretical bases of measured effects of faith-infused services, and the transferability of faith-based interventions across religious and secular applications in order to satisfy constitutional issues and client choice. PMID- 20963481 TI - No significant association results obtained from significant association evidence: the ongoing uncertainty of TP53 codon 72 polymorphism and breast cancer risk. PMID- 20963482 TI - Monitoring of flow field based on stable isotope geochemical characteristics in deep groundwater. AB - The water circulation in deep aquifers controls not only chemical composition of the groundwater, but also stable isotope composition. In order to analyze the flow field in the process of the deep groundwater circulation in different aquifers, specimens belonging to the fourth aquifer in the Quaternary (the fourth aquifer for short), the coal and sandstone cranny aquifer in the Permian, and Carboniferous (the coal catena aquifer for short), the Taiyuan group limestone aquifer in the Carboniferous (the Taiyuan limestone aquifer for short), and the limestone aquifer in the Ordovician (the Ordovician limestone aquifer for short) were gained from the top down in Renlou colliery and local Linhuan coalmine district, northern Anhui, China, in the study. deltaD, delta(18)O, and the content of tall dissolve solids (TDS for short) of these specimens were tested. The experimental results had revealed that the groundwater in the fourth aquifer and the Taiyuan limestone aquifer takes on (18)O excursion and the coal catena aquifer takes on D excursion in Linhuan coalmine district, while excursion characteristic in the Ordovician limestone aquifer is not evident in the coalmine district. By analysis, delta(18)O and the content of TDS are in negative relationship in the groundwater of the fourth aquifer and the Taiyuan limestone aquifer in Linhuan coalmine district, yet deltaD and the content of TDS are in positive relationship in the coal catena aquifer. Mining greatly influences the fourth aquifer and the coal catena aquifer so the groundwater in the fourth aquifer flows from northwest and southeast to mining areas and the groundwater in the coal catena aquifer flows from around to mining areas. However, mining does not influence the Taiyuan limestone aquifer evidently so the groundwater flows from east to west still. PMID- 20963483 TI - Simultaneous determination of malachite green, enrofloxacin and ciprofloxacin in fish farming water and fish feed by liquid chromatography with solid-phase extraction. AB - An effective and sensitive method for simultaneous analysis of malachite green (MG), enrofloxacin (ENFLX) and ciprofloxacin (CPFLX) by liquid chromatography diode array detection with solid-phase extraction (SPE) is developed. The conditions of SPE and LC were investigated and optimised. The effective separation of these compounds was achieved using a ZY1104 C18 column (250 * 4.6 mm, 5 MUm) with 20 mM tetrabutyl ammonium bromide (pH 3.0)-acetonitrile as mobile phase and gradient elution. The diode array detection was used at 278 nm for ENFLX and CPFLX and at 613 nm for MG. Under the optimal conditions, the method LOD values of MG, ENFLX and CPFLX were 0.01, 0.07 and 0.10 MUg L( -1) for fish farming water samples and 1.5, 10.5 and 15 MUg kg( -1) for fish feed samples, respectively. The relative recoveries of the three analytes were achieved to be 76.7-82.3% with the RSDs (n = 5) of 3.2-4.6% for spiked fish farming water samples and 78.8-93.7% with the RSDs (n = 5) of 3.1-4.8% for spiked fish feed samples. PMID- 20963484 TI - Analysis of spatio-temporal land cover changes for hydrological impact assessment within the Nyando River Basin of Kenya. AB - The spatio-temporal changes in the land cover states of the Nyando Basin were investigated for auxiliary hydrological impact assessment. The predominant land cover types whose conversions could influence the hydrological response of the region were selected. Six Landsat images for 1973, 1986, and 2000 were processed to discern the changes based on a methodology that employs a hybrid of supervised and unsupervised classification schemes. The accuracy of the classifications were assessed using reference datasets processed in a GIS with the help of ground based information obtained through participatory mapping techniques. To assess the possible hydrological effect of the detected changes during storm events, a physically based lumped approach for infiltration loss estimation was employed within five selected sub-basins. The results obtained indicated that forests in the basin declined by 20% while agricultural fields expanded by 16% during the entire period of study. Apparent from the land cover conversion matrices was that the majority of the forest decline was a consequence of agricultural expansion. The model results revealed decreased infiltration amounts by between 6% and 15%. The headwater regions with the vast deforestation were noted to be more vulnerable to the land cover change effects. Despite the haphazard land use patterns and uncertainties related to poor data quality for environmental monitoring and assessment, the study exposed the vast degradation and hence the need for sustainable land use planning for enhanced catchment management purposes. PMID- 20963485 TI - Analysis of cyprodinil in leek and pepper and its decline under field conditions. AB - A HPLC-UV method for determination of cyprodinil in leek, pepper, and soil was developed and the decline of cyprodinil under field conditions in China was investigated. The samples were extracted with acetonitrile. For leek and pepper samples, further clean-up with a florisil SPE column was necessary. Average recoveries of cyprodinil were found in the range of 82.92-107.43% with relative standard deviations of 2.48-14.55%. The pesticide cyprodinil showed a relatively fast decline rate. The half lives were from 2 to 4 days in leek and pepper, from 2-5 days in soil except in Beijing (14.7 days). So the decline of cyprodinil in leek and pepper was almost same in different experiment plots. However, the decline in soil was much complicated, and affected by the precipitation and other climate condition. The results could provide guidance to safe and reasonable use of this pesticide in agriculture. PMID- 20963486 TI - Oxidative damage in rat brain during aging: interplay between energy and metabolic key target proteins. AB - Aging is characterized by a gradual and continuous loss of physiological functions and responses particularly marked in the central nervous system. Reactive oxygen species (ROS) can react with all major biological macromolecules such as carbohydrates, nucleic acids, lipids, and proteins. Since proteins are the major components of biological systems and regulate multiple cellular pathways, oxidative damage of key proteins are considered to be the principal molecular mechanisms leading to age-related deficits. Recent evidences support the notion that a decrease of energy metabolism in the brain contribute to neuronal loss and cognitive decline associated with aging. In the present study we identified selective protein targets which are oxidized in aged rats compared with adult rats. Most of the oxidatively modified proteins we found in the present study are key proteins involved in energy metabolism and ATP production. Oxidative modification of these proteins was associated with decreased enzyme activities. In addition, we also found decreased levels of thiol reducing system. Our study demonstrated that oxidative damage to specific proteins impairs energy metabolism and ATP production thus contributing to shift neuronal cells towards a more oxidized environment which ultimately might compromise multiple neuronal functions. These results further confirm that increased protein oxidation coupled with decreased reducing systems are characteristic hallmarks of aging and aging related degenerative processes. PMID- 20963488 TI - Effects of bufalin on the proliferation of human lung cancer cells and its molecular mechanisms of action. AB - Bufalin, a naturally occurring small-molecule compound from Traditional Chinese Medicine (TCM) Chansu showed inhibitory effects against human prostate, hepatocellular, endometrial and ovarian cancer cells, and leukemia cells. However, whether or not bufalin has inhibitory activity against the proliferation of human non-small cell lung cancer (NSCLC) cells is unclear. The aim of this study is to study the effects of bufalin on the proliferation of NSCLC and its molecular mechanisms of action. The cancer cell proliferation was measured by MTT assay. The apoptosis and cell cycle distribution were analyzed by flow cytometry. The protein expressions and phosphorylation in the cancer cells were detected by Western blot analysis. In the present study, we have demonstrated that bufalin suppressed the proliferation of human NSCLC A549 cell line in time- and dose dependent manners. Bufalin induced the apoptosis and cell cycle arrest by affecting the protein expressions of Bcl-2/Bax, cytochrome c, caspase-3, PARP, p53, p21WAF1, cyclinD1, and COX-2 in A549 cells. In addition, bufalin reduced the protein levels of receptor expressions and/or phosphorylation of VEGFR1, VEGFR2, EGFR and/or c-Met in A549 cells. Furthermore, bufalin inhibited the protein expressions and phosphorylation of Akt, NF-kappaB, p44/42 MAPK (ERK1/2) and p38 MAPK in A549 cells. Our results suggest that bufalin inhibits the human lung cancer cell proliferation via VEGFR1/VEGFR2/EGFR/c-Met-Akt/p44/42/p38-NF-kappaB signaling pathways; bufalin may have a wide therapeutic and/or adjuvant therapeutic application in the treatment of human NSCLC. PMID- 20963487 TI - Neurochemicals for the investigation of GABA(C) receptors. AB - GABA(C) receptors are being investigated for their role in many aspects of nervous system function including memory, myopia, pain and sleep. There is evidence for functional GABA(C) receptors in many tissues such as retina, hippocampus, spinal cord, superior colliculus, pituitary and the gut. This review describes a variety of neurochemicals that have been shown to be useful in distinguishing GABA(C) receptors from other receptors for the major inhibitory neurotransmitter GABA. Some selective agonists (including (+)-CAMP and 5-methyl IAA), competitive antagonists (such as TPMPA, (+/-)-cis-3-ACPBPA and aza-THIP), positive (allopregnanolone) and negative modulators (epipregnanolone, loreclezole) are described. Neurochemicals that may assist in distinguishing between homomeric rho1 and rho2 GABA(C) receptors (2-methyl-TACA and cyclothiazide) are also covered. Given their less widespread distribution, lower abundance and relative structural simplicity compared to GABA(A) and GABA(B) receptors, GABA(C) receptors are attractive drug targets. PMID- 20963489 TI - Simple assessment of patient's stage of chronic kidney disease using eGFR-MDRD nomograms. AB - European as well as US guidelines recommend the Modification of Diet in Renal Disease (MDRD) formula to determine the glomerular filtration rate (GFR) and, based on this, the staging of chronic kidney disease (CKD). The diagnosis of CKD is only established when a reduced eGFR has been observed for 3 months or longer. Because the MDRD equation is very complex, the calculation of eGFR is not possible without help from calculators or computers. Therefore, we converted this equation into simple, easy to use colour nomograms. These were drawn separately for men and women, on one hand, and for whites and blacks, on the other. These nomograms allow the determination of a patient's eGFR in a quick and easy way and at any location. PMID- 20963490 TI - The effect of prostate cancer screening on stage IV disease in America. AB - OBJECTIVE: Some studies have found that prostate cancer (PCa) screening provides little or no change in PCa-related mortality during the 7-10 years following diagnoses. However, most men are diagnosed with PCa at low-stage disease and die of unrelated causes during this period. Men diagnosed at stage IV are at much higher risk of dying of the disease. Therefore, stage IV rates at first diagnoses may be a surrogate marker of PCa-related mortality over a time span less than 10 years. The study objective is to examine the association between PCa screening and stage IV disease rates in new cases to explore potential benefits for PCa screening. MATERIALS AND METHODS: The percent of stages I, II, III, IV and unclassified PCa diagnosed in white males in 2005 was compared to PCa screening rates on a state-by-state basis. To consider access to medical care and socioeconomic status, median family income, degree of urbanization, urologist population density and health insurance status were included in the analysis. RESULTS: PCa stage IV disease correlated inversely with PCa screening rates (r = 0.42, P = 0.006) where r is the correlation coefficient and P is the probability. Stage I PCa correlated with lack of health insurance (r = 0.37, P = 0.02). CONCLUSIONS: The results of this study suggest that with PCa screening may be associated with reduced rates of stage IV disease. PMID- 20963491 TI - Bacillus beringensis sp. nov., a psychrotolerant bacterium isolated from the Bering Sea. AB - Psychrotolerant Bacillus-like strains BR035(T) and BR011 were isolated from seawater of the Bering Sea and were characterized by means of a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences revealed that these strains were related to the members of the genus Bacillus and had the highest 16S rRNA gene sequence similarity with Bacillus korlensis ZLC-26(T). DNA DNA hybridization experiments confirmed that strains BR035(T) and BR011 belonged to the same species and were distinct from their closest relatives. The cells were Gram-positive, rods, motile, spore-forming and psychrotolerant. The temperature range for growth was 4-42 degrees C. The main respiratory quinone was MK-7. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, an unknown aminolipid and two unknown phospholipids. The major cellular fatty acids were iso-C15:0, anteiso-C15:0, iso-C14:0 and C16:1omega7c alcohol. The diagnostic diamino acid in the cell-wall peptidoglycan was meso-diaminopimelic acid. The genomic DNA G + C content was 37.6-37.8 mol%. On the basis of the phenotypic characteristics, phylogenetic analysis and DNA-DNA relatedness data, a novel species Bacillus beringensis is proposed and the type strain is BR035(T) (=CGMCC 1.9126(T)=DSM 22571(T)). PMID- 20963492 TI - Wickerhamomyces anomalus in the sourdough microbial ecosystem. AB - We previously found that Wickerhamomyces anomalus (formerly Hansenula anomala, Pichia anomala) was the second most frequently isolated yeast in Belgian artisan bakery sourdoughs and that the yeast dominated laboratory sourdough fermentations. Such findings are of interest in terms of the advantage of W. anomalus over other commonly encountered sourdough yeasts and its potential introduction into the sourdough ecosystem. Here, we provide a brief overview of current knowledge on yeast ecology and diversity in sourdough in the context of the potential natural habitat of W. anomalus. Insight into the population structure of W. anomalus was obtained by comparing internal transcribed spacer rDNA sequences of selected sourdough isolates with publicly available database sequences. PMID- 20963493 TI - Who is prone to react to coinciding threats of terrorism and war? Exploring vulnerability through global versus differential reactivity. AB - This study addressed reactions of Israelis to terrorism and the confrontation with Iraq when these threats coincided in 2003. A sample of 471 participants (age range 19-88) rated affective, cognitive, and behavioral reactions to each threat. Stronger reactions related to higher neuroticism, lower education, and being a woman; reactions to the confrontation with Iraq also related to lower extraversion and being a Holocaust survivor. Participants reacting predominantly to terrorism revealed higher conscientiousness and better subjective health. The study suggests that global reactivity to a critical dual-stressor situation is linked with risk factors of vulnerability whereas differential reactivity may indicate adaptability. PMID- 20963494 TI - Laser-assisted cryosurgery in ex vivo mice hepatic tissue: viability assays using green fluorescent protein. AB - An experimental investigation is carried out to develop a novel approach to cryosurgery, where laser heating counteracts tissue freezing to better confine damage to the targeted cancerous tissue within a lethal low-temperature isothermal boundary-an approach we refer to as laser-assisted cryosurgery (LAC). The advantage of this procedure relative to conventional cryosurgery assisted with urethral warmers or cryoheaters is that laser heating provides volumetric rather than superficial heating, which leads to deeper penetration, more homogeneous tissue protection and better demarcation of the destructive freezing effect to a well-defined targeted volume. Tissue viability assays are performed using green fluorescence protein (GFP) as a viability marker and correlated with temperature history after performing LAC procedures on ex vivo mice hepatic tissue. The limit for cell denaturation at the irradiated surface predicted by GFP analysis is further confirmed using reverse transcription polymerase chain reaction (RT-PCR). In addition, the correlation between GFP fluorescence and cell viability and loss of GFP fluorescence in non-viable cells has been tested and validated by histological analysis using a standard cell viability measuring method (hematoxylin and eosin staining). Analysis of our experimental measurements show that reproducible thermal gradients (of 236 degrees C/cm) and predictable tissue necrosis can be reliably produced by LAC without exceeding temperature thresholds for cell denaturation (of T (surf) ~ 48 degrees C) beyond preset tissue boundaries (with resolution of 0.1 degrees C/mm). The results have shown the feasibility of controlling temperatures at specified tissue locations to prevent hyperthermal or freezing damage. PMID- 20963495 TI - The effect of noisy flow on endothelial cell mechanotransduction: a computational study. AB - Flow in the arterial system is mostly laminar, but turbulence occurs in vivo under both normal and pathological conditions. Turbulent and laminar flow elicit significantly different responses in endothelial cells (ECs), but the mechanisms allowing ECs to distinguish between these different flow regimes remain unknown. The authors present a computational model that describes the effect of turbulence on mechanical force transmission within ECs. Because turbulent flow is inherently "noisy" with random fluctuations in pressure and velocity, our model focuses on the effect of signal noise (a stochastically changing force) on the deformation of intracellular transduction sites including the nucleus, cell-cell adhesion proteins (CCAPs), and focal adhesion sites (FAS). The authors represent these components of the mechanical signaling pathway as linear viscoelastic structures (Kelvin bodies) connected to the cell surface via cytoskeletal elements. The authors demonstrate that FAS are more sensitive to signal noise than the nucleus or CCAP. The relative sensitivity of these various structures to noise is affected by the nature of the cytoskeletal connections within the cell. Finally, changes in the compliance of the nucleus dramatically affect nuclear sensitivity to noise, suggesting that pathologies that alter nuclear mechanical properties will be associated with abnormal EC responsiveness to turbulent flow. PMID- 20963496 TI - BNip3 is a mediator of TNF-induced necrotic cell death. AB - Tumor necrosis factor (TNF) is a pleiotropic cytokine involved in immune modulation, inflammatory reactions, and target cell death in many pathologic conditions. The cell death pathways triggered by TNF include the caspase-8/Bid dependent apoptotic pathway and the caspase-independent necrosis pathway (necroptosis). While the signaling pathways activated after binding of TNF to the TNF receptor (TNFR) and subsequent insertion of Bid/Bax/Bik into the outer mitochondrial membrane are relatively well known, other cell death pathways and the participating signaling molecules remain to be clarified. BNip3 is a pro death protein and a member of the BH3-only Bcl-2 family. When ectopically overexpressed or induced by hypoxia, BNip3 induces various types of cell death via mitochondrial or non-mitochondrial death cascades. In this study using A549 alveolar epithelial cells of the lung, we show that BNip3 is transcriptionally and translationally upregulated by TNF, and its expression level determines the sensitivity to necroptosis induced by TNF. However, BNip3 does not appear to be involved in caspase-8/Bid-dependent apoptotic cell death in these alveolar lung cells. Finally, we show that the generation of reactive oxygen species (ROS) is essential for mitochondrial insertion of BNip3, which is an important step in BNip3-induced mitochondrial catastrophe. Our results indicate that BNip3 is a candidate therapeutic target in pathologic conditions in which TNF causes tissue damage. PMID- 20963497 TI - Acetylcholine prevents angiotensin II-induced oxidative stress and apoptosis in H9c2 cells. AB - Apoptosis of cardiomyocytes plays an important role in the development of cardiovascular diseases (CVD). Numerous studies have shown that generation of reactive oxygen species (ROS) induced by the renin-angiotensin system (RAS) is involved in this pathological process. Recent studies also suggested that acetylcholine (ACh) prevented the hypoxia-induced apoptosis of mouse ES cells by inhibiting the ROS production. However, whether ACh can inhibit the action of angiotensin II (Ang II) and subsequently prevent CVD development remains unclear. In this study, H9c2 cells were stimulated by 10(-6) M Ang II for 24 h with or without 10(-5) M ACh, 10(-5) M ACh + 10(-4) M atropine respectively. The results demonstrated that Ang II increased apoptosis index by fourfold (vs. the control group, P < 0.01), which were significantly diminished by ACh. However, the atropine (ACh receptor [AChR] inhibitor) treatment blocked the protective effect of ACh. Subsequently, Ang II significantly increases the expression and activity of NADPH oxidase so that ROS production is increased by sevenfold (vs. control group, P < 0.01). The activity and expression of caspase-3 along with the Bax/Bcl2 ratio and the levels of p38 mitogen activated protein kinase (MAPK) phosphorylation also appeared to follow a similar trend. Furthermore, we observed that ACh could reduce up-regulation of AT1 receptor expression induced by Ang II. However, all these effects of ACh were inhibited by atropine. In conclusion, ACh prevents Ang II-induced H9c2 cells apoptosis through down-regulation of the AT1 receptor and inhibition of ROS-mediated p38 MAPK activation as well as regulation of Bcl-2, Bax and caspase-3. PMID- 20963498 TI - Apoptosis of human fibrosarcoma HT-1080 cells by epigallocatechin-3-O-gallate via induction of p53 and caspases as well as suppression of Bcl-2 and phosphorylated nuclear factor-kappaB. AB - Animal tumor bioassays and in vitro cell culture systems have demonstrated that epigallocatechin-3-O-gallate (EGCG), the predominant catechin in green tea, possesses anti-proliferative and pro-apoptotic effects on various cancer cells and tumors. In this study, we investigated the effects of EGCG on cell growth, cell cycle progression, and apoptosis in human fibrosarcoma HT-1080 cells. The involvement of p53, Bcl-2, Bax, caspases, and nuclear factor-kappaB (NF-kappaB) was examined as a mechanism for the anti-cancer activity of EGCG. Time-dependent intracellular trafficking of EGCG was also determined using fluorescein isothiocyanate (FITC)-conjugated EGCG (FITC-EGCG). Our data show that EGCG treatment caused dose-dependent cell growth inhibition, cell cycle arrest at the G(0)/G(1) phase, and DNA fragmentation suggesting the induction of apoptosis in HT-1080 cells. Immunoblot analysis revealed that the expression of p53, caspase-7 and -9 as well as the ratio of Bax/Bcl-2 protein increased significantly with higher EGCG concentrations and longer incubation times. Moreover, expression of phosphorylated NF-kappaB/p65 in HT-1080 cells was inhibited by EGCG treatment in a dose-dependent manner, while that of unphosphorylated NF-kappaB/p65 remained unaffected. Here we also reveal time-dependent internalization of FITC-EGCG into the cytosol of HT-1080 cells and its subsequent nuclear translocation. These results suggest that EGCG may interrupt exogenous signals directed towards genes involved in proliferation and cell cycle progression. Taken together, our data indicate that HT-1080 apoptosis may be mediated through the induction of p53 and caspases by the pro-oxidant activity of internalized EGCG, as well as suppression of Bcl-2 and phosphorylated NF-kappaB by the antioxidant activity of EGCG. PMID- 20963499 TI - Insulin-like growth factor 1 protects human neuroblastoma cells SH-EP1 against MPP+-induced apoptosis by AKT/GSK-3beta/JNK signaling. AB - Parkinson's disease (PD) is primarily caused by severe degeneration and loss of dopamine neurons in the substantia nigra pars compacta. Thus, preventing the death of dopaminergic neurons is thought to be a potential strategy to interfere with the development of PD. In the present work, we studied the effect of insulin like growth factor-1 (IGF-1) on 1-methyl-4-phenylpyridinium (MPP+)-induced apoptosis in human neuroblastoma SH-EP1 cells. We found that the PI3K/AKT pathway plays a central role in IGF-mediated cell survival against MPP+ neurotoxicity. Furthermore, we demonstrated that the protective effect of AKT is largely dependent on the inactivation of GSK-3beta, since inhibition of GSK-3beta by its inhibitor, BIO, could mimic the protective effect of IGF-1 on MPP+-induced cell death in SH-EP1 cells. Interestingly, the IGF-1 potentiated PI3K/AKT activity is found to negatively regulate the JNK related apoptotic pathway and this negative regulation is further shown to be mediated by AKT-dependent GSK-3beta inactivation. Thus, our results demonstrated that IGF-1 protects SH-EP1 cells from MPP+-induced apoptotic cell death via PI3K/AKT/GSK-3beta pathway, which in turn inhibits MPP+-induced JNK activation. PMID- 20963500 TI - Interpretation and inference: towards an understanding of methods. PMID- 20963501 TI - Molecular cloning and characterization of Izumo1 gene from sheep and cashmere goat reveal alternative splicing. AB - We cloned the cDNA and genomic DNA encoding for Izumo1 of cashmere goat (Capra hircus) and sheep (Ovis aries). Analysis of 4.6 kb Izumo1 genomic sequences in sheep and goat revealed a canonical open reading frame (ORF) of 963 bp spliced by eight exons. Sheep and goat Izumo1 genes share >99% identity at both DNA and protein levels and are also highly homologous to the orthologues in cattle, mouse, rat and human. Extensive cloning and analysis of Izumo1 cDNA revealed three (del 69, del 182 and del 217) and two (del 69 and ins 30) alternative splicing isoforms in goat and sheep, respectively. All of the isoforms are derived from splicing at typical GT-AG sites leading to partial or complete truncation of the immunoglobulin (Ig)-like domain. Bioinformatics analysis showed that caprine and ovine Izumo1 proteins share similar structure with their murine orthologue. There are a signal peptide at the N-terminus (1-22 aa), a transmembrane domain at the C-terminus (302-319 aa), and an extracellular Ig-like region in the middle (161-252 aa) with a putative N-linked glycosylation site (N(205)-N-S). Alignment of Izumo1 protein sequences among 15 mammalian species displayed several highly conserved regions, including LDC and YRC motifs with cysteine residues for potential disulfide bridge formation, CPNKCG motif upstream of the Ig-like domain, GLTDYSFYRVW motif upstream of the putative N-linked glycosylation site, and a number of scattered cysteine residues. These distinctive features are very informative to pinpoint the important gene motifs and functions. The C-terminal regions, however, are more variable across species. Izumo1 cDNA sequences of goat, sheep, and cow were found to be largely homologous, and the molecular phylogenetic analysis is consistent with their morphological taxonomy. This implies the Izumo1 gene evolves from the same ancestor, and the mechanism of sperm-egg fusion in mammals may be under the same principle in which Izumo1 plays an important role. PMID- 20963502 TI - Regulation of MMP-2 expression and activity by beta-1,3-N acetylglucosaminyltransferase-8 in AGS gastric cancer cells. AB - beta-1,3-N-acetylglucosaminyltransferase-8(beta3Gn-T8) catalyzes the transfer of GlcNAc to the non-reducing terminus of the Galbeta1-4GlcNAc of tetraantennary N glycan in vitro. It has been reported to be involved in malignant tumors, but a comprehensive understanding of how the glycolsyltransferase correlates with the invasive potential of human gastric cancer is not currently available. Therefore, we investigated the ability and possible mechanism involved with beta3Gn-T8 in modulating matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) in AGS gastric cancer cells. Here, we found out that siRNA-mediated suppression of the beta3Gn-T8 could directly reduce the MMP-2 expression and activity as observed in RT-PCR, western blot and gelatin zymography analysis. Meanwhile, TIMP-2 expression had been increased. Cell invasion assay using matrigel matrix-coated transwell inserts showed that the invasive property was greatly suppressed in beta3Gn-T8 siRNA transfected cells. Furthermore, cells overexpressing beta3Gn-T8 gene (when transfected with pEGFP-C1 plasmid) also expressed MMP-2 gene, but TIMP-2 expression had been inhibited. The invasive ability of these cells was also enhanced. Protein-protein interaction analysis using STRING database showed that beta3Gn-T8 and MMP-2 may have related signal pathway. In summary, our results reveal a new mechanism by which beta3Gn T8 can regulate MMP-2 and TIMP-2. We suggest that beta3Gn-T8 can be used as a novel therapeutic target for human gastric treatment. PMID- 20963503 TI - Relationship between surfactant protein A polymorphisms and allergic rhinitis in a Chinese Han population. AB - The development of allergic rhinitis is considered to be determined by the interaction between genetic and environmental factors. Surfactant protein A (SP A), a member of the collectin family of proteins, plays an important role in immune regulation. The purpose of this study was to investigate the association between SP-A polymorphisms and allergic rhinitis. We conducted a case-control association study on a Chinese Han population, comprising 216 adult individuals with AR and 84 healthy controls. A total of 9 single-nucleotide polymorphisms (SNPs) mapped to the SP-A were genotyped using PCR-based molecular identification methods. The frequency of A allele at amino acid 223 in the patient group was significantly higher than that in the control group after correcting for multiple testing (P = 0.006). The 1A(2) allele haplotype in SFTPA2 was associated with decreased risk for allergic rhinitis, after applying Bonferroni corrections (P = 0.003). However, genetic variants of the SFTPA1 genes were not found to be associated with AR. In addition, no significant associations were established between any of the 9 SFTPA gene polymorphisms and the skin-prick test responses (P > 0.05). Further, no association was established between the 9 SNP loci and the levels of total serum immunoglobulin E (IgE) (P > 0.05). These results indicate that the gene polymorphism at the residue 223 in the carbohydrate recognition domain of SFTPA2 may be a genetic marker for the development of AR in the adult Chinese Han population. PMID- 20963504 TI - Development and initial validation of Perceived Rehabilitation Needs Questionnaire for people with schizophrenia. AB - PURPOSE: The Perceived Rehabilitation Needs Questionnaires for people with schizophrenia (PRNQ-S), a culturally relevant and multi-faceted assessment tool for measuring perceived needs of people with schizophrenia, was developed and initially validated. METHODS: A total of 43 participants including people with schizophrenia, their caregivers, and mental health professionals were recruited for six rounds of focus group discussion to identify issues pertaining to rehabilitation needs of schizophrenia. Results were then used to develop PRNQ-S. An initial validation study among a convenience sample consisting of 219 people with schizophrenia was conducted to examine its psychometric properties. RESULTS: Exploratory Factor Analysis yielded a seventeen-factor solution accounting for 70.7% of the total variance which resulted in a 75-item PRNQ-S. The instrument had excellent internal consistencies and intra-rater reliability. CONCLUSIONS: The PRNQ-S has been developed and psychometrically tested in Hong Kong. It can be used to assess perceived rehabilitation needs for individuals with schizophrenia in Hong Kong. Upon further validations, it may be applied in other Chinese societies such as Singapore and the mainland. Similar research methodology can also be used for assessing needs in other types of psychiatric disability groups. PMID- 20963505 TI - Is left ventricular dysfunction reversed after treatment of active acromegaly? AB - It has been suggested that control of GH and IGF excess can arrest the progression of cardiovascular abnormalities and normalize cardiac performance. The aim of the present study was to investigate the reversibility of acromegalic cardiomyopathy in patients with active and inactive disease and to evaluate the effect of the inactivity of the disease on left ventricular (LV) diastolic dysfunction, irrespective of the applied treatment. The patient population consisted of 55 patients who were studied in the active and/or inactive phase. A complete M-mode, two-dimensional and color-flow Doppler echocardiographic examination was performed. LV mass index and posterior wall index were significantly lower in patients with inactive acromegaly compared to those with active disease (P < 0.03 respectively). Diastolic dysfunction was improved in patients with inactive compared to those with active disease (E/A ratio P < 0.009). IGF was positively correlated with LV mass index (r = 0.28, P < 0.02). Multivariate linear regression analysis showed that in active patients the E/A ratio was independently related to age (beta = -0.674, P < 0.001) and GH (beta = 0.282, P < 0.03), whereas in inactive patients none of the parameters were related significantly with the E/A ratio. In a subgroup of 15 patients who were studied in both the active and inactive phase of the disease, the reduction in GH levels was correlated positively with the reduction in LV mass index (r = 0.89, P < 0.0001) and negatively with the improvement in E/A ratio (r = -0.74, P < 0.001). In conclusion, the results of the present study indicate an improvement of left ventricular diastolic function and a significant improvement of cardiac hypertrophy in patients with inactive acromegaly and normal systolic cardiac function compared to those with active disease. PMID- 20963506 TI - [Epidemiology and morbidity of mycoplasma as causative agent for community acquired pneumonia in hospitalized children in a Community Hospital in Vienna]. AB - BACKGROUND: Epidemiology and morbidity of mycoplasma-associated pneumonia in youths and children in Vienna are not known. The first objective was to elucidate the incidence and the second was to evaluate a standard antibiotic regimen with addition of a macrolid in children over 5 years. METHODS: Hospitalized patients were evaluated prospectively during 3 winter seasons. In a clinical routine setting microbiologic tests were performed, nasal secretions were tested for viruses, Chlamydia pneumoniae and Mycoplasma pneumoniae, and clinical parameters were documented. RESULTS: Mycoplasma pneumoniae was identified in 12 patients out of 279 (4.3%). All were 5 years and older. The mean number of days in hospital was 4.6, the number of days with fever > 38.5 degrees was 1.2, the maximal value of C-reactive protein was 48 mg/L, no complications occurred, and all children recovered completely. CONCLUSION: Mycoplasma pneumoniae was identified in 4.3% of children and youths. The antibiotic regimen is appropriate as initial therapy. PMID- 20963507 TI - Lipid classes and fatty acid patterns are altered in the brain of gamma-synuclein null mutant mice. AB - The well-documented link between alpha-synuclein and the pathology of common human neurodegenerative diseases has increased attention to the synuclein protein family. The involvement of alpha-synuclein in lipid metabolism in both normal and diseased nervous system has been shown by many research groups. However, the possible involvement of gamma-synuclein, a closely-related member of the synuclein family, in these processes has hardly been addressed. In this study, the effect of gamma-synuclein deficiency on the lipid composition and fatty acid patterns of individual lipids from two brain regions has been studied using a mouse model. The level of phosphatidylserine (PtdSer) was increased in the midbrain whereas no changes in the relative proportions of membrane polar lipids were observed in the cortex of gamma-synuclein-deficient compared to wild-type (WT) mice. In addition, higher levels of docosahexaenoic acid were found in PtdSer and phosphatidylethanolamine (PtdEtn) from the cerebral cortex of gamma synuclein null mutant mice. These findings show that gamma-synuclein deficiency leads to alterations in the lipid profile in brain tissues and suggest that this protein, like alpha-synuclein, might affect neuronal function via modulation of lipid metabolism. PMID- 20963508 TI - Discrimination of n-3 rich oils by gas chromatography. AB - Exploring the capabilities of instrumental techniques for discriminating n-3 rich oils derived from animals is a very important though much neglected area that was emphasized more than 100 years ago. In this study the potential of gas chromatography (GC) for discriminating full fatty acid methyl ester (FAME) profiles from fish (cod liver and salmon) and marine mammal (seal and whale) oils is evaluated by means of principal component analysis (PCA). The FAME profiles from plant oils such as rapeseed, linseed and soy oils and seven different brands of n-3 supplements are also used in the discrimination process. The results from the PCA plots can reliably distinguish between plant, n-3 supplements, fish and marine mammal oils. By removing the contribution of the n-3 supplements and plant oils it is possible to discriminate between types of fish and marine animal oils. GC offers a rapid, simple and convenient means of discriminating oils from different species, brands and grades. PMID- 20963509 TI - Valve failure in an injection port. PMID- 20963510 TI - Pneumothorax and empyema complicating Scedosporium apiospermum mycetoma: not just a problem in the immunocompromised patients. PMID- 20963511 TI - First reported deliveries in Ireland using surgically retrieved sperm for non obstructive azoospermia. AB - Couples presenting with male factor infertility comprise an important proportion of clinical reproductive endocrinology consultations. Indeed, a problem with the male is the only cause, or a contributing cause, of infertility in ~40% of infertility evaluations. Here we present the first published deliveries obtained from IVF utilising surgically retrieved sperm in Ireland; pregnancy and delivery are also described following transfer of cryopreserved/thawed embryos derived from such sperm. Finding no sperm from a semen analysis in a man without a vasectomy can be a devastating event, and substantially influences the scope of the reproductive endocrinology consultation. Successful treatment of non obstructive azoospermia is possible without reliance on anonymous donor sperm. PMID- 20963512 TI - Clinical evaluation of targeted arterial infusion of verapamil in the interventional chemotherapy of primary hepatocellular carcinoma. AB - This study evaluates the clinical effectiveness of targeted arterial infusion of verapamil in interventional treatment of primary hepatocellular carcinoma. For this purpose, in 273 patients with middle- or late-stage primary hepatocellular carcinoma, verapamil, IL-2, and chemotherapeutic agents were infused into the target tumor vasculature through femoral artery using Seldinger technique. The medications were infused as serial dilutions, and effectiveness was evaluated after two treatment cycles. Among these 273 patients, 76 cases showed clinical cure or significant improvement, 119 cases improved, 64 cases stabilized, while 14 cases progressed or deteriorated. In 238 patients, KPS score and body weights were stabilized. Regarding side effects, 99 patients (36.3%) developed leukopenia; 160 patients had gastrointestinal reactions (58.6%); 80 patients (29.3%) presented with elevated ALT/AST profile; and 65 cases (23.8%) had pyrexia; however, these side effects abated quickly. No elevations in BUN/Cr and/or allergic reactions were observed. Pre- and post-intervention cardiac function did not change in all the patients. No significant change was observed in ECG. Liver function was also improved after two cycles of treatment. It was concluded that verapamil management via targeted arterial infusion could effectively reverse the multidrug resistance in cancer cells in primary hepatocellular carcinoma patients and therefore enhanced the efficacy of chemotherapy. PMID- 20963513 TI - Exploring leukocyte mitochondrial membrane potential in type 1 diabetes families. AB - Proper cellular function requires the maintenance of mitochondrial membrane potential (MMP) sustained by the electron transport chain. Mitochondrial dysfunction is believed to play a role in the development of diabetes and diabetic complications possibly because of the active generation of free radicals. Since MMP can be investigated in clinical settings using fluorescent probes and living whole blood cells, mitochondrial membrane alterations have been observed in some chronic disorders. We have used the mitochondrial indicator 5,5',6,6'-tetra chloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide (JC 1) in conjunction with flow cytometry to measure the MMP in peripheral blood granulocytes from type 1 diabetes (T1D) families. The intracellular ROS levels and the respiratory burst activity were also measured. Leukocyte MMP was elevated in 20 T1D patients and their 20 non-diabetic siblings compared with 25 healthy subjects without family history of T1D. Fasting plasma glucose was the only correlate of MMP. If confirmed by further observations, the functional implications of mitochondrial hyperpolarisation (probably different among different cells) will require extensive investigation. PMID- 20963514 TI - Screening and identification of a fungal beta-glucosidase and the enzymatic synthesis of gentiooligosaccharide. AB - After screening with 0.1% esculoside and 0.03% FeCl(3), we identified from rotten wood a fungal isolate HML0366 that produces high amount of beta-glucosidase. Phenotypic and rDNA internal transcribed spacer sequence analyses indicated that the isolate belongs to Aspergillus oryzae. The beta-glucosidase produced by HML0366 had an activity of 128 U/g. high performance liquid chromatography analysis also demonstrated a high transglycosylation activity of the crude enzyme. The beta-glucosidase was stable between pH 4-10 at 60 degrees C. A gentiobiose yield of 30.86 g/L was achieved within 72 h of the enzymatic reaction at pH 5 and 55 degrees C using 50% glucose as the substrate. For the first time, we report here the isolation of an A. oryzae strain producing beta-glucosidase with high hydrolytic activities. The crude enzyme has a high transglycosylation activity, which enables the enzymatic synthesis of gentiooligosaccharides. PMID- 20963515 TI - Hepatitis B virus-associated hepatocellular carcinoma from India: role of viral genotype and mutations in CTNNB1 (beta-catenin) and TP53 genes. AB - PURPOSE: Chronic hepatitis B virus (HBV) infection is the major risk factor for hepatocellular carcinoma (HCC) in India. Studies from other countries have linked HBV genotype C to a higher risk for HCC. This study was carried out to determine the association between genotype and HCC and also the frequency of mutations in CTNNB1 (beta-catenin) and TP53 genes in HBV-related HCC. METHODS: Formalin-fixed paraffin-embedded (FFPE) tissues from 20 (15 autopsy, five resected specimens) cases of HBV-associated HCC were examined. Viral genotype was determined by sequencing portions of the HBV S gene using four overlapping PCR amplicons. Exon 3 of CTNNB1 and exon 7 of TP53 were sequenced. RESULTS: HBV genotyping was possible in 14 of 20 cases; genotype D was most common (n = 11) followed by C (n = 2) and A (n = 1). CTNNB1 mutations were noted in two of 15 amplifiable cases while two of 10 specimens showed TP53 mutations. CONCLUSIONS: HBV genotype can be ascertained from FFPE sections by sequencing multiple overlapping fragments to avoid the limitation of fragmented DNA. Genotype D was the common genotype in HBV associated HCC. The very low frequency of TP53 mutation suggests low levels of aflatoxin B1 exposure. The beta-catenin pathway appears not to be significantly involved in HBV-related HCC in India. However, further larger studies are required to confirm these findings. PMID- 20963516 TI - Subacute combined degeneration of the spinal cord in a child. PMID- 20963517 TI - Discord from ACCORD? PMID- 20963518 TI - Insulin sensitizers and heart failure: an engine flooded with fuel. PMID- 20963519 TI - Obesity and diabetes in mothers and their children: can we stop the intergenerational cycle? AB - Obesity prevalence in the United States has reached an alarming level. Consequently, more young women are entering pregnancy with body mass indices of at least 30 kg/m(2). While higher maternal weight entering pregnancy is related to several adverse pregnancy outcomes, some of the strongest and most compelling data to date have linked prepregnancy obesity to gestational diabetes mellitus (GDM). The mechanisms by which excess maternal weight influences metabolic dysfunction in pregnancy are similar to those in obese nonpregnant women; adipocytes are metabolically active and release a number of hormones implicated in insulin resistance. Heavier mothers are also more likely to have higher glucose levels that do not exceed the cutoff for GDM, but nevertheless predict poor perinatal outcomes. Longer-term complications of GDM include increased risk of maternal type 2 diabetes and offspring obesity. Promising intervention studies to decrease the intergenerational cycle of obesity and diabetes are currently underway. PMID- 20963520 TI - Joint hypermobility and anxiety: the state of the art. AB - Joint hypermobility (JH) is considered a common benign, hereditary, overlap, connective tissue disorder with a prevalence in the general population of about 10% in European populations and 25% in other ethnic groups. JH shows an association with mitral valve prolapse and fibromyalgia. However, the most significant and important association between joint hypermobility syndrome (JHS) and any other disorder from a clinical point of view is with panic disorder. This article summarizes all published studies on JHS and anxiety, analyzing the main results and limitations. An overview of the etiologic explanation of the association between JH and anxiety, with special focus on genetic findings, is also included. The most relevant conclusions are the following: JHS is more prevalent in individuals with panic disorder/agoraphobia, and patients with JHS present with greater prevalence of panic disorder/agoraphobia. In addition, there is an association between JHS severity and severity of anxiety, and mitral valve prolapse plays a secondary role in the association between JHS and anxiety. New fields of research based on these data are suggested. PMID- 20963521 TI - Biomarkers to predict antidepressant response. AB - During the past several years, we have achieved a deeper understanding of the etiology/pathophysiology of major depressive disorder (MDD). However, this improved understanding has not translated to improved treatment outcome. Treatment often results in symptomatic improvement, but not full recovery. Clinical approaches are largely trial-and-error, and when the first treatment does not result in recovery for the patient, there is little proven scientific basis for choosing the next. One approach to enhancing treatment outcomes in MDD has been the use of standardized sequential treatment algorithms and measurement based care. Such treatment algorithms stand in contrast to the personalized medicine approach, in which biomarkers would guide decision making. Incorporation of biomarker measurements into treatment algorithms could speed recovery from MDD by shortening or eliminating lengthy and ineffective trials. Recent research results suggest several classes of physiologic biomarkers may be useful for predicting response. These include brain structural or functional findings, as well as genomic, proteomic, and metabolomic measures. Recent data indicate that such measures, at baseline or early in the course of treatment, may constitute useful predictors of treatment outcome. Once such biomarkers are validated, they could form the basis of new paradigms for antidepressant treatment selection. PMID- 20963523 TI - Radiofrequency ablation therapy for primary breast cancer: expectations and problems as a novel breast conservation therapy. PMID- 20963522 TI - Post-transplantation lymphoproliferative disorders: diagnosis, prognosis, and current approaches to therapy. AB - Post-transplantation lymphoproliferative disorders (PTLD) are a heterogenous group of abnormal lymphoid proliferations that occur after solid organ transplant (SOT) or hematopoietic transplantation. PTLDs consist of a disease spectrum ranging from hyperplasia to aggressive lymphomas with 60-70% being Epstein-Barr virus positive. The majority of cases are B-cell, although 10-15% are of T-cell origin or rarely Hodgkin lymphoma. Recent SOT series suggest PTLD occurs at a median of 36-40 months after transplant. Clinically, extra-nodal disease is common (up to 75-85%) including CNS involvement, which is seen in 10-15% of all cases. Since the first report over 40 years ago, PTLD has remained one of the most morbid complications associated with SOT. However, recent data suggests improved survival in the modern era, especially with the integration of early rituximab-based therapy. These studies utilized first line rituximab (+/- chemotherapy) together with reduced immune suppression (RI) for monomorphic and polymorphic PTLD. It will be critical in future studies to determine which PTLDs are most amenable to initial therapy with RI alone, versus RI/rituximab, versus RI/rituximab/chemotherapy. Additionally, novel therapeutics, such as adoptive immunotherapy, should continue to be explored. PMID- 20963524 TI - Primary systemic chemotherapy of breast cancer: indication and predictive factors. AB - Primary systemic chemotherapy has become a standard of care for operable breast cancer patients who are candidates for adjuvant chemotherapy. Induction of pathological complete response (pCR) is one of the main goals of primary systemic chemotherapy because patients with pCR have shown a better prognosis. The definition of pCR has varied across clinical trials. It would be ideal for all researchers to use the same terminology in describing pathologic response. Identification of accurate predictive factors of pCR to primary systemic chemotherapy is urgent, because patients with a low chance of pCR and clinical response should be spared unnecessary toxicity. Early response to primary systemic chemotherapy might be correlated with a high probability of a pCR. Therefore, evaluation of early response is useful to avoid unnecessary toxicity without potential benefit from chemotherapy. PMID- 20963525 TI - Are anidulafungin or voriconazole released from polymethylmethacrylate in vitro? AB - BACKGROUND: Depot delivery of antimicrobial agents is used for treatment and prevention of bacterial orthopaedic infections; there is little information regarding newer antifungal agents and their potential use in polymethylmethacrylate (PMMA) depot delivery. QUESTIONS/PURPOSES: We determined the percent of anidulafungin or voriconazole present after polymerization in PMMA beads loaded with anidulafungin or voriconazole, and we assessed elution of anidulafungin or voriconazole from beads loaded with anidulafungin or voriconazole. MATERIALS AND METHODS: Beads containing 7.5% anidulafungin or voriconazole were pulverized and incubated in Kreb's ringer buffer for 48 hours; the buffer was assayed for anidulafungin or voriconazole concentration. The in vitro release of anidulafungin and voriconazole from PMMA beads loaded with 7.5% anidulafungin or voriconazole was determined in triplicate in a continuous flow chamber. RESULTS: 0.7% of anidulafungin and 5.6% of voriconazole loaded in the beads were detected after polymerization. No anidulafungin was detected in the elution studies. The mean peak voriconazole concentration in the elution studies was 0.9 MUg/mL. CONCLUSIONS: Anidulafungin may not be suitable for depot delivery in PMMA. PMID- 20963526 TI - Growth diagrams for individual finger strength in children measured with the RIHM. AB - BACKGROUND: Although grip and pinch strength provide a more global measure of a large number of digits and muscles, measuring strength of individual fingers or the thumb can provide additional and more detailed information regarding hand strength. QUESTIONS/PURPOSES: We developed growth diagrams for individual finger strength in children. PATIENTS AND METHODS: We measured thumb palmar abduction, thumb opposition, and thumb flexion in the metacarpophalangeal joint, and abduction of the index and little fingers in 101 children (4-12 years old) using a myometer. We recorded hand dominance, gender, height, and weight. All measurements were performed in a randomized order by the same researcher. We developed statistical models for drawing growth diagrams using estimated percentiles for each strength measurement. Separate models for dominant and nondominant hands of boys and girls were developed, in addition to a combined model. RESULTS: Because there was no difference in strength between boys and girls and between dominant and nondominant hands, both hands and genders were combined in one growth diagram for each measurement. The normative data were presented in a table format and in growth diagrams for each myometer measurement. CONCLUSIONS: These diagrams can be used for pediatric patients such as patients with congenital malformations or neuromuscular disorders who receive interventions or therapy aimed at function of the hand, fingers, or thumb. The growth diagrams facilitate distinguishing between the effects of growth and intervention on strength development. PMID- 20963527 TI - The sensitivity and specificity of ultrasound for the diagnosis of carpal tunnel syndrome: a meta-analysis. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is the most commonly diagnosed compression neuropathy of the upper extremity. Current AAOS recommendations are to obtain a confirmatory electrodiagnostic test in patients for whom surgery is being considered. Ultrasound has emerged as an alternative confirmatory test for CTS; however, its potential role is limited by lack of adequate data for sensitivity and specificity relative to electrodiagnostic testing. QUESTIONS/PURPOSES: In this meta-analysis we determined the sensitivity and specificity of ultrasound in the diagnosis of CTS. METHODS: A PubMed/MEDLINE search identified 323 articles for review. After applying exclusion criteria, 19 articles with a total sample size of 3131 wrists were included for meta-analysis. Three groups were created: a composite of all studies, studies using clinical diagnosis as the reference standard, and studies using electrodiagnostic testing as the reference standard. RESULTS: The composite sensitivity and specificity of ultrasound for the diagnosis of CTS, using all studies, were 77.6% (95% CI 71.6 83.6%) and 86.8% (95% CI 78.9-94.8%), respectively. CONCLUSIONS: The wide variations of sensitivities and specificities reported in the literature have prevented meaningful analysis of ultrasound as either a screening or confirmatory tool in the diagnosis of CTS. The sensitivity and specificity of ultrasound in the diagnosis of CTS are 77.6% and 86.8%, respectively. Although ultrasound may not replace electrodiagnostic testing as the most sensitive and specific test for the diagnosis of CTS given the values reported in this meta-analysis, it may be a feasible alternative to electrodiagnostic testing as the first-line confirmatory test. LEVEL OF EVIDENCE: Level III, systematic review of Level III studies. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20963528 TI - Limb lengthening and deformity correction by the Ilizarov technique in type III fibular hemimelia: an alternative to amputation. AB - BACKGROUND: Fibular hemimelia is partial or total aplasia of the fibula; it represents the most frequent congenital defect of the long bones. It usually is associated with other anomalies of the tibia, femur, and foot. QUESTIONS/PURPOSES: We reviewed 32 patients with Type III fibular hemimelia treated by successive lower limb lengthening and deformity correction using the Ilizarov method. We had three aims; first, to analyze complications, including the need for reoperation. The second was to assess knee and ankle function, specifically addressing knee ROM and stability and function of the foot and ankle. The third was assessment of overall patient satisfaction. PATIENTS AND METHODS: Thirty-two patients underwent 56 tibia lengthenings and 14 ipsilateral femoral lengthenings. Their mean age and mean functional leg-length discrepancy at initial treatment were 6.7 years and 6.2 cm, respectively. Activity level, pain, patient satisfaction with function, pain, and cosmesis, complications, and residual length discrepancy were assessed at the end of treatment. RESULTS: The mean number of surgeries was six per case. The healing index was 44.9 days/cm. Although complications were observed during 60 lengthenings (82%), the highly versatile system overcame most of them. Nearly equal limb length and a plantigrade foot were achieved by 16 patients. For two patients, a Syme's amputation was performed. The outcome was considered satisfactory in 17 patients (53%) and relatively good in eight patients (25%). CONCLUSIONS: The Ilizarov technique has satisfactory results for treatment of Type III congenital fibular hemimelia and can be considered a good alternative to amputation. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 20963529 TI - Papers presented at the Hip Society Meetings 2010: editorial comment. PMID- 20963531 TI - Hip resurfacing in patients who have osteonecrosis and are 25 years or under. AB - BACKGROUND: Young patients with osteonecrosis (ON) treated with THA often have suboptimal function and radiographic failure with eventual revision. Resurfacing may be an option because of potentially increased functionality and decreased radiographic failure, although neither has been confirmed in the literature. QUESTIONS/PURPOSES: We therefore compared the clinical scores and radiographic failures of resurfacing patients 25 years or younger with osteonecrosis with those for patients with ON treated with THA. METHODS: We identified 17 patients (20 resurfaced hips) who were 25 years or younger and treated by resurfacing for ON. Mean followup was 62 months (range, 32-103 months). This group was matched by gender, age, BMI, and followup to 16 patients (20 hips) treated with THA with a mean 61 month followup (range, 34-88 months). Additionally, the group was compared to 78 patients (87 hips) with ON over age 25 who underwent resurfacing during the same time with a mean followup of 61 months (range, 27-112 months). RESULTS: The mean Harris score improved from 48 points preoperatively to 93 points with a 100% 7.5 year survivorship in the young resurfacing group. In the THA cohort, the mean score improved from 44 points preoperatively to 94 points postoperatively, with a 93.3% 7.5 year survivorship; similar to the results for all resurfacing patients. Radiographs did not reveal malalignment or progressive radiolucencies in any cohort. CONCLUSION: At approximately 5 year followup, young resurfacing patients were similar to other resurfacing patients and standard THA patients regarding clinical ratings and radiographic failures. PMID- 20963530 TI - Femoral head size does not affect ion values in metal-on-metal total hips. AB - BACKGROUND: Metal-on-metal articulations can release substantial amounts of particles containing cobalt and chromium into the surrounding milieu, causing concern for cellular toxicity and adverse local soft tissue reactions. The diameter of the femoral head has been one of the variables that inversely affects wear of metal-on-metal total hip arthroplasty (THA). The oxidative stress of increased metal ions can be measured with serum markers. It is still controversial if larger femoral head diameters decrease wear rates in patients with metal-on-metal THA and if the increased metal ions alter the body's antioxidant status. QUESTIONS/PURPOSES: We therefore (1) determined whole blood metal ions in patients with small (28 mm and 36 mm) and large (40 mm and 44 mm) diameter femoral heads; (2) measured oxidative stress markers (total antioxidants, nitrotyrosine, and peroxides); and (3) determined whether acetabular version or inclination influenced ion levels. METHODS: One hundred four patients were retrospectively studied. We recorded Harris hip scores and UCLA activity scores. All patients were followed at 1 year. RESULTS: The activity scores were similar in the two groups. There was no difference in metal ion levels or oxidative stress markers between patients with small- or large-diameter femoral heads. Acetabular inclination and anteversion had no effect on the metal ion levels. CONCLUSIONS: The data suggest there is no difference in ion values in patients with large or small metal-on-metal THA and the increased metal ions do not alter the oxidant status of the patient. PMID- 20963532 TI - Are there benefits to one- versus two-stage procedures in bilateral hip resurfacing? AB - BACKGROUND: Short-term studies report comparable complication rates of one-stage bilateral versus two-stage procedures in hip resurfacing, although the long-term effects of such procedures on survivorship, quality of life, and disease-specific scores are currently unknown. QUESTIONS/PURPOSES: We compared clinical scores, length of stay, complication rates, and survivorship in patients who underwent bilateral hip resurfacing grouped on the basis of one-stage versus two-stage operation. PATIENTS AND METHODS: We retrospectively reviewed 75 patients who underwent a one-stage procedure and 87 patients who had both hips resurfaced in separate procedures. The demographics and etiologies were similar for the two groups. The mean followup time was longer in the two-stage group (7.3 years; range, 2.6-12.3 years) than in the one-stage group (6.6 years; range, 2.6-10.9 years). RESULTS: We found no differences in the latest postoperative UCLA pain, walking function, and activity scores; Harris hip scores; or SF-12 scores between the two groups. The average length of stay was shorter for the one-stage group. The early complication rates were similar between the two groups. One-stage patients had a higher revision rate than the patients in the two-stage group (14 versus four hips, respectively), but this was not true for patients with femoral components 48 mm or greater in size. CONCLUSIONS: We found a greater rate of revisions in the one-stage group, suggesting possible long-term detrimental effects of the one-stage procedure. Our data suggest selecting patients with large component sizes if the surgeries are to be performed under one anesthesia. PMID- 20963533 TI - Does acetabular inclination angle affect survivorship of alumina-ceramic articulations? AB - BACKGROUND: Reports in the literature have linked high acetabular inclination angles to increased wear of ceramic-on-ceramic bearings. However, many of these studies were only conducted in vitro and did not address the clinical relevance of such findings. QUESTIONS/PURPOSES: We therefore determined: (1) whether the cup inclination angle influences survival or function in patients with ceramic-on ceramic implants; (2) the incidence of radiolucencies, osteolysis, and subsidence of ceramic-on-ceramic implants; and (3) whether the survival rate higher for ceramic-on-ceramic THAs than for conventional metal-on-polyethylene THAs. METHODS: We retrospectively reviewed 537 THAs performed in 512 prospectively followed patients having THA between October 1996 and October 2000. Eleven patients (12 hips) were lost to followup before 2 years, leaving 501 patients (525 THAs); of these, 421 were alumina ceramic-on-ceramic articulations and 104 cobalt-chromium-on-polyethylene. The mean age was 54 years. We determined acetabular cup inclination angles, Harris hip scores, Health-Status-Questionnaire 12 scores, and presence and location of any radiolucencies, osteolysis, or radiographic subsidence. We compared survival using the Kaplan-Meier method. The minimum followup was 24 months (mean, 59 months; range, 24-120 months). RESULTS: Twenty-two of the 424 THAs (4.2%) were revised. We observed no difference in clinical or radiographic outcomes with respect to cup inclination angles. Radiographically, two loose acetabular components and two femoral components had subsided. The 5-year survival rate was slightly higher for ceramic-on-ceramic bearings (98%) than for metal-on-polyethylene (92%). CONCLUSIONS: Although there may be a link between acetabular inclination angles and wear rates as reported by some authors, we found no differences in patient function or radiographic survivorship using alumina-on-alumina articulations. PMID- 20963534 TI - How to treat a tibial post fracture in total knee arthroplasty? A systematic review. AB - BACKGROUND: Posterior-stabilized TKAs, which use a polyethylene tibial post to articulate against a metal femoral cam, are used regularly. Reported complications are related to the patellofemoral articulation or the tibial post cam mechanism. Fracture of the tibial post is an uncommon but disabling complication after posterior-stabilized TKA that requires operative treatment. QUESTIONS/PURPOSES: The literature was reviewed to determine the frequency of tibial post fracture and address three questions: (1) Is there a specific prosthetic design or patient demographics in knees with a fracture of the tibial post? (2) What are the common presenting complaints and methods of diagnosis? (3) What methods of treatment have been used? METHODS: A PubMed search of English language articles from February 1982 to April 2010 was performed and 20 articles, all Level IV studies, were identified. RESULTS: One specific design of posterior stabilized tibial post with a central screw hole had a 12.4% incidence of fracture. Tibial post fracture has been reported with other designs, but with an incidence of 1% or less. The most common presenting symptoms include effusion, instability, or patella clunk syndrome. The most common method of diagnosis was clinical examination followed by arthroscopic examination. Treatment with revision to a new tibial polyethylene liner generally has been successful at short-term followup. CONCLUSIONS: Tibial post fracture is a relatively uncommon complication after posterior-stabilized TKA that usually is treated successfully with liner exchange. The low quality of available literature makes it difficult to recommend a specific treatment protocol. PMID- 20963535 TI - Pharmacodynamics-mediated drug disposition (PDMDD) and precursor pool lifespan model for single dose of romiplostim in healthy subjects. AB - The objective of this study was to characterize the pharmacokinetics and pharmacodynamics (PK-PD) of romiplostim after single-dose administration in healthy subjects. The mean serum romiplostim concentrations (PK data) and mean platelet counts (PD data) collected from 32 subjects receiving a single intravenous (0.3, 1 and 10 MUg/kg) or subcutaneous (0.1, 0.3, 1, and 2 MUg/kg) dose were fitted simultaneously to a mechanistic PK-PD model based on pharmacodynamics-mediated drug disposition (PDMDD) and a precursor pool lifespan concept. The two-compartment PK model incorporated receptor-mediated endocytosis and linear mechanisms as parallel elimination pathways. The maximal concentration of receptors (assumed to be proportional to the platelet count), the equilibrium dissociation constant, and the first-order internalization rate constant for endocytosis of the drug-receptor complex were 0.022 fg/platelet, 0.131 ng/mL, and 0.173 h-1, respectively. Romiplostim concentration stimulates the production of platelet precursors via the Hill function, where the SC50 was 0.052 ng/mL and S (max) was 11.2. The estimated precursor cell and platelet lifespans were 5.9 and 10.5 days, respectively. Model-based simulations revealed that the romiplostim exposure and the platelet response are both dependent on the dose administered and the baseline platelet counts. Also, weekly dosing produced a sustained PD response while dosing intervals >=2 weeks resulted in fluctuating platelet counts. Thus, the mechanistic PK-PD model was suitable for describing the romiplostim PK-PD interplay (PDMDD), the dose-dependent platelet stimulation, and the lifespans of thrombopoietic cell populations. PMID- 20963536 TI - Lights that guide us. PMID- 20963537 TI - Automatic and visual reproducibility of perfusion and function measures for myocardial perfusion SPECT. AB - BACKGROUND: We define the repeatability coefficients (RC) of key quantitative and visual perfusion and function parameters that can be derived by the QGS/QPS automated software and by expert visual observer from gated myocardial perfusion SPECT (MPS) scans. METHODS: Standard QGS/QPS algorithms have been applied to derive quantitative perfusion and function parameters in 200 99mTc-tetrofosmin rest/stress MPS scans, obtained in 100 consecutive patients who underwent 2 separate gated rest/stress scans on the same camera. Variables included stress, rest, and ischemic total perfusion deficit (TPD), ejection fraction, motion, and thickening. Visual perfusion/motion scores were derived by an expert reader using randomized scan order and normalized to % myocardium. RESULTS: Quantitative and visual parameters were highly reproducible with smaller RC for some quantitative measures as compared to visual measures (P < .0001). RC for quantitative measures were 3.3% for stress TPD, 1.8% for rest TPD, and 3.2% for ischemic TPD and for visual scoring 4.8% for stress, 3.8% for rest, and 4.3% for ischemic (P <= .002). The results in each vessel territory showed that in the right coronary artery (RCA) territory the quantitative approach had improved reproducibility as compared to visual reading. Visual thickening scoring was more reproducible than motion scoring (P < .0001). CONCLUSIONS: This study demonstrates that standard perfusion and function parameters derived from MPS by visual or quantitative analysis are highly reproducible with some advantages to the quantitative approach. PMID- 20963538 TI - Early insights of cardiac risk and treatment response with quantitative PET monitoring of coronary-specific endothelial dysfunction and myocardial perfusion reserve. PMID- 20963539 TI - Duration and type of therapy for diabetes: impact on cardiac risk stratification with stress electrocardiographic-gated SPECT myocardial perfusion imaging. AB - BACKGROUND: Stress electrocardiogram(ECG)-gated single photon emission computed tomography (SPECT) imaging is highly effective in risk stratification of diabetic patients for adverse cardiac events. While patients with diabetes are predisposed to a more aggressive progression of vascular disease, the impact of its duration and type of therapy on risk stratification are unknown. METHODS: From the Hartford Hospital Nuclear Cardiology clinical database, 886 diabetic patients who underwent exercise or pharmacologic stress ECG-gated SPECT were identified, with complete follow-up regarding the occurrence of adverse cardiac events and information regarding the duration of diabetes and the type of therapy (insulin vs oral medication only) at the time of testing. Images were interpreted using the American College of Cardiology/ASNC standard 17-segment scoring model. RESULTS: Of the 886 diabetic patients, 98 (11%) suffered cardiac death or non fatal myocardial infarction during follow-up (2.5 +/- 1.6 years). A receiver operator characteristics curve demonstrated that diabetes >=10 years in duration provided the maximal sum of sensitivity and specificity for the prediction of adverse cardiac outcomes. Multivariate analysis identified the following as independent predictors of adverse outcome: Post-stress ejection fraction (EF) <40% (P = .001), age (P = .004), insulin therapy (P = .031), diabetes duration >10 years (P = .038), summed stress score (SSS) >8 (P = .046). For patients with an SSS >8, diabetes duration and type of therapy significantly enhanced risk stratification. Similar findings emerged for patients with a post-stress EF <40%. CONCLUSION: For diabetic patients undergoing stress ECG-gated SPECT myocardial perfusion imaging, disease duration and type of therapy provide independent and incremental prognostic information. Integration of these variables with this cardiovascular imaging technology significantly enhances cardiac risk stratification. PMID- 20963540 TI - The superficial brachial artery passing superficially to the pectoral ansa, the highest superficial brachial artery (Arteria brachialis superficialis suprema). AB - The human superficial brachial artery passes superficially to the median nerve and can be classified into three subtypes according to its topographical relationship to the pectoral ansa. When the superficial brachial artery passes superficially to the pectoral ansa, it is defined as the highest superficial artery. We found the highest superficial brachial arteries in both arms of a single cadaver. The right one coexisted with a normal axillary artery, and its identification was not difficult. The left one ran medially to the brachial plexus proximally and became superficial to the brachial plexus after branching off the artery, which gave the subscapular artery, then passed between the radial nerve and its accessory root from deep to superficial and ended as an inferior collateral ulnar artery. We also found a muscular axillary arch in each of the arms, both of which were innervated by the medialmost branch from the pectoral ansa. The right highest superficial brachial artery passed deep to the nerve to the muscular axillary arch. We conjectured that the left axillary artery is where the highest superficial brachial artery, as found on the right, coexists with the axillary artery in the case of Adachi's C-type brachial plexus (AxC). Then, the highest superficial brachial artery develops as a main stem, and the latter remains as a rudimentary AxC. Because the left axillary artery is caught on neither the pectoral ansa nor its branches, the left axillary artery can shift medially to the brachial plexus, and its true form is not obvious. PMID- 20963541 TI - Long-term effects of traumatic injuries to incisors and periodontal tissues during childhood: a retrospective study. AB - AIM: The purpose of this study was to investigate the incidence of dentoalveolar growth disturbances, loss of teeth and esthetic impairment after the end of growth following traumatic injuries to incisors and periodontal tissues during childhood. MATERIALS AND METHODS: 41 patients having sustained dentoalveolar trauma before age 10 and who were now at least aged 16 years, and a total of 68 traumatized teeth were documented by clinical examination, dental casts and photographs. We determined the three-dimensional position of the traumatized teeth on the casts, as well as the traumatized teeth's pulp sensibility, percussive sound and sensitivity, shape and color. RESULTS: 82% of the traumatized teeth were in the upper dentition. 45% of the traumatized teeth experienced subluxation, nearly 30% luxation, 16% avulsion. At the time of the follow-up examination (mean 17.0 years post-trauma), 57% of the traumatized teeth were still in situ. Immediately after trauma 7.4% of the teeth were lost; up to 16 years post-trauma 35.6% of the teeth were lost because of failed root canal filling, root resorption or ankylosis. We observed no functional deviations. Dentoalveolar growth disturbances were rare. Three teeth were markedly discolored. CONCLUSION: Following dentoalveolar trauma during childhood, negative effects on growth, function and esthetics can be minimized by timely interdisciplinary treatment and by follow-up controls until the end of growth to achieve an outcome satisfying both the patient and clinician. PMID- 20963542 TI - Tensile properties of orthodontic elastomeric chains. AB - AIM: Orthodontic elastomeric chains are a main component in orthodontic therapy employing labial or lingual appliances. The aim of this study was to investigate the tensile properties of orthodontic elastomeric chains with a test setup according to ISO 21606:2007. MATERIAL AND METHODS: Orthodontic elastomeric chains of eight manufacturers with and without an intermodular link were obtained from commercially-available stock, yielding 23 groups with ten specimens each. Samples were mounted in a universal testing machine and extended at a rate of 100 mm/min to four times the initial length and held for 5 seconds. After 5 seconds, the chain lengths were reduced to an extension of three times the initial length and held for 30 seconds before extension until failure. Forces at four times the test length (Fmax1), three times the initial length (Fmin) as well as force (Fmax2) and length (Lmax) at failure were recorded. Data were statistically analyzed by one-way analysis of variance using SPSS(r) 17. The level of significance was set at p = 0.05. RESULTS: Statistical analysis revealed significant differences in Fmax1, Fmin, Fmax2 and Lmax among the various manufacturers. Fmax1 ranged between 9.1 N and 23.2 N, Fmin ranged between 1.5 N and 3.0 N, Fmax2 ranged between 15.7 N and 34.0 N, and Lmax ranged between 425% and 629% of the initial length. CONCLUSIONS: The tensile properties of different manufacturers of elastomeric orthodontic chains differ statistically significantly. Hence the amount of orthodontic force that is applied depends significantly on the type of elastomeric chains used in combination with labial or lingual appliances. PMID- 20963543 TI - Applicative characteristics of new microelectronic sensors Smart Retainer(r) and TheraMon(r) for measuring wear time. AB - OBJECTIVE: To ascertain the extent to which the new microelectronic sensors Smart Retainer(r) and TheraMon(r) are suitable for measuring wear times in orthodontic treatment. MATERIALS AND METHODS: The Smart Retainer(r) wear-time sensor and a prototype of the TheraMon(r) microsensor were each polymerized into upper plates. The orthodontic appliances were exposed to periodically altered temperatures in a thermostatic water bath. RESULTS: The wear-time sensors recorded the changes in water temperatures as "wear time" (~35 degrees C) or "non-wear time" (room temperature). The wear times stored in the sensors were displayed and printed outside the water bath as "wear-time graphs" via readout stations and computers. To be better able to predict their reliability and applicability in orthodontic treatment, we measured the accuracy of the two wear-time sensors by comparing the wear times recorded by the Smart Retainer(r) and TheraMon(r) with the programmed water temperatures. CONCLUSION: Both microelectronic sensors fulfilled the basic requirements for use as objective wear-time sensors in orthodontic appliances in clinical trials and routine orthodontic practice. As it can be incorporated into different orthodontic appliances, the smaller TheraMon(r) system offers greater versatility than the Smart Retainer(r). The TheraMon(r) also permits the accurate documentation and analysis of wear times down to the minute. PMID- 20963544 TI - Therapeutic accuracy of individualized brackets in lingual orthodontics. AB - OBJECTIVE: Verification of the therapeutic accuracy of the Incognito (r) bracket system. MATERIAL AND METHODS: The therapeutic set-up casts and final treatment casts were digitalized using a 3D scanner, and the scans were subsequently superimposed. The deviations in rotation and translation of each tooth in the three spatial dimensions were calculated. RESULTS: The front teeth showed deviations in rotations of less than 4.6 degrees and in translations under 0.5 mm. In addition, influences such as upper or lower jaw, growth, type of tooth, anterior tooth position, bracket generation, 3D scanner hardware and finishing archwires were analyzed. CONCLUSION: The clinical impression was confirmed by the measurements taken in this study. The final results following lingual orthodontic treatment using individualized brackets correlate satisfactorily with the therapeutic set-ups. PMID- 20963545 TI - Experimental analysis of torque characteristics of orthodontic wires. AB - BACKGROUND AND OBJECTIVE: A major requirement for orthodontic wires is superior elasticity. The question arises whether today's nickel titanium wires display a distinctively superelastic plateau also under torsional loading, and whether typical torsion angles are sufficient to produce adequate torquing moments with superelastic wires. The objective of this study was to compare various nickel titanium and steel wires in a pure torsion experiment. MATERIAL AND METHODS: To experimentally examine the torque characteristic of orthodontic wires, we used nickel titanium wires manufactured by Dentaurum (Tensic(r)) and ODS (Euro Arch NiTi) measuring 0.40 * 0.40 mm2, 0.40 * 0.56 mm2, 0.43 * 0.64 mm2, 0.46 * 0.64 mm2, 0.48 * 0.64 mm2, 0.51 * 0.51 mm2, and steel wires made by Dentaurum (remanium(r)), 3M Unitek (HI-TTM II Stainless Steel) measuring 0.40 * 0.40 mm2, 0.40 * 0.56 mm2, 0.43 * 0.56 mm2, 0.43 * 0.64 mm2, 0.46 * 0.64 mm2, 0.48 * 0.64 mm2, 0.51 * 0.51 mm2. Torque was measured at an ambient temperature of 37 degrees C for the nickel titanium wires. The distance between the bearing points was 10 mm for all measurements. The steel wires' torquing moments were determined at a torsion angle of 20 degrees , the torquing moments of the nickel titanium wires were investigated on the plateau, and we compared the results of the means and the standard deviations of all wires. Starting and end points of the loading and unloading plateau were determined for all nickel titanium wires. RESULTS: The torquing moment/torsion angle diagrams of the nickel titanium wires by different manufacturers displayed the curves typical of superelastic wires. The torquing moments of the wires with a smaller cross-section yielded values below 5 Nmm and thus appear obviously too small (e.g. Dentaurum Tensic(r), 0.40 * 0.40 mm2: 1.3 Nmm). The mean values of the loading plateau's starting point yielded values of about 20 degrees . CONCLUSIONS: As the torsional play in the bracket slot of the wires with a smaller cross-section is typically about 10 degrees , we doubt whether these wires reach the superelastic plateau. Moreover, we observed production-associated variations in the material properties of various nickel titanium wires. It is thus difficult for the practitioner to draw a correlation between a wire's crosssection and the actual torquing moment delivered. PMID- 20963546 TI - Interdental spacing and orthodontic treatment in competitive athletes: clues to doping with growth hormones? AB - The aim of this report is to examine clues of a suspected link between the artificial ingestion of human growth hormone (rh- GH) and resulting interdental spaces in adult athletes. We conducted an electronic search in the German language versions of the search engines Google and Google Scholar as well as in the database PubMed. While no explicit articles could be identified in PubMed, the search in Google and Google Scholar produced 1370 and 6 hits, respectively. Original quotes from 20 sources show that in the media the wearing of orthodontic multibracket appliances among athletes is largely attributed to changes in tooth position as a consequence of the illegal ingestion of rhGH. On the other hand, there are few references to the possibility that orthodontic treatments with fixed appliances might be carried out for reasons unrelated to doping. CONCLUSION: A definitive assessment of this issue is not possible at present. In view of its major importance of the subject, the relationships depicted here should be investigated in greater depth. PMID- 20963550 TI - Pharma rebates, pharmacy benefit managers and employer outcomes. AB - Corporate employers contract with pharmacy benefit managers (PBMs) with the goals of lowering their employee prescription drug coverage costs while maintaining health care quality. However, little is known about how employer-PBM contract elements and brand drugmakers' rebates combine to influence a profit-maximizing PBM's actions, and the impact of those actions on the employer's outcomes. To shed more light on these issues, the authors build and analyze a mathematical simulation model of a competitive pharmaceutical market comprised of one generic and two branded drugs, and involving a PBM contracted by a corporate employer to help it lower prescription drug costs while achieving a minimum desired quality of health care for its employees. The brand drugmakers' rebate offers, the PBM's assignment of drugs to formulary tiers, and the resulting employer outcomes under varying contracts and pharma brand marketing mix environmental scenarios are analyzed to provide insights. The findings include that the pharma brands offer rebates for the PBM's ability to move prescription share away from the unpreferred brand, but reduce these offers when the PBM's contract requires it to proactively influence physicians to prescribe the generic drug alternative. Further, Pareto optimal contracts that provide the highest health benefit for a given employer cost budget for the employer are analyzed to provide managerial implications. They are found to involve strong PBM influence on physician prescribing to discourage unpreferred brands, as well as high patient copayment requirements for unpreferred brands to align the patient prescription fill probability with the formulary, while other copayment requirements provide an instrument to determine the level of desired health benefit-cost tradeoff. PMID- 20963551 TI - Using simulation-optimization to construct screening strategies for cervical cancer. AB - Cervical cancer is the second most common cancer in women worldwide. Cervical screening is critical for preventing this type of cancer. Traditionally, screening strategies are evaluated from an economic point of view through cost effectiveness analysis. However, cost-effectiveness analysis is typically performed on a limited number of de facto or predetermined screening policies. We develop a simulation-optimization model to determine the ages at which screening should be performed, resulting in dynamic, age-based screening policies. We consider three performance measures: cervical cancer incidence, the number of cervical cancer deaths, and the number of life years lost due to cervical cancer death. Using each performance measure, we compare our optimal, dynamic screening strategies to standard policies considered in the health screening literature that are static and predetermined. We also evaluate the anticipated impact of vaccinations for preventing cervical cancer. The strategies that are developed are compared to those used in practice or considered in the literature. The Centers for Disease Control and Prevention recommends one screening every 3 years, resulting in 14 scheduled lifetime screenings. Our dynamic screening strategies provide approximately the same health benefits as this but with four to six fewer scheduled screenings, depending on the performance measure considered. Our dynamic strategies also provide approximately the same health benefits as screening every 2 years, but with six to nine fewer scheduled screenings. The results suggest that dynamic, age-based cervical cancer screening policies offer substantial economic savings in order to offer the same health benefits as equally spaced screening strategies. PMID- 20963552 TI - Does substituting home care for institutional care lead to a reduction in Medicaid expenditures? AB - In 1981 Congress introduced Home and Community Based Services (HCBS) waivers in an attempt to contain Medicaid long-term care expenditures. This paper analyzes the efficacy of the waiver program. To date, little is known about its impact on cost containment. Using state-level Medicaid data on expenditures and the number of individuals participating in HCBS waivers between 1992 and 2000, this study estimates the impact of HCBS waivers on total Medicaid expenditures as well as on Medicaid institutional, home health and pharmaceutical expenditures. A fixed effects model is used to analyze Medicaid expenditures using variation in the size of HCBS waiver programs across states and over time. The results, robust across multiple specifications, show increases rather than decreases in total Medicaid spending as well as increases in the other Medicaid spending categories analyzed. This implies that there is no evidence of substitution from institutional care to the HCBS waiver program or that cost-shifting is occurring. In fact, the large magnitude of the estimated spending increases suggests the waivers may induce more people to enter the Medicaid program. PMID- 20963553 TI - Potential gains from hospital mergers in Denmark. AB - The Danish hospital sector faces a major rebuilding program to centralize activity in fewer and larger hospitals. We aim to conduct an efficiency analysis of hospitals and to estimate the potential cost savings from the planned hospital mergers. We use Data Envelopment Analysis (DEA) to estimate a cost frontier. Based on this analysis, we calculate an efficiency score for each hospital and estimate the potential gains from the proposed mergers by comparing individual efficiencies with the efficiency of the combined hospitals. Furthermore, we apply a decomposition algorithm to split merger gains into technical efficiency, size (scale) and harmony (mix) gains. The motivation for this decomposition is that some of the apparent merger gains may actually be available with less than a full scale merger, e.g., by sharing best practices and reallocating certain resources and tasks. Our results suggest that many hospitals are technically inefficient, and the expected "best practice" hospitals are quite efficient. Also, some mergers do not seem to lower costs. This finding indicates that some merged hospitals become too large and therefore experience diseconomies of scale. Other mergers lead to considerable cost reductions; we find potential gains resulting from learning better practices and the exploitation of economies of scope. To ensure robustness, we conduct a sensitivity analysis using two alternative returns-to-scale assumptions and two alternative estimation approaches. We consistently find potential gains from improving the technical efficiency and the exploitation of economies of scope from mergers. PMID- 20963554 TI - Partial remission of metastatic papillary thyroid carcinoma with sunitinib. Report of a case and review of the literature. AB - Tyrosine kinase receptors have been implicated in thyroid cancer. Therefore, tyrosine kinase inhibitors may be used for the treatment of advanced metastatic thyroid carcinoma. The aim is to present a case of metastatic papillary thyroid carcinoma responding to the administration of sunitinib, a multi-targeted protein kinase inhibitor. A patient presented with metastatic papillary thyroid carcinoma and hyperthyroidism. After euthyroidism was achieved the patient was treated by the administration of therapeutic radioiodine (131)I, radiotherapy and sunitinib, a multi-targeted tyrosine kinase inhibitor. Thyroglobulin levels decreased from 9,594 to 6,816 ng/ml after 1 month, 6 months later being 2,776 ng/ml. The lesion in the pelvis was 12.5 * 9 cm before treatment decreasing thereafter and the patient improved clinically. The administration of sunitinib resulted in partial disease response in a patient with progressive metastatic papillary thyroid carcinoma. Protein kinase inhibitors may prove useful in the management of advanced metastatic papillary thyroid carcinoma. PMID- 20963556 TI - Raloxifene inhibits bone loss and improves bone strength through an Opg independent mechanism. AB - The osteoblast-derived paracrine factor osteoprotegerin (OPG) is considered to play a key role in inhibition of osteoclast formation and activity. Recently, raloxifene, a nonsteroidal benzothiophene, was found to exert anti-resorptive effects via modulating OPG expression in osteoblasts. To explore whether raloxifene regulates bone metabolism via an OPG-dependant pathway in vivo, we investigated the effects of raloxifene on bone loss in Opg-deficient mice. The results show that bone mineral density and bone strength are increased in mice deficient for Opg after treatment with raloxifene for 30 days. Histomorphometric analysis shows that raloxifene can increase bone trabecular area and decrease the number of osteoclasts in Opg (-/-) mice. Moreover, raloxifene reduces Rankl transcription and serum level of Rankl, which is dramatically increased in Opg knockout mice. These results suggest that raloxifene-induced inhibition of bone resorption may be independent of Opg pathway in mice. PMID- 20963557 TI - A direct neuronal connection between the subparafascicular and ventrolateral arcuate nuclei in non-lactating female rats. Could this pathway play a role in the suckling-induced prolactin release? AB - The neuronal pathways, through which prolactin secretion is regulated during lactation, have still not been fully explored. Studies indicate that the suckling stimulus travels through the spinal cord, the brain stem, and then reaches the hypothalamus. The focus of this present experiment is to further explore the neuronal connections between the brain stem and the arcuate nucleus that may be involved in suckling-induced prolactin release. Ante- and retrograde tracing techniques were used. To chemically characterize the explored neurons neuropeptide immunohistochemistry was applied. Previous studies have indicated that the peripeduncular nucleus is a relay of the suckling stimulus in the midbrain, conveying the information to the hypothalamus. In our experiments, we have found an additional cell group in the subparafascicular parvocellular nucleus located just behind the posterior thalamus that projects to the arcuate neurons. The injection of the retrograde tracer into the ventrolateral part of the arcuate nucleus labeled cells in the lateral subdivision of the subparafascicular parvocellular nucleus. Anterograde tracing from the subparafascicular parvocellular nucleus resulted in fiber labeling in the arcuate nucleus in close apposition with dynorphin immunopositive neurons. Double labeling revealed that a subpopulations of the subparafascicular parvocellular neurons projecting to the arcuate nucleus contained tuberoinfundibular peptide of 39 residues or calcitonin gene-related peptide. The presented findings suggest that the ascending fibers from the subparafascicular parvocellular nucleus might be in the pathway involved in the suckling-induced prolactin release. PMID- 20963558 TI - Interleukin 1 beta (IL-1beta) promoter C [-511] T polymorphism but not C [+3953] T polymorphism is associated with polycystic ovary syndrome. AB - PCOS is a complex multifactorial disorder involving a number of genetic and environmental factors. One of the genetic factors that has been associated with PCOS is Interleukin 1 beta (IL-1beta), is an important inflammatory cytokine that plays a regulatory role in both the body's immune and the inflammatory responses. All these responses appear to be are also affected in at least some women with PCOS. To investigate the possible association of polymorphisms of the IL-1beta gene with the occurrence and clinical characteristics of PCOS, we evaluated two common polymorphisms of the IL-1beta gene (promoter C [-511] T and exon 5 position [+3953]) in 200 Chinese women with PCOS and 177 healthy Chinese controls. We found the frequency of IL-1beta C/C [-511] genotype in PCOS was significantly higher than that in the controls (chi(2) = 15.48, df = 1, P < 0.001 OR = 2.73 95% CI: 1.64-4.56 by genotype; chi(2) = 10.21, df = 1, P = 0.001 by allele). However in contrast, no association between genotype and relative allele frequencies was observed for the C [+3953] T polymorphism for Chinese women with PCOS when compared to that for a similar group of Chinese women without PCOS (P = 0.35). PMID- 20963555 TI - Adiponectin action from head to toe. AB - Adiponectin, the most abundant protein secreted by white adipose tissue, is known for its involvement in obesity-related disorders such as insulin resistance, type 2 diabetes mellitus and atherosclerosis. Moreover, modulation of the circulating adiponectin concentration is observed in pathologies that are more or less obesity-related, such as cancer and rheumatoid arthritis. The wide distribution of adiponectin receptors in various organs and tissues suggests that adiponectin has pleiotropic effects on numerous physiological processes. Besides its well known insulin-sensitizing, anti-inflammatory and antiatherosclerotic properties, accumulating evidence suggests that adiponectin may also have anticancer properties and be cardioprotective. A beneficial effect of adiponectin on female reproductive function was also suggested. Since adiponectin has numerous beneficial biological functions, its use as a therapeutic agent has been suggested. However, the use of adiponectin or its receptors as therapeutic targets is complicated by the presence of different adiponectin oligomeric isoforms and production sites, by multiple receptors with differing affinities for adiponectin isoforms, and by cell-type-specific effects in different tissues. In this review, we discuss the known and potential roles of adiponectin in various tissues and pathologies. The therapeutic promise of administration of adiponectin and the use of its circulating levels as a diagnostic biomarker are further discussed based on the latest experimental studies. PMID- 20963559 TI - Study on pancreatic islet adaptation and gene expression during pregnancy in rats. AB - During pregnancy, the pancreatic islets undergo major structural and functional changes in response to increased peripheral resistance to insulin. In this study, we investigated the adaptive changes of the pancreatic islet beta-cell mass during pregnancy in rats, and explored profiles of islet gene expression at various stages of pregnancy. Some differentially expressed genes were verified by RT-PCR and Real-time PCR. Our results showed that compared with the non-pregnant control group, insulin synthesis, glucose-stimulated insulin secretion, islet beta-cell proliferation, and islet size were all increased in pregnant rats. The study also demonstrated that expression of several-hundred islet genes were changed during pregnancy, especially at day 14.5. The differentially expressed genes identified were distributed into eight main categories according to their biological functions: (1) genes involved in apoptosis or tumor; (2) genes related to binding; (3) genes involved in metabolism; (4) genes related to cell cycle; (5) genes for signal transducer activity; (6) genes related to structural molecule activity; (7) genes involved in transcription regulator activity; (8) genes for transporter activity. Among these genes, regenerating islet-derived 3 alpha (Reg3a) was remarkably increased during pregnancy. We hypothesize that differentially expressed genes may play an important role in adaptation of pancreatic islets during pregnancy in rats. In addition, the markedly increased expression of gene Reg3a is probably related to islet regeneration. PMID- 20963560 TI - Analysis of TPO gene in Turkish children with iodide organification defect: identification of a novel mutation. AB - The objective was to determine molecular genetic analysis of the TPO gene in Turkish children with iodide organification defect (IOD). Patients with a diagnosis of primary hypothyroidism were evaluated. Subjects having a definite diagnosis of autoimmune thyroiditis, thyroid gland dysplasia and, or iodine deficiency were excluded. A total of 10 patients from nine unrelated Turkish families, with an unknown etiology of hypothyroidism, and with a presumptive diagnosis of IOD were included in the study. A perchlorate discharge test (PDT) was performed to all subjects, and sequence analysis of TPO gene was applied in patients with a positive PDT. Five out of 10 patients have a total IOD, while the five remaining patients have a partial IOD according to PDT results. In two sisters, one has a partial and the other one has a total IOD a novel homozygous nonsense p.Q315X mutation was found in exon 8. Additionally, a previously known homozygous missense p.R314W mutation was detected in the same exon in another patient with a total IOD. No TPO gene mutation was detected in any of the seven remaining patients. Two different TPO gene mutations were found to be responsible for IOD in two unrelated Turkish families from the same ethnic background. More subjects should be screened for detecting the prevalence and spectrum profile of TPO mutations in our population that might be helpful for understanding the pathophysiology of congenital hypothyroidism. PMID- 20963561 TI - Age, body mass index, and serum level of DHEA-S can predict glucocorticoid receptor function in women with polycystic ovary syndrome. AB - Glucocorticoid receptor (GR) transduces the glucocorticoid (GC) signal that could lead to metabolic derangements depending on the tissue responsiveness to GC. We aimed to investigate possible causative relation of the GR functional properties in peripheral blood mononuclear cells of women with polycystic ovary syndrome (PCOS), with their clinical and biochemical characteristics. Thirty women with PCOS [mean age: 26.5 +/- 5.1 years, mean body mass index (BMI) 24.5 +/- 5 kg/m(2)], and thirty respective controls were analyzed for the number of GR sites per cell (B (max)), apparent equilibrium dissociation constant (K (d)), and binding potency (GR potency). A strong association between B (max) and K (d) (r = 0.70, P < 0.0001), and GR potency with age (r = 0.49, P = 0.009) was observed in PCOS women. The multiple regression analyses within the PCOS group revealed that independent predictors for K (d) were BMI, total cholesterol, and dehydroepiandrosterone-sulfate (DHEA-S) (r = 0.58, P = 0.038), while for GR potency (r = 0.687, P = 0.013) were age, BMI, DHEA-S, and basal cortisol concentration. The results suggest that PCOS pathophysiology may be related to alterations of a cross stalk between glucocorticoid signaling, age, and metabolic parameters. These findings should be further explored in studies on the role of GR in PCOS-related metabolic derangements. PMID- 20963562 TI - Comparison of lymphomononuclear cell energy metabolism between healthy, impaired glucose intolerance and type 2 diabetes mellitus patients. AB - Diabetes mellitus (DM) is a complex disease that affects many systems. The most important cells of the immune system are lymphomononuclear (LMN) cells. Here, we aimed to evaluate the energy metabolism of LMN cells in patients with diabetes and impaired glucose tolerance. We measured LMN cell energy metabolism in patients with type 2 diabetes mellitus, impaired glucose tolerance (IGT) and healthy subjects. Cells were freshly isolated from peripheral blood and the subgroups were determined by flow cytometric method. Lactate production and glycogen utilization were significantly increased in the LMN cells of patients with type 2 DM and IGT when compared with healthy volunteers. No statistical difference was observed between the patients with type 2 DM and IGT. There was a significant correlation between fasting plasma glucose and lactate production in LMN cells. LMN cells changed their energy pathway in a diabetic state and preferred anaerobic glycolysis. Prediabetic range also affected energy metabolism in LMN cells. This abnormal energy production might cause dysfunction in LMN cells and the immune system in diabetic and prediabetic patients. In conclusion, we concluded that impaired glucose metabolism could change energy metabolism. PMID- 20963563 TI - Discrimination of prolactinoma from hyperprolactinemic non-functioning adenoma. AB - The objective of this study was to evaluate characteristics that discriminate prolactinoma from non-functioning pituitary macroadenoma with hyperprolactinemia. We included 117 patients with hyperprolactinemic pituitary macroadenomas. Patients were divided into three groups according to treatment outcomes and pathologic results: (A) prolactinoma that responded to dopamine agonist (DA) treatment (PRDA); (B) prolactinoma requiring surgical treatment (PRS); and (C) non-functioning pituitary adenoma with hyperprolactinemia (NFPAH). Old age, low serum prolactin levels, and extrasellar extension were associated with NFPAH. Most patients with NFPAH had serum prolactin levels less than 100 ng/ml. Visual defects and GH deficiency were more common in patients with NFPAH compared with patients with PRS and PRDA, without difference of tumor size. Galactorrhea and amenorrhea were less frequent in patients with NFPAH than in patients with PRS and PRDA. Post-operative remission of hyperprolactinemia was achieved in 100% of patients with NFPAH and in 72.5% of patients with PRS. DA administration was required in 25.5% of patients with PRS; however, no patients with NFPAH required DA administration. In conclusion, old age, extrasellar tumor extension with relatively low prolactin levels, visual defect, and GH deficiency were considered suggestive of non-functioning pituitary adenoma rather than prolactinoma in hyperprolactinemic pituitary macroadenoma. PMID- 20963564 TI - Relationship between RANKL and neuroendocrine activation in elderly males with heart failure. AB - The main cytokines regulating bone remodeling are the receptor activator of nuclear factor-kappaB ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG). Recent data have linked RANKL and OPG to cardiovascular disease as well. NT-pro-BNP and adiponectin are well-established biomarkers of heart failure reflecting neuroendocrine activation in this multi-complex disorder. The objective of this article was to investigate whether RANKL is associated with neuroendocrine activation in 75 elderly males with mild to moderate congestive heart failure (CHF) and left ventricular ejection fraction <40%. The control group consisted of 20 healthy male volunteers with matching age and body mass index (BMI). Serum RANKL (sRANKL), OPG, NT-pro-BNP, adiponectin, leptin, clinical, and echocardiography parameters were evaluated. In comparison to the control group, the CHF patients showed significantly increased sRANKL levels [126.8 (122.6) vs. 47.8 (44.4) pg/ml, P < 0.0001]. There was a significant relative risk of systolic CHF in elderly males associated with increased sRANKL above the calculated cut-off of 83 pg/ml [OR = 10.286 (95%CI 3.079-34.356), P < 0.0001; RR = 3.600 (95%CI = 1.482-8.747)]. In the CHF patients, the log transformed values of sRANKL levels correlated positively with the log transformed values of the serum NT-pro-BNP and adiponectin levels (P = 0.004, r = 0.326 and P = 0.037, r = 0. 241, respectively), while inversely correlated with the BMI and creatinine clearance (P = 0.015, r = -0.281 and P = 0.042, r = 0.236, respectively). In multivariate regression model, sRANKL was a significant determinant of NT-pro-BNP independent of age, BMI and creatinine clearance (P = 0.002, R (2) = 0.546). In conclusion, our study suggests that in elderly males with systolic heart failure sRANKL was significantly associated with parameters of neuroendocrine activation such as NT-pro-BNP and adiponectin. Further studies are needed to elucidate the potential role of sRANKL in the complex pathogenesis of heart failure. PMID- 20963565 TI - Overactivation of NF-kappaB impairs insulin sensitivity and mediates palmitate induced insulin resistance in C2C12 skeletal muscle cells. AB - Lipid-induced insulin resistance is associated with inflammatory state in epidemiological studies. However, it is still unclear whether the activation of NF-kappaB, a pivotal transcription factor of inflammation, plays a crucial role in mediating skeletal muscle insulin resistance. This study addressed what was the role of NF-kappaB in lipid-induced insulin resistance and whether NF-kappaB activation was sufficient to cause insulin resistance in C2C12 myotubes. A 16 h exposure of myotubes to palmitate reduced net insulin-stimulated glucose uptake by 48%, GLUT4 translocation by 52%, Akt phosphorylation by 54%, induced a 1.8 fold increase in insulin-stimulated insulin receptor substrate (IRS) phosphorylation, and doubled NF-kappaB activation. Myotubes transfected with NF kappaB p65 siRNA for 24 h and followed by a treatment with palmitate for 16 h efficiently blocked NF-kappaB activation, and prevented the detrimental effects of palmitate on the metabolic actions of insulin. Transfection of myotubes with I kappaBalpha siRNA for 24 h also led to a twofold induction of NF-kappaB activation, and reduced net insulin-stimulated glucose uptake by 30%, GLUT4 translocation by 35%, Akt phosphorylation by 31%, induced a 0.7-fold increase in insulin-stimulated IRS phosphorylation. These findings suggest that NF-kappaB overexpression per se is sufficient to impair insulin sensitivity and palmitate induced insulin resistance is mediated by NF-kappaB in skeletal muscle cells. PMID- 20963566 TI - Activation of orexin neurons through non-NMDA glutamate receptors evidenced by c Fos immunohistochemistry. AB - Orexin neuropeptides participate in the regulation of feeding as well as the regulation and maintenance of wakefulness and the cognitive functions. Orexin A and B share a common precursor, prepro-orexin and neurons are localized in the lateral hypothalamus. Physiological studies showed that these neurons are regulated by glutamatergic innervations. We aimed to assess the effects of kainic acid as a potent agonist for non-NMDA glutamate receptors in the activation of orexin neurons. We also analyzed the effect of glutamate antagonist CNQX, injected prior to kainic acid, on this activation. Expression of c-Fos protein was used as a marker for neuronal activation. Dual immunohistochemical labeling was performed for prepro-orexin and c-Fos and the percentages of c-Fos-expressing orexin neurons were obtained for control, kainic acid, and CNQX groups. Kainic acid injection caused statistically significant increase in the number of c-Fos positive neurons when compared to control group (62.69 and 36.31%, respectively). Activation of orexin neurons was blocked, in part, by CNQX (43.36%). In the light of these results, it is concluded that glutamate takes part in the regulation of orexin neurons and partially exerts its effects through non-NMDA glutamate receptors and that orexin neurons express functional non-NMDA receptors. PMID- 20963567 TI - Fatty acid pattern of pancreatic islet lipids in Goto-Kakizaki rats. AB - Perturbations of fatty acid content and pattern were recently documented in epididymal and parametrial lipids, as well as plasma, liver, spleen, and brain phospholipids and triglycerides of Goto-Kakizaki rats (GK). This study extends such an investigation to pancreatic islets from both control and GK rats. Groups of 5,500-14,560 islets were obtained from either control or GK rats (n = 3 in each case) and examined for their lipid fatty acid content. In the islet triglycerides, the major difference between control and GK rats, i.e., a higher C18:2omega6 content in GK rats, was similar to that found in liver triglycerides. In the islet phospholipids, however, a number of differences between control and GK rats, concerning saturated, monodesaturated, and long-chain polyunsaturated omega3 and omega6 fatty acids, were often not similar to those found in liver phospholipids. The present study reveals a number of anomalies in the fatty acid pattern of islet phospholipids in GK rats, often differing from those encountered in liver phospholipids. Such a tissue specificity was borne out by the finding that, even in control animals, the situation found in islet phospholipids differed from that recorded in liver phospholipids. PMID- 20963568 TI - The effect of the alendronate on OPG/RANKL system in differentiated primary human osteoblasts. AB - Alendronate is a well-established treatment for osteoporosis and suppresses bone resorption by a direct effect on osteoclasts and their precursors. The effect of alendronate on osteoclasts is produced, at least in part, by the receptor activator of nuclear factor kappaB ligand (RANKL) and the osteoprotegerin (OPG) synthesized by the osteoblasts. This study analyzes the effect of alendronate in cell viability, phosphatase alkaline (ALP) activity and RANKL, and OPG expression in primary human osteoblasts (hOB). Alendronate at concentrations lower than 10( 5) M did not have a toxic effect on hOB in vitro and did not modify the ALP activity at least for 72 h. Alendronate did not change OPG expression in basal, 10% FBS, and vitamin D-treated cultures. Similar results were observed at the protein level. Unexpectedly, alendronate at 10(-7) and 10(-5) M concentrations increased the RANKL expression with the presence of vitamin D in differentiated hOB and this induction of RANKL mRNA levels by alendronate was dose-dependent. However, this effect was not observed in basal and 10% FBS culture conditions. Thus, we conclude that alendronate does not affect the ALP activity and OPG gene expression in differentiated hOB, but may increase RANKL gene expression induced by vitamin D. PMID- 20963569 TI - Inhibitory effect of valproic acid on ovarian androgen biosynthesis in rat theca interstitial cells. AB - The objective of the study was to evaluate the effect of valproic acid (VPA) on ovarian androgen biosynthesis in primary cultures of theca-interstitial (T-I) cells isolated from rat ovaries. Ovarian T-I cells were cultured with VPA in the presence or absence of hCG. VPA did not increase basal or hCG-stimulated androgen synthesis when added to primary cultures of T-I cells. However, the addition of VPA caused a marked concentration-dependent inhibitory effect on hCG-stimulated androstendione synthesis. Treatment of T-I cells with 8-Bromo-cAMP resulted in a marked increase in the production of androstenedione, and VPA inhibited this stimulatory effect, suggesting that the mechanism of VPA's inhibitory effect on androstenedione production occurs at a step after second messenger activation. Treatment of T-I cells with hCG resulted in a significant increase in the mRNA expression of steroidogenic enzymes CYP17A1 and 17beta-hydroxysteroid dehydrogenase. Addition of VPA sharply blunted the stimulatory effect of hCG, reducing the mRNA expression of the steroidogenic enzymes to basal levels. In conclusion, VPA exerts an inhibitory effect on hCG-stimulated androgen synthesis in rat T-I cells. PMID- 20963570 TI - Progesterone and estradiol effects on SRC-1 and SRC-3 expression in human astrocytoma cell lines. AB - Progesterone (P(4)) and estradiol (E(2)) regulate many cell functions through their interaction with specific intracellular receptors, which require the participation of coactivators such as SRC-1 and SRC-3 for enhancing their transcriptional activity. Coactivator expression is altered in many cancers and in some of them their expression is regulated by P(4) and E(2). In this study, we determined progesterone and estrogen receptor isoform expression in two human astrocytoma cell lines with different evolution grade (U373, grade III; and D54, grade IV) by Western Blot. We studied the role of P(4) and E(2) on SRC-1 and SRC 3 expression in U373 and D54 cell lines by RT-PCR and Western blot. In U373 cells, P(4) did not modify SRC-1 expression, but in D54 cells it increased SRC-1 mRNA expression after 12 h of treatment without significant changes after 24 h. P(4) also increased SRC-1 protein content after 24 h, but reduced it after 48 h. E(2) did not change SRC-1 expression in any cell line. SRC-3 expression was not regulated by either E(2) or P(4). Our data suggest that SRC-1 and SRC-3 expression is differentially regulated by sex steroid hormones in astrocytomas and that P(4) regulates SRC-1 expression depending on the evolution grade of human astrocytoma cells. PMID- 20963571 TI - Relationships between glucose excursion and the activation of oxidative stress in patients with newly diagnosed type 2 diabetes or impaired glucose regulation. AB - The effect of glucose excursions on oxidative stress is an important topic in diabetes research. We investigated this relationship by analyzing markers of oxidative stress and glycemic data from a continuous glucose monitoring system (CGMS) in 30 individuals with normal glucose regulation (NGR), 27 subjects with impaired glucose regulation (IGR), and 27 patients with newly diagnosed type 2 diabetes (T2DM). We compared the mean amplitude of glycemic excursion (MAGE), mean postprandial glucose excursion (MPPGE), and mean postprandial incremental area under the curve (IAUC) with plasma levels of oxidative stress markers 8-iso PGF2alpha, 8-OH-dG, and protein carbonyl content in the study subjects. Patients with T2DM or IGR had significantly higher glucose excursions and plasma levels of oxidative stress markers compared to normal controls (P < 0.01 or 0.05). Multiple linear regression analyses showed significant relationships between MAGE and plasma 8-iso-PGF2alpha, and between MPPGE and plasma 8-OH-dG in patients with IGR or T2DM (P < 0.01 or 0.05). Furthermore, 2h-postprandial glucose level and IAUC were related to plasma protein carbonyl content in the study cohort including T2DM and IGR (P < 0.01). We demonstrate that glucose excursions in subjects with IGR and T2DM trigger the activation of oxidative stress. PMID- 20963572 TI - Fatal hypoglycemia in malignant pheochromocytoma: direct glucose consumption as suggested by (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography imaging. AB - We present a patient with metastatic pheochromocytoma, who developed progressive and fatal hypoglycemia most likely secondary to direct tumor glucose consumption that did not respond to high-dose glucose infusion, corticosteroids, or glucagon therapy. The pattern of glucose uptake on (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography, with preferential tumor glucose uptake in association with a marked reduction in normal uptake in the heart, muscles, and brain, is highly suggestive of direct consumption of glucose by the tumor rather than insulin-like growth factor-2 mediated hypoglycemia. In patients with large volume metastatic malignancies, direct tumor glucose consumption should be considered in the differential diagnosis of hypoglycemia. Nuclear medicine imaging techniques can illustrate the pathophysiology of hypoglycemia in such cases. PMID- 20963573 TI - Pheochromocytoma crisis after a dexamethasone suppression test for adrenal incidentaloma. AB - A 61-year-old woman was referred to our department for evaluation of an incidental adrenal mass. An abdominal CT scan revealed a 4.1 cm right adrenal mass. The patient had been diagnosed with hypertension 7 years earlier and had taken antihypertensive medications intermittently. Her physical examination demonstrated a round face, central obesity, and mild hypertension. Serum catecholamines, renin, aldosterone, ACTH and 24-h urine-free cortisol, vanillylmandelic acid levels were within normal limits. However, serum cortisol level was markedly elevated and the circadian rhythm was disturbed. Successive low-dose and high-dose dexamethasone suppression tests were ordered for evaluation of a functioning adrenal incidentaloma. About 2 h after taking the second dose of 2 mg dexamethasone, she suddenly developed nausea and vomiting, palpitations, and anxiety with severe hypertension. On the same day, we measured serum catecholamines, which were markedly elevated. An elective laparoscopic right adrenalectomy was performed and pathologic examination confirmed the diagnosis of pheochromocytoma. One week after surgery, serum and urine catecholamine levels returned to normal. The patient has remained normotensive without any medications and clinically well. Patients with adrenal incidentalomas may have a functional mass that does not always manifest as a full symptomatic disease. During the investigation of adrenal incidentalomas, pheochromocytoma should ideally be ruled out before administering corticosteroids. PMID- 20963574 TI - Pancreatic neuronal melanocortin-4 receptor modulates serum insulin levels independent of leptin receptor. AB - The leptin-regulated melanocortin (MC) system modulates energy homeostasis and hypothalamic MC neuronal circuits regulate insulin secretion. We therefore hypothesized that MC system components were present in the pancreas. In order to determine the veracity of the hypothesis, we examined c-Fos, melanocortin-4 receptor (Mc4r), and alpha-melanocyte-stimulating hormone (alpha-MSH) expression levels in nondiabetic (intact leptin receptor signaling) and Zucker diabetic fatty (ZDF; leptin receptor deficiency) rats. We infused rats via the third ventricle with the alpha-MSH analog Nle4, D-Phe7-alpha-MSH (NDP-MSH), a Mc4r agonist. Subsequently, both hypothalamic and pancreatic c-Fos and Mc4r mRNAs were upregulated. Likewise, immunohistochemical analysis showed that an increased Mc4r and alpha-MSH expression in nerves surrounding the pancreatic vasculature and islets. Increases in c-Fos, alpha-MSH, and Mc4r expression were independent of leptin receptor function. Conversely, serum insulin was significantly reduced by NDP-MSH treatment, an effect which was reversed by the Mc4r specific blocker HS014. Finally, proopiomelanocortin (POMC) mRNA, the precursor of alpha-MSH, was detected by RT-PCR in pancreatic tissue homogenates. These findings suggest that pancreatic Mc4r and autonomic neurons participate in a communication pathway between the central MC system and pancreatic islets to regulate insulin secretion. PMID- 20963575 TI - Age-related changes in hypothalamic-pituitary-adrenal axis activity in patients with manifest arterial disease. AB - Reports on age-related changes of hypothalamic-pituitary-adrenal (HPA) axis activity are equivocal. In addition, subtle changes in HPA axis activity are associated with cardiovascular risk factors. This study evaluates the effect of age in a large sample of patients with arterial disease on several parts of the circadian rhythm of the HPA axis. Within the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study, a prospective cohort study among patients with manifest arterial disease, cross-sectional analyses were performed in 419 patients (age 63 +/- 9 years). Circadian cortisol rhythm was assessed with six saliva samples, collected at awakening and 30, 45, and 60 min thereafter and at 10 and 11 pm. Furthermore, a low dose of dexamethasone (0.5 mg) was administered at 11 pm, and saliva was sampled the next morning to test the cortisol suppression. Linear regression analyses adjusted for sex, awakening time, workday, smoking, blood pressure, BMI, diabetes mellitus, and dyslipidemia showed that older age was associated with a blunted cortisol awakening response. Per year increase, the rise (beta = -0.15 nmol/l; 95%CI -0.25 to -0.05) and diurnal pattern (beta = -0.14 nmol/l; 95%CI -0.25 to -0.02) decreased. Furthermore, older age was associated with higher evening levels (beta log transformed = 0.01; 95%CI 0.01-0.02) and higher mean cortisol after dexamethasone (beta log transformed = 0.01; 95%CI 0.002-0.02). In patients with arterial disease, HPA axis activity showed reduced variability with older age, independent of cardiovascular risk factors. PMID- 20963577 TI - Yellowjackets use nest-based cues to differentially exploit higher-quality resources. AB - While foraging, social insects encounter a dynamic array of food resources of varying quality and profitability. Because food acquisition influences colony growth and fitness, natural selection can be expected to favor colonies that allocate their overall foraging effort so as to maximize their intake of high quality nutrients. Social wasps lack recruitment communication, but previous studies of vespine wasps have shown that olfactory cues influence foraging decisions. Odors associated with food brought into the nest by successful foragers prompt naive foragers to leave the nest and search for the source of those odors. Left unanswered, however, is the question of whether naive foragers take food quality into account in making their decisions about whether or not to search. In this study, two different concentrations of sucrose solutions, scented differently, were inserted directly into each of three Vespula germanica nests. At a feeder away from the nest, arriving foragers were given a choice between two 1.5 M sucrose solutions with the same scents as those in the nest. We show that wasps chose higher-quality resources in the field using information in the form of intranidal food-associated odor cues. By this simple mechanism, the colony can bias the allocation of its foraging effort toward higher-quality resources in the environment. PMID- 20963578 TI - The influence of posterior-inferior tibial slope in ACL injury. AB - PURPOSE: To explore the effect of different posterior-inferior tibial slope (PITS) angles on ACL injury at non-contact sports, knee laxity and the need for ACL reconstruction. METHODS: One hundred patients with an acute, arthroscopically verified total ACL rupture were followed prospectively with the intention of treating the injury without reconstruction. Knee laxity was assessed with the Lachman and pivot shift tests with the patients under general anesthesia within 10 days of injury. After 15 years, 22 patients of 94 available for follow-up had undergone reconstruction a mean of 4 years after injury. Reconstruction was performed in case of repeated giving-way episodes (n = 16) or meniscus lesions suitable for fixation (n = 6). Knee radiographs were available from 82 patients. Two independent readers determined the PITS angle. RESULTS: Patients injured in contact sports had a greater mean PITS angle than those injured in non-contact sports (10.5 degrees and 9.3 degrees , respectively, P = 0.03). The mean PITS angle was 10.1 (SD = 2.3) for non-reconstructed knees and 9.1 (SD = 3.0) for reconstructed knees (P = NS). Eight of 17 reconstructed knees showed a PITS angle of less than 7.6 degrees (P = 0.006), and the odds ratio of need for reconstruction was 3.9 (CI 1.26-12.3, P = 0.02). No significant difference in PITS angle was found between patients with low- and high-grade instability. CONCLUSION: The main finding of the study was that reconstructed knees were overrepresented in knees with extremely low PITS angles. Additionally, patients injured in contact sports had higher PITS angles than those injured in non contact sports, and PITS angle did not influence knee laxity. PMID- 20963579 TI - Tuning of ventral premotor cortex neurons to distinct observed grasp types: a TMS priming study. AB - The ventral premotor cortex is known to be involved in the observation of others' actions. We tested the tuning properties of neuronal populations in the premotor cortex to distinct observed hand-object interactions with a transcranial magnetic stimulation (TMS)-priming protocol. Participants were asked to classify as "fast" or "slow" target pictures preceded by prime pictures both representing a spectrum of grasp types from precision grip (PG) to whole-hand grasp (WHG). Single TMS pulses time-locked to targets were delivered over the left ventral premotor (L PMv) and left dorsal premotor (L-PMd) cortices or as sham stimulation. Without TMS and with sham stimulation, a clear priming effect was observed as a shortening of reaction times and as a bias towards the priming grasp type in the classification responses. The perceptual advantage of priming was reversed by TMS over PMv but not over PMd. According to the TMS-priming paradigm, these results show that distinct neural populations in L-PMv but not in L-PMd are selectively tuned to different observed grasp types as PG or WHG. PMID- 20963580 TI - Tapping effects on numerical bisection. AB - Numerical magnitude is believed to be represented along a mental number line (MNL), and there is evidence to suggest that the activation of the MNL affects the perception and representation of external space. In the present study, we investigated whether a spatial motor task affects numerical processing in the auditory modality. Blindfolded participants were presented with a numerical interval bisection task, while performing a tapping task with either their left or right hand, either in the fronto-central, fronto-left, or fronto-right peripersonal space. Results showed that tapping significantly influenced the participants' numerical bisection, with tapping in the left side of space increasing the original tendency to err leftward, and tapping to the right reducing such bias. Importantly, the effect depended on the side of space in which the tapping activity was performed, regardless of which hand was used. Tapping with either the left or right hand in the fronto-central space did not affect the participants' bias. These findings offer novel support for the existence of bidirectional interactions between external and internal representations of space. PMID- 20963581 TI - Influence of previous target motion on anticipatory pursuit deceleration. AB - During visual pursuit of a moving target, expected changes in its trajectory often evoke anticipatory smooth pursuit responses. In the present study, we investigated characteristics of anticipatory smooth pursuit decelerations before a change or the end of a target trajectory. Healthy humans had to pursue with the eyes a target moving along a circular path that predictably or unpredictably reversed direction and then retraced its movement back to the starting position. We found that anticipatory eye decelerations were often evoked in temporal expectation of target reversal and of the end of the trajectory. The latency of anticipatory decelerations initiated before target reversal was variable, had poor temporal accuracy and depended on the history of previous trials. Anticipations of the end of the trajectory were more accurate, more precise and were not influenced by previous trials. In this case, subjects probably based their estimate of the end of the trajectory on the duration just experienced before target motion reversal. These results suggest that anticipatory eye decelerations are based on the characteristics of the current or preceding trials depending on the most reliable information available. PMID- 20963582 TI - Feeling good: on the role of C fiber mediated touch in interoception. AB - The human skin is innervated by a network of thin, slow-conducting afferent (C and Adelta) fibers, transmitting a diverse range of information. Classically, these fibers are described as thermo-, noci- or chemoreceptive, whereas mechanoreception is attributed exclusively to thick, fast-conducting (Abeta) afferents. A growing body of evidence, however, supports the notion that C tactile afferents comprise a second anatomically and functionally distinct system signaling touch in humans. This review discusses established as well as recent findings which highlight fundamental differences in peripheral and central information coding and processing between Abeta and C mechanoreception. We conclude that from the skin through the brain, C touch shares more characteristics with interoceptive modalities (e.g. pain, temperature, and itch) than exteroceptive Abeta touch, vision or hearing. In this light, we discuss the motivational-affective role of C touch as an integral part of a thin-fiber afferent homeostatic network for the maintenance of physical and social well being. PMID- 20963583 TI - Responses of salt marsh plant rhizosphere diazotroph assemblages to changes in marsh elevation, edaphic conditions and plant host species. AB - An important source of new nitrogen in salt marsh ecosystems is microbial diazotrophy (nitrogen fixation). The diazotroph assemblages associated with the rhizospheres (sediment directly affected by the roots) of salt marsh plants are highly diverse, somewhat stable, and consist mainly of novel organisms. In Crab Haul Creek Basin, North Inlet, SC, the distribution of plant types into discrete zones is dictated by relatively minor differences in marsh elevation and it was hypothesized that the biotic and abiotic properties of the plant zones would also dictate the composition of the rhizosphere diazotroph assemblages. Over a period of 1 year, rhizosphere sediments were collected from monotypic stands of the black needlerush, Juncus roemerianus, the common pickleweed, Salicornia virginica, the short and tall growth forms of the smooth cordgrass Spartina alterniflora, and a mixed zone of co-occurring S. virginica and short form, S. alterniflora. DNA was extracted, purified and nifH sequences PCR amplified for denaturing gradient gel electrophoresis (DGGE) analysis to determine the composition of the diazotroph assemblages. The diazotroph assemblages were strongly influenced by season, abiotic environmental parameters and plant host. Sediment chemistry and nitrogen fixation activity were also significantly influenced by seasonal changes. DGGE bands that significantly affected seasonal and zone specific clustering were identified and most of these sequences were from novel diazotrophs, unaffiliated with any previously described organisms. At least one third of the recovered nifH sequences were from a diverse assemblage of Chlorobia, and gamma-, alpha-, beta- and delta-Proteobacteria. Diazotrophs that occurred throughout the growing season and among all zones (frequently detected) were also mostly novel. These significant sequences indicated that diazotrophs driving the structure of the assemblages were diverse, versatile, and some were ubiquitous while others were seasonally responsive. Several ubiquitous sequences were closely related to sequences of actively N(2) fixing diazotrophs previously recovered from this system. These sequences from ubiquitous and versatile organisms likely indicate the diazotrophs in these rhizosphere assemblages that significantly contribute to ecosystem function. PMID- 20963584 TI - Inflammatory bowel disease: value in diagnosis and management of MDCT enteroclysis and 99mTc-HMPAO labeled leukocyte scintigraphy. AB - OBJECTIVES: The aims of this study are: (a) to evaluate the reliability of Multidetector Computed Tomography Enteroclysis (MDCT-E) and (99m)Tc-HMPAO labeled leukocyte scintigraphy (TLLS), in inflammatory bowel disease, (b) to test the accuracy of the two techniques with regard to their histological results, (c) to define how each technique can influence the natural course of inflammatory bowel disease (IBD), (d) to assess the potential value of the two techniques combined. MATERIALS AND METHODS: Thirty-seven patients with suspected IBD underwent MDCT-E and TLLS. We made a separate assessment of the results shown by the two methods and then compared and contrasted the histological results of the two. The latter, however, were either disappointing or not available in 15 patients who, for this reason, had to be dismissed from the study. As result, the number of participants eventually dropped to 22 subjects: 12 women, 10 men with an average age of 44 years. RESULTS: MDCT-E and TLLS were successful in all patients. Sensitivity, specificity, and efficiency values have been reported as follows: MDCT-E: 62%, 100%, 64%,100%, 11%, respectively. TLLS: 90%, 100%, 91%, 100%, 33%, respectively. The two methods combined: 95%, 100%, 95%, 100%, 50%, respectively. CONCLUSIONS: The two techniques can be employed in different stages of the natural course of the disease. In our experience, TLLS proved itself to be useful in the diagnosis of the disease and the assessment of its development. Conversely, MDCT-E proved itself to be more reliable in identifying the seat and the extent of the disease inside and outside the bowel wall as well as potential intra-peritoneal and extra intestinal complications. The combined use of the two methods represents the Criterion Standard for diagnosing IBD with imaging. PMID- 20963586 TI - Re: A time-saving technique for specimen extraction in sleeve gastrectomy. PMID- 20963587 TI - Immediate placement of a temporary covered stent for the management of iatrogenic malignant esophageal perforation. PMID- 20963588 TI - Reply to the article entitled "Emergency renal ablation for life-threatening hemorrhage from multiple capsular branches during renal artery stenting" by Aytekin et al. PMID- 20963589 TI - Single-institution results of image-guided nonplugged percutaneous versus transjugular liver biopsy. AB - PURPOSE: To retrospectively review patients who underwent transjugular and image guided percutaneous biopsy and compare the relative risk of ascites, thrombocytopenia, and coagulopathy. MATERIALS AND METHODS: From August 2001 through February 2006, a total of 238 liver biopsies were performed. The radiologist reviewed all patient referrals for transjugular biopsy. These patients either underwent transjugular biopsy or were reassigned to percutaneous biopsy (crossover group). Patients referred to percutaneous image-guided liver biopsy underwent this same procedure. Biopsies were considered successful if a tissue diagnosis could be made from the samples obtained. RESULTS: A total of 36 transjugular biopsies were performed with 3 total (8.3%) and 1 major (2.8%) complications. A total of 171 percutaneous biopsies were performed with 10 (5.8%) total and 3 (1.8%) major complications. The crossover group showed a total of 4 (12.9%) complications with 1 (3.2%) major complication. Sample adequacy was 91.9% for transjugular and 99.5% for percutaneous biopsy. CONCLUSION: Both transjugular and percutaneous liver biopsy techniques are efficacious and safe. Contraindications such as thrombocytopenia, coagulopathy, and ascites are indicators of greater complications but are not necessarily prevented by transjugular biopsy. Percutaneous biopsy more frequently yields a diagnostic specimen than transjugular biopsy. PMID- 20963591 TI - The role of the Major Histocompatibility Complex in the spread of contagious cancers. AB - Major Histocompatibility Complex (MHC) genes play a key role in immune response to infectious diseases, immunosurveillance, and self/nonself recognition. Matching MHC alleles is critical for organ transplantation, while changes in the MHC profile of tumour cells allow effective evasion of the immune response. Two unique cancers have exploited these features to become transmissible. In this review I discuss the functional role of MHC molecules in the emergence and evolution of Devil Facial Tumour Disease (DFTD) and Canine Transmissible Venereal Tumour (CTVT). High levels of genetic diversity at MHC genes play a critical role in protecting populations of vertebrate species from contagious cancer. However, species that have undergone genetic bottlenecks and have lost diversity at MHC genes are at risk of transmissible tumours. Moreover, evolution and selection for tumour variants capable of evading the immune response allow contagious cancers to cross MHC barriers. Transmissible cancers are rare but they can provide unique insights into the genetics and immunology of tumours and organ transplants. PMID- 20963592 TI - A missense mutation in LRR8 of RXFP2 is associated with cryptorchidism. AB - Using genome-wide mutagenesis with N-ethyl-N-nitrosourea (ENU), a mouse mutant with cryptorchidism was identified. Genome mapping and exon sequencing identified a novel missense mutation (D294G) in Relaxin/insulin-like family peptide receptor 2 (Rxfp2). The mutation impaired testicular descent and resulted in decreased testis weight in Rxfp2 ( DG/DG ) mice compared to Rxfp2 (+/DG ) and Rxfp2 (+/+) mice. Testicular histology of the Rxfp2 ( DG/DG ) mice revealed spermatogenic defects ranging from germ cell loss to tubules with Sertoli-cell-only features. Genetic complementation analysis using a loss-of-function allele (Rxfp2 (-)) confirmed causality of the D294G mutation. Specifically, mice with one of each mutant allele (Rxfp2 ( DG/-)) exhibited decreased testis weight and failure of the testes to descend compared to their Rxfp2 (+/-) littermates. Total and cell surface expression of mouse RXFP2 protein and intracellular cAMP accumulation were measured. Total expression of the D294G protein was minimally reduced compared to wild-type, but cell-surface expression was markedly decreased. When analyzed for cAMP accumulation, the EC50 was similar for cells transfected with wild-type and mutant RXFP2 receptor. However, the maximum cAMP response that the mutant receptor reached was greatly reduced compared to the wild-type receptor. In silico modeling of leucine rich repeats (LRRs) 7-9 indicated that aspartic acid 294 is located within the beta-pleated sheet of LRR8. We thus postulate that mutation of D294 results in protein misfolding and aberrant trafficking. The ENU induced D294G mutation underscores the role of the INSL3/RXFP2-mediated pathway in testicular descent and expands the repertoire of mutations known to affect receptor trafficking and function. PMID- 20963593 TI - Association of serum levels of arachidonic acid and eicosapentaenoic acid with prevalence of major adverse cardiac events after acute myocardial infarction. AB - We studied the association of serum levels of arachidonic acid (AA) and eicosapentaenoic acid (EPA) with the prevalence of major adverse cardiac events (MACE) after acute myocardial infarction (AMI). We measured serum AA and EPA on admission in 146 consecutive AMI patients. The primary clinical endpoint was occurrence of MACE, defined as cardiac death, occurrence of heart failure, reinfarction, recurrent angina pectoris, and requirement of coronary intervention. Common logarithmic transformed serum levels of AA (logAA) and EPA (logEPA) were used in the analyses. The optimum cutoff point of each fatty acid used to distribute patients into two groups for Kaplan-Meier analysis was determined by receiver operating characteristic curves analysis. MACE occurred in 40 patients (27.4%). Kaplan-Meier analysis disclosed that the group with a logAA above the cutoff point [145.3 MUg/mL (logAA 2.162)] showed a higher prevalence of MACE than those with a logAA below the cutoff point (P < 0.01). Conversely, the prevalence of MACE was significantly higher in the group with a logEPA below the cutoff point [52.3 MUg/mL (logEPA 1.719)] compared to the group with a logEPA above it (P < 0.01). Similar to logAA, logAA/logEPA showed significant differences in the MACE-free curve between the two groups (cutoff 1.301, P < 0.001). Cox proportional hazards regression analysis suggested that logAA, logEPA, and logAA/logEPA were independently associated with the prevalence of MACE. Although the present study included a limited number of patients with single-time point measurement, the results suggested an association of logAA, logEPA, and logAA/logEPA with the prevalence of MACE after AMI. The present study warrants further studies involving a large number of patients to confirm that the serum levels of these fatty acids and their ratios are predictors of MACE after AMI. PMID- 20963594 TI - Effect of mini-tyrosyl-tRNA synthetase/mini-tryptophanyl-tRNA synthetase on ischemic angiogenesis in rats: proliferation and migration of endothelial cells. AB - The purpose of this study was to determine the mechanism of mini-tyrosyl-tRNA synthetase/mini-tryptophanyl-tRNA synthetase (mini-TyrRS/mini-TrpRS) on ischemic angiogenesis in rats with acute myocardial infarction and proliferation, migration, potential signaling pathways of rat coronary venular endothelial cells (RCVECs). The effects of mini-TyrRS/mini-TrpRS on RCVECs proliferation were evaluated using the MTT colorimetric assay. Cell migration was assayed using a modified Boyden chamber technique. The potential involvement of Erk and PI3K signaling pathways was explored using selective chemical inhibitor or Western blot analysis. Left coronary artery ligation was used to establish the model of acute myocardial infarction in rats (Sprague-Dawley male rats, 200-250 g, 2-3 months old), 20 MUl of mini-TyrRS, mini-TrpRS, or PBS (vehicle) was injected subcutaneously every 12 h. The rats were randomly divided into four experimental groups: sham operated group; coronary artery ligation (CAL); CAL + mini-TyrRS (20 MUl, twice daily, 600 MUg kg(-1) day(-1)); and CAL + mini-TrpRS (20 MUl, twice daily, 600 MUg kg(-1) day(-1)). The experiment was carried out at four time points on the 3rd, 7th, 14th, and 28th day after ligation. To determine whether mini-TyrRS/mini-TrpRS affected the angiogenesis activity of rats with myocardial infarction, we measured the myocardial infarction size by TTC staining, and microvessel density (MVD) was determined by CD34 staining. The results show that proliferation and migration in RCVECs could be promoted by mini-TyrRS at concentrations of 1-100 MUg/ml, and inhibited by mini-TrpRS. Phospho-PI3-kinase and Erk expression increased significantly when mini-TyrRS was added, but could be attenuated by mini-TrpRS. Compared to the CAL group, the myocardial infarction size of the mini-TyrRS group at the 3rd, 7th, 14th, and 28th day were decreased, while mini-TrpRS increased, but only in days 14 and 28 was there a significant difference. Except that, the microvessel density of RCVECs was promoted in mini TyrRS group but inhibited in the mini-TrpRS group. These results indicated that angiogenesis could be either stimulated by mini-TyrRS or inhibited by mini-TrpRS. PMID- 20963595 TI - Percutaneous coronary intervention for unprotected left main disease in very high risk patients: safety of drug-eluting stents. AB - Percutaneous treatment of unprotected left main coronary artery (ULMCA) stenosis using drug-eluting stents (DES) has been suggested as the best approach for patients who are poor surgical candidates. Some concerns have recently been raised regarding the risk of stent thrombosis following DES implantation. This study was performed in order to evaluate the safety of DES, as compared to bare metal stents (BMS), for ULMCA stenosis treatment in very high risk patients with a high likelihood of stent thrombosis. Forty-two consecutive patients were treated with either BMS (20) or DES (22) for ULMCA critical stenosis. Inclusion criteria were: ST elevation myocardial infarction, non-ST elevation myocardial infarction, cardiogenic shock, or logistic European System for Cardiac Operative Risk Evaluation >= 13%. At 1 year, one case of late thrombosis and three cases of restenosis were reported in the BMS group and none in the DES group, leading to a significantly inferior rate of target lesion revascularization (20.0 vs. 0%, p = 0.048) and major adverse cardiac events (65.0 vs. 19%, p = 0.004). DES placement for ULMCA stenosis also appears to be a safe therapeutic choice in very high-risk patients, as it provides the benefit of a reduction in restenosis without increasing the risk of early or late stent thrombosis. PMID- 20963596 TI - Rapid ventricular pacing: a fast, reliable, and safe technique for optimization of image acquisition during rotational angiography for catheter ablation of atrial fibrillation. AB - Rotational angiography is a novel method for three-dimensional reconstruction of the left atrium and pulmonary veins during catheter ablation for atrial fibrillation, but is still hampered by suboptimal reconstructions in a considerable number of patients. We describe the results of rapid pacing of the right ventricle for optimization of image acquisition during rotational angiography. PMID- 20963597 TI - A porcine model of ischemic heart failure produced by intracoronary injection of ethyl alcohol. AB - We have developed a porcine model of acute myocardial infarction (AMI) and ischemic heart failure by transcatheter intracoronary injection of ethyl alcohol and observed pathologic changes induced in the alcohol-injured coronary artery and infarcted myocardium. In a total of 12 female pigs, anteroseptal AMI was induced by transcatheter delivery of 1 mL of 99.9% ethyl alcohol using a 2.5 mm diameter over-the-wire balloon catheter in the left anterior descending artery (LAD). Another five pigs underwent the sham operation, and the differences in left ventricular (LV) dimension and LV ejection fraction between these pigs and those injected with ethyl alcohol were evaluated. Follow-up coronary and LV angiography, echocardiography and histopathology were performed at 4 weeks after the procedure. Myocardial SPECT using (201)Tl (and (99m)Tc-MIBI) and triphenyl tetrazolium chloride (TTC) stain were performed and compared. Procedure-related death occurred in two pigs with proximal LAD occlusion. Four pigs suffered from ventricular tachycardia, which converted to sinus rhythm by DC cardioversion. Follow-up coronary angiography at 4 weeks revealed persistent total occlusion in all pigs. Echocardiogram showed decreased apicoanteroseptal wall motion with an ejection fraction of 46.5 +/- 3.3% and nonsignificantly changed LV dimensions. Myocardial SPECT revealed a perfusion defect in the apicoanterior wall in all subjects (percent area of the perfusion defect = 22.1 +/- 2.50%). The percentage of myocardium not stained by TTC was 23.1 +/- 2.25%. Histologic examination revealed severe fibrosis in the infarcted myocardium and massive thrombus with organization and calcification in the alcohol-injured coronary artery. The porcine model of AMI obtained by intracoronary alcohol injection provides a safe and reproducible method for the research and development of new therapeutic modalities for MI and end-stage heart failure. PMID- 20963598 TI - Adherence of hospital-based cardiologists to lipid guidelines in patients at high risk for cardiovascular events (2L registry). AB - OBJECTIVES: According to various national and international guidelines, the target LDL-C level is <100 mg/dl for patients with established coronary heart disease (CHD) or CHD risk equivalent (CE). We aimed to investigate aspects of the lipid-lowering management of patients at high cardiovascular risk in-hospital care and the achievement of target values. METHODS: In the internet-based 2L registry in Germany (2005-2006), cardiologists in 42 hospitals documented at a single visit 3,131 consecutive patients with known CHD, and/or diabetes mellitus, peripheral arterial disease, or a 10-year CHD risk >20% (summarized as CE), who were on chronic statin treatment. They received instructions on the guidelines and instant feedback on the effect of their treatment decisions (educational study component). RESULTS: The three groups comprised 1,458 patients with CHD + CE (46.6%; median LDL-C 107 mg/dl), 1,104 patients with CHD only (35.3%; median LDL-C 104 mg/dl), and 569 with CE only (18.2%; median LDL-C 111 mg/dl). At admission, LDL-C levels <100 mg/dl were observed in 43.1, 44.8 and 37.9% of patients in the three groups, respectively. Statin doses at admission were usually in the low to intermediate range (e.g., simvastatin 10-20 mg/day). Cardiologists switched to another statin in 14.6%, increased the dose of statins (if same drug) in 22.9% (mean increase from 26.8 mg/day at baseline to 31.6 mg/day) and/or added a cholesterol absorption inhibitor (CAI) in 11.6%. The cardiologists' intervention improved estimated LDL-C levels (using a lipid calculator); however, the 100 mg/dl LDL-C target was only reached in 49.0, 48.5, and 42.9%. CONCLUSIONS: When compared with earlier studies in the outpatient setting, the treatment to target for LDL-C of high-risk CHD patients has improved, but is not satisfactory. PMID- 20963599 TI - Vestibular-evoked myogenic potentials eliciting: an overview. AB - Recently, the favoured approach for unilateral testing of saccular function is the recently developed method of vestibular-evoked myogenic potentials (VEMPs). VEMP testing is a reliable technique, since it selectively stimulates and investigates each lateral canal in isolation from the other, providing information for the assessment of otolith function and inferior vestibular nerve integrity. The aim of this study was to provide a current review of the different methods used to record VEMPs. We noticed discrepancies in relation to the ways used to record the VEMPs in relation to the following factors: types of stimuli used (clicks or tone bursts) and body muscles tested, patient position at the time of recording, response, type of phone used and way of stimulus presentation (mono or binaural, ipsi or contralateral) and others. As a conclusion, despite the numerous studies in the field, there is no consensus in the literature as to the best recording method for VEMPs. However, the new ocular VEMPs in response to bone conducted vibration seem to be of clinical importance for the evaluation of utricular function. Further research is needed to support its clinical usefulness. PMID- 20963600 TI - Osteoprotegerin expression and sensitivity in otosclerosis with different histological activity. AB - Otosclerosis is a complex bone dystrophy of the human otic capsule leading to conductive and sensorineural hearing loss. Since otosclerosis may, at least in part, be considered as an autoimmune-inflammatory disease, disturbed balance of TNF-alpha and osteoprotegerin (OPG) expression has been implicated in the pathological bone remodeling. It has been supposed that active otosclerosis is characterized by decreased or missing local OPG production with invariable OPG sensitivity of the otosclerotic foci. Ankylotic stapes footplates (n = 41) removed by stapedectomy were processed to histological examination, OPG-specific RT-PCR, tissue culturing and alkaline-phosphatase (AP) activity assessment, respectively. OPG concentration of serum specimens (n = 41) was measured by ELISA. Cortical bone fragments harvested from the external ear canal were used as negative controls of otosclerosis. Among 41 ankylotic stapes footplates, 22 active and 19 inactive otosclerosis cases were histologically diagnosed. OPG expression was significantly lower (p < 0.001) in active otosclerosis compared to inactive cases. Osteoclast cultures originated from active otosclerotic foci showed a considerable susceptibility against external OPG dosage, which resulted in a significant decrease of AP activity (p < 0.001). In contrast, OPG serum levels were in the normal range (5-100 ng/ml) indicating a non-systemic bone resorption. In conclusion, secondary decreased local OPG production might play an important role in the pathogenesis of otosclerotic bone remodeling disorder. As to previous and current results, decreased OPG sensitivity of lesion-forming cells should be excluded. These observations may indicate the potential role of recombinant OPG treatment in early stages of otosclerosis. PMID- 20963601 TI - Laryngeal cancer and passive smoking: the neglected factor? AB - In the present paper we investigate the relationship of environmental tobacco smoke (ETS) exposure to laryngeal cancer. 209 patients who were diagnosed with laryngeal cancer from 2000 to 2009 at the University Hospital of Patras, Western Greece, were reviewed with regard to patient age, disease stage at presentation, tumor differentiation, tobacco product use, alcohol consumption, occupation, and ETS exposure in the working environment. Pearson Chi-square method was used to determine the effect of ETS exposure on cancer stage, TNM classification and tumor differentiation in the dichotomized population (exposed vs. not exposed) and in groups of low, medium and high ETS exposure. ETS exposure in the working environment was found to significantly affect overall disease stage and T stage (p < 0.01) both in the dichotomic analysis and the group analysis. Minor significance was also noted for N stage (p = 0.047) in the exposure group analysis. Our data suggest that occupational ETS exposure presents a contributing risk factor for laryngeal cancer that requires further research to determine its significance. PMID- 20963602 TI - Role of intra-operative ultrasound-guided reduction of nasal bone fracture in patient satisfaction and patient nasal profile (a randomized clinical trial). AB - The objective of this study was to evaluate the benefits of intra-operative ultrasonic guidance in the management of isolated nasal bone fractures. A prospective, randomized, controlled, double blinded study was designed. Sixty eight patients who had isolated fracture nose were treated by either a simple closed reduction or by ultrasound-guided reduction (34 patients each) with a follow up for an average of 4.5 and 5.5 months, respectively. Post-traumatic and post-reduction nasal profiles were compared (by blinded photographer), and patient's satisfaction was analyzed after reduction in both groups. We used Student's t test for independent groups to compare between the average patient's scores. The average patient's nasal profile score for closed reduction group was 2.31. Thirteen patients (40.6%) had scored 3, 16 (50%) had scored 2, and three (9.4%) patients had scored 1. The average patient's nasal profile score for ultrasonic assisted group was 2.72. Twenty-four patients (75%) had scored 3, 7 (22%) had scored 2, and one (3%) patient had scored 1. The average patient's satisfaction score for closed reduction was 2.62. Twenty-four patients (75%) had scored 3, 4 (12.5%) patients had scored 2, and 4 (12.5%) patients had scored 1. The average patient's satisfaction score for ultrasonic assisted group was 2.78. Twenty-six patients (81%) scored 3, 5 (16%) patients scored 2, and one (3%) patient scored 1. Patients undergoing ultrasonic nasal bone reduction scored significantly better nasal profile scores than patients undergoing simple closed reduction, on the other hand, patient satisfaction scores had no significant difference between both groups. Treating nasal bone fractures with the assistance of intra-operative ultrasound resulted in a significantly better nasal profile appearance, than treating it by simple closed reduction. PMID- 20963603 TI - The relation of cognitive load and pupillary unrest. AB - OBJECTIVE: This study examines the relationship between pupillary unrest (PU) and cognitive load. BACKGROUND: PU represents a measure of reduced central nervous tonic arousal (sleepiness). A loss of tonic arousal can be associated with difficulties in maintaining the required level of performance. Thus, the measurement of tonic arousal in occupational contexts can help to prevent overload or errors. METHOD: We compared a group with high cognitive load (30 apron controllers of an international airport) with a control group with low cognitive load (63 healthy people during their free time) in a non-randomized experimental design with pre- and post-test assessment of PU. PU was scanned by an infrared sensor with a frequency of 25 Hz and a resolution of .05 mm. To control for circadian effects, measurements for both groups were taken at the same time of the day. RESULTS: High PU at the start of the shift correlated with high perceived load during the shift. There were no indications of reverse effects. Analyses of group x time effects with generalized linear models (repeated measures) revealed that cognitive load did in no way affected PU. CONCLUSION: Initially low tonic arousal (indicated by high PU) may predict subsequent workload, but being exposed to high cognitive load does not influence tonic arousal after the end of the shift. With that, the study contributes to valid interpretations of pupillary unrest measurements in occupational contexts. PMID- 20963604 TI - Beryllium in urine by ICP-MS: a comparison of low level exposed workers and unexposed persons. AB - PURPOSE: To develop a sensitive and reproducible method for urinary beryllium and to use this method to establish levels in workers at an aluminium smelter and in unexposed persons. METHODS: A method was developed for urinary beryllium using a Thermo ICP-MS Series 1, which was used to determine beryllium concentrations in urine from 62 people with no known occupational exposure to beryllium and 167 workers with potential exposure to beryllium at an aluminium smelter, where beryllium exists as an impurity in the bauxite ore. RESULTS: The analytical method has a detection limit (based on three times the background equivalent concentration of the blank) for beryllium in urine of 6 ng/L. The mean and 90th percentiles of urinary beryllium for workers were 19.5 and 42.0 ng/L and compared with 11.6 and 20.0 ng/L in people not occupationally exposed to beryllium. Statistical analysis using mixed effects models showed that workers had 47% (in 135 paired samples) higher levels of urinary beryllium at the end of the working week compared to the start of week and that the workers who smoked also had significantly higher levels of urinary beryllium compared to those that did not smoke. There was also a statistically significant difference between workers and controls in urinary beryllium concentrations not corrected for creatinine. CONCLUSIONS: A sensitive and reliable analytical method was developed for urinary beryllium by ICP-MS. The workers in this study were exposed to beryllium at very low levels. PMID- 20963605 TI - A nested case-control study of low birthweight among cosmetologists. AB - OBJECTIVE: This study was designed to determine whether licensed female cosmetologists with a low birthweight child were more likely to perform specific occupational tasks during pregnancy than cosmetologists who had a normal weight child. We also investigated certain salon characteristics in relation to low birthweight status. METHODS: This nested case-control study followed-up a positive association of low birthweight children among cosmetologists found in a retrospective cohort study previously reported. Cases were cosmetologists with children born between 1997 and 2003 weighing <2,500 g, selected from the retrospective cohort study. Controls were cosmetologists with full-term children who weighed >2,500 grams at birth, frequency matched on year of birth of the child. A mailed questionnaire gathered information on potential confounders and detailed exposure information about work environment and occupational tasks of cosmetologists. Frequency of product use was dichotomized into daily/less than daily for each task. Number of hours worked per week was also considered. Birth certificate data were used for information on some potential confounders and birthweight. Using logistic regression, adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were obtained. RESULTS: A total of 125 (30%) cases and 158 (35%) controls agreed to participate. Responders and non-responders were similar on birthweight and most demographic characteristics. None of the specific cosmetology tasks studied were associated with low birthweight. Working in a salon located in a house/building with other businesses was associated with having a low birthweight child [OR = 2.20, 95% CI (1.21, 4.02)]. CONCLUSIONS: We did not find any associations between specific tasks of cosmetologists and low birthweight. PMID- 20963606 TI - An Arabidopsis senescence-associated protein SAG29 regulates cell viability under high salinity. AB - The plasma membrane is an important cellular organ that perceives incoming developmental and environmental signals and integrates these signals into cellular regulatory mechanisms. It also acts as a barrier against unfavorable extracellular factors to maintain cell viability. Despite its importance for cell viability, molecular components determining cell viability and underlying mechanisms are largely unknown. Here, we show that a plasma membrane-localized MtN3 protein SAG29 regulates cell viability under high salinity in Arabidopsis. The SAG29 gene is expressed primarily in senescing plant tissues. It is induced by osmotic stresses via an abscisic acid-dependent pathway. Whereas the SAG29 overexpressing transgenic plants (35S:SAG29) exhibited an accelerated senescence and were hypersensitive to salt stress, the SAG29-deficient mutants were less sensitive to high salinity. Consistent with this, the 35S:SAG29 transgenic plants showed reduced cell viability in the roots under normal growth condition. In contrast, cell viability in the SAG29-deficient mutant roots was indistinguishable from that in the roots of control plants. Notably, the mutant roots exhibited enhanced cell viability under high salinity. Our observations indicate that the senescence-associated SAG29 protein is associated with cell viability under high salinity and other osmotic stress conditions. We propose that the SAG29 protein may serve as a molecular link that integrates environmental stress responses into senescing process. PMID- 20963607 TI - Molecular and functional analyses of rice NHX-type Na+/H+ antiporter genes. AB - We previously cloned a vacuolar Na+/H+ antiporter gene (OsNHX1) from rice (Oryza sativa). Here we identified four additional NHX-type antiporter genes in rice (OsNHX2 through OsNHX5) and performed molecular and functional analyses of those genes. The exon-intron structure of the OsNHX genes and the phylogenetic tree of the OsNHX proteins suggest that the OsNHX proteins are categorized into two subgroups (OsNHX1 through OsNHX4 and OsNHX5). OsNHX1, OsNHX2, OsNHX3, and OsNHX5 can suppress the Na+, Li+, and hygromycin sensitivity of yeast nhx1 mutants and their sensitivity to a high K+ concentration. The expression of OsNHX1, OsNHX2, OsNHX3, and OsNHX5 is regulated differently in rice tissues and is increased by salt stress, hyperosmotic stress, and ABA. When we studied the expression of beta glucuronidase (GUS) driven by either the OsNHX1 or the OsNHX5 promoter, we observed activity in the stele, the emerging part of lateral roots, the vascular bundle, the water pore, and the basal part of seedling shoots with both promoters. In addition, each promoter had a unique expression pattern. OsNHX1 promoter-GUS activity only was localized to the guard cells and trichome, whereas OsNHX5 promoter-GUS activity only was localized to the root tip and pollen grains. Our results suggest that the members of this gene family play important roles in the compartmentalization into vacuoles of the Na+ and K+ that accumulate in the cytoplasm and that the differential regulation of antiporter gene expression in different rice tissues may be an important factor determining salt tolerance in rice. PMID- 20963608 TI - Conservation of a rare plant requires different methods in different habitats: demographic lessons from Actaea elata. AB - Understanding species decline and conserving endangered species requires demographic information, and variation in the environment may affect demography. Actaea elata is a globally rare, perennial herb found in a range of Pacific Northwest forest stand types that differ in canopy openness. Canopy openness increases reproductive output in this species and so was expected to have demographic impact. We performed a demographic analysis of A. elata in contrasting forest stands (broadleaved vs. coniferous) over two annual intervals, and predicted that population growth rate would be higher in the open-canopy broadleaved stand. Population growth was determined using stage-based matrix models, and the most influential transitions were identified using elasticity analyses. The finite rate of population increase (lambda) was lower for the two transition periods at the broadleaved stand than at the coniferous stand (lambda = 0.86 and 0.87 vs. 0.94 and 0.98), even though the former population was more fecund. The decline in the broadleaved stand reflects greater mortality and retrogression to previous stages, partly as a consequence of herbivory. In contrast, lower recruitment occurred in the coniferous stand, but there was also less mortality and retrogression. Our results suggest that management decisions for conservation of A. elata should be tailored to differing habitats, with a focus on preventing mortality in some populations and increasing recruitment in others. PMID- 20963609 TI - A test of the niche dimension hypothesis in an arid annual grassland. AB - The niche dimension hypothesis predicts that greater numbers of limiting factors can allow greater numbers of species to coexist through species' tradeoffs for different limiting factors. A prediction that follows is that addition of multiple limiting resources to plant communities will increase productivity and simultaneously decrease diversity. Species loss due to limiting resource enrichment might occur through reducing the number of resources that species compete for or by changing the identity of limiting factors. We tested these predictions of the niche dimension hypothesis in an arid annual grassland by adding combinations of nutrients: nitrogen (N), phosphorus (P), and potassium with other elements (O). We found that species number decreased while biomass increased with greater numbers of added resources. In particular, N in combinations with P or O resulted in the greatest species loss, while biomass increased super-additively with N and P together. The addition of greater numbers of added nutrients decreased the availability of light and soil moisture, consistent with a potential shift in the identity of limiting resources. Species also differed in their responses to different combinations of N, P, and O, supporting predictions of resource-ratio tradeoffs. These results are particularly notable because this experiment was conducted during a drought year in an arid grassland (226 mm annual rainfall), which might have been expected to be water-rather than nutrient-limited. Our results support the hypothesis that plant diversity may be maintained by high-dimensional tradeoffs among species in their abilities to compete for multiple limiting factors. PMID- 20963610 TI - Extreme longevity in trees: live slow, die old? AB - We have examined the extreme longevity displayed by trees in relation to a theory mainly developed in animals, namely, the controversial rate of living (ROL) theory of aging which proposes that longevity is negatively correlated to metabolic rate. Plant metabolism implies respiration and photosynthesis; both are susceptible to negatively impact longevity. The relationship between longevity and metabolism was studied in leaves and stems of several species with the aim of challenging the ROL theory in trees. Leaf and stem life spans were found to be highly correlated to metabolism (R(2) = 0.97), and stems displayed a much lower metabolism than leaves. Analysis of covariance (ANCOVA), with metabolism as the covariate, revealed no difference between mean leaf and stem life spans, which would appear to conform to the expectations of the ROL theory. Consequently, the extremely high longevity of trees may be explained by the lower metabolism displayed by the stems. These results clearly reflect different energy allocation and energy expenditure rate strategies between leaves and stems, which may result in different senescence rates (and life spans) in these organs. They also suggest that, in contrast to animals, the ROL theory of aging may apply to woody plants at the organ level, thereby opening a promising new line of research to guide future studies on plant senescence. PMID- 20963611 TI - Predicting tropical plant physiology from leaf and canopy spectroscopy. AB - A broad regional understanding of tropical forest leaf photosynthesis has long been a goal for tropical forest ecologists, but it has remained elusive due to difficult canopy access and high species diversity. Here we develop an empirical model to predict sunlit, light-saturated, tropical leaf photosynthesis using leaf and simulated canopy spectra. To develop this model, we used partial least squares (PLS) analysis on three tropical forest datasets (159 species), two in Hawaii and one at the biosphere 2 laboratory (B2L). For each species, we measured light-saturated photosynthesis (A), light and CO(2) saturated photosynthesis (A(max)), respiration (R), leaf transmittance and reflectance spectra (400-2,500 nm), leaf nitrogen, chlorophyll a and b, carotenoids, and leaf mass per area (LMA). The model best predicted A [r(2) = 0.74, root mean square error (RMSE) = 2.9 MUmol m(-2) s(-1))] followed by R (r(2) = 0.48), and A(max) (r(2) = 0.47). We combined leaf reflectance and transmittance with a canopy radiative transfer model to simulate top-of-canopy reflectance and found that canopy spectra are a better predictor of A (RMSE = 2.5 +/- 0.07 MUmol m(-2) s(-1)) than are leaf spectra. The results indicate the potential for this technique to be used with high-fidelity imaging spectrometers to remotely sense tropical forest canopy photosynthesis. PMID- 20963612 TI - [Analgesic therapy of calciphylaxis with levomethadone : a case study]. AB - Calciphylaxis, or calcific uremic arteriopathy, is a rare complication of end stage renal impairment. It is characterized by calcification of arterioles and development of intensely painful subcutaneous ischemic ulcerations. While symptomatic management is the mainstay of treatment, particular emphasis is placed on adequate analgesia. Conventional analgesic concepts have mostly proved to be insufficient which increases the extreme suffering of patients. This case report describes the successful analgesic treatment of calciphylaxis with levomethadone. PMID- 20963613 TI - Completion of the full-length genome sequence of human parainfluenza virus types 4A and 4B: sequence analysis of the large protein genes and gene start, intergenic and end sequences. AB - We have already reported the nucleotide sequences of the NP, P/V, M, F and HN genes of human parainfluenza virus type 4A (hPIV-4A) and type 4B (hPIV-4B). Here, we have determined the sequences of the L protein genes as well as the gene start, intergenic and end sequences, thereby completing the full-length genome sequence of hPIV-4A and 4B. hPIV-4A and 4B have 17,052 and 17,304 nucleotides, respectively. The end sequence of hPIV-4, especially 4B, was extraordinarily long. In a comparison with members of the genus Rubulavirus, the hPIV-4 L proteins were closely related to those of mumps virus (MUV) and hPIV-2, less closely related to those of Menangle virus and Tioman virus, and more distantly related to those of Mapuera virus and porcine rubulavirus. PMID- 20963614 TI - Clostridium perfringens bacteriophages PhiCP39O and PhiCP26F: genomic organization and proteomic analysis of the virions. AB - Poultry intestinal material, sewage and poultry processing drainage water were screened for virulent Clostridium perfringens bacteriophages. Viruses isolated from broiler chicken offal washes (O) and poultry feces (F), designated PhiCP39O and PhiCP26F, respectively, produced clear plaques on host strains. Both bacteriophages had isometric heads of 57 nm in diameter with 100-nm non contractile tails characteristic of members of the family Siphoviridae in the order Caudovirales. The double-strand DNA genome of bacteriophage PhiCP39O was 38,753 base pairs (bp), while the PhiCP26F genome was 39,188 bp, with an average GC content of 30.3%. Both viral genomes contained 62 potential open reading frames (ORFs) predicted to be encoded on one strand. Among the ORFs, 29 predicted proteins had no known similarity while others encoded putative bacteriophage capsid components such as a pre-neck/appendage, tail, tape measure and portal proteins. Other genes encoded a predicted DNA primase, single-strand DNA-binding protein, terminase, thymidylate synthase and a transcription factor. Potential lytic enzymes such as a fibronectin-binding autolysin, an amidase/hydrolase and a holin were encoded in the viral genomes. Several ORFs encoded proteins that gave BLASTP matches with proteins from Clostridium spp. and other Gram-positive bacterial and bacteriophage genomes as well as unknown putative Collinsella aerofaciens proteins. Proteomics analysis of the purified viruses resulted in the identification of the putative pre-neck/appendage protein and a minor structural protein encoded by large open reading frames. Variants of the portal protein were identified, and several mycobacteriophage gp6-like protein variants were detected in large amounts relative to other virion proteins. The predicted amino acid sequences of the pre-neck/appendage proteins had major differences in the central portion of the protein between the two phage gene products. Based on phylogenetic analysis of the large terminase protein, these phages are predicted to be pac type, using a head-full DNA packaging strategy. PMID- 20963615 TI - Artefacts induced on c-type haem proteins by electrode surfaces. AB - In this work it is demonstrated that the characterization of c-type haem containing proteins by electrochemical techniques needs to be cautiously performed when using pyrolytic graphite electrodes. An altered form of the cytochromes, which has a redox potential 300 mV lower than that of the native state and displays peroxidatic activity, can be induced by interaction with the pyrolytic graphite electrode. Proper control experiments need to be performed, as altered conformations of the enzymes containing c-type haems can show activity towards the enzyme substrate. The work was focused on the study of the activation mechanism and catalytic activity of cytochrome c peroxidase from Paracoccus pantotrophus. The results could only be interpreted with the assignment of the observed non-turnover and catalytic signals to a non-native conformation state of the electron-transferring haem. The same phenomenon was detected for Met-His monohaem cytochromes (mitochondrial cytochrome c and Desulfovibrio vulgaris cytochrome c-553), as well as for the bis-His multihaem cytochrome c(3) from Desulfovibrio gigas, showing that this effect is independent of the axial coordination of the c-type haem protein. Thus, the interpretation of electrochemical signals of c-type (multi)haem proteins at pyrolytic graphite electrodes must be carefully performed, to avoid misassignment of the signals and incorrect interpretation of catalytic intermediates. PMID- 20963616 TI - Metalloporphyrin intercalation in liposome membranes: ESR study. AB - Liposomes characterized by membranes featuring diverse fluidity (liquid crystalline and/or gel phase), prepared from egg yolk lecithin (EYL) and dipalmitoylphosphatidylcholine (DPPC), were doped with selected metalloporphyrins and the time-related structural and dynamic changes within the lipid double layer were investigated. Porphyrin complexes of Mg(II), Mn(III), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), and the metal-free base were embedded into the particular liposome systems and tested for 350 h at 24 degrees C using the electron spin resonance (ESR) spin probe technique. 5-DOXYL, 12-DOXYL, and 16-DOXYL stearic acid methyl ester spin labels were applied to explore the interior of the lipid bilayer. Only the 16-DOXYL spin probe detected evident structural changes inside the lipid system due to porphyrin intercalation. Fluidity of the lipid system and the type of the porphyrin complex introduced significantly affected the intermolecular interactions, which in certain cases may result in self-assembly of metalloporphyrin molecules within the liposome membrane, reflected in the presence of new lines in the relevant ESR spectra. The most pronounced time related effects were demonstrated by the EYL liposomes (liquid-crystalline phase) when doped with Mg and Co porphyrins, whereas practically no spectral changes were revealed for the metal-free base and both the Ni and Zn dopants. ESR spectra of the porphyrin-doped gel phase of DPPC liposomes did not show any extra lines; however, they indicated the formation of a more rigid lipid medium. Electronic configuration of the porphyrin's metal center appeared crucial to the degree of molecular reorganization within the phospholipid bilayer system. PMID- 20963617 TI - Direct biliopancreatoduodenal invasion by hepatocellular carcinoma: report of the first resected case and review of the literature. AB - A rare resected case of hepatocellular carcinoma (HCC) invading the duodenum, the common bile duct (CBD), the gallbladder, and the pancreas is described. A 63-year old man presented with a painful upper abdominal mass. Radiologic findings showed a 25-cm liver tumor arising from segment IV with an invasive extension to the hepatoduodenal ligament and pancreatoduodenal region, with a single intrahepatic metastasis. The patient successfully underwent a left hepatectomy in conjunction with a pylorus-preserving pancreatoduodenectomy (PD). As an unusual procedure, liver parenchymal transection was followed by PD to explore tumor resectability, because the overhanging liver mass precluded full hepatoduodenal ligament dissection. He was discharged without surgical complications, being free from antianalgesics, which had been used preoperatively. The main tumor was histologically diagnosed to be a poorly differentiated HCC with sarcomatous change invading the duodenum, the CBD, the gallbladder, and the pancreas. Unfortunately, aggressive hepatic and nodal recurrence, which was resistant to salvage chemotherapy, caused the patient's death at 8 months postoperatively. This is the first documented case of HCC with biliopancreatoduodenal invasion resected by hepatopancreatoduodenectomy. Literature review suggests a significant role of resection in selected patients with HCC with contiguous gastrointestinal tract invasion, particularly when the HCCs are naive without any forms of previous treatment. However, further surgical and nonsurgical experience is necessary to determine the oncological validity of aggressive surgery for HCC invading the biliopancreatoduodenal region. PMID- 20963623 TI - The orthotropic viscoelastic behavior of aortic elastin. AB - In this paper, we studied the viscoelastic behaviors of isolated aortic elastin using combined modeling and experimental approaches. Biaxial stress relaxation and creep experiments were performed to study the time-dependent behavior of elastin. Experimental results reveal that stress relaxation preconditioning is necessary in order to obtain repeatable stress relaxation responses. Elastin exhibits less stress relaxation than intact or decellularized aorta. The rate of stress relaxation of intact and decellularized aorta is linearly dependent on the initial stress levels. The rate of stress relaxation for elastin increases linearly at stress levels below about 60 kPa; however, the rate changes very slightly at higher initial stress levels. Experimental results also show that creep response is negligible for elastin, and the intact or decellularized aorta. A quasi-linear viscoelasticity model was incorporated into a statistical mechanics based eight-chain microstructural model at the fiber level to simulate the orthotropic viscoelastic behavior of elastin. A user material subroutine was developed for finite element analysis. Results demonstrate that this model is suitable to capture both the orthotropic hyperelasticity and viscoelasticity of elastin. PMID- 20963618 TI - Tumor-infiltrating lymphocytes and hepatocellular carcinoma: pathology and clinical management. AB - The presence of tumor-infiltrating lymphocytes (TILs) in hepatocellular carcinoma (HCC) is relatively rare. The prognosis of patients with HCC and marked TILs is better than that of patients with HCC without TILs. TILs in HCC tissues are mainly T cells, and previous reports suggested that TILs might be important antitumor effector cells. TILs have been extensively analyzed, and subpopulations of CD3(+), CD4(+), and CD8(+) T cells are often present in HCC. Some studies have reported that the percentage of CD8(+) T cells, which might have cytotoxic activity, is decreased in tumors with TILs, as compared with noncancerous tissues. Although the antitumor effects of TILs seem to be impaired in HCCs, the underlying mechanism has remained unclear until quite recently. Pathological and in vitro studies have now shown that regulatory T cells play important roles in the deterioration of the antitumor effects of TILs. The aim of this review is to introduce recent pathological findings for TILs in HCC and to evaluate new therapeutic strategies in this field. PMID- 20963624 TI - beta-1,4-Galactosyltransferase-involved in lipopolysaccharide-induced adhesion of Schwann cells. AB - OBJECTIVE AND DESIGN: The carbohydrate moieties of glycoprotein are associated with some inflammatory diseases by affecting a wide range of biological functions of cells. This study aimed to investigate the role of beta-1,4 galactosyltransferase-I (beta-1,4-GalT-I) in adhesion of Schwann cells during inflammation. SUBJECTS: A rat Schwann cell line, RSC 96 was used. METHODS: We used western blotting to detect the expression of beta-1,4-GalT-I. Flow cytomety was used to measure the galactosylation of glycoproteins on cell surfaces. Immunofluorescent staining was used to examine the expression of alpha6 integrin, focal adhesion kinase (FAK) and F-actin. Tyrosine phosphorylation of FAK was detected by immunoprecipitation. An adhesion assay was performed to investigate the adhesion of Schwann cells. One-way ANOVA was used to compare differences between the operated and the control group. RESULTS: Schwann cell adhesion was induced by LPS stimulation and was accompanied by upregulation of beta-1,4-GalT-I expression and galactosylation of glycoproteins. There was a change of localization of FAK and cytoskeleton organization in LPS treated cells compared with control cells. The pretreated cells enhanced tyrosine phosphorylation of FAK compared with control cells in the adhesion process. With the increased cell surface expression of alpha6 integrin and beta-1,4-GalT-I, the adhesion of Schwann cells on laminin was increased as well. CONCLUSIONS: These results suggested that beta-1,4-GalT-I may play an important role in adhesion of Schwann cells during inflammation. PMID- 20963625 TI - Myocardial NOS activity and connexin-43 expression in untreated and omega-3 fatty acids-treated spontaneously hypertensive and hereditary hypertriglyceridemic rats. AB - The purpose of this study is to investigate myocardial nitric oxide synthase (NOS) activity and connexin-43 (Cx43) expression in young and old spontaneously hypertensive rats (SHR), adult hereditary hypertriglyceridemic (HTG) rats, and age-matched healthy rats without and with omega-3 PUFA supplementation for 2 months. Results showed that comparing to healthy rats the myocardial NOS activity was significantly increased in young SHR (8.2 +/- 1.16 vs. 1.37 +/- 0.67 pmol/min/mg) as well as old SHR (3.21 +/- 0.75 vs. 2.22 +/- 0.56 pmol/min/mg) and to much lesser extent in HTG rats, i.e., 1.87 +/- 0.42 vs. 1.34 +/- 0.1 pmol/min/mg. In parallel, there was a significant decline of total and phosphorylated forms of Cx43 in both groups of SHR while not in HTG rat hearts in which phosphorylated form of Cx43 was increased. Elevated NOS activity was suppressed (P < 0.05) in young and old SHR supplemented with omega-3 PUFA and it was associated with up-regulation of Cx43. In contrast to SHR, elevation of NOS activity in HTG rat hearts was not affected by treatment with omega-3 PUFA. However, increase of phosphorylated form of Cx43 was suppressed. In conclusion, there is an inverse relationship between myocardial NOS activity and Cx43 expression in SHR while not HTG rat hearts and omega-3 PUFA modulate both NOS activity and Cx43 expression. Whether over-expression of inducible NOS might account for down-regulation of myocardial Cx43 and whether its up-regulation is associated with an increase of endothelial NOS should be explored in further study. PMID- 20963626 TI - Nobiletin, a citrus flavonoid, suppresses invasion and migration involving FAK/PI3K/Akt and small GTPase signals in human gastric adenocarcinoma AGS cells. AB - Nobiletin, a compound isolated from citrus fruits, is a polymethoxylated flavone derivative shown to have anti-inflammatory, antitumor, and neuroprotective properties. This study has investigated that nobiletin exerted inhibitory effects on the cell adhesion, invasion, and migration abilities of a highly metastatic AGS cells under non-cytotoxic concentrations. Data also showed nobiletin could inhibit the activation of focal adhesion kinase (FAK) and phosphoinositide-3 kinase/Akt (PI3K/Akt) involved in the downregulation of the enzyme activities, protein expressions, messenger RNA levels of matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-2 (MMP-9). Also, our data revealed that nobiletin inhibited FAK/PI3K/Akt with concurrent reduction in the protein expressions of Ras, c-Raf, Rac-1, Cdc42, and RhoA by western blotting, whereas the protein level of RhoB increased progressively. Otherwise, nobiletin-treated AGS cells showed tremendously decreased in the phosphorylation and degradation of inhibitor of kappaBalpha (IkappaBalpha), the nuclear level of NF-kappaB, and the binding ability of NF-kappaB to NF-kappaB response element. Furthermore, nobiletin significantly decreased the levels of phospho-Akt and MMP-2/9 in Akt1-cDNA transfected cells concomitantly with a marked reduction in cell invasion and migration. These results suggest that nobiletin can reduce invasion and migration of AGS cells, and such a characteristic may be of great value in the development of a potential cancer therapy. PMID- 20963627 TI - Links between cyclosporin exposure in tissues and graft-versus-host disease in pediatric bone marrow transplantation: analysis by a PBPK model. AB - PURPOSE: In hematopoietic stem cell transplantation (HSCT), cyclosporin is used to prevent graft-versus-host disease (GVHD). However, cyclosporin distribution in tissues is not linear, resulting in uncertainty regarding optimal dosing and monitoring. The objective of this study was to link the probability and severity of acute GVHD to cyclosporin exposure in blood, GVHD target organs, and lymphoid organs. METHODS: A physiologically based pharmacokinetic model of cyclosporin disposition and logistic regression models were used. Sixty-one pediatric patients undergoing HSCT were studied. Cyclosporin was administered by intermittent (n = 31) or continuous infusion (n = 30). RESULTS: At steady state (1 day before acute GVHD), exposures in all organs were related with the probability and severity of acute GVHD. Average cyclosporin concentration or, equivalently, its area under the curve (AUC) was the pharmacokinetic index best correlated with the anti-GVHD effect. Cyclosporin AUC in interstitial fluid of lymphoid organs was a superior index than that in blood, but marginally. CONCLUSION: Hence, AUC in blood maybe used as an index of cyclosporin efficacy. Using our model, target AUCs in blood could be defined for malignant and non malignant diseases, as well as the equivalent target values for C(2) and C(0) concentrations. PMID- 20963628 TI - Convection and retro-convection enhanced delivery: some theoretical considerations related to drug targeting. AB - Delivery of drugs and macromolecules into the brain is a challenging problem, due in part to the blood-brain barrier. In this article, we focus on the possibilities and limitations of two infusion techniques devised to bypass the blood-brain barrier: convection enhanced delivery (CED) and retro-convection enhanced delivery (R-CED). CED infuses fluid directly into the interstitial space of brain or tumor, whereas R-CED removes fluid from the interstitial space, which results in the transfer of drugs from the vascular compartment into the brain or tumor. Both techniques have shown promising results for the delivery of drugs into large volumes of tissue. Theoretical approaches of varying complexity have been developed to better understand and predict brain interstitial pressures and drug distribution for these techniques. These theoretical models of flow and diffusion can only be solved explicitly in simple geometries, and spherical symmetry is usually assumed for CED, while axial symmetry has been assumed for R CED. This perspective summarizes features of these models and provides physical arguments and numerical simulations to support the notion that spherical symmetry is a reasonable approximation for modeling CED and R-CED. We also explore the potential of multi-catheter arrays for delivering and compartmentalizing drugs using CED and R-CED. PMID- 20963629 TI - Predicting the effect of fed-state intestinal contents on drug dissolution. AB - PURPOSE: There are several endogenous and exogenous species in the gastrointestinal (GI) tract which can act as solubilizing agents and thereby affect drug dissolution. The purpose of this study is to understand food effects on drug dissolution and provide insight into their anticipated overall effect on absorption and bioavailability. METHODS: Dissolution kinetics of 15 drugs of variable logP, charge, and molecular weight were tested in simulated intestinal environment. The ability of a film-equilibrium-based model to predict the influence of a simulated intestinal environment on drug dissolution was examined. RESULTS: The most significant improvement in dissolution kinetics and solubility (up to 6-fold) was evident with highly hydrophobic compounds (logP > 4). Improvement in solubility did not always constitute improvement in dissolution kinetics on a relevant time scale. Comparison of simulation and experimental results indicates that a model considering micelle partitioning as a pseudo equilibrium process can predict trends in the influence of food-related solubilizing agents on drug dissolution kinetics. CONCLUSIONS: The significance of food-related solubilizing agents to drug dissolution is not always obvious, as it depends on multiple physicochemical parameters; however, simple modeling may provide insight into food effects on dissolution and, ultimately, overall absorption and bioavailability of compounds considered for oral formulation. PMID- 20963630 TI - Do social support, stress, disclosure and stigma influence retention in HIV care for Latino and African American men who have sex with men and women? AB - Limited research has examined the role that social support, stress, stigma and HIV disclosure play in retention in HIV care for African Americans and Latinos. Among 398 Latino and African American men who have sex with men (MSM) and women, the major predictor of retention in HIV care was disclosure of HIV status to more social network members (OR = 1.5; 95% CI: 1.1, 1.9). Among those who had disclosed (n = 334), female gender (OR = 1.8, 95% CI: 1.1, 3.1) and disclosure of HIV status to more network members (OR = 1.5, 95% CI: 1.1, 1.9) was associated with retention in HIV care. General stress was associated with retention in care (OR = 1.2; 95% CI: 1.1, 1.3) for African American MSM who had disclosed. More MSM stigma was associated with poorer retention (OR = 0.9; 95% CI: 0.8, 0.9) for Latino MSM. Interventions that help patients safely disclose their HIV status to more social network members may improve HIV care retention as would social network counseling for Latino MSM to reduce MSM-stigma. PMID- 20963631 TI - Genetic structure of brown trout (Salmo trutta) populations from Turkey based on microsatellite data. AB - This present study investigated micro- and macro-geographic microsatellite DNA variations using five polymorphic microsatellite loci from 27 brown trout populations in Turkey. Average number of alleles and average observed heterozygosity were 7.4 and 0.254, respectively. Even populations from the same sea basin and river system (the so called micro-geographic regions) had unique alleles. Genetic variation among the populations from macro-geographic regions (different sea basins and river systems) was 45.78%. The mtDNA lineages of brown trout that have previously been identified by mtDNA analyses were supported by the analysis of the microsatellite DNA data in general. The Catak population, which belongs to the Tigris lineage, was clustered together with the Euphrates populations within the Adriatic mtDNA lineage, based on microsatellite data. Both mitochondrial and microsatellite DNA analyses have made it possible to determine a secondary contact between Adriatic and Tigris lineages. PMID- 20963632 TI - Plasma cortisol and hypothalamic monoamine responses in yellow perch Perca flavescens after intraperitoneal injection of lipopolysaccharide. AB - The concentrations of monoamines in the hypothalamus were determined in yellow perch Perca flavescens before and after injection with lipopolysaccharide (LPS; 3 mg kg-1 fish weight) or saline to test for the presence of neurochemical changes potentially associated with changes in plasma cortisol characteristic of intraperitoneal (ip) challenge with LPS. In the first experiment, yellow perch were injected with saline or LPS and the hypothalamus removed and plasma sampled before and at 0.5, 1.5, 3.0, and 6 h after injection. Plasma cortisol was elevated in both saline- and LPS-injected fish through 1.5 h after injection and returned to levels resembling pre-injection by 3 h after injection. Significantly higher amounts of cortisol in plasma from LPS-injected relative to saline injected fish were observed 6 h following injection. A significant decrease relative to levels observed 0.5-3 h after handling was observed in serotonin concentrations at 6 h following LPS and saline injection with a concomitant increase in the ratio of 5-hydroxyindoleacetic acid:serotonin. In the second experiment, hypothalamic monoamines were sampled before and at 3, 6, 9, 12, and 24 h after injection with LPS or saline. Significant increases from pre-injection levels were observed in the ratio 5-hydroxyindoleacetic acid:serotonin at 9, 12, and 24 h after injection, but no differences were detected between LPS- and saline-injected fish. These results support a model linking serotonergic system activation following handling stress, but no correlations with the sustained elevations of plasma cortisol associated with inflammatory challenge were observed. PMID- 20963633 TI - Genetic analysis for growth traits of prolific Garole * Malpura (GM) sheep. AB - The FecB gene of Garole sheep was introgressed into non-prolific Malpura sheep to evolve a new prolific sheep strain Garole * Malpura (GM), suitable for semi-arid conditions. The present study was conducted to evaluate the impact of breeding program on production profile of GM sheep and to estimate the genetic parameters for growth traits of GM sheep. Overall prolificacy increased significantly in the new strain as compared to the native Malpura sheep. In the GM flock of F2 and F2 onwards generation 35.31% single, 55.83% twins, 8.16% triplet and 0.70% quadruplets were obtained during lambing. Over the years, prolificacy in the flock has increased significantly. Over all least squares means for birth weight, 3, 6, 9, 12 month weight, pre-weaning gain (ADG1) and post-weaning gain (ADG2) were 1.82 +/- 0.03, 9.44 +/- 0.18, 14.00 +/- 0.24, 16.56 +/- 0.33, and 19.32 +/- 0.35 kg, and 84.08 +/- 1.84 and 35.19 +/- 0.99 g, respectively. Majority of the fixed effects had significant influence on the performance traits. The heritability estimates for birth, 3, 6, 9, 12 month weight, ADG1 and ADG2 were 0.30 +/- 0.11, 0.22 +/- 0.09, 0.23 +/- 0.10, 0.27 +/- 0.10, 0.30 +/- 0.11, 0.17 +/- 0.08, and 0.17 +/- 0.10, respectively. Modest rate of genetic progress seems possible for these traits under selection. The genetic and phenotypic correlations among different body weights were moderate to high and positive. The genetic correlation of pre and post-weaning daily gains with body weight traits were also high and positive. PMID- 20963634 TI - Evaluation of three brands of drug interaction software for use in intensive care units. AB - OBJECTIVE: To evaluate drug interaction software programs and determine their accuracy in identifying drug-drug interactions that may occur in intensive care units. Setting The study was developed in Brazil. METHOD: Drug interaction software programs were identified through a bibliographic search in PUBMED and in LILACS (database related to the health sciences published in Latin American and Caribbean countries). The programs' sensitivity, specificity, and positive and negative predictive values were determined to assess their accuracy in detecting drug-drug interactions. The accuracy of the software programs identified was determined using 100 clinically important interactions and 100 clinically unimportant ones. Stockley's Drug Interactions 8th edition was employed as the gold standard in the identification of drug-drug interaction. MAIN OUTCOME: Sensitivity, specificity, positive and negative predictive values. RESULTS: The programs studied were: Drug Interaction Checker (DIC), Drug-Reax (DR), and Lexi Interact (LI). DR displayed the highest sensitivity (0.88) and DIC showed the lowest (0.69). A close similarity was observed among the programs regarding specificity (0.88-0.92) and positive predictive values (0.88-0.89). The DIC had the lowest negative predictive value (0.75) and DR the highest (0.91). CONCLUSION: The DR and LI programs displayed appropriate sensitivity and specificity for identifying drug-drug interactions of interest in intensive care units. Drug interaction software programs help pharmacists and health care teams in the prevention and recognition of drug-drug interactions and optimize safety and quality of care delivered in intensive care units. PMID- 20963635 TI - Why should we respect the privacy of donors of biological material? AB - Why should we respect the privacy of donors of biological material? The question is answered in the present article in general philosophical terms from the point of view of an ethics of honour, a libertarian theory of rights, a view of respect for privacy based on the idea that autonomy is of value in itself, and utilitarianism respectively. For different reasons the ethics of honour and the idea of the value of autonomy are set to one side. It surfaces that the moral rights theory and utilitarianism present conflicting answers to the question. The main thrust of the argument is that there is no way of finding an overlapping consensus, so politicians have to take decisions that are bound to be controversial in that they can be questioned on reasonable philosophical grounds. PMID- 20963636 TI - CSF liver pseudocyst as a complication of a ventriculoperitoneal shunt. AB - We have a 30-year-old female patient suffering from secondary hydrocephalus. She has had a ventriculoperitoneal shunt (VPS) implanted following a rupture and a successful clipping of the aneurysm of the anterior communicating artery (ACoA). Three weeks after implanting of the VPS, respiratory and abdominal difficulties with febrility appeared. We diagnosed cerebrospinal fluid liver pseudocyst using ultrasound (US) and computer tomography scan (CT). Given that we found bacteria in the cerebrospinal fluid (CSF), we converted VPS into an external ventricular drain (EVD). After that, we conducted a US-guided punction and drainage of the CSF liver pseudocyst. The subsequent CT of abdomen showed a regression of the cystic form. The patient died following the septic condition with multiple organ failures (MOF) a month after the cerebrospinal fluid liver pseudocyst diagnosis.The perforation of parenhimatose abdominal organs with distal part of VPS is a rare complication which is most likely a consequence of a shunt infection and of an immunological reaction that took place during the process of localizing an infection. PMID- 20963637 TI - Giant schwannoma of the cauda equina without neurological deficits -- case report and review of the literature. AB - Schwannomas and ependymomas are the most frequent tumours of the filum terminale. Giant schwannomas, however, are very rare in this location with less than 30 cases reported in the literature, most of them presenting with preoperative neurological deficits. We present the case of a giant schwannoma in a 75-year-old lady extending from the level of lower D12 to upper L3 vertebra with low-back pain as the only symptom. Microsurgical removal of the tumour was accomplished via an L1-L2 laminotomy without permanent neurological deficits. Giant schwannoma of the cauda equina is a rare tumour with variable symptoms. Early diagnosis is crucial to obtain good postoperative results. Total removal without additional neurological deficits can be achieved by appropriate microsurgical techniques. PMID- 20963639 TI - Status of toxic metals in biological samples of diabetic mothers and their neonates. AB - The mechanism of transport of trace elements from the mother to the newborn is still not well known. The aim of present study was to compare the status of trace toxic elements, arsenic (As), cadmium (Cd), and lead (Pb) in biological samples (whole blood, urine and scalp hair) of insulin-dependent diabetic mothers (age ranged 30-40) and their newly born infants (n = 76). An age and socioeconomics matched 68 nondiabetic mothers and their infants, residing in the same locality, who were selected as referents. The elemental concentrations in all three biological samples were determined by an electrothermal atomic absorption spectrometer, prior to microwave-assisted acid digestion. The mean values of As, Cd, and Pb in all biological samples of diabetic mothers and their infants were significantly higher as compared to the referent mother-infant pair samples (p < 0.01). The high levels of As, Cd, and Pb in biological samples of diabetic women may play a role in the pathogenesis of diabetes mellitus and impacts on their neonates. PMID- 20963638 TI - Intensified adjuvant IFADIC chemotherapy in combination with radiotherapy versus radiotherapy alone for soft tissue sarcoma: long-term follow-up of a prospective randomized feasibility trial. AB - Adjuvant chemotherapy for grade 2 and 3 soft tissue sarcoma (STS) patients still has to be considered experimental. Fifty-nine patients underwent primary surgery by wide or marginal excision and were subsequently randomized to receive radiotherapy alone or in combination with six courses of chemotherapy consisting of ifosfamide, DTIC, and doxorubicin administered in 14-day intervals supported by G-CSF on days 5-13. Twenty-eight patients received radiotherapy (control group) and 31 patients were treated with additional chemotherapy. After a median observation period of 97 months (range: 13-158 months), 58 patients were followed up to assess long-term relapse-free survival (RFS), time to local failure (TLF), time to distant failure (TDF), and overall survival (OS). Fifteen patients (56%) in the control group vs. 19 patients (61%) in the chemotherapy group were free of disease. Within the control group, tumor relapses occurred in 12 patients (44%) vs. 12 patients (39%) in the chemotherapy group. RFS (P = 0.87), TLF (P = 0.58), TDF (P = 0.60) as well as OS (P = 0.99) did not differ significantly between the two groups. Adjuvant chemotherapy was not translated into a significant benefit concerning RFS, TLF, TDF, and OS for STS patients. PMID- 20963640 TI - Determination of arsenic in scalp hair of children and its correlation with drinking water in exposed areas of Sindh Pakistan. AB - This study was focused on the analysis of arsenic (As) levels in scalp hair of children (age, <10 years) collected from two towns of Khairpur, Pakistan, to evaluate the effects of As-contaminated groundwater. For comparative purposes, scalp hair samples of children were also collected from that area having low levels of As (<10 MUg/L) in drinking water. Groundwater and scalp hair samples of children were collected and analyzed by electrothermal atomic absorption spectrometry prior to microwave-assisted acid digestion. The average As concentrations in groundwater samples of two towns, Thari Mirwah and Gambat, were found to be 28.5 and 98.3 MUg/L, respectively. The range of As concentrations in scalp hair samples of children who belong to Thari Mirwah and Gambat was 1.25 1.61 MUg/g and 1.73-3.63 MUg/g, respectively. Twenty percent of the total children who belong to Gambat have skin lesions on their hands and feet. A positive correlation coefficient (R = 0.91-0.99) was obtained between As contents in drinking water and scalp hairs of children of both towns. PMID- 20963641 TI - Demographic and clinico-pathological characteristics in patients with triple negative and non-triple-negative breast cancer. AB - We investigate retrospectively the demographic and clinico-pathological characteristics of patients with triple-negative breast cancer (TNBC) compared to those with non-TNBC. Patients with breast cancer diagnosed from 1981 to 2008 in our clinic were retrospectively analyzed. Patient demographics including survival data and tumor characteristics were obtained from charts. A total of 795 patients were assessed in the study, including 140 patients (17.6%) with TNBC and 655 patients (82.4%) with non-TNBC. Patients with non-TNBC were further classified into 3 groups according to hormone receptor (HR) and HER-2 status. Median age was 49 (range 38-60 years) and similar between patients with TNBC and non-TNBC. Patients with TNBC had an increased likelihood of a higher histological grade III compared with HR(+) HER-2(-) subgroup (P > 0.001) and lower stage compared with HR(+)/HER2(+) and HR(-)/HER2(+) subgroups (P < 0.001 and P = 0.002, respectively). In patients with TNBC, the disease-free survival (DFS) rate was 66% at 5 years. In subgroup analysis of non-TNBCs, 5-year-DFS rates of the patients in HR(+)/HER2(-), HR(+)/HER2(+) and HR(-)/HER2(+) subgroups were 59, 66, and 57%, respectively. There was no significant difference between the TNBC and non-TNBC subgroups (P = 0.238). In multivariate analysis, nodal involvement (RR = 2.8, 95% CI: 0.99-8.3, P = 0.052) and the presence of lymphovascular invasion (RR = 3.2, 95% CI: 1.1-9.2, P = 0.029) were significantly associated with increased recurrence risk in patients with TNBC. Although there are differences in patient and tumor features, patients with TNBC had similar clinical course with those with non-TNBC. PMID- 20963642 TI - Failure of vitamin supplementation to lower the risk of recurrent stroke. PMID- 20963643 TI - Expanded distribution of the T315I mutation among hematopoietic stem cells and progenitors in a chronic myeloid leukemia patient during imatinib treatment. AB - T315I mutation of the ABL-kinase domain in chronic myeloid leukemia (CML) confers resistance to imatinib (IM) as well as second-generation tyrosine kinase inhibitors (TKIs). We report a chronic-phase CML patient undergoing IM treatment, who showed the overt existence of the T315I mutation after 15 months. We retrospectively analyzed the distribution of the T315I mutation using the invader assay and direct DNA sequencing among FACSAria-sorted populations from bone marrow cells: total mononuclear cells (TMC), hematopoietic stem cells (HSC)/Thy 1(+), HSC/Thy-1-, common myeloid progenitors (CMP), granulocyte macrophage progenitors (GMP), and megakaryocyte erythroid progenitors (MEP), at 0, 3, 6, 9, and 12 months after IM treatment. T315I was barely detectable by 12 months in TMC, but detectable in 19.2% of HSC/Thy-1- and 46.4% of MEP at diagnosis, and finally expanded into all populations. These results suggest that the monitoring of gene mutations in HSC and progenitors at diagnosis might be helpful for the early detection of TKI-resistant CML patients and facilitate appropriate therapeutic decision. PMID- 20963645 TI - A critical role of Sp1 transcription factor in regulating the human Ki-67 gene expression. AB - Ki-67 plays a crucial role in cell proliferation as well as maintenance or regulation of cell division. The mechanism governing the Ki-67 gene expression remains unknown. Thus, we cloned the core promoter of the human Ki-67 gene and further investigated its transcriptional regulation. The putative Sp1 binding sites were confirmed by electrophoretic mobility shift assay together with an anti-Sp1 antibody-mediated supershift assay. Deletion mutagenesis and firefly luciferase reporter gene assay demonstrated the essential contribution of Sp1 on transcriptional activation of the Ki-67 gene. In this study, we first confirm that there are three Sp1 binding sites in the Ki-67 core promoter. Two Sp1 sites (one at position -159 to -145 nt and the other at position -14 to +12 nt) are mainly involved in transcriptional regulation of the Ki-67 gene. Overexpression of Sp1 can enhance the Ki-67 promoter activity. However, down-regulation of Sp1 expression using siRNA-Sp1 and mithramycin effectively inhibits the Ki-67 gene transcription. Our results suggest that Sp1 is essential for basal promoter activity of the human Ki-67 gene. Inhibition of the Ki-67 transcriptional activity through abolishment of Sp1 may provide the useful prospect for gene therapy. PMID- 20963647 TI - The experimental model for studying of human age retinal degeneration (Japanese quail C. Japonica). PMID- 20963646 TI - Part II. Initial molecular and cellular characterization of high nitric oxide adapted human tongue squamous cell carcinoma cell lines. AB - It is not understood why some head and neck squamous cell carcinomas, despite having identical morphology, demonstrate different tumor aggressiveness, including radioresistance. High levels of the free radical nitric oxide (NO) and increased expression of the NO-producing enzyme nitric oxide synthase (NOS) have been implicated in tumor progression. We previously adapted three human tongue cancer cell lines to high NO (HNO) levels by gradually exposing them to increasing concentrations of an NO donor; the HNO cells grew faster than their corresponding untreated ("parent") cells, despite being morphologically identical. Herein we initially characterize the HNO cells and compare the biological properties of the HNO and parent cells. HNO/parent cell line pairs were analyzed for cell cycle distribution, DNA damage, X-ray and ultraviolet radiation response, and expression of key cellular enzymes, including NOS, p53, glutathione S-transferase-pi (GST-pi), apurinic/apyrimidinic endonuclease-1 (APE1), and checkpoint kinases (Chk1, Chk2). While some of these properties were cell line-specific, the HNO cells typically exhibited properties associated with a more aggressive behavior profile than the parent cells (greater S-phase percentage, radioresistance, and elevated expression of GST-pi/APE1/Chk1/Chk2). To correlate these findings with conditions in primary tumors, we examined the NOS, GST-pi, and APE1 expression in human tongue squamous cell carcinomas. A majority of the clinical samples exhibited elevated expression levels of these enzymes. Together, the results herein suggest cancer cells exposed to HNO levels can develop resistance to free radicals by upregulating protective mechanisms, such as GST-pi and APE1. These upregulated defense mechanisms may contribute to their aggressive expression profile. PMID- 20963648 TI - Ex vivo screening of prospective peptide drugs: new approaches. PMID- 20963644 TI - Extracellular heat shock proteins, cellular export vesicles, and the Stress Observation System: a form of communication during injury, infection, and cell damage. It is never known how far a controversial finding will go! Dedicated to Ferruccio Ritossa. AB - Heat shock proteins (hsp) have been found to play a fundamental role in the recovery from multiple stress conditions and to offer protection from subsequent insults. The function of hsp during stress goes beyond their intracellular localization and chaperone role as they have been detected outside cells activating signaling pathways. Extracellular hsp are likely to act as indicators of the stress conditions, priming other cells, particularly of the immune system, to avoid the propagation of the insult. Some extracellular hsp, for instance Hsp70, are associated with export vesicles, displaying a robust activation of macrophages. We have coined the term Stress Observation System (SOS) for the mechanism for sensing extracellular hsp, which we propose is a form of cellular communication during stress conditions. An enigmatic and still poorly understood process is the mechanism for the release of hsp, which do not contain any consensus secretory signal. The export of hsp appears to be a very complex phenomenon encompassing different alternative pathways. Moreover, extracellular hsp may not come in a single flavor, but rather in a variety of physical conditions. This review addresses some of our current knowledge about the release and function of extracellular hsp, in particular those associated with vesicles. PMID- 20963649 TI - Dependence of the lymphocyte proliferative response on the endogenous cortisol level and sensitivity to beta-adrenergic regulation in vitro in the early period of penetrating eye injury. PMID- 20963650 TI - The role of oxidative stress in development of Parkinsonian-like states. PMID- 20963651 TI - Characteristic of the active and passive mechanical properties of the lymph node capsule. PMID- 20963652 TI - Effects of the vagus nerve stimulation on amygdalohypothalamic and amygdalobulbular influences. PMID- 20963653 TI - Chemical interactions between two dominant species in Lake Shira: Gammarus lacustris sars (Crustacea: Amphipoda) and Arctodiaptomus salinus Daday (Crustacea: Copepoda). PMID- 20963654 TI - Constitutive expression of the sunflower and chrysanthemum genes of the AP1/FUL group changes flowering timing in transgenic tobacco plants. PMID- 20963655 TI - Triboluminescence of spicules of hexactinellid sponges. PMID- 20963656 TI - Release of a somatostatin-like peptide by cells of Bacillus subtilis B-8130, an intestinal symbiont of the wild bird Tetrao urogallus: the influence of the bacillus on the animal. PMID- 20963657 TI - Vibration-induced stimulation of wheat growth. PMID- 20963658 TI - The use of symbiotic pea mutants to improve nodulation and nitrogen fixation. PMID- 20963659 TI - Involvement of sugars in the antioxidant defense against paraquat-induced oxidative stress in potato transformed with yeast invertase gene. PMID- 20963661 TI - Egg cocoons of the earthworm Dendrodrilus rubidus tenuis (Lumbricidae, Oligochaeta) withstand the temperature of liquid nitrogen. PMID- 20963660 TI - Fractionation of humic acids by clay minerals assayed by (13)C-NMR spectroscopy. PMID- 20963662 TI - Fractal characteristics of the species structure of ichneumon wasp communities in the middle Urals. PMID- 20963663 TI - Ecological modeling of Yamal tundra ecosystems: traditional nature use as a factor of instability. PMID- 20963664 TI - Comparative study of thermoresistances' cellular mechanisms in representatives of the Gammarus lacustris Sars populations inhabiting saline Lake Shira (Republic of Khakassia) and a fresh water body in the Cis-Baikal region. PMID- 20963665 TI - VEGFR-2 expression in tumor tissue of breast cancer patients. PMID- 20963666 TI - Ghrelin regulation of in vitro human monocyte functional activity. PMID- 20963667 TI - Effect of exogenous cardiolipin on the growth and viability of Mycobacterium tuberculosis H37Rv in vitro. PMID- 20963668 TI - [Communication between patients and providers in medical rehabilitation]. PMID- 20963669 TI - [Patient-provider communication in chronic illness: current state of research in selected areas]. AB - Communication between patient and providers is extremely important, especially for the treatment of chronically ill patients, characterized by a biopsychosocial disease model. This article presents an overview of the current status of research on patient-provider communication in 3 selected areas: the communication preferences of chronically ill persons, the correlation between communication and relevant endpoints, and interventions to improve patient-provider communication. One major result of the research is that patients display a rather high degree of inter- and intra-individual variability with respect to the preference of certain communication styles (e.g. patient participation); there are differences among them, and they develop varying preferences in the course of their illness. However, communicative behavior of the provider that is generally perceived by many patients to be positive can also be identified: affective behavior (for example, asking the patient about his/her feelings, being sensitive to these feelings and responding to them), providing information in an understandable, proactive manner, and attempting to understand the patient's perceptions, expectations, and cognitive concepts. Successful communication requires a certain congruence between the patient's communication preferences and the provider's behavior. It has been sufficiently documented in literature that successful communication leads to greater adherence. The correlation to patient satisfaction is not documented quite as clearly but has often been shown. The findings vary with respect to the improvement in the patient's health status. The effectiveness of communication training for providers has been documented quite well regarding the immediate endpoints in patient-provider interaction (e.g., patient-oriented behavior); the evidence with respect to medium-term endpoints such as patient satisfaction varies, also due to the number of possible operationalizations of the endpoints. Supplementing provider training with communication-related training for patients appears to be an important and useful method as many studies have shown that the behavior of providers can be influenced using relatively simple measures that start with the patient. There is a need for further development of research on patient-provider communication, in particular with respect to a more solid theoretical basis, integration of methods including qualitative and quantitative methods, self-evaluations, and interaction analyses, and also concerning conducting more longitudinal studies. PMID- 20963670 TI - [Development, implementation and use of an intervention procedure for providing needs-based patient information for rehabilitation patients]. AB - PURPOSE: Patients have a great need for information that is often not satisfied by providing "standard" information. In order to reach the patients better, it is increasingly necessary to tailor patient information to the individual needs of patients and make stronger use of patients' "common sense" models. This article reports on the development and implementation of an intervention procedure for providing needs-based patient information as well as on initial results of its use. METHODS: Both the intervention concept and the operationalization of its contents are based on the common sense self-regulation model (CSM). The intervention aims to link the information given to patients to the existing illness beliefs and treatment beliefs of the rehabilitation patients. To do this, the illness and treatment representations held by the patients before rehabilitation are assessed, automatically analyzed using a computer programme, and aggregated in a "response questionnaire". This feedback is then passed on to the information-providing therapists well in advance of admission of the rehab patients. The contents and key organizational data of the intervention procedure were discussed with the treatment providers in a feasibility analysis before implementation. In addition, intervention training was also conducted before the start of the intervention. Since August 2009 the procedure has been implemented and evaluated in 9 cooperating rehab centres. Process documentation provides criteria relative to the feasibility of the intervention. RESULTS: The results on implementation of the intervention as well as on its feasibility have thus far been relatively encouraging. The treatment providers ascribe high relevance to the contents of the intervention and assess the major components to be generally feasible. From the treatment provider viewpoint, the rehabilitation patients benefit from the intervention, and it is also considered to be helpful for planning further treatment. CONCLUSION: The intervention procedure for needs based patient information presents an option for making information available to patients as needed. It is based on theory and accepted by treatment providers. The strengths and weaknesses of the intervention are discussed. PMID- 20963671 TI - [The communication of chronically III patients in an internet chat for aftercare of inpatient psychosomatic treatment]. AB - AIM: E-Health applications open new avenues for seamless care of patients with a chronic disease. This study examines the demand and the usage pattern of an Internet-assisted aftercare group-treatment following inpatient treatment. METHODS: The analysis uses data from telephone interviews which were conducted 12 months after discharge. 168 study participants of the prospective controlled effectiveness study (73.7%) participated. The frequency and the time of beginning an outpatient psychotherapy are compared between controls and chat participants. Computerized text-analyses of the chat-scripts are used to examine the usage pattern of the chat-aftercare. Statements of the patients with chronic symptoms at the beginning and at the end of their chat participation are quoted for illustration of the contents of the group therapy sessions. RESULTS: Patients with chronic course of illness utilize the online-based aftercare more frequently and more actively than patients with short durations of illness. Words indicating cognitive processes are used more frequently by chat participant with chronic illness. Chat participants with chronic course of illness who are receiving no additional outpatient psychotherapy, relapse considerably less frequently than controls without any psychotherapeutic support. CONCLUSION: Patients with chronic course of illness use online aftercare treatment to sustainably improve their health status. PMID- 20963672 TI - [Gender-specific aspects of the physician-patient interaction]. AB - This article aims at shedding light on the role of physician and patient gender in the medical consultation. Because of the scarce amount of studies concentrating on gender aspects of the physician-patient interaction in rehabilitation or chronic disease, mostly results from general medicine are reported. Female physicians have a more emotional and less dominant communication style. Female patients bring up more psychosocial topics and disclose more information about themselves in general. Both female and male physicians give more information and apply a more partnership-oriented communication style when seeing a female patient. Female and male patients communicate more partnership oriented with female physicians and share more psychosocial and medical information with them. Same-gender dyads seem beneficial most of the time for physician-patient communication. Mixed-gender dyads are more difficult, especially when a younger female physician sees a male patient. There is no single good communication style recommendable for all physicians. Rather, the research results presented should be applied to communication trainings for physicians. This could provide physicians with a flexible choice of communication styles to apply according to different situations. PMID- 20963673 TI - [Patient-doctor interaction in rehabilitation: is there a relationship between perceived interaction quality and long term treatment results?]. AB - OBJECTIVES: A body of evidence suggests that good interaction is crucial for high quality medical practice and that it has a considerable impact on treatment outcomes. Less is known about the role and significance of doctor-patient interaction in rehabilitation. The study's aim was to capture perceived quality of doctor-patient interaction in rehabilitation by a rating instrument (P.A.INT Questionnaire) and to examine the relationship between perceived quality of interaction and long-term treatment outcomes. METHODS: Referring to the approach of Bensing (1990) and Rogers (1972) we defined "quality of interaction" in terms of 3 dimensions: (1) affective behaviour, i. e., empathy, positive regard and coherence; (2) instrumental behaviour: providing and collecting information, structuring and reinforcement; (3) participation and involvement of patients. 2 parallel versions of the Questionnaire were developed for patients and physicians. 7 rehabilitation clinics in north-western Germany participated in the multi-centre study. 61 doctors and their 470 patients evaluated both their shared dialogues upon admission, discharge and at least one ward round. Furthermore, patients rated their health status on admission (t0), discharge (t1) and 6 months after discharge (t2) using the IRES-3 (Indicators of Rehabilitation Status Questionnaire Version 3). RESULTS: (1) Comparisons of patient and physician evaluations on admission revealed the following: Affective quality of contact (empathy and coherence) was rated positively and without discrepancies by both patients and physicians. On the other hand, instrumental behaviour (information and structuring) was rated less positively by patients than by physicians. (2) Patients who rated the dialogue on admission more positively showed stronger treatment effects with respect to pain, to anxiety and depression 6 months after discharge. Also disability days decreased about 40% stronger in the group of positive raters. (3) Patient ratings of quality of interaction showed low but significant correlations with patient-related aspects like coping with disease, health-related knowledge and former positive experiences with physicians. A stepwise regression analysis revealed that interaction quality seems to contribute to enhanced treatment results independently of patients' competences. DISCUSSION: Our results suggest a positive relationship between perceived interaction quality as defined by the P.A.INT-Questionnaire and treatment effects 6 months after discharge. Comparisons of patient and physician evaluations showed that physicians seem to be successful in building relationships on the affective level but less successful on the instrumental level (i. e., information, structuring and reinforcement). Our data underline the importance of interaction quality for the success of rehabilitation and thus the importance of specific skills such as providing and collecting information, recognizing patients' concerns and goals as well as reinforcement of health-related action. This is especially important when knowledge of disease and coping with disease on patients' side is poor. Interaction quality seems to contribute to better treatment results independently of patients' competences. PMID- 20963674 TI - [Relevance and barriers of physician empathy in daily practice - current state of research and qualitative survey of physicians]. AB - AIMS OF THE STUDY: The aim of this study was to investigate the relevance and the barriers of physician empathy in medical rehabilitation by conducting a narrative literature review and a qualitative survey in physicians. METHODS: First, we described the current state of research of physician empathy in medical rehabilitation based on a narrative (non-systematic) review of the literature. Additionally, the questions of relevance and barriers of physician empathy were examined in a qualitative short survey with physicians from Rehabilitation Medicine, Internal Medicine, Pediatric and Family Medicine. The qualitative data were analyzed according to the summarizing content analysis of Mayring. RESULTS: Only n=13 studies of physician empathy were conducted in Rehabilitation Medicine; of those, just a few were from Germany and a small number investigated the influence of empathy on patient health outcomes. The qualitative survey's results regarding the definition, patient outcomes and barriers of physician empathy are similar to other theoretical and empirical studies on those issues. Moreover, they show many new, practical aspects, particularly in the field of barriers of physician empathy. CONCLUSION: Although physician empathy has been shown to be an outcome-relevant factor in acute health care, less attention has been paid to it in Rehabilitation research. Physicians from Rehabilitation Medicine, Internal Medicine, Pediatric and Family Medicine perceive empathic behavior also as an outcome-relevant ability, which is particularly hindered by time pressure and stress but also by personal and patient-specific factors. PMID- 20963675 TI - [Diagnosis and therapy of retinal vein occlusions]. PMID- 20963676 TI - [Refractometry by the pediatrician?]. PMID- 20963677 TI - [Idiopathic orbital inflammation syndrome in childhood--case report and literature review]. AB - BACKGROUND: Idiopathic orbital inflammation syndrome (IOIS) is a rare disease in childhood. There are only ca. 70 case reports in the scientific literature. METHOD: We present a case report and review of literature. CASE REPORT: A 6-year old girl developed within one week beginning with a discrete, non-traumatic haemorrhage of the lower palpebra a painful proptosis, periorbital swelling, conjunctival chemosis and injection and motility restriction to lateral gaze of the right eye. MRI showed a retrobulbar and eyelid mass with enhancement and signs of haemorrhage without optic nerve involvement. A rapidly performed biopsy excluded malignancies and confirmed the diagnosis of non-specific inflammation. With high-doses of intravenous and later oral prednisolone the symptoms improved significantly. Because of an impairment under tapering of prednisolone an interim elevation of the dose was necessary, but with very slow tapering over 4.5 months the girl became symptom-free except for a minimal, non-relevant abduction deficit. There has been no recurrence in the last 1.5 years. DISCUSSION: In comparison to the clinical features of adults the rarely reported childhood cases show no relevant differences in orbital signs, frequency of bilaterality and pain, recurrence rate and success of therapy. Only iritis and papilloedema seem to be special features of childhood IOIS, these cases tend to a higher rate of recurrences. Histopathological examination is much more necessary than in adults because of the need for exclusion of rhabdomyosarcoma. Our case shows that haemorrhages can also be a sign for an IOIS. PMID- 20963678 TI - [Results of late onset amblyopia therapy for excentric fixation in different forms of amblyopia]. AB - BACKGROUND: The objective of this study was to describe the therapeutic prognoses for excentric fixation in relation to the underlying diagnoses. PATIENTS AND METHODS: We investigated the clinical development of therapy for permanent occlusion (90%) or standard occlusion (10%) in 32 children up to a maximum age of 7 years with the following: strabismus convergens: n = 12, microstrabismus: n = 10, secondary sensory esotropia: n = 2, anisometropias: n = 6, and congenital partial clouding of the optical axis: n = 2. The mean age of all patients at the time of the first visit to the clinic (EV) was 61 +/- 12 (37-86) months, with no significant difference in the sub-groups (n > 2) except for the comparison microstrabismus/anisomyopia (p = 0.05). The mean period of the follow-up examinations, obtained with the aid of a survey of the doctors performing these examinations, was 5 years and 10 months +/- 4 years and 6 months (6-253 months). RESULTS: Central fixation was achieved for 20 of 32 (63%) of the patients: for 10 of 12 children with infantile esotropia, 1 of 2 children with secondary sensory esotropia, 3 of 10 children with microesotropia, and 5 of 6 children with anisometropia and 1 (already with standard occlusion) of 2 children with partial clouding of the optical axis. The mean time required to achieve central fixation was 4.5 +/- 3.6 (1-11) months. The poorest success rate was found for slightly nasal excentric fixation or fixation on the nasal macular wall, and the best rate for fixation on the temporal macular wall, above the foveola or above the papilla. Achieving central fixation correlated significantly--inversely proportional--to the level of refraction of the amblyopic eye (r = -0.4, p = 0.03), as well as with the difference between the refraction of the amblyopic eye and the dominant eye (r = -0.4, p = 0.02) and with the occurrence of astigmatism in the amblyopic eye (r = -0.4, p = 0.04). CONCLUSIONS: The typical age at the time of the first visit to the clinic in this study was around 5 years for most of the excentric fixations investigated. This requires greater intervention of occlusion therapy. In this study, the patients with anisomyopia and infantile esotropia showed the best success rates, and the children with microstrabismus showed the poorest success rates. The fixations close to the papilla, temporal macular wall, and over the foveola were shown to be favourable in relation to the prognosis. With microstrabism, a quasi-burned in nasal excentric fixation with binocularity dominated the unsuccessful attempts. With the primary forms of esotropia, a highly hyperopic amblyopic eye is unfavourable in relation to the prognosis. PMID- 20963679 TI - [Electronically recorded occlusion treatment in amblyopes older than 7 years: acuity gain after more than 4 months of treatment?]. AB - BACKGROUND: According to the ROTAS study most of the improvement in visual acuity (VA) during amblyopia therapy of children aged 3 to 8 years occurs during the first 6 to 8 weeks . Sattler reported a VA gain in 11-year olds even during the second year of treatment . So far there are no standards concerning the intensity and duration of the treatment of patients older than 7 years of age. After a report on electronic monitoring of occlusion treatment in patients aged 7 to 16 years for 4 months , we now analyse whether this age group benefits from a longer lasting treatment. MATERIALS AND METHODS: In this pilot study the progression of VA was analysed in 11 patients (age range 7.18 to 15.76 years; median 11.42 years) during 12 months of occlusion therapy (types of amblyopia: 5 anisometropic, 1 strabismic, 5 combined). The daily occlusion times were recorded using the occlusion dose monitor (ODM) . At the beginning of treatment the prescription of the occlusion regime (median) was 6 h/d (range 4 to 7 h/d), the (decimal) VA 0.2 (range 0.02 to 0.63) for single and 0.16 (range 0.02 to 0.8) for crowded optotypes. RESULTS: The recorded occlusion time (median) was 4.4 h/d during the 12 months of treatment, the VA gain (median) was 0.4 log units for single (range 0.2 to 0.7 log units) and 0.3 for crowded optotypes (range--0.1 to 0.6). During the period of 4 to 12 months of treatment (received occlusion 4.12 h/d) the VA gain was 0.1 log units for single and for crowded optotypes. The maximum VA gain during the interval of 4 to 12 months of treatment was 0.2 log units, both single and crowded. The interocular difference for crowded VA (median) decreased from 0.9 to 0.6 log units during treatment, however only one patient achieved an interocular difference of < 0.2 log units. CONCLUSION: The patients presented here were able to integrate daily occlusion lasting several hours and the electronic monitoring of occlusion treatment into their daily routine over a period of 12 months. During this period the VA of all included types of amblyopia improved significantly, both from a clinical and statistical point of view. Further long-term studies using ODMs with larger groups of patients may identify factors for success of treatment, reveal the long-term stability of the improvement and contribute to a standardised treatment in this age group. PMID- 20963680 TI - [Changes of the anterior eye segment after eye muscle surgery--evaluation by optical coherence tomography in adults]. AB - BACKGROUND: In the light of studies in children which showed no significant changes concerning anterior chamber depth, central corneal thickness and chamber angle width after eye muscle surgery, the aim of this study was to evaluate such changes in adults by means of optical coherence tomography. PATIENTS AND METHODS: Using the VisanteTM OCT (Carl Zeiss, Meditec, Jena) we measured central corneal thickness (CCT), anterior chamber depth (ACD) and chamber angle width at 0 degrees (CW0) and 180 degrees (CW180) in 17 patients who had undergone eye muscle surgery on a minimum of one horizontal muscle preoperatively, one week and four months postoperatively. Exclusion criteria were an age under fifteen years at the time of surgery, previous intraocular surgery and other pathological conditions of the anterior segment. The median age at surgery was 43 years (min: 15; max: 67 years). RESULTS: In all eyes (one and two muscles), no significant differences of mean values taken preoperatively, one week and four months postoperatively were seen: CCT: 538 +/- 51 mm; 535 +/- 39 mm; 535 +/- 46 mm (p = 0.77); ACD: 2.98 +/- 0.44 MUm; 3.01 +/- 0.45 MUm; 3.01 +/- 0.40 MUm (p = 0.42); KW 0: 38.0 +/- 5.2 degrees 38.4 +/- 6.0 degrees 37.8 +/- 5.2 degrees (p = 0.98); KW 180: 33.7 +/- 5.6 degrees 35.6 +/- 5.7 degrees 34.5 +/- 6.8 degrees (p = 0.32). The differences between the corresponding data of both subgroups (one vs. two muscles) concerning central corneal thickness (p-value: 0.74; 0.89; 0.42), anterior chamber depth (p-value: 0.31; 0.23; 0.36) as well as chamber angle width at 0 degrees (p-value: 0.73; 0.27; 0.81) and at 180 degrees (p value: 0.87; 0.67; 0.89) were not significant. CONCLUSION: Using optical coherence tomography of the anterior eye segment in adults after muscle surgery, either in one or in two muscles - in accord with the results in children - no significant changes concerning central corneal thickness, anterior chamber depth and chamber angle width were seen. PMID- 20963681 TI - [Neuro-ophthalmological and ophthalmological findings in Joubert syndrome]. AB - BACKGROUND: Joubert syndrome (JS) belongs to the ciliopathies and is a mostly autosomal recessively inherited disease (in the case of OFD1 mutations, JS is an X-linked trait). It is characterised by midbrain-hindbrain malformations with developmental delay, hypotonia and ataxia and a broad spectrum of other facultative findings. The aim of our study was to examine the ophthalmological and neuro-ophthalmological features of JS in our patients and to compare our findings to those of other studies. METHODS: In a retrospective study we evaluated the ophthalmological and neuro-ophthalmological findings of 9 consecutive patients who met the diagnostic criteria of JS. RESULTS: All patients had abnormalities of ocular motility, 4/9 used head thrusts to shift gaze (oculomotor apraxia OMA). In 6/8 patients, the optokinetic reflex (OKN) was absent. Furthermore, 8/9 children showed nystagmus, mostly see-saw nystagmus. Manifest strabismus was found in 8/9 while 3/9 had a retinopathy with either abnormal ERG and/or fundus appearance with or without visual impairment. Chorioretinal colobomata were present in 5/9 cases. Two patients showed a unilateral congenital ptosis, one a facial nerve paresis. CONCLUSIONS: The early neuro-ophthalmological findings in JS are not pathognonomic, but may lead to the diagnosis of JS. The syndrome should be suspected in patients with nystagmus, especially see-saw nystagmus, and abnormal OKN and/or OMA, and/or colobomata of the fundus, and further paediatric examinations should be initiated. PMID- 20963682 TI - [Accuracy of two autorefractors--Pediatric Autorefractor plusoptiX and Retinomax- in cycloplegic children in comparison to retinoscopy]. AB - HISTORY: In children, measuring refraction is of interest particularly with regard to the risk of amblyopia. Cycloplegic retinoscopy is the gold standard method for this age group. In a prospective study we compared readings from two hand-held photorefractors, the Pediatric Autorefractor and the Retinomax, to those from retinoscopy. PATIENTS AND METHODS: 74 patients were recruited consecutively at the outpatient department of Heidelberg University Eye Hospital's Section for Strabismology and Neuroophthalmology. All patients underwent standardised cycloplegia measurements first by the Pediatric Autorefractor plusoptiX A 08 in 1 metre working distance, then adding an infrared filter to reduce interferences, followed by the Retinomax K-plus 3 in 5 cm working distance and retinoscopy as reference on the right eye. RESULTS: Spherical equivalents measured by the Pediatric Autorefractor plusoptiX A 08 coincided in 51.2% with retinoscopy (+/- 0.5 D). Adding an infrared filter increased this to 60.0%. However, the success rate of measurement decreased to 47% on adding an infrared filter as compared to 55.4% in cycloplegia alone. Children showed no cooperation in 11% and 16% with the infrared filter, respectively. The remaining children were not measurable by means of the device. With regard to spherical equivalents, the measurements done with Retinomax K-plus 3 coincide in 57% with those done in retinoscopy. The success rate of measurements with the Retinomax was 91%. The remaining children showed no cooperation. CONCLUSION: Retinoscopy in cycloplegia is still the method of choice when determining refraction in children. Autorefractors quickly provide results for comparison which coincide with retinoscopy in 50-60% in spherical equivalent and in 80-90% in cylindrical values. The Pediatric Autorefractor is not suited for everyday clinical routine due to a low success rate of 50% and tight measuring range of + 5.0 to -7.0 D in spherical equivalents. PMID- 20963683 TI - [Detection of amlyogenic risk factors with the vision screener S 04]. AB - INTRODUCTION: The Vision Screener(r) (Plusoptix) was developed for the recognition of amblyogenic refractive errors without cycloplegia. The aim of this study was to evaluate the sensitivity and specitifity for the detection of amblygenic refractive errors in preschool children. Furthermore it was investigated whether small angle strabismus as another cause for amblyopia could be detected by manual evaluation of corneal reflex images on printouts. PATIENTS AND METHODS: 83 children aged between 0.5 and 6 years without strabismus had undergone 3 measurements without cycloplegia with the Vision Screener before cyclplegic retinoscopy was performed. In a second group of 72 children with orthotropia or a manifest strabismus < 10 degrees the position of the eyes without correction was evaluated in a complete orthoptic and ophthalmological examination. Three measurements with the Vision Screener were performed in non cycloplegic status. The centre of the "cloud of viewing directions" was determined on print-outs and the distance to the points of origin (middle of pupil) measured for each eye. The sum of distances of right and left eyes was taken for determination of total deviation and the assymetry was calculated by the difference of distances of the right and left eyes. RESULTS: There was a total sensitivity of 75% (specifity 91%) for amblyogenic refractive error (prevalence: astigmatism 22%, hyperopia 6%, anisometropia 6%). A change of threshold criteria increased the total sensitivity to 86% and 93%, whereas specifity was lowered to 80% and 76%, respectively. Eight children showed a manifest strabismus. In 75% of these cases the determined deviation of corneal reflex images in the horizontal direction was outside of the normal range; analysis of asymmetry showed an abnormal result in 37.5% of the cases. CONCLUSION: The examination using the Vision Screener may detect refractive errors and partially small angle strabismus as amblyogenic risk factors; however, additional tests should be added for screening examinations. An ophthalmological examination including cycloplegic retinoscopy cannot be replaced. Despite acceptable sensitivity and specifity the major portion of positively screened children will be without pathological findings at cycloplegic controls, because the amount of "false-positive" results exceeds the amount of "true-positive" results based on a prevalence of 5% for amblyopia. PMID- 20963684 TI - [Development of an anamnestic questionnaire for psychotherapeutic patients with comorbid somatic diseases]. AB - The assessment of patients' mental and physical history is an important task of the psychodiagnostic process. Aim of the present study was to develop an anamnestic questionnaire for psychotherapeutic patients with comorbid somatic diseases (ANKER). The development of the ANKER was based on a qualitative, two stepped design according to the grounded theory comprising a needs assessment and an evaluation of the first ANKER-version. Content analysis strategies were used to summarize results. An anamnestic questionnaire should: 1) be a guideline and reminder 2) provide information for health insurance application 3) be time saving. Thereby, at least the following topics should be covered: "conditions and diseases", "family of origin", "school and career", "partnership", "friends and acquaintances". The ANKER was evaluated positively as being feasible, helpful and economic. PMID- 20963685 TI - [Comparison of Rebound tonometry versus Perkins tonometry in the supine glaucoma patient]. AB - BACKGROUND: The aim of this study was to evaluate the concordance of intraocular pressure (IOP) measurements in the supine glaucoma patient using a Perkins applanation tonometer (PAT) compared to the iCare(r) rebound tonometer (RT), a hand-held device requiring no local anaesthesia. METHODS: 73 left eyes of 73 glaucoma patients were included in this consecutive case study and measured both by supine Perkins applanation tonometry and by right lateral posture rebound tonometry in the supine position (RLP). The patients were divided into three subgroups dependent on IOP (SG-1: 0 - 15 mmHg, SG-2: 16 - 22 mmHg, SG-3: more than 23 mmHg). RESULTS: The mean deviation between RT and PAT was 2.6 +/- 4.0 mmHg, the 95 % confidence interval was -5.3 to 10.4 mmHg. 69 % of the measurements showed deviations within 3 mmHg between the two devices. Deviation was smallest in SG-2, and largest in SG-3. CONCLUSIONS: Rebound tonometry is comfortable to use even in supine patients. RT measurement agreed overall significantly with those of Perkins applanation tonometry, generally overestimating PAT measurement. In high IOP values, RT did not correlate as well with PAT as in moderate IOP levels. PMID- 20963686 TI - [Ultrasound for surveillance after endovascular repair of abdominal aortic aneurysm--simple and safe?]. AB - In the past, multislice computed tomography angiography (CTA) with arterial and venous phase was recommended as the gold standard in follow-up after endovascular abdominal aneurysm repair (EVAR). Iodine-containing contrast agents and frequent radiation exposure are limitations for use in elderly patients with chronic renal insufficiency. Colour-coded Doppler sonography (CCDS) and, especially, contrast enhanced ultrasound (CEUS) are non-invasive methods that are time and cost effective. Both provide a reliable alternative to CTA in surveillance after EVAR. CEUS seems to be superior in characterisation of the type of endoleaks and can be established in order to reduce iodine-containing contrast agent and radiation exposure in follow-up. In contrast to CTA scans, CEUS can be offered to patients with chronic renal insufficiency and allows a dynamic examination and perfusion analysis (e. g., in fenestrated and branched stentgrafts). Routine combination with X-ray allows control of stentgraft material and location of the branches. PMID- 20963687 TI - [Modern didactics in surgical education--between demand and reality]. AB - Surgical residency contains an inadequate amount of hands-on training in the operating room and time constraints further make this type of education on the floor unlikely. Due to these deficits in residency training, private surgical courses outside of the established residency programmes are in high demand. Therefore, surgical residents must spend their own resources and time in addition to their residency training in order to receive adequate clinical exposure. Didactic approaches like problem-based learning have begun to influence our modern education. These novel education approaches along with visualisation training, video-based presentations, and multimedia-based training can be useful adjuncts to traditional surgical training. PMID- 20963688 TI - [Agenesis of the gallbladder - is an operation avoidable?]. PMID- 20963689 TI - Profound blockage of CXCR4 signaling at multiple points using the synergy between plerixafor, mirtazapine, and clotrimazole as a new glioblastoma treatment adjunct. AB - CXCL12 signaling at CXCR4 is important in glioblastoma growth promotion as a migration-directing chemokine and as a mitosis-stimulating cytokine system. Recent developments in other areas of medicine may have made it now possible to comprehensively block glioblastoma's use of CXCL12 signaling. CXCL12 signaling at CXCR4 requires an active intermediate conductance Ca2+-activated K+ channel to function. Plerixafor (AMD3100) is a new small molecular weight inhibitor of CXCR4, FDA approved to aid in stem cell mobilization. Inhibition of CXCR4 by plerixafor is expected to inhibit particularly the glioblastoma stem cell population by inhibiting that sub-population's homing to the protective hypoxic niche. Histamine signals through the H1 receptor in glioblastoma cells to activate the intermediate conductance Ca2+-activated K+ channel also, thereby forming a potential bypass for inhibition of CXCR4-initiated signaling. The antidepressant mirtazapine is perhaps the most potent H1 antagonist in common clinical use. By inhibiting H1 stimulation of intermediate conductance Ca2+ activated K+ channels, it could prevent circumvention of CXCR4 inhibition by that path. The anti-fungal clotrimazole directly inhibits the intermediate conductance Ca2+- activated K+ channel at clinically achievable and well-tolerated doses. These three drugs used simultaneously are potential low morbidity paths to deeply inhibit CXCR4/CXCL12 signaling during cytotoxic glioblastoma treatment. PMID- 20963690 TI - Basilar skull fracture: outcome of acute care without antibiotic prophylaxis in a Nigerian neurosurgical unit. AB - AIM: A prospective observational study of the in-hospital outcome of the management of BSF without antibiotic prophylaxis in a Nigerian neurosurgical unit. MATERIAL AND METHODS: All cases of HI with clinical diagnosis of BSF over an 8-month period were reviewed. Their demographic, clinical, and in-hospital outcome parameters were analysed. We also compared some clinical and outcome characteristics between this study group and a contemporary cohort of patients in our unit with Head Injury but without CSF leak RESULTS: There were 47 cases. The CSF leak was from the nostrils in 18 (38.3%), the ears in 16 (34.04%), and both ears and nostrils in 12 (25.53%). The cause of injury was road accidents in 91%, and the severity of the Head Injury was mild, moderate and severe respectively in 42.55, 25.53 and 31.91%. Meningitis occurred in 2 patients (4.25%); in-hospital outcome was good in 68.1% and poor in 31.9% and this was significantly (p < 0.05) affected primarily by the severity of the brain injuries. These in-hospital outcome rates and their determinants were similar to those in our unit's contemporary cohort of Head Injury without BSF. CONCLUSION: Management of traumatic BSF without antibiotic prophylaxis in a developing country setting has not been accompanied with an increased rate of unfavourable outcome. PMID- 20963691 TI - Low back pain and sciatica related with the premenstrual period in patients with lumbar disc herniation. AB - AIM: We examined the clinical progress of low back pain and radicular pain during the premenstrual period in patients with lumbar disc protrusion and discussed the probable effective physiopathological mechanisms and laboratory results reported in the literature. MATERIAL AND METHODS: Fifty female patients with complaints of low back and leg pain, and with lumbar disc protrusion in their MRI investigations were included in the study. The pain was assessed using the modified "Low Back Outcome Scale of Greenough and Fraser" in the premenstrual and the normal postmenstrual periods. RESULTS: There was an increase in the use of analgesic drugs and the need for rest during the premenstrual period (p < 0.05). The severity of pain was significantly different between the two periods and it was more severe at the premenstrual period (p < 0.05). CONCLUSION: All the criteria that we chose from the modified "Low Back Outcome Scale of Greenough and Fraser" to assess the pain showed a significant difference between the premenstrual period and the normal period in our patients. This difference should be considered in the treatment strategies in the clinical setting. Patients should be re-evaluated for surgical decisions after the premenstrual period if possible. PMID- 20963692 TI - The effect of repetitious concussions on cognitive functions in rats. AB - AIM: In this study, we aimed to investigate the effect of repetitious concussions on the spatial learning and memory function in rats. MATERIAL AND METHODS: 46 adult, male Sprague-Dawley rats were assigned to three homogenous groups by stratified random sampling according to their basal performance during the first four days of the Morris water maze (MWM), as Control (n=10), Sham (n=10) and Concussion (n=26) groups. On the 12th day, the MWM experiment was repeated to evaluate the memory function. Rats in the concussion group were then subjected to the first head trauma. Some of the trauma-applied rats were sacrificed for histopathological examination 4 hours (n=4) and 24 hours (n=3) after the trauma. The spatial memory function of the rest of the rats was re-evaluated by MWM on the 20th day. Some of the rats were then subjected to the second head trauma (n=13), four of which were then sacrificed at the 4th hour, and three of which were sacrificed at the 24th hour. On the 27th day, six rats that had received single concussion and the remaining six that had received two concussions were re evaluated for retention development by the third MWM experiment. RESULTS: Escape latency curves showed a decrease in Sham and Control groups on the 20th and 27th days, and an increase in concussion group on the 20th day but no statistical significance was found between the groups. CONCLUSION: Repetitious concussions did not significantly affect spatial learning-memory functions in rats, and may lead to a counter-adaptive mechanism against concussive injury. PMID- 20963693 TI - Microanatomical study of the intracranial abducens nerve: clinical interest and surgical perspective. AB - AIM: The microanatomy of the abducens nerve (AN) is important for clinical reasons and surgical approaches as it is located in the petroclival region. The incidence of branching and duplication of the abducens nerve are unknown and mechanisms relating to paralysis of the nerve in indirect conditions are yet to be clarified. MATERIAL AND METHODS: Microanatomical details (anatomical observations and morphometric measurements) of the AN were obtained from 20 cadaveric skull bases (40 specimens). RESULTS: 55% of the intracranial abducens nerves had branching, with type 2 and 3 branching occurring in 10%. The nerve coursed below the petrosphenoidal ligament in all but one, and was located at the lateral third below the ligament in 82.5% of the specimens. The mean AN diameter was 1.3+/-0.2 mm, and the mean diameter of the dural entrance pore was 1.8+/-0.3 mm, the right being significantly larger than the left. The mean distance of the AN from the posterior clinoid process was 8.4+/-2.5 mm and from the petrous apex 3.6+/-2.1 mm. CONCLUSION: Branching of the AN was present in a significant number of specimens; the branching pattern at the cavernous segment may be called "pseudobranching". The AN is at risk for paresis in indirect conditions because of its angles and fixations on its course. PMID- 20963694 TI - Comparison of the effects of an adhesion barrier and chitin on experimental epidural fibrosis. AB - AIM: Epidural fibrosis is an important factor for postoperative failed back syndrome development and causes clinical complaints in 6-25% of cases. An effective treatment modality has not been found yet. The aim of this study is to investigate the anti-adhesive effects of a novel agent chitin and compare these effects with a popular adhesion barrier collagen matrix. MATERIAL AND METHODS: 21 rabbits were allocated into three groups including 7 rabbits each. L5 total laminectomy was performed to all groups. No treatment was given to Group 1 (Control group). Collagen matrix was used in Group 2 and chitin was used in Group 3. Six weeks later all rabbits were sacrificed and the laminectomy areas were entirely resected and investigated histopathologically. RESULTS: He and Revel grade III epidural fibrosis was detected in the control group. Statistically significant reduction of epidural fibrosis was achieved with both of the anti adhesive agents, collagen matrix and chitin, when compared with the control group (p < 0.05). The results were not different between treatment groups (p > 0.05). CONCLUSION: The novel agent chitin was found effective for preventing epidural fibrosis and this effect was not significantly different from the collagen matrix. In light of our findings we suggest that chitin is an effective alternative for adhesion barriers. PMID- 20963695 TI - Vertebroplasty and kyphoplasty under local anesthesia: review of 91 patients. AB - AIM: Vertebroplasty (VP) and kyphoplasty (KP) are minimally invasive methods for the treatment of vertebral compression fractures (VCF). In this study, we aimed to present our experience with VP and KP performed under local anesthesia and percutaneously. MATERIAL AND METHODS: Between 2002 and 2008, 91 patients (total 112 vertebrae) with VCF due to osteoporosis, tumor and trauma underwent VP or KP. After radiological and routine evaluations, all patients were operated under local anesthesia. Mean operation time was 20 minutes per vertebrae. We never stopped the operation because of intolerance of any patient and all of them were discharged on the day of operation or the next day except one. RESULTS: All patients had severe back pain. Mean preoperative Visual Analogue Scale (VAS) score for pain was 8.3 and the mean postoperative value was 2.7. Mean anterior wall and mid-vertebral body heights increased by 32% and 43%, respectively. The mean kyphotic angle decreased from 15.4 to 11.2. Cement leakage was observed in 4 patients and one of them underwent an open operation (decompression and stabilization) because of cement leakage to the epidural space. There was no other complication. CONCLUSION: Vertebroplasty and kyphoplasty are safe, effective and minimally invasive procedures. Elderly patients can thefore avoid the potential complications of general surgery and be mobilized and discharged early. PMID- 20963696 TI - Repair of the peripheral nerve defect with the combination of allogeneic nerve and autologous neuroma. AB - AIM: To explore the effect of nerve regeneration through repairing the defect of sciatic nerve in rats with the combination of optimized acellular allogeneic nerve and autologous neuroma. MATERIAL AND METHODS: 30 SD rats were randomly divided into two groups A and B, with 15 in each, which were used in preparing the models of the autologous neuroma and the defect of sciatic nerve. In the group A, the combination of allogeneic nerve and autologous neuroma was transplanted; in the group B, the autogenous nerve was transplanted. 15 Wistar rats were used to provide acellular allogeneic nerve, which came from the sciatic nerve in one side of the leg. The electrophysiology examination, the evaluation of sciatic nerve function index and the histological examination were done at the 8th weeks and the 16th weeks after the operation. RESULTS: At the 8th week, the limb escape response appeared in all rats; at the 16th week, there were many nerve fibers passing through the transplant in group A and group B. There was no significant difference in the number of the regenerated nerve fiber, diameter and the thickness of medullary sheath. At the 8th week, the conduction velocity of the regenerative nerve in group A were lower than that in group B (p < 0.05), and there was no statistical difference in two groups at the 16th week; there was no significant deviation in the function index of sciatic nerve in group A and group B(P > 0.05). CONCLUSION: The combination of allogeneic nerve and autologous neuroma, which repairs the defect of peripheral nerve, can promote the regeneration of nerve, and the function of nerve conduction can be recovered, which is a good substitute of nerve grafts. PMID- 20963697 TI - Intraoperative neurophysiological monitoring during surgery for tethered cord syndrome. AB - AIM: The tethered cord syndrome refers to a variety of lesions that can cause the conus medullaris to be low-lying or incapable of movement within the spinal canal. Permanent or temporary neurological complications were reported following surgical release. In this report, peri- and postoperative results in cases with tethered cord syndrome that were followed by multimodal intraoperative neurophysiological monitoring (MIONM) methods are presented. MATERIAL AND METHODS: An IONM system (Nicolet CR Endeavor) was used for monitoring during tethered cord surgery. Somatosensory evoked potentials (SEPs), motor evoked potentials (MEPs), direct nerve root/rootlet stimulation, free-run electromyography (EMG) and F-waves were used during tethered cord surgery of 10 cases to prevent possible nerve injuries. RESULTS: MEP and SEP recordings did not change in any of the cases during surgery. The nervous tissue was identified and differentiated from connective tissue in three cases when motor responses were elicited with direct stimulation of nerve roots. None of the cases had neurological deficits following the operation. CONCLUSION: Direct nerve root/rootlet stimulation should be one of the components of MIONM during surgery for tethered cord syndrome to prevent postoperative neurological deficits. PMID- 20963698 TI - Radiological and histopathological comparison of microporous polysaccharide hemospheres and oxidized regenerated cellulose in the rabbit brain: a study of efficacy and safety. AB - AIM: Topical hemostatic agents are widely used in brain surgery but they have some disadvantages such as foreign body reaction, being a focus for infection and causing artifacts in radiological examinations. The purpose of this study is to compare the effectiveness and safety of microporous polysaccharide hemospheres (MPH) with a well known agent, oxidized regenerated cellulose (ORC), histopathologically and radiologically. MATERIAL AND METHODS: Standard brain lesions (4x1mm) were created in 24 hemispheres in 12 New-Zealand rabbits. Animals were divided into three groups; control, ORC and MPH. Twenty-four hours later, all rabbits magnetic resonance brain imaging. After imaging, the animals were sacrificed and the brains were removed for histopathological analysis. RESULTS: Histopathological analysis showed no significant difference between the groups. Radiological examination showed no significant difference between the MPH and ORC groups in terms of edema but the edema in control group was significantly prominent than MPH and ORC groups (p < 0.001). CONCLUSION: A new agent (MPH) provides safe and effective hemostasis in the brain in this study. The most important advantage of microporous polysaccharide hemospheres is their rapid clearance from the surgical field and therefore having the potential of causing less imaging artifacts. PMID- 20963699 TI - Catabolic cytokine expressions in patients with degenerative disc disease. AB - AIM: Lumbar degenerative disc disease (DDD) is a common disease of advanced age characterized by progressive changes in the intervertebral disc and associated structures. There have been great efforts for years to explain its pathophysiological mechanism(s). This study aims to provide cytokine profile and in addition to the lymphocytes in a population of patients with lumbar DDD. MATERIAL AND METHODS: Twenty-six patients whose clinical and radiological features were suggestive of lumbar DDD that underwent surgery and 14 autopsy cases as control were included. Patient disc samples were obtained during surgery whilst disc materials were collected during autopsy procedures from the controls. Major cytokines and lymphocytes were studied by using the flow cytometry method. RESULTS: Significantly higher levels in disc samples in relation to IL-1beta, IL 2, IL-4, IL-10, IL-12, TNF-alpha, CD8, CD56, CD19, and CD40 were found in the patients compared to the controls. Positive correlations were shown between CD3/CD4, CD25/CD3, CD25/CD4, CD19/CD4 but negative correlations were shown between CD19/CD3 and CD25/CD19 in both groups. CONCLUSION: The findings suggest that both local inflammatory responses occur in lumbar DDD. Using specific cytokines either by local or systemic application may reverse the degenerative process. PMID- 20963700 TI - Postoperative computed tomography assessment of pedicle screw placement accuracy. AB - AIM: Pedicle screw instrumentation is widely used in the lumbar spine as a means of stabilization to enhance arthrodesis and has gained acceptance in the thoracic spine in recent years. The purposes of this study were to determine the incidence of screw misplacement, complications, the accuracy and usefulness of CT scan in evaluation of pedicle screw placement. MATERIAL AND METHODS: Postoperative CT was performed in all 53 cases to evaluate implant position within first month after surgery. The CT scans were obtained with 2-mm axial slices of the instrumented levels. These images were then inspected for evidence of pedicle violation. RESULTS: In assessing 247 pedicle screws inserted in 53 patients, lateral screw misplacement was observed in 59 screws (67.82%) and medial pedicle wall violation in 28 screws (32.18%). Of the 87 misplaced screws, 41 cases were classified as minor (cortical perforation <= 2 mm), 41 cases as moderate (2.1-4 mm), and 5 cases as severe penetration ( > 4 mm).Nerve root injury with radicular pain and neurological deficits was observed in 8 patients with malpositioned screws (15.09% of all patients). CONCLUSION: Pedicle screw placement is a technically demanding procedure with a high complication rate. Fortunately, most complications are not severe. PMID- 20963701 TI - Clinical, radiological and endocrinological findings in a case of McCune-Albright syndrome. AB - The McCune-Albright syndrome was described as a syndrome of polyostotic fibrous dysplasia, cafe au lait skin pigmentation, and autonomous endocrine hyperfunction in 1937. We report a 17-year girl with early menarche and accelerated growth for the past three years. The endocrinological examination showed slight rise of growth hormone with other hormones in normal range. The CT showed an expansive bony lesion over the left parietal area. The bone mass was excised with bone cement cranioplasty performed for the defect. Histology confirmed it was fibrous dysplasia. Although uncommon, this syndrome must be kept in mind in cases with bony abnormalities and extensive endocrinological workup done and treatment given for best results. PMID- 20963702 TI - Endoscopic management of posterior fossa arachnoid cyst in an adult: case report and technical note. AB - The authors report a case of large arachnoid cysts of the posterior fossa treated by endoscopic surgery. A 40-year-old man was admitted with a 3-month history of headache and progressive gait imbalance, with no significant medical history. At the time of admission, neurological examination revealed no abnormalities except for tandem imbalance. Brain computerized tomography (CT) scan and magnetic resonance imaging (MRI) revealed a posterior fossa arachnoid cyst (PFAC) causing brain stem compression accompanied by hydrocephalus. The patient was treated by endoscopic fenestration of the cyst with a paramedian suboccipital transcortical approach. Postoperatively the patient's complaints showed improvement and he was discharged with no complications. Follow up MRI showed a decrease in the cyst's size and the hydrocephalus with decompression of the brain stem. PMID- 20963703 TI - Chronic ossified epidural hematoma after ventriculoperitoneal shunt insertion: a case report. AB - Chronic calcified/ossified epidural hematoma is an uncommon complication of ventricular shunt surgery. There are only 4 cases related to valve-regulated shunt operations in the literature. It may be seen especially in young patients with chronic hydrocephalus, probably due to craniocerebral disproportion. The precise mechanism of the calcification or ossification of the hematoma is not known, however, the dura mater seems to play a part in this process. A 17-year old girl with triventricular hydrocephalus was treated with a ventriculoperitoneal shunt system including a medium pressure flow control valve. She was admitted with a complaint of severe headache after three years and a bifrontal calcified/ossified epidural hematoma was seen. The calcifying hematoma was removed and the patient's headache resolved. Although the use of high or medium pressure valves, valves with an antisiphon device, adjustable pressure valves or flow control valves have been recommended to prevent this complication in previous reports, it was seen that our case had been treated with a medium pressure flow control valve. PMID- 20963704 TI - Residue bone wax simulating spinal tumour: a case report. AB - Bone wax is primarily used in case of bleeding of the diploic vessels of the bones in surgical procedures. It is useful in neurosurgical procedures because of its inert, nonreactive characteristics. Bone wax is safe material and its use rarely leads to complications but there may be complications of over use. It can cause direct pressure of neural tissue as a mass, simulating tumour with the symptoms and on MRI. In the present case the authors evaluated the signs and symptoms, diagnosis, surgical treatment, and outcome in a patient with an unusual sequestered mass simulating a spinal tumour or another space-occupying lesion on preoperative MR imaging. A 64-year-old was woman admitted to the Neurosurgery Clinic with a 10 year history of low back pain, 1-year history of gait disorder, leg weakness, paraparesis, and 1-month history of urinary incontinence and weight loss. T1- weighted sagittal MRI showed the L3 hemilaminectomy, discectomy defect, heterogeneous hyperintense extradural mass and spinal stenosis extending from L2. A hypointense mass relative to the spinal structures was detected in T2- weighted axial MR images.The provisional diagnosis of a cauda equina syndrome and intra- or extradural spinal tumour was made. The patient underwent an L2 total laminectomy. In our case the fragment was seen in the epidural space, under the lamina of L2. The histopathology showed granulation tissue, inflammatory cells, macrophages and multinuclear giant cells. Postoperatively the patient's neurological findings recovered quickly and she began to walk more comfortably. PMID- 20963705 TI - Total resection of inferiorly located sacral chordoma with posterior only approach: case report and review of the literature. AB - Chordoma is a primary sacral neoplasm of ectodermal origin and makes up %1- 4 of all primary bone tumors. It is usually present on the midline cerebrospinal axis and the most common locations are the spheno-clival region and the sacrum. The treatment of primary sacral tumors represents a challenge because of a large tumor mass at presentation and a hemorrhage risk in surgery. Sacral tumors may present a difficult problem to the surgeon who desires to obtain a clear margin of excision. Using the retrorectal fat tissue as a cleavage line in the posterior approach guides the neurosurgeon to resect the tumor totally and reduce the hemorrhage in sacral chordomas. In this case report, we tried to discuss the advantages of using of retrorectal fat tissue as a cleavage line in sacral chordomas under the literature. PMID- 20963706 TI - Bilateral Temporal Bone Xanthomas in Type II Hypercholesterolemia. AB - We present a very rare case of intracranial xanthoma with bilateral temporal bone involvement. The lesion caused destruction and remodelling in mastoid air cells. On the right side, cerebellar compression was obvious. The patient was operated on the symptomatic side and the lesion was totally removed. PMID- 20963707 TI - Diffuse cerebral arteriovenous malformation. AB - Diffuse cerebral arteriovenous malformation (AVM) is a rare disorder of the brain and defined as diffuse infiltration of brain by complex vascular structures. It is usually associated with hereditary syndromes and presented with hemorrhage or seizure. We report a 20-year-old male patient who presented with drooping of the left eyelid. He had no skin lesion. The ophthalmological examination was within normal limits except periorbital bruit on oscultation. Radiological examination revealed a diffuse AVM comprising multiple arteriovenous shunts, draining bihemispherically through numerous dilated veins but without a typical arteriovenous malformation nidus. No hereditary disorder was detected. No treatment was performed and the patient is still under follow-up. PMID- 20963708 TI - A long-segment string of bead- like schwannoma of cauda equina: a case report. AB - Spinal schwannomas are one of the most common intradural extramedullary spinal tumors. However, a string of bead-like intradural extramedullary schwannoma is highly uncommon. In the paper we present a case of a long-segment string of bead like intradural extramedullary schwannoma of cauda equina from L2 to S2.The patient had been suffering progressive low back pain and sciatica with progressive neurological deficits for three years. She was misdiagnosed as lumbar disc herniation at her first time of hospitalization after a simple lumbar computed tomography (CT) scanning and a discectomy. We found her tumor by magnetic resonance imaging (MRI) and totally removed it. We therefore emphasize differentiating this almost completely curable tumor from other lumbar diseases such as lumbar disc herniation. It is suggested that a reasonable and careful strategy of surgery for these tumors is important. PMID- 20963709 TI - Multiple middle meningeal artery aneurysms associated with fistulous galenic arteriovenous malformation: a case report. AB - Non-traumatic multiple saccular aneurysms of the middle meningeal artery are extremely rare lesions. In our case the patient was a 51-year-old woman admitted with complaints of progressive headache. Magnetic resonance imaging showed a dilatation of the vein of galen malformation. Cerebral angiography revealed multiple saccular aneurysms of the middle meningeal artery and fistulous type of galenic arteriovenous malformation. Only one case of non-traumatic multiple middle meningeal artery aneurysms has been reported until now and this case of multiple multiple middle meningeal artery aneurysms associated with the fistulous type of galenic arteriovenous malformation is unique. PMID- 20963710 TI - Foreign body within sphenoid sinus: multidetector-row computed tomography (MDCT) demonstration. AB - Trans-nasal sphenoid sinus foreign body is a rare condition. We report a case of trans-nasal gun bullet within the sphenoid sinus with breach of the floor of the sella turcica. A 42-year-old soldier presented a few weeks after a gun battle with a history of headache. The skull x-ray demonstrated a foreign body in the region of sphenoid sinus and sella. Multidetector-row CT with multiplanar reformats demonstrated a bullet within the sphenoid sinus with its tip penetrating into the sella turcica. A few days later the patient coughed up the bullet as it came out spontaneously without any intervention. This is perhaps the unique occurrence of such a foreign body. PMID- 20963711 TI - A case of intracranial hypotension complicated with hydrocephalus. AB - AIM: Intracranial hypotension may have variable clinical presentation. The imaging characteristics of intracranial hypotension are especially well depicted on magnetic resonance imaging studies. Although the clinical and radiological manifestations of spontaneous intracranial hypotension are increasingly recognized in many reports, many other abnormalities in this disorder and complicating cases still exist. MATERIAL AND METHODS: A 16-year-old patient suffering from nausea vomiting and blurred consciousness was admitted to the hospital. MRI showed diffuse pachymeningeal thickening resembling intracranial hypotension and ventricular enlargement like compensated hydrocephalus. The patient was investigated and treated using endoscopic third ventriculostomy. CONCLUSION: The authors presented a case of intracranial hypotension complicated with hydrocephalus. Specific causes for intracranial hypotension as well as additional new treatment options will also be discussed. PMID- 20963712 TI - Is spontaneous spinal epidural hematoma in elderly patients an emergency surgical case? AB - Spontaneous spinal epidural hematoma (SSEH) is a rare condition requiring urgent diagnosis and treatment. Patients with SSEH typically present with acute onset of severe back pain and rapidly develop signs of compression of the spinal cord. The authors present a case with spontaneous resolution of SSEH which is extremely rare. We discuss a man who presented to our clinic with mild paraparesis at the seventh day of his symptoms. He had a history of poorly controlled hypertension and hypercholestrolemia requiring an antihyperlipidemic agent and anticoagulation. His upper level of hypoesthesia was at the third thoracic segment. Cervicothoracic SSEH was diagnosed by magnetic resonance imaging. Since there was a gradual recovery of the neurological deficits beginning 12 hours after the onset of symptoms, surgery was obviated and strict bed rest, serial neurological examinations, and pain controls with opiates were instituted. The neurological deficits showed complete recovery on the 25th day of the clinical course. SSEH is rare and immediate surgical decompression is suggested. Rapid neurological deterioration followed by early and progressive neurological recovery, confirmed by radiological resolution of the lesion, may indicate nonoperative treatment. PMID- 20963713 TI - Syringomyelia and intradural extramedullary tuberculoma of the spinal cord as a late complication of tuberculous meningitis. AB - Intradural extramedullary (IDEM) tuberculomas account for only 1% of all spinal tuberculomas. Concurrent IDEM tuberculoma and syringomyelia arising as a complication of tuberculous meningitis (TM) is extremely rare and only two cases have been reported to date. There is yet no report in the literature describing syringomyelia presenting as a delayed complication of IDEM tuberculoma. Here we present such a case. A 21 year-old male patient underwent partial decompression for thoracolumbar IDEM tuberculoma as a late complication of tuberculous meningitis. Spinal magnetic resonance imaging (MRI) of the patient suffering from progression of paraparesia six months after the operation revealed a syringomyelia occupying the space from T1 to T9, remote from the operation site, and syringo-peritoneal shunt placement was performed. PMID- 20963714 TI - Cauda equina syndrome caused by a migrated bullet in dural sac. AB - Cauda equina syndrome (CES) is a serious neurological condition and the most common cause is a central disc herniation. Migration of a bullet down the spinal canal is uncommon. In this report, the authors present an unusual case of cauda equina syndrome caused by a migrated bullet in dural sac. The patient's cauda equina syndrome was related to possible compression of cauda equina resulting from both bone fragments in L1 level and bullet itself in S2 level. The patient's symptoms and neurological deficits resolved considerably after surgery. In our opinion, it is important to pay attention to diversity of injury when confronted with a gunshot wound. It is essential to perform early and sufficient surgical decompression of the cauda equina to provide a better postoperative neurological recovery. PMID- 20963715 TI - Aplasia cutis congenita of the scalp. PMID- 20963716 TI - [New diagnostic concept of adjustment disorders in psychosomatic outpatients- symptom severity, willingness to change, psychotherapy motivation]. AB - OBJECTIVES: Adjustment disorders (AD) represent a frequently diagnosed type of disorder for which scientific interest has been limited because of insufficient diagnostic criteria. This study presents a concept comprising cognitive, behavioural, and emotional criteria (ADNM) which investigates differences in symptom severity, willingness to change, and motivation for psychotherapy in subjects with adjustment disorders. METHOD: 331 outpatients were examined with a number of tools (ADNM, SCL-90-R, FPTM-23, FEVER). The ADNM is evaluated on the basis of theoretical assumptions and divides the sample into subjects with elevated and normal scores. RESULTS: The sample comprised patients with elevated scores (61%) and normal scores (39%).Subjects with AD scored higher on depression, anxiety, and impulsivity as well as exhibiting elevated scores on the SCL-90-R, for contemplation/action, and for psychotherapy motivation. CONCLUSION: The ADNM identifies patients experiencing stress. Further longitudinal studies should examine whether patients more frequently enter psychotherapy or not. PMID- 20963717 TI - [Initial and extension applications for psychodynamic therapy according to the German Guidelines for Psychotherapy]. AB - RESEARCH QUESTION: According to the German Guidelines for Psychotherapy, psychotherapists need the consent of the respective insurance company to commence outpatient therapy. They have two options: (1) To begin a so-called short-term therapy (KZT) for up to 25 sessions--a quick and easy procedure requiring few formal expenses. Afterwards the therapist must provide the reasons for extending the therapy in a formal expert assessment request (extension request). (2) It is also possible to obtain the consent of the insurance company at the beginning of therapy (initial request) for up to 50 sessions (psychodynamic long-term therapy) or even for up to 160 sessions (analytical psychotherapy), both of which require the same expert assessment to be filled out beforehand (LZT). This study examines the initial and extension requests submitted for evaluation for psychodynamic therapies according to the German Guidelines for Psychotherapy. The question is posed as to what influences are important in the selection of therapists for these two types of request. METHODOLOGY: In the context of the MARS study, we evaluated a total of 362 randomly chosen requests submitted between May 2007 and June 2008, 128 of which were initial requests and 234 of which were requests for an extension. The evaluation of the reports proceeded on the basis of a previously developed documentation system with various modules comprising information on the sociodemographics and morbidity of the patients as well as information on the therapists themselves. Further modules are assessed in this review. RESULTS: There were many more requests for an extension submitted than initial requests. Initial requests were preferably made when planning analytical psychotherapy. Patients for whom initial requests were submitted were also distinctly younger. The morbidity of the patients had no noticeable influence on the choice of procedure. In particular, diagnoses that could require crisis intervention were not more common in the requests for an extension than in the initial requests. Variables among the therapists had no influence on the form of procedure. These results were confirmed by a multivariate statistical analysis. DISCUSSION: The inconsistencies found in the reported and encoded morbidity of the patients confirm earlier results. Basic conditions, like the guidelines themselves or the payment of trial treatment, seem to determine therapists' behaviour. We also discuss whether or not the advantages of the current procedures to both the patient and the therapist outweigh the possible disadvantages.. PMID- 20963718 TI - [Frequency and consequences of financial problems in patients undergoing outpatient psychosomatic treatment]. AB - OBJECTIVES: About seven million people in Germany are affected by overindebtedness and insolvency. Being severely in debt is a very stressful situation that can result in social marginalisation, reducted overall activity, and physical and mental illness. The present study investigated the frequency of financial problems and their effects on physical and mental disorders at a university psychosomatic clinic. METHODS: The study included a total of 659 patients. Their mental status was assessed with the Symptom Checklist (SCL-90-R), their physical status with the Giebetaener Beschwerdebogen (GBB). RESULTS: 37 percent of the subjects reported experiencing financial problems. We found that subjects with financial problems reported more physical and mental disorders than those without financial problems. Furthermore, therapists more often recommended that patients with financial problems receive inpatient therapy than patients without financial problems. CONCLUSION: The study suggests that financial problems should be included in any anamnesis, therapeutic recommendation, and actual therapy of patients in psychosomatic treatment. PMID- 20963719 TI - [Subjective experiences following organ transplantation--a qualitative study of 120 heart, lung, liver, and kidney recipients]. AB - OBJECTIVES: The communication with patients who have undergoned transplantation is greatly influenced by their subjective experience. This paper deals with this subjective transplant-specific experience six months after surgery. METHODS: Following their heart, lung, liver, or kidney transplantation, 120 patients were questioned concerning their experiences regarding the transplantation, the organ itself, and changes in their personal life. Their statements were investigated by qualitative content analysis. RESULTS: Generally, the statements concerning the transplantation were positive. Interpersonal contact with the medical staff and or family members was perceived as very helpful. Two-thirds of the patients spoke openly about their organ. For the most part, their statements about changes in their personal life were positive, expressed in the sense of personal growth. Fears and insecurities occurred as negative changes. CONCLUSIONS: On the whole, the majority of the patients expressed positive experiences regarding their transplantation. Interpersonal and supportive relationships played a significant role. PMID- 20963720 TI - [Age-, gender- and diagnosis-specific differences in the body image of psychosomatic outpatients]. AB - OBJECTIVE: This study investigates body image with respect to the age, gender, and psychiatric diagnosis (ICD-10) of psychosomatic outpatients based on apriori formulated hypotheses. METHODS/SAMPLE: 865 of the 1114 patients examined over the course of 10 months in a psychosomatic clinic agreed to participate in the study and filled in the Frankfurt Body Concept Scales (FKKS, Deusinger 1998). RESULTS: Patients with one or more psychiatric diagnoses showed significantly more impaired body images than did healthy controls examined with the FKKS. Especially patients with eating disorders stood out. Men generally had more positive body images than women. Higher age was related to some subscales, but not to the sumscore of the FKKS. DISCUSSION: We discuss the complex relationship between gender- and age-related differences, mental disorders and body image, as well as their therapeutic implications. PMID- 20963721 TI - [Psychotherapy research in the German-speaking community--a bibliometric analysis of three journals]. AB - OBJECTIVES: Psychotherapy research has often been considered a neglected topic in clinical psychology, psychosomatic medicine, and psychiatry because of its massive organizational and financial demands. However, it is unclear whether this assumption actually reflects the research activities in the field. METHODS: We conducted a bibliometric analysis of the annual volumes for 2008 and 2009 of three clinical journals published in German. All publications referring to facets of psychotherapy research were analysed. RESULTS: About 30% of the publications dealt with issues of psychotherapy research. Outcome and process studies were about equally distributed. Process research frequently focused on patient variables as outcome predictors. Outcome studies most often presented effectiveness studies with rather small sample sizes. CONCLUSION: Psychotherapy research is a well-represented and multifaceted field in the German speaking research community. However, the traditional distinction between efficacy and process research among the various schools of psychotherapy research may be hampering further developments in this branch. The government-funded research networks may turn out to be promising approaches to overcoming some of the obstacles of classic psychotherapy research. PMID- 20963722 TI - Host defense against implant infection: the ambivalent role of phagocytosis. AB - Bacteria embedded in biofilms resist both antibiotics and host defense mechanisms. However, biofilms are not inherently protected against the attack of phagocytic cells. The weapons that polymorphonuclear neutrophils employ against implant infection are phagocytosis, degranulation, with release of antimicrobial molecules, and formation of Neutrophil Extracellular Traps (NETs). NETs contain DNA, histones, and neutrophil elastase, which enable neutrophils to fulfill their role of limiting both microbial spread and the collateral damage from granular contents. It is not yet clear whether the DNA released by neutrophils would support biofilm formation by adding to bacterial extracellular DNA (eDNA), an integral part of the biofilm extracellular matrix. In spite of the evidence of somewhat effective phagocytosis around an implant infection, biofilm-embedded staphylococci persist, tissue destruction occurs and, in the case of orthopedic implant infection, osteolysis prevails. The mechanism for tissue destruction is based on the infiltration and persistence at the site of infection of neutrophils which are unable to effectively perform phagocytosis, but able to inflict tissue damage and cause osteolysis by the release of proteolytic and collagenolytic enzymes. Phagocytosis thus has an ambiguous and ambivalent role: it carries out an antibacterial strategy and at the same time is responsible for osteolysis. PMID- 20963723 TI - Rapid identification of staphylococci from prosthetic joint infections using MALDI-TOF mass-spectrometry. AB - Hospital-acquired infections associated with implanted medical devices are most commonly caused by staphylococci. Current methods of species identification are slow, costly, and sometimes unreliable. We evaluated the ability of a Bruker Daltonics Microflex MALDI-TOF/MS in conjunction with MALDI Biotyper software to identify 158 characterized staphylococcal isolates from prosthetic joint infections, including 36 Staphylococcus aureus, 100 Staphylococcus epidermidis, 10 Staphylococcus capitis, 8 Staphylococcus lugdunensis, 2 Staphylococcus warneri, and 2 Staphylococcus haemolyticus isolates using the extraction method recommended by Bruker Daltonics. The suggested species identification by the MALDI Biotyper software was correct for all isolates, indicating reliable differentiation between S. aureus and coagulase-negative staphylococci. Applying the recommended criteria of the MALDI Biotyper software all 158 isolates gave scores >=2.0, implying secure genus and probable species identification for all isolates. 34/36 S. aureus, 36/100 S. epidermidis, 5/10 S. capitis, 6/8 S. lugdunensis, 2/2 S. haemolyticus, 0/2 S. warneri displayed scores >=2.3 implying highly probable species identification. For S. epidermidis 25/100 additional isolates had a score close to 2.3. It appears that additional clinically relevant staphylococcal isolates in the data base might aid in identification at scores implying highly probable species identification. The ability of the MALDI Biotyper software to recognize clonally-related strains within a species group (i.e. sub-typing) was investigated, and showed great potential. In conclusion, the MALDI-TOF/MS MALDI Biotyper system provides a promising rapid and reliable method of identifying clinical isolates from prosthetic joint infections to the species level, and has potential for sub-typing. PMID- 20963724 TI - Characterization of 26 Staphylococcus warneri isolates from orthopedic infections. AB - Staphylococcus warneri is a coagulase negative Staphylococcus (CNS) commonly present in the flora of human epithelia and mucosal membranes. Over the last two decades, similarly to other CNS species, S. warneri has been reported as a new emerging pathogen, capable of causing serious infections usually in association with the presence of implant materials, but, at times, even in the absence of a foreign body and in patients considered immunocompetent. At present, there is still a lack of scientific data on the pathogenesis and epidemiology of this species. The present study investigated a collection of 26 clinical isolates derived from orthopedic infections, some associated with implant materials and others not. Automated ribotyping showed the existence of 5 distinct ribogroups. Except for the least numerous ribogroup consisting of a single isolate, all other ribogroups included at least one strain obtained from an infection not associated with implant materials, suggesting that putative virulence factors necessary for infections even in the absence of a foreign body could be transversal to most ribogroup categories. Orthopedic infections were found to involve S. warneri strains with low antibiotic resistance potential, differing in this respect from the strains isolated at neonatal intensive care units, where this species has been described to figure among the principal causative agents and exhibit an alarming profile of antibiotic resistance. PMID- 20963725 TI - Molecular mechanisms of RIP, an effective inhibitor of chronic infections. AB - Non-healing bacterial infections are often associated with the formation of a biofilm, where bacteria are more resistant to conventional treatment modalities and to host immune responses. We show here that RNAIII inhibiting peptide (RIP), a linear heptapeptide, is very effective in treating severe polymicrobial infections, including drug-resistant staphylococci like MRSA. By functional genomics studies (microarray analysis) on Staphylococcus aureus, we show here that RIP downregulates the expression of genes involved in biofilm formation and toxin production, and upregulates genes involved in stress response. This pattern of gene regulation may explain why RIP has been so effective in treating severe infections and hopefully through the addition of RIP to existing protocols, a new way of tackling chronic persistent infections will be established. PMID- 20963726 TI - YhgC protects Bacillus anthracis from oxidative stress. AB - Bacillus anthracis can cause lethal inhalational anthrax and can be used as a bioweapon due to its ability to form spores and to survive under various environmental stress conditions. YhgC in bacilli are structural homologues of TRAP, a protein involved in stress response in staphylococci. To test the role of YhgC in B. anthracis, yhgC gene was deleted in B. anthracis strain Sterne and parent and mutant strains tested. Immunolocalization studies indicated that YhgC is clustered both on the cell surface and within the cytoplasm. Phenotypic analyses indicated that YhgC is an important factor for oxidative stress tolerance and for macrophage infection in vitro. Accordingly, transcriptomics studies indicated that yhgC has a profound effect on genes encoding for stress response regulatory proteins where it negatively regulates the expression of genes encoding for Class I and Class III stress response proteins belonging to the regulons hrcA (hrcA, grpE, dnaK, dnaJ, groEL and groES) and ctsR (ctsR, mcsA, mcsB, clpC/mecB, clpP1). Proteomics studies also indicated that YhgC positively regulates the expression of ClpP-2 and camelysin, which are proteins involved in adaptive responses and pathogenesis in various Gram-positive bacteria. Put together, these results suggest that YhgC is important for the survival of B. anthracis under oxidative stress conditions and thus inhibition of YhgC may compromise the ability of the bacteria to survive within the host. PMID- 20963727 TI - Efficacy of local rifampin/minocycline delivery (AIGIS(RX)(r)) to eliminate biofilm formation on implanted pacing devices in a rabbit model. AB - PURPOSE: Device-related infections represent a significant clinical challenge. Once established, these infections prove difficult to treat with existing antibiotic regimens, compromising the health of device recipients, and usually requiring surgical intervention to resolve. The purpose of this study was to determine the ability of the AIGIS(RX)(r) Anti-Bacterial envelope to reduce the formation of bacterial biofilm on implanted pacing devices. METHODS: An infection was established in a rabbit model by creating bilateral subcutaneous implant pockets, into which a pacing device with or without AIGIS(RX)(r) was placed. The incisions were closed, and a defined dose of bacteria was infused into each implant pocket. After seven days, devices were explanted and assessed for viable bacteria by a sonication/vortex procedure to quantify bacteria, and by imaging of the device surface by scanning electron microscopy and laser scanning confocal microscopy. RESULTS: The presence of the AIGIS(RX)(r) envelope eliminated recoverable, viable bacteria from the explanted devices using a vortex/sonication technique from in vivo models of Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus capitis, and Escherichia coli infections. Scanning electron microscopy and confocal microscopy demonstrate greatly reduced biological material on the pacemaker surfaces in the presence of the AIGIS(RX)(r) envelope compared to untreated controls. CONCLUSION: These results demonstrate that in this animal model, the AIGIS(RX)(r) device reduces the formation of adherent bacteria and reduces bioburden on implanted, infected pacemaker devices. PMID- 20963728 TI - Photodynamic action of Tri-meso (N-methyl-pyridyl), meso (N-tetradecyl-pyridyl) porphine on Staphylococcus epidermidis biofilms grown on Ti6Al4V alloy. AB - Staphylococcus epidermidis is a leading cause of nosocomial infections, and its virulence is attributable to formation of biofilm, especially on implanted devices. Photodynamic treatment (PDT) has been actively investigated for the eradication of bacterial biofilm growing on dental plaques and oral implants. In this study, we used Tri-meso (N-methyl-pyridyl), meso (N-tetradecyl-pyridyl) porphine (C14) for inactivation of two structurally distinct S. epidermidis biofilms grown on Ti6Al4V alloy and compared its photosensitizing efficiency with that of the parent molecule, tetra-substituted N-methyl-pyridyl-porphine (C1). A more significant reduction in bacterial survival was observed when both bacterial biofilms were exposed to a lower dose of C14, and simultaneously to visible light in comparison with C1. The different responses of both staphylococcal biofilms to C1- or C14-treatment appeared to depend on photosensitizer endocellular concentration. C14 bound to both biofilms to a greater extent than C1. Moreover, C14 penetrates deeper into the bacterial membranes, as determined by fluorescence quenching experiments with methylviologen, allowing for better bacterial killing photoefficiency. Confocal laser scanning microscope (CLSM) analysis indicated damage to bacterial cell membranes in both photodynamically treated biofilms, while disruption of PDT-treated biofilm was confirmed by scanning electron microscopy (SEM). In summary, C14 may be a potential photosensitizer for the inactivation of staphylococcal biofilms for many device-related infections which are accessible to visible light. PMID- 20963729 TI - Antimicrobial activity of sodium hypochlorite-based irrigating solutions. AB - PURPOSE: The objective of the present study was the in vitro evaluation of the antimicrobial activity of three different NaOCl-based endodontic irrigating solutions: a 5.25% conventional sodium hypochlorite solution; and two new irrigating solutions, a 5.25% sodium hypochlorite solution with the addition of a proteolytic enzyme and a surfactant; and a 5.25% sodium hypochlorite gel with inorganic silicate. METHODS: Enterococcus faecalis, Staphylococcus aureus and Streptococcus mutans strains were selected to evaluate the antimicrobial activity of the endodontic irrigating solutions by the agar disc diffusion test. Paper disks were saturated with each one of the tested solutions (at room temperature and pre-warmed at 45 degrees C) and placed onto culture agar-plates pre-adsorbed with bacterial cells and further incubated for 24 h at 37 degrees C. The growth inhibition zones around each irrigating solution were recorded and compared for each bacterial strain. RESULTS: The results were significantly different among the tested irrigating solutions: 5.25% sodium hypochlorite solution produced the highest inhibition areas; 5.25% sodium hypochlorite solution with a proteolytic enzyme and a surfactant, and 5.25% sodium hypochlorite gel with inorganic silicate showed the lowest zones of inhibition. CONCLUSIONS: Even if all tested irrigating solution possessed antibacterial activity versus all tested bacterial strains, 5.25% sodium hypochlorite solution with a proteolytic enzyme and a surfactant, and 5.25% sodium hypochlorite gel with inorganic silicate showed lower in vitro efficacy than 5.25% conventional sodium hypochlorite solution. PMID- 20963730 TI - SEM evaluation of the root canal walls after treatment with Tetraclean. AB - PURPOSE: In this ex vivo study, the surface cleanliness of root canal walls after shaping with Ni-Ti instruments and irrigating with different endodontic solutions was evaluated by SEM. METHODS: 50 single-rooted teeth were divided into 5 groups. All root canals were shaped with Revo-STM (MICRO-MEGA(r), Besancon, France) rotary Ni-Ti instruments and irrigated with NaOCl, varying the final rinse: NaOCl, Tetraclean, 17% EDTA, Cloreximid, Tetraclean liquid not mixed with powder. Specimens were fractured longitudinally and prepared for SEM analysis in order to evaluate the presence/absence of smear layer and the presence/absence of open tubules at the coronal, middle, and apical third of each canal, using a 3-step scale for scores. Numeric data were analyzed using Kruskall-Wallis test and Mann Whitney U test and significance was predetermined at p<0.05. RESULTS: This study showed significant differences between the various groups. The 5.25% NaOCl + Tetraclean and 5.25% NaOCl + 17% E.D.T.A. groups had significantly lower scores than other groups (p<0.001), with no significant difference between them. CONCLUSIONS: Final rinse with Tetraclean is effective in removing the smear layer, leaving a high number of opened dentin tubules. PMID- 20963731 TI - Solubility of root canal sealers: a comparative study. AB - INTRODUCTION: Root canal sealers used in odontological applications are capable of providing an apical seal, thus inhibiting potential bacterial penetration into the periradicular tissues. Since insolubility is the ideal characteristic for a root canal sealer material, in dentistry the sealability of the material depends on its solubility. PURPOSE: This study tested the solubility of six different root canal sealers: two ZnOE-based sealers (Endomethasone C and Argoseal), two calcium hydroxide-containing sealers (Bioseal Normal and Acroseal), and two resin based sealers (AH Plus and MM Seal). METHODS: Ten specimens of each material were prepared using stainless steel ring molds with the same internal diameter and the same height in order to obtain similar samples, and immersed in water. Solubility was determined by using sample weight loss (%) after 24 hours and after 2 months. The test was performed according to the International Standards Organization 6876 standard and the American Dental Association specifications No. 30 and No. 57. Data were statistically analyzed with a one-way analysis of variance test (ANOVA). RESULTS: The ANOVA test showed significant differences between the various groups. The post-hoc test showed that resin-based root canal sealers had significantly lower solubility percentages than other groups (p<0.05), and showed no difference between them (p>0.05). CONCLUSIONS: All the materials fulfilled the requirements of International Standard 6876 and ANSI/ADA specifications demonstrating a weight loss of less than 3%. Under the conditions of the present study, all root canal sealers were of low solubility, but the lowest solubility percentages were recorded in resin-based root canal sealers, which can be considered virtually insoluble, and thanks to this physical property, ideal for use as endodontic sealer. PMID- 20963732 TI - Performance of statistical methods for analysing survival data in the presence of non-random compliance. AB - Noncompliance often complicates estimation of treatment efficacy from randomized trials. Under random noncompliance, per protocol analyses or even simple regression adjustments for noncompliance, could be adequate for causal inference, but special methods are needed when noncompliance is related to risk. For survival data, Robins and Tsiatis introduced the semi-parametric structural Causal Accelerated Life Model (CALM) which allows time-dependent departures from randomized treatment in either arm and relates each observed event time to a potential event time that would have been observed if the control treatment had been given throughout the trial. Alternatively, Loeys and Goetghebeur developed a structural Proportional Hazards (C-Prophet) model for when there is all-or nothing noncompliance in the treatment arm only. Whitebiet al. proposed a 'complier average causal effect' method for Proportional Hazards estimation which allows time-dependent departures from randomized treatment in the active arm. A time-invariant version of this estimator (CHARM) consists of a simple adjustment to the Intention-to-Treat hazard ratio estimate. We used simulation studies mimicking a randomized controlled trial of active treatment versus control with censored time-to-event data, and under both random and non-random time-dependent noncompliance, to evaluate performance of these methods in terms of 95 per cent confidence interval coverage, bias and root mean square errors (RMSE). All methods performed well in terms of bias, even the C-Prophet used after treating time-varying compliance as all-or-nothing. Coverage of the latter method, as implemented in Stata, was too low. The CALM method performed best in terms of bias and coverage but had the largest RMSE. PMID- 20963733 TI - Analysis of recurrent gap time data using the weighted risk-set method and the modified within-cluster resampling method. AB - The gap times between recurrent events are often of primary interest in medical and epidemiology studies. The observed gap times cannot be naively treated as clustered survival data in analysis because of the sequential structure of recurrent events. This paper introduces two important building blocks, the averaged counting process and the averaged at-risk process, for the development of the weighted risk-set (WRS) estimation methods. We demonstrate that with the use of these two empirical processes, existing risk-set based methods for univariate survival time data can be easily extended to analyze recurrent gap times. Additionally, we propose a modified within-cluster resampling (MWCR) method that can be easily implemented in standard software. We show that the MWCR estimators are asymptotically equivalent to the WRS estimators. An analysis of hospitalization data from the Danish Psychiatric Central Register is presented to illustrate the proposed methods. PMID- 20963734 TI - Reduction from copper(II) to copper(I) upon collisional activation of (pyridine)(2) CuCl(+). AB - Electrospray ionization of dilute aqueous solutions of copper(II) chloride containing traces of pyridine (py) as well as ammonia permits the generation of the gaseous ions (py)(2) Cu(+) and (py)(2) CuCl(+) , of which the latter is a formal copper(II) compound, whereas the former contains copper(I). Collision induced dissociation of the mass-selected ions in an ion-trap mass spectrometer (IT-MS) leads to a loss of pyridine from (py)(2) Cu(+) , whereas an expulsion of atomic chlorine largely prevails for (py)(2) CuCl(+) . Theoretical studies using density functional theory predict a bond dissociation energy (BDE) of BDE[(py)(2) Cu(+) -Cl] = 125 kJ mol(-1) , whereas the pyridine ligand is bound significantly stronger, i.e. BDE[(py)CuCl(+) -py] = 194 kJ mol(-1) and BDE[(py)Cu(+) -py] = 242 kJ mol(-1) . The results are discussed with regard to the influence of the solvation on the stability of the Cu(I) /Cu(II) redox couple. PMID- 20963735 TI - Log-linear, logistic model fitting and local score statistics for cluster detection with covariate adjustments. AB - The standard method for p-value computation of spatial scan statistics, with adjustments for covariate effects, is to conduct Monte Carlo simulations with these effects estimated under the null hypothesis of no clustering. However when the covariates are geographically unbalanced, the proposed Monte Carlo p-value estimates are too conservative, with corresponding loss of power, due to excessive adjustments for confounding between covariates and location. We show that the use of an alternative procedure that involves local score statistics, with parameters fitted on a log-linear or logistic model, addresses this problem. We also discuss extensions of the procedure when there are multiple or continuous covariates. PMID- 20963736 TI - Testing Hardy-Weinberg equilibrium: an objective Bayesian analysis. AB - We analyze the general (multiallelic) Hardy-Weinberg equilibrium problem from an objective Bayesian testing standpoint. We argue that for small or moderate sample sizes the answer is rather sensitive to the prior chosen, and this suggests to carry out a sensitivity analysis with respect to the prior. This goal is achieved through the identification of a class of priors specifically designed for this testing problem. In this paper, we consider the class of intrinsic priors under the full model, indexed by a tuning quantity, the training sample size. These priors are objective, satisfy Savage's continuity condition and have proved to behave extremely well for many statistical testing problems. We compute the posterior probability of the Hardy-Weinberg equilibrium model for the class of intrinsic priors, assess robustness over the range of plausible answers, as well as stability of the decision in favor of either hypothesis. PMID- 20963737 TI - Concise and diversity-oriented route toward polysubstituted 2-aminoimidazole alkaloids and their analogues. PMID- 20963738 TI - Towards selective ethylene tetramerization. PMID- 20963739 TI - Short diastereoselective synthesis of the C1-C13 (AB spiroacetal) and C17-C28 fragments (CD spiroacetal) of spongistatin 1 and 2 through double chain elongation reactions. AB - A unique and practical synthetic sequence for rapid access to polyketides and to further the spiroacetals derived from them, which utilizes a bidirectional Hosomi Sakurai allylation approach around key allylsilanes in the synthesis of the AB and CD ring systems of spongistatin 1 and 2, is reported. The synthesis of the AB spiroacetal 9 requires 13 steps, with a longest linear sequence of seven steps in an overall yield of 27%. The synthesis of the CD spiroacetal 13 requires 15 steps, with a longest linear sequence of 11 steps in an overall yield of 30%. Both syntheses start from but-3-enol. PMID- 20963740 TI - Real-time SNP analysis in secondary-structure-folded nucleic acids. PMID- 20963741 TI - Three-component assembly and divergent ring-expansion cascades of functionalized 2-iminooxetanes. PMID- 20963742 TI - Mechanism of glucose isomerization using a solid Lewis acid catalyst in water. PMID- 20963745 TI - Trap-closing chemical factors of the Venus flytrap (Dionaea muscipulla Ellis). PMID- 20963744 TI - Rate coefficients for the reaction of iodine oxide with methyl peroxy radicals. AB - Pulsed laser photolysis radical generation is used to study the title reaction IO+CH(3)O(2)->products. Sensitive and selective laser-induced fluorescence detection of IO allows excess CH(3)O(2) conditions to be maintained throughout, ensuring minimal interference from other fast IO reactions. The rate coefficients, k(5)(296 K)=(3.4+/-1.4)*10(-12) cm(3) molecule(-1) s(-1), are obtained relative to a well-characterised reference value (k(3) for IO+HO(2)). This result agrees well with a previous determination from this laboratory and demonstrates that the above reaction proceeds an order of magnitude slower than suggested in other recent experimental and theoretical studies. Implications for HOx production/O(3) destruction within the marine boundary layer are briefly discussed. PMID- 20963746 TI - Two-photon fluorescent probes for metal ions. AB - Two-photon microscopy (TPM) has become an indispensible tool in biology and medicine owing to the capability of imaging the intact tissue for a long period of time. To make it a versatile tool in biology, a variety of two-photon probes for specific applications are needed. In this context, many research groups are developing two-photon probes for various applications. In this Focus Review, we summarize recent results on model studies and selected examples of two-photon probes that can detect intracellular free metal ions in live cells and tissues to provide a guideline for the design of useful two-photon probes for various in vivo imaging applications. PMID- 20963747 TI - Ring like octadecanuclear mixed-valence manganese cluster with a spin ground state of 20. PMID- 20963748 TI - Confidence intervals for random effects meta-analysis and robustness to publication bias. AB - The DerSimonian-Laird confidence interval for the average treatment effect in meta-analysis is widely used in practice when there is heterogeneity between studies. However, it is well known that its coverage probability (the probability that the interval actually includes the true value) can be substantially below the target level of 95 per cent. It can also be very sensitive to publication bias. In this paper, we propose a new confidence interval that has better coverage than the DerSimonian-Laird method, and that is less sensitive to publication bias. The key idea is to note that fixed effects estimates are less sensitive to such biases than random effects estimates, since they put relatively more weight on the larger studies and relatively less weight on the smaller studies. Whereas the DerSimonian-Laird interval is centred on a random effects estimate, we centre our confidence interval on a fixed effects estimate, but allow for heterogeneity by including an assessment of the extra uncertainty induced by the random effects setting. Properties of the resulting confidence interval are studied by simulation and compared with other random effects confidence intervals that have been proposed in the literature. An example is briefly discussed. PMID- 20963749 TI - Cluster size variability and imbalance in cluster randomized controlled trials. AB - Cluster randomized controlled trials are increasingly used to evaluate medical interventions. Research has found that cluster size variability leads to a reduction in the overall effective sample size. Although reporting standards of cluster trials have started to evolve, a far greater degree of transparency is needed to ensure that robust evidence is presented. The use of the numbers of patients recruited to summarize recruitment rate should be avoided in favour of an improved metric that illustrates cumulative power and accounts for cluster variability. Data from four trials is included to show the link between cluster size variability and imbalance. Furthermore, using simulations it is demonstrated that by randomising using a two block randomization strategy and weighting the second by cluster size recruitment, chance imbalance can be minimized. PMID- 20963750 TI - Parameterization of treatment effects for meta-analysis in multi-state Markov models. AB - Standard approaches to analysis of randomized controlled trials (RCTs) using Markov models make it difficult to generalize treatment effects to new patient groups and synthesize evidence across trials. This paper demonstrates how pair wise and mixed treatment comparison meta-analysis can be applied to event history data for disease progression reported by RCTs. The data, in the form of aggregated discrete time transitions, have a multi-nomial likelihood. In order for evidence synthesis to be performed a structured approach to modelling the differences in the effects of the different treatments must be taken. A multi state continuous-time Markov model similar to others used in published economic evaluations of asthma treatments is developed, with transition rates related to the likelihood via Kolmogorov's forward equations. The formulation in terms of rates allows a flexible characterization of summary treatment effects. These ideas are applied to an illustrative data set consisting of a set of five trials comparing eight different treatments for asthma. A range of models is developed in which the relative treatment effects act on forward, backward transitions, or both, and models are compared using the DIC. Bayesian inferential techniques are used and the parameters are estimated using MCMC simulation in WinBUGS. An intuitively appealing mechanism of action involving a single parameter acting on all backward transitions was identified for the relative effects of the treatments, which allowed the estimation of a pooled treatment effect, allowing us to rank the different treatment options within each connected evidence network to ascertain which were the most clinically effective. PMID- 20963751 TI - A stochastic multiple imputation algorithm for missing covariate data in tree structured survival analysis. AB - Missing covariate data present a challenge to tree-structured methodology due to the fact that a single tree model, as opposed to an estimated parameter value, may be desired for use in a clinical setting. To address this problem, we suggest a multiple imputation algorithm that adds draws of stochastic error to a tree based single imputation method presented by Conversano and Siciliano (Technical Report, University of Naples, 2003). Unlike previously proposed techniques for accommodating missing covariate data in tree-structured analyses, our methodology allows the modeling of complex and nonlinear covariate structures while still resulting in a single tree model. We perform a simulation study to evaluate our stochastic multiple imputation algorithm when covariate data are missing at random and compare it to other currently used methods. Our algorithm is advantageous for identifying the true underlying covariate structure when complex data and larger percentages of missing covariate observations are present. It is competitive with other current methods with respect to prediction accuracy. To illustrate our algorithm, we create a tree-structured survival model for predicting time to treatment response in older, depressed adults. PMID- 20963752 TI - Smooth estimation of survival functions and hazard ratios from interval-censored data using Bayesian penalized B-splines. AB - We discuss the use of Bayesian P-spline and of the composite link model to estimate survival functions and hazard ratios from interval-censored data. If one further assumes proportionality of the hazards, the proposed strategy provides a smoothed estimate of the baseline hazard along with estimates of global covariate effects. The frequentist properties of our Bayesian estimators are assessed by an extensive simulation study. We further illustrate the methodology by two examples showing that the proportionality of the hazards might also be found inappropriate from interval-censored data. PMID- 20963753 TI - Copula-based regression models for a bivariate mixed discrete and continuous outcome. AB - This paper is concerned with regression models for correlated mixed discrete and continuous outcomes constructed using copulas. Our approach entails specifying marginal regression models for the outcomes, and combining them via a copula to form a joint model. Specifically, we propose marginal regression models (e.g. generalized linear models) to link the outcomes' marginal means to covariates. To account for associations between outcomes, we adopt the Gaussian copula to indirectly specify their joint distributions. Our approach has two advantages over current methods: one, regression parameters in models for both outcomes are marginally meaningful, and two, the association is 'margin-free', in the sense that it is characterized by the copula alone. By assuming a latent variable framework to describe discrete outcomes, the copula used still uniquely determines the joint distribution. In addition, association measures between outcomes can be interpreted in the usual way. We report results of simulations concerning the bias and efficiency of two likelihood-based estimation methods for the model. Finally, we illustrate the model using data on burn injuries. PMID- 20963754 TI - Measurement of protein sulfenic acid content. AB - Protein sulfenic acids are reactive, reversibly oxidized cysteinyl residues with roles in redox catalysis and regulation. Detection and quantification of these species in proteins is accomplished through chemical modification by reagents such as 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD chloride), 2-nitro-5 thiobenzoate (TNB), dimedone, or derivatives of dimedone, followed by UV-visible spectroscopy or mass spectrometric analysis. PMID- 20963755 TI - Histopathology of the male reproductive system I: techniques. AB - Fixation and sampling of the male reproductive system for routine histopathological examination requires special procedures including the use of nonroutine fixatives and nonroutine stains. High-resolution light microscopy and electron microscopy require additional specialized techniques including perfusion fixation and plastic embedding. Aspects of comparative anatomy are also important for ensuring that specific structures within the reproductive tract are sampled adequately in various species. This unit provides methodology and guidance on what structures to sample and how to fix and prepare tissues from the male reproductive tract for routine and special investigations. PMID- 20963756 TI - Histopathology of the male reproductive system II: interpretation. AB - Histopathology is acknowledged as the most sensitive endpoint for detecting testicular toxicity. However, identification and interpretation of chemically induced changes in the testis require fundamental knowledge of spermatogenesis, its dynamics and regulation. Changes in the rest of the reproductive tract are also frequently inter-related, being the result of or cause of disturbance in testicular spermatogenesis. This unit provides practical guidelines on how to evaluate testicular histopathology and how to utilize staging in a qualitative evaluation. It also provides an overview of the most common chemically induced lesions and their potential significance with respect to etiology and functional consequences. PMID- 20963757 TI - Monitoring endocrine function in males: using intra-atrial cannulas to monitor plasma hormonal dynamics in toxicology experiments. AB - Intra-atrial cannulation provides assessment of endocrine change within animals. Protocols for permanent tethers used in short-term 5- to 10-day experiments and permanent vascular access used in long-term (>10 days) experiments are presented. A protocol for blood processing is also included. Data from a longitudinal endocrine baseline assessment (LEBA) and an endocrine challenge test (ECT) are presented as well. PMID- 20963758 TI - Epididymal sperm count. AB - Making Epididymal Sperm Counts (Yefan Wang, TherImmune Research Corporation, Gaithersberg, Maryland). Epididymal sperm counts are a widely used, simple and sensitive method of assessing the effects of male reproductive toxicants on the epididymal and/or testicular site of action. After careful dissection of the tissues and further processing, the sperm suspensions are counted using a hemacytometer and analyzed for effect. PMID- 20963759 TI - Performing a testicular spermatid head count. AB - Procedure of counting spermatid heads using hemacytometer. PMID- 20963760 TI - Transgenerational (in utero/lactational) exposure to investigate the effects of endocrine disrupting compounds (EDCS) in rats. AB - This protocol is designed to evaluate the effects of endocrine disrupting compounds (EDCs) through fetal (transplacental) and/or neonatal (via the dam's milk) exposure during the critical periods of reproductive organogenesis in the rat. Continued direct exposure to the F1 pups after weaning is an option that can also be included. Reproductive indices, growth, and viability are monitored throughout the life of the F1 generation and an extensive necropsy is conducted after sexual maturity is attained. The endpoints evaluated are designed to detect compounds such as androgen receptor antagonists or steroid hormone synthesis inhibitors which inhibit normal development of the male reproductive system and growth stimulating hormones which masculinize females and facilitate development of male reproductive tissues. Data collected from these studies can be used to determine the no and lowest observed effects levels and predict potential adverse consequences of EDCs in human and wildlife populations. The information also provides a foundation for future studies designed to identify mechanism(s) of action, specific genes and or proteins involved, and susceptible populations these compounds might target. PMID- 20963761 TI - Formation and functions of protein sulfenic acids. AB - Protein sulfenic acids are generated as reversibly oxidized cysteinyl residues formed upon reaction of thiols with peroxides, nitric oxide, peroxynitrite, and other reactive oxygen or nitrogen species. They can be stabilized within the protein environment, irreversibly oxidized to sulfinic and sulfonic acids by additional oxidant, condensed with protein or exogenous thiol groups to form disulfide bonds, or directly reduced back to thiols. Sulfenic acids in proteins can act as intermediates in redox catalysis or as critical components in cysteine dependent redox regulation. PMID- 20963762 TI - Fluorescence microplate reader measurement of tissue susceptibility to lipid peroxidation. AB - This unit describes a method for the measurement of cellular membrane antioxidant capacity or susceptibility of tissue samples to lipid peroxidation using a fluorescence microplate reader. The assay is simple and has the advantage of monitoring susceptibility to lipid peroxidation in a large number of samples in real time. PMID- 20963763 TI - Hershberger assay to investigate the effects of endocrine-disrupting compounds with androgenic or antiandrogenic activity in castrate-immature male rats. AB - The protocol described in this unit is designed to evaluate the effects of androgenic and antiandrogenic endocrine-disrupting compounds (EDCs) in the castrate-immature male rat. Continuous 10-day exposure of the prepubertal male to chemicals is used to identify androgenic or antiandrogenic activities based on the weights of several androgen-dependent tissues on the day after treatment is ended. Androgen-dependent organ weights and growth, along with kidney, liver, and adrenal weights are measured at necropsy. The androgen-dependent tissues include the ventral prostate, seminal vesicles (with fluid plus coagulating glands), levator ani plus bulbocavernosus muscles, Cowper's glands, and glans penis. Optional measures, which facilitate interpretation of the data when positive effects are detected, include serum testosterone and luteinizing hormone levels. Androgenic chemicals cause increases in one or all of the androgen-dependent tissue weights after being administered by oral gavage or subcutaneously (s.c.) to castrate-immature male rats. Antiandrogenic chemicals cause reductions in androgen-dependent tissue weights after being coadministered with testosterone propionate (s.c.). PMID- 20963764 TI - Estimating treatment difference for binary responses in the presence of surrogate endpoints. AB - Surrogate endpoint is chosen as a measure or indicator of a biological process that is obtained sooner, at less cost or less invasively than a true endpoint of health outcome, and is used to arrive at conclusions about the effect of intervention on the true endpoint. Following the work of Begg and Leung (J. R. Stat. Soc. Ser. A 2000; 163:15-28), we introduce a new motivation to analyse the surrogate and true endpoints together, to have a better estimate of the treatment difference where both the endpoints are binary. Several estimators are studied and compared. Some real data sets are analysed. PMID- 20963765 TI - A robust TDT-type association test under informative parental missingness. AB - Many family-based association tests rely on the random transmission of alleles from parents to offspring. Among them, the transmission/disequilibrium test (TDT) may be considered to be the most popular statistical test. The TDT statistic and its variations were proposed to evaluate nonrandom transmission of alleles from parents to the diseased children. However, in family studies, parental genotypes may be missing due to parental death, loss, divorce, or other reasons. Under some missingness conditions, nonrandom transmission of alleles may still occur even when the gene and disease are not associated. As a consequence, the usual TDT type tests would produce excessive false positive conclusions in association studies. In this paper, we propose a novel TDT-type association test which is not only simple in computation but also robust to the joint effect of population stratification and informative parental missingness. Our test is model-free and allows for different mechanisms of parental missingness across subpopulations. We use a simulation study to compare the performance of the new test with TDT and point out the advantage of the new method. PMID- 20963766 TI - Adaptive trimmed t-statistics for identifying predominantly high expression in a microarray experiment. AB - Often, interesting candidate tumor markers are not only genes that show homogeneously higher expression (HHE) in tumor samples compared to control samples, but also genes with only predominantly higher expression (PHE), i.e. genes which exhibit higher expression in at least 80 per cent of tumor samples. Standard parametric test statistics used in the analysis of microarray experiments may fail with PHE as a consequence of the mixture of distributions present in the tumor group. As alternative we consider trimmed t-statistics which compare group mean values after removing outliers in each group. The trimming proportion can be chosen adaptively, either based on a boxplot outlier detection rule or by optimization over a series of tests with varying trimming proportions. The trimmed t-statistics can be plugged into the 'significance analysis of microarrays' (SAM) procedure, yielding the modified boxplot rule test (modBox) and the modified optimization test (modOpt), respectively. By means of simulation of microarray experiments, we show that modOpt is superior to contenders in detecting PHE, while there is only little loss in efficiency under HHE compared to SAM. Analysis of a real microarray experiment revealed that, out of nearly 29 000 genes, about 417 genes exhibiting PHE are detected by modOpt but missed by SAM. PMID- 20963767 TI - Comparative determination of energy production rates and mitochondrial function using different 31P MRS quantitative methods in sedentary and trained subjects. AB - Muscle energetics has been largely and quantitatively investigated using (31)P MRS. Various methods have been used to estimate the corresponding rate of oxidative ATP synthesis (ATP(ox)); however, potential differences among methods have not been investigated. In this study, we aimed to compare the rates of ATP production and energy cost in two groups of subjects with different training status using four different methods: indirect method (method 1), ADP control model (method 2) and phosphate potential control model (method 3). Method 4 was a modified version of method 3 with the introduction of a correction factor allowing for similar values to be obtained for the end-exercise oxidative ATP synthesis rate inferred from exercise measurements and the initial recovery phosphocreatine resynthesis rate. Seven sedentary and seven endurance-trained subjects performed a dynamic standardised rest-exercise-recovery protocol. We quantified the rates of ATP(ox) and anaerobic ATP synthesis (ATP(ana)) using (31)P MRS data recorded at 1.5 T. The rates of ATP(ox) over the entire exercise session were independent of the method used, except for method 4 which provided significantly higher values in both groups (p < 0.01). In addition, methods 1-3 were cross-correlated, thereby confirming their statistical agreement. The rate of ATP(ana) was significantly higher with method 1 (p < 0.01) and lower with method 4 (p < 0.01). As a result of the higher rate of ATP(ox), EC (method 4) calculated over the entire exercise session was higher and initial EC (method 1) was lower in both groups compared with the other methods. We showed in this study that the rate of ATP(ox) was independent of the calculation method, as long as no corrections (method 4) were performed. In contrast, results related to the rates of ATP(ana) were strongly affected by the calculation method and, more exactly, by the estimation of protons generated by ATP(ox). Although the absolute EC values differed between the methods, within- or between-subject comparisons are still valid given the tight relationships between them. PMID- 20963768 TI - Gist reasoning training in cognitively normal seniors. AB - OBJECTIVE: Cognitive impairment is a key factor that threatens functionality and quality of life in seniors. Given the projection that the population of individuals 65 years of age and older will double within the next 25 years, a critical need exists to identify and test effectiveness of protocols that target higher-order cognitive skills such as gist reasoning to maximize cognitive capacity in later life. METHODS: This study examined the effects of eight hours of gist reasoning training in 26 cognitively normal seniors between the ages of 64-85 years (M = 74.23, SD = 6.67). RESULTS: Findings suggest that top-down strategy-based gist reasoning training significantly improved abstraction ability, a skill relevant to everyday life, as well as generalized to untrained measures of executive function including concept abstraction, cognitive switching, and verbal fluency. Individuals with lower baseline ability to abstract gist showed the greatest gain in the target domain trained. CONCLUSIONS: These findings highlight the potential value of engaging in cognitively challenging activities that involve gist reasoning, to strengthen and preserve cognitive capacity with aging. PMID- 20963769 TI - Luminescence studies on Al4B2O9:Eu2+ phosphor crystals. AB - A novel blue-emitting phosphor, Eu(2+)-doping Al(4)B(2)O(9), was prepared via a modified solid-state reaction. Al(4)B(2)O(9):Eu(2+) nanoparticles with diameters varying in a range from 20 to 50 nm were obtained using urea as an auxiliary reagent at the optimum temperature of 850 degrees C. The crystallization and particle sizes of Al(4)B(2)O(9):Eu(2+) were investigated using powder X-ray diffraction (XRD) and transmission electron microscopy (TEM). Photoluminescence (PL) results showed that Al(4)B(2)O(9):Eu(2+) phosphor could be efficiently excited by the ultraviolet region from 240 to 410 nm, exhibiting bright blue emission. Further investigation on concentration-dependent emission spectra indicated that the Al(3.997) B(2)O(9):Eu(2+)(0.003) phosphor exhibited the strongest luminescent, and the relative PL intensity decreased with increasing Eu(2+) concentration due to concentration quenching. In addition, the concentration quenching for the one-Eu-site emission centers was caused by the electric multipole-multipole interaction. PMID- 20963770 TI - One-stage parametric meta-analysis of time-to-event outcomes. AB - Methodology for the meta-analysis of individual patient data with survival end points is proposed. Motivated by questions about the reliance on hazard ratios as summary measures of treatment effects, a parametric approach is considered and percentile ratios are introduced as an alternative to hazard ratios. The generalized log-gamma model, which includes many common time-to-event distributions as special cases, is discussed in detail. Likelihood inference for percentile ratios is outlined. The proposed methodology is used for a meta analysis of glioma data that was one of the studies which motivated this work. A simulation study exploring the validity of the proposed methodology is available electronically. PMID- 20963771 TI - A Bayesian approach for estimating bioterror attacks from patient data. AB - Terrorist attacks using an aerosolized pathogen have gained credibility as a national security concern after the anthrax attacks of 2001. Inferring some important details of the attack quickly, for example, the number of people infected, the time of infection, and a representative dose received can be crucial to planning a medical response. We use a Bayesian approach, based on a short time series of diagnosed patients, to estimate a joint probability density for these parameters. We first test the formulation with idealized cases and then apply it to realistic scenarios, including the Sverdlovsk anthrax outbreak of 1979. We also use simulated outbreaks to explore the impact of model error, as when the model used for generating simulated epidemic curves does not match the model subsequently used to characterize the attack. We find that in all cases except for the smallest attacks (fewer than 100 infected people), 3-5 days of data are sufficient to characterize the outbreak to a specificity that is useful for directing an emergency response. PMID- 20963772 TI - Determination of 3-hydroxy pterocarpan, a novel osteogenic compound in rat plasma by liquid chromatography-tandem mass spectrometry: application to pharmacokinetics study. AB - A rapid, sensitive and selective LC-MS/MS method for the quantitative analysis of 3-hydroxy pterocarpan (S006-1709) in female rat plasma has been developed and validated. A Discovery RP18 column was used for the chromatographic elution using acetonitrile and 0.1% acetic acid in water as mobile phase (80:20 v/v) at the flow rate of 0.5 mL/min. MS/MS analysis was performed using a triple quadrupole mass spectrometer with electrospray ionization in negative ion mode using biochanin as an internal standard (IS). Extraction of S006-1709 and IS from rat plasma was done by liquid-liquid extraction method using diethyl ether. The LC MS/MS method was sensitive with 1.95 ng/mL as the limit of detection and 3.9 ng/mL as the lower limit of quantification. The method was linear in the concentration range of 3.9-1000 ng/mL. The percentage bias for intraday and interday accuracy was not greater than 4.2 and the %RSD for intraday and interday precision was not greater than 13.2. The recoveries of S006-1709 and IS were 73.9 79.3 and 85.7%, respectively. S006-1709 was found to be stable in various stability studies. The validated LC-MS/MS method was successfully applied for the oral pharmacokinetics study of S006-1709 at 10 mg/kg in female Sprague-Dawley rats. PMID- 20963775 TI - Naturally occurring triterpenoid saponins. AB - Naturally occurring new triterpenoid saponins reported from mid-1996 to March, 2007 are reviewed including their physical constants and plant sources, and are compiled in Table 1. New saponins are arranged in Table 1 on the basis of the skeletal structures of their aglycones, e.g., oleanane type, ursane type, lupane type, hopane type, taraxastane type, cycloartane type, lanostane type, tirucallane type, dammarane type, cucurbitane type, and holostane type. The known triterpenoid saponins and prosapogenins of the new saponins, the biological and pharmacological activities of which were published during 1996-2007, are also reviewed together with their plant sources listed in Table 2 according to the skeletal structures of their aglycones in the same fashion as in Table 1. The plant and animal sources of both new and known bioactive triterpenoid saponins are collected in Table 3 in alphabetical order. The biological and pharmacological activities such as antiallergic, antiatherosclerosis and antiplatelet, antibacterial, anticomplementary, antidiabetic, contraceptive, antifungal, anti-inflammatory, antileishmanial, antimalarial/antiplasmodial, anti obesity, anti-proliferative, antipsoriatic, antispasmodic, antisweet, antiviral, cytotoxic/antitumor, detoxication, gastroprotective, haemolytic, hepatoprotective, immunomodulatory, anti-enzyme, anti-osteoporotic, insecticidal, insulin-like, membrane-porosity, molluscicidal, neuropharmacological, anti endothelial dysfunction, snake venom antidote, and sweet activities of these saponins or derived prosapogenins are discussed briefly after Table 3. PMID- 20963776 TI - Chemistry on nucleic acid templates. PMID- 20963777 TI - Efficient synthesis of the tRNA nucleoside preQ0, 7-cyano-7-deazaguanosine, via microwave-assisted iodo->carbonitrile exchange. AB - The naturally occurring tRNA nucleoside preQ(0), 7-cyano-7-deazaguanosine, which is a central intermediate for other natural occurring 7-deazapurine nucleosides was synthesized via a copper(I)-ion-mediated iodo->carbonitrile exchange. The reaction was performed on the easily accessible 7-iodo-7-deazaguanosine under microwave conditions. The overall reaction yield was 30% starting with the glycosylation reaction of the nucleobase. Corresponding 2'-deoxyribonucleosides were prepared following the same route. PMID- 20963781 TI - Monitoring serum chondroitin sulfate levels in patients submitted to coronary artery bypass surgery. AB - Glycosaminoglycans (GAGs) are functionally important molecules of the arterial wall and play a crucial role in atherogenesis. Chondroitin sulfate/dermatan sulfate proteoglycans (CS/DSPGs) participate in several biological events through their GAG chains, and are also involved in the development of atherosclerosis. The aim of this study was to compare the pre- and post-operative levels of CS in serum of patients after coronary artery bypass graft surgery using a highly sensitive reversed-polarity capillary electrophoresis method and to investigate the correlation of CS with common biochemical lipid markers. It was found that CS values were significantly higher for all patients post-operatively and, furthermore, CS levels were statistically correlated to apolipoprotein A and B levels. Notably, the pre-operational lipid profile of the patient may be indicative of the values of 4-sulfated CS post-operationally. Furthermore, the obtained results highlight the clinical significance of CS levels in serum, since they may provide complementary information for the latent inflammatory state of the patient. PMID- 20963782 TI - Global strategy for the diagnosis and management of asthma in children 5 years and younger. AB - Asthma is the most common chronic disease of childhood and the leading cause of childhood morbidity from chronic disease as measured by school absences, emergency department visits, and hospitalisation. During the past two decades, many scientific advances have improved our understanding of asthma and our ability to manage and control it effectively. However, in children 5 years and younger, the clinical symptoms of asthma are variable and non-specific. Furthermore, neither airflow limitation nor airway inflammation, the main pathologic hallmarks of the condition, can be assessed routinely in this age group. For this reason, to aid in the diagnosis of asthma in young children, a symptoms-only descriptive approach that includes the definition of various wheezing phenotypes has been recommended. In 1993, the Global Initiative for Asthma (GINA) was implemented to develop a network of individuals, organizations, and public health officials to disseminate information about the care of patients with asthma while at the same time assuring a mechanism to incorporate the results of scientific investigations into asthma care. Since then, GINA has developed and regularly revised a Global Strategy for Asthma Management and Prevention. Publications based on the Global Strategy for Asthma Management and Prevention have been translated into many different languages to promote international collaboration and dissemination of information. In this report, Global Strategy for Asthma Management and Prevention in Children 5 Years and Younger, an effort has been made to present the special challenges that must be taken into account in managing asthma in children during the first 5 years of life, including difficulties with diagnosis, the efficacy and safety of drugs and drug delivery systems, and the lack of data on new therapies. Approaches to these issues will vary among populations in the world based on socioeconomic conditions, genetic diversity, cultural beliefs, and differences in healthcare access and delivery. Patients in this age group are often managed by pediatricians and general practitioners routinely faced with a wide variety of issues related to childhood diseases. PMID- 20963783 TI - Impact of environmental tobacco smoke on children admitted with status asthmaticus in the pediatric intensive care unit. AB - INTRODUCTION: Environmental tobacco smoke (ETS) and allergens are risk factors in children with critical status asthmaticus. Genetic studies support that ETS associated asthma is a special inflammatory entity, causing significant number of hospital admissions and relapses. Accordingly, the course and outcome of patients with ETS-induced status asthmaticus might also be different. HYPOTHESIS: We hypothesized that the progression, course, and outcome of patients with ETS induced status asthmaticus would be worse than those of patients without ETS exposure. METHODS: Medical records of children who were admitted to the Pediatric Intensive Care Unit (PICU) with the diagnosis of asthma at the Children's Hospital of Winnipeg, Manitoba, over 10 years were audited after Institutional Review Board (IRB) approval. Two hundred thirty records were reviewed. We extracted data including demographics and analyzed the patient's deterioration defined as clinical asthma score (CAS) drift between the ED and PICU. We computed the treatment response, expressed as length of stay (LOS) in the PICU and in hospital. The risk factors were stratified as none, ETS exposure, allergies, and ETS with allergies. RESULTS: There were 55 (25%) patients with no risk factors, 66 (30%) with ETS exposure only, 46 (21%) with allergies only, and 53 (24%) with both. There was a 25% decrease in CAS deterioration when patients were exposed to ETS (P < 0.05). For patients with or without allergies but with exposure to ETS, both the PICU and overall hospital LOS were ~15% longer (P < 0.05) than for those not exposed to ETS. Stratifying for gender and race in multivariate analysis did not alter the results. CONCLUSIONS: Patients with ETS-associated critical status asthmaticus deteriorate and recover slower than non-ETS-exposed patients. PMID- 20963784 TI - Iron and CF-related anemia: expanding clinical and biochemical relationships. AB - INTRODUCTION: This cross-sectional study was conducted to assess the relationship between iron levels in the plasma and sputum of cystic fibrosis (CF) patients. METHODS: Demographic, clinical, and iron-related laboratory data were prospectively obtained from 25 patients with stable clinical features and 14 patients with worsened clinical features since their most recent evaluations. RESULTS: Compared to patients with stable clinical features, those who experienced clinical deterioration demonstrated significantly worse lung function and were more frequently malnourished and diabetic. Members of the latter group were also significantly more hypoferremic and had higher sputum iron content than patients with stable clinical features. No significant correlation was found between plasma and sputum iron levels when the groups were analyzed together and separately. CONCLUSIONS: Sputum iron content does not correlate with iron-related hematologic tests. Hypoferremia is common in CF and correlates with poor lung function and overall health. PMID- 20963785 TI - Segmentation of ascidian notochord cells in DIC timelapse images. AB - We have developed a method to automatically segment notochord cell boundaries from differential interference contrast (DIC) timelapse images of the elongating ascidian tail. The method is based on a specialized parametric active contour, the network snake, which can be initialized as a network of arbitrary but fixed topology and provides an effective framework for simultaneously segmenting multiple touching cells. Several modifications to the original network snake were necessary for high-quality segmentation, including linear Gaussian derivative filtering to reconstruct edge maps from DIC images and a new energy function to improve the segmentation of critical cell-cell vertices. We find that post intercalation ascidian notochord cells exhibit two distinct cell behaviors: lateral cell edges expand along the AP axis while showing a rapid pulsatile behavior, whereas anterior and posterior cell edges contract smoothly. PMID- 20963786 TI - Changes in histone acetylation and methylation that are important for persistent but not transient expression of CCR4 in human CD4+ T cells. AB - Although regulation of CXCR3 and CCR4 is related to Th1 and Th2 differentiation, respectively, many CXCR3(+) and CCR4(+) cells do not express IFN-gamma and/or IL 4, suggesting that the chemokine receptor genes might be inducible by mechanisms that are lineage-independent. We investigated the regulation of CXCR3 versus IFNG, and CCR4 versus IL4 in human CD4(+) T cells by analyzing modifications of histone H3. In naive cord-blood cells, under nonpolarizing conditions not inducing IL4, CCR4 was induced to high levels without many of the activation associated changes in promoter histone H3 found for both IL4 and CCR4 in Th2 cells. Importantly, CCR4 expression was stable in Th2 cells, but fell in nonpolarized cells after the cells were rested; this decline could be reversed by increasing histone acetylation using sodium butyrate. Patterns of histone H3 modifications in CXCR3(+) CCR4(-) and CXCR3(-) CCR4(+) CD4(+) T-cell subsets from adult blood matched those in cells cultured under polarizing conditions in vitro. Our data show that high-level lineage-independent induction of CCR4 can occur following T-cell activation without accessibility-associated changes in histone H3, but that without such changes expression is transient rather than persistent. PMID- 20963787 TI - The association between length of benzodiazepine use and sleep quality in older population. AB - BACKGROUND: Sleep disturbances are frequently reported in the older adult population and benzodiazepines are the drugs most often prescribed to treat these problems. Nearly 25% of the older adult population uses these drugs and 83% of benzodiazepine users report sleep problems. Although the College des Medecins du Quebec suggests a maximum length of use of 3 months, according to most studies the mean length of benzodiazepine use is longer. The goal of this study was to document the association between length of benzodiazepine use and sleep quality as reported by adults 65 years older and over. METHODS: Data used in this study came from the Seniors' Health Survey (ESA) conducted in a representative sample of the community-dwelling older population in Quebec, Canada. Inclusion criteria included the ability to speak and understand French. Data were analyzed using a structural equation modeling strategy. RESULTS: Long-term benzodiazepine users were more likely to report poor sleep quality. Sleep quality of initial probable problematic sleepers tended to increase over 1 year but sleep quality in benzodiazepines users increased less rapidly than in non-users. Also, women were more likely to report using benzodiazepines and having poorer sleep quality. CONCLUSION: Longitudinal studies using incident cases of benzodiazepine use should be conducted to better determine the causal relationship between sleep quality and benzodiazepine use in the older population. PMID- 20963788 TI - Observation of symmetric denaturation of hemoglobin subunits by electrospray ionization mass spectrometry. AB - Electrospray ionization mass spectrometry (ESI-MS) has been used to characterize the denaturation of porcine hemoglobin (Hb) induced by solvent changes. This work provides evidence for the symmetric nature of Hb denaturation and demonstrates that heme losses from alpha- and beta-monomers occur in parallel, in response to the addition of acid and organic co-solvents in solution. When subject to one of the following solution conditions (pH 3.2-4.0 or 15-30% acetonitrile-water or 30 45% methanol-water solution), alpha- and beta-globins undergo symmetric dissociation to release the heme groups, which is detected by ESI-MS. Circular dichroism (CD) and fluorescence spectroscopy (FS) data show that the acid-induced and organic solvent-induced heme release, as observed in the mass spectra, can probably be ascribed to different aspects of the conformational changes taking place in the protein. The acidity of the solvent has a significant effect on the secondary structure, whereas organic content level in solution (15-30% acetonitrile or 30-45% methanol) tends to destroy the tertiary structure of Hb globins, both leading to release of the heme from each subunit. PMID- 20963789 TI - A flow cytometry based in vitro micronucleus assay in TK6 cells--validation using early stage pharmaceutical development compounds. AB - The micronucleus test (MNT) is a well established test for detecting clastogenic and aneugenic compounds. Despite the assay's advantages, the MNT may produce false positive and false negative results in some conditions. This fact may be related to the underestimation of apoptosis or necrosis, the p53 status of the cell system or the cytotoxicity assay, and the top dose selection. The purpose of our studies was to contribute to the validation efforts of the flow cytometry based MNT. To identify the most reliable cytotoxicity assay for the top dose selection five parameters for relative survival were tested: relative cell count, relative population doubling, trypan blue supravital staining, relative ratio of scored nuclei to latex beads, and ethidium monoazide staining. For all compounds the least sensitive method was the relative cell count and the most reliable was the nuclei/beads ratio. The comparative evaluation of micronuclei induction in TK6 cells, analyzed with microscopy and flow cytometry, was performed with reference compounds and internal Novartis early development compounds with positive, weak positive, equivocal, and negative genotoxic effects. Our data document a good correlation between the MNT results obtained by flow cytometry and by microscopy. The results confirm that the method may be applied for routine testing in the pharmaceutical industry for the tested group of compounds, including compounds which require metabolic activation. However, further validation and miniaturization may be required. PMID- 20963790 TI - Mutation spectrum in FE1-MUTA(TM) Mouse lung epithelial cells exposed to nanoparticulate carbon black. AB - It has been shown previously that carbon black (CB), Printex 90 exposure induces cII and lacZ mutants in the FE1-Muta(TM) Mouse lung epithelial cell line and causes oxidatively damaged DNA and the production of reactive oxygen species (ROS). The purpose of this study was to determine the mutation spectrum in the cII gene of Printex 90 exposed cells. Cells exposed to CB have a substantially different mutation spectrum in the cII gene compared with vehicle exposed controls. The mutation spectra differ both in the positions (P < 0.0001) and types of the mutations (P < 0.0001). Exposure to Printex 90 increased the number of single base deletions by 2.3-fold and larger deletions by 1.9-fold. Most single base deletions were within two repetitive sequences in cII, but the large deletions were not. The mechanism behind the large deletions is not yet known. The largest increases in base substitutions were observed in G:C->T:A, G:C->C:G, and A:T->T:A transversion mutations; this is in keeping with a genetic finger print of ROS and is further substantiated by the observations that Printex 90 generates ROS and oxidatively damaged DNA. PMID- 20963791 TI - Aerosol route to functional nanostructured inorganic and hybrid porous materials. AB - The major advances in the field of the designed construction of hierarchically structured porous inorganic or hybrid materials wherein multiscale texturation is obtained via the combination of aerosol or spray processing with sol-gel chemistry, self-assembly and multiple templating are the topic of this review. The available materials span a very large set of structures and chemical compositions (silicates, aluminates, transition metal oxides, nanocomposites including metallic or chalcogenides nanoparticles, hybrid organic-inorganic, biohybrids). The resulting materials are manifested as powders or smart coatings via aerosol-directed writing combine the intrinsic physical and chemical properties of the inorganic or hybrid matrices with defined multiscale porous networks having a tunable pore size and connectivity, high surface area and accessibility. Indeed the combination of soft chemical routes and spray processing provides "a wind of change" in the field of "advanced materials". These strategies give birth to a promising family of innovative materials with many actual and future potential applications in various domains such as catalysis, sensing, photonic and microelectronic devices, nano-ionics and energy, functional coatings, biomaterials, multifunctional therapeutic carriers, and microfluidics, among others. PMID- 20963792 TI - Heteroepitaxial growth of core-shell and core-multishell nanocrystals composed of palladium and gold. AB - The heteroepitaxial growth of the core-shell nanocrystals composed of Pd and Au is developed. Pd nanocubes or Au nano-octahedrons are utilized as the cores. The growths of the Au and Pd shells are realized under similar conditions, where the same reducing agent and stabilizing surfactant are employed. The preparation is highly controllable, and the epitaxial growth is repeated up to three times to yield Pd@Au@Pd@Au and Au@Pd@Au@Pd core-trishell nanocrystals. The thickness of each shell is readily varied by changing the amount of the metal salts used for growth. All of the nanocrystal products have narrow size distributions and are single crystalline. The plasmon resonance properties of these nanocrystals are mainly determined by the exterior shell. The plasmon of the Pd-shell-terminated nanocrystals is suppressed, while that of the Au-shell-terminated ones is recovered and is stronger when the Au shell becomes thicker. This growth method can potentially be extended to other metals for the synthetic design of more complex core-multishell metal nanostructures with desirable optical, catalytic, and magnetic properties. PMID- 20963793 TI - Transition voltage spectroscopy of porphyrin molecular wires. AB - Measurements are presented of the current-voltage (I-V) characteristics of individual thiol-tethered porphyrin molecules (isolated in an alkanethiol matrix) and of self-assembled monolayers. In both cases, it is found that I/V(2) displays a minimum at a characteristic "transition voltage" V(m). Repeated measurements of the transition voltage enable both its time development and statistical behavior to be determined. For isolated molecules, the transition voltage shows a multipeaked distribution of values, indicating the presence of a small number of distinct molecular/contact configurations, each having different transport characteristics. For self-assembled monolayers, in contrast, a single-peaked distribution was observed, which is consistent with parallel conduction through many molecules. PMID- 20963794 TI - A general synthesis of high-quality inorganic nanocrystals via a two-phase method. AB - A two-phase method is exploited to prepare many kinds of nearly monodisperse, highly crystalline, size- and shape-controlled, surface-property-tunable inorganic nanocrystals, such as metal, semiconducting, magnetic, dielectric, and rare earth nanocrystals. The reaction of the two-phase system happens at the interface between the oil (nonpolar) and water (polar) phases and the interface is an exclusive site for both nucleation and growth. Interestingly, many solvent pairs with a clear interface can be applied to synthesize inorganic nanocrystals successfully. Generally, as-prepared nanocrystals with organic ligands are soluble in nonpolar solvents. Furthermore, exchange of ligands can also be realized readily and the final nanocrystals can be soluble in polar solvents. This two-phase method is a simple, reproducible, and general route and is becoming as powerful an approach as other solution-based synthetic approaches to high-quality inorganic nanocrystals. PMID- 20963795 TI - An on-nanoparticle rolling-circle amplification platform for ultrasensitive protein detection in biological fluids. PMID- 20963796 TI - Tunable bandgap in graphene by the controlled adsorption of water molecules. PMID- 20963797 TI - Relationship between polychlorinated dibenzo-p-dioxin, polychlorinated dibenzofuran, and dioxin-like polychlorinated biphenyl concentrations in vegetation and soil on residential properties. AB - The University of Michigan Dioxin Exposure Study was undertaken to address concerns that the industrial discharge of dioxin-like compounds in the Midland, Michigan, USA area had resulted in the contamination of soil and vegetation in the Tittabawassee River floodplain and downwind of the incinerator in the City of Midland. The study included the analysis of 597 vegetation samples, predominantly grass and weeds, from residential properties selected through a multistage probabilistic sample design in the Midland area, and in Jackson and Calhoun Counties (Michigan), as a background comparison, for 29 polychlorinated dibenzo-p dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs). The mean toxic equivalent (TEQ) of the house perimeter vegetation samples ranged from 4.2 to 377 pg/g. The ratio of TEQs (vegetation to soil) was about 0.3, with a maximum of 3.5. Based on a calculation of the similarity of the congener patterns between the soil and the vegetation, it appeared that the source of the contamination on the vegetation was the surrounding soil. This conclusion was supported by linear regression analysis, which showed that the largest contributor to the R(2) for the outcome variable of log(10) of the vegetation concentration was log(10) of the surrounding soil concentration. Models of vegetation contamination usually focus on atmospheric deposition and partitioning. The results obtained here suggest that the deposition of soil particles onto vegetation is a significant route of contamination for residential herbage. Thus, the inclusion of deposition of soil particles onto vegetation is critical to the accurate modeling of contamination residential herbage in communities impacted by historic industrial discharges of persistent organic compounds. PMID- 20963798 TI - Metabolomic profiling with NMR discriminates between biphosphonate and doxorubicin effects on B16 melanoma cells. AB - The metabolomic profiles of B16 melanoma cells were investigated in vitro with high resolution-magic angle spinning proton magnetic resonance spectroscopy and OPLS multivariate statistical analyse. We compared the profiles for untreated melanoma B16-F10 cells and Ca(2+) chelating EGTA, doxorubicin or BP7033 bisphosphonate treated cells. The two last molecules are known to induce anti proliferative effects by different mechanisms of action in cells. Untreated and EGTA treated cells had similar profiles and were considered together as control cells. Several spectral regions could discriminate control from doxorubicin as well as BP7033 treated cells. Doxorubicin and BP7033 displayed distinct metabolic profiles. Important changes in neutral lipids and inositol were related to doxorubicin activity whereas BP7033 affected essentially phospholipids and alanine/lactate metabolism. These results provide new putative targets for both drugs. Metabolomics by NMR is shown here to be a good tool for the investigation of the mechanisms of action of drugs in pre-clinical studies. PMID- 20963799 TI - Proton MRS of large multiple sclerosis lesions reveals subtle changes in metabolite T(1) and area. AB - The T(1) values of metabolites were measured in eight subjects with clinically definite multiple sclerosis (MS) having at least one large brain lesion (2.6 +/- 0.7 mL) and in eight age- and sex-matched healthy controls. MRS examinations were conducted at 1.5 T using point-resolved spectroscopy (PRESS) (TE = 30 ms, TR = 530, 750, 1200, 1500, 3500, 5000 ms). Spectra were acquired from a voxel placed in the largest lesion in the subject with MS, and in a corresponding voxel (same size and region) in normal white matter (NWM) in the matched control, and were fitted using LCModel. As there are regional variations in metabolite and water T(1) and metabolite signal areas, careful placement of the control voxel was necessary to measure subtle differences between the lesions and NWM. The T(1) and T(1)-corrected signal areas of creatine were the same in MS lesions as in controls. The T(1) values of choline were significantly shorter in MS lesions located in occipital and parietal, but not in frontal, white matter. N Acetylaspartate (NAA) and myoinositol T(1) values in MS lesions were similar to those in NWM; however, the area of myoinositol correlated directly with lesion water T(1), and the area of NAA correlated inversely with lesion water T(1). MR spectra acquired at short TR require T(1) correction of choline for accurate quantification. Careful voxel placement in controls to match lesion location in subjects with MS enables a clearer view of the subtle changes in lesions. PMID- 20963800 TI - Improvement of resolution for brain coupled metabolites by optimized (1)H MRS at 7T. AB - Resolution enhancement for glutamate (Glu), glutamine (Gln) and glutathione (GSH) in the human brain by TE-optimized point-resolved spectroscopy (PRESS) at 7 T is reported. Sub-TE dependences of the multiplets of Glu, Gln, GSH, gamma aminobutyric acid (GABA) and N-acetylaspartate (NAA) at 2.2-2.6 ppm were investigated with density matrix simulations, incorporating three-dimensional volume localization. The numerical simulations indicated that the C4-proton multiplets can be completely separated with (TE(1), TE(2)) = (37, 63) ms, as a result of a narrowing of the multiplets and suppression of the NAA 2.5 ppm signal. Phantom experiments reproduced the signal yield and lineshape from simulations within experimental errors. In vivo tests of optimized PRESS were conducted on the prefrontal cortex of six healthy volunteers. In spectral fitting by LCModel, Cramer-Rao lower bounds (CRLBs) of Glu, Gln and GSH were 2 +/- 1, 5 +/- 1 and 6 +/- 2 (mean +/- SD), respectively. To evaluate the performance of the optimized PRESS method under identical experimental conditions, stimulated-echo spectra were acquired with (TE, TM) = (14, 37) and (74, 68) ms. The CRLB of Glu was similar between PRESS and short-TE stimulated-echo acquisition mode (STEAM), but the CRLBs of Gln and GSH were lower in PRESS than in both STEAM acquisitions. PMID- 20963801 TI - Changes in the MR relaxation rate R(2)* induced by respiratory challenges at 3.0 T: a comparison of two quantification methods. AB - The consistent determination of changes in the transverse relaxation rate R(2)* (DeltaR(2)*) is essential for the mapping of the effect of hyperoxic and hypercapnic respiratory challenges, which enables the noninvasive assessment of blood oxygenation changes and vasoreactivity by MRI. The purpose of this study was to compare the performance of two different methods of DeltaR(2)* quantification from dynamic multigradient-echo data: (A) subtraction of R(2)* values calculated from monoexponential decay functions; and (B) computation of DeltaR(2)* echo-wise from signal intensity ratios. A group of healthy volunteers (n = 12) was investigated at 3.0 T, and the brain tissue response to carbogen and CO(2)-air inhalation was registered using a dynamic multigradient-echo sequence with high temporal and spatial resolution. Results of the DeltaR(2)* quantification obtained by the two methods were compared with respect to the quality of the voxel-wise DeltaR(2)* response, the number of responding voxels and the behaviour of the 'global' response of all voxels with significant R(2)* changes. For the two DeltaR(2)* quantification methods, we found no differences in the temporal variation of the voxel-wise DeltaR(2)* responses or in the detection sensitivity. The maximum change in the 'global' response was slightly smaller when DeltaR(2)* was derived from signal intensity ratios. In conclusion, this first methodological comparison shows that both DeltaR(2)* quantifications, from monoexponential approximation as well as from signal intensity ratios, are applicable for the monitoring of R(2)* changes during respiratory challenges. PMID- 20963802 TI - PROPELLER for motion-robust imaging of in vivo mouse abdomen at 9.4 T. AB - In vivo high-field MRI in the abdomen of small animals is technically challenging because of the small voxel sizes, short T(2) and physiological motion. In standard Cartesian sampling, respiratory and gastrointestinal motion can lead to ghosting artefacts. Although respiratory triggering and navigator echoes can either avoid or compensate for motion, they can lead to variable TRs, require invasive intubation and ventilation, or extend TEs. A self-navigated fast spin echo (FSE)-based periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) acquisition was implemented at 9.4 T to enable high resolution in vivo MRI of mouse abdomen without the use of additional navigators or triggering. T(2)-weighted FSE-PROPELLER data were compared with single-shot FSE and multi-shot FSE data with and without triggering. Single-shot methods, although rapid and robust to motion, demonstrated strong blurring. Multi-shot FSE data showed better resolution, but suffered from marked blurring in the phase encoding direction and motion in between shots, leading to ghosting artefacts. When respiratory triggering was used, motion artefacts were largely avoided. However, TRs and acquisition times were lengthened by up to approximately 20%. The PROPELLER data showed a 25% and 61% improvement in signal-to-noise ratio and contrast-to-noise ratio, respectively, compared with multi-shot FSE data, together with a 35% reduction in artefact power. A qualitative comparison between acquisition methods using diffusion-weighted imaging was performed. The results were similar, with the exception that respiratory triggering was unable to exclude major motion artefacts as a result of the sensitisation to motion by the diffusion gradients. The PROPELLER data were of consistently higher quality. Considerations specific to the use of PROPELLER at high field are discussed, including the selection of practical blade widths and the effects on contrast, resolution and artefacts. PMID- 20963803 TI - Direct in vivo measurement of glycine and the neurochemical profile in the rat medulla oblongata. AB - The medulla oblongata (MO) contains a high density of glycinergic synapses and a particularly high concentration of glycine. The aims of this study were to measure directly in vivo the neurochemical profile, including glycine, in MO using a spin-echo-based (1)H MRS sequence at TE = 2.8 ms and to compare it with three other brain regions (cortex, striatum and hippocampus) in the rat. Glycine was quantified in MO at TE = 2.8 ms with a Cramer-Rao lower bound (CRLB) of approximately 5%. As a result of the relatively low level of glycine in the other three regions, the measurement of glycine was performed at TE = 20 ms, which provides a favorable J-modulation of overlapping myo-inositol resonance. The other 14 metabolites composing the neurochemical profile were quantified in vivo in MO with CRLBs below 25%. Absolute concentrations of metabolites in MO, such as glutamate, glutamine, gamma-aminobutyrate, taurine and glycine, were in the range of previous in vitro quantifications in tissue extracts. Compared with the other regions, MO had a three-fold higher glycine concentration, and was characterised by reduced (p < 0.001) concentrations of glutamate (-50 +/- 4%), glutamine (-54 +/- 3%) and taurine (-78 +/- 3%). This study suggests that the functional specialisation of distinct brain regions is reflected in the neurochemical profile. PMID- 20963806 TI - Efficient replication and generation of recombinant bovine adenovirus-3 in nonbovine cotton rat lung cells expressing I-SceI endonuclease. AB - BACKGROUND: The rigorous evaluation of recombinant bovine adenovirus (BAdV)-3 as a gene delivery vector requires quick and efficient method of isolating recombinants. This requires both a suitable cell line and an efficient method of rescuing recombinant BAdV-3. To facilitate rapid isolation of recombinant BAdV-3, we have developed an efficient system for generating recombinants using newly identified nonbovine cell line permissive for replication of BAdV-3. METHODS: Nonbovine cotton rat lung (CRL) cells in comparison to Madin-Darby bovine kidney cells and VIDO R2 cells were analyzed for the production of progeny virus and DNA transfection efficiency. In addition, lentiviral expression system was used to generate stable nonbovine CRL cell line expressing endonuclease I-SceI as examined by western blotting. Transfection of this cell line with circular or linear plasmid containing full-length BAdV-3 genome was used to generate recombinant BAdV-3. RESULTS: We demonstrate that nonbovine CRL cells are permissive for replication of BAdV-3 and can be efficiently transfected with plasmid DNA. Second, we constructed CRL cell line (VIDO DT1) expressing an intron encoding endonuclease I-SceI. Finally, we demonstrate that transfection of VIDO DT1 cells with a circular plasmid containing recombinant BAdV-3 genome flanked by I-SceI recognition sites can efficiently rescue recombinant virus. CONCLUSIONS: The use of circular molecular clones together with I-SceI endonuclease expressing, BAdV-3 permissive CRL cell line not only increased the viral genome transfection efficiency, but also reduced the viral rescue time and amount of DNA required for rescuing recombinant BAdV-3s. PMID- 20963807 TI - Hybrid herpes simplex virus/Epstein-Barr virus amplicon viral vectors confer enhanced transgene expression in primary human tumors and human bone marrow derived mesenchymal stem cells. AB - BACKGROUND: Herpes simplex virus type-1 (HSV-1) amplicon vectors are attractive tools for gene transfer because of their large DNA insert capacity, their broad host range of vector transduction and a minimal immune response as a result of the absence of helper viruses during viral packaging. However, the transient gene expression remains a challenge for the translation of HSV-1 amplicon based therapeutic strategies to a clinical setting. Although oriP/EBV nuclear antigen (EBNA)-1 elements of Epstein-Barr virus (EBV) have been successfully employed to achieve prolonged transgene expression, little is known about the stability of the EBNA-1 elements in the context of HSV-1 amplicon viral vectors. METHODS: We have generated HSV/EBV hybrid vectors expressing the mutant EBNA-1 gene with the luciferase reporter gene bicistronically to enable monitoring of EBNA-1 expression in real-time, both in vitro and in vivo. RESULTS: The results obtained showed that the HSV/EBV hybrid vectors could mediate high levels of transgene expression (ranging from approximately two-fold to nine-fold) in primary human tumor cells and human bone marrow-derived mesenchymal stem cells compared to the control vector. Prolonged transgene expression could also be observed in primary patient-derived human hepatocellular carcinoma xenografts and in the mouse brain parenchyma up to a period of 17 and 365 days, respectively. CONCLUSIONS: Taken together, we have demonstrated that these hybrid vectors could be promising tools as carriers of therapeutic genes in mesenchymal stem cells or even provide an alternative non-integrating platform for the generation of induced pluripotent stem cells. PMID- 20963809 TI - Influence of multimorbidity on cognition in a normal aging population: a 12-year follow-up in the Maastricht Aging Study. AB - OBJECTIVE: The prevalence of multimorbidity has risen considerably because of the increase in longevity and the rapidly growing number of older individuals. Today, only little is known about the influence of multimorbidity on cognition in a normal healthy aging population. The primary aim of the present study was to investigate the effect of multimorbidity on cognition over a 12-year period in an adult population with a large age range. METHODS: Data were collected as part of the Maastricht Aging Study (MAAS), a prospective study into the determinants of cognitive aging. Eligible MAAS participants (N = 1763), 24-81 years older, were recruited from the Registration Network Family Practices (RNH) which enabled the use of medical records. The association between 96 chronic diseases, grouped into 23 disease clusters, and cognition on baseline, at 6 and 12 years of follow-up, were analyzed. Cognitive performance was measured in two main domains: verbal memory and psychomotor speed. A multilevel statistical analysis, a method that respects the hierarchical data structure, was used. RESULTS: Multiple disease clusters were associated with cognition during a 12-year follow-up period in a healthy adult population. The disease combination malignancies and movement disorders multimorbidity also appeared to significantly affect cognition. CONCLUSIONS: The current results indicate that a variety of medical conditions adversely affects cognition. However, these effects appear to be small in a normal healthy aging population. PMID- 20963810 TI - Selective introduction of organic groups to C60 and C70 using organoboron compounds and rhodium catalyst: a new synthetic approach to organo(hydro)fullerenes. AB - A Rh-catalyzed reaction of C(60) and C(70) with organoboron compounds is described. This new catalytic method enables introduction of various organic groups onto C(60) and C(70). [Rh(cod)(MeCN)(2)]BF(4) proved to be the most effective catalyst in terms of productivity and selectivity. The reaction generally proceeds with a high regioselectivity and in a mono-addition selective manner. It was found that water is an essential additive to promote the reaction. By X-ray crystal structure analysis, we have confirmed the reaction site of organometallic-based hydroarylation of C(70) for the first time. Various functional fullerenes, such as fullerene-tagged amino acids and fullerene-capped pi systems, can be synthesized. The X-ray crystal structure of biphenyl-attached C(60) revealed an interesting opportunity for the well-organized alignment of bucky balls by taking advantage of CH-pi interactions. PMID- 20963811 TI - Follow-up actions from positive results of in vitro genetic toxicity testing. AB - Appropriate follow-up actions and decisions are needed when evaluating and interpreting clear positive results obtained in the in vitro assays used in the initial genotoxicity screening battery (i.e., the battery of tests generally required by regulatory authorities) to assist in overall risk-based decision making concerning the potential effects of human exposure to the agent under test. Over the past few years, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Project Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity (IVGT) Testing developed a decision process flow chart to be applied in case of clear positive results in vitro. It provides for a variety of different possibilities and allows flexibility in choosing follow-up action(s), depending on the results obtained in the initial battery of assays and available information. The intent of the Review Subgroup was not to provide a prescriptive testing strategy, but rather to reinforce the concept of weighing the totality of the evidence. The Review Subgroup of the IVGT committee highlighted the importance of properly analyzing the existing data, and considering potential confounding factors (e.g., possible interactions with the test systems, presence of impurities, irrelevant metabolism), and chemical modes of action when analyzing and interpreting positive results in the in vitro genotoxicity assays and determining appropriate follow-up testing. The Review Subgroup also examined the characteristics, strengths, and limitations of each of the existing in vitro and in vivo genotoxicity assays to determine their usefulness in any follow-up testing. PMID- 20963812 TI - Comparison of in vitro micronucleus and gene mutation assay results for p53 competent versus p53-deficient human lymphoblastoid cells. AB - The high frequency of false or irrelevant positive results in in vitro mammalian cell genotoxicity tests is a critical concern for regulators. Here, we tested whether such results may be due to the mammalian cells used in the tests being deficient in p53, which is involved in the maintenance of genomic stability. We compared the in vitro responses of two human lymphoblastoid cell lines derived from the same progenitor cell-p53-competent (TK6) and p53-deficient (WTK-1) cells in a micronucleus (MN) test and a thymidine kinase gene (TK) mutation assay. We tested 14 chemicals including three mutagens and 11 clastogens and spindle poisons. The three mutagens evoked clear positive responses in both assays in both cell lines. The responses to the clastogens and spindle poisons, on the other hand, depended on the assay endpoint and/or the cell line. Most of clastogens and spindle poisons were positive in the MN test in both cell lines. In the TK mutation assay, on the other hand, WTK-1 cells but not TK6 cells detected spindle poisons, which may have been due to the disturbance of the spindle checkpoint and lack of apoptosis in the p53-deficient cells. Some chemicals that induced chromosome aberrations in rodent cells were negative in both TK6 and WTK-1 cells, indicating that a species-specific factor rather than p53 status was associated with the response. In conclusion, the p53 status did not seriously influence the MN test results but it did influence the TK mutation assay results. PMID- 20963813 TI - In vitro micronucleus screening of pharmaceutical candidates by flow cytometry in Chinese hamster V79 cells. AB - We previously reported a high concordance of in vitro micronucleus (MNvit) results obtained by flow cytometry to the known cytogenetic activity often commercially available compounds mentioned as validation compounds in an early draft of the OECD MNvit TG487 [Bryce et al., 2010; Organization for Economic Co operation and Development(OECD), 2007]. The current study investigated this method in Chinese hamster V79 cells with pharmaceutical compounds of unknown genotoxic potential. Twenty-five compounds from several therapeutic areas such as oncology, neuroscience and immunological research were tested in the flow cytometry assay, and for comparison using the cytokinesis-block microscopy assay. Five of these 25 compounds were considered positive for micronucleus induction by the microscopy assessment. In all cases, the results from the flow cytometry assess ment matched the results of the microscopy assay. Thus, flow cytometry is a viable method for assessing the aneugenic/clastogenic potential of pharmaceutical drug candidates. The flow method offered several advantages over traditional microscopy. For instance, the ratio of micronuclei (MN) to 10,000 nuclei was evaluated in less than 2 min vs.15 min to manually assess 600 binucleate cells. Evaluation by flow cytometry can be automated,freeing resources and eliminating scorer fatigue.The assay may also provide for mechanistic understanding of MN formation based on size and the ratio of nuclei with sub-2N DNA content, allowing for discrimination between aneugenic and clastogenic compounds. PMID- 20963814 TI - Curcuminoids rescue long-term potentiation impaired by amyloid peptide in rat hippocampal slices. AB - Curcuminoids are vital constituent of turmeric, with therapeutic potential in the treatment of Alzheimer's disease. Electrically, stimulus train-elicited plastic changes in hippocampal CA1 excitability were used as an experimental paradigm to study the effects of curcuminoid mixture and individual components on functional failure induced by Abeta peptide in vitro. Electrical stimulation was applied on Schaffer collaterals, and population spikes (PS) were recorded from stratum pyramidale. To induce long-term potentiation (LTP) of PS, primed burst stimulation (PBs) was used. Abeta peptide inhibited PS LTP induction. Sinking PS LTP due to Abeta peptide was rescued when curcuminoid mixture was applied before PBs only at lower dose (0.1 MUM) resulting in PS potentiation to 127.42% +/- 1.83% at 5 min and 123.98% +/- 1.06% at 60-min post-PBs. Similarly, when bisdemethoxycurcumin was applied, PS LTP was induced and lasted only at a single dose (0.1 MUM). Demethoxycurcumin was effective at a middle dose (1 MUM), so that the PS amplitude was changed to 140.15% +/- 2.68% and 129.82% +/- 0.44% at 5 and 60 min, respectively. PS LTP was effectively induced in the presence of curcumin at middle and high doses (1 and 30 MUM) with resultant PS LTP to 155.68% +/- 1.23% and 127.72% +/- 1.23%, respectively, at 60-min post-PBs. These results showed that curcuminoids can restore susceptibility for plastic changes in CA1 excitability that is injured by exposure to Abeta peptide and rescue sinking PS LTP in Abeta-peptide-exposed hippocampal CA1 neurons. PMID- 20963815 TI - Vitamin C protects against ethanol and PTZ-induced apoptotic neurodegeneration in prenatal rat hippocampal neurons. AB - Exposure to alcohol during brain development may cause a neurological syndrome called fetal alcohol syndrome, characterized by pre- and postnatal growth deficiencies, craniofacial anomalies, and evidence of CNS dysfunction. The objective of this study was to evaluate pentylenetetrazol (PTZ) and ethanol effects on Bax, Bcl-2 expression, which further induced activation of caspase-3, release of cytochrome-c from mitochondria, and to observe the protective effects of vitamin C (vit-C) against PTZ and ethanol-induced apoptotic neurodegeneration in primary-cultured neuronal cells at gestational day 17.5. Apoptotic neurodegeneration and neuroprotective effect of vit-C were measured by using 3 [4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay, Western blot analysis, which further conformed by the measurement of mitochondrial membrane potential using JC-1 detection kit and immunofluorescence analysis. The results showed that PTZ and ethanol produced extensive Bax-dependent caspase-9 and caspase-3 activation and caused neuronal apoptosis. Furthermore, the cotreatment of vit-C along with ethanol and PTZ showed significantly decreased expression of Bax, caspase-9, caspase-3, cytochrome-c, and significantly increased expression of antiapoptotic Bcl-2 protein when compared with control group. Our findings indicate that PTZ and ethanol activate an intrinsic apoptotic death program in neurons that is likely to contribute to the neuropathologic effects in fetal alcohol exposure, and vit-C can prevent some of the deleterious effects of PTZ and ethanol on the developing brain. The available experimental evidence and the safety of vit-C in pregnancy suggest the experimental use of ascorbic acid as a new and effective protective agent ethanol and PTZ-induced apoptotic neurodegeneration. PMID- 20963816 TI - Test-retest variability of [11C]raclopride-binding potential in nontreatment seeking alcoholics. AB - Knowledge of the reproducibility of striatal [11C]raclopride (RAC) binding is important for studies that use RAC PET paradigms to estimate changes in striatal dopamine (DA) during pharmacological and cognitive challenges. To our knowledge, no baseline test-retest data exist for nontreatment-seeking alcoholics (NTS). We determined the test-retest reproducibility of baseline RAC binding potential (BP(ND) ) in 12 male NTS subjects. Subjects were scanned twice with single-bolus RAC PET on separate days. Striatal RAC BP (BP(ND) ) for left and right dorsal caudate, dorsal putamen, and ventral striatum was estimated using the Multilinear Reference Tissue Method (MRTM) and Logan Graphical Analysis (LGA) with a reference region. Test-retest variability (TRV), % change in BP(ND) between scan days, and the intraclass correlation coefficient (ICC) were used as metrics of reproducibility. For MRTM, TRV for striatal RAC binding in NTS subjects was +/ 6.5% and +/-7.1% for LGA. Average striatal ICCs were 0.94 for both methods (P < 0.0001). Striatal BP(ND) values were similar to those reported previously for detoxified alcoholics. The results demonstrate that baseline striatal RAC binding is highly reproducible in NTS subjects, with a low variance similar to that reported for healthy control subjects. PMID- 20963818 TI - Detection and characterization of single-trial fMRI bold responses: paradigm free mapping. AB - This work presents a novel method of mapping the brain's response to single stimuli in space and time without prior knowledge of the paradigm timing: paradigm free mapping (PFM). This method is based on deconvolution of the hemodynamic response from the voxel time series assuming a linear response and using a ridge-regression algorithm. Statistical inference is performed by defining a spatio-temporal t-statistic and by controlling for multiple comparisons using the false discovery rate procedure. The methodology was validated on five subjects who performed self-paced and visually cued finger tapping at 7 Tesla, with moderate (TR = 2 s) and high (TR = 0.4 s) temporal resolution. The results demonstrate that detection of single-trial BOLD events is feasible without a priori information on the stimulus paradigm. The proposed method opens up the possibility of designing temporally unconstrained paradigms to study the cortical response to unpredictable mental events. PMID- 20963817 TI - Preweaning Mn exposure leads to prolonged astrocyte activation and lasting effects on the dopaminergic system in adult male rats. AB - Little is known about the effects of manganese (Mn) exposure over neurodevelopment and whether these early insults result in effects lasting into adulthood. To determine if early Mn exposure produces lasting neurobehavioral and neurochemical effects, we treated neonate rats with oral Mn (0, 25, or 50 mg Mn/kg/d over PND 1-21) and evaluated (1) behavioral performance in the open arena in the absence (PND 97) and presence (PND 98) of a d-amphetamine challenge, (2) brain dopamine D1 and D2-like receptors and dopamine transporter densities in the prefrontal cortex, striatum, and nucleus accumbens (PND 107), and (3) astrocyte marker glial fibrillary acidic protein (GFAP) levels in these same brain regions (PND 24 and 107). We found that preweaning Mn exposure did not alter locomotor activity or behavior disinhibition in adult rats, though Mn-exposed animals did exhibit an enhanced locomotor response to d-amphetamine challenge. Preweaning Mn exposure led to increased D1 and D2 receptor levels in the nucleus accumbens and prefrontal cortex, respectively, compared with controls. We also found increased GFAP expression in the prefrontal cortex in Mn-exposed PND 24 weanlings, and increased GFAP levels in prefrontal cortex, medial striatum and nucleus accumbens of adult (PND 107) rats exposed to preweaning Mn, indicating an effect of Mn exposure on astrogliosis that persisted and/or progressed to other brain regions in adult animals. These data show that preweaning Mn exposure leads to lasting molecular and functional impacts in multiple brain regions of adult animals, long after brain Mn levels returned to normal. PMID- 20963819 TI - In vitro screening of organotin compounds and sediment extracts for cytotoxicity to fish cells. AB - The present study reports an in vitro screening method for contaminants in sediment samples utilizing an RTG-2 cell line. This technique integrates cytotoxicity testing with analytical chemistry with the aim of achieving a toxicity evaluation of the sediment sample. The toxic effect of individual organotin (OT) compounds and their presence in the sediment sample is the focus of the present study; however, other contaminants are also discussed. The following OT compounds: tributyltin (TBT), dibutyltin (DBT), monobutyltin (MBT), triphenyltin (TPT), diphenyltin (DPT), and a sediment solvent extract are exposed to the RTG-2 fish cell line. Both the alamar blue (AB) and neutral red (NR) assays are used to assess cytotoxicity after 24-h and 96-h exposure. Methodology for preparation of a sediment solvent extract suitable for biological testing and analytical determination is also described. With the RTG-2 cells, the AB and NR assays had comparable sensitivity for each individual OT compound exposure after 24 h, with TPT being the most toxic compound tested. The individual OT compound concentrations required to induce a 50% toxic effect on the cells (369 ng ml-1 TBT, 1,905 ng ml-1 DBT) did not equate to the concentrations of these contaminants present in the sediment extract that induced a 50% effect on the cells (294 ng ml-1 TBT, 109 ng ml-1 DBT). The solvent extract therefore exhibited a greater toxicity, and this suggests that the toxic effects observed were not due to OT compounds alone. The presence of other contaminants in the solvent extract is confirmed with chemical analysis, warranting further toxicity testing of contaminant mixtures and exposure to the cell line to further elucidate a complete toxicity evaluation. PMID- 20963820 TI - Effects of dietary uranium on reproductive endpoints--fecundity, survival, reproductive success--of the fish Danio rerio. AB - Exposure to metal-contaminated water has been shown to result in a number of reproductive abnormalities in adult and larvae fish, such as failure of oocyte maturation and teratogenic effects. Recently, dietary uptake of metals by fish has been recognized as a critical route of exposure, however, the mechanisms of metal uptake and toxicity are poorly understood and in need of further investigation. The objectives of the present study are to quantify uranium (U dietary transfers from spiked artificial diets) in Danio rerio tissues and embryos, as well as establish its effect on reproduction and embryonic development. Uranium's environmental prominence is currently increasing because of new mining and milling activities. Uranium concentrations range from 0.02 ug/L in natural waters to 2 mg/L. The focus of this study was to examine the trophic transfer and effects of U following exposure modalities (dose, exposure duration 1 to 20 d). Two different isotopes were used to distinguish between chemical and radioactivity toxicity of U. Results showed that U trophic transfer was low (0.52%). Uranium tissue distributions showed that accumulation occurred in digestive organs (liver, digestive tract) following dietary exposure. High levels of U were measured in the gonads (female in particular, >20% of relative burden). High U accumulation levels in eggs indicated maternal transfer of the contaminant. Moreover, U trophic exposure led to a reduction in reproduction success as a function of U accumulated levels. High U exposure conditions strongly reduced the total number of eggs (50%) and their viability at 10 d (reduction of the clutch number, low quality of eggs). PMID- 20963821 TI - Nestin is required for the proper self-renewal of neural stem cells. AB - The intermediate filament protein, nestin, is a widely employed marker of multipotent neural stem cells (NSCs). Recent in vitro studies have implicated nestin in a number of cellular processes, but there is no data yet on its in vivo function. Here, we report the construction and functional characterization of Nestin knockout mice. We found that these mice show embryonic lethality, with neuroepithelium of the developing neural tube exhibiting significantly fewer NSCs and much higher levels of apoptosis. Consistent with this in vivo observation, NSC cultures derived from knockout embryos show dramatically reduced self-renewal ability that is associated with elevated apoptosis but no overt defects in cell proliferation or differentiation. Unexpectedly, nestin deficiency has no detectable effect on the integrity of the cytoskeleton. Furthermore, the knockout of Vimentin, which abolishes nestin's ability to polymerize into intermediate filaments in NSCs, does not lead to any apoptotic phenotype. These data demonstrate that nestin is important for the proper survival and self-renewal of NSCs, and that this function is surprisingly uncoupled from nestin's structural involvement in the cytoskeleton. PMID- 20963824 TI - Establishment of mice expressing EGFP in the placode-derived inner ear sensory cell lineage and FACS-array analysis focused on the regional specificity of the otocyst. AB - In this study, we established a novel enhanced green fluorescent protein (EGFP) reporter mouse line that enables the visualization of the placode-derived inner ear sensory cell lineage. EGFP was initially expressed in the otic placode and throughout its differentiation process into the inner ear sensory patches. At embryonic day 10.5 (E10.5), EGFP was expressed in the ventral and dorsomedial region of the otocyst. These regions could mainly give rise to the cochlea, including the organ of Corti, and the saccule, including the macula and the endolymphatic duct. The region could also give rise to cells that will develop as either prosensory cells or statoacoustic ganglion neuroblasts. By using this line and fluorescence-activated cell sorting (FACS)-array technology, we developed a new gene expression profile of the regional specificity of the otocyst. EGFP positive regions include the Otx1-positive region, which could be clearly distinguished from EGFP-negative regions. The signal log ratio of microarray data showed high efficiency in predicting the genes expressed mainly in the ventral and/or dorsomedial otocyst and the data could be mined to uncover many novel genes involved in inner ear morphogenesis and cell fate regulation. Additionally, these data suggest that some novel genes enriched in EGFP-positive regions may be potentially involved in human congenital sensorineural hearing loss. This reporter line could play important roles in the use of animal models for detailed analysis of the differentiation process into the sensory patches and the identification of regional-specific gene networks and novel gene functions in the developing inner ear. PMID- 20963823 TI - Target selection of proprioceptive and motor axon synapses on neonatal V1-derived Ia inhibitory interneurons and Renshaw cells. AB - The diversity of premotor interneurons in the mammalian spinal cord is generated from a few phylogenetically conserved embryonic classes of interneurons (V0, V1, V2, V3). Their mechanisms of diversification remain unresolved, although these are clearly important to understand motor circuit assembly in the spinal cord. Some Ia inhibitory interneurons (IaINs) and all Renshaw cells (RCs) derive from embryonic V1 interneurons; however, in adult they display distinct functional properties and synaptic inputs, for example proprioceptive inputs preferentially target IaINs, while motor axons target RCs. Previously, we found that both inputs converge on RCs in neonates, raising the possibility that proprioceptive (VGLUT1 positive) and motor axon synapses (VAChT-positive) initially target several different V1 interneurons populations and then become selected or deselected postnatally. Alternatively, specific inputs might precisely connect only with predefined groups of V1 interneurons. To test these hypotheses we analyzed synaptic development on V1-derived IaINs and compared them to RCs of the same age and spinal cord levels. V1-interneurons were labeled using genetically encoded lineage markers in mice. The results show that although neonatal V1-derived IaINs and RCs are competent to receive proprioceptive synapses, these synapses preferentially target the proximal somato-dendritic regions of IaINs and postnatally proliferate on IaINs, but not on RCs. In contrast, cholinergic synapses on RCs are specifically derived from motor axons, while on IaINs they originate from Pitx2 V0c interneurons. Thus, motor, proprioceptive, and even some interneuron inputs are biased toward specific subtypes of V1-interneurons. Postnatal strengthening of these inputs is later superimposed on this initial preferential targeting. PMID- 20963826 TI - Differential distribution of neurons in the gyral white matter of the human cerebral cortex. AB - The neurons in the cortical white matter (WM neurons) originate from the first set of postmitotic neurons that migrates from the ventricular zone. In particular, they arise in the subplate that contains the earliest cells generated in the telencephalon, prior to the appearance of neurons in gray matter cortical layers. These cortical WM neurons are very numerous during development, when they are thought to participate in transient synaptic networks, although many of these cells later die, and relatively few cells survive as WM neurons in the adult. We used light and electron microscopy to analyze the distribution and density of WM neurons in various areas of the adult human cerebral cortex. Furthermore, we examined the perisomatic innervation of these neurons and estimated the density of synapses in the white matter. Finally, we examined the distribution and neurochemical nature of interneurons that putatively innervate the somata of WM neurons. From the data obtained, we can draw three main conclusions: first, the density of WM neurons varies depending on the cortical areas; second, calretinin immunoreactive neurons represent the major subpopulation of GABAergic WM neurons; and, third, the somata of WM neurons are surrounded by both glutamatergic and GABAergic axon terminals, although only symmetric axosomatic synapses were found. By contrast, both symmetric and asymmetric axodendritic synapses were observed in the neuropil. We discuss the possible functional implications of these findings in terms of cortical circuits. PMID- 20963825 TI - Endogenous GluR1-containing AMPA receptors translocate to asymmetric synapses in the lateral amygdala during the early phase of fear memory formation: an electron microscopic immunocytochemical study. AB - Although glutamate receptor 1 (GluR1)-containing alpha-amino-3-hydroxyl-5-methyl 4-isoxazole-propionate receptors (GluR1-AMPARs) are implicated in synaptic plasticity, it has yet to be demonstrated whether endogenous GluR1-AMPARs undergo activity-dependent trafficking in vivo to synapses to support short-term memory (STM) formation. The paradigm of pavlovian fear conditioning (FC) can be used to address this question, because a discrete region-the lateral amygdala (LA)-has been shown unambiguously to be necessary for the formation of the associative memory between a neutral stimulus (tone [CS]) and a noxious stimulus (foot shock [US]). Acquisition of STM for FC can occur even in the presence of protein synthesis inhibitors, indicating that redistribution of pre-existing molecules to synaptic junctions underlies STM. We employed electron microscopic immunocytochemistry to evaluate alterations in the distribution of endogenous AMPAR subunits at LA synapses during the STM phase of FC. Rats were sacrificed 40 minutes following three CS-US pairings. In the LA of paired animals, relative to naive animals, the proportion of GluR1-AMPAR-labeled synapses increased 99% at spines and 167% in shafts. In the LA of unpaired rats, for which the CS was never associated with the US, GluR1 immunoreactivity decreased 84% at excitatory shaft synapses. GluR2/3 immunoreactivity at excitatory synapses did not change detectably following paired or unpaired conditioning. Thus, the early phase of FC involves rapid redistribution specifically of the GluR1-AMPARs to the postsynaptic membranes in the LA, together with the rapid translocation of GluR1 AMPARs from remote sites into the spine head cytoplasm, yielding behavior changes that are specific to stimulus contingencies. PMID- 20963827 TI - Neuroprotective effects of testosterone in a naturally occurring model of neurodegeneration in the adult avian song control system. AB - Seasonal regression of the avian song control system, a series of discrete brain nuclei that regulate song learning and production, serves as a useful model for investigating the neuroprotective effects of steroids. In seasonally breeding male songbirds, the song control system regresses rapidly when males are transferred from breeding to nonbreeding physiological conditions. One nucleus in particular, the HVC, regresses in volume by 22% within days of castration and transfer to a nonbreeding photoperiod. This regression is mediated primarily by a 30% decrease in neuron number, a result of a caspase-dependent process of programmed cell death. Here we examine whether testosterone (T) can act locally in the brain to prevent seasonal-like neurodegeneration in HVC. We began to infuse T intracerebrally near HVC on one side of the brain in breeding-condition male white-crowned sparrows 2 days prior to T withdrawal and shifting them to short-day photoperiods. The birds were killed 3 or 7 days later. Local T infusion significantly protected ipsilateral HVC from volume regression and neuron loss. In addition, T infusion significantly reduced the number, density, and number/1,000 neurons of activated caspase-3 cells and cells positive for cleaved PARP, both markers for programmed cell death, in the ipsilateral HVC. T infusion near HVC also prevented regression of ipsilateral efferent targets of HVC neurons, including the volumes of robust nucleus of the arcopallium (RA) and Area X and the soma area and density of RA neurons. Thus T can act locally in the brain to have a neuroprotective effect and act transsynaptically to prevent regression of efferent nuclei. PMID- 20963828 TI - Differential postsynaptic compartments in the laterocapsular division of the central nucleus of amygdala for afferents from the parabrachial nucleus and the basolateral nucleus in the rat. AB - Neurons in the laterocapsular division of the central nucleus of the amygdala (CeC), which is known as the "nociceptive amygdala," receive glutamatergic inputs from the parabrachial nucleus (PB) and the basolateral nucleus of amygdala (BLA), which convey nociceptive information from the dorsal horn of the spinal cord and polymodal information from the thalamus and cortex, respectively. Here, we examined the ultrastructural properties of PB- and BLA-CeC synapses identified with EGFP-expressing lentivirus in rats. In addition, the density of synaptic AMPA receptors (AMPARs) on CeC neurons was studied by using highly sensitive SDS digested freeze-fracture replica labeling (SDS-FRL). Afferents from the PB made asymmetrical synapses mainly on dendritic shafts (88%), whereas those from the BLA were on dendritic spines (81%). PB-CeC synapses in dendritic shafts were significantly larger (median 0.072 MUm(2)) than BLA-CeC synapses in spines (median 0.058 MUm(2); P = 0.02). The dendritic shafts that made synapses with PB fibers were also significantly larger than those that made synapses with BLA fibers, indicating that the PB fibers make synapses on more proximal parts of dendrites than the BLA fibers. SDS-FRL revealed that almost all excitatory postsynaptic sites have AMPARs in the CeC. The density of AMPAR-specific gold particles in individual synapses was significantly higher in spine synapses (median 510 particles/MUm(2)) than in shaft synapses (median 427 particles/MUm(2); P = 0.01). These results suggest that distinct synaptic impacts from PB- and BLA-CeC pathways contribute to the integration of nociceptive and polymodal information in the CeC. PMID- 20963829 TI - Direct projections of omnipause neurons to reticulospinal neurons: a double labeling light microscopic study in the cat. AB - Omnipause neurons (OPNs) are inhibitory neurons located in the midline region of the caudal pons. Their role in gating the discharges of saccade-related burst neurons is well known, but there is no agreement concerning their influence on brainstem neurons that control other muscle groups participating in rapid gaze shifts. In the present study, we inquired whether OPNs project directly to pontobulbar reticulospinal neurons (RSNs) in the cat. Retrograde transport of horseradish peroxidase from the cervical spinal cord was used to label RSNs and an anterograde tracer (biocytin) was iontophoresed at sites of extracellular recording of the OPN activity. Somadendritic characteristics of biocytin-labeled OPNs were largely similar to those obtained previously with intracellular labeling. Three-dimensional reconstruction of axonal trajectories and collaterals revealed that projections of OPNs, regarded as a population, are bilateral. Their terminals were restricted to the reticular formation and midline structures throughout the rostral bulbar and pontine tegmentum. Appositions of synaptic boutons originating from five fully stained OPNs were detected on 38 retrogradely labeled RSNs, each of the OPNs contacting 3-13 cells. The numbers of boutons (1 46; mean 11.8) on the RSN somata and proximal dendrites indicate that the anatomical strength of paired OPN-RSN connections is comparable to that of other similarly studied inhibitory neurons in the cat. The existence of connections with RSNs supports the hypothesis of a generalized influence of OPNs on several effectors participating in orienting gaze shifts as opposed to the idea of their strict specialization for the control of eye saccades. PMID- 20963830 TI - Tracer coupling of intrinsically photosensitive retinal ganglion cells to amacrine cells in the mouse retina. AB - Intrinsically photosensitive retinal ganglion cells (ipRGCs) are a subtype of ganglion cell in the mammalian retina that expresses the photopigment melanopsin and drives non-image-forming visual functions. Three morphological subtypes of ipRGCs (M1, M2, and M3) have been described based on their dendritic stratifications in the inner plexiform layer (IPL), but the question of their potential interactions via electrical coupling remains unsettled. In this study, we have addressed this question in the mouse retina by, injecting the tracer Neurobiotin into ipRGCs that had been genetically labelled with the fluorescent protein, tdTomato. We confirmed the presence of the M1-M3 subtypes of ipRGCs based on their distinct dendritic stratifications. All three subtypes were tracer coupled to putative amacrine cells situated within the ganglion cell layer (GCL) but not the inner nuclear layer (INL). The cells tracer coupled to the M1 and M2 cells were shown to be widefield GABA-immunoreactive amacrine cells. We found no evidence of homologous tracer coupling of ipRGCs or heterologous coupling to other types of ganglion cells. PMID- 20963831 TI - Tobramycin inhalation powder for P. aeruginosa infection in cystic fibrosis: the EVOLVE trial. AB - Tobramycin inhalation solution is used to treat chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients. We evaluated the efficacy and safety of a novel, light-porous particle, dry-powder formulation of tobramycin, which was developed to improve delivery efficiency to the airways and substantially reduce the delivery time. In this randomized, double-blind study, patients with CF (age 6-21 years) received tobramycin inhalation powder (112 mg tobramycin) twice daily (n = 46) or placebo (n = 49) via the T-326 Inhaler for one cycle, followed by two open-label cycles (all patients). Cycles were 28 days on, 28 days off treatment. The primary endpoint was change in forced expiratory volume in 1 sec (FEV1) % predicted from baseline to Day 28 of Cycle 1. The study was terminated early based on positive results in the interim analysis. Tobramycin inhalation powder significantly improved FEV1 % predicted versus placebo at Day 28 (difference 13.3, 95% CI: 5.31-21.28; P = 0.0016). Similar changes in FEV1 were seen in patients switching from placebo to tobramycin inhalation powder in Cycle 2; improvements were maintained over time. Tobramycin inhalation powder also reduced sputum P. aeruginosa density, respiratory-related hospitalization and antipseudomonal antibiotic use versus placebo. The most common adverse event was cough; the frequency of cough was higher in patients receiving placebo (26.5%) versus tobramycin inhalation powder (13.0%) in Cycle 1. Tobramycin inhalation powder was not associated with ototoxicity or nephrotoxicity. Administration time was between 4 and 6 min. In conclusion, tobramycin inhalation powder was effective and well tolerated in CF patients, and may offer an important treatment option to decrease the treatment burden of CF pseudomonas lung infections. PMID- 20963832 TI - Use of a lung model to assess mechanical in-exsufflator therapy in infants with tracheostomy. AB - BACKGROUND: The mechanical in-exsufflator (MIE) is commonly used to augment cough in patients with neuromuscular disease from infancy to adulthood. Little is known about the alveolar pressures, lung volumes, and expiratory flow rates generated by the MIE when used via tracheostomy tube in infants and children. METHODS: A high-fidelity mechanical lung model was programmed to simulate infants with tracheostomy tubes. Generated pressures, volumes, and expiratory flows using the MIE device at variable insufflation/exsufflation pressures and times were recorded. The primary measure of interest was maximal expiratory flow (MEF). RESULTS: Pressure equilibration across the tracheostomy tube did not occur with insufflation time <1 sec. Longer insufflation time significantly increased measured alveolar pressures, lung volume, and MEF until TLC was reached. Longer exsufflation time did not significantly increase MEF. Higher insufflation pressures resulted in greater lung volumes, with >70% vital capacity attained at insufflation pressures as low as 20 cmH2 O. Though higher insufflation pressures resulted in increased expiratory flow rates, more negative exsufflation pressure had a greater absolute impact on MEF. CONCLUSIONS: Using the MIE via tracheostomy tube in an infant lung model, we found that an insufflation time of >1 sec is required for equilibration of insufflation pressure and alveolar pressure. Longer exsufflation time does not significantly alter MEF. Higher insufflation and exsufflation pressures both increased MEF, but greater exsufflation pressure had more substantial impact. PMID- 20963833 TI - Nasal high frequency percussive ventilation versus nasal continuous positive airway pressure in transient tachypnea of the newborn: a pilot randomized controlled trial (NCT00556738). AB - OBJECTIVE: To determine whether nasal high frequency percussive ventilation (NHFPV) would decrease duration of transient tachypnea of the newborn (TTN) compared to nasal continuous positive airway pressure (NCPAP) in newborn infants. METHODS: A prospective, unmasked, randomized, controlled clinical trial was conducted in 46 eligible newborn infants who were hospitalized for TTN in the University Hospital of Bordeaux (France) between 2007 and 2009. Infants born by cesarian section >=37 GA, >=2,000 g with diagnosis of TTN and with a transcutaneous saturation <90% at 20 min after birth were eligible. Infants were randomized to either NHFPV or NCPAP. The primary endpoint was a reduction of the duration of TTN. Secondary endpoints were the duration of oxygen therapy and the minimal level required to obtain a saturation between 90% and 96% integrated into an index which included a time factor: [(FiO2 -21)/time of O2 therapy]. RESULTS: In the NHFPV group the duration of TTN was half the time of NCPAP group (105 min +/- 20 and 377 min +/- 150, respectively; P < 0.0001). There was a significant decrease in duration of oxygen supplementation in the NHFPV group (6.3 min +/- 3.3) compared to the NCPAP group (19.1 min +/- 8.1; P < 0.001), and a significant decrease in level of oxygen supplementation [(FiO2 -0.21)/time of O2 therapy] in the NHFPV group (0.29 min(-1) +/- 0.16) compared to the NCPAP group (0.46 min( 1) +/- 0.50; P < 0.001). There was no complication and NHFPV was as well tolerated as NCPAP. CONCLUSION: NHFPV is well tolerated and more effective than NCPAP in treatment of TTN. NHFPV might be a novel and safe tool to manage TTN. Pediatr Pulmonol. PMID- 20963834 TI - Hospitalized children with 2009 influenza a (H1N1) infection in Shenzhen, China, November-December 2009. AB - OBJECTIVES: During the winter outbreak of 2009 influenza A (H1N1) infection in China, the number of confirmed cases and the fatal cases has grown rapidly. We describe the clinical characteristics of hospitalized children with 2009 influenza A (H1N1) infection in Shenzhen, China, November-December 2009. METHODS: Using a standardized form, we collected data on 148 hospitalized children. 2009 influenza A (H1N1) infection was confirmed in nasopharyngeal swab specimens with the use of a real-time reverse transcriptase-polymerase chain reaction assay. RESULTS: Of the 148 hospitalized children with 2009 influenza A (H1N1) infection, 81 (55%) were 5 years of age or older and 85% of the patients were previously healthy. The common presenting symptoms were fever (94%), cough (89%), runny nose (36.5%), vomiting (24%), sore throat (19.6%), wheezing (18%), abdominal pain (16%), mental status changes (9%), seizures (6%), diarrhea (6%), myalgia (6%), and chest pain (4%). Twenty-nine (20%) patients were admitted to an ICU, 10 (7%) patients required mechanical ventilation. The overall complication rate was 65.5%, they were pneumonia in 94 (64%), neurologic complications in 18 (12%), parapneumonic effusion in 12 (8%) and myocarditis in 7 (5%). One hundred seven (72%) patients received oseltamivir treatment, 34 (23%) received within 48 hr after the onset of symptoms. All patients received antibiotics before admission or on admission. One hundred forty-four (97%) patients were discharged; four (3%) previously healthy patients died, three died from severe encephalopathy, one died from secondary fungal meningitis. CONCLUSION: Hospitalized children with 2009 influenza A (H1N1) infection can have a wide range of presentation and clinical complications including neurologic complications. The severe cases and deaths concentrate in previously healthy older children. PMID- 20963835 TI - Early wheeze reduces lung function: or is it viral infection? PMID- 20963837 TI - Influenza a (H1N1) virus pneumonia in newborns: experience of a referral level III neonatal intensive care unit in Turkey. PMID- 20963838 TI - Relationship between chlorinated pools and bronchial asthma. PMID- 20963839 TI - Airway hyperresponsiveness to methacholine in 7-year-old children: sensitivity and specificity for pediatric allergist-diagnosed asthma. AB - BACKGROUND: The operating characteristics of PC(20) values used as cut-offs to define airway hyperresponsiveness, as it informs the diagnosis of asthma in children, are poorly understood. We examine data from a unique cohort to inform this concern. OBJECTIVE: Determine the sensitivity and specificity of incremental PC(20) cut-offs for allergist-diagnosed asthma. METHODS: Airway reactivity at age 7 was assessed in children within a birth cohort at high risk for asthma; PC(20) for methacholine was determined by standard technique including interpolation. The diagnosis of asthma was considered by the pediatric allergist without knowledge of the methacholine challenge results. Sensitivity and specificity were calculated using a cross-tabulation of asthma diagnosis with incremental PC(20) cut-off values, from 1.0 to 8.0 mg/ml, and plotted as receiver operator characteristic (ROC) curves. The "optimal" cut-off was defined as that PC(20) conferring maximal value for sensitivity plus specificity while the "balanced" cut-off was defined as that PC(20) at which sensitivity and specificity were most equal. RESULTS: 70/348 children (20.1%) were diagnosed with asthma. The optimal and balanced PC(20) cut-offs, both for all children and for females alone, were respectively 3 mg/ml (sensitivity 80.0%, specificity 49.1%) and 2 mg/ml (sensitivity 63.1%, specificity 64.7%). For males alone, the "optimal" and "balanced" PC(20) cut-offs were both 2 mg/ml. CONCLUSION: For this cohort of 7 year olds at high risk for asthma, methacholine challenge testing using a cut-off value of PC(20) 3 mg/ml conferred the maximal sum of specificity plus sensitivity. For contexts in which higher sensitivity or specificity is desired, other cut-offs may be preferred. PMID- 20963840 TI - Use of azithromycin for the prevention of bronchopulmonary dysplasia in preterm infants: a randomized, double-blind, placebo controlled trial. AB - OBJECTIVE: Since preventive therapies for bronchopulmonary dysplasia (BPD) are limited we treated preterm infants with azithromycin to decrease the incidence of BPD. METHODS: Infants less than 1,250 g birth weight were randomized to azithromycin or placebo within 12 hr of beginning mechanical ventilation and within 72 hr of birth. The treatment group received azithromycin 10 mg/kg/day for 7 days followed by 5 mg/kg/day for a maximum of 6 weeks. Aspirates were collected during the study to assay for Ureaplasma. The primary endpoints were incidence of BPD or mortality. (Clinical Trials Identifier: NCT00319956.) RESULTS: A total of 220 infants were enrolled (n=111 azithromycin, and 109 placebo). Mortality was 18% for the azithromycin group versus 22% for the placebo group (P = 0.45). Incidence of BPD was 76% for the azithromycin group versus 84% for the placebo group (P=0.2). The multiple logistic regression analysis demonstrated an odds ratio of 0.46 decrease in the chance of developing BPD or death for the azithromycin group, but was not statistically significant. The incidence of BPD in the Ureaplasma subgroup was 73% in the azithromycin group versus 94% in the placebo group (P=0.03). Analysis of patients in the Ureaplasma subgroup only, using the exact logistic model demonstrated a decrease in BPD or death in the azithromycin group with an estimated odds ratio of 0.026 (0.001-0.618, 95% confidence interval). CONCLUSIONS: Routine use of azithromycin therapy for the prevention of BPD cannot be recommended. The early treatment of Ureaplasma colonized/infected patients might be beneficial, but a larger multi-centered trial is required to assess this more definitively. PMID- 20963841 TI - Pattern recognition receptors and genetic risk for rsv infection: value for clinical decision-making? AB - Respiratory syncytial virus (RSV) causes respiratory tract infections, especially among young infants. Practically, all infants are infected during epidemics and the clinical presentation ranges from subclinical to fatal infection. Known risk factors for severe RSV infection include prematurity, age of <2 months, underlying chronic lung or heart diseases, serious neurological or metabolic disorders, immune deficiency (especially a disorder of cellular immunity), crowded living conditions, and indoor smoke pollution. Twin studies indicate that host genetic factors affect susceptibility to severe RSV infection. Pattern recognition receptors (PRRs) are the key mediators of the innate immune response to RSV. In the distal respiratory tract, RSV is recognized by the transmembrane Toll-like receptor 4 (TLR4) and adapter proteins, which lead to production of proinflammatory cytokines and subsequent activation of the adaptive immune response. Surfactant proteins A and D are able to bind both RSV and TLR4, modulating the inflammatory response. Genetic variations in TLR4, SP-A, and SP-D have been associated with the risk of severe RSV bronchiolitis, but the results have varied between studies. Both the homozygous hyporesponsive 299Gly genotype of TLR4 and the non-synonymous SP-A and SP-D polymorphism influence the presentation of RSV infection. The reported relative risks associated with these markers are not robust enough to justify clinical use. However, current evidence indicates that innate immune responses including pattern recognition receptors (PRRs) and other components in the distal airways and airspaces profoundly influence the innate immune responses, playing a key role in host resistance to RSV in young infants. This information is useful in guiding efforts to develop better means to identify the high-risk infants and to treat this potentially fatal infection effectively. PMID- 20963842 TI - A bedside assay to detect streptococcus pneumoniae in children with empyema. AB - BACKGROUND: Empyema is a complication of pneumonia, commonly caused by Streptococcus pneumoniae. AIMS: To validate the utility of an immunochromatographic test for the detection of S. pneumoniae antigen in the pleural fluid of children with empyema. METHODS: Empyema patients had blood and pleural fluid cultured, and polymerase chain reaction (PCR) to detect the S. pneumoniae autolysin gene, lytA, in pleural fluid. Pleural fluid was tested using the Binax NOW S. pneumoniae antigen detection assay and compared with lytA PCR results and/or culture in blood or pleural fluid. RESULTS: S. pneumoniae was detected by PCR in pleural fluid of 68 of 137 (49.6%) patients, by culture in 11 of 135 (8.1%) pleural specimens and 16 of 120 (13.3%) blood specimens. Pleural fluid Binax NOW testing from 130 patients demonstrated a sensitivity of 83.8% and specificity of 93.5% (positive predictive value of 93.4% and negative predictive value of 84.1%). CONCLUSIONS: In pediatric empyema, high predictive values of pleural fluid Binax NOW S. pneumoniae antigen test suggest that this test may help rationalize antibiotic choice in these patients. PMID- 20963844 TI - An investigation into the morphology of loxapine in a thermal aerosolization process from crystalline to amorphous. AB - A highly pure aerosol of the antipsychotic drug, loxapine, can be thermally generated through vaporization from a thin coating of loxapine on a stainless steel substrate with the formation of a condensation aerosol. Because loxapine can exist in two polymorphic forms, the morphological time course from loxapine drug substance to coating on the substrate (intermediate product) and ultimately to the aerosol was investigated using differential scanning calorimetery, X-ray diffraction (XRD), Fourier transform infrared, and Raman spectroscopy. Monoclinic and orthorhombic crystalline forms of loxapine were confirmed by single crystal and powder XRD. A mixture of both loxapine crystalline polymorphs was formed on the substrate, independent of the initial loxapine crystalline morphology, and demonstrated to be stable. The loxapine aerosols generated from the thermal aerosolization process were demonstrated to be amorphous, regardless of the initial polymorph of loxapine active pharmaceutical ingredient used. In humans, the amorphous aerosol was reported to be rapidly absorbed and the particle size resulted in rapid delivery to the deep lung. PMID- 20963843 TI - Randomized trial of biofilm testing to select antibiotics for cystic fibrosis airway infection. AB - RATIONALE: In cystic fibrosis (CF), conventional antibiotic susceptibility results correlate poorly with clinical outcomes. We hypothesized that biofilm testing would more accurately reflect the susceptibilities of bacteria infecting CF airways. METHODS: A multicenter randomized pilot trial was conducted to assess the efficacy and safety of using biofilm susceptibility testing of Pseudomonas aeruginosa sputum isolates to guide antibiotic regimens for chronic airway infections in clinically stable adolescent and adult CF patients. Thirty-nine participants were randomized to biofilm or conventional treatment groups; 14-day courses of two antibiotics were selected according to an activity-based algorithm using the corresponding susceptibility results. RESULTS: Of the agents tested, meropenem was most active against biofilm-grown bacteria, and was included in regimens for about half of each study group. For 19 of 39 randomized participants, randomization to the other study group would not have changed the antibiotic classes of the assigned regimen. Study groups were comparable at baseline, and had similar mean decreases in bacterial density, measured in log(10) colony forming units per gram of sputum (biofilm, -2.94 [SD 2.83] vs. conventional, -3.27 [SD 3.09]), and mean increases in forced expiratory volume in 1 sec, measured in liters (0.18 [SD 0.20] vs. 0.12 [SD 0.22]). CONCLUSIONS: In this pilot study, antibiotic regimens based on biofilm testing did not differ significantly from regimens based on conventional testing in terms of microbiological and clinical responses. The predictive value of biofilm testing may nonetheless warrant evaluation in an adequately powered clinical trial in younger CF patients or those experiencing acute pulmonary exacerbation. PMID- 20963845 TI - Application of the aqueous porous pathway model to quantify the effect of sodium lauryl sulfate on ultrasound-induced skin structural perturbation. AB - This study investigated the effect of sodium lauryl sulfate (SLS) on skin structural perturbation when utilized simultaneously with low-frequency sonophoresis (LFS). Pig full-thickness skin (FTS) and pig split-thickness skin (STS) treated with LFS/SLS and LFS were analyzed in the context of the aqueous porous pathway model to quantify skin perturbation through changes in skin pore radius and porosity-to-tortuosity ratio (epsilon/tau). In addition, skin treatment times required to attain specific levels of skin electrical resistivity were analyzed to draw conclusions about the effect of SLS on reproducibility and predictability of skin perturbation. We found that LFS/SLS-treated FTS, LFS/SLS treated STS, and LFS-treated FTS exhibited similar skin perturbation. However, LFS-treated STS exhibited significantly higher skin perturbation, suggesting greater structural changes to the less robust STS induced by the purely physical enhancement mechanism of LFS. Evaluation of epsilon/tau values revealed that LFS/SLS-treated FTS and STS have similar transport pathways, whereas LFS-treated FTS and STS have lower epsilon/tau values. In addition, LFS/SLS treatment times were much shorter than LFS treatment times for both FTS and STS. Moreover, the simultaneous use of SLS and LFS not only results in synergistic enhancement, as reflected in the shorter skin treatment times, but also in more predictable and reproducible skin perturbation. PMID- 20963846 TI - Coping strategies and self-efficacy as predictors of outcome in osteoarthritis: a systematic review. AB - OBJECTIVE: Systematically to review the literature, investigating the prognostic value of self-efficacy and coping strategies used by adults with osteoarthritis (OA) recruited within the community or primary care. METHODS: An online electronic search was performed from inception to August 2009, using EMBASE, CINAHL, PsycINFO and MEDLINE databases. A search of keywords and key authors was performed to find related articles, and experts in the field were contacted to identify additional literature. Three reviewers blindly assessed the quality of the included studies, using pre-determined criteria. Data on coping strategies and self-efficacy were extracted and tabulated. RESULTS: Eight studies were identified and included in this review. Six of the papers were rated as being of acceptable methodological quality. Strong evidence was identified for the role of self-efficacy in predicting disability, but no evidence was found for the relationship between self-efficacy and pain. Although problem-solving coping had no effect on pain, there was weak evidence that active coping strategies predict increased pain and worsened mood. There was also weak evidence demonstrating that problem avoidance, wishful thinking, social withdrawal, self-criticism and turning to religion are predictors of depressed mood. This review also presents evidence for catastrophizing, self-efficacy and passive coping strategies as predictors of mood. CONCLUSION: Coping strategies and self-efficacy are important prognostic factors for people with OA. This review highlights the need for further research to ascertain the predictive values of coping strategies that, to date, have been less well investigated. This may, in turn, result in a better understanding of the role of coping in OA and enable clinicians and patients to manage the condition more effectively. PMID- 20963848 TI - Deployment experiences and postdeployment PTSD symptoms in National Guard/Reserve service members serving in operations Enduring Freedom and Iraqi Freedom. AB - This report provides basic data about risk and protective factors for posttraumatic stress disorder (PTSD) in 189 Utah National Guard and Reserve troops who served during Operations Enduring Freedom (OEF) and Iraqi Freedom (OIF). Based on comparisons with other published reports of active duty and National Guard/Reserve troops from prior conflicts, results suggest that OEF- and OIF-era National Guard and Reserve troops' combat and postbattle experiences are similar to those of active duty troops from prior conflicts (and higher than those of National Guard and Reserve troops from prior conflicts). Additionally, reported family and career concerns during deployment appeared higher in this sample than in prior samples of active duty or National Guard and Reserve troops. Moreover, such concerns accounted for unique variance in postdeployment PTSD when controlling for combat experiences, postbattle experiences, and perceived threat. PMID- 20963847 TI - Age at trauma exposure and PTSD risk in young adult women. AB - The aim of the current study was to test the independent and joint contributions of 8 different types of trauma to posttraumatic stress disorder (PTSD) risk using data from a young adult female cohort. Associations of traumatic events with PTSD onset were examined using Cox proportional hazards models. Differences in risk as a function of age at trauma were tested. Childhood sexual assault, physical abuse, and neglect were stronger predictors of PTSD onset than adolescent and early adult occurrence of these events in individual models. In a model including all traumatic events, differential risk by age remained for sexual assault and physical abuse. Early sexual assault was the strongest predictor of risk, but additional traumatic events increased risk even in its presence. PMID- 20963849 TI - Strong neurogenesis, angiogenesis, synaptogenesis, and antifibrosis of hepatocyte growth factor in rats brain after transient middle cerebral artery occlusion. AB - Hepatocyte growth factor (HGF) and glial cell line-derived neurotrophic factor (GDNF) are strong neurotrophic factors. However, their potentials in neurogenesis, angiogenesis, synaptogenesis, and antifibrosis have not been compared. Therefore, we investigated these effects of HGF and GDNF in cerebral ischemia in the rat. Wistar rats were subjected to 90 min of transient middle cerebral artery occlusion (tMCAO). Immediately after reperfusion, HGF or GDNF was given by topical application. BrdU was injected intraperitoneally twice daily 1, 2, and 3 days after tMCAO. On 14 day, we histologically evaluated infarct volume, antiapoptotic effect, neurogenesis, angiogenesis, synaptogenesis, and antifibrosis. Both HGF and GDNF significantly reduced infarct size and the number of TUNEL-positive cells, but only HGF significantly increased the number of BrdU positive cells in the subventricular zone, and 5'-bromo-2'-deoxyuridine -positive cells differentiated into mature neurons on the ischemic side. Enhancement of angiogenesis and synaptogenesis at the ischemic boundary zone was also observed only in HGF-treated rats. HGF significantly decreased the glial scar formation and scar thickness of the brain pia mater after tMCAO, but GDNF did not. Our study shows that both HGF and GDNF had significant neurotrophic effects, but only HGF can promote the neurogenesis, angiogenesis, and synaptogenesis and inhibit fibrotic change in brains after tMCAO. PMID- 20963851 TI - Predicting chemical impacts on vertebrate endocrine systems. AB - Animals have evolved diverse protective mechanisms for responding to toxic chemicals of both natural and anthropogenic origin. From a governmental regulatory perspective, these protective responses complicate efforts to establish acceptable levels of chemical exposure. To explore this issue, we considered vertebrate endocrine systems as potential targets for environmental contaminants. Using the hypothalamic-pituitary-thyroid (HPT), hypothalamic pituitary-gonad (HPG), and hypothalamic-pituitary-adrenal (HPA) axes as case examples, we identified features of these systems that allow them to accommodate and recover from chemical insults. In doing so, a distinction was made between effects on adults and those on developing organisms. This distinction was required because endocrine system disruption in early life stages may alter development of organs and organ systems, resulting in permanent changes in phenotypic expression later in life. Risk assessments of chemicals that impact highly regulated systems must consider the dynamics of these systems in relation to complex environmental exposures. A largely unanswered question is whether successful accommodation to a toxic insult exerts a fitness cost on individual animals, resulting in adverse consequences for populations. Mechanistically based mathematical models of endocrine systems provide a means for better understanding accommodation and recovery. In the short term, these models can be used to design experiments and interpret study findings. Over the long term, a set of validated models could be used to extrapolate limited in vitro and in vivo testing data to a broader range of untested chemicals, species, and exposure scenarios. With appropriate modification, Tier 2 assays developed in support of the U.S. Environmental Protection Agency's Endocrine Disruptor Screening Program could be used to assess the potential for accommodation and recovery and inform the development of mechanistically based models. PMID- 20963850 TI - Species extrapolation for the 21st century. AB - Safety factors are used in ecological risk assessments to extrapolate from the toxic responses of laboratory test species to all species representing that group in the environment. More accurate extrapolation of species responses is important. Advances in understanding the mechanistic basis for toxicological responses and identifying molecular response pathways can provide a basis for extrapolation across species and, in part, an explanation for the variability in whole organism responses to toxicants. We highlight potential short- and medium term development goals to meet our long-term aspiration of truly predictive in silico extrapolation across wildlife species' response to toxicants. A conceptual approach for considering cross-species extrapolation is presented. Critical information is required to establish evidence-based species extrapolation, including identification of critical molecular pathways and regulatory networks that are linked to the biological mode of action and species' homologies. A case study is presented that examines steroidogenesis inhibition in fish after exposure to fadrozole or prochloraz. Similar effects for each compound among fathead minnow, medaka, and zebrafish were attributed to similar inhibitor pharmacokinetic/pharmacodynamic distributions and sequences of cytochrome P45019A1/2 (CYP19A1/2). Rapid advances in homology modeling allow the prediction of interactions of chemicals with enzymes, for example, CYP19 aromatase, which would eventually allow a prediction of potential aromatase toxicity of new compounds across a range of species. Eventually, predictive models will be developed to extrapolate across species, although substantial research is still required. Knowledge gaps requiring research include defining differences in life histories (e.g., reproductive strategies), understanding tissue-specific gene expression, and defining the role of metabolism on toxic responses and how these collectively affect the power of interspecies extrapolation methods. PMID- 20963852 TI - Reverse engineering adverse outcome pathways. AB - The toxicological effects of many stressors are mediated through unknown, or incompletely characterized, mechanisms of action. The application of reverse engineering complex interaction networks from high dimensional omics data (gene, protein, metabolic, signaling) can be used to overcome these limitations. This approach was used to characterize adverse outcome pathways (AOPs) for chemicals that disrupt the hypothalamus-pituitary-gonadal endocrine axis in fathead minnows (FHM, Pimephales promelas). Gene expression changes in FHM ovaries in response to seven different chemicals, over different times, doses, and in vivo versus in vitro conditions, were captured in a large data set of 868 arrays. Potential AOPs of the antiandrogen flutamide were examined using two mutual information-based methods to infer gene regulatory networks and potential AOPs. Representative networks from these studies were used to predict network paths from stressor to adverse outcome as candidate AOPs. The relationship of individual chemicals to an adverse outcome can be determined by following perturbations through the network in response to chemical treatment, thus leading to the nodes associated with the adverse outcome. Identification of candidate pathways allows for formation of testable hypotheses about key biological processes, biomarkers, or alternative endpoints that can be used to monitor an AOP. Finally, the unique challenges facing the application of this approach in ecotoxicology were identified and a road map for the utilization of these tools presented. PMID- 20963853 TI - Adverse outcome pathways and ecological risk assessment: bridging to population level effects. AB - Maintaining the viability of populations of plants and animals is a key focus for environmental regulation. Population-level responses integrate the cumulative effects of chemical stressors on individuals as those individuals interact with and are affected by their conspecifics, competitors, predators, prey, habitat, and other biotic and abiotic factors. Models of population-level effects of contaminants can integrate information from lower levels of biological organization and feed that information into higher-level community and ecosystem models. As individual-level endpoints are used to predict population responses, this requires that biological responses at lower levels of organization be translated into a form that is usable by the population modeler. In the current study, we describe how mechanistic data, as captured in adverse outcome pathways (AOPs), can be translated into modeling focused on population-level risk assessments. First, we describe the regulatory context surrounding population modeling, risk assessment and the emerging role of AOPs. Then we present a succinct overview of different approaches to population modeling and discuss the types of data needed for these models. We describe how different key biological processes measured at the level of the individual serve as the linkage, or bridge, between AOPs and predictions of population status, including consideration of community-level interactions and genetic adaptation. Several case examples illustrate the potential for use of AOPs in population modeling and predictive ecotoxicology. Finally, we make recommendations for focusing toxicity studies to produce the quantitative data needed to define AOPs and to facilitate their incorporation into population modeling. PMID- 20963854 TI - Defining and modeling known adverse outcome pathways: Domoic acid and neuronal signaling as a case study. AB - An adverse outcome pathway (AOP) is a sequence of key events from a molecular level initiating event and an ensuing cascade of steps to an adverse outcome with population-level significance. To implement a predictive strategy for ecotoxicology, the multiscale nature of an AOP requires computational models to link salient processes (e.g., in chemical uptake, toxicokinetics, toxicodynamics, and population dynamics). A case study with domoic acid was used to demonstrate strategies and enable generic recommendations for developing computational models in an effort to move toward a toxicity testing paradigm focused on toxicity pathway perturbations applicable to ecological risk assessment. Domoic acid, an algal toxin with adverse effects on both wildlife and humans, is a potent agonist for kainate receptors (ionotropic glutamate receptors whose activation leads to the influx of Na(+) and Ca2(+)). Increased Ca2(+) concentrations result in neuronal excitotoxicity and cell death, primarily in the hippocampus, which produces seizures, impairs learning and memory, and alters behavior in some species. Altered neuronal Ca2(+) is a key process in domoic acid toxicity, which can be evaluated in vitro. Furthermore, results of these assays would be amenable to mechanistic modeling for identifying domoic acid concentrations and Ca2(+) perturbations that are normal, adaptive, or clearly toxic. In vitro assays with outputs amenable to measurement in exposed populations can link in vitro to in vivo conditions, and toxicokinetic information will aid in linking in vitro results to the individual organism. Development of an AOP required an iterative process with three important outcomes: a critically reviewed, stressor-specific AOP; identification of key processes suitable for evaluation with in vitro assays; and strategies for model development. PMID- 20963855 TI - Synthesis and characterization of a 'fluorous' (fluorinated alkyl) affinity reagent that labels primary amine groups in proteins/peptides. AB - Strong non-covalent interactions such as biotin-avidin affinity play critical roles in protein/peptide purification. A new type of 'fluorous' (fluorinated alkyl) affinity approach has gained popularity due especially to its low level of non-specific binding to proteins/peptides. We have developed a novel water soluble fluorous labeling reagent that is reactive (via an active sulfo-N hydroxylsuccinimidyl ester group) to primary amine groups in proteins/peptides. After fluorous affinity purification, the bulky fluorous tag moiety and the long oligoethylene glycol (OEG) spacer of this labeling reagent can be trimmed via the cleavage of an acid labile linker. Upon collision-induced dissociation, the labeled peptide ion yields a characteristic fragment that can be retrieved from the residual portion of the fluorous affinity tag, and this fragment ion can serve as a marker to indicate that the relevant peptide has been successfully labeled. As a proof of principle, the newly synthesized fluorous labeling reagent was evaluated for peptide/protein labeling ability in phosphate-buffered saline (PBS). Results show that both the aqueous environment protein/peptide labeling and the affinity enrichment/separation process were highly efficient. PMID- 20963856 TI - [Thromboxane A2 (TXA2), thromboxane B2(TXB2)]. PMID- 20963857 TI - [Granulocyte-macrophage colony-stimulating factor]. PMID- 20963859 TI - [From interleukin-19 (IL-19) to the latest cytokine IL-35]. PMID- 20963858 TI - [Interleukin-11, 12, 13, 14, 15, 16, 17, 18 (IL-11, 12, 13, 14, 15, 16, 17, 18)]. PMID- 20963860 TI - [Transforming growth factor (TGF)]. PMID- 20963861 TI - [Platelet-derived growth factor (PDGF)]. PMID- 20963862 TI - [Sialomucin family]. PMID- 20963863 TI - [Soluble tumor necrosis factor receptor-I, II (sTNF-RI, -RII)]. PMID- 20963864 TI - [Growth hormone (GH, hGH)]. PMID- 20963865 TI - [Growth hormone-releasing hormone (GHRH)]. PMID- 20963866 TI - [Somatostatin]. PMID- 20963867 TI - [Insulin-like growth factor (IGF)-I and IGF-II]. PMID- 20963868 TI - [Follicle stimulating hormone (FSH)]. PMID- 20963869 TI - [Corticotropin-releasing hormone (CRH)]. PMID- 20963870 TI - [Lipotropin (lipotropic hormone: LPH) and melanocyte-stimulating hormone (MSH)]. PMID- 20963871 TI - [Methionine-enkephalin (Met5-Enk) and leucine-enkephalin (Leu5-Enk)]. PMID- 20963872 TI - [beta-Endorphin (beta-End)]. PMID- 20963873 TI - [Thyroid stimulating hormone (TSH)]. PMID- 20963874 TI - [Thyrotropin-releasing hormone (TRH)]. PMID- 20963875 TI - [Total triiodothyronine (TT3), free triiodothyronine (FT3), reverse T3 (rT3)]. PMID- 20963876 TI - [Thyroxine binding globulin (TBG), triiodothyronine uptake (T3U), thyroxine binding capacity (TBC)]. PMID- 20963877 TI - [Calcitonin (CT), procalcitonin (PCT)]. PMID- 20963878 TI - [Calcitonin gene-related peptide (CGRP)]. PMID- 20963879 TI - [11-Deoxycortisol]. PMID- 20963880 TI - [18-Hydroxycortisol, 18-oxocortisol, and 6beta-hydroxycortisol]. PMID- 20963881 TI - [Aldosterone]. PMID- 20963882 TI - [17alpha-Hydroxypregnenolone]. PMID- 20963883 TI - [Metanephrine (M), normetanephrine (NM), and fractionated metanephrines]. PMID- 20963884 TI - [5-Hyroxyindol acetic acid (5HIAA)]. PMID- 20963885 TI - [Neuropeptide Y]. PMID- 20963886 TI - [Progesterone]. PMID- 20963887 TI - [Sex hormone binding globulin (SHBG)]. PMID- 20963888 TI - [Human chorionic gonadotropin (hCG) and subunit]. PMID- 20963889 TI - [Proinsulin]. PMID- 20963890 TI - [GLP-1 (glucagon-like peptide 1)]. PMID- 20963891 TI - [Gastrin]. PMID- 20963892 TI - [Vasoactive intestinal polypeptide (VIP)]. PMID- 20963893 TI - [Secretin]. PMID- 20963894 TI - [Protein tyrosine phosphatase (ICA512/IA-2) antibody]. PMID- 20963895 TI - [Angiotensin I, angiotensin II, angiotensin III]. PMID- 20963896 TI - [Measurements of human kallikrein-kininogen-kinin]. PMID- 20963897 TI - [Orexin (ORX)]. PMID- 20963898 TI - [Urocortin]. PMID- 20963899 TI - [FGF23]. PMID- 20963900 TI - [Aquaporin-2]. PMID- 20963901 TI - [Cyclic Amp(cAMP), cyclic GMP (cGMP)]. PMID- 20963902 TI - [PIVKA-II]. PMID- 20963903 TI - [CA15-3]. PMID- 20963904 TI - [CYFRA21-1]. PMID- 20963905 TI - [HER2 protein in the serum and nipple discharge]. PMID- 20963906 TI - [CA72 -4 (TAG72)]. PMID- 20963907 TI - [gamma-Seminoprotein (gamma-Sm)]. PMID- 20963908 TI - [Polyamines and ornithine decarboxylase]. PMID- 20963909 TI - [Human chorionic gonadotropin beta-core fragment (hCGbetacf)]. PMID- 20963910 TI - [Basic fibroblast growth factor(bFGf/FGF-2) in urine]. PMID- 20963911 TI - [Nuclear matrix protein 22]. PMID- 20963912 TI - [Nitric oxide (NO) and its related compounds]. PMID- 20963913 TI - [Protein carbonyls]. PMID- 20963914 TI - Past, present and future of myoblast transplantation in the treatment of Duchenne muscular dystrophy. AB - DMD is a genetic X-linked recessive disease that affects approximately one in 3500 male births. Boys with DMD have progressive and predictable muscle destruction because of the absence of Dys, a protein present under the muscle fiber membrane. Dys deficiency induces contraction-related membrane damages, activation of inflammatory-necrosis-fibrosis up to the cardiac-diaphragmatic failure and death. This review supports the therapeutic role of MT associated with immunosuppression in DMD patients, describing the history and the rationale of such approach. The authors underline the importance to evaluate a protocol of myoblast intradermal multi-injection to apply in young DMD patients PMID- 20963915 TI - Bibliography. Stomach and duodenum. Current world literature. PMID- 20963916 TI - Managing wound odor #218. PMID- 20963917 TI - Selection for medical schools: re-imaging as an international discourse. PMID- 20963918 TI - Learning professionalism by role-modelling. PMID- 20963919 TI - What are we missing? On our problems of definition in health professions education. PMID- 20963920 TI - Pen, brush and camera: outcomes-based medical humanities. PMID- 20963921 TI - Cardiac auscultation: a new method for instruction. PMID- 20963922 TI - Getting out there: developing an abstract editing circle. PMID- 20963923 TI - A way to assess students' clinical reasoning. PMID- 20963924 TI - [Proceedings of the 21st Congress of the French Society of Radiation Oncology. October 6-8, 2010. Paris, France]. PMID- 20963925 TI - Blood transfusion and the anaesthetist: management of massive haemorrhage. PMID- 20963926 TI - Proceedings of the ISMB (Intelligent Systems for Molecular Biology) 2010 Conference. July 11-13, 2010. Boston, Massachusetts, USA. PMID- 20963927 TI - Robotic reconstructive urology: possibilities for the urological surgeon beyond the prostate. PMID- 20963928 TI - 11C-methionine positron-emission tomography and computed tomography (PET-CT) in evaluating metastatic transitional cell carcinoma response to sunitinib therapy. PMID- 20963929 TI - Proceedings of the First International Conference on D-Amino Acid Research. Awaji City, Japan, July 2009. PMID- 20963930 TI - The biorefinery: sustainably renewable route to commodity chemicals, energy, and materials. Proceedings of the Second International Biorefinery Conference. Syracuse, New York, USA. October 6-9, 2009. PMID- 20963931 TI - Proceedings of the annual meeting of the Spanish Association of Animal Reproduction. June 2-5, 2010. Caceres, Spain. PMID- 20963932 TI - Proceedings of the IXth International Conference on Lactoferrin Structure, Function, and Applications. October 18-22, 2009. Beijing, China. PMID- 20963933 TI - Proceedings of the 4th International Moscow Conference on Computational Molecular Biology MCCMB'09. July 20-23, 2009. Moscow, Russia. PMID- 20963934 TI - What it takes to nurse a nest egg. PMID- 20963935 TI - Proceedings of the First Combined Meeting of the International Society of Limb Salvage (ISOLS) and the Musculoskeletal Tumor Society (MSTS). Boston, Massachusetts, USA. September 2009. PMID- 20963936 TI - Proceedings of the 15th European Carbohydrate Symposium. Vienna, Austria. July 19 24, 2009. PMID- 20963946 TI - [Identification and characterization of Panton-Valentine leukocidin-positive Staphylococcus aureus isolated in Okinawa, Japan]. AB - We experienced hospital-acquired infection in March 2008 that three nurses became infected with Panton-Valentine leukocidin (PVL)-positive methicillin-resistant Staphylococcus aureus (MRSA). Accordingly, we performed the retrospective study to determine the prevalence of PVL-positive S. aureus in Okinawa. A total of 731 clinical isolates, consisting of 600 MRSA and 131 methicillin-susceptible isolates in Okinawa, were included. Of the isolates, 16 were positive for PVL gene (lukS-PV-lukF-PV). All the PVL-positive isolates were MRSA, and the first appeared in March 2008. The isolates from the University Hospital were characterized as staphylococcal chromosomal cassette mec type IVa. Through the analysis of pulsed-field gel electrophoresis (PFGE), 16 PVL-positive MRSA isolates were divided in three groups. One isolate (the first group) from the other hospital was less similar (< 40% similarity) when compared with the remaining 15 isolates from the University Hospital. The second group consisted of two respective paired isolates from the same department wards, and those were very similar with each other, indicating possible patient-to-patient transmission. The 11 isolates were characterized as the third group with >80% similarity. The DiversiLab system (bioMerieux) based on repetitive-sequence-based PCR typing demonstrated that the isolates of the third group were similar and indistinguishable with the strains of USA300 clone. However, the first and second groups were not determinable which USA clone was the origin. With these, we could conclude that the PVL-positive MRSA close to USA300 clone first appeared in Okinawa in 2008 and is now becoming prevalent multi-focally. Also, person-to person transmission is already likely in a hospital setting. PMID- 20963937 TI - B cells from HIV-infected patients with primary central nervous system lymphoma display an activated phenotype and have a blunted TNF-alpha response to TLR9 triggering. AB - Each cell in HIV-associated primary central nervous system lymphoma (PCNSL) harbors latent EBV. Notably, the triggering of TLR9, a key event in HIV pathogenesis, also promotes EBV latency and transformation. We hypothesized that because only a minority of HIV-infected patients develops PCNSL, their B cells exhibit aberrant signaling responses to TLR9 triggering. We found higher levels of IL-6, CD80, and CD86 expression at baseline in B cells of those patients than in B cells of matched controls, whereas TNF-a expression was lower. Notably, on TLR9 triggering with CpG 2006, CD80 and TNF-alpha were up-regulated to a lesser extent in B cells of the former than in those of matched controls. The reduced up regulation of CD80 might be explained by its higher baseline expression resulting in a more blunted response rather than a specific deficit of the signaling response to TLR9 triggering. However, this cannot explain the blunted TNF-alpha response, which warrants further investigation. Finally, since increased IL-6 expression is linked to EBV-associated Hodgkin's lymphoma, the enhanced baseline expression of IL-6 might be important in the pathogenesis of PCNSL in HIV infected patients. PMID- 20963947 TI - [Clinical significance of apolipoprotein B-48 (apoB-48) in chronic kidney disease patients]. AB - OBJECTIVES: Apolipoprotein B-48 (apoB-48) is a constituent of chylomicrons and their remnants, and high levels of serum apoB-48 are thought to be one of the risk factors for atherosclerosis. In the current study we examined whether serum apoB-48 level is associated with renal dysfunction. METHODS AND RESULTS: Patients were separated by eGFR into each stage of chronic kidney disease (CKD). Serum apoB-48 levels were measured by chemiluminescence enzyme immunoassay (CLEIA), and serum lipid levels were compared between each stage of CKD. Serum triglyceride (TG) levels were high at stage 4 and stage 5. Serum total cholesterol, HDL cholesterol (HDL-C), and LDL-cholesterol (LDL-C) levels were not significantly different. Serum apoB-48 level was significantly higher at stage 4 (Median: 8.3 microg/ml) and stage 5 (9.7 microg/ml) than at stage 1(4.2 microg/ml). Serum apoB 48 levels (10.7 microg/ml) in patients undergoing hemodialysis were not significantly higher than CKD patient of nondialysis (6.9 microg/ml). CONCLUSION: Serum apoB-48 level was strongly associated with renal dysfunction. Therefore, increased serum apoB-48 concentrations may contribute to the increased risk of atherosclerosis and coronary artery disease in the CKD patients. PMID- 20963948 TI - [Performance evaluation of the CellaVision DM96 system in WBC differentials]. AB - Though differential counting of peripheral blood cells is an important diagnostic tool, this technique requires highly trained staff. Automation of differentials is desirable for economic and time-saving reasons. Recently, the CellaVision DM96 (DM96, CellaVision AB, Lund, Sweden) has been introduced as an automated cell analysis system capable of morphological classification of WBCs and RBCs in pheripheral blood smears. In this study, we routinely analyzed the blood samples from 216 patients by the DM96. The overall preclassification of WBC analysis accuracy value for the DM96 was 90.3%. Good correlation coefficients between final results of the DM96 and manual differentiation were observed. The DM96 system performed high sensitivity and specificity for blasts and immature granulocytes. Although the DM96 system operates more effectively in the normal blood samples than pathological ones, its ability of review slides on the computer screen with a cell-by-cell basis provides real-time collaboration between colleagues when they face the abnormal cells. PMID- 20963949 TI - [Software for illustrating a cost-quality balance carried out by clinical laboratory practice]. AB - We have no proper reference indicating the quality of clinical laboratory practice, which should clearly illustrates that better medical tests require more expenses. Japanese Society of Laboratory Medicine was concerned about recent difficult medical economy and issued a committee report proposing a guideline to evaluate the good laboratory practice. According to the guideline, we developed software that illustrate a cost-quality balance carried out by clinical laboratory practice. We encountered a number of controversial problems, for example, how to measure and weight each quality-related factor, how to calculate costs of a laboratory test and how to consider characteristics of a clinical laboratory. Consequently we finished only prototype software within the given period and the budget. In this paper, software implementation of the guideline and the above-mentioned problems are summarized. Aiming to stimulate these discussions, the operative software will be put on the Society's homepage for trial PMID- 20963950 TI - [Survey of patients with obstructive ventilatory disturbance by spirometry and cooperation among departments in university hospital]. AB - The purpose in this study was to reveal the number of chronic obstructive pulmonary diseases (COPD) among the patients who examined spirometry in Shinshu University Hospital. We prospectively picked up the patients over 40 years of age who showed obstructive ventilatory disturbance on spirometry who examined for about 6 months, and send the results with the comments to introduce the patients to the department of respiratory medicine to the doctors who ordered spirometry. Spirometry was examined in 1,657 patients, and 246 patients (14.8%) who showed their FEV1/FVC < 70%. Among 246 patients, 177 patients were ordered spirometry from the departments (83.6%; pre-operative spirometry) except for respiratory medicine. Seventy-two of 177 patients (40.7%) were introduced to the department of respiratory medicine following the comments, and 43 and 13 patients were diagnosed as COPD and asthma, respectively. These findings suggest that laboratory technologist can contribute to the early intervention of COPD by supporting corporation among departments in hospital. PMID- 20963951 TI - [A case of bronchiolitis obliterans caused by allogeneic hematopoietic stem cell transplantation diagnosed with a body plethysmograph]. AB - A 19-year-old woman with acute myeloid leukemia (M1) was treated with allogeneic hematopoietic stem cell transplantation. She was diagnosed with skin graft-versus host disease 27 days after the transplantation. She was admitted to the Dept. of Respiratory Medicine at Kanazawa University Hospital, because she complained of progressive obstructive ventilatory impairment. A high-resolution computed tomography (CT) scan showed centrilobular small nodules. A chest CT scan (inspiratory phase and expiratory phase) revealed hyperlucent areas forming a mosaic pattern. A ventilation-perfusion scan showed matched unequal distribution. The pathological diagnosis made using biopsied lung, obtained by a right lower partial lobectomy, was constrictive bronchiolitis. Pulmonary function tests on admission showed mixed ventilatory impairment. %Residual volume(RV)/total lung capacity(TLC) was measured by the closed-circuit helium dilution method and was within the upper limit of the normal range. However, %RV/TLC measured by a body plethysmograph indicated a value of 258.1%. We believe that the difference in the %RV/TLC values reflected air trapping caused by bronchiolitis obliterans. Thus, the lung volume fraction measured by body plethysmograph was useful for diagnosing bronchiolitis obliterans in this case. [Rinsho Byori 58 : 906'-911, 2010]. PMID- 20963952 TI - [Survey of costs of laboratory tests aiming at revision of medical treatment fees and improvement of work]. AB - The costs of laboratory tests were surveyed, aiming at realizing medical treatment fees corresponding to the costs of hospital laboratory tests. Using exclusive application software, the costs of blood cell count, peripheral blood and bone marrow, PT, general urinalysis, urine sediment, AST, glucose, HbA1c, AFP, CEA, microbial, and chromosomal tests were surveyed in 13 hospitals. The costs of tests using automatic devices were lower than the medical treatment fees (operation fees) in many hospitals, but those of tests requiring manual manipulation and the skills of clinical technologists, such as peripheral blood, bone marrow, urine sediment, microbial, and chromosomal tests, exceeded the medical fees (operation fees) in many hospitals. Accurate surveys of costs in many hospitals may lead to the moderation of medical treatment fees, and investigation of the test costs at individual hospitals may be useful for improving the medicoeconomics of hospitals and test-based work. [Rinsho Byori 58 : 920-924, 20101 PMID- 20963953 TI - [Active engagements in proffering for the most effective medical care- involvement of the department of clinical laboratory medicine]. AB - What is the most effective medical care for patients? That which immediately comes to one's mind may be that people can receive medical help by consulting a respected clinician whenever necessary, and can get proper medical care without financial difficulties. However, high-quality medical care is not always provided, even if clinicians are very capable. For improvements in medical quality and services for patients, it is essential for experts in all medical fields to carry out their responsibilities, and establish a medical team approach through close communication and cooperation. It seems that, particularly in the department of clinical laboratory, the following are necessary: prompt and accurate medical examinations, promoting and enhancing support such as through advisory services(clinical laboratory consulting services), interpretive comments (the clinical meaning of examination results), and other clinical services, as well as the provision of information related to clinical laboratory testing to medical staff via workshops and Internet websites, innovation of new methods and advanced technologies, and attempting to improve medicoeconomic efficiency. As for the contributions of such clinical support, it is expected that they will be increasingly required for the development of the medical team approach. This report introduces our institution's approach regarding medical support and clinical services for patients and medical personnel during routine work. PMID- 20963954 TI - [The effective and the promotion of proper use on laboratory at Surugadai Nihon University Hospital]. AB - It is well known that laboratory data is essential to medical diagnosis and treatments. The use of laboratory tests is related to almost every process of medicine such as diagnosis, treatment, prognostic expectation, and health checkup. Since diagnoses are based on evidence now, it is obvious that the laboratory data are extremely important as objective evidence. It is necessary to have a number of laboratory tests to be conducted in order to collect the information as much as possible. However, there is 'simplification of the tests' in health insurance, or that medical institutions introducing DPC have no alternative but to restrict the number of tests. This restriction by insurance occasionally leads to the atrophic condition of laboratory tests selection. However, in primary education, proper selection of tests for first year residents is important. Surugadai Nihon University Hospital conceives this contrariety as good occasion, and is working to disseminate efficiently in order to conduct the test properly and effectively. This paper presents some specific activities which Surugadai Nihon University Hospital undertakes. PMID- 20963955 TI - [The future of psychiatry: a financial dictatorship?]. PMID- 20963956 TI - [Treatment of anorexia nervosa in both an inpatient and outpatient setting: benefits of family therapy]. AB - Anorexia nervosa is characterized by an important morbidity, with somatical and psychological complications. This article explains the collaboration of two university units, one in hospital, the second in an ambulatory psychotherapeutical programme. The two of them work with a systemic approach, which has largely proved its efficiency in anorexia nervosa. The authors describe a clinical case during which they have experienced a different way of treatment, dissociating individual hospitalisation and family therapy. This sort of intervention requires a close collaboration between all interveners. PMID- 20963957 TI - [Psychological treatment of gambling]. AB - Pathological gambling is of serious public health concern with major implications for society and the individual. Brief intervention, motivational interviewing and cognitive and behaviour therapy are effective treatments. Treatment could be delivered in individual or group-format. Most studies proposed abstinence-based treatments. It appears, however, that controlled gambling is also a viable treatment goal. Although effective therapies exist, their uptake is limited to a small part of the target population. Screening procedure will be encouraged and followed by a tailored treatment. New interventions aiming to improve treatment accessibility have to be implemented and evaluated. PMID- 20963958 TI - [What place is there for psychotherapy in public psychiatry?]. AB - The question of the place of psychotherapy in psychiatric public care is posed in this article. We will address this question first by presenting two clinical and research programmes which were implemented in a clinical psychiatric unit, section Karl Jaspers (Service of General Psychiatry) of the Department of Psychiatry CHUV, in Lausanne with the collaboration of the University Institute of Psychotherapy. The first one puts forward psychodynamic psychotherapy of depressed inpatients; the clinical programme and the research questions on efficacy of this treatment are discussed. The second focuses on the early treatment of patients with Borderline Personality Disorder, in particular in its research question on the effect of the motive-oriented therapeutic relationship in this process. We conclude by underlining the convergences of the two programmes. PMID- 20963959 TI - [Psychiatry and psychoanalysis: psychopathology among inpatients]. AB - Most patients receiving psychiatric care are in need of a complex form of treatment combining psychiatry and psychotherapy. When these patients are admitted to hospital, this combination should not be lost: the patient will be examined and his medication regulated. However, and in contrast to classical medical care, the in-patient treatment in itself must have a positive psychotherapeutic impact on the patient. To date, psychoanalysis could provide an important contribution in maximizing the psychotherapeutic aspect of the psychiatric treatment if it takes into account current evolutions of medicine and society. Two short examples illustrate the way we combine psychoanalysis and psychiatry today. PMID- 20963960 TI - [Psychotherapy in the somatic field--what specificities?]. AB - This article illustrates some of the specific aspects of the psychotherapeutic approach with medically ill patients. Our considerations are based on our daily work in CL Psychiatry and refer to the psychodynamic model, rooted in Freudian's thought. Characteristics are the setting, as well as the relationship with the patient and the interactions with the physicians as the "emergence" of the suffering body within the therapy. We therefore adopt specific approaches such as the work with the Auxiliary Ego and the narrative reconstruction. This paper illustrates our experiences applying the mentioned tools with patients suffering from chronic pain and cancer. PMID- 20963961 TI - [Psychotherapy and forensic psychiatry]. AB - Psychotherapists in the forensic field are in an uncomfortable position. The reluctance of patients to be subjected to such obligatory treatments and to face their own violence contributes to this difficult position. The mission of public safety assigned to these treatments, their assessment through risk of recidivism rather than therapeutic effectiveness as well as misconception by lawyers and authorities of what psychotherapy really is reinforce the difficulty of such a practice. However, a clarification of the nature of each type of interventions allows the establishment of viable psychotherapeutic framework adapted to penal constraints. The developments of approaches specifically tailored to prison settings as well as to sexual offenders are illustrations of this point. PMID- 20963962 TI - ["Make haste slowly..." or attention to destructive anticipation]. PMID- 20963963 TI - [Why practice?]. PMID- 20963964 TI - [Houellebecq: "copy-paste": is it cheating; is it creating?]. PMID- 20963965 TI - [All drugs banned soon allowed? (2)]. PMID- 20963966 TI - [Research on the virtues of resveratrol]. PMID- 20963967 TI - [The bubble of addictions]. PMID- 20963968 TI - [Balance sheet at the half-way point concerning the nursing law]. PMID- 20963969 TI - [Stigma and public health]. AB - Illnesses have always nourished phenomena of stigmatization, to which public health has occasionally contributed. This observation remains true today, in particular for risk-taking behaviour, and signals the emergence of a new preventive strategy: stigmatizing for encouraging behaviour change more greatly But does this strategy not give rise to ethical issues? And is its preventive effectiveness guaranteed? PMID- 20963970 TI - [Pressure ulcer prevalence and incidence, instructions for use]. AB - Pressure ulcer prevalence and incidence surveys are more and more frequently conducted and used as indicators in order to evaluate healthcare quality and effectiveness of implementation of prevention measures (guidelines and recommendations). The ever-increasing use of such surveys over the last ten years justifies the necessity for a better understanding of definitions and what can be expected from these results in order to optimise their use as epidemiological indicators. PMID- 20963971 TI - [Understanding and treating skin diseases. Dermatitis, the affliction should not be neglected]. PMID- 20963972 TI - [Anatomy of normal skin]. PMID- 20963973 TI - [Activity in dermatology, epidemiologic inquiries in city and hospital]. PMID- 20963974 TI - [The various ages of our skin]. AB - From the day we are born, our skin is exposed to an unknown environment. Its development is predominantly based on characteristics which are inherent to the various age phases of life. Totally covering a human being, it acts as a protector throughout its lifetime, without ever being protected itself. PMID- 20963975 TI - [Dermatoses, multiple conditions with various causes]. AB - Frequent or rare, minor or serious, numerous skin conditions exist. Allergic, inflammatory, infectious or bullous, dermatoses may also reveal underlying pathologies. PMID- 20963976 TI - [The main types of skin allergies]. AB - Incidence of skin allergies is increasing today. Often provoked by environmental factors, to which skin is highly-sensitive, as an interface, they may also express internal processes that are inherent to an individual. We will focus here on three of them: eczema, atopic dermatitis and urticaria. PMID- 20963977 TI - [Dermatology and skin color]. AB - Melanin is the pigment that is responsible for skin, hair and eye colours. Genetics and sun exposure are the two key factors that determine skin pigmentation. In dermatology, skin colours is significant, not only for semiology and diagnosis, but also for epidemiology and wounds healing. PMID- 20963978 TI - [Cutaneous infections]. AB - The epidermis, the human being's primary protection against infection and aggression, can crack or split, and result in microbial bacteria penetrating it. Infections may, however, stem from other sources, such as viruses which enter the body via the respiratory tract, and then appear on the skin. PMID- 20963979 TI - [Dermatology and the effects of medication on the skin]. AB - Skin diseases may be treated locally or generally. Skin can also be affected by treatments that are used for healing other diseased organs; thus opening the field of drug eruptions. PMID- 20963981 TI - [Concerning the biological membrane that envelopes the psyche]. PMID- 20963980 TI - [The role of nurses in dermatology]. AB - The range of care provided to patients by the dermatology nursing team is wide. Alleviation of pain and itching, improvement of skin integrity through hygiene care and local treatments, the cleaning of wounds and the changing of dressings, psychological treatment and therapeutic education are the main areas in which the nurse is involved. PMID- 20963982 TI - [Malignant skin tumours]. AB - The constant increase in the incidence of malignant skin tumours is a public health problem. The main known causal agent of these tumours is sun exposure. Preventive action therefore consists in raising people's awareness of the dangers of the sun and promoting sun protection. PMID- 20963983 TI - [Dermatology in the time of multiple therapies]. PMID- 20963984 TI - [Elements of bibliography. Books]. PMID- 20963985 TI - [Nursing: a profession, a discipline, a science]. AB - The debates which drive the nursing profession often put forward the notions of profession, discipline and science to qualify nursing. It is advisable to clarify each of these concepts, as well as to highlight the importance of structuring them in order for nurses to be able to assume as best as possible the role entrusted to them within society. PMID- 20963986 TI - [7/10 Problems treated in collaboration and nursing diagnostics]. PMID- 20963987 TI - [Treatment progress of fractures and dislocation of elbow joint]. PMID- 20963988 TI - [Diagnosis and therapy of the terrible triads of the elbow]. PMID- 20963989 TI - [Clinical outcome of surgical treatment of terrible triad of elbow]. AB - OBJECTIVE: To evaluate the clinical outcome of surgical treatment of the posterior dislocation of the elbow with coroniod and radial head fractures. METHODS: From January 2004 to March 2009, 9 patients with terrible triad of the elbow were reviewed. There were 7 males and 2 females (4 left elbows and 5 right elbows), with an average age of 41.2 years, ranged from 21 to 67 years. The radial head fractures were classified according to the Schatzker-Tile criteria: 4 patients had the fractures of type I, 3 patients had type II and 2 patients had type III. The ulnar coronoid fractures were classified according to the Regan Morrey criteria: 2 patients had the fractures of type I, 5 patients had type II and 2 patients had type III. The general approach was used to repair the damaged structures sequentially from deep to superficial, through coronoid, anterior capsule, radial head, and lateral ligament complex to common extensor origin. If there was valgus instability in the elbow after the operation, the medial collateral ligament should be repaired with nonabsorption sutures. The plaster was applied for 7 to 10 days with elbow flexion in 90 degrees and the forearm in full pronation. Unrestricted motions and rehabilitation began at the 8th week after operation. Recovery of regular occupation depended on the degree of physical activity required, and it typically took 3 months for heavy physical laborers to return to work. RESULTS: All the patients were followed up from 6 months to 5 years, with a mean duration of (31 +/- 6) months. At the 3rd month after operation, the mean rang of motion in flexion and extension of the elbow was (102 +/- 3) degrees (ranged from 80 degrees to 110 degrees), and the mean range of motion in pronation and supination of the forearm was (135 +/- 6) degrees (100 degrees to 150 degrees). According to the criteria of the Mayo scoreing system, the results were excellent in 5 cases, good in 3 cases, and fair in 1 case. Three patients had heterotopic ossification at the 6th month after operation. Among them, 2 patients had no effects on elbow function and were not treated, 1 patient had effects on flexion-extension of the elbow and was treated with resection of heterotopic ossification through lateral approach combined with early rehabilitation, the MEP score of the patient improved from fair to good. CONCLUSION: The key points for treating the terrible triad of the elbow are to restore the elbow normal anatomy and early rehabilitation to avoid the elbow stiff. PMID- 20963990 TI - [Diagnosis and treatment of terrible triad of elbow]. AB - OBJECTIVE: To study diagnosis and treatment methods of terrible triad of elbow. METHODS: From June 2001 to June 2009, 7 patients with terrible triad of elbow were reviewed. Among the patients, 6 patients were male and 1 patient was female, ranging in age from 20 to 68 years, averaged 36.5 years. All the fractures were fresh. All the patients were treated through a single lateral approach. The general approach was used to repair the damaged structures sequentially from deep to superficial, from coronoid to anterior capsule, to radial head, lateral ligament complex, and common extensor origin. The coronoid fractures and the radial head fractures were fixed with different methods according to fragments. The curative effiency were evaluated by Mayo elbow performance score (MEPS). RESULTS: All the patients were followed up, and the duration ranged from 5 to 36 months, with a mean of 16.3 months. All the fractures were healed, and the healing time ranged from 3 to 6 months after operation (averaged 4.5 months). Four patients had heterotopic ossificatio. According to evaluation criteria, 2 patients got an excellent result, 4 fair and 1 bad. The average range of motion in elbow flexion-extension were 106.5 degrees (from -20 to 130 degrees), and the range of motion in forearm pronation-supination were 121 degrees (from 70 to 140 degrees). The patient with bad results were treated with radial head excised, and Kirschner fixation from posterior to anterior after reduction, which was found separate dislocation of the coronoid fracture on the X-ray after operation, and subluxation and instability of the elbow joint. CONCLUSION: The patients with terrible triad of elbow should be treated with operation actively. Follows are key to get an excellent result: treatment of bone and soft tissues at the same time, early rehabilitation after operation. PMID- 20963991 TI - [Retrograde locked intramedullary nail for the treatment of middle or distal fractures of humeral shaft]. AB - OBJECTIVE: To study therapeutic effects of retrograde locked intramedullary nail for the treatment of middle or distal fractures of humeral shaft. METHODS: From October 2002 to February 2005, 21 patients with middle or distal fractures of humeral shaft were treated with AO retrograde locked intramedullary nail. Among the patients, 13 patients were male and 8 patients were female, ranging in age from 23 to 56 years, with an average of 34.5 years. Nineteen patients were fresh fractures, and 2 patients were old fractures. Eleven patients had middle fractures of humeral shaft, and other 10 patients had distal fractures of humeral shaft. Two patients with old fractures were non-union and treated with autoallergic bone grafting; 5 patients combined with radial nerve injury underwent exploration. The therapeutic effects were evaluated according to Constant-Murley shoulder score and Mayo elbow score. RESULTS: All the patients were followed up, ranging from 18 to 24 months, with an average of 20.8 months. The fractures were healed except 1 patient with old fracture and 1 patient with extremely distal acute fracture. The shoulders and elbows had satisfactory recovery except 1 patient with old fracture. The mean Constant-Murley score was (83.6 +/- 13.4) points (50-97), 12 patients got an excellent result, 5 good, 4 fair and no bad; the mean Mayo elbow score was (88.6 +/- 9.8) points (65-95), 13 patients got an excellent result, 5 good, 3 fair and no bad. CONCLUSION: The retrograde locked intramedullary nail offers an ideal treatment method for middle and distal fractures of humeral shaft. Strict operative indication, precise surgical techniques and stable locking are the keys to a successful treatment results. PMID- 20963992 TI - [Supercondylar humeral osteotomy and tension band fixation for the treatment of cubitus varus in adults]. PMID- 20963993 TI - [A medium-term analysis on of therapeutic effects of locking proximal humerus plate for the treatment of comminuted fractures of proximal humerus]. AB - OBJECTIVE: To investigate the medium-term curative effects of locking proximal humerus plate for the treatment of comminuted fractures of proximal humerus, and provide evidences for the clinical practice. METHODS: From August 2005 and April 2008, 23 patients with comminuted fractures of proximal humerus were treated with locking plates, including 12 males and 11 females, aged 27 to 76 years old (averaged 51.5 years old). There were 18 cases of traffic accident injuries, 4 cases of falls injuries, and 1 case injured after heavy pressure. According to Neer classification, 11 cases were three-part fractures, and 12 cases were four part fractures. Outcomes were assessed with radiography and the Constant-Murley (C-M) shoulder evaluation. RESULTS: All the patients got primary healing of incisions. Twenty-three patients were followed up, and the duration ranged from 17 to 49 months, with an average of 35.25 months. Twenty patients had fracture healing during 4 to 7 months after operation. There was no significant differences among 3, 6 and 12 months after operation in C-M scoring. The average C-M score was (79.85 +/- 17.23) points (38 to 100 points) at the 12th month after operation, 8 cases got an excellent result, 8 good, 5 fair, and 2 poor. In the LPHP plus bone graft group 6 cases got an excellent result, 4 good, 3 fair, and 1 poor; in LPHP fixation group 2 excellent, 4 good, 2 fair,and 1 poor. CONCLUSION: The medium-term curative effect of the locking proximal humerus plate in the treatment of proximal humeral fractures is significant. For the comminuted fractures of proximal humerus combined with osteoporosis and bone defects, bone graft should be performed routinely. PMID- 20963994 TI - [Reticulum cell sarcoma misdiagnosed as acute osteomyelitis: a report of 1 case]. PMID- 20963996 TI - [Case-control study on therapeutic effects between clavicular hook plate and tension band fixation for the treatment of sternoclavicular joint dislocation]. AB - OBJECTIVE: To compare therapeutic effects between clavicular hook plate and tension band fixation for the treatment of Allman type II to III sternoclavicular joint dislocations. METHODS: A retrospective survey was analyzed from May 2000 to September 2008. A total of 31 patients with Allman type II to III sternoclavicular joint dislocations were followed up. Sixteen patients were fixed with the clavicular hook plate (Group A) including 11 males and 5 females, with a mean age of (37.4 +/- 7.3) years. Fifteen patients were treated with tension band fixation (Group B) including 9 males and 6 females, with a mean age of (35.6 +/- 5.1) years. The indexes of intra-operation and during the hospital stay, the clinical outcomes and postoperative complications were statistically compared. RESULTS: All the patients were followed up for 12 to 37 months, with an average of 20 months. There was no significant differences in data of operative time, blood loss and length of incision between the two group (P > 0.05); however, the economic cost was significantly much more in Group A (P < 0.01). Also, there was statistically difference in the incidence of complications between the two groups (P = 0.023), which were 2 patients in Group A and 8 patients in Group B. According to Rockwood evaluation criteria, in group A, 13 patients got an excellent result, 2 good and 1 poor; in group B, 10 patients got an excellent result, 3 good, 1 poor and 1 bad. There were no statistical difference in good and excellent rate. CONCLUSION: The clavicular hook plate for the treatment of Allman type II to III sternoclavicular joint dislocation is believed to be as good as tension band fixation, but there are fewer complications and in favor of early exercise. PMID- 20963995 TI - [Grading treatment of hip osteoarthritis]. AB - OBJECTIVE: To investigate therapeutic effects of intra-articular injection of sodium hyaluronate, arthroscopy and total hip replacement for the treatment of different severity hip osteoarthritis. METHODS: Eighty-nine patients were treated with the three methods from June 2004 to August 2008. There were 33 males and 56 females, ranging in age from 30 to 72 years, averaged 51.8 years. The disease course ranged from 3 to 360 months, with a mean of 58.7 months. All the patients had hip pain and limited movement of hip joint. The patients were treated according to ISOA score and Kellgren-Lawrance (K-L) grades of hip osteoarthritis. The preoperative and postoperative Harris scores were compared. RESULTS: After the operation, 83 patients were followed up, and the duration ranged from 3 to 58 months. The Harris scores results: the patients with slight hip osteoarthritis and K-L grade I got an averaged preoperative score of (70.50 +/- 4.62) and postoperative score of (91.75 +/- 4.01); the patients with slight hip osteoarthritis and K-L grade II got an averaged preoperative score of (70.15 +/- 3.79) and postoperative score of (82.18 +/- 3.92). The patients with moderate hip osteoarthritis and K-L grade III got an averaged preoperative score of (57.12 +/- 2.19) and postoperative score of (89.94 +/- 1.13) score. The patients with serious hip osteoarthritis and K-L grade IV got an averaged preoperative score of (48.63 +/- 2.21) and postoperative score of (90.76 +/- 1.14); the patients with very serious hip osteoarthritis and K-L grade IV got an averaged preoperative score of (42.67 +/- 3.17) and postoperative score of (91.97 +/- 2.24); the patients with extremely serious hip osteoarthritis and K-L grade IV got an averaged preoperative score of (36.46 +/- 2.96) and postoperative score of (82.69 +/- 1.19). There were significant differences in scores of all groups before and after treatment. CONCLUSION: The hip osteoarthritis should be treated according to its serious degree such as slight, moderate and severe, as well as based on its X-ray classification, which is the best method to get satisfactory results. PMID- 20963997 TI - [Controlled clinical trials on effective means of drainage after total hip arthroplasty]. AB - OBJECTIVE: To explore effective means of drainage after total hip arthroplasty (THA). METHODS: From March 2009 to September 2009, fifty patients who underwent primary total hip arthroplasty in one side were randomly divided into two groups. In the natural drainage group, there were 12 males and 13 females with a mean age of (58.0 +/- 15.2) years (from 23 to 79 years) and in the routine negative pressure drainage group there were 10 males and 15 females with a mean age of (55.0 +/- 17.8) years (from 30 to 75 years). The drainage volume, wound infection, abnormal exudation, the change of hemoglobin and the blood transfusion volume after operation were all observed and compared. RESULTS: The wound of all patients in two groups got primary healing without infections. There were no differences in the changes of hemoglobin between the two groups (t = 0.532, P > 0.05). However, in the natural drainage group the drainage volume was much less than that in the routine negative pressure drainage group; moreover, less patients in this group needed blood transfusion. There were obvious differences in the two groups (t = 4.405, 2.496, P < 0.05). CONCLUSION: After THA, the natural drainage can decrease the volume of blood loss and incidence of transfusion, and can not increase the infection rate, making it an ideal and deserved popularized drainage method. PMID- 20963998 TI - [Case-control study on cannulated screw fixation and percutaneous autogenous bone marrow grafting for the treatment of femoral neck fractures]. AB - OBJECTIVE: To compare clinical results of two methods for the treatment of femoral neck fracture, which are cannulated screw fixation combined with percutaneous autogenous bone marrow grafting, and simple cannulated screw fixation. To investigate the curative effects of cannulated screw fixation combined with percutaneous autogenous bone marrow garfting to promote fracture healing and reducing femoral neck necrosis. METHODS: The clinical data of 60 cases, which were enrolled from December 2000 to December 2008 consecutively in our hospital, were analyzed retrospectively. Thirty patients with femoral neck fractures were treated with cannulated screw fixation and percutaneous autogenous bone marrow grafting. There were 20 males and 10 females, ranging in ages from 18 to 89 years,with an average of (52.3 +/- 0.2) years. There were 13 patients with traffic accident, 3 patients with falling injuries and 14 patients with tumble. Based on the Garden classification for femoral neck fractures, 1 patient was type I, 6 patients were type II, 12 patients were type III and 11 patients were type IV. Among 30 patients in the control group, 16 patients were male and 14 patients were female, ranging in age from 18 to 91 years, with an average of (51.9 +/- 0.1) years. Twelve patients injured with traffic accident, 1 patient with falling injuries and 17 patients with tumble. Based on the Garden classification for femoral neck fractures, 5 patients were type I, 2 patients were type II,15 patients were type III, and 8 patients were type IV. Patients in the control group were treated with cannulated screw fixation only. All the patients were followed up for 2 years after operation. The fracture healing and complications were evaluated and compared between the two groups. RESULTS: The average healing time was (7.1 +/- 1.2) months in the observing group and (8.0 +/- 1.4) months in the control group. The healing of femoral neck fracture occurred in 29 cases in observing group while in 24 cases in the control group contrast to femoral head necrosis occurred in 1 case in the observing group while in 6 cases in the control group. According to Harris scoring system, the good and excellent rate of the two groups had statistical difference (P < 0.05). CONCLUSION: Cannulated screw fixation and percutaneous autogenous bone marrow grafting is a more efficient method for accelerating healing of femoral neck fractures and reducing femoral head necrosis. PMID- 20963999 TI - [Case-control study on transcatheter artery embolization for massive bleeding due to pelvic fractures]. AB - OBJECTIVE: To investigate the techniques and curative effects of transcatheter artery embolization (TAE) for massive bleeding due to pelvic fractures. METHODS: The clinical data of 92 patients with haemorrhage due to pelvic fractures from March 1998 to February 2008 were retrospectively analyzed. Among 53 patients treated conservatively such as massive transfusion and fluid infusion in the control group, 43 patients were male and 10 patients were female, ranging in age from 27 to 61 years, averaged (37.2 +/- 5.7) years. Among 39 patients who were hemodynamically unstable or had evidences of ongoing hemorrhage required TAE, 26 patients were male and 13 patients were female, ranging in age from 26 to 62 years, with a mean age of (35.3 +/- 9.5) years. The clinical date such as blood or fluid transfusion volume, shock redress time and survival rate were compared between the two groups. The hemostatic efficiency and complications of the surgery were also analyzed. RESULTS: The average hemostasis time of TAE group was 2 hours. There were no intraoperative injuries of blood vessels, nerve or vital organs. Three patients had lower limbs numbness and 5 patients had gluteal skin redness after the operation. The blood transfusion or fluid infusion volume, shock redress time and survival rate were all significantly better than those in the conservative group. CONCLUSIONS: TAE is an early,rapid and effective method in controlling haemorrhage due to pelvic fractures. PMID- 20964000 TI - [Mechanisms of autologous chondrocytes mass transplantation in the repair of cartilage defects of rabbits' knee]. AB - OBJECTIVE: To trace the pathological changes of the cultured autologous chondrocytes mass after implanted in cartilage defects and investigate the pathophysiological mechanisms of the antologous chondrocytes mass transplantation in the repair of cartilage defects. METHODS: Twenty-four New Zealand white rabbits of 4 to 6 month-old and weighing more than 3.0 kg (female and male was unrestricted) were randomly divided into experiment group and the control group. For 12 rabbits of experiment group, the cartilage defects were repaired with the autologous chondrocytes mass and sealed with one piece of periosteum. Firstly, cartilage tissue of 10 to 30 mg was obtained from the shoulder of the rabbits after anaesthetized by 1 mg/kg 20% sumianxin. Then, chondrocytes were isolated from the cartilage tissue with 0.2% type II collagenase digestion and were cultured in DMEM/F-12 supplemented with 20% fetal bovine serum (FBS), 50 microg/ml ascorbic acid-2-phosphate, 0.4 mM proline, 5 microg/ml insulin and 1 mM non-essential amino acids (NEAA) in flasks in vitro. The cells were harvested until a thin film of the cells covered the bottom of the flask could be seen with naked eyes. Then the film was collected with a curled glass stick and formed a solid mass. On this time, the animal was anaesthetized again and the full thickness cartilage square defect of 4.0 mm x 6.0 mm was fabricated in the patellar grove of distal femur, and then the cellular mass was transplanted into the defect covered by one piece of periosteum which obtained from the upper anterior of tibia and sealed with the femoral condyles. For 12 rabbits of the control group, the defects were sealed with one piece of periosteum only. The animals were sacrificed in the 1st, 3rd, 6th and 12th weeks after the operation respectively. The histologic sections were stained with safranin O-fast green, hematoxylin-eosin (H&E) and picric acid-Sirius red and immunostained for type II collagen and aggrecan. RESULTS: In the 1st week, the transplanted cells oriented to articular surface differentiated to matured hyaline chondrocytes and excrete large amount cartilage matrix. In the 3rd week, the trend was more obvious and the periosteum was union to the cell mass. In the 12th week, the defects were repaired with hyaline-like cartilage tissue, and in the 24th week, the repair tissue turned to matured hyaline cartilage. In the control group, the defects were repaired with fibrocartilage tissues. CONCLUSION: It was evidenced that the defects were repaired by the autologous chondrocytes mass transplantation. The procedure was gradual and initialed from up toward joint to down to the deep of the defect. PMID- 20964001 TI - [Effect of Osthol on the proliferation and differentiate of osteoblasts in vitro]. AB - OBJECTIVE: To investigate the effects of Osthol on the proliferation and differentiation of osteoblasts of rats (rat calvarial osteoblasts, ROB) cultured in vitro. METHODS: The neonatal SD rat skull was segregated, and enzyme digestion was used to obtain bone cells which were cultured in MEM containing 10% FBS. The medium was changed every three days, and serial subcultivation was performed when cells covered with 90% of the culture dish. The Osthol was added to 96-well plates with final concentration of 1 x 10(-4) mol/L, 1 x 10(-5) mol/L, 1 x l0(-6) mol/L and 1 x10(-7) mol/L, and MTT method was used to evaluate the proliferation. Differentiation analysis: the alkaline phosphatase (ALP) activity was determined at the 3rd, 6th, 9th, 12th and 15th days separately after osteogenic induction culture. The synthesis of type I collagen was observed using immunohistochemical method at the 8th day. The ALP stain was performed at the 12th day. The alizarin red staining was done and calcified nodules was counted at the 14th day. RESULTS: The Osthol with final concentration of 1 x 10(-4) mo/L inhibit the proliferation of ROB. The Osthol with final concentration of 1 x 10(-5) mol/L had no obvious influence on the proliferation of ROB, but it significantly promoted the activity of ALP, enhanced the synthesis of collagen type I and increased the number of calcified nodules. CONCLUSION: The Osthol with final concentration of 1 x 10(-5) mol/L can promote differentiation and maturation of ROB, which may be active ingredients of Chinese drugs for the osteoporosis prophylaxis. PMID- 20964002 TI - [Effects of small needle knife on the substance P in the dorsal root ganglion and spinal cord of rats]. AB - OBJECTIVE: To study the mechanism of synthesis of substance P (SP) in the dorsal root ganglion (DRG) and the release of it in the dorsal horn of the spinal cord of rats after compression of skeletal muscle, and to observe the influence of small needle knife. METHODS: Sustained pressure of 70 kPa was applied to rats, muscular tissues for 2 hours. The rats were divided into three groups: normal, control and experiment group respectively. In all rats except the six normal ones, the lower legs were compressed once one day. The left leg was considered as the control group, the right left was experiment group, which were divided into the 1st day, the 2nd day and the 3rd day within the two groups. Experiment group was treated with small needle knife after the muscular tissue was compressed. After completing the stimulation, the DRG related to the muscle and part of spinal cord were removed for the qualification of SP-like immunoreactivity using immunohistochemistry. The dark brown stains on the DRG and on the REXed laminae I and II in the dorsal horn of the spinal cord were counted by Image-Pro Plus software. RESULTS: SP-like immunoreactivity in the side treated by the small needle knife was enhanced comparing with the counterpart in DRG in normal group (P < 0.01). The integrated optical density of SP like immunoreactivity of the DRG in the experiment group were significantly reduced compared with the control group (P < 0.05). However, the release of SP from spinal cord in experiment group was lower than that in the control group at the 1st day and the 3rd day (P < 0.01), with the opposite result of the 2nd day. CONCLUSION: Based on the fact that SP is a nociceptive neurotransmitter, the present study suggests that tension relaxation by small needle knife reduces expression of SP in the DRG, and shows no effects on the release of SP from the spinal cord in short-term (3 days). PMID- 20964003 TI - [Systematic review of clinical randomized controlled trials on manipulative treatment of lumbar disc herniation]. AB - OBJECTIVE: To evaluate the efficacy and safety of the manipulative treatment on lumbar disc herniation and analyze the current status of clinical studies. METHODS: The PubMed, OVID, Cochrane Library, CBM - disc database, CNKI database and VIP Database were retrieved, and 832 literatures on manipulative treatment for lumbar disc herniation were collected, in which 8 articles met the inclusion criteria. Cochrane systematic review was used to evaluate the quality; and RevMan 4.2 was used for Meta Analysis of Literatures. RESULTS: There were total 911 patients in the 8 articles. The summary OR for the combined cure rate of the 8 articles was 3.65, and the 95% CI was [2.15, 6.20]. The summary OR for the combined efficiency was 3.56, and the 95% CI was [2.35, 5.38]. The cure rate and effective rate of the patients in manipulative group were superior to those of patients treated with other methods such as drugs, traction, acupuncture, microwave thermotherapy (all the methods were called as "other therapies"). CONCLUSION: This study shows that manipulative treatment on lumbar disc herniation is safe, effective, and both cure rate and the effective rate is better than other therapies. But the number of documents is limited and the quality is not very high, and the conclusion is still uncertain, high-quality evidence is needed to be further validated. PMID- 20964004 TI - [Surgical treatment of thoracic ossification of ligamentum flavum and therapeutic effects analysis]. AB - OBJECTIVE: To investigate the surgical treatment of thoracic ossification of the ligamentum flavum (TOLF) and analysis of the therapeutic effects. METHODS: Six patients with thoracic ossification of the ligamentum flavum were retrospectively studied from October 2006 to October 2009. All of the patients in this group were treated by en bloc hemi-articular process laminectomy. There were 4 males and 2 females, ranging in age from 45 to 66 years, averaged 55.2 years. The evaluate factors including the preoperative and postoperative JOA scores,and the function of the urinary bladder were analyzed. RESULTS: All the 6 patients were followed after operation. The mean followed-up duration was 10.5 months, ranging from 2 to 18 months. According to JOA evaluation criteria, 4 patients got an excellent result, 1 good and 1 bad. The one patient with bad result had spinal cord compressed for too long time, and the T2-weight MRI showed nonreversible degeneration of spinal cord and combined with schizophrenia. The clinical symptoms improved with varying degrees. CONCLUSION: The en bloc hemi-articular process laminectomy is an effective method for ossification of the thoracic ligamentum flavum. A thorough decompression and real-time protection of the spinal cord is the key to the success of surgery. PMID- 20964005 TI - [Treatment of avascular necrosis of femoral head by impacting granular bone grafting via window in femoral neck]. AB - OBJECTIVE: To evaluate the clinical results of continuing skeletal traction and impaction granular bone grafting via window in femoral neck for the treatment of avascular necrosis of femoral head. METHODS: From August 2000 to October 2004, 23 patients (35 hips) with femoral head necrosis were treated by continuing skeletal traction and impacting granular bone grafting via bone window on femoral neck. There were 18 males, 5 females, with an average age of 32 years ranging from 19 to 52 years, which included 7 hips of stage II, 28 hips of stage III. All patients had various degrees of hip joint pain and suffered from limited hip motion. The necrotic bone, granulation tissue and hardening zone were completely cleaned via bone window on the femoral neck. The autogenous granular iliac bone was grafted, and impacted persistently. Skeletal traction through femur condyles was applied continually after the operations. The effects before and after operation were compared by the hip pain, function, joint activity and X-ray. RESULTS: Regular follow-up was carried out after the patients were dismissed from the hospital. The follow-up period was 6 months, 1 year, 2 years, 3 years, 4 years, 5 years respectively. According to Wang's standard, the average score was increased from (52.66 +/- 12.53) preoperatively to (88.94 +/- 5.84) preoperatively at half a year, (89.78 +/- 6.18) at 1 year, (86.37 +/- 7.46) at 2 years, (84.08 +/- 7.57) at 3 years, (83.76 +/- 8.08) at 4 years, and (76.83 +/- 8.98) at 5 years. Scores of operation were greatly increased and the difference had statistical significance. CONCLUSION: Continuing skeletal traction after the operation, completely cleaning the necrotic bone and impacting granular bone grafting via window on femoral neck can greatly raise the satisfactory rate of clinical effect and delay the progression of disease for avascular necrosis of femoral head. PMID- 20964006 TI - [Treatment of unstable pelvic posterior ring fractures with percutaneous reconstruction plate internal fixation]. AB - OBJECTIVE: To analyze the method and clinical effect of percutaneous reconstruction plate internal fixation for the treatment of unstable pelvic posterior ring fractures. METHODS: From March 2004 to October 2008, 36 patients with unstable pelvic posterior ring fractures were treated with percutaneous reconstruction plate internal fixation. Heavy traction was used to correct vertical displacement of sacrum, then arc incisions (3-5 cm) were made from both sides of posterior superior iliac spine to ipsilateral inferior iliac spine along iliac crest. The reconstruction plate was pushed through the cutaneously tunnel to the other incision. There were 26 males and 10 females, the age ranged from 10 to 65 years, with an average of 37.3 years old. RESULTS: All the patients were followed up, the duration ranged from 12 to 36 months (means 17.8 months). There were no infection, no vascular nerve injuries and loosening or breakage of the external fixation. All cases attained bone union and lower limbs were equal. The average length of incisions, operative time and intraoperative blood loss were (4.36 +/- 0.99) cm, (42.61 +/- 7.97) min, (168.61 +/- 40.44) ml, respectively. According to the Majeed standards, the functional recovery was excellent in 12, good in 18 and fair in 6. CONCLUSION: Percutaneous reconstruction plate internal fixation is an ideally safe and effective way to treat unstable pelvic posterior ring fractures, it has many advantages such as minimal invasion, less complications and quicker recovery. PMID- 20964007 TI - [DHS combined with anti-rotation screws and calcium phosphate cement for the treatment of proximal femoral fractures in senile osteoporosis]. PMID- 20964008 TI - [Treatment of Gartland type III supracondylar fractures of the humerus in children by closed reduction]. PMID- 20964009 TI - [Experience of improved Dewar procedure and clavicular hook plate for the treatment of acromioclavicular joint dislocation of type III of Tossy]. PMID- 20964010 TI - [Clinical effects of repairing bone and soft tissue defects in leg with skin flap and bone transport]. PMID- 20964011 TI - [Closed reduction and micro-incision for the treatment of distal tibia fractures]. PMID- 20964012 TI - [Progress of research on percutaneous fixation for the treatment of pelvic ring and acetabular injuries]. AB - Percutaneous pelvic fixation is possible with the advances in intraoperative fluoroscopic imaging and other technologies. Percutaneously inserted screws in medullary pubic ramus,iliac wing, and iliosacral bone can stabilize pelvic or acetabular disruptions directly mean while can diminish operative blood loss, shorten operative time, and allow patient's early activity. Complications associated with open surgical procedures are similarly avoided by using percutaneous techniques. Stable and safe percutaneous fixation techniques depend on accurate closed reduction, excellent intraoperative fluoroscopic imaging, and detailed preoperative planning. A thorough knowledge of pelvic osseous anatomy, injury patterns, deformities, and the related intraoperative imagery techniques are essential for doctors to fulfill the operation of percutaneous pelvic fixation. This paper presents an overview of the technique of percutaneous surgery of the pelvis and acetabulum. PMID- 20964013 TI - [Hyperesthesia of back induced by cervical spondylopathy]. PMID- 20964014 TI - [Clinical scores, medical homes and managed care]. PMID- 20964015 TI - [Validation of clinical scores: theoretical and practical basic notions]. AB - Physicians are using clinical scores on a regular basis. These scores are generally helpful in making medical decisions. However, the process of validation of clinical scores is often unknown to the physicians. This paper reviews the theory of validation of clinical scores and proposes practical exercises. PMID- 20964016 TI - [Child-Pugh, MELD and Maddrey scores]. AB - The Child-Pugh score is largely validated and easy to use. Despite two subjective variables, this score is widely used to predict the survival of patients suffering from cirrhosis. The MELD (Model for End Stage Liver Disease) is a more objective prognostic score, requiring however a calculation software. It is currently used in prioritizing allocation of organs for liver transplantation. The Maddrey score allows identifying the severe forms of alcoholic hepatitis, which can benefit from a corticotherapy to reduce the high short-term mortality. PMID- 20964017 TI - [Cardiovascular risk scores: why, how and when to use them?]. AB - Prevention of cardiovascular diseases is a priority for primary care physicians. Scores that stratify individual cardiovascular risk, such as PROCAM/CSLA and SCORE, are simple tools to help physicians to treat patients with multiple cardiovascular risk factors in clinical practice. These scores allow physicians to assess individual cardiovascular risk and to prescribe cholesterol-lowering drugs and aspirin appropriately and cost-efficiently. They also allow to set target cholesterol levels according to the estimated risk. Each score is a practical tool to support decisions with its advantages and limits. PMID- 20964018 TI - [Which patients with atrial fibrillation need anticoagulation?]. AB - Atrial fibrillation is the most frequent cardiac arrhythmia and its prevalence increases with age. It is essential to prevent the thromboembolic events, stroke in particular, considered as its most serious complication. Vitamin K antagonists are currently the most effective drugs to prevent them. However, despite their proven efficacy, they carry a risk of bleeding complications. Consequently, it is essential to balance individual thromboembolic risk with the hemorrhagic risk, taking into consideration age, cardiac diseases, hypertension, diabetes, history of cerebral vascular accident, history of hemorrhagic disease and also patient's compliance. The CHADS2 score is a stratification model for stroke risk in patients with non-valvular atrial fibrillation that is the easiest score to use in clinical practice and the most used one. PMID- 20964019 TI - [Screening and evaluation questionnaires for psychoactive substance use]. AB - There is ample evidence for the interest of screening for psycho-active substance use in primary care, coupled with a brief intervention. The screening can be done during the medical consultation (focusing on frequency and quantity of substance use, loss of control and medical and psychosocial consequences) or with standardised screening instruments. The use of a questionnaire can be helpful for the physician. This article describes some validated questionnaires that allow a rapid and non-stigmatising screening for use of one or several substances. The ASSIST questionnaire, developed by WHO, accessible online, can be particularly useful; it allows the screening, evaluation and orientation for substance use and related problems in primary and general medical care settings. PMID- 20964020 TI - [Depressive disorder across the lifespan in primary care: screening, diagnostic and follow-up tools]. AB - Recognizing and treating depression is particularly important for primary care physicians since the prevalence of this disease reaches about 10% in this setting. Screening tools are likely to improve patients' health only if followed by a comprehensive therapy. The 3 Aroll's questions for adults, the geriatric depression scale for the elderly and the Edinburgh depression scale for postpartum women are the most useful and validated screening tools. Data are insufficient to recommend screening in children and teenagers. A positive screening must be confirmed by DSM-IV or ICM-10 criteria. Initial evaluation and follow-up are facilitated by Beck's and PHQ9 scales, the most validated ones for primary care physicians. Psychiatric and psychotherapeutic treatment by a specialist is required for severe depression. PMID- 20964022 TI - [Managed care or network of integrated care]. PMID- 20964021 TI - [When D-dimers within normal limits do not equate to normal D-dimers]. AB - Pulmonary embolism is a difficult diagnosis that may be missed because of an aspecific clinical presentation. Being the most accurate to confirm or exclude the disease is a matter of concern, as effective treatment exists and a possibly fatal outcome without it. Scores and guidelines can help us. However, they cannot replace clinical sense. What are the options when laboratory results put us on the wrong track, such as in a patient with a clinical presentation suggestive of a pulmonary embolism, but whose D-dimers are within the normal range? PMID- 20964023 TI - [Prevention of malaria in travellers: which antimalarial is best?]. PMID- 20964024 TI - [The fight against HIV: new contradictions (1)]. PMID- 20964025 TI - [When a father "explains sex" to his daughter]. PMID- 20964026 TI - [All drugs banned soon allowed? (3)]. PMID- 20964027 TI - [Sharpen our sensitivity to suffering and dignity]. PMID- 20964028 TI - [That so-called papanicolaou: women's social representations about the screening test for cervical cancer]. AB - This research aims to identify women's social representations of women regarding cervical cancer and describe the relationship of these social representations with preventive care. The study used a qualitative-exploratory approach, with the theory of social representations as the theoretical-conceptual support. Data collection was performed using two techniques: the free association of words and the semi-directed interview with open questions. The thematic analysis technique was used for data interpretation. The research resulted in two thematic units: cervical cancer: an early treatable wound and the screening test: taking because of fearing. It was observed that women have great fear of having cervical cancer and, therefore, recognize the importance of the screening test and see it as an act of self-care towards their health. PMID- 20964029 TI - [Voluntary work, demographic, social and economic features and health self perception by elderly people from Porto Alegre (Brazil)]. AB - The objective of this cross-sectional, comparative study was to describe the demographic, socioeconomic and health characteristics of elderly voluntary workers of a Non-governmental organization of Porto Alegre, and investigate the influence of voluntary work and the referred characteristics on the subjects' self-perception of health, compared to a paired group of elderly individuals who did not perform any voluntary work. Through interviews it was found that 87.4% of the elderly voluntary workers were women, with complete secondary education, had their own income and followed a religion and a healthy lifestyle. The comparison of data from both groups showed that self-perception of great health was more common among voluntary workers (30.5% compared to 6.1%, p = 0.054). Multivariate analysis revealed that performing voluntary work and having fewer diseases influenced the individuals' having a positive self-perception of their health (p < 0.05). Study results support the hypothesis that voluntary work may be a mechanism of health promotion among the elderly. PMID- 20964030 TI - [Assessment of self-esteem in pregnant women using Rosenberg's Self-Esteem Scale]. AB - The objective of this descriptive, cross-sectional study was to evaluate the self esteem of 127 pregnant women seen in a prenatal care program conducted in a public school hospital. Data collection was performed using the Rosenberg's Self esteem Scale; unsatisfactory self-esteem was related to socio-demographic and health variables of the pregnant woman, and to the presence or absence of support systems. Descriptive and univariate statistical analysis were used to assess possible associations. Pregnant women who had low scores for self-esteem were 60% of all subjects. As for the sociodemographic data, women with fewer years of education presented higher frequency of lower self-esteem scores, which disagrees with other studies. Pregnant women who report having an unplanned pregnancy presented higher prevalence of low self-esteem than those who reported having planned their pregnancy. The lack of support from the partner to look after the baby was also associated to the pregnant women's low self-esteem. Other associations between variables were not statistically significant. PMID- 20964031 TI - [The experience of sexuality by visually impaired adolescents]. AB - The combination between transformations in adolescence, the indefiniteness they are accompanied by and the visual impairment justifies a study about the sexual experience of female, visually impaired adolescents included in society and in the school community. Five adolescents were interviewed at a Pedagogical Support Center. Questions attempted to find out their knowledge and understanding about the cause of their visual impairment, family composition and orientations, affective-sexual experience, level of knowledge about sexuality-related issues, including contraceptive methods and sexually transmitted diseases. Results revealed that these adolescents display the same sexuality development characteristics of their age group, though they have particular characteristics. It was observed there is a lack of knowledge regarding contraceptive methods and sexually transmitted diseases, of which the adolescents have superficial information. Making knowledge on the referred issues accessible to this population is indispensible. PMID- 20964032 TI - [Development of an instrument to measure psychosocial determinants of physical activity behavior among coronary heart disease patients]. AB - The aim of this study was to report the development and the analysis of content validity and reliability of the Psychosocial Determinants of Physical Activity among Coronary Heart Disease Patients Questionnaire, based on an extension of the Theory of Planned Behavior. In the content validity step, three experts evaluated the instrument which was, afterwards, pre-tested with five subjects in order to obtain a conceptually appropriate and easily understood instrument. Fifty-one patients participated in the evaluation of internal consistency of the reviewed instrument. Cronbach's alpha coefficients above 0.75 were observed for the constructs: Intention, Attitude, Subjective Norm, Self-efficacy and Habit. The new instrument demonstrated acceptable evidence of content validity and reliability. PMID- 20964033 TI - [Permanent education in nursing: survey to identify the necessities and the expected results based on the workers conception]. AB - This study analyzed the educational activities of nursing workers with the objective to survey the needs and expected outcomes, according to the workers' perception. This is a qualitative research, in which data was collected by means of semi-structured interviews performed with twenty-five workers in a teaching hospital in the municipality of Sao Paulo. The empirical material was submitted to thematic analysis. Results show that the needs are surveyed mainly based on technical performance issues and on the acquisition of new equipment; and that the expected outcomes, in the short term, are mostly the improvement in procedure performance and, in mid and long term, increasing their critical thinking towards work. In conclusion, there is a general perception about continuing education in terms of surveying the needs as well as for outcome expectations. PMID- 20964034 TI - [Women hospitalized due to abortion in a maternity teaching hospital in Recife, Brazil]. AB - This cross-sectional study was performed with 160 women between 2005-2006. The objective was to describe the social-demographic and reproductive characteristics of women hospitalized due to abortions, and their knowledge about contraceptive methods and abortion induction. In order to determine the association between the abortion classification and social-demographic variables, Pearson's chi-square test was used, with a significance level of 5%. A frequency of 56.3% was found for probably induced abortions. Most cases of abortion occurred before 12 weeks (55.7%). As for the women's profiles: 48.9% were between 20-29 years old, 72.0% had eight years or more of schooling, 90.1% had a partner, 52.0% had 1-3 children, 100% knew about oral contraceptives and condoms and 80.0% had heard about misoprostol. The social-demographic and reproductive profile of women hospitalized at the referred service due to abortion did not change over the last years. Misoprostol remains the most known method for abortion induction. PMID- 20964035 TI - [Social representations of community health agents regarding drug use]. AB - This paper discusses on the social representations of community health agents (CHAs) about drug use as part of a qualitative, ethnographic study with data collected by means of a set of research techniques among health professionals including 22 CHAs in a basic health unit in Salvador, Bahia (Brazil) from January, 2006 to January, 2007. The Theory of Social Representations was adopted as the theoretical framework whereas gender was the chosen analytical category. CHAs were found to recognize the women's proximity and participation in the drug phenomenon in the community where they live and act, although they take no professional measures towards such an issue. Their social representations were shown to reproduce stereotypes and prejudices towards drug users and drug use, especially gender- and social class-related, while highlighting the invisibility of drug use as a health problem for the population under study. PMID- 20964036 TI - [Sleep quality of elders living in long-term care institutions]. AB - This study was aimed at evaluating sleep quality and identifying sleep related problems among elderly people living in long-term care institutions in the city of Sao Paulo, Brazil. Subjects were 38 cognitively preserved elders living in these institutions for at least a year. Data collection was performed using the following instruments: Identification Form, Katz Index and Pittsburgh Sleep Quality index (PSQI). Results showed that 81.6% of the studied elders reported their sleep quality was good or very good. Nevertheless, there was an elevated frequency of sleep related problems such as: getting up to go to the bathroom (63.2%); getting up in the middle of the night or very early in the morning (50%); feeling too hot (23.7%); feeling pain (21.1%). These findings show an evident contradiction between elders' perception of their sleep quality and the actual elevated number of identified sleep problems. PMID- 20964037 TI - [Stressors at the intensive care unit: the Brazilian version of The Environmental Stressor Questionnaire]. AB - The objective of the present study was to perform the cultural adaptation of The Environmental Stressor Questionnaire-ESQ for the Brazilian Portuguese, as well as to verify its reliability and validity. In order to ensure the equivalence between the original instrument and the Brazilian version, all methodological steps recommended in the literature regarding cultural adaptation were followed. The Brazilian version of the ESQ was applied to 106 ICU patients in two hospitals (public and private) in the interior of Sao Paulo State. Reliability was evaluated in relation to internal consistency and stability (test e retest) and the convergent validity was determined by the correlation between ESQ and generic questions about ICU stress. Reliability was satisfactory with Cronbach's Alfa = 0.94 and stability (ICC = 0.861; IC 95% 0.723; 0.933). ESQ total score displayed strong correlation with the generic questions about stress (r = 0.70; p < 0.0001), thus confirming the convergent validity. The conclusion was that the ESQ adapted for Brazilian culture is a reliable instrument for evaluation of stressors in the ICU. PMID- 20964038 TI - [Profile of mothers of newborns with blood glucose control in the first hours of life]. AB - Some maternal factors associated with neonatal hypoglycemia justify monitoring blood glucose levels in the first 24 hours of life. The objective of this study was to describe the socio-demographic and obstetric characteristics of mothers to newborns undergoing capillary blood glucose control in the first 24 hours of life, hospitalized in a rooming-in maternity ward of a Baby Friendly Hospital. This is a descriptive exploratory study which involved the analysis of data from 380 medical records of mothers hospitalized from July to December, 2006 at the maternity ward of the University of Sao Paulo Teaching Hospital. It was found that 18 (5.6%) mothers developed gestational diabetes, none of them were treated with oral hypoglycemic agents, 53 (16.2%) had hypertension during pregnancy and 17 (32.1%) used anti-hypertensive medication, 215 (56.6%) received glucose 5% continuous infusion during labor and delivery. Correlation studies linking maternal variables and neonatal hypoglycemia are needed to identify the predicting factors of this neonatal morbidity. PMID- 20964039 TI - [Epidemiological profile of Haemophilus influenzae B meningitis in Regional Health Board of Piracicaba--Sao Paulo-Brazil]. AB - The objective of the present study was to characterize the population affected by Hib meningitis from 1992 to 2001, in the Regional Health Board of Piracicaba (Sao Paulo-Brazil) in terms of variables regarding demographics and the health-disease process. Data were collected from disease notification reports, and arranged using the SINAN Data Program. It was observed there was a peak in the incidence of meningitis in 1994 and a peak of deaths in 1999, before the vaccine had been introduced. The most affected group were male children under the age of 5 years, which is in agreement with literature. Most patients received care at public hospitals in the municipalities of Piracicaba and Limeira, which are references for the community of the entire region, which puts into effect one of the axes of the Health System of Brazil (SUS): regionalization. The introduction of the vaccine reduced incidence in about 73%, which corroborates its importance and shows that is necessary to encourage adherence to vaccination. PMID- 20964040 TI - [Comprehensive care from the perspective of health care workers from Belo Horizonte]. AB - The objective of this qualitative case study was to present the understanding that health care workers and administrators of Belo Horizonte have about comprehensive care. Thirty-two workers were interviewed using a semi-structured questionnaire. Data analysis showed that comprehensiveness permeates the various levels of health care, adding the concept of health promotion. Interdisciplinary work emerges as a key element for the health care practice, which is made effective by sharing feelings. On the other hand, data show that comprehensive health care is only made effective provided that basic conditions are present, and services often do not provide those conditions. In conclusion, it is necessary to eliminate the fragmentations that exist in the form of health care organization as well as in the everyday practice of health care workers at the referred services so that it is possible to offer comprehensive, problem-solving care and humanize health care practices always aiming at the quality of life of the population. PMID- 20964041 TI - [Work situations experienced by family health strategy professionals in Ceara Mirim]. AB - The purpose of this study was to analyze the work situations experienced by Family Health Strategy (FHS) professionals. This descriptive study was performed in Ceara-Mirim, Rio Grande do Norte state, in 2007. The population consisted of 190 FHS professionals, in which a questionnaire with closed-questions was applied. The results showed that 83.2% of the professionals consider that knowing the geographical area under their responsibility is a positive aspect that helps performing their activities, while 40.5% consider the number of families that each team has to follow to be a difficulty. Regarding work conditions, 93.2% reported the presence of professionals with a public health profile and 86.6% reported there is a lack of equipment and instruments. Of professionals who work exclusively with the FHS, 74% are community health agents. The commitment and responsibility to replace the traditional care practices should concern everyone, and there is a need for an interaction between historical, political, social, economic, and cultural factors. PMID- 20964042 TI - [Managing the basic health unit in tuberculosis control: a field of challenges]. AB - In this study we analyzed the management of Basic Health Units in terms of Tuberculosis (TB) control in a city in the interior of Sao Paulo state. Fourteen managers participated in the study. A closed questionnaire was administered and an open question was also applied. The interview was carried out after obtaining free and informed consent. Data analysis was performed using the Statsoft software Statistica 8.0 and thematic content analysis was used for the qualitative data. It was found there is a clear technical-bureaucratic management, deficient in the activity planning and organization dimensions at the BHU. Hence, health care managers in this study should include management aspects of planning and organization as ways to make TB control feasible. PMID- 20964043 TI - [Nurses' practice in health audit]. AB - The objective of this investigation was to identify nurses' practice in heath audit. The hermeneutic-dialectic method was used for the analysis. The study was performed in three loci: the internal audit service of a hospital; the external audit service of a private health service buyer, and the state audit service of the public health system (SUS, acronym in Portuguese for Sistema Unico de Saude Unique Health System), in Bahia. Nine audit nurses were interviewed. In the SUS audit, the nurses report being fulfilled with their practice and with the valorization of their professional role. In the private audit--both inside and outside of health organizations--the nurses' activities are focused on meeting the interests of their contractors, and do not get much involved with the care delivered by the nursing team and with the needs of service users. PMID- 20964044 TI - [Political pedagogical project: conception, construction and evaluation in nursing]. AB - Nursing education and nurses' articulation with the working market are guided on the premise that the quality of nursing service is related to training workers to be reflexive subjects. The main object of the study was to understand nursing education based on the current political pedagogical projects (PPPs) of nursing courses and, more specifically, to verify with coordinators and/or former coordinators of the referred nursing courses the conception, construction and evaluation of the PPPs and the inclusion of the reflective subject as a proposition when developing the PPPs. An analysis was performed on the PPP of nursing courses of the State (UECE) and Federal (UFC) Universities of Ceara, and interviews were performed with nine coordinators and/or former-coordinators of those courses. Data showed that the PPP is considered a guiding element of educational activities and that its construction results from collective but not permanent initiatives. There is much concern about the critical-reflexive character of nursing education, as well as the evaluation of the PPP. PMID- 20964045 TI - [Teaching care in nursing graduation according to the perspective of complexity]. AB - This study highlights the teaching of care in Nursing Graduation according to the Complexity Theory, supported by Edgar Morin. This is a qualitative study using Thematic Content Analysis. Twelve individual semi-structured interviews were performed at a private university in the city of Sao Paulo, Brazil. Data collection was performed between 2004 and 2005, using a guiding question. Data analysis revealed categories, herein referred to as Complex Pedagogical Indicators, which assigned meanings to complex care. Results showed that the interviewees realized and expressed sensitive care in nursing, making relations and interrelations of the parts with the whole and the whole with the parts, thus approaching complex care. PMID- 20964046 TI - [Nursing images and representations concerning stress and influence on work activity]. AB - The objectives of this study were: to identify the representations related to working stress factors attributed by nursing professionals and to discuss the influence of those factors on their work activities. The investigation was developed through a descriptive study with a qualitative approach, using the premises of social representations. The performed studies were used as the framework for the analyses. Data collection was performed using individual semi structured interviews. The content analysis technique was used to understand the images as representations of nursing workers, the meaning of the stressing factors and their influence on occupational activity. The studied population regularly faces the lack of appropriate working conditions, the scarcity of human and material resources and untrained personnel; Nursing workers feel dissatisfied and present mental and physical fatigue, which are situations that may cause stress when performing occupational activities. PMID- 20964047 TI - [Care delivery to newborns with myelomeningocele according to Roy's Adaptation Model]. AB - This case study aimed to identify the Nursing diagnoses, addressing physiological aspects according to Roy's Adaptation Theory, of a baby with meningomyelocele hospitalized at a Neonatal Intensive Care Unit (NICU), and to elaborate pertinent nursing actions for these aspects. The study was developed at the NICU of the Maternity Teaching Hospital Assis Chateaubriand, located in Fortaleza-Ceara, Brazil, between December 2007 and March 2008, when a script was used to survey data. During the analysis, the following diagnoses were recognized: ineffective breathing pattern; imbalanced nutrition: less than body requirements; impaired skin integrity; risk for infection and disturbed sensory perception. The use of this theory permitted recognizing that the newborn can produce positive or negative responses to stimuli and that the implemented targets and interventions were important to replace ineffective by adaptive responses. PMID- 20964048 TI - [Preliminary study about qualify of life of physicians and nurses working in pediatric and neonatal intensive care units]. AB - Compare the Quality of Life (QL) of doctors and nurses who work in Pediatric (PED) and Neonatal (NEO) Intensive Care Units, and to evaluate whether there are differences between the QL in the same job category, but differing according to the work unit. This descriptive study was performed with 37 physicians and 20 nurses. The WHOQOL100 was used. Physicians from the PED differ statistically in the field VI (p = 0.003) compared with physicians from the NEO. Physicians and nurses from the PED showed a statistically significant difference in field V (p < 0.01), while physicians and nurses from the NEO showed a statistically significant difference in field VI (p = 0.05). The QL assessment of physicians and nurses working in pediatric and neonatal intensive care units was below the scores found in scientific literature, compared to studies that evaluated patients with chronic pain and mental health disorders, indicating the occurrence of occupational stress. PMID- 20964049 TI - [Functional evaluation of aged with fractures at hospitalization and at home]. AB - Trauma is often related to functional impairment, representing an important social, economic and health issue. This study intended to evaluate the functional independence of aged individuals with fractures, at admission, discharge and after one month from their regressing home. Furthermore, this study also intended to verify the relationship between functional independence and demographic and health variables. Thirty-four aged individuals hospitalized at the Orthopedics and Traumatology Institute of the University of Sao Paulo Faculty of Medicine were interviewed and submitted to the application of the Functional Independence Measure (FIM). Among all fractures, 67.6% were femur fractures. The motor and total FIM scores increased at discharge; on the other hand, the total FIM score decreased one month after their returning home. Functional impairment increased with age and also with longer length of stay. Hypothyroidism was related to cognitive impairment, while dementia and depression were related to motor impairment. PMID- 20964050 TI - [Epidemiological aspects of the occurrence of vancomycin-resistant enterococci]. AB - This descriptive study was conducted in a public hospital from May 2005 to October 2007, with the purpose to determine the epidemiological aspects that involve vancomycin-resistant enterococci (VRE) and describe the evolution of patients. The data was obtained from registers on patient records and then processed in SPSS. Frequency distribution and measures of central tendency were used. A total 122 patients participated of the study, the majority were males with an average age of 43 years (SD = 18.8), and 16.3% developed VRE infection. Vancomycin has been the most used antibiotic (62.3%), 97.5% used invasive procedures, 45.0% were dependent on intensive care nursing, 77.9% had at least one open wound and 50.8% progressed to death. The data suggests that recommendations for bacterial resistance control should be encouraged to reduce mortality, morbidity, hospital costs and thus provide better quality care to patients. PMID- 20964051 TI - [Maternal mortality in the state of Paraiba-Brazil: association between variables]. AB - Maternal mortality has been established as one of the priority problems of public health, directly affecting women in the pregnant puerperal cycle and belonging to underprivileged social classes. Considering this situation, the aim of the present study was to identify associations between the race of women living in the state of Paraiba and age, educational level and type of death of women who died of maternal death in the period 2000 to 2004. This cross-sectional study used as a source of data declarations of 109 maternal deaths. Bivariate and multivariate statistical analyses were performed to evaluate the association between variables using multiple logistic regression. The odds ratio to investigate the association between variables was calculated. It was observed that there was no statistical significance between race and age variables or with educational level, but there was significant evidence that nonwhite women from Paraiba were more likely to die from direct obstetric death than white women, (OR = 3.55; IC: 1.20-10.5). The results showed that the risk of maternal mortality in Paraiba was higher among non-white women, revealing an important expression of social inequality. PMID- 20964052 TI - [Strategy in the care of cardiac surgical patients: evaluation of the sense of coherence]. AB - Sense of coherence is the construct proposed by Antonovsky to assess individuals' capacity of dealing with stress. This study aimed to measure the sense of coherence and evaluate its association to sociodemographic variables and the use of psychotropic drugs among 127 patients in the preoperative period of cardiac surgeries. The mean value of sense of coherence was 149.6 (S.D. = 24.6), ranging from 98 to 191 (possible range was 21 to 203), with higher values indicating higher sense of coherence. Higher values were observed among male patients, older than 60 years, married and who did not use psychotropic drugs. Statistically significant differences occurred only for gender and use of psychotropic drugs. Results suggest that female and young patients need more attention from nurses in the planning of their perioperative care. PMID- 20964053 TI - [Cost management: the implementation of the activity-based costing method in sterile processing department]. AB - This exploratory case study was performed aiming at implementing the Activity based Costing (ABC) method in a sterile processing department (SPD) of a major teaching hospital. Data collection was performed throughout 2006. Documentary research techniques and non participant closed observation were used. The ABC implementation allowed for learning the activity-based costing of both the chemical and physical disinfection cycle/load: (dollar 9.95) and (dollar 12.63), respectively; as well as the cost for sterilization by steam under pressure (autoclave) (dollar 31.37) and low temperature steam and gaseous formaldehyde sterilization (LTSF) (dollar 255.28). The information provided by the ABC method has optimized the overall understanding of the cost driver process and provided the foundation for assessing performance and improvement in the SPD processes. PMID- 20964054 TI - [Nursing diagnosis: impaired physical mobility in patients with stroke]. AB - The study aimed to investigate the occurrence of Nursing Diagnosis Impaired Physical Mobility in patients with stroke. This exploratory study was developed at rehabilitation units from November 2007 to march 2008, through an interview and physical examination. Nursing diagnoses were made using NANDA Taxonomy II. A total 121 patients were evaluated. Subjects' average age was 62.1 years, 52.3% were males with an average 1.5 stroke events in 3.4 years. The diagnosis was present in 90%, with an average of 5.8 defining characteristic. Difficulty turning was the most present characteristic and there were 3.4 related factors per patient, and most reported decreased strength and endurance besides neuromuscular impairment (100%). There should be a closer look towards this diagnosis when planning interventions after a stroke with aiming at health promotion for these patients. PMID- 20964055 TI - [Living with the difference: the impact of serodiscordance on the affective and sexual life of HIV/AIDS patients]. AB - The purpose of this descriptive-exploratory qualitative study was to describe and analyze the impact of serodiscordance on the affective-sexual life of HIV/AIDS patients who have HIV seronegative heterosexual partners. Eleven HIV/AIDS carriers in outpatient clinic follow-up were interviewed, in a reference university-hospital in the state of Sao Paulo. Data were collected through recorded individual interviews and analyzed according to Prose analysis. Living with HIV/AIDS serodiscordance implies these couples have to deal with several intimacy-related difficulties, due to the possibility of HIV transmission to the seronegative partner. This has a negative effect on serodiscordant partners, reflecting in changes in human sexual response, which could lead to sexual abstinence. Interdisciplinary care should be provided to HIV/AIDS carriers and their partners, thus providing comprehensive care regarding their sexuality and difficulties caused by serodiscordance. PMID- 20964056 TI - [(Dis)satisfaction of users: duplication and simultaneous use of services in family health]. AB - This descriptive and exploratory study was performed with the purpose to identify the pattern of use of health services: duplication and simultaneous use in a District Reference Unit (URD, acronym in Portuguese) and four Family Health Units (USF, acronym in Portuguese). Secondary data were collected in two stages: the first stage involved identifying the Service Files of the District Reference Unit for 15 days of the month of June 2006; and the second stage involved verifying 856 services delivered among the selected USF to users who were seen at the URD. It was found that there was duplication in the use of health services corresponding to 0.35% of the users seen at the group of services, as well as simultaneous use, corresponding to 3.27% of users. The duplication of health service use is considered to be an indirect indicator for the analysis of user satisfaction, i.e., service use duplication may be understood as an expression of user dissatisfaction. PMID- 20964057 TI - [Elderly attention to health strategy in the family: action of nurses]. AB - This study aimed to describe the nursing consultation for the elderly provided at the Family Health Strategy (ESF, acronym in Portuguese); identify possible difficulties in delivering health care to the elderly, as well as the professional qualification courses performed and the learning needs. Data were collected through semi-structured interviews and submitted to descriptive and thematic analysis. Interviews were performed with 12 nurses, most with ages between 23/-28 years (66%), with 1/-2 years since graduation (41%) in private institutions (75%). Two thematic categories emerged from the analysis: nursing consultation for the elderly performed at ESF and professional qualification in health care for the elderly. Obtaining reliable data in the nursing consultation, resolution and family support were considered as challenges. The courses to qualify professionals for elderly care occurred during their graduation course, highlighting the lack of opportunity, the short supply and the need for deeper studies about the aging process. PMID- 20964058 TI - [Ageing and dementia: what do community health workers know?]. AB - The objective of this qualitative study was to assess the knowledge of community health workers (CHW) with respect to aging and dementia, with the purpose of assisting the implantation of caregiving services focused on dementia, in a city in the State of Sao Paulo. All ethical guidelines were followed. In all, 51 CHW were evaluated. Semi-structured interviews were conducted. The data analysis was based on content analysis. In response to the question, What does elderly mean, for you?, the majority of the workers associated old age with chronologically advanced age and with negative aspects of aging, such as physical and social dependence. With respect to the concept of dementia, the majority of those interviewed defined dementia as a biological problem that affects the brain, compromising memory functions and resulting in dependency. The results demonstrate the need for an educational program for CHW, in the area of gerontology. PMID- 20964059 TI - [The Surveillance in Health Basic: perspectives to reach the Surveillance in Health]. AB - The Surveillance in Health is constituted as an Assistance Model with potential to reorganize the working processes. This study was developed to identify and analyze surveillance practices in the Primary Health Care field, in a region of Sao Paulo City-Brazil. Interviews were performed with 14 individual, from February to April 2006: health workers and administrators who had been operating in the Epidemiologic Surveillance area of health basic units. The speeches were analyzed based on the social theory of the health-disease process and by the materialistic interpretation of the labor process. It was verified that their work was fragmented. The precariousness of the working structure, the lack of professional qualification and of management-political support, besides the lack of participation from the population were all identified as barriers that limit health surveillance practices. It was concluded that, in a local level, there is a potential to change the organization of the working process in health and meet the health needs of the population through a Health Surveillance Model. PMID- 20964060 TI - [Emergency Psychiatric Service in general hospitals: a retrospective study]. AB - The Emergency Psychiatric Service in General Hospitals (SEPHG, acronym in Portuguese) is a service included in the psychiatric reform movement. The purpose of the present study was to characterize patients with psychological distress treated at the Dr. Estevam SEPHG, located in Sobral, Cear state. This exploratory study was performed using documental analyses with a quantitative approach, and involved 191 clients treated at the referred SEPHG from January to December 2007. Data collection was performed using a client register book, which contained information obtained from the patients' medical record. There was a predominance of male patients (70.15%), aged 30-49 years (48.71%) and single (74.86%). Most patients were from the city of Sobral (69.64%). In 42.40% of cases, the diagnosis was of alcohol use/abuse. Most clients (66.50%) sought the service voluntarily. After being evaluated at the SEPHG, 43.45% of patients were referred to the local Center for Psychosocial Care-Alcohol and other Drugs. The results emphasize the importance of mental health. PMID- 20964061 TI - [Conflict situations experienced at hospital: the view of nursing technicians and auxiliaries]. AB - This study was developed at the Federal University of Minas Gerais Hospital with the purpose to analyze how nurses deal with the conflicts that occur in the work environment. The research was developed in two data collection stages. Authors applied a questionnaire, followed by a semi-structured interview. Data was organized according to their thematic content. According to the interviewed workers, the term conflict has a negative denotation. Some subjects pointed out the following types of conflict: intrapersonal, interpersonal and intergroup. Some of them also reported that nurses are prepared to face conflict situations using dialogue and negotiation. However, others answered that nurses are not prepared, due to professional inexperience and the lack of interaction with the team. Authors considered that these results must encourage nurses towards reflecting about their management practice. PMID- 20964062 TI - [Maternal and perinatal outcomes of an alongside hospital birth center in the city of Sao Paulo, Brazil]. AB - The aim of this study was to describe the maternal and perinatal results of care in the alongside hospital birth center Casa de Maria (CPN-CM), located in the city of Sao Paulo. The random sample included 991 women and their newborns, attended between 2003 and 2006. The results showed that 92.2% of women had a companion of her choice during childbirth and the practices commonly used were shower or immersion bath (92.9%), amniotomy (62.6%), walking (47.6%), massage comfort (29.8%) and episiotomy (25.7%). Regarding newborns, 99.9% of them had Apgar scores =7 in the fifth minute, 9.3% received aspiration of the upper airway, no one needed to be intubated and 1.4% were removed to the hospital. The model of care in the CPN-CM provides maternal and perinatal outcomes expected for low obstetric risk women, and means a safe option and less interventionist model in normal childbirth. PMID- 20964063 TI - [Medication advertisements in the illustrated press and the image of Brazilian nurses (1920-1925)]. AB - This is a historical and social study about the symbolic effect of medication advertisements presented by women using object representations used by nurses, featured on Fon-Fon Magazine, which describes the medication advertisements featured on Fon-Fon Magazine; analyzes the object representations of the nurse image present in the referred advertisements and discusses on the symbolic effect of those representations on the consumption of medication by the Brazilian society. The document sources were in print, iconographic and literature referring to the History of Brazil, the Press, Advertising and of Nursing. The medication advertisements, analyzed using an analysis matrix based on concepts of semiotics, were obtained from the Fon-Fon Magazine. The study showed that the analyzed advertisements invested in object representations used by nurses to gain reliability regarding the medication being announced. PMID- 20964064 TI - [Patient safety in oncology surgery: experience of the Sao Paulo State Cancer Institute]. AB - Patient safety concerns in surgery are increasing. The frequency of surgery related adverse events and errors is high, and most could be avoided. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) proposed the Universal Protocol (UP-JCAHO) for preventing wrong site, wrong procedure, and wrong person surgery. In Brazil, very few health-care institutions have adopted this Protocol. Thus, there is a need to improve its dissemination and assess its effectiveness. The aim of the present study was to report the experiences of the Sao Paulo State Cancer Institute (ICESP, acronym in Portuguese) in implementing the UP-JCAHO. The Protocol comprises three steps: pre-operative verification process, marking the operative site and Time out immediately before starting the procedure. The ICESP surgical center (SC) has been functioning since November 2008. The UP-JCAHO is applied to all surgeries. A total 1019 surgeries were performed up to June 2009. No errors or adverse events were registered. The implementation of the UP-JCAHO is simple. It can be a useful tool to prevent error and adverse events in SC. PMID- 20964065 TI - [Family groups in nursing graduation teaching practice]. AB - The centers of psychosocial care (CAPS, acronym in Portuguese) are strategic devices for mental health care currently available in Brazil. Nurses are professionals required to compose the minimum staff of this device, which values the group activities involving users. This study presents a report of the experience of nursing undergraduates from Universidade Federal do Mato Grosso (UFMT) on their conducting waiting-room group sessions with relatives of users of a CAPS from Cuiaba, Mato Grosso state. This experience is justified by the fact that nursing students have few opportunities to develop group approach abilities during their graduation course, which focuses mainly on clinical individual care. The aim of the experience was to provide theoretical-practical learning of all the work stages of group work: recognizing the need and possibility of conducting the activity, planning, coordination and group evaluation. The results confirm the need and possibility of performing group experiences in mental health care and in nursing education. PMID- 20964066 TI - [Homophobia among nursing students]. AB - Homophobia is defined as a general negative attitude towards homosexual persons, with implications on public health. This fact has been less investigated among nursing students. The objective of this review was to learn about the prevalence of homophobia and its associated variables among nursing students. A systematic review was performed on original articles published in EBSCO, Imbiomed, LILACS, MEDLINE, Ovid, and ProQuest, including articles published between 1998 and 2008 in English, Portuguese and Spanish. Keywords used were homophobia, homosexuality, and nursing students. Descriptive analysis was performed. Eight studies were analyzed. The incidence of homophobia in nursing students is between 7% and 16%. Homophobia is more common among males and religious conservatism people. Homophobia is quite frequent in nursing students. This negative attitude toward homosexuality may affect services and care giving by nursing professions and could have negative implications in nursing practice. PMID- 20964067 TI - [The "morning after pill": the impact of the Supreme Court ruling in the medical field]. AB - This article summarizes the Court's ruling regarding the constitutionality of the Official Norm "NOM-046-SSA2-2005". Jalisco's Governor challenged the validity of the referred norm arguing that it was against articles 4, 5, 14, 16, 20, 21, 29, 31-V, 49, 73, 74, 89-I, 123, 124 y 133 of the Federal Constitution. The Supreme Court disregarded Governor's claim and determined that the members of the National Health System are obliged to offer and give the "day after pill" to sexual violation victims. According to article 5 of General Health Law, the National Health System includes private and public hospitals, whether they are local or federal. This means that all these health institutions have the obligation to observe the dispositions contained in the appealed Official Norm Given the significance of the Court's ruling in the medical sphere, in this article the most relevant issues of the Court decision and its implications are analyzed. PMID- 20964068 TI - [Comparison of school trajectories as a complement in the evaluation of curricula changes]. AB - OBJECTIVE: Analyze the effect of curricular changes introduced at the beginning of the 2004-2005 academic year on the trajectory of students attending the School of Medicine at the UASLP. METHODS: We compared the academic trajectories of the first four years of undergraduate studies among a cohort of students (1999-2004) and analyzed the following indicators: dropout, failure, promotion, academic performance, and terminal efficiency. The 1999 cohort started before the curricular change, the 2004 cohort, after. RESULTS: For the first year of study: the 2004 cohort lost more students (p = 0.003), had higher rates of poor school performance (p < 0.001) and failure (p = 0.006) rates, lower promotion (p = 0.003) rates, and a trend towards a lower dropout rate, but without statistical significance (p = 0.107). It also displayed higher academic performance in the first (p = 0.019), second (p = 0.001), and third (p = 0.001) years. Terminal efficiency at the end of the fourth year was lower for the 2004 cohort (p = 0.024). CONCLUSIONS: The curricular change aggravated dropout, failure, and low promotion problems in the first year and, consequently, had an effect on terminal efficiency. Yet it also helped improve academic performance during the first three years. PMID- 20964069 TI - [Tooth loss and periodontal status variables among policemen from Campeche, Mexico]. AB - OBJECTIVE: Identify the variables associated with periodontal status and tooth loss among a sample of adults. MATERIAL AND METHODS: We carried out a cross sectional study among 161 policemen. Our sample was representative of socioeconomics status and lifestyle among policemen in Campeche, Mexico. All periodontal clinical examinations were assessed using the Florida Probe System using a fixed dental chair and one examiner. The variables we measured included presence of dental plaque, calculus, probing deep, gingival insertion, loss of attachment, gingival retraction, suppuration, and probing blood. We examined six sites surrounding all teeth available in the mouth (maximum 168 sites and excluded third molars). Statistical analyses were performed with STATA 8.2 using a bivariate negative binomial regression model due to over-dispersion in the dependent variable. RESULTS: The mean age was 38.36 +/- 10.99 (range: 20-78). The mean of tooth and sites examined in participants was 24.45 +/- 4.63 and 146.72 +/ 27.80, respectively. The prevalence of tooth loss was 73.3%. 571 teeth were missing and the overall mean of missing teeth was 3.55 +/- 4.63 and within subjects with tooth loss was 4.84 +/- 4.80. The prevalence of functional dentition (21 tooth or more) was 83.8%. To have > 20% gingivitis, > 5% of sites with probing deep > or = 4 mm, > 5% of sites with gingival retraction, > 70% of sites with attachment loss > 2 mm, and each unit of age increase the mean expected of tooth loss by 70.6%, 41.8, 156.4%, 86.9%, and 3.6%, respectively. CONCLUSIONS: Our study findings confirm that lost teeth are common among study participants. Higher prevalence and average of tooth loss was observed among this adult population. Several variables of periodontal status were associated with tooth loss. PMID- 20964070 TI - [Bacterial drug resistance and etiology of non-complicated urinary tract infections]. AB - INTRODUCTION: Bacterial resistance to antibiotics is associated with morbidity, mortality, and an increase in cost. Our objective was to assess bacterial resistance from cultures of patients with non-complicated urinary tract infection (UTI). METHODS: We analyzed antibiotic resistance using the VITEK-II system among patients attending the internal medicine unit with non-complicated UTI. RESULTS: 1,479 urine cultures were performed; we excluded: 98 due to contamination, 924 had no bacterial growth, and 57 had missing data. Among the 404 samples that were positive, 240 were found among out patients and 164 among hospitalized patients. E coli were the most frequent pathogen, followed by Enterococcus, and K pneumonia, in out patients; E coli, P aeruginosa, and fungal infections (23% of cases) in hospitalized patients. Samples with E coli among out patients displayed resistance of 50% to fluoroquinolones and 55% to sulfas. Among hospitalized patients, resistance was observed in 71 and 66% respectively. Resistance to P aeruginosa was 38% for amynoglucosides and carbapenems and 100% for piperacillin; Enterococcus had 50% for fluoroquinolones. CONCLUSION: E. coli is the most common pathogen among UTI patients. We must adapt guidelines to recommend antibiotics and design a comprehensive control program to reduce the high levels of bacterial antibiotic resistance among our population. PMID- 20964071 TI - [Association between penoscopy data and urethral cytology among men with partners who had cervical lesions associated with human papilloma virus]. AB - OBJECTIVE: The aim of this study was to identify human papillomavirus lesions in a group of men whose sexual partners had cervical intraepithelial lesions associated with low-grade HPV confirmed by PCR-DNA. We carried out a correlation between urethral cytology penoscopy data and PCR-DNA results. METHODS: We studied 100 male volunteers with an age range of 21-45 (median 30 years) and divided them into two groups according to the identified virus; two groups were conformed, a high risk and a low risk virus. RESULTS: For the penoscopy data we included the following: type of hirsutoide papillomatosis in 40 (40%) cases, common warts in 24 (24%) cases, papillomatosis in plaque in 6 (6%) and 47% displayed an urethra with a foamy appearance. In urethral cytology we did not find evidence of koilocytes in 58% and 42% showed no koilocytes. Inflammation was observed in 44 cases; an added infection was noted among 60 cases. Depending on the type of infection we found non-specific bacteria in 8%, bacillary in 10%, mixed infection in 12%, changes suggestive of Gardnerella vs 24%, and Chlamydia treatment in 6%. Dyskeratosis was noted in 47% of study participants. 67 patients were treated with imiquimod cream 5% and 33% received non-specific treatment. Regarding improvement we noted that 67 (67%) cases showed 46/67 hypochromic stains after treatment with imiquimod. Disappearance of the lesions in the penis were observed among 65 cases and only 35 remained with lesions. Regarding high-risk HPV we found a significant difference in odor (p = .004, phi = .004), urethral discharge (p = .007), pearly papules in raphe (p = .023), with inflammation, dyskeratosis and added infection (p = .000 respectively). We also noted hypochromic spots or skin discoloration after treatment with imiquimod among 5% of subjects (p = .046). CONCLUSIONS: In our study we observed that high-risk HPV is associated with increased penile lesions and frank evidence of koilocytes in urethral cytology. We recommend that sexual partners of women with cervical lesions associated with HPV complete a control study with penoscopy data and urethral cytology, since most have concurrent infections and lesions that can treated in early stages. PMID- 20964072 TI - [Dietary trans fatty acids and its metabolic implications]. AB - Fats are important nutrients in our diet, they have wide chemical properties that drive diverse metabolic effects. The trans fatty acids (TFA) are common compounds found in industrialized food, and recent research has shown they should be avoided due to their increased risk of cardiovascular disease (CVD). Some of the mechanisms involved include: reduction of c-HDL concentration, increase of low density lipoprotein, Lp (a), triglycerides; disturbance in prostaglandin balance and they may also promote insulin resistance. Obese subjects are prone to increased CVD risk associated with a state of chronic inflammation that can be worsened by TFA intake. The US population consumes approximately 5.3 g TFA per day (2.6% of their total energy intake and 7.4% of their fat energy). Recently, WHO recommendations suggest the intake of TFA should be lower than 1% of energy per day. Current fast food industry products have to decrease the amount of TFA content, and the experience from different countries shows that the elimination of trans fatty acids is a cost effective and feasible public health intervention. PMID- 20964073 TI - [A 63 year old male with abdominal pain and atrial fibrillation]. PMID- 20964074 TI - [Chronic nasal obstruction: ethmoidal encephalocele in an adult patient]. AB - Nasal obstruction is a frequent cause of referral to the ear, nose and throat specialist. When this symptom is resistant to medical management and common causes have been ruled out, the presence of neural structures should be investigated In the nasoethmoidal meningoencephalocele, a congenital defect of the ethmoid lamina cribrosa allows the herniation of the intracranial contents into the nasal fossa. The key to clinical diagnosis is the presence of nasal obstruction with rhinorrhea and recurrent meningitis. We describe the case of a 33-year old female who was long treated for nasal polyposis and underwent a successful surgical treatment of ethmoidal meningoencephalocele. PMID- 20964075 TI - [Tribute to Dr. Manuel Carpio on the CL anniversary of his death]. AB - This year marks de CL anniversary of de death of Dr. Don Manuel Carpio (1791 1860), native Cosamaloapan, Veracruz, Mexico. The spirit that is researched and practiced medicine in Mexico would not be so gifted with humanism, without the contributions of mister Carpio, doctor who devotes his life to academia and research, putting aside traditional medicine, to take the decisive step to anatomic-pathological medicine. This paper aims to capture the character of Dr. Carpio, forged in an emerging Mexico, where medicine just left behind atavistic traditions. PMID- 20964076 TI - [The unexpected: chronic renal insufficiency, parasitism, and selective advantage]. PMID- 20964077 TI - [The increase of effectiveness of a clinical lecture]. PMID- 20964078 TI - [The treatment costume of axial loading in the neurorehabilitation]. PMID- 20964079 TI - [Effectiveness of rehabilitation measures in the acute period of cerebral ischemic stroke]. PMID- 20964081 TI - [Problem of neuroplasticity in neurology]. PMID- 20964080 TI - [Xeomin in the treatment of poststroke spasticity]. PMID- 20964082 TI - [Neuropsychiatric disorders in systemic lupus erythematosus]. PMID- 20964083 TI - [Does psychiatry need psychiatrists?]. PMID- 20964084 TI - Seduction, prostitution, and the control of female desire in popular Antebellum fiction. AB - During the antebellum era, increased attention to the prostitute coincided with a prevalent conception of women as, in Nancy Cott's words, essentially "passionless" unless aroused by sincere romantic love. Yet it seems paradoxical that this ideology existed alongside an increasing awareness of women whose livelihood depended upon manufacturing and marketing sexual desire. In this essay I argue that the prostitute became an object of antebellum fascination and concern less because of her defiance of the ideology of passionlessness and more because of the extent to which she could be made to reinforce this ideology. Casting the prostitute as a victim of seduction preserved predominant beliefs about the dependency of female desire on male impetus. The popular novels of George Thompson and Osgood Bradbury elide the sexual autonomy of the prostitute by making her a victim of men, but they do so in different ways. Thompson employs two variants of the seduction narrative that differ according to class, but both result in the subjection of female desire to male control. His indigent females are chaste victims of violent forms of sexual exploitation, while his licentious rich women reveal an inherent tendency toward monogamy or an inability to command their own aberrant desires. Bradbury, in contrast, is remarkable for his willingness to allow fallen women and prostitutes the chance to reform. As refreshingly progressive as Bradbury's novels seem, however, his adherence to the seduction narrative ultimately suggests that female desire is doomed to dissatisfaction unless properly channeled toward working-class men. PMID- 20964086 TI - "This immense expense of art": George Eliot and John Ruskin on consumption and the limits of sympathy. AB - This essay attempts to better our understanding of George Eliot's conservatism by examining a body of ideas about consumption and moral obligation that she and John Ruskin share. I use a discussion of consumer ethics to explore the moral logic of their conservatism by examining the role of the aesthetic within it. Economic consumption and the aesthetic are subjects inextricably connected, not just because the discourses of political economy and aesthetics have a shared origin in eighteenth-century moral philosophy, but also because the discourse of aesthetics has long served to legitimize select modes and acts of consumption. By marking out a limit where one may reasonably cease to sympathize and instead devote energy (and money) to personal gratification, the treatment of consumption in George Eliot's Middlemarch (1871) offers an important articulation of moral thought. Eliot suggests that aesthetic pleasure can make consumption morally defensible, but she also anticipates Pierre Bourdieu's critique of the aesthetic: her novel represents both the display of cultural capital and the exercise of the aesthetic disposition as ways of maintaining social and economic hierarchies. She thus at once critiques and participates in the system within which the aesthetic functions to preserve social and political stasis. Using John Ruskin's economic writings to expose Middlemarch as a novel of consumer ethics, this essay examines Eliot's representation of personal economic consumption as an emergent mode of social and political agency that might operate productively within that stasis. PMID- 20964087 TI - A primer on pain relief. PMID- 20964089 TI - Unique tumor-associated molecule supports the growth and progression of oral carcinoma. PMID- 20964088 TI - Health insurance: how to pick a plan in these changing times. PMID- 20964090 TI - High clusterin levels predate evidence of Alzheimer's disease. PMID- 20964091 TI - Is a generic UK e-portfolio for dentistry desirable and achievable? PMID- 20964092 TI - In Memoriam: Anna-Marie Gron, 1928-2010. PMID- 20964093 TI - Keeping the doors to the community open. AB - Polls show that Americans of all races now believe that social class and national origin are more potent bases for discrimination than race. However, this assessment is rendered more complicated by (a) the high rate of exclusion of people on the basis of behavioral characteristics and (b) the strikingly disparate impact of such decisions on people of color. America's high rates of (a) incarceration in the criminal and juvenile justice system, (b) visa denials, detention, and removal in the immigration system, and (c) suspensions and expulsions in the schools all have the effect of excluding many Latinos and African Americans from ordinary life in the community. Although norms of inclusion are adaptive for communities, such an approach is intrinsically difficult to achieve. Attention should be given to (a) facilitation of the exercise of moral leadership and (b) design of settings that ''demand'' notice of, and care for, all participants. PMID- 20964094 TI - Innovations, respect, and personal renewal. PMID- 20964095 TI - Health situation in Indonesian penitentiary. PMID- 20964096 TI - HIV and injection drugs use in Indonesia. PMID- 20964097 TI - Year in review:communicable disease surveillance, NSW, 2009. PMID- 20964098 TI - Primary health care in the age of reform. PMID- 20964099 TI - Health disparities and the Affordable Care Act. PMID- 20964100 TI - Waterborne disease among Aboriginal people. PMID- 20964101 TI - Health costs: a new look at payment reform options. PMID- 20964102 TI - Dental caries in children. PMID- 20964103 TI - Ureteritis cystica: an interesting case with diagnostic dilemma. AB - Ureteritis cystica is a rare, benign, proliferative condition. We report the case of a 51-year-old female who complained of dysuria and frequency for the last 10 years. The symptoms, however, increased in severity and frequency over the past one year. Urine culture and sensitivity showed presence of Escherichia Coli which was sensitive to augmentin and ciproflaxocin. The urinary tract ultrasonography and intravenous urography revealed bladder diverticula with multiple small, smooth well defects with sharp borders that protruded into the lumen along the proximal and mid left ureter. This finding was later confirmed by retrograde pyelogram. She was treated and currently is on long term antibiotic therapy. The diagnostic features and management of ureteritis cystic is being discussed in detail. PMID- 20964104 TI - Schools' mental health services and young children's emotions, behavior, and learning. AB - Recent empirical research has found that children's noncognitive skills play a critical role in their own success, young children's behavioral and psychological disorders can severely harm their future outcomes, and disruptive students harm the behavior and learning of their classmates. Yet relatively little is known about wide-scale interventions designed to improve children's behavior and mental health. This is the first nationally representative study of the provision, financing, and impact of school-site mental health services for young children. Elementary school counselors are school employees who provide mental health services to all types of students, typically meeting with students one-on-one or in small groups. Given counselors' nonrandom assignment to schools, it is particularly challenging to estimate the impact of these counselors on student outcomes. First, cross-state differences in policies provide descriptive evidence that students in states with more aggressive elementary counseling policies make greater test score gains and are less likely to report internalizing or externalizing problem behaviors compared to students with similar observed characteristics in similar schools in other states. Next, difference-in differences estimates exploiting both the timing and the targeted grade levels of states' counseling policy changes provide evidence that elementary counselors substantially influence teachers' perceptions of school climate. The adoption of state-funded counselor subsidies or minimum counselor-student ratios reduces the fraction of teachers reporting that their instruction suffers due to student misbehavior and reduces the fractions reporting problems with students physically fighting each other, cutting class, stealing, or using drugs. These findings imply that there may be substantial public and private benefits derived from providing additional elementary school counselors. PMID- 20964105 TI - Molecular diagnosis of familial hypercholesterolemia: an important tool for cardiovascular risk stratification. AB - Familial hypercholesterolemia (FH) is associated with an increased risk of premature coronary heart disease. Molecular identification of these patients can reduce the burden of mortality from cardiovascular disorders simply by the correct identification of the disease early in life, followed by counseling and appropriate lifestyle modifications, and therapeutic measures when required. Recent studies show that, in Portugal, this disease is severely under-diagnosed. After more than 10 years of research through the Portuguese FH Study, it is now possible to translate the original research results into clinical application. AIMS: The main aims of the present work were to determine whether clinical characterization is sufficient to identify these individuals at high risk of developing CHD and to evaluate the clinical applicability of molecular diagnosis for FH. METHODS: All patients described in this study were recruited for the Portuguese FH Study. The diagnostic criteria used to select the index patients were adapted from the Simon Broome Heart Research Trust. To analyze the usefulness of the molecular diagnosis, graphs of total and LDL cholesterol values by age were constructed for 622 possible FH patients. The lipid profile of patients genetically identified as having FH, before and under medication, were analyzed to assess whether these patients were receiving appropriate treatment. The data are shown separately for children and adults and for female and male propositi (index cases and hypercholesterolemic relatives), both with and without a detectable mutation in the LDLR gene. RESULTS: The Portuguese FH Study has already genetically identified 404 individuals (171 index patients and 233 relatives) among more than one thousand individuals sent for study. A total of 78 different mutations in the LDLR gene were found in 171 index patients, 2 different mutations were found in the apoB gene of 4 patients and 2 patients had a unique PCSK9 mutation. Statistical analysis revealed that there are significant differences between total cholesterol (p < 0.001) and apoB (p = 0.026) values in the group of children (male and female) with and without a mutation in LDLR. For female children LDL values were also significantly different (p < 0.001) between subgroups but for male children this difference did not reach statistical significance. In adult women there is a statistically significant difference for total cholesterol (p = 0.049), LDL cholesterol (p = 0.031) and apoB (p = 0.003) values in the subgroups with and without a LDLR mutation. In adult males there is a statistical difference for total cholesterol (p = 0.002). LDL cholesterol (p = 0.003) and apoB (p = 0.0023) in subgroups with and without an LDLR mutation. Nevertheless there was considerable dispersion of values and individually it is not possible to distinguish between patients with and without a mutation in the LDLR gene, based only on lipid profile. CONCLUSIONS: By analysis of the clinical data of 696 possible FH patients, the present report shows evidence that clinical characterization is not sufficient to distinguish between patients with genetic or environmental dyslipidemia, and so molecular diagnosis is useful in clinical practice, allowing correct identification of FH patients and their relatives, and the early implementation of therapeutic measures to reduce the elevated cardiovascular risk of these patients. In general, molecular diagnosis of FH is feasible and could be obtained in 1-2 months if the technology is available. In Portugal the test will be offered to the population by our Institute at a cost of about 500 euros, like many other genetic tests or exams such as nuclear magnetic resonance. PMID- 20964106 TI - Knowledge, behavior and ethical responsibility of health professionals with regard to smoking. AB - OBJECTIVE: This is the first study after the implementation of a more restrictive Tobacco Law in Portugal, carried out in collaboration with the Program for Prevention and Treatment of Smoking of the Northern Region Health Authority. The aim of the study was to characterize the attitudes and practices of health professionals with regard to tobacco consumption, given their importance in smoking reduction. The high prevalence of risk factors associated with circulatory diseases, particularly smoking, highlights the need for preventive measures. METHODS: This was a cross-sectional study assessing knowledge of the harmful effects of tobacco consumption and exposure to environmental tobacco smoke, ethical and professional behavior, and agreement with tobacco control measures. Participants were 101 physicians and 524 nurses from the primary health centers (PHCs) and Hospital S. Joao in the city of Porto. RESULTS: Smoking rates of 23.1% and 13.0% were found among nurses and physicians, respectively. There was a lower proportion of smokers in PHCs (14.5% vs. 23.9%, p = 0.014). Most participants agreed with prohibition of smoking inside and outside the building (70.7% vs. 53.3%), but smokers were more skeptical regarding the benefits, especially nurses. Knowledge of the consequences of tobacco consumption and environmental tobacco smoke was reasonable, but 40.0% of physicians and only 26.5% of nurses did not agree that ventilation systems can eliminate tobacco smoke (p = 0.009). Most participants acknowledged the inappropriateness of smoking in the presence of patients. In PHCs there was a higher percentage of health professionals who saw themselves as role models (80.6% vs. 66.7%, p = 0.001), and of nurses who agreed with the inappropriateness of smoking in the presence of the public (61.9% vs. 42.3%, p = 0.001). Health care professionals supported tobacco control programs, although smokers were less supportive. In PHCs there was a higher percentage of professionals who received training on tobacco, and this appears to have had some impact on nurses' belief that they are seen as role models (OR = 2.431, p = 0.024). DISCUSSION AND CONCLUSIONS: These findings support the need for new campaigns to reduce smoking among health care professionals. The reasons for their skepticism concerning their ethical responsibility must be clarified. Greater investment is required in training on tobacco for pre- and post-graduate health professionals, in order to increase their awareness of the importance of their role in reducing tobacco consumption in society. PMID- 20964107 TI - Acute coronary syndrome in young adults. AB - INTRODUCTION: The aim of this study was to assess the features of acute coronary syndrome (ACS) in patients younger than 46 years of age. METHODS: This was a retrospective study of clinical features, complications and diagnostic and therapeutic strategies of patients hospitalized between 1999 and 2007 with a diagnosis of ACS in a non-tertiary hospital. Data were collected from clinical records. RESULTS: The study population included 128 patients. The male/female ratio was 94%/6% and mean age was 40 +/- 3.9 years. The distribution of ACS was as follows: ST-elevation acute myocardial infarction (AMI) 69%, non-ST elevation AMI 20%, unstable angina 9%, AMI with undetermined ECG 1%, and Prinzmetal angina 1%. The prevalence of cardiovascular risk factors was as follows: smoking 82.8%, dyslipidemia 42.2%, hypertension 28.9%, and diabetes 4.7%. Thrombolysis was the main myocardial reperfusion therapy, used in 76.1%. Echocardiography during hospitalization revealed normal left ventricular (LV) function in 66.1%, mild LV dysfunction in 14.5%, moderate LV dysfunction in 10.5% and severe LV dysfunction in 8.9%. Predischarge exercise testing was performed in 64.1% of patients and was normal in 85.4%, abnormal in 13.4% and inconclusive in 1.2%. Only 3.9% underwent single photon emission computed tomography (SPECT) myocardial perfusion imaging, which was positive for ischemia in 60% and negative in 40%. Elective catheterization was performed in 22.7% of patients; 44.9% underwent percutaneous coronary intervention and 6.9% were referred for cardiac surgery. Medication prescribed at discharge was as follows: aspirin 97.7%, beta-blockers 90.6%, statins 84.4%, angiotensin-converting enzyme inhibitors 50% and clopidogrel 25%. Arrhythmias were the main complication of ACS and no deaths occurred during hospitalization. CONCLUSIONS: As expected, ACS in young adults had a higher incidence in males. ST-elevation AMI was the main type. Most patients were smokers. Thrombolysis was the main myocardial reperfusion therapy. Echocardiography and predischarge exercise testing were the main complementary diagnostic tests for risk stratification. Prescription rates of drugs that improve prognosis were high. PMID- 20964108 TI - Acute coronary syndrome in younger patients: an avoidable atherothrombotic complication. PMID- 20964109 TI - Sensitivity and specificity of the Manchester Triage System for patients with acute coronary syndrome. AB - INTRODUCTION: Monitoring the performance of triage systems is essential to optimize their usefulness in each hospital. The objective of this study was to assess the sensitivity of the Manchester Triage System in assigning high priority to patients with acute coronary syndrome, and the sensitivity and specificity of the combinations of flowcharts and discriminators routinely used for triage in the Emergency Department of Hospital de S. Joao, Porto. METHODS: We analyzed a systematic sample of one third of emergency department episodes in 2007, corresponding to 53,039 episodes, of which 307 were cases of acute coronary syndrome. For each episode, we considered the final diagnosis by the Emergency Department attending physician, which was confirmed in 95% of cases. The combinations of flowchart and discriminators suggestive of acute coronary syndrome were defined, based on typical symptoms, including precordial chest pain with or without radiation and/or syncope. RESULTS: The sensitivity of the Manchester Triage System in assigning high priority (immediate--red, or very urgent--orange) to patients with acute coronary syndrome was 87.3% (95% confidence interval [CI]: 83.1-90.6). The proportion of false negatives was higher in extreme age-groups. The sensitivity of combinations of flowchart and discriminators suggestive of acute coronary syndrome was 74.3% (95% CI: 69.1 78.8), lower in women (67.3% vs. 77.7%), and the specificity was 97.4% (95% CI: 97.2-97.5). The likelihood ratio of combinations of flowchart and discriminators suggestive of acute coronary syndrome was 28.3 (95% CI: 26.0-30.8) and that of other combinations was 0.26 (95% CI: 0.22-0.32), less informative in ruling out acute coronary syndrome in women (0.33 vs. 0.23). DISCUSSION: The main limitations of this study derive from the impossibility of including only patients who came directly to this Emergency Department and of testing the validity of the final diagnosis when acute coronary syndrome was not identified in the Emergency Department. However, using electronic data records completed as a matter of routine enabled analysis of a large database, which reflects the practical value of the Manchester Triage System in this context, and most cases identified as acute coronary syndrome were confirmed. CONCLUSIONS: The Manchester Triage System has a high sensitivity in assigning high priority (immediate/very urgent) to patients with acute coronary syndrome. The combinations of flowchart and discriminators defined as suggestive of acute coronary syndrome have very high specificity and moderate sensitivity, but the system has the potential to become more sensitive with no loss in specificity. PMID- 20964110 TI - Coronary artery bypass grafting in octogenarians: long-term results. AB - INTRODUCTION: As surgical revascularization is becoming more frequent in octogenarians, we reviewed our data to analyze the impact of coronary artery bypass grafting on short- and long-term morbidity and mortality. METHODS: We performed a retrospective study of 101 consecutive patients aged 80 years or older, who underwent coronary artery bypass in a single cardiac center between January 2002 and December 2007. The patients were divided into two groups: off pump (64.4%) and on-pump (35.6%), depending on whether the surgery was performed with cardiopulmonary bypass. Early results and those up to 6 years after surgery were assessed. RESULTS: Baseline characteristics were similar between the groups and follow-up was 90% complete. There were no significant differences between groups in mean age (off-pump = 82.7 +/- 18 years vs. on-pump = 82.2 +/- 2.2 years; p = NS) or in logistic EuroSCORE (off-pump = 11.2 +/- 12.3 vs. on-pump = 8.5 +/- 5.1; p = NS). However, the off-pump group had less complete revascularization (off-pump = 43.1% vs. on-pump = 83.3%, p = 0.0001) and shorter mean hospital stay (off-pump = 9.3 +/- 5.4 days vs. on-pump = 11.5 +/- 7.3 days; p = 0.09). Both groups showed low hospital mortality (off-pump = 1.5% vs. on-pump = 2.8%, p = NS). At 6-year follow-up, off-pump surgery patients had the same late prognosis (total survival: off-pump = 80% vs. on-pump = 77.4%, p = NS; cardiovascular mortality: off-pump = 15% vs. on-pump = 16.1%, p = NS). CONCLUSION: In octogenarians coronary artery bypass grafting had excellent results. The off-pump technique, even though it can mean less complete revascularization, leads to shorter hospital stay and has the same 6-year results as in patients operated under cardiopulmonary bypass. PMID- 20964111 TI - Impact of obesity on results after primary angioplasty in patients with ST segment elevation acute myocardial infarction. AB - INTRODUCTION: Obesity is an important risk factor for the development of diabetes, hypertension, coronary disease, left ventricular dysfunction, stroke and cardiac arrhythmias. Paradoxically, previous studies in patients undergoing elective coronary angioplasty showed a reduction in hospital and long-term mortality in obese patients. The relation with body mass index (BMI) has been less studied in the context of primary angioplasty. OBJECTIVES: To evaluate the impact of obesity on the results of ST-segment elevation acute myocardial infarction treated by primary angioplasty. METHODS: This was a study of 464 consecutive patients with ST-segment elevation acute myocardial infarction undergoing primary angioplasty, 78% male, mean age 61 +/- 13 years. We assessed in-hospital, 30-day and one-year mortality according to BMI. Patients were divided into three groups according to BMI: normal--18-24.9 kg/m2 (n = 171); overweight--25-29.9 kg/m2 (n = 204); and obese-- > 30 kg/m2 (n = 89). RESULTS: Obese patients were younger (ANOVA, p < 0.001) and more frequently male (p = 0.014), with more hypertension (p = 0.001) and dyslipidemia (p = 0.006). There were no differences in the prevalence of diabetes, previous cardiac history, heart failure on admission, anterior location, multivessel disease, peak total CK or medication prescribed, except that obese patients received more beta-blockers (p = 0.049). In-hospital mortality was 9.9% for patients with normal BMI, 3.4% for overweight patients and 6.7% for obese patients (p = 0.038). Mortality at 30 days was 11 4.4% and 7.8% (p = 0.032) and at one year 12.9%, 4.9% and 9% (p = 0.023), respectively. On univariate analysis, overweight was the only BMI category with a protective effect; however, after multivariate logistic regression analysis, adjusted for confounding variables, none of the BMI categories could independently predict outcome. CONCLUSIONS: Overweight patients had a better prognosis after primary angioplasty for ST-segment elevation acute myocardial infarction compared with other BMI categories, but this was dependent on other potentially confounding variables. PMID- 20964112 TI - Echocardiographic variables predictive of appropriate therapies for ventricular tachyarrhythmia in patients undergoing combined cardiac resynchronization therapy. AB - INTRODUCTION: The significant risk of sudden arrhythmic death in patients with congestive heart failure and electromechanical ventricular dyssynchrony has led to increased use of combined cardiac resynchronization therapy defibrillator (CRT D) devices. OBJECTIVES: To evaluate the echocardiographic variables in patients undergoing CRT-D that predict the occurrence of appropriate therapies (AT) for ventricular tachyarrhythmia. METHODS: We analyzed 38 consecutive patients (mean age 60 +/- 12 years, 63% male) with echocardiographic evaluation before and 6 months after CRT-D implantation. Patients with AT were identified in a mean follow-up of 471 +/- 323 days. A standard echocardiographic study was performed including tissue Doppler imaging (TDI). Responders were defined as patients with improvement in NYHA class of < or = 1 in the first six months, and reverse remodeling as a decrease in left ventricular end-systolic volume of < or = 15% and/or an increase in left ventricular ejection fraction of > 25%. RESULTS: The responder rate was 74%, and the reverse remodeling rate was 55%. AT occurred in 21% of patients, who presented with greater left ventricular end-diastolic internal diameter (LVEDD) before implantation (86 +/- 8 vs. 76 +/- 11 mm, p = 0.03) and at 6 months (81 +/- 8 vs. 72 +/- 14 mm, p = 0.08), and increased left ventricular end-systolic internal diameter (66 +/- 14 vs. 56 +/- 14 mm, p = 0.03) and lower ejection fraction (24 +/- 6 vs. 34 +/- 14%, p = 0.08) at 6 months. In the group with AT, the responder rate was lower (38 vs. 83%, p = 0.03), without significant differences in reverse remodeling (38% for the AT group vs. 60%, p = 0.426) or in the other variables. By univariate analysis, predictors of AT were LVEDD before implantation and E' after implantation. Age, gender, ischemic etiology, use of antiarrhythmic drugs, reverse remodeling and the other echocardiographic parameters did not predict AT. In multivariate logistic regression analysis, both LVEDD before implantation (OR 1.24, 95% CI 1.04-1.48, p = 0.019) and postimplantation E' (OR 0.27, 95% CI 0.09-0.76, p = 0.014) remained as independent predictors of AT. CONCLUSIONS: In patients undergoing CRT-D, episodes of ventricular tachyarrhythmia occur with high incidence, independently of echocardiographic response, with LVEDD before implantation and E' after implantation as the only independent predictors of AT in the medium-term. These results highlight the importance of combined devices with defibrillation capability. PMID- 20964113 TI - Marfan syndrome: clinical manifestations, pathophysiology and new outlook on drug therapy. AB - Marfan Syndrome (MFS) is a genetic disorder of the connective tissue with multisystemic manifestations, which typically involves the skeletal, cardiovascular and ocular systems. It is usually associated with fibrillin-1 (FBN1) gene mutations, an extracellular matrix protein, and its diagnosi requires the presence of several clinical criteria, called the Ghent criteria. Studies with animal models have helped understand some of the pathophysiologic mechanisms of the syndrome, and the core role of transforming growth factor, (TGF-beta) signalling pathways in these mutations. These findings created new therapeutic opportunities, like the use of losartan, known to have an antagonistic effect on TGF-beta. With the aging of this population, new clinical manifestations are expected, requiring close and continued MFS patient monitoring. PMID- 20964114 TI - The reduction of infarct size--forty years of research. AB - Advances in electrocardiography and enzymology in the 1940s and 1950s have provided better knowledge of the clinical evolution of myocardial infarction and recognition of the prognostic relevance of acute phase arrhythmias. This prompted the creation of intensive coronary care units in the subsequent decade. After the successful resolution of acute phase arrhythmias, it became clear that the myocardium necrotic area size was a determining factor in the long-term prognosis. The Killip-Kimball clinical classification in the 60s helped to clarify the role of infarct size on left ventricle (LV) dysfunction, from Class I for small infarcts to Class IV with major necrosis, (involving more than 30% of the LV free wall area, the majority of these being fatal). Along with these advances, a series of experimental studies have shown that myocardial ischemia depends on the oxygen supply-demand imbalance, highlighting the factors affecting oxygen consumption. The study of various physiological, pharmacological or mechanical interventions on these factors became the next step towards optimizing the supply-demand relation. Several animal experiments were conducted in the 1970s, followed by the first clinical studies to reduce infarct size, particularly by increasing the oxygen supply either with fibrinolytic agents or with mechanical coronary angioplasty. The clinical experience of coronary reperfusion showed that left ventricle function did not normalize in 30% of the patients. In spite of unblocking the epicardial vessel, demonstrated hemodynamically, no equivalent myocardial perfusion was observed in these studies. New concepts emerged such as reperfusion injury, microvascular dysfunction, "no-reflow" phenomenon, stunned myocardium, and hibernating myocardium, which have become the target of basic research and clinical investigation. The replication of these phenomena in experimental models has attempted on the one hand to improve characterization with the use of different technologies, e.g. contrast echocardiography, isotopic studies including positron tomography, and magnetic resonance. On the other hand it has tested new therapeutic approaches as adjuvants of coronary reperfusion. Reperfusion injury is responsible for 50% of infarct size, so it became the target of research on cardiac protection. Post-reperfusion arrhythmias, stunned myocardium, microvascular obstruction that translates into the "no-reflow" phenomenon, are reperfusion injury manifestations. Imaging technology developments made it possible to demonstrate that microvascular obstruction occurs in 40% of patients who underwent primary angioplasty. Several therapeutic approaches to prevent microembolization have been studied such as glycoprotein IIb/IIIa receptor blockers. Ischemic myocardium conditioning is one of the new strategies to reduce reperfusion injury. The concept of pre-conditioning, defined experimentally in 1986, establishes that multiple brief episodes of ischemia may protect the heart from a subsequent prolonged infarction. Several observations have proved that pre conditioning occurs in cardiac patients, for example, during coronary angioplasty and coronary bypass graft surgery, and so it is regarded as a promising approach to reducing infarct size. The concept of pre-conditioning was then enlarged by the demonstration, experimentally, that producing ischemia in a vascular bed could induce pre-conditioning in another vascular bed. Ischemia resulting from repeated successive insufflations of a blood pressure cuff on a lim, reduces myocardial necrosis after coronary angioplasty or coronary bypass graft surgery. This remote pre-conditioning seems to be a safe and effective non-invasive way of reducing the reperfusion injury. In 2002 a hypothesis was tested in studies on dogs that multiple repeated episodes of ischemia, produced in the beginning of reperfusion, would attenuate the reperfusion injury. This technique, called post conditioning, was first used in patients in 2005, in AMI reperfusion, with beneficial short and long-term results. In the last 15 years, a large number of clinical studies have been carried with different pharmacologic groups to explore association pre- and post-conditioning concepts. Four agents were studied in particular: adenosine, nicorandil, atrial natriuretic peptide, and statins. The most important studies are reviewed, calling attention to disparities in results and discussing possible causes of negative outcomes. Cyclosporine, recently tested, opens a new field of investigation since it inhibits mitochondrial permeability and may directly attenuate the reperfusion injury. Microvascular dysfunction occurs in many patients after coronary angioplasty and is caused, in the first place, by distal embolization. The purpose of thrombectomy is to reduce the probability of distal embolization during angioplasty and stent placement. Available devices for clinical use include thrombus aspiration and thrombectomy catheters. Initial studies did not have the expected impact, but the number of patients studied was limited. A recent series involving more than 1000 AMI patients undergoing coronary angioplasty and thrombus aspiration has shown an improvement of myocardial perfusion indices and a reduction of mortality at 30 days. Distal embolization protection systems aim to prevent the embolic material entering the circulation and causing macro-or microembolization. The present small and controversial experience does not yet recommend the routine use of this technique. Reduction of infarct size has been the main objective of research on ischemic myocardial disease during the last 40 years. Myocardial reperfusion is a major accomplishment in this field. But it is like a double-edged sword because reperfusion injury significantly reduces the potential benefits of reperfusion. The huge amount of research undertaken in the past 20 years constitutes a paradigm of the relationship between experimental work and clinical practice, and has improved the prospects for diminishing infarct size, in both the short and long-term. PMID- 20964115 TI - Left ventricular pseudoaneurysm in a complicated post-myocardial infarction period. PMID- 20964116 TI - A teenager with a t(X;17)(q22;q25) and ovarian failure. AB - BACKGROUND: The effects of a balanced X; Autosome translocation [t(X;A)] on the fertility of carrier females led to the definition of the Xq13-->q27 region as critical for ovarian function and reproductive lifespan. We describe here a teenager with ovarian failure likely due to a balanced t(X;17)(q22;q25). CASE: The 16 year-old patient presented with secondary amenorrhea. She exhibited height of 164 cm, slender habitus, and sexual development Tanner 2. METHODS: Hormonal determinations, GTG- and RBG-banded karyotypes, fluorescence in situ hybridization, and human androgen receptor assay. RESULTS: FSH of 141 mIU/ml and LH of 46 mIU/ml); karyotype 46,X,t(X;17)(q22;q25)[30].ish der(X)t(X;1 7)(17qsubt el+); skewed inactivation of the normal X which was the maternal one as shown by the HUMARA assay. The maternal chromosomes were 46,XX; the father was unavailable. CONCLUSIONS: The patient's (X;17) translocation likely accounts for her ovarian failure via an epigenetic downregulation of ovary expressed 17q25 genes relocated next to the Xq21 POF Critical Region 1 and related to ovarian development and function. Her otherwise inconspicuous phenotype agrees with the preferential inactivation of the normal X-chromosome that preserves the gene homeostasis in women with a balanced t(X;A). Finally, the normal maternal karyotype along with the HUMARA results and the sterility of males carrying a t(X;A) strongly suggests that this t(X;17) was a paternal de novo mutation. PMID- 20964117 TI - The variable phenotype in tetrasomy 18p syndrome. A propos of a subtle dysmorphic case. AB - The variable phenotype in tetrasomy 18p syndrome. Apropos of a subtle dysmorphic case: Tetrasomy 18 is a rare chromosomal syndrome. Its frequency is 1/40,000 newborns and more than 40 cases have been reported. In this paper we report a 25 month-old female patient referred for chromosome examination essentially because of delayed psychomotor development. The physical examination showed: microcephaly, mild generalized spasticity, arched eyebrows, horizontal palpebral fissures with unilateral convergent strabismus, bilateral epicanthic folds, small nose, well placed ears, oral cavity with high arched palate and upper vestibular frenula, tented mouth with slightly everted upper lip, hands with normal palmar creases and long fingers. All the blood tests were normal, while the magnetic resonance imaging reported mild demyelination and polymicrogyria. The karyotype was 47,XX,+i(18)(p10).ish i(18)(plO)(D18Z1+) de novo. PMID- 20964118 TI - A male newborn infant with fatco syndrome (fibular aplasia, tibial campomelia and oligodactyly): a case report. AB - We report a male infant with fibular aplasia, tibial campomelia, and oligosyndactyly (FATCO syndrome). Radiographs showed a short angulated left tibia with fibular aplasia and ipsilateral oligodactyly. We consider our case the 7th patient with FATCO syndrome. PMID- 20964119 TI - An uncommon association of vacterl complex with hypertrophic pyloric stenosis and horseshoe lung. AB - We report a case of VACTERL complex which had concomitant horseshoe lung, laryngeal cleft, and hypertrophic pyloric stenosis, which has not been previously reported. PMID- 20964120 TI - A trisomy 13 case with Robertsonian translocation presenting with atypical findings. AB - A trisomy 13 case with Robertsonian translocation presenting with atypical findings: Trisomy 13 is an autosomal trisomy caused by the presence of an extra copy of chromosome 13. Anomalies associated with this syndrome are severe mental retardation, coloboma, hypotonia, skeletal anomalies, midline anomalies, facial defects, holoprosencephaly, cardiac defects, omphalocele and polydactyly. Here we report a case of trisomy 13 with Robertsonian translocation, 160 day old, presenting with atypical findings like posterior fusion defect of the vertebra, hyperplasia of the right lobe of the liver, dilatation at pelvicalyxial system, scoliosis and complex heart disease including cardiomyopathy. PMID- 20964121 TI - A familial reciprocal translocation t(1;15) in three generations identified in a regular trisomy 21 patient. AB - The concurrence of a reciprocal translocation and an aneuploidy represent a rare coincidence and an interchromosome effect between these two events has been suggested. We report the case of a family with a t(1;15) in three generations which was identified through the evaluation ofa patient with classical trisomy 21 or Down syndrome. The cytogenetic analysis with GTG banding showed that the proband had a regular trisomy 21 and a balanced translocation t(1;15). FISH and microsatellite analysis were carried out in the family in order to discard an interchromosomal effect. The implications for genetic assessment are discussed. PMID- 20964122 TI - Coexistence of neurofibromatosis type 1 and mosaic trisomy 8 in the same patient. AB - We described trisomy 8 mosaicism in a 6-month-old boy with left corneal leukoma, strabismus, posterior urethral valve, tibial bowing and congenital pseudarthrosis of the tibia (CPT) on graphic of left tibia. The patient also had some minor anomalies such as short philtrum, full everted lower lip, microretrognathia, flexion contracture on his left thumb, deep palmar and plantar creases and three cafe-au-lait macules (CALM) larger than 1 cm on the abdomen. Peripheral blood karyotype analysis of the patient showed 46,XY(10%)/47,XY,+8 (90%)). Mosaic trisomy 8 is a rare syndrome characterized by renal, cardiac, ophthalmologic anomalies, dysmorphic facial features and some skeletal manifestations. When re evaluated at 2 years of age, his gross motor development was delayed and he also had 12 CALM larger than 1 cm, hence the patient fulfilled NIH diagnostic criteria for Neurofibromatosis type 1 (NF 1) based on the CALM and CPT. A truncating mutation was found through comprehensive NF1 mutation analysis, i.e., c.1019_1020delCT (p.Ser340CysfsX12). Here we report a patient with both mosaic trisomy 8 and NF1, which was not described previously. PMID- 20964123 TI - Partial deletion of the long arm of chromosome 13 (q32q33.2) associated with mental retardation, choanal atresia and fish mouth. AB - 13q deletion syndrome is characterized by mental and motor retardation, craniofacial dysmorphic facial appearance and various congenital malformations. In this article, we present a new case with 13q deletion syndrome phenotypically characterized by fish mouth, choanal atresia and severe mental and motor retardation. In order to determine the certain localization of deleted region high resolution multicolor-banding technique was performed and the karyotype determined as 46,XX,del(13)(q32q33.2). To come in future to a genotype-phenotype correlation, it is very important to delineate the deleted region in such cases in detail by cytogenetic/ molecular cytogenetic methods. PMID- 20964124 TI - A case of otocephaly with anencephaly and meningomyelocele. AB - A case of otocephaly with anencephaly and meningomyelocele: Otocephaly is a rare lethal syndrome with microstomia, aglossia, agnathia, and synotia as major clinical features due to arrest in development of the first branchial arch. Some associated anomalies may be present as cyclopia, holoprosencephaly, cerebellar hypoplasia, situs inversus, and other visceral anomalies. We describe a case of fetus, spontaneously aborted in the 14th week of gestation with otocephaly complex (agnathia, synotia, microstomia) and associated anencephaly and meningomyelocele. PMID- 20964125 TI - Hallermann-Streiff syndrome with hemihypertrophy. AB - We report on a five year old girl with Hallermann-Streiff syndrome and hemihypertrophy. Hemihypertrophy does not appear to have ever been associated with Hallermann-Streiff syndrome. PMID- 20964126 TI - Primary amenorrhoea in a patient with mosaicism for monosomy X and a derivative X chromosome. AB - Primary amenorrhoea is defined as the absence of menstruation in phenotypic women aged 16 years or older, if secondary sexual characteristics are present. X chromosome abnormalities probably comprise about one half of all cases, including Turner syndrome and X chromosome rearrangements. Conventional banding cytogenetic methods might miss the accurate detection of structural chromosome abnormalities. The fluorescence in situ hybridization (FISH) and multicolor FISH techniques are required to interpret specific chromosomal rearrangement. As far as we know, we report the first case with chromosome mosaicism for monosomy X and terminal deletion of Xq26 with duplication of Xp11-->pter. In spite of the fact that a 45,X karyotype was detected in 46% of lymphocytes, she was tall and her secondary sexual characteristics were moderately developed, including breast, pubic and axillary hair stages. Cytogenetic and FISH analyses should be considered for patients presenting primary amenorrhoea even if there are no other clinical features suggestive of chromosome abnormality. PMID- 20964127 TI - A collodion baby with hypothyroidism. AB - Collodion baby is a rare keratinizing congenital disorder. Although it is milder in degree than harlequin fetus, the infant is at risk for increased water loss, thermal instability, percutaneous toxicity, and infection as a result of an impaired skin barrier function. Here we report on an 11 days-old collodion baby with hypernatremic dehydratation, septicemia and congenital hypothyroidism. To our knowledge congenital hypothyroidism associated with collodion baby is reported in only one case up to date. PMID- 20964128 TI - Freeman-Sheldon (whistling face) syndrome with hyperpyrexia in the newborn: case report. AB - Freeman Sheldon syndrome (FSS) is a rare, multiple congenital contracture syndrome that is relatively well-known, since affected children have a striking appearance. This entity was historically referred to as the "whistling-face syndrome". Malignant hyperthermia and hyperpyrexia have been documented in FSS after general anesthesia related to the neuropathy. We report a male neonate with FSS and hyperpyrexia without anesthesia. To our knowledge, our patient is the first in the literature with hyperpyrexia in the newborn period without anesthesia. PMID- 20964129 TI - Prenatal diagnosis of satellited 21q derived from pericentric inversion involving the satellite stalk region and terminal 21q. PMID- 20964130 TI - Parental relationships in fragile families. AB - As nonmarital childbearing escalated in the United States over the past half century, fragile families--defined as unmarried couples with children--drew increased interest from researchers and policy makers. Sara McLanahan and Audrey Beck discuss four aspects of parental relationships in these families: the quality of parents' intimate relationship, the stability of that relationship, the quality of the co-parenting relationship among parents who live apart, and nonresident fathers' involvement with their child. At the time of their child's birth, half of the parents in fragile families are living together and another third are living apart but romantically involved. Despite high hopes at birth, five years later only a third of parents are still together, and new partners and new children are common, leading to high levels of instability and complexity in these families. Drawing on findings from the Fragile Families and Child Wellbeing Study, McLanahan and Beck highlight a number of predictors of low relationship quality and stability in these families, including low economic resources, government policies that discourage marriage, gender distrust and acceptance of single motherhood, sex ratios that favor men, children from previous unions, and psychological factors that make it difficult for parents to maintain healthy relationships. No single factor appears to have a dominant effect. The authors next discuss two types of experiments that attempt to establish causal effects on parental relationships: those aimed at altering economic resources and those aimed at improving relationships. What can be done to strengthen parental relationships in fragile families? The authors note that although economic resources are a consistent predictor of stable relationships, researchers and policy makers lack good causal information on whether increasing fathers' employment and earnings will increase relationship quality and union stability. They also note that analysts need to know more about whether relationship quality in fragile families can be improved directly and whether doing so will increase union stability, father involvement, and co-parenting quality. PMID- 20964131 TI - Mothers' economic conditions and sources of support in fragile families. AB - Rising rates of nonmarital childbirth in the United States have resulted in a new family type, the fragile family. Such families, which include cohabiting couples as well as single mothers, experience significantly higher rates of poverty and material hardship than their married counterparts. Ariel Kalil and Rebecca Ryan summarize the economic challenges facing mothers in fragile families and describe the resources, both public and private, that help them meet these challenges. The authors explain that the economic fragility of these families stems from both mothers' and fathers' low earnings, which result from low education levels, as well as from physical, emotional, and mental health problems. Mothers in fragile families make ends meet in many ways. The authors show that various public programs, particularly those that provide in-kind assistance, do successfully lessen economic hardship in fragile families. Single mothers also turn to private sources of support--friends, family, boyfriends--for cash and in-kind assistance. But though these private safety nets are essential to many mothers' economic survival, according to the authors, private safety nets are not always consistent and dependable. Thus, assistance from private sources may not fundamentally improve mothers' economic circumstances. Policy makers, say Kalil and Ryan, must recognize that with rates of nonmarital childbirth at their current level, and potentially rising still, the fragile family is likely an enduring fixture in this country. It is thus essential to strengthen policies that both support these families' economic self-sufficiency and alleviate their hardship during inevitable times of economic distress. The most important first step, they say, is to strengthen the public safety net, especially such in-kind benefits as food stamps, Medicaid, housing, and child care. A next step would be to bolster community-based programs that can provide private financial support, such as emergency cash assistance, child care, and food aid, when mothers cannot receive it from their own private networks. PMID- 20964132 TI - Capabilities and contributions of unwed fathers. AB - Young, minority, and poorly educated fathers in fragile families have little capacity to support their children financially and are hard-pressed to maintain stability in raising those children. In this article, Robert Lerman examines the capabilities and contributions of unwed fathers, how their capabilities and contributions fall short of those of married fathers, how those capabilities and contributions differ by the kind of relationship the fathers have with their child's mother, and how they change as infants grow into toddlers and kindergartners. Unwed fathers' employment and earnings vary widely among groups but generally rise over time. At the child's birth, cohabiting fathers earn nearly 20 percent more than noncohabiting unwed fathers, and the gap widens over time. Still, five years after an unwed birth, the typical unwed father is working full time for the full year. Although most unwed fathers spend considerable time with their children in the years soon after birth, explains Lerman, over time their involvement erodes. Men who lose touch with their children are likely to see their earnings stagnate, provide less financial support, and often face new obligations when they father children with another partner. By contrast, the unwed fathers who marry or cohabit with their child's mother earn considerably higher wages and work substantially more than unwed fathers who do not marry or cohabit. These results suggest that unwed fathers' earnings are affected by family relationships as well as their education and work experience. Lerman notes that several factors influence the extent to which unwed fathers stay involved with their children. Better-educated fathers, those who most identify with the father's role, and those with good relationships with the child's mother, are most likely to sustain a relationship with their children. Some studies even find that strong child support enforcement increases father involvement. For many years, policy makers approached the problem of noncustodial, unwed fathers on a single track--by trying to increase their child support payments. Today's policy makers are recognizing the limits of that strategy. New programs focus on improving the relationship and communication skills of unwed fathers. In addition, targeted training programs, such as apprenticeships, enable unwed fathers to earn a salary while they learn skills. PMID- 20964133 TI - Fragile families and child wellbeing. AB - Jane Waldfogel, Terry-Ann Craigie, and Jeanne Brooks-Gunn review recent studies that use data from the Fragile Families and Child Wellbeing Study (FFCWS) to examine why children who grow up in single-mother and cohabiting families fare worse than children born into married-couple households. They also present findings from their own new research. Analysts have investigated five key pathways through which family structure might influence child well-being: parental resources, parental mental health, parental relationship quality, parenting quality, and father involvement. It is also important to consider the role of the selection of different types of men and women into different family types, as well as family stability. But analysts remain uncertain how each of these elements shapes children's outcomes. In addition to providing an overview of findings from other studies using FFCWS, Waldfogel, Craigie, and Brooks-Gunn report their own estimates of the effect of a consistently defined set of family structure and stability categories on cognitive, behavioral, and health outcomes of children in the FFCWS study at age five. The authors find that the links between fragile families and child outcomes are not uniform. Family instability, for example, seems to matter more than family structure for cognitive and health outcomes, whereas growing up with a single mother (whether that family structure is stable or unstable over time) seems to matter more than instability for behavior problems. Overall, their results are consistent with other research findings that children raised by stable single or cohabiting parents are at less risk than those raised by unstable single or cohabiting parents. The authors conclude by pointing to three types of policy reforms that could improve outcomes for children. The first is to reduce the share of children growing up in fragile families (for example, through reducing the rate of unwed births or promoting family stability among unwed parents). The second is to address the pathways that place such children at risk (for example, through boosting resources in single parent homes or fostering father involvement in fragile families). The third is to address directly the risks these children face (for example, through high quality early childhood education or home-visiting policies). PMID- 20964134 TI - Race and ethnicity in fragile families. AB - Robert Hummer and Erin Hamilton note that the prevalence of fragile families varies substantially by race and ethnicity. African Americans and Hispanics have the highest prevalence; Asian Americans, the lowest; and whites fall somewhere in the middle. The share of unmarried births is lower among most foreign-born mothers than among their U.S.-born ethnic counterparts. Immigrant-native differences are particularly large for Asians, whites, and blacks. The authors also find racial and ethnic differences in the composition and stability of fragile families over time. Although most parents of all racial and ethnic groups are romantically involved at the time of their child's birth, African American women are less likely to be in a cohabiting relationship than are white and Hispanic mothers. Over time, these racial and ethnic differences become more pronounced, with African American mothers having the lowest rates of marriage and cohabitation and the highest breakup rates, and Mexican immigrant mothers having the highest rates of marriage and cohabitation and the lowest breakup rates. Fragile families have far fewer socioeconomic resources than married families, though resources vary within fragile families by race and ethnicity. White mothers, in general, have more socioeconomic resources than black, Mexican American, and Mexican immigrant mothers; they are more likely to have incomes above the poverty limit, more likely to own a car, less likely to have children from a prior relationship, and more likely to report living in a safe neighborhood. Access to health care and child care follows a similar pattern. The exception is education; black and white unmarried mothers are equally likely to have finished high school, and Mexican immigrant and Mexican American mothers are less likely to have done so. The authors argue that socioeconomic differences are by far the biggest driver of racial and ethnic differences in marriage and family stability, and they support reforms to strengthen parents' economic security. They also discuss how sex ratios and culture affect family formation and stability. In particular, they note that despite severe poverty, Mexican immigrant families have high rates of marriage and cohabitation--an advantage that erodes by the second generation with assimilation. To address the paradox that marriage declines as socioeconomic status improves, they support policies that reinforce rather than undermine the family ties of Mexican immigrants. PMID- 20964135 TI - An ounce of prevention: policy prescriptions to reduce the prevalence of fragile families. AB - Isabel Sawhill, Adam Thomas, and Emily Monea believe that given the well documented costs of nonmarital births to the children and parents in fragile families, as well as to society as a whole, policy makers' primary goal should be to reduce births to unmarried parents. The authors say that the nation's swiftly rising nonmarital birth rate has many explanations--a cultural shift toward acceptance of unwed childbearing; a lack of positive alternatives to motherhood among the less advantaged; a sense of fatalism or ambivalence about pregnancy; a lack of marriageable men; limited access to effective contraception; a lack of knowledge about contraception; and the difficulty of using contraception consistently and correctly. Noting that these explanations fall generally into three categories--motivation, knowledge, and access--the authors discuss policies designed to motivate individuals to avoid unintended pregnancies, to improve their knowledge about contraception, and to remove barriers to contraceptive access. Some motivational programs, such as media campaigns, have been effective in changing behavior. Some, but not all, sex education programs designed to reduce teen pregnancy have also been effective at reducing sexual activity or increasing contraceptive use, or both. Programs providing access to subsidized contraception have also been effective and would be even more so if they could increase the use not just of contraceptives, but of long-acting, reversible contraceptive methods such as intrauterine devices (IUDs) and implants. Finally, the authors present simulations of the costs and effects of three policy initiatives--a mass media campaign that encourages men to use condoms, a teen pregnancy prevention program that discourages sexual activity and educates participants about proper contraceptive use, and an expansion in access to Medicaid-subsidized contraception. All three have benefit-cost ratios that are comfortably greater than one, making them excellent social investments that can actually save taxpayer dollars. PMID- 20964136 TI - Incarceration in fragile families. AB - Since the mid-1970s the U.S. imprisonment rate has increased roughly fivefold. As Christopher Wildeman and Bruce Western explain, the effects of this sea change in the imprisonment rate--commonly called mass imprisonment or the prison boom--have been concentrated among those most likely to form fragile families: poor and minority men with little schooling. Imprisonment diminishes the earnings of adult men, compromises their health, reduces familial resources, and contributes to family breakup. It also adds to the deficits of poor children, thus ensuring that the effects of imprisonment on inequality are transferred intergenerationally. Perversely, incarceration has its most corrosive effects on families whose fathers were involved in neither domestic violence nor violent crime before being imprisoned. Because having a parent go to prison is now so common for poor, minority children and so negatively affects them, the authors argue that mass imprisonment may increase future racial and class inequality--and may even lead to more crime in the long-term, thereby undoing any benefits of the prison boom. U.S. crime policy has thus, in the name of public safety, produced more vulnerable families and reduced the life chances of their children. Wildeman and Western advocate several policy reforms, such as limiting prison time for drug offenders and for parolees who violate the technical conditions of their parole, reconsidering sentence enhancements for repeat offenders, and expanding supports for prisoners and ex-prisoners. But Wildeman and Western argue that criminal justice reform alone will not solve the problems of school failure, joblessness, untreated addiction, and mental illness that pave the way to prison. In fact, focusing solely on criminal justice reforms would repeat the mistakes the nation made during the prison boom: trying to solve deep social problems with criminal justice policies. Addressing those broad problems, they say, requires a greater social commitment to education, public health, and the employment opportunities of low-skilled men and women. The primary sources of order and stability--public safety in its wide sense--are the informal social controls of family and work. Thus, broad social policies hold the promise not only of improving the wellbeing of fragile families, but also, by strengthening families and providing jobs, of contributing to public safety. PMID- 20964137 TI - Unmarried parents in college. AB - Noting that access to higher education has expanded dramatically in the past several decades, Sara Goldrick-Rab and Kia Sorensen focus on how unmarried parents fare once they enter college. Contrary to the expectation that access to college consistently promotes family stability and economic security, the authors argue that deficiencies in current policy lead college attendance to have adverse consequences for some families headed by unmarried parents. Although rates of college attendance have increased substantially among unmarried parents, their college completion rates are low. One explanation is inadequate academic preparation. Another is financial constraints, which can force unmarried students to interrupt their studies or increase their work hours, both of which compromise the quality of their educational experiences and the outcomes for their children. The authors point out that although many public programs offer support to unmarried parents attending college, the support is neither well coordinated nor easily accessed. Over the past three decades, loans have increasingly replaced grants as the most common form of federal and state financial aid. Confusion about what is available leads many low-income students to the two most "straightforward" sources of income--loans and work, both of which involve significant costs and can operate at cross-purposes with public forms of support. Too much work can lead to reductions in public benefits, and earnings do not always replace the lost income. A growing body of experimental evidence shows that providing social, financial, and academic supports to vulnerable community college students can improve achievement and attainment. Contextualized learning programs, for example, have enabled participants not only to move on from basic skills to credit-bearing coursework, but also to complete credits, earn certificates, and make gains on basic skills tests. Another successful initiative provided low-performing students with special counseling services and a small stipend of $150 per semester when they used those services. And researchers are conducting experimental performance-based financial aid programs at community colleges to test their effectiveness. Goldrick-Rab and Sorensen conclude that more effective support could enable unmarried students to complete college degree and certificate programs. PMID- 20964138 TI - Marriage and fatherhood programs. AB - To improve the quality and stability of couple and father-child relationships in fragile families, researchers are beginning to consider how to tailor existing couple-relationship and father-involvement interventions, which are now targeted on married couples, to the specific needs of unwed couples in fragile families. The goal, explain Philip Cowan, Carolyn Pape Cowan, and Virginia Knox, is to provide a more supportive developmental context for mothers, fathers, and, especially, the children in fragile families. The authors present a conceptual model to explain why couple-relationship and father-involvement interventions developed for middle- and low-income married couples might be expected to provide benefits for children of unmarried parents. Then they summarize the extensive research on existing couple-relationship and father-involvement interventions, noting that only a few of the programs for couples and a handful of fatherhood programs have been systematically evaluated. Of those that have been evaluated, few have included unmarried couples as participants, and none has investigated whether interventions may have different effects when unmarried fathers live with or apart from the child. Furthermore, although the funders and creators of most programs for couples or for fathers justify their offerings in terms of potential benefits for children, the authors note that the programs rarely assess child outcomes systematically. Next, the authors consider whether interventions for working-class or middle-class fathers or couples that have shown benefits for family members and their relationships might be helpful to fragile families, in which the parents are not married at the time of their child's birth. Because evidence suggests that couple-oriented programs also have a positive effect on father involvement, the authors recommend integrating couple and fatherhood interventions to increase their power to reduce the risks and enhance the protective factors for children's development and well-being. The authors emphasize the need for more research on program development to understand the most effective ways to strengthen co-parenting by couples who are the biological parents of a child but who have relatively tenuous, or already dissolved, relationships with one another. In closing, the authors summarize how far the family-strengthening field has come and offer suggestions for where it might go from here to be helpful to fragile families. PMID- 20964139 TI - The effect of neuraminidase blocker on gabazine-induced seizures in rat hippocampus. AB - Concentration of neuraminidase (NEU), an enzyme which cleaves negatively charged sialic acids from carbohydrate moieties of the cellular membrane, could vary depending on physiological conditions. Multiple evidences suggest that fluctuations of NEU extracellular concentrations can influence neuronal activity. In the present study we examined the effect of down regulation of endogenous NEU activity on seizure-like activity (SLA) induced by gabazine (specific blocker of inhibitory synaptic transmission) in the hippocampal CA1 pyramidal region of cultured slices. We show that in slices pretreated with the blocker of endogenous NEU, N-acetyl-2,3-dehydro-2-deoxyneuraminic acid (NADNA), duration of synchronous oscillations induced by gabazine was considerably increased comparatively to control untreated slices. This study adds further information that changes in the level of NEU activity is an important factor, which can affect neuronal network excitability. PMID- 20964140 TI - Advanced degree. Rethinking the academic medical center. PMID- 20964141 TI - From good to great. PMID- 20964142 TI - Positive performance. PMID- 20964143 TI - Floored! PMID- 20964144 TI - Iconic investigations. PMID- 20964145 TI - Easy does it. PMID- 20964146 TI - Peer support, education, and mentoring. PMID- 20964147 TI - Frugal cooking. The cost of convenience. PMID- 20964148 TI - Adopting a vegetarian meal plan. An option to consider. PMID- 20964149 TI - Top 10 tips for better blood glucose control. PMID- 20964150 TI - Improving your recipes one step at a time. PMID- 20964151 TI - Tomato products. PMID- 20964152 TI - Getting started exercising. PMID- 20964153 TI - Public and private. PMID- 20964154 TI - Strange deathbedfellows. PMID- 20964155 TI - One city, two worlds. PMID- 20964156 TI - The national individual health insurance mandate. PMID- 20964157 TI - When time won't tell. PMID- 20964158 TI - The prospects for personalized medicine. PMID- 20964159 TI - Personalized medicine's ragged edge. PMID- 20964160 TI - A patient's experience. PMID- 20964161 TI - Hospice and physician-assisted death: collaboration, compliance, and complicity. AB - Although the overwhelming majority of terminally ill patients in Oregon who seek a physician's aid in dying are enrolled in hospice programs, hospices do not take a major role in this practice. An examination of fifty-five Oregon hospices reveals that both legal and moral questions prevent hospices from collaborating fully with physician-assisted death. PMID- 20964162 TI - Can we improve treatment decision-making for incapacitated patients? AB - When patients cannot make their own treatment decisions, surrogates typically step in to do it for them. Surrogate decision-making is far from ideal, of course, as the surrogate may not know what the patient prefers or what best promotes her interests. One way to improve it would be to arm surrogates with information about what patients in similar circumstances tend to prefer, allowing them to make empirically grounded predictions about what their patient would want. PMID- 20964163 TI - 100 years later, the Flexner report is still relevant. PMID- 20964164 TI - Trick or treat? Enjoying halloween when you have diabetes. PMID- 20964165 TI - Oversaturated. The facts on fats and your health. PMID- 20964166 TI - Why me? Understanding the causes of diabetes. PMID- 20964167 TI - Getting serious. Actor Anthony Anderson takes on diabetes. PMID- 20964168 TI - How to stir up a satisfying soup. PMID- 20964169 TI - Point/counterpoint. Ultrasonography is soon likely to become a viable alternative to x-ray mammography for breast cancer screening. PMID- 20964170 TI - Automated registration of diagnostic to prediagnostic x-ray mammograms: evaluation and comparison to radiologists' accuracy. AB - PURPOSE: To compare and evaluate intensity-based registration methods for computation of serial x-ray mammogram correspondence. METHODS: X-ray mammograms were simulated from MRIs of 20 women using finite element methods for modeling breast compressions and employing a MRI/x-ray appearance change model. The parameter configurations of three registration methods, affine, fluid, and free form deformation (FFD), were optimized for registering x-ray mammograms on these simulated images. Five mammography film readers independently identified landmarks (tumor, nipple, and usually two other normal features) on pairs of diagnostic and corresponding prediagnostic digitized images from 52 breast cancer cases. Landmarks were independently reidentified by each reader. Target registration errors were calculated to compare the three registration methods using the reader landmarks as a gold standard. Data were analyzed using multilevel methods. RESULTS: Between-reader variability varied with landmark (p < 0.01) and screen (p = 0.03), with between-reader mean distance (mm) in point location on the diagnostic/prediagnostic images of 2.50 (95% CI 1.95, 3.15)/2.84 (2.24, 3.55) for nipples and 4.26 (3.43, 5.24)/4.76 (3.85, 5.84) for tumors. Registration accuracy was sensitive to the type of landmark and the amount of breast density. For dense breasts (> or = 40%), the affine and fluid methods outperformed FFD. For breasts with lower density, the affine registration surpassed both fluid and FFD. Mean accuracy (mm) of the affine registration varied between 3.16 (95% CI 2.56, 3.90) for nipple points in breasts with density 20%-39% and 5.73 (4.80, 6.84) for tumor points in breasts with density < 20%. CONCLUSIONS: Affine registration accuracy was comparable to that between independent film readers. More advanced two-dimensional nonrigid registration algorithms were incapable of increasing the accuracy of image alignment when compared to affine registration. PMID- 20964171 TI - Optimization in hyperthermia treatment planning: the impact of tissue perfusion uncertainty. AB - PURPOSE: Hyperthermia treatment planning (HTP) potentially provides a valuable tool for monitoring and optimization of treatment. However, one of the major problems in HTP is that different sources of uncertainty degrade its reliability. Perfusion uncertainty is one of the largest uncertainties and hence there is an ongoing debate whether optimization should be limited to power-based strategies. In this study a systematic analysis is carried out addressing this question. METHODS: The influence of perfusion uncertainty on optimization was analyzed for five patients with cervix uteri carcinoma heated with the AMC-8 70 MHz phased array waveguide system. The effect of variations (up to +/- 50%) in both the muscle and tumor perfusion level was investigated. For every patient, reference solutions were calculated using constrained temperature-based optimization for 25 different and known perfusion distributions. Reference solutions were compared to those found by temperature-based optimization using standard perfusion values and four SAR-based optimization methods. The effect of heterogeneity was investigated by creating 5 x 100 perfusion distributions for different levels of local variation (+/- 25% and +/- 50%) and scale (1 and 2 cm). Here the performance of the temperature-based optimization method was compared to a SAR-based method that showed good performance in the previous analysis. RESULTS: Solutions found with temperature-based optimization using a deviating perfusion distribution during optimization were found within 1.0 degrees C from the true optimum. For the SAR based methods, deviations up to 2.9 degrees C were found. The spread found in these deviations was comparable, typically 0.5-1.0 degrees C. When applying intramuscle variation to the perfusion, temperature-based optimization proved to be the best strategy in 95% of the evaluated cases applying +/- 50% local variation. CONCLUSIONS: Temperature-based optimization proves to be superior to SAR-based optimization both under variation of perfusion level as well as under the application of intratissue variation. The spread in achieved temperatures is comparable. These results are valid under the assumption of constant perfusion at hyperthermic levels. Although similar results are expected from models including thermoregulation, additional analysis is required to confirm this. In view of uncertainty in tissue perfusion and other modeling uncertainties, the authors propose feedback guided temperature-based optimization as the best candidate to improve thermal dose delivery during hyperthermia treatment. PMID- 20964172 TI - Fast-MICP for frameless image-guided surgery. AB - PURPOSE: In image-guided surgery (IGS) systems, image-to-physical registration is critical for reliable anatomical information mapping and spatial guidance. Conventional stereotactic frame-based or fiducial-based approaches provide accurate registration but are not patient-friendly. This study proposes a frameless cranial IGS system that uses computer vision techniques to replace the frame or fiducials with the natural features of the patient. METHODS: To perform a cranial surgery with the proposed system, the facial surface of the patient is first reconstructed by stereo vision. Accuracy is ensured by capturing parallel line patterns projected from a calibrated LCD projector. Meanwhile, another facial surface is reconstructed from preoperative computed tomography (CT) images of the patient. The proposed iterative closest point (ICP)-based algorithm [fast marker-added ICP (Fast-MICP)] is then used to register the two facial data sets, which transfers the anatomical information from the CT images to the physical space. RESULTS: Experimental results reveal that the Fast-MICP algorithm reduces the computational cost of marker-added ICP (J.-D. Lee et al., "A coarse-to-fine surface registration algorithm for frameless brain surgery," in Proceedings of International Conference of the IEEE Engineering in Medicine and Biology Society, 2007, pp. 836-839) to 10% and achieves comparable registration accuracy, which is under 3 mm target registration error (TRE). Moreover, two types of optical-based spatial digitizing devices can be integrated for further surgical navigation. Anatomical information or image-guided surgical landmarks can be projected onto the patient to obtain an immersive augmented reality environment. CONCLUSION: The proposed frameless IGS system with stereo vision obtains TRE of less than 3 mm. The proposed Fast-MICP registration algorithm reduces registration time by 90% without compromising accuracy. PMID- 20964173 TI - Deformable image registration of heterogeneous human lung incorporating the bronchial tree. AB - PURPOSE: To investigate the effect of the bronchial tree on the accuracy of biomechanical-based deformable image registration of human lungs. METHODS: Three dimensional finite element models have been developed using four dimensional computed tomography image data of ten lung cancer patients. Each model is built of a body, left and right lungs, tumor, and bronchial trees. Triangular shell elements are used for the bronchial trees while tetrahedral elements are used for other components. Hyperelastic material properties based on experimental investigation on human lungs are used for the lung parenchyma. Different material properties are assigned for the bronchial tree using five values for the modulus of elasticity of 0.01, 0.12, 0.5, 10, and 18 MPa. Lungs are modeled to slide inside chest cavities by applying frictionless contact surfaces between each lung and corresponding chest cavity. The accuracy of the models is examined using an average of 40 bronchial bifurcation points identified on inhale and exhale images. Relative accuracy is evaluated by comparing the displacement of all nodes within the lungs as well as the dosimetric difference at the exhale position predicted by the model. RESULTS: There is no significant effect of bronchial tree on the model accuracy based on the bifurcation points analysis. However, on the local level, using an average of 38 000 nodes, there is a maximum difference of 8.5 mm in the deformation of the bronchial trees, as the modulus of elasticity of the bronchial trees increases from 0.01 to 18 MPa; however, more than 96% of nodes are within a 2.5 mm difference in each direction. The average dose difference at the predicted exhale position is less than 35 cGy between the models. CONCLUSIONS: The bronchial tree has little effect on the global deformation and the accuracy of deformable image registration of lungs. Hence, the homogenous model is a reasonable assumption. Since there are some local deformation differences between nodes as the material properties of the bronchial tree change that may affect the accuracy of dosimetric results, heterogeneity may be required for a smaller scale modeling of lungs. PMID- 20964174 TI - Semiautomatic technique for defining the internal gross tumor volume of lung tumors close to liver/spleen cupola by 4D-CT. AB - PURPOSE: It has been shown that in cases of lung tumors close to the liver cupola, the four dimensional (4D)-CT postprocessing maximum intensity projection (MIP) algorithm does not fully recover the radiotherapy internal gross tumor volume (IGTV). In this work, a semiautomatic technique was evaluated by which the residual IGTV that was not included into the IGTV by MIP algorithm was actually added. METHODS: A moving phantom and five selected patients were considered. The various IGTVs produced by the semiautomatic approach were compared to those generated by 4D-CT manual contouring. RESULTS: In all cases, the radiation oncologist qualitatively concurred with the semiautomatic IGTV. A quantitative difference in volume of 2.6% was found in the phantom study, whereas a mean difference of 0.1 +/- 4.6% was obtained in the patient studies. CONCLUSIONS: A semiautomatic technique to include the residual part of IGTV covered by liver/spleen cupola when using MIP algorithm was validated on phantom and on selected patients, revealing the possibility of defining the IGTV for patients with lesions located near liver/spleen cupola by performing only the contours on the MIP series. PMID- 20964175 TI - Design of iterative ROI transmission tomography reconstruction procedures and image quality analysis. AB - PURPOSE: An iterative edge-preserving CT reconstruction algorithm for high resolution imaging of small regions of the field of view is investigated. It belongs to a family of region-of-interest reconstruction techniques in which a low-cost pilot reconstruction of the whole field of view is first performed and then used to deduce the contribution of the region of interest to the projection data. These projections are used for a high-resolution reconstruction of the region of interest (ROI) using a regularized iterative algorithm, resulting in significant computational savings. This paper examines how the technique by which the pilot reconstruction of the full field of view is obtained affects the total runtime and the image quality in the region of interest. METHODS: Previous contributions to the literature have each focused on a single approach for the pilot reconstruction. In this paper, two such approaches are compared: the filtered backprojection and a low-resolution regularized iterative reconstruction method. ROI reconstructions are compared in terms of image quality and computational cost over simulated and physical phantom (Catphan600) studies, in order to assess the compromises that most impact the quality of the ROI reconstruction. RESULTS: With the simulated phantom, new artifacts that appear in the ROI images are caused by significant errors in the pilot reconstruction. These errors include excessive coarseness of the pilot image grid and beam hardening artifacts. With the Catphan600 phantom, differences in the imaging model of the scanner and that of the iterative reconstruction algorithm cause dark border artifacts in the ROI images. CONCLUSIONS: Inexpensive pilot reconstruction techniques (analytical algorithms, very-coarse-grid penalized likelihood) are practical choices in many common cases. However, they may yield background images altered by edge degradation or beam hardening, inducing projection inconsistency in the data used for ROI reconstruction. The ROI images thus have significant streak and speckle artifacts, which adversely affect the resolution-to-noise compromise. In these cases, edge-preserving penalized likelihood methods on not-too-coarse image grids prove to be more robust and provide the best ROI image quality. PMID- 20964176 TI - Spatially weighted mutual information image registration for image guided radiation therapy. AB - PURPOSE: To develop a new metric for image registration that incorporates the (sub)pixelwise differential importance along spatial location and to demonstrate its application for image guided radiation therapy (IGRT). METHODS: It is well known that rigid-body image registration with mutual information is dependent on the size and location of the image subset on which the alignment analysis is based [the designated region of interest (ROI)]. Therefore, careful review and manual adjustments of the resulting registration are frequently necessary. Although there were some investigations of weighted mutual information (WMI), these efforts could not apply the differential importance to a particular spatial location since WMI only applies the weight to the joint histogram space. The authors developed the spatially weighted mutual information (SWMI) metric by incorporating an adaptable weight function with spatial localization into mutual information. SWMI enables the user to apply the selected transform to medically "important" areas such as tumors and critical structures, so SWMI is neither dominated by, nor neglects the neighboring structures. Since SWMI can be utilized with any weight function form, the authors presented two examples of weight functions for IGRT application: A Gaussian-shaped weight function (GW) applied to a user-defined location and a structures-of-interest (SOI) based weight function. An image registration example using a synthesized 2D image is presented to illustrate the efficacy of SWMI. The convergence and feasibility of the registration method as applied to clinical imaging is illustrated by fusing a prostate treatment planning CT with a clinical cone beam CT (CBCT) image set acquired for patient alignment. Forty-one trials are run to test the speed of convergence. The authors also applied SWMI registration using two types of weight functions to two head and neck cases and a prostate case with clinically acquired CBCT/ MVCT image sets. The SWMI registration with a Gaussian weight function (SWMI-GW) was tested between two different imaging modalities: CT and MRI image sets. RESULTS: SWMI-GW converges 10% faster than registration using mutual information with an ROI. SWMI-GW as well as SWMI with SOI-based weight function (SWMI-SOI) shows better compensation of the target organ's deformation and neighboring critical organs' deformation. SWMI-GW was also used to successfully fuse MRI and CT images. CONCLUSIONS: Rigid-body image registration using our SWMI GW and SWMI-SOI as cost functions can achieve better registration results in (a) designated image region(s) as well as faster convergence. With the theoretical foundation established, we believe SWMI could be extended to larger clinical testing. PMID- 20964177 TI - Near-field radiofrequency thermoacoustic tomography with impulse excitation. AB - PURPOSE: Imaging performance of radiofrequency and microwave-based thermoacoustic tomography systems is mainly determined by the ability to deposit a substantial amount of electromagnetic energy within ultrashort time duration. Pulses of nanosecond-range duration that can carry hundreds of millijoules energy are ideal for obtaining good signal-to-noise and spatial resolution in many biological imaging applications. However, existing implementations are based on modulated carrier-frequency amplification solutions, which are generally costly and cannot achieve ultrahigh-peak-power requirements essential for optimal thermoacoustic signal generation. METHODS: Herein the authors suggest and experimentally validate a near-field radiofrequency tomography (NRT) method for high resolution imaging of biological tissues using ultrashort electromagnetic impulses. The solution includes a low-cost pulsing system while the imaged objects are placed in the near field of the energy-emitting aperture for improved coupling using nonradiative fields. RESULTS: In the current design, the authors were able to achieve excitation impulse energies of hundreds of millijoules with durations in the order of a few nanoseconds, corresponding to peak power levels of multiple megawatts. The phantom imaging experiments demonstrated image features with characteristic sizes of around 170 microm, but the impulse durations used herein allow in principle spatial resolutions in the order of a few tens of microns when using an appropriate ultrasonic detection bandwidth. CONCLUSIONS: The proposed NRT method makes it possible to attain very high spatial resolution without compromising the thermoacoustic signal strength. This makes the imaging performance to be limited by the available bandwidth of the ultrasonic detector rather than by the microwave pulse duration. It is overall expected that the combination of pulsed near-field coupling with optimal choice of energy dissipation elements will generate a practical modality that can scale its application to small and larger volumes alike, while optimally adjusting the resolution to match the acoustic resolution possible. Such an approach should find several applications in small animal and clinical imaging. PMID- 20964178 TI - Special report: workshop on 4D-treatment planning in actively scanned particle therapy--recommendations, technical challenges, and future research directions. AB - This article reports on a 4D-treatment planning workshop (4DTPW), held on 7-8 December 2009 at the Paul Scherrer Institut (PSI) in Villigen, Switzerland. The participants were all members of institutions actively involved in particle therapy delivery and research. The purpose of the 4DTPW was to discuss current approaches, challenges, and future research directions in 4D-treatment planning in the context of actively scanned particle radiotherapy. Key aspects were addressed in plenary sessions, in which leaders of the field summarized the state of-the-art. Each plenary session was followed by an extensive discussion. As a result, this article presents a summary of recommendations for the treatment of mobile targets (intrafractional changes) with actively scanned particles and a list of requirements to elaborate and apply these guidelines clinically. PMID- 20964179 TI - Polymer coated fiber Bragg grating thermometry for microwave hyperthermia. AB - PURPOSE: Measuring tissue temperature distribution during electromagnetically induced hyperthermia (HT) is challenging. High resistance thermistors with nonmetallic leads have been used successfully in commercial HT systems for about three decades. The single 1 mm thick temperature sensing element is mechanically moved to measure tissue temperature distributions. By employing a single thermometry probe containing a fixed linear sensor array temperature, distributions during therapy can be measured with greater ease. While the first attempts to use fiber Bragg grating (FBG) technology to obtain multiple temperature points along a single fiber have been reported, improvement in the detection system's stability were needed for clinical applications. The FBG temperature sensing system described here has a very high temporal stability detection system and an order of magnitude faster readout than commercial systems. It is shown to be suitable for multiple point fiber thermometry during microwave hyperthermia when compared to conventional mechanically scanning probe HT thermometry. METHODS: A polymer coated fiber Bragg grating (PFBG) technology is described that provides a number of FBG thermometry locations along the length of a single optical fiber. The PFBG probe developed is tested under simulated microwave hyperthermia treatment to a tissue equivalent phantom. Two temperature probes, the multiple PFBG sensor and the Bowman probe, placed symmetrically with respect to a microwave antenna in a tissue phantom are subjected to microwave hyperthermia. Measurements are made at start of HT and 85 min later, when a 6 degrees C increase in temperature is registered by both probes, as is typical in clinical HT therapy. The optical fiber multipoint thermometry probe performs highly stable, real-time thermometry updating each multipoint thermometry scan over a 5 cm length every 2 s. Bowman probe measurements are acquired simultaneously for comparison. In addition, the PFBG sensor's detection system drift over 10 h is measured separately to evaluate system stability for clinical applications. RESULTS: The temperature profiles measured by the two probes simultaneously under microwave HT are in good agreement showing mean differences of 0.25 degrees C. The stability of the detection system is better than 0.3 degrees C with response times of the PFBG sensor system of 2 s for each scan over ten points. CONCLUSIONS: The single fixed multipoint fiber thermometry capability compares favorably with the scanning Bowman probe data. This offers an enabling alternative to either scanning or bundled single point temperature probes for distributed thermometry in clinical applications. PMID- 20964180 TI - Estimation of organ doses from kilovoltage cone-beam CT imaging used during radiotherapy patient position verification. AB - PURPOSE: The purpose of this study was to develop a practical method for estimating organ doses from kilovoltage cone-beam CT (CBCT) that can be performed with readily available phantoms and dosimeters. The accuracy of organ dose estimates made using the ImPACT patient dose calculator was also evaluated. METHODS: A 100 mm pencil chamber and standard CT dose index (CTDI) phantoms were used to measure the cone-beam dose index (CBDI). A weighted CBDI (CBDI(W)) was then calculated from these measurements to represent the average volumetric dose in the CTDI phantom. By comparing CBDI(W) to the previously published organ doses, organ dose conversion coefficients were developed. The measured CBDI values were also used as inputs for the ImPACT calculator to estimate organ doses. All CBDI dose measurements were performed on both the Elekta XVI and Varian OBI at three clinically relevant locations: Head, chest, and pelvis. RESULTS: The head, chest, and pelvis protocols yielded CBDI(W) values of 0.98, 16.62, and 24.13 mGy for the XVI system and 5.17, 6.14, and 21.57 mGy for the OBI system, respectively. Organ doses estimated with the ImPACT CT dose calculator showed a large range of variation from the previously measured organ doses, demonstrating its limitations for use with CBCT. CONCLUSIONS: The organ dose conversion coefficients developed in this work relate CBDI(W) values to organ doses previously measured using the same clinical protocols. Ultimately, these coefficients will allow for the quick estimation of organ doses from routine measurements performed using standard CTDI phantoms and pencil chambers. PMID- 20964181 TI - SPECT region of interest reconstruction with truncated transmission and emission data. AB - PURPOSE: The aim of this article is to propose an exact SPECT region of interest (ROI) reconstruction method using truncated transmission and truncated emission data. METHODS: Recently, the authors published two articles in Physics in Medicine and Biology with two results in SPECT ROI emission image reconstruction. The first result states that if the transmission data are truncated but the emission data are not truncated, the emission image can be exactly reconstructed, provided the entire emission image is inside the region where the transmission data are not truncated. The second result states that if the transmission data are not truncated, the emission ROI can be exactly reconstructed with truncated emission data. This article combines these two results and obtains a new result that the emission ROI can be exactly reconstructed if both transmission and emission data are truncated. RESULTS: Computer simulations are performed to verify the proposed ROI image reconstruction algorithm. CONCLUSIONS: Exact SPECT ROI image reconstruction is possible using truncated transmission and emission projections with some prior information about the attenuator and the emission distribution. PMID- 20964182 TI - Intensity modulated dose calculation with an improved experimental pencil-beam kernel. AB - PURPOSE: This article presents an improved pencil-beam dose calculation formalism based on an experimental kernel obtained by deconvolution. The new algorithm makes it possible to calculate the absorbed dose for all field sizes. METHODS: The authors have enhanced their previous work [J. D. Azcona and J. Burguete, Med. Phys. 35, 248-259 (2008)] by correcting the kernel tail representing the contribution to the absorbed dose far from the photon interaction point. The correction was performed by comparing the calculated and measured output factors. Dose distributions and absolute dose values calculated using the new formalism have been compared to measurements. The agreement between calculated and measured dose distributions was evaluated according to the gamma-index criteria. In addition, 35 individual intensity-modulated radiation therapy (IMRT) fields were calculated and measured in polystyrene using an ionization chamber. Furthermore, a series of 541 IMRT fields was calculated using the algorithm proposed here and using a commercial IMRT optimization and calculation software package. Comparisons were made between the calculations at single points located at the isocenter for all the beams, as well as between beams grouped by anatomic location. RESULTS: The percentage of points passing the gamma-index criteria (3%, 3 mm) when comparing calculated and measured dose distributions is generally greater than 99% for the cases studied. The agreement between the calculations and the experimental measurements generally lies in the +/- 2% interval for single points, with a mean value of 0.2%. The agreement between calculations using the proposed algorithm and using a commercial treatment planning system is also between +/- 5%. CONCLUSIONS: An improved algorithm based on an experimental pencil-beam kernel obtained by deconvolution has been developed. It has been validated clinically and promises to be a valuable tool for IMRT quality assurance as an independent calculation system for monitor units and dose distributions. An important point is that the algorithm presented here uses an experimental kernel, which is therefore independent of Monte-Carlo-calculated kernels. PMID- 20964183 TI - Standardized evaluation methodology for 3D/2D registration based on the Visible Human data set. AB - PURPOSE: A new image database with a reference-based standardized evaluation methodology for objective evaluation and comparison of three-dimensional/two dimensional (3D/2D) registration methods has been introduced. METHODS: Computed tomography (CT) images of a male and female from the Visible Human Project were used and 16 subvolumes, each containing one of vertebrae T3-T12 and L1-L5 and the pelvis, were defined from the CTs. Six pairs of 2D fluoroscopic x-ray images from different views, showing the thoracic, lumbar, and pelvic regions, were rendered from the CT data using a ray-casting algorithm with an energy conversion function. Furthermore, a single 13-gauge needle was analytically simulated and projected onto the 2D images. By the novel standardized evaluation methodology, a 3D/2D registration method is evaluated by four evaluation criteria: Accuracy, reliability, robustness, and algorithm complexity. RESULTS: To demonstrate the usefulness of the proposed data set and the standardized evaluation methodology, a part of the data set was used in an evaluation study of two gradient-based 3D/2D registration methods. It was shown that the use of a failure criterion to calculate the registration accuracy and reliability is not required, since all the information about a registration method can be determined from the estimated distribution of registration errors. CONCLUSIONS: The proposed simulated image data set with quite realistic synthetic 2D images, depicting soft tissues and outliers, is especially suitable for preliminary testing of 3D/2D registration algorithms. Since the aim of this article is to provide objective comparison and unbiased evaluation of 3D/2D registration methods, the standardized evaluation methodology is available upon request from the authors. PMID- 20964184 TI - Characterization of the ringing artifacts in rotator-based reconstruction with Monte Carlo-based resolution compensation for PET. AB - PURPOSE: Studies have shown that Monte Carlo-based reconstruction could effectively improve the image quality of positron emission tomography. The authors have previously used a Gaussian rotator-based algorithm to efficiently reduce the computational cost for system matrix (SM) calculation and to meet the large memory requirements for SM storage. However, pronounced ringing artifacts were observed in the reconstructed image. In this article, the authors investigated and characterized these artifacts. METHODS: The authors proposed an "ideal" rotator and used it as a baseline in the artifacts evaluation. This ideal rotator produces perfectly rotated images. The Gaussian rotator method was evaluated by a full system model and a partial system model without positron range and acolinearity, which could be compensated for by the blurring of the Gaussian rotator for 18F studies. Noiseless data, Monte Carlo simulation data, as well as acquired experimental data were used to quantitatively characterize the behavior of the artifacts. RESULTS: The study of the noiseless data indicated that the artifacts were mainly attributed to the rotator, which further blurred the simulated system responses. The simulation study suggested that the artifacts become less pronounced and not quantitatively significant in practice. This result is consistent with the experimental data study. Better contrast recovery was achieved with an over-compensated system model. Traditionally, an undercompensated system model was preferred to avoid artifacts. The authors' studies suggest that the Gaussian rotator with the full system model yields the best image quality among the evaluated methods with considerably reduced quantitative error and quantitatively insignificant artifacts in practice. CONCLUSIONS: The authors' investigation indicated that a moderately overcompensated system model (about 2 mm FWHM in this study) yielded better contrast recovery and quantitatively insignificant artifacts in practice. PMID- 20964185 TI - Computerized assessment of pulmonary fissure integrity using high resolution CT. AB - PURPOSE: Knowledge of pulmonary interlobar fissure integrity is of interest in a number of clinical and investigational applications. The authors developed and tested a high resolution CT based automated computerized scheme for this purpose. METHODS: The fissure integrity assessment scheme consists of the following steps: (1) Fissure detection, (2) individual fissure identification, (3) fissure type determination, (4) "complete" interlobe surface estimation, and (5) fissure integrity estimation. For evaluation purposes, 50 anonymized chest CT examinations were ascertained and the complete and "incomplete" regions of the fissures of interest were manually marked by two experienced radiologists. After applying the scheme to the same examinations, differences among fissure percent completeness estimates based on the radiologists' manual markings and the automated computerized scheme were computed and compared. RESULTS: Average differences in estimated fissure percent completeness (integrity) between the results of the computerized scheme and that based on each of the two radiologists' markings were 6.88% +/- 5.86%, 9.57% +/- 7.77%, and 4.19% +/- 5.64% for the right major fissures, the right minor fissures, and the left major fissures, respectively. The differences between results based on radiologists' markings for the same fissures were 4.27% +/- 3.32%, 7.02% +/- 5.54%, and 4.23% +/- 4.93%, respectively. The difference among the three matched measurement sets for each fissure were statistically significant (Friedman's test, p < or = 0.005) but paired comparisons showed that much of the observed difference was related to inter-reader differences rather than reader-computerized scheme differences. Computerized estimates were correlated with each of the radiologist's estimates (Spearman, p < 0.0001). CONCLUSIONS: While variability between readers-based estimates of fissure integrity was smaller than differences between the computerized scheme and each of the readers, the result reported here are quite encouraging in that the magnitude of these differences were in the same magnitude, demonstrating the feasibility of using a computerized scheme for this purpose. PMID- 20964186 TI - Real-time monitoring and control on deep inspiration breath-hold for lung cancer radiotherapy--combination of ABC and external marker tracking. AB - PURPOSE: In this article, the breath-hold and gating concepts were combined for application of lung cancer radiation treatment. The tumor movement was immobilized based on deep inspiration breath hold (DIBH), in which the breath hold consistency and stability were monitored by infrared (IR) tracking and controlled by gating with a predefined threshold. The authors' goal is to derive the benefits from both techniques, namely, the minimized treatment margin and the known advantages of deep inspiration. The efficacy of the technique in terms of tumor immobility and treatment setup accuracy was evaluated in the study. METHODS: Fourteen patients who were diagnosed with non small cell lung cancer were included in this study. The control of tumor immobility was investigated interfractionally and intrafractionally. The intrabreath-hold tumor motion was devised based on the external marker movement, in which the tumor-marker correlation was studied. The margin of the planning target volume (PTV) was evaluated based on two factors: (1) The treatment setup error accounts for the patient setup and interbreath-hold variations and (2) the intrabreath-hold tumor motion in which the residual tumor motion during irradiation was studied. RESULTS: As the result of the study, the group systematic error and group random error of treatment setup measured at the isocenter were 0.2(R) +/- 1.6, 1.0(A) +/ 2.0, and 0.3(S) +/- 1.5 mm in the left-right (LR), anterior-posterior (AP), and caudal-cranial (CC) directions, respectively. The Pearson correlation coefficient were 0.81 (LR), 0.76 (AP), and 0.85 (CC) mm and suggest tendency in linear correlation of tumor and marker movement. The intrabreath-hold tumor was small in all directions. The group PTV margins of 3.8 (LR), 4.6 (AP), and 4.8 (CC) mm were evaluated to account for both setup errors and residual tumor motion during irradiation. CONCLUSIONS: The study applies the DIBH technique in conjunction with IR positional tracking for tumor immobilization and treatment setup localization. The technique not only proved to be reliable in terms of good tumor immobility and accurate treatment positioning but also to be potentially useful for dose escalation treatment as regarding of the substantially reduced PTV margin and minimizing radiation toxicity from the fully expanded lung volume. PMID- 20964187 TI - Dosimetric characterization of a multileaf collimator for a new four-dimensional image-guided radiotherapy system with a gimbaled x-ray head, MHI-TM2000. AB - PURPOSE: To present the dosimetric characterization of a multileaf collimator (MLC) for a new four-dimensional image-guided radiotherapy system with a gimbaled x-ray head, MHI-TM2000. METHODS: MHI-TM2000 has an x-ray head composed of an ultrasmall linear accelerator guide and a system-specific MLC. The x-ray head can rotate along the two orthogonal gimbals (pan and tilt rotations) up to +/- 2.5 degrees, which swings the beam up to +/- 41.9 mm in each direction from the isocenter on the isocenter plane perpendicular to the beam. The MLC design is a single-focus type, has 30 pairs of 5 mm thick leaves at the isocenter, and produces a maximum field size of 150 x 150 mm2. Leaf height and length are 110 and 260 mm, respectively. Each leaf end is circular, with a radius of curvature of 370 mm. The distance that each leaf passes over the isocenter is 77.5 mm. Radiation leakage between adjacent leaves is minimized by an interlocking tongue and-groove (T&G) arrangement with the height of the groove part 55 mm. The dosimetric characterizations including field characteristics, leaf position accuracy, leakage, and T&G effect were evaluated using a well-commissioned 6 MV photon beam, EDR2 films (Kodak, Rochester, NY), and water-equivalent phantoms. Furthermore, the field characteristics and leaf position accuracy were evaluated under conditions of pan or tilt rotation. RESULTS: The differences between nominal and measured field sizes were within +/- 0.5 mm. Although the penumbra widths were greater with wider field size, the maximum width was < 5.5 mm even for the fully opened field. Compared to the results of field characteristics without pan or tilt rotation, the variation in field size, penumbra width, flatness, and symmetry was within +/- 1 mm/l% at the maximum pan or tilt rotational angle. The leaf position accuracy was 0.0 +/- 0.1 mm, ranging from 0.3 to 0.2 mm at four gantry angles of 0 degrees, 90 degrees, 180 degrees, and 270 degrees with and without pan or tilt rotation. The interleaf leakage was up to 0.21%, whereas the intraleaf leakage was < 0.12%. T&G decreased the doses by 10.7%, on average. CONCLUSIONS: This study demonstrated that MHI-TM2000 has the capability for high leaf position accuracy and low leakage, leading to highly accurate intensity-modulated radiotherapy delivery. Furthermore, substantial changes in the dosimetric data on field characteristics and leaf position accuracy were not observed even at the maximum pan or tilt rotation. PMID- 20964188 TI - Comparison of GEANT4 very low energy cross section models with experimental data in water. AB - PURPOSE: The GEANT4 general-purpose Monte Carlo simulation toolkit is able to simulate physical interaction processes of electrons, hydrogen and helium atoms with charge states (H0, H+) and (He0, He+, He2+), respectively, in liquid water, the main component of biological systems, down to the electron volt regime and the submicrometer scale, providing GEANT4 users with the so-called "GEANT4-DNA" physics models suitable for microdosimetry simulation applications. The corresponding software has been recently re-engineered in order to provide GEANT4 users with a coherent and unique approach to the simulation of electromagnetic interactions within the GEANT4 toolkit framework (since GEANT4 version 9.3 beta). This work presents a quantitative comparison of these physics models with a collection of experimental data in water collected from the literature. METHODS: An evaluation of the closeness between the total and differential cross section models available in the GEANT4 toolkit for microdosimetry and experimental reference data is performed using a dedicated statistical toolkit that includes the Kolmogorov-Smirnov statistical test. The authors used experimental data acquired in water vapor as direct measurements in the liquid phase are not yet available in the literature. Comparisons with several recommendations are also presented. RESULTS: The authors have assessed the compatibility of experimental data with GEANT4 microdosimetry models by means of quantitative methods. The results show that microdosimetric measurements in liquid water are necessary to assess quantitatively the validity of the software implementation for the liquid water phase. Nevertheless, a comparison with existing experimental data in water vapor provides a qualitative appreciation of the plausibility of the simulation models. The existing reference data themselves should undergo a critical interpretation and selection, as some of the series exhibit significant deviations from each other. CONCLUSIONS: The GEANT4-DNA physics models available in the GEANT4 toolkit have been compared in this article to available experimental data in the water vapor phase as well as to several published recommendations on the mass stopping power. These models represent a first step in the extension of the GEANT4 Monte Carlo toolkit to the simulation of biological effects of ionizing radiation. PMID- 20964189 TI - A PET supersets data framework for exploitation of known motion in image reconstruction. AB - PURPOSE: Motion during PET data acquisition is either introduced by design (e.g., couch wobble to enrich data sampling) or through unintentional motion of the object under study (e.g., subject head motion). Prior to this present work, such effects have been considered within distinctly different frameworks in PET imaging, with a rather basic approach having been devised for the cases of intentional motion (such as couch wobble or bed translation) in contrast to the relatively advanced modeling approaches devised for object motion. This article unifies the treatment of these different types of acquisition motion within a generalized framework through the use of the PET supersets data format. From this general framework, a range of conventional motion-compensation methods can be examined as special cases, permitting a revealing investigation into both the suboptimality of commonly adopted approximations, as well as the beneficial impact of known acquisition motion on image quality. METHODS: The PET superset data format is a data representation ideally suited for the (potentially lossless) combination of conventional PET data with complementary motion information. Different practical implementations for the reconstruction from PET superset data involving varying levels of approximation to facilitate computation are identified and their impact on the final reconstructed image quality is assessed. Three main simulated case studies are investigated: (i) Motion compensation for subject head motion for 18F-FDG imaging, (ii) motion exploitation using either couch wobble or random motion, and (iii) motion exploitation using involuntary object motion both with and without couch wobble occurring. The motion exploitation case study goes beyond merely correcting for motion: The motion is directly modeled by the iterative reconstruction to exploit the increased sampling which is available to the benefit of reconstructed image quality. RESULTS: Reconstruction from superset data was successfully demonstrated for the case of motion correction for a 18F-FDG brain phantom simulation. Building on this success, the methodology was then applied to the case of motion exploitation. The case study resulted in three important findings. First, only reconstruction implementations which model the motion directly within the iterative reconstruction can succeed in significantly improving image resolution and contrast recovery for a given reconstructed noise level. Therefore, the commonly adopted approximation of binning the motion-adjusted data (which is the only method reported to date in the literature) is suboptimal and underestimates the beneficial impact of methods such as wobble during acquisition. Second, similar improvements were found for both types of motion patterns: Periodic wobble motion as well as random motion. Finally, for the case of simulated realistic involuntary object motion, similar resolution improvements were found (both with and without couch wobble). CONCLUSIONS: The proposed superset framework allows comprehensive analysis of the commonly adopted approximations when considering motion in PET reconstruction. The findings demonstrate that the supersets data format successfully unify reconstruction in the presence of different sources of known acquisition motion into one framework, and as a result leads to hitherto unreported image quality improvements for all the cases tested where the object motion is accurately known. PMID- 20964190 TI - Lung dosimetry in a linac-MRI radiotherapy unit with a longitudinal magnetic field. AB - PURPOSE: There is interest in developing linac-MR systems for MRI-guided radiation therapy. To date, the designs for such linac-MR devices have been restricted to a transverse geometry where the static magnetic field is oriented perpendicular to the direction of the incident photon beam. This work extends possibilities in this field by proposing and examining by Monte Carlo simulations, a probable longitudinal configuration where the magnetic field is oriented in the same direction as the photon beam. METHODS: The EGSnrc Monte Carlo (MC) radiation transport codes with algorithms implemented to account for the magnetic field deflection of charged particles were used to compare dose distributions for linac-MR systems in transverse and longitudinal geometries. Specifically, the responses to a 6 MV pencil photon beam incident on water and lung slabs were investigated for 1.5 and 3.0 T magnetic fields. Further a five field lung plan was simulated in the longitudinal and transverse geometries across a range of magnetic field strengths from 0.2 through 3.0 T. RESULTS: In a longitudinal geometry, the magnetic field is shown to restrict the radial spread of secondary electrons to a small degree in water, but significantly in low density tissues such as lung in contrast to the lateral shift in dose distribution seen in the transverse geometry. These effects extend to the patient case, where the longitudinal configuration demonstrated dose distributions more tightly confined to the primary photon fields, which increased dose to the planning target volume (PTV), bettered dose homogeneity within a heterogeneous (in density) PTV, and reduced the tissue interface effects associated with the transverse geometry. CONCLUSIONS: Dosimetry issues observed in a transverse linac MR geometry such as changes to the depth dose distribution and tissue interface effects were significantly reduced or eliminated in a longitudinal geometry on a representative lung plan. Further, an increase in dose to the PTV, resulting from the magnetic field confining electrons to the forward direction, shows potential for a reduction in dose to the surrounding tissues. PMID- 20964191 TI - Dosimetric impact of an 192Ir brachytherapy source cable length modeled using a grid-based Boltzmann transport equation solver. AB - PURPOSE: To evaluate the dose distributions of an 192Ir source (model VS2000) in homogeneous water geometry calculated using a deterministic grid-based Boltzmann transport equation solver (GBBS) in the commercial treatment planning system (TPS) (BRACHYVISION-ACUROS V8.8). METHODS: Using percent dose differences (%deltaD), the GBBS (BV-ACUROS) was compared to the (1) published TG-43 data, (2) MCNPX Monte Carlo (MC) simulations of the 192Ir source centered in a 15 cm radius water sphere, and (3) TG-43 output from the TPS using vendor supplied (BV-TG43 vendor) and user extended (BV-TG43-extended) 2D anisotropy functions F(r, theta). BV-ACUROS assumes 1 mm of NiTi cable, while the TPS TG-43 algorithm uses data based on a 15 cm cable. MC models of various cable lengths were simulated. RESULTS: The MC simulations resulted in > 20% dose deviations along the cable for 1, 2, and 3 mm cable lengths relative to 15 cm. BV-ACUROS comparisons with BV TG43-vendor and BV-TG43-extended yielded magnitude of differences, consistent with those seen in MC simulations. However, differences > 20% extended further (theta < or = 10 degrees) when using the vendor supplied anisotropy function F(ven0(r, theta). These differences were also seen in comparisons of F(r, theta) derived from the TPS output. CONCLUSIONS: The results suggest that %deltaD near the cable region is larger than previously estimated. The spatial distribution of the dose deviation is highly dependent on the reference TG-43 data used to compare to GBBS. The differences observed, while important to realize, should not have an impact on clinical dosimetry in homogeneous water. PMID- 20964192 TI - The accuracy and safety aspects of a novel robotic needle guide manipulator to perform transrectal prostate biopsies. AB - PURPOSE: To introduce a new in-house developed pneumatically controlled magnetic field compatible manipulator as an aid to perform magnetic resonance (MR)-guided biopsies of the prostate. METHODS: A pneumatic controlled manipulator with five degrees of freedom constructed of plastic to achieve magnetic field compatibility was developed to guide biopsies. A risk analysis, mechanical tests, and RF safety tests with respect to needle tip heating were performed to assure future patient safety and to meet standard safety requirements for the use in a medical environment. The accuracy of needle positioning with the needle guide manipulator to sample a predefined target was measured in agar phantoms on a 3 T whole body MR system. The in-plane error was used to evaluate the accuracy, which is defined as the orthogonal distance between target and biopsy needle. The time for each step in the biopsy procedure was recorded to evaluate the procedure time. The influence of the insertion angle with respect to the static field of the MR scanner on the needle artifact was investigated. RESULTS: The risk analyses met patient safety requirements. No RF induced local heating around the needle tip was observed. The average in-plane error in 19 measurements was 3.0 mm (range 0 5.6 mm). The average time needed for manipulation to place the needle guide in the desired position was 5 min (range 3-8 min). Total procedure time was 30 min. The needle artifact size increases with the insertion angle with respect to the static field of the MR scanner. CONCLUSIONS: The new MR compatible manipulator can be used safely for patient care. It showed a high accuracy and short total procedure time, demonstrating great potential to improve the transrectal prostate biopsy procedure. PMID- 20964193 TI - Waveguide detuning caused by transverse magnetic fields on a simulated in-line 6 MV linac. AB - PURPOSE: Due to the close proximity of the linear accelerator (linac) to the magnetic resonance (MR) imager in linac-MR systems, it will be subjected to magnet fringe fields larger than the Earth's magnetic field of 5 x 10(-5) T. Even with passive or active shielding designed to reduce these fields, some magnitude of the magnetic field is still expected to intersect the linac, causing electron deflection and beam loss. This beam loss, resulting from magnetic fields that cannot be eliminated with shielding, can cause a detuning of the waveguide due to excessive heating. The detuning, if significant, could lead to an even further decrease in output above what would be expected strictly from electron deflections caused by an external magnetic field. Thus an investigation of detuning was performed through various simulations. METHODS: According to the Lorentz force, the electrons will be deflected away from their straight course to the target, depositing energy as they impact the linac copper waveguide. The deposited energy would lead to a heating and deformation of the copper structure resulting in resonant frequency changes. PARMELA was used to determine the mean energy and fraction of total beam lost in each linac cavity. The energy deposited into the copper waveguide from the beam losses caused by transverse magnetic fields was calculated using the Monte Carlo program DOSRZnrc. From the total energy deposited, the rise in temperature and ultimately the deformation of the structure was estimated. The deformed structure was modeled using the finite element method program COMSOL MULTIPHYSICS to determine the change in cavity resonant frequency. RESULTS: The largest changes in resonant frequency were found in the first two accelerating cavities for each field strength investigated. This was caused by a high electron fluence impacting the waveguide inner structures coupled with their low kinetic energies. At each field strength investigated, the total change in accelerator frequency was less than a manufacturing tolerance of 10 kHz and is thus not expected to have a noticeable effect on accelerator performance. CONCLUSIONS: The amount of beam loss caused by magnetic fringe fields for a linac in a linac-MR system depends on the effectiveness of its magnetic shielding. Despite the best efforts to shield the linac from the magnetic fringe fields, some persistent magnetic field is expected which would result in electron beam loss. This investigation showed that the detuning of the waveguide caused by additional electron beam loss in persistent magnetic fields is not a concern. PMID- 20964194 TI - Magnetic decoupling of the linac in a low field biplanar linac-MR system. AB - PURPOSE: The integration of a low field biplanar magnetic resonance (MR) imager and linear accelerator (linac) causes magnetic interference at the linac due to the MR fringe fields. In order to eliminate this interference, passive and active magnetic shielding designs are investigated. METHODS: The optimized design of passive magnetic shielding was performed using the finite element method. The design was required to achieve no greater than a 20% electron beam loss within the linac waveguide and electron gun, no greater than 0.06 T at the multileaf collimator (MLC) motors, and generate a distortion of the main MR imaging volume of no greater than 300 ppm. Through the superposition of the analytical solution for a single current carrying wire loop, active shielding designs in the form of three and four sets of coil pairs surrounding the linac waveguide and electron gun were also investigated. The optimized current and coil center locations that yielded the best cancellation of the MR fringe fields at the linac were determined using sequential quadratic programming. RESULTS: Optimized passive shielding in the form of two steel cylinders was designed to meet the required constraints. When shielding the MLC motors along with the waveguide and electron gun, the thickness of the cylinders was less than 1 mm. If magnetically insensitive MLC motors are used, no MLC shielding would be required and the waveguide shield (shielding the waveguide and electron gun) became 1.58 mm thick. In addition, the optimized current and coil spacing for active shielding was determined for both three and four coil pair configurations. The results of the active shielding optimization produced no beam loss within the waveguide and electron gun and a maximum MR field distortion of 91 ppm over a 30 cm diameter spherical volume. CONCLUSIONS: Very simple passive and active shielding designs have been shown to magnetically decouple the linac from the MR imager in a low field biplanar linac-MR system. The MLC passive shielding produced the largest distortion of the MR field over the imaging volume. With the use of magnetically insensitive motors, the MR field distortion drops substantially since no MLC shield is required. The active shielding designs yielded no electron beam loss within the linac. PMID- 20964195 TI - A wavelet-based SPECT reconstruction algorithm for nonuniformly attenuated Radon transform. AB - PURPOSE: Single photon emission computed tomography (SPECT) is a tomography technique that can greatly show information about the metabolic activity in the body and improve the clinical diagnosis. In SPECT, because of photoelectric absorption and Compton scattering, the emitted gamma photons are attenuated inside the body before arriving at the detector. The goal of quantitative SPECT reconstruction is to obtain an accurate image of the radioactivity distribution in the interested area of a human body, so the compensation for nonuniform attenuation and the treatment of Poisson noise are necessary in the quantitative SPECT reconstruction. METHODS: The authors know that the wavelet transform has characteristics of multiresolution and localized nature, and these characteristics can be applied for denoising and localized reconstruction. Based on the explicit inversion formula for the attenuated Radon transform, the authors present a wavelet-based SPECT reconstruction algorithm with compensation for nonuniform attenuation. RESULTS: The wavelet-based SPECT reconstruction algorithm offers the ability for denoising in the reconstruction processing. In simulation, 128 projections were simulated evenly spaced over 360 degrees by a circular orbit, each with 128 bins. Simulation results show that the wavelet-based denoising is effective in SPECT reconstruction. CONCLUSIONS: The authors present a wavelet-based SPECT reconstruction algorithm with compensation for nonuniform attenuation. The reconstruction results from computer simulations show that the wavelet-based SPECT reconstruction algorithm is accurate. PMID- 20964196 TI - Comparison between diffusion-weighted imaging, T2-weighted, and postcontrast T1 weighted imaging after MR-guided, high intensity, focused ultrasound treatment of uterine leiomyomata: preliminary results. AB - PURPOSE: To investigate the comparison between diffusion-weighted imaging (DWI), T2-weighted imaging, (T2WI) and contrast T1-weighted imaging (cT1WI) in uterine leiomyoma following treatment by magnetic resonance imaging-guided, high intensity focused ultrasound surgery (MRg-HIFUS). METHODS: Twenty one patients (45 +/- 5 yrs) with clinical symptoms of uterine leiomyoma (fibroids) were treated by MRg-HIFUS using an integrated 1.5T MRI-HIFUS system. MRI parameters consisted of DWI, T2WI, and T1-weighted fast spoiled gradient echo before and after contrast. The post-MRg-HIFUS treatment volume in the fibroid was assessed by cT1WI and DWI. Trace apparent diffusion coefficient maps were constructed for quantitative analysis. The regions of the treated uterine tissue were defined by a semisupervised segmentation method called the "eigenimage filter," using both cT1WI and DWI. Signal-to-noise ratios were determined for the T2WI pretreatment images. Segmented regions were tested by a similarity index for congruence. Descriptive, regression, and Bland-Altman statistics were calculated. RESULTS: All the patients exhibited heterogeneously increased DWI signal intensity localized in the treated fibroid regions and were colocalized with the cT1WI defined area. The mean pretreatment T2WI signal intensity ratios were T2WI/muscle = 1.8 +/- 0.7 and T2WI/myometrium = 0.7 +/- 0.4. The congruence between the regions was significant, with a similarity of 84% and a difference of 8% between the regions. Regression analyses of the cT1WI and DWI segmented treatment volume were found to be significantly correlated (r2 = 0.94, p < 0.05) with the linear equation, (cT1WI) = 1.1 (DWI)-0.66. There is good agreement between the regions defined by cT1WI and DWI in most of the cases as shown from the Bland-Altman plots. CONCLUSIONS: Diffusion-weighted imaging exhibited excellent agreement, congruence, and correlation with the cT1WI-defined region of treatment in uterine fibroid. Therefore, DWI could be useful as an adjunct for assessing treatment of uterine fibroids by MRg-HIFUS. PMID- 20964197 TI - In vivo imaging and treatment of solid tumor using integrated photoacoustic imaging and high intensity focused ultrasound system. AB - PURPOSE: The purpose of this study is to show the feasibility of combined contrast imaging and treatment of solid tumor in vivo by an integrated photoacoustic imaging and high intensity focused ultrasound (HIFU) system. METHODS: During this study, photoacoustic imaging was performed to identify the location of a CT26 tumor, which was subcutaneously inoculated on the hip of a BALB/c mouse. Then the CT26 tumor was ablated by HIFU with the guidance of photoacoustic images. To enhance the contrast and specificity of photoacoustic imaging, gold nanorods were used as the contrast agents during the experiment. After being injected into the blood stream, gold nanorods passively accumulated around the tumor region, and therefore outlined the location and shape of the tumor in the photoacoustic images, which were used to guide the subsequent HIFU therapy. RESULTS: The experiment results showed that the tumor was clearly visible on photoacoustic images after the injection of gold nanorods and HIFU was able to ablate the tumor under the guidance of photoacoustic imaging. CONCLUSIONS: The authors demonstrated that their integrated photoacoustic imaging and HIFU system has the potential for contrast imaging with gold nanorods with possible diagnosis and treatment of solid tumors. PMID- 20964198 TI - Implementation of radiochromic film dosimetry protocol for volumetric dose assessments to various organs during diagnostic CT procedures. AB - PURPOSE: The authors present a means to measure high-resolution, two-dimensional organ dose distributions in an anthropomorphic phantom of heterogeneous tissue composition using XRQA radiochromic film. Dose distributions are presented for the lungs, liver, and kidneys to demonstrate the organ volume dosimetry technique. XRQA film response accuracy was validated using thermoluminescent dosimeters (TLDs). METHODS: XRQA film and TLDs were first exposed at the center of two CTDI head phantoms placed end-to-end, allowing for a simple cylindrical phantom of uniform scatter material for verification of film response accuracy and sensitivity in a computed tomography (CT) exposure geometry; the TLD and film dosimeters were exposed separately. In a similar manner, TLDs and films were placed between cross-sectional slabs of a 5 yr old anthropomorphic phantom's thorax and abdomen regions. The anthropomorphic phantom was used to emulate real pediatric patient geometry and scatter conditions. The phantom consisted of five different tissue types manufactured to attenuate the x-ray beam within 1%-3% of normal tissues at CT beam energies. Software was written to individually calibrate TLD and film dosimeter responses for different tissue attenuation factors, to spatially register dosimeters, and to extract dose responses from film for TLD comparison. TLDs were compared to film regions of interest extracted at spatial locations corresponding to the TLD locations. RESULTS: For the CTDI phantom exposure, the film and TLDs measured an average difference in dose response of 45% (SD +/- 2%). Similar comparisons within the anthropomorphic phantom also indicated a consistent difference, tracking along the low and high dose regions, for the lung (28%) (SD +/- 8%) and liver and kidneys (15%) (SD +/- 4%). The difference between the measured film and TLD dose values was due to the lower response sensitivity of the film that arose when the film was oriented with its large surface area parallel to the main axis of the CT beam. The consistency in dose response difference allowed for a tissue specific correction to be applied. Once corrected, the average film response agreed to better than 3% (SD +/- 2%) for the CTDI scans, and for the anthropomorphic phantom scans: 3% (SD +/- 3%) for the lungs, 5% (SD +/- 3%) for the liver, and 4% (SD +/- 3%) for the kidneys. Additionally, XRQA film measured a heterogeneous dose distribution within the organ volumes. The extent of the dose distribution heterogeneity was not measurable with the TLDs due to the limitation on the number of TLDs loadable in the regions of the phantom organs. In this regard, XRQA film demonstrated an advantage over the TLD method by discovering a 15% greater maximum dose to lung in a region unmeasured by TLDs. CONCLUSIONS: The films demonstrated a lower sensitivity to absorbed dose measurements due to the geometric inefficiency of measuring dose from a beam situated end-on to the film. Once corrected, the film demonstrated equivalent dose measurement accuracy as TLD detectors with the added advantage of relatively simple measurement of high-resolution dose distributions throughout organ volumes. PMID- 20964199 TI - Longitudinal assessment of lung cancer progression in the mouse using in vivo micro-CT imaging. AB - PURPOSE: Small animal micro-CT imaging is being used increasingly in preclinical biomedical research to provide phenotypic descriptions of genomic models. Most of this imaging is coincident with animal death and is used to show the extent of disease as an end point. Longitudinal imaging overcomes the limitation of single time-point imaging because it enables tracking of the natural history of disease and provides qualitative and, where possible, quantitative assessments of the effects of an intervention. The pulmonary system is affected by many disease conditions, such as lung cancer, chronic obstructive pulmonary disease, asthma, and granulomatous disorders. Noninvasive imaging can accurately assess the lung phenotype within the living animal, evaluating not only global lung measures, but also regional pathology. However, imaging the lung in the living animal is complicated by rapid respiratory motion, which leads to image based artifacts. Furthermore, no standard mouse lung imaging protocols exist for longitudinal assessment, with each group needing to develop their own systematic approach. METHODS: In this article, the authors present an outline for performing longitudinal breath-hold gated micro-CT imaging for the assessment of lung nodules in a mouse model of lung cancer. The authors describe modifications to the previously published intermittent isopressure breath-hold technique including a new animal preparation and anesthesia protocol, implementation of a ring artifact reduction, variable scanner geometry, and polynomial beam hardening correction. In addition, the authors describe a multitime-point data set registration and tumor labeling and tracking strategy. RESULTS: In vivo micro-CT data sets were acquired at months 2, 3, and 4 posturethane administration in cancer mice (n = 5) and simultaneously in control mice (n = 3). 137 unique lung nodules were identified from the cancer mice while no nodules were detected in the control mice. A total of 411 nodules were segmented and labeled over the three time-points. Lung nodule metrics including RECIST, Ortho, WHO, and 3D volume were determined and extracted. A tumor incidence rate of 30.44 +/- 1.93 SEM for n = 5 was found with identification of nodules as small as 0.11 mm (RECIST) and as large as 1.66 mm (RECIST). In addition, the tumor growth and doubling rate between months 2-3 and 3-4 were calculated. Here, the growth rate was slightly higher in the second period based on the 3D volume data (0.12 +/- 0.13 to 0.13 +/- 0.17 microl) but significantly less based on the linear diameter metrics [RECIST (0.33 +/- 0.19 to 0.17 +/- 0.18 mm); Ortho (0.24 +/- 0.15 to 0.16 +/- 0.15 mm)], indicating the need to understand how each metric is obtained and how to correctly interpret change in tumor size. CONCLUSIONS: In conclusion, micro-CT imaging provides a unique platform for in vivo longitudinal assessment of pulmonary lung cancer progression and potentially tracking of therapies at very high resolutions. The ability to evaluate the same subject over time provides for a sensitive assay that can be carried out on a smaller sample size. When integrated with image processing and analysis routines as detailed in this study, the data acquired from micro-CT imaging can now provide a very powerful assessment of pulmonary disease outcomes. PMID- 20964200 TI - QA procedures for multimodality preclinical tumor drug response testing. AB - PURPOSE: There are growing expectations that imaging biomarkers for tumor therapeutic drug response assessment will speed up preclinical testing of anticancer drugs in rodent models. The only imaging biomarker presently approved by the U.S. Food and Drug Administration is tumor size measurement based on either World Health Organization (WHO) criteria or Response Evaluation Criteria in Solid Tumors (RECIST). Frequently, preclinical data are accumulated from multiple research centers on multiple continents using scanners from different manufacturers and sometimes even using different imaging modalities. Very expensive cancer drug response studies can be compromised by inadequate controls to assure precision and accuracy of tumor size measurements. This project was undertaken to develop standardized quality assurance (QA) procedures using a multimodality preclinical tumor response phantom to validate the accuracy of tumor size measurements based on WHO criteria, RECIST, or global tumor volume criteria for evaluation of cytostatic drugs. METHODS: A tumor response phantom containing five low contrast test objects designed to simulate animal tumor models was made of tissue-mimicking materials. Imaging of the phantom was performed using three modalities in two institutions to evaluate size measurement of tumor-simulating test objects. RESULTS: Evaluation of tumor measurements from the three commonly used imaging devices in two different institutions for monitoring tumor size changes showed that a single phantom for multiple modalities was feasible. The tumor response phantom validated precision and accuracy of tumor response data input from ultrasound, computed tomography, and/or magnetic resonance imaging devices. CONCLUSIONS: Measurement results show that the standardized QA procedures using the tumor response phantom can provide a rationale check of data that excludes input from poorly maintained instruments, inadequate measurement protocols, or random operator error that frequently introduce unacceptable variability or systematic error in multiple institutions trials. PMID- 20964201 TI - QA for helical tomotherapy: report of the AAPM Task Group 148. AB - Helical tomotherapy is a relatively new modality with integrated treatment planning and delivery hardware for radiation therapy treatments. In view of the uniqueness of the hardware design of the helical tomotherapy unit and its implications in routine quality assurance, the Therapy Physics Committee of the American Association of Physicists in Medicine commissioned Task Group 148 to review this modality and make recommendations for quality assurance related methodologies. The specific objectives of this Task Group are: (a) To discuss quality assurance techniques, frequencies, and tolerances and (b) discuss dosimetric verification techniques applicable to this unit. This report summarizes the findings of the Task Group and aims to provide the practicing clinical medical physicist with the insight into the technology that is necessary to establish an independent and comprehensive quality assurance program for a helical tomotherapy unit. The emphasis of the report is to describe the rationale for the proposed QA program and to provide example tests that can be performed, drawing from the collective experience of the task group members and the published literature. It is expected that as technology continues to evolve, so will the test procedures that may be used in the future to perform comprehensive quality assurance for helical tomotherapy units. PMID- 20964202 TI - The inter- and intrafraction reproducibilities of three common IMRT delivery techniques. AB - PURPOSE: Intensity modulated radiation therapy (IMRT) treatment delivery requires higher precision than conventional 3D treatment delivery because of the sensitivity of the resulting dose to small geometric misalignment of the modulated beamlets. The chosen treatment delivery technique will affect the treatment precision in different ways, based on the characteristics of the delivery method. Delivery using a multileaf collimator (MLC) can reduce treatment time and therapist workload, but typically requires a greater number of monitor units and the fields are prone to both systematic and random leaf positioning errors. An alternative to MLC-based fields, patient specific brass compensators, do not suffer from these leaf positioning errors. In our study, we set out to investigate which delivery method will provide the highest levels of dosimetric reproducibility and the minimum amount of interfraction variability. METHODS: In our study, a seven field IMRT plan for a head and neck treatment was created using the Pinnacle3 treatment planning system and the intensity maps for each field were obtained. The intensity maps of the fields were delivered with a Varian 2100C/D linear accelerator, using solid compensators and sliding window (SW) and step-and-shoot (SS) MLC segments. Three fields were selected from the seven-beam IMRT plan for comparison. Analysis was carried out using the MatriXX ion chamber array, radiochromic film, and Varian dynalog files. RESULTS: Our results show that the error in MLC leaf positioning has no gantry angle dependence. The compensator and SW deliveries showed excellent agreement, even when stricter than usual gamma criteria were applied. However, we noted that under these strict conditions, the SS field had at least ten times more pixels out of range than did the compensators. When using step-and-shoot MLC fields, it was observed that the increase in dose rate or the increase of MU/segment degrades the quality of the plan. Analysis of the dynalog files showed that while each individual field had its own propensity for error, all fields showed the same trend: a greater percentage of time the leaves are out of position as dose rate increases, MUs decrease, or both. CONCLUSIONS: The compensator-based field and both types of MLC-based fields have MatriXX results that are within the clinically acceptable tolerance of 3% dose difference and 2 mm DTA. However, when the criteria are tightened, it becomes evident that the compensators have a definite advantage over their comparable MLC-based competitors in terms of interfraction reproducibility. Fewer monitor units are required to deliver each portal, potentially improving patient outcomes and reducing unwanted side effects to both patients and therapists. In centers without MLC, compensators represent a simple and cost effective way to offer patients state of the art treatment. Based on the results of this study, compensator-based IMRT is a reliable, viable option for use in clinics both with and without MLC-equipped linacs. PMID- 20964204 TI - A gamma dose distribution evaluation technique using the k-d tree for nearest neighbor searching. AB - PURPOSE: The authors propose an algorithm based on the k-d tree for nearest neighbor searching to improve the gamma calculation time for 2D and 3D dose distributions. METHODS: The gamma calculation method has been widely used for comparisons of dose distributions in clinical treatment plans and quality assurances. By specifying the acceptable dose and distance-to-agreement criteria, the method provides quantitative measurement of the agreement between the reference and evaluation dose distributions. The gamma value indicates the acceptability. In regions where gamma < or = 1, the predefined criterion is satisfied and thus the agreement is acceptable; otherwise, the agreement fails. Although the concept of the method is not complicated and a quick naive implementation is straightforward, an efficient and robust implementation is not trivial. Recent algorithms based on exhaustive searching within a maximum radius, the geometric Euclidean distance, and the table lookup method have been proposed to improve the computational time for multidimensional dose distributions. Motivated by the fact that the least searching time for finding a nearest neighbor can be an O (log N) operation with a k-d tree, where N is the total number of the dose points, the authors propose an algorithm based on the k-d tree for the gamma evaluation in this work. RESULTS: In the experiment, the authors found that the average k-d tree construction time per reference point is O (log N), while the nearest neighbor searching time per evaluation point is proportional to O (N(1/k), where k is between 2 and 3 for two-dimensional and three-dimensional dose distributions, respectively. CONCLUSIONS: Comparing with other algorithms such as exhaustive search and sorted list O (N), the k-d tree algorithm for gamma evaluation is much more efficient. PMID- 20964203 TI - Radiation dose estimation using preclinical imaging with 124I metaiodobenzylguanidine (MIBG) PET. AB - PURPOSE: A pretherapy 124I-metaiodobenzylguanidine (MIBG) positron emission tomography (PET)/computed tomography (CT) provides a potential method to estimate radiation dose to normal organs, as well as tumors prior to 131I-MIBG treatment of neuroblastoma or pheochromocytoma. The aim of this work was to estimate human equivalent internal radiation dose of 124I-MIBG using PET/CT data in a murine xenograft model. METHODS: Athymic mice subcutaneously implanted with NB1691 cells that express high levels of human norepinephrine transporter (n = 4) were imaged using small animal microPET/CT over 96 h (approximate imaging time points: 0.5, 2, 24, 52, and 96 h) after intravenous administration of 3.07-4.84 MBq of 124I MIBG via tail vein. The tumors did not accumulate 124I-MIBG to a detectable level. All four animals were considered as control and organ radiation dosimetry was performed. Volumes of interest were drawn on the coregistered CT images for thyroid, heart, lung, liver, kidney, and bladder, and transferred to PET images to obtain pharmacokinetic data. Based on tabulated organ mass distributions for both mice and adult male human, preclinical pharmacokinetic data were extrapolated to their human-equivalent values. Radiation dose estimations for different age groups were performed using the OLINDA/EXM software with modified tissue weighting factors in the recent International Commission on Radiological Protection (ICRP) Publication 103. RESULTS: The mean effective dose from 124I MIBG using weighting factors from ICRP 103 to the adult male was estimated at 0.25 mSv/MBq. In different age groups, effective doses using values from ICRP 103 were estimated as follows: Adult female: 0.34, 15-yr-old: 0.39 mSv/MBq, 10-yr old: 0.58 mSv/MBq, 5-yr-old: 1.03 mSv/MBq, 1-yr-old: 1.92 mSv/MBq, and newborn: 3.75 mSv/ MBq. For comparison, the reported effective dose equivalent of 124I-NaI for adult male (25% thyroid uptake, MIRD Dose Estimate Report No. 5) was 6.5 mSv/MBq. CONCLUSIONS: The authors estimated human-equivalent internal radiation dose of 124I-MIBG using preclinical imaging data. As a reference, the effective dose estimation showed that 124I-MIBG would deliver less radiation dose than 124I NaI, a radiotracer already being used in patients with thyroid cancer. PMID- 20964205 TI - Moving target irradiation with fast rescanning and gating in particle therapy. AB - PURPOSE: In moving target irradiation with pencil beam scanning, the interplay effect between the target motion and the scanned beam is a problem because this effect causes over or under dosage in the target volume. To overcome this, we have studied rescanning using a gating technique. METHODS: A simulation and experimental study was carried out. In the experiment, we used the fast scanning system developed at the HIMAC to verify the validity of phase controlled rescanning method, in which the time for rescanning irradiation of each slice is matched to the gating duration. RESULTS: Simulation and experimental results showed that controlling the scan speed to match the respiration cycle with rescans can deliver the blurred dose distribution. In the comparison between the static measurements and the moving measurements with the phase controlled rescanning method, the dose difference was less than 2% for pinpoint chambers in the target volume. CONCLUSIONS: The simulation and experimental results demonstrated that the phase controlled rescanning method makes it possible to deliver the dose distribution close to the expected one. As an experimental result for 3D irradiation, it was estimated that blurring by the probability density function was not only for a lateral distribution, but also for a distal distribution, even in the lateral rescanning. PMID- 20964206 TI - Dosimetric evaluation of the OneDoseTM MOSFET for measuring kilovoltage imaging dose from image-guided radiotherapy procedures. AB - PURPOSE: The purpose of this study is to investigate the feasibility of using a single-use dosimeter, OneDose MOSFET designed for in vivo patient dosimetry, for measuring the radiation dose from kilovoltage (kV) x rays resulting from image guided procedures. METHODS: The OneDose MOSFET dosimeters were precalibrated by the manufacturer using Co-60 beams. Their energy response and characteristics for kV x rays were investigated by using an ionization chamber, in which the air kerma calibration factors were obtained from an Accredited Dosimetry Calibration Laboratory (ADCL). The dosimetric properties have been tested for typical kV beams used in image-guided radiation therapy (IGRT). RESULTS: The direct dose reading from the OneDose system needs to be multiplied by a correction factor ranging from 0.30 to 0.35 for kilovoltage x rays ranging from 50 to 125 kVp, respectively. In addition to energy response, the OneDose dosimeter has up to a 20% reduced sensitivity for beams (70-125 kVp) incident from the back of the OneDose detector. CONCLUSIONS: The uncertainty in measuring dose resulting from a kilovoltage beam used in IGRT is approximately 20%; this uncertainty is mainly due to the sensitivity dependence of the incident beam direction relative to the OneDose detector. The ease of use may allow the dosimeter to be suitable for estimating the dose resulting from image-guided procedures. PMID- 20964207 TI - Direction-dependent localization errors in SPECT images. AB - PURPOSE: Single photon emission computed tomography (SPECT) is being investigated for imaging inside radiation therapy treatment rooms to localize biological targets. Here, computer simulations were used to analyze locational and directional dependencies in localization errors and to assess the effects of spatial resolution modeling and observer normalization on localization performance. METHODS: SPECT images of the XCAT phantom, containing 12 hot tumors, were reconstructed with detector response function compensation (DRC) and without DRC (nDRC). Numerical observers were forced to select the most suspicious tumor location, using normalized cross correlation (NXC) or un-normalized cross correlation (XC), from 3 cm diameter search volumes that each contained only one tumor. For each tumor site, localization was optimized as a function of the iteration number and postreconstruction smoothing. Localization error, the distance between true and estimated tumor positions, was calculated across the ensembles of 80 images. Direction-dependent localization bias and precision were estimated from the image ensemble. RESULTS: For the six superficial tumors in close proximity to the detector trajectory, mean localization errors were < 2 mm and were lowest or comparable using DRC-NXC, though differences from DRC-XC and nDRC-NXC were not statistically significant. DRC-NXC did provide statistically significantly better localization than nDRC-XC for five of these six tumors. At the other six sites where attenuation was more severe and the distance was generally greater between the tumor and detector, DRC typically did not show better localization than nDRC. Observer normalization improved the localization substantially for a tumor near the hotter heart. Localization errors were anisotropic and dependent on tumor location relative to the detector trajectory. CONCLUSIONS: This computer-simulation study compared localization performance for normalized and un-normalized numerical observers, which were used to estimate tumor positions in SPECT images, reconstructed with and without DRC. For tumors localized to < 2 mm on average, which are good candidates for SPECT-guided radiation therapy, localization performance typically improved by compensating for the detector response function and by using a normalized observer. The observed direction-dependent localization errors have important implications for radiation therapy and are relevant to SPECT imaging in general. PMID- 20964208 TI - Overcorrection of iodinated contrast attenuation in SPECT-CT: phantom studies. AB - PURPOSE: The authors investigated the effects of iodinated contrast agents on the quantification of radioactivity obtained using a combined single photon emission tomography (SPECT) and high resolution 16 slice computed tomography (CT) scanner. METHODS: Two conditions were evaluated: Contrast media mixed with radioisotope and the contrast media, and the radioisotope solution confined in adjacent but distinct volumes. Phantoms containing combinations of 99mTc, 111In, and 131I solutions in normal saline and contrast solutions in normal saline corresponding to the two conditions were prepared and scanned. Images were reconstructed by iterative reconstruction (ordered subset expectation maximization), with and without CT-derived attenuation maps. The reconstructed counts encoded in the reconstructed images were compared. RESULTS: Compared to normal saline, the presence of an iodinated contrast agent resulted in the underestimation of reconstructed counts in all nonattenuation corrected SPECT images. Compared to normal saline, the presence of a contrast agent resulted in the overestimation of reconstructed counts in all attenuation corrected SPECT images. The largest underestimation of reconstructed counts was 12.8% and the largest overestimation value was 35.9%. CONCLUSIONS: High concentrations of a contrast agent caused errors in the measurement of actual radiotracer reconstructed counts in phantoms. These errors could have important consequences for the use of oral and intravenous contrast in both diagnostic (qualitative) and dosimetric (quantitative) SPECT-CT imaging. The authors' findings suggest that noncontrast imaging or alternative contrast-specific attenuation correction approaches should be considered for optimal SPECT activity quantification. PMID- 20964209 TI - 4D XCAT phantom for multimodality imaging research. AB - PURPOSE: The authors develop the 4D extended cardiac-torso (XCAT) phantom for multimodality imaging research. METHODS: Highly detailed whole-body anatomies for the adult male and female were defined in the XCAT using nonuniform rational B spline (NURBS) and subdivision surfaces based on segmentation of the Visible Male and Female anatomical datasets from the National Library of Medicine as well as patient datasets. Using the flexibility of these surfaces, the Visible Human anatomies were transformed to match body measurements and organ volumes for a 50th percentile (height and weight) male and female. The desired body measurements for the models were obtained using the PEOPLESIZE program that contains anthropometric dimensions categorized from 1st to the 99th percentile for US adults. The desired organ volumes were determined from ICRP Publication 89 [ICRP, "Basic anatomical and physiological data for use in radiological protection: reference values," ICRP Publication 89 (International Commission on Radiological Protection, New York, NY, 2002)]. The male and female anatomies serve as standard templates upon which anatomical variations may be modeled in the XCAT through user-defined parameters. Parametrized models for the cardiac and respiratory motions were also incorporated into the XCAT based on high-resolution cardiac- and respiratory-gated multislice CT data. To demonstrate the usefulness of the phantom, the authors show example simulation studies in PET, SPECT, and CT using publicly available simulation packages. RESULTS: As demonstrated in the pilot studies, the 4D XCAT (which includes thousands of anatomical structures) can produce realistic imaging data when combined with accurate models of the imaging process. With the flexibility of the NURBS surface primitives, any number of different anatomies, cardiac or respiratory motions or patterns, and spatial resolutions can be simulated to perform imaging research. CONCLUSIONS: With the ability to produce realistic, predictive 3D and 4D imaging data from populations of normal and abnormal patients under various imaging parameters, the authors conclude that the XCAT provides an important tool in imaging research to evaluate and improve imaging devices and techniques. In the field of x-ray CT, the phantom may also provide the necessary foundation with which to optimize clinical CT applications in terms of image quality versus radiation dose, an area of research that is becoming more significant with the growing use of CT. PMID- 20964210 TI - Effect of longitudinal magnetic fields on a simulated in-line 6 MV linac. AB - PURPOSE: Linac-magnetic resonance (MR) systems have been proposed in order to achieve realtime image guided radiotherapy. The design of a new linac-MR system with the in-line 6 MV linac generating x-rays along the symmetry axis of an open MR imager is outlined. This new design allows for a greater MR field strength to achieve better quality images while reducing hot and cold spots in treatment planning. An investigation of linac's performance in the longitudinal fringe magnetic fields of the MR imager is given. METHODS: The open MR imager fringe magnetic field was modeled using the analytic solution of the magnetic field generated from current carrying loops. The derived solution was matched to the magnetic fringe field isolines provided for a 0.5 T open MR imager through Monte Carlo optimization. The optimized field solution was then added to the previously validated 6 MV linac simulation to quantify linac's performance in the fringe magnetic field of a 0.5 T MR imager. To further the investigation, linac's performance in large fringe fields expected from other imagers was investigated through the addition of homogeneous longitudinal fields. RESULTS: The Monte Carlo optimization of the analytic current loop solution provided good agreement with the magnetic fringe field isolines supplied by the manufacturer. The range of magnetic fields the linac is expected to experience when coupled to the 0.5 T MR imager was determined to be from 0.0022 to 0.011 T (as calculated at the electron gun cathode). The effect of the longitudinal magnetic field on the electron beam was observed to be only in the electron gun. The longitudinal field changed the electron gun optics, affecting beam characteristics, such as a slight increase in the injection current and beam diameter, and an increasingly nonlaminar transverse phase space. Although the target phase space showed little change in its energy spectrum from the altered injection phase space, a reduction in the target current and spatial distribution peak intensity was observed. Despite these changes, the target phase space had little effect on the depth dose curves or dose profiles calculated for a 40 x 40 cm2 field at 1.5 cm depth. At longitudinal fields larger than 0.012 T, a drastic reduction in the injection current from the electron gun was observed due to a large fraction of electrons striking the anode. This further reduced the target current, which reached a minimum of 28 +/- 2 mA at 0.06 T. A slow increase in the injection and target currents was observed at fields larger than 0.06 T due to greater beam collimation in the anode beam tube. CONCLUSIONS: In an effort to achieve higher quality images and a reduction in hot and cold spots in the treatment plan, a parallel configuration linac-MR system is presented. The longitudinal magnetic fields of the MR imager caused large beam losses within the electron gun. These losses may be eliminated through a redesign of the electron gun optics incorporating a longitudinal magnetic field, or through magnetic shielding, which has already been proven successful for the transverse configuration. PMID- 20964211 TI - Technical note: calculation of normal tissue complication probability using Gaussian error function model. AB - PURPOSE: The Gaussian error function was first used and verified in normal tissue complication probability (NTCP) calculation to reduce the dose-volume histogram (DVH) database by replacing the dose-volume bin set with the error function parameters for the differential DVH (dDVH). METHODS: Seven-beam intensity modulated radiation therapy (IMRT) treatment planning was performed in three patients with small (40 cm3), medium (53 cm3), and large (87 cm3) prostate volume, selected from a group of 20 patients. Rectal dDVH varying with the interfraction prostate motion along the anterior-posterior direction was determined by the treatment planning system (TPS) and modeled by the Gaussian error function model for the three patients. Rectal NTCP was then calculated based on the routine dose-volume bin set of the rectum by the TPS and the error function model. The variations in the rectal NTCP with the prostate motion and volume were studied. RESULTS: For the ranges of prostate motion of 8-2, 4-8, and 4-3 mm along the anterior-posterior direction for the small, medium, and large prostate patient, the rectal NTCP was determined varying in the ranges of 4.6% 4.8%, 4.5%-4.7%, and 4.6%-4.7%, respectively. The deviation of the rectal NTCP calculated by the TPS and the Gaussian error function model was within +/- 0.1%. CONCLUSIONS: The Gaussian error function was successfully applied in the NTCP calculation by replacing the dose-volume bin set with the model parameters. This provides an option in the NTCP calculation using a reduced size of dose-volume database. Moreover, the rectal NTCP was found varying in about +/- 0.2% with the interfraction prostate motion along the anterior-posterior direction in the radiation treatment. The dependence of the variation in the rectal NTCP with the interfraction prostate motion on the prostate volume was found to be more significant in the patient with larger prostate. PMID- 20964212 TI - Assessment of 2D and 3D fractal dimension measurements of trabecular bone from high-spatial resolution magnetic resonance images at 3 T. AB - PURPOSE: In vivo two-dimensional (2D) fractal dimension (D2D) analysis of the cancellous bone at 1.5 T has been related to bone structural complexity and shown to be a potential imaging-based biomarker for osteoporosis. The objectives of this study were to assess at 3 T the in vivo feasibility of three-dimensional (3D) bone fractal dimension (D3D) analysis, analyze the relationship of D2D and D3D with osteoporosis, and investigate the relationship of D3D with spinal bone mineral density (BMD). METHODS: A total of 24 female subjects (67 +/- 7 yr old, mean +/- SD) was included in this study. The cohort consisted of 12 healthy volunteers and 12 patients with osteoporosis. MR image acquisitions were performed in the nondominant metaphysis of the distal radius with a 3 T MR scanner and an isotropic resolution of 180 microm. After segmentation and structural reconstruction, 2D and 3D box-counting algorithms were applied to calculate the fractal complexity of the cancellous bone. D2D and D3D values were compared between patients with osteoporosis and healthy subjects, and their relationship with radius BV/TV and spinal BMD was also assessed. RESULTS: Significant differences between healthy subjects and patients with osteoporosis were obtained for D3D (p < 0.001), with less differentiation for D2D (p = 0.04). The relationship between fractal dimension and BMD was not significant (r = 0.43, p = 0.16 and r = 0.23, p = 0.48, for D2D and D3D, respectively). CONCLUSIONS: The feasibility of trabecular bone D3D calculations at 3 T and the relationship of both D2D and D3D parameters with osteoporosis were demonstrated, with a better differentiation for the 3D method. Furthermore, the D3D parameter has probably a different nature of information regarding the trabecular bone status not directly explained by BMD alone. Future studies with subjects with osteopenia and larger sample sizes are warranted to further establish the potential of D2D and D3D in the study of osteoporosis. PMID- 20964213 TI - A fast optimization algorithm for multicriteria intensity modulated proton therapy planning. AB - PURPOSE: To describe a fast projection algorithm for optimizing intensity modulated proton therapy (IMPT) plans and to describe and demonstrate the use of this algorithm in multicriteria IMPT planning. METHODS: The authors develop a projection-based solver for a class of convex optimization problems and apply it to IMPT treatment planning. The speed of the solver permits its use in multicriteria optimization, where several optimizations are performed which span the space of possible treatment plans. The authors describe a plan database generation procedure which is customized to the requirements of the solver. The optimality precision of the solver can be specified by the user. RESULTS: The authors apply the algorithm to three clinical cases: A pancreas case, an esophagus case, and a tumor along the rib cage case. Detailed analysis of the pancreas case shows that the algorithm is orders of magnitude faster than industry-standard general purpose algorithms (MOSEK'S interior point optimizer, primal simplex optimizer, and dual simplex optimizer). Additionally, the projection solver has almost no memory overhead. CONCLUSIONS: The speed and guaranteed accuracy of the algorithm make it suitable for use in multicriteria treatment planning, which requires the computation of several diverse treatment plans. Additionally, given the low memory overhead of the algorithm, the method can be extended to include multiple geometric instances and proton range possibilities, for robust optimization. PMID- 20964214 TI - Response of lithium formate EPR dosimeters at photon energies relevant to the dosimetry of brachytherapy. AB - PURPOSE: To investigate experimentally the energy dependence of the detector response of lithium formate EPR dosimeters for photon energies below 1 MeV relative to that at 60Co energies. High energy photon beams are used in calibrating dosimeters for use in brachytherapy since the absorbed dose to water can be determined with high accuracy in such beams using calibrated ion chambers and standard dosimetry protocols. In addition to any differences in mass-energy absorption properties between water and detector, variations in radiation yield (detector response) with radiation quality, caused by differences in the density of ionization in the energy imparted (LET), may exist. Knowledge of an eventual deviation in detector response with photon energy is important for attaining high accuracy in measured brachytherapy dose distributions. METHODS: Lithium formate EPR dosimeters were irradiated to known levels of air kerma in 25-250 kV x-ray beams and in 137Cs and 60Co beams at the Swedish Secondary Standards Dosimetry Laboratory. Conversions from air kerma free in air into values of mean absorbed dose to the detectors were made using EGSnrc MC simulations and x-ray energy spectra measured or calculated for the actual beams. The signals from the detectors were measured using EPR spectrometry. Detector response (the EPR signal per mean absorbed dose to the detector) relative to that for 60Co was determined for each beam quality. RESULTS: Significant decreases in the relative response ranging from 5% to 6% were seen for x-ray beams at tube voltages < or = 180 kV. No significant reduction in the relative response was seen for 137Cs and 250 kV x rays. CONCLUSIONS: When calibrated in 60Co or MV photon beams, corrections for the photon energy dependence of detector response are needed to achieve the highest accuracy when using lithium formate EPR dosimeters for measuring absorbed doses around brachytherapy sources emitting photons in the energy range of 20-150 keV such as 169Yb and electronic sources. PMID- 20964215 TI - An MCNPX Monte Carlo model of a discrete spot scanning proton beam therapy nozzle. AB - PURPOSE: The purposes of this study were to validate a discrete spot scanning proton beam nozzle using the Monte Carlo (MC) code MCNPX and use the MC validated model to investigate the effects of a low-dose envelope, which surrounds the beam's central axis, on measurements of integral depth dose (IDD) profiles. METHODS: An accurate model of the discrete spot scanning beam nozzle from The University of Texas M. D. Anderson Cancer Center (Houston, Texas) was developed on the basis of blueprints provided by the manufacturer of the nozzle. The authors performed simulations of single proton pencil beams of various energies using the standard multiple Coulomb scattering (MCS) algorithm within the MCNPX source code and a new MCS algorithm, which was implemented in the MCNPX source code. The MC models were validated by comparing calculated in-air and in-water lateral profiles and percentage depth dose profiles for single pencil beams with their corresponding measured values. The models were then further tested by comparing the calculated and measured three-dimensional (3-D) dose distributions. Finally, an IDD profile was calculated with different scoring radii to determine the limitations on the use of commercially available plane-parallel ionization chambers to measure IDD. RESULTS: The distance to agreement, defined as the distance between the nearest positions of two equivalent distributions with the same value of dose, between measured and simulated ranges was within 0.13 cm for both MCS algorithms. For low and intermediate pencil beam energies, the MC simulations using the standard MCS algorithm were in better agreement with measurements. Conversely, the new MCS algorithm produced better results for high energy single pencil beams. The IDD profile calculated with cylindrical tallies with an area equivalent to the area of the largest commercially available ionization chamber showed up to 7.8% underestimation of the integral dose in certain depths of the IDD profile. CONCLUSIONS: The authors conclude that a combination of MCS algorithms is required to accurately reproduce experimental data of single pencil beams and 3-D dose distributions for the scanning beam nozzle. In addition, the MC simulations showed that because of the low-dose envelope, ionization chambers with radii as large as 4.08 cm are insufficient to accurately measure IDD profiles for a 221.8 MeV pencil beam in the scanning beam nozzle. PMID- 20964216 TI - Feasibility of high temporal resolution breast DCE-MRI using compressed sensing theory. AB - PURPOSE: To investigate the feasibility of high temporal resolution breast DCE MRI using compressed sensing theory. METHODS: Two experiments were designed to investigate the feasibility of using reference image based compressed sensing (RICS) technique in DCE-MRI of the breast. The first experiment examined the capability of RICS to faithfully reconstruct uptake curves using undersampled data sets extracted from fully sampled clinical breast DCE-MRI data. An average approach and an approach using motion estimation and motion compensation (ME/MC) were implemented to obtain reference images and to evaluate their efficacy in reducing motion related effects. The second experiment, an in vitro phantom study, tested the feasibility of RICS for improving temporal resolution without degrading the spatial resolution. RESULTS: For the uptake-curve reconstruction experiment, there was a high correlation between uptake curves reconstructed from fully sampled data by Fourier transform and from undersampled data by RICS, indicating high similarity between them. The mean Pearson correlation coefficients for RICS with the ME/MC approach and RICS with the average approach were 0.977 +/- 0.023 and 0.953 +/- 0.031, respectively. The comparisons of final reconstruction results between RICS with the average approach and RICS with the ME/MC approach suggested that the latter was superior to the former in reducing motion related effects. For the in vitro experiment, compared to the fully sampled method, RICS improved the temporal resolution by an acceleration factor of 10 without degrading the spatial resolution. CONCLUSIONS: The preliminary study demonstrates the feasibility of RICS for faithfully reconstructing uptake curves and improving temporal resolution of breast DCE-MRI without degrading the spatial resolution. PMID- 20964217 TI - A solid-state amorphous selenium avalanche technology for low photon flux imaging applications. AB - PURPOSE: The feasibility of a practical solid-state technology for low photon flux imaging applications was investigated. The technology is based on an amorphous selenium photoreceptor with a voltage-controlled avalanche multiplication gain. If this photoreceptor can provide sufficient internal gain, it will be useful for an extensive range of diagnostic imaging systems. METHODS: The avalanche photoreceptor under investigation is referred to as HARP-DRL. This is a novel concept in which a high-gain avalanche rushing photoconductor (HARP) is integrated with a distributed resistance layer (DRL) and sandwiched between two electrodes. The avalanche gain and leakage current characteristics of this photoreceptor were measured. RESULTS: HARP-DRL has been found to sustain very high electric field strengths without electrical breakdown. It has shown avalanche multiplication gains as high as 10(4) and a very low leakage current (< or = 20 pA/mm2). CONCLUSIONS: This is the first experimental demonstration of a solid-state amorphous photoreceptor which provides sufficient internal avalanche gain for photon counting and photon starved imaging applications. PMID- 20964218 TI - A hierarchical evolutionary algorithm for multiobjective optimization in IMRT. AB - PURPOSE: The current inverse planning methods for intensity modulated radiation therapy (IMRT) are limited because they are not designed to explore the trade offs between the competing objectives of tumor and normal tissues. The goal was to develop an efficient multiobjective optimization algorithm that was flexible enough to handle any form of objective function and that resulted in a set of Pareto optimal plans. METHODS: A hierarchical evolutionary multiobjective algorithm designed to quickly generate a small diverse Pareto optimal set of IMRT plans that meet all clinical constraints and reflect the optimal trade-offs in any radiation therapy plan was developed. The top level of the hierarchical algorithm is a multiobjective evolutionary algorithm (MOEA). The genes of the individuals generated in the MOEA are the parameters that define the penalty function minimized during an accelerated deterministic IMRT optimization that represents the bottom level of the hierarchy. The MOEA incorporates clinical criteria to restrict the search space through protocol objectives and then uses Pareto optimality among the fitness objectives to select individuals. The population size is not fixed, but a specialized niche effect, domination advantage, is used to control the population and plan diversity. The number of fitness objectives is kept to a minimum for greater selective pressure, but the number of genes is expanded for flexibility that allows a better approximation of the Pareto front. RESULTS: The MOEA improvements were evaluated for two example prostate cases with one target and two organs at risk (OARs). The population of plans generated by the modified MOEA was closer to the Pareto front than populations of plans generated using a standard genetic algorithm package. Statistical significance of the method was established by compiling the results of 25 multiobjective optimizations using each method. From these sets of 12-15 plans, any random plan selected from a MOEA population had a 11.3% +/- 0.7% chance of dominating any random plan selected by a standard genetic package with 0.04% +/- 0.02% chance of domination in reverse. By implementing domination advantage and protocol objectives, small and diverse populations of clinically acceptable plans that approximated the Pareto front could be generated in a fraction of 1 h. Acceleration techniques implemented on both levels of the hierarchical algorithm resulted in short, practical runtimes for multiobjective optimizations. CONCLUSIONS: The MOEA produces a diverse Pareto optimal set of plans that meet all dosimetric protocol criteria in a feasible amount of time. The final goal is to improve practical aspects of the algorithm and integrate it with a decision analysis tool or human interface for selection of the IMRT plan with the best possible balance of successful treatment of the target with low OAR dose and low risk of complication for any specific patient situation. PMID- 20964219 TI - Detailed analysis of latencies in image-based dynamic MLC tracking. AB - PURPOSE: Previous measurements of the accuracy of image-based real-time dynamic multileaf collimator (DMLC) tracking show that the major contributor to errors is latency, i.e., the delay between target motion and MLC response. Therefore the purpose of this work was to develop a method for detailed analysis of latency contributions during image-based DMLC tracking. METHODS: A prototype DMLC tracking system integrated with a linear accelerator was used for tracking a phantom with an embedded fiducial marker during treatment delivery. The phantom performed a sinusoidal motion. Real-time target localization was based on x-ray images acquired either with a portal imager or a kV imager mounted orthogonal to the treatment beam. Each image was stored in a file on the imaging workstation. A marker segmentation program opened the image file, determined the marker position in the image, and transferred it to the DMLC tracking program. This program estimated the three-dimensional target position by a single-imager method and adjusted the MLC aperture to the target position. Imaging intervals deltaT(image) from 150 to 1000 ms were investigated for both kV and MV imaging. After the experiments, the recorded images were synchronized with MLC log files generated by the MLC controller and tracking log files generated by the tracking program. This synchronization allowed temporal analysis of the information flow for each individual image from acquisition to completed MLC adjustment. The synchronization also allowed investigation of the MLC adjustment dynamics on a considerably finer time scale than the 50 ms time resolution of the MLC log files. RESULTS: For deltaT(image) = 150 ms, the total time from image acquisition to completed MLC adjustment was 380 +/- 9 ms for MV and 420 +/- 12 ms for kV images. The main part of this time was from image acquisition to completed image file writing (272 ms for MV and 309 ms for kV). Image file opening (38 ms), marker segmentation (4 ms), MLC position calculation (16 ms), and MLC adjustment (52 ms) were considerably faster. For deltaT(image) = 1000 ms, the total time from image acquisition to completed MLC adjustment increased to 1030 +/- 62 ms (MV) and 1330 +/- 52 ms (kV) mainly because of delayed image file writing. The MLC adjustment duration was constant 52 ms (+/- 3 ms) for MLC adjustments below 1.1 mm and increased linearly for larger MLC adjustments. CONCLUSIONS: A method for detailed time analysis of each individual real-time position signal for DMLC tracking has been developed and applied to image-based tracking. The method allows identification of the major contributors to latency and therefore a focus for reducing this latency. The method could be an important tool for the reconstruction of the delivered target dose during DMLC tracking as it provides synchronization between target motion and MLC motion. PMID- 20964220 TI - Comparison of three strategies in management of independent movement of the prostate and pelvic lymph nodes. AB - PURPOSE: Concurrent irradiation of the prostate and pelvic lymph nodes is technically challenging due to treating one moving target and one immobile target. The purposes of this article are to propose a new management strategy and to compare this strategy to the conventional isocenter shift method and the previously proposed MLC-shifting method. METHODS: To cope with two target volumes (one moving and one immobile), the authors propose a new management strategy referred to as multiple adaptive plans (MAPs). This strategy involves the creation of a pool of plans for a number of potential prostate locations. Without requiring any additional hardware or software, the MAP strategy is to choose a plan from the pool that most closely matches the "prostate position of the day." This position can be determined by dual image registrations: One aligned to the implant markers in the prostate and the other aligned to the pelvic bones. This strategy was clinically implemented for a special patient with high risk prostate cancer and pathologically confirmed positive pelvic lymph nodes, requiring concurrent IMRT treatment of the prostate and pelvic lymph nodes. Because this patient had an abdominal kidney, small planning margins around the both targets were desired. Using 17 daily acquired megavoltage cone beam CTs (CBCTs), three sets of validation plans were calculated to retrospectively evaluate the MAP strategy as well as the isoshifting and MLC-shifting strategies. RESULTS: According to the validation plans, MAP, isoshifting, and MLC-shifting strategies resulted in D95 of the prostate > 95% of the daily dose on 65%, 100%, and 100% treatment days, respectively. Similarly, D95 of the pelvic lymph nodal was > 95% of the daily dose on 100%, 75%, and 94% of treatment days, respectively. CONCLUSIONS: None of the above strategies simultaneously achieved all treatment goals. Among the three strategies, the MLC shifting was most successful. Validation plans based on daily CBCTs are useful to evaluate the effectiveness of the motion management strategies and to provide additional dose guidance if further dose compensation is needed. PMID- 20964221 TI - Hybrid referenceless and multibaseline subtraction MR thermometry for monitoring thermal therapies in moving organs. AB - PURPOSE: Magnetic resonance thermometry using the proton resonance frequency (PRF) shift is a promising technique for guiding thermal ablation. For temperature monitoring in moving organs, such as the liver and the heart, problems with motion must be addressed. Multi-baseline subtraction techniques have been proposed, which use a library of baseline images covering the respiratory and cardiac cycle. However, main field shifts due to lung and diaphragm motion can cause large inaccuracies in multi-baseline subtraction. Referenceless thermometry methods based on polynomial phase regression are immune to motion and susceptibility shifts. While referenceless methods can accurately estimate temperature within the organ, in general, the background phase at organ/tissue interfaces requires large polynomial orders to fit, leading to increased danger that the heated region itself will be fitted by the polynomial and thermal dose will be underestimated. In this paper, a hybrid method for PRF thermometry in moving organs is presented that combines the strengths of referenceless and multi-baseline thermometry. METHODS: The hybrid image model assumes that three sources contribute to image phase during thermal treatment: Background anatomical phase, spatially smooth phase deviations, and focal, heat induced phase shifts. The new model and temperature estimation algorithm were tested in the heart and liver of normal volunteers, in a moving phantom HIFU heating experiment, and in numerical simulations of thermal ablation. The results were compared to multi-baseline and referenceless methods alone. RESULTS: The hybrid method allows for in vivo temperature estimation in the liver and the heart with lower temperature uncertainty compared to multi-baseline and referenceless methods. The moving phantom HIFU experiment showed that the method accurately estimates temperature during motion in the presence of smooth main field shifts. Numerical simulations illustrated the method's sensitivity to algorithm parameters and hot spot features. CONCLUSIONS: This new hybrid method for MR thermometry in moving organs combines the strengths of both multi-baseline subtraction and referenceless thermometry and overcomes their fundamental weaknesses. PMID- 20964222 TI - Event (error and near-miss) reporting and learning system for process improvement in radiation oncology. AB - PURPOSE: The value of near-miss and error reporting processes in many industries is well appreciated and typically can be supported with data that have been collected over time. While it is generally accepted that such processes are important in the radiation therapy (RT) setting, studies analyzing the effects of organized reporting and process improvement systems on operation and patient safety in individual clinics remain scarce. The purpose of this work is to report on the design and long-term use of an electronic reporting system in a RT department and compare it to the paper-based reporting system it replaced. METHODS: A specifically designed web-based system was designed for reporting of individual events in RT and clinically implemented in 2007. An event was defined as any occurrence that could have, or had, resulted in a deviation in the delivery of patient care. The aim of the system was to support process improvement in patient care and safety. The reporting tool was designed so individual events could be quickly and easily reported without disrupting clinical work. This was very important because the system use was voluntary. The spectrum of reported deviations extended from minor workflow issues (e.g., scheduling) to errors in treatment delivery. Reports were categorized based on functional area, type, and severity of an event. The events were processed and analyzed by a formal process improvement group that used the data and the statistics collected through the web-based tool for guidance in reengineering clinical processes. The reporting trends for the first 24 months with the electronic system were compared to the events that were reported in the same clinic with a paper-based system over a seven-year period. RESULTS: The reporting system and the process improvement structure resulted in increased event reporting, improved event communication, and improved identification of clinical areas which needed process and safety improvements. The reported data were also useful for the evaluation of corrective measures and recognition of ineffective measures and efforts. The electronic system was relatively well accepted by personnel and resulted in minimal disruption of clinical work. Event reporting in the quarters with the fewest number of reported events, though voluntary, was almost four times greater than the most events reported in any one quarter with the paper-based system and remained consistent from the inception of the process through the date of this report. However, the acceptance was not universal, validating the need for improved education regarding reporting processes and systematic approaches to reporting culture development. CONCLUSIONS: Specially designed electronic event reporting systems in a radiotherapy setting can provide valuable data for process and patient safety improvement and are more effective reporting mechanisms than paper-based systems. Additional work is needed to develop methods that can more effectively utilize reported data for process improvement, including the development of standardized event taxonomy and a classification system for RT. PMID- 20964224 TI - An investigation of 4D cone-beam CT algorithms for slowly rotating scanners. AB - PURPOSE: To evaluate several algorithms for 4D cone-beam computed tomography (4D CBCT) with slow rotating devices. 4D CBCT is used to perform phase-correlated (PC) reconstructions of moving objects, such as breathing patients, for example. Such motion phase-dependent reconstructions are especially useful for updating treatment plans in radiation therapy. The treatment plan can be registered more precisely to the motion of the tumor and, in consequence, the irradiation margins for the treatment, the so-called planning target volume, can be reduced significantly METHODS: In the study, several algorithms were evaluated for kilovoltage cone-beam CT units attached to linear particle accelerators. The reconstruction algorithms were the conventional PC reconstruction, the McKinnon Bates (MKB) algorithm, the prior image constrained compressed sensing (PICCS) approach, a total variation minimization (ASD-POCS) algorithm, and the auto adaptive phase correlation (AAPC) algorithm. For each algorithm, the same motion affected raw data were used, i.e., one simulated and one measured data set. The reconstruction results from the authors' implementation of these algorithms were evaluated regarding their noise and artifact levels, their residual motion blur, and their computational complexity and convergence. RESULTS: In general, it turned out that the residual motion blur was lowest in those algorithms which exclusively use data from a single motion phase. Algorithms using the image from the full data set as initialization or as a reference for the reconstruction were not capable of fully removing the motion blurring. The iterative algorithms, especially approaches based on total variation minimization, showed lower noise and artifact levels but were computationally complex. The conventional methods based on a single filtered backprojection were computationally inexpensive but suffered from higher noise and streak artifacts which limit the usability. In contrast, these methods showed to be less demanding and more predictable in their outcome than the total variation minimization based approaches. CONCLUSIONS: The reconstruction algorithms including at least one iterative step can reduce the 4 CBCT specific artifacts. Nevertheless, the algorithms that use the full data set, at least for initialization, such as MKB and PICCS in the authors' implementation, are only a trade-off and may not fully achieve the optimal temporal resolution. A predictable image quality as seen in conventional reconstruction methods, i.e., without total variation minimization, is a desirable property for reconstruction algorithms. Fast, iterative approaches such as the MKB can therefore be seen as a suitable tradeoff. PMID- 20964223 TI - Quiescent period respiratory gating for PET/CT. AB - PURPOSE: To minimize respiratory motion artifacts, this work proposes quiescent period gating (QPG) methods that extract PET data from the end-expiration quiescent period and form a single PET frame with reduced motion and improved signal-to-noise properties. METHODS: Two QPG methods are proposed andevaluated. Histogram-based quiescent period gating (H-QPG) extracts a fraction of PET data determined by a window of the respiratory displacement signal histogram. Cycle based quiescent period gating (C-QPG) extracts data with a respiratory displacement signal below a specified threshold of the maximum amplitude of each individual respiratory cycle. Performances of both QPG methods were compared to ungated and five-bin phase-gated images across 21 FDG-PET/CT patient data sets containing 31 thorax and abdomen lesions as well as with computer simulations driven by 1295 different patient respiratory traces. Image quality was evaluated in terms of the lesion SUV(max) and the fraction of counts included in each gate as a surrogate for image noise. RESULTS: For all the gating methods, image noise artifactually increases SUV(max) when the fraction of counts included in each gate is less than 50%. While simulation data show that H-QPG is superior to C QPG, the H-QPG and C-QPG methods lead to similar quantification-noise tradeoffs in patient data. Compared to ungated images, both QPG methods yield significantly higher lesion SUV(max). Compared to five-bin phase gating, the QPG methods yield significantly larger fraction of counts with similar SUV(max) improvement. Both QPG methods result in increased lesion SUV(max) for patients whose lesions have longer quiescent periods. CONCLUSIONS: Compared to ungated and phase-gated images, the QPG methods lead to images with less motion blurring and an improved compromise between SUV(max) and fraction of counts. The QPG methods for respiratory motion compensation could effectively improve tumor quantification with minimal noise increase. PMID- 20964225 TI - Phantom-based experimental validation of computational fluid dynamics simulations on cerebral aneurysms. AB - PURPOSE: Recently, image-based computational fluid dynamics (CFD) simulation has been applied to investigate the hemodynamics inside human cerebral aneurysms. The knowledge of the computed three-dimensional flow fields is used for clinical risk assessment and treatment decision making. However, the reliability of the application specific CFD results has not been thoroughly validated yet. METHODS: In this work, by exploiting a phantom aneurysm model, the authors therefore aim to prove the reliability of the CFD results obtained from simulations with sufficiently accurate input boundary conditions. To confirm the correlation between the CFD results and the reality, virtual angiograms are generated by the simulation pipeline and are quantitatively compared to the experimentally acquired angiograms. In addition, a parametric study has been carried out to systematically investigate the influence of the input parameters associated with the current measuring techniques on the flow patterns. RESULTS: Qualitative and quantitative evaluations demonstrate good agreement between the simulated and the real flow dynamics. Discrepancies of less than 15% are found for the relative root mean square errors of time intensity curve comparisons from each selected characteristic position. The investigated input parameters show different influences on the simulation results, indicating the desired accuracy in the measurements. CONCLUSIONS: This study provides a comprehensive validation method of CFD simulation for reproducing the real flow field in the cerebral aneurysm phantom under well controlled conditions. The reliability of the CFD is well confirmed. Through the parametric study, it is possible to assess the degree of validity of the associated CFD model based on the parameter values and their estimated accuracy range. PMID- 20964226 TI - Assessment of variation in Elekta plastic spherical-calibration phantom and its impact on the Leksell Gamma Knife calibration. AB - PURPOSE: Traditionally, the dose-rate calibration (output) of the Leksell Gamma Knife (LGK) unit is performed using a 160 mm diameter plastic spherical phantom provided by the vendor of the LGK, Elekta Instrument AB. The purpose of this study was to evaluate variations in the Elekta spherical phantom and to assess its impact and use for the LGK calibration. METHODS: Altogether, 13 phantoms from six different centers were acquired, 10 of these phantoms were manufactured within the past 10 years and the last 3 approximately 15-20 years ago. To assess variation in phantoms, the diameter and mass densities were measured. To assess the impact on LGK calibration, the output of two models of LGK (LGK Perfexion and LGK 4C) were measured under identical irradiation conditions using all 13 phantoms for each LGK model. RESULTS: The mean measured deviation in diameter from expected nominal 160 mm for 13 phantoms was 0.51 mm (range of 0.09-1.51 mm). The mean measured phantom mass density for 13 phantoms was 1.066 +/- 0.019 g/cm3 (range of 1.046-1.102 g/cm3). The percentage deviation of output for individual phantom from mean of 13 phantom outputs ranged from -0.37% to 0.55% for LGK Perfexion. Similarly, the percentage deviation of output for individual phantom from mean of 13 phantom outputs ranged from -0.72% to 0.47% for LGK 4C. CONCLUSIONS: This study demonstrated that small variations in terms of phantom size and mass density of the phantom material do not have a significant impact on dose-rate measurements of the Leksell Gamma Knife. Also, date of manufacture of the phantom did not show up to be a significant factor in this study. PMID- 20964227 TI - A simple method for estimating the noise level in a signal region of an MR image. AB - PURPOSE: A simple extension to the NEMA MS-1 "difference of neighboring pixels" SNR method is presented, which can accurately determine the noise level within a signal region over a wide range of noise levels, image nonuniformities, and artifact levels, as demonstrated by simple simulations and experimental phantom images. METHODS: The new method computes difference of neighboring pixels in the read, phase, and diagonal directions. The variance of these three sets of pixel differences appear to contain the simple sum of the underlying variance of noise and any additional component unique to the read and phase directions, respectively, while the diagonal set of pixel differences contains all three components. By solving a set of three equations with three unknowns, it is possible to extract the components and isolate the desired noise variance term. RESULTS: Simulations show that the technique produces good results even when various artifact mechanisms present singly or jointly. Experimental results also demonstrate the technique works well but, depending on the severity of the artifact, cannot be guaranteed to always produce accurate results. CONCLUSIONS: Simulations and experimental results show the method to be accurate and robust. This method is applicable to multichannel receiver images, but not parallel reconstructed images. PMID- 20964228 TI - Optimizing principal component models for representing interfraction variation in lung cancer radiotherapy. AB - PURPOSE: To optimize modeling of interfractional anatomical variation during active breath-hold radiotherapy in lung cancer using principal component analysis (PCA). METHODS: In 12 patients analyzed, weekly CT sessions consisting of three repeat intrafraction scans were acquired with active breathing control at the end of normal inspiration. The gross tumor volume (GTV) and lungs were delineated and reviewed on the first week image by physicians and propagated to all other images using deformable image registration. PCA was used to model the target and lung variability during treatment. Four PCA models were generated for each specific patient: (1) Individual models for the GTV and each lung from one image per week (week to week, W2W); (2) a W2W composite model of all structures; (3) individual models using all images (weekly plus repeat intrafraction images, allscans); and (4) composite model with all images. Models were reconstructed retrospectively (using all available images acquired) and prospectively (using only data acquired up to a time point during treatment). Dominant modes representing at least 95% of the total variability were used to reconstruct the observed anatomy. Residual reconstruction error between the model-reconstructed and observed anatomy was calculated to compare the accuracy of the models. RESULTS: An average of 3.4 and 4.9 modes was required for the allscans models, for the GTV and composite models, respectively. The W2W model required one less mode in 40% of the patients. For the retrospective composite W2W model, the average reconstruction error was 0.7 +/- 0.2 mm, which increased to 1.1 +/- 0.5 mm when the allscans model was used. Individual and composite models did not have significantly different errors (p = 0.15, paired t-test). The average reconstruction error for the prospective models of the GTV stabilized after four measurements at 1.2 +/- 0.5 mm and for the composite model after five measurements at 0.8 +/- 0.4 mm. CONCLUSIONS: Retrospective PCA models were capable of reconstructing original GTV and lung shapes and positions within several millimeters with three to four dominant modes, on average. Prospective models achieved similar accuracy after four to five measurements. PMID- 20964229 TI - Clinical application and validation of an iterative forward projection matching algorithm for permanent brachytherapy seed localization from conebeam-CT x-ray projections. AB - PURPOSE: To experimentally validate a new algorithm for reconstructing the 3D positions of implanted brachytherapy seeds from postoperatively acquired 2D conebeam-CT (CBCT) projection images. METHODS: The iterative forward projection matching (IFPM) algorithm finds the 3D seed geometry that minimizes the sum of the squared intensity differences between computed projections of an initial estimate of the seed configuration and radiographic projections of the implant. In-house machined phantoms, containing arrays of 12 and 72 seeds, respectively, are used to validate this method. Also, four 103Pd postimplant patients are scanned using an ACUITY digital simulator. Three to ten x-ray images are selected from the CBCT projection set and processed to create binary seed-only images. To quantify IFPM accuracy, the reconstructed seed positions are forward projected and overlaid on the measured seed images to find the nearest-neighbor distance between measured and computed seed positions for each image pair. Also, the estimated 3D seed coordinates are compared to known seed positions in the phantom and clinically obtained VariSeed planning coordinates for the patient data. RESULTS: For the phantom study, seed localization error is (0.58 +/- 0.33) mm. For all four patient cases, the mean registration error is better than 1 mm while compared against the measured seed projections. IFPM converges in 20-28 iterations, with a computation time of about 1.9-2.8 min/ iteration on a 1 GHz processor. CONCLUSIONS: The IFPM algorithm avoids the need to match corresponding seeds in each projection as required by standard back-projection methods. The authors' results demonstrate approximately 1 mm accuracy in reconstructing the 3D positions of brachytherapy seeds from the measured 2D projections. This algorithm also successfully localizes overlapping clustered and highly migrated seeds in the implant. PMID- 20964230 TI - Detectability of perfusion defect in five-dimensional gated-dynamic cardiac SPECT images. AB - PURPOSE: In previous work, the authors developed and demonstrated the concept of an image reconstruction procedure aimed to unify gated and dynamic nuclear cardiac imaging, which the authors have termed five-dimensional (5D) SPECT. Gated imaging permits the clinician to evaluate wall motion and, through the use of stress and rest scans, allows perfusion defects to be observed. Dynamic imaging depicts kinetics in the myocardium, which can be used to evaluate perfusion, but traditional dynamic images are motionless and do not depict wall motion. In this article, the authors investigate the degree to which perfusion defects can be detected from the dynamic information conveyed by 5D images, a problem that is particularly challenging in the absence of multiple fast camera rotations. METHODS: The authors first demonstrate the usefulness of dynamic reconstructed images for perfusion detection by using linear discriminant analyses (Fisher linear discriminant analysis and principal component analysis) and a numerical channelized Hotelling observer. The authors then derive three types of discriminant metrics for characterizing the temporal kinetic information in reconstructed dynamic images for differentiating perfusion defects from normal cardiac perfusion, which are the Fisher linear discriminant map, temporal derivative map, and kinetic parametric images. RESULTS: Results are based on the NURBS-based cardiac-torso phantom with simulation of Tc99m-teboroxime as the imaging agent. The derived metric maps and quantitative contrast-to-noise ratio results demonstrate that the reconstructed dynamic images could yield higher detectability of the perfusion defect than conventional gated reconstruction while providing wall motion information simultaneously. CONCLUSIONS: The proposed metrics can be used to produce new types of visualizations, showing wall motion and perfusion information, that may potentially be useful for clinical evaluation. Since 5D imaging permits wall motion and kinetics to be observed simultaneously, it may ultimately obviate the need for separate stress and rest scans. PMID- 20964231 TI - Compressed sensing based cone-beam computed tomography reconstruction with a first-order method. AB - PURPOSE: This article considers the problem of reconstructing cone-beam computed tomography (CBCT) images from a set of undersampled and potentially noisy projection measurements. METHODS: The authors cast the reconstruction as a compressed sensing problem based on l1 norm minimization constrained by statistically weighted least-squares of CBCT projection data. For accurate modeling, the noise characteristics of the CBCT projection data are used to determine the relative importance of each projection measurement. To solve the compressed sensing problem, the authors employ a method minimizing total variation norm, satisfying a prespecified level of measurement consistency using a first-order method developed by Nesterov. RESULTS: The method converges fast to the optimal solution without excessive memory requirement, thanks to the method of iterative forward and back-projections. The performance of the proposed algorithm is demonstrated through a series of digital and experimental phantom studies. It is found a that high quality CBCT image can be reconstructed from undersampled and potentially noisy projection data by using the proposed method. Both sparse sampling and decreasing x-ray tube current (i.e., noisy projection data) lead to the reduction of radiation dose in CBCT imaging. CONCLUSIONS: It is demonstrated that compressed sensing outperforms the traditional algorithm when dealing with sparse, and potentially noisy, CBCT projection views. PMID- 20964232 TI - Assessment of normal tissue complications following prostate cancer irradiation: comparison of radiation treatment modalities using NTCP models. AB - PURPOSE: Normal tissue complication probability (NTCP) of the rectum, bladder, urethra, and femoral heads following several techniques for radiation treatment of prostate cancer were evaluated applying the relative seriality and Lyman models. METHODS: Model parameters from literature were used in this evaluation. The treatment techniques included external (standard fractionated, hypofractionated, and dose-escalated) three-dimensional conformal radiotherapy (3D-CRT), low-dose-rate (LDR) brachytherapy (I-125 seeds), and high-dose-rate (HDR) brachytherapy (Ir-192 source). Dose-volume histograms (DVHs) of the rectum, bladder, and urethra retrieved from corresponding treatment planning systems were converted to biological effective dose-based and equivalent dose-based DVHs, respectively, in order to account for differences in radiation treatment modality and fractionation schedule. RESULTS: Results indicated that with hypofractionated 3D-CRT (20 fractions of 2.75 Gy/fraction delivered five times/week to total dose of 55 Gy), NTCP of the rectum, bladder, and urethra were less than those for standard fractionated 3D-CRT using a four-field technique (32 fractions of 2 Gy/fraction delivered five times/week to total dose of 64 Gy) and dose-escalated 3D-CRT. Rectal and bladder NTCPs (5.2% and 6.6%, respectively) following the dose escalated four-field 3D-CRT (2 Gy/fraction to total dose of 74 Gy) were the highest among analyzed treatment techniques. The average NTCP for the rectum and urethra were 0.6% and 24.7% for LDR-BT and 0.5% and 11.2% for HDR-BT. CONCLUSIONS: Although brachytherapy techniques resulted in delivering larger equivalent doses to normal tissues, the corresponding NTCPs were lower than those of external beam techniques other than the urethra because of much smaller volumes irradiated to higher doses. Among analyzed normal tissues, the femoral heads were found to have the lowest probability of complications as most of their volume was irradiated to lower equivalent doses compared to other tissues. PMID- 20964233 TI - Improved accuracy of cortical bone mineralization measured by polychromatic microcomputed tomography using a novel high mineral density composite calibration phantom. AB - PURPOSE: Microcomputed tomography (micro-CT) is increasingly used as a nondestructive alternative to ashing for measuring bone mineral content. Phantoms are utilized to calibrate the measured x-ray attenuation to discrete levels of mineral density, typically including levels up to 1000 mg HA/cm3, which encompasses levels of bone mineral density (BMD) observed in trabecular bone. However, levels of BMD observed in cortical bone and levels of tissue mineral density (TMD) in both cortical and trabecular bone typically exceed 1000 mg HA/cm3, requiring extrapolation of the calibration regression, which may result in error. Therefore, the objectives of this study were to investigate (1) the relationship between x-ray attenuation and an expanded range of hydroxyapatite (HA) density in a less attenuating polymer matrix and (2) the effects of the calibration on the accuracy of subsequent measurements of mineralization in human cortical bone specimens. METHODS: A novel HA-polymer composite phantom was prepared comprising a less attenuating polymer phase (polyethylene) and an expanded range of HA density (0-1860 mg HA/cm3) inclusive of characteristic levels of BMD in cortical bone or TMD in cortical and trabecular bone. The BMD and TMD of cortical bone specimens measured using the new HA-polymer calibration phantom were compared to measurements using a conventional HA-polymer phantom comprising 0-800 mg HA/cm3 and the corresponding ash density measurements on the same specimens. RESULTS: The HA-polymer composite phantom exhibited a nonlinear relationship between x-ray attenuation and HA density, rather than the linear relationship typically employed a priori, and obviated the need for extrapolation, when calibrating the measured x-ray attenuation to high levels of mineral density. The BMD and TMD of cortical bone specimens measured using the conventional phantom was significantly lower than the measured ash density by 19% (p < 0.001, ANCOVA) and 33% (p < 0.05, Tukey's HSD), on average, respectively. The BMD and TMD of cortical bone specimens measured using the HA-polymer phantom with an expanded range of HA density was significantly lower than the measured ash density by 8% (p < 0.001, ANCOVA) and 10% (p < 0.05, Tukey's HSD), on average, respectively. CONCLUSIONS: The new HA-polymer calibration phantom with a less attenuating polymer and an expanded range of HA density resulted in a more accurate measurement of micro-CT equivalent BMD and TMD in human cortical bone specimens compared to a conventional phantom, as verified by ash density measurements on the same specimens. PMID- 20964234 TI - Comment on "Monte Carlo dosimetry of 60Co HDR brachytherapy sources" [Med. Phys. 30, 712-721 (2003)] PMID- 20964235 TI - Why board diversity matters. Practical ways to meet community needs. AB - Finding trustees who reflect the hospital's patient base is more important than ever. Experts offer new sources for recruitment. PMID- 20964236 TI - A tale of two hospitals. AB - Outcomes from CMS audits at two health systems illustrate the necessity of board education and crisis preparation. PMID- 20964237 TI - 2011 AHA environmental scan. AB - An annual look at trends in demographics, technology, insurance and more. PMID- 20964238 TI - Quality's moving target. AB - Reform legislation links payment to quality, and hospitals will be challenged to keep up with ever-changing measures. PMID- 20964239 TI - For hospitals and meaningful use, context is everything. AB - The final meaningful use rule aims for quality and safety gains. PMID- 20964240 TI - Driving transformational change: lessons for boards and leaders. AB - A major health care corporation shares the lessons behind its transformational change. PMID- 20964241 TI - An end to unsafe care. AB - Only accountability in the C-suite will bring an end to patient safety failures. PMID- 20964242 TI - Six essentials for managing internal candidates. AB - Internal candidates for leadership positions require special considerations. PMID- 20964243 TI - [Nursing research, taking up the definition of legitimacy]. PMID- 20964244 TI - [Re-entering movement for nurse anesthetists]. PMID- 20964245 TI - [Closing the small operative blocks, the decrees will finally be published]. PMID- 20964246 TI - Abstracts of the 35th European Society for Medical Oncology Conference. October 8 12, 2010. Milan, Italy. PMID- 20964247 TI - Stem cells: chondrogenesis induced from human embryonic stem cells. PMID- 20964248 TI - Retraction. Intralesional immunotherapy of plantar warts: report of a new antigen combination. PMID- 20964250 TI - Abstracts of WARM 2010, the 5th Congress of the World Association of Reproductive Medicine. Moscow, Russia. October 10-13, 2010. PMID- 20964249 TI - Temporal bone osteoradionecrosis after surgery and radiotherapy for malignant parotid tumors. AB - OBJECTIVE: To assess the incidence of osteoradionecrosis (ORN) of the temporal bone after surgery with radiotherapy for malignant parotid tumors. SETTING: A tertiary care, academic medical center. PATIENTS: All patients who underwent surgical resection with postoperative radiotherapy (RT) for a malignant parotid tumor between July 1988 and July 2007. INTERVENTIONS: A retrospective chart analysis to determine the extent of surgery, the RT parameters, and the incidence of ORN of the temporal bone. MAIN OUTCOME MEASURES: The incidence of ORN in 3 subgroups of patients. RESULTS: The 221 patients with malignant parotid tumors who underwent surgical resection with postoperative RT were divided into groups 1, parotidectomy only; 2, parotidectomy with mastoidectomy; and 3, parotidectomy with subtotal petrosectomy. The overall incidence of temporal bone ORN in group 1 was 2 (2%) of 106; in group 2, 8 (13%) of 64; and in group 3, 0 (0%) of 51. CONCLUSION: The incidence of temporal bone ORN is higher after mastoidectomy for facial nerve identification or resection in patients undergoing parotidectomy with postoperative radiotherapy. Oversew of the ear canal with mastoid obliteration should be considered in this subgroup of patients to avoid this long term complication of radiotherapy used in the treatment of malignant parotid tumors. PMID- 20964251 TI - Few waterproof bandages make the cut. PMID- 20964252 TI - Abstracts of the 21st International Symposium on ALS/MDS. December 11-13, 2010. Orlando, Florida, USA. PMID- 20964253 TI - Circulating proteins predict liver fibrosis in hepatitis C infection. PMID- 20964254 TI - SNPs in the APM1 gene promoter are associated with adiponectin levels in HIV infected individuals receiving HAART. AB - OBJECTIVE: This study aimed to investigate the association between 4 polymorphisms in the leptin, leptin receptor, and adiponectin (APM1) genes and the occurrence of lipodystrophy and dyslipidemia in HIV-infected patients receiving highly active antiretroviral therapy (HAART). MATERIALS AND METHODS: Genotypes of 410 HIV-infected patients on HAART were investigated. Anthropometric (weight, height, waist circumference and skinfolds thickness) and biochemical (blood lipids, glucose, leptin, and adiponectin levels) parameters were evaluated. Genotype frequencies were compared between patients with or without lipodystrophy. Mean biochemical and anthropometric parameters were compared between the different genotypes. RESULTS: Lipodystrophy prevalence was 53.4%. Genotype frequencies were not different between patients with or without lipodystrophy. Carriers of the A allele for the APM1-11391 G.A and of the C allele for APM1-11377 C.G presented higher adiponectin levels compared to other genotypes, and carriers of the -11391A-11377C haplotype when compared with carriers of other haplotypes. CONCLUSIONS: SNPs in APM1 gene are associated with adiponectin levels in HIV-infected patients receiving HAART and may thus affect the occurrence of metabolic alterations in these patients. No influence of the leptin and leptin receptor gene polymorphisms on the occurrence of lipodystrophy and dyslipidemia was observed. PMID- 20964255 TI - Proceedings of the 13th Clinicopathological Conference on Renal Allograft Pathology. July 18, 2009, Tokyo, Japan. PMID- 20964256 TI - Does needling sensation (de qi) affect treatment outcome in pain? Analysis of data from a larger single-blind, randomised controlled trial. AB - BACKGROUND: Insertion of an acupuncture needle into an acupuncture point typically generates a range of sensations called 'de qi'. Most acupuncturists are taught that obtaining de qi is important when treating patients with pain but this can be quite uncomfortable for patients. OBJECTIVE: This study assesses the importance of the strength of de qi, on the clinical outcome in osteoarthritic pain. METHOD: This study was part of a larger randomised, single-blind, multifactorial trial involving three interventions: real acupuncture (RA), Streitberger needle (SN) and mock electrical stimulation for the treatment of patients with osteoarthritis (OA) of the hip and knee. Patients were treated twice a week for 4 weeks. The two outcomes relevant to this study were pain reduction assessed by visual analogue scale and the Park needling sensation questionnaire, both measured at completion of the study. Two arms of the trial were analysed (RA and SN). Reduction in pain was correlated against strength of de qi for both RA and SN. Those who felt de qi were compared with those who did not. RESULTS: 147 patients were recruited to the study (140 completed) with a mean pain reduction of 15.2 mm and mean de qi score of 6.2. There was no significant correlation between the strength of de qi and improvement in pain (p=0.49). There was also no significant difference in pain relief (p=0.52) between those who felt de qi and those who did not using the de qi subscale of the Park questionnaire. CONCLUSION: These data suggest that the presence and intensity of de qi has no effect on the pain relief obtained for patients with OA. This result may have implications for both acupuncture treatment and for future trial methodology. PMID- 20964257 TI - Proceedings of the 13th Taishotoyama International Symposium on Gastroenterology. Shimoda, Japan. April 17 and 18, 2009. PMID- 20964258 TI - Changes in the epidemiology of hepatitis A in Spain (2005-2008): trends of acute hepatitis A hospitalizations, comorbidities, and costs associated with the hospitalization. AB - INTRODUCTION: The objective of this study is to analyze data related to hospitalization, comorbidities, median stays and costs associated with the hospitalization cases of hepatitis A in Spain, during the 2005-2008 periods. METHODS: A retrospective study of the characteristics of acute hepatitis A patients admitted to Spanish hospitals was performed using the minimum basic dataset. Costs were calculated using the diagnosis-related groups for the disease. RESULTS: The total number of hospitalized patients diagnosed with acute hepatitis A was 2395 (2.66/100,000 inhabitants); 61.5% were diagnosed in men. The highest rate corresponds to the group aged 20-39 years (4.01/100,000 inhabitants). When compared with year 2005 ascending tendencies in hospitalization was found for the year 2008 (incidence rate ratio 1.36 confidence interval 95% 1.32-1.39). Twenty-four deaths (1%) were reported out of the total of hospitalized patients. The median hospital stay was 5 days. An increase of cost from euro 1.272.608 in the year 2005 to euro 2.586.657 in 2008 was observed. Therefore, the total cost derived from these hospitalizations, above the retail price index, has increased by 90%. CONCLUSION: The incidence of hospitalized patients diagnosed with acute hepatitis A in Spain has remained stable from 2005 to 2007 and increased significantly in the year 2008. Therefore, a change in the epidemiology of hepatitis A may be taking place in Spain and this disease could become a public problem in the young adult population. It is necessary to conduct a cost-effectiveness study to assess the need for including hepatitis A in the universal immunizations schedule. PMID- 20964259 TI - High rate of adefovir-lamivudine combination therapy in nucleoside-naive patients with chronic hepatitis B in France: results of a national survey in 1730 patients. AB - BACKGROUND/AIMS: This study describes the types of therapy used in chronic hepatitis B (CHB) in France and patient characteristics according to therapy. METHODS: This was a descriptive, multicenter, retrospective study in 1730 patients (54 centers). We collected information about demographics, epidemiology, severity of hepatitis B virus-related liver disease, antiviral therapy, response (hepatitis B viral DNA and alanine aminotransferase normalization changes), dose modification, or treatment interruption. RESULTS: Approximately, 60% of patients enrolled had never been treated for CHB and 33.1% were currently receiving treatment (47% first line). Of those receiving treatment, 30% were receiving adefovir-lamivudine combination. Of those receiving first-line therapy, 40, 30, and 15% were receiving lamivudine, adefovir, or adefovir-lamivudine combination, respectively. Complete and partial virological responses were seen in 59 and 13% of patients, respectively. In patients having been treated at least once, biochemical response was seen in 45%. Lamivudine or adefovir-resistant mutants were detected in 32.6 and 22.1% of patients treated by these antiviral agents, respectively. CONCLUSION: In France, among patients with CHB, we observed that one-third were receiving therapy, and, of these, 30% were receiving first-line (15%) or second-line (15%) adefovir-lamivudine combination therapy. This observation highlights that clinical practice is influenced by available scientific data on resistance induced by monotherapy. PMID- 20964260 TI - Treatment of chronic hepatitis C with pegylated interferon and ribavirin in treatment-naive patients in 'true life': a plea in favor of independent postmarketing evaluations. AB - BACKGROUND: Results of treatments for chronic hepatitis C virus are only estimated and disclosed from pivotal trials. AIM: To report the 'true life' results of pegylated interferon and ribavirin in treatment-naive patients. METHODS: A prospective, multicenter observatory in 22 general hospitals. RESULTS: Five-hundred and one patients were included, with 309 men (62%), aged 46 +/- 11 years, weighting 70 +/- 13 kg, infected with the following hepatitis C virus genotypes: 1 (50%), 2 (12%), 3 (28%), 4 (7.5%), 5 (0.6%). Liver biopsy, available in 436 patients showed stage F3 fibrosis in 24% and F4 in 13%. Two-hundred and seven patients had a comorbid condition. Treatment consisted of interferon alpha 2b in 340 patients and interferon alpha 2a in 161 patients. Dose reductions were necessary in 145 patients (29%). Treatment was prematurely interrupted in 145 patients (29%) owing to lack of efficacy (n =72) or side-effects (n =73). Sustained virological response (SVR) rates were 50% for all patients, and 37.1, 70.5, and 71% for patients with genotype 1, 2 and 3, respectively. At multivariate analysis, age, genotype, and fibrosis severity were the only independent factors of SVR. CONCLUSION: In true life, patients are older and more severe, and SVR is about 10% lower than in pivotal trials. PMID- 20964262 TI - Exitus acta probat? PMID- 20964261 TI - Infliximab for Crohn's disease in the Swiss IBD Cohort Study: clinical management and appropriateness. AB - OBJECTIVE: Antitumor necrosis factor a agents have significantly improved the management of Crohn's disease (CD), but not all patients benefit from this therapy. We used data from the Swiss Inflammatory Bowel Disease Cohort Study and predefined appropriateness criteria to examine the appropriateness of use of infliximab (IFX) in CD patients. METHODS: EPACT II (European Panel on the Appropriateness of CD Therapy, 2007; www.epact.ch) appropriateness criteria have been developed using a formal explicit panel process combining evidence from the published literature and expert opinion. Questionnaires relating to EPACT II criteria were used at enrollment and follow-up of all Swiss Inflammatory Bowel Disease Cohort Study patients. A step-by-step analysis of all possible indications for IFX therapy in a given patient allowed identification of the most appropriate indication and final classification in a single appropriateness category (appropriate, uncertain, inappropriate). RESULTS: Eight hundred and twenty-one CD patients were prospectively enrolled between November 2006 and March 2009. IFX was administered to 146 patients (18%) at enrollment and was most frequently used for complex fistulizing disease and for the maintenance of remission induced by biological therapy. IFX therapy was considered appropriate in 44%, uncertain in 44%, and inappropriate in 10% of patients. CONCLUSION: In this cohort, 9 out of 10 indications for IFX therapy were clinically generally acceptable (appropriate or uncertain) according to EPACT II criteria. Uncertain indications resulted mainly from the current more liberal use of IFX in clinical practice as compared with the EPACT II criteria. PMID- 20964263 TI - Exitus acta probat? PMID- 20964264 TI - Against one-size-fits-all research ethics. PMID- 20964265 TI - Case study. When time won't tell. Commentary. PMID- 20964266 TI - Case study. When time won't tell. Commentary. PMID- 20964267 TI - Personalized cancer care in an age of anxiety. PMID- 20964268 TI - Wanted: human biospecimens. PMID- 20964269 TI - Direct-to-consumer genetic tests and the right to know. PMID- 20964270 TI - Mortality among members of a truck driver trade association. AB - Previous studies report that truck drivers are at increased risk for illness and on-the-job mortality. It is unknown whether owner-operator truck drivers face the same risks as employee drivers, yet few studies have targeted owner-operators as a study population. This study examined the overall and cause-specific mortality ratios for a cohort with owner-operator truck drivers constituting 69% of the study population. Of the 26 major disease classifications and 92 specific causes of death examined, only mortality due to transportation accidents was significantly elevated (standardized mortality ratio=1.52, 95% confidence interval=1.36-1.70). Leading causes of death were ischemic heart disease and lung cancer, although risk was below that of the general population. Transportation accidents pose a particular hazard for members of the trade association. The absence of excess disease mortality deserves careful interpretation, and may be due to both a strong healthy worker effect and a short monitoring period. PMID- 20964271 TI - The prevalence of seatbelt use among pediatric hospital workers. AB - Eighteen percent of drivers do not consistently wear their seatbelts when driving. The purpose of this article is to report the problem of noncompliance with seatbelt use among health care workers at a Level I pediatric trauma center in the midwest United States with evidence from a non-experimental, observational study. Results showed that 84% (n=3,641) of drivers and 73% (n=113) of passengers wore their seatbelts. A significant correlation was found between driver seatbelt use and passenger seatbelt use (p=.272, p<.001). Drivers from primary seatbelt legislation states wore their seatbelts significantly more often than drivers from the secondary seatbelt legislation state, chi(1)=0.913, p=.012. Non compliance with seatbelt use among pediatric health care workers is a problem equal to that of the general population. It may be necessary to adopt and enforce mandatory seatbelt use policies at the organizational level to increase seatbelt use in this population of hospital workers. PMID- 20964272 TI - An evidence-based approach to physician etiquette in pediatric ophthalmology. AB - PURPOSE: Little objective evidence exists to guide physician etiquette in pediatric ophthalmology. This article describes the preferences of families visiting a pediatric ophthalmology clinic for the first time. METHODS: Review of 149 questionnaires completed by the families of patients visiting a pediatric ophthalmology clinic in a tertiary care center. The Fisher exact and chi-square tests were used to compare subpopulations. RESULTS: Most respondents preferred that their physician wear a white coat. Men preferred a handshake to a verbal greeting (P = .0264) and professional to business casual attire for both male and female physicians (P = .01, both). African-American parents were more likely to prefer being addressed by surname than other races (P = .008). No statistically significant differences were found comparing the preferences of parents with an advanced education (bachelor and graduate degrees) to those without. CONCLUSION: Pediatric ophthalmologists may wish to consider wearing white coats and business casual attire in clinic and addressing parents informally as "mom" or "dad" or by their first name, although etiquette should ultimately be determined on an individual patient basis. PMID- 20964273 TI - Lack of ocular side effects after 2 years of topical steroids for allergic rhinitis. AB - PURPOSE: The aim of this study was to investigate ocular side effects in children with allergic rhinitis taking chronic intermittent nasal corticosteroids. METHODS: The study group included 150 children who had used intermittent intranasal budesonide for more than 2 years for allergic rhinitis. Ninety patients who were newly diagnosed as having allergic rhinitis without any treatment comprised the control group. Central corneal thickness, Schirmer test results, visual acuity, intraocular pressure, cataract formation, keratometry, and tear break-up time were compared in the two groups. RESULTS: The ages of the 150 study patients (85 boys) were between 8 and 15 years. The average age (+/- standard error of the mean [SEM]) was 11.7 +/- 0.7 years and the mean (+/- SEM) steroid dosage used was 93.3 +/- 7.0 MUg daily with 42.2 +/- 3.2 g total steroid use during treatment. The ages of the 90 control patients (54 boys) were between 7 and 15 years. There was no statistically significant difference between the study and control groups according to ocular findings (P > .05). Eye functions including cataract formation, corneal ectasia, ocular hypertension or glaucoma, and dry eye were not observed in any of the patients in the study group and were not correlated with total steroid dosage (r = 0.125, P = .447). CONCLUSION: A 2 year treatment of children with allergic rhinitis prescribed intermittent intranasal budesonide at an average daily dose of approximately 100 MUg is not associated with ocular side effects such as cataract, glaucoma, corneal ectasia, and abnormal tear function. PMID- 20964274 TI - New developments in the management of periocular capillary hemangioma in children. AB - The authors describe the theories of pathogenesis for capillary hemangioma and discuss the benefits and side effects of current treatment options, such as systemic and intralesional corticosteroids, laser therapy, and surgical excision. They also evaluate the recent systemic and topical applications of beta-blockers to treat infantile hemangioma. Although no major adverse events from beta-blocker treatment have been reported, the incidence of potential side effects such as bronchospasm, hypoglycemia, heart block, bradycardia, and congestive heart failure is unknown due to the novelty of the treatment. It has been postulated that topical application for localized superficial tumor may reduce systemic effects. Further research is necessary to compare the effectiveness of different treatments and to find the optimal dosing and delivery methods to minimize adverse effects in the treatment of this disorder. PMID- 20964275 TI - Postoperative convergence after recovery from general anesthesia in exotropia surgery. AB - PURPOSE: To compare eye position at the end of surgery under general anesthesia with strabismic angles on postoperative day 1 in exotropia surgery. METHODS: Seventy-eight patients between 3 and 58 years of age who had undergone surgery were divided into two groups (group A = 46 patients with bilateral rectus recession, group B = 32 patients with surgery that included medial rectus resection). Strabismic angles were measured at the end of surgery under general anesthesia using the Hirschberg test and the alternate prism cover test was performed on postoperative day 1. RESULTS: Mean strabismic angle was 3.15 prism diopters (PD) under general anesthesia and -6.78 PD on postoperative day 1 in group A and -0.31 and -0.37 PD, respectively, in group B. Mean postoperative convergence was 9.93 PD in group A and 0.06 PD in group B, and the differences were statistically significant (P < .001). CONCLUSION: All patients receiving lateral rectus recession showed approximately 10 PD of convergence. Those who received surgery that included medial rectus resection showed much less convergence and a tendency to be the same as at the end of surgery on postoperative day 1. PMID- 20964276 TI - Raman spectroscopic studies of liquid phase ordering and dynamics for solutions of ME6N liquid crystal: the approach to simple molecule behavior at high dilutions. AB - We have measured the Raman isotropic profiles of the nu(C=N) band at 2235 cm(-1) for five solutions of ME6N (4-cyanophenyl-4'-hexylbenzoate) liquid crystal dissolved in CCl(4) in the range from x = 0.12 to 0.007 (x, mole fraction of ME6N) and then obtained the corresponding vibrational correlation functions, C(v)(t), by time Fourier transformation. The increase with dilution of the dephasing times tau(v) complies with the behavior of the nonmonotonic concentration dependence predicted by the fluctuation concentration model for this concentration range (x < 0.5). The interpretation of C(v)(t) within the Kubo stochastic theory which, being based on the assumption that the environmental modulation arises from a single relaxation process, e(-t/tau(c)), applies to simple liquids, has proved to be inadequate except for the most diluted solutions where the environmental correlation time tau(c) amounted to 1.16 ps. On the other hand, we have found that the vibrational correlation functions for these ME6N/CCl(4) solutions comply, in the whole concentration range, with the approach proposed by Rothschild, which, being based on the assumption that the environmental modulation is described by a stretched exponential decay e( (t/tau(0))(alpha)), is more appropriate for the interpretation of the vibrational correlation function arising from a distribution of relaxation processes caused, as in the present case, by the persistence of pseudonematic domains. With dilution the dispersion parameter alpha and the average correlation time tau(0) progressively increases and decreases, respectively, and tend to converge to the values appropriate for simple liquids, as given by the Kubo theory, i.e., alpha to unity and tau(0) to approximately 1.16 ps. The relaxation time probability distribution h(tau) progressively shrinks and shifts down with dilution. The evolution of alpha and tau(0) parameters and, contextually, of h(tau) with dilution offers a complete picture of the way a complex liquid attains the condition of a simple one. PMID- 20964277 TI - Phase behavior and 13C NMR spectroscopic analysis of the mixed methane + ethane + propane hydrates in mesoporous silica gels. AB - In this study, the phase behavior and quantitative determination of hydrate composition and cage occupancy for the mixed CH(4) + C(2)H(6) + C(3)H(8) hydrates were closely investigated through the experimental measurement of three-phase hydrate (H)-water-rich liquid (L(W))-vapor (V) equilibria and (13)C NMR spectra. To examine the effect of pore size and salinity, we measured hydrate phase equilibria for the quaternary CH(4) (90%) + C(2)H(6) (7%) + C(3)H(8) (3%) + water mixtures in silica gel pores of nominal diameters of 6.0, 15.0, and 30.0 nm and for the quinary CH(4) (90%) + C(2)H(6) (7%) + C(3)H(8) (3%) + NaCl + water mixtures of two different NaCl concentrations (3 and 10 wt %) in silica gel pores of a nominal 30.0 nm diameter. The value of hydrate-water interfacial tension for the CH(4) (90%) + C(2)H(6) (7%) + C(3)H(8) (3%) hydrate was found to be 47 +/- 4 mJ/m(2) from the relation of the dissociation temperature depression with the pore size of silica gels at a given pressure. At a specified temperature, three phase H-L(W)-V equilibrium curves of pore hydrates were shifted to higher pressure regions depending on pore sizes and NaCl concentrations. From the cage dependent (13)C NMR chemical shifts of enclathrated guest molecules, the mixed CH(4) (90%) + C(2)H(6) (7%) + C(3)H(8) (3%) gas hydrate was confirmed to be structure II. The cage occupancies of each guest molecule and the hydration number of the mixed gas hydrates were also estimated from the (13)C NMR spectra. PMID- 20964278 TI - Total synthesis of clavicipitic acid and aurantioclavine: stereochemistry of clavicipitic acid revisited. AB - The stereocontrolled total synthesis of clavicipitic acid and aurantioclavine from a common azepino[5,4,3-cd]-indole intermediate is reported. This key azepinoindole nucleus was constructed via a one-pot Heck/Boc deprotection/aminocyclization process from the 4-iodotryptophan derivative, which was assembled by a Pd-catalyzed indole synthesis procedure. After two or three additional deprotection steps from the azepinoindole intermediates, (-)-trans- and (-)-cis-clavicipitic acid were prepared. The syntheses of both (-)- and (+) aurantioclavine were achieved with the same azepinoindole intermediates utilizing the Barton decarboxylation reaction as the key step to remove the stereohindered carboxylic acid. During the course of our synthesis, mis-assigned configurations of the synthesized clavicipitic acids and their derivatives in the literature were identified. Extensive studies including 2D-NMR study, X-ray diffraction analysis, titration experiment, and Rf value comparison unambiguously confirmed the new configuration assignment. The trans and cis configuration assignments of the synthesized clavicipitic acids and their derivatives in the past literature should be switched. PMID- 20964280 TI - Optimal efficiency of self-assembling light-harvesting arrays. AB - Using a classical master equation that describes energy transfer over a given lattice, we explore how energy transfer efficiency along with the photon capturing ability depends on network connectivity, on transfer rates, and on volume fractions-the numbers and relative ratio of fluorescence chromophore components, e.g., donor (D), acceptor (A), and bridge (B) chromophores. For a one dimensional AD array, the exact analytical expression (derived in Appendix A) for efficiency shows a steep increase with a D-to-A transfer rate when a spontaneous decay is sufficiently slow. This result implies that the introduction of B chromophores can be a useful method for improving efficiency for a two-component AD system with inefficient D-to-A transfer and slow spontaneous decay. Analysis of this one-dimensional system can be extended to higher-dimensional systems with chromophores arranged in structures such as a helical or stacked-disk rod, which models the self-assembling monomers of the tobacco mosaic virus coat protein. For the stacked-disk rod, we observe the following: (1) With spacings between sites fixed, a staggered conformation is more efficient than an eclipsed conformation. (2) For a given ratio of A and D chromophores, the uniform distribution of acceptors that minimizes the mean first passage time to acceptors is a key point to designing the optimal network for a donor-acceptor system with a relatively small D-to-A transfer rate. (3) For a three-component ABD system with a large B to-A transfer rate, a key design strategy is to increase the number of the pathways in accordance with the directional energy flow from D to B to A chromophores. These conclusions are consistent with the experimental findings reported by Francis, Fleming, and their co-workers and suggest that synthetic architectures of self-assembling supermolecules and the distributions of AD or ABD chromophore components can be optimized for efficient light-harvesting energy transfer. PMID- 20964279 TI - Photochemical and thermal stability of green and blue proteorhodopsins: implications for protein-based bioelectronic devices. AB - The photochemical and thermal stability of the detergent-solubilized blue- and green-absorbing proteorhodpsins, BPR and GPR, respectively, are investigated to determine the viability of these proteins for photonic device applications. Photochemical stability is studied by using pulsed laser excitation and differential UV-vis spectroscopy to assign the photocyclicity. GPR, with a cyclicity of 7 * 10(4) photocycles protein(-1), is 4-5 times more stable than BPR (9 * 10(3) photocycles protein(-1)), but is less stable than native bacteriorhodopsin (9 * 10(5) photocycles protein(-1)) or the 4-keto bacteriorhodopsin analogue (1 * 10(5) photocycles protein(-1)). The thermal stabilities are assigned by using differential scanning calorimetry and thermal bleaching experiments. Both proteorhodopsins display excellent thermal stability, with melting temperatures above 85 degrees C, and remain photochemically stable up to 75 degrees C. The biological relevance of our results is also discussed. The lower cyclicity of BPR is found to be adequate for the long-term biological function of the host organism at ocean depths of 50 m or more. PMID- 20964281 TI - Effects of plasticization and shear stress on phase structure development and properties of soy protein blends. AB - In this study, soy protein concentrate (SPC) was used as a plastic component to blend with poly(butylene adipate-co-terephthalate) (PBAT). Effects of SPC plasticization and blend composition on its deformation during mixing were studied in detail. Influence of using water as the major plasticizer and glycerol as the co-plasticizer on the deformation of the SPC phase during mixing was explored. The effect of shear stress, as affected by SPC loading level, on the phase structure of SPC in the blends was also investigated. Quantitative analysis of the aspect ratio of SPC particles was conducted by using ImageJ software, and an empirical model predicting the formation of percolated structure was applied. The experimental results and the model prediction showed a fairly good agreement. The experimental results and statistic analysis suggest that both SPC loading level and its water content prior to compounding had significant influences on development of the SPC phase structure and were correlated in determining the morphological structures of the resulting blends. Consequently, physical and mechanical properties of the blends greatly depended on the phase morphology and PBAT/SPC ratio of the blends. PMID- 20964282 TI - High-throughput detection and sizing of individual low-index nanoparticles and viruses for pathogen identification. AB - Rapid, chip-scale, and cost-effective single particle detection of biological agents is of great importance to human health and national security. We report real-time, high-throughput detection and sizing of individual, low-index polystyrene nanoparticles and H1N1 virus. Our widefield, common path interferometer detects nanoparticles and viruses over a very large sensing area, orders of magnitude larger than competing techniques. We demonstrate nanoparticle detection and sizing down to 70 nm in diameter. We clearly size discriminate nanoparticles with diameters of 70, 100, 150, and 200 nm. We also demonstrate detection and size characterization of hundreds of individual H1N1 viruses in a single experiment. PMID- 20964283 TI - Plasma-enhanced catalytic CuO nanowires for CO oxidation. AB - We report the first experimental study of catalytic CO oxidation over copper oxide (CuO) nanowires (NWs) grown directly on copper meshes. The catalytic activity of CuO NWs is significantly improved by a brief argon or hydrogen radio frequency plasma treatment. The plasma enhancement effect comes from the generation of grain boundaries and the reduction of Cu(II) to the more active oxidation state Cu(I) according to our TEM, XPS, and kinetic study. PMID- 20964284 TI - One-step continuous flow synthesis of highly substituted pyrrole-3-carboxylic acid derivatives via in situ hydrolysis of tert-butyl esters. AB - The first one-step, continuous flow synthesis of pyrrole-3-carboxylic acids directly from tert-butyl acetoacetates, amines, and 2-bromoketones is reported. The HBr generated as a byproduct in the Hantzsch reaction was utilized in the flow method to hydrolyze the t-butyl esters in situ to provide the corresponding acids in a single microreactor. The protocol was used in the multistep synthesis of pyrrole-3-carboxamides, including two CB1 inverse agonists, directly from commercially available starting materials in a single continuous process. PMID- 20964285 TI - Diastereoselective nitrenium ion-mediated cyclofunctionalization: total synthesis of (+)-castanospermine. AB - The asymmetric total synthesis of the alpha-glucosidase inhibitor (+) castanospermine is reported. The central theme in our approach to this polyhydroxylated alkaloid is the simultaneous generation of the piperidine ring and the C-1/8a erythro stereodiad through the diastereoselective, oxamidation of an unsaturated O-alkyl hydroxamate. This process is believed to proceed sequentially via singlet acylnitrenium and aziridinium ion intermediates. PMID- 20964286 TI - Comparison of byproduct formation in waters treated with chlorine and iodine: relevance to point-of-use treatment. AB - Due to their efficacy in deactivating a range of microbial pathogens, particularly amoebic cysts, iodine-based disinfectants have been a popular option for point-of-use (POU) drinking water disinfection by campers, the military, and rural consumers in developing countries. Recently, concerns regarding the formation of cytotoxic and genotoxic iodinated disinfection byproducts (I-DBPs) have arisen during chloramine disinfection of iodide-containing waters in the developed world; similar concerns should pertain to iodine-based POU disinfection. Because there are alternative POU disinfection techniques, including chlorine-based disinfectants, this paper compared disinfection byproduct formation from a range of iodine-based disinfectants at their recommended dosages to chlorination and chloramination under overdosing conditions. Just as chloroform was the predominant trihalomethane (THM) forme during chlorination or chloramination, iodoform was the predominant THM formed during iodination. Conditions fostering THM formation were similar between these treatments, except that THM formation during chlorination increased with pH, while it was slightly elevated at circumneutral pH during iodination. Iodoform formation during treatment with iodine tincture was higher than during treatment with iodine tablets. On a molar basis, iodoform formation during treatment with iodine tincture was 20-60% of the formation of chloroform during chlorination, and total organic iodine (TOI) formation was twice that of total organic chlorine (TOCl), despite the 6-fold higher oxidant dose during chlorination. Based upon previous measurements of chronic mammalian cell cytotoxicity for the individual THMs, consumers of two waters treated with iodine tincture would receive the same THM-associated cytotoxic exposure in 4-19 days as a consumer of the same waters treated with a 6-fold higher dose of chlorine over 1 year. Iodoacetic acid, diiodoacetic acid, and other iodo-acids were also formed with iodine tincture treatment, but at levels <11% of iodoform. However, testing of a Lifestraw Personal POU device, which combines an iodinated anion exchange resin with activated carbon post-treatment, indicated minimal formation of I-DBPs and no iodine residual. Although N-nitrosamines have been associated with oxidant contact with anion exchange resins, N-nitrosamine formation rapidly declined to low levels (4 ng/L) using the Lifestraw device after the first few flushes of water. PMID- 20964287 TI - Nanofriction visualized in space and time by 4D electron microscopy. AB - In this letter, we report a novel method of visualizing nanoscale friction in space and time using ultrafast electron microscopy (UEM). The methodology is demonstrated for a nanoscale movement of a single crystal beam on a thin amorphous membrane of silicon nitride. The movement results from the elongation of the crystal beam, which is initiated by a laser (clocking) pulse, and we examined two types of beams: those that are free of friction and the others which are fixed on the substrate. From observations of image change with time we are able to decipher the nature of microscopic friction at the solid-solid interface: smooth-sliding and periodic slip-stick friction. At the molecular and nanoscale level, and when a force parallel to the surface (expansion of the beam) is applied, the force of gravity as a (perpendicular) load cannot explain the observed friction. An additional effective load being 6 orders of magnitude larger than that due to gravity is attributed to Coulombic/van der Waals adhesion at the interface. For the case under study, metal-organic crystals, the gravitational force is on the order of piconewtons whereas the static friction force is 0.5 MUN and dynamic friction is 0.4 MUN; typical beam expansions are 50 nm/nJ for the free beam and 10 nm/nJ for the fixed beam. The method reported here should have applications for other materials, and for elucidating the origin of periodic and chaotic friction and their relevance to the efficacy of nano(micro) scale devices. PMID- 20964288 TI - Viscous state effect on the activity of Fe nanocatalysts. AB - Many applications of nanotubes and nanowires require controlled bottom-up engineering of these nanostructures. In catalytic chemical vapor deposition, the thermo-kinetic state of the nanocatalysts near the melting point is one of the factors ruling the morphology of the grown structures. We present theoretical and experimental evidence of a viscous state for nanoparticles near their melting point. The state exists over a temperature range scaling inversely with the catalyst size, resulting in enhanced self-diffusion and fluidity across the solid liquid transformation. The overall effect of this phenomenon on the growth of nanotubes is that, for a given temperature, smaller nanoparticles have a larger reaction rate than larger catalysts. PMID- 20964289 TI - Bis(2-sulfanylethyl)amino native peptide ligation. AB - The reaction of a peptide featuring a bis(2-sulfanylethyl)amino (SEA) group on its C-terminus with a cysteinyl peptide in water at pH 7 and 37 degrees C leads to the chemoselective and regioselective formation of a native peptide bond. This method called SEA ligation enriches the native peptide ligation repertoire available to the peptide chemist. Preparation of an innovative solid support which allows the straightforward synthesis of peptide SEA fragments using standard Fmoc/tert-butyl solid phase peptide synthesis procedures is also described. PMID- 20964290 TI - Characterization of multiporous structure and oxygen transfer inside aerobic granules with the percolation model. AB - The characteristics of aerobic granules for wastewater treatment are greatly related to their complex internal structure. However, due to the limitation of characterizing methods, information about the granule internal morphology and structure is very sparse, and mechanism of mass transfer process is yet unclear. In this work, the internal structure of aerobic granules was explored using nitrogen adsorption method and confocal laser scanning microscopy technique. It was found that aerobic granules had multiporous structure with cross-linked gel matrix structure. With a consideration of the hydrodynamic regime and the porous structure of granules, a two-dimensional percolation model was established to describe the mass transfer in granules. With the approaches, interesting and useful results regarding the pore distribution and mass transfer in aerobic granules have been obtained. The results demonstrate that the intragranule convection could enhance mass transfer, hence ensure an efficient and stable operation of aerobic-granule-based reactors. Such approaches might also be applicable to characterizing the multiporous structure and mass transfer of other microbial aggregates for wastewater treatment. PMID- 20964291 TI - Perfluorinated compounds in the environment and the blood of residents living near fluorochemical plants in Fuxin, China. AB - A fluorochemical industrial park was built in 2004 in Fuxin, China, for the production of polytetrafluoroethylene (PTFE) and perfluorobutane sulfonate (PFBS). Yet little is known about the distribution of fluorochemicals in the environment and in people living in and around the park. In this study, environmental samples were collected from 22 sites in Fuxin to investigate the extent of perfluorinated compound (PFC) contamination in the environment around the park, and in drinking water from the public water supply system and groundwater in shallow aquifers from private wells near the park. Serum samples were also collected from nonoccupationally exposed residents living in Fuxin to determine the PFC load of local residents. As the dominant contaminant of eight target PFCs, the maximum concentrations of perfluorooctanoic acid (PFOA) in sediment and river water of the River Xi along the industrial park were 48 ng/g dry weight and 668 ng/L, respectively; the highest PFOA concentration in groundwater beneath the park was 524 ng/L; and the PFOA levels in drinking water from the public water supply system ranged between 1.3 and 2.7 ng/L. In human serum, PFOA had the geometric mean at 4.3 ng/mL, ranging from 0.02 to 93 ng/mL. This study serves to document what should be the beginning of a long-term surveillance effort to minimize potential exposure of residents living in Fuxin. PMID- 20964292 TI - Gulf oil spill air quality monitoring: lessons learned to improve emergency response. PMID- 20964293 TI - Synthesis and magnetic properties of Gd doped EuS nanocrystals with enhanced Curie temperatures. AB - EuS nanocrystals (NCs) were doped with Gd resulting in an enhancement of their magnetic properties. New EuS and GdS single source precursors (SSPs) were synthesized, characterized, and employed to synthesize Eu(1-x)Gd(x)S NCs by decomposition in oleylamine and trioctylphosphine at 290 degrees C. The doped NCs were characterized using X-ray diffraction, transmission electron microscopy, and scanning transmission electron microscopy, which support the uniform distribution of Gd dopants through electron energy loss spectroscopy (EELS) mapping. X-ray absorption spectroscopy (XAS) revealed the dopant ions in Eu(1 x)Gd(x)S NCs to be predominantly Gd(3+). NCs with a variety of doping ratios of Gd (0 <= x < 1) were systematically studied using vibrating sample magnetometry and the observed magnetic properties were correlated with the Gd doping levels (x) as quantified with ICP-AES. Enhancement of the Curie temperature (T(C)) was observed for samples with low Gd concentrations (x <= 10%) with a maximum T(C) of 29.4 K observed for NCs containing 5.3% Gd. Overall, the observed T(C), Weiss temperature (theta), and hysteretic behavior correspond directly to the doping level in Eu(1-x)Gd(x)S NCs and the trends qualitatively follow those previously reported for bulk and thin film samples. PMID- 20964294 TI - Oxidation does not (always) kill reactivity of transition metals: solution-phase conversion of nanoscale transition metal oxides to phosphides and sulfides. AB - Unexpected reactivity on the part of oxide nanoparticles that enables their transformation into phosphides or sulfides by solution-phase reaction with trioctylphosphine (TOP) or sulfur, respectively, at temperatures of <=370 degrees C is reported. Impressively, single-phase phosphide products are produced, in some cases with controlled anisotropy and narrow polydispersity. The generality of the approach is demonstrated for Ni, Fe, and Co, and while manganese oxides are not sufficiently reactive toward TOP to form phosphides, they do yield MnS upon reaction with sulfur. The reactivity can be attributed to the small size of the precursor particles, since attempts to convert bulk oxides or even particles with sizes approaching 50 nm were unsuccessful. Overall, the use of oxide nanoparticles, which are easily accessed via reaction of inexpensive salts with air, in lieu of organometallic reagents (e.g., metal carbonyls), which may or may not be transformed into metal nanoparticles, greatly simplifies the production of nanoscale phosphides and sulfides. The precursor nanoparticles can easily be produced in large quantities and stored in the solid state without concern that "oxidation" will limit their reactivity. PMID- 20964295 TI - Propulsion of microobjects by dynamic bipolar self-regeneration. AB - Dynamic bipolar self-regeneration is a new mechanism that allows controlled motion of metallic microobjects to be induced. This technique is based on the concept of bipolar electrochemistry, in which different redox reactions occur at the two extremities of a substrate under the influence of an external electric field. To create the motion of a metallic object, one end has to be the site of metal deposition and the other the site of metal dissolution. Propulsion of zinc macro- and microswimmers at speeds of up to 80 MUm s(-1) has been achieved. PMID- 20964296 TI - Nitroxide-substituted nitronyl nitroxide and iminonitroxide. AB - We report on the highly compact nitroxide-substituted nitronyl nitroxide 1 and iminonitroxide 2; they have isoelectronic structures with trimethylenemethane. These diradicals are stable under aerated conditions at room temperature and have large positive exchange interactions: J/k(B) = +390 K (H = -2JS(1)(/)(2).S(1/2)) for 1 and J/k(B) ~ +550 K for 2. PMID- 20964297 TI - Effects of harvesting date and storage on the amounts of polyacetylenes in carrots, Daucus carota. AB - The amounts of three main polyacetylenes in carrots; falcarinol, falcarindiol, and falcarindiol-3-acetate, were determined by HPLC, during three seasons, in carrots harvested several times per season and at different locations in Sweden. The amounts of falcarindiol first decreased from a relatively high level and then increased later in the harvest season. The amounts of falcarindiol-3-acetate showed similar variations, whereas the amounts of falcarinol did not exhibit any significant variation during the harvest season. During storage the amount of polyacetylenes leveled off, increasing in samples initially low and decreasing in samples initially high in polyacetylenes. The amounts of all polyacetylenes varied significantly due to external factors and between stored and fresh samples. This variation opens up possibilities to achieve a chemical composition of polyacetylenes at harvest that minimizes the risk of bitter off-taste and maximizes the positive health effects reported in connection with polyacetylenes in carrots. PMID- 20964298 TI - Adsorption of polyetheramines on montmorillonite at high pH. AB - Adsorption of a series of polyetheramines on montmorillonite in aqueous suspension was investigated by a range of methods: elemental analysis, atomic absorption spectroscopy, measurement of pH, conductivity and electrophoretic mobility, and small-angle X-ray scattering. Adsorption proceeds through an ion exchange mechanism. The maximum surface coverage attained is equivalent to about 40% of the cationic exchange capacity of the clay. Adsorption of the poly(oxypropylene) block adjacent to the amine group onto the clay surface may contribute to this. Surprisingly the adsorption takes place at pH conditions well above the pK(a) of the amine surfactants, where they are not protonated in the bulk solution. The surface coverage as a function of molar mass broadly agrees with predictions assuming adsorbed polymers adopt a densely packed mushroom configuration at the clay surface. PMID- 20964299 TI - One-dimensional protein-based nanoparticles induce lipid bilayer disruption: carbon nanotube conjugates and amyloid fibrils. AB - Along with recent progress of nanotechnology, concern has risen about biological impacts of nanoparticles deriving from their interaction with cell membranes. Nanoparticles tend to adsorb proteins in vivo. Therefore, the physical properties of the conjugates to cell membranes must be investigated to elucidate and assess their properties. We examined whether one-dimensional protein-based nanoparticles induce liposome leakage in physiological saline. Carbon nanotube conjugates with adsorbed lysozyme interacted with the liposome through electrostatic interaction, leading to liposome leakage. Surprisingly, amyloid fibrils of lysozyme resembled the conjugate in terms of their effects on liposome leakage. Results described herein provide new insight into the interaction between nanoparticles and cell membranes in terms of their shape, mechanical properties, and noncovalent interactions. PMID- 20964300 TI - Microphase separation in mixed monolayers of DPPG with a double hydrophilic block copolymer at the air-water interface: a BAM, LSCFM, and AFM study. AB - Phase separation and interactions in mixed monolayers of dipalmitoylphosphatidylglycerol (DPPG) with the rhodamine B end-labeled double hydrophilic block copolymer (DHBC), poly(N,N-dimethylacrylamide)-block-poly(N,N diethylacrylamide) (RhB-PDMA(207)-b-PDEA(177)), was studied at the air-water interface. Surface pressure versus area isotherms indicate that both components behave almost independently. Brewster angle microscopy (BAM) images show a random distribution of liquid condensed (LC) domains of DPPG in an apparent homogeneous matrix of DHBC, excluding the macroscopic phase separation. The laser scanning confocal fluorescence microscopy (LSCFM) of the rhodamine dye at the end of the PDMA chain showed how the DHBC is distributed in Langmuir-Blodgett (LB) mixed monolayers. The high spatial resolution of atomic force microscopy (AFM) combined with the LCSFM images indicates that DHBC incorporates in the expanded phase of DPPG to form mixed domains, being excluded from the condensed regions. Upon compression, nanosized LC domains of DPPG nucleate inside the mixed domains corralled in the nanopatterning of pure DHBC. The negatively charged polar group of DPPG inhibits rhodamine aggregation, while the long polymer chains promote the formation of corralled nanodomains of DPPG in two dimensions. PMID- 20964301 TI - Thermoresponsive copolymer nanofilms for controlling cell adhesion, growth, and detachment. AB - This study reports the development and use of a novel thermoresponsive polymeric nanofilm for controlling cell adhesion and growth at 37 degrees C, and then cell detachment for cell recovery by subsequent temperature drop to the ambient temperature, without enzymatic cleavage or mechanical scraping. A copolymer, poly(N-isopropylacrylamide-co-hydroxypropyl methacrylate-co-3 (trimethoxysilyl)propyl methacrylate) (abbreviated PNIPAAm copolymer), was synthesized by free radical polymerization. The thermoresponses of the copolymer in aqueous solution were demonstrated by dynamic light scattering (DLS) through detecting the sensitive changes of copolymer aggregation against temperature. The DLS measurements revealed the lower critical solution temperature (LCST) at approximately 30 degrees C. The PNIPAAm film stability and robustness was provided through silyl cross-linking within the film and with the hydroxyl groups on the substrate surface. Film thickness, stability, and reversibility with respect to temperature switches were examined by spectroscopic ellipsometry (SE), atomic force microscopy (AFM), and contact angle measurements. The results confirmed the high extent of thermosensitivity and structural restoration based on the alterations of film thickness and surface wettability. The effective control of adhesion, growth, and detachment of HeLa and HEK293 cells demonstrated the physical controllability and cellular compatibility of the copolymer nanofilms. These PNIPAAm copolymer nanofilms could open up a convenient interfacial mediation for cell film production and cell expansion by nonenzymatic and nonmechanical cell recovery. PMID- 20964303 TI - Contact angles of liquid drops on super hydrophobic surfaces: understanding the role of flattening of drops by gravity. AB - Measurement of contact angles on super hydrophobic surfaces by conventional methods can produce ambiguous results. Experimental difficulties in constructing tangent lines, gravitational distortion or erroneous assumptions regarding the extent of spreading can lead to underestimation of contact angles. Three models were used to estimate drop shape and perceived contact angles on completely nonwetting super hydrophobic surfaces. One of the models employed the classic numerical solutions from Bashforth and Adams. Additionally, two approximate models were derived as part of this work. All three showed significant distortion of microliter-sized drops and similar trends in perceived contact angles. Liquid drops of several microliters are traditionally used in sessile contact angle measurements. Drops of this size are expected to and indeed undergo significant flattening on super hydrophobic surfaces, even if the wetting interactions are minimal. The distortion is more pronounced if the liquid has a lesser surface tension or greater density. For surfaces that are completely nonwetting, underestimation of contact angles can be tens of degrees. Our modeling efforts suggest that accurate contact angle measurements on super hydrophobic surfaces would require very small sessile drops, on the order of hundreds of picoliters. PMID- 20964302 TI - Comparative features of copper ATPases ATP7A and ATP7B heterologously expressed in COS-1 cells. AB - ATP7A and ATP7B are P-type ATPases required for copper homeostasis and involved in the etiology of Menkes and Wilson diseases. We used heterologous expression of ATP7A or ATP7B in COS-1 cells infected with adenovirus vectors to characterize differential features pertinent to each protein expressed in the same mammalian cell type, rather than to extrinsic factors related to different cells sustaining expression. Electrophoretic analysis of the expressed protein, before and after purification, prior or subsequent to treatment with endoglycosidase, and evidenced by protein or glycoprotein staining as well as Western blotting, indicates that the ATP7A protein is glycosylated while ATP7B is not. This is consistent with the prevalence of glycosylation motifs in the ATP7A sequence, and not in ATP7B. ATP7A and ATP7B undergo copper-dependent phosphorylation by utilization of ATP, forming equal levels of an "alkali labile" phosphoenzyme intermediate that undergoes similar catalytic (P-type ATPase) turnover in both enzymes. In addition, incubation with ATP yields an "alkali stable" phosphoprotein fraction, attributed to phosphorylation of serines. Alkali stable phosphorylation occurs at lower levels in ATP7A, consistent with a different distribution of serines in the amino acid sequence. Immunostaining of COS-1 cells sustaining heterologous expression shows initial association of both ATP7A and ATP7B with Golgi and the trans-Golgi network. However, in the presence of added copper, ATP7A undergoes prevalent association with the plasma membrane while ATP7B exhibits intense trafficking with cytosolic vesicles. Glycosylation of ATP7A and phosphorylation of ATP7B apparently contribute to their different trafficking and membrane association when expressed in the same cell type. PMID- 20964304 TI - Creation of highly stable selenium nanoparticles capped with hyperbranched polysaccharide in water. AB - Water-dispersible selenium nanoparticles (SeNPs) were created by using natural hyperbranched polysaccharide (HBP) as the stabilizer and capping agent under extremely safe conditions. The structure, morphology, size, and stability of the nanocomposites were investigated by transmission electron microscopy (TEM), atomic force microscopy (AFM), and static and dynamic light scattering (DLS) measurements. The results revealed that the spherical selenium nanoparticles (mean particle size of about 24 nm) were ligated with HBP to form nanocomposites (Se-HBP) in aqueous solution and were stable for over one month. In our findings, supported by the results of FTIR, TEM, AFM, and DLS, SeNPs were capped with the HBP macromolecules, as a result of strong physical adsorption of OH groups on Se surfaces, leading to a highly stable structure of Se nanoparticles in water. This work provided reaction sites for the complexation between HBP and Se to fabricate well-dispersed Se nanoparticles in aqueous system with potential bioapplications. PMID- 20964305 TI - Polymersomes with ionic liquid interiors dispersed in water. AB - We describe polymersomes with ionic liquid interiors dispersed in water. The vesicles are prepared via a simple and spontaneous migration of poly(butadiene-b ethylene oxide) (PB-PEO) block copolymer vesicles from a hydrophobic ionic liquid, 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][TFSI]), to water at room temperature. As PB is insoluble in both water and [EMIM][TFSI] and PEO is well solvated in both media, the vesicles feature a PB membrane with PEO brushes forming both interior and exterior coronas. The robust and stable PB-PEO vesicles migrate across the liquid-liquid interface with their ionic liquid interiors intact and form a stabilized aqueous dispersion of vesicles enclosing microscopic ionic liquid pools. The nanostructure of the vesicles with ionic liquid interiors dispersed in water is characterized by direct visualization using cryogenic transmission electron microscopy. Upon heating, the vesicles can be quantitatively transferred back to [EMIM][TFSI], thus enabling facile recovery. The reversible transport capability of the shuttle system is demonstrated by the use of distinct hydrophobic dyes, which are selectively and simultaneously loaded in the vesicle membrane and interior. Furthermore, the fluorescence of the loaded dyes in the vesicles enables probing of the microenvironment of the vesicular ionic liquid interior through solvatochromism and direct imaging of the vesicles using laser scanning confocal microscopy. This vesicle system is of particular interest as a nanocarrier or nanoreactor for reactions, catalysis, and separations using ionic liquids. PMID- 20964306 TI - Control over charge transfer through molecular wires by temperature and chemical structure modifications. AB - A series of electron donor-acceptor arrays containing pi-conjugated oligofluorenes (oFL) of variable length between a zinc porphyrin (ZnP) as electron donor and fullerene (C(60)) as electron acceptor have been prepared by following a convergent synthesis. The electronic interactions between the electroactive species were determined by cyclic voltammetry, UV-visible, fluorescence, and femto/nanosecond transient absorption spectroscopy. Our studies clearly confirm that, although the C(60) units are connected to the ZnP donor through pi-conjugated oFL frameworks, no significant electronic interactions prevail in the ground state. Theoretical calculations predict that a long-range electron transfer occurs primarily due to a maximized pi-conjugated pathway from the donor to the acceptor. Photoexcitation of ZnP-oFL(n)-C(60) results in transient absorption maxima at 715 and 1010 nm, which are unambiguously attributed to the photolytically generated radical ion pair state, [ZnP(*+) oFL(n)-C(60)(*-)], with lifetimes in the microsecond time regime. Temperature dependent photophysical experiments have shown that the charge-transfer mechanism is controllable by temperature. Both charge separation and charge recombination processes give rise to a molecular wire behavior of the oFL moiety with an attenuation factor (beta) of 0.097 A(-1). The correlation beta to the connection pattern between the ZnP donor and the oFL linker revealed that even small alterations of the linker pi-electron system break the homogeneous pi-conjugation pattern, leading to higher values of beta. PMID- 20964307 TI - The role of oxygen stoichiometry on phase stability, structure, and magnetic properties of Sr2CoIrO(6-delta). AB - The phase stability, crystal structure, and magnetic properties of perovskite like nonstoichiometric Sr(2)CoIrO(6-delta) were studied. Oxygen deficiency can be well controlled and reversibly varied up to delta = 0.33. A single phase exists at least for partial oxygen pressures between 10(-5) and 1 bar at 1273 K, followed by phase decomposition at higher temperature with the elimination of metallic Ir and the formation of a new phase with approximately Sr(3)CoIrO(6) composition crystallizing in K(4)CdCl(6) structure type. The structural features of Sr(2)CoIrO(6-delta) are dependent on both temperature and oxygen content and were determined by synchrotron and neutron powder diffraction. Both the increasing amount of oxygen vacancies at constant temperature and increasing temperature at constant oxygen content result in the same higher crystal symmetry of Sr(2)CoIrO(6-delta): (1) The oxygen-stoichiometric phase Sr(2)CoIrO(6.00) is monoclinic (I2/m or P2(1)/n) at room temperature but cubic (Fm-3m) for Sr(2)CoIrO(5.67). (2) A sequence of phase transitions [Formula: see text] was observed for Sr(2)CoIrO(6.00) in air. All Sr(2)CoIrO(6-delta) compositions show weak ferromagnetism at low temperature with a canted but predominantly antiferromagnetic ground state. The magnetic ordering temperature decreases monotonously with increasing oxygen deficiency, while pronounced extrema are observed for the paramagnetic moment and the Curie-Weiss temperature at an oxygen deficiency delta ~ 0.10, which corresponds to the P2(1)/n <-> I2/m phase transformation. PMID- 20964308 TI - Thermoresponsive luminescent electrospun fibers prepared from poly(DMAEMA-co-SA co-StFl) multifunctional random copolymers. AB - We report novel thermoresponsive electrospun (ES) fibers prepared from multifunctional random copolymers of poly((2-(dimethylamino)ethyl methacrylate) co-(stearyl acrylate) -co-(9,9-dihexyl-2-(4-vinylpenyl)-9H-fluorene)) (poly(DMAEMA-co-SA-co-StFl)). The moieties of DMAEMA, SA, and StFl were designed to exhibit the thermoresponsive, physical cross-linking, and fluorescent functionality, respectively. The effects of the copolymer compositions on the morphology and photoluminescence of the prepared ES fibers were explored. The prepared P4 copolymer with the DMAEMA/SA/StFl mole ratio of 92/3/5 showed the lower critical solution temperature (LCST) of 32.5 degrees C. A significant temperature-dependent swelling and de-swelling behavior was found in the P4 ES fibers, which had the diameter of 753 +/- 174 nm and 5-10 nm StFl aggregated domain. Accompanied with volume-changing on the P4 ES fibers, a reversible photoluminescence (PL) quenching was also observed during the heating and cooling cycle between 40 and 60 degrees C. Such reversible switching of the "on-off" PL intensity was probably due to the light absorption ability of the StFl moiety, resulted from the extended/compact structural transformation on the PDMAEMA moiety. Furthermore, the high surface/volume ratio of the ES fibers led a much better temperature response compared with the corresponding spin-coated film. The present study demonstrated that the ES fibers prepared from multifunctional copolymers exhibited the thermoreversible variation on both volume and photoluminescence intensity. PMID- 20964309 TI - Structural, electronic, and magnetic properties of UFeS3 and UFeSe3. AB - Black prisms of UFeS(3) and UFeSe(3) have been synthesized by solid-state reactions of U, Fe, and S or Se with CsCl as a flux at 1173 K. The structure of these isostructural compounds consists of layers of edge- and corner-sharing FeS(6) or FeSe(6) octahedra that are separated by layers of face- and edge sharing US(8) or USe(8) bicapped trigonal prisms. The isomer shifts in the iron 57 Mossbauer spectra of both UFeS(3) and UFeSe(3) are consistent with the presence of high-spin iron(II) ions octahedrally coordinated to S or Se. The XANES spectra of UFeS(3) and UFeSe(3) are consistent with uranium(IV). Single crystal magnetic susceptibility measurements along the three crystallographic axes of UFeSe(3) reveal a substantial magnetic anisotropy with a change of easy axis from the a-axis above 40 K to the b-axis below 40 K, a change that results from competition between the iron(II) and uranium(IV) anisotropies. The temperature dependence of the magnetic susceptibility along the three axes is characteristic of two-dimensional magnetism. A small shoulder-like anomaly is observed in the magnetic susceptibilities along the a- and b-axes at 96 and 107 K, respectively. Below 107 K, the iron-57 Mossbauer spectra of UFeS(3) and UFeSe(3) show that the iron nuclei experience a magnetic hyperfine field that results from long-range magnetic ordering of at least the iron(II) magnetic moments because the field exhibits Brillouin-like behavior. Below 40 K there is no significant change in the Mossbauer spectra as a result of change in magnetic anisotropy. The complexity of the iron-57 Mossbauer spectra and the temperature and field dependencies of the magnetic properties point toward a complex long range magnetic structure of two independent iron(II) and uranium(IV) two dimensional sublattices. The temperature dependence of the single-crystal resistivity of UFeSe(3) measured along the a-axis reveals semiconducting behavior between 30 and 300 K with an energy gap of about 0.03 eV below the 53 K maximum in susceptibility, of about 0.05 eV between 50 and 107 K, and of 0.03 eV above 107 K; a negative magnetoresistance was observed below 60 K. PMID- 20964310 TI - H2 evolution and molecular electrocatalysts: determination of overpotentials and effect of homoconjugation. AB - In an effort to standardize the determination of overpotential values for H(2) evolving catalysts in non-aqueous solvents and allow a reliable comparison of catalysts prepared and assayed by different groups, we propose to adopt the half wave potential as reference potential. We provide a simple method for measuring it from usual stationary cyclic voltammograms, and we derive the formulas to which the measured potential should be compared, taking into account the effect of homoconjugation. We also revisit tabulated values of the standard reduction potential of protons in nonaqueous solvents, E(H+/H(2)) degrees . PMID- 20964311 TI - Novel approach to aminocarboranes by mild amidation of selected iodo-carboranes. AB - A mild protocol for the palladium-catalyzed Buchwald-Hartwig amidation of icosahedral carboranes is described. Employing 2-dicyclohexylphosphino-2'-(N,N dimethylamino)biphenyl (1) as a ligand and K(3)PO(4) as a base, benzamide, trifluoroacetamide, acetamide, and formamide were coupled to a series of mono- and di-iodo carboranes furnishing the respective carborane derivatives in good to excellent yields. Subsequent base-mediated saponification of the trifluoroacetamide derivatives was shown to provide the free aminocarboranes. The structures of N-(1,7-dicarba-closo-dodecaboran-9-yl)benzamide (8a), N-(1,7 dicarba-closo-dodecaboran-9-yl)trifluoroacetamide (8b), N-(1,12-dicarba-closo dodecaboran-2-yl)benzamide (10a), N-(1,2-dicarba-closo-dodecaboran-9-yl)benzamide (12a), N-(1,2-dicarba-closo-dodecaboran-9-yl)acetamide (12c), N-(1,2-dicarba closo-dodecaboran-9-yl)formamide (12d), N-(1,2-dicarba-closo-dodecaboran-3 yl)benzamide (13a), N,N'-(1,7-dicarba-closo-dodecaboran-9,10-diyl)dibenzamide (15a), and N,N'-(1,7-dicarba-closo-dodecaboran-9,10-diyl)bis(trifluoroacetamide) (15b) have been established through X-ray single-crystal diffraction studies. PMID- 20964312 TI - Spectroscopic and magnetic properties of a series of MU-cyano bridged bimetallic compounds of the type M(II)-NC-Fe(III) (M = Mn, Co, and Zn) using the building block [Fe(III)(CN)5imidazole]2-. AB - In this contribution, we describe the preparation and single-crystal X-ray diffraction of a new building block for bimetallic solid state materials. X-ray diffraction data of these complexes indicate that (PPh(4))(2)[Fe(CN)(5)imidazole].2H(2)O crystallizes in the triclinic space group P1 with a = 9.8108(15) A, b = 11.1655(17) A, c = 23.848(4) A, alpha = 87.219(2) degrees , beta = 85.573(2) degrees , gamma = 70.729(2) degrees , and Z = 2, while its precursor Na(3)[Fe(CN)(5)(en)].5H(2)O crystallizes in the monoclinic space group P2(1)/n with a = 8.3607(7) A, b = 11.1624(9) A, c = 17.4233(14) A, beta = 90.1293(9) degrees , and Z = 4. Spectroscopic and magnetic properties of a series of bimetallic materials were obtained by reaction of the complex [Fe(CN)(5)imidazole](2-) with hydrated transition metal ions [M(H(2)O)(n)](2+) (M = Mn, Co, Zn; n = 4 or 6). The new bimetallic materials obtained are [Co(H(2)O)(2)][Fe(CN)(5)imidazole].2H(2)O (1), [Mn(CH(3)OH)(2)][Fe(CN)(5)imidazole] (2), Zn[Fe(CN)(5)imidazole].H(2)O (3), and [Mn(bpy)][Fe(CN)(5)imidazole].H(2)O (4). All of the complexes crystallize in the orthorhombic system. X-ray single-crystal analysis of the compounds identified the Imma space group with a = 7.3558(10) A, b = 14.627(2) A, c = 14.909(2) A, and Z = 4 for 1; the P2(1)2(1)2(1) space group with a = 7.385(5) A, b = 13.767(9) A, c = 14.895(10) A, and Z = 4 for 2; the Pnma space group with a = 13.783(2) A, b = 7.167(11) A, c = 12.599(2) A, and Z = 4 for 3; and the Pnma space group with a = 13.192(3) A, b = 7.224(16) A, c = 22.294(5) A, and Z = 4 for 4. The structures of 1, 2, and 4 consist of two-dimensional network layers containing, as the repeating unit, a cyclic tetramer [M(2)Fe(2)(CN)(4)] (M = Mn, Co). H bonding between the layers in the structure of 1 results in a quasi-three-dimensional network. The structure of 3 was found to be three-dimensional, where all of the cyano ligands are involved in bridging between the metal centers. The bridging character of the cyano is confirmed spectroscopically. The magnetic properties have been investigated for all of the bimetallic systems. Compound 1 shows ferromagnetic behavior with an ordering temperature at 25 K, which is higher than the corresponding Prussian Blue analogue Co(x)[Fe(CN)(6)](y) .zH(2)O. Compound 2 shows weak ferromagnetic behavior and an interlayer antiferromagnetic character, while 3, as expected, shows paramagnetic character due to the diamagnetic character of Zn(2+). Compound 4 shows antiferromagnetic behavior. PMID- 20964313 TI - Copper corroles: the question of noninnocence. AB - In this paper, the results are presented from a comparative study of the electronic and geometric structure of copper corroles by means of either density functional theory (DFT, using both pure and hybrid functionals) and multiconfigurational ab initio methods, starting from either a complete active space (CASSCF) or restricted active space (RASSCF) reference wave function and including dynamic correlation by means of second-order perturbation theory (CASPT2/RASPT2). DFT geometry optimizations were performed for the lowest singlet and triplet states of copper corrole, both unsubstituted and meso-substituted with three phenyl groups. The effect of saddling on the electronic structure was investigated by comparing the results obtained for planar (C(2v)) and saddled (C(2)) structures. With DFT, the origin of the saddling distortion is found to be dependent on the applied functional: covalent Cu 3d-corrole pi interactions with pure functionals (BP86, OLYP), antiferromagnetic exchange coupling between an electron in the corrolate (C(2)) b type pi orbital, and an unpaired Cu(II) 3d electron with hybrid functionals (B3LYP, PBE0). The CASPT2 results essentially confirm the suggestion from the hybrid functionals that copper corroles are noninnocent, although the contribution of diradical character to the copper corrole bond is found to be limited to 50% or less. The lowest triplet state is calculated at 0-10 kcal/mol and conform with the experimental observation (variable temperature NMR) that this state should be thermally accessible. PMID- 20964314 TI - Platinum-catalyzed, one-pot tandem synthesis of indoles and isoquinolines via sequential rearrangement of amides and aminocyclization. AB - By using platinum(II) chloride as a Lewis acid catalyst, concise and efficient syntheses of indole carbamates, 1,2-dihydroisoquinoline carbamates, macrocyclic indole carbamates, indole ureas, and indole phosphoranes have been achieved via tandem Hofmann-type rearrangement of 2-alkynylbenzamides and 2 alkynylbenzylamides, nucleophilic addition of alcohols and amines to the isocyanate intermediates, and intramolecular aminocyclization of the thus-formed carbamates and ureas to 2-alkynyl functions. A variety of nucleophiles such as alcohols, amines, and stable Wittig reagents could be introduced to the highly electrophilic carbon of the isocyanate intermediates derived from amides. We observed enhancement of the reaction rates when the reactions were run under microwave irradiation. PMID- 20964316 TI - Near-infrared imaging of water in a polymer electrolyte membrane during a fuel cell operation. AB - A novel technique of spectroscopic imaging using a near-infrared (NIR) laser sheet beam was developed for visualization of liquid water in a proton-exchange membrane (PEM) sandwiched between two opaque electrodes set in a polymer electrolyte fuel cell (PEFC). In-plane two-dimensional distribution of water in the thin membrane was clearly visualized during the fuel cell operation. Under the condition of fuel feeding into the PEFC without humidification, water was generated by the fuel cell reaction in the whole electrode area. In contrast, under the condition of fuel feeding with humidification, the PEM got wet in the vicinity of a gas flow field locally. PMID- 20964315 TI - Mutations in the Saccharomyces cerevisiae succinate dehydrogenase result in distinct metabolic phenotypes revealed through (1)H NMR-based metabolic footprinting. AB - Metabolomics is a powerful method of examining the intricate connections between mutations, metabolism, and disease. Metabolic footprinting examines the extracellular metabolome or exometabolome. We employed NMR-based metabolic footprinting and multivariate statistical analysis to examine a yeast model of mitochondrial dysfunction. Succinate dehydrogenase (SDH) is a component of both the tricarboxylic acid cycle and the mitochondrial respiratory chain. Mutations in the human SDH are linked to a variety of cancers or neurodegenerative disorders, highlighting the genotype/phenotype complexity associated with SDH dysfunction. To gain insight into the underlying global metabolic consequences of SDH dysfunction, we examined the metabolic footprints of SDH3 and SDH4 mutants. We identified and quantified 36 metabolites in the exometabolome. Our results indicate that SDH mutations cause significant alterations to several areas of yeast metabolism. Multivariate statistical analysis allowed us to discriminate between the different metabotypes of individual mutants, including mutants that were phenotypically indistinguishable. Metabotypes were highly correlated to mutant growth yields, suggesting that the characterization of metabotypes offers a rapid means of investigating the phenotype of a new mutation. Our study provides novel insight into the metabolic effects of SDH dysfunction and highlights the effectiveness of metabolic footprinting for examining complex disorders, such as mitochondrial diseases. PMID- 20964317 TI - Sensitized enantioselective laser-induced phosphorescence detection in chiral capillary electrophoresis. AB - The sensitivity of enantioselective cyclodextrin-induced room-temperature phosphorescence detection of camphorquinone (CQ) is enhanced using sensitization via a donor with a high extinction coefficient. The enantiomeric distinction is based on the different phosphorescence lifetimes of (+)-CQ and (-)-CQ after their complexation with alpha-cyclodextrin (alpha-CD). The collisional Dexter energy transfer from the selected donor 2,6-naphthalenedisulfonic acid (2,6-NS) to the acceptor CQ is still very efficient despite the inclusion of the acceptor into CD. For coupling to the chiral separation of (+/-)-CQ in cyclodextrin-based electrokinetic chromatography, the donor was added to the deoxygenated background electrolyte that consisted of 20 mM alpha-CD, 10 mM carboxymethyl-beta-CD, and 25 mM borate buffer at pH 9.0. Time-resolved batch studies on sensitized phosphorescence show a significant enantioselectivity for (+)- and (-)-CQ in the presence of both alpha-CD and CM-beta-CD although the lifetime difference is somewhat reduced with respect to direct excitation. The enantiomers were distinguished after their separation using an online time-resolved detection system. Excitation was performed at 266 nm with a pulsed, small-sized, quadrupled Nd:YAG laser. With 1 * 10(-5) M 2,6-NS, limits of detection of 4.1 * 10(-8) M and 5.2 * 10(-8) M were found for (+)-CQ and (-)-CQ, respectively. The online measured lifetimes were 238 +/- 8 MUs for (+)-CQ and 126 +/- 10 MUs for (-)-CQ. The method was used to determine the concentration of (+/-)-CQ leaching from a cured dental resin into water. The extracts contained 4.7 +/- 0.1 * 10(-7) M of both (+)-CQ and (-)-CQ. PMID- 20964318 TI - Synthesis and biological evaluation of oleanolic acid derivatives as inhibitors of protein tyrosine phosphatase 1B. AB - Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator in the process of insulin signaling and a promising drug target for diabetes and obesity. Derivatives of oleanolic acid were synthesized and evaluated as PTP1B inhibitors. Several derivatives exhibited moderate to good inhibitory activities against PTP1B, with 25f displaying the most promising inhibition (IC(50) = 3.12 MUM). Structure-activity relationship analyses of these derivatives demonstrated that the integrity of the A ring and 12-ene moieties was important in the retention of PTP1B enzyme inhibitory activities. In addition, hydrophilic and acidic groups as well as the distance between the oleanene and acid moieties were associated with PTP1B inhibitory activities. Possible binding modes of 25f were explored by molecular docking simulations. PMID- 20964319 TI - Citrusosides A-D and furanocoumarins with cholinesterase inhibitory activity from the fruit peels of Citrus hystrix. AB - Four new compounds, citrusosides A-D (1-4), and 15 known compounds were isolated from the hexanes and CH(2)Cl(2) extracts of the peels of Citrus hystrix fruits. Compound 1 is a 1-O-isopropyl-6-O-beta-D-glucopyranosyl ester of 5'',9''-dimethyl 2'',8''-decadienoic acid. Compounds 2-4 possess a 1-O-isopropyl-beta-D glucopyranosyl and a dihydroxyprenylfuranocoumarin moiety conjugated to the 3 hydroxy-3-methylglutaric acid as diesters. Several furanocoumarins were evaluated for their cholinesterase inhibitory activity. (R)-(+)-6'-Hydroxy-7' methoxybergamottin, (R)-(+)-6',7'-dihydroxybergamottin, and (+)-isoimparatorin showed IC(50) values of 11.2 +/- 0.1, 15.4 +/- 0.3, and 23 +/- 0.2 MUM, respectively. Bioassay results indicated that the presence of a dioxygenated geranyl chain in the test compounds is crucial for the inhibitory activity. PMID- 20964320 TI - Synthesis of azafluorenone antimicrobial agents. AB - A flexible synthesis of the azafluorenone alkaloids 1, 2, 3, and 4 is described. PMID- 20964321 TI - Copper-catalyzed cross dehydrogenative coupling reactions of tertiary amines with ketones or indoles. AB - A novel cross dehydrogenative coupling (CDC) reaction of N,N-dimethylanilines with methyl ketones by cooperative copper and aminocatalysis has been developed, which leads to the formation of beta-arylamino ketones in 42-73% yields. Moreover, the copper-catalyzed alkylation of free (NH) indoles with N,N dimethylanilines via CDC reaction is also presented, affording alkylated indoles in 52-78% yields. PMID- 20964322 TI - On-plate desalting and SALDI-MS analysis of peptides with hydrophobic silicate nanofilms on a gold substrate. AB - We report the use of silicate nanofilms for on-plate desalting and subsequently direct laser desorption/ionization-mass spectrometric (LDI-MS) analysis of peptides. A hydrophobic octadecyltrichlorosilane (OTS) monolayer is formed on a calcinated nanofilm on a gold substrate to facilitate sample deposition and interaction with the surface that allows effective removal of MS-incompatible contaminants such as salts and surfactants by simple on-plate washing while the peptides are retained on the spot. By elimination of interferences from matrix related ions and contaminants, sensitivity of MS analysis has been enhanced over ca. 20 times, leading to improved detection of peptides at the low-femtomolar level. A high recovery rate of the peptides is obtained by using relatively rough nanofilms, which are prepared through a modified layer-by-layer deposition/calcination process. The performance of the films has been investigated with peptide samples in the presence of high salts (NaCl and sodium acetate) and urea. Compared to matrix-assisted laser desorption/ionization analysis with CHCA matrix, LDI with on-plate desalting offers marked improvement for analysis of peptides due to low background ions and reduction of sample complexity. Additionally, selective capture of the hydrophobic components of a protein can be achieved, providing a highly useful strategy for specific peptide enrichment. LDI with on-plate desalting approach has also been successfully applied to peptide analysis from protein digests. PMID- 20964323 TI - Synthesis and photophysical properties of thioglycosylated chlorins, isobacteriochlorins, and bacteriochlorins for bioimaging and diagnostics. AB - The facile synthesis and photophysical properties of three nonhydrolyzable thioglycosylated porphyrinoids are reported. Starting from meso perfluorophenylporphyrin, the nonhydrolyzable thioglycosylated porphyrin (PGlc4), chlorin (CGlc4), isobacteriochlorin (IGlc4), and bacteriochlorin (BGlc4) can be made in 2-3 steps. The ability to append a wide range of targeting agents onto the perfluorophenyl moieties, the chemical stability, and the ability to fine tune the photophysical properties of the chromophores make this a suitable platform for development of biochemical tags, diagnostics, or as photodynamic therapeutic agents. Compared to the porphyrin in phosphate buffered saline, CGlc4 has a markedly greater absorbance of red light near 650 nm and a 6-fold increase in fluorescence quantum yield, whereas IGlc4 has broad Q-bands and a 12-fold increase in fluorescence quantum yield. BGlc4 has a similar fluorescence quantum yield to PGlc4 (<10%), but the lowest-energy absorption/emission peaks of BGlc4 are considerably red-shifted to near 730 nm with a nearly 50-fold greater absorbance, which may allow this conjugate to be an effective PDT agent. The uptake of CGlc4, IGlc4, and BGlc4 derivatives into cells such as human breast cancer cells MDA-MB-231 and K:Molv NIH 3T3 mouse fibroblast cells can be observed at nanomolar concentrations. Photobleaching under these conditions is minimal. PMID- 20964324 TI - Enantioselective synthesis of anti-beta-hydroxy-alpha-amido esters via transfer hydrogenation. AB - The asymmetric transfer hydrogenation of alpha-amido-beta-keto esters to provide the corresponding anti-beta-hydroxy-alpha-amido esters in good to excellent yields, diastereoselectivity, and enantioselectivity is reported. The procedure is operationally simple, and delicate handling of the catalyst is not necessary. PMID- 20964325 TI - Monamphilectine A, a potent antimalarial beta-lactam from marine sponge Hymeniacidon sp: isolation, structure, semisynthesis, and bioactivity. AB - Monamphilectine A (1), a new diterpenoid beta-lactam alkaloid showing potent antimalarial activity, was isolated in milligram quantities following bioassay directed extraction of a Puerto Rican marine sponge Hymeniacidon sp. Its structure, established by interpretation of spectral data, was confirmed unequivocally by chemical interconversion and comparison of physical, chemical, and bioactivity data with the natural product. The one-step semisynthesis of monamphilectine A was based on a multicomponent Ugi reaction that also established its absolute stereostructure. PMID- 20964326 TI - Novel graphene-like electrodes for capacitive deionization. AB - Capacitive deionization (CDI) is a novel technology that has been developed for removal of charged ionic species from salty water, such as salt ions. The basic concept of CDI, as well as electrosorption, is to force charged ions toward oppositely polarized electrodes through imposing a direct electric field to form a strong electrical double layer and hold the ions. Once the electric field disappears, the ions are instantly released back to the bulk solution. CDI is an alternative low-energy consumption desalination technology. Graphene-like nanoflakes (GNFs) with relatively high specific surface area have been prepared and used as electrodes for capacitive deionization. The GNFs were synthesized by a modified Hummers' method using hydrazine for reduction. They were characterized by atomic force microscopy, N2 adsorption at 77 K and electrochemical workstation. It was found that the ratio of nitric acid and sulfuric acid plays a vital role in determining the specific surface area of GNFs. Its electrosorption performance was much better than commercial activated carbon (AC), suggesting a great potential in capacitive deionisation application. Further, the electrosorptive performance of GNFs electrodes with different bias potentials, flow rates and ionic strengths were measured and the electrosorption isotherm and kinetics were investigated. The results showed that GNFs prepared by this process had the specific surface area of 222.01 m2/g. The specific electrosorptive capacity of the GNFs was 23.18 umol/g for sodium ions (Na+) when the initial concentration was at 25 mg/L, which was higher than that of previously reported data using graphene and AC under the same experimental condition. In addition, the equilibrium electrosorption capacity was determined as 73.47 umol/g at 2.0 V by fitting data through the Langmuir isotherm, and the rate constant was found to be 1.01 min-1 by fitting data through pseudo first-order adsorption. The results suggested that the chemically synthesized GNFs can be used as effective electrode materials in CDI process for brackish water desalination. PMID- 20964327 TI - Lipid domain specific recruitment of lipophilic nucleic acids: a key for switchable functionalization of membranes. AB - Lipid domains in mammalian plasma membranes serve as platforms for specific recruitment or separation of proteins involved in various functions. Here, we have applied this natural strategy of lateral separation to functionalize lipid membranes at micrometer scale in a switchable and reversible manner. Membrane anchored peptide nucleic acid and DNA, differing in their lipophilic moieties, partition into different lipid domains in model and biological membranes. Separation was visualized by hybridization with the respective complementary fluorescently labeled DNA strands. Upon heating, domains vanished, and both lipophilic nucleic acid structures intermixed with each other. Reformation of the lipid domains by cooling led again to separation of membrane-anchored nucleic acids. By linking appropriate structures/functions to complementary strands, this approach offers a reversible tool for triggering interactions among the structures and for the arrangement of reactions and signaling cascades on biomimetic surfaces. PMID- 20964328 TI - Single crystal-to-single crystal irreversible transformation from a discrete vanadium(V)-alcoholate to an aldehydic-vanadium(IV) oligomer. AB - An unprecedented single crystal-to-single crystal transformation occurs when a binuclear oxovanadium(V) compound [V(V)(2)O(2)(L)(2)] 1 involving 2,6 bis(hydroxymethyl)-p-cresol (H(3)L) as a bridging ligand is exposed simultaneously to white light and aerial oxygen to generate an oligomeric compound [V(IV)(2)O(2)(L*)(2)] 2 (H(2)L* is 3-hydroxymethyl-5 methylsalicylaldehyde). Each vanadium(V) center in 1 is reduced to vanadium(IV) in 2 at the expense of a two-electron alcohol-to-aldehyde oxidation in the coordinated ligand. The additional electron being released is possibly consumed by molecular oxygen to generate hydrogen peroxide. PMID- 20964329 TI - Acidic polysaccharide mimics via ring-opening metathesis polymerization. AB - An efficient and general synthetic strategy for the preparation of high-molecular weight hydrophilic polymers bearing both carboxylic acid and hydroxyl pendant groups is described. Specifically, poly(5,6-dihydroxyoxanorbornane carboxylic acid) with molecular weight ranging from ~100 000 to 5 000 000 g/mol was prepared by ring-opening metathesis polymerization of methyl 5-oxanorbornene-2-carboxylate in the presence of Grubbs catalyst II and subsequently modified to tune the hydrophobic/hydrophilic properties by the introduction of either hydroxyl or carboxylic acid functionalities. These polymers mimic the natural acidic polysaccharide alginate and form hydrogels with polylysine. These polymers belong to a class of carbohydrate-like polymers, which are of interest for investigating the relationships between chemical structure and rheological properties as well as for providing new synthetic polysaccharide substitutes for applications in the biotechnology and pharmaceutical industries. PMID- 20964330 TI - Intricate role of water in proton transport through cytochrome c oxidase. AB - Cytochrome c oxidase (CytcO), the final electron acceptor in the respiratory chain, catalyzes the reduction of O(2) to H(2)O while simultaneously pumping protons across the inner mitochondrial or bacterial membrane to maintain a transmembrane electrochemical gradient that drives, for example, ATP synthesis. In this work mutations that were predicted to alter proton translocation and enzyme activity in preliminary computational studies are characterized with extensive experimental and computational analysis. The mutations were introduced in the D pathway, one of two proton-uptake pathways, in CytcO from Rhodobacter sphaeroides . Serine residues 200 and 201, which are hydrogen-bonded to crystallographically resolved water molecules halfway up the D pathway, were replaced by more bulky hydrophobic residues (Ser200Ile, Ser200Val/Ser201Val, and Ser200Val/Ser201Tyr) to query the effects of changing the local structure on enzyme activity as well as proton uptake, release, and intermediate transitions. In addition, the effects of these mutations on internal proton transfer were investigated by blocking proton uptake at the pathway entrance (Asp132Asn replacement in addition to the above-mentioned mutations). Even though the overall activities of all mutant CytcO's were lowered, both the Ser200Ile and Ser200Val/Ser201Val variants maintained the ability to pump protons. The lowered activities were shown to be due to slowed oxidation kinetics during the P(R) -> F and F -> O transitions (P(R) is the "peroxy" intermediate formed at the catalytic site upon reaction of the four-electron-reduced CytcO with O(2), F is the oxoferryl intermediate, and O is the fully oxidized CytcO). Furthermore, the P(R) -> F transition is shown to be essentially pH independent up to pH 12 (i.e., the apparent pK(a) of Glu286 is increased from 9.4 by at least 3 pK(a) units) in the Ser200Val/Ser201Val mutant. Explicit simulations of proton transport in the mutated enzymes revealed that the solvation dynamics can cause intriguing energetic consequences and hence provide mechanistic insights that would never be detected in static structures or simulations of the system with fixed protonation states (i.e., lacking explicit proton transport). The results are discussed in terms of the proton-pumping mechanism of CytcO. PMID- 20964331 TI - A bulky DNA lesion derived from a highly potent polycyclic aromatic tumorigen stabilizes nucleosome core particle structure. AB - The impact of a bulky DNA lesion on the structure and dynamics of a nucleosome core particle (NCP) containing a lesion derived from the unusually potent tumorigen dibenzo[a,l]pyrene that resists nucleotide excision repair (NER) in free DNA was investigated using 65 ns molecular dynamics simulations. Our results reveal that, relative to unmodified NCP, the lesion stabilizes the nucleosome via stacking interactions, improved Watson-Crick base pairing, hydrogen bonding between DNA and histones, and damped dynamics. These findings suggest that such lesions should be as resistant to NER in the nucleosome environment as they are in free DNA. PMID- 20964332 TI - Hysteretic spin crossover between a bisdithiazolyl radical and its hypervalent sigma-dimer. AB - The bisdithiazolyl radical 1a is dimorphic, existing in two distinct molecular and crystal modifications. The alpha-phase crystallizes in the tetragonal space group P42(1)m and consists of pi-stacked radicals, tightly clustered about 4 points and running parallel to c. The beta-phase belongs to the monoclinic space group P2(1)/c and, at ambient temperature and pressure, is composed of pi-stacked dimers in which the radicals are linked laterally by hypervalent four-center six electron S...S-S...S sigma-bonds. Variable-temperature magnetic susceptibility chi measurements confirm that alpha-1a behaves as a Curie-Weiss paramagnet; the low-temperature variations in chi can be modeled in terms of a 1D Heisenberg chain of weakly coupled AFM S = (1)/(2) centers. The dimeric phase beta-1a is essentially diamagnetic up to 380 K. Above this temperature there is a sharp hysteretic (T?= 380 K, T? = 375 K) increase in chi and chiT. Powder X-ray diffraction analysis of beta-1a at 393 K has established that the phase transition corresponds to a dimer-to-radical conversion in which the hypervalent S...S-S...S sigma-bond is cleaved. Variable-temperature and -pressure conductivity measurements indicate that alpha-1a behaves as a Mott insulator, but the ambient-temperature conductivity sigma(RT) increases from near 10(-7) S cm( 1) at 0.5 GPa to near 10(-4) S cm(-1) at 5 GPa. The value of sigma(RT) for beta 1a (near 10(-4) S cm(-1) at 0.5 GPa) initially decreases with pressure as the phase change takes place, but beyond 1.5 GPa this trend reverses, and sigma(RT) increases in a manner which parallels the behavior of alpha-1a. These changes in conductivity of beta-1a are interpreted in terms of a pressure-induced dimer-to radical phase change. High-pressure, ambient-temperature powder diffraction analysis of beta-1a confirms such a transition between 0.65 and 0.98 GPa and establishes that the structural change involves rupture of the dimer in a manner akin to that observed at high temperature and ambient pressure. The response of the S...S-S...S sigma-bond in beta-1a to heat and pressure is compared to that of related dimers possessing S...Se-Se...S sigma-bonds. PMID- 20964333 TI - Multiphoton-absorption-induced-luminescence (MAIL) imaging of tumor-targeted gold nanoparticles. AB - We demonstrate that multiphoton-absorption-induced luminescence (MAIL) is an effective means of monitoring the uptake of targeted nanoparticles into cells. Gold nanoparticles (AuNPs) with diameters of 4.5 and 16 nm were surface functionalized with monocyclic RGDfK, an RGD peptide analogue that specifically targets the alpha(v)beta3 integrin, a membrane protein that is highly overexpressed in activated endothelial cells during tumor angiogenesis. To determine whether cyclic RGD can enhance the uptake of the functionalized AuNPs into activated endothelium, human umbilical vein endothelial cells (HUVECs) were used as a model system. MAIL imaging of HUVECs incubated with AuNPs demonstrates differential uptake of AuNPs functionalized with RGD analogues: RGDfK-modified nanoparticles are taken up by the HUVECs preferentially compared to AuNPs modified with linear RGD (GRGDSP) conjugates or with no surface conjugates. The luminescence counts observed for the AuNP-RGDfK conjugates are an order of magnitude greater than for AuNP-GRGDSP conjugates. Transmission electron microscopy shows that, once internalized, the AuNP-RGDfK conjugates remain primarily within endosomal and lysosomal vesicles in the cytoplasm of the cells. Significant aggregation of these particles was observed within the cells. MAIL imaging studies in the presence of specific uptake inhibitors indicate that AuNP RGDfK conjugate uptake involves a specific binding event, with alpha(v)beta3 integrin-mediated endocytosis being an important uptake mechanism. PMID- 20964334 TI - Synthesis, characterization, and thermodynamic study of a polyvalent lytic peptide-polymer conjugate as novel anticancer agent. AB - We designed and synthesized a new polyvalent lytic peptide-polymer conjugate as a novel chemotherapeutic agent capable of overcoming multidrug resistance. A hexapeptide (KWKWKW or (KW)3) was designed and conjugated to dextran in multiple copies to afford a polyvalent conjugate. A robust synthesis procedure involving click chemistry and the detailed characterization of the conjugate were reported here. The conjugate Dex-(KW)3 exhibited significantly enhanced anticancer potency in vitro by up to 500-fold compared to monomeric (KW)3. The LC50 value was comparable to that of conventional lytic peptides which have more than 20 residues. No hemolytic activity was shown by the conjugates up to 300 MUM. Thermodynamic study indicated that the binding of conjugates was predominantly entropy-driven while the binding of free peptides was mainly enthalpy-driven, implying a deeper penetration of conjugate into the core of lipid bilayer. The binding affinity of conjugate to neutral membrane is much higher than that to free peptide (K(conj) ~ 8822.9 M-1, K(pep) ~ 1884.7 M-1). In binding to negatively charged membrane, the conjugate surpassed free peptides at high concentrations when the binding of free peptides became saturated. The higher binding capability, attributed to the high local concentration of peptides mounted on a polymer backbone, explains the superior anticancer activity of polyvalent Dex-(KW)3. PMID- 20964335 TI - Targeted delivery of siRNA to hepatocytes and hepatic stellate cells by bioconjugation. AB - Previously, we successfully conjugated galactosylated poly(ethylene glycol) (Gal PEG) to oligonucleotides (ODNs) via an acid labile ester linker (Zhu et al., Bioconjugate Chem. 2008, 19, 290-8). In this study, sense strands of siRNA were conjugated to Gal-PEG and mannose 6-phosphate poly(ethylene glycol) (M6P-PEG) for targeted delivery of siRNAs to hepatocytes and hepatic stellate cells (HSCs), respectively. These siRNA conjugates were purified by ion exchange chromatography and verified by gel retardation assay. To evaluate their RNAi functions, the validated siRNA duplexes targeting firefly luciferase and transforming growth factor beta 1 (TGF-beta1) mRNA were conjugated to Gal-PEG and M6P-PEG, and their gene silencing efficiencies were determined after transfection into HepG2 and HSC T6 cells. The disulfide bond between PEG and siRNA was cleaved by dithiothreitol, leading to the release of intact siRNA. Both Gal-PEG-siRNA and M6P-PEG-siRNA conjugates could silence luciferase gene expression by about 40% without any transfection reagents, while the gene silencing effects reached more than 98% with the help of cationic liposomes at the same dose. Conjugation of TGF-beta1 siRNA with Gal-PEG and M6P-PEG could silence endogenous TGF-beta1 gene expression as well. In conclusion, these siRNA conjugates have the potential for targeted delivery of siRNAs to hepatocytes and hepatic stellate cells for efficient gene silencing in vivo. PMID- 20964336 TI - A stilbene that binds selectively to transthyretin in cells and remains dark until it undergoes a chemoselective reaction to create a bright blue fluorescent conjugate. AB - We describe a non-fluorescent, second generation stilbene that very selectively binds to transthyretin in complex biological environments and remains dark until it chemoselectively reacts with the pK(a)-perturbed Lys-15 epsilon-amino group of transthyretin to form a bright blue fluorescent conjugate. Stilbene A2 is mechanistically unusual in that it remains non-fluorescent in cell lysates lacking transthyretin, even though there is likely some proteome binding. Thus, it is especially useful for cellular imaging, as background fluorescence is undetectable until A2 reacts with transthyretin. The mechanistic basis for the effective lack of environment-sensitive fluorescence of A2 when bound to, but before reacting with, transthyretin is reported. Stilbene A2 exhibits sufficiently rapid transthyretin conjugation kinetics at 37 degrees C to enable pulse-chase experiments to be performed, in this case demonstrating that transthyretin is secreted from HeLa cells. As the chase compound, we employed C1, a cell-permeable, highly selective, non-covalent, transthyretin-binding dihydrostilbene that cannot become fluorescent. The progress reported is viewed as a first and necessary step toward our long-term goal of creating a one-chain, one-binding-site transthyretin tag, whose fluorescence can be regulated by adding A2 or an analogous molecule. Fusing proteins of interest to a one-chain, one binding-site transthyretin tag regulated by A2 should be useful for studying folding, trafficking, and degradation in the cellular secretory pathway, utilizing pulse-chase experiments. Immediate applications of A2 include utilizing its conjugate fluorescence to quantify transthyretin concentration in human plasma, reflecting nutritional status, and determining the binding stoichiometry of kinetic stabilizer drugs to transthyretin in plasma. PMID- 20964337 TI - A mechanistic study of electron transfer from the distal termini of electrode bound, single-stranded DNAs. AB - Electrode-bound, redox-reporter-modified oligonucleotides play roles in the functioning of a number of electrochemical biosensors, and thus the question of electron transfer through or from such molecules has proven of significant interest. In response, we have experimentally characterized the rate with which electrons are transferred between a methylene blue moiety on the distal end of a short, single-stranded polythymine DNA to a monolayer-coated gold electrode to which the other end of the DNA is site-specifically attached. We find that this rate scales with oligonucleotide length to the -1.16 +/- 0.09 power. This weak, approximately inverse length dependence differs dramatically from the much stronger dependencies observed for the rates of end-to-end collisions in single stranded DNA and through-oligonucleotide electron hopping. It instead coincides with the expected length dependence of a reaction-limited process in which the overall rate is proportional to the equilibrium probability that the end of the oligonucleotide chain approaches the surface. Studies of the ionic strength and viscosity dependencies of electron transfer further support this "chain flexibility" mechanism, and studies of the electron transfer rate of methylene blue attached to the hexanethiol monolayer suggest that heterogeneous electron transfer through the monolayer is rate limiting. Thus, under the circumstances we have employed, the flexibility (i.e., the equilibrium statistical properties) of the oligonucleotide chain defines the rate with which an attached redox reporter transfers electrons to an underlying electrode, an observation that may be of utility in the design of new biosensor architectures. PMID- 20964338 TI - Reaction of chlorosulfonyl isocyanate with fluorosubstituted alkenes: evidence of a concerted pathway. AB - Concerted reactions are indicated for the electrophilic addition of chlorosulfonyl isocyanate with monofluoroalkenes. A vinyl fluorine atom on an alkene raises the energy of a stepwise transition state more than the energy of the competing concerted pathway. This energy shift induces CSI to react with monofluoroalkenes by a one-step process. The low reactivity of CSI with monofluoroalkenes, stereospecific reactions, the absence of 2:1 uracil products with neat fluoroalkenes, and quantum chemical calculations support a concerted pathway. PMID- 20964339 TI - A theoretical investigation of the photophysical consequences of major plant light-harvesting complex aggregation within the photosynthetic membrane. AB - Spectroscopic measurements of Arabidopsis leaves have shown that the energy dependent component of non-photochemical quenching (NPQ), known as qE, is associated with an absorption change at 535 nm (DeltaA(535)). Identical measurements on the zeaxanthin-deficient mutant npq1 reveal a similar spectroscopic signature at 525 nm (DeltaA(525)). We investigated whether these red-shifts may arise from excitonic interactions among homodimers of xanthophylls, zeaxanthin, and violaxanthin, bound at the peripheral V1 binding site on adjacent light-harvesting complex II (LHCII) trimers. Estimates of the relative geometries of these pigment pairs were obtained from the structure of LHCII. The excitonic couplings of zeaxanthin and violaxanthin dimers were probed using the time-dependent density functional theory method (TD-DFT). Calculations indicated that dimers formed between zeaxanthin or violaxanthin molecules using the published LHCII structure resulted in absorption blue shifts, typical of an H type (parallel) geometry. In contrast, if the volume of the LHCII structure was modified to reflect the change in membrane thickness that occurs upon DeltapH formation, then both zeaxanthin and violaxanthin dimers adopted a J-type (collinear) geometry, and the resulting spectral shift was to the red region. The magnitudes of these predicted red-shifts are in good agreement with the experimental magnitudes. We therefore conclude that the observed xanthophyll red shift results from the combination of both LHCII aggregation and changes in membrane thickness during qE. DeltaA(535) may therefore be considered a "marker of aggregation" between LHCII trimers upon qE formation. PMID- 20964340 TI - Surface functionalization using catalyst-free azide-alkyne cycloaddition. AB - The utility of catalyst-free azide-alkyne [3 + 2] cycloaddition for the immobilization of a variety of molecules onto a solid surface and microbeads was demonstrated. In this process, the surfaces are derivatized with aza dibenzocyclooctyne (ADIBO) for the immobilization of azide-tagged substrates via a copper-free click reaction. Alternatively, ADIBO-conjugated molecules are anchored to the azide-derivatized surface. Both immobilization techniques work well in aqueous solutions and show excellent kinetics under ambient conditions. We report an efficient synthesis of aza-dibenzocyclooctyne (ADIBO), thus far the most reactive cyclooctyne in cycloaddition to azides. We also describe convenient methods for the conjugation of ADIBO with a variety of molecules directly or via a PEG linker. PMID- 20964341 TI - Water oxidation by photosystem II: H(2)O-D(2)O exchange and the influence of pH support formation of an intermediate by removal of a proton before dioxygen creation. AB - Understanding the chemistry of photosynthetic water oxidation requires deeper insight into the interrelation between electron transfer (ET) and proton relocations. In photosystem II membrane particles, the redox transitions of the water-oxidizing Mn complex were initiated by nanosecond laser flashes and monitored by absorption spectroscopy at 360 nm (A(360)). In the oxygen evolution transition (S(3) + hnu -> S(0) + O(2)), an exponential decrease in A(360) (tau(O(2)) = 1.6 ms) can be assigned to Mn reduction and O(2) formation. The corresponding rate-determining step is the ET from the Mn complex to a tyrosine radical (Y(Z)(ox)). We find that this A(360) decrease is preceded by a lag phase with a duration of 170 +/- 40 MUs (tau(lag) at pH 6.2), indicating formation of an intermediate before ET and O-O bond formation and corroborating results obtained by time-resolved X-ray spectroscopy. Whereas tau(O(2)) exhibits a minor kinetic isotope effect and negligible pH dependence, formation of the intermediate is slowed significantly both in D(2)O (tau(lag) increase of ~140% in D(2)O) and at low pH (tau(lag) of 30 +/- 20 MUs at pH 7.0 vs tau(lag) of 470 +/- 80 MUs at pH 5.5). These findings support the fact that in the oxygen evolution transition an intermediate is created by deprotonation and removal of a proton from the Mn complex, after Y(Z)(ox) formation but before the onset of electron transfer and O-O bond formation. PMID- 20964342 TI - Influence of industrial and alternative farming systems on contents of sugars, organic acids, total phenolic content, and the antioxidant activity of red beet (Beta vulgaris L. ssp. vulgaris Rote Kugel). AB - The contents of sugars, organic acids, total phenolic content, and the antioxidant activity were quantified in the flesh of red beet from conventional (CON), integrated (INT), organic (ORG), biodynamic (BD), and control farming systems using established methods. Significant differences were measured for malic acid, total phenolic content (TPC), and total antioxidant activity, where malic acid content ranged from 2.39 g kg(-1) FW (control) to 1.63 g kg(-1) FW (CON, ORG, and INT). The highest TPC was measured in BD and control samples (0.677 and 0.672 mg GAE g(-1), respectively), and the lowest in CON samples (0.511 mg GAE g(-1)). Antioxidant activity was positively correlated with TPC (r2=0.6187) and ranged from 0.823 MUM TE g(-1) FW to 1.270 MUM TE g(-1) FW in CON and BD samples, respectively, whereas total sugar content ranged from 21.03 g kg( 1) FW (CON) to 31.58 g kg(-1) FW (BD). The importance of sugars, organic acids, phenols, and antioxidants for human health, as well as for plant resilience and health, gained from this explorative study, is discussed and put into perspective. PMID- 20964343 TI - Selenium speciation in soil and rice: influence of water management and Se fertilization. AB - Rice (Oryza sativa) is the staple food for half of the world's population, but the selenium (Se) concentrations in rice grain are low in many rice-growing regions. This study investigated the effects of water management on the Se speciation dynamics in the soil solution and Se uptake and speciation in rice in a pot experiment. A control containing no Se or 0.5 mg kg(-1) of soil of selenite or selenate was added to the soil, and plants were grown under aerobic or flooded conditions. Flooding soil increased soluble Se concentration when no Se or selenite was added to the soil, but decreased it markedly when selenate was added. Selenate was the main species in the +selenate treatment, whereas selenite and selenomethionine selenium oxide were detected in the flooded soil solutions of the control and +selenite treatments. Grain Se concentration was 49% higher in the flooded than in the aerobic treatments without Se addition. In contrast, when selenate or selenite was added, the aerobically grown rice contained 25- and 2 fold, respectively, more Se in grain than the anaerobically grown rice. Analysis of Se in rice grain using enzymatic hydrolysis followed by HPLC-ICP-MS and in situ X-ray absorption near-edge structure (XANES) showed selenomethionine to be the predominant Se species. The study showed that selenate addition to aerobic soil was the most effective way to increase Se concentration in rice grain. PMID- 20964344 TI - Reduction of venom alkaloids in Solenopsis richteri*Solenopsis invicta hybrid: an attempt to identify new alkaloidal components. AB - The alkaloid chemistry of the venom of hybrid fire ant, Solenopsis richteri * Solenopsis invicta, was investigated using silica gel chromatography and GC-MS techniques. In addition to most cis alkaloids of parental species, S. richteri Forel and S. invicta Buren, the cis alkaloid fraction of the body extract of hybrid fire ants also contains five significant new alkaloids. Hydrogenation of the cis alkaloid fraction yielded only five piperidines, 4', 12', 12, 20', and 20. Sodium borohydride and lithium aluminum hydride selectively reduced C?N double bond in piperideine alkaloids to give a mixture of cis and trans piperidines. However, reduction of the five new components yielded several new peaks with much longer retention times and increasing molecular weights over 30. It is evident that the chemical identities of the five new peaks are quite different from those known piperidines or piperideines found in Solenopsis fire ants. PMID- 20964345 TI - "Deterministic" quantum plasmonics. AB - We demonstrate "deterministic" launching of propagative quantum surface-plasmon polaritons at freely chosen positions on gold plasmonic receptacles. This is achieved by using as a plasmon launcher a near-field scanning optical source made of a diamond nanocrystal with two nitrogen-vacancy color-center occupancy. Our demonstration relies on leakage-radiation microscopy of a thin homogeneous gold film and on near-field optical microscopy of a nanostructured thick gold film. Our work paves the way to future fundamental studies and applications in quantum plasmonics that require an accurate positioning of single-plasmon sources and may open a new branch in plasmonics and nanophotonics, namely scanning quantum plasmonics. PMID- 20964346 TI - Kinetics of moisture-induced hydrolysis in powder blends stored at and below the deliquescence relative humidity: investigation of sucrose-citric acid mixtures. AB - Previous studies have shown that deliquescent organic compounds frequently exhibit chemical instability when stored in environmental conditions above their deliquescence relative humidity (RH). The goal of the current study was to investigate the effect of atmospheric moisture on the long-term chemical stability of crystalline sucrose-citric acid mixtures following storage at RHs at and below the mutual deliquescence relative humidity (MDRH). Interestingly, it was found that sucrose hydrolysis can occur below the MDRH of 64% and was observed for samples stored at 54% RH. However, hydrolysis was not seen for samples stored at 33 or 43% RH. The rate of sucrose hydrolysis could be modeled by taking into account the rate and extent of moisture uptake, which in turn was dependent on the composition of the powder and the storage RH. A reaction mechanism initiated by capillary condensation and involving additional deliquescence lowering by the degradation products formed as a result of sucrose hydrolysis (glucose and fructose) was proposed. PMID- 20964347 TI - Method development and application to determine potential plant uptake of antibiotics and other drugs in irrigated crop production systems. AB - Studies have shown the detection of emerging contaminants (ECs), of which pharmaceuticals are a subset, in surface waters across the United States. The objective of this study was to develop methods, and apply them, to evaluate the potential for food chain transfer when EC-containing waters are used for crop irrigation. Greenhouse experiments were performed in which select food crops were irrigated with water spiked with three antibiotics. Field experiments, at two different sites, were conducted. Select crops were irrigated with wastewater effluent known to contain ECs, EC-free well water, and Colorado River water containing trace-level ECs. The results of the greenhouse studies show the potential for uptake of one or more of the antibiotics evaluated, albeit at very low levels. In those food crops watered with wastewater effluent, only an industrial flavoring agent, N,N'-dimethylphenethylamine (DMPEA), was consistently found. None of the evaluated contaminants were found in crops irrigated with Colorado River water. PMID- 20964348 TI - Energy transfer between surface-immobilized light-harvesting chlorophyll a/b complex (LHCII) studied by surface plasmon field-enhanced fluorescence spectroscopy (SPFS). AB - The major light-harvesting chlorophyll a/b complex (LHCII) of the photosynthetic apparatus in green plants can be viewed as a protein scaffold binding and positioning a large number of pigment molecules that combines rapid and efficient excitation energy transfer with effective protection of its pigments from photobleaching. These properties make LHCII potentially interesting as a light harvester (or a model thereof) in photoelectronic applications. Most of such applications would require the LHCII to be immobilized on a solid surface. In a previous study we showed the immobilization of recombinant LHCII on functionalized gold surfaces via a 6-histidine tag (His tag) in the protein moiety. In this work the occurrence and efficiency of Forster energy transfer between immobilized LHCII on a functionalized surface have been analyzed by surface plasmon field-enhanced fluorescence spectroscopy (SPFS). A near-infrared dye was attached to some but not all of the LHC complexes, serving as an energy acceptor to chlorophylls. Analysis of the energy transfer from chlorophylls to this acceptor dye yielded information about the extent of intercomplex energy transfer between immobilized LHCII. PMID- 20964349 TI - Multilayer coating of gold nanoparticles with drug-polymer coadsorbates. AB - The aim of our present study was the development of a drug multilayer-based carrier system for delivery of water-insoluble drugs. As drug, we applied the anticancer drug 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin, mTHPP, which is a model photosensitizer for photodynamic therapy. Gold nanoparticles (AuNP) with a diameter of 14.5 +/- 0.9 nm were prepared and used as template for the layer-by layer approach. The drug and the negatively charged polyelectrolyte (PE) poly(styrene sulfonate) sodium salt (PSS) were complexed with a new developed method using freeze-drying. The complexation efficiency was determined to be ~11 12 monomers PSS per mTHPP molecule by CHNS analysis and UV/vis measurement. Molecular docking simulations revealed pi-pi interactions and H-bonding to be the responsible mechanisms. A drug multilayer system based on the layer-by-layer (LbL) technique utilized the water-soluble complex as anionic layer material and poly(allylamine hydrochloride) (PAH) as cationic layer. The modified AuNP were characterized by different physicochemical techniques such as UV/vis, zeta potential, ICP-OES, and TEM. To the best of our knowledge, we could demonstrate for the first time the adsorption of three drug layers to a nanoparticulate system. Furthermore, the adaptation of the LbL-technique resulted in drastically increased drug deposition efficiency (factor of 100). Furthermore, we developed a new and comfortable way to solubilize water-insoluble drugs in water. PMID- 20964350 TI - Reactivity and selectivity in hydrovinylation of strained alkenes. AB - The scope of Ni(II)-catalyzed hydrovinylation has been extended to strained alkenes such as heterobicyclic [2.2.1]heptanes and cylobutenes. Reactions involving the heterobicyclic compounds are rare examples for this class of compounds where the metal-catalyzed C-C bond-forming reactions proceed without a concomitant ring-opening process. While the enantioselectivity in these systems remains modest, hydrovinylation of endo-5,6--bis benzyloxymethylbicyclo[2.2.1]hept-2-ene gives excellent yield (>90%) of the product with one of the highest enantioselectivities (95-99% ee) reported for a C C bond-forming reaction of norbornenes. PMID- 20964351 TI - Inducing single-molecule magnetism in a family of loop-of-loops aggregates: heterometallic Mn(40)Na(4) clusters and the homometallic Mn(44) analogue. AB - The syntheses, crystal structures, and magnetic properties of a new family of heterometallic Mn(40)Na(4) and homometallic Mn(44) loop-of-loops aggregates are reported. The reactions of [Mn(3)O(O(2)CMe)(6)(py)(3)].py with 1,3-propanediol (pdH(2)) and 2-methyl-1,3-propanediol (mpdH(2)) in the presence of NaN(3) afforded [Mn(10)Na(MU(3)-O)(2)(O(2)CMe)(13)(pd)(6)(py)(2)](4) (1)(4) and [Mn(10)Na(MU(3)-O)(2)(O(2)CMe)(13)(mpd)(6)(py)(H(2)O)](4) (2)(4), respectively. Mn(40)Na(4) complexes (1)(4) and (2)(4) consist of four Mn(10) loops linked through Na(+) ions to give a supramolecular aggregate with a saddle-like topology. Magnetic characterization of compound (1)(4) showed that each Mn(10) loop has an S = 4 ground-state spin and displays frequency-dependent in-phase and out-of-phase ac susceptibility signals. It also exhibits hysteresis loops that, however, are not typical of single-molecule magnets (SMMs) due to the existence of interloop interactions between the neighboring Mn(10) units of (1)(4) through the diamagnetic Na(+) ions, and also intermolecular interactions between different Mn(40)Na(4) aggregates. The magnetically discrete Mn(44) analogue was targeted with high priority and finally prepared from the reaction of [Mn(3)O(O(2)CMe)(6)(py)(3)].py with pdH(2) in the presence of Mn(ClO(4))(2).6H(2)O. The loop-of-loops structure of [Mn(44)(MU(3) O)(8)(O(2)CMe)(52)(pd)(24)(py)(8)](ClO(4))(OH)(3) (3) is essentially identical to those of (1)(4) and (2)(4), with the most significant difference being that the four Na(+) ions of (1)(4) and (2)(4) have been replaced with Mn(2+) ions. Compound 3 is thus best described magnetically as a Mn(44) cluster. In accord with this description and the stronger exchange coupling between the four Mn(10) loops expected through the connecting Mn(2+) ions, magnetic susceptibility measurements revealed that 3 has an S = 6 ground-state spin and displays frequency-dependent in-phase and out-of-phase ac signals. Magnetization vs dc field sweeps on single-crystals of 3 displayed scan rate- and temperature dependent hysteresis loops confirming that complex 3 is a new SMM, and is thus the second largest Mn cluster and SMM reported to date. PMID- 20964353 TI - Mechanism of formation and construction of self-assembled myoglobin/hyaluronic acid multilayer films: an electrochemical QCM, impedance, and AFM study. AB - Self-assembled multilayer films of hyaluronic acid (HA) and the protein myoglobin (Mb) were built up layer by layer on Au covered quartz crystal microbalance (AuQCM) electrode substrates. Film formation and growth were monitored by an electrochemical quartz crystal microbalance (EQCM), and the step-by-step construction was investigated through quantification of the mass variation corresponding to adsorption of each monolayer together with cyclic voltammetry. A decrease of friction at the liquid/electrode interface was observed, indicating that the electrode surface becomes less rough after deposition of several monolayers. The properties of the {HA/Mb}(n) films were evaluated by electrochemical impedance spectroscopy (EIS). Modeling of the impedance spectra shows smoothing of the modified electrode surface with reorganization of the film structure after few monolayers, and the contribution of each layer to the electron transfer process was analyzed. The smoothing of the surfaces and the structural differences between successive bilayers was confirmed by morphological observations by using atomic force microscopy. PMID- 20964352 TI - Targeted imaging and therapy of brain cancer using theranostic nanoparticles. AB - The past decade has seen momentous development in brain cancer research in terms of novel imaging-assisted surgeries, molecularly targeted drug-based treatment regimens or adjuvant therapies and in our understanding of molecular footprints of initiation and progression of malignancy. However, mortality due to brain cancer has essentially remained unchanged in the last three decades. Thus, paradigm-changing diagnostic and therapeutic reagents are urgently needed. Nanotheranostic platforms are powerful tools for imaging and treatment of cancer. Multifunctionality of these nanovehicles offers a number of advantages over conventional agents. These include targeting to a diseased site thereby minimizing systemic toxicity, the ability to solubilize hydrophobic or labile drugs leading to improved pharmacokinetics and their potential to image, treat and predict therapeutic response. In this article, we will discuss the application of newer theranostic nanoparticles in targeted brain cancer imaging and treatment. PMID- 20964354 TI - Binding of 239Pu and 90Sr to organic colloids in soil solutions: evidence from a field experiment. AB - Colloidal transport has been shown to enhance the migration of plutonium in groundwater downstream from contaminated sites, but little is known about the adsorption of 90Sr and plutonium onto colloids in the soil solution of natural soils. We sampled soil solutions using suction cups, and separated colloids using ultrafiltration to determine the distribution of 239Pu and 90Sr between the truly dissolved fraction and the colloidal fraction of the solutions of three Alpine soils contaminated only by global fallout from the nuclear weapon tests. Plutonium was essentially found in the colloidal fraction (>80%) and probably associated with organic matter. A significant amount of colloidal 90Sr was detected in organic-rich soil solutions. Our results suggest that binding to organic colloids in the soil solutions plays a key role with respect to the mobility of plutonium in natural alpine soils and, to a lesser extent, to the mobility of 90Sr. PMID- 20964355 TI - X-ray absorption spectroscopic investigation of molybdenum multinuclear sorption mechanism at the Goethite-water interface. AB - Understanding in situ metalloid surface speciation on mineral surfaces is critical to predicting the bioavailability in surface and subsurface environments. In this study, Mo K-edge X-ray absorption spectroscopy (XAS) was used to elucidate Mo(VI) surface speciation at the goethite-water interface. Effects of pH and loading levels were investigated. X-ray absorption near edge structure (XANES) analysis indicated that the Mo(VI) coordination environment changes from tetrahedral to octahedral with decreasing pH. At near neutral pH, Mo(VI) predominantly remains as tetrahedral molecules, forming inner-sphere surface species via corner- and edge-sharing attachment with iron octahedral structures (interatomic distance of Mo-Fe (R(Mo-Fe)) at ~2.8 and ~3.4 A, respectively). In contrast, a mixture of surface species comprising tetrahedrally and octahedrally coordinated Mo(VI) exists at pH ~3-4. While the same Mo(VI) tetrahedral surface species are present at acidic pH, there was an additional MoO(6) polymer attachment on iron octahedral structures, resulting in a R(Mo-Fe) at 3.53 A. The coordination number (CN) of a Mo-Mo backscatterer gradually increased with increasing loading level, suggesting the formation of surface polymerization. Overall, there seems to be a transition from Mo(VI) tetrahedral to octahedral coordination environment with decreasing pH. The XAS findings further support a Mo(VI) inner-sphere adsorption mechanism that was previously suggested in the pressure-jump relaxation study by Zhang and Sparks (Soil Sci. Soc. Am. J. 1989, 53 (4), 1028-1034). pH-Dependent multinuclear Mo(VI) surface speciation may be important in predicting Mo(VI) transport process in the soil water environment. PMID- 20964356 TI - Electrical power from sea and river water by reverse electrodialysis: a first step from the laboratory to a real power plant. AB - Electricity can be produced directly with reverse electrodialysis (RED) from the reversible mixing of two solutions of different salinity, for example, sea and river water. The literature published so far on RED was based on experiments with relatively small stacks with cell dimensions less than 10 * 10 cm(2). For the implementation of the RED technique, it is necessary to know the challenges associated with a larger system. In the present study we show the performance of a scaled-up RED stack, equipped with 50 cells, each measuring 25 * 75 cm(2). A single cell consists of an AEM (anion exchange membrane) and a CEM (cation exchange membrane) and therefore, the total active membrane area in the stack is 18.75 m(2). This is the largest dimension of a reverse electrodialysis stack published so far. By comparing the performance of this stack with a small stack (10 * 10 cm(2), 50 cells) it was found that the key performance parameter to maximal power density is the hydrodynamic design of the stack. The power densities of the different stacks depend on the residence time of the fluids in the stack. For the large stack this was negatively affected by the increased hydrodynamic losses due to the longer flow path. It was also found that the large stack generated more power when the sea and river water were flowing in co current operation. Co-current flow has other advantages, the local pressure differences between sea and river water compartments are low, hence preventing leakage around the internal manifolds and through pinholes in the membranes. Low pressure differences also enable the use of very thin membranes (with low electrical resistance) as well as very open spacers (with low hydrodynamic losses) in the future. Moreover, we showed that the use of segmented electrodes increase the power output by 11%. PMID- 20964357 TI - Impacts of traffic and rainfall characteristics on heavy metals build-up and wash off from urban roads. AB - An investigation into the effects of changes in urban traffic characteristics due to rapid urbanisation and the predicted changes in rainfall characteristics due to climate change on the build-up and wash-off of heavy metals was carried out in Gold Coast, Australia. The study sites encompassed three different urban land uses. Nine heavy metals commonly associated with traffic emissions were selected. The results were interpreted using multivariate data analysis and decision making tools, such as principal component analysis (PCA), fuzzy clustering (FC), PROMETHEE, and GAIA. Initial analyses established high, low, and moderate traffic scenarios as well as low, low to moderate, moderate, high, and extreme rainfall scenarios for build-up and wash-off investigations. GAIA analyses established that moderate to high traffic scenarios could affect the build-up, while moderate to high rainfall scenarios could affect the wash-off of heavy metals under changed conditions. However, in wash-off, metal concentrations in 1-75 MUm fraction were found to be independent of the changes to rainfall characteristics. In build-up, high traffic activities in commercial and industrial areas influenced the accumulation of heavy metal concentrations in particulate size range from 75 - >300 MUm, whereas metal concentrations in finer size range of <1 75 MUm were not affected. As practical implications, solids <1 MUm and organic matter from 1 - >300 MUm can be targeted for removal of Ni, Cu, Pb, Cd, Cr, and Zn from build-up, while organic matter from <1 - >300 MUm can be targeted for removal of Cd, Cr, Pb, and Ni from wash-off. Cu and Zn need to be removed as free ions from most fractions in wash-off. PMID- 20964358 TI - Evidence for strong but dynamic iron-humic colloidal associations in humic-rich coastal waters. AB - This study investigated the physicochemical forms of dissolved iron in the coastal plume (salinity = 28-35) of a small river draining a peat-rich catchment. Speciation information was obtained through a combination of fractionation by crossflow filtration (CFF) along with voltammetric detection of either naturally occurring iron-humic complexes (July survey) or known, synthetic complexes (September survey) formed by titrating the samples with the competing ligand 2-(2 thiazolylazo)-p-cresol (TAC). The majority of colloidal iron (>5000 Da) was present as iron-humic complexes supplied by the river and showing uniform conditional stability constants throughout the plume (log K'(Fe'HS) = 11.3 +/- 0.1, i.e. log K(Fe3+HS) = 21.3 +/- 0.1). Noncolloidal or soluble iron was strongly complexed to ligands of marine origin with log K'(Fe'HS) = 11.9 +/- 0.1. Equilibrium of the total iron pool with the added TAC ligand was achieved in all but the highest salinity sample, albeit more slowly for colloidal than for soluble iron. In addition, measurements of humic like fluorescence suggested that the conformation of colloids could change over time as a result of dissociation of the iron-humic associations. These results are consistent with the concept that iron in coastal waters is strongly but reversibly bound to humic substances and therefore may be available for complexation by siderophore-type ligands released by microorganisms. PMID- 20964359 TI - No evidence for cerium dioxide nanoparticle translocation in maize plants. AB - The rapidly increasing production of engineered nanoparticles has raised questions regarding their environmental impact and their mobility to overcome biological important barriers. Nanoparticles were found to cross different mammalian barriers, which is summarized under the term translocation. The present work investigates the uptake and translocation of cerium dioxide nanoparticles into maize plants as one of the major agricultural crops. Nanoparticles were exposed either as aerosol or as suspension. Our study demonstrates that 50 MUg of cerium/g of leaves was either adsorbed or incorporated into maize leaves. This amount could not be removed by a washing step and did not depend on closed or open stomata investigated under dark and light exposure conditions. However, no translocation into newly grown leaves was found when cultivating the maize plants after airborne particle exposure. The use of inductively coupled mass spectrometer allowed detection limits of less than 1 ng of cerium/g of leaf. Exposure of plants to well-characterized nanoparticle suspensions in the irrigation water resulted also in no detectable translocation. These findings may indicate that the biological barriers of plants are more resistant against nanoparticle translocation than mammalian barriers. PMID- 20964360 TI - Empirical models for estimating mercury flux from soils. AB - Multiple parameters have been suggested to influence the exchange of mercury (Hg) between the atmosphere and soils. However, models applied for estimating soil Hg flux are simple and do not consider the potential synergistic and antagonist relationships between factors controlling the exchange. This study applied a two level factorial experimental design in a gas exchange chamber (GEC) to investigate the individual and combined effects of three environmental factors (temperature, light, and soil moisture) on soil Hg flux. It was shown that individually irradiation, soil moisture, and air temperature all significantly enhance Hg evasive flux (by 90-140%). Synergistic effects (20-30% of additional flux enhancement) were observed for all two-factor interactions, with air temperature/soil moisture and air temperature/irradiation being the most significant. Results from the factorial experiments suggest that a model incorporating the second-order interactions can appropriately explain the flux response to the changes of the studied factors. Based on the factorial experiment results and using the flux data for twelve soil materials measured with a dynamic flux chamber (DFC) at various temperatures, soil moisture contents, solar radiation exposures, and soil Hg contents, two empirical models for estimating Hg flux from soils were developed. Model verification with ambient flux data not used to develop the models suggested that the models were capable of estimating dry soil Hg flux with a high degree of predictability (r ~ 0.9). PMID- 20964361 TI - High-sensitivity method for determination of tetrabromobisphenol-S and tetrabromobisphenol-A derivative flame retardants in great lakes herring gull eggs by liquid chromatography-atmospheric pressure photoionization-tandem mass spectrometry. AB - Tetrabromobisphenol-A-bis(2,3-dibromopylether) (TBBP-A-dbpe), tetrabromobisphenol A-bis(allyl ether) (TBBP-A-ae), and tetrabromobisphenol-S-bis(2,3-dibromopropyl ether) (TBBP-S-dbpe) are derivatives of tetrabromobisphenol-A (TBBP-A), and are all used as brominated flame retardants (BFRs). Using high-performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry with atmospheric pressure photoionization (APPI) in the negative mode (LC-APPI(-)-Q-TOF-MS) and the novel use of pure acetone as dopant and LC mobile phase, full scan mass spectra showed that for these BFRs the dominant isotopic ion cluster was [M + O2](-), and with other lesser abundant [M + O2 - HBr](-), and [M - H](-) fragment ions. Subsequently, highly sensitive quantification of TBBP-A-dbpe, TBBP-A-ae, and TBBP-S-dbpe was accomplished via LC-triple quadrupole mass spectrometry with APPI(-) (LC-APPI(-)-MS/MS) via multiple ion monitoring based on the [M + O2](-) > [Br](-) transition. Low to sub ng/g (wet weight (w.w.)) method limits of detection (LODs) were achieved, i.e., 0.07, 0.03, and 1.28 ng/g w.w. for TBBP-A dbpe, TBBP-A-ae, and TBBP-S-dbpe, respectively. A variety of herring gull eggs were screened for these BFRs. The eggs were collected during 2008-2009 from several colony sites in the eastern Laurentian Great Lakes (Ontario) and in the St. Lawrence River (Quebec). All egg samples had TBBP-S-dbpe concentrations below the LOD, and TBBP-A-ae and TBBP-A-dbpe were quantifiable in 67%-83% of the samples at concentrations up to 0.56 ng/g wet weight. Thus, TBBP-A-ae and TBBP-A dbpe are present in herring gull eggs from these populations, bioaccumulate in the herring gull food chain, and are transferred from gull to egg. PMID- 20964362 TI - Methyl-nitrocatechols: atmospheric tracer compounds for biomass burning secondary organic aerosols. AB - Detailed chemical analysis of wintertime PM10 collected at a rural village site in Germany showed the presence of a series of compounds that correlated very well with levoglucosan, a known biomass burning tracer compound. Nitrated aromatic compounds with molecular formula C7H7NO4 (M(w) 169) correlated particularly well with levoglucosan, indicating that they originated from biomass burning as well. These compounds were identified as a series of methyl-nitrocatechol isomers (4 methyl-5-nitrocatechol, 3-methyl-5-nitrocatechol, and 3-methyl-6-nitrocatechol) based on the comparison of their chromatographic and mass spectrometric behaviors to those from reference compounds.Aerosol chamber experiments suggest that m cresol, which is emitted from biomass burning at significant levels, is a precursor for the detected methyl-nitrocatechols. The total concentrations of these compounds in the wintertime PM10were as high as 29 ng m-3, indicating the secondary organic aerosol (SOA) originating from the oxidation of biomass burning VOCs contributed non-negligible amounts to the regional organic aerosol loading. PMID- 20964363 TI - The State of Multimedia Mass-Balance Modeling in Environmental science and decision-making. PMID- 20964364 TI - Loop 2 of Ophiophagus hannah toxin b binds with neuronal nicotinic acetylcholine receptors and enhances intracranial drug delivery. AB - Three-finger snake neurotoxins have been widely investigated for their high binding affinities with nicotinic acetylcholine receptors (nAChRs), which are widely expressed in the central nervous system including the blood-brain barrier and thus mediate intracranial drug delivery. The loop 2 segments of three-finger snake neurotoxins are considered as the binding domain with nAChRs, and thus, they may have the potential to enhance drug or drug delivery system intracranial transport. In the present work, binding of the synthetic peptides to the neuronal nAChRs was assessed by measuring their ability to inhibit the binding of (125)I alpha-bungarotoxin to the receptor. The loop 2 segment of Ophiophagus hannah toxin b (KC2S) showed high binding affinity, and the competitive binding IC(50) value was 32.51 nM. Furthermore, the brain targeting efficiency of KC2S had been investigated in vitro and in vivo. The specific uptake by brain capillary endothelial cells (BCECs) demonstrated that KC2S could be endocytosized after binding with nAChRs. In vivo, the qualitative and quantitative biodistribution results of fluorescent dyes (DiR or coumarin-6) indicated that KC2S modified poly(ethylene glycol)-poly(lactic acid) micelles (KC2S-PEG-PLA micelles) could enhance intracranial drug delivery. Furthermore, intravenous treatment with paclitaxel-encapsulated KC2S-PEG-PLA micelles (KC2S-PEG-PLA-PTX micelles) afforded robust inhibition of intracranial glioblastoma. The median survival time of KC2S-PEG-PLA-PTX-micelle-treated mice (47.5 days) was significantly longer than that of mice treated by mPEG-PLA-PTX micelles (41.5 days), Taxol (38.5 days), or saline (34 days). Compared with the short peptide derived from rabies virus glycoprotein (RVG29) that has been previously reported as an excellent brain targeting ligand, KC2S has a similar binding affinity with neuronal nAChRs but fewer amino acid residues. Thus, we concluded that the loop 2 segment of Ophiophagus hannah toxin b could bind with neuronal nAChRs and thus enhance intracranial drug delivery for the treatment of central nervous system diseases. PMID- 20964365 TI - Activation of the pacidamycin PacL adenylation domain by MbtH-like proteins. AB - Nonribosomal peptide synthetase (NRPS) assembly lines are major avenues for the biosynthesis of a vast array of peptidyl natural products. Several hundred bacterial NRPS gene clusters contain a small (~70-residue) protein belonging to the MbtH family for which no function has been defined. Here we show that two strictly conserved Trp residues in MbtH-like proteins contribute to stimulation of amino acid adenylation in some NRPS modules. We also demonstrate that adenylation can be stimulated not only by cognate MbtH-like proteins but also by homologues from disparate natural product pathways. PMID- 20964366 TI - Comment on "Assessment of PDMS-water partition coefficients: implications for passive environmental sampling of hydrophobic compounds". PMID- 20964367 TI - Reaction mechanism for chlorination of urea. AB - Experiments were conducted to elucidate the mechanism of the reaction between free chlorine and urea. In combination with findings of previous investigations, the results of these experiments indicate a process by which urea undergoes multiple N-chlorination steps. The first of these steps results in the formation of N-chlorourea; this step appears to require Cl2 to proceed and is the overall rate-limiting step in the reaction for conditions that correspond to most swimming pools. N-Chlorourea then appears to undergo further chlorine substitution; the fully N-chlorinated urea molecule is hypothesized to undergo hydrolysis and additional chlorination to yield NCl3 as an intermediate. NCl3 is hydrolyzed to yield NH2Cl and NHCl2, with subsequent decay to stable end products, including N2 and NO3-. Conversion of urea-N to nitrate is pH-dependent. The pattern of nitrate yield is believed to be attributable to the fact that when urea serves as the source of reduced-N, entry into the reactions that describe chlorination of ammoniacal nitrogen is through NCl3, whereas when NH3 is the source of reduced-N, entry to these reactions is through NH2Cl. PMID- 20964368 TI - Molecular insights on the cyclic peptide nanotube-mediated transportation of antitumor drug 5-fluorouracil. AB - Self-assembled cyclic peptide nanotubes (CPNs) show a potential use in drug delivery. In this study, the CPN composed of (Trp-D-Leu)(4)-Gln-D-Leu was synthesized and tested for the transport of the antitumor drug 5-fluorouracil (5 FU). CPN-mediated release of 5-FU from liposomes experimentally tested the transportation function of the synthetic CPNs. To explore the transportation mechanism of CPNs, computational studies have been performed on the CPN models stacked by 8 subunits, including conventional molecular dynamics (CMD) simulations, and steered molecular dynamics (SMD) simulations in the environment of hydrated dimyristoylphosphatidylcholine (DMPC) lipid bilayer. Our CMD simulations demonstrated that the ortho-CPN is the most stable nanotube, in which the Gln residue is in the ortho-position relative to other residues. The calculated diffusion coefficient value for inner water molecules was 1.068 * 10( 5) cm(2).s(-1), almost half that of the bulky water and 24 times faster than that of the typical gramicidin A channel. The CPN conserved its hollow structure along the 10 ns CMD simulations, with a tile angle of 50 degrees relative to the normal of DMPC membrane. Results from SMD simulations showed that the 5-FU molecule was transported by hopping through different potential energy minima distributed along subunits, and finally exited the nanotube by escaping from the kink region at the last two subunits. The hopping of 5-FU was driven by switching from hydrophobic interactions between 5-FU and the interior wall of the nanotube to hydrogen bonding interactions of 5-FU with the backbone carbonyl group and amide group of ortho-CPN. The calculated binding free energy profile of 5-FU interacting with the CPN indicated that there was an energy well near the outer end of the nanotube. PMID- 20964369 TI - Safety of glucocorticoids in cancer patients treated with oncolytic adenoviruses. AB - Oncolytic adenoviruses are an emerging treatment option for advanced and refractory cancer. Such patients are often treated with corticosteroids to ameliorate tumor associated symptoms. Thus, it is important to evaluate whether safety is affected by immunosuppression possibly induced by corticosteroids. Concurrent low-dose cyclophosphamide, appealing for its immunomodulatory effects, could also impact safety. In a retrospective case-control study, we evaluated the effect of systemic corticosteroid use in cancer patients receiving oncolytic virotherapy. Four treatment groups were identified: (1) oncolytic adenovirus with oral glucocorticoids, (2) virus alone, (3) virus with glucocorticoids and cyclophosphamide and (4) virus with cyclophosphamide. Adverse events, neutralizing antibody titers, viral DNA in circulation and tumor responses were evaluated. The most common adverse effects were grade 1-2 fatigue, nausea, fever and abdominal pain. Common asymptomatic findings included self-limiting grade 1-3 hyponatremia and aspartate aminotransferase increase. Safety was good and no significant differences were observed between the groups. All patients had an increase in neutralizing antibody titers post-treatment, and no trends for differences between groups were observed. There were fewer post-treatment virus genomes circulating in patients receiving glucocorticoids when compared to their control groups. Overall, glucocorticoid use in cancer patients receiving oncolytic adenovirus, with or without low-dose cyclophosphamide, seems safe. PMID- 20964370 TI - beta-propeller phytase hydrolyzes insoluble Ca(2+)-phytate salts and completely abrogates the ability of phytate to chelate metal ions. AB - Phytate is an antinutritional factor that influences the bioavailability of essential minerals by forming complexes with them and converting them into insoluble salts. To further our understanding of the chemistry of phytate's binding interactions with biologically important metal cations, we determined the stoichiometry, affinity, and thermodynamics of these interactions by isothermal titration calorimetry. The results suggest that phytate has multiple Ca(2+) binding sites and forms insoluble tricalcium- or tetracalcium-phytate salts over a wide pH range (pH 3.0-9.0). We overexpressed the beta-propeller phytase from Hahella chejuensis (HcBPP) that hydrolyzes insoluble Ca(2+)-phytate salts. Structure-based sequence alignments indicated that the active site of HcBPP may contain multiple calcium-binding sites that provide a favorable electrostatic environment for the binding of Ca(2+)-phytate salts. Biochemical and kinetic studies further confirmed that HcBPP preferentially recognizes its substrate and selectively hydrolyzes insoluble Ca(2+)-phytate salts at three phosphate group sites, yielding the final product, myo-inositol 2,4,6-trisphosphate. More importantly, ITC analysis of this final product with several cations revealed that HcBPP efficiently eliminates the ability of phytate to chelate several divalent cations strongly and thereby provides free minerals and phosphate ions as nutrients for the growth of bacteria. Collectively, our results provide significant new insights into the potential application of HcBPP in enhancing the bioavailability and absorption of divalent cations. PMID- 20964371 TI - Structural analysis of an unusual bioactive N-acylated lipo-oligosaccharide LOS IV in Mycobacterium marinum. AB - Although lipo-oligosaccharides (LOSs) are recognized as major parietal components in many mycobacterial species, their involvement in the host-pathogen interactions have been scarcely documented. In particular, the biological implications arising from the high degree of structural species-specificity of these glycolipids remain largely unknown. Growing recognition of the Mycobacterium marinum-Danio rerio as a specific host-pathogen model devoted to the study of the physiopathology of mycobacterial infections prompted us to elucidate the structure-to-function relationships of the elusive end-product, LOS IV, of the LOS biosynthetic pathway in M. marinum. Combination of physicochemical and molecular modeling methods established that LOS-IV resulted from the differential transfer on the caryophyllose-containing LOS-III of a family of very unusual N-acylated monosaccharides, naturally present as different diastereoisomers. In agreement with the partial loss of pathogenecity previously reported in a LOS-IV-deficient M. marinum mutant, we demonstrated that this terminal monosaccharide conferred to LOS-IV important biological functions, including macrophage activating properties. PMID- 20964373 TI - Fluorescence decay dynamics of flavin adenine dinucleotide in a mixture of alcohol and water in the femtosecond and nanosecond time range. AB - Fluorescence decays of flavin adenine dinucleotide (FAD) that is a typical autofluorescent species in cells and tissues have been measured in a mixture of alcohol and water in the femtosecond and nanosecond time range. The fluorescence lifetimes of both the stacked conformation between the isoalloxazine and adenine moieties in close proximity and the extended open conformation in water are affected by the addition of alcohol. The nanosecond fluorescence lifetime of the open conformation increases with decreasing dielectric constant of the medium, contributing to the enhancement of the fluorescence intensity of FAD in less dielectric media. The fluorescence lifetime of the open conformation is also affected by medium viscosity, suggesting that the photoexcited open conformation is quenched by the dynamic interaction between the two aromatic rings. The fluorescence component decaying in tens of picoseconds is attributed to the stacked conformation that shows the efficient fluorescence quenching due to the intramolecular electron transfer. The picosecond fluorescence lifetime of the stacked conformation increases with decreasing dielectric constant, suggesting the shift of the distribution of the stacked conformation to a longer intramolecular distance between the two aromatic rings in less dielectric media. The pre-exponential factor of the picosecond decaying component relative to that of the nanosecond one decreases with the increase of the alcohol concentration in the femtosecond time-resolved fluorescence, which demonstrates the increase in the population of the open conformation with the reduction of the dielectric constant. The possibility to evaluate the polar environment in a cell by the fluorescence lifetime of FAD is discussed based on the results obtained. PMID- 20964374 TI - Fluorescence resonance energy transfer in gaseous, mass-selected polyproline peptides. AB - Despite the many successes of mass spectrometry in the analysis of biological samples, the need to better understand the correlation between condensed-phase properties and those of electrospray species remains. In particular, the link between structures in the condensed phase and in the gaseous environment of the mass spectrometer is still elusive. Here, we show that fluorescence resonance energy transfer (FRET) can be used to probe the conformations of gaseous biopolymers which are formed by electrospray ionization (ESI) and manipulated in a quadrupole ion trap mass spectrometer. A rhodamine dye pair suitable for gas phase FRET is characterized. Both steady state spectra and lifetime measurements are used to monitor energy transfer in a series of dye-labeled polyproline-based peptides. FRET efficiency is explored as a function of peptide chain length and charge state. For the peptide with eight proline repeats, virtually complete energy transfer is observed. For the peptide with 14 proline repeats, energy transfer decreases as the charge state increases, consistent with Coulomb repulsion induced elongation of the peptide backbone. FRET measurements of the longest peptide examined, which has 20 proline repeats, indicates that the peptide adopts a bent configuration. Evidence for multiple conformations present within the ensemble of trapped ions is provided by fluorescence lifetime measurements. Gas-phase FRET measurements promise to be a new route to probe the conformations of large gaseous ions. PMID- 20964377 TI - Hard/soft heterometallic network complex of a macrocycle with endo/exocyclic coordination. AB - One-pot assembly reactions of an S(2)O(4) macrocycle with CuI in the absence and presence of KI afforded an emissive one-dimensional looped coordination polymer linked with a cubane-type copper iodide cluster and an endocoordinated potassium(I) coordination polymer linked with a ribbon-type copper iodide cluster, respectively. PMID- 20964375 TI - Structural origins of nitroxide side chain dynamics on membrane protein alpha helical sites. AB - Understanding the structure and dynamics of membrane proteins in their native, hydrophobic environment is important to understanding how these proteins function. EPR spectroscopy in combination with site-directed spin labeling (SDSL) can measure dynamics and structure of membrane proteins in their native lipid environment; however, until now the dynamics measured have been qualitative due to limited knowledge of the nitroxide spin label's intramolecular motion in the hydrophobic environment. Although several studies have elucidated the structural origins of EPR line shapes of water-soluble proteins, EPR spectra of nitroxide spin-labeled proteins in detergents or lipids have characteristic differences from their water-soluble counterparts, suggesting significant differences in the underlying molecular motion of the spin label between the two environments. To elucidate these differences, membrane-exposed alpha-helical sites of the leucine transporter, LeuT, from Aquifex aeolicus, were investigated using X-ray crystallography, mutational analysis, nitroxide side chain derivatives, and spectral simulations in order to obtain a motional model of the nitroxide. For each crystal structure, the nitroxide ring of a disulfide-linked spin label side chain (R1) is resolved and makes contacts with hydrophobic residues on the protein surface. The spin label at site I204 on LeuT makes a nontraditional hydrogen bond with the ortho-hydrogen on its nearest neighbor F208, whereas the spin label at site F177 makes multiple van der Waals contacts with a hydrophobic pocket formed with an adjacent helix. These results coupled with the spectral effect of mutating the i +/- 3, 4 residues suggest that the spin label has a greater affinity for its local protein environment in the low dielectric than on a water-soluble protein surface. The simulations of the EPR spectra presented here suggest the spin label oscillates about the terminal bond nearest the ring while maintaining weak contact with the protein surface. Combined, the results provide a starting point for determining a motional model for R1 on membrane proteins, allowing quantification of nitroxide dynamics in the aliphatic environment of detergent and lipids. In addition, initial contributions to a rotamer library of R1 on membrane proteins are provided, which will assist in reliably modeling the R1 conformational space for pulsed dipolar EPR and NMR paramagnetic relaxation enhancement distance determination. PMID- 20964378 TI - Tri- and tetraprotonated ethane (C2H9(3+) and C2H10(4+)) containing five- and six coordinate carbons. AB - Triprotonated ethane (C(2)H(9)(3+)) 4 and tetraprotonated ethane (C(2)H(10)(4+)) 6 were found by ab initio MP2/cc-pVTZ calculations as viable energy minima. Their structure has three and four two-electron three-center (2e-3c) bonds, respectively. In contrast, calculations showed no minimum-energy structure on the potential energy surface of pentaprotonated ethane (C(2)H(11)(5+)). Charge-charge repulsion may approach its limit in this case. Sufficient stabilization of polycations by Schmidbaur-type auration with (C(6)H(5))(3)PAu, an isolobal analogue of H(+), should be possible for the preparation of the polyaurate derivatives of poly protonated ethane allowing their structural study. PMID- 20964379 TI - Fast assembly of ordered block copolymer nanostructures through microwave annealing. AB - Block copolymer self-assembly is an innovative technology capable of patterning technologically relevant substrates with nanoscale precision for a range of applications from integrated circuit fabrication to tissue interfacing, for example. In this article, we demonstrate a microwave-based method of rapidly inducing order in block copolymer structures. The technique involves the usage of a commercial microwave reactor to anneal block copolymer films in the presence of appropriate solvents, and we explore the effect of various parameters over the polymer assembly speed and defect density. The approach is applied to the commonly used poly(styrene)-b-poly(methyl methacrylate) (PS-b-PMMA) and poly(styrene)-b-poly(2-vinylpyridine) (PS-b-P2VP) families of block copolymers, and it is found that the substrate resistivity, solvent environment, and anneal temperature all critically influence the self-assembly process. For selected systems, highly ordered patterns were achieved in less than 3 min. In addition, we establish the compatibility of the technique with directed assembly by graphoepitaxy. PMID- 20964380 TI - A paradigm for blue- or red-shifted absorption of small molecules depending on the site of pi-extension. AB - Benzannulation of aromatic molecules is often used to red-shift absorption and emission bands of organic and inorganic, molecular, and polymeric materials; however, in some cases, either red or blue shifts are observed, depending on the site of benzannulation. A series of five platinum(II) complexes of the form (N(?)N(?)N)PtCl are reported here that illustrate this phenomenon, where N(?)N(?)N represents the tridentate monoanionic ligands 2,5-bis(2 pyridylimino)3,4-diethylpyrrolate (1), 1,3-bis(2-pyridylimino)isoindolate (2), 1,3-bis(2-pyridylimino)benz(f)isoindolate (3), 1,3-bis(2 pyridylimino)benz(e)isoindolate (4), and 1,3-bis(1-isoquinolylimino) isoindolate (5). For this series of molecules, either a blue shift (2 and 3) or a red shift (4 and 5) in absorption and emission maxima, relative to their respective nonbenzannulated compounds, was observed that depends on the site of benzannulation. Experimental data and first principles calculations suggest that a similar HOMO energy level and a destabilized or stabilized LUMO with benzannulation is responsible for the observed trends. A rationale for LUMO stabilization/destabilization is presented using simple molecular orbital theory. This explanation is expanded to describe other molecules with this unusual behavior. PMID- 20964381 TI - Donor-acceptor complexes of borazines. AB - Donor-acceptor complexes of borazine (BZ) and its substituted derivatives with Lewis acids (A = MCl(3), MBr(3); M = B, Al, Ga) and Lewis bases (D = NH(3), Py) have been theoretically studied at the B3LYP/TZVP level of theory. The calculations showed that complexes with Lewis bases only are unstable with respect to dissociation into their components, while complexes with Lewis acids only (such as aluminum and gallium trihalides) are stable. It was shown that formation of ternary D->BZ->A complexes may be achieved by subsequent introduction of the Lewis acid (acceptor A) and the Lewis base (donor D) to borazine. The nature of substituents in the borazine ring, their number, and position were shown to have only minor influence on the stability of ternary D >BZ->A complexes due to the compensation effect. Much weaker acceptor properties of borazine are explained in terms of large endothermic pyramidalization energy of the boron center in the borazine ring. In contrast to borazine, binary complexes of the isoelectronic benzene were predicted to be weakly bound even in the case of very strong Lewis acids; ternary DA complexes of benzene were predicted to be unbound. The donor-acceptor complex formation was predicted to significantly reduce both the endothermicity (by 70-95 kJ mol(-1)) and the activation energy (by 40-70 kJ mol(-1)) for the borazine hydrogenation. Thus, activation of the borazine ring by Lewis acids may be a facile way for the hydrogenation of borazines and polyborazines. PMID- 20964382 TI - Plant cell-wall cross-links by REDOR NMR spectroscopy. AB - We present a new method that integrates selective biosynthetic labeling and solid state NMR detection to identify in situ important protein cross-links in plant cell walls. We have labeled soybean cells by growth in media containing l-[ring d(4)]tyrosine and l-[ring-4-(13)C]tyrosine, compared whole-cell and cell-wall (13)C CPMAS spectra, and examined intact cell walls using (13)C{(2)H} rotational echo double-resonance (REDOR) solid-state NMR. The proximity of (13)C and (2)H labels shows that 25% of the tyrosines in soybean cell walls are part of isodityrosine cross-links between protein chains. We also used (15)N{(13)C} REDOR of intact cell walls labeled by l-[epsilon-(15)N,6-(13)C]lysine and depleted in natural-abundance (15)N to establish that the side chains of lysine are not significantly involved in covalent cross-links to proteins or sugars. PMID- 20964383 TI - QM/MM study of dehydro and dihydro beta-ionone retinal analogues in squid and bovine rhodopsins: implications for vision in salamander rhodopsin. AB - Visual pigment rhodopsin provides a decisive crossing point for interaction between organisms and environment. Naturally occurring visual pigments contain only PSB11 and 3,4-dehydro-PSB11 as chromophores. Therefore, the ability of visual opsin to discriminate between the retinal geometries is investigated by means of QM/MM incorporation of PSB11, 6-s-cis and 6-s-trans forms of 3,4-dehydro PSB11, and 3,4-dehydro-5,6-dihydro-PSB11 and 5,6-dihydro-PSB11 analogues into squid and bovine rhodopsin environments. The analogue-protein interaction reveals the binding site of squid rhodopsin to be malleable and ductile, while that of bovine rhodopsin is rigid and stiff. On the basis of these studies, a tentative model of the salamander rhodopsin binding site is also proposed. PMID- 20964384 TI - Rhenium complexes with 2-(diphenylphosphinomethyl)aniline: formation of a cyclic, trinuclear oxorhenium(V) core. AB - Reactions of 2-(diphenylphosphinomethyl)aniline, H(2)L(2), with (NBu(4))[ReOCl(4)] yield different oxo rhenium(V) complexes depending on the conditions applied. This comprises monomeric compounds such as [ReOCl(3)(H(2)L(2))] (1), [ReOCl(2)(OMe)(H(2)L(2))] (2), or [ReO(2)(H(2)L(2))(2)]Cl (5) as well as the dimeric MU-oxo complex [{ReOCl(2)(H(2)L(2))}(2)]O] (3) and the oxo-bridged trimer [{ReOCl(H(2)L(2))}O](3) (4). The latter compound represents the first example of a hitherto unknown trinuclear, cyclic oxo(V) core. [{ReOCl(H(2)L(2))}O](3) contains a tensed 6-membered metallacycle, which readily undergoes rearrangements and reactions with additional ligands. Compounds of the compositions 5 and [ReO(2)(H(2)L(2))(H(2)L(1))]Cl (6) were isolated either from the decomposition of 4 in CH(2)Cl(2)/n-pentane or from reactions with 2-(diphenylphosphino)aniline, H(2)L(1). PMID- 20964386 TI - Half-sandwich iridium complexes for homogeneous water-oxidation catalysis. AB - Iridium half-sandwich complexes of the types Cp*Ir(N-C)X, [Cp*Ir(N-N)X]X, and [CpIr(N-N)X]X are catalyst precursors for the homogeneous oxidation of water to dioxygen. Kinetic studies with cerium(IV) ammonium nitrate as primary oxidant show that oxygen evolution is rapid and continues over many hours. In addition, [Cp*Ir(H(2)O)(3)]SO(4) and [(Cp*Ir)(2)(MU-OH)(3)]OH can show even higher turnover frequencies (up to 20 min(-1) at pH 0.89). Aqueous electrochemical studies on the cationic complexes having chelate ligands show catalytic oxidation at pH > 7; conversely, at low pH, there are no oxidation waves up to 1.5 V vs NHE for the complexes. H(2)(18)O isotope incorporation studies demonstrate that water is the source of oxygen atoms during cerium(IV)-driven catalysis. DFT calculations and kinetic experiments, including kinetic-isotope-effect studies, suggest a mechanism for homogeneous iridium-catalyzed water oxidation and contribute to the determination of the rate-determining step. The kinetic experiments also help distinguish the active homogeneous catalyst from heterogeneous nanoparticulate iridium dioxide. PMID- 20964387 TI - Synthesis of water-tolerant indium homoenolate in aqueous media and its application in the synthesis of 1,4-dicarbonyl compounds via palladium-catalyzed coupling with acid chloride. AB - The first water-tolerant, ketone-type indium homoenolate was synthesized via the oxidative addition of In/InCl(3) to enones. The reaction proceeds exclusively in aqueous media. Both indium and indium(III) chloride are necessary for the smooth conversion of the reaction. Similar results were obtained when InCl or InCl(2) was used in place of In/InCl(3). The synthetic utility of the indium homoenolate was demonstrated through the synthesis of 1,4-dicarbonyl compounds via palladium catalyzed coupling of indium homoenolate with acid chloride. PMID- 20964388 TI - Dramatic thermal stability of virus-polymer conjugates in hydrophobic solvents. AB - We have developed a method for integrating the self-assembling tobacco mosaic virus capsid into hydrophobic solvents and hydrophobic polymers. The capsid was modified at tyrosine residues to display an array of linear poly(ethylene glycol) chains, allowing it to be transferred into chloroform. In a subsequent step, the capsids could be transferred to a variety of hydrophobic solvents, including benzyl alcohol, o-dichlorobenzene, and diglyme. The thermal stability of the material against denaturation increased from 70 degrees C in water to at least 160 degrees C in hydrophobic solvents. With a view toward material fabrication, the polymer-coated TMV rods were also incorporated into solid polystyrene and thermally cast at 110 degrees C. Overall, this process significantly expands the range of processing conditions for TMV-based materials, with the goal of incorporating these templated nanoscale systems into conductive polymer matrices. PMID- 20964389 TI - Perfluorophenyl azide immobilization chemistry for single molecule force spectroscopy of the concanavalin A/mannose interaction. AB - The versatility of perfluorophenyl azide (PFPA) derivatives makes them useful for attaching a wide variety of biomolecules and polymers to surfaces. Herein, a single molecule force spectroscopy (SMFS) study of the concanavalin A/mannose interaction was carried out using PFPA immobilization chemistry. SMFS of the concanavalin A/mannose interaction yielded an average unbinding force of 70-80 pN for loading rates between 8000 and 40,000 pN/s for mannose surfaces on aminated glass, and an unbinding force of 57 +/- 20 pN at 6960 pN/s for mannose surfaces on gold-coated glass. Dynamic force spectroscopy was used to determine the dissociation rate constant, k(off), for this interaction to be 0.16 s(-1). PMID- 20964390 TI - Rotationally resolved S1-S0 electronic spectra of 2,6-diaminopyridine: a four fold barrier problem. AB - A comparison of the electronic properties of the nitrogen-containing rings aniline, 2-aminopyridine, and 2,6-diaminopyridine (26DAP) shows that the potential energy surface of the molecule is significantly affected as more nitrogen atoms are added to the system. High resolution, rotationally resolved spectra of four vibrational bands in the S(1)-S(0) electronic transition of 26DAP were obtained in order to explain these changes. The zig-zagging inertial defects point to a double minimum excited state potential energy surface along the coupled amino group inversion vibrational mode, which becomes a four-fold well (and barrier) problem when the existence of two nearly degenerate isomers is taken into account. Assuming that the molecules are in the lower energy, opposite side configuration, ab initio calculations were performed using the MP2/6-31G** level of theory to create a potential energy surface modeling the simultaneous antisymmetric NH(2)-inversion mode. The calculated potential energy surface shows a ground electronic state barrier to simultaneous NH(2) inversion of ~220 cm(-1), and a fit to experimental vibrational energy level spacings and relative intensities produces an excited electronic state barrier of ~400 cm(-1). The ground state barrier is less than that in aniline, but the excited state barrier is larger. PMID- 20964391 TI - Enhancing the optical excitation efficiency of a single self-assembled quantum dot with a plasmonic nanoantenna. AB - We demonstrate how the controlled positioning of a plasmonic nanoparticle modifies the photoluminescence of a single epitaxial GaAs quantum dot. The antenna particle leads to an increase of the luminescence intensity by about a factor of 8. Spectrally and temporally resolved photoluminescence measurements prove an increase of the quantum dot's excitation rate. PMID- 20964392 TI - "Naked-eye" screening of metal-based chemosensors for biologically important anions. AB - A two-step "naked-eye" screening of selective metal-based chemosensors for biologically important anions such as cyanide, phosphate, and oxalate from commercially available metal indicators and metal ions has been developed. Applications in food safety control have been demonstrated. PMID- 20964393 TI - Direct writing of sub-5 nm hafnium diboride metallic nanostructures. AB - Sub-5 nm metallic hafnium diboride (HfB(2)) nanostructures were directly written onto Si(100)-2 * 1:H surfaces using ultrahigh vacuum scanning tunneling microscope (UHV-STM) electron beam induced deposition (EBID) of a carbon-free precursor molecule, tetrakis(tetrahydroborato)hafnium, Hf(BH(4))(4). Scanning tunneling spectroscopy data confirm the metallic nature of the HfB(2) nanostructures, which have been written down to lateral dimensions of ~2.5 nm. To our knowledge, this is the first demonstration of sub-5 nm metallic nanostructures in an STM-EBID experiment. PMID- 20964394 TI - Synthesis of conformationally locked L-deoxythreosyl phosphonate nucleosides built on a bicyclo[3.1.0]hexane template. AB - Two conformationally locked versions of l-deoxythreosyl phosphonate nucleosides (2 and 3) were synthesized to investigate the preference of HIV reverse transcriptase for a conformation displaying either a fully diaxial or fully diequatorial disposition of substituents. Synthesis of the enantiomeric 4-(6 amino-9H-purin-9-yl)bicyclo[3.1.0]hexan-2-ol carbocyclic nucleoside precursors (diaxially disposed) proceeded straightforwardly from commercially available (1R,4S)-4-hydroxy-2-cyclopent-2-enyl-1-yl acetate employing a hydroxyl-directed Simmons-Smith cyclopropanation that culminated with a Mitsunobu coupling of the purine base. For the more complicated 1-(6-amino-9H-purin-9 yl)bicyclo[3.1.0]hexan-3-ol carbocyclic nucleoside precursors (diequatorially disposed), the obligatory linear approach required the syntheses of key 1 aminobicyclo[3.1.0.]hexan-3-yl benzoate precursors that were assembled via the amide variant of the Kulinkovich reaction involving the intramolecular cyclopropanation of a substituted delta-vinylamide. Completion of the purine ring was achieved by conventional approaches but with much improved yields through the use of a microwave reactor. The syntheses of the phosphonates and the corresponding diphosphates were achieved by conventional means. None of the diphosphates, which were supposed to act as nucleoside triphosphate mimics, could compete with dATP even when present in a 10-fold excess. PMID- 20964395 TI - Laterally extended naphthalene tetracarboxylic bisimides. AB - The colorless naphthalene tetracarboxylic bisimides were laterally extended with imidazole rings to give colored and highly fluorescent materials. Donor substituted phenyl groups at the imidazole rings cause further bathochromic shifts in fluorescence where the strong solvent influence in the spectra is typical for a TICT process. Applications are discussed. PMID- 20964396 TI - A divergent strategy for the synthesis of secologanin derived natural products. AB - The syntheses of D,L-geissoschizol, D,L-corynantheidol, D,L-dihydrocorynantheol, D,L-protoemetinol, and D,L-3-epi-protoemetinol have been accomplished from a single synthetic intermediate. PMID- 20964397 TI - Highly enantioselective mutant carbonyl reductases created via structure-based site-saturation mutagenesis. AB - A carbonyl reductase from Sporobolomyces salmonicolor reduced para-substituted acetophenones with low enantioselectivity. Enzyme-substrate docking studies revealed that residues M242 and Q245 were in close proximity to the para substituent of acetophenones in the substrate binding site. Site-saturation mutagenesis of M242 or Q245, and double mutation of M242 and Q245 were performed in order to enhance the enzyme's enantioselectivity toward the reduction of para substituted acetophenones. Three Q245 mutants were obtained, which inverted the enantiopreference of product alcohols from (R)- to (S)-configuration with high ee values (Org. Lett. 2008, 10, 525-528). Four M242 mutant enzymes also showed greater preference for the formation of (S)-enantiomeric alcohols than the wild type enzyme, but to a much less extent than Q245 mutants. M242/Q245 double variations not only greatly affect the enantiomeric purity of the product alcohols, but also invert the enantiopreference, demonstrating that these residues play a critical role in determining the enantioselectivity of these ketone reductions. The kinetic parameters of these mutant enzymes indicated that residues 242 and 245 also exert an effect on the catalytic activity of this carbonyl reductase. Highly enantioselective mutant carbonyl reductases were created by site-saturation mutagenesis, among which the one bearing double mutations, M242L/Q245P, showed the highest enantioselectivity that catalyzed the reduction of the tested para-substituted acetophenones to give (S)-enantiomeric products in >=99% ee with only one exception of p-fluoroacetophenone (92% ee). PMID- 20964398 TI - Application of stochastic multiattribute analysis to assessment of single walled carbon nanotube synthesis processes. AB - The unprecedented uncertainty associated with engineered nanomaterials greatly expands the need for research regarding their potential environmental consequences. However, decision-makers such as regulatory agencies, product developers, or other nanotechnology stakeholders may not find the results of such research directly informative of decisions intended to mitigate environmental risks. To help interpret research findings and prioritize new research needs, there is an acute need for structured decision-analytic aids that are operable in a context of extraordinary uncertainty. Whereas existing stochastic decision analytic techniques explore uncertainty only in decision-maker preference information, this paper extends model uncertainty to technology performance. As an illustrative example, the framework is applied to the case of single-wall carbon nanotubes. Four different synthesis processes (arc, high pressure carbon monoxide, chemical vapor deposition, and laser) are compared based on five salient performance criteria. A probabilistic rank ordering of preferred processes is determined using outranking normalization and a linear-weighted sum for different weighting scenarios including completely unknown weights and four fixed-weight sets representing hypothetical stakeholder views. No single process pathway dominates under all weight scenarios, but it is likely that some inferior process technologies could be identified as low priorities for further research. PMID- 20964399 TI - Multiexcitonic dual emission in CdSe/CdS tetrapods and nanorods. AB - CdSe/CdS semiconductor nanocrystal heterostructures are currently of high interest for the peculiar electronic structure offering unique optical properties. Here, we show that nanorods and tetrapods made of such material combination enable efficient multiexcitonic emission, when the volume of the nanoparticle is maximized. This condition is fulfilled by tetrapods with an arm length of 55 nm and results in a dual emission with comparable intensities from the CdS arms and CdSe core. The relative intensities of the dual emission, originating from exciton phase-space filling and reduced Auger recombination, can be effectively modulated by the photon fluence of the pump laser. The results, obtained under steady-state detection conditions, highlight the properties of tetrapods as multiexciton dual-color emitters. PMID- 20964400 TI - Au@Ag core-shell nanocubes with finely tuned and well-controlled sizes, shell thicknesses, and optical properties. AB - This paper describes a facile method for generating Au@Ag core-shell nanocubes with edge lengths controllable in the range of 13.4-50 nm. The synthesis involved the use of single-crystal, spherical Au nanocrystals of 11 nm in size as the seeds in an aqueous system, with ascorbic acid serving as the reductant and cetyltrimethylammonium chloride (CTAC) as the capping agent. The thickness of the Ag shells could be finely tuned from 1.2 to 20 nm by varying the ratio of AgNO(3) precursor to Au seeds. We also investigated the growth mechanism by examining the effects of seeds (capped by CTAC or cetyltrimethylammonium bromide(CTAB)) and capping agent (CTAC vs CTAB) on both size and shape of the resultant core-shell nanocrystals. Our results clearly indicate that CTAC worked much better than CTAB as a capping agent in both the syntheses of Au seeds and Au@Ag core-shell nanocubes. We further studied the localized surface plasmon resonance properties of the Au@Ag nanocubes as a function of the Ag shell thickness. By comparing with the extinction spectra obtained from theoretical calculations, we derived a critical value of ca. 3 nm for the shell thickness at which the plasmon excitation of the Au cores would be completely screened by the Ag shells. Moreover, these Au@Ag core-shell nanocubes could be converted into Au-based hollow nanostructures containing the original Au seeds in the interiors through a galvanic replacement reaction. PMID- 20964401 TI - 14N NQR study of polymorphism and hydrogen bonding in molecular complex isonicotinamide-oxalic acid (2:1). AB - The complete (14)N nuclear quadrupole resonance (NQR) spectra have been measured in the two polymorphic crystalline phases of the molecular complex isonicotinamide-oxalic acid (2:1) by nuclear quadrupole double resonance. The observed NQR frequencies, quadrupole coupling constants, and asymmetry parameters (eta) have been assigned to the two nitrogen positions (ring and amide) in a molecule on the basis of the intensity and multiplicity of the double resonance signals. The NQR data for the ring nitrogen in both polymorphic phases deviate from the correlation relations observed in substituted pyridines. This deviation is analyzed in a model, where it is assumed that an additional electric charge on the nitrogen atom changes the NQR parameters. The model suggests that this additional electric charge is negative so that the N...H-O hydrogen bond seem to be partially ionic, of the type N(-)...H-O. PMID- 20964402 TI - Atomic force microscopy nanomanipulation of shape persistent, spherical, self assembled aggregates of gold nanoparticles. AB - Gold (Au) nanoparticles have been synthesized that are stabilized by an organic ligand bearing a dithiolane functional group for binding to Au, an oligo(p phenylene vinylene) (OPV) chromophoric group to drive self-assembly via pi-pi interactions, and a hydroxy functionality for interparticle hydrogen bonding. The OPV-Au particles reversibly self-assemble in n-heptane solution, forming shape persistent, spherical, nanometer-sized aggregates that do not collapse on a substrate. Optical absorption and transmission electron microscopy tomography studies show that the size and shape persistency can be tuned by modification of the ligands, adjustment of the core size, and variation of the concentration. The spherical assemblies can be manipulated with the tip of an atomic force microscope: an aggregate can be pushed over the surface for at least 20 times with nanometer precision and without substantial loss of material. PMID- 20964403 TI - Cu exposure under field conditions coselects for antibiotic resistance as determined by a novel cultivation-independent bacterial community tolerance assay. AB - Environmental reservoirs of antibiotic resistance are important to human health, and recent evidence indicates that terrestrial resistance reservoirs have expanded during the antibiotic era. Our aim was to study the impact of Cu pollution as a selective driver for the spread of antibiotic resistance in soil. Bacteria were extracted from a well-characterized soil site solely contaminated with CuSO4 more than 80 years ago and from a corresponding control soil. Pollution-induced bacterial community tolerance (PICT) to Cu and a panel of antibiotics was determined by a novel cultivation-independent approach based on [3H]bromodeoxyuridine (BrdU) incorporation into DNA and by resistance profiling of soil bacterial isolates on solid media. High Cu exposure selected for Cu tolerant bacterial communities but also coselected for increased community-level tolerance to tetracycline and vancomycin. Cu-resistant isolates showed significantly higher incidence of resistance to five out of seven tested antibiotics (tetracycline, olaquindox, nalidixic acid, chloramphenicol, and ampicillin) than Cu-sensitive isolates. Our BrdU-PICT data demonstrate for the first time that soil Cu exposure coselects for resistance to clinically important antibiotics (e.g., vancomycin) at the bacterial community-level. Our study further indicates that Cu exposure provides a strong selection pressure for the expansion of the soil bacterial resistome. PMID- 20964404 TI - Alkyl chains of surface ligands affect polytypism of cdse nanocrystals and play an important role in the synthesis of anisotropic nanoheterostructures. AB - We show that the length of the alkyl chain of surface ligands can shift the equilibrium between the wurtzite and zinc blende polytypes of CdSe nanocrystals. In-situ wide-angle X-ray scattering measurements reveal that short-chain (e.g., propyl) phosphonic acids stabilize CdSe nanocrystals with the zinc blende phase whereas octadecylphosphonic acid stabilize nanocrystals with the wurtzite phase. We also demonstrate how this effect can be used to improve the shape selectivity in the synthesis of anisotropic CdSe/CdS and ZnSe/CdS nanoheterostructures. PMID- 20964405 TI - A wild blueberry-enriched diet (Vaccinium angustifolium) improves vascular tone in the adult spontaneously hypertensive rat. AB - The effect of a wild blueberry-enriched diet on vasoconstriction and vasorelaxation was examined in the adult, 20-week-old spontaneously hypertensive rat (SHR) after 8 weeks of a control (C) or an 8% wild blueberry (WB) diet. Nitric oxide (NO)- and cyclooxygenase (COX)-mediated aortic responses were examined ex vivo with the agonists L-phenylephrine (Phe) and acetylcholine (Ach), in the absence or presence of the NO synthase (NOS) inhibitor L-NG-monomethyl arginine (L-NMMA) or the COX inhibitor mefenamic acid (MFA). The vasoconstriction elicited by Phe was reduced in the WB group, attributed to the NO pathway, favoring a lower vascular tone under basal conditions. Acetylcholine-induced vasorelaxation in the WB group was possibly mediated through the COX, but not the NO pathway. These findings document the potential of wild blueberries to modify major pathways of vasomotor control and improve the vascular tone in the adult SHR with endothelial dysfunction. PMID- 20964407 TI - Copper-catalyzed synthesis of quinazoline derivatives via Ullmann-type coupling and aerobic oxidation. AB - A simple and efficient copper-catalyzed approach to quinazoline derivatives has been developed, and the protocol uses readily available substituted (2 bromophenyl)methylamines and amides as the starting materials, and the cascade reactions were performed under air via sequential Ullmann-type coupling and aerobic oxidation without addition of any ligand or additive. The present method provides a convenient and practical strategy for synthesis of quinazoline derivatives. PMID- 20964406 TI - Synthesis of a 6-methyl-7-deaza analogue of adenosine that potently inhibits replication of polio and dengue viruses. AB - Bioisosteric deaza analogues of 6-methyl-9-beta-D-ribofuranosylpurine, a hydrophobic analogue of adenosine, were synthesized and evaluated for antiviral activity. Whereas the 1-deaza and 3-deaza analogues were essentially inactive in plaque assays of infectivity, a novel 7-deaza-6-methyl-9-beta-D ribofuranosylpurine analogue, structurally related to the natural product tubercidin, potently inhibited replication of poliovirus (PV) in HeLa cells (IC(50) = 11 nM) and dengue virus (DENV) in Vero cells (IC(50) = 62 nM). Selectivity against PV over cytotoxic effects to HeLa cells was >100-fold after incubation for 7 h. Mechanistic studies of the 5'-triphosphate of 7-deaza-6 methyl-9-beta-D-ribofuranosylpurine revealed that this compound is an efficient substrate of PV RNA-dependent RNA polymerase (RdRP) and is incorporated into RNA mimicking both ATP and GTP. PMID- 20964408 TI - Synthesis and biological evaluation of polyenylpyrrole derivatives as anticancer agents acting through caspases-dependent apoptosis. AB - A class of polyenylpyrroles and their analogues were designed from a hit compound identified in a fungus. The compounds synthesized were evaluated for their cell cytotoxicity against human non-small-cell lung carcinoma cell lines A549. Two compounds were found to exhibit high cytotoxicity against A549 cells with IC(50) of 0.6 and 0.01 MUM, respectively. The underlying mechanisms for the anticancer activity were demonstrated as caspases activation dependent apoptosis induction through loss of mitochondrial membrane potential, release of cytochrome c, increase in B-cell lymphoma-2-associated X protein (Bax) level, and decrease in B cell lymphoma-2 (Bcl-2) level. The two compounds were nontoxic to normal human lung Beas-2b cells (IC(50) > 80 MUM), indicating that they are highly selective in their cytotoxicity activities. Furthermore, one compound showed in vivo anticancer activity in human-lung-cancer-cell-bearing mice. These results open promising insights on how these conjugated polyenes mediate cytotoxicity and may provide a molecular rationale for future therapeutic interventions in carcinogenesis. PMID- 20964409 TI - Electronic effects on atom tunneling: conformational isomerization of monomeric para-substituted benzoic acid derivatives. AB - We present the first generation and spectroscopic identification of the higher lying E conformer of the simplest aromatic carboxylic acid, benzoic acid (1a), as its O-deuterated isotopologue (E)-d(1)-1a using matrix-isolation techniques; the parent (E)-1a could not be observed because of fast H-tunneling to the more stable conformer (Z)-1a. Even deuterated (E)-d(1)-1a converts quickly back to (Z) d(1)-1a through D-tunneling with a half-life (tau) of ~12 min in Ar at 11 K. Tunneling computations using an Eckart barrier in conjunction with a CCSD(T)/cc pVTZ//MP2/cc-pVDZ + ZPVE intrinsic reaction path revealed that tau of (E)-1a is only ~10(-5) min, in marked contrast to those of simple aliphatic acids, which are in the range of minutes. The electronic substituent effects on D-tunneling in para-substituted benzoic acid derivatives (p-X-PhCOOD, d(1)-1) were systematically studied in Ar matrices at 11 K to derive the first Hammett relationships for atom tunneling. sigma-Electron donors (X = alkyl) increase the half-life of d(1)-1, while sigma-acceptor/pi-donor groups (X = OD, NH(2), halogen) and to an even greater extent a sigma-/pi-acceptor group (X = NO(2)) decrease tau. The latter finding is in line with the smaller E-to-Z reaction barriers and narrower reaction widths for the isomerization. Tunneling substituent constants (sigma(t)) for this conformational isomerization were derived experimentally and computationally. PMID- 20964410 TI - Gas-phase compaction and unfolding of protein structures. AB - Ion-mobility mass spectrometry is emerging as a powerful tool for studying the structures of less established protein assemblies. The method provides simultaneous measurement of the mass and size of intact protein assemblies, providing information not only on the subunit composition and network of interactions but also on the overall topology and shape of protein complexes. However, how the experimental parameters affect the measured collision cross sections remains elusive. Here, we present an extensive systematic study on a range of proteins and protein complexes with differing sizes, structures, and oligomerization states. Our results indicate that the experimental parameters, T wave height and velocity, influence the determined collision cross-section independently and in opposite directions. Increasing the T-wave height leads to compaction of the protein structures, while higher T-wave velocities lead to their expansion. These different effects are attributed to differences in energy transmission and dissipation rates. Moreover, by analyzing proteins in their native and denatured states, we could identify the lower and upper boundaries of the collision cross-section, which reflect the "maximally packed" and "ultimately unfolded" states. Together, our results provide grounds for selecting optimal experimental parameters that will enable preservation of the nativelike conformation, providing structural information on uncharacterized protein assemblies. PMID- 20964411 TI - Microfluidic glycosyl hydrolase screening for biomass-to-biofuel conversion. AB - The hydrolysis of biomass to fermentable sugars using glycosyl hydrolases such as cellulases and hemicellulases is a limiting and costly step in the conversion of biomass to biofuels. Enhancement in hydrolysis efficiency is necessary and requires improvement in both enzymes and processing strategies. Advances in both areas in turn strongly depend on the progress in developing high-throughput assays to rapidly and quantitatively screen a large number of enzymes and processing conditions. For example, the characterization of various cellodextrins and xylooligomers produced during the time course of saccharification is important in the design of suitable reactors, enzyme cocktail compositions, and biomass pretreatment schemes. We have developed a microfluidic-chip-based assay for rapid and precise characterization of glycans and xylans resulting from biomass hydrolysis. The technique enables multiplexed separation of soluble cellodextrins and xylose oligomers in around 1 min (10-fold faster than HPLC). The microfluidic device was used to elucidate the mode of action of Tm_Cel5A, a novel cellulase from hyperthermophile Thermotoga maritima . The results demonstrate that the cellulase is active at 80 degrees C and effectively hydrolyzes cellodextrins and ionic-liquid-pretreated switchgrass and Avicel to glucose, cellobiose, and cellotriose. The proposed microscale approach is ideal for quantitative large-scale screening of enzyme libraries for biomass hydrolysis, for development of energy feedstocks, and for polysaccharide sequencing. PMID- 20964412 TI - Complexation of lactate with neodymium(III) and europium(III) at variable temperatures: studies by potentiometry, microcalorimetry, optical absorption, and luminescence spectroscopy. AB - The complexation of neodymium(III) and europium(III) with lactate was studied at variable temperatures by potentiometry, absorption spectrophotometry, luminescence spectroscopy, and microcalorimetry. The stability constants of three successive lactate complexes (ML(2+), ML(2)(+), and ML(3)(aq), where M stands for Nd and Eu and L stands for lactate) at 10, 25, 40, 55, and 70 degrees C were determined. The enthalpies of complexation at 25 degrees C were determined by microcalorimetry. Thermodynamic data show that the complexation of trivalent lanthanides (Nd(3+) and Eu(3+)) with lactate is exothermic and the complexation becomes weaker at higher temperatures. Results from optical absorption and luminescence spectroscopy suggest that the complexes are inner-sphere chelate complexes in which the protonated alpha-hydroxyl group of lactate participates in the complexation. PMID- 20964413 TI - Glucose biosensor from covalent immobilization of chitosan-coupled carbon nanotubes on polyaniline-modified gold electrode. AB - An amperometric glucose biosensor was prepared using polyaniline (PANI) and chitosan-coupled carbon nanotubes (CS-CNTs) as the signal amplifiers and glucose oxidase (GOD) as the glucose detector on a gold electrode (the Au-g-PANI-c-(CS CNTs)-GOD biosensor). The PANI layer was prepared via oxidative graft polymerization of aniline from the gold electrode surface premodified by self assembled monolayer of 4-aminothiophenol. CS-CNTs were covalently coupled to the PANI-modified gold substrate using glutaradehyde as a bifunctional linker. GOD was then covalently bonded to the pendant hydroxyl groups of chitosan using 1,4 carbonyldiimidazole as the bifunctional linker. The surface functionalization processes were ascertained by X-ray photoelectron spectroscopy (XPS) analyses. The field emission scanning electron microscopy (FESEM) images of the Au-g-PANI-c (CS-CNTs) electrode revealed the formation of a three-dimensional surface network structure. The electrode could thus provide a more spatially biocompatible microenvironment to enhance the amount and biocatalytic activity of the immobilized enzyme and to better mediate the electron transfer. The resulting Au g-PANI-c-(CS-CNTs)-GOD biosensor exhibited a linear response to glucose in the concentration range of 1-20 mM, good sensitivity (21 MUA/(mM.cm(2))), good reproducibility, and retention of >80% of the initial response current after 2 months of storage. PMID- 20964414 TI - Supramolecular effects on anion-dependent spin-state switching properties in heteroleptic iron(II) complexes. AB - We describe the preparations, characterizations, and spin-state properties of heteroleptic Fe(II) complexes containing 2,2'-bi-1,4,5,6-tetrahydropyrimidine (H(2)bip) and 2-(aminomethyl)pyridine (pic): [(H(2)bip)(2)Fe(pic)]X(2) (X = Br (1), BPh(4) (2)) and [(H(2)bip)(1.75)Fe(pic)(1.25)](BPh(4))(2) (3). The ditopic H(2)bip ligand serves as an anion binding group while pic is intended to adjust the Fe(II) ion's ligand field close to the thermal spin-crossover region. The solid state magnetic behavior of each complex salt is found to be heavily influenced by anion and solvate molecules, and is correlated with the first coordination sphere molecular structure, intermolecular interactions, and solvate induced packing effects. Anion-dependent spin-state switching is observed in dichloromethane solution for samples of 2 treated with (n)Bu(4)NBr, albeit at significantly lower temperatures than what would be expected based on ligand field considerations alone. The origins of this behavior are discussed: circumstantial evidence points to unintended effects of anion-mediated complex pairing in solution as a significant contributor to the lower-than-expected operating temperatures. PMID- 20964415 TI - Enhancement of ethanol vapor sensing of TiO2 nanobelts by surface engineering. AB - TiO(2) nanobelts were prepared by a hydrothermal process, and the structures were manipulated by surface engineering, including surface coarsening by an acid corrosion procedure and formation of Ag-TiO(2) heterostuctures on TiO(2) nanobelts surface by photoreduction. Their performance in the detection of ethanol vapor was then examined and compared by electrical conductivity measurements at varied temperatures. Of the sensors based on the four nanobelt samples (TiO(2) nanobelts, Ag-TiO(2) nanobelts, surface-coarsened TiO(2) nanobelts, and surface-coarsened Ag-TiO(2) nanobelts), they all displayed improved sensitivity, selectivity, and short response times for ethanol vapor detection, in comparison with sensors based on other oxide nanostructures. Importantly, the formation of Ag-TiO(2) heterostuctures on TiO(2) nanobelts surface and surface coarsening of TiO(2) nanobelts were found to lead to apparent further enhancement of the sensors sensitivity, as well as a decrease of the optimal working temperature. That is, within the present experimental context, the vapor sensor based on surface-coarsened Ag-TiO(2) composite nanobelts exhibited the best performance. The sensing mechanism was interpreted on the basis of the surface depletion model, and the improvement by oxide surface engineering was accounted for by the chemical sensitization mechanism. This work provided a practical approach to the enhancement of gas sensing performance by one-dimensional oxide nanomaterials. PMID- 20964416 TI - Is the Cassie-Baxter formula relevant? AB - The utility of the Cassie-Baxter formula to predict the apparent contact angle of a drop on rough hydrophobic surfaces has been questioned recently. To resolve this issue, experimental and numerical data for advancing and receding contact angles are reported. In all cases considered it is seen that contact angles follow the overall trend of the Cassie-Baxter formula, except for the advancing front on pillar type roughness. It is shown that deviations from the Cassie Baxter angle have a one-to-one correlation with microscopic distortions of the contact line with respect to its configuration in the Cassie-Baxter state. PMID- 20964417 TI - Heteroleptic copper switches. AB - Heteroleptic copper compounds have been designed and synthesized on solid supports. Chemical redox agents were used to change the oxidation state of the SiO(2)-immobilized heteroleptic copper compounds from Cu(I) to Cu(II) and then back to Cu(I). Optical spectroscopy of a dimethyl sulfoxide suspension demonstrated the reversibility of the Cu(I)/Cu(II) SiO(2)-immobilized compounds by monitoring the metal-to-ligand charge transfer peak at about 450 nm. Electron paramagnetic resonance spectroscopy was used to monitor the isomerization of Cu(I) tetrahedral to Cu(II) square planar. This conformational change corresponds to a 90 degrees rotation of one ligand with respect to the other. Conductive atomic force microscopy and macroscopic gold electrodes were used to study the electrical properties of a p(+) Si-immobilized heteroleptic copper compound where switching between the Cu(I)/Cu(II) states occurred at -0.8 and +2.3 V. PMID- 20964418 TI - Synthesis and coordination chemistry of two N2-donor chelating di(indazolyl)methane ligands: structural characterization and comparison of their metal chelation aptitudes. AB - The N(2)-donor bidentate ligands di(1H-indazol-1-yl)methane (L(1)) and di(2H indazol-2-yl)methane (L(2)) (L in general) have been synthesized, and their coordination behavior toward Zn(II), Cd(II), and Hg(II) salts has been studied. Reaction of L(1) and L(2) with ZnX(2) (X = Cl, Br, or I) yields [ZnX(2)L] species (1-6), that, in the solid state, show a tetrahedral structure with dihapto ligand coordination via the pyrazolyl arms. The reaction of L(1) and L(2) with Zn(NO(3))(2).6H(2)O is strongly dependent on the reaction conditions and on the ligand employed. Reaction of L(1) with equimolar quantities of Zn(NO(3))(2).6H(2)O yields the neutral six-coordinate species [Zn(NO(3))(2)(L(1))], 7. On the other hand the use of L(1) excess gives the 2:1 adduct [Zn(NO(3))(2)(L(1))(2)], 8 where both nitrates act as a unidentate coordinating ligand. Analogous stoichiometry is found in the compound obtained from the reaction of L(2) with Zn(NO(3))(2).6H(2)O which gives the ionic [Zn(NO(3))(L(2))(2)](NO(3)), 10. Complete displacement of both nitrates from the zinc coordination sphere is observed when the reaction between L(1) excess and the zinc salt was carried out in hydrothermal conditions. The metal ion type is also determining structure and stoichiometry: the reaction of L(2) with CdCl(2) gave the 2:1 adduct [CdCl(2)(L(2))(2)] 11 where both chlorides complete the coordination sphere of the six-coordinate cadmium center; on the other hand from the reaction of L(1) with CdBr(2) the polynuclear [CdBr(2)(L(1))](n) 12 is obtained, the Br(-) anion acting as bridging ligands in a six-coordinate cadmium coordination environment. The reaction of L(1) and L(2) with HgX(2) (X = Cl, I, SCN) is also dependent on the reaction conditions and the nature of X, two different types of adducts being formed [HgX(L)] (14: L = L(1), 16, 17: L = L(1) or L(2), X = I, 19: L = L(2), X = SCN) and [HgX(L)(2)] (15: L = L(2), X = Cl, 18: L = L(1), X = SCN). The X-ray diffraction analyses of compounds 1, 2, 4, 5, 7, 8, 10-12, 14, 15, and 19 are also reported. The variations of the coordination geometry parameters in the complexes are compared and discussed. PMID- 20964419 TI - Bioinorganic chemistry of Parkinson's disease: structural determinants for the copper-mediated amyloid formation of alpha-synuclein. AB - The aggregation of alpha-synuclein (AS) is a critical step in the etiology of Parkinson's disease (PD). A central, unresolved question in the pathophysiology of PD relates to the role of AS-metal interactions in amyloid fibril formation and neurodegeneration. Our previous works established a hierarchy in alpha synuclein-metal ion interactions, where Cu(II) binds specifically to the protein and triggers its aggregation under conditions that might be relevant for the development of PD. Two independent, non-interacting copper-binding sites were identified at the N-terminal region of AS, with significant difference in their affinities for the metal ion. In this work we have solved unknown details related to the structural binding specificity and aggregation enhancement mediated by Cu(II). The high-resolution structural characterization of the highest affinity N terminus AS-Cu(II) complex is reported here. Through the measurement of AS aggregation kinetics we proved conclusively that the copper-enhanced AS amyloid formation is a direct consequence of the formation of the AS-Cu(II) complex at the highest affinity binding site. The kinetic behavior was not influenced by the His residue at position 50, arguing against an active role for this residue in the structural and biological events involved in the mechanism of copper-mediated AS aggregation. These new findings are central to elucidate the mechanism through which the metal ion participates in the fibrillization of AS and represent relevant progress in the understanding of the bioinorganic chemistry of PD. PMID- 20964420 TI - Addition of water across Si-Ir bonds in iridium complexes with kappa-P,P,Si (biPSi) pincer ligands. AB - Electrophiles such as Me(+), Ag(+), or protons react with the five-coordinate Ir(III) complex [IrClH(biPSi)] (biPSi = kappa-P,P,Si-Si(Me){(CH(2))(3)PPh(2)}(2)) by abstracting its chloride ligand. The resulting species can be stabilized by a variety of L ligands to give the cationic complexes [IrH(biPSi)L(2)](+). The derivative [IrH(biPSi)(NCMe)(2)](+) has been subjected to a kinetic study regarding the facile dissociations of its acetonitrile ligands. The presence of water changes the course of the reaction producing dihydride complexes that contain the silanol ligand kappa-O,P,P-HOSi(Me){(CH(2))(3)PPh(2)}(2) (biPSiOH). The water activation product [IrH(2)(biPSiOH)(NCMe)](CF(3)SO(3)) undergoes insertion reactions with ethylene and phenylacetylene. The use of hydrolyzable fluorinated counterions such as PF(6)(-) or BF(4)(-) further modifies the reaction by provoking the incorporation of fluoride at the silicon atom of the former biPSi ligand. The dihydride resulting after such a process, [IrH(2)(biPSiF)(NCMe)(2)]BF(4) (biPSiF = kappa-P(2) FSi(Me){(CH(2))(3)PPh(2)}(2)), displays a trans-chelating diphosphine ligand. When dehydrogenating the Ir center, spontaneously or using ethylene as hydrogen acceptor, the diphosphine backbone undergoes a Si-C bond cleavage leading to a new Ir(III) species with kappa-P,Si and kappa-C,P chelate ligands. PMID- 20964421 TI - Ruthenium-oxygen coordination-driven self-assembly of a Ru(II)8 incomplete prism: synthesis, structure, and shape-selective molecular recognition study. AB - Coordination-driven self-assembly of 1,3,5-benzenetricarboxylate (tma; 1) and oxalato-bridged p-cymeneruthenium(II) building block [Ru(2)(MU-eta(4) C(2)O(4))(MeOH)(2)(eta(6)-p-cymene)(2)](O(3)SCF(3))(2) (2) affords an unusual octanuclear incomplete prism [Ru(8)(eta(6)-p-cymene)(8)(tma)(2)(MU-eta(4) C(2)O(4))(2)(OMe)(4)](O(3)SCF(3))(2) (3), which exhibits a remarkable shape selective binding affinity for neutral phenolic compounds via hydrogen-bonding interactions (p-cymene = p-(i)PrC(6)H(4)Me). Such a binding was confirmed by single-crystal X-ray diffraction analysis using 1,3,5-trihydroxybenzene as an analyte. PMID- 20964422 TI - Solution study of engineered quartz binding peptides using replica exchange molecular dynamics. AB - We use replica-exchange molecular dynamics (REMD) to interrogate molecular structures and properties of four engineered dodecapeptides (in solution, in the absence of a surface) that have been shown to bind to quartz with different propensities. We find that all of the strong-binding peptides feature some polyproline type II secondary structure, have less conformational freedom, and feature fewer intrapeptide hydrogen bonds compared with the weak binder. The regions of contiguous proline content in a given sequence appear to play a role in fostering some of these properties of the strong binders. For preliminary insights into quartz binding, we perform lattice-matching studies between a grid corresponding with the quartz (100) surface and the strong-binding peptide REMD structures. Our findings indicate a commonality among the putative contact residues, even for peptide structures with very different backbone conformations. Furthermore, interpeptide interactions in solution are studied. Our preliminary findings indicate that the strong-binder interpeptide contacts are dominated by weak, nonspecific hydrophobic interactions, while the weak-binding peptide shows more variable behavior due to the distribution of charged residues. In summary, the solution structures of peptides appear to be significant. We propose that these differences in their intra- and interpeptide interactions can influence their propensity to bind onto a solid substrate. PMID- 20964423 TI - Site specific X-ray anomalous dispersion of the geometrically frustrated kagome magnet, herbertsmithite, ZnCu(3)(OH)(6)Cl(2). AB - Structural characterization, exploiting X-ray scattering differences at elemental absorption edges, is developed to quantitatively determine crystallographic site specific metal disorder. We apply this technique to the problem of Zn-Cu chemical disorder in ZnCu(3)(OH)(6)Cl(2). This geometrically frustrated kagome antiferromagnet is one of the best candidates for a spin-liquid ground state, but chemical disorder has been suggested as a mundane explanation for its magnetic properties. Using anomalous scattering at the Zn and Cu edges, we determine that there is no Zn occupation of the intralayer Cu sites within the kagome layer; however there is Cu present on the Zn intersite, leading to a structural formula of (Zn(0.85)Cu(0.15))Cu(3)(OH)(6)Cl(2). The lack of Zn mixing onto the kagome lattice sites lends support to the idea that the electronic ground state in ZnCu(3)(OH)(6)Cl(2) and its relatives is nontrivial. PMID- 20964424 TI - A-type proanthocyanidins from lychee seeds and their antioxidant and antiviral activities. AB - Two new A-type trimeric proanthocyanidins with two doubly bonded interflavanoid linkages, litchitannin A1 [epicatechin-(2beta->O->7,4beta->6)-epicatechin-(2beta >O->7,4beta->8)-catechin] (1) and litchitannin A2 [epicatechin-(2beta->O->7,4beta >6)-epicatechin-(2beta->O->7,4beta->6)-epicatechin] (2), were isolated from lychee (Litchi chinensis Sonn. cv. Heiye) seeds together with aesculitannin A (3), epicatechin-(2beta->O->7,4beta->8)-epiafzelechin-(4alpha->8)-epicatechin (4), proanthocyanidin A1 (5), proanthocyanidin A2 (6), proanthocyanidin A6 (7), epicatechin-(7,8-bc)-4beta-(4-hydroxyphenyl)-dihydro-2(3H)-pyranone (8), and epicatechin (9). Their structures were elucidated on the basis of spectroscopic and chemical evidence. It is the first time that compounds 1-4, 7, and 8 have been reported in this species. Compounds 1-9 showed more potent antioxidant activity than L-ascorbic acid with ferric reducing antioxidant power (FRAP) values of 3.71-24.18 mmol/g and IC50 values of 5.25-20.07 MUM toward DPPH radicals. Moreover, litchitannin A2 (2) was found to exhibit in vitro antiviral activity against coxsackie virus B3 (CVB3) and compounds 3 and 6 displayed antiherpes simplex virus 1 (HSV-1) activity. PMID- 20964425 TI - Photooxidative coupling of thiophenol derivatives to disulfides. AB - Disulfide bonds play an important role in determining the structure and stability of proteins and nanoparticles. Despite extensive studies on the oxidation of thiols for the synthesis of disulfides, little is known about the photooxidation of thiols, which may be a clean, safe, and economical alternative to the use of harmful and expensive metal-containing oxidants and catalysts. In this paper, we report the photooxidative coupling of thiophenol derivatives to disulfides. Para substituted thiophenol derivatives, p-SHC(6)H(4)X (X = NO(2), COOH, Cl, and OCH(3)), are irradiated, and disulfides, X(2)(C(6)H(4))(2)S(2), are identified as the major photoproducts using Raman, UV-vis, IR, and NMR spectroscopies. For p nitrothiophenol (pNTP), 4,4'-dinitrodiphenyldisulfide (DNDPDS) is produced in 81% yield. The product yield changes with pH, being the highest at pH ~ 5, suggesting that both neutral thiol and anionic thiolate forms of pNTP are required for the photoreaction to occur. Excitation at 455 nm, at which the thiolate form of pNTP absorbs strongly, leads to the largest yield of DNDPDS, whereas very little DNDPDS is formed by excitation of the thiol form of pNTP at 325 nm. Our observations suggest that the photooxidation occurs via collisions of the electronically excited thiolate form of pNTP with the surrounding neutral thiol forms of pNTP. The photooxidation reaction happens regardless of the electron withdrawing or electron-donating properties of the substituents if the pH and excitation wavelengths are properly chosen. The versatility of light and generality of the photooxidative coupling reaction of thiophenol derivatives may open new possibilities for selective and site-specific photocontrol of disulfide bond formation in biology and nanomaterial science as well as in synthetic chemistry. PMID- 20964426 TI - Phase equilibria and modeling of pyridinium-based ionic liquid solutions. AB - The phase diagrams of the ionic liquid (IL) N-butyl-4-methylpyridinium bis{(trifluoromethyl)sulfonyl}imide ([BM(4)Py][NTf(2)]) with water, an alcohol (1 butanol, 1-hexanol, 1-octanol, 1-decanol), an aromatic hydrocarbon (benzene, toluene, ethylbenzene, n-propylbenzene), an alkane (n-hexane, n-heptane, n octane), or cyclohexane have been measured at atmospheric pressure using a dynamic method. This work includes the characterization of the synthesized compound by water content and also by differential scanning calorimetry. Phase diagrams for the binary systems of [BM(4)Py][NTf(2)] with all solvents reveal eutectic systems with regards to (solid-liquid) phase equilibria and show immiscibility in the liquid phase region with an upper critical solution temperature (UCST) in most of the mixtures. The phase equilibria (solid, or liquid-liquid) for the binary systems containing aliphatic hydrocarbons reported here exhibit the lowest solubility and the highest immiscibility gap, a trend which has been observed for all ILs. The reduction of experimental data has been carried out using the nonrandom two-liquid (NRTL) correlation equation. The phase diagrams reported here have been compared with analogous phase diagrams reported previously for systems containing the IL N-butyl-4-methylpyridinium tosylate and other pyridinium-based ILs. The influence of the anion of the IL on the phase behavior has been discussed. PMID- 20964427 TI - Free energy surfaces from single-distance information. AB - We propose a network-based method for determining basins and barriers of complex free energy surfaces (e.g., the protein folding landscape) from the time series of a single intramolecular distance. First, a network of transitions is constructed by clustering the points of the time series according to the short time distribution of the signal. The transition network, which reflects the short time kinetics, is then used for the iterative determination of individual basins by the minimum-cut-based free energy profile, a barrier-preserving one dimensional projection of the free energy surface. The method is tested using the time series of a single C(beta)-C(beta) distance extracted from equilibrium molecular dynamics (MD) simulations of a structured peptide (20 residue three stranded antiparallel beta-sheet). Although the information of only one distance is employed to describe a system with 645 degrees of freedom, both the native state and the unfolding barrier of about 10 kJ/mol are determined with remarkable accuracy. Moreover, non-native conformers are identified by comparing long-time distributions of the same distance. To examine the applicability to single molecule Forster resonance energy transfer (FRET) experiments, a time series of donor and acceptor photons is generated using the MD trajectory. The native state of the beta-sheet peptide is determined accurately from the emulated FRET signal. Applied to real single-molecule FRET measurements on a monomeric variant of lambda-repressor, the network-based method correctly identifies the folded and unfolded populations, which are clearly separated in the minimum-cut-based free energy profile. PMID- 20964428 TI - The first step in glycine solvation: the glycine-water complex. AB - The jet-cooled spontaneous Raman spectrum of a glycine-water complex (Gly + H(2)O), the first step in amino acid hydration, is reported. The low-frequency vibrational spectrum (below 500 cm(-1)) of the solvated molecule is recorded and assigned using quantum chemical data calculated from ab initio (MP2) and DFT (B3LYP, BLYP, PBE0 = PBE1PBE). Anharmonic corrections or Raman and infrared (IR) active vibrations are calculated using second-order perturbation theory at the MP2/6-31+G(d) level. The acquired spectra at medium resolution (hwhm of ~4 cm( 1)) allow different conformers of the glycine-water heterodimer to be distinguished. Three different dimer conformations are observed and identified; selective collision-induced relaxation processes are used to estimate their relative stability. The results are compared with recent theoretical predictions and microwave (MW) spectroscopy data. The premise that the acidic character of the OH group of the carboxylic acid dominates the interaction between water and glycine is confirmed. The addition of a water molecule is found to greatly change the potential energy surface and conformational preferences of H(2)NCH(2)COOH. Water stabilizes conformations in which formation of a closed-ring, H-bonded structure is possible. Simultaneous participation by the carboxyl oxygen of the amino acid in two hydrogen bonds is found to be unfavorable. It may be expected that the addition of extra water molecules could ultimately lead to the stabilization of the Gly zwitterion. PMID- 20964429 TI - Hierarchical self-assembly of a biomimetic diblock copolypeptoid into homochiral superhelices. AB - The aqueous self-assembly of a sequence-specific bioinspired peptoid diblock copolymer into monodisperse superhelices is demonstrated to be the result of a hierarchical process, strongly dependent on the charging level of the molecule. The partially charged amphiphilic diblock copolypeptoid 30-mer, [N-(2 phenethyl)glycine](15)-[N-(2-carboxyethyl)glycine](15), forms superhelices in high yields, with diameters of 624 +/- 69 nm and lengths ranging from 2 to 20 MUm. Chemical analogs coupled with X-ray scattering and crystallography of a model compound have been used to develop a hierarchical model of self-assembly. Lamellar stacks roll up to form a supramolecular double helical structure with the internal ordering of the stacks being mediated by crystalline aromatic side chain-side chain interactions within the hydrophobic block. The role of electrostatic and hydrogen bonding interactions in the hydrophilic block is also investigated and found to be important in the self-assembly process. PMID- 20964430 TI - Vibrational Stark effect spectroscopy at the interface of Ras and Rap1A bound to the Ras binding domain of RalGDS reveals an electrostatic mechanism for protein protein interaction. AB - Electrostatic fields at the interface of the Ras binding domain of the protein Ral guanine nucleotide dissociation stimulator (RalGDS) with the structurally analogous GTPases Ras and Rap1A were measured with vibrational Stark effect (VSE) spectroscopy. Eleven residues on the surface of RalGDS that participate in this protein-protein interaction were systematically mutated to cysteine and subsequently converted to cyanocysteine in order to introduce a nitrile VSE probe in the form of the thiocyanate (SCN) functional group. The measured SCN absorption energy on the monomeric protein was compared with solvent-accessible surface area (SASA) calculations and solutions to the Poisson-Boltzmann equation using Boltzmann-weighted structural snapshots from molecular dynamics simulations. We found a weak negative correlation between SASA and measured absorption energy, indicating that water exposure of protein surface amino acids can be estimated from experimental measurement of the magnitude of the thiocyanate absorption energy. We found no correlation between calculated field and measured absorption energy. These results highlight the complex structural and electrostatic nature of the protein-water interface. The SCN-labeled RalGDS was incubated with either wild-type Ras or wild-type Rap1A, and the formation of the docked complex was confirmed by measurement of the dissociation constant of the interaction. The change in absorption energy of the thiocyanate functional group due to complex formation was related to the change in electrostatic field experienced by the nitrile functional group when the protein-protein interface forms. At some locations, the nitrile experiences the same shift in field when bound to Ras and Rap1A, but at others, the change in field is dramatically different. These differences identify residues on the surface of RalGDS that direct the specificity of RalGDS binding to its in vivo binding partner, Rap1A, through an electrostatic mechanism. PMID- 20964431 TI - Low-temperature, mineral-catalyzed air oxidation: a possible new pathway for PAH stabilization in sediments and soils. AB - Reactivity of polycyclic aromatic hydrocarbons (PAHs) in the subsurface is of importance to environmental assessment, as they constitute a highly toxic hazard. Understanding their reactivity in the long term in natural recovering systems is thus a key issue. This article describes an experimental investigation on the air oxidation of fluoranthene (a PAH abundant in natural systems polluted by industrial coal use) at 100 degrees C on different mineral substrates commonly found in soils and sediments (quartz sand, limestone, and clay). Results demonstrate that fluoranthene is readily oxidized in the presence of limestone and clay, leading to the formation of high molecular weight compounds and a carbonaceous residue as end product especially for clay experiments. As demonstrated elsewhere, the experimental conditions used permitted the reproduction of the geochemical pathway of organic matter observed under natural conditions. It is therefore suggested that low-temperature, mineral-catalyzed air oxidation is a mechanism relevant to the stabilization of PAHs in sediments and soils. PMID- 20964432 TI - Use of surface plasmon resonance (SPR) to study the dissociation and polysaccharide binding of casein micelles and caseins. AB - Tests were made to determine whether surface plasmon resonance (SPR) could be used as a technique to study the dissociation properties of bovine casein micelles or of sodium caseinate and the interactions between these protein particles and different polysaccharides. Surfaces of bound micelles or caseinate were made, and the changes in refractive index of these layers were used to define changes in the structures of the chemisorbed material. The technique appears to have some potential for studying details of the dissociation of casein micelles and of the binding of different polysaccharides to caseins. PMID- 20964433 TI - Selective delivery of cargo entities to tumor cells by nanoscale artificial oil bodies. AB - Artificial oil bodies (AOBs) are oil droplets that result from self-assembly of a mixture containing triacylglycerols, phospholipids, and membrane proteins of plant seeds. Owing to their small size, stability, hydrophobic core, biocompatibility, and biodegradability, AOBs were explored to examine their feasibility as a drug delivery carrier. This was approached by fusion sesame oleosin (Ole), the primary membrane protein of seed oil bodies, with a small domain consisting of the arginine-glycine-aspartic acid (RGD) motif. The resulting Ole-RGD fusion protein was overproduced in Escherichia coli and then isolated for reconstitution of AOBs. At the optimal condition, the size of stable AOBs was within the range of 100-400 nm. Furthermore, AOBs entrapped with a hydrophobic fluorescence dye were incubated with human tumor cells. As visualized by fluorescent microscopy and confocal microscopy, the RGD-tagged AOBs were able to selectively target cells expressing the alphavbeta3 integrin. Moreover, these AOBs were effectively internalized and the fluorescence dye that they carried was subsequently released inside the cells. The percentage of cells internalized by AOBs could reach 80% as analyzed by flow cytometry. Taken together, it illustrates a great promise of this proposed approach for targeted delivery of cargo entities to tumor cells. PMID- 20964434 TI - Analytical approaches for an important shellfish poisoning agent: domoic Acid. AB - Domoic acid (DA), a neurotoxic amino acid produced by some strains of phytoplankton, is responsible for the human toxic syndrome amnesic shellfish poisoning. This exocitotoxin results in neuronal degeneration and necrosis in specific regions of the hippocampus. Because DA accumulates mostly in shellfish, causing outbreaks in different countries, screening for DA has been carried out with various assays. Although bioassays and immunoassays have been developed, several liquid chromatographic methods for the determination of DA in different matrices such as shellfish, algae, or seawater have been reported. Additionally, other alternative methods such as capillary electrophoresis and capillary electrochromatography have been described. This paper summaries the toxicology, the chemistry, and the developed determination methods of DA. PMID- 20964435 TI - Variation of glucosinolates in wild radish (Raphanus raphanistrum) accessions. AB - Glucosinolate composition was determined in wild radish accessions from eight states in the northeastern and southern United States to determine the variability of production among accessions. Glucosinolates were evaluated from roots, leaves, flowers, primary, and secondary branches. Seventeen glucosinolates were identified, with glucoerucin, glucoraphenin, glucobrassicin, and gluconasturtiin contributing 90% to 100% of the total glucosinolates. Flowers contained the highest glucosinolate concentrations, 12.07 to 55.36 MUmol/g, but flowers contributed only 5.3 to 21.3% to the total glucosinolates. Of the eight accessions, the Mississippi accession produced significantly higher levels of total glucosinolates and glucosinolates which can be degraded to isothiocyanates per plant, totals of 618.97 and 563.53 MUmol/plant, respectively. Total plant biomass did not differ between accessions indicating a difference in the ability of the Mississippi accession to produce glucosinolates. Further studies are needed to determine if this accession would consistently produce higher glucosinolate levels under different environmental conditions. PMID- 20964436 TI - Physical structures in soybean oil and their impact on lipid oxidation. AB - The oxidation of edible oil yields both primary and secondary oxidation products (e.g., hydroperoxides, carbonyls, hydrocarbons, and epoxides), which produce undesirable sensory and biological effects. Consequently, the suppression of lipid oxidation in food matrices is of great importance. The rate and extent of lipid oxidation in many heterogeneous foods are strongly affected by the physicochemical characteristics of water-oil interfaces. This study examined the ability of dioleoylphosphatidylcholine (DOPC) and water to form association colloids within bulk oil, as well as their impact on lipid oxidation kinetics. Attenuation was used to show the DOPC and water concentrations at which association colloids existed without altering the optical properties of the oil. Interfacial tension and fluorescence spectrometry showed the critical micelle concentration (CMC) of DOPC in stripped soybean oil was around 650 MUM at room temperature. Small-angle X-ray scattering (SAXS) and fluorescence probes showed that water had a very strong impact on the properties of the association colloids formed by DOPC. Measurement of primary and secondary lipid oxidation products revealed that the association colloids formed by DOPC had a pro-oxidant effect. The characterization of association colloids could provide a better understanding of the mechanisms of lipid oxidation in bulk oils and provide insights into new antioxidant technologies. PMID- 20964437 TI - Bioavailability of organoclay formulations of atrazine in soil. AB - Pesticide formulations based on organoclays have been proposed to prolong the efficacy and reduce the environmental impact of pesticides in soil. This research addressed the question of whether atrazine in organoclay-based formulations is irreversibly sorbed or is bioavailable for bacterial degradation in soil. Different cations of l-carnitine (CAR), tyramine (TYRAM), hexadimethrine (HEXADIM), phenyltrimethylammonium (PTMA), hexadecyltrimethylammonium (HDTMA), and Fe(III) were incorporated into Na-rich Wyoming montmorillonite (SWy-2) and Ca rich Arizona montmorillonite (SAz-1) at 100% of the cation exchange capacity (CEC) of the clays as a strategy to enhance the affinity of the clay minerals for atrazine. A Buse loam soil from Becker, MN, was treated with three organoclay based formulations of 14C-atrazine or free herbicide and incubated for 2 weeks. To determine the bioavailability of 14C-atrazine, the soil was inoculated with Pseudomonas sp. strain ADP, which rapidly mineralizes atrazine. At day 0, and after a 2 week incubation, mineralization and the amount of 14C-atrazine residues distributed between the aqueous-extractable, methanol-extractable, and bound fractions in the soil were determined to characterize the availability of nonaged and aged atrazine residues. By the end of the 2 week incubation, the microorganisms had mineralized >80% of the initial readily available (water extractable) and >70% of the less readily available (methanol-extractable) 14C atrazine in the soil. Bound residues increased from <4% at day 0 to ~17% after the 2 week incubation for both the formulated and free forms of atrazine. The results of these incubation experiments show that the bioavailabilities of atrazine were similar in the case of the organoclay formulations and as free atrazine. This indicated that whereas more atrazine was sorbed and less likely to be transported in soil, when formulated as organoclay complexes, it was ultimately accessible to degrading bacteria, so that the herbicide is likely to be naturally attenuated by soil microorganisms. PMID- 20964439 TI - Colloidal photonic crystal pigments with low angle dependence. AB - Poly(methyl methacrylate) (PMMA)-based colloidal photonic crystals have an incomplete photonic band gap (PBG) and typically appear iridescent in the visible range. As powders, synthetic PMMA opals are white, but when infiltrated with carbon black nanoparticles, they exhibit a well-defined color that shows little dependence on the viewing angle. The quantity of black pigment determines the lightness of the color by controlling scattering. The combined effects of internal order within each particle and random orientation among the particles in the powder are responsible for this behavior. These pigments were employed as paints, using a mixture of polyvinyl acetate as a binder and deionized water as the solvent, and were applied to wood and paper surfaces for color analysis. PMID- 20964441 TI - Resistive glass IM-TOFMS. AB - The design of a new ion mobility mass spectrometer (IM-MS) is presented. This new design features an ambient-pressure resistive glass ion mobility drift tube (RGIMS) coupled to a high-resolution time-of-flight mass spectrometer (TOFMS) by an enhanced interface that includes two segmented quadrupoles. The interface design demonstrates an increase in sensitivity while maintaining high resolving power typically achieved for ambient-pressure IMS drift tubes. Performance of the prototype instrument was evaluated and the analytical figures of merit for standard solutions as well as complex samples such as human blood were determined. For a 3 MUM solution of caffeine, the peak was collected in 36 s and gave a response of 10 counts/s. The detection limit (defined as 1 count/s) was calculated to be 300 nM concentration of caffeine from the response rate from the 36 s run. Controlled fragmentation of caffeine was achieved through adjustment of voltages applied on the interface lenses. Over 300 tentative metabolites were detected in human blood along with 80 isomers/isobars with ion counts >5. Isotope ratios from extracted mass spectra of selected mobility peaks were used to identify selected metabolite compounds. High separation power for both IMS (resolving power, t(d)/Deltat(w1/2), was 85) and MS (mass resolving power, m/Deltam, maximum was 7000 with a mass accuracy between 2 and 10 ppm) was measured. Developed software for data acquisition, control and display allowed flexibility in instrument control, data evaluation and visualization. PMID- 20964440 TI - Formation of deoxyguanosine cross-links from calf thymus DNA treated with acrolein and 4-hydroxy-2-nonenal. AB - Acrolein (AC) and 4-hydroxy-2-nonenal (HNE) are endogenous bis-electrophiles that arise from the oxidation of polyunsaturated fatty acids. AC is also found in high concentrations in cigarette smoke and automobile exhaust. These reactive alpha,beta-unsaturated aldehyde (enal) covalently modify nucleic acids, to form exocyclic adducts, where the three-carbon hydroxypropano unit bridges the N1 and N(2) positions of deoxyguanosine (dG). The bifunctional nature of these enals allows them to undergo reaction with a second nucleophilic group and form DNA cross-links. These cross-linked enal adducts are likely to contribute to the genotoxic effects of both AC and HNE. We have developed a sensitive mass spectrometric method to detect cross-linked adducts of these enals in calf thymus DNA (CT DNA) treated with AC or HNE. The AC and HNE cross-linked adducts were measured by the stable isotope dilution method, employing a linear quadrupole ion trap mass spectrometer and consecutive reaction monitoring at the MS(3) or MS(4) scan stage. The lower limit of quantification of the cross-linked adducts is ~1 adduct per 10(8) DNA bases, when 50 MUg of DNA is assayed. The cross-linked adducts occur at levels that are ~1-2% of the levels of the monomeric 1,N(2)-dG adducts in CT DNA treated with either enal. PMID- 20964442 TI - Silicon rice-straw array emitters and their superior electron field emission. AB - Free standing and vertically aligned silicon rice-straw- like array emitters were fabricated by modified electroless metal deposition (EMD), using HF-H(2)O(2) as an etching solution to reduce the emitter density and to make the emitter end of the formed silicon rice-straw arrays shaper than those formed by conventional EMD. These silicon rice-straw array emitters can be turned on at E(0) = 4.7 V/MUm, yielding an EFE (electron field emission) current density of J(e) = 139 MUA/cm(2) in an applied field of 12.8 V/MUm. According to a simple simulation, the excellent EFE performance of the silicon rice-straw array emitters originates in not only the favorable distribution of emitter arrays, but also the shape of the emitter apexes. The modified-EMD method is easily scaled up without expensive equipment, so silicon rice-straw array emitters are a promising alternative to silicon-based field emitters. PMID- 20964443 TI - Microfluidic protein preconcentrator using a microchannel-integrated nafion strip: experiment and modeling. AB - We propose a simple microfluidic device for protein preconcentration based on the electrokinetic trapping principle. It comprises a narrow Nafion strip that is simply cut from a commercial membrane and is integrated into a molded poly(dimethylsiloxane) (PDMS) microfluidic structure using a guiding channel. Mechanically clamping the PDMS/Nafion assembly with a glass substrate results in a rapid prototypable, leak-tight, and easily disposable device. Our device preconcentrates negatively charged fluorescent proteins located at the anodic microfluidic compartment side of the Nafion strip within a few minutes and up to a concentration factor of 10(4). Moreover, we present a numerical study of the preconcentration effect by solving the coupled Poisson, Nernst-Planck, and Navier Stokes equations for our type of device, which provides microscopic insight into the mechanism of preconcentration. The electrical field across the ion permselective Nafion generates concentration polarization, i.e., ion depletion at the anodic side and ion enrichment at the cathodic side for both types of ions, with a local excess of mobile positive ions in the depleted concentration polarization zone, inducing a nonequilibrium electrical double layer in close proximity to the Nafion membrane. A voltage difference applied over the anodic compartment is used to generate the electrophoretic flow velocity of the negatively charged tracer biomolecules. This, in combination with the electroosmotic flow in the opposite direction, which originates from the fixed charges on the channel walls and the induced space charge near the membrane, provides the basis for the local preconcentration of the negative tracer biomolecules. PMID- 20964444 TI - Effect of temperature on the self-assembly of the Escherichia coli ClpA molecular chaperone. AB - Protein quality control pathways rely upon ATP-dependent proteases, such as Escherichia coli ClpAP, to perform maintenance roles in the cytoplasm of the cell. ATP-dependent proteases remove misfolded and partially synthesized proteins. This action is particularly important in situations where an unregulated accumulation of such proteins will have a deleterious effect on the cell. ClpAP is composed of a tetradecameric serine protease, ClpP (21.6 kDa monomer), and the ATPase/protein unfoldase ClpA (84.2 kDa monomer). ClpA also uses its protein unfolding activity to remodel proteins and protein complexes; thus, in the absence of the proteolytic component, ClpA is considered a molecular chaperone. Previous reports, by others, suggested that ClpA exists in a monomer dimer equilibrium at 4 degrees C. In contrast, using a combination of sedimentation velocity, sedimentation equilibrium, and dynamic light scattering, we recently reported that ClpA exists in a monomer-tetramer equilibrium at 25 degrees C. Here we report an investigation of the effect of temperature on the self-association of the E. coli ClpA protein unfoldase using analytical ultracentrifugation techniques. The results of sedimentation velocity and sedimentation equilibrium experiments performed at multiple loading concentrations of ClpA over a range of temperatures from 3.9 to 38.2 degrees C are discussed. Sedimentation velocity experiments show a decrease in weight average s(20,w) at the extremes of temperature. This result, along with extensive sedimentation equilibrium data and analysis, suggests the presence of a dimeric intermediate of ClpA that is differentially populated as a function of temperature. Further, analysis of sedimentation equilibrium data as a function of temperature led us to propose a monomer-dimer-tetramer equilibrium to describe the temperature dependence of ClpA self-assembly in the absence of nucleotide. PMID- 20964446 TI - Disordered versus fibril-like amyloid beta (25-35) dimers in water: structure and thermodynamics. AB - Alzheimer's disease is associated with the precipitation of the amyloid beta (Abeta) (1-40) peptide in the form of fibrils. Among the full length peptide, smaller fragments such as Abeta (25-35) which retains the toxicity of the full length peptide are also present. Abeta's toxicity is attributed to soluble oligomers which, however, are difficult to study experimentally due to their transient nature. Here we present replica exchange molecular dynamics simulations of Abeta (25-35) dimers in explicit water. Similar to a previous study, dimers are found to exist as disordered compact in equilibrium with ordered extended fibril-like conformations. In addition, our results suggest effects from slight differences in ionic conditions and yield insights on this system in unprecedented detail. In the compact state, the peptides adopt beta-hairpin or unstructured U-shaped conformations with different relative orientations. In the extended state, the peptides are outstretched and form antiparallel in- or out-of register intermolecular beta-sheets. In addition to the previous study, we reveal the driving forces governing the equilibrium between the disordered and the fibril-like state. In particular, it is shown that the compact state is favored by a high entropy while the fibril-like state is lower in energy arising from favorable covalent and electrostatic interactions between and within the peptides. Our results suggest that the transition from the compact to the fibril like state involves reptation, i.e., a change in register of an intermolecular beta-sheet without dissociation of the peptides. PMID- 20964445 TI - Purification of recombinant acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) from H293 cells and binding studies between the enzyme and substrates using difference intrinsic fluorescence spectroscopy. AB - Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) is a membrane-bound enzyme utilizing long-chain fatty acyl-coenzyme A and cholesterol to form cholesteryl esters and coenzyme A. Previously, we had expressed tagged human ACAT1 (hACAT1) in CHO cells and purified it to homogeneity; however, only a sparse amount of purified protein could be obtained. Here we report that the hACAT1 expression level in H293 cells is 18-fold higher than that in CHO cells. We have developed a milder purification procedure to purify the enzyme to homogeneity. The abundance of the purified protein enabled us to conduct difference intrinsic fluorescence spectroscopy to study the binding between the enzyme and its substrates in CHAPS/phospholipid mixed micelles. The results show that oleoyl-CoA binds to ACAT1 with K(d) = 1.9 MUM and elicits significant structural changes of the protein as manifested by the significantly positive changes in its fluorescence spectrum; stearoyl-CoA elicits a similar spectrum change but much lower in magnitude. Previously, kinetic studies had shown that cholesterol is an efficient substrate and an allosteric activator of ACAT1, while its diastereomer epicholesterol is neither a substrate nor an activator. Here we show that both cholesterol and epicholesterol induce positive changes in the ACAT1 fluorescence spectrum; however, the magnitude of spectrum changes induced by cholesterol is much larger than epicholesterol. These results show that stereospecificity, governed by the 3beta-OH moiety in steroid ring A, plays an important role in the binding of cholesterol to ACAT1. PMID- 20964447 TI - HEHEHE-tagged affibody molecule may be purified by IMAC, is conveniently labeled with [99(m)Tc(CO)3](+), and shows improved biodistribution with reduced hepatic radioactivity accumulation. AB - Affibody molecules are a class of small (ca. 7 kDa) robust scaffold proteins suitable for radionuclide molecular imaging of therapeutic targets in vivo. A hexahistidine tag at the N-terminus streamlines development of new imaging probes by enabling facile purification using immobilized metal ion affinity chromatography (IMAC), as well as convenient [99(m)Tc(CO)3](+)-labeling. However, previous studies in mice have demonstrated that Affibody molecules labeled by this method yield higher liver accumulation of radioactivity, compared to the same tracer lacking the hexahistidine tag and labeled by an alternative method. Two variants of the HER2-binding Affibody molecule Z(HER)2(:)342 were made in an attempt to create a tagged tracer that could be purified by immobilized metal affinity chromatography, yet would not result in anomalous hepatic radioactivity accumulation following labeling with [99(m)Tc(CO)3](+). In one construct, the hexahistidine tag was moved to the C-terminus. In the other construct, every second histidine residue in the hexahistidine tag was replaced by the more hydrophilic glutamate, resulting in a HEHEHE-tag. Both variants, denoted Z(HER)2(:)342-H6 and (HE)3-Z(HER)2(:)342, respectively, could be efficiently purified using IMAC and stably labeled with [99(m)Tc(CO)3](+) and were subsequently compared with the parental H6-Z(HER)2(:)342 having an N-terminal hexahistidine tag. All three variants were demonstrated to specifically bind to HER2-expressing cells in vitro. The hepatic accumulation of radioactivity in a murine model was 2-fold lower with [99(m)Tc(CO)3](+)-Z(HER2:342)-H6 compared to [99(m)Tc(CO)3](+)-H6-Z(HER)2(:)342, and more than 10-fold lower with [99(m)Tc(CO)3](+)-(HE)3-Z(HER)2(:)342. These differences translated into appreciably superior tumor-to-liver ratio for [99(m)Tc(CO)3](+)-(HE)3 Z(HER)2(:)342 compared to the alternative conjugates. This information might be useful for development of other scaffold-based molecular imaging probes. PMID- 20964448 TI - Combining azide, carboxylate, and 2-pyridyloximate ligands in transition-metal chemistry: ferromagnetic Ni(II)5 clusters with a bowtie skeleton. AB - The combined use of the anion of phenyl(2-pyridyl)ketone oxime (ppko(-)) and azides (N(3)(-)) in nickel(II) carboxylate chemistry has afforded two new Ni(II)(5) clusters, [Ni(5)(O(2)CR')(2)(N(3))(4)(ppko)(4)(MeOH)(4)] [R' = H (1), Me (2)]. The structurally unprecedented {Ni(5)(MU-N(3))(2)(MU(3)-N(3))(2)}(6+) cores of the two clusters are almost identical and contain the five Ni(II) atoms in a bowtie topology. Two N(3)(-) ions are end-on doubly bridging and the other two ions end-on triply bridging. The end-on MU(3)-N(3)(-) groups link the central Ni(II) atoms with the two peripheral metal ions on either side of the molecule, while the Ni...Ni bases of the triangles are each bridged by one end-on MU-N(3)( ) group. Variable-temperature, solid-state direct- (dc) and alternating-current (ac) magnetic susceptibility, and magnetization studies at 2.0 K were carried out on both complexes. The data indicate an overall ferromagnetic behavior and an S = 5 ground state for both compounds. The ac susceptibility studies on 1 reveal nonzero, frequency-dependent out-of-phase (chi(M)") signals at temperatures below ~3.5 K; complex 2 reveals no chi(M)" signals. However, single-crystal magnetization versus dc field scans at variable temperatures and variable sweep rates down to 0.04 K on 1 reveal no noticeable hysteresis loops, except very minor ones at 0.04 K assignable to weak intermolecular interactions propagated by nonclassical hydrogen bonds. PMID- 20964449 TI - Reinvestigation of the M(II) (M = Ni, Co)/tetrathiafulvalenetetracarboxylate system using high-throughput methods: isolation of a molecular complex and its single-crystal-to-single-crystal transformation to a two-dimensional coordination polymer. AB - A high-throughput methodology combined with X-ray powder diffraction measurements was used to investigate the reactivity of the TetraThiaFulvalene TetraCarboxylic acid ((TTF-TC)H(4)) with divalent metals (M = Ni, Co) under various reaction conditions (stoichiometry, pH, temperature). Two new crystalline phases were identified and then studied by single crystal X-ray diffraction. Whereas the first one appears to be a simple salt, the second one, formulated {[M(H(2)O)(4)](2)(TTF-TC)}.4H(2)O, is built of 2:1 M:TTF-TC molecular complexes and labeled MIL-136(Ni, Co) (MIL stands for Materials Institute Lavoisier). The combination of thermogravimetric analysis and thermodiffraction studies reveals that MIL-136(Ni) exhibits a complex dehydration behavior. Indeed, a partial dehydration/rehydration process led to the single-crystal-to-single-crystal transformation of the molecular compound in a two-dimensional coordination polymer formulated {[Ni(2)(H(2)O)(5)(TTF-TC)]}.H(2)O (MIL-136'(Ni)). Magnetic and redox properties of MIL-136(Ni, Co) were investigated. Magnetic measurements indicate that all the magnetic coupling, intra- and intermolecular, are very weak; thus, the magnetic data of MIL-136(Ni, Co) have been interpreted in term of single-ion spin orbit coupling. Solid state cyclic voltammetry of MIL-136(Ni, Co) presents three reversible waves which were assigned to the redox activity of the TTF core and the metallic cations. In contrast to solids based on TTF linkers and alkaline ions, the MIL-136(Ni, Co) complexes do not act as excellent positive electrode materials for Li batteries, but present two reversible electron oxidation of the TTF core. These observations were tentatively related to the strength of the metal-carboxylate bond. PMID- 20964450 TI - Carbohydrate recognition through H-bonding and CH-pi interactions by porphyrin based receptors. AB - Porphyrin-based synthetic receptors containing urea, carbamate, or amide groups were designed and synthesized for carbohydrate recognition. The receptors have equatorially and convergently directed hydrogen-bonding sites into which the urea, carbamate, or amide groups were introduced above the porphyrin plane. The receptors exhibited remarkable affinities to pyranoside/furanoside derivatives in organic media, demonstrating not only the importance of multiple hydrogen-bonding interactions but also CH-pi interactions in carbohydrate recognition. Among the three hydrogen-bonding groups, urea NHs were used as the strongest H-bonding donors for sugar hydroxyl oxygens, and the porphyrin plane was used for mimicking CH-pi interactions with sugar CHs, which are found in sugar-binding proteins. The binding interactions between the artificial receptors and carbohydrates were elucidated by various spectroscopic analyses such as UV-vis titration, (1)H NMR titration, CD measurement, and computer-assisted modeling. PMID- 20964451 TI - An intramolecular PIFA-mediated metal-free allylic oxycarbonylation reaction and its application to the preparation of furopyrimidinones. AB - The preparation of a series of furo[3,4-d]pyrimidinones by an unprecedented PIFA mediated intramolecular allylic oxycarbonylation reaction developed on 5 carbamoyl-substituted Biginelli adducts is presented. The construction of the fused lactone by a metal-free C-H activation process, without the need of an additional functionalization step, is featured in the present work. PMID- 20964452 TI - Femtosecond to microsecond photochemistry of a [FeFe]hydrogenase enzyme model compound. AB - The photochemistry and dynamics of a model compound of the active site of the [FeFe]hydrogenase enzyme system have been studied on a wide range of time scales using a unique combination of femtosecond time-resolved infrared spectroscopy, nanosecond time-resolved infrared spectroscopy, and steady-state UV-FTIR methods. Using three different solvents, heptane, acetonitrile, and cyanoheptane, we have observed the rapid formation of solvent adduct species from the first solvation shell of the solute following photolysis of a carbonyl ligand and global fitting techniques have been employed to provide new insights into the ultrafast dynamics of this process. In addition, the use of solvent mixtures has enabled the observation of competitive ligand substitution processes at the newly created coordination site on time scales of a few nanoseconds, shedding new light on the chemical behavior of these enzyme models. PMID- 20964453 TI - Dienogest: a review of its use in the treatment of endometriosis. AB - Dienogest (Visanne(r)) is a synthetic oral progestogen with unique pharmacological properties that is indicated at a dosage of 2 mg/day for the treatment of endometriosis. It is generally highly selective for the progesterone receptor and displays strong progestational effects and moderate antigonadotrophic effects, but no androgenic, glucocorticoid or mineralocorticoid activity. Dienogest has moderate affinity for progesterone receptors (10% that of progesterone) and at a dosage of 2 mg/day only moderately suppresses estradiol levels. It has high oral bioavailability and a half-life suitable for once-daily administration. In randomized clinical trials, oral dienogest was significantly more effective than placebo in reducing pelvic pain in patients with confirmed endometriosis. In trials comparing oral dienogest for 16 or 24 weeks with gonadotropin-releasing hormone (GnRH) agonists commonly used in the treatment of endometriosis, dienogest was noninferior to depot leuprorelin in reducing pelvic pain and was not significantly different from intranasal buserelin and depot triptorelin in improving combined symptoms/signs scores or revised American Fertility Society (rAFS) staging scores, respectively. Improvements were also noted in some measures of health-related quality of life. The efficacy of dienogest was sustained during long-term treatment for more than 1 year. Dienogest was generally well tolerated and was not considered to be associated with clinically relevant androgenic effects. It appeared to have fewer hypoestrogenic effects than the GnRH agonists. Dienogest was associated with a high incidence of abnormal menstrual bleeding patterns, although this was generally well tolerated by patients, with few discontinuing therapy, and the bleeding intensity and frequency decreased over time. Therefore, oral dienogest offers an effective, generally well tolerated therapeutic option for the long term treatment of endometriosis. PMID- 20964454 TI - Vildagliptin: a review of its use in type 2 diabetes mellitus. AB - Vildagliptin (Galvus(r), Jalra(r), Xiliarx(r)) is an orally administered dipeptidyl peptidase-4 (DPP-4) inhibitor. In patients with type 2 diabetes mellitus, vildagliptin 50 mg twice daily is indicated for use in combination with metformin or a thiazolidinedione, and vildagliptin 50 mg once daily is indicated for use in combination with a sulfonylurea. A fixed-dose combination of vildagliptin/metformin (Eucreas(r), Icandra(r), Zomarist(r)) is also available. This article reviews the clinical efficacy and tolerability of vildagliptin in patients with type 2 diabetes, as well as summarizing its pharmacological properties. The efficacy of monotherapy or combination therapy with oral vildagliptin in patients with type 2 diabetes has been examined in randomized, double-blind, multicentre trials. Monotherapy with vildagliptin 50 mg once or twice daily reduced glycosylated haemoglobin (HbA(1c)) from baseline to a significantly greater extent than placebo, according to the results of 12- to 52 week trials in patients with type 2 diabetes. In terms of the reduction from baseline in HbA(1c) seen in active comparator trials of 12-104 weeks' duration, the noninferiority of vildagliptin 50 mg twice daily was established versus acarbose or rosiglitazone, the noninferiority of vildagliptin 100 mg once daily (an off-label dosage) versus metformin was established in elderly patients and vildagliptin 50 mg twice daily was more effective than voglibose; however, the noninferiority of vildagliptin 50 mg twice daily versus metformin or gliclazide was not established in two other trials. Combination therapy with vildagliptin 50 mg twice daily plus metformin improved HbA(1c) to a significantly greater extent than monotherapy with metformin and/or vildagliptin alone in patients with type 2 diabetes whose disease was inadequately controlled by metformin monotherapy or who were treatment naive, according to the results of 12- or 24-week trials. In addition, vildagliptin 50 mg twice daily plus metformin demonstrated noninferiority to pioglitazone plus metformin, glimepiride plus metformin or gliclazide plus metformin in terms of the change from baseline in HbA(1c) after 24 or 52 weeks' therapy in patients with inadequately controlled type 2 diabetes. The addition of vildagliptin 50 mg twice daily to pioglitazone or vildagliptin 50 mg once daily to glimepiride improved HbA(1c) to a significantly greater extent than a thiazolidinedione or glimepiride alone in patients with type 2 diabetes whose disease was inadequately controlled, according to the results of 24-week trials. Oral vildagliptin 50 mg once or twice daily was generally well tolerated in patients with type 2 diabetes. In particular, vildagliptin was associated with a low risk of hypoglycaemia and was weight neutral. Increases in transaminase levels were sometimes observed with a vildagliptin dosage of 100 mg once daily in clinical trials, and liver function should be monitored in patients receiving vildagliptin. However, meta-analyses of clinical trial data suggested that vildagliptin 50 mg once or twice daily was not associated with an increased risk of hepatic adverse events, transaminase elevations >=3 * the upper limit of normal, pancreatitis, cardiovascular or cerebrovascular events, infections or skin-related toxicity. In conclusion, vildagliptin is an important option for use in combination with metformin, a sulfonylurea or a thiazolidinedione in patients with type 2 diabetes who require combination therapy. PMID- 20964455 TI - Lidocaine/tetracaine medicated plaster: in minor dermatological and needle puncture procedures. AB - The lidocaine/tetracaine medicated plaster comprises a lidocaine/tetracaine 70 mg/70 mg patch and a controlled heat-assisted drug delivery pod that increases the diffusion of lidocaine and tetracaine into the dermis. Following a 1-hour application period, systemic absorption of lidocaine or tetracaine from the plaster was minimal. The lidocaine/tetracaine medicated plaster provided effective pain relief for adult (including elderly) patients undergoing minor dermatological procedures and for adult and paediatric patients undergoing vascular access procedures. In randomized, double-blind clinical trials, patient reported median pain scores were significantly lower with the lidocaine/tetracaine medicated plaster than with an identical plaster containing placebo in patients undergoing minor dermatological or vascular access procedures. Furthermore, patient-reported median pain scores were significantly lower with the lidocaine/tetracaine medicated plaster than with a lidocaine/prilocaine cream in patients undergoing vascular access procedures. In a large, randomized, double-blind trial in paediatric patients undergoing venipuncture, the overall incidence of pain was significantly lower with the lidocaine/tetracaine medicated plaster than with a lidocaine/prilocaine plaster. The lidocaine/tetracaine medicated plaster was well tolerated, with the most frequent treatment-related adverse events resolving spontaneously. PMID- 20964456 TI - Co-stimulation blockade as a new strategy in kidney transplantation: benefits and limits. AB - New immunosuppressive drugs have greatly decreased the frequency of graft failure due to acute rejection but have had little impact on long-term graft survival. This is due, at least in part, to the broad non-immune effects of the current immunosuppressive drugs, which are involved in the death of patients and in chronic allograft dysfunction, particularly due to their nephrotoxicity. Recent progress in the development of biologicals, i.e. antibodies and fusion proteins, allows precise targeting of the immune system, preventing the non-immune side effects encountered with current protocols. In particular, targeting of the two most important co-stimulation pathways critical for T-cell activation, i.e. B7/CD28 and CD40/CD40L, has provided excellent results in many experimental models of organ transplantation. This has led to the clinical development of belatacept, a cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin (CTLA4 Ig) fusion protein, which has proved to be efficient in preventing acute rejection in kidney transplant recipients. Its use is associated with improved renal function and a better metabolic profile than calcineurin inhibitors. However, because belatacept does not selectively target alloreactive T lymphocytes and must be combined with classical immunosuppressive drugs, infectious and neoplastic complications may occur, particularly post transplantation lymphoproliferative disorders. We also address the current development of molecules targeting other co-stimulatory pathways (CD40/CD40L, leukocyte function-associated antigen [LFA]-1/intercellular adhesion molecule [ICAM], CD2/LFA-3). Many unresolved issues regarding the use of co-stimulation blocking agents are also discussed, e.g. their long half-life, which can be problematic in cases of serious adverse events, their long-term safety and efficacy, and the lack of monitoring tools to allow modulation of their use over time. PMID- 20964457 TI - Ciclopirox: recent nonclinical and clinical data relevant to its use as a topical antimycotic agent. AB - Ciclopirox is a topical antimycotic agent belonging to the chemical class of hydroxypyridones and not related to azoles or any other class of antifungal agents. Its antimicrobial profile includes nearly all of the clinically relevant dermatophytes, yeasts and moulds, and is therefore broader than that of most other antimycotics. It is also active against certain frequently azole-resistant Candida species and against some bacteria. The mechanism of action of ciclopirox is different from that of other topical antifungal drugs, which generally act through ergosterol inhibition. The high affinity of ciclopirox for trivalent metal cations, resulting in inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell, appears to be the major determinant of its antimicrobial activity. This unique and multilevel mechanism of action provides a very low potential for the development of resistance in pathogenic fungi, with cases of resistance rarely reported. Ciclopirox also displays mild anti-inflammatory effects in biochemical and pharmacological models; effects also shown in small clinical studies. Scavenging of reactive oxygen species released from inflammatory cells is a likely contributor to these anti-inflammatory effects. Ciclopirox, and its olamine salt, is available in multiple topical formulations, suitable for administration onto the skin and nails and into the vagina. The pharmaceutical forms most widely investigated are 1% ciclopirox olamine cream and 8% ciclopirox acid nail lacquer, but lotion, spray, shampoo, pessary, solution, gel and douche formulations have also been used. Ciclopirox penetrates into the deep layers of the skin, mucosal membranes and nail keratin, reaching concentrations exceeding the minimal fungicidal concentrations for most medically important fungi. A large number of clinical trials were and are still being performed with ciclopirox, starting in the early 1980s. Ciclopirox was first developed for fungal skin infections and vaginal candidiasis, and is currently well established in these indications. More recently, the drug has been clinically investigated in seborrhoeic dermatitis and onychomycosis, showing good efficacy and excellent tolerability. Emphasis in this review is given to a ciclopirox medicated nail lacquer, which is based on an original technology and has superior properties in terms of its affinity to keratin and nail permeation. It has been found to have superior efficacy and safety to another commercially available formulation in the treatment of onychomycosis. The safety features of ciclopirox are well known. The topical drug is devoid of systemic adverse reactions. Mild local reactions characterized by a burning sensation of the skin, irritation, redness, pain or pruritus, generally in less than 5% of treated patients, can be observed following skin and vaginal application. With nail application, the most common adverse event is the appearance of mild erythema in 5% of the treated population. As a general conclusion, although less effective than some oral antimycotic agents in various indications, ciclopirox compares very well in terms of the benefit/risk ratio due to its excellent tolerability and complete absence of serious adverse effects. PMID- 20964458 TI - Clinical pharmacology of direct and indirect factor Xa inhibitors. AB - The limitations of conventional anticoagulants have stimulated the development of new anticoagulants. The central position of factor Xa (FXa) at the junction of the intrinsic and extrinsic pathways in the coagulation cascade means that direct and indirect FXa inhibitors have increasingly changed antithrombotic strategies. FXa inhibitors potently and selectively inhibit thrombin formation rather than thrombin activity. Direct FXa inhibitors may directly bind to FXa, whereas indirect inhibitors are dependent on antithrombin. Direct inhibitors may bind free FXa and, in contrast to indirect inhibitors, FXa within the prothrombinase complex or within clots as well. Fondaparinux is the prototype indirect FXa inhibitor and has been extensively studied in the prevention and treatment of thromboembolic diseases, including acute coronary syndromes. Due to a favourable efficacy and safety profile and convenient once-daily dosing without the need for monitoring, fondaparinux is preferentially recommended in recent guidelines dealing with antithrombotic treatment. A number of small-molecule direct FXa inhibitors are currently at different stages of clinical development. After an extensive clinical trial programme demonstrating superior efficacy without a significant increase in major bleeds compared with enoxaparin, rivaroxaban is now available for the prevention of thromboembolic events in patients undergoing orthopaedic surgery. Rivaroxaban also offers the convenience of oral once-daily dosing without the need for monitoring. Whereas most direct FXa inhibitors are orally active, otamixaban is administered intravenously, offering rapid on-off anticoagulant activity. Other compounds under development may offer additional options for tailored antithrombotic strategies according to differing indications, clinical situations and patient variables. PMID- 20964460 TI - Stroke prevention in atrial fibrillation: putting the guidelines into practice. AB - Atrial fibrillation confers a 5-fold increase in risk of stroke. A number of drugs aimed at reducing this risk have been tested in randomized controlled trials. These include antiplatelet agents (singly and in combination); anticoagulants, including vitamin K antagonists and direct thrombin inhibitors; and anticoagulants with antiplatelet agents. Guidelines recommend that the choice of therapy should be determined by an assessment of underlying risk of stroke, with antiplatelet agents being indicated for people at low risk of stroke and anticoagulants for those at higher risk. The treatment decision is complicated by considerations of haemorrhage risk, with factors that increase risk of stroke also associated with increased risk of haemorrhage. Evidence from recent studies confirms that patients at high risk of stroke should be treated with anticoagulants, including elderly patients, provided that good international normalized ratio (INR) control can be maintained. Newer agents may enable a higher proportion of patients at high risk of stroke to be treated with anticoagulants than is currently the case. Decision making about people at moderate risk of stroke is less clear cut, and a choice of either an antiplatelet agent or an anticoagulant can be justified. For people at low risk of stroke, anticoagulation is not indicated. PMID- 20964459 TI - Current approaches to the management of diabetic retinopathy and diabetic macular oedema. AB - Diabetic retinopathy (DR) is a major cause of blindness in Europe and North America, and the incidence is expected to increase in parallel with the rising incidence of diabetes mellitus. This article reviews the current state of knowledge of the epidemiology, clinical presentation and pathophysiology of DR and its principal associated complications, diabetic macular oedema (DME) and neovascularization, and then proceeds to the primary focus of clinical management. A series of major randomized controlled trials conducted over the past few decades has confirmed that tight glycaemic regulation is the most effective measure to reduce the risk of developing DR and to minimize the likelihood of its progression, and that control of blood pressure is also an important feature of preventive management. Laser-based therapies remain the cornerstone of treatment, with panretinal photocoagulation indicated for proliferative and severe nonproliferative DR and focal photocoagulation indicated for treatment of DME. For patients who do not benefit from these approaches, vitrectomy may provide therapeutic benefits. Medical therapies include two broad classes of agents: anti-inflammatory drugs and agents with molecular targets. The utility of oral anti-inflammatory drugs remains to be established, as dose finding studies have yet to provide definitive conclusions. Intravitreal corticosteroids may be of value in specific circumstances, although adverse effects include cataract progression and elevated intraocular pressure. However, these complications appear to have been limited with new extended-release technologies. With respect to molecular targets, evidence has been adduced for the roles of vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF)-alpha and protein kinase C (PKC)-beta2 in the pathogenesis of DR, and agents targeting these factors are under intense investigation. The role of VEGF in mediating pathological angiogenesis and vascular hyperpermeability has been best defined. Preliminary efficacy of pegaptanib and ranibizumab in the treatment of DME is being confirmed in additional clinical trials with these agents and with the off-label use of bevacizumab, another monoclonal antibody related to ranibizumab. Moreover, other agents targeting VEGF, as well as drugs directed against TNFalpha and PKC-beta2, are under study. Evaluation of the ultimate utility of these approaches will await the efficacy and safety results of properly designed phase III trials. PMID- 20964461 TI - Polypharmacy and combination therapy in the management of hypertension in elderly patients with co-morbid diabetes mellitus. AB - The demographic shift towards an older population increases the public health burden. Two conditions, commonly occurring together, that contribute to this burden are hypertension and diabetes mellitus. Effective blood pressure (BP) control is particularly important in this patient population, with a recommended BP goal of <130/80 mmHg. Most of these patients will require treatment with a combination of antihypertensive agents to reach this goal. Polypharmacy can be defined as the use of two or more medications, and it is commonly seen in this patient population. The risks of polypharmacy and the potential for inappropriate therapy must be considered and balanced against the possible benefits of multiple drug therapies. An optimal approach to reducing the risks and maximizing the benefits of polypharmacy should include regular reviews of patients' medication lists, which can be changed to include, where appropriate, combination therapy and the use of single-pill combinations. Combination therapy can achieve greater BP reductions than monotherapy and can also enhance the safety and tolerability of pharmacotherapy. The safety and efficacy of numerous antihypertensive combinations in elderly patients have been demonstrated in a number of clinical trials. Single-pill formulations can simplify the medication regimen, and specific combinations can offer further benefits, such as enhanced reduction of macrovascular and microvascular complications, independent of BP reductions. Rational combination therapy can maximize BP control along with glycaemic control and help maximize the benefits of polypharmacy on outcomes in elderly patients with hypertension and co-morbid diabetes. PMID- 20964462 TI - Risk of hospitalization for stroke associated with antipsychotic use in the elderly: a self-controlled case series. AB - BACKGROUND: Antipsychotics are commonly used in the elderly despite a lack of safety data from randomized trials, particularly for the typical antipsychotics. Observational studies have investigated the association between antipsychotics and stroke but results vary, which may be due to lack of control for unmeasured confounding. OBJECTIVE: To estimate the risk of hospitalization for stroke in elderly users of antipsychotics. STUDY DESIGN AND SETTING: Using the Australian Government Department of Veterans' Affairs administrative claims dataset we utilized a self-controlled case series design to risk-adjust for potential unmeasured confounding. Risk periods prior to antipsychotic initiation were also included to search for evidence of confounding by indication. Unexposed patients were included to adjust for the increasing incidence of hospitalization for stroke with age. RESULTS: There were 10 638 patients aged >=65 years with at least one hospitalization for stroke identified during the 4-year period from 1 January 2003 to 31 December 2006. Of these, 514 patients were initiated on typical antipsychotics and 564 patients were initiated on atypical antipsychotics. Hospitalization for stroke was increased in the first week after initiation of a typical antipsychotic (incidence rate ratio [IRR] 2.3; 95% CI 1.3, 3.8). There was no evidence of an increased risk of hospitalization for stroke after initiation of atypical antipsychotics. The risk of hospitalization for stroke progressively increased in the weeks leading up to first-time antipsychotic treatment. However, while the risk of hospitalization for stroke in the week prior to initiating antipsychotic therapy was significantly increased for patients initiated on typical antipsychotics (IRR 7.2; 95% CI 5.3, 9.8), patients initiated on atypical antipsychotics had no excess risk in the same period (IRR 1.2; 95% CI 0.7, 2.3). CONCLUSIONS: The results of this study are consistent with randomized controlled trial evidence indicating that there is no increased risk of serious cerebrovascular events requiring hospitalization in patients taking atypical antipsychotics. No randomized controlled trial evidence is available on the risk of hospitalization for stroke with use of typical antipsychotics in the elderly. This study found a small but significantly increased risk of hospitalization for stroke immediately following the initiation of typical antipsychotics. Antipsychotics are likely to be initiated after hospitalization for stroke. This practice is likely to reflect the prescribing of antipsychotics during hospital admission for post-stroke complications such as delirium; however, the long-term effects of this practice are unknown. PMID- 20964463 TI - Laxatives as a risk factor for iatrogenic falls in elderly subjects: myth or reality? AB - BACKGROUND: The multifactorial nature of falls is well known, and several studies on falls in the elderly have reported that laxatives can be a risk factor, but without attempting to discuss possible mechanisms to explain this role. OBJECTIVE: We aimed to isolate studies in which the risk factors for falls in the elderly related to laxatives have been evaluated and to carry out a meta-analysis combining the results of all identified good-quality studies. METHODS: Systematic literature review using the keywords 'accidental fall/numerical data' and 'risk factors'. This was followed by a manual search for articles cited in the previously identified publications. Articles were analysed if they had study populations aged >=60 years, reported on falls occurring in everyday life, were observational or interventional studies that identified laxatives as a risk factor for falls, and were written in French or English. Articles of this type that were considered to be of good quality were included in the meta-analysis. RESULTS: 3747 indexed articles published between 1981 and 2007 were identified. Of these, seven articles met all inclusion criteria and were analysed. The odds ratio (95% CI) for the association between use of laxatives and fall occurrence in subjects participating in the good-quality trials (n = 4) included in the meta analysis was 2.03 (1.52, 2.72). This result was statistically homogeneous (percentage of the total variation across studies due to heterogeneity [I2] = 0). CONCLUSIONS: Elderly subjects treated with laxatives were twice as likely to fall compared with non-laxative users. The causal relationship was probably not directly attached to a side effect of the substance used, but rather a reflection of other pathologies (e.g. older age, confinement to bed, concomitant Parkinson's disease) that may themselves cause falls. PMID- 20964464 TI - Use of antipsychotic drugs in patients with Alzheimer's disease treated with rivastigmine versus donepezil: a retrospective, parallel-cohort, hypothesis generating study. AB - BACKGROUND AND OBJECTIVE: Rivastigmine and donepezil are two cholinesterase inhibitors (ChEIs) indicated for the treatment of mild-to-moderate Alzheimer's disease. Dementia-related behavioural issues are typically managed by environmental modification and the use of psychotropics including antipsychotic medications. However, ChEIs have also been associated with reductions in behavioural symptoms in Alzheimer's disease patients. This retrospective, parallel-cohort, hypothesis-generating study investigated whether treatment with rivastigmine is associated with reduced prescription of antipsychotic medications compared with treatment with donepezil. METHODS: A combined analysis of two claims databases was conducted. Patients were included if they had a diagnosis of Alzheimer's disease and were newly initiated on either rivastigmine or donepezil. Patients with prior use of memantine and/or antipsychotics were excluded. Kaplan Meier and Cox analyses were conducted to compare the rate of antipsychotic drug use between the rivastigmine and donepezil groups. RESULTS: A total of 956 patients receiving rivastigmine and 12 778 patients receiving donepezil formed the study population. Analysis revealed that 64 (6.7%) rivastigmine and 989 (7.7%) donepezil recipients received antipsychotic medications (log-rank test from Kaplan-Meier analysis, p = 0.2289). The Cox regression analysis showed that rivastigmine was associated with a statistically significant reduction in the prescription of antipsychotic drugs relative to donepezil (hazard ratio 0.73; p = 0.044). Older age, longer time between Alzheimer's disease diagnosis and first ChEI dispensing, lower dose of ChEI at treatment initiation and the presence of baseline depression and neuropsychiatric symptoms were associated with a significantly increased likelihood of antipsychotic drug use. CONCLUSIONS: In this retrospective analysis, Alzheimer's disease patients with no prior use of antipsychotics initiated on rivastigmine had a significantly lower rate of prescription of antipsychotic drugs than those treated with donepezil. PMID- 20964465 TI - Hypnosedative use and predictors of successful withdrawal in new patients attending a falls clinic: a retrospective, cohort study. AB - BACKGROUND: Many older individuals suffer from difficulty initiating and maintaining sleep, and consequently use hypnosedative medication. The use of sleeping tablets, usually benzodiazepines (BZs) and the newer Z drugs such as zolpidem, is largely unnecessary and problematic since their efficacy is not maintained over an extended period of time and they increase the risk of falls. Withdrawing these medications is challenging because of their propensity for causing dependence and rebound insomnia. OBJECTIVES: To describe the use of anxiolytic and hypnosedative medications by patients attending a falls clinic, determine the success of recommendations to cease or reduce use of these medications, and evaluate patient characteristics influencing the success of these recommendations. METHODS: Patients with a first appointment at an Australian falls clinic between January 2006 and December 2008 were identified from letters written by the geriatrician or rehabilitation physician who ran the clinic. Patients who were taking a BZ/Z drug, had attended a follow-up appointment at least 2 months after their index appointment and had received a documented recommendation to alter their BZ/Z drug use at the index appointment were included in this study. The associations between compliance with the specialist physician's recommendation to alter the BZ/Z drug and BZ/Z drug dose, frequency and duration, patient's age, sex, residence, co-morbidities and number of regular medications were assessed. Inter-clinician variation in the proportion of patients receiving a follow-up appointment, recording of BZ/Z drug use and the proportion of patients given a recommendation to alter BZ/Z drug use were also analysed in the broader population of all patients receiving a first appointment at the falls clinic in the study period. RESULTS: Data from 302 patient records revealed that 21.5% of patients were using a BZ/Z drug and 27.8% were using any drug for its hypnosedative properties. Over the 3-year study period there was a reduction in BZ use, which was countered by an increase in the use of zolpidem, so that the overall use of BZ/Z drugs did not change. Of those patients taking a BZ/Z drug, 48% (31/65) were followed up and had a documented recommendation to alter their BZ/Z drug use. At least 68% (21/31) of these patients were compliant at follow-up. Patients who were assessed by a geriatrician were more likely to be advised to alter their BZ use than those assessed by a rehabilitation specialist (p = 0.002). Patients were more likely to be compliant if they were given a recommendation to cease their BZ/Z drug compared with advice to reduce the dose or to gradually reduce the dose with the aim of cessation (p = 0.019). There were no sex- or age-specific differences in compliance. Patients who were successful in ceasing or reducing BZ/Z drug use showed nonsignificant trends toward having a reduced number of co-morbidities and regular medications, and lower frequency of use of BZ/Z drugs. CONCLUSIONS: We observed a constant proportion of falls clinic patients taking BZs or Z drugs between 2006 and 2008. Specialist recommendation to cease or reduce dosage of these medications was associated with a high success rate. PMID- 20964466 TI - Hyaluronic acid (Supartz(r)): a review of its use in osteoarthritis of the knee. AB - Hyaluronic acid (Supartz(r); molecular weight 620-1170 kDa) is a sterile, viscoelastic, non-pyogenic solution that is indicated as a medical device for the treatment of pain in patients with osteoarthritis of the knee who have failed to respond adequately to conservative nonpharmacological therapy and simple analgesics. Intra-articular injections of Supartz(r) were significantly more effective than control injections, according to an integrated longitudinal analysis of pooled data from five randomized, double-blind, vehicle-controlled, multicentre trials in patients with osteoarthritis of the knee. Supartz(r), compared with the phosphate-buffered saline control, significantly reduced the total Lesquesne Index score in the post-injection period. Data from the individual trials demonstrated that the reduction in the total Lesquesne Index score was significantly greater than the control in two of the five studies. According to another efficacy endpoint (the mean reduction in the Western Ontario and McMaster Universities Osteoarthritis Index), which was assessed in only one of these trials, Supartz(r) was significantly more effective than the control in reducing the pain and stiffness subscale scores. Clinical scores of pain/inflammation and visual analogue scale (VAS) scores of pain during walking improved from baseline values for up to 6 months after treatment with Supartz(r) or a corticosteroid, with no significant between-group differences, in a small, randomized, open-label, multicentre trial in patients with osteoarthritis of the knee. Intra-articular injections of both Supartz(r) and Synvisc(r), as well as a phosphate-buffered saline control, significantly reduced VAS scores of weight bearing pain versus baseline after 26 weeks of therapy in a well designed trial; however, there were no significant differences between the three treatment groups. Neither hyaluronic acid formulation had a longer duration of clinical benefit than the saline control. Supartz(r) was well tolerated in patients with osteoarthritis of the knee. An integrated analysis of the five, well designed clinical trials demonstrated no significant difference between the Supartz(r) or control groups in the incidence of adverse events. The most common adverse events reported in Supartz(r) recipients were arthralgia, arthropathy/arthrosis/arthritis, back pain, nonspecific pain, injection-site reaction, headache and injection-site pain. PMID- 20964467 TI - Work disability prevention in rural healthcare workers. AB - INTRODUCTION: Approximately 20% of healthcare workers in high-income countries such as Australia, Canada and the USA work in rural areas. Healthcare workers are known to be vulnerable to occupational injury and poor work disability outcomes; given their rural-urban distribution, it is possible to compare work disability prevention in rural and urban areas. However, little attention has been paid to work disability prevention issues specific to rural workers, including rural healthcare workers. A comprehensive review of the literature was conducted to identify rural-urban differences in work disability outcomes (defined as the incidence of occupational injury and the duration of associated work absence), as well as risk factors for poor work disability outcomes in rural healthcare workers. METHODS: The databases MEDLINE, CINAHL, and EMBASE were searched, as were relevant research centers and government agencies, to identify all quantitative and qualitative English-language studies published between 1 January 2000 and 6 October 2009 that discussed occupational injury, work absence duration, work disability management, or risk factors for poor work disability outcomes, for rural workers specifically, or in comparison with urban workers. To ensure inclusion of studies of healthcare workers as a distinct group among other sector-specific groups, a broad search for literature related to all industrial sectors was conducted. RESULTS: Of 860 references identified, 5 discussed work disability outcomes and 25 discussed known risk factors. Known risk factors were defined as factors firmly established to be associated with poor work disability outcomes in the general worker population based on systematic reviews, well established conceptual models of work disability prevention, and public health literature. Although somewhat conflicting, the evidence suggests that rural healthcare workers experience higher rates of occupational injury compared with urban healthcare workers, within occupational categories. Rural workers also appear to be more vulnerable to prolonged work absence although the data are limited. No studies directly compared risk factors for work disability prevention outcomes between rural and urban healthcare workers. However, potential risk factors were identified at the level of the environment, worker, job, organization, worker compensation system and healthcare access. Important methodological limitations were noted, including unclear definitions of rurality, inadequate methods of urban-rural comparisons such as comparing samples from different countries, and a paucity of studies applying longitudinal or multivariate designs. CONCLUSIONS: There is a notable lack of evidence about work disability prevention issues for healthcare workers in rural areas. Available evidence supports the hypothesis that rural healthcare workers are vulnerable to occupational injury, and suggests they are vulnerable to prolonged work absence. They may be particularly vulnerable to poor work disability prevention outcomes due to complex patient needs in the context of risk factors such as heavy workloads, long hours, heavy on-call demands, high stress levels, limited support and workplace violence. Additional vulnerability may occur because their work conditions are managed in distant urban administrative centers, and due to barriers in their own healthcare access. Although rural healthcare workers seem generally at greater risk of injury, one study suggests that urban emergency medical service workers experience a high vulnerability to injury that may outweigh the effects of rurality. Additional research is needed to document rural urban disparities in work disability outcomes and to identify associated sources and risk factors. Other issues to address are access to and quality of healthcare for rural healthcare workers, streamlining the compensation system, the unique needs of Aboriginal healthcare workers, and the management of prolonged work absence. Finally, occupational injury and work absence duration programs should be tailored to meet the needs of rural workers. PMID- 20964468 TI - Shared Savings Program for accountable care organizations: a bridge to nowhere? PMID- 20964469 TI - Mental health services utilization among women experiencing intimate partner violence. AB - OBJECTIVE: To examine the patient and provider characteristics associated with utilization of mental health services (MHS) among women experiencing intimate partner violence (IPV). STUDY DESIGN: Cross-sectional study among 6870 women aged 18 to 65 years with first IPV identification between May 2004 and December 2009 in Kaiser Permanente Northern California. METHODS: Utilization of MHS within 60 days after first IPV identification was determined. Multivariate generalized estimating equation logistic regression models that controlled for patient and provider characteristics were used to determine predictors of utilization. RESULTS: Thirty-seven percent of women utilized MHS. In multivariate generalized estimating equation models, the strongest predictor of utilization was electronic referral (odds ratio [OR], 4.40; 95% confidence interval [CI], 3.66-5.28). Odds of utilization were lower among black (OR, 0.71; 95% CI, 0.57-0.89), Latina (OR, 0.62; 95% CI, 0.41-0.95), and Spanish-speaking (OR, 0.71; 95% CI, 0.57-0.89) patients and were higher among those with prior posttraumatic stress disorder (OR, 2.38; 95% CI, 1.17-3.44) or depression (OR, 1.35; 95% CI, 1.17-1.57). Emergency department identification of IPV was associated with lower odds of MHS utilization (OR, 0.46; 95% CI, 0.37-0.59), while older provider identification of IPV was associated with higher odds of MHS utilization (OR, 1.33; 95% CI, 1.07 1.65). CONCLUSIONS: Additional training for providers, particularly those who are younger or are practicing in emergency departments, may be needed to increase rates of MHS utilization among patients affected by IPV. Addressing language barriers to care and cultural appropriateness may improve MHS utilization. PMID- 20964470 TI - Variation in prescription use and spending for lipid-lowering and diabetes medications in the Veterans Affairs Healthcare System. AB - OBJECTIVES: To examine variation in outpatient prescription use and spending for hyperlipidemia and diabetes mellitus in the Veterans Affairs Healthcare System (VA) and its association with quality measures for these conditions. STUDY DESIGN: Cross-sectional. METHODS: We compared outpatient prescription use, spending, and quality of care across 135 VA medical centers (VAMCs) in fiscal year 2008, including 2.3 million patients dispensed lipid-lowering medications and 981,031 patients dispensed diabetes medications. At each facility, we calculated VAMC-level cost per patient for these medications, the proportion of patients taking brand-name drugs, and Healthcare Effectiveness Data and Information Set (HEDIS) scores for hyperlipidemia (low-density lipoprotein cholesterol level <100 mg/dL) and for diabetes (glycosylated hemoglobin level >9% or not measured). RESULTS: The median cost per patient for lipid-lowering agents in fiscal year 2008 was $49.60 and varied from $39.68 in the least expensive quartile of VAMCs to $69.57 in the most expensive quartile (P < .001). For diabetes agents, the median cost per patient was $158.34 and varied from $123.34 in the least expensive quartile to $198.31 in the most expensive quartile (P < .001). The proportion of patients dispensed brand-name oral drugs among these classes in the most expensive quartile of VAMCs was twice that in the least expensive quartile (P < .001). There was no correlation between VAMC-level prescription spending and performance on HEDIS measures for lipid-lowering drugs (r = 0.12 and r = 0.07) or for diabetes agents (r = -0.10). CONCLUSIONS: Despite the existence of a closely managed formulary, significant variation in prescription spending and use of brand-name drugs exists in the VA. Although we could not explicitly risk-adjust, there appears to be no relationship between prescription spending and quality of care. PMID- 20964471 TI - Retail clinic versus office setting: do patients choose appropriate providers? AB - OBJECTIVE: To assess whether health plan members who used retail clinics chose that setting for minor conditions and continued to see other providers for more complex conditions. STUDY DESIGN: Retrospective analysis of claims data in a commercially insured population. METHODS: Health plan enrollment data were used to identify and describe the analysis population. Episode Treatment Groups were used to identify members with chronic conditions and to analyze reasons for retail clinic use, complexity of retail clinic visits, and care for chronic conditions in non-retail clinic settings. Logistic regression was used to study predictors of retail clinic use. RESULTS: Retail clinic users differed significantly from nonusers. The most significant predictors of retail clinic use were age, sex, and proximity to a retail clinic. Episodes of care treated in the retail clinic appeared to be less complex than similar episodes treated in other settings. Chronically ill members who used the retail clinic saw another provider for their chronic condition at rates similar to or higher than those of members who did not use the retail clinic. CONCLUSIONS: Individuals may be able to identify when conditions are minor enough to be treated in a retail clinic and serious enough to be treated by a traditional provider. PMID- 20964473 TI - Costs of heart failure-related hospitalizations in patients aged 18 to 64 years. AB - OBJECTIVE: To examine the costs of hospitalizations related to heart failure (HF) among patients aged 18 to 64 years by diagnosis status. BACKGROUND: There are few reports on HF-related hospitalization costs in patients aged 18 to 64 years, although this group has had increased HF hospitalization rates in recent decades. METHODS: Using the 2005 MarketScan Commercial Claims and Encounters inpatient data set, we identified 23,216 hospitalizations for which HF was the primary or secondary diagnosis among patients aged 18 to 64 years who had a noncapitated health insurance plan. We used multivariate regression to analyze the association between patient characteristics and both hospitalization costs and length of stay (LOS). RESULTS: For the entire population, the mean cost of hospitalization was $23,077; the cost was higher when HF was a secondary rather than the primary diagnosis ($25,325 vs $17,654; P <.001). After controlling for covariates, hospitalizations with HF as a secondary diagnosis resulted in $3944 higher costs than those with HF as the primary diagnosis (P <.001). Among those with HF as a secondary diagnosis, the cost of hospitalization with the primary diagnosis of ischemic heart disease was $14,989 higher than it was when the primary diagnosis was noncardiovascular disease and nonrespiratory conditions (P <.001). However, patients in the latter group had a longer LOS. CONCLUSIONS: Information on the costs of HF-related hospitalizations can be used as inputs in economic evaluations such as cost-effectiveness analyses and as references for policy makers in making resource allocation decisions. PMID- 20964472 TI - Scheduled and unscheduled hospital readmissions among patients with diabetes. AB - OBJECTIVES: To describe rates of scheduled and unscheduled readmissions among midlife and older patients with diabetes and to examine associated socioeconomic and clinical factors. STUDY DESIGN: Population-based data set study. METHODS: Using the 2006 California State Inpatient Dataset, we identified 124,967 patients 50 years or older with diabetes who were discharged from acute care hospitals between April and September 2006 and examined readmissions in the 3 months following their index hospitalizations. RESULTS: About 26.3% of patients were readmitted within the 3-month period following their index hospitalizations, 87.2% of which were unscheduled readmissions. Patients with unscheduled readmissions were more likely to have a higher comorbidity burden, be members of racial/ethnic minority groups with public insurance, and live in lower-income neighborhoods. Having a history of hospitalization in the 3 months preceding the index hospitalization was also a strong predictor of unscheduled readmissions. Almost one-fifth of unscheduled readmissions (constituting approximately 27,500 inpatient days and costing almost $72.7 million) were potentially preventable based on definitions of Prevention Quality Indicators by the Agency for Healthcare Research and Quality. Scheduled readmissions were less likely to occur among patients 80 years or older, the uninsured, and those with an unscheduled index hospitalization. CONCLUSIONS: The predictors of scheduled and unscheduled readmissions are different. Transition care to prevent unscheduled readmissions in acutely ill patients with diabetes may help reduce rates, improving care. Further studies are needed on potential disparities in scheduled readmissions. PMID- 20964474 TI - Hospital readmission among participants in a transitional case management program. AB - OBJECTIVE: To examine the relationship between participation in a large wellness and care management company's transitional case management (TCM) program and hospital readmission. STUDY DESIGN: Retrospective cohort study. METHODS: A total of 10,258 members were identified as either participants or nonparticipants in TCM from data archives of a large healthcare company. Engagement and claims data were analyzed using multivariable logistic regression. Readmission predictors that were studied included TCM engagement, the major diagnostic categories of "musculoskeletal" and "digestive," length of stay for the initial hospitalization, cost of initial inpatient stay, risk score, age, and sex. RESULTS: Readmission rates were lower among individuals who were engaged in TCM compared with those who were not engaged. Within 30 days, 12.66% of individuals participating in TCM were readmitted to the hospital compared with 35.85% of those not participating (P <.0001). In the first 30 days, individuals who did not participate in TCM were almost 4 times more likely to have a hospital readmission than those who did participate. The most important predictor of hospital readmission was engagement in TCM. Individuals who were engaged in the program were less likely to be readmitted than those not engaged in the program (P <.0001). CONCLUSION: Implementation of a telephonic TCM program was associated with lower rates of readmission within 30 days. Timely engagement in TCM was associated with a lower likelihood of readmission. PMID- 20964475 TI - Assessing the accuracy of drug profiles in an electronic medical record system of a Washington state hospital. AB - OBJECTIVES: To determine the accuracy of patients' electronic medical record (EMR) drug profiles, to assess the relationship of copayment status with errors of commission and omission within drug profiles, and to evaluate the association between errors of commission in primary and secondary sections of the drug profiles. STUDY DESIGN: Cross-sectional analysis of patients' EMR drug profiles at a 46-bed hospital in Washington state. METHODS: Patients' drug profiles were compared against hospital staff interviews. Drug profiles listing each medication the patient was taking, without listing drugs the patient was not taking, exhibited perfect accuracy. We evaluated associations between errors of commission and omission, copayment status between errors of commission and omission, and associations between errors of commission in primary and secondary sections of the drug profiles. RESULTS: Demographics of study patients are similar to previously published research, and accuracy outcomes seem to be better than those of previously published studies. Fifty-six percent of drug profiles in our study hospital exhibited perfect accuracy. Errors of commission and omission were unassociated with copayment status; errors of commission in the primary section of the drug profile were unassociated with errors of commission in the secondary section of the drug profile. CONCLUSIONS: A medication reconciliation program may have led to a high rate of perfectly accurate drug profiles; while its purpose is to increase accuracy and to decrease errors, it may also assist in reducing adverse drug events. Results show that copayment amounts influence drug utilization; these may be associated with errors of commission and omission and not simply with copayment status. PMID- 20964476 TI - Initial experience with a first-to-market member accountability-based insurance product. AB - We describe the initial experience with a first-to-market health insurance product design based on principles of both member and purchaser accountability. Two benefit levels were offered, enhanced and standard. Qualification for the enhanced benefit level was obtained through members' commitment to follow their physicians' recommended treatment plan. Employers were offered a discount of 10% in exchange for offering this new product and promoting a healthy work environment. Membership in the product grew beyond expectations, and several health improvements were noted. PMID- 20964477 TI - Effect of a patient panel-support tool on care delivery. AB - OBJECTIVE: To evaluate the effect of a patient panel-support tool (PST) on care delivery for diabetes mellitus (DM) and cardiovascular disease (CVD). STUDY DESIGN: Retrospective longitudinal cohort study among primary care providers (PCPs), with 2005 as the preintervention, 2006 as the implementation, and 2007 as the postintervention period. METHODS: We estimated the intervention effect using electronic medical record data and hierarchical linear models. The intervention was a PST displaying "care gaps" and recommendations for glycosylated hemoglobin, low-density lipoprotein cholesterol, and blood pressure screening and control; retinopathy, nephropathy, and foot screening; aspirin, statin, and angiotensin converting enzyme inhibitor or beta-blocker use; and influenza and pneumococcal vaccination. Participants were qualifying PCPs and health maintenance organizations; patients. Patients had DM or CVD and 12 months of membership (n = 30,273 DM; 26,414 CVD). Main measures were mean percentages of care recommendations that were met by PCPs per patient per month (the care score). RESULTS: From 2005 to 2007, the mean care score (95% confidence interval) increased for both DM and CVD, from 63.5 (62.7, 64.3) to 70.6 (69.8, 71.4) and from 67.9 (67.2, 68.7) to 72.6 (71.9, 73.3), respectively. After adjustments, DM and CVD patients had improvements in the care score of 7.6 and 5.1, respectively, in 2007 compared with 2005 (P < .001). CONCLUSIONS: Delivery of care recommendations for DM and CVD improved after implementation of a PST. More research is necessary to optimize results and determine whether patient outcomes improve. PMID- 20964478 TI - Elite controllers display higher activation on central memory CD8 T cells than HIV patients successfully on HAART. AB - T cell activation plays an important role in driving CD4 depletion during the course of HIV infection. There is scarce information about activation of different T cell subsets in HIV(+) individuals experiencing distinct disease progression. The activation of different CD4(+) and CD8(+) T cell subsets and its contribution to total T cell activation were examined measuring CD38 expression by flow cytometry in 120 HIV-infected individuals and 9 uninfected healthy controls. HIV-infected patients were divided into four groups: 11 elite controllers (EC), 14 viremic controllers (VC), 61 antiretroviral-naive typical progressors (TP), and 34 progressors with viral suppression (VS) under antiretroviral therapy. EC displayed significantly greater activation levels than VS, with a higher contribution of central memory subsets to the activation of total CD8 T cells (p = 0.002). The activation of central memory CD8(+) T cells significantly correlated with viral load in TP regardless of CD4 counts. In contrast with VS, proviral load was undetectable in all EC. Compared to VS, EC display abnormal and higher activation levels of different CD8(+) T cell subsets. Factors other than the size of the viral reservoir should explain the high level of activation of central memory CD8(+) T cells characteristically seen in HIV(+) individuals with spontaneous control of viral replication. PMID- 20964479 TI - Impact of HIV type 1 subtype on drug resistance mutations in Nigerian patients failing first-line therapy. AB - A diverse array of non-subtype B HIV-1 viruses circulates in Africa and dominates the global pandemic. It is important to understand how drug resistance mutations in non-B subtypes may develop differently from the patterns described in subtype B. HIV-1 reverse transcriptase and protease sequences from 338 patients with treatment failure to first-line ART regimens were evaluated. Multivariate logistic regression was used to examine the effect of subtype on each mutation controlling for regimen, time on therapy, and total mutations. The distribution of HIV-1 subtypes included CRF02_AG (45.0%), G (37.9%), CRF06_cpx (4.4%), A (3.6%), and other subtypes or recombinant sequences (9.2%). The most common NRTI mutations were M184V (89.1%) and thymidine analog mutations (TAMs). The most common NNRTI mutations were Y181C (49.7%), K103N (36.4%), G190A (26.3%), and A98G (19.5%). Multivariate analysis showed that CRF02_AG was less likely to have the M41L mutation compared to other subtypes [adjusted odds ratio (AOR) = 0.35; p = 0.022]. Subtype A patients showed a 42.5-fold increased risk (AOR = 42.5, p = 0.001) for the L210W mutation. Among NNRTI mutations, subtype G patients had an increased risk for A98G (AOR = 2.40, p = 0.036) and V106I (AOR = 6.15, p = 0.010), whereas subtype CRF02_AG patients had an increased risk for V90I (AOR = 3.16; p = 0.003) and a decreased risk for A98G (AOR = 0.48, p = 0.019). Five RT mutations were found to vary significantly between different non-B West African subtypes. Further study to understand the clinical impact of subtype-specific diversity on drug resistance will be critically important to the continued success of ART scale-up in resource-limited settings. PMID- 20964481 TI - Generation of healthy cloned mice using enucleated cryopreserved oocytes. AB - The successful generation of cloned animals and the establishment of embryonic stem (ES) cell lines from somatic cells suggest that these techniques may be used in human regenerative medicine. However, the fact that oocytes must be donated by women undergoing infertility treatment remains a fundamental ethical objection, as they might be concerned about the potential exploitation of their genome. Here, we investigated the reprogramming potential of enucleated and cryopreserved oocytes for the development of full-term cloned mice. BDF1 strain mouse oocytes were cryopreserved at metaphase II, before and after enucleation. After thawing, cumulus cell nuclei were microinjected to generate clones. Although the rate of development of cloned embryos to the blastocyst stage using the treated oocytes was lower than that obtained using fresh oocytes, three live pups were delivered after embryo transfer into pseudopregnant females (0.4% of the oocytes used). Thus, although cryopreservation reduces the potential of oocytes, these cells retain the ability to support the full-term development of cloned embryos. In addition, the removal of DNA from human oocytes may alleviate the ethical and psychological problems for women who are undergoing infertility treatment and are considering oocyte donation for research or therapeutic purposes. PMID- 20964480 TI - HIV Type 1 Nef is released from infected cells in CD45(+) microvesicles and is present in the plasma of HIV-infected individuals. AB - HIV-1 Nef has been demonstrated to be integral for viral persistence, infectivity, and the acceleration of disease pathogenesis (AIDS) in humans. Nef has also been detected in the plasma of HIV-infected individuals and is released from infected cells. The form in which Nef is released from infected cells is unknown. However, Nef is a myristoylated protein and has been shown to interact with the intracellular vesicular trafficking network. Here we show that Nef is released in CD45-containing microvesicles. This microvesicular Nef (mvNef) is detected in the plasma of HIV-infected individuals at relatively high concentrations (10 ng/ml). It is also present in tissue culture supernatants of Jurkat cells infected with HIV(MN). Interestingly, plasma mvNef levels in HIV(+) patients did not significantly correlate with viral load or CD4 count. Microvesicular Nef levels persisted in the plasma of HIV-infected individuals despite the use of antiretroviral therapy, even in individuals with undetectable viral loads. Using cell lines, we found Nef microvesicles induce apoptosis in Jurkat T-lymphocytes but had no observed effect on the U937 monocytic cell line. Given the large amount of mvNef present in the plasma of HIV-infected individuals, the apoptotic effect of mvNef on T cells, and the observed functions of extracellular soluble Nef in vitro, it seems likely that in vivo mvNef may play a significant role in the pathogenesis of AIDS. PMID- 20964482 TI - Enhanced reprogramming and cardiac differentiation of human keratinocytes derived from plucked hair follicles, using a single excisable lentivirus. AB - Induced pluripotent stem cells (iPSCs) represent an ideal cell source for future cell therapy and regenerative medicine. However, most iPSC lines described to date have been isolated from skin fibroblasts or other cell types that require harvesting by surgical intervention. Because it is desirable to avoid such intervention, an alternative cell source that can be readily and noninvasively isolated from patients and efficiently reprogrammed, is required. Here we describe a detailed and reproducible method to derive iPSCs from plucked human hair follicle keratinocytes (HFKTs). HFKTs were isolated from single plucked hair, then expanded and reprogrammed by a single polycistronic excisable lentiviral vector. The reprogrammed HFKTs were found to be very sensitive to human embryonic stem cell (hESC) growth conditions, generating a built-in selection with easily obtainable and very stable iPSCs. All emerging colonies were true iPSCs, with characteristics typical of human embryonic stem cells, differentiated into derivatives of all three germ layers in vitro and in vivo. Spontenaeouly differentiating functional cardiomyocytes (CMs) were successfully derived and characterized from these HFKT-iPSCs. The contracting CMs exhibited well-coordinated intracellular Ca2+ transients and contractions that were readily responsive to beta-adrenergic stimulation with isoproterenol. The introduction of Cre-recombinase to HFKT-iPSC clones was able to successfully excise the integrated vector and generate transgene-free HFKT-iPSC clone that could be better differentiated into contracting CMs, thereby revealing the desired cells for modeling human diseases. Thus, HFKTs are easily obtainable, and highly reprogrammed human cell source for all iPSC applications. PMID- 20964483 TI - The role of PCA3 testing in patients with a raised prostate-specific antigen level after Greenlight photoselective vaporization of the prostate. AB - BACKGROUND AND PURPOSE: Greenlight((r)) photoselective vaporization of the prostate (PVP) is an effective method for treating men with lower urinary tract symptoms. A rise in prostate specific antigen (PSA) levels, however, may be noticed in some patients during follow-up. The aim of this study was to determine whether the prostate cancer gene 3 (PCA3) urinary test would help identify patients who were in need of a prostate biopsy. PATIENTS AND METHODS: The PSA of all patients undergoing PVP were analyzed. Patients with an elevated (above reference range) or rising PSA level (defined as > 0.75 ng/mL/year if the PSA was between 4.1 and 10 or a doubling time of less than 2 years) were offered a transrectal ultrasonography (TRUS) guided prostate biopsy. Before the biopsy procedure, all patients had a PCA3 test. The relationships between PSA, PCA3, and TRUS prostate biopsy findings were analyzed to determine sensitivity and specificity for the PCA3 test in this setting. RESULTS: 50 patients were identified. The mean age was 69.97 (range 57-83) years. The mean PSA level was 10.1 ng/mL (range 3.03-44.2 ng/mL). Six patients were found to have prostate cancer. Of those, five patients had a positive PCA3 test. One patient had a negative PCA3 test but positive biopsy findings. This gives a sensitivity of 83.3%, and a positive predictive value of 21.7%. The negative predictive value was 96%. CONCLUSION: The results suggest that a negative PCA3 test in our group of patients is a good predictor of negative biopsy results. The low positive predictive value may be an artefact of the group size. This will need further investigation and greater patient numbers to determine. PMID- 20964484 TI - Percutaneous minimally invasive management of iatrogenic ureteral injuries. AB - PURPOSE: To present experience with the percutaneous management of iatrogenic ureteral injuries. PATIENTS AND METHODS: Eighteen women and six men with a mean age of 59.3 years (range 33-80 years) received a diagnosis of ureteral injury sustained during gynecologic, urologic, and general surgical procedures. In a total of 25 injured ureters, 12 had interruption of continuity of their lumen, 10 were associated with contrast extravasation, and 3 were related to both. A standard percutaneous nephrostomy tract was established on the side of the afflicted kidney. Combined use of hydrophilic guidewires and balloon dilations were performed to achieve antegrade recanalization of the ureteral lesion. Then, a ureteral stent was inserted to assure patency. RESULTS: Average stricture length was 1.21 (range 0.5-1.9 cm). Success of the aforementioned technique was possible in 18 ureters. Successful management in one session took place in 14 ureters. Average hospitalization time was 1.8 days (range 0-5 d). The follow-up period ranged between 12 and 18 months, with mean follow-up time of 12.9 months. Ureteral patency was evident at 1 week follow-up in six patients with obstructed ureters. In the remaining patients, balloon dilation of the stricture was repeated, and another stent was placed. Extravasation of contrast was observed in two patients with extravasating ureters in the same period. Nephrostomy tubes were removed after a mean indwelling period of 5.9 weeks (range 1-12 wks). Two patients treated by the described method died during their hospitalization in the intensive care unit because of sepsis from peritonitis that was related to colon injury and multiple concomitant injuries. Major complications were not observed in the remaining 22 patients during the follow-up period. CONCLUSION: The minimally invasive management of ureteral injuries is a safe and efficient method for both ureteral obstruction and/or laceration in a wide range of iatrogenic ureteral injuries. PMID- 20964485 TI - Laparoendoscopic single-site partial nephrectomy without ischemia. AB - BACKGROUND AND PURPOSE: Nephron-sparing surgery (NSS) ensures excellent oncologic and functional outcomes in small renal masses. Laparoendoscopic single-site surgery (LESS) is one of the major advances in the evolution of minimally invasive surgery. We describe our initial surgical experience and assess the feasibility of LESS unclamp-NSS. PATIENTS AND METHODS: From April to September 2009, all consecutive patients with solitary, exophytic, enhancing, small (<=4.0 cm) renal masses and normal contralateral kidney were selected to receive LESS unclamp-NSS. A multichannel port provided intra-abdominal transperitoneal access. Rigid and articulable instruments were used for dissection, tumor exposure, and excision under normal renal perfusion. Perioperative, pathologic, hematologic data together with a subjective evaluation of pain and scar were collected and evaluated. RESULTS: Six patients underwent LESS unclamp-NSS (mean operative time, 148 min; mean blood loss, 201 mL; mean renal masses size, 2.1cm). One patient needed conversion to standard laparoscopy because of excessive bleeding. Postoperatively, a cerebrovascular accident developed in one patient. No transfusion was necessary. Pathologic examination revealed two clear-cell carcinoma, three benign cysts, and one angiomyolipoma (surgical margin positive). A 2.7 g/dL hemoglobin level decrease was recorded with minimal pain and great patient satisfaction. Mean length of stay was 6 days. CONCLUSION: LESS unclamp NSS in selected renal masses is feasible, provides postoperative outcomes overlapping the standard counterpart, and ensures subjective satisfaction. Additional trocars should be considered for the hemostatic stitches and for liver retraction. A wider experience and longer follow-up are necessary to establish the role of this technique. PMID- 20964486 TI - Does Greenlight HPS(TM) laser photoselective vaporization prostatectomy affect sexual function? AB - PURPOSE: We evaluate the impact of GreenLight High-Performance System (HPSTM) laser photoselective vaporization prostatectomy (PVP) on sexual function after treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: We prospectively evaluated our initial single surgeon experience with GreenLight HPSTM laser PVP. All patients had American Urological Association Symptom Score (AUASS), Sexual Health Inventory for Men (SHIM), maximum flow rate (Qmax), and postvoid residual (PVR) determinations. Transurethral PVP was performed using a 120W GreenLight HPSTM side-firing laser system. AUASS, SHIM, Qmax, and PVR were evaluated 1, 4, 12, 24, and 52 weeks postsurgery. Wilcoxon signed rank test and the Student t-test were used to assess the changes from baseline. RESULTS: Seventy-two patients completed 52 weeks of follow-up, having a median age of 69 (45-89) years. The median prostate volume was 62 (21-263) mL. Median AUASS improved significantly from 23 to 8, 6, 5, 5, and 4 (P < 0.05) at 1, 4, 12, 24, and 52 weeks, respectively. Median SHIM changed from 15 to 12, 16, 19, 16, and 17 during the follow-up period (P = 0.032, 0.427, 0.074, 0.081, and 0.259). Minimum change (0 +/- 5) in SHIM occurred in 85.5%, 90.5%, 78.8%, 77.5%, and 73.7% of patients; 11.3%, 6.3%, 6.0%, 4.8%, and 7.0% of patients had deterioration of erectile function (SHIM reduction >5); and 3.2%, 3.2%, 15.2%, 17.7%, and 19.3% of patients had improvement of erectile function (SHIM increase >5). Incidence of new-onset retrograde ejaculation was 30%. CONCLUSION: GreenLight HPSTM laser PVP appears to not have a detrimental effect on erectile function. PMID- 20964487 TI - Community-acquired Salmonella bacteraemia in patients with sickle-cell disease 1969-2008: a single centre study. AB - We document the aetiology of community-acquired bacteraemia in sickle-cell disease (SCD) patients and present clinical aspects of 11 cases of Salmonella bacteraemia. Prospective computerized records of all significant bacteraemic episodes presenting to our institution from 1969 to 2008 were analysed. Additional clinical information was drawn from hospital medical records. Six thousand three hundred and sixty-nine community-acquired bacteraemic episodes were documented, with 66 occurring in SCD patients. Salmonella species were the third most frequently isolated organism in SCD patients; 18% of bacteraemias in SCD patients were caused by Salmonella species vs 3% in non-SCD patients (p < 0.0001). Moreover, the proportion of community-acquired Salmonella bacteraemic episodes caused by non-Typhi species was significantly higher in SCD compared to other patients (p = 0.0015). Focal infection was identified in 7 of the 11 cases of Salmonella bacteraemia in SCD patients, with bone and joint accounting for 6 of these. Infection may have been acquired during travel to the tropics in 4 patients. Our study supports the view that SCD patients are particularly susceptible to Salmonella infection. These infections frequently require multiple surgical interventions and prolonged hospital stays. SCD patients should be advised to pay particular attention to food hygiene while travelling to the tropics. PMID- 20964488 TI - Pre-vaccination prevalence of human papillomavirus types in the genital tract of 15-23-year-old women attending a youth health clinic in Stockholm, Sweden. AB - Knowledge of the prevalence of different human papillomavirus (HPV) types in young girls is important for the early detection of changes in HPV prevalence, e.g. due to HPV vaccines. The purpose of this study was to obtain information on the prevalence of 24 different genital HPV types in a group of sexually active young women (aged 15-23 y) attending a major youth healthcare centre in Stockholm, before the introduction of public HPV vaccination of young women in the autumn of 2010. A total of 615 women were analyzed for 24 different, mainly high-risk HPV (HR-HPV) types using multiplex polymerase chain reaction and Luminex technology. A high HPV prevalence in this cohort was demonstrated, particularly with regard to HPV16, but also to all included HR-HPV types. Of the 544 successfully analyzed samples from non-vaccinated individuals, 70% were positive for the HPV types assayed for, and 62% were positive for HR-HPV types. Over a third (34.7%) of the women were infected with HPV16, and a high frequency of infections with HR-HPV types 51 (10.7%), 18 (10.1%), 52 (9.9%) and 73 (9.4%) was also observed. At least 9 different non-vaccine HR-HPV types were present with a prevalence of >6% in this selected group of young women. PMID- 20964489 TI - Emerging transmitted drug resistance in treatment-naive human immunodeficiency virus-1 CRF06_cpx-infected patients in Estonia. AB - Human immunodeficiency virus (HIV)-1 transmitted drug resistance in the drug naive population is of growing relevance in Estonia, where the number of antiretroviral (ARV) treatment-experienced subjects has been exponentially increasing during the last 10 y. The aim of this study was to estimate the rate of transmitted drug resistance among newly diagnosed subjects in Estonia in 2008. Genotypic resistance testing for viral genomic RNA was conducted for 201 subjects tested HIV-positive between 1 April and 30 November 2008. Of 145 genotyped viral strains in newly diagnosed patients, 123 were CRF06_cpx, 2 were subtype A1 and 3 were subtype B; in 17 cases viral sequences revealed recombinant structures similar to CRF06_cpx, subtype A1 and CRF02_AG. Resistance mutations were found in 8 (5.5%) virus strains, and 3 strains were resistant to at least 2 ARV classes. A total of 2.8% of sequences harboured mutations indicating nucleoside/nucleotide reverse transcriptase inhibitor resistance (M41L, M184V, M184I, T215C and T215D), 2.1% non-nucleoside reverse transcriptase inhibitor resistance (K103N, P225H) and 2.8% protease inhibitor resistance (M46I, L90M). These data suggest the need to extend genotypic HIV-1 drug resistance testing to newly diagnosed HIV-positive subjects to prevent potential ARV treatment failure. PMID- 20964491 TI - Response to Cox-North's comments on "A novel approach to evaluate TCM treatment outcomes using pattern identification". PMID- 20964490 TI - Chronic ulcerative dermatitis caused by Fusarium sporotrichioides. AB - The present study describes the isolation of Fusarium sporotrichioides from a canine cutaneous ulceration. A 2-year-old male Beagle dog weighing 8.6 kg, with a history of immune-mediated hemolytic anemia (IMHA), had been treated with prednisone for 9 months. Physical examination revealed cutaneous ulceration on the left foreleg. Histopathological examination of skin samples from the ulcerative area revealed many branching hyphae surrounding neutrophils. Since itraconazole (ITZ) is recommended for miscellaneous fungal infections, the dog was treated with ITZ. However, the ulcerative lesions did not improve and after 3 weeks of treatment the dog died due to renal failure. No autopsy was performed. Since the isolate recovered from the biopsy specimen was identified as Fusarium species by morphological characteristics, the animal was diagnosed as having had an infection caused by this mould. The dog's prior prednisone treatment may have played a role in establishing the fungal infection. Comparative sequence analyses of the ITS regions of the clinical isolate with those in GenBank showed that it was 100% identical to F. sporotrichioides and less than 96% similar to ITS of other Fusarium species. Based on these findings, F. sporotrichioides was established as the etiologic agent of the canine infection, a situation that has not been previously reported in dogs, as well as humans. PMID- 20964492 TI - Availability of e-information for women's health services: assessment of California State University Student Health Centers. AB - BACKGROUND: We sought to determine the availability of e-information for women's health services and discuss the implications for access to essential preventive health services for college-age women. METHODS: California State University (CSU) Campus Student Health Center (SHC) websites are evaluated against a set of criteria developed from national directives for women's health issues. An analysis of these websites was conducted in January-July 2009. A review of related literature was also conducted. RESULTS: Inclusion of essential women's health services (EWHS) on SHC websites varies significantly across services and campuses, and no guidance exists for material to include despite well-documented concern about quality of web information and the importance of this information for college-age women. CONCLUSIONS: Our findings point to the need to more broadly assess campus health center use of the Internet to provide health service information to students and establish guidelines for SHCs to communicate EWHS to the female student population. PMID- 20964493 TI - Relationship between the margin of manoeuvre and the return to work after a long term absence due to a musculoskeletal disorder: an exploratory study. AB - PURPOSE: The application of the margin of manoeuvre (MM) concept in work rehabilitation is new. It allows for variations in both health status and work demands, and the interaction between the two, to be taken into account. The objective of this exploratory study was to document the relationship between the presence of an MM in the workplace and the return to work (RTW), after a long term absence. METHODS: This study used the data collected during an earlier study that sought to identify the dimensions and indicators of the MM. The data were analysed on three levels, and the convergences and divergences in the MM indicators and dimensions in relation to the RTW were grouped accordingly. RESULTS: Eleven workers and five clinicians participated in this study. The results support the proposition that the presence of a sufficient MM in the workplace is associated with RTW of individuals at the end of a rehabilitation programme despite a long-term absence (n = 6), and conversely, that its absence would appear to be associated with a non-return to work (n = 4). CONCLUSIONS: A better understanding of this concept will help further the development of a tool to assist clinicians in their task of assessing a worker's capacity to return to a given job. PMID- 20964494 TI - Disentangling the effects of disability and age on health service utilisation. AB - PURPOSE: This article examines two competing hypotheses for the impact of disability and age on health service utilisation in Canada: the double jeopardy and age-as-leveller hypotheses. METHOD: The study uses a retrospective cohort design to examine the effect of age and disability on four aspects of health service utilisation: family doctor, medical specialist, hospital and homecare. The cohort was assembled from the longitudinal component of the National Population Health Survey. The effective sample size for this analysis was 1629. RESULTS: This study showed that disability is a stronger predictor of doctor and hospital utilisation than age. No significant relationship was found between age and specialist use, and there were only small to moderate increases in the use of family doctors and hospitals with each 5-year increment of age over 65. There is a strong association between the use of home care and both age and disability. Results support the age-as-leveller hypothesis, in that negative interaction effects were found between age and disability for use of both family physicians and medical specialists. In other words, age and disability together have an effect that is less than would be expected, given the main effects of each. CONCLUSION: The results of this study support the importance of disability as an indicator of health service utilisation. Rehabilitation practitioners are encouraged to continue to sensitise other members of the health care team to the importance of disability as a way of understanding health and health service use. PMID- 20964498 TI - Association of fetuin-A and cardiac calcification and inflammation levels in hemodialysis patients. AB - BACKGROUND: Vascular calcification is commonly found in chronic kidney disease (CKD) patients and it is one of the predictors of cardiovascular death. Recently, several studies have demonstrated that low fetuin-A levels are associated with mortality in uremic patients. Objectives. To investigate the importance of non traditional risk factors of calcification including fetuin-A, IL-6 and high sensitivity CRP (hsCRP) in hemodialysis patients and their relationship to the extent of cardiac calcification by means of multislice computed tomography (MSCT), and echocardiography. PATIENTS AND METHODS: The study was conducted on 70 hemodialysis patients as well as 20 healthy control subjects. All patients were subjected to MSCT for evaluation of calcium score in the coronary arteries as well as echocardiography for detecting valvular calcification. In addition, the patients were sampled for evaluation of inflammatory markers such as hsCRP and IL 6 and also fetuin-A. RESULTS: Mean serum fetuin-A was significantly lower in hemodialysis patients than controls subjects. By dividing the patients into tertiles of serum fetuin-A, a significant association between low levels of fetuin-A and high calcium score and valvular calcification were found. Multiple regression analysis showed that calcium scoring and IL-6 were the most independent risk factors for serum fetuin-A levels. CONCLUSION: Serum fetuin-A showed important association with coronary, valvular calcification and inflammation in hemodialysis patients. Assessment of both cardiac calcification and serum levels of fetuin-A may be of value to identify those subjects at higher risk of development and progression of vascular lesion and may be a novel therapeutic approach. PMID- 20964495 TI - Temporal aspects of the action of ASA404 (vadimezan; DMXAA). AB - IMPORTANCE OF THE FIELD: Tumor vascular disrupting agents (tumor VDAs) act by selective induction of tumor vascular failure. While their action is distinct from that of antiangiogenic agents, their clinical potential is likely to reside in improving the efficacy of combination therapy. AREAS COVERED IN THIS REVIEW: This review describes the preclinical development, clinical trial and mode of action of ASA404, a flavonoid class tumor VDA. This class has a unique dual action, simultaneously disrupting vascular endothelial function and stimulating innate tumor immunity. This review covers the early development of ASA404, through to Phase III trial. WHAT THE READER WILL GAIN: The reader will gain insight into the sequence of ASA404-induced changes in tumor tissue. Early events include increased vascular permeability, increased endothelial apoptosis and decreased blood flow, while later effects include the induction of serotonin, tumor necrosis factor, other cytokines and chemokines, and nitric oxide. This cascade of events induces sustained reduction of tumor blood flow, induction of tumor hypoxia and increased inflammatory responses. The reader will also gain an appreciation of how the potentiation of radiation and chemotherapeutic effects by ASA404 in murine tumors shaped the development of combination clinical trials. TAKE HOME MESSAGE: Although there are species differences in ASA404 activity, many features of its action in mice translate to human studies. The future of ASA404 as an effective clinical agent will rely on the development of an appreciation of its ability to optimize the complex interaction between tumor vasculature and tumor immunity during therapy. PMID- 20964499 TI - Amisulpride versus moclobemide in treatment of clozapine-induced hypersalivation. AB - OBJECTIVES: Previous publications demonstrated substitute benzamides as effective agents in treatment of clozapine-induced sialorrhea (CIS). The aim of this study was to compare efficacy of amisulpride and moclobemide (both from the substitute benzamide group) in controlling, or at least minimizing, CIS. METHODS: The study was designed as a 6-week, two-center, fixed-dose, comparison study of 400 mg/day of amisulpride versus 300 mg/day of moclobemide as an adjunctive treatment in 53 schizophrenia and schizoaffective disorder patients (diagnosed according to DSM IV) suffering from CIS. The patients were treated with each medication during 2 weeks, followed by a washout period of 2 weeks. Primary outcome measures included the reduction in the five-point Nocturnal Hypersalivation Rating Scale (NHRS). Secondary outcomes included the Positive and Negative Syndrome Scale (PANSS), Manic State Assessment Scale, and Extrapyramidal Symptom Rating Scale (ESRS). RESULTS: Both amisulpride and moclobemide were very effective in reducing CIS. Almost 74% of patients treated with amisulpride and 83% of patients treated with moclobemide showed some level of improvement on NHRS. Only in one patient treated with amisulpride, CIS worsened. CONCLUSIONS: Both medications were safe and effective as treatment of CIS. Although moclobemide exceeded amisulpride in antisalivation activity, treatment of CIS with amisulpride leads to improvement in psychotic symptoms. PMID- 20964500 TI - Efficacy studies of Reactive Skin Decontamination Lotion, M291 Skin Decontamination Kit, 0.5% bleach, 1% soapy water, and Skin Exposure Reduction Paste Against Chemical Warfare Agents, part 2: guinea pigs challenged with soman. AB - OBJECTIVE: This report, the second in a series of five, directly compares the efficacy of Reactive Skin Decontamination Lotion (RSDL), the M291 Skin Decontamination Kit (SDK), 0.5% bleach (sodium or calcium hypochlorite solution), 1% soapy water, and Skin Exposure Reduction Paste Against Chemical Warfare Agents (SERPACWA) in the haired guinea pig model following exposure to soman (GD). METHODS: In all experiments, guinea pigs were close-clipped and given anesthesia. In the decontamination experiments, the animals were challenged with GD and decontaminated after a 2-minute delay for the standard procedure or at longer times for the delayed-decontamination experiments. Positive control animals were challenged with GD in the same manner as the treated animals, except that they received no treatment. All animals were observed during the first 4 hours and again at 24 hours after exposure for signs of toxicity and death. The protective ratio (PR, defined as the median lethal dose [LD(50)] of the treatment group divided by the LD(50) of the untreated positive control animals) was calculated from the derived probit dose-response curves established for each treatment group and nontreated control animals. SERPACWA was applied as a thin coating (0.1 mm thick), allowed to dry for 15 minutes, and challenged with GD. After a 2-hour challenge, any remaining GD was blotted off the animal, but no additional decontamination was done. Significance in this report is defined as p <.05. Neat (undiluted) GD was used to challenge all animals in these studies. RESULTS: In the standard 2-minute GD decontamination experiments, the calculated PRs for RSDL, 0.5% bleach, 1% soapy water, and M291 SDK were 14, 2.7, 2.2, and 2.6, respectively. RSDL was by far the most effective decontamination product tested and significantly better than any of the other products. Bleach, soapy water, and the M291 SDK provided equivalent and modest protection. Since only RSDL provided at least good protection (PR > 5), it was the only decontamination product evaluated for delayed decontamination. In the GD delayed-decontamination experiments, the calculated LT(50) (the delayed-decontamination time at which 50% of the animals die in the test population following a 5-LD(50) challenge) value for RSDL was only 4.0 minutes. CONCLUSIONS: Several conclusions can be drawn from this study: 1) Reactive Skin Decontamination Lotion provided superior protection against GD compared with the other products tested; 2) The 0.5% bleach solution, the 1% soapy water solution, and the M291 SDK were less effective than RSDL, but still provided modest (2 < PR < 5) protection against GD; 3) Reactive Skin Decontamination Lotion, the best product tested, did not provide significant protection against GD when decontamination was delayed for more than 3 minutes; 4) Skin Exposure Reduction Paste Against Chemical Warfare Agents provided significant, but modest, protection against GD; 5) There was good correlation between using the rabbit model and the guinea pig model for decontamination efficacy evaluations; and 6) Soman (GD) is an agent of real concern because it is very difficult to decontaminate and the effects of exposure are difficult to treat. PMID- 20964501 TI - Health on the Web: An examination of health content and mobilising information on local television Websites. AB - The Internet plays a crucial role in the communication of health news and information. This study is the first to examine the volume and scope of health coverage on local television news Websites. Mobilising information (MI), information found in news that can cue people to act on pre-existing attitudes, was also explored. Specifically, this study analysed the content of 278 health stories on 79 local television news Websites during September and October 2007. Data revealed that health stories were present on 64% of the sites examined. Only 30%, however, took advantage of the interactive nature of the Internet by linking the reader to other health sites or giving an e-mail address to obtain additional information. Thirty-two percent of the stories contained MI. Of those stories, locational MI (24%) was significantly more likely to be present than tactical (17%) or identificational (14%) (p < 0.05). There were also significant differences between large and small media markets regarding specific health content. Television news Websites produced by large market stations (designated market size (DMA) 1-50) were significantly more likely than very small market stations (DMA 151+) to contain health stories and have a separate health-related Web page. PMID- 20964503 TI - Verbal repetitions and echolalia in Alzheimer's discourse. AB - This article reports on an investigation of echolalic repetition in Alzheimer's disease (AD). A qualitative analysis of data from spontaneous conversations with MHI, a woman with AD, is presented. The data come from the DALI Corpus, a corpus of spontaneous conversations involving subjects with AD. This study argues that echolalic effects can be explained through an analysis of their formal linguistic aspects, such as intonational-prosodic and enunciative-syntactic features. The analysis shows that the description of echolalic repetitions in these terms can help find parameters for the description of the linguistic and communicative characteristics of AD. This analysis even shows how a previous speech turn serves as a base for the elaboration of the next turn by the participant with AD. It also contributes to the understanding of echolalic productions in AD. PMID- 20964504 TI - Acoustic markers of prosodic boundaries in Spanish spontaneous alaryngeal speech. AB - Prosodic information aids segmentation of the continuous speech signal and thereby facilitates auditory speech processing. Durational and pitch variations are prosodic cues especially necessary to convey prosodic boundaries, but alaryngeal speakers have inconsistent control over acoustic parameters such as F0 and duration, being as a result noisy and less intelligible than normal speech. This case study has investigated whether one Spanish alaryngeal speaker proficient in both oesophageal and tracheoesophageal speech modes used the same acoustic cues for prosodic boundaries in both types of voicing. Pre-boundary lengthening, F0-excursions and pausing (number of pauses and position) were measured in spontaneous speech samples, using Praat. The acoustic analysis has revealed that the subject has relied on a different combination of cues in each type of voicing to convey the presence of prosodic boundaries. PMID- 20964505 TI - The perfective past tense in Greek adolescents with Down syndrome. AB - This study investigates the ability of a group of eight Greek-speaking adolescents with Down Syndrome (DS) (aged 12.1-18.7) to handle the perfective past tense using an acceptability judgement task. The performance of the DS participants was compared with that of 16 typically-developing children whose chronological age was matched with the mental age of the DS group. For existing verbs, both groups showed high accuracy scores for the sigmatic past tense whilst for (potential but non-existing) nonce verbs the DS group performed differently from the controls. Specifically, their judgements were unaffected by a nonce verb's similarity to existing verbs, unlike those of the controls, suggesting that the DS participants were less reliant on similarity-based generalisations when encountering a nonce word than the controls. Apart from that, it was found that people with DS did not show any kind of morphological impairment, replicating previous findings on past tense production in DS. PMID- 20964506 TI - Syllable structure in dysfunctional Portuguese children's speech. AB - The goal of this work is to investigate whether children with speech dysfunctions (SD) show a deficit in planning some Portuguese syllable structures (PSS) in continuous speech production. Knowledge of which aspects of speech production are affected by SD is necessary for efficient improvement in the therapy techniques. The case-study is focused on PSS as C1C2V syllable sequences (consonant-consonant vowel), in which C2 is [l] or [r]. To identify specific speech patterns that are sensitive to SD, coarticulation effects using formant trajectories, intensity, and durational structure are investigated. To explore the characteristics of continuous speech processes in SD speech output, the methodology uses acoustic analysis. Preliminary findings show systematic specific coarticulation in the child with SD when compared to the normal speech (NS) child. This also suggests that the traditional focus on a single word production in the SD assessment needs to be modified to allow more detailed consideration of speech production in continuous speech. It is the purpose of the authors in the future to develop an application that can be an optimal start for SD treatment/counselling programmes. The work reported here proves the importance of clinic linguistic knowledge in that way. This study is the result of a multidisciplinary-team whose work allies linguist, clinical therapy and engineering knowledge. PMID- 20964507 TI - Revisiting 'The influence of literacy in paraphasias of aphasic speakers'. AB - Literature suggests that illiterate subjects are unaware of the phonological structure of language. This fact may influence the characteristics of aphasic speech, namely the structure of paraphasias. A battery of tests was developed for this study to be used with aphasic subjects (literate and illiterate), in order to explore this topic in more detail. This article aims to present the experimental design and the results of this test battery composed of two sub tests: (i) a naming test with words that belong to three distinct groups: high frequency simple words (HFSW), low frequency simple words (LFSW), and low frequency complex words (LFCW); and (ii) a word repetition test. The variables of literacy, frequency and word morphology, and their effect on the performance of aphasic groups, were correlated in this study. Morphology was the variable that exercised the greatest influence on the verbal production of the participants. PMID- 20964508 TI - Recursion in aphasia. AB - This study investigates how aphasic impairment impinges on syntactic and/or semantic recursivity of human language. A series of tests has been conducted with the participation of five Hungarian speaking aphasic subjects and 10 control subjects. Photographs representing simple situations were presented to subjects and questions were asked about them. The responses are supposed to involve formal structural recursion, but they contain semantic-pragmatic operations instead, with 'theory of mind' type embeddings. Aphasic individuals tend to exploit the parallel between 'theory of mind' embeddings and syntactic-structural embeddings in order to avoid formal structural recursion. Formal structural recursion may be more impaired in Broca's aphasia and semantic recursivity may remain selectively unimpaired in this type of aphasia. PMID- 20964509 TI - A computer-aided evaluation of error patterns in aphasic speech. AB - The objective of this research is to provide an improved automated computational tool to study aphasic production. Using the speech production of Italian aphasic patients, the present study demonstrates the possibility of applying an integrated algorithm to automatically assess and generate error patterns typical of aphasic speech. Philological studies and aphasia studies share one common point: errors (or variants) are informative, and the intention of the authors (in the case of philology) or of the patients (in the case of aphasiology) is to be established. For this precise reason, the present study adapts a tool, originally used in computational philology for the alignment of textual variants (Boschetti, 2007, 2008), and puts it to use for assessing aphasic patient's speech error patterns. As is demonstrated, this tool is effective and analytical. The authors expect this to be beneficial for the use of analysing aphasic production in both clinical and academic settings. PMID- 20964510 TI - Linguistic reflections of social engagement in Asperger discourse and narratives: A quantitative analysis of two cases. AB - The present linguistic analyses of two children (aged 8 and 10) with Asperger Syndrome (AS) and their two matched controls are based on dyadic therapist-child conversations and on picture description tasks. The circa 100 analysis features covering aspects of (i) lexicon (e.g. prominalization), (ii) structural characteristics of turns, (iii) co-operation features (e.g. shared/non-shared elaboration of themes), (iv) prosody, (v) cognitive aspects (e.g. involvement/commitment, world of discourse) and (vi) affect features, show that the AS speakers describe, rather than narrate their conceptualizations, whether (practically) self-initiated (dyadic discourse) or prompted through pictures (narratives). In previous experimental studies of spatially deictic expressions and spatial orientation, it has been shown that the spatial and low-level social cognition of these AS subjects was unimpaired. However, in the present study AS discourse carries features of impaired inter-personal and inter-subjective performance, manifest, for example, in linguistic deixis, atypical power-oriented features and lack of joint activity. PMID- 20964511 TI - Verbal inflection, articles and object clitics in Italian specific language impairment. AB - Morphosyntactic skills in spontaneous and elicited production of a 7-year-old boy with specific language impairment (SLI) were examined and compared to those of younger, mean length of utterance (MLU)-matched, typically-developing children. This study focused on inflectional phrase structures as well as complex constructions in order to investigate hypotheses which suggest verbal inflection is a key deficit underlying SLI. It analysed the most affected morphemes in Italian: articles and direct and indirect object clitics. A deficit was found in verbal inflection as well as in articles and object clitics. The difficulties with verbal inflection found were expected given the child's MLU. Problems with articles and clitics were unexpected for MLU, presenting a challenge for hypotheses that focus on verbal inflection. PMID- 20964512 TI - Cross-linguistic expression of contrastive accent: Clinical assessment in Spanish and English. AB - Well-documented Romance-Germanic differences in the use of accent in speech to convey information-structure and focus cause problems for the assessment of prosodic skills in populations with clinical disorders. The strategies for assessing the ability to use lexical and contrastive accent in English and Spanish are reviewed, and studies in the expression of contrastive accent in Spanish- and English-speaking typically-developing children are described. These studies used similar tasks requiring pre-final contrastive accent. Results were, however, strikingly different (English > Spanish). Using the same tasks, studies of English-speaking individuals with autism and Williams syndrome showed marked difficulty with the expression of contrastive stress, but the use of such tasks with Spanish speakers may merely reflect cross-linguistic differences. This study presents the methodology and results of these tasks, and suggests alternative methods of assessing the ability to discern and use contrastive accents in Spanish. PMID- 20964513 TI - Metabolic syndrome in severe mental disorders. AB - The concept of metabolic syndrome in psychiatry provides a united front for confronting a series of metabolic changes that are predictive of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM), which are highly prevalent in severe mental disorders (SMDs), such as schizophrenia, bipolar disorders, and severe depression. This review attempts to answer the following questions: (1) Is there evidence of significantly increased risk of metabolic syndrome in SMDs? (2) How is this evidence explained by stress theory and functional polymorphism? (3) What role can psychopharmacology and psychosocial therapies play in minimizing the problem? We have done a historical review using related literature from Medline. Compared with the general population, metabolic syndrome is two to three times more common in SMDs. The evidence for this predates the era of antipsychotic drugs. Altered glucose metabolism and dyslipidemia seem to be integral to SMDs. However, major psychotropic drugs are associated with metabolic syndrome, because of their activity at the appetite-stimulating receptors. SMDs seem to trigger a pathogenic cycle that fuels metabolic syndrome. To explain these findings, a neural diathesis-stress model has been proposed. Furthermore, candidate genes associated with receptors for weight gain are implicated. Using metformin (>=750 mg/day) may significantly reduce metabolic risks, and the data support consideration of this intervention for psychiatric patients taking antipsychotics. The obstacles to the implementation of the available guidelines for monitoring metabolic effects and changing unhelpful lifestyles need to be overcome by making monitoring mandatory and integration of physical exercise into routine care. Drug development and genotyping for the risk factors are future solutions. PMID- 20964514 TI - A multivariate model of determinants of change in gross-motor abilities and engagement in self-care and play of young children with cerebral palsy. AB - A multivariate model of determinants of change in gross-motor ability and engagement in self-care and play provides physical and occupational therapists a framework for decisions on interventions and supports for young children with cerebral palsy and their families. Aspects of the child, family ecology, and rehabilitation and community services may influence children's activity and participation. Aspects of the child include primary and secondary impairments, associated and comorbid health conditions, and adaptive behaviors. Literature support for the model is reviewed. A clinical scenario illustrates the use of the model as a framework for practice. The model encourages therapists to broaden the focus of rehabilitation services for young children with CP to include not only development of motor abilities but also comprehensive interventions and supports to enhance participation in daily activities and routines. Therapists are encouraged to consider how child, family, and service factors interact when planning interventions and evaluating outcomes. PMID- 20964515 TI - The involvement of people with lifelong disability and communication impairment in lecturing to speech-language pathology students. AB - In order to provide appropriate service and support to people with lifelong disability, including those who use augmentative and alternative communication (AAC), speech-language pathologists need to develop positive attitudes to people with disability and a holistic approach. The aim of this paper was to explore final year students' and new graduates' perceptions of the impact of lectures by people with lifelong disability on their attitudes and learning. Fourteen final year speech-language pathology students and nine graduates who had been practising for a year participated in four focus groups to discuss their perceptions of four 50-minute lectures by people with lifelong disability and communication impairment. A content analysis of the focus group transcripts revealed five themes; understanding the perspectives of people with disability, seeing the person as a whole, attitudes, working in the field, and gaps in the lectures. Overall there were few differences between the groups that were not accounted for by clinical experience. Participants agreed that the lectures were interesting and informative and provided new insights into lifelong disability, but were an adjunct to a learning process that also required theoretical lectures or clinical practice. PMID- 20964517 TI - Computational allergenicity prediction of transgenic proteins expressed in genetically modified crops. AB - Development of genetically modified (GM) crops is on increase to improve food quality, increase harvest yields, and reduce the dependency on chemical pesticides. Before their release in marketplace, they should be scrutinized for their safety. Several guidelines of different regulatory agencies like ILSI, WHO Codex, OECD, and so on for allergenicity evaluation of transgenics are available and sequence homology analysis is the first test to determine the allergenic potential of inserted proteins. Therefore, to test and validate, 312 allergenic, 100 non-allergenic, and 48 inserted proteins were assessed for sequence similarity using 8-mer, 80-mer, and full FASTA search. On performing sequence homology studies, ~94% the allergenic proteins gave exact matches for 8-mer and 80-mer homology. However, 20 allergenic proteins showed non-allergenic behavior. Out of 100 non-allergenic proteins, seven qualified as allergens. None of the inserted proteins demonstrated allergenic behavior. In order to improve the predictability, proteins showing anomalous behavior were tested by Algpred and ADFS separately. Use of Algpred and ADFS softwares reduced the tendency of false prediction to a great extent (74-78%). In conclusion, routine sequence homology needs to be coupled with some other bioinformatic method like ADFS/Algpred to reduce false allergenicity prediction of novel proteins. PMID- 20964518 TI - Coexpression of CD14 and CD326 discriminate hepatic precursors in the human fetal liver. AB - The molecular and cellular profile of liver cells during early human development is incomplete, complicating the isolation and study of hepatocytes, cholangiocytes, and hepatic stem cells from the complex amalgam of hepatic and hematopoietic cells, that is, the fetal liver. Epithelial cell adhesion molecule, CD326, has emerged as a marker of hepatic stem cells, and lipopolysaccharide receptor CD14 is known to be expressed on adult hepatocytes. Using flow cytometry, we studied the breadth of CD326 and CD14 expression in midgestation liver. Both CD45(+) hematopoietic and CD45(-) nonhematopoietic cells expressed CD326. Moreover, diverse cell types expressing CD326 were revealed among CD45(-) cells by costaining for CD14. Fluorescence-activated cell sorting was used to isolate nonhematopoietic cells distinguished by expression of high levels of CD326 and low CD14 (CD326(++)CD14(lo)), which were characterized for gene expression associated with liver development. CD326(++)CD14(lo) cells expressed the genes albumin, alpha-fetoprotein, hepatic nuclear factor 3alpha, prospero related homeobox 1, cytochrome P450 3A7, alpha(1)-antitrypsin, and transferrin. Proteins expressed included cell-surface CD24, CD26, CD29, CD34, CD49f, CD243, and CD324 and, in the cytoplasm, cytokeratins-7/8 (CAM 5.2 antigen) and some cytokeratin-19. Cultured CD326(++)CD14(lo) cells yielded albumin(+) hepatocytes, cytokeratin-19(+) cholangiocytes, and hepatoblasts expressing both markers. Using epifluorescence microscopy we observed CD326 and CD14 expression on fetal hepatocytes comprising the liver parenchyma, as well as on cells associated with ductal plates and surrounding large vessels. These findings indicate that expression of CD14 and CD326 can be used to identify functionally distinct subsets of fetal liver cells, including CD326(++)CD14(lo) cells, representing a mixture of parenchymal cells, cholangiocytes, and hepatoblasts. PMID- 20964522 TI - Modeling the probability of sustained virological response to therapy with pegylated interferon plus ribavirin in patients coinfected with hepatitis C virus and HIV. AB - BACKGROUND: A single-nucleotide polymorphism (SNP) near the IL28B gene (rs12979860) strongly predicts sustained virological response to pegylated interferon plus ribavirin (pegIFN-RBV) treatment for chronic hepatitis C virus (HCV) infection. Given that therapy is poorly tolerated and rates of response are lower in patients coinfected with HCV and human immunodeficiency virus (HIV), the recognition of predictors of response is a high priority in this population. METHODS: A baseline noninvasive index was derived on the basis of the probability of achieving sustained virological response in a group of 159 HIV-HCV-coinfected patients treated at one clinic in Spain. The index was then validated using data from a separate cohort of 86 coinfected individuals. Only individuals who had completed a course of pegIFN-RBV therapy and had validated outcomes were considered. RESULTS: The final score included 4 variables: 2 host-related variables (IL28B SNP rs12979860 and liver stiffness) and 2 HCV-related variables (genotype and viral load). The area under the receiver operating characteristic curve was 0.89 in the derivation group and 0.85 in the validation group. CONCLUSIONS: The probability of achieving sustained virological response with pegIFN-RBV therapy in HIV-HCV-coinfected patients can be reliably estimated prior to initiation of therapy using an index that includes 4 noninvasive parameters. PMID- 20964523 TI - Low risk of bacterial meningitis in children with a positive enteroviral polymerase chain reaction test result. PMID- 20964521 TI - The infection attack rate and severity of 2009 pandemic H1N1 influenza in Hong Kong. AB - BACKGROUND: Serial cross-sectional data on antibody levels to the 2009 pandemic H1N1 influenza A virus from a population can be used to estimate the infection attack rates and immunity against future infection in the community. METHODS: From April through December 2009, we obtained 12,217 serum specimens from blood donors (aged 16-59 years), 2520 specimens from hospital outpatients (aged 5-59 years), and 917 specimens from subjects involved in a community pediatric cohort study (aged 5-14 years). We estimated infection attack rates by comparing the proportions of specimens with antibody titers >= 1:40 by viral microneutralization before and after the first wave of the pandemic. Estimates were validated using paired serum samples from 324 individuals that spanned the first wave. Combining these estimates with epidemiologic surveillance data, we calculated the proportion of infections that led to hospitalization, admission to the intensive care unit (ICU), and death. RESULTS: We found that 3.3% and 14% of persons aged 5-59 years had antibody titers >= 1:40 before and after the first wave, respectively. The overall attack rate was 10.7%, with age stratification as follows: 43.4% in persons aged 5-14 years, 15.8% in persons aged 15-19 years, 11.8% in persons aged 20-29 years, and 4%-4.6% in persons aged 30-59 years. Case hospitalization rates were 0.47%-0.87% among persons aged 5-59 years. Case-ICU rates were 7.9 cases per 100,000 infections in persons aged 5-14 years and 75 cases per 100,000 infections in persons aged 50-59 years, respectively. Case fatality rates were 0.4 cases per 100,000 infections in persons aged 5-14 years and 26.5 cases per 100,000 infections in persons aged 50-59 years, respectively. CONCLUSIONS: Almost half of all school-aged children in Hong Kong were infected during the first wave. Compared with school children aged 5-14 years, older adults aged 50-59 years had 9.5 and 66 times higher risks of ICU admission and death if infected, respectively. PMID- 20964524 TI - Photodynamic therapy for the treatment of endoanal condylomata acuminata. PMID- 20964525 TI - New Delhi metallo 1: have carbapenems met their doom? PMID- 20964526 TI - Serological response to H1N1 influenza virus infections in adults treated with oseltamivir. PMID- 20964527 TI - Nutritional supplementation in HIV-infected individuals can be beneficial in certain patient groups. PMID- 20964531 TI - Propensity to work among chronically unemployed adult drug users. AB - Analyses were conducted to compare rates of employment before, during, and after employment at the therapeutic workplace, which is a novel employment-based treatment for drug misuse. Participants in two clinical trials attended the therapeutic workplace at higher rates than they worked before intake and six months after discharge. These data suggest that unemployed chronic drug misusers will attend work at higher rates at the therapeutic workplace than in the community when paid modest wages, and that the failure of chronic drug misusers to obtain employment in the community may not result from lack of interest in work. PMID- 20964532 TI - Heavy episodic drinking in early adolescence: gender-specific risk and protective factors. AB - This longitudinal study examined possible gender differences regarding risk and protective factors for heavy episodic drinking among 1,222 seventh-grade students (aged 13) in the City of Stockholm, Sweden, with follow-up 2 years later. Logistic regression analyses showed that several factors predicted heavy episodic drinking. The strongest predictors for boys' heavy episodic drinking in the ninth grade were heavy episodic drinking (odds ratio [OR] = 5.30) and smoking in the seventh grade (OR = 5.80). Drinking peers (OR = 2.47) and smoking (OR = 2.44) in the seventh grade showed the strongest association for girls. Furthermore, high parental monitoring and having a secure attachment to parents may have a protective effect when risk factors are present. Our results lend support to prevention initiatives to strengthen the parent-child relation and focus on adolescents' ability to resist peer pressure and of limiting parental provision of alcohol. The study's limitations are noted. PMID- 20964533 TI - Heroin dependence and bloodborne virus transmission behaviors for HIV infection among newly incarcerated injection drug users in Taiwan. AB - The purpose of the study was to determine heroin dependence and risky behaviors associated with human immunodeficiency virus (HIV) infection among newly incarcerated injection drug users (IDUs). Three self-administrated questionnaires were collected among 450 newly incarcerated male heroin users during 2005-2007. Inmates were categorized as heroin-dependent if they met three or more of the six ICD-10 criteria. Heroin-dependent inmates had higher scores of bloodborne virus transmission risk than non-dependent IDUs (12.8 +/- 16.0 vs. 7.2 +/- 11.5, p < 0.001). Multiple logistic regression analysis indicated that heroin dependence was a significant moderator of the association between risky injection behaviors and HIV infection. It is crucial to integrate substance treatment with behavioral interventions into harm reduction programs to prevent bloodborne virus transmission among IDUs. PMID- 20964534 TI - Dilantin therapy in an experimental model of traumatic brain injury: effects of limited versus daily treatment on neurological and behavioral recovery. AB - The mechanisms by which Dilantin confers anticonvulsant benefits may also be neuroprotective by attenuating the acute excitatory insult in cortical and subcortical structures when the drug is given in the acute phase after traumatic brain injury (TBI). However, when Dilantin is used for prolonged periods, we hypothesized that it may impede recovery, synaptic plasticity may be impaired, and neuroprotective benefits may be lost. As such, we assessed the effect of daily chronic administration (75 mg/kg day 0 followed by 50 mg/kg daily i.p.) and acute administration (75 mg/kg day 0 followed by 50 mg/kg i.p. day 1) of Dilantin in young adult male rats on motor performance, y-maze exploration, Morris Water Maze (MWM), hippocampal (HC) cell survival, contusion size, and regional expression of neuroplasticity markers after controlled cortical impact (CCI) injury. Chronic daily Dilantin administration resulted in beam walking impairments on day 6, whereas acute Dilantin administration resulted in beam walking impairments on days 3 and 4. Chronic Dilantin administration also resulted in worse MWM performance, more HC cell loss and no increases in neuroplasticity markers compared to rats with CCI receiving chronic vehicle. Conversely, rats receiving acute Dilantin administration exhibited more novel arm exploration in the y-maze, greater HC cell sparing, and greater growth-associated protein 43 (GAP-43) expression in the HC ipsilateral to the CCI, compared to injured rats receiving vehicle. MWM was not influenced by acute Dilantin administration. These results suggest that there are beneficial effects of limited acute Dilantin therapy after TBI, and that extended daily Dilantin therapy has deleterious effects on neural recovery. These findings support clinical guidelines for limited use of Dilantin in seizure prophylaxis after TBI. PMID- 20964535 TI - Electrocortical pathology in a rat model of penetrating ballistic-like brain injury. AB - Traumatic brain injury (TBI) causes severe disruption of cerebral electrical activity and electroencephalography (EEG) is emerging as a standard tool to monitor TBI patients in the acute period of risk for secondary injuries. However, animal studies of EEG pathology in the context of TBI are surprisingly sparse, largely because of the lack of real-time continuous EEG (cEEG) monitoring in animal TBI models. Here, we performed long-term EEG monitoring to study nonconvulsive seizures (NCS), periodic epileptiform discharges (PED), and EEG power spectra following three injury severity levels in a rat model of penetrating ballistic-like brain injury (PBBI). EEG signals were recorded continuously from bilateral hemispheres of freely behaving rats for 72 h and for 2 h on days 7 and 14 after the injury. We report that the incidence of NCS and PED positively correlated with the injury severity, where 13%, 39%, and 59% of the animals exhibited NCS, and 0%, 30%, and 65% of the animals exhibited PED following 5%, 10% and 12.5% PBBI, respectively. Similar correlations existed for the number of NCS and PED events and their duration. NCS and PED occurred either independently or in tandem. Longer NCS durations were associated with larger lesion volumes. Significant EEG slowing evidenced by the EEG power shift toward the delta frequency band (0.5-4 Hz) occurred within 2 h after PBBI, which resolved over time but persisted longer after greater injury severity. In contrast, decreases in higher frequency power (i.e., 30-35 Hz) remained depressed throughout 14 days. This is the first long-term cEEG study of the acute injury phase in a rat model of severe TBI, demonstrating common occurrences of clinically observed electrocortical pathology, such as NCS, PED, and cortical slowing. These EEG pathologies may serve as critical care biomarkers of brain injury, and offer clinically relevant metrics for studying acute therapeutic interventions. PMID- 20964537 TI - Picbreeder: a case study in collaborative evolutionary exploration of design space. AB - For domains in which fitness is subjective or difficult to express formally, interactive evolutionary computation (IEC) is a natural choice. It is possible that a collaborative process combining feedback from multiple users can improve the quality and quantity of generated artifacts. Picbreeder, a large-scale online experiment in collaborative interactive evolution (CIE), explores this potential. Picbreeder is an online community in which users can evolve and share images, and most importantly, continue evolving others' images. Through this process of branching from other images, and through continually increasing image complexity made possible by the underlying neuroevolution of augmenting topologies (NEAT) algorithm, evolved images proliferate unlike in any other current IEC system. This paper discusses not only the strengths of the Picbreeder approach, but its challenges and shortcomings as well, in the hope that lessons learned will inform the design of future CIE systems. PMID- 20964536 TI - Phenylephrine infusion prevents impairment of ATP- and calcium-sensitive potassium channel-mediated cerebrovasodilation after brain injury in female, but aggravates impairment in male, piglets through modulation of ERK MAPK upregulation. AB - Traumatic brain injury (TBI) contributes to morbidity in children and boys, and hypotension worsens outcome. Extracellular signal-related kinase (ERK) mitogen activated protein kinase (MAPK) is upregulated more in males and reduces cerebral blood flow (CBF) after fluid percussion injury (FPI). Increased cerebral perfusion pressure (CPP) via phenylephrine (Phe) sex-dependently improves impairment of the cerebral autoregulation seen after FPI through modulation of ERK MAPK upregulation, which is aggravated in males, but is blocked in females. Activation of ATP- and calcium-sensitive (Katp and Kca) channels produces cerebrovasodilation and contributes to autoregulation, both of which are impaired after FPI. Using piglets equipped with a closed cranial window, we hypothesized that potassium channel functional impairment after FPI is prevented by Phe in a sex-dependent manner through modulation of ERK MAPK upregulation. The Katp and Kca agonists cromakalim and NS 1619 produced vasodilation that was impaired after FPI more in males than in females. Phe prevented reductions in cerebrovasodilation after cromakalim and NS 1619 in females, but reduced dilation after these potassium channel agonists were given to males after FPI. Co administration of U 0126, an ERK antagonist, and Phe fully restored dilation to cromakalim, calcitonin gene-related peptide (CGRP), and NS 1619, in males after FPI. These data indicate that Phe sex-dependently prevents impairment of Katp and Kca channel-mediated cerebrovasodilation after FPI in females, but aggravates impairment in males, through modulation of ERK MAPK upregulation. Since autoregulation of CBF is dependent on intact functioning of potassium channels, these data suggest a role for sex-dependent mechanisms in the treatment of cerebral autoregulation impairment after pediatric TBI. PMID- 20964538 TI - Model-based decoding, information estimation, and change-point detection techniques for multineuron spike trains. AB - One of the central problems in systems neuroscience is to understand how neural spike trains convey sensory information. Decoding methods, which provide an explicit means for reading out the information contained in neural spike responses, offer a powerful set of tools for studying the neural coding problem. Here we develop several decoding methods based on point-process neural encoding models, or forward models that predict spike responses to stimuli. These models have concave log-likelihood functions, which allow efficient maximum-likelihood model fitting and stimulus decoding. We present several applications of the encoding model framework to the problem of decoding stimulus information from population spike responses: (1) a tractable algorithm for computing the maximum a posteriori (MAP) estimate of the stimulus, the most probable stimulus to have generated an observed single- or multiple-neuron spike train response, given some prior distribution over the stimulus; (2) a gaussian approximation to the posterior stimulus distribution that can be used to quantify the fidelity with which various stimulus features are encoded; (3) an efficient method for estimating the mutual information between the stimulus and the spike trains emitted by a neural population; and (4) a framework for the detection of change point times (the time at which the stimulus undergoes a change in mean or variance) by marginalizing over the posterior stimulus distribution. We provide several examples illustrating the performance of these estimators with simulated and real neural data. PMID- 20964539 TI - Efficient Markov chain Monte Carlo methods for decoding neural spike trains. AB - Stimulus reconstruction or decoding methods provide an important tool for understanding how sensory and motor information is represented in neural activity. We discuss Bayesian decoding methods based on an encoding generalized linear model (GLM) that accurately describes how stimuli are transformed into the spike trains of a group of neurons. The form of the GLM likelihood ensures that the posterior distribution over the stimuli that caused an observed set of spike trains is log concave so long as the prior is. This allows the maximum a posteriori (MAP) stimulus estimate to be obtained using efficient optimization algorithms. Unfortunately, the MAP estimate can have a relatively large average error when the posterior is highly nongaussian. Here we compare several Markov chain Monte Carlo (MCMC) algorithms that allow for the calculation of general Bayesian estimators involving posterior expectations (conditional on model parameters). An efficient version of the hybrid Monte Carlo (HMC) algorithm was significantly superior to other MCMC methods for gaussian priors. When the prior distribution has sharp edges and corners, on the other hand, the "hit-and-run" algorithm performed better than other MCMC methods. Using these algorithms, we show that for this latter class of priors, the posterior mean estimate can have a considerably lower average error than MAP, whereas for gaussian priors, the two estimators have roughly equal efficiency. We also address the application of MCMC methods for extracting nonmarginal properties of the posterior distribution. For example, by using MCMC to calculate the mutual information between the stimulus and response, we verify the validity of a computationally efficient Laplace approximation to this quantity for gaussian priors in a wide range of model parameters; this makes direct model-based computation of the mutual information tractable even in the case of large observed neural populations, where methods based on binning the spike train fail. Finally, we consider the effect of uncertainty in the GLM parameters on the posterior estimators. PMID- 20964540 TI - A graphical model framework for decoding in the visual ERP-based BCI speller. AB - We present a graphical model framework for decoding in the visual ERP-based speller system. The proposed framework allows researchers to build generative models from which the decoding rules are obtained in a straightforward manner. We suggest two models for generating brain signals conditioned on the stimulus events. Both models incorporate letter frequency information but assume different dependencies between brain signals and stimulus events. For both models, we derive decoding rules and perform a discriminative training. We show on real visual speller data how decoding performance improves by incorporating letter frequency information and using a more realistic graphical model for the dependencies between the brain signals and the stimulus events. Furthermore, we discuss how the standard approach to decoding can be seen as a special case of the graphical model framework. The letter also gives more insight into the discriminative approach for decoding in the visual speller system. PMID- 20964541 TI - Broken symmetries in a location-invariant word recognition network. AB - We studied the feedforward network proposed by Dandurand et al. (2010), which maps location-specific letter inputs to location-invariant word outputs, probing the hidden layer to determine the nature of the code. Hidden patterns for words were densely distributed, and K-means clustering on single letter patterns produced evidence that the network had formed semi-location-invariant letter representations during training. The possible confound with superseding bigram representations was ruled out, and linear regressions showed that any word pattern was well approximated by a linear combination of its constituent letter patterns. Emulating this code using overlapping holographic representations (Plate, 1995) uncovered a surprisingly acute and useful correspondence with the network, stemming from a broken symmetry in the connection weight matrix and related to the group-invariance theorem (Minsky & Papert, 1969). These results also explain how the network can reproduce relative and transposition priming effects found in humans. PMID- 20964542 TI - A framework for simulating and estimating the state and functional topology of complex dynamic geometric networks. AB - We introduce a framework for simulating signal propagation in geometric networks (networks that can be mapped to geometric graphs in some space) and developing algorithms that estimate (i.e., map) the state and functional topology of complex dynamic geometric networks. Within the framework, we define the key features typically present in such networks and of particular relevance to biological cellular neural networks: dynamics, signaling, observation, and control. The framework is particularly well suited for estimating functional connectivity in cellular neural networks from experimentally observable data and has been implemented using graphics processing unit high-performance computing. Computationally, the framework can simulate cellular network signaling close to or faster than real time. We further propose a standard test set of networks to measure performance and compare different mapping algorithms. PMID- 20964543 TI - Least-squares independent component analysis. AB - Accurately evaluating statistical independence among random variables is a key element of independent component analysis (ICA). In this letter, we employ a squared-loss variant of mutual information as an independence measure and give its estimation method. Our basic idea is to estimate the ratio of probability densities directly without going through density estimation, thereby avoiding the difficult task of density estimation. In this density ratio approach, a natural cross-validation procedure is available for hyperparameter selection. Thus, all tuning parameters such as the kernel width or the regularization parameter can be objectively optimized. This is an advantage over recently developed kernel-based independence measures and is a highly useful property in unsupervised learning problems such as ICA. Based on this novel independence measure, we develop an ICA algorithm, named least-squares independent component analysis. PMID- 20964544 TI - A multiscale correlation of wavelet coefficients approach to spike detection. AB - Extracellular chronic recordings have been used as important evidence in neuroscientific studies to unveil the fundamental neural network mechanisms in the brain. Spike detection is the first step in the analysis of recorded neural waveforms to decipher useful information and provide useful signals for brain machine interface applications. The process of spike detection is to extract action potentials from the recordings, which are often compounded with noise from different sources. This study proposes a new detection algorithm that leverages a technique from wavelet-based image edge detection. It utilizes the correlation between wavelet coefficients at different sampling scales to create a robust spike detector. The algorithm has one tuning parameter, which potentially reduces the subjectivity of detection results. Both artificial benchmark data sets and real neural recordings are used to evaluate the detection performance of the proposed algorithm. Compared with other detection algorithms, the proposed method has a comparable or better detection performance. In this letter, we also demonstrate its potential for real-time implementation. PMID- 20964545 TI - Modeling multivariate time series on manifolds with skew radial basis functions. AB - We present an approach for constructing nonlinear empirical mappings from high dimensional domains to multivariate ranges. We employ radial basis functions and skew radial basis functions for constructing a model using data that are potentially scattered or sparse. The algorithm progresses iteratively, adding a new function at each step to refine the model. The placement of the functions is driven by a statistical hypothesis test that accounts for correlation in the multivariate range variables. The test is applied on training and validation data and reveals nonstatistical or geometric structure when it fails. At each step, the added function is fit to data contained in a spatiotemporally defined local region to determine the parameters--in particular, the scale of the local model. The scale of the function is determined by the zero crossings of the autocorrelation function of the residuals. The model parameters and the number of basis functions are determined automatically from the given data, and there is no need to initialize any ad hoc parameters save for the selection of the skew radial basis functions. Compactly supported skew radial basis functions are employed to improve model accuracy, order, and convergence properties. The extension of the algorithm to higher-dimensional ranges produces reduced-order models by exploiting the existence of correlation in the range variable data. Structure is tested not just in a single time series but between all pairs of time series. We illustrate the new methodologies using several illustrative problems, including modeling data on manifolds and the prediction of chaotic time series. PMID- 20964546 TI - The mean time to express synaptic plasticity in integrate-and-express, stochastic models of synaptic plasticity induction. AB - Stochastic models of synaptic plasticity propose that single synapses perform a directed random walk of fixed step sizes in synaptic strength, thereby embracing the view that the mechanisms of synaptic plasticity constitute a stochastic dynamical system. However, fluctuations in synaptic strength present a formidable challenge to such an approach. We have previously proposed that single synapses must interpose an integration and filtering mechanism between the induction of synaptic plasticity and the expression of synaptic plasticity in order to control fluctuations. We analyze a class of three such mechanisms in the presence of possibly non-Markovian plasticity induction processes, deriving expressions for the mean expression time in these models. One of these filtering mechanisms constitutes a discrete low-pass filter that could be implemented on a small collection of molecules at single synapses, such as CaMKII, and we analyze this discrete filter in some detail. After considering Markov induction processes, we examine our own stochastic model of spike-timing-dependent plasticity, for which the probability density functions of the induction of plasticity steps have previously been derived. We determine the dependence of the mean time to express a plasticity step on pre- and postsynaptic firing rates in this model, and we also consider, numerically, the long-term stability against fluctuations of patterns of neuronal connectivity that typically emerge during neuronal development. PMID- 20964547 TI - Is overoxidation of peroxiredoxin physiologically significant? AB - Eukaryotic peroxiredoxins are highly susceptible to sulfinic acid formation. This overoxidation, which is thought to convert peroxiredoxins into chaperones, can be reversed by sulfiredoxins. Several organisms, including Caenorhabditis elegans, lack sulfiredoxins but encode sestrins, proteins proposed to be functionally equivalent. We induced peroxiredoxin overoxidation in C. elegans with a short peroxide pulse. We found that reduction of overoxidized peroxiredoxin 2 (PRDX-2) was extremely slow and sestrin-independent, strongly implying that worms lack an efficient repair system. Analysis of PRDX-2's overoxidation status during C. elegans lifespan revealed no accumulation of overoxidized PRDX-2 at any point, questioning whether PRDX-2 overoxidation in worms is physiologically relevant. PMID- 20964548 TI - Adherence and persistence in patients with postmenopausal osteoporosis treated with raloxifene. AB - OBJECTIVE: A major impediment in osteoporosis care is poor therapeutic adherence. Real-life surveys show that adherence and persistence with oral bisphosphonates decrease to 30-60% within 1 year. The aim of this study was to analyze the adherence and persistence with raloxifene in patients visiting our outpatient clinic. MATERIAL AND METHODS: A total of 342 patients were evaluated from the conventional osteoporosis practice receiving treatment with raloxifene. Patient self-reporting was combined with the medication possession ratio (MPR) assessed via prescription refill counts. In addition, persistence and other self-reported and patient file-based data were assessed. RESULTS: The final analysis comprised 300 patients with a mean age of 66.3 years (standard deviation +/- 7.2 years). At 6 months 84%, at 12 months 81%, at 24 months 78% and at 36 months 77% of patients were persistent with therapy according to patients' self-reports. If MPR and self reported data were combined, 56%, 48% and 35% of patients remained on therapy at 12, 24 and 36 months, respectively. The mean duration of therapy was 19 months with a mean MPR of 52.8%. Finally, 31.7% of all patients were classified as adherent. Significant correlation to adherence was found for tolerability and motivational factors. CONCLUSION: This study revealed that approximately half of the patients treated with raloxifene in regular clinical practice stay on therapy for the first 2 years. Furthermore, the patients do not adhere sufficiently to the recommended dosage, and reduced clinical efficacy in clinical practice is presumable. The reasons for non-adherence comprise tolerability and motivational factors but further investigation is needed. PMID- 20964549 TI - Vitamin D: a hormone for all seasons. AB - Vitamin D is principally obtained from skin through the action of ultraviolet B irradiation on 7-dehydrocholesterol. It is further metabolized to 25 hydroxyvitamin D, the major circulating vitamin D compound, and then to 1,25 dihydroxyvitamin D, the hormonal form. The major function of vitamin D compounds is to enhance active absorption of calcium (and phosphate) from the gut, ensuring that bone does not need to be resorbed to maintain blood calcium concentrations despite obligatory urinary losses. Vitamin D compounds have direct effects to enhance bone and muscle function. Based on good evidence, target levels for 25 hydroxyvitamin D in blood are at least 50 nmol/l and there may be a case for higher targets of 75-80 nmol/l. Adequate calcium intakes help to reduce vitamin D degradation. Vitamin D and calcium together reduce the risk of falls and fractures in older people. There are vitamin D receptors in most nucleated cells and preliminary evidence that adequate vitamin D levels may be important in reducing the incidence of, or mortality from, some cancers, and in reducing autoimmune disease. Adequate vitamin D may also allow for a normal innate immune response to pathogens, improve cardiovascular function and mortality, and reduce type 2 diabetes. Supplemental vitamin D seems to work in a generally similar manner to skin-derived vitamin D. PMID- 20964550 TI - Value of transvaginal ultrasonography in endometrial evaluation of non-bleeding postmenopausal women. AB - OBJECTIVE: To investigate the value of transvaginal ultrasonography (TVU) in the evaluation of the endometrium in postmenopausal women without vaginal bleeding. METHODS: This was a prospective, cohort, observational study which included 259 consecutive, asymptomatic, postmenopausal women who were referred to the outpatient clinics of Shiraz University of Medical Sciences. All the participants underwent TVU by the same gynecologist at the same time as hysteroscopy and endometrial biopsy were performed. Both 3 mm and 5 mm were considered as cut-off values. Endometrial histopathology was considered the gold-standard diagnosis and the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of TVU were calculated on the basis of pathologic reports. RESULTS: The mean age of the patients was 54.2 +/- 7.46 years (range 36-79 years). The mean endometrial thickness was found to be 3.83 +/- 2.95 mm (range 1 25 mm); it was > 5 mm in 41 (15.8%) patients. The sensitivity, specificity, PPV and NPV were 62.2%, 93.9%, 68.3% and 92.2%, respectively. The receiver-operating characteristics curve showed an area under the curve of 0.853 (95% confidence interval 0.788-0.917), indicating a moderate accuracy. Conclusion TVU is a moderately accurate test in asymptomatic postmenopausal women. Due to its high false-positive rate, its positive results cannot be interpreted. PMID- 20964551 TI - Prevalence of depression among postmenopausal women and related characteristics. AB - OBJECTIVE: To estimate the prevalence of depression in postmenopausal women and to evaluate the relation between postmenopausal depression and some sociodemographic characteristics. METHODS: This cross-sectional study was conducted in 744 postmenopausal women aged 45-65 years residing within Sivrihisar, Eskisehir, a town in western Turkey. The study was conducted between May 1 and June 30, 2009. Depression was measured with a Turkish version of the Beck Depression Inventory. Data were gathered during routine visits to the women's homes. Following the completion of the questionnaires and scales, the women's body mass indices were calculated by measuring their heights and weights. Statistical analysis used the chi(2) test and the Wald backward stepwise method. A value of p < 0.05 was considered statistically significant. RESULTS: The prevalence of depression was 24.7% (184/744). The average age of the women at menopause was 46 years. Significantly important risk factors for depression were primary-school education level (odds ratio (OR) 1.681), not being married (OR 1.653), having a history of psychiatric illness (OR 2.186), entering into menopause at the age of <=39 years (OR 2.705), having irregular menstruation before menopause (OR 1.729), and having no children (OR 3.316). CONCLUSION: Depression among postmenopausal women is an important public health problem that requires attention; furthermore, women are at risk in terms of depression after entering into menopause. PMID- 20964552 TI - Autophagy, reactive oxygen species and the fate of mammalian cells. AB - The paper reviews the rapidly expanding pool of information on cellular and molecular mechanisms of autophagy, including autophagy types, macroautophagy induction, formation of autophagosomes and cross-talk between autophagy and apoptosis. Special attention is given to generation of reactive oxygen species (ROS) in various cellular compartments of cells under stress conditions inducing autophagy. The roles of hydrogen peroxide and superoxide in autophagy are analysed based on the recent experimental work. The relation between ROS and life span prolongation is briefly discussed, with the final conclusion that the paradox of dual role of ROS in life and death may be solved to a considerable extent due to research on autophagy. PMID- 20964553 TI - Succination of proteins in diabetes. AB - Cysteine is arguably the most reactive amino acid in protein. A wide range of cysteine derivatives is formed in vivo, resulting from oxidation, nitrosation, alkylation and acylation reactions. This review describes succination of proteins, an irreversible chemical modification of cysteine by the Krebs cycle intermediate, fumarate, yielding S-(2-succinyl)cysteine (2SC). Intracellular fumarate concentration and succination of proteins are increased by hyperpolarization of the inner mitochondrial membrane and develop in concert with mitochondrial and oxidative stress in diabetes. Increased succination of glyceraldehyde-3-phosphate dehydrogenase explains the loss in specific activity of this enzyme in muscle of streptozotocin-diabetic rats and increased succination of adiponectin may explain the decreased secretion of adiponectin from adipose tissue in type 2 diabetes. In addition to GAPDH and adiponectin, other succinated proteins identified in adipocytes include cytoskeletal proteins (tubulin, actin) and chaperone proteins in the endoplasmic reticulum. Succination of adipocyte protein in vitro is inhibited by uncouplers of oxidative phosphorylation and by inhibitors of ER stress. 2SC serves as a biomarker of mitochondrial stress and recent studies suggest that succination is the mechanistic link between mitochondrial and ER stress in diabetes. PMID- 20964554 TI - Vitamin-D-free regimen intensifies the spatial learning deficit in Alzheimer's disease. AB - Evidences support a link between nutrition and risk of neurodegenerative Alzheimer's disease (AD). This work was designed to find out if food regimens lacking vitamin D or with a supplement of vitamin D could affect spatial performances in the Alzheimeric animals. The experiment was done on the control and Alzheimeric (ALZ) animals on a normal regimen of food, as well as the Alzheimeric rats fed with regimens lacking vitamin D (ALZ-D) or supplemented with 1,25(OH)2D3 (ALZ+D). For learning the spatial task the animals were trained to locate a hidden platform in the Morris water maze. We found that the ALZ rats had an obvious lower performance compared with the control ones. Generally, the ALZ-D rats displayed a poorer spatial learning compared with either the ALZ or the ALZ+D rats. Vitamin D supplement did not significantly influence the spatial performance. We conclude that although vitamin D deficiency strengthens the spatial learning deficit in AD, a supplement of 1,25(OH)2D3 does not effectively underlie the maze performance. It can be concluded that subjects with AD must be protected from vitamin D inadequacy. PMID- 20964555 TI - In vitro effects of ethanol with aspirin on rat brain synaptosomes: the potential protective role of betaine. AB - Physicians recommend aspirin for prevention of heart attacks and stroke in people above the age of 40 years. In some cases, alcohol consumption accompanies aspirin intake. In this study, the in vitro effects of different doses of ethanol (50, 100, and 200 mM) and 100 microg/mL of aspirin and the possible protective role of betaine (0.5 and 1 mM) were investigated on rat cerebral synaptosomes. Synaptosomally enriched fractions, derived from Sprague Dawley rat brains, were incubated with ethanol and aspirin so as to measure sialic acid (SA), nitric oxide levels, and adenosine deaminase (ADA) activities, which are known to be the markers of alcohol damage. When combined with aspirin, ethanol increased SA levels compared with the control group at all doses, resulting in loss of SA residue from synaptosomal membrane. Betaine (0.5 mM) decreased SA levels with respect to the ethanol (200 mM) plus aspirin group (p < .05), thereby preventing SA loss. Moreover, betaine reversed the destructive effects of ethanol by elevating reduced nitric oxide levels. Aspirin, when combined with all doses of ethanol, increased ADA activity, which is crucial for purine metabolism. ADA activities were also elevated in betaine-administered groups. We propose that betaine is an effective compound in protecting the rat brain synaptosomes against ethanol and aspirin together. PMID- 20964556 TI - Implications of efavirenz for neuropsychiatry: a review. AB - Antiretroviral therapy has revolutionized the treatment of the human immunodeficiency virus because it has improved the clinical outcomes of patients. It is essential that these drugs cross the blood-brain barrier, since the virus is present in the central nervous system (CNS). Efavirenz passes through this barrier satisfactorily and can reduce the deleterious central effects of the human immunodeficiency virus. However, patients treated with efavirenz have been observed to experience psychiatric symptoms such as mania, depression, suicidal thoughts, psychosis, and hallucinations. The aim of this review is to describe the pharmacokinetic and pharmacodynamic properties of efavirenz and its major neuropsychiatric symptoms and the neurochemical pathways associated with these changes in the CNS. The databases Medline and Lilacs were used to search for review articles and preclinical and clinical research articles published from January 1996 to 2010. The search terms used were efavirenz, central nervous system, neuropsychiatry, neurotransmitters, adverse effects, and neurochemistry. Subject categories considered included effects on viral replication, pharmacokinetic and pharmacodynamic properties of efavirenz, and neuropsychiatric adverse effects including time course, duration, and probable mechanisms involved. The mechanisms involved in these changes include interference with cytochrome P450 enzymes, cytokines, tryptophan-2-3-dioxygenase, and brain creatine kinase. PMID- 20964557 TI - Reversible postvaccination paraneoplastic encephalomyelitis in a patient with lung adenocarcinoma. AB - Encephalomyelitis occurs in paraneoplastic syndrome and acute disseminated encephalomyelitis through different autoimmune mechanisms. No postvaccinal encephalomyelitis other than acute disseminated encephalomyelitis has been reported in patients with malignancy. A 68-year-old woman was admitted because of a headache followed by a gait disturbance and psychomotor retardation 2 days after she had received an influenza vaccination followed by abulia, limb rigidity and hyperreflexia of both legs, and meningeal irritation. Cerebrospinal fluid studies showed increased intracranial pressure, elevated immunoglobulins G and A, and pleocytosis. Contrasted brain magnetic resonance imaging revealed ventriculomegaly and multiple symmetric leptomeningeal enhancement, without demyelinating changes or cortical ribbon signs. Somatosensory evoked potentials and nerve conduction velocity studies suggested myelitis. Encephalomyelitis was diagnosed on the basis of clinical and laboratory examinations. The etiological survey identified a lung adenocarcinoma. Both the encephalomyelitis and the lung adenocarcinoma simultaneously progressed after the vaccination and then, after targeted therapy for lung cancer, simultaneously subsided. In conclusion, postinfluenza-vaccination paraneoplastic encephalomyelitis may occur in patients with lung adenocarcinoma. PMID- 20964558 TI - Abstracts of the 33rd Scandinavian Congress of Rheumatology. Bergen, Norway. May 9 - 12, 2010. PMID- 20964559 TI - Clinically symptomatic vasitis: clinical correlations in a rare condition. AB - Vasitis, or inflammation of the vas deferens, is a rare condition. When diagnosed pathologically, it has been linked to vasectomy, prostatectomy, and herniorrhaphy. When diagnosed clinically, relationships with potential causative factors are unclear. We investigated the clinical factors associated with clinically symptomatic vasitis in a retrospective series of patients. From the history, physical examination, and clinical course, we analyzed associated risk factors. Clinical care patterns were also examined to assess the effectiveness of different treatments. Among 11 patients, the mean patient age at presentation was 47 years (range 29-60 years). The mean diameter of the affected vas deferens was 0.97 cm. Associated procedures included ipsilateral herniorrhaphy (4 patients), radical prostatectomy (2 patients), perianal fistulectomy (1 patient), and bilateral testicular biopsy (1 patient). Furthermore, epididymitis was reported in one patient after testicular trauma, and another patient had congenital unilateral absence of the vas deferens. No patient had a history of vasectomy. Three patients were HIV positive and 6 were active smokers. Six of the 11 patients improved with medical management that included nonsteroidal and steroidal anti-inflammatories and antibiotics. One patient was lost to follow-up. Similar to studies of pathologically detected vasitis, this unique study of clinical vasitis suggests that prior herniorrhaphy, prostatectomy, and possibly HIV infection may be risk factors for its development. In addition, the use of anti-inflammatories and antibiotics warrants further investigation as potentially effective treatments. PMID- 20964560 TI - Transumbilical single port laparoscopic cholecystectomy with a simple technique: initial experience of 33 cases. AB - Transumbilical single port laparoscopic cholecystectomy is a novel laparoscopic surgical technique for cholecystectomy utilizing only a transumbilical incision, which eliminates any visible abdominal scars and improves cosmesis. As the true single port laparoscopic technique, we presented an easy and feasible method for transumbilical laparoscopic cholecystectomy. A total of 33 patients were presented for transumbilical single port laparoscopic cholecystectomy. A 1.5 cm incision was made at the umbilicus. We used one sterile glove and designed a simple method for this procedure. All the operations were completed successfully. The operative time of the first case was 189 min, the average time of the following two cases was 90 min, and the mean of the latest ten cases was 50 min. Operative blood loss was <30 ml for all patients. No drainage tube was placed and no postoperative complications such as bleeding or biliary leakage occurred after three to six months of follow-up. All the patients were discharged 24h after the operation. There were no visible scars on the abdominal wall at the second weekend. Transumbilical single port laparoscopic cholecystectomy by our designed methods was technically simple, feasible and safe. Furthermore, development of newer instruments, accumulation of experience and enhancement of operative technique may facilitate this new operative approach. PMID- 20964561 TI - Feasibility study on single-port access (SPA) laparoscopic cholecystectomy using transanal endoscopic microsurgery (TEM) instruments. AB - Transanal endoscopic microsurgery (TEM) is a procedure for the treatment of rectal villous adenoma and early rectal tumours. It is actually the first single port access surgery (SPA) as well as a true Natural Orifice Transluminal Endoscopic Surgery (NOTES) in standard use for the last twenty years. The use of this technique and instrumentation in cholecystectomy is revisited. A feasibility study was done on porcine model. Peri-umbilical approach with the articulated TEM instruments was used for cholecystectomy. An in vivo study was started after the successful feasibility study. Cholecystectomy was performed on three consecutive porcine models using TEM instruments. Median operation time was 26.6 min. The post-op mean wound length was 3.7 cm. One gallbladder was perforated during the operation and the others were delivered intact. The instrument length was noted and the difficulty in instrument handling was documented. SPA cholecystectomy is feasible with Transanal Endoscopic Microsurgery (TEM) instruments. The special TEM technique of manipulation within a confined space is ideal for single port surgery. The TEM rectoscope can be used as a reusable single port and the instruments can be used as well but modification is suggested. PMID- 20964562 TI - A combined biomarker pattern improves the discrimination of lung cancer. AB - A total of 227 sera were analysed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) to find novel serum biomarkers for lung cancer. The results showed that the 11.53, 11.70, 13.78, 13.90 and 14.07 k m/z peaks identified as native serum amyloid A (SAA), SAA with N-terminal Arg cleaved, native transthyretin (TTR) and its two variants significantly differentiated lung cancer sera from normal control sera (p <0.01). A 'biomarker pattern' combining SAA and TTR was tested to distinguish lung cancer patients from normal control individuals, and the diagnostic positive rate of lung cancer was improved to 91.6%. PMID- 20964563 TI - Interventions to promote upper limb recovery in stroke survivors with severe paresis: a systematic review. AB - PURPOSE: To investigate the effect of interventions that promote upper limb (UL) recovery in stroke survivors with severe paresis. METHODS: A systematic search of the scientific literature from January 1970 to March 2009 was conducted using CINAHL, Cochrane, PEDro, Pubmed and Web of Science. keywords used included stroke, severe, hemiplegia, UL, task-oriented, robot, non-robot and electrical stimulation. Methodological quality of the studies was assessed using the PEDro rating scale. Studies were grouped into one of three intervention categories: robotic therapy, electrical stimulation or 'other' therapy. RESULTS: Seventeen randomised controlled trials met the inclusion criteria. A 'best evidence synthesis' indicated strong evidence that robotic therapy provides a large beneficial effect and limited evidence that electrical stimulation and 'other' interventions provide a large beneficial effect on function. There is no evidence that these interventions influence use of the arm in everyday tasks. CONCLUSION: There are a number of newly developed interventions that enable stroke survivors with severe paresis to actively participate in task-oriented practice to promote UL recovery. While these interventions offer some promise for stroke survivors with severe paresis, ultimately, the effectiveness of these interventions will be dependent on whether they lead to restoration of function to the point at which the stroke survivor can practice everyday tasks. PMID- 20964564 TI - Moderate rhinophyma successfully treated with a Smoothbeam laser. PMID- 20964565 TI - Comparison of the efficacy of 5% topical spironolactone gel and placebo in the treatment of mild and moderate acne vulgaris: a randomized controlled trial. AB - BACKGROUND: Topical spironolactone may be effective for the treatment of acne patients with increased sebum secretion. OBJECTIVE: To evaluate the efficacy of 5% spironolactone gel in the treatment of mild to moderate acne vulgaris. METHODS: This study was a double-blind clinical trial, performed randomly in two demographically equivalent groups. In this study, 78 patients with mild to moderate acne vulgaris participated. The patients, as groups of cases (38 patients) and controls (40 patients), took 5% spironolactone gel and placebo, respectively. The response to treatment was evaluated by the total acne lesions (TLC) and acne severity index (ASI). RESULTS: The mean age of the case patients was 21.5 +/- 4.2 years and of the control patients was 22.2 +/- 4.06 years. The difference in TLC was statistically significant between the two groups (p = 0.007), but no statistically significant difference was seen between the two groups for ASI (p = 0.052). CONCLUSION: The 5% spironolactone topical gel resulted in a decrease in the TLC in acne vulgaris, while it had no significant efficacy in the ASI. PMID- 20964566 TI - Exogenous stimulations change nude mouse hair cycle pattern. AB - The pattern of murine hair growth has been seen as an unpredictable and irregular process. In this study, nude mice were used to investigate the hair growth pattern and find the impact of exogenous stimulations on changing the hair growth pattern. We found nude mouse hair appeared in waves from the head to the posterior part of the back for the first time. Amongst all of the six groups, male nude mice had a more regular hair cycle pattern than females: from the head to the posterior part of the back. When there was no hair on the back of a nude mouse, we named this time the 'no-hair phase' and the opposite was the 'hair existing phase'. Exogenous stimulations significantly elongated the hair-existing time and shortened the no-hair time but did not work on the hair growth pattern. For male mice, topical application of minoxidil created a shorter no-hair phase and a longer hair-existing phase than other treatment methods. For female nude mice, minoxidil had little more effect than a wound in shortening the no-hair phase. A wound was better than minoxidil in elongating the hair-existing phase in female nude mice, and this effect was indistinctive. PMID- 20964567 TI - Primary frontal hyperhidrosis successfully treated with low doses of botulinum toxin A as a useful alternative to surgical treatment. AB - Frontal hyperhidrosis appears to be a special and rare form of focal hyperhidrosis. These patients may suffer greatly from the condition so an efficient treatment is highly demanded. Surgical treatment may solve this problem permanently, but the possibility of serious complications and low satisfactory results makes it less advisable than in other types of hyperhidrosis where surgery has shown great benefits. We report a case of primary frontal hyperhidrosis in a young man who refused surgery and was treated with low doses of botulinum toxin type A injected into the forehead. The patient noted a high level of satisfaction, with the abolishment of sweating and a long effect that was maintained for up to 10 months without any complications. In conclusion, we consider that low doses of botulinum toxin A is a well tolerated, safe and very effective treatment for primary frontal hyperhidrosis and it should be offered as an alternative to patients who suffer from this disorder. PMID- 20964568 TI - Is topical nitric oxide and cryotherapy more effective than cryotherapy in the treatment of old world cutaneous leishmaniasis? AB - BACKGROUND: Current systemic treatments for cutaneous leishmaniasis are limited by their toxicity, high cost, side effects and the emergence of drug resistance. New approaches, including topical therapies, are urgently needed. Nitric oxide (NO) produced by human and canine macrophages has long been demonstrated to be involved in the intracellular killing of Leishmania. OBJECTIVE: This study was designed to determine the clinical responses (healing, or non-healing) and effectiveness of NO plus cryotherapy for the treatment of old world cutaneous leishmaniasis (CL). METHODS: A double-blind, randomized, placebo-controlled clinical trial was performed for the evaluation of therapy with topical nitric oxide 3% and cryotherapy in 63 Iranian patients with CL in the south of Iran. RESULTS: Thirty of 36 participants (83.3%) had complete improvement in the treatment group as did 20 of 27 (74.1%) from the control group (p = 0.627). Erythema, a burning sensation and irritation occurred in seven participants from the treatment group and one patient from the placebo group (p = 0.063). CONCLUSION: This study could not show any more effectiveness from combining a 12 week course of treatment with 3% nitric oxide cream and a once-weekly treatment with cryotherapy in comparison with cryotherapy and placebo in patients with CL. PMID- 20964569 TI - Disseminated superficial actinic porokeratosis: a treatment review. AB - Disseminated superficial actinic porokeratosis (DSAP) is a chronic disorder of keratinization characterized by numerous papules and plaques distributed over sun exposed sites. Treatments are poorly standardized and several investigational therapies have demonstrated limited success in treating DSAP. To our knowledge, there have been no systematic reviews of the literature regarding the treatment of this disease. Herein, we review recent studies pertaining to the treatment of DSAP and evaluate the level of evidence for each of these therapeutic modalities. PMID- 20964570 TI - Immunocryosurgery for patients with therapeutically challenging basal cell carcinomas: report of two representative cases. PMID- 20964571 TI - Laser treatment of amateur tattoos in Arabs in Kuwait: effectiveness and safety. AB - BACKGROUND: Laser treatment of amateur tattoos on Fitzpatrick type V skin produces a considerable risk of complications because of the increased incidence of adverse pigmentary changes. The principle of selective photothermolysis predicts that the Q-switched alexandrite laser should be effective in removing tattoo ink with minimal side effects in patients with skin phototype V. OBJECTIVE: To study the effectiveness of the Q-switched alexandrite (755 nm, 50 ns) laser in the treatment of amateur tattoos in Arabs in Kuwait. METHODS: One hundred patients, each with multiple tattoos, were treated until total clearance. Fluences used ranged from 5 to 7 J/cm(2) with a spot size of 3 mm. Clinical evaluation was performed at baseline and at each follow-up visit until dyspigmentation resolved. RESULTS: Total clearing was observed in all tattoos after an average of six sessions. Both tattoo clearing and post-laser hypopigmentation (29%) and hyperpigmentation (38%) increased with higher fluences. CONCLUSION: In this prospective study, our findings suggest that the Q switched alexandrite laser is an effective laser in removing amateur tattoos in patients with skin phototype V, but with a high incidence of pigmentary changes. PMID- 20964572 TI - Natural peroxisome proliferator-activated receptor-alpha agonist cream demonstrates similar therapeutic response to topical steroids in atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) requires permanent skin care. OBJECTIVE: A cream containing 2% SO (sunflower oleodistillate), with peroxisome proliferator activated receptor-alpha (PPAR-alpha) agonist properties, has been compared to a topical steroid (hydrocortisone butyro-propionate 1 mg/g). METHODS: An open, randomized study included two groups of 40 children (aged 3 months to 4 years). Group A applied the steroid and group B applied the 2% SO cream, twice a day. SCORAD (SCORing Atopic Dermatitis) was determined at D0, D7 and D21 and quality of life (QoL) at D0 and D21. RESULTS: SCORAD was similar at D0 (37.2 versus 36.9), D7 (18.9 versus 19.2) (-49% and -48%) and D21 (11 versus 9.4) (-70% and 75%) (p < 0.01 versus D0). The Infant Dermatitis Quality of Life and Dermatitis Family Impact Questionnaire improved similarly by 65%/67% in group A and 72%/75% in group B at D21 (p < 0.01 versus D0). CONCLUSION: A 2% SO cream has demonstrated therapeutic properties, using clinical scores and QoL, comparable to those of a topical steroid. PMID- 20964573 TI - Chronic urticaria and irregular menstrual cycle: a case report of effective therapy with oral contraception. AB - It has been reported that urticaria may be associated with some conditions characterized by sex hormone changes. The case presented concerns a 19-year-old patient who had severe symptoms of chronic urticaria for 3 years, concomitant with an irregular menstrual cycle and functional ovarian cysts. After a laparoscopic ovarian cystectomy the patient was treated with hormonal contraceptives. After 3 weeks the symptoms of urticaria withdrew. The patient continues to receive oral contraceptive treatment, has regular menstruation and shows no symptoms of urticaria. A diagnosis with an urticaria origin should take into consideration any changes in hormone balance as one of the possible reasons for the disease. In such cases, treatment with sex hormones may positively influence the course of the illness. PMID- 20964574 TI - Cutaneous complication after BCG vaccination: case report and review of the literature. AB - The bacille Calmette-Guerin (BCG) vaccination protects against tuberculosis (TB) related meningitis and disseminated tuberculosis. While severe complications after BCG vaccination are relatively rare, different cutaneous reactions have been reported. We report a patient with a 7-mm erythematous nodule at a distance of 4 cm from the BCG injection site. Histopathologically, a necrotizing granulomatous reaction pattern was seen in the dermis. Although complementary stainings did not detect acid fast bacilli, we suspected the lesion was caused by the attenuated strains of Mycobacterium bovis from the vaccine. This specific complication is called BCG-itis in the literature. After the excisional biopsy, the lesion disappeared and further treatment was not necessary. In defining the best treatment for this boy, we discovered a lack of knowledge on BCG-related lesions and their subsequent treatment options in the literature. We will list existing literature on this topic and demonstrate that treatment of BCG-related complications is poorly defined. PMID- 20964575 TI - Treatment of pediculosis capitis with topical albendazole. AB - Pediculosis capitis, or head lice infestation, caused by Pediculus humanus capitis, is a common and ubiquitous health concern. Increasing resistance and treatment failures are reported with available topical pediculicides and may prove challenging to manage. Recent data indicate that the oral anti-helmintic agents thiabendazole and albendazole could represent new therapeutic options against pediculosis capitis. We report a novel treatment modality in four patients with head lice who were successfully treated with a topical application of albendazole. PMID- 20964576 TI - Treatment of hidradenitis suppurativa: is oral isoniazid an option? PMID- 20964577 TI - Effect of substrate composition and alignment on corneal cell phenotype. AB - Corneal blindness is a significant problem treated primarily by corneal transplants. Donor tissue supply is low, creating a growing need for an alternative. A tissue-engineered cornea made from patient-derived cells and biopolymer scaffold materials would be widely accessible to all patients and would alleviate the need for donor sources. Previous work in this lab led to a method for electrospinning type I collagen scaffolds for culturing corneal fibroblasts ex vivo that mimics the microenvironment in the native cornea. This electrospun scaffold is composed of small-diameter, aligned collagen fibers. In this study, we investigate the effect of scaffold nanostructure and composition on the phenotype of corneal stromal cells. Rabbit-derived corneal fibroblasts were cultured on aligned and unaligned collagen type I fibers ranging from 50 to 300 nm in diameter and assessed for expression of alpha-smooth muscle actin, a protein marker upregulated in hazy corneas. In addition, the optical properties of the cell-matrix constructs were assessed using optical coherence microscopy. Cells grown on collagen scaffolds had reduced myofibroblast phenotype expression compared to cells grown on tissue culture plates. Cells grown on aligned collagen type I fibers downregulated alpha-smooth muscle actin protein expression significantly more than unaligned collagen scaffolds, and also exhibited reduced overall light scattering by the tissue construct. These results suggest that aligned collagen type I fibrous scaffolds are viable platforms for engineering corneal replacement tissue. PMID- 20964578 TI - Correlation between compositional and mechanical properties of human mesenchymal stem cell-collagen microspheres during chondrogenic differentiation. AB - Mesenchymal stem cell (MSC)-based engineering is promising for cartilage repair. However, the compositional mechanical relationship of the engineered structures has not been extensively studied, given the importance of such relationship in native cartilage tissues. In this study, a novel human MSC-collagen microsphere system was used to study the compositional mechanical relationship during in vitro chondrogenic differentiation using histological and biochemical methods and a microplate compression assay. The mechanical property was found positively correlating with newly deposited cartilage-relevant matrices, glycosaminoglycan, and type II collagen, and with the collagen crosslinker density, in agreement with the presence of thick collagen bundles upon structural characterization. On the other hand, the mechanical property negatively correlates with type I collagen and total collagen, suggesting that the initial collagen matrix scaffold of the microsphere system was being remodeled by the differentiating human MSCs. This study also demonstrated the application of a simple, sensitive, and nondestructive tool for monitoring the progression of chondrogenic differentiation of MSCs in tissue-engineered constructs and therefore contributes to future development of novel cartilage repair strategies. PMID- 20964579 TI - Human adipose-derived side population stem cells cultured on demineralized bone matrix for bone tissue engineering. AB - BACKGROUND: Tissue engineering of new bone relies on the combination and application of osteoconductive, osteoinductive, and osteogenic elements. Natural scaffolds, such as demineralized bone matrix (DBM), contain collagenous networks with growth factors such as bone morphogenetic protein-2. Stem cells from readily available sources, including discarded adipose tissue, have the propensity to differentiate into bone. The present study examines a multi-component technique consisting of a novel side population of adipose stem cells cultured on DBM for tissue engineering applications. METHODS: Adipose-derived side population stem cells were cultured on DBM for up to 14 days. Cell proliferation, alkaline phosphatase activity, extracellular matrix protein production, and calcium containing mineral deposit formation were assayed. Ectopic bone formation in a rat model was also evaluated. RESULTS: Side population stem cells attached to and proliferated on DBM while generating markers of new bone formation. When these cell/substrate composites were implanted into an ectopic model, newly formed bone was 30% greater than that of DBM alone. CONCLUSIONS: Novel populations of adipose derived stem cells cultured on DBM compose a system that develops new bone matrix in vitro and in vivo. This strategy provides a novel approach using naturally occurring materials for bone repair in tissue engineering applications. PMID- 20964580 TI - In vitro biomimetic construction of hydroxyapatite-porcine acellular dermal matrix composite scaffold for MC3T3-E1 preosteoblast culture. AB - The application of porous hydroxyapatite-collagen (HAp-Collagen) as a bone tissue engineering scaffold is hindered by two main problems: its high cost and low initial strength. As a native 3-dimenssional collagen framework, purified porcine acellular dermal matrix (PADM) has been successfully used as a skin tissue engineering scaffold. Here we report its application as a matrix for the preparation of HAp to produce a bone tissue scaffold through a biomimetic chemical process. The HAp-PADM scaffold has two-level pore structure, with large channels (~100 MUm in diameter) inherited from the purified PADM microstructure and small pores (<100 nm in diameter) formed by self-assembled HAp on the channel surfaces. The obtained HAp-PADM scaffold (S15D) has a compressive elastic modulus as high as 600 kPa. The presence of HAp in sample S15D reduces the degradation rate of PADM in collagenase solution at 37 degrees C. After 7 day culture of MC3T3-E1 pre-osteroblasts, MTT data show no statistically significant difference on pure PADM framework and HAp-PADM scaffold (p > 0.05). Because of its high strength and nontoxicity, its simple preparation method, and designable and tailorable properties, the HAp-PADM scaffold is expected to have great potential applications in medical treatment of bone defects. PMID- 20964582 TI - Myocardial infarction events and cardiovascular risk factor levels in Finnish- and Swedish-speaking populations of Finland. AB - BACKGROUND. The Swedish-speaking minority of Finland is unique, because it has a higher socioeconomic status (SES) and longer life expectancy than the Finnish speaking majority. We hypothesized that this minority may have a lower attack rate of coronary events and analysed whether this could be explained by their higher SES. METHODS. The population-based myocardial infarction (MI) registers recorded 4,845 MI events in Turku during 1988-1998. Individual-level indicators of SES were obtained from Statistics Finland. The population-based FINRISK surveys recorded cardiovascular risk factors and native languages of 10,432 people in 1987, 1997, and 2002. RESULTS. The age-standardized attack rate of MI was lower among the 35-64-year-old Swedish-speaking men than among Finnish speaking men (rate ratio 0.66; 95% confidence interval 0.47-0.85) and the difference remained significant after adjustment for SES. The Swedish-speaking inhabitants had higher age-, sex-, and SES-adjusted high-density lipoprotein cholesterol, and lower triglycerides, body mass index, and diastolic blood pressure. Conclusion. The Swedish-speaking inhabitants of Turku had lower MI morbidity and coronary mortality than the Finnish-speaking inhabitants. After controlling for SES, these differences remained significant among men, suggesting that other factors, such as differences in the risk factor profiles may also play a role. PMID- 20964581 TI - Delivery of plasmid DNA encoding bone morphogenetic protein-2 with a biodegradable branched polycationic polymer in a critical-size rat cranial defect model. AB - This study investigated the delivery of plasmid DNA (pDNA) encoding bone morphogenetic protein-2 in the form of polyplexes with a biodegradable branched triacrylate/amine polycationic polymer (TAPP) that were complexed with gelatin microparticles (GMPs) loaded within a porous tissue engineering scaffold. More specifically, the study investigated the interplay between TAPP degradation, gelatin degradation, pDNA release, and bone formation in a critical-size rat cranial defect model. The pDNA release kinetics in vitro were not affected by the crosslinking density of the GMPs but depended, rather, on the degradation rates of the TAPPs. Besides the initial release of polyplexes not bound to the GMPs and the minimal release of polyplexes through diffusion or dissociation from the GMPs, the pDNA was likely released as naked pDNA or as part of an incomplete polyplex, after the degradation of fragments of the polycationic polymer. After 30 days, significantly higher amounts of pDNA were released (93%-98%) from composite scaffolds containing naked pDNA or pDNA complexed with P-AEPZ (synthesized with 1-[2-aminoethyl]piperazine, a faster degrading TAPP) compared with those containing pDNA complexed with P-DED (synthesized with N,N dimethylethylenediamine, a slower degrading TAPP) (74%-82%). Composite scaffolds containing GMPs complexed with TAPP/pDNA polyplexes did not result in enhanced bone formation, as analyzed by microcomputed tomography and histology, in a critical-size rat cranial defect at 12 weeks postimplantation compared with those loaded with naked pDNA. The results demonstrate that polycationic polymers with a slow degradation rate can prolong the release of pDNA from the composite scaffolds and suggest that a gene delivery system comprising biodegradable polycationic polymers should be designed to release the pDNA in an intact polyplex form. PMID- 20964583 TI - Absolute value of visceral fat area measured on computed tomography scans and obesity-related cardiovascular risk factors in large-scale Japanese general population (the VACATION-J study). AB - BACKGROUND: The management of cardiovascular risk factors is important for prevention of atherosclerotic cardiovascular diseases (ACVD). Visceral fat accumulation plays an important role in the clustering of cardiovascular risk factors, leading to ACVD. The present study investigated the gender- and age specific relationship between obesity-related cardiovascular risk factor accumulation and computed tomography (CT)-measured fat distribution in a large scale Japanese general population. METHODS AND RESULTS: Fat distribution was measured on CT scans in 12,443 subjects (males/females = 10,080/2,363), who underwent medical health check-up at 9 centers in Japan. The investigated obesity related cardiovascular risk factors were hyperglycemia, dyslipidemia, and elevated blood pressure. Visceral fat area (VFA) for all males and old females showed almost symmetric distribution, while that of young females showed skewed distribution with a marked left shift. Only a small proportion of young females had large visceral fat and cardiovascular risk accumulation. The mean number of risk factors exceeded 1.0 at around 100 cm(2) for VFA in all groups, irrespective of gender, age (cut-off age 55), and BMI (cut-off BMI 25 kg/m(2)). CONCLUSIONS: In this large-scale Japan-wide general population study, an absolute VFA value of about 100 cm(2) equated with obesity-related cardiovascular risk factor accumulation, irrespective of gender, age, and BMI. PMID- 20964584 TI - Endocrine disorders: causes of hyponatremia not to neglect. AB - Hyponatremia is a common electrolyte abnormality with the potential for significant morbidity and mortality. Endocrine disorders, including adrenal deficiency and hypothyroidism, are uncommon causes of hyponatremia. Primary adrenal insufficiency (i.e. Addison's disease) may well be recognized by clear hall-marks of the disease, such as pigmentation, salt craving, hypotension, and concomitant hyperkalemia. Addison's disease is an important diagnosis not to be missed since the consequences can be grave. On the other hand, hypothyroidism and secondary adrenocortical insufficiency originating from diseases of the hypothalamus and/or pituitary (hypopituitarism) require a high index of suspicion, because the clinical signs can be quite subtle. This review focuses on clinical and pathophysiological aspects of hyponatremia due to endocrine disorders. PMID- 20964585 TI - Durability and factors associated with long term response after splenectomy for primary immune thrombocytopenia (ITP) and outcome of relapsed or refractory patients. AB - Splenectomy is the usual form of therapy for immune thrombocytopena (ITP) after steroid failure. We retrospectively studied the data in adult patients who underwent splenectomy for ITP from July 1996 to June 2008 to evaluate the long term responses, clinical and laboratory factors associated with long term responses and outcome of relapsed or refractory patients. Thirty eight patients, 30 (79%) females, with a median age of 23 years (range 15-69), underwent splenectomy. The procedure was laparoscopic in 28 (73.5%) and open in 10 patients. Splenectomy resulted in a response in 34/38 (89.5%) patients and failed in four (10.5%) patients. After a median follow-up of 58 months (range 7-144), 24 (63%) patients had a maintained response without treatment (platelet count of >50 * 109)/l). Most of the relapses occurred during the first year but two patients had late relapses. There were procedure-related complications in seven (18.0%) patients but no cases of overwhelming sepsis. Only four relapsed or refractory patients had a platelet count below 50 * 109/l at the last follow-up indicating response to alternative therapies. Responsiveness to steroids before the procedure (p = 0.025) along with a platelet count of >= 150 * 109/l at 4 weeks (p = < 0.0001) and a highest platelet count of >= 400 * 109/l at any time post splenectomy (p = 0.005), were associated with a long term response in univariate analysis. In conclusion, splenectomy remains an effective treatment for ITP after steroid failure in terms of long term responses, and the majority of relapsed or refractory patients respond to alternative therapies. PMID- 20964586 TI - Facial affect recognition in anorexia nervosa: is obsessionality a missing piece of the puzzle? AB - OBJECTIVE: Socio-emotional difficulties are thought to be important maintaining factors of eating disorders. Several studies point to deficits in facial affect recognition in anorexia nervosa (AN). However, the majority of these studies fail to control for comorbidity and its effect on emotional processing. This study aims to explore how patients with AN recognize happiness and sadness in human faces, controlling for different comorbidities, namely anxiety, depression, and obsessive-compulsive symptoms. METHODS: Thirty patients with AN, and 40 healthy participants completed a facial emotion recognition task. This task measured discrimination accuracy, response bias and response time towards sad and happy faces presented at different durations (500 ms, 2000 ms). The associations between facial affect recognition and clinical symptoms and intelligence quotient were explored. RESULTS: Regression analysis showed that discrimination accuracy of sad faces presented for 500 ms was significantly associated with AN diagnosis, body mass index, and Obsessive-compulsive symptoms. However, the level of Obsessive-compulsive symptoms was the strongest predictor of a poor discrimination of briefly presented sad faces. CONCLUSIONS: Our results support previous studies that report emotional processing deficits in AN with obsessionality playing a pivotal role in this deficit. PMID- 20964587 TI - Erythrocyte membrane AChE, Na(+), K(+)-ATPase and Mg(2+) ATPase activities in mothers and their premature neonates in relation to the mode of delivery. AB - AIM: To investigate erythrocyte membrane AChE, Na(+), K(+)-ATPase and Mg(2+) ATPase activities in mothers and their full-term or premature newborns in relation to the mode of delivery. METHODS: Blood was obtained from mothers pre- and post-delivery and the umbilical cord (CB) of their full-term newborns: Group A1 (n = 16) born with vaginal delivery (VD), Group B1 (n = 14) full-terms with scheduled cesarean section (CS), Group A2 (n = 12) prematures with VD, Group B2 (n = 14) prematures with CS. Total Antioxidant Status (TAS) and common laboratory tests were measured with routine methods, and the membrane enzyme activities spectrophotometrically. RESULTS: TAS was reduced in mothers post VD and in the CB whereas remained unaltered in CS mothers and their newborns. AChE and Na(+), K(+) ATPase were increased in mothers post VD. AChE was lower in the CB of prematures than that of full-terms independently of the mode of delivery. Na(+), K(+)-ATPase activity was increased in the groups of mothers post VD and decreased in prematures. The enzyme was higher in prematures with CS than that with VD. Mg(2+) ATPase activity was unchanged. CONCLUSION: The increased maternal AChE and Na(+), K(+)-ATPase activities may be due to the low TAS determined post VD, whereas their decreased activities in prematures to their immaturity. PMID- 20964588 TI - Development of cytarabine prodrugs and delivery systems for leukemia treatment. AB - IMPORTANCE OF THE FIELD: Cytarabine is a polar nucleoside drug used for the treatment of myeloid leukemia and non-Hodgkin's lymphoma. The drug has a short plasma half-life, low stability and limited bioavailability. Overdosing of patients with continuous infusions may lead to side effects. Thus, various prodrug strategies and delivery systems have been explored extensively to enhance the half-life, stability and delivery of cytarabine. Among the recent cytarabine prodrugs, amino acid conjugate ValCytarabine and fatty acid derivative CP-4055 (in Phase III trials) have been investigated for the treatment of leukemia and solid tumors, respectively. Alternatively, delivery systems of cytarabine have emerged for the treatment of different cancers. The liposomal-cytarabine formulation (DepoCyt(r), Pacira Pharmaceuticals Inc., New Jersey, USA) has been approved for the treatment of lymphomatous meningitis. AREAS COVERED IN THIS REVIEW: Various prodrug strategies evaluated for cytarabine are discussed. Then, the review summarizes the drug delivery systems that have been used for more effective cancer therapy. WHAT THE READER WILL GAIN: This review provides in depth discussion of the prodrug strategy and delivery systems of cytarabine derivatives for the treatment of cancer. The design of cytarabine prodrugs and delivery systems provides insights for designing the next generation of more effective anticancer agents with enhanced delivery and stability. TAKE HOME MESSAGE: Strategies on designing cytarabine prodrug and delivery formulations showed great promise in developing effective anticancer agents with better therapeutic profile. Similar studies with other anticancer nucleosides can be an alternative approach to gaining access to more effective anticancer agents. PMID- 20964589 TI - The Nick Norgan Award 2010. PMID- 20964590 TI - Maturational constraints on the recruitment of early processes for syntactic processing. AB - An enduring question in the study of second-language acquisition concerns the relative contributions of age of acquisition (AOA) and ultimate linguistic proficiency to neural organization for second-language processing. Several ERP and neuroimaging studies of second-language learners have found that neural organization for syntactic processing is sensitive to delays in second-language acquisition. However, such delays in second-language acquisition are typically associated with lower language proficiency, rendering it difficult to assess whether differences in AOA or proficiency lead to these effects. Here we examined the effects of delayed second-language acquisition while controlling for proficiency differences by examining participants who differ in AOA but who were matched for proficiency in the same language. We compared the ERP response to auditory English phrase structure violations in a group of late learners of English matched for grammatical proficiency with a group of English native speakers. In the native speaker group, violations elicited a bilateral and prolonged anterior negativity, with onset at 100 msec, followed by a posterior positivity (P600). In contrast, in the nonnative speaker group, violations did not elicit the early anterior negativity, but did elicit a P600 which was more widespread spatially and temporally than that of the native speaker group. These results suggest that neural organization for syntactic processing is sensitive to delays in language acquisition independently of proficiency level. More specifically, they suggest that both early and later syntactic processes are sensitive to maturational constraints. These results also suggest that late learners who reach a high level of second-language proficiency rely on different neural mechanisms than native speakers of that language. PMID- 20964591 TI - White matter microstructure in superior longitudinal fasciculus associated with spatial working memory performance in children. AB - During childhood and adolescence, ongoing white matter maturation in the fronto parietal cortices and connecting fiber tracts is measurable with diffusion weighted imaging. Important questions remain, however, about the links between these changes and developing cognitive functions. Spatial working memory (SWM) performance improves significantly throughout the childhood years, and several lines of evidence implicate the left fronto-parietal cortices and connecting fiber tracts in SWM processing. Here we report results from a study of 76 typically developing children, 7 to 13 years of age. We hypothesized that better SWM performance would be associated with increased fractional anisotropy (FA) in a left fronto-parietal network composed of the superior longitudinal fasciculus (SLF), the regional white matter underlying the dorsolateral pFC, and the posterior parietal cortex. As hypothesized, we observed a significant association between higher FA in the left fronto-parietal network and better SWM skills, and the effect was independent of age. This association was mainly accounted for by variability in left SLF FA and remained significant when FA measures from global fiber tracts or right SLF were included in the model. Further, the effect of FA in left SLF appeared to be mediated primarily by decreasing perpendicular diffusivity. Such associations could be related to individual differences among children in the architecture of fronto-parietal connections and/or to differences in the pace of fiber tract development. Further studies are needed to determine the contributions of intrinsic and experiential factors to the development of functionally significant individual differences in fiber tract structure. PMID- 20964592 TI - Network alterations supporting word retrieval in patients with medial temporal lobe epilepsy. AB - Although the hippocampus is not considered a key structure in semantic memory, patients with medial-temporal lobe epilepsy (mTLE) have deficits in semantic access on some word retrieval tasks. We hypothesized that these deficits reflect the negative impact of focal epilepsy on remote cerebral structures. Thus, we expected that the networks that support word retrieval tasks would be altered in left mTLE patients. We measured brain activity with fMRI while participants (13 controls, 13 left mTLE, and 13 right mTLE) performed a verb generation task. We examined functional connectivity during this task in relation to language performance on an off-line clinical test of lexical access (Boston Naming Test, BNT). Using task-seed-behavior partial least squares, we identified a canonical language network that was more active during verb generation than the baseline condition, but this network did not correlate with variability in BNT performance in either controls or patients. Instead, additional networks were identified for each group, with more anterior temporal and prefrontal regions recruited for controls and more posterior temporal regions for both left and right mTLE patients. Our findings go beyond the literature emphasizing differences in laterality of language processes in mTLE patients and, critically, highlight how network changes can be used to account for performance variation among patients on clinically relevant measures. This strategy of correlating network changes and off-line behavior may provide a powerful tool for predicting a postoperative decline in language performance. PMID- 20964593 TI - Intrameatal thrombosed anterior inferior cerebellar artery aneurysm mimicking a vestibular schwannoma. AB - Aneurysms of the anterior inferior cerebellar artery (AICA) are a rare entity. Purely intrameatal aneurysms are even rarer. The authors report an intrameatal thrombosed AICA aneurysm mimicking a vestibular schwannoma that was treated by resection and end-to-end anastomosis. This 22-year-old man presented with acute hearing loss, vertigo, and moderate facial palsy. Magnetic resonance imaging showed an atypical intrameatal lesion with dilation of the internal auditory canal. Microsurgical inspection via a retrosigmoid approach and drilling of the posterior wall of the internal auditory canal revealed a thrombosed AICA aneurysm. The aneurysm was excised, and an end-to-end suture was performed to restore AICA continuity. Intraoperative indocyanine green videoangiography as well as postoperative digital substraction angiography showed a good revascularization. Intrameatal AICA aneurysms may present with symptoms similar to vestibular schwannomas. End-to-end reanastomosis after aneurysm resection is a treatment option when clipping is impossible. PMID- 20964594 TI - Intraoperative magnetic resonance imaging-guided tractography with integrated monopolar subcortical functional mapping for resection of brain tumors. Clinical article. AB - OBJECT: The object of this study was to describe the utility and safety of using a single probe for combined intraoperative navigation and subcortical mapping in an intraoperative MR (iMR) imaging environment during brain tumor resection. METHODS: The authors retrospectively reviewed those patients who underwent resection in the iMR imaging environment, as well as functional electrophysiological monitoring with continuous motor evoked potential (MEP) and direct subcortical mapping combined with diffusion tensor imaging tractography. RESULTS As a navigational tool the monopolar probe used was safe and accurate. Positive subcortical fiber MEPs were obtained in 10 (83%) of the 12 cases. In 10 patients in whom subcortical MEPs were recorded, the mean stimulus intensity was 10.4 +/- 5.2 mA and the mean distance from the probe tip to the corticospinal tract (CST) was 7.4 +/- 4.5 mm. There was a trend toward worsening neurological deficits if the distance to the CST was short, and a small minimum stimulation threshold was recorded indicating close proximity of the CST to the resection margins. Gross-total resection (95%-100% tumor removal) was achieved in 11 cases (92%), whereas 1 patient (8%) had at least a 90% tumor resection. At the end of 3 months, 2 patients (17%) had persistent neurological deficits. CONCLUSIONS: The monopolar probe can be safely implemented in an iMR imaging environment both for navigation and stimulation purposes during the resection of intrinsic brain tumors. In this study there was a trend toward worsening neurological deficits if the distance from the probe to the CST was short (< 5 mm) indicating close proximity of the resection cavity to the CST. This technology can be used in the iMR imaging environment as a surgical adjunct to minimize adverse neurological outcomes. PMID- 20964595 TI - Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. Clinical article. AB - OBJECT: The authors assessed the safety and maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of bevacizumab after osmotic disruption of the blood-brain barrier (BBB) with mannitol in patients with recurrent malignant glioma. METHODS: A total of 30 patients with recurrent malignant glioma were included in the current study. RESULTS: The authors report no dose-limiting toxicity from a single dose of SIACI of bevacizumab up to 15 mg/kg after osmotic BBB disruption with mannitol. Two groups of patients were studied; those without prior bevacizumab exposure (naive patients; Group I) and those who had received previous intravenous bevacizumab (exposed patients; Group II). Radiographic changes demonstrated on MR imaging were assessed at 1 month postprocedure. In Group I patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 34.7%, a median reduction in the volume of tumor enhancement of 46.9%, a median MR perfusion (MRP) reduction of 32.14%, and a T2-weighted/FLAIR signal decrease in 9 (47.4%) of 19 patients. In Group II patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 15.2%, a median volume reduction of 8.3%, a median MRP reduction of 25.5%, and a T2-weighted FLAIR decrease in 0 (0%) of 11 patients. CONCLUSIONS: The authors conclude that SIACI of mannitol followed by bevacizumab (up to 15 mg/kg) for recurrent malignant glioma is safe and well tolerated. Magnetic resonance imaging shows that SIACI treatment with bevacizumab can lead to reduction in tumor area, volume, perfusion, and T2-weighted/FLAIR signal. PMID- 20964596 TI - Reconstructive endovascular treatment of intracranial aneurysms with the Willis covered stent: medium-term clinical and angiographic follow-up. AB - OBJECT: Placement of covered stents has emerged as a promising therapeutic option for cerebrovascular diseases. However, the medium- and long-term efficacy and safety of covered stents in the treatment of these diseases remain unclear. The purpose of this study was to evaluate the medium-term clinical and angiographic outcomes of covered stent placement for the treatment of intracranial aneurysms. METHODS: The authors' institutional review board approved the study. Thirty-four patients (13 females and 21 males; mean age 41.9 years) with 38 intracranial aneurysms were treated with the Willis covered stent. Clinical and angiographic follow-up were performed at 3 months, at 6-12 months, and annually thereafter. The initial procedural and follow-up outcomes were collected and analyzed retrospectively. RESULTS: Forty-two covered stents were successfully implanted into the target artery in 33 patients with 37 aneurysms, and 1 covered stent navigation failed in 1 patient. A complete aneurysm exclusion was initially achieved in 24 patients with 28 aneurysms, and a minor endoleak occurred in 9 patients with 9 aneurysms. Postoperatively, 2 patients died of complications related to the procedure. Angiographic and clinical follow-up data are available in 30 patients. The angiographic follow-up (17.5 +/- 9.4 months [mean +/- SD]) exhibited complete occlusion in 28 patients with 31 aneurysms, and incomplete occlusion in 2 aneurysms, with an asymptomatic in-stent stenosis in 3 patients (10%). The clinical follow-up (26.7 +/- 13 months [mean +/- SD]) demonstrated that 16 patients (53.3%) experienced a full recovery, and 14 patients (46.7%) improved. No aneurysm rupture, thromboembolic events, or neurological deficits resulting from closure of a perforating vessel by covered stent placement occurred. CONCLUSIONS: Endovascular reconstruction with the Willis covered stent represents a safe, durable, and curative treatment option for selected intracranial aneurysms, yielding an excellent medium-term patency of the parent artery and excellent clinical outcomes. PMID- 20964597 TI - Receptor-mediated gene delivery by folate-poly(ethylene glycol)-grafted-trimethyl chitosan in vitro. AB - Folate-poly(ethylene glycol)-grafted-trimethyl chitosan (F-PEG-g-TMC) and methoxypolyethylene glycol-grafted-trimethyl chitosan (mPEG-g-TMC)/pDNA complexes were prepared and characterized concerning physicochemical properties including cytotoxicity, condensation efficiency, particle size, and zeta potential. Furthermore, cellular uptake and transfection efficiency of the complexes were evaluated in vitro and compared with that of folate-trimethyl chitosan (folate TMC) synthesized by our group to elucidate the effect of PEGylation. The cellular uptake of the F-PEG-g-TMC/pDNA with a copolymer nitrogen-to-DNA phosphate ratio (N/P ratio) of 20 in KB cells was specifically increased up to 1.68-fold compared with that of the mPEG-g-TMC/pDNA (N/P ratio 20) resulting in 1.5-fold and 1.4 fold increased transfection efficiency in KB cells and SKOV3 cells (folate receptor-overexpressing cell lines), respectively. The intracellular uptake and transfection efficiency of the F-PEG-g-TMC/pDNA were significantly enhanced relative to the folate-TMC/pDNA in folate receptor-overexpressing cells due to stabilizing effect of PEGylation. Subcellular localization of the complexes in the process of intracellular transportation was observed by confocal laser scanning microscopy suggesting quicker association of the F-PEG-g-TMC/pDNA. In conclusion, the F-PEG-g-TMC/pDNA complexes are potential vehicles for improving the transfection efficiency and specificity of gene. PMID- 20964598 TI - Regulation of human mesenchymal stem cell functions by an autocrine loop involving NAD+ release and P2Y11-mediated signaling. AB - In several cell types, a regulated efflux of NAD(+) across Connexin 43 hemichannels (Cx43 HC) can occur, and extracellular NAD(+) (NAD(+)(e)) affects cell-specific functions. We studied the capability of bone marrow-derived human mesenchymal stem cells (MSC) to release intracellular NAD(+) through Cx43 HC. NAD(+) efflux, quantified by a sensitive enzymatic cycling assay, was significantly upregulated by low extracellular Ca(2+) (5-6-fold), by shear stress (13-fold), and by inflammatory conditions (3.1- and 2.5-fold in cells incubated with lipopolysaccharide (LPS) or at 39 degrees C, respectively), as compared with untreated cells, whereas it was downregulated in Cx43-siRNA-transfected MSC (by 53%) and by cell-to-cell contact (by 45%). Further, we show that NAD(+)(e) activates the purinergic receptor P2Y(11) and a cyclic adenosin monophosphate (cAMP)/cyclic ADP-ribose/[Ca(2+)](i) signaling cascade, involving the opening, unique to MSC, of L-type Ca(2+) channels. Extracellular NAD(+) enhanced nuclear translocation of cAMP/Ca(2+)-dependent transcription factors. Moreover, NAD(+), either extracellularly added or autocrinally released, resulted in stimulation of MSC functions, including proliferation, migration, release of prostaglandin E(2) and cytokines, and downregulation of T lymphocyte proliferation compared with controls. No detectable modifications of MSC markers and of adipocyte or osteocyte differentiation were induced by NAD(+)(e). Controls included Cx43-siRNA transfected and/or NAD(+)-glycohydrolase-treated MSC (autocrine effects), and NAD(+)-untreated or P2Y(11)-siRNA-transfected MSC (exogenous NAD(+)). These findings suggest a potential beneficial role of NAD(+)(e) in modulating MSC functions relevant to MSC-based cell therapies. PMID- 20964599 TI - Great expectations: using massively parallel sequencing to solve inherited disorders. PMID- 20964600 TI - Genetic testing for autism: recent advances and clinical implications. PMID- 20964601 TI - AntibioDx. PMID- 20964603 TI - Inaugural Genomics Automation Congress and the coming deluge of sequencing data. AB - Presentations at Select Biosciences's first 'Genomics Automation Congress' (Boston, MA, USA) in 2010 focused on next-generation sequencing and the platforms and methodology around them. The meeting provided an overview of sequencing technologies, both new and emerging. Speakers shared their recent work on applying sequencing to profile cells for various levels of biomolecular complexity, including DNA sequences, DNA copy, DNA methylation, mRNA and microRNA. With sequencing time and costs continuing to drop dramatically, a virtual explosion of very large sequencing datasets is at hand, which will probably present challenges and opportunities for high-level data analysis and interpretation, as well as for information technology infrastructure. PMID- 20964604 TI - Applications of nucleic acids technologies in molecular diagnostics; multiplex assays in real time format. AB - The conference Applications of Nucleic Acids Technologies in Molecular Diagnostics (part of TIDES) consisted of four sessions: Regulatory Pathways and Quality Strategies, Manufacturing and Business Considerations for Successful Launch in the Clinical Market, Analytical Methods and Validation, and New Technologies. The conference brought together approximately 100 representatives from academia, clinical laboratories and industry and comprised 26 presentations. This article only focuses on new developments discussed in the session regarding New Technologies, with special emphasis on presentations highlighting real-time amplification and detection. PMID- 20964605 TI - Genes associated with multiple sclerosis: 15 and counting. AB - Evaluation of: The International Multiple Sclerosis Genetics Consortium (IMSGC). IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci. Genes Immun. 11(5), 397-405 (2010). Multiple sclerosis (MS) develops in genetically susceptible populations as a result of environmental exposures, and discovering these genetic and/or environmental factors will provide fundamental new insights into the pathogenesis, diagnosis and treatment of this disabling disease. With the introduction of genome-wide association studies, the number of genes found to be associated with MS has increased rapidly. In all of these genes, in a study by the International Multiple Sclerosis Genetics Consortium, the classic MS risk locus, HLA-DRB1, stood out with remarkably strong statistical significance, but they also identified 12 other loci and/or genes associated with MS. However, all of these alleles have a very modest odds ratio and they explain approximately 3% of the variance in MS risk. Recently, the International Multiple Sclerosis Genetics Consortium provided evidence for three new loci that show significant association at a genome-wide level: RGS1, IL12A and MPHOSPH9/CDK2AP1. In this article, we will review the three newly discovered susceptibility loci and the implications of genome-wide association studies in MS on clinical practice. PMID- 20964606 TI - Immunoassays using polypeptide conjugate binders with tuned affinity. AB - Evaluation of: Albrecht C, Fechner P, Honcharenko D et al. A new assay design for clinical diagnostics based on alternative recognition elements. Biosens. Bioelectron. 25(10), 2302-2308 (2010). This article focuses on a novel concept regarding the use of polypeptide conjugates as high-affinity binders to recognize targets in immunoassays. The polypeptide conjugate binder is a hybrid molecule in which a small recognition ligand is covalently linked to a synthetic polypeptide, which binds to a protein target of interest with high affinity and selectivity. Affinity of the polypeptide conjugate to its target can be tuned by changing the length of the aliphatic spacer in between the small recognition ligand and the polypeptide. Other pros and cons of this new approach for protein recognition and sensing are compared with other immunoassays such as ELISA, the bio-barcode assay and the aptamer-based barcode assay. It is anticipated that there will be more innovation and integration using new materials and technologies to provide novel ways to detect disease markers. PMID- 20964607 TI - New trends in bioanalytical microdevices to assess platelet function. AB - Cardiovascular disease is the major cause of mortality globally. The role of platelets and antiplatelet drugs in the treatment of cardiovascular disease is widely appreciated. Platelets have a less well-known role in cancer and inflammation and as the role of platelets in cancer and inflammation is increasingly understood, there is a compelling need to develop diagnostic assays of platelet function to guide clinical management. Most current platelet-function tests are focused on platelet aggregation, are cumbersome, require dedicated laboratory personnel, measure a single response to a single agonist and artificially separate platelets from blood, thus, these assays do not reflect the pathophysiolgical environment of complex disease states. New technology platforms are emerging that address the physiological adhesive function of platelets to vascular-specific matrices using small volumes of whole blood, giving rapid results. These technologies will guide therapy in the prevention of cardiovascular disease and probably in risk management in both cancer and atherosclerosis. PMID- 20964608 TI - Is there a niche for DNA microarrays in molecular diagnostics? AB - DNA microarrays, 15 years after their appearance, have achieved presence in a number of medical settings. Several tests have been introduced and have obtained regulatory approval, mostly in the fields of bacterial identification, mutation detection and the global assessment of genome alterations, a particularly successful case being the whole-genome assay of copy-number variations. Gene expression applications have been less successful because of technical issues (e.g., reproducibility, platform-to-platform consistency and statistical issues in data analysis) and difficulties in demonstrating the clinical utility of expression signatures. In their different applications, DNA arrays have faced competition from PCR-based assays for low and intermediate multiplicity. Now they have a new competitor, new-generation sequencing, that can provide a wealth of direct sequence information, or digital gene-expression data, at a constantly decreasing cost. In this article we evaluate the strengths and weaknesses of the DNA microarray approach to diagnostics, and highlight the fields in which it is most likely to achieve a durable presence. PMID- 20964609 TI - Neoplasms of the hepatobiliary system: clinical presentation, molecular pathways and diagnostics. AB - Neoplasms of the hepatobiliary system include primary tumors, such as hepatocellular carcinoma and cholangiocarcinoma, and secondary lesions from the metastatic spread of a cancer of nonhepatobiliary origin. Surgical excision remains the mainstay of long-term survival for primary tumors whereas secondary lesions can be treated by multiple modalities, including resection, radiotherapy and radiofrequency ablation. However, diagnosis of hepatobiliary neoplasms often occurs late in the disease process. In this article we will focus on the diagnostic approaches and new molecular diagnostics of primary hepatobiliary cancers and we will discuss how these new developments may impact the detection and management of these recalcitrant cancers. PMID- 20964610 TI - Immune-related biomarkers for diagnosis/prognosis and therapy monitoring of cutaneous melanoma. AB - Skin melanoma, a life-threatening disease, has a recently reported worldwide increase in incidence, despite primary prevention. Skin melanoma statistics emphasize the need for finding markers related to the immune response of the host. The mechanisms that are able to over-power the local immune surveillance comprise molecules that can be valuable markers for diagnosis and prognosis. This article summarizes the immune markers that can monitor the disease stage and evaluate the efficacy of therapeutic interventions. Recent data regarding immunotherapy are presented in the context of tumor escape from immune surveillance and the immune molecules that are both targets and a means of monitoring. Perspectives for developing immune interventions for skin melanoma management and the position of tissue or soluble immune markers as a diagnostic/prognostic panel are evaluated. State-of-the-art technology is emphasized for developing immune molecular signatures for a complex characterization of the patient's immunological status. PMID- 20964611 TI - Molecular methods in the diagnosis and management of chronic hepatitis B. AB - Chronic hepatitis B (CHB) infection remains a major global problem but the recent advances in molecular methods have revolutionized the diagnosis and management of CHB. Hepatitis B virus (HBV) DNA quantitation is the most useful molecular marker for the diagnosis and management of CHB. There is increasing evidence that the clinical outcome and efficacy of antiviral therapy for CHB could vary with the infecting HBV genotype, core promoter and precore mutations. Early identification of drug resistance is imperative in the management of CHB. The molecular methods for HBV DNA quantitation, HBV genotyping, the identification of mutants, genotypic and phenotypic methods for monitoring drug resistance and their utility and limitations for use in the diagnosis and monitoring of CHB are discussed in this article. PMID- 20964612 TI - Xpert((r)) MTB/RIF for point-of-care diagnosis of TB in high-HIV burden, resource limited countries: hype or hope? AB - Despite the identification of Mycobacterium tuberculosis as the cause of tuberculosis (TB) more than a century ago, diagnosing TB in resource-poor countries remains a challenge, especially in people living with HIV. In the past decade, important research investments have been made towards the development of new diagnostics for TB and the Xpert((r)) MTB/RIF assay (Cepheid, CA, USA) has emerged as one of the most promising. In this article, we review the current knowledge on Xpert MTB/RIF, discuss the potential value of Xpert MTB/RIF as a point-of-care diagnostic for drug-sensitive and drug-resistant TB, and outline the potential indications for the assay in resource-limited, high-HIV burden settings. We also discuss key research questions that need to be addressed prior to possible large-scale implementation of the assay. PMID- 20964613 TI - Characteristics of the level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1. AB - In cancer, the serine protease urokinase-type plasminogen activator, its inhibitor (plasminogen activator inhibitor type-1) and the receptor (CD87), among other proteolytic factors, are involved in tumor cell dissemination and turnover of the extracellular matrix. Unsurprisingly, a battery of very uniform data, amassed since the end of the 1990s, has put these members of the plasminogen activation system into the forefront of prognostic/predictive cancer biomarkers relevant to predict the clinical course of cancer patients and their response to cancer therapy. The present review focuses on the molecular characteristics of the disease forecast biomarkers urokinase-type plasminogen activator and plasminogen activator inhibitor type-1, and techniques to quantitatively assess these cancer biomarkers, in the context of potential clinical application and personalized disease management. PMID- 20964615 TI - Favorable maternal and fetal effects of danshensu in an experimental mice model of preeclampsia. AB - BACKGROUND: Preeclampsia is a serious pregnancy-specific complication that results in high maternal and neonatal mortality and morbidity worldwide. Till date, there is no satisfactory pharmacotherapeutic treatment, except for aspirin and heparin, to stop the preeclampsia progression. Although the mechanism of preeclampsia is poorly understood, it has proved to be associated with coagulation activation. Researches on prophylactic and remedial application of anticoagulants maybe benefit the clinical aspects of preeclampsia individuals. METHODS: Sixty-six preeclampsia-like pregnant mice, induced by phosphatidyleserine/phosphatidylcholine (PS/PC) microvesicle administration, were randomly divided into six groups as follows: control group (group C), preeclampsia model group (group PE), group treated with heparin (group H), group treated with aspirin (group A), group treated with low-dose danshensu (group LD), and group treated with high-dose danshensu (group HD). Systolic blood pressure (SBP), proteinuria, mean platelet counts, plasma antithrombin III activity (AT III), D-dimmer levels, thrombin time (TT), fibrin deposition with phosphotungstic acid hematoxylin (PTAH) staining, and thrombomodulin (TM) expression with immunohistochemistry staining in placentas were examined as indices for maternal syndrome. Meanwhile, the number of potentially viable fetuses, weight of fetuses and placentas, weight of fetal brains, nose-breech length, ponderal index (PI), and neurons with hematoxylin-eosin (H/E) and toluidine blue-eosin (Nissl's) staining were all evaluated as indices for fetal syndrome. RESULTS: Heparin presents significant effects on maternal syndrome of preeclampsia such as hypertension and proteinuria, and different dose danshensu also presents the certain effects. High-dose danshensu and aspirin all process better effects than low-dose danshensu on decreasing blood pressure to normal level, whereas high dose danshensu process better effects than aspirin and low-dose danshensu on decreasing proteinuria to normal level. As to danshensu's effects on hemostatic function, high- and low-dose danshensu's marked effects on increasing the plasma AT III activity are same as that of aspirin and inferior to heparin. High-dose danshensu's better effect on elevating the platelet counts is superior to low dose danshensu and aspirin. Low-dose danshensu's obvious effect on decreasing D dimmer levels is close to heparin and superior to high-dose danshensu and aspirin. High- and low-dose danshensu's significant effects on reduced TT level are same to that of heparin. Different anticoagulants all have the improvement roles on placental fibrin depositions, but heparin and high-dose danshensu's roles on lowering thrombomodulin expression in placentas are superior to low-dose danshensu and aspirin. But anticoagulant function of high-dose danshensu is still inferior to heparin. Furthermore, we found the following changes: increasing fetal body weight and length in every group, obvious overall improvement in group H, greater amelioration equaling to that in heparin group on maternal body weight, fetal nose-breech length and fetal brain weight in group HD, better changes on survival fetal number in group LD than in other groups, and more corrected brain development in group HD than in group A. We found long-term use of heparin and aspirin, in spite of low-dose administration, can raise the risk of bleeding such as placental abruption and intestinal hemorrhage. But no side effect was observed in mice treated with different dose of danshensu in our study. CONCLUSIONS: Danshensu has proven effective in ameliorating the prognosis of maternal syndrome and fetal syndrome in the PE mouse model. We suggest long term provision of low-dose danshensu in pregnancy, leading to an improvement of preeclampsia syndrome with considerable maternal safety. PMID- 20964616 TI - Can a low-resource-use blood pressure device impact on global maternal mortality? AB - BACKGROUND: Hypertension in pregnancy in the developing world is largely underreported, misdiagnosed, and untreated, especially in rural settings, though it contributes significantly to maternal and perinatal morbidity and mortality. To reduce general global cardiovascular and cerebrovascular morbidity and mortality, the World Health Organization aims to develop and validate low resource-use blood pressure devices for use in developing nations. OBJECTIVE AND METHODS: To describe how existing antenatal care systems provide a useful and relevant model through which to evaluate the potential for this initiative to be applied in low-resource settings and to offer opportunities for much needed further research. PMID- 20964617 TI - Treatment with chlorhexidine modifies the healing of colon anastomosis in rats. AB - PURPOSE: To investigate the effects of chlorhexidine on the healing of colon anastomosis in the presence of peritonitis. METHODS: Peritonitis was induced in male Wistar rats by cecal ligation and puncture (CLP). The abdominal cavities of experimental animals were irrigated with warm solutions containing 0.9% saline (SAL group; n = 8) or 0.05% chlorhexidine (CHD group; n = 8), following which colon anastomosis was performed. Rats of the control group (n = 8) were submitted to colon anastomosis but not to CLP. Animals were euthanized seven days after surgery, and healing was assessed by histopathological examination and by measuring anastomotic burst pressure. RESULTS: Post-operative survival rates were 100, 87.5 and 75% for the control, SAL, and CHD groups, respectively. The degree of inflammation was significantly lower (rho = 0.01) in the CHD group compared with the other groups, whilst the anastomotic burst pressure within the CHD group (156.7 +/- 53.2 mmHg) was lower than, but not significantly different from, those of the control and SAL groups (196.3 +/- 49.8, 208.6 +/- 72.7 mmHg, respectively). CONCLUSIONS: Peritoneal irrigation with chlorhexidine solution is effective in the control of inflammation promoted by peritonitis but does not improve healing of colon anastomosis in rats. PMID- 20964619 TI - Fluorescence nanoparticles "quantum dots" as drug delivery system and their toxicity: a review. AB - Fluorescence nanocrystals or quantum dots (QDs) are engineered nanoparticles (NP) that have shown great promise with potential for many biological and biomedical applications, especially in drug delivery/activation and cellular imaging. The use of nanotechnology in medicine directed to drug delivery is set to expand in the coming years. However, it is unclear whether QDs, which are defined as NPs rather than small molecules, can specifically and effectively deliver drugs to molecular targets at subcellular levels. When QDs are linked to suitable ligands that are site specific, it has been shown to be brighter and photostable when compared with organic dyes. Interestingly, pharmaceutical sciences are exploiting NPs to minimize toxicity and undesirable side effects of drugs. The unforeseen hazardous properties of the carrier NPs themselves have given rise to some concern in a clinical setting. The kind of hazards encountered with this new nanotechnology materials are complex compared with conventional limitations created by traditional delivery systems. The development of cadmium-derived QDs shows great potential for treatment and diagnosis of cancer and site-directed delivery by virtue of their size-tunable fluorescence and with highly customizable surface for directing their bioactivity and targeting. However, data regarding the pharmacokinetic and toxicology studies require further investigation and development, and it poses great difficulties to ascertain the risks associated with this new technology. Additionally, nanotechnology also displays yet another inherent risk for toxic cadmium, which will enter as a new form of hazard in the biomedical field. This review will look at cadmium-derived QDs and discuss their future and their possible toxicities in a disease situation. PMID- 20964618 TI - Nitric oxide receptor soluble guanylyl cyclase undergoes splicing regulation in differentiating human embryonic cells. AB - Nitric oxide (NO), an important mediator molecule in mammalian physiology, initiates a number of signaling mechanisms by activating the enzyme soluble guanylyl cyclase (sGC). Recently, a new role for NO/cyclic guanosine monophosphate signaling in embryonic development and cell differentiation has emerged. The changes in expression of NO synthase isoforms and various sGC subunits has been demonstrated during human and mouse embryonic stem (ES) cells differentiation. Previously, our laboratory demonstrated that nascent alpha1 sGC transcript undergoes alternative splicing and that expression of alpha1 sGC splice forms directly affects sGC activity. Expression of sGC splice variants in the process of human ES (hES) cells differentiation has not been investigated. In this report, we demonstrate that alpha1 sGC undergoes alternative splicing during random hES differentiation for the first time. Our results indicate that C-alpha1 sGC splice form is expressed at high levels in differentiating cells and its intracellular distribution varies from canonical alpha1 sGC subunit. Together, our data suggest that alternative splicing of sGC subunits is associated with differentiation of hES cells. PMID- 20964620 TI - Activation of CYP3A-mediated testosterone 6beta-hydroxylation by tanshinone IIA and midazolam 1-hydroxylation by cryptotanshinone in human liver microsomes. AB - This study evaluated the in vitro activation of CYP3A-mediated midazolam 1 hydroxylation and testosterone 6beta-hydroxylation by tanshinone I, tanshinone IIA, and cryptotanshinone. The abilities of tanshinones to activate CYP3A mediated midazolam 1-hydroxylation and testosterone 6beta-hydroxylation in human liver microsomes (HLMs) were tested. Substrate- and effector-dependent activation of CYP3A by tanshinones were both observed. Cryptotanshinone was shown to activate CYP3A-mediated midazolam 1-hydroxylation in a concentration-dependent manner. In contrast, tanshinone IIA and tanshinone I did not activate this hydroxylation reaction. In addition, tanshinone IIA activated CYP3A-mediated testosterone 6beta-hydroxylation, whereas cryptotanshinone and tanshinone I did not. The results from our study enhance the understanding of CYP3A activation by tanshinone IIA and cryptotanshinone in HLMs. Additionally, these data allow for an accurate prediction of the magnitude and likelihood of Danshen-drug interactions. PMID- 20964621 TI - Implanted neurosphere-derived precursors promote recovery after neonatal excitotoxic brain injury. AB - Brain damage through excitotoxic mechanisms is a major cause of cerebral palsy in infants. This phenomenon usually occurs during the fetal period in human, and often leads to lifelong neurological morbidity with cognitive and sensorimotor impairment. However, there is currently no effective therapy. Significant recovery of brain function through neural stem cell implantation has been shown in several animal models of brain damage, but remains to be investigated in detail in neonates. In the present study, we evaluated the effect of cell therapy in a well-established neonatal mouse model of cerebral palsy induced by excitotoxicity (ibotenate treatment on postnatal day 5). Neurosphere-derived precursors or control cells (fibroblasts) were implanted into injured and control brains contralateral to the site of injury, and the fate of implanted cells was monitored by immunohistochemistry. Behavioral tests were performed in animals that received early (4 h after injury) or late (72 h after injury) cell implants. We show that neurosphere-derived precursors implanted into the injured brains of 5-day-old pups migrated to the lesion site, remained undifferentiated at day 10, and differentiated into oligodendrocyte and neurons at day 42. Although grafted cells finally die there few weeks later, this procedure triggered a reduction in lesion size and an improvement in memory performance compared with untreated animals, both 2 and 5 weeks after treatment. Although further studies are warranted, cell therapy could be a future therapeutic strategy for neonates with acute excitotoxic brain injury. PMID- 20964622 TI - Matrix dimensions bias demographic inferences: implications for comparative plant demography. AB - While the wealth of projection matrices in plant demography permits comparative studies, variation in matrix dimensions complicates interspecific comparisons. Collapsing matrices to a common dimension may facilitate such comparisons but may also bias the inferred demographic parameters. Here we examine how matrix dimension affects inferred demographic elasticities and how different collapsing criteria perform. We analyzed 13 x 13 matrices representing nine plant species, collapsing these matrices (i) into even 7 x 7, 5 x 5, 4 x 4, and 3 x 3 matrices and (ii) into 5 x 5 matrices using different criteria. Stasis and fecundity elasticities increased when matrix dimension was reduced, whereas those of progression and retrogression decreased. We suggest a collapsing criterion that minimizes dissimilarities between the original- and collapsed-matrix elasticities and apply it to 66 plant species to study how life span and growth form influence the relationship between matrix dimension and elasticities. Our analysis demonstrates that (i) projection matrix dimension has significant effects on inferred demographic parameters, (ii) there are better-performing methods than previously suggested for standardizing matrix dimension, and (iii) herbaceous perennial projection matrices are particularly sensitive to changes in matrix dimensionality. For comparative demographic studies, we recommend normalizing matrices to a common dimension by collapsing higher classes and leaving the first few classes unaltered. PMID- 20964623 TI - IL-3 controls tau modifications and protects cortical neurons from neurodegeneration. AB - Interleukin-3 (IL-3) regulates the proliferation, survival and differentiation of haematopoietic cells via interaction with specific cell-surface receptors. IL-3 is expressed in several non-hematopoietic cell types. Studies have demonstrated the presence of IL-3 in the central nervous system, however, its physiological role in these cells is poorly understood. Previously we have been demonstrated that IL-3 prevents neuronal death induced by fibrillary beta amyloid in these cells, by PI 3-kinase and Jak/STAT pathway activation. In this study, we demonstrated that IL-3 significantly reduced Abeta-promoted neurite degeneration and toxicity. Thus, this cytokine provides cellular protection against Abeta neurotoxicity in primary cortical neuronal cells, by modulating microtubular dynamics and prevention of tau cleavage and hyperphosphorylation. We also demonstrates that IL-3 is expressed in the "in vivo" mouse model of AD, Tg2576, which also expresses human AbetaPP with the Swedish mutation. In summary, these results suggest that IL-3 could play a neuroprotective role in AD. PMID- 20964624 TI - Dynein LIC1 localizes to the mitotic spindle and midbody and LIC2 localizes to spindle poles during cell division. AB - CD-1 (cytoplasmic dynein-1) is a multisubunit motor protein complex involved in intracellular trafficking and mitosis. The dynein LIC (light intermediate chain) subunits, LIC1 (DLIC-1, gene symbol DYNC1LI1) and LIC2 (DLIC-2, gene symbol DYNC1LI2), associate with the dynein HC (heavy chain) in a mutually exclusive manner and thus define distinct functional CD-1 complexes. Here, we analysed the mitotic distribution of LIC1 and LIC2. We found that from metaphase through anaphase, LIC1 localizes to the mitotic spindle and concentrates within the midbody during the abscission step of cytokinesis. Conversely, LIC2 strongly localizes to the spindle poles from prophase through telophase. These data suggest distinct functions for LIC1 and LIC2-containing CD-1 complexes during cell division. PMID- 20964625 TI - Translational control gone awry: a new mechanism of tumorigenesis and novel targets of cancer treatments. AB - Translational control is one of primary regulation mechanisms of gene expression. Eukaryotic translational control mainly occurs at the initiation step, the speed limiting step, which involves more than ten translation initiation factors [eIFs (eukaryotic initiation factors)]. Changing the level or function of these eIFs results in abnormal translation of specific mRNAs and consequently abnormal growth of cells that leads to human diseases, including cancer. Accumulating evidence from recent studies showed that the expression of many eIFs was associated with malignant transformation, cancer prognosis, as well as gene expression regulation. In the present paper, we perform a critical review of recent advances in understanding the role and mechanism of eIF action in translational control and cancer as well as the possibility of targeting eIFs for therapeutic development. PMID- 20964626 TI - New developments on the TNFalpha-mediated signalling pathways. AB - TNFalpha (tumour necrosis factor alpha) is an extensively studied pleiotropic cytokine associated with the pathogenesis of a variety of inflammatory diseases. It elicits a wide spectrum of cellular responses which mediates and regulates inflammation, immune response, cell survival, proliferation and apoptosis. TNFalpha initiates its responses by binding to its receptors. TNFalpha-induced effector responses are mediated by the actions and interactions among the various intracellular signalling mediators in the cell. TNFalpha induces both survival and apoptotic signal in a TRADD (TNF receptor-associated DD)-dependent and independent way. The signals are further transduced via a variety of signalling mediators, including caspases, MAPKs (mitogen-activated protein kinases), phospholipid mediators and miRNA/miR (microRNA), whose roles in specific functional responses is not fully understood. Elucidating the complexity and cross talks among signalling mediators involved in the TNFalpha-mediated responses will certainly aid in the identification of molecular targets, which can potentially lead to the development of novel therapeutics to treat TNFalpha associated disorders and in dampening inflammation. PMID- 20964628 TI - Hsp70 binds to PrPC in the process of PrPC release via exosomes from THP-1 monocytes. AB - PrPC (cellular prion protein) is a GPI (glycophosphatidylinositol)-anchored protein present on the surface of a number of peripheral blood cells. PrPC must be present for the generation and propagation of pathogenic conformer [PrPSc (scrapie prion protein)], which is a conformational conversion form of PrPC and has a central role in transmissible spongiform encephalopathies. It is important to determine the transportation mechanism of normal PrPC between cells. Exosomes are membrane vesicles released into the extracellular space upon fusion of multivesicular endosomes with the plasma membrane. We have identified that THP-1 monocytes can secrete exosomes to culture medium, and the secreted exosomes can bear PrPC. We also found that Hsp70 interacts with PrPC not only in intracellular environment, but in the secreted exosomes. However, the specific markers of exosomes, Tsg101 and flotillin-1, were found with no interaction with PrPC. Our results demonstrated that PrPC can be released from THP-1 monocytes via secreted exosomes, and in this process, Hsp70 binds to PrPC, which suggests that Hsp70 may play a potential functional role in the release of PrPC. PMID- 20964627 TI - Expression of CtBP family protein isoforms in breast cancer and their role in chemoresistance. AB - BACKGROUND INFORMATION: CtBPs [C-terminal (of E1A) binding protein] have roles in the nucleus as transcriptional co-repressors, and in the cytoplasm in the maintenance of vesicular membranes. CtBPs are expressed from two genes, CTBP1 and CTBP2, mRNA products of which are alternatively spliced at their 5'-ends to generate distinct protein isoforms. Extensive molecular and cellular analyses have identified CtBPs as regulators of pathways critical for tumour initiation, progression and response to therapy. However, little is known of the expression or regulation of CtBP isoforms in human cancer, nor of the relative contributions of CTBP1 and CTBP2 to the tumour cell phenotype. RESULTS: Expression of CtBP proteins and CTBP1 and CTBP2 mRNA splice forms in breast cancer cell lines and tumour tissue was examined. CtBP1 proteins are identifiable as a single band on Western blots and are ubiquitously detectable in breast tumour samples, by both Western blotting and immunohistochemistry. CtBP1 is present in six of six breast cancer cell lines, although it is barely detectable in SKBr3 cells due to reduced CTBP1 mRNA expression. In the cell lines, the predominant CTBP1 mRNA splice form encodes CtBP1-S protein; in tumours, both major CTBP1 mRNA splice forms are variably expressed. CtBP2 proteins are ubiquitously expressed in all lines and tumour samples. The predominant CTBP2 mRNA encodes CtBP2-L, although an alternatively spliced form that encodes CtBP2-S, previously unidentified in humans, is expressed at low abundance. Both CtBP2-L and CtBP2-S are readily detectable as two distinct bands on Western blots; here we show that the CTBP2-L mRNA is translated from two AUG codons to generate both CtBP2-L and CtBP2-S. We have also identified an autoregulatory feedback mechanism whereby CtBP protein abundance is maintained in proliferating breast cancer cells through the post transcriptional regulation of CtBP2. This feedback is disrupted by UV-C radiation or exposure to cisplatin. Finally, we demonstrate that CtBP1 and CtBP2 both have p53-dependent and -independent roles in suppressing the sensitivity of breast cancer cells to mechanistically diverse cancer chemotherapeutic agents. CONCLUSIONS: These studies support recent evidence that CtBP family proteins represent potential targets for therapeutic strategies for the treatment of cancer in general, and breast cancer in particular. PMID- 20964629 TI - Specific amino acids in the BAR domain allow homodimerization and prevent heterodimerization of sorting nexin 33. AB - SNX33 (sorting nexin 33) is a homologue of the endocytic protein SNX9 and has been implicated in actin polymerization and the endocytosis of the amyloid precursor protein. SNX33 belongs to the large family of BAR (Bin/amphiphysin/Rvs) domain-containing proteins, which alter cellular protein trafficking by modulating cellular membranes and the cytoskeleton. Some BAR domains engage in homodimerization, whereas other BAR domains also mediate heterodimerization between different BAR domain-containing proteins. The molecular basis for this difference is not yet understood. Using co-immunoprecipitations we report that SNX33 forms homodimers, but not heterodimers, with other BAR domain-containing proteins, such as SNX9. Domain deletion analysis revealed that the BAR domain, but not the SH3 (Src homology 3) domain, was required for homodimerization of SNX33. Additionally, the BAR domain prevented the heterodimerization between SNX9 and SNX33, as determined by domain swap experiments. Molecular modelling of the SNX33 BAR domain structure revealed that key amino acids located at the BAR domain dimer interface of the SNX9 homodimer are not conserved in SNX33. Replacing these amino acids in SNX9 with the corresponding amino acids of SNX33 allowed the mutant SNX9 to heterodimerize with SNX33. Taken together, the present study identifies critical amino acids within the BAR domains of SNX9 and SNX33 as determinants for the specificity of BAR domain-mediated interactions and suggests that SNX9 and SNX33 have distinct molecular functions. PMID- 20964630 TI - Cell surface heparan sulfates mediate internalization of the PWWP/HATH domain of HDGF via macropinocytosis to fine-tune cell signalling processes involved in fibroblast cell migration. AB - HDGF (hepatoma-derived growth factor) stimulates cell proliferation by functioning on both sides of the plasma membrane as a ligand for membrane receptor binding to trigger cell signalling and as a stimulator for DNA synthesis in the nucleus. Although HDGF was initially identified as a secretory heparin binding protein, the biological significance of its heparin-binding ability remains to be determined. In the present study we demonstrate that cells devoid of surface HS (heparan sulfate) were unable to internalize HDGF, HATH (N-terminal domain of HDGF consisting of amino acid residues 1-100, including the PWWP motif) and HATH(K96A) (single-site mutant form of HATH devoid of receptor binding activity), suggesting that the binding of HATH to surface HS is important for HDGF internalization. We further demonstrate that both HATH and HATH(K96A) could be internalized through macropinocytosis after binding to the cell surface HS. Interestingly, HS-mediated HATH(K96A) internalization is found to exhibit an inhibitory effect on cell migration and proliferation in contrast with that observed for HATH action on NIH 3T3 cells, suggesting that HDGF exploits the innate properties of both cell surface HS and membrane receptor via the HATH domain to affect related cell signalling processes. The present study indicates that MAPK (mitogen-activated protein kinase) signalling pathways could be affected by the HS-mediated HATH internalization to regulate cell migration in NIH 3T3 fibroblasts, as judged from the differential effect of HATH and HATH(K96A) treatment on the expression level of matrix metalloproteases. PMID- 20964632 TI - Sensitive measurement of unmethylated repeat DNA sequences by end-specific PCR. AB - We describe a new method that is well-suited for the determination of the methylation level of repetitive sequences such as human Alu elements. We have applied the method to the analysis of cell and tissue DNAs and expect it to have wide utility in studies of DNA methylation in cancer and other disease states, in monitoring response to epigenetic cancer therapies and in epidemiological studies. Only 1 ng DNA is needed for a duplex, one-tube real-time PCR in which methylation level and the amount of input DNA are concurrently measured. The relative cutting by the methylation-sensitive enzyme BstUI is compared with that of the methylation-insensitive enzyme DraI to give a measure of DNA methylation. The method depends upon the use of 5'-tailed, 3'-blocked oligonucleotides called facilitator oligonucleotides (Foligos). Only cut DNAs with specific matching sequences at their 3' ends can copy the tails of the Foligos and thus become tagged and available for subsequent PCR. Both the tagging and PCR are carried out by the same enzyme, Taq DNA polymerase. Because amplification only occurs if suitable ends have been generated in the target DNA, we have called this method end-specific PCR (ESPCR). ESPCR avoids the bisulfite treatment step that is usually required to measure methylation. PMID- 20964631 TI - Advances in genome-wide DNA methylation analysis. AB - The covalent DNA modification of cytosine at position 5 (5-methylcytosine; 5mC) has emerged as an important epigenetic mark most commonly present in the context of CpG dinucleotides in mammalian cells. In pluripotent stem cells and plants, it is also found in non-CpG and CpNpG contexts, respectively. 5mC has important implications in a diverse set of biological processes, including transcriptional regulation. Aberrant DNA methylation has been shown to be associated with a wide variety of human ailments and thus is the focus of active investigation. Methods used for detecting DNA methylation have revolutionized our understanding of this epigenetic mark and provided new insights into its role in diverse biological functions. Here we describe recent technological advances in genome-wide DNA methylation analysis and discuss their relative utility and drawbacks, providing specific examples from studies that have used these technologies for genome-wide DNA methylation analysis to address important biological questions. Finally, we discuss a newly identified covalent DNA modification, 5-hydroxymethylcytosine (5hmC), and speculate on its possible biological function, as well as describe a new methodology that can distinguish 5hmC from 5mC. PMID- 20964633 TI - One-step split GFP staining for sensitive protein detection and localization in mammalian cells. AB - Although epitope tags are useful to detect intracellular proteins and follow their localization with antibodies, background and nonspecific staining often remain problematic. We describe a simple assay based on the split GFP complementation system. Proteins tagged with the 15-amino acid GFP 11 fragment are detected with a solution of the recombinant nonfluorescent complementary GFP 1-10 fragment to reconstitute a fluorescent GFP. In contrast to antibody-based staining methods, this one-step assay presents high specificity and very low background of fluorescence, thus conferring higher signal-to-noise ratios. We demonstrate that this new application of the split GFP tagging system facilitates detection of proteins displaying various subcellular localizations using flow cytometry and microscopy analysis. PMID- 20964634 TI - A nerve clamp electrode design for indirect stimulation of skeletal muscle. AB - A nerve clamp electrode was developed to indirectly stimulate skeletal muscle innervated by alpha motor neurons as an alternative to conventional electrodes. The stimulating electrode device consists of a spring coil-activated nerve clamp mounted inside a 1-mL syringe barrel. Supramaximal pulses were generated by a Grass stimulator and delivered to the nerve segment via the nerve clamp electrode. The salient feature of the electrode is its ability to produce muscle contractions indirectly through stimulation of the attached nerve. Indirect muscle stimulation is critical for studying the paralytic actions of presynaptic acting toxins such as botulinum neurotoxins (BoNT), a potent inhibitor of acetylcholine (ACh) release from alpha motor neurons. This device enables stimulation of muscle contraction indirectly as opposed to contraction from direct muscle stimulation. The electrode is able to stimulate indirect muscle contraction when tested on ex vivo preparations from rodent phrenic nerve hemidiaphragm muscle in similar fashion to conventional electrodes. In addition, the electrode stimulated external intercostal nerve-muscle preparations. This was confirmed after applying BoNT serotype A, a potent inhibitor of ACh release, to induce muscle paralysis. Alternative methods, including suction and bipolar loop electrodes, were unsuccessful in stimulating indirect muscle contraction. Therefore, this novel electrode is useful for physiological assessment of nerve agents and presynaptic actions of toxins that cause muscle paralysis. This electrode is useful for stimulating nerve-muscle preparations for which the length of nerve is a concern. PMID- 20964635 TI - V-fusion: a convenient, nontoxic method for cell fusion. AB - Cell-to-cell fusion (cell fusion) is a fundamental biological process that also has been used as a versatile experimental tool to dissect a variety of cellular mechanisms, including the consequences of cell fusion itself, and to produce cells with desired properties, such as hybridomas and reprogrammed progenitors. However, current methods of cell fusion are not satisfactory because of their toxicity, inefficiency, or lack of flexibility. We describe a simple, versatile, scalable, and nontoxic approach that we call V-fusion, as it is based on the ability of the vesicular stomatitis virus G protein (VSV-G), a viral fusogen of broad tropism, to become rapidly and reversibly activated. We suggest that this approach will benefit a broad array of studies that investigate consequences of cell fusion or use cell fusion as an experimental tool. PMID- 20964636 TI - Reduction of non-insert sequence reads by dimer eliminator LNA oligonucleotide for small RNA deep sequencing. AB - Here we describe a method for constructing small RNA libraries for high throughput sequencing in which we have made a significant improvement to commonly available standard protocols. We added a locked nucleic acid (LNA) oligonucleotide--named dimer eliminator--that is complementary to the adapter dimer ligation products during the reverse transcription reaction. It reduces adapter-dimers, which often contaminate standard libraries and increase the number of non-insert sequence reads. This simple technology can be used for simultaneous multiplex sequencing of various barcoded samples as well as nonbarcoded small RNA library sequencing. In this study we also evaluated the reproducibility and quantitative design of the eight barcoded tags by comparing the Pearson's correlation values in the expression analysis between each barcoded sample. This method improves the sequencing yield and efficiency, while simplifying library construction, and makes it easier to perform large-scale small RNA analysis under multiple conditions with next-generation sequencers. PMID- 20964637 TI - Are we using our brains? Diagnosis of postoperative cognitive dysfunction. PMID- 20964638 TI - Rapid detection, enrichment and propagation of specific T cell subsets based on cytokine secretion. AB - T cell lines with defined cytokine profiles are an invaluable tool for assessing the control of immune responses both in vitro and in vivo. Production of such cell lines can be complex and time-consuming. Here we present a powerful technique to assay the cytokines produced by T cells activated polyclonally or with specific antigens. This paper presents a detailed methodology for the identification and isolation of cytokine-producing T cells activated with the artificial superantigen, CytoStim, or viral and fungal antigens. These cells can be analysed for different cytokines simultaneously, or cultured further to rapidly establish T cell lines making known cytokine types. We highlight the enumeration, isolation and phenotype of interleukin-17-producing T cells, and the rapid generation of virus-specific Th1 T cell lines. PMID- 20964639 TI - Mifepristone (RU486) restores humoral and T cell-mediated immune response in endotoxin immunosuppressed mice. AB - Sepsis and septic shock can be caused by Gram-positive and -negative bacteria and other microorganisms. In the case of Gram-negative bacteria, endotoxin, a normal constituent of the bacterial wall, also known as lipopolysaccharide (LPS), has been considered as one of the principal agents causing the undesirable effects in this critical illness. The response to LPS involves a rapid secretion of proinflammatory cytokines such as tumour necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, interferon (IFN)-gamma and the concomitant induction of anti inflammatory mediators such as IL-10, transforming growth factor (TGF)-beta or glucocorticoids, which render the host temporarily refractory to subsequent lethal doses of LPS challenge in a process known as LPS or endotoxin tolerance. Although protective from the development of sepsis or systemic inflammation, endotoxin tolerance has also been pointed out as the main cause of the non specific humoral and cellular immunosuppression described in these patients. In this report we demonstrate, using a mouse model, that mifepristone (RU486), a known glucocorticoid receptor antagonist, could play an important role in the restoration of both adaptive humoral and cellular immune response in LPS immunosuppressed mice, suggesting the involvement of endogenous glucocorticoids in this phenomenon. On the other hand, using cyclophosphamide and gemcitabine, we demonstrated that regulatory/suppressor CD4(+) CD25(+) forkhead boxP3(+) and GR 1(+) CD11b(+) cells do not play a major role in the establishment or the maintenance of endotoxin tolerance, a central mechanism for inducing an immunosuppression state. PMID- 20964641 TI - Were monocytes responsible for initiating the cytokine storm in the TGN1412 clinical trial tragedy? AB - The precise biological mechanisms that caused the TGN1412 clinical trial tragedy (also known as 'The Elephant Man Clinical Trial') in March 2006 remain a mystery to this day. It is assumed widely that the drug used in this trial (TGN1412) bound to CD28 on T lymphocytes and following activation of these cells, a massive 'cytokine storm' ensued, leading ultimately to multi-organ failure in all recipients. The rapidity of this in vivo response (within 2 h), however, does not fit well with a classical T lymphocyte response, suggesting that other 'faster acting' cell types may have been involved. In this study we have activated purified human peripheral blood leucocyte populations using various clones of mouse monoclonal anti-CD28 presented to cells in the form of a multimeric array. Cytokines were measured in cell-free supernatants at 2 h, and specific mRNA for tumour necrosis factor (TNF)-alpha, thought to be the initiator of the cytokine storm, was also measured in cell lysates by reverse transcription-polymerase chain reaction (RT-PCR). Monocytes were the only cell type found to show significant (P < 0.05) up-regulation of TNF-alpha at 2 h. Eleven other monocyte cytokines were also up-regulated by anti-CD28 within this time-frame. It therefore seems likely that monocytes and not T cells, as widely believed, were probably responsible, at least in part, for initiating the cytokine storm. Furthermore, we propose that a multimeric antibody array may have formed in vivo on the vascular endothelium via an interaction between TGN1412 and CD64 (FcgammaRI), and we provide some evidence in support of this hypothesis. PMID- 20964640 TI - The influence of early life factors on the risk of developing rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease that develops as a result of the interaction between genetic and environmental risk factors. Although increasing evidence shows the importance of genes in determining the risk of RA, it is clear that environmental factors also have a vital role. Studies to date have tended to concentrate on environmental influences around the time of disease onset. However, a number of pieces of evidence, including the fact that autoantibodies, such as rheumatoid factor (RF), can develop several years before the onset of clinical disease, suggest that environmental factors may influence disease susceptibility during early life. Several recent studies lend weight to this possibility, with an increased risk of RA in the offspring of mothers who smoked during pregnancy and in those with higher birth weight. There has also been a suggestion that the risk of RA is reduced in breast-fed infants. We describe the evidence surrounding the effect of early life factors on the risk of developing RA and possible mechanisms by which they may act. PMID- 20964642 TI - Efficacy of intravenous immunoglobulin (IVIG) affinity-purified anti-desmoglein anti-idiotypic antibodies in the treatment of an experimental model of pemphigus vulgaris. AB - Pemphigus vulgaris is a rare life-threatening autoimmune bullous disease caused by immunoglobulin G (IgG) autoantibodies directed against desmogleins 1 and 3. Previously, we showed that intravenous immunoglobulin (IVIG) ameliorates anti desmoglein-induced experimental pemphigus vulgaris in newborn naive mice. The aim of this study was to examine the efficacy of anti-anti-desmoglein-specific IVIG in a similar model. Pemphigus-vulgaris-specific IVIG (PV-sIVIG) was affinity purified from IVIG on a column of single-chain variable fragment (scFv) anti desmogleins 1 and 3. The anti-idiotypic activity of PV-sIVIG was confirmed by enzyme-linked immunosorbent assay, inhibition assay. After induction of pemphigus by injection of anti-desmogleins 1 and 3 scFv to newborn mice, the animals were treated with PV-sIVIG, IVIG (low or high dose) or IgG from a healthy donor (n = 10 each). The skin was examined 24-48 h later, and samples of affected areas were analysed by histology and immunofluorescence. In vitro study showed that PV-sIVIG significantly inhibited anti-desmogleins 1 and 3 scFv binding to recombinant desmoglein-3 in a dose-dependent manner. Specificity was confirmed by inhibition assay. In vivo analysis revealed cutaneous lesions of pemphigus vulgaris in mice injected with normal IgG (nine of 10 mice) or low-dose IVIG (nine of 10 mice), but not in mice treated with PV-sIVIG (none of 10) or high-dose IVIG (none of 10). On immunopathological study, PV-sIVIG and regular IVIG prevented the formation of acantholysis and deposition of IgG in intercellular spaces. In conclusion, the PV-sIVIG preparation is more effective than native IVIG in inhibiting anti-desmoglein-induced pemphigus vulgaris in mice and might serve as a future therapy in patients with the clinical disease. PMID- 20964643 TI - The interferon-alpha and interleukin-10 responses in neonates differ from adults, and their production remains partial throughout the first 18 months of life. AB - Previous studies have suggested that the susceptibility of newborns to infections is linked to the immaturity of their immune system, but very few data are available on the early stages of maturation of the immune response. Therefore, we decided to investigate the evolution of the interferon (IFN)-alpha and interleukin (IL)-10 responses in neonatal mononuclear cells. To this end, mononuclear cells isolated from cord blood and peripheral blood of 2-, 6- and 18 month-old children and adults were stimulated with unmethylated cytosine phosphate-guanosine oligodeoxynucleotide (CpG-ODN) 2216 (IFN-alpha response) or lipopolysaccharide (LPS) (IL-10 response) for 24 h. The production of IFN-alpha and IL-10 was then measured in culture supernatants using enzyme-linked immunosorbent assay (ELISA) or a 6-plex cytokine array, respectively. Compared to adults, we found a significant impairment in both the IFN-alpha and IL-10 responses of neonatal mononuclear cells. Interestingly, both responses had increased significantly after 2 months, but remained lower than the adult responses throughout the first 18 months of life. This study shows that although the immune response of neonates tends to mature fairly quickly, it remains different when compared to the adult immune response throughout the first 18 months of life. This could have important consequences on children's ability to mount an appropriate immune response to various challenges and to establish tolerance and immune homeostasis. PMID- 20964644 TI - Captopril increases the intensity of monocyte infection by Trypanosoma cruzi and induces human T helper type 17 cells. AB - The anti-hypertensive drug captopril is used commonly to reduce blood pressure of patients with severe forms of Chagas disease, a cardiomyopathy caused by chronic infection with the intracellular protozoan Trypanosoma cruzi. Captopril acts by inhibiting angiotensin-converting enzyme (ACE), the vasopressor metallopeptidase that generates angiotensin II and promotes the degradation of bradykinin (BK). Recent studies in mice models of Chagas disease indicated that captopril can potentiate the T helper type 1 (Th1)-directing natural adjuvant property of BK. Equipped with kinin-releasing cysteine proteases, T. cruzi trypomastigotes were shown previously to invade non-professional phagocytic cells, such as human endothelial cells and murine cardiomyocytes, through the signalling of G protein coupled bradykinin receptors (B(2) KR). Monocytes are also parasitized by T. cruzi and these cells are known to be important for the host immune response during infection. Here we showed that captopril increases the intensity of T. cruzi infection of human monocytes in vitro. The increased parasitism was accompanied by up-regulated expression of ACE in human monocytes. While T. cruzi infection increased the expression of interleukin (IL)-10 by monocytes significantly, compared to uninfected cells, T. cruzi infection in association with captopril down-modulated IL-10 expression by the monocytes. Surprisingly, studies with peripheral blood mononuclear cells revealed that addition of the ACE inhibitor in association with T. cruzi increased expression of IL-17 by CD4(+) T cells in a B(2) KR-dependent manner. Collectively, our results suggest that captopril might interfere with host-parasite equilibrium by enhancing infection of monocytes, decreasing the expression of the modulatory cytokine IL-10, while guiding development of the proinflammatory Th17 subset. PMID- 20964645 TI - Long-term follow-up of patients with type 1 diabetes transplanted with neonatal pig islets. AB - Pancreas transplantation is an option to achieve better metabolic control and decrease chronic complications in patients with diabetes. Xenotransplantation becomes an important alternative. In this study, we show the clinical outcome of patients with type 1 diabetes transplanted with neonatal pig islets without immunosuppression. In a longitudinal study of 23 patients with type 1 diabetes, who received porcine islets between 2000 and 2004, we registered demographic and clinical characteristics every 3 months and chronic complications evaluation yearly. Porcine C-peptide was measured in urine samples under basal conditions and after stimulation with l-arginine. More than 50% were female, median current age was 20.8 years, median diabetes duration at transplantation 5.5 years, median current diabetes duration 11 years and median time post-transplantation 5.7 years. Their media of glycosylated haemoglobin reduced significantly after the first transplantation. Insulin doses remain with a reduction greater than 33% in more than 50% of the patients. Before transplantation, 14 of the 21 patients presented mild chronic complications and currently only two patients presented these complications. Porcine C-peptide was present in all urine samples under basal conditions and increased post-stimulation with l-arginine. These patients achieved an excellent metabolic control after the first transplantation. This could explain, as well as the remaining function of transplanted cells, the low frequency of chronic complications compared to patients with similar diabetes duration and age. PMID- 20964646 TI - Actinic cheilitis: a treatment review. AB - All other factors being equal, the presence of actinic cheilitis, a pre-invasive malignant lesion of the lips, doubles the risk of squamous cell carcinoma developing in this anatomic area. Various forms of local ablation,immunomodulation and surgical extirpation have been proposed as therapeutic interventions. This paper critically evaluates the available medical literature to highlight the evidence-based strength of each recommended therapy for actinic cheilitis. Vermilionectomy remains the gold standard for efficacy; trichloroacetic acid application is easy and convenient, but the least efficacious overall. PMID- 20964647 TI - Statins in dermatology. AB - Statins are competitive inhibitors of 3-hydroxy-3-methylyglutaryl-coenzyme A reductase and reduce low-density lipoprotein-C levels. Statins are well-tolerated drugs used for prevention of atherosclerosis and cardiovascular events. Statins possess anti-inflammatory, immunomodulatory, antioxidant, metabolic, and possible anticancer effects. Statins are reported to be effective against psoriasis, dermatitis, graft-versus-host disease, uremic pruritus, vitiligo, and hirsutism. Topical forms of statins are employed in the treatment of acne, seborrhea, rosacea, and rhinophyma. Animal studies show the beneficial effect of statins against contact dermatitis and wound healing. They have promising anti-HIV effects as well. This article succinctly reviews the various cellular and molecular effects of statins, their applications in cutaneous medicine and their side effects. PMID- 20964648 TI - Responsiveness of nonHerlitz junctional epidermolysis bullosa to topical gentian violet. AB - BACKGROUND: Gentian violet (GV), a mixture of crystal violet and methyl violet, a dye belonging to the di- and triaminophenylmethanes class and has been widely used for its bactericidal and fungicidal properties. To date, there have been no reports of long-term therapeutic use of GV in epidermolysis bullosa (EB). METHODS: Two brothers with nonHerlitz junctional epidermolysis bullosa (JEB) aged 12 and 14 tried topical GV to one lower leg with conventional silicone dressings and this was compared with leaving the other leg with silicone dressings alone, over 4 weeks. Wounds were photographed and measured using Visitrak analysis. Pain, ooze, and appearance were assessed using visual analog scales (VAS) scales and Quality of life using Dermatology Life Quality Index and QOLEB (2) tools. RESULTS: The side treated with dressings and GV reduced to 14.9 cm(2) (-20.74%) and to 9.5 cm(2) (-56.62%) for dressings alone in the older brother (EB-012) and to 4.2 cm(2) (+20%) and 12.5 cm(2) (-7%) for the younger brother (EB-011) in ulcer size, respectively. Both patients did complain of stinging on the sites treated within a few days. QOL measures and VAS scores did not show any significant change. CONCLUSIONS: GV may be considered to be a therapeutic option for ulcers in nH-JEB patients and potentially other EB subtypes. A formal randomized controlled trial and long-term safety study of GV in EB is recommended. PMID- 20964649 TI - Identification of a novel mutation in a Chinese patient with mild Darier's disease. PMID- 20964650 TI - Mycetoma in South India: retrospective analysis of 13 cases and description of two cases caused by unusual pathogens: Neoscytalidium dimidiatum and Aspergillus flavus. AB - BACKGROUND: Mycetoma is a chronic suppurative and/or granulomatous inflammatory lesion of skin, subcutaneous tissue, fascia, and tendons caused by the traumatic inoculation of either fungal (eumycotic) or bacterial (actinomycotic) organisms present in the soil. The disease is characterized by triad of tumefaction, discharging sinuses, and grains. MATERIAL AND METHODS: Thirteen new cases of biopsy proven mycetomas were analyzed, retrospectively, from January 2000 to October 2009. Clinical parameters, bone involvement, microbiological properties, and histopathological features were evaluated. Categorization into eumycotic or actinomycotic was based upon features on hematoxylin and eosin stained sections with special stains. Therapeutic outcome was presented wherever available. RESULTS: There were eight actinomycetomas and five eumycetoma cases including 11 men and two women. Foot and lower extremities were the most common site of involvement (9 of 13, 69%). Culture results were available in 8 of 13 cases (61.5%). Madurella mycetomatis, Neoscytalidium dimidiatum, and Aspergillus flavus were the isolates among eumycetomas whereas Acinomadura madurae, Actinomadura pelletieri, and Nocardia species were the isolates among actinomycetomas. Two cases had underlying bone involvement. On follow-up, four of five eumycetoma cases showed partial improvement following surgery and antifungal therapy, one had amputation of the lower leg. Of the actinomycetomas, six of eight had dramatic improvement following sulfamethoxazole-trimethoprim based therapy, one had complete cure, and one was lost to follow-up. CONCLUSION: Strong clinical suspicion, exact categorization of lesion into eumycotic or actinomycotic along with culture correlation, is essential for prognosis and effective therapy. PMID- 20964651 TI - Serum cytokine profile during Mycobacterium ulcerans infection (Buruli ulcer). AB - BACKGROUND: Buruli Ulcer (BU) is a severe cutaneous and subcutaneous disease due to Mycobacterium ulcerans infection, mainly distributed in sub-Saharan Africa and tropical areas. The role of T helper (TH) cytokines in the development and clinical course of the disease has been previously studied by investigating the in vitro immune response of lymphocytes from affected patients and immunohistochemical analyses of bioptic samples. METHODS: TH cytokine levels (IFNgamma, TNF-alpha, IL-2, IL-10, IL-4, IL-5, IL-17) were evaluated in serum of 34 Beninese subjects by cytofluorimetric and immunoenzymatic assays: 16 patients affected with active BU, 4 patients who had healed after specific therapy, and 14 matched controls. RESULTS: Levels of IFNgamma were higher in patients with late BU (>2 months from onset) and healed patients than in controls, and in ulcerative than in pre-ulcerative patients. Analysis of 4 patients with "late" disease evaluated both at the beginning of antibiotic therapy and 6 months later showed that IFNgamma levels were always lower in the second evaluation. By contrast, no differences were found in levels of the other cytokines. CONCLUSIONS: IFNgamma production is low in early BU, and increases in late BU and healing, suggesting a role of this cytokine in infection clearance. Moreover, evaluation of IFNgamma serum levels may be a useful tool to monitor the immune response during the BU course. PMID- 20964652 TI - Long live Chinese herbal medicine. PMID- 20964653 TI - Subepidermal calcified nodules with different morphological types in an adult female. PMID- 20964654 TI - Human immunodeficiency virus (HIV)-associated eosinophilic folliculitis and follicular mucinosis in a black woman. PMID- 20964655 TI - Rare presentation in an adult patient with neurocutaneous melanosis. PMID- 20964656 TI - Erythema ab igne mimicking livedo reticularis. PMID- 20964657 TI - Rapidly progressing malignant melanoma influenced by pregnancy. PMID- 20964658 TI - Secondary syphilis resembling erythema multiforme. AB - BACKGROUND: Secondary syphilis, which typically begins 4-10 weeks after initial exposure to Treponema pallidum, manifests with a range of cutaneous patterns. One unusual variation features oval, targetoid plaques that may resemble erythema multiforme (EM). METHODS: We describe a 23-year-old woman with an EM-like eruption, a mucous patch, and a prominent alopecia somewhat moth-eaten in appearance. She had positive rapid plasma reagin and fluorescent treponemal antibody absorption (FTA-ABS) tests, and a skin biopsy revealed swollen endothelial cells with a superficial perivascular infiltrate containing plasma cells. Response to intramuscular penicillin therapy was consistent with the empiric diagnosis of secondary syphilis. CONCLUSIONS: One should consider secondary syphilis in the differential diagnosis of an eruption resembling EM. PMID- 20964659 TI - Postinflammatory depigmentation: excellent results with suction blister grafting. AB - Depigmentation over the face of young females is usually not acceptable from an Indian social perspective. We are reporting a case of postinflammatory depigmentation over face of young female that was successfully treated. The patient developed depigmentation following inflammation as a result of a local application. She underwent three sessions of epidermal suction blister grafting with PUVA therapy instituted after the grafting to assist in the spreading of the pigmentation. First two sitting resulted in total repigmentation. She underwent a third sitting recently. Pigment spread is continuing with PUVA therapy in the area of the third session. The patient is satisfied with the outcome. In conclusion, we suggest that suction blister epidermal grafting can be tried in the treatment of postinflammatory depigmentation. PMID- 20964661 TI - Localized mycosis fungoides of the bilateral thumbs and nail units treated with orthovoltage radiation. PMID- 20964660 TI - A calcipotriene/betamethasone dipropionate two-compound scalp formulation in the treatment of scalp psoriasis in Hispanic/Latino and Black/African American patients: results of the randomized, 8-week, double-blind phase of a clinical trial. AB - The calcipotriene/betamethasone dipropionate two-compound scalp formulation has been shown to be safe and effective in the treatment of scalp psoriasis over 8 weeks, but the patients studied were mainly White and non-Hispanic. The aim of this study was to evaluate the efficacy and safety of the two-compound scalp formulation in the treatment of scalp psoriasis in Hispanic/Latino and Black/African American patients. A total of 99 Hispanic/Latino and 78 Black/African American patients were randomized double-blind in a 3:1 ratio to 8 weeks of once daily treatment of scalp psoriasis with either the two-compound scalp formulation (n=135) or its vehicle (n=42). In the two-compound group, 71.9% of patients had cleared or minimal disease at week 8 by the investigator's global assessment compared to 40.5% in the vehicle group (odds ratio 3.30; 95% CI 1.62 6.72; P<0.001). For the five secondary efficacy response criteria, three (total sign score, thickness of scalp psoriasis, patient's global assessment) showed that two-compound scalp formulation was statistically significantly more effective than its vehicle, and the other two (redness and scaliness of scalp psoriasis) approached statistical significance in favor of the two-compound scalp formulation. There was no statistically significant difference (P=1.00) between the percentage of patients with adverse reactions in the two-compound group (7.0%) and the vehicle group (7.9%). The two-compound scalp formulation is safe and effective in the treatment of scalp psoriasis over 8 weeks in Hispanic/Latino and Black/African American patients. PMID- 20964662 TI - Blastomycosis-like pyoderma: response to systemic retinoid therapy. AB - Blastomycosis-like pyoderma is a proliferative tissue response with multifactorial etiologies that may mimic other inflammatory and neoplastic skin disorders. It often occurs on sun damaged skin of immunocompromised patients. We report a case of blastomycosis-like pyoderma in a patient with underlying metastatic medullary carcinoma of the thyroid receiving treatment with sorafenib (a multikinase inhibitor). Prior treatments were unsuccessful. Our treatment with oral acitretin resulted in significant improvement. PMID- 20964663 TI - Ductal breast cancer in a male patient. PMID- 20964664 TI - Lipid levels in women with androgenetic alopecia. PMID- 20964665 TI - A novel mutation of the keratin 9 gene in a Chinese family with epidermolytic palmoplantar keratoderma. PMID- 20964666 TI - Erythema nodosum leprosum, Sweet's syndrome, and human immunodeficiency virus may be related through an overlap in immunopathogenesis. PMID- 20964669 TI - Alexander disease with periventricular calcification: a novel mutation of the GFAP gene. AB - Alexander disease is a rare neurodegenerative leucoencephalopathy caused by de novo mutations in the GFAP gene. Infantile, juvenile, and adult subtypes have been described and the clinical and radiological phenotypes are broad. Here we report on a single case of juvenile-onset Alexander disease associated with a novel frameshift mutation in the GFAP gene. The 8-year-old male patient had a relatively mild clinical phenotype characterized by dystonia, intermittent episodes of raised intracranial pressure, and characteristic radiological changes. He also presented with the additional and to our knowledge previously unreported, neuroimaging finding of periventricular calcification. We postulate that in children with leucoencephalopathy and periventricular calcification of undetermined aetiology, the diagnosis of Alexander disease should be considered. If the magnetic resonance imaging findings are compatible with Alexander disease, then DNA analysis of the GFAP gene should be performed even if the full criteria for a neuroradiological diagnosis are not met. PMID- 20964670 TI - Gastrostomy feeding in cerebral palsy: enough and no more. AB - AIM: gastrostomy feeding children with spastic quadriplegic cerebral palsy (SQCP) improves weight gain but may cause excess deposition of body fat. This study was designed to investigate whether weight gain could be achieved without an adverse effect on body composition by using a low-energy feed in gastrostomy-fed children with SQCP. METHOD: ourteen children (seven male; seven female; median age 2y; range 10mo-11y) with SQCP were studied, 13 of whom were classified as Gross Motor Function Classification Score (GMFCS) level V and one as GMFCS level IV. Children were eligible for the study if they weighed between 8 and 30kg with a diagnosis of severe SQCP and significant feeding difficulties in whom a clinical decision had been made to insert a gastrostomy feeding tube. The feed used in the study had an energy concentration of 0.75kcal/mL (Nutrini Low Energy Multi Fibre). Assessments were performed before gastrostomy insertion (baseline) and after 6months, and included body composition, growth, nutritional intake, and gastrointestinal symptoms. RESULTS: there was a significant increase in weight (median difference 1.9kg; 95% confidence interval [CI] 0.85-3.03kg; p=0.012), mid upper arm circumference (median difference 1.45cm; 95% CI -0.36cm to 3.47cm; p=0.043), and lower leg length (median difference 1.62cm; 95% CI 0.44-3.95cm; p=0.012) over the 6 months. There was no significant increase in fat mass index (median diff 1.21, 95% CI -1.15 to 2.94, p=0.345) or fat free mass index (median diff -1.43, 95% CI -1.15 to 2.94, p=0.249). Micronutrient levels remained within reference ranges with the exception of elevated chromium. The median percentage intake of the estimated average requirements for energy (kcal) was 43% at the beginning of the study and 48.8% after 6 months on the low-energy feed. INTERPRETATION: children with SQCP who are fed a low-energy, micronutrient complete, high-fibre feed continue to grow even with energy intakes below 75% of the estimated average requirements. This was not associated with a disproportionate rise in fat mass or fat percentage, and the majority of micronutrient levels remained within the reference range. PMID- 20964671 TI - Factor- and item-level analyses of the 38-item activities scale for kids performance. AB - AIM: Children and adolescents highly value their ability to participate in relevant daily life and recreational activities. The Activities Scale for Kids performance (ASKp) instrument measures the frequency of performance of 30 common childhood activities, and has been shown to be valid and reliable. A revised and expanded 38-item ASKp (ASKp38) version has been reported in recent literature and is currently used in clinical research. The aim of this paper is to assess the factor structure and item-level statistics of the ASKp38. METHOD: Our study used factor analyses and Rasch analyses to determine the item-set dimensionality and to calculate item-level statistics respectively, for existing ASKp38 data from 200 children (104 males; 96 females; mean age 12y 7mo; SD 2y 8mo; range 6-20y) with physical disabilities. The children had a variety of physical impairments including cerebral palsy (n = 105; range 8-13 y), limb salvage (n = 18; range 11 20y), arthrogryposis (n = 13; 6-17y), and other, including individuals with spina bifida and spinal cord injury (n = 64; 8-19 y). RESULTS: A two-factor model, with components of activities of daily living and play, most optimally fit the data. Item-fit statistics based on this two-factor model demonstrated adequate fit and content coverage. INTERPRETATION: The ASKp38 appears to consist of two factors, defined as (1) activities of daily living and (2) play, and may be used to measure the frequency of activity performance on two corresponding subscales. PMID- 20964672 TI - Gross motor performance and physical fitness in children with psychiatric disorders. AB - AIM: Gross motor performance appears to be impaired in children with psychiatric disorders but little is known about which skill domains are affected in each disorder, nor about possible accompanying deficits in physical fitness. The present study has sought to provide information about these issues in children with emotional, behavioural, and pervasive developmental disorders (PDD). METHOD: One hundred children receiving psychiatric care (81 males, 19 females, mean age 9y 11mo, SD 1y 8mo) completed both the Test of Gross Motor Development, measuring locomotion and object control, and the Motor Performance test, measuring neuromotor and aerobic fitness. The emotional disorders, behavioural disorders (BD), and PDD subgroups consisted of 17, 44 and 39 children respectively. RESULTS: The mean gross motor performance scores of the BD and PDD group were significantly (p < 0.05) lower than the score of the emotional disorders group, but even the latter score was significantly lower (p < 0.05) than the population norm score. Physical fitness was poor in all subgroups. The subdomains locomotion and object control were unusually highly correlated in the PDD group (r = 0.68). Moreover, only in the PDD group were the locomotion scores significantly correlated with neuromotor fitness (r = 0.47, p = 0.02). INTERPRETATION: The specific combinations of impairments in gross motor skills and physical fitness in children with psychiatric disorders indicate the importance of the assessment of these domains in order to provide interventions tailored to the specific profile of each individual child. PMID- 20964673 TI - Factors associated with treatment lag in infantile spasms. AB - AIM: the aim of this study was to evaluate the conditions in which infantile spasms are diagnosed and their possible impact on the course of the disease. METHOD: we carried out a retrospective study of the reasons for delayed treatment of infantile spasms (treatment lag) in western France over the period 1990-2003. A total of 156 infants, 87 male (55%) and 69 female (45%), with infantile spasms were identified, in 45 (29%) of whom the spasms were symptomatic. They were aged 1 week to 24 months (median 20wks, mean 22.4, SD 13.3) at first symptoms. To be included in the study, participants had to exhibit a combination of clusters of spasms, altered psychomotor development, and paroxysmal electroencephalographic (EEG) activity, as defined by the International League Against Epilepsy. We did not restrict onset to the first year of life as infantile spasms may begin after the age of 1 year. RESULTS: the mean time from appearance of first symptom to first visit to a medical practitioner was 4 weeks. In 14% of cases, the reason for the visit was non-neurological, the parents having noticed no neurological symptoms before the visit. The diagnosis was missed at first visit in 38% of the cases examined, with the incorrect diagnosis mostly commonly being gastro oesophageal reflux or no abnormality. This increased to 74% after a second visit, in all cases based on an abnormal EEG. However, in 5% the time between first presentation and diagnosis was over 2 months and up to 10 visits were required. The time lag between first presentation and diagnosis was significantly longer for individuals presenting to general practitioners than to paediatricians (p=0.03). Response to treatment was poorer in those in whom diagnosis was delayed. INTERPRETATION: various steps could be taken to reduce treatment lag such as training general practitioners, informing the parents of individuals at risk about the possibility of infantile spasms, and recommending that EEG is performed before brain imaging in children with unexplained psychomotor delay. PMID- 20964674 TI - Prevalence of autism in children of Somali origin living in Stockholm: brief report of an at-risk population. AB - This work was a follow-up study (birth years 1999-2003) of the prevalence of autism in children of Somali background living in the county of Stockholm, Sweden. In a previous study (birth years 1988-98), the prevalence of autism associated with learning disability* was found to be three to four times higher among Somali children compared with other ethnicities in Stockholm. We examined all records of children of Somali background, born from 1999 to 2003, registered at the centre for schoolchildren with autism and learning disability. The census day was 31 December 2009. The prevalence of autism and PDDNOS (with learning disability) was 0.98% (18/1836) in the Somali group and 0.21% (232/111555) in the group of children of non-Somali origin (p<0.001). The increased prevalence remained and was now between four and five times higher in children of Somali background. A clinical observation was that more than 80%, in addition to autism and learning disability, had a profound hyperactivity. The findings accord with many other studies reporting higher prevalence rates of autism in children of immigrant mothers. We discuss the need for further research of underlying mechanisms. PMID- 20964675 TI - Localization of the motor endplate zone in human skeletal muscles of the lower limb: anatomical guidelines for injection with botulinum toxin. AB - AIM: Botulinum toxin gives a local tone reduction by blocking neurotransmission at the motor endplate (MEP). The importance of using MEP-targeted injections is demonstrated in animal models and in a clinical human study. The goal of this review is to present the available data on the localization of the MEP zone of frequently injected muscles of the lower limb and to compare this with current practice. METHOD: Current knowledge on the localization of the MEP zone is based on some older histological studies, and for some of the more frequently injected muscles also on more recent anatomical dissection. RESULTS: We find that for some muscles the MEP zone can be more precisely demarcated, and for many other muscles that its location is somewhat different than the currently injected areas in clinical practice. Optimal injection sites are presented for gastrocnemius, soleus, tibialis posterior, semitendinosus, semimembranosus, gracilis, biceps femoris, rectus femoris, adductor longus, brevis and magnus, and psoas muscles. INTERPRETATION: We propose optimal injection sites in relation to external anatomical landmarks for the frequently injected muscles of the human lower limb to facilitate the efficiency of botulinum toxin injections. PMID- 20964676 TI - Determinants of intensity of participation in leisure and recreational activities by children with cerebral palsy. AB - AIM: To test a model of child, family, and service determinants of intensity of participation in leisure and recreational activities by children with cerebral palsy (CP). METHOD: Participants were 288 children with CP, age range 6 to 12 years (mean 9y 8mo, SD 2y), and their parents from seven children's hospitals. The sample comprised 166 (57.6%) males and 122 (42.4%) females, and between 40 (13.9%) and 74 (25.7%) children in each of the five levels of the Gross Motor Function Classification System. Children completed the Children's Assessment of Participation and Enjoyment by interview. Parents completed the Pediatric Outcomes Data Collection Instrument, Family Environment Scale, Coping Inventory, Measure of Processes of Care, and two questionnaires. Structural equation modeling was used to test the model. RESULTS: Fit statistics indicated a good model fit. The model explains 32% of the variance in intensity of participation. Path coefficients (p <= 0.05) indicate that higher gross motor function, higher enjoyment, more effective adaptive behavior, younger age, and higher family activity orientation are associated with higher intensity of participation. The path between services and participation was not significant. INTERPRETATION: Intensity of participation of children with CP is influenced by multiple child and family determinants. Children's gross motor function and behavior in life situations are important for participation; knowledge of activities the child and family enjoy has implications for opportunities for participation. Professionals are encouraged to address priorities for leisure and recreation identified by children with CP and their families. PMID- 20964677 TI - Perinatal, maternal, and fetal characteristics of children diagnosed with attention-deficit-hyperactivity disorder: results from a population-based study utilizing the Swedish Medical Birth Register. AB - AIM: The aim of this study was to evaluate the impact of pre- and perinatal factors on the risk of developing attention-deficit-hyperactivity disorder (ADHD). METHOD: We investigated the medical history of 237 children (206 male; 31 female) from Malmo, Sweden born between 1986 and 1996 and in whom a diagnosis of ADHD (Diagnostic and Statistical Manual of Mental Disorders-IIIR or IV) was subsequently made at the Department of Child and Adolescent Psychiatry, Lund University, and a reference group of 31,775 typically developing children from Malmo using data from the Swedish Medical Birth Register. RESULTS: The results of multiple logistic regression analysis revealed that ADHD was significantly associated with a young maternal age (odds ratio [OR] for 5 y increase 0.87; 95% confidence interval [CI] 0.76-0.99), maternal smoking (OR 1.35; 95% CI 1.14 1.60), maternal birthplace in Sweden (OR 2.04; 95% CI 1.45-2.94), and preterm birth <32 weeks (OR 3.05; 95% CI 1.39-6.71), and a male predominance (OR 6.38; 95% CI 4.37-9.32). Apgar scores at 5 minutes below 7 were significantly associated with ADHD in the univariable analysis (OR 2.60; 95% CI 1.15-5.90). The population-attributable fraction of ADHD caused by the perinatal factors studied was estimated to be 2.8%. INTERPRETATION: The results indicate that the studied factors constitute weak risk factors for developing ADHD. PMID- 20964678 TI - The nonthyroidal illness syndrome in the non-critically ill patient. AB - BACKGROUND: The nonthyroidal illness syndrome (NTIS) is a very common clinical entity among hospitalized patients and has been reported in practically every severe illness and acute or chronic stressful event. There is a large body of data associating the presence of NTIS with the severity of the underlying disease. Most of these studies concern intensive care unit (ICU) patients, whereas the non-critically ill patients outside the ICU setting are less well studied. DESIGN: We provide a review of the existing literature focusing on studies examining NTIS in non-critically ill patients and attempt to summarize the pathophysiological pathways underlying the syndrome, its prognostic role, as well as the current intervention studies mainly from a clinical standpoint. RESULTS: The aetiology of the NTIS is multifactorial and varies among different groups of patients. Experimental and clinical findings suggest that inflammatory cytokines are implicated in the pathogenesis of the syndrome, whereas recent evidence re-evaluate the role of deiodinases in thyroid hormone metabolism not only in the periphery but also in the hypothalamus and the pituitary and thus in the alterations accompanying NTIS. Clinical data examining the effectiveness of thyroid hormone supplementation in NTIS remain controversial. CONCLUSIONS: As long as there is no clear evidence of benefit from thyroid hormone replacement and until well-designed studies confirm its efficacy, thyroxine supplementation should not be recommended for the treatment of NTIS. PMID- 20964679 TI - Fibroscan: a new noninvasive method for evaluation of liver dysfunction in Turner syndrome. AB - BACKGROUND: Raised liver enzyme value is frequently detected in patients with Turner syndrome (TS), but its clinical importance is still unclear. OBJECTIVE: To investigate the entity of liver involvement in TS and to avoid the invasiveness of liver biopsy, we planned to measure liver stiffness by transient elastography (TE). DESIGN: Cross-sectional study. PATIENTS AND METHODS: Twenty-five consecutive patients with TS and a chronological age >= 12.5 years (mean age = 21.7 years), full pubertal development and final height's achievement were enrolled and investigated by blood biochemical analyses [glucose, insulin, aspartate-aminotransferase (AST), alanine-aminotransferase (ALT), gamma-glutamil transferase (GGT), alkaline phosphatase, cholesterol, triglyceride, HDL cholesterol], ultrasonography and TE of the liver. RESULTS: Of 25, 7 subjects (28%) showed liver enzyme levels higher than the normal upper limit. Mean liver stiffness value in the entire study group was 4.5 +/- 1.7 kPa, being significantly higher in patients with abnormal liver enzymes than in those with normal liver biochemistry (6.0 +/- 2.9 vs. 4.0 +/- 0.9, P < 0.05). Strong correlations were found between TE values and ALT (P < 0.005), GGT (P < 0.0001), Body mass index (P < 0.05), HOMA index (P < 0.05), HDL-cholesterol (P < 0.05) and triglycerides (P < 0.0001). CONCLUSIONS: We can assert that (i) liver stiffness, measured by TE, strongly correlates with liver enzyme levels in patients with TS ; (ii) the increased liver stiffness in patients with TS with biochemical signs of liver dysfunction is significantly related to metabolic syndrome parameters; (iii) TE may be an useful tool to select among patients with TS with elevated liver enzymes or other metabolic risk factors, those who deserve more invasive diagnostic procedures, namely liver biopsy, for the best characterisation of liver damage. PMID- 20964680 TI - Potential clinical applications of siRNA technique: benefits and limitations. AB - BACKGROUND: RNA interference (RNAi) has become the method of choice for researchers wishing to target specific genes for silencing and has provided immense potential as therapeutic tools. This narrative review article aimed to understand potential benefits and limitations of RNAi technique for clinical application and in vivo studies through reading the articles published during the recent 3 years. MATERIALS AND METHODS: Medline database was searched by using 'siRNA' or 'RNAi' and 'in vivo' with limits of dates 'published in the last 3 years', language 'English' and article type 'clinical trial' for obtaining articles on in vivo studies on the use of RNAi technique. Characteristics of clinical trials on siRNA registered at the http://www.ClinicalTrials.gov were analysed. RESULTS: The only three clinical studies published so far and many in vivo studies in animals showed that the RNAi technique is safe and effective in treatment of cancers of many organ/systems and various other diseases including viral infection, arterial restenosis and some hereditary diseases with considerable benefits such as high specificity, many possible routes of administration and possibility of silencing multiple genes at the same time. Limitations and uncertainty include efficiency of cellular uptake, specific guidance to the target tissue or cell, long-term safety, sustained efficacy and rapid clearance from the body. CONCLUSIONS: RNAi technique will become an important and potent weapon for fighting against various diseases. RNAi technique has benefits and limitations in its potential clinical applications. Overcoming the obstacles is still a formidable task. PMID- 20964681 TI - Unbalanced expression of the translation complex eEF1 subunits in human cardioesophageal carcinoma. AB - BACKGROUND: The signalling role of individual subunits released from some stable translation multi-molecular complexes under unfavourable circumstances is known. The disease-related role of the translation elongation factor 1 complex (eEF1) as a whole is never researched; however, its subunits possess apparent regulatory potency. Whether the individual eEF1 subunits can exist and function in cell beyond the complex is not known. MATERIALS AND METHODS: The protein and mRNA levels of the A1, Balpha, Bbeta or Bgamma subunits of eEF1 were analysed by Western and Northern blot techniques in the same specimens of cardioesophageal carcinoma and correspondingly paired normal tissues. Cancer-induced changes in localization patterns of the eEF1 subunits were examined immunohistochemically. RESULTS: Changes in different eEF1 subunits expression were found to be unbalanced, indicating cancer-related emergence of individual components of the eEF1 complex. Independent overexpression of at least one eEF1 component was observed in 72% clinical samples. Noncomplexed eEF1B subunits were also detected by immunohistochemical analysis. In the normal tissue, localization of the Balpha, Bbeta and Bgamma subunits was nuclear-cytoplasmic while in the cancer tissue the only Bgamma subunit stayed in nucleus. CONCLUSIONS: Our data are first to indicate that the individual subunits can exist separately from the eEF1B complex in cancer tissues and that disintegration of eEF1B could be an important sign of cancer development. Nuclear localization of Bgamma both in normal and in cancer tissues suggests its previously unknown nucleus-specific role in human cells. PMID- 20964682 TI - Immunohistochemical analysis of paraoxonases-1 and 3 in human atheromatous plaques. AB - BACKGROUND: The paraoxonase (PON) enzyme family comprising PON1, PON2 and PON3 are antioxidant enzymes that degrade bioactive oxidised lipids and are thus antiatherogenic. MATERIALS AND METHODS: We investigated the localisation of the PON proteins during the development of atherosclerosis by immunohistochemical analysis. RESULTS: In normal aortas, PON1 and PON3 were localised to smooth muscle cells (SMC) and endothelial cells. PON3 staining was stronger than that of PON1. During atherosclerosis development, SMC staining for PON1 and PON3 was greatly reduced, while macrophage staining for both proteins increased with PON1 predominating. Macrophage staining for PON1 and PON3 was significantly and positively related to the amount of aortic inflammation (both P<0.001). CONCLUSIONS: Our data add support to the growing body of evidence for a cellular protective effect of PON1 and PON3 against the proinflammatory/proatherosclerotic effects of lipid peroxidation. PMID- 20964683 TI - Conservative coevolution of Mullerian mimicry in a group of rift lake catfish. AB - Biological mimicry has long been viewed as a powerful example of natural selection's ability to drive phenotypic evolution, although continuing debates surround the mechanisms leading to its development and the nature of these mimetic relationships. Mullerian mimicry, in which unpalatable species derive a mutual selective benefit through evolved phenotypic similarity, has alternatively been proposed to evolve through either a two-step process initiated by a large mutational change, or through continuous gradual evolution toward a common aposematic phenotype. I exposed a model predatory fish species to two species of endemic Lake Tanganyikan Synodontis to provide evidence for aposematism and the presence of Mullerian mimicry in these species. Predators quickly became conditioned to avoid the venomous catfish and did not discriminate between the two species when they were switched, supporting a hypothesis of functional Mullerian mimicry in this group of similarly colored fish. Ancestral state reconstructions and statistical comparisons of color pattern divergence in Tanganyikan Synodontis indicate that Mullerian mimicry in these catfish has developed through diversification of an aposematic common ancestor with subsequent conservative mutualistic coevolution among its daughter lineages, rather than advergent evolution of a mimic toward a nonrelated model, as assumed by widely accepted models of Mullerian mimicry evolution. PMID- 20964684 TI - Thermally contingent plasticity: temperature alters expression of predator induced colour and morphology in a Neotropical treefrog tadpole. AB - 1. Behavioural, morphological and coloration plasticity are common responses of prey to predation risk. Theory predicts that prey should respond to the relative magnitude of risk, rather than a single level of response to any risk level. In addition to conspecific and predator densities, prey growth and differentiation rates affect the duration of vulnerability to size- and stage-limited predators and therefore the relative value of defences. 2. We reared tadpoles of the Neotropical treefrog Dendropsophus ebraccatus with or without cues from a predator (Belostoma sp.) in ecologically relevant warm or cool temperatures. To track phenotypic changes, we measured morphology, tail coloration and developmental stage at three points during the larval period. 3. Cues from predators interacted with growth conditions causing tadpoles to alter their phenotype, changing only tail colour in response to predators in warm water, but both morphology and colour in cool growth conditions. Tadpoles with predators in warm water altered coloration early but converged on the morphology of predator free controls. Water temperature alone had no effect on tadpole phenotype. 4. We demonstrate that seemingly small variation in abiotic environmental conditions can alter the expression of phenotypic plasticity, consistent with predictions about how growth rate affects risk. Predator-induced tadpole phenotypes depended on temperature, with strong expression only in temperatures that slow development. Thermal modulation of plastic responses to predators may be broadly relevant to poikilotherm development. It is important to include a range of realistic growth conditions in experiments to more fully understand the ecological and evolutionary significance of plasticity. PMID- 20964685 TI - Contrasting covariation of above- and belowground invertebrate species across plant genotypes. AB - 1. Invertebrate species generally do not respond independently to genotypic variation in plants, giving rise to clusters of species that naturally associate with or avoid certain genotypes. This covariation causes coevolution to be diffuse rather than pairwise. Studies on this topic, however, have never considered the belowground invertebrate community, leaving a critical gap in our understanding. 2. We investigated the covariation among naturally colonising above- and belowground invertebrate species across six genetically distinct populations of the dune grass Ammophila arenaria. After having grown from seed in a common garden, plants were randomised in a single field site to exclude all but broad-sense genetic variation. 3. Strong positive covariation across genotypes among both above- and belowground invertebrates was detected, while correlations between these two groups were negative. This clustering of above- and belowground species matched well with order level taxonomy. Host range, trophic level and food type on the other hand did not correspond well with the clusters. Within the cluster of aboveground fauna, subsequent groupings were not related to any phylogenetic or ecological characteristic, although correlations within these subgroups were very high. We furthermore demonstrated significant differences in multiple invertebrate species occurrence between plant genotypes, in general as well as at the above- and belowground level. 4. The observed strong covariation suggests diffuse coevolution between A. arenaria and its associated invertebrate species. The trade-off between root and shoot invertebrates could however hamper directional selection on resistance to either group. 5. Our results clearly demonstrate the need for studies of plant-animal interactions to include the belowground fauna, as this might drastically alter our general conception of how plants and their associated animal communities interact and how these interactions shape the process of evolution. PMID- 20964686 TI - Parasitoid developmental mortality in the field: patterns, causes and consequences for sex ratio and virginity. AB - 1. Sex ratio theory predicts that developmental mortality can affect sex ratio optima under Local Mate Competition and also lead to 'virgin' broods containing only females with no sibling-mating opportunities on maturity. 2. Estimates of developmental mortality and its sex ratio effects have been laboratory based, and both models and laboratory studies have treated mortality as a phenomenon without identifying its biological causes. 3. We contribute a large set of field data on Metaphycus luteolus Timberlake (Hymenoptera: Encyrtidae), an endoparasitoid of soft scale insects (Hemiptera: Coccidae), which has sex allocation conditional on host quality and female-biased brood sex ratios. Developmental mortality within broods can be both assessed and attributed to distinct causes, including encapsulation by the host and larval-larval competition. 4. Thirty per cent of M. luteolus offspring die during development with 65% of this mortality because of encapsulation and 28% because of larval competition. The distributions of mortality overall and for each cause of mortality separately were overdispersed. 5. The probability of an individual being encapsulated increased with clutch size, while the probability of being killed by a brood mate declined with increasing clutch size and with increasing per capita availability of resources. 6. The sexual compositions of broods at emergence were influenced by both the degree and the type of mortality operating. At higher levels of mortality, single sex broods were more common and sex ratios were less precise. Overall, virginity was more prevalent than predicted and was more greatly affected by the occurrence of competition than by other sources of mortality, almost certainly because competition tended to eliminate males. 7. The reproductive and developmental biology of M. luteolus appears to be influenced by a complex interplay of maternal clutch size and sex allocation strategies, offspring-offspring developmental interactions, host defence mechanisms and postemergence mating behaviour. Despite the great sophistication of sex ratio theory, it has not yet evolved to the point where it is capable of considering all of these influences simultaneously. PMID- 20964687 TI - Density-dependent population dynamics and dispersal in heterogeneous metapopulations. AB - 1. Metapopulation microcosms were constructed to test the effect of four different types of habitat heterogeneity on the dynamics and dispersal in spatially extended systems; homogeneity, spatial heterogeneity, temporal heterogeneity and spatio-temporal heterogeneity. Resources were distributed across discrete habitat patches in bruchid beetle (Callosobruchus maculatus) metapopulations, and long-term time series were recorded. 2. Mathematical models were fitted to the long-term time series from the experimental systems using a maximum likelihood approach. Models were composed of separate birth, death, emigration and immigration terms all of which incorporated stochasticity drawn from different probability distributions. Models with density-dependent and density-independent birth, death and emigration terms were investigated and, in each case, the model that best described the empirical data was identified. 3. At the local scale, population sizes differed between patches depending on the type of heterogeneity. Larger populations were associated with higher resource availabilities. As a result of this, the variation between local population sizes was greatest when there was spatial heterogeneity in which mean resource abundance varied from patch to patch. Variation in population sizes within patches was largest when there was temporal heterogeneity. 4. Density-dependent processes leading to the regulation of local population dynamics in our experimental systems were strongest in homogeneity or temporal heterogeneity treatments. Associated with this, we found that these systems were best described using mathematical models with density dependence acting on mortality. In contrast, spatial and spatio-temporal time series were adequately described using density-independent population processes. 5. Experimental metapopulations showed varying degrees of density-dependent dispersal. Local net dispersal each week was primarily driven by the local population size and secondarily affected by neighbourhood population density. Mathematical population models illustrated the importance of explicit description of density-dependent dispersal in all systems except the homogeneous metapopulations. PMID- 20964688 TI - Administration of thiazolidinediones for neuroprotection in ischemic stroke: a pre-clinical systematic review. AB - Thiazolidinediones (TZDs) may prevent or attenuate CNS injury arising from an ischemic event. We performed meta-analysis of experimental studies in which a TZD (either rosiglitazone or pioglitazone) was administered in a rodent model of focal or global cerebral ischemia. Infarct volume was the primary endpoint for analysis of drug efficacy, and neurological outcome was also assessed. We identified 31 studies through the use of PubMed and Embase, 22 of which met our pre-specified inclusion criteria and were analyzed with the Cochrane Review Manager software. Treatment with TZDs decreased infarct volume and improved neurological outcome regardless of study quality, dose timing, or ischemia model (transient or permanent). Rosiglitazone and pioglitazone were similarly effective in reducing infarct volume and protecting neurologic function. Importantly, the collective data suggest that pre-treatment with a TZD is not required for neuroprotection, although additional studies are clearly needed to define the breadth of the therapeutic window. The data warrant further studies into the potential acute use of TZDs for ischemic stroke therapy in the general population. PMID- 20964689 TI - Regulation of protein kinase C Apl II by serotonin receptors in Aplysia. AB - Serotonin (5-hydroxytryptamine, 5HT) is the neurotransmitter that mediates dishabituation in Aplysia. Serotonin mediates this behavioral change through the reversal of synaptic depression in sensory neurons (SNs). However, the 5HT receptors present in SNs and in particular, the receptor important for activation of protein kinase C (PKC) have not been fully identified. Using a recent genome assembly of Aplysia, we identified new receptors from the 5HT(2) , 5HT(4) , and 5HT(7) families. Using RT-PCR from isolated SNs, we found that three 5HT receptors, 5HT(1Apl(a)) , 5HT(2Apl) , and 5HT(7Apl) were expressed in SNs. These receptors were cloned and expressed in a heterologous system. In this system, 5HT(2Apl) could significantly translocate PKC Apl II in response to 5HT and this was blocked by pirenperone, a 5HT(2) receptor antagonist. Surprisingly, pirenperone did not block 5HT-mediated translocation of PKC Apl II in SNs, nor 5HT-mediated reversal of depression. Expression of 5HT(1Apl(a)) in SNs or genistein, an inhibitor of tyrosine kinases inhibited both PKC translocation and reversal of depression. These results suggest a non-canonical mechanism for the translocation of PKC Apl II in SNs. PMID- 20964690 TI - Angiostrongylus vasorum infection in dogs: continuing spread and developments in diagnosis and treatment. AB - Disease caused by Angiostrongylus vasorum is increasingly diagnosed in dogs, as the geographic range of the parasite increases along with awareness among clinicians. Diagnosis, treatment and prevention are not always straightforward, although recent developments offer hope for improved options in future. Understanding of the epidemiology and pathogenesis remains poor. This paper provides an overview of the current state of knowledge of this parasitic disease, focussing on the most recent developments and advances. PMID- 20964691 TI - Tuber melanosporum: mating type distribution in a natural plantation and dynamics of strains of different mating types on the roots of nursery-inoculated host plants. AB - * In light of the recent finding that Tuber melanosporum, the ectomycorrhizal ascomycete that produces the most highly prized black truffles, is a heterothallic species, we monitored the spatial distribution of strains with opposite mating types (MAT) in a natural truffle ground and followed strain dynamics in artificially inoculated host plants grown under controlled conditions. * In a natural truffle ground, ectomycorrhizas (ECMs), soil samples and fruit bodies were sampled and genotyped to determine mating types. Simple sequence repeat (SSR) markers were also used to fingerprint ECMs and fruit bodies. The ECMs from nursery-inoculated host plants were analysed for mating type at 6 months and 19 months post-inoculation. * In open-field conditions, all ECMs from the same sampling site showed an identical mating type and an identical haploid genotype, based on SSR analysis. Interestingly, the gleba of fruit bodies always demonstrated the same genotype as the surrounding ECMs. Although root tips from nursery-grown plants initially developed ECMs of both mating types, a dominance of ECMs of the same MAT were found after several months. * The present study deepens our understanding of the vegetative and sexual propagation modes of T. melanosporum. These results are highly relevant for truffle cultivation. PMID- 20964692 TI - Alcohol dehydrogenase and hydrogenase transcript fluctuations during a day-night cycle in Chlamydomonas reinhardtii: the role of anoxia. AB - * The unicellular green alga Chlamydomonas reinhardtii contains two iron (Fe) hydrogenases which are responsible for hydrogen production under anoxia. In the present work the patterns of expression of alcohol dehydrogenase, a typical anaerobic gene in plants, of the hydrogenases genes (HYD1, HYD2) and of the genes responsible for their maturation (HYDEF, HYDG), were analysed. * The expression patterns were analysed by real-time reverse-transcription polymerase chain reaction in Chlamydomonas cultures during the day-night cycle, as well as in response to oxygen availability. * The results indicated that ADH1, HYD1, HYD2, HYDEF and HYDG were expressed following precise day-night fluctuations. ADH1 and HYD2 were modulated by the day-night cycle. Low oxygen plays an important role for the induction of HYD1, HYDEF and HYDG, while ADH1 and HYD2 expression was relatively insensitive to oxygen availability. * The regulation of the anaerobic gene expression in Chlamydomonas is only partly explained by responses to anoxia. The cell cycle and light-dark cycles are equally important elements in the regulatory network modulating the anaerobic response in Chlamydomonas. PMID- 20964693 TI - Jasmonate biosynthesis in legume and actinorhizal nodules. AB - Jasmonic acid (JA) is a plant signalling compound that has been implicated in the regulation of mutualistic symbioses. In order to understand the spatial distribution of JA biosynthetic capacity in nodules of two actinorhizal species, Casaurina glauca and Datisca glomerata, and one legume, Medicago truncatula, we determined the localization of allene oxide cyclase (AOC) which catalyses a committed step in JA biosynthesis. In all nodule types analysed, AOC was detected exclusively in uninfected cells. The levels of JA were compared in the roots and nodules of the three plant species. The nodules and noninoculated roots of the two actinorhizal species, and the root systems of M. truncatula, noninoculated or nodulated with wild-type Sinorhizobium meliloti or with mutants unable to fix nitrogen, did not show significant differences in JA levels. However, JA levels in all plant organs examined increased significantly on mechanical disturbance. To study whether JA played a regulatory role in the nodules of M. truncatula, composite plants containing roots expressing an MtAOC1-sense or MtAOC1-RNAi construct were inoculated with S. meliloti. Neither an increase nor reduction in AOC levels resulted in altered nodule formation. These data suggest that jasmonates are not involved in the development and function of root nodules. PMID- 20964694 TI - The degree of mycoheterotrophic carbon gain in green, variegated and vegetative albino individuals of Cephalanthera damasonium is related to leaf chlorophyll concentrations. AB - * Achlorophyllous variants of some forest orchids are known to reach almost the same size as their green forms. These vegetative albino forms cover their entire carbon (C) demand through fungi that simultaneously form ectomycorrhizae with trees, while green variants partially draw on C from photosynthesis and C from fungal hosts. Here, we investigate whether the amount of C derived from either source is proportional to leaf chlorophyll concentration. The discovery of two Cephalanthera damasonium populations with variegated leaves enabled a continuous bridging of leaf chlorophyll concentrations between green and albino forms. * Leaves of 27 green, variegated and albino individuals of C. damasonium were compared for chlorophyll concentrations, C sources (as characterized by (13)C abundances) and total C and nitrogen (N) concentrations. * We found a linear relationship between leaf chlorophyll concentrations and the proportional reliance on fungi as a C source. Furthermore, we show that the shift in C gain through mycoheterotrophic means significantly changes leaf total C and N concentrations. * Our results document that partial mycoheterotrophy in C. damasonium is not a static nutritional mode but a flexible mechanism related inter alia to leaf chlorophyll concentrations. The change in proportional reliance on fungi as a C source affects leaf chemical composition. PMID- 20964695 TI - Cognitive deficits in relation to personality type and hypothalamic-pituitary adrenal (HPA) axis dysfunction in women with stress-related exhaustion. AB - Exhaustion caused by long-term work-related stress may cause cognitive dysfunction. We explored factors that may link chronic stress and cognitive impairment. Personality, psychiatric screening, and behavior were assessed by self-reporting measures in 20 female patients (mean age 39.3 years; range 26-53) with a preliminary diagnosis of stress-related exhaustion and in 16 healthy matched controls. Cognitive performance was investigated with a detailed neuropsychological test battery. Cortisol axis function was assessed by urinary and saliva collections of cortisol, dexamethasone suppression, Synacthen response, and corticotropin-releasing hormone (CRH) tests. Proinflammatory cytokines were measured. Hippocampal volumes were estimated by magnetic resonance imaging. Multivariate and univariate statistical methods were used to explore putative differences between groups and factors linked to cognitive impairment. Cognitive function clearly differed between groups, with decreased attention and visuospatial memory in the patient group, suggesting frontal cortex/medial temporal cortex-network dysfunction. Increased harm avoidance and persistence was present among patients, with lowered self-directedness linked to lower quality of life, increased anxious and depressive tendencies, and experiences of psychosocial stress. Attention was decreased with concomitantly impaired visuospatial memory. The pituitary (adrenocorticotropic hormone, ACTH) response to CRH was decreased in patients, with an increased cortisol/ACTH response to CRH. However, cortisol production rates, diurnal or dexamethasone-suppressed saliva cortisol levels, and the cortisol response to Synacthen were unaltered. Hippocampal volumes did not differ between groups. These findings suggest that cognitive dysfunction in stress-related exhaustion is linked to distinct personality traits, low quality of life, and a decreased ACTH response to CRH. PMID- 20964696 TI - Cerebral cortical dynamics during visuomotor transformation: adaptation to a cognitive-motor executive challenge. AB - EEG was employed during cognitive-motor adaptation to a visuomotor transformation that required inhibition of an established motor plan. Performance was positively related to frontal alpha and theta power during both planning and execution of reaching movements to visual targets. EEG changes suggest initial involvement of frontal executive functioning to suppress established visuomotor mappings followed by progressive idling (i.e., alpha synchrony). Also, progressive idling of the temporal and parietal sites over the trials was observed, suggesting a decreasing role of working memory and encoding of the new visuomotor map, respectively. The regional changes in the cortical dynamics translated into the quality of motor behavior. This study expands our understanding of the role of frontal executive processes beyond the cognitive domain to the cognitive-motor domain. PMID- 20964697 TI - Highlights of the American Society for Artificial Internal Organs 2010 Conference. PMID- 20964698 TI - Flow analysis of ventricular assist device inflow and outflow cannula positioning using a naturally shaped ventricle and aortic branch. AB - Tip geometry and placement of rotary blood pump inflow and outflow cannulae influence the dynamics of flow within the ventricle and aortic branch. Cannulation, therefore, directly influences the potential for thrombus formation and end-organ perfusion during ventricular assist device (VAD) support or cardiopulmonary bypass (CPB). The purpose of this study was to investigate the effect of various inflow/outflow cannula tip geometries and positions on ventricular and greater vessel flow patterns to evaluate ventricular washout and impact on cerebral perfusion. Transparent models of a dilated cardiomyopathic ventricle and an aortic branch were reconstructed from magnetic resonance imaging data to allow flow measurements using particle image velocimetry (PIV). The contractile function of the failing ventricle was reproduced pneumatically, and supported with a rotary pump. Flow patterns were visualized around VAD inflow cannulae, with various tip geometries placed in three positions in the ventricle. The outflow cannula was placed in the subclavian artery and at several positions in the aorta. Flow patterns were measured using PIV and used to validate an aortic flow computational fluid dynamic study. The PIV technique indicated that locating the inflow tip in the left ventricular outflow tract improved complete ventricular washout while the tip geometry had a smaller influence. However, side holes in the inflow cannula improved washout in all cases. The PIV results confirmed that the positioning and orientation of the outflow cannula in the aortic branch had a high impact on the flow pattern in the vessels, with a negative blood flow in the right carotid artery observed in some cases. Cannula placement within the ventricle had a high influence on chamber washout. The positioning of the outflow cannula directly influences the flow through the greater vessels, and may be responsible for the occasional reduction in cerebral perfusion seen in clinical CPB. PMID- 20964699 TI - Interaction of an idealized cavopulmonary circulation with mechanical circulatory assist using an intravascular rotary blood pump. AB - This study evaluated the performance of an intravascular, percutaneously inserted, axial flow blood pump in an idealized total cavopulmonary connection (TCPC) model of a Fontan physiology. This blood pump, intended for placement in the inferior vena cava (IVC), is designed to augment pressure and blood flow from the IVC to the pulmonary circulation. Three different computational models were examined: (i) an idealized TCPC without a pump; (ii) an idealized TCPC with an impeller pump; and (iii) an idealized TCPC with an impeller and diffuser pump. Computational fluid dynamics analyses of these models were performed to assess the hydraulic performance of each model under varying physiologic conditions. Pressure-flow characteristics, fluid streamlines, energy augmentation calculations, and blood damage analyses were evaluated. Numerical predictions indicate that the pump with an impeller and diffuser blade set produces pressure generations of 1 to 16 mm Hg for rotational speeds of 2000 to 6000 rpm and flow rates of 1 to 4 L/min. In contrast, for the same flow range, the model with the impeller only in the IVC demonstrated pressure generations of 1 to 9 mm Hg at rotational speeds of 10,000 to 12,000 rpm. Influence of blood viscosity was found to be insignificant at low rotational speeds with minimal performance deviation at higher rotational speeds. Results from the blood damage index analyses indicate a low probability for damage with maximum damage index levels less than 1% and maximum fluid residence times below 0.6 s. The numerical predictions further indicated successful energy augmentation of the TCPC with a pump in the IVC. These results support the continued design and development of this cavopulmonary assist device. PMID- 20964700 TI - In vitro, computational, and in vivo thrombosis. PMID- 20964702 TI - Activation of the neutrophil respiratory burst by plasma from periodontitis patients is mediated by pro-inflammatory cytokines. AB - AIM: To determine the effect of periodontitis patients' plasma on the neutrophil oxidative burst and the role of albumin, immunoglobulins (Igs) and cytokines. MATERIALS AND METHODS: Plasma was collected from chronic periodontitis patients (n=11) and periodontally healthy controls (n=11) and used with/without depletion of albumin and Ig or antibody neutralization of IL-8, GM-CSF or IFN-alpha to prime/stimulate peripheral blood neutrophils, isolated from healthy volunteers. The respiratory burst was measured by lucigenin-dependent chemiluminescence. Plasma cytokine levels were determined by ELISA. RESULTS: Plasmas from patients were significantly more effective in both directly stimulating neutrophil superoxide production and priming for subsequent formyl-met-leu-phe (fMLP) stimulated superoxide production than plasmas from healthy controls (p<0.05). This difference was maintained after depletion of albumin and Ig. Plasma from patients contained higher mean levels of IL-8, GM-CSF and IFN-alpha. Individual neutralizing antibodies against IL-8, GM-CSF or IFN-alpha inhibited the direct stimulatory effect of patients' plasma, whereas the ability to prime for fMLP stimulated superoxide production was only inhibited by neutralization of IFN alpha. The stimulating and priming effects of control plasma were unaffected by antibody neutralization. CONCLUSIONS: This study demonstrates that plasma cytokines may have a role in inducing the hyperactive (IL-8, GM-CSF, IFN-alpha) and hyper-reactive (IFN-alpha) neutrophil phenotype seen in periodontitis patients. PMID- 20964703 TI - Degradation of phenanthrene via meta-cleavage of 2-hydroxy-1-naphthoic acid by Ochrobactrum sp. strain PWTJD. AB - The present study describes the assimilation of phenanthrene by an aerobic bacterium, Ochrobactrum sp. strain PWTJD, isolated from municipal waste contaminated soil sample utilizing phenanthrene as a sole source of carbon and energy. The isolate was identified as Ochrobactrum sp. based on the morphological, nutritional and biochemical characteristics as well as 16S rRNA gene sequence analysis. A combination of chromatographic analyses, oxygen uptake assay and enzymatic studies confirmed the degradation of phenanthrene by the strain PWTJD via 2-hydroxy-1-naphthoic acid, salicylic acid and catechol. The strain PWTJD could also utilize 2-hydroxy-1-naphthoic acid and salicylic acid, while the former was metabolized by a ferric-dependent meta-cleavage dioxygenase. In the lower pathway, salicylic acid was metabolized to catechol and was further degraded by catechol 2,3-dioxygenase to 2-hydroxymuconoaldehyde acid, ultimately leading to tricarboxylic acid cycle intermediates. This is the first report of the complete degradation of a polycyclic aromatic hydrocarbon molecule by Gram negative Ochrobactrum sp. describing the involvement of the meta-cleavage pathway of 2-hydroxy-1-naphthoic acid in phenanthrene assimilation. PMID- 20964704 TI - Pseudomonas aeruginosa and their small diffusible extracellular molecules inhibit Aspergillus fumigatus biofilm formation. AB - Aspergillus fumigatus is often isolated from the lungs of cystic fibrosis (CF) patients, but unlike in severely immunocompromised individuals, the mortality rates are low. This suggests that competition from bacteria within the CF lung may be inhibitory. The purpose of this study was to investigate how Pseudomonas aeruginosa influences A. fumigatus conidial germination and biofilm formation. Aspergillus fumigatus biofilm formation was inhibited by direct contact with P. aeruginosa, but had no effect on preformed biofilm. A secreted heat-stable soluble factor was also shown to exhibit biofilm inhibition. Coculture of P. aeruginosa quorum-sensing mutants (PAO1:DeltaLasI, PAO1:DeltaLasR) did not significantly inhibit A. fumigatus biofilms (52.6-58.8%) to the same extent as that of the PA01 wild type (22.9-30.1%), both by direct and by indirect interaction (P<0.001). Planktonic and sessile inhibition assays with a series of short carbon chain molecules (decanol, decanoic acid and dodecanol) demonstrated that these molecules could both inhibit and disrupt biofilms in a concentration dependent manner. Overall, this suggests that small diffusible and heat-stable molecules may be responsible for the competitive inhibition of filamentous fungal growth in polymicrobial environments such as the CF lung. PMID- 20964705 TI - Melatonin attenuates apoptotic liver damage in fulminant hepatic failure induced by the rabbit hemorrhagic disease virus. AB - Hepatocyte apoptosis plays an important role in the development of fulminant hepatic failure (FHF). The objective of this study was to investigate the antiapoptotic effect of melatonin in an animal model of FHF of viral origin induced by the rabbit hemorrhagic disease virus (RHDV). Rabbits were experimentally infected with 2 * 10(4) hemagglutination units of a RHDV isolate and received melatonin at two concentrations of 10 and 20 mg/kg at 0, 12, and 24 hr postinfection. RHDV infection induced liver apoptosis, with increased caspase 3 immunoexpression and activity and poly(ADP-ribose)polymerase-1 (PARP-1) proteolysis. These effects were attenuated by melatonin in a concentration dependent manner. Antiapoptotic effects of melatonin were related to a reduced expression of Bax and cytosolic cytochrome c release, increased expression of Bcl 2 and Bcl-xL, and inhibition of caspase-9 activity. Increased thiobarbituric reactive acid substances concentration and oxidized-to-reduced glutathione ratio were significantly prevented by melatonin administration. Melatonin treatment also resulted in a reduction in caspase-8 activity, tumor necrosis factor receptor-1 (TNF-R1) expression, and phosphorylated Janus kinase (JNK) expression, and increased expression of cellular FLICE-inhibitory protein (c-FLIP). Our findings show that inhibition of apoptotic mechanisms contributes to the beneficial effects of melatonin in rabbits with experimental infection by RHDV and supports a potential hepatoprotective role of melatonin in FHF. PMID- 20964706 TI - Oral melatonin attenuates lung inflammation and airway hyperreactivity induced by inhalation of aerosolized pancreatic fluid in rats. AB - Melatonin is a free radical scavenger with potent antioxidant properties and immunomodulatory effects. The purpose of this study was to determine the effects of orally administered melatonin in a pancreatic fluid (PF)-induced lung inflammation and airway hyperreactivity model. Aerosolized PF was introduced into airways to induce inflammation in rats. Animals were randomized into three experimental groups: sham treated; PF treated (200 MUL/kg); and PF with melatonin (10 mg/kg) pretreatment. Airway reactivity to methacholine, airflow and airway resistance, bronchoalveolar lavage (BAL) cellular differential, the tumor necrosis factor alpha (TNFalpha) level, lavage nitric oxide, hydroxyl radical, and lactic dehydrogenase (LDH) were compared among groups. mRNA expressions of inducible nitric oxide synthase (iNOS) and TNFalpha in lung tissues were determined by real-time polymerase chain reaction. Protein expressions of iNOS and nitrotyrosine and lung tissue myeloperoxidase (MPO) activity were determined using an ELISA assay. Oral melatonin treatment indicated anti-inflammatory efficacy as evidenced by decreased methacholine sensitivity by 24% and airway obstruction by 28%, reduction in BAL eosinophil (P < 0.01) and neutrophil counts (P < 0.05), LDH (P < 0.05), and TNFalpha concentrations (P < 0.05) when compared to levels in sham-treated rats. Melatonin-treated animals also had reduced nitric oxide and hydroxyl radical concentrations (P < 0.05) in lavage fluid. Oral melatonin significantly reduced mRNA and protein expression of iNOS (P < 0.05 and P < 0.01, respectively), TNFalpha (P < 0.05), nitrotyrosine (P < 0.05), and MPO activity (P < 0.05) in lung tissues when compared with the sham-treated animals. These results suggest that oral treatment with melatonin had a beneficial effect on PF-induced obstructive ventilatory insufficiency by attenuating nitrosative and oxidative stress. PMID- 20964707 TI - Melatonin triggers PKA activation in the rodent malaria parasite Plasmodium chabaudi. AB - Calcium (Ca(2+) ) is a critical regulator of many aspects of the Plasmodium reproductive cycle. In particular, intra-erythrocyte Plasmodium parasites respond to circulating levels of the melatonin in a process mediated partly by intracellular Ca(2+) . Melatonin promotes the development and synchronicity of parasites, thereby enhancing their spread and worsening the clinical implications. The signalling mechanisms underlying the effects of melatonin are not fully established, although both Ca(2+) and cyclic AMP (cAMP) have been implicated. Furthermore, it is not clear whether different strains of Plasmodium use the same, or divergent, signals to control their development. The aim of this study was to explore the signalling mechanisms engaged by melatonin in P. chabaudi, a virulent rodent parasite. Using parasites at the throphozoite stage acutely isolated from mice erythrocytes, we demonstrate that melatonin triggers cAMP production and protein kinase A (PKA) activation. Interestingly, the stimulation of cAMP/PKA signalling by melatonin was dependent on elevation of Ca(2+) within the parasite, because buffering Ca(2+) changes using the chelator BAPTA prevented cAMP production in response to melatonin. Incubation with melatonin evoked robust Ca(2+) signals within the parasite, as did the application of a membrane-permeant analogue of cAMP. Our data suggest that P. chabaudi engages both Ca(2+) and cAMP signalling systems when stimulated by melatonin. Furthermore, there is positive feedback between these messengers, because Ca(2+) evokes cAMP elevation and vice versa. Melatonin more than doubled the observed extent of parasitemia, and the increase in cAMP concentration and PKA activation was essential for this effect. These data support the possibility to use melatonin antagonists or derivates in therapeutic approach. PMID- 20964708 TI - Protective role of endogenous melatonin in the early course of human acute pancreatitis. AB - Melatonin plays a protective role in experimental acute pancreatitis (AP) because of its antioxidative, antiinflammatory, and immunomodulatory effects. This study presents the first data on the dynamic changes of endogenous melatonin in the early phase of human AP. Morning (08:00 hr) serum melatonin concentrations were measured by ELISA in 75 patients with AP for the first 5 days after the onset of pain. According to the Atlanta classification, 26 patients suffered a mild AP (MAP). The other 49 developed a severe AP (SAP). Median melatonin concentrations of healthy volunteers were used as a control. Median melatonin level in healthy controls was 18.5 pg/mL. Levels of melatonin were significantly higher in the first 24 hr after onset of disease in patients with MAP compared to those with SAP, 51.2 versus 8.7 pg/mL (P = 0.01). Melatonin values were the same in MAP and SAP during the remainder of the study period. Melatonin concentrations during the first 24 hr after the onset of pain in younger patients (<35 yrs old) were significantly higher than levels in older patients (>35 yrs): 73 versus 8.7 pg/mL (P = 0.01). No correlation existed between melatonin levels and the following parameters: gender, etiology (biliary versus alcohol induced), and histological findings (edematous versus necrotizing versus infected necrosis). High endogenous melatonin serum levels in the first 24 hr after the onset of AP played a protective role and favoured a mild course of the disease in humans, especially in young patients. PMID- 20964709 TI - Matrix metalloproteinases in health and disease: regulation by melatonin. AB - Matrix metalloproteinases (MMPs) are part of a superfamily of metal-requiring proteases that play important roles in tissue remodeling by breaking down proteins in the extracellular matrix that provides structural support for cells. The intricate balance in protease/anti-protease stoichiometry is a contributing factor in a number of diseases. Melatonin possesses multifunctional bioactivities including antioxidative, anti-inflammatory, endocrinologic and behavioral effects. As melatonin affects the redox status of tissues, the association of reactive oxygen species (ROS) with tissue injury under different circumstances may be mitigated by melatonin. Redox signaling is expanding into all areas of basic and clinical sciences, and this timely review focuses on the topic of regulation of MMP activities by melatonin. This is a rapidly growing field. Accumulating evidence indicates that oxidative stress plays an important role in regulating the activities of MMPs that are involved in various cellular processes such as cellular proliferation, angiogenesis, apoptosis, invasion and metastasis. This review offers sections on MMPs, melatonin, major physiological and pathophysiological conditions in the context to MMPs, followed by redox signaling mechanisms that are known to influence the cellular processes. Finally, we discuss the emerging molecular mechanisms relevant to regulatory actions of melatonin on the activities of MMPs. The possibility that melatonin might have therapeutic significance via regulation of MMPs may be a novel approach in the treatment of some diseases. PMID- 20964710 TI - Melatonin or silymarin reduces maneb- and paraquat-induced Parkinson's disease phenotype in the mouse. AB - Oxidative stress is reported as one of the most widely accepted mechanisms of maneb (MB)- and paraquat (PQ)-induced nigrostriatal dopaminergic neurodegeneration leading to the Parkinson's disease (PD) phenotype. The study investigated the effects of silymarin, an antioxidant of plant origin, and melatonin, an indoleamine produced in all species, in MB- and PQ-induced mouse model of PD. The mice were treated intraperitoneally daily with silymarin (40mg/kg) or melatonin (30mg/kg) along with respective controls for 9wk. Subsets of these animals were also treated with MB (30mg/kg) and PQ (10mg/kg), twice a week, for 9wk, 2hr after silymarin/melatonin treatment. Locomotor activities along with striatal dopamine content, tyrosine hydroxylase (TH) immunoreactivity, number of degenerating neurons, lipid peroxidation and nitrite content were estimated. Additionally, mRNA expression of vesicular monoamine transporter, cytochrome P-450 2E1 (CYP2E1), and glutathione-S-transferase A4-4 (GSTA4-4), catalytic activities of CYP2E1 and GSTA4-4 and protein expressions of unphosphorylated and phosphorylated p53 (p53 and P-p53), Bax and caspase 9 were measured in control and MB- and PQ-treated mice with either silymarin or melatonin treatments. Silymarin/melatonin significantly offset MB- and PQ mediated reductions in locomotor activities, dopamine content, TH immunoreactivity, VMAT 2 mRNA expression and the expression of p53 protein. Silymarin/melatonin attenuated the increases in lipid peroxidation, number of degenerating neurons, nitrite content, mRNA expressions of cytochrome P-450 2E1 (CYP2E1) and GSTA4-4, catalytic activities of CYP2E1 and GST and P-p53, Bax and caspase 9 protein expressions. The results demonstrate that silymarin and melatonin offer nigrostriatal dopaminergic neuroprotection against MB- and PQ induced PD by the modulation of oxidative stress and apoptotic machinery. PMID- 20964711 TI - High endogenous melatonin concentrations enhance sperm quality and short-term in vitro exposure to melatonin improves aspects of sperm motility. AB - Although human seminal fluid contains melatonin and spermatozoa reportedly possess membrane melatonin receptors, there are no experimental studies that have ascertained the relationship between melatonin and male infertility. This study evaluated whether urinary 6-sulfatoxymelatonin and urinary total antioxidant capacity correlate with different seminal parameters including sperm concentration, motility and morphology. Also, the in vitro effects of melatonin on human sperm motility were investigated. Semen samples from 52 men who were counselled for infertility were obtained. Sperm concentration was determined using the haemocytometer method, motility kinematic parameters were assessed using a computer-aided semen analysis system, while morphology and vitality were evaluated after Diff-Quick and Eosin-Nigrosin vital staining, respectively. For the quantification of urinary 6-sulfatoxymelatonin, a commercial ELISA kit was used, and urinary total antioxidant capacity was evaluated by means of a colorimetric assay kit. For the in vitro effects of melatonin, samples were incubated for 30min in the presence or absence of 1mm melatonin. Both urinary 6 sulfatoxymelatonin and total antioxidant capacity levels positively correlated with sperm concentration, motility and morphology, as well as negatively correlated with the number of round cells. Additionally, 30-min exposure of sperm to 1mm melatonin improved the percentage of motile and progressively motile cells and decreased the number of static cells, thereby promoting the proportion of rapid cells. Therefore, melatonin improves semen quality, which is important because melatonin supplementation may be potentially used to obtain a successful assisted reproductive technique outcome. PMID- 20964712 TI - Limitations of gravity models in predicting the spread of Eurasian watermilfoil. AB - The effects of non-native invasive species are costly and environmentally damaging, and resources to slow their spread and reduce their effects are scarce. Models that accurately predict where new invasions will occur could guide the efficient allocation of resources to slow colonization. We assessed the accuracy of a model that predicts the probability of colonization of lakes in Wisconsin by Eurasian watermilfoil (Myriophyllum spicatum). We based this predictive model on 9 years (1990-1999) of sequence data of milfoil colonization of lakes larger than 25 ha (n =1803). We used milfoil colonization sequence data from 2000 to 2006 to test whether the model accurately predicted the number of lakes that actually were colonized from among the 200 lakes identified as being most likely to be colonized. We found that a lake's predicted probability of colonization was not correlated with whether a lake actually was colonized. Given the low predictability of colonization of specific lakes, we compared the efficacy of preventing milfoil from leaving occupied sites, which does not require predicting colonization probability, with protecting vacant sites from being colonized, which does require predicting colonization probability. Preventing organisms from leaving colonized sites reduced the likelihood of spread more than protecting vacant sites. Although we focused on the spread of a single species in a particular region, our results show the shortcomings of gravity models in predicting the spread of numerous non-native species to a variety of locations via a wide range of vectors. PMID- 20964713 TI - Complementarity of no-take marine reserves and individual transferable catch quotas for managing the line fishery of the great barrier reef. AB - Changes in the management of the fin fish fishery of the Great Barrier Reef motivated us to investigate the combined effects on economic returns and fish biomass of no-take areas and regulated total allowable catch allocated in the form of individual transferable quotas (such quotas apportion the total allowable catch as fishing rights and permits the buying and selling of these rights among fishers). We built a spatially explicit biological and economic model of the fishery to analyze the trade-offs between maintaining given levels of fish biomass and the net financial returns from fishing under different management regimes. Results of the scenarios we modeled suggested that a decrease in total allowable catch at high levels of harvest either increased net returns or lowered them only slightly, but increased biomass by up to 10% for a wide range of reserve sizes and an increase in the reserve area from none to 16% did not greatly change net returns at any catch level. Thus, catch shares and no-take reserves can be complementary and when these methods are used jointly they promote lower total allowable catches when harvest is relatively high and encourage larger no-take areas when they are small. PMID- 20964714 TI - Value plurality among conservation professionals. AB - Debate on the values that underpin conservation science is rarely based on empirical analysis of the values conservation professionals actually hold. We used Q methodology to investigate the values held by international conservation professionals who attended the annual Student Conference in Conservation Science at the University of Cambridge (U.K.) in 2008 and 2009. The methodology offers a quantitative means of examining human subjectivity. It differs from standard opinion surveys in that individual respondents record the way they feel about statements relative to other statements, which forces them to focus their attention on the issues they believe are most important. The analysis extracts the diverse viewpoints of the respondents, and factor analysis is used to reduce the viewpoints to a smaller set of factors that reflect shared ways of thinking. The junior conservation professionals attending the conference did not share a unifying set of core values; rather, they held a complex series of ideas and a plurality of opinions about conservation and how it should be pursued. This diversity of values empirically challenges recent proposals for conservation professionals to unite behind a single philosophy. Attempts to forge an artificial consensus may be counterproductive to the overall goals conservation professionals are pursuing. PMID- 20964715 TI - Plasma adiponectin concentration and left ventricular hypertrophy in kidney transplant patients. AB - BACKGROUND: Low plasma adiponectin concentration is associated with more frequent occurrence of left ventricular hypertrophy (LVH) and more exaggerated intima media thickness of common carotid artery (IMT). IMT is an early surrogate marker of atherosclerosis. This study aimed to assess the relationship between plasma adiponectin concentration and left ventricular mass index (LVMI) and IMT in kidney transplant patients (KTP). METHODS: In 88 adult KTP, plasma adiponectin concentration, LVMI, and IMT were estimated. LVH was defined as LVMI >110 or >125 g/m(2) for females and males, respectively. Data presented are means and 95% CI. RESULTS: Plasma adiponectin concentration was similar in KTP with (n = 42) or without LVH (n = 46) (13.5 [11.4-15.6] vs. 13.1 [11.6-14.6] MUg/mL, respectively), as well as in KTP subgroups divided according to the IMT value tertiles (p = 0.42) (11.7 [10.0-13.3], 14.2 [11.7-16.6], and 14.0 [11.7-16.4] MUg/mL in the lowest, middle, and highest tertiles, respectively). Plasma glucose concentrations were similar in KTPs with LVH or without LVH. No significant correlation was found between plasma adiponectin concentration and both LVMI (R = -0.02; p = 0.87) and IMT (R = 0.09; p = 0.38), respectively. CONCLUSION: Results of this cross-sectional study do not confirm the roles of low adiponectin and high glucose in the pathogenesis of LVH and atherosclerosis in KTP. PMID- 20964716 TI - Accepting a donor kidney: an evaluation of patients' and transplant surgeons' priorities. AB - BACKGROUND: Despite a trend toward patient autonomy in clinical practice, the decision whether or not to accept a kidney for transplantation is made predominantly by the transplant surgeon. The purpose of this study is to examine how patients and surgeons prioritize relevant factors when deciding to accept or decline an available kidney. METHODS: We elicited patient and surgeon rankings for a list of factors involved in the decision using a validated computer survey. We computed the relative importance of each factor and examined associations between patient characteristics and priorities using Spearman's correlation coefficient and the Mann-Whitney U-test for continuous and categorical variables, respectively. RESULTS: Patients placed the greatest value on kidney quality and predictors of transplant outcome. Patients who were on the waiting list longer gave less importance to kidney quality and function. Surgeons placed the greatest value on kidney quality, difficulty for the patient to be matched to a kidney, and the age of the donor. CONCLUSION: The results of this study suggest that decision support tools can be used to improve the understanding of patient priorities in the decision to accept a donor kidney. PMID- 20964717 TI - The relative risk of overall graft loss and acute rejection among African American renal transplant recipients is attenuated with advancing age. AB - BACKGROUND: Graft loss rates are elevated among African American (AA) kidney transplant recipients. This may be attributable to immunological responses, socioeconomic disparities, comorbid conditions and access to care, but it is unclear whether risks are uniform in the AA population. METHODS: We utilized multivariable models with the national SRTR database for adult recipients transplanted from 2000 to 2009 (n = 112,120) to investigate whether risks of graft loss, death and acute rejection between AAs and Caucasians vary with age. RESULTS: Relative to Caucasians, AA recipients had significantly higher risk of overall graft loss among patients aged 18-49 (AHR = 1.37, 95% CI 1.30-1.43) but comparable risk among patients aged >65 (AHR = 1.04, 95% CI 0.96-1.13). Among recipients aged 18-34, AAs had higher risk of acute rejection (AOR = 1.33, 95% CI 1.12-1.57) but similar likelihood among recipients aged >65 (AOR = 0.94, 95% CI 0.75-1.17). Differences between race groups, as well as the relatively higher risks among younger AAs, were most pronounced following one yr post transplantation and diminished with presence of other risk factors. CONCLUSIONS: Elevated risks of overall graft loss and acute rejection are present among younger but not older AA kidney transplant recipients. These findings may have important implications for treatment decisions, follow-up protocols and designation of "high-risk" patients. PMID- 20964719 TI - Extensive soft-tissue involvement by plasmablastic myeloma arising from displaced humeral fractures. AB - A 44-yr-old man with IgG-lambda multiple myeloma reached a complete response after induction chemotherapy and autologous stem cell transplantation and maintenance therapy with interferon alpha2b and prednisone 4 yr later, he presented an increase in the M-protein plus extramedullary myeloma involvement with sacrum and clivus plasmacytomas. Treatment with bortezomib, cyclophosphamide and dexamethasone plus local radiotherapy was initiated. The patient developed a bilateral humeral pathological fracture. Surgical osteosynthesis of both humeri was performed with no immediate complications. Two months later, he developed a prominent swelling in both deltoid areas with fever and high serum LDH levels. X ray examination showed a displacement of bone fragments of both humeri. Humerus CT scan showed a bilateral fracture in proximal diaphysis with posterior displacement. A magnetic resonance of right scapular region revealed a very extensive infiltration originated in the humerus. A fine-needle punction showed a diffuse plasmablastic infiltration. This case illustrates an atypical presentation of extramedullary myeloma with extensive soft-tissue involvement, originated at the fractured lytic lesions, which was likely triggered by bone surgery. This direct mechanism of myeloma spread has been observed in experimental myeloma mouse models. PMID- 20964718 TI - Macrophage activation is associated with poorer long-term outcomes in renal transplant patients. AB - Long-term graft and patient survival after renal transplantation are largely determined by progression of chronic allograft dysfunction and cardiovascular disease. Inflammation plays a crucial role in both disease processes. We prospectively analyzed the association of early peri-transplant inflammatory burden on long-term outcomes in 144 consecutive deceased donor renal allograft recipients. Single time point and cumulative levels of markers of acute phase response (serum amyloid A [SAA] and C-reactive protein [SCRP]) and macrophage activation (serum and urine neopterin) were measured daily during the immediate post-operative period. Mean patient follow-up was 16 yr. Graft and patient survival rates at one-, five-, and 10-yr were 90%, 70%, and 51%, and 97%, 77%, and 59%, respectively. Graft loss occurred in 90 patients, of whom 71 died with a functioning graft and 19 returned to dialysis. CRP, SAA and neopterin (NEOP) levels were all elevated post-operatively. High levels of NEOP, in contrast to SAA or SCRP, were associated with poorer graft and patient survival (p < 0.05), specifically with death from cardiovascular events and cytomegalovirus IgG positivity. These findings strongly suggest that early post-transplant macrophage activation, as reflected by NEOP levels, is associated with poorer long-term graft and patient survival. PMID- 20964720 TI - Howell-Jolly-like bodies in leucocytes: first description in leucocytes other than neutrophils. PMID- 20964721 TI - Cryptic splice site usage leading to truncated TMPRSS6 is responsible for iron refractory iron deficiency anaemia in an Italian Family. PMID- 20964722 TI - Structure and gene cluster of the O-antigen of Escherichia coli O109; chemical and genetic evidences of the presence of L-RhaN3N derivatives in the O-antigens of E. coli O109 and O119. AB - O-antigen representing the O-polysaccharide chain of the lipopolysaccharide is the most variable constituent on the cell surface of Gram-negative bacteria and a player in their pathogenicity. The O-polysaccharide of Escherichia coli O109 was studied by sugar analysis and nuclear magnetic resonance spectroscopy and found to contain a rarely occurring monosaccharide, 2,3-diacetamido-2,3,6-trideoxy-l mannose (l-RhaNAc3NAc). The following structure of the tetrasaccharide repeating unit of the O-polysaccharide was established, which is closely related to that of Proteus penneri O66: Ac--4-beta-L-RhapNAc3NAc -->4)-alpha-D-Glcp-(1-->3)-alpha-L 6dTalp-(1-->3)-beta-D-GlcpNAc-(1-->. The O-antigen gene cluster of E. coli O109 was sequenced and all 14 genes found were assigned functions based on their similarity to genes from the available databases. Putative genes for synthesis of l-RhaN3N were found in E. coli O109 and their homologues in E. coli O119, whose O antigen has been reported earlier to contain 2-acetamido-2,3,6-trideoxy-3 formamido-d-mannose (d-RhaNAc3NFo). Analysis by GLC of the (S)-2-octyl glycosides confirmed that the absolute configuration of RhaN3N in E. coli O119 should be revised from D TO L. PMID- 20964723 TI - Analysis of apoptosis and Bcl-2 expression in polar forms of leprosy. AB - Apoptosis eliminates pathogen-infected cells. Its modulation can influence the course of infections, permitting the survival of intracellular pathogens. In leprosy, which presents several clinical manifestations related to bacillary burden and host immune status, the mechanisms responsible for the persistence of the bacillus are unknown. Few studies have focused on apoptosis over the disease spectrum and as a defense mechanism against Mycobacterium leprae. We evaluated apoptosis using terminal transferase dUTP nick end labeling and the expression of Bcl-2 by immunohistochemistry in skin lesions from 11 tuberculoid and 15 lepromatous leprosy patients. Each specimen was evaluated by determining the number of positive cells in 10 fields at * 400 magnification. We observed a higher number of apoptotic cells in tuberculoid lesions in comparison with lepromatous leprosy (42.5 cells per 10 fields vs. 11.5 cells per 10 fields, P<0.0001). Expression of Bcl-2, conversely, was larger in lepromatous than in tuberculoid samples (172.0 cells per 10 fields vs. 17.7 cells per 10 fields, P<0.0001). These observations suggest modulation of apoptosis in leprosy, primarily in lepromatous patients, for which the decrease in cell death could support M. leprae survival and contribute to the success of infection. Conversely, in tuberculoid patients, apoptosis could contribute to reducing propagation of the bacillus. PMID- 20964724 TI - Analysis of the attitudes and motivations of the Spanish population towards organ donation after death. AB - Starting with the relevance of the Spanish experience, this study analyses the population's disposition towards organ donation after death by means of a representative survey of the adult Spanish population (N = 1206, estimated error +/-2.87%, P < 0.05). Of the participants, 8.1% were declared donors, 59.3% were likely to donate, 14.5% were against donating and 18.1% did not know or did not respond; 87.3% would donate relative's organs if the deceased favoured donation, 50.2% if the deceased's wishes were unknown and 13.1% even if the deceased opposed donation. Among people who were favourable towards donation, the main motives expressed were the will to save other people's lives, solidarity and knowing they might someday need a donation. The most important motives for not donating among participants who were against it were the fear of premature organ extraction, of premature pronouncement of death and of mutilation. Reticence to donate is associated with low socio-economic and cultural level, advanced age and high religious commitment; it is also associated with a low perception of transplant efficacy, not directly knowing any transplanted people and the lack of qualified information. The results support diverse potentially effective strategies for promoting donation in the general population. PMID- 20964725 TI - A more selective costimulatory blockade of the CD28-B7 pathway. AB - Progress from the last decade in the understanding of T-cell activation has led to new immunotherapeutic strategies for the treatment of immunological diseases. Since the discovery of costimulatory molecules in the 1980s, the field of T-cell costimulation blockade has literally exploded and now spanned 'from bench to bedside'. Such alternative therapies result in more selective effects specializing their action on Ag-experienced T lymphocytes. This can potentially prevent the progression of autoimmune diseases, allograft rejection and may even induce immune tolerance. In the 1990 s, the CD28/B7/CTLA-4 pathway was identified as a crucial regulator of T-cell activation and tolerance induction. Here, we have summarized our current understanding of this complex costimulatory pathway involving co-stimulatory and co-inhibitory molecules and the way we can manipulate these molecules to inhibit, stimulate or kill target cells in experimental preclinical models as well as in clinical trials. We have also reviewed the role of costimulation in the biology of CD4+ CD25+ Foxp3+ regulatory T cells. PMID- 20964726 TI - Moment of addition of LH to the culture medium improves in vitro survival and development of secondary goat pre-antral follicles. AB - The present study investigated the effects of time of addition of luteinizing hormone (LH) to culture medium on the in vitro development of caprine pre-antral follicles. Pre-antral follicles (>= 150 MUm) were isolated from fragments of the goat ovarian cortex and individually cultured for 18 days in the absence (control) or presence of 100 ng/ml LH, added on days 0, 6 or 12 of culture. Follicular development was assessed based on antral cavity formation, increased follicular diameter as well as follicular and fully grown oocyte (>110 MUm) viability. The results showed that after 18 days of culture, the percentage of surviving follicles in the control treatment was significantly lower when compared to other treatments (p < 0.05). There were no significant differences in antrum formation, follicular diameter and oocyte viability. The addition of LH at D6 of culture significantly increased the rates of oocytes >= 110 MUm and the resumption of meiosis (p < 0.05). In contrast, when LH was added at the onset of culture, only germinal vesicle oocytes were obtained. In conclusion, the moment of addition of LH to the culture medium affects the performance of in vitro culture of caprine pre-antral follicles. The addition of LH to the medium from day 6 of culture onward improved the rates of follicular survival, as well as the ability of oocytes to resume meiosis. However, prolonged exposure to LH (addition at the onset of culture onward) showed detrimental effects for the meiotic resumption. PMID- 20964727 TI - Clinical use of GnRH agonists in canine and feline species. AB - GnRH (gonadotrophin releasing hormone) is a key hormone of reproductive function in mammals; agonist forms have been largely developed, and data concerning their use in small animal reproduction are now abundant. GnRH agonists act by a two step mechanism. First, their agonist properties on the pituitary will cause marked LH (luteinizing hormone) and FSH (follicle-stimulating hormone) secretion into the bloodstream, accompanied by an increase in the concentrations of sex steroid hormones. Then, in case of constant administration, GnRH agonists will lead to pituitary desensitization, and FSH and LH levels will collapse. These two effects have been widely documented, and these compounds have many potential benefits in a clinical context, capitalizing both on their stimulating and sterilizing effects. PMID- 20964728 TI - Influence of the semen deposition site on the calves' sex ratio in Simmental dairy cattle. AB - It has been suggested that the time of insemination has effect on the calves' sex ratio because of the differences in timing of capacitation, motility and survival time of the X and Y spermatozoa in the female reproductive tract. We have conducted a field trial to study the effects of different semen deposition sites on the sex ratio and fertility in cattle. Two groups of 450 cows were inseminated via artificial insemination: group A was inseminated into the uterine body and group B was inseminated deep into the uterine horn ipsilateral to the ovary with dominant follicle. After applying several exclusion criteria, a total of 607 pregnant cows were considered for data analysis (group A = 318 and group B = 289 cows). The conception rate was 7% higher (p < 0.05) in the group A, with 23% more of the male calf pregnancies (p < 0.001). At the same time, 18% more of the female calves were calved in the group B (p < 0.005). The difference in male calves between the two groups was 21% and in female calves was 20% (p < 0.001). We conclude that semen deposition site plays a significant role in differences in gender ratio observed after calving. Intracornual semen deposition resulted in a higher ratio of female calves, whereas uterine body deposition site resulted in higher male calves ratio, probably contributing physiologically to the differences in motility, capacitation time, the lifespan of X vs Y spermatozoa and to the pronounced shift of X spermatozoa in the female genital tract. PMID- 20964729 TI - Polarized targeting of L1-CAM regulates axonal and dendritic bundling in vitro. AB - Proper axonal and dendritic bundling is essential for the establishment of neuronal connections and the synchronization of synaptic inputs, respectively. Cell adhesion molecules of the L1-CAM (L1-cell adhesion molecule) family regulate axon guidance and fasciculation, neuron migration, dendrite morphology, and synaptic plasticity. It remains unclear how these molecules play so many different roles. Here we show that polarized axon-dendrite targeting of an avian L1-CAM protein, NgCAM (neuron-glia cell adhesion molecule), can regulate the switch of bundling of the two major compartments of rat hippocampal neurons. Using a new in-vitro model for studying neurite-neurite interactions, we found that expressed axonal NgCAM induced robust axonal bundling via the trans homophilic interaction of immunoglobulin domains. Interestingly, dendritic bundling was induced by the dendritic targeting of NgCAM, caused by either deleting its fibronectin repeats or blocking activities of protein kinases. Consistent with the NgCAM results, expression of mouse L1-CAM also induced axonal bundling and blocking kinase activities disrupted its axonal targeting. Furthermore, the trans-homophilic interaction stabilized the bundle formation, probably through recruiting NgCAM proteins to contact sites and promoting guided axon outgrowth. Taken together, our results suggest that precise localization of L1-CAM is important for establishing proper cell-cell contacts in neural circuits. PMID- 20964730 TI - Nigral and striatal regulation of angiotensin receptor expression by dopamine and angiotensin in rodents: implications for progression of Parkinson's disease. AB - The basal ganglia have a local renin-angiotensin system and it has been shown that the loss of dopaminergic neurons induced by neurotoxins is amplified by local angiotensin II (AII) via angiotensin type 1 receptors (AT1) and nicotinamide adenine dinucleotide phosphate (NADPH) complex activation. Recent studies have revealed a high degree of counter-regulatory interactions between dopamine and AII receptors in non-neural cells such as renal proximal tubule cells. However, it is not known if this occurs in the basal ganglia. In the striatum and nigra, depletion of dopamine with reserpine induced a significant increase in the expression of AT1, angiotensin type 2 receptors (AT2) and the NADPH subunit p47(phox) , which decreased as dopamine function was restored. Similarly, 6-hydroxydopamine-induced chronic dopaminergic denervation induced a significant increase in expression of AT1, AT2 and p47(phox) , which decreased with L-dopa administration. A significant reduction in expression of AT1 mRNA was also observed after administration of dopamine to cultures of microglial cells. Transgenic rats with very low levels of brain AII showed increased AT1, decreased p47 (phox) and no changes in AT2 expression, whereas mice deficient in AT1 exhibited a decrease in the expression of p47 (phox) and AT2. The administration of relatively high doses of AII (100 nm) decreased the expression of AT1, and the increased expression of AT2 and p47(phox) in primary mesencephalic cultures. The results reveal an important interaction between the dopaminergic and local renin angiotensin system in the basal ganglia, which may be a major factor in the progression of Parkinson's disease. PMID- 20964731 TI - Increased excitability of cortical neurons induced by associative learning: an ex vivo study. AB - In adult mice, classical conditioning in which whisker stimulation is paired with an electric shock to the tail results in a decrease in the frequency of head movements, induces expansion of the cortical representation of stimulated vibrissae and enhances inhibitory synaptic interactions within the 'trained' barrels. We investigated whether such a simple associative learning paradigm also induced changes in neuronal excitability. Using whole-cell recordings from ex vivo slices of the barrel cortex we found that layer IV excitatory cells located in the cortical representation of the 'trained' row of vibrissae had a higher frequency of spikes recorded at threshold potential than neurons from the 'untrained' row and than cells from control animals. Additionally, excitatory cells within the 'trained' barrels were characterized by increased gain of the input-output function, lower amplitudes of fast after-hyperpolarization and decreased effect of blocking of BK channels by iberiotoxin. These findings provide new insight into the possible mechanism for enhanced intrinsic excitability of layer IV excitatory neurons. In contrast, the fast spiking inhibitory cells recorded in the same barrels did not change their intrinsic excitability after the conditioning procedure. The increased excitability of excitatory neurons within the 'trained' barrels may represent the counterpart of homeostatic plasticity, which parallels enhanced synaptic inhibition described previously. Together, the two mechanisms would contribute to increase the input selectivity within the conditioned cortical network. PMID- 20964732 TI - Cell cycle and cell death in disease: past, present and future. AB - Cell division and cell death are the two predominant physiological processes that regulate tissue homeostasis in the adult organism. The importance of dysregulation of these processes in the pathogenesis of major diseases, such as cancer, myocardial infarction, stroke, atherosclerosis, infection, inflammation and neurodegenerative disorders, is becoming increasingly evident. Hence, attempts to find modulators of the cell cycle and cell death programmes are being made with the hope of creating novel therapeutic approaches to the treatment of these diseases. It is clear that improved understanding of how cells balance life and-death processes is crucial for this development. In view of this, a Nobel Symposium entitled 'The Cell Cycle and Apoptosis in Disease' was organized in conjunction with the celebration of the 200-year anniversary of the Karolinska Institute in 2010. The symposium focused on the importance of dysregulation of cell cycle/cell death programmes in the pathogenesis of human disease. Three comprehensive reviews based on presentations at this symposium are presented in this issue of the Journal of Internal Medicine. They include a discussion of autophagy in anticancer therapy, the description of a role for type 2 transglutaminase in Huntington's disease and the proposal that 'redox-sensing' mechanisms might act as an orthogonal control in cell cycle and apoptosis signalling. PMID- 20964733 TI - The role of autophagy in anticancer therapy: promises and uncertainties. AB - Autophagy (literally self-eating) is a catabolic mechanism involved in the recycling and turnover of cytoplasmic constituents. Although often referred to as type II programmed cell death, autophagy is primarily a survival rather than a cell death mechanism in response to different stress stimuli. Autophagy is a process in which part of the cytoplasm or entire organelles are sequestered into double-membrane vesicles, called autophagosomes, which ultimately fuse with lysosomes to degrade their contents. Studies show that autophagy is associated with a number of pathological conditions, including cancer, infectious diseases, myopathies and neurodegenerative disorders. With respect to cancer, it has been suggested that the early stages of tumourigenesis are associated with downregulation of autophagy-related (ATG) genes. Indeed, several ATG genes display tumour suppressor function, including Beclin1, which is frequently hemizygously deleted in breast cancer cells. Conversely, in advanced stages of tumourigenesis or during anticancer therapy, autophagy may promote survival of tumour cells in adverse environmental conditions. Therefore, a thorough understanding of autophagy in different cancer types and stages is a prerequisite to determine an autophagy-activating or autophagy-inhibiting treatment strategy. PMID- 20964734 TI - Type 2 transglutaminase in Huntington's disease: a double-edged sword with clinical potential. AB - Huntington's disease (HD) is a dominant genetic neurodegenerative disorder. The pathology affects principally neurons in the basal ganglia circuits and terminates invariably in death. There is compelling necessity for safe and effective therapeutic strategies to arrest, or even retard the progression of the pathogenesis. Recent findings indicate the autophagy-lysosome systems as appealing targets for pharmacological intervention. Autophagy exerts a critical role in controlling neuronal protein homeostasis, which is perturbed in HD, and is compromised in the pathogenesis of several neurodegenerative diseases. Type 2 transglutaminase (TG2) plays an important role both in apoptosis and autophagy regulation, and accumulates at high levels in cells under stressful conditions. TG2 inhibition, achieved either via drug treatments or genetic approaches, has been shown to be beneficial for the treatment of HD in animal models. In this review we will discuss the relevance of TG2 to the pathogenesis of HD, in an effort to define novel therapeutic avenues. PMID- 20964735 TI - Redox sensing: orthogonal control in cell cycle and apoptosis signalling. AB - Living systems have three major types of cell signalling systems that are dependent upon high-energy chemicals, redox environment and transmembranal ion gating mechanisms. Development of integrated systems biology descriptions of cell signalling require conceptual models incorporating all three. Recent advances in redox biology show that thiol-disulphide redox systems are regulated under dynamic, nonequilibrium conditions, progressively oxidized with the life cycle of cells and distinct in terms of redox potentials amongst subcellular compartments. This article uses these observations as a basis to distinguish 'redox-sensing' mechanisms, which are more global biologic redox control mechanisms, from 'redox signalling', which involves conveyance of discrete activating or inactivating signals. Both redox sensing and redox signalling use sulphur switches, especially cysteine (Cys) residues in proteins which are sensitive to reversible oxidation, nitrosylation, glutathionylation, acylation, sulfhydration or metal binding. Unlike specific signalling mechanisms, the redox-sensing mechanisms provide means to globally affect the rates and activities of the high-energy, ion-gating and redox-signalling systems by controlling sensitivity, distribution, macromolecular interactions and mobility of signalling proteins. Effects mediated through Cys residues not directly involved in signalling means redox-sensing control can be orthogonal to the signalling mechanisms. This provides a capability to integrate signals according to cell cycle and physiologic state without fundamentally altering the signalling mechanisms. Recent findings that thiol-disulphide pools in humans are oxidized with age, environmental exposures and disease risk suggest that redox-sensing thiols could provide a central mechanistic link in disease development and progression. PMID- 20964736 TI - The epidemic of chronic kidney disease: looking at ageing and cardiovascular disease through kidney-shaped lenses. AB - In recent years, a 'silent' chronic kidney disease (CKD) epidemic has been proposed by many authors. The 'outbreak' is because of the inclusion of a large proportion of the elderly population within stage 3 CKD according to the Kidney Disease Outcomes Quality Initiative staging system. Unfortunately, this does not take into account the fact that renal function normally declines with age; in addition, the Modification of Diet in Renal Disease formula used to calculate glomerular filtration rate underestimates renal function in the elderly. Because population preventive strategies need a precise definition of the target for screening, a more accurate tool to detect CKD in the general population is required. Considerable interest in CKD has been generated by the evidence that predialysis CKD is associated with increased risk of cardiovascular disease (CVD). Such an association per se does not imply that CKD is a causal determinant of CVD. As CKD has been detected particularly in elderly individuals, it is tempting to speculate that an association may exist between age and cardiovascular outcomes in patients with CKD. Furthermore, the definition of CKD is a nosographic simplification that includes diseases with different causes and pathogenetic mechanisms. The aetiologies of renal diseases can affect cardiovascular outcomes, and the two major causes of end-stage renal disease, diabetes mellitus and hypertension, indeed do so. These findings point to a need for a better definition of CKD to optimize the allocation of healthcare resources and to clarify the nature of the association between CKD and CVD. PMID- 20964737 TI - Glycemia and cardiovascular diseases in type 2 diabetes. PMID- 20964738 TI - Inflammation-related effects of adjuvant influenza A vaccination on platelet activation and cardiac autonomic function. AB - BACKGROUND: Inflammation, platelet reactivity and cardiac autonomic dysfunction increase the risk of cardiovascular events, but the relationships between these prognostic markers are poorly defined. In this study, we investigated the effect of an inflammatory stimulus (influenza A vaccine) on platelet activation and cardiac autonomic function. METHODS: We measured serum C-reactive protein (CRP) and interleukin-6 levels, monocyte-platelet aggregates (MPAs) and monocyte/platelet receptor expression before and after adjuvant influenza A vaccination in 28 patients with type II diabetes (mean age 62.1 +/- 8 years, 18 men). Twenty-four-hour Holter electrocardiogram was recorded 24 h before and after vaccination; heart rate variability (HRV) was assessed as a measure of cardiac autonomic function. RESULTS: Inflammatory cytokines, MPA formation and monocyte/platelet receptor expression increased after vaccination. CRP was 2.6 +/ 2.8 and 7.1 +/- 5.7 mg L-1 48 h before and after vaccination, respectively (P < 0.0001). HRV parameters decreased after vaccination compared to baseline, with very low-frequency amplitude showing the most significant change (34.6 +/- 11.8 and 31.0 +/- 10.2 ms 48 h before and after vaccination, respectively; P = 0.002). A significant correlation was found between percentage changes in CRP levels and in most HRV variables, with the most significant correlations between changes in CRP levels and changes in standard deviation of all normal RR intervals (r = 0.43; P = 0.02). CONCLUSIONS: Together with an inflammatory reaction, influenza A vaccine induced platelet activation and sympathovagal imbalance towards adrenergic predominance. Significant correlations were found between CRP levels and HRV parameters, suggesting a pathophysiological link between inflammation and cardiac autonomic regulation. The vaccine-related platelet activation and cardiac autonomic dysfunction may transiently increase the risk of cardiovascular events. PMID- 20964739 TI - Circulating cardiovascular biomarkers in recurrent atrial fibrillation: data from the GISSI-atrial fibrillation trial. AB - OBJECTIVE: we evaluated the prognostic role of circulating cardiovascular biomarkers in patients with a history of recent atrial fibrillation (AF). BACKGROUND: predicting long-term maintenance of sinus rhythm in patients with AF is difficult. METHODS: plasma concentrations of three specific cardiac markers [high-sensitivity troponin T (hsTnT), N-terminal probrain natriuretic peptide (NT proBNP) and mid-regional proatrial natriuretic peptide (MR-proANP)] and three stable fragments of vasoactive peptides [mid-regional proadrenomedullin (MR proADM), copeptin (CT-proAVP) and CT-proendothelin-1 (CT-proET-1)] were measured at baseline and after 6 and 12 months in 382 patients enrolled in the GISSI-AF study, a prospective randomized trial to determine the effect of valsartan to reduce the recurrence of AF. The association between these markers, clinical characteristics and recurrence of AF was tested by univariate and multivariate Cox models. RESULTS: mean patient age was 68 +/- 9 years (37.2% females). A total of 84.8% of patients had a history of hypertension. In total, 59.7% qualified for history of AF because of successful cardioversion, 11.8% because of two or more episodes of AF in the 6 months preceding randomization and 28.5% because of both. Patients in AF at 6 or 12 months (203 (53.1%) with first recurrence) had significantly higher concentrations of most biomarkers. Despite low baseline levels, higher concentrations of hsTnT {adjusted hazard ratio (HR) [95% confidence intervals (CIs) for 1 SD increment] (1.15 [1.04-1.28], P = 0.007), MR proANP (1.15 [1.01-1.30], P = 0.04), NT-proBNP (1.24 [1.11-1.39], P = 0.0001) and CT-proET-1 (1.16 [1.01-1.33], P = 0.03) independently predicted higher risk of a first recurrence of AF. Changes over time of MR-proANP tended to predict subsequent recurrence (adjusted HR [95%CI]) (1.53 [0.98-2.37], P = 0.06). CONCLUSION: circulating markers of cardiomyocyte injury/strain and endothelin are related to recurrence of AF in patients in sinus rhythm with a history of recent AF. PMID- 20964740 TI - Effects of a healthy Nordic diet on cardiovascular risk factors in hypercholesterolaemic subjects: a randomized controlled trial (NORDIET). AB - OBJECTIVE: the aim of this study was to investigate the effects of a healthy Nordic diet (ND) on cardiovascular risk factors. DESIGN AND SUBJECTS: in a randomized controlled trial (NORDIET) conducted in Sweden, 88 mildly hypercholesterolaemic subjects were randomly assigned to an ad libitum ND or control diet (subjects' usual Western diet) for 6 weeks. Participants in the ND group were provided with all meals and foods. Primary outcome measurements were low-density lipoprotein (LDL) cholesterol, and secondary outcomes were blood pressure (BP) and insulin sensitivity (fasting insulin and homeostatic model assessment-insulin resistance). The ND was rich in high-fibre plant foods, fruits, berries, vegetables, whole grains, rapeseed oil, nuts, fish and low-fat milk products, but low in salt, added sugars and saturated fats. RESULTS: the ND contained 27%, 52%, 19% and 2% of energy from fat, carbohydrate, protein and alcohol, respectively. In total, 86 of 88 subjects randomly assigned to diet completed the study. Compared with controls, there was a decrease in plasma cholesterol (-16%, P < 0.001), LDL cholesterol (-21%, P < 0.001), high-density lipoprotein (HDL) cholesterol (-5%, P < 0.01), LDL/HDL (-14%, P < 0.01) and apolipoprotein (apo)B/apoA1 (-1%, P < 0.05) in the ND group. The ND reduced insulin (-9%, P = 0.01) and systolic BP by -6.6 +/- 13.2 mmHg (-5%, P < 0.05) compared with the control diet. Despite the ad libitum nature of the ND, body weight decreased after 6 weeks in the ND compared with the control group (-4%, P < 0.001). After adjustment for weight change, the significant differences between groups remained for blood lipids, but not for insulin sensitivity or BP. There were no significant differences in diastolic BP or triglyceride or glucose concentrations. CONCLUSIONS: a healthy ND improves blood lipid profile and insulin sensitivity and lowers blood pressure at clinically relevant levels in hypercholesterolaemic subjects. PMID- 20964741 TI - Adrenal incidentalomas and cardiometabolic morbidity: an emerging association with serious clinical implications. AB - Adrenal incidentalomas (AIs) represent adrenal masses that are incidentally discovered whilst investigating symptoms and signs unrelated to adrenal pathology. The onset and natural course of AIs are unknown, and the possible underlying cardiometabolic abnormalities have not been examined in depth. A growing body of clinical and experimental evidence supports the notion that both functioning and, paradoxically, nonfunctioning AIs are associated with a partially expressed or even full-blown metabolic syndrome (MS) phenotype, through yet unclear mechanisms. Subtle, subclinical or even profound adrenal hormone excess and an increased proinflammatory state might explain to some extent the development of MS disturbances. The emerging association between AIs and MS appears to be important in determining the optimal clinical management of these patients and raises speculation about the exact mechanisms of this interesting cause-effect relationship. PMID- 20964742 TI - Neonatal immune function and inflammatory illnesses in later life: lessons to be learnt from the developing world? AB - With the emergence of allergic and autoimmune diseases in populations that have started to transit to a western lifestyle, there has been an increasing interest in the role of environmental factors modulating early immune function. Yet, most of the information concerning neonatal immune function has been derived from studies in westernized countries. We postulate that comparative studies of early immune development in children born under conditions that are typical for a westernized vs. that of a still more traditional setting will provide a crucial insight into the environmental-driven immunological mechanisms that are responsible for the world-wide rise in inflammatory disorders. In this review, we summarize the current understanding of early-life immune function in humans in general and the literature on some major lifestyle factors that may influence neonatal immune function and potentially the risk for disease in later life. An understanding of the mechanisms of 'prenatal/early-life programming' in populations living in traditional compared with modern societies is crucial to develop strategies to prevent a further rise in 'western diseases' such as allergic disorders. Indications exist that prenatal conditioning of the innate immune system by low-grade inflammatory responses is key to inducing more tightly regulated postnatal adaptive immune responses. PMID- 20964743 TI - Review of negative and low-grade cervical smears in women with invasive cervical cancer after the first 3 years of the national cervical screening programme in Slovenia. AB - OBJECTIVE: The purpose of the study was to perform a national review of negative, low-grade and inadequate smears reported during the latest screening period before cervical cancer diagnosis in 2006, after the first 3 years of the screening programme. METHODS: Among 162 new cervical cancer cases there were 47 (29%) without previous cytology, 47 (29%) with one high-grade smear prior to diagnosis and 68 (42.0%) with at least one previous negative, low-grade, atypical or inadequate smear 1-40 months before diagnosis. Of the latter 68 cases, 37 patients with 59 smears (together with 118 control slides) were included in the review as 31 had smears reported at laboratories no longer operating. Findings were related to the last cytology report before diagnosis as well as to histological type and stage of the cancer. RESULTS: In our study group, 19 (51%) of 37 patients had squamous cell carcinoma, 15 (41%) adenocarcinoma and 3 (8%) adenosquamous carcinoma, compared with 121 (75%), 26 (16%), 12 (7%), respectively, and 3 (2%) other types, for all carcinomas. Twenty-one of 37 women also had high-grade cytology prior to diagnosis of cancer. Women with previous cytology (with or without recent high-grade smears) were more likely to have stage I cancers than those without cytology (P < 0.0001). The expert group upgraded 17/33 smears in the patients with squamous carcinomas, which was more than in those with adeno- and adenosquamous carcinomas (5/24, P < 0.05). CONCLUSION: As expected, a higher proportion of smears preceding adenocarcinomas were true negative. Under-diagnosed smears were not related to cancer stage or last cytology report before diagnosis. PMID- 20964744 TI - Clinical librarians as facilitators of nurses' evidence-based practice. AB - AIM: The aim of this study was to explore nurses' and ward-based clinical librarians' reflections on ward-based clinical librarians as facilitators for nurses' use of evidences-based practice. BACKGROUND: Nurses' use of evidence based practice is reported to be weak. Studies have suggested that clinical librarians may promote evidence-based practice. To date, little is known about clinical librarians participating nurses in the wards. DESIGN: A descriptive, qualitative design was adopted for the study. METHOD: In 2007, 16 nurses who had been attended by a clinical librarian in the wards were interviewed in focus groups. Two clinical librarians were interviewed by individual interviews. In the analysis, a content analysis was used. RESULTS: Three themes were generated from the interviews with nurses: 'The grip of everyday work', 'To articulate clinical nursing issues' and 'The clinical librarians at a catalyst'. The nurses experienced the grip of everyday work as a hindrance and had difficulties to articulate and formulate relevant nursing issues. In such a state, the nurses found the clinical librarian presence in the ward as enhancing the awareness of and the use of evidence-based practice. Three themes emerged from the analysis with the librarians. They felt as outsiders, had new knowledge and acquired a new role as ward-based clinical librarians. CONCLUSIONS: Facilitation is needed if nurses' evidence-based practice is going to increase. The combined use of nurses and clinical librarians' knowledge and skills can be optimised. To achieve this, nurses' skills in consuming and implementing evidence ought to be strengthened. RELEVANCE TO CLINICAL PRACTICE: The fusion of the information and knowledge management skill of the ward-based clinical librarian and the clinical expertise of the nurses can be of value. With such a collaborative model, nurse and ward based clinical librarian might join forces to increase the use of evidence-based practice. PMID- 20964745 TI - Continuing connections: the experiences of retired and senior working nurse mentors. AB - AIMS AND OBJECTIVES: This paper reports the benefits and challenges of a mentoring programme through which retired and senior nurses continued to support and nurture nurses and midwives currently working in the health system. BACKGROUND: Nursing has an ageing workforce and faces significant loss of expertise because of retirements. Previously, mentoring programmes have been instituted in a range of nursing contexts and they have been a retention strategy for older nurses and midwives. DESIGN: Mentors and their mentees worked together towards mutually agreed on professional and personal goals. They were asked to meet or speak together a minimum of twice per month for at least six months. METHOD: As part of a collective case study, 15 mentoring dyads were established. Participants and mentors took part in qualitative, semi-structured interviews about their perceptions and experiences of the mentoring programme. Interviews were audio-taped, transcribed and analysed thematically. RESULTS: Mentors reported the mentoring experience to be rewarding experience that enabled them to re-connect with nursing-related activities and brought new challenges in retirement. They perceived the mentees were visibly helped by their support and influence. CONCLUSIONS: The mentors studied reinforced a positive self-concept as nurses and midwives in their mentees and assisted their development. Retired nurses and midwives in particular may have several characteristics that make them effective mentors. RELEVANCE TO CLINICAL PRACTICE: Potential benefits are demonstrated for nurses and midwives vulnerable to workplace adversity, especially those new to Australia who may have limited professional and social networks. For health organisations, mentoring programmes may be an innovative method of retention that engages both mid-career nurses and midwives and those recently retired. PMID- 20964746 TI - Is the ward sister role still relevant to the quality of patient care? A critical examination of the ward sister role past and present. AB - AIMS AND OBJECTIVES: To examine the UK ward sister role in contemporary and historical context. BACKGROUND: The ward sister role once key to nursing is now confused. DESIGN: A critical examination of the changing role of the ward sister. Sources consulted: nursing textbooks 1877-1971, nursing and medical periodicals 1912-2010, official government reports 1947-2010, research studies on nursing 1960-2010, secondary works on nursing history. METHOD: An historiographical analysis of archival sources which interrogates primary and secondary evidence to make transparent interconnection, coherence, consistency and reliability. RESULTS: As a consequence of professional, educational and managerial changes, the traditional authority of the ward sister for nursing standards, ward services and ward facilities is diminished. Ward sisters are primarily motivated by nursing rather than managerial values. Hence, there is disparity in the title 'ward sister' espoused by ward sisters and the public and the title 'ward manager' espoused by non-nursing managers. This is not just terminology, but concerns the kind of values enshrined by the term and entrusted to the role. CONCLUSIONS: Until the late 1970s, the ward sister was key to maintaining standards of care. She was the trustee of a tradition and transmitted its values. Subsequent organisational and professional changes have diminished the authority of the role. History may suggest the need to examine and strengthen the ward sister role in the light of its original orientation. RELEVANCE TO CLINICAL PRACTICE: The ward sister role could have a fundamental effect on the quality of patient care if it were to regain its former scope and authority. PMID- 20964747 TI - The relationships between organisational citizenship behaviour, job satisfaction and turnover intention. AB - AIM: This study aims to explore the relationships between organisational citizenship behaviour, job satisfaction and turnover intention. BACKGROUND: Because of the changing health policies landscape, Taiwan's hospital administrators are facing major cost reduction challenges. Specifically, the high turnover rate of nurses represents a hindrance and a human resource cost. This study focuses on ways of reducing the employee turnover rate through enhanced organisational citizenship behaviour and job satisfaction. DESIGN: A cross sectional study. METHODS: This study focuses on hospital nurses in Taiwan. Our research samples were obtained from one medical centre, three regional hospitals and seven district hospitals. Out of 300 questionnaires distributed among samples, 237 were completed and returned. Pearson's correlation was used to test for relationships among the main variables. One-way analysis of variance and Scheffe's post hoc analysis were employed to test the influence of demographic data on the main variables. RESULTS: The results reveal that the nurses' job satisfaction has a significantly positive correlation with organisational citizenship behaviour and a negative correlation with turnover intention. CONCLUSIONS: This study has proven that the turnover intention of clinical nurses is related to their organisational citizenship behaviour and job satisfaction. Hospital administrators can reduce the turnover intention by meeting nurses' needs and by promoting their organisational citizenship behaviour. RELEVANCE TO CLINICAL PRACTICE: Organisational citizenship behaviour involves behaviour that encourages staff to endeavour to voluntarily improve organisational performance without lobbying for compensation. Employees' job satisfaction includes satisfaction with the working environment or welfare programme in the context of human resource initiatives. Similarly, human resource protocols may serve as the starting point for promoting staff organisational citizenship behaviour. Administrators in clinical healthcare are encouraged to meet their employees' working needs through human resource practices. PMID- 20964748 TI - The perceived threat of the risk for graft rejection and health-related quality of life among organ transplant recipients. AB - AIMS: This study was primarily aimed for developing and testing a valid and reliable instrument that measures perceived threat of the risk for graft rejection after organ transplantation. A second aim was to report descriptive data regarding graft rejection and Health-Related Quality of Life. BACKGROUND: The most serious risk connected with transplantations besides infection is graft rejection. DESIGN: Non experimental, descriptive involving instrument development and psychometric assessment. METHOD: Questionnaires about perceived threat of the risk for graft rejection and Health-Related Quality of Life were mailed to 229 OTRs between 19-65 years old. The items were formed from a previous interview study. Patients were transplanted with a kidney, a liver or a heart and/or a lung. All patients with follow-up time of one year +/- three months and three years +/- three months were included. RESULTS: With an 81% response rate, the study comprised of 185 OTRs, who had received either a kidney (n = 117), a liver (n = 39) or heart or lung (n = 29). Three homogenous factors of perceived threat for graft rejection were revealed, labelled 'intrusive anxiety', 'graft-related threat' and 'lack of control'. Tests of internal consistency showed good item scale convergent and discriminatory validity. A majority of the OTRs scored low levels for 'intrusive anxiety'. The kidney transplant recipients experienced more 'graft-related threat' by acute graft rejection than those transplanted with a liver, heart or lung. CONCLUSION: In conclusion, this study suggests that it is possible to measure the perceived threat of the risk for graft rejection in three homogenous factors. Relevance to clinical practice. The instrument perceived threat of the risk for graft rejection, might be usable to measure the impact of fear of graft rejection, to predict needs of pedagogical intervention strategies to reduce fear and to improve Health-Related Quality of Life related to graft rejection. PMID- 20964749 TI - Nurses' performance in classifying heart failure patients based on physical exam: comparison with cardiologist's physical exam and levels of N-terminal pro-B-type natriuretic peptide. AB - AIM: The purpose of this study is to compare clinical assessment of congestion performed by a nurse to that performed by cardiologist and correlate them with NT ProBNP levels. BACKGROUND: The nurses' role in heart failure has been strongly focused in therapeutic, educational and self-care interventions. The diagnostic performance of nurses in heart failure outpatients is not well explored. N terminal pro-B-type natriuretic peptide is a cardiac marker that reflects elevated filling pressures. DESIGN: Cross-sectional contemporaneous study. METHODS: Heart failure outpatients underwent a systematic clinical assessment of clinical congestion score performed by cardiologist and nurse during the same visit. Assessments were performed independently and N-terminal pro-B-type natriuretic peptide levels obtained. The nurses' ability to classify patients in hemodynamic profile was compared to the cardiologist's. RESULTS: Eighty-nine assessments were performed in 63 patients with heart failure. The correlation of clinical congestion scores obtained by nurse with those obtained by cardiologist was rs=0.86; p<0.001. The correlation of clinical congestion scores from nurse and cardiologist with levels of N-terminal pro-B-type natriuretic peptide were as follows: rs=0.45; p<0.0001 and rs=0.51, respectively, p<0.0001. Patients with clinical congestion score>=3 had levels of NT-ProBNP significantly higher than those with clinical congestion score<3, in the assessment performed by the cardiologist (1866 SD 1151 vs. 757 SD 988 pg/ml; p<0.0001) and by the nurse (1720 SD 1228 vs. 821 SD 914 pg/ml; p<0.0001). The nurse and cardiologist had similar capacity in classifying patients in congested quadrants (p=0.027) or in dry quadrants (p=0.03), according to the levels of N-terminal pro-B-type natriuretic peptide. Area under the receiver-operating characteristic curve of the nurse and cardiologist to detect congestion was, respectively, 0.77 and 0.72. CONCLUSIONS: Our data suggests that nurses trained in heart failure may have a similar performance to that of the cardiologist for the clinical detection of congestion and assessment of the hemodynamic profile in patients with chronic heart failure. RELEVANCE TO CLINICAL PRACTICE: Considering that consistent clinical assessment can identify congested or hypovolemic patients with reasonable reliability, as well as patients with low or normal cardiac output, our results may help confirm nurses' capability in performing reliable clinical assessment in heart failure patients. While nurses' led heart failure programmes are usually focused on the management of patients, nurses' ability to perform accurate assessment would expand nurses' role in these programmes. As many institutions now focus on home visits by heart failure nurses, accurate assessment would benefit patients and improve their clinical outcomes. PMID- 20964750 TI - An exploratory study of the follow-up care needs of patients treated for colorectal cancer. AB - AIMS AND OBJECTIVES: To explore patient perceptions of their experiences of follow-up care after treatment for colorectal cancer. BACKGROUND: The optimal follow-up strategy for colorectal cancer is not known, and although patients are seen in traditional outpatient follow-up clinics, this system may not meet psycho social and information needs. DESIGN: An exploratory qualitative study. METHOD: In-depth interviews were conducted with 27 patients who had completed treatment for colorectal cancer. The data were analysed using thematic analysis. RESULTS: One dominant theme emerged from the data with several sub-themes. The dominant theme was 'knowing what to expect' after bowel surgery. The subthemes related to 'living with altered bowel function', the ways patients gathered information about their condition through 'trial and error' and 'information and support from specialist nurses'. Patients who did not have a stoma were particularly vulnerable and expressed a need for more information on knowing what to expect after surgery. The role of the colorectal nurse specialist was vital in providing information and support; in particular, nurse-led clinics provided continuity of care and information that was tailored to individual need. CONCLUSIONS: Traditional hospital follow-up does not always address patients' psycho-social and information needs. Nurse-led services were commented on favourably in terms of providing information that was tailored to individual need as well as being responsive to urgent patient concerns; future innovative strategies for providing follow-up care for patients with colorectal cancer should draw on the specialist knowledge and skills of these nurses. RELEVANCE TO CLINICAL PRACTICE: Nurse-led clinics and/or telephone follow-up by specialist nurses may be effective models of care for this particular patient group, providing appropriate access for meeting clinical, psycho-social and information needs. PMID- 20964752 TI - Organisation of care for Swedish patients with an implantable cardioverter defibrillator, a national survey. AB - AIM: To describe the clinical aspects of implantable cardioverter defibrillators care in Sweden with focus on organisation, the role and education of nurses, patient information and education and areas in need of improvement. BACKGROUND: Implantable cardioverter defibrillators implantations have developed rapidly in recent years and are now an established arrhythmia treatment. The expanding indication for implantable cardioverter defibrillators implantation demands new competencies and resources in the implantable cardioverter defibrillators team members. METHODS: Participants were recruited among physicians and nurses in all of the hospitals implanting implantable cardioverter defibrillators (n = 16). Data were collected by a questionnaire. Additionally, all written educational materials provided to patients pre- and postimplant were collected from all 16 hospitals. Deductive content analysis using Sarvimaki and Stenbock-Hult's five holistic dimensions was employed to ascertain how information was provided in brochures and information materials. RESULTS: Half of the hospitals (n=8) had nurse-based outpatient clinics and several others planned to introduce them. Three hospitals carried out distance follow-ups by means of tele-monitoring. The nurses had received specific implantable cardioverter defibrillators education from implantable cardioverter defibrillators companies and/or various university courses. The biophysical dimension dominated in the information material, while the emotional, intellectual and socio-cultural dimensions were scarcely described, and the spiritual-existential was not referred to at all. CONCLUSION: Holistic care of implantable cardioverter defibrillators patients can be achieved by means of a multidisciplinary implantable cardioverter defibrillators team and more patient-centred educational strategies. In Sweden, the organisation of implantable cardioverter defibrillators care and follow-up is developing towards more nurse-based clinics. RELEVANCE TO CLINICAL PRACTICE: Development and implementation of structured care programmes with a more holistic approach can improve future implantable cardioverter defibrillators care. The content of the written educational materials need to be more holistic, rather than mainly focusing on the biophysical and technical aspects of living with an implantable cardioverter defibrillators. PMID- 20964751 TI - The handling of peripheral venous catheters--from non-compliance to evidence based needs. AB - AIM: To study nurses' compliance to national guidelines (Sweden) for peripheral venous catheters and to establish the complication frequency connected to time in situ and bore size. BACKGROUND: Worldwide, there are no standard peripheral venous catheters guidelines, and the need for elective replacement has been challenged. Furthermore, the time interval and need for elective change of peripheral venous catheters has cost implications for hospitals. DESIGN: Prospective register study. METHODS: The health care professionals in one surgical ward in a university hospital in the south of Sweden prospectively registered peripheral venous catheters parameters. Four hundred and thirteen peripheral venous catheters were registered for time in situ, size and complications. A cost analysis was performed. Non-parametric statistics were used, and p<0.05 was regarded as significant. RESULT: Compliance to the guideline of time in situ was 30.2%, and the frequency of thrombophlebitis was 6.5%. Peripheral venous catheters left in situ for more than 72 hours caused more thrombophlebitis (p=0.03). There was no difference in thrombophlebitis rate when peripheral venous catheters were changed within 24 hours compared with peripheral venous catheters that were changed within 72 hours. No difference was seen regarding complications between peripheral venous catheters sized 0.9 mm/22 gauge or 1.1 mm/20 gauge. CONCLUSION: The present Swedish national guidelines, advocating peripheral venous catheter change every 24 hours, should be altered since peripheral venous catheters left in situ for up to 72 hours were not found to be related to a greater risk of developing thrombophlebitis. Nor is it compatible with a greater risk to use a peripheral venous catheter of 1.1 mm/20 gauge instead of 0.9 mm/22 gauge. The change in guidelines would decrease money spent, 250 100 Euro in Sweden, thus allowing time for the nurses to do other tasks and save discomfort for the patients. RELEVANCE TO CLINICAL PRACTICE: National guidelines should be based on evidence and current facts, and evaluation of guidelines should be given priority. PMID- 20964753 TI - Migration, isolation and hybridization in island crop populations: the case of Madagascar rice. AB - Understanding how crop species spread and are introduced to new areas provides insights into the nature of species range expansions. The domesticated species Oryza sativa or Asian rice is one of the key domesticated crop species in the world. The island of Madagascar off the coast of East Africa was one of the last major Old World areas of introduction of rice after the domestication of this crop species and before extensive historical global trade in this crop. Asian rice was introduced in Madagascar from India, the Malay Peninsula and Indonesia approximately 800-1400 years ago. Studies of domestication traits characteristic of the two independently domesticated Asian rice subspecies, indica and tropical japonica, suggest two major waves of migrations into Madagascar. A population genetic analysis of rice in Madagascar using sequence data from 53 gene fragments provided insights into the dynamics of island founder events during the expansion of a crop species' geographic range and introduction to novel agro-ecological environments. We observed a significant decrease in genetic diversity in rice from Madagascar when compared to those in Asia, likely the result of a bottleneck on the island. We also found a high frequency of a unique indica type in Madagascar that shows clear population differentiation from most of the sampled Asian landraces, as well as differential exchange of alleles between Asia and Madagascar populations of the tropical japonica subspecies. Finally, despite partial reproductive isolation between japonica and indica, there was evidence of indica/japonica recombination resulting from their hybridization on the island. PMID- 20964754 TI - Constraints on speciation suggested by comparing lake-stream stickleback divergence across two continents. AB - Adaptation to ecologically distinct environments can coincide with the emergence of reproductive barriers. The outcome of this process is highly variable and can range along a continuum from weak population differentiation all the way to complete, genome-wide divergence. The factors determining how far diverging taxa will move along this continuum remain poorly understood but are most profitably investigated in taxa under replicate divergence. Here, we explore determinants of progress towards speciation by comparing phenotypic and molecular divergence within young (<150 years) lake-stream stickleback pairs from Central Europe to divergence in older (thousands of years) archetypal lake-stream pairs from Vancouver Island, Canada. We generally find relatively weak divergence in most aspects of foraging morphology (gill raker number, body shape) in the European pairs, although substantial adaptive divergence is seen in gill raker length. Combined with striking overall phenotypic differences between the continents, this argues for genetic and time constraints on adaptive divergence in the European pairs. The European lake-stream pairs also do not display the strong habitat-related differentiation in neutral (microsatellite) markers seen in the Canadian watersheds. This indicates either the lack of strong reproductive barriers owing to weak adaptive divergence, or alternatively that neutral markers are poorly suited for detecting reproductive barriers if these emerge rapidly. Overall, our comparative approach suggests constraints on speciation due to genetic architecture and limited time for divergence. The relative importance of these factors remains to be quantified by future investigation. PMID- 20964755 TI - Similarity of contemporary and historical gene flow among highly fragmented populations of an endangered rattlesnake. AB - Populations of endangered taxa in recently fragmented habitats often show high levels of genetic structure, but the role that contemporary versus historical processes play in generating this pattern is unclear. The eastern massasauga rattlesnake (Sistrurus c. catenatus) is an endangered snake that presently occurs throughout central and eastern North America in a series of populations that are isolated because of habitat fragmentation and destruction. Here, we use data from 19 species-specific microsatellite DNA loci to assess the levels of genetic differentiation, genetic effective population size, and contemporary and historical levels of gene flow for 19 populations sampled across the range of this snake. Eastern massasaugas display high levels of genetic differentiation (overall theta(Fst) = 0.21) and a Bayesian clustering method indicates that each population represents a unique genetic cluster even at regional spatial scales. There is a twofold variation in genetically effective population sizes but little genetic evidence that populations have undergone recent or historical declines in size. Finally, both contemporary and historical migration rates among populations were low and similar in magnitude even for populations located <7 km apart. A test of alternate models of population history strongly favours a model of long term drift-migration equilibrium over a recent isolation drift-only model. These results suggest that recent habitat fragmentation has had little effect on the genetic characteristics of these snakes, but rather that this species has historically existed in small isolated populations that may be resistant to the long-term negative effects of inbreeding. PMID- 20964756 TI - Long-distance seed and pollen dispersal inferred from spatial genetic structure in the very low-density rainforest tree, Baillonella toxisperma Pierre, in Central Africa. AB - We analysed the spatial distribution of genetic diversity to infer gene flow for Baillonella toxisperma Pierre (Moabi), a threatened entomophilous pollinated and animal-dispersed Central African tree, with typically low density (5-7 adults trees/km(2)). Fifteen nuclear and three universal chloroplast microsatellites markers were used to type 247 individuals localized in three contiguous areas with differing past logging intensity. These three areas were within a natural forest block of approximately 2886 km(2) in Gabon. Expected heterozygosity and chloroplast diversity were He(nuc) = 0.570 and H(cp) = 0.761, respectively. F(IS) was only significant in one area (F(IS) = 0.076, P < 0.01) and could be attributed to selfing. For nuclear loci, Bayesian clustering did not detect discrete gene pools within and between the three areas and global differentiation (F(STnuc) = 0.007, P > 0.05) was not significant, suggesting that they are one population. At the level of the whole forest, both nuclear and chloroplast markers revealed a weak correlation between genetic relatedness and spatial distance between individuals: Sp(nuc) = 0.003 and Sp(cp) = 0.015, respectively. The extent of gene flow (sigma) was partitioned into global gene flow (sigma(g)) from 6.6 to 9.9 km, seed dispersal (sigma(s)) from 4.0 to 6.3 km and pollen dispersal (sigma(p)) from 9.8 to 10.8 km. These uncommonly high dispersal distances indicate that low-density canopy trees in African rainforests could be connected by extensive gene flow, although, given the current threats facing many seed disperser species in Central Africa, this may no longer be the case. PMID- 20964757 TI - Effects of genotyping errors on parentage exclusion analysis. AB - Genetic markers are widely used to determine the parentage of individuals in studies of mating systems, reproductive success, dispersals, quantitative genetic parameters and in the management of conservation populations. These markers are, however, imperfect for parentage analyses because of the presence of genotyping errors and undetectable alleles, which may cause incompatible genotypes (mismatches) between parents and offspring and thus result in false exclusions of true parentage. Highly polymorphic markers widely used in parentage analyses, such as microsatellites, are especially prone to genotyping errors. In this investigation, I derived the probabilities of excluding a random (related) individual from parentage and the probabilities of Mendelian-inconsistent errors (mismatches) and Mendelian-consistent errors (which do not cause mismatches) in parent-offspring dyads, when a marker having null alleles, allelic dropouts and false alleles is used in a parentage analysis. These probabilities are useful in evaluating the impact of various types of genotyping errors on the information content of a set of markers in and thus the power of a parentage analysis, in determining the threshold number of genetic mismatches that is appropriate for a parentage exclusion analysis and in estimating the rates of genotyping errors and frequencies of null alleles from observed mismatches between known parent offspring dyads. These applications are demonstrated by numerical examples using both hypothetical and empirical data sets and discussed in the context of practical parentage exclusion analyses. PMID- 20964758 TI - Monophyletic origin of multiple clonal lineages in an asexual fish (Poecilia formosa). AB - Despite the advantage of avoiding the costs of sexual reproduction, asexual vertebrates are very rare and often considered evolutionarily disadvantaged when compared to sexual species. Asexual species, however, may have advantages when colonizing (new) habitats or competing with sexual counterparts. They are also evolutionary older than expected, leaving the question whether asexual vertebrates are not only rare because of their 'inferior' mode of reproduction but also because of other reasons. A paradigmatic model system is the unisexual Amazon molly, Poecilia formosa, that arose by hybridization of the Atlantic molly, Poecilia mexicana, as the maternal ancestor, and the sailfin molly, Poecilia latipinna, as the paternal ancestor. Our extensive crossing experiments failed to resynthesize asexually reproducing (gynogenetic) hybrids confirming results of previous studies. However, by producing diploid eggs, female F(1) hybrids showed apparent preadaptation to gynogenesis. In a range-wide analysis of mitochondrial sequences, we examined the origin of P. formosa. Our analyses point to very few or even a single origin(s) of its lineage, which is estimated to be approximately 120,000 years old. A monophyletic origin was supported from nuclear microsatellite data. Furthermore, a considerable degree of genetic variation, apparent by high levels of clonal microsatellite diversity, was found. Our molecular phylogenetic evidence and the failure to resynthesize the gynogenetic P. formosa together with the old age of the species indicate that some unisexual vertebrates might be rare not because they suffer the long-term consequences of clonal reproduction but because they are only very rarely formed as a result of complex genetic preconditions necessary to produce viable and fertile clonal genomes and phenotypes ('rare formation hypothesis'). PMID- 20964759 TI - Evolutionary history of the conifer root rot fungus Heterobasidion annosum sensu lato. AB - We investigated two hypotheses for the origin of the root rot fungus Heterobasidion annosum species complex: (i) that geology has been an important factor for the speciation (ii) that co-evolutionary processes with the hosts drove the divergence of the pathogen species. The H. annosum species complex consists of five species: three occur in Europe, H. annosum s.s., Heterobasidion parviporum and Heterobasidion abietinum, and two in North America, Heterobasidion irregulare and Heterobasidion occidentale; all with different but partially overlapping host preferences. The evolution of the H. annosum species complex was studied using six partially sequenced genes, between 10 and 30 individuals of each species were analysed. Neighbour-joining trees were constructed for each gene, and a Bayesian tree was built for the combined data set. In addition, haplotype networks were constructed to illustrate the species relationships. For three of the genes, H. parviporum and H. abietinum share haplotypes supporting recent divergence and/or possible gene flow. We propose that the H. annosum species complex originated in Laurasia and that the H. annosum s.s./H. irregulare and H. parviporum/H. abietinum/H. occidentale ancestral species emerged between 45 and 60 Ma in the Palaearctic, well after the radiation of the host genera. Our data imply that H. irregulare and H. occidentale were colonizing North America via different routes. In conclusion, plate tectonics are likely to have been the main factor influencing Heterobasidion speciation and biogeography. PMID- 20964760 TI - Differential threshold effects of habitat fragmentation on gene flow in two widespread species of bush crickets. AB - Effects of habitat fragmentation on genetic diversity vary among species. This may be attributed to the interacting effects of species traits and landscape structure. While widely distributed and abundant species are often considered less susceptible to fragmentation, this may be different if they are small sized and show limited dispersal. Under intensive land use, habitat fragmentation may reach thresholds at which gene flow among populations of small-sized and dispersal-limited species becomes disrupted. Here, we studied the genetic diversity of two abundant and widespread bush crickets along a gradient of habitat fragmentation in an agricultural landscape. We applied traditional (G(ST), theta) and recently developed (G'ST', D) estimators of genetic differentiation on microsatellite data from each of twelve populations of the grassland species Metrioptera roeselii and the forest-edge species Pholidoptera griseoaptera to identify thresholds of habitat fragmentation below which genetic population structure is affected. Whereas the grassland species exhibited a uniform genetic structuring (G(ST) = 0.020-0.033; D = 0.085-0.149) along the whole fragmentation gradient, the forest-edge species' genetic differentiation increased significantly from D < 0.063 (G(ST) < 0.018) to D = 0.166 (G(ST) = 0.074), once the amount of suitable habitat dropped below a threshold of 20% and its proximity decreased substantially at the landscape scale. The influence of fragmentation on genetic differentiation was qualitatively unaffected by the choice of estimators of genetic differentiation but quantitatively underestimated by the traditional estimators. These results indicate that even for widespread species in modern agricultural landscapes fragmentation thresholds exist at which gene flow among suitable habitat patches becomes restricted. PMID- 20964761 TI - Predation- and competition-mediated brain plasticity in Rana temporaria tadpoles. AB - An increasing number of studies have demonstrated phenotypic plasticity in brain size and architecture in response to environmental variation. However, our knowledge on how brain architecture is affected by commonplace ecological interactions is rudimentary. For example, while intraspecific competition and risk of predation are known to induce adaptive plastic modifications in morphology and behaviour in a wide variety of organisms, their effects on brain development have not been studied. We studied experimentally the influence of density and predation risk on brain development in common frog (Rana temporaria) tadpoles. Tadpoles grown at low density and under predation risk developed smaller brains than tadpoles at the other treatment combinations. Further, at high densities, tadpoles developed larger optic tecta and smaller medulla oblongata than those grown at low densities. These results demonstrate that ecological interactions - like intraspecific competition and predation risk - can have strong effects on brain development in lower vertebrates. PMID- 20964762 TI - Recombination and selection in the maintenance of the adaptive value of inversions. AB - A huge amount of data seem to confirm the adaptive value of inversions in Drosophila. The inhibition of recombination in heterokaryotypes mediated by inversions seems fundamental in maintaining their adaptive role. This study shows that recombination is highly suppressed in Drosophila subobscura because of chromosomal inversions, not only inside the inversions but also outside them. It seems that the region outside the inversion where recombination is inhibited is asymmetrical and independent of the inversion length. Despite the difficulty of crossovers taking place near inversion breakpoints, the only two recombination events detected inside inversions were located close to the breakpoint. Thus, selection could be largely responsible for the recombination reduction maintaining sets of adaptive alleles inside the inverted region. Heterokaryotype descendants were always in higher frequency than inbred or outbred homokaryotypes, regardless of the geographical origin of the chromosome, suggesting that chromosomes carrying the same arrangement, although with a different set of alleles for neutral markers, could be submitted to the same selection processes. PMID- 20964763 TI - Intraspecific conflict over host manipulation between different larval stages of an acanthocephalan parasite. AB - Competitive interactions between coinfecting parasites are expected to be strong when they affect transmission success. When transmission is enhanced by altering host behaviour, intraspecific conflict can lead to 'coinfection exclusion' by the first-in parasite or to a 'sabotage' of behavioural manipulation by the youngest noninfective parasite. We tested these hypotheses in the acanthocephalan parasite Pomphorhynchus laevis, reversing phototaxis in its intermediate host Gammarus pulex. No evidence was found for coinfection exclusion in gammarids sequentially exposed to infection. Behavioural manipulation was slightly weakened but not cancelled in gammarids infected with mixed larval stages. Therefore, coinfecting infective and noninfective larvae both suffered competition, potentially resulting in delayed transmission and increased risk of mortality, respectively. Consequently, noninfective larva is not just a 'passive passenger' in the manipulated host, which raises interesting questions about the selective pressures at play and the mechanisms underlying manipulation. PMID- 20964764 TI - A novel isotonic-balanced electrolyte solution with 1% glucose for intraoperative fluid therapy in children: results of a prospective multicentre observational post-authorization safety study (PASS). AB - BACKGROUND: The recommendations for intraoperative fluid therapy in children have been adapted from hypotonic to isotonic electrolyte solutions with lower glucose concentrations (1-2.5% instead of 5%) to avoid hyponatremia and hyperglycemia. OBJECTIVE: The objective of this prospective multicentre observational post authorization safety study was to evaluate the intraoperative use of a novel isotonic-balanced electrolyte solution with 1% glucose (BS-G1) with a particular focus on changes in acid-base status, electrolyte and glucose concentrations. METHODS: Following local ethics committee approval, pediatric patients aged up to 4 years with an ASA risk score of I-III undergoing intraoperative administration of BS-G1 were enrolled. Patient demographics, the performed procedure, adverse drug reactions, hemodynamic data, and the results of blood gas analysis before and after infusion were documented with a focus on changes in acid-base status, electrolyte and glucose concentrations. RESULTS: In 107 patients (ASA I-III; age 16.2 +/- 15.4, range day of birth to 47.7 months; body weight 8.8 +/- 4.8, range 1.6-18.8 kg), the mean volume infused was 20 +/- 12.6 (range 3.6-83.3) ml.kg(-1) BS-G1. During the infusion, hemoglobin, hematocrit, anion gap, strong ion difference, and calcium decreased and chloride and glucose increased significantly within the physiologic range. All other measured parameters including sodium, bicarbonate, base excess, and lactate remained stable. Neither hypoglycemia (glucose <2.5 mmol.l(-1) ) nor hyperglycemia (glucose >10 mmol.l(-1) ) was documented after BS-G1 infusion. No adverse drug reactions were reported. CONCLUSION: The studied isotonic-balanced electrolyte solution with 1% glucose helps to avoid perioperative acid-base imbalance, hyponatremia, hyperglycemia, and ketoacidosis in infants and toddlers and may therefore enhance patient safety. PMID- 20964765 TI - Anesthetic management of the pediatric bleeding tonsil. AB - BACKGROUND: Anesthetic management of the child with post-tonsillectomy hemorrhage is challenging and fraught with hazards such as anemia, hypovolemia, and risk of difficult airway. The aim of this retrospective cohort study was to determine the incidence and further define the anesthetic complications in this population. METHODS: Retrospective cohort study of all children who underwent operative intervention for post-tonsillectomy hemorrhage (with or without adenoidectomy) from 1998 to 2005 at The Children's Hospital of Philadelphia. Anesthetic records were examined for independent (anesthetic techniques and patient characteristics) and dependent variables (ventilatory and hemodynamic complications). RESULTS: Four hundred and seventy-five patients required surgery for exploration of post tonsillectomy hemorrhage (incidence 2.9%). Intravenous rapid sequence induction was used in 401 (84.4%) patients. Succinylcholine was used in 420 (88%) patients. The most common adverse event (9.9%) was hypoxemia; most episodes occurred during emergence or extubation. Bradycardia during anesthetic induction occurred in 20 (4.2%) patients, and hypotension was noted in 12 (2.5%) patients. Thirteen (2.7%) patients were noted to be difficult to intubate, none of whom were difficult to intubate during the initial tonsillectomy. CONCLUSIONS: We determined our incidence of ventilatory and hemodynamic complications in a relatively large cohort of children with post-tonsillectomy hemorrhage. Transient hypoxemia was the most common complication and was not related to difficult intubation. PMID- 20964766 TI - Experience with a propofol-ketamine mixture for sedation during pediatric orthopedic surgery. AB - BACKGROUND: Various combinations of propofol and ketofol have been described for the provision of procedural sedation in both adults and children. Utilization of 'ketofol' for deep sedation during prolonged pediatric orthopedic procedures has not previously been described. METHODS: During an orthopedic aid trip, a 1:1 mixture of propofol and ketamine (200 mg of each drawn up to 22 ml) was utilized to provide deep sedation or general anesthesia as an adjunct to regional analgesia for lower limb surgery. Details for 18 patients having a total of 19 procedures were recorded with a record of intraoperative and postoperative parameters including initial bolus doses and infusion rates of ketofol required to produce deep sedation. RESULTS: Mean operating time was 153.7 min (range 64 241 min). The mean initial bolus dose of ketofol was 0.19 ml.kg(-1) (range 0.1 0.5 ml.kg(-1) ) or 1.7 mg.kg(-1) each of propofol and ketamine (range 0.9-4.5 mg.kg(-1) ). The mean upper limit of the infusion rate required to maintain deep sedation was 0.19 ml.kg(-1) .h(-1) (range 0.07-0.26 ml.kg(-1) .h(-1) ) or 1.7 mg.kg(-1) .h(-1) (range 0.6-2.4 mg.kg(-1) .h(-1) ) and the mean lower limit of the infusion rate was 0.08 ml.kg(-1) .h(-1) (range 0.02-0.13 ml.kg(-1) .h(-1) ) or 0.7 mg.kg(-1) .h(-1) (range 0.2-1.2 mg.kg(-1) .h(-1) ). The mean initial bolus dose of ketofol was 0.19 ml.kg(-1) (range 0.1-0.5 ml.kg(-1) ). There were no episodes of hypo- or hypertension or of desaturation. Mean time to eye opening after infusion cessation was 5.1 min (median 2 min; range 0-17 min). CONCLUSION: Ketofol successfully produced deep sedation for prolonged pediatric orthopedic procedures in conjunction with regional analgesia. Further research to confirm its safety and applicability to a wider range of settings is required. PMID- 20964767 TI - The effect of volume of local anesthetic on the anatomic spread of caudal block in children aged 1-7 years. AB - OBJECTIVES: To examine the anatomic spread of caudal local anesthetic solution in children aged 1-7 years. AIM: To determine whether incremental increases in the volume of caudal injections of 0.5, 0.75, and 1.0 ml.kg(-1) result in reliable (>90%) and potentially clinically significant increases in the number of vertebral segments reached. BACKGROUND: Caudal block is one of the most frequently performed pediatric regional analgesic techniques. Traditional formulae suggest that changes in the volume of caudal injectate in the range 0.5 1.0 ml.kg(-1) would have clinically useful effects. METHODS: In a single blind design, 45 children aged 1-7 years undergoing caudal block received one of the three predetermined volumes (0.5, 0.75, and 1 ml.kg(-1) ) of local anesthetic solution containing radio-opaque contrast under controlled conditions. Following X-ray examination, the anatomic spread of the block was reported by a radiologist blinded to the volume of solution received. RESULTS: There were 15 children in each group, and they were similar in terms of age, height, and weight. Spread was observed between the 5th lumbar (L5) and 12th thoracic (T12) vertebral levels. A volume of 1 ml.kg(-1) results in a small but significantly greater spread of solution than 0.5 ml.kg(-1) (P < 0.05), but there was no difference between 0.5 and 0.75 ml or between 0.75 and 1.0 ml. No volume reliably reached a level higher than the second lumbar vertebra (L2). CONCLUSIONS: Incrementally increasing the volume of injectate between 0.5 and 1.0 results in a modest increase in the spread of the caudal solution. It is unlikely that volumes of <1 ml will reliably reach a vertebral level that is higher than L2. PMID- 20964768 TI - Improved analgesia with the ilioinguinal block compared to the transversus abdominis plane block after pediatric inguinal surgery: a prospective randomized trial. AB - BACKGROUND: Ultrasound-guided transversus abdominis plane (TAP) block has shown promise for analgesia after pediatric inguinal surgery. This prospective, randomized study tested the hypothesis that the TAP block would provide comparable analgesia after pediatric inguinal surgery compared with a conventional ultrasound-guided ilioinguinal block. METHODS: After induction of general anesthesia, infants and children presenting for elective inguinal surgery were randomly assigned to receive an ultrasound-guided TAP block (needle cephalad of the iliac crest at the anterior axillary line) (n = 20) or ilioinguinal block (needle immediately anteromedial to the anterior superior iliac spine) (n = 21). Supplemental analgesia consisted of as-required intraoperative fentanyl, regular acetaminophen, as-required ibuprofen, and rescue morphine. Patients were assessed in the recovery room, the day-stay unit (30 min to 2 h after surgery) and at 24 h for age appropriate numerical pain score, analgesic consumption, and parental satisfaction. RESULTS: In the day-stay unit, pain was more frequent (76% vs 45%, P = 0.040), and ibuprofen use was higher (62% vs 30%, P = 0.037) in the TAP group. Recovery room pain, morphine consumption and postdischarge ibuprofen use, comfort and satisfaction scores were similar between groups. Ultrasound image quality was poorer, and needle time under the skin was longer (median [interquartile range] 81 [66-120] vs 46 [40-51], P < 0.001) for the ilioinguinal group. CONCLUSIONS: Following pediatric inguinal surgery, ilioinguinal block provides more effective analgesia than the TAP block. PMID- 20964769 TI - Two-agent analgesia versus acetaminophen in children having bilateral myringotomies and tubes surgery. AB - OBJECTIVES: The objective of this study was to determine whether the incidence of emergence agitation (EA) can be reduced by adding an additional, faster onset, non-IV analgesic, intranasal fentanyl or intramuscular (im) ketorolac to rectal acetaminophen. AIM: To compare the incidence of EA after analgesia with two agents vs acetaminophen alone in pediatric patients after bilateral myringotomy procedures (BM&T). BACKGROUND: Anesthesia for BM&T is usually performed with volatile anesthetics as a single agent without securing intravenous access. The anesthetic agent most commonly used is sevoflurane; however, EA has been reported in up to 67% of patients. Emergence agitation is distressing for parents, can impair the ability of nursing staff to adequately monitor the child, and can result in a child injuring him/herself if it is severe. METHODS/MATERIALS: A standardized anesthetic was used with oral midazolam premedication and sevoflurane for induction, and maintenance of anesthesia. All patients received 40 mg.kg(-1) rectal acetaminophen, group 1 received acetaminophen alone, group 2 received acetaminophen and 1 mcg.kg(-1) of intranasal fentanyl, and group 3 received acetaminophen and 1 mg.kg(-1) of intramuscular ketorolac. Incidence of EA was compared using chi-square test between the acetaminophen group alone vs the two-agent analgesia groups combined. RESULTS: There were no differences in demographic and clinical characteristics between the two groups. There were no statistically significant differences between the three groups for the incidence of EA at any time point during recovery from anesthesia nor were there any significant differences in pain scores or side effects. No significant side effects because of the administration of a second analgesic agent were reported. CONCLUSIONS: We conclude that two-agent analgesia is not superior to acetaminophen alone for decreasing the incidence of EA after inhalation anesthesia with sevoflurane for BM&T surgery. Our overall incidence of EA was low compared to previous studies, which could potentially have decreased our ability to detect differences between groups. PMID- 20964770 TI - Spinal anesthesia in children: no longer an anathema! AB - BACKGROUND: Spinal anesthesia is underutilized for surgery in children in Nigeria. Until recently, only caudal and general anesthesia are employed in the pediatric age group, and the thought of spinal anesthesia was an anathema. This study evaluated cardiovascular changes, duration of spinal block, the length of surgery, length of spinal needle to establish lumbar puncture, and the incidence of complications associated with this procedure. METHODS: Thirty-two children ASA 1 and 2 between the ages of 2 and 12 had spinal block from August 1, 2008 to February 28, 2010 for orthopedic and plastic surgical procedures. Spinal block was carried out at L5/S1 interspace, and the dose of bupivacaine was 0.5 mg.kg( 1). RESULT: Satisfactory surgical anesthesia was achieved in 31 of 32 children. There was no sensory or motor block within 10 min in one child, despite an easy lumbar puncture necessitating the use of general anesthesia. No patient showed oxygen desaturation, bradycardia, or hypotension. Two (6.5%) children aged 5 and 8 reported mild, position-dependent headaches, 3 (9.7%) had nausea and vomiting, and 5 (16.1%) had postspinal shivering. There was a positive correlation between the size of the child and the needle length to establish spinal anesthesia (r = 0.7, P = 0.0001). CONCLUSION: This study demonstrates that spinal anesthesia in children causes minimal hemodynamic disruption and therefore is a safe technique for lower extremity surgeries. This technique that hitherto has not been popular with children in our environment has been found to be safe and equally effective. PMID- 20964771 TI - Cerebral NIRS as a marker of superior vena cava oxygen saturation in neonates with congenital heart disease. AB - OBJECTIVES: To investigate the correlation between cerebral near-infrared spectroscopy (NIRS) (rSO2c) and superior vena cava venous oxygen saturation (ScvO2) in newborn patients with congenital heart disease (CHD). BACKGROUND: NIRS is a noninvasive method to monitor hemoglobin oxygen saturation using nonpulsatile oximetry. METHODS: We retrospectively analyzed perioperative data from 100 newborn patients who underwent cardiac surgery for CHD. rSO2c, ScvO2 from 24 h before to 72 h after surgery were recorded. RESULTS: rSO2c had a fair correlation with ScvO2 (r 0.37; P <0.001). The relationship between rSO2c and ScvO2 did not change when analyzed between patients with cyanotic or acyanotic CHD. During the preoperative period, rSO2c levels overestimated ScvO2; in the first 18 postoperative hours, rSO2c underestimated ScvO2; after that period, they showed very close trends. Hypocapnia caused rSO2c to underestimate ScvO2; in normocapnic patients, rSO2c-ScvO2 average differences were close to zero; in hypercapnic neonates, rSO2c tended to overestimate ScvO2. The best performance of rSO2c as a surrogate of ScvO2 was found in the venous saturation ranges from 40% to 60% (r 0.3, P: 0.03). CONCLUSIONS: rSO2c in newborn patients with cyanotic and acyanotic CHD provides a continuous noninvasive information with a fair correlation with ScvO2%: some predictable variables (i.e., time from surgery, carbon dioxide, and venous saturation levels), should guide the operators to adjust rSO2c values in terms of ScvO2. Serial measures of ScvO2 seem recommended to tailor rSO2c information on actual venous saturation percentage. PMID- 20964773 TI - Another cause of hypercapnia during induction of anesthesia. PMID- 20964772 TI - Complications of anesthesia for children with malignant infantile osteopetrosis before and after hematopoietic stem cell transplantation. AB - OBJECTIVES AND AIMS: The primary aim was to determine the frequency of anesthetic related complications for patients with malignant infantile osteopetrosis (MIOP) before and after hematopoietic stem cell transplant (HSCT). The secondary aims were to describe the types of complications that occurred, to determine whether the risk of anesthetic complications was altered by HSCT, and to determine the frequency of difficult intubation. BACKGROUND: Patients with MIOP undergo HSCT, often in infancy, and anesthesia is frequently required for investigations and procedures associated with transplantation. Although MIOP has adverse implications for anesthetic management, the literature describing the anesthetic management of MIOP patients is limited. METHODS: A retrospective review of medical and anesthetic records was undertaken between November 2000 and March 2008. RESULTS: Eleven patients underwent 127 anesthetics. The overall complication rate was 11%. Before HSCT, there were 12 complications in 62 anesthetics (19.3%). After HSCT, there were two complications in 65 anesthetics (3.2%). This difference was not statistically significant. All of the complications were airway or respiratory events. Of the 26 intubations associated with anesthesia, 23 (88.5%) were easy, 1 (3.8%) was moderately difficult, and 2 (7.7%) were difficult. CONCLUSION: Complications associated with anesthesia for infants and children with MIOP having HSCT are fairly common and are usually airway or respiratory related. Difficult endotracheal intubation is also common. PMID- 20964774 TI - The L-Tap - a new two-way tap to prevent inadvertent over transfusion and fluid overload in neonates and infants. PMID- 20964775 TI - What parents think about physical restraint of their child to facilitate induction of anesthesia. PMID- 20964776 TI - A simple measure to facilitate use of a preformed oral tube for tracheal intubation using the Airtraq laryngoscope in children. PMID- 20964777 TI - Ultrasound-guided proximal tibial paravenous saphenous nerve block in pediatric patients. PMID- 20964778 TI - Consequences of genetic erosion on fitness and phenotypic plasticity in European tree frog populations (Hyla arborea). AB - The detrimental effects of genetic erosion on small isolated populations are widely recognized contrary to their interactions with environmental changes. The ability of genotypes to plastically respond to variability is probably essential for the persistence of these populations. Genetic erosion impact may be exacerbated if inbreeding affects plastic responses or if their maintenance were at higher phenotypic costs. To understand the interplay 'genetic erosion-fitness phenotypic plasticity', we experimentally compared, in different environments, the larval performances and plastic responses to predation of European tree frogs (Hyla arborea) from isolated and connected populations. Tadpoles from isolated populations were less performant, but the traits affected were environmental dependant. Heterosis observed in crosses between isolated populations allowed attributing their low fitness to inbreeding. Phenotypic plasticity can be maintained in the face of genetic erosion as inducible defences in response to predator were identical in all populations. However, the higher survival and developmental costs for isolated populations in harsh conditions may lead to an additional fitness loss for isolated populations. PMID- 20964779 TI - Within-host viral evolution in a heterogeneous environment: insights into the HIV co-receptor switch. AB - A virus infecting a host faces a heterogeneous and a spatially structured environment. Using a mathematical model that incorporates two types of target cells and spatial structuring, we investigate conditions for viral within-host diversification. We show that branching occurs for a wide range of parameters but that it always requires some spatial structure. Applying our model to the case of HIV, we show that it captures three main properties of the 'co-receptor switch' observed in many HIV infections: the initial dominance of virus strains that infect CCR5(+) cells, the late switch in some (but, importantly, not all) HIV infections and the associated drop in the number of uninfected T-cells. This suggests that the co-receptor switch could result from gradual adaptation of the virus population to target cell heterogeneity. More generally, we argue that evolutionary ecology can help us better understand the course of some infections. PMID- 20964780 TI - Experimental evolution of protozoan traits in response to interspecific competition. AB - Decades of experiments have demonstrated the ecological effect of competition, but experimental evidence for competitive effects on trait evolution is rare. I measured the evolution of six protozoan traits in response to competitors from the inquiline community of pitcher plants. Replicate populations of Colpoda, a ciliated protozoan, were allowed to evolve in response to intra- and interspecific competition for 20 days (approximately 100 generations), before traits were measured in two common garden environments. Populations that evolved with interspecific competition had smaller cell sizes, produced fewer cysts and had higher population growth rates relative to populations grown in monoculture. The presence of interspecific competitors led to differential lineage sorting, most likely by increasing the strength of selection. These results are the first to demonstrate protozoan evolution in response to competition and may have implications for species coexistence in this system. PMID- 20964781 TI - Allen's rule revisited: quantitative genetics of extremity length in the common frog along a latitudinal gradient. AB - Ecogeographical rules linking climate to morphology have gained renewed interest because of climate change. Yet few studies have evaluated to what extent geographical trends ascribed to these rules have a genetic, rather than environmentally determined, basis. This applies especially to Allen's rule, which states that the relative extremity length decreases with increasing latitude. We studied leg length in the common frog (Rana temporaria) along a 1500 km latitudinal gradient utilizing wild and common garden data. In the wild, the body size-corrected femur and tibia lengths did not conform to Allen's rule but peaked at mid-latitudes. However, the ratio of femur to tibia length increased in the north, and the common garden data revealed a genetic cline consistent with Allen's rule in some trait and treatment combinations. While selection may have shortened the leg length in the north, the genetic trend seems to be partially masked by environmental effects. PMID- 20964782 TI - Phylogenetic comparative approaches for studying niche conservatism. AB - Analyses of phylogenetic niche conservatism (PNC) are becoming increasingly common. However, each analysis makes subtly different assumptions about the evolutionary mechanism that generates patterns of niche conservatism. To understand PNC, analyses should be conducted with reference to a clear underlying model, using appropriate methods. Here, we outline five macroevolutionary models that may underlie patterns of PNC (drift, niche retention, phylogenetic inertia, niche filling/shifting and evolutionary rates) and link these to published phylogenetic comparative methods. For each model, we give recent examples from the literature and suggest how the methods can be practically applied. We hope that this will help clarify the niche conservatism literature and encourage people to think about the evolutionary models underlying niche conservatism in their study group. PMID- 20964783 TI - Incipient allochronic speciation in the pine processionary moth (Thaumetopoea pityocampa, Lepidoptera, Notodontidae). AB - A plausible case of allochronic differentiation, where barrier to gene flow is primarily attributable to a phenological shift, was recently discovered in Portugal for the pine processionary moth Thaumetopoea pityocampa. Previous results suggested that the observed 'summer population' (SP) originated from the sympatric winter population (WP). Our objectives were to finely analyse these patterns and test their stability in time, through field monitoring and genetic analyses of larvae and adults across different years. Reproductive activity never overlapped between SP and WP. Microsatellites showed a clear differentiation of the SP, consistent with a strong reduction in gene flow owing to the phenological shift. Assignment tests suggested that some individuals shift from the SP to the WP phenology, causing some hybridization. We discuss these patterns and their maintenance over time. This could be a first stage of allochronic speciation, and SP should be considered as a distinct phenological race. PMID- 20964784 TI - The genetic structure of Borrelia afzelii varies with geographic but not ecological sampling scale. AB - The genetic structure of a pathogen is an important determinant of its potential rate of adaptation and can thereby influence the dynamics of host-parasite interactions. We investigated how the genetic structure of Borrelia afzelii varies with geographic and ecological sampling scale. Genetic structure was measured as the degree of linkage disequilibrium (LD) across three loci. To test for the effects of geographic and ecological scale, we calculated LD across or within populations 4-82 km apart and across or within different mammal host species. There was highly significant LD across populations and host species. However, there was also evidence for genome-wide recombination, and the LD largely resulted from epidemic spread of certain haplotypes, rather than lack of recombination. Interestingly, the degree of LD was higher in each population than in the sample as a whole, i.e. LD increased with decreasing geographic scale. In contrast, there was no effect of ecological sampling scale on LD. Strong LD may impede the rate of adaptive evolution. Our results suggest this effect might be particularly strong at a small geographic scale. PMID- 20964785 TI - Nuptial coloration varies with ambient light environment in a freshwater fish. AB - Visual signals play a vital role in many animal communication systems. Signal design, however, often varies within species, raising evolutionarily important questions concerning the maintenance of phenotypic diversity. We analysed nuptial colour variation within and among nine populations of southern pygmy perch (Nannoperca australis Gunther) along an environmental light gradient. Within populations, larger males were redder and blacker, and better-condition males were blacker. Among populations, red colour was positively correlated with the amount of orange-red light present, suggesting that males are likely optimizing signal conspicuousness by producing proportionally larger and redder patches in broad spectrum environments with more orange-red light. Signal contrast, in this regard, is maximized when red colour, appearing bright because of the prevalence of red wavelengths, is viewed against the water-column background. Together, our results are concordant with the sensory drive hypothesis; selection favours signal adaptations or signal plasticity to ensure communication efficacy is maximized in different light environments. PMID- 20964786 TI - Alteration of pathogenicity-linked life-history traits by resistance of its host Solanum tuberosum impacts sexual reproduction of the plant pathogenic oomycete Phytophthora infestans. AB - Although sexual reproduction implies a cost, it represents an evolutionary advantage for the adaptation and survival of facultative sexual pathogens. Understanding the maintenance of sex in pathogens requires to analyse how host resistance will impact their sexual reproduction through the alteration of their life-history traits. We explored this experimentally using potato (Solanum tuberosum) and one of its pathogens, the heterothallic oomycete Phytophthora infestans. Sexual reproduction was highest on hosts favouring asexual multiplication of the pathogen, suggesting similar nutritional requirements for both sexual and asexual sporulation. Sexual reproduction was also highest on hosts decreasing the latent period, probably because of a trade-off between growth and reproduction. Distinguishing host effects on each pathogenic trait remains however uneasy, as most life-history traits linked to pathogenicity were not independent of each other. We argue that sexual reproduction of P. infestans is an adaptation to survive when the host is susceptible and rapidly destroyed. PMID- 20964787 TI - Fitness disadvantages to disrupted embryogenesis impose selection against suboptimal nest-site choice by female grass snakes, Natrix natrix (Colubridae). AB - Phenotypic traits of hatchling reptiles are strongly influenced by incubation regimes (e.g. of temperature and moisture), suggesting that maternal choice of suitable nest-sites should be under intense selection. Our laboratory incubation of 209 eggs (17 clutches) from wild-caught Swedish grass snakes (Natrix natrix) showed that scale abnormalities (half-scales on one side of the body, often reflecting lateral asymmetry in the number of ribs) occurred more frequently if eggs were incubated under cooler conditions. Especially at low incubation temperatures, individuals with scale asymmetries took longer to hatch than did symmetric conspecifics, were smaller in body length at hatching and were slower in trials of locomotor speed. Anti-predator tactics also covaried with scale asymmetry. These patterns suggest that individuals with asymmetric scales should have lower fitness and hence should rarely survive to adulthood in the wild. We tested this prediction by examining 201 field-collected snakes from museum collections. As predicted, scale asymmetries were seen primarily in small snakes, and rarely in larger animals. We interpret these data to suggest that scale asymmetries in this species offer an index of developmental instability and that fitness disadvantages to disrupted embryogenesis impose selection against suboptimal nest-site choice by females. PMID- 20964788 TI - Neurocognitive function in patients with beta-thalassemia major. AB - BACKGROUND: Children with beta-thalassemia major (beta-TM) have multiple risk factors for developing cognitive impairment. The aim of the present study was to evaluate cognitive function in patients with beta-TM. METHODS: Twenty children with beta-TM were enrolled into the study and were compared with a control group consisting of 21 healthy children. All participants were evaluated with neuropsychological tests and event-related potentials (ERP). RESULTS: All of the participants had normal IQ scores, but the patient group had significantly lower full-scale, performance, and verbal IQs compared with the control group (P < 0.05). The number of children with visuomotor dysfunction was higher in the patient group compared with the control group (P < 0.05). In the P300 test, the patient group had significantly prolonged N1, P2 and N2 latencies at the FZ, and a prolonged N1 latency at the Cz compared with the control group (P < 0.05). The patient group also had lower N1 and P3N4 amplitudes at the Fz, and lower N1, N1P2 and P3N4 amplitudes at the Cz when compared with the control group (P < 0.05). Mismatch negativity latency and duration were longer in the patient group (P < 0.05). CONCLUSIONS: Neuropsychological tests are safe, and reliable for the diagnosis of cognitive impairment in beta-TM patients, and the use of ERP may facilitate early diagnosis. The number of beta-TM patients in the present study was limited, however, and larger numbers of patients are required in further studies. PMID- 20964789 TI - Low-dose carcinogenicity of 2-amino-3-methylimidazo[4,5-f ]quinoline in rats: Evidence for the existence of no-effect levels and a mechanism involving p21(Cip / WAF1). AB - The carcinogenicity of the low amounts of genotoxic carcinogens present in food is of pressing concern. The purpose of the present study was to determine the carcinogenicity of low doses of the dietary genotoxic carcinogen 2-amino-3 methylimidazo[4,5-f]quinoline (IQ) and to investigate mechanisms by which IQ exerts its carcinogenic effects. A total of 1595 male F344 rats were divided into seven groups and administered with IQ at doses of 0, 0.001, 0.01, 0.1, 1, 10 and 100 p.p.m. in the diet for 16 weeks. We found that IQ doses of 1 p.p.m. and below did not induce preneoplastic lesions in either the liver or the colon, while IQ doses of 10 and 100 p.p.m. induced preneoplastic lesions in both of these organs. These results demonstrate the presence of no-effect levels of IQ for both liver and colon carcinogenicity in rats. The finding that p21(Cip/WAF1) was significantly induced in the liver at doses well below those required for IQ mediated carcinogenic effects suggests that induction of p21(Cip/WAF1) is one of the mechanisms responsible for the observed no-effect of low doses of IQ. Furthermore, IQ administration caused significant induction of CYP1A2 at doses of 0.01-10 p.p.m., but administration of 100 p.p.m. IQ induced CYP1A1 rather than CYP1A2. This result indicates the importance of dosage when interpreting data on the carcinogenicity and metabolic activation of IQ. Overall, our results suggest the existence of no-effect levels for the carcinogenicity of this genotoxic compound. PMID- 20964790 TI - CGRP1 receptor activation induces piecemeal release of protease-1 from mouse bone marrow-derived mucosal mast cells. AB - BACKGROUND: The parasitized or inflamed gastrointestinal mucosa shows an increase in the number of mucosal mast cells (MMC) and the density of extrinsic primary afferent nerve fibers containing the neuropeptide, calcitonin gene-related peptide (CGRP). Currently, the mode of action of CGRP on MMC is unknown. METHODS: The effects of CGRP on mouse bone marrow-derived mucosal mast cells (BMMC) were investigated by measurements of intracellular Ca(2+)[Ca(2+)](i) and release of mMCP-1. KEY RESULTS: Bone marrow-derived mucosal mast cells responded to the application of CGRP with a single transient rise in [Ca(2+)](i). The proportion of responding cells increased concentration-dependently to a maximum of 19 +/- 4% at 10(-5)mol L(-1) (mean +/-SEM; C48/80 100%; EC(50)10(-8) mol L(-1) ). Preincubation with the CGRP receptor antagonist BIBN4096BS (10(-5) mol L(-1)) completely inhibited BMMC activation by CGRP [range 10(-5) to 10(-11) mol L(-1); analysis of variance (ANOVA) P < 0.001], while preincubation with LaCl(3) to block Ca(2+) entry did not affect the response (P = 0.18). The presence of the CGRP1 receptor on BMMC was confirmed by simultaneous immunofluorescent detection of RAMP1 or CRLR, the two components of the CGRP1 receptor, and mMCP-1. Application of CGRP for 1 h evoked a concentration-dependent release of mMCP-1 (at EC(50) 10% of content) but not of beta-hexosaminidase and alterations in granular density indicative of piecemeal release. CONCLUSIONS & INFERENCES: We demonstrate that BMMC express functional CGRP1 receptors and that their activation causes mobilization of Ca(2+) from intracellular stores and piecemeal release of mMCP-1. These findings support the hypothesis that the CGRP signaling from afferent nerves to MMC in the gastrointestinal wall is receptor-mediated. PMID- 20964791 TI - A bi-directional assessment of the human brain-anorectal axis. AB - BACKGROUND: Brain-gut dysfunction has been implicated in gastrointestinal disorders but a comprehensive test of brain-gut axis is lacking. We developed and tested a novel method for assessing both afferent anorectal-brain function using cortical evoked potentials (CEP), and efferent brain-anorectal function using motor evoked potentials (MEP). METHODS: Cortical evoked potentials was assessed following electrical stimulations of anus and rectum with bipolar electrodes in 26 healthy subjects. Anorectal MEPs were recorded following transcranial magnetic stimulation (TMS) over paramedian motor cortices bilaterally. Anal and rectal latencies/amplitudes for CEP and MEP responses and thresholds for first sensation and pain (mA) were analyzed and compared. Reproducibility and interobserver agreement of responses were examined. KEY RESULTS: Reproducible polyphasic rectal and anal CEPs were recorded in all subjects, without gender differences, and with negative correlation between BMI and CEP amplitude (r -0.66, P=0.001). Transcranial magnetic stimulation evoked triphasic rectal and anal MEPs, without gender differences. Reproducibility for CEP and MEP was excellent (CV <10%). The inter-rater CV for anal and rectal MEPs was excellent (ICC 97-99), although there was inter-subject variation. CONCLUSIONS & INFERENCES: Combined CEP and MEP studies offer a simple, inexpensive and valid method of examining bidirectional brain-anorectal axes. This comprehensive method could provide mechanistic insights into lower gut disorders. PMID- 20964792 TI - A role for endothelin receptor type A in migraine without aura susceptibility? A study in Portuguese patients. AB - BACKGROUND AND PURPOSE: Migraine is a common neurological disabling disorder, and anomalies of vascular function have been implied in its pathophysiology. Several findings point to a possible role of the endothelin receptor type A (EDNRA) in migraine. We aim to assess the involvement of endothelin receptor type A (EDNRA) in migraine susceptibility in a sample of Portuguese migraineurs. METHODS: Three tagging SNPs (rs702757, rs5333 and rs5335) were analysed in 188 cases - 111 without aura (MO) and 77 with aura (MA) - and 287 controls. A multivariable logistic regression was performed, including the three SNPs, adjusted for gender. Allelic and haplotypic frequencies were compared between cases and controls. Significant or promising results were confirmed by a multifactor dimensionality reduction analysis (MDR). RESULTS: We found a nominal association for the rs702757 T-allele [odds ratio (OR) = 1.44, 95% confidence intervals (CI): 1.05 1.99] and for the TT-genotype (OR = 2.34, 95% CI: 1.12-4.90) for MO, that do not remain significant after multiple test correction. A trend towards an increased risk for MA regarding the C-allele of rs5333 was also found. However, an additional MDR analysis was performed, and highly significant results were found for the two SNPs. The T-C-G haplotype (rs702757-rs5333-rs5335) was found to be significantly overrepresented in the MO subgroup, even after permutation was performed. CONCLUSIONS: Our results show additional findings for a role of EDNRA as a susceptibility factor for MO, although we cannot exclude the involvement of this gene in MA susceptibility in our population. Our study also emphasizes the need for replication of association findings in different populations. PMID- 20964793 TI - The influence of hepatitis C and alcohol on liver-related morbidity and mortality in Glasgow's injecting drug user population. AB - Infection with the hepatitis C virus (HCV) is associated with the development of severe liver disease, but cofactors--namely alcohol abuse--in Scotland's HCV positive population complicate estimation of the unique contribution of HCV. We compared the risk of hospital admission/death for a liver-related cause in a large cohort of Glasgow's injecting drug users (IDUs) testing HCV-positive with IDUs testing HCV negative. Data for 6566 current/former IDUs who had been tested for anti-HCV and/or HCV RNA by polymerase chain reaction in Greater Glasgow health board between 1993 and 2007 were linked to the national hospitalization database and deaths registry to identify all admissions and deaths from a liver related condition. Relative risks were estimated using Cox proportional hazards regression for recurrent events. Time at risk was censored at 2 years following an HCV test to address bias owing to unobserved seroconversion. The risk of hospitalization/death from a liver-related or an alcoholic liver-related condition following HCV testing was greater for those IDUs with no prior alcohol related hospitalization who tested positive [adjusted hazard ratio (HR) = 3.2, 95% CI: 1.5-6.7; 4.9, 95% CI: 1.8-13.1, respectively], compared with those who tested anti-HCV negative, but not for those IDUs with a prior alcohol admission (HR = 0.8, 95% CI: 0.4-1.5; 0.8, 95% CI: 0.4-1.6). There was little evidence for an increased risk of hospitalization/death for an exclusively nonalcoholic liver condition for those testing positive (HR = 1.5, 95% CI: 0.8-2.7), after adjustment for previous alcohol-related admission. Within Glasgow's IDU population, HCV positivity is associated with an increased risk of a liver related outcome, but this is not observed for those IDUs whose problem alcohol use already increases their risk. PMID- 20964794 TI - Single live-bacterial cell assay of promoter activity and regulation. AB - Laboratory cultures of a single species of bacteria harboring the same genetic background include heterogeneous cell populations, each differing in apparent morphology and physiology, as found in natural environments. To get insights into difference in the genome expression between individual cells, we constructed various types of the cell chip for monitoring the growth and fate of individual bacterial cells. Immobilization of portions of Escherichia coli culture within these cell chips was established after raising the local temperature in the presence of poly-(N-isopropylacrylamide) (PNIPAAm). The newly developed cell-chip system allows the investigation of activity and regulation of green fluorescent protein (GFP)-fused promoter in single live-bacterial cells for prolonged time under controlled culture conditions. Using this single-cell observation system, we succeeded, for the first time, the real-time single-cell assay of promoter activity of the E. coli gcl gene encoding glyoxylate carboligase as a model system, and the kinetics of gcl induction by an effector glyoxylate. Marked heterogeneity was found in the expression level of the gcl promoter. The heterogeneity in gcl promoter activity was, however, confirmed by Flow cytometry of suspension cultures. Our success provides an experimental system for the increased demand of single-cell biology in bacterial studies. PMID- 20964795 TI - Necl-5/PVR enhances PDGF-induced attraction of growing microtubules to the plasma membrane of the leading edge of moving NIH3T3 cells. AB - Microtubules (MTs) search for and grow toward the leading edge of moving cells, followed by their stabilization at a specific structure at the rear site of the leading edge. This dynamic re-orientation of MTs is critical to directional cell movement. We previously showed that Necl-5/poliovirus receptor (PVR) interacts with platelet-derived growth factor (PDGF) receptor and integrin alpha(v) beta(3) at the leading edge of moving NIH3T3 cells, resulting in an enhancement of their directional movement. We studied here the role of Necl-5 in the PDGF-induced attraction of growing MTs to the leading edge of NIH3T3 cells. Necl-5 enhanced the PDGF-induced growth of MTs and attracted them near to the plasma membrane of the leading edge of NIH3T3 cells in an integrin alpha(v) beta(3) -dependent manner. Furthermore, Necl-5 enhanced the PDGF-induced attraction of the plus-end tracking proteins (+TIPs), including EB1, CLIP170, an intermediate chain subunit of cytoplasmic dynein, and p150(Glued) , a subunit of dynactin, near to the plasma membrane of the leading edge. Thus, Necl-5 plays a role in the attraction of growing MTs to the plasma membrane of the leading edge of moving cells. PMID- 20964796 TI - Caenorhabditis elegans ortholog of the p24/p22 subunit, DNC-3, is essential for the formation of the dynactin complex by bridging DNC-1/p150(Glued) and DNC 2/dynamitin. AB - Dynactin is a multisubunit protein complex required for the activity of cytoplasmic dynein. In Caenorhabditis elegans, although 10 of the 11 dynactin subunits were identified based on the sequence similarities to their orthologs, the p24/p22 subunit has not been detected in the genome. Here, we demonstrate that DNC-3 (W10G11.20) is the functional counterpart of the p24/p22 subunit in C. elegans. RNAi phenotypes and subcellular localization of DNC-3 in early C. elegans embryos were nearly identical to those of the known dynactin components. All other dynactin subunits were co-immunoprecipitated with DNC-3, indicating that DNC-3 is a core component of dynactin. Furthermore, the overall secondary structure of DNC-3 resembles to those of the mammalian and yeast p24/p22. We found that DNC-3 is required for the localization of the DNC-1/p150(Glued) and DNC-2/dynamitin, the two components of the projection arm of dynactin, to the nuclear envelope of meiotic nuclei in the adult gonad. Moreover, DNC-3 physically interacted with DNC-1 and DNC-2 and significantly enhanced the binding ability between DNC-1 and DNC-2 in vitro. These results suggest that DNC-3 is essential for the formation of the projection arm subcomplex of dynactin. PMID- 20964797 TI - The struggle for iron - a metal at the host-pathogen interface. AB - Iron holds a central position at the host-pathogen interface because mammalian and microbial cells have an essential demand for the metal, which is required for many metabolic processes. In addition, cross-regulatory interactions between iron homeostasis and immune function are evident. While iron affects the secretion of cytokines and the activity of transcription factors orchestrating immune responses, immune cell-derived mediators and acute-phase proteins control both systemic and cellular iron homeostasis. Additionally, immune-mediated strategies aim at restricting the supply of the essential nutrient iron to pathogens, which represents an effective strategy of host defence. On the other hand, microbes have evoked multiple strategies to utilize iron because a sufficient supply of this metal is linked to pathogen proliferation, virulence and persistence. The control over iron homeostasis is a central battlefield in host-pathogen interplay influencing the course of an infectious disease in favour of either the mammalian host or the pathogenic invader. This review summarizes our current knowledge on the combat of host cells and pathogens for the essential nutrient iron focusing on the immune-regulatory roles of iron on cell-mediated immunity necessary to control intracellular microbes, the host's mechanisms of iron restriction and on the counter-acting iron-acquisition strategies employed by intracellular microbes. PMID- 20964798 TI - FISH analysis reveals aneuploidy and continual generation of chromosomal mosaicism in Leishmania major. AB - The protozoan parasite Leishmania is generally considered to be diploid, although a few chromosomes have been described as aneuploid. Using fluorescence in situ hybridization (FISH), we determined the number of homologous chromosomes per individual cell in L. major (i) during interphase and (ii) during mitosis. We show that, in Leishmania, aneuploidy appears to be the rule, as it affects all the chromosomes that we studied. Moreover, every chromosome was observed in at least two ploidy states, among monosomic, disomic or trisomic, in the cell population. This variable chromosomal ploidy among individual cells generates intra-strain heterogeneity, here precisely chromosomal mosaicism. We also show that this mosaicism, hence chromosome ploidy distribution, is variable among clones and strains. Finally, when we examined dividing nuclei, we found a surprisingly high rate of asymmetric chromosome allotments, showing that the transmission of genetic material during mitosis is highly unstable in this 'divergent' eukaryote: this leads to continual generation of chromosomal mosaicism. Using these results, we propose a model for the occurrence and persistence of this mosaicism. We discuss the implications of this additional unique feature of Leishmania for its biology and genetics, in particular as a novel genetic mechanism to generate phenotypic variability from genomic plasticity. PMID- 20964799 TI - Combined action of the type IV secretion effector proteins BepC and BepF promotes invasome formation of Bartonella henselae on endothelial and epithelial cells. AB - Bartonella henselae (Bhe) can invade human endothelial cells (ECs) by two distinguishable entry routes: either individually by endocytosis or as large bacterial aggregates by invasome-mediated internalization. Only the latter process is dependent on a functional VirB/VirD4 type IV secretion system (T4SS) and the thereby translocated Bep effector proteins. Here, we introduce HeLa cells as a new cell system suitable to study invasome formation. We describe a novel route to trigger invasome formation by the combined action of the effectors BepC and BepF. Co-infections of either HUVEC or HeLa cells with the Bep-deficient DeltabepA-G mutant expressing either BepC or BepF restores invasome formation. Likewise, ectopic expression of a combination of BepC and BepF in HeLa cells enables invasome-mediated uptake of the Bhe DeltabepA-G mutant strain. Further, eGFP-BepC and eGFP-BepF fusion proteins localize to the cell membrane and, upon invasome formation, to the invasome. Furthermore, the combined action of BepC and BepF inhibits endocytic uptake of inert microspheres. Finally, we show that BepC and BepF-triggered invasome formation differs from BepG-triggered invasome formation in its requirement for cofilin1, while the Rac1/Scar1/WAVE/Arp2/3 and Cdc42/WASP/Arp2/3 signalling pathways are required in both cases. PMID- 20964800 TI - Self-protection and survival of arbovirus-infected mosquito cells. AB - Arboviruses are serious pathogens for men but cause little damage to their arthropod vectors. We have studied how a mosquito cell line derived from one of the relevant vectors for arboviruses responds to Bunyamwera virus, a well characterized arbovirus. Confocal, live cell microscopy and electron microscopy showed that Bunyamwera virus induces deep changes in mosquito cells. Early in infection these cells develop long projections and create new intercellular connections where cell organelles and viral proteins are detected. Live cell microscopy shows that these connections are developed before viral protein can be detected by immunofluorescence. Interestingly, their proliferation is accompanied by a progressive trapping of the nucleocapsid and RNA polymerase viral proteins into large cytoplasmic aggregates. A significant drop in the release of infectious virions then follows. Before that, numerous viruses assemble in peripheral Golgi stacks and they apparently exit the cells immediately since they do not accumulate intracellularly. This mechanism of assembly seems to cause little damage to the integrity of cell endomembranes. The characterization of the antiviral mechanisms operating in mosquito cells can be of great help in the fight against pathogenic arboviruses. PMID- 20964801 TI - Adjustable bulbourethral male sling: experience after 101 cases of moderate-to severe male stress urinary incontinence. AB - OBJECTIVES: * To report our experience using an adjustable bulbourethral sling since April 2005 for male stress urinary incontinence (SUI) after prostatic surgery. * To evaluate the safety, efficacy and health-related quality of life in recipients of the Argus(r) (Promedon SA; Cordoba, Argentina) adjustable bulbourethral sling. PATIENTS AND METHODS: * Between April 2005 and April 2009, 101 men with moderate-to-severe SUI after prostatic surgery were implanted with the Argus sling. * The radio-opaque Argus system comprises a thick silicone-foam pad for soft bulbar urethral support. The pad is attached to silicone columns that, after being passed with needles from the perineum to the abdominal wall, are adjusted with silicone washers to maintain the desired position. * Between prostatic surgery and Argus sling placement, most patients (74.3%) had undergone various procedures for SUI or bladder neck pathologies: 22 had undergone secondary irradiation therapy after surgery (19 after retropubic radical prostatectomy [RP], one after perineal RP and two after transurethral resection of the prostate). * All patients were evaluated before and after sling placement with 20-min pad tests, the Urinary Incontinence Quality of Life Scale (I-QoL), cystoscopy and uroflowmetry. The study was designed in a retrospective longitudinal fashion. RESULTS: * The mean (range) follow-up was 2.1 (0.1-4.5) years. The mean (range) sling surgery duration was 49 (28-105) min. * Adjustment was necessary in 39 cases (38.6%), either loosening (10/101; 9.9%) or tightening (29/101; 28.7%) at a mean of 104.3 (14-910) days after the initial implantation. * The sling had to be removed in 16/101 patients (15.8%) at a mean of 371.1 (20 1260) days after implantation due to urethral erosion or infection. However, six of the 16 patients were within the first 22 placements and probably represent the 'learning curve'. In all, 13 of these patients received later successful treatment (seven with an artificial urinary sphincter, five with re-implantation of the sling). Four of these patients were lost for follow-up. * After a median (mean) follow-up of 2.2 (2.1) years, 80/101 (79.2%) patients were considered as dry, with a pad test of 0-1 g (70 patients, 0 g; 10 patients, 1 g). The I-QoL score improved from a mean of 28.8 (14.5-61.8) to 63.2 (16.4-115) points after sling placement. * Both the 20-min pad-weight tests and I-QoL responses improved significantly compared with baseline (P < 0.001). CONCLUSION: * We think that the Argus male bulbourethral sling system is an excellent first- or second-line treatment for moderate-to-severe male SUI, even after external beam radiation treatment. PMID- 20964802 TI - Prognostic significance of circumferential cell surface immunoreactivity of glypican-3 in hepatocellular carcinoma. AB - BACKGROUND: GC33 is a recently developed monoclonal antibody against human glypican-3 (GPC3), which is significantly upregulated in hepatocellular carcinoma (HCC). GC33 recognizes a GPC3 ectodomain and shows significant antitumour activity in vivo. Thus, humanized GC33 antibody may be a promising tool for treating HCC having cell surface GPC3 expression. AIMS: This study aims to determine the specificity, subcellular localization and prognostic impact of GPC3 immunoreactivity detected by GC33 in HCC clinical specimens. METHODS: Immunohistochemical analysis was performed for 194 cases of resected HCC and prognostic analysis was performed for 185 eligible cases. Two antigen retrieval methods (autoclave and protease pretreatments) were used for immunohistochemistry and compared. The immunoscore system reflecting circumferential membranous GPC3 immunoreactivity was developed using either the autoclave or protease methods. The GPC3 mRNA level was analysed by quantitative real-time reverse transcription polymerase chain reaction. RESULTS: GC33 immunostaining after autoclave is a sensitive method and revealed the GPC3 expression (>=20% of tumour cells) in the majority (77%) of HCC samples tested. Alternatively, protease pretreatment showed lower sensitivity, but was superior for evaluating the intensity and subcellular localization of GPC3. Correlation between immunoscores and the GPC3 mRNA level was also confirmed. Subsequent clinicopathological analysis revealed worse prognoses in HCC patients with circumferential membranous GPC3 immunoreactivity. For HCC patients with hepatitis C virus (HCV) infection in particular, the high membranous GPC3 immunoreactivity was an independent prognostic factor for disease free survival. CONCLUSIONS: Circumferential membranous GPC3 immunoreactivity in HCC indicates poorer prognosis particularly in patients with HCV infection. PMID- 20964803 TI - Implant restoration 3 months after one stage sinus lift surgery in severely resorbed maxillae: 2-year results of a multicenter prospective clinical study. AB - OBJECTIVES: This multicenter prospective study was aimed to clinically evaluate implant behavior inserted in severely resorbed maxillae and restored 3 months after sinus grafting. MATERIALS AND METHODS: In three clinical centers, 67 totally rough wide diameter implants were inserted during 30 consecutive sinus lifts. Computed tomography and panoramic analysis were preoperatively requested for each patient. Sinus grafting was performed using a nano-crystalline hydroxyapatite sole bone filler; no membrane was used to cover the buccal window. Preoperative residual bone height ranged between 1-4 mm (mean value: 2.70 mm, standard deviation [SD]: 0.9 mm). Uncovering procedure was carried out following 3 months of healing; 2 weeks later, a definitive restoration was seated using platform switching concept. To monitor stability changes, resonance frequency analysis was performed and implant stability quotient (ISQ) values were collected at the first surgery (baseline, T(0) ), at the abutment connection (T(1) ), and at 2-year follow-up (T(2) ). To measure bone changes, patients underwent panoramic analysis after 2-year follow-up. The image analysis software calculated the grafted bone height changes at level of implant site comparing preoperative and follow-up panoramic films; the software compensated for eventual radiographic distortion. RESULTS: Mean ISQ value was 35.7 (SD: 8.8) at baseline, 66.61 (SD: 4.76) at T(1) , and 77.9 (SD: 4.7) at T(2) . Statistically significant differences (p <= 0.005) regarding ISQ mean values were found between T(1) and T(0) , as well as between T(1) and T(2) . After 24 months of functional loading, only two implants were lost (cumulative survival rate: 97%). During the same observation period, the mean value of radiographic vertical height of grafted sinus was 13.75 mm (SD = 1.3 mm), with a mean gain of 11 mm. CONCLUSIONS: Within the limits of this study, despite preoperative residual bone height ranging 1 to 4 mm and absence of the membrane covering the buccal bone wall, maxillary sinus lift restoration 14 weeks after first surgery seems to be a reliable procedure using totally-rough surfaced implants restored using platform switching concept and nano-structured hydroxyapatite as sole bone filler. PMID- 20964804 TI - Combining theoretical analysis and experimental data generation reveals IRF9 as a crucial factor for accelerating interferon alpha-induced early antiviral signalling. AB - Type I interferons (IFN) are important components of the innate antiviral response. A key signalling pathway activated by IFNalpha is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Major components of the pathway have been identified. However, critical kinetic properties that facilitate accelerated initiation of intracellular antiviral signalling and thereby promote virus elimination remain to be determined. By combining mathematical modelling with experimental analysis, we show that control of dynamic behaviour is not distributed among several pathway components but can be primarily attributed to interferon regulatory factor 9 (IRF9), constituting a positive feedback loop. Model simulations revealed that increasing the initial IRF9 concentration reduced the time to peak, increased the amplitude and enhanced termination of pathway activation. These model predictions were experimentally verified by IRF9 over-expression studies. Furthermore, acceleration of signal processing was linked to more rapid and enhanced expression of IFNalpha target genes. Thus, the amount of cellular IRF9 is a crucial determinant for amplification of early dynamics of IFNalpha-mediated signal transduction. PMID- 20964805 TI - Promoting effects of Ganoderma lucidum polysaccharides on B16F10 cells to activate lymphocytes. AB - The immune system in patients with cancer often fails to control tumour growth because of deficient immunogenicity of tumour cells. Ganoderma lucidum polysaccharides (Gl-PS) are believed to have anti-tumour effects by boosting host immune function. Additionally, Gl-PS may have some direct effects on tumour cells in the activation of lymphocytes, thus enhancing the immunogenicity of tumour cells. We tested the effects of Gl-PS in lymphocyte activation by incubating Gl PS with a tumour cell line deficient in antigen presentation. Our study showed that Gl-PS can promote B16F10 melanoma cells to induce lymphocyte proliferation, CD69 and FasL expression and IFN-gamma production, indicating that Gl-PS can improve the nature of B16F10 cells to activate lymphocytes. Furthermore, H-2D(b) [a major histocompatibility (MHC) class I molecule], and B7-1 and B7-2 (two prominent co-stimulatory molecules expressed on B16F10 cells) were enhanced by Gl PS, suggesting that these molecules may at least partially be involved in the process of Gl-PS on B16F10 cells to activate lymphocytes. PMID- 20964806 TI - Bond-based 2D quadratic fingerprints in QSAR studies: virtual and in vitro tyrosinase inhibitory activity elucidation. AB - In this report, we show the results of quantitative structure-activity relationship (QSAR) studies of tyrosinase inhibitory activity, by using the bond based quadratic indices as molecular descriptors (MDs) and linear discriminant analysis (LDA), to generate discriminant functions to predict the anti-tyrosinase activity. The best two models [Eqs (6) and (12)] out of the total 12 QSAR models developed here show accuracies of 93.51% and 91.21%, as well as high Matthews correlation coefficients (C) of 0.86 and 0.82, respectively, in the training set. The validation external series depicts values of 90.00% and 89.44% for these best two equations (6) and (12), respectively. Afterwards, a second external prediction data are used to perform a virtual screening of compounds reported in the literature as active (tyrosinase inhibitors). In a final step, a series of lignans is analysed using the in silico-developed models, and in vitro corroboration of the activity is carried out. An issue of great importance to remark here is that all compounds present greater inhibition values than Kojic acid (standard tyrosinase inhibitor: IC50 = 16.67 MUm). The current obtained results could be used as a framework to increase the speed, in the biosilico discovery of leads for the treatment of skin disorders. PMID- 20964807 TI - Spontaneous regression of congenital epulis: a case report and review of the literature. AB - INTRODUCTION: Congenital epulis is a rare lesion found on the alveolar process of a newborn child, diagnosed soon after birth. The lesion has a site predilection for the anterior maxillary alveolar process and a 9:1 sex predilection for females. Once diagnosed the traditional management of the lesion has been surgical excision under general anesthesia. CASE PRESENTATION: The purpose of this case report is to describe spontaneous regression of congenital epulis in a three week old healthy African American female child. She presented with a 1.5 cm bilobed sessile nodular lesion in the region of the right maxillary cuspid. The clinical impression was congenital epulis. Since the lesion was not interfering with feeding and respiration, a conservative approach was taken. The child was followed-up for 18 months, during which the lesion progressively regressed. CONCLUSIONS: Conservative management prevented unnecessary surgery and anesthesia exposure in a neonate. PMID- 20964808 TI - Neighbourhood characteristics, social capital and self-rated health--a population based survey in Sweden. AB - BACKGROUND: In previous public health surveys large differences in health have been shown between citizens living in different neighbourhoods in the Orebro municipality, which has about 125000 inhabitants. The aim of this study was to investigate the determinants of health with an emphasis on the importance of neighbourhood characteristics such as the influence of neighbourhood social cohesion and social capital. The point of departure in this study was a conceptual model inspired by the work of Carpiano, where different factors related to the neighbourhood have been used to find associations to individual self-rated health. METHODS: We used data from the survey 'Life & Health 2004' sent to inhabitants aged 18-84 years in Orebro municipality, Sweden. The respondents (n = 2346) answered a postal questionnaire about living conditions, housing conditions, health risk factors and individual health. The outcome variable was self-rated health. In the analysis we applied logistic regression modelling in various model steps following a conceptual model. RESULTS: The results show that poor self-rated health was associated with social capital, such as lack of personal support and no experience of being made proud even after controlling for strong factors related to health, such as age, disability pension, ethnicity and economic stress. Also the neighbourhood factors, housing area and residential stability were associated with self-rated health. Poor self rated health was more common among people living in areas with predominately large blocks of flats or areas outside the city centre. Moreover, people who had lived in the same area 1-5 years reported poor health more frequently than those who had lived there longer. CONCLUSIONS: The importance of the neighbourhood and social capital for individual health is confirmed in this study. The neighbourhoods could be emphasized as settings for health promotion. They can be constructed to promote social interaction which in turn supports the development of social networks, social support and social capital--all important determinants of health. PMID- 20964809 TI - Acute hepatocellular and cholestatic injury during therapy with hydrochlorothiazide - clinicohistopathologic findings: a case report. AB - INTRODUCTION: Hydrochlorothiazide and thiazide-like diuretics are considered first-line drugs for initial therapy in uncomplicated arterial hypertension. Acute cholecystitis is a well-known complication during treatment with thiazide, and these drugs are also reported to be followed by pronounced insulin resistance. CASE PRESENTATION: We describe a case of acute cholestatic hepatitis in a 68-year-old Caucasian man who was receiving olmesartan and hydrochlorothiazide for arterial hypertension. From the clinical and histologic findings, we diagnosed him as having hepatocellular-cholestatic injury and a disorder of glucose metabolism in the liver. To the best of our knowledge, no histopathologic description of hydrochlorothiazide hepatotoxicity has previously been documented in the literature. CONCLUSION: In the differential diagnosis of cholestatic hepatitis, clinicians should be aware of the possibility of liver damage in patients receiving hydrochlorothiazide therapy. PMID- 20964810 TI - Lower respiratory tract infection and rapid expansion of an abdominal aortic aneurysm: a case report. AB - INTRODUCTION: The rate of abdominal aortic aneurysm expansion is related to multiple factors. There is some evidence that inflammation can accelerate aneurysm expansion. However, the association between pulmonary sepsis and rapid abdominal aortic aneurysm expansion is rarely reported. CASE PRESENTATION: Here we present a case of a rapidly expanding abdominal aortic aneurysm in a 68-year old Caucasian man with a concomitant lower respiratory tract infection and systemic sepsis requiring intensive monitoring and urgent endovascular intervention. Our patient had an uncomplicated post-operative recovery and a follow-up computed tomography scan at one month demonstrated no evidence of an endoleak. CONCLUSION: This case highlights the potential association between pulmonary sepsis and rapid abdominal aortic aneurysm expansion. In such cases, a policy of frequent monitoring should be adopted to identify those patients requiring definitive management. PMID- 20964811 TI - Hemolytic anemia due to acute cytomegalovirus infection in an immunocompetent adult: a case report and review of the literature. AB - INTRODUCTION: Cytomegalovirus is a common virus responsible for a wide range of clinical manifestations. Hemolysis is a rare but potentially life-threatening complication of cytomegalovirus infection, described mostly in immunocompromised patients, the pathogenesis of which is still unclear.We performed a review of the literature regarding cases of hemolytic anemia during acute cytomegalovirus infection in apparently immunocompetent individuals. We searched for relevant articles in PubMed for the period of 1980 through 2008. CASE PRESENTATION: We describe a case of Coombs-negative hemolytic anemia in a 44-year-old Caucasian immunocompetent man with acute cytomegalovirus infection. CONCLUSION: Clinicians should consider cytomegalovirus infection in the differential diagnosis of hemolytic anemia in immunocompetent adults. Possible therapeutic options include antiviral therapy and steroids, although the best treatment strategy is still controversial. PMID- 20964813 TI - Eosinophilic and neutrophilic leukemoid reaction in a woman with spindle cell sarcoma: a case report. AB - INTRODUCTION: We report a case of a patient with marked eosinophilia and neutrophilia as a manifestation of a spindle cell sarcoma. CASE PRESENTATION: A 41-year-old African American woman presented with an enlarging, painful mass in her right knee area. Four years previously, she had had a mass similar to this diagnosed as an osteosarcoma, and had undergone a radical resection and hinge knee replacement. Before the surgery, she was treated with neoadjuvant docetaxel and gemcitabine. A biopsy was taken from the recurrent mass, and histological examination revealed high-grade soft-tissue sarcoma. The patient received no further treatment. Complete blood counts revealed a white blood cell (WBC) count of 13.6 to 17.9 * 109/L, with neutrophils being 8.2 to 10.9 * 109/L and eosinophils 1.8 to 1.9 * 109/L. At readmission six months later, WBC was 126.7 * 109/L, with neutrophils being 57.02 * 109/L and eosinophils 60.82 * 109/L. The eosinophils peaked at 77.79 * 109/L two days later. Evaluations for allergies, infection, and autoimmune mechanisms were negative. Bone marrow revealed increased eosinophils without blasts. After resection, blood counts abruptly decreased to the normal range. Pathology confirmed high-grade spindle cell sarcoma. Approximately one year after resection, the patient was readmitted with metastatic disease to her lungs. During this presentation, her eosinophil and neutrophil count was again increased. WBC was 107.8 * 109/L, with eosinophil count of 47.43 * 109/L and neutrophil count of 44.10 * 109/L. Interleukin-5 was normal, and granulocyte-macrophage colony-stimulating factor (GM-CSF) was elevated at 208.8 (normal < 4.8). CONCLUSION: In our case, the patient had eosinophilia and neutrophilia associated with a spindle cell sarcoma, possibly representing a paraneoplastic syndrome secondary to GM-CSF. There were no signs of infectious, allergic, or autoimmune causes for the eosinophilia or neutrophilia. Even though the occurrence of eosinophilia and neutrophilia with malignancy is rare, patients who have either condition without an apparent cause should be checked for malignancy. PMID- 20964812 TI - Alternative splicing and nonsense-mediated decay regulate telomerase reverse transcriptase (TERT) expression during virus-induced lymphomagenesis in vivo. AB - BACKGROUND: Telomerase activation, a critical step in cell immortalization and oncogenesis, is partly regulated by alternative splicing. In this study, we aimed to use the Marek's disease virus (MDV) T-cell lymphoma model to evaluate TERT regulation by splicing during lymphomagenesis in vivo, from the start point to tumor establishment. RESULTS: We first screened cDNA libraries from the chicken MDV lymphoma-derived MSB-1 T- cell line, which we compared with B (DT40) and hepatocyte (LMH) cell lines. The chTERT splicing pattern was cell line-specific, despite similar high levels of telomerase activity. We identified 27 alternative transcripts of chicken TERT (chTERT). Five were in-frame alternative transcripts without in vitro telomerase activity in the presence of viral or chicken telomerase RNA (vTR or chTR), unlike the full-length transcript. Nineteen of the 22 transcripts with a premature termination codon (PTC) harbored a PTC more than 50 nucleotides upstream from the 3' splice junction, and were therefore predicted targets for nonsense-mediated decay (NMD). The major PTC-containing alternatively spliced form identified in MSB1 (ie10) was targeted to the NMD pathway, as demonstrated by UPF1 silencing. We then studied three splicing events separately, and the balance between in-frame alternative splice variants (d5f and d10f) plus the NMD target i10ec and constitutively spliced chTERT transcripts during lymphomagenesis induced by MDV indicated that basal telomerase activity in normal T cells was associated with a high proportion of in-frame non functional isoforms and a low proportion of constitutively spliced chTERT. Telomerase upregulation depended on an increase in active constitutively spliced chTERT levels and coincided with a switch in alternative splicing from an in-frame variant to NMD targeted variants. CONCLUSIONS: TERT regulation by splicing plays a key role in telomerase upregulation during lymphomagenesis, through the sophisticated control of constitutive and alternative splicing. Using the MDV T-cell lymphoma model, we identified a chTERT splice variant as a new NMD target. PMID- 20964814 TI - Planning for the next influenza H1N1 season: a modelling study. AB - BACKGROUND: The level of herd immunity before and after the first 2009 pandemic season is not precisely known, and predicting the shape of the next pandemic H1N1 season is a difficult challenge. METHODS: This was a modelling study based on data on medical visits for influenza-like illness collected by the French General Practitioner Sentinel network, as well as pandemic H1N1 vaccination coverage rates, and an individual-centred model devoted to influenza. We estimated infection attack rates during the first 2009 pandemic H1N1 season in France, and the rates of pre- and post-exposure immunity. We then simulated various scenarios in which a pandemic influenza H1N1 virus would be reintroduced into a population with varying levels of protective cross-immunity, and considered the impact of extending influenza vaccination. RESULTS: During the first pandemic season in France, the proportion of infected persons was 18.1% overall, 38.3% among children, 14.8% among younger adults and 1.6% among the elderly. The rates of pre exposure immunity required to fit data collected during the first pandemic season were 36% in younger adults and 85% in the elderly. We estimated that the rate of post-exposure immunity was 57.3% (95% Confidence Interval (95%CI) 49.6%-65.0%) overall, 44.6% (95%CI 35.5%-53.6%) in children, 53.8% (95%CI 44.5%-63.1%) in younger adults, and 87.4% (95%CI 82.0%-92.8%) in the elderly.The shape of a second season would depend on the degree of persistent protective cross-immunity to descendants of the 2009 H1N1 viruses. A cross-protection rate of 70% would imply that only a small proportion of the population would be affected. With a cross-protection rate of 50%, the second season would have a disease burden similar to the first, while vaccination of 50% of the entire population, in addition to the population vaccinated during the first pandemic season, would halve this burden. With a cross-protection rate of 30%, the second season could be more substantial, and vaccination would not provide a significant benefit. CONCLUSIONS: These model-based findings should help to prepare for a second pandemic season, and highlight the need for studies of the different components of immune protection. PMID- 20964815 TI - Antibiotic use, resistance development and environmental factors: a qualitative study among healthcare professionals in Orissa, India. AB - BACKGROUND: Antibiotic resistance is a major public health problem affecting both current and future generations. The influence of environmental factors on antibiotic use and resistance development in bacteria is largely unknown. This study explored the perceptions of healthcare providers on antibiotic use and resistance development in relation to environmental factors i.e. physical, natural, social and behavioural factors. METHODS: A qualitative interview study was conducted using face-to-face, semi-structured interviews among registered allopathic doctors, veterinarians and drug dispensers in Orissa, India. The interview transcripts were analyzed using latent content analysis. RESULTS: The main findings of this study relate to two themes: 'Interrelationship between antibiotic use, resistance development and environment' and 'Antibiotic management contributing to the development and spread of resistance'. The interviewees viewed the following as possible contributors to antibiotic use/misuse and resistance development: changes in the natural and physical environment i.e. climate variability, pollution, physiography and population growth; the socioeconomic environment affecting health-seeking behaviour and noncompliance with medication; a lack of healthcare facilities and poor professional attitudes; and ineffective law enforcement regarding medicine dispensing and disposal. CONCLUSIONS: Generally, the interviewees perceived that although behavioural and social environmental factors are major contributors to resistance development, changes in the physical and natural environment also influence development of antibiotic resistance. The respondents also perceived that there is a lack of information about, and poor awareness of, what constitutes prudent use of antibiotics. They suggested a need for information, education, dissemination and proper implementation and enforcement of legislation at all levels of the drug delivery and disposal system in order to improve antibiotic use and prevent pharmaceutical contamination of the environment. PMID- 20964816 TI - Increasing melanism along a latitudinal gradient in a widespread amphibian: local adaptation, ontogenic or environmental plasticity? AB - BACKGROUND: The thermal benefits of melanism in ectothermic animals are widely recognized, but relatively little is known about population differentiation in the degree of melanism along thermal gradients, and the relative contributions of genetic vs. environmental components into the level of melanism expressed. We investigated variation in the degree of melanism in the common frog (Rana temporaria; an active heliotherm thermoregulator) by comparing the degree of melanism (i) among twelve populations spanning over 1500 km long latitudinal gradient across the Scandinavian Peninsula and (ii) between two populations from latitudinal extremes subjected to larval temperature treatments in a common garden experiment. RESULTS: We found that the degree of melanism increased steeply in the wild as a function of latitude. Comparison of the degree of population differentiation in melanism (PST) and neutral marker loci (FST) revealed that the PST >FST, indicating that the differences cannot be explained by random genetic drift alone. However, the latitudinal trend observed in the wild was not present in the common garden data, suggesting that the cline in nature is not attributable to direct genetic differences. CONCLUSIONS: As straightforward local adaptation can be ruled out, the observed trend is likely to result from environment-driven phenotypic plasticity or ontogenetic plasticity coupled with population differences in age structure. In general, our results provide an example how phenotypic plasticity or even plain ontogeny can drive latitudinal clines and result in patterns perfectly matching the genetic differences expected under adaptive hypotheses. PMID- 20964817 TI - Impact of a multifaceted intervention to improve the clinical management of osteoporosis. The ESOSVAL-F study. AB - BACKGROUND: A study to evaluate the impact of a combined intervention (in-class and on-line training courses, a practicum and economic incentives) to improve anti-osteoporosis treatment and to improve recordkeeping for specific information about osteoporosis. METHODS/DESIGN: A before/after study with a non-equivalent control group to evaluate the impact of the interventions associated with participation in the ESOSVAL-R cohort study (intervention group) compared to a group receiving no intervention (control group). The units of analysis are medical practices identified by a Healthcare Position Code (HPC) referring to a specific medical position in primary care general medicine in a Healthcare Department of the Region of Valencia, Spain. The subjects of the study are the 400 participating "practices" (population assigned to health care professionals, doctors and/or nurses) selected by the Healthcare Departments of the Valencia Healthcare Agency for participation as associate researchers in the ESOSVAL-R study (intervention group), compared to 400 participating "practices" assigned to primary care professionals NOT selected for participation as associate researchers in the ESOSVAL-R study, who are selected on the basis of their working in the same Healthcare Centers as the practices receiving the interventions (control group). The study's primary endpoint is the appropriateness of treatment according by the Spanish National Health System guide (2010) and the National Osteoporosis Foundation (NOF, 2008) and International Osteoporosis Foundation guidance (IOF, 2008).The study will also evaluate a series of secondary and tertiary endpoints. The former are the suitability of treatment and evaluation of the risk of fracture; and the latter are the volume of information registered in the electronic clinical records, and the evaluation of risks and the suitability of treatment. PMID- 20964818 TI - Challenges to conservation: land use change and local participation in the Al Reem Biosphere Reserve, West Qatar. AB - One response to humanity's unsustainable use of natural resources and consequent degradation, even destruction of the environment, is to establish conservation areas to protect Nature and preserve biodiversity at least in selected regions. In Qatar, the government has shown strong support for this approach, confronted by the environmental consequences of oil and gas extraction and rapid urban development, by designating about one-tenth of the country a conservation area. Located in the west of the peninsula, it comprises the Al Reem Reserve, subsequently declared a UNESCO Biosphere Reserve. Several approaches have figured in conservation, currently popular is co-management featuring participation of the local population, which recognises that people's activities often contribute to today's environment, with the promotion of bio-cultural diversity. However, these assumptions may not hold where rapid social and cultural change occurs, as in Qatar. We explore the implications of such change, notably in land use. We detail changes resulting with the move from nomadic to sedentary lifestyles: in land access, which now features tribal-state control, and herding strategies, which now feature migrant labour and depend on imported fodder and water, underwritten by the country's large gas and oil revenues. Current stocking arrangements - animals herded in much smaller areas than previously - are thought responsible for the degradation of natural resources. The place of animals, notably camels, in Qatari life, has also changed greatly, possibly further promoting overstocking. Many local people disagree. What are the implications of such changes for the participatory co-management of conservation areas? Do they imply turning the clock back to centrally managed approaches that seek to control access and local activities? PMID- 20964819 TI - A widespread peroxiredoxin-like domain present in tumor suppression- and progression-implicated proteins. AB - BACKGROUND: Peroxide turnover and signalling are involved in many biological phenomena relevant to human diseases. Yet, all the players and mechanisms involved in peroxide perception are not known. Elucidating very remote evolutionary relationships between proteins is an approach that allows the discovery of novel protein functions. Here, we start with three human proteins, SRPX, SRPX2 and CCDC80, involved in tumor suppression and progression, which possess a conserved region of similarity. Structure and function prediction allowed the definition of P-DUDES, a phylogenetically widespread, possibly ancient protein structural domain, common to vertebrates and many bacterial species. RESULTS: We show, using bioinformatics approaches, that the P-DUDES domain, surprisingly, adopts the thioredoxin-like (Thx-like) fold. A tentative, more detailed prediction of function is made, namely, that of a 2-Cys peroxiredoxin. Incidentally, consistent overexpression of all three human P-DUDES genes in two public glioblastoma microarray gene expression datasets was discovered. This finding is discussed in the context of the tumor suppressor role that has been ascribed to P-DUDES proteins in several studies. Majority of non redundant P-DUDES proteins are found in marine metagenome, and among the bacterial species possessing this domain a trend for a higher proportion of aquatic species is observed. CONCLUSIONS: The new protein structural domain, now with a broad enzymatic function predicted, may become a drug target once its detailed molecular mechanism of action is understood in detail. PMID- 20964820 TI - Immortalized, pre-malignant epithelial cell populations contain long-lived, label retaining cells that asymmetrically divide and retain their template DNA. AB - INTRODUCTION: During selective segregation of DNA, a cell asymmetrically divides and retains its template DNA. Asymmetric division yields daughter cells whose genome reflects that of the parents', simultaneously protecting the parental cell from genetic errors that may occur during DNA replication. We hypothesized that long-lived epithelial cells are present in immortal, premalignant cell populations, undergo asymmetric division, retain their template DNA strands, and cycle both during allometric growth and during pregnancy. METHODS: The glands of 3-week old immune competent Balb/C female mice were utilized intact or cleared of host epithelium and implanted with ductal-limited, lobule-limited, or alveolar ductal progenitor cells derived from COMMA-D1 pre-malignant epithelial cells. 5 bromo-2-deoxyuridine (5-BrdU) was administered to identify those cells which retain their template DNA. Nulliparous mice were then either injected with [(3)H] thymidine ((3)H-TdR) to distinguish 5-BrdU-label retaining cells that enter the cell cycle and euthanized, or mated, injected with (3)H-TdR, and euthanized at various days post-coitus. Sections were stained for estrogen receptor-alpha(ER alpha) or progesterone receptor (PR) via immunohistochemistry. Cells labelled with both 5-BrdU and (3)H-TdR were indicative of label-retaining epithelial cells (LREC). RESULTS: Cells that retained a 5-BrdU label and cells labelled with [(3)H]-thymidine were found in all mice and were typically detected along the branching epithelium of mature mouse mammary glands. Cells containing double labelled nuclei (LREC) were found in the intact mammary gland of both pregnant and nulliparous mice, and in mammary glands implanted with pre-malignant cells. Double-labelled cells ((3)H-TdR/5-BrdU) represent a small portion of cells in the mammary gland that cycle and retain their template DNA (5-BrdU). Some label retaining cells were also ER-alpha or PR positive. LRECs distributed their second label ((3)H-TdR) to daughter cells; and this effect persisted during pregnancy. LRECs, and small focal hyperplasia, were found in all immortalized premalignant mammary implant groups. CONCLUSIONS: The results indicate that a subpopulation of long-lived, label-retaining epithelial cells (LRECs) is present in immortal premalignant cell populations. These LRECs persist during pregnancy, retain their original DNA, and a small percentage express ER-alpha and PR. We speculate that LRECs in premalignant hyperplasia represent the long-lived (memory) cells that maintain these populations indefinitely. PMID- 20964821 TI - The origins of a research community in the Majengo Observational Cohort Study, Nairobi, Kenya. AB - BACKGROUND: Since the 1980s the Majengo Observational Cohort Study (MOCS) has examined sexually transmitted infections, in particular HIV/AIDS, in a cohort of sex workers in Majengo, an impoverished urban village in Nairobi, Kenya. The MOCS investigators have faced criticism since the women have remained in the sex trade for the duration of their participation in the study, prompting concerns about exploitation. Yet despite these concerns, the cohort has survived for almost 30 years. METHODS: In this retrospective qualitative case study, we examine the community engagement practices of the MOCS and explore the factors that account for its durability. RESULTS: Women in sex work in Kenya were a highly stigmatized and disfranchised community. As a result, there was no natural 'community' of sex workers either in Nairobi or in the Majengo village. The Majengo clinic aimed to reduce the barriers to health care the women experienced at the STC clinic by bringing the services closer to them and by providing a non-discriminatory environment. The women acknowledged the fact they had hoped their participation in the MOCS would have helped them find a path out of the sex trade. But our findings also add another dimension to this debate, since every cohort member we interviewed expressed her gratitude for the deep impact the MOCS has had on her life, much of it beyond the improved health status made possible by access to quality healthcare services. Participation in the MOCS has improved and enriched their lives. The CE activities have played a central role in creating a community that did not exist independently of the MOCS. CONCLUSIONS: Our case study identified 3 distinct phases of community engagement in the MOCS: (1) reaching out: mobilization, dialogue and education; (2) foundations of trust through relationships of care; and (3) leveraging existing social capital to form a cohort community. The findings demonstrate the importance of some of the less obvious benefits of participation in research, namely the evolving experience of community and the accompanying gains in personal security and solidarity that have kept the women in the cohort, some for 20 years or more. PMID- 20964822 TI - Mapping the cellular and molecular heterogeneity of normal and malignant breast tissues and cultured cell lines. AB - INTRODUCTION: Normal and neoplastic breast tissues are comprised of heterogeneous populations of epithelial cells involving various degrees of maturation and differentiation. While cultured cell lines have been derived from both normal and malignant tissues, it remains unclear whether they retain a similar cellular heterogeneity as to that found within breast tissues. METHODS: We used 12 reduction mammoplasty tissues, 15 primary breast cancer tissues, and 20 human breast epithelial cell lines (16 cancer lines, 4 normal lines) to perform flow cytometry for CD44, CD24, epithelial cell adhesion molecule (EpCAM), and CD49f expression as well as immunohistochemistry, and in vivo tumor xenograft formation studies to extensively analyze the molecular and cellular characteristics of breast epithelial cell lineages. RESULTS: Human breast tissues contain four distinguishable epithelial differentiation states (two luminal phenotypes and two basal phenotypes) that differ on the basis of CD24, EpCAM and CD49f expression. Primary human breast cancer tissues also contain these four cellular states, but in altered proportions compared to normal tissues. In contrast, cultured cancer cell lines are enriched for rare basal and mesenchymal phenotypes, which are normally present in small numbers within human tissues. Similarly, cultured normal human mammary epithelial cell lines were enriched for rare basal and mesenchymal phenotypes that represent a minor fraction of cells within reduction mammoplasty tissues. Although normal human mammary epithelial cell lines exhibited features of bi-potent progenitor cells they were unable to differentiate into mature luminal breast epithelial cells. CONCLUSIONS: As a group breast cancer cell lines represent the heterogeneity of human breast tumors, but individually they exhibit increased lineage-restricted profiles that fall short of truly representing the intratumoral heterogeneity of individual breast tumors. Additionally, normal human mammary epithelial cell lines fail to retain much of the cellular diversity found in human breast tissues and are enriched for differentiation states that are a minority in breast tissues, although they do exhibit features of bi-potent basal progenitor cells. These findings suggest that collections of cell lines representing multiple cell types can be used to model the cellular heterogeneity of tissues. PMID- 20964823 TI - TRIzol treatment of secretory phase endometrium allows combined proteomic and mRNA microarray analysis of the same sample in women with and without endometriosis. AB - BACKGROUND: According to mRNA microarray, proteomics and other studies, biological abnormalities of eutopic endometrium (EM) are involved in the pathogenesis of endometriosis, but the relationship between mRNA and protein expression in EM is not clear. We tested for the first time the hypothesis that EM TRIzol extraction allows proteomic Surface Enhanced Laser Desorption/Ionisation Time-of-Flight Mass Spectrometry (SELDI-TOF MS) analysis and that these proteomic data can be related to mRNA (microarray) data obtained from the same EM sample from women with and without endometriosis. METHODS: Proteomic analysis was performed using SELDI-TOF-MS of TRIzol-extracted EM obtained during secretory phase from patients without endometriosis (n = 6), patients with minimal-mild (n = 5) and with moderate-severe endometriosis (n = 5), classified according to the system of the American Society of Reproductive Medicine. Proteomic data were compared to mRNA microarray data obtained from the same EM samples. RESULTS: In our SELDI-TOF MS study 32 peaks were differentially expressed in endometrium of all women with endometriosis (stages I-IV) compared with all controls during the secretory phase. Comparison of proteomic results with those from microarray revealed no corresponding genes/proteins. CONCLUSION: TRIzol treatment of secretory phase EM allows combined proteomic and mRNA microarray analysis of the same sample, but comparison between proteomic and microarray data was not evident, probably due to post-translational modifications. PMID- 20964824 TI - Lower paraoxonase 1 activity in Tunisian bipolar I patients. AB - BACKGROUND: The purpose of this study was to investigate the variations of paraoxonase activity and lipid profile in bipolar I patients, and the association of this activity with the sociodemographic, clinical and therapeutic characteristics of this population. PATIENTS AND METHODS: Our study included 66 patients with bipolar I disorder and 64 controls aged 37.9 +/- 12.6 and 36.3 +/- 18.2 years, respectively. Paraoxonase activity was determined by kinetic methods; high-density lipoprotein cholesterol (c-HDL), low-density lipoprotein cholesterol (c-LDL), triglycerides and total cholesterol were determined by enzymatic methods; apolipoprotein (Apo)A1, ApoB and lipoprotein (a) (Lp(a)) were determined by immunoturbidimetry using Konelab 30 equipment (Thermo Scientific). RESULTS: Compared with controls, patients had a significantly lower paraoxonase activity and ApoA1 level, and significantly higher total cholesterol, c-LDL and Lp(a) level and ApoB/ApoA1 ratio. Furthermore, paraoxonase activity was significantly correlated with c-HDL values (r = 0.5612; P < 0.001). The lowest paraoxonase activity was noted in relation to age and body mass index (BMI). Moreover, it was associated with gender but not with smoking and alcohol consumption status. In patients, there was no significant change in paraoxonase activity in relation to illness episodes, whereas the lowest values of this activity were seen in manic patients. In contrast, paraoxonase activity was significantly associated with treatment. Indeed, patients taking lithium had the lowest levels. CONCLUSIONS: Bipolar patients had a significant decrease in paraoxonase activity and perturbations in their lipid profile that contribute to increased risk of cardiovascular diseases. Decrease in this activity was significantly associated with treatment with lithium but not with sociodemographic and clinical characteristics. Therefore, such patients require specific care, particularly with regard to their lipid profile. PMID- 20964825 TI - Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis. AB - Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors (PRR) that play a key role in innate and adaptive immunity by recognizing structural components unique to bacteria, fungi and viruses. TLR4 is the most studied of the TLRs, and its primary exogenous ligand is lipopolysaccharide, a component of Gram-negative bacterial walls. In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling. In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis. In liver, TLR4 is expressed by all parenchymal and non parenchymal cell types, and contributes to tissue damage caused by a variety of etiologies. Intact TLR4 signaling was identified in hepatic stellate cells (HSCs), the major fibrogenic cell type in injured liver, and mediates key responses including an inflammatory phenotype, fibrogenesis and anti-apoptotic properties. Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies. PMID- 20964826 TI - Transperineal prostate brachytherapy, using I-125 seed with or without adjuvant androgen deprivation, in patients with intermediate-risk prostate cancer: study protocol for a phase III, multicenter, randomized, controlled trial. AB - BACKGROUND: The optimal protocol for 125I-transperineal prostatic brachytherapy (TPPB) in intermediate-risk prostate cancer (PCa) patients remains controversial. Data on the efficacy of combining androgen-deprivation therapy (ADT) with 125I TPPB in this group remain limited and consequently the guidelines of the American Brachytherapy Society (ABS) provide no firm recommendations. METHODS/DESIGN: Seed and Hormone for Intermediate-risk Prostate Cancer (SHIP) 0804 is a phase III, multicenter, randomized, controlled study that will investigate the impact of adjuvant ADT following neoadjuvant ADT and 125I-TPPB. Prior to the end of March, 2011, a total of 420 patients with intermediate-risk, localized PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from 20 institutions, all of which have broad experience of 125I-TPPB. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will initially undergo 3-month ADT prior to 125I-TPPB. Those randomly assigned to adjuvant therapy will subsequently undergo 9 months of adjuvant ADT. All participants will be assessed at baseline and at the following intervals: every 3 months for the first 24 months following 125I-TPPB, every 6 months during the 24- to 60-month post-125I-TPPB interval, annually between 60 and 84 months post-125I-TPPB, and on the 10th anniversary of treatment.The primary endpoint is biochemical progression-free survival (BPFS). Secondary endpoints are overall survival (OS), clinical progression-free survival, disease specific survival, salvage therapy non-adaptive interval, acceptability (assessed using the international prostate symptom score [IPSS]), quality of life (QOL) evaluation, and adverse events. In the correlative study (SHIP36B), we also evaluate biopsy results at 36 months following treatment to examine the relationship between the results and the eventual recurrence after completion of radiotherapy. DISCUSSION: These two multicenter trials (SHIP0804 & SHIP36B) are expected to provide crucial data regarding the efficacy, acceptability and safety of adjuvant ADT. SHIP36B will also provide important information about the prognostic implications of PSA levels in intermediate-risk PCa patients treated with 125I-TPPB. TRIAL REGISTRATION: NCT00664456, NCT00898326, JUSMH-BRI-GU05-01, JUSMH-TRIGU0709. PMID- 20964827 TI - Early alterations in vascular contractility associated to changes in fatty acid composition and oxidative stress markers in perivascular adipose tissue. AB - AIM: To test the early effect of fructose-induced changes in fatty acid composition and oxidative stress markers in perivascular adipose tissue (PVAT) upon vascular contractility. METHODS: Adult male Wistar rats were fed a commercial diet without (CD) or with 10% fructose (FRD) in the drinking water for 3 weeks. We measured plasma metabolic parameters, lipid composition and oxidative stress markers in aortic PVAT. Vascular contractility was measured in aortic rings sequentially, stimulated with serotonin (5-HT) and high K+-induced depolarization using intact and thereafter PVAT-deprived rings. RESULTS: Comparable body weights were recorded in both groups. FRD rats had increased plasma triglyceride and fructosamine levels. Their PVAT had an increased saturated to mono- or poly-unsaturated fatty acid ratio, a significant decrease in total superoxide dismutase and glutathione peroxidase activities and in the total content of glutathione. Conversely, lipid peroxidation (TBARS), nitric oxide content, and gluthathione reductase activity were significantly higher, indicating an increase in oxidative stress. In aortic rings, removal of PVAT increased serotonin-induced contractions, but the effect was significantly lower in rings from FRD rats. This effect was no longer observed when the two contractions were performed in PVAT-deprived rings. PVAT did not affect the contractions triggered by high K+-induced depolarization either in CD or FRD rats. CONCLUSIONS: FRD induces multiple metabolic and endocrine systemic alterations which also alter PVAT and the vascular relaxant properties of this tissue. The changes in PVAT would affect its paracrine modulation of vascular function. PMID- 20964828 TI - Effects of aluminum on nucleoli in root tip cells and selected physiological and biochemical characters in Allium cepa var. agrogarum L. AB - BACKGROUND: Increased Al concentration causes reduction of mitotic activity, induction of nucleolar alteration, increase of the production of ROS and alteration of several antioxidant enzyme activities in plant cells. Allium cepa is an excellent plant and a useful biomarker for environmental monitoring. Limited information is available about the effects of Al on nucleoli, antioxidant enzyme system, contents of MDA and soluble protein in A. cepa. Therefore, we carried out the investigation in order to better understand the effects of Al on the growth, nucleoli in root tip cells and selected physiological and biochemical characters. RESULTS: The results showed that the root growth exposed to 50 MUM Al was inhibited significantly. 50 MUM Al could induce some particles of argyrophilic proteins scattered in the nuclei and extruded from the nucleoli into the cytoplasm. The nucleolus did not disaggregate normally and still remained its characteristic structure during metaphase. Nucleolar reconstruction was inhibited. 50 MUM Al induced high activities of SOD and POD in leaves and roots significantly (P < 0.05) when compared with control, whereas the level of CAT was low significantly (P < 0.05). At 50 MUM Al the content of MDA in leaves was high significantly (P < 0.05) at 9(th) day and in roots increased (P < 0.05) with prolonging the treatment time during 6-12 days. The soluble protein content in leaves treated with 50 MUM Al was high significantly (P < 0.05) at 6(th) day and increased with prolonging the treatment time. CONCLUSIONS: We suggest that variations in nucleoli and the alterations of antioxidant enzyme activities, MDA and soluble protein contents in Allium cepa can serve as useful biomarkers, which can provide valuable information for monitoring and forecasting effects of exposure to Al in real scenarios conditions. Among the antioxidant enzymes SOD and POD appear to play a key role in the antioxidant defense mechanism under Al toxicity condition. Data from MDA concentration show that Al indirectly produces superoxide radicals, resulting in increased lipid peroxidative products and oxidative stress. PMID- 20964829 TI - Characterisation of the nociceptive phenotype of suppressible galanin overexpressing transgenic mice. AB - The neuropeptide galanin is widely expressed in both the central and peripheral nervous systems and is involved in many diverse biological functions. There is a substantial data set that demonstrates galanin is upregulated after injury in the DRG, spinal cord and in many brain regions where it plays a predominantly antinociceptive role in addition to being neuroprotective and pro-regenerative. To further characterise the role of galanin following nerve injury, a novel transgenic line was created using the binary transgenic tet-off system, to overexpress galanin in galaninergic tissue in a suppressible manner. The double transgenic mice express significantly more galanin in the DRG one week after sciatic nerve section (axotomy) compared to WT mice and this overexpression is suppressible upon administration of doxycycline. Phenotypic analysis revealed markedly attenuated allodynia when galanin is overexpressed and an increase in allodynia following galanin suppression. This novel transgenic line demonstrates that whether galanin expression is increased at the time of nerve injury or only after allodynia is established, the neuropeptide is able to reduce neuropathic pain behaviour. These new findings imply that administration of a galanin agonist to patients with established allodynia would be an effective treatment for neuropathic pain. PMID- 20964830 TI - A prospective study of methamphetamine use as a predictor of high school non attendance in Cape Town, South Africa. AB - BACKGROUND: This prospective study investigated the association between life-long methamphetamine and other drug use and high school non-attendance, in a sample of high school students in Cape Town, South Africa. METHODS: A random sample of 1535 high school students completed a baseline questionnaire in 2006, and were asked to complete a follow-up questionnaire 12 months later. The questionnaire included questions on substance use, including tobacco, alcohol, methamphetamine and cannabis use, demographic factors, and questions relating to school attendance and performance. RESULTS: Forty-three percent of the students surveyed at baseline did not complete a follow-up questionnaire after 12 months. Compared with students who were not using selected substances, an adjusted logistic regression model showed that life-time methamphetamine use in addition to other substances was significantly associated with non-attendance (OR = 2.58, 95% CI: 1.24-5.36) when other non-substance use factors (repeating a year at school and being older than the norm for current grade) were taken into account. CONCLUSIONS: Early identification of students with methamphetamine and other substance use problems, and a supportive rather than punitive school policy, may be valuable in improving high school completion and student retention rates. PMID- 20964831 TI - The potential for pathogenicity was present in the ancestor of the Ascomycete subphylum Pezizomycotina. AB - BACKGROUND: Previous studies in Ascomycetes have shown that the function of gene families of which the size is considerably larger in extant pathogens than in non pathogens could be related to pathogenicity traits. However, by only comparing gene inventories in extant species, no insights can be gained into the evolutionary process that gave rise to these larger family sizes in pathogens. Moreover, most studies which consider gene families in extant species only tend to explain observed differences in gene family sizes by gains rather than by losses, hereby largely underestimating the impact of gene loss during genome evolution. RESULTS: In our study we used a selection of recently published genomes of Ascomycetes to analyze how gene family gains, duplications and losses have affected the origin of pathogenic traits. By analyzing the evolutionary history of gene families we found that most gene families with an enlarged size in pathogens were present in an ancestor common to both pathogens and non pathogens. The majority of these families were selectively maintained in pathogenic lineages, but disappeared in non-pathogens. Non-pathogen-specific losses largely outnumbered pathogen-specific losses. CONCLUSIONS: We conclude that most of the proteins for pathogenicity were already present in the ancestor of the Ascomycete lineages we used in our study. Species that did not develop pathogenicity seemed to have reduced their genetic complexity compared to their ancestors. We further show that expansion of gained or already existing families in a species-specific way is important to fine-tune the specificities of the pathogenic host-fungus interaction. PMID- 20964832 TI - Correction: Targeting the angiotensin II type 2 receptor (AT2R) in colorectal liver metastases. PMID- 20964833 TI - Infliximab therapy increases body fat mass in early rheumatoid arthritis independently of changes in disease activity and levels of leptin and adiponectin: a randomised study over 21 months. AB - INTRODUCTION: Rheumatoid arthritis (RA) is associated with changes in body composition and bone mineral density (BMD). The purpose of the present study was to evaluate whether anti-TNF treatment in early RA has an impact on body composition and BMD besides that which could be achieved by intensive disease modifying anti-rheumatic drug (DMARD) combination therapy. METHODS: Forty patients with early RA who failed treatment with methotrexate up to 20 mg/week for 3 months were randomised to addition of sulphasalazine and hydroxychloroquine (treatment A) or addition of infliximab (treatment B). At 3, 12 and 24 months, body composition and BMD were assessed by total-body dual-energy X-ray absorptiometry. At the same time points, leptin, adiponectin, apolipoproteins, insulin-like growth factor-1 (IGF-1) and markers of bone remodelling were analysed. Compliance to treatment was considered in the analyses. Data were analysed with a mixed, linear model. RESULTS: Patients treated with anti-TNF had a significant increase in fat mass at 2 years, 3.8 (1.6 to 5.9) kg, in contrast to patients in treatment A, 0.4 (-1.5 to 2.2) kg (P = 0.040), despite similar reduction in disease activity. Both treatment strategies prevented loss of muscle mass and bone. Leptin concentrations increased significantly in both groups at 2 years and adiponectin increased significantly at 2 years in treatment A and at 1 year in treatment B. There were no significant changes in apolipoproteins or IGF 1. The markers of bone resorption decreased at 12 months in both treatment groups with no significant difference between the treatment groups. CONCLUSIONS: Infliximab therapy increased body fat mass, an effect that was not achieved with the combination of DMARDs, despite a similar reduction in disease activity, and thus seemed to be drug specific. The increase of fat mass was not associated with an exacerbated atherogenic lipid profile. Leptin and adiponectin concentrations increased in both treatment groups. The increase of adiponectin may partially explain the reduced frequency of cardiovascular diseases found when disease activity is reduced in RA. TRIAL REGISTRATION: ISRCTN39045408. PMID- 20964834 TI - Neuroprotective properties of levosimendan in an in vitro model of traumatic brain injury. AB - BACKGROUND: We investigated the neuroprotective properties of levosimendan, a novel inodilator, in an in vitro model of traumatic brain injury. METHODS: Organotypic hippocampal brain slices from mouse pups were subjected to a focal mechanical trauma. Slices were treated after the injury with three different concentrations of levosimendan (0.001, 0.01 and 0.1 MUM) and compared to vehicle treated slices. After 72 hrs, the trauma was quantified using propidium iodide to mark the injured cells. RESULTS: A significant dose-dependent reduction of both total and secondary tissue injury was observed in cells treated with either 0.01 or 0.1 MUM levosimendan compared to vehicle-treated slices. CONCLUSION: Levosimendan represents a promising new pharmacological tool for neuroprotection after brain injury and warrants further investigation in an in vivo model. PMID- 20964835 TI - The VHL-dependent regulation of microRNAs in renal cancer. AB - BACKGROUND: The commonest histological type of renal cancer, clear cell renal cell carcinoma (cc RCC), is associated with genetic and epigenetic changes in the von Hippel-Lindau (VHL) tumour suppressor. VHL inactivation leads to induction of hypoxia-inducible factors (HIFs) and a hypoxic pattern of gene expression. Differential levels of specific microRNAs (miRNAs) are observed in several tumours when compared to normal tissue. Given the central role of VHL in renal cancer formation, we examined the VHL-dependent regulation of miRNAs in renal cancer. METHODS: VHL-dependent miRNA expression in cc RCC was determined by microarray analysis of renal cell line RCC4 with mutated VHL (RCC4-VHL) and reintroduced wild-type VHL (RCC4 + VHL). Five miRNAs highly upregulated in RCC4 + VHL and five miRNAs highly downregulated in RCC4 + VHL were studied further, in addition to miR-210, which is regulated by the HIF-VHL system. miRNA expression was also measured in 31 cc RCC tumours compared to adjacent normal tissue. RESULTS: A significant increase in miR-210, miR-155 and miR-21 expression was observed in the tumour tissue. miR-210 levels also showed a correlation with a HIF-regulated mRNA, carbonic anhydrase IX (CAIX), and with VHL mutation or promoter methylation. An inverse correlation was observed between miR-210 expression and patient survival, and a putative target of miR-210, iron-sulfur cluster assembly protein (ISCU1/2), shows reciprocal levels of mRNA expression in the tumours. CONCLUSIONS: We have identified VHL-regulated miRNAs and found that for some the regulation is HIF-dependent and for others it is HIF-independent. This pattern of regulation was also seen in renal cancer tissue for several of these miRNAs (miR-210, miR-155, let-7i and members of the miR-17-92 cluster) when compared with normal tissue. miR-210 showed marked increases in expression in renal cancer and levels correlated with patient survival. The inverse correlation between miR-210 levels and ISCU1/2 provides support for the hypothesis that ISCU1/2 is a target of miR-210 and that it may contribute to the anaerobic respiration seen in renal (and other) tumours.See Commentary: http://www.biomedcentral.com/1741-7015/8/65. PMID- 20964836 TI - solQTL: a tool for QTL analysis, visualization and linking to genomes at SGN database. AB - BACKGROUND: A common approach to understanding the genetic basis of complex traits is through identification of associated quantitative trait loci (QTL). Fine mapping QTLs requires several generations of backcrosses and analysis of large populations, which is time-consuming and costly effort. Furthermore, as entire genomes are being sequenced and an increasing amount of genetic and expression data are being generated, a challenge remains: linking phenotypic variation to the underlying genomic variation. To identify candidate genes and understand the molecular basis underlying the phenotypic variation of traits, bioinformatic approaches are needed to exploit information such as genetic map, expression and whole genome sequence data of organisms in biological databases. DESCRIPTION: The Sol Genomics Network (SGN, http://solgenomics.net) is a primary repository for phenotypic, genetic, genomic, expression and metabolic data for the Solanaceae family and other related Asterids species and houses a variety of bioinformatics tools. SGN has implemented a new approach to QTL data organization, storage, analysis, and cross-links with other relevant data in internal and external databases. The new QTL module, solQTL, http://solgenomics.net/qtl/, employs a user-friendly web interface for uploading raw phenotype and genotype data to the database, R/QTL mapping software for on the-fly QTL analysis and algorithms for online visualization and cross referencing of QTLs to relevant datasets and tools such as the SGN Comparative Map Viewer and Genome Browser. Here, we describe the development of the solQTL module and demonstrate its application. CONCLUSIONS: solQTL allows Solanaceae researchers to upload raw genotype and phenotype data to SGN, perform QTL analysis and dynamically cross-link to relevant genetic, expression and genome annotations. Exploration and synthesis of the relevant data is expected to help facilitate identification of candidate genes underlying phenotypic variation and markers more closely linked to QTLs. solQTL is freely available on SGN and can be used in private or public mode. PMID- 20964837 TI - Incidence, risk factors and clinical epidemiology of melioidosis: a complex socio ecological emerging infectious disease in the Alor Setar region of Kedah, Malaysia. AB - BACKGROUND: Melioidosis, a severe and fatal infectious disease caused by Burkholderia pseudomallei, is believed to an emerging global threat. However, data on the natural history, risk factors, and geographic epidemiology of the disease are still limited. METHODS: We undertook a retrospective analysis of 145 confirmed cases extracted from a hospital-based Melioidosis Registry set up from 2005 in Hospital Sultanah Bahiyah, Alor Setar, Kedah state, Malaysia, in order to provide a first description of the contemporary incidence, risk factors, and clinical epidemiology of the disease in this putatively high risk region of the country. RESULTS: The incidence of melioidosis in Alor Setar is remarkably high at 16.35 per 100,000 population per year. The mean age of patients was 50.40 years, with infection varying nonlinearly with age. Males (75.2%; P < 0.0001) predominated and the majority of cases were Malays (88.9%). The overall, crude mortality rate among the study patients was 33.8%. The proportions of cases and deaths were significantly greater among patients involved in farming, forestry and fishing and the unemployed (chi2 = 30.57, P < 0.0001). A majority of cases (62.75%) were culture positive, with mortality in these patients being 45.05%. A large proportion (83.0%) of culture positives was also bacteremic. Pneumonia accounted for 42.06% of primary diagnoses followed in importance by soft tissue abscess. In patients with pneumonia and who were culture positive, the mortality rate was as high as 65.00%. Diabetes mellitus constituted the major underlying risk factor for developing and dying from melioidosis, occurring in 57% of all diagnosed cases. The age distribution of diabetes paralleled that of melioidosis cases. There were linear associations between cases and deaths with monthly rainfall. CONCLUSIONS: Melioidosis represents a complex socio-ecological public health problem in Kedah, being strongly related with age, occupation, rainfall and predisposing chronic diseases, such as diabetes mellitus. Among cases, bacteremic patients were associated with significantly high mortality despite provision of the recommended antibacterial therapy. The burden of this disease is likely to grow in this region unless better informed interventions targeted at high-risk groups and associated diseases are urgently implemented. PMID- 20964838 TI - Maternal immune system adaptation to pregnancy--a potential influence on the course of diabetic retinopathy. AB - BACKGROUND: Progression of diabetic retinopathy occurs at least temporarily during pregnancy. Although the cause of this progression is not entirely understood, the immune phenomenon and chronic inflammation may play a significant role. During pregnancy in order to avoid fetus rejection, certain components of the immune system that are knowingly implicated in the pathogenesis of diabetic retinopathy are activated including generalized leukocyte activation and an increase in certain cytokine plasma levels. Activated leukocytes with up regulated adhesion molecules have an increased potential to bind to the endothelium cells of blood vessels. Leukocyte-endothelial interaction and the consequent leukostasis with capillary occlusion, ischemia and vascular leakage have a substantial role in the development of diabetic retinopathy. Furthermore, certain increased cytokines are known to cause blood-retinal-barrier breakdown whilst others promote angiogenic and fibrovascular proliferation and thereby can also be implicated in the pathogenesis of this diabetic complication. PRESENTATION OF THE HYPOTHESIS: We hypothesized that the activation of the immune system during gestation may have an influence on the course of retinopathy in pregnant diabetic women. TESTING THE HYPOTHESIS: We suggest two prospective follow up studies conducted on women with type 1 diabetes mellitus. The first study would include a group of non-pregnant women and a group of diabetic women undergoing normal pregnancy matched for age and duration of diabetes. In the second study pregnant women would be divided into two groups: one with normal pregnancy and the other with preeclampsia. The procedure and data collection in both studies will be identical: a complete ophthalmological examination, glycaemic control, blood pressure measurement and venous blood samples for the determination of plasma levels of cytokines (TNF-alpha, IL-1beta, IL-6, IL-8) and adhesion molecules (ICAM-1, VCAM-1). IMPLICATIONS OF THE HYPOTHESIS: Considering the present assumption, the gestational immune activation could be suggested as a potential risk factor for the development and progression of retinopathy in diabetic women. A better understanding of immunomodulatory effects of pregnancy on diabetic retinopathy pave the way for further investigations of the mechanism of its pathogenesis and could be essential for novel approaches to the treatment of this serious sight threatening complication of diabetes mellitus. PMID- 20964839 TI - MicroRNAs: exploring a new dimension in the pathogenesis of kidney cancer. AB - Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. The role of the von-Hippel-Lindeau (VHL) tumour suppressor gene is well established in RCC with a loss of VHL protein leading to accumulated hypoxia-induced factor (HIF) and the subsequent transcriptional activation of multiple downstream targets. Recently, microRNAs (miRNAs) have been shown to be differentially expressed in RCC and their role in RCC pathogenesis is emerging. This month, in BMC Medicine, Gleadle and colleagues show that certain miRNAs are regulated by VHL in either a hypoxia-inducible factor (HIF)-dependent or HIF-independent manner in RCC. They also show that miRNA expression correlates with the survival of RCC patients.In this commentary, we discuss the current understanding of the role of miRNAs in RCC and the different possible scenarios of their involvement in RCC pathogenesis. We also address their clinical significance as tumour markers, together with the potential use of miRNAs as therapeutic targets. Finally, we discuss some of the challenges that face the fast-evolving field of miRNAs, including the identification and validation of miRNA targets and the difficulties associated with establishing a link between miRNA expression and biological effects. A more thorough understanding of the biological nature of miRNAs and careful experimental planning will help us to reveal the complex role that miRNAs play in RCC pathogenesis. See research article: http://www.biomedcentral.com/1741-7015/8/64. PMID- 20964840 TI - Attitudes of undergraduate health science students towards patients with intellectual disability, substance abuse, and acute mental illness: a cross sectional study. AB - BACKGROUND: There is a long history of certain medical conditions being associated with stigma, stereotypes, and negative attitudes. Research has shown that such attitudes can have a detrimental effect on patients presenting with stigmatised medical conditions and can even flow on to impact their family. The objective of this study was to measure the attitudes of undergraduate students enrolled in six different health-related courses at Monash University toward patients with intellectual disability, substance abuse, and acute mental illness. METHODS: A convenience sample of undergraduate students enrolled in six health related courses in first, second and third years at Monash University were surveyed. The Medical Condition Regard Scale--a valid and reliable, self-report measure of attitudes--was administered to students along with a brief demographic form. Mean scores, t-tests, and ANOVA were used to analyse student attitudes. Ethics approval was granted. RESULTS: 548 students participated. Statistically significant differences were found between the courses (p = 0.05), year of the course (p = 0.09), and gender (p = 0.04) for the medical condition of intellectual disability. There was no statistically significant difference between the courses, year of the course, gender, and age group for substance abuse or acute mental illness conditions. CONCLUSION: The findings suggest that students in undergraduate health-related courses, as a group, have a strong regard for patients with intellectual disability and some regard for patients with acute mental illness, but not for patients presenting with substance abuse problems. PMID- 20964841 TI - FusionSeq: a modular framework for finding gene fusions by analyzing paired-end RNA-sequencing data. AB - We have developed FusionSeq to identify fusion transcripts from paired-end RNA sequencing. FusionSeq includes filters to remove spurious candidate fusions with artifacts, such as misalignment or random pairing of transcript fragments, and it ranks candidates according to several statistics. It also has a module to identify exact sequences at breakpoint junctions. FusionSeq detected known and novel fusions in a specially sequenced calibration data set, including eight cancers with and without known rearrangements. PMID- 20964842 TI - Caloric beverage consumption patterns in Mexican children. AB - BACKGROUND: Mexico has seen a very steep increase in child obesity level. Little is known about caloric beverage intake in this country as well as all other countries outside a few high income countries. This study examines overall patterns and trends in all caloric beverages from two nationally representative surveys from Mexico. METHODS: The two nationally representative dietary intake surveys (1999 and 2006) from Mexico are used to study caloric beverage intake in 17, 215 children. The volume (ml) and caloric energy (kcal) contributed by all beverages consumed by the sample subjects were measured. Results are weighted to be nationally representative. RESULTS: The trends from the dietary intake surveys showed very large increases in caloric beverages among pre-school and school children. The contribution of whole milk and sugar-sweetened juices was an important finding. Mexican pre-school children consumed 27.8% of their energy from caloric beverages in 2006 and school children consumed 20.7% of their energy from caloric beverages during the same time. The three major categories of beverage intake are whole milk, fruit juice with various sugar and water combinations and carbonated and noncarbonated sugared-beverages. CONCLUSION: The Mexican government, greatly concerned about obesity, has identified the large increase in caloric beverages from whole milk, juices and soft drinks as a key target and is initiating major changes to address this problem. They have already used the data to shift 20 million persons in their welfare and feeding programs from whole to 1.5% fat milk and in a year will shift to nonfat milk. They are using these data to revise school beverage policies and national regulations and taxation policies related to an array of less healthful caloric beverages. PMID- 20964843 TI - Cytomorphometric changes in the dorsal raphe neurons after rapid eye movement sleep deprivation are mediated by noradrenalin in rats. AB - OBJECTIVES: This study was carried out to investigate the effect of rapid eye movement sleep (REMS) deprivation (REMSD) on the cytomorphology of the dorsal raphe (DR) neurons and to evaluate the possible role of REMSD-induced increased noradrenalin (NA) in mediating such effects. METHODS: Rats were REMS deprived by the flowerpot method; free moving normal home cage rats, large platform and post REMS-deprived recovered rats were used as controls. Further, to evaluate if the effects were induced by NA, separate sets of experimental rats were treated (i.p.) with alpha1-adrenoceptor antagonist, prazosin (PRZ). Histomorphometric analysis of DR neurons in stained brain sections were performed in experimental and control rats; neurons in inferior colliculus (IC) served as anatomical control. RESULTS: The mean size of DR neurons was larger in REMSD group compared to controls, whereas, neurons in the recovered group of rats did not significantly differ than those in the control animals. Further, mean cell size in the post-REMSD PRZ-treated animals was comparable to those in the control groups. IC neurons were not affected by REMSD. CONCLUSIONS: REMS loss has been reported to impair several physiological, behavioral and cellular processes. The mean size of the DR neurons was larger in the REMS deprived group of rats than those in the control groups; however, in the REMS deprived and prazosin treated rats the size was comparable to the normal rats. These results showed that REMSD induced increase in DR neuronal size was mediated by NA acting on alpha1 adrenoceptor. The findings suggest that the sizes of DR neurons are sensitive to REMSD, which if not compensated could lead to neurodegeneration and associated disorders including memory loss and Alzheimer's disease. PMID- 20964844 TI - Evolution and functional divergence of the anoctamin family of membrane proteins. AB - BACKGROUND: The anoctamin family of transmembrane proteins are found in all eukaryotes and consists of 10 members in vertebrates. Ano1 and ano2 were observed to have Ca2+ activated Cl- channel activity. Recent findings however have revealed that ano6, and ano7 can also produce chloride currents, although with different properties. In contrast, ano9 and ano10 suppress baseline Cl- conductance when co-expressed with ano1 thus suggesting that different anoctamins can interfere with each other. In order to elucidate intrinsic functional diversity, and underlying evolutionary mechanism among anoctamins, we performed comprehensive bioinformatics analysis of anoctamin gene family. RESULTS: Our results show that anoctamin protein paralogs evolved from several gene duplication events followed by functional divergence of vertebrate anoctamins. Most of the amino acid replacements responsible for the functional divergence were fixed by adaptive evolution and this seem to be a common pattern in anoctamin gene family evolution. Strong purifying selection and the loss of many gene duplication products indicate rigid structure-function relationships among anoctamins. CONCLUSIONS: Our study suggests that anoctamins have evolved by series of duplication events, and that they are constrained by purifying selection. In addition we identified a number of protein domains, and amino acid residues which contribute to predicted functional divergence. Hopefully, this work will facilitate future functional characterization of the anoctamin membrane protein family. PMID- 20964845 TI - The association of mast cells and serotonin in children with chronic abdominal pain of unknown etiology. AB - BACKGROUND: Abdominal pain of unknown origin affects up to 20% of school-aged children. Evaluation of children is symptom-based without clear guidelines to investigate molecular mechanisms of abdominal pain. Aberrant molecular mechanisms may increase intestinal permeability leading to interactions between the immune and nervous systems, subclinical inflammation, and visceral pain. This study evaluated the association between interleukin-6 (IL-6), mast cell infiltrates, and serotonin (5-HT) levels in gastrointestinal (GI) biopsies, with perceived abdominal pain in a pediatric cohort. METHODS: Clinical data and biopsy samples from pediatric patients (n = 48) with chronic abdominal pain, with and without inflammation were included. Formalin-fixed paraffin-embedded GI biopsies were sectioned and immunohistochemistry performed for IL-6 and 5-HT; mast cells were identified with toluidine blue stain. Histological findings were compared to self reported abdominal pain between groups. RESULTS: There was significantly greater IL-6 immunoreactivity in biopsies with confirmed histologic inflammation (p = 0.004). There was a greater number of mast cells per HPF in non-inflammatory biopsies (3.5 +/- 2.9) compared to the inflammatory biopsies (2.6 +/- 1.8) p = 0.049. The non-inflammatory biopsy group was significantly less likely to respond to standard treatment as evidenced by higher pain reports (p = .018). Mast cells (p = .022) and 5-HT (p = .02) were significantly related to abdominal pain scores. CONCLUSIONS: A potential association between self-reported abdominal pain, number of mast cells, and 5-HT levels, which may contribute to perceived GI pain in pediatric patients may exist. PMID- 20964846 TI - Low coverage but few inclusion errors in Burkina Faso: a community-based targeting approach to exempt the indigent from user fees. AB - BACKGROUND: User fees were generalized in Burkina Faso in the 1990s. At the time of their implementation, it was envisioned that measures would be instituted to exempt the poor from paying these fees. However, in practice, the identification of indigents is ineffective, and so they do not have access to care. Thus, a community-based process for selecting indigents for user fees exemption was tested in a district. In each of the 124 villages in the catchment areas of ten health centres, village committees proposed lists of indigents that were then validated by the health centres' management committees. The objective of this study is to evaluate the effectiveness of this community-based selection. METHODS: An indigent-selection process is judged effective if it minimizes inclusion biases and exclusion biases. The study compares the levels of poverty and of vulnerability of indigents selected by the management committees (n = 184) with: 1) indigents selected in the villages but not retained by these committees (n = 48); ii) indigents selected by the health centre nurses (n = 82); and iii) a sample of the rural population (n = 5,900). RESULTS: The households in which the three groups of indigents lived appeared to be more vulnerable and poorer than the reference rural households. Indigents selected by the management committees and the nurses were very comparable in terms of levels of vulnerability, but the former were more vulnerable socially. The majority of indigents proposed by the village committees who lived in extremely poor households were retained by the management committees. Only 0.36% of the population living below the poverty threshold and less than 1% of the extremely poor population were selected. CONCLUSIONS: The community-based process minimized inclusion biases, as the people selected were poorer and more vulnerable than the rest of the population. However, there were significant exclusion biases; the selection was very restrictive because the exemption had to be endogenously funded. PMID- 20964847 TI - A statistical approach to finding overlooked genetic associations. AB - BACKGROUND: Complexity and noise in expression quantitative trait loci (eQTL) studies make it difficult to distinguish potential regulatory relationships among the many interactions. The predominant method of identifying eQTLs finds associations that are significant at a genome-wide level. The vast number of statistical tests carried out on these data make false negatives very likely. Corrections for multiple testing error render genome-wide eQTL techniques unable to detect modest regulatory effects. We propose an alternative method to identify eQTLs that builds on traditional approaches. In contrast to genome-wide techniques, our method determines the significance of an association between an expression trait and a locus with respect to the set of all associations to the expression trait. The use of this specific information facilitates identification of expression traits that have an expression profile that is characterized by a single exceptional association to a locus. Our approach identifies expression traits that have exceptional associations regardless of the genome-wide significance of those associations. This property facilitates the identification of possible false negatives for genome-wide significance. Further, our approach has the property of prioritizing expression traits that are affected by few strong associations. Expression traits identified by this method may warrant additional study because their expression level may be affected by targeting genes near a single locus. RESULTS: We demonstrate our method by identifying eQTL hotspots in Plasmodium falciparum (malaria) and Saccharomyces cerevisiae (yeast). We demonstrate the prioritization of traits with few strong genetic effects through Gene Ontology (GO) analysis of Yeast. Our results are strongly consistent with results gathered using genome-wide methods and identify additional hotspots and eQTLs. CONCLUSIONS: New eQTLs and hotspots found with this method may represent regions of the genome or biological processes that are controlled through few relatively strong genetic interactions. These points of interest warrant experimental investigation. PMID- 20964848 TI - Comparative survival analysis of breast cancer microarray studies identifies important prognostic genetic pathways. AB - BACKGROUND: An estimated 12% of females in the United States will develop breast cancer in their lifetime. Although, there are advances in treatment options including surgery and chemotherapy, breast cancer is still the second most lethal cancer in women. Thus, there is a clear need for better methods to predict prognosis for each breast cancer patient. With the advent of large genetic databases and the reduction in cost for the experiments, researchers are faced with choosing from a large pool of potential prognostic markers from numerous breast cancer gene expression profile studies. METHODS: Five microarray datasets related to breast cancer were examined using gene set analysis and the cancers were categorized into different subtypes using a scoring system based on genetic pathway activity. RESULTS: We have observed that significant genes in the individual studies show little reproducibility across the datasets. From our comparative analysis, using gene pathways with clinical variables is more reliable across studies and shows promise in assessing a patient's prognosis. CONCLUSIONS: This study concludes that, in light of clinical variables, there are significant gene pathways in common across the datasets. Specifically, several pathways can further significantly stratify patients for survival. These candidate pathways should help to develop a panel of significant biomarkers for the prognosis of breast cancer patients in a clinical setting. PMID- 20964849 TI - Artesunate-mefloquine combination therapy in acute Plasmodium falciparum malaria in young children: a field study regarding neurological and neuropsychiatric safety. AB - BACKGROUND: Mefloquine-artesunate combination therapy for uncomplicated falciparum malaria is one of the treatments used in African children. Data concerning neurological safety in adults and children treated with mefloquine and artesunate combination therapy is well documented in Asia. Safety data for neurological and neuropsychiatric side effects of mefloquine and artesunate combination therapy in African children are scarce, although WHO recommends this therapy in Africa. METHODS: A phase IV, open label, single arm study was conducted among African children between 10 and 20 kg with acute uncomplicated falciparum malaria. They were treated over three consecutive days with a paediatric fixed-dose combination of artesunate (50 mg/d) and mefloquine (125 mg/d). Parasitological, clinical and neurological examinations and standardized questions about neuropsychiatric symptoms were carried out on days 0, 4, 7, 28 and 63. The primary objective was to assess the neurological and neuropsychiatric safety of artesunate-mefloquine combination therapy in young children. RESULTS: From December 2007 to March 2009, 220 children with uncomplicated Plasmodium falciparum malaria were treated with artesunate and mefloquine. 213 children were analysed according to study protocol. 50 neurological and neuropsychiatric adverse events occurred in 28 patients. Eleven drug-related neurological and neuropsychiatric adverse events occurred in eight patients. Sleeping disorders were present in 2.3%, neurological disorders in 1.4%, neuropsychiatric disorders in 1% and eating disorders in 0.5% of the patients. Adverse events were of mild to moderate intensity and resolved spontaneously. CONCLUSION: African children showed a low percentage of self-limited neurological and neuropsychiatric adverse events, confirming studies on neurological safety in Asian children treated with artesunate and mefloquine. Sleeping disorders were most frequently observed. PMID- 20964850 TI - Universality of interpersonal psychotherapy (IPT) problem areas in Thai depressed patients. AB - BACKGROUND: Many studies have shown the efficacy of interpersonal psychotherapy (IPT) on depression; however, there are limited studies concerning the universality of the IPT problem areas in different countries. This study identifies whether the interpersonal problem areas defined in the IPT manual are endorsed by Thai depressed patients. METHODS: The Thai Hamilton Rating Scale for Depression (Thai HRSD) and Thai Interpersonal Questionnaire were used to assess 90 depressed and 90 non-depressed subjects in King Chulalongkorn Memorial Hospital, during July 2007 - January 2008. The association between interpersonal problem areas/sociodemographic variables and depressive disorder were analyzed by chi-square test. A multivariable analysis was performed by using logistic regression to identify the remaining factors associated with depressive disorder. RESULTS: Most of the subjects were young to middle-aged females living in Bangkok and the Central Provinces. All four interpersonal problem areas (grief, interpersonal role disputes, role transitions, and interpersonal deficits) were increased in the depressed subjects as compared to the non-depressed subjects, as were the sociodemographic variables (low education, unemployment, low income, and having a physical illness). Logistic regression showed that all interpersonal problem areas still remained problems associated with depression (grief: adjusted OR = 6.01, 95%CI = 1.93 - 18.69, p < 0.01; interpersonal role disputes: adjusted OR = 6.01, 95%CI = 2.18 - 16.52, p < 0.01; role transitions: adjusted OR = 26.30, 95%CI = 7.84 - 88.25, p < 0.01; and interpersonal deficits: adjusted OR = 2.92, 95%CI = 1.12 - 7.60, p < 0.05). CONCLUSION: All four interpersonal problem areas were applicable to Thai depressed patients. PMID- 20964851 TI - CCRaVAT and QuTie-enabling analysis of rare variants in large-scale case control and quantitative trait association studies. AB - BACKGROUND: Genome-wide association studies have been successful in finding common variants influencing common traits. However, these associations only account for a fraction of trait heritability. There has been a shift in the field towards studying low frequency and rare variants, which are now widely recognised as putative complex trait determinants. Despite this increasing focus on examining the role of low frequency and rare variants in complex disease susceptibility, there is a lack of user-friendly analytical packages implementing powerful association tests for the analysis of rare variants. RESULTS: We have developed two software tools, CCRaVAT (Case-Control Rare Variant Analysis Tool) and QuTie (Quantitative Trait), which enable efficient large-scale analysis of low frequency and rare variants. Both programs implement a collapsing method examining the accumulation of low frequency and rare variants across a locus of interest that has more power than single variant analysis. CCRaVAT carries out case-control analyses whereas QuTie has been developed for continuous trait analysis. CONCLUSIONS: CCRaVAT and QuTie are easy to use software tools that allow users to perform genome-wide association analysis on low frequency and rare variants for both binary and quantitative traits. The software is freely available and provides the genetics community with a resource to perform association analysis on rarer genetic variants. PMID- 20964852 TI - The role of advance directives in end-of-life decisions in Austria: survey of intensive care physicians. AB - BACKGROUND: Currently, intensive care medicine strives to define a generally accepted way of dealing with end-of-life decisions, therapy limitation and therapy discontinuation.In 2006 a new advance directive legislation was enacted in Austria. Patients may now document their personal views regarding extension of treatment. The aim of this survey was to explore Austrian intensive care physicians' experiences with and their acceptance of the new advance directive legislation two years after enactment (2008). METHODS: Under the aegis of the OEGARI (Austrian Society of Anaesthesiology, Resuscitation and Intensive Care) an anonymised questionnaire was sent to the medical directors of all intensive care units in Austria. The questions focused on the physicians' experiences regarding advance directives and their level of knowledge about the underlying legislation. RESULTS: There were 241 questionnaires sent and 139 were turned, which was a response rate of 58%. About one third of the responders reported having had no experience with advance directives and only 9 directors of intensive care units had dealt with more than 10 advance directives in the previous two years. Life supporting measures, resuscitation, and mechanical ventilation were the predominantly refused therapies, wishes were mainly expressed concerning pain therapy. CONCLUSION: A response rate of almost 60% proves the great interest of intensive care professionals in making patient-oriented end-of-life decisions. However, as long as patients do not make use of their right of co-determination, the enactment of the new law can be considered only a first important step forward. PMID- 20964854 TI - CIP2A expression is increased in prostate cancer. AB - BACKGROUND: The CIP2A protein is a recently characterized oncoprotein which inhibits protein phosphatase 2A activity. Expression of CIP2A has been detected in several carcinomas, but its expression and significance in prostate cancer has not been examined so far. METHODS: Expression of the CIP2A protein was studied using immunohistochemistry in prostate cancer (n = 59) and in benign prostatic hyperplasia (n = 20) specimens. The CIP2A staining scores were compared with several clinicopathological parameters. RESULTS: Expression of CIP2A was increased in prostate cancer epithelium as compared with the benign hyperplastic epithelium (p < 0.001). The expression of CIP2A was associated with high Gleason scores (p < 0.001) and among patients treated with radical prostatectomy, CIP2A expression was associated with pre-treatment risk stratification (p = 0.011) and pathological T-class (p = 0.031). No statistically significant association was detected between CIP2A expression and prostate specific antigen concentrations. CONCLUSIONS: Expression of the CIP2A protein is increased in prostate cancer specimens and its expression is associated with poorly differentiated and high risk tumors. PMID- 20964853 TI - Neighborhood socioeconomic status, Medicaid coverage and medical management of myocardial infarction: atherosclerosis risk in communities (ARIC) community surveillance. AB - BACKGROUND: Pharmacologic treatments are efficacious in reducing post-myocardial infarction (MI) morbidity and mortality. The potential influence of socioeconomic factors on the receipt of pharmacologic therapy has not been systematically examined, even though healthcare utilization likely influences morbidity and mortality post-MI. This study aims to investigate the association between socioeconomic factors and receipt of evidence-based treatments post-MI in a community surveillance setting. METHODS: We evaluated the association of census tract-level neighborhood household income (nINC) and Medicaid coverage with pharmacologic treatments (aspirin, beta [beta]-blockers and angiotensin converting enzyme [ACE] inhibitors; optimal therapy, defined as receipt of two or more treatments) received during hospitalization or at discharge among 9,608 MI events in the ARIC community surveillance study (1993-2002). Prevalence ratios (PR, 95% CI), adjusted for the clustering of hospitalized MI events within census tracts and within patients, were estimated using Poisson regression. RESULTS: Seventy-eight percent of patients received optimal therapy. Low nINC was associated with a lower likelihood of receiving beta-blockers (0.93, 0.87-0.98) and a higher likelihood of receiving ACE inhibitors (1.13, 1.04-1.22), compared to high nINC. Patients with Medicaid coverage were less likely to receive aspirin (0.92, 0.87-0.98), compared to patients without Medicaid coverage. These findings were independent of other key covariates. CONCLUSIONS: nINC and Medicaid coverage may be two of several socioeconomic factors influencing the complexities of medical care practice patterns. PMID- 20964855 TI - Methods of competing risks analysis of end-stage renal disease and mortality among people with diabetes. AB - BACKGROUND: When a patient experiences an event other than the one of interest in the study, usually the probability of experiencing the event of interest is altered. By contrast, disease-free survival time analysis by standard methods, such as the Kaplan-Meier method and the standard Cox model, does not distinguish different causes in the presence of competing risks. Alternative approaches use the cumulative incidence estimator by the Cox models on cause-specific and on subdistribution hazards models. We applied cause-specific and subdistribution hazards models to a diabetes dataset with two competing risks (end-stage renal disease (ESRD) or death without ESRD) to measure the relative effects of covariates and cumulative incidence functions. RESULTS: In this study, the cumulative incidence curve of the risk of ESRD by the cause-specific hazards model was revealed to be higher than the curves generated by the subdistribution hazards model. However, the cumulative incidence curves of risk of death without ESRD based on those three models were very similar. CONCLUSIONS: In analysis of competing risk data, it is important to present both the results of the event of interest and the results of competing risks. We recommend using either the cause specific hazards model or the subdistribution hazards model for a dominant risk. However, for a minor risk, we do not recommend the subdistribution hazards model and a cause-specific hazards model is more appropriate. Focusing the interpretation on one or a few causes and ignoring the other causes is always associated with a risk of overlooking important features which may influence our interpretation. PMID- 20964856 TI - Functional annotation, genome organization and phylogeny of the grapevine (Vitis vinifera) terpene synthase gene family based on genome assembly, FLcDNA cloning, and enzyme assays. AB - BACKGROUND: Terpenoids are among the most important constituents of grape flavour and wine bouquet, and serve as useful metabolite markers in viticulture and enology. Based on the initial 8-fold sequencing of a nearly homozygous Pinot noir inbred line, 89 putative terpenoid synthase genes (VvTPS) were predicted by in silico analysis of the grapevine (Vitis vinifera) genome assembly 1. The finding of this very large VvTPS family, combined with the importance of terpenoid metabolism for the organoleptic properties of grapevine berries and finished wines, prompted a detailed examination of this gene family at the genomic level as well as an investigation into VvTPS biochemical functions. RESULTS: We present findings from the analysis of the up-dated 12-fold sequencing and assembly of the grapevine genome that place the number of predicted VvTPS genes at 69 putatively functional VvTPS, 20 partial VvTPS, and 63 VvTPS probable pseudogenes. Gene discovery and annotation included information about gene architecture and chromosomal location. A dense cluster of 45 VvTPS is localized on chromosome 18. Extensive FLcDNA cloning, gene synthesis, and protein expression enabled functional characterization of 39 VvTPS; this is the largest number of functionally characterized TPS for any species reported to date. Of these enzymes, 23 have unique functions and/or phylogenetic locations within the plant TPS gene family. Phylogenetic analyses of the TPS gene family showed that while most VvTPS form species-specific gene clusters, there are several examples of gene orthology with TPS of other plant species, representing perhaps more ancient VvTPS, which have maintained functions independent of speciation. CONCLUSIONS: The highly expanded VvTPS gene family underpins the prominence of terpenoid metabolism in grapevine. We provide a detailed experimental functional annotation of 39 members of this important gene family in grapevine and comprehensive information about gene structure and phylogeny for the entire currently known VvTPS gene family. PMID- 20964857 TI - High-throughput microarray technology in diagnostics of enterobacteria based on genome-wide probe selection and regression analysis. AB - BACKGROUND: The Enterobacteriaceae comprise a large number of clinically relevant species with several individual subspecies. Overlapping virulence-associated gene pools and the high overall genome plasticity often interferes with correct enterobacterial strain typing and risk assessment. Array technology offers a fast, reproducible and standardisable means for bacterial typing and thus provides many advantages for bacterial diagnostics, risk assessment and surveillance. The development of highly discriminative broad-range microbial diagnostic microarrays remains a challenge, because of marked genome plasticity of many bacterial pathogens. RESULTS: We developed a DNA microarray for strain typing and detection of major antimicrobial resistance genes of clinically relevant enterobacteria. For this purpose, we applied a global genome-wide probe selection strategy on 32 available complete enterobacterial genomes combined with a regression model for pathogen classification. The discriminative power of the probe set was further tested in silico on 15 additional complete enterobacterial genome sequences. DNA microarrays based on the selected probes were used to type 92 clinical enterobacterial isolates. Phenotypic tests confirmed the array-based typing results and corroborate that the selected probes allowed correct typing and prediction of major antibiotic resistances of clinically relevant Enterobacteriaceae, including the subspecies level, e.g. the reliable distinction of different E. coli pathotypes. CONCLUSIONS: Our results demonstrate that the global probe selection approach based on longest common factor statistics as well as the design of a DNA microarray with a restricted set of discriminative probes enables robust discrimination of different enterobacterial variants and represents a proof of concept that can be adopted for diagnostics of a wide range of microbial pathogens. Our approach circumvents misclassifications arising from the application of virulence markers, which are highly affected by horizontal gene transfer. Moreover, a broad range of pathogens have been covered by an efficient probe set size enabling the design of high-throughput diagnostics. PMID- 20964859 TI - Development and validation of a flax (Linum usitatissimum L.) gene expression oligo microarray. AB - BACKGROUND: Flax (Linum usitatissimum L.) has been cultivated for around 9,000 years and is therefore one of the oldest cultivated species. Today, flax is still grown for its oil (oil-flax or linseed cultivars) and its cellulose-rich fibres (fibre-flax cultivars) used for high-value linen garments and composite materials. Despite the wide industrial use of flax-derived products, and our actual understanding of the regulation of both wood fibre production and oil biosynthesis more information must be acquired in both domains. Recent advances in genomics are now providing opportunities to improve our fundamental knowledge of these complex processes. In this paper we report the development and validation of a high-density oligo microarray platform dedicated to gene expression analyses in flax. RESULTS: Nine different RNA samples obtained from flax inner- and outer-stems, seeds, leaves and roots were used to generate a collection of 1,066,481 ESTs by massive parallel pyrosequencing. Sequences were assembled into 59,626 unigenes and 48,021 sequences were selected for oligo design and high-density microarray (Nimblegen 385K) fabrication with eight, non overlapping 25-mers oligos per unigene. 18 independent experiments were used to evaluate the hybridization quality, precision, specificity and accuracy and all results confirmed the high technical quality of our microarray platform. Cross validation of microarray data was carried out using quantitative qRT-PCR. Nine target genes were selected on the basis of microarray results and reflected the whole range of fold change (both up-regulated and down-regulated genes in different samples). A statistically significant positive correlation was obtained comparing expression levels for each target gene across all biological replicates both in qRT-PCR and microarray results. Further experiments illustrated the capacity of our arrays to detect differential gene expression in a variety of flax tissues as well as between two contrasted flax varieties. CONCLUSION: All results suggest that our high-density flax oligo-microarray platform can be used as a very sensitive tool for analyzing gene expression in a large variety of tissues as well as in different cultivars. Moreover, this highly reliable platform can also be used for the quantification of mRNA transcriptional profiling in different flax tissues. PMID- 20964860 TI - Study protocol for the evaluation of an Infant Simulator based program delivered in schools: a pragmatic cluster randomised controlled trial. AB - BACKGROUND: This paper presents the study protocol for a pragmatic randomised controlled trial to evaluate the impact of a school based program developed to prevent teenage pregnancy. The program includes students taking care of an Infant Simulator; despite growing popularity and an increasing global presence of such programs, there is no published evidence of their long-term impact. The aim of this trial is to evaluate the Virtual Infant Parenting (VIP) program by investigating pre-conceptual health and risk behaviours, teen pregnancy and the resultant birth outcomes, early child health and maternal health. METHODS AND DESIGN: Fifty-seven schools (86% of 66 eligible secondary schools) in Perth, Australia were recruited to the clustered (by school) randomised trial, with even randomisation to the intervention and control arms. Between 2003 and 2006, the VIP program was administered to 1,267 participants in the intervention schools, while 1,567 participants in the non-intervention schools received standard curriculum. Participants were all female and aged between 13-15 years upon recruitment. Pre and post-intervention questionnaires measured short-term impact and participants are now being followed through their teenage years via data linkage to hospital medical records, abortion clinics and education records. Participants who have a live birth are interviewed by face-to-face interview. Kaplan-Meier survival analysis and proportional hazards regression will test for differences in pregnancy, birth and abortion rates during the teenage years between the study arms. DISCUSSION: This protocol paper provides a detailed overview of the trial design as well as initial results in the form of participant flow. The authors describe the intervention and its delivery within the natural school setting and discuss the practical issues in the conduct of the trial, including recruitment. The trial is pragmatic and will directly inform those who provide Infant Simulator based programs in school settings. TRIAL REGISTRATION: ISRCTN24952438. PMID- 20964858 TI - Design and conduct of Caudwell Xtreme Everest: an observational cohort study of variation in human adaptation to progressive environmental hypoxia. AB - BACKGROUND: The physiological responses to hypoxaemia and cellular hypoxia are poorly understood, and inter-individual differences in performance at altitude and outcome in critical illness remain unexplained. We propose a model for exploring adaptation to hypoxia in the critically ill: the study of healthy humans, progressively exposed to environmental hypobaric hypoxia (EHH). The aim of this study was to describe the spectrum of adaptive responses in humans exposed to graded EHH and identify factors (physiological and genetic) associated with inter-individual variation in these responses. METHODS: DESIGN: Observational cohort study of progressive incremental exposure to EHH. SETTING: University human physiology laboratory in London, UK (75 m) and 7 field laboratories in Nepal at 1300 m, 3500 m, 4250 m, 5300 m, 6400 m, 7950 m and 8400 m. PARTICIPANTS: 198 healthy volunteers and 24 investigators trekking to Everest Base Camp (EBC) (5300 m). A subgroup of 14 investigators studied at altitudes up to 8400 m on Everest. MAIN OUTCOME MEASURES: Exercise capacity, exercise efficiency and economy, brain and muscle Near Infrared Spectroscopy, plasma biomarkers (including markers of inflammation), allele frequencies of known or suspected hypoxia responsive genes, spirometry, neurocognitive testing, retinal imaging, pupilometry. In nested subgroups: microcirculatory imaging, muscle biopsies with proteomic and transcriptomic tissue analysis, continuous cardiac output measurement, arterial blood gas measurement, trans-cranial Doppler, gastrointestinal tonometry, thromboelastography and ocular saccadometry. RESULTS: Of 198 healthy volunteers leaving Kathmandu, 190 reached EBC (5300 m). All 24 investigators reached EBC. The completion rate for planned testing was more than 99% in the investigator group and more than 95% in the trekkers. Unique measurements were safely performed at extreme altitude, including the highest (altitude) field measurements of exercise capacity, cerebral blood flow velocity and microvascular blood flow at 7950 m and arterial blood gas measurement at 8400 m. CONCLUSIONS: This study demonstrates the feasibility and safety of conducting a large healthy volunteer cohort study of human adaptation to hypoxia in this difficult environment. Systematic measurements of a large set of variables were achieved in 222 subjects and at altitudes up to 8400 m. The resulting dataset is a unique resource for the study of genotype:phenotype interactions in relation to hypoxic adaptation. PMID- 20964861 TI - Assessing nonresponse bias at follow-up in a large prospective cohort of relatively young and mobile military service members. AB - BACKGROUND: Nonresponse bias in a longitudinal study could affect the magnitude and direction of measures of association. We identified sociodemographic, behavioral, military, and health-related predictors of response to the first follow-up questionnaire in a large military cohort and assessed the extent to which nonresponse biased measures of association. METHODS: Data are from the baseline and first follow-up survey of the Millennium Cohort Study. Seventy-six thousand, seven hundred and seventy-five eligible individuals completed the baseline survey and were presumed alive at the time of follow-up; of these, 54,960 (71.6%) completed the first follow-up survey. Logistic regression models were used to calculate inverse probability weights using propensity scores. RESULTS: Characteristics associated with a greater probability of response included female gender, older age, higher education level, officer rank, active duty status, and a self-reported history of military exposures. Ever smokers, those with a history of chronic alcohol consumption or a major depressive disorder, and those separated from the military at follow-up had a lower probability of response. Nonresponse to the follow-up questionnaire did not result in appreciable bias; bias was greatest in subgroups with small numbers. CONCLUSIONS: These findings suggest that prospective analyses from this cohort are not substantially biased by non-response at the first follow-up assessment. PMID- 20964862 TI - Spontaneous preterm labor is associated with an increase in the proinflammatory signal transducer TLR4 receptor on maternal blood monocytes. AB - BACKGROUND: Localized inflammation and increased expression of TLR4 receptors within the uterus has been implicated in the pathogenesis of preterm labor. It remains unclear whether intrauterine inflammatory responses activate the maternal peripheral circulatory system. Therefore we determined whether increased TLR4 expression is present in the peripheral maternal white blood cells of women with spontaneous preterm labor. METHODS: This is a cross-sectional study of 41 preterm labor cases and 41 non-preterm controls. For each case and control sample, RNA was purified from white blood cells and TLR4 mRNA pool size was evaluated by quantitative PCR. Protein expression levels were determined by flow cytometry. Statistical evaluation using multiple linear regressions was used to determine any significant differences between the cases and controls. The purpose was to determine association prevalence of TLR4 levels and preterm labor. RESULTS: Adjusted mean TLR4 mRNA levels of 0.788 +/- 0.037 (standard error) for preterm labor and 0.348 +/- 0.038 for the corresponding pregnant control women were statistically significantly different (P = 0.002). Using the lower 95% confidence interval of the mean expression level in PTL subjects (0.7) as a cutoff value for elevated TLR4 mRNA levels, 25/41 (60.9%) of PTL patients expressed elevated TLR4 mRNA as compared to 0/41 (0%) in control subjects. The TLR4 receptor levels in the granulocyte fraction of white blood cells from preterm labor and pregnant controls were similar. However, TLR4+/CD14+monocytes were 2.3 times more frequent (70% vs. 30%) and TLR4 also had a 2.6-fold higher density (750 vs. 280 molecules per cell) in preterm labor women compared with pregnant controls. There was no difference in the levels of TLR4 in patients at term. CONCLUSIONS: Patients with preterm labor exhibited elevated levels of CD14+ maternal blood monocytes each bearing enhanced expression of TLR4, indicating that the peripheral circulatory system is activated in patients with preterm labor. Elevated leukocyte TLR4 levels may be a useful biomarker associated with preterm labor. PMID- 20964863 TI - Decoding subtle forearm flexions using fractal features of surface electromyogram from single and multiple sensors. AB - BACKGROUND: Identifying finger and wrist flexion based actions using a single channel surface electromyogram (sEMG) can lead to a number of applications such as sEMG based controllers for near elbow amputees, human computer interface (HCI) devices for elderly and for defence personnel. These are currently infeasible because classification of sEMG is unreliable when the level of muscle contraction is low and there are multiple active muscles. The presence of noise and cross talk from closely located and simultaneously active muscles is exaggerated when muscles are weakly active such as during sustained wrist and finger flexion. This paper reports the use of fractal properties of sEMG to reliably identify individual wrist and finger flexion, overcoming the earlier shortcomings. METHODS: SEMG signal was recorded when the participant maintained pre-specified wrist and finger flexion movements for a period of time. Various established sEMG signal parameters such as root mean square (RMS), Mean absolute value (MAV), Variance (VAR) and Waveform length (WL) and the proposed fractal features: fractal dimension (FD) and maximum fractal length (MFL) were computed. Multi variant analysis of variance (MANOVA) was conducted to determine the p value, indicative of the significance of the relationships between each of these parameters with the wrist and finger flexions. Classification accuracy was also computed using the trained artificial neural network (ANN) classifier to decode the desired subtle movements. RESULTS: The results indicate that the p value for the proposed feature set consisting of FD and MFL of single channel sEMG was 0.0001 while that of various combinations of the five established features ranged between 0.009 - 0.0172. From the accuracy of classification by the ANN, the average accuracy in identifying the wrist and finger flexions using the proposed feature set of single channel sEMG was 90%, while the average accuracy when using a combination of other features ranged between 58% and 73%. CONCLUSIONS: The results show that the MFL and FD of a single channel sEMG recorded from the forearm can be used to accurately identify a set of finger and wrist flexions even when the muscle activity is very weak. A comparison with other features demonstrates that this feature set offers a dramatic improvement in the accuracy of identification of the wrist and finger movements. It is proposed that such a system could be used to control a prosthetic hand or for a human computer interface. PMID- 20964864 TI - Incidence of primary hepatitis C infection and risk factors for transmission in an Australian prisoner cohort. AB - BACKGROUND: Hepatitis C virus (HCV) infection is common in prisoner populations, particularly those with a history of injecting drug use (IDU). Previous studies of HCV incidence have been based on small case numbers and have not distinguished risk events in prison from those in the community. METHODS: HCV incidence was examined in a longitudinal cohort of 488 Australian prisoners with a history of IDU and documented to be seronegative within 12 months prior to enrollment. Inmates were tested for anti-HCV antibodies and viremia, and interviewed about demographic and behavioral risk factors for transmission. RESULTS: The cohort was predominantly male (65%) with high rates of prior imprisonment (72%) and tattooing (73%), as well as longstanding IDU (mean 8.5 years). Ninety-four incident HCV cases were identified (incidence 31.6 per 100 person years). Independent associations were observed between incident infection and prior imprisonment (p = 0.02) and tattooing (p = 0.03), and surprisingly also with methadone maintenance treatment (MMT) (p < 0.001). CONCLUSIONS: High rates of new HCV infection were found in this prisoner cohort reflecting their substantive risk behavior profile, despite having remained uninfected for many years. The association with MMT is challenging and highlights the need for better understanding of prison-specific HCV transmission risks, as well as the uptake and effectiveness of prevention programs. PMID- 20964865 TI - A trial assessing N-3 as treatment for injury-induced cachexia (ATLANTIC trial): does a moderate dose fish oil intervention improve outcomes in older adults recovering from hip fracture? AB - BACKGROUND: Proximal femoral fractures are associated with increased morbidity and mortality. Pre-existing malnutrition and weight loss amongst this patient group is of primary concern, with conventional nutrition support being largely ineffective. The inflammatory response post proximal femoral fracture surgery and the subsequent risk of cachexia may explain the inability of conventional high energy high protein management to produce an anabolic response amongst these patients. Omega-3 fatty acids derived from fish oils have been extensively studied for their anti-inflammatory benefits. Due to their anti-inflammatory properties, the benefit of fish oil combined with individualized nutrition support amongst proximal femoral fracture patients post surgery is an attractive potential therapeutic strategy. The aim of the ATLANTIC trial is to assess the potential benefits of an anti-inflammatory dose of fish oil within the context of a 12 week individualised nutrition program, commencing seven days post proximal femoral fracture surgery. METHODS/DESIGN: This randomized controlled, double blinded trial, will recruit 150 community dwelling elderly patients aged >=65 years, within seven days of surgery for proximal femoral fracture. Participants will be randomly allocated to receive either a 12 week individualized nutrition support program complemented with 20 ml/day anti-inflammatory dose fish oil (~3.6 g eicosapentaenoic acid, ~2.4 g docosahexanoic acid; intervention), or, a 12 week individualized nutrition support program complemented with 20 ml/day low dose fish oil (~0.36 g eicosapentaenoic acid, ~0.24 g docosahexanoic acid; control). DISCUSSION: The ATLANTIC trial is the first of its kind to provide fish oil combined with individualized nutrition therapy as an intervention to address the inflammatory response experienced post proximal femoral fracture surgery amongst elderly patients. The final outcomes of this trial will assist clinicians in the development of effective and alternative treatment methods post proximal femoral fracture surgery which may ultimately result in a reduction in systemic inflammation, loss of weight and lean muscle and improvements in nutritional status, mobility, independence and quality of life among elderly patients. TRIAL REGISTRATION: ACTRN12609000241235. PMID- 20964866 TI - The presentation order of cue and target matters in deception study. AB - BACKGROUND: Two experimental procedures (cue-target and target-cue) were used in studying the processes of deception. How the task will affect participants' performances is not clear. This study was conducted to investigate the effect of the order of presentation of cue and target on the processes of deception. METHODS: A face evaluation task was employed to test and compare the order effect of the deception-indicating cue and the target stimulus in studying deception (i.e., which research procedure is more sensitive in distinguishing different experimental conditions and which is more likely to represent the deception process in daily life). Behavioral responses and event-related potentials (ERP) were recorded while participants made truthful and deceptive responses about their evaluation. RESULTS: Response-locked ERP showed that both deceptive conditions in cue-target and target-cue procedures elicited medial frontal negativities. However, the results in the ERP distribution regions, the ERP amplitudes and source estimation results were different in the two procedures. The cue-target procedure elicited a more negative ERP deflection between 40 ms and 90 ms over the central-frontal scalp regions than the target-cue procedures. Source localizations in cue-target were identified in three clusters, namely, medial frontal gyrus, dorsal anterior cingulate cortex, and ventral medial frontal gyrus. In the target-cue procedure, the sources were identified in the frontal areas. DISCUSSION: Different presenting orders of the cue and target stimuli induced different neural activities. Further, the cue-target procedure could represent the process of deception better than the target-cue procedure. PMID- 20964867 TI - Ibandronate increases cortical bone density in patients with systemic lupus erythematosus on long-term glucocorticoid. AB - INTRODUCTION: The purpose of this research is to assess the effects of oral ibandronate on bone microarchitecture by using high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with systemic lupus erythematosus (SLE) taking a long-term glucocorticoid. METHODS: In this double blind placebo-controlled study, 40 Chinese female SLE patients taking prednisolone were randomly assigned to receive either monthly oral ibandronate (150 mg) or placebo with daily 1-hydroxycholecalciferol (Alfacalcidol; 1 MUg) and calcium supplement for 12 months. Assessments of bone microarchitecture by using HR-pQCT and area bone mineral density (aBMD) of the lumbar spine and hip with dual-energy x-ray absorptiometry (DXA) were performed at baseline and 12 months. RESULTS: No differences in baseline characteristics were found between the two groups. After 12 months, no statistical differences were noted in any of the bone densities, microarchitectural parameters, or percentage changes of these parameters, as measured with HR-pQCT or DXA between the two groups. However, within the active group, the percentage improvement was significant in cortical bone density (P = 0.023) which was absent in the placebo group. Improvement was also seen in the aBMD of both the lumbar spine (P < 0.0001) and the hip (P < 0.005). In the placebo group, the percentage increase in trabecular separation was significant (P = 0.04), and the percentage improvement in aBMD in the spine also was significant (P = 0.049). CONCLUSIONS: Oral ibandronate treatment improves microarchitecture in SLE patients taking long-term glucocorticoid assessed with HR-pQCT, and this new technology may have a role in assessing bony changes in future longitudinal studies in SLE patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00668330. PMID- 20964868 TI - M1 muscarinic receptor for the development of auditory cortical function. AB - The sensory cortex is subject to continuous remodelling during early development and throughout adulthood. This process is important for establishing normal brain function and is dependent on cholinergic modulation via muscarinic receptors. Five muscarinic receptor genes encode five unique receptor subtypes (M1-5). The distributions and functions of each subtype vary in central and peripheral systems. In the brain, the M1 receptor is most abundant in the cerebral cortex, where its immunoreactivity peaks transiently during early development. This likely signifies the importance of M1 receptor in the development and maintenance of normal cortical function. Several lines of study have outlined the roles of M1 receptors in the development and plasticity of the auditory cortex. For example, M1-knockout reduces experience-dependent plasticity and disrupts tonotopic mapping in the adult mouse auditory cortex. Further evidence demonstrates a role for M1 in neurite outgrowth and hence determining the structure of cortical neurons. The disruption of tonotopic maps in M1-knockout mice may be linked to alterations in thalamocortical connectivity, because the targets of thalamocortical afferents (layer IV cortical neurons) appear less mature in M1 knockouts. Herein we review the literature to date concerning M1 receptors in the auditory cortex and consider some future directions that will contribute to our understanding. PMID- 20964869 TI - The impact of generic substitution on the activities of pharmaceutical companies a survey from the companies' perspective one year and five years after the introduction of generic substitution in finland. AB - BACKGROUND: Mandatory generic substitution (GS) was introduced in Finland on 1 April 2003. The aim of this study was to explore and compare the impacts of GS on the activities of pharmaceutical companies representing mainly original or generic pharmaceutical products in Finland. The self-reported impact of GS from pharmaceutical companies' perspective was explored with a focus on the number of employees, the range of sales packages on the market, the marketing activities, the research and development of new pharmaceutical products and storage of pharmaceuticals. METHODS: A cross-sectional postal survey was conducted among pharmaceutical companies with an office in Finland and substitutable medicines in the Finnish pharmaceutical market one year (2004) and five years (2008) after the introduction of GS. Completed questionnaires were returned by 16 original and 7 generic product companies in 2004 (response rate 56%, n = 41) and by 16 original and 6 generic product companies in 2008 (response rate 56%, n = 39). Descriptive statistical analyses were performed. RESULTS: The number of employees (2004: n = 6/16, 2008: n = 7/16) and the amount of prescription medicine marketing (2004: n = 7/16, 2008: n = 8/16) decreased in many of the original product companies after the introduction of GS. GS resulted in problems related to the storage of pharmaceuticals in the original product companies shortly after GS was introduced (p = 0.032 between 2004 and 2008). In the generic product companies, the prescription medicine representatives' visits to pharmacies increased at the beginning of GS (p = 0.021 between 2004 and 2008). In addition, GS caused problems with the storage of pharmaceuticals one year and five years after the reform (2004: n = 4/7, 2008: n = 3/6). The differences between original and generic product companies regarding the impacts of GS were not, however, statistically significant. GS did not affect on the range of sales packages on the market or the research activities of the majority of companies. CONCLUSIONS: The study suggests that GS has had impacts on the activities of pharmaceutical companies in Finland. There were also some differences, although not statistically significant, between the surveyed original and generic product companies regarding the self-reported impacts of GS. More investigations are needed in this field. PMID- 20964870 TI - Interleukins, laminin and Epstein - Barr virus latent membrane protein 1 (EBV LMP1) promote metastatic phenotype in nasopharyngeal carcinoma. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is a type of neoplasm that is highly prevalent in East Asia and Africa with Epstein-Barr virus (EBV), genetic, and dietary factors implicated as possible aetiologic factors. Previous studies suggested the association of certain cytokines with the invasion and metastatic properties of NPC. The present study examined the roles of EBV latent membrane protein-1 (LMP1), interleukin-6 (IL-6), interleukin-10 (IL-10), transforming growth factor-beta 1 (TGF-beta1) and laminin in the regulation of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) in NPC. The effects of these factors on bmi-1, an oncogene, and ngx6, a tumour suppressor gene, were also investigated. METHODS: TW01 cells expressing LMP1 (TW01-LMP1) were established via transfection with the B95.8 EBV LMP1 gene. Both TW01 and TW01-LMP1 cells were treated with 100 pg/ml IL-6, 1000 pg/ml IL-10 and 100 pg/ml TGF-beta1, separately and also in combination at their respective concentration for 48 hours. Treated cells were subjected to laminin adherence assay. The cells were also cultured with and without laminin and assayed for MMP-3, MMP-9 and VEGF production using enzyme-linked immunosorbent assay (ELISA). The cellular apoptotic property was analysed using caspase-3 apoptosis assay. The expression of bmi-1 and ngx6 gene was investigated using real time reverse transcriptase polymerase chain reaction. RESULTS: LMP1 was found to reduce the adherence of NPC cells towards laminin (p < 0.05) as compared to control. Treatment with IL-6 at 100 pg/ml enhanced the production of MMP-9 in both TW01 and TW01-LMP1 cells (p < 0.05). When cultured on laminin, the levels of MMP-3 and VEGF were significantly increased (p < 0.05) in TW01-LMP1 cells. TW01-LMP1 cells had relatively greater resistance to apoptosis as compared to TW01 cells (p < 0.05). Laminin, IL-6 and LMP1 were found to up-regulate the expression of bmi-1 and suppressed the expression of ngx6. CONCLUSIONS: We conclude that IL-6 reduced cell adherence towards laminin and increased MMP-9 production in NPC cells. Our data suggested that EBV LMP1 was able to confer resistance of apoptosis and increased MMP-9 production in NPC cells. When cultured on laminin, TW01 cells expressing the EBV LMP1 (TW0-LMP1) that were treated with IL-6 at 100 pg/ml displayed increased MMP 9 production, up-regulation of bmi-1 oncogene expression and down-regulation of ngx6 tumour suppressor gene expression. These findings implicate the roles of EBV LMP1, laminin and IL-6 in the promotion of invasion and metastasis in NPC. PMID- 20964871 TI - Social influences on mental health help-seeking after interpersonal traumatization: a qualitative analysis. AB - BACKGROUND: Despite frequent and serious mental health problems after interpersonal traumatization, only a fraction of those affected by interpersonal violence seek formal help after the event. Reasons for this mismatch can be found in the individual help-seeking process but also in the individual's social environment. These social factors are explored based on a model describing the survivor's help-seeking process. METHOD: Survivors of interpersonal traumatization and professionals providing help for this population were asked about factors influencing the ease of seeking and receiving professional help after interpersonal traumatization. A deductive and inductive content analysis of the experiences of 43 survivors of interpersonal traumatization and 16 professionals providing help for this population was carried out. RESULTS: The analysis suggested a clear distinction of an individual and a social system level of influencing variables. At the system level three main factors were identified: factors of the help-system, dominant attitudes in society and public knowledge about traumatization and available help. CONCLUSIONS: The results confirmed a complex interaction of variables on the individual and system level in the help seeking process. The system level affects the individual's help-seeking through multiple pathways, especially through the individual's representation of the traumatization, through the reactions of the individual's social network and through barriers the individual perceives or experiences in the formal help system. PMID- 20964872 TI - The exchangeability of shape. AB - BACKGROUND: Landmark based geometric morphometrics (GM) allows the quantitative comparison of organismal shapes. When applied to systematics, it is able to score shape changes which often are undetectable by traditional morphological studies and even by classical morphometric approaches. It has thus become a fast and low cost candidate to identify cryptic species. Due to inherent mathematical properties, shape variables derived from one set of coordinates cannot be compared with shape variables derived from another set. Raw coordinates which produce these shape variables could be used for data exchange, however they contain measurement error. The latter may represent a significant obstacle when the objective is to distinguish very similar species. RESULTS: We show here that a single user derived dataset produces much less classification error than a multiple one. The question then becomes how to circumvent the lack of exchangeability of shape variables while preserving a single user dataset. A solution to this question could lead to the creation of a relatively fast and inexpensive systematic tool adapted for the recognition of cryptic species. CONCLUSIONS: To preserve both exchangeability of shape and a single user derived dataset, our suggestion is to create a free access bank of reference images from which one can produce raw coordinates and use them for comparison with external specimens. Thus, we propose an alternative geometric descriptive system that separates 2-D data gathering and analyzes. PMID- 20964873 TI - Association of polymorphisms of interleukin-18 gene promoter region with polycystic ovary syndrome in chinese population. AB - BACKGROUND: Recent research shows that polycystic ovary syndrome (PCOS) may have an association with low-grade chronic inflammation, and that PCOS may induce an increase in serum interleukin-18 (IL-18) levels. METHODS: To investigate the polymorphisms of the IL-18 gene promoters with PCOS, two single nucleotide polymorphisms (SNPs) in the promoter of the IL-18 gene (at positions -607C/A and 137G/C) in 118 Chinese women with PCOS and 79 controls were evaluated using polymerase chain reaction (PCR). RESULTS: No significant differences were found in the genotype distribution, allele frequency and haplotype frequency between the PCOS and control groups. Further analysis demonstrated a relationship between IL-18 gene promoter polymorphisms and PCOS insulin resistance (IR). Regarding the -137 allele frequency, G and C allele frequencies were 93.5% and 6.5%, respectively, in the PCOS with IR patients; G and C allele frequencies were 85.4% and 14.6%, respectively, in PCOS patients without IR (chi2 = 3.601, P = 0.048). CONCLUSIONS: The presence of a polymorphism in the IL-18 gene was found to have no correlation with the occurrence of PCOS. Carriage of the C allele at position 137 in the promoter of the IL-18 gene may play a protective role from the development of PCOS IR. PMID- 20964875 TI - Abstracts of the 5th European Conference on Rare Diseases (ECRD 2010). Krakow, Poland. May 13-15, 2010. PMID- 20964876 TI - The development and validation of the Beliefs about Paranoia Scale (Short Form). AB - BACKGROUND: This study reports the development and revision of the Beliefs about Paranoia Scale (BaPS), a self-report measure to assess metacognitive beliefs about paranoia in non-patients. We aimed to confirm the factor structure of a revised 50-item version of the measure and test the specific hypotheses that positive beliefs about paranoia would predict frequency of paranoia, and that negative beliefs about paranoia would predict distress associated with paranoia. METHOD: 185 non-patient participants completed questionnaires assessing beliefs about paranoia, thought control, self-consciousness, anxiety, depression and paranoia. RESULTS: The results showed that the original four-factor solution could not be replicated. Instead a three-factor solution comprising Negative Beliefs about Paranoia, Paranoia as a Survival Strategy, and Normalizing Beliefs was developed. The revised 18-item measure showed good internal consistency. Stepwise regression analysis showed that, BaPS-negative beliefs accounted for 34% of the variance with R2 of 0.339, with a multiple R of 0.585 in relation to frequency of paranoia. In relation to distress arising from paranoia, stepwise regression analysis showed that BaPS-negative beliefs accounted for 34% of the variance with R2 of 0.339, with a multiple R of 0.585. In both analyses, BaPS Survival strategy showed a small but significant incremental increase in the variance accounted for in the overall model. CONCLUSIONS: These findings suggest that a metacognitive approach to the conceptualization of paranoia as a strategy for managing interpersonal threat may have some utility. The clinical implications of the findings are also discussed. PMID- 20964874 TI - Significance of Cuscutain, a cysteine protease from Cuscuta reflexa, in host parasite interactions. AB - BACKGROUND: Plant infestation with parasitic weeds like Cuscuta reflexa induces morphological as well as biochemical changes in the host and the parasite. These modifications could be caused by a change in protein or gene activity. Using a comparative macroarray approach Cuscuta genes specifically upregulated at the host attachment site were identified. RESULTS: One of the infestation specific Cuscuta genes encodes a cysteine protease. The protein and its intrinsic inhibitory peptide were heterologously expressed, purified and biochemically characterized. The haustoria specific enzyme was named cuscutain in accordance with similar proteins from other plants, e.g. papaya. The role of cuscutain and its inhibitor during the host parasite interaction was studied by external application of an inhibitor suspension, which induced a significant reduction of successful infection events. CONCLUSIONS: The study provides new information about molecular events during the parasitic plant--host interaction. Inhibition of cuscutain cysteine proteinase could provide means for antagonizing parasitic plants. PMID- 20964877 TI - Advantages of clustering in the phase classification of hyperspectral materials images. AB - Despite the many demonstrated applications of factor analysis (FA) in analyzing hyperspectral materials images, FA does have inherent mathematical limitations, preventing it from solving certain materials characterization problems. A notable limitation of FA is its parsimony restriction, referring to the fact that in FA the number of components cannot exceed the chemical rank of a dataset. Clustering is a promising alternative to FA for the phase classification of hyperspectral materials images. In contrast with FA, the phases extracted by clustering do not have to be parsimonious. Clustering has an added advantage in its insensitivity to spectral collinearity that can result in phase mixing using FA. For representative energy dispersive X-ray spectroscopy materials images, namely a solder bump dataset and a braze interface dataset, clustering generates phase classification results that are superior to those obtained using representative FA-based methods. For the solder bump dataset, clustering identifies a Cu-Sn intermetallic phase that cannot be isolated using FA alone due to the parsimony restriction. For the braze interface sample that has collinearity among the phase spectra, the clustering results do not exhibit the physically unrealistic phase mixing obtained by multivariate curve resolution, a commonly utilized FA algorithm. PMID- 20964878 TI - Early spreading and propagation of human bone marrow stem cells on isotropic and anisotropic topographies of silica thin films produced via microstamping. AB - While there has been rapid development of microfabrication techniques to produce high-resolution surface modifications on a variety of materials in the last decade, there is still a strong need to produce novel alternatives to induce guided tissue regeneration on dental implants. High-resolution microscopy provides qualitative and quantitative techniques to study cellular guidance in the first stages of cell-material interactions. The purposes of this work were (1) to produce and characterize the surface topography of isotropic and anisotropic microfabricated silica thin films obtained by sol-gel processing, and (2) to compare the in vitro biological behavior of human bone marrow stem cells on these surfaces at early stages of adhesion and propagation. The results confirmed that a microstamping technique can be used to produce isotropic and anisotropic micropatterned silica coatings. Atomic force microscopy analysis was an adequate methodology to study in the same specimen the sintering derived contraction of the microfabricated coatings, using images obtained before and after thermal cycle. Hard micropatterned coatings induced a modulation in the early and late adhesion stages of cell-material and cell-cell interactions in a geometry-dependent manner (i.e., isotropic versus anisotropic), as it was clearly determined, using scanning electron and fluorescence microscopies. PMID- 20964879 TI - The field of microscopy research. Introduction. PMID- 20964880 TI - Where does your food come from? PMID- 20964881 TI - Linking agriculture and nutrition. PMID- 20964882 TI - Neural reuse: a fundamental organizational principle of the brain. AB - An emerging class of theories concerning the functional structure of the brain takes the reuse of neural circuitry for various cognitive purposes to be a central organizational principle. According to these theories, it is quite common for neural circuits established for one purpose to be exapted (exploited, recycled, redeployed) during evolution or normal development, and be put to different uses, often without losing their original functions. Neural reuse theories thus differ from the usual understanding of the role of neural plasticity (which is, after all, a kind of reuse) in brain organization along the following lines: According to neural reuse, circuits can continue to acquire new uses after an initial or original function is established; the acquisition of new uses need not involve unusual circumstances such as injury or loss of established function; and the acquisition of a new use need not involve (much) local change to circuit structure (e.g., it might involve only the establishment of functional connections to new neural partners). Thus, neural reuse theories offer a distinct perspective on several topics of general interest, such as: the evolution and development of the brain, including (for instance) the evolutionary-developmental pathway supporting primate tool use and human language; the degree of modularity in brain organization; the degree of localization of cognitive function; and the cortical parcellation problem and the prospects (and proper methods to employ) for function to structure mapping. The idea also has some practical implications in the areas of rehabilitative medicine and machine interface design. PMID- 20964912 TI - Person as scientist, person as moralist. AB - It has often been suggested that people's ordinary capacities for understanding the world make use of much the same methods one might find in a formal scientific investigation. A series of recent experimental results offer a challenge to this widely-held view, suggesting that people's moral judgments can actually influence the intuitions they hold both in folk psychology and in causal cognition. The present target article distinguishes two basic approaches to explaining such effects. One approach would be to say that the relevant competencies are entirely non-moral but that some additional factor (conversational pragmatics, performance error, etc.) then interferes and allows people's moral judgments to affect their intuitions. Another approach would be to say that moral considerations truly do figure in workings of the competencies themselves. I argue that the data available now favor the second of these approaches over the first. PMID- 20964940 TI - Life course studies of psychopathology: consolidation and concern. PMID- 20964941 TI - Life course perspectives on the epidemiology of depression. AB - Life course epidemiology seeks to understand how determinants of health and disease interact across the span of a human life, and has made significant contributions to understanding etiological mechanisms in many chronic diseases, including schizophrenia. The life course approach is ideal for understanding depression: causation in depression appears to be multifactorial, including interactions between genes and stressful events, or between early life trauma and later stress in life; timing of onset and remission of depression varies widely, indicating differing trajectories of symptoms over long periods of time, with possible differing causes and differing outcomes; and early life events and development appear to be important risk factors for depression, including exposure to acute and chronic stress in the first years of life. To better understand etiology and outcome of depression, future research must move beyond basic epidemiologic techniques that link specific exposures to specific outcomes and embrace life course principles and methods. Time-sensitive modelling techniques that are able to incorporate multiple interacting factors across long periods of time, such as structural equation models, will be critical in understanding the complexity of causal and influencing factors from early development to the end stages of life. Using these models to identify key pathways that influence trajectories of depression across the life course will help guide prevention and intervention. PMID- 20964942 TI - Risk factors for conduct disorder and delinquency: key findings from longitudinal studies. AB - Conduct disorder (CD) and delinquency are behavioural problems involving violation of major rules, societal norms, and laws. The prevalence of CD and delinquency peaks in mid-to-late adolescence. Both show considerable continuity over time. The most important studies of CD and delinquency have prospective longitudinal designs, large community samples, repeated personal interviews, measures of many possible risk factors, and both self-reports and official measures of antisocial behaviour. The most important risk factors that predict CD and delinquency include impulsiveness, low IQ and low school achievement, poor parental supervision, punitive or erratic parental discipline, cold parental attitude, child physical abuse, parental conflict, disrupted families, antisocial parents, large family size, low family income, antisocial peers, high delinquency rate schools, and high crime neighbourhoods. However, for many risk factors, it is not known whether they have causal effects. Future research should examine changes in risk factors and changes in CD and delinquency to identify the risk factors that are causes and those that are merely markers of other risk mechanisms. PMID- 20964943 TI - Association between antidepressant use during pregnancy and infants born small for gestational age. AB - OBJECTIVE: To measure the association between the class of antidepressant (AD) used according to trimester of exposure during pregnancy and infants born small for gestational age (SGA). METHODS: A case-control study was performed using data from the Quebec Pregnancy Registry, which includes 152,107 pregnant women between January 1, 1998, and December 31, 2002. For this study, eligible women were aged 15 to 45 years on the first day of gestation, had drug plan coverage from the Regie de l'Assurance Maladie du Quebec for 12 months or more prior to and during pregnancy, had at least 1 psychiatric disorder diagnosis before pregnancy, used ADs for at least 30 days in the year prior to pregnancy, and delivered a live singleton. AD exposure during pregnancy was defined according to trimester of use and class (selective serotonin reuptake inhibitors [SSRIs], tricyclic AD, or other ADs). SGA cases were defined as newborns with a birth weight of less than the 10th percentile according to Canadian charts. Relative risks, adjusted for potential confounders, were estimated using modified Poisson regression. RESULTS: Among the 938 eligible pregnancies, 128 (13.6%) infants were born SGA. Other ADs, mainly venlafaxine, used by women during the second trimester were associated with an increased risk of infants born SGA, compared with nonusers of ADs (adjusted relative risk = 2.41; 95% CI 1.07 to 5.43). Regardless of the trimester of use, no association was found between SSRIs or tricyclics and the risk of SGA. CONCLUSIONS: This study suggests that use of venlafaxine during the second trimester of pregnancy may increase the risk of infants born SGA. PMID- 20964944 TI - Clinical factors that predict cognitive function in patients with major depression. AB - OBJECTIVES: To compare the performance of depressed patients to healthy control subjects on discrete cognitive domains derived from factor analysis and to examine the factors that may influence the performance of depressed patients on cognitive domains in a large sample. METHODS: We compared the cognitive performance of 149 patients with major depression to 104 healthy control subjects using multivariate ANCOVA. We used principal component factor analysis to group the cognitive variables into cognitive domains. Finally, we conducted regression analysis to examine the contribution of predictor factors to the cognitive domains that were impaired in the depressed group. RESULTS: Verbal memory and speed of processing were impaired in depressed patients, compared with healthy control subjects. Patient IQ, duration of depressive illness, and number of hospitalizations significantly contributed to the performance of patients on verbal memory and speed of processing. The severity of mood symptoms did not correlate with performance on any cognitive domain. CONCLUSIONS: Understanding the factors that predict cognitive performance of patients with depression may provide an insight into the processes by which depression leads to cognitive dysfunction. Our study showed that premorbid IQ and factors related to burden of illness are strong independent predictors of cognitive dysfunction in patients with major depression. PMID- 20964945 TI - A controlled before-and-after evaluation of a mobile crisis partnership between mental health and police services in Nova Scotia. AB - OBJECTIVES: Police are often the front-line response to people experiencing mental health crises. This study examined the impact of an integrated mobile crisis team formed in partnership between mental health services, municipal police, and emergency health services. The service offered short-term crisis management, with mobile interventions being attended by a plainclothes police officer and a mental health professional. METHODS: We used a mixed-methods design encompassing: a controlled before-and-after quantitative comparison of the intervention area with a control area without access to such a service, for 1 year before and 2 years after program implementation; and qualitative assessments of the views of service recipients, families, police officers, and health staff at baseline and 2 years afterward. RESULTS: The integrated service resulted in increased use by people in crisis, families, and service partners (for example, from 464 to 1666 service recipients per year). Despite increased service use, time spent on-scene and call-to-door time were reduced. At year 2, the time spent on-scene by police (136 minutes) was significantly lower than in the control area (165 minutes) (Student t test = 3.4, df = 1649, P < 0.001). After adjusting for confounders, people seen by the integrated team (n = 295) showed greater engagement than control subjects as measured by outpatient contacts (b = 1.3, chi square = 92.7, df = 1, P < 0.001). The service data findings were supported by the qualitative results of focus groups and interviews. CONCLUSIONS: Partnerships between the police department and mental health system can improve collaboration, efficiency, and the treatment of people with mental illness. PMID- 20964946 TI - Predictors of the longitudinal course of major depression in a Canadian population sample. AB - OBJECTIVE: Most psychiatric epidemiologic studies have used cross-sectional methods, resulting in a lack of information about the longitudinal course of depressive disorders. The objective of our study was to describe the longitudinal epidemiology of major depressive episodes (MDEs) in a Canadian sample using data from the National Population Health Survey (NPHS). METHODS: The NPHS started data collection in 1994 and has evaluated past-year MDE using repeat interviews of the same cohort every 2 years since then. In our study, we examined the number of weeks depressed during years when MDEs occurred, the proportion of respondents having MDEs at consecutive cycles, and MDE counts during follow-up. RESULTS: A sizable proportion of MDEs were brief: about one-half of respondents with past year MDE reported 8 or fewer weeks of depression during that year. Less than 10% reported that they were depressed for the entire year. However, a larger proportion (19.1%) fulfilled criteria for MDE on consecutive interview cycles, suggesting either persistence or rapid recurrence. The mean number of detected MDEs among those with at least 1 detected MDE up to 2006 was 2. Positive family history, evidence of comorbidity, negative cognitive style, stress, pain, and smoking were associated with a more negative course. CONCLUSIONS: The longitudinal course of MDE in the general population is heterogeneous, including a mixture of brief and more protracted MDEs. Many risk factors for MDE are also associated with a negative course, exceptions being (younger) age and sex. These epidemiologic observations may assist with identification of patients requiring more intensive management in clinical practice. PMID- 20964947 TI - Where to position clozapine: re-examining the evidence. AB - OBJECTIVE: To review clozapine's position in treatment algorithms for schizophrenia. METHOD: Clozapine's status is reviewed in the context of its initial discovery and unique clinical and (or) pharmacological profile, withdrawal and link with hematologic concerns, reintroduction with monitoring guidelines, prototype for atypicality, positioning in treatment algorithms, and current evidence regarding efficacy, effectiveness, and side effects. RESULTS: The hematologic monitoring implemented with clozapine's reintroduction here in North America has proven successful in preventing clozapine-related deaths secondary to agranulocytosis. While its other side effects are not without concern, present evidence does not link clozapine to increased mortality rates; indeed, it appears better than other antipsychotics in this regard. Moreover, its clinical superiority compared with all other antipsychotics has been confirmed both in efficacy and in effectiveness trials. CONCLUSIONS: Schizophrenia continues to represent a treatment challenge, with many people demonstrating suboptimal response and poor functional outcome. Clozapine is routinely positioned as a third-line treatment in schizophrenia, but in light of existing evidence this warrants re-examination. PMID- 20964950 TI - The burden of hospitalizations and emergency department visits with hereditary angioedema and angioedema in the United States, 2007. AB - Hereditary angioedema (HAE) is a rare inherited disorder of complement factor C1 inhibitor. HAE is frequently confused with angioedema (AE), and little is known about emergency department (ED) or hospital utilization by patients with attacks in the United States. We examined hospitalizations and ED utilization for HAE and AE in two large nationally representative databases. We evaluated annual rate and resource use of HAE (International Classification of Diseases, Version 9, Clinical Modification [ICD-9-CM] code 277.6) and AE (ICD-9-CM code 995.1) hospitalizations within Nationwide Inpatient Sample (NIS), part of the Agency of Healthcare Research and Quality's Healthcare Costs and Utilization Project (AHRQ HCUP), for 2007. We also used AHRQ-HCUP's 2007 Nationwide Emergency Department Sample (NEDS) to study annual rates of ED visits and subsequent hospitalizations with these conditions. There were 1691 hospitalizations with HAE and 22,572 with AE (4.25 HAE and 57.08 AE cases/100,000 hospitalizations). HAE was the principal diagnosis (PD) in 46.0% and AE in 62.5%. In aggregate, HAE and AE PD hospitalizations accrued 35,000 hospital days and hospital costs of $63 million. There were 2282 ED visits with HAE and 112,105 ED visits with AE (1.87 HAE and 91.64 AE cases/100,000 ED visits). HAE occurred as a PD in 51.2% and AE occurred as a PD in 80.0%. Forty-five percent of HAE patients and 18.3% of AE patients required hospitalization. HAE and AE ED use and hospitalization burden are substantial. Because diagnostic uncertainty is likely, HAE-related proportion of patients and resource use are probably underestimated. Clinical validation of current case definition would be useful, because administrative data may present an attractive source for investigating these populations. PMID- 20964952 TI - Structural MRI correlates for vulnerability and resilience to major depressive disorder. AB - BACKGROUND: In major depressive disorder (MDD), it is unclear to what extent structural brain changes are associated with depressive episodes or represent part of the mechanism by which the risk for illness is mediated. The aim of this study was to investigate whether structural abnormalities are related to risk for the development of MDD. METHODS: We compared healthy controls with a positive family history for MDD (HC-FHP), healthy controls with no family history of any psychiatric disease (HC-FHN) and patients with MDD. Groups were age- and sex matched. We analyzed data from high-resolution magnetic resonance imaging using voxel-based morphometry. We performed small volume corrections for our regions of interest (hippocampus, dorsolateral [DLPFC] and dorsomedial prefrontal cortex [DMPFC], anterior cingulate cortex [ACC] and basal ganglia) using a family-wise error correction (p < 0.05) to control for multiple comparisons. RESULTS: There were 30 participants in the HC-FHP group, 64 in the HC-FHN group and 33 patients with MDD. The HC-FHP group had smaller right hippocampal and DLPFC grey matter volumes compared with the HC-FHN group, and even smaller right hippocampal volumes compared with patients with MDD. In addition, the HC-FHP group exhibited smaller white matter volumes in the DLPFC and left putamen but also greater volumes in 2 areas of the DMPFC compared with the HC-FHN group. Patients with MDD exhibited smaller volumes in the ACC, DMPFC, DLPFC and the basal ganglia compared with healthy controls. LIMITATIONS: The retrospective identification of family history might result in a bias toward unidentified participants in the control group at risk for MDD, diminishing the effect size. CONCLUSION: Volume reductions in the hippocampus and DLPFC might be associated with a greater risk for MDD. The HC-FHP group had smaller hippocampal volumes compared with patients with MDD, which is suggestive for neuroplastic effects of treatment. The HC-FHP group had not yet experienced a depressive episode and therefore might have been resilient and might have had some protective strategies. Whether resilience is associated with the larger white matter volumes in the DMPFC (e.g., owing to compensatory, neuroplastic remodelling mechanisms) needs to be confirmed in future studies. PMID- 20964953 TI - Pervasive microstructural abnormalities in autism: a DTI study. AB - BACKGROUND: Recent studies have reported abnormal functional connectivity patterns in the brains of people with autism that may be accompanied by decreases in white matter integrity. Since autism is a developmental disorder, we aim to investigate the nature and location of decreases in white and grey matter integrity in an adolescent sample while accounting for age. METHODS: We used structural (T1) imaging to study brain volumetrics and diffusion tensor imaging (DTI) to investigate white and grey matter integrity in people with autism. We obtained magnetic resonance images for adolescents aged 12-18 years with high functioning autism and from matched controls. Fractional anisotropy and mean diffusivity, as well as grey and white matter volumetrics were analyzed. RESULTS: There were 17 participants with autism and 25 matched controls included in this study. Participants with autism had lower fractional anisotropy in the left and right superior and inferior longitudinal fasciculus, but this effect was not significant after adjusting for age and intelligence quotient (IQ). The kurtosis of the white matter fractional anisotropy probability distribution was higher in this participant group, with and without adjustment for age and IQ. Most notably, however, the mean diffusivity levels were markedly increased in the autism group throughout the brain, and the mean diffusivity probability distributions of both grey and white matter were shifted toward a higher value, particularly with age and IQ adjustment. No volumetric differences in grey and white matter were found. LIMITATIONS: We corrected for age and IQ using a linear model. The study was also limited by its sample size, investigated age range and cross-sectional design. CONCLUSION: The findings suggest that autism is characterized by a generalized reduction of white matter integrity that is associated with an increase of interstitial space. The generalized manifestation of the white matter abnormalities provides an important new perspective on autism as a connectivity disorder. PMID- 20964954 TI - Effects of trauma-related cues on pain processing in posttraumatic stress disorder: an fMRI investigation. AB - BACKGROUND: Imaging studies of pain processing in primary psychiatric disorders are just emerging. This study explored the neural correlates of stress-induced analgesia in individuals with posttraumatic stress disorder (PTSD). It combined functional magnetic resonance imaging (fMRI) and the traumatic script-driven imagery symptom provocation paradigm to examine the effects of trauma-related cues on pain perception in individuals with PTSD. METHODS: The study included 17 patients with PTSD and 26 healthy, trauma-exposed controls. Participants received warm (nonpainful) or hot (painful) thermal stimuli after listening to a neutral or a traumatic script while they were undergoing an fMRI scan at a 4.0 T field strength. RESULTS: Between-group analyses revealed that after exposure to the traumatic scripts, the blood oxygen level-dependent (BOLD) signal during pain perception was greater in the PTSD group than the control group in the head of the caudate. In the PTSD group, strong positive correlations resulted between BOLD signal and symptom severity in a number of brain regions previously implicated in stress-induced analgesia, such as the thalamus and the head of the caudate nucleus. Trait dissociation as measured by the Dissociative Experiences Scale correlated negatively with the right amygdala and the left putamen. LIMITATIONS: This study included heterogeneous traumatic experiences, a different proportion of military trauma in the PTSD versus the control group and medicated patients with PTSD. CONCLUSION: These data indicate that in patients with PTSD trauma recall will lead in a state-dependent manner to greater activation in brain regions implicated in stress-induced analgesia. Correlational analyses lend support to cortical hyperinhibition of the amygdala as a function of dissociation. PMID- 20964955 TI - Default mode alterations in posttraumatic stress disorder related to early-life trauma: a developmental perspective. PMID- 20964956 TI - ApoE and cholesterol in schizophrenia and bipolar disorder: comparison of grey and white matter and relation with APOE genotype. AB - BACKGROUND: Apolipoprotein E (apoE) and cholesterol play a critical role in synapse and myelin maintenance and integrity and are thus appealing candidates in the pathogenesis of schizophrenia and bipolar disorder. To explore the role of these 2 molecules, we quantified cholesterol and apoE levels in prefrontal grey and white matter in patients with schizophrenia, bipolar disorder and healthy controls. Furthermore, we investigated the relations between apoE and cholesterol levels and the APOE genotype. METHODS: We obtained dorsolateral prefrontal grey and white matter from the Stanley Medical Research Institute Brain Collection (schizophrenia n = 35, bipolar disorder n = 35 and controls n = 35). Cholesterol levels were quantified using high-pressure liquid chromatography, whereas apoE was measured by enzyme-linked immunosorbent assay. RESULTS: We found no significant differences in cholesterol or apoE levels among the groups. ApoE levels were higher in grey matter than in white matter in all groups; conversely, levels of cholesterol were higher in white matter than in grey matter. We observed a significant inverse correlation between apoE and cholesterol levels in both grey and white matter. Furthermore, in grey matter, apoE levels were significantly higher in APOE epsilon2 carriers compared with APOE epsilon3 or APOE epsilon4 carriers, with cholesterol levels following the opposite trend. LIMITATIONS: LIMITATIONS of our study include our inability to control for potential confounding variables and the small numbers of APOE epsilon2 and epsilon4 carriers in each group. CONCLUSION: Although large amounts of cholesterol are present in white matter, apoE expression is limited. The APOE genotype may play a role in the regulation of both cholesterol and apoE levels in grey matter. The impact of APOE polymorphisms on lipid homeostasis in people with psychiatric disorders warrants further investigation. PMID- 20964957 TI - Abnormal small-world architecture of top-down control networks in obsessive compulsive disorder. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder that is characterized by recurrent intrusive thoughts, ideas or images and repetitive ritualistic behaviours. Although focal structural and functional abnormalities in specific brain regions have been widely studied in populations with OCD, changes in the functional relations among them remain poorly understood. This study examined OCD-related alterations in functional connectivity patterns in the brain's top-down control network. METHODS: We applied resting-state functional magnetic resonance imaging to investigate the correlation patterns of intrinsic or spontaneous blood oxygen level-dependent signal fluctuations in 18 patients with OCD and 16 healthy controls. The brain control networks were first constructed by thresholding temporal correlation matrices of 39 brain regions associated with top-down control and then analyzed using graph theory-based approaches. RESULTS: Compared with healthy controls, the patients with OCD showed decreased functional connectivity in the posterior temporal regions and increased connectivity in various control regions such as the cingulate, precuneus, thalamus and cerebellum. Furthermore, the brain's control networks in the healthy controls showed small-world architecture (high clustering coefficients and short path lengths), suggesting an optimal balance between modularized and distributed information processing. In contrast, the patients with OCD showed significantly higher local clustering, implying abnormal functional organization in the control network. Further analysis revealed that the changes in network properties occurred in regions of increased functional connectivity strength in patients with OCD. LIMITATIONS: The patient group in the present study was heterogeneous in terms of symptom clusters, and most of the patients with OCD were medicated. CONCLUSION: Our preliminary results suggest that the organizational patterns of intrinsic brain activity in the control networks are altered in patients with OCD and thus provide empirical evidence for aberrant functional connectivity in the large-scale brain systems in people with this disorder. PMID- 20964958 TI - Is there a role for estrogen in treating depression during menopause? PMID- 20964959 TI - Epigenetics in mental illness: hope or hype? PMID- 20964960 TI - Perceived early-life maternal care and the cortisol response to repeated psychosocial stress. AB - BACKGROUND: In the past decade, a body of animal and human research has revealed a profound influence of early-life experiences, ranging from variations in parenting behaviour to severe adversity, on hypothalamic-pituitary-adrenal axis regulation in adulthood. In our own previous studies, we have shown how variations in early-life parental care influence the development of the hippocampus and modify the cortisol awakening response. METHODS: In the present study, we investigated the influence of early-life maternal care on cortisol, heart rate and subjective psychological responses to the repeated administration of a psychosocial laboratory stressor in a population of 63 healthy young adults. Low, medium and high early-life maternal care groups were identified using the Parental Bonding Instrument. RESULTS: Controlling for the effect of sex, we found an inverted u-shaped relation between increasing levels of maternal care and cortisol stress responsivity. Specifically, overall and stress-induced cortisol levels went from below normal in the low maternal care, to normal in the medium care, back to below normal in the high maternal care groups. We found no group differences with respect to heart rate and subjective psychological stress measures. Whereas low and high maternal care groups exhibited similarly low endocrine stress responses, their psychological profiles were opposed with increased levels of depression and anxiety and decreased self-esteem in the low care group. LIMITATIONS: Sex was unequally distributed among maternal care groups, whereby the number of men with low maternal care was too small to allow introducing sex as a second between-group variable. CONCLUSION: We discuss the potential significance of this dissociation between endocrine and psychological parameters with respect to stress vulnerability and resistance for each maternal care group. PMID- 20964961 TI - Neural responses to emotional and neutral facial expressions in chronically violent men. AB - BACKGROUND: Abnormal neural responses to others' emotions, particularly cues of threat and distress, have been implicated in the development of chronic violence. We examined neural responses to several emotional cues within a prospectively identified group of chronically violent men. We also explored the association between neural responses to social emotions and psychopathic features. METHODS: We compared neural responses to happy, sad, angry, fearful and neutral faces between chronically violent (n = 22) and nonviolent (n = 20) men using functional magnetic resonance imaging (fMRI). Participants were prospectively identified from a longitudinal study based on information collected from age 7 to 27 years. We assessed psychopathic features using a self-report measure administered in adulthood. RESULTS: The chronically violent men exhibited significantly reduced neural responses in the dorsomedial prefrontal cortex to all faces, regardless of the emotional content, compared with nonviolent men. We also observed a hyperactive amygdala response to neutral faces in chronically violent men, but only within the context of viewing happy faces. Moreover, they exhibited a greater dorsomedial prefrontal cortex response to mildly fearful faces than nonviolent men. These abnormalities were not associated with psychopathic features in chronically violent men. LIMITATIONS: It remains unclear whether the observed neural abnormalities preceded or are a consequence of persistent violence, and these results may not generalize to chronically violent women. CONCLUSION: Chronically violent men exhibit a reduced neural response to facial cues regardless of emotional content. It appears that chronically violent men may view emotionally ambiguous facial cues as potentially threatening and implicitly re-interpret subtle cues of fear in others so they no longer elicit a negative response. PMID- 20964962 TI - Interphalangeal joint lengthening arthrodesis for the treatment of the flail toe. AB - BACKGROUND: Flail toe is a bothersome complication following PIP resection arthroplasty, usually as a result of excessive bone resection. Patients complain of toe instability and catching on socks or shoes. We describe a PIP joint lengthening arthrodesis using structural bone graft for treatment of this condition. MATERIALS AND METHODS: The results of 13 toe lengthening arthrodesis procedures in 13 patients were reviewed. Twelve patients were available for final followup, ranging from 6 to 70 (average, 31) months. RESULTS: Relief of instability symptoms occurred in all of the patients. The union rate was 75% (9/12 toes). Infection occurred in four patients, all treated successfully with oral antibiotics and pin removal when necessary. Two patients presented with ischemic complications in the tip of the toe which resolved spontaneously with good final results. Eleven of 12 patients were satisfied with the procedure and stated that they would do the surgery again. CONCLUSION: We believe toe lengthening arthrodesis is a good salvage operation for a flail toe following PIP resection arthroplasty. PMID- 20964963 TI - Pedobarographic analysis and quality of life after Lisfranc fracture dislocation. AB - BACKGROUND: Few studies on tarsometatarsal fracture dislocations report on plantar pressure analysis and quality of life. The primary aim of this study was to determine the added value of plantar pressure analysis. The secondary aim was to determine quality of life and functional outcome. MATERIALS AND METHODS: With a median followup of 76 months, 26 patients with an isolated Lisfranc injury participated. The Short Form 36 (SF-36) was used to determine the health related quality of life. Functional outcome was assessed with the American Orthopaedic Foot Ankle Society (AOFAS) midfoot score and a Visual Analog Scale (VAS). A Wilcoxon Signed Rank test was used to assess whether plantar pressure and foot position variables differed between the injured and uninjured foot. Correlations between outcome data were identified using Spearman Rank Correlation. RESULTS: With respect to the plantar pressure analysis, a reduced contact time of the forefoot was found for the injured foot compared with the contralateral side (p = 0.045). The injured side showed reduced contact surface of the forefoot (p = 0.048) and an increased contact surface for the midfoot (p = 0.019). The latter was paralleled by higher maximum pressures at the midfoot (p = 0.016). Patients reported a median score of 101 for the SF-36, 72 for the AOFAS midfoot score, and 7 for the VAS. CONCLUSION: Plantar pressure measurements showed an adjusted walking pattern. Despite a fair outcome score, the quality for life of patients following a Lisfranc fracture dislocation returned to normal compared with normative data for the general population. PMID- 20964964 TI - Magnetic resonance imaging in plantar heel pain. AB - BACKGROUND: Magnetic Resonance Imaging (MRI) is generally only indicated in patients with plantar heel pain who have atypical symptoms or who do not improve with appropriate management. MATERIALS AND METHODS: This study retrospectively reviewed the MRI findings of 112 patients with heel pain divided into two groups consisting of 50 patients with persistent pain despite appropriate treatment and 62 patients with atypical heel pain. RESULTS: Of the 50 patients with persistent heel pain, 38 (76%) of MRIs confirmed the diagnosis of plantar fasciitis. Of the 62 patients who had presented with atypical symptoms or signs, 21 patients had presented with night pain and the remaining 41 had presented with acute pain, tenderness of the lateral or medial aspect of the heel, significant swelling, neurological features or pain posterior to the insertion of the plantar fascia. Patients with night pain were shown to have plantar fasciitis associated with calcaneal marrow edema in 15 (71.4%) cases (p < 0.05). One patient presenting with night pain was found to have a plantar arterio-venous malformation. Acute pain was associated with plantar fascia tears in 4 out of 9 (p < 0.05). CONCLUSION: MRI may provide reassurance in cases of persistent heel pain but rarely changes the management. In cases of atypical heel pain, MRI may demonstrate other pathology such as plantar fascia tearing, calcaneal edema or arteriovenous malformation. PMID- 20964965 TI - Clinical relevance of hindfoot alignment view in total ankle replacement. AB - BACKGROUND: Alignment is instrumental for success and long-term survival of Total Ankle Replacement (TAR). At this point in TAR, only coronal alignment in the region of the tibiotalar joint or above has been assessed because inframalleolar deformity is difficult to visualize radiographically. The Hindfoot Alignment View (HAV) allows visualization of the hindfoot position relative to the tibia. The purpose of this study was to evaluate the clinical relevance of this view in assessing patients with TAR. MATERIALS AND METHODS: Twenty-eight consecutive patients with a Hintegra-TAR with an average followup of 4.1 +/- 1.5 years were followed with (1) AOFAS and SF-36 scores, (2) visual judgment of the hindfoot position, (3) HAV and AP/lateral radiographs, (4) dynamic pedobarography (Novel emed m/E, Munich, Germany). RESULTS: The HAV position correlated well with different load parameters on heel strike (r = 0.44 to 0.62) but not with the varus-valgus load pattern of the rest of the foot. Visual judgment and TAR joint line did not correlate to radiographic hindfoot alignment or to pedobarographic load distribution. The hindfoot alignment measured by the HAV correlated significantly to the Physical Function and Role Physical of SF-36. No correlation was found to other SF36-qualities or the AOFAS-score. CONCLUSION: Inframalleolar alignment, as assessed by the HAV, influenced the dynamic pedobarographic load pattern and clinical outcome. Visual judgment and TAR joint line were not accurate enough to estimate the hindfoot alignment or dynamic load pattern. We believe adjusting the hindfoot correctly with HAV might improve long-term outcome and survival of TAR. PMID- 20964966 TI - Location of the sural nerve during posterolateral approach to the ankle. AB - BACKGROUND: There is no consensus regarding the most appropriate surgical approach for the treatment of posterior malleolar fractures. The posterolateral approach facilitates more accurate reduction, but the sural nerve is potentially at risk during the approach. The location of this nerve in relation to this approach has not been clearly described in the literature. MATERIALS AND METHODS: We performed cadaveric dissection of 12 legs using the posterolateral approach, a 10-cm incision midway between the tendo-achilles and the lateral malleolus, commencing at the tip of the lateral malleolus and extending proximally. The horizontal distances of the sural nerve and the short saphenous vein to the incision were measured at the proximal and distal ends and at the mid-point of the incision (positive towards the Achilles and negative towards the lateral malleolus). RESULTS: In ten of the 12 cases, the sural nerve and short saphenous vein crossed the incision at an average of 56.7 mm and 61.0 mm along the incision, respectively. The median distances from the proximal end of the wound were -9.9 mm and -12.7 mm, 0.9 mm and -1.7 mm from the midpoint, and 6.3 mm and 7.7 mm from the distal end of the incision, respectively. CONCLUSION: The sural nerve and saphenous vein are at risk of iatrogenic injury over the whole length of the incision for the posterolateral approach for posterior malleolar fractures. CLINICAL RELEVANCE: When performing a posterolateral approach to the ankle, particular care should be taken at the midpoint of the incision. PMID- 20964967 TI - Reliability of the Maestro radiographic measuring tool. AB - INTRODUCTION: Maestro et al. presented a detailed preoperative measuring and classification technique for the forefoot. The purpose of this paper was to determine if the PACS system will allow the Maestro measuring technique and classification system to be reliable and precise. MATERIALS AND METHODS: This radiographic study was conducted on 73 subjects (36 females, 37 males, age 30.4 +/- 9.9) who had given informed consent. The geometrical progression was measured for each foot of each subject by the two observers according to the measuring methodology of Maestro. The intraclass correlation coefficient (ICC), and the 95% lower confidence limit (95% LCL) were calculated for the geometrical progression variables of the lesser metatarsals. Once the feet were classified by each observer, the accordance in classification of the feet was analyzed between the two observers. RESULTS: The radiographic measuring technique of Maestro was a reliable method for analyzing the mathematical progression of the lesser metatarsals through the use of the PACS system. A 92.6% concordance in the classification of the radiological forefoot morphotypes was found between the two observers. CONCLUSION: We found Maestro et al.'s measuring technique and classification system precise and reproducible using PACS digital radiographs. It is hoped that utilization of this technique will lead to better forefoot outcomes and patient satisfaction. PMID- 20964968 TI - Comparison of standard screw fixation versus suture button fixation in Lisfranc ligament injuries. AB - BACKGROUND: The standard operative treatment for Lisfranc injuries is to openly reduce them and use screw fixation. Due to the current trend of applying a more physiologic fixation and decreasing the need for screw removal, a recent interest has developed in suture-button fixation. The purpose of this study was to compare the suture button technique for Lisfranc fracture fixation to the traditional interfragmentary screw fixation. MATERIALS AND METHODS: Eight fresh-frozen matched paired cadavers with an average age of 50 (range, 37 to 55) years were tested. For each specimen, the distance between marked points on the base of the first metatarsal and second metatarsal was measured. The distance was then re measured when a 600 Newton load was applied to the specimen with an intact ligament, a sectioned Lisfranc ligament, and after the fixation method. RESULTS: Fixed loaded measurement displacements were significantly (p < 0.00) smaller with screw fixation compared to their respective intact loaded measurements. Fixed loaded measurement displacements were significantly (p = 0.001) smaller than the fixed unloaded measurements in the screw group when compared to the suture button group. CONCLUSION: In the current cadaveric model, standard interfragmentary screw fixation with a 4.0 cannulated screw had less displacement than the Arthrex Mini Tightrope in isolated Lisfranc ligament injuries. Therefore, we conclude that until more comparative studies are performed with more accurate measuring devices, open reduction and screw fixation of these injuries should continue to be the accepted treatment. PMID- 20964969 TI - Arthroscopic-controlled navigation for retrograde drilling of osteochondral lesions of the talus. AB - BACKGROUND: Retrograde drilling of symptomatic osteochondral lesions (OCL) is usually controlled by fluoroscopy. Due to the limited visualization of the OCLs in the acquired images and the narrow access to the talar dome, this approach can be demanding. Several navigation procedures have been reported (2D- or 3D- fluoroscopy or intraoperative CT-based) to increase the accuracy and reduce the radiation exposure. We developed a new arthroscopic-controlled navigation procedure which is free of radiation exposure and free of a reference base rigidly fixed to the bone. We hypothesized that this procedure (Fluoro-Free) is at least as precise as the standard 2D-Fluoro navigation (2D-Fluoro). Furthermore, our first clinical experiences are described and discussed. MATERIAL AND METHODS: Sixteen drillings per group (standard 2D-Fluoro vs. Fluoro-Free) were performed in artificial sawbones. Times for the different steps of each drilling procedure were recorded and the precision evaluated by measuring the deviation and depth of drilling. RESULTS: The accuracy of the Fluoro-Free navigation was as precise as the standard 2D-Fluoro based navigation (axis deviation of drill tip to the target point: 1.07 +/- 0.11 versus 1.14 +/- 0.15 mm). Due to the simplified workflow without radiation exposure and fixation of a reference base, the Fluoro-Free procedure was significantly faster (mean procedure time per drilling: 23.7 +/- 11.6 versus 165 +/- 9 seconds) and easy to use. Its clinical usefulness was demonstrated during three retrograde drillings of a talar OCL in a 16-year-old patient. CONCLUSION: The Fluoro-Free navigation procedure is a simplified approach for retrograde drilling of OCL in the talus under arthroscopic control without radiation exposure and without the need for fixation of a dynamic reference base to the bone. PMID- 20964970 TI - Panoramic ultrasound to measure in vivo tendo Achilles strain. AB - BACKGROUND: The tendo Achilles (TA) is a tendon very susceptible to injury. Biomechanical methodologies for exploring tendon strain are limited, however, as they are typically performed in vitro or by indirectly measuring the displacement of reference markers. By using panoramic ultrasound, this study reports a novel approach to acquire direct, in vivo tendon extension data. MATERIALS AND METHODS: Sonographic scans were acquired between two in vivo landmarks following a consistent pathway along the long axis of the distal TA. Ten subjects were scanned with an unloaded tendon and then when resisting a range of loads. Tendon cross-sectional area was measured following coronal scans of the TA in three subjects, allowing for calculation and plotting of stress versus strain. Coefficients of variation were also calculated to measure the reliability and robustness of the protocol. RESULTS: Data from all ten subjects were found to fit with classic tendon force versus extension trend. The stress versus strain plot indicated that the wavy collagen fibers were fully straightened at 4% to 6% strain, which is comparable to results reported in other studies. The Young's modulus of 0.5 to 2.1 GPa also compared favorably to published data. CONCLUSION: Coefficients of variation indicated that the protocol was repeatable, although the technique for measuring cross-sectional area could be improved. CLINICAL RELEVANCE: As the reported data is comparable to previous invasive and in vitro studies, we believe sports medicine specialists and orthopaedic surgeons can utilize panoramic ultrasound to directly measure in vivo tendon strain. PMID- 20964971 TI - Von Willebrand disease in foot and ankle surgery. PMID- 20964972 TI - Limited open achilles tendon repair with modified ring forceps: technique tip. PMID- 20964973 TI - Medial approach to the fibular sesamoid. PMID- 20964974 TI - Mini locking plate as "medial buttress'' for oblique osteotomy for hallux valgus. PMID- 20964975 TI - Early range of motion after subcutaneous rupture of extensor hallux longus tendon repair: a case report. PMID- 20964976 TI - Pre- and postoperative gait analysis following conversion of tibiotalocalcaneal fusion to total ankle arthroplasty. PMID- 20964977 TI - Current concepts review: insertional achilles tendinopathy. PMID- 20964979 TI - The second definition of Sjogren's syndrome as an autoimmune disorder. PMID- 20964981 TI - The tear film and the optical quality of the eye. AB - The stability of the tear film plays an important role in the optical quality of the eye. Various methods have been developed to quantify the contribution of the tear film to optical quality, including the double-pass optical method, Hartmann Shack wavefront sensing, videokeratoscopy, retroillumination analysis, and interferometry. In addition to assessing the effect of tear film irregularities, these methods can aid in the diagnosis of dry-eye related conditions and the monitoring of therapy. This review describes the methodologies used to assess the relationship between the tear film and optical quality of the eye and summarizes the most important findings obtained with these methods with regard to the healthy human eye, the dry eye, and the effect of artificial tear instillation. PMID- 20964980 TI - Fuchs endothelial corneal dystrophy. AB - Fuchs endothelial corneal dystrophy (FECD) is characterized by progressive loss of corneal endothelial cells, thickening of Descement's membrane and deposition of extracellular matrix in the form of guttae. When the number of endothelial cells becomes critically low, the cornea swells and causes loss of vision. The clinical course of FECD usually spans 10-20 years. Corneal transplantation is currently the only modality used to restore vision. Over the last several decades genetic studies have detected several genes, as well as areas of chromosomal loci associated with the disease. Proteomic studies have given rise to several hypotheses regarding the pathogenesis of FECD. This review expands upon the recent findings from proteomic and genetic studies and builds upon recent advances in understanding the causes of this common corneal disorder. PMID- 20964982 TI - The ophthalmologist's role in the management of acute Stevens-Johnson syndrome and toxic epidermal necrolysis. AB - Stevens-Johnson syndrome (SJS) and its more severe variant, toxic epidermal necrolysis (TEN), are relatively rare but have high mortality rates. Survivors are frequently afflicted with severe blinding ocular surface diseases. Recent literature in the areas of ophthalmology and dermatology illustrate that the ophthalmologist's role should no longer be considered secondary in the acute management of SJS/TEN. Accurately differentiating SJS or TEN from erythema multiforme majus (EMM) at the onset of the disease is important, because the management approach to these disease entities differs. Systemic cyclosporine and intravenous immunoglobulin have shown some potential as treatments for SJS/TEN, but their efficacies remain controversial. Amniotic membrane transplantation and intravenous corticosteroid pulse therapy at the acute stage have shown promise for preventing late sight-threatening cicatricial complications. An improved staging system for the ocular surface involvement of acute SJS/TEN, as well as better understanding of the underlying destructive pathogenic mechanism, should further improve our ability to predict ocular involvement and develop new therapeutics to abort destructive processes at the acute stage. PMID- 20964983 TI - The accelerated drug approval. PMID- 20964984 TI - James P. McCulley, MD, FACS, FRCOPHTH (UK). Interview by The Ocular Surface. PMID- 20964985 TI - [Advances in the prevention of cerebral ischaemia due to atrial fibrillation]. AB - INTRODUCTION: Stroke and atrial fibrillation (AF) are a real vascular epidemic, and the consequences are disastrous. The most common complication of AF is stroke. BACKGROUND: The correct aetiological diagnosis of stroke is essential for adequate prevention. The percentage of cryptogenic ischaemic strokes is far too high and the detection of AF needs to be improved. Cardio-embolic cerebral ischaemia due to AF is preventable, however due to medical inertia, the lack of compliance by the patient, and the problems with oral vitamin K antagonist anticoagulants, means that many patients with AF are at risk of suffering from a stroke. CONCLUSIONS: The significant recent advances with drugs such as dronedarone and dabigatran, provide real hope for an improvement in its prevention, and for this reason neurologists must know about them. PMID- 20964986 TI - [Differential diagnosis of encephalitis due to anti-NMDA receptor antibodies]. AB - INTRODUCTION: Anti-NMDA receptor (NMDAR) encephalitis usually develops as a multistage syndrome with a broad differential diagnosis. PATIENTS: We report 2 patients with anti-NMDAR encephalitis and a clinical picture typical of this disorder but whose initial evaluation suggested other aetiologies. DISCUSSION: The frequent development of this disorder in young individuals presenting with psychiatric manifestations often suggests other diagnostic possibilities, most commonly viral encephalitis, psychiatric disorders, and neuroleptic malignant syndrome. In addition, several less clearly defined syndromes or descriptively reported disorders in adult and paediatric patients were likely cases of anti NMDAR encephalitis. CONCLUSIONS: Anti-NMDAR encephalitis should be considered in young individuals with subacute presentation of psychiatric symptoms, abnormal movements, and autonomic dysfunction. The clinical and immunological characterization of this disorder has lead to the identification of new antibodies that affect memory, learning, behaviour and psychosis. PMID- 20964987 TI - [(123)I-MIBG myocardial scintigraphy in the diagnosis of Lewy body dementia]. AB - INTRODUCTION: Lewy body dementia (LBD) is the second most common cause of neurodegenerative dementia after Alzheimer's disease (AD). A cardiac post ganglionic sympathetic denervation has been described in this condition which can be quantified by MIBG (metaiodobenzylguanidine) myocardial scintigraphy. The aim of our work was to retrospectively evaluate cardiac MIBG uptake (expressed as the heart-to-mediastinum ratio at 4h (HMR) in patients with suspected LBD, and to examine its relationship with clinical and para-clinical data. MATERIAL AND METHODS: A total of 77 patients with clinical suspicion of LBD evaluated at our centre between September 2005 and June 2008 to whom a MIBG myocardial scintigraphy has been performed were retrospectively reviewed. International Consensus Criteria of LBD were applied to divide the sample into probable LBD, possible LBD and non-LBD. HMR values and their relationships with clinical and neuropsychological data were analysed. A subgroup of patients had FP-CIT (fluoropropyl-carbomethoxy-3beta-4-iodophenyltropane) SPECT as a part of the evaluation. RESULTS: Mean HMR values were significantly lower in probable LBD group than in possible LBD and non-LBD groups. Low HMR values were associated only with reduced FP-CIT uptake in the striatum, but not with any clinical or neuropsychological item. CONCLUSIONS: Low MIBG myocardial scintigraphy uptake is a robust measure in LBD, and it is not largely affected by medical conditions, or by the stage of the disease. In LBD reduced MIBG myocardial uptake is associated with nigrostriatal degeneration. PMID- 20964988 TI - [Vascular risk factors and cognitive performance in patients 50 to 65 years-old]. AB - INTRODUCTION: Vascular risk factors (VRF) have been related to cognitive deficits and an increased risk of dementia. Cognitive impairment is considered to be one of the earliest manifestations of cerebrovascular disease. In Spain there is a high prevalence of VRF, but also one of the lowest incidences of cerebrovascular disease in Europe. This is the first study that investigates the relationship between VRF and cognition in a Spanish sample. METHODS: A total of 90 people aged between 50-65 years with a low-to-moderate cardiovascular risk underwent a neuropsychological evaluation. None of them had a history of cardiovascular disease. The battery included tests assessing executive, attentional, mnesic, visuospatial and motor-speed/coordination functions. We used correlation and inter-groups comparison to relate VRF to multiple cognitive domains0120. RESULTS: Higher stroke risk was significantly related to a lowered profile in visuo constructive functions and motor-speed/coordination. Moreover, the group with moderate cardiovascular risk showed a lower performance in visuoconstructive functions compared to the low-risk group. After statistical adjustment for age, sex and years of scholarship VRF were only related to motor-speed/coordination. CONCLUSIONS: In healthy, middle-aged adults, VRF are related with impairment in two cognitive domains. This effect is slight and tends to appear in people with moderate cardiovascular risk. PMID- 20964989 TI - [Brain atrophy in clinically isolated syndrome]. AB - INTRODUCTION: Previous reports have shown that brain atrophy appears early in the course of multiple sclerosis (MS). The aim of the present study was to evaluate whether brain atrophy already exists in clinically isolated syndrome (CIS) by comparing with a control sample. METHODS: Patients with CIS were included prospectively from June 2008 to June 2009. A control group of healthy persons, matched by age and gender with CIS, was also included during the same period of time. An automated analysis tool, SIENAX, was used to obtain total brain volume (TBV), gray matter volume (GMV) and white matter volume (WMV). Mann-Whitney U test was used to analyze the data. RESULTS: Twenty CIS patients and 30 healthy controls were included (8 vs. 17 females, p=0.11). Mean age for CIS was 35 +/- 6 years vs. 34.4+/-5 in controls (p=0.61). Mean EDSS in CIS was 1.1 +/- 0.5. Eighteen patients with CIS (90%) had abnormal baseline MRI. The TBV in CIS was 1.6.l +/- 0.22.l * 106 vs.1.65 +/- 0.15 * 106 in controls (p=0.005), the GMV in CIS was 0.58 +/- 0.05 * 106 vs. 0.67 +/- 0.03 * 106 in controls (p <= 0.001) and the WMV in CIS was 1 +/- 0.1 * 106 vs. 1.12 +/- 0.02 * 106 in controls (p=0.03). CONCLUSIONS: This is the first study dealing with brain atrophy in a CIS sample from Latin America in which brain atrophy, mainly grey matter atrophy, was shown in early stages of the disease compared with healthy individuals. PMID- 20964990 TI - [Global adherence project to disease-modifying therapies in patients with relapsing multiple sclerosis: 2-year interim results]. AB - BACKGROUND: In this article we report adherence data from the first 2 years in a subset of patients from the Global Adherence Project (GAP; n=2,648) in Spain. METHODS: A questionnaire assessing adherence to Disease-modifying therapies (DMTs), was distributed annually to patients and their treating neurologists. Non adherence was defined as missing a DMT injection or changing a dose in the four weeks prior to completing the survey. Patients signed informed consent and Ethics Committees approved annual follow-ups, visit 1 (V1) and visit 2 (V2) in 15 out of 18 centres in Spain. RESULTS: A total of 254 patients were enrolled in Spain. Patients had a mean age of 37.9 years and 70.4% were female, and had been on their treatment for a median time of 28 months, and the overall adherence rate was 85.4%. Patients taking intramuscular interferon beta (IFNB)-1a (Avonex(r)) were significantly more adherent (94.6%) compared with patients taking subcutaneous (s.c.) IFNB-1a 22.g (Rebif(r)22) (79.1%; p=0.0064), s.c. IFNB-1a 44.g (Rebif(r)44) (79.6%; p=0.0064) and glatiramer acetate (GA) (82.7%; p=0.0184). At V1 (n=142), the overall adherence rate was 86.6% and patients on Avonex(r) were significantly more adherent than patients on Rebif(r)22 (93.9% versus 66.7%; p=0.0251). At V2 (n=131), the overall adherence rate was 82.4% (Avonex(r), 87.5%; Rebif(r)22, 80%; Rebif(r)44, 77.8%; Betaferon(r), 85.2%, and Copaxone(r), 80%) without significant differences. CONCLUSIONS: Adherence remained high over the first 2 years of the study. It was highest with Avonex(r), being significant on first assessment, after 40.5 months of therapy, on average compared with other DMTs and at year 1 compared with Rebif(r)22. PMID- 20964991 TI - [Bilingualism and the brain: myth and reality]. AB - INTRODUCTION: The description of bilingual aphasic patients goes back to the 19th century. Since then, the study of the relationship between bilingualism and the brain has questioned whether the neuroanatomical representation of two languages in the same brain is similar or different. The answer to this question has generated erroneous interpretations based on the results of the investigations carried out on this topic. DEVELOPMENT: The present paper will try to distinguish between myth and reality of the following statements: a) the neuroanatomical organization of language in bilinguals is different from that of monolinguals, and b) language is less lateralized in bilingual speakers. RESULTS: There is no reason to believe in the existence of qualitative differences in the cerebral organization of language between bilinguals and monolinguals. It is mostly likely that two languages are represented as different microanatomical subsystems in the same cerebral regions. CONCLUSIONS: The differences are quantitative rather than qualitative, that is, the degree of participation of the different neurofunctional mechanisms involved in the use of language, such as metalinguistic knowledge and implicit linguistic competence. PMID- 20964992 TI - [Temporal arteritis: treatment controversies]. AB - INTRODUCTION: Although giant cell or temporal arteritis represents 5-10% of ischaemic optic neuropathies and is the most common arteritis in people over 60 years old. Currently there is no established treatment with oral glucocorticoids available. BACKGROUND: Glucocorticoid (GC) is still the treatment of choice but has to be started without delay in order to prevent neurological or systemic complications. However, we can resort to intravenous treatment in cases where there is loss of sight or other neurological symptoms. In cases refractory to GC or in those in whom we wish to decrease the dose due to adverse effects, individualised treatment with methotrexate or TNF blockers could be indicated. There is insufficient evidence to recommend other treatments, such as azathioprine, dapsone, cyclosporine, cyclophosphamide or imitinib. In patients with vascular risk factors, anti-platelet therapy with ASA should be assessed. Surgical treatment should be considered in selected cases with symptoms due to arterial stenosis. CONCLUSIONS: The corticoids continue to be the treatment of choice in temporal arteritis, however, given the clinical variability of the disease and the special characteristics of this group of patients, usually elderly and with systemic diseases, we believe that individualised treatment with coherent therapeutic guidelines are essential. Currently there is not only treatment with oral glucocorticoids available, although in our patients we can choose to use intravenous mega-doses, anti-platelet treatment, resort to methotrexate or TNF inhibitors in refractory cases, or even consider surgical approaches. PMID- 20964993 TI - [Pharmacological Parkinsonism vs. dementia with Lewy bodies]. PMID- 20964994 TI - [Hemiconvulsion-hemiplegia-epilepsy syndrome. Follow up of a case to adulthood]. PMID- 20964995 TI - [Pseudo-subarachnoid haemorrhage. A need for clinical-radiological diagnostic criteria]. PMID- 20964996 TI - [Cell therapy in amyotrophic lateral sclerosis: science and controversy]. AB - Stem cell therapy is seen as a possible alternative for the treatment of different degenerative diseases, among which includes amyotrophic lateral sclerosis (ALS). Despite there being basic research works with this therapy in ALS, the mechanism of action of the implanted cells are still unclear. It is also unclear which type of cells to use (bone marrow, fat, dental pulp, etc.), or the most ideal administration route. Furthermore, clinical trials with mesenchymal stem cells are not very conclusive, therefore it has not been convincingly established as an alternative therapy in ALS or any other neurodegenerative disease. Despite the scientific evidence, several clinical trials have been conducted in the last few years that offer stem cell treatments for neurodegenerative diseases, giving rise to what is known as "cellular tourism". This phenomenon has set off alarms and reactions in the scientific community. The application of these therapies must be performed following the good clinical practice guidelines in research, evidence based methodology and international ethical and scientific recommendations. PMID- 20964997 TI - [Etiology and risk factors for a first episode of cerebral isquemia in young adults]. AB - INTRODUCTION: To determinate the etiology and risk factors for a first episode of cerebral ischemia in young adults at three hospitals of Lima and Callao-Peru. METHODS: Multicentric study carried out at three national hospitals in Lima. The sample included 30 patients with a first episode of stroke and 60 controls matched by age and sex 2:1 with the patients. Serum biochemistry studies, EKGs and echocardiograms were done. Etiologies were classified based on the classification of Baltimore-Washington Cooperative Young Stroke Study. RESULTS: The most frequent etiologies were cardiac embolism and atherosclerotic valvular heart disease, which were 30% of the cases (9 patients) each one. Hypertriglyceridemia (p=0.014), valvular heart disease (p=0.001) and hormonal contraception/replacement therapy (p=0.002) were independent risk factors for a first episode of cerebral ischemia in peruvian young adults. Motor deficiency was the most frequent presentation (50.0%). Intracraneal hypertension and urinary tract infection were the most frequent complications during acute ischemia and mortality was raised up to 10%. CONCLUSIONS: The hypertriglyceridemia, valvular heart disease and the use of oral contraceptives are independent risk factors for a first episode of ischemia in young adults from three hospitals of Lima and Callao. The most frequent etiologies were cardiac embolism and atheroesclerotic valvular heart disease. PMID- 20964998 TI - [Convulsive status epilepticus: clinico-epidemiologic characteristics and risk factors in Peru]. AB - INTRODUCTION: Convulsive status epilepticus constitutes a medical emergency that requires a fast and aggressive management with the objective to prevent neuronal damage and systemic complications. The objective is to determine clinico epidemiologic characteristics and risk factors associated with convulsive status epilepticus in adults attended in a National Hospital from Lima-Peru in a period of four years. METHODS: Case-control study. Cases were constituted by patients admitted for convulsive status epilepticus in the Adult Emergency Service of National Hospital Dos de Mayo between January 2003 and December 2007. Controls were patients with diagnoses of epilepsy that received treatment in outpatient service of neurology, couplet by age and sex with the group of cases. Medical histories were reviewed and patients were interviewed obtaining clinical, epidemiologic and possible risk factors to convulsive status epilepticus that were registered in an instrument of data recorded. RESULTS: 41 cases of convulsive status epilepticus were presented. 68.3% were male, 28.6% had age between 20 and 29 years old and 15.5% resided in endemic areas of neurocysticercosis. The more frequent aetiologies were remote symptomatic secondary crisis to cranio encephalic trauma and neurocysticercosis and idiopathic; 26.8% showed some intercurrent infection; while, mortality was of 7.3%. Factors associated with a convulsive status epilepticus were the abrupt interruption or suspension of drugs used for the control of convulsions (p=0.038), chronic intake of alcohol (p=0.030) and irregular antiepileptic treatment (p=0.006). CONCLUSIONS: Aetiologies more frequent in the hospital studied from Lima-Peru are remote symptomatic secondary crisis to cranio encephalic trauma, neurocysticercosis and idiopathic. The irregular antiepilepticus treatment constitutes a risk factor to convulsive status epilepticus. PMID- 20964999 TI - [Carotid revascularisation using angioplasty and stent in 134 consecutive cases in a reference hospital: a risky technique?]. AB - INTRODUCTION: Carotid revascularisation (CR) using angioplasty and stent (ASC) is an effective procedure in the prevention of ischaemic stroke, but with a controversial morbidity and mortality in the different studies conducted in this field. METHODS: The results of the ASCs performed in the Virgen de la Arrixaca University Hospital (Murcia) between January 2006 and April 2009 were analysed (epidemiology, indication, grade of residual stenosis and procedure complications). All patients subjected to ASC were pre-selected and followed up by neurologists, and they followed a strict medical protocol for performing the procedure. All ASCs were performed by a team consisting of two surgeons, an anaesthetist and a nurse. RESULTS: A total of 134 ASC were performed. The mean age of our patients was 72.7 years, with the large majority (75%) being male. The most prevalent diseases were, high blood pressure (81%), smoking (66.4%), and diabetes (38.1%). The most common indications for CR were symptomatic carotid stenosis with a level of stenosis of 75-99%, either in the left (33.6%) or right (32.1%), followed by asymptomatic stenosis combined with risk factors (11.2% in the left side and 10.4% in the right side). A level of stenosis less than 30% was achieved in 132 of the 134 ASC (98.5%). performed. Five patients (3.7%) had complications associated with the procedure, of which four were different clinical presentations of a re-perfusion syndrome and one an asymptomatic thrombosis of the stent. CONCLUSIONS: ASC is a complex technique that must be performed by appropriately trained specialists. The performing a minimum number of procedures per year and an admission protocol controlled by Neurology are essential conditions for a low rate of complications. Under these conditions, the morbidity and mortality of the technique is no higher than that of endarterectomy. PMID- 20965000 TI - [Zolpidem-induced sleep-related behavioural disorders]. AB - OBJECTIVE: To present five patients with zolpidem-induced sleep-related behavioural disorders. METHODS: Evaluation using a questionnaire designed to study sleep behaviours and past medical history in all patients. RESULTS: The patients performed complex actions while sleep-walking (telephoning, house cleaning, feeding the dog or waxing their legs). Inappropriate feeding behaviour with excessive food intake during the night were reported by all patients. All had weight gain, which in one patient led to extreme obesity. Two patients suffered injuries (knife cuts and burns) related to attempting to prepare food. One patient took a laxative. CONCLUSION: Withdrawal of zolpidem resolved the behaviours in all cases, highlighting the importance of an adequate diagnosis of this side effect. PMID- 20965001 TI - [Drug consumption and cognitive function in non-institutionalized elderly: a population-based study]. AB - BACKGROUND: Drug consumption in the general population is concentrated in the elderly. The aim of this study was to assess the pharmacological profile of elderly people 75 years of age and older, to assess the relationship with the cognitive function and the variables associated with drug consumption. METHODS: This is an epidemiological, cross-sectional, door-to-door study among the non institutionalised population in a rural area. Participants were inhabitants aged 75 and older from the Angles Primary Healthcare Area (Girona). Drug prescriptions were recorded from participants' medicine chest. Cognitive function was assessed using the Mini-Mental State Examination. RESULTS: A total of 875 individuals took part (82%). Participants with mild and moderate cognitive impairment consumed an average of 4.6 (SD=2.9) and 5.2 (SD=3.2) drugs, participants without cognitive impairment consumed an average of 4 (SD=2.7) drugs (P < 0.005). In the bivariate analysis, taking into account the degree of cognitive impairment, there was a change in drugs acting on the digestive tract and metabolism (P=0.003) and nervous system (P=0.001). Multivariate analysis identified four variables associated with the central nervous system drugs: age, sex, comorbidity and suspicion of depression (P <0.05). CONCLUSIONS: Participants with severe cognitive impairment had a higher frequency of anti-psychotic and antidepressant drug consumption. However, the multivariate analysis shows that advanced age, female sex and suspicion of depression are variables associated with a higher central nervous system drug consumption. PMID- 20965002 TI - [Neurology and literature]. AB - INTRODUCTION: Literature complements medical literature in the academic and clinical development of neurologists. The present article explores the contributions of writers of fiction on neurology. SOURCES: Literary works of fiction with particular reference to neurology. DEVELOPMENT: A symbiosis between writers of fiction and doctors has been well recognised. From Shakespeare to Cervantes by way of Dickens and Cela to writer - physicians such as Anton Chekhov or Antonio Lobo Antunes have contributed through their medically informed literature to the better understanding of neurology. Some writers like Dostoevsky, Machado de Assis and Margiad Evans have written about their own experiences with disease thus bringing new insights to medicine. Furthermore, some neurological disorders have been largely based on literary descriptions. For instance, Dostoevsky's epilepsy has been retrospectively analysed by famous neurologists including Freud, Alajouanine or Gastaut, whilst his writings and biography have prompted others like Waxman and Geschwind to describe typical behavioural changes in temporal lobe epilepsy, finding their source of inspiration in Dostoevsky. Likewise, Cirignotta et al have named an unusual type of seizure after the Russian novelist. Inspired by Lewis Carroll, Todd introduced the term Alice in Wonderland Syndrome to refer to visual distortions generally associated with migraine. CONCLUSIONS: Writers of fiction offer a humanised perception of disease by contributing new insights into the clinical history, informing about the subjective experience of the illness and helping to eradicate the stigma associated to neurological disorders. PMID- 20965003 TI - [CSF fistula in a woman with a history of idiopathic intracranial hypertension]. PMID- 20965004 TI - [Corectopia as a neuro-ophthalmological sign of polyradiculopathy]. PMID- 20965005 TI - [Congenital arthrogryposis multiplex and gastroschisis in the same patient]. PMID- 20965006 TI - [Peripheral ischaemia after chronic ergot poisoning]. PMID- 20965007 TI - [Optical neuritis secondary to a rhinosinus disease]. PMID- 20965008 TI - [Nonalcoholic fatty liver disease and psoriasis]. PMID- 20965009 TI - [Update on photoprotection]. AB - Photoprotection is the primary preventive and therapeutic strategy against photoaging and skin cancer. This review presents the most important new advances in both topical and systemic photoprotection. Starting with innovations in the traditional physical and chemical filtering agents, we go on to discuss the growing number of antioxidants, the novel strategies for repairing light-induced DNA damage, and current research on substances that stimulate melanogenesis. A final section deals with protection against infrared radiation. PMID- 20965010 TI - [Immunofluorescence mapping for diagnosis of congenital epidermolysis bullosa]. AB - The tools for diagnosis of epidermolysis bullosa have advanced greatly since Hintner's group introduced antigen mapping as a diagnostic test for this family of genodermatoses. Monoclonal or polyclonal antibodies raised against some of the specific proteins found in the epidermis and basement membrane of the epidermis have allowed 4 types of epidermolysis bullosa de be identified and all variants to be classified. When a newborn baby presents with blisters, many conditions are implicated in the differential diagnosis. Examination under an optical microscope can suggest epidermolysis bullosa, but immunofluorescence mapping and electron microscopy are required for confirmation of the diagnosis and further classification of congenital epidermolysis bullosa. This article explains the importance of immunofluorescence antigen mapping and describes the methods employed for classification and subclassification of epidermolysis bullosa. PMID- 20965011 TI - [Surgical vs nonsurgical treatment of basal cell carcinoma]. AB - Numerous therapeutic options are now available for the treatment of basal cell carcinoma. However, few randomized controlled trials with 5-year follow-up have compared the effectiveness of the different treatments. Such a comparison is difficult, probably because efficacy depends on several factors: those related to the tumor, the patient, the technique, and the dermatologist's experience. We first describe the available therapeutic options, including certain innovative treatments. We have divided them into 2 main groups-surgical and nonsurgical-and focus on the indications, advantages, and disadvantages of each one, as well as on the cure and recurrence rates. Then, based on the evidence reviewed, we attempt to provide an outline of the therapeutic strategies recommended in basal cell carcinoma, and the approach to be used in specific situations. We also describe our own experience. PMID- 20965012 TI - [Lymphomatoid papulosis in children: report of 9 cases and review of the literature]. AB - BACKGROUND: Lymphomatoid papulosis is a rare lymphoproliferative T cell CD30+ disease with excellent prognosis which affects almost exclusively adult patients, being rarely in the childhood; thus the clinic and pathologic spectrum and the risk of evolution to another type of lymphoma are not well defined in the pediatric group. OBJECTIVE: The aim of this article is to analyze the characteristics of infantile lymphomatoid papulosis and review the literature. MATERIAL AND METHOD: A retrospective study analyzing the characteristics of 9 patients aged up to 18 diagnosed of lymphomatoid papulosis attended in our department from 1995 to 2009 was performed. RESULTS: The study included 7 boys and 2 girls aged between 2 and 17. Pityriasis lichenoides acuta's lesions appeared associated before and after lymphomatoid papulosis' development in 2 and 1 cases respectively. The lesions resolved spontaneously, leaving a postinflammatory hyperpigmentation (77%) or hypopigmentation (23%). The development of varioliform scars occurred in over 77% of cases. Histologically, all cases showed features compatible with type A of lymphomatoid papulosis. Molecular studies showed monoclonality in the 3 cases in which this technique was done. CONCLUSIONS: Infantile lymphomatoid papulosis is a rare entity clinically manifested as the adult form. This lymphoproliferative disease, which is occasionally associated with pityriasis lichenoides acuta, shows features compatible with the type A or histiocytoid pattern in the histological analysis. The development of other lymphoproliferative disorders is less frequent in the infantile form than in the adulthood. The prevalent association among pityriasis lichenoides and lymphomatoid papulosis observed in our analysis, as well as the difficulties which supposed to differentiate between these two pathologies in various cases, suggest that those entities could be part of a common clinical and pathological spectrum. PMID- 20965013 TI - [Current prevalence and characteristics of dermatoses associated with human immunodeficiency virus infection]. AB - INTRODUCTION: The introduction of highly active antiretroviral therapy has produced a substantial change in the natural history of human immunodeficiency virus (HIV) infection. The frequency of opportunistic infections and AIDS-related cancers has fallen, though new health problems have developed. Likewise, there has been a change in the spectrum of skin diseases now observed in these patients. OBJECTIVE: To analyze the prevalence and characteristics of skin disease in a group of HIV-infected outpatients. METHODS: A cross-sectional, observational study was performed. All patients who attended the day care unit of the infectious diseases department over a 6-month period (May-October, 2003) were offered the possibility of complete dermatologic examination. Epidemiologic and clinical variables were recorded in all participants, together with the findings on examination of the skin. A comparative study was performed, grouping the patients according to CD4-lymphocyte count and antiretroviral treatment. RESULTS: The prevalence of dermatoses in the study patients was 98.3%. The most common conditions were xerosis (114 patients, 37.6%), seborrheic dermatitis (94 patients, 31%), distal subungual onychomycosis (80 patients, 26.4%), and viral warts (65 patients, 21.4%). Grouped by etiology, infectious diseases were the most common (68.6%), followed by inflammatory diseases (47.5%). CONCLUSION: Mucocutaneous lesions continue to be very common in HIV-infected patients, although there has been a qualitative change in the conditions that these patients present. PMID- 20965014 TI - [Increased risk of developing a second primary cutaneous nevus-associated melanoma in patients previously diagnosed with the disease]. AB - BACKGROUND: Patients diagnosed with primary cutaneous melanoma have a greater lifetime risk of developing further melanomas. Most of these melanomas appear to arise de novo, but a proportion of them develop in pre-existing melanocytic nevi. OBJECTIVE: To determine risk factors associated with the development of a second cutaneous melanoma arising on a nevus in patients diagnosed with cutaneous melanoma. PATIENTS AND METHODS: A series of 981 patients diagnosed with cutaneous melanoma was selected; 47 of them had been diagnosed with a second melanoma. These 47 patients were classified into 2 groups according to whether or not there was histological evidence that the melanoma was associated with a nevus. RESULTS: Age at diagnosis less than 40 years, tumor location on the trunk, and superficial spreading subtype were independent risk factors for the appearance of a primary melanoma on a nevus. The only factor associated with the appearance of a second nevus-associated melanoma was that the first melanoma was also associated with a nevus (odds ratio, 9.51; 95% confidence interval 1.6-56.56; P=.042). CONCLUSIONS: Nevus-associated melanomas develop mainly in young patients, on the trunk, and are of the superficial spreading subtype. A history of primary cutaneous melanoma arising on a nevus is associated with a 9-fold increase in the risk of developing a second nevus-associated melanoma. These findings highlight the need for careful follow-up of all melanocytic lesions in patients who have had a primary nevus associated melanoma. PMID- 20965015 TI - [Pyoderma gangrenosum associated with hidradenitis suppurativa: a case report and review of the literature]. AB - Pyoderma gangrenosum is an inflammatory disease that has been found to be associated with many systemic illnesses. The case presented here is of a man with a 20-year history of hidradenitis suppurativa who developed pyoderma gangrenosum. The pyoderma lesions appeared as a single outbreak which resolved totally after immunosuppressive treatment. This association has been reported only rarely in the literature. Furthermore, in the cases reported, no relationship was apparent between the activity of both diseases. In all cases the clinical course appeared independent, with no apparent overlap in inflammatory activity or response to the drugs administered. PMID- 20965016 TI - [Widespread nodules]. PMID- 20965017 TI - [Long-standing widespread purpura]. PMID- 20965018 TI - [Leukemia cutis arising at the site of injection of a tetanus vaccine booster]. PMID- 20965019 TI - Randomized double-blind comparative study of 8-methoxypsoralen bath plus UV-A treatment regimens. PMID- 20965020 TI - [Reactive arthritis associated with Chlamydia trachomatis infection: Importance of screening and treating the partner]. PMID- 20965021 TI - [Multiple cutaneous granular cell tumors]. PMID- 20965022 TI - [Smooth muscle hamartoma associated with acquired Blaschkoid nevus spilus]. PMID- 20965023 TI - [Oral venous malformation treated with pulsed-dye and neodymium:Yttrium-aluminum garnet sequential laser]. PMID- 20965030 TI - Words of wisdom. Re: Clinical phenotyping in chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis: a management strategy for urologic chronic pelvic pain syndromes. PMID- 20965031 TI - Words of wisdom. Re: Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. PMID- 20965032 TI - Words of wisdom. Re: The relationship between premature ejaculation and hyperthyroidism. PMID- 20965033 TI - Words of wisdom. Re: Temporary balloon occlusion of the inferior vena cava in resection of renal tumor with vena cava thrombus extension. PMID- 20965034 TI - Words of wisdom. Re: Systematic review of pretreatment prostate-specific antigen velocity and doubling time as predictors for prostate cancer. PMID- 20965035 TI - Words of wisdom. Re: Nomogram predicting the probability of early recurrence after radical prostatectomy for prostate cancer. PMID- 20965037 TI - Words of wisdom. Re: The number of cores positive for high grade prostatic intraepithelial neoplasia on initial biopsy is associated with prostate cancer on second biopsy. PMID- 20965038 TI - Words of wisdom. Re: Bladder cancer screening in a high risk asymptomatic population using a point of care urine based protein tumour marker. PMID- 20965039 TI - Words of wisdom. Re: Testicular microlithiasis and carcinoma in situ overview and proposed clinical guidelines. PMID- 20965040 TI - Words of wisdom. Re: Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. PMID- 20965041 TI - Words of wisdom. Re: Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. PMID- 20965042 TI - Words of wisdom. Re: copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. PMID- 20965043 TI - Words of wisdom. Re: final results of sequential doxorubicin plus gemcitabine and ifosfamide, paclitaxel, and cisplatin chemotherapy in patients with metastatic or locally advanced transitional cell carcinoma of the urothelium. PMID- 20965044 TI - Words of wisdom. Re: sex and racial differences in bladder cancer presentation and mortality in the US. PMID- 20965045 TI - Words of wisdom. Re: treatment of non-muscle invading bladder cancer: do physicians in the United States practice evidence based medicine? PMID- 20965046 TI - Words of wisdom. Re: prostate-sparing cystectomy: long-term oncological results. PMID- 20965047 TI - Words of wisdom. Re: corporal "snake" maneuver: corporaglanular shunt surgical modification for ischemic priapism. PMID- 20965048 TI - Words of wisdom. Re: reduced bladder cancer recurrence rate with cardioprotective aspirin after intravesical bacille Calmette-Guerin. PMID- 20965049 TI - Words of Wisdom. Re: urinary diversion and morbidity after radical cystectomy for bladder cancer. PMID- 20965050 TI - Words of wisdom. Re: randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. PMID- 20965051 TI - Words of wisdom. Re: laparoscopic versus open nephroureterectomy: perioperative and oncologic outcomes from a randomised prospective study. PMID- 20965052 TI - Words of wisdom. Re: comparative effectiveness of minimally invasive versus open radical prostatectomy. PMID- 20965053 TI - Words of wisdom. Re: the role of short frenulum and the effects of frenulectomy on premature ejaculation. PMID- 20965054 TI - Fungal Biology. Editorial. PMID- 20965055 TI - Live-cell imaging of conidial fusion in the bean pathogen, Colletotrichum lindemuthianum. AB - Fusion of conidia and conidial germlings by means of conidial anastomosis tubes (CATs) is a common phenomenon in filamentous fungi, including many plant pathogens. It has a number of different roles, and has been speculated to facilitate parasexual recombination and horizontal gene transfer between species. The bean pathogen Colletotrichum lindemuthianum naturally undergoes CAT fusion on the host surface and within asexual fruiting bodies in anthracnose lesions on its host. It has not been previously possible to analyze the whole process of CAT fusion in this or any other pathogen using live-cell imaging techniques. Here we report the development of a robust protocol for doing this with C. lindemuthianum in vitro. The percentage of conidial germination and CAT fusion was found to be dependent on culture age, media and the fungal strain used. Increased CAT fusion was correlated with reduced germ tube formation. We show time-lapse imaging of the whole process of CAT fusion in C. lindemuthianum for the first time and monitored nuclear migration through fused CATs using nuclei labelled with GFP. CAT fusion in this pathogen was found to exhibit significant differences to that in the model system Neurospora crassa. In contrast to N. crassa, CAT fusion in C. lindemuthianum is inhibited by nutrients (it only occurs in water) and the process takes considerably longer. PMID- 20965056 TI - Metarhizium anisopliae lipolytic activity plays a pivotal role in Rhipicephalus (Boophilus) microplus infection. AB - Lipases secreted by Metarhizium anisopliae, an important biological control agent, could potentially be involved in the host infection process. Here, we present the activity profile during the host infection process and the effect of lipase activity inhibitor ebelactone B on infection. The previous treatment of spores with lipase activity inhibitor, ebelactone B, completely inhibited lipolytic activity and prevented the infection of the Rhipicephalus (Boophilus) microplus host. The results herein presented prove, for the first time, the importance of lipase activity in M. anisopliae host infection process. The filamentous fungus Metarhizium anisopliae is one of the most important and studied biological agents for the control of several arthropod pests, including the cattle tick Rhipicephalus (Boophilus) microplus. Lipases secreted by M. anisopliae could potentially be involved in the host infection process. This work presents the activity profile during the host infection process and the effect of lipase activity inhibitor ebelactone B on infection. During the course of tick exposure to spores (6-120 h) lipase activity increased from 0.03 +/- 0.00 U to 0.312 +/- 0.068 U using rho NP palmitate as substrate. In zymograms, bands of lipase activity were detected in ticks treated with spores without inhibitor. The previous treatment of spores with lipase activity inhibitor, ebelactone B, completely inhibited lipolytic activity, at all times specified, and prevented the infection of the R. microplus host. Spores treated with the inhibitor did not germinate on the tick, although this effect was not observed in the culture medium. The results herein presented prove, for the first time, the importance of lipase activity in M. anisopliae host infection process. PMID- 20965057 TI - Heterobasidion occidentale sp. nov. and Heterobasidion irregulare nom. nov.: a disposition of North American Heterobasidion biological species. AB - The genus Heterobasidion includes some of the most important pathogens of conifers in the world, and as such it is one of the most intensely studied genera of fungi. Because of the remarkable paucity of distinguishing morphological traits, the taxonomy of species within this genus has always been problematic. A partial resolution of the taxonomic issues regarding this genus was achieved by defining the most important and first described species within it, Heterobasidion annosum, as a species complex containing at least two partially intersterile biological species defined as intersterility groups (ISGs). With time, the number of ISGs has increased to include at least two distinct North American and three distinct Eurasian ISGs. Two additional, yet unnamed, taxonomic groups within Heterobasidion have been recently described in Japan. ISGs are distinguishable either by minor morphological differences, by partial intersterility, by ecological traits including host preference, and/or by their geographic range. Several studies employing a variety of molecular tools and analyses have confirmed the distinct genetic divergence among ISGs, identifying each of them as a monophyletic group. Using genetic markers, genotypes can always be unambiguously assigned to one ISG, and very few inter-ISG hybrids have been identified. In this paper, we summarize the available information, both genetic and ecological, that differentiates the two North American ISGs from each other and from other taxonomic units within the genus. We demonstrate that morphometric characteristics such as pore density and pore shape differentiate the two ISGs. Based on the cumulative genetic, ecological, and morphological evidence, we propose a disposition of ISGs of the North American H. annosum by replacing the P ISG with Heterobasidion irregulare, and the S ISG with Heterobasidion occidentale. PMID- 20965058 TI - A comparison of Olpidium isolates from a range of host plants using internal transcribed spacer sequence analysis and host range studies. AB - Olpidium brassicae is a ubiquitous obligate root-infecting fungal pathogen. It is an important vector of a wide range of plant viruses. Olpidium isolates that infected brassica plants did not infect lettuce plants and vice-versa. Host range tests, PCR amplification and sequencing of the internal transcribed spacer (ITS) and 5.8S regions of 25 Olpidium isolates from brassica, carrot, cucumber and lettuce originating from four continents revealed differences between isolates. Based on their ability to infect lettuce and brassicas and the differences between their ITS1, 5.8S and ITS2 regions they could be separated into a number of distinct groups. Comparisons with other published sequences revealed two distinct genetic groups of brassica-infecting isolates, two distinct groups of lettuce-infecting isolates, one of which contained a carrot-infecting isolate and a distinct group comprising a cucumber-infecting isolate and a melon-infecting isolate. The possibility of the isolates belonging to three distinct species is discussed. PMID- 20965059 TI - Entomotoxic effects of fungal lectin from Rhizoctonia solani towards Spodoptera littoralis. AB - The effects of the Rhizoctonia solani lectin (RSA) on the growth, development and survival of an economically important caterpillar in agriculture and horticulture, the cotton leafworm, Spodoptera littoralis were studied. The high lectin concentration present in the sclerotes of the soil pathogen R. solani allowed the purification of large amounts of the pure lectin for feeding experiments with cotton leafworm. Rearing of insects on a diet containing different concentrations of RSA exerted a strong effect on the larval weight gain. This effect was visible at the lowest concentration of 0.1 % RSA at day 8 and day 11. Interestingly with 1 % RSA, there was a dramatic reduction in larval weight of 89 % at the end of L6 which was followed by a high mortality rate of 82 % in the treated larvae. Furthermore, the other developmental stages of pupation and adult formation were also affected. In addition, the data demonstrated that the combination of RSA with Bt toxin yielded synergistic effects. For instance, 0.03 % RSA+0.005 % Bt toxin caused reduced growth rate and higher mortalities. These findings suggest that RSA is an interesting tool that can be used for bioengineering insect resistance in important agronomical crops. PMID- 20965060 TI - Claviradulomyces, a new genus of Odontotremataceae from West African rainforest. AB - A new genus, Claviradulomyces, morphologically typical of Odontotremataceae, is proposed to accommodate the new species Claviradulomyces dabeicola. The genus is characterised by its ornamented periphysoids, and long-cylindric, sigmoid, acuminate ascospores. Genetically, C. dabeicola falls within the Ostropales, but the Odontotremataceae have been very poorly sampled genetically and their phylogenetic relationship within the order is unclear. C. dabeicola has been collected consistently and exclusively on the rainforest tree Erythroxylum mannii in the Cote d'Ivoire and Ghana, where it is associated with bark abnormalities on branches and stems of living trees. PMID- 20965061 TI - The effect of temperature and relative humidity on the formation of Metarhizium anisopliae chlamydospores in tick eggs. AB - The influence of ambient conditions on the development of Metarhizium anisopliae chlamydospores in tick eggs is reported for the first time. The infection of tick eggs by M. anisopliae involves common events, such as adhesion, conidial germination, appressoria formation, invasion, and development within the eggs. However, the final stage of fungal development differs according to the environmental conditions. At high humidity (close to 100%) and moderate temperature (25 degrees C) the fungus emerged from the eggs and formed conidiophores and conidia externally on the dead eggs. Elevating the temperature to 30 degrees C or reducing humidity to 55-75% induced the production of chlamydospores inside the eggs, without conidiogenesis. When eggs with mature chlamydospores were returned to the appropriate conditions (25 degrees C and 100% RH), conidiogenesis was recovered. Formation of chlamydospores, observed by means of histology and TEM, began with the thickening and septation of hyphae. As the chlamydospore wall thickened a new external undulated wall layer appeared. The mature chlamydospore in eggs has an oval shape (5.3 +/- 0.9 microm long, 2.5 +/- 0.2 microm wide); its wall comprises three distinct layers. The ability of M. anisopliae to produce chlamydospores under harsh conditions is advantageous and should be considered in application. PMID- 20965062 TI - Why mushrooms form gills: efficiency of the lamellate morphology. AB - Gilled mushrooms are produced by multiple orders within the Agaricomycetes. Some species form a single array of unbranched radial gills beneath their caps, many others produce multiple files of lamellulae between the primary gills, and branched gills are also common. In this largely theoretical study we modeled the effects of different gill arrangements on the total surface area for spore production. Relative to spore production over a flat surface, gills achieve a maximum 20-fold increase in surface area. The branching of gills produces the same increase in surface area as the formation of free-standing lamellulae (short gills). The addition of lamellulae between every second gill would offer a slightly greater increase in surface area in comparison to the addition of lamellulae between every pair of opposing gills, but this morphology does not appear in nature. Analysis of photographs of mushrooms demonstrates an excellent match between natural gill arrangements and configurations predicted by our model. PMID- 20965063 TI - Transcriptional regulation of elsinochrome phytotoxin biosynthesis by an EfSTE12 activator in the citrus scab pathogen Elsinoe fawcettii. AB - Elsinochrome (ESC), produced by the citrus pathogen Elsinoe fawcettii, is a nonhost-selective, light-dependent, polyketide-derived phytotoxin and plays a crucial role for full virulence. The biosynthesis of ESC is regulated by a wide array of environmental stimuli and is primarily governed by the pathway-specific TSF1 transcription regulator whose coding gene is clustered with the EfPKS1 gene encoding a polyketide synthase and other biosynthetic genes in the genome. In this report, an EfSTE12 gene, encoding a polypeptide resembling the yeast STE12 transcription factor, was cloned and characterized to play a role, independent of TSF1, for ESC production in E. fawcettii. The loss-of-function mutant, specifically disrupted at the EfSTE12 locus, displays reduced ESC accumulation, elevated activities for pectinase and proteolytic enzymes but unaltered in conidiation and fungal pathogenicity. Impairment of the EfSTE12 gene decreased the abundance of the EfPKS1 but not the TSF1 gene transcript. In contrast, expression of the EfSTE12 gene appears normal in the EfPKS1 or TSF1 disruptants. The results indicate that EfSTE12 is functioning for ESC biosynthesis by directly activating the biosynthetic genes without regulating the pathway-specific TSF1 regulator. The defective phenotypes were fully reverted when a functional copy of EfSTE12 was re-introduced into the disrupted mutant. A hypothetical model underlying intertwined regulatory pathways via TSF1, EfSTE12, and other potent transcriptional activators led to the ESC biosynthesis and conidiation is described. PMID- 20965064 TI - A molecular based strategy for rapid diagnosis of toxigenic Fusarium species associated to cereal grains from Argentina. AB - Fusarium species are worldwide causal agents of ear rot in cereals. Their toxigenic potential is a health risk for both humans and animals. In Argentina, most identification of these fungi has been based on morphological and cross fertility criteria which are time consuming and require considerable expertise in Fusarium taxonomy and physiology. DNA based approaches have been reported as rapid, sensitive and specific alternatives to identify the main fumonisin and trichothecene-producing Fusarium species. In this work, we used PCR assays and the partial sequence of TEF1-alpha gene (Translation Elongation Factor-1 alpha) to identify the fumonisin and trichothecene-producing species in Fusarium isolates from diverse regions of Argentina. The relative efficiency and reliability of those methods to improve mycotoxin risk prediction in this country were also assessed. Species-specific PCR assays were targeted toward multicopy IGS (Intergenic Spacer of rDNA units) and on the toxin biosynthetic genes FUM1 (fumonisins) and TRI13 and TRI7 genes (trichothecenes). PCR assays based on FUM1 gene and IGS sequences allowed detection and discrimination of the fumonisin producers Fusarium proliferatum and Fusarium verticillioides. Molecular identification of nonfumonisin producers from Gibberella fujikuroi species complex was possible after determination of TEF1-alplha gene sequences, which indicated the presence of Fusarium subglutinans, Fusarium andiyazi and Fusarium thapsinum. TEF-1 alpha gene sequences also allowed discrimination of the different species of the Fusarium graminearum complex (F. graminearum sensu lato) as F. graminearum sensu stricto, Fusarium meridionale and Fusarium boothii. The last two species belonged to NIV chemotype and were detected for the first time in the subtropical region of Argentina while F. graminearum sensu stricto was DON producer only, which was also confirmed by specific PCR assays based on TRI137/TRI7 genes. Our results indicated that the PCR assays evaluated in this work are reliable diagnostic tools to detect the main toxigenic Fusarium species associated to cereal grains in Argentina. An extensive epidemiological survey based on the approach presented in this work is currently in progress to know the mycotoxigenic hazard of Fusarium species in cereal grains from the subtropical region of Argentina. PMID- 20965065 TI - Genetic covariation of the marine fungal symbiont Haloguignardia irritans (Ascomycota, Pezizomycotina) with its algal hosts Cystoseira and Halidrys (Phaeophyceae, Fucales) along the west coast of North America. AB - The fungal endophyte Haloguignardia irritans induces gall formation on the brown algal genera Cystoseira and Halidrys occurring from Oregon to Baja California, Mexico. Here we examine genetic covariation and compare rDNA phylogenies to investigate the coevolutionary histories of H. irritans and its algal hosts. Despite recognition of H. irritans as a single morphological species, internal transcribed spacer rDNA sequences representative of its geographic range are characterized by sequence variation at the intraspecific to intrageneric levels. An assessment of parallel cladogenesis between endophyte and host phylogenies provides evidence for a combination of independent fungal divergence and host jumping, similar to that observed in terrestrial lichens. Our results suggest that reduced gene flow due to geographic isolation is a major contributing factor to more concerted covariation observed at one island site, rather than to differences among algal host species alone. Because geography and its effects on gene flow can create heterogeneous mosaics of coevolution for symbioses in terrestrial environments, our results support the notion that conservation efforts toward the maintenance of genetic diversity in marine environments should likewise consider geographic complexity and its effects on coevolving marine species. PMID- 20965066 TI - Phylogenetic relationships of Fusarium poae based on EF-1 alpha and mtSSU sequences. AB - A molecular phylogenetic analysis of Fusarium poae isolates from South America (Argentina) and Europe (mainly England, Germany, Italy) was performed using 98 F. poae, four Fusarium culmorum, two Fusarium sporotrichioides and one Fusarium langsethiae isolates. Phylogenetic analyses were performed using nuclear (translation elongation factor 1-alpha, EF-1 alpha) and mitochondrial (mitochondrial small subunit rDNA, mtSSU) sequences. Partitioned (each dataset separately) and combined (EF-1 alpha+mtSSU) analyses did not reveal any clear correlations from the inferred branching topology, between the distribution of observed haplotypes and the geographic origin and/or host species. Results from the present study confirmed that isolates from F. poae form a monophyletic group, and the low variability within isolates from a broad geographic range suggests a common lineage history. Among F. poae isolates from Argentina, however, some were found to possess an insert within mtSSU with structural similarities to group IC2 introns. F. poae isolates differing by the presence/absence of a mtSSU insertion were characterized further by analysis of a portion of the Tri5 gene, but this sequence was unable to reveal variability. The presence of this insert only within isolates from Argentina suggests that evolutionary events (insertions/deletions) are probably taking place within the Argentinian F. poae isolates, and that the acquisition of this insert occurred after geographic isolation of the Argentinian and European populations. PMID- 20965067 TI - A rapid infection assay for Armillaria and real-time PCR quantitation of the fungal biomass in planta. AB - Slow and unreliable infection in the greenhouse has been a barrier to research on Armillaria root disease. The existing infection assay takes 7-18 months for detectable infection, during which time the inoculum often dies, resulting in unequal challenge among plants. Because symptom expression and mortality are rare, presence or absence of infection, determined by culturing, is the only datum derived from the existing infection assay. This limits both routine comparisons of strain virulence and complex investigations of pathogenesis, neither of which have been done for Armillaria mellea. We tested a new infection assay, in which grape rootstocks growing in tissue culture medium are inoculated, and compared to rootstocks previously characterized from the existing infection assay as tolerant (Freedom) or susceptible (3309C). Culture media of 25 plants per rootstock was inoculated and five plants per rootstock were harvested 0, 2, 4, 6, and 8 weeks postinoculation; the experiment was completed twice. Confocal microscopy and quantitative PCR (Q-PCR) were used to quantify infection. Roots were treated with WGA-AlexaFluor488, hyphae and roots were scanned on green and red channels on a confocal microscope, and percent root colonization was quantified. A fungal gene (EF1?) was determined to have a single copy in A. mellea, and both EF1? and a single-copy grape gene (UFGT) were amplified by Q PCR; fungal DNA: plant DNA served as a measure of fungal biomass. Armillaria was detected by culture, microscopy, and Q-PCR starting 2 weeks postinoculation from all inoculated plants, demonstrating that the new infection assay is rapid and plants do not escape infection. Our findings of higher percent root colonization (as measured by microscopy) of 3309C than Freedom at all harvests (P<0.0001), consistently higher fungal biomass (as measured by Q-PCR) of 3309 than Freedom, and a significant positive correlation between percent root colonization and fungal biomass (P=0.01) suggests that the quantitative methods of our new assay give similar results to the qualitative method of the existing infection assay. PMID- 20965068 TI - Correlation of the aphicidal activity of Beauveria bassiana SFB-205 supernatant with enzymes. AB - The supernatant of Beauveria bassiana SFB-205 reduced the population of cotton aphid, Aphis gossypii Glover, with a dosage-dependent manner, which allowed a quality control (QC) factor to be determined for the evaluation of the supernatant as the first step of a development. Enzymes were assumed as possible QC factors based on 1) the comparable aphicidal activity of the supernatant protein pellet to the raw supernatant, 2) the supernatant-induced degradation of the insect cuticles, observed by transmission electron microscopy, and 3) the confirmation of enzymes related to the fungal penetration - chitinase, and the Pr1- and Pr2 proteases - in the supernatant. Finally, from the bioassay with the enzyme-inhibited supernatants processed by substrate inhibition one by one, decreased aphicidal activities were observed for all three enzyme-inhibited treatments. This phenomenon, furthermore, was more remarkable in the chitinase inhibited supernatant. This finding provides that those enzymes (and most particularly the chitinase) in the supernatant were strongly involved in the aphicidal activity. Consequently, the amount of the chitinase may be used as one of the QC factors to determine the insecticidal activity of the supernatant of B. bassiana SFB-205 in the optimization of mass production. PMID- 20965069 TI - Importance of natural disturbance for recovery of the rare polypore Antrodiella citrinella Niemela & Ryvarden. AB - Most strictly protected areas world-wide have been established in former commercial forests, but there is little evidence that this strongly advocated tool of conservation has had positive effects on endangered species in the short run of decades. One of the major reasons for the failure of habitat improvement in most of these reserves is a lack of natural disturbance. Consequently, only a few studies of species recovery in protected areas after natural disturbance are available. We demonstrate how natural dynamics in the oldest national park in Germany allows the area-wide recovery of the rare wood-inhabiting fungus Antrodiella citrinella. Our analyses showed that an increase of dead wood at >134 224 m(3)ha(-1), amounts known from primeval forests, allowed the fungus, which has barely survived as 'living dead' in two remnants of pristine forests, to spread from this small relict populations to the whole national park, within a radius of more than 30 km. Our result demonstrate that natural disturbance, even in former commercial forests, allowed the recovery of this rare species and fully supports the use of passive management in protected areas, even if natural dynamics often evokes debates on salvage logging. PMID- 20965070 TI - The coevolution of plants and viruses: resistance and pathogenicity. AB - Virus infection may damage the plant, and plant defenses are effective against viruses; thus, it is currently assumed that plants and viruses coevolve. However, and despite huge advances in understanding the mechanisms of pathogenicity and virulence in viruses and the mechanisms of virus resistance in plants, evidence in support of this hypothesis is surprisingly scant, and refers almost only to the virus partner. Most evidence for coevolution derives from the study of highly virulent viruses in agricultural systems, in which humans manipulate host genetic structure, what determines genetic changes in the virus population. Studies have focused on virus responses to qualitative resistance, either dominant or recessive but, even within this restricted scenario, population genetic analyses of pathogenicity and resistance factors are still scarce. Analyses of quantitative resistance or tolerance, which could be relevant for plant-virus coevolution, lag far behind. A major limitation is the lack of information on systems in which the host might evolve in response to virus infection, that is, wild hosts in natural ecosystems. It is presently unknown if, or under which circumstances, viruses do exert a selection pressure on wild plants, if qualitative resistance is a major defense strategy to viruses in nature, or even if characterized genes determining qualitative resistance to viruses did indeed evolve in response to virus infection. Here, we review evidence supporting plant virus coevolution and point to areas in need of attention to understand the role of viruses in plant ecosystem dynamics, and the factors that determine virus emergence in crops. PMID- 20965071 TI - Assessment of the benefits and risks for engineered virus resistance. AB - Viral diseases of cultivated crops are responsible for the worldwide loss of billions of US dollars in agricultural productivity every year. Historically, this loss has been reduced or minimized principally by the implementation of specific agricultural/phytosanitary measures, and by the introduction of naturally occurring virus-resistance genes into appropriate cultivars by plant breeding. Since the first report of virus-resistant transgenic plants (VRTPs) in 1986, a remarkable diversity of virus-resistance transgenes has been developed. Despite this, to a large part due to controversy surrounding the use of genetically modified organisms, the number of commercially available VRTPs remains small. However, since the potential risks associated with VRTPs were first formulated in the early 1990s, fundamental research on plant-virus interactions and also research specifically aimed at resolving biosafety issues have greatly circumscribed the potential impact of the risks envisaged. Yet, in spite of the advances, both in strategies for creating VRTPs and in the assessment of potential risks, it remains remarkably difficult to weigh the risks/costs and benefits of different means to manage plant viral diseases, and even to make scientifically well-founded choices of the most appropriate strategy for creating VRTPs. Many of the outstanding issues concern the lack of sufficient knowledge of the breadth and durability of the resistance of VRTPs under field conditions. VRTPs will only take their appropriate place in modern agriculture when their potential users will be able to base their choices on realistic assessments of their efficacy, durability, and safety. PMID- 20965072 TI - Signaling in induced resistance. AB - Induced mechanisms are by definition imperceptible or less active in uninfected, unstressed, or untreated plants, but can be activated by pathogen infection, stress, or chemical treatment to inhibit the replication and movement of virus in the host. In contrast, defenses that are pre-existing or serve to limit virus propagation and spread in otherwise susceptible hosts are considered to be "basal" in nature. Both forms of resistance can be genetically determined. Most recessive resistance genes that control resistance to viruses appear not to depend upon inducible mechanisms but rather maintain basal resistance by producing nonfunctional variants of factors, specifically translation initiation factors, required by the virus for successful exploitation of the host cell protein synthetic machinery. In contrast, most dominant resistance genes condition the induction of broad-scale changes in plant biochemistry and physiology that are activated and regulated by various signal transduction pathways, particularly those regulated by salicylic acid, jasmonic acid, and ethylene. These induced changes include localized plant cell death (associated with the hypersensitive response, HR) and the upregulation of resistance against many types of pathogen throughout the plant (systemic acquired resistance, SAR). Unfortunately, it is still poorly understood how virus infection is inhibited and restricted during the HR and in plants exhibiting SAR. Resistance to viruses is not always genetically predetermined and can be highly adaptive in nature. This is exemplified by resistance based on RNA silencing, which appears to play roles in both induced and basal resistance to viruses. To counter inducible resistance mechanisms, viruses have acquired counter-defense factors to subvert RNA silencing. Some of these factors may affect signal transduction pathways controlled by salicylic acid and jasmonic acid. In this chapter, we review current knowledge of defensive signaling in resistance to viruses including the nature and roles of low molecular weight, proteinaceous, and small RNA components of defensive signaling. We discuss the differences and similarities of defenses and defensive signaling directed against viral versus nonviral pathogens, the potential role of RNA silencing as an effector in resistance and possible regulator of defensive signaling, crosstalk and overlap between antiviral systems, and interference with and manipulation of host defensive systems by the viruses themselves. PMID- 20965073 TI - Global genomics and proteomics approaches to identify host factors as targets to induce resistance against Tomato bushy stunt virus. AB - The success of RNA viruses as pathogens of plants, animals, and humans depends on their ability to reprogram the host cell metabolism to support the viral infection cycle and to suppress host defense mechanisms. Plus-strand (+)RNA viruses have limited coding potential necessitating that they co-opt an unknown number of host factors to facilitate their replication in host cells. Global genomics and proteomics approaches performed with Tomato bushy stunt virus (TBSV) and yeast (Saccharomyces cerevisiae) as a model host have led to the identification of 250 host factors affecting TBSV RNA replication and recombination or bound to the viral replicase, replication proteins, or the viral RNA. The roles of a dozen host factors involved in various steps of the replication process have been validated in yeast as well as a plant host. Altogether, the large number of host factors identified and the great variety of cellular functions performed by these factors indicate the existence of a truly complex interaction between TBSV and the host cell. This review summarizes the advantages of using a simple plant virus and yeast as a model host to advance our understanding of virus-host interactions at the molecular and cellular levels. The knowledge of host factors gained can potentially be used to inhibit virus replication via gene silencing, expression of dominant negative mutants, or design of specific chemical inhibitors leading to novel specific or broad-range resistance and antiviral tools against (+)RNA plant viruses. PMID- 20965074 TI - Resistance to aphid vectors of virus disease. AB - The majority of plant viruses rely on vectors for their transmission and completion of their life cycle. These vectors comprise a diverse range of life forms including insects, nematodes, and fungi with the most common of these being insects. The geographic range of many of these vectors is continually expanding due to climate change. The viruses that they carry are therefore also expanding their range to exploit novel and naive plant hosts. There are many forms of naturally occurring vector resistance ranging from broad nonhost resistance to more specific types of inducible resistance. Understanding and exploiting the many and varied forms of natural resistance to virus vectors is therefore extremely important for current and future agricultural production systems. To demonstrate the range and extent of these resistance mechanisms, this chapter will primarily focus on aphids to highlight key developments appropriate to plant insect-virus interactions. PMID- 20965075 TI - Cross-protection: a century of mystery. AB - Cross-protection is a phenomenon in which infection of a plant with a mild virus or viroid strain protects it from disease resulting from a subsequent encounter with a severe strain of the same virus or viroid. In this chapter, we review the history of cross-protection with regard to the development of ideas concerning its likely mechanisms, including RNA silencing and exclusion, and its influence on the early development of genetically engineered virus resistance. We also examine examples of the practical use of cross-protection in averting crop losses due to viruses, as well as the use of satellite RNAs to ameliorate the impact of virus-induced diseases. We also discuss the potential of cross-protection to contribute in future to the maintenance of crop health in the face of emerging virus diseases and related threats to agricultural production. PMID- 20965077 TI - A comparative study of nursing attitudes towards young male survivors of brain injury: A questionnaire survey. AB - BACKGROUND: The attitudes members of the nursing profession hold towards survivors of brain injury may impact on the level of help, and degree of involvement they are willing to have. Given that the manner in which an individual receives their brain injury has been shown to impact on public prejudices, the importance of exploring nursing attitudes to this vulnerable group, and the subsequent impact this may have on the caring role, requires investigation. OBJECTIVE: To investigate the attitudes held by members of the nursing profession towards young male survivors of brain injury whose behaviour either contributed, or did not contribute, to their injury. DESIGN: Independent groups design. SETTING AND PARTICIPANTS: Ninety trainee and sixty-nine qualified nurses respectively drawn from a university in the south west of England and the emergency, orthopaedic and paediatric Departments of the Royal Devon and Exeter Hospital, UK. METHODS: Participants were randomly assigned to one of four fictional brain injury scenarios. A young male character was portrayed as sustaining a brain injury as a result of either an aneurysm, or through drug taking, with their behaviour being either a contributory or non-contributory factor. On reading these, participants were asked to complete the prejudicial evaluation scale, the social interaction scale and the helping behaviour scale. RESULTS: Analysis of variance showed that qualified nurses held more prejudicial attitudes than student nurses towards survivors of brain injury. Mean scores indicated that individuals seen as contributing towards their injury were likely to experience more prejudice (blame total=42.35 vs. no blame total=38.34), less social interaction (blame total=37.54 vs. no blame total=41.10), and less helping behaviour (blame total=21.49 vs. no blame total=22.34) by both groups. CONCLUSIONS: Qualified nurses should be mindful of the impact their attitudes and judgements of survivors of brain injury may have on the subsequent care they provide. Greater emphasis on the effects of negative attitudes on patient interactions during training may provide nurses with the understanding to recognise and avoid challenges to their caring role in the future. PMID- 20965079 TI - Determination of the number of binding sites and binding constant between diltiazem hydrochloride and human serum albumin by ultrasonic microdialysis coupled with online capillary electrophoresis electrochemiluminescence. AB - A simple, sensitive and selective determination of diltiazem hydrochloride (DLT) is described using capillary electrophoresis electrochemiluminescence (CE-ECL). The CE-ECL parameters that affect separation and detection were optimized. Under the optimized conditions, the linear range of DLT was from 0.02 to 100 MUmol/L (r(2) = 0.9983), with the detection limit of 5.1 nmol/L (3sigma). The relative standard deviations of ECL intensity and the migration time were <2% for 0.1 MUmol/L and 22 MUmol/L DLT (n = 11). A new technique for determining of the number of binding sites and binding constant between DLT and HSA was developed using ultrasonic microdialysis coupled with CE-ECL. The number of binding sites and binding constant were 5.9 and 6.3 * 10(4) L/mol, respectively. The time required for ultrasonic microdialysis was 10 times less than that for traditional dialysis. Compared with traditional dialysis, ultrasonic microdialysis is simple, rapid, and should be applicable to a wide range of interactions of drugs and biomacromolecules. PMID- 20965080 TI - Determination and quantification of active phenolic compounds in pigeon pea leaves and its medicinal product using liquid chromatography-tandem mass spectrometry. AB - A novel method using liquid chromatography coupled to electrospray ionization mass spectrometry (LC-ESI-MS) has been optimized and established for the qualitative and quantitative analysis of ten active phenolic compounds originating from the pigeon pea leaves and a medicinal product thereof (Tongluo Shenggu capsules). In the present study, the chromatographic separation was achieved by means of a HiQ Sil C18V reversed-phase column with a mobile phase consisting of methanol and 0.1% formic acid aqueous solution. Low-energy collision-induced dissociation tandem mass spectrometry (CID-MS/MS) using the selected reaction monitoring (SRM) analysis was employed for the detection of ten analytes which included six flavonoids, two isoflavonoids and two stilbenes. All calibration curves showed excellent coefficients of determination (r(2) >= 0.9937) within the range of tested concentrations. The intra- and inter-day variations were below 5.36% in terms of relative standard deviation (RSD). The recoveries were 95.08-104.98% with RSDs of 2.06-4.26% for spiked samples of pigeon pea leaves. The method developed was a rapid, efficient and accurate LC MS/MS method for the detection of phenolic compounds, which can be applied for quality control of pigeon pea leaves and related medicinal products. PMID- 20965081 TI - Functional amino acid ionic liquids as solvent and selector in chiral extraction. AB - Amino acid ionic liquids (AAILs) have received great attention due to their potentials in catalysis and separations. In this work, functional AAILs were used as solvent and selector in chiral liquid-liquid extraction for the first time. The AAILs have shown distinct enantioselectivity in amino acid extraction. Using these functional AAILs as acceptor phase and ethylacetate as donor phase, more L enantiomer of amino acid was extracted into the ionic liquid phase than that of D enantiomer. The influencing factors, including AAILs structure, copper ion concentration, organic phase and amino acid concentration, were investigated. We found that the enantioselective enrichment of racemic amino acids was achieved through a chiral ligand-exchange mechanism. The enantioselectivity of single-step extraction was up to enantiomeric excess value of 50.6%. Moreover, the functional AAILs were found to be efficient extraction solvents for amino acids. The logarithm of distribution coefficient for L-Phe was in the range of 3.4-3.6 in the ionic liquid-ethylacetate two-phase system. This liquid-liquid extraction approach may extend the application of ionic liquids in chiral separations. PMID- 20965082 TI - Leukocyte and platelet changes following low-dose lipopolysaccharide administration in five dogs. AB - Effects of low-dose LPS (0.1 MUg/kg i.v.) on leukocyte and platelet parameters measured using an Advia 120 hematology analyzer were investigated. Five dogs received a saline sham treatment prior to LPS, and blood was collected before and 3, 6, and 24 h post-treatment. LPS-treated dogs had mild neutrophil toxic change and increased neutrophil bands at 3 and 6 h. Compared to saline-treated controls, total leukocyte, neutrophil, and monocyte counts of LPS-treated dogs were significantly decreased at 3 h and increased at 24 h. Compared to baseline, total leukocyte counts of LPS-treated dogs were significantly decreased at 3 h and increased at 24 h. Mean platelet volume was significantly increased and mean platelet component concentration was decreased at 3 h compared to baseline. Platelet count was significantly decreased at 3 and 6 h; plateletcrit did not change significantly. High dosage is not required in order to detect LPS-mediated hematologic effects in dogs. Low-dose LPS administration causes significant changes in leukocyte and platelet indices in dogs without causing severe clinical signs or death. PMID- 20965092 TI - Does speciation matter for tungsten ecotoxicology? AB - Tungsten is a widely used transition metal that has not been thoroughly investigated with regards to its ecotoxicological effects. Tungsten anions polymerize in environmental systems as well as under physiological conditions in living organisms. These polymerization/condensation reactions result in the development of several types of stable polyoxoanions. Certain chemical properties (in particular redox and acidic properties) differentiate these polyanions from monotungstates. However, our current state of knowledge on tungsten toxicology, biological and environmental effects is based entirely on experiments where monotungstates were used and assumed by the authors to be the form of tungsten that was present and that produced the observed effect. Recent discoveries indicate that tungsten speciation may be important to ecotoxicology. New results obtained by different research groups demonstrate that polytungstates develop and persist in environmental systems, and that polyoxotungstates are much more toxic than monotungstates. This paper reviews the available toxicological information from the standpoint of tungsten speciation and identifies knowledge gaps and pertinent future research directions. PMID- 20965091 TI - The level of expressed emotion scale: a useful measure of expressed emotion in adolescents? AB - Research has suggested that self-report measures of expressed emotion (EE) may be employed as a proxy measure of environmental stress in the home. The appropriateness of the Level of Expressed Emotion scale as a measure of perceived expressed emotion was examined in a sample of adolescents. Participants were 239 male and 422 female adolescents with a mean age of 15.9 years (SD = 1.26). Principal component analysis and confirmatory factor analysis suggested a shortened thirty three item scale with three subscales, interpreted as Lack of Emotional Support, Irritability and Intrusiveness. The Intrusiveness and Irritability subscales were positively correlated with adolescents' self reports of psychological symptoms. Researchers seeking adolescents' reports of the family environment should consider the use of this shortened LEE scale. PMID- 20965095 TI - Expression and function of CXCR7 in the mouse forebrain. AB - The chemokine CXCL12/CXCR4 signaling system is important for the regulation of neuron migration in the developing forebrain. In particular it is crucial for correct distribution of Cajal-Retzius cells and migration of cortical interneurons. Here we investigated the expression of CXCR7, the second receptor for CXCL12, in comparison to CXCR4. We found that shifts in the expression of both receptors in the above cited cell populations coincide with major changes in their migratory behavior. Furthermore, we demonstrated that postnatally generated olfactory interneuron precursors express CXCR7 but not CXCR4 and that their distribution in the rostral migratory stream is affected by CXCR7 downregulation. This suggests an involvement of CXCR7 in neuronal cell migration and indicates a possible action of CXCR7 independently of CXCR4 as a mediator of CXCL12 signaling. PMID- 20965093 TI - Prevalence rates and socioeconomic characteristics of post-partum depression in Hungary. AB - The rapid socioeconomic transition in post-communist Hungary adversely affected the overall morbidity and mortality rates in the 1990s. Prevalence data on depressive disorders from the region are still scarce, however. This study reports the findings of the first epidemiological survey, using the Edinburgh Postnatal Depression Scale (EPDS) and the Beck Depression Inventory (BDI), on the prevalence of post-partum depression and the associated risk factors in Hungary. A total of 1030 mothers who delivered their babies between May and July 1999 in 16 counties in Hungary were screened for depressive symptoms 3-26 weeks post partum. The survey found that 10.81% of the sample was above the cut-off score of 13, and the EPDS detected post-partum depressive symptoms with 76% (95% confidence interval (CI)=60.5-87.1) sensitivity and 92% (95% CI=90.5-94.1) specificity. In addition, 24 socio-demographic, socio-psychiatric data and personal and obstetric variables were surveyed. Results of a hierarchical logistic regression analysis showed that depression of the mother during pregnancy was the strongest predictor of depressive symptoms post-partum. Depression before pregnancy, housing conditions, marital relationship status and family history of alcohol problems were also identified as predictors for post partum depressive symptoms. PMID- 20965096 TI - Explaining the ineffectiveness of a Tai Chi fall prevention training for community-living older people: a process evaluation alongside a randomized clinical trial (RCT). AB - The results of a randomized clinical trial (RCT) on the effects of a Tai Chi fall prevention in community-living older people with a high risk of falling in the Netherlands showed no beneficial effects on falls and secondary outcomes (e.g., balance, fear of falling). The aim of this study is to provide insight in process related factors that may have influenced the effectiveness of the intervention. The intervention consisted of Tai Chi Chuan (TCC) training for 1 h twice a week for 13 weeks. We used self-administered questionnaires and registration forms to collect data from participants and instructors. We analyzed quantitative data by means of descriptive statistics and categorized qualitative data based on the content of the answers given. Of the participants, that started the program 89 (79%) completed the intervention, but a minority of 47% attended 80% of more of the lessons. All participants and instructors were positive about the program and most participants reported benefits from the intervention. Suggestions for improvements mainly relate to adjustments of training aspects. The main process related factors that may be have influenced the lack of beneficial effects on falls and secondary outcomes are the relatively high withdrawal and the low adherence rates. PMID- 20965097 TI - Reduction of verotoxigenic Escherichia coli by process and recipe optimisation in dry-fermented sausages. AB - Outbreaks of verotoxigenic Escherichia coli (VTEC) linked to dry-fermented sausages (DFSs) have emphasized the need for DFS manufacturers to introduce measures to obtain enhanced safety and still maintain the sensory qualities of their products. To our knowledge no data have yet been reported on non-O157:H7 VTEC survival in DFS. Here, the importance of recipe and process variables on VTEC (O157:H7 and O103:H25) reductions in two types of DFS, morr and salami, was determined through three statistically designed experiments. Linear regression and ANOVA analyses showed that no single variable had a dominant effect on VTEC reductions. High levels of NaCl, NaNO(2), glucose (low pH) and fermentation temperature gave enhanced VTEC reduction, while high fat and large casing diameter (a(w)) gave the opposite effect. Interaction effects were small. The process and recipe variables showed similar effects in morr and salami. In general, recipes combining high batter levels of salt (NaCl and NaNO(2)) and glucose along with high fermentation temperature that gave DFS with low final pH and a(w), provided approximately 3 log(10) reductions compared to approximately 1.5 log(10) reductions obtained for standard recipe DFS. Storage at 4 degrees C for 2months provided log(10) 0.33-0.95 additional VTEC reductions and were only marginally affected by recipe type. Sensory tests revealed only small differences between the various recipes of morr and salami. By optimisation of recipe and process parameters, it is possible to obtain increased microbial safety of DFS while maintaining the sensory qualities of the sausages. PMID- 20965098 TI - Preliminary results of a novel enhancement method for high-frequency hearing loss. AB - In this study, a software program was developed for high-frequency hearing loss subjects that includes a detailed audiogram and novel enhancement methods. The software performs enhancements of the audibility of high-frequency sounds according to the subject's detailed 31-point audiogram. This provides subject specific gains in the entire frequency spectrum, and especially for high frequencies, of sounds. Amplification, compression, and transposition are the three main processing methods used to obtain the desired enhancements for the subjects. For low frequencies, only the amplification method was used according to the dB value of the input. For mid and high frequencies, the compression and transposition methods were used together. To obtain the preliminary results of the study, 10 subjects were enrolled in a detailed audiogram study for five weeks. In the study, environmental, music, and speech sounds were used. While the perceptual mean performances of the subjects were in the range of 25.33-63.77% in the first week, those values increased to 68.75-95.75% in the fifth week. In particular, all noisy and speech sounds were more significantly identified and understood by the subjects with the enhancement method (from 25.33% to 87.5% and from 42.33% to 90.5%, respectively). Three subjects had dropped out at the end of the study and small number of participants are the limitations of this study; however, as a preliminary result, some ideas can be inferred from the results for a smaller set of subjects obtained in the five weeks of the study. Thus, the reliability of the study needs to be tested with more subjects and a comparison with their own hearing aids should be conducted. PMID- 20965099 TI - Immune depression of the SJL/J mouse, a radioresistant and immunologically atypical inbred strain. AB - As the inbred mouse strain SJL/J displays increased resistance to several pathogens and as its immune system shows multiple specificities, it is tempting to infer a causal link between these observations. The first question that comes to mind is whether adaptive immunity plays a role, and a way to answer this question is to see if the resistance phenotype persists when adaptive immunity is depressed. Although it has long been known that irradiation causes repression of leukopoiesis in mice, the technical data available in the literature are of no help in the case of strain SJL/J, because it displays exceptional radioresistance. Here we show that exposure of SJL/J to ~9Gy, an intensity corresponding to the lethal dose 50 for the species Mus musculus, leads to serious but reversible alteration of leukopoiesis. This conclusion stems from an examination of the effects, 1-11 days post-exposure, of whole-body gamma-ray irradiation on leukocyte populations in the thymus and peripheral blood of young adult females. Immunodepression was most severe 4 days post-exposure. As in other strains, leukocyte populations displayed differential radiosensitivity, B (CD19(+)) cells being most sensitive, T (CD4(+)/CD8(+)) cells moderately sensitive, and natural killer (NK1.1(+)) cells most resistant. Surprisingly, however, the helper/inducer T lymphocytes proved more resistant than the cytotoxic/suppressor T lymphocytes, contrarily to what is observed in other strains. The procedure described will make it possible to refute or establish reliably the existence of causal links between SJL-specific phenotypic traits and immune aberrations and to elucidate further the respective roles of innate and acquired immunity in determining the resistance of this strain to an array of viral diseases. PMID- 20965101 TI - Risk factors for treatment failure in patients with prosthetic joint infections. AB - A retrospective, observational cohort study was conducted to describe the incidence, clinical and microbiological findings and to evaluate risk factors for treatment failure associated with prosthetic joint infections (PJIs). We retrospectively reviewed the medical records of all patients undergoing total knee or total hip prosthesis implantation in our institution between 1994 and 2008. Our institution is a 1950-bed tertiary care university hospital and referral centre. A total of 93 patients with PJIs was identified although only 68 patients had undergone prosthesis implantation at our hospital. The overall infection rate was 0.63%. The most common organisms isolated were Gram positive (76.5%), including meticillin-resistant staphylococci. Two-stage arthroplasty was performed in 48 (51.6%) patients, and debridement and retention of the prosthesis in 34 (36.5%) patients. When 43 patients followed up for more than two years after treatment were included in treatment outcome analysis, the overall treatment failure rate was 41.8% (18/43). Staphylococcus aureus infection was the only clinical variable associated with treatment failure (odds ratio: 11.9; 95% confidence interval: 1.07-133.9; P=0.044), after adjustment for the other variables. In conclusion, S. aureus was the most common pathogen isolated in patients with PJI, and an independent risk factor for treatment failure in patients with PJI. PMID- 20965102 TI - [Transient apical dysfunction syndrome (Tako-Tsubo) simulating acute myocardial infarction]. AB - Transient apical dysfunction syndrome (TADS) is frequently misdiagnosed as an acute coronary syndrome (ACS). It is characterized by electrocardiographic alterations and elevated myocardial necrosis markers, accompanied by hypokinesia, akinesia or anteroapical dyskinesia, in absence of significant coronary disorders. It generally resolves in days or weeks with individualized support measures. We present the case of a female patient referred to our service for a myocardial perfusion imaging study due to a history suggestive of an acute coronary syndrome after a stressful event. PMID- 20965103 TI - Nursing the patient, the room and the doctor: Assessing New Zealand nurses' practical capability, 1900-1945. AB - Assessing nurses' practical capability was a challenge in the past as it is today. In 1901 New Zealand established state registration of nurses, with a standardised three-year hospital-based training system and state final examinations. Nurses' practical capability was assessed in an oral and practical examination and in general nursing questions in written medical and surgical nursing papers. This historical research identifies the practical component of nursing assessed in these examinations, categorising it as nursing the patient, the room and the doctor. It considers changes in the nursing profession's view, 1900-1945, of the best way to assess nurses' practical capability. This shifted from the artificial setting of the oral and practical examination held by doctors and matrons, to a process of senior nurses assessing candidates in the more realistic setting of a ward. The research also considers whether the nursing or medical profession defined nursing practice. By the end of the time period, the nursing profession was claiming for itself the right to both determine and assess the practical component of nursing. PMID- 20965105 TI - Stability of dental implants in grafted bone in the anterior maxilla: longitudinal study. AB - We aimed to assess the stability over time of dental implants placed in grafted bone in the maxilla using resonance frequency analysis, and to compare the stability of implants placed in grafted and non-grafted bone. Data were collected from 23 patients (15 test and 8 controls) in whom 64 implants (Branemark system, Nobel Biocare, Goteborg, Sweden) were placed in accordance with the two-stage surgical protocol. In the test group 36 fixtures were placed in grafted bone, and in the control group 28 fixtures were placed in non-grafted bone. Resonance frequency analysis was used to assess the test sites at implant placement and abutment connection. The mean (SD) implant stability quotient (ISQ) for test sites at the time of implant placement was 61.91 (6.68), indicating excellent primary stability, and was 63.53 (5.76) at abutment connection. ISQ values at abutment connection were similar for test and control sites. Implants placed in grafted bone compared favourably with those in non-grafted bone, and showed excellent stability. PMID- 20965107 TI - Loss in childbearing among Gambia's kanyalengs: using a stratified reproduction framework to expand the scope of sexual and reproductive health. AB - This paper draws on ethnographic fieldwork with Gambian women who have experienced infertility and/or child mortality and who have consequently become kanyalengs. Kanyaleng kafoos are groups of women united by their reproductive difficulties whose bold public performances are designed to "beg God" for fertility and for children who will survive. I situate 'kanyalengs' disrupted childbearing within a framework of stratified reproduction, which reveals the tensions between ongoing demands to meet norms of high fertility, women's heavy burden of reproductive disease and the limits of a reproductive public health agenda narrowly focused on family planning and HIV prevention. To ameliorate these tensions, I call for an expansion of the sexual and reproductive health (SRH) agenda in Gambia to include RTI/STI prevention, diagnosis and management. This expansion reflects the goals set out by the Cairo International Conference on Population and Development for a broader approach to reproductive health, the productive potential of linkages between SRH and HIV prevention efforts, as well as the reproductive objectives of Gambian women and men. PMID- 20965109 TI - Pseudomonas aeruginosa bacteraemia in burns patients: Risk factors and outcomes. AB - INTRODUCTION: We aimed to identify the risk factors for, and outcomes of Pseudomonas aeruginosa bacteraemia in adult burns patients. METHOD: All adult burns patients who developed a Gram-negative bacteraemia over a period of 7 years were included. Retrospective data analysed included patient demographics, organisms cultured, antibiotic susceptibility patterns, isolation of P. aeruginosa in non-blood isolates, treatment, length of stay and mortality. RESULTS: Forty-three patients developed a Gram-negative bacteraemia over the study period, 12 of whom had Pseudomonas bacteraemia during the course of their admission. In eight patients (18.6%) P. aeruginosa was the first Gram-negative isolated. The only factor predicting P. aeruginosa bacteraemia as a first episode (compared to another Gram-negative) was prior isolation of Pseudomonas at other sites (wound sites, urine or sputum). Overall length of stay was less in patients who developed P. aeruginosa as a first episode, mainly because of increased mortality in this group. Prior non-blood isolates of P. aeruginosa could have correctly predicted the sensitivity pattern of the strain of P. aeruginosa organism in 75% of patients who did not receive appropriate initial antibiotics. CONCLUSION: Prior colonisation with P. aeruginosa predicts P. aeruginosa in blood cultures, as opposed to other Gram-negative bacteria. Clinicians should have a high index of suspicion for P. aeruginosa bacteraemia where a septic burns patient has a prior history of non-blood P. aeruginosa cultures. Empirical antibiotic regimes based on the antibiotic-sensitivity patterns of previous non blood P. aeruginosa isolates in each patient should be given at the time blood cultures are taken. PMID- 20965112 TI - MRI assessment of changes in liver iron deposition post-venesection. AB - OBJECTIVE: The aim of this study was to determine if changes in hepatic iron content in patients with hemochromatosis pre- and post-venesection could be detected by changes in liver signal intensity with MRI. MATERIALS AND METHODS: The study was performed with institutional ethics approval and with informed consent. Gradient echo images were performed on 20 patients with hemochromatosis pre- and post-venesection and 10 control subjects: gradient echo T1-weighted in- and out-phases (4.54 (in)/2.27 (out), 167 [TE/TR], Flip 70 degrees ) and gradient echo T2* (5/18 [TE/TR], Flip 10 degrees ). The liver to muscle signal ratio was compared pre- and post-venesection. RESULTS: All MRI sequences showed significant correlation between the liver to muscle signal intensity ratio and the serum ferritin pre-venesection [r=-0.70, -0.65, -0.74, -0.72, in/out/T2*r/T2*, respectively]. There was a significant increase on all sequences in the liver to muscle signal intensity ratio post-venesection (p<0.001). The control group and patients post-venesection had almost identical liver to muscle signal intensity ratios. CONCLUSION: The reduction in liver signal intensity caused by iron excess in hemochromatosis returns to normal post-venesection. Measurement of liver to muscle signal intensity ratios may be a useful tool in assessing treatment response in iron overload states. PMID- 20965114 TI - The impact of young age on breast cancer outcome. AB - AIMS: We conducted a retrospective analysis in order to evaluate the impact of age on women aged less than 35 years affected by breast cancer. MATERIALS AND METHODS: Between January 1972 and December 2006, 346 patients aged less than 35 years underwent adjuvant treatment at Florence University. The mean age of the patient population was 32 years (range 22-35): 76 patients were under 30 years old, the remaining were above 30 years old. RESULTS: In our series, 215 patients received adjuvant radiotherapy to whole breast after conservative surgery, 131 patients underwent mastectomy without subsequent radiation therapy and 323 patients had lymphadenectomy; 191 patients received adjuvant chemotherapy, 73 with anthracycline-containing regimen. With a median time of 2.5 years (range 6 months to 27.6 years) local relapses were observed in 67 cases (19.4%). At the multivariate analysis of local disease-free survival, ductal and ductal plus lobular histotypes, having more than 3 positive nodes, and age emerged as independent significant relapse predictors (p=0.018, p=0.0005, p=0.003 and p=0.024, respectively). For the DSS analysis, the median follow-up was 6.8 years (range 0.6-36.7 years). At the multivariate analysis, age (p=0.0038), positive nodes (p=0.0035) and distant metastases (p<0.0001) resulted to be independent death predictors. Patients younger than 30 had a worse prognosis. At the univariate analysis also local relapse resulted to be statistically significant (p=0.0004). CONCLUSIONS: Anthracycline-based chemotherapy seems to improve the outcome of these patients. However, there is an urgent need for tailored treatment investigations within the framework of randomized, controlled clinical trials. PMID- 20965116 TI - [Liver transplantation and pregnancy]. AB - Patients with liver failure have menstrual cycle irregularities or amenorrhea. Liver transplantation restores menstrual pattern among women with cirrhosis in childbearing years. It is now accepted that a planned pregnancy is possible among liver transplant recipients at least 1 year after liver transplantation, with stable allograft function and under immunosuppressive regimens, to minimize the risks of preterm delivery and pregnancy-induced hypertension. After 1 year, the risk of graft loss decreases and is not related to pregnancy. It is a high-risk pregnancy which requires a specific and regular multidisciplinary joint follow-up (obstetrician, hepatologist, and anaesthesiologist), which leads in most cases to successful outcome for mother and child. But, early prevention and multidisciplinary management of the most common complications (pregnancy-induced hypertension, preeclampsia, and fetal growth restriction) is essential. The prematurity rate, maternal morbidity and mortality are higher than in the general population. Usual immunosuppressive treatments (corticoids, cyclosporine, tacrolimus, azathioprine or mycophenolate mofetil) may require dose adaptation during pregnancy. Immunosuppressive drugs are not teratogenic, but breast feeding is not allowed. PMID- 20965118 TI - Treatment of atypical depression: post-hoc analysis of a randomized controlled study testing the efficacy of sertraline and cognitive behavioural therapy in mildly depressed outpatients. AB - OBJECTIVE: Atypical features are common among depressed primary care patients, but clinical trials testing the efficacy of psychopharmacological and/or psychotherapeutic treatment are lacking. This paper examines the efficacy of sertraline and cognitive behavioural therapy (CBT) among depressed patients with atypical features. SUBJECTS AND METHODS: Analyses involve a double-blind comparison of sertraline versus placebo (N=47) and a single-blind comparison between CBT versus a guided self-help group (GSG) (N=48), with primary efficacy endpoints being the Inventory of Depressive Symptomatology (IDS(C)) and Hamilton Depression Scale (HAMD-17). RESULTS: In intent-to-treat (ITT) analyses, the decrease on the IDS(C) scale (and HAMD-17) was greater after CBT compared to GSG: p=0.01 (HAMD-17: p=0.01). The difference between selective serotonin reuptake inhibitors (SSRI) versus placebo was not significant: p=0.22 (HAMD-17: p=0.36). LIMITATIONS: The number of cases in each treatment group was small, thereby limiting statistical power. Patients medicated with sertraline were 10 to 15 years younger than those included in the other groups of treatment. CONCLUSIONS: CBT may be an effective alternative to GSG for mildly depressed patients with atypical features. Although SSRI were not superior to placebo, it would be premature to rule out SSRI as efficacious in atypical depression. PMID- 20965119 TI - How to improve clinical practice on involuntary hospital admissions of psychiatric patients: suggestions from the EUNOMIA study. AB - Number and procedures of involuntary hospital admissions vary in Europe according to the different socio-cultural contexts. The European Commission has funded the EUNOMIA study in 12 European countries in order to develop European recommendations for good clinical practice in involuntary hospital admissions. The recommendations have been developed with the direct and active involvement of national leaders and key professionals, who worked out national recommendations, subsequently summarized into a European document, through the use of specific categories. The need for standardizing the involuntary hospital admission has been highlighted by all centers. In the final recommendations, it has been stressed the need to: providing information to patients about the reasons for hospitalization and its presumable duration; protecting patients' rights during hospitalization; encouraging the involvement of family members; improving the communication between community and hospital teams; organizing meetings, seminars and focus-groups with users; developing training courses for involved professionals on the management of aggressive behaviors, clinical aspects of major mental disorders, the legal and administrative aspects of involuntary hospital admissions, on communication skills. The results showed the huge variation of involuntary hospital admissions in Europe and the importance of developing guidelines on this procedure. PMID- 20965120 TI - Hypoglycemic activity of Buchholzia coriacea (Capparaceae) seeds in streptozotocin-induced diabetic rats and mice. AB - The present study evaluates the possible hypoglycemic activity and ameliorative effects of oral administration of ethanol extracts (EEBC) and butanol fraction (BFBC) of Buchholzia coriacea seeds, a plant in use traditionally for treating diabetes, hypertension, rheumatism, cold, cough and catarrh, in streptozotocin (STZ)-induced diabetic mice and rats. Fasting blood glucose (FBG) levels were evaluated before and after extracts administration. EEBC and BFBC significantly decreased (P<0.05) FBG in hyperglycemic mice and normoglycemic rats within 4 and 12 h, respectively after extract administration. The administration of EEBC, BFBC and glibenclamide (a standard antidiabetic drug) for 10 days significantly lowered (P<0.05) FBG level in STZ-induced diabetic rats by 55%, 64% and 56%, respectively. EEBC and BFBC significantly (P<0.05) decreased hepatic injury induced by STZ as evident in the decreased activity of serum alanine amino transferase and aspartate amino transferase compared to in the STZ-only treated group. Similarly, both extracts significantly decreased (P<0.05) the elevated levels of serum creatinine, urea, total cholesterol, triglyceride and thiobarbituric acid reactive species (TBARS) products in diabetic rats. Serum superoxide dismutase activity was significantly enhanced (P<0.05) by treatments with EEBC, BFBC and glibenclamide. Overall, the results suggest that B. coriacea seeds contain a potent hypoglycemic and antioxidant agent suggested to be a flavone glycoside concentrated in BFBC which may find clinical application in amelioration of diabetes-induced secondary complications. PMID- 20965125 TI - Viability of probiotic bacteria in maple sap products under storage and gastrointestinal conditions. AB - This study was undertaken to develop new probiotic products based on liquid maple sap or its concentrate. Sap and concentrate, with or without inulin (2%) were inoculated with Bifidobacterium lactis Bb12 and Lactobacillus rhamnosus GG valio at initial counts of 107-108 CFU/ml. Viability was assessed over four weeks of storage at 4 degrees C and under in vitro simulated gastrointestinal conditions using dynamic gastrointestinal model known as TIM-1. Viability was maintained throughout the storage period at the same order of 107 to 108 CFU/ml. Inulin significantly enhanced the survivability during passage through the gastrointestinal tract simulator. The developed products could be an excellent alternative for delivering probiotics, especially for individuals suffering from lactose intolerance to dairy products. PMID- 20965126 TI - Bioethanol from the Portuguese forest residue Pterospartum tridentatum--an evaluation of pretreatment strategy for enzymatic saccharification and sugars fermentation. AB - Under the current energy scenario, the development of alternatives to fossil fuels, like bioethanol from lignocellulosic materials, is highly relevant. Therefore it is important to search and study new raw materials and to optimize the different steps that lead to bioethanol production. In this work, acid diluted pretreatment was optimized considering the release of sugars. Under the optimal conditions, the reducing sugars yield was of 293.4mg/g of dry biomass in liquid fraction. The tested pretreated samples of Pterospartum tridentatum that presented a higher glucose yield in enzymatic saccharification where those that were subject to a pretreatment at 180 degrees C for 75min with 2.75% (w/w) of sulfuric acid when using a biomass/liquid ratio of 2.25g/10mL leading to a maximum yield of glucose that was 92% of the theoretical maximum. From the fermentation of filtrates it was possible to obtain a maximum ethanol yield of 0.26g ethanol/g total sugars, without previous detoxification. PMID- 20965128 TI - Comparison and reproducibility of sEMG during manual muscle testing on land and in water. AB - The objectives of this study were to: (1) compare the sEMG recordings from maximal voluntary contractions (MVC), and (2) examine the reproducibility of sEMG recordings from MVCs for selected lower extremity muscles derived from manual muscle testing (MMT) on dry land, and in water prior to and following aquatic treadmill running. Twelve healthy recreational male runners participated. The selected muscles were: M. quadriceps-vastus medialis (VM) and rectus femoris (RF), M. biceps femoris (BF), M. tibialis anterior (TA) and the M. gastrocnemius caput mediale (GAS) of the right leg. The MVC testing conditions were: dry land, underwater prior to (Water 1) and following an aquatic exercise trial (Water 2). For each muscle, a one-way analysis of variance with repeated measures was used to compare MVC scores between testing conditions, and the intra-class correlation coefficient (ICC) and typical error (CV%) were calculated to determine the reproducibility and precision of MVC scores, respectively, between conditions. For all muscles, no significant differences were observed between land and water MVC scores (p=0.88-0.97), and high reliability (ICC=0.96-0.98) and precision (CV%=7.4-12.6%) were observed between MVC conditions. Under MMT conditions it appears that comparable MVC sEMG values were achieved on land and in water and the integrity of the EMG recordings were maintained during water immersion. Future studies using sEMG waterproofing procedures should conduct MVC testing in water for data normalization and perform post-exercise verification of sEMG signal integrity. PMID- 20965129 TI - A biological alternative to alloplastic grafts in dialysis therapy: evaluation of an autologised bioartificial haemodialysis shunt vessel in a sheep model. AB - OBJECTIVES: To evaluate bioartificial haemodialysis access grafts in a sheep model with respect to patency and morphology. MATERIAL AND METHODS: Bovine internal thoracic arteries (n=28) were decellularised. Fourteen grafts (DC grafts) were directly implanted as cervical AV shunts, the remaining were re seeded with endothelial cells (ECs) derived from blood samples of the later ovine recipient (EC grafts) first. Following simulated punctures and duplex ultrasound scans to determine patency, grafts were explanted for immunohistochemical characterisation after 3 and 6 months, respectively. DC grafts underwent biomechanical testing for compliance (C), suture retention strength (SRT), and burst pressure (BP) before (n=6) and after (n=6) implantation. RESULTS: Following 3 and 6 months, the majority of EC (n=6/6; n=6/7) and DC grafts (n=5/6; n=5/7) were patent and not relevantly stenosed (peak systolic velocity: EC grafts=76 cm s(-1)+/-4; DC grafts=77 cm s(-1)+/-5). Simulated haemodialysis punctures revealed significantly shorter bleeding times in all bioartificial grafts than in native jugular veins (P>0.001). Comparing native carotid arteries with DC grafts prior to and post-implantation, the latter differed significantly with respect to C (P>0.001; P=0.005), whereas only pre-implant DC grafts differed regarding BP (P=0.002); no differences were observed for SRT. Histology revealed complete endothelial surface coverage of EC, but not DC grafts. Furthermore, DC grafts exhibited areas of pronounced tissue calcification. CONCLUSION: The preclinical development of a bioartificial haemodialysis access graft with promising mechanical and morphological properties in a sheep model is feasible. PMID- 20965130 TI - The effect of nocturia on sleep. AB - Sleep plays a vital role in physical and mental functioning. It is increasingly recognized that disturbed sleep is a highly prevalent and chronic condition that merits greater awareness due to the wide-ranging and serious repercussions associated with it. Nocturia is one of the causes of sleep disturbance and has been shown to impair functioning, quality of life, health and productivity, with those experiencing two or more voids per night reporting significant 'bother'. Nocturia warrants full consideration as a significant target for intervention, aiming to reduce the burden of disturbed sleep on individuals, families and society. Currently, however, a definitive evaluation of the most relevant sleep endpoints in nocturia therapy is lacking. One endpoint often used is the duration of the initial sleep period, which when evaluated in combination with the number of voiding episodes per night, might be an indication of the severity of sleep disruption in patients with nocturia. PMID- 20965131 TI - A systematic review of insomnia and complementary medicine. AB - In concert with growing public interest in complementary and alternative medicine (CAM), these therapies and products have been increasingly studied over the past two decades for the treatment of sleep disorders. While systematic reviews have been conducted on acupuncture and valerian in the treatment of insomnia, to date no comprehensive review has been conducted on all major CAM treatments. We sought to address this via a rigorous systematic review of hypnotic CAM interventions, including herbal and nutritional medicine, acupuncture, acupressure, yoga, tai chi, massage, aromatherapy and homoeopathy. The electronic databases MEDLINE (PubMed), CINAHL, PsycINFO, and The Cochrane Library were accessed during late 2009 for CAM randomized controlled trials (RCTs) in the treatment of chronic insomnia. Sixty-four RCTs were identified, of which 20 studies involving eight CAM interventions met final inclusion criteria. Effect size calculations (where possible) and a quality control analysis using a modified Jadad scale were undertaken. Many RCTs lacked methodological rigor, and were commonly excluded due to small sample size or an inadequate control condition. Among the studies that met inclusion criteria, there was evidentiary support in the treatment of chronic insomnia for acupressure (d=1.42-2.12), tai chi (d=0.22-2.15), yoga (d=0.66 1.20), mixed evidence for acupuncture and L-tryptophan, and weak and unsupportive evidence for herbal medicines such as valerian. Surprisingly, studies involving several mainstream CAM therapies (e.g., homoeopathy, massage, or aromatherapy) were not located or did not meet basic inclusion criteria. If CAM interventions are to be considered as viable stand-alone or adjuvant treatments for sleep disorders, future researchers are urged to use acceptable methodology, including appropriate sample sizes and adequate controls. RCTs evaluating other untested CAM therapies such as massage, homoeopathy, or osteopathy are encouraged, as is the exploration of using CAM therapies adjuvantly with conventional therapies. PMID- 20965132 TI - Mycobacterium tuberculosis infection in grazing cattle in central Ethiopia. AB - A preliminary study to characterise mycobacteria infecting tuberculous cattle from two different management systems in central Ethiopia was carried out. Approximately 27% of isolates from grazing cattle were Mycobacterium tuberculosis, while cattle in a more intensive-production system were exclusively infected with M. bovis. The practice of local farmers discharging chewed tobacco directly into the mouths of pastured cattle was identified as a potential route of human-to-cattle transmission of M. tuberculosis. PMID- 20965133 TI - Pain and other symptoms of CRPS can be increased by ambiguous visual stimuli--an exploratory study. AB - BACKGROUND: Visual disturbance, visuo-spatial difficulties, and exacerbations of pain associated with these, have been reported by some patients with Complex Regional Pain Syndrome (CRPS). AIMS: We investigated the hypothesis that some visual stimuli (i.e. those which produce ambiguous perceptions) can induce pain and other somatic sensations in people with CRPS. METHODS: Thirty patients with CRPS, 33 with rheumatology conditions and 45 healthy controls viewed two images: a bistable spatial image and a control image. For each image participants recorded the frequency of percept change in 1 min and reported any changes in somatosensation. RESULTS: 73% of patients with CRPS reported increases in pain and/or sensory disturbances including changes in perception of the affected limb, temperature and weight changes and feelings of disorientation after viewing the bistable image. Additionally, 13% of the CRPS group responded with striking worsening of their symptoms which necessitated task cessation. Subjects in the control groups did not report pain increases or somatic sensations. CONCLUSIONS: It is possible to worsen the pain suffered in CRPS, and to produce other somatic sensations, by means of a visual stimulus alone. This is a newly described finding. As a clinical and research tool, the experimental method provides a means to generate and exacerbate somaesthetic disturbances, including pain, without moving the affected limb and causing nociceptive interference. This may be particularly useful for brain imaging studies. PMID- 20965135 TI - New developments in pathogenicity and virulence of necrotrophs. AB - It was generally considered that necrotrophic plant pathogenic fungi possessed simplistic pathogenic mechanisms being typically reliant on 'blasting' their way through host tissue with a battery of lytic and degradative enzymes. However recent studies have suggested that this is not true and that necrotrophic fungal pathogens can subtly manipulate the host during infection in a manner similar to biotrophic pathogens. For example, it has been demonstrated that the wheat pathogens Stagonospora nodorum and Pyrenophora tritici-repentis secrete small unique proteins (effectors) that are internalised by host cells and interact with the host in a gene-for-gene relationship to initiate disease, albeit in an inverse manner compared to biotrophs. This paper reviews recent developments in necrotrophic fungal pathogenicity throughout a critical period that arguably saw this field come of age. PMID- 20965139 TI - Spectral iEEG markers precede SSEP events during surgery for subarachnoid hemorrhage. AB - OBJECTIVE: During neurosurgical intracranial vascular manipulations, surgeons need early feed-back on the effects of temporary vascular occlusion. In surgical practice, commonly the amplitude of somatosensory evoked potentials (SSEP) is monitored. However, the latency between an ischemic event and the drop of SSEP amplitude may amount to several minutes. Therefore intracranial electroencephalogram (iEEG) is tested for its predictive value. METHODS: During surgery in 13 patients, SSEP was recorded simultaneously with iEEG. iEEG was analyzed real-time in the frequency domain. Spectral observables of the iEEG were validated on the basis of SSEP by computing the statistical correlation first for the whole data set, then for salient events occurring in the SSEP in the group of patients, and finally for salient events occurring in single patients. RESULTS: Placement of subdural strip electrodes was compatible with standard surgical routine. Maximal correlation between time series of iEEG and SSEP was found for relative alpha power, which preceded the drop of SSEP by 7min. CONCLUSIONS: iEEG is feasible during neurosurgical intracranial vascular manipulations. Monitoring relative alpha power detects salient events earlier than SSEP. SIGNIFICANCE: Early detection of salient events facilitates early reaction of the surgeon and may thereby aid to further reduce intraoperative morbidity. PMID- 20965140 TI - Urethroplasty for failed hypospadias repair: a matched cohort analysis. AB - OBJECTIVE: To determine the outcome of urethroplasty for failed hypospadias repair and to compare this with a matched cohort of patients treated with urethroplasty for other reasons. PATIENTS AND METHODS: Between January 2000 and August 2007, 25 patients with a failed hypospadias repair were treated with urethroplasty (A). This cohort of patients was matched with a cohort of 25 patients who underwent urethroplasty for other reasons (B). The patients were matched for stricture location, stricture length, duration of follow up and type of urethroplasty. The outcomes were analysed and compared. A P-value < 0.05 was considered statistically significant. RESULTS: There were no significant differences between the two cohorts in stricture location, stricture length, follow up and previous interventions. Patients in cohort A however were significantly younger. The surgical technique used was exactly the same in A and B. Failure was observed in 7 patients (28%) in A compared to 4 patients (16%) in B (P = 0.45). CONCLUSIONS: Although a higher failure rate was observed after failed hypospadias repair, this is not proof of a worse outcome for urethroplasty after failed hypospadias repair due to the lack of statistical significance. PMID- 20965141 TI - Redefining gigantomastia. AB - Gigantomastia is a rare but disabling condition characterised by excessive breast growth. Most definitions of gigantomastia refer to a particular weight of excess breast tissue. We speculate that in gigantomastia the weight of the breasts contributes significantly to the BMI, which has implications for healthcare rationing. This study aims to establish the contribution breast tissue makes to BMI in gigantomastia. In so doing, we propose a new definition of gigantomastia. Retrospective data was collected from the case notes of 68 females who underwent breast reduction or therapeutic mastectomy for gigantomastia. For the purposes of patient inclusion, gigantomastia is arbitrarily defined as excessive breast growth of over 1.5kg per breast. The difference between pre- and post-operative BMI is statistically significant (P<0.001). Mean pre-operative BMI is 38.7 with a mean specimen weight of 4506g. Mean contribution of specimen to body weight is 4.29%. There is no correlation between pre-operative body weight and the percentage contribution the breast resection specimen makes to body weight. Based on our data, we define gigantomastia as excess breast tissue that contributes 3% or more to the patient's total body weight, approximately one standard deviation below the mean. We suggest that the estimated excess breast tissue weight is taken into account when calculating pre-operative BMI in the gigantomastia population. The challenge of estimating excess breast weight pre-operatively may be met by 3D photography coupled with computer-assisted volumetry. PMID- 20965142 TI - Genetic analysis of 15 autosomal and 12 Y-STR loci in the Espirito Santo State population, Brazil. AB - This study provides population genetic data for individuals of Vitoria, Espirito Santo, Brazil, a location not yet characterized for STR frequencies used for genetic identification studies. Allelic frequencies and other population data analysis are reported for the 15 autosomal-STR loci included in the PowerPlex((r))16 kit (CSF1PO, D13S317, D16S539, D18S51, D21S11, D3S1358, D5S818, D7S820, D8S1179, FGA, Penta D, Penta E, TPOX, TH01 and vWA). Allele and haplotype frequencies, gene diversity and discrimination capacity were also estimated for the PowerPlex((r)) Y System (DYS19, DYS385, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438 and DYS439). Blood samples were obtained from 226 unrelated volunteers (135 males and 91 females) residents in the city of Vitoria, representing a typical sample of the mixed ethnicity present in the Espirito Santo State, Brazil. Within the tested population, the total number of individuals typed for specific markers is: 226 for D13S317, D21S11, D3S1358, D7S820, D8S1179 and FGA; 225 for D16S539 and D5S818; 224 for D18S51; 223 for CSF1PO; 222 for Penta D and vWA; 220 for Penta E; 207 for TPOX and 142 for TH01. Y-STR haplotypes were analyzed for 102 unrelated males, being 71 of them present in the 135 autosomal-STR sample, and 31 new males tested only for Y-STR markers. All autosomal markers were in Hardy-Weinberg Equilibrium. Y-STR analysis identified 101 haplotypes, being 100 of them unique. PMID- 20965143 TI - Near-miss event assessment in orthopedic surgery: Antimicrobial prophylaxis noncompliance. AB - INTRODUCTION: Antimicrobial prophylaxis is one of the main safety measures to be enforced when implanting any medical device; surveys of practice, however, have found poor compliance. MATERIAL AND METHODS: This study is based on analysis of 153 dedicated in-depth analysis forms sent to orthopedic surgeons who had reported an antimicrobial prophylaxis-related near-miss event (NME) during the year 2008 as part of their certification report to the official organization, Orthorisq (orthopaedic Patient safety risk management agency). RESULTS: Antimicrobial prophylaxis guidelines exist in 95% of French centers, but in 14% are not available in the right place. 88% of orthopedic surgeons consider them well-adapted to their practice. Most declarations follow fortuitous discovery by the surgeon of an immediate peri-operative malfunction. Human causes were found in 92% of declarations, general organizational causes in 50% and material causes in 28%. Regarding corrective action, 65% of respondents reported implementing a second-order procedure, and only 20% were able to resume truly regular antimicrobial prophylaxis. CONCLUSION: The main reason for poor or non performance of antimicrobial prophylaxis was "omission by negligence or oversight", reported in 56% of declarations. Proposals for improvement were: revised antimicrobial prophylaxis guidelines specifying "who does what"; guideline awareness checks on new, temporary and locum-tenens staff; patient involvement in personal data collection; and implementation of a check-list in line with WHO and French Health Authority recommendations. These improvement proposals were taken on board in the antimicrobial prophylaxis consensus update currently being drawn up by the French Society for Anesthesia and Intensive Care. LEVEL OF EVIDENCE: Level IV, Decision Analyses Study. PMID- 20965145 TI - Role of sulfurous mineral water and sodium hydrosulfide as potent inhibitors of fibrosis in the heart of diabetic rats. AB - This study examined the downstream signaling whereby hyperglycemia may lead to myocardial fibrosis and apoptosis in the left ventricle of diabetic rats. The effects of sulfurous mineral water or sodium hydrosulfide (NaHS) as possible modulators were also examined. Sulfurous mineral water (as drinking water) and NaHS (14MUmol/kg/day, IP) were administered for 7 week to rats with streptozotocin (STZ)-induced diabetes. Hyperglycemia, overproduction of glycated hemoglobin (HbA1C) and serum decline in insulin, C-peptide and insulin like growth factor-I (IGF-I) were observed in diabetic rats. Up-regulation of gene expressions of nuclear factor (NF-kappaB), profibrogenic growth factor such as transforming growth factor-beta1 (TGF-beta1), matrix metalloproteniase-2 (MMP-2), procollagen-1 and Fas ligand (Fas-L) were observed in the left ventricle of diabetic rats. A linear positive correlation between TGF-beta1 and MMP-2 was also detected in diabetic group. An increase in hydroxyproline level and a disturbance in oxidative balance were detected in heart of diabetic rats. Sulfurous mineral water and NaHS treatment possibly, by improving cardiac GSH level, counteracted the enhanced expression of NF-kappaB, the profibrogenic and apoptotic parameters. Histopathological examination was in accordance with the biochemical and molecular findings of this study. We suggest a novel therapeutic approach of sulfurous mineral water and exogenous supplementation of H(2)S in diabetic cardiomyopathy. PMID- 20965144 TI - Troponin T isoforms and posttranscriptional modifications: Evolution, regulation and function. AB - Troponin-mediated Ca2(+)-regulation governs the actin-activated myosin motor function which powers striated (skeletal and cardiac) muscle contraction. This review focuses on the structure-function relationship of troponin T, one of the three protein subunits of the troponin complex. Molecular evolution, gene regulation, alternative RNA splicing, and posttranslational modifications of troponin T isoforms in skeletal and cardiac muscles are summarized with emphases on recent research progresses. The physiological and pathophysiological significances of the structural diversity and regulation of troponin T are discussed for impacts on striated muscle function and adaptation in health and diseases. PMID- 20965146 TI - Supplement of TCA cycle intermediates protects against high glucose/palmitate induced INS-1 beta cell death. AB - The aim of this study is to investigate the effect of mitochondrial metabolism on high glucose/palmitate (HG/PA)-induced INS-1 beta cell death. Long-term treatment of INS-1 cells with HG/PA impaired energy-producing metabolism accompanying with depletion of TCA cycle intermediates. Whereas an inhibitor of carnitine palmitoyl transferase 1 augmented HG/PA-induced INS-1 cell death, stimulators of fatty acid oxidation protected the cells against the HG/PA-induced death. Furthermore, whereas mitochondrial pyruvate carboxylase inhibitor phenylacetic acid augmented HG/PA-induced INS-1 cell death, supplementation of TCA cycle metabolites including leucine/glutamine, methyl succinate/alpha-ketoisocaproic acid, dimethyl malate, and valeric acid or treatment with a glutamate dehydrogenase activator, aminobicyclo-heptane-2-carboxylic acid (BCH), significantly protected the cells against the HG/PA-induced death. In particular, the mitochondrial tricarboxylate carrier inhibitor, benzene tricarboxylate (BTA), also showed a strong protective effect on the HG/PA-induced INS-1 cell death. Knockdown of glutamate dehydrogenase or tricarboxylate carrier augmented or reduced the HG/PA-induced INS-1 cell death, respectively. Both BCH and BTA restored HG/PA-induced reduction of energy metabolism as well as depletion of TCA intermediates. These data suggest that depletion of the TCA cycle intermediate pool and impaired energy producing metabolism may play a role in HG/PA-induced cytotoxicity to beta cells and thus, HG/PA-induced beta cell glucolipotoxicity can be protected by nutritional or pharmacological maneuver enhancing anaplerosis or reducing cataplerosis. PMID- 20965147 TI - 1,25-Dihydroxyvitamin D is not responsible for toxicity caused by vitamin D or 25 hydroxyvitamin D. AB - Vitamin D intoxication was produced with oral doses of either vitamin D3 or 25 hydroxyvitamin D3 in CYP27B1 -/- (1alpha-hydroxylase knockout) and wild-type mice. These compounds were equally toxic in wild-type and the mutant mice. Since the null mutant mice are unable to produce 1,25-dihydroxyvitamin D, it is clear 1,25-dihydroxyvitamin D is not responsible for vitamin D intoxication. On the other hand, 25-hydroxyvitamin D rises to levels of 400-700 ng/ml or 1000-1750 nM in the serum of both groups of mice. Toxicity was evidenced by severe hypercalcemia and weight loss. Measurement of 1,25-dihydroxyvitamin D3 in serum confirmed its absence from serum of the CYP27B1 -/- mice given 25-hydroxyvitamin D3. Since high concentrations of 25-hydroxyvitamin D can bind the vitamin D receptor and can induce transcription, 25-hydroxyvitamin D is likely responsible for toxicity of vitamin D excess. PMID- 20965148 TI - MELAS syndrome, cardiomyopathy, rhabdomyolysis, and autism associated with the A3260G mitochondrial DNA mutation. AB - The A to G transition mutation at position 3260 of the mitochondrial genome is usually associated with cardiomyopathy and myopathy. One Japanese kindred reported the phenotype of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS syndrome) in association with the A3260G mtDNA mutation. We describe the first Caucasian cases of MELAS syndrome associated with the A3260G mutation. Furthermore, this mutation was associated with exercise induced rhabdomyolysis, hearing loss, seizures, cardiomyopathy, and autism in the large kindred. We conclude that the A3260G mtDNA mutation is associated with wide phenotypic heterogeneity with MELAS and other "classical" mitochondrial phenotypes being manifestations. PMID- 20965149 TI - Generation and characterization of T1R2-LacZ knock-in mouse. AB - Taste cells are chemosensory epithelial cells that sense distinct taste quality such as umami, sweet, bitter, sour and salty. Taste cells utilize G protein coupled receptors to detect umami, sweet and bitter taste whereas ion channels are responsible for detecting salty and sour taste. Among these taste receptors, taste receptor type 2, T1R2 (or Tas1r2), has been identified as a sole sweet taste receptor in mammals that mediates sweet signals upon dimerization with T1R3. However, because of limited availability of reliable antibodies and low expression level of G protein-coupled receptors, it is uneasy to identify the cell-types that express these receptors in non-taste tissues. In this study, we have generated a T1R2-LacZ reporter knock-in mouse to investigate tissue distribution of T1R2 at a single-cell level. We found that the LacZ gene expression in these mice was faithful to the expression of T1R2 in the taste tissue and in the gastrointestinal tract where T1R3 expression has been reported. Surprisingly, T1R2 expression was also found in the testis. Mice homozygous for T1R2 deletion lacked T1R2 protein analyzed by the antibody raised against T1R2 peptide sequences. In summary, the T1R2 knock-in mouse is a powerful tool to analyze the putative targets for sweeteners as well as to study the physiological roles of T1R2 in detecting sugars. PMID- 20965150 TI - Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model. AB - Recently, T cell cytokines such as IL-17 and IFN-gamma have been shown to play important roles in the progression of brain injury induced by ischemia. We have shown that IL-23 from infiltrated macrophages activates gammadeltaT cells, thereby inducing IL-17 from these cells. However, deletion of the IL-23 gene in mice showed a more dramatic protective effect against brain ischemia reperfusion (I/R) model than gammadeltaT cell depletion did, suggesting that IL-23 plays some other pivotal role in brain injury in addition to its role in IL-17 induction. To develop therapeutic methods based on these findings, we examined the effect of the JAK kinase inhibitor CP-690550 and an anti-IL12/23 monoclonal antibody on an I/R model. CP-690550 efficiently inhibited IL-17 production from memory T cells in vitro and partly suppressed infarct volume increase after I/R. Anti-p40 antibody, which blocks both IL-12 and IL-23, efficiently suppressed I/R injury and improved recovery of neurological deficits. The number of IL-17-producing cells was decreased by anti-p40 antibody treatment. Thus the JAK inhibitor and anti-p40 antibody, both of which have already been under trial for the treatment of several human inflammatory diseases, appear to be promising therapeutic agents for the amelioration of stroke. PMID- 20965151 TI - The human bitter taste receptor, hTAS2R16, discriminates slight differences in the configuration of disaccharides. AB - Sweetness and bitterness are key determinants of food acceptance and rejection, respectively. Sugars, such as sucrose and fructose, are generally recognized as sweet. However, not all sugars are sweet, and even anomers may have quite different tastes. For example, gentiobiose is bitter, whereas its anomer, isomaltose, is sweet. Despite this unique sensory character, the molecular basis of the bitterness of gentiobiose remains to be clarified. In this study, we used calcium imaging analysis of human embryonic kidney 293T cells that heterologously expressed human taste receptors to demonstrate that gentiobiose activated hTAS2R16, a bitter taste receptor, but not hT1R2/hT1R3, a sweet taste receptor. In contrast, isomaltose activated hT1R2/hT1R3. As a result, these anomers elicit different taste sensations. Mutational analysis of hTAS2R16 also indicated that gentiobiose and beta-D-glucopyranosides, such as salicin share a common binding site of hTAS2R16. PMID- 20965152 TI - SID1 transmembrane family, member 2 (Sidt2): a novel lysosomal membrane protein. AB - In a recent proteomic study of lysosomal proteins [10], we identified SID1 transmembrane family, member 2 (Sidt2) as a novel lysosomal membrane protein candidate. The Sidt2 gene encodes an 832-amino acid residues protein with a calculated molecular mass of 94.5kDa. Bioinformatic analysis showed that Sidt2 is a multipass transmembrane protein that contains 10 putative N-glycosylation sites (NxS/T) and two potential tyrosine-based sorting signals (YGSF and YDTL). Using specific anti-Sidt2 antibody and lysosomal markers, the lysosomal localization of Sidt2 was determined by immunofluorescence. Furthermore, using subcellular fractionation techniques, we demonstrated that Sidt2 is a lysosomal integral membrane protein. Endogenous Sidt2 was detected in multiple tissues of mouse and rat with approximately 120-130kDa molecular weights due to extensive glycosylation. After digestion with PNGase F, the apparent molecular mass of Sidt2 decreased to the predicted value of 95kDa. In rats, Sidt2 was highly expressed in the liver, brain, and kidney, whereas no or little expression was found in the skeletal muscles, heart, and other tissues. In summary, Sidt2 is a highly glycosylated lysosomal integral membrane protein that shows tissue specific expression. PMID- 20965153 TI - Signaling mechanisms of inhibition of phospholipase D activation by CHS-111 in formyl peptide-stimulated neutrophils. AB - A selective phospholipase D (PLD) inhibitor 5-fluoro-2-indolyl des chlorohalopemide (FIPI) inhibited the O(2)(-) generation and cell migration but not degranulation in formyl-Met-Leu-Phe (fMLP)-stimulated rat neutrophils. A novel benzyl indazole compound 2-benzyl-3-(4-hydroxymethylphenyl)indazole (CHS 111), which inhibited O(2)(-) generation and cell migration, also reduced the fMLP- but not phorbol ester-stimulated PLD activity (IC(50) 3.9+/-1.2MUM). CHS 111 inhibited the interaction of PLD1 with ADP-ribosylation factor (Arf) 6 and Ras homology (Rho) A, and reduced the membrane recruitment of RhoA in fMLP stimulated cells but not in GTPgammaS-stimulated cell-free system. CHS-111 reduced the cellular levels of GTP-bound RhoA, membrane recruitment of Rho associated protein kinase 1 and the downstream myosin light chain 2 phosphorylation, and attenuated the interaction between phosphatidylinositol 4 phosphate 5-kinase (PIP5K) and Arf6, whereas it only slightly inhibited the guanine nucleotide exchange activity of human Dbs (DH/PH) protein and did not affect the arfaptin binding to Arf6. CHS-111 inhibited the interaction of RhoA with Vav, the membrane association and the phosphorylation of Vav. CHS-111 had no effect on the phosphorylation of Src family kinases (SFK) but attenuated the interaction of Vav with Lck, Hck, Fgr and Lyn. CHS-111 also inhibited the interaction of PLD1 with protein kinase C (PKC) alpha, betaI and betaII isoenzymes, and the phosphorylation of PLD1. These results indicate that inhibition of fMLP-stimulated PLD activity by CHS-111 is attributable to the blockade of RhoA activation via the interference with SFK-mediated Vav activation, attenuation of the interaction of Arf6 with PLD1 and PIP5K, and the activation of Ca(2+)-dependent PKC in rat neutrophils. PMID- 20965154 TI - ERP correlates of source memory: unitized source information increases familiarity-based retrieval. AB - Source memory tests typically require subjects to make decisions about the context in which an item was encoded and are thought to depend on recollection of details from the study episode. Although it is generally believed that familiarity does not contribute to source memory, recent behavioral studies have suggested that familiarity may also support source recognition when item and source information are integrated, or "unitized," during study (Diana, Yonelinas, and Ranganath, 2008). However, an alternative explanation of these behavioral findings is that unitization affects the manner in which recollection contributes to performance, rather than increasing familiarity-based source memory. To discriminate between these possibilities, we conducted an event-related potential (ERP) study testing the hypothesis that unitization increases the contribution of familiarity to source recognition. Participants studied associations between words and background colors using tasks that either encouraged or discouraged unitization. ERPs were recorded during a source memory test for background color. The results revealed two distinct neural correlates of source recognition: a frontally distributed positivity that was associated with familiarity-based source memory in the high-unitization condition only and a parietally distributed positivity that was associated with recollection-based source memory in both the high- and low-unitization conditions. The ERP and behavioral findings provide converging evidence for the idea that familiarity can contribute to source recognition, particularly when source information is encoded as an item detail. PMID- 20965155 TI - Greater endogenous estrogen exposure is associated with longer telomeres in postmenopausal women at risk for cognitive decline. AB - Longer duration of reproductive years of life and thus greater exposure to endogenous estrogen may be associated with a lower risk of age-related diseases in women. The present study examined the relationship between estimated endogenous estrogen exposure and telomere length (TL) and telomerase activity, two biomarkers of cellular aging, in a sample of postmenopausal women at risk for cognitive decline. Telomere length was measured using a quantitative PCR method and telomerase activity by TRAP (Telomere-Repeats Amplification Protocol) assay in peripheral blood mononuclear cells (PBMCs). Study subjects were 53 postmenopausal women (35 with natural and 18 with surgical menopause) receiving hormone therapy (HT) for at least one year or longer. Length of reproductive years of life, computed as the difference between age at menopause and age at menarche, was used as a proxy of duration of exposure to endogenous estrogen. Length of time on HT was the measure used for duration of exogenous estrogen exposure. We found that longer endogenous estrogen exposure was associated with greater TL (standardized beta=0.06, Wald chi(2)=3.7, p=0.04) and with lower telomerase activity (standardized beta=-0.09, Wald chi(2)=5.0, p=0.03). Length of reproductive years was also inversely associated with the combination of short TL and high telomerase (OR=0.78, 95% CI: 0.63, 0.97, p=0.02). Length of HT use was not associated with TL or telomerase activity in this study. The results suggest that the endogenous estrogens may be associated with deceleration of cellular aging. This is the first study to examine associations between endogenous estrogens, telomere length and telomerase activity. PMID- 20965157 TI - GABAA receptors in VTA mediate the morphine-induced release of ascorbic acid in rat nucleus accumbens. AB - Local perfusion of morphine produces increased levels of extracellular ascorbic acid (AA) in the nucleus accumbens (NAc) of freely moving rats. However, the pathways that regulate morphine-induced AA release in the NAc are unclear. In the present study, we used high performance liquid chromatography with electrochemical detection (HPLC-ECD) to examine the effects of intra-ventral tegmental area (VTA) administration of a GABA(A) agonist and antagonist on morphine-induced increases in AA of the NAc. Also, using high performance liquid chromatography with fluorescent detection (HPLC-FD) and HPLC-ECD, the releases of gamma-aminobutyric acid (GABA) and dopamine (DA) in the NAc induced by intra-VTA administration of a GABA(A) agonist and antagonist were also investigated. The results obtained showed that morphine (1 mM), locally perfused into the NAc, significantly increased AA release in the NAc and also GABA release. Intra-VTA infusion of bicuculline (150 ng/rat), a GABA receptor antagonist, not only abolished the enhanced extracellular AA and GABA levels produced by local perfusion of morphine but also decreased the basal release of extracellular GABA and increased the basal release of extracellular DA in the NAc. Muscimol (100 ng/rat), a GABA receptor agonist, affected the basal release of GABA and DA, but not the basal AA levels, or the morphine-induced changes in AA and GABA levels. These findings suggest that the GABA(A) receptors in the VTA play an important role in the modulation of morphine-induced AA release in the NAc, and the effect of morphine on AA release in the NAc is partially regulated by the GABA(A) receptor-mediated action of DA afferents from the VTA. PMID- 20965156 TI - Oophorectomy, menopause, estrogen treatment, and cognitive aging: clinical evidence for a window of opportunity. AB - The neuroprotective effects of estrogen have been demonstrated consistently in cellular and animal studies but the evidence in women remains conflicted. We explored the window of opportunity hypothesis in relation to cognitive aging and dementia. In particular, we reviewed existing literature, reanalyzed some of our data, and combined results graphically. Current evidence suggests that estrogen may have beneficial, neutral, or detrimental effects on the brain depending on age at the time of treatment, type of menopause (natural versus medically or surgically induced), or stage of menopause. The comparison of women who underwent bilateral oophorectomy with referent women provided evidence for a sizeable neuroprotective effect of estrogen before age 50 years. Several case-control studies and cohort studies also showed neuroprotective effects in women who received estrogen treatment (ET) in the early postmenopausal stage (most commonly at ages 50-60 years). The majority of women in those observational studies had undergone natural menopause and were treated for the relief of menopausal symptoms. However, recent clinical trials by the Women's Health Initiative showed that women who initiated ET alone or in combination with a progestin in the late postmenopausal stage (ages 65-79 years) experienced an increased risk of dementia and cognitive decline regardless of the type of menopause. The current conflicting data can be explained by the window of opportunity hypothesis suggesting that the neuroprotective effects of estrogen depend on age at the time of administration, type of menopause, and stage of menopause. Therefore, women who underwent bilateral oophorectomy before the onset of menopause or women who experienced premature or early natural menopause should be considered for hormonal treatment until approximately age 51 years. PMID- 20965158 TI - Activation of tyrosine hydroxylase (TH) gene transcription induced by brain derived neurotrophic factor (BDNF) and its selective inhibition through Ca(2+) signals evoked via the N-methyl-D-aspartate (NMDA) receptor. AB - Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the biosynthesis of catecholamine but its transcriptional regulation is not fully understood. Using a reporter assay with cultured rat cortical neurons, we demonstrated that the TH gene promoter was activated by brain-derived neurotrophic factor (BDNF), through its specific receptor TrkB and the ERK/MAP kinase pathway. Using a series of mutant TH gene promoters, we found that the cAMP-response element (CRE) plays a crucial role in the TH promoter activity and the Egr-1-responsive element (ERE), at least in part, is responsible for the BDNF-induced activation. Notably, the influx of Ca(2+) evoked via the N-methyl-D-aspartate receptor (NMDA-R) but not via the L-type voltage-dependent Ca(2+) channel (L-VDCC) selectively antagonized the activation of the gene promoter, suggesting a new link between the catecholaminergic and glutamatergic systems. The Ca(2+) signals evoked via NMDA-R did not affect the phosphorylation of ERK1/2 induced by BDNF. These results suggest that the TH gene's transcription is positively regulated by BDNF, through the CRE and ERE of the promoter, but selectively antagonized by the Ca(2+) signals evoked via NMDA-R without disturbing the ERK/MAP kinase pathway, the regulation by which may underlie the development of the catecholaminergic system in the brain. PMID- 20965159 TI - Usefulness of glycated albumin as an indicator of glycemic control status in patients with hemolytic anemia. AB - BACKGROUND: In patients with hemolytic anemia (HA), glycated hemoglobin (HbA(1C)) presents lower values in relation to glycemia because the lifespan of erythrocytes is shortened, whereas glycated albumin (GA) is not affected. In the present study, we examined the usefulness of GA as an indicator of glycemic control status in patients with HA. METHODS: We enrolled 21 patients with HA. A total of 202 patients with type 2 diabetes mellitus (T2DM) without complications were used as controls. RESULTS: We identified a significant correlation between GA and HbA(1C) in the patients with HA. However, in a comparison between the patients with HA and those with T2DM, the regression line showed a leftward shift in the former group. There was a significant positive correlation between hemoglobin (Hb) and HbA(1C) in the patients with HA (R=0.541, p=0.025), although there was no significant correlation between Hb and GA. There was an inverse correlation between Hb levels and GA/HbA(1C) ratio (R=-0.710, p=0.001). The measured HbA(1C) levels were lower than the HbA(1C) levels estimated from mean plasma glucose levels, whereas the GA/3 levels were close to the estimated HbA(1C) levels. CONCLUSIONS: GA is a useful indicator of glycemic control status in patients with HA. PMID- 20965160 TI - Vitamin D status of county hospital patients assessed by the DiaSorin LIAISON(r) 25-hydroxyvitamin D assay. AB - BACKGROUND: Vitamin D is an essential nutrient, and there is a growing appreciation of its clinical significance. In addition, there has recently been a discussion as to the best method of measuring this analyte in serum: immunoassay, HPLC or LC-MS/MS. Due to the increased interest in vitamin D, there has been an exponential increase in the number of clinicians testing their patients and therefore also in the volume of this test run in clinical laboratories. METHODS: Vitamin D levels were determined by chemiluminescence immunoassay in a reference laboratory and a subset by LC-MS/MS at San Francisco General Hospital. RESULTS: We developed a robust and rapid LC-MS/MS assay to detect 25-hydroxyvitamin D3 and D2 in serum for use in the routine clinical laboratory. Additionally, we determined that 71% of patients served by San Francisco General Hospital have insufficient serum vitamin D levels (<=29 ng/ml) and that these levels are significantly associated with parathyroid hormone levels, total calcium concentration, age and ethnicity. CONCLUSIONS: The high degree of vitamin D insufficiency at San Francisco General Hospital may be reflective of the status of the patients served by this county hospital; largely an underserved, multi ethnic urban population. PMID- 20965161 TI - Transient development of ovotestes in XX Sox9 transgenic mice. AB - The sex of an individual results from the paternal transmission of the SRY gene located on the Y chromosome. In turn, SRY initiates Sox9 expression, a transcription factor required for testicular differentiation. Ectopic activation of SOX9 in XX Wt1:Sox9 transgenic mice induces female-to-male sex reversal in adult mice. Here we show that complete sex reversal is preceded by a transient phase of ovotestis differentiation with XX Wt1:Sox9 transgenic gonads containing a testicular central region and one or both ovarian poles indicating that Wt1:Sox9 is not as efficient as Sry to induce male development. In XX Wt1:Sox9(Tg/+) gonads, transgenic Sox9 is expressed earlier than Sox9 in XY gonads and is able to induce the expression of EGFP, knocked into the 3' UTR of Sox9 indicating that SOX9 is involved in the initiation and maintenance of its own expression. However, the delayed onset of expression of endogenous Sox9-EGFP suggests that this activation requires other factors, whose expression depends on SOX9. In the testicular regions of the XX Wt1:Sox9 ovotestes, proliferation of the XX fetal germ cells is hampered and they differentiate as pro-spermatogonia. This indicates that XX germ cells are not competent to respond to proliferative signals released from a testicular environment. In the ovarian regions, despite the continuous mRNA expression of the WT1:Sox9 transgene, the SOX9 protein does not accumulate suggesting that regulation of this gene in ovarian cells involves post-transcriptional mechanisms. Finally, ovarian cells of the XX Wt1:Sox9 ovotestis undergo apoptosis during late embryogenesis leading to complete female to-male sex reversal of the transgenic mice at birth. PMID- 20965162 TI - The ameliorating effect of rosiglitazone on experimental nonalcoholic steatohepatitis is associated with regulating adiponectin receptor expression in rats. AB - Although nonalcoholic steatohepatitis (NASH) is associated with insulin resistance partly due to reduced levels of circulating adiponectin, the role of adiponectin receptors including adiponectin receptor 1 and adiponectin receptor 2 in adipose tissues in NASH remains controversial. The present study showed that there was a marked decline in adiponectin receptor 1 and adiponectin receptor 2 expressions in liver and visceral fat, and these expressions were elevated in muscle of NASH rats 12weeks after oral administration of a high-fat diet. An 8 week continuous treatment with rosiglitazone, a peroxisome proliferator-activated receptors gamma (PPAR gamma) agonist improved the histological lesions markedly in liver of NASH rats, and concurrently increased mRNA and protein expressions of adiponectin receptor 1 and adiponectin receptor 2 in liver and visceral fat, with down-regulation of the two receptors in muscle. There was a negative correlation between the ratio of adiponectin receptors/beta-actin protein and serum TNF-alpha in the liver and visceral fat, and a positive correlation in muscle. Additionally, rosiglitazone increased circulating adiponectin, which was negatively correlated with serum TNF-alpha. These results indicated that rosiglitazone improved NASH by directly modulating adiponectin receptor 1 and adiponectin receptor 2 in various adipose tissues, or indirectly possibly via decreasing serum TNF-alpha. PMID- 20965163 TI - Honokiol inhibits H(2)O(2)-induced apoptosis in human lens epithelial cells via inhibition of the mitogen-activated protein kinase and Akt pathways. AB - Oxidative stress-induced apoptosis in lens epithelial cells plays an important role in cataract formation, and its prevention may be of therapeutic interest. This study was performed to investigate the protective effect and mechanisms of honokiol on H(2)O(2)-induced apoptosis in human lens epithelial (HLE) cells. HLE cells (SRA01-04) were pretreated with honokiol at concentrations of 5MUM, 10MUM and 20MUM before 50MUM H(2)O(2) treatment. The results demonstrated that pretreatment of honokiol inhibited the activation of caspase-3 and caspase-9 and downregulated the expression of Bcl-2. Mechanistically, honokiol suppressed H(2)O(2)-induced phosphorylation of ERK1/2, p38 mitogen-activated protein kinase (MAPK), JNK and Akt. Honokiol also inhibited H(2)O(2)-induced nuclear factor kappaB (NF-kappaB)/p65 phosphorylation and translocation in HLE cells. These results demonstrate that honokiol suppresses H(2)O(2)-induced HLE cell apoptosis via interference with the MAPKs, Akt and NF-kappaB signaling, suggesting that honokiol might have a potential effect against cataract formation. PMID- 20965164 TI - The study of ISO induced heart failure rat model, Exp Mol Pathol. 2010;88:299 304. PMID- 20965165 TI - The effect of S-nitrosoglutathione and L-cysteine on chloride efflux from cystic fibrosis airway epithelial cells. AB - The endogenous bronchodilator, S-nitrosoglutathione (GSNO), has been proposed as a possible pharmacological remedy that reverses the DeltaF508-CFTR (cystic fibrosis transmembrane conductance regulator) maturation defect and increases CFTR-mediated chloride efflux in cultured cystic fibrosis airway epithelial cells (CFBE41o(-)). It has also been reported that L-cysteine enhanced S-nitrosothiol uptake and increased the intracellular S-nitrosothiol levels, likely through transnitrosation chemistry. The present study investigated whether L-cysteine augmented the effect of GSNO on chloride efflux from CF airway epithelial cells. Treatment with 10 MUM GSNO combined with 20 MUM L-cysteine resulted in increased chloride efflux from CFBE41o(-) cells after 5 minutes exposure compared to the control efflux rate and to the efflux rate in the presence of L-cysteine alone as measured using the fluorescent dye N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE). Chloride efflux rates from these cells after 4h exposure to GSNO and L-cysteine were not different from control. Treatment with 10 MUM GSNO alone increased chloride efflux from CFBE41o(-) cells after 4h but not at shorter incubation times. GSNO with or without L-cysteine did not alter epithelial tight junction integrity. In conclusion, a combination of GSNO with L-cysteine led to significant increase in chloride efflux in CFBE41o(-) cells but the effect was transient and not sustained beyond minutes. PMID- 20965166 TI - Immunological aspect of cardiac remodeling: T lymphocyte subsets in inflammation mediated cardiac fibrosis. AB - Cardiac fibrosis is defined as a progressive accumulation of fibrillar extracellular matrix (ECM) in the myocardium. The regulation of extracellular matrix remodeling is primarily mediated by cardiac fibroblasts (CF). Evidences suggest that various T lymphocyte phenotypes differentially affect organ fibrosis through modulating CF collagen and MMP/TIMP gene expression, MMP activity and cardiac collagen cross-linking, leading to altered ECM composition. In regard to the importance of cytokines in cardiac fibrosis and heart failure, in this review, we will address the role of different T cell subsets in inflammation mediated cardiac fibrosis, from a distinct perspective of T cell and fibroblast interaction. We conclude that in addition to preventive strategies, therapies based on deviation of Th1/Th2 paradigm, and manipulation of Tregs and Th17 would show promising results in future studies. PMID- 20965167 TI - Community effect triggers terminal differentiation of myogenic cells derived from muscle satellite cells by quenching Smad signaling. AB - A high concentration of bone morphogenetic proteins (BMPs) stimulates myogenic progenitor cells to undergo heterotopic osteogenic differentiation. However, the physiological role of the Smad signaling pathway during terminal muscle differentiation has not been resolved. We report here that Smad1/5/8 was phosphorylated and activated in undifferentiated growing mouse myogenic progenitor Ric10 cells without exposure to any exogenous BMPs. The amount of phosphorylated Smad1/5/8 was severely reduced during precocious myogenic differentiation under the high cell density culture condition even in growth medium supplemented with a high concentration of serum. Inhibition of the Smad signaling pathway by dorsomorphin, an inhibitor of Smad activation, or noggin, a specific antagonist of BMP, induced precocious terminal differentiation of myogenic progenitor cells in a cell density-dependent fashion even in growth medium. In addition, Smad1/5/8 was transiently activated in proliferating myogenic progenitor cells during muscle regeneration in rats. The present results indicate that the Smad signaling pathway is involved in a critical switch between growth and differentiation of myogenic progenitor cells both in vitro and in vivo. Furthermore, precocious cell density-dependent myogenic differentiation suggests that a community effect triggers the terminal muscle differentiation of myogenic cells by quenching the Smad signaling. PMID- 20965169 TI - Interaction between alpha-synuclein and tau in Parkinson's disease comment on Wills et al.: elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson's disease brains with and without dementia. Exp Neurol 2010; 225: 210 218. AB - Recent neurochemical studies in postmortem brains of patients with Parkinson's disease (PD), PD with dementia (PDD) and age-matched controls revealed significant decrease of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in striatum, confirming previous studies indicating substantial loss of dopaminergic neurons and terminals. Insoluble alpha-synuclein (alphaSyn) was significantly increased in both striata and inferior frontal gyrus (IFG), more severe in PDD, probably related to Lewy body (LB) burden discussed as one cause of dementia in PD. Parkin levels frequently related to recessive and young-onset PD were unchanged, suggesting no link to sporadic PD. Novel and most interesting data showed elevated tauopathy in striata of both PD and PDD, associated with increased levels of phosphorylated GSK-3beta and reduced 20S proteasomal subunits but - despite increased cortical alphaSyn - unchanged pTau in IFG, related to increased pGSK-3beta and decreased 19S proteasome subunits. These data, recently confirmed in PDGF-alphaSyn transgenic mice (Haggerty et al., submitted) suggest tauopathy in PD and PDD restricted to the dopaminergic nigrostriatal system and in various animal models of PD show topographic differences from a global tauopathy in Alzheimer's disease (AD) (and other tauopathies). Although some of these data are at variance to current neuropathologic findings in PD and PDD, they confirm frequently discussed correlations/overlaps between AD and PD/PDD and synergistic effects of alphaSyn, pTau, beta-amyloid, and other pathologic proteins, suggesting a dualism or triad of neurodegeneration, the basic molecular pathogenesis remains to be elucidated. PMID- 20965168 TI - Pioglitazone attenuates mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation following traumatic brain injury. AB - Following traumatic brain injury (TBI) there is significant neuropathology which includes mitochondrial dysfunction, loss of cortical gray matter, microglial activation, and cognitive impairment. Previous evidence has shown that activation of the peroxisome proliferator-activated receptors (PPARs) provide neuroprotection following traumatic brain and spinal injuries. In the current study we hypothesized that treatment with the PPAR ligand Pioglitazone would promote neuroprotection following a rat controlled cortical impact model of TBI. Animals received a unilateral 1.5mm controlled cortical impact followed by administration of Pioglitazone at 10mg/kg beginning 15min after the injury and subsequently every 24h for 5days. Beginning 1day after the injury there was significant impairment in mitochondrial bioenergetic function which was attenuated by treatments with Pioglitazone at 15min and 24h (p<0.05). In an additional set of animals, cognitive function was assessed using the Morris Water Maze (MWM) and it was observed that over the course of 4days of testing the injury produced a significant increase in both latency (p<0.05) and distance (p<0.05) to the platform. Animals treated with Pioglitazone performed similarly to sham animals and did not exhibit any impairment in MWM performance. Sixteen days after the injury tissue sections through the lesion site were quantified to determine the size of the cortical lesion. Vehicle-treated animals had an average lesion size of 5.09+/-0.73mm(3) and treatment with Pioglitazone significantly reduced the lesion size by 55% to 2.27+/-0.27mm(3) (p<0.01). Co-administration of the antagonist T0070907 with Pioglitazone blocked the protective effect seen with administration of Pioglitazone by itself. Following the injury there was a significant increase in the number of activated microglia in the area of the cortex adjacent to the site of the lesion (p<0.05). Treatment with Pioglitazone prevented the increase in the number of activated microglia and no difference was observed between sham and Pioglitazone-treated animals. From these studies we conclude that following TBI Pioglitazone is capable ameliorating multiple aspects of neuropathology. These studies provide further support for the use of PPAR ligands, specifically Pioglitazone, for neuroprotection. PMID- 20965170 TI - Utilizing natural activity to dissect the pathophysiology of acute oxaliplatin induced neuropathy. AB - Oxaliplatin is first-line chemotherapy for colorectal cancer, but produces dose limiting neurotoxicity. Acute neurotoxicity following infusion produces symptoms including cold-triggered fasciculations and cramps, with subsequent chronic neuropathy developing at higher cumulative doses. Axonal excitability studies were undertaken in 15 oxaliplatin-treated patients before and immediately after oxaliplatin infusion to determine whether the mechanisms underlying acute neurotoxicity altered resting membrane potential or Na(+)/K(+) pump function. Excitability properties were assessed before and after maximal voluntary contraction (MVC) of the abductor pollicis brevis. Following oxaliplatin infusion, abnormalities developed in the recovery cycle with refractoriness markedly increased. Following activity, changes developed consistent with axonal hyperpolarization, with proportional changes pre- and post-oxaliplatin in normalized threshold. However, recovery cycle parameters following activity were significantly and disproportionally enhanced post-oxaliplatin, with partial normalization of the recovery cycle curve post-activity. Patients with the most abnormal change in the recovery cycle after infusion demonstrated the greatest changes post-contraction. Prominent abnormalities developed in Na(+) channel associated parameters in response to natural activity, without significant alteration in axonal membrane potential or Na(+)/K(+) pump function. Findings from the present series suggest that oxaliplatin affects nerve excitability through voltage-dependent mechanisms, with specific effects mediated through axonal Na(+) channel inactivation. PMID- 20965171 TI - Molecular dynamics simulations of human and dog gastric lipases: insights into domain movements. AB - Mammalian gastric lipases are stable and active under acidic conditions and also in the duodenal lumen. There has been considerable interest in acid stable lipases owing to their potential application in the treatment of pancreatic exocrine insufficiency. In order to gain insights into the domain movements of these enzymes, molecular dynamics simulations of human gastric lipase was performed at an acidic pH and under neutral conditions. For comparative studies, simulation of dog gastric lipase was also performed at an acidic pH. Analyses show, that in addition to the lid region, there is another region of high mobility in these lipases. The potential role of this novel region is discussed. PMID- 20965172 TI - Methyl-beta-cyclodextrin induces mitochondrial cholesterol depletion and alters the mitochondrial structure and bioenergetics. AB - There is growing evidence of mitochondrial membrane raft-like microdomains that are involved in the apoptotic pathway. The aim of this study was to investigate the effect of methyl-beta-cyclodextrin (MbetaCD), being a well-known lipid microdomain disrupting agent and cholesterol chelator, on the structure and bioenergetics of rat liver mitochondria (RLM). We observed that MbetaCD decreases the function of RLM, induces changes in the mitochondrial configuration state and decreases the calcium chloride-induced swelling. These data suggest that disruption of mitochondrial raft-like microdomains by cholesterol efflux on one hand impairs mitochondrial bioenergetics, but on the other hand it protects the mitochondria from swelling. PMID- 20965173 TI - SKIP is required for TGF-beta1-induced epithelial mesenchymal transition and migration in transformed keratinocytes. AB - Transforming growth factor-beta1 (TGF-beta1) potently induces the epithelial mesenchymal transition (EMT) during tumoral progression. Although Sky-interacting protein (SKIP) regulates TGF-beta1-induced Smad activation, its role in the induction of cell malignance remains uncertain. We found that TGF-beta1 increases SKIP expression in PDV cells. In cells stably transfected with SKIP antisense, AS S, Smad3 activation decreased, along with an inhibition of TGF-beta1-induced EMT, and the cells were sensitized to the TGF-beta1-dependent inhibition of proliferation. Also, AS-S cells showed a weaker migration and invasion response. Moreover, TGF-beta1-induced urokinase-type plasminogen activator expression was inhibited, concomitantly with a TGF-beta1-independent increment of the plasminogen-activator inhibitor-1 expression. Thus, these results suggest that SKIP is required for EMT and invasiveness induced by TGF-beta1 in transformed cells. PMID- 20965174 TI - Determination of substrate binding energies in individual subsites of a family 18 chitinase. AB - Thermodynamic parameters for binding of N-acetylglucosamine (GlcNAc) oligomers to a family 18 chitinase, ChiB of Serratia marcescens, have been determined using isothermal titration calorimetry. Binding studies with oligomers of different lengths showed that binding to subsites -2 and +1 is driven by a favorable enthalpy change, while binding to the two other most important subsites, +2 and +3, is driven by entropy with unfavorable enthalpy. These remarkable unfavorable enthalpy changes are most likely due to favorable enzyme-substrate interactions being offset by unfavorable enthalpic effects of the conformational changes that accompany substrate-binding. PMID- 20965175 TI - Signaling microdomains in T cells. AB - Sub-micron scale signaling domains induced in the plasma membrane of cells are thought to play important roles in signal transduction. In T cells, agonist MHC peptide complexes induce small diffraction-limited domains enriched in T cell receptor (TCR) and signaling molecules. These microclusters serve as transient platforms for signal initiation and are required for sustained signaling in T cells, although each microcluster functions for only a couple of minutes. How they are formed, and what mechanisms promote and regulate signaling within TCR microclusters is largely unknown, although it is clear that TCR engagement and dynamic reorganization of cortical actin are involved. Here, we review current understanding of signaling within microclusters in T cells, and speculate on how these structures may form, initiate biochemical signals, and serve as sites of both signal integration and amplification, while also facilitating appropriate termination of TCR and related signaling. PMID- 20965176 TI - Computational analysis of T cell receptor signaling and ligand discrimination- past, present, and future. AB - Signaling through the T cell receptor for antigen (TCR) has been studied for years by conventional biochemical means. More recently, attempts have been made to develop computational models of signaling through this receptor, with a specific focus on understanding how this recognition system discriminates between closely related (self and non-self) ligands. Here we discuss recent advances centered on the role of feedback regulation, especially the key finding that a combination of digital and analog control circuits is fundamental to the discrimination properties of the TCR. We end by pointing to future, more biologically accurate models that incorporate spatial aspects of molecular organization in antigen-engaged T lymphocytes with this underlying biochemistry. PMID- 20965177 TI - Hip2 interacts with cyclin B1 and promotes its degradation through the ubiquitin proteasome pathway. AB - Hip2, a ubiquitin conjugating enzyme, is involved in the suppression of cell death. The present study revealed that Hip2 regulates the stability of the apoptotic and cell cycle regulator cyclin B1. Hip2 was found to interact with cyclin B1 to promote its degradation through the ubiquitin proteasome pathway. As a result, Hip2 significantly blocked cell death induced by the cyclin B1 protein, suggesting that Hip2 is involved in the regulation of cyclin B1-mediated cell death. PMID- 20965178 TI - A free radical-generating system regulates APP metabolism/processing. AB - Oxidative stress, a risk factor in the pathophysiology of Alzheimer's disease, is intimately associated with aging. We previously reported that the X-XOD free radical generating system acts as a modulator of lipid metabolism and a mild inducer of apoptotic death. Using the same cell model, the present study examines the metabolism/processing of the amyloid precursor protein (APP). Prior to inducing cell death, X-XOD promoted the secretion of alpha-secretase-cleaved soluble APP (sAPPalpha) and increased the level of APP carboxy-terminal fragments produced by alpha and gamma secretase (alphaCTF and gammaCTF/AICD). In contrast, it reduced the activity of beta-secretase and the level of secreted Abeta. The present results indicate that mild oxidative stress maintained throughout culturing regulates APP metabolism/processing in SK-N-MC human neuroblastoma cells. PMID- 20965179 TI - Understanding signal integration through targeted mutations of an adapter protein. AB - Immunoreceptor engagement leads to the activation of multiple second messenger cascades, and integration of these pathways requires proper function of a number of adapter proteins. Although adapters possess no intrinsic enzymatic function, they nucleate the formation of multi-molecular protein complexes to support downstream signaling. Since adapters contain functionally distinct domains, intense investigation has been devoted to understanding how these regions act to integrate signals. This review describes the evolution of studies investigating one of these adapters, the SH2 domain-containing leukocyte protein of 76 kDa. Through utilizing biochemical, genetic and imaging techniques, a model has emerged describing how this adapter regulates signals resulting in complex immune responses. PMID- 20965180 TI - Candida albicans PHO81 is required for the inhibition of hyphal development by farnesoic acid. AB - Farnesoic acid is a signaling molecule that inhibits the transition from budding yeast to filament formation in Candida albicans, but the molecular mechanism regulated by this substance is unknown. In this study, we analyzed the function of CaPHO81, which is induced by farnesoic acid. The pho81Delta mutant cells existed exclusively as filaments under favorable yeast growth conditions. Furthermore, the inhibition of hyphal growth and repression of CPH1, EFG1, HWP1, and GAP1 mRNA expression in response to farnesoic acid were defective in pho81Delta mutant cells. These data suggest a role for CaPHO81 in the inhibition of hyphal development by farnesoic acid. PMID- 20965181 TI - Regulation of nuclear localization signal-importin alpha interaction by Ca2+/S100A6. AB - Although the precise intracellular roles of S100 proteins are not fully understood, these proteins are thought to be involved in Ca(2+)-dependent diverse signal transduction pathways. In this report, we identified importin alpha as a novel target of S100A6. Importin alpha contains armadillo repeats, essential for binding to nuclear localization signals. Based on the results from GST pull-down assay, gel-shift assay, and co-immunoprecipitation, we demonstrated that S100A6 specifically interacts with the armadillo repeats of importin alpha in a Ca(2+) dependent manner, resulting in inhibition of the nuclear localization signal (NLS)-importin alpha complex formation in vitro and in vivo. These results indicate S100A6 may regulate the nuclear transport of NLS-cargos in response to increasing concentrations of intracellular Ca(2+). PMID- 20965182 TI - ATP dependent charge movement in ATP7B Cu+-ATPase is demonstrated by pre-steady state electrical measurements. AB - ATP7B is a copper dependent P-type ATPase, required for copper homeostasis. Taking advantage of high yield heterologous expression of recombinant protein, we investigated charge transfer in ATP7B. We detected charge displacement within a single catalytic cycle upon ATP addition and formation of phosphoenzyme intermediate. We attribute this charge displacement to movement of bound copper within ATP7B. Based on specific mutations, we demonstrate that enzyme activation by copper requires occupancy of a site in the N-terminus extension which is not present in other transport ATPases, as well as of a transmembrane site corresponding to the cation binding site of other ATPases. PMID- 20965183 TI - Reduced Ran expression in Ran(+/-) fibroblasts increases cytokine-stimulated nuclear abundance of the AP-1 subunits c-Fos and c-Jun. AB - Ran (Ras-related nuclear protein), a Ras family GTPase, is involved in multiple cellular functions, including the regulation of DNA replication, cell cycle progression, nuclear structure formation, RNA processing-exportation, and nuclear protein importation. Ran(+/-) embryonic stem (ES) cells were produced in an attempt to generate Ran null mutant mice. Even after an extremely large number of blastocyst injections, no Ran(+/-) chimeric mice could be generated. Ran(+/-) ES cell-derived fibroblasts showed reduced Ran protein expression, and manifested augmented nuclear abundance of AP-1 factors (c-Jun and c-Fos) upon cytokine stimulation. Our experiments demonstrated that intracellular Ran protein levels controlled the nuclear presence of certain transcription factors, such as c-Fos and c-Jun. PMID- 20965186 TI - Level of activation of the unfolded protein response correlates with Paneth cell apoptosis in human small intestine exposed to ischemia/reperfusion. AB - BACKGROUND & AIMS: In the intestine, Paneth cells participate in the innate immune response. Their highly secretory function makes them susceptible to environmental conditions that cause endoplasmic reticulum (ER) stress. We investigated whether intestinal ischemia/reperfusion (I/R) induces ER stress, thereby activating the unfolded protein response (UPR), and whether excessive UPR activation affects Paneth cells. In addition, we investigated the consequences of Paneth cell compromise during physical barrier damage. METHODS: Jejunal I/R was studied using a human experimental model (n = 30 patients). Activation of the UPR was assessed using immunofluorescence for binding protein and quantitative polymerase chain reaction analyses for C/EBP homologous protein (CHOP), growth arrest and DNA-damage inducible protein 34 (GADD34), and X-box binding protein 1 (XBP1) splicing. Paneth cell apoptosis was assessed by double staining for lysozyme and M30. Male Sprague-Dawley rats underwent either intestinal I/R to investigate UPR activation and Paneth cell apoptosis, or hemorrhagic shock with or without intraperitoneal administration of dithizone, to study consequences of Paneth cell compromise during physical intestinal damage. In these animals, bacterial translocation and circulating tumor necrosis factor-alpha and interleukin-6 levels were assessed. RESULTS: In jejunum samples from humans and rats, I/R activated the UPR and resulted in Paneth cell apoptosis. Apoptotic Paneth cells showed signs of ER stress, and Paneth cell apoptosis correlated with the extent of ER stress. Apoptotic Paneth cells were shed into the crypt lumen, significantly lowering their numbers. In rats, Paneth cell compromise increased bacterial translocation and inflammation during physical intestinal damage. CONCLUSIONS: ER stress-induced Paneth cell apoptosis contributes to intestinal I/R-induced bacterial translocation and systemic inflammation. PMID- 20965190 TI - Probiotics in perspective. PMID- 20965184 TI - Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity. AB - BACKGROUND & AIMS: Idiopathic gastroparesis (IG) is a common but poorly understood condition with significant morbidity. We studied characteristics of patients with IG enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium Registry. METHODS: Data from medical histories, symptom questionnaires, and 4-hour gastric emptying scintigraphy studies were obtained from patients with IG. RESULTS: The mean age of 243 patients with IG studied was 41 years; 88% were female, 46% were overweight, 50% had acute onset of symptoms, and 19% reported an initial infectious prodrome. Severe delay in gastric emptying (>35% retention at 4 hours) was present in 28% of patients. Predominant presenting symptoms were nausea (34%), vomiting (19%), an abdominal pain (23%). Women had more severe nausea, satiety, constipation, and overall gastroparesis symptoms. Patients who experienced acute-onset IG had worse nausea than those with insidious onset. Overweight patients had more bloating and gastric retention at 2 hours but less severe loss of appetite. Patients with severely delayed gastric emptying had worse vomiting and more severe loss of appetite and overall gastroparesis symptoms. Severe anxiety and depression were present in 36% and 18%, respectively. A total of 86% met criteria for functional dyspepsia, primarily postprandial distress syndrome. CONCLUSIONS: IG is a disorder that primarily affects young women, beginning acutely in 50% of cases; unexpectedly, many patients are overweight. Severe delay in gastric emptying was associated with more severe symptoms of vomiting and loss of appetite. IG is a diverse syndrome that varies by sex, body mass, symptom onset, and delay in gastric emptying. PMID- 20965192 TI - Physiological and genetic correlates of boldness: characterising the mechanisms of behavioural variation in rainbow trout, Oncorhynchus mykiss. AB - Bold, risk-taking animals have previously been putatively linked with a proactive stress coping style whereas it is suggested shyer, risk-averse animals exhibit a reactive coping style. The aim of this study was to investigate whether differences in the expression of bold-type behaviour were evident within and between two lines of rainbow trout, Oncorhynchus mykiss, selectively bred for a low (LR) or high (HR) endocrine response to stress, and to link boldness and stress responsiveness with the expression of related candidate genes. Boldness was determined in individual fish over two trials by measuring the latency to approach a novel object. Differences in plasma cortisol concentrations and the expression of eight novel candidate genes previously identified as being linked with divergent behaviours or stress were determined. Bold and shy individuals, approaching the object within 180 s or not approaching within 300 s respectively, were evident within each line, and this was linked with activity levels in the HR line. Post-stress plasma cortisol concentrations were significantly greater in the HR line compared with the LR line, and six of the eight tested genes were upregulated in the brains of LR fish compared with HR fish. However, no direct relationship between boldness and either stress responsiveness or gene expression was found, although clear differences in stress physiology and, for the first time, gene expression could be identified between the lines. This lack of correlation between physiological and molecular responses and behavioural variation within both lines highlights the complexity of the behavioural physiological complex. PMID- 20965191 TI - Dynamic glucoregulation and mammalian-like responses to metabolic and developmental disruption in zebrafish. AB - Zebrafish embryos are emerging as models of glucose metabolism. However, patterns of endogenous glucose levels, and the role of the islet in glucoregulation, are unknown. We measured absolute glucose levels in zebrafish and mouse embryos, and demonstrate similar, dynamic glucose fluctuations in both species. Further, we show that chemical and genetic perturbations elicit mammalian-like glycemic responses in zebrafish embryos. We show that glucose is undetectable in early zebrafish and mouse embryos, but increases in parallel with pancreatic islet formation in both species. In zebrafish, increasing glucose is associated with activation of gluconeogenic phosphoenolpyruvate carboxykinase1 (pck1) transcription. Non-hepatic Pck1 protein is expressed in mouse embryos. We show using RNA in situ hybridization, that zebrafish pck1 mRNA is similarly expressed in multiple cell types prior to hepatogenesis. Further, we demonstrate that the Pck1 inhibitor 3-mercaptopicolinic acid suppresses normal glucose accumulation in early zebrafish embryos. This shows that pre- and extra-hepatic pck1 is functional, and provides glucose locally to rapidly developing tissues. To determine if the primary islet is glucoregulatory in early fish embryos, we injected pdx1-specific morpholinos into transgenic embryos expressing GFP in beta cells. Most morphant islets were hypomorphic, not a genetic, but embryos still exhibited persistent hyperglycemia. We conclude from these data that the early zebrafish islet is functional, and regulates endogenous glucose. In summary, we identify mechanisms of glucoregulation in zebrafish embryos that are conserved with embryonic and adult mammals. These observations justify use of this model in mechanistic studies of human metabolic disease. PMID- 20965193 TI - Validation of multiplex microbead immunoassay for simultaneous serodetection of multiple infectious agents in laboratory mouse. AB - Multiplex methodologies enable simultaneous detection of antibodies against several infectious agents allowing sample conservation, cost effectiveness, and amenability to high-throughput/automation. We have previously described a multiplex microbead immunoassay for serodetection of ten, high-priority mouse infectious pathogens. Here, we present a validation of this multiplex diagnostic system using approximately four hundred serum samples from different groups of mice. Computer assisted multivariate analysis of the resulting high volume data (8000 data points) was performed. This computational approach enabled presentation of data in a variety of easily interpretable formats (e.g., correlation tables and heat maps). Importantly, this computer aided approach was instrumental for the evaluation of assay accuracy, sensitivity, specificity, and robustness during the study. Crucial pieces of information were obtained to make timely adjustments for assay refinement. This progressive approach to developing an implementation-ready clinical assay, facilitated by computational analysis, produced a highly efficient, accurate and dependable serodiagnostics system. This system has effectively replaced the current state-of-the-art methodology (ELISA) used in mouse colony health management at the University of California and the Jackson Laboratory. A pathway to develop multiplex serology tests for infectious disease diagnosis described here serves as a model for multiplex immunoassay design, clinical validation, refinement and implementation. PMID- 20965194 TI - Trehalase-2 protein contributes to trehalase activity enhanced by diapause hormone in developing ovaries of the silkworm, Bombyx mori. AB - Diapause hormone (DH) targets developing ovaries in female pupae to induce embryonic diapause immediately after completion of mesoderm segregation of the silkworm, Bombyx mori. At the same time, DH enhances trehalase activity on the oolemma, which leads to higher concentrations of glycogen in oocytes through the stimulated incorporation of hemolymph trehalose. In B. mori, the treh-1 and -2 genes encoding soluble trehalase (68 kDa) and integral-membrane trehalase (74kDa) have been isolated. DH stimulates mRNA expression of both of these genes. In this study, we aimed to clarify whether ovarian trehalase originates from Treh-1 or Treh-2. Western blotting of the developing ovaries showed positive bands in the membrane-bound fraction, containing trehalase activity, only with antibodies against Treh-1&2 and Treh-2, but not Treh-1, irrespective of nondiapause or diapause egg-producers. The intensities of the positively stained 74 kDa bands were increased approximately 4-fold in ovaries from pupae with intact subesophageal ganglion (SG, a unique DH-biosynthesizing organ), and from pupae that were injected with DH at the middle pupal stage after their SGs were removed on the day of pupation. Furthermore, quantitative real-time PCR data showed that in developing ovaries, copy number of treh-2 mRNA per one copy of rp49 mRNA was approximately 1000-fold higher than that of treh-1 mRNA. These results demonstrate that trehalase activities enhanced by DH originate mainly from treh-2 protein regulated at the transcriptional level. PMID- 20965195 TI - Feel the heat: The effect of temperature on development, behavior and central pattern generation in 3rd instar Calliphora vicina larvae. AB - Like in all poikilothermic animals, higher temperatures increase developmental rate and activity in Calliphora vicina larvae. We therefore could expect temperature to have a persistent effect on the output of the feeding and crawling central pattern generators (CPGs). When confronted with a steep temperature gradient, larvae show evasive behavior after touching the substrate with the cephalic sense organs. Beside this reflex behavior the terminal- and dorsal organ might also mediate long term CPG modulation. Both organs were thermally stimulated while their response was recorded from the maxillary- or antennal nerve. The terminal organ showed a tonic response characteristic while the dorsal organ was not sensitive to temperature. Thermal stimulation of the terminal organ did not affect the ongoing patterns of fictive feeding or crawling, recorded from the antennal- or abdominal nerve respectively. A selective increase of the central nervous system (CNS) temperature accelerated the motor patterns of both feeding and crawling. We propose that temperature affects centrally generated behavior via two pathways: short term changes like thermotaxis are mediated by the terminal organ, while long term adaptations like increased feeding rate are caused by temperature sensitive neurons in the CNS which were recently shown to exist in Drosophila larvae. PMID- 20965196 TI - Nosema ceranae, a new parasite in Thai honeybees. AB - Adult workers of Apis cerana, Apis florea and Apis mellifera from colonies heavily infected with Nosema ceranae were selected for molecular analyses of the parasite. PCR-specific 16S rRNA primers were designed, cloned, sequenced and compared to GenBank entries. The sequenced products corresponded to N. ceranae. We then infected A. cerana with N. ceranae spores isolated from A. florea workers. Newly emerged bees from healthy colonies were fed 10,000, 20,000 and 40,000 spores/bee. There were significant dosage dependent differences in bee infection and survival rates. The ratio of infected cells to non-infected cells increased at 6, 10 and 14 d post infection. In addition, hypopharyngeal glands of bees from the control group had significantly higher protein concentrations than infected groups. Bees infected with 40,000 spores/bee had the lowest protein concentrations. Thus, N. ceranae isolated from A. florea is capable of infecting another bee species, impairing hypopharyngeal gland protein production and reducing bee survival in A. cerana. PMID- 20965197 TI - Functional characterization of truncated fragments of Bacillus sphaericus binary toxin BinB. AB - Bacillus sphaericus produces a mosquitocidal binary toxin composed of two subunits, BinA (42 kDa) and BinB (51 kDa). Both components are required for maximum toxicity against mosquito larvae. BinB has been proposed to provide specificity by binding to the epithelial gut cell membrane, while BinA may be responsible for toxicity. To identify regions in BinB responsible for receptor binding and for interaction to BinA, we used six BinB shorter constructs derived from both the N-terminal and the C-terminal halves of the protein. All constructs expressed as inclusion bodies in Escherichia coli, similarly to the wild-type protein. A marked decrease in larvicidal activity was observed when BinA was used in combination with these BinB constructs, used either individually or in pairs from both N and C-halves of BinB. Nevertheless, immunohistochemistry analyses demonstrate that these constructs are able to bind to the epithelium gut cell membrane, and in vitro protein-protein interaction assays revealed that these constructs can bind to BinA. These results show that fragments corresponding to both halves of BinB are able to bind the receptor and to interact with BinA, but both halves are required by the toxin to exhibit full larvicidal activity. PMID- 20965198 TI - Study of the Bacillus thuringiensis Vip3Aa16 histopathological effects and determination of its putative binding proteins in the midgut of Spodoptera littoralis. AB - The bacterium Bacillus thuringiensis produces, at the vegetative stage of its growth, Vip3A proteins with activity against a broad spectrum of lepidopteran insects. The Egyptian cotton leaf worm (Spodoptera littoralis) is an important agricultural pest that is susceptible to the Vip3Aa16 protein of Bacillus thuringiensis kurstaki strain BUPM95. The midgut histopathology of Vip3Aa fed larvae showed vacuolization of the cytoplasm, brush border membrane destruction, vesicle formation in the apical region and cellular disintegration. Biotinylated Vip3Aa toxin bound proteins of 55- and 100-kDa on blots of S. littoralis brush border membrane preparations. These binding proteins differ in molecular size from those recognized by Cry1C, one of the very few Cry proteins active against the polyphagous S. littoralis. This result supports the use of Vip3Aa16 proteins as insecticidal agent, especially in case of Cry-resistance management. PMID- 20965199 TI - The extended conformation of the 2.9-A crystal structure of the three-PASTA domain of a Ser/Thr kinase from the human pathogen Staphylococcus aureus. AB - PASTA (penicillin-binding protein and serine/threonine kinase associated) modules are found in penicillin-binding proteins and bacterial serine/threonine kinases mainly from Gram-positive Firmicutes and Actinobacteria. They may act as extracellular sensors by binding peptidoglycan fragments. We report here the first crystal structure of a multiple-PASTA domain from Ser/Thr kinase, that of the protein serine/threonine kinase 1 (Stk1) from the Firmicute Staphylococcus aureus. The extended conformation of the three PASTA subunits differs strongly from the compact conformation observed in the two-PASTA domain of penicillin binding protein PBP2x, whereas linear conformations were also reported for two subunit fragments of the four-PASTA domain of the Actinobacteria Mycobacterium tuberculosis studied by liquid NMR. Thus, a stretched organization appears to be the signature of modular PASTA domains in Ser/Thr kinases. Signal transduction to the kinase domain is supposed to occur via dimerization and ligand binding. A conserved X-shaped crystallographic dimer stabilized by intermolecular interactions between the second PASTA subunits of each monomer is observed in the two crystal forms of Stk1 that we managed to crystallize. Extracellular PASTA domains are composed of at least two subunits, and this molecular assembly is a plausible candidate for the biological dimer. We have also performed docking experiments, which predict that the hinge regions of the PASTA domain can accommodate peptidoglycan. Finally, a three-dimensional homology molecular model of full-length Stk1 was generated, suggesting an interaction between the kinase domain and the cytoplasmic face of the plasma membrane via a eukaryotic-like juxtamembrane domain. A comprehensive activation mechanism for bacterial Ser/Thr kinases is proposed with the support of these structural data. PMID- 20965200 TI - Enhanced specificity of mint geranyl pyrophosphate synthase by modifying the R loop interactions. AB - Isoprenoids, most of them synthesized by prenyltransferases (PTSs), are a class of important biologically active compounds with diverse functions. The mint geranyl pyrophosphate synthase (GPPS) is a heterotetramer composed of two LSU.SSU (large/small subunit) dimers. In addition to C(10)-GPP, the enzyme also produces geranylgeranyl pyrophosphate (C(20)-GGPP) in vitro, probably because of the conserved active-site structures between the LSU of mint GPPS and the homodimeric GGPP synthase from mustard. By contrast, the SSU lacks the conserved aspartate rich motifs for catalysis. A major active-site cavity loop in the LSU and other trans-type PTSs is replaced by the regulatory R-loop in the SSU. Only C(10)-GPP, but not C(20)-GGPP, was produced when intersubunit interactions of the R-loop were disrupted by either deletion or multiple point mutations. The structure of the deletion mutant, determined in two different crystal forms, shows an intact (LSU.SSU)(2) heterotetramer, as previously observed in the wild-type enzyme. The active-site of LSU remains largely unaltered, except being slightly more open to the bulk solvent. The R-loop of SSU acts by regulating the product release from LSU, just as does its equivalent loop in a homodimeric PTS, which prevents the early reaction intermediates from escaping the active site of the other subunit. In this way, the product-retaining function of R-loop provides a more stringent control for chain-length determination, complementary to the well-established molecular ruler mechanism. We conclude that the R-loop may be used not only to conserve the GPPS activity but also to produce portions of C(20)-GGPP in mint. PMID- 20965201 TI - Commentary on "Structure of a conserved retroviral RNA packaging element by NMR spectroscopy and cryo-electron tomography" by Y. Miyazaki et al. PMID- 20965202 TI - Comparison and content of the Wright-Fisher model of random genetic drift, the diffusion approximation, and an intermediate model. AB - We investigate the detailed connection between the Wright-Fisher model of random genetic drift and the diffusion approximation, under the assumption that selection and drift are weak and so cause small changes over a single generation. A representation of the mathematics underlying the Wright-Fisher model is introduced which allows the connection to be made with the corresponding mathematics underlying the diffusion approximation. Two 'hybrid' models are also introduced which lie 'between' the Wright-Fisher model and the diffusion approximation. In model 1 the relative allele frequency takes discrete values while time is continuous; in model 2 time is discrete and relative allele frequency is continuous. While both hybrid models appear to have a similar status and the same level of plausibility, the different nature of time and frequency in the two models leads to significant mathematical differences. Model 2 is mathematically inconsistent and has to be ruled out as being meaningful. Model 1 is used to clarify the content of Kimura's solution of the diffusion equation, which is shown to have the natural interpretation as describing only those populations where alleles are segregating. By contrast the Wright-Fisher model and the solution of the diffusion equation of McKane and Waxman cover populations of all categories, namely populations where alleles segregate, are lost, or fix. PMID- 20965203 TI - Altruistic punishment in patients with Parkinson's disease with and without impulsive behaviour. AB - Punishing violators of social norms when there is personal cost is known as altruistic punishment. We tested patients with Parkinson's disease (PD) with and without impulsive-compulsive behaviours (ICBs) and matched control subjects, on and off their regular dopamine replacement therapy on a task, in which the patients decided whether or not to invest a sum of money with a trustee. The sum was then quadrupled and the trustee could decide whether or not to return a portion of the investment. Participants could punish the trustee after they were informed of the trustee's decision. We found that PD patients without ICBs on or off medication punished more often than controls, whereas PD patients with ICBs punished more than controls on medication, but similar to controls off medication. These results suggest a role for dopamine in altruistic punishment decisions in PD patients with impulsive compulsive behaviour. PMID- 20965204 TI - Bisections in two languages: when number processing, spatial representation, and habitual reading direction interact. AB - Calabria and Rossetti (2005) demonstrated that spatial biases related to the mental number line can be seen even when bisecting strings of number words. Strings of smaller magnitude number words were bisected further to the left than strings of larger magnitude number words. The current study investigated whether the left-to-right mental number line associated with number processing will result in similar spatial biases despite a habitual, right-to-left reading direction. Monolingual left-to-right readers were compared to bidirectional readers of English and Hebrew. Strings of Arabic numerals and of number words (e.g., THREE, EIGHT) were presented in separate conditions of English and Hebrew. Significant rightward biases were seen among native Hebrew readers, regardless of English reading level; whereas native English readers (both bidirectional and monodirectional) did not show significant biases to either the left or the right. The spatial bias in bisecting either Arabic numeral strings or number words was related to the habitual reading direction of the participant. There was no difference in spatial bias or for frequency of spatial bias based on numerical magnitude for either condition. We discuss the influence of cultural factors, such as reading direction and proficiency, on the representation of spatial and numerical material. PMID- 20965205 TI - Phonological processing and arithmetic fact retrieval: evidence from developmental dyslexia. AB - The triple-code model, cognitive neuroimaging and developmental behavioral data suggest a specific association between phonological processing and arithmetic fact retrieval. Accordingly, individuals with deficits in phonological processing, such as individuals with developmental dyslexia, are expected to show difficulties in arithmetic fact retrieval. The present study tested this proposal in 25 adults with developmental dyslexia and 25 matched controls by examining strategy use during single-digit multiplication and subtraction and its associations with phonological processing. Findings revealed that individuals with dyslexia retrieved fewer arithmetic facts from memory and were less efficient in doing so. At the same time, they showed deficits in phonological processing. Phonological processing, particularly phonological awareness, was related to arithmetic fact retrieval. This association was especially prominent in multiplication, indicating that fact retrieval in multiplication rather than subtraction is mediated by phonological processes. These data provide ground for future neuroimaging studies, who should examine the neural overlap between phonological processing and multiplication fact retrieval in the same sample of participants. PMID- 20965206 TI - Sodium arsenite delays the differentiation of C2C12 mouse myoblast cells and alters methylation patterns on the transcription factor myogenin. AB - Epidemiological studies have correlated arsenic exposure with cancer, skin diseases, and adverse developmental outcomes such as spontaneous abortions, neonatal mortality, low birth weight, and delays in the use of musculature. The current study used C2C12 mouse myoblast cells to examine whether low concentrations of arsenic could alter their differentiation into myotubes, indicating that arsenic can act as a developmental toxicant. Myoblast cells were exposed to 20 nM sodium arsenite, allowed to differentiate into myotubes, and expression of the muscle-specific transcription factor myogenin, along with the expression of tropomyosin, suppressor of cytokine signaling 3 (Socs3), prostaglandin I2 synthesis (Ptgis), and myocyte enhancer 2 (Mef2), was investigated using QPCR and immunofluorescence. Exposing C2C12 cells to 20 nM sodium arsenite delayed the differentiation process, as evidenced by a significant reduction in the number of multinucleated myotubes, a decrease in myogenin mRNA expression, and a decrease in the total number of nuclei expressing myogenin protein. The expression of mRNA involved in myotube formation, such as Ptgis and Mef2 mRNA, was also significantly reduced by 1.6-fold and 4-fold during differentiation. This was confirmed by immunofluorescence for Mef2, which showed a 2.6-fold reduction in nuclear translocation. Changes in methylation patterns in the promoter region of myogenin (-473 to +90) were examined by methylation specific PCR and bisulfite genomic sequencing. Hypermethylated CpGs were found at -236 and -126 bp, whereas hypomethylated CpGs were found at -207 bp in arsenic exposed cells. This study indicates that 20 nM sodium arsenite can alter myoblast differentiation by reducing the expression of the transcription factors myogenin and Mef2c, which is likely due to changes in promoter methylation patterns. The delay in muscle differentiation may lead to developmental abnormalities. PMID- 20965207 TI - New CYP1 genes in the frog Xenopus (Silurana) tropicalis: induction patterns and effects of AHR agonists during development. AB - The Xenopus tropicalis genome shows a single gene in each of the four cytochrome P450 1 (CYP1) subfamilies that occur in vertebrates, designated as CYP1A, CYP1B1, CYP1C1, and CYP1D1. We cloned the cDNAs of these genes and examined their expression in untreated tadpoles and in tadpoles exposed to waterborne aryl hydrocarbon receptor agonists, 3,3',4,4',5-pentachlorobiphenyl (PCB126), beta naphthoflavone (betaNF), or indigo. We also examined the effects of PCB126 on expression of genes involved in stress response, cell proliferation, thyroid homeostasis, and prostaglandin synthesis. PCB126 induced CYP1A, CYP1B1, and CYP1C1 but had little effect on CYP1D1 (77-, 1.7-, 4.6- and 1.4-fold induction versus the control, respectively). betaNF induced CYP1A and CYP1C1 (26- and 2.5 fold), while, under conditions used, indigo tended to induce only CYP1A (1.9 fold). The extent of CYP1 induction by PCB126 and betaNF was positively correlated to the number of putative dioxin response elements 0-20 kb upstream of the start codons. No morphological effect was observed in tadpoles exposed to 1 nM-10 MUM PCB126 at two days post-fertilization (dpf) and screened 20 days later. However, in 14-dpf tadpoles a slight up-regulation of the genes for PCNA, transthyretin, HSC70, Cu-Zn SOD, and Cox-2 was observed two days after exposure to 1 MUM PCB126. This study of the full suite of CYP1 genes in an amphibian species reveals gene- and AHR agonist-specific differences in response, as well as a much lower sensitivity to CYP1 induction and short-term toxicity by PCB126 compared with in fish larvae. The single genes in each CYP1 subfamily may make X. tropicalis a useful model for mechanistic studies of CYP1 functions. PMID- 20965208 TI - Do we track what we see? Common versus independent processing for motion perception and smooth pursuit eye movements: a review. AB - Many neurophysiological studies in monkeys have indicated that visual motion information for the guidance of perception and smooth pursuit eye movements is - at an early stage - processed in the same visual pathway in the brain, crucially involving the middle temporal area (MT). However, these studies left some questions unanswered: Are perception and pursuit driven by the same or independent neuronal signals within this pathway? Are the perceptual interpretation of visual motion information and the motor response to visual signals limited by the same source of neuronal noise? Here, we review psychophysical studies that were motivated by these questions and compared perception and pursuit behaviorally in healthy human observers. We further review studies that focused on the interaction between perception and pursuit. The majority of results point to similarities between perception and pursuit, but dissociations were also reported. We discuss recent developments in this research area and conclude with suggestions for common and separate principles for the guidance of perceptual and motor responses to visual motion information. PMID- 20965209 TI - Aging impairs myocardium-induced dilation in coronary arterioles: role of hydrogen peroxide and angiotensin. AB - The mechanisms that drive age-related modifications of coronary circulation by myocardium have not been fully defined. To elucidate the aging effect on myocyte induced vascular response, we measured changes in the diameter of isolated coronary arterioles to supernatant collected from isolated cardiac myocytes of young (2 mo) and old (24 mo) rats (stimulated at 400 beats/min, n=10, each). The H(2)O(2) level in pacing myocyte supernatant was greater in old rats than in young ones (15.9+/-1.8 vs. 9.5+/-0.7MUM, P<0.01). Catalase activity in myocytes decreased 38.6+/-5.2% in old rats compared to that in young rats. Vasodilation with young-myocyte supernatant (M) (response to 500MUl; young-arterioles (A) 20.5+/-1.6%, old-A 18.2+/-1.2%) was more potent compared to that with old-M (young-A 10.3+/-0.8%, old-A 9.4+/-1.0%, P<0.01, respectively). Treatment with an angiotensin II receptor antagonist, olmesartan, in a vessel bath augmented vasodilation in old-M+young-A (34.9+/-4.0%, P<0.01) and old-M+old-A (27.2+/-2.8%, P<0.01). Administration of catalase converted vasodilation to vasoconstriction in old-M and eliminated vasodilation in young-M. Vascular responses with authentic H(2)O(2) and angiotensin II were similar between old- and young-A. Thus, aging increases both angiotensin and the H(2)O(2) release from myocardium. In conclusion, cardiac myocyte-dependent signaling plays an important role in determining coronary vascular tone in the aging heart. PMID- 20965210 TI - Pluripotent stem cell differentiation into vascular cells: a novel technology with promises for vascular re(generation). AB - Several types of stem and progenitor cells are currently under investigation for their potential to accomplish vascular regeneration. This review focuses on embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). We will discuss the technologies allowing for their derivation, culture expansion and maintenance in a pluripotent status. Moreover, both ESCs and iPSCs can be differentiated in endothelial cells (ECs) and mural cell, including vascular smooth muscle cells (VSMCs). Here, we will describe the involvements of growth factors (vascular endothelial growth factors-VEGFs-, platet-derived growth factors-PDGFs-), Wnt and Notch signal pathways, reactive oxygen species (ROS), histone deacetylases (HDACs), and microRNAs (miRNAs) in vascular cell differentiation from pluripotent stem cells. We will additionally describe the therapeutic potential of stem cells for vascular medicine. PMID- 20965211 TI - At the stem of youth and health. AB - Cellular senescence is a specialized form of growth arrest, confined to mitotic cells, induced by various stressful stimuli and characterized by a permanent growth arrest, resistance to apoptosis, an altered pattern of gene expression and the expression of some markers that are characteristic, although not exclusive, to the senescent state. Senescent cells profoundly modify neighboring and remote cells through the production of an altered secretome, eventually leading to inflammation, fibrosis and possibly growth of neoplastic cells. Mammalian aging has been defined as a reduction in the capacity to adequately maintain tissue homeostasis or to repair tissues after injury. Tissue homeostasis and regenerative capacity are nowadays considered to be related to the stem cell pool present in every tissue. For this reason, pathological and patho-physiological conditions characterized by altered tissue homeostasis and impaired regenerative capacity can be viewed as a consequence of the reduction in stem cell number and/or function. Last, cellular senescence is a double-edged sword, since it may inhibit the growth of transformed cells, preventing the occurrence of cancer, while it may facilitate growth of preneoplastic lesions in a paracrine fashion; therefore, interventions targeting this cell response to stress may have a profound impact on many age-related pathologies, ranging from cardiovascular disease to oncology. Aim of this review is to discuss both molecular mechanisms associated with stem cell senescence and interventions that may attenuate or reverse this process. PMID- 20965212 TI - SDF-1alpha as a therapeutic stem cell homing factor in myocardial infarction. AB - Myocardial infarction is associated with persistent muscle damage, scar formation and depressed cardiac performance. Recent studies have demonstrated the clinical significance of stem cell-based therapies after myocardial infarction with the aim to improve cardiac remodeling and function by inducing the reconstitution of functional myocardium and formation of new blood vessels. Stem cell homing signals play an important role in stem cell mobilization from the bone marrow to the ischemic cardiac environment and are therefore crucial for myocardial repair. To date, the most prominent stem cell homing factor is the chemokine SDF 1alpha/CXCL12. This protein was shown to be significantly upregulated in many experimental models of myocardial infarction and in patients suffering from ischemic cardiac diseases, suggesting the involvement in the pathophysiology of these disorders. A number of studies focused on manipulating SDF-1alpha and its receptor CXCR4 as central regulators of the stem cell mobilization process. Targeted expression of SDF-1alpha after myocardial infarction was shown to result in increased engraftment of bone marrow-derived stem cells into infarcted myocardium. This was accompanied by beneficial effects on cardiomyocyte survival, neovascularization and cardiac function. Thus, the SDF-1/CXCR4 axis seems to be a promising novel therapeutic approach to improve post-infarction therapy by attracting circulating stem cells to remain, survive and possibly differentiate in the infarct area. This review will summarize clinical trials of stem cell therapy in patients with myocardial infarction. We further discuss the basic findings about SDF-1alpha in stem cell recruitment and its therapeutic implications in experimental myocardial infarction. PMID- 20965214 TI - Individual variability in the disposition of and response to clopidogrel: pharmacogenomics and beyond. AB - The widespread use of clopidogrel alone or in combination with aspirin has significantly benefited patients with acute coronary syndrome who are managed medically or by percutaneous coronary intervention and stent implantation, greatly improving their survival. Emerging data have documented that the clopidogrel response may vary from person to person and even from disease to disease, and that genetic and nongenetic factors contribute to that variability. Genetic polymorphisms affecting clopidogrel metabolic bioactivation and platelet function may be responsible, each exerting a small effect. CYP2C19 *2, *3 and *17, CYP2C9 *2 and *3, MDR1*2, and functional variants in the genes encoding platelet membrane receptors and intracellular signaling proteins are involved, and other genetic factors remain to be identified. In addition, nongenetic factors may be influential covariates, such as ethnicity, gender, age, body weight, co-existing diseases, drug-drug interactions, and other factors to be determined. Each piece of the puzzle would be useful to bridge and delineate identified knowledge gaps and to determine future research needs for the risk prediction of fatal complications associated with inadequate clopidogrel therapy in patient care. PMID- 20965215 TI - Two novel fusion inhibitors of human respiratory syncytial virus. AB - To search for novel drugs against human respiratory syncytial virus (RSV), we have screened a diversity collection of 16,671 compounds for anti-RSV activity in cultures of HEp-2 cells. Two of the hit compounds, i.e., the N-(2-hydroxyethyl)-4 methoxy-N-methyl-3-(6-methyl[1,2,4]triazolo[3,4-a]phthalazin-3 yl)benzenesulfonamide (designated as P13) and the 1,4-bis(3-methyl-4-pyridinyl) 1,4-diazepane (designated as C15), reduced the virus infectivity with IC50 values of 0.11 and 0.13MUM respectively. The concentration of P13 and C15 that reduced the viability of HEp-2 cells by 50% was 310 and 75MUM respectively. Both P13 and C15 exhibited no direct virucidal activity or inhibitory effects on the virus attachment to cells. However, to inhibit formation of RSV-induced syncytial plaques P13 and C15 had to be present during the virus entry into the cells and the cell-to-cell transmission of the virus. The RSV multiplication in HEp-2 cells in the presence of P13 or C15 resulted in rapid selection of viral variants that were ~1000 times less sensitive to these drugs than original virus. Sequencing of resistant viruses revealed presence of amino acid substitutions in the F protein of RSV, i.e., the D489G for C15-selected, and the T400I and N197T (some clones) for the P13-selected virus variants. In conclusion, we have identified two novel fusion inhibitors of RSV, and the detailed understanding of their mode of antiviral activity including selection for the drug resistant viral variants may help to develop selective and efficient anti-RSV drugs. PMID- 20965216 TI - Antidepressant-like properties of alpha2-containing GABA(A) receptors. AB - Growing evidence suggests that altered function of the GABAergic system can contribute to the pathophysiology of depression. Many GABAergic effects are mediated via ionotropic GABA(A) receptors, which are functionally defined by their alpha subunit (alpha1-alpha6). Although it remains unknown which specific GABA(A) receptor population mediates depressive-like effects, we posit that alpha2-containing GABA(A) receptors, which are highly expressed in limbic regions, may underlie these behaviors. We hypothesized that genetic inactivation of alpha2-containing GABA(A) receptors would generate a depressive-like phenotype in mice. Male and female wild type, alpha2 heterozygous, and alpha2 homozygous knockout mice generated on the 129X1/SvJ background were examined in the novelty suppressed feeding (NSF) test, the forced swim test (FST) and the tail suspension test (TST). Male alpha2 knockout mice took longer to eat in the NSF test and became immobile faster and remained immobile longer when challenged in the FST and the TST compared to wild types. In females significant genotypic differences were only observed in the FST. We conclude that GABAergic inhibition acting via alpha2-containing GABA(A) receptors has an antidepressant-like effect in vivo and that these receptors represent a specific molecular substrate that can regulate depressive-like states. alpha2-containing GABA(A) receptors may therefore represent a novel target for the development of more effective antidepressants. PMID- 20965217 TI - Reprint of: Catestatin: a multifunctional peptide from chromogranin A. AB - In 1997, we identified a novel peptide, catestatin (CST: bovine chromogranin A [CHGA]344-364: RSMRLSFRARGYGFRGPGLQL; human CHGA352-372: SSMKLSFRARGYGFRGPGPQL), which is a potent inhibitor of nicotinic-cholinergic-stimulated catecholamine secretion. CST shows characteristic inhibitory effects on nicotinic cationic (Na+, Ca2+) signal transduction, which are specific to the neuronal nicotinic receptor. Utilizing systematic polymorphism discovery at the human CHGA locus we discovered three human variants of CST: G364S, P370L, and R374Q that showed differential potencies towards the inhibition of catecholamine secretion. In humans, CHGA is elevated and its processing to CST is diminished in hypertension. Diminished CST is observed not only in hypertensive individuals but also in the early-normotensive offspring of patients with hypertension, suggesting that an early deficiency of CST might play a pathogenic role in the subsequent development of the disease. Consistent with human findings, prevention of endogenous CST expression by targeted ablation (knockout) of the mouse Chga locus (Chga-KO) resulted in severe hypertension that can be "rescued" specifically by replacement of the CST peptide. CST acts directly on the heart to inhibit the inotropic and lusitropic properties of the rodent heart and also acts as a potent vasodilator in rats and humans. While the G364S CST variant caused profound changes in human autonomic activity and seemed to reduce the risk of developing hypertension, CST replacement rescued Chga-KO mice from dampened baroreflex sensitivity. In addition, CST has been shown to induce chemotaxis and acts as an antimicrobial as well as an antimalarial peptide. The present review summarizes these multiple actions of CST. PMID- 20965213 TI - Targeting stem cell niches and trafficking for cardiovascular therapy. AB - Regenerative cardiovascular medicine is the frontline of 21st-century health care. Cell therapy trials using bone marrow progenitor cells documented that the approach is feasible, safe and potentially beneficial in patients with ischemic disease. However, cardiovascular prevention and rehabilitation strategies should aim to conserve the pristine healing capacity of a healthy organism as well as reactivate it under disease conditions. This requires an increased understanding of stem cell microenvironment and trafficking mechanisms. Engagement and disengagement of stem cells of the osteoblastic niche is a dynamic process, finely tuned to allow low amounts of cells move out of the bone marrow and into the circulation on a regular basis. The balance is altered under stress situations, like tissue injury or ischemia, leading to remarkably increased cell egression. Individual populations of circulating progenitor cells could give rise to mature tissue cells (e.g. endothelial cells or cardiomyocytes), while the majority may differentiate to leukocytes, affecting the environment of homing sites in a paracrine way, e.g. promoting endothelial survival, proliferation and function, as well as attenuating or enhancing inflammation. This review focuses on the dynamics of the stem cell niche in healthy and disease conditions and on therapeutic means to direct stem cell/progenitor cell mobilization and recruitment into improved tissue repair. PMID- 20965219 TI - PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect. AB - As mortality due to cancer continues to rise, advances in nanotechnology have significantly become an effective approach for achieving efficient drug targeting to tumour tissues by circumventing all the shortcomings of conventional chemotherapy. During the past decade, the importance of polymeric drug-delivery systems in oncology has grown exponentially. In this context, poly(lactic-co glycolic acid) (PLGA) is a widely used polymer for fabricating 'nanoparticles' because of biocompatibility, long-standing track record in biomedical applications and well-documented utility for sustained drug release, and hence has been the centre of focus for developing drug-loaded nanoparticles for cancer therapy. Such PLGA nanoparticles have also been used to develop proteins and peptides for nanomedicine, and nanovaccines, as well as a nanoparticle-based drug and gene-delivery system for cancer therapy, and nanoantigens and growth factors. These drug-loaded nanoparticles extravasate through the tumour vasculature, delivering their payload into the cells by the enhanced permeability and retention (EPR) effect, thereby increasing their therapeutic effect. Ongoing research about drug-loaded nanoparticles and their delivery by the EPR effect to the tumour tissues has been elucidated in this review with clarity. PMID- 20965218 TI - Targeting adenovirus gene delivery to activated tumour-associated vasculature via endothelial selectins. AB - Clinical experience with adenovirus vectors has highlighted the need for improved delivery and targeting. Tumour-associated endothelium offers an additional mechanism for enhanced viral uptake into tumours which is accessible for systemic gene delivery. Building on expertise in using polymer 'stealthed' viruses for targeting in vivo, adenovirus expressing luciferase (Adluc) was coated with an amino-reactive polymer based on poly [N-(2-hydroxypropyl) methacrylamide] to ablate normal infection pathways. Direct linkage of a monoclonal antibody against E-selectin (MHES) demonstrated E-selectin-specific transduction of tumour necrosis factor-alpha (TNF-alpha)-activated endothelial cells. A two-component targeting system using protein G was developed, to provide optimal antibody orientation. We report an enhancement in transduction of TNF-alpha-activated endothelium in vitro and ex vivo in a human umbilical vein cord model using the MHES antibody. Similarly a virus retargeted using a chimeric P-selectin Glycoprotein Ligand-1-Fc fusion (PSGL-1) protein showed better circulation kinetics and significant uptake into HepG2 xenografts following systemic administration in mice, with 36-fold higher genome copies, compared with non modified virus. Immunohistochemistry staining of tumour sections from mice treated with PSGL-1-retargeted virus showed a co-localisation of firefly luciferase with CD31 suggesting selective endothelial targeting. Employment of optimal viral modification using protein G will enable exploration and comparison of alternative targeting ligands targeting tumour-associated endothelium. PMID- 20965220 TI - Arginine vasopressin in hypothalamic paraventricular nucleus is transferred to the caudate nucleus to participate in pain modulation. AB - Arginine vasopressin (AVP), which is synthesized and secreted in the hypothalamic paraventricular nucleus (PVN), is the most important bioactive substance in the pain modulation. Our pervious study had shown that AVP plays an important role in pain modulation in caudate nucleus (CdN). The experiment was designed to investigate the source of AVP in CdN by the nucleus push-pull perfusion and radioimmunoassay. The results showed that: (1) pain stimulation increased the AVP concentration in the CdN perfusion liquid, (2) PVN decreased the effect of pain stimulation which was stronger in both sides than in one side of PVN cauterization; and (3) L-glutamate sodium would excited the PVN neurons by the PVN microinjection that could increase the AVP concentration in the CdN perfusion liquid. The data suggested that AVP in the CdN might come from the PVN in the pain process, i.e., AVP in the PVN might be transferred to the CdN to participate in the pain modulation. PMID- 20965221 TI - Altered dipsogenic responses and expression of angiotensin receptors in the offspring exposed to prenatal high sucrose. AB - The present study determined water and salt intake as well as expression of AT(1) and AT(2) receptors in the brain and kidney in the adult offspring rats prenatally exposed to high sucrose. Following the exposure during pregnancy, water intake and salt intake at baseline levels were not changed in the adult offspring. However, after 24h water deprivation, consumption of water and salt was significantly increased compared to that of the control. Plasma sodium and osmolality levels remained the same between the offspring in the control and the exposed groups, while hematocrit was higher in the offspring exposed to prenatal high sucrose immediately following water deprivation. Density of renal AT(1) receptor protein was the same between the control and the exposed group, while AT(2) receptor protein in the kidney was significantly increased in the offspring exposed to prenatal high sucrose in association of thicker basal membrane of glomerular. In the forebrain, both AT(1) and AT(2) receptor levels were significantly increased in the offspring with history of prenatal high sucrose. In addition, water deprivation induced more c-fos expression in the central dipsogenic areas, including the paraventricular and supraoptic nuclei in the offspring exposed to prenatal high sucrose. The results suggested that prenatal high intake of sucrose may affect development of pathways in regulation of dipsogenic behavior in face of dehydration, which was associated with altered expression of AT(1) or/and AT(2) receptors in the kidney and brain. PMID- 20965222 TI - Worsening psychosis after adding aripiprazole to clozapine. PMID- 20965223 TI - Activation of the opioid MU1, but not delta or kappa, receptors is required for nicotine reinforcement in a rat model of drug self-administration. AB - There has long been an interest in examining the involvement of opioid neurotransmission in nicotine rewarding process and addiction to nicotine. Over the past 3 decades, however, clinical effort to test the effectiveness of nonselective opioid antagonists (mainly naloxone and naltrexone) for smoking cessation has yielded equivocal results. In light of the fact that there are three distinctive types of receptors mediating actions of the endogenous opioid peptides, this study, using a rat model of nicotine self-administration, examined involvement of different opioid receptors in the reinforcement of nicotine by selective blockade of the MU1, the delta, and the kappa opioid receptors. Male Sprague-Dawley rats were trained in daily 1h sessions to intravenously self administer nicotine (0.03 mg/kg/infusion) on a fixed-ratio 5 schedule. After establishment of stable nicotine self-administration behavior, the effects of the opioid antagonists were tested. Separate groups of rats were used to test the effects of naloxanazine (selective for MU1 receptors, 0, 5 and 15 mg/kg), naltrindole (selective for delta receptors, 0, 0.5 and 5mg/kg), and 5' guanidinonaltrindole (GNTI, selective for kappa receptors, 0, 0.25 and 1mg/kg). In each individual drug group, the 3 drug doses were tested by using a within subject and Latin-Square design. The effects of these antagonists on food self administering behavior were also examined in the same rats in each respective drug group after retrained for food self-administration. Pretreatment with naloxonazine, but not naltrindole or GNTI, significantly reduced responses on the active lever and correspondingly the number of nicotine infusions. None of these antagonists changed lever-pressing behavior for food reinforcement. These results indicate that activation of the opioid MU1, but not the delta or the kappa, receptors is required for the reinforcement of nicotine and suggest that opioid neurotransmission via the MU1 receptors would be a promising target for the development of opioid ligands for smoking cessation. PMID- 20965224 TI - Amisulpride therapeutic dose-induced asymptomatic bradycardia. PMID- 20965225 TI - Determination of some traces metal levels in cheese samples packaged in plastic and tin containers by ICP-OES after dry, wet and microwave digestion. AB - The concentrations of Cd, Co, Cr, Cu, Mn, Ni, Pb, Se and Zn in cheese samples packaged in plastic and tin containers were analyzed using inductively coupled plasma-optical emission spectrometry after microwave, wet and dry digestion processes. In order to evaluate the best digestion method, the relationships between the concentrations of trace metals in cheese samples after microwave digestion was compared by wet and dry ashings. Microwave digestion was found fast, reliable, simple, and excellent procedure in comparison with dry and wet ashing methods. The accuracy of the digestion procedures was determined by using standard reference material (GBW 07605-Tea). The order of levels of the elements in the white cheese samples packaged in tin containers was determined to be Cd=16 cells at day 5 after insemination but did not provide thermoprotection to two-cell embryos. Failure of IGF1 to alter embryo survival after heat shock was not associated with reduced expression of genes involved in IGF1 signaling (IGF1R, RAF1, PI3K, and MAPK) or immunoreactive IGF1R protein. Treatment with IGF1 had little effect on the transcriptome at the blastocyst stage of development, with a total of 102 differentially expressed genes identified. Among the differentially expressed genes were several involved in apoptosis, protection against free radicals and development. Changes in gene expression were consistent with IGF1 acting to induce an anti-apoptotic state and inhibit neurulation. In conclusion, thermoprotective actions of IGF1 are developmentally regulated. Failure of IGF1 to protect the two-cell embryo from heat shock could reflect the fact that these embryos are maximally sensitive to damage caused by heat shock or reflect the quiescence of the embryonic genome at this stage of development. Changes in gene expression at the blastocyst stage induced by IGF1 could contribute to the increased survival of IGF1-treated embryos when transferred during periods of heat stress. PMID- 20965228 TI - Regulation of SMRT corepressor dimerization and composition by MAP kinase phosphorylation. AB - The SMRT (Silencing Mediator of Retinoid and Thyroid hormone receptors) corepressor mediates gene repression by nuclear receptors and other transcriptional factors. The SMRT protein serves as a key nucleating core that organizes the assembly of a larger corepressor complex. We report here that SMRT interacts with itself to form a protein dimer, and that Erk2, a mitogen-activated protein (MAP) kinase, disrupts this SMRT self-dimerization in vitro and in vivo. Notably Erk2 phosphorylation also results in a re-organization of the overall corepressor complex, characterized by a reduced sedimentation coefficient, partial release of HDAC3, TBL-1, and TBLR-1, and inhibition of transcriptional repression. We propose that SMRT dimers form the central platform on which additional corepressor components assemble, and that kinase signaling modifies the architecture, composition, and function of this complex. These observations contribute to our understanding of how the SMRT corepressor complex assembles and is regulated during cell proliferation and differentiation. PMID- 20965230 TI - The natural compounds atraric acid and N-butylbenzene-sulfonamide as antagonists of the human androgen receptor and inhibitors of prostate cancer cell growth. AB - Extracts from the plant Pygeum africanum are widely used in the therapy of benign prostate hyperplasia (BPH) and in combinational therapy for prostate cancer, the second leading cause of cancer death and the mostly diagnosed form of cancer in men. The androgen receptor (AR) plays a crucial role in the development of the prostate as well as in prostate diseases. Even though the extracts from P. africanum are considered as beneficial for prostate diseases in clinical trials, and some active compounds for treatment of BPH could be identified, compounds responsible for AR inhibition and the molecular mechanism for inhibition of prostatitis need to be identified. Recently, atraric acid and N-butylbenzene sulfonamide were isolated from a selective dichlormethane extract of P. africanum as two novel AR antagonistic compounds. The molecular mechanisms of AR inhibition were analyzed and are summarized here. Both compounds are the first known natural, complete and specific AR antagonist. PMID- 20965231 TI - Sensory stimulus evokes inhibition rather than excitation in cerebellar Purkinje cells in vivo in mice. AB - Cerebellar Purkinje cells (PC) response precisely to tactile stimulus via granule cells, however, the interaction between sensory evoked synaptic input and the resulting pattern of output spikes in cerebellar cortex is unclear. In this study, we used electrophysiological recording and pharmacological methods to investigate the cerebellar PC in response to natural stimulus on ipsilateral whisker pad in urethane-anesthetized mice. We found that air-puff stimulus on ipsilateral whisker pad evoked neither complex spikes nor simple spike firing, but indeed evoked a strong GABA(A) receptor-mediated inhibition in PCs in cerebellar cortex folium Crus II. Field potential recordings from both molecular layer and PC layer showed that air-puff stimulus evoked a sequence of parallel fiber volley followed by a GABA(A) receptor-mediated inhibition, which completely blocked by AMPA receptor antagonist, NBQX. Cell-attached recordings showed that air-puff stimulus evoked a pause of simple spike firing, GABA(A) receptor antagonist abolished the pause, revealed the tactile stimulus-evoked spike firing in PCs. These results indicated that natural stimulus of whisker pad neither evoked complex spikes, nor fired simple spikes, but induced inhibition in PCs, suggesting that the interneuron network are rapid activated and involved in controlling the spread of sensory information processing in mouse cerebellar cortex folium Crus II. PMID- 20965232 TI - The timing of retroviral silencing correlates with the quality of induced pluripotent stem cell lines. AB - BACKGROUND: Induced pluripotent stem (iPS) cells can be generated from somatic cells by introducing the four transcription factors Oct4, Sox2, Klf4, and c-Myc. Given that iPS cell technology may be useful for medical applications, the quality of iPS cells needs to be maintained during prolonged cultivation. However, it is unclear whether there are any differences in stability among different iPS clones. METHODS: We infected mouse embryonic and adult fibroblasts with retroviruses encoding Oct4, Sox2, Klf4, c-Myc, and green fluorescent protein (GFP). We obtained embryonic stem (ES) cell-like colonies with silenced retroviral transgenes and divided these colonies into two groups: ES cell-like colonies that underwent retroviral silencing (i) on around day 14 (called early iPS) or (ii) on around day 30 (called late iPS), after infection. We compared morphology, proliferation efficiency, pluripotency marker expression, and karyotype between early iPS and late iPS cells. RESULTS: Early iPS cells were more stable than late iPS cells. At passage 20, most of the early iPS clones maintained ES cell-like morphology, expressed pluripotency markers, and showed proliferation efficiency similar to ES cells. Furthermore, early iPS clones derived from both embryonic and adult fibroblasts gave rise to chimeras and could show germ line competency. In contrast, late iPS clones tended to lose their ES cell-like morphology and normal karyotype in prolonged culture. GENERAL SIGNIFICANCE: Our results provide useful information on the efficient derivation of stable iPS cells that may be useful for germline transmission in mouse. This study suggests that early completion of full reprogramming allows for superior iPS cell generation. PMID- 20965233 TI - Changes in neostriatal and hippocampal synaptic densities in perinatal asphyctic male and female young rats: Role of hypothermia. AB - Perinatal asphyxia (PA) may cause long-term neurological and psychiatric diseases. We evaluated, by ethanolic phosphotungstic acid (E-PTA) staining, whether PA affects postsynaptic densities (PSDs), ultrastructure of neostriatum and hippocampus of 45-day-old post-PA male and female rats. PA was induced by placing the uterine horns containing the fetuses in a 37 degrees C bath for 10, 15, 19 and 20 min and a 15 degrees C bath for 20 min (hypothermia). Striatal synaptic disorganization and PSDs thickness increase were evident after 10 and 19 min of PA in male and female rats, respectively, but striatal female PSDs thickness was lower than in males. These changes were associated with increments of the PSDs area in both sexes at 19 and 20 min PA. Thickness and PSDs area from hippocampal PA males was affected more negatively than in females. Intrahypoxic hypothermia was able to protect the brain from effects of PA. In conclusion, early PA affects neostriatal and hippocampal PSDs in a time and sex-dependent manner, while hypothermia during asphyxia is able to prevent synaptic changes by providing protection from damage. PMID- 20965234 TI - Involvement of IRE1alpha signaling in the hippocampus in patients with mesial temporal lobe epilepsy. AB - Cumulative evidence suggests that programmed cell death (apoptosis) may contribute to the progressive hippocampal sclerosis seen in patients with refractory mesial temporal lobe epilepsy (MTLE). The endoplasmic reticulum (ER) stress-mediated cell apoptotic pathway has recently emerged as a vital intrinsic pathway, but the molecular mechanisms underlying this process in the epileptic brain remain unclear. We investigated inositol-requiring protein 1alpha (IRE1alpha)-mediated ER stress pro-and anti-apoptotic signaling pathways in resected hippocampi from 32 patients with intractable MTLE. Immunoreactivity for the ER stress markers glucose-regulated proteins 78 and 94 was significantly higher in MTLE hippocampi than in controls. The levels of IRE1alpha, tumor necrosis factor receptor associated factor 2 (TRAF2), apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK), which together constitute the IRE1alpha/TRAF2/ASK1/JNK pro-apoptotic signaling pathway, were significantly upregulated in patients with MTLE. Immunoreactivity for caspase-4, a homologue of caspase-12 that is possibly activated by IRE1alpha via TRAF2 following ER stress, and caspase-3 which was a downstream effector of caspase-4, were both detected in MTLE tissue samples. In contrast, immunoreactivity for caspase-4 and caspase-3 were low or absent in control samples. Simultaneously, the X-box binding protein 1 (XBP1), a basic leucine zipper (bZIP) family transcription factor downstream of IRE1alpha which can promote cell survival by upregulation of multiple ER-targeted genes, was also overexpressed and activated in MTLE hippocampi. Our data suggest that chronic epilepsy is associated with ER stress, as well as induction of both IRE1alpha-mediated pro- and anti-apoptotic signaling pathways. PMID- 20965235 TI - A new isoflavanone from Iresine herbstii. AB - A new isoflavanone 2',2,5-trimethoxy-6,7-methylenedioxyisoflavanone was isolated from the aerial parts of Iresine herbstii, together with isoflavone tlatlancuayin (2',5-dimethoxy-6,7-methylenedioxyisoflavone). The structure was identified using spectroscopic analysis. This is the first description of a methoxy group occurrence at position 2 of the isoflavanone skeleton. Both isolated compounds were tested for alpha-glucosidase inhibitory activity, but showed only a low effect compared to hyperoside. PMID- 20965236 TI - The diversity of bovine MHC class II DRB3 and DQA1 alleles in different herds of Japanese Black and Holstein cattle in Japan. AB - In cattle, bovine leukocyte antigens (BoLAs) have been extensively used as markers for bovine diseases and immunological traits. In this study, we sequenced alleles of the BoLA class II loci, BoLA-DRB3 and BoLA-DQA1, from 650 Japanese cattle from six herds [three herds (507 animals) of Japanese Black cattle and three herds (143 animals) of Holstein cattle] using polymerase chain reaction sequence-based typing (PCR-SBT) methods. We identified 26 previously reported distinct DRB3 alleles in the two populations: 22 in Japanese Black and 17 in Holstein. The number of DRB3 alleles detected in each herd ranged from 9 to 20. Next, we identified 15 previously reported distinct DQA1 alleles: 13 in Japanese Black and 10 in Holstein. The number of alleles in each herd ranged from 6 to 10. Thus, allelic divergence is significantly greater for DRB3 than for DQA1. A population tree on the basis of the frequencies of the DRB3 and DQA1 alleles showed that, although the genetic distance differed significantly between the two cattle breeds, it was closely related within the three herds of each breed. In addition, Wu-Kabat variability analysis indicated that the DRB3 gene was more polymorphic than the DQA1 gene in both breeds and in all herds, and that the majority of the hypervariable positions within both loci corresponded to pocket forming residues. The DRB3 and DQA1 heterozygosity for both breeds within each herd were calculated based on the Hardy-Weinberg equilibrium. Only one Japanese Black herd showed a significant difference between the expected and observed heterozygosity at both loci. This is the first report presenting a detailed study of the allelic distribution of BoLA-DRB3 and -DQA1 genes in Japanese Black and Holstein cattle from different farms in Japan. These results may help to develop improved livestock breeding strategies in the future. PMID- 20965237 TI - cAMP and fibroblast growth factor 2 regulate bone sialoprotein gene expression in human prostate cancer cells. AB - Bone sialoprotein (BSP) is a noncollagenous protein of the extracellular matrix in mineralized connective tissues that has been implicated in the nucleation of hydroxyapatite. Forskolin (FSK), an activator of adenylate cyclase, increased the intracellular cAMP level, which stimulates the proliferation and differentiation of osteoblasts. Fibroblast growth factor 2 (FGF2) is a potent mitogen in many cell types, including osteoblasts. In human prostate cancer DU145 cells, FSK (1 MUM) and FGF2 (10 ng/ml) increased BSP and Runx2 mRNA and protein levels at 3 and 12h, respectively. Transient transfection analyses were performed using chimeric constructs of the human BSP gene promoter linked to a luciferase reporter gene. Treatment of DU145 cells with FSK (1 MUM) and FGF2 (10 ng/ml) increased the luciferase activities of constructs between -60LUC to -927LUC and -108LUC to 927LUC, including the human BSP gene promoter. Effects of FSK and FGF2 abrogated in constructs included 2bp mutations in the two cAMP response elements (CRE1 and CRE2). Luciferase activities induced by FSK and FGF2 were blocked by protein kinase A and tyrosine kinase inhibitors. Gel mobility shift analyses showed that FSK and FGF2 increased the binding of CRE1 and CRE2. CRE1-protein complexes were supershifted by phospho-CREB1 and c-Fos antibodies, and disrupted by CREB1, c Jun, JunD, Fra2, p300, Runx2, Dlx5 and Smad1 antibodies. CRE2-protein complexes were disrupted by CREB1, phospho-CREB1, c-Fos, c-Jun, JunD, Fra2, p300, Runx2, Dlx5 and Smad1 antibodies. These studies demonstrate that FSK and FGF2 stimulate BSP transcription in DU145 human prostate cancer cells by targeting the CRE1 and CRE2 elements in the human BSP gene promoter. PMID- 20965238 TI - HMC05 attenuates vascular contraction through inhibition of RhoA/Rho-kinase signaling pathway. AB - AIM OF THE STUDY: HMC05, an extract from eight different herbal mixtures, has been developed to treat cardiovascular disease. This extract has a vasorelaxant and anti-atherosclerotic action. We hypothesized that HMC05 attenuates vascular contraction through inhibition of the RhoA/Rho-kinase signaling pathway. MATERIALS AND METHODS: Rat aortic ring preparations were mounted in organ baths and subjected to contraction and relaxation. Phosphorylation of 20 kDa myosin light chains (MLC(20)) and myosin phosphatase targeting subunit 1 (MYPT1) were examined by immunoblot. We also measured the amount of GTP RhoA as a marker for RhoA activation. RESULTS: In endothelium-denuded aortic ring preparations, HMC05 relaxed vascular contraction induced by 6.0 mM NaF, 100 nM phenylephrine, 30 nM thromboxane A(2) agonist U46619 or 1.0 MUM protein kinase C (PKC) activator phorbol-12,13-dibutyrate (PDBu) in a decreasing order. HMC05 relaxed aortic ring preparations precontracted with sodium fluoride (NaF) whether endothelium was intact or denuded. Pre-incubation with HMC05 for 30 min dose-dependently inhibited the NaF-induced contractile response. In vascular strips, HMC05 decreased the phosphorylation level of both MLC(20) and MYPT1(Thr855) induced by 6.0 mM NaF. Furthermore, HMC05 decreased the amount of GTP RhoA activated by NaF. CONCLUSIONS: HMC05 attenuates vascular contraction through inhibition of the RhoA/Rho-kinase signaling pathway. HMC05 may be useful for the treatment and/or prevention of cardiovascular diseases associated with activation of RhoA/Rho kinase signaling pathway. PMID- 20965239 TI - Analysis of ethnoveterinary treatments for cattle (Bos indicus) diseases referred in Sanrimgyeongje including twelve volumes of literature from the 7th to the 18th century. AB - AIM OF THE STUDY: This study aims at a comprehensive analysis of ethnoveterinary treatment in the cattle-raising section of Sanrimgyeongje which covers 12 different volumes of literature including 4 Korean and 8 Chinese literatures from the 7th to the 18th century, with a special attention to the treatments for cattle diseases. MATERIALS AND METHODS: The above mentioned literature was analyzed through several steps: translation of the Chinese text into Korean, identification of diseases, verification of medicinal materials and confirmation of scientific names. RESULTS: As recorded in the thirteen references, this study shows that there are 143 medicinal materials which have been used as therapies for cattle diseases. Of these, 55 plant species belonging to 52 genera in 29 families had 100 modes of usages, while one species of fungus was used in one way. Likewise, 11 species of animals belonging to 11 genera in 10 families were utilized in 18 different methods. Lastly, 9 kinds of inorganic matters were used in 11 ways with another 4 kinds being useful in 14 different ways. Consequently, each of rinderpests, murrains, and hooves has been treated, respectively with 14, 10 and 3 types of medicinal decoctions made from 35, 18 and 15 kinds of medicinal materials. CONCLUSION: This diversified usage of various medicinal materials is incomparable to the modern ethnoveterinary investigation which tends to focus strictly in plants. If additional studies were to be conducted on these treatments and all the medicinal materials used within them, various new treatments and medicines can be developed to supplement the pharmacopoeia of contemporary veterinary medicine. PMID- 20965240 TI - Antidiabetic activity of alcoholic stem extract of Nervilia plicata in streptozotocin-nicotinamide induced type 2 diabetic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Nervilia plicata (Orchidaceae) has long been used in the antidiabetic medicinal preparations of traditional healers of Wayanad (Kerala), but recuperative potential of the plant was remained undefined. We demonstrated the regenerative potential of the plant extract on kidney affected by type 2 diabetes besides lowering blood glucose. AIM OF THE STUDY: The aim of the current study was to investigate the recuperative and regenerative potential of alcoholic stem extract of Nervilia plicata on streptozotocin-nicotinamide induced type 2 diabetic models. MATERIALS AND METHODS: Non insulin dependent diabetes mellitus (NIDDM) was induced in overnight fasted rats by intramuscular injection (IMI) of 60 mg/kg STZ and 120 mg/kg of nicotinamide after 5 min interval. Blood glucose was assessed by a glucometer, serum urea and creatinine levels were determined by diacetylmonooxime method and Jaffe reaction respectively. Kidney sections were taken and stained with Masson's tri-dye and Periodic Acid Schiff (PAS) and examined for structural changes. Also lipid peroxidation product (LPP) levels were determined as thio barbituric acid reactive substance levels (TBARS) method. RESULTS: On administration of 5 mg/kg of plant extract, blood glucose levels of the NIDDM rats showed 62.00 and 76.29% decrease in the blood glucose levels on day 0 and day 30 respectively. Damages caused to the kidney tissue were negligible or not seen. Serum urea and creatinine levels showed 61.49 and 70.96% decrease on day 30. LPP levels of kidney and pancreas showed 70.58 and 77.41% decrease respectively. CONCLUSION: These results demonstrate significant antidiabetic and regenerative potential of the Nervilia plicata, justifying the use of plant in the indigenous system of medicine. Isolation and characterisation of the compound(s) playing pivotal role in the cure would open new vistas in the therapy of type 2 diabetes. PMID- 20965241 TI - Ethnobotany and trade of medicinal plants in the Qaysari Market, Kurdish Autonomous Region, Iraq. AB - AIM OF STUDY: Marketplaces epitomize a region's culture and trade, and can give a rapid insight into traditions and salience of commercialized medicinal products. The Qaysari bazaar, bordering the citadel in Erbil city in the Kurdistan Autonomous Region, Iraq, has 21 herbalist shops trading natural medicinal products, wild-crafted and cultivated from all over the Middle East and Asia Minor. MATERIALS AND METHODS: Freelist surveys were conducted with 18 of these herbalists to determine diversity and salience of traded traditional medicinal plants. Interviews were conducted to document use, trade volume, origin, stock and value of the reported species. Plant species were identified using a combination of morphological identification and molecular barcoding using the ITS region. RESULTS: Vouchers were collected for a total of 158 samples, corresponding to 82 species of plants, 5 animal products, 8 types of stones, minerals or chemicals, as well as 16 mixtures of plant products. Consensus Analysis of the herbalist interviews shows strong support for a single culture of herbalist plant use. CONCLUSIONS: Most reported plant species are known to have been used since antiquity, and uses are identical or similar to previously documented uses. Herbalists report a steady year-on-year increase in trade due to the economic stability in recent times. A majority (64%) of medicinal plants is imported from outside Iraq, and the data shows that imported plants trade at a higher price than locally-sourced species, and that these species are stocked in higher volumes by the herbalists to ensure a steady supply to consumers. A strong tradition of herbal medicine exists in Kurdistan today exemplified by the diverse and vigorous trade in medicinal plants commercialized from the provinces around Erbil to countries as far away as India, Spain and Libya. PMID- 20965242 TI - Tetrahydroamentoflavone (THA) from Semecarpus anacardium as a potent inhibitor of xanthine oxidase. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Seed of Semecarpus anacardium L. is widely used in Indian traditional medicine; Ayurveda and Sidha, for treatment of inflammatory disorders and gout. AIM OF THE STUDY: The present study was aimed at isolation of a compound for its potential to inhibit xanthine oxidase (XO), over expression of which lead to inflammation and gout. MATERIALS AND METHODS: Activity guided fractionation of S. anacardium seed was conducted using liquid-liquid partition and preparative HPLC. The fractions were evaluated for their XO inhibition and antioxidant activity. The ethyl acetate fraction with the highest XO activity yielded a biflavonoid compound tetrahydroamentoflavone (THA). Lineweaver-Burk (LB) plot for the XO inhibition of THA and allopurinol was constructed from the kinetic data. RESULTS: IC50 values of THA and allopurinol for XO inhibition were 92 and 100 nM respectively and their corresponding values for K(i) were 0.982 and 0.612 MUM respectively. CONCLUSION: THA was a potent XO inhibitor which could be considered as a drug candidate or chemopreventive agent, after establishing its pharmacological and clinical evaluation. The study results appear to support the claim of the traditional medicine with respect to the efficacy of S. anacardium seed against inflammation and gout. PMID- 20965243 TI - The expression change of beta-arrestins in fibroblast-like synoviocytes from rats with collagen-induced arthritis and the effect of total glucosides of paeony. AB - AIM OF THE STUDY: To investigate the expression of beta-arrestins in fibroblast like synoviocytes (FLS) from collagen-induced arthritis (CIA) rats and the effect of total glucosides of paeony (TGP). MATERIALS AND METHODS: TGP and glucosides of tripterygium wilfordii (GTW) were intragastriclly administrated to collagen induced arthritis (CIA) rats after immunization. The secondary inflammatory reaction was evaluated by hind paw swelling, polyarthritis index and histopathological changes. Antibodies to type II collagen (CII) were determined by enzyme-linked immunosorbent assay (ELISA). Synoviocyte proliferations were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl (MTT) assay. The expression of beta-arrestins in synoviocytes from CIA rats was measured by western blot. RESULTS: The administration of TGP (25, 50, 100 mg/kg) depressed hind paw swelling and decreased the arthritis scores of CIA rats. TGP improved the pathologic manifestations of CIA. Serum anti-CII antibodies level increased significantly in CIA rats, while TGP had no effect on it. Fibroblast-like synoviocytes (FLS) proliferation was inhibited by TGP (50, 100 mg/kg). On d14, d28 after immunization, beta-arrestins expression greatly up-regulated in synoviocytes from CIA rats and then returned to baseline levels on d42 after immunization. TGP (50, 100 mg/kg) significantly reduced the expression of beta arrestins. CONCLUSION: An inflammatory process in vivo induces an up-regulation of beta-arrestins in synoviocytes from CIA rats while TGP can inhibit this change, which might be one of the important mechanisms for TGP to produce a marked therapeutic effect on RA. PMID- 20965244 TI - Honeybee trophocytes and fat cells as target cells for cellular senescence studies. AB - Trophocytes and fat cells are distributed around the abdominal segments in honeybees (Apis mellifera). Whether these cells are a good model for cellular senescence studies is unknown. Here we used histochemical, biochemical, and genetic techniques to investigate the fluctuation of age-related molecules in trophocytes and fat cells of newly emerged and old worker bees. Histochemical studies revealed that old worker trophocytes and fat cells exhibited more senescence-associated beta-galactosidase, lipofuscin granules, and non homogeneous cellular morphology compared to the same cells in newly emerged workers. Biochemical assays demonstrated that trophocytes and fat cells of old workers expressed more lipid peroxidation and protein oxidation than those of newly emerged workers. Molecular genetic analyses detected no difference in telomerase activity or telomere length in trophocytes and fat cells between newly emerged and old workers, showing that these cells do not divide in adulthood. These results suggest that the expression of age-related molecules in trophocytes and fat cells is associated with the senescence of the cells and that honeybee trophocytes and fat cells can serve as a mode for cellular senescence. PMID- 20965245 TI - Developmental and environmental origins of breast cancer: DDT as a case study. AB - More than 20 studies of serum "DDT" and breast cancer have found little support for the hypothesis that exposure influences risk of breast cancer. However, studies share common limitations including the inability to account for exposure in early life when the breast may be most vulnerable and the inability to measure exposure to the primary components of commercial DDT. This paper (1) summarizes evidence regarding critical windows of exposure for breast cancer (2) summarizes lessons learned from initial efforts to study DDT and breast cancer (3) reviews evidence from the Child Health and Development Studies (CHDS) where exposure was measured in young women using blood samples obtained during active exposure, 1-3 days after delivery and (4) suggests approaches for human studies that might advance understanding of environmental stressors in the developmental origins of disease. PMID- 20965246 TI - Perinatal exposure of rats to Bisphenol A affects fertility of male offspring--an overview. AB - Endocrine disruptors (ED) induce both functional and behavioral reproductive abnormalities. Bisphenol A (BPA) is a known ED that leaches from polycarbonate plastics, as such human exposure is common. Maternal BPA exposure has been shown to have negative effects on the fertility of male offspring. Pregnant rats exposed perinatally to environmentally relevant doses of BPA gave birth to offspring with significantly impaired spermatogenesis and fertility. Perinatal exposure had deleterious effects on the male germ line which manifested as impairments in the fertility of F(1) male offspring and subsequent F(2) and F(3) generations. This overview is an attempt to summarize the currently available data in the literature with regards to perinatal BPA exposure and male fertility. PMID- 20965247 TI - Connective tissue growth factor induction by lysophosphatidic acid requires transactivation of transforming growth factor type beta receptors and the JNK pathway. AB - Transforming growth factor beta (TGF-beta) is a very strong pro-fibrotic factor which mediates its action, at least in part, through the expression of connective tissue growth factor (CTGF/CCN2). Along with these cytokines, the involvement of phospholipids in wound healing and the development of fibrosis has been revealed. Among them, lysophosphatidic acid (LPA) is a novel, potent regulator of wound healing and fibrosis that has diverse effects on many types of cells. We decided to evaluate the effect of LPA together with TGF-beta on CTGF expression. We found that myoblasts treated with LPA and TGF-beta1 produced an additive effect on CTGF expression. In the absence of TGF-beta, the induction of CTGF expression by LPA was abolished by a dominant negative form of the TGF-beta receptor type II (TGF betaRII) and by the use of SB 431542, a specific inhibitor of the serine/threonine kinase activity of TGF-betaRI, suggesting that CTGF induction is dependent on LPA and requires active TGF-betaRs. Moreover, we show that LPA requires Smad-2/3 proteins for the induction of CTGF expression, but not their phosphorylation or their nuclear translocation. The requirement of TGF-betaRI for LPA mediated-effects is differential, since treatment of myoblasts with LPA in the presence of SB 431542 abolished the induction of stress fibers but not the induction of proliferation. Finally, we demonstrated that CTGF induction in response to LPA requires the activation of JNK, but not ERK, signaling pathways. The JNK requirement is independent of TGF-betaRI-mediated activity. These novel results for the mechanism of action of LPA and TGF-beta are important for understanding the role of pro-fibrotic growth factors and phospholipids involved in wound healing and related diseases. PMID- 20965248 TI - PKCepsilon acts as negative allosteric modulator of EGF receptor signalling. AB - Protein kinase C epsilon (PKCepsilon) is a transforming oncogene and plays a pivotal role in numerous cellular processes including proliferation, invasion and differentiation. Recently, we described a function of PKCepsilon as a scaffold protein linking PLCgamma1 to the EGFR module. Here, in the head and neck squamous carcinoma cell line (HNSCC) FaDu we demonstrate that over-expressed PKCepsilon may be associated with the EGFR. This is linked with the consecutive inhibition of the recruitment of PLCgamma1 to the EGFR, of the catalytical activation of PLCgamma1 by EGF, and of the PLCgamma1-mediated effect of EGF on cell proliferation. These effects are independent of the catalytical as well as the scaffold activity of PKCepsilon but are a function of the cellular expression level of PKCepsilon. In contrast to FaDu cells where the PLCgamma1 pathway was selectively affected, in three other HNSCC cell lines investigated over expression of PKCepsilon resulted in association with EGFR and, subsequently, in either partial (ERK and Akt or PLCgamma1 and Akt) or complete (ERK, PLCgamma1 and Akt) inhibition of the main EGFR signalling pathways. Together, our data suggest that in particular carcinoma cells highly expressed PKCepsilon may act as negative allosteric modulator of EGFR signalling. This novel function of PKCepsilon provides also the first indication that the EGFR may be a target for allosteric modulation by accessory proteins. PMID- 20965249 TI - The Autism Psychodynamic Evaluation of Changes (APEC) scale: a reliability and validity study on a newly developed standardized psychodynamic assessment for youth with Pervasive Developmental Disorders. AB - The present study was designed to examine the reliability and validity of the Autism Psychodynamic Evaluation of Changes (APEC) scale, developed to assess the evolution in individuals with autism under treatment. The APEC scale focuses on the key role of impairment in body image construction, which requires cross-modal sensory integration through emotional communication with motor representations. Thus, the body image construction is associated simultaneously with spatial and temporal organization and allows the emergence of self- and others representations. The use of the APEC scale, with its seven domains (expression of emotion in relationships, eye contact, body image, graphic productions, exploration of space and objects, time perception, and verbal language), underlines the importance in autistic disorder of anxieties related to body and spatial representations, and of impairment in the body ego construction which is closely linked to the emergence of individuation/separation processes. This study was conducted on 73 children and adolescents with autistic disorder. They were recruited in day care facilities where two caregivers independently gave their ratings based on their clinical observation on a daily basis during the same month. Analyses included assessing construct validity through correspondence analyses and inter-rater reliability using kappa coefficients. The APEC scale offers a reliable and validated psychodynamic assessment of interest for professionals (such as child psychiatrists, caregivers, therapists or teachers) and researchers working with children, adolescents and adults with autistic disorder, especially in the follow-up of their evolution. The APEC scale provides an approach at the interface of psychoanalysis and neuroscience, and is also of interest for clinical and developmental psychology. Using the APEC scale in a range of different practical and research settings will foster links between psychoanalytic perspectives and educational training for children with autistic disorder, and will contribute to the dialogue between psychoanalysis, neuroscience and psychology. PMID- 20965250 TI - Nanostructured porous silicon microparticles enable sustained peptide (Melanotan II) delivery. AB - Peptide molecules can improve the treatment of a number of pathological conditions, but due to their physicochemical properties, their delivery is very challenging. The study aim was to determine whether nanostructured porous silicon could sustain the release and prolong the duration of action of a model peptide Melanotan II (MTII). Thermally hydrocarbonized nanoporous silicon (THCPSi) microparticles (38-53 MUm) were loaded with MTII. The pore diameter, volume, specific surface area and loading degree of the microparticles were analyzed, and the peptide release was evaluated in vitro. The effects of MTII on heart rate and water consumption were investigated in vivo after subcutaneous administration of the MTII loaded microparticles. A peptide loading degree of 15% w/w was obtained. In vitro studies (PBS, pH 7.4, 37 degrees C) indicated sustained release of MTII from the THCPSi microparticles. In vivo, MTII loaded THCPSi induced an increase in the heart rate 2 h later than MTII solution, and the effect lasted 1 h longer. In addition, MTII loaded THCPSi changed the water consumption after 150 min, when the immediate effect of MTII solution was already diminished. The present study demonstrates that MTII loading into nanosized PSi pore structure enables sustained delivery of an active peptide. PMID- 20965251 TI - Hereditary dystonia as a neurodevelopmental circuit disorder: Evidence from neuroimaging. AB - Primary dystonia has traditionally been viewed as a basal ganglia disorder, but recent studies suggest that the cerebellum plays a crucial role in the disease. Primary dystonia is associated with several genotypes. Among those, DYT1 and DYT6 are inherited in autosomal dominant fashion with reduced penetrance. Extensive structural and functional imaging studies have been performed on manifesting and non-manifesting carriers of these mutations. The results suggest that primary dystonia can be viewed as a neurodevelopmental circuit disorder, involving the cortico-striato-pallido-thalamo-cortical and cerebello-thalamo-cortical pathways. Anatomical disruption of the cerebellar outflow is found in non-manifesting and manifesting mutation carriers, and a second downstream disruption in thalamo cortical projections appears clinically protective in non-manifesting carriers. The microstructural deficits in cerebellar outflow are linked to an abnormally elevated sensorimotor network (NMRP) in dystonia patients. Abnormal expression of this network is reduced by successful treatment with deep brain stimulation. This article is part of a Special Issue entitled "Advances in dystonia". PMID- 20965252 TI - Cortisol modulates the induction of inflammatory gene expression in a rainbow trout macrophage cell line. AB - Glucocorticoid actions on the immune system are diverse and cell type dependent, and little is known about cell type-specific interactions and cross-talk between hormones and cytokines. In this study we have analyzed the gene expression patterns of the rainbow trout macrophage cell line RTS-11 by quantitative PCR, after exposure to combinations of cortisol plus a pro-inflammatory cytokine (e.g. recombinant trout IL-1beta, IFN-gamma), type I IFN or a PAMP (LPS or poly I:C). Several key genes of the inflammatory process were targetted to assess whether any modulation of their expression occurred due to the addition of cortisol to this cell line. Incubation of macrophages for 3 or 6 h with a physiological concentration of cortisol caused a decrease in expression of IL-6 and IL-8, but no significant changes were observed for the other genes examined. Co-stimulation of cortisol with the inflammatory agents resulted in a general suppression of genes related to the inflammatory response. Cortisol inhibited the up-regulation of IL-8 by all the stimulants after 3 h of co-incubation. Suppression of the up regulation of IL-6 by rIL-1beta, rIFN-gamma and poly I:C, of gammaIP by rIFN gamma or poly I:C, and of Cox-2 by rIL-1beta was seen after 6 h. In contrast, cortisol in combination with the pro-inflammatory agents has a synergistic effect on IL-10 expression, an anti-inflammatory molecule, suggesting that the activation of certain macrophage functions that lead to the resolution of inflammation occurs in fish macrophages in response to cortisol treatment. PMID- 20965253 TI - Semantic memory involvement in the default mode network: a functional neuroimaging study using independent component analysis. AB - The Default Mode Network (DMN) is a higher order functional neural network that displays activation during passive rest and deactivation during many types of cognitive tasks. Accordingly, the DMN is viewed to represent the neural correlate of internally-generated self-referential cognition. This hypothesis implies that the DMN requires the involvement of cognitive processes, like declarative memory. The present study thus examines the spatial and functional convergence of the DMN and the semantic memory system. Using an active block-design functional Magnetic Resonance Imaging (fMRI) paradigm and Independent Component Analysis (ICA), we trace the DMN and fMRI signal changes evoked by semantic, phonological and perceptual decision tasks upon visually-presented words. Our findings show less deactivation during semantic compared to the two non-semantic tasks for the entire DMN unit and within left-hemispheric DMN regions, i.e., the dorsal medial prefrontal cortex, the anterior cingulate cortex, the retrosplenial cortex, the angular gyrus, the middle temporal gyrus and the anterior temporal region, as well as the right cerebellum. These results demonstrate that well-known semantic regions are spatially and functionally involved in the DMN. The present study further supports the hypothesis of the DMN as an internal mentation system that involves declarative memory functions. PMID- 20965255 TI - Young adults born preterm with very low birth weight demonstrate widespread white matter alterations on brain DTI. AB - Preterm birth with very low birth weight (VLBW, <=1500 g) is connected to reduced white matter (WM) integrity in childhood and adolescence. These changes in WM are correlated to motor, sensory and neuropsychological impairments. CNS myelination continues into the early twenties, but the consequences of this for WM integrity in VLBWs have not been explored. DTI and tract based spatial statistics (TBSS) was carried out to test for voxelwise differences in fractional anisotropy (FA), eigenvalues and mean diffusivity (MD) between a preterm VLBW group (n=49) and a control group born at term (n=59) at 18-22 years of age. TBSS was also used to explore the relationship between perinatal clinical data and general cognitive ability (total IQ), respectively, and the DTI metrics (FA and MD), with gender and age as a confounder. In the VLBW group several major WM tracts particularly in the posterior region had significantly reduced FA caused by an increase in the two lowest eigenvalues. MD was significantly increased in the VLBWs in 50% of the same regions as the FA changes, but encompassing also more peripheral WM. In the VLBW group, FA was found to correlate positively with birth weight and negatively with number of days in intensive care and on mechanical ventilator, particularly in the corpus callosum. FA was found to correlate positively with total IQ in the young preterm adults. In the controls there was no correlation between FA and total IQ. Our results indicate that the neurologic sequelae of preterm birth with VLBW are a lifelong condition inducing structural and functional impairments also in adulthood in VLBW survivors. The greatest risk of having reduced WM integrity in adulthood was found in the most immature VLBW neonates requiring mechanical ventilation and long-term intensive care. PMID- 20965254 TI - beta-Amyloid affects frontal and posterior brain networks in normal aging. AB - Although deposition of beta-amyloid (Abeta), a pathological hallmark of Alzheimer's disease (AD), has also been reported in cognitively intact older people, its influence on brain structure and cognition during normal aging remains controversial. Using PET imaging with the radiotracer Pittsburgh compound B (PIB), structural MRI, and cognitive measures, we examined the relationships between Abeta deposition, gray matter volume, and cognition in older people without AD. Fifty-two healthy older participants underwent PIB-PET and structural MRI scanning and detailed neuropsychological tests. Results from the whole-brain voxel-based morphometry (VBM) analysis revealed that gray matter volume in the left inferior frontal cortex was negatively associated with amyloid deposition across all participants whereas reduced gray matter volume was shown in the posterior cingulate among older people with high amyloid deposition. When gray matter density measures extracted from these two regions were related to other brain regions by applying a structural covariance analysis, distinctive frontal and posterior brain networks were seen. Gray matter volume in these networks in relation to cognition, however, differed such that reduced frontal network gray matter volume was associated with poorer working memory performance while no relationship was found for the posterior network. The present findings highlight structural and cognitive changes in association with the level of Abeta deposition in cognitively intact normal elderly and suggest a differential role of Abeta-dependent gray matter loss in the frontal and posterior networks in cognition during normal aging. PMID- 20965256 TI - Effect of attention on cortical processing of sound motion: an EEG study. AB - The onset of motion in an otherwise continuous sound elicits a prominent auditory evoked potential, the so-called motion onset response (MOR). The MOR has recently been shown to be modulated by stimulus-dependent factors, such as velocity, while the possible role of task-dependent factors has remained unclear. Here, the effect of spatial attention on the MOR was investigated in 19 listeners. In each trial, the subject initially heard a free-field sound, consisting of a stationary period and a subsequent period of motion. Then, two successive stationary test tones were presented that differed in location and pitch. Subjects either judged whether or not the starting and final positions of the preceded motion matched the positions of the two test tones ('motion-focused condition'), or whether or not the test tones were identical in pitch, irrespective of the preceded motion stimulus ('baseline condition'). These two tasks were presented in separate experimental blocks. The performance level in both tasks was similar. However, especially later portions of the MOR were significantly increased in amplitude when auditory motion was task-relevant. Cortical source localization indicated that this extra activation originated in dorsofrontal areas that have been proposed to be part of the dorsal auditory processing stream. These results support the assumption that auditory motion processing is based on a complex interaction of both stimulus-specific and attentional processes. PMID- 20965257 TI - Imaging the deep cerebellar nuclei: a probabilistic atlas and normalization procedure. AB - The deep cerebellar nuclei (DCN) are a key element of the cortico-cerebellar loop. Because of their small size and functional diversity, it is difficult to study them using magnetic resonance imaging (MRI). To overcome these difficulties, we present here three related methodological advances. First, we used susceptibility-weighted imaging (SWI) at a high-field strength (7T) to identify the dentate, globose, emboliform and fastigial nucleus in 23 human participants. Due to their high iron content, the DCN are visible as hypo intensities. Secondly, we generated probabilistic maps of the deep cerebellar nuclei in MNI space using a number of common normalization techniques. These maps can serve as a guide to the average location of the DCN, and are integrated into an existing probabilistic atlas of the human cerebellum (Diedrichsen et al., 2009). The maps also quantify the variability of the anatomical location of the deep cerebellar nuclei after normalization. Our results indicate that existing normalization techniques do not provide satisfactory overlap to analyze the functional specialization within the DCN. We therefore thirdly propose a ROI driven normalization technique that utilizes both information from a T1-weighted image and the hypo-intensity from a T2*-weighted or SWI image to ensure overlap of the nuclei. These techniques will promote the study of the functional specialization of subregions of the DCN using MRI. PMID- 20965258 TI - Selection of independent components representing event-related brain potentials: a data-driven approach for greater objectivity. AB - Following the development of increasingly precise measurement instruments and fine-grain analysis tools for electroencephalographic (EEG) data, analysis of single-trial event-related EEG has considerably widened the utility of this non invasive method to investigate brain activity. Recently, independent component analysis (ICA) has become one of the most prominent techniques for increasing the feasibility of single-trial EEG. This blind source separation technique extracts statistically independent components (ICs) from the EEG raw signal. By restricting the signal analysis to those ICs representing the processes of interest, single-trial analysis becomes more flexible. Still, the selection criteria for in- or exclusion of certain ICs are largely subjective and unstandardized, as is the actual selection process itself. We present a rationale for a bottom-up, data-driven IC selection approach, using clear-cut inferential statistics on both temporal and spatial information to identify components that significantly contribute to a certain event-related brain potential (ERP). With time-range being the only necessary input, this approach considerably reduces the pre-assumptions for IC selection and promotes greater objectivity of the selection process itself. To test the validity of the approach presented here, we present results from a simulation and re-analyze data from a previously published ERP experiment on error processing. We compare the ERP-based IC selections made by our approach to the selection made based on mere signal power. The comparison of ERP integrity, signal-to-noise ratio, and single-trial properties of the back projected ICs outlines the validity of the approach presented here. In addition, functional validity of the extracted error-related EEG signal is tested by investigating whether it is predictive for subsequent behavioural adjustments. PMID- 20965259 TI - Robust clustering of massive tractography datasets. AB - This paper presents a clustering method that detects the fiber bundles embedded in any MR-diffusion based tractography dataset. Our method can be seen as a compressing operation, capturing the most meaningful information enclosed in the fiber dataset. For the sake of efficiency, part of the analysis is based on clustering the white matter (WM) voxels rather than the fibers. The resulting regions of interest are used to define subset of fibers that are subdivided further into consistent bundles using a clustering of the fiber extremities. The dataset is reduced from more than one million fiber tracts to about two thousand fiber bundles. Validations are provided using simulated data and a physical phantom. We see our approach as a crucial preprocessing step before further analysis of huge fiber datasets. An important application will be the inference of detailed models of the subdivisions of white matter pathways and the mapping of the main U-fiber bundles. PMID- 20965260 TI - Unified segmentation based correction of R1 brain maps for RF transmit field inhomogeneities (UNICORT). AB - Quantitative mapping of the longitudinal relaxation rate (R1=1/T1) in the human brain enables the investigation of tissue microstructure and macroscopic morphology which are becoming increasingly important for clinical and neuroimaging applications. R1 maps are now commonly estimated from two fast high resolution 3D FLASH acquisitions with variable excitation flip angles, because this approach is fast and does not rely on special acquisition techniques. However, these R1 maps need to be corrected for bias due to RF transmit field (B1(+)) inhomogeneities, requiring additional B1(+) mapping which is usually time consuming and difficult to implement. We propose a technique that simultaneously estimates the B1(+) inhomogeneities and R1 values from the uncorrected R1 maps in the human brain without need for B1(+) mapping. It employs a probabilistic framework for unified segmentation based correction of R1 maps for B1(+) inhomogeneities (UNICORT). The framework incorporates a physically informed generative model of smooth B1(+) inhomogeneities and their multiplicative effect on R1 estimates. Extensive cross-validation with the established standard using measured B1(+) maps shows that UNICORT yields accurate B1(+) and R1 maps with a mean deviation from the standard of less than 4.3% and 5%, respectively. The results of different groups of subjects with a wide age range and different levels of atypical brain anatomy further suggest that the method is robust and generalizes well to wider populations. UNICORT is easy to apply, as it is computationally efficient and its basic framework is implemented as part of the tissue segmentation in SPM8. PMID- 20965262 TI - Where sound position influences sound object representations: a 7-T fMRI study. AB - Evidence from human and non-human primate studies supports a dual-pathway model of audition, with partially segregated cortical networks for sound recognition and sound localisation, referred to as the What and Where processing streams. In normal subjects, these two networks overlap partially on the supra-temporal plane, suggesting that some early-stage auditory areas are involved in processing of either auditory feature alone or of both. Using high-resolution 7-T fMRI we have investigated the influence of positional information on sound object representations by comparing activation patterns to environmental sounds lateralised to the right or left ear. While unilaterally presented sounds induced bilateral activation, small clusters in specific non-primary auditory areas were significantly more activated by contra-laterally presented stimuli. Comparison of these data with histologically identified non-primary auditory areas suggests that the coding of sound objects within early-stage auditory areas lateral and posterior to primary auditory cortex AI is modulated by the position of the sound, while that within anterior areas is not. PMID- 20965263 TI - AFLP phylogeny of the snubnose darters and allies (Percidae: Etheostoma) provides resolution across multiple levels of divergence. AB - The snubnose darters (Percidae: subgenus Ulocentra) are a group of small, brightly colored North American freshwater fish belonging to the genus Etheostoma. Phylogenetic relationships among snubnose species have been a challenge to resolve at all levels of divergence, from the monophyly of species to deeper relationships among subgenera. Here, we used amplified fragment length polymorphisms (AFLPs) to estimate phylogenetic relationships among species from three closely related subgenera: Ulocentra, Etheostoma, and Nanostoma. With nearly complete sampling of recognized species, our analysis yielded a robust tree with statistical support at all nodes. Support was strongest for shallower relationships; support for internal nodes was either comparable to or greater than that of previous studies based on mitochondrial sequence data. Most recovered relationships were consistent with earlier hypotheses based on morphology or mtDNA sequences, with the exception of Etheostoma histrio, which was recovered as sister to Ulocentra. Our analysis indicates that careful use of AFLPs can yield statistically robust estimates of evolutionary relationships across multiple levels of divergence. PMID- 20965261 TI - Hippocampal degeneration is associated with temporal and limbic gray matter/white matter tissue contrast in Alzheimer's disease. AB - Recent studies have demonstrated alterations in cortical gray to white matter tissue contrast with nondemented aging and in individuals with Alzheimer's disease (AD). However, little information exists about the clinical relevance of such changes. It is possible that changes in MRI tissue contrast occur via independent mechanisms from those traditionally used in the assessment of AD associated degeneration such as hippocampal degeneration measured by more traditional volumetric magnetic resonance imaging (MRI). We created cortical surface models of 95 cognitively healthy individuals and 98 individuals with AD to characterize changes in regional gray and white matter T1-weighted signal intensities in dementia and to evaluate how such measures related to classically described hippocampal and cortical atrophy. We found a reduction in gray matter to white matter tissue contrast throughout portions of medial and lateral temporal cortical regions as well as in anatomically associated regions including the posterior cingulate, precuneus, and medial frontal cortex. Decreases in tissue contrast were associated with hippocampal volume, however, the regional patterns of these associations differed for demented and nondemented individuals. In nondemented controls, lower hippocampal volume was associated with decreased gray/white matter tissue contrast globally across the cortical mantle. In contrast, in individuals with AD, selective associations were found between hippocampal volume and tissue contrast in temporal and limbic tissue. These results demonstrate that there are strong regional changes in neural tissue properties in AD which follow a spatial pattern including regions known to be affected from pathology studies. Such changes are associated with traditional imaging metrics of degeneration and may provide a unique biomarker of the tissue loss that occurs as a result of AD. PMID- 20965264 TI - The phylogenetic placement of Hollandichthys Eigenmann 1909 (Teleostei: Characidae) and related genera. AB - The phylogenetic relationships among characids are complex with many genera remaining of uncertain systematic position inside the family. The genus Hollandichthys is one of these problematic genera. It has been considered as incertae sedis inside this family until two recently published phylogenies, one morphological and one molecular, arrived at alternative hypothesizes as to the relationships of Hollandichthys with Pseudochalceus or Rachoviscus, respectively. In this paper, we infer the phylogenetic relations of these taxa based on five genes (three mitochondrial - COI, ND2 and 16S; and two nuclear - Sia and Trop), totaling up to 2719 bp. The 41 analyzed species in the Characidae include four incertae sedis characid taxa once hypothesized as related to Hollandichthys, but never analyzed in a single phylogeny (Rachoviscus, Pseudochalceus, Nematocharax and Hyphessobrycon uruguayensis). Here we propose Rachoviscus as the sister-group of Hollandichthys, grouped in the large clade C previously defined, along with the remaining incertae sedis taxa studied here. In addition, we support the evidence that insemination evolved independently at least three times in the Characidae. PMID- 20965265 TI - Forebrain circuits and control of feeding by learned cues. AB - Professor Richard F. Thompson and his highly influential work on the brain substrates of associative learning and memory have critically shaped my research interests and scientific approach. I am tremendously grateful and thank Professor Thompson for the support and influence on my research and career. The focus of my research program is on associative learning and its role in the control of fundamental, motivated behaviors. My long-term research goal is to understand how learning enables environmental cues to control feeding behavior. We use a combination of behavioral studies and neural systems analysis approach in two well-defined rodent models to study how learned cues are integrated with homeostatic signals within functional forebrain networks, and how these networks are modulated by experience. Here, I will provide an overview of the two behavioral models and the critical neural network components mapped thus far, which include areas in the forebrain, the amygdala and prefrontal cortex, critical for associative learning and decision-making, and the lateral hypothalamus, which is an integrator for feeding, reward and motivation. PMID- 20965266 TI - A phase I trial of high-dose clofarabine, etoposide, and cyclophosphamide and autologous peripheral blood stem cell transplantation in patients with primary refractory and relapsed and refractory non-Hodgkin lymphoma. AB - Clofarabine has significant single-agent activity in patients with indolent and aggressive non-Hodgkin lymphoma and synergizes with DNA-damaging drugs. Treatment, however, may be associated with severe and prolonged myelosuppression. We conducted a phase I trial to determine the maximum tolerated dose (MTD) of clofarabine in combination with high-dose etoposide and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with refractory non-Hodgkin lymphoma (NHL). Patients received clofarabine at 30-70 mg/m(2)/day on days -6 to -2 in successive cohorts, in combination with etoposide 60 mg/kg (day -8), and cyclophosphamide 100 mg/kg (day -6), followed by filgrastim-mobilized PBSC on day 0. Sixteen patients of median age 57 (range: 32 67) years with diffuse large B cell (n = 8), follicular (n = 5), or mantle cell (n = 3) lymphoma that was either primary refractory (n = 2) or relapsed and refractory (n = 14) were treated at 5 clofarabine dose levels: 30 (n = 3), 40 (n = 3), 50 (n = 3), 60 (n = 3), and 70 mg/m(2)/day (n = 4) in combination with etoposide and cyclophosphamide. All patients had grade 4 neutropenia and thrombocytopenia. Grade 3-4 nonhematologic toxicity was evenly distributed across all 5 dose levels, and included diarrhea (n = 3), mucositis (n = 1), nausea (n = 1), reversible elevation of alanine aminotranferease/aspartate aminotransferase (AST/ALT) (n = 1) or bilirubin (n = 1), and hemorrhagic cystitis (n = 1); all resolved by day +30 following transplantation. The MTD was not reached. No treatment-related deaths occurred. At day +30, 13 patients achieved a complete remission (CR) or unconfirmed CR (CR(U)), and 2 patients achieved a partial response, for an overall response rate of 94%. After a median follow-up of 691 days, the 1-year progression-free survival (PFS) and overall survival (OS) were 63% (95% confidence interval [CI]: 43%-91%) and 68% (95% CI: 49%-96%), respectively. We recommend clofarabine 70 mg/m(2)/day * 5 days as a phase II dose in combination with high-dose etoposide and cyclophosphamide for further testing as a preparative regimen in NHL patients undergoing autologous PBSC transplantation. PMID- 20965267 TI - Distribution and localization of microsatellites in the Perigord black truffle genome and identification of new molecular markers. AB - The level of genetic diversity and genetic structure in the Perigord black truffle (Tuber melanosporum Vittad.) has been debated for several years, mainly due to the lack of appropriate genetic markers. Microsatellites or simple sequence repeats (SSRs) are important for the genome organisation, phenotypic diversity and are one of the most popular molecular markers. In this study, we surveyed the T. melanosporum genome (1) to characterise its SSR pattern; (2) to compare it with SSR patterns found in 48 other fungal and three oomycetes genomes and (3) to identify new polymorphic SSR markers for population genetics. The T. melanosporum genome is rich in SSRs with 22,425 SSRs with mono-nucleotides being the most frequent motifs. SSRs were found in all genomic regions although they are more frequent in non-coding regions (introns and intergenic regions). Sixty out of 135 PCR-amplified mono-, di-, tri-, tetra, penta, and hexa-nucleotides were polymorphic (44%) within black truffle populations and 27 were randomly selected and analysed on 139 T. melanosporum isolates from France, Italy and Spain. The number of alleles varied from 2 to 18 and the expected heterozygosity from 0.124 to 0.815. One hundred and thirty-two different multilocus genotypes out of the 139 T. melanosporum isolates were identified and the genotypic diversity was high (0.999). Polymorphic SSRs were found in UTR regulatory regions of fruiting bodies and ectomycorrhiza regulated genes, suggesting that they may play a role in phenotypic variation. In conclusion, SSRs developed in this study were highly polymorphic and our results showed that T. melanosporum is a species with an important genetic diversity, which is in agreement with its recently uncovered heterothallic mating system. PMID- 20965268 TI - Thyroid hormone-responsive genes mediate otolith growth and development during flatfish metamorphosis. AB - Flatfish begin life as up-right swimming, bilaterally symmetrical larvae that metamorphose into asymmetrically shaped juveniles that swim with a highly lateralized posture. We have previously shown that TH induces abrupt growth and mineralization of one component of the vestibular system, the otoliths, during early larval development and metamorphosis. Here we report that four of five vestibular-specific genes that we tested (alpha-tectorin, otogelin, otolith matrix protein, and otopetrins 1 and 2 that are known to be associated with otolith development in other vertebrates are up-regulated 1.5- to 7-fold in larval flatfish during spontaneous metamorphosis and/or following 72 h of TH treatment. These findings suggest that otolith growth and development are mediated by diverse TH-responsive genes during flatfish metamorphosis. PMID- 20965269 TI - Purification and characterization of an intracellular lipase from pleopods of whiteleg shrimp (Litopenaeus vannamei). AB - An intracellular lipase present in the whiteleg shrimp Litopenaeus vannamei was detected in pleopods. The lipase from pleopods was purified and characterized by biochemical and kinetic parameters. Purified intracellular lipase has a molecular mass of 196kDa, the polypeptide is assembled by two monomers, 95.26 and 63.36kDa. The enzyme lacks glycosylation, and it has an isoelectric point of 5.0. The enzyme showed the highest activity at a temperature range of 30-40 degrees C at pH 8.0-10.0. Activity was completely inhibited by tetrahydrolipstatin and diethyl p-nitrophenyl phosphate, suggesting that the intracellular lipase is a serine lipase. The lipase hydrolyzes short and long-chain triacylglycerides, as well as naphthol derivatives at comparable rates in contrast to other sources of lipases. Specific activity of 930U mg(-1) and 416.56U mg(-1) was measured using triolein and tristearin at pH 8.0 at 30 degrees C as substrates, respectively. The lipase showed a K(M,app) of 41.03mM and k(cat)/K(M,app) ratio of 4.88 using MUF-butyrate as the substrate. The intracellular lipase described for shrimp has a potential role in hydrolysis of triacylglycerides stored as fat body, as has been shown in humans. PMID- 20965270 TI - MitoQ10 induces adipogenesis and oxidative metabolism in myotube cultures. AB - Coenzyme Q(10) (CoQ(10)) plays an essential role in determination of mitochondrial membrane potential and substrate utilization in all metabolically important tissues. The objective of the present study was to investigate the effect of Coenzyme Q analog (MitoQ(10)) on oxidative phenotype and adipogenesis in myotubes derived from fast-glycolytic Pectoralis major (PM) and slow-oxidative Anterior latissimus dorsi (ALD) muscles of the turkey (Meleagris gallopavo). The myotubes were subjected to the following treatments: fusion media alone, fusion media+125 nM MitoQ(10), and 500 nM MitoQ(10). Lipid accumulation was visualized by Oil Red O staining and quantified by measuring optical density of extracted lipid at 500 nm. Quantitative Real-Time PCR was utilized to quantify the expression levels of peroxisome proliferator-activated receptor (PPARgamma) and PPARgamma co-activator-1alpha (PGC-1alpha). MitoQ(10) treatment resulted in the highest (P<0.05) lipid accumulation in PM myotubes. MitoQ(10) up-regulated genes controlling oxidative mitochondrial biogenesis and adipogenesis in PM myotube cultures. In contrast, MitoQ(10) had a limited effect on adipogenesis and down regulated oxidative metabolism in ALD myotube cultures. Differential response to MitoQ(10) treatment may be dependent on the cellular redox state. MitoQ(10) likely controls a range of metabolic pathways through its differential regulation of gene expression levels in myotubes derived from fast-glycolytic and slow oxidative muscles. PMID- 20965271 TI - Sudden blindness due to bilateral optic neuropathy associated with cryptococcal meningitis in an AIDS patient. AB - BACKGROUND: Cryptococcosis is one of the most frequent and severe AIDS defining illnesses. AIMS: We present a patient with advanced HIV/AIDS disease and a diffuse meningoencephalitis due to Cryptococcus neoformans. The patient developed an acute and bilateral blindness associated with high cerebrospinal fluid pressure and optic neuropathy. METHODS: Post-mortem anatomopathologic study revealed a high number of Cryptococcus in the central nervous system, including the optic nerves and the optic chiasm. CONCLUSION: The patient's sudden visual loss appeared to be related to the perineuritic arachnoiditis and the massive invasion of the optic nerves by the fungus. PMID- 20965272 TI - The biosynthesis of the selectin-ligand sialyl Lewis x in colorectal cancer tissues is regulated by fucosyltransferase VI and can be inhibited by an RNA interference-based approach. AB - Sialyl Lewis x (sLex) is a selectin ligand whose overexpression in epithelial cancers mediates metastasis formation. The molecular basis of sLex biosynthesis in colon cancer tissues is still unclear. The prerequisite for therapeutic approaches aimed at sLex down-regulation in cancer, is the identification of rate limiting steps in its biosynthesis. We have studied the role of alpha1,3 fucosyltransferases (Fuc-Ts) potentially involved in sLex biosynthesis in specimens of normal and cancer colon as well as in experimental systems. We found that: (i) in colon cancer, but not in normal mucosa where the antigen was poorly expressed, sLex correlated with a Fuc-T which, like Fuc-TVI, was active on 3'sialyllactosamine at a low concentration (Fuc-T(SLN)); (ii) competitive RT-PCR analysis revealed that the level of Fuc-T mRNA expression in both normal and cancer colon was Fuc-TVI>Fuc-TIII>Fuc-TIV; Fuc-TV and Fuc-TVII expression was negligible; (iii) sLex was expressed only by the gastrointestinal cell lines displaying both Fuc-TVI mRNA and Fuc-T(SLN) activity, but not by those expressing only Fuc-TIII mRNA; (iv) transfection with Fuc-TVI cDNA, but not with Fuc-TIII cDNA, induced sLex expression in gastrointestinal cell lines; (v) Fuc-TVI knock down with specific siRNA induced down-regulation of Fuc-TVI mRNA and Fuc-T(SLN) activity and a dramatic inhibition of sLex expression. These data indicate that in colon cancer tissues Fuc-TVI is a key regulator of sLex biosynthesis which can be the target of RNA-interference-based gene knock-down approaches. PMID- 20965273 TI - From analgesia to myopathy: When local anesthetics impair the mitochondrion. AB - The expanding utilization of local anesthesia and analgesia revealed the occurrence of myopathies induced by local anesthetics. Such iatrogenic effect encouraged anesthesiologists to study the toxicity of local anesthetics and to reevaluate their protocols in order to reduce muscle pain and dysfunction. Studies performed in rats and human cells showed that bupivacaine induces muscle histological damages with sarcomers disruption along with structural alteration of mitochondria, the powerplant of the cell. Bupivacaine-induced myopathies (BIM) are underestimated as patients are not examined by the anesthesiologist after the surgery. Biochemical analyses indicate that BIM could be explained both by the alteration of mitochondrial energetics with consecutive oxidative stress and mitophagy, and the modification of sarcoplasmic reticulum activity with perturbations of calcium homeostasis. BIM is time-dependent, local anesthetic concentration-dependent, enhanced by preexisting metabolism alteration or young age, and could be prevented in part by antioxidant agents and rhEPO. These observations suggest that adapted changes in postoperative analgesia protocols, including the adjustment of LA concentration and volume, a more precise delivery of the drug and an adapted duration of analgesia, may prevent myopathies consecutive to local anesthesia. PMID- 20965274 TI - Intraperitoneal Echinococcus multilocularis infection in mice modulates peritoneal CD4+ and CD8+ regulatory T cell development. AB - Intraperitoneal proliferation of the metacestode stage of Echinococcus multilocularis in experimentally infected mice is followed by an impaired host immune response favoring parasite survival. We here demonstrate that infection in chronically infected mice was associated with a 3-fold increase of the percentages of CD4+ and CD8+ peritoneal T (pT) cells compared to uninfected controls. pT cells of infected mice expressed high levels of IL-4 mRNA, while only low amounts of IFN-gamma mRNA were detected, suggesting that a Th2-biased immune response predominated the late stage of disease. Peritoneal dendritic cells from infected mice (AE-pDCs) expressed high levels of TGF-beta mRNA and very low levels of IL-10 and IL-12 (p40) mRNA, and the expression of surface markers for DC-maturation such as MHC class II (Ia) molecules, CD80, CD86 and CD40 was down-regulated. In contrast to pDCs from non-infected mice, AE-pDCs did not enhance Concanavalin A (ConA)-induced proliferation when added to CD4+ pT and CD8+ pT cells of infected and non-infected mice, respectively. In addition, in the presence of a constant number of pDCs from non-infected mice, the proliferation of CD4+ pT cells obtained from infected animals to stimulation with ConA was lower when compared to the responses of CD4+ pT cells obtained from non infected mice. This indicated that regulatory T cells (Treg) may interfere in the complex immunological host response to infection. Indeed, a subpopulation of regulatory CD4+ CD25+ pT cells isolated from E. multilocularis-infected mice reduced ConA-driven proliferation of CD4+ pT cells. The high expression levels of Foxp3 mRNA by CD4+ and CD8+ pT cells suggested that subpopulations of regulatory CD4+ Foxp3+ and CD8+ Foxp3+ T cells were involved in modulating the immune responses within the peritoneal cavity of E. multilocularis-infected mice. PMID- 20965275 TI - Characterization of Hsp70 gene in Chironomus riparius: expression in response to endocrine disrupting pollutants as a marker of ecotoxicological stress. AB - We characterized the Hsp70 cDNA in Chironomus riparius and evaluated its expression profile under different environmental stressors. It is highly conserved, at both DNA and protein levels, displaying many of the hallmarks of Hsps and sharing 80-96% of overall amino acid identities with homologous sequences from other diptera. The changes are mainly concentrated in the C terminal domain of the protein. Phylogenetic analysis was consistent with the known classification of insects. The Hsp70 gene was located by in situ hybridization in region III-3A at the third polytene chromosome, a locus activated upon heat shock as shown by RNA pol II binding. As C. riparius is widely used in aquatic ecotoxicology testing, we studied Hsp70 gene induction in fourth instar aquatic larvae submitted to heat shock and selected environmental pollutants classified as potential endocrine disruptors. RT-PCR analysis showed that Hsp70 mRNA levels increased significantly (p<0.05) after short-term acute exposures to a temperature shift (HS), cadmium chloride (Cd), butyl benzyl phthalate (BBP), diethylhexyl phthalate (DEHP), bisphenol A (BPA), 4-nonylphenol (NP) and ethinylestradiol (EE). However, neither pentachlorophenol (PCP) nor tributyltin (TBTO) treatments were able to activate the Hsp70 gene. The cognate form, Hsc70, was also analysed and, unlike Hsp70, was not altered by any of the different treatments assayed. Moreover, at the times tested, there was no significant mortality of the larvae. The rapid upregulation of the Hsp70 gene suggests that it is sensitive and selective for different environmental pollutants, and could be used as an early molecular endpoint in ecotoxicological studies. PMID- 20965277 TI - Endocrine disrupting chemicals modulate expression of O6-methylguanine DNA methyltransferase (O6-MGMT) gene in the hermaphroditic fish, Kryptolebias marmoratus. AB - O6-methylguanine-DNA methyltransferase (O6-MGMT; EC 2.1.1.63) is a key repair enzyme that helps to protect the cell against alkylation on DNA by removing a methyl group from the O6-position of guanine. Here, we cloned and sequenced the full-length O6-MGMT cDNA from the hermaphroditic fish, Kryptolebias marmoratus. Complete Km-O6-MGMT cDNA was 1324 bp in length, and the open reading frame of 567 bp encoded a polypeptide of 188 amino acid residues. Phylogenetic analysis revealed that Km-O6-MGMT was clustered with those of other fish species. Embryo, juveniles, and aged secondary fish had low levels of Km-O6-MGMT mRNA than adults, indicating more susceptibility to DNA damage by alkylating agent exposure during these developmental stages. Km-O6-MGMT mRNA levels differed according to tissue type and was highest in the liver. Exposure to an alkylating agent, N-methyl-N nitrosourea (MNU) exposure increased the mRNA expression of tumor suppressor gene such as p53 and oncogenes such as R-ras1, R-ras3, N-ras, c-fos as well as Km-O6 MGMT mRNA in a time-dependent manner. On the contrary, several (anti)estrogenic compounds (17beta-estradiol 100 ng/L, tamoxifen 10 MUg/L, bisphenol A 600 MUg/L, and 4-tert-octylphenol 300 MUg/L) suppressed mRNA expression of Km-O6-MGMT in most tissues, especially the liver. In juvenile fish, 17beta-estradiol, bisphenol A, and 4-tert-octylphenol also decreased the expression of Km-O6-MGMT mRNA in a time-dependent manner. Overall, our finding shows that Km-O6-MGMT mRNA levels can be modulated by environmental estrogenic compounds as well as alkylating agents. This finding will be helpful to improve our knowledge of the effects of estrogenic compounds that contain the genotoxic ability to inhibit the DNA repair process in aquatic animals. PMID- 20965278 TI - A type of sample size design in cancer clinical trials for response rate estimation. AB - During the early stage of cancer clinical trials, when it is not convenient to construct an explicit hypothesis testing, a study on a new therapy often calls for a response rate (p) estimation concurrently with or right before a typical phase II study. We consider a two-stage process, where the acquired information from Stage I (with a small sample size (m)) would be utilized for sample size (n) recommendation for Stage II study aiming for a more accurate estimation. Once a sample size design and a parameter estimation protocol are applied, we study the overall utility (cost-effectiveness) in connection with the cost due to patient recruitment and treatment as well as the loss due to mean squared error from parameter estimation. Two approaches will be investigated including the posterior mixture method (a Bayesian approach) and the empirical variance method (a frequentist approach). We also discuss response rate estimation under truncated parameter space using maximum likelihood estimation with regard to sample size and mean squared error. The profiles of p-specific expected sample size, mean squared error and risk under different approaches motivate us to introduce the concept of "admissible sample size (design)". PMID- 20965276 TI - Ethanol-induced attenuation of oxidative stress is unable to alter mRNA expression pattern of catalase, glutathione reductase, glutathione-S-transferase (GST1A), and superoxide dismutase (SOD3) enzymes in Japanese rice fish (Oryzias latipes) embryogenesis. AB - Although the mechanism of ethanol toxicity during embryogenesis is unknown, our earlier studies on Japanese rice fish (Oryzias latipes) embryos indicated that the effects might be mediated through oxidative stress. In this study we have determined the oxidative stress and the mRNA content of four antioxidant enzymes (catalase, glutathione reductase, glutathione-S-transferase, and superoxide dismutase) during Japanese rice fish embryogenesis (from 0 day post-fertilization to hatching) and after exposing the embryos to ethanol (100 and 300 mM) for 48 h at three stages (0-2, 1-3 and 4-6 days post-fertilization, dpf) of organogenesis. We observed that oxidative stress was minimal in blastula, gastrula or neurula stages, increased gradually with the advancement of morphogenesis and reached its maximum level in hatchlings. The antioxidant enzyme mRNAs were constitutively expressed throughout development; however, the expression pattern was not identical among the enzymes. Catalase and superoxide dismutase (SOD) mRNAs were minimal in the fertilized eggs, but increased significantly in 1 dpf and then either sharply dropped (SOD) or maintained a steady-state (catalase). Glutathione S-transferase (GST) was very high in fertilized eggs and sharply dropped 1 dpf and then gradually increased thereafter. Glutathione reductase (GR) maintained a steady-state throughout the development. Ethanol was able to attenuate oxidative stress in embryos exposed only to 300 mM 1-3 dpf; no significant difference with controls was observed in other ethanol-treated groups. The antioxidant enzyme mRNAs also remained unaltered after ethanol treatment. From these data we conclude that the attenuation of oxidative stress by ethanol is probably due to the inhibition of normal growth of the embryos rather than by inhibiting catalase, GST, GR or SOD-dependent activities. PMID- 20965279 TI - Diversity and antibiotic susceptibility pattern of cultivable anaerobic bacteria from soil and sewage samples of India. AB - Soil and sewage act as a reservoir of animal pathogens and their dissemination to animals profoundly affects the safety of our food supply. Moreover, acquisition and further spread of antibiotic resistance determinants among pathogenic bacterial populations is the most relevant problem for the treatment of infectious diseases. Bacterial strains from soil and sewage are a potential reservoir for antimicrobial resistance genes. Accurate species determination for anaerobes from environmental samples has become increasingly important with the re-emergence of anaerobic bacteremia and prevalence of multiple-drug-resistant microorganisms. Soil samples were collected from various locations of planar India and the diversity of anaerobic bacteria was determined by 16S rRNA gene sequencing. Viable counts of anaerobic bacteria on anaerobic agar and SPS agar ranged from 1.0 * 10(2)cfu/g to 8.8 * 10(7)cfu/g and nil to 3.9 * 10(6)cfu/g, respectively. Among clostrdia, Clostridium bifermentans (35.9%) was the most dominant species followed by Clostridium perfringens (25.8%). Sequencing and phylogenetic analysis of C. perfringens beta2 toxin gene (cpb2) fragment indicated specific phylogenetic affiliation with cluster Ia for 5 out of 6 strains. Antibiotic susceptibility for 30 antibiotics was tested for 74 isolates, revealing resistance for as high as 16-25 antibiotics for 35% of the strains tested. Understanding the diversity of the anaerobic bacteria from soil and sewage with respect to animal health and spread of zoonotic pathogen infections is crucial for improvements in animal and human health. PMID- 20965280 TI - Material properties and electrical stimulation regimens of polycaprolactone fumarate-polypyrrole scaffolds as potential conductive nerve conduits. AB - The mechanical and electrical properties of polycaprolactone fumarate-polypyrrole (PCLF-PPy) scaffolds were studied under physiological conditions to evaluate their ability to maintain the material properties necessary for application as conductive nerve conduits. PC12 cells cultured on PCLF-PPy scaffolds were stimulated with regimens of 10 MUA of either a constant or a 20 Hz frequency current passed through the scaffolds for 1h per day. PC12 cellular morphologies were analyzed by fluorescence microscopy after 48 h. PCLF-PPy scaffolds exhibited excellent mechanical properties at 37 degrees C which would allow suturing and flexibility. The surface resistivity of the scaffolds was 2 kOmega and the scaffolds were electrically stable during the application of electrical stimulation (ES). In vitro studies showed significant increases in the percentage of neurite bearing cells, number of neurites per cell and neurite length in the presence of ES compared with no ES. Additionally, extending neurites were observed to align in the direction of the applied current. This study shows that electrically conductive PCLF-PPy scaffolds possess the material properties necessary for application as nerve conduits. Additionally, the capability to significantly enhance and direct neurite extension by passing an electrical current through PCLF-PPy scaffolds renders them even more promising as future therapeutic treatments for severe nerve injuries. PMID- 20965281 TI - Development of nano- and microscale chondroitin sulfate particles for controlled growth factor delivery. AB - Size scale plays an important role in the release properties and cellular presentation of drug delivery vehicles. Because negatively charged chondroitin sulfate (CS) is capable of electrostatically sequestering positively charged growth factors, CS-derived nanoscale micelles and microscale spheroids were synthesized as potential growth factor carriers to enhance differentiation of stem cells. Particles were characterized for morphology, size distribution, surface charge and cytocompatibility, as well as release of transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor-alpha (TNF-alpha). CS micelles were spherical and negatively charged with a bimodal distribution of 324.1+/-8.5 and 73.2+/-4.4 nm diameters, and CS microspheres possessed a rounded morphology and a diameter of 4.3+/-0.93 MUm. Positively charged TGF-beta1 demonstrated minimal release after loading in CS microspheres, while negatively charged TNF alpha exhibited substantial release over the first 15 h, suggesting that TGF beta1 electrostatically complexed with CS. The micelles and microparticles were found to be cytocompatible at moderate concentrations with marrow stromal cell monolayers and within embryonic stem cell embryoid bodies. These synthesis techniques, which allow the formation of CS-based carriers over a variety of nano and microscale sizes, offer versatility for tailored release of positively charged growth factors and controlled CS presentation for a variety of stem cell based applications in tissue engineering and regenerative medicine. PMID- 20965282 TI - Folic acid-conjugated core/shell ZnS:Mn/ZnS quantum dots as targeted probes for two photon fluorescence imaging of cancer cells. AB - This work presents a novel approach to producing water soluble manganese-doped core/shell ZnS/ZnS quantum dots (ZnS:Mn/ZnS). The Mn-doped ZnS core was prepared through a nucleation doping strategy and a ZnS shell was grown on ZnS:Mn d-dots by decomposition of Zn(2+)-3-mercaptopropionic acid (MPA) complexes at 100 degrees C. It was found that the Mn2+(4)T1->6A1 fluorescence emission at ~590 nm significantly increased after growth of the shell when the Mn2+ doping content was 4.0 at.%. A photoluminescence quantum yield of ~22% was obtained for core/shell nanocrystals. The nanoparticles were structurally and compositionally characterized by transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and dynamic light scattering. The surface MPA molecules favor the dispersion of ZnS:Mn/ZnS QDs in aqueous media and make possible conjugation with targeting folic acid molecules. The folate receptor mediated delivery of folic acid-conjugated ZnS:Mn/ZnS QDs was demonstrated using confocal microscopy with biphotonic excitation. Bare and folate-conjugated QDs exhibit only weak cytotoxicity towards folate receptor-positive T47D cancer cells and MCF-7 cells, used as a reference, at high concentrations (mmolar range) after 72h incubation. PMID- 20965283 TI - Hydrogen release from titanium hydride in foaming of orthopedic NiTi scaffolds. AB - Titanium hydride powders are utilized to enhance the foaming process in the formation of orthopedic NiTi scaffolds during capsule-free hot isostatic pressing. In order to study the formation mechanism, the thermal behavior of titanium hydride and hydrogen release during the heating process are systematically investigated in air and argon and under vacuum by X-ray diffraction (XRD), thermal analysis, including thermogravimetric analysis and differential scanning calorimetry, energy dispersive X-ray spectroscopy, and transmission electron microscopy. Our experiments reveal that hydrogen is continuously released from titanium hydride as the temperature is gradually increased from 300 to 700 degrees C. Hydrogen is released in two transitions: TiH1.924->TiH1.5/TiH1.7 between 300 degrees C and 400 degrees C and TiH1.5/TiH1.7->alpha-Ti between 400 degrees C and 600 degrees C. In the lower temperature range between 300 degrees C and 550 degrees C the rate of hydrogen release is slow, but the decomposition rate increases sharply above 550 degrees C. The XRD patterns obtained in air and under vacuum indicate that the surface oxide layer can deter hydrogen release. The pressure change is monitored in real time and the amount of hydrogen released is affected by the processing temperature and holding time. Holding processes at 425 degrees C, 480 degrees C, 500 degrees C, 550 degrees C, and 600 degrees C are found to significantly improve the porous structure in the NiTi scaffolds due to the stepwise release of hydrogen. NiTi scaffolds foamed by stepwise release of hydrogen are conducive to the attachment and proliferation of osteoblasts and the resulting pore size also favor in-growth of cells. PMID- 20965284 TI - Control of cellular activity of fibroblasts on size-tuned fibrous hydroxyapatite nanocrystals. AB - We controlled the performance of L929 mouse fibroblasts using various hydroxyapatite (HA) nanocrystals, such as nanofibers, nanoneedles, and nanosheets, to better understand the effects of size and shape of the HA nanocrystals on the cells. The cellular activity on nanofibers with a diameter of 50-100 nm was significantly enhanced relative to that on a flat HA surface because large amounts of the proteins needed for adhesion and proliferation could be stored in the substrate. On the other hand, initial adhesion and subsequent proliferation were inhibited on surfaces consisting of fine nanoneedles and nanosheets with a diameter/thickness of less than 30 nm due to the limited area available for the formation of focal adhesions. These facts indicate that fibroblast activity is highly sensitive to the surface topography. Therefore, size tuning of the nanoscale units composing the substrate is essential to enhance cellular performance. PMID- 20965285 TI - Design and in vivo evaluation of a molecularly defined acellular skin construct: reduction of early contraction and increase in early blood vessel formation. AB - Skin substitutes are of great benefit in the treatment of patients with full thickness wounds, but there is a need for improvement with respect to wound closure with minimal contraction, early vascularisation, and elastin formation. In this study we designed and developed an acellular double-layered skin construct, using matrix molecules and growth factors to target specific biological processes. The epidermal layer was prepared using type I collagen, heparin and fibroblast growth factor 7 (FGF7), while the porous dermal layer was prepared using type I collagen, solubilised elastin, dermatan sulfate, heparin, fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF). The construct was biochemically and morphologically characterised and evaluated in vivo using a rat full thickness wound model. The results were compared with the commercial skin substitute IntegraDRT and untreated wounds. The double layered construct was prepared according to the design specifications. The epidermal layer was about 40 MUm thick, containing 9% heparin and 0.2 MUg FGF7 mg per layer, localised at the periphery. The dermal layer was 2.5 mm thick, had rounded pores and contained 10% dermatan sulfate+heparin, and 0.7 MUg FGF2+VEGF mg per layer. The double-layered skin construct was implanted in a skin defect and on day 7, 14, 28 and 112 the (remaining) wound area was photographed, excised and (immuno) histologically evaluated. The double-layered skin construct showed more cell influx, significantly less contraction and increased blood vessel formation at early time points in comparison with IntegraDRT and/or the untreated wound. On day 14 the double-layered skin construct also had the fewest myofibroblasts present. On day 112 the double-layered skin construct contained more elastic fibres than IntegraDRT and the untreated wound. Structures resembling hair follicles and sebaceous glands were found in the double-layered skin construct and the untreated wound, but hardly any were found in IntegraDRT. The results provide new opportunities for the application of acellular skin constructs in the treatment of surgical wounds. PMID- 20965286 TI - Polarized Raman analysis of the molecular rearrangement and residual strain on the surface of retrieved polyethylene tibial plates. AB - The response to applied strain of EtO-sterilized and gamma-irradiated polyethylene materials belonging to tibial inserts has been studied by polarized Raman spectroscopy. Initial calibrations on as-received samples from three different makers were employed to clarify the rearrangement of molecular chains under strain, expressed in terms of Euler angular displacements in space and orientation distribution functions. This body of information was then applied to a quantitative analysis of four tibial inserts (from the same three makers of the unused samples) retrieved after in vivo exposures ranging between 7 months and 5 years 8 months. The main results of the Raman analysis can be summarized as follows: (i) gamma-irradiated samples experienced lower texturing on the molecular scale compared to EtO-sterilized samples, likely due to a higher strain recovery capability; and (ii) independent of sterilization method, the amount of plastic strain was mainly developed early after in vivo implantation, whereby out of-plane molecules rotated under load onto planes parallel to the sample surface until saturation of angular displacements was reached. PMID- 20965287 TI - Consensus-based management of differentiated thyroid cancer in a tertiary care set-up. AB - INTRODUCTION: This study describes the experience of a tertiary care hospital in the management of differentiated thyroid cancer. Thyroid cancer accounts for less than 1% of all human malignancy. Nevertheless, it is the commonest endocrine malignancy constituting 90% of endocrine cancers. It is the commonest cancer in Saudi Arabian women second to breast cancer. This fact makes differentiated thyroid cancer an important tumor and a challenging disease. METHODS: The medical records of patients diagnosed to have differentiated thyroid cancer in King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia between 1st January 2000 and 30th September 2006 were reviewed retrospectively. The data included patient's demographic details, clinical diagnoses, co-morbid conditions, relevant investigations, imaging studies, medical and surgical treatment offered, types of surgeries performed, radioactive iodine therapy given, and the complications and outcome of management. Management of these patients follows a clinical care pathway set up by the hospital Thyroid Cancer Group representing various multidisciplinary team members. RESULTS: One hundred and eight medical records were reviewed. Of these, 72 (66.7%) patients were females and 36 (33.3%) were males. Median age for the females was 40 years, and for males 45 years. Ninety patients (83.3%) had a papillary carcinoma, four patients (3.7%) had a follicular carcinoma and fourteen patients (13%) had other types, namely medullary thyroid carcinoma, anaplastic carcinoma and lymphoma. A total of 78 patients underwent various forms of surgery in our hospital and the remaining patients underwent operation in the district hospitals before they were referred to our centre for further management. Complications included bleeding (1.8%), voice changes (4.5%), and hypocalcaemia (3.8%). The overall outcome showed that 99 patients (91.7%) were alive and well at the time of analysis, 4 patients (3.7%) died and 5 patients (4.6%) were lost to follow up. CONCLUSIONS: This hospital-based epidemiological study, the largest one done in the western part of Saudi Arabia, showed that differentiated thyroid cancer behavior and the management approach we adopt is not different from other centres of excellence. In spite of the relatively higher number of redo surgery we performed in these patients, yet the incidence of recurrent laryngeal nerve injury and hypocalcaemia are similar to what is published in the literature. PMID- 20965288 TI - Cross-clamp time is an independent predictor of mortality and morbidity in low- and high-risk cardiac patients. AB - OBJECTIVES: We sought to assess the effects of aortic cross-clamp time (XCL) on outcome following cardiac surgery in low- and high-risk patients. METHODS: This is a retrospective review of prospectively collected departmental data of all patients who underwent cardiac surgery over 8-year period. Our cohort consisted of 3799 consecutive patients subdivided into low-risk (Euro SCORE < 6, n = 2691, 71%) and high-risk (Euro SCORE >= 6, n = 1108, 29%). Each class was further stratified into three groups based on their corresponding XCL time. Group 1 (XCL <= 60 min), group 2 (XCL > 60 but <= 90 min) and group 3 (XCL >90 min). Postoperative morbidity and in-hospital mortality were analysed. RESULTS: Univariate analysis showed the following to be significantly associated with increased XCL time in both low- and high-risk patients: low cardiac output, prolonged ventilation time, renal complications, prolonged hospital stay, blood transfusion and increased mortality (p < 0.05). By using multiple logistic regression, aortic XCL time >60 min was independent risk factor for low cardiac output, prolonged ventilation, renal complication, blood transfusion, mortality and prolonged hospital stay in both groups. By using XCL time as a continuous variable, an incremental increase of 1 min interval in XCL time was associated with a 2% increase in mortality in both groups. CONCLUSION: Prolonged cross-clamp time significantly correlates with major post-operative morbidity and mortality in both low- and high-risk patients. This effect increases with increasing XCL time. Prior knowledge on this effect can help in preventing some of these complications. PMID- 20965289 TI - Esophagoplasty using previously resected stomach proposed by A.A. Rusanov: history and the current state. AB - To perform esophageal reconstruction in patients after distal gastrectomy colonic or jejunal transplant is usually used. But the use of remnant stomach in esophagoplasty appears to be an interesting idea. This method preserves some advantages of esophagogastroplasty as such. It is possible to pull-up the remnant stomach to the needed level, using mobilization with the spleen and pancreatic tail and its transposition into the left pleural cavity. This type of esophageal replacement, currently widely adopted in China, was proposed and first performed in 1958 by Professor A.A. Rusanov from Russia (former USSR). Different aspects of this method including historical are discussed in the literature review. PMID- 20965290 TI - Evaluation of early surgical management of complicated appendicitis by appendicular mass. AB - AIM: This prospective study was done to evaluate the feasibility and safety of immediate appendicectomy in the presence of appendicular mass. METHODS: A prospective, nonrandomized study was conducted over 46 consecutive patients (mean age: 24 +/- 8.76 years) presenting with an appendicular mass over a 4-year period. They were subjected for immediate appendicectomy within 24 h of admission. RESULTS: The appendix was identified and removed in all 46 patients at operation. Peri-appendiceal abscesses were present in 25% (11 of 46). There was difficulty with adhesolysis and localization of the appendix in 10%(4) of patients. Superficial wound infection had occurred in 8(17%) while deep wound infection had occurred in 9%(4) patients. The mean hospital stay was 3 +/- 0.25 day. No major complications had occurred. CONCLUSIONS: Early surgical intervention in patients with an appendicular mass is feasible, safe and avoids the consequences of the misdiagnosis and mistreatment of other surgical pathologies. PMID- 20965291 TI - When brachytherapy met genetic oncology. Can radiation oncologists improve the detection of hereditary non-polyposis colorectal cancer? AB - Between January 1994 and December 2004, 696 patients with localized endometrial carcinoma have been treated at the Institute Jean-Godinot. Patients were selected on the following criteria: histologically proven adenocarcinoma of the endometrium; age at onset under 60 years; patient not deceased at the time of the study. One hundred twelve patients met these criteria and received a mailed specific questionnaire to establish their pedigree. Thirty-one patients (35.5%) were eventually found eligible for a genetic counselling but only 13 patients agreed to be informed later on. According to the obtained pedigrees and MSI test results, 7 genetic tests have been carried out and so far, 3 MMR mutations were detected. This study suggested the feasibility of a step by step screening of endometrial cancers to select patients at risk for Lynch syndrome and for whom a genetic test would be recommended. Authors suggest that either Amsterdam or Bethesda criteria should be systematically used prospectively in every newly diagnosed endometrial cancer and retrospectively using clinical databases available on endometrial cancers. PMID- 20965293 TI - Can clinical assessment detect 22q11.2 deletions in patients with cardiac malformations? A review. AB - INTRODUCTION: No consensus exists regarding the ability to detect the 22q11 deletion syndrome based on clinical assessment. Traditionally, diagnosis depends on clinical referral. Thus, individuals with typical manifestations are easily identified, but when manifestations are atypical or subclinical, diagnosis may be delayed or even missed. The aim of the present literature review was to evaluate the validity of clinical assessment as a method of predicting 22q11.2 deletions in individuals with congenital cardiac malformations. METHODS: We identified 14 studies in which clinical assessment was blinded to the result from the genetic analysis. RESULTS: Among 1458 patients, 159 (11% [9-13%]) carried the 22q11.2 deletion. The clinicians correctly identified 110 (69% [62-76%]) of them, whereas 49 (31% [24-38%]) would have remained undiagnosed if genetic screening had not been performed. Sensitivity, specificity, predictive value of positive and negative tests ranged from 0-100%, 43-100%, 7-100%, and 79-100%, respectively. CONCLUSIONS: Clinical assessment identifies less than 3/4 patients with a 22q11.2 deletion, whereas more than 1/4 remain undiagnosed if genetic tests are not performed on a routine basis. In this review, we found that clinical assessment is not suited for detecting individuals to be tested for 22q11.2 deletions. PMID- 20965292 TI - Psychiatric adverse effects of rimonobant in adults with Prader Willi syndrome. AB - BACKGROUND: Prader Willi syndrome (PWS) without strict environmental modifications can lead to obesity associated with significant morbidity and mortality. In addition to increased appetite, these individuals have decreased energy expenditure with lower insulin like growth factor 1 (IGF1), which contributes to adiposity. No effective treatment is available for this condition. Endocannabinoid receptor CB1 antagonist, rimonobant, has been effective for treatment of obesity in adult subjects. Rimonabant promotes weight loss by multiple proposed mechanisms, including decreased appetite and lipogenesis, and increased energy expenditure. Therefore, we conducted this pilot study to evaluate the effect of rimonabant on body weight and composition of adults with PWS. METHOD: This was a double blind placebo controlled study. Body weight, total fat mass, fasting ghrelin, leptin, IGF1 and insulin like growth factor binding protein (IGFBP-3) were collected at baseline, and after 90 and 180 days of treatment with placebo or 20 mg of rimonabant. RESULTS: Due to psychiatric adverse effects, 50% of subjects in the rimonabant group withdrew, and the study was terminated early (N=10) for safety concerns. There was a trend for weight loss, lower fat mass and higher IGF1 level at the end of study in this group. Leptin followed the fat mass and decreased with rimonabant treatment. CONCLUSION: Rimonabant administration may be efficacious for weight loss in adults with PWS; unfortunately it is associated with an unacceptably high risk of psychiatric side effects. Future CB1 antagonists will need a better psychiatric profile before considered in the treatment of obesity in this genetic condition. PMID- 20965294 TI - Protein lysine acetylation in cellular function and its role in cancer manifestation. AB - Lysine acetylation appears to be crucial for diverse biological phenomena, including all the DNA-templated processes, metabolism, cytoskeleton dynamics, cell signaling, and circadian rhythm. A growing number of cellular proteins have now been identified to be acetylated and constitute the complex cellular acetylome. Cross-talk among protein acetylation together with other post translational modifications fine-tune the cellular functions of different protein machineries. Dysfunction of acetylation process is often associated with several diseases, especially cancer. This review focuses on the recent advances in the role of protein lysine acetylation in diverse cellular functions and its implications in cancer manifestation. PMID- 20965296 TI - Prevalence of densitometric osteoporosis and osteopenia in Spain. PMID- 20965295 TI - Paternal uniparental isodisomy of the entire chromosome 20 as a molecular cause of pseudohypoparathyroidism type Ib (PHP-Ib). AB - Pseudohypoparathyoridism type Ib (PHP-Ib) typically defines the presence of end organ resistance to parathyroid hormone in the absence of Albright's hereditary osteodystrophy. Patients affected by this disorder present with imprinting defects in the complex GNAS locus. Microdeletions within STX16 or GNAS have been identified in familial cases with PHP-Ib, but the molecular cause of the GNAS imprinting defects in sporadic PHP-Ib cases remains poorly defined. We now report a case with sporadic PHP-Ib for whom a SNPlex analysis revealed loss of the maternal GNAS allele. Further analysis of the entire genome with a 100K SNP chip identified a paternal uniparental isodisomy affecting the entire chromosome 20 without evidence for another chromosomal abnormality. Our findings explain the observed GNAS methylation changes and the patient's hormone resistance, and furthermore suggest that chromosome 20 harbors, besides GNAS, no additional imprinted region that contributes to the clinical and laboratory phenotype. PMID- 20965297 TI - Drug interactions associated with methadone, buprenorphine, cocaine, and HIV medications: implications for pregnant women. AB - Pregnancy in substance-abusing women with HIV/AIDS presents a complex clinical challenge. Opioid-dependent women need treatment with opioid therapy during pregnancy to protect the health of mother and developing fetus. However, opioid therapies, methadone and buprenorphine, may have drug interactions with some HIV medications that can have adverse effects leading to suboptimal clinical outcomes. Further, many opioid-dependent individuals have problems with other forms of substance abuse, for example, cocaine abuse, that could also contribute to poor clinical outcomes in a pregnant woman. Physiological changes, including increased plasma volume and increased hepatic and renal blood flow, occur in the pregnant woman as the pregnancy progresses and may alter medication needs with the potential to exacerbate drug interactions, although there is sparse literature on this issue. Knowledge of possible drug interactions between opioids, other abused substances such as cocaine, HIV therapeutics, and other frequently required medications such as antibiotics and anticonvulsants is important to assuring the best possible outcomes in the pregnant woman with opioid dependence and HIV/AIDS. PMID- 20965298 TI - The role of membrane fusion activity of a whole inactivated influenza virus vaccine in (re)activation of influenza-specific cytotoxic T lymphocytes. AB - Induction of cytotoxic T lymphocyte (CTL) activity against conserved influenza antigens, e.g. nucleoprotein (NP) could be a step towards cross-protective influenza vaccine. The major challenge for non-replicating influenza vaccines aiming for activation of CTLs is targeting of antigen to the MHC class I processing and presentation pathway of professional antigen presenting cells, in particular dendritic cells (DCs). Intrinsic fusogenic properties of the vaccine particle itself can enable direct cytosolic delivery of the antigen by enhancing release of the antigen from the endosome to the cytosol. Alternatively, the vaccine particle would need to possess the capacity to activate DCs thereby triggering cell-intrinsic mechanisms of cross-presentation, processes that do not require fusion. Here, using fusion-active and fusion-inactive whole inactivated virus (WIV) as a vaccine model, we studied the relative contribution of these two pathways on priming and reactivation of influenza NP-specific CTLs in a murine model. We show that activation of bone marrow-derived DCs by WIV, as well as reactivation of NP-specific CTLs in vitro and in vivo were not affected by inactivation of membrane fusion of the WIV particles. However, in vivo priming of naive CTLs was optimal only upon vaccination with fusion-active WIV. Thus, DC intrinsic mechanisms of cross-presentation are involved in the activation of CTLs upon vaccination with WIV. However, for optimal priming of naive CTLs these mechanisms should be complemented by delivery of antigen to the cytosol mediated by the membrane fusion capacity of the WIV particles. PMID- 20965299 TI - A novel adjuvant for vaccine development in the aged. AB - A conformationally-biased, response-selective agonist of human C5a(65-74) (EP67) activated antigen presenting cells (APC) from aged C57Bl/6 mice in vitro and the generation of antigen (Ag)-specific antibody (Ab) responses in aged mice in vivo. EP67, induced the release of the pro-inflammatory cytokines IL-6, TNFalpha, and INFgamma from splenic APCs obtained from both aged and young mice. Both aged and young mice produced high Ag-specific IgG Ab titers when immunized with EP67 containing vaccines to ovalbumin (OVA-EP67) and to a protein (rPrp1) from the cell wall of Coccidioides (rPrp1-EP67). Immunization with EP67-containing vaccines resulted in higher IgG titers in both young and aged mice compared to mice immunized with OVA adsorbed to alum (OVA/alum) and Prp1 admixed with CpG (rPrp1 +CpG). Aged and young mice immunized with the EP67-containing vaccines generated higher titers of IgG1 and IgG2b relative to their aged-matched counterparts immunized with OVA/alum or Prp1 +CpG. These results indicate that EP67 induces humoral immunity in aged mice not obtainable with alum and CpG. These results support the use of EP67 as a potential vaccine adjuvant suited to the elderly. PMID- 20965300 TI - Compliance and schizophrenia: the predictive potential of insight into illness, symptoms, and side effects. AB - BACKGROUND: Personal beliefs about medication compliance have been reliably associated with emotional and behavioral response to mental health problems and health outcomes. This notion has been extensively explored in relation to mental illness. In the current study, a questionnaire designed to assess beliefs about medication compliance (the medication adherence rating scale [MARS]) was translated into Taiwanese to explore beliefs about compliance in schizophrenic patients. METHODS: In this cross-sectional study, 104 patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for schizophrenic disorders were recruited and independently interviewed. We first determined the psychometric properties of the translated MARS, including internal consistency, test-retest reliability, and construct validity. In addition, we investigated the relationships between medication compliance and clinical variables through correlation and regression analyses. RESULTS: We found that the translated MARS was a simple and reliable self-reported compliance scale. Furthermore, in this exploratory study, we found that patients with better medication compliance had better insight into mental illness, less severe psychopathologic condition, and less negative subjective response to side effects of antipsychotics. CONCLUSIONS: Additional research focusing on these patient outcomes will be of great interest and value in elucidating the role of medication compliance in management of schizophrenic patients. PMID- 20965301 TI - Predictors of excessive exercise in anorexia nervosa. AB - OBJECTIVE: The aim of the present study was to replicate and amalgamate findings from previous research into a comprehensive regression model predicting excessive exercise in individuals with anorexia nervosa (AN). METHOD: Participants were 153 patients admitted to an inpatient treatment program for AN. Excessive exercise status was defined as a minimum of 1 hour of obligatory exercise aimed at controlling shape and weight, 6 days per week in the month before admission. RESULTS: Thirty-four percent (n = 52) of participants met criteria for excessive exercise. A logistic regression was conducted with excessive exercise status as the dependent variable and a number of variables previously found to be predictors of excessive exercise entered as independent variables on the same step. The overall regression model was statistically significant (P < .0005) and explained 31% of the variance in exercise status. Higher levels of dietary restraint (P = .03), depression (P = .04), and self-esteem (P = .02); lower levels of obsessive-compulsive symptomatology (P = .04); and the restricting subtype of AN (P = .03) were significantly associated with excessive exercise. CONCLUSIONS: Excessive exercise is associated with a number of independent psychologic and behavioral variables, some that suggest a negative impact and others that suggest positive effects. PMID- 20965302 TI - Personality and psychopathology in children with and without loss of control over eating. AB - BACKGROUND: In children with loss of control (LOC) over eating, recent research has revealed evidence for distinct personality features, such as more impulsivity. The aim of this study was to assess parent- and child-report personality profiles in children with and without LOC over eating and to relate these profiles to general and eating-disorder psychopathology. METHOD: A total of 120 children (60 with LOC over eating; 68 girls) aged 8 to 13 years were recruited from the community. Clinical interview, self-report, and parent-report questionnaires were administered to assess personality as well as both general and eating-disorder psychopathology. RESULTS: The group with LOC over eating showed lower self-directedness and cooperativeness compared to the group without LOC. The children with LOC were significantly more impulsive. Personality dimensions were significantly correlated with greater general but not eating disorder psychopathology and frequency of LOC over eating. CONCLUSION: A distinct pattern of personality traits in children with LOC over eating was found that is partly in line with research on binge-eating disorder, bulimia nervosa, and obesity in adulthood. The findings suggest that longitudinal studies should examine whether certain patterns of personality in children with LOC over eating account for differences in psychopathology later in life. PMID- 20965303 TI - Body image and borderline personality disorder among psychiatric inpatients. AB - OBJECTIVE: With the exclusion of studies in individuals with eating disorders, few investigators have examined body image issues in patients with borderline personality disorder (BPD). In this study, we examined among psychiatric inpatients relationships between body image and BPD. METHOD: In a cross-sectional sample of convenience, we surveyed 126 women in an inpatient psychiatric unit using 5 measures for body image and 2 measures for BPD. RESULTS: Using standardized cutoffs for BPD diagnosis, participants with BPD demonstrated a number of differentiating features with regard to body image issues. Explicitly, BPD did not seem to be related to being self-conscious about one's appearance, although BPD was related to being more self-conscious, in general. Individuals with BPD were not more invested in their appearance as a source of self definition but evaluated their own appearance more negatively and were more likely to believe that attractiveness is an important factor for happiness and acceptance. Although BPD was not related to perceptions about the strength and competence of one's own body, those with BPD indicated less comfort and trust in their own bodies. In general, it appeared that body image measures that were more perceptually grounded were more likely to be similar to non-BPD participants, whereas body image measures that were more cognitively grounded were more likely to be statistically significantly different in comparison with non-BPD participants. CONCLUSIONS: Psychiatric inpatients with BPD demonstrate a number of disturbances in body image. PMID- 20965304 TI - Personality heterogeneity in female adolescent inpatients with features of eating disorders. AB - OBJECTIVE: This study examined evidence for personality variability in adolescents with eating disorder features in light of previous evidence that personality variability in adult women with eating disorder symptoms carries important clinical implications. METHOD: Millon Adolescent Clinical Inventory personality data from adolescent girls with disturbed eating who were psychiatrically hospitalized were cluster analyzed, and resulting groups were compared in eating and comorbid psychopathology. RESULTS: Three subgroups were identified among the 153 patients with eating disorder features: high functioning, internalizing, and externalizing. The internalizing group was marked by eating-related and mood dysfunction; the externalizing group by elevated eating and mood psychopathology as well as impulsivity, aggression, and substance use; and the high-functioning group by lower levels of psychopathology and relatively high self-esteem. CONCLUSIONS: These findings converge with previous research using different personality models in adult samples and highlight the clinical use of considering personality heterogeneity among adolescent and adult women with disturbed eating. PMID- 20965305 TI - Complex personality disorder in bulimia nervosa. AB - OBJECTIVE: Recent research has suggested a move toward a dimensional system for the classification of personality disorders (PDs). Tyrer's dimensional model using severity as a form of categorizing PDs was used to compare eating disorder outcome in women with bulimia nervosa (BN) over 3 years. METHOD: One hundred thirty-four women with BN were divided into 4 groups based on PD severity: no PD (n = 32), personality difficulty (n = 27), simple PD (n = 29), and complex PD (n = 46). Eating disorder symptoms and attitudes, general psychosocial functioning, and depressive symptoms were examined at pretreatment and at 1-year and 3-year follow-up (posttreatment). RESULTS: The complex PD group had greater Axis I comorbidity and psychopathology than the remaining 3 groups at pretreatment. At 1 year and 3-year follow-up, there were no differences in eating disorder outcome, general psychosocial functioning, and depressive symptoms across the 4 groups. CONCLUSION: These results suggest that having an increased number of PDs comorbid with BN does not influence eating disorder outcome up to 3 years after treatment. PMID- 20965306 TI - Prevalence of psychiatric disorders in patients with polycystic ovary syndrome. AB - OBJECTIVE: To investigate the prevalence of psychiatric disorders among women in ambulatory treatment for polycystic ovary syndrome (PCOS) and to correlate its clinical and demographic aspects with mental disorders. METHODOLOGY: Seventy-two patients in ambulatory treatment at the Endocrinal and Gynaecological Institute of the Federal University of Rio de Janeiro were evaluated using Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition criteria by means of MINI (Mini International Neuropsychiatric Interview, version 4.4). Polycystic ovary syndrome was confirmed according to the ultrasonographic criteria of Adams and by clinical parameters. RESULTS: Forty-one patients (57%) presented at least one psychiatric diagnosis. Among them, the prevalence of mood disorder reached 78%. The most prevalent diagnostics were major depression (26.4%) and bipolar disorder (11.1%). CONCLUSION: A high prevalence of mental disorders was observed, especially major depression and bipolar disorder. The data obtained regarding the relationship between PCOS and mood disorders in a Brazilian sample is in accordance with recent research findings in the same area. PMID- 20965307 TI - Relations of internalized stigma with temperament and character in patients with schizophrenia. AB - OBJECTIVE: The aim of the study was to assess the associations between self stigma and temperament and character dimensions. METHODS: One hundred twenty outpatients with diagnosis of schizophrenia, established with Mini International Neuropsychiatric Interview were consecutively included in the study. Self-stigma was assessed with Internalized Stigma of Mental Illness (ISMI), personality dimensions with Temperament and Character Inventory, and psychopathology with Positive and Negative Symptom Scale. RESULTS: The results showed that higher level of harm avoidance, lower self-directedness, and persistence correlated with ISMI and all its subscales. Self-transcendence correlated with ISMI subscales alienation, discrimination, and stigma resistance. Regression analyses controlling for psychopathology, age, length of illness, and number of hospitalizations revealed that higher level of harm avoidance and low self directedness predicted internalized stigma. CONCLUSION: The finding suggests that the experience of self-stigma is related to personality dimensions. Interpretations of these findings include the possibility that, irrespective of patients' psychopathology or functional characteristics, experience of self stigma and its consequences might depend on personality dimensions. Further studies are needed. PMID- 20965308 TI - Temperament and character in patients with bipolar II disorder and recurrent brief depression. AB - OBJECTIVES: We compared the temperament and character profiles of 21 patients with bipolar II disorder, 40 patients with recurrent brief depression (RBD; at least monthly depressive episodes meeting the diagnostic criteria for major depressive episode except for duration that is less than 2 weeks, typically 2-3 days, without fixed relation to menstrual cycle) of which 21 had no history of hypomania and 19 had experienced hypomanic episodes, and 21 age- and sex-matched controls. METHODS: Assessments included the Montgomery-Asberg Depression Rating Scale, Hypomania Checklist, and Temperament and Character Inventory-125. Patients with cluster A and B personality disorders were excluded. RESULTS: Bipolar II and RBD patients had higher harm avoidance (HA) and lower self-directedness (SD) compared with controls. Excluding panic disorder comorbidity effaced this difference in HA and SD (bipolar II only) and harm avoidance. No other differences were found. CONCLUSIONS: In this first study comparing personality profiles of patients with bipolar II vs RBD, when controlling for confounders, neither bipolar II nor RBD patients differed significantly from healthy controls. The lower SD scores among RBD patients may reflect sampling bias (a higher rate of Axis 2 cluster C disorders). PMID- 20965309 TI - The Greek version of the Defense Style Questionnaire: psychometric properties in three different samples. AB - BACKGROUND: The Defense Style Questionnaire (DSQ) was designed to assess behavior indicative of conscious derivatives of defensive styles. This study aimed to assess the factor structure and the main psychometric properties of its Greek version in 3 different samples. METHODS: The DSQ-88 was translated into Greek using back-translation, and it was administered to 2308 participants (984 healthy subjects, 1084 medical patients, and 240 psychiatric patients). Exploratory factor analyses were performed; Symptom Distress Checklist-90-R and Minnesota Multiphasic Personality Inventory (MMPI) ego strength scales were administered for testing criterion and concurrent validity, followed by hierarchical multiple regression analysis. RESULTS: Four factors were identified, largely corresponding to the original version's maladaptive, image-distorting, self-sacrificing, and adaptive styles, showing a remarkable stability in all 3 samples. Adaptive style was positively correlated to ego strength, whereas maladaptive, image-distorting, and self-sacrificing styles were negatively correlated, in descending order. This, along with the intercorrelations observed between the 4 styles, provides evidence that this version supports the hierarchical organization of defensive functioning. Test-retest reliabilities were adequate for all styles (r(1i)'s = 0.88, 0.81, 0.77, and 0.81, respectively). Internal consistencies were satisfactory for maladaptive style (0.82), sufficient for self-sacrificing (0.76), and rather low for image-distorting (0.68) and adaptive (0.66) styles. Maladaptive, image-distorting, and self-sacrificing-but not adaptive-styles could differentiate nonpatients from psychiatric patients. Maladaptive style was positively and adaptive style was negatively independently associated with psychological distress. CONCLUSIONS: The present findings support the applicability of the Greek version of DSQ-88 within the Greek population. Future studies could improve its psychometric properties by finding new items for image distorting and, especially, adaptive styles. PMID- 20965310 TI - Evaluation of the psychometric properties of the Social Phobia Inventory in university students. AB - OBJECTIVE: The aim of the study was to study the psychometric properties of the Social Phobia Inventory (SPIN) in its version for the context of Brazilian adults. METHODS: A sample of Brazilian university students from the general population (n = 2314) and a sample of university students identified as cases (n = 88) and noncases (n = 90) of social phobia were assessed, using as a parameter the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The different instruments were applied individually in the presence of a rater. RESULTS: The SPIN showed adequate internal consistency (.63-.90) and concurrent validity with different instruments of auto- and hetero-evaluation of social phobia. Discriminative validity showed 0.84 to 0.86 sensitivity and 0.84 to 0.87 specificity for cutoff notes between 19 and 21. Factorial analysis showed the presence of a variable number of factors as a function of the different samples. CONCLUSIONS: The version of the SPIN studied is quite adequate for use in the context of Brazilian university students, favoring the screening of social phobia. However, further studies using more diverse samples are needed. PMID- 20965311 TI - Spanish adaptation of the Dimensional Yale-Brown Obsessive-Compulsive Scale. AB - BACKGROUND: The Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) is a promising new instrument that allows patient and clinician ratings of dimension specific symptom severity, as well as estimates of global symptom severity in patients with obsessive-compulsive disorder (OCD). The goal of this study was to further explore the psychometric properties of the DY-BOCS in a Spanish sample. METHODS: The internal consistency, reliability, and convergent and divergent validity of the Spanish adaptation of the DY-BOCS were assessed in a sample of 51 Spanish adult patients with OCD. RESULTS: All the subscales of the Spanish DY BOCS showed high internal consistency. The interrater reliability was excellent for all component scores, and the level of agreement between self-report and expert ratings was high for most symptom dimensions. The subscales of the DY-BOCS were largely independent from one another and from global OCD severity. The convergent and divergent validities of the DY-BOCS subscales were adequate. CONCLUSIONS: The Spanish version of the DY-BOCS is a reliable and valid clinical tool for the assessment of obsessive-compulsive symptom dimensions. PMID- 20965312 TI - Cross-cultural validation of the revised Temperament and Character Inventory: Serbian data. AB - OBJECTIVE: In this work, we report data on construct validity and cross cultural applicability of the revised Temperament and Character Inventory (TCI R) (Cloninger, C.R., Przybeck, T.R., Svrakic, D.M., & Wetzel, R.D. (1999). The Temperament and Character Inventory-revised, Washington University, St. Louis), a 5-point scale scoring formatrevision of the original, true-false version TCI (Cloninger, C.R., Przybeck, T.R., Svrakic, D.M., & Wetzel, R.D. (1994). The Temperament and Character Inventory-A guide to its development and use, Washington University, St. Louis). Both versions are based on the seven factor Psychobiological Model of Personality (Cloninger CR, Svrakic, DM & Przybeck TR (1993). A Psychobiological Model of temperament and Character, Archives of General Psychiatry, 50, 975-990). METHODS: The sample consisted of 473 normal adult subjects representing a number of Serbian cities and towns, recruited consecutively while registering at the National Employment Center, located in Belgrade, Serbia. The sample was the designed to be highly representative of urban and suburban population in Serbia to match to TCI R sample in the US. The 240-item, 5-point scale scoring TCI R was used to assess temperament and character traits. In addition to a number of other revisions, the scoring format in the TCI R was changed into a 5-point Likert scale to increase its sensitivity to subtle variations in personality expression. The TCI R mean scores and standard deviations were compared between Serbian and US subjects, internal consistency of the TCI R scales was estimated using Cronbach's alpha coefficients, and principal component analysis was used separately for temperament and character (because of their non-linear relationship) to test the underlying factorial structure of the TCI R. Parallel analysis and randomized simulation data were used to determine the number of factors for temperament and character. RESULTS: The results generally supported the construct validity and the cross cultural applicability of the TCI R in Serbia. With a few exceptions, the observed internal consistency for the TCI R scales was acceptable. For the most part, the US and Serbian subjects manifested comparable temperament traits, whereas US subjects had higher character scores. The observed differences are understood as partly reflective of local culture and partly of dramatic socio economic change in Serbia over the last 20 years. Principal component analysis fully supported the four factor structure of temperament and the three factor structure of character, as postulated by theory. The inadequacy of using linear statistical methods in studying complex non-linear systems such as personality is discussed in some detail. PMID- 20965314 TI - Invited review: Plasmin protease in milk: current knowledge and relevance to dairy industry. AB - Plasmin is by far the predominant and most completely studied endogenous protease in bovine milk. Plasmin-induced proteolysis can have either beneficial or detrimental effects on the texture and flavor of dairy products, depending on the extent of hydrolysis and type of dairy product. In cheese, the breakdown of protein can help develop desirable flavors and texture during ripening, whereas in pasteurized milk and ultra-high-temperature milk, proteolysis causes undesirable gelation. Plasmin is part of a complex protease-protease inhibitor system in milk that consists of active and inactive forms of the enzyme, activators, and inhibitors. Considerable research has been done to isolate and characterize components of the plasmin system, determine how they interact, develop and compare quantitation methods, and determine how they are affected by cow characteristics, processing conditions, other milk components, storage conditions, and bacterial proteases. Considerable research has focused on enhancing or minimizing the activity of plasmin system components. The intent has been to control protease activity in casein and whey fractions, depending on the final food or ingredient application. Controlling the activity of plasmin has a great potential to improve dairy product quality and reduce their processing costs. PMID- 20965315 TI - Effect of whey pH at drainage on physicochemical, biochemical, microbiological, and sensory properties of Mozzarella cheese made from buffalo milk during refrigerated storage. AB - The objective of this research was to determine the effect of drainage pH on physicochemical, biochemical, microbiological and sensory properties of Mozzarella cheese made from buffalo milk during refrigerated storage. Four vats of cheese were made at 4 different whey drainage pH (6.2, 5.9, 5.6, and 5.2). Lower drainage pH caused higher pH 4.4-soluble N and pH 4.4-soluble N:total N. Interaction of drainage pH at d 1 and 30 of storage on all soluble nitrogen fractions was significant. Degradation of caseins in samples made at a drainage pH of 6.2 was lower than that of other cheese samples. The decreasing whey drainage pH significantly increased counts of thermophilic and mesophilic lactobacilli of the samples during refrigerated storage. No coliforms or Escherichia coli were detected in the cheeses. The average sensory property scores of all cheese samples were very close, and, as expected, storage time had a negative effect on all sensory scores. PMID- 20965316 TI - Two strains of nonstarter lactobacilli increased the production of flavor compounds in soft cheeses. AB - The contribution to flavor generation and secondary proteolysis of 2 strains of mesophilic lactobacilli isolated from cheese was studied. Miniature soft cheeses (200 g) were produced with or without the inclusion of a culture of Lactobacillus plantarum I91 or Lactobacillus casei I90 in the starter composed of Streptococcus thermophilus. During ripening, cheeses containing the added lactobacilli showed an increased content of total free amino acids, but this increase was only significant in cheeses with Lb. plantarum I91. In addition, free amino acid profiles were modified by selective increases of some amino acids, such as Asp, Ser, Arg, Leu, and Phe. Cheeses inoculated with Lb. plantarum I91 or Lb. casei I90 were also characterized by a significantly higher concentration of diacetyl, a key flavor compound, and an increased content of acetoin. Results suggest an increase in the catabolism of either citrate or aspartate, with the production of the derived aroma compounds. Overall, aspartate content increased in both lactobacilli-added cheeses, whereas citrate was more or less constant, suggesting that aspartate could be the source of increased diacetyl and acetoin. A triangle aroma test showed that the addition of the lactobacilli strains significantly changed the sensory attributes of cheeses. At least 11 of 12 panelists commented that the aroma of cheeses with adjuncts was more buttery than that of control cheeses, which is desirable in most soft cheeses. Both Lb. plantarum I91 and Lb. casei I90 performed well as adjunct cultures by influencing cheese aroma development and cheese proteolysis. PMID- 20965317 TI - Angiotensin-converting enzyme inhibitory activity of milk fermented by wild and industrial Lactococcus lactis strains. AB - Angiotensin I-converting enzyme inhibitory (ACEI) activity was evaluated and compared in <3 KDa water-soluble extracts (WSE) isolated from milk fermented by wild and commercial starter culture Lactococcus lactis strains after 48 h of incubation. The highest ACEI activities were found in WSE from milk inoculated with wild L. lactis strains isolated from artisanal dairy products and commercial starter cultures. On the other hand, the lowest ACEI activities were found in WSE from milk inoculated with wild strains isolated from vegetables. Moreover, the IC(50) values (concentration that inhibits 50% activity) of WSE from artisanal dairy products were the lowest, indicating that these fractions were the most effective in inhibiting 50% of ACE activity. In fact, a strain isolated from artisanal cheese presented the lowest IC(50) (13 MUg/mL). Thus, it appears that wild L. lactis strains isolated from artisanal dairy products and commercial starter cultures showed good potential for the production of fermented dairy products with ACEI properties. PMID- 20965318 TI - The characterization of the most-liked reduced-fat Havarti-type cheeses. AB - In Finland, official recommendations state that reduced-fat cheese should be used in the everyday diet. Finnish consumers are increasingly willing to consume food with a reduced fat content, and sales of reduced-fat cheeses have been increasing. The consumers who participated in this study (n=153; 17 to 78 yr old) ate reduced-fat cheeses on a weekly basis. They were recruited from supermarket customers living in a metropolitan area in Finland. The object of this study was to determine which kind of reduced-fat Havarti-type cheeses were most liked. The study consisted of a consumer test, sensory descriptive analysis, and chemical analysis of commercial reduced-fat Havarti-type cheeses (n=10). The results of the sensory quantitative descriptive analysis were compared with consumer hedonic ratings by external preference mapping. In addition, information on composition (fat, salt, and free amino acids) was gathered and compared with the hedonic ratings. The preferred sensory properties were a pale appearance, sticky texture, and rich flavor. However, the consumers could be grouped according to their preferences on appearance and consistency. The main attributes contributing to the grouping of consumers were stickiness, hardness, and yellow color. The least preferred cheeses among all Finnish consumers were those with the lowest flavor intensities. The consumers preferred the cheeses with the highest salt content. PMID- 20965319 TI - Lactobacillus gasseri [corrected] CHO-220 and inulin reduced plasma total cholesterol and low-density lipoprotein cholesterol via alteration of lipid transporters. AB - This randomized, double-blind, placebo-controlled, and parallel-designed study was conducted to investigate the effect of a synbiotic product containing Lactobacillus gasseri [corrected] CHO-220 and inulin on lipid profiles of hypercholesterolemic men and women. Thirty-two hypercholesterolemic men and women with initial mean plasma cholesterol levels of 5.7+/-0.32 mmol/L were recruited for the 12-wk study. The subjects were randomly allocated to 2 groups; namely the treatment group (synbiotic product) and the control group (placebo), and each received 4 capsules of synbiotic or placebo daily. Our results showed that the mean body weight, energy, and nutrient intake of the subjects did not differ between the 2 groups over the study period. The supplementation of synbiotic reduced plasma total cholesterol and low-density lipoprotein (LDL)-cholesterol by 7.84 and 9.27%, respectively, compared with the control over 12 wk. Lipoproteins were subsequently subfractionated and characterized. The synbiotic supplementation resulted in a lower concentration of triglycerides in the very low, intermediate, low, and high-density lipoprotein particles compared with the control over 12 wk. The concentration of triglycerides in lipoproteins is positively correlated with an increased risk of atherosclerosis. Our results showed that the synbiotic might exhibit an atheropreventive characteristic. Cholesteryl ester (CE) in the high-density lipoprotein particles of the synbiotic group was also higher compared with the control, indicating greater transport of cholesterol in the form of CE to the liver for hydrolysis. This may have led to the reduced plasma total cholesterol level of the synbiotic group. The supplementation of synbiotic also reduced the concentration of CE in the LDL particles compared with the control, leading to the formation of smaller and denser particles that are more easily removed from blood. This supported the reduced LDL-cholesterol level of the synbiotic group compared with the control. Our present study showed that the synbiotic product improved plasma total- and LDL-cholesterol levels by modifying the interconnected pathways of lipid transporters. In addition, although Lactobacillus gasseri [corrected] CHO-220 could deconjugate bile, our results showed a statistically insignificant difference in the levels of conjugated, deconjugated, primary, and secondary bile acids between the synbiotic and control groups over 12 wk, indicating safety from bile-related toxicity. PMID- 20965320 TI - Processing optimization of probiotic yogurt containing glucose oxidase using response surface methodology. AB - Exposure to oxygen may induce a lack of functionality of probiotic dairy foods because the anaerobic metabolism of probiotic bacteria compromises during storage the maintenance of their viability to provide benefits to consumer health. Glucose oxidase can constitute a potential alternative to increase the survival of probiotic bacteria in yogurt because it consumes the oxygen permeating to the inside of the pot during storage, thus making it possible to avoid the use of chemical additives. This research aimed to optimize the processing of probiotic yogurt supplemented with glucose oxidase using response surface methodology and to determine the levels of glucose and glucose oxidase that minimize the concentration of dissolved oxygen and maximize the Bifidobacterium longum count by the desirability function. Response surface methodology mathematical models adequately described the process, with adjusted determination coefficients of 83% for the oxygen and 94% for the B. longum. Linear and quadratic effects of the glucose oxidase were reported for the oxygen model, whereas for the B. longum count model an influence of the glucose oxidase at the linear level was observed followed by the quadratic influence of glucose and quadratic effect of glucose oxidase. The desirability function indicated that 62.32 ppm of glucose oxidase and 4.35 ppm of glucose was the best combination of these components for optimization of probiotic yogurt processing. An additional validation experiment was performed and results showed acceptable error between the predicted and experimental results. PMID- 20965321 TI - Impact of fat reduction on flavor and flavor chemistry of Cheddar cheeses. AB - A current industry goal is to produce a 75 to 80% fat-reduced Cheddar cheese that is tasty and appealing to consumers. Despite previous studies on reduced-fat cheese, information is critically lacking in understanding the flavor and flavor chemistry of reduced-fat and nonfat Cheddar cheeses and how it differs from its full-fat counterpart. The objective of this study was to document and compare flavor development in cheeses with different fat contents so as to quantitatively characterize how flavor and flavor development in Cheddar cheese are altered with fat reduction. Cheddar cheeses with 50% reduced-fat cheese (RFC) and low-fat cheese containing 6% fat (LFC) along with 2 full-fat cheeses (FFC) were manufactured in duplicate. Cheeses were ripened at 8 degrees C and samples were taken following 2 wk and 3, 6, and 9 mo for sensory and instrumental volatile analyses. A trained sensory panel (n=10 panelists) documented flavor attributes of cheeses. Volatile compounds were extracted by solid-phase microextraction or solvent-assisted flavor evaporation followed by separation and identification using gas chromatography-mass spectrometry and gas chromatography-olfactometry. Selected compounds were quantified using external standard curves. Sensory properties of cheeses were distinct initially but more differences were documented as cheeses aged. By 9 mo, LFC and RFC displayed distinct burnt/rosy flavors that were not present in FFC. Sulfur flavor was also lower in LFC compared with other cheeses. Forty aroma-active compounds were characterized in the cheeses by headspace or solvent extraction followed by gas chromatography olfactometry. Compounds were largely not distinct between the cheeses at each time point, but concentration differences were evident. Higher concentrations of furanones (furaneol, homofuraneol, sotolon), phenylethanal, 1-octen-3-one, and free fatty acids, and lower concentrations of lactones were present in LFC compared with FFC after 9 mo of ripening. These results confirm that flavor differences documented between full-fat and reduced-fat cheeses are not due solely to differences in matrix and flavor release but also to distinct differences in ripening biochemistry, which leads to an imbalance of many flavor contributing compounds. PMID- 20965322 TI - Vitamin D content and variability in fluid milks from a US Department of Agriculture nationwide sampling to update values in the National Nutrient Database for Standard Reference. AB - This study determined the vitamin D(3) content and variability of retail milk in the United States having a declared fortification level of 400 IU (10 MUg) per quart (qt; 1 qt=946.4 mL), which is 25% daily value per 8 fluid ounce (236.6 mL) serving. In 2007, vitamin D(3) fortified milk (skim, 1%, 2%, whole, and 1% fat chocolate milk) was collected from 24 statistically selected supermarkets in the United States. Additionally, 2% milk samples from an earlier 2001 USDA nationwide collection were reanalyzed. Vitamin D(3) was determined using a specifically validated method involving HPLC with UV spectroscopic detection and vitamin D(2) as an internal standard. Quality control materials were analyzed with the samples. Of the 120 milk samples procured in 2007, 49% had vitamin D(3) within 100 to 125% of 400 IU (10 MUg)/qt (label value), 28% had 501 to 600 IU (12.5-15 MUg)/qt, 16% had a level below the label amount, and 7% had greater than 600 IU (15 MUg)/qt (>150% of label). Even though the mean vitamin D(3) content did not differ statistically between milk types, a wide range in values was found among individual samples, from nondetectable [<20 IU (0.5 MUg)/qt] for one sample to almost 800 IU (20 MUg)/qt, with a trend toward more samples of whole milk having greater than 150% of the labeled content. On average, vitamin D(3) in 2% milk was higher in 2007 compared with in 2001 [473 vs. 426 IU (11.8 vs. 10.6 MUg)/qt]. PMID- 20965323 TI - Development and application of a processing model for the Irish dairy industry. AB - A processing-sector model was developed that simulates (i) milk collection, (ii) standardization, and (iii) product manufacture. The model estimates the product yield, net milk value, and component values of milk based on milk quantity, composition, product portfolio, and product values. Product specifications of cheese, butter, skim and whole milk powders, liquid milk, and casein are met through milk separation followed by reconstitution in appropriate proportions. Excess cream or skim milk are used in other product manufacture. Volume-related costs, including milk collection, standardization, and processing costs, and product-related costs, including processing costs per tonne, packaging, storage, distribution, and marketing, are quantified. Operating costs, incurred irrespective of milk received and processing activities, are included in the model on a fixed-rate basis. The net milk value is estimated as sale value less total costs. The component values of fat and protein were estimated from net milk value using the marginal rate of technical substitution. Two product portfolio scenarios were examined: scenario 1 was representative of the Irish product mix in 2000, in which 27, 39, 13, and 21% of the milk pool was processed into cheese (? 3,291.33/t), butter (? 2,766.33/t), whole milk powder (? 2,453.33/t), and skim milk powder (? 2,017.00/t), respectively, and scenario 2 was representative of the 2008 product mix, in which 43, 30, 14, and 13% was processed into cheese, butter, whole milk powder, and skim milk powder, respectively, and sold at the same market prices. Within both scenarios 3 milk compositions were considered, which were representative of (i) typical Irish Holstein-Friesian, (ii) Jersey, and (iii) the New Zealand strain of Holstein-Friesian, each of which had differing milk constituents. The effect each milk composition had on product yield, processing costs, total revenue, component values of milk, and the net value of milk was examined. The value per liter of milk in scenario 1 was 24.8, 30.8, and 27.4 cents for Irish Holstein-Friesian, Jersey, and New Zealand strain of Holstein-Friesian milk, respectively. In scenario 2 the value per liter of milk was 26.1, 32.6, and 28.9 cents for Irish Holstein-Friesian, Jersey, and New Zealand strain of Holstein-Friesian milk, respectively. PMID- 20965324 TI - Protein oxidative changes in whole and skim milk after ultraviolet or fluorescent light exposure. AB - We investigated how protein changes occur, at the primary or higher structural levels, when proteins are exposed to UV or fluorescent (FL) light while in the complex matrix, milk. Whole milk (WM) or skim milk (SM) samples were exposed to FL or UV light from 0 to 24h at 4 degrees C. Protein oxidation was evaluated by the formation of protein carbonyls (PC), dityrosine bond (DiTyr), and changes in molecular weight (protein fragmentation and polymerization). Oxidative changes in AA residues were measured by PC. Dityrosine and N'-formylkynurenine (NFK), a carbonylation derivative of Trp, were measured by fluorometry. Protein carbonyls increased as a function of irradiation time for both WM and SM. The initial rate for PC formation by exposure to FL light (0.25 or 0.27 nmol/h for WM and SM, respectively) was slower than that following exposure to UV light (1.95 or 1.20 nmol/h, respectively). The time course of NFK formation resembled that of PC. After 24h of UV exposure, SM had significantly higher levels of NFK than did WM. In contrast, WM samples irradiated with UV had higher levels of DiTyr than did SM samples, indicating different molecular pathways. The formation of intra- or intermolecular DiTyr bonds could be indicative of changes in the tertiary structure or oligomerization of proteins. The existence of NFK suggests the occurrence of protein fragmentation. Thus, proteolysis and oligomerization were analyzed by sodium dodecyl sulfate-PAGE. After 24h of exposing WM to UV or FL light, all the proteins were affected by both types of light, as evidenced by loss of material in most of the bands. Aggregates were produced only by UV irradiation. Hydrolysis by pepsin and enzyme-induced coagulation by rennet were performed to evaluate altered biological properties of the oxidized proteins. No effect on pepsin digestion or rennet coagulation was found in irradiated SM or WM. The oxidative status of proteins in milk and dairy products is of interest to the dairy industry and consumers. These findings provide knowledge that could be useful in determining the optimal lighting conditions in the dairy industry in general and in cheese making in particular. PMID- 20965325 TI - Short communication: Temperature sensibility of Prototheca blaschkeae strains isolated from bovine mastitic milk. AB - Dairy cow mastitis associated with microalgae of the genus Prototheca has been reported worldwide. This alga is extremely resistant to most antimicrobials commonly used in mastitis therapy. In milk processing, different thermal treatments are generally efficient at inactivating and eliminating microorganisms. Until recently, no reports on Prototheca blaschkeae susceptibility to heat treatment have been described. Thus, considering the potential zoonotic risk that Prototheca may represent, the objective of this study was to test the susceptibility of P. blaschkeae field isolates retrieved from bovine mastitis to different temperature/time ratios that are generally used in the milk processing industry: 62 degrees C/15 min and 30 min; 70 degrees C/20s, 15 min, and 30 min; 75 degrees C/20s; 90 degrees C/1s; and 100 degrees C/1s. The results showed a growth reduction of all isolates after the heat treatments, but only at 100 degrees C was a total growth inhibition observed. PMID- 20965326 TI - Short communication: The water footprint of dairy products: case study involving skim milk powder. AB - In the context of global water scarcity and food security concerns, water footprints are emerging as an important sustainability indicator in the agriculture and food sectors. Using a recently developed life cycle assessment based methodology that takes into account local water stress where operations occur, the normalized water footprints of milk products from South Gippsland, one of Australia's major dairy regions, were 14.4 L/kg of total milk solids in whole milk (at farm gate) and 15.8 L/kg of total milk solids in skim milk powder (delivered to export destination). These results demonstrate that dairy products can be produced with minimal potential to contribute to freshwater scarcity. However, not all dairy production systems are alike and the variability in water footprints between systems and products should be explored to obtain strategic insights that will enable the dairy sector to minimize its burden on freshwater systems from consumptive water use. PMID- 20965327 TI - Energy expenditure, urea kinetics, and body weight gain within a segregating resource family population. AB - Beef and dairy cattle represent divergent metabolic types that disseminate nutrients into either meat or milk and differ in nutrient accretion. To investigate nutrient flow and turnover in an animal model combining beef and dairy cattle, a crossbred experiment has been started. An F(2) resource population was generated from Charolais (beef breed) sires and German Holstein (dairy breed) cows as P(0) founders by consistent use of embryo transfer to establish the F(1) and F(2) generations, which accordingly comprised half- and full-sib offspring. In 64 bulls of 5F(2) families, dry matter intake and growth performance were measured monthly, and carcass composition was determined after slaughtering at 18 mo of age. Energy expenditure and urea kinetics were investigated via stable isotope tracer techniques using an intravenous single bolus dose of sodium [(13)C]bicarbonate [2.5 MUmol/kg of body weight (BW), 99 atom% (13)C] at 8 and 18 mo of age and of [(15)N]urea (0.28 mg/kg of BW, 99 atom% (15)N) at 8 mo of age, respectively. Insulin responses were measured via glucose tolerances tests at the age of 8 mo. The results revealed significant differences between families for growth performance, energy expenditure, and urea kinetics. In summary, low energy expenditure was associated with high average body mass gain and high insulin response. A greater urea loss was associated with reduced muscle protein in carcass. In addition, corresponding half-sib and full-sib sisters from bulls with highest growth rate indicated highest milk production. In conclusion, we have demonstrated that differences in energy expenditure and urea kinetics result in differences in average daily gain and carcass traits and vice versa in F(2) crossbred bulls with common beef and dairy genetic backgrounds. PMID- 20965328 TI - Evaluation of data loggers, sampling intervals, and editing techniques for measuring the lying behavior of dairy cattle. AB - Lying behavior in dairy cattle can provide insight into how cows interact with their environment. Although lying behavior is a useful indicator of cow comfort, it can be time consuming to measure. In response to these time constraints, using data loggers to automate behavioral recording has become increasingly common. We tested the accuracy of the Onset Pendant G data logger (Onset Computer Corporation, Bourne, MA) for measuring lying behavior in dairy cattle (n=24 cows; 12 in each of 2 experiments). Cows wore the logger on the lateral (experiment 1) or medial (experiment 2) side of the hind leg above the metatarsophalangeal joint. Loggers recorded behavior at 4 sampling intervals (6, 30, 60, and 300 s) for at least 1.5 d. Data were smoothed using 3 editing methods to examine the effects of short, potentially erroneous readings. For this purpose, Microsoft Excel macros (Microsoft Corp., Redmond, WA) converted readings (i.e., lying events bordered by standing or vice versa) occurring singly or in consecutive runs of <=2 or <=6. Behavior was simultaneously recorded with digital video equipment. The logger accurately measured lying and standing. For example, predictability, sensitivity, and specificity were >99% using 30-s sampling and the single-event filter compared with continuously scored video recordings. The 6 and 30-s sampling intervals were comparable for all aspects of lying behavior when short events were filtered from the data set. Estimates of lying time generated from the 300-s interval unfiltered regimen were positively related (R(2) >= 0.99) to estimates of lying time from video, but this sampling regimen overestimated the number of lying bouts. This is likely because short standing and lying bouts were missed (12 and 34% of lying and standing bouts were <300 s in experiment 1 and 2, respectively). In summary, the data logger accurately measured all aspects of lying behavior when the sampling interval was <=30 s and when short readings of lying and standing were filtered from the data set. PMID- 20965329 TI - Effect of flunixin meglumine and carprofen on pregnancy rates in dairy cattle. AB - Embryonic losses contribute considerably to low pregnancy rates. Between d 8 and 17 after breeding, the conceptus secretes interferon-tau as a mechanism for maternal recognition of pregnancy and maintenance of the corpus luteum. Nonsteroidal antiinflammatory drugs inhibit the synthesis of prostaglandin F(2alpha) by suppressing the enzyme cyclooxygenase. Flunixin meglumine (FM) has been demonstrated to delay luteolysis and to support embryonic survival. The objective of this study was to evaluate the effect of FM and carprofen on conception rates in dairy heifers and cows, respectively. In experiment 1, the effect of FM on pregnancy rates and progesterone concentrations in dairy heifers was tested. A total of 391 heifers were randomly assigned to 1 of 2 groups. Heifers in the treatment group (n=197) received 2.2 mg of FM i.m./kg of body weight twice on d 14/15 and 15/16 after insemination, whereas heifers in the control group (n=194) remained untreated. Blood samples from 388 heifers were taken on d 14/15 and 21/22 after artificial insemination and analyzed for progesterone. Pregnancy rates were 58.2 and 54.8% for the control and treatment groups, respectively. Mean progesterone concentrations were not affected by treatment and number of artificial insemination service (first or second artificial insemination service), but were affected by time and time * pregnancy status. In experiment 2, the objective was to verify the effects of carprofen, a longer acting nonsteroidal antiinflammatory drug and to evaluate its effect on conception rate to first service in dairy cows. A total of 380 cows were randomly assigned to 1 of 2 treatment groups. Cows in the treatment group (n=194) received 1.4 mg of carprofen s.c./kg of body weight on d 15 after insemination, whereas cows in the control group (n=186) remained untreated. Pregnancy was diagnosed between d 40 and 47 after insemination. Conception rates to first service were 35.5 and 33.0% in the control and treatment groups, respectively. Neither flunixin meglumine nor carprofen improved conception rates to first service in dairy cattle in the dosage and administration schedule tested. PMID- 20965330 TI - Feeding rolled barley grain steeped in lactic acid modulated energy status and innate immunity in dairy cows. AB - Feeding dairy cows large proportions of cereal grain is commonly associated with rumen acidosis, activation of innate immunity, and perturbation of intermediary metabolism. We previously showed that steeping barley grain in 0.5% lactic acid (LA) decreased the rate of starch degradation, lowered the risk of subacute rumen acidosis, modulated rumen fermentation profile, and increased milk fat content in dairy cows. This study sought to investigate whether feeding of LA-treated barley grain would affect carbohydrate and lipid metabolism as well as innate immunity. Eight rumen-fistulated late-lactation (approximately 217 d in milk, DIM) Holstein cows were randomly assigned, in a 2 * 2 crossover design, to 1 of the 2 dietary treatments consisting of 27% (dry matter basis) rolled barley grain steeped for 48 h in an equal volume (wt/vol) of tap water (CTR) or 0.5% LA (TRT). Each experimental period lasted 21 d, with the first 11 d for diet adaptation. Blood and rumen samples were collected on d 12, 15, 17, and 21 of the experimental period before the morning feeding to evaluate the effects of dietary treatment on preprandial day-to-day variation of plasma and rumen variables. To establish the effect of treatment on diurnal variation of plasma variables, blood samples were collected on the last day of each period at 0, 2, 4, 6, 8, 10, and 12h after the morning feeding (i.e., 0800 h). Results of the day-to-day study showed that cows fed the TRT diet had greater overall preprandial concentrations of glucose, cholesterol, and insulin, and a lower concentration of haptoglobin in plasma. Diurnal data indicated lower concentrations of haptoglobin and serum amyloid A and a tendency for greater plasma lactate in cows fed the TRT diet. A treatment by time interaction was observed for glucose, lactate, insulin, haptoglobin, and lipopolysaccharide-binding protein, suggesting a role for both the processing of grain and the time of sampling on those variables. No effect of diet on plasma concentrations of cortisol, beta-hydroxybutyrate, and nonesterified fatty acids or rumen endotoxin was evidenced. Taken together, our results demonstrated that feeding barley grain steeped in 0.5% LA modulated both energy status and innate immunity of dairy cows fed relatively high levels (45% of dry matter) of dietary concentrate. PMID- 20965331 TI - Readability of visual and electronic leg tags versus rumen boluses and electronic ear tags for the permanent identification of dairy goats. AB - Murciano-Granadina dairy goats (n=220) were used to assess the performance of visual and electronic identification devices: 1) leg tags (LT) on the shank of the right hind leg (metatarsus) consisting of plastic bands (181 * 39mm, 21g; n=220) printed with a 3-digit code and closed with 2 types of electronic button tags (ET1, 3.9 g, 26 mm o.d., n=90; ET2, 5.5 g, 25 mm o.d., n=130); 2) electronic rumen boluses (RB, 75 g, 68 * 21 mm, n=220) containing 32 * 3.8 mm transponders; 3) electronic ear tags (EE, button-button, 4.8 g, 24 mm, n=47); and 4) visual plastic ear tags (VE, flag-button, 4.2 g, 40 * 38 mm, n=220). The shank circumference of 47 replacement kids (5 to 6 mo of age) and 103 adult goats was measured to evaluate the proper circumference for fastened LT. Goats were identified with RB and VE before the experiment. Time for leg tagging, reading, and data recording with a handheld transceiver was measured. Readability [(read/readable) * 100] was monitored for 1 yr with goats restrained in the milking parlor. Reading time and errors of RB and ET2 in the milking parlor using the handheld transceiver were recorded. Shank circumference of kids (70+/-1 mm) was 79.5% of that in adult goats (88+/-1 mm), thus LT (107+/-1 mm inner circumference) were only applied to adult goats as they were inadequate for 6-mo old kids. Time for leg tagging and data recording was 53+/-3 s. At 1 yr, readability of RB was 96.5%. No LT losses occurred and all were visually readable, although 3 (1.5%) had to be removed due to limping, leading to a final LT retention of 98.5%. Moreover, 7 (3.6%) LT were found open and electronically unreadable. Readability of button transponders, excluding removed LT, was 93.6% (3 lost and 2 unreadable) for ET1, and 98.3% (2 lost) for ET2. Readability was 95.7 and 97.0% in EE and VE ear tags, respectively. Only LT and ET1 readabilities differed. Reading time and reading errors (0.3 vs. 0%) in the milking parlor were greater for RB (61.2s) than for ET2 (45.9s). In conclusion, LT were not adequate for the identification of goat kids under 6 mo of age. Only LT with ET2 transponders met International Committee for Animal Recording requirements for official identification of adult goats (readability >98%) under the conditions of this experiment. PMID- 20965332 TI - Characterization of glucagon-like peptide 2 pathway member expression in bovine gastrointestinal tract. AB - Glucagon-like peptide 2 (GLP-2), secreted by enteroendocrine cells, has several physiological effects on the intestine of monogastric species, including promotion of growth of intestinal epithelium, reduction of epithelial cell apoptosis, and enhancement of intestinal blood flow, nutrient absorption, and epithelial barrier function. The regulatory functions of GLP-2 in the ruminant gastrointestinal tract (GIT) have not been well studied. The objectives of this investigation were to characterize the mRNA expression of 4 members of the GLP-2 pathway throughout the bovine GIT, including (1) proglucagon (GCG), the parent peptide from which GLP-2 is derived through cleavage by prohormone convertase; (2) prohormone convertase (PCSK1); (3) GLP-2 receptor (GLP2R); and (4) dipeptidyl peptidase IV (DPP4), the enzyme that inactivates GLP-2. Gene expression was evaluated in rumen, reticulum, omasum, abomasum, duodenum, jejunum, ileum, cecum, and rectum collected at slaughter from prepubertal heifers, mature cows in early, mid, and late lactation, and nonlactating cows (n=3 per stage) by a gene expression profiling assay. In addition, mRNA expression of 14 genes involved in nutrient transport, enzyme activity, blood flow, apoptosis, and proliferation were evaluated in the 9 GIT tissues for their association with GCG and GLP2R mRNA expression. Immunohistochemistry was used to localize GLP2R protein in tissues of the lower GIT. Results indicated that mRNA expression of GCG, PCSK1, GLP2R, and DPP4 varies across the 9 GIT tissues, with greatest expression in small and large intestines, and generally nondetectable levels in forestomachs. Expression of DPP4 and GLP2R mRNA varied by developmental stage or lactational state in intestinal tissues. Expression of GCG or GLP2R mRNA was correlated with molecular markers of proliferation, apoptosis, blood flow, enzyme activity, and urea transport, depending on the tissue examined, which suggests a potential for involvement of GLP-2 in these physiological processes in the ruminant GIT. The GLP2R protein was expressed in intestinal crypts of the bovine GIT, which is consistent with the distribution in monogastric species. Our findings support a functional role of the GLP-2 pathway in bovine GIT and the potential for use of GLP-2 as a therapy to improve intestinal function and nutrient absorption in ruminants. PMID- 20965333 TI - Effect of milk yield characteristics, breed, and parity on success of the first insemination in Dutch dairy cows. AB - The objective of this study was to determine the contribution of cow factors to the probability of a successful first insemination (SFI). The investigation was performed with 51,791 lactations from 1,396 herds obtained from the Dutch dairy cow database of the Cattle Improvement Co-operative (CRV). Cows that had the first insemination (AI) between 40 and 150 d postpartum were selected. The first AI was classified as successful when cows were not reinseminated and either calved between 267 and 295 d later or were culled within 135 to 295 d after first AI. The lactation curve characteristics of individual lactations were estimated by Wilmink's curve using the test-day milk records from CRV. The lactation curve characteristics (peak milk yield, milk yield at the first-AI date, time of peak yield (PT), and milk persistency) were calculated. Breed, parity, interval from calving to first AI (CFI), lactation curve characteristics, milk production traits, moment of AI related to PT (before or after PT), calf status, month of AI, and month of calving were selected as independent variables for a model with SFI as a dependent variable. A multivariable logistic regression model was used with farm as a random effect. Overall SFI was 44%. The effect of parity on SFI depended on CFI. The first-parity cows had the greatest SFI (0.43) compared with other parities (0.32-0.39) at the same period of CFI before 60 d in milk (DIM), and cows in parity >=5 had the least SFI (0.38-0.40) when AI was after 60 DIM. After 60 DIM, extending CFI did not improve SFI in the first-parity cows, but SFI was improved in multiparous cows. Holstein-Friesian cows had lesser SFI (0.37) compared with cross-breed cows (0.39-0.46). Twin and stillbirth calving reduced SFI (0.39) compared with a single female calf (0.45) or a male calf (0.43) calving. The SFI in different months of AI varied and depended on CFI. Cows that received AI before 60 DIM had a lesser SFI, especially in March, June, and July (0.18, 0.35, and 0.34, respectively). Artificial insemination before PT reduced SFI (0.39) in comparison with AI after PT (0.44). The effect of milk yield at the first-AI date on SFI varied depending on CFI. After 60 DIM at the same period of CFI, a high level of milk yield at the first-AI date reduced SFI. In conclusion, knowledge of the contribution of cow factors on SFI can be applied to support decision making on the moment of insemination of an individual cow in estrus. PMID- 20965334 TI - Ethyl pyruvate diminishes the endotoxin-induced inflammatory response of bovine mammary endothelial cells. AB - The endotoxin-induced inflammatory response during coliform mastitis is difficult to control with the currently available therapeutics. Endothelial cells are among the first cell type to be engaged in the inflammatory response and can modulate the severity of inflammation by producing proinflammatory mediators upon endotoxin exposure. Ethyl pyruvate, an ethyl ester of pyruvic acid, can ameliorate endotoxin-induced inflammatory responses by inhibiting the production of proinflammatory mediators in several in vitro and in vivo endotoxemia models. The objective of this study was to determine the effect of ethyl pyruvate on the production of vascular proinflammatory mediators that are associated with the pathogenesis of coliform mastitis. The ability of ethyl pyruvate to reduce the expression of proinflammatory mediators was evaluated in cultured bovine mammary endothelial cells (BMEC) stimulated with endotoxin. Treatment of endotoxin stimulated BMEC with ethyl pyruvate significantly reduced gene expression of IL 6, IL-8, and intercellular adhesion molecule 1 as well as expression of eicosanoid-producing enzymes, including cyclooxygenase 2 and 15-lipoxygenase 1. This is the first time that the effect of ethyl pyruvate was evaluated in an in vitro BMEC model of coliform mastitis. The ability of ethyl pyruvate to effectively inhibit gene and protein expression of potent vascular proinflammatory mediators in vitro warrants further investigations to assess in vivo efficacy. Ethyl pyruvate is safe for human consumption, and it may be an attractive candidate as a therapeutic in ameliorating the severe pathogenesis associated with coliform mastitis. PMID- 20965335 TI - A field study on characteristics and diversity of gene expression in the liver of dairy cows during the transition period. AB - Metabolic and endocrine adaptations to support milk production during the transition period vary between individual cows. This variation between cows to adapt to lactation may have a genetic basis. The present field study was carried out to determine hepatic adaptations occurring from late pregnancy through early lactation by measuring mRNA abundance of candidate genes in dairy cows on-farm. Additionally, the objective was to observe the diversity in inter-individual variation for the candidate genes that may give indications where individual adaptations at a molecular level can be found. This study was carried out on-farm including 232 dairy cows (parity >3) from 64 farms in Switzerland. Blood and liver samples were collected on d 20+/-7 before parturition, on d 24+/-2, and on d 89+/-4 after parturition. Blood plasma was assayed for concentrations of glucose, nonesterified fatty acids, beta-hydroxybutyrate, cholesterol, triglycerides, urea, albumin, protein, insulin, insulin-like growth factor-1, leptin, 3,5,3'-triiodothyronine, and thyroxine. Liver samples were obtained at the same time points and were measured for mRNA abundance of 26 candidate genes encoding enzymes and nuclear receptors involved in gluconeogenesis, fatty acid beta-oxidation, fatty acid and triglyceride synthesis, ketogenesis, citric acid cycle, cholesterol synthesis, and the urea cycle. The cows in the present study experienced a marked metabolic load in early lactation, as presented by changes in plasma metabolites and hormones, and responded accordingly with upregulation and downregulation of almost all candidate genes involved in metabolic processes in the liver. The observed inter-individual variation for the candidate genes, which was highest for acetyl-CoA-carboxylase and glycerol-3-phosphate dehydrogenase 2, should be further investigated to unravel the regulation at molecular level for optimal adaptive performance in dairy cows. PMID- 20965336 TI - Risk factors for dirty dairy cows in Norwegian freestall systems. AB - Cow cleanliness is important for ensuring hygienic milk production and the well being of dairy cows. The aim of this cross-sectional field study was to describe cow cleanliness in freestall-housed dairy herds and to examine risk factors related to thigh cleanliness. Cow cleanliness (n=2,335), management-related variables (e.g., ventilation and use of sawdust-bedded stalls), and housing related variables (e.g., freestall design and number of cows per stall) were recorded in 232 Norwegian freestall-housed dairy herds. Cleanliness was scored on a 4-point scale ranging from clean (1) to very dirty (4). The cows were relatively clean on the udder and belly, dirtier on thigh and the rear part of the body, and dirtiest on the legs, with cleanliness scores (mean +/- SD) of 1.64+/-0.62, 1.62+/-0.65, 2.02+/-0.75, 1.77+/-0.58, and 2.30+/-0.59, respectively. With dirty thighs as the response variable, several variables were tested in a logistic regression mixed model and with repeated measurements within herd and cow. A high number of cows per freestall [odds ratio (OR)=3.45], no use of sawdust as bedding (OR=3.24) versus use of sawdust, and a low-positioned (<0.85 m above stall floor) upper head rail "enclosing" the front of the stall (OR=1.42 to 2.13) versus a position >0.85 m were all risk factors for dirty thighs on the cows. Furthermore, liquid manure (score 2) versus more consistent manure (score 1; OR=1.66) and less tame cows (score 2) versus tame cows (score 1) were associated with an increased risk of dirty thighs (OR=1.24). The cleanest cows were associated with indoor temperatures in the range from 10 to 15 degrees C. For each 10-percentage-unit increase in relative air humidity, the risk of dirty thighs increased (OR=1.32). Freestalls with a construction hindering normal lying, rising, and standing movements should be avoided. Furthermore, focus is needed on indoor climate and manure consistency to obtain cows with clean thighs. PMID- 20965337 TI - Definitions and diagnosis of postpartum endometritis in dairy cows. AB - The objectives of this observational study were to determine and compare diagnostic criteria for postpartum endometritis in dairy cows. Data generated from 1,044 Holstein cows (6 herds) enrolled in a randomized clinical trial were used. Cows were examined for endometritis at 35+/-3 d (exam 1) and 56+/-3 d (exam 2) after parturition, using endometrial cytology (cytobrush technique), vaginal discharge scoring (Metricheck device; Simcrotech, Hamilton, New Zealand), and cervical diameter measurement (transrectal palpation). Reproductive data were recorded until 200 d after parturition. Diagnostic criteria for cytological and clinical endometritis were determined based on detrimental effect on subsequent reproductive performance, using logistic regression and Cox proportional hazard models accounting for the effect of herd clustering. Comparison of diagnostic criteria was performed using endometrial cytology as reference test or by quantifying the agreement between diagnostic approaches. At exam 1, diagnostic criteria were >=6% polymorphonuclear cells and mucopurulent or worse (purulent or foul) vaginal discharge for cytological and clinical endometritis, respectively. At exam 2, diagnostic criteria were >=4% polymorphonuclear cells and mucopurulent or worse vaginal discharge for cytological and clinical endometritis, respectively. Cows were classified as having cytological endometritis only, clinical endometritis only, or both cytological and clinical endometritis. Prevalence at exam 1 was 13.5, 9.4, and 5.8% for cytological endometritis only, clinical endometritis only, and both cytological and clinical endometritis, respectively. The detrimental effects of cytological and clinical endometritis on reproductive performance were additive. Among cows with clinical endometritis, only 38 and 36% had cytological endometritis at exam 1 and exam 2, respectively. Combination of diagnostic criteria improved neither the accuracy for predicting cytological endometritis nor the agreement between cytological and clinical endometritis. Overall, these results suggested that cytological and clinical endometritis may represent different manifestations of reproductive tract disease. They also suggested that use of the terminology clinical endometritis may not be accurate and that purulent vaginal discharge may be more descriptive. PMID- 20965338 TI - Efficacy of in vitro embryo transfer in lactating dairy cows using fresh or vitrified embryos produced in a novel embryo culture medium. AB - Objectives were to determine whether pregnancy success could be improved in lactating cows with timed embryo transfer when embryos were produced in vitro using a medium designed to enhance embryo development and survival after cryopreservation. In experiment 1, embryos (n=569 to 922) were cultured in either modified synthetic oviduct fluid or a serum-free medium, Block-Bonilla-Hansen-7 (BBH7). Development to the blastocyst stage was recorded at d 7, and selected blastocysts (n=79 to 114) were vitrified using open pulled straws. Culture of embryos in BBH7 increased development to the blastocyst stage (41.9+/-2.0 vs. 14.7+/-2.0%) and advanced blastocyst stages (expanded, hatching, hatched; 31.1+/ 1.3 vs. 6.4+/-1.3%) at d 7 and resulted in higher hatching rates at 24h postwarming compared with embryos cultured in modified synthetic oviduct fluid (59.0+/-0.5 vs. 26.7+/-0.5%). In experiment 2, embryos were produced using X sorted semen and cultured in BBH7. At d 7 after insemination, embryos were transferred fresh or following vitrification. Lactating Holstein cows were either subjected to timed artificial insemination (TAI) on the day of presumptive ovulation or used as embryo recipients 7 d later. Embryo recipients received an embryo if a corpus luteum was present. The percentage of cows pregnant at d 32, 46, and 76 of gestation was higher among cows that received fresh embryos compared with TAI cows or cows that received vitrified embryos. At d 76, for example, the proportion and percentage pregnant was 47/150 (31.3%) for cows subjected to TAI, 48/95 (50.5%) for cows receiving fresh embryos, and 39/141 (27.7%) for cows receiving a vitrified embryo. No difference was observed in the percentage of cows pregnant among TAI cows and those that received vitrified embryos. There was a service or transfer number * treatment interaction because differences in pregnancy rate between embryo transfer recipients and cows bred by TAI were greater for cows with more than 3 services or transfers. Pregnancy success in lactating cows can be improved by transferring fresh embryos produced in BBH7 compared with TAI. Moreover, no decline in fertility was observed when cryopreserved embryos were transferred compared with TAI. Embryo transfer is particularly efficacious for infertile cows that have previously experienced several failed breeding attempts. PMID- 20965339 TI - Short communication: Fluoroquinolone susceptibility of Staphylococcus aureus strains isolated from caprine clinical mastitis in southeast Spain. AB - The antibiotic susceptibility of 32 strains of Staphylococcus aureus isolated from the mastitic milk of dairy goats was evaluated. The antibiotics tested were 3 fluoroquinolones that have been developed especially for use in veterinary medicine: danofloxacin, marbofloxacin, and orbifloxacin. Minimum inhibitory concentration (MIC) tests were performed according to the microdilution broth method. The MIC(90) (concentration at which 90% inhibition is achieved) values obtained were 0.5, 1, and 1 mg/L for danofloxacin, marbofloxacin, and orbifloxacin, respectively. Danofloxacin was the most active fluoroquinolone tested against Staph. aureus strains isolated from milk; however, specific testing is required before using these drugs as therapy for the control of clinical mammary infections in goats. PMID- 20965340 TI - Technical note: Comparison of rectal and vaginal temperatures in lactating dairy cows. AB - A method commonly used to identify illness in dairy cows is measuring body temperatures with a rectal thermometer, but vaginal measures are becoming common in research. The primary objective of this study was to validate vaginal measures of body temperature by comparing them with rectal temperatures. Data loggers used to collect vaginal temperatures can be programmed to collect many readings per day, providing an opportunity to interpret effects of health in relation to diurnal differences in temperatures. Thus, a secondary objective was to compare the diurnal pattern in body temperatures for cows with and without retained placenta (RP). Body temperature was monitored for 8 d in 29 cows that had recently calved (enrolled 2 d after calving; 7 of these cows were diagnosed with RP) and in 13 cows in peak lactation (98+/-8 d in milk). Rectal temperatures were taken at 0630, 0930, 1230, 1530, 1830, and 2130h (+/-30 min) with a digital thermometer for 8 d consecutively. During the same period, vaginal temperatures were measured every 10 min with a microprocessor-controlled data logger attached to a modified vaginal controlled internal drug release insert. Values from the vaginal loggers were averaged over 1h and paired with the corresponding rectal temperature. There was a relationship between rectal and vaginal temperatures for fresh cows (n=1,393; r=0.81) and for peak-lactation cows (n=556; r=0.46). Cows with RP had higher body temperatures (39.2+/-0.01) compared with healthy cows (39.1+/-0.01). Body temperature was higher at night, and lower between 0800 to 1000 h for healthy cows (39.0+/-0.02) and between 1100 to 1300 h for RP cows (39.1+/-0.02). In summary, vaginal temperatures were associated with rectal measures, and provided the advantage of capturing dirurnal changes in body temperature. PMID- 20965341 TI - Technical note: Effects of an epinephrine infusion on eye temperature and heart rate variability in bull calves. AB - Changes in autonomic nervous system (ANS) activity are one of the first phases of a stress response, but they are rarely used to assess the welfare of farm animals. Eye temperature measured using infrared thermography (IRT) is proposed as an indicator of ANS activity because it may reflect changes in blood flow in the capillary beds of the conjunctiva. The aim was to determine whether epinephrine infusion would initiate eye temperature changes in calves. Sixteen 4 mo-old Friesian calves (124+/-5 kg) were assigned randomly to receive a jugular infusion of either epinephrine (4 MUg/kg per min for 5 min) or saline. Eye temperature ( degrees C), heart rate (HR), and HR variability (HRV) were recorded from 15 min before infusion until 10 min after it was completed. Blood samples collected via jugular catheter were assayed for epinephrine, norepinephrine, and cortisol concentrations, and packed cell volume (PCV) was measured. No changes in any variable were observed with the saline infusion. Plasma epinephrine concentrations increased 90-fold with epinephrine infusion, which was associated with a decrease in eye temperature of 1.4+/-0.05 degrees C. During epinephrine infusion, plasma norepinephrine concentrations decreased by half and HR decreased by 9.3+/-3.3 beats/min. The HRV measure, the root mean square of successive differences, increased by 49.7+/-9.2 ms, indicating a compensatory increase in parasympathetic activity. After epinephrine infusion, plasma cortisol concentrations increased by 10.4+/-1.7 ng/mL and PCV was higher (38 vs. 31+/ 0.1%, epinephrine vs. saline, respectively). These results support the hypothesis that changes in eye temperature are mediated by the sympathetic component of the ANS. Infrared thermography is a noninvasive method to assess ANS activity for evaluating welfare of cattle. PMID- 20965342 TI - In vitro evaluation of cashew nut shell liquid as a methane-inhibiting and propionate-enhancing agent for ruminants. AB - Cashew nut shell liquid (CNSL) containing antibacterial phenolic compounds was evaluated for its potency as a feed additive for ruminants. In experiment 1, ruminal responses to CNSL supplementation were assessed using a batch culture system. Rumen fluid from cattle was diluted with artificial saliva and incubated for 18h in a batch culture with a mixed diet containing a 30:70 hay:concentrate diet to which raw or heated CNSL was added at a final concentration of 500 MUg/mL. In experiment 2, a Rusitec, using rumen fluid from the same cattle, was operated over a period of 7 d during which only raw CNSL was tested at concentrations of 0, 50, 100, or 200 MUg/mL, and variations in fermentation and bacterial population were assessed. In experiment 3, a pure culture study was conducted using selected bacteria to determine their susceptibility to CNSL. In experiment 1, methane production was inhibited by raw CNSL (56.9% inhibition) but not by heated CNSL. Total volatile fatty acid concentration was not affected, whereas increased concentrations of propionate and decreased concentrations of acetate and butyrate were observed using either raw or heated CNSL. These changes were more obvious when raw CNSL was tested. In experiment 2, raw CNSL inhibited methanogenesis and increased propionate production in a dose-dependent manner, showing maximum methane inhibition (70.1%) and propionate enhancement (44.4%) at 200 MUg/mL supplementation. Raw CNSL increased total volatile fatty acid concentration and dry matter digestibility. Raw CNSL also appeared to induce a dramatic shift in the population of rumen microbiota, based on decreased protozoa numbers and changes in quantitative PCR assay values for representative bacterial species. In experiment 3, using pure cultures, raw CNSL prevented the growth of hydrogen-, formate-, and butyrate-producing rumen bacteria, but not the growth of bacteria involved in propionate production. Based on these data, raw CNSL, rich in the antibacterial phenolic compound anacardic acid, is a potential candidate feed additive with selective activity against rumen microbes, leading to fermentation that results in decreased methane and enhanced propionate production. PMID- 20965343 TI - Effect of prepartum anionic supplementation on periparturient feed intake, health, and milk production. AB - Our objectives were to determine if dietary cation-anion difference (DCAD) and source of anions influence periparturient feed intake and milk production of dairy cattle during the transition period. Diets differed in DCAD (cationic or anionic) and anionic supplement. The 4 diets used prepartum were (1) control [DCAD +20 mEq/100g of dry matter (DM)], (2) Bio-Chlor (DCAD -12 mEq/100g of DM; Church & Dwight Co. Inc., Princeton, NJ), (3) Fermenten (DCAD -10 mEq/100g of DM; Church & Dwight Co. Inc.), and (4) salts (DCAD -10 mEq/100g of DM). Urine pH was lower for cows that consumed an anionic diet prepartum compared with control. Prepartum diet had no effect on prepartum dry matter intake (DMI) of multiparous or primiparous cows. Postpartum DMI and milk yield for multiparous cows fed anionic diets prepartum were greater compared with those fed the control diet. Postpartum DMI and milk yield of primiparous cows were similar for prepartum diets. Feeding prepartum anionic diets did not affect plasma Ca at or near calving. However, cows fed anionic diets began their decline in plasma Ca later than control cows. Postpartum beta-hydroxybutyrate and nonesterified fatty acids were lower for primiparous cows fed prepartum anionic diets compared with those fed the control diet. Prepartum and postpartum plasma glucose concentrations were not affected by prepartum diet for all cows. Liver triglyceride differed for parity by day. Parities were similar at 21 d prepartum, but at 0 d and 21 d postpartum, levels were greater for multiparous cows. Results indicate that decreasing the DCAD of the diet during the prepartum period can increase postpartum DMI and milk production of multiparous cows without negatively affecting performance of primiparous cows. PMID- 20965344 TI - Effect of feeding alfalfa hay or Tifton 85 bermudagrass haylage with or without a cellulase enzyme on performance of Holstein cows. AB - Forty-four lactating Holstein cows (173+/-30 DIM, 42.5+/-6.8 kg of milk, 4.03+/ 0.69% fat, 674+/-78 kg of body weight) were used in an 8-wk, completely randomized trial with a 2 * 2 factorial arrangement of treatments to determine the effect of forage source and supplemental cellulase enzyme on performance. Treatments included 2 forage combinations (corn silage plus 12.2% dry matter, DM, from either alfalfa hay or Tifton 85 bermudagrass haylage) with or without a commercial cellulase enzyme applied to the total mixed ration at the rate of 4 g/head per day (Promote N.E.T.-L, Cargill Animal Nutrition, Minneapolis, MN). Experimental diets were formulated to provide similar concentrations of protein (16.5% of DM), energy (1.63 Mcal of net energy for lactation/kg of DM), and neutral detergent fiber (41.7% of DM) and were fed once daily as a total mixed ration behind Calan doors for ad libitum intake. The cellulase enzyme provided 1,200 cellulase units of activity/g of product and was applied to the total mixed ration and allowed to mix for 5min before feeding. Before beginning the trial, all cows were trained to use Calan (American Calan, Northwood, NH) doors and then fed the alfalfa hay-based diet for 2 wk. Data collected during wk 2 were used as a covariate in the statistical analysis. At the beginning of the 6-wk experimental period, cows were assigned randomly to 1 of the 4 experimental diets. No interactions were observed between forage and enzyme for any measures. Daily DM intake; milk yield; concentrations of milk fat, true protein, lactose, and solids not fat; energy-corrected milk yield; and dairy efficiency were not different among alfalfa or Tifton 85 bermudagrass rations with or without cellulase enzyme supplementation. The results of this trial indicate that Tifton 85 bermudagrass haylage can replace alfalfa hay in diets fed to high-producing, lactating dairy cows without depressing DM intake or milk yield when rations are balanced for NDF. Although supplemental cellulase enzymes have been shown to improve ration digestibility and animal performance in previous trials, no advantages were observed in the current trial. PMID- 20965345 TI - Effects of chemically or technologically treated linseed products and docosahexaenoic acid addition to linseed oil on biohydrogenation of C18:3n-3 in vitro. AB - Rumen biohydrogenation kinetics of C18:3n-3 from several chemically or technologically treated linseed products and docosahexaenoic acid (DHA; C22:6n-3) addition to linseed oil were evaluated in vitro. Linseed products evaluated were linseed oil, crushed linseed, formaldehyde treated crushed linseed, sodium hydroxide/formaldehyde treated crushed linseed, extruded whole linseed (2 processing variants), extruded crushed linseed (2 processing variants), micronized crushed linseed, commercially available extruded linseed, lipid encapsulated linseed oil, and DHA addition to linseed oil. Each product was incubated with rumen liquid using equal amounts of supplemented C18:3n-3 and fermentable substrate (freeze-dried total mixed ration) for 0, 0.5, 1, 2, 4, 6, 12, and 24h using a batch culture technique. Disappearance of C18:3n-3 was measured to estimate the fractional biohydrogenation rate and lag time according to an exponential model and to calculate effective biohydrogenation of C18:3n-3, assuming a fractional passage rate of 0.060/h. Treatments showed no differences in rumen fermentation parameters, including gas production rate and volatile fatty acid concentration. Technological pretreatment (crushing) followed by chemical treatment applied as formaldehyde of linseed resulted in effective protection of C18:3n-3 against biohydrogenation. Additional chemical pretreatment (sodium hydroxide) before applying formaldehyde treatment did not further improve the effectiveness of protection. Extrusion of whole linseed compared with extrusion of crushed linseed was effective in reducing C18:3n-3 biohydrogenation, whereas the processing variants were not different in C18:3n-3 biohydrogenation. Crushed linseed, micronized crushed linseed, lipid encapsulated linseed oil, and DHA addition to linseed oil did not reduce C18:3n-3 biohydrogenation. Compared with the other treatments, docosahexaenoic acid addition to linseed oil resulted in a comparable trans11,cis15-C18:2 biohydrogenation but a lesser trans10+11 C18:1 biohydrogenation. This suggests that addition of DHA in combination with linseed oil was effective only in inhibiting the last step of biohydrogenation from trans10+11-C18:1 to C18:0. PMID- 20965346 TI - A high dose of monensin does not reduce methane emissions of dairy cows offered pasture supplemented with grain. AB - The primary objective of our research was to determine the effect of a high dose of monensin supplementation on enteric CH(4) emissions of dairy cows offered a ryegrass pasture diet supplemented with grain. An additional objective was to evaluate effects on milk production and rumen function, because a commensurate improvement in milk production could lead to adoption of monensin as a profitable strategy for methane abatement. Two experiments were conducted (grazing and respiratory chambers) and in both experiments monensin (471 mg/d) was topdressed on 4 kg (dry matter)/d of rolled barley grain offered in a feed trough twice daily at milking times. In the grazing experiment, 50 Holstein-Friesian cows were assigned randomly to 1 of 2 groups (control or monensin). Cows grazed together as a single herd on a predominantly ryegrass sward and received monensin over a 12 wk period, during which time measurements of milk production and body weight change were made. The SF(6) tracer technique was used to estimate methane production of 30 of the 50 cows (15 control cows and 15 monensin cows) for 3 consecutive days in wk 3, 5, 8, and 12 of treatment. Samples of rumen fluid were collected per fistula from 8 of the 50 cows (4 per diet) on 2 consecutive days in wk 3, 5, 8, and 12 of treatment and analyzed for volatile fatty acids and ammonia N. In the metabolic chamber experiment, 10 pairs of lactating dairy cows (control and monensin) were used to determine the effects of monensin on methane emissions, dry matter intake, milk production, and body weight change over a 10 wk period. Methane emissions were measured by placing cows in respiration chambers for 2 d at wk 5 and 10 of treatment. Cows received fresh ryegrass pasture harvested daily. Monensin did not affect methane production in either the grazing experiment (g/d, g/kg of milk) or the chamber experiment (g/d, g/kg of dry matter intake, g/kg of milk). In both experiments, milk production did not increase with addition of monensin to the diet. Monensin had no effect on body weight changes in either experiment. Monensin did not affect volatile fatty acids or ammonia-N in rumen fluid, but the acetate to propionate ratio tended to decrease. Monensin did not improve milk production of grazing dairy cows and no effect on enteric methane emissions was observed, indicating that monensin cannot be promoted as a viable mitigation strategy for dairy cows grazing ryegrass pasture supplemented with grain. PMID- 20965347 TI - Pigeon peas as a supplement for lactating dairy cows fed corn silage-based diets. AB - Holstein rumen-cannulated cows [n=7; initial body weight (BW) 640.56+/-71.43 kg] were fed a corn silage basal diet with 1 of 3 concentrates (C=control; P10=10% pigeon peas; P20=20% pigeon peas). Cows were randomly assigned to treatments in a replicated 3*3 Latin square and individually fed using Calan gates. Each experimental period was 21 d with 7 d for adaption and 14 d for sample collection. Ruminal fluid samples were taken the last day of each experimental period and analyzed for pH, ammonia, long-chain fatty acids, and volatile fatty acids (VFA). Consecutive a.m. and p.m. milk samples were taken during the last 2 wk of the 21-d period and analyzed for fat, protein, long-chain fatty acids, and somatic cell count. Dry matter intake (kg/d) was reduced during the second period and was greater for P10 diets. Milk protein was greater for cows fed P20 compared with P10. Energy-corrected milk was greater for cows fed the control diet compared with P10. Treatment had no effect on milk yield. Ruminal fluid pH decreased over sampling times; however, pH remained at or above 5.5. Diets did not affect ruminal fluid pH; however, pH was different for sampling periods. Ruminal ammonia decreased until 8h postfeeding at which time it peaked consistent with changes in ammonia concentrations that usually peak 3 to 5h postfeeding on diets high in plant proteins. Dietary treatments altered ruminal fluid VFA with reduced concentrations of acetate and greater concentrations of propionate for control diet, resulting in reduced acetate:propionate ratio. Isobutyrate exhibited an hour by treatment interaction, in which isobutyrate decreased until 8h postfeeding and then tended to be greater for P10 than for other treatments. Animals fed the P10 diet had greater concentrations of ruminal isovalerate. Ruminal cis-9,trans-11 and trans-10,cis-12 conjugated linoleic acid (CLA) isomers were not affected by dietary treatments. The P10 diet had greatest ruminal synthesis of cis-9,trans-11, but control cows had greatest ruminal synthesis of trans-10,cis-12. Milk CLA isomers were similar among treatments. Trends were observed for greater cis-9,trans-11 and trans-10,cis-12 for the P10 diet. Pigeon peas may be used as a protein supplement in dairy diets without affecting milk production, dry matter intake, or ruminal environment when they replace corn and soybean meal. PMID- 20965348 TI - The effect of body condition score at calving and supplementation with Saccharomyces cerevisiae on milk production, metabolic status, and rumen fermentation of dairy cows in early lactation. AB - The objective of this study was to examine the effects of live yeast (LY) supplementation and body condition score (BCS, 1-5 scale) at calving on milk production, metabolic status, and rumen physiology of postpartum (PP) dairy cows. Forty Holstein-Friesian dairy cows were randomly allocated to a 2 * 2 factorial design and blocked by yield, parity, BCS, and predicted calving date. Treatments were body condition at calving (low for BCS <=3.5 or high for BCS >=3.75; n=20) and supplementation with LY (2.5 and 10 g of LY/d per cow for pre- and postcalving, respectively; control, no LY supplementation; n=20). The supplement contained 10(9) cfu of Saccharomyces cerevisiae/g (Yea-Sacc(1026) TS, Alltech Inc., Nashville, TN). Daily milk yield, dry matter intake, milk composition, BCS, body weight, and backfat thickness were recorded. Blood samples were harvested for metabolite analysis on d 1, 5, 15, 25, and 35 PP. Liver samples were harvested by biopsy for triacylglycerol (TAG) and glycogen analysis on d 7 precalving, and on d 7 and 21 PP. Rumen fluid was sampled by rumenocentesis for all cows on d 7 and 21 PP. Supplementation with LY had no effect on milk yield, dry matter intake, rumen fluid pH, or blood metabolites concentration of dairy cows with high or low BCS at calving. Feeding LY increased rumen acetate proportion and protozoal population, tended to increase liver glycogen, and decreased rumen ammonia nitrogen during early lactation. Over-conditioned cows at calving had greater body reserve mobilization and milk production and lower feed intake, whereas cows with a moderate BCS at calving had greater feed intake, lower concentrations of nonesterified fatty acids and beta-hydroxybutyrate, lower liver TAG and TAG:glycogen ratio, and faster recovery from body condition loss. Additionally, the data suggest that concentrations of liver enzymes in blood might be used as an indicator for liver TAG:glycogen ratio. Results indicate that in the case of this experiment, where the control treatment was associated with an acceptable rumen pH, feeding yeast did not significantly improve indicators of energy status in dairy cows. PMID- 20965349 TI - Effects of feeding increasing levels of wet corn gluten feed on production and ruminal fermentation in lactating dairy cows. AB - An experiment was conducted to evaluate the effects of increasing dietary inclusion rates of wet corn gluten feed (WCGF; Sweet Bran; Cargill Inc., Blair, NE) on milk production and rumen parameters. Four primiparous and 4 multiparous ruminally cannulated Holstein cows averaging 90+/-13 d in milk (mean +/- SD) were randomly assigned to 1 of 4 sequences in a replicated 4 * 4 Latin square experiment with 28-d periods. Treatments were diets containing 0, 11, 23, and 34% WCGF on a dry matter basis; alfalfa hay, corn silage, corn grain, soybean meal, expeller soybean meal, and mineral supplements were varied to maintain similar nutrient concentrations across diets. Performance and measures of ruminal fermentation were monitored. Linear and quadratic effects of increasing WCGF inclusion rate were assessed using mixed-model analysis. Increasing dietary WCGF linearly increased dry matter intake (26.7, 25.9, 29.3, and 29.7 kg/d for 0, 11, 23, and 34% WCGF, respectively) and milk production (36.8, 37.0, 40.1, and 38.9 kg/d). Concentrations of milk components did not differ among treatments; however, protein and lactose yields increased linearly and fat yield tended to increase linearly when more WCGF was fed. This led to greater production of energy-corrected milk (38.2, 38.8, 41.7, and 40.4 kg/d) and solids-corrected milk (35.2, 35.7, 38.5, and 37.2 kg/d), but efficiency of production linearly decreased. Increased WCGF in the diet tended to linearly decrease ruminal pH (6.18, 6.12, 6.14, and 5.91), possibly because mean particle size was below typical recommendations for all diets, and diets with greater proportions of WCGF had a smaller mean particle size. Ruminal acetate concentration decreased linearly and propionate increased linearly as WCGF inclusion rate increased. Treatments had a quadratic effect on ammonia concentration, with greater concentrations for the 0 and 34% WCGF diets. In situ digestibility of soybean hulls showed a significant diet-by-time interaction, and increasing dietary levels of WCGF linearly decreased in situ neutral detergent fiber disappearance at 24h. Change in body condition score increased linearly with increasing WCGF inclusion rate. Results indicate that adding WCGF to dairy rations can increase energy-corrected milk yield, and this increase appears to be driven, at least in part, by an increase in dry matter intake. PMID- 20965350 TI - Transfer of melamine from feed to milk and from milk to cheese and whey in lactating dairy cows fed single oral doses. AB - A study was conducted to evaluate the excretion pattern, after a single oral dose, of melamine from feed into milk, and the subsequent transfer to cheese and whey. The transfer of cyanuric acid was also investigated. Twenty-four lactating Holstein cows were randomly allocated to 4 treatments and received single doses of melamine as follows: 0.05, 0.50, 5.00, and 50.00 g/cow for groups D1, D2, D3, and D4, respectively. Individual milk samples were collected for melamine and cyanuric acid analyses on d 1, 2, 3, 4, 5, and 7. Milk collected individually from the second milking after melamine ingestion was used to make cheese on a laboratory scale. Melamine and cyanuric acid were extracted using a solid-phase extraction cartridge, and analyses were carried out by liquid chromatography-mass spectrometry/mass spectrometry. Maximal melamine concentrations occurred between 6 and 18 h after treatment and increased with log dose (linear and quadratic), ranging from 0.019 to 35.105 mg/kg. More than 60% of the melamine that was transferred to the milk was observed within 30 h after melamine ingestion. Melamine was not detected (limit of detection was 0.002 mg/kg) in milk 5 d after treatment in group D1, and 7 d after treatment in groups D2, D3, and D4. Blood urea nitrogen was not influenced by melamine ingestion. During cheese making, melamine was transferred mainly to the whey fraction. Cyanuric acid was not detected in any of the samples (milk, cheese, or whey). The excretion pattern of melamine in milk and whey may represent a health concern when cows ingest more than 0.50 g of melamine/d. However, only at intake levels of 5 and 50 g/d did cheese exceed the limits as set forth by the European Union. The results confirmed that melamine contamination of milk and milk products may be related not only to direct contamination, but also to adulteration of animal feeds. PMID- 20965351 TI - Variability in feed and total mixed ration neutral detergent fiber and crude protein analyses among commercial laboratories. AB - The objective of this study was to assess the variability in amylase-treated neutral detergent fiber (aNDF) and crude protein (CP) analyses of feed and total mixed ration (TMR) samples among feed analysis laboratories. Two TMR were prepared that varied in the dry matter proportion of forage and concentrates: 45% forage (LF-TMR) versus 60% forage (HF-TMR). Replicated TMR and individual feed samples were dried, ground through a 4-mm screen, and sent to 10 commercial and 4 research or development laboratories for aNDF and CP analyses. Laboratories were asked to complete a detailed questionnaire regarding the aNDF procedure used. Variability in aNDF and CP analyses was assessed using univariate statistics and mixed modeling procedures. Significant variability in the aNDF analysis of individual feeds was found among the participating laboratories. The variability was particularly large for low-aNDF feeds such as distillers and barley grains. The variability among laboratories in the aNDF analysis of low-fiber TMR was greater than of high-fiber TMR, with the most likely reason being their greater proportions of grains and protein concentrates and the effect of variation in the aNDF protocols, particularly alpha-amylase use, on the analysis of these types of feeds. Variability due to the technique used for aNDF analysis was not statistically significant when outlier labs using the filter bag technique were removed; however, laboratories using the filter bag technique tended to produce more variable results than did laboratories using variation of the crucible technique (SE=2.542 vs. 0.930, respectively). Calculated aNDF values for TMR, based on proportions and aNDF analysis of individual feeds, were slightly greater than analyzed aNDF values for TMR. Results from this ringtest emphasize the need for feed analysis laboratories to follow the official aNDF method exactly. Variation within and among laboratories can be reduced by replicating analysis and including reference materials in each analytical run. Results of CP analysis were more consistent among laboratories, and variability in CP analysis of individual feeds or TMR was marginally acceptable. PMID- 20965352 TI - Relationships between endometritis and metabolic state during the transition period in pasture-grazed dairy cows. AB - The primary objective of this study was to identify relationships between endometritis and metabolic state during the calving transition and early lactation periods. A subset of mixed age and breed dairy cows (n=78) from a seasonal, pasture-grazed herd of 389 cows was examined. The selected cows were grouped as having endometritis at d 42 postpartum or being unaffected by endometritis. Endometritis was defined as >6% (upper quartile) of uterine nucleated cells being polymorphonuclear cells (H-PMN; n=38); unaffected by endometritis was defined as <=1% of nucleated cells being polymorphonuclear (L PMN; n=40). Milk yield was determined at each milking, and milk composition (fat and protein) was determined at 2-wk intervals. Blood samples collected on d -14, 0 (d of calving), 4, 7, 14, 28, and 42 were analyzed for indicators of energy status (nonesterified fatty acids, glucose, and urea), liver function (albumin, globulin, glutamate dehydrogenase, and aspartate aminotransferase), inflammation (haptoglobin), and mineral status (Ca and Mg). Samples collected weekly from d 21 to 63 or 70 were analyzed for progesterone content. The postpartum anovulatory interval was defined to end on the first day postpartum that plasma progesterone concentration was >=1 ng/mL. A greater percentage of H-PMN cows failed to ovulate before d 63 or 70 (34%) compared with L-PMN cows (10%), although the proportions of cows ovulating within either polymorphonuclear group was similar through d 56 postpartum. Plasma concentrations of albumin and the albumin:globulin ratio were consistently lower in H-PMN cows. Plasma Mg was lower, whereas glutamate dehydrogenase and aspartate aminotransferase were higher, in H-PMN cows during early lactation compared with L-PMN cows. Circulating metabolites indicative of energy status (nonesterified fatty acids, glucose, and urea) were not different between polymorphonuclear groups. Among 3- to 5-yr-old cows, daily milk yield for the first 42 d after calving was lower for H-PMN cows than for L-PMN cows. Among cows >5 yr old, protein percentage was lower in H-PMN cows compared with L-PMN cows. In summary, endometritis at 42 d postpartum in the herd studied was associated with an increased likelihood of remaining anovulatory. These cows had lower albumin concentrations throughout the calving transition period, perhaps indicating impaired liver function, with lower plasma Mg and evidence of hepatocellular damage in early lactation. Similar profiles of nonesterified fatty acids and glucose indicated that energy status was not a risk factor for endometritis. PMID- 20965353 TI - Evaluation of potential carryover effects associated with limit feeding of gravid Holstein heifers. AB - Ninety-six Holstein heifers (400+/-6kg, 15.2+/-0.1 mo), including 9 with ruminal cannulas, were offered 1 of 3 diets for 180+/-8 d in a randomized replicated pen design. Dietary treatments included a control diet (C100) and 2 independent limit fed (LF) diets. The LF diets included one offered at 85% of C100 intake (L85) without an ionophore, and a second containing an ionophore (325 mg/head per day of lasalocid) that was offered at 80% of C100 intake (L80+I). Heifers were evaluated for growth, rumen digesta volume, nutrient excretion, and subsequent lactation performance. Limit-fed heifers consumed less dry matter and neutral detergent fiber, and had greater respective average daily gains (0.96 or 0.89 vs. 0.81 kg/d), and lower feed:gain ratios (9.1 or 9.3 vs. 13.0 kg/kg) compared with heifers offered the C100 diet. No differences in rumen pH, NH(3)-N, or volatile fatty acid concentrations were observed between C100 and LF heifers. Rumen digesta volume, density, and weight were unaffected by LF, and feeding L85 or L80+I did not result in carryover effects for rumen digesta volume when these heifers were offered a common high-fiber diet immediately after the 180-d growth trial. At parturition, no differences were observed for dystocia index, calf body weight, or 7-d postpartum body weight between cows offered LF or C100 diets as heifers. Lactation body weight, dry matter intake, and feed efficiency of cows did not differ between treatments at 45 or 90 d in milk. Milk yield and milk components also were not different between cows that were offered C100 or LF diets as gravid heifers. At 45 d in milk, rumen digesta volume was greater (99.1 vs. 66.1L) for cows offered L85 compared with cows offered L80+I as gravid heifers, but this effect was not observed at 90 d in milk. Limit feeding of gravid Holstein heifers for 180 d did not result in any carryover effects during their first lactation for rumen digesta volume, dry matter intake, or milk yield. PMID- 20965354 TI - Antilipolytic and lipolytic effects of administering free or ruminally protected nicotinic acid to feed-restricted Holstein cows. AB - The objectives were to determine effects of 12 hourly infusions of different quantities of nicotinic acid (NA) on plasma nonesterified fatty acid (NEFA; experiment 1) and whether longer (108 h) continuous infusions of NA could induce sustained reductions of plasma NEFA (experiment 2) in nonlactating, nongestating Holstein cows that were feed restricted. Experiment 1 was a 5*5 Latin square with 6-d periods and 9 recovery days between each period. Each period consisted of 5 d of partial feed restriction to increase plasma NEFA concentration. Treatments were abomasal infusions of 0, 0.25, 0.5, 1, or 3 mg of NA/h per kilogram of body weight (BW), infused as hourly boluses for 12 h, starting 4 d after initiation of partial feed restriction. Plasma NEFA was decreased for the highest dose: from 448 MUEq/L to 138+/-75 MUEq/L at 1 h after the first bolus of 3mg of NA/h per kilogram of BW. This initial reduction in plasma NEFA concentration was followed by an increase in concentration at 2, 3, and 4 h relative to initiation of infusions. Plasma NEFA then decreased to 243 MUEq/L 6h after initiation of treatments and remained low until termination of infusions. A rebound in plasma NEFA concentration occurred at 3 and 4 h after termination of infusion for cows that received 3 mg of NA/h per kilogram of BW. Experiment 2 was a 5*5 Latin square with 7-d periods and 9 recovery days between each period. Each period consisted of 5 d of partial feed restriction to increase plasma NEFA concentration. Treatments were continuous abomasal infusion of 0, 0.5, 1, or 3 mg of free NA/h per kilogram of BW for 4.5 d starting at feed restriction or 0.5 mg of NA/h per kilogram of BW infused directly into the rumen in a form protected from microbial degradation. The ruminal administration of protected NA was initiated 2 d before abomasal infusions and initiation of feed restriction to establish steady postruminal delivery of NA by start of abomasal infusions. Plasma NEFA was approximately 70 MUEq/L before initiation of feed restriction and increased to 509, 587, 442, 850, and 108 MUEq/L at 4.5 d for cows that received 0, 0.5 (protected NA), 0.5 (free NA), 1, and 3 mg of NA/h per kilogram of BW, respectively. An antilipolytic response was achieved with the highest abomasal dose, which maintained plasma NEFA concentration lower than the control group. An increase in plasma NEFA concentration was observed after termination of infusions for cows that received 1 and 3 mg of NA/h per kilogram of BW. Plasma NEFA was 1,900 MUEq/L at 4h after termination of infusion for cows receiving 1 mg of NA/h per kilogram of BW and 1,360 MUEq/L at 5h after termination of infusion for cows receiving 3 mg of NA/h per kilogram of BW. In nongestating, nonlactating cows it is unlikely that a dose of NA exists that will reduce plasma NEFA concentration and prevent the rebound that occurs following termination of NA administration. PMID- 20965355 TI - Effects of corn silage hybrids and dietary nonforage fiber sources on feed intake, digestibility, ruminal fermentation, and productive performance of lactating Holstein dairy cows. AB - This experiment was conducted to determine the effects of corn silage hybrids and nonforage fiber sources (NFFS) in high forage diets formulated with high dietary proportions of alfalfa hay (AH) and corn silage (CS) on ruminal fermentation and productive performance by early lactating dairy cows. Eight multiparous Holstein cows (4 ruminally fistulated) averaging 36+/-6.2 d in milk were used in a duplicated 4 * 4 Latin square design experiment with a 2 * 2 factorial arrangement of treatments. Cows were fed 1 of 4 dietary treatments during each of the four 21-d replicates. Treatments were (1) conventional CS (CCS)-based diet without NFFS, (2) CCS-based diet with NFFS, (3) brown midrib CS (BMRCS)-based diet without NFFS, and (4) BMRCS-based diet with NFFS. Diets were isonitrogenous and isocaloric. Sources of NFFS consisted of ground soyhulls and pelleted beet pulp to replace a portion of AH and CS in the diets. In vitro 30-h neutral detergent fiber (NDF) degradability was greater for BMRCS than for CCS (42.3 vs. 31.2%). Neither CS hybrids nor NFFS affected intake of dry matter (DM) and nutrients. Digestibility of N, NDF, and acid detergent fiber tended to be greater for cows consuming CCS-based diets. Milk yield was not influenced by CS hybrids and NFFS. However, a tendency for an interaction between CS hybrids and NFFS occurred, with increased milk yield due to feeding NFFS with the BMRCS-based diet. Yields of milk fat and 3.5% fat-corrected milk decreased when feeding the BMRCS-based diet, and a tendency existed for an interaction between CS hybrids and NFFS because milk fat concentration further decreased by feeding NFFS with BMRCS-based diet. Although feed efficiency (milk/DM intake) was not affected by CS hybrids and NFFS, an interaction was found between CS hybrids and NFFS because feed efficiency increased when NFFS was fed only with BMRCS-based diet. Total volatile fatty acid production and individual molar proportions were not affected by diets. Dietary treatments did not influence ruminal pH profiles, except that duration (h/d) of pH <5.8 decreased when NFFS was fed in a CCS-based diet but not in a BMRCS-based diet, causing a tendency for an interaction between CS hybrids and NFFS. Overall measurements in our study reveal that high forage NDF concentration (20% DM on average) may eliminate potentially positive effects of BMRCS. In the high forage diets, NFFS exerted limited effects on productive performance when they replaced AH and CS. Although the high quality AH provided adequate NDF (38.3% DM) for optimal rumen fermentative function, the low NDF concentration of the AH and the overall forage particle size reduced physically effective fiber and milk fat concentration. PMID- 20965356 TI - Short communication: Feed restriction around insemination did not alter birth sex ratio in lactating dairy cows. AB - Studies investigating variation in birth sex ratio indicate that the energy status of the dam prebreeding can influence the sex of the subsequent offspring. The Trivers-Willard hypothesis suggests that dams in good condition would produce more male offspring, whereas dams in poor condition (relative to dams in good condition) would produce more female offspring. However, results testing this hypothesis are associative in nature, with no data available from controlled experiments. Hence, this study tested the hypothesis that feed allowance around the time of conception alters birth sex ratio in lactating dairy cows. Cows (n=770 on 2 farms) were randomly allocated to 2 treatments before the seasonal breeding period and offered either unrestricted (UnRes; n=453, across 4 herd replicates) or restricted (Res; n=317, across 3 herd replicates) allowance of fresh pasture for the first 14 d of breeding. Restricted cows responded by reducing milk yields throughout the treatment period and took 3 to 4 wk to recover. The birth sex ratio of resultant offspring was evaluated for cows that conceived in the first 21 d of breeding (UnRes n=234; Res n=142). Birth sex ratio was not different between UnRes and Res treatments. Association analysis, within treatments, identified that cows had a greater odds of producing a male offspring if they had lower milk fat to protein ratio before conception, were in a lower body condition score precalving, and gained condition from calving to the breeding period. No relationship between body condition score prebreeding and birth sex ratio was identified. In the current study, no difference in the birth sex ratio was observed following a short-term feed restriction around the conception. However, alternative indirect measures of energy balance (e.g., milk fat:protein ratio) may be a useful tool when examining the relationships between energy balance in dairy cows and birth sex ratio. PMID- 20965357 TI - Genetic correlations between measures of Mycobacterium bovis infection and economically important traits in Irish Holstein-Friesian dairy cows. AB - Mycobacterium bovis is the primary agent of tuberculosis (TB) in cattle. The failure of Ireland and some other countries to reach TB-free status indicates a need to investigate complementary control strategies. One such approach would be genetic selection for increased resistance to TB. Previous research has shown that considerable genetic variation exists for susceptibility to the measures of M. bovis infection, confirmed M. bovis infection, and M. bovis-purified protein derivative (PPD) responsiveness. The objective of this study was to estimate the genetic and phenotypic correlations between economically important traits and these measures of M. bovis infection. A total of 20,148 and 17,178 cows with confirmed M. bovis infection and M. bovis-PPD responsiveness records, respectively, were available for inclusion in the analysis. First- to third parity milk, fat, and protein yields, somatic cell count, calving interval, and survival, as well as first-parity body condition score records, were available on cows that calved between 1985 and 2007. Bivariate linear-linear and threshold linear sire mixed models were used to estimate (co)variance components. The genetic correlations between economically important traits and the measures of M. bovis infection estimated from the linear-linear and threshold-linear sire models were similar. The genetic correlations between susceptibility to confirmed M. bovis infection and economically important traits investigated in this study were all close to zero. Mycobacterium bovis-PPD responsiveness was positively genetically correlated with fat production (0.39) and body condition score (0.36), and negatively correlated with somatic cell score (-0.34) and survival ( 0.62). Hence, selection for increased survival may indirectly reduce susceptibility to M. bovis infection, whereas selection for reduced somatic cell count and increased fat production and body condition score may increase susceptibility to M. bovis infection. PMID- 20965358 TI - Accuracy of direct genomic values derived from imputed single nucleotide polymorphism genotypes in Jersey cattle. AB - The objective of the present study was to evaluate the predictive ability of direct genomic values for economically important dairy traits when genotypes at some single nucleotide polymorphism (SNP) loci were imputed rather than measured directly. Genotypic data consisted of 42,552 SNP genotypes for each of 1,762 Jersey sires. Phenotypic data consisted of predicted transmitting abilities (PTA) for milk yield, protein percentage, and daughter pregnancy rate from May 2006 for 1,446 sires in the training set and from April 2009 for 316 sires in the testing set. The SNP effects were estimated using the Bayesian least absolute selection and shrinkage operator (LASSO) method with data of sires in the training set, and direct genomic values (DGV) for sires in the testing set were computed by multiplying these estimates by corresponding genotype dosages for sires in the testing set. The mean correlation across traits between DGV (before progeny testing) and PTA (after progeny testing) for sires in the testing set was 70.6% when all 42,552 SNP genotypes were used. When genotypes for 93.1, 96.6, 98.3, or 99.1% of loci were masked and subsequently imputed in the testing set, mean correlations across traits between DGV and PTA were 68.5, 64.8, 54.8, or 43.5%, respectively. When genotypes were also masked and imputed for a random 50% of sires in the training set, mean correlations across traits between DGV and PTA were 65.7, 63.2, 53.9, or 49.5%, respectively. Results of this study indicate that if a suitable reference population with high-density genotypes is available, a low-density chip comprising 3,000 equally spaced SNP may provide approximately 95% of the predictive ability observed with the BovineSNP50 Beadchip (Illumina Inc., San Diego, CA) in Jersey cattle. However, if fewer than 1,500 SNP are genotyped, the accuracy of DGV may be limited by errors in the imputed genotypes of selection candidates. PMID- 20965359 TI - Genetic analysis of calf and heifer losses in Danish Holstein. AB - Mortality in dairy cattle is not only relevant with regard to economic losses but also to animal health and welfare. Thus, the aim of this investigation was to explore the genetic background of postnatal mortality in calves and replacement heifers in different age groups until first calving in Danish Holsteins. Records of Danish Holstein heifer calves born in the years 1998 to 2007 were extracted from the Danish Cattle database (Danish Cattle, Skejby, Denmark). The following periods (P) were defined for analyses: P1=d 1 to 30, P2=d 31 to 180, P3=d 181 to 365, P4=d 366 until the day before first calving or a maximum age of 1,200 d if no calving was reported, and the full period P5=d 1 until the day before first calving or a maximum age of 1,200 d if no calving was reported. Records of animals slaughtered or exported within a defined period were set to missing for this and following periods, whereas their records were kept for preceding periods. After further data editing, more than 840,000 calves and heifers born in the years 1998 to 2007 were investigated. Mortality rates were 3.23, 2.66, 0.97, 1.92, and 9.36% for the defined periods P1 to P5, respectively. For the estimation of genetic parameters, linear and threshold sire models were applied. Effects accounted for were the random effects herd * year * season and sire as well as the fixed effects year * month, number of dam's parity (parities >5 were set to 5), calf size, and calving ease. In total, the pedigree consisted of 4,643 sires and 20,821 animals. Heritabilities for the linear model were low, ranging from 0.006 (P3) to 0.042 (P5). Heritabilities estimated by threshold models showed a wider range, from not significantly different from zero for periods with low frequencies to 0.082 for P1. The mortality rate until first calving was higher than the stillbirth rate. Genetic and phenotypic variation seemed to be sufficiently high to genetically improve the trait calf and heifer mortality. Hence, a routine genetic evaluation would be valuable for monitoring and for selecting fitter animals in the Danish Holstein cattle population. PMID- 20965360 TI - Imputation of genotypes from different single nucleotide polymorphism panels in dairy cattle. AB - Imputation of missing genotypes is important to join data from animals genotyped on different single nucleotide polymorphism (SNP) panels. Because of the evolution of available technologies, economical reasons, or coexistence of several products from competing organizations, animals might be genotyped for different SNP chips. Combined analysis of all the data increases accuracy of genomic selection or fine-mapping precision. In the present study, real data from 4,738 Dutch Holstein animals genotyped with custom-made 60K Illumina panels (Illumina, San Diego, CA) were used to mimic imputation of genotypes between 2 SNP panels of approximately 27,500 markers each and with 9,265 SNP markers in common. Imputation efficiency increased with number of reference animals (genotyped for both chips), when animals genotyped on a single chip were included in the training data, with regional higher marker densities, with greater distance to chromosome ends, and with a closer relationship between imputed and reference animals. With 0 to 2,000 animals genotyped for both chips, the mean imputation error rate ranged from 2.774 to 0.415% and accuracy ranged from 0.81 to 0.96. Then, imputation was applied in the Dutch Holstein population to predict alleles from markers of the Illumina Bovine SNP50 chip with markers from a custom made 60K Illumina panel. A cross-validation study performed on 102 bulls indicated that the mean error rate per bull was approximately equal to 1.0%. This study showed the feasibility to impute markers in dairy cattle with the current marker panels and with error rates below 1%. PMID- 20965361 TI - Deterministic models of breeding scheme designs that incorporate genomic selection. AB - A deterministic model to calculate rates of genetic gain and inbreeding was used to compare a range of breeding scheme designs under genomic selection (GS) for a population of 140,000 cows. For most schemes it was assumed that the reliability of genomic breeding values (GEBV) was 0.6 across 4 pathways of selection. In addition, the effect of varying reliability on the ranking of schemes was also investigated. The schemes considered included intense selection in male pathways and genotyping of 1,000 young bulls (GS-Y). This scheme was extended to include selection in females and to include a "worldwide" scheme similar to GS-Y, but 6 times as large and assuming genotypes were freely exchanged between 6 countries. An additional worldwide scheme was modeled where GEBV were available through international genetic evaluations without exchange of genotypes. Finally, a closed nucleus herd that used juvenile in vitro embryo transfer in heifers was modeled so that the generation interval in female pathways was reduced to 1 or 2 yr. When the breeding schemes were compared using a GEBV reliability of 0.6, the rates of genetic gain were between 59 and 130% greater than the rate of genetic gain achieved in progeny testing. This was mainly through reducing the generation interval and increasing selection intensity. Genomic selection of females resulted in a 50% higher rate of genetic gain compared with restricting GS to young bulls only. The annual rates of inbreeding were, in general, 60% lower than with progeny testing, because more sires of bulls and sires of cows were selected, thus increasing the effective population size. The exception was in nucleus breeding schemes that had very short generation intervals, resulting in higher rates of both gain and inbreeding. It is likely that breeding companies will move rapidly to alter their breeding schemes to make use of genomic selection because benefits to the breeding companies and to the industry are considerable. PMID- 20965362 TI - Genetic variation of natural antibodies in milk of Dutch Holstein-Friesian cows. AB - Defense mechanisms of dairy cows against diseases partly rest on their naturally present disease resistance capacity. Natural antibodies (NAb) form a soluble part of the innate immune system, being defined as antibodies circulating in animals without prior intentional antigenic stimulation. Genetic selection on NAb titers in milk, therefore, might improve disease resistance. We estimated genetic parameters of NAb titers binding lipopolysaccharide, lipoteichoic acid (LTA), peptidoglycan, and keyhole limpet hemocyanin, and titers of the NAb isotypes IgG1, IgM, and IgA binding LTA in milk of Dutch Holstein-Friesian heifers. Natural antibody titers were measured in 1 milk sample from each of 1,939 Holstein-Friesian heifers and used for estimating genetic parameters of NAb titers. The data show that phenotypic variation exists among heifers in NAb titers binding lipopolysaccharide, LTA, peptidoglycan, and keyhole limpet hemocyanin, and the NAb isotypes IgG1, IgM, and IgA binding LTA in milk. High genetic correlations among NAb (ranging from 0.45 to 0.99) indicated a common genetic basis for the levels of different NAb in bovine milk. Intra-herd heritability estimates for NAb ranged from 0.10 to 0.53. The results indicated that NAb levels have potential for genetic selection. PMID- 20965363 TI - Recursive relationships between milk yield and somatic cell score of Canadian Holsteins from finite mixture random regression models. AB - Finite mixture, multiple-trait, random regression animal models with recursive links between phenotypes for milk yield and somatic cell score (SCS) on the same test-day were applied to first lactation Canadian Holstein data. All models included fixed herd-test-day effects and fixed regressions within region-age at calving-season of calving classes, and animal additive genetic and permanent environmental regressions with random coefficients. Causal links between phenotypes for milk yield and SCS were fitted separately for records from healthy cows and cows with a putative, subclinical form of mastitis. Bayesian methods via Gibbs sampling were used for the estimation of model parameters. Bayes factors indicated superiority of the model with recursive link from milk to SCS over the reciprocal recursive model and the standard multiple-trait model. Differences between models measured by other, single-trait model comparison criteria (i.e., weighted mean squared error, squared bias, and correlation between observed and expected data) were negligible. Approximately 20% of test-day records were classified as originating from cows with mastitis in recursive mixture models. The proportion of records from cows infected with mastitis was largest at the beginning of lactation. Recursive mixture models exhibited different distributions of data from healthy and infected cows in different parts of lactation. A negative effect of milk to SCS (up to -0.15 score points for every kilogram of milk for healthy cows from 5 to 45 d in milk) was estimated for both mixture components (healthy and infected) in all stages of lactation for the most plausible model. The magnitude of this effect was stronger for healthy cows than for cows infected with mastitis. Different patterns of genetic and environmental correlations between milk and SCS for healthy and infected records were revealed, due to heterogeneity of structural coefficients between mixture components. Estimated breeding values for SCS from the best fitting model for sires of infected daughters were more related to estimated breeding values for the same trait from the regular multiple-trait model than evaluations for sires of mastitis-free cows. PMID- 20965364 TI - Marker imputation with low-density marker panels in Dutch Holstein cattle. AB - The availability of high-density bovine genotyping arrays made implementation of genomic selection possible in dairy cattle. Development of low-density single nucleotide polymorphism (SNP) panels will allow the extension of genomic selection to a larger portion of the population. Prediction of ungenotyped markers, called imputation, is a strategy that allows using the same low-density chips for all traits (and for different breeds). In the present study, we evaluated the accuracy of imputation with low-density genotyping arrays in the Dutch Holstein population. Five different sizes of genotyping arrays were tested, from 384 to 6,000 SNP. According to marker density, the overall allelic imputation error rate obtained with the program DAGPHASE, which relies on linkage disequilibrium and linkage, ranged from 11.7 to 2.0%, and that obtained with the program CHROMIBD, which relies on linkage and the set of all genotyped ancestors, ranged from 10.7 to 3.3%. However, imputation efficiency was influenced by the relationship between low-density and high-density genotyped animals. Animals with both parents genotyped had particularly low imputation error rates: <1% with 1,500 SNP or more. In summary, missing marker alleles can be predicted with 3 to 4% errors with approximately 1 SNP/Mb (approximately 3,000 markers). The CHROMIBD program proved more efficient than DAGPHASE only at lower marker densities or when several genotyped ancestors were available. Future studies are required to measure the effect of these imputation error rates on accuracy of genomic selection with low-density SNP panels. PMID- 20965365 TI - Relationships between milk protein composition, milk protein variants, and cow fertility traits in Dutch Holstein-Friesian cattle. AB - Selective breeding can change milk protein composition to improve the manufacturing properties of milk. However, the effects of such breeding strategies on other economically important traits should be investigated before implementation. The objectives of this study were to examine the association between cow fertility traits and (1) milk protein composition and (2) milk protein variants (beta-lactoglobulin, beta-casein, kappa-casein, and beta-kappa casein) in commercial Dutch Holstein-Friesian cattle. Data on 1,644 first lactation cows were analyzed by fitting linear mixed models. Greater relative concentration of alpha(S1)-casein within total milk protein had a positive phenotypic relationship with nonreturn rates and calving rate after first insemination. Furthermore, results showed virtually no significant relationship between cow fertility and concentration of other milk proteins or milk protein variants. Results of this study can be used to assess the correlated effects of breeding for improved milk protein composition on reproduction, thereby allowing for better evaluation of breeding programs before implementation. Our findings suggest that selecting cows based on milk protein composition or milk protein variants for improved manufacturing properties would have no negative influence on reproductive performance. PMID- 20965366 TI - Digesters and demographics: identifying support for anaerobic digesters on dairy farms. AB - The dairy industry in the United States is amidst a long-running trend toward fewer, larger dairy farms. This development has created a backlash in some communities over concerns such as odor, waste management, and environmental degradation. Separately, anaerobic digestion has advanced as a waste management technology that potentially offers solutions to some of these issues, providing odor control and a combustible biogas among other things. These digesters require significant capital investments. Voluntary consumer premiums for the renewable energy produced have been used in some instances as a means to move adoption of such systems toward financial feasibility. This project employed a survey to measure Ohio consumers' willingness to pay a premium for renewable energy produced by anaerobic digesters on dairy farms. Cluster analysis was used to segment consumers by willingness to pay, age, education, income, self-identified political inclination, and a composite variable that served as a proxy for respondents' environmental stewardship. Four distinctive groups emerged from the data. Older, less educated respondents were found to have the least amount of support for digesters on dairy farms, whereas politically liberal, environmentally proactive respondents demonstrated the strongest support. Well educated, affluent respondents and young respondents fell between these 2 groups. Most large dairy farms are generally met with fairly negative responses from their local communities; in contrast, this research finds some popular support for anaerobic digestion technology. Going forward, establishing a positive link between support for anaerobic digesters and for their use on large dairies could open up a new route for less-contested large dairy farm developments. Evaluation of community demographics could become an important part of finding an optimal location for a large dairy farm. PMID- 20965367 TI - Evaluation of calf milk pasteurization systems on 6 Pennsylvania dairy farms. AB - Waste milk has been fed to calves for many years, but concerns with bacterial contamination as well as possible transmission of diseases have discouraged widespread use of this feed. Pasteurization of waste milk is one option to reduce management risk while utilizing a valuable, low-cost, liquid feed source for calves. However, many farms currently pasteurizing waste milk lack a system to adequately monitor the efficiency of the process. A study was carried out to evaluate 6 on-farm pasteurization systems, including high-temperature, short-time pasteurizers and low-temperature, batch pasteurizers. Milk samples were taken pre and postpasteurization as well as from the calf buckets and immediately frozen for later bacterial culture. Samples were collected twice daily for 15 d. Milk samples were examined for standard plate count (SPC), coagulase-negative staphylococci count, environmental streptococci count, coliform count, gram negative noncoliform count, Streptococcus agalactiae count, and Staphylococcus aureus count. Before pasteurization, 68% of the samples had SPC <20,000 cfu/mL, and 39% of samples contained <100 cfu/mL of coliform bacteria. After pasteurization, 96% of samples had SPC <20,000 cfu/mL, and 92% had coliform counts <100 cfu/mL. Bacteria counts were significantly reduced by pasteurization, and pasteurized milk contained acceptable numbers of bacteria in >90% of samples. These results indicate that pasteurization can be very effective in lowering bacterial contamination of milk. However, bacteria numbers significantly increased after pasteurization and, in some cases, bacteria counts in milk fed to calves were similar to prepasteurization levels. Milk handling after pasteurization was identified as an important issue on the farms studied. PMID- 20965368 TI - [Highlights of the 60th meeting of the French National Society of Internal Medicine]. PMID- 20965369 TI - [Immunoglobulins: multiple potential therapeutic proteins for use in autoimmune disorders]. PMID- 20965370 TI - [Prothrombin complex concentrate or treatment of a iatrogenic disease]. PMID- 20965371 TI - [Albumin: more than a volume expander?]. PMID- 20965372 TI - [Blood transfusions]. PMID- 20965373 TI - [The division and the investments in clinical research of various blood derivative products at Octapharma]. PMID- 20965374 TI - [Immunoglobulins: multiple potential therapeutic proteins for use in immune deficits]. PMID- 20965375 TI - Vaccination deep into a pandemic wave potential mechanisms for a "third wave" and the impact of vaccination. AB - BACKGROUND: In December 2009, when the H1N1 influenza pandemic appeared to be subsiding, public health officials and unvaccinated individuals faced the question of whether continued H1N1 immunization was still worthwhile. PURPOSE: To delineate what combinations of possible mechanisms could generate a third pandemic wave and then explore whether vaccinating the population at different rates and times would mitigate the wave. METHODS: As part of ongoing work with the Office of the Assistant Secretary for Preparedness and Response at the USDHHS during the H1N1 influenza pandemic, the University of Pittsburgh Models of Infectious Disease Agent Study team employed an agent-based computer simulation model of the Washington DC metropolitan region to delineate what mechanisms could generate a "third pandemic wave" and explored whether vaccinating the population at different rates and times would mitigate the wave. This model included explicit representations of the region's individuals, school systems, workplaces/commutes, households, and communities. RESULTS: Three mechanisms were identified that could cause a third pandemic wave; substantially increased viral transmissibility from seasonal forcing (changing influenza transmission with changing environmental conditions, i.e., seasons) and progressive viral adaptation; an immune escape variant; and changes in social mixing from holiday school closures. Implementing vaccination for these mechanisms, even during the down-slope of the fall epidemic wave, significantly mitigated the third wave. Scenarios showed the gains from initiating vaccination earlier, increasing the speed of vaccination, and prioritizing population subgroups based on Advisory Committee on Immunization Practices recommendations. CONCLUSIONS: Additional waves in an epidemic can be mitigated by vaccination even when an epidemic appears to be waning. PMID- 20965376 TI - Knowledge and adoption of community mitigation efforts in Mexico during the 2009 H1N1 pandemic. AB - BACKGROUND: The public's ability and willingness to adopt community mitigation efforts during a pandemic are debated in the literature. PURPOSE: Awareness and adoption of community mitigation efforts in Mexico during the 2009 pandemic influenza A (H1N1) (pH1N1) outbreak were measured to evaluate if the population received, understood, and acted on public health messages. METHODS: A cross sectional representative household survey in Mexico City; San Luis Potosi (high case ratio); and Queretaro (low case ratio) was conducted in May and June 2009. Accounting for the complex survey design, percentages and 95% CI for answers to all questions were generated and compared based on living inside or outside Mexico City, high versus low prevalence of infection in the community, and perceived severity and knowledge of the virus. RESULTS: Greater than 90% of respondents received community mitigation messages and adopted one or more community mitigation efforts. There were few differences among cities. Respondents reported high cost of masks, soaps, and gels as barriers to community mitigation-effort adoption. Nearly one fifth of respondents, disproportionally from the lower socioeconomic tertile, found some messages confusing. Half of all households reported a negative economic impact resulting from the outbreak. CONCLUSIONS: Mexico's community mitigation campaign reached the majority of the population in three surveyed cities. Confusion regarding messages and economic barriers to community mitigation-effort adoption were sometimes reported. PMID- 20965377 TI - The economic implications of influenza vaccination for adults with asthma. AB - BACKGROUND: Influenza vaccination is recommended for adults with asthma. PURPOSE: This study estimates the effect of influenza vaccination on utilization of medical services and expenditures for acute and chronic respiratory conditions (ACRC) among adults with asthma. METHODS: The sample was adults aged >=18 years self-reporting asthma in the 2003 through 2006 Medical Expenditure Panel Survey (MEPS), covering four complete influenza seasons. The dependent variables were indicators for any ACRC claims within service category and ACRC expenditures. The main independent variable was an indicator of influenza vaccination. To control for selection bias in the observational data, a nonlinear instrumental variables approach was used. The instruments were indicators for influenza in the first year of MEPS and vaccination in the year prior to MEPS. Data were analyzed in 2009. RESULTS: Adults with asthma vaccinated for influenza were 4.4 percentage points less likely to have an inpatient stay due to ACRC (95% CI = -10.8, -1.0). Influenza vaccination was associated with a $492 decrease (95% CI = -$1591, -$56) in annual ACRC nonprescription expenditures, a $224 increase (95% CI = $70, $360) in annual ACRC prescription expenditures, and a nonsignificant $216 decrease (95% CI = -$854, $248) in overall annual ACRC expenditures. CONCLUSIONS: Although there was no evidence that vaccination reduced overall ACRC expenditures, the study suggests that efforts to increase the percentage of adults with asthma who are vaccinated may bring substantial benefits in terms of reducing the prevalence and costs of hospitalization although raising prescription medication costs, possibly through improvement in compliance. PMID- 20965378 TI - U.S. primary care physicians' lung cancer screening beliefs and recommendations. AB - BACKGROUND: No high-quality study to date has shown that screening reduces lung cancer mortality, and expert groups do not recommend screening for asymptomatic individuals. Nevertheless, lung cancer screening tests are available in the U.S., and primary care physicians (PCPs) may have a role in recommending them to patients. PURPOSE: This study describes U.S. PCPs' beliefs about and recommendations for lung cancer screening and examines characteristics of PCPs who recommend screening. METHODS: A nationally representative survey of practicing PCPs was conducted in 2006-2007. Mailed questionnaires were used to assess PCPs' beliefs about lung cancer screening guidelines and the effectiveness of screening tests and to determine whether PCPs would recommend screening for asymptomatic patients. Data were analyzed in 2009. RESULTS: Nine hundred sixty two PCPs completed the survey (absolute response rate=70.6%; cooperation rate=76.8%). One quarter said that major guidelines support lung cancer screening. Two thirds said that low-radiation dose spiral computed tomography (LDCT) screening is very or somewhat effective in reducing lung cancer mortality in current smokers; LDCT was perceived as more effective than chest x-ray or sputum cytology. Responding to vignettes describing asymptomatic patients of varying smoking exposure, 67% of PCPs recommended lung cancer screening for at least one of the vignettes. Most PCPs recommending screening said they would use chest x-ray; up to 26% would use LDCT. In adjusted analyses, PCPs' beliefs and practice style were strongly associated with their lung cancer screening recommendations. CONCLUSIONS: Many PCPs' lung cancer screening beliefs and recommendations are inconsistent with current evidence and guidelines. Provider education regarding the evidence base and guideline content of lung cancer screening is indicated. PMID- 20965379 TI - New moves-preventing weight-related problems in adolescent girls a group randomized study. AB - BACKGROUND: Weight-related problems are prevalent in adolescent girls. PURPOSE: To evaluate New Moves, a school-based program aimed at preventing weight-related problems in adolescent girls. DESIGN: School-based group-randomized controlled design. SETTING/PARTICIPANTS: 356 girls (mean age=15.8+/-1.2 years) from six intervention and six control high schools. More than 75% of the girls were racial/ethnic minorities and 46% were overweight or obese. Data were collected in 2007-2009 and analyzed in 2009-2010. INTERVENTION: An all-girls physical education class, supplemented with nutrition and self-empowerment components, individual sessions using motivational interviewing, lunch meetings, and parent outreach. MAIN OUTCOME MEASURES: Percentage body fat, BMI, physical activity, sedentary activity, dietary intake, eating patterns, unhealthy weight control behaviors, and body/self-image. RESULTS: New Moves did not lead to significant changes in the girls' percentage body fat or BMI but improvements were seen for sedentary activity, eating patterns, unhealthy weight control behaviors, and body/self-image. For example, in comparison to control girls, at 9-month follow up, intervention girls decreased their sedentary behaviors by approximately one 30-minute block a day (p=0.050); girls increased their portion control behaviors (p=0.014); the percentage of girls using unhealthy weight control behaviors decreased by 13.7% (p=0.021); and improvements were seen in body image (p=0.045) and self-worth (p=0.031). Additionally, intervention girls reported more support by friends, teachers, and families for healthy eating and physical activity. CONCLUSIONS: New Moves provides a model for addressing the broad spectrum of weight-related problems among adolescent girls. Further work is needed to enhance the effectiveness of interventions to improve weight status of youth. PMID- 20965380 TI - Age-related changes in types and contexts of physical activity in middle school girls. AB - BACKGROUND: Because girls are less physically active than boys, it is important to understand the types of activities preferred by girls, and changes in those preferences over time, in order to design effective physical activity interventions. PURPOSE: To describe developmental trends in participation in specific forms of physical activity in 6th- and 8th-grade girls. METHODS: Data for this study are from the Trial of Activity for Adolescent Girls. Self-reported physical activity, anthropometric, and demographic data were collected from random cross sections of 6th-grade girls in 36 middle schools in six U.S. communities. The same data were collected 2 years later from random cross sections of 8th-grade girls, as well as in previously measured 6th-grade girls who remained in the schools. Analyses were conducted with SAS using mixed-model ANOVAs to determine differences between 6th- and 8th-grade girls. Data were collected in 2002-2003 and 2004-2005 and analyzed in 2008-2009. RESULTS: The top physical activities reported by 6th- and 8th-grade girls were similar. Of the top 13 activities reported by 6th- or 8th-grade girls, 8th-grade girls reported participating in more 30-minute blocks for ten of the activities and were more likely to report participating as part of an organized program. CONCLUSIONS: The activities reported by 6th- and 8th-grade girls were similar, but the way they participated in them changed from 6th to 8th grade. Eighth-grade girls were more likely to participate in activities that are often part of school-based team sports, and the time of participation in these activities was greater. Interventions to increase physical activity in adolescent girls should be informed by the factors that influence their participation in organized school sports programs and community-based activities that promote physical activity. PMID- 20965381 TI - Psychological well-being, cardiorespiratory fitness, and long-term survival. AB - BACKGROUND: Psychological well-being is associated with mortality/survival. Although cardiorespiratory fitness (CRF) is one of the strongest predictors of mortality, studies examining the relationship between well-being and survival seldom account for the possible effects of CRF. PURPOSE: This study examined the independent associations of psychological well-being components (low level of negative emotion and high level of positive emotion) and CRF, as well as their combined effects, with survival. METHODS: Participants (N=4888) were examined in 1988-1997 and followed up for a median period of ~15 years (212 deaths, 4.3%). CRF was assessed by a maximal exercise test on a treadmill. Low-level negative emotion was defined as the minimum score of the negative emotion subscale of the CES-D scale and high-level positive emotion as the maximum score of the positive emotion subscale. Results are presented as hazard ratios (95% CIs). Data were analyzed in 2009. RESULTS: After adjustment for a set of established risk factors, men and women with low levels of negative emotion had lower risk of death than those with higher levels of negative emotion, 0.66 (95% CI=0.50, 0.87). The association persisted after additional adjustment for CRF and positive emotion. High level of positive emotion was not associated with survival. A high level of CRF independently predicted lower risk of death, 0.54 (95% CI=0.37, 0.79), compared to a low level of CRF. The risk of death in participants with both a low level of negative emotion and a high level of CRF was 0.37 (95% CI=0.22, 0.63), compared to their peers with higher levels of negative emotion/low levels of CRF. CONCLUSIONS: Low levels of negative emotion and high levels of CRF are independent predictors of long-term survival in men and women. A strong combined effect was observed, as individuals with both a low level of negative emotion and a high level of CRF had a 63% lower risk of premature death than those with higher levels of negative emotion and a low level of CRF. PMID- 20965382 TI - Adoption of policies to treat tobacco dependence in U.S. medical groups. AB - BACKGROUND: There remains an ongoing need to reduce tobacco use in the U.S. Physician organizations, such as medical groups, can support healthcare providers to be more effective in their delivery of tobacco cessation by adopting practices recommended in the Public Health Service Clinical Practice Guideline for Treating Tobacco Use and Dependence (PHS Guideline). PURPOSE: To document the extent to which activities to reduce tobacco use, as recommended in the PHS Guideline as system-level interventions, are provided within large medical groups in the U.S. METHODS: During 2006-2007, data were collected on 339 medical groups operating in the U.S., with 20 or more physicians treating at least one of four chronic conditions. Organizations were surveyed regarding activities to reduce tobacco use as recommended in the PHS Guideline as system-level interventions (i.e., tobacco-use status documentation, policies to promote provider interventions, and staff dedicated to treating tobacco dependence). Between 2008 and 2009, bivariate associations and multivariate logistic regression models assessed the relationship of organizational characteristics and external incentives with adoption of systems strategies for treating tobacco dependence. RESULTS: Nearly 83% of medical groups with 20 or more physicians operating in the U.S. in 2006 2007 have adopted one or more strategies recommended as effective to support the treatment of tobacco dependence. However, only 5.6% of medical groups engage in all eight tobacco control activities examined in this study. The two factors that were associated most consistently with medical group policies to treat tobacco dependence were the patient-centeredness of the organization and participation in a quality demonstration program. CONCLUSIONS: There is much room for improvement in increasing medical group adoption of systems strategies to reduce tobacco use. The findings in this paper suggest recommendations to achieve these improvements. PMID- 20965383 TI - The bikeability and walkability evaluation table reliability and application. AB - BACKGROUND: With increased research on the influence of the built environment on physical activity, methods of assessing environmental attributes have to be developed according to different research requirements. PURPOSE: The purpose of this paper is to describe the approach to develop and test a simple and efficient audit tool to get a quick overview of environmental characteristics along a route or in a neighborhood. METHODS: Based on a selection of existing audit instruments, the Bikeability and Walkability Evaluation Table (BiWET) was developed in 2007 at the University of Graz, Austria. The BiWET is designed for fast assessment of 15 predetermined characteristics of 10-m street segments. Inter-rater and Intra-rater reliability was calculated in 2008 based on the auditing data of 152 km of commuting routes of city dwellers in 2007. Observer agreement was used as statistical parameter for reliability. RESULTS: The mean auditing pace was 16.4 minutes/km. The mean test-retest accordance was 95%, and the inter-rater agreement was 89%. CONCLUSIONS: The BiWET is a reliable and time efficient audit instrument to determine accurately and relatively quickly the physical characteristics of an area or route, which is potentially useful for the study of the relationship between the built environment and physical activity behavior. PMID- 20965384 TI - Walk scoreTM as a global estimate of neighborhood walkability. AB - BACKGROUND: Walk Score recently has been demonstrated as a valid and reliable tool for estimating access to nearby facilities, a critical component of the physical activity environment. It has not yet been determined whether Walk Score relates to other critical components of the physical activity environment, including street connectivity, access to public transit, residential density, and crime. PURPOSE: The aim of this study was to explore the relationship between Walk Score and objective/subjective measures of the physical activity environment. METHODS: Walk Scores were calculated for residential addresses of 296 participants of two RCTs (2006-2009). Street connectivity, residential density, access to public transit provisions, and crime were objectively measured (GIS) and cross-referenced with Walk Scores and participant's perceptions of the environment (e.g., perceived crime, access to physical activity facilities, perceived neighborhood walkability). Pairwise Pearson correlations were calculated in March 2010 to compare Walk Score to subjective/objective measures of neighborhood walkability. RESULTS: Significant positive correlations were identified between Walk Score and several objective (e.g., street connectivity, residential density and access to public transit provisions) and subjective (e.g., summed score of the physical activity environment) measures of the physical activity environment. However, positive correlations also were observed between Walk Score and crime. CONCLUSIONS: Collectively, these findings support Walk Score as a free, easy-to-use, and quick proxy of neighborhood density and access to nearby amenities. However, positive associations between Walk Score and reported crime highlight a limitation of Walk Score and warrant caution of its use. PMID- 20965385 TI - Young adult eating and food-purchasing patterns food store location and residential proximity. AB - BACKGROUND: Young adulthood is a critical age for weight gain, yet scant research has examined modifiable contextual influences on weight that could inform age appropriate interventions. PURPOSE: The aims of this research included describing where young adults eat and purchase food, including distance from home, and estimating the percentage of eating/purchasing locations contained within GIS generated buffers traditionally used in research. METHODS: Forty-eight participants (aged 18-23 years, n=27 women) represented diverse lifestyle groups. Participants logged characteristics of all eating/drinking occasions (including location) occurring over 7 days (n=1237) using PDAs. In addition, they recorded addresses for stores where they purchased food to bring home. Using GIS, estimates were made of distances between participants' homes and eating/purchasing locations. Data collection occurred in 2008-2009 and data analysis occurred in 2010. RESULTS: Among participants living independently or with family (n=36), 59.1% of eating occasions were at home. Away-from-home eating locations averaged 6.7 miles from home; food-shopping locations averaged 3.1 miles from home. Only 12% of away-from-home eating occasions fell within -mile residential buffers, versus 17% within 1 mile and 34% within 2 miles. In addition, 12%, 19%, and 58% of shopping trips fell within these buffers, respectively. Results were similar for participants residing in dormitories. CONCLUSIONS: Young adults often purchase and eat food outside of commonly used GIS-generated buffers around their homes. This suggests the need for a broader understanding of their food environments. PMID- 20965386 TI - Symptoms of heat illness among Latino farm workers in North Carolina. AB - BACKGROUND: Symptoms of occupational heat illness provide an early warning that workers are in potentially life-threatening environmental conditions. PURPOSE: This analysis was designed to assess the extent to which strategies to reduce the health impact of extreme heat were associated with the prevalence of heat illness among Latino farm workers. METHODS: Between June and September 2009, a total of 300 Latino men and women participated in a cross-sectional survey about farm worker health. Participants reported whether they were employed through the H-2A temporary agricultural worker program and whether they had ever worked in conditions of extreme heat during their work in the U.S. agricultural industry. Workers who had worked in extreme heat also responded to questions about selected activities and behaviors and whether they experienced symptoms of heat illness. Data analysis was conducted in 2009 to assess associations of altering work hours and activities, drinking more water, resting in shaded areas, and going to air conditioned places during or after work, with the prevalence of symptoms of heat illness among H-2A and non-H-2A workers. RESULTS: Working in extreme heat was reported by 281 respondents (94%), among whom 112 (40%) reported symptoms of heat illness. Changes in work hours and activities during hot conditions were associated with a lower prevalence of heat illness among H-2A workers but not among non-H-2A workers. CONCLUSIONS: These findings suggest the need to improve the understanding of working conditions for farm workers and to assess strategies to reduce agricultural workers' environmental heat exposure. PMID- 20965388 TI - Male circumcision and HIV prevention insufficient evidence and neglected external validity. PMID- 20965387 TI - Durable improvements in prostate cancer screening from online spaced education a randomized controlled trial. AB - CONTEXT: Prostate cancer screening with prostate-specific antigen (PSA) is frequently performed, counter to clinical practice guidelines. BACKGROUND: It was hypothesized that an e-mail-based intervention termed "spaced education" could reduce clinicians' inappropriate screening for prostate cancer. DESIGN: The study was conducted as an RCT. SETTING/PARTICIPANTS: The study involved 95 primary care clinicians in eight Veterans Affairs medical centers from January 2007 to February 2009. INTERVENTION: Participants were randomized into two cohorts: spaced education clinicians received four isomorphic cycles of nine e-mails over 36 weeks (zero to two e-mails per week), whereas control clinicians received no intervention. Each e-mail presented a clinical scenario and asked whether it was appropriate to obtain a PSA test. Participants received immediate feedback after submitting their answers. MAIN OUTCOME MEASURES: The primary outcome was the number and percentage of inappropriate PSA screening tests ordered. Inappropriate testing was defined as use of PSA for prostate cancer screening in patients aged >76 or <40 years. Appropriateness of screening was dichotomized based on patient age at time of screening. Patients with PSA testing for non-screening reasons were excluded using a validated protocol. Logistic regression with adjustment for patient clustering by clinician was performed. Analyses were conducted in 2009. RESULTS: During the intervention period (Weeks 1-36), clinicians receiving spaced education e-mails ordered significantly fewer inappropriate PSA screening tests than control clinicians (10.5% vs 14.2%, p=0.041). Over the 72-week period following the intervention (Weeks 37-108), spaced education clinicians continued to order fewer inappropriate tests compared to controls (7.8% vs 13.1%, respectively, p=0.011), representing a 40% relative reduction in inappropriate screening. CONCLUSIONS: Spaced education durably improves the prostate cancer screening behaviors of clinicians and represents a promising new methodology to improve patient care across healthcare systems. PMID- 20965389 TI - U.S. military public health surveillance and response to pandemic influenza A (H1N1). PMID- 20965390 TI - Community mitigation of disease outbreaks health communication perspectives. PMID- 20965391 TI - Does cost savings mean cost effective? PMID- 20965392 TI - Epidemiology of invasive aspergillosis and risk factors in non neutropaenic patients. AB - INTRODUCTION: Invasive aspergillosis is a major cause of mortality in allogeneic bone marrow transplant recipients and patients treated for blood malignancies. The diagnostic tools, treatments and preventive strategies, essentially developed for neutropaenic patients, have not been assessed in populations whose immune systems are considered to be competent. STATE OF THE ART: Beside the standard picture of chronic Aspergillus infection, the incidence of invasive aspergillosis is increasing in non neutropaenic patients, such as those with chronic lung diseases or systemic disease treated with long-term immunosuppressive drugs and solid organ transplant recipients. This study reviews the specific features of invasive aspergillosis in non neutropaenic subjects (NNS) and discusses the value of the diagnostic tools and treatment in this population. PROSPECTS: A better understanding of the pathophysiology and the epidemiological characteristics of invasive aspergillosis would provide a means of adapting the staging and classification of the disease for NNS. CONCLUSIONS: Invasive aspergillosis is under diagnosed in NNS who may already be colonised when they receive immunosuppressive treatment; this can lead to an adverse outcome in patients who are considered to be a moderate risk population. PMID- 20965393 TI - Contribution of positron emission tomography in pleural disease. AB - INTRODUCTION: Positron emission tomography (PET) now plays a clear role in oncology, especially in chest tumours. We discuss the value of metabolic imaging in characterising pleural pathology in the light of our own experience and review the literature. BACKGROUND: PET is particularly useful in characterising malignant pleural pathologies and is a factor of prognosis in mesothelioma. Metabolic imaging also provides clinical information for staging lung cancer, in researching the primary tumour in metastatic pleurisy and in monitoring chronic or recurrent pleural pathologies. CONCLUSIONS: PET should therefore be considered as a useful tool in the diagnosis of liquid or solid pleural pathologies. PMID- 20965394 TI - Inhaled insulin: a model for pulmonary systemic absorption? AB - The European Union recently approved a form of insulin intended to be inhaled. This innovative presentation has the potential to partially or completely replace the injections and thus facilitate starting insulin therapy which is considered with apprehension and often differed. On this occasion, we reviewed the issues raised by this pulmonary route for systemic absorption (anatomical and cytological limits, cellular mechanisms, relevant physical parameters, facilitating chemical cofactors, role of tobacco smoking and of common respiratory diseases). The pharmacokinetics of inhaled and injectable insulins are comparable, apart from an appreciably faster absorption of the former, and both show the same intra-individual variability. The total bioavailability is definitely lower with the inhaled route but is notably increased in smokers. These characteristics can vary according to the inhalation system used. A frequent induced cough, the increase in circulating anti-insulin antibodies, and a potentially higher cost are not really determining obstacles. The indications will have to be clearly specified and the long-term innocuousness of repeated inhalation of such a mitogen, especially in children and former smokers, remains to be fully proven. PMID- 20965395 TI - Respiratory involvement in systemic lupus erythematosus. AB - Respiratory involvement in systemic lupus erythematosus (SLE) is not as well known as the cutaneous, rheumatological and renal manifestations. It occurs frequently but the diagnosis may be difficult because of the heterogeneity of the anatomical and clinical presentations. A precise diagnosis is crucial as new immunosuppressive drugs have considerably improved the prognosis. The pathology involves genetic, endocrine, environmental, pharmacological and immunological factors with a cytotoxic reaction of auto-antibodies against complement, a circulating immune complex reaction and a hyperactivity of B lymphocytes. Respiratory involvement in SLE can be classified in five groups based on the anatomy: pleural involvement, infiltrating pneumonia (lymphoid interstitial pneumonia, bronchiolitis obliterans with organizing pneumonia and acute lupus pneumonitis), airways involvement (upper airways, bronchi), vascular involvement (pulmonary hypertension, acute reversible hypoxaemia, alveolar haemorrhage, and antiphospholipid syndrome), muscular and diaphragmatic involvement (shrinking lung syndrome).Treatment is based, depending upon the type of involvement and its severity, on steroids which may be combined with immunosuppressants and plasmapherisis. PMID- 20965396 TI - Pulmonary arterial hypertension in women. AB - INTRODUCTION: Pulmonary arterial hypertension (PAH) is a rare condition characterized by sustained elevation in pulmonary arterial resistance leading to right heart failure. BACKGROUND: PAH afflicts predominantly women. Echocardiography is the initial investigation of choice for non-invasive detection of PAH but right-heart catheterization is necessary to confirm the diagnosis. Conventional treatment includes non-specific drugs (warfarin, diuretics, oxygen). The endothelin-1 receptor antagonist bosentan, the phosphodiesterase-5 inhibitor sildenafil, and prostanoids have been shown to improve symptoms, exercise capacity and haemodynamics. Intravenous prostacyclin is the first-line treatment for the most severely affected patients. Despite the most modern treatment, the overall mortality rate of pregnant women with severe PAH remains high. Therefore, pregnancy is contraindicated in women with PAH and an effective method of contraception is recommended in women of childbearing age. Therapeutic abortion should be offered, particularly when early deterioration occurs. If this option is not accepted, intravenous prostacyclin should be considered promptly. VIEWPOINTS AND CONCLUSION: Recent advances in the management of PAH have markedly improved prognosis and have resulted in more women of childbearing age considering pregnancy. A multidisciplinary approach should give new insights into cardiopulmonary, obstetric and anaesthetic management during pregnancy, delivery and the postpartum period. PMID- 20965397 TI - [Flexible fiberoptic bronchoscope: a new instrument in thoracic surgery?]. PMID- 20965398 TI - [Fighting air pollution: a possible return on investment]. PMID- 20965399 TI - [On the frontier between respiratory and intensive care medicine: for an optimised care of patients between two disciplines]. PMID- 20965400 TI - [Lung transplantation: lessons from the past and advances to come]. PMID- 20965401 TI - [Chronic obstructive pulmonary disease (COPD) in the elderly]. AB - Chronic obstructive pulmonary disease (COPD) is a chronic disease characterized by incompletely reversible airflow limitation, measured by a decrease of FEV(1)/FVC ratio. International consensus does not agree on a single threshold for this ratio, which can define airflow obstruction. Although the prevalence of COPD in the elderly population varies according to the definition used, it definitely increases with age and could reach 15% in those over 65 years of age. Therefore, ageing of the population should result in increased prevalence and socioeconomical costs of COPD during coming years. In France, diagnosis of COPD in the elderly is difficult, late and insufficient. Management, which has the same goals as in younger populations, has to be global and coordinated. Some points should be considered with particular attention considering the cumulative risks related on the one hand to COPD and on the other to ageing: pharmacological side-effects, decreased physical and social autonomy, nutritional impairment, comorbidities. Given the lack of specific data in elderly populations, pharmacological indications are generally considered to be the same as in younger populations, but some additional precautionary measures are necessary. Pulmonary rehabilitation seems to be beneficial at any age. Palliative care comes up against important difficulties: an indefinite beginning of the palliative stage in COPD; insufficient palliative care resources; insufficient communication; insufficient utilization of palliative care resources. Global COPD management in elderly requires coordination, best reached in health care network organizations involving medical and/or social professionals. PMID- 20965402 TI - [Initiation of domiciliary non-invasive ventilation: proposals of the Casavni working party]. AB - INTRODUCTION: In France, there are no good practice guidelines or a regulatory framework for the initiation of long term non-invasive ventilation (NIV). METHODS: The ANTADIR federation set up a working party to examine the feasibility of new methods of initiation of NIV and to consider the possibility of initiation in the home. Two problems were considered: (1) logistical and technical requirements, (2) the responsibilities of the professions involved and the regulatory framework. RESULTS: Clinical effectiveness, improvement in quality of life and adherence to treatment are similar whether NIV is initiated in hospital or at home. Domiciliary management is possible only when the patient is clinically stable. It should be undertaken by a competent physician or, on medical prescription, by a physiotherapist. A nurse or trained technician may check the apparatus but should not initiate NIV alone. Installation of domiciliary NIV should be considered under the following conditions: patients with spontaneous ventilation, availability of urgent assistance and appropriate family support. Close surveillance of the quality of ventilation is necessary, whether in hospital or at home. For the initiation of domiciliary NIV each professional involved needs a clear understanding of his/her role. CONCLUSION: Academic societies should propose good practice guidelines for the initiation of NIV. Domiciliary initiation is possible under certain conditions and the results are as good as those obtained in hospital. PMID- 20965403 TI - [Asthma and Mycoplasma pneumoniae]. AB - INTRODUCTION: A growing body of basic and clinical science implicates Mycoplasma pneumonia in asthma, but its exact contribution to asthma development, exacerbation and persistence is as yet unclear. STATE OF THE ART: M. pneumoniae infection, with the induction of bronchial hyperresponsiveness, seems to be a precipitating factor for asthma development in predisposed subjects. M. pneumoniae has been seen both in acute exacerbation (18-20%) and in chronically infected adults with stable asthma, where it may be enhancing chronic airway inflammation. PERSPECTIVES: If M. pneumoniae plays a role in the development or progression of asthma, its eradication might influence the clinical course of the disease and improve symptoms. Macrolide treatment, with antimicrobial and anti inflammatory properties, could have a place in the management of asthma, especially steroid-dependent asthma. CONCLUSIONS: M. pneumoniae infection seems to be important in asthma pathogenesis and the clinical course of the disease. Difficulty in detecting the pathogen complicates investigations. Ongoing research will further determine the place of macrolide antibiotics in asthma management. PMID- 20965404 TI - [Exercise-induced bronchoconstriction in non-asthmatic athletes]. AB - INTRODUCTION: A new clinical entity, exercise-induced bronchoconstriction (EIB), has been recently defined which describes bronchoconstriction occurring in association with exercise in susceptible non-asthmatic persons. STATE OF ART: There is considerable evidence that the pathogenesis of this condition is related to airway injury, due to prolonged hyperventilation and aggressive environmental factors. If the objective diagnostic tests are identical for the diagnosis of exercise induced asthma and EIB, the diagnoses are established differently, according to the high sensitivity of provocation by exercise "in the field" or the eucapnic voluntary hyperventilation provocation test. PERSPECTIVES: Current pharmacological treatment is based upon the inhalation of beta2-agonists prior to exercise, but to be granted permission to use them, athletes are required to provide documentation of objective evidence of EIB. Therefore, the diagnostic pathway in athletes is essential and respiratory physicians need to know the specific features of this new clinical entity. CONCLUSIONS: EIB distinct from the presence of asthma is prevalent in elite athletes and its determinants should be well known by their health care providers to assure an optimal management of this peculiar disease, in respect to drug doping regulations. PMID- 20965405 TI - [Consequences of atmospheric pollution fluctuations in patients with COPD]. AB - INTRODUCTION: Fluctuations in atmospheric pollution are responsible for an important morbidity and mortality in the patients suffering from chronic obstructive pulmonary disease (COPD). BACKGROUND: Epidemiological studies show a significant increase in the mortality and hospitalization rates in COPD patients in relation to moderate increases in atmospheric pollution. In vitro and in vivo studies demonstrate a pro-inflammatory role and an oxidative toxicity of atmospheric particles and secondary morphological and functional changes in the respiratory epithelium and the immune system. An excess of particulate matter, ozone, NO(2), SO(2) and CO is directly correlated to the number of episodes of acute respiratory failure in different countries all over the world. The mechanisms implicated are complex and variable, dependent on the different pollutant agents, climatic variations and inter-individual susceptibility. VIEWPOINT: Further experimental studies are necessary in order to clarify our fundamental understanding and, alongside better control of air quality, to reduce short-term respiratory complications. CONCLUSION: The consequences of atmospheric pollution fluctuations on the exacerbation rate and therefore on the morbidity and mortality of patients with COPD emphasize the importance of preventive environmental management in the field of public health. PMID- 20965406 TI - [Relationships between indoor allergens, sensitization, and allergic asthma and rhinitis symptoms]. AB - INTRODUCTION: There is a strong and consistent association between immediate hypersensitivity, asthma and exposure to allergens. However, the role that the inhaled allergen plays and the timing of events related to sensitization are still controversial. BACKGROUND: Information obtained by studies of the follow-up of cohorts underlines the fact that there is no continuum between specific IgE responses and the development of childhood asthma. Allergic rhinitis and asthma result from a complex and multifactorial interaction between genetic factors, exposure to allergens, and many biological or chemical co-factors. However, when the child is exposed to an allergen, sensitization to the allergen is a risk factor for childhood asthma and severity of the disease. CONCLUSIONS AND VIEWPOINTS: Despite numerous epidemiological studies, the association and links between atopy, allergens, environment, sensitization and allergic rhinitis and/or asthma remain difficult to evaluate and poorly understood. Complementary studies are also necessary for the standardization of therapeutic strategies. PMID- 20965407 TI - [Results of lung transplantation]. AB - INTRODUCTION: Lung transplantation has experienced an increasing expansion with a significant improvement in results with the passage of time. Evaluation of these results consists of several domains: survival, function, quality of life and cost effectiveness. BACKGROUND: The success of lung transplantation is confirmed by a median survival that currently exceeds 5 years. Cystic fibrosis is the disease associated with the best results with, in France, a survival of 76% at 1 year, 56% at 5 years and 47% at 10 years and a median survival of 8 years. According to French data the 5-year survival is 46% for PAHT, 42% for COPD and 36% for pulmonary fibrosis. Studies have shown a survival benefit for cystic fibrosis and interstitial lung disease but definitive conclusions cannot be drawn for patients with COPD. Lung transplantation brings similar benefits in terms of quality of life and cost-effectiveness. VIEWPOINTS: New statistical methods would allow a better estimate in terms of years of survival and quality of life to be made for each candidate on an individual basis. CONCLUSIONS: Lung transplantation improves survival and quality of life compared to medical treatment, at an acceptable cost. These outcomes should be assessed at both an individual and social level to justify the resources involved. PMID- 20965408 TI - [Management of acute exacerbations of COPD]. AB - Exacerbations of COPD are common and cause a considerable burden to the patient and the healthcare system. To optimize the hospital care of patients with exacerbations of COPD, clinicians should be aware of some key points: management of exacerbations is broadly based on clinical features and severity. Initial clinical evaluation is crucial to define those patients requiring hospital admission and those who could be managed as outpatients. In hospitalized patients, the appropriate level of care should be determined by the initial severity and response to initial medical treatment. Medical treatment should follow recent recommendations, including rest, titrated oxygen therapy, inhaled or nebulized short-acting bronchodilators (Beta2-agonists and anticholinergic agents), DVT prevention with LMWH, steroids in most severely ill patients, unless there are contraindications and antibiotics in the case of a clear bacterial infectious aetiology. Severe exacerbations may lead to acute hypercapnic respiratory failure. Unless contraindicated, non-invasive ventilation (NIV) should be the first line ventilatory support for these patients. NIV should be commenced early, before severe acidosis ensues, to avoid the need for endotracheal intubation and to reduce mortality and treatment failures. Several randomised controlled clinical trials support the use of NIV in the management of acute exacerbations of COPD, demonstrating a decreased need for mechanical ventilation and an improved survival. In most severe cases, NIV should be provided in ICU. Although it has been shown that for less severe patients (with pH values>7.30), NIV can be administered safely and effectively on general medical wards, a lead respiratory consultant and trained nurses are mandatory. Mechanical ventilation through an endotracheal tube should be considered when patients have contraindications to the use of NIV or fail to improve on NIV. The duration of mechanical ventilation should be shortened as much as possible by an early weaning process, including preventive post-extubation NIV in hypercapnic patients. hospital stay could be shortened by non-invasive treatments. Future exacerbations should be avoided by respiratory specialist management of the patients, including education, optimization of long-term medical treatment, vaccinations, nutritional support, and pulmonary rehabilitation. PMID- 20965409 TI - [Molecular biology of lung cancer series]. AB - INTRODUCTION: MAGE-A3 (Melanoma Associated Antigen-A3) is expressed in cancer cells but not in normal tissues except male germ line cells which are devoid of Major Histocompatibility Complex molecules and therefore do not present MAGE-A3 antigens. BACKGROUND: MAGE-A3 is expressed in 30 to 60% of non-small cell lung cancers but its function is unknown. Its recognition by cytotoxic T lymphocytes implies its presentation on the cell surface by HLA type A1 molecules that are absent from germ cells. VIEWPOINTS: MAGE-A3 represents a good target for active anticancer immunotherapy. Some trials, which used MAGE-A3 and an adjuvant showed a strong antigen-specific T-cell response with, perhaps, an improved survival. CONCLUSION: This needs to be confirmed as an adjuvent therapy by current phase III randomized controlled trials. PMID- 20965410 TI - [Targeting insulin-like growth factors in the treatment of cancer]. AB - INTRODUCTION: The insulin-like growth factor I receptor (IGF-IR) pathway plays a major role in cancer growth, tumor cell survival and resistance to therapy. BACKGROUND: Preclinical evidence that targeting the IGF-IR is effective in cancer treatment has been accumulating for almost 2 decades. Early clinical trials revealed an acceptable safety profile together with pharmacodynamic evidence that the receptor can be targeted successfully. It is premature to draw conclusions regarding the therapeutic potential of this class of compounds but well documented single-agent activity was noted during phase I evaluations, and recent evidence from a phase-II study suggests that co-administration of an anti-IGF-1R antibody with chemotherapy for non-small-cell lung cancer (NSCLC) improves objective response rate and progression-free survival. VIEWPOINTS: These early results are a strong indication for continued research on the targeting of IGF-R, particularly in the treatment of NSCLC. CONCLUSIONS: Today, IGF-1R targeting appears a promising approach, more than two dozen compounds have been developed and clinical trials are underway. PMID- 20965411 TI - [Volumetric computed tomography: Principles, parameters]. AB - CT has become the chest imaging technique of reference after chest radiograph performed on the frontline. Technological developments have resulted in shortening the duration of image acquisition to a few seconds, and allow imaging the entire chest in patients unable to take a long breath. This fact-sheet aims to present the basic principles of formation of the CT image, the various embodiments of this imaging technique, and its main pitfalls and constraints. PMID- 20965413 TI - Cellular stress responses: a balancing act. PMID- 20965414 TI - Stress in biomedical research: six impossible things. AB - Biomedical research may not be more stressful than other disciplines, but our stress is compounded by some of the inherent features of biology. We consider six impossible things and what we might be able to do about them, provided they are believed by lunchtime or, with practice, before breakfast. PMID- 20965415 TI - The DNA damage response: making it safe to play with knives. AB - Damage to our genetic material is an ongoing threat to both our ability to faithfully transmit genetic information to our offspring as well as our own survival. To respond to these threats, eukaryotes have evolved the DNA damage response (DDR). The DDR is a complex signal transduction pathway that has the ability to sense DNA damage and transduce this information to the cell to influence cellular responses to DNA damage. Cells possess an arsenal of enzymatic tools capable of remodeling and repairing DNA; however, their activities must be tightly regulated in a temporal, spatial, and DNA lesion-appropriate fashion to optimize repair and prevent unnecessary and potentially deleterious alterations in the structure of DNA during normal cellular processes. This review will focus on how the DDR controls DNA repair and the phenotypic consequences of defects in these critical regulatory functions in mammals. PMID- 20965416 TI - MicroRNA functions in stress responses. AB - MicroRNAs (miRNAs) are a class of ~22 nucleotide short noncoding RNAs that play key roles in fundamental cellular processes, including how cells respond to changes in environment or, broadly defined, stresses. Responding to stresses, cells either choose to restore or reprogram their gene expression patterns. This decision is partly mediated by miRNA functions, in particular by modulating the amount of miRNAs, the amount of mRNA targets, or the activity/mode of action of miRNA-protein complexes. In turn, these changes determine the specificity, timing, and concentration of gene products expressed upon stresses. Dysregulation of these processes contributes to chronic diseases, including cancers. PMID- 20965417 TI - The nucleolus under stress. AB - Cells typically respond quickly to stress, altering their metabolism to compensate. In mammalian cells, stress signaling usually leads to either cell cycle arrest or apoptosis, depending on the severity of the insult and the ability of the cell to recover. Stress also often leads to reorganization of nuclear architecture, reflecting the simultaneous inhibition of major nuclear pathways (e.g., replication and transcription) and activation of specific stress responses (e.g., DNA repair). In this review, we focus on how two nuclear organelles, the nucleolus and the Cajal body, respond to stress. The nucleolus senses stress and is a central hub for coordinating the stress response. We review nucleolar function in the stress-induced regulation of p53 and the specific changes in nucleolar morphology and composition that occur upon stress. Crosstalk between nucleoli and CBs is also discussed in the context of stress responses. PMID- 20965418 TI - Translational regulation of gene expression during conditions of cell stress. AB - A number of stresses, including nutrient stress, temperature shock, DNA damage, and hypoxia, can lead to changes in gene expression patterns caused by a general shutdown and reprogramming of protein synthesis. Each of these stress conditions results in selective recruitment of ribosomes to mRNAs whose protein products are required for responding to stress. This recruitment is regulated by elements within the 5' and 3' untranslated regions of mRNAs, including internal ribosome entry segments, upstream open reading frames, and microRNA target sites. These elements can act singly or in combination and are themselves regulated by trans acting factors. Translational reprogramming can result in increased life span, and conversely, deregulation of these translation pathways is associated with disease including cancer and diabetes. PMID- 20965419 TI - Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms. AB - In cells, both newly synthesized and pre-existing proteins are constantly endangered by misfolding and aggregation. The accumulation of damaged proteins can perturb cellular homeostasis and provoke aging, pathological states, and even cell death. To avert these dangers, cells have developed powerful quality control strategies that counteract protein damage in a compartment-specific way. Here, we compare the protein quality control systems of the eukaryotic cytosol and the endoplasmic reticulum, focusing on the principles of damage recognition, the triage decisions between chaperone-mediated refolding and proteolytic elimination of damaged proteins, the repair of misfolded and aggregated protein species, and the mechanisms by which perturbations of protein homeostasis are sensed to induce compartment-specific stress responses. PMID- 20965420 TI - The heat shock response: life on the verge of death. AB - Organisms must survive a variety of stressful conditions, including sudden temperature increases that damage important cellular structures and interfere with essential functions. In response to heat stress, cells activate an ancient signaling pathway leading to the transient expression of heat shock or heat stress proteins (Hsps). Hsps exhibit sophisticated protection mechanisms, and the most conserved Hsps are molecular chaperones that prevent the formation of nonspecific protein aggregates and assist proteins in the acquisition of their native structures. In this Review, we summarize the concepts of the protective Hsp network. PMID- 20965421 TI - Membranes in balance: mechanisms of sphingolipid homeostasis. AB - Sphingolipids and their metabolites play key cellular roles both as structural components of membranes and as signaling molecules that mediate responses to physiologic cues and stresses. Despite progress during the last two decades in defining the enzymatic machinery responsible for synthesizing and degrading sphingolipids, comparatively little is known about how these enzymes are regulated to ensure sphingolipid homeostasis. Here, we review new insights into how cells sense and control sphingolipid biosynthesis and transport. We also discuss emerging evidence that sphingolipid metabolism is closely coordinated with that of sterols and glycerolipids and with other processes that occur in the secretory pathway. An improved understanding of sphingolipid homeostasis promises to shed light on basic processes in cell biology and disease, including how cells establish and maintain the complex membrane composition and architecture that is a defining feature of eukaryotic cell biology. PMID- 20965422 TI - Autophagy and the integrated stress response. AB - Autophagy is a tightly regulated pathway involving the lysosomal degradation of cytoplasmic organelles or cytosolic components. This pathway can be stimulated by multiple forms of cellular stress, including nutrient or growth factor deprivation, hypoxia, reactive oxygen species, DNA damage, protein aggregates, damaged organelles, or intracellular pathogens. Both specific, stimulus-dependent and more general, stimulus-independent signaling pathways are activated to coordinate different phases of autophagy. Autophagy can be integrated with other cellular stress responses through parallel stimulation of autophagy and other stress responses by specific stress stimuli, through dual regulation of autophagy and other stress responses by multifunctional stress signaling molecules, and/or through mutual control of autophagy and other stress responses. Thus, autophagy is a cell biological process that is a central component of the integrated stress response. PMID- 20965423 TI - Hypoxia-inducible factors and the response to hypoxic stress. AB - Oxygen (O(2)) is an essential nutrient that serves as a key substrate in cellular metabolism and bioenergetics. In a variety of physiological and pathological states, organisms encounter insufficient O(2) availability, or hypoxia. In order to cope with this stress, evolutionarily conserved responses are engaged. In mammals, the primary transcriptional response to hypoxic stress is mediated by the hypoxia-inducible factors (HIFs). While canonically regulated by prolyl hydroxylase domain-containing enzymes (PHDs), the HIFalpha subunits are intricately responsive to numerous other factors, including factor-inhibiting HIF1alpha (FIH1), sirtuins, and metabolites. These transcription factors function in normal tissue homeostasis and impinge on critical aspects of disease progression and recovery. Insights from basic HIF biology are being translated into pharmaceuticals targeting the HIF pathway. PMID- 20965424 TI - Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. AB - The large serine/threonine protein kinase mTOR regulates cellular and organismal homeostasis by coordinating anabolic and catabolic processes with nutrient, energy, and oxygen availability and growth factor signaling. Cells and organisms experience a wide variety of insults that perturb the homeostatic systems governed by mTOR and therefore require appropriate stress responses to allow cells to continue to function. Stress can manifest from an excess or lack of upstream signals or as a result of genetic perturbations in upstream effectors of the pathway. mTOR nucleates two large protein complexes that are important nodes in the pathways that help buffer cells from stresses, and are implicated in the progression of stress-associated phenotypes and diseases, such as aging, tumorigenesis, and diabetes. This review focuses on the key components of the mTOR complex 1 pathway and on how various stresses impinge upon them. PMID- 20965425 TI - Cellular metabolic stress: considering how cells respond to nutrient excess. AB - Nutrient stress is generally considered from the standpoint of how cells detect and respond to an insufficient supply of nutrients to meet their bioenergetic needs. However, cells also experience stress as a result of nutrient excess, during which reactive oxygen species (ROS) production exceeds that required for normal physiological responses. This may occur as a result of oncogene activation or chronic exposure to growth factors combined with high levels of nutrients. As a result, multiple mechanisms have evolved to allow cells to detect and adapt to elevated levels of intracellular metabolites, including promotion of signaling and proliferation by ROS, amino acid-dependent mTOR activation, and regulation of signaling and transcription through metabolite-sensitive protein modifications. We discuss how each of these responses can contribute to the development and/or progression of cancer under conditions of cellular nutrient excess and their potential roles in linking chronic organismal over-nutrition (obesity) with cancer. PMID- 20965427 TI - [The diagnostic trap of vulvar dermatoses]. PMID- 20965428 TI - [Progress in urogenital health: sensitive skin and urinary incontinence]. PMID- 20965426 TI - The aging stress response. AB - Aging is the outcome of a balance between damage and repair. The rate of aging and the appearance of age-related pathology are modulated by stress response and repair pathways that gradually decline, including the proteostasis and DNA damage repair networks and mitochondrial respiratory metabolism. Highly conserved insulin/IGF-1, TOR, and sirtuin signaling pathways in turn control these critical cellular responses. The coordinated action of these signaling pathways maintains cellular and organismal homeostasis in the face of external perturbations, such as changes in nutrient availability, temperature, and oxygen level, as well as internal perturbations, such as protein misfolding and DNA damage. Studies in model organisms suggest that changes in signaling can augment these critical stress response systems, increasing life span and reducing age-related pathology. The systems biology of stress response signaling thus provides a new approach to the understanding and potential treatment of age-related diseases. PMID- 20965429 TI - Changing complexities of challenges for clinical practice. PMID- 20965430 TI - How much is dementia care worth? PMID- 20965431 TI - Diagnosis of posterior reversible encephalopathy syndrome: does DWI help? PMID- 20965432 TI - Telemedicine in 2010: robotic caveats. PMID- 20965434 TI - Health-care reform in the USA: what does it mean for neurologists? PMID- 20965435 TI - Jes Olesen: the people's neurologist. PMID- 20965437 TI - Aetiological diagnosis of ischaemic stroke in young adults. AB - Despite improvements in diagnosis and treatment, ischaemic stroke in young adults remains a catastrophic event from the patients' perspective. Stroke can cause death, disability, and hamper quality of life. For the neurologist treating a young adult with suspected ischaemic stroke, the diagnostic challenge is to identify its cause. Contemporary neuroimaging of the brain and its vessels, and a comprehensive cardiac assessment, will enable identification of the most frequent causes of stroke in this age group: cardioembolism and arterial dissection. Specific diagnostic tests for the many other rare causes of ischaemic stroke in young adults (angiography, CSF examination, screening for vasculitis and thrombophilia, genetic testing, and ophthalmological examination) should be guided by suspected clinical findings or by the high prevalence of diseases associated with stroke in some countries. PMID- 20965438 TI - Clinical features, diagnosis, and management of enterovirus 71. AB - Although poliomyelitis has been mostly eradicated worldwide, large outbreaks of the related enterovirus 71 have been seen in Asia-Pacific countries in the past 10 years. This virus mostly affects children, manifesting as hand, foot, and mouth disease, aseptic meningitis, poliomyelitis-like acute flaccid paralysis, brainstem encephalitis, and other severe systemic disorders, including especially pulmonary oedema and cardiorespiratory collapse. Clinical predictors of severe disease include high temperature and lethargy, and lumbar puncture might reveal pleocytosis. Many diagnostic tests are available, but PCR of throat swabs and vesicle fluid, if available, is among the most efficient. Features of inflammation, particularly in the anterior horns of the spinal cord, the dorsal pons, and the medulla can be clearly seen on MRI. No established antiviral treatment is available. Intravenous immunoglobulin seems to be beneficial in severe disease, perhaps through non-specific anti-inflammatory mechanisms, but has not been tested in any formal trials. Milrinone might be helpful in patients with cardiac dysfunction. PMID- 20965439 TI - Expanding the modern synthesis. AB - The Modern Evolutionary Synthesis formalizes the role of variation, heredity, differential reproduction and mutation in population genetics. Here we explore a mathematical structure, based on the asymptotic limit theorems of communication theory, that instantiates the punctuated dynamic relations of organisms with their embedding environments, including the possibility of the transfer of heritage information between different classes of organism. The approach applies a standard coevolutionary argument to genes, environment, and gene expression reconfigured as interacting information sources. In essence, we provide something of a formal roadmap for the modernization of the Modern Synthesis, making applications to both relatively rapid evolutionary punctuated equilibrium and to the conservation of ecological interactions across deep evolutionary time. PMID- 20965440 TI - Evaluation of the genetic trend of milk yield in the multiple ovulation and embryo transfer populations of dairy cows, using stochastic simulation. AB - Stochastic modeling of dairy cattle populations using multiple ovulation and embryo transfer (MOET) was used to compare 15-year genetic responses with an artificial insemination (AI) program. MOET and AI techniques were simulated in four populations, two with 100 breeding females each and two with 400 breeding females. The selection goal was to maximize genetic progress in milk yield. The reduction in genetic variation due to inbreeding and linkage disequilibrium was accounted for in the simulation process. All four MOET breeding schemes studied achieved larger genetic responses than the realized and theoretical genetic gains from the current AI progeny testing populations. Strict restriction against inbred matings slowed genetic progress significantly in the small population but would not be consequential in the larger population. However, allowing inbred matings in the smaller population caused a rapid accumulation of inbreeding. Linkage disequilibrium was as important as inbreeding in reducing genetic variation. Genetic drift variance was much smaller in the larger population. PMID- 20965441 TI - A novel Ta.AGP.S.1b transcript in Chinese common wheat (Triticum aestivum L.). AB - ADP-glucose pyrophosphorylase (AGPase), the key enzyme of starch synthesis in plants, is composed of two small and two large subunits, and has plastidial and cytosolic isoforms. In kernels of wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.), transcripts for cytosolic (Ta.AGP.S1a) and plastidial (Ta.AGP.S1b) small subunits of AGPase were encoded by the same gene (Ta.AGP.S.1) by use of the alternative first exons. In this study, a cDNA sequence (1631 bp) [NCBI: EU586278] encoding a novel Ta.AGP.S1b transcript was isolated in kernels of Chinese common wheat cultivars. Compared with another Ta.AGP.S1b transcript [NCBI: FJ643609] isolated in kernels of non-Chinese wheat cultivars, EU586278 lacked a long fragment (117 bp) at its 5'terminal, resulting in a shorten transit peptide. The lacked fragments of Ta.AGP.S1b (EU586278) were universally found in surveyed 22 Chinese common wheat cultivars. Partial genomic DNA sequence [NCBI: FJ907395] of Ta.AGP.S.1 gene, which was corresponded to 5'terminal of EU586278 transcript, was also isolated in Chinese common cultivars and sequencing indicated that FJ907395 contained the corresponding lacked fragment of EU586278 transcript, inferring the lacked fragment in EU586278 transcript was not present in the genome, but possibly occurred at transcription level. Using TargetP software, the predicated transit peptide of putative plastidial SSU encoded by EU586278 contained merely 25 amino acids, considerably shorter than those of other plant AGP. S.1bs (54-70 amino acids). Phylogenetic tree analysis indicated that the amino acid sequence of EU586278 transit peptide was not clustered together with those of other wheat Ta.AGP.S1bs [NCBI: AF536819 and FJ643609] and barley AGP.S1b [NCBI: Z48563]. These implied that EU586278 could be a novel Ta.AGP.S1b transcript. Semi-quantitative PCR analysis indicated that transcripts of EU586278 were abundantly expressed in leaf, moderately in endosperm and stem, and weakly in root. PMID- 20965442 TI - Digestive enzymes activity in larvae of Cameraria ohridella (Lepidoptera: Gracillariidae). AB - This article presents the activity of carbohydratases and proteases in the midgut of Cameraria ohridella larvae--an oligophagous pest whose preferred feeding is horse chestnuts leaves. Optimal media pH of the assayed enzymes were similar to those of other Lepidopterans. Relatively high amylase activity, as well as maltase and sucrase activities, indicates that starch and sucrose are the main digested saccharides. Trehalase activity was similar to that described in other Lepidopterans. Activities of glycosidases were significantly lower than those of disaccharidases what suggests that neither cellulose nor glycosides are important for C. ohridella. Trypsin is the main endoprotease of this pest. Like in other leaf-eaters carboxypeptidase activity was higher than that of aminopeptidase. The activity of the majority of examined enzymes increased in the following successive pest generations, which could be explained by the decreased nutritional value of older leaves. Probably this phenomenon in hydrolases activity in Cameraria is a nonspecific mechanism present at this stage of co evolution of the horse chestnut and its pest. PMID- 20965443 TI - [Primary pharmacological screening of an endemic plant from the Southern Morocco (Tetraena gaetula [Emb. & Maire] Beier & Thulin)]. AB - Tetraena gaetula (Emb. & Maire) Beier & Thulin (Zygophyllum gaetulum Emb. & Maire, Zygophyllaceae) is an endemic plant from the southern Morocco. This plant is widely used in Moroccan traditional medicine as an antispasmodic and antidiabetic. Our work aims to evaluate several pharmacological properties of extracts of T. gaetula such pro- or antiproliferative, immunomodulatory, analgesic and antidepressant effects. Initially, we studied intraperitoneally the acute toxicity of aqueous extract of T. gaetula in mice; the lethal dose 50 is 1.2 g/kg of body weight. Our results also showed a stimulating proliferative activity of T. gaetula, particularly at 6 MUg/MUL of the proteic extract on T lymphocytes. However, this same concentration of proteic extract induced rather cytotoxicity on B cells and macrophages. Our ex vivo results showed a dose dependent response: (i) stimulation of lymphocyte subpopulations and monocytes in a dose 600 mg/kg, and (ii) immunosuppression at a dose 300 mg/kg. The pharmacological results in vivo showed a pronounced antidepressant effect of the proteic extract at all doses. However, the aqueous extract showed analgesic and anti-depressant effects, mainly at doses 300 and 600 mg/kg. PMID- 20965444 TI - [Pollen analysis from two littoral marshes (Bourdim and Garaat El-Ouez) in the El Kala wet complex (North-East Algeria). Lateglacial and Holocene history of Algerian vegetation]. AB - The study of two pollen sequences from El-Kala marshes allowed the reconstruction of the regional vegetation history supported by eight radiocarbon dates. Pollen assemblages from Bourdim site were dominated by local input of Alnus and Salix, while regional vegetation was characterized by scattered Quercus suber forests with a well-developed Erica arborea matorral. While the vegetation dynamics recorded at Bourdim is recent (Late Holocene), the majority of the pollen diagram from Garaat El-Ouez is contemporaneous to the Late Pleniglacial and is characterized by open woodlands with Pinus, Poaceae and several heliophilous herbs. The significant values of Cedrus pollen identified in this period indicate that the region of El-Kala most probably played the role of a refugium for this tree. PMID- 20965445 TI - The phylogenetic position of the 'living fossils' Neoglyphea and Laurentaeglyphea (Decapoda: Glypheidea). AB - The Glypheidea is a group of lobster-like decapods that appeared in the Triassic and that was thought to be extinct until 1975, when a specimen of the species Neoglyphea inopinata was caught off the Philippines. More recently, in 2005, a specimen of another glypheid species, Laurentaeglyphea neocaledonica, was discovered near New Caledonia. Here, we construct a decapod molecular data set including the two extant glypheid species sequenced from eight nuclear and mitochondrial genes. Our study strongly shows that the two extant genera of glypheids cluster together, and further confirms the status of Glypheidea as a separate infraorder. Moreover the reptantian decapods are divided into two major groups, one including Brachyura, Anomura, and Axiidea, and the other including Astacidea, Polychelida, Achelata, and Glypheidea. Although commonly nicknamed 'Jurassic shrimps' and considered as 'living fossils', glypheids are therefore a derived decapod lineage. PMID- 20965446 TI - Time course of therapeutic response, and durability, of the different brain stimulation methods--from the Editor-in Chief's desk. PMID- 20965447 TI - Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant major depression: assessment of relapse during a 6-month, multisite, open-label study. AB - BACKGROUND: Although transcranial magnetic stimulation (TMS) can be an effective acute antidepressant treatment, few studies systematically examine persistence of benefit. OBJECTIVE: We assessed the durability of antidepressant effect after acute response to TMS in patients with major depressive disorder (MDD) using protocol-specified maintenance antidepressant monotherapy. METHODS: Three hundred one patients were randomly assigned to active or sham TMS in a 6-week, controlled trial. Nonresponders could enroll in a second, 6-week, open-label study. Patients who met criteria for partial response (i.e., >25% decrease from the baseline HAMD 17) during either the sham-controlled or open-label study (n = 142) were tapered off TMS over 3 weeks, while simultaneously starting maintenance antidepressant monotherapy. Patients were then followed for 24 weeks in a naturalistic follow-up study examining the long-term durability of TMS. During this durability study, TMS was readministered if patients met prespecified criteria for symptom worsening (i.e., a change of at least one point on the CGI-S scale for 2 consecutive weeks). Relapse was the primary outcome measure. RESULTS: Ten of 99 (10%; Kaplan-Meier survival estimate = 12.9%) patients relapsed. Thirty-eight (38.4%) patients met criteria for symptom worsening and 32/38 (84.2%) reachieved symptomatic benefit with adjunctive TMS. Safety and tolerability were similar to acute TMS monotherapy. CONCLUSIONS: These initial data suggest that the therapeutic effects of TMS are durable and that TMS may be successfully used as an intermittent rescue strategy to preclude impending relapse. PMID- 20965448 TI - Can a behavioral intervention enhance the effect of repetitive transcranial magnetic stimulation on mood? AB - BACKGROUND: One of the few novel treatments developed for major depression in recent years has been repetitive transcranial magnetic stimulation (rTMS). Despite mostly promising results, 50-60% of patients do not respond to rTMS. Therefore, it is important to investigate ways of enhancing the effectiveness of this treatment. To date, attempting to enhance the mood effects of rTMS via behavioral means has not been investigated. One such intervention involves concurrent exposure to affective stimuli that have been shown to result in activation of brain regions associated with emotion. This pilot study of ten participants investigates such an intervention. OBJECTIVES: The aim of this pilot study was to investigate whether exposing participants to affective stimuli while they were receiving 5 Hz rTMS resulted in greater mood change compared with rTMS or affective stimuli alone. METHODS: Ten healthy male and female participants were exposed to affective stimuli while receiving rTMS. All participants took part in three counterbalanced conditions conducted a week apart in which they received rTMS (active or sham) delivered to the left dorsolateral prefrontal cortex (DLPFC) combined with affective stimuli (positive or neutral). To measure the impact of the dual intervention visual analogue mood scales and an affective go no go task were conducted pre- and post intervention for each session. RESULTS: There was no effect of any rTMS condition on performances on the affective go no go task, or on any of the visual analogue scales. CONCLUSIONS: The current data do not provide support for the use of affective stimuli during rTMS. Methodological limitations that may have contributed to the lack of significant findings are discussed. PMID- 20965449 TI - Feasibility of simultaneous cognitive behavioral therapy and left prefrontal rTMS for treatment resistant depression. PMID- 20965450 TI - Response to deep TMS in depressive patients with previous electroconvulsive treatment. AB - BACKGROUND: The efficacy of transcranial magnetic stimulation (TMS) in the treatment of major depression has already been shown. Novel TMS coils allowing stimulation of deeper brain regions have recently been developed and studied. OBJECTIVE: Our study is aimed at exploring the possible efficacy of deep TMS in patients with resistant depression, who previously underwent electroconvalsive therapy (ECT). METHODS: Using Brainsway's deep TMS H1 coil, six patients who previously underwent ECT, were treated with 120% power of the motor threshold at a frequency of 20 Hz. Patients underwent five sessions per week, up to 4 weeks. Before the study, patients were evaluated using the Hamilton depression rating scale (HDRS, 24 items), the Hamilton anxiety scale, and the Beck depression inventory and were again evaluated after 5, 10, 15, and 20 daily treatments. Response to treatment was considered a reduction in the HDRS of at least 50%, and remission was considered a reduction of the HDRS-24 below 10 points. RESULTS: Two of six patients responded to the treatment with deep TMS, including one who achieved full remission. CONCLUSIONS: Our results suggest the possibility of a subpopulation of depressed patients who may benefit from deep TMS treatment, including patients who did not respond to ECT previously. However, the power of the study is small and similar larger samples are needed. PMID- 20965451 TI - A numerically optimized active shield for improved transcranial magnetic stimulation targeting. AB - Transcranial magnetic stimulation (TMS) devices suffer of poor targeting and penetration depth. A new approach to designing TMS coils is introduced in order to improve the focus of the stimulation region through the use of actively shielded probes. Iterative optimization techniques were used to design different active shielding coils for TMS probes. The new approach aims to increase the amount of energy deposited in a thin cylindrical region below the probe relative to the energy deposited elsewhere in the region ("sharpness"), whereas, simultaneously increase the induced electric field deep in the target region relative to the surface ("penetration"). After convergence, the resulting designs showed that there is a clear tradeoff between sharpness and penetration that can be controlled by the choice of a tuning parameter. The resulting designs were tested on a realistic human head conductivity model, taking the contribution from surface charges into account. The design of choice reduced penetration depths by 16.7%. The activated surface area was reduced by 24.1% and the volume of the activation was reduced from 42.6% by the shield. Restoring the lost penetration could be achieved by increasing the total power to the coil by 16.3%, but in that case, the stimulated volume reduction was only 13.1% and there was a slight increase in the stimulated surface area (2.9%). PMID- 20965452 TI - Involvement of the human ventrolateral thalamus in the control of visually guided saccades. PMID- 20965453 TI - Brain-derived neurotrophic factor (BDNF) gene polymorphisms shape cortical plasticity in humans. AB - BACKGROUND: The brain-derived neurotrophic factor (BDNF) gene is involved in mechanisms of synaptic plasticity in the adult brain. It has been demonstrated that BDNF also plays a significant role in shaping externally induced human brain plasticity. Plasticity induced in the human motor cortex by intermittent theta burst stimulation (iTBS) was impaired in individuals expressing the Val66Met polymorphism. METHODS: To explore whether this polymorphism is also important for other neuroplasticity-inducing tools in humans with modes of action differing from that of iTBS, namely, transcranial direct current (tDCS) and random noise stimulation (tRNS), we retrospectively analyzed the data of 64 subjects studied in our laboratory with regard to BDNF genotype. RESULTS: Fifteen subjects with the Val66Met allele, 46 subjects with the Val66Val allele, and 3 Met66Met carriers were identified. The response of the Val66Met allele carriers to stimulation differed in two protocols compared with the response of Val66Val individuals. For iTBS (15 subjects, 5 heterozygotes), plasticity could be only induced in the Val66Val allele carriers. However, for facilitatory tDCS (24 subjects, 10 heterozygotes), as well as for inhibitory tDCS, (19 subjects, 8 heterozygotes), carriers of the Val66Met allele displayed enhanced plasticity, whereas for transcranial random noise stimulation (29 subjects, 8 heterozygotes), the difference between groups was not so pronounced. CONCLUSIONS: BDNF polymorphism has a definite impact on plasticity in humans, which might differ according to the mechanism of plasticity induction. This impact of BDNF on plasticity should be taken into account for future studies, as well as having wider ranging implications for the treatment of neuropsychiatric disorders with transcranial stimulation tools, as it may predetermine their efficacy for the treatment of disease and rehabilitation. PMID- 20965454 TI - Successful switch to maintenance rTMS after maintenance ECT in refractory bipolar disorder. PMID- 20965455 TI - Clopidogrel pharmacogenomics: next steps: a clinical algorithm, gene-gene interactions, and an elusive outcomes trial. AB - Clopidogrel pharmacogenomics has received significant attention since a black box warning was announced by the Food and Drug Administration in March. This has left clinicians in a difficult situation where many questions remain unanswered. In this brief viewpoint article, we ask some pointed questions of our own and outline the pathway that needs to be taken for clinical translation to occur. PMID- 20965456 TI - Pilot study of the antiplatelet effect of increased clopidogrel maintenance dosing and its relationship to CYP2C19 genotype in patients with high on treatment reactivity. AB - OBJECTIVES: The objective of this study was to evaluate the antiplatelet effect of clopidogrel 150 mg/day in patients with high on-treatment reactivity (OTR) and to further assess this effect according to CYP2C19 genotype. BACKGROUND: High OTR is associated with ischemic events in clopidogrel-treated patients after percutaneous coronary intervention. Alternative dosing regimens might enhance platelet inhibition. METHODS: Patients with high OTR receiving a standard clopidogrel regimen were identified with the VerifyNow P2Y12 assay and administered clopidogrel 150 mg daily for 7 days, after which OTR was reassessed. Comprehensive CYP2C19 genotyping was performed with the BeadXpress platform (Illumina, San Diego, California) for the *2, *3, *4, *5, *6, *7, *8, and *17 variants. RESULTS: A total of 41 subjects were enrolled, 20 of whom were carriers of a CYP2C19 loss-of-function (LoF) allele. High-dose clopidogrel significantly reduced OTR from 285 +/- 47 P2Y(12) reaction units (PRU) to 220 +/- 91 PRU (p < 0.001). There were no significant differences in antiplatelet effect according to CYP2C19 status, although the reduction in reactivity was minimal in the small number of patients homozygous for LoF alleles (n = 3, 28 +/- 31 PRU, p = NS). Increasing body mass index was independently and negatively associated with the reduction in OTR (p = 0.009). CONCLUSIONS: In patients with high OTR, clopidogrel 150 mg/day results in a significant reduction in platelet reactivity. Carriage of an LoF CYP2C19 polymorphism does not seem to have a major influence on dose effect. The observed lack of effect in patients with 2 copies of a CYP2C19 LoF allele must be confirmed by larger studies. PMID- 20965457 TI - Acceptance of high platelet reactivity as a risk factor: now, what do we do about it? PMID- 20965458 TI - Economic impact of same-day home discharge after uncomplicated transradial percutaneous coronary intervention and bolus-only abciximab regimen. AB - OBJECTIVES: This study sought to estimate the economic impact of same-day home discharge compared with overnight hospitalization after transradial percutaneous coronary intervention (PCI). BACKGROUND: Same-day home discharge after transradial PCI and a bolus-only abciximab regimen was found to be clinically noninferior to the abciximab standard therapy and overnight hospitalization in patients with various forms of acute coronary syndromes. METHODS: In the EASY (Early Discharge After Transradial Stenting of Coronary Arteries) trial, 1,005 patients were randomized after a bolus of abciximab and uncomplicated transradial coronary stenting, either to same-day home discharge and no infusion (outpatient group) or to overnight hospitalization and 12-h abciximab infusion (overnight stay group). We estimated post-PCI health care cost (in Canadian dollars) of trial subjects and short-term economic impact of same-day home discharge. As randomization was done after the procedure, outcomes were similar, and PCI resource use showed minimal and nonsignificant differences, a post-PCI cost minimization analysis was conducted. Detailed per-patient information of health care resources used immediately after PCI up to 30 days was collected. RESULTS: Mean post-PCI hospital stay was 8.9 h for outpatients versus 26.5 h for overnight stay patients (p < 0.001). At 30-day follow-up, the mean cumulative medical cost per outpatient was $1,117 +/- $1,554 versus $2,258 +/- $1,328 for overnight-stay patients. The mean difference of $1,141 (95% confidence interval: $962 to $1,320) was mainly due to the extra night for overnight hospital stay. CONCLUSIONS: In a real-world setting, same-day home discharge after uncomplicated transradial PCI and a bolus-only abciximab regimen resulted in a 50% relative reduction in medical costs. Extension of this outpatient strategy would be welcomed by the hospitals and reimbursement systems in a context of increasing demand for health care cost reduction. (Early Discharge After Transradial Stenting of Coronary Arteries [EASY]; NCT00169819). PMID- 20965459 TI - Outpatient percutaneous coronary interventions: hospital and health system costs saving while maintaining patient safety. PMID- 20965460 TI - Transradial approach for coronary angiography and interventions: results of the first international transradial practice survey. AB - OBJECTIVES: The aim of this study was to evaluate practice of transradial approach (TRA). BACKGROUND: TRA has been adopted as an alternative access site for coronary procedures. METHODS: A questionnaire was distributed worldwide with Internet-based software. RESULTS: The survey was conducted from August 2009 to January 2010 among 1,107 interventional cardiologists in 75 countries. Although pre-TRA dual hand circulation testing is not uniform in the world, >85% in the U.S. perform Allen or oximetry testing. Right radial artery is used in almost 90%. Judkins catheters are the most popular for left coronary artery angiographies (66.5%) and right coronary artery angiographies (58.8%). For percutaneous coronary intervention (PCI), 6-F is now standard. For PCI of left coronary artery, operators use standard extra back-up guiding catheters in >65% and, for right coronary artery 70.4% use right Judkins catheters. Although heparin remains the routine antithrombotic agent in the world, bivalirudin is frequently used in the U.S. for PCI. The incidence of radial artery occlusion before hospital discharge is not assessed in >50%. Overall, approximately 50% responded that their TRA practice will increase in the future (68.4% in the U.S.). CONCLUSIONS: TRA is already widely used across the world. Diagnostic and guiding-catheters used for TRA remain similar to those used for traditional femoral approach, suggesting that specialized radial catheters are not frequently used. However, there is substantial variation in practice as it relates to specific aspects of TRA, suggesting that more data are needed to determine the optimal strategy to facilitate TRA and optimize radial artery patency after catheterization. PMID- 20965461 TI - Transradial catheterization's grass roots epidemic. PMID- 20965462 TI - Transradial versus transfemoral method of percutaneous coronary revascularization for unprotected left main coronary artery disease: comparison of procedural and late-term outcomes. AB - OBJECTIVES: This study intended to compare outcomes between transradial (TR) and transfemoral (TF) percutaneous revascularization in high-risk coronary anatomy. BACKGROUND: The feasibility, efficacy and safety between TR and TF methods of percutaneous coronary revascularization for unprotected left main coronary artery (UPLM]) disease have not been compared. METHODS: Among 821 consecutive patients with UPLM disease treated with percutaneous revascularization by either TR (n = 353) or TF (n = 468) vascular access, procedural outcomes, resource use, in hospital bleeding, and late clinical events were compared according to vascular access method. RESULTS: Clinical and angiographic characteristics were similar between groups, except that TR patients less commonly presented with unstable angina and had less UPLM bifurcation disease requiring treatment with 2 stents. No significant differences were observed between TR and TF methods for procedural success (97% TF vs. 96% TR, p = 0.57) or total procedural time. However, duration of hospital stay and in-hospital occurrence of Thrombosis In Myocardial Infarction (TIMI) major or minor bleeding (0.6% vs. 2.8%, p = 0.02) were significantly lower with TR access. Using propensity score modeling (254 matched pairs), over a mean follow-up period of 17 months, rates of cardiovascular death (1.2% vs. 2.0%, p = 0.48), nonfatal myocardial infarction (4.7% vs. 2.4%, p = 0.16), stent thrombosis (0.8% vs. 2.8%, p = 0.10) and any target vessel revascularization (6.0% vs. 6.7%, p = 0.72) did not statistically differ among TR and TF groups, respectively. CONCLUSIONS: In contrast to TF vascular access, TR percutaneous coronary revascularization for UPLM disease is feasible and associated with similar procedural success, abbreviated hospitalization, reduced bleeding, and comparable late-term clinical safety and efficacy. PMID- 20965463 TI - Improved late clinical safety with zotarolimus-eluting stents compared with paclitaxel-eluting stents in patients with de novo coronary lesions: 3-year follow-up from the ENDEAVOR IV (Randomized Comparison of Zotarolimus- and Paclitaxel-Eluting Stents in Patients With Coronary Artery Disease) trial. AB - OBJECTIVES: The increased frequency of very late (>1 year) stent thrombosis (VLST) has raised concerns with regard to the safety of sirolimus-eluting stents and paclitaxel-eluting stents (PES). BACKGROUND: Experimental and preliminary clinical findings with the zotarolimus-eluting stent (ZES) have suggested a favorable safety profile. METHODS: The ENDEAVOR IV (Randomized Comparison of Zotarolimus- and Paclitaxel-Eluting Stents in Patients With Coronary Artery Disease) trial is a single-blind randomized ZES versus PES clinical trial in 1,548 patients with de novo native coronary lesions; the primary end point-9 month target vessel failure-was previously reported, annual clinical follow-up is planned for 5 years, and this report describes the 3-year outcomes. RESULTS: The ZES compared with PES reduced target vessel failure (12.3% vs. 15.9%, hazard ratio [HR]: 0.76, 95% confidence interval [CI]: 0.58 to 1.00, p = 0.049), myocardial infarctions (MI) (2.1% vs. 4.9%, HR: 0.44, 95% CI: 0.25 to 0.80, p = 0.005), and cardiac death plus MI (3.6% vs. 7.1%, HR: 0.52, 95% CI 0.32 to 0.82, p = 0.004). Although the overall 3-year rate of Academic Research Consortium definite/probable stent thrombosis did not differ significantly (1.1% vs. 1.7%, HR: 0.67, 95% CI 0.28 to 1.64, p = 0.380), VLST (between 1 and 3 years) was significantly reduced in ZES patients (1 event vs. 11 events; 0.1% vs. 1.6%, HR: 0.09, 95% CI: 0.01 to 0.71, p = 0.004). Ischemia-driven target lesion revascularization at 3 years was similar with ZES versus PES (6.5% vs. 6.1%, HR: 1.10, 95% CI: 0.73 to 1.65, p = 0.662). CONCLUSIONS: Three-year follow-up results from the ENDEAVOR IV trial indicate similar antirestenosis efficacy but improved clinical safety associated with ZES compared with PES, due to significantly fewer peri-procedural and remote MIs associated with fewer VLST events. (A Randomized, Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Taxus Paclitaxel-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions; NCT00217269). PMID- 20965464 TI - The unrestricted use of sirolimus- and paclitaxel-eluting stents results in better clinical outcomes during 6-year follow-up than bare-metal stents: an analysis of the RESEARCH (Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital) and T-SEARCH (Taxus-Stent Evaluated At Rotterdam Cardiology Hospital) registries. AB - OBJECTIVES: The aim of this study was to assess the 6-year clinical outcome after unrestricted use of sirolimus-eluting stents (SES) or paclitaxel-eluting stents (PES) as compared with bare-metal stents (BMS) in consecutive de novo patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: SES and PES have been shown to significantly decrease target vessel revascularization (TVR) rates compared with BMS in "real-world" registries. However, possible higher rates of very-late stent thrombosis and a restenosis "catch-up" trend might jeopardize the benefit. METHODS: Three PCI cohorts, each with exclusive use of 1 stent type (BMS = 450; SES = 508; PES = 576), were systematically followed for the occurrence of major adverse cardiac events (MACE). RESULTS: Very-late stent thrombosis was more common in SES and PES patients than BMS patients (2.4% vs. 0.9% vs. 0.4%, respectively; p = 0.02); however, there were no significant differences between the stent types for all-cause mortality and all-cause mortality/myocardial infarction at 6-year follow-up. Sixty-nine SES patients (Kaplan-Meier estimate 14%) and 72 PES patients (14%) had a TVR, as compared with 79 BMS patients (18%; log-rank p = 0.02), which maintained significance after adjustment for (potential) confounders. Multivariate analysis showed that DES implantation is associated with lower incidence of TVR and MACE than BMS implantation (hazard ratio: 0.65, 95% confidence interval: 0.49 to 0.86; p = 0.003; hazard ratio: 0.79, 95% confidence interval: 0.65 to 0.97; p = 0.02, respectively). Incidence of MACE was also lower in SES and PES patients (30% and 30%, respectively) than in BMS patients (34%); however, significance was borderline. CONCLUSIONS: The unrestricted use of both DES resulted in a sustained advantage in decreasing TVR and, to a lesser extent, MACE compared with BMS at 6 years. The SES and PES are equally safe and effective in the treatment of coronary lesions. PMID- 20965465 TI - Surgical versus percutaneous revascularization for multivessel disease in patients with acute coronary syndromes: analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. AB - OBJECTIVES: The aim of this study was to evaluate outcomes of patients with moderate- and high-risk acute coronary syndromes (ACS) and multivessel coronary artery disease managed with percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG). BACKGROUND: There is uncertainty about the preferred revascularization strategy for high-risk patients with multivessel disease. METHODS: Among 13,819 moderate- and high-risk ACS patients enrolled in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, 5,627 had multivessel disease (including left anterior descending artery involvement) and were managed by PCI (n = 4,412) or CABG (n = 1,215). Propensity score matching was applied to adjust for differences in baseline clinical and angiographic characteristics, yielding a total of 1,056 patients (528 managed by PCI, and 528 managed by CABG). RESULTS: Propensity-matched patients undergoing CABG had higher 1-month rates of stroke (1.1% vs. 0.0%, p = 0.03) and myocardial infarction (13.3% vs. 8.8%, p = 0.03), received more blood transfusions (40.3% vs. 6.3%, p < 0.0001) and more frequently developed acute renal injury (31.7% vs. 14.2%, p < 0.0001), whereas PCI was associated with higher rates of unplanned revascularization at both 1 month and at 1 year (0.8% vs. 5.2%, p < 0.0001; and 3.8% vs. 16.5%, p < 0.0001, respectively). There were no significant differences between the CABG and PCI groups in 1-month or 1-year mortality (2.5% vs. 2.1%, p = 0.69; and 4.4% vs. 5.7%, p = 0.58, respectively). CONCLUSIONS: In this propensity-matched comparison from the ACUITY trial, moderate- and high-risk patients with ACS and multivessel disease treated with PCI rather than CABG had lower rates of peri-procedural stroke, myocardial infarction, major bleeding, and renal injury, with comparable 1-month and 1-year rates of mortality, but more frequently developed recurrent ischemia requiring repeat revascularization procedures during follow-up. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes [ACS]; NCT00093158). PMID- 20965466 TI - Frequency and predictors of drug-eluting stent use in saphenous vein bypass graft percutaneous coronary interventions: a report from the American College of Cardiology National Cardiovascular Data CathPCI registry. AB - OBJECTIVES: We examined a large registry to determine the frequency and factors associated with drug-eluting stents (DES) use in saphenous vein graft (SVG) in contemporary practice. BACKGROUND: Prospective trials comparing DES with bare metal stents in SVG lesions have provided conflicting conclusions regarding safety and efficacy leading to potential variation in stent choice for these lesions. METHODS: We analyzed the frequency and factors associated with DES use in patients undergoing SVG stenting from January 1, 2004, to March 31, 2009, in the National Cardiovascular Data Registry. Generalized estimating equations logistic regression modeling was used to generate independent variables associated with DES use in SVGs. RESULTS: During the study period, percutaneous coronary intervention (PCI) of a SVG represented 5.7% of the total PCI volume (91,355 of 1,596,966). Of the 84,875 patients who received a SVG stent, a DES was used in 64.5%. From 2005 to 2009, DES use in SVG PCI changed from 80% to 62%. Unfractionated heparin was used in 46%, enoxaparin in 17%, bivalirudin in 42%, and a glycoprotein IIb/IIIa inhibitor in 40% of cases. On multivariable analysis, several parameters (including the period, multivessel PCI, prior PCI, no acute myocardial infarction, and no smoking) were associated with DES use. CONCLUSIONS: Currently, DES are used in nearly two-thirds of SVG interventions. Several clinical parameters (such as the period of implantation and the complexity of coronary artery disease) are associated with the decision to implant a DES in these challenging lesions. PMID- 20965467 TI - Different patterns of vascular response between patients with or without diabetes mellitus after drug-eluting stent implantation: optical coherence tomographic analysis. AB - OBJECTIVES: We performed this study to investigate with optical coherence tomography (OCT) the vascular response after sirolimus-eluting stent (SES) implantation between patients with and those without diabetes mellitus (DM). BACKGROUND: The difference in vascular response after SES implantation between patients with and those without DM has not been fully evaluated with OCT. METHODS: Optical coherence tomography was performed to examine 74 nonrestenotic SES implanted in 63 patients (32 with DM and 31 without DM) at 9 months after SES implantation. For struts showing neointimal coverage, the neointimal thickness on the luminal side of each strut section was measured, and neointimal characteristics were classified into high, low, and layered signal pattern. RESULTS: Baseline patient characteristics and lesion and procedural characteristics data were similar between the 2 groups. In total, 11,422 struts were analyzed. High signal neointima was observed in 90.2 +/- 13.9%, low signal neointima in 7.3 +/- 10.0%, and layered neointima in 2.7 +/- 5.8%/stents. There was higher incidence of low signal neointima (10.5 +/- 10.3% vs. 4.5 +/- 5.6%, p = 0.003), neointimal thickness was larger (median: 106.8 MUm, interquartile range: 79.3 to 130.4 MUm vs. median: 83.5 MUm, interquartile range: 62.3 to 89.3 MUm; p < 0.0001), and neointimal coverage of stent struts was higher (92.1 +/- 6.2% vs. 87.2 +/- 11.9%; p = 0.03) in DM patients. CONCLUSIONS: High signal neointimal pattern was predominantly observed, and low or layered signal pattern was observed in some cases. In DM patients, low signal neointima was observed with high frequency. Neointimal coverage and neointimal thickness was also higher in DM patients as compared with non-DM patients. PMID- 20965468 TI - Anatomic and technical predictors of stent malposition during implantation for vascular obstruction in patients with congenital and acquired heart disease. AB - OBJECTIVES: We evaluated the anatomic and technical factors predicting stent malposition and embolization in patients undergoing endovascular stent implantation for relief of noncoronary vascular obstruction. BACKGROUND: Endovascular stent implantation provides a highly effective, minimally invasive solution to vascular obstruction in patients with structural heart disease. However, stent implantation is technically challenging and stent embolization occurs in up to 5.5% of cases. METHODS: We reviewed patient and procedural characteristics of all endovascular stent implantations performed for relieving noncoronary vascular obstruction from January 1, 1999, through December 31, 2009. Univariate and multivariate predictors of stent malposition or embolization were explored through logistic regression methods. RESULTS: During the 10-year study period, 429 stents were implanted. Of these, 399 were placed for relief of vascular obstruction in 267 patients during 322 procedures. Initial implantation failure occurred in 33 patients (8.3%), including stent malposition in 18 (4.5%) and stent embolization in 15 (3.8%). Patient size and vascular obstruction caused by external compression or a vascular fold were independent predictors of stent malposition or embolization. All malpositioned and embolized stents were successfully managed without surgery, and none resulted in death, sustained hemodynamic instability, or important vascular injury. CONCLUSIONS: Endovascular stent implantation is a highly effective and safe means of relieving noncoronary vascular obstruction in patients with congenital and acquired structural heart disease. Stent embolization occurs in approximately 3.8% of implantation procedures but can be managed successfully without surgical intervention. Anatomic and technical factors predict stent malposition, and consideration of these factors may improve procedural results. PMID- 20965469 TI - Still working on our short game: technique and accuracy of stent placement in congenital heart disease. PMID- 20965470 TI - Occlusion of a large expanding saphenous vein bypass graft aneurysm with percutaneously injected ethylene-vinyl alcohol copolymer. PMID- 20965471 TI - Successful revascularization by pulse infusion thrombolysis in a patient with Kawasaki disease combined with acute myocardial infarction. PMID- 20965472 TI - Reperfusion in acute myocardial infarction: should the guidelines be modified? PMID- 20965473 TI - Pre-hospital thrombolysis rather than primary percutaneous intervention is the treatment of choice for patients with ST-segment elevation myocardial infarction presenting early after the onset of symptoms. PMID- 20965476 TI - Timing of staged percutaneous coronary intervention in multivessel coronary artery disease. PMID- 20965477 TI - Trust me, I'm a doctor. PMID- 20965478 TI - [Papillomas & laryngeal papillomatosis. Treatment with CO2 laser surgery. Our experience over 15 years]. AB - OBJECTIVES: The study goal was to evaluate the efficacy of CO2 laser surgery in the treatment of laryngeal papillomatosis. We analysed several parameters such as gender, average age, relapse rate and viral serotype. MATERIAL AND METHODS: A total of 26 diagnosed patients were included in this retrospective descriptive review. All of them were treated with CO2 laser for laryngeal papillomas between 1995 and 2010. RESULTS: This pathology was more prevalent in males (65.5%), with a slight predominance of a single larynx localisation over multiple lesion locations. Human papillomavirus (HPV) DNA was detected in 75.8% of the cases; genotypes 6 and 11 prevailed. Of the patients in this review, 44.8% relapsed; the relapse average was 2-3 episodes per patient. A total of 20.7% of cases were in remission (no relapse in the last 2 months); 34.5%, clearing (no apparent relapse in the last 3 years); and 41.3% in the healing stage (without relapse in the last 5 years). There was only one case that showed malignancy. CONCLUSION: Papillomatosis is characterised as a pathology with an unpredictable course and with a low probability of malignancy. CO2 laser surgery has meant a revolution in symptomatic treatment, but there is presently no curative treatment. PMID- 20965479 TI - Language can mediate eye movement control within 100 milliseconds, regardless of whether there is anything to move the eyes to. AB - The delay between the signal to move the eyes, and the execution of the corresponding eye movement, is variable, and skewed; with an early peak followed by a considerable tail. This skewed distribution renders the answer to the question "What is the delay between language input and saccade execution?" problematic; for a given task, there is no single number, only a distribution of numbers. Here, two previously published studies are reanalysed, whose designs enable us to answer, instead, the question: How long does it take, as the language unfolds, for the oculomotor system to demonstrate sensitivity to the distinction between "signal" (eye movements due to the unfolding language) and "noise" (eye movements due to extraneous factors)? In two studies, participants heard either 'the man...' or 'the girl...', and the distribution of launch times towards the concurrently, or previously, depicted man in response to these two inputs was calculated. In both cases, the earliest discrimination between signal and noise occurred at around 100ms. This rapid interplay between language and oculomotor control is most likely due to cancellation of about-to-be executed saccades towards objects (or their episodic trace) that mismatch the earliest phonological moments of the unfolding word. PMID- 20965480 TI - Orthography, phonology, short-term memory and the effects of concurrent articulation on rhyme and homophony judgements. AB - The role of phonological short-term memory (pSTM) in phonological judgement tasks of print has been widely explored using concurrent articulation (CA). A number of studies have examined the effects of CA on written word/nonword rhyme and homophone judgements but the findings have been mixed and few studies have examined both tasks within subjects. Also important is the influence of orthographic similarity on such tasks (i.e., items that share phonology often strongly overlap on orthography). Although there are reports of orthographic similarity effects (e.g., LOAD-TOAD vs. DIAL-MILE) on rhyme judgements, it is unknown whether (a) similar orthographic effects are present with homophone judgements, (b) the degree to which such orthographic effects interact with CA, and (c) the degree to which such orthographic effects interact with lexical status (words vs. nonwords). The present work re-examines these three issues in a within subject design. CA and orthographic similarity yielded subtle differences across tasks. CA impaired accuracy for both homophone and rhyme judgement, but only slowed RTs on the rhyme judgement task, and then only for words. Orthographic similarity yielded an increase in false positives for similar items and vice versa for dissimilar items, suggesting a general impact of an orthographically based 'bias' in choosing similar or dissimilar sounding items. This pattern was amplified under CA but only on the homophone judgement task. These results highlight important interactions between phonological and orthographic representations in phonological judgement tasks, and the findings are considered both with reference to earlier studies and several models of pSTM. PMID- 20965481 TI - Mesh contraction: myth or reality? AB - OBJECTIVE: Mesh implants are widely used in surgery for female pelvic organ prolapse. Mesh shrinkage is thought to be common and caused by immunological processes. In this longitudinal study, we examined mesh dimensions at 2 time points after implantation. STUDY DESIGN: We analyzed translabial 4-dimensional ultrasound (US) volume datasets of women seen 3-52 months after anterior compartment mesh. Datasets of first and last postoperative appointments were analyzed, with the operator blinded against all other data. RESULTS: Forty women were assessed at least twice, comprising 59.6 woman-years. Thirty-seven of 40 (93%) were satisfied at their last appointment. Eighteen of 40 considered themselves cured, and 18 of 40 felt improved. Objective recurrence (cystocele stage 2 or greater) was seen in 16 of 40. Midsagittal mesh length increased significantly (35.8 vs 32.7; P = .006), and coronal mesh diameters increased nonsignificantly (37.4 vs 36.6 mm; P = .44). CONCLUSION: Over an observation period of almost 60 woman-years, we found no evidence of mesh contraction. PMID- 20965482 TI - Cost-effectiveness of elective induction of labor at 41 weeks in nulliparous women. AB - OBJECTIVE: To investigate the cost-effectiveness of elective induction of labor at 41 weeks in nulliparous women. STUDY DESIGN: A decision analytic model comparing induction of labor at 41 weeks vs expectant management with antenatal testing until 42 weeks in nulliparas was designed. Baseline assumptions were derived from the literature as well as from analysis of the National Birth Cohort dataset and included an intrauterine fetal demise rate of 0.12% in the 41st week and a cesarean rate of 27% in women induced at 41 weeks. One-way and multiway sensitivity analyses were conducted to examine the robustness of the findings. RESULTS: Compared with expectant management, induction of labor is cost-effective with an incremental cost of $10,945 per quality-adjusted life year gained. Induction of labor at 41 weeks also resulted in a lower rate of adverse obstetric outcomes, including neonatal demise, shoulder dystocia, meconium aspiration syndrome, and severe perineal lacerations. CONCLUSION: Elective induction of labor at 41 weeks is cost-effective and improves outcomes. PMID- 20965483 TI - First-trimester 3-dimensional power Doppler for the screening of preeclampsia: the analysis of a greater proportion of the uteroplacental unit might improve the accuracy of the method. PMID- 20965484 TI - Role of GPR30 in endometrial pathology after tamoxifen for breast cancer. AB - OBJECTIVE: This study was undertaken to evaluate the potential role of G-protein coupled estrogen receptor in endometrial pathology associated with tamoxifen treatment of breast cancer patients. STUDY DESIGN: We investigated whether G protein-coupled estrogen receptor plays a role in mediating proliferating effect of tamoxifen in endometrial carcinoma cells. These results were compared with the G-protein-coupled estrogen receptor expression pattern in endometrial tissue from a cohort of 95 breast cancer patients, who received tamoxifen or another adjuvant therapy. RESULTS: In vitro tamoxifen significantly stimulated the mitogen activated protein kinase phosphorylation and cell proliferation of endometrial cell lines via G-protein-coupled estrogen receptor. In vivo, there was a significant correlation between G-protein-coupled estrogen receptor expression and the tamoxifen-induced endometrial pathology (P = .006). Moreover, G-protein coupled estrogen receptor positivity was predictive of an earlier development of symptoms, such as bleeding or suspect endometrial thickness, induced by tamoxifen therapy (P = .019). CONCLUSION: G-protein-coupled estrogen receptor plays an important role in tamoxifen-induced endometrial abnormalities. PMID- 20965485 TI - Decreased term and postterm birthweight. PMID- 20965488 TI - Is uterine artery Doppler investigation a useful predictor of complications in severe early onset preeclampsia? PMID- 20965486 TI - Pregnancy outcome at extremely advanced maternal age. AB - OBJECTIVE: The purpose of this study was to evaluate pregnancy outcome in women at extremely advanced maternal age (>= 45 years). STUDY DESIGN: We compared the condition of women aged >= 45 years (n = 177) in a 10:1 ratio (20-29, 30-39, and 40-44 years.). Subgroup analysis compared the condition of women aged 45-49 years with those women aged >= 50 years. RESULTS: The rates of gestational diabetes mellitus and hypertensive complications were higher for the study group, compared with the whole group (17.0% vs 5.6% and 19.7% vs 4.5%, respectively; P < .001), as was the rate of preterm delivery at <37 and <34 weeks of gestation (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.2-3.6 and OR, 3.5; 95% CI, 1.4-9.0, respectively). The rates of cesarean delivery (OR, 31.8; 95% CI, 18.0-56.1), placenta previa, postpartum hemorrhage, and adverse neonatal outcome were significantly higher among the study group. The risk for gestational diabetes mellitus, preeclampsia toxemia, preterm delivery, and neonatal intensive care unit admission was increased for women aged >= 50 years. CONCLUSION: Pregnancy at extreme advanced maternal age is associated with increased maternal and fetal risk. PMID- 20965489 TI - Hyaluronidase modifies the biomechanical properties of the rat cervix and shortens the duration of labor independent of myometrial contractility. AB - OBJECTIVE: To investigate the effect of intracervical hyaluronidase on the biomechanical properties of the cervix and on uterine contractility. STUDY DESIGN: Sprague-Dawley rats (n = 33, term day 22) were injected with hyaluronidase (100 IU) or saline solution on day 18 of gestation (n = 8-9/group). On day 21, labor was induced with mifepristone (8 mg/rat). Injection-to-delivery times were recorded. Biomechanical properties of the cervix were assessed using stretch-tension analysis. Myometrial contractility was investigated in response to hyaluronidase (0.2-200 IU/mL), oxytocin (10(-10)M to 10(-5)M), and potassium chloride (60 mM). RESULTS: Delivery times were shorter in the hyaluronidase group (P = .03). Cervices of the treated animals showed higher measures of elasticity and plasticity (P = .02 for both). Myometrial sensitivity to hyaluronidase, oxytocin, or potassium chloride was not affected by the cervical application of hyaluronidase (P > .05 for all). CONCLUSION: Cervical hyaluronidase treatment shortens labor and alters the biomechanical properties of the cervix, independent of the myometrium. PMID- 20965490 TI - Adverse events in pregnant women following administration of trivalent inactivated influenza vaccine and live attenuated influenza vaccine in the Vaccine Adverse Event Reporting System, 1990-2009. AB - OBJECTIVE: The objective of the study was to characterize reports to the Vaccine Adverse Event Reporting System (VAERS) in pregnant women who received seasonal influenza vaccines to assess for potential vaccine safety concerns. STUDY DESIGN: We searched VAERS for reports of adverse events (AEs) in pregnant women who received trivalent inactivated influenza vaccine (TIV) from July 1, 1990 through June 30, 2009, or live attenuated influenza vaccine (LAIV) from July 1, 2003, through June 30, 2009. RESULTS: A total of 148 reports after TIV and 27 reports after LAIV were identified. Twenty TIV (13.5%) and 1 LAIV (4%) reports were classified as serious. No specific AEs were reported in 30 TIV (20.3%) and 16 LAIV (59%) reports. The most common pregnancy-specific AE was spontaneous abortion: 17 after TIV (11.5%) and 3 after LAIV (11%). The reporting rate of spontaneous abortion was 1.9 per million pregnant women vaccinated. CONCLUSION: No unusual patterns of pregnancy complications or fetal outcomes were observed in the VAERS reports of pregnant women after the administration of TIV or LAIV. PMID- 20965491 TI - Trocar-guided mesh repair of vaginal prolapse using partially absorbable mesh: 1 year outcomes. AB - OBJECTIVE: To evaluate anatomic and functional outcomes at 1-year following trocar-guided transvaginal prolapse repair using a partially absorbable mesh. STUDY DESIGN: Prospective multicentre cohort study at 11 international sites. One hundred twenty-seven patients with pelvic organ prolapse stage >= III had surgery and were evaluated at 3 months and 1-year postsurgery compared with baseline. Instruments of measurements: Pelvic Organ Prolapse Quantification, Pelvic Floor Distress Inventory-20, Pelvic Floor Impact Questionnaire-7, Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire-12, and Patients Global Impression of Change. RESULTS: Anatomic success, defined as prolapse stage <= I in the treated vaginal compartments, was 77.4% (95% confidence interval, 69.0-84.4%). Significant improvements in bother, quality of life, and sexual function were detected at 3 months and 1 year compared with baseline. At 1-year after surgery, 86.2% of patients indicated their prolapse situation to be "much better." Mesh exposure rate was 10.2% and rate of de novo dyspareunia 2% at 1 year. CONCLUSION: These results demonstrate improved anatomic support, associated with excellent functional improvements, without apparent safety concerns. PMID- 20965493 TI - Distinct DNA methylation profiles in ovarian serous neoplasms and their implications in ovarian carcinogenesis. AB - OBJECTIVE: The purpose of this study was to analyze DNA methylation profiles among different types of ovarian serous neoplasm, which is a task that has not been performed. STUDY DESIGN: The Illumina beads array (Illumina Inc, San Diego, CA) was used to profile DNA methylation in enriched tumor cells that had been isolated from 75 benign and malignant serous tumor tissues and 6 tumor-associated stromal cell cultures. RESULTS: We found significantly fewer hypermethylated genes in high-grade serous carcinomas than in low-grade serous carcinoma and borderline tumors, which in turn had fewer hypermethylated genes than serous cystadenoma. Unsupervised analysis identified that serous cystadenoma, serous borderline tumor, and low-grade serous carcinomas tightly clustered together and were clearly different from high-grade serous carcinomas. We also performed supervised analysis to identify differentially methylated genes that may contribute to group separation. CONCLUSION: The findings support the view that low-grade and high-grade serous carcinomas are distinctly different with low grade, but not high-grade, serous carcinomas that are related to serous borderline tumor and cystadenoma. PMID- 20965494 TI - Reproducibility of retinal thickness measurements on normal and pathologic eyes by different optical coherence tomography instruments. AB - PURPOSE: To compare retinal thickness measurements produced by different time domain and spectral-domain optical coherence tomography (TD-OCT and SD-OCT) devices when imaging normal and pathologic eyes. DESIGN: Prospective, observational study in an academic institutional setting. METHODS: A total of 110 eyes were imaged by 6 different OCT devices: Stratus and Cirrus (Carl Zeiss Meditec Inc), Spectralis HRA+OCT (Heidelberg Engineering), RTVue-100 (Optovue Inc), SDOCT Copernicus HR (Optopol Technology S.A.), and 3D OCT-1000 (Topcon Corporation). Eyes were normal or affected by different pathologies of the retina, including exudative and nonexudative age-related macular degeneration, epiretinal membrane, cystoid macular edema, and macular hole. For each instrument we used standard analysis protocols for macular thickness evaluation. Mean retinal thickness values between the instruments in the ETDRS central circular 1000-MUm-diameter areas and in the ETDRS midperipheral circular 3000-MUm-diameter areas were compared. RESULTS: The 6 different devices produced measurements that differ in variance (Bartlett test, P = .006), and mean values (Friedman test, P < .001). Bland-Altman analysis revealed that the limits of agreement for all the comparisons were not acceptable. Regression was calculated and it was elaborated into a conversion table, despite a high standard error for both intercepts and slope conversion values. CONCLUSIONS: This study suggests that retinal thickness measurements obtained with various OCT devices are different beyond clinical practice tolerance, according to Bland-Altman analysis. Furthermore, regression analysis reveals high standard error values. These differences appear to be primarily attributable to the analysis algorithms used to set retinal inner and outer boundaries. PMID- 20965495 TI - Nursing staff's movement awareness, attitudes and reported behaviour in patient transfer before and after an educational intervention. AB - The objective was to evaluate changes after a two half-day patient transfer course regarding nursing staff's movement and body awareness, attitudes, reported behaviour, strain, disorder and sick leave. The course aimed at increasing staff's self-awareness of movements and body, and their communication competence, with the intention to promote the patient's independent mobility. Ninety-nine staff in an intervention group and 77 staff in two control groups answered a questionnaire before and after the intervention. After one year there was a significant increase in the number of instructions given and nursing staff's movement awareness in the intervention group compared to the control group. Reported physical disorders decreased significantly in the intervention group compared with both control groups. Increased movement awareness and frequent use of instructions during transfers may encourage patients to move independently and thereby reduce the strain in nursing staff. PMID- 20965496 TI - Differentiating frontostriatal and fronto-cerebellar circuits in attention deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) has long been conceptualized as a neurobiological disorder of the prefrontal cortex and its connections. Circuits with the prefrontal cortex relevant to ADHD include dorsal frontostriatal, orbitofronto-striatal, and fronto-cerebellar circuits. Dorsal frontostriatal circuitry has been linked to cognitive control, whereas orbitofronto-striatal loops have been related to reward processing. Fronto-cerebellar circuits have been implicated in timing. Neurobiological dysfunction in any of these circuits could lead to symptoms of ADHD, as behavioral control could be disturbed by: 1) deficits in the prefrontal cortex itself; or 2) problems in the circuits relaying information to the prefrontal cortex, leading to reduced signaling for control. This article suggests a model for differentiating between interlinked reciprocal circuits with the prefrontal cortex in ADHD. If such a differentiation can be achieved, it might permit a neurobiological subtyping of ADHD, perhaps by defining "dorsal fronto-striatal," "orbitofronto-striatal," or "fronto cerebellar" subtypes of ADHD. This could be useful as a template for investigating the neurobiology of ADHD and, ultimately, clinically. PMID- 20965497 TI - Immediate and sustained improvements in working memory after selective stimulation of alpha7 nicotinic acetylcholine receptors. AB - BACKGROUND: Nicotine improves cognition in humans and animal models of neuropsychiatric disorders. Here, we sought to establish whether selective stimulation of the neuronal nicotinic alpha7 receptor could improve spatial working memory in nonhuman primates. METHODS: Beginning with an estimated dose range from rodent studies, the dose of the alpha7 agonist AZD0328 was titrated for a significant impact on working memory in rhesus macaques after acute administration. After training to stability on the spatial delayed response task, subjects were administered AZD0328 (1.6 ng/kg-.48 mg/kg; intramuscular) or vehicle 30 min before cognitive testing. AZD0328 (1 ng/kg-1.0 MUg/kg; intramuscular) was then administered in a repeated, intermittent ascending dose regimen where each dose was given in two bouts for 4 days with a 1-week washout in between bouts, followed by 2-week washout. RESULTS: Acute AZD0328 improved cognitive performance when the dose was titrated down to .0016 and .00048 mg/kg from a cognitively impairing dose of .48 mg/kg. In a subgroup, sustained enhancement of working memory was evident for 1 month or more after acute treatment. Immediate and sustained cognitive enhancement was also found during and after repeated administration of AZD0328 at .001 mg/kg. CONCLUSIONS: These findings demonstrate that extremely low doses of a nicotinic alpha7 agonist can have profound acute and long-lasting beneficial consequences for cognition, dependent upon the integrity of dorsolateral prefrontal cortex. Thus, the alpha7 receptor might have a fundamental role in the neural circuitry of working memory and in the synaptic plasticity upon which it might depend. PMID- 20965498 TI - Remember the future: working memory training decreases delay discounting among stimulant addicts. AB - BACKGROUND: Excessive discounting of future rewards has been observed in a variety of disorders and has been linked both to valuation of the past and to memory of past events. METHODS: To explore the functionality of discounting and memory, we examined whether training of working memory would result in less discounting of future rewards. In this study, 27 adults in treatment for stimulant use were randomly assigned to receive either working memory training or control training according to a yoked experimental design. Measures of delay discounting and several other cognitive behaviors were assessed pre- and posttraining. RESULTS: Rates of discounting of delayed rewards were significantly reduced among those who received memory training but were unchanged among those who received control training; other cognitive assessments were not affected by memory training. Discount rates were positively correlated with memory training performance measures. CONCLUSIONS: To our knowledge, this is the first study demonstrating that neurocognitive training on working memory decreases delay discounting. These results offer further evidence of a functional relationship between delay discounting and working memory. PMID- 20965499 TI - Reactions of nonsymmetrical bidentate linkers having a phthalimidoyl and acid chloride group or a 2-benzothiazole group with alpha-D-glucoside derivatives and their application for the modification of cellulose. AB - The reaction of 'active ester' bidentate cross-linking reagents, phthalimido 4 chloroformylbutanoate (1) and phthalimido 4-(2 benzothiazolyloxycarbonyl)butanoate (2) with several protected D-glucose derivatives is described. These reactions are used to introduce the reactive group into cellulose (filter paper) with the aim of linking proteins and cellulose. PMID- 20965500 TI - [Single port laparoscopic cholecystectomy in major ambulatory surgery (MAS)]. AB - INTRODUCTION: Natural orifice endoscopic surgery is a new surgical procedure still in the development phase. The most natural entry for surgeons is to use an already existing scar, such as the navel. The recent introduction of trocars designed for this purpose has made it possible to put this into practice. MATERIAL AND METHODS: We present our preliminary experience in single trans umbilical incision laparoscopic cholecystectomy, by means of a prospective study which included 26 patients operated on between January 2009 and January 2010. We also attempt to find out whether it can be performed in a MAS programme. RESULTS: All patients had uncomplicated cholelithiasis, although in 5 of them cholecystitis was identified during the surgery. The mean surgical time was 51.2 min. The mean hospital stay was 25.7h, and 76.92% of patients were admitted for less than 24h. There were no re-admissions or significant intra-operative or post operative complications. CONCLUSIONS: On looking at our results, single port laparoscopic cholecystectomy could be included in a major ambulatory surgery programme. PMID- 20965501 TI - Males outperform females in translating social relations into spatial positions. AB - Research indicates that human males interact in groups, whereas females form one on-one relationships. Whereas females excel in understanding intimate verbally mediated social information, we hypothesized that males would be more sensitive to the spatial positions of friends within a group. In Study 1, we demonstrate that after a very brief exposure, compared to females, males more accurately recalled the spatial positions of individuals who were friendly with one another when their relative positions mirrored their friendship structures. In Study 2, we demonstrate that females were as accurate as males in reconstituting the positions of individuals who were not friends with one another. In Study 3, we demonstrate that the male advantage remains when indirect cues to positive group relations are used. These results support the idea that the group-based social structure of males renders them more sensitive than females to the use of relational information in reconstituting the short-term spatial locations of group members. PMID- 20965502 TI - Gaze allocation in a dynamic situation: effects of social status and speaking. AB - Human visual attention operates in a context that is complex, social and dynamic. To explore this, we recorded people taking part in a group decision-making task and then showed video clips of these situations to new participants while tracking their eye movements. Observers spent the majority of time looking at the people in the videos, and in particular at their eyes and faces. The social status of the people in the clips had been rated by their peers in the group task, and this status hierarchy strongly predicted where eye-tracker participants looked: high-status individuals were gazed at much more often, and for longer, than low-status individuals, even over short, 20-s videos. Fixation was temporally coupled to the person who was talking at any one time, but this did not account for the effect of social status on attention. These results are consistent with a gaze system that is attuned to the presence of other individuals, to their social status within a group, and to the information most useful for social interaction. PMID- 20965503 TI - Assessment of the genotoxic potential of contaminated estuarine sediments in fish peripheral blood: laboratory versus in situ studies. AB - Juvenile Senegalese soles (Solea senegalensis) were exposed to estuarine sediments through 28-day laboratory and in situ (field) bioassays. The sediments, collected from three distinct sites (a reference plus two contaminated) of the Sado Estuary (W Portugal) were characterized for total organic matter, redox potential, fine fraction and for the levels of metals, polycyclic aromatic hydrocarbons (PAHs) and organochlorines, namely polychlorinated biphenyls (PCBs) and dichloro diphenyl tricholoethane plus its main metabolites (DDTs). Genotoxicity was determined in whole peripheral blood by the single-cell gel electrophoresis (SCGE or "comet") assay and by scoring erythrocytic nuclear abnormalities (ENA). Analysis was complemented with the determination of lipid peroxidation in blood plasma by the thiobarbituric acid reactive substances (TBARS) protocol and cell type sorting. The results showed that exposure to contaminated sediments induced DNA fragmentation and clastogenesis. Still, laboratory exposure to the most contaminated sediment revealed a possible antagonistic effect between metallic and organic contaminants that might have been enhanced by increased bioavailability. The laboratory assay caused a more pronounced increase in ENA whereas a very significant increase in DNA fragmentation was observed in field-tested fish exposed to the reference sediment, which is likely linked to increased lipid peroxidation that probably occurred due to impaired access to food. Influence of natural pathogens was ruled out by unaltered leukocyte counts. The statistical integration of data correlated lipid peroxidation with biological variables such as fish length and weight, whereas the genotoxicity biomarkers were more correlated to sediment contamination. It was demonstrated that laboratory and field bioassays for the risk assessment of sediment contamination may yield different genotoxicity profiles although both provided results that are in overall accordance with sediment contamination levels. While field assays may provide more ecologically relevant data, the multiple environmental variables may produce sufficient background noise to mask the true effects of contamination. PMID- 20965504 TI - CYP1A1 polymorphism in adolescents with polycystic ovary syndrome. AB - OBJECTIVE: To evaluate the rates of the CYP1A1 Ile/Val polymorphism in Turkish adolescent females. METHODS: The CYP1A1 Ile/Val polymorphism was analyzed by collecting DNA samples from 44 adolescents with polycystic ovary syndrome (PCOS)- according to the Rotterdam criteria--and 120 healthy female controls aged 13-18 years in Ankara, Turkey. RESULTS: There was a 2.5-fold increase in the frequency of the CYP1A1 Ile/Val genotype in adolescents with PCOS compared with the control group (odds ratio [OR] 2.54; 95% confidence interval [CI], 1.143-5.637; P<0.001), in addition to a 2.4-fold increase in the frequency of the Val allele (OR 2.43; 95% CI, 1.099-5.397; P<0.001). CONCLUSION: The data show an association between CYP1A1 and PCOS, indicating that variant alleles of the gene may affect the metabolic and transport pathway of estrogens, thus causing PCOS. PMID- 20965505 TI - Thyroid function in the third trimester of pregnancy and after delivery in an area of adequate iodine intake. AB - OBJECTIVE: To establish whether the higher thyroid stimulating hormone (TSH) levels and lower levels of the 2 free thyroid hormones noted toward the end of pregnancy are in relation with iodine supply. METHODS: We compared these hormones' levels in the third trimester of pregnancy and 4 months after delivery in 116 consecutive women without thyroid disease and otherwise healthy. The study was conducted in Slovenia, an iodine-sufficient area. The Mann-Whitney test, the Kruskal-Wallis rank test, and Spearman analysis were used for statistical analysis. RESULTS: In the third trimester TSH was significantly higher and both free thyroid hormones were significantly lower than after delivery (P=0.003 and P<0.001), but the free thyroxine to free triiodothyronine ratios in the third trimester and 4 months after delivery did not significantly differ. Urinary iodine concentration (UIC) was significantly higher during pregnancy than after delivery (P=0.044). We found no significant correlations between UIC and TSH or between UIC and both free thyroid hormones during pregnancy or after delivery. CONCLUSION: The decrease of both free thyroid hormones in the third trimester of pregnancy is most likely due to reasons that are not related to iodine supply. PMID- 20965506 TI - Cardiac and arterial calcifications and all-cause mortality in the elderly: the PROTEGER Study. AB - OBJECTIVE: To investigate the association of overall mortality with the presence and extent of cardiovascular calcifications. METHODS: We investigated the association of cardiac (mitral annulus, aortic valve) and arterial calcifications (abdominal aorta, carotid and femoral arteries) by ultrasonography, with all cause mortality in a population of 331 high-risk elderly subjects (86.8 +/- 6.9 years). After a mean follow-up of 378 days, 110 deaths occurred. RESULTS: A simple calcification score, defined by the presence of cardiac and arterial calcifications, was significantly associated with all-cause mortality (HR=1.47, 95% CI: 1.08-1.99), independent of low plasma albumin, increased plasma glucose and creatinine, as well as low diastolic blood pressure. Moreover, arterial calcifications showed negligible prognostic value with a high prevalence >89%, while cardiac calcifications significantly predicted overall mortality (HR=1.92, 95% CI: 1.28-2.87) at a prevalence of 36%. In another Cox regression, mitral annular calcification was proved to be a significant predictor of total mortality (HR=1.61, 95% CI: 1.02-2.54). CONCLUSION: The independent association between the extent of calcification and all-cause mortality is consistently significant in this frail elderly population. Arterial calcification presents a very high prevalence but a low predictive value, whereas in cardiac calcification, prevalence is lower but predictive value is much higher. PMID- 20965507 TI - The mechanical heterogeneity of the hard callus influences local tissue strains during bone healing: a finite element study based on sheep experiments. AB - During secondary fracture healing, various tissue types including new bone are formed. The local mechanical strains play an important role in tissue proliferation and differentiation. To further our mechanobiological understanding of fracture healing, a precise assessment of local strains is mandatory. Until now, static analyses using Finite Elements (FE) have assumed homogenous material properties. With the recent quantification of both the spatial tissue patterns (Vetter et al., 2010) and the development of elastic modulus of newly formed bone during healing (Manjubala et al., 2009), it is now possible to incorporate this heterogeneity. Therefore, the aim of this study is to investigate the effect of this heterogeneity on the strain patterns at six successive healing stages. The input data of the present work stemmed from a comprehensive cross-sectional study of sheep with a tibial osteotomy (Epari et al., 2006). In our FE model, each element containing bone was described by a bulk elastic modulus, which depended on both the local area fraction and the local elastic modulus of the bone material. The obtained strains were compared with the results of hypothetical FE models assuming homogeneous material properties. The differences in the spatial distributions of the strains between the heterogeneous and homogeneous FE models were interpreted using a current mechanobiological theory (Isakson et al., 2006). This interpretation showed that considering the heterogeneity of the hard callus is most important at the intermediate stages of healing, when cartilage transforms to bone via endochondral ossification. PMID- 20965508 TI - Fast determination of arsenosugars in algal extracts by narrow bore high performance liquid chromatography-inductively coupled plasma mass spectrometry. AB - The potential of narrow bore high-performance liquid chromatography (HPLC) with detection by inductively coupled plasma mass spectrometry (ICP-MS) for fast determination of arsenosugars in algal extracts was explored. The retention behavior of four naturally occurring dimethylarsinoylribosides on an anion exchange microbore column was investigated, with the mobile phase flow rate ranging from 60 to 200MULmin(-1). A low sample consumption system consisting of a micronebulizer and a low inner volume cyclonic spray chamber was used as the interface between the micro-column and the ICP mass spectrometer. Both the high efficiency nebulizer, HEN, and the PFA micronebulizer were tested, with the former providing 20-50% greater sensitivity than PFA (depending on the liquid flow rate), but comparable limits of detection and slightly lower chromatographic resolution. With the setup employed and under the optimal conditions, a satisfactory separation of the arsenosugars was achieved in less than 5min. The instrumental limit of detection was 0.20MUgAsL(-1) and the precision was better than 3% (RSD%, n=5). The accuracy of the determination was verified by the analysis of a reference algal extract, obtaining values in good agreement with the reference ones. PMID- 20965509 TI - Influence of carrier gas on the prediction of gas chromatographic retention times based on thermodynamic parameters. AB - We present an investigation into the influence of carrier gas on the thermodynamics governing a capillary gas chromatographic separation. Thermodynamic parameters are estimated for a series of alkanes and alcohols on three common stationary phases using helium, hydrogen, and nitrogen carrier gases. It is shown that the substitution of carrier gases for one another results in a change in the thermodynamic parameters governing the separation. The effect of the carrier gas on the thermodynamic parameters is large enough to compromise the accuracy of the retention time calculations based on thermodynamic parameters collected in a carrier gas other than the one actually in use in a specific gas chromatographic system. A possible kinetic explanation for these observations is also investigated. PMID- 20965510 TI - Preparation and application of solid-phase microextraction fiber based on molecularly imprinted polymer for determination of anabolic steroids in complicated samples. AB - A relatively selective, chemically and physically robust SPME fiber was developed in a simple way with testosterone-imprinted polymer, and then directly coupled with gas chromatography-mass spectrometry (GC-MS) for selective extraction and analysis of anabolic steroids. The factors influencing polymerization (i.e., cross-linker, polymerization solvent, polymerization time) were optimized in detail and the polymer was characterized by scanning electron microscope, infrared spectrometer and thermogravimetric analyzer. Furthermore, the extraction performance of the MIP-coated SPME fibers such as extraction ability and selectivity was evaluated. Moreover, the interaction mode between target analytes and fiber coating was deducted. Finally, the method for extraction and determination of androsterone, stanolone, androstenedione and methyltestosterone by the homemade MIP-coated SPME fibers with GC-MS was obtained. It was applied to the simultaneous analysis of four anabolic steroids in the spiked human urine with the satisfactory recoveries. PMID- 20965511 TI - On the stability of the polymer brushes formed by adsorption of ionomer complexes on hydrophilic and hydrophobic surfaces. AB - We have studied the effect of normal forces and shear forces on the stability and functionality of a polymer brush layer formed upon adsorption of polymeric micelles on hydrophilic and hydrophobic surfaces. The micelles consist of oppositely charged polyelectrolyte blocks (poly(acrylic acid) and poly(N-methyl 2 vinyl pyridinium iodide), and a neutral block (poly(vinyl alcohol)) or neutral grafts (poly(ethylene oxide)). The strength of the attachment of the micellar layers to various substrates was evaluated with Atomic Force Microscopy. Flow cell experiments allowed for the evaluation of long-term stability of coatings in lateral flow. Fixed angle optical reflectometry was used to quantify protein (BSA) adsorption on the micellar layers after their exposure to flow. The results show that adsorbed micellar layers are relatively weakly attached to hydrophobic surfaces and much stronger to hydrophilic surfaces, which has a significant impact on their stability. Adsorbed layers maintain their ability to suppress protein adsorption on hydrophilic surfaces but not on hydrophobic surfaces. Due to the relatively weak attachment to hydrophobic surfaces the structure of adsorbed layers may easily be disrupted by lateral forces, such that the complex coacervate-brush structure no longer exists. PMID- 20965512 TI - Time-dependent shrinkage of polymeric micelles of amphiphilic block copolymers containing semirigid oligocholate hydrophobes. AB - Alkyne-derivatized poly(ethylene glycol) (M.W. 5000) was coupled to several azide terminated oligocholates by the click reaction to form amphiphilic block copolymers. A copolymer with a cholate hexamer as the hydrophobic block formed polymeric micelles that shrank by ~50% over a period of 10 h at 25 degrees C. Shrinkage was faster and more dramatic at 35 degrees C. Shortening the oligocholate by two units or inserting a 4-aminobutyroyl spacer in the hexacholate eliminated or diminished the shrinkage. Metastable aggregates were proposed to form when the block copolymers began to aggregate in water. The large hydrophobic surface, awkward shape, rigidity, and facial amphiphilicity of the cholate repeat unit and the long chain made it difficult for the oligocholates to adjust within the micellar core. As the oligocholates rearranged to maximize hydrophobic interactions and hydrogen-bonding while minimizing conformational strain, the polymeric micelles became more compact over time. PMID- 20965513 TI - Photoinduced electron and energy transfer from coumarin 153 to perylenetetracarboxylic diimide in bmimPF6/TX-100/water microemulsions. AB - A perylenetetracarboxylic diimide (PDI) compound with an attached hydrophilic polyoxyethylene group at the imide nitrogen position was designed and synthesized. Photoinduced electron and energy transfer between coumarin 153 (C 153) and PDI in a ternary microemulsion with an ionic liquid (bmimPF(6)/TX 100/H(2)O) were investigated by steady state electronic absorption and fluorescence spectroscopy. The results revealed that both PDI and C-153 resided at the interface between the surfactant TX-100 and the ionic liquid bmimPF(6) in the ternary microemulsions. The absorption spectra suggested no interactions between C-153 and PDI in the ground states, but the fluorescence spectra revealed the presence of an efficient electron transfer and a less efficient energy transfer from C-153 to PDI. Moreover, the electron transfer was much more efficient in microemulsions than that in homogeneous conventional organic solvents due to the unique micro-environment of the microemulsion. PMID- 20965515 TI - Diffusion tensor imaging and tract-based spatial statistics in obsessive compulsive disorder. AB - There is increasing evidence of white matter abnormalities in patients with obsessive-compulsive disorder (OCD). The results of previous diffusion tensor imaging (DTI) studies, however, are inconsistent. Reasons for this inconsistency may include methodological issues such as misregistration, the differences in smoothing voxel-based morphometry style analysis or both. To date there are no DTI studies with tract-based spatial statistics (TBSS) which overcome these issues. In addition, previous studies had few drug-free patients, thus potentially reducing their power and obscuring their findings. Therefore, the aim of present study was to investigate white matter abnormalities using DTI and TBSS analysis in a large sample of drug-free patients with OCD. Thirty drug-free patients with OCD and 30 healthy controls underwent DTI. Fourteen of 30 patients were drug naive. Voxel-wise group comparison of white matter fractional anisotropy (FA) was performed using TBSS. Compared to healthy volunteers, OCD patients had statistically less FA in the anterior body of corpus callosum (CC) (p < .05, corrected). They also had a trend for a lower FA in the large portion of CC, the right cingulum, and the left anterior limb of internal capsule (ALIC). There were no areas of the brain with significantly higher FA. This is the first study that has investigated white matter abnormalities in non-medicated patients with OCD using DTI and TBSS analyses. Microstructural white matter abnormalities in the CC, the cingulum, and the ALIC might be involved in the pathophysiology of OCD. PMID- 20965514 TI - Perinatal events and early magnetic resonance imaging in therapeutic hypothermia. AB - OBJECTIVE: To compare the association between perinatal events and the pattern and extent of brain injury on early magnetic resonance imaging in newborn infants with and without therapeutic hypothermia for hypoxic-ischemic encephalopathy. STUDY DESIGN: We performed a cohort study of 35 treated and 25 nontreated neonates who underwent magnetic resonance imaging. The injury patterns were defined a priori as: normal, watershed, or basal ganglia/thalamus-predominant, as well as a dichotomous outcome of moderate-to-severe versus mild-no injury. RESULTS: Neonates with hypothermia had less extensive watershed and basal ganglia/thalamus injuries and a greater proportion had normal imaging. Therapeutic hypothermia was associated with a decreased risk of both basal ganglia/thalamus injury (relative risk, 0.29; 95% CI, 0.10 to 0.81, P = .01) and moderate-severe injury. Neonates with sentinel events showed a decrease in basal ganglia/thalamus-predominant injury and an increase in normal imaging. All neonates with decreased fetal movements had injury, predominantly watershed, regardless of therapeutic hypothermia. CONCLUSIONS: These results validate reports of reduced brain injury after therapeutic hypothermia and suggest that perinatal factors are important indicators of response to treatment. PMID- 20965516 TI - Prevalence of small cerebral bleeds in patients with a neurodegenerative dementia: a neuropathological study. AB - BACKGROUND: Small cerebral bleeds are frequently observed on magnetic resonance imaging in patients with Alzheimer dementia (AD). Histological confirmations in post-mortem brains are scarce. This study describes the prevalence of cerebrovascular lesions and the quantification of the "bleeding load" in post mortem brains of patients with neurodegenerative dementias. PATIENTS AND METHODS: Forty-five brains of AD patients, 8 of dementia with Lewy bodies (DLB) and 12 of fronto-temporal dementia (FTD) were compared to 10 controls. Histological examination was performed for the evaluation of cerebral amyloid angiopathy (CAA), white matter changes (WMCs), micro-infarcts, and cerebral micro- and mini bleeds (MnBs). The latter were evaluated semi-quantitatively on a coronal section of a whole cerebral hemisphere and on a horizontal section through the pons and cerebellum. RESULTS: Arterial hypertension (AH) was the main vascular risk factor in the patients with AD and DLB (P<0.05). MnBs, consisting of small perivascular bleeds, were significantly more frequent (P<0.001) in AD brains. They were mainly and equally present in the cerebral cortex of AD and DLB brains (P=0.04). Combined AD and DLB pathologies were present in 15%. CAA and WMCs occurred more frequently in AD brains (P<0.001). Occasional MnBs were observed in 60% of the controls. CONCLUSIONS: This neuropathological study confirms the frequent presence of MnBs and WMCs in AD brains. The relative high incidence of cortical MnBs in DLB brains is probably due to the high incidence of AH and the frequent association with AD and CAA. PMID- 20965517 TI - Left ventricular pacing lead insertion via the coronary sinus cardioplegia cannula: a novel method for temporary biventricular pacing during reoperative cardiac surgery. AB - OBJECTIVE: Temporary biventricular pacing to treat low output states after cardiac surgery is an active area of investigation. Reoperative cases are not studied due to adhesions, which preclude left ventricular mobilization to place epicardial pacing wires. In such patients, inserting a temporary left ventricular lead via the coronary sinus cardioplegia cannula may allow for biventricular pacing. We developed a novel technique for intraoperative left ventricular lead placement. METHODS: Eight domestic pigs underwent median sternotomy and pericardiotomy. Temporary pacing wires were sewn to the right atrium and right ventricle. Complete heart block was induced by ethanol ablation of the atrioventricular node. A 13-French retrograde cardioplegia catheter was introduced via the right atrial free wall into the coronary sinus. A 6-French left ventricular pacing lead was inserted into the cardioplegia catheter and advanced into the coronary sinus during biventricular pacing until left ventricular capture was detected by electrocardiogram and arterial pressure monitoring. Left ventricular capture success rate and electrical performance were recorded during five placement attempts. RESULTS: Left ventricular capture was achieved on 80% of insertion attempts. Left ventricular capture without diaphragmatic pacing was achieved in 7 pigs. Lead tip locations were mostly in lateral and posterior basal coronary vein branches. There were no arrhythmias, bleeding, or perforation associated with lead insertion. CONCLUSIONS: Intraoperative biventricular pacing with a left ventricular pacing lead inserted via the coronary sinus cardioplegia cannula is feasible, using standard instrumentation and without requiring cardiac manipulation. This approach merits further study in patients undergoing reoperative cardiac surgery. PMID- 20965518 TI - A simplified categorization for common arterial trunk. AB - OBJECTIVE: A common arterial trunk is a solitary trunk that exits the heart through a common ventriculo-arterial junction and supplies directly the systemic, pulmonary, and coronary arterial pathways. It remains to be determined, however, how best to subclassify those hearts fulfilling this definition. The time-honored classification is based on the morphology of the pulmonary arteries, but an alternative approach also places emphasis on the nature of the systemic pathways. We evaluated our experience to establish whether these different approaches can be reconciled. METHODS: We examined 28 autopsied hearts with common arterial trunks; the specimens were drawn from the archives of three institutions. Based on our analysis, we simplified classification into hearts with aortic or pulmonary dominance. We used this approach to categorize 42 patients who had undergone surgical correction at Children's Memorial Hospital in Chicago. RESULTS: All autopsied hearts could be assigned to groups with either aortic or pulmonary dominance of the common arterial trunk, with 20 and 8 specimens, respectively, fitting into these categories. Pulmonary dominance was found only when the aortic component of the trunk was hypoplastic and an arterial duct supplied the majority of flow to the descending aorta. Only in this setting did we observe pulmonary arteries arising from the sides of the major pathway, and only in this setting was the aortic component discrete from the pulmonary component within the pericardial cavity. CONCLUSIONS: This simple approach to classification reconciles the existing disparate categorizations of patients having common arterial trunks and it emphasizes the principal morphologic determinant of surgical outcome. PMID- 20965520 TI - Truly stentless autologous pericardial aortic valve replacement: an alternative to standard aortic valve replacement. AB - OBJECTIVE: The aim of this study was to determine the feasibility and durability of truly stentless aortic valve replacement using autologous pericardium sutured directly onto the aortic wall. METHODS: Eleven patients (mean age, 55.9 years) requiring aortic valve replacement were recruited. A circular piece of pericardium about 8 cm in diameter was harvested and treated in 0.6% glutaraldehyde for 10 minutes. The aortic valve was excised and, with the use of specially designed instruments (CardioMend LLC, Santa Barbara, Calif), the sinotubular junction was sized and the pericardium was tailored to the required size and shape and then sutured directly onto the aortic wall. The reconstructed valve was assessed directly and by echocardiography at the end of the operation; it was assessed by echocardiography and cardiac magnetic resonance imaging at 6 months and yearly. Computed tomographic scan of the aortic valve to assess for valve calcification was performed at last follow-up. RESULTS: Hospital mortality was 0%. Mean follow-up was 6.5 years (range, 5.3-7.5 years). Freedom from structural valve deterioration, thromboembolism, endocarditis and reoperation was 100%, 100%, 72.7%, and 63.6%, respectively. There were 4 reoperations at 4, 13, 15, and 46 months, 3 of them owing to endocarditis and 1 owing to technical failure noted at the time of surgery. The remaining 7 patients are alive and well with a mean New York Heart Association class of 1.3 and normally functioning aortic valves with no calcification. CONCLUSIONS: Truly stentless aortic valve replacement using autologous pericardium sutured directly onto the aortic wall is safe and feasible and has excellent durability up to 7.5 years with no calcification. PMID- 20965521 TI - Are urodynamics needed before surgery for straightforward female stress incontinence? PMID- 20965522 TI - Potential benefits to fisheries and biodiversity of the Chagos Archipelago/British Indian Ocean Territory as a no-take marine reserve. AB - On 1st April 2010, the British Government announced designation of the British Indian Ocean Territory--or Chagos Archipelago--as the world's largest marine protected area (MPA). This near pristine ocean ecosystem now represents 16% of the worlds fully protected coral reef, 60% of the world's no-take protected areas and an uncontaminated reference site for ecological studies. In addition these gains for biodiversity conservation, the Chagos/BIOT MPA also offers subsidiary opportunities to act as a fisheries management tool for the western Indian Ocean, considering its size and location. While the benefits of MPAs for coral-reef dwelling species are established, there is uncertainty about their effects on pelagic migratory species. This paper reviews the increasing body of evidence to demonstrate that positive, measurable reserve effects exist for pelagic populations and that migratory species can benefit from no-take marine reserves. PMID- 20965523 TI - Distribution of petroleum hydrocarbons and organochlorinated contaminants in marine biota and coastal sediments from the ROPME Sea Area during 2005. AB - The composition and spatial distribution of various petroleum hydrocarbons (PHs), comprising both aliphatic and polycyclic aromatic hydrocarbons (PAHs), and selected chlorinated pesticides and PCBs were measured in biota and coastal sediments from seven countries in the Persian Gulf and the Gulf of Oman (Bahrain, Iran, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates). Evidence of extensive marine contamination with respect to organochlorinated compounds and PHs was not observed. Only one site, namely the BAPCO oil refinery in Bahrain, was considered to be chronically contaminated. Comparison of the results from this survey for Sigma DDTs and Sigma PCBs in rock oysters from the Gulf of Oman with similar measurements made at the same locations over the past two decades indicates a temporal trend of overall decreasing Sigma PCB concentrations in oysters, whereas Sigma DDTs levels have little changed during that period. PMID- 20965524 TI - Marine management--towards an integrated implementation of the European Marine Strategy Framework and the Water Framework Directives. AB - Through implementing environmental Directives, Europe has moved towards coordinated and integrated catchment-to-coast management, following the most novel legislation on ecosystem-based approaches worldwide. The novel joint synthesis of this direction reviewed here allows us to regard the Water Framework Directive (WFD) as a 'deconstructing structural approach' whereas the Marine Strategy Framework Directive (MSFD) is a 'holistic functional approach', i.e. the WFD has split the ecosystem into several biological quality elements, then it compares the structure of these (such as species complement) individually before combining them and attempting to determine the overall condition. In contrast the MSFD concentrates on the set of 11 descriptors which together summarize the way in which the whole system functions. We emphasize that both Directives are frameworks on which many other directives are linked but that they need to be fully and seamlessly integrated to give a land to open sea system of assessment and management. Hence, by taking account of the experience gained in the WFD implementation, together with that from regional sea conventions, such as OSPAR (North East Atlantic) or HELCOM (Baltic Sea), we propose in this contribution an integrative approach for the environmental status assessment, within the MSFD. PMID- 20965526 TI - Cycloartane glycosides from the rhizomes of Curculigo orchioides. AB - Cycloartane glycosides (1-9) were isolated from rhizomes of Curculigo orchioides (Hypoxidaceae), and this structures were determined by spectroscopic analysis and a few chemical transformations. Cytotoxic activity of glycosides (1-9) and their common aglycone (1a) against HL-60 human promyelocytic leukemia cells was also examined. PMID- 20965525 TI - Body fat redistribution and metabolic abnormalities in HIV-infected patients on highly active antiretroviral therapy: novel insights into pathophysiology and emerging opportunities for treatment. PMID- 20965527 TI - Gibberellin 3-oxidases in developing embryos of the southern wild cucumber, Marah macrocarpus. AB - Immature seeds of the southern wild cucumber, Marah macrocarpus, are a rich source of gibberellins (GAs) and were used in some of the earliest experiments on GA biosynthesis. The main biologically active GAs in developing embryos and endosperm of M. macrocarpus are GA(4) and GA(7), which have been shown previously to be formed from GA(9) in separate pathways, GA(4) being formed directly by 3beta-hydroxylation, while GA(7) is produced in two steps via 2,3-didehydroGA(9). In order to identify the enzymes responsible for these conversions, three cDNA clones encoding functionally different GA 3-oxidases, MmGA3ox1, -2 and -3, were obtained from young immature M. macrocarpus embryos. Their biochemical functions were determined by expression of the cDNAs in Escherichia coli and incubation of cell lysates with (14)C-labelled substrates. MmGA3ox1 and MmGA3ox3 converted GA(9) to GA(4) as sole product, while MmGA3ox2 produced several products, including GA(4), 2,3-didehydroGA(9), 2,3-epoxyGA(9), GA(20) and GA(5), these last two products requiring 13-hydroxylation of GA(9) and 2,3-didehydroGA(9), respectively. MmGA3ox1 converted 2,3-didehydroGA(9) to GA(7), while MmGA3ox3 converted this substrate to the 2,3-epoxide, and MmGA3ox2 also formed the epoxide, but also GA(5.) Thus, formation of GA(7) requires the sequential activities of MmGA3ox2 and MmGA3ox1, while MmGA3ox3 is not involved in GA(7) production. The enzymes catalysed similar reactions when incubated with 13 hydroxylated GAs, although with reduced efficiencies. The 13-hydroxylase activity of MmGA3ox2 may be responsible for the production of GA(1) and GA(3), which are present at low levels in developing M. macrocarpus seeds. PMID- 20965529 TI - 2-Methoxy-3-isobutylpyrazine in grape berries and its dependence on genotype. AB - 2-Methoxy-3-isobutylpyrazine (MIBP) contributes a bell pepper aroma to many grape cultivars and has a reported aroma threshold of ~2 ng L(-1) in water. The purpose of this study was twofold: (1) develop a procedure using headspace solid phase micro-extraction combined with GC-MS in the selected ion monitoring mode (HS-SPME GC-MS-SIM) for analysis of MIBP in grape berries, and (2) determine the location of MIBP biosynthesis in grapevines by approach grafting clusters of Vitis vinifera L. cvs Cabernet Sauvignon and Muscat blanc onto each other. The soluble solids and pH of the grape juice/homogenate matrix from different grape berry developmental stages influenced the method precision; therefore, quantification via the method of standard addition was used. Using our developed method, the limit of detection (LOD) and limit of quantitation (LOQ) of MIBP were 0.1 ng L( 1) and 2 ng L(-1), respectively, measured in a model juice and non-MIBP containing Chardonnay juice. Spiked recoveries averaged between 91% and 112% in Cabernet Sauvignon and Pinot noir homogenates and the overall relative standard deviation was less than 10%. The method was used to analyze MIBP in 29 grape cultivars and in fruit from clusters grafted to Cabernet Sauvignon or Muscat vines. Quantifiable levels were found only in Cabernet franc, Cabernet Sauvignon, Merlot, Sauvignon blanc and Semillon, providing information on the genetic connection for the occurrence of MIBP in grapes. No MIBP was detected in the berries of Muscat blanc clusters grafted onto Cabernet Sauvignon vines when sampled at fruit maturity. MIBP was detected in all berries of Cabernet Sauvignon regardless the graft configuration. The data indicate that MIBP or its precursors originate in the berry and its formation depends upon grape genotype. PMID- 20965528 TI - Hapalindole-related alkaloids from the cultured cyanobacterium Fischerella ambigua. AB - Four hapalindole-related alkaloids, namely fischambiguines A and B, ambiguine P, ambiguine Q nitrile as well as ambiguine G nitrile were identified from the cultured cyanobacterium Fischerella ambigua (UTEX 1903). The structures were determined by spectroscopic analysis including MS, 1D and 2D NMR and X-ray crystallography. The alkaloids possessed fused pentacyclic and hexacyclic carbon skeletons. Fischambiguine B displayed a strong inhibitory activity against Mycobacterium tuberculosis with an MIC value of 2 MUM, with no detectable cytotoxicity in a Vero cell line. PMID- 20965530 TI - [Leopard syndrome and hypertrophic cardiomyopathy]. PMID- 20965531 TI - [The specialty program as a training tool: an individual training plan for each resident]. AB - The official training program for the specialty "Diagnostic Imaging" establishes minimum learning objectives that must be fulfilled. Each accredited teaching unit is responsible for designing and carrying out a curriculum to ensure that these objectives are met, and this approach permits a degree of flexibility. Various aspects must be considered in the individual training plans for each resident: the rotation scheme according to the way the department is organized, plans for recovering missed material or reinforcing weak points, optional rotations, increasing degrees of responsibility as skills are acquired during training, and accommodating special needs of handicapped persons. Nevertheless, the individual plan must be fitted to the established curriculum and guarantee that the content of the official program is covered and that the objectives stipulated therein are met. Furthermore, the methods of teaching must be adapted to the individual characteristics of the residents, and this is the most important aspect of the individualization of training. To this end, it is fundamental for residents to take on an active role in their training, guided by their tutor and with the participation of all the radiologists in the department including the other residents, all of whom should act as teachers. PMID- 20965532 TI - [Urogenital imaging case presented at the General Case Reading Session of the XXX National Congress of the SERAM, A Coruna. May 2010]. PMID- 20965533 TI - Matrix metalloprotease-9 activity in the cerebrospinal fluid and spinal injury severity in dogs with intervertebral disc herniation. AB - We investigated whether matrix metalloproteinase (MMP)-9 expression in the cerebrospinal fluid (CSF) of dogs with intervertebral disc herniation (IVDH) is associated with the severity of neurological signs and prognosis. CSF from the cisterna magna (C-CSF) and the lumbar spine (L-CSF) of 34 dogs with IVDH was analyzed using zymography. Activity of MMP-9 in L-CSF was detected in 6 of 34 dogs with IVDH, often for more than 7 days after injury. MMP-9 activity was not detected from any of the C-CSF samples. Of the six cases that were MMP-9 positive, all four cases with grade V that had loss of deep pain were non ambulatory 6 months after treatment. The remaining two cases with grade III and IV could recover mobility. In dogs with grade V thoracolumbar IVDH, MMP-9 expression in the CSF may indicate severe spinal cord injury with poor prognosis. PMID- 20965534 TI - Normal vitamin D receptor function with increased expression of 25-hydroxyvitamin D(3)-24-hydroxylase in Corriedale sheep with inherited rickets. AB - A likely inherited disease with gross and microscopic features of rickets has been recognised in Corriedale sheep in New Zealand, and a defect in end-organ responsiveness to vitamin D has been proposed as a likely mechanism. The aim of the present study was to characterize the mode of inheritance and determine the disease mechanism. Breeding trials showed that the mode of inheritance was autosomal recessive. Serum chemistry testing using different methodology and studies in cultured skin fibroblasts did not support our previous hypothesis of a defect in end-organ responsiveness. The studies revealed normal serum 1,25 dihydroxyvitamin D concentrations, normal vitamin D receptor function, and the presence of 24-hydroxylase mRNA in cells from affected sheep, even without induction by 1,25-dihydroxyvitamin D(3). In addition, osteocalcin mRNA expression was similar in both affected and control sheep. It was concluded that increased expression of 25-hydroxyvitamin D(3)-24-hydroxylase, the enzyme that breaks down vitamin D, may be involved in the pathogenesis of inherited rickets in Corriedale sheep, but its role requires further clarification. PMID- 20965535 TI - Mice overexpressing the gene for heparin-binding epidermal growth factor-like growth factor (HB-EGF) have increased resistance to hemorrhagic shock and resuscitation. AB - BACKGROUND: The aim of the current study was to determine whether overexpression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) could protect the intestines from injury after hemorrhagic shock and resuscitation in mice. METHODS: Hemorrhagic shock and resuscitation was induced in HB-EGF transgenic and wild type mice. Cross-reacting material 197 (5 mg/kg) was administered to a subset of HB-EGF transgenic mice to block the overexpressed HB EGF. Intestinal histologic injury scores, intestinal epithelial cell apoptosis indices, and gut barrier function were determined. The Student t test and 1-way analysis of variance were employed to compare the differences between groups. RESULTS: All mice subjected to hemorrhagic shock and resuscitation had significantly increased intestinal histologic injury scores, apoptosis indices, and intestinal permeability compared with sham-operated mice. Compared with wild type mice, HB-EGF transgenic mice had significantly decreased histologic injury (mean injury grade 2.79 +/- 0.84 vs 3.88 +/- 1.43, P = .02), apoptosis indices (mean apoptosis index 8.77 +/- 5.23 vs 17.91 +/- 13.23, P = .03), and mucosal permeability (FITC-dextran 4 clearance 13.06 +/- 5.67 vs 20.03 +/- 7.81 nL/min/ m(2), P = .02) at 3 hours of reperfusion. HB-EGF transgenic mice subjected to hemorrhagic shock and resuscitation and treated with cross-reacting material 197 had a significantly increased histologic injury (mean injury grade 3.63 +/- 1.00 vs 2.79 +/- 0.84, P = .04) and mucosal permeability (FITC-dextran 4 clearance 22.87 +/- 9.69 vs 13.06 +/- 5.67 nL/min/cm2, P = .01) at 3 hours of reperfusion compared with non-cross-reacting material 197 treated transgenic mice, with no significant changes in apoptosis indices. Cross-reacting material 197 did not reverse the decreased apoptosis observed in HB-EGF transgenic mice subjected to hemorrhagic shock and resuscitation, which suggests that mechanisms in addition to decreased apoptosis may be responsible for the intestinal cytoprotective effects of endogenous HB-EGF overexpression. CONCLUSION: Overexpression of HB-EGF increases resistance to hemorrhagic shock and resuscitation in mice. PMID- 20965536 TI - Radioguided surgery using an intraoperative PET probe for tumor localization and verification of complete resection in differentiated thyroid cancer: a pilot study. AB - BACKGROUND: The major concerns in the surgical treatment of extensive or recurrent thyroid cancer include the difficulty of precise intraoperative and real-time tumor localization, the possibility of missing small metastatic lymph nodes during the operation, the need for reoperation due to recurrence, and complications. The usefulness and feasibility of an intraoperative PET probe have been reported for many other cancers; however, a standard, radioguided, operative protocol using a PET probe in thyroid cancer has not been established. The purpose of the current study was to evaluate the feasibility of an intraoperative PET probe with respect to precise tumor localization, verification of complete resection, and a decrease in unnecessary reoperations and complications. METHODS: This was a prospective, controlled study. Inclusion criteria were thyroid cancer requiring a total thyroidectomy with a modified radical neck dissection (MRND) and recurrent thyroid cancer after thyroid surgery. The types of procedures included total thyroidectomy with MRND, selective neck dissection (SND), and excision of recurrent thyroid masses. The PET probe NodeSeeker((r)) is a high energy gamma probe seeking 511 keV photons. Operative exploration was carried out between 2 and 6 h after injection of (18)F-FDG. The surgeon calculated the target to-background ratio (T/B ratio) by checking the 10-sec accumulated count using the PET probe. We performed a re-exploration if the T/B ratio was >1.3 in the operative bed. RESULTS: Twelve patients underwent PET probe-guided operation. SNDs, mass excisions, total thyroidectomy with MRND, and MRND were performed on 7, 4, and 1 patient, respectively. All tumors were localized by the PET probe precisely in real time, and the lesions not observed on preoperative PET were detected by the PET probe in 7 patients. Furthermore, additional lymph nodes that were not identified on preoperative ultrasonography were detected in 1 patient. The mean T/B ratio of thyroid carcinoma was 1.51 +/- 0.53 (range, 1.17-4.03) and the postoperative serum thyroglobulin off thyroid hormone was <2.0 ng/ml. CONCLUSION: Radioguided surgery using an intraoperative PET probe in thyroid cancer appears to be a useful method for real-time tumor localization, verification of complete excision, and minimization of the possibility of residual cancer. Therefore, an intraoperative PET probe in thyroid cancer may decrease unnecessary reoperations and complications due to persistent disease. PMID- 20965537 TI - Osteogenic differentiation of rat bone marrow stromal cells by various intensities of low-intensity pulsed ultrasound. AB - Bone growth and repair are under the control of biochemical and mechanical signals. Low-intensity pulsed ultrasound (LIPUS) stimulation at 30mW/cm(2) is an established, widely used and FDA approved intervention for accelerating bone healing in fractures and non-unions. Although this LIPUS signal accelerates mineralization and bone regeneration, the actual intensity experienced by the cells at the target site might be lower, due to the possible attenuation caused by the overlying soft tissue. The aim of this study was to investigate whether LIPUS intensities below 30mW/cm(2) are able to provoke phenotypic responses in bone cells. Rat bone marrow stromal cells were cultured under defined conditions and the effect of 2, 15, 30mW/cm(2) and sham treatments were studied at early (cell activation), middle (differentiation into osteogenic cells) and late (biological mineralization) stages of osteogenic differentiation. We observed that not only 30mW/cm(2) but also 2 and 15mW/cm(2), modulated ERK1/2 and p38 intracellular signaling pathways as compared to the sham treatment. After 5 days with daily treatments of 2, 15 and 30mW/cm(2), alkaline phosphatase activity, an early indicator of osteoblast differentiation, increased by 79%, 147% and 209%, respectively, compared to sham, indicating that various intensities of LIPUS were able to initiate osteogenic differentiation. While all LIPUS treatments showed higher mineralization, interestingly, the highest increase of 225% was observed in cells treated with 2mW/cm(2). As the intensity increased to 15 and 30mW/cm(2), the increase in the level of mineralization dropped to 120% and 82%. Our data show that LIPUS intensities lower than the current clinical standard have a positive effect on osteogenic differentiation of rat bone marrow stromal cells. Although ExogenTM at 30mW/cm(2) continues to be effective and should be used as a clinical therapy for fracture healing, if confirmed in vivo, the increased mineralization at lower intensities might be the first step towards redefining the most effective LIPUS intensity for clinical use. PMID- 20965538 TI - Amino acids contributing to antigenic drift in the infectious bursal disease Birnavirus (IBDV). AB - We examined the effect of amino acids 222 and 254 on antigenicity of the variant Del-E strain of infectious bursal disease virus (IBDV). Using molecular epidemiology, we identified a virus designated as Del-E-222 that was identical to Del-E except for alanine at position 222. A second virus was generated using reverse genetics of the Del-E backbone to create Del-E-254 that contained an asparagine at amino acid 254. The Del-E-222 and Del-E-254 viruses were tested for their ability to escape neutralizing immunity provided by parenteral vaccination. The bursas from birds vaccinated with parental Del-E and challenged with Del-E 222 or Del-E-254 had macroscopic lesions typical of an IBDV infection, and their B-BW ratios were significantly smaller than the controls. Microscopic lesions included lymphocyte depletion and confirmed the ability of Del-E-222 and Del-E 254 to break through the immunity induced by the parental Del-E virus vaccination. Both mutations appear to be contributing to antigenic drift. PMID- 20965539 TI - Genetic analysis of West Nile virus containing a complete 3'CSI RNA deletion. AB - We report a genetic interplay among three pairs of long-distance RNA interactions that are involved in West Nile virus (WNV) genome cyclization and replication: 5'CS/3'CSI (conserved sequence), 5'UAR/3'UAR (upstream AUG region), and 5'DAR/3'DAR (downstream AUG region). Deletion of the complete 3'CSI element is lethal for WNV replication, but the replication of the 3'CSI deletion virus could be rescued by second site mutations. Functional analysis, using a genome-length RNA and replicon, mapped the compensatory mutations to the 5'UAR/3'UAR and 5'DAR/3'DAR regions. Biochemical analysis showed that the 3'CSI deletion abolished the 5' and 3' RNA interaction of the genome; the compensatory mutations could partially restore the 5' and 3' genome cyclization. These results demonstrate, for the first time, that a flavivirus without 3'CSI could restore genome cyclization and viral replication through enhancement of the 5'UAR/3'UAR and 5'DAR/3'DAR interactions. PMID- 20965540 TI - Autographa californica multiple nucleopolyhedrovirus core gene ac92 (p33) is required for efficient budded virus production. AB - Autographa californica multiple nucleopolyhedrovirus (AcMNPV) ac92 is a core gene encoding a protein associated with occlusion derived virus (ODV), binds human P53 and also has flavin adenine dinucleotide linked sulfhydryl oxidase activity but its role in the virus life cycle is not known. To determine ac92 function a deletion virus (vAc(92KO)) was generated and transfected Sf9 cells revealed that vAc(92KO) infection was restricted primarily to single cells and budded virus (BV) titer was reduced over 99.99%. However, viral DNA replication was unaffected and development of occlusion bodies in vAc(92KO)-transfected cells evidenced progression to very late phases of viral infection. AC92 localized to both the cytoplasm and nucleus, and was also associated with BV as well as ODV. In BV AC92 was detected in BV envelope and nucleocapsid fractions. Finally it was shown that the ac92 homologue from the Group II alphabaculovirus Mamestra configurata NPV maco96 could only partially rescue vAc(92KO). PMID- 20965541 TI - Applying an electric field in a built-in zero valent iron--anaerobic reactor for enhancement of sludge granulation. AB - A zero valent iron (ZVI) bed with a pair of electrodes was installed in an upflow anaerobic sludge blanket (UASB) reactor to create an enhanced condition to increase the rate of anaerobic granulation. The effects of an electric field and ZVI on granulation were investigated in three UASB reactors operated in parallel: an electric field enhanced ZVI-UASB reactor (reactor R1), a ZVI-UASB reactor (reactor R2) and a common UASB reactor (reactor R3). When a voltage of 1.4 V was supplied to reactor R1, COD removal dramatically increased from 60.3% to 90.7% over the following four days, while the mean granule size rapidly grew from 151.4 MUm to 695.1 MUm over the following 38 days. Comparatively, COD removal was lower and the increase in granule size was slower in the other two reactors (in the order: R1 > R2 > R3). The electric field caused the ZVI to more effectively buffer acidity and maintain a relatively low oxidation-reduction potential in the reactor. In addition, the electric field resulted in a significant increase in ferrous ion leaching and extracellular polymeric substances (EPS) production. These changes benefited methanogenesis and granulation. Scanning electron microscopy (SEM) images showed that different microorganisms were dominant in the external and internal layers of the reactor R1 granules. Additionally, fluorescence in situ hybridization (FISH) analysis indicated that the relative abundance of methanogens in reactor R1 was significantly greater than in the other two reactors. Taken together, these results suggested that the use of ZVI combined with an electric field in an UASB reactor could effectively enhance the sludge granulation. PMID- 20965542 TI - Immobilization of Hg(II) in water with polysulfide-rubber (PSR) polymer-coated activated carbon. AB - An effective mercury removal method using polymer-coated activated carbon was studied for possible use in water treatment. In order to increase the affinity of activated carbon for mercury, a sulfur-rich compound, polysulfide-rubber (PSR) polymer, was effectively coated onto the activated carbon. The polymer was synthesized by condensation polymerization between sodium tetrasulfide and 1,2 dichloroethane in water. PSR-mercury interactions and Hg-S bonding were elucidated from x-ray photoelectron spectroscopy, and Fourier transform infra-red spectroscopy analyses. The sulfur loading levels were controlled by the polymer dose during the coating process and the total surface area of the activated carbon was maintained for the sulfur loading less than 2 wt%. Sorption kinetic studies showed that PSR-coated activated carbon facilitates fast reaction by providing a greater reactive surface area than PSR alone. High sulfur loading on activated carbon enhanced mercury adsorption contributing to a three orders of magnitude reduction in mercury concentration. MU-X-ray absorption near edge spectroscopic analyses of the mercury bound to activated carbon and to PSR on activated carbon suggests the chemical bond with mercury on the surface is a combination of Hg-Cl and Hg-S interaction. The pH effect on mercury removal and adsorption isotherm results indicate competition between protons and mercury for binding to sulfur at low pH. PMID- 20965543 TI - Toxicity and metabolism of copper pyrithione and its degradation product, 2,2' dipyridyldisulfide in a marine polychaete. AB - We conducted acute toxicity tests and sediment toxicity tests for copper pyrithione (CuPT) and a metal pyrithione degradation product, 2,2' dipyridyldisulfide [(PS)2], using a marine polychaete Perinereis nuntia. The acute toxicity tests yielded 14-d LC50 concentrations for CuPT and (PS)2 of 0.06 mg L(-1) and 7.9 mg L(-1), respectively. Sediment toxicity tests resulted in 14-d LC50 concentrations for CuPT and (PS)2 of 1.1 mg kg(-1) dry wt. and 14 mg kg(-1) dry wt., respectively. In addition to mortality, sediment avoidance behavior and decreases in animal growth rate were observed; growth rate was the most susceptible endpoint in the sediment toxicity tests of both toxicants. Thus, we propose lowest observed effect concentrations of 0.3 mg kg(-1) dry wt. and 0.2 mg kg(-1) dry wt. for CuPT and (PS)2, respectively, and no observed effect concentrations of 0.1 mg kg(-1) dry wt. for both CuPT and (PS)2. The difference in the toxicity values between CuPT and (PS)2 observed in the acute toxicity test was greater than the difference in these values in the sediment toxicity test, and we attribute this to (PS)2 being more hydrophilic than CuPT. In addition to the toxicity tests, we analyzed conjugation activity of several polychaete enzymes to the toxicants and marked activity of palmitoyl coenzyme-A:biocides acyltransferase and UDP-glucuronosyl transferase was observed. PMID- 20965544 TI - Direct VUV photodegradation of gaseous alpha-pinene in a spiral quartz reactor: intermediates, mechanism, and toxicity/biodegradability assessment. AB - Photodegradation of gaseous alpha-pinene by a vacuum ultraviolet (VUV) in a spiral reactor was investigated under various gaseous reaction media and residence time, and their respective effects on types and biodegradability of the intermediates were studied. Analysis of carbon amounts showed that about 33% and 43% of total carbon were converted to soluble organic carbon in the air medium with a relative humidity (RH) of 35-40% at empty bed residence times (EBRTs) of 18 and 45 s. Based on the identified intermediates by GC/MS and IC, a photodegradation pathway was proposed by the combined roles of photolysis, OH. photooxidation and O3 photooxidation. Biodegradability to active sludge, toxicity to Chlorella vulgaris and 96-well microplates showed that alpha-pinene could be largely converted to more biodegradable and less toxic compounds through photodegradation in the air reaction medium with a RH of 35-40% at an EBRT of 18s, in which the initial concentration was 600 mg m-3. Therefore, VUV photodegradation could be applied as an effective pre-treatment method for detoxification and biodegradability improvement under the optimized photodegradation conditions. Such results supported the potential use of VUV photodegradation to improve the removal capacity of conventional biological treatments for hydrophobic and poorly biodegradable compounds. PMID- 20965545 TI - Sociodemographic, reproductive and dietary predictors of organochlorine compounds levels in pregnant women in Spain. AB - Organochlorine pesticides and polychlorinated biphenyls (PCBs) are consistently found in human tissues. Serum levels of organochlorine compounds (OC) in pregnant women in particular have raised concern about possible harm to humans in the early phases of physical and behavioural development. The objective of the present study was to evaluate the association between concentration of OCs in serum of two cohorts of pregnant women from Gipuzkoa and Sabadell in Spain and socioeconomic, reproductive and dietary variables. Concentration of polychlorinated biphenyls (PCBs: 28, 52, 101, 118, 138, 153 and 180), hexachlorobenzene (HCB), beta and gamma-hexachlorocyclohexane (beta-HCH and gamma HCH), heptachlor epoxide, dichlorodiphenyl dichloroethylene (p,p'-DDE) and dichlorodiphenyl trichloroethane (p,p'-DDT) were measured in the serum of 1259 pregnant women. Associations between OCs and potential predictor variables were assessed using linear regression models adjusted for potential confounders. The compounds most commonly found in the serum were p,p'-DDE (99% of the samples) and PCB-153 (95% of the samples). Geometric means of serum concentrations (ng g-1 lipid) of organochlorine pesticides were 110.0, 19.1, and 33.5 for p,p'-DDE, beta HCH, and HCB respectively, while the geometric means of PCBs were 21.8, 38.9 and 26.9 for PCB 138, 153, and 180 respectively. The levels of all OCs increased with age. BMI was positively associated with the concentration of organochlorine pesticides but inversely related to PCB concentrations. The serum levels of OCs fell only after a cumulative period of breastfeeding of over a year. Levels of PCBs were related to fish intake, but in general dietary factors did not improve the explained variability of the concentrations of OCs. Overall, the levels of OCs found in the study are at the lower end of the range reported in Spain and other countries. PMID- 20965546 TI - Cypermethrin has the potential to induce hepatic oxidative stress, DNA damage and apoptosis in adult zebrafish (Danio rerio). AB - Cypermethrin (CYP), a widely used Type II pyrethroid pesticide, is one of the most common contaminants in the freshwater aquatic system. We studied the effects of CYP exposure on the induction of hepatic oxidative stress, DNA damage and the alteration of gene expression related to apoptosis in adult zebrafish. Hepatic mRNA levels for the genes encoding antioxidant proteins, such as Cu/Zn-Sod, Mn Sod, Cat, and Gpx, were significantly upregulated when zebrafish were exposed to various concentrations of CYP for 4 or 8 days. In addition, the main genes related to fatty acid beta-oxidation and the mitochondrial genes related to respiration and ATP synthesis were also significantly upregulated after exposure to high concentrations (1 and 3 MUg L(-1)) of CYP for 4 or 8 days. Moreover, in a comet assay of zebrafish hepatocytes, tail DNA, tail length, tail moment and Olive tail moment increased in a concentration-dependent manner. The significant induction (p<0.01) of all four parameters observed with CYP concentrations of 0.3 MUg L(-1) or higher suggests that heavy DNA damage was induced even at low levels. Furthermore, several apoptosis- related genes, such as p53, Apaf1 and Cas3, were significantly upregulated after CYP exposure, and Bcl2/Bax expression ratio decreased, especially in groups treated with 1 and 3 MUg L(-1) CYP for 8 days. Taken together, our results suggested that CYP has the potential to induce hepatic oxidative stress, DNA damage and apoptosis in zebrafish. This information will be helpful in fully understanding the mechanism of aquatic toxicology induced by CYP in fish. PMID- 20965547 TI - The costal skeleton of Homo antecessor: preliminary results. AB - The Lower Pleistocene TD6 level at the Gran Dolina site in the Sierra de Atapuerca (Burgos, Spain) has yielded nine ribs that represent a minimum of three individuals of the species, Homo antecessor. We present a detailed morphological and metric study of these costal elements, including the siding and anatomical position of all of the rib remains. The adult or nearly adult ribs are also metrically compared with other fossil hominins and with modern comparative samples. The costal elements recovered to date from the TD6 level at Gran Dolina can neither confirm nor reject the hypothesis that H. antecessor had a large thorax, similar to that of Neandertals. However, the fragmentary evidence of the H. antecessor thoracic skeleton is not inconsistent with this suggestion based on other skeletal elements, such as clavicles. PMID- 20965548 TI - Indoor and outdoor air concentrations of BTEX and determinants in a cohort of one year old children in Valencia, Spain. AB - BTEX is the commonly used term for a group of toxic compounds (benzene, toluene, ethyl benzene, ortho-xylene and meta- and para-xylene), some of which, most notably benzene, are known carcinogens. The aim of this study is to measure the BTEX levels both inside and outside the homes of 352 one-year old children from the Valencia cohort of the INMA study (Spain) and to analyze the determinants of these levels. Passive samplers were used to measure BTEX levels during a 15day period and a questionnaire was administered to gather information on potentially associated factors (sociodemographics, residential conditions, and lifestyle). The average concentrations of benzene, toluene, ethyl benzene, ortho-xylene, and meta- and para-xylene were 0.9, 3.6, 0.6, 0.6, and 1.0MUg/m(3), respectively. On average, the indoor levels of all the compounds were approximately 2.5 times higher than those observed outdoors. Factors associated with higher BTEX concentrations inside the home were being the child of a mother of non-Spanish origin, living in a house that had been painted within the last year, living in an apartment, and not having air conditioning. Higher outdoor concentrations of BTEX depend on the residence being situated in a more urban zone, being located within the city limits, having living in a building with more than one story, residing in an area with a greater frequency of traffic, and the season of the year in which the sample was taken. The data thus obtained provide helpful information not only for implementing measures to reduce exposure to these pollutants, but also for evaluating the relation between such exposure and possible health risks for the children in the cohort. PMID- 20965549 TI - Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis. AB - OBJECTIVES: To assess the prevalence of the 19 neuropsychiatric (NP) syndromes in systemic lupus erythematosus (SLE) patients, as defined by the American College of Rheumatology (ACR) in 1999, and better understand the reasons for interstudy variability of prevalence estimates, by performing a meta-analysis of relevant publications. METHODS: A literature search from April 1999 to May 2008 was performed to identify studies investigating NP syndromes in patients with definite SLE, applying the 1999 ACR case definitions and having a sample size of at least 30 patients. Excluded were studies that did not relate to all 19 NPSLE syndromes, presented duplicate data, or were irrelevant. RESULTS: Seventeen of 112 identified studies matched the inclusion criteria, reporting on a total of 5057 SLE patients, including 1439 NPSLE patients, with 2709 NPSLE syndromes. In a subanalysis of the 10 higher quality prospective and elicited studies (2049 patients) using the random-effects model, the prevalence of NP syndromes in SLE patients was estimated to be 56.3% (95% CI 42.5%-74.7%), and the most frequent NP syndromes were headache 28.3% (18.2%-44.1%), mood disorders 20.7% (11.5%-37.4%), cognitive dysfunction 19.7% (10.7%-36%), seizures 9.9% (4.8%-20.5%), and cerebrovascular disease 8.0% (4.5%-14.3%), although significant between-study heterogeneity was present (P < 0.05). Autonomic disorder and Guillain-Barre syndrome carried a prevalence of less than 0.1%. No case of plexopathy was reported. CONCLUSIONS: NP syndromes were estimated to exist in more than half of SLE patients. The most prevalent manifestations were headache, mood disorders, and cognitive dysfunction. A major limitation of the study was the significant heterogeneity of prevalence estimates between studies. PMID- 20965550 TI - Posterior interosseous nerve palsy: an unusual complication of rheumatoid arthritis: case report and review of the literature. AB - OBJECTIVES: Posterior interosseous nerve (PIN) palsy is a very rare complication of rheumatoid arthritis affecting the elbow joint. It results in weakness of extension of the fingers and may be confused with extensor tendon rupture and wrist drop due to radial nerve damage. METHODS: We present a case of PIN palsy secondary to rheumatoid synovitis and review the previously reported cases. RESULTS: Eighteen cases of PIN palsy due to rheumatoid arthritis have been reported so far in the literature. CONCLUSIONS: It is important to recognize this complication and early intervention is necessary to prevent permanent damage. PMID- 20965551 TI - Allergen-specific immunotherapy for respiratory allergies: from meta-analysis to registration and beyond. AB - Allergen-specific immunotherapy (SIT) is an etiology-based treatment for respiratory and Hymenoptera-allergic diseases. Although introduced a century ago, SIT was not widely accepted for many years until its efficacy in the treatment of both allergic rhinoconjunctivitis and allergic asthma was demonstrated in appropriate double-blind, placebo-controlled trials and its mechanism of action was better understood. The indications for allergen-specific immunotherapy have been specified in consensus reports. Allergen-specific immunotherapy is primarily targeted to benefit patients with Hymenoptera allergy or severe upper and mild to moderate lower allergic respiratory diseases that are poorly controlled by pharmacologic treatments or who are unable or unwilling to use the latter. Several recent developments have helped to reinforce the position of SIT in the overall therapeutic management of respiratory allergies: (1) improvement in the quality of allergen extracts as a result of standardization, (2) better understanding of SIT's mechanism of action, (3) the introduction of sublingual tablets and their rigorous registration as pharmaceutical therapies by regulatory agencies, and (4) rationalization of prescribing patterns. There is a requirement for additional well designed, well executed, randomized trials in adults and children with allergic rhinitis and asthma, with a special focus on optimal patient selection, dosage, and treatment duration. In this review, the authors put into perspective current international expert recommendations on the use of SIT (in relation to levels of clinical evidence) and analyze what is needed for the future. PMID- 20965552 TI - Ability of chicken spermatozoa to undergo acrosome reaction after liquid storage or cryopreservation. AB - The effects of in vitro storage on the sperm's ability to undergo the acrosome reaction (AR) have never been studied in avian species despite its major importance for reproduction management. The ability of chicken sperm to undergo the AR was measured after liquid storage at 4 degrees C and after cryopreservation, and its relationship with other semen quality parameters, including viability, mass motility and objective motility parameters measured by computer semen analyser (CASA) was analysed in two different flocks. The percentage of intact acrosome-reacting spermatozoa (IAR) was dramatically decreased by 48 h liquid storage (loss of 2/3 among the spermatozoa initially able to undergo the AR) whereas motility, viability and morphological integrity were reduced by 10-15%. By contrast, cryopreservation did not affect the induction of AR in flock 1 (29% IAR) whereas it was strongly affected in flock 2 (7% IAR). Motility parameters, viability and morphology were considerably altered by freezing in every case (more that 50% loss). Positive correlations were found between the percentage of intact acrosome-reacting spermatozoa and viability, mass motility and many objective motility parameters. Our results showed that the sperm's ability to undergo the AR was much more affected than other sperm functions after storage at 4 degrees C, while cryopreservation only had an effect in semen with the lowest initial quality. These results raise questions regarding the specific features of chicken sperm biology that must be taken into account in the treatment of semen. PMID- 20965553 TI - Identification of genes targeted by FSH and oocytes in porcine granulosa cells. AB - In the mammalian ovarian follicle maturing oocytes are nurtured and supported by surrounding somatic cells, the mural granulosa cells and the cumulus cells. These cells are regulated by follicle-stimulating hormone (FSH), originating from the pituitary, and paracrine factors derived from the oocyte. To gain insight into the mechanisms involved in the regulation of granulosa cell function, this study aimed to identify genes in mural granulosa cells that are regulated by FSH and oocyte secreted factors using the pig as a model organism. Mural granulosa cells were collected from 3-6 mm follicles from sow ovaries and cultured in serum free medium in the presence or absence of FSH and/or isolated cumulus oocyte complexes (COCs). FSH significantly increased both the metabolic activity and progesterone production of granulosa cells, while the presence of COCs reversed these FSH effects. Expression levels of mRNA in the absence/presence of FSH and COCs were analyzed on porcine specific microarrays representing 11,300 genes. Both previously identified and novel FSH target genes as well as some oocyte affected genes were found. Expression of inhibitor of DNA binding protein 2 and 3, ID2 and ID3, was decreased by FSH but increased by COCs, as validated by quantitative PCR. These proteins function as dominant negative basic helix loop helix (bHLH) transcription factors and since all regulated genes contain the consensus E-box sequence that can bind bHLH factors, our data suggest that FSH and COCs may regulate granulosa cell function by tuning the activity of bHLH factors, through ID2 and ID3. PMID- 20965554 TI - Collection of gametes from live axolotl, Ambystoma mexicanum, and standardization of in vitro fertilization. AB - This study established the first protocol for collection of gametes from live axolotl, Ambystoma mexicanum, by gentle abdominal massage and in vitro fertilization. To stimulate spermiation and ovulation, human chorionic gonadotrophin (hCG) and Ovopel pellets, which are commercially used to stimulate spawning in fish, were tested. The hCG was more effective than Ovopel pellets and yielded a higher semen volume in the injected males and a shorter response time in the females. Collected semen by this method was already motile and fertile. Fertile eggs could be collected in 3-4 successive collection times after the female has started the typical spawning behaviour. The fertilization condition that yielded the highest hatching rate was mixing semen with eggs before the addition of a fertilization saline solution (20 mmol/l NaCl, 1 mmol/l KCl, 1 mmol/l Mg(2)SO(4), 1 mmol Ca(2)Cl, 3 mmol NaHCO(3), 10 mmol/l Tris, pH 8.5 - Osmolality = 65 mosmol/kg). When the pH of the fertilization solution was increased to >= 10, the hatching rate was significantly increased. The use of fertilization solutions with osmolalities of >= 150 and >= 182 were accompanied with a significant decrease in hatching rates and the appearance of deformed larvae, respectively. In conclusion, a reliable protocol for gamete collection from live axolotl is established as a laboratory model of in vitro fertilization for urodele amphibians. This protocol may be transferable to endangered urodeles. PMID- 20965555 TI - Effects of radiographic contrast media on domestic cat epididymidal sperm. AB - Laparoscopic artificial insemination has an important role in felid conservation but it is costly and includes surgical risk. Therefore, radiographic contrast medium combined with non-surgical transcervical AI to verify intrauterine gamete placement could be a viable alternative. Gamete-rescued fresh and frozen-thawed sperm were extended with one of two commercial contrast media (nonionic and ionic), with osmolarity adjusted to 320-330 mOsm, or feline optimized culture medium (control). Percent motility, forward progression status, and acrosomal integrity were recorded every 30 min for 4 h. Sperm penetration abilities were assessed by coincubating treated sperm with conspecific in vitro matured oocytes for 18 to 20 h, and presumptive zygotes and embryos were fixed and stained to determine sperm penetration and fertilization rate. There was reduced motility and acrosomal integrity in frozen-thawed versus fresh sperm (P < 0.05). Neither radiographic contrast medium induced adverse effects on fresh sperm motility relative to control medium (P > 0.05), but motility of frozen-thawed sperm decreased when treated with nonionic radiographic contrast medium compared to control medium (P < 0.05). There were no differences in acrosomal integrity between radiographic contrast and control media in fresh (P > 0.05) or frozen sperm (P > 0.05). Neither radiographic contrast media decreased the numbers of morphologically normal sperm (P > 0.05) or reduced the ability of domestic cat sperm to penetrate (P > 0.05) or fertilize (P > 0.05) conspecific oocytes. Ionic radiographic contrast medium can be added to fresh or frozen-thawed domestic cat sperm with no adverse effect on motility, morphology, acrosomal integrity or oocyte penetration rates, and thus may be used to facilitate further development of transcervical AI procedures. PMID- 20965556 TI - Validation and usefulness of the Sperm Quality Analyzer V equine for equine semen analysis. AB - Routine semen analysis includes evaluation of concentration combined with seminal volume, morphology and motility. Subjective analysis of these parameters is known to be inaccurate, imprecise and subject to variability. Automated semen analysis could lead to an increased standardization in and between laboratories but for that to happen automated devices need to be validated. A new device, the sperm quality analyzer V equine (SQA-Ve) version 1.00.43, was evaluated for its repeatability and agreement with light microscopy (LM), for raw and extended equine semen. Results were compared with computer assisted sperm analysis (CASA), which was also tested for its repeatability and agreement with LM. The SQA-Ve showed a good repeatability and fine agreement for assessing sperm concentration of raw semen based on scatter and Bland-Altman plots. This was in contrast with the motility parameters, which had a low repeatability. Morphology assessment with SQA-Ve was poorly repeatable as well as in poor agreement with LM. For extended semen, the findings were comparable. The SQA-Ve did well for concentration, whereas for the motility parameters repeatability was only just acceptable, with no agreement with LM. This sharply contrasted the CASA findings that were highly repeatable and almost in perfect agreement with LM. Based on these findings, the tested version of the SQA-Ve is insufficiently accurate to be used for analyzing raw or extended equine semen. PMID- 20965557 TI - Luteal blood flow increases during the first three weeks of pregnancy in lactating dairy cows. AB - The objectives of this experiment were to characterize luteal blood flow in pregnant and non-pregnant cows and to determine its value for early pregnancy diagnosis. Lactating dairy cows (n = 54), 5.2 +/- 0.2 y old (mean +/- SEM), average parity 2.4 +/- 0.2, and >= 6 wk postpartum at the start of the study, were used. The corpus luteum (CL) was examined with transrectal color Doppler ultrasonography (10.0-MHz linear-array transducer) on Days 3, 6, 9, 11, 13, 15, 18, and 21 of the estrus cycle (estrus = Day 0). Artificially inseminated cows (n = 40) were retrospectively classified as pregnant (embryonic heartbeat on Day 25; n = 18), nonpregnant (interestrus interval 15 to 21 d, n = 18), or having an apparent early embryonic loss (interestrus interval >25 d, n = 4). There was a group by time interaction (P < 0.001) for luteal blood flow from Days 3 to 18; it was approximately 1.10 +/- 0.08 cm(2) (mean +/- SEM) on Day 3, and increased to approximately 2.00 +/- 0.08 cm(2) on Day 13 (similar among groups). Thereafter, luteal blood flow was numerically (albeit not significantly) greater in pregnant cows, remained constant in those with apparent embryonic loss, and declined (not significantly) between Days 15 and 18 in nonpregnant cows. Luteal blood flow was greater in pregnant than in nonpregnant (P < 0.05) and nonbred cows (P < 0.05, n = 14) on Day 15 (2.50 +/- 0.16, 2.01 +/- 0.16, and 2.00 +/- 0.18 cm(2), respectively) and on Day 18 (2.40 +/- 0.19, 1.45 +/- 0.19, and 0.95 +/- 0.21 cm(2)). In cows with apparent early embryonic loss, luteal blood flow was 2.00 +/ 0.34 and 2.05 +/- 0.39 cm(2) on Days 15 and 18, which was less (not significantly) than in pregnant cows, but greater (P < 0.05) than in nonbred cows on Day 18. Although mean luteal blood flow was significantly greater in pregnant than nonpregnant (and nonbred) cows on Days 15 and 18, due to substantial variation among cows, it was not an appropriate diagnostic tool for pregnancy status. PMID- 20965558 TI - Interplay between acoustic/phonetic and semantic processes during spoken sentence comprehension: an ERP study. AB - When listening to speech in everyday-life situations, our cognitive system must often cope with signal instabilities such as sudden breaks, mispronunciations, interfering noises or reverberations potentially causing disruptions at the acoustic/phonetic interface and preventing efficient lexical access and semantic integration. The physiological mechanisms allowing listeners to react instantaneously to such fast and unexpected perturbations in order to maintain intelligibility of the delivered message are still partly unknown. The present electroencephalography (EEG) study aimed at investigating the cortical responses to real-time detection of a sudden acoustic/phonetic change occurring in connected speech and how these mechanisms interfere with semantic integration. Participants listened to sentences in which final words could contain signal reversals along the temporal dimension (time-reversed speech) of varying durations and could have either a low- or high-cloze probability within sentence context. Results revealed that early detection of the acoustic/phonetic change elicited a fronto-central negativity shortly after the onset of the manipulation that matched the spatio-temporal features of the Mismatch Negativity (MMN) recorded in the same participants during an oddball paradigm. Time reversal also affected late event-related potentials (ERPs) reflecting semantic expectancies (N400) differently when words were predictable or not from the sentence context. These findings are discussed in the context of brain signatures to transient acoustic/phonetic variations in speech. They contribute to a better understanding of natural speech comprehension as they show that acoustic/phonetic information and semantic knowledge strongly interact under adverse conditions. PMID- 20965559 TI - Inside out. PMID- 20965560 TI - A sandwiched microarray platform for benchtop cell-based high throughput screening. AB - The emergence of combinatorial chemistries and the increased discovery of natural compounds have led to the production of expansive libraries of drug candidates and vast numbers of compounds with potentially interesting biological activities. Despite broad interest in high throughput screening (HTS) across varied fields of biological research, there has not been an increase in accessible HTS technologies. Here, we present a simple microarray sandwich system suitable for screening chemical libraries in cell-based assays at the benchtop. The microarray platform delivers chemical compounds to isolated cell cultures by 'sandwiching' chemical-laden arrayed posts with cell-seeded microwells. In this way, an array of sealed cell-based assays was generated without cross-contamination between neighbouring assays. After chemical exposure, cell viability was analyzed by fluorescence detection of cell viability assays on a per microwell basis using a standard microarray scanner. We demonstrate the efficacy of the system by generating four hits from toxicology screens towards MCF-7 human breast cancer cells. Three of the hits were identified in a combinatorial screen of a library of natural compounds in combination with verapamil, a P-glycoprotein inhibitor. A fourth hit, 9-methoxy-camptothecin, was identified by screening the natural compound library in the absence of verapamil. The method developed here miniaturizes existing HTS systems and enables the screening of a wide array of individual or combinatorial libraries in a reproducible and scalable manner. We anticipate broad application of such a system as it is amenable to combinatorial drug screening in a simple, robust and portable platform. PMID- 20965561 TI - In vivo efficacy of a chitosan/IL-12 adjuvant system for protein-based vaccines. AB - Vaccines based on recombinant proteins require adjuvant systems in order to generate Th1-type immune responses. We have developed a vaccine adjuvant system using a viscous chitosan solution and interleukin (IL)-12, a Th1-inducing cytokine. The chitosan solution is designed to create a depot of antigen and IL 12 at a subcutaneous injection site. We measured the in vivo immune response of a vaccine containing 0.25, 1, or 4 MUg murine IL-12 and 75 MUg ovalbumin (OVA), formulated in a 1.5% chitosan glutamate solution. The chitosan/IL-12/OVA vaccine, in comparison to chitosan/OVA, IL-12/OVA, or OVA alone, elicited greater antigen specific CD4(+) and CD8(+) T-cell responses, as determined by CD4(+) splenocyte proliferation, Th1 cytokine release, CD8(+) T-cell interferon-gamma release, and MHC class I peptide pentamer staining. The combination of chitosan and IL-12 also enhanced IgG2a and IgG2b antibody responses to OVA. Co-formulation of chitosan and IL-12 thus promoted the generation of a Th1 immune response to a model protein vaccine. PMID- 20965562 TI - Gadonanotubes as magnetic nanolabels for stem cell detection. AB - Stem cell-based therapies have emerged as a promising approach in regenerative medicine. In the development of such therapies, the demand for imaging technologies that permit the noninvasive monitoring of transplanted stem cells in vivo is growing. Here, we report the performance of gadolinium-containing carbon nanocapsules, or gadonanotubes (GNTs), as a new T1-weighted magnetic resonance imaging (MRI) intracellular labeling agent for pig bone marrow-derived mesenchymal stem cells (MSCs). Without the use of a transfection agent, micromolar concentrations of GNTs can deliver up to 109 Gd(3+) ions per cell without compromising cell viability, differentiation potential, proliferation pattern, and phenotype. Imaging 10 * 106 GNT-labeled MSCs demonstrates a nearly two-fold reduction in T1 relaxation time when compared to unlabeled MSCs at 1.5 T in a clinical MRI scanner, which easily permits the discrimination of GNT-labeled MSCs in a T1-weighted MR image. It is anticipated that GNTs will allow in vivo tracking of GNT-labeled MSCs, as well as other mammalian cell types, by T1 weighted imaging with greater efficacy than other current technologies now allow. PMID- 20965563 TI - Fluorine-18-labeled Gd3+/Yb3+/Er3+ co-doped NaYF4 nanophosphors for multimodality PET/MR/UCL imaging. AB - Molecular imaging modalities provide a wealth of information that is highly complementary and rarely redundant. To combine the advantages of molecular imaging techniques, (18)F-labeled Gd(3+)/Yb(3+)/Er(3+) co-doped NaYF(4) nanophosphors (NPs) simultaneously possessing with radioactivity, magnetic, and upconversion luminescent properties have been fabricated for multimodality positron emission tomography (PET), magnetic resonance imaging (MRI), and laser scanning upconversion luminescence (UCL) imaging. Hydrophilic citrate-capped NaY(0.2)Gd(0.6)Yb(0.18)Er(0.02)F(4) nanophosphors (cit-NPs) were obtained from hydrophobic oleic acid (OA)-coated nanoparticles (OA-NPs) through a process of ligand exchange of OA with citrate, and were found to be monodisperse with an average size of 22 * 19 nm. The obtained hexagonal cit-NPs show intense UCL emission in the visible region and paramagnetic longitudinal relaxivity (r(1) = 0.405 s(-1).(mM)(-1)). Through a facile inorganic reaction based on the strong binding between Y(3+) and F(-), (18)F-labeled NPs have been fabricated in high yield. The use of cit-NPs as a multimodal probe has been further explored for T(1)-weighted MR and PET imaging in vivo and UCL imaging of living cells and tissue slides. The results indicate that (18)F-labeled NaY(0.2)Gd(0.6)Yb(0.18)Er(0.02) is a potential candidate as a multimodal nanoprobe for ultra-sensitive molecular imaging from the cellular scale to whole body evaluation. PMID- 20965564 TI - Drug delivery with upconversion nanoparticles for multi-functional targeted cancer cell imaging and therapy. AB - Upconversion nanoparticles (UCNPs) with unique multi-photon excitation photoluminescence properties have recently been intensively explored as novel contrast agents for low-background biomedical imaging. In this work, we functionalize UCNPs with a polyethylene glycol (PEG) grafted amphiphilic polymer. The PEGylated UCNPs are loaded with a commonly used chemotherapy molecule, doxorubicin (DOX), by simple physical adsorption via a supramolecular chemistry approach for intracellular drug delivery. The loading and releasing of DOX from UCNPs are controlled by varying pH, with an increased drug dissociation rate in acidic environment, favorable for controlled drug release. Upconversion luminescence (UCL) imaging by a modified laser scanning confocal microscope reveals the time course of intracellular delivery of DOX by UCNPs. It is found that DOX is shuttled into cells by the UCNP nano carrier and released inside cells after endocytosis. By conjugating nanoparticles with folic acid, which targets folate receptors over expressed on various types of cancer cells, we further demonstrate targeted drug delivery and UCL cell imaging with UCNPs. Besides DOX, this non-covalent drug loading strategy can also be used for loading of photosensitizer molecules on UCNPs for potential near-infrared light induced photodynamic therapy. Our results suggest the promise of UCNPs as interesting nano carriers for multi-functional cancer therapy and imaging. PMID- 20965565 TI - Cardiomyocyte-specific disruption of Serca2 in adult mice causes sarco(endo)plasmic reticulum stress and apoptosis. AB - Reduced sarco(endo)plasmic reticulum (SR) Ca(2+) ATPase (SERCA2) contributes to the impaired cardiomyocyte Ca(2+) homeostasis observed in heart failure. We hypothesized that a reduction in SERCA2 also elicits myocardial ER/SR stress responses, including unfolded protein responses (UPR) and cardiomyocyte apoptosis, which may additionally contribute to the pathophysiology of this condition. Left ventricular myocardium from mice with cardiomyocyte-specific tamoxifen-inducible disruption of Serca2 (SERCA2 KO) was compared with aged matched controls. In SERCA2 KO hearts, SERCA2 protein levels were markedly reduced to 2% of control values at 7 weeks following tamoxifen treatment. Serca2 disruption caused increased abundance of the ER stress-associated proteins CRT, GRP78, PERK, and eIF2alpha and increased phosphorylation of PERK and eIF2alpha, indicating UPR induction. Pro-apoptotic signaling was also activated in SERCA2 KO, as the abundance of CHOP, caspase 12, and Bax was increased. Indeed, TUNEL staining revealed an increased fraction of cardiomyocytes undergoing apoptosis in SERCA2 KO. ER-Tracker staining additionally revealed altered ER structure. These findings indicate that reduction in SERCA2 protein abundance is associated with marked ER/SR stress in cardiomyocytes, which induces UPR, apoptosis, and ER/SR structural alterations. This suggests that reduced SERCA2 abundance or function may contribute to the phenotype of heart failure also through induction of ER/SR stress responses. PMID- 20965566 TI - Effects of minocycline and its degradation products on the growth of Microcystis aeruginosa. AB - This work aimed to investigate the influence of Microcystis aeruginosa on the rate of minocycline (MNC) removal (abiotic degradation, physical binding or chemical transformation by cells) and the toxicity of MNC and its degradation products to the cyanobacterium. Most of the work was carried out in culture media in the presence or in the absence of M. aeruginosa. The rate of the MNC abiotic degradation in culture media strongly decreased with the increase of the MNC initial concentration. The exudates did not influence the rate of MNC degradation in the media. For concentrations >=0.48 MUM, the rate of the MNC removal from the media was faster in the presence of M. aeruginosa. Biotic MNC removal occurs by both physical binding by the cells (10%) and chemical transformations. EC(50) and EC(20) for MNC on the growth of M. aeruginosa were 0.92 and 0.13 MUM, respectively. Interestingly, MNC degradation products might promote M. aeruginosa growth. PMID- 20965567 TI - Mercury contamination in the riparian zones along the East Fork Poplar Creek at Oak Ridge. AB - Oak Ridge (Tennessee, USA) has a history of mercury (Hg) contamination in its aquatic and soil environment associated with past nuclear-weapons production activities at its Department of Energy (DOE) sites. Three different riparian zones along the Lower East Fork Poplar Creek were investigated in order to study Hg distribution and transformation in surface soils. The surface soil samples collected from these areas showed higher total Hg on an average (129.08 mg/kg) and higher total organic carbon (5.50%) in the upstream soils compared to the other two downstream locations that contained only 31.78 and 19.98 mg/kg total Hg and 2.88% and 1.65% of TOC on average, respectively. Further, methyl Hg concentrations were also comparatively higher in case of the upstream soils (30.10 MUg/kg) than that of the downstream sites (5.69 and 4.05 MUg/kg). The study showed a plume-like dispersion of Hg in the terrestrial environment along the creek, with decreasing Hg concentrations with distance from the Hg source zone. Also, the transformation of Hg in the soils was found to have been influenced by the soil TOC contents. PMID- 20965568 TI - Promising practices for delivery of court-supervised substance abuse treatment: perspectives from six high-performing California counties operating Proposition 36. AB - Operative for nearly a decade, California's voter-initiated Proposition 36 program offers many offenders community-based substance abuse treatment in lieu of likely incarceration. Research has documented program successes and plans for replication have proliferated, yet very little is known about how the Proposition 36 program works or practices for achieving optimal program outcomes. In this article, we identify policies and practices that key stakeholders perceive to be most responsible for the successful delivery of court-supervised substance abuse treatment to offenders under Proposition 36. Data was collected via focus groups conducted with 59 county stakeholders in six high-performing counties during 2009. Discussion was informed by seven empirical indicators of program performance and outcomes and was focused on identifying and describing elements contributing to success. Program success was primarily attributed to four strategies, those that: (1) fostered program engagement, monitored participant progress, and sustained cooperation among participants; (2) cultivated buy-in among key stakeholders; (3) capitalized on the role of the court and the judge; and (4) created a setting which promoted a high-quality treatment system, utilization of existing resources, and broad financial and political support for the program. Goals and practices for implementing each strategy are discussed. Findings provide a "promising practices" resource for Proposition 36 program evaluation and improvement and inform the design and study of other similar types of collaborative justice treatment efforts. PMID- 20965569 TI - Increased relative cerebral blood volume (rCBV) in brain lymphoma. PMID- 20965570 TI - The Global Great Society and the US commitment to smallpox eradication. AB - In 1965, Lyndon B. Johnson announced that the United States would join the fledgling global program to eradicate smallpox, beginning with a program in West Africa. The American commitment to smallpox eradication represented a broader effort in the United States and the developing world to expand international health programs and build a Global Great Society. The Global Great Society came to grief, but global smallpox eradication would ultimately succeed. PMID- 20965571 TI - Fusion protein of TLR5-ligand and allergen potentiates activation and IL-10 secretion in murine myeloid DC. AB - Toll-like receptor ligands are immune-modulatory components linking innate and adaptive immune responses and are considered to be promising vaccine components. Objective of this study was to investigate the adjuvant activity of Listeria monocytogenesis-derived TLR5-ligand flagellin A (flaA) genetically fused to ovalbumin (Ova, major chicken white egg allergen) in a murine in vitro system. Recombinant flaA, rOva, and a fusion protein of rflaA and rOva (rflaA:Ova) were over-expressed in Escherchia coli and purified by FPLC. LPS depletion was confirmed by LAL test. TLR5-binding was evaluated by human and murine TLR5 transgenic HEK 293 cells. The immune-modulatory effect of rflaA:Ova and rflaA:Ova modified by reduction and alkylation on purified BALB/c bone marrow-derived myeloid (mDC) and plasmacytoid dendritic cells (pDC) was investigated by flow cytometry and intracellular cytokine staining (ICS). Dose-dependent IL-8 secretion from transgenic HEK 293 cells confirmed binding of rflaA and rflaA:Ova molecules to human and murine TLR5. Recombinant flaA showed similar biological reactivity to TLR5-ligand fliC derived from Salmonella typhimurium applied as positive control. Compared to rflaA, both rflaA:Ova preparations induced higher expression of maturation markers (CD40, CD69, CD80, and CD86) on mDC, whereas only CD69 and CD40 were upregulated on pDC. Moreover, IL-6 and IL-10 production by mDC was enhanced upon stimulation with rflaA:Ova constructs in comparison to an equimolar mixture of both proteins whereas pDC did not show secretion of the investigated cytokines. Any immunological effects of LPS can be excluded by depletion of endotoxins and the lack of IL-10 production upon proteinase K digestion of rflaA:Ova. In summary, the rflaA:Ova fusion proteins showed an enhanced immune modulating capacity in comparison to rflaA or the mixture of rflaA and antigen. Since the rflaA:Ova fusion proteins induce strong IL-10 induction they are considered as potential vaccine candidates to improve allergen specific immunotherapy. PMID- 20965572 TI - Interplay of cytokine polymorphisms and bacterial vaginosis in the etiology of preterm delivery. AB - Recent findings suggest that the association between inflammation-related genes and preterm delivery may be stronger in the presence of bacterial vaginosis (BV). Tumor necrosis factor-alpha (TNFalpha) and interleukin 1-beta (IL-1beta) are pro inflammatory cytokines capable of inducing preterm labor in non-human primates. In this study the authors tested associations among two TNFalpha promoter polymorphisms (-G308A and -G238A), a single IL-1beta polymorphism (+C3954T), vaginal microbial findings, and risk of preterm delivery. Data were from the Pregnancy Outcomes and Community Health (POUCH) Study (n=777 term and n=230 preterm deliveries). Vaginal smears collected at mid-pregnancy (15-27 weeks gestation) were scored according to Nugent's criteria. A Nugent score of >= 4 was modeled as the cut-point for intermediate and positive BV. Logistic regression was used to estimate odds ratios for associations among independent covariates (vaginal flora, genotype) and preterm delivery. Results showed that women with a Nugent score of>= 4 and the TNFalpha -238 A/G or A/A were at increased risk of delivering preterm (race/ethnicity adjusted OR 2.6, 95% CI 1.2, 5.8). The p-value for the genotype and Nugent score interaction=0.02. This study points to one more example of a potential gene-environment interaction in a preterm delivery pathway. Future tests of this finding will determine the robustness of these results. PMID- 20965573 TI - Perceived threat mediates the relationship between psychosis proneness and aggressive behavior. AB - Psychotic symptoms are associated with aggressive tendencies, but this relationship is both complex and imperfect. In contrast to psychotic disorders, little is known about aggressive behavior and sub-clinical psychotic symptoms (e.g., "psychosis proneness"), which are relatively common in the general population. Threat/control-override (TCO), which is the propensity to overestimate the likelihood that an outside agent will (1) inflict harm (threat) or (2) control one's behaviors (control-override), has been associated with aggression in both psychiatric and community samples. The purpose of this study was to determine if psychosis proneness is related to aggression, and if one or both aspects of TCO mediate this relationship. We hypothesized that the propensity to overestimate threat would mediate this relationship, but control override would not. Sixty men and sixty women (mean age=20.00 years, sd=3.00) with no history of psychotic disorder completed measures assessing psychosis proneness, threat control/override, aggressive history, aggressive ideation, and aggressive behavior. Three structural equation models were tested: (1) Threat and control-override modeled as separate mediating variables, (2) TCO as a unitary mediating latent construct, and (3) TCO considered as part of a psychosis proneness latent variable. Results indicated that psychosis proneness is positively related to aggression and that the best model fit was obtained when threat and control-override were modeled as separate variables, with mediation through threat alone. The utility of TCO for explaining the relation between psychosis spectrum symptoms and aggression is discussed. PMID- 20965574 TI - Impact of Helicobacter pylori on chronic hepatitis C-related cognitive dysfunction. PMID- 20965575 TI - Localized retinal neuropeptide regulation of macrophage and microglial cell functionality. AB - The functionality of immune cells is manipulated within the ocular microenvironment to protect the sensitive and non-regenerating light-gathering tissue from the collateral damage of inflammation. This is mediated partly by the constitutive presence of immunomodulating neuropeptides. Treating primary resting macrophages with soluble factors produced by the posterior eye induced co expression of Arginase1 and NOS2. The neuropeptides alpha-melanocyte stimulating hormone and Neuropeptide Y alternatively activated the macrophages to co-express Arginase1 and NOS2 like myeloid suppressor cells. Similar co-expressing cells were found within healthy, but not in wounded retinas. Therefore, the healthy retina regulates macrophage functionality to the benefit of ocular immune privilege. PMID- 20965576 TI - Early B-cell factor regulates the expression of Hemokinin-1 in the olfactory epithelium and differentiating B lymphocytes. AB - Hemokinin-1, encoded by the TAC4 gene, is a tachykinin most closely related to substance P. Previous studies have shown that TAC4 distinguishes itself from other tachykinins by its predominantly non-neuronal expression profile, particularly in cells of the immune system. Here we report for the first time that the highest levels of TAC4 expression are found in the olfactory epithelium. Furthermore, we identify olfactory neuron-specific transcription factor (Olf-1), also known as early B-cell factor (EBF), as a novel regulator of TAC4 expression. EBF present in the olfactory epithelium and in B cells binds to two sites in the TAC4 promoter and modulates expression in developing B cells. Our findings suggest a role for TAC4 in cell differentiation, and represent a regulatory bridge between the nervous system and the immune system. PMID- 20965577 TI - RTL therapy for multiple sclerosis: a Phase I clinical study. AB - A human recombinant T cell receptor ligand (RTL1000) consisting of DR2 alpha1 and beta1 domains linked covalently to MOG-35-55 peptide can reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE), and was evaluated for safety in a Phase 1 randomized, placebo-controlled, escalating dose study in 34 subjects with multiple sclerosis (MS). RTL1000 was safe and well tolerated at a dose of <=60 mg that is well within the effective dose range for EAE and did not cause worsening of MS disease at doses <=200 mg. RTL1000 represents a novel approach for the treatment of MS that promises potent immunoregulation and CNS repair without global immunosuppression. PMID- 20965578 TI - Otitis media across nine countries: disease burden and management. AB - OBJECTIVE: To assess the perceived disease burden and management of otitis media (OM) among an international cohort of experienced physicians. METHODS: A cross sectional survey conducted in France, Germany, Spain, Poland, Argentina, Mexico, South Korea, Thailand and Saudi Arabia. Face-to-face interviews conducted with 1800 physicians (95% paediatricians, 5% family practitioners).Main outcome measures were the perceived burden on clinical practice (number of cases, complications and referrals) and first- and second-line management strategies for OM. Results are expressed as mean and range across the nine countries over three continents. RESULTS: Respondents estimated an average annual caseload of 375 (range 128-1003) children under 5 years of age with OM; 54% (range 44-71%) with an initial episode and 38% (range 27-54%) with recurrent OM (ROM). OM with complications was estimated to be approximately 20 (range 7-49) cases per year and an estimated 15% (8-41%) of children with OM was recalled as needing specialist referral. There was high awareness of Streptococcus pneumoniae and Haemophilus influenzae as causative bacterial pathogens: 77% (range 65-91%) and 74% (range 68-83%), respectively, but less recognition of non-typeable H. influenzae (NTHi); 59% (range 45-67%). Although concern over antimicrobial resistance was widespread, empirical treatment with antibiotics was the most common first-line treatment (mean 81%, range 40-96%). The burden of disease is substantial enough that many physicians would consider vaccination to prevent OM (mean score 5.1, range 4.3-6.2 on 1-7 scale). CONCLUSIONS: This large, multinational survey shows that OM remains a significant burden for clinical practice. Despite awareness of shortcomings, antimicrobial therapy remains the most frequent treatment for OM. PMID- 20965579 TI - Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis. AB - There is a well-established connection between smoking and depression. Depressed individuals are over-represented among smokers, and ex-smokers often experience increased depressive symptoms immediately after stopping smoking. Nicotine in tobacco binds, activates and desensitizes nicotinic acetylcholine receptors (nAChRs), but it is not known whether activation or desensitization is more important for the effects of nicotine on depressive symptoms. Here we review, based on clinical and preclinical studies of nicotinic drugs, the hypothesis that blockade (rather than activation) of neuronal nAChRs might be important for the effects of nicotinic agents on depressive symptoms. The endogenous neurotransmitter for nAChRs is acetylcholine, and the effects of nicotine on depression-like behaviors support the idea that dysregulation of the cholinergic system might contribute to the etiology of major depressive disorder. Thus, pharmacological agents that limit acetylcholine signaling through neuronal nAChRs might be promising for the development of novel antidepressant medications. PMID- 20965580 TI - Investigations of transcript expression in fathead minnow (Pimephales promelas) brain tissue reveal toxicological impacts of RDX exposure. AB - Production, usage and disposal of the munitions constituent (MC) cyclotrimethylenetrinitramine (RDX) has led to environmental releases on military facilities. The chemical attributes of RDX are conducive for leaching to surface water which may put aquatic organisms at risk of exposure. Because RDX has been observed to cause aberrant neuromuscular effects across a wide range of animal phyla, we assessed the effects of RDX on central nervous system (CNS) functions in the representative aquatic ecotoxicological model species, fathead minnow (Pimephales promelas). We developed a fathead minnow brain-tissue cDNA library enriched for transcripts differentially expressed in response to RDX and trinitrotoluene (TNT) exposure. All 4,128 cDNAs were sequenced, quality filtered and assembled yielding 2230 unique sequences and 945 significant blastx matches (E <=10(-5)). The cDNA library was leveraged to create custom-spotted microarrays for use in transcript expression assays. The impact of RDX on transcript expression in brain tissue was examined in fathead minnows exposed to RDX at 0.625, 2.5, 5, 10mg/L or an acetone-spike control for 10 days. Overt toxicity of RDX in fathead minnow occurred only at the highest exposure concentration resulting in 50% mortality and weight loss. Conversely, Bayesian analysis of microarray data indicated significant changes in transcript expression at concentrations as low as 0.625 mg/L. In total, 154 cDNAs representing 44 unique transcripts were differentially expressed in RDX exposures, the majority of which were validated by reverse transcriptase-quantitative PCR (RT-qPCR). Investigation of molecular pathways, gene ontology (GO) and individual gene functions affected by RDX exposures indicated changes in metabolic processes involved in: oxygen transport, neurological function, calcium binding/signaling, energy metabolism, cell growth/division, oxidative stress and ubiquitination. In total, our study indicated that RDX exposure affected molecular processes critical to CNS function in fathead minnow. PMID- 20965581 TI - Comprehensive biological effects of a complex field poly-metallic pollution gradient on the New Zealand mudsnail Potamopyrgus antipodarum (Gray). AB - The Lot River is known to be contaminated by metals, mainly cadmium and zinc, due to a former Zn ore treatment plant in the watershed of the Riou-Mort, a tributary of the Lot River. Many studies have been performed to characterize contamination, but few have assessed its consequences on the biological responses of organisms along the gradient. We exposed adult and juvenile New Zealand freshwater mudsnails Potamopyrgus antipodarum at several sites along the gradient of metal contamination for 28 days. Biological responses were monitored at different levels: individual (survival, growth and fecundity), tissue and biochemical (energy status and vertebrate-like sex steroid levels) to better understand the toxicity mechanisms involved. Accumulation of Cd and Zn was high during exposure. Most of the biological effects observed could be linked to this contamination and were concentration-dependent. Histological lesions of the digestive gland were observed, with hypertrophy of calcium cells and vacuolization of digestive cells. Such effects are likely to explain the decrease of energy status (triglycerides and proteins), juvenile growth and adult fecundity observed at the most polluted site. However the magnitude of the fall in fecundity cannot be attributed only to these tissular effects, indicating another mode of action of Cd or possible confounding factors. Steroid accumulation in snails indicated only organic pollution. Histopathological effects proved the most sensitive endpoint to metal (Cd and Zn) contamination. PMID- 20965583 TI - Brugada syndrome unmasked by pneumonia. PMID- 20965582 TI - Source and impact of lead contamination on delta-aminolevulinic acid dehydratase activity in several marine bivalve species along the Gulf of Cadiz. AB - Coastal areas and estuaries are particularly sensitive to metal contamination from anthropogenic sources and in the last few decades the study of space-time distribution and variation of metals has been extensively researched. The Gulf of Cadiz is no exception, with several rivers draining one of the largest concentrations of sulphide deposits in the world, the Iberian Pyrite Belt (IPB). Of these rivers, the Guadiana, one of the most important in the Iberian Peninsula, together with smaller rivers like the Tinto and Odiel, delivers a very high metal load to the adjacent coastal areas. The purpose of this work was to study the source and impact of lead (Pb) drained from historical or active mining areas in the IPB on the activity of a Pb inhibited enzyme (delta-aminolevulinic acid dehydratase, ALAD) in several bivalve species along the Gulf of Cadiz. Seven marine species (Chamelea gallina, Mactra corallina, Donax trunculus, Cerastoderma edule, Mytilus galloprovincialis, Scrobicularia plana and Crassostrea angulata) were collected at 12 sites from Mazagon, near the mouth of the rivers Tinto and Odiel (Spain), to Cacela Velha (Ria Formosa lagoon system, Portugal). Lead concentrations, ALAD activity and lead isotope ratios ((206)Pb/(204)Pb, (207)Pb/(204)Pb and (208)Pb/(204)Pb) were determined in the whole soft tissues. The highest Pb concentrations were determined in S. plana (3.50+/-1.09 MUg g(-1) Pb d.w.) and D. trunculus (1.95+/-0.10 MUg g(-1) Pb d.w.), while M. galloprovincialis and C. angulata showed the lowest Pb levels (<0.38 MUg g(-1) Pb d.w.). In general, ALAD activity is negatively correlated with total Pb concentration. However this relationship is species dependent (e.g. linear for C. gallina ALAD=-0.36[Pb]+0.79; r=0.837; or exponential for M. galloprovincialis ALAD=2.48e(-8.3[Pb]); r=0.911). This indicates that ALAD activity has considerable potential as a biomarker of Pb and moreover, in marine bivalve species with different feeding habits. Lead isotope data showed significant seasonal and spatial changes in bivalve isotopic composition reflecting seasonal and geographic differences in bioaccumulation. Within the study area, Pb can be modelled as a mixing between geogenic Pb and mine-related, discharges of Pb from the IPB. For some sites at the mouth of the Guadiana River, the bivalves show contamination from other anthropogenic sources, such as leaded boat/aviation fuel and/or leaded paint. Finally, the study demonstrates convincingly the need to consider species-specific variation when using bivalve ALAD activity as a biomarker for Pb. PMID- 20965584 TI - Proteomic analysis of serum in patients with apical ballooning syndrome. PMID- 20965586 TI - "The heart is simply a muscle" and first description of the tetralogy of "Fallot". Early contributions to cardiac anatomy and pathology by bishop and anatomist Niels Stensen (1638-1686). AB - BACKGROUND: Many are familiar with the parotid duct and the Danish physician/anatomist's name associated with it. However, most are unaware of Niels Stensen's life and his significant contributions to the early study of the heart. For example, he found that the heart is simply muscle and was the first to describe what we now refer to as the tetralogy of Fallot. METHODS: A review of germane literature regarding this pioneer of cardiac anatomy was performed. CONCLUSIONS: This physician of the Medici court was clearly ahead of his time and found errors in the publications of such giants as Varolius and Willis. The tetralogy of Fallot should rightfully, be termed the tetralogy of Stensen. The present review discusses the life of this 17th century anatomist, physician and priest/bishop and highlights his contributions to cardiac anatomy and pathology. PMID- 20965585 TI - Hemostatic markers are associated with the risk and prognosis of atrial fibrillation: the ARIC study. AB - BACKGROUND: Various hemostatic markers are associated with the risk of cardiovascular disease; however, limited information exists on their relationship with the occurrence and prognosis of atrial fibrillation (AF). OBJECTIVES: To assess whether hemostatic markers are associated with the incidence and prognosis of AF. METHODS: We studied 14,858 men and women in the Atherosclerosis Risk in Communities cohort, aged 45-64 and free of AF at baseline (1987-1989). Fibrinogen, von Willebrand factor (vWf), factor VII activity (VIIc), factor VIII activity (VIIIc), protein C, antithrombin III (ATIII), and activated partial thromboplastin time (aPTT) were measured in blood samples at baseline. AF and other cardiovascular outcomes through 2005 were determined following standardized protocols. RESULTS: During a median follow-up of 16.8 years, 1209 cases of AF were identified. In multivariable Cox models, the hazard ratios (HR) and 95% confidence intervals (CI) of incident AF associated with a 1-standard deviation (SD) increase in each marker were 1.13 (1.07-1.20) for fibrinogen, 1.17 (1.11 1.23) for vWf, 1.17 (1.11-1.24) for factor VIIIc, 0.93 (0.88-1.00) for factor VIIc, 0.98 (0.92-1.04) for protein C, 1.00 (0.94-1.06) for aPTT and 1.00 (0.95 1.06) for ATIII. Greater factor VIIIc, fibrinogen and vWf were consistently associated with a higher risk of cardiovascular outcomes and mortality in those with and without incident AF, while greater protein C was associated with a lower risk of ischemic stroke. CONCLUSION: Several hemostatic markers are associated with the incidence of AF independently of other cardiovascular risk factors. Their role in the risk stratification of AF patients should be further studied. PMID- 20965587 TI - Reduced body iron stores and atherosclerosis in patients with cyanotic congenital heart disease. PMID- 20965588 TI - Interhospital stabilization of adult patients with refractory cardiogenic shock by veno-arterial extracorporeal membrane oxygenation. PMID- 20965589 TI - Papillary muscle late enhancement on MRI. PMID- 20965590 TI - Absence of metal allergy in patients with very late drug-eluting stent thrombosis: a pilot study. PMID- 20965591 TI - Quality of life after percutaneous coronary intervention in the elderly with acute coronary syndrome. AB - BACKGROUND: Health-related quality of life (HRQoL) is an important but often neglected outcome measure in acute coronary syndrome (ACS) management. The prevalence of elderly presenting with ACS and undergoing percutaneous coronary intervention (PCI) is rising. We aimed to explore the impact of PCI on health status in elderly ACS patients. METHODS: We prospectively enrolled 624 patients admitted to our institution with ACS from February 2006 to May 2008. Short Form (SF)-36 health survey was used to assess HRQoL at baseline and 6 months. Baseline characteristics and HRQoL were compared for patients treated with PCI within 30 days of index ACS admission vs. medical therapy across 3 age groups (<60, 60-79 and >=80 years). RESULTS: PCI was performed in 73.6%, 55.7% and 21.3% in patients aged <60, 60-79 and older than 80 years, respectively (p<0.01). Elderly patients were more likely to be female (16.9 vs. 35.4 vs. 54.6%, p<0.01) and had more co morbidities (p<0.01). Older patients were less likely to undergo angiography (84.8 vs. 65.2 vs. 24.8%, p<0.01). Baseline HRQoL decreased with advancing age (p<0.01). However, elderly patients who underwent PCI experienced the most improvement in physical health than younger age groups. PCI was an independent predictor (Odds Ratio = 1.79, 95% CI: 1.10-2.92) of better physical health status at 6 months. CONCLUSION: Elderly ACS patients who underwent PCI experienced the most improvement in physical health compared to younger patients. Our findings suggest that age per se should not deter against revascularization because of potential benefits in HRQOL. PMID- 20965592 TI - Electrophysiological interactions between implantable cardioverter defibrillators and left ventricular assist device. PMID- 20965593 TI - Lifecourse predictors of adult fibrinogen levels: the Newcastle Thousand Families Study. AB - BACKGROUND: Research investigating early life effects on fibrinogen levels in adult life has produced conflicting results. The aim of this study was to examine and quantify the direct and indirect associations between fetal, infancy and adult risk factors and fibrinogen levels, at age 49-51 years, using data from the Newcastle Thousand Families Study. METHODS: Detailed information was collected prospectively during childhood, including birth weight, duration of being breast fed and socio-economic conditions. At age 49-51 years, 574 study members returned self-completion questionnaires and 412 attended for clinical examination, including the measurement of plasma fibrinogen concentrations in 173 men and 221 women. These data were analysed using linear regression and path analyses. RESULTS: Poorer quality housing conditions at birth (p=0.001), longer duration of being breast fed (p=0.025), lower current body fat percentage (p<0.001), not being a current smoker (p<0.001) and moderate current alcohol consumption (p=0.002) were significant independent predictors of lower plasma fibrinogen concentration at age 49-51 years. No association was observed between plasma fibrinogen concentration and standardised birth weight or with time since stopping smoking among former smokers. CONCLUSION: Concentration of plasma fibrinogen in adulthood is influenced by a range of factors from different stages of life. Although birth weight was not a predictor, there were significant associations with housing conditions in early life and duration of being breast fed. Regardless, the strongest predictors were smoking and contemporary percent body fat. Therefore, modification of these factors would be the most likely way to reduce concentrations of plasma fibrinogen in adulthood. PMID- 20965594 TI - Complex ventricular arrhythmias in patients after heterotopic heart transplantation. PMID- 20965595 TI - Osteogenic differentiation of mesenchymal stem cells is preserved by partial, but not full peroxisome proliferator-activated receptor-gamma agonist. PMID- 20965596 TI - Retiring early with cardiovascular disease--impact on individual's financial assets. PMID- 20965597 TI - Recurrent mid-ventricular Tako-Tsubo cardiomyopathy: three episodes of a uniform cardiac response to varying stressors. PMID- 20965598 TI - High diagnostic performance of a high-sensitivity cardiac troponin T assay in patients with suspected acute coronary syndrome. PMID- 20965599 TI - Predicting prolonged bovine tuberculosis breakdowns in Great Britain as an aid to control. AB - Bovine tuberculosis (bTB) is an important notifiable disease in cattle in Great Britain (GB), and is subject to statutory control measures. Despite this, disease incidence has increased since the mid-1980s, and around 30% of herd breakdowns continue for more than 240 days. This is twice the shortest possible time for confirmed breakdowns to test clear from infection (~120 days), and four times the shortest possible time for unconfirmed breakdowns (~60 days). These "prolonged" breakdowns consume substantial resources and may act as an ongoing source of infection. It is not clear why some breakdowns become prolonged. Existing detailed case-control data have been re-analysed to determine risk factors for breakdowns lasting longer than 240 days, the strongest of which was the confirmation status of the breakdown: OR 12.6 (95%CI: 6.7-25.4). A further model restricted to data available early on in a breakdown for all breakdowns nationally, can predict 82-84% of prolonged breakdowns with a positive predictive value of 44-49% when validated using existing national datasets over a 4-year period. Identification of prolonged breakdowns at an earlier stage could help to target bTB controls in GB. PMID- 20965600 TI - Growth of Listeria monocytogenes on a RTE-meat matrix enhances cell invasiveness to mouse J774A.1 macrophages. AB - It remains unclear whether the growth of Listeria monocytogenes on a ready-to-eat (RTE) meat matrix has an impact on the bacterium's pathogenic abilities. In this study, we investigated the impact of environments on virulence by growing L. monocytogenes (F2365 strain) on brain heart infusion agar (BHI), tryptic soy agar (TSA), and RTE turkey meat matrices. Bacteria cultured from these media were harvested and used to infect mouse macrophage cell line J774A.1 with different MOIs to examine their invasion ability. At MOI=10 and 50, the numbers of bacteria recovered from cells infected with turkey-meat-grown Listeria were significantly higher than those from the two nutrient-rich growth media. Additionally, MOI played a role in determining L. monocytogenes recovery rates, since significant differences were found amongst all three groups at low MOI, while no significant differences were found between BHI and TSA groups at high MOI. These results indicate that environmental changes affect the ability of L. monocytogenes to invade and survive intracellularly while grown on RTE-meat matrix. PMID- 20965601 TI - Peripheral neuropathy, decreased muscle strength and obesity are strongly associated with walking in persons with type 2 diabetes without manifest mobility limitations. AB - AIMS: We evaluated the associations of diabetic complications and underlying pathology with daily walking activity in type 2 diabetic patients without manifest mobility limitations. METHODS: 100 persons with type 2 diabetes (mean age 64.5 +/- 9.4 years) were studied. Persons with manifest mobility limitations were excluded. Possible determinants measured: peripheral neuropathy, neuropathic pain, peripheral arterial disease, cardiovascular disease, decreased muscle strength (handgrip strength), BMI, depression, falls and fear of falling. Walking activity was measured during one week with a pedometer. Functional capacity was measured with the 6 min walk test, the timed "up and go" test and a stair climbing test. RESULTS: prevalence of neuropathy (40%) and obesity (53%) was high. Persons took a median of 6429 steps/day. In multivariate regression analysis, adjusted for age and sex, neuropathy was associated with a reduction of 1967 steps/day, decreased muscle strength with 1782 steps/day, and an increase in BMI of 1 kg/m(2) with a decrease of 210 steps/day (all p<0.05). Decreased muscle strength and BMI, but not neuropathy, were associated with outcome of functional capacity tests in multiple regression analysis. CONCLUSIONS: peripheral neuropathy, decreased muscle strength and obesity are strongly associated with walking in persons with type 2 diabetes without manifest mobility limitations. PMID- 20965602 TI - Mutual health insurance in Rwanda: evidence on access to care and financial risk protection. AB - OBJECTIVE: Rwanda has expanded mutual health insurance considerably in recent years, which has a great potential for making health services more accessible. In this paper, we examine the effect of mutual health insurance (MHI) on utilization of health services and financial risk protection. METHODS: We used data from a nationally representative survey from 2005-2006. We analysed this data through summary statistics as well as regression models. FINDINGS: Our statistical modelling shows that MHI coverage is associated with significantly increased utilization of health services. Indeed, individuals in households that had MHI coverage used health services twice as much when they were ill as those in households that had no insurance coverage. Additionally, MHI is also associated with a higher degree of financial risk protection and the incidence of catastrophic health expenditure was almost four times less than in households with no coverage. Nonetheless, the limitations of the MHI coverage also become apparent. CONCLUSION: These promising results indicate that MHI has had a strong positive impact on access to health care and can continue to improve health of Rwandans even more if its limitations are addressed further. PMID- 20965603 TI - The role of institutional design and organizational practice for health financing performance and universal coverage. AB - Many low- and middle income countries heavily rely on out-of-pocket health care expenditure. The challenge for these countries is how to modify their health financing system in order to achieve universal coverage. This paper proposes an analytical framework for undertaking a systematic review of a health financing system and its performance on the basis of which to identify adequate changes to enhance the move towards universal coverage. The distinctive characteristic of this framework is the focus on institutional design and organizational practice of health financing, on which health financing performance is contingent. Institutional design is understood as formal rules, namely legal and regulatory provisions relating to health financing; organizational practice refers to the way organizational actors implement and comply with these rules. Health financing performance is operationalized into nine generic health financing performance indicators. Inadequate performance can be caused by six types of bottlenecks in institutional design and organizational practice. Accordingly, six types of improvement measures are proposed to address these bottlenecks. The institutional design and organizational practice of a health financing system can be actively developed, modified or strengthened. By understanding the incentive environment within a health financing system, the potential impacts of the proposed changes can be anticipated. PMID- 20965604 TI - Inhibitory effect of radiotherapy combined with weekly recombinant human endostatin on the human pulmonary adenocarcinoma A549 xenografts in nude mice. AB - The aim of this study was to investigate the inhibitory effect of radiotherapy combined with weekly recombinant human endostatin (RHES) on the human pulmonary adenocarcinoma A549 xenografts in nude mice. The 40 A549 xenograft nude mice models were randomly divided into 4 groups (each group with 10 nude mice). Single radiotherapy group (group 1) was given a single external irradiation (6MV-X ray, 10 Gy) and peritumoral subcutaneous injection of 0.2 ml normal saline every day for 7 days. Single RHES group (group 2) was given peritumoral subcutaneous injection of 0.2 ml RHES (0.75 mg/ml) for 7 days. Combination therapy group (group 3) was given radiotherapy as the same as group 1 and RHES as the same as group 2. Control group was given normal saline as the same as group 1. The tumor volume was smaller in group 3 than in control group from the 8th day after treatment (P<0.05) and tumor regression occurred from the second week after treatment in group 3. On the 15th day after treatment, the inhibitory rates of tumor volume were 69.65%, 92.64% and 116.4% in groups 2, 1 and 3, respectively; MVD number was lower in group 3 than in group 1 (P<0.05); there was no statistical significance in VEGF expression between group 2 and control group as well as between group 3 and group 1 (P>0.05). Apoptosis was marked in group 3. Radiotherapy combined with weekly RHES can significantly inhibit tumor growth and earlier induce tumor regression, which may be related to the improvement of tumor hypoxia and the inhibition of radiation-induced tumor angiogenesis. Short-term application (1 week) of RHES is beneficial to clinical practice. PMID- 20965605 TI - Different Staphylococcus aureus whole bacteria mutated in putative pro inflammatory membrane components have similar cytokine inducing activity. AB - The role of the different major cell wall components of Gram-positive bacteria for immune stimulation is controversial. We thus compared the cytokine inducing capacity of different Staphylococcus aureus (SA) mutants lacking either lipoproteins (SA 113Deltalgt), or wall teichoic acids (WTA) (DeltaTA), or possessing a reduced d-alanine content in lipoteichoic acid (LTA) (SA 113Deltadlt) to its corresponding wildtype (SA 113wt). Inactivated whole bacteria and their purified cell wall components peptidoglycan and LTA, were used to stimulate human whole blood and macrophages from TLR2 knock-out mice. We found that all S. aureus strains induced similar amounts of TNF, IL-8 and IL-10 and none of them was dependent on the presence of TLR2. Surprisingly, in case of SA 113Deltalgt a significant attenuated release of only IL-1beta protein and mRNA in human whole blood was observed. Highly purified peptidoglycan from all strains in contrast to LTA had a very low activity in stimulating cytokine release. Taken together these results demonstrate that major cell wall alterations like lack of WTA, lipoproteins or alterations in d-alanine content do not affect the overall cytokine inducing potential of whole bacteria and thus cytokine induction is initiated by redundant mechanisms. PMID- 20965606 TI - T lymphocyte proliferation is suppressed by the opioid growth factor ([Met(5)] enkephalin)-opioid growth factor receptor axis: implication for the treatment of autoimmune diseases. AB - Opioid peptides function as immunomodulatory molecules. Reports have linked the opioid growth factor (OGF), [Met(5)]-enkephalin, and its receptor OGFr to autoimmune diseases. OGF repressed the incidence and magnitude of myelin oligodendrocyte-induced experimental autoimmune encephalomyelitis in mice. Given the extensive connection between the immune system and autoimmune diseases, the present study was conducted to examine the relationship of the OGF-OGFr axis and T lymphocyte proliferation. Splenic-derived mouse lymphocytes were stimulated with phytohemagglutin (PHA). All non-stimulated and PHA-stimulated T lymphocytes had immunoreactivity for OGF-like enkephalin and OGFr. OGF markedly suppressed T lymphocyte number in a dose-dependent manner. However, PHA-stimulated T lymphocytes were not altered in cell number by a variety of natural and synthetic opioid-related compounds, some specific for MU, delta, and kappa opioid receptors. Persistent blockade of opioid receptors with the general opioid antagonist naltrexone (NTX), as well as antibody neutralization of OGF-like peptides, had no effect on cell number. Non-stimulated T lymphocytes exhibited no change in cell number when subjected to OGF or NTX. Treatment of T lymphocytes with siRNAs for MU, delta, or kappa opioid receptors did not affect cell number, and the addition of OGF to these siRNA-exposed cultures depressed the population of cells. T lymphocytes treated with OGFr siRNA also had a comparable number of cells to control cultures, but the addition of OGF did not alter cell number. DNA synthesis in PHA-stimulated T lymphocytes exposed to OGF was markedly decreased from PHA-stimulated cultures receiving vehicle, but the number of cells undergoing apoptosis or necrosis in these cultures was similar to control levels. T lymphocytes subjected to siRNA for p16 and/or p21 had a comparable number of cells compared to controls, and treatment with OGF did not depress cell number in preparations transfected with both p16 and p21 siRNA. These data reveal that the OGF-OGFr axis is present in T lymphocytes and is capable of suppressing cell proliferation. However, T lymphocytes are not dependent on the regulation of cell proliferation by this system. The results showing that the OGF-OGFr axis is an immunosuppressant, offers explanation for reports that autoimmune diseases can be modulated by this system. PMID- 20965607 TI - Controlling actin cytoskeletal organization and dynamics during neuronal morphogenesis. AB - Coordinated functions of the actin cytoskeleton and microtubules, which need to be carefully controlled in time and space, are required for the drastic alterations of neuronal morphology during neuromorphogenesis and neuronal network formation. A key process in neuronal actin dynamics is filament formation by actin nucleators, such as the Arp2/3 complex, formins and the brain-enriched, novel WH2 domain-based nucleators Spire and cordon-bleu (Cobl). We here discuss in detail the currently available data on the roles of these actin nucleators during neuromorphogenesis and highlight how their required control at the plasma membrane may be brought about. The Arp2/3 complex was found to be especially important for proper growth cone translocation and axon development. The underlying molecular mechanisms for Arp2/3 complex activation at the neuronal plasma membrane include a recruitment and an activation of N-WASP by lipid- and F actin-binding adaptor proteins, Cdc42 and phosphatidyl-inositol-(4,5) bisphosphate (PIP(2)). Together, these components upstream of N-WASP and the Arp2/3 complex ensure fine-control of N-WASP-mediated Arp2/3 complex activation and control distinct functions during axon development. They are counteracted by Arp2/3 complex inhibitors, such as PICK, which likewise play an important role in neuromorphogenesis. In contrast to the crucial role of the Arp2/3 complex in proper axon development, dendrite formation and dendritic arborization was revealed to critically involve the newly identified actin nucleator Cobl. Cobl is a brain-enriched protein and uses three Wiskott-Aldrich syndrome protein homology 2 (WH2) domains for actin binding and for promoting the formation of non-bundled, unbranched filaments. Thus, cells use different actin nucleators to steer the complex remodeling processes underlying cell morphogenesis, the formation of cellular networks and the development of complex body plans. PMID- 20965608 TI - Conditional ablation of integrin alpha-6 in mouse epidermis leads to skin fragility and inflammation. AB - Hemidesmosomes (HDs) are essential anchorage junctions which mediate the firm attachment of epithelia to the underlying basement membranes, of which one main component is the integrin alpha6beta4. These specific junctions are also able to trigger signalling pathways, via the recruitment and interactions of signalling molecules with HD components such as the cytoplasmic tail of the beta4 integrin or the plakin plectin. HDs must also assemble and disassemble depending on the tissue context for example during tissue remodelling. Alterations of HD components or their loss result in skin blistering disorders known as epidermolysis bullosa. Since mice lacking integrin alpha6 die at birth with severe skin blistering, we have produced a mouse line in which epidermal deletion of integrin alpha6 can be controlled by tamoxifen injection. We observed that the deletion was mosaic, but that hairless skin such as ears, tails and paws were affected and showed chronic inflammation associated with hyperproliferation, and expression of laminin-111. Interestingly, two cytokines, amphiregulin and epiregulin, previously found increased in integrin alpha6 deficient cultured keratinocytes, were also increased here in the affected skin. In detached areas, we validate clearly that the absence of integrin alpha6 leads to a delocalisation of plectin, and the complete disappearance of HD structures. PMID- 20965609 TI - Changing epidemiology of carbapenem-resistant Enterobacteriaceae carriage during an outbreak of carbapenem-resistant Klebsiella pneumoniae. PMID- 20965610 TI - Assessing the sustainability of hand hygiene adherence prior to patient contact in the emergency department: A 1-year postintervention evaluation. AB - BACKGROUND: Health care-associated infection is one of the most important patient safety problems in the world. While many methods exist to prevent health care associated infection, most experts believe that improving hand hygiene is paramount. We previously published the results of a successful before-and-after hand hygiene interventional study performed in the pediatric emergency department of the Meyer Hospital in Florence, Italy. The goal of the current study is to assess the longer term sustainability of the previously described intervention. METHODS: Direct observation was used to assess hand hygiene compliance for both doctors and nurses in the emergency department using the same methods and observers as previously employed. RESULTS: In addition to the 420 preintervention and 463 immediately postintervention observations previously reported, we observed another 456 clinician-patient interactions approximately 1 year after the intervention. Among all health care workers, there was no significant difference between hand hygiene compliance immediately postintervention (44.9%) compared with 1 year after the intervention (45.2%). Adherence among nurses, however, increased from 40.7% to 49.8% (P = .03), whereas adherence among doctors decreased from 50.5% to 36.5% (P = .008). CONCLUSION: The overall effects of the intervention were sustained over a 1-year period, although a marked difference was observed between nurses and doctors. PMID- 20965611 TI - A prospective clinical trial on prevention of catheter contamination using the hub protection cap for needleless injection device. AB - BACKGROUND: Catheter hub contamination has been recognized as a source of catheter-related bloodstream infections. We have investigated the efficacy of a protection cap for a needleless injection device in preventing intraluminal catheter contamination, compared with a conventional 3-way stopcock. METHODS: Adult patients requiring an intravascular catheter placement for at least 48 hours in an intensive care unit were randomly assigned to receive either the needleless injection device with protection cap (test group, n = 31, number of devices = 151) or with a conventional 3-way stopcock (comparator group, n = 33, number of devices = 179). To evaluate intraluminal contamination, we examined the bacteria isolated in the inline bacterial filters, which were attached downstream of the injection ports. RESULTS: The incidence of bacterial contamination was significantly different between the groups (test group 2/151 (1.3%) vs comparator group 11/179 (6.2%), P = .04). There was no correlation between the microbial contamination rate and the in situ time of catheter or numbers of injections. CONCLUSION: The protection cap for needleless injection devices decreased microbial transfer from the injection port to the intraluminal fluid pathway and lowered the risk of catheter-related bloodstream infections. PMID- 20965612 TI - The specificity of amyloid imaging in the diagnosis of neurodegenerative diseases. PMID- 20965613 TI - Elevated 4-hydroxyhexenal in Alzheimer's disease (AD) progression. AB - Multiple studies have demonstrated elevations of alpha, beta-unsaturated aldehydes including 4-hydroxynonenal (HNE) and acrolein, in vulnerable regions of mild cognitive impairment (MCI), preclinical Alzheimer's disease (PCAD), and late stage Alzheimer's disease (LAD) brain. However, there has been limited study of a third member, 4-hydroxyhexenal (HHE), a diffusible lipid peroxidation product of the omega-3 polyunstataturated fatty acids (PUFAs). In the present study levels of extractable and protein-bound HHE were quantified in the hippocampus/parahippocampal gyrus (HPG), superior and middle temporal gyri (SMTG), and cerebellum (CER) of MCI, PCAD, LAD, and normal control (NC) subjects. Levels of extractable and protein-bound HHE were increased in multiple regions in the progression of Alzheimer's disease (AD). Extractable HHE was significantly elevated in the hippocampus/parahippocampal gyrus (HPG) of PCAD and LAD subjects and protein-bound HHE was significantly higher in MCI, PCAD, and LAD HPG. A time- and concentration-dependent decrease in survival and a concentration-dependent decrease in glucose uptake were observed in primary cortical cultures treated with HHE. Together these data support a role for lipid peroxidation in the progression of Alzheimer's disease. PMID- 20965614 TI - [Gender-related achievements and challenges in the 2006 National Health Survey: analysis of adults and households]. AB - OBJECTIVES: To examine the ability of the 2006 Spanish Health Survey (SHS-2006) to analyze the population's health from a gender perspective and identify gender related inequalities in health, and to compare the 2006 version with that of 2003. METHOD: A contents analysis of the adults and households questionnaires was performed from the gender perspective, taking gender as (a) the basis of social norms and values, (b) the organizer of social structure: gender division of labor, double workload, vertical/horizontal segregation, and access to resources and power, and (c) a component of individual identity. RESULTS: The 2006 SHS uses neutral language. The referent is the interviewee, substituting the head of the family/breadwinner of past surveys. A new section focuses on reproductive labor (caregiving and domestic tasks) and the time distribution for these tasks. However, some limitations in the questions about time distribution were identified, hampering accurate estimations. The time devoted to paid labor is not recorded. The 2006 version includes new information about family commitments as an obstacle to accessing healthcare and on the delay between seeking and receiving healthcare appointments. CONCLUSIONS: The SHS 2006 introduces sufficient variations to confirm its improvement from a gender perspective. Future surveys should reformulate the questions about the time devoted to paid and reproductive labor, which is essential to characterize gender division of labor and double workload. Updating future versions of the SHS will also involve gathering information on maternity/paternity and parental leave. The 2006 survey allows delays in receiving healthcare to be measured, but does not completely allow other delays, such as diagnostic and treatment delays, to be quantified. PMID- 20965615 TI - [Modeling critical episodes of air pollution by PM10 in Santiago, Chile. Comparison of the predictive efficiency of parametric and non-parametric statistical models]. AB - OBJECTIVE: To evaluate the predictive efficiency of two statistical models (one parametric and the other non-parametric) to predict critical episodes of air pollution exceeding daily air quality standards in Santiago, Chile by using the next day PM10 maximum 24h value. Accurate prediction of such episodes would allow restrictive measures to be applied by health authorities to reduce their seriousness and protect the community's health. METHODS: We used the PM10 concentrations registered by a station of the Air Quality Monitoring Network (152 daily observations of 14 variables) and meteorological information gathered from 2001 to 2004. To construct predictive models, we fitted a parametric Gamma model using STATA v11 software and a non-parametric MARS model by using a demo version of Salford-Systems. RESULTS: Both models showed a high correlation between observed and predicted values. However, the Gamma model predicted PM10 values below 240 MUg/m3 more accurately than did MARS. The latter was more efficient in predicting PM10 values above 240 MUg/m3 throughout the study period. CONCLUSION: MARS models are more efficient in predicting extreme PM10 values and allow health authorities to adopt preventive methods to reduce the effects of these levels on the population's health. The reason for this greater accuracy may be that MARS models correct variations in the series over time, thus better fitting the curve associated with PM10 concentrations. PMID- 20965616 TI - [Changes in public health: the role of the state and the autonomous governments. SESPAS Report 2010]. AB - The first responsibilities in health passed on to the autonomous governments were those referring to public health. However, the decentralization process has not been accompanied by an updated management of the collective efforts to promote and protect health, or by a greater weight of public health within the system. To carry out such a reform, public health authorities and the central and autonomic administrations must assume their corresponding roles. The leading role should correspond to the central administration and includes the coordination and evaluation of the entire process, while the regional public health authorities should be in charge of providing public health services to the population, promoting innovations, and collaborating among themselves as well as with the central administration. Recent legal initiatives show some political sensitivity and may provide an opportunity, in addition to those provided by the economic crisis, to emphasize the role of guarantor rather than that of supplier for the state. Paradoxically, the marginality of public health could facilitate the necessary political agreements, even though party interests may be an obstacle. The influence of professional associations could be important. PMID- 20965617 TI - Novel insights for dihydroorotate dehydrogenase class 1A inhibitors discovery. AB - The enzyme dihydroorotate dehydrogenase (DHODH) has been suggested as a promising target for the design of trypanocidal agents. We report here the discovery of novel inhibitors of Trypanosoma cruzi DHODH identified by a combination of virtual screening and ITC methods. Monitoring of the enzymatic reaction in the presence of selected ligands together with structural information obtained from X ray crystallography analysis have allowed the identification and validation of a novel site of interaction (S2 site). This has provided important structural insights for the rational design of T. cruzi and Leishmania major DHODH inhibitors. The most potent compound (1) in the investigated series inhibits TcDHODH enzyme with Kiapp value of 19.28 MUM and possesses a ligand efficiency of 0.54 kcal mol(-1) per non-H atom. The compounds described in this work are promising hits for further development. PMID- 20965618 TI - Multivariate SAR/QSAR of 3-aryl-4-hydroxyquinolin-2(1H)-one derivatives as type I fatty acid synthase (FAS) inhibitors. AB - Two multivariate studies, a PCA-SAR and a PLS-QSAR, of 3-aryl-4-hydroxyquinolin 2(1H)-one derivatives described as type I fatty acid synthase (FAS) inhibitors, are presented in this work. The variable selection was performed with the Fisher's weight and Ordered Predictors Selection (OPS) algorithm, respectively. In the PCA, a separation between active and inactive compounds was obtained by six descriptors (topological and geometrical). The PLS model presented five descriptors and two Latent Variables. Leave-N-out cross validation and y randomization test showed that the model presented robustness and no chance correlation, respectively, and the descriptors indicated that the FAS inhibition depends on electronic distribution of the investigated compounds. The model obtained in this study may provide a guidance for proposition of new FAS inhibitors. PMID- 20965619 TI - Molecular properties prediction, synthesis and antimicrobial activity of some newer oxadiazole derivatives. AB - In present investigation a series of 28 oxadiazole analogues (AB1-AB28) were subjected to molecular properties prediction, drug-likeness by Molinspiration (Molinspiration, 2008) & MolSoft (MolSoft, 2007) softwares, lipophilicity and solubility parameters using ALOGPS 2.1 program. Out of 28 analogues only 16 were chosen on the basis of Lipinski "Rule of Five" (Ro5) for the synthesis and antimicrobial screening as oral bioavailable drugs/leads. Maximum drug-likeness model score (1.22) was found to be of compound AB13. Selected compounds (AB1 AB2), (AB5-AB9), (AB12-AB16), (AB18-AB21) were synthesized and characterized by IR, NMR and mass spectral analysis followed by antibacterial and antifungal screening. It was observed that compounds showed moderate to good antibacterial activity, but their antifungal activity was somewhat moderate. Compounds AB13 and AB20 showed pronounced activity against all bacterial and fungal strains. We had noticed that compounds (AB13, AB20) bearing OH group at one of the phenyl ring of oxadiazole exhibited good antimicrobial properties and their drug-likeness model score were also predicted maximum among the series. PMID- 20965620 TI - Structure-based approach to nanomolar, water soluble matrix metalloproteinases inhibitors (MMPIs). AB - N-arylsulfonyl-based MMPs inhibitors (MMPIs) are among the most prominent inhibitors possessing nanomolar affinity. However, their poor bioavailability remains critical for the drug development of this family of molecules. The structural analysis of the complex of NNGH (the most representative member of the family) with MMP-12 provided us with the basis to effectively design simple NNGH analogues with enhanced solubility in water. Following this approach, the sec butyl residue, not directly involved in the binding with MMP, has been replaced with hydrophilic residues thus yielding new potent inhibitors soluble in water. PMID- 20965621 TI - Supplementation of amino acids to prevent reperfusion injury after liver surgery and transplantation--where do we stand today? AB - BACKGROUND & AIMS: Functional liver failure remains one of the major complications after liver surgery. Ischemia/reperfusion injury (IRI) is strongly associated with increased morbidity and mortality after liver resection and transplantation. An ischemia induced activation of Kupffer cells with subsequent release of toxic mediators leads to disturbance of intrahepatic microcirculation, increased oxygen consumption of the liver and depletion of hepatic glycogen reserves. Aim of this review was to summarize the evidence for prevention of IRI by amino acid supplement and to give an overview on potential clinical use in liver surgery. METHODS: A systematic literature search (Medline, Embase, and The Cochrane Central Register of Controlled Trials) was performed to identify the relevant literature. RESULTS: Amino acid supplement has hepatoprotective effects and is non-toxic. Up to now heterogenic results have been reported from clinical trials. However, positive effects on microcirculation, leukoycte-endothelial interaction, Kupffer cells and pro-inflammatory mediator release have been described in trials investigating glycine supplementation. The data for N acetylcysteine remain heterogenic. CONCLUSION: An effective protection against IRI by amino acid supplementation has been demonstrated in experimental and several clinical studies. However, further clinical trials are warranted to identify the most promising approach for a routine clinical application. PMID- 20965622 TI - Radionuclide transfer to freshwater biota species: review of Russian language studies. AB - Around 130 publications reporting studies on radionuclide transfer to freshwater biota species conducted in the former USSR were reviewed to provide the concentration ratio values. None of these studies were available up to now in the English language reviews or publications. The values derived have been compared with the CR values used for freshwater systems in the International reviews. For some radionuclides reviewed in this paper, the data are in good agreement with the mean CR values presented earlier, however for some of them, in particular, for 241Am (bivalve molluscs, gastropods and pelagic fish), 60Co (gastropods, benthic fish and insect larvae), 90Sr and 137Cs (benthic fish and zooplankton), the mean values given here are substantially different from those presented earlier. The data reported in this paper for thirty five radionuclides and eleven groups of freshwater species markedly improve the extent of available data for evaluation of radiation impact on freshwater species. PMID- 20965623 TI - Non-surgical management of stage 3 biphosphonate-related oroantral fistula. AB - We describe the case of a patient with an oroantral fistula that healed successfully after conservative treatment. PMID- 20965624 TI - Surgical complications of segmental Le Fort I osteotomy. AB - Segmental maxillary osteotomy is a useful adjunct in orthognathic surgery for the correction of vertical and transverse maxillary deformities, but we know of few published reports that document complications. We evaluated the complication rates associated with segmental maxillary surgery in our unit by retrospective review of medical records, radiographs, and study models of 85 consecutive patients (mean age 23.3 years, range 14-51; male:female ratio 1:2) treated from 1995 to 2009. Types of deformity were anterior open bite (n=30, 35%), transverse maxillary deficiency (n=24, 28%), anterior open bite with transverse maxillary deficiency (n=28, 33%), and anterior vertical maxillary excess (n=3, 4%). There were 70 tripartite (82%), 13 bipartite (15%), and two quadripartite (2%) maxillas. Twenty-one patients (25%) had bone grafts. Fixation was done using titanium miniplates in 80 patients (94%), and titanium miniplates and resorbable plates in five (6%). The overall complication rate was 27%. Three patients (4%) had devitalisation of teeth, three (4%) developed minor periodontal defects, and one had tooth loss. Eight patients (9%) had plates removed, and two patients developed persistent postoperative palatal fistula. There was no segmental loss of bone or teeth. Our results show that complications in this cohort were relatively low, and that segmental maxillary surgery is safe as an adjunct in carefully selected cases. PMID- 20965625 TI - Niyith NiyithWatmam [corrected] (the quiet story): exploring the experiences of Aboriginal women who give birth in their remote community. AB - OBJECTIVE: to investigate the beliefs and practices of Aboriginal women who decline transfer to urban hospitals and remain in their remote community to give birth. DESIGN: an ethnographic approach was used which included: the collection of birth histories and narratives, observation and participation in the community for 24 months, field notes, training and employment of an Aboriginal co researcher, and consultation with and advice from a local reference group. SETTING: a remote Aboriginal community in the Northern Territory, Australia. PARTICIPANTS: narratives were collected from seven Aboriginal women and five family members. FINDINGS: findings showed that women, through their previous experiences of standard care, appeared to make conscious decisions and choices about managing their subsequent pregnancies and births. Women took into account their health, the baby's health, the care of their other children, and designated men with a helping role. KEY CONCLUSIONS: narratives described a breakdown of traditional birthing practices and high levels of non-compliance with health system-recommended care. IMPLICATION FOR PRACTICE: standard care provided for women relocating for birth must be improved, and the provision of a primary maternity service in this particular community may allow Aboriginal Women's Business roles and cultural obligations to be recognised and invigorated. International examples of primary birthing services in remote areas demonstrate that they can be safe alternatives to urban transfer for childbirth. A primary maternity service would provide a safer environment for the women who choose to avoid standard care. PMID- 20965626 TI - Changes in infraspinatus cross-sectional area and shoulder range of motion with repetitive eccentric external rotator contraction. AB - BACKGROUND: Repetitive eccentric loading results in muscle damage and subsequent changes in muscle stiffness and edema accumulation, which manifest as reduced joint range of motion and increased muscle cross-sectional area. The purpose of the study was to evaluate changes in shoulder range of motion and the infraspinatus cross-sectional area with repetitive eccentric contraction. METHODS: Twenty physically active participants performed 9 sets of 25 repetitions of eccentric external rotator contractions. The ultrasonographic measurement of the infraspinatus cross-sectional area, and shoulder internal/external rotation and horizontal adduction range of motion were measured before, immediately after, and 24h after the intervention. FINDINGS: Infraspinatus cross-sectional area significantly increased from baseline immediately after exercise (P<0.001), and remained elevated from baseline at the 24-hour follow up (P<0.001). Internal rotation and horizontal adduction range of motion did not change significantly between baseline and post-exercise (P>0.05), but were significantly decreased at the 24-hour follow up from the baseline (internal rotation: P<0.001, horizontal adduction: P<0.001) and the immediate post-exercise (internal rotation: P=1.012, horizontal adduction: P=0.016). INTERPRETATION: These changes observed after the eccentric contractions may have implications for injury development in pitchers, because 1) the infraspinatus endures repetitive eccentric loading with pitching and 2) decreased internal rotation and horizontal adduction range of motion have been linked to upper extremity injuries. However, since the muscle response after eccentric loading varies by the task and previous exposure to similar stress, future study needs to investigate the time course of recovery of the muscle cross sectional area and range of motion after pitching in competitive pitchers. PMID- 20965627 TI - Gait adaptation in chronic anterior cruciate ligament-deficient patients: Pivot shift avoidance gait. AB - BACKGROUND: A variety of biomechanical adaptations of the knee during gait have been reported in ACL-deficient patients to cope with anteroposterior knee instability. However, strategies to prevent rotatory knee instability are less recognized. We hypothesized that ACL-deficient patients would make distinctive gait changes to prevent anterolateral rotatory knee instability. Specifically, we hypothesized that during the terminal stance phase of the gait cycle, ACL deficient patients would reduce the internal rotation knee joint moment and exhibit a higher knee flexion angle. We call this altered gait a pivot-shift avoidance gait. We also hypothesized that patients would not be able to adapt their knee biomechanics as efficiently at a fast gait speed. METHODS: Twenty-nine patients with chronic ACL deficiency and 15 healthy volunteers took part in a treadmill gait analysis. The terminal stance phase was analyzed under both comfortable and fast gait speed conditions. FINDINGS: At both gait speeds, ACL deficient patients significantly reduced the internal rotation knee joint moment and showed larger knee flexion angles during the terminal stance phase of the gait cycle than did the control group. However, the difference in the minimum knee flexion angle between groups under the fast gait speed condition was not statistically significant. INTERPRETATION: ACL-deficient patients adopted the proposed pivot-shift avoidance gait, possibly to prevent anterolateral rotatory knee instability. The patients were not able to adapt their knee biomechanics as effectively during fast-paced walking. This study reinforces the pertinence of gait analysis in ACL-deficient knees to acquire more information about the function of the knee joint. PMID- 20965629 TI - Habitat-specific bioaccumulation of methylmercury in invertebrates of small mid latitude lakes in North America. AB - We examined habitat-specific bioaccumulation of methylmercury (MeHg) in aquatic food webs by comparing concentrations in pelagic zooplankton to those in littoral macroinvertebrates from 52 mid-latitude lakes in North America. Invertebrate MeHg concentrations were primarily correlated with water pH, and after controlling for this influence, pelagic zooplankton had significantly higher MeHg concentrations than littoral primary consumers but lower MeHg than littoral secondary consumers. Littoral primary consumers and pelagic zooplankton are two dominant prey for fish, and greater MeHg in zooplankton is likely sufficient to increase bioaccumulation in pelagic feeders. Intensive sampling of 8 lakes indicated that habitat-specific bioaccumulation in invertebrates (of similar trophic level) may result from spatial variation in aqueous MeHg concentration or from more efficient uptake of aqueous MeHg into the pelagic food web. Our findings demonstrate that littoral-pelagic differences in MeHg bioaccumulation are widespread in small mid-latitude lakes. PMID- 20965628 TI - Molecular pathogenesis and targeted therapies for NOTCH1-induced T-cell acute lymphoblastic leukemia. AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic tumor resulting from the malignant transformation of immature T-cell progenitors. Originally associated with a dismal prognosis, the outcome of T-ALL patients has improved remarkably over the last two decades as a result of the introduction of intensified chemotherapy protocols. However, these treatments are associated with significant acute and long-term toxicities, and the treatment of patients presenting with primary resistant disease or those relapsing after a transient response remains challenging. T-ALL is a genetically heterogeneous disease in which numerous chromosomal and genetic alterations cooperate to promote the aberrant proliferation and survival of leukemic lymphoblasts. However, the identification of activating mutations in the NOTCH1 gene in over 50% of T-ALL cases has come to define aberrant NOTCH signaling as a central player in this disease. Therefore, the NOTCH pathway represents an important potential therapeutic target. In this review, we will update our current understanding of the molecular basis of T-ALL, with a particular focus on the role of the NOTCH1 oncogene and the development of anti-NOTCH1 targeted therapies for the treatment of this disease. PMID- 20965630 TI - Influence of arbuscular mycorrhizal fungi on the growth and nutrient status of bermudagrass grown in alkaline bauxite processing residue. AB - A nursery experiment was conducted to evaluate the potential role of arbuscular mycorrhizal (AM) fungi in encouraging the vegetation cover on bauxite residue (red mud) sites. An alkali tolerant bermudagrass (Cynodon dactylon) adapted to local conditions were grown in red mud with different amendments with and without AM fungi to assess mycorrhizal effects on plant growth, mineral nutrition, metal uptake and neutralization of bauxite residue. Inoculation of AM fungi significantly increased the plant growth, nutrient uptake and reduced Fe, Al accumulation in plant tissue and also improved the soil physico-chemical and biochemical properties. Gypsum and sludge amended treatments inoculated with AM fungi had maximum biomass, nutrient uptake and reduced accumulation of metals. The neutralization of red mud was significant in presence of AM fungi than control. The experiment provided evidence for the potential use of bermudagrass in combination with AM fungi for ecological restoration of bauxite residue sites. PMID- 20965631 TI - Assessing the nature of the combined effects of copper and zinc on estuarine infaunal communities. AB - Elevated levels of copper and zinc in sediment have been shown to adversely affect estuarine infauna. We investigated the additivity of the combined effects of copper and zinc on infaunal recolonisation through a manipulative field experiment in Orewa estuary, New Zealand, using defaunated sediment discs treated with these metals. The nature of their combined effects varied among infaunal taxa and the particular variables being examined. Additive effects were detected for species richness, for the mean log abundances of the polychaetes Prionospio sp. and Scoloplos cylindrifer and for the multivariate response of the community as a whole. Antagonistic effects were detected for the mean log abundances of total infauna and the polychaete Heteromastus sp. Characterising the potentially interactive nature of the combined effects of multiple heavy metals is essential in order to build predictive models of future environmental impacts of metal accumulation in estuarine sediments. PMID- 20965632 TI - Accumulation and maternal transfer of polychlorinated biphenyls in Steller Sea Lions (Eumetopias jubatus) from Prince William Sound and the Bering Sea, Alaska. AB - The western stock of the Steller sea lion (Eumetopias jubatus) in the northern Pacific Ocean has declined by approximately 80% over the past 30 years. This led to the listing of this sea lion population as an endangered species in 1997. Chemical pollution is [corrected] one of several contributing causes. In the present study, 145 individual PCBs were determined in tissues of male sea lions from Tatitlek (Prince William Sound) and St. Paul Island (Bering Sea), and placentae from the Aleutian Islands. PCBs 90/101, 118, and 153 were abundant in all the samples. The mean toxic equivalents (TEQ) were 2.6, 4.7 and 7.4 pg/g lw in the kidney, liver, and blubber samples, respectively. The mean TEQ in placentae was 8 pg/g lw. Total PCBs concentrations (2.6-7.9 MUg/g lw) in livers of some males were within a range known to cause physiological effects, further [corrected] suggesting the possibility of adverse effects on this stock. PMID- 20965633 TI - Urban-rural differences in dental caries of 5-year old children in Scotland. AB - Previous research suggests there are significant differences between urban and rural areas in Scotland for health outcomes including heart disease, cancer and self reported health. The aim of this study was to describe the contemporary urban/rural variation in obvious decay experience amongst 5-year-olds in Scotland. Scotland was split into 6 geographies, ranging from 'The 4 Cities' (Glasgow, Edinburgh, Dundee and Aberdeen) to 'Remote Rural' areas. Data derived from the 2007/08 National Dental Inspection Programme, representative of the whole of Scotland, were modelled using Bayesian multilevel zero-inflated Negative Binomial and multilevel Poisson modelling, adjusting for age, sex and deprivation. The outcome variables modelled were d(3)mft (carious, extracted or filled deciduous teeth), d(3)t (carious teeth), mt (missing teeth, extracted due to caries) and ft (filled teeth). The proportion of 5-year old children in Scotland with d(3)mft = 0 was 58% in 2008. Adjusting for age and sex, the odds of a child in a Remote Rural area having d(3)mft>0 was 0.52 that of a city dweller. However, when deprivation was included in the model, the odds of having d(3)mft >0 rose to 0.74. The odds of d(3)mft>0 in 'Accessible Rural' areas also remained significantly lower than in the 4 Cities after adjustment for deprivation. For those with d(3)mft>0, the relative risk of additional d(3)mft was also significantly lower in Remote Rural areas, however this was explained by deprivation, while in Accessible Rural areas this remained significant even after adjustment for deprivation. The odds of having any extractions was lower in Rural areas, even after adjustment for deprivation, while the Care Index (ft/d(3)mft) was higher in Remote Towns. Deprivation, therefore, accounted for much but not all of the geographical difference in d(3)mft which exist in Scotland. Children in Remote and Rural areas appear to have better dental health and a higher proportion of filled teeth when compared with those living in Cities. Possible reasons for these differences and recommendations for future research are discussed. PMID- 20965634 TI - Initial study on facilitating wound healing after tooth extraction by using microbial fiber membrane-flagyl. AB - PURPOSE: The aim of the present study was to investigate the efficacy of microbial fiber membrane-Flagyl (MF-FLA) on facilitating hemostasis and wound healing and its anti-inflammatory ability after tooth extraction. MATERIALS AND METHODS: For the animal experiment, 60 healthy male rabbits were randomly divided into control and treatment groups. Each group included 5 subgroups corresponding to different experimental periods (1, 2, 4, 8, and 12 weeks) and each subgroup had 6 rabbits. After the different experimental periods, the rabbits were killed, and the mandible was removed for histologic examination and analysis. For the human trial, 80 patients (32 males and 48 females; age range, 13 to 32 years), who were undergoing orthodontic treatment and who had undergone bilateral extraction of teeth were included. For every patient, the left tooth socket was treated with biting gauze for 30 to 60 minutes as the control group. The right fossa was covered with MF-FLA as the treatment group. The wound was inspected visually, its depth was measured, and radiographs were taken at the different experimental periods (1, 2, 4, 8, and 12 weeks) to evaluate the wound healing effect. RESULTS: In the animal experiment, the results of the histologic examination indicated MF-FLA could facilitate the growth of fibroblasts and osteoblasts and inhibit inflammatory cells. In the human trial, the clinical observation indicated that the MF-FLA treatment showed better hemostatic ability than the biting gauze. After 4 weeks, the wound depth of the control and treatment groups was 3.08 +/- 0.05 mm and 1.26 +/- 1.06 mm (P < .01), respectively. The radiographs showed that the treatment group was superior to control group in the degree and rate of wound healing. CONCLUSION: The results of our study have shown that the MF-FLA can promote early wound healing and reduce the incidence of postextraction complications because of its biocompatibility, isolating and anti-inflammatory ability, and supporting the formation of blood clot in the tooth socket. PMID- 20965635 TI - Distinct neural correlates for two types of inhibition in bilinguals: response inhibition versus interference suppression. AB - To examine the effects of bilingualism on cognitive control, we studied monolingual and bilingual young adults performing a flanker task with functional MRI. The trial types of primary interest for this report were incongruent and no go trials, representing interference suppression and response inhibition, respectively. Response times were similar between groups. Brain data were analyzed using partial least squares (PLS) to identify brain regions where activity covaried across conditions. Monolinguals and bilinguals activated different sets of brain regions for congruent and incongruent trials, but showed activation in the same regions for no-go trials. During the incongruent trials, monolinguals activated the left temporal pole and left superior parietal regions. In contrast, an extensive network including bilateral frontal, temporal and subcortical regions was active in bilinguals during the incongruent trials and in both groups for the no-go trials. Correlations between brain activity and reaction time difference relative to neutral trials revealed that monolinguals and bilinguals showed increased activation in different brain regions to achieve less interference from incongruent flankers. Results indicate that bilingualism selectively affects neural correlates for suppressing interference, but not response inhibition. Moreover, the neural correlates associated with more efficient suppression of interference were different in bilinguals than in monolinguals, suggesting a bilingual-specific network for cognitive control. PMID- 20965636 TI - [Facial rejuvenation using L-polylactic acid: about 298 successive cases]. AB - AIM OF THE STUDY: Patients seeking care of facial ageing demand an aesthetic result that appears natural and is very safe, with techniques the less invasive possible. Our series of cases helps analyse the efficiency and safety of L polylactic acid in the management of facial ageing. PATIENTS AND METHOD: Retrospective analysis of a single series of patients treated with L-polylactic acid (SculptraTM) between September 2000 and September 2007. All patients over 18 years, consulting for facial ageing and/or loss of volume and treated with L polylactic acid injections, were included in our evaluation. Patients with facial lipoatrophy related to HIV were excluded from this evaluation. RESULTS: The series consist of 298 patients who received a total of 582 injections of L polylactic acid. The reason for consultation was basically facial ageing (85.9%) and loss of facial volume (12.1%). Ninety-one percent patients were satisfied with the correcting effect. Fourteen patients (4.7%) showed a late adverse event: palpable but non-visible subcutaneous indurations (11 patients, 3.7%) and deep, little visible, multiple granuloma-like nodules that required treatment (three patients, 1%). CONCLUSION: L-polylactic acid is a filler that facilitates natural correction of ageing with minimum adverse event. Its mechanism of action gives it a special place among other injectable materials. The surgeon who conducts adipocyte grafting will appreciate its ease of use and remodelling volumising effect. PMID- 20965637 TI - [A five years experience of subcutaneous chemical lipolysis with phosphatidylcholine injections]. AB - Instead the fact that chemical lipolysis through phosphatidylcholin injections really works, this procedure eliminating limited fat deposits remains confidential in France. Inconstant results, necessity to repeat injections, unclear legacy may explain that this very basic procedure remains unsuccessful. We have proceeded to lipolysis injections for five years on a very limited number of patients: in our hands, it may be efficient on puffy cheeks, double chin, superficial cellulitis, liposuction and lipofilling sequellaes. Eyelid bags may also be considered but not recommended. On the other hand, chemical lipolysis cannot compete with liposuction. We have not noticed any drawbacks or complications which confirm the lipolysis network practitioners' opinion in more than 1000 users. PMID- 20965638 TI - [Peer review journals in the digital age]. PMID- 20965639 TI - Efficacy of the neonatal resuscitation program (NRP) course on knowledge retained by residents: comparison among pediatrics, anesthesia and gynecology. PMID- 20965640 TI - Knowledge of adrenaline (epinephrine) administration in anaphylaxis in adults is still deficient. Has there been any improvement? PMID- 20965641 TI - Does postoperative radiotherapy provide any survival advantage over observation in stage IC endometrial cancer after comprehensive surgical staging? AB - OBJECTIVE: To compare postoperative radiotherapy and observation for survival and recurrence rates in stage IC endometrial carcinoma patients who underwent comprehensive surgical staging. STUDY DESIGN: Fifty-seven stage IC endometrial cancer patients who underwent surgical staging were included in this study. Twenty cases (35%) received postoperative radiotherapy and 37 (65%) were observed without additional therapy. The two groups were compared for survival and recurrence rates. RESULTS: Mean follow-up times for the radiotherapy and observation groups were 52.05 and 38.71 months, respectively. Five-year disease free survival rates for the radiotherapy and observation groups were 91% and 63%, respectively, and 5-year overall survival rates for the radiotherapy and observation groups were 90.0% and 80.8%, respectively. Both the disease-free and overall survival rates were similar between the two groups (p > 0.05). One (5%) of the 20 patients in the radiotherapy group, and four (10.8%) of the 37 patients in the observation group had recurrences and there was no statistical difference for the recurrence rates (p > 0.05). Disease grade had no prognostic significance in terms of survival after surgical staging. CONCLUSIONS: Comprehensive surgical staging might minimize the unfavorable role of deep myometrial invasion and grade. After surgical staging, postoperative observation without radiotherapy may be an appropriate approach in stage IC, all grades, endometrial carcinoma. PMID- 20965642 TI - Confronting socially generated uncertainty in adaptive management. AB - As more and more organizations with responsibility for natural resource management adopt adaptive management as the rubric in which they wish to operate, it becomes increasingly important to consider the sources of uncertainty inherent in their endeavors. Without recognizing that uncertainty originates both in the natural world and in human undertakings, efforts to manage adaptively at the least will prove frustrating and at the worst will prove damaging to the very natural resources that are the management targets. There will be more surprises and those surprises potentially may prove at the very least unwanted and at the worst devastating. We illustrate how acknowledging uncertainty associated with the natural world is necessary but not sufficient to avoid surprise using case studies of efforts to manage three wildlife species; Hector's Dolphins, American Alligators and Pallid Sturgeon. Three characteristics of indeterminism are salient to all of them; non-stationarity, irreducibility and an inability to define objective probabilities. As an antidote, we recommend employing a holistic treatment of indeterminism, that includes recognizing that uncertainty originates in ecological systems and in how people perceive, interact and decide about the natural world of which they are integral players. PMID- 20965643 TI - Urban ecological systems: scientific foundations and a decade of progress. AB - Urban ecological studies, including focus on cities, suburbs, and exurbs, while having deep roots in the early to mid 20th century, have burgeoned in the last several decades. We use the state factor approach to highlight the role of important aspects of climate, substrate, organisms, relief, and time in differentiating urban from non-urban areas, and for determining heterogeneity within spatially extensive metropolitan areas. In addition to reviewing key findings relevant to each state factor, we note the emergence of tentative "urban syndromes" concerning soils, streams, wildlife and plants, and homogenization of certain ecosystem functions, such as soil organic carbon dynamics. We note the utility of the ecosystem approach, the human ecosystem framework, and watersheds as integrative tools to tie information about multiple state factors together. The organismal component of urban complexes includes the social organization of the human population, and we review key modes by which human populations within urban areas are differentiated, and how such differentiation affects environmentally relevant actions. Emerging syntheses in land change science and ecological urban design are also summarized. The multifaceted frameworks and the growing urban knowledge base do however identify some pressing research needs. PMID- 20965644 TI - Luring anglers to enhance fisheries. AB - Current fisheries management is, unfortunately, reactive rather than proactive to changes in fishery characteristics. Furthermore, anglers do not act independently on waterbodies, and thus, fisheries are complex socio-ecological systems. Proactive management of these complex systems necessitates an approach--adaptive fisheries management--that allows learning to occur simultaneously with management. A promising area for implementation of adaptive fisheries management is the study of luring anglers to or from specific waterbodies to meet management goals. Purposeful manipulation of anglers, and its associated field of study, is nonexistent in past management. Evaluation of different management practices (i.e., hypotheses) through an iterative adaptive management process should include both a biological and sociological survey to address changes in fish populations and changes in angler satisfaction related to changes in management. We believe adaptive management is ideal for development and assessment of management strategies targeted at angler participation. Moreover these concepts and understandings should be applicable to other natural resource users such as hunters and hikers. PMID- 20965645 TI - Detection and quantification of rotator cuff tears with ultrasonography and magnetic resonance imaging - a prospective study in 77 consecutive patients with a surgical reference. AB - The aim of this study was to compare the accuracy of ultrasonography (US) and magnetic resonance artrography (MRA) for the detection and measurement of rotator cuff tears, using surgical findings as a standard. A total of 77 consecutive patients with suspected rotator cuff tears were prospectively studied with US and MRA. Rotator cuff tears were identified by US with sensitivity, specificity, positive predictive and negative predictive values of 92%, 45%, 91% and 50%, respectively, and by MRA with values of 97%, 82%, 97% and 82%, respectively. US was not reliable for differentiating between partial and full thickness tears. US and MRA underestimated the tear sizes by an average of 15 mm and 4 mm, respectively. Our results suggest that US could be used as a screening test to confirm a suspected rotator cuff tear. In patients with negative findings, an MRA should be considered for substantiation. PMID- 20965646 TI - A competing-risks analysis of survival after alternative treatment modalities for prostate cancer patients: 1988-2006. AB - BACKGROUND: The efficacy of prostate cancer (PCa) treatment modalities is a subject of continuous debate. OBJECTIVE: We tested the hypothesis that significant differences in survival rates may exist among PCa patients treated with radical prostatectomy (RP), radiation therapy (RT), and observation. DESIGN, SETTING, AND PARTICIPANTS: We focused on 404,604 patients with clinically localized PCa within 17 Surveillance, Epidemiology and End Results registries. MEASUREMENTS: Competing-risks survival analyses were used to estimate cancer specific mortality (CSM) and other-cause mortality (OCM) rates. Patients were stratified according to treatment type, age group, and PCa risk group (high risk: T2c and/or Gleason score 8-10; low to intermediate risk: all others). RESULTS AND LIMITATIONS: The 10-yr CSM and OCM rates were 6.1% and 29.2%, respectively. In RP, RT, and observation patients, CSM rates were 3.6%, 6.5%, and 10.8% (p<0.001), respectively; OCM rates were 17.1%, 32.4%, and 48.9% (p<0.001), respectively. In low- to intermediate-risk patients, the lowest CSM (1.3-3.7%) and OCM (6.9-31.6%) rates within all age categories except octogenarians (8.9% and 62.8%, respectively) were recorded in RP. In high-risk patients, the lowest CSM (5.8 7.2%) and OCM (8.7-16.1%) rates in patients aged <=69 yr were also recorded in RP. RT was equally favorable to RP in the 70-79 age category and appeared ideal in all octogenarian patients. CONCLUSIONS: Our results showed that RP provides the most favorable survival rates in most patients. The exception is octogenarian men, in whom RT provides the best results. Finally, the least-favorable outcomes were recorded after observation. However, these findings must be interpreted within the context of the limitations of observational data. PMID- 20965647 TI - Single-portal access laparoscopic radical nephrectomy for renal cell carcinoma in transplant patients: the first experience. AB - We present the details of the first three single-portal access laparoscopic radical nephrectomies (S-Portal-RN) performed in patients with a malignant renal tumour that developed after a renal transplant. The mean operative time was 171.6 +/- 37.5 min, with a mean blood loss of 126.6 +/- 25.1 ml. A single small skin incision (5 cm) was performed to remove the kidney. No significant difference in glomerular filtration rate was observed postoperatively. The postoperative recovery was uneventful with favourable short-term outcomes and high patient satisfaction at the 2-mo follow-up. We believe that S-Portal-RN for renal cancer after a renal transplant can be performed without increased risks for the patients or for the transplanted kidney. PMID- 20965648 TI - Analysis of risk factors influencing the development of severe dizziness in patients with vestibular schwannomas in the immediate postoperative phase. AB - OBJECTIVE: Dizziness, a common postoperative symptom in patients with vestibular schwannomas (VSs) has a negative effect on the course of recovery, particularly in patients with severe symptoms. Reports on incidence and possible risk factors contributing to these symptoms are inconsistent and sometimes even contradictory. In order to establish a profile of patients at risk of severe symptoms in the immediate postoperative phase we retrospectively analyzed data of patients with unilateral VSs focusing on the incidence of severe dizziness and nausea during the immediate postoperative period and up to 1 year after surgery. METHODS: In a retrospective study data of 104 consecutive patients with VSs were analyzed. All patients underwent microsurgical tumor resection via a lateral-suboccipital approach. Factors that were assumed to affect the development of severe dizziness, such as age, gender, tumor size, tumor side, and cranial nerve function, were analyzed by means of univariate and multivariate logistic regression analyses. A three step grading system was used to describe symptoms of patients included in this study: 0=no symptoms of dizziness, 1=slight dizziness including light-headedness or feeling of disequilibrium and 2=severe dizziness with nausea including imbalance or insecurity when walking, requiring antiemetic treatment. RESULTS: Data of 92 patients, 41 men and 51 women, were available for analyses. Mean age of treated patients was 53 years (range 17-81). There was no predilection of side (52.2% right/47.8% left). Before surgery 39 patients (42.4%) were symptom free (grade 0), 13 patients (14.1%) had slight symptoms (grade 1) and 40 patients (43.5%) suffered from severe symptoms (grade 2). Immediately after surgery two patients (2.2%) where symptom free (grade 0), 19 patients (20.7%) had slight symptoms (grade 1) and 71 patients (77.2%) suffered from severe symptoms (grade 2). All patients with grade 2 symptoms required antiemetic treatment ranging between 1 and 10 days (mean 4 days). Logistic regression analyses showed young age, large tumor size (T3/T4), female gender, and severe preoperative symptoms to be main factors increasing the odds for patients to develop severe symptoms postoperatively. CONCLUSION: Patients at risk to develop severe symptoms should receive antiemetic treatment even before surgery. If in doubt about the actual risk for a specific patient with a large tumor (T3 or T4) available data suggests that patients will benefit if antiemetic treatment is started early, even before surgery. PMID- 20965649 TI - Valsalva-maneuver induced recurrent transient bilateral visual loss. PMID- 20965650 TI - Diaphragmatic weakness caused by neuroborreliosis. PMID- 20965652 TI - Biosorption of heavy metals from aqueous solutions by chemically modified orange peel. AB - Equilibrium, thermodynamic and kinetic studies were carried out for the biosorption of Pb(2+), Cd(2+) and Ni(2+) ions from aqueous solution using the grafted copolymerization-modified orange peel (OPAA). Langmuir and Freundlich isotherm models were applied to describe the biosorption of the metal ions onto OPAA. The influences of pH and contact time of solution on the biosorption were studied. Langmuir model fitted the equilibrium data better than the Freundlich isotherm. According to the Langmuir equation, the maximum uptake capacities for Pb(2+), Cd(2+) and Ni(2+) ions were 476.1, 293.3 and 162.6 mg g(-1), respectively. Compared with the unmodified orange peel, the biosorption capacity of the modified biomass increased 4.2-, 4.6- and 16.5-fold for Pb(2+), Cd(2+) and Ni(2+), respectively. The kinetics for Pb(2+), Cd(2+) and Ni(2+) ions biosorption followed the pseudo-second-order kinetics. The free energy changes (DeltaG degrees ) for Pb(2+), Cd(2+) and Ni(2+) ions biosorption process were found to be -3.77, -4.99 and -4.22 kJ mol(-1), respectively, which indicates the spontaneous nature of biosorption process. FTIR demonstrated that carboxyl and hydroxyl groups were involved in the biosorption of the metal ions. Desorption of Pb(2+), Cd(2+) and Ni(2+) ions from the biosorbent was effectively achieved in a 0.05 mol L(-1) HCl solution. PMID- 20965651 TI - MicroRNAs, cancer and cancer stem cells. AB - MicroRNAs regulate self-renewal, differentiation, and division of cells via post transcriptional gene silencing. Aberrant microRNA levels, specifically an overall downregulation, are present in many cancers, as compared to their normal tissue counterparts. Therefore, a potential therapeutic use of microRNAs is to correct these aberrant transcript levels involved in the signaling pathways of cancer. This review focuses on the current knowledge of microRNAs and their involvement with cancer cells and cancer stem cells. The methods currently being used to develop miRNA-based cancer therapeutics are examined, and the limitations halting further progress are also discussed. PMID- 20965653 TI - Influence of nitromethane concentration on ignition energy and explosion parameters in gaseous nitromethane/air mixtures. AB - The aim of this paper is to provide new experimental data of the minimum ignition energy (MIE) of gaseous nitromethane/air mixtures to discuss the explosion pressure and the flame temperature as a function of nitromethane concentration. Observations on the influence of nitromethane concentration on combustion pressure and temperature through the pressure and temperature measure system show that peak temperature (the peak of combustion temperature wave) is always behind peak pressure (the peak of the combustion pressure wave) in arrival time, the peak combustion pressure of nitromethane increases in the range of its volume fraction 10-40% as the concentration of nitromethane increases, and it slightly decreases in the range of 40-50%. The maximum peak pressure is equal to 0.94 MPa and the minimum peak pressure 0.58 MPa. Somewhat similar to the peak pressure, the peak combustion temperature increases with the volume fraction of nitromethane in the range of 10-40%, and slightly decreases in 40-50%. The maximum peak temperature is 1340 degrees C and the minimum 860 degrees C. The combustion temperature rise rate increases with the concentration of nitromethane in 10-30%, while decreases in 30-50% and its maximum value of combustion temperature rise rate in 10-50% is 4200 degrees C/s at the volume fraction of 30%. Influence of the concentration of nitromethane on the combustion pressure rise rate is relatively complicated, and the maximum value of rise rate of combustion pressure wave in 10-50% is 11 MPa/s at the concentration 20%. PMID- 20965654 TI - Simultaneous nitrification-denitrification and phosphorus removal in a fixed bed sequencing batch reactor (FBSBR). AB - Biological nutrient removal (BNR) was investigated in a fixed bed sequencing batch reactor (FBSBR) in which instead of activated sludge polypropylene carriers were used. The FBSBR performance on carbon and nitrogen removal at different loading rates was significant. COD, TN, and phosphorus removal efficiencies were at range of 90-96%, 60-88%, and 76-90% respectively while these values at SBR reactor were 85-95%, 38-60%, and 20-79% respectively. These results show that the simultaneous nitrification-denitrification (SND) is significantly higher than conventional SBR reactor. The higher total phosphorus (TP) removal in FBSBR correlates with oxygen gradient in biofilm layer. The influence of fixed media on biomass production yield was assessed by monitoring the MLSS concentrations versus COD removal for both reactors and results revealed that the sludge production yield (Y(obs)) is significantly less in FBSBR reactors compared with SBR reactor. The FBSBR was more efficient in SND and phosphorus removal. Moreover, it produced less excess sludge but higher in nutrient content and stabilization ratio (less VSS/TSS ratio). PMID- 20965655 TI - Pin-evoked tachycardia: a new measure of neuropathic pain. PMID- 20965656 TI - Baroreceptor activation attenuates attentional effects on pain-evoked potentials. AB - Focused attention typically enhances neural nociceptive responses, reflected electroencephalographically as increased amplitude of pain-evoked event-related potentials (ERPs). Additionally, pain-evoked ERPs are attenuated by hypertension and baroreceptor activity, through as yet unclear mechanisms. There is indirect evidence that these two effects may interact, suggesting that baroreceptor related modulation of nociception is more than a low-level gating phenomenon. To address this hypothesis, we explored in a group of healthy participants the combined effects of cue-induced expectancy and baroreceptor activity on the amplitude of pain-evoked ERPs. Brief nociceptive skin stimuli were delivered during a simple visual task; half were preceded by a visual forewarning cue, and half were unpredictable. Nociceptive stimuli were timed to coincide either with systole (maximum activation of cardiac baroreceptors) or with diastole (minimum baroreceptor activation). We observed a strong interaction between expectancy and cardiac timing for the amplitude of the P2 ERP component; no effects were observed for the N2 component. Cued stimuli were associated with larger P2 amplitude, but this effect was abolished for stimuli presented during baroreceptor activation. No cardiac timing effect was observed for un-cued stimuli. Taken together, these findings suggest a close integration of cognitive affective aspects of expectancy and baroreceptor influences on pain, and as such may cast further light on mechanisms underlying mental and physiological contributions to clinical pain. PMID- 20965657 TI - Development of a severity score for CRPS. AB - The clinical diagnosis of Complex Regional Pain Syndrome (CRPS) is a dichotomous (yes/no) categorization necessary for clinical decision-making. However, such dichotomous diagnostic categories do not convey an individual's subtle and temporal gradations in severity of the condition, and have poor statistical power when used as an outcome measure in research. This study evaluated the validity and potential utility of a continuous type score to index severity of CRPS. Psychometric and medical evaluations were conducted in 114 CRPS patients and 41 non-CRPS neuropathic pain patients. Based on the presence/absence of 17 clinically-assessed signs and symptoms of CRPS, an overall CRPS Severity Score (CSS) was derived. The CSS discriminated well between CRPS and non-CRPS patients (p<.001), and displayed strong associations with dichotomous CRPS diagnoses using both IASP diagnostic criteria (Eta=0.69) and proposed revised criteria (Eta=0.77 0.88). Higher CSS was associated with significantly higher clinical pain intensity, distress, and functional impairments, as well as greater bilateral temperature asymmetry and thermal perception abnormalities (p's<.05). In an archival prospective dataset, increases in anxiety and depression from pre surgical baseline to 4 weeks post-knee arthroplasty were found to predict significantly higher CSS at 6- and 12-month follow-up (p's<.05). Results indicate the CSS corresponds with and complements currently accepted dichotomous diagnostic criteria for CRPS, and support its validity as an index of CRPS severity. Its utility as an outcome measure in research studies is also suggested, with potential statistical advantages over dichotomous diagnostic criteria. PMID- 20965658 TI - Reference data for quantitative sensory testing (QST): refined stratification for age and a novel method for statistical comparison of group data. AB - Clinical use of quantitative sensory testing (QST) requires standardization. The German research network on neuropathic pain (DFNS) solves this problem by defining reference data stratified for test site, gender and age for a standardized QST protocol. In this report we have targeted two further problems: how to adjust for age-related sensory changes, and how to compare groups of patients with the reference database. We applied a moving average across ages to define reference values per decade. This analysis revealed that women were more sensitive to heat pain independent of age. In contrast, functions were converging at older age for blunt pressure pain, but diverging for punctate mechanical pain (pin prick). The probability that an individual patient dataset is within the range of normal variability is calculated by z-transform using site-, gender- and age-specific reference data. To compare groups of patients with reference data, we evaluated two techniques: A: paired t-test versus fixed mean; i.e. the reference mean value is considered as the known population mean, B: non-paired t test versus the reference dataset and number of cases restrained to the same number of cases as the patient data set. Simulations for various sample sizes and variances showed that method B was more conservative than method A. We present a simple way of calculating method B for data that have been z-normalized. This technique makes the DFNS reference data bank applicable for researchers beyond the DFNS community without a need for subsampling of subjects from the database. PMID- 20965659 TI - Failure to observe cross-fertilization between the Echinococcus granulosus G1 and G6 strains after an experimental mixed infection of the definitive host. AB - The classification within Echinococcus granulosus is currently under debate. To assess the reproductive potential between the G1 and G6 strains, an experimental double infection was carried out in a dog. First, two fertile hydatid cysts were collected in Algeria from a cow and a dromedary. They were identified as being G1 and G6 with the markers coxI and nadI. Subsequently, a dog was inoculated with protoscoleces from these two cysts. Sixty days after infection, 85 adult worms were recovered from the intestine of the dog. Then, the two cysts and each of these individual parasites were characterized with the multilocus microsatellite EmsB and compared. For all worms, the scolex and the gravid proglottids, separately analyzed, provided an identical profile: the G1 profile was observed in 70 adults, and the G6 profile in the 15 others. No single worm exhibited a hybrid G1/G6 profile. This result suggests the absence of cross-fertilizing between the two taxa under the given experimental conditions, and so, the presence of a strong cross-reproductive barrier. This observation corroborates with the recent reclassification of G1 and G6 within two distinct species. PMID- 20965660 TI - Toxoplasma gondii in feral American minks at the Maullin river, Chile. AB - American mink (Neovison vison) is a widely distributed invasive species in southern Chile. Thirty four feral minks were trapped at two distinct sites (rural and peri-urban), diet analyzed and Toxoplasma gondii exposure compared using PCR and specific antibodies. Serum samples were evaluated using a commercial latex agglutination test where a titer >= 1:32 was considered positive. Of 30 mink analyzed, 21 (70%) were positive to T. gondii antibodies, with titers ranging from 1:32 to 1:2048. As expected, adult mink showed higher seroprevalence of exposure to T. gondii (18/21) than young mink (3/9) (P=0.008). There was not statistically significant difference between sex groups (P=0.687). Differences in seroprevalence were observed between the two sample sites with a higher proportion of positive individuals in the peri-urban area, and therefore, closer to human settlements (35.7% vs. 100%, P=0.0001). Individuals positive to T. gondii using PCR and/or serology showed similar differences by site with higher infected individuals in peri-urban areas (58.8% vs. 100%, P=0.007). Diet of American mink based in fecal composition analyses was mainly based on crustaceans (frequency of occurrence: crustaceans=100%, birds and rodents<7%), suggesting that the high observed prevalence of T. gondii infection might be more associated with its aquatic behavior (e.g. ingestion of oocysts in contaminated fresh water) than with their trophic behavior (e.g. preying over species that can have T. gondii cysts in their tissues). As an invasive species potentially subject to routine culling to maintain population sizes under control, minks could be used as a sentinel species to monitor pathogens of public and wildlife health importance, such as T. gondii, in aquatic environments. PMID- 20965661 TI - Theileria sergenti. PMID- 20965662 TI - Histoacryl glue: a burning issue. PMID- 20965663 TI - Exhaust burns in children. AB - BACKGROUND: Contact thermal injuries appear the second most frequent cause for burns in children seen at our unit. Burns caused by hot exhaust systems represent an important subgroup, as these injuries carry the potential for considerable morbidity. METHODS: A retrospective review of the Burns Unit database was conducted from January 2003 to January 2008. All patients referred to our unit with burns caused by contact with an exhaust system were included. The morbidity associated with each injury was determined by recording the need for surgical intervention, days taken to heal and the number of hospital visits required. RESULTS: A total of 97 patients were identified, of which 71 were male (M:F; 2.7:1). Age ranged from 5 months to 15 years. The mechanisms involved were contacts with the exhaust systems of motorbikes, including mini-bikes and Pee-Wee bikes (77), cars (14), lawnmowers (5) and quad-bikes (1). The injuries most commonly occurred during the summer holiday months (n=36, 37%). The Total Body Surface Area (TBSA) ranged from 0.5% to 8%, although injuries measuring 1% or less accounted for 60% of the total. More than two-thirds of the injuries were located on the lower extremity, with the calf being the most common site. Surgical intervention was required in 33% of the cases. The average time taken for complete healing was 20 days with an average of 3.5 visits made for each injury. CONCLUSIONS: The rate of surgical intervention and days to healing clearly demonstrate the morbidity associated with these injuries. In addition the time, effort and money spent for their management appear considerable. A concerted effort must be made to raise public awareness regarding these injuries with a focus on educating people on the hazards of the equipment and the use of appropriate protective gear. PMID- 20965664 TI - Rhabdomyolysis and acute renal failure in severely burned patients. AB - Rhabdomyolysis (RML) is a precarious complication in severely burned patients and the principal treatment goal is prevention of acute renal failure (ARF). This 10 year retrospective study analyses the causes for RML in severely burned patients and evaluates treatment algorithms. Eight of 714 patients (1%) were diagnosed with RML. Percentage TBSA burn was 25 +/- 13%. The mean abbreviated burn severity index score (ABSI) was 9 +/- 2. ARF was found in 75% (6/8) of the patients. Serum myoglobin (MB) was reduced by 41 +/- 16% after 24-h treatment by solitary volume repletion (VR) and by 44 +/- 20% through VR+continuous veno-venous hemodiafiltration (CVVHDF). Mortality was 50% (4/8). Peak mean CPK-levels were more than two and MB-levels more than four times higher in non-survivors than in survivors. Burns associated with RML result in poor survival. VR and CVVHDF are effective measures in treating RML. CVVHDF is effective in removing MB when using high flux filter membranes. Early CVVHDF (within 24h of diagnosis) with high-cut off membranes could reduce the risk of ARF and mortality. PMID- 20965665 TI - Differences in the smoking identities of adolescent boys and girls. AB - OBJECTIVE: To assess sex-disaggregated differences in youths' characterizations of their own smoking behavior. METHOD: Cross-sectional data including demographics (sex, age, and grade level), perceived addiction to tobacco, Dimensions of Tobacco Dependence Scale (DTDS) scores, the Modified Fagerstrom Tolerance Questionnaire (M-FTQ) scores, smoking history, and self-reported smoking identity were collected from questionnaires administered to 7246 students in British Columbia, Canada. Differences in tobacco dependence by sex and by smoking identity were examined. RESULTS: Girls were more likely to report being ex-, social, irregular, or regular smokers than were boys; and were more likely to select more than one smoking identity to describe their smoking behavior. Among the current smokers, the boys smoked more cigarettes each day, on average, and had significantly higher scores on the social and sensation dependence dimensions of the DTDS, and the M-FTQ, compared with the girls. Girls in each smoking identity group had lower scores on every tobacco dependence measure, except the emotional dependence dimension of the DTDS. CONCLUSION: Adolescent boys and girls appear to understand and subscribe to 'smoking identity' groups in similar patterns. However, there may be differences in the ways boys and girls conceptualize, describe, and endorse smoking identities. Researchers should examine the consistency between adolescents' smoking identities and researcher derived categorizations of their smoking in planning and selecting appropriate interventions. Future research should explore qualitative gender differences in the smoking identities of adolescents. PMID- 20965666 TI - Potential role of statins for the management of immune reconstitution syndrome. AB - It has become evident that while a robust inflammatory response plays a critical role in eradicating invading microbes, dysregulated immunity can be detrimental to the host if an optimal balance between the inflammatory and anti-inflammatory reactions is disrupted. Opportunistic infection-associated immune reconstitution syndrome is characterized by an aggressive inflammatory immune response and its management remains challenging and largely unknown. Statins, in addition to their lipid lower effects have anti-inflammatory attributes and there is precedence for the use of these agents as a therapeutic modality for autoimmune inflammatory disorders which have similar underlying pathogenesis as immune reconstitution syndrome. We hypothesize that statins may have a potential role for the management of immune reconstitution syndrome. Our proposal has biologic and translational implications for optimizing outcomes in patients with immune reconstitution syndrome. PMID- 20965667 TI - Nucleotides and their degradation products during processing of dry-cured ham, measured by HPLC and an enzyme sensor. AB - The aim of this work was to study how nucleotide degradation during the processing of dry-cured ham is affected when using three types of salting (100% NaCl; 50% NaCl and 50% KCl; 55% NaCl, 25% KCl, 15% CaCl2 and 5% MgCl2). Divalent salts in the salting mixture depressed the breakdown rate from the beginning of the process (salting and post-salting) up to the ripening stage (7 months) when the inosine (Ino), hypoxanthine (Hx) and xanthine (X) concentrations matched for the three treatments. The evolution of Hx and Hx+X were analysed by HPLC and an enzyme sensor, respectively, during processing. Time and temperature conditions during the curing time did not affect Hx stability. The usefulness of the enzyme sensor was confirmed and it is a practical tool to determine Hx + X in dry-cured ham, as an index of minimum curing time. A good correlation between enzyme sensor and HPLC data was observed. PMID- 20965668 TI - Immunohistological analysis of HPV L1 capsid protein and p16 protein in low-grade dysplastic lesions of the uterine cervix. AB - Human papillomavirus (HPV) L1 capsid protein (L1) is associated with the productive phase of HPV infection. However, the expression of L1 and its relationship to p16 expression, a surrogate marker for HPV infection, are unknown. We examined the relationship between L1 and p16 expression in cervical intraepithelial neoplasia. Tissues were divided into four categories: regressive lesions (n=48), progressive lesions (n=40), and randomly selected CIN1-2 (n=67) and CIN3 (n=44). P16 positivity in the progression cases was significantly higher than that in the regression cases, and p16 positivity in the CIN3 cases was significantly higher than that in any other categories. L1 positivity was not significant between each category. The staining pattern was divided into the following four groups: L1-/p16-, L1+/p16-, L1+/p16+, L1-/p16+. The L1-/p16- pattern was significantly associated with the regression nature in CIN1-2. Some CIN3 cases showing a feature of L1+/p16+, which are still HPV-productive, are likely to exist. The combination of both L1 and p16 may be useful in the evaluation of the progression risk of low-grade cervical dysplasia. PMID- 20965669 TI - Potential role of viral surface glycoproteins in the replication of H3N2 triple reassortant influenza A viruses in swine and turkeys. AB - The H3N2 triple reassortant (TR) influenza viruses emerged in swine in 1998 and then in turkeys in 2003. It was then hypothesized that these viruses crossed the species barrier and transmitted from pigs to turkeys. In previous work we identified viruses with different transmission behavior between the two species, of which A/turkey/Ohio/313053/04 (TK04) transmitted both ways between swine and turkeys, and A/swine/North Carolina/03 (SW03) did not transmit either way between the two species. Utilizing the 12-plasmid reverse genetics (RG) system, we rescued two viruses (TK04 and SW03) with potentially different transmission behavior between pigs and turkeys. Single gene reassortants (SGR) were generated by switching the hemagglutinin (HA) or the neuraminidase (NA) genes between both viruses, and were evaluated for replication in vitro (pig and turkey tracheal/bronchial epithelial cells) and in vivo (pigs and turkeys). RG-created TK04 replicated more efficiently than SW03 in vitro and in vivo. Additionally, TK04 exhibited better binding affinity to plasma membrane preparations (PMP) from pig and turkey tracheal/bronchial epithelial cells compared to SW03. In study with SGR viruses, the HA protein was found to be essential for TK04 virus transmission amongst turkeys, but not sole factor contributing to the efficient replication of virus in turkeys and pigs. Such findings further highlight the polygenic nature of influenza virus pathogenesis. PMID- 20965670 TI - Serological evidence of pig-to-human influenza virus transmission on Thai swine farms. AB - We investigated influenza interspecies transmission in two commercial swine farms in Thailand. Sera from swine-exposed workers (n=78), age-matched non-swine exposed healthy people (n=60) and swine populations in both farms (n=85) were studied. Hemagglutination-inhibition (HI) assay was performed on Thai swine H1 viruses (swH1N1 and swH1N2) isolated from both farms. Thai human H1N1 (huH1N1) and pandemic H1N1 2009 (pH1N1) were also used as test antigens. The hemagglutinin (HA) 1 genes of swH1N1 and swH1N2 viruses were sequenced and shown to be genetically distinct from the Thai huH1N1 and pH1N1 viruses. Evidence of pig-to human influenza virus transmission was found in farm workers with increased odds of elevated antibody titers to both swH1N1 (OR 42.63, 95% CI, 14.65-124) and swH1N2 (OR 58, 95% CI, 13.12-256.3) viruses. No evidence of human-to-pig influenza virus transmission was detected in this study. PMID- 20965671 TI - Effect of gender and hand laterality on pain processing in human neonates. AB - BACKGROUND: Previous studies in adults have reported that handedness and gender can affect pain perception. However, it is currently unclear when these differences emerge in human development. Therefore, we examined prefrontal responses to pain stimulation among newborns during their first acute pain experience after birth. METHODS: Forty newborns at 4-6 days postnatal age were observed during clinically required blood sampling while prefrontal activation was measured with near infrared spectroscopy. Blood sampling in this study was the first experience of a procedure involving skin breaking for these infants. We divided subjects into a right-hand stimulation group (n=21) and a left-hand stimulation group (n=19), depending on whether blood was sampled from the right or the left hand. A three-way analysis of variance (ANOVA) was conducted to examine the effects of several variables on the magnitude of the oxy-Hb value in response to pain stimulus, including stimulus side (right hand or left hand), gender (male or female), recording side (right prefrontal area or left prefrontal area) and interactions between these variables. RESULTS: The data revealed a significant effect of stimulus side (F (1, 72)=9.892, P=0.002), showing that the right-hand stimulation induced a greater prefrontal activation than the left-hand stimulation. No significant gender difference or interactions were found. CONCLUSION: Our findings suggest that hand laterality affects pain perception even in neonates. However, gender differences in pain perception did not appear to occur during the neonatal period. Further investigations using brain-imaging techniques are required to identify laterality- or gender-related differences in pain processing in humans. PMID- 20965672 TI - Toxicological analysis of 17 autopsy cases of hydrogen sulfide poisoning resulting from the inhalation of intentionally generated hydrogen sulfide gas. AB - Although many cases of fatal hydrogen sulfide poisoning have been reported, in most of these cases, it resulted from the accidental inhalation of hydrogen sulfide gas. In recent years, we experienced 17 autopsy cases of fatal hydrogen sulfide poisoning due to the inhalation of intentionally generated hydrogen sulfide gas. In this study, the concentrations of sulfide and thiosulfate in blood, urine, cerebrospinal fluid and pleural effusion were examined using GC/MS. The sulfide concentrations were blood: 0.11-31.84, urine: 0.01-1.28, cerebrospinal fluid: 0.02-1.59 and pleural effusion: 2.00-8.59 (MUg/ml), while the thiosulfate concentrations were blood: 0-0.648, urine: 0-2.669, cerebrospinal fluid: 0.004-0.314 and pleural effusion: 0.019-0.140 (MUmol/ml). In previous reports, the blood concentration of thiosulfate was said to be higher than that of sulfide in hydrogen sulfide poisoning cases, although the latter was higher than the former in 8 of the 14 cases examined in this study. These results are believed to be strongly influenced by the atmospheric concentration of hydrogen sulfide the victims were exposed to and the time interval between exposure and death. PMID- 20965673 TI - Quantitative assessment of evidential weight for a fingerprint comparison I. Generalisation to the comparison of a mark with set of ten prints from a suspect. AB - The authors have published elsewhere a quantitative method for assessing weight of evidence in the case where a finger mark from a crime scene is compared with a control print taken from a single finger of a suspect. The approach is based on the notion of calculating a likelihood ratio (LR) that addresses a pair of propositions relating to the single finger that was the origin of the crime mark. In practice, things are rather different because the crime mark will not just be compared with a single finger from a suspect but with a set of prints from all of his/her fingers; likewise, when the mark is compared with a database, this will consist of ten print records from random individuals. It is clear that "finger propositions" are not realistic in this situation and we show how our approach may be generalised to address a pair of propositions that relate to the person that made the crime mark. It often is the case that information is present at the crime scene that enables some inference to be drawn relating to which of the offender's ten fingers left a particular mark of interest. This kind of inference may profitably be drawn into the formal analysis. We illustrate our approach with an example. PMID- 20965674 TI - Value of clinical assessment in the diagnostic evaluation of Global Developmental Delay (GDD) using a Likelihood Ratio Model. AB - OBJECTIVE: A selective approach is recommended for investigating children with GDD. Our objective is to identify clinical markers to improve the diagnostic yield of evaluation of children with GDD. METHOD: Children with GDD (delay>2 S.D. in>1 domain) followed up in our centre were reviewed retrospectively. We selected nine clinical markers (sex, severity of GDD, parental consanguinity, family history, behavioral problems, head size, facial dysmorphism, non-facial anomalies and neurological deficits) and looked into the likelihood of finding an underlying etiology during follow-up. RESULTS: There were 577 children with 63%, 33% and 4% having mild, moderate and severe grade GDD. An identifiable etiology is detected in 53%. Genetic disease (25%) was the commonest cause identified. We have found that severity of GDD (severe and moderate versus mild grade [LR+=1.92 (95% C.I.=1.49-2.48); LR-=0.72(0.64-0.81)], behavioral problems [LR+=0.24 (95% C.I.=0.17-0.34); LR-=1.67 (1.48-1.88)], facial dysmorphism [LR+=2.66 (95% C.I.=1.10-3.54); LR-=0.65 (0.58-0.73)] and neurological deficits [LR+=2.85 (95% C.I.=2.32-3.50); LR-=0.31(0.25-0.39)] were clinical markers associated with increased chance of identifying an underlying etiology by multivariate analysis. CONCLUSION: These four clinical markers are useful in selecting patients with GDD for further diagnostic tests. Using the LR model, clinical markers in the first clinical evaluation of any child with GDD can potentially improve the etiological yield using targeted investigations. PMID- 20965675 TI - Evaluation of subjective image quality in relation to diagnostic task for cone beam computed tomography with different fields of view. AB - AIMS: To evaluate subjective image quality for two diagnostic tasks, periapical diagnosis and implant planning, for cone beam computed tomography (CBCT) using different exposure parameters and fields of view (FOVs). MATERIALS AND METHODS: Examinations were performed in posterior part of the jaws on a skull phantom with 3D Accuitomo (FOV 3 cm*4 cm) and 3D Accuitomo FPD (FOVs 4 cm*4 cm and 6 cm*6 cm). All combinations of 60, 65, 70, 75, 80 kV and 2, 4, 6, 8, 10 mA with a rotation of 180 degrees and 360 degrees were used. Dose-area product (DAP) value was determined for each combination. The images were presented, displaying the object in axial, cross-sectional and sagittal views, without scanning data in a random order for each FOV and jaw. Seven observers assessed image quality on a six-point rating scale. RESULTS: Intra-observer agreement was good (kappaw=0.76) and inter observer agreement moderate (kappaw=0.52). Stepwise logistic regression showed kV, mA and diagnostic task to be the most important variables. Periapical diagnosis, regardless jaw, required higher exposure parameters compared to implant planning. Implant planning in the lower jaw required higher exposure parameters compared to upper jaw. Overall ranking of FOVs gave 4 cm*4 cm, 6 cm*6 cm followed by 3 cm*4 cm. CONCLUSIONS: This study has shown that exposure parameters should be adjusted according to diagnostic task. For this particular CBCT brand a rotation of 180 degrees gave good subjective image quality, hence a substantial dose reduction can be achieved without loss of diagnostic information. PMID- 20965676 TI - Assessment of contrast-enhanced ultrasonography in diagnosis and preoperative localization of insulinoma. AB - OBJECTIVE: This study was to evaluate the value of contrast-enhanced ultrasonography (CEUS) in the diagnosis and preoperative localization of insulinoma and explore the enhancement patterns of the tumors. METHODS: Unenhanced and contrast-enhanced ultrasonographic examinations of 31 patients who underwent resection of insulinomas were retrospectively reviewed. The diagnosis sensitivity and localization specificity of CEUS for insulinomas were determined. Results of unenhanced ultrasonography and CEUS were compared by Chi-square test. RESULTS: Unenhanced ultrasonography could display 9 of 37 (24.3%) surgically verified insulinomas in 31 patients, while the diagnosis sensitivity and localization specificity of preoperative CEUS was 33 (89.2%) and 32 (86.5%) of the 37 tumors, respectively. In contrast to the unenhanced ultrasonography, the improvement of CEUS in the diagnosis and preoperative localization of insulinomas was significant (p<0.0001). The enhancement pattern of insulinoma on CEUS was fast wash-in and slow wash-out. All the tumors were homogeneous hypervascularity in the earlier arterial phase, while the tumors still displayed hyperenhancing pattern in the late phase. CONCLUSION: Our study demonstrates the great potential of CEUS in the diagnosis and preoperative localization of insulinomas. Since CEUS is a convenient, inexpensive, effective and non-invasive modality, the study supports the use of CEUS as a primary tool in the evaluation of patients with insulinomas. PMID- 20965677 TI - Comparison of thin-section CT and pathological findings in small solid-density type pulmonary adenocarcinoma: prognostic factors from CT findings. AB - OBJECTIVE: We divided pulmonary adenocarcinoma of <= 20 mm into air-containing and solid-density types based on a percentage reduction of the maximum tumor diameter in the mediastinal window image compared to the area in the lung window image on thin-section (TS) CT of >= 50% (air-containing type) and <50% (solid density type). No relapse occurred in patients with air-containing type. The prognosis of solid-density type may be poor even when the tumor size is 20mm or smaller. We investigated whether CT findings for these tumors could serve as prognostic factors. METHODS: The subjects were 105 patients with solid-density type pulmonary adenocarcinoma that was identified on TSCT and found to have a diameter of 20mm or smaller after surgical resection during the period from April 1997 to November 2004. Notches, air bronchogram, pleural retraction, spiculation, venous involvement, and ground glass opacity were examined on TSCT, and their associations with pathological findings (i.e., pleural invasion, lymphatic permeation, vascular invasion, lymph node metastasis, and Noguchi's classification) and relapse were investigated using chi-square test and Cox proportional hazards model. RESULTS: The incidence of relapse was significantly higher in cases with notches. The incidence of notches increased with tumor growth and notches were frequent in Noguchi type D tumors, reflecting poorly differentiated adenocarcinoma. Lymphatic permeation and type D cases were independent factors associated with a poor prognosis using Cox proportional hazards model. CONCLUSIONS: TSCT findings may be useful for prediction of the prognosis of solid-density type pulmonary adenocarcinoma. PMID- 20965678 TI - Radiographic study of severe Influenza-A (H1N1) disease in children. AB - OBJECTIVE: To characterize the radiographic findings of pediatric patients with severe Influenza-A (H1N1) disease. METHODS: A retrospective study of data from chest X-ray, CT and MRI exam of 29 pediatric patients treated in intensive care unit for severe Influenza-A (H1N1) disease. RESULTS: Disease developed quickly at early stage. Here are four types of radiographic findings. The disease continued to progress for 2-3 days and X-ray showed that all 29 patients had increased solid lesions with the existence of interstitial lesions. Four days later, all lung lesions showed absorption to certain degree. Fifteen days later, X-ray and CT showed complete or significant absorption in 19 cases (85.5%); delayed recovery was identified in 8 cases (27.6%), pulmonary fibrosis was found in 3 cases (10.3%), and 3 patients (10.3%) died. But the latter identified more lesions. Cranial CT and MRI were performed for 8 patients who had neurological symptoms. Of them, 3 cases (10.3%) were abnormal, showed symmetrical long T1 and T2 signal shadow in bilateral thalamus and longer T1 and T2 signals in the between. 3 cases had autopsy completed. CONCLUSION: The severe Influenza-A (H1N1) among children progression was generally rapid in the first 3 days. The overall radiographic findings are similar to acute respiratory distress syndrome (ARDS). A small portion of the patients occurred acute necrotizing encephalopathy and plastic bronchitis. PMID- 20965679 TI - Avascular necrosis (AVN) of the proximal fragment in scaphoid nonunion: is intravenous contrast agent necessary in MRI? AB - PURPOSE: The purpose of this prospective study is to assess the diagnostic value of intravenously applied contrast agent for diagnosing osteonecrosis of the proximal fragment in scaphoid nonunion, and to compare the imaging results with intraoperative findings. MATERIALS AND METHODS: In 88 patients (7 women, 81 men) suffering from symptomatic scaphoid nonunion, preoperative MRI was performed (coronal PD-w FSE fs, sagittal-oblique T1-w SE nonenhanced and T1-w SE fs contrast-enhanced, sagittal T2*-w GRE). MRI interpretation was based on the intensity of contrast enhancement: 0 = none, 1 = focal, 2 = diffuse. Intraoperatively, the osseous viability was scored by means of bleeding points on the osteotomy site of the proximal scaphoid fragment: 0=absent, 1 = moderate, 2 = good. RESULTS: Intraoperatively, 17 necrotic, 29 compromised, and 42 normal proximal fragments were found. In nonenhanced MRI, bone viability was judged necrotic in 1 patient, compromised in 20 patients, and unaffected in 67 patients. Contrast-enhanced MRI revealed 14 necrotic, 21 compromised, and 53 normal proximal fragments. Judging surgical findings as the standard of reference, statistical analysis for nonenhanced MRI was: sensitivity 6.3%, specificity 100%, positive PV 100%, negative PV 82.6%, and accuracy 82.9%; statistics for contrast enhanced MRI was: sensitivity 76.5%, specificity 98.6%, positive PV 92.9%, negative PV 94.6%, and accuracy 94.3%. Sensitivity for detecting avascular proximal fragments was significantly better (p<0.001) in contrast-enhanced MRI in comparison to nonenhanced MRI. CONCLUSION: Viability of the proximal fragment in scaphoid nonunion can be significantly better assessed with the use of contrast enhanced MRI as compared to nonenhanced MRI. Bone marrow edema is an inferior indicator of osteonecrosis. Application of intravenous gadolinium is recommended for imaging scaphoid nonunion. PMID- 20965680 TI - Diverse rhizobia associated with Sophora alopecuroides grown in different regions of Loess Plateau in China. AB - A total of seventy-five symbiotic bacterial strains isolated from root nodules of wild Sophora alopecuroides grown in different regions of China's Loess Plateau were characterized. Based on the combined RFLP patterns, thirty-five genotypes were defined among the rhizobia and they were classified into nine genomic species, including Mesorhizobium alhagi and M. gobiense as the main groups, as well as Agrobacterium tumefaciens, M. amorphae, Phyllobacterium trifolii, Rhizobium giardinii, R. indigoferae, Sinorhizobium fredii and S. meliloti as the minor groups according to the 16S rRNA and recA gene analyses. Five and three lineages of nodA and nifH were found, respectively, in these strains, implying that the symbiotic genes of the S. alopecuroides rhizobia had different origins or had divergently evolved. Results of correspondence analysis showed that there was a correlation between rhizobial genotypes and the geographic origins. Possible lateral transfer of the recA and 16S rRNA genes between the P. trifolii and A. tumefaciens strains, and that of symbiotic genes (nodA, nifH) between different genera, was shown by discrepancies of the phylogenetic relationships of the four gene loci. These results revealed diverse rhizobia associated with wild S. alopecuroides grown in different regions of China's Loess Plateau, and demonstrated for the first time the existence of symbiotic A. tumefaciens strains in root nodules of S. alopecuroides. PMID- 20965681 TI - In vitro influence of fatty acids and bilirubin on binding of mycophenolic acid to human serum albumin. AB - Mycophenolic acid (MPA) is 98-99% bound to albumin. Because MPA is restrictively cleared and has a low extraction coefficient, increase in its free fraction related to decreased albumin binding results in lower total concentrations but unchanged unbound concentrations. Multiple factors, including hypoalbuminemia, impaired renal function, and accumulated mycophenolic acid glucuronide are known to reduce MPA protein binding. Little is known about the influence of fatty acids and bilirubin on this issue. By using quenching fluorescence method, the aims of this study were to investigate in vitro the binding properties of MPA, then the influence of myristic acid and bilirubin on MPA binding to albumin. The estimate of dissociation constant (Kd) of MPA was 13.2 [CI 95 12.7-13.8] MUM. In the presence of myristic acid (concentration range 4-100 MUM), apparent Kd (Kd(app)) of MPA was approximately 1.5-10-fold greater. For myristic acid/albumin molar ratio reachable in clinical settings (2:1 and 5:1), Kd(app) of MPA rose about a factor 1.5 and 2.2, respectively. In the presence of bilirubin (concentration range 0.5-5 MUM), Kd(app) of MPA was approximately 1.5-5-fold greater than MPA Kd. For bilirubin/albumin molar ratio reachable in clinical settings (1:4 and 1:2), Kd(app) of MPA rose about a factor 1.5 and 1.9, respectively. These data suggest that hypertriglyceridemia or cholestasis may significantly increase MPA free fraction in clinical settings, thereby lowering MPA total concentration in plasma while the free concentration remains unchanged. These results may help to optimize the therapeutic drug monitoring of MPA. PMID- 20965682 TI - Tablet potency of Tianeptine in coated tablets by near infrared spectroscopy: model optimisation, calibration transfer and confidence intervals. AB - A near infrared (NIR) method was developed for determination of tablet potency of active pharmaceutical ingredient (API) in a complex coated tablet matrix. The calibration set contained samples from laboratory and production scale batches. The reference values were obtained by high performance liquid chromatography (HPLC) and partial least squares (PLS) regression was used to establish a model. The model was challenged by calculating tablet potency of two external test sets. Root mean square errors of prediction were respectively equal to 2.0% and 2.7%. To use this model with a second spectrometer from the production field, a calibration transfer method called piecewise direct standardisation (PDS) was used. After the transfer, the root mean square error of prediction of the first test set was 2.4% compared to 4.0% without transferring the spectra. A statistical technique using bootstrap of PLS residuals was used to estimate confidence intervals of tablet potency calculations. This method requires an optimised PLS model, selection of the bootstrap number and determination of the risk. In the case of a chemical analysis, the tablet potency value will be included within the confidence interval calculated by the bootstrap method. An easy to use graphical interface was developed to easily determine if the predictions, surrounded by minimum and maximum values, are within the specifications defined by the regulatory organisation. PMID- 20965683 TI - Simultaneous determination of three steroidal glycoalkaloids in Solanum xanthocarpum by high performance thin layer chromatography. AB - A new high-performance thin-layer chromatographic (HPTLC) method has been developed for the simultaneous quantitation of three bioactive steroidal glycoalkaloid (SGA) markers, solasonine (SN), solamargine (SM) and khasianine (KN) in the plant Solanum xanthocarpum. Extraction efficiency of targeted SGAs from plant matrix using methanol and acidified methanol were studied using percolation, ultrasonication and microwave techniques. The separation was achieved on silica gel 60F(254) TLC plates using chloroform-methanol-water as mobile phase. The quantitation of SGAs was carried out using the densitometric reflection/absorption mode at 520 nm after post chromatographic derivatization using Dragendorff's reagent. The method was validated for peak purity, precision, accuracy, robustness, limit of detection (LOD) and quantitation (LOQ). Method specificity was confirmed using retention factor (R(f)), Vis spectral correlation and electrospray ionization mass spectra (ESI-MS) of marker compounds in the sample track. PMID- 20965684 TI - The Family Education Rights and Privacy Act's impact on residency applicant behavior and recommendations: a pilot study. AB - BACKGROUND: The Family Education Rights and Privacy Act (FERPA) provides residency applicants the right to view letters of recommendation. Applicants must indicate whether they waive this right. OBJECTIVES: We determined how frequently applicants to an emergency medicine residency program waived the right to view letters of recommendation and whether such decisions impacted the letters' contents. METHODS: A retrospective, observational review of all letters of recommendation submitted to an emergency medicine residency program in 2005-2006 determined applicants' FERPA declaration, use of the Standardized Letter of Recommendation (SLOR), and the SLOR Global Assessment ranking. The percentage of applicants waiving FERPA rights was determined. Chi-squared tests of independence assessed whether applicants' decisions influenced the SLOR Global Assessment. All statistical analysis used a 5% level of significance. RESULTS: There were 367 applications received; 1120 letters of recommendation accompanied 264 US medical school applications, 449 (40%) using the SLOR format. Of the SLORs, only 6% stated that the applicant did not waive his FERPA right; 426 SLORs included a Global Assessment. Of those waiving FERPA rights, 30% were ranked "Outstanding," 50% "Excellent," 17% "Very Good," and 3% "Good." For those not waiving FERPA rights, 35% were ranked as "Outstanding," 46% "Excellent," 15% "Very Good," and 4% "Good." There was no statistical difference in Global Assessment ranking between applicants who waived FERPA rights and those who did not (p = 0.934). CONCLUSIONS: In this pilot study, the vast majority of applicants waived FERPA rights to view letters of recommendation. The applicants' decisions did not influence their SLOR Global Assessment ranking. PMID- 20965685 TI - The influence of polyvascular disease on the obesity paradox in vascular surgery patients. AB - BACKGROUND: Obesity is a risk factor for atherosclerosis, a polyvascular process associated with reduced survival. In nonvascular surgery populations, a paradox between body mass index (BMI) and survival is described. This paradox includes reduced survival in underweight patients, whereas overweight and obese patients have a survival benefit. No clear explanation for this paradox has been given. Therefore, we evaluated the presence of the obesity paradox in vascular surgery patients and the influence of polyvascular disease on the obesity paradox. METHODS: In this retrospective study, 2933 consecutive patients were classified according to their preoperative BMI (kg/m(2)) and screened for polyvascular disease and cardiovascular risk factors before surgery. In addition, medication use at the time of discharge was noted. Outcome was all-cause mortality during a median follow-up of 6.0 years (interquartile range, 2-9 years). RESULTS: BMI (kg/m(2)) groups included 68 (2.3%) underweight (BMI <18.5), 1379 (47.0%) normal (BMI 18.5-24.9, reference), 1175 (40.0%) overweight (BMI 25-29.9), and 311 (10.7%) obese (BMI >= 30) patients. No direct interaction between BMI, polyvascular disease, and long-term outcome was observed. Underweight was an independent predictor of mortality (hazard ratio, 1.65; 95% confidence interval, 1.22-2.22). In contrast, overweight protected for all-cause mortality (hazard ratio, 0.79; 95% confidence interval, 0.700-0.89). Cardioprotective medication usage in underweight patients was the lowest (P < .001), although treatment targets for risk factors were equally achieved within all treated groups. CONCLUSION: Overweight patients referred for vascular surgery were characterized by an increased incidence of polyvascular disease and required more extensive medical treatment for cardiovascular risk factors at discharge. Long-term follow up showed a paradox of reduced mortality in overweight patients. PMID- 20965686 TI - The impact of ischemic intervals on neuromuscular recovery in a porcine (Sus scrofa) survival model of extremity vascular injury. AB - BACKGROUND: Despite advances in revascularization following extremity vascular injury, the relationship between time to restoration of flow and functional limb salvage is unknown. The objectives of this study are to describe a large animal survival model of hind limb ischemia/reperfusion and define neuromuscular recovery following increasing ischemic periods. METHODS: Sus scrofa swine (N = 38; weight, 87 +/- 6.2 kg) were randomized to iliac artery occlusion for 0 (Control), 1 (1HR), 3 (3HR), or 6 (6HR) hours, followed by vessel repair and 14 days of recovery. Additionally, one group underwent iliac artery division with no restoration of flow (Ligation), and one group underwent iliac artery exposure only without intervention (Sham). A composite physiologic measure of recovery (PMR) was generated to assess group differences over 14 days of survival. PMR included limb function (Tarlov score) and electrophysiologic measures (compound muscle action potential amplitude, sensory nerve action potential amplitude, and nerve conduction velocity). Using the PMR and extrapolating the point at which recovery following ligation crosses the slope connecting recovery after 3 and 6 hours of ischemia, an estimate of the ischemic threshold for the hind limb is made. These results were correlated with peroneus muscle and peroneal nerve histology. RESULTS: Baseline physiologic characteristics were similar between groups. Neuromuscular recovery in groups with early restoration of flow (Control, 1HR, 3HR) was similar and nearly complete (92%, 98%, and 88%, respectively; P > .45). While recovery was diminished in both 6HR and Ligation, Ligation, rather than repair, exhibited greater recovery (68% vs 53%; P < .05). These relationships correlated with the pathologic grade of degeneration, necrosis, and fibrosis (P < .05). The PMR model predicts minimal and similar persistent loss of function in groups undergoing early surgical restoration of flow (Control 8%, 1HR 1%, 3HR 12%; P > .45). In contrast, the Ligation group exhibited the greatest degree of injury early in the reperfusion period, followed by more complete recovery and at a faster rate than 6HR. Extrapolating from the PMR the point at which Ligation (68% recovery) crosses the slope connecting 3 hours (84% recovery) and 6 hours (53% recovery) of ischemia estimates the ischemic threshold to be 4.7 hours. Restoration of flow at ischemic intervals exceeding this are associated with less physiologic recovery than ligation. CONCLUSION: In this model, surgical and therapeutic adjuncts to restore extremity perfusion early (1-3 hours) after extremity vascular injury are most likely to provide outcomes benefit compared with delayed restoration of flow or ligation. Furthermore, the ischemic threshold of the extremity after which neuromuscular recovery is significantly diminished is less than 5 hours. Additional studies are necessary to determine the effect of other factors such as shock or therapeutic measures on this ischemic threshold. PMID- 20965687 TI - [Obstructive sleep-apnoea syndrome in adult and its perioperative management]. AB - Obstructive sleep apnoea (OSA) syndrome in adult is defined as an Apnoea Hypopnoea Index (AHI) of 5 or more per hour of sleep in a context of excessive daytime sleepiness and snoring. OSA is considered as mild with an AHI of 5-15, moderate with an AHI of 15-30, and severe with an AHI greater than 30. OSA is a highly prevalent disease since it should affect 7-15% of the middle-aged population, but most patients are not yet diagnosed for OSA. Middle age, male gender, obesity and arterial hypertension are main risk factors for OSA in adults. OSA patients are exposed to higher neurological and cardiovascular morbidity, including stroke, depression, hypertension, coronary artery disease, heart failure, arrhythmias. Because OSA may lead to life-threatening problems if undiagnosed, anaesthesiologists should be aware of their screening role in the preoperative period. In that way, the STOP-BANG questionnaire is a well-adapted instrument to screen patients for OSA during the preoperative visit. OSA patients are exposed to higher preoperative morbidity in relation with OSA severity, particularly difficult manual ventilation with mask, difficult tracheal intubation and postoperative upper airway obstruction. The unknown diagnosis of OSA is one major contributor to facilitate the occurrence of those events. In the postoperative period, early resuming continuous positive airway pressure and installing the OSA patient in a nonsupine position could be effective in preventing pharyngeal obstruction. Considering the timing of postoperative complications, a careful monitoring in the post-anesthesia care unit for three hours is an appropriate strategy for a majority of OSA patients. Alternatives to opioids should be promoted for postoperative pain control. PMID- 20965688 TI - Hidradenitis suppurativa. AB - Hidradenitis suppurativa, or Verneuil's disease, is somewhat common, especially in women, but it often unrecognized. Clinical manifestations include painful nodules, abscesses, sinus tracts, and ropelike hypertrophic scars in the apocrine gland-bearing areas. It is a chronic disease. Smoking and overweight are risk factors, but the cause is unknown: it is a disease of the follicular apparatus, neither infectious nor hormonal. Severe dramatic forms are rare. Quality of life is severely affected even in the mild forms. Treatment is both medical and surgical: wide-spectrum antibiotics and excisions tailored to the extent of involvement. Anti-TNFalpha drugs are effective, but their risk-benefit ratio is still in question. Laser treatment is under study. PMID- 20965689 TI - Thalidomide. PMID- 20965690 TI - Use of methadone for uncontrolled pain: an alternative dosing regimen. PMID- 20965691 TI - United States lags on palliative care at the end of life. PMID- 20965692 TI - Pain documentation and predictors of analgesic prescribing for elderly patients during emergency department visits. AB - CONTEXT: Inappropriate pain documentation is likely to be an important contributor to the poor management of pain in elderly patients in the emergency department (ED). Failure to assess pain limits ability to treat pain. OBJECTIVES: The objectives of this study were to examine the relationship between visit characteristics of elderly patients and pain score documentation in the ED, and to determine predictors of analgesic use in the ED. METHODS: This was a cross sectional analysis of documented ED visits by elderly patients from the National Hospital Ambulatory Medical Care Survey (2003-2006). The study included 5661 ED visits by patients aged 65 years and older, representing an estimated 18 million ED visits during the four-year study period. Univariate logistic regression was used to analyze associations among independent variables and documentation of pain. Multivariate logistic regression was used to determine whether nonopioid and opioid analgesic prescribing disparities existed and were associated with pain level. RESULTS: Pain score documentation was found to be suboptimal in the elderly population in this study, with only 75% of visits having documented pain scores. Older age, self-pay, patients residing in the Western region of the United States, and emergent ED visits were associated with decreased pain score documentation. Documentation of pain score was associated with increased odds of an analgesic prescription and opioid analgesic prescription. Odds of prescribing an opioid increased significantly with increasing level of pain severity. CONCLUSION: ED pain score documentation is suboptimal in the elderly population. Disparity in the use of analgesic prescriptions and opioid analgesics exists and may result in patients not receiving analgesics. Improving pain assessment and documentation, changes in attitude toward analgesic prescribing, and recognition of ethnic, racial, and age differences in patients with pain have the potential to contribute to effective management of pain in the ED. PMID- 20965693 TI - Symptoms of opioid withdrawal syndrome after switch from oxycodone to alfentanil. PMID- 20965694 TI - Soft tissue cephalometric norms for a North Indian population group using Legan and Burstone analysis. AB - Cephalometric norms are used for providing guidance to clinicians during diagnosis and treatment planning. Most classical norms are not applicable to diverse racial and ethnic population hence the purpose of this study was to establish the soft tissue norms of a North Indian population group using Legan and Burstone soft tissue analysis. The study was conducted on 60 adult subjects with esthetically pleasing profiles aged 18-25 years. Standardized lateral cephalograms were taken in a natural head position and analyzed. North Indians were found to have more convex faces, protrusive lips and acute nasolabial angles compared with Caucasians. Males had more convex faces and protrusive lips than females. This North Indian population group had significant deviations from the Caucasian standards. Considerable diversity was also found for some of the soft tissue variables in males and females. PMID- 20965695 TI - The use of botulinum toxin type A in cosmetic facial procedures. AB - Over the past decade, facial cosmetic procedures have become more commonplace in dentistry and oral and maxillofacial surgery. An increasing number of patients seek minimal invasive procedures. One of the most requested procedures is treatment with botulinum toxin type A (BoNTA). Treatment of dynamic rhytids and lines with BoNTA is effective and produces high rates of improvement with rapid onset and long duration of action (longer than 4 months for some patients) compared with placebo. This paper considers the history and pharmacology of this neurotoxin, and focusses on the literature concerning the treatment of different facial areas with BoNTA. It also presents clinical guidelines on the treatment of glabellar lines, the frontalis muscle, peri-orbital lines, gummy smile and masseter muscle hypertrophy. Knowledge about the mechanisms of action and the ability to use BoNTA as an adjunctive treatment are mandatory for those working in the field of cosmetic facial surgery. PMID- 20965696 TI - Unique discrepancy between cerebral blood flow and glucose metabolism in hemimegalencephaly. AB - Hemimegalencephaly (HME) presents as severe refractory seizures and requires early surgical treatment to prevent progression to catastrophic epilepsy. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are useful imaging techniques for the presurgical evaluation of patients with intractable epilepsy. However, the results in HME are variable and no study has compared SPECT and PET performed at around the same time. We performed SPECT and PET for nine patients with HME, which was defined as a whole or part of affected hemisphere enlargement (three males, six females; age range 0.5-20 years). The ictal and interictal states were determined based on the presence or absence of clinical seizures during all PET examinations and majority of SPECT examinations. The perfusion pattern in the malformed hemisphere was increased or equal, despite the reduced glucose metabolism in six out of nine patients. Five of the six patients who underwent early surgical treatment showed this kind of perfusion/metabolism discrepancy. Importantly, even the non-affected hemisphere in early infantile cases already lacked the normal hypoperfusion and hypometabolism patterns of immature frontal lobes, which was most prominent in case with poor surgical prognosis. In all six surgical patients, epileptic seizures appeared before 4 months of age. By contrast, none of the non-surgical patients had seizures before 4 months of age. In conclusion, although the number of patients examined is small and the result is still preliminary, the perfusion/metabolism discrepancy found in this study may show potential characteristic aspect of HME and further study with simultaneous EEG recording will make clear if this finding can be useful indicator for early surgical treatment in HME. PMID- 20965697 TI - Executive functioning correctly classified diagnoses in patients with first episode psychosis: evidence from a 2-year longitudinal study. AB - Few studies have analysed factors that predict the ultimate clinical diagnosis in first-episode psychosis (FEP), and none has included cognitive factors. Eighty six FEP patients and 34 healthy controls were recruited and followed up for two years. Positive and negative symptoms, depression, mania, duration of untreated psychosis (DUP), premorbid functioning, functional outcome and neurocognition were assessed over 2 years. Logistic regression models revealed that Wisconsin Card Sorting Test correctly distinguished the patients ultimately diagnosed with schizophrenia (87%) from those with bipolar disorder (80%) and those with other psychoses (85%), for an overall correct-diagnosis rate of 84.4%. The prediction was stable despite the inclusion of clinical and affective symptoms, DUP, clinical impression, and functional outcome scores. Results highlight the importance of reconsidering neurocognition as a diagnostic criterion for psychosis and schizophrenia. PMID- 20965698 TI - Are cavum septum pellucidum abnormalities more common in schizophrenia spectrum disorders? A systematic review and meta-analysis. AB - Magnetic resonance imaging (MRI) studies have reported a variety of brain abnormalities in association with schizophrenia. These include a higher incidence of cavum septum pellucidum (CSP), which is consistent with a neurodevelopmental model for this disorder. In this meta-analytic review, we describe and discuss the main CSP MRI findings in schizophrenia spectrum disorders (SSDs) to date. We adopted as keywords cavum and schizophrenia or psychosis, and the inclusion criteria were articles in English, with samples of SSD patients compared to healthy subjects, which used MRI to assess CSP, without time limit. From 18 potential reports, fifteen were eligible to be part of the current review. These studies included 1054 patients with SSD and 866 healthy volunteers. Six out of 15 studies pointed to a higher prevalence of CSP of any size in SSD patients, while five out of 15 showed that subjects with SSD had a greater occurrence of a large CSP than healthy individuals. However, the meta-analysis demonstrated that only the incidence of a large CSP was significantly higher in SSD relative to healthy comparisons (odds ratio=1.59; 95%CI 1.07-2.38; p=0.02). Overall our results suggest that only a large CSP is associated with SSD while a small CSP may be considered a normal neuroanatomical variation. Our review revealed a large degree of variability in the methods employed across the MRI studies published to date, as well as evidence of publication bias. Studies in large, community-based samples with greater standardization of methods should clarify the true significance of CSP in SSD. PMID- 20965699 TI - A path model investigation of neurocognition, theory of mind, social competence, negative symptoms and real-world functioning in schizophrenia. AB - Problems in real-world functioning are pervasive in schizophrenia and much recent effort has been devoted to uncovering factors which contribute to poor functioning. The goal of this study was to examine the role of four such factors: social cognition (theory of mind), neurocognition, negative symptoms, and functional capacity (social competence). 178 individuals with schizophrenia or schizoaffective disorder completed measures of theory of mind, neurocognition, negative symptoms, social competence, and self-reported functioning. Path models sought to determine the relationships among these variables. Theory of mind as indexed by the Hinting Task partially mediated the relationship between neurocognition and social competence, and negative symptoms and social competence demonstrated significant direct paths with self-reported functioning. Study results suggest theory of mind serves as an important mediator in addition to previously investigated social cognitive domains of emotional and social perception. The current study also highlights the need to determine variables which mediate the relationship between functional capacity and real-world functioning. PMID- 20965700 TI - Neutrophil elastase contributes to extracellular matrix damage induced by chronic low-dose UV irradiation in a hairless mouse photoaging model. AB - BACKGROUND: Repeated exposure to ultraviolet (UV) rays damages skin connective tissue, which is thought to be associated with wrinkle formation. We hypothesized that repeated mild inflammation may cause the connective tissue alterations in photoaging. OBJECTIVE: To clarify the behavior of neutrophils and neutrophil elastase (NE) activity in the photoaging process and to examine the mechanisms of connective tissue damage resulting from NE in photoaging. METHODS: Mouse dorsal skin was irradiated with a suberythemal dose of UVB three times a week. After 5 or 10 weeks of irradiation, neutrophils were investigated by light microscopy and transmission electron microscopy. NE activity was examined by in situ zymography. Activation of proMMP-2 and proMMP-1 by NE both in the purified enzyme and in human skin fibroblast culture was examined by gelatin zymography or immunoblotting respectively. RESULTS: Both neutrophil infiltration and NE activity were elevated in photoaging. Furthermore, activated MMP-2 and MMP-1 were increased by NE treatment in a dose-dependent manner. CONCLUSIONS: In the present study, we demonstrated that neutrophil infiltration and NE activity are elevated in the chronic UVB-irradiated skin of hairless mice and we confirmed the involvement of NE in MMP activation. These data suggest that NE indirectly plays a role in skin photoaging through MMP activation. PMID- 20965701 TI - Isolation rearing-induced deficits in sensorimotor gating and social interaction in rats are related to cortico-striatal oxidative stress, and reversed by sub chronic clozapine administration. AB - Social isolation rearing (SIR) in rats induces behavioral and glutamatergic changes akin to schizophrenia. We studied the effects of 8 weeks SIR on cortico striatal redox and social and cognitive behaviors in rats. SIR increased superoxide dismutase activity, decreased oxidized:reduced glutathione ratio and increased lipid peroxidation in both brain regions, and induced deficits in prepulse inhibition and social and self-directed interactive behaviors. Both behavioral and cortico-striatal redox disturbances were corrected by clozapine (5 mg/kg/day*11days). Behavioral changes evoked by SIR are associated with cortico striatal oxidative stress that is reversed by clozapine treatment, providing novel insight into the neurobiology and treatment of schizophrenia. PMID- 20965702 TI - Direct electron transfer and voltammetric determination of roxithromycin at a single-wall carbon nanotube coated glassy carbon electrode. AB - The electrochemical behavior of roxithromycin (RM) at a single-wall carbon nanotube (SWNT) coated glassy carbon (GC) electrode was studied. It was found that RM could produce an irreversible anodic peak at the electrode. When the pH of supporting electrolyte (i.e. phosphate buffer solution) was 7 the peak potential was 0.86V (vs. SCE). The electrochemical reaction contained electron and proton transfer, and the electron-transfer coefficient (alpha) was ca. 0.87. The anodic peak depended on the adsorption of RM, the maximum adsorption amount was about 3.99*10(-10)molcm(-2). The adsorbed RM could be removed by cycling between 0.1 and 1.1V in a blank solution for about two minutes, and the electrode thus could be regenerated. Under the optional conditions, the anodic peak current was linear to RM concentration over the range of 5.0*10(-6) to 1.0*10(-4)M. The limit of detection was 5.0*10(-7)M (S/N=3) for 180s accumulation at -0.8V. The modified electrode had good stability and repeatability, and it was successfully applied to the determination of RM in medicine samples. PMID- 20965703 TI - A novel method to synthesize hydroxyapatite coating with hierarchical structure. AB - A novel process has been developed for the preparation of a hydroxyapatite (HA) coating with a hierarchical structure on a Ti substrate. The Ti substrate was first subjected to electrolytic deposition at -1.6V (versus Ag/AgCl/KCl) in a solution of 0.042M Ca(NO(3))(2).4H(2)O and 0.025M NH(4)H(2)PO(4) at 85 degrees C for 3min, and then post-treated in a 0.25M NaOH solution, with the addition of 0.05M Na(3)Cit at 85 degrees C for 5h. The experimental results showed that the coating experienced a phase conversion from octacalcium phosphate to HA after the post-treatment step. The HA coating had well-distributed, micro-sized pores comprising three-dimensional interconnected mesoporous HA belts, which would greatly increase the porosity and surface area of the coating. PMID- 20965704 TI - Simulations of lipid vesicle rupture induced by an adjacent supported lipid bilayer patch. AB - Using a simple phenomenological model of a lipid bilayer and a surface, simulations were performed to study the bilayer-induced vesicle rupture probability as a vesicle adsorbs adjacently to a bilayer patch already adsorbed on the surface. The vesicle rupture probability was studied as a function of temperature, vesicle size, and surface-bilayer interaction strength. From the simulation data, estimates of the apparent activation energy for bilayer-induced vesicle rupture were calculated, both for different vesicle sizes and for different surface-bilayer interaction strengths. PMID- 20965705 TI - ["There are 3 kinds of lies": comments on the article "Teenage suicides and suicide attempts: finding one's way in the epidemiologic data"]. PMID- 20965706 TI - Perspectives in medical optics. PMID- 20965707 TI - Diet modification and its influence on metabolic and related pathological alterations in the SHR/NDmcr-cp rat, an animal model of the metabolic syndrome. AB - SHR/NDmcr-cp (SHR/NDcp) rats, which carry a nonsense mutation of the leptin receptor gene, are known to spontaneously develop hypertension, obesity and hyperlipidemia, and have therefore found use as an animal model of the metabolic syndrome and type 2 diabetes. However, some recent studies on SHR/NDcp rats revealed only mild elevation of blood glucose levels. To investigate whether metabolic factors including blood glucose and histopathological alterations of SHR/NDcp rats deteriorate with a diabetogenic diet, biochemical and histopathological examinations were conducted with animals fed normal or diabetogenic diets for 20 weeks. SHR/NDcp rats receiving the normal diet displayed obesity, hypertension, hyperlipidemia, and mild elevation of blood glucose and HbA1c levels. Urinary glucose excretion was noted in only 1 out of 6 animals. Histologically, macro- and micro-vesicular steatosis in the liver, glomerular and tubular damages in the kidney and islet hyperplasia mainly of beta cells in the pancreas were characteristically noted. In SHR/NDcp rats fed the diabetogenic diet, obesity was more severe, with higher blood glucose and HbA1c levels, increased numbers of animals with urinary glucose excretion, and more pronounced hepatic steatosis and renal tubular changes. However, elevation of blood glucose levels and urinary glucose excretion proved transient. These observations indicate that the diabetic state and associated histopathological alterations in SHR/NDcp rats are exacerbated by feeding a diabetogenic diet, but the effects are limited. Elevated islet function with compensative insulin secretion might be related to amelioration of the hyperglycemic state. Further diet modification could be needed to induce a more prominent and persistent diabetic state in SHR/NDcp rats. PMID- 20965708 TI - Experimental switching of copper status in laboratory rodents. AB - There is an emerging link between copper metabolism, tumor growth and efficiency of antitumor treatment with platinum drugs or copper chelators. So there is an urgent need for well-defined and reproduced animal models with different states of copper metabolism. In the present study an animal model (rats and mice) with switching copper status in blood serum (copper concentration, oxidase activity and ceruloplasmin (Cp) protein content) is characterized. The drop of copper status is caused by addition of AgCl to fodder (Ag-animals). In rats and mice, the influence of silver ions on oxidase and ferroxidase activity of blood serum is similar, but copper concentration is reduced by 90% in rats, and by 60% in mice. The absorbed silver ions are transported to liver cells and included to Cp polypeptides, which are secreted to blood serum then. Cp, which circulates in bloodstream of Ag-animals contains silver atoms, and is misfolded, as judged by circular dichroism spectroscopy and differential scanning calorimetry. Single intraperitoneal or per oral injection of Cu(II) salt to Ag-animals causes recovery of oxidase and ferroxidase activity of blood serum within 4 hours in both rodent species, presumably by rapid metabolic insertion of copper into forming Cp in liver. The recovered copper status persists for 3 days under the continuing Ag-diet. The possibilities of use of Ag-rodents with switching copper status in investigation of influence of copper status on tissue-specific intracellular copper metabolism and role of copper in tumor genesis, bone metabolism and neurodegenerative diseases are discussed. PMID- 20965709 TI - Lung function and disability in neuromuscular patients at first admission to a respiratory clinic. AB - BACKGROUND: Respiratory failure is the most common cause of morbidity and mortality in patients with neuromuscular diseases (NMD). Non-invasive mechanical ventilation is considered highly effective for treating chronic respiratory failure. Perception and knowledge of risks associated with respiratory derangements may be underestimated. OBJECTIVE: The aim of our study was to evaluate the association among respiratory function, general clinical disability and need of home mechanical ventilation (HMV) in patients with slowly progressive NMD admitted for the first time to dedicated respiratory outpatient clinics. METHODS: Anthropometrics, lung function, respiratory muscle function, daytime blood gases data, and general clinical disability assessed by means of a clinical interview were recorded. Indication for HMV was an arterial CO(2) tension >45mmHg and/or a vital capacity <50% predicted, and/or maximal inspiratory pressure <60cmH(2)O. RESULTS: Two out of 5 patients complained of dyspnoea during daily activity and dysphagia, while more than 1/3 had ineffective cough and speech difficulties. Two-third of the whole group were considered to need HMV. By applying one or more criteria for NMD diagnosis, great variability was found for indication to HMV. Clinical disability was inversely related to dynamic and static lung volumes, and to respiratory muscle function. CONCLUSIONS: About two third of NMD patients admitted to a respiratory clinic is a candidate for home mechanical ventilation being their clinical derangement inversely related with respiratory function. The use of a simple dedicated clinical disability interview may reduce underestimation of HMV need. PMID- 20965710 TI - Small fiber neuropathy in sarcoidosis: Something beneath the surface. PMID- 20965711 TI - Dyspnea perception in asthma: role of airways inflammation, age and emotional status. AB - OBJECTIVES: Dyspnea perception in asthmatics differs between subjects. Poor perception is usually associated with increased risk of asthma attack/exacerbation. The advanced stage of the disease and the presence of eosinophilic airways inflammation have been recently recognized as being responsible for poor dyspnea perception. However, few studies are available on this topic. DESIGN: The aim of this study was to analyse the influence of inflammatory pattern, age and affective status on dyspnea perception in asthmatic subjects. SUBJECTS AND INTERVENTIONS: Seventy-one consecutive asthmatic patients were recruited and underwent induced sputum, exhaled NO measurement and breath condensate collection. Perception of dyspnea was evaluated as a BORG-VAS/FEV(1) slope before and after the broncho-reversibility test and correlated with the stage of asthma, inflammatory markers, age and depression scale. RESULTS: Dyspnea perception decreases with the worsening of asthma, with the advance of age and of depression status. Furthermore, airways inflammation plays a key role in the decline of dyspnea perception as proved by the negative correlation observed between inflammatory cells in sputum, exhaled pH and NO and BORG-VAS/FEV(1) slope. CONCLUSIONS: The results of our study suggested that airways inflammation, depression status, advance age and severity of asthma influence dyspnea perception and suggest a straight control to identify and better manage poor preceptor asthmatics. PMID- 20965712 TI - Beclomethasone/formoterol in the management of COPD: a randomised controlled trial. AB - OBJECTIVES: To evaluate the effect of beclomethasone/formoterol versus budesonide/formoterol (non-inferiority) and versus formoterol (superiority) in patients with severe stable chronic obstructive pulmonary disease (COPD). METHODS: A double-blind, double-dummy, randomised, active-controlled, parallel group study. After 4 weeks run-in with ipratropium/salbutamol (40/200 MUg, three times daily) patients were randomised to receive beclomethasone/formoterol (200/12 MUg pressurised metered dose inhaler), budesonide/formoterol (400/12 MUg dry powder inhaler) or formoterol (12 MUg dry powder inhaler) twice daily for 48 weeks. Co-primary efficacy variables were change from baseline to 48 weeks in pre dose morning forced expiratory volume in 1 s (FEV(1)) and mean rate of COPD exacerbations. RESULTS: Of 718 patients randomised, 703 (232 beclomethasone/formoterol, 238 budesonide/formoterol, 233 formoterol) were in the ITT analysis. Improvement in pre-dose morning FEV(1) was 0.077 L, 0.080 L and 0.026 L for beclomethasone/formoterol, budesonide/formoterol and formoterol respectively (LS mean from the ANCOVA model). Beclomethasone/formoterol was not inferior to budesonide/formoterol (95% CI of the difference -0.052, 0.048) and superior to formoterol (p = 0.046). The overall rate of COPD exacerbations/patient/year was similar and not statistically significantly different among treatments (beclomethasone/formoterol 0.414, budesonide/formoterol 0.423 and formoterol 0.431). Quality of life and COPD symptoms improved in all groups and use of rescue medication decreased. Safety profiles were as expected and treatments well-tolerated. CONCLUSIONS: Beclomethasone/formoterol (400/24 MUg) treatment for 48 weeks improved pulmonary function, reduced symptoms compared to formoterol, was safe and well-tolerated in patients with severe stable COPD. Neither of the long-acting beta2 agonist/inhaled corticosteroid combinations affected the low exacerbation rate seen in this population. PMID- 20965713 TI - Activated AMPK and prostaglandins are involved in the response to conjugated linoleic acid and are sufficient to cause lipid reductions in adipocytes. AB - trans-10, cis-12 Conjugated linoleic acid (t10c12 CLA) reduces triglyceride levels in adipocytes. AMP-activated protein kinase (AMPK) and inflammation were recently demonstrated to be involved in the emerging pathways regulating this response. This study further investigated the role of AMPK and inflammation by testing the following hypotheses: (1) a moderate activation of AMPK and an inflammatory response are sufficient to reduce triglycerides, and (2) strong activation of AMPK is also sufficient. Experiments were performed by adding compounds that affect these pathways and by measuring their effects in 3T3-L1 adipocytes. A comparison of four AMPK activators (metformin, phenformin, TNF alpha and t10c12 CLA) found a correlation between AMPK activity and triglyceride reduction. This correlation appeared to be modulated by the level of cyclo oxygenase (COX)-2 mRNA produced. Inhibitors of the prostaglandin (PG) biosynthetic pathway interfered with t10c12 CLA's ability to reduce triglycerides. A combination of metformin and PGH2, or phenformin alone, efficiently reduced triglyceride levels in adipocytes. Microarray analysis indicated that the transcriptional responses to phenformin or t10c12 CLA were very similar, suggesting similar pathways were activated. 3T3-L1 fibroblasts were found to weakly induce the integrated stress response (ISR) in response to phenformin or t10c12 CLA and to respond robustly as they differentiated into adipocytes. This indicated that both chemicals required adipocytes at the same stage of differentiation to be competent for this response. These results support the above hypotheses and suggest compounds that moderately activate AMPK and increase PG levels or robustly activate AMPK in adipocytes may be beneficial for reducing adiposity. PMID- 20965714 TI - Evolution of organic matter during composting of different organic wastes assessed by CPMAS 13C NMR spectroscopy. AB - In this paper, the evolution of organic matter (OM) during composting of different mixtures of various organic wastes was assessed by means of chemical analyses and CPMAS (13)C NMR spectroscopy measured during composting. The trends of temperatures and C/N ratios supported the correct evolution of the processes. The CPMAS (13)C NMR spectra of all composting substrates indicated a reduction in carbohydrates and an increase in aromatic, phenolic, carboxylic and carbonylic C which suggested a preference by microorganisms for easily degradable C molecules. The presence of hardly degradable pine needles in one of the substrates accounted for the lowest increase in alkyl C and the lowest reduction in carbohydrates and carboxyl C as opposite to another substrate characterized by the presence of a highly degradable material such as spent yeast from beer production, which showed the highest increase of the alkyl C/O-alkyl C ratio. The highest increase of COOH deriving by the oxidative degradation of cellulose was shown by a substrate composed by about 50% of plant residues. The smallest increases in alkyl C/O alkyl C ratio and in polysaccharides were associated to the degradation of proteins and lipids which are major components of sewage sludge. Results obtained were related to the different composition of fresh organic substrates and provided evidence of different OM evolution patterns as a function of the initial substrate composition. PMID- 20965715 TI - DNA biosensors based on water-soluble conjugated polymers. AB - Conjugated polymers (CPs) with large, delocalised molecular structures exhibit unique optical and electrochemical characteristics that can be used as excellent sensing elements. Recently, research on chemical and biological sensors that use water-soluble CPs as transducers has generated intense interest. Two main sensing mechanisms are used for the detection of DNA-related events, such as hybridisation, mismatch, single nucleotide polymorphism (SNP), SNP genotyping, conformational changes, and cleavage of the nucleic acids. One mechanism takes advantage of the fluorescence resonance energy transfer (FRET) between CPs and a chromophore label on the nucleic acid probes in which a series of cationic polyfluorene, polythiophene and polyarylene derivatives are frequently used. The other mechanism relies on the conformational effects of CPs, which is induced by combination of the specific targets in which cationic polythiophene derivatives are often used. The electron transfer property of CPs are always used to design high sensitive electrochemical DNA biosensors. Here we review recent progress in the development of optical and electrochemical DNA biosensors based on water soluble CPs. PMID- 20965717 TI - Blockade of CXCR4 in oral squamous cell carcinoma inhibits lymph node metastases. AB - We have previously demonstrated that a stromal cell-derived factor-1 (SDF-1; CXCL12)/CXCR4 system is involved in the establishment of lymph node metastasis in oral squamous cell carcinoma (OSCC). In this study, we investigated whether the blockade of CXCR4 inhibits lymph node metastasis in B88 OSCC cells. These cells harbour a functional CXCR4 and have the potential to metastasise to the lymph node in vivo. Following introduction of a vector that expresses short hairpin small interfering RNA (shRNA) against CXCR4, we isolated three clones (shCXCR4 16, -17 and -21) that showed decreased expression of CXCR4 mRNA. These clones also had reduced CXCR4 protein levels and showed impairments in calcium flux and cell migration in response to SDF-1. These cells were orthotopically inoculated into the masseter muscle of nude mice. Lymph node metastases, loss in body weight and tumour volumes were significantly inhibited in mice inoculated with shCXCR4 17 cells compared to mice inoculated with control cells. SDF-1-induced migration of B88 cells was significantly inhibited in vitro by the treatment with 1,1'-[1,4 phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD3100), a CXCR4 antagonist. Subcutaneous administration of AMD3100 significantly inhibited the lymph node metastases of B88 cells when they were orthotopically inoculated into the masseter muscle of nude mice. Moreover, the enhanced production of interleukin (IL)-6 and IL-8 in response to SDF-1 was inhibited by shRNA against CXCR4 or by treatment with AMD3100. These results suggest that blockade of CXCR4 may be a potent anti-metastatic therapy against lymph node metastases in cases of CXCR4-related OSCC. PMID- 20965716 TI - A self referencing platinum nanoparticle decorated enzyme-based microbiosensor for real time measurement of physiological glucose transport. AB - Glucose is the central molecule in many biochemical pathways, and numerous approaches have been developed for fabricating micro biosensors designed to measure glucose concentration in/near cells and/or tissues. An inherent problem for microsensors used in physiological studies is a low signal-to-noise ratio, which is further complicated by concentration drift due to the metabolic activity of cells. A microsensor technique designed to filter extraneous electrical noise and provide direct quantification of active membrane transport is known as self referencing. Self-referencing involves oscillation of a single microsensor via computer-controlled stepper motors within a stable gradient formed near cells/tissues (i.e., within the concentration boundary layer). The non-invasive technique provides direct measurement of trans-membrane (or trans-tissue) analyte flux. A glucose micro biosensor was fabricated using deposition of nanomaterials (platinum black, multiwalled carbon nanotubes, Nafion) and glucose oxidase on a platinum/iridium microelectrode. The highly sensitive/selective biosensor was used in the self-referencing modality for cell/tissue physiological transport studies. Detailed analysis of signal drift/noise filtering via phase sensitive detection (including a post-measurement analytical technique) are provided. Using this highly sensitive technique, physiological glucose uptake is demonstrated in a wide range of metabolic and pharmacological studies. Use of this technique is demonstrated for cancer cell physiology, bioenergetics, diabetes, and microbial biofilm physiology. This robust and versatile biosensor technique will provide much insight into biological transport in biomedical, environmental, and agricultural research applications. PMID- 20965719 TI - PAM fluorometry as a tool to assess microalgal nutrient stress and monitor cellular neutral lipids. AB - This study investigated the use of Pulse Amplitude Modulated (PAM) fluorometry to measure nutrient induced physiological stress and subsequent synthesis of cellular neutral lipids. A freshwater Chlorella sp. was subjected to complete nutrient stress (distilled H2O) and selective nutrient stress in modified BG-11 media (BG-11-N, BG-11-P and BG-11-Fe). Physiological stress was recorded using parameters, rETR, Fv/Fm, Ek, alpha and NPQ. Induced stress became evident when these parameters were significantly altered, suggesting the onset of neutral lipid synthesis. Complete nutrient stress induced the highest yield of cellular neutral lipids (~49%) compared to absence of selected nutrients (~30%). Physiological stress was recorded by a significant decrease in rETR (75%), Fv/Fm (36%), and Ek (60%) and an increase in NPQ (83%). Optimization of neutral lipids occurred by initially maximizing the biomass and subsequently subjecting the harvested biomass to complete nutrient stress. PMID- 20965718 TI - Genetic variability of the fatty acid synthase pathway is not associated with prostate cancer risk in the European Prospective Investigation on Cancer (EPIC). AB - A western lifestyle, characterised by low rates of energy expenditure and a high energy diet rich in animal protein, saturated fats and refined carbohydrates, is associated with high incidence of prostate cancer in men. A high-energy nutritional status results in insulin/IGF signalling in cells, which in turn stimulates synthesis of fatty acids. We investigated whether the genetic variability of the genes belonging to the fatty acid synthesis pathway is related to prostate cancer risk in 815 prostate cancer cases and 1266 controls from the European Prospective Investigation on Cancer (EPIC). Using a tagging approach and selecting 252 SNPs in 22 genes, we covered all the common genetic variation of this pathway. None of the SNPs reached statistical significance after adjusting for multiple comparisons. Common SNPs in the fatty acid synthase pathway are not major contributors to prostate cancer risk. PMID- 20965720 TI - Immobilization of penicillin G acylase on macro-mesoporous silica spheres. AB - In this study, macro-mesoporous silica spheres were prepared with a micro-device and used as the support for the immobilization of penicillin G acylase (PGA). To measure the enzymatic activity, the silica spheres with immobilized PGA were placed into a packed-bed reactor, in which the hydrolysis of penicillin G was carried out. The influences of the residence time, the initial concentration of the substrate, the accumulation of the target product 6-aminopenicillanic acid, and the enzyme loading amount on the performance of the immobilized PGA were investigated. The introduction of macropores increased the enzyme loading amount and decreased the internal mass transfer resistance, and the results showed that the enzyme loading amount reached 895 mg/g (dry support), and the apparent enzymatic activity achieved up to 1033 U/g (dry support). In addition, the immobilized PGA was found to have great stability. PMID- 20965721 TI - Evaluation of bacterial surfactant toxicity towards petroleum degrading microorganisms. AB - The acute toxicity of bacterial surfactants LBBMA111A, LBBMA155, LBBMA168, LBBMA191 and LBBMA201 and the synthetic surfactant sodium dodecyl sulfate (SDS) on the bioluminescent bacterium Vibrio fischeri was evaluated by measuring the reduction of light emission (EC(20)) by this microorganism when exposed to different surfactant concentrations. Moreover, the toxic effects of different concentrations of biological and synthetic surfactants on the growth of pure cultures of isolates Acinetobacter baumannii LBBMA04, Acinetobacter junni LBBMA36, Pseudomonas sp. LBBMA101B and Acinetobacter baumanni LBBMAES11 were evaluated in mineral medium supplemented with glucose. The EC(20) values obtained confirmed that the biosurfactants have a significantly lower toxicity to V. fischeri than the SDS. After 30 min of exposure, bacterial luminescence was almost completely inhibited by SDS at a concentration of 4710 mg L(-1). Growth reduction of pure bacterial cultures caused by the addition of biosurfactants to the growth medium was lower than that caused by SDS. PMID- 20965722 TI - Use of cloth-media filter for membrane bioreactor treating municipal wastewater. AB - This study evaluated three different textile materials (Acrylate, Polyester, and Nylon) as filter media for MBR treating municipal wastewater. Chemical oxygen demand (COD) loading rates were 1.71, 1.65 and 1.84 g/l d while feed/microorganisms (F/M) ratios were 0.32, 0.31 and 0.33 in Reactor 1, Reactor 2 and Reactor 3, respectively. The actual hydraulic retention times were 8.6, 8.9 and 8.0 h in R1, R2 and R3. At 5.3-5.5 g/l mixed liquor suspended (MLSS) and 26.3 days solid retention time (SRT) the membrane bioreactors were effective in removing 93-95% of COD, 99% of total suspended solids (TSS) and turbidity, 89-94% of total kjeldahl nitrogen (TKN) and 90-96% of total ammonia nitrogen. Phosphorous removal was limited to 51-55% while faecal coliform was reduced by four logs. Quality of the treated effluents met both Saudi and Egyptian reuse standards for restricted irrigation and could be easily disinfected to meet the unrestricted irrigation standards. PMID- 20965723 TI - Biarylimidazoles as inhibitors of microsomal prostaglandin E2 synthase-1. AB - Microsomal prostaglandin E(2) synthase (mPGES-1) represents a potential target for novel analgesic and anti-inflammatory agents. High-throughput screening identified several leads of mPGES-1 inhibitors which were further optimized for potency and selectivity. A series of inhibitors bearing a biaryl imidazole scaffold exhibits excellent inhibition of PGE(2) production in enzymatic and cell based assays. The synthesis of these molecules and their activities will be discussed. PMID- 20965724 TI - Identification of potent ITK inhibitors through focused compound library design including structural information. AB - A series of novel compound libraries inhibiting interleukin-2 inducible T cell kinase (ITK) were designed, synthesized and evaluated. In the first design cycle two library scaffolds were identified showing low micromolar inhibition of ITK. Further iterative design cycles including crystal structure information of ITK and structurally related kinases led to the identification of indolylindazole and indolylpyrazolopyridine compounds with low nanomolar ITK inhibition. PMID- 20965725 TI - Synthesis, antiviral and contraceptive activities of nucleoside-sodium cellulose sulfate acetate and succinate conjugates. AB - Chemical conjugates between sodium cellulose sulfate (CS), displaying contraceptive and HIV-entry inhibiting properties, and nucleoside reverse transcriptase inhibitors (NRTIs) (3'-azido-2',3'-dideoxythymidine (AZT), 3' fluoro-2',3'-dideoxythymidine (FLT), or 2',3'-dideoxy-3'-thiacytidine (3TC)) were designed to simultaneously provide contraceptive and anti-HIV activity. Two linkers, acetate and succinate, were used to conjugate the nucleoside analogs with CS. The conjugates containing cellulose sulfate-acetate (CSA) (e.g., AZT-CSA and FLT-CSA) were found to be more potent than CS and other conjugates (e.g., AZT succinate-CS, and FLT-succinate-CS). The presence of both sulfate and the acetate groups on cellulose were critical for generating maximum anti-HIV activity. In addition to showing equal potency against wild-type and multidrug resistant HIV 1, the AZT-CSA conjugate displayed significant contraceptive activity in an animal model, providing the initial proof-of-concept for the design and synthesis of dual-activity compounds based on these combinations. PMID- 20965726 TI - 5-benzyloxytryptamine as an antagonist of TRPM8. AB - 5-Benzyloxytryptamine 19 was found to act as an antagonist of the TRPM8 ion channel. For example, 19 had an IC(50) of 0.34 MUM when menthol was used as the stimulating agonist. Related commercially-available tryptamine derivatives showed diminished, or no antagonist activity at TRPM8. The structural similarity of 5 benzyloxytryptamine to other literature TRPM8 antagonists was noted. PMID- 20965728 TI - Repeatability of a multi-segment foot protocol in adult subjects. AB - Despite the numerous protocols for multi-segment kinematic analysis of the foot, the literature is scarce regarding relevant measures of reliability. The aim of the present work was to assess the inter-trial, inter-session and inter-examiner variability of one of these protocols by an established method. The kinematics of the joints of the foot of two volunteers were analyzed by four examiners with different degrees of experience in three sessions, two-to-four weeks apart. In each session the data of five trials of level walking were collected and the rotations in the three anatomical planes between foot segments were calculated. The mean value over stance phase duration of the standard deviation of these rotations was calculated for groups of trials according to the statistical method as in Schwartz et al. [6]. For each rotation, the inter-examiner variability was larger than the inter-session, and the latter larger than the inter-trial. The inter-session variability was found in the same order of magnitude for standard lower limb protocols for the two expert examiners, but much higher for the inexperienced examiners. PMID- 20965727 TI - Engineered materials and the cellular microenvironment: a strengthening interface between cell biology and bioengineering. AB - Cells constantly probe and respond to a myriad of cues that are present in their local surroundings. The effects of soluble cues are relatively straightforward to manipulate, yet teasing apart how cells transduce signals from the extracellular matrix and neighboring cells has proven to be challenging due to the spatially and mechanically complex adhesive interactions. Over the years, advances in the engineering of biocompatible materials have enabled innovative ways to study adhesion-mediated cell functions, and numerous insights have elucidated the significance of the cellular microenvironment. Here, we highlight some of the major approaches and discuss the potential for future advancement. PMID- 20965729 TI - Endocytosis of HIV: anything goes. AB - The major pathway for HIV internalization in CD4+ T cells has been thought to be the direct fusion of virus and cell membranes, because the cell surface is the point of entry of infectious particles. However, the exact contribution of endocytic pathways to the infection of CD4+ T lymphocytes is unknown, and the mechanisms involved in endocytosis of HIV particles are unclear. Recent evidence suggests that endocytosis of cell-free and cell-associated virus particles could lead to effective virus entry and productive infections. Such observations have, in turn, spurred a debate on the relevance of endosomal entry as a mechanism of escape from the immune system and HIV entry inhibitors. In this paper, we review the endocytosis of HIV and discuss its role in HIV infection and pathogenesis. PMID- 20965730 TI - Melanoma of the sellar region. AB - Metastatic melanoma has a propensity for multiple intra cranial deposits. Rarely, metastatic melanoma to the pituitary gland has been reported, usually in conjunction with widespread systemic metastases. We describe a patient with metastatic melanoma to the pituitary gland as the first clinical presentation of widespread metastatic disease and review the relevant literature. PMID- 20965731 TI - Expression of AQP1 and AQP4 in paediatric brain tumours. AB - Aquaporins (AQP) are water-channel proteins with roles in tumour cell migration, angiogenesis, cerebral oedema and cell-cell adhesion. We aimed to determine the expression of AQP1 and AQP4 in paediatric brain tumours. Twenty tumour bank specimens were subject to Western blot analysis and quantitative polymerase chain reaction (PCR) to determine the expression of AQP1 and 4. Immunohistochemical staining was used to determine the distribution of AQP1 and 4 expression. Medulloblastomas, primitive neuroectodermal tumour, germinomas and higher grade gliomas did not express AQP1 and 4. Of the ependymomas, those in the posterior fossa all demonstrated markedly increased expression of AQP1 and 4. A supratentorial ependymoma demonstrated a moderate increase in AQP1 but not AQP4. Pilocytic astrocytomas demonstrated high levels of AQP1 and 4 but had a more variable pattern of staining. AQP1 and 4 have relevance to paediatric brain tumours and are worthy of further investigation in developing potential therapeutic strategies. PMID- 20965732 TI - Contralateral femoral nerve compression: An unrecognized complication after extreme lateral interbody fusion (XLIF). AB - Extreme lateral interbody fusion (XLIF) is a relatively new procedure for the treatment of degenerative disc disease avoiding the morbidity of anterior approaches. Ipsilateral L2-5 nerve root irritation and injury are well-described complications. We describe two patients with contralateral extremity symptoms, not reported so far. In the first patient the injury was caused by a displaced endplate fragment compressing the contralateral nerve root; in the second patient, the injury resulted from a far-lateral herniation after the XLIF procedure. Both patients experienced resolution of their symptoms after being reoperated. Overall, this complication was encountered in 2/32 levels treated during the study period. Overzealous endplate removal and breaking of the osteophytes in the opposite corner of the intervertebral disc, although desirable for maximal coronal deformity correction, may lead to irritation of the contralateral nerve roots. Attention is needed especially where the interbody cage is placed posteriorly or diagonally towards the neuralforamen. PMID- 20965734 TI - Complex visual hallucinations as a presentation of temporal low-grade glioma. AB - We report a patient with an unusual presentation of a temporal low-grade glioma with visual symptoms of formed, coloured meaningful images without coexistent psychiatric symptoms or epileptiform activity consistent with a diagnosis of visual hallucinosis. The location and extent of the lesion on the MRI differs from the lesions commonly associated with this diagnosis. PMID- 20965735 TI - Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists. AB - A series of chiral non-racemic dexoxadrol analogues with various substituents in position 4 of the piperidine ring was synthesized and pharmacologically evaluated. Only the enantiomers having (S)-configuration at the 2-position of the piperidine ring and 4-position of the dioxolane ring were considered. Key steps in the synthesis were an imino-Diels-Alder reaction of enantiomerically pure imine (S)-13, which had been obtained from d-mannitol, with Danishefsky's Diene 14 and the replacement of the p-methoxybenzyl protective group with a Cbz-group. It was shown that (S,S)-configuration of the ring junction (position 2 of the piperidine ring and position 4 of the dioxolane ring) and axial orientation of the C-4-substituent ((4S)-configuration) are crucial for high NMDA receptor affinity. 2-(2,2-Diphenyl-1,3-dioxolan-4-yl)piperidines with a hydroxy moiety ((S,S,S)-5, K(i)=28nM), a fluorine atom ((S,S,S)-6, WMS-2539, K(i)=7nM) and two fluorine atoms ((S,S)-7, K(i)=48nM) in position 4 represent the most potent NMDA antagonists with high selectivity against sigma(1) and sigma(2) receptors and the polyamine binding site of the NMDA receptor. The NMDA receptor affinities of the new ligands were correlated with their electrostatic potentials, calculated gas phase proton affinities (negative enthalpies of deprotonation) and dipole moments. According to these calculations decreasing proton affinity and increasing dipole moment are correlated with decreasing NMDA receptor affinity. PMID- 20965736 TI - Synthesis and antioxidant properties of pulvinic acids analogues. AB - The synthesis of three types of pulvinic acid analogues, using a diversity oriented strategy starting from a single compound, dimethyl l-tartrate, is described. Lacey-Dieckmann condensation, alcohol dehydration and Suzuki-Miyaura cross-couplings were employed in the course of the analogues syntheses. The evaluation of the antioxidant properties of the 28 synthesized analogues was carried out using antioxidant capacity assays (protection of thymidine and beta carotene) and free radical scavenging assays (DPPH radical and ABTS radical cation). This allowed to assess the relative influence of the groups bonded to the tetronic ring and to the exocyclic double bond on the activity, as well as the importance of this exocyclic double bond. It was shown that the presence of an electron-donating group on the 3-position of the tetronic ring had a beneficial effect. It was shown in several assays that the presence of the exocyclic bond was not crucial to the activity. PMID- 20965737 TI - Structure-activity relationships of benzimidazole-based selective inhibitors of the mitogen activated kinase-5 signaling pathway. AB - In a prior communication we identified a novel class of benzimidazole-based inhibitors of EGF-induced phosphorylation of ERK5. In this paper we examine the biological activity of several 1-isopropyl-4-amino-6-ether linked benzimidazole based compounds for their ability to selectively inhibit EGF-mediated ERK5 phosphorylation; potential utility of variation at the 6-position was indicated by the initial structural feature survey. Modification of EGF-induced formation of pERK1/2 and pERK5 in HEK293 cells were analyzed by Western blot analysis. Subsequent analysis of selected compounds in a high-throughput multiple kinase scan and the NCI 60-cell-line screen is presented. PMID- 20965738 TI - Discovery and biological evaluation of potent, selective, orally bioavailable, pyrazine-based blockers of the Na(v)1.8 sodium channel with efficacy in a model of neuropathic pain. AB - Na(v)1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons. It has been implicated in the pathophysiology of inflammatory and neuropathic pain, and we envisioned that selective blockade of Na(v)1.8 would be analgesic, while reducing adverse events typically associated with non-selective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 6-aryl-2-pyrazinecarboxamides, which are potent blockers of the human Na(v)1.8 channel and also block TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons. Selected derivatives display selectivity versus human Na(v)1.2. We further demonstrate that an example from this series is orally bioavailable and produces antinociceptive activity in vivo in a rodent model of neuropathic pain following oral administration. PMID- 20965739 TI - Conformationally constrained NR2B selective NMDA receptor antagonists derived from ifenprodil: Synthesis and biological evaluation of tetrahydro-3-benzazepine 1,7-diols. AB - NR2B selective NMDA receptor antagonists with tetrahydro-3-benzazepine-1,7-diol scaffold have been designed by formal cleavage and reconstitution of the piperidine ring of the lead compound ifenprodil (1). The secondary amine 10 represents the central building block for the synthesis of more than 25 tetrahydro-3-benzazepin-1-ols. Generally 7-hydroxy derivatives display higher NR2B receptor affinities than the corresponding 7-benzyloxy compounds. A distance of four atoms (five bond lengths) between the basic amino group and the terminal aryl moiety led to highest NR2B affinity. 3-(4-Phenylbutyl)-2,3,4,5-tetrahydro-1H 3-benzazepine-1,7-diol (WMS-1410, 25) represents the most promising NR2B antagonist of this series showing a K(i)-value of 14nM. Compound 25 reveals excellent selectivity over more than 100 further relevant target proteins, antagonizes glutamate induced excitotoxicity (IC(50)=18.4nM) and is metabolically more stable than ifenprodil. Up to a dose of 100mg/kg 25 is well tolerated by mice and it shows dose dependent analgesic activity in the late neuropathic pain phase of the formalin assay. PMID- 20965740 TI - The electron beam irradiation damage on nanomaterials synthesized by hydrothermal and thermal evaporation methods--an example of ZnS nanostructures. AB - Using transmission electron microscopy-related techniques, we have compared the degradation behaviors of several different types of ZnS nanostructures, including the ZnS nanosheets synthesized by hydrothermal method (with different oxygen impurity concentration) and ZnS nanobelts grown using thermal evaporation. We have identified that displacement damage, sputtering, and oxidation mechanisms exist during the electron irradiation process. While oxidation of the nanostructure is always observed, displacement damage appears to be the dominant mechanism contributing to the final structural collapse of ZnS nanosheets (synthesized via hydrothermal methods), but sputtering mechanism becomes critical in changing the surface roughness of the ZnS nanobelts (grown by thermal evaporation). The specific damage mechanisms of these nanomaterials disclose that different synthesis process results in different structure quality (particularly impurity related interior defects) of the ZnS nanostructures, which determines their specific degradation behaviors under the electron beam irradiation. PMID- 20965741 TI - Automated radiochemical synthesis of [18F]FBEM: a thiol reactive synthon for radiofluorination of peptides and proteins. AB - The automated radiochemical synthesis of N-[2-(4 [(18)F]fluorobenzamido)ethyl]maleimide ([(18)F]FBEM, IUPAC name: N-maleoylethyl-4 [(18)F]fluorobenzamide), a prosthetic group for radiolabeling the free sulfhydryl groups of peptides and proteins, is herein described. 4-[(18)F]fluorobenzoic acid was first prepared by nucleophilic displacement of a trimethylammonium moiety on a pentamethylbenzyl benzoate ester with [(18)F]fluoride. In the second step the ester was cleaved under acidic conditions. Finally, 4-[(18)F]fluorobenzoic acid was coupled to N-(2-aminoethyl)maleimide using diethylcyanophosphate and diisopropylethyl amine. Following high-performance liquid chromatography (HPLC) purification, [(18)F]FBEM was obtained in 17.3+/-7.1% yield (not decay corrected) in approximately 95 min. Isolation from the HPLC eluate and preparation for subsequent use, which was conducted manually, required an additional 10-15 min. The measured specific activity for three batches was 181.3, 251.6, and 351.5 GBq/MUmol at the end of bombardment (EOB). PMID- 20965742 TI - Editorial comment: primary major airway tumors; management and results. PMID- 20965743 TI - Photochemical and phototoxic properties of ethyl 1,4-dihydro-8-nitro-4 oxoquinoline-3-carboxylate, a new quinoline derivative. AB - The present study demonstrates photoinduced generation of superoxide radical anion and singlet oxygen upon UVA irradiation of ethyl 1,4-dihydro-8-nitro-4 oxoquinoline-3-carboxylate (DNQC), and its cytotoxic/phototoxic effects on murine leukemia L1210 cells. The formation of reactive oxygen species (ROS) was investigated by EPR spectroscopy using in situ spin trapping technique and 4 hydroxy-2,2,6,6-piperidine (TMP) for singlet oxygen ((1)O(2)) detection. The EPR spectra monitored upon photoexcitation of aerated solutions of DNQC in dimethylsulfoxide evidenced the efficient activation of molecular oxygen via Types I and II mechanisms. The cytotoxic/phototoxic effects of DNQC, analysis of cell cycle, induction of apoptosis/necrosis, DNA damage and molecular mechanism of apoptotic death of L1210 cells in dark and in the presence of UVA irradiation were compared. DNQC induced a different cytotoxic/phototoxic effect, which was concentration- and time-dependent. The four highest tested concentrations of non photoactivated and photoactivated DNQC induced immediate cytotoxic/phototoxic effect after 24h cultivation of L1210 cells. This effect decreased with the time of treatment. The irradiation increased the sensitivity of leukemia cell line on DNQC, but the cell sensitivity decreased with time of processing. Quinolone derivative DNQC significantly induced direct DNA strand breaks in L1210 cells, which were increased with the irradiation of cells. The DNA damage generated by DNQC alone/with combination of UVA irradiation induced cell arrest in G(0)/G(1) and G(2)/M phases, decrease in the number of L1210 cells in Sphase and apoptotic cell death of certain part of cell population after 24 h of influence. DNQC alone/with combination of UVA irradiation induced apoptosis in L1210 cells through ROS-dependent mitochondrial pathway. PMID- 20965744 TI - Antibacterial activity of anthraquinone derivatives from Heterophyllaea pustulata (Rubiaceae). AB - Photosensitizing anthraquinones isolated from Heterophyllaea pustulata Hook f. (Rubiaceae), namely soranjidiol, rubiadin, damnacanthal and 5,5'-bisoranjidiol, showed antibacterial activity (bacteriostatic/bactericide) on Staphylococcus aureus. The mechanism of action seems to involve an increase in the levels of superoxide anion (O(2)(.-)) and/or singlet molecular oxygen ((1)O(2)). Moreover, the effect of actinic irradiation as a boosting agent for the production of both reactive species of oxygen as well as its influence on antibacterial activity was assessed. The routine susceptibility assay (minimum inhibitory concentration determination) was carried out by means of the broth macrodilution method. Bactericide activity was determined counting the colony-forming units per milliliter (cfu/mL) in plate. The O(2)(.-) production was determined by means of an indirect photobiological assay (Nitroblue Tetrazolium test), and the production of (1)O(2) was followed using an indirect steady-state method, with methionine as the (1)O(2) chemical quencher. PMID- 20965745 TI - Nasopharyngeal cancer around the Mediterranean area: role of newer radiation techniques. AB - Primary radiotherapy has been the mainstay of treatment of patients with nondisseminated nasopharyngeal cancer (NPC). Novel techniques, such as intensity modulated and image guided radiotherapy has the capability to generate steep dose gradients, leading to an improved therapeutic index, especially in NPC. Although it is widely accepted as the treatment of choice in NPC in the modern world, in developing countries the financing of these innovative delivery systems still continues to be a major problem. The purpose of this article is to discuss the difficulties one may experience during the transition from 2D way of thinking to the 3D conformal era and to review the clinical outcome and toxicity profile of these promising new radiation techniques. PMID- 20965746 TI - Effectiveness of Brucella abortus lipopolysaccharide as an adjuvant for tuberculin PPD. AB - Bacterial lipopolysaccharide (LPS) has T-helper 1 (Th1) immunostimulatory activities but because of toxicity and pyrogenicity cannot be used as an adjuvant. Brucella abortus LPS has less toxicity and no pyrogenic properties in comparison to other bacterial LPS. In the current study, the immunostimulatory properties of B. abortus LPS were evaluated for its adjuvant activity. Tuberculin purified protein derivative (PPD) from Mycobacterium tuberculosis was extracted and after anion-exchange chromatography on Q-sepharose column, two fractions (17 and 23), which dominantly contained 30- and 70-kDa antigens, were collected for immunological studies. BALB/c mice were immunized with four different antigen preparations (BCG, PPD, 17th and 23rd PPD fractions) along with complete Freund's adjuvant or B. abortus LPS. The T-cell immune response of mice was assessed by measurement of Th1-type cytokine (IFN-gamma) and Th2-type cytokines (IL-5 and IL 10) levels. Also, the humoral immunity was evaluated by measuring the specific IgG levels. Our results showed that immunization of mice with 17th PPD fraction along with B. abortus LPS can induce a Th1-type cytokine response characterized with a high IFN-gamma/IL-5 ratio, while immunization with PPD or 23rd PPD fraction along with the same adjuvant resulted to a mixed Th1/Th2-type cytokine response. PMID- 20965747 TI - Effect of storage conditions on the stability of recombinant human MCP-1/CCL2. AB - Monocyte chemoattractant protein-1 (MCP-1) is commercially available in a form of recombinant protein. This makes it more convenient to study the functions of MCP 1 and its involvement in many cell functions. However, when using MCP-1 in experimental studies, if the analysis is not performed immediately, the stability of recombinant MCP-1 may become an issue. In this study, the stability of recombinant MCP-1 at different concentrations and storage conditions was investigated. Results show that no significant loss of MCP-1 is observed when MCP 1 solutions were stored at non-freezing condition (4 degrees C) for seven days. However, for storage at freezing conditions (-20 degrees C or -81 degrees C), it appears that the first freeze-thaw cycle may contribute to some loss of MCP-1 in the solutions, and such loss may be concentration and time dependent. The effect of multiple freeze-thaw cycles for storage at freezing conditions was also examined. Data reveal that the second freeze-thaw cycle causes approximately 50% loss of MCP-1 in the solutions. This finding confirms that multiple freeze-thaw cycles should be avoided. The findings of this study provide an outline of how storage can affect the stability of recombinant proteins and should be taken into account during the evaluation of the concentration of recombinant proteins. PMID- 20965748 TI - Mechanical valvular dysfunction detected by intraoperative transesophageal echocardiography after valvular replacement in patients with congenital heart disease. PMID- 20965749 TI - The sound of time: cross-modal convergence in the spatial structuring of time. AB - In a new integration, we show that the visual-spatial structuring of time converges with auditory-spatial left-right judgments for time-related words. In Experiment 1, participants placed past and future-related words respectively to the left and right of the midpoint on a horizontal line, reproducing earlier findings. In Experiment 2, neutral and time-related words were presented over headphones. Participants were asked to indicate whether words were louder on the left or right channel. On critical experimental trials, words were presented equally loud binaurally. As predicted, participants judged future words to be louder on the right channel more often than past-related words. Furthermore, there was a significant cross-modal overlap between the visual-spatial ordering (Experiment 1) and the auditory judgments (Experiment 2), which were continuously related. These findings provide support for the assumption that space and time have certain invariant properties that share a common structure across modalities. PMID- 20965750 TI - A mind to go out of: reflections on primary and secondary consciousness. AB - Dreaming and waking are two brain-mind states, which are characterized by shared and differentiated properties at the levels of brain and consciousness. As part of our effort to capitalize on a comparison of these two states we have applied Edelman's distinction between primary and secondary consciousness, which we link to dreaming and waking respectively. In this paper we examine the implications of this contrastive analysis for theories of mental illness. We conclude that while dreaming is an almost perfect model of organic psychosis, it is less so for schizophrenia and major affective disorder where it must serve a primarily heuristic role helping us to model hallucinations and delusions but not the diseases themselves. PMID- 20965751 TI - Creativity, vision, and survival. PMID- 20965752 TI - The rare t(5;11) with a new breakpoint in an adult with refractory acute lymphoblastic leukemia. PMID- 20965753 TI - N-methyl-D-aspartate receptor-mediated modulations of the anti-allodynic effects of 5-HT1B/1D receptor stimulation in a rat model of trigeminal neuropathic pain. AB - Previous studies showed that triptans and other 5-HT(1B/1D)-receptor agonists attenuate hyper-responsiveness to mechanical stimulation of the face in a rat model of trigeminal neuropathic pain, probably by activating 5-HT(1B/1D) receptors on primary afferent nociceptive fibers. We now tested whether blockade of post-synaptic receptors for the excitatory amino acid glutamate released by these fibers would increase this action. We thus evaluated whether (+/-)1-hydroxy 3-aminopyrrolidine-2-one (HA-966), an antagonist at the glycine/D-serine site of N-methyl-D-aspartate (NMDA)-receptors, would potentiate the anti-allodynic action of dihydroergotamine and zolmitriptan in rats with chronic constriction injury to the infraorbital nerve (CCI-ION). Complementary studies were performed with other NMDA-receptor ligands and in rats with chronic constriction injury to the sciatic nerve (CCI-SN) for comparison. Injury was produced by loose ligatures of the nerves. Responsiveness to mechanical stimulation (vibrissae or hindpaw territories) with von Frey filaments was used to evaluate allodynia 2 weeks after nerve ligature. Rats received NMDA-receptor ligands or saline 20 min before dihydroergotamine (25-100 MUg/kg, i.v.) or zolmitriptan (25-100 MUg/kg, s.c.). HA 966 (2.5mg/kg, s.c.), inactive on its own, enhanced the anti-allodynic effects of dihydroergotamine (eightfold increase) and zolmitriptan (threefold increase) in CCI-ION rats, but these drugs exerted no effects in allodynic CCI-SN rats. NMDA receptor blockade by memantine (5mg/kg, i.p.) also enhanced, whereas activation at glycine/NMDA site by D-cycloserine (3mg/kg, i.p.) reduced the anti-allodynic properties of zolmitriptan in CCI-ION rats. Combined administration of NMDA receptor antagonist and 5-HT(1B/1D)-receptor agonist may be a promising approach for alleviating trigeminal neuropathic pain. PMID- 20965754 TI - A novel rat forelimb model of neuropathic pain produced by partial injury of the median and ulnar nerves. AB - The vast majority of human peripheral nerve injuries occur in the upper limb, whereas the most animal studies have been conducted using the hindlimb models of neuropathic pain, involving damages of the sciatic or lumbar spinal nerve(s). We attempted to develop a rat forelimb model of peripheral neuropathy by partial injury of the median and ulnar nerves. The halves of each nerve were transected by microscissors at about 5mm proximal from the elbow joint and behavioral signs of neuropathic pain, such as mechanical and cold allodynia, and heat hyperalgesia, were monitored up to 126 days following nerve injury. Mechanical allodynia was assessed by measuring the forepaw withdrawal threshold to von Frey filaments, and cold allodynia was evaluated by measuring the time spent in lifting or licking the forepaw after applying acetone to it. Heat hyperalgesia was also monitored by investigating the forepaw withdrawal latencies using the Hargreaves' test. After the nerve injury, the experimental animals exhibited long lasting clear neuropathic pain-like behaviors, such as reduced forepaw withdrawal threshold to von Frey filaments, the increased response duration of the forepaw to acetone application, and the decreased withdrawal latency to radiant heat stimulation. These behaviors were significantly alleviated by administration of gabapentin (5 or 50mg/kg, i.p.) in a dose-dependent manner. Therefore, these abnormal sensitivities are interpreted as the signs of neuropathic pain following injury of the median and ulnar nerves. Our rat forelimb model of neuropathic pain may be useful for studying human neuropathic pain and screening for valuable drug candidates. PMID- 20965755 TI - Oral nitric-oxide donor glyceryl-trinitrate induces sensitization in spinal cord pain processing in migraineurs: a double-blind, placebo-controlled, cross-over study. AB - Nitric-oxide donor glyceryl-trinitrate (GTN) modulates cerebral and spinal regions that are involved in migraine and pain processing. We hypothesized that in migraineurs, the susceptibility to develop a migraine attack after GTN administration should parallel with an high sensitivity to GTN-induced change in the pain processing at spinal level. We used the temporal summation threshold (TST) of the lower limb nociceptive withdrawal reflex (NWR) and the related pain sensation to study in parallel the time-course of the effect of the GTN administration on the pain processing at spinal level in migraine and healthy subjects. Twenty-eight (21 F; 7M; mean age 34.2 +/- 8.2) migraine and 15 (11 F; 4M; mean age 35.9 +/- 8.9) healthy subjects were recruited in a double-blind, placebo-controlled, cross-over trial. Neurophysiological examinations were carried out before (baseline) and 30', 60', 120', 180' and 240' after GTN (0.9 mg sublingual) or placebo administration during two different sessions. In migraineurs, GTN administration was associated to a significant facilitation in temporal summation of pain (reduced TST and increased painful sensation) 60', 120' and 180' after drug intake when compared to baseline, to placebo condition and to controls after GTN intake. Furthermore, in migraineurs who developed migraine after GTN, a significant facilitation in temporal summation of pain was detected 60', 120' and 180' after drug intake when compared to patients without clinical response. In migraineurs the susceptibility to develop migraine attack after GTN administration seems to be a specific trait of a subgroup of patients linked to a supersensitivity of the pain system to GTN. PMID- 20965756 TI - Evaluation of various inverse docking schemes in multiple targets identification. AB - The lack of accurate and efficient methods for target identification has been the bottleneck in drug discovery. In recent years, inverse docking has been applied as an efficient method in target identification, and several specific inverse docking strategies have been employed in academic and industrial researches. However, the effectiveness of these docking strategies in multiple targets identification is unclear. In this study, five inverse docking schemes were evaluated to find out the most effective approach in multiple targets identification. A target database containing a highly qualified dataset that is composed of 1714 entries from 1594 known drug targets covering 18 biochemical functions was collected as a testing pool for inverse docking. The inverse docking engines including GOLD, FlexX, Tarfisdock and two in-house target search schemes TarSearch-X and TarSearch-M were evaluated by eight multiple target systems in the dataset. The results show that TarSearch-X is the most effective method in multiple targets identification and validation among these five schemes, and the effectiveness of GOLD in multiple targets identification is also acceptable. Moreover, these two inverse docking strategies will also be helpful in predicting the undesirable effects of drugs, such as toxicity. PMID- 20965757 TI - Prediction of protein-ligand binding affinities using multiple instance learning. AB - Accurate prediction of protein-ligand binding affinities for lead optimization in drug discovery remains an important and challenging problem on scoring functions for docking simulation. In this paper, we propose a data-driven approach that integrates multiple scoring functions to predict protein-ligand binding affinity directly. We then propose a new method called multiple instance regression based scoring (MIRS) that incorporates unbound ligand conformations using multiple scoring functions. We evaluated the predictive performance of MIRS using 100 protein-ligand complexes and their binding affinities. The experimental results showed that MIRS outperformed the 11 conventional scoring functions including LigScore, PLP, AutoDock, G-Score, D-Score, LUDI, F-Score, ChemScore, X-Score, PMF, and DrugScore. In addition, we confirmed that MIRS performed well on binding pose prediction. Our results reveal that it is indispensable to incorporate unbound ligand conformations in both binding affinity prediction and binding pose prediction. The proposed method will accelerate efficient lead optimization on structure-based drug design and provide a new direction to designing of new scoring score functions. PMID- 20965758 TI - 4-Hydroxybutyric aciduria associated with catheter usage: a diagnostic pitfall in the identification of SSADH deficiency. AB - Succinic semialdehyde dehydrogenase deficiency is a slowly progressive to static neurological disorder featuring elevated concentrations of 4-hydroxybutyric acid in body fluids. We present two patients with elevated 4-hydroxybutyric acid in urine which was later shown to be linked to catheter usage. PMID- 20965759 TI - ff1b, the SF1 ortholog, is important for pancreatic islet cell development in zebrafish. AB - The adrenal cortex and pancreatic islets have endocrine functions, producing steroid-based hormones and insulin, respectively. Cells of the adrenal cortex originate in the mesoderm while the cells of pancreatic islets originate in the endoderm. The zebrafish is a powerful model for understanding organ development due to its ease of genetic and molecular manipulation, transparent embryos, and large number of progeny for statistically powerful experiments. Like humans, the zebrafish pancreas has both exocrine and endocrine functions; unlike humans, there is only one endocrine islet cell group, instead of multiple islets. Using an eGFP-transgenic line of zebrafish, we have observed that the steroidogenic factor 1 (SF1) ortholog, ff1b, which is critical for adrenal cortex development and function in the zebrafish, is also implicated in zebrafish pancreatic islet development. We show that interruption of ff1b expression using an ff1b morpholino (MO) disrupts development of insulin expressing cells. We conclude that ff1b-MO alters pancreatic islet development in zebrafish, demonstrating the utility of the zebrafish as a model for studying pancreatic development. This work is consistent with previous studies in mouse and human that have suggested SF1 participates in the vascular and ductal development of the pancreas, and disruption of SF1 function leads to abnormal development of the pancreatic islets due to poor vascularization. PMID- 20965761 TI - [Adverse effects prevalence study: pressure ulcers in an acute hospital]. AB - OBJECTIVE: The pressure ulcers (PU) are one of the adverse effects associated with hospitalisation. The aims of this study are, to determine the prevalence of PU in patients admitted to a tertiary hospital, to describe the characteristics of the injuries, to find out the frequency of use of special surfaces for managing pressure (SSMP), and to establish lines of action for their prevention. METHOD: This is a cross-sectional study of adults patients admitted to hospital between May 11 and 15, 2009. Collected variables are: demographic data, number of PU, admission unit, risk level (measured by modified Gosnell's scale), stage, location, cause, origin of the injury and SSMP. RESULTS: A total of 683 patients were studied, of which 70 (10.3%) of them had at least one wound. The risk of developing PU in patients evaluated as high risk, is more than those patients evaluated as no or low risk (OR: 6.26; 95% CI; 3.54-11.08; p<0.001). Most of the wounds they were stage I (39.1%) and stage II (35.2%), located mostly in the heel and sacrum, and (83.8 %) of the PU were of hospital origin. Only 28.1% of the available SSMP were used. CONCLUSIONS: The overall percentage of PU is greater than that reported in other studies, but with less severe injuries. Patients at risk need to be identified and early preventive measures applied. In our hospital the use of SSMP is low in relation to the number of patients at risk. PMID- 20965762 TI - [Conceptual models; a power strategy with professional implications]. AB - Conceptual models and nursing theories are considered by some authors as standards that guide the thinking on how to be a nurse and practice nursing. Some authors defend that without the use of nursing models it could be difficult to improve the discipline and nursing practice, and even to transform a professional identity linked to submission, obedience and humility. The purpose of this article is not to argue about the truth or falseness, the usefulness, or not, of conceptual nursing models, but to analyse, from a post-structuralist perspective, their use as a power strategy exercised mainly by nurses since the 1970's in Spain and the unintentional professional implications of their adoption by the nursing profession. The basis of this analysis is from the results obtained in the PhD thesis of the author, in which it analysed the processes of continuity and transformation which constituted the professional identity of nurses in Spain between 1956 and 1976. Some political and social consequences are highlighted on nursing practices, on the holistic, humanist and moralist discourses transmitted by nursing models, on occasions compared with bio-pathological, technical and clinical discourses. PMID- 20965760 TI - Identification of a novel TPM1 mutation in a family with left ventricular noncompaction and sudden death. AB - Left ventricular noncompaction (LVNC) is a cardiomyopathy morphologically characterized by 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses communicating with the left ventricular cavity. The purpose of this study was to investigate patients with LVNC for possible disease causing mutations. We screened 4 genes (TAZ, LDB3, DTNA and TPM1) in 51 patients with LVNC for mutations by polymerase chain reaction and direct DNA sequencing. A novel missense substitution in exon 1 of TPM1 (c.109A>G: p.Lys37Glu) was identified in three affected members of a family with isolated LVNC. The substitution brings about a change in amino acid charge at a highly conserved residue and could result in aberrant mRNA splicing. This variant was not identified in 200 normal control samples. Pathologic analysis of a right ventricular myocardial specimen from the proband's maternal aunt revealed endocardial and subendocardial fibrosis with prominent elastin deposition, as well as the presence of adipose tissue between muscle layers, pathologic changes that are distinct from those seen in patients with HCM or DCM. Screening of the proband and her mother for variants in other sarcomeric protein-encoding candidate genes, MYH7, MYBPC3, TNNT2, TNNI3, ACTC, MYL2, and MYL3, did not identify any other non-synonymous variants or variants in splice donor-acceptor sequences that were potentially disease causing. We conclude TPM1 is a potential candidate disease-causing gene for isolated LVNC, especially in patients experiencing sudden death. PMID- 20965763 TI - [Experiences of mastectomised women. A phenomenological study]. AB - OBJECTIVE: To understand the life experience of women with mastectomy in relation to their disease, analysing what leads some women to have breast reconstruction and others not to do so. Identify the situation of mastectomised women with lymphoedemas, alopecia and other problems. METHOD: Phenomenological qualitative research. Twenty-nine in-depth interviews were conducted on the women through specific informants in the oncology services of the Hospital Vall d'Hebron; and the gynaecology unit at the Salud La Mina Primary Care Centre in Barcelona. The age range was between 20 and 69 years. RESULTS: Through the analysis of the interviews it was possible to reveal the phenomenon in research. The following subjects were those of most relevance: there women with reconstructed and non reconstructed breasts, and a mutilated body image through the loss of one or both breasts. Participation of women in social occasions, use of clothing and lifestyle. The cancer is visualised: lymphoedemas, loss of hair with an affect on the public image. CONCLUSIONS: Younger women, graduates and middle class ladies and those over 40 with a primary education are those that have a breast reconstruction. Middle-high and high class graduates do not have a breast reconstruction. They negotiate their relationship with their partner in other ways. PMID- 20965764 TI - [Friendly hospitals for adolescents: patients' preferences]. AB - OBJECTIVE: To determine the preferences and priorities of a sample of hospitalized adolescents on potential ways to improve their stay in the hospital. METHOD: We performed a prospective, cross-sectional, descriptive study. The participants completed a questionnaire on their preferences and priorities regarding hospitalization, which included data about age, sex, and hospitalization experience. There were 15 questions (Likert-type scale) to score from 1 to 5 the importance they gave to different aspects of the hospital stay, 6 questions with various response options on their preferences concerning roommates and accompanying person at night in the hospital, and 5 open questions to indicate positive and negative aspects on hospitalization and suggestions to improve it. RESULTS: A total of 96 adolescents completed the questionnaire, which was 76% of the eligible sample. The importance of friendliness of clinical staff and medical tests not to suffer any delay were the aspects that were considered most important to improve adolescents' hospitalization. If they had to share the hospital room, 86.4% (95% CI: 77.9-92.5) preferred to share with someone of the same age. Among the noteworthy suggestions to improve hospitalization were those involving leisure services in the hospital for adolescent patients (56.2% of the references). As a positive aspect of hospitalization, half (50.0%) referred to the relationship with the clinical staff. CONCLUSIONS: Adolescents express a hospital user perspective that should be taken into account in developing improvements in the health care they receive. PMID- 20965765 TI - [Genotyping of 21,000 blood donors in Quebec and RHD analysis]. AB - STUDY GOAL: A repeat blood donor genotyping project was launched by Hema-Quebec in October 2007. The objective was to screen 21,000 samples for 22 polymorphisms for red blood cell and platelet blood groups to build a database to easily find compatible donors. MATERIALS AND METHODS: Donors who have donated at least three times during the last year were selected. A drop of blood was spotted on FTA paper and sent to the Pharmacogenomic Centre at the Montreal Heart Institute for analysis. All genotype results were compared to the known phenotype. In parallel, the RHD gene of D negative blood donors was examined. RESULTS: Less than two years were necessary to complete the database. The genotype/phenotype concordance was 99.6% with only 165 discrepancies observed and further analysed. More than 55% of these discrepancies confirmed the initial genotype. The RHD study done on D negative samples found 13 donors positive for a variant RHD gene. Four were RHD*Psi positive, while the other nine presented variant polymorphisms precluding a reduced expression of the D antigen. CONCLUSION: Thanks to this project, Hema Quebec is able to answer increasing demands for compatible blood more rapidly. The organisation has also demonstrated the security of its D negative inventory. PMID- 20965766 TI - [Results of partial transfusion exchange in 42 homozygous sickle cell patients at university hospital of Brazzaville]. AB - The standard of care for major sickle cell diseases in crisis is based on blood transfusion, but this remains a risky therapy in sub-Saharan Africa. The objective of this retrospective and prospective study was to assess exchange transfusion (ET) in homozygous sickle cell disease between 1st July 2005 and 30th June 2008 at the transfusion centre of university hospital of Brazzaville. The ET technique used was manual and made of three stages: bleeding, infusion of solution, and infusion of red cell concentrate. Clinical and biological assessments were done before and after exchanges. The indication for ET were: pregnancy (19 cases); strokes (seven cases); vaso-occlusive crisis (five cases), priapism (four cases), cardiac failure (three cases) and miscellaneous (four cases), the values of hematocut in red cell blood bag between 0.55 and 0.70 (median 0.65). The median haemoglobin level before exchange was about 5.8 g/dl (4.1-7.4 g/dl), that of HbS from haemoglobin electrophoresis about 98.4 % (94.6 100 %). Before the exchanges, viral serological tests were done with the following results: two patients with HBV antigen positive and one patient antibodies to HCV. In acute situation interval between exchanges is 3 to 10 days, whereas during chronic situation is between 14 to 28 days. No major immediate complications have been observed. Clinical situation after exchange characterized by stabilization of cerebral vascular stroke and over and control of one case of priapism complications. Assessment after exchange showed the following results: medium rate of Hb level: 9.5 g/dl (an increase of 3.7 g/dl); medium percentage of HbS reduced to 46.8 % (approximately a decrease of 51.6 %). Patient's serological status to HCV changed for one patient. This study illustrates the benefit and the limitations of the transfusion exchange during sickle cell disease in sub-Saharan Africa. PMID- 20965767 TI - [Characteristics of transfusion recipients in Bordeaux University Hospital. A descriptive study using hospital claims and haemovigilance system databases]. AB - OBJECTIVE: The steady increase of the blood demand since 2001 requires to study the clinical characteristics of blood components recipients. The objective was to describe patients transfused in 2006 in Bordeaux University Hospital, and to identify the diseases which justified the transfusion practice, using French hospital claims database. STUDY DESIGN: Data from haemovigilance system were linked to hospital claims databases in order to describe patients transfused in 2006. To target diseases related to transfusion, a list of diagnoses considered as markers for transfusion was drawn up, and validated by physicians prescribing blood components. RESULTS: Among the 100,004 patients admitted to hospital in 2006, 6275 (6.3%) received blood components; 46,727 blood units were transfused to these patients, including 67% of red blood cell, 13% of platelet concentrates and 20% of fresh-frozen plasma; 69% of blood units were prescribed in medical wards, 30% in surgery wards and 1% in gynaecology and obstetrics. The main diagnoses associated with blood transfusion were circulatory complications after cardiac surgery (80% of patients with this diagnosis were transfused), bone marrow aplasia (76% of patients), anaemia (55%), and gastro-intestinal bleeding (48%). The highest numbers of blood units were transfused to patients with hypovolemic, traumatic or postoperative shock, anaemia, hemopathy, or coagulation disorders. CONCLUSION: This study provided a clinical profile of the transfused patients. Data collected could be used to plan blood collection and to define objectives and resources of healthcare establishments. PMID- 20965768 TI - What links vascular calcifications to osteoporotic fractures? PMID- 20965769 TI - Pericarditis induced by prophylactic administration of isoniazid in a patient with rheumatoid arthritis. PMID- 20965770 TI - [Review: Repetitive hydatidiform moles]. AB - Repetitive moles are rare. They are either sporadic or familial, with or without consanguinity. Some of them can be explained by a NLRP7 mutation, which causes genomic parental imprinting alteration, with a preferential paternal phenotypic expression. Currently, no effective therapeutic solution has been developed. Among the 1687 patients declared to the French Trophoblastic Disease Reference Center, 13 presented at least two hydatidiform moles, thus less than 1% of the patients. A mutation of the NLRP7 gene was shown in six of 12 tested patients (50%) among whom three presented a homozygous mutation and three a heterozygous mutation. For an affected patient, type of mole can indifferently be a complete hydatidiform mole or a partial hydatidiform mole. We describe these cases and compare them to those already published. PMID- 20965771 TI - [Para-aortic lymphadenectomy in advanced-stage cervical cancer: standard procedure in 2010?]. AB - With tumour size, node involvement is the most important prognosis factor in advanced stage cervical cancer. Para-aortic (PA) disease is observed in 15 to 30% of these patients. CT scan and magnetic resonance imaging (MRI) are not efficient enough to detect these lesions and PET CT have false negatives. Surgical staging is useful to detect carcinosis associated and to adapt therapy (radiotherapy fields are extended if PA nodes are involved). Laparoscopy was crucial to develop this staging because its morbidity associated to chemoradiotherapy is limited. If prognosis impact of PA lymphadenectomy is well established, therapeutic impact is still discussed. The systematic extension of this staging to pelvic nodes that are included in the basic radiotherapy fields is debated because it does not modify therapeutic management and is morbid. Radiotherapy progress, especially with boost and combination to MRI (MRIT), will impact on future therapeutic management. PMID- 20965772 TI - WD40 and CUL4-based E3 ligases: lubricating all aspects of life. AB - The ubiquitin proteasome pathway is one of the major regulatory tools used by eukaryotic cells. E3 ligases, which allow controlled modification of proteins with ubiquitin, are crucial for the specificity of the pathway. Recently, an additional plant cullin-based E3 ligase complex was described which contains cullin 4 (CUL4) and DAMAGED DNA BINDING 1 protein as core subunits. Our knowledge of this E3 ligase has increased tremendously since its first description, and it seems to be involved in many developmental and physiological processes. Here, we review the most recent studies on CUL4 E3 complexes, with a focus on their substrate recognition and the plethora of processes that they regulate in plants, such as photomorphogenesis, flowering and abiotic stress response. PMID- 20965773 TI - Studies of ion channels using expressed protein ligation. AB - Expressed protein ligation (EPL) is a semisynthetic technique for the chemoselective ligation of a synthetic peptide to a recombinant peptide that results in a native peptide bond at the ligation site. EPL therefore allows us to engineer proteins with chemically defined, site-specific modifications. While EPL has been used mainly in investigations of soluble proteins, in recent years it has been increasingly used in investigations of integral membrane proteins. These include studies on the KcsA K(+) channel, the non-selective cation channel NaK, and the porin OmpF. These studies are discussed in this review. PMID- 20965774 TI - Surface-enhanced Raman spectroscopy of omethoate adsorbed on silver surface. AB - We have investigated surface-enhanced Raman spectroscopy (SERS) spectrum of Omethoate (O,O-dimethyl-S-methylcarbamoylmethylthiophosphate). It is found significant signals in the ordinary Raman spectrum for solid-state Omethoate as well as strong vibrational signals absorbed on the silver sol surface which is prepared by gamma-irradiation technique at a very low concentration. Effects of pH and anions (Cl-, Br-, I-) on the adsorption orientation are investigated as well. Two different adsorption mechanisms are deduced, depending on the experimental conditions. The sulfur atom or the sulfur and two oxygen atoms are adsorbed onto the silver sol surface. Among halide ions, Br- and I- are more strongly adsorbed onto the silver sol surface. As a result, the adsorption of Omethoate is less effective due to their steric hindrance. PMID- 20965775 TI - Black painted pottery, Kildehuse II, Odense County, Denmark. AB - This work aimed at characterization of a black layer covering a Bronze Age (period VI) pot surface. To solve research problems plane polarized light microscopy (PLM), scanning microscopy with X-ray microanalyser (SEM/EDS), Raman and FTIR microspectroscopies were applied. Observation of the black layer under the PLM suggests that we deal with an opaque, isotropic layer, purposely put on leather-hard, burnished surface of a pot. No traces of organic substances that might have modified a pot surface before painting were detected. The black layer coats the pot with a continuous 0.2-0.4 MUm thick layer. The black layer must have been applied while warm or hot. It is recognized that the black layer is a true painting layer. Spectroscopic analyses (Raman and FTIR) point that birch tar or a birch-pine tar had been applied. Carbon black should be definitely excluded. The analyzed organic substance is structurally ordered in various degrees, due to varying temperature influence. Some Raman spectra reveal, in second-order region of the spectrum (>2000 cm(-1)), the graphite presence. Scarce points reveal the presence of inorganic admixtures: clay minerals, feldspars and quartz. The next question is: Is it an organic paint or a carbon-based, "mixed" paint? Inorganic admixtures are only casual. Relatively high concentration of alumina is expected to have appeared due to aluminum mobility in acidic environment and this was provided by organic tar/pitch substances. Phosphorus (usually with calcium) mostly concentrates together with clay minerals. Thus, hypothesis on bone powder or ash addition to tar/pitch should be excluded. Some elements may originate not only from inorganic substances but also from wood ashes. PMID- 20965776 TI - DNA binding studies of new valine derived chiral complexes of tin(IV) and zirconium(IV). AB - Valine derived chiral complexes of SnCl4 (1) and ZrCl4 (2) were designed as potent antitumor agents. These complexes were characterized by elemental analysis, IR, 1H NMR, 119Sn NMR and ESI mass spectroscopy. In vitro binding studies of complexes 1 and 2 under physiological conditions at room temperature with CT-DNA were carried out employing UV-vis absorption titration, fluorescence studies and viscosity measurements. The extent of binding was quantified by Kb values of complexes 1 and 2 which were found to be 1.97*10(4) and 1.17*10(3) M( 1), respectively, suggesting that complex 1 has significantly greater DNA binding propensity in contrast to the complex 2. The mode of action at the molecular level was ascertained by the interaction of complex 1 with 5'GMP and 5'TMP which revealed that complex 1 binds via electrostatic mode with the oxygen of the negatively charged surface phosphate group of the DNA helix. The supercoiled pBR322 plasmid DNA cleavage activity of complex 1 was ascertained by gel electrophoresis assay. PMID- 20965777 TI - Presence of Merkel cell polyomavirus in Japanese cutaneous squamous cell carcinoma. AB - BACKGROUND: Merkel cell polyomavirus (MCPyV) was first identified in Merkel cell carcinoma (MCC) as a new tumor virus. Studies have also reported differing frequencies of MCPyV detection in other skin cancers in western countries. OBJECTIVES: Little is known about geographical differences of MCPyV prevalence in non-MCC tumors. We examined the existence of MCPyV in non-MCC skin cancers including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in Japanese patients. STUDY DESIGN: Paraffin-embedded tissues of cutaneous SCC (n=30) and BCC (n=10) from Japanese patients were tested for the presence of MCPyV by polymerase chain reaction (PCR) with primer sets directed against the genes encoding large-T antigen 3 (LT3) and viral protein 1 (VP1). This was followed by DNA fragment sequencing and immunohistochemistry. RESULTS: PCR analysis targeting the LT3 gene showed that the viral sequences were found in 4 of 30 (13%) SCC cases. Nested PCR detected the VP1 region in four cases. Sequencing analysis of these PCR-amplified fragments showed a close homology to the previously published MCPyV sequences. Immunohistochemistry with the monoclonal antibody to MCPyV LT-antigen showed positive staining in 2 of 4 LT3 PCR-positive cases. On the other hand, our BCC samples were all negative for MCPyV. CONCLUSION: This study suggested that Japanese cutaneous SCC is infrequently associated with MCPyV. Further worldwide epidemiological surveys are warranted to determine the possible association of MCPyV with pathogenesis of non MCC skin cancers. PMID- 20965778 TI - Recordings of long-latency trigeminal somatosensory-evoked potentials in patients under general anaesthesia. AB - OBJECTIVE: The reliability of intra-operative recordings of trigeminal scalp induced somatosensory-evoked potentials (T-SSEP) is controversial. This investigation aimed to provide evidence that T-SSEP recordings are stable using standardised neurophysiological methodology and anaesthesiological regime. METHODS: We investigated 99 patients undergoing carotid endarterectomy under total intravenous anaesthesia (propofol/remifentanil infusion). Long-latency T SSEPs were recorded from the scalp after simultaneously stimulating 2nd and 3rd branches of the trigeminal nerve. The analysis included visual assessments of traces and measurements of latencies and amplitudes of the N13 and P19 peaks of T SSEP. Furthermore, additional groups of patients were investigated to identify changes in the parameters of T-SSEP that might correspond to different states of anaesthesia and artificial muscle activity. RESULTS: We reproducibly recorded T SSEP responses in 99 patients with a mean latency of 12.4 ms (SD=0.93) and amplitude of 5.7 MUV (SD=4.7). Collateral investigations concerning changes of T SSEP caused by neuromuscular blockade improved independence of T-SSEP recordings to muscle relaxation in contrast to facial and cervical muscle activity. CONCLUSIONS: We demonstrated the reliability of recording stable intra-operative T-SSEP responses with standardised electrophysiological and anaesthesiological regimes. SIGNIFICANCE: We provided evidence of the non-muscular origin of T-SSEPs recorded from the scalp. PMID- 20965779 TI - Daytime consequences of insomnia symptoms among outpatients in primary care practice: EQUINOX international survey. AB - OBJECTIVE: To assess the daytime consequences in outpatients suffering from different insomnia symptoms in primary care practice. METHODS: An international cross-sectional survey was conducted in 5293 outpatients complaining of sleep disturbances in primary care practice. A sleep questionnaire addressing daytime consequences, insomnia symptoms, socio-demographic characteristics, and other sleep variables was administered by 647 physicians in 10 countries. RESULTS: Overall, 20-33% of subjects reported "severe" daytime impairments associated with sleep disturbances. Approximately 45% of patients complaining of sleep disturbances in primary care practice suffered from a combination of insomnia symptoms. Patients suffering from all insomnia symptoms reported the most severe daytime functioning impairments compared with patients suffering from initiation or maintenance insomnia only. Conversely, the majority of patients suffering from non-restorative sleep reported little daytime functioning impairments compared to the patients suffering from other combinations of insomnia symptoms. The strongest risk factor associated with "severe" daytime functioning impairments was sleep quality perception. CONCLUSIONS: Primary insomnia disturbs subjective daytime functioning. A report of combined insomnia symptoms reflected the most damaging insomnia subtype and had a negative impact on a wide range of daytime functioning consequences. PMID- 20965780 TI - Randomized trial of pramipexole for patients with restless legs syndrome (RLS) and RLS-related impairment of mood. AB - OBJECTIVES: Patients with restless legs syndrome (RLS) have an elevated prevalence of mood disorders compared with the general population. We investigated the change of RLS-related mood impairment during treatment of RLS with pramipexole, a dopamine D(3)/D(2) agonist. METHODS: Adults with moderate to very severe RLS were enrolled in a 12-week, double-blind, placebo-controlled Phase IV pramipexole trial. A moderate to very severe RLS-related mood disturbance at baseline (score >=2 on Item 10 of the International RLS Study Group Rating Scale [IRLS]) was also required. Pramipexole (0.125 to 0.75 mg once daily) was flexibly titrated over the first 4 weeks. RESULTS: The intent-to-treat population comprised 199 patients on placebo and 203 on pramipexole. At week 12, adjusted mean total-score changes on IRLS were -14.2+/-0.7 for pramipexole and 8.1+/-0.7 for placebo (p<0.0001), and on the Beck Depression Inventory version II, -7.3+/-0.4 for pramipexole and -5.8+/-0.5 for placebo (p=0.0199). For IRLS item 10, the 12-week responder rate (reduction to no or mild mood disturbance) was 75.9% for pramipexole and 57.3% for placebo (p<0.0001). Study withdrawal rates were higher for placebo (20.5%) than for pramipexole (12.8%). CONCLUSIONS: In patients with RLS-related mood disturbance, pramipexole improved RLS while also improving RLS-related mood impairment. Tolerability of pramipexole was similar to that in previous studies. PMID- 20965781 TI - GamA is a eukaryotic-like glucoamylase responsible for glycogen- and starch degrading activity of Legionella pneumophila. AB - Legionella pneumophila (Lp) is the causative agent of Legionnaires' disease, an atypical pneumonia. Lp is found in freshwater habitats and replicates within different protozoa (amoebae). It is known that Lp uses amino acids as primary energy and carbon sources for replication. However, very recently it was reported that Lp is able to metabolize also carbohydrates (glucose). Here, we present for the first time experimental evidence that the lpp0489 [gamA] gene encodes a eukaryotic-like glucoamylase (GamA) responsible for the glycogen- and starch degrading activities of Lp. Although not essential for intra- and extracellular growth, we showed that GamA is expressed and active during intracellular replication in Acanthamoeba castellanii, suggesting that Lp is degrading glycogen during intracellular replication. Altogether, these findings indicate that Lp is indeed able to degrade exogenous polysaccharides and to utilize carbohydrates (glucose). PMID- 20965782 TI - Reference intervals for blood Cd and Pb in the general population of Sardinia (Italy). AB - The reference values (RVs) for blood Cd and Pb of 215 adult subjects non occupationally exposed and living in Sardinia (insular Italy) were assessed. Age, sex, smoking, alcohol drinking and living area were used to stratify the reference group. After collection from volunteers, samples were acid digested in a microwave oven and metals were determined by sector field inductively coupled plasma mass spectrometry. The RVs expressed as 5th-95th percentiles (geometric mean, GM) were 0.24-1.82 MUg/l (0.53 MUg/l) for blood Cd and 13.2-87.3 MUg/l (33.4 MUg/l) for blood Pb. Females had GM levels of Cd (0.58 MUg/l) higher than males (0.49 MUg/l); subjects aged <40 years had less Cd (0.44 MUg/l) than old subjects (>60 years; 0.56 MUg/l); Cd in smokers (1.23 MUg/l) was 3-times higher than in non-smokers (0.42 MUg/l) and correlated with the number of cigarettes per day. The alcohol intake and place of living did not influence blood Cd. The GM values of blood Pb in males (44.4 MUg/l) were higher than in females (24.7 MUg/l); subjects less than 40 years-old (27.5 MUg/l) showed lower Pb than elderly individuals (>60 years, 41.2 MUg/l); drinkers (42.2 MUg/l) had Pb 2-times higher than non-drinkers (24.4 MUg/l). Blood Pb was not significantly affected by smoking and place of living. As revealed by multiple linear regression, the predictor variables were, in order of weight, smoke ? age for blood Cd levels, and sex = age ? alcohol for blood Pb levels. PMID- 20965783 TI - The potential role of echocardiographic strain imaging for evaluating cardiotoxicity due to cancer therapy. AB - Refinements to conventional treatment and the development of new therapies have led to significant improvements in cancer survival. Yet, many frontline cancer treatments continue to be hindered by their significant side effects, amongst which cardiotoxicity is particularly important. Therefore, the focus of cancer management has changed; treatment is no longer aimed solely at overcoming malignancy, but emphasises early identification and treatment of potential side effects. In this regard, the cardiotoxic potential of certain anticancer agents mandate close monitoring of cardiac function, and the method of choice for monitoring is transthoracic echocardiography. Whilst this method has its limitations, a newer echocardiographic technique called myocardial strain imaging has the potential to detect early sub-clinical changes in cardiac function due to cardiotoxicity. Strain analysis has been the subject of several recent studies to evaluate its potential in monitoring cardiotoxicity, and this article reviews the recent literature and explores the potential role of myocardial strain imaging in cancer management and avenues for future research. PMID- 20965784 TI - Exploring the curative potential of BCR-ABL1-targeting drugs for chronic myeloid leukaemia. PMID- 20965785 TI - Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. AB - BACKGROUND: Imatinib treatment significantly improves survival in patients with chronic myeloid leukaemia (CML), but little is known about whether treatment can safely be discontinued in the long term. We aimed to assess whether imatinib can be discontinued without occurrence of molecular relapse in patients in complete molecular remission (CMR) while on imatinib. METHODS: In our prospective, multicentre, non-randomised Stop Imatinib (STIM) study, imatinib treatment (of >2 years duration) was discontinued in patients with CML who were aged 18 years and older and in CMR (>5-log reduction in BCR-ABL and ABL levels and undetectable transcripts on quantitative RT-PCR). Patients who had undergone immunomodulatory treatment (apart from interferon alpha), treatment for other malignancies, or allogeneic haemopoietic stem-cell transplantation were not included. Patients were enrolled at 19 participating institutions in France. In this interim analysis, rate of relapse was assessed by use of RT-PCR for patients with at least 12 months of follow-up. Imatinib was reintroduced in patients who had molecular relapse. This study is registered with ClinicalTrials.gov, number NCT00478985. FINDINGS: 100 patients were enrolled between July 9, 2007, and Dec 17, 2009. Median follow-up was 17 months (range 1-30), and 69 patients had at least 12 months follow-up (median 24 months, range 13-30). 42 (61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7, and one at month 19). At 12 months, the probability of persistent CMR for these 69 patients was 41% (95% CI 29-52). All patients who relapsed responded to reintroduction of imatinib: 16 of the 42 patients who relapsed showed decreases in their BCR-ABL levels, and 26 achieved CMR that was sustained after imatinib rechallenge. INTERPRETATION: Imatinib can be safely discontinued in patients with a CMR of at least 2 years duration. Imatinib discontinuation in this setting yields promising results for molecular relapse-free survival, raising the possibility that, at least in some patients, CML might be cured with tyrosine kinase inhibitors. PMID- 20965786 TI - Ensemble-based methods for describing protein dynamics. AB - Molecular dynamics (MD) simulation is a natural approach for studying protein dynamics, and coupled with the ideas of multiscale modeling, MD proves to be the gold standard in computational biology to investigate mechanistic details related to protein function. In principle, if MD trajectories are long enough, the ensemble of protein conformations generated allows thermodynamic and kinetic properties to be predicted. We know from experiments that proteins exhibit a high degree of fidelity in function, and that empirical kinetic models are successful in describing kinetics, suggesting that the ensemble of conformations cluster into well-defined thermodynamic states, which are frequently metastable. The experimental evidence suggest that more efficient computational models that retain only essential properties of the protein can be constructed to faithfully reproduce the relatively few observed thermodynamic states, and perhaps describe transition states if the model is sufficiently detailed. Indeed, there are many so-called ensemble-based methods that attempt to generate more complete ensembles than MD can provide by focusing on the most important driving forces through simplified representations of how elements within the protein interact. Although coarse-graining is employed in MD and other approaches, such as in elastic network models, the key distinguishing factor of ensemble-based methods is that they are meant to efficiently generate a large ensemble of conformations without solving explicit equations of motion. This review highlights three types of ensemble-based methods, illustrated by 'COREX' and the Wako-Saito-Munoz-Eaton (WSME) model, the Framework Rigidity Optimized Dynamic Algorithm (FRODA) and the distance constraint model (DCM). PMID- 20965787 TI - The association between family meals, TV viewing during meals, and fruit, vegetables, soda, and chips intake among Latino children. AB - OBJECTIVE: Examine the relationship of family meals to children's consumption of fruit and vegetables as well as soda and chips. Additionally, to assess the relationship between viewing TV during family meals and children's diet. DESIGN: Cross-sectional study that used a questionnaire completed by parents. SETTING: Thirteen schools in San Diego, California. PARTICIPANTS: Seven hundred ninety four children and their parents. ANALYSIS: Ordinal regression assessed associations between children's intake of fruit, vegetables, soda, and chips with family meal frequency and TV viewing during family meals. RESULTS: Children who consumed breakfast, lunch, or dinner with their family at least 4 days per week ate fruit and vegetables 5 or more times a week 84%, 85%, and 80%, respectively. Of those children who ate breakfast, lunch, or dinner with their family at least 4 days per week, 40%, 44%, and 43% consumed soda and chips 5 or more times a week, respectively. Children who ate breakfast with their families at least 4 times a week were more likely to consume fruit and vegetables, and children whose TV was never or rarely on during family meals were less likely to consume soda and chips (P = .04 and P < .001, respectively). CONCLUSIONS: Interventions geared at increasing the frequency of eating breakfast as a family and decreasing the amount of TV watched during family meals are needed, especially among acculturating Latino families. PMID- 20965788 TI - Belief systems of epilepsy and attitudes toward people living with epilepsy in a rural community of northern Tanzania. AB - The social stigma toward people with epilepsy (PWE) varies greatly between cultures. In this study, 167 people (59 PWE, 62 relatives, 46 villagers) in a rural area of northern Tanzania were interviewed at the hospital and in the community regarding their prevailing beliefs about epilepsy and attitudes toward PWE. Seventy-eight of those interviewed (46.7%) thought that epilepsy was due to supernatural causes, but 86 (51.5%) assumed that epilepsy is caused by brain disorders or is inherited. According to the interviewees, epilepsy impacts on the lives of affected people. 65.3% (n=109) thought that PWE should not attend school or go to work and 38.3% (n=64) were of the opinion that PWE had decreased chances of getting married. A minority (11.4%; n=19) thought that epilepsy was a reason not to have children. In summary, supernatural and more scientific ideas about the causes of epilepsy seem to coexist. Nevertheless, there is considerable stigma toward PWE, which needs to be interpreted within the sociocultural context of the study. PMID- 20965789 TI - A wake-up call for memory. PMID- 20965790 TI - A novel crossed rod configuration incorporating translaminar screws for occipitocervical internal fixation: an in vitro biomechanical study. AB - BACKGROUND CONTEXT: Occipitocervical (OC) spinal instrumentation involving the axis (C2) entails the use of transarticular screws through C1-C2 or lateral mass screws at C1 and pedicle screws at C2 to achieve fusion. Because of the anatomical complexity, interpatient anomalous variation, and danger to the vertebral artery injury, there has been an increased interest in alternate sites for fixation. Recent studies have involved the placement of screws bilaterally into the C2 lamina. Several biomechanical studies have been carried out to evaluate the performance of C2 translaminar screws (TLSs). PURPOSE: The aim of the study was to compare the biomechanics of an OC2 rigid construct using C2 pedicle screws and C2 TLSs. Also, this study included a new construct in which the OC2 fixation was carried out by connecting rods to the contralateral TLS. STUDY DESIGN: Human cadaveric cervical spines were tested in an in vitro biomechanical flexibility experiment to investigate the biomechanical stability provided by a novel crossed rod (CR) configuration incorporating TLSs for OC2 internal fixation. METHODS: Seven fresh human cadaver occipitocervical spines (occiput-C3) were tested by applying pure moments of +/-1.5 Nm. After intact specimen testing, an occipital plate was implanted. Each specimen was then tested in the following modes: bilateral pedicle screws (BPSs) and rods at C2; TLSs at C2 with rods in parallel configuration (TLS+parallel rod); and TLSs at C2 with rods in crossed configuration (TLS+CR). OC2 range of motion (ROM) for each construct was obtained by applying pure moments in flexion-extension, lateral bending, and axial rotation. RESULTS: All three instrumented constructs significantly reduced ROM in all physiological planes when compared with the intact spine. The BPS construct similarly reduced ROM when compared with both the translaminar constructs. There was no significant difference in ROM between the translaminar constructs in all loading modes. CONCLUSIONS: A cadaveric model was used to investigate the stability offered by a novel CR construct by using TLS fixation in an OC2 fusion construct. The results were compared with BPS fixation. All three constructs significantly decreased motion as compared with the intact state. There was no statistically significant difference in flexibility among any of the constructs. The novel CR construct provides as much stability as traditional constructs and may be a viable alternative for clinical use. PMID- 20965791 TI - Discontinuation of diabetes and lipid-lowering medications after bariatric surgery at Veterans Affairs medical centers. AB - BACKGROUND: Bariatric surgery has largely been performed on middle-age female populations and been associated with significant medication discontinuation; however, it is unknown whether similar medication discontinuation rates could be achieved in men. The purpose of the present analysis was to examine the discontinuation rate of diabetes or lipid-lowering medications and the patient factors associated with medication discontinuation among veterans undergoing bariatric surgery. METHODS: We identified the demographic and health status information for 284 veterans with diabetes and 298 veterans with hyperlipidemia who had undergone bariatric surgery at 1 of 12 Veterans Affairs bariatric centers in 2000 to 2006 from the Veterans Affairs National Surgical Quality Improvement Program data. We also identified the medications that had been prescribed and discontinued using the Veterans Affairs administrative data. Medication discontinuation was estimated using a logistic regression model. RESULTS: Of the 284 veterans with diabetes and 298 with hyperlipidemia, 52% and 40% had discontinued their medications at 1 year, respectively. The veterans with diabetes were more likely to discontinue medication if they had been taking oral hypoglycemic agents alone (odds ratio 2.77, P <.001) than were those taking insulin or oral hypoglycemic agents and insulin. The veterans with hyperlipidemia were more likely to discontinue medication if they had only been taking fibrates (odds ratio 6.15, P <.01) than were those veterans taking statins and fibrates. CONCLUSION: Bariatric surgery led to significant medication discontinuation within 1 year for high-risk veterans with diabetes or hyperlipidemia. PMID- 20965793 TI - Outcomes and complications of transvaginal and abdominal custom-shaped light weight polypropylene mesh used in repair of pelvic organ prolapse. AB - STUDY OBJECTIVE: To assess the outcomes and complications of transvaginally placed custom-shaped light-weight polypropylene mesh for repair of pelvic organ prolapse. DESIGN: Retrospective review of medical records (Canadian Task Force classification II-2). SETTING: Two urogynecologic centers. PATIENTS: Between March 2006 and September 2007, 154 women with anterior, posterior, or apical prolapse underwent vaginal reconstructive surgery using custom-shaped transvaginal or abdominal mesh. Surgical procedures were chosen after informed consent. The primary outcome for the study was recurrence of prolapse, defined as POP-Q (Pelvic Organ Prolapse Quantitative) stage II or greater. Secondary end points included perioperative and postoperative complications. INTERVENTIONS: Anterior compartment repair was performed in 94 patients (61%), and posterior compartment repair in 60 (39%). Combined anterior and posterior repairs were performed in 25 patients. Hysterectomy was performed in 27 patients (18%) (abdominal in 1, vaginal in 19, and laparoscopy-assisted in 7). Apical support techniques included sacrospinous fixation in 69 patients (45%), abdominal sacral colpopexy in 30 (19%), and vaginal culdoplasty in 7 (5%). Transobturator sling procedures were performed in 65 patients (42%). MEASUREMENTS AND MAIN RESULTS: Postoperative follow-up exceeded 24 months in all patients. The overall success of these procedures was 97.4%. There were 4 failures (2.6%), defined as stage II prolapse or greater. Comparison of POP-Q points Aa, Ba, C, Ap, and Bp preoperatively and postoperatively revealed statistically significant improvement at each point (p <.001). Complications were observed in 17 patients (11%), with mesh extrusion in 1 (0.7%). CONCLUSIONS: Long-term follow-up demonstrated that use of custom-shaped light-weight polypropylene mesh is safe and effective, with a low rate of complications. PMID- 20965792 TI - Laparoendoscopic single-site surgery in gynecology: review of literature and available technology. AB - The objective of this article was to review the published literature on laparoendoscopic single-site surgery (LESS) in gynecology and to present current advances in instruments used in LESS surgery. Inasmuch as LESS surgery is relatively new, the current literature on use of this technique in gynecology is somewhat limited. Sixteen articles were available for the literature review: 10 case series, 2 comparative studies, 3 case reports, and 1 surgical technique demonstration. In recent years, however, improvements in traditional laparoscopic techniques and availability of more advanced instruments has made single-incision laparoscopy more feasible and safer for the patient. There is increasing interest in LESS surgery both as an alternative to traditional laparoscopy and as an adjunct to robotic surgery when performing complicated procedures through a single incision. Although LESS surgery provides another option in the arena of minimally invasive gynecologic surgery, the ultimate role of this approach remains to be determined. PMID- 20965794 TI - Laparoscopic posterior exenteration in advanced gynecologic malignant disease. AB - STUDY OBJECTIVE: To study the feasibility, morbidity, and oncologic outcome of laparoscopic posterior exenteration in patients with advanced gynecologic malignant diseases. DESIGN: Retrospective study based on clinical experience (Canadian Task Force classification III). SETTING: Private hospital. PATIENTS: The medical records for 10 patients who underwent laparoscopic posterior exenteration because of advanced gynecologic malignant disease were retrospectively reviewed. INTERVENTION: Laparoscopic posterior exenteration involving selective resection of the uterus, ovaries, vagina, and rectum was performed using a 6-port technique that included harmonic shears, the LigaSure device, and a circular endostapling instrument. MEASUREMENTS AND MAIN RESULTS: Histopathologic diagnosis included carcinoma of the cervix in 5 patients, ovary in 4 patients, and vagina in 1 patient. Indication for surgery was primary disease in 7 patients and secondary disease in 3 patients. Complications included delayed bladder recovery in 4 patients, and anastomotic leak, wound infection, and prolonged ileus in 1 patient each. No conversions to open surgery were required. The extent of resection was supralevator in 8 patients and infralevator in 2. Median operative time was 210 minutes. Median length of hospital stay was 9 days. Median blood loss was 360 mL. Disease recurred in 1 patient. After a median follow-up of 26 months, 9 patients were alive, and 8 were free of disease. CONCLUSION: Laparoscopic posterior exenteration is feasible in advanced gynecologic malignant disease with rectal involvement. In addition to the known benefits of laparoscopic surgery, carefully selected patients could achieve a survival benefit following R0 resection. PMID- 20965795 TI - Development and validation of a gas chromatography/ion trap-mass spectrometry method for simultaneous quantification of cocaine and its metabolites benzoylecgonine and norcocaine: application to the study of cocaine metabolism in human primary cultured renal cells. AB - Acute renal failure is a common finding in cocaine abusers. While cocaine metabolism may contribute to its nephrotoxic mechanisms, its pharmacokinetics in kidney cells is hitherto to be clarified. Primary cultures of human proximal tubular cells (HPTCs) provide a well-characterized in vitro model, phenotypically representative of HPTCs in vivo. Thus, the present work describes the first sensitive gas chromatography/ion trap-mass spectrometry (GC/IT-MS) method for measurement of cocaine and its metabolites benzoylecgonine (BE) and norcocaine (NCOC) using a primary culture of HPTCs as cellular matrix, following solid phase extraction (SPE) and derivatization with N-methyl-N (trimethylsilyl)trifluoroacetamide (MSTFA). The application of this methodology also enables the identification of two other cocaine metabolites: ecgonine methyl ester (EME) and anhydroecgonine methyl ester (AEME). The validation of the method was performed through the evaluation of selectivity, linearity, precision and accuracy, limit of detection (LOD), and limit of quantification (LOQ). Its applicability was demonstrated through the quantification of cocaine, BE and NCOC in primary cultured HPTCs after incubation, at physiological conditions, with 1 mM cocaine for 72 h. The developed GC/IT-MS method was found to be linear (r2 > 0.99). The intra-day precision varied between 3.6% and 13.5% and the values of accuracy between 92.7% and 111.9%. The LOD values for cocaine, BE and NCOC were 0.97+/-0.09, 0.40+/-0.04 and 20.89+/-1.81 ng/mL, respectively, and 3.24+/-0.30, 1.34+/-0.14 and 69.62+/-6.05 ng/mL as LOQ values. PMID- 20965796 TI - Comprehensive separation and identification of chemical constituents from Apocynum venetum leaves by high-performance counter-current chromatography and high performance liquid chromatography coupled with mass spectrometry. AB - High-performance counter-current chromatography (HPCCC) and high performance liquid chromatography coupled with mass spectrometry (HPLC-MS) was efficiently utilized for the separation and identification of the chemical components with a wide range of polarity from the mixed extract of Chinese medicinal herb Apocynum venetum. For HPCCC separation, four sets of solvent systems, n-hexane-ethyl acetate-acetonitrile-water (1.5:3.5:2:4.5, v:v:v:v), ethyl acetate-methanol-water (5:2:5, v:v:v) and n-butanol-methanol-water (5:1:5, v:v:v) were used for the one step separation by four stages. The HPCCC separation was initiated by filling the column with the lower phase of n-hexane-ethyl acetate-acetonitrile-water (1.5:3.5:2:5, v:v:v:v) as a stationary phase followed by elution with the upper phase of n-hexane-ethyl acetate-acetonitrile-water (1.5:3.5:2:5, v:v:v:v) to separate the hydrophobic compounds (tail to head). Then the mobile phase was switched to the upper phase of ethyl acetate-acetonitrile-water (5:3:7, v:v:v) to eluted the moderate hydrophobic compounds, then the mobile phase was switched to the upper phase of ethyl acetate-methanol-water (5:2:5, v:v:v) to eluted the moderate hydrophilic compounds, and finally the hydrophilic compounds still retained in the column was eluted by the upper phase of n-butanol-methanol-water (5:1:5, v:v:v). A total of 16 named compounds including adhyperforin, hyperforin, amentoflavone, biapigenin, quercetin, avicularin, acetylated isoquercetin, acetylated hyperoside, astragalin, trifolin, isoquercetin, hyperoside, querciturone, rutin, chlorogenic acid and quercetin-3-O-beta-D-glucosyl-beta-D glucopyranoside were successfully separated via the four sets of solvent systems in one step operation for 130 min. The compounds separated by HPCCC were identified by comparing with mixed standards data of HPLC-MS as well as NMR data. PMID- 20965797 TI - Determination of 1,2-bis (2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA free acid) in rat plasma, urine and feces by liquid chromatography with UV and tandem mass spectrometric detection. AB - BAPTA free acid was identified as the main metabolic product of 1,2-bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(actoxymethyl ester) (BAPTA AM), a neuroprotective agent in cerebral ischemia, in rats. In this paper, liquid chromatography-ultraviolet (LC-UV) and mass spectrometry/mass spectrometry (LC MS/MS) methods were employed for the determination of BAPTA free acid in rat urine and feces and rat plasma, respectively. By liquid-liquid extraction and LC UV analysis, a limit of quantitation of 1000 ng/ml using 0.2 ml rat urine for extraction and 250 ng/ml using 1 ml rat fecal homogenate supernatant for extraction could be reached. The assay was linear in the range of 1000-50,000 ng/ml for rat urine and 250-10,000 ng/ml for rat fecal homogenate supernatant. Because the sensitivity of the LC-UV method was apparently insufficient for evaluating the pharmacokinetic profile of BAPTA in rat plasma, a LC-MS/MS method was subsequently developed for the analysis of BAPTA free acid. By protein precipitation and LC-MS/MS analysis, the limit of quantitation was 5 ng/ml using 0.1 ml rat plasma and the linear range was 5.0-500 ng/ml. Both methods were validated and can be used to support a thorough preclinical pharmacokinetic evaluation of BAPTA-AM liposome injection. PMID- 20965798 TI - LC-MS/MS determination of etravirine in rat plasma and its application in pharmacokinetic studies. AB - Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is active against NNRT-resistant HIV-1. A simple, sensitive, and specific LC-MS/MS method was developed and validated for the analysis of etravirine in rat plasma using itraconazole as the internal standard. The analytes were extracted with ethyl acetate and chromatographed on a reverse-phase XTerra MS C18 column. Elution was achieved with a mobile phase gradient varying the proportion of a 2 mM ammonium acetate aqueous solution containing 0.1% formic acid (solvent A) and a 0.1% formic acid in methanol solution (solvent B) at a flow rate of 300 MUL/min. The analytes were monitored by tandem-mass spectrometry with positive electrospray ionization. The precursor/product transitions (m/z) in the positive ion mode were 435.9->163.6 and 706.7->392.6 for etravirine and the internal standard, respectively. Calibration curves were linear over the etravirine rat plasma concentration range of 1-100 ng/mL. The inter- and intra-day accuracy and precision were within +/-10%. The assay has been successfully used for pharmacokinetic evaluation of etravirine using the rat as an animal model. PMID- 20965800 TI - Comparison between distally based peroneus brevis and sural flaps for reconstruction of foot, ankle and distal lower leg: an analysis of donor-site morbidity and clinical outcome. AB - BACKGROUND: Skin defects of the foot, ankle and distal lower leg often require coverage by local or distant flaps. We aimed to compare functional outcome and donor-site morbidity following transfer of distally based delayed sural (DSFs) or peroneus brevis flaps (PBFs). METHODS: Between 2003 and 2006, 52 patients (24 DSFs and 28 PBFs) were included. For increased reliability, all extended sural flaps were delayed for 3-15 days. At the end of the follow-up period (minimum 12 months), patients were asked to fill out a modified foot and ankle score (Foot and Ankle Outcome Score (FAOS)) questionnaire. In addition, a chart review and a physical examination were performed. RESULTS: Total hospital stay and total number of operations were significantly lower in the PBF group. Minor flap necrosis (<10%) was observed in 21% of the DSF and 7% of the PBF group, and partial (>10%) or total flap loss occurred in one and three patients from the DSF group, respectively. Patient satisfaction, FAOS results and range of motion were comparable in both groups. Defect aetiology and patient age did not influence surgical outcome. CONCLUSION: Donor-site morbidity and functional outcome after DSF and PBF are comparable. A higher rate of complications was observed in the DSF group. Based on our findings, the PBF is recommended as first-line procedure for reconstruction of small- to medium-sized defects at the distal tibia, fibula, ankle and heel. The sural flap might be chosen for extended skin defects especially when a larger arc of rotation is required. PMID- 20965799 TI - MALDI imaging mass spectrometry--painting molecular pictures. AB - MALDI Imaging Mass Spectrometry is a molecular analytical technology capable of simultaneously measuring multiple analytes directly from intact tissue sections. Histological features within the sample can be correlated with molecular species without the need for target-specific reagents such as antibodies. Several studies have demonstrated the strength of the technology for uncovering new markers that correlate with disease severity as well as prognosis and therapeutic response. This review describes technological aspects of imaging mass spectrometry together with applications in cancer research. PMID- 20965801 TI - Management of infections in type 2 diabetes from the patient's perspective: a qualitative approach. AB - AIM: To explore the knowledge, and health beliefs of patients with type 2 diabetes mellitus (T2DM) regarding management of infections of the urinary tract (UTIs) and lower respiratory tract (LRTIs). METHODS: Three semi-structured focus groups with 23 patients with T2DM were conducted and analyzed. RESULTS: Only a few patients mentioned specific preventive measures for UTIs and LRTIs, like not smoking and taking enough fluids (n=3). Making a nuisance of oneself, denying the seriousness of the disease and fear of insulin therapy were barriers to health seeking behaviour. Some people did not complete the course of antibiotics (n=2) or forgot to take the tablets, especially when tablets had to be taken more than once a day (n=4). CONCLUSION: Our results showed that patients with T2DM lack knowledge and realistic health beliefs about common infections such as UTIs and LRTIs. Health education should aim to help patients with T2DM to interpret symptoms of infections correctly in order to take the appropriate action such as taking preventive measures or taking antibiotics. Identifying patients at high risk of a complicated infection may target education towards those who need it most. PMID- 20965803 TI - Electrocardiographic ST-segment depression and exposure to traffic-related aerosols in elderly subjects with coronary artery disease. AB - BACKGROUND: Air pollutants have not been associated with ambulatory electrocardiographic evidence of ST-segment depression >= 1 mm (probable cardiac ischemia). We previously found that markers of primary (combustion-related) organic aerosols and gases were positively associated with circulating biomarkers of inflammation and ambulatory blood pressure in the present cohort panel study of elderly subjects with coronary artery disease. OBJECTIVES: We specifically aimed to evaluate whether exposure markers of primary organic aerosols and ultrafine particles were more strongly associated with ST-segment depression of >= 1 mm than were secondary organic aerosols or PM2.5 (particulate matter with aerodynamic diameter <= 2.5 um) mass. METHODS: We evaluated relations of air pollutants to ambulatory electrocardiographic evidence of cardiac ischemia over 10 days in 38 subjects without ST depression on baseline electrocardiographs. Exposures were measured outdoors in retirement communities in the Los Angeles basin, including daily size-fractionated particle mass and hourly markers of primary and secondary organic aerosols and gases. Generalized estimating equations were used to estimate odds of hourly ST-segment depression (>= 1 mm) from hourly air pollution exposures and to estimate relative rates of daily counts of ST-segment depression from daily average exposures, controlling for potential confounders. RESULTS: We found significant positive associations of hourly ST-segment depression with markers of combustion-related aerosols and gases averaged 1-hr through 3-4 days, but not secondary (photochemically aged) organic aerosols or ozone. The odds ratio per interquartile increase in 2-day average primary organic carbon (5.2 ug/m3) was 15.4 (95% confidence interval, 3.5 68.2). Daily counts of ST-segment depression were consistently associated with primary combustion markers and 2-day average quasi-ultrafine particles < 0.25 um. CONCLUSIONS: Results suggest that exposure to quasi-ultrafine particles and combustion-related pollutants (predominantly from traffic) increase the risk of myocardial ischemia, coherent with our previous findings for systemic inflammation and blood pressure. PMID- 20965804 TI - Home characteristics as predictors of bacterial and fungal microbial biomarkers in house dust. AB - BACKGROUND: Measurement of fungal and bacterial biomarkers can be costly, but it is not clear whether home characteristics can be used as a proxy of these markers, particularly if the purpose is to differentiate specific classes of biologic exposures that have similar sources but may have different effects on allergic disease risk. OBJECTIVE: We evaluated home characteristics as predictors of multiple microbial biomarkers, with a focus on common and unique determinants and with attention to the extent of their explanatory ability. METHODS: In 376 Boston-area homes enrolled in a cohort study of home exposures and childhood asthma, we assessed the relationship between home characteristics gathered by questionnaire and measured gram-negative bacteria (GNB) (endotoxin and C10:0, C12:0, and C14:0 3-hydroxy fatty acids), gram-positive bacteria (GPB) (N-acetyl muramic acid), and fungal biomarkers [ergosterol and (1->6) branched, (1->3) beta D glucans] in bed and family room dust. RESULTS: Home characteristics related to dampness were significant predictors of all microbial exposures; water damage or visible mold/mildew in the home was associated with a 20-66% increase in GNB levels. Report of cleaning the bedroom at least once a week was associated with reduced GNB, GPB, and fungi. Presence of dogs or cats predicted increases in home bacteria or fungi. The proportion of variance in microbial biomarkers explained by home characteristics ranged from 4.2% to 19.0%. CONCLUSIONS: Despite their associations with multiple microbial flora, home characteristics only partially explain the variability in microbial biomarker levels and cannot substitute for specific microbial measurements in studies concerned with distinguishing effects of specific classes of microbes. PMID- 20965805 TI - SMOC2 gene variant and the risk of vitiligo in Jordanian Arabs. AB - Generalized vitiligo is a common autoimmune disorder, characterized by patchy loss of pigmentation due to melanocyte death. It is a multifactorial disorder in which multiple genes and environmental triggers contribute to the expression of the phenotype. Different genetic variants can have varying effects on having vitiligo. Recently, an SMOC2 variant (rs13208776) was reported to be associated with vitiligo in Caucasian patients from an isolated founder population. In this study, we investigate the association of SMOC2 variant with Jordanian Arab vitiligo patients. Forty-four patients with generalized vitiligo and 151 matched normal controls were recruited. DNA samples were obtained from patients and controls and samples were genotyped for SMOC2 variant by restriction fragment length polymorphism. Allelic frequency of the less common allele (A allele) was 29.5% in patients compared to 19.6% in the controls (p = 0.27). Genotypic frequency for AA was 4.5% in patients and 7.9% in controls while heterozygous genotypes were 50% for patients and 33.1% in controls. Genotypes did not show statistical difference in patients versus control (p = 0.12). Our data shows that the variant rs13208776 in SMOC2 gene does not play a major role in increasing the risk of vitiligo in Jordanian Arab patients. This is in contrast to the previous association reported for Caucasian patients from an isolated patient population in Romania. This signifies genetic differences in the two populations. PMID- 20965806 TI - Lactobacillus paracasei CNCM I-2116 (ST11) inhibits substance P-induced skin inflammation and accelerates skin barrier function recovery in vitro. AB - Over the past few decades the number of people presenting reactive skin has increased in industrial countries. Skin inflammation mediated by neuropeptides and impaired skin barrier function are both underlying features of reactive skin conditions. Live microorganisms defined as probiotics have been successfully used to improve health status in humans. Beyond the effects on intestinal microbiota, some probiotic strains display potent immune-modulatory properties at the skin level. The aim of this study was to evaluate whether Lactobacillus paracasei CNCM I 2116 (ST11) could modulate reactive skin-associated inflammatory mechanisms. The Caco-2/PBMC co-culture cell system was stimulated on the apical side with probiotics. The resulting medium collected from the basolateral compartment of the cell culture system, so called conditioned medium, was tested in ex vivo human abdominal plastic skin explant models of substance P-induced skin inflammation and skin barrier reconstruction. We show that ST11 was able to abrogate vasodilation, edema, mast cell degranulation and TNF-alpha release induced by substance P, compared to control. Moreover, using ex vivo skin organ culture, we show that ST11-conditioned medium induced a significantly faster barrier function recovery after SLS disruption, compared to control. These results support a beneficial role of ST11 on key biological processes associated with barrier function and skin reactivity. PMID- 20965807 TI - Small vessel vasculitis related to 5-fluorouracil and folinic acid. PMID- 20965808 TI - [Cluster analysis in micrangium detection in malignant nasal and paranasal sinus tumor]. AB - OBJECTIVE: To study the application of cluster analysis in micrangium detection in malignant nasal and paranasal sinus tumor. METHODS: Microvessel density (MVD) counting and cluster analysis were used to detect the micrangium in patients with malignant nasal and paranasal sinus tumor to assess the association between the malignancy and MVD. RESULTS: According to cluster analysis, the MVD counting could be clustered into two groups, and the MVD showed significant differences between the tumor tissues, adjacent normal tissue and the control group (P<0.01), a result consistent with that by analysis of variance of the MVD. CONCLUSION: Cluster analysis can be used in clustering of MVD counting in malignant nasal and paranasal sinus tumor to simplify MVD counting, and offers an important analytic method for micrangium analysis in tumors. PMID- 20965809 TI - [Preparation and identification of monoclonal antibodies against Chlamydia trachomatis Tarp protein]. AB - OBJECTIVE: To obtain monoclonal antibodies (mAbs) against Chlamydia trachomatis Tarp protein. METHODS: Chlamydia trachomatis serovar D recombinant Tarp fusion protein was cloned and expressed. Balb/c mice were immunized with recombinant Tarp fusion protein, and the spleen cells of the immunized mice were fused with SP2/0 mouse myeloma cells. The hybridoma cell lines secreting mAbs against Tarp protein were screened by an indirect immunofluorescence assay and subcloned by limiting dilution culture. The specificities of these mAbs to Tarp were determined by ELISA, and their isotype and chlamydial species specificity identified by an indirect immunofluorescence assay. RESULTS: Recombinant GST-Tarp fusion protein with a relative molecular mass of about 136 000 was successfully cloned and expressed. Seven hybridoma cell lines stably secreting specific mAbs against Tarp protein were obtained. All the 7 mAbs reacted strongly with Tarp protein but not with other chlamydial proteins. Two mAbs were identified to belong to IgG2a isotype and the other 5 to IgG1 isotype. All the 7 mAbs reacted strongly with chlamydia serovar A, D, and L2, but not with MoPn, 6BC, or AR39. CONCLUSION: The highly specific mAbs against Tarp protein have been obtained to facilitate further study of the structure and function of Chlamydia Tarp protein. PMID- 20965810 TI - [Sparse angular CT projection onto convex set reconstruction using nonlocal means iterative modification]. AB - Based on the fact that nonlocal means (NL-means) filtered image can likely produce an acceptable priori solution, we propose a sparse angular CT projection onto convex set (POCS) reconstruction using NL-means iterative modification. The new reconstruction scheme consists of two components, POCS and NL-means filter. In each phase of the sparse angular CT iterative reconstruction, we first used POCS algorithm to meet the identity and non-negativity of projection data, and then performed NL-means filter to the image obtained by POCS method for image quality improvement. Simulation experiments showed that the proposed POCS scheme can significantly improve the quality of sparse angular CT image by suppressing the noise and removing the streak-artifacts. PMID- 20965811 TI - [Evaluation of jaws-only intensity-modulated radiation therapy for nasopharyngeal carcinoma]. AB - OBJECTIVE: To investigate the feasibility and efficiency of jaws-only intensity modulated radiation therapy (JO-IMRT) in treatment of nasopharyngeal carcinoma (NPC) using direct aperture optimization (DAO) technique and the independent jaws of linear accelerator. METHODS: Both JO-IMRT and MLC-IMRT were planed in 10 NPC cases. The differences in the target coverage and dose uniformity, as well as the total monitor units and delivery times of the two IMRT plans were compared. RESULTS: All the tested plans met the clinical requirement of the designed simplified IMRT (sIMRT). The conformal index (CI) of JO-IMRT and MLC-IMRT were 0.941+/-0.015 and 0.981+/-0.013, respectively (P<0.001), showing a minor superiority of MLC-IMRT. While controlling the total segment numbers to approach the limitation of sIMRT, the two therapies showed a total MU of 474.3 and 419.6 (P<0.05) with delivery times of 8.0 and 7.5 min (P<0.01), respectively. The efficiency of JO-IMRT was slightly lower than that of MLC-IMRT. CONCLUSION: JO IMRT can meet the sIMRT requirement in NPC treatment, and is feasible as an alternative treatment modality for the centers not equipped with MLC in their accelerators. PMID- 20965812 TI - [Surface modification and DNA-binding assessment of nano-hydroxyapatite]. AB - OBJECTIVE: To evaluate the impact of surface modification on the DNA-binding ability of nano-hydroxyapatite (nHA). METHODS: Chemical co-precipitation hydrothermal synthesis was utilized to prepare the nHA particles, and polyethylenimine (PEI) was used for surface modification of the nHA. Transmission electron microscopic (TEM) observation and zeta potential detection of the nHA were carried out before and after surface modification. The abilities of the nanoparticles, at different pH values and different concentrations, for DNA binding and DNA protection against nuclease digestion were assessed before and after surface modification by electrophoresis. RESULTS: TEM observation showed a short rod-like morphology of PEI-modified nHA with uniform particle size and good dispersion; the nHA without the modification tended to aggregate with poor dispersion. With a positive zeta potential, the PEI-modified nHA showed an obviously enhanced ability of DNA binding at different pH values and concentrations, with strong capacity to protect the DNA against Dnase I digestion. At the concentration of 250 ug/ml and a pH value of 7.0, the nHA-PEI showed an optimal efficiency of DNA-binding and DNA protection. CONCLUSION: nHA with surface modification by PEI can serve as an effective vector for DNA binding and transfer. PMID- 20965813 TI - [A survey of the resources of medicinal plants in Luoding City]. AB - OBJECTIVE: To investigate the common resource of Chinese herbal medicine in western of Luoding City, Guangdong Province, and propose pertinent suggestions concerning the exploitation,utilization and conservation of the medicinal resources. METHODS: With plant taxonomy method, we selected the JiaYi town as the center for local common Chinese herbal medicine resources, ecological environment and non-governmental investigation of medicinal. RESULTS: There were 123 species of medicinal plants in Jiayi Town, including pteridophyte 11 species, gymnosperm 5 species, dicotyledon 97 species,and monocotyledon 12 species. CONCLUSION: This region has an excellent ecological environment and forest plant communities preserved relatively intact suitable for the growth of Lingnan Chinese herbal medicine, as well as a profound cultural background of folk medicine. The resources should be actively protected for further rational development and utilization. PMID- 20965814 TI - [Clinical application of anticoagulation treatment with warfarin after prosthetic heart valve replacement: a single center-based survey]. AB - OBJECTIVE: To investigate the clinical application of anticoagulation treatment with warfarin after prosthetic heart valve replacement and compare the effect and safety of different anticoagulant intensities. METHODS: A total of 845 Chinese patients receiving oral warfarin for anticoagulant treatment after prosthetic heart valve replacement in Guangdong General Hospital between 2000 and 2008 were enrolled in this survey. The general data, clinical data, medications, international normalized ratio (INR) and results of echocardiogram of these patients were followed up to observe the incidence of complication of thrombo embolism and such adverse effect as hemorrhage. RESULTS: All the patients were of Han nationality, and Cantonese accounted for 88.04%. The daily mean maintenance dose of warfarin was 2.92?0.88 mg in these patients with a median INR of 2.09?0.39. Of these patients, 44.62% received low-intensity anticoagulant treatment with warfarin with the INR maintained between 1.5 and 2.0, and 56.45% had standard anticoagulant intensity with the INR maintained between 2.0 and 3.0. The total incidence of thrombo-embolism was 4.14%. Severe hemorrhage occurred in 14 cases (1.66%), most frequently in the alimentary tract. The events of hemorrhage were correlated to the type of prosthetic heart valve replacement, occurring more frequently in patients with mechanical prosthetic heart valve replacement than in those with biological ones. No significant difference was found in the incidence of thrombo-embolism and server hemorrhage between the two groups receiving low and standard intensity therapy anticoagulant. CONCLUSION: The effect and safety of low-intensity anticoagulant treatment are comparable to that of standard intensity treatment in Chinese Han patients, and anticoagulation treatment with warfarin is effective and safe to maintain the INR between 1.8 3.0. PMID- 20965815 TI - [TrxR2 gene polymorphisms may not be associated with the susceptibility to Kashin Beck disease]. AB - OBJECTIVE: To study the association between single nucleotide polymorphisms of thioredoxin reductase-2 (TrxR2) gene and the susceptibility to Kashin-Beck disease (KBD). METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to analyze the genotype frequencies of rs5748469 in TrxR2 gene in 84 KBD patients and 109 healthy control subjects. RESULTS: The genotype frequencies of A/A, A/C, and C/C in the KBD patients were 83.33%, 15.48% and 1.19%, as compared with the frequencies of 74.31%, 25.69%, and 0.00% in the healthy control, respectively, showing no significant difference in the single nucleotide polymorphisms of TrxR2 gene between the two groups (P=0.13). CONCLUSION: No obvious correlation can be found between rs5748469 polymorphisms in TrxR2 gene and the susceptibility to KBD. PMID- 20965816 TI - [Alterations of peripheral blood T cell subsets in patients with sepsis and the clinical implications]. AB - OBJECTIVE: To observe the dynamic changes of CD3+, CD4+, and CD8+ T lymphocytes in the peripheral blood of patients with sepsis and discuss the clinical significance. METHODS: Sixty-four patients admitted in the Emergency Center and Emergency Intensive Care Unit of the Second Hospital of Wenzhou Medical University between August, 2007 and July, 2009 were enrolled in this study. CD3+, CD4+, and CD8+ T lymphocytes in the peripheral blood were detected by flow cytometry on days 1, 7 and 14 after admission, and the results were compared between the patients with improvement of the condition and those without improvement, with 20 healthy subjects as the control group. RESULTS: On day 1 after admission, CD3+ and CD4+ T lymphocytes and CD4+/CD8+ T cell ratio were obviously lower in the 2 groups of patients with sepsis than in the control group (P<0.05), but no significant difference was found in CD8+ T lymphocytes. The sepsis patients with clinical improvement showed significant higher CD3+ and CD4+ T lymphocyte percentages and CD4+/CD8+ T cell ratio than those without improvement on day 1. In the patients with clinical improvement, CD3+ and CD4+T lymphocytes and CD4+/CD8+ T cell ratio increased gradually with time and till day 14, they were comparable with the control levels; in the patients without improvement, CD3+ and CD4+ T lymphocytes and CD4+/CD8+ T cell ratio showed no obvious alterations in the course of observation. CONCLUSION: Immune imbalance occurs in patients with sepsis represented by lowered CD3+ and CD4+T lymphocyte percentages and CD4+/CD8+ T cell ratio in relation to the severity of the condition. CD3+ and CD4+ T lymphocytes and CD4+/CD8+ T cell ratio can be used as the indicators for assessing the severity of sepsis. PMID- 20965817 TI - [Improved weighted cross-correlation coefficient with a new kernel and its application in predicting T cell epitopes]. AB - We designed a weighted cross-correlation coefficient considering the "anchor" of the T cell epitopes, and used an evolutionary algorithm to search for an optimal weight vector. A SVM model with this new peptide similarity kernel was evaluated on a T-cell data set. The results demonstrated a good performance of this method. PMID- 20965818 TI - [Immunophenotypic comparison of adipose-derived mesenchymal stem cells from the greater omentums and subcutaneous adipose tissues of rats]. AB - OBJECTIVE: To compare the adipose-derived mesenchymal stem cells (ADMSCs) isolated from the greater omentums and subcutaneous adipose tissues of rats for their characteristics in cell morphology, growth kinetics and immunophenotypes. METHODS: ADMSCs were isolated from the greater omentums and inguinal fat pads of 6 SD rats and cultured in vitro. The morphologies of the ADMSCs were observed using phase-contrast microscopy, and their growth curves were generated and the doubling times determined. The phenotypic marker profiles including CD11b, CD29, CD45, CD49d, CD90 and CD106 of the ADMSCs in the fourth passage were determined using flow cytometry. RESULTS: The ADMSCs harvested from the greater omentums and inguinal fat pads showed almost identical morphologies. The growth curves and the mean doubling time of the ADMSCs from the two different sources showed no obvious difference. With similar positivity rates for CD11b, CD29, CD106 and CD90, the two ADMSCs exhibited different expression rates of CD45 and CD49d. CONCLUSIONS: The immunophenotypic characteristics of the ADMSCs from the greater omentums and subcutaneous adipose tissues are not totally identical. PMID- 20965819 TI - [Hemodynamic changes of pregnant rats with pre-eclampsia after treatment with low energy laser irradiation of the chest]. AB - OBJECTIVE: To observe the hemodynamic changes and liver and kidney function variations in pregnant rats with pre-eclampsia after treatment with low-energy laser irradiation. METHODS: Forty pregnant SD rats were randomly divided into the experimental group (group A), experimental control group (group B), blank control group (group C) and blank exposure group (group D) (n=10). The rats in groups A and B were injected with 1 ug/kg endotoxin via the tail vein at the 14th day of gestation, and those in groups C and D received normal saline injections. In groups A and B, low-energy laser irradiation of the chest was carried out since day 16 of gestation. Blood pressure, urine protein, liver and kidney function and the hemodynamic changes in the rats were observed. RESULTS: After the treatment, blood pressure, urine protein, ALT, BUN and Cr of group A were lower than those of group B (P<0.05), but similar with those in groups C and D (P>0.05). The blood and plasma viscosity and hematocrit of group A were also lower than those of group B (P<0.01), but comparable with those in groups C and D. CONCLUSION: Low energy laser irradiation in the chest area may improve the hemodynamic indices, decrease blood pressure and urine protein, and ameliorate liver and kidney functions in pregnant rats with pre-eclampsia. PMID- 20965820 TI - [In vitro fertilization versus intracytoplasmic sperm injection for primary and secondary infertility using sibling oocytes: clinical analysis of the outcomes]. AB - OBJECTIVE: To evaluate the clinical outcomes of intracytoplasmic sperm injection (ICSI) and conventional in vitro fertilization (IVF) using sibling oocytes for treatment of primary and secondary infertility. METHODS: A total of 149 cycles of IVF and ICSI were conducted between January, 2003 and December, 2008 in our center, including 98 cycles in patients with primary infertility and 51 in those with secondary infertility. According to the embryos derived from ICSI, IVF and their combination, the clinical pregnancy rate, delivery rate and birth defect of the 3 groups were analyzed. RESULTS: The fertilization failure rate of IVF was significantly higher in primary infertility group than in secondary infertility group (10.2% vs 3.9%, P<0.05). No fertilization failure occurred in ICSI group. The fertilization rates and good quality embryo rates in ICSI group were significant higher than those in IVF group, and the abnormal fertilization rate was significantly lower in ICSI group (P<0.05). No significant difference were found in the implantation rates, clinical pregnancy rates, delivery rates or the rates of birth defects of the offsprings between IVF, ICSI and IVF+ICSI groups. CONCLUSION: IVF combined with ICSI may result in increased fertilization rate and avoid total fertilization failure with favorable clinical outcomes in patients with long-term infertility, and ICSI may not increase the birth defects of the offspring in these patients. PMID- 20965821 TI - [Colloidal gold and dot-ELISA rapid tests for screening influenza A virus]. AB - OBJECTIVE: To evaluate the diagnostic efficiency of colloidal gold and dot ELISA rapid tests in clinical screening of influenza A virus. METHODS: The pharyngeal swabs were collected from 297 outpatients suspected of influenza between June and October, 2009 for detection with colloid gold and dot ELISA rapid test, with real time PCR as the golden methods. The discrepant results of colloid gold and dot ELISA methods were confirmed by sequencing, and the diagnostic efficiency of the two methods was evaluated. RESULTS: Among the 166 samples with influenza A virus infection as confirmed by real-time PCR and sequencing, the diagnostic sensitivity of dot ELISA and colloid gold methods was 54.82% (91/166) and 4.22% (7/166), respectively. The total concordance rate with PCR was 66.67% (Kappa value of 0.35). Among the 133 samples negative for influenza A virus, the specificity of dot ELISA and colloid gold methods was 81.68% (107/131) and 98.47% (129/131), respectively, with a total concordance rate with PCR of 45.79% (Kappa value 0.02). Of the 99 H1N1 influenza samples confirmed by real-time PCR, the detection rate of dot ELISA was 67.3%, whereas that of colloid gold was 5.1%. Out of the 107 dot ELISA-positive but colloid gold-negative samples, 84 were confirmed to be influenza A virus-positive by real-time PCR and sequencing. One sample negative for dot ELISA but positive for colloid gold test was confirmed to be influenza A virus-negative. The detection rate and diagnostic concordance rate for influenza A virus by dot ELISA were significantly higher than those of colloid gold (P<0.05). CONCLUSION: Dot ELISA is better than colloid gold in influenza A virus detection and shows great prospect in clinical screening. PMID- 20965822 TI - [A novel method for hepatitis C virus genotyping using RT-PCR reverse dot blot hybridization technique]. AB - OBJECTIVE: To develop a rapid and specific method for hepatitis C virus ( HCV) genotyping using reverse dot blot hybridization technique and investigate the distribution of HCV genotypes and subtypes in Guangdong. METHODS: The primers and the probes targeting the 5'untranslated region (5'UTR) and core region of HCV genotypes 1b, 2a, 3a, 3b and 6a were designed, and the RT-PCR reverse dot blot hybridization (PCR-RDH) method for HCV genotyping was established. A total of 115 patients with hepatitis C were genotyped using this method, and 38 of them were also genotyped by sequencing and phylogenetic analysis to evaluate the accuracy and specificity of the method. RESULTS: Of the 115 patients, 111 were successfully genotyped to be 1b, 2a, 3a, 3b, 6a and mix-infection of 1b/2a at frequencies of 56.8%, 8.1 %, 3.6%, 5.4%, 25.2% and 0.9% respectively, and all the 15 healthy control samples showed negative results. The accuracy and reliability of the genotyping method of PCR-RDH was confirmed in 38 cases by amplification of HCV core and NS5B regions followed by DNA sequencing and phylogenetic analysis. CONCLUSION: This method for HCV genotyping, with high reliability and specificity, is suitable for clinical and epidemiological investigations. The prevalence of HCV genotypes 1b and 2a decreases while 1b remains the dominant genotype in Guangdong, where the prevalence of 6a significantly increases as compared with that 10 years ago. PMID- 20965823 TI - [Establishment of a three-dimensional finite element model and stress analysis of the talus during normal gait]. AB - OBJECTIVE: To develop a three-dimensional (3D) finite element model of the human ankle with fine details and analyze the stress distribution on the talus during different gait phases. METHODS: Mimics13.0 and Geomagic10.0 software were used for geometric reconstruction of the ankle based on the 3D CT data of the foot. The model was meshed and assigned with the material properties in Hypermesh10.0 software. The model was then imported to Abaqus6.9, and the stress condition of the talus during the 3 phases (heel-strike, midstance, push-off) of normal gait was simulated to calculate the stress distribution within the bone. RESULTS: The three-dimensional finite element model of the ankle established consisted of 21 865 nodes and 73 440 elements. The stress distribution within the bone in 3 phases of normal gait differed significantly. The peak von Mises stress on the talus dome, from the heel-strike to push-off phases, was 3.0 MPa, 4.3 MPa and 4.8 MPa, as compared to 1.3 MPa, 1.9 MPa and 2.8 MPa on the talar neck, 2.8 MPa, 3.0 MPa, and 3.4 MPa on the talonavicular joint surface, and 2.2 MPa, 1.8 MPa and 1.5 MPa on the subtalar joint, respectively. CONCLUSION: The finite element model of the talus shows a good response against the experimental data and can be used to simulate the biomechanic experiment of the talus. PMID- 20965824 TI - [Exercise-induced changes of T lymphocytes subgroups and immune factors]. AB - OBJECTIVE: To investigate the changes in white blood cell populations, lymphocyte subsets and stress-related cytokines after long-term exercise training and address the association between blood cell changes and stress-related cytokines in relation to exercise. METHODS: A total of 1038 professional athletes were examined for CBC with Sysmex XE2100, and the T, B, and NK lymphocyte subsets were analyzed with flow cytometry. The testees' RNA were extracted from 1 ml whole blood, and the stress-related cytokines such as CRP, SELL,TNF-alpha, IL8, IL4, ICAM1, PECAM1, IL6, and NOS were tested by multi-RT-PCR and fragments separated by capillary electrophoresis using Beckman Coulter GeXP system. RESULTS: No obvious difference was found in WBC count between the athletes, all within normal range. The proportion of lymphocytes was increased in the athletes by 20%-40% in comparison with the normal level, and the CD3+, CD3+CD4+, and CD3+CD8+ T, B, and NK lymphocyte subsets were all lower in the athletes than the normal range. The cytokine expressions exhibited no significant gender-related difference. IL-8, TNF-alpha and SELL expressions increased while IL-4 decreased in the athletes. Correlations were noted between the changes of the cells and the cytokine expressions. CONCLUSION: Long-term exercise training affects the immune system and cause stress, which may potentially increase the risks of some chronic diseases. PMID- 20965825 TI - [Effects of three types of veneering porcelain on bending strength of KAVO(TM) Y TZP/porcelain bilayered structure]. AB - OBJECTIVE: To investigate the effect of three types of veneering porcelain on the bending strength of KAVO Y-TZP/porcelain layered structure. METHODS: KAVO zirconia ceramics were used as the substructure. To form Y-TZP/porcelain bilayered structure, a leucite-based veneering porcelain was fired on the zirconia substructures by slip-casting technique with dentin washbake, and two nano-fluorapatite-based veneering porcelains were fired on the zirconia substructures by either slip-casting or pressed-on technique with or without liner coverage. The bending strength was tested according to ISO 6872 standard, and the veneered surfaces of the fracture samples were analyzed by scanning electron microscopy (SEM). RESULTS: For covering KAVO zirconia core material, the conventional veneering slurry-porcelain combined with liner or wash firing had significant higher bending strength than pressed-on porcelain. SEM showed that the main failure type at the interface was adhesive failure. CONCLUSION: Thin layer sintering using washbake program or liner on KAVO zirconia surface increases the surface wettability, and this procedure may be indispensable when veneering on the surface of dental zirconia. PMID- 20965826 TI - [Effect of nuclear factor-kappa B decoy oligodeoxynucleotides on IL-10, IL-13 and nuclear factor-kappa B protein expressions in rabbits with severe lung contusion]. AB - OBJECTIVE: To explore the effect of nuclear factor-kappa B (NF-kappaB) decoy oligodeoxynucleotides (ODN) on serum NF-kappaB, IL-10, IL-13 and pulmonary NF kappaB protein expression in rabbits with severe lung contusion. METHODS: Forty New Zealand rabbits were randomly divided into severe lung contusion group (group A, n=12), lung contusion with NF-kappaB scrambled decoy ODN group (group B, n=12), lung contusion with sense NF-kappaB decoy ODN group (group C, n=12), and normal control group (n=4). After establishment of the contusion injury model, the sense and scrambled NF-kappaB decoy ODN were infused into the rabbits via the jugular vein accordingly. Serum NF-kappaB, IL-10, and IL-13 and NF-kappaB protein expressions in the lung tissue were detected before and at 1, 2, 3, and 4 h after the contusion. RESULTS: Two hours after sense NF-kappaB decoy ODN intervention, the expression of NF-kappaB began to decrease and reached the lowest level at 3 h; pulmonary IL-10 and IL-13 expressions decreased at 1 h after contusion, to the lowest level at 2 and 4 h, respectively. After sense NF-kappaB decoy ODN intervention, the expression of IL-10 and IL-13 increased and NF-kappaB protein expression decreased significantly in comparison with those in groups A and B (P<0.01). CONCLUSION: Sense NF-kappaB decoy ODN can significantly reduce the serum NF-kappaB expression, increase serum IL-10 and IL-13 levels and decrease pulmonary NF-kappaB protein expression in the early stages after severe lung contusion in rabbits. PMID- 20965827 TI - [Effects of pulsed magnetic field on insulin-like growth factor-1 (IGF-1) in cerebrospinal fluid and effects of IGF-1 on functional recovery]. AB - OBJECTIVE: To study the effects of pulsed magnetic field on insulin-like growth factor-1 (IGF-1) level in the cerebrospinal fluid (CSF) and the association of IGF-1 alterations with the activities of daily living (ADL) of patients with brain injury. METHODS: Sixty-five patients with brain injury were divided randomly into the control group (n=30) and magnetic therapy group (n=35), both receiving conventional therapy and in the latter group, daily pulsed magnetic field treatment (20-40 mT, 50 Hz, 20 min per time, 1 time per day) for 14 consecutive days were administered. On the first and 14th days of the treatment, 2 ml CSF was collected from the cases patients for IGF-1 measurement by radioimmunoassay, and Barthel index (BI) was used to assess the ADL of the patients. RESULTS: After a 14-day treatment, IGF-1 level in the CSF were significantly increased in the magnetic group in comparison with the level before the treatment and with those in the control group (P<0.05). IGF-1 in the CSF underwent no significant changes in the control group (P>0.05). The scores of BI increased significantly in both groups after the treatment (P<0.01), but the increment was more obvious in the magnetic therapy group (P<0.05). A significant positive correlation was found between IGF-1 level in the CSF and BI in these patients (r=0.283, P=0.022). CONCLUSION: Pulsed magnetic field might increase IGF 1 level in the CSF of patients with brain injury to promote the recovery of the patients ADL, suggesting its potential clinical value in the treatment of brain injury. PMID- 20965828 TI - [Adriamycin enhances the sonodynamic effect of chlorin e6 against the proliferation of human breast cancer MDA-MB-231 cells in vitro]. AB - OBJECTIVE: To evaluate the effect of adriamycin (ADM) in enhancing the sonodynamic effect of chlorin e6 against the proliferation of human breast cancer MDA-MB-231 cells in vitro. METHODS: MDA-MB-231 cells were treated with ultrasound/Chlorin e6 alone or in combination with ADM, and the changes in the cell proliferation was determined by MTT assay. RESULTS: Ultrasound (1.0 MHz) at the power intensity of 0.5-2.0 W/cm2 inhibited the proliferation of MDA-MB-231 cells in an intensity-dependent manner, and chlorin-e6 (0.05-1.6 mg/ml) and ADM (0.1-0.4 g/ml) alone both inhibited the proliferation of MDA-MB-231 cells dose dependently. Compared with ultrasound (0.5 W/cm2, 1.0 MHz, 60 s) or chlorin-e6 (0.05-0.2 mg/ml) alone, a combined treatment with ultrasound and chlorin e6 significantly enhanced the inhibitory effect on the proliferation of MDA-MB-231 cells (P<0.05). ADM significantly enhanced the sonodynamic effect of chlorin e6 (0.1 mg/ml) against the cell proliferation of MDA-MB-231 cells (P<0.05), and the effect was schedule-dependent, which was greater when ADM was added after the sonodynamic treatment (P<0.05). CONCLUSION: ADM can enhance the sonodynamic effect of chlorin e6 against the proliferation of MDA-MB-231 cells in vitro. PMID- 20965829 TI - [Feasibility of proton magnetic resonance spectroscopy of the myocardium in vivo]. AB - OBJECTIVE: To investigate the feasibility of proton magnetic resonance spectroscopy ((1)H-MRS) of the myocardium in vivo. METHODS: A total of 100 volunteers were examined with 1H-MRS scan using a 1.5T MR scanner, and the magnetic resonance spectra were analyzed. RESULTS: All the volunteers completed the examinations, and the spectral peaks were identified with the chemical shifts of water (4.7 ppm), choline (3.2 ppm), creatine (3.0 ppm), and triglyceride (0.9 1.6 ppm), whose presentation ratios were 100%, 86%, 90%, and 98%, respectively. In 86 cases the spectra showed all the chemical shifts. The myocardial metabolite contents were expressed as the ratio of metabolites to water (%), and the contents of choline, creatine, and triglyceride were 1.94%, 1.95%, and 9.41%, respectively. CONCLUSION: (1)H-MRS can be used in detecting the metabolic products of myocardium in vivo. PMID- 20965830 TI - [T cell receptor constant alpha chain gene +1592C/T polymorphism may not be associated with IgA nephropathy]. AB - OBJECTIVE: To investigate the relationship between T cell receptor constant alpha chain (TCRCalpha) gene +1592C/T polymorphism and IgA nephropathy. METHODS: TCRCalpha +1592C/T genotypes were identified by PCR-RFLP and direct sequencing in 244 Chinese Han patients with IgA nephropathy, who were classified according to their genotype into CC (188 cases), CT (54 cases) and TT (2 cases) groups. The clinical and pathological data of the patients were analyzed in relation to the TCRCalpha +1592C/T genotypes. RESULTS: No significant differences in the clinical and biochemical indices were found in these patients with different TCRCalpha gene +1592C/T genotypes. TCRCalpha +1592C/T polymorphism was not found to contribute to severity or manifestations of renal pathology. CONCLUSIONS: TCRCalpha+1592C/T polymorphism may not be associated with the susceptibility to IgA nephropathy in the Chinese Han population. PMID- 20965832 TI - [An optoelectronic cervical cancer screening system for screening cervical cancer: comparison with cervical cytology]. AB - OBJECTIVE: To study the clinical value of optoelectronic cervical cancer screening system (TruScreen, TS) in the screening of cervical cancer in comparison with cervical cytology test. METHODS: A total of 392 patients were screened by TS, Pap, TCT, and HPV using the pathological and colposcopical results as the golden standard. The sensitivity, specificity, Kappa value and the area of under ROC of each method and their combinations (parallel tests) were compared. RESULTS: The sensitivity of TS, Pap, TCT and HPV were 32.2%, 42.2%, 74.4% and 47.8%, with specificity of 96.7%, 93.7%, 78.8% and 84.8% in detecting cervical cancer, respectively. The sensitivity of the parallel tests, namely TCT/HPV, TCT/TS, Pap/TS and HPV/TS were 65.6%, 87.8%, 82.2% and 86.7%, with the specificity of 81.1%, 74.5%, 75.8% and 67.2%, respectively. In light of the areas of under ROC, significant differences were noted between the parallel tests of TS/Pap and TS/TCT (P<0.05), but not between TCT/Pap and TCT/TS (P>0.05); significant differences were found between the parallel tests with TS and those without TS (P<0.05), but not between TS alone and the parallel tests incorporating TS (P>0.05), nor between the 4 parallel tests (P>0.05). CONCLUSION: As a new modality for early screening of cervical carcinoma, TS offers a means for real-time cancer detection with better diagnostic efficacy than Pap and HPV and equivalent efficacy to TCT. The combination of TS and cytological tests can further enhance the diagnostic accuracy. PMID- 20965831 TI - [Relationship between D2-40-labeled lymphatic vessel invasion and lymph node metastasis of breast cancer]. AB - OBJECTIVE: To investigate the feasibility of D2-40 labeling for detecting lymphatic vessels in breast cancer tissues and the clinicopathological implications of lymphatic vessel invasion (LVI). METHODS: Immunohistochemistry was used to detect the expression of D2-40 and lymphatic invasion in 72 cases of breast cancer and 15 benign breast tumor tissues, and their correlations to the clinicopathological factors were analyzed. RESULTS: The positivity rate of LVI was 69.4% in breast cancer tissue. In patients with lymph node metastasis, the positivity rate of LVI was significantly higher than that in patients without lymph node involvement (85.7% vs 54.1%, P<0.01), and LVI was found to be positively correlated to axillary lymph node metastasis (r=0.382). CONCLUSION: D2 40 can specially and reliably mark the lymphatic vessels in breast cancer tissues. LVI is positively correlated to axillary lymph node metastasis and occurs earlier than the latter, therefore should be included in routine clinicopathological testing. PMID- 20965833 TI - [High glucose induces INS-1 cell apoptosis by activating nuclear factor-kappaB]. AB - OBJECTIVE: To study of the role of nuclear transcription factor-kappaB (NF kappaB) in high glucose-induced apoptosis in INS-1 cells. METHODS: Rat insulinoma (INS-1) cells cultured in RPMI 1640 medium were treated with 11.1 mmol/L glucose, 33.3 mmol/L glucose, or 33.3 mmol/L glucose plus 5 umol/L NF-kappaB inhibitors for 48 h. The expression of NF-kappaB subunit P65 protein in the cell nuclei was detected by Western blotting, IKK belta mRNA level by quantitative RT-PCR, and cell apoptosis by Annexin V-PI double staining. RESULTS: Compared with the control levels, IKK belta mRNA levels of the cells significantly increased in response to 33.3 mmol/L glucose exposure (P<0.01), which also resulted in significantly increased P65 protein expression in the cell nuclei (P<0.01) and cell apoptosis rate (P<0.05). Compared with those in the high glucose group, the expression of IKK belta mRNA and P65 protein and cell apoptosis rate decreased significantly after treatment with 33.3 mmol/L glucose plus 5 umol/L NF-kappaB inhibitors (P<0.05). CONCLUSION: High glucose induces NF-kappaB activation in INS 1 cells, and inhibition of NF-kappaB activation may protect INS-1 cells from high glucose-induced cell apoptosis. PMID- 20965834 TI - [Construction of pNTAP-MK2 eukaryotic expression plasmid and establishment of a cell line for its stable expression]. AB - OBJECTIVE: To construct pNTAP-MK2 eukaryotic expression plasmid and establish a HEK293 cell line stably expressing tandem affinity purification (TAP)-tagged MK2. METHODS: The MK2-encoding region was subcloned into the vector pNTAP to construct the recombinant plasmid pNTAP-MK2, which was subsequently transformed into DH5 alpha.E.coli. After identification by PCR, digestion with restriction endonuclease and sequencing, the recombinant expression plasmid was transfected into HEK293 cells via liposome, and the cell line with stable expression of exogenous TAP tag-MK2 gene was selected by antibiotic G418. The expression and localization of the fusion protein TAP tag-MK2 were detected by Western blotting and immunofluorescence assay. RESULTS: The results of PCR, restriction endonuclease digestion and sequencing all confirmed the correct construction of the recombinant eukaryotic expression plasmid pNTAP-MK2. Western blotting showed that the recombinant plasmid was expressed stably in HEK293 cells after transfection with G418 selection. Immunofluorescence assay identified the expression product TAP tag-MK2 mainly in the cell nuclei. CONCLUSION: The eukaryotic expression vector pNTAP-MK2 has been successfully constructed, and in the established cell line with stable expression of TAP tag-MK2, TAP tag does not influence the localization of exogenous MK2. PMID- 20965835 TI - [Reactive oxygen species participates in low glucose-induced injury of ECV304 cells]. AB - OBJECTIVE: To investigate the mechanism of low glucose-induced injury in human ECV304 cells. METHODS: Human umbilical vein endothelial cell line ECV304 were stimulated with low concentrations of glucose. The level of reactive oxygen species (ROS) in cells was detected at different time points within 12 h by kinetic measurement of dichlorofluorescein (DCF) fluorescence produced by oxidation of an oxidant-sensitive dye 2,7-dichlorofluorescein (DCFH). ECV304 cell viability was assessed with MTT assay and NADPH oxidase activity detected using lucigenin-enhanced chemiluminescence assay following cell stimulation with low glucose and apocynin. RESULTS: Low-glucose exposure of ECV304 cells time- and dose-dependently induced ROS production, and which was decreased by apocynin treatment. Apocynin pretreatment of the cells inhibited ROS production by 44% in cells exposed to 2.8 mmol/L glucose and by 60% in cells without glucose exposure. CONCLUSIONS: Low glucose of ECV304 cells induces ROS production to cause cell injury, which is mediated partially by NADPH oxidase activation. PMID- 20965836 TI - [Variations of the amount of sialic acids on hepatocellular carcinoma cell membrane]. AB - OBJECTIVE: To observe the change in the amount of sialic acids on hepatocellular carcinoma (HCC) cell membrane. METHODS: Surgical specimens of HCC and liver cirrhosis tissues were obtained from 28 patients to prepare carcinoma cell and hepatocyte suspensions by collagenase digestion. For assay of alpha2, 3 and alpha2, 6-sialic acids, the cells were suspended in the staining buffer containing either fluorescein isothiocyanate-Maackia amurensis lectin (FITC-MAL) or fluorescein isothiocyanate-Sambucus nigra bark lectin (FITC-SNA) and incubated for 1 h, respectively. Flow cytometric analysis was carried out to measure the mean fluorescence intensity (MFI) on the cell surface. RESULTS: In both FITC-MAL- and FITC-SNA-incubated HCC cells, the MFI on the cell surface was greater than that of the hepatocytes. CONCLUSION: Both of alpha2, 3 and alpha2, 6- sialic acids increases significantly on the hepatocyte membrane after the carcinomatous change. PMID- 20965837 TI - [Ultrasound-mediated microbubble destruction enhances LMP-1 gene transfection into dendritic cells in vivo]. AB - OBJECTIVE: To investigate the transfection efficiency and the optimal conditions of delivering latent membrane protein-1 (LMP-1) gene to dendritic cells (DCs) by ultrasound exposure combined with contrast agent. METHODS: Human DCs were cultured in vivo and transfected with the recombinant plasmid pEGFP-C3-LMP1 under varying conditions including ultrasound intensities, exposure time and microbubble contrast agent concentration. The transfection efficiency was assessed by fluorescent microscopy and flow cytometry, and the cell viability by trypan blue exclusion test. RESULTS: An exposure time of 60 s at MI 1.0 with a microbubble contrast agent concentration of 20% resulted in the optimal effect of delivering the recombinant plasmid pEGFP-C3-LMP1 into the DCs, with a transfection efficiency of (14.37?2.12)%. Over 90% of the transfected cells were viable after the transfection. CONCLUSION: Microbubble contrast agent combined with ultrasound exposure can enhance the delivery of recombinant plasmid pEGFP-C3 LMP1 into the DCs. PMID- 20965838 TI - [Effects of heme oxygenase-1 on proteins related to apoptosis in INS-1 cells exposed to intermittent high glucose]. AB - OBJECTIVE: To study the effect of heme oxygenase-1(HO-1) on proteins related to apoptosis in INS-1 cells with exposure to intermittent high glucose. METHODS: INS 1 cells cultured in vitro were divided into control group, persistent high glucose group (PHG), intermittent high glucose group (IHG), CoPP + intermittent high glucose group (CoPP+IHG), and ZnPP+ intermittent high glucose group (ZnPP+IHG). After 72 h of treatment with the corresponding protocols, the cells were examined for expressions of HO-1 protein by Western blotting and for expressions of Bax and Bcl-2 by immunocytochemistry. RESULTS: In comparison with the control group, the cells in both PHG group and IHG group showed significantly increased expressions of HO-1 (P<0.01) and decreased Bcl-2/Bax ratios (P<0.05). The cells in CoPP+ IHG group exhibited a greater HO-1 protein expression but a lower Bcl-2/Bax ratio than those in IHG group (P<0.05) The ZnPP+IHG group demonstrated opposite changes in terms of HO-1, Bax and Bcl-2 expressions compared with the CoPP+IHG group. CONCLUSION: Intermittent high glucose can lower Bcl-2/Bax ratio in INS-1 cells, and HO-1 may protect INS-1 cells against apoptosis possibly by up-regulating the Bcl-2/Bax ratio. PMID- 20965839 TI - [Molecular mechanism of Wulongdan for improving the learning and memory abilities of rats with chronic cerebral ischemia]. AB - OBJECTIVE: To evaluate the effect of Wulongdan on the learning and memory abilities of rats with chronic cerebral ischemia and explore the mechanisms. METHODS: Male SD Rat models of chronic cerebral ischemia were established by permanent ligation of the bilateral carotid arteries. Three weeks after the operation, the rats were randomly divided into sham-operated group, chronic cerebral ischemia group (model group), high-dose drug group, low-dose drug group and Yinxingye group and received the corresponding treatments on a daily basis for 5 consecutive weeks. Morris water maze was used to assess the learning and memory abilities of the rats, and Western blotting was carried out for detecting the expressions of NR1 and NR2B in the hippocampus and cerebral cortex. RESULTS: Compared with the model group, the rats in high-dose drug, low-dose drug and Yinxingye groups showed significantly shorter time of finding platform in Morris water maze test (P<0.05 or 0.01). The rats in the model group showed significantly lowered expressions of NR1 and NR2B of the cortex and hippocampus than those in the sham-operated group (P<0.01). In comparison with the model group, the high-dose Wulongdan group and Yinxingye group both showed significantly increase expressions of NR1 and NR2B (P<0.01), but their expression levels still remained significantly lower than those in the sham-operated group (P<0.01). CONCLUSION: Wulongdan can enhance the learning and memory abilities of rats with chronic cerebral ischemia, the mechanisms of which may involve increased expressions of NR1 and NR2B in the hippocampus and cortex. PMID- 20965840 TI - [Protective effect of Na2SeO3 against cerebral ischemia-reperfusion injury to the hippocampal neurons in rats]. AB - OBJECTIVE: To investigate the protective effects of selenium on rat hippocampal neurons against ischemia-reperfusion (IR) injury. METHODS: Thirty-two rats were randomly divided into sham-operated group, IR group and selenium-treated group, and in the latter two groups, cerebral IR injury was induced by middle cerebral artery occlusion; Na2SeO3 treatment was administer in selenium-treated group. At 14 days after reperfusion, the brain tissues were harvested from the rats and hippocampal neuron injuries were observed by TUNEL and Methylene Blue staining. The levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL 1beta) and nerve growth factor (NGF) in the hippocampal tissues were measured by ELISA. RESULTS: Compared with IR group, the rats in selenium-treated group showed no significant increase in the expression of m-NGF (P>0.05), but pro-NGF expression was significantly increased (P<0.05) in the hippocampal tissue. Na2SeO3 treatment significantly inhibited the expressions of TNF-alpha and IL 1beta and decreased the apoptosis of hippocampal neurons following cerebral IR injury (P<0.05). CONCLUSION: Selenium produces antiapoptotic effect to protect the hippocampal neurons following cerebral IR injury possibly not by increasing the level of m-NGF but by decreasing the expressions of the inflammatory factors. PMID- 20965841 TI - [Construction and screening of specific short hairpin RNA vector targeting heparanase gene]. AB - OBJECTIVE: To construct short hairpin RNA (shRNA) expression vectors of RNA for specific silencing of heparanase (HPA) gene. METHODS: The genomic sequence of HPA gene was retrieved from GenBank and the cDNA encoding shRNA for HPA gene silencing was designed. Five specific interference sequences and a random negative control sequence were inserted into the vector pGPU6/GFP/Neo. After verification by restriction enzyme digestion and sequence analysis, the recombinant vectors were transfected into MDA-MB-231 cells via lipofectamine. Fluorescent quantitative PCR and Western blotting were employed to detect the expression of HPA gene expressions in the transfected cells at the mRNA and protein levels, respectively. RESULTS: Both restriction analysis and sequencing confirmed correct construction of the shRNA vectors. Transfected with the specific siRNA vectors HPSE-1 and HPSE-5 resulted in significantly decreased expression level of HPA protein in MDA-MB-231 cells, while negative control vector produced no significant changes in HPA expressions. CONCLUSION: We have obtained two shRNA vectors which can significantly down-regulate HPA expressions in MDA-MB-231 cells, which facilitates further investigation of the role HPA may play in the invasiveness and metastasis of human breast cancer. PMID- 20965842 TI - [Diagnosis of intramural pregnancy by endoluminal color Doppler ultrasonography and review of the literature]. AB - OBJECTIVE: To explore the ultrasound characteristics of intramural pregnancy and evaluate its diagnostic value. METHODS: Intramural pregnancy was diagnosed by endoluminal ultrasonography and confirmed by surgery and pathological examination in 6 patients. The position of the gestational sac, ultrasound findings, distribution of color Doppler flow signals were observed and analyzed together with their surgical and pathological results based on literature review. RESULTS: There were three types of ultrasound characteristics: gestational cyst type, mass type and uterine rupture type. The gestational cyst type or mass type presented with an empty uterus and a gestational sac or mixed mass was found in the myometrium, which can be separated from the endometrium. The sac or mass did not communicate with the uterine cavity, and abundant blood flow was observed about the sac or in the mass, while massive hemoperitoneum was found in the uterine rupture type. CONCLUSION: Endoluminal ultrasound is of high value in the diagnosis of intramural pregnancy. PMID- 20965843 TI - [B-type natriuretic peptides and subclinical target organ damage in essential hypertensive patients]. AB - OBJECTIVE: To investigate the relationship between B-type natriuretic peptides (BNP) and subclinical target organ damage in essential hypertensive (EH) patients. METHODS: A total of 317 EH patients were divided into 3 groups according to BNP levels, namely normal (BNP<600 ng/L) group (n=102), moderate (600-883.5 ng/L) group (n=116), and elevated BNP (>883.5 ng/L) group (n=99). The blood pressure, left ventricular mass index (LVMI), the intima media thickness (IMT) of the common carotid artery, the plaque size in the coronary artery (CS) and microalbuminuria levels were analyzed in these patients. RESULTS: The EH patients with moderate and elevated BNP showed significantly higher LVMI, IMT, CS and microalbuminuria levels than those with normal BNP level (LVMI: 102.8?23.12 and 123.9?26.47 vs 91.09?18.71 g/m2; IMT: 0.95?0.32 and 1.16?0.37 vs 0.84?0.28 mm; microalbuminuria: 31.36?20.55 and 36.73?22.07 vs 23.21?18.68, P<0.01). After adjustment, BNP was positively correlated to LVMI, IMT, CS and microalbuminuria level (r=0.45, 0.43, 0.39 and 0.41, respectively, P<0.01). Multivariate logistic regression analysis showed that age, systolic blood pressure, BNP, FPG, and microalbuminuria, LDL-C, and BMI were all related to the occurrence of subclinical target organ damages. CONCLUSION: BNP is positively correlated to subclinical target organs damages in EH patients. PMID- 20965844 TI - [Clinical characteristics and therapy of pan-drug resistant Acinetobacter baumannii infection]. AB - OBJECTIVE: To analyze clinical characteristics and therapy of pan-resistant Acinetobacter baumannii (PDRAB) infection and explore the methods for effective therapy and prevention of this infection. METHODS: Nine hospitalized patients with PDRAB infection confirmed by pathogen and susceptibility testing were analyzed for the risk factors and the treatment outcomes were assessed by case analysis. RESULTS: PDRAB infections occurred mainly in patients with severe complications, most of whom had complications by diabetes or hypertension or damaged mucosal integrity due to mechanical ventilation, surgery and catheterization. The polymyxin sensitivity were 100% for these infections, but all the bacteria identified showed a antimicrobial resistance rates of 100%. The majority of the infections were acquired during hospitalization occurring mainly in the lungs; all the patients had prolonged hospitalization and received antibiotic treatments with high proportions of broad-spectrum antimicrobial agents especially third-generation cephalosporins and quinolones. Exclusive or sequential use of carbapenems and sulbactam in combination with quinolone or aminoglycoside produced favorable effects. CONCLUSIONS: The prevalence of hospital-acquired pan-resistance of PDRAB infections increased significantly in recent years, particularly in patients with high risk factors. The widespread use of broad-spectrum antibiotics may have some relevance to drug resistant occurrence. The application of carbapenems or sulbactam, or their sequential use, in combination with other agents may produce good effects. PMID- 20965845 TI - [Imaging diagnosis of pelvic eosinophilic granuloma and analyses of the misdiagnoses]. AB - OBJECTIVE: To explore the imaging diagnosis of pelvic eosinophilic granuloma and improve diagnosis accuracy. METHODS: A retrospective analysis of the plain film, CT and MRI was conducted in 24 cases of pathologically confirmed eosinophilic granuloma. All the patients received radiography, CT scan was performed in 17 cases and MRI was done 9 cases. RESULTS: In the 24 cases of eosinophilic granuloma, 6 lesions were located in the pubis, 5 in the ischium and 13 in the iliac region. The lesion showed bony destruction or irregular bony destruction, with periosteal reaction and soft tissue mass. CONCLUSION: Pelvic eosinophilic granuloma has characteristic imaging features, and combination of the imaging findings can improve the diagnosing accuracy. PMID- 20965846 TI - [A prospective randomized trial of poly-DL-lactic acid absorbable and metallic screws for treatment of syndesmotic disruptions]. AB - OBJECTIVE: To compare the clinical effect of poly-DL-lactic acid (PDLLA) absorbable screws and titanium metallic screws in the treatment of syndesmotic disruptions in ankle fractures. METHODS: In this prospective, randomized clinical trial, 58 patients with or suspected of syndesmotic disruption associated with ankle fractures were randomly allocated to receive either bioabsorbable PDLLA or metallic titanium screwing fixation. Using preoperative radiography and intraoperative hook test, syndesmotic disruption was confirmed in 47 cases (25 with metallic screwing and 22 with PLLA screwing). Statistical analyses were performed at 6 months postoperatively to compare the AOFAS score, range of motion of the joint, TFCS width and TFO width on anteroposterior view radiographs, and inflammatory reactions between the two groups. RESULTS: The PDLLA screws showed good therapeutic effect similar to that of titanium metallic screws in syndesmosis fixation in these patients. No significant differences were found in the AOFAS score, range of motion of the joint, or TFCS width or TFO width between two groups (P>0.05). One patient in PDLLA screw group showed inflammatory reactions to the implants. CONCLUSION: PDLLA screws allow effective and reliable stabilization of syndesmotic disruptions without a second operation for screw removal. PMID- 20965847 TI - [Estimation of spike wave reduction in electrocorticography for predicting the outcomes of epilepsy surgery]. AB - OBJECTIVE: To investigate spike wave reduction in electrocorticography (EcoG) monitoring for evaluating the outcomes of epilepsy surgery. METHODS: The epileptogenesis lesions in the target cortex was localized accurately using an EcoG monitoring system in 20 surgical patients with intractable EP. The spike numbers within 60 s were recorded before and after surgical resection of the epileptogenic focus. In cases where the spike number within 60 s was reduced by over 80% after the resection, the surgery was terminated, otherwise extended lesion resection, corpus callosotomy or multiple subpial transection (MST) was carried out with ECoG monitoring, and the spike number within 60 s was recorded. Antiepileptic drugs were routinely prescribed after the operations. RESULTS: Twelve patients exhibited a spike wave reduction by over 80% after resection or extended resection of the lesions, including 4 with cavernomas in the nonfunctional area, who showed a spike wave reduction by over 80% after extended resection of the cortex around the tumor. The reduction was still less than 80% in 4 patients with hippocampal sclerosis and 3 with neurogliocytoma in the functional area after the operations. According to the Engel assessments, 13 cases were in level I, 3 cases in level II, 1 in level III, and 3 in level IV. Seventeen patients responded favorably to the treatment, with a total effective rate of 85%. CONCLUSION: For extra-temporal lobe epilepsy, a postoperative spike wave reduction beyond 80% indicate favorable outcome of the surgery, otherwise poor prognosis is expected. But in cases of temporal lobe epilepsy, no direct association is found between spike wave reduction and the prognosis of the patients. PMID- 20965848 TI - [Percutaneous intratumoral injection with pingyangmycin lipiodol emulsion for treatment of recurrent sacrococcygeal chordomas]. AB - OBJECTIVE: To evaluate the effectiveness and safety of fluoroscopy-guided percutaneous intratumor injection of pingyangmycin lipiodol emulsion (PLE) in the management of recurrent sacrococcygeal chordomas. METHODS: Seven patients with recurrent sacrococcygeal chordomas presenting with severe local pain with visual analogue score (VAS)>=8 received treatment sessions of fluoroscopy-guided percutaneous intratumor injection of PLE. The patients were followed up every 3 months after the last session to assess their clinical responses and observe the changes in the tumor size measured by computed tomography. The changes in the VAS, tumor necrosis and pain relief as well as the adverse events were recorded. RESULTS: A total of 22 sessions of fluoroscopy-guided percutaneous intratumoral PLE injection was performed in these cases (3 or 4 sessions in each case). The total average pingyangmycin dose delivered was 48.0 mg and the average lipiodol dose was 40.0 ml in each case. Five patients showed low fever and vomiting 48 after the injection. During the follow-up (median time of 21.7 months, range 10 26 months), all the patients showed obviously reduced tumor size and VAS, and partial remission was achieved in 6 patients and stable disease (SD) in 1 patient. None of the patients had complications during the follow-up. CONCLUSION: Fluoroscopy-guided percutaneous intratumoral injection of PLE can be effective and safe and may serve as a alternative for treatment of recurrent sacrococcygeal chordomas. PMID- 20965849 TI - [Application of Smart Plug lacrimal plug in the treatment of dry eye]. AB - OBJECTIVE: To evaluate the clinical efficacy of Smart Plug lacrimal plug in the treatment of dry eye. METHODS: Twenty-nine patients with dry eyes (58 eyes) were treated with Smart Plug lacrimal plug. All the patients were follow up for 6-10 months (average 7.8 months). Schirmer I test (SIT), tear break-up time (TBUT) and corneal fluorescein staining were used for evaluation of the clinical efficacy. RESULTS: The SIT was 3.35?2.60 mm and 6.35?4.15 mm, TBUT was 3.14?1.22 s and 5.46?1.26 s, and corneal fluorescein staining was 2.15?0.09 and 0.05?0.01 before and after the treatment, respectively (P<0.05). The subjective symptoms were improved in most of the patients. CONCLUSION: Smart Plug lacrimal plug is effective in the treatment of dry eye due to aqueous tear deficiency, and can be one of the choice of dry eye treatment. PMID- 20965850 TI - [Therapeutic effects of FOLFOX6 versus TLF regimen as the first line chemotherapy for advanced gastric cancer]. AB - OBJECTIVE: To compare the efficacy, time to disease progression (TTP), overall survival (OS) and toxicity of FOLFOX6 and TLF regimens for advanced gastric cancer. METHODS: The clinical data of 81 chemotherapy-naive patients with advanced gastric cancer were analyzed. Of the 81 patients, 41 were treated with FOLFOX6 regimen and 40 with TLF regimen. The patients in FOLFOX6 group received intravenous infusion of L-OHP(100 mg/m2) at day 1, bolus injection of 5-FU (400 mg/m2) at day 1, and continuous intravenous infusion of 5-FU (1200 mg/m2/d) for 22 h at days 1-2, each treatment cycle lasting 14 days. The patients in TCF group received TAX (90 mg/m2) at day 1, bolus injection of 5-FU (400 mg/m2) at days 1 2, and continuous intravenous infusion of 5-FU (400 mg/m2/d) for 22 h at days 1 2, and each treatment cycle also lasted 14 days. RESULTS: The objective response rates were 48.8% in FOLFOX6 group and 50.0% in TLF group (P=0.962). The median TTP in the two groups was 6.30 months and 6.50 months (P=0.958), with median survival time of 9.80 months and 10.70 months (P=0.578), respectively. The most frequent adverse events were nausea, vomiting and hematologic toxicities. The incidences of grade III-IV leucopenia and neutropenia were lower in FOLFOX6 group than in TLF group, but the difference was not statistically significant (12.2% vs 30.0%, P=0.112; 14.6% vs 32.5%, P=0.126). Three patients in FOLFOX6 group developed intestinal obstruction during the chemotherapy. CONCLUSION: Both FOLFOX6 and TLF regimens are effective in treating advanced gastric cancer and the toxicities can be tolerated. PMID- 20965851 TI - [Effect of invasive and non-invasive positive pressure ventilation on plasma brain natriuretic peptide in patients with chronic obstructive pulmonary disease and severe respiratory failure]. AB - OBJECTIVE: To investigate the change in plasma brain natriuretic peptide (BNP) in patients with chronic obstructive pulmonary disease (COPD) and severe respiratory failure receiving invasive or non-invasive positive pressure ventilation. METHODS: Fifty-six patients with COPD and severe respiratory failure were randomized into non-invasive ventilation group (n=28) to receive facial mask ventilation and invasive ventilation group (n=28) to have mechanical ventilation by tracheal intubation or tracheal incision. The changes of blood gas and BNP before and 24 h after the ventilation were observed. RESULTS: The indexes of blood gas analysis such as pH, PO2 and PaCO2 in the invasive ventilation group were better than those in the non-invasive ventilation group (P<0.05). The plasma levels of BNP of the invasive ventilation group were much lower 24 h after the treatment than that of the non-invasive ventilation group (P<0.05). CONCLUSION: Invasive ventilation produces better effect than non-invasive ventilation in the treatment of COPD with severe respiratory failure. Plasma concentrations of BNP has significant clinical value to evaluate the effect of mechanical ventilation. PMID- 20965852 TI - [A comparative study of botulinum toxin A and denervation-induced masseter muscle atrophy in rabbits]. AB - OBJECTIVE: To compare the effect of botulinum neurotoxin A (BTA) and denervation in inducing masseter muscle atrophy in rabbits to provide experimental evidence for the safe clinical application of BTA. METHODS: Seventy-five healthy adult New Zealand white rabbits were randomized equally into denervation group, BTA group and normal control group. In the former two groups, the rabbits were subjected to right masseter muscle denervation and botulinum (3 ug/kg) injection at the muscle, respectively, with the left side as the control. The thickness of the denervated masseter was determined using B type ultrasound and its weight measured after the treatment. RESULTS: The thickness of the masseter muscle on the experimental side was significantly decreased to 50.80% and 54.07%, and its weight to 66.80% and 56.16% of the normal level after denervation and BTA injection, respectively. CONCLUSION: BTA-induced denervation produces less potent atrophy-inducing effect on skeletal muscle than surgical denervation. BTA causes atrophy mainly at the injection site of the target muscle without significant diffusion or toxicity to the muscular cells. PMID- 20965853 TI - [Effect of chronoexercise on circadian expression of clock genes]. AB - OBJECTIVE: To investigate the molecular biological mechanism of chronoexercise regulating circadian. METHODS: Expressions of mPer1 and mPer2 in the diencephalon of golden hamster were determined 2 hours after acute exhaustive exercise (circadian time 6) by quantitative RT-PCR. RESULTS: Chronoexercise at CT6 significantly decreased expressions of mPer1 and mPer2 in the diencephalon of golden hamster. CONCLUSION: Inhibitory effect of chronoexercise on Per1 and Per2 mRNA levels in the diencephalon of golden hamster at CT6 may be achieved transcription-translation-based autoregulatory negative feedback loop. PMID- 20965854 TI - [Influences of hypertension and diabetes on arterial compliances and endothelial microparticle level]. AB - OBJECTIVE: To study the influences of hypertension and diabetes on arterial compliances and endothelial microparticle level. METHODS: Fifty patients with hypertension and diabetes, 46 with hypertension, and 48 with diabetes were enrolled in this study, with 50 healthy volunteers group serving as the normal control. Large arterial compliance (C1) and small arterial compliance (C2) were measured using CVProfilor DO2020 cardiovascular profiling system, and the levels of CD31+/CD42- endothelial microparticles (EMPs) were determined by flow cytometry in these subjects. RESULTS: Compared with the hypertensive patients, diabetic patients and healthy volunteers, the patients with both hypertension and diabetes showed significantly decreased C1 and C2. C1 and C2 were significantly decreased in the hypertensive patients in comparison with those in the diabetic patients and the healthy volunteers. Compared with the healthy volunteers group, the diabetic patients showed markedly decreased C2 but normal C1. The levels of CD31+/CD42- EMPs were significantly increased in patients with both hypertension and diabetes compared with the other groups, and the diabetic patients had higher EMPs levels than the hypertensive patients. Pearson regression analysis indicated that C1 and C2 were inversely, while the levels of EMPs positively, correlated to the pulse pressure and 2 h plasma glucose; the levels of EMPs were not related with fasting glycemia. CONCLUSION: Hypertension appears to have greater impact on arterial compliance, especially C1, while diabetes is the major factor responsible for increased release of EMPs. PMID- 20965855 TI - [Correlation between PTPN22 gene polymorphism and systemic lupus erythematosus in Chinese Han patients]. AB - OBJECTIVE: To investigate the association between 1858C/T single nucleotide polymorphism on exon 14 of the protein tyrosine phosphatase nonreceptor-22 (PTPN22) gene and systemic lupus erythematosus in Chinese Han patients. METHODS: Forty Chinese Han patients with SLE and 20 normal control subjects were enrolled in the study, and PTPN22 gene 1858 C/T polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: No significant difference was found in the CC, CT, and TT genotype frequencies or in the C and T allele frequencies between the SLE patients and the normal controls. CONCLUSION: 1858C/T on PTPN22 gene might not be associated with the susceptibility of SLE in Chinese Han population. PMID- 20965856 TI - [Automated peripheral arteriovenous exchange transfusion for treatment of severe hyperbilirubinemia in neonates]. AB - OBJECTIVE: To study the effect of automated peripheral arteriovenous exchange transfusion for treatment of severe hyperbilirubinemia in neonates. METHODS: Fifty-three neonates with severe hyperbilirubinemia underwent automated peripheral arteriovenous exchange transfusion, and the changes in the blood gas, electrolytes and some biochemical indices after the exchange transfusion were evaluated. RESULTS: Treatment with the exchange transfusion resulted in a significant reduction in the total serum bilirubin with an exchange rate of 53.12% (P<0.01). The levels of serum kalium, calcium, magnesium, white blood cell count, platelets, and pH showed reductions while blood glucose exhibited a significant elevation changes after the transfusion (P<0.01), which all recovered the normal levels within 48 h. No obvious alterations occurred in the respiration, heart rate, blood pressure, or saturation of blood oxygen during the transfusion. CONCLUSION: Automated peripheral arteriovenous exchange transfusion can rapidly reduce serum bilirubin levels in neonates with severe hyperbilirubinemia without obviously affecting the blood gas balance or blood electrolyte or glucose levels. PMID- 20965857 TI - [Diagnosis and treatment of esthesioneuroblastoma in the nasal cavity and sinuses]. AB - OBJECTIVE: To discuss the clinical characteristics, diagnosis and treatment of esthesioneuroblastoma (ENB). METHODS: The clinical data of 7 patients with ENB were analyzed retrospectively, and the clinical characteristics, diagnosis, surgical approaches and prognosis of the disease were discussed. RESULTS: The 7 patients received surgical treatment combined with radiotherapy and chemotherapy. Tumor relapse occurred within one year in two cases, which were treated with a second operation combined with radiotherapy, and one patient died and one survived with tumor after a one-year follow-up. CONCLUSION: Early diagnosis of ENB can be difficult. Transnasal-frontal approach with nasal endoscope is effective approach to ENB treatment, and the patients may benefit from postoperative radiotherapy and chemotherapy to improve the prognosis. PMID- 20965858 TI - [Therapeutic effect of intradiscal electrothermal therapy for discogenic low back pain]. AB - OBJECTIVE: To observe the clinical efficacy and complications of intradiscal electrothermal therapy for treatment of discogenic low back pain. METHODS: Forty patients with discogenic low back pain were treated with intradiscal electrothermal therapy, and the changes in the VAS, functional status and complications after the treatment were analyzed. RESULTS The VAS score was decreased and the functional status improved obviously after the treatment, which caused no severe complications. CONCLUSION: Intradiscal electrothermal therapy is safe and effective to rapidly achieve pain relief and obviously improve the functional status of patients with discogenic low back pain with few complications. PMID- 20965859 TI - [Effects of estrogen on P-Tau, ChAT and nerve growth factor protein expressions in the brain tissue of rats with Alzheimer's disease]. AB - OBJECTIVE: To examine the effect of estrogen on the expressions of phosphorylated Tau (P-Tau), ChAT and nerve growth factor (NGF) protein in the brain tissue of rat models of Alzheimer disease (AD). METHODS: Rat models of AD were established by injecting Abeta1-42 protein fragments in the right lateral ventricle. Two weeks later, 17beta-estradiol tablets were implanted subcutaneously at the neck of the rats and maintained for 30 days. The pathological changes in the rats' brain neurons and alterations in the expressions of P-Tau, ChAT and NGF proteins were observed using HE staining and immunohistochemistry, respectively. RESULTS: In the AD rats, neurofibrillary tangles occurred in the brain tissue, and estrogen treatment significantly reduced the formation of neurofibrillary tangles. Estrogen treatment also resulted in lowered P-Tau expression and increased ChAT and NGF protein expressions in comparison with those in the AD model rats. CONCLUSION: Estrogen can up-regulate ChAT and NGF and down-regulate tau protein expression, thus producing obvious therapeutic effect on AD in rats. PMID- 20965860 TI - [Analysis of the diagnosis and treatment of recurrent vulvovaginal candidiasis in 80 cases]. AB - OBJECTIVE: To investigate the appropriate therapy for treating recurrent vulvovaginal candidiasis (RVVC). METHODS: Individual consolidated and maintenance therapy were chosen according to fungal culture of vaginal secretion and antifungal drug sensitivity per month as one therapy duration. Drugs were used orally and vaginally together to consolidate the therapy. Oral drugs were fluconazole (0.15 qw after 0.15 q3d for 2 times) or ketoconazole (0.2, bid for 3 days ) or itraconazole (0.2 bid for 3 days ). After Nystain (400 000 unit qn for 7 days ) or clotrimazole(0.1 qn for 7 days) or amphotericin B (0.01 qn for 6 days ) being vaginally used, Living preparation of lactobacillus (0.25 qn for 5 days) was vaginally used. The therapy was continued for 2 to 5 therapy durations after the symptoms disappeared with negative fungal culture. RESULTS: Among 80 cases of RVVC, C. albicans was mostly detected (74%), C. glabrata was 20%. The susceptivity to candidas of oral agents revealed that the sensitive rare of ketoconazole, fluconazole and itraconazole were (91.3%), (81.3%) and (62.5%), respectively. As for vaginal agents, nystain and amphotericin B were 100% sensitive, clotrimazole was 92.5%sensitive, miconazole was 55.0% sensitive. The remote cure of 3 and 6 therapy durations after discontinuing for 12 months was 78.9% and 90.4% CONCLUSION: The predominant pathogen in RVVC is C. albicans. The effective measures to cure RVVC are to choose sensitive drugs for individual consolidated, maintenance therapy and restore vaginal acidic environment. PMID- 20965861 TI - [Principles of the management of adult inguinal hernia--recommendations by the European Hernia Society]. AB - The European Hernia Society (EHS) presented the EHS Guidelines for the Treatment of Inguinal Hernia in Adult Patients. The Guidelines contain recommendations for the management of inguinal hernia from diagnosis to aftercare. These have been developed by a Working Group consisting of expert surgeons with representatives of 14 member countries of the EHS. The Guidelines are evidence-based and, when necessary, a consensus of all members was reached. The Guidelines have been reviewed by a Steering Committee as well. Before finalisation, feedback from the relevant national hernia societies was obtained. The Guidelines can be used to adjust local protocols, training purposes as well as quality control. In order to keep them updated the next revision will be published in 2012. A short update of new high-level evidence will be provided by the Working Group during the EHS annual congress until the next revision. PMID- 20965862 TI - [Long-term results of open tension-free or tension repair of inguinal hernias- retrospective study]. AB - Authors discuss long-term results of inguinal hernia repairs. Patients were asked to fill in a questionnaire to compare five-year outcomes after tension-free and non-mesh inguinal hernia reconstructions. RESULTS: the trial is based on the assessement of 155 patients' replies. Recurrence rate in tension-free (TF) cases is 3.4% (4/116), while in suture repair (non-mesh - NM) group is 12.8% (5/39). The ratios of totally symptom-free patients are 83% (97/116 - TF) and 89% (35/39 NM). Severe chronic pain occurred in 1.7% (2/116 - TF) and 7.7% (3/39 - NM). Early return to normal activity was 34% (39/116 - TF) and 29% (11/39 - NM). CONCLUSION: Based on this retrospective study Lichtenstein repair is superior to non-mesh open inguinal reconstruction, as regards recurrence rates, but chronic pain and recovery time show similar long term results in both groups, which is different from the relevant published literature. PMID- 20965863 TI - ["Onlay" mesh provides significantly better results than "sublay" reconstruction. Prospective randomized multicenter study of abdominal wall reconstruction with sutures only, or with surgical mesh--results of a five-years follow-up]. AB - BACKGROUND: There are several well-known procedures to treat abdominal wall hernias, but the results are quite controversial. The aim of study was to compare the results of different surgical modalities - mesh (onlay vs. sublay position) and suture repair - in the treatment of abdominal wall hernias. METHODS: A five year randomized, multicentric, internet-based, clinical trial was started in 2002. 953 patients were included in the study and divided into two groups according to the size of hernia orifice. In group 'A' ( n = 494) the surface of hernia orifice was between 5-25 cm 2 (small hernia), and in group 'B' ( n = 459) it was above 25 cm 2 (large hernia). Patients of these two groups were randomized according to surgery: group 'A' (suture vs. mesh) and in group 'B' (mesh in onlay vs. sublay position). In group 'A' suture repair was performed in 247, and sublay mesh implantation in 247 cases. In group 'B' sublay ( n = 235) and onlay ( n = 224) mesh reconstruction was performed. The patients were followed-up for five years. RESULTS: 734 patients - 77% of all randomized cases - have completed the study. In the small hernia group significantly ( p < 0.001) higher recurrences occurred after suture repair ( n = 50-27%) than in mesh repair ( n = 15-8%). In the large hernia group onlay mesh reconstruction provided significantly better ( p < 0.05) results than sublay reconstruction, recurrence rate was much lower in onlay group [ n = 22 (12%) vs. n = 38 (20%)]. CONCLUSION: Mesh repair provides better results than suture repair. In case of large hernias the recurrence rate is higher after sublay reconstruction. The randomized trial was registered on www.ClinicalTrials.gov - ID number: NCT01018524. PMID- 20965864 TI - [The use of mesh in the surgical treatment of hiatal hernias]. AB - Primary suture repair of large hiatal hernias is associated with high recurrence rate, but the use of mesh may improve the results. There is no agreement about the ideal size, shape, or material of these mesh prosthesis, or the way those should be fixed to the crura. One of the biggest concerns of insetting a prosthetic material at the hiatus is erosion into the stomach, esophagus, or both. Cardiac injury at the time of mesh anchorage is a rare but potentially fatal complication. Introduction of biomaterials into clinical practise has completely changed the outlook of these surgical procedures. PMID- 20965865 TI - [Repairs of inguinofemoral and ventral hernias--review]. AB - In this article the author reviews the results, technology and latest achievements in the history of laparoscopic hernia repair. In conclusion, having considered the advantages and disadvantages, laparoscopic hernia repair offers the best results in terms of early rehabilitation, early and long-term postoperative pain and a very low recurrence rate (less than 1% and 5%). In the hands of experienced laparoscopic surgeons, it remains the gold standard for hernia repairs indisputably. PMID- 20965866 TI - [Laparoscopic repair of abdominal wall hernias]. AB - Repair of abdominal wall defects is a challenge for all general surgeons and a variety of methods have been described in the past. Traditionally, primary suture repair was shown to have a high recurrence rate in long-term follow-up studies. Herniorrhaphies that apply a large prosthetic mesh are appear to have a lower failure rate, but extensive dissection of soft tissue contributes to an increased incidence of wound infections and wound-related complications. The method of laparoscopic incisional hernia repair was developed in the early 1990s. This technique is based on the same physical and surgical principles as the open underlay procedure. The laparoscopic intraperitoneal onlay mesh (IPOM) technique and mesh materials were developed further in subsequent years, and there have been numerous reports on successful use of the IPOM technique even for extremely large hernia openings in obese and elderly patients. Reduced surgical trauma and lower infection and recurrence rates are key advantages of the minimally invasive repair. Therefore, this operation has increased in popularity promising shorter hospital stay, improved outcome, and fewer complications than traditional open procedures. PMID- 20965867 TI - [Parastomal hernias]. AB - The overall incidence of parastomal hernias is 35-50%. Different methods of hernia repairs (local fascial repair, stoma relocation and various types of mesh repairs) did not provide satisfactory results. Laparoscopic approach makes peristomal incision unnecessary and decreases the potential risk of mesh infection as well. In spite of all attempts the incidence of recurrent parastomal hernias is as high as 12-35%. These unsatisfactory results supported the idea of mesh implantation at the time of the initial stoma formation. In this study the authors inserted a self-designed two-layered special meshin 17 cases as a prevention and after 5 years follow-up period no parastomal hernias were recorded. The only complication noted was a minor stricture on the surface of the skin, that could have easily been corrected. Therefore, the authors support the idea of preventive mesh insertion at time of definitive stoma formation. PMID- 20965868 TI - [Tissue integration of various silicone-coated polypropylene surgical mesh]. AB - INTRODUCTION/AIM: Laparoscopic ventral hernia repair requires a surgical mesh implanted in intraperitoneal position. The combined, double layer meshes are promising in animal models as well as in human practice. The aim of this study was to compare the biological behaviour of two different textured silicone covered polypropylene mesh. MATERIALS AND METHODS: 3 * 4 cm big full thickness defect of the abdominal wall was created in New Zealand White rabbits. The defect was covered in 20 animals with a polypropylene mesh with laminar silicone layer on the visceral surface (LSPP), while the remaining 20 cases the defects were covered with a macroporous textured silicone impregnated polypropylene mesh (MSPP). Intraperitoneal adhesion formation and tissue ingrowth in the meshes were investigated. Immunohistochemistry was used to detect proliferation activity (Ki 67), neovascularization (VEGF), and to visualize mesothelial layer (CK) over the mesh. Scanning electron microscopy was used to investigate the visceral surface of the meshes. RESULTS: While intraperitoneal adhesion formation showed no difference after 1 week, LSPP mesh induced significantly less adhesions after 21 days. The Ki-67 positivity was significantly lower and the number of the VEGF positive cells increased with time in the MSPP group, this was missing in the LSPP group. The thin neoperitoneum layer was detected over MSPP mesh only with CK antibody. CONCLUSION: The material and texture of the mesh are responsible for tissular incorporation which is in accordance with the generated foreign body reaction. PMID- 20965872 TI - The establishment of an ethical guideline for genetic testing through citizen consensus via the Internet in Taiwan. AB - BACKGROUND: With the rapid advance of genetics, the application of genetic testing has become increasingly popular. Test results have had a tremendous impact on individuals who receive the test and his or her family. The ethical, legal, and social implications (ELSI) of genetic testing cannot be overlooked. The Internet is a potential tool for public engagement. OBJECTIVES: This study aimed at establishing ethical guidelines for genetic testing in Taiwan through a participatory citizen consensus approach via the Internet. METHODS: The research method used was a citizen consensus conference modified by an Internet application and the Delphi technique. The citizen consensus conference is one of the public participation mechanisms. The draft ethical guidelines for genetic testing were written by an expert panel of 10. The Delphi technique was applied to a citizen panel recruited via the Internet until a consensus was reached. Our research population was restricted to people who had Internet access. RESULTS: Included in the citizen panel were 100 individuals. A total of 3 individuals dropped out of the process. The citizen panel was exposed to the issues through Internet learning and sharing. In all, 3 rounds of anonymous questionnaires were administered before a consensus was reached in terms of importance and feasibility. The result was ethical guidelines composed of 4 categories and 25 items. The 4 categories encompassed decision making (6 items), management of tissue samples (5 items), release of results (8 items), and information flow (6 items). On a scale of 1 to 10, the average (SD) importance score for the decision making category was 9.41 (SD 0.58); for the management of tissue samples category, the average score was 9.62 (SD 0.49); for the release of results category, the average score was 9.34 (SD= 0.59); and for the information flow category, the average score was 9.6 (SD = 0.43). Exploratory analyses indicated that participants with higher education tended to attribute more importance to these guidelines. CONCLUSIONS: The resulting recommended ethical guidelines had 4 categories and 25 items. We hope through the implementation of these guidelines that mutual trust can be established between health care profession and the general public with respect to genetic tests. PMID- 20965873 TI - The influence of response mode on study results: offering cigarette smokers a choice of postal or online completion of a survey. AB - BACKGROUND: It is unclear whether offering online data collection to study participants affects compliance or produces bias. OBJECTIVE: To compare response rates, baseline characteristics, test-retest reliability, and outcomes between cigarette smokers who chose to complete a survey by mail versus those who chose to complete it online. METHODS: We surveyed cigarette smokers who intended to stop smoking within the next 30 days to determine barriers to calling a smoking quit line. Participants were offered the choice of completing a paper version of the survey sent through the mail or an online version at a password-protected website. Participants were called 2 months later to determine if they had made a quit attempt and/or called a smoking quit line since the baseline survey. We compared characteristics and outcomes among those who chose postal versus online completion. We measured test-retest reliability of the baseline survey by re surveying a semi-random sample of participants within 10 days of the original survey. RESULTS: Of 697 eligible respondents to newspaper ads in 12 US cities, 438 (63%) chose to receive a mailed paper survey and 259 (37%) chose an Internet survey. Survey return rates were the same for the 2 modes (92% versus 92%, P = .82). Online respondents were younger (mean of 46 versus 51 years old for postal, P < .001), more likely to be white (76% versus 62%, P < .001), less likely to be African American (18% versus 30%, P < .001), more highly educated (34% college graduate versus 23%, P < .001), more likely to intend to stop smoking in the next 30 days (47% definitely versus 30%, P < .001), and more likely to have heard of a smoking quit line (51% versus 40%, P = .008). Participants did not differ on gender (54% female for online versus 55% for postal, P = .72) or cigarettes smoked per day (mean of 19 versus 21, P = .30). Online respondents had slightly fewer missing items on the 79-item survey (mean of 1.7% missing versus 2.3%, P = .02). Loss to follow-up at 2 months was similar (16% for online and 15% for postal, P = .74). There was no significant difference between online and postal respondents in having called a smoking quit line during the 2-month follow-up period (20% versus 24%, P = .22) or in having made a quit attempt (76% versus 79%, P = .41). CONCLUSIONS: Cigarette smokers who chose to complete a survey using the Internet differed in several ways from those who chose mailed surveys. However, more importantly, online and postal responses produced similar outcomes. PMID- 20965874 TI - To resect or not to resect? That is the question. Telangiectatic adenoma. PMID- 20965875 TI - Running-related injuries in school-age children and adolescents treated in emergency departments from 1994 through 2007. AB - Running for exercise is a popular way to motivate children to be physically active. Running-related injuries are well studied in adults but little information exists for children and adolescents. Through use of the National Electronic Injury Surveillance System database, cases of running-related injuries were selected by using activity codes for exercise (which included running and jogging). Sample weights were used to calculate national estimates. An estimated 225 344 children and adolescents 6 to 18 years old were treated in US emergency departments for running-related injuries. The annual number of cases increased by 34.0% over the study period. One third of the injuries involved a running-related fall and more than one half of the injuries occurred at school. The majority of injuries occurred to the lower extremities and resulted in a sprain or strain. These findings emphasize the need for scientific evidence-based guidelines for pediatric running. The high proportion of running-related falls warrants further research. PMID- 20965876 TI - Urinary 8-hydroxy-2'-deoxyguanosine reflects symptomatic status and severity of systolic dysfunction in patients with chronic heart failure. AB - AIMS: Oxidative stress is known to play a crucial role in the pathogenesis of heart failure (HF). We investigated whether urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), a product of oxidative DNA damage, is a clinically useful biomarker of the severity of chronic heart failure (CHF) and oxidative stress levels in failing hearts. METHODS AND RESULTS: We measured 8-OHdG in the serum obtained from the coronary sinus (CS) and aortic root (Ao) in small groups of control subjects and CHF patients. We then measured urinary 8-OHdG and other biomarkers (brain natriuretic peptide, 8-isoplastane, high-sensitivity C-reactive protein, interleukin-6, and tumour necrosis factor-alpha) in 31 control subjects and 194 patients with CHF [left-ventricular ejection fraction (LVEF): 28.3 +/- 8.1%]. Serum 8-OHdG was significantly higher in the CS than the Ao in CHF patients only. Urinary 8-OHdG was also significantly higher in CHF patients than in control subjects, and urinary 8-OHdG became higher as New York Heart Association class increased. Moreover, there was a significant correlation between urinary 8-OHdG and LVEF (r = -0.27), pulmonary capillary wedge pressure (r = 0.31), or left ventricular end-diastolic volume index (r = 0.22). In contrast, there was poor correlation between the severity of CHF and the other neurohumoral biomarkers. CONCLUSION: In HF, urinary 8-OHdG seems to reflect the level of oxidative stress and various parameters related to symptomatic status and functional severity of CHF. PMID- 20965877 TI - 2010 focused update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC Guidelines for cardiac and resynchronization therapy. Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association. PMID- 20965878 TI - Diabetes mellitus in patients with myocardial infarction complicated by heart failure: a 'low ejection fraction' equivalent? PMID- 20965879 TI - The inter-relationship of diabetes and left ventricular systolic function on outcome after high-risk myocardial infarction. AB - AIMS: Diabetes is a potent risk factor for death and heart failure (HF) hospitalization following myocardial infarction (MI). Whether diabetes modifies the relationship between left ventricular ejection fraction (LVEF) and outcomes in the post-MI population is unknown. METHODS AND RESULTS: The Valsartan in Acute Myocardial Infarction trial (VALIANT) enrolled 14 703 patients with acute MI complicated by HF, systolic dysfunction, or both. We compared the risk of death, HF hospitalization, and/or recurrent MI among patients with and without diabetes using Cox proportional hazards models. To assess the relationship between diabetes, LVEF and outcomes, we assessed the relative influence of baseline LVEF on outcomes in diabetic and non-diabetic patients. Totally, 11 325 subjects (3095 diabetics) with site-reported LVEF and known diabetes status were included. At any given LVEF, diabetes was associated with a higher risk of all-cause mortality [adjusted hazard ratio (HR) 1.37, 95% CI 1.25-1.51], death or HF hospitalization (adjusted HR 1.42, 95% CI 1.31-1.51), and death or recurrent MI (adjusted HR 1.36, 95% CI 1.24-1.48). Diabetes modified the relationship between LVEF and death or HF hospitalization (P for interaction = 0.0109), such that the association between diabetes and increased risk was greater in magnitude at higher LVEF. No interaction was noted between diabetes and LVEF on risk of all cause mortality or death or recurrent MI. CONCLUSION: Diabetes is associated with a higher risk of death or HF hospitalization across the spectrum of LVEF in high risk post-MI patients. The magnitude of reduction in risk of death or HF hospitalization associated with increasing LVEF is significantly attenuated among patients with diabetes when compared to patients without diabetes. PMID- 20965880 TI - Clinical trials update from the European Society of Cardiology Meeting 2010: SHIFT, PEARL-HF, STAR-heart, and HEBE-III. AB - This article provides information and a commentary on key trials relevant to the pathophysiology, prevention, and treatment of heart failure (HF) presented at the annual meeting of the European Society of Cardiology held in Stockholm in 2010. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. The SHIFT study supports the use of ivabradine in patients with HF due to left ventricular systolic dysfunction and resting sinus rhythm rate >=70 b.p.m. despite treatment with beta-blockers or where beta blockers are contra-indicated. Results from PEARL-HF suggest that the potassium binding polymer RLY5016 may be useful for both prevention and treatment of hyperkalaemia in HF patients with or without concomitant chronic kidney disease. The STAR-heart study provides encouraging observational data about the potential for intracoronary stem cell transplantation in patients with HF. Results from HEBE-III showed no effect of erythropoietin on ejection fraction measured 6 weeks post-MI; although there were fewer cardiovascular events in patients assigned to erythropoietin, the study was too small to provide conclusive evidence of effect. PMID- 20965881 TI - A patient with recurrent atrial fibrillation and monomorphic ventricular tachycardia treated successfully with dronedarone. PMID- 20965882 TI - Hepatitis B transmission event in an English prison and the importance of immunization. AB - Immunization against hepatitis B virus (HBV) is recommended for all sentenced prisoners and all new entrants to prison in the UK. In November 2008, acute hepatitis B was confirmed serologically in a 27-year-old man (Case 1) who had been incarcerated since February 2007. The cell mate of Case 1, a 26-year-old man was an established HBV carrier. A home-made tattoo gun was confiscated from their prison cell. In the absence of other clearly identifiable risk behaviours, tattooing was deemed to be a possible route of HBV transmission. Transmission of hepatitis B in a prison setting is a real concern and this report highlights the importance of immunizing prisoners against hepatitis B and should encourage health professionals to communicate the benefits of immunization to inmates to increase vaccine uptake. PMID- 20965883 TI - Trends in admission to hospital for assault in Northern Ireland, 1996/97-2008/09. AB - BACKGROUND: The aim of the study is to investigate in-patient admission trends for assaults in Northern Ireland. Of particular interest was whether trends in the hospital data increased in line with police statistics, or decreased in line with the Northern Ireland Crime Survey, and paramilitary style punishment attacks. METHODS: Time-series analysis of Northern Ireland hospital inpatient data, 1 April 1996 until 31 March 2009, obtained from the Northern Ireland Department of Health, Social Services and Public Safety was performed. For comparative purposes, police data for 'wounding/grievous bodily harm with intent' and punishment attacks were obtained from the Police Service of Northern Ireland. Data were standardized using rate per 100 000 people. RESULTS: The hospital in patient data set comprised a total of 25 412 cases, over the period of 1 April 1996-31 March 2009. Inpatient admissions for assault-related injuries peaked in 2001/02 (n = 2297). The majority of assaults treated over the entire period was from bodily force (62%, n = 15 874). A 23% decline was observed for hospital admission rates for assault-related injuries. This decreasing trend was found for all types of assaults. The greatest decline was for assault by firearm discharge (55%). CONCLUSION: The decline in assault-related hospital admissions is in contrast to the increase reported police data, supporting findings from previous studies. Similar decreasing trends in the hospital and punishment attack data are also identifiable, particularly for Belfast. PMID- 20965884 TI - Toxic effects of inhaled manganese on the olfactory bulb: an ultrastructural approach in mice. AB - Olfactory dysfunction is a common symptom reported by patients with neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Despite the knowledge gathered about the pathology of these diseases, little information has been generated regarding the ultrastructure modifications of the granule cells that regulate the information for odor identification. Swollen organelles and nuclear invaginations identified the exposed mice. Necrosis was evidenced at 4th week of exposure, whereas apoptosis arose at 8th week of exposure. A ruffled electron-dense membrane changes were also found. The changes observed could be explained by the reactive oxygen species generated by manganese and its effects on the membrane's structure and on the cytoskeleton's function. This study contributes to correlate metal air pollution and neurodegenerative changes with olfactory affection. PMID- 20965885 TI - Twisting arms to angiotensin receptor blockers/antagonists: the turn of cancer. PMID- 20965886 TI - Signal transducer and activator of transcription 3-mediated regulation of miR 199a-5p links cardiomyocyte and endothelial cell function in the heart: a key role for ubiquitin-conjugating enzymes. AB - AIMS: Mice with a cardiomyocyte (CM)-restricted knockout of signal transducer and activator of transcription 3 (STAT3-KO) develop spontaneous heart failure. We investigated the impact of STAT3-mediated regulation of microRNAs for pathophysiological alterations in the heart. METHODS AND RESULTS: MicroRNAchip and qRT-PCR analysis revealed elevated cardiac expression of miR-199a in STAT3-KO mice. Lentiviral shRNA-mediated STAT3-knock-down in neonatal rat CMs markedly increased miR-199a promoter activity and miR-199a levels indicative of a suppressive effect of STAT3 on miR-199a transcription. Up-regulated miR-199a in CM by pre-miR-199a transfection (pre-miR-199a-CM) reduced expression of components of the ubiquitin-proteasome system (UPS), i.e. the ubiquitin conjugating enzymes Ube2g1 (mRNA and protein) and Ube2i (protein). Pre-miR-199a CM or CM with siRNA-mediated down-regulation of Ube2i and Ube2g1 (siRNA-Ube2i/2g1 CM) displayed massive down-regulation of alpha- and beta-myosin heavy chain expression associated with disrupted sarcomere structures. In addition, protein arginine methyltransferase I (PRMT-I) expression and asymmetric dimethylarginine (ADMA) synthesis were increased in pre-miR-199a-CM or in siRNA-Ube2i/2g1-CM. Increased ADMA in cell culture supernatant (SN) from pre-miR-199a-CM or siRNA Ube2i/2g1-CM lowered nitric oxide (NO) bioavailability of rat cardiac endothelial cells while lowering ADMA concentration in CM SNs by the PRMT inhibitor arginine methyltransferase inhibitor 1 (AMI-1) (100 uM) improved NO bioavailability. In STAT3-KO hearts Ube2i and Ube2g1 expression were markedly reduced. Human terminal failing hearts harbouring low STAT3 protein levels displayed increased miR-199a levels and decreased Ube2g1 expression. CONCLUSION: This study identifies a novel pathophysiological circuit in the heart between reduced STAT3 protein levels, increased miR-199a expression, and subsequent impairment of the UPS that disrupts CM sarcomere structure and impairs via the release of ADMA endothelial cell function. PMID- 20965887 TI - Acute coronary syndrome in human immunodeficiency virus-infected patients: characteristics and 1 year prognosis. AB - AIMS: Natural history and prognosis of acute coronary syndrome (ACS) in HIV infected patients remain to be determined. We sought to compare coronary risk factors, angiographic features, acute results of percutaneous coronary intervention, in-hospital outcomes, and pre-specified 1 year prognosis of HIV infected and HIV-uninfected patients with ACS. METHODS AND RESULTS: HIV-infected and HIV-uninfected patients with a first episode of ACS were matched for age (+/ 5 years), sex, and type of ACS. The primary endpoint was the rate of major adverse cardiac and cerebral events (MACCE), comprising cardiac death, recurrent ACS, recurrent coronary revascularization, and stroke. Overall, 103 HIV-infected and 195 HIV-uninfected patients were enrolled (mean age 49.0 +/- 9.4 years, 94% men). Coronary risk factors were well balanced, but HIV-infected patients more frequently used illicit drugs (23 vs. 6%, P = 0.001) and had higher triglyceride concentrations (246 +/- 189 vs. 170 +/- 139 mg/dL, P = 0.002) compared with HIV uninfected patients. Angiographic features of coronary artery disease were similar (multivessel disease 41 vs. 39%, P = 0.96; ACC/AHA type culprit lesion >=B2, both 77%, P = 0.83). At 1 year, the rate of occurrence of first MACCE did not differ between groups [hazard ratio (HR) 1.4, 95% CI 0.6-3.0]. Recurrent ACS was more frequent in HIV-infected patients (HR 6.5, 95% CI 1.7-23.9) with no difference in the rate of clinical restenosis. CONCLUSIONS: These results suggest that the acute management of ACS in HIV-infected patients can routinely be the same as that of HIV-uninfected patients, but that specific secondary prevention measures are needed to alleviate the increased risk of recurrent ACS. PMID- 20965888 TI - Assessment of myocardial ischaemia and viability: role of positron emission tomography. AB - In developed countries, coronary artery disease (CAD) continues to be a major cause of death and disability. Over the past two decades, positron emission tomography (PET) imaging has become more widely accessible for the management of ischemic heart disease. Positron emission tomography has also emerged as an important alternative perfusion imaging modality in the context of recent shortages of molybdenum-99/technetium-99m ((99m)Tc). The clinical application of PET in ischaemic heart disease falls into two main categories: first, it is a well-established modality for evaluation of myocardial blood flow (MBF); second, it enables assessment of myocardial metabolism and viability in patients with ischaemic left ventricular dysfunction. The combined study of MBF and metabolism by PET has led to a better understanding of the pathophysiology of ischaemic heart disease. While there are potential future applications of PET for plaque and molecular imaging, as well as some clinical use in inflammatory conditions, this article provides an overview of the physical and biological principles behind PET imaging and its main clinical applications in cardiology, namely the assessment of MBF and metabolism. PMID- 20965889 TI - Lipoprotein(a) as a cardiovascular risk factor: current status. AB - AIMS: The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies. METHODS AND RESULTS: The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/coronary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated Lp(a), like elevated LDL-cholesterol, is causally related to premature CVD/CHD. The association is continuous without a threshold or dependence on LDL- or non-HDL cholesterol levels. Mechanistically, elevated Lp(a) levels may either induce a prothrombotic/anti-fibrinolytic effect as apolipoprotein(a) resembles both plasminogen and plasmin but has no fibrinolytic activity, or may accelerate atherosclerosis because, like LDL, the Lp(a) particle is cholesterol-rich, or both. We advise that Lp(a) be measured once, using an isoform-insensitive assay, in subjects at intermediate or high CVD/CHD risk with premature CVD, familial hypercholesterolaemia, a family history of premature CVD and/or elevated Lp(a), recurrent CVD despite statin treatment, >=3% 10-year risk of fatal CVD according to European guidelines, and/or >=10% 10-year risk of fatal + non-fatal CHD according to US guidelines. As a secondary priority after LDL-cholesterol reduction, we recommend a desirable level for Lp(a) <80th percentile (less than ~50 mg/dL). Treatment should primarily be niacin 1-3 g/day, as a meta-analysis of randomized, controlled intervention trials demonstrates reduced CVD by niacin treatment. In extreme cases, LDL-apheresis is efficacious in removing Lp(a). CONCLUSION: We recommend screening for elevated Lp(a) in those at intermediate or high CVD/CHD risk, a desirable level <50 mg/dL as a function of global cardiovascular risk, and use of niacin for Lp(a) and CVD/CHD risk reduction. PMID- 20965890 TI - In vitro activity of cethromycin against Burkholderia pseudomallei and investigation of mechanism of resistance. AB - OBJECTIVES: most Burkholderia pseudomallei strains are intrinsically resistant to macrolides, mainly due to AmrAB-OprA- and/or BpeAB-OprB-mediated efflux. We assessed the in vitro anti-B. pseudomallei efficacy of cethromycin, a novel ketolide with broad-spectrum activity against Gram-negative and Gram-positive pathogens. METHODS: the 2-fold broth microdilution technique was used to assess the in vitro cethromycin susceptibility of a prototype strain, efflux mutants, and a panel of 60 clinical and environmental strains. Time-kill curves were used to assess the mode of action. Spontaneous resistant mutants were isolated and AmrAB-OprA efflux pump expression assessed by quantitative real-time PCR. Deletion and complementation analyses were performed to demonstrate AmrAB-OprA efflux pump mutant involvement in high-level cethromycin resistance. RESULTS: in contrast to macrolides, cethromycin was a weak substrate of AmrAB-OprA and BpeAB OprB. Cethromycin was bactericidal at high concentrations and bacteriostatic at MIC levels. The ketolide showed efficacy against clinical and environmental strains of B. pseudomallei, with MIC values ranging from 4 to 64 mg/L. Environmental isolates were consistently more susceptible than clinical isolates. High-level cethromycin resistance (MIC 128 mg/L) was due to constitutive AmrAB OprA efflux pump overexpression, but other mechanisms also seem to contribute. CONCLUSIONS: in contrast to macrolides, which are readily effluxed, cethromycin is weakly extruded in wild-type strains and thus demonstrates significant in vitro anti-B. pseudomallei activity against diverse strains. Acquired high-level cethromycin resistance is caused by constitutive AmrAB-OprA efflux pump overexpression and other, probably non-efflux, mechanisms may also contribute to lower-level acquired resistance. PMID- 20965892 TI - Solitary rectal ulcer syndrome mimicking rectal neoplasm on MRI. AB - Solitary rectal ulcer syndrome (SRUS) is a rare condition that typically affects young adults and describes a spectrum of clinicopathological abnormalities. The diagnosis of SRUS is usually made on the basis of a combination of presenting symptoms and endoscopic and histological appearances. Characteristic radiological appearances have been described on transrectal and endoanal ultrasound, defecating proctography and barium enema. The radiological appearance of solitary rectal ulcer on MRI has not been previously described. MRI appearance of thickened ulcerated mucosa in the anterior rectal wall are non-specific and was indistinguishable from a malignant process. However, given that solitary rectal ulcer has a pre-disposition to occur in the anterior rectal wall, the presence on MRI of thickened rectal mucosa in this location could suggest solitary rectal ulcer in the correct clinical context. PMID- 20965891 TI - Increasing prevalence of transmitted drug resistance mutations and non-B subtype circulation in antiretroviral-naive chronically HIV-infected patients from 2001 to 2006/2007 in France. AB - OBJECTIVES: To estimate the prevalence of transmitted drug resistance mutations and non-B subtype circulation in antiretroviral-naive chronically HIV-1-infected patients in France. METHODS: Resistance mutations were sought in samples from 530 newly diagnosed HIV-1-infected patients from October 2006 to March 2007. Protease and reverse transcriptase mutations were identified from the 2007 Stanford Resistance Surveillance list. RESULTS: Reverse transcriptase and protease resistance mutations were determined in 466 patients with duration of seropositivity <5 years. 42% of patients were infected with non-B subtype strains (CRF02 18.3%). The overall prevalence of viruses with protease or reverse transcriptase mutations was 10.6% (95% confidence interval 6.7-16.3). The prevalence of protease inhibitor, nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor resistance-associated mutations was 4.7%, 5.8% and 2.8%, respectively. Frequency of resistance was not different in patients infected with B (9.5%) and non-B (CRF02 7.8% and other 11.2%) subtypes. Baseline characteristics such as gender, age, transmission group, country of transmission, disease stage, CD4 counts and viral load were not associated with the prevalence of transmitted drug resistance. CONCLUSIONS: In France in 2006/2007, the prevalence of transmitted drug-resistant variants was 10.6%. Prevalence of transmitted drug resistance was comparable in B and non-B subtypes. Prevalence of non-B subtypes is still rising. PMID- 20965893 TI - Intravascular embolisation and surgical resection of a giant neurofibroma with intratumoural haemorrhage. AB - The use of pre-operative embolisation has been described for small neurofibromas, but not for giant lesions. Advances in embolisation techniques are extending the indications for this procedure, in particular to assist with operative intervention on a range of lesions. This case report describes a 45-year-old male with a giant neurofibroma who underwent embolisation to stabilise intratumoural haemorrhage and to assist with haemostasis during the subsequent surgical resection. Minimal transfusion was required and the patient has made a good recovery. This case demonstrates that pre-operative embolisation of these large and challenging lesions is technically feasible and appears to be beneficial in reducing perioperative blood loss and morbidity. PMID- 20965895 TI - Pseudoaneurysm of internal mammary artery caused by pulmonary actinomycosis. AB - Although internal mammary artery pseudoaneurysms are a rare vascular abnormality, they are sometimes seen after sternotomy, diagnostic and therapeutic vascular access or penetrating chest trauma. To our knowledge, internal mammary artery pseudoaneurysm caused by pulmonary actinomycosis has not been reported previously. We report a case of pseudoaneurysm of the left internal mammary artery caused by pulmonary actinomycosis. A 50-year-old woman initially presented with clinical and radiological features of pneumonia, for which she was treated empirically with antibiotics. Later, she developed haemoptysis along with pain and swelling in the left upper chest wall. Multidetector CT (MDCT) with CT angiography showed a cavitating mass in the left upper lobe of the lung that infiltrated into the chest wall and a pseudoaneurysm of the left internal mammary artery. Imaging suggested that the lung mass resulted from pulmonary actinomycosis, which was confirmed by the histopathology of a fine-needle aspiration specimen. PMID- 20965894 TI - Primary cardiac angiosarcoma arising from the interatrial septum: magnetic resonance imaging appearances. AB - We present a case of primary cardiac angiosarcoma arising from the interatrial septum that had imaging features overlapping with those of right atrial myxoma. The mass was initially discovered on a thoracic CT study. Further evaluation with echocardiography was limited by poor acoustic windows and cardiac magnetic resonance (CMR) imaging was performed prior to surgical resection. CMR provided a detailed morphological assessment; imaging features included a frond-like surface architecture, a narrow attachment point at the interatrial septum, mild signal hyperintensity compared with that of myocardium on T(1) weighted sequences, patchy foci of delayed gadolinium enhancement and a haemorrhagic pericardial effusion. To the best of our knowledge, this is the first reported case of angiosarcoma arising from the interatrial septum that has undergone evaluation with CMR. PMID- 20965896 TI - MR imaging of psychosurgery: rostral atrophy following stereotacic subcaudate tractotomy. AB - There are few reports of MR imaging findings following psychosurgery. Here, we report the findings of 3T MR imaging of the sequelae of stereotactic subcaudate tractotomy (SST). Rostral atrophy is noted on conventional imaging. Diffusion tensor (DT) tractography demonstrated no communicating white matter tracts between the inferior frontal lobes, which appeared normally as thick fibre bundles in age-matched controls. DT tractography provides a unique tool for the evaluation of sequelae of ablative psychosurgical procedures. PMID- 20965897 TI - Large pulmonary masses containing varicose veins: a rare presentation of benign metastasising leiomyomas. AB - A 48-year-old woman presented with cough and chest pain. A chest radiograph and CT scans showed bilateral lung masses containing massive venous varices. A core biopsy specimen revealed benign metastasising leiomyoma with strong expression of progesterone receptors. A review of her medical history revealed a hysterectomy 11 years earlier. The lung masses showed significant reduction in size after induction of artificial menopause, although the pulmonary varices persisted. PMID- 20965898 TI - Short- and long-term responses to molybdenum-99 shortages in nuclear medicine. AB - Most nuclear medicine studies use (99)Tc(m), which is the decay product of (99)Mo. The world supply of (99)Mo comes from only five nuclear research reactors and availability has been much reduced in recent times owing to problems at the largest reactors. In the short-term there are limited actions that can be taken owing to capacity issues on alternative imaging modalities. In the long-term, stability of (99)Mo supply will rely on a combination of replacing conventional reactors and developing new technologies. PMID- 20965899 TI - Incidental fleurodeoxyglucose uptake in the prostate. AB - This commentary confirms the rarity of prostatic cancer associated with incidental prostatic fleurodeoxyglucose (FDG) uptake. The study adds to the literature by showing that even if a prostate lesion is FDG avid it is unlikely to be due to cancer. The commentary considers the management of incidental prostate FDG uptake on the basis of the available evidence. PMID- 20965900 TI - Decision support systems for clinical radiological practice -- towards the next generation. AB - The huge amount of information that needs to be assimilated in order to keep pace with the continued advances in modern medical practice can form an insurmountable obstacle to the individual clinician. Within radiology, the recent development of quantitative imaging techniques, such as perfusion imaging, and the development of imaging-based biomarkers in modern therapeutic assessment has highlighted the need for computer systems to provide the radiological community with support for academic as well as clinical/translational applications. This article provides an overview of the underlying design and functionality of radiological decision support systems with examples tracing the development and evolution of such systems over the past 40 years. More importantly, we discuss the specific design, performance and usage characteristics that previous systems have highlighted as being necessary for clinical uptake and routine use. Additionally, we have identified particular failings in our current methodologies for data dissemination within the medical domain that must be overcome if the next generation of decision support systems is to be implemented successfully. PMID- 20965901 TI - Significance of incidental focal uptake in prostate on 18-fluoro-2-deoxyglucose positron emission tomography CT images. AB - To evaluate the clinical significance of incidental focal prostate fluorodeoxyglucose (FDG) uptake, we reviewed 18-F-FDG positron emission tomography (PET)/CT scans from 2003 to 2007 and selected cases with focal FDG uptake in prostate. Cases of known prostate cancer were excluded. The maximum standardised uptake value (SUV(max)), site (central or peripheral) and pattern (discrete or ill-defined) of FDG uptake, calcification (present or absent) and prostate volume (<30 or >=30 cc) were recorded. The PET/CT findings were correlated with serum prostate-specific antigen (PSA) levels, imaging studies, clinical follow-up and biopsy. Of a total of 5119 cases, 63 (1.2%) demonstrated focal FDG uptake in prostate. Eight cases were lost to follow-up. Among the 55 cases with follow-up, malignancy was confirmed by biopsy in 3 (5.4%). The three malignant cases had SUV(max) values of 3.3, 3.6 and 2.3, and all were noted in the peripheral portion of prostate; two of these cases had a discrete FDG uptake pattern, none had calcification corresponding to the FDG uptake area and one had a prostatic volume greater than 30 cc. The mean SUV(max) of 52 benign cases was 3.2 +/- 1.7 and focal FDG uptake was noted in the peripheral portion in 34 (65%), 20 (38%) cases showed a discrete FDG uptake pattern, 35 (67%) were accompanied by calcification and 32 (62%) had a prostatic volume greater than 30 cc. The majority of cases demonstrating focal FDG uptake in prostate were benign and no PET/CT finding could reliably differentiate benign from malignant lesions; however, when discrete focal FDG uptake without coincidental calcification is seen, particularly in the peripheral zone of the prostate, further clinical evaluation is recommended. PMID- 20965902 TI - MRI appearance of the pancreas in patients with cystic fibrosis: a comparison of pancreas volume in diabetic and non-diabetic patients. AB - We investigated differences in the volume of the pancreas in cystic fibrosis (CF) patients with and without diabetes using MRI to study the natural history of CF related diabetes (CFRD). We investigated 29 pancreas-insufficient adult CF patients, 13 with CFRD and 16 without diabetes. Patients with CFRD were receiving insulin therapy at the time of study. None of the non-diabetic CF patients had evidence of impaired glucose tolerance. Pancreas volume was estimated by MRI scans using T1 weighted fat-suppression sequences and assessed by an examiner who was unaware of the patients' diabetes status. Pancreas volume of CF patients was measured and subsequently compared with that of non-CF age-matched Type 1 diabetes (T1DM) patients and healthy controls previously investigated. The two CF groups were matched for age and gender. There were no differences in spirometry values, body mass index or pancreatic exocrine function. The pancreas was visible by MRI in only 3 of 13 (23.1%) patients with CFRD and in 5 of 16 (31.3%) patients without diabetes (p-value = 0.7). In total, the pancreas was not detected by MRI as an anatomical entity in 21 of 29 (72.4%) CF patients, irrespective of their diabetes status. When comparing the four study groups, the pancreas was significantly smaller in CF patients than in T1DM patients and healthy controls. PMID- 20965903 TI - Evaluating lingual carcinoma for surgical management: what does volumetric measurement with MRI offer? AB - MRI plays a crucial but under utilized role in the surgical management of lingual squamous cell carcinoma (SCC). Measurement of three-dimensional tumour volume (TV) has the potential to guide management of clinically negative cervical lymph nodes and address deficiencies in current TNM staging criteria This work studied the value of MRI-measured TV as a predictor of 2 year disease-related survival (DRS) and disease-free survival (DFS), as well as occult cervical lymph node metastasis (OM) in lingual cancer. TV was determined by manually segmenting the tumour contour in each image slice and using the resulting pixel value to calculate the three-dimensional extent of disease. TV was also compared with the more established measure of tumour thickness (TT) Significant differences in DRS (chi2(1) = 7.7, Hazard ratio (HR) = 7.3, p = 0.005) and DFS (chi2(1) = 5.6, HR = 4.3, p = 0.02) at two years were found using a cut-off of 8 cm3. Similarly, a significant relationship between TV and occult cervical lymph node metastasis was discovered using a 3 cm3 cut-off (OR = 6.7, p = 0.02, Fisher's Exact Test). PMID- 20965904 TI - Scintimammography in conjunction with ultrasonography for local breast cancer recurrence in post-mastectomy breast. AB - The aim of this study was to compare the usefulness of (99)Tc(m)-methoxy-isobutyl isonitrile (MIBI) scintimammography and ultrasonography, alone and in combination, for the detection of chest wall recurrence in the post-mastectomy breast. A total of 41 consecutive post-mastectomy patients (mean age 46.6 years; median age 45 years) with clinical suspicion of breast cancer recurrence were evaluated. For scintimammography all patients received a 740-900 MBq iv injection of (99)Tc(m)-MIBI; planar images were taken 5-10 min post-injection followed by supine single photon emission CT. Breast ultrasonography was performed in each patient using a 7.5 MHz transducer. Both MIBI uptake and ultrasound findings were documented using standard protocols. All patients had fine needle aspiration cytology biopsy (FNAC), core biopsy or excision biopsy for final tissue diagnosis. Of the 41 patients, 24 had true positive signs of local breast cancer recurrence upon ultrasonography, 10 were diagnosed as true negatives, a sensitivity of 86%, specificity 77%, positive predictive value (PPV) 89%, negative predictive value (NPV) 71% and accuracy 83% (p = 0.001). By comparison, scintimammography findings were found to be true positive in 25 patients and true negative in 12 patients - sensitivity 89%, specificity 92%, PPV 96%, NPV 80% and accuracy 90% (p = 0.001). Using a combination of these two modalities, the combined sensitivity was 100%, specificity 77%, PPV 90%, NPV 100% and accuracy 93%. The high NPV of the two studies in combination implies a potential use of this approach to exclude recurrent disease in patients with a low initial index of suspicion and/or when histology is indeterminate. PMID- 20965905 TI - Practical guidelines for routine intensity-modulated radiotherapy verification: pre-treatment verification with portal dosimetry and treatment verification with in vivo dosimetry. AB - The purpose of this work is to provide guidelines for the routine use of portal dosimetry and in vivo diode measurements to verify intensity-modulated radiotherapy (IMRT) treatments. To achieve tolerance levels that are sensitive enough to intercept problems, both the portal dosimetry and the in vivo procedure must be optimised. Portal dosimetry was improved by the introduction of an optimised two-dimensional (2D) profile correction, which also accounted for the effect of backscatter from the R-arm. The scaled score, indicating the fraction of points not meeting the desired gamma evaluation criteria within the field opening, was determined as the parameter of interest. Using gamma criteria of a 3% dose difference and 3 mm distance to agreement, a "scaled score" threshold value of 1.5% was chosen to indicate excessive tongue and groove and other problems. The pre-treatment portal dosimetry quality assurance (QA) does not encompass verification of the patient dose calculation or position, and so it is complemented by in vivo diode measurements. Diode positioning is crucial in IMRT, and so we describe a method for diode positioning at any suitable point. We achieved 95% of IMRT field measurements within +/-5% and 99% within +/-8%, with improved accuracy being achieved over time owing to better positioning. Although the careful preparation and setup of the diode measurements can be time consuming, this is compensated for by the time efficiency of the optimised procedure. Both methods are now easily absorbed into the routine work of the department. PMID- 20965906 TI - Risk of deterministic effects during endovascular aortic stent graft implantation. AB - Since the 1990s, stent graft implantation for aortic pathology has become an alternative to extensive surgical procedures in some patients. Indeed, many patients with such pathology are now treated endovascularly. Only limited data concerning the risk of a deterministic effect during aortic stent graft implantation are available Accordingly, 179 consecutive patients treated in our institute between October 2002 and July 2008 with endovascular aortic stent grafts were included in this study. Dosimetric data (kerma area product (KAP) and cumulative dose at the interventional reference point (CD(irp))) from radiograph reports were analysed for 172 patients. On a group of 19 patients, GAFCHROMIC XR type dosimetric films were also used to verify the automatic measurements. Readings from the integrated KAP meter were found to be too high and were therefore corrected - KAP to dose area product (DAP) and CD(irp) to entrance skin dose (ESD). Median DAP was 153 Gy cm2 (35-700 Gy cm2) and median ESD was 0.44 Gy (0.12-2.73 Gy). Recorded dosimetric quantities were found to be good predictors of the skin dose and highlighted 4 patients (2.3%) who received skin doses that might cause possible deterministic effects. Endovascular stent graft implantation is less invasive than a surgical procedure and is widely used; mid-term results are encouraging. In a small number of patients, deterministic effects can occur even in departments with well-trained staff. Operators should inform the patients of possible skin injury after receiving high doses of ionising radiation and proper support must be available should that occur. PMID- 20965907 TI - Does primary tumour volumetry performed early in the course of definitive concomitant chemoradiotherapy for head and neck squamous cell carcinoma improve prediction of primary site outcome? AB - Although previous studies have documented correlations between pre-treatment or post-treatment primary tumour volumes and local outcome following definitive concomitant chemoradiotherapy (CCRT) in head and neck squamous cell carcinoma (HNSCC), no study has included and compared tumour volumes during CCRT. We reviewed the MRIs of 69 HNSCC patients treated with a 6 weeks course of CCRT and who underwent successful MRI pre-treatment (n = 69), 2 weeks intra-treatment (n = 48) and 6 weeks post-treatment (n = 61). Primary tumour volumes on MRI at the three time points were calculated and compared for their predictive value for primary site outcome. Volume thresholds optimised to predict failure with the highest accuracy and positive predictive value (PPV) were calculated. The mean pre-treatment volume was 24.6 cm3 (range, 1.1-187.9 cm3) and the mean follow-up interval was 41 months (range, 12-100 months). 23 primary tumours failed treatment (33%). Volumes before, during and after CCRT were positively associated with local failure (p = 0.015, p = 0.009, p<0.0001). Volume reductions during and after CCRT were negatively associated with local failure (p = 0.021, p = 0.001). Pre-treatment and intra-treatment volume thresholds achieved the highest accuracy and produced intermediate PPVs (51-64%) for predicting local failure. Optimised intra-treatment thresholds did not identify any more treatment failures than the pre-treatment thresholds. By comparison, a 6 weeks post-treatment volume reduction (<35%) achieved 100% PPV for failure, albeit with 26% sensitivity. In conclusion, primary tumour volumetry performed early in CCRT provides minimal additional information compared with pre-treatment volumetry, with respect to predicting post-treatment local failures. Therefore, volumetry during CCRT is unlikely to be useful for guiding individual response-based therapeutic modifications. PMID- 20965908 TI - Design and construction of a multipath vessel phantom for interventional training. AB - This short communication reports on the design and construction of a catheter manipulation skill enhancement phantom for use by residents and fellows outside the clinical environment. The phantom contains a variety of path trajectories and vessel diameter transitions, allowing trainees to manipulate catheters through vessel paths of varying difficulty. The multipath phantom, which is easy to construct and provides easily visualised paths, provides a simple, cost-effective training platform to facilitate and accelerate interventional training. PMID- 20965909 TI - Diagnosis of colonic volvulus: findings on multidetector CT with three dimensional reconstructions. AB - Large bowel volvulus is a rare condition that can occur in patients who present with acute abdominal pain. Radiologists should be able to recognise its appearance on multidetector CT (MDCT) images so that the correct diagnosis can be made and catastrophic consequences can be avoided. In this article, we discuss and illustrate the MDCT and three-dimensional appearance of the various forms of large bowel volvulus. As MDCT allows the precise diagnosis of topography, mechanism and severity, this technique can provide an accurate assessment of large bowel volvulus. PMID- 20965910 TI - Can leopards change their spots? PMID- 20965911 TI - Promoting critical consciousness and social mobilization in HIV/AIDS programmes: lessons and curricular tools from a South African intervention. AB - The development of critical consciousness is seen as a key stage in communities increasing levels of dialogue about priority problems and effecting structural change for health. However, relatively little research identifies concrete methods for programmes to build critical consciousness. We examined how a South African structural intervention used critical consciousness as a tool for prevention of intimate partner violence and HIV infection. We collected qualitative data in the form of in-depth interviews with managers, trainers, and participants of the Intervention with Microfinance for AIDS and Gender Equity intervention (IMAGE) in rural South Africa. The data were analysed through a coding structure developed in QSR NVivo. We draw practical lessons from IMAGE to guide other HIV programmes aiming to promoting critical consciousness and social mobilization. This research suggests that specific curricular tools can work towards critical consciousness and that mobilization efforts in future programmes can be strengthened by including individual and collective efforts by participants. PMID- 20965912 TI - Reporting diet-related health issues through newspapers: portrayal of cardiovascular disease and Type 2 diabetes. AB - This study identifies (i) the extent to which newsprint media communicate to their readers the lifestyle factors associated with the development of cardiovascular disease and Type 2 diabetes and (ii) newspaper portrayal of social determinants affecting onset of disease. A content analysis of five leading UK national newspapers and their Sunday equivalents was conducted over a 3-month period between January and March 2008. This study shows that cardiovascular disease had much higher press interest than Type 2 diabetes. 'Middle-market' and 'Quality' papers had higher levels of reporting than the 'Popular' press, but the patterns were more complex when the comprehensiveness of reporting was measured within each article. Social determinants affecting disease onset were poorly reported by newspapers, supporting similar research conducted in other countries. This research identifies that there is potential for newspapers to improve their reporting of lifestyle diseases, by including individual and social determinants of disease onset. Lower social classes who read the popular press receive the lowest frequency of reporting and could benefit most from this information. While the research identifies that newspapers are missing the potential to actively communicate and reinforce government health policy, it recognises that the commercial context of the print media may counter such behaviour. PMID- 20965913 TI - Human infection with Delftia tsuruhatensis isolated from a central venous catheter. AB - We present the case of a patient with catheter-related infection caused by Delftia tsuruhatensis, a newly described species closely related to Delftia acidovorans (formerly Comamonas acidovorans). To date, D. tsuruhatensis has not been described as a pathogen. To the best of our knowledge, this is the first report describing D. tsuruhatensis as the causative agent of a human infection. PMID- 20965914 TI - Bacteriophage versus antimicrobial agents for the treatment of murine burn wound infection caused by Klebsiella pneumoniae B5055. AB - This study was planned to evaluate the efficacy of silver nitrate and gentamicin in the treatment of burn wound infection and to compare it with phage therapy using an isolated and well-characterized Klebsiella-specific phage, Kpn5. A full thickness burn wound was induced in mice and infected with Klebsiella pneumoniae B5055 via the topical route. Different concentrations of silver nitrate or gentamicin were applied topically daily after establishment of infection. Phage Kpn5 mixed in hydrogel was also applied topically at an m.o.i. of 200 on the burn wound site. The efficacy of these antimicrobial agents was assessed on the basis of percentage survival of infected mice following treatment. The results showed that a single dose of phage Kpn5 resulted in a significant reduction in mortality (P<0.001). Daily applications of silver nitrate and gentamicin at 0.5 % and 1000 mg l(-1), respectively, provided significant protection (P<0.001) compared to lower concentrations of the two agents. However, the level of protection given by these two agents was lower than that given by the phage therapy. The results strongly suggest that phage Kpn5 has therapeutic utility in treating burn wound infection in mice as a single topical application of this phage was able to rescue mice from infection caused by K. pneumoniae B5055 in comparison to multiple applications of silver nitrate and gentamicin. PMID- 20965915 TI - Rhodococcus erythropolis septicaemia in a patient with acute lymphocytic leukaemia. AB - Rhodococcus erythropolis rarely causes infection in humans. We report the second case of R. erythropolis septicaemia in a 7-year-old child. However, to our knowledge it is the first case in a patient with acute lymphocytic leukaemia who had been undergoing chemotherapy. The identification was performed using 16S rRNA gene sequencing. Even though R. erythropolis is rarely associated with human infections, it should be considered as a potential causative agent of bacteraemia, rather than overlooked as a contaminant. PMID- 20965916 TI - Antibiotic resistance patterns of intestinal Escherichia coli isolates from Nicaraguan children. AB - In developing countries, diarrhoeal diseases are one of the major causes of death in children under 5 years of age. It is known that diarrhoeagenic Escherichia coli (DEC) is an important aetiological agent of infantile diarrhoea in Nicaragua. However, there are no recent studies on antimicrobial resistance among intestinal E. coli isolates in Nicaraguan children. The aim of the present study was to determine the antimicrobial resistance pattern in a collection of 727 intestinal E. coli isolates from the faeces of children in Leon, Nicaragua, between March 2005 and September 2006. All samples had been screened previously for the presence of DEC by multiplex PCR. Three hundred and ninety-five non-DEC isolates (270 from children with diarrhoea and 125 from children without diarrhoea) and 332 DEC isolates (241 from children with diarrhoea and 91 from children without diarrhoea) were analysed in this study. In general, antimicrobial resistance among the 727 intestinal E. coli isolates was high for ampicillin (60 %), trimethoprim-sulfamethoxazole (64 %) and chloramphenicol (11 %). Among individual E. coli categories, enteroaggregative E. coli isolates from children with and without diarrhoea exhibited significantly higher levels of resistance (P<0.05) to ampicillin and trimethoprim-sulfamethoxazole compared to the other E. coli categories. Resistance to ceftazidime and/or ceftriaxone and a pattern of multi-resistance was related to CTX-M-5- or CTX-M-15-producing E. coli isolates. The results suggest that E. coli isolates from Nicaraguan children have not reached the high levels of resistance to the most common antibiotics used for diarrhoea treatment as in other countries. PMID- 20965917 TI - Differences in expression of virulence genes amongst invasive and colonizing isolates of meticillin-resistant Staphylococcus aureus. PMID- 20965919 TI - Evaluation of a liquid bead array system for high-risk human papillomavirus detection and genotyping in comparison with Hybrid Capture II, DNA chip and sequencing methods. AB - Since persistent infection with high-risk human papillomavirus (HPV) is a known cause of high-grade cervical intraepithelial neoplasia and cervical cancer, several HPV DNA detection methods have been developed during the last decade. The Hybrid Capture II (HCII) assay, which allows detection of 13 high-risk HPVs, has been well validated; however, it does not provide any genotype-specific information. The oncogenic activity of HPV is dependent on its genotype. The prophylactic effects of HPV vaccines are based on L1 virus-like particles and are limited mainly to infections corresponding to the HPV type used to develop the immunogen. Therefore, accurate detection and genotyping are important for treatment as well as screening. A newly developed HPV genotyping system using a liquid bead array was evaluated with 286 cervical samples and the results were compared to two commercially available methods, i.e. the HCII and HPV DNA chip assays, and sequencing. The sensitivity for detection of high-risk HPV was 85.3 % (HCII), 94.7 % (DNA chip) and 99.0 % (liquid bead array). The liquid bead array showed almost perfect agreement (kappa=0.95) with genotype information confirmed by sequencing, while substantial agreement (kappa=0.8) was observed between DNA chip and sequencing. Furthermore, the liquid bead array had superior detection of 26 HPVs (16 high-risk and 10 low-risk types) and has proven to be as accurate as sequencing in identifying individual HPV types, even in cases with multiple HPV infections. PMID- 20965918 TI - Co-regulation of {beta}-lactam resistance, alginate production and quorum sensing in Pseudomonas aeruginosa. AB - Development of beta-lactam resistance, production of alginate and modulation of virulence factor expression that alters host immune responses are the hallmarks of chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. In this study, we propose that a co-regulatory network exists between these mechanisms. We compared the promoter activities of ampR, algT/U, lasR, lasI, rhlR, rhlI and lasA genes, representing the beta-lactam antibiotic resistance master regulatory gene, the alginate switch operon, the las and rhl quorum-sensing (QS) genes, and the LasA staphylolytic protease, respectively. Four isogenic P. aeruginosa strains, the prototypic Alg(-) PAO1, Alg(-) PAOampR, the mucoid Alg(+) PAOmucA22 (Alg(+) PDO300) and Alg(+) PAOmucA22ampR (Alg(+) PDOampR) were used. We found that in the presence of AmpR regulator and beta-lactam antibiotic, the extracytoplasmic function sigma factor AlgT/U positively regulated P(ampR), whereas AmpR negatively regulated P(algT/U). On the basis of this finding we suggest the presence of a negative feedback loop to limit algT/U expression. In addition, the functional AlgT/U caused a significant decrease in the expression of QS genes, whereas loss of ampR only resulted in increased P(lasI) and P(lasR) transcription. The upregulation of the las QS system is likely to be responsible for the increased lasA promoter and the LasA protease activities in Alg(-) PAOampR and Alg(+) PDOampR. The enhanced expression of virulence factors in the ampR strains correlated with a higher rate of Caenorhabditis elegans paralysis. Hence, this study shows that the loss of ampR results in increased virulence, and is indicative of the existence of a co-regulatory network between beta-lactam resistance, alginate production, QS and virulence factor production, with AmpR playing a central role. PMID- 20965920 TI - Corynebacterium jeikeium pacemaker infection associated with antineutrophil cytoplasmic antibodies: a single positive blood culture could be sufficient for diagnosis. AB - Corynebacterium jeikeium, a member of the non-diphtheria corynebacteria, has been rarely reported as being responsible for cardiovascular-device infection. Here, we report what is believed to be the first case of C. jeikeium pacemaker infection associated with the presence of proteinase-3 antineutrophil cytoplasmic antibodies. The diagnosis was established based on the positivity of a single positive blood culture and led to pacemaker extraction. This observation highlights the difficulty in the diagnosis of cardiac-device infection in the presence of a single positive blood culture with a fastidious microorganism that could be considered as a contaminant. It also underscores the need for device extraction to ensure healing. PMID- 20965921 TI - Role of efflux in macrolide resistance in {beta}-haemolytic streptococci of groups A, B, C and G collected in an Irish teaching hospital. PMID- 20965922 TI - Effect of frameshift mutagen acriflavine on control of resistance genes in Acinetobacter baumannii. AB - Acinetobacter baumannii is a Gram-negative pathogenic bacterium that often exhibits a multidrug-resistant phenotype causing infections at various sites of the body and increasingly leading to septicaemic shock. This study evaluated the role of acriflavine, a frameshift mutagen, on the movement of insertion sequence ISAba1 in clinical isolates of A. baumannii, with the focus on changes in expression levels of the bla(ADC) and bla(OXA-51-like) genes. Resistance profiles were assessed with consideration of ISAba1 acting as a promoter upstream of the bla(ADC) or bla(OXA-51-like) gene. ISAba1 movement was observed in the acriflavine mutants Ab153M and Ab1225M. Ab153M exhibited an increase in the MIC values of carbapenems and ceftazidime, with ISAba1 gained upstream of the bla(ADC) and bla(OXA-51-like) genes, correlating with an increase in gene expression. Reduced expression of the 17, 23 and 25 kDa outer-membrane proteins (OMPs) was also observed in Ab153M. There was a significant decrease in MIC values of carbapenems with the loss of ISAba1 upstream of the bla(ADC) and bla(OXA-51-like) genes in strain Ab1225M, and a significant decrease in bla(OXA 51-like) gene expression and, to a lesser extent, in bla(ADC) expression. Ab1225M and a serially subcultured Ab1225 strain (Ab1225s) exhibited overexpression of the 17, 23, 25 and 27 kDa OMPs. There was a decrease in MIC values of the carbapenems and piperacillin/tazobactam but not of ceftazidime in Ab1225s, which had ISAba1 upstream of the bla(ADC) and bla(OXA-51-like) genes. A significant decrease in bla(OXA-51-like) expression was observed in Ab1225s, whereas the expression of bla(ADC) was similar to that in the Ab1225 parental strain. The attenuation in this strain may be due to overexpression of OMPs and it is clear that, even if ISAba1 is present upstream of an antibiotic resistance gene, it may not necessarily contribute towards the overexpression of antibiotic resistance genes (bla(OXA-51-like) in Ab1225s). Movement of the IS element within the A. baumannii chromosome may be an important regulatory mechanism employed by the bacterium under particular stress conditions, and the ability to upregulate the expression of antibiotic resistance genes is likely to be an important factor in the pathogenicity of this bacterium. PMID- 20965923 TI - Continued control of pneumococcal disease in the UK - the impact of vaccination. AB - Streptococcus pneumoniae, also known as the pneumococcus, is an important cause of morbidity and mortality in the developed and developing world. Pneumococcal conjugate vaccines were first introduced for routine use in the USA in 2000, although the seven-valent pneumococcal conjugate vaccine (PCV7) was not introduced into the UK's routine childhood immunization programme until September 2006. After its introduction, a marked decrease in the incidence of pneumococcal disease was observed, both in the vaccinated and unvaccinated UK populations. However, pneumococci are highly diverse and serotype prevalence is dynamic. Conversely, PCV7 targets only a limited number of capsular types, which appears to confer a limited lifespan to the observed beneficial effects. Shifts in serotype distribution have been detected for both non-invasive and invasive disease reported since PCV7 introduction, both in the UK and elsewhere. The pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, Synflorix; GlaxoSmithKline) and 13-valent pneumococcal conjugate vaccine (PCV13, Prevenar 13; Pfizer) have been newly licensed. The potential coverage of the 10- and 13-valent conjugate vaccines has also altered alongside serotype shifts. Nonetheless, the mechanism of how PCV7 has influenced serotype shift is not clear cut as the epidemiology of serotype prevalence is complex. Other factors also influence prevalence and incidence of pneumococcal carriage and disease, such as pneumococcal diversity, levels of antibiotic use and the presence of risk groups. Continued surveillance and identification of factors influencing serotype distribution are essential to allow rational vaccine design, implementation and continued effective control of pneumococcal disease. PMID- 20965924 TI - BCG vaccination: 90 years on and still so much to learn ... PMID- 20965927 TI - Pneumococcal conjugate vaccine-induced regulatory T cells suppress the development of allergic airways disease. AB - BACKGROUND: Infections with some bacteria, including Streptococcus pneumoniae, have been associated with a reduced incidence of asthma. Components of S pneumoniae may have the potential to modulate allergic inflammatory responses and suppress the development of asthma. OBJECTIVES: To determine if human S pneumoniae vaccines have the potential to suppress asthma by elucidating their effect on allergic airways disease (AAD) in mouse models. METHODS: AAD was induced in BALB/c mice by intraperitoneal sensitisation and intranasal challenge with ovalbumin. Pneumococcal conjugate or polysaccharide vaccines were administered at the time of sensitisation or during established AAD. Hallmark features of AAD were assessed. Levels of regulatory T cells (Tregs) were quantified by fluorescence-activated cell sorting, and their immunoregulatory capacity was assessed using proliferation assays and anti-CD25 antibody treatment. RESULTS: Intranasal administration of the conjugate vaccine, but not the polysaccharide vaccine, suppressed the hallmark features of AAD, including: eosinophilic and T helper 2-mediated inflammation; airway hyper-responsiveness; circulating immunoglobulin E (IgE) levels; and mucus hypersecretion. Intramuscular administration of the conjugate vaccine had limited protective effects. The conjugate vaccine increased Tregs in the lung-draining lymph nodes, lung and spleen. Furthermore, conjugate vaccine-induced Tregs had an enhanced capacity to suppress T effector responses. Anti-CD25 administration reversed the suppressive effects of the conjugate vaccine. CONCLUSIONS: A currently available human conjugate vaccine suppresses the hallmark features of AAD through the induction of Tregs. Thus targeted administration may provide a novel immunoregulatory treatment for asthma. PMID- 20965928 TI - Long-term low-dose erythromycin in patients with unexplained chronic cough: a double-blind placebo controlled trial. AB - AIMS: Unexplained chronic cough is a common condition with no satisfactory treatments. Previous work has suggested that cough may be linked to neutrophilic airway inflammation. This study tested the hypothesis that long-term low-dose erythromycin reduces the induced sputum neutrophil count and 24 h cough frequency in patients with unexplained chronic cough. METHODS: 30 patients with an unexplained chronic cough lasting more than 8 weeks were randomly assigned to take 250 mg erythromycin once daily (n=15) or placebo (n=15) for 12 weeks in a double-blind parallel group study. Cough frequency, cough reflex sensitivity and cough severity were assessed at baseline, 6, 12 and 24 weeks. The primary outcome measure was change in 24 h cough frequency at 12 weeks. RESULTS: There was no difference in the change in cough frequency between the erythromycin and placebo groups at 12 weeks (mean difference in fold change 1.1; 95% CI 0.7 to 1.5; p=0.585) or at other times. There was a statistically significant between treatment difference in the change in sputum neutrophils at 12 weeks (-10.2% vs +6.6% with erythromycin and placebo; mean difference 16.8%; 95% CI 1.6 to 32.1; p=0.03) but not at other times. There was no difference in the change in other measures of cough between treatments. CONCLUSIONS: Treatment with low-dose erythromycin for 12 weeks reduces the induced sputum neutrophil count but not cough frequency or severity in patients with unexplained chronic cough. PMID- 20965929 TI - An unusual case of diaphragm paralysis. PMID- 20965930 TI - Management of severe community-acquired pneumonia of children in developing and developed countries. AB - Childhood community-acquired pneumonia (CAP) is common, and recent data have shown that the number of children with severe CAP is increasing worldwide. Regardless of geographical area, severe cases are those at the highest risk of hospitalisation, prolonged hospitalisation and death, and therefore require prompt identification and the most effective treatment in order to reduce CAP related morbidity and mortality. This review evaluates the available data concerning the diagnosis and treatment of severe and/or complicated cases of paediatric CAP in developed and developing countries. It also underlines the fact that any evidence-based recommendations require more research in various areas, including the aetiology of severe cases and the reasons for the complications, the better definition of first-choice antibiotic treatment and when surgery may be useful, and the role of chest physiotherapy. PMID- 20965931 TI - On the shoulders of (real) giants. PMID- 20965932 TI - Predicting mortality in the elderly with community-acquired pneumonia: should we design a new car or set a new 'speed limit'? PMID- 20965933 TI - Atrophy and hypertrophy signalling of the quadriceps and diaphragm in COPD. AB - BACKGROUND: Factors involved in the regulation of muscle mass in chronic obstructive pulmonary disease (COPD) are still poorly understood. Comparing the signalisation involved in muscle mass regulation between two muscles with different levels of activation within the same subjects is an interesting strategy to tease out the impact of local (muscle activity) versus systemic factors in the regulation of muscle mass. A study was undertaken to measure and compare the protein levels of p-AKT, AKT, Atrogin-1, p-p70S6K, p-4E-BP1, p GSK3beta as well as the mRNA expression of Atrogin-1, MuRF1 and FoxO-1 in the quadriceps and the diaphragm of 12 patients with COPD and 7 controls with normal lung function. METHODS: Diaphragm biopsies were obtained during thoracic surgery and quadriceps samples were obtained from needle biopsies. Protein content and mRNA expression were measured by western blot and quantitative PCR, respectively. RESULTS: Increased mRNA expressions of Atrogin-1, MuRF1 and FoxO-1 were found in the quadriceps compared with the diaphragm only in patients with COPD. The quadriceps/diaphragm ratio for MuRF1 was higher in COPD. The protein level of p p70S6K was decreased in the quadriceps compared with the diaphragm in patients with COPD. The quadriceps/diaphragm ratios of p-p70S6K and p-GSK3beta were lower in patients with COPD than in controls. CONCLUSIONS: These results indicate a greater susceptibility to a catabolic/anabolic imbalance favouring muscle atrophy in the quadriceps compared with the diaphragm in patients with COPD. The balance between the atrophy and hypertrophy signalling is inhomogeneous between respiratory and lower limb muscles, suggesting that local factors are likely to be involved in the regulation of muscle mass in COPD. PMID- 20965934 TI - Comparison of clinical characteristics and performance of pneumonia severity score and CURB-65 among younger adults, elderly and very old subjects. AB - BACKGROUND: Age-related alterations in the clinical characteristics and performance of severity scoring systems for community-acquired pneumonia (CAP) are unknown. METHODS: Consecutive patients with CAP presenting to the emergency department were prospectively studied. Patients were classified as younger adults (age 18-64 years), elderly (age 65-84 years) and very old subjects (age >=85 years). Clinical characteristics, complications, outcomes and validity of the pneumonia severity index (PSI) and CURB-65 categories were compared across these three age categories. RESULTS: Analysis involved 348 (35.3%) younger adult patients, 438 (44.3%) elderly patients and 201 (20.0%) very old patients. Compared with younger adults, elderly and very old patients had a higher burden of comorbidities and a higher incidence of CAP-related complications. The 30-day mortality rate was 5.2% in younger adults, 7.1% in elderly patients and 9.5% in very old patients. The area under the ROC curve (AUCs) for PSI were 0.87 (95% CI 0.77 to 0.97), 0.85 (95% CI 0.803 to 0.897) and 0.69 (95% CI 0.597 to 0.787) and the AUCs for CURB-65 were 0.80 (95% CI 0.67 to 0.93), 0.73 (95% CI 0.65 to 0.82) and 0.60 (95% CI 0.47 to 0.73) in the younger adult, elderly and very old patients, respectively. A modified PSI or CURB-65 excluding the age variable increased the AUC in most age categories. There was no significant effect of age on 30-day mortality after adjusting for other PSI or CURB-65 variables. CONCLUSION: Elderly patients with CAP have more atypical clinical manifestations and worse outcomes. The underperformance of the PSI in elderly patients may be due to the inappropriate weight given to the age variable. A modification of the cut-off point for PSI or CURB-65 to define severe pneumonia may improve the score performance in elderly patients. PMID- 20965935 TI - Epidemiology of obstructive sleep apnoea syndrome in Chinese children: a two phase community study. AB - OBJECTIVE: To determine the prevalence and risk factors of obstructive sleep apnoea syndrome (OSAS) in Chinese children using a two-phase community-based study design. METHODS: Children from 13 primary schools were randomly recruited. A validated OSAS screening questionnaire was completed by their parents. Children at high risk of OSAS and a randomly chosen low-risk group were invited to undergo overnight polysomnographic study and clinical examination. The the sex-specific prevalence rate was measured using different cutoffs (obstructive apnoea hypopnoea index >= 1, >= 1.5, >= 3 and >= 5 and obstructive apnoea index >= 5) and risk factors associated with OSAS were evaluated with logistic regression. RESULTS: 6447 completed questionnaires were returned (out of 9172 questionnaires; 70.3%). 586 children (9.1%; 405 boys and 181 girls) children belonged to the high risk group. A total of 619 (410 and 209 from the high and low-risk group, respectively) subjects underwent overnight polysomnagraphy. Depending on the cutoffs, the prevalence rate of childhood OSAS varied from 4.8% to 40.3%. Using the International Criteria of Sleep Disorders version II, the OSAS prevalence for boys and girls was 5.8% and 3.8%, respectively. Male gender, body mass index z score and increased adenoid and tonsil size were independently associated with OSAS. CONCLUSIONS: The prevalence rate of OSAS in children was contingent on the cutoff used. The inclusion of symptoms as a part of the diagnostic criteria greatly reduced the prevalence. A further prospective and outcome study is needed to define a clinically significant diagnostic cutoff for childhood OSAS. PMID- 20965936 TI - Persistent cough: an unusual cause. Idiopathic hypereosinophilic syndrome (HES). PMID- 20965938 TI - Intermediate outcome and dynamic computerised tomography after chest wall reconstruction with the STRATOS titanium rib bridge system: video demonstration of preserved bucket-handle rib motion. AB - We report the intermediate clinical outcome following resection of a chest wall sarcoma and layered reconstruction with a deep expanded polytetrafluroethylene patch, four STRATOS titanium rib bridges and an overlying muscle flap. After 21 months there is no evidence of recurrence. The reconstruction remains intact despite trauma sufficient to fracture the ipsilateral scapula and elbow. Exercise capacity, pain control and quality of life are good. We developed a functional computed tomography (CT) algorithm which allowed dynamic imaging. Video images for the first time demonstrate preserved physiological type bucket-handle movement of the ribs in continuity with the rib bridges. PMID- 20965939 TI - Hereditary non-polyposis colorectal cancer/Lynch syndrome in Korean patients with endometrial cancer. AB - OBJECTIVE: We investigate the frequency of hereditary non-polyposis colorectal cancer among Korean endometrial cancer patients according to two clinical criteria and the uptake rate of a genetic test and genetic status of such patients in routine clinical practice. METHODS: This was a retrospective study involving 161 consecutive endometrial cancer patients. Patients were classified into clinical and suspected hereditary non-polyposis colorectal cancer. Using direct sequencing, germline mutations were analyzed in the MLH1 and MSH2 genes. RESULTS: There were four (2.5%) clinical hereditary non-polyposis colorectal cancer patients, three of whom underwent genetic testing, and a mutation (c.882delT) in the MSH2 gene was identified in one patient. There were also 14 (8.7%) suspected hereditary non-polyposis colorectal cancer patients, 6 of whom underwent genetic testing; 1 [1/6 (16.7%)] patient had a mutation (c.1757_1758insC) in the MLH1 gene and 1 patient had a sequence variant of unknown significance (c.1886A < G) in the MSH2 gene. Half of the patients (9 of 18) who met clinical or suspected hereditary non-polyposis colorectal cancer criteria declined genetic testing mainly for the reason of financial factor (8 of 9). CONCLUSIONS: The proportion of hereditary non-polyposis colorectal cancer [11.2% (18 of 161)] was significant to offer genetic counseling and genetic testing in Korean endometrial cancer patients. Optimal financial support is crucial to increase the uptake rate of a genetic test. PMID- 20965940 TI - Phase I/II study of FOLFIRI in Japanese patients with advanced colorectal cancer. AB - OBJECTIVE: This phase I/II study determined the recommended dose of FOLFIRI (irinotecan, infusional 5-fluorouracil and leucovorin) for Japanese patients with advanced colorectal cancer, and evaluated safety at the recommended dose in patients without the UDP-glucuronosyltransferase 1A1*28 allele which caused reduced enzyme expression. METHODS: The phase I part assessed the maximum tolerated dose of FOLFIRI to determine the recommended doses of irinotecan and infusional 5-fluorouracil. The doses were escalated from 150 to 180 mg/m(2) (irinotecan) and 2000 to 2400 mg/m(2) (5-fluorouracil). UDP glucuronosyltransferase 1A1*6 and *28, and pharmacokinetics of irinotecan were observationally examined. In the phase II part, patients without the UDP glucuronosyltransferase 1A1*28 allele received FOLFIRI at the recommended dose to evaluate safety. RESULTS: Among 15 patients in the phase I part, dose-limiting toxicity (diarrhea) occurred in one patient who received 150 mg/m(2) irinotecan and 2400 mg/m(2) infusional 5-fluorouracil. The respective recommended doses were 180 and 2400 mg/m(2) for irinotecan and infusional 5-fluorouracil, without reaching the maximum tolerated dose. Twenty-five patients received FOLFIRI at the recommended doses. Grade 3 or 4 neutropenia occurred in 44%, and Grade 3 diarrhea in 4%. CONCLUSIONS: This phase I/II study demonstrates that the recommended doses of irinotecan and infusional 5-fluorouracil in FOLFIRI for Japanese patients with advanced colorectal cancer who do not possess the UDP-glucuronosyltransferase 1A1*28 allele are 180 and 2400 mg/m(2), respectively. Toxicities occurring at the recommended doses are manageable in these patients. PMID- 20965941 TI - Phase III trial of everolimus in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from RECORD-1. AB - OBJECTIVE: To assess the efficacy and safety of everolimus in Japanese patients with metastatic renal cell carcinoma. METHODS: A subgroup analysis of the pivotal Phase III, randomized, double-blind, placebo-controlled trial of everolimus 10 mg/day in patients with disease progression after treatment with sorafenib, sunitinib or both assessed outcomes in Japanese participants. Results were compared with those for the overall study population. RESULTS: The final trial analysis included 24 Japanese patients (everolimus, n= 15; placebo, n = 9). Median progression-free survival in the Japanese subpopulation was 5.75 months (95% confidence interval, 4.90 months to not reached) with everolimus and 3.61 months (95% confidence interval, 1.91-9.03 months) with placebo (hazard ratio, 0.19; 95% confidence interval, 0.05-0.83). Median overall survival was not reached with everolimus and was 14.9 months (95% confidence interval, 11.0-16.8 months) with placebo (hazard ratio, 0.30; 95% confidence interval, 0.07-1.27). Overall, efficacy and safety were similar when comparing the Japanese and overall populations. In the Japanese subpopulation, the most common adverse events with everolimus were stomatitis, infections and rash. Four Japanese subjects (27%) developed Grade 1 (n = 2) or 2 (n = 2) pneumonitis (all reversible and allowing for continuation of therapy, after interruption, steroids and dose reduction for both Grade 2 cases), with a lower pneumonitis incidence of 14% in the overall population (albeit associated with a Grade 3 incidence of 4%). CONCLUSIONS: These findings suggest that the demonstrated benefits of everolimus in the overall trial population are similar in Japanese patients with metastatic renal cell carcinoma. PMID- 20965942 TI - Physician-assisted dying. PMID- 20965943 TI - Death, dying, and statistics: quality measures versus quality of life. PMID- 20965944 TI - Is LEAFY a useful marker gene for the flower-inflorescence boundary in the Euphorbia cyathium? AB - The flower-like reproductive structure of Euphorbia s.l. (Euphorbiaceae) is widely believed to have evolved from an inflorescence, and is therefore interpreted as a special type of pseudanthium, termed a cyathium. However, fuzzy morphological boundaries between the inflorescence, individual flowers, and organs have fuelled the suggestion that the cyathium does not merely superficially resemble a flower but could actually share developmental genetic pathways with a conventional flower. To test this hypothesis, immunolocalizations of FLORICAULA/LEAFY (LFY), a protein associated with floral identity in many angiosperm species, were performed in developing cyathia of different species of Euphorbia. Expression of the LFY protein was found not only in individual floral primordia (as predicted from results in the model organisms Arabidopsis and Anthirrhinum), but also in the cyathium primordium and in the primordia of partial male inflorescences. These results provide further evidence that the evolution of floral traits in pseudanthial inflorescences often involves expression of floral development genes in the inflorescence apex. This finding blurs the conventional rigid distinction between flowers and inflorescences. PMID- 20965945 TI - Arkadia complexes with clathrin adaptor AP2 and regulates EGF signalling. AB - Arkadia is a positive regulator of transforming growth factor (TGF)-beta signalling that induces ubiquitin-dependent degradation of several inhibitory proteins of TGF-beta signalling through its C-terminal RING domain. We report here that, through yeast-two-hybrid screening for Arkadia-binding proteins, the u2 subunit of clathrin-adaptor 2 (AP2) complex was identified as an interacting partner of Arkadia. Arkadia was located in both the nucleus and the cytosol in mammalian cells. The C-terminal YXXPhi-binding domain of the u2 subunit associated with the N-terminal YALL motif of Arkadia. Arkadia ubiquitylated the u2 subunit at Lys130. In addition, Arkadia interacted with the AP2 complex, and modified endocytosis of epidermal growth factor receptor (EGFR) induced by EGF. Arkadia thus appears to regulate EGF signalling by modulating endocytosis of EGFR through interaction with AP2 complex. PMID- 20965946 TI - Mental health in the workforce: an occupational psychiatric study. AB - BACKGROUND: Prevalence of mental disorders at work is commonly reported on the subclinical level. Data on clinical caseness as to ICD-10 among employees is scarce. AIMS: (i) To establish the prevalence of psychiatric morbidity in the Danish workforce in large enterprises based on a self-report measure. (ii) To verify the screening results by use of a structured diagnostic interview. (iii) To analyze associations with demographics and work- and health-related characteristics. METHODS: A two-phase design study was carried out in three Danish counties. Ten large enterprises within private and public sectors participated. A questionnaire was administrated to 1,500 employees. The Present State Examination (PSE) interview was conducted with selected respondents according to their scores on Symptom Checklist 90-revised (SCL-90R) and CAGE. RESULTS: Nine hundred and seventy six (65%) employees responded. A large proportion (28.6%) was identified as sub-cases and 77 as cases as to ICD-10. Absenteeism and work dissatisfaction were associated with ICD-10 diagnoses. CONCLUSIONS: Common mental disorders caseness as to ICD-10 provides evidence for the clinical nature of occupational mental health phenomena. There were strong associations between some demographic and work- and health-related factors. PMID- 20965947 TI - Nitric oxide stimulates human sperm motility via activation of the cyclic GMP/protein kinase G signaling pathway. AB - Nitric oxide (NO), a modulator of several physiological processes, is involved in different human sperm functions. We have investigated whether NO may stimulate the motility of human spermatozoa via activation of the soluble guanylate cyclase (sGC)/cGMP pathway. Sperm samples obtained by masturbation from 70 normozoospermic patients were processed by the swim-up technique. The kinetic parameters of the motile sperm-rich fractions were assessed by computer-assisted sperm analysis. After a 30-90 min incubation, the NO donor S-nitrosoglutathione (GSNO) exerted a significant enhancing effect on progressive motility (77, 78, and 78% vs 66, 65, and 62% of the control at the corresponding time), straight linear velocity (44, 49, and 48 MUm/s vs 34, 35, and 35.5 MUm/s), curvilinear velocity (81, 83, and 84 MUm/s vs 68 MUm/s), and average path velocity (52, 57, and 54 MUm/s vs 40, 42, and 42 MUm/s) at 5 MUM but not at lower concentrations, and in parallel increased the synthesis of cGMP. A similar effect was obtained with the NO donor spermine NONOate after 30 and 60 min. The GSNO-induced effects on sperm motility were abolished by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (a specific sGC inhibitor) and mimicked by 8-bromo-cGMP (8-Br-cGMP; a cell permeating cGMP analog); the treatment with Rp-8-Br-cGMPS (an inhibitor of cGMP dependent protein kinases) prevented both the GSNO- and the 8-Br-cGMP-induced responses. On the contrary, we did not observe any effect of the cGMP/PRKG1 (PKG) pathway modulators on the onset of hyperactivated sperm motility. Our results suggest that NO stimulates human sperm motility via the activation of sGC, the subsequent synthesis of cGMP, and the activation of cGMP-dependent protein kinases. PMID- 20965948 TI - Exercise improves hemodynamic profiles and increases red blood cell concentrations of purine nucleotides in a rodent model. AB - OBJECTIVE: To study the effect of exercise on hemodynamic profiles and red blood cell (RBC) concentrations of adenosine-5'-triphosphate (ATP). METHODS: Male Sprague-Dawley (SD) rats (n = 9) were exercised on a treadmill for 15 min at a speed of 10 m/min with a 5% gradient after an hour settling down in a restrainer. Blood samples were collected via an indwelling carotid artery catheter using a 'Stopping Solution' from each rat before, during and after exercise. Hemodynamic recordings were collected continuously throughout the experiment. Concentrations of ATP and other purine nucleotides in the RBCs were determined by a validated high-performance liquid chromatography (HPLC) assay. A control group (n = 12) was treated the same way except without the exercise. Data between groups were analyzed by analysis of variance (ANOVA) and Student's t-test, and differences were considered significant when p < 0.05. RESULTS: Exercise increased systolic blood pressure (SBP; 141+/-23 vs. 132+/-17 mmHg) and heart rate (HR; 420+/-33 vs. 397+/-41 bpm), but decreased diastolic blood pressure (DBP; 105+/-18 vs. 110+/-14 mmHg). This was followed by a postexercise condition when SBP, DBP, and HR were decreased for the remainder of the experiment. RBC concentrations of ATP and guanosine-5'-triphosphate (GTP) increased significantly during exercise and continued to increase for 5 hours postexercise (1.5+/-0.75 vs. 0.96 vs. 0.36 mM for ATP; and 0.14+/-0.061 vs. 0.058+/-0.030 mM) (p < 0.05). CONCLUSION: Exercise increased RBC ATP concentrations in a rodent model, which was correlated with the decrease in BP and HR postexercise. PMID- 20965949 TI - Valve anatomy and function with transthoracic three-dimensional echocardiography: advantages and limitations of instantaneous full-volume color Doppler imaging. AB - Three-dimensional echocardiography (3DE) is becoming part of everyday clinical practice worldwide. However, 3DE requires adequate electrocardiographic and respiratory gating and it complements instead of replacing bidimensional echocardiography (2D). The instantaneous full-volume echocardiography technique is trying to overcome some of these limitations and to present an effective alternative to 2D echocardiography. In this article we aim to review the contribution of 3DE to our knowledge of anatomic and functional valvular anatomy and the potential advantages of instantaneous full-volume color Doppler echocardiography. PMID- 20965950 TI - Management of dyslipidemia in the elderly population. AB - The elderly population is increasing worldwide. Despite a major decrease in deaths from coronary heart disease (CHD), this malady remains the major cause of death in elderly men and women. In this paper, we review the role of dyslipidemia as a major known risk factor in the pathogenesis of CHD, age-related changes in lipoprotein metabolism, and differences in changes in lipids that occur in men and women during aging. Next we provide an overview of the available studies and recommendations from ATP III. Finally, we comment on the screening and management, cost and side effects of therapy as it applies to an aging population. PMID- 20965951 TI - Renin-angiotensin-aldosterone system blockade in high-risk hypertensive patients: current approaches and future trends. AB - Agents that block the renin-angiotensin-aldosterone system (RAAS) are the cornerstones of antihypertensive therapy in patients at high risk for cardiovascular or renal disease. Recently, it was shown that activation of RAAS may occur through alternate pathways not inhibited by angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs), and that ACEIs, ARBs, or MRAs may actually cause a reactive increase in plasma renin concentration and activity. While these agents, alone or in combination, decrease blood pressure and cardiovascular events to varying degrees, the direct renin inhibitor is a new class of RAAS blocking agent. Aliskiren is the first US Food and Drug Administration-approved direct renin inhibitor with good oral bioavailability. ASPIRE HIGHER is an ongoing series of clinical trials designed to investigate the effect of aliskiren on cardiovascular/renal surrogate endpoints and morbidity/mortality in patients with hypertension and high risk for cardiovascular or renal disease. PMID- 20965952 TI - Recent advances in oral anticoagulation for atrial fibrillation. AB - Atrial fibrillation is the most common sustained rhythm disturbance. Thromboembolic events related to atrial fibrillation result in significant morbidity, mortality and increases in the cost of healthcare. Anticoagulants are pivotal agents for the prevention and treatment of thromboembolic disorders. The latest American College of Cardiology/American Heart Association guidelines recommend antithrombotic therapy to prevent thromboembolism for all patients with atrial fibrillation, except those with lone atrial fibrillation or contraindications. Vitamin K antagonists were first synthesized in 1948 and for the past six decades they have been the only agents used for long-term oral anticoagulant therapy. Although these drugs are effective, they have numerous limitations, which have led to the development of newer anticoagulant therapies. The emerging oral anticoagulant agents are target selective. They have predictable pharmacokinetic and pharmacodynamic parameters and do not require routine monitoring. They are not associated with significant food and drug interactions, and can be administered in simple fixed daily or twice daily doses. This article reviews the current literature on various targets for anticoagulant therapy and newer oral anticoagulants for atrial fibrillation. PMID- 20965953 TI - Changes of mitochondrial ultrastructures and function in central nervous tissue of hens treated with tri-ortho-cresyl phosphate (TOCP). AB - Tri-ortho-cresyl phosphate (TOCP), an organophosphorus ester, is capable of producing organophosphorus ester-induced delayed neurotoxicity (OPIDN) in humans and sensitive animals. The mechanism of OPIDN has not been fully understood. The present study has been designed to evaluate the role of mitochondrial dysfunctions in the development of OPIDN. Adult hens were treated with 750 mg/kg.bw TOCP by gavage and control hens were given an equivalent volume of corn oil. On day 1, 5, 15, 21 post-dosing, respectively, hens were anesthetized by intraperitoneal injection of sodium pentobarbital and perfused with 4% paraformaldehyde. The cerebral cortex cinerea and the ventral horn of lumbar spinal cord were dissected for electron microscopy. Another batch of hens were randomly divided into three experimental groups and control group. Hens in experimental groups were, respectively, given 185, 375, 750 mg/kg.bw TOCP orally and control group received solvent. After 1, 5, 15, 21 days of administration, they were sacrificed and the cerebrum and spinal cord dissected for the determination of the mitochondrial permeability transition (MPT), membrane potential (Deltapsi(m)) and the activity of succinate dehydrogenase. Structural changes of mitochondria were observed in hens' nervous tissues, including vacuolation and fission, which increased with time post-dosing. MPT was increased in both the cerebrum and spinal cord, with the most noticeable increase in the spinal cord. Deltapsi(m) was decreased in both the cerebrum and spinal cord, although there was no significant difference in the three treated groups and control group. The activity of mitochondrial succinate dehydrogenase assayed by methyl thiazolyl tetrazolium (MTT) reduction also confirmed mitochondrial dysfunctions following development of OPIDN. The results suggested mitochondrial dysfunction might partly account for the development of OPIDN induced by TOCP. PMID- 20965954 TI - Multicentric Castleman's disease representing effusion at initial clinical presentation: clinicopathological study of seven cases. AB - We present here seven cases of idiopathic multicentric Castleman's disease (MCD) showing effusion at the initial clinical presentation. This series includes a high proportion of middle-aged and elderly females (5/7). Various autoantibodies were detected in six cases. Anemia (Hb < 10 g/dl) was detected in four cases, leukocytosis (WBC > 10 * 10(9)/l) in three and thrombycytopenia (<100 * 10(9)/l) in five. Positivity for C-reactive protein or elevated erythrocyte sedimentation rate was recorded in all seven cases. Elevated serum IgG level (>2000 mg/dl) was recorded in only three cases. Elevated serum interleukin-6 level was recorded in all four cases examined. At the onset of disease, four cases were associated with idiopathic thrombocytic purpura. During the course of disease, one case each was diagnosed as systemic sclerosis + Sjogren's syndrome (SJS) and SJS. Histologically, five lesions exhibited a mixed type of Castleman's disease, and one case each exhibited a hyaline-vascular type and plasma cell type. The non neoplastic nature of the B-lymphocytes was demonstrated by immunohistochemistry and polymerase chain reaction. There were no human herpes type-8 virus-positive cells in any of the seven lesions. Good responsiveness to glucocorticoid therapy has been seen in all six cases treated. From a therapeutic perspective, it is important to discriminate this subtype of MCD. PMID- 20965955 TI - Oxygenated hypothermic pulsatile perfusion versus cold static storage for kidneys from non heart-beating donors tested by in-line ATP resynthesis to establish a strategy of preservation. AB - AIM: The scarcity of kidneys for transplantation impels an expansion of the donor source to include the use of organs from Maastricht II and Maastricht I non heart beating donors. The aim of this study was to establish the best method to preserve kidneys from non heart-beating donors (NHBD): cold static storage (CSS) or perfusion. ATP production during kidney preservation has been retained as a measure of their energetic levels and, consequently, their viability. The presence of warm ischemia with both types of preservation was studied. METHODS: Porcine kidneys presenting no warm ischemia or 30 minutes of warm ischemia were submitted to immediate oxygenated hypothermic pulsatile perfusion or immediate cold static storage. The study was divided into four groups. ATP resynthesis was measured after 8 h. of perfusion. ATP was assessed by in-line (31)P nuclear magnetic resonance spectroscopy (NMRS) during the preservations. RESULTS: Only oxygenated perfusion could restore ATP in organs with warm ischemia. Initial cold static storage seems deleterious on organs having suffered from warm ischemia. DISCUSSION: Only oxygenated perfusion could restore ATP in organs with warm ischemia. Initial cold static storage seems deleterious to organs having suffered from warm ischemia. Oxygenated perfusion must be introduced immediately after kidney removal from non heart-beating donors. In organs without warm ischemia, any kind of preservation is equivalent. PMID- 20965956 TI - Complement activation on the surface of cell-derived microparticles during cardiac surgery with cardiopulmonary bypass - is retransfusion of pericardial blood harmful? AB - OBJECTIVES: To investigate whether cell-derived microparticles play a role in complement activation in pericardial blood of patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and whether microparticles in pericardial blood contribute to systemic complement activation upon retransfusion. METHODS: Pericardial blood of 13 patients was retransfused in 9 and discarded in 4 cases. Microparticles were isolated from systemic blood collected before anesthesia (T1) and at the end of CPB (T2), and from pericardial blood. The microparticles were analyzed by flow cytometry for bound complement components C1q, C4 and C3, and bound complement activator molecules C-reactive protein (CRP), serum amyloid P component (SAP), immunoglobulin (Ig)M and IgG. Fluid-phase complement activation products (C4b/c, C3b/c) and activator molecules were determined by ELISA. RESULTS: Compared with systemic T1 blood, pericardial blood contained increased C4b/c and C3b/c, and increased levels of microparticles with bound complement components. In systemic T1 samples, microparticle-bound CRP, whereas in pericardial blood, microparticle-bound SAP and IgM were associated with complement activation. At the end of CPB, increased C3b/c (but not C4b/c) was present in systemic T2 blood compared with T1, while concentrations of microparticles binding complement components and of those binding complement activator molecules were similar. Concentrations of fluid-phase complement activation products and microparticles were similar in patients whether or not retransfused with pericardial blood. CONCLUSIONS: In pericardial blood of patients undergoing cardiac surgery with CPB, microparticles contribute to activation of the complement system via bound SAP and IgM. Retransfusion of pericardial blood, however, does not contribute to systemic complement activation. PMID- 20965957 TI - Acute ischemic stroke treatment: State of the art. AB - Stroke is among the leading causes of death and serious disability in the United States. Treatment of the acute ischemic stroke patient requires a multidisciplinary approach involving first-responders, emergency department personnel, neurologists, advanced imaging experts and endovascular specialists with neurosurgical support. Contemporary stroke treatment is a rapidly advancing field. New developments in pharmacologic and endovascular stroke therapy require thoughtful trial design and expeditious trial implementation to assess clinical outcomes. This manuscript reviews the state of the art in acute stroke therapy. PMID- 20965958 TI - Critical limb ischemia: does long-term patency matter? AB - In critical limb ischemia (CLI), an underlying principle of treatment is that it takes more oxygenated blood to heal a wound than to maintain tissue integrity. Urgent restoration of perfusion to the ischemic territory, not long-term patency of the target vessel, is the primary treatment goal. However, in patients with CLI treated by surgical bypass, loss of graft patency is associated with poor outcomes. We decided to address the conventional wisdom that restenosis is not a major concern in CLI as long as tissue healing occurs in patients undergoing endovascular revascularization. We retrospectively reviewed the records of consecutive patients treated for CLI with infra-popliteal percutaneous revascularization from 2007 to 2009. Those with prior ipsilateral percutaneous revascularization for CLI formed the study population. Among 29 CLI patients treated for infra-popliteal revascularization, six patients had a history of prior successful ipsilateral revascularization for CLI. All six patients were free of rest pain and ulcers at the 60-day follow-up. The median time interval between the two percutaneous revascularization procedures was 21 months (quartile ranges: 25th = 4.5 months, 75th = 36 months). Five of the six patients had restenosis of a previous lesion, while the sixth patient had a de novo lesion causing recurrent CLI. In conclusion, we found that one in five patients receiving infra-popliteal angioplasty for CLI has had a similar percutaneous revascularization procedure in the past. Among these patients most cases were for restenosis rather than de novo lesions. Further research is needed to determine whether the incidence of recurrent CLI is due to de novo lesions or restenosis. Close clinical follow-up of these patients and maintaining long-term patency with endovascular techniques will likely reduce CLI recurrence. PMID- 20965959 TI - Gender effects on intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis: analysis of 1406 patients. AB - BACKGROUND: We aimed to evaluate effects of gender on efficacy and safety of intramuscular (IM) interferon beta (IFNbeta)-1a in patients with relapsing remitting MS (RRMS) or clinically isolated syndromes (CIS) characteristic of early MS. METHODS: Pooled data from 1406 (1027 women; 379 men) patients enrolled in five clinical studies of IM IFNbeta-1a were analyzed. One analysis examined data for all patients treated with IM IFNbeta-1a from all studies. Separate analyses were conducted of pooled IM IFNbeta-1a-treated groups from all studies and pooled IFNbeta-1a-treated and placebo-treated patients from the placebo controlled studies. Outcome measures included time to first relapse, annualized relapse rate, time to disability progression, number of gadolinium-enhanced lesions, adverse events, laboratory evaluations, and neutralizing antibodies. RESULTS: All efficacy assessments indicated similar treatment effects of IM IFNbeta-1a in men and women with no significant treatment-by-gender interactions. Women reported more headaches, urinary tract infections, and depression in the analysis; however, these were also common in women who received placebo. Men reported more frequent flu-like symptoms in the placebo-controlled studies only. There were no other differences in the safety profile of IM IFNbeta-1a between men and women. CONCLUSIONS: We conclude that no significant gender-related differences were found in the efficacy and safety of IM IFNbeta-1a in patients with RRMS or CIS. PMID- 20965960 TI - Prognostic value of cerebrospinal fluid analysis at the time of a first demyelinating event. AB - BACKGROUND AND OBJECTIVE: This study aimed to assess the value of cerebrospinal fluid (CSF) findings for predicting conversion to clinically definite multiple sclerosis (CDMS). METHODS: From a database of 447 patients with a first demyelinating event, the records of 208 patients less than 51 years old who had baseline magnetic resonance imaging (MRI) and CSF examinations and a follow-up of at least 1 year were included. A multivariable Cox model was used to assess the short-term risk of CDMS according to baseline CSF findings after adjustment for prognostic factors (including brain MRI) and to provide a simple classification for predicting CDMS. RESULTS: During a median follow-up of 3.5 years, 141 (67.8%) patients converted to CDMS. In multivariate analysis, younger age (hazard ratio [HR]: 1.44 [95% CI 1.02-2.01]), spatial dissemination on brain MRI (HR: 2.07 [95% CI 1.47-2.91]) and more than 4 WBC/mm3 in CSF (HR: 1.44 [95% CI 1.03-2.02]) were independently associated with CDMS. The Cox score obtained from these three predictors enabled patients to be divided into three groups with significant increased risks of CDMS at 1, 2 and 3 years; groups were classified as high-risk (64.7%, 77.4%, 96.1%), intermediate-risk (33.3%, 51.5%, 61.5%), and low-risk (11.1%, 18.3%, 40.3%). CONCLUSIONS: Age at onset, spatial dissemination on brain MRI and CSF white blood cell count are independently associated with short-term conversion to CDMS. The three proposed risk group classifications could be a useful tool to select patients for early therapeutic intervention. PMID- 20965961 TI - Pathological basis of diffusely abnormal white matter: insights from magnetic resonance imaging and histology. AB - BACKGROUND: The pathological basis of diffusely abnormal white matter (DAWM) in multiple sclerosis (MS) has not been elucidated in detail, but may be an important element in disability and clinical progression. METHODS: Fifty-three subjects with MS were examined with T1, multi-echo T2 and magnetization transfer (MT). Twenty-three samples of formalin-fixed MS brain tissue were examined with multi-echo T2 and subsequently stained for myelin phospholipids using luxol fast blue, for axons using Bielschowsky, immunohistochemically for the myelin proteins myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3' phosphohydrolase (CNP) and for astrocytes using glial fibrillary acidic protein (GFAP). Regions of interest in DAWM were compared with normal appearing white matter. RESULTS: Fourteen of 53 subjects with MS in the in vivo study showed the presence of DAWM. Subjects with DAWM were found to have a significantly lower Expanded Disability Status Scale (EDSS) and shorter disease duration (DD) when compared with subjects without DAWM (EDSS: 1.5 versus 3.0, p = 0.031; DD: 5.4 versus 10.3 years, p = 0.045). DAWM in vivo had reduced myelin water and MT ratio, and increased T2 and water content. Histological analysis suggests DAWM, which shows a reduction of the myelin water fraction, is characterized by selective reduction of myelin phospholipids, but with a relative preservation of myelin proteins and axons. CONCLUSIONS: These findings suggest that the primary abnormality in DAWM is a reduction or perturbation of myelin phospholipids that correlates with a reduction of the myelin water fraction. PMID- 20965962 TI - Plasma pentosidine: a potential biomarker in the management of multiple sclerosis. AB - BACKGROUND: The chronic inflammation associated with multiple sclerosis (MS) may lead to the upregulation of pentosidine. OBJECTIVES: This cross-sectional study compares plasma pentosidine levels among healthy controls (HCs) and patients with MS at different disease stages. The study also determines pentosidine's usefulness as a biomarker of MS disease activity and/or severity via its correlation with a number of indicators of MS disease. METHODS: Pentosidine levels were analyzed in 98 MS patients and 43 HCs using reverse-phase high pressure liquid chromatography with fluorescence detection. RESULTS: Plasma pentosidine levels were significantly higher in MS patients when compared with HCs (p = 0.02). Patients on disease-modifying therapies (DMTs) had lower plasma pentosidine levels when compared with DMT-naive patients (p = 0.01). Pentosidine plasma levels correlated with indicators of MS disease severity, including Extended Disability Status Scale (p = 0.03), MS Severity Scale (p = 0.01), and MS Functional Composite (p = 0.03). No correlation between pentosidine levels and age, rate of clinical relapse, and disease duration was observed. CONCLUSIONS: Our results suggest that pentosidine could be a novel, inflammatory biomarker in MS clinical practice. Longitudinal studies are warranted to determine any causal relationship between changes in plasma pentosidine levels and MS disease pathology. These studies may pave the way for use of advanced glycation end product (AGE) inhibitors and AGE-breaking agents as new therapeutic modalities in MS. PMID- 20965963 TI - 3did: identification and classification of domain-based interactions of known three-dimensional structure. AB - The database of three-dimensional interacting domains (3did) is a collection of protein interactions for which high-resolution three-dimensional structures are known. 3did exploits the availability of structural data to provide molecular details on interactions between two globular domains as well as novel domain peptide interactions, derived using a recently published method from our lab. The interface residues are presented for each interaction type individually, plus global domain interfaces at which one or more partners (domains or peptides) bind. The 3did web server at http://3did.irbbarcelona.org visualizes these interfaces along with atomic details of individual interactions using Jmol. The complete contents are also available for download. PMID- 20965964 TI - FragmentStore--a comprehensive database of fragments linking metabolites, toxic molecules and drugs. AB - Consideration of biomolecules in terms of their molecular building blocks provides valuable new information regarding their synthesis, degradation and similarity. Here, we present the FragmentStore, a resource for the comparison of fragments found in metabolites, drugs or toxic compounds. Starting from 13,000 metabolites, 16,000 drugs and 2200 toxic compounds we generated 35,000 different building blocks (fragments), which are not only relevant to their biosynthesis and degradation but also provide important information regarding side-effects and toxicity. The FragmentStore provides a variety of search options such as 2D structure, molecular weight, rotatable bonds, etc. Various analysis tools have been implemented including the calculation of amino acid preferences of fragments' binding sites, classification of fragments based on the enzyme classification class of the enzyme(s) they bind to and small molecule library generation via a fragment-assembler tool. Using the FragmentStore, it is now possible to identify the common fragments of different classes of molecules and generate hypotheses about the effects of such intersections. For instance, the co occurrence of fragments in different drugs may indicate similar targets and possible off-target interactions whereas the co-occurrence of fragments in a drug and a toxic compound/metabolite could be indicative of side-effects. The database is publicly available at: http://bioinformatics.charite.de/fragment_store. PMID- 20965965 TI - REDfly v3.0: toward a comprehensive database of transcriptional regulatory elements in Drosophila. AB - The REDfly database of Drosophila transcriptional cis-regulatory elements provides the broadest and most comprehensive available resource for experimentally validated cis-regulatory modules and transcription factor binding sites among the metazoa. The third major release of the database extends the utility of REDfly as a powerful tool for both computational and experimental studies of transcription regulation. REDfly v3.0 includes the introduction of new data classes to expand the types of regulatory elements annotated in the database along with a roughly 40% increase in the number of records. A completely redesigned interface improves access for casual and power users alike; among other features it now automatically provides graphical views of the genome, displays images of reporter gene expression and implements improved capabilities for database searching and results filtering. REDfly is freely accessible at http://redfly.ccr.buffalo.edu. PMID- 20965966 TI - An integrated transcriptomic and computational analysis for biomarker identification in gastric cancer. AB - This report describes an integrated study on identification of potential markers for gastric cancer in patients' cancer tissues and sera based on: (i) genome scale transcriptomic analyses of 80 paired gastric cancer/reference tissues and (ii) computational prediction of blood-secretory proteins supported by experimental validation. Our findings show that: (i) 715 and 150 genes exhibit significantly differential expressions in all cancers and early-stage cancers versus reference tissues, respectively; and a substantial percentage of the alteration is found to be influenced by age and/or by gender; (ii) 21 co expressed gene clusters have been identified, some of which are specific to certain subtypes or stages of the cancer; (iii) the top-ranked gene signatures give better than 94% classification accuracy between cancer and the reference tissues, some of which are gender-specific; and (iv) 136 of the differentially expressed genes were predicted to have their proteins secreted into blood, 81 of which were detected experimentally in the sera of 13 validation samples and 29 found to have differential abundances in the sera of cancer patients versus controls. Overall, the novel information obtained in this study has led to identification of promising diagnostic markers for gastric cancer and can benefit further analyses of the key (early) abnormalities during its development. PMID- 20965967 TI - Selection of Shine-Dalgarno sequences in plastids. AB - Like bacterial genes, most plastid (chloroplast) genes are arranged in operons and transcribed as polycistronic mRNAs. Plastid protein biosynthesis occurs on bacterial-type 70S ribosomes and translation initiation of many (but not all) mRNAs is mediated by Shine-Dalgarno (SD) sequences. To study the mechanisms of SD sequence recognition, we have analyzed translation initiation from mRNAs containing multiple SD sequences. Comparing translational efficiencies of identical transgenic mRNAs in Escherichia coli and plastids, we find surprising differences between the two systems. Most importantly, while internal SD sequences are efficiently recognized in E. coli, plastids exhibit a bias toward utilizing predominantly the 5'-most SD sequence. We propose that inefficient recognition of internal SD sequences provides the raison d'etre for most plastid polycistronic transcripts undergoing post-transcriptional cleavage into monocistronic mRNAs. PMID- 20965968 TI - Microhomology-mediated deletion and gene conversion in African trypanosomes. AB - Antigenic variation in African trypanosomes is induced by DNA double-strand breaks (DSBs). In these protozoan parasites, DSB repair (DSBR) is dominated by homologous recombination (HR) and microhomology-mediated end joining (MMEJ), while non-homologous end joining (NHEJ) has not been reported. To facilitate the analysis of chromosomal end-joining, we established a system whereby inter allelic repair by HR is lethal due to loss of an essential gene. Analysis of intrachromosomal end joining in individual DSBR survivors exclusively revealed MMEJ-based deletions but no NHEJ. A survey of microhomologies typically revealed sequences of between 5 and 20 bp in length with several mismatches tolerated in longer stretches. Mean deletions were of 54 bp on the side closest to the break and 284 bp in total. Break proximity, microhomology length and GC-content all favored repair and the pattern of MMEJ described above was similar at several different loci across the genome. We also identified interchromosomal gene conversion involving HR and MMEJ at different ends of a duplicated sequence. While MMEJ-based deletions were RAD51-independent, one-sided MMEJ was RAD51 dependent. Thus, we describe the features of MMEJ in Trypanosoma brucei, which is analogous to micro single-strand annealing; and RAD51 dependent, one-sided MMEJ. We discuss the contribution of MMEJ pathways to genome evolution, subtelomere recombination and antigenic variation. PMID- 20965969 TI - TcoF-DB: dragon database for human transcription co-factors and transcription factor interacting proteins. AB - The initiation and regulation of transcription in eukaryotes is complex and involves a large number of transcription factors (TFs), which are known to bind to the regulatory regions of eukaryotic DNA. Apart from TF-DNA binding, protein protein interaction involving TFs is an essential component of the machinery facilitating transcriptional regulation. Proteins that interact with TFs in the context of transcription regulation but do not bind to the DNA themselves, we consider transcription co-factors (TcoFs). The influence of TcoFs on transcriptional regulation and initiation, although indirect, has been shown to be significant with the functionality of TFs strongly influenced by the presence of TcoFs. While the role of TFs and their interaction with regulatory DNA regions has been well-studied, the association between TFs and TcoFs has so far been given less attention. Here, we present a resource that is comprised of a collection of human TFs and the TcoFs with which they interact. Other proteins that have a proven interaction with a TF, but are not considered TcoFs are also included. Our database contains 157 high-confidence TcoFs and additionally 379 hypothetical TcoFs. These have been identified and classified according to the type of available evidence for their involvement in transcriptional regulation and their presence in the cell nucleus. We have divided TcoFs into four groups, one of which contains high-confidence TcoFs and three others contain TcoFs which are hypothetical to different extents. We have developed the Dragon Database for Human Transcription Co-Factors and Transcription Factor Interacting Proteins (TcoF-DB). A web-based interface for this resource can be freely accessed at http://cbrc.kaust.edu.sa/tcof/ and http://apps.sanbi.ac.za/tcof/. PMID- 20965970 TI - Phospho3D 2.0: an enhanced database of three-dimensional structures of phosphorylation sites. AB - Phospho3D is a database of three-dimensional (3D) structures of phosphorylation sites (P-sites) derived from the Phospho.ELM database, which also collects information on the residues surrounding the P-site in space (3D zones). The database also provides the results of a large-scale structural comparison of the 3D zones versus a representative dataset of structures, thus associating to each P-site a number of structurally similar sites. The new version of Phospho3D presents an 11-fold increase in the number of 3D sites and incorporates several additional features, including new structural descriptors, the possibility of selecting non-redundant sets of 3D structures and the availability for download of non-redundant sets of structurally annotated P-sites. Moreover, it features P3Dscan, a new functionality that allows the user to submit a protein structure and scan it against the 3D zones collected in the Phospho3D database. Phospho3D version 2.0 is available at: http://www.phospho3d.org/. PMID- 20965971 TI - NGSmethDB: a database for next-generation sequencing single-cytosine-resolution DNA methylation data. AB - Next-generation sequencing (NGS) together with bisulphite conversion allows the generation of whole genome methylation maps at single-cytosine resolution. This allows studying the absence of methylation in a particular genome region over a range of tissues, the differential tissue methylation or the changes occurring along pathological conditions. However, no database exists fully addressing such requirements. We propose here NGSmethDB (http://bioinfo2.ugr.es/NGSmethDB/gbrowse/) for the storage and retrieval of methylation data derived from NGS. Two cytosine methylation contexts (CpG and CAG/CTG) are considered. Through a browser interface coupled to a MySQL backend and several data mining tools, the user can search for methylation states in a set of tissues, retrieve methylation values for a set of tissues in a given chromosomal region, or display the methylation of promoters among different tissues. NGSmethDB is currently populated with human, mouse and Arabidopsis data, but other methylomes will be incorporated through an automatic pipeline as soon as new data become available. Dump downloads for three coverage levels (1, 5 or 10 reads) are available. NGSmethDB will be useful for experimental researchers, as well as for bioinformaticians, who might use the data as input for further research. PMID- 20965972 TI - Stimuli-responsive controlled-release system using quadruplex DNA-capped silica nanocontainers. AB - A novel proton-fueled molecular gate-like delivery system has been constructed for controlled cargo release using i-motif quadruplex DNA as caps onto pore outlets of mesoporous silica nanoparticles. Start from simple conformation changes, the i-motif DNA cap can open and close the pore system in smart response to pH stimulus. Importantly, the opening/closing and delivery protocol is highly reversible and a partial cargo delivery can be easily controlled at will. A pH switchable nanoreactor has also been developed to validate the potential of our system for on-demand molecular transport. This proof of concept might open the door to a new generation of carrier materials and could also provide a general route to use other functional nucleic acids/peptide nucleic acids as capping agents in the fields of versatile controlled delivery nanodevices. PMID- 20965973 TI - Tomato Functional Genomics Database: a comprehensive resource and analysis package for tomato functional genomics. AB - Tomato Functional Genomics Database (TFGD) provides a comprehensive resource to store, query, mine, analyze, visualize and integrate large-scale tomato functional genomics data sets. The database is functionally expanded from the previously described Tomato Expression Database by including metabolite profiles as well as large-scale tomato small RNA (sRNA) data sets. Computational pipelines have been developed to process microarray, metabolite and sRNA data sets archived in the database, respectively, and TFGD provides downloads of all the analyzed results. TFGD is also designed to enable users to easily retrieve biologically important information through a set of efficient query interfaces and analysis tools, including improved array probe annotations as well as tools to identify co expressed genes, significantly affected biological processes and biochemical pathways from gene expression data sets and miRNA targets, and to integrate transcript and metabolite profiles, and sRNA and mRNA sequences. The suite of tools and interfaces in TFGD allow intelligent data mining of recently released and continually expanding large-scale tomato functional genomics data sets. TFGD is available at http://ted.bti.cornell.edu. PMID- 20965975 TI - Triple vessel primary PCI. PMID- 20965974 TI - Common and divergent features in transcriptional control of the homologous small RNAs GlmY and GlmZ in Enterobacteriaceae. AB - Small RNAs GlmY and GlmZ compose a cascade that feedback-regulates synthesis of enzyme GlmS in Enterobacteriaceae. Here, we analyzed the transcriptional regulation of glmY/glmZ from Yersinia pseudotuberculosis, Salmonella typhimurium and Escherichia coli, as representatives for other enterobacterial species, which exhibit similar promoter architectures. The GlmY and GlmZ sRNAs of Y. pseudotuberculosis are transcribed from sigma(54)-promoters that require activation by the response regulator GlrR through binding to three conserved sites located upstream of the promoters. This also applies to glmY/glmZ of S. typhimurium and glmY of E. coli, but as a difference additional sigma(70) promoters overlap the sigma(54)-promoters and initiate transcription at the same site. In contrast, E. coli glmZ is transcribed from a single sigma(70)-promoter. Thus, transcription of glmY and glmZ is controlled by sigma(54) and the two component system GlrR/GlrK (QseF/QseE) in Y. pseudotuberculosis and presumably in many other Enterobacteria. However, in a subset of species such as E. coli this relationship is partially lost in favor of sigma(70)-dependent transcription. In addition, we show that activity of the sigma(54)-promoter of E. coli glmY requires binding of the integration host factor to sites upstream of the promoter. Finally, evidence is provided that phosphorylation of GlrR increases its activity and thereby sRNA expression. PMID- 20965976 TI - The right ventricle in Fabry disease: natural history and impact of enzyme replacement therapy. AB - BACKGROUND: Storage of globotriaosylceramides is present in the left and right ventricles of patients with Fabry disease. Improvement of left ventricular morphology and function during enzyme replacement therapy (ERT) has previously been reported. OBJECTIVES: To analyse the effects of long term ERT on right ventricular morphology and function. METHODS: This was a prospective follow-up of 75 genetically confirmed consecutive Fabry patients for 3.1+/-1.8 years. According to treatment guidelines the natural history was followed in 18 patients, whereas 57 patients received ERT. Standard echocardiography, strain rate imaging for regional deformation of the right and left ventricle, and magnetic resonance tomography with late enhancement (LE) imaging for the detection of fibrosis were all performed at yearly intervals. RESULTS: Right ventricular hypertrophy was evident in 53 patients (71%) at baseline. A significant positive correlation was found between left and right ventricular wall thickness (r=0.76; p<0.0001). LE was detected in half of the patients (n=38) in the left ventricle at baseline while no patient ever had LE of the right ventricle. Patients with LE in the left ventricle presented with the lowest right ventricular deformation properties. In contrast to the left ventricle, there was no change in right ventricular wall thickness (baseline 6.9+/-1.6 mm vs follow-up 6.7+/-1.5 mm; p=0.44) or systolic strain rate (2.2+/-0.7/s vs 2.1+/-0.8/s; p=0.31) during follow-up with ERT. CONCLUSION: The degree of right ventricular involvement in Fabry disease is related to the left ventricular cardiomyopathy stage. ERT seems to have no direct impact on right ventricular morphology and function. PMID- 20965977 TI - Assessment of severe reperfusion injury with T2* cardiac MRI in patients with acute myocardial infarction. AB - BACKGROUND: In patients with acute myocardial infarction, restoration of coronary flow by primary coronary intervention (PCI) can lead to profound ischaemia reperfusion injury with detrimental effects on myocardial salvage. Non-invasive assessment of interstitial myocardial haemorrhage by T2* cardiac MRI (T2*-CMR) provides a novel and specific biomarker of severe reperfusion injury which may be of prognostic value. OBJECTIVE: To characterise the determinants of acute ischaemia-reperfusion injury following ST elevation myocardial infarction (STEMI) using CMR. METHODS AND RESULTS: Fifty patients with acute STEMI who had been successfully treated by PCI were studied. T2*-CMR was used to identify the presence of reperfusion haemorrhage and contrast enhancement was used to measure microvascular obstruction (MVO) and infarct size. Haemorrhagic ischaemia reperfusion injury was present in 29 patients (58%) following PCI and occurred despite rapid revascularisation (mean 4.2+/-3.3 h). Haemorrhage was only present when the infarct involved at least 80% (mean+/-SD 91+/-5.3%) of the left ventricular wall thickness. There was a strong association between the extent of MVO and reperfusion haemorrhage (r(2)=0.87, p<0.001). Transmural infarcts (n=43) showed significantly impaired systolic wall thickening at the infarct mid point when reperfusion haemorrhage was present (21.5+/-16.7% vs 3.7+/-12.9%), p<0.0001) compared with non-haemorrhagic infarcts. CONCLUSIONS: Severe reperfusion injury may occur when there is near-transmural myocardial necrosis despite early and successful revascularisation. Reperfusion haemorrhage is closely associated with the development of MVO. These findings indicate that, once advanced necrosis has developed, the potential for severe myocardial reperfusion injury is significantly enhanced. PMID- 20965979 TI - Pre-stenting with a bare metal stent before percutaneous pulmonary valve implantation: acute and 1-year outcomes. AB - OBJECTIVES: To determine the feasibility and safety of pre-stenting with a bare metal stent (BMS) before percutaneous pulmonary valve implantation (PPVI), and to analyse whether this approach improves haemodynamic outcomes and impacts on the incidence of PPVI stent fractures. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Tertiary paediatric and adult congenital heart cardiac centre. PATIENTS AND INTERVENTIONS: 108 consecutive patients with congenital heart disease underwent PPVI between September 2005 and June 2008 (54 with PPVI alone, 54 with BMS pre-stenting before PPVI). RESULTS: There were no significant differences in procedural complication rates. Acutely, there was no difference in haemodynamic outcomes. Serial echocardiography revealed that in the subgroups of 'moderate' (26-40 mm Hg) and 'severe' (>40 mm Hg) right ventricular outflow tract (RVOT) obstruction, patients with pre-stenting showed a tendency towards lower peak RVOT velocities compared to patients after PPVI alone (p=0.01 and p=0.045, respectively). The incidence of PPVI stent fractures was not statistically different between treatment groups at 1 year (PPVI 31% vs BMS+PPVI 18%; p=0.16). However, pre-stenting with BMS was associated with a lower risk of developing PPVI stent fractures (HR 0.35, 95% CI 0.14 to 0.87, p=0.024). The probability of freedom from serious adverse follow-up events (death, device explantation, repeat PPVI) was not statistically different at 1 year (PPVI 92% vs BMS+PPVI 94%; p=0.44). CONCLUSIONS: Pre-stenting with BMS before PPVI is a feasible and safe modification of the established implantation protocol. Pre stenting is associated with a reduced risk of developing PPVI stent fractures. PMID- 20965978 TI - Predicting atrial fibrillation recurrence with circulating inflammatory markers in patients in sinus rhythm at high risk for atrial fibrillation: data from the GISSI atrial fibrillation trial. AB - BACKGROUND: Inflammation may play a significant role in the pathogenesis of atrial fibrillation (AF). OBJECTIVES: To examine the roles of three systemic inflammatory markers in predicting recurrent AF. METHODS: The association between the plasma concentrations of high-sensitivity C reactive protein (hsCRP), interleukin-6 (IL-6) and pentraxin-3 (PTX3) with echocardiographic parameters and with the time to first recurrence of AF was tested in 382 patients with a history of AF but in sinus rhythm at randomisation, enrolled in the GISSI-AF biohumoral study. RESULTS: Baseline PTX3 was related to left atrial, but not to left ventricular chamber volume. During one year of follow-up, 204 patients (53.1%) had a recurrent AF. There were no significant differences in baseline median [Q1 Q3] plasma concentrations of IL-6, hsCRP and PTX3 among patients with (2.11 [1.47 3.74] pg/ml, 3.30 [1.40-6.80] mg/l and 4.66 [3.27-6.97] ng/ml, respectively) or without recurrent AF (2.09 [1.37-2.90] pg/ml, p=0.182; 3.00 [1.10-6.20] mg/l, p=0.333; 5.09 [3.22-7.98] ng/ml, p=0.637). At 6 and 12 months follow-up, AF patients had significantly higher concentrations of IL-6 and PTX3 than those in sinus rhythm, and those with most recent episodes of AF had higher hsCRP. Baseline levels of IL-6, hsCRP or PTX3 were not significantly associated with a higher risk of recurrence of AF. CONCLUSION: In patients with a history of AF, but without significant left ventricular dysfunction or heart failure, inflammatory biomarkers may be raised but are, at best, weak predictors of the risk for first recurrence of AF. PMID- 20965980 TI - Images in cardiology. Right atrial "mass" after minimally invasive mitral valve repair with use of BioGlue. PMID- 20965981 TI - Rabbitpox: a model of airborne transmission of smallpox. AB - Smallpox is a human disease caused by infection with variola virus, a member of the genus Orthopoxvirus. Although smallpox has been eradicated, concern that it might be reintroduced through bioterrorism has therefore led to intensive efforts to develop new vaccines and antiviral drugs against this disease. Because these vaccines and therapeutics cannot be tested in human trials, it is necessary to test such medical countermeasures in different animal models. Although several orthopoxviruses cause disease in laboratory animals, only rabbitpox virus (RPXV) infection of rabbits shows patterns of natural airborne transmission similar to smallpox. Studies have shown that a smallpox-like disease can be produced in rabbits in a controlled fashion through exposure to a small-particle RPXV aerosol, and rabbitpox spreads from animal to animal by the airborne route in a laboratory setting. This model can therefore be utilized to test drugs and vaccines against variola virus and other aerosolized orthopoxviruses. PMID- 20965982 TI - Molecular characterization of adenovirus from clinical samples through analysis of the hexon and fiber genes. AB - Human adenoviruses (HAdVs) are common pathogens associated with a variety of clinical manifestations. Although most infections are self-limiting, HAdVs can cause severe or lethal infections in immunocompromised as well as in healthy individuals. Several HAdVs have recently been characterized as emerging pathogens. In Italy, epidemiological, and especially molecular epidemiological, information on this pathogen is scarce. This study describes the characterization by cell culture, PCR and phylogenetic analysis of HAdV strains originating from a small collection of clinical samples gathered between 2008 and 2009. The distribution of different HAdV species was studied and the possible presence of newly emerging types was ascertained. A broad-range primer pair was used, targeting a portion of the hexon gene, in combination with species-specific primer pairs targeting a portion of the fiber gene. Human and animal reference AdV strains were included in the study. The broad-range assay identified all HAdV strains (study and reference samples), as well as three out of four animal AdV reference strains. Seven different types belonging to three HAdV species (B, C and F) were identified in the study samples. Species C was by far the most frequent. Two co-infections were detected, each with two serotypes within species C (types 1/2 and 2/6). The combined use of these two PCR assays--allowing not only the identification of known types but also, potentially, the discovery of newly emerging ones--can provide valuable epidemiological information on the spread of HAdVs. PMID- 20965983 TI - Antiserum against the conserved nine amino acid N-terminal peptide of influenza A virus matrix protein 2 is not immunoprotective. AB - The recent emergence and rapid spread of the pandemic H1N1 swine influenza virus reminded us once again of the need for a universal influenza vaccine that can elicit heterosubtypic protection. Here, we show the superior immunogenicity and immunoprotective capacity of the full-length matrix protein 2 ectodomain (M2e) peptide coupled to keyhole limpet haemocyanin (KLH) compared with the N-terminal 9 aa residues of M2e (SP1). Immunization with M2e-KLH protected mice against a lethal challenge with influenza A virus and significantly reduced weight loss and lung virus titres. In addition, passive transfer of serum raised in rabbits against M2e-KLH protected mice against a lethal influenza virus challenge, whereas serum from rabbits immunized with SP1-KLH did not. Nevertheless, immunofluorescence staining revealed that rabbit serum raised against SP1-KLH bound specifically to infected Madin-Darby canine kidney cells. We conclude that the peptide SP1 contains an immunogenic epitope that is not sufficient for immunoprotection. PMID- 20965984 TI - A complex hepatitis B virus (X/C) recombinant is common in Long An county, Guangxi and may have originated in southern China. AB - Recently, a complex (X/C) hepatitis B virus (HBV) recombinant, first reported in 2000, was proposed as a new genotype; although this was refuted immediately because the strains differ by less than 8 % in nucleotide distance from genotype C. Over 13.5 % (38/281) of HBV isolates from the Long An cohort in China were not assigned to a specific genotype, using current genotyping tools to analyse surface ORF sequences, and these have about 98 % similarity to the X/C recombinants. To determine whether this close identity extends to the full-length sequences and to investigate the evolutionary history of the Long An X/C recombinants, 17 complete genome sequences were determined. They are highly similar (96-99 %) to the Vietnamese strains and, although some reach or exceed 8 % nucleotide sequence difference from all known genotypes, they cluster together in the same clade, separating in a phylogenetic tree from the genotype C branch. Analysis of recombination reveals that all but one of the Long An isolates resembles the Vietnamese isolates in that they result from apparent recombination between genotype C and a parent of unknown genotype (X), which shows similarity in part to genotype G. The exception, isolate QL523, has a greater proportion of genotype C parent. Phylogeographic analysis reveals that these recombinants probably arose in southern China and spread later to Vietnam and Laos. PMID- 20965985 TI - Lipopolysaccharide stress induces cell-type specific production of murine leukemia virus type-endogenous retroviral virions in primary lymphoid cells. AB - Some murine-endogenous retroviruses, making up ~10 % of the mouse genome, are induced during the course of experimental sepsis in which lipopolysaccharide (LPS), a pathogenic component of gram-negative bacteria, often plays a critical role. In this study, we investigated whether LPS stress induces the production of murine leukemia virus type-endogenous retrovirus (MuLV-ERV) virions in primary lymphoid cells. LPS treatment of cells (single-cell suspensions and sorted B- and T-cells) isolated from seven lymphoid organs of C57BL/6J mice resulted in a differential increase in the production of MuLV-ERV virions in most cells examined. Interestingly, among the 34 unique MuLV-ERV U3 sequences cloned from the viral genomic RNAs, the nuclear respiratory factor 1 (transcription factor) element was present only in the 20 U3 sequences that were derived from the LPS induced MuLV-ERV U3 bands. Using the U3 sequences as a probe, 55 putative MuLV ERV loci were mapped onto the C57BL/6J mouse genome and 15 of them retained full coding potential. Furthermore, one full-length recombinant MuLV-ERV originating from a locus on chromosome 13 was determined to be responsive to LPS stress. The findings from this study suggest that LPS stress differentially activates MuLV ERV virion production in lymphoid organs in a cell type- and MuLV-ERV-specific manner. Further investigation is needed to define the role of MuLV-ERVs in the LPS signalling pathway(s) in general, as well as in the pathogenesis of sepsis. PMID- 20965986 TI - Passaging of a Newcastle disease virus pigeon variant in chickens results in selection of viruses with mutations in the polymerase complex enhancing virus replication and virulence. AB - Some Newcastle disease virus (NDV) variants isolated from pigeons (pigeon paramyxovirus type 1; PPMV-1) do not show their full virulence potential for domestic chickens but may become virulent upon spread in these animals. In this study we examined the molecular changes responsible for this gain of virulence by passaging a low-pathogenic PPMV-1 isolate in chickens. Complete genome sequencing of virus obtained after 1, 3 and 5 passages showed the increase in virulence was not accompanied by changes in the fusion protein--a well known virulence determinant of NDV--but by mutations in the L and P replication proteins. The effect of these mutations on virulence was confirmed by means of reverse genetics using an infectious cDNA clone. Acquisition of three amino acid mutations, two in the L protein and one in the P protein, significantly increased virulence as determined by intracerebral pathogenicity index tests in day-old chickens. The mutations enhanced virus replication in vitro and in vivo and increased the plaque size in infected cell culture monolayers. Furthermore, they increased the activity of the viral replication complex as determined by an in vitro minigenome replication assay. Our data demonstrate that PPMV-1 replication in chickens results in mutations in the polymerase complex rather than the viral fusion protein, and that the virulence level of pigeon paramyxoviruses is directly related to the activity of the viral replication complex. PMID- 20965987 TI - Serological markers for papillomavirus infection and skin tumour development in the rodent model Mastomys coucha. AB - This study used the rodent Mastomys coucha latently infected with Mastomys natalensis papillomavirus (MnPV) and Mastomys coucha PV2 (McPV2), which induce skin papillomas and anogenital condylomas, respectively, to investigate PV antibody responses as serological markers during pathogenesis. In a case-control study (137 animals), virus and tumour prevalence correlated with the seroresponse against the early E2 and late L1 viral proteins. A prospective study (53 animals) revealed for the first time the course of these antibody responses during all stages of a natural PV infection. Numerous tumour entities were observed on the eyelid and in the oral cavity. DNA analyses indicated that McPV2 was not restricted to condylomas but was also present in these mucosa-associated papillomas. The serological survey using a recently established glutathione S transferase-capture ELISA detected a strong correlation between MnPV L1-specific antibodies and the presence of papillomas on the skin, eye and ear (P<0.001). Notably, extensive antibody responses to MnPV E2 were also detected in these cases. A prospective study revealed that E2 reactivity occurred by the age of 1 month. MnPV L1 antibodies were found at 2.5 months, indicating the initiation of productive viral infection. Thirty-one out of 34 L1-seropositive animals at the age of 4.5 months developed MnPV-associated tumours (positive predictive value=77 %), and none of the seronegative animals developed skin papillomas (negative predictive value=100 %). MnPV E2 and L1 serology thus provides a powerful tool for monitoring early infection and skin tumour progression in M. coucha. PMID- 20965988 TI - Horizontal transmission of deformed wing virus: pathological consequences in adult bees (Apis mellifera) depend on the transmission route. AB - Recent reports on a steady decline of honeybee colonies in several parts of the world caused great concern. There is a consensus that pathogens are among the key players in this alarming demise of the most important commercial pollinator. One of the pathogens heavily implicated in colony losses is deformed wing virus (DWV). Overt DWV infections manifested as deformed-wing syndrome started to become a threat to honeybees only in the wake of the ectoparasitic mite Varroa destructor, which horizontally transmits DWV. However, a direct causal link between the virus and the symptom 'wing deformity' has not been established yet. To evaluate the impact of different horizontal transmission routes, and especially the role of the mite in the development of overt DWV infections, we performed laboratory infection assays with pupae and adult bees. We could demonstrate that pupae injected with DWV dose-dependently developed overt infections characterized by deformed wings in adult bees, suggesting that DWV, if transmitted to pupae by the mite, is the causative agent of the deformed-wing syndrome. The OID(50) (overt infection dosage) was approximately 2500 genome equivalents. Injecting more than 1*10(7) DWV genome equivalents into adult bees also resulted in overt infections while the same viral dosage fed to adult bees only resulted in covert infections. Therefore, both infection of adult bees through DWV-transmitting phoretic mites and infection of nurse bees through their cannibalizing DWV-infected pupae might represent possible horizontal transmission routes of DWV. PMID- 20965989 TI - African swine fever viruses with two different genotypes, both of which occur in domestic pigs, are associated with ticks and adult warthogs, respectively, at a single geographical site. AB - The role of the ancestral sylvatic cycle of the African swine fever virus (ASFV) is not well understood in the endemic areas of eastern Africa. We therefore analysed the ASF infection status on samples collected from 51 free-ranging warthogs (Phacocherus africanus) and 1576 Ornithodorus porcinus ticks from 26 independent warthog burrows at a single ranch in Kenya. Abattoir samples from 83 domestic pigs without clinical symptoms, originating from specific locations with no recent reported ASF outbreaks were included in this study. All samples were derived from areas of central Kenya, where ASF outbreaks have been reported in the past. Infection with ASFV was confirmed in 22 % of O. porcinus pools, 3.22 % of adult warthog serum samples and 49 % of domestic pig serum samples by using p72-based PCR. All of the warthog sera were positive for anti-ASFV antibodies, investigated by using ELISA, but none of the domestic pig sera were positive. Twenty O. porcinus-, 12 domestic pig- and three warthog-derived viruses were genotyped at four polymorphic loci. The ASFV isolates from ticks and domestic pigs clustered within p72 genotype X. By contrast, ASF viruses genotyped directly from warthog sera, at same locality as the tick isolates, were within p72 genotype IX and genetically similar to viruses causing recent ASF outbreaks in Kenya and Uganda. This represents the first report of the co-existence of different ASFV genotypes in warthog burrow-associated ticks and adult wild warthogs. The data from this and earlier studies suggest transfer of viruses of at least two different p72 genotypes, from wild to domestic pigs in East Africa. PMID- 20965990 TI - Bovine papillomavirus E7 oncoprotein binds to p600 in naturally occurring equine sarcoids. AB - Studies regarding the functions of the bovine papillomavirus (BPV) E7 oncoprotein in vivo are lacking and no E7-mediated mechanism underlying mesenchymal carcinogenesis is known. Here, we show that the interaction between the 600 kDa retinoblastoma protein-associated factor (p600) and BPV E7, described in vitro in cultured cells, takes place in vivo in naturally occurring equine sarcoids. In these cancers we detect the expression of E7 and p600, and demonstrate that E7 and p600 co-localize and physically interact. Furthermore, intracellular signals involved in p600 functional activity are found not to be overexpressed, suggesting a different functional activity of p600 in naturally occurring carcinogenesis. Our results demonstrate, for the first time, that E7-p600 interaction occurs during the natural history of BPV-induced equine tumours, suggesting an important role for E7 in carcinogenesis. Finally, the system provides a suitable animal model of papillomavirus-associated cancer to test therapeutic vaccination against E7. PMID- 20965991 TI - Predictors of survival from out-of-hospital cardiac arrest. PMID- 20965992 TI - Atrial septal defect closure is associated with a reduced prevalence of atrial tachyarrhythmia in the short to medium term: a systematic review and meta analysis. AB - Atrial tachyarrhythmias are a common complication of atrial septal defects. The objective was to determine the effect of atrial septal defect closure on pre existing atrial tachyarrhythmias and to investigate if such an effect is present after either surgical or percutaneous closure. Medline, EMBASE, Cochrane Library, and Google Scholar databases were searched between 1967 and 2009. The search was expanded using the 'related articles' function and reference lists of key studies. All studies reporting pre- and post- closure incidence (or prevalence) of atrial tachyarrhythmias in the same patient groups were included. Data were independently extracted by two authors according to a pre-defined protocol. Incongruities were settled by consensus decision. Twenty six studies were identified including 1841 patients who underwent surgical closure and 945 who underwent percutaneous closure. Meta-analysis using a random effects model demonstrated a reduction in the prevalence of atrial tachyarrhythmias following atrial septal defect closure [OR = 0.66 (95% CI 0.57-0.77)]. This effect was demonstrated after both percutaneous [OR = 0.49 (95% CI 0.32-0.76)] and surgical closure [OR = 0.72 (95% CI 0.60-0.87)]. Immediate (<30 days) and mid-term (30 days - 5 years) follow-up also demonstrated a reduction in AT prevalence [ORs of 0.80 (95% CI 0.66-0.97) and 0.47 (95% CI 0.36-0.62) respectively]. Atrial septal defect closure, whether surgical or percutaneous, is associated with a reduction in the post-closure prevalence of pre-existing atrial tachyarrhythmias and atrial fibrillation in the short to medium term. PMID- 20965993 TI - Impact of early statin therapy on development of atrial fibrillation at the acute stage of myocardial infarction: data from the FAST-MI register. AB - BACKGROUND: Atrial fibrillation developing at the acute stage of myocardial infarction is associated with untoward clinical outcomes. The aim of this study was to determine correlations between early statin therapy and atrial fibrillation in acute myocardial infarction. METHODS: Patients (3396) with sinus rhythm developing acute myocardial infarction were enrolled in the French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction (FAST MI). RESULTS: Atrial fibrillation developed in 7.0% of patients without and 3.9% of patients with early (<=48 h of admission) statin therapy (p<0.001). Multivariable analysis, including the propensity score for early statin treatment, showed that statin therapy was associated with reduced risk of atrial fibrillation (OR 0.64; 95% CI 0.45 to 0.92, p=0.017). Compared to patients without early statin therapy, the OR for atrial fibrillation were 0.72 (0.49 to 1.04, p=0.080), 0.52 (0.28 to 0.95, p=0.034) and 0.40 (0.18 to 0.92, p=0.030) in patients on conventional, intermediate and high doses respectively. CONCLUSIONS: This study is the first to document a correlation between early statin therapy and atrial fibrillation at the early stage of acute myocardial infarction. PMID- 20965994 TI - Optimal medical management around the time of surgery. PMID- 20965995 TI - Transcatheter valve implantation for patients with aortic stenosis. PMID- 20965996 TI - Sudden coronary death-not always atherosclerotic. PMID- 20965997 TI - Particular significance of SRD2-dependent snRNA accumulation in polarized pattern generation during lateral root development of Arabidopsis. AB - Lateral root primordia are initiated by anticlinal division of cells in the pericycle and are constructed through an ordered set of cell divisions. At the completion of the development of the primordium, cell division ceases, after which the lateral root meristem is activated. In Arabidopsis, this course of lateral root morphogenesis was found to be significantly susceptible to srd2-1, a temperature-sensitive mutation of the SRD2 gene encoding an activator of small nuclear RNA (snRNA) transcription. The srd2-1 mutation altered the organization of cells of the root primordium and, importantly, maintained primordial cell division for a long period, resulting in the formation of abnormal hemispherical laterals. Expression patterns of various reporter genes suggested that both the apical-basal and radial axes were not well established in the lateral root primordia of the srd2-1 mutant. In the early stages of development of the primordium, the srd2-1 mutation reduced the amount of the auxin efflux facilitator PIN-FORMED (PIN) and, probably by this means, interfered with the generation of an auxin gradient. Spliceosomal snRNAs accumulated at high levels throughout young root primordia and then decreased in association with the arrest of cell division, and finally increased again when the apical meristem became activated. The accumulation of snRNAs was severely suppressed by the srd2-1 mutation, and this was detectable before any morphological defect became evident. These findings suggest that high-level accumulation of snRNA involving the SRD2 function is particularly important for expression of PINs in polarized pattern generation during the development of lateral root primordia. PMID- 20965998 TI - Mitogen-activated protein kinase regulated by the CLAVATA receptors contributes to shoot apical meristem homeostasis. AB - In Arabidopsis, the CLAVATA (CLV) pathway operates in the regulation of the size of the stem cell population in the shoot apical meristem (SAM). CLV3 functions as a small peptide ligand to negatively regulate the expression of the WUSCHEL (WUS) transcription factor through three major receptor kinase complexes of CLV1, CLV2 SUPPRESSOR OF LLP1-2 (SOL2)/CORYNE (CRN) and recently identified RECEPTOR-LIKE PROTEIN KINASE 2 (RPK2)/TOADSTOOL 2 (TOAD2). Aiming to understand the precise molecular details of CLV3 signaling, we investigated the contribution of phospho signaling, potentially regulated by these kinase complexes, to the CLV pathway. We detected CLV3-triggered CLV1 phosphorylation, which is also conditioned by the rest of the CLV receptors, presumably by their direct association. Our comprehensive analysis of the activities of the respective CLV receptors on mitogen-activated protein kinases (MAPKs) suggested that the precise balanced regulation of MAPK activity by the CLV receptors is likely to be key for SAM homeostasis. PMID- 20965999 TI - Social pathway annotation: extensions of the systems biology metabolic modelling assistant. AB - High-throughput experiments have produced large amounts of heterogeneous data in the life sciences. These data are usually represented in different formats (and sometimes in technical documents) on the Web. Inevitably, life science researchers have to deal with all these data and different formats to perform their daily research, but it is simply not possible for a single human mind to analyse all these data. The integration of data in the life sciences is a key component in the analysis of biological processes. These data may contain errors, but the curation of the vast amount of data generated in the 'omic' era cannot be done by individual researchers. To address this problem, community-driven tools could be used to assist with data analysis. In this article, we focus on a tool with social networking capabilities built on top of the SBMM (Systems Biology Metabolic Modelling) Assistant to enable the collaborative improvement of metabolic pathway models (the application is freely available at http://sbmm.uma.es/SPA). PMID- 20966000 TI - The GTPB training programme in Portugal. AB - The Gulbenkian Training Programme in Bioinformatics has been offering hands-on training courses in Oeiras, PT for more than a decade. This article is a review of its functional organization and evolution. We aim to share our experience with people considering setting-up similar training facilities elsewhere. More than 1600 course attendees, so far, have attended our courses. Their experiences have helped us to know how to satisfy their training requirements and what is feasible with very limited resources. PMID- 20966001 TI - Commentary: in pursuit of the 'best' possible evidence in investigations of breast implants and connective tissue disease. PMID- 20966002 TI - Commentary: effect of initial breastfeeding on cardiovascular risk in later life- a perspective from lower-middle-income countries. PMID- 20966003 TI - CNAseg--a novel framework for identification of copy number changes in cancer from second-generation sequencing data. AB - MOTIVATION: Copy number abnormalities (CNAs) represent an important type of genetic mutation that can lead to abnormal cell growth and proliferation. New high-throughput sequencing technologies promise comprehensive characterization of CNAs. In contrast to microarrays, where probe design follows a carefully developed protocol, reads represent a random sample from a library and may be prone to representation biases due to GC content and other factors. The discrimination between true and false positive CNAs becomes an important issue. RESULTS: We present a novel approach, called CNAseg, to identify CNAs from second generation sequencing data. It uses depth of coverage to estimate copy number states and flowcell-to-flowcell variability in cancer and normal samples to control the false positive rate. We tested the method using the COLO-829 melanoma cell line sequenced to 40-fold coverage. An extensive simulation scheme was developed to recreate different scenarios of copy number changes and depth of coverage by altering a real dataset with spiked-in CNAs. Comparison to alternative approaches using both real and simulated datasets showed that CNAseg achieves superior precision and improved sensitivity estimates. AVAILABILITY: The CNAseg package and test data are available at http://www.compbio.group.cam.ac.uk/software.html. PMID- 20966004 TI - R/qtl: high-throughput multiple QTL mapping. AB - MOTIVATION: R/qtl is free and powerful software for mapping and exploring quantitative trait loci (QTL). R/qtl provides a fully comprehensive range of methods for a wide range of experimental cross types. We recently added multiple QTL mapping (MQM) to R/qtl. MQM adds higher statistical power to detect and disentangle the effects of multiple linked and unlinked QTL compared with many other methods. MQM for R/qtl adds many new features including improved handling of missing data, analysis of 10,000 s of molecular traits, permutation for determining significance thresholds for QTL and QTL hot spots, and visualizations for cis-trans and QTL interaction effects. MQM for R/qtl is the first free and open source implementation of MQM that is multi-platform, scalable and suitable for automated procedures and large genetical genomics datasets. AVAILABILITY: R/qtl is free and open source multi-platform software for the statistical language R, and is made available under the GPLv3 license. R/qtl can be installed from http://www.rqtl.org/. R/qtl queries should be directed at the mailing list, see http://www.rqtl.org/list/. CONTACT: kbroman@biostat.wisc.edu. PMID- 20966005 TI - SmashCell: a software framework for the analysis of single-cell amplified genome sequences. AB - SUMMARY: Recent advances in single-cell manipulation technology, whole genome amplification and high-throughput sequencing have now made it possible to sequence the genome of an individual cell. The bioinformatic analysis of these genomes, however, is far more complicated than the analysis of those generated using traditional, culture-based methods. In order to simplify this analysis, we have developed SmashCell (Simple Metagenomics Analysis SHell-for sequences from single Cells). It is designed to automate the main steps in microbial genome analysis-assembly, gene prediction, functional annotation-in a way that allows parameter and algorithm exploration at each step in the process. It also manages the data created by these analyses and provides visualization methods for rapid analysis of the results. AVAILABILITY: The SmashCell source code and a comprehensive manual are available at http://asiago.stanford.edu/SmashCell CONTACT: eoghanh@stanford.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 20966006 TI - Discovering homotypic binding events at high spatial resolution. AB - MOTIVATION: Clusters of protein-DNA interaction events involving the same transcription factor are known to act as key components of invertebrate and mammalian promoters and enhancers. However, detecting closely spaced homotypic events from ChIP-Seq data is challenging because random variation in the ChIP fragmentation process obscures event locations. RESULTS: The Genome Positioning System (GPS) can predict protein-DNA interaction events at high spatial resolution from ChIP-Seq data, while retaining the ability to resolve closely spaced events that appear as a single cluster of reads. GPS models observed reads using a complexity penalized mixture model and efficiently predicts event locations with a segmented EM algorithm. An optional mode permits GPS to align common events across distinct experiments. GPS detects more joint events in synthetic and actual ChIP-Seq data and has superior spatial resolution when compared with other methods. In addition, the specificity and sensitivity of GPS are superior to or comparable with other methods. AVAILABILITY: http://cgs.csail.mit.edu/gps. PMID- 20966007 TI - Chinese health care in rural areas. PMID- 20966008 TI - New evidence on the impact of China's New Rural Cooperative Medical Scheme and its implications for rural primary healthcare: multivariate difference-in difference analysis. AB - OBJECTIVES: To determine whether China's New Rural Cooperative Medical Scheme (NCMS), which aims to provide health insurance to 800 million rural citizens and to correct distortions in rural primary care, and the individual policy attributes have affected the operation and use of village health clinics. DESIGN: We performed a difference-in-difference analysis using multivariate linear regressions, controlling for clinic and individual attributes as well as village and year effects. SETTING: 100 villages within 25 rural counties across five Chinese provinces in 2004 and 2007. Participants 160 village primary care clinics and 8339 individuals. MAIN OUTCOME MEASURES: Clinic outcomes were log average weekly patient flow, log average monthly gross income, log total annual net income, and the proportion of monthly gross income from medicine sales. Individual outcomes were probability of seeking medical care, log annual "out of pocket" health expenditure, and two measures of exposure to financial risk (probability of incurring out of pocket health expenditure above the 90th percentile of spending among the uninsured and probability of financing medical care by borrowing or selling assets). RESULTS: For village clinics, we found that NCMS was associated with a 26% increase in weekly patient flow and a 29% increase in monthly gross income, but no change in annual net revenue or the proportion of monthly income from drug revenue. For individuals, participation in NCMS was associated with a 5% increase in village clinic use, but no change in overall medical care use. Also, out of pocket medical spending fell by 19% and the two measures of exposure to financial risk declined by 24-63%. These changes occurred across heterogeneous county programmes, even in those with minimal benefit packages. CONCLUSIONS: NCMS provides some financial risk protection for individuals in rural China and has partly corrected distortions in Chinese rural healthcare (reducing the oversupply of specialty services and prescription drugs). However, the scheme may have also shifted uncompensated new responsibilities to village clinics. Given renewed interest among Chinese policy makers in strengthening primary care, the effect of NCMS deserves greater attention. PMID- 20966009 TI - Population fund stresses women's key role in recovering from conflict and disasters. PMID- 20966011 TI - Ethnic density and mental health. PMID- 20966013 TI - The costs of the reverberating bedpan. PMID- 20966012 TI - Understanding the effect of ethnic density on mental health: multi-level investigation of survey data from England. AB - OBJECTIVES: To determine if living in areas where higher proportions of people of the same ethnicity reside is protective for common mental disorders, and associated with a reduced exposure to discrimination and improved social support. Finally, to determine if any protective ethnic density effects are mediated by reduced exposure to racism and improved social support. DESIGN: Multi-level logistic regression analysis of national survey data, with area-level, own-group ethnic density modelled as the main exposure. Participants and setting 4281 participants of Irish, black Caribbean, Indian, Pakistani, Bangladeshi, and white British ethnicity, aged 16-74 years, randomly sampled from 892 "middle layer super output areas" in England. MAIN OUTCOME MEASURES: Common mental disorders (assessed via structured interviews); discrimination (assessed via structured questionnaire); and social support and social networks (assessed via structured questionnaire). RESULTS: Although the most ethnically dense areas were also the poorest, for each 10 percentage point increase in own-group ethnic density, there was evidence of a decreased risk of common mental disorders, for the full ethnic minority sample (odds ratio 0.94 (95% confidence interval 0.89 to 0.99); P=0.02, trend), for the Irish group (odds ratio 0.21 (0.06 to 0.74); P=0.01, trend), and for the Bangladeshi group (odds ratio 0.75 (0.62 to 0.91); P=0.005, trend), after adjusting for a priori confounders. For some groups, living in areas of higher own-group density was associated with a reduction in the reporting of discrimination and with improved social support and improved social networks. However, none of these factors mediated ethnic density effects. CONCLUSIONS: A protective effect of living in areas of higher own-group ethnic density was present for common mental disorders for some minority groups. People living in areas of higher own-group density may report improved social support and less discrimination, but these associations did not fully account for density effects. PMID- 20966014 TI - Medicine and the Media. What's keeping the Chilean miners down? PMID- 20966017 TI - Doctors can force woman to have lifesaving treatment. PMID- 20966019 TI - Intervening via chat: an opportunity for adolescents' mental health promotion? AB - Mental health problems are highly prevalent among adolescents, but a majority of adolescents is reluctant to seek help at mental health services because of shame and lack of anonymity. Intervening via chat (i.e. offering online support) could be a solution to remove these barriers and to reach adolescents. The dimensions of the RE-AIM model (reach, efficacy, adoption, implementation and maintenance) served as a guiding principle for discussing the potential of offering online support via chat. It appeared that the use of chat may be an appropriate way to reach adolescents and may have a positive impact on outcome measures related to mental health. Additional efforts are needed to stimulate adoption at the individual level (target group, intermediaries) and the organizational level. Future research needs to focus on the dissemination of chat-based interventions, differences between online peer support and online professional support, and the content of conversations via chat about mental health problems. PMID- 20966020 TI - Magnetic resonance mammography. PMID- 20966021 TI - Estimates of familial risks from family data are biased when ascertainment of families is not independent of family history. PMID- 20966022 TI - Bacterial infection causes stress-induced memory dysfunction in mice. AB - BACKGROUND: The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. OBJECTIVE: To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non spatial memory formation. METHODS: Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. RESULTS: No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. CONCLUSIONS: The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline. PMID- 20966023 TI - You deserve what you eat: lessons learned from the study of the melanin concentrating hormone (MCH)-deficient mice. AB - OBJECTIVES: Diet plays a crucial role in the development of obesity and insulin resistance via multiple mechanisms. Saturated fatty acids can directly trigger tissue specific proinflammatory pathways via Toll-like receptor-4 (TLR4) dependent mechanisms. Moreover, diet can change the gut microbiome and increase gut permeability. However, very few studies have addressed the obesity independent role of diet. Dissecting the effects of diet from those of obesity per se will enhance our understanding of the underlying pathogenesis, and, at the translational level, advance our treatment approaches for obesity and its co morbidities. METHODS: Melanin-concentrating hormone (MCH) is an important regulator of appetite and energy balance. MCH-deficient mice are resistant to diet-induced obesity, primarily due to increased locomotor activity. We took advantage of the unique phenotype of these mice to examine the metabolic and inflammatory consequences of a 15-week consumption of a diet high in saturated fat. RESULTS: MCH-deficient mice chronically exposed to a high-fat diet gain less weight compared to their wild-type littermates, despite similar food intake, and are protected from hepatosteatosis. They also lack obesity-associated upregulation of serum leptin and insulin levels and have improved total body insulin sensitivity. Nevertheless, we found indistinguishable liver-specific innate immune responses in both genotypes associated with high-fat feeding, which involved activation of TLR4 and its downstream effectors, MyD88, p38 MAP kinase and STAT-3. CONCLUSIONS: Our findings indicate that high-fat feeding is deleterious to the liver, independently of the obesity status. They also suggest that MCH is not necessary for the TLR4-dependent immune response triggered by the high-fat diet. PMID- 20966024 TI - Antibiotic use and inflammatory bowel diseases in childhood. AB - BACKGROUND: The composition of the intestinal microflora has been proposed as an important factor in the development of inflammatory bowel diseases (IBD). Antibiotics have the potential to alter the composition of the intestinal microflora. A study was undertaken to evaluate the potential association between use of antibiotics and IBD in childhood. METHODS: A nationwide cohort study was conducted of all Danish singleton children born from 1995 to 2003 (N=577,627) with individual-level information on filled antibiotic prescriptions, IBD and potential confounding variables. Using Poisson regression, rate ratios (RRs) of IBD were calculated according to antibiotic use. Antibiotic use was classified according to time since use, type, number of courses used and age at use. RESULTS: IBD was diagnosed in 117 children during 3,173,117 person-years of follow-up. The RR of IBD was 1.84 (95% CI 1.08 to 3.15) for antibiotic users compared with non-users. This association appeared to be an effect on Crohn's disease (CD) alone (RR 3.41) and was strongest in the first 3 months following use (RR 4.43) and among children with >=7 courses of antibiotics (RR 7.32). CONCLUSIONS: Antibiotic use is common in childhood and its potential as an environmental risk factor for IBD warrants scrutiny. This is the first prospective study to show a strong association between antibiotic use and CD in childhood. However, as with any observational study, causality cannot be inferred from our results and confounding by indication--in particular, prescribing of antibiotics to children with intestinal symptoms of as yet undiagnosed CD--should also be considered as a possible explanation. PMID- 20966025 TI - Stromal biology and therapy in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease. One explanation for the devastating prognosis is the failure of many chemotherapies, including the current standard of care therapy gemcitabine. Although our knowledge of the molecular events underlying multistep carcinogenesis in PDA has steadily increased, translation into more effective therapeutic approaches has been inefficient over the last several decades. Evidence for this innate resistance to systemic therapies was recently provided in an accurate mouse model of PDA by the demonstration that chemotherapies are poorly delivered to PDA tissues because of a deficient vasculature. This vascular deficiency correlated with the presence of a dense stromal matrix that is a prominent histological hallmark of PDA tumours. Therapeutic targeting of stromal cells decreased the stroma from pancreatic tumours, resulting in increased intratumoral perfusion and therapeutic delivery of gemcitabine. Stromal cells contained within the PDA tumour microenvironment therefore represent an additional constituent to neoplastic cells that should be critically evaluated for optimal therapeutic development in preclinical models and early clinical trials. PMID- 20966026 TI - Kinase inhibitors in the treatment of chronic hepatitis C virus. PMID- 20966027 TI - Insulin resistance and necroinflammation drives ductular reaction and epithelial mesenchymal transition in chronic hepatitis C. AB - OBJECTIVE: To study the mechanism(s) linking insulin resistance (IR) to hepatic fibrosis and the role of the epithelial component in tissue repair and fibrosis in chronic hepatitis C (CHC). DESIGN: Prospective observational study. SETTING: Tertiary care academic centre. PATIENTS: 78 consecutive patients with CHC. MAIN OUTCOME MEASURES: IR, calculated by the oral glucose insulin sensitivity during oral glucose tolerance test; necroinflammatory activity and fibrosis, defined according to Ishak's score; steatosis, graded as 0 (<5% of hepatocytes), 1 (5 33%), 2 (33-66%) and 3 (>66%). To evaluate the role of the epithelial component in tissue repair and fibrosis, the expansion of the ductular reaction (DR) was calculated by keratin-7 (CK7) morphometry. Nuclear expression of Snail, downregulation of E-cadherin and expression of fibroblast specific protein-1 (FSP1) and vimentin by CK7-positive cells were used as markers of epithelial mesenchymal transition in DR elements. RESULTS: IR, the degree of necroinflammation and expansion of the DR (stratified as reactive ductular cells (RDCs), hepatic progenitor cells and intermediate hepatobiliary cells according to morphological criteria) were all associated with the stage of fibrosis. Nuclear Snail expression, E-cadherin downregulation and vimentin upregulation were observed in RDCs. By dual immunofluorescence for CK7 and FSP1, the number of RDCs undergoing epithelial-mesenchymal transition progressively increased together with the necroinflammatory score. By multivariate analysis, total inflammation and insulin resistance were the only factors significantly predicting the presence of advanced fibrosis (Ishak score >=3) and the expansion of RDCs. CONCLUSION: This study indicates that IR is associated with the degree of necroinflammatory injury in CHC and contributes to hepatic fibrosis by stimulating the expansion of RDCs that express epithelial-mesenchymal transition markers. PMID- 20966028 TI - New 2010 British Society of Gastroenterology colitis surveillance guidelines: costs and surveillance intervals. PMID- 20966029 TI - Sustained virological response with 29 days of Debio 025 monotherapy in hepatitis C virus genotype 3. PMID- 20966030 TI - Management of variceal haemorrhage in cirrhosis: the relevance of the risk stratification. PMID- 20966031 TI - An investigation of health anxiety in families where children have recurrent abdominal pain. AB - OBJECTIVES: To explore health anxiety in children with recurrent abdominal pain (RAP) using a symbolic play assessment. METHODS: Children with RAP and two control groups (with asthma and well children) were recruited. Eighty-four families completed play and questionnaire assessments of health anxiety and psychological functioning. RESULTS: Children with RAP demonstrated less use of psychological descriptions for feelings than control children, and were more likely to represent serious outcomes to health scenarios than well children, but not children with asthma. Mothers of children with RAP had higher levels of health anxiety, and rated their children as having more physical symptoms and anxiety. CONCLUSIONS: The symbolic play paradigm provided discriminating insights into health anxiety in children. The findings suggest that childhood RAP may be associated with higher levels of parental health anxiety. These aspects of family functioning might usefully be explored in families where a child has RAP. PMID- 20966032 TI - Basolateral potassium (IKCa) channel inhibition prevents increased colonic permeability induced by chemical hypoxia. AB - Major liver resection is associated with impaired intestinal perfusion and intestinal ischemia, resulting in decreased mucosal integrity, increased bacterial translocation, and an increased risk of postoperative sepsis. However, the mechanism by which ischemia impairs intestinal mucosal integrity is unclear. We therefore evaluated the role of Ca(2+)-sensitive, intermediate-conductance (IK(Ca)) basolateral potassium channels in enhanced intestinal permeability secondary to chemical hypoxia. The effects of chemical hypoxia induced by 100 MUM dinitrophenol (DNP) and 5 mM deoxyglucose (DG) on basolateral IK(Ca) channel activity and whole cell conductance in intact human colonic crypts, and paracellular permeability (G(S)) in isolated colonic sheets, were determined by patch-clamp recording and transepithelial electrical measurements, respectively. DNP and DG rapidly stimulated IK(Ca) channels in cell-attached basolateral membrane patches and elicited a twofold increase (P = 0.004) in whole cell conductance in amphotericin B-permeabilized membrane patches, changes that were inhibited by the specific IK(Ca) channel blockers TRAM-34 (100 nM) and clotrimazole (CLT; 10 MUM). In colonic sheets apically permeabilized with nystatin, DNP elicited a twofold increase (P = 0.005) in G(S), which was largely inhibited by the serosal addition of 50 MUM CLT. We conclude that, in intestinal epithelia, chemical hypoxia increases G(S) through a mechanism involving basolateral IK(Ca) channel activation. Basolateral IK(Ca) channel inhibition may prevent or limit increased intestinal permeability during liver surgery. PMID- 20966034 TI - Examining Sport Concussion Assessment Tool ratings for male and female youth hockey players with and without a history of concussion. AB - BACKGROUND: Concussion is one of the most commonly occurring injuries in sport today. The Sport Concussion Assessment Tool (SCAT) is a commonly used paper neurocognitive tool. To date, little is known about SCAT baseline normative values in youth athletes. OBJECTIVE: The purpose of this study was to determine normative values on the SCAT for male and female youth hockey players. METHODS: This is a secondary data analysis of pooled data from three prospective cohort studies examining the risk of injury in paediatric ice hockey players aged 9-17 years. A preseason baseline demographic and injury history questionnaire was completed by each player. RESULTS: A total of 4193 players completed SCATs at baseline and were included in the analysis. 781 players (18.6%) reported a previous history of concussion. Fatigue and low energy followed by headache were the most commonly reported symptoms in all players. The majority of youth players could recite all five words immediately but only three words when delayed. A smaller proportion of the males were able to report the months of the year in reverse order compared with females of a similar age. The median number of digits recited in reverse order was 4. CONCLUSIONS: Youth ratings varied between age groups, gender and from previously reported ratings of varsity athletes, possibly reflecting developmental and gender differences. An understanding of these differences in youth athletes is important to ensure appropriate performance expectations on the SCAT and when making clinical decisions following a concussion. PMID- 20966033 TI - Heme oxygenase-1 is induced in peripheral blood mononuclear cells of patients with acute pancreatitis: a potential therapeutic target. AB - Heme oxygenase-1 (HO-1) induction by hemin or Panhematin protects against experimental pancreatitis. As a preclinical first step toward determining whether HO-1 upregulation is a viable target in acute pancreatitis (AP) patients, we tested the hypothesis that HO-1 expression in peripheral blood mononuclear cell (PBMC) subsets of hospitalized patients with mild AP is upregulated then normalizes upon recovery and that cells from AP patients have the potential to upregulate their HO-1 ex vivo if exposed to Panhematin. PBMCs were isolated on days 1 and 3 of hospitalization from the blood of 18 AP patients, and PMBC HO-1 levels were compared with PMBCs of 15 hospitalized controls (HC) and 7 volunteer healthy controls (VC). On day 1 of hospitalization, AP patients compared with VCs had higher HO-1 expression in monocytes and neutrophils. Notably, AP monocyte HO 1 levels decreased significantly upon recovery. Panhematin induced HO-1 in ex vivo cultured AP PBMCs more readily than in HC or VC PBMCs. Furthermore, PBMCs from acutely ill AP patients on day 1 were more responsive to HO-1 induction compared with day 3 upon recovery. Similarly, mouse splenocytes had enhanced HO-1 inducibility as their pancreatitis progressed from mild to severe. In conclusion, AP leads to reversible PBMC HO-1 upregulation that is associated with clinical improvement and involves primarily monocytes. Leukocytes from AP patients or mice with AP are primed for HO-1 induction by Panhematin, which suggests that Panhematin could offer a therapeutic benefit. PMID- 20966035 TI - Get a kick out of this: the spectrum of knee extensor mechanism injuries. AB - At the end of this article, the reader should be able to (1) recognise normal anatomy and anatomical variants of the extensor mechanism of the knee on various imaging modalities, including plain film, ultrasound and MRI; (2) diagnose a broad spectrum of EM injuries in adult and paediatric patients including patellar and quadriceps tendinopathy, Osgood-Schlatter disease, Sindig-Larsen-Johansson syndrome, chondromalacia patellae and patellar fractures on various imaging modalities; and (3) appreciate the important role of imaging in the diagnosis of musculoskeletal injuries. PMID- 20966036 TI - A short history of dapsone, or an alternative model of drug development. AB - From 1936 until 1996, the drug dapsone treated a diverse array of diseases, including tuberculosis, leprosy, malaria, and AIDS-related pneumonia. This article explores how dapsone transformed from a cure for one disease into a treatment for a totally different malady. This process of reinvention in the clinic represents an alternative model of drug development that the historical literature, focused on success in the laboratory, has largely ignored. The core of the paper discusses the reinvention of dapsone as an antimalarial in the Vietnam War through trials led by Robert J. T. Joy, a physician and military officer. As a case study, it offers a fresh perspective on the clinic-as laboratory approach that other scholars have addressed in a civilian context. Viewing the randomized clinical trial (RCT) through a military prism will demonstrate how a combat environment combined with the regimentation of the armed forces affected the standard methodology of the RCT. PMID- 20966037 TI - Differential signaling defects associated with the M201V polymorphism in the cysteinyl leukotriene type 2 receptor. AB - The cysteinyl-leukotrienes (cysLTs) LTC(4), LTD(4), and LTE(4), are involved in a variety of inflammatory diseases, including asthma, and act on at least two distinct receptors, CysLT(1) and CysLT(2). Specific antagonists of CysLT(1) are currently used to control bronchoconstriction and inflammation in asthmatic patients. The potential role of CysLT(2) in asthma remains poorly understood. A polymorphism in the CysLT(2) gene, resulting in a single amino acid substitution (M201V), was found to be associated with asthma in three separate population studies. Here, we investigated whether the M201V mutation affected the affinity of CysLT(2) for its natural ligands and its signaling efficiency. Human embryonic kidney 293 cells were stably transfected with either wild-type (wt) or mutant (M201V) CysLT(2). Affinity of the M201V receptor for LTC(4) was reduced by 50%, whereas affinity for LTD(4) was essentially lost. LTC(4)-induced production of inositol phosphates (IPs) in M201V-expressing cells was significantly decreased at suboptimal concentrations of the ligand, but no difference was observed at high concentrations. In contrast, LTD(4)-induced IP production was 10- to 100 fold less in M201V- than in wt-expressing cells. Similar results were also observed with the transactivation of the interleukin-8 promoter induced by LTC(4) or LTD(4). Moreover, in contrast to wt-expressing cells, phosphorylation of nuclear factor kappaB p65 was absent in LTD(4)-stimulated M201V-expressing cells. Likewise, phosphorylation of c-Jun N-terminal kinase was not induced in LTD(4) stimulated M201V cells, whereas activation of extracellular response kinase and p38 was maintained, at least at higher LTD(4) concentrations. Our results indicate that the M201V polymorphism drastically affects CysLT(2) responses to LTD(4) and less to LTC(4). PMID- 20966038 TI - Fatty acid amide hydrolase (FAAH) inhibition reduces L-3,4-dihydroxyphenylalanine induced hyperactivity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lesioned non-human primate model of Parkinson's disease. AB - Dopaminergic therapies remain the most efficacious symptomatic treatments for Parkinson's disease (PD) but are associated with motor complications, including dyskinesia, and nonmotor complications, such as psychosis, impulse control disorders (ICD), and dopamine dysregulation syndrome (DDS). Nondopaminergic neurotransmitter systems, including the endocannabinoid system, are probably critical to the development of these complications. The role of fatty acid amide hydrolase (FAAH) in mediating l-3,4-dihydroxyphenylalanine (L-DOPA)-induced behaviors was explored in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lesioned marmoset model of PD. Pharmacodynamic and locomotor effects of the selective FAAH inhibitor [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (URB597) were assessed via bioanalytical (liquid chromatography-tandem mass spectrometry) and behavioral observation approaches. URB597 (3, 10, 30, or 60 mg/kg p.o.) increased plasma levels of the FAAH substrates N-arachidonoyl ethanolamide (anandamide), N-oleoyl ethanolamide, and N-palmitoyl ethanolamide by 10.3 +/- 0.3-, 7.8 +/- 0.2-, and 1.8 +/- 0.1-fold (mean of URB597 groups +/- S.E.M.), respectively, compared with vehicle (all p < 0.001) 4 h after administration. Treatment with L-DOPA (20 mg/kg s.c.) alleviated parkinsonism but elicited dyskinesia, psychosis-like-behaviors and hyperactivity, a potential correlate of ICD and DDS. During the 2 to 4 h after L-DOPA, corresponding to 4 to 6 h after URB597 administration, URB597 reduced total L-DOPA-induced activity and the magnitude of hyperactivity by 32 and 52%, respectively, to levels equivalent to those seen in normal animals. Treatment with URB597 (10 mg/kg p.o.) did not modify the antiparkinsonian actions of L-DOPA or L-DOPA-induced dyskinesia and psychosis. URB597 did not alter plasma L-DOPA levels and was without behavioral effects when administered alone. Inhibition of FAAH may represent a novel approach to reducing L-DOPA-induced side effects, such as ICD and DDS, while maintaining the antiparkinsonian benefits of L-DOPA treatment. PMID- 20966039 TI - Natural history of pulmonary fibrosis in two subjects with the same telomerase mutation. AB - Previous studies have identified subclinical lung disease in family members of probands with familial pulmonary fibrosis, but the natural history of preclinical pulmonary fibrosis is uncertain. The purpose of this study was to determine whether individuals with preclinical lung disease will develop pulmonary fibrosis. After a 27-year interval, two subjects with manifestations of preclinical familial pulmonary fibrosis, including asymptomatic alveolar inflammation and alveolar macrophage activation, were reevaluated for lung disease. CT scans of the chest, pulmonary function tests, and BAL were performed, and genomic DNA was analyzed for mutations in candidate genes associated with familial pulmonary fibrosis. One subject developed symptomatic familial pulmonary fibrosis and was treated with oxygen; her sister remained asymptomatic but had findings of pulmonary fibrosis on high-resolution CT scan of the chest. High concentrations of lymphocytes were found in BAL fluid from both subjects. Genetic sequencing and analyses identified a novel heterozygous mutation in telomerase reverse transcriptase (TERT, R1084P), resulting in telomerase dysfunction and short telomeres in both subjects. In familial pulmonary fibrosis, asymptomatic preclinical alveolar inflammation associated with mutation in TERT and telomerase insufficiency can progress to fibrotic lung disease over 2 to 3 decades. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00071045; URL: www.clinicaltrials.gov. PMID- 20966040 TI - Mediastinal lymphadenopathy in patients undergoing cardiac transplant evaluation. AB - BACKGROUND: We evaluated the association between hemodynamic parameters of chronic congestive heart failure (CHF) and mediastinal lymphadenopathy (MLA) in heart transplantation (HT) candidates and the effect of HT on MLA. We also described the results of lymph node (LN) biopsies of MLA in the patients. METHODS: Patients who underwent HT evaluation over an 8-year period and had chest CT scans were evaluated retrospectively. Data collected included LN sizes pre-HT and post-HT, echocardiographic measurements, radionuclide-derived ejection fraction, and right-sided heart catheterization hemodynamics. MLA was defined as LNs > 1 cm in smallest dimension. RESULTS: Of 118 patients, 53 patients had MLA. MLA had weak statistically significant correlations with elevated mean pulmonary artery pressure (MPAP), mitral regurgitation (MR), tricuspid regurgitation (TR), right atrial pressure (RAP), and pulmonary capillary wedge pressure (PCWP). Thirty-six patients with MLA underwent HT, and nine of the 36 had post-HT chest CT scans. All nine patients showed a decrease in LN size post-HT (mean LN diameter pre-HT = 1.16 +/- 0.137 cm, post-HT = 0.75 +/- 0.32 cm). Seven of 53 patients with MLA underwent biopsies. Four had benign LNs, one had sarcoidosis, and two had lung cancer. CONCLUSIONS: MPAP, MR, TR, RAP, and PCWP had weak statistically significant correlations with MLA. HT led to regression of MLA in patients who underwent CT scans post-HT, implying that MLA is related to CHF. However, we also identified clinically important causes of MLA; therefore, biopsy should be considered if enlarged LNs fail to regress after maximal medical management of CHF. PMID- 20966041 TI - Persistent airway inflammation and emphysema progression on CT scan in ex-smokers observed for 4 years. AB - BACKGROUND: Tobacco smoking is a principal cause of COPD-emphysema (COPD-E). Whether discontinuing smoking for at least 4 years halts airway inflammation and progression of COPD-E in prior smokers is unknown. In this study we investigated whether discontinuing smoking for approximately 4 years in ex-smokers with GOLD (Global Initiative for Chronic Lung Disease) stage IIb (moderately severe) COPD-E stopped airway inflammation (ie, sputum biomarkers) and halted the progression of COPD-E on chest CT scan. METHODS: Ten ex-smokers with COPD-E who had quit smoking underwent chest CT scans to document the extent of COPD-E, assessment of lung function (FEV(1) and diffusing capacity of lung for carbon monoxide), sputum induction for biomarkers of inflammation (measured by enzyme-linked immunosorbent assay), and blood cotinine levels at baseline and approximately 4 years later. Normal healthy subjects (n = 7) and normal current smokers with no CT scan evidence of COPD-E (n = 8) served as sputum biomarker comparison groups. RESULTS: After approximately 4 years of not smoking (documented by cotinine levels), ex smokers with COPD-E had persistent increased levels of mediators of inflammation in sputum (myeloperoxidase, leukotriene B4, IL-8, monocyte chemoattractant protein-1, matrix metalloprotease-9), which was associated with significant progression of COPD-E on chest CT scan. CONCLUSIONS: Cessation of tobacco smoking in heavy smokers with moderately severe COPD-E is associated with evidence of persistent airway inflammation and progression of COPD-E on CT scan 4 years later. Discontinuing smoking may slow the rate of progression of moderate severity COPD-E, but it does not prevent persistent airway inflammation and significant progression of COPD-E on CT scan. PMID- 20966042 TI - Determinants of exhaled breath condensate pH in a large population with asthma. AB - BACKGROUND: Exhaled breath condensate (EBC) pH is 2 log orders below normal during acute asthma exacerbations and returns to normal with antiinflammatory therapy. However, the determinants of EBC pH, particularly in stable asthma, are poorly understood. We hypothesized that patients with severe asthma would have low EBC pH and that there would be an asthma subpopulation of patients with characteristically low values. METHODS: We studied the association of EBC pH with clinical characteristics in 572 stable subjects enrolled in the Severe Asthma Research Program. These included 250 subjects with severe asthma, 291 with nonsevere asthma, and 31 healthy control subjects. RESULTS: Overall, EBC in this population of stable, treated study subjects was not lower in severe asthma (8.02; interquartile range [IQR], 7.61-8.41) or nonsevere asthma (7.90; IQR, 7.52 8.20) than in control subjects (7.9; IQR, 7.40-8.20). However, in subjects with asthma the data clustered below and above pH 6.5. Subjects in the subpopulation with pH < 6.5 had lower fraction of exhaled NO (FeNO) values (FeNO = 22.6 +/- 18.1 parts per billion) than those with pH >= 6.5 (39.9 +/- 40.2 parts per billion; P < .0001). By multiple linear regression, low EBC pH was associated with high BMI, high BAL neutrophil counts, low prebronchodilator FEV(1) ratio, high allergy symptoms, race other than white, and gastroesophageal reflux symptoms. CONCLUSION: Asthma is a complex syndrome. Subjects who are not experiencing an exacerbation but have low EBC pH appear to be a unique subpopulation. PMID- 20966043 TI - Identification of clinically used drugs that activate pregnane X receptors. AB - The pregnane X receptor (PXR) binds xenobiotics and regulates the expression of several drug-metabolizing enzymes and transporters. Human PXR (hPXR) activation and CYP3A4 induction can be involved in drug-drug interactions, resulting in reduced efficacy or increased toxicity. However, there are known species-specific differences with regard to PXR activation that should be taken into account when animal PXR data are extrapolated to humans. We profiled 2816 clinically used drugs from the National Institutes of Health Chemical Genomics Center Pharmaceutical Collection for their ability to activate hPXR and rat PXR (rPXR) at the cellular level, induce human CYP3A4 at the cellular level, and bind human PXR at the protein level. From 6 to 11% of drugs were identified as active across the four assays, which included assay-specific and pan-active compounds. The lowest concordance was observed between the hPXR and rPXR assays, and many compounds active in both assays nonetheless demonstrated significant potency differences between species. Analysis based on clustering potency values demonstrated the greatest activity correlation between the hPXR activation and CYP3A4 induction assays. Structure-activity relationship analysis identified chemical scaffolds that were pan-active (e.g., dihydropyridine calcium channel blockers) and others that were uniquely active in individual assays (e.g., steroids and fatty acids). These results provide important information on PXR activation by clinically used drugs, highlight the species specificity of PXR activation by xenobiotics, and provide a means of prioritizing compounds for follow-up studies and optimization efforts. PMID- 20966044 TI - Cigarette smoke extract induces CYP2B6 through constitutive androstane receptor in hepatocytes. AB - Smoking induces a wide range of drug-metabolizing enzymes. Among them, CYP2B6 as well as CYP1A2 is well known to be up-regulated in smokers. Although the induction of CYP1A2 is mediated by the aryl hydrocarbon receptor, the molecular mechanisms of CYP2B6 induction by smoking remain to be fully elucidated. In this study, by preparing cigarette smoke extract (CSE), we addressed the possibility that human constitutive androstane receptor (hCAR) is involved in smoking mediated induction of CYP2B6. In HepG2 cells, CSE induced CYP1A2 but not CYP2B6, suggesting that CYP2B6 expression is differentially regulated from CYP1A2. Compared with liver in vivo, hCAR expression is dramatically reduced in cultured hepatocytes, such as HepG2. Therefore, to reconstitute hCAR signaling pathways in vitro, we generated adenovirus vector expressing hCAR. Real-time reverse transcription-polymerase chain reaction analyses revealed that the adenoviral transfection of hCAR resulted in the up-regulation of CYP2B6 mRNA, even in the absence of CSE. It is interesting to note that CSE stimulation augmented hCAR mediated induction of CYP2B6. In contrast, the expression of CYP2B6 was not enhanced by adenovirus vector expressing beta-galactosidase, a control vector, either in the presence or absence of CSE. In summary, hCAR mediated the CYP2B6 induction by CSE in Hep2G cells. These data suggest that smoking up-regulates CYP2B6 through hCAR in vivo. PMID- 20966045 TI - Control of programmed cell death by distinct electrical activity patterns. AB - Electrical activity and sufficient supply with survival factors play a major role in the control of apoptosis in the developing cortex. Coherent high-frequency neuronal activity, which efficiently releases neurotrophins, is essential for the survival of immature neurons. We studied the influence of neuronal activity on apoptosis in the developing cortex. Dissociated cultures of the newborn mouse cerebral cortex were grown on multielectrode arrays to determine the activity patterns that promote neuronal survival. Cultures were transfected with a plasmid coding for a caspase-3-sensitive fluorescent protein allowing real-time analysis of caspase-3-dependent apoptosis in individual neurons. Elevated extracellular potassium concentrations (5 and 8 mM), application of 4-aminopyridine or the gamma-aminobutyric acid-A receptor antagonist Gabazine induced a shift in the frequency distribution of activity toward high-frequency bursts. Under these conditions, a reduction or delay in caspase-3 activation and an overall increase in neuronal survival could be observed. This effect was dependent on the activity of phosphatidylinositol-3 kinase, as blockade of this enzyme abolished the survival-promoting effect of high extracellular potassium concentrations. Our data indicate that increased network activity can prevent apoptosis in developing cortical neurons. PMID- 20966046 TI - Mediation of CTCF transcriptional insulation by DEAD-box RNA-binding protein p68 and steroid receptor RNA activator SRA. AB - CCCTC-binding factor (CTCF) is a DNA-binding protein that plays important roles in chromatin organization, although the mechanism by which CTCF carries out these functions is not fully understood. Recent studies show that CTCF recruits the cohesin complex to insulator sites and that cohesin is required for insulator activity. Here we showed that the DEAD-box RNA helicase p68 (DDX5) and its associated noncoding RNA, steroid receptor RNA activator (SRA), form a complex with CTCF that is essential for insulator function. p68 was detected at CTCF sites in the IGF2/H19 imprinted control region (ICR) as well as other genomic CTCF sites. In vivo depletion of SRA or p68 reduced CTCF-mediated insulator activity at the IGF2/H19 ICR, increased levels of IGF2 expression, and increased interactions between the endodermal enhancer and IGF2 promoter. p68/SRA also interacts with members of the cohesin complex. Depletion of either p68 or SRA does not affect CTCF binding to its genomic sites, but does reduce cohesin binding. The results suggest that p68/SRA stabilizes the interaction of cohesin with CTCF by binding to both, and is required for proper insulator function. PMID- 20966047 TI - Roles for the Yb body components Armitage and Yb in primary piRNA biogenesis in Drosophila. AB - PIWI-interacting RNAs (piRNAs) protect genome integrity from transposons. In Drosophila ovarian somas, primary piRNAs are produced and loaded onto Piwi. Here, we describe roles for the cytoplasmic Yb body components Armitage and Yb in somatic primary piRNA biogenesis. Armitage binds to Piwi and is required for localizing Piwi into Yb bodies. Without Armitage or Yb, Piwi is freed from the piRNAs and does not enter the nucleus. Thus, piRNA loading is required for Piwi nuclear entry. We propose that a functional Piwi-piRNA complex is formed and inspected in Yb bodies before its nuclear entry to exert transposon silencing. PMID- 20966048 TI - Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression. AB - Although the PR-Set7/Set8/KMT5a histone H4 Lys 20 monomethyltransferase (H4K20me1) plays an essential role in mammalian cell cycle progression, especially during G2/M, it remained unknown how PR-Set7 itself was regulated. In this study, we discovered the mechanisms that govern the dynamic regulation of PR Set7 during mitosis, and that perturbation of these pathways results in defective mitotic progression. First, we found that PR-Set7 is phosphorylated at Ser 29 (S29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinB complex, primarily from prophase through early anaphase, subsequent to global accumulation of H4K20me1. While S29 phosphorylation did not affect PR-Set7 methyltransferase activity, this event resulted in the removal of PR-Set7 from mitotic chromosomes. S29 phosphorylation also functions to stabilize PR-Set7 by directly inhibiting its interaction with the anaphase-promoting complex (APC), an E3 ubiquitin ligase. The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis. This event is important for proper mitotic progression, as constitutive phosphorylation of PR-Set7 resulted in a substantial delay between metaphase and anaphase. Collectively, we elucidated the molecular mechanisms that control PR-Set7 protein levels during mitosis, and demonstrated that its orchestrated regulation is important for normal mitotic progression. PMID- 20966049 TI - Probing the initiation and effector phases of the somatic piRNA pathway in Drosophila. AB - Combining RNAi in cultured cells and analysis of mutant animals, we probed the roles of known Piwi-interacting RNA (piRNA) pathway components in the initiation and effector phases of transposon silencing. Squash associated physically with Piwi, and reductions in its expression led to modest transposon derepression without effects on piRNAs, consistent with an effector role. Alterations in Zucchini or Armitage reduced both Piwi protein and piRNAs, indicating functions in the formation of a stable Piwi RISC (RNA-induced silencing complex). Notably, loss of Zucchini or mutations within its catalytic domain led to accumulation of unprocessed precursor transcripts from flamenco, consistent with a role for this putative nuclease in piRNA biogenesis. PMID- 20966050 TI - Cumulative radiation dose in patients with aneurysmal subarachnoid hemorrhage. PMID- 20966051 TI - Radiologic and neuropathologic findings in patients in a family with dentatorubral-pallidoluysian atrophy. AB - We describe the cases of 2 patients, a father and his son, with DRPLA who underwent MR examinations prior to death and in whom postmortem examinations of the brain were obtained. MR imaging findings had the following features: 1) atrophy of the cerebellum and brain stem were the common findings, 2) high-signal intensity lesions in the cerebral white matter and brain stem were observed on T2 weighted images in the patient with adult-onset DRPLA, 3) signal-intensity changes in the cerebral white matter were restricted to the periventricular white matter in the patient with juvenile-onset DRPLA, but these changes appear in the advanced stage, and 4) progressive cerebral atrophy was more marked in the patient with juvenile-onset DRPLA. In the patients with DRPLA, the abnormal high signal intensity of the cerebral white matter or brain stem on MR images reflect the loss of myelinated fibers. Cerebral atrophy mainly reflects atrophy of the neuropile. PMID- 20966052 TI - In vivo evaluation of the first dedicated combined flow-restoration and mechanical thrombectomy device in a swine model of acute vessel occlusion. AB - BACKGROUND AND PURPOSE: The use of self-expanding retrievable stents is an emerging and promising treatment strategy for acute stroke treatment. The concept combines the advantages of stent deployment with immediate flow-restoration and of mechanical thrombectomy with definitive thrombus removal. The present study was performed to gain more knowledge about the principle of combined flow restoration and thrombectomy in an established animal model using radiopaque thrombi evaluating efficiency, thrombus-device interaction and possible complications of the first dedicated flow-restoration and mechanical thrombectomy device. MATERIALS AND METHODS: The Solitaire FR (4 * 20 mm) was evaluated in 15 vessel occlusions in an established animal model in swine. Flow-restoration effect at T0, T5, and T10; recanalization rate after retrieval; thromboembolic events; and complications were assessed. Radiopaque thrombi (10-mm length) were used for visualization of thrombus-device interaction during application and retrieval. RESULTS: Immediate flow restoration was achieved in 80% of occlusions. Mean percentage of recanalization compared with the initial vessel diameter at T0 was 30.8%; at T5, 30.7%; and at T10, 25.4%. Re-occlusion occurred in 20.0% between T0 and T5 and in 13.3% between T5 and T10. Complete recanalization (TICI 3) after retrieval was achieved in 86.7%. In 2 cases (13.3%), partial recanalization was achieved, with the remaining thrombus in a side branch (TICI 2b). No thromboembolic event was observed. The assessment of thrombus-device interaction illustrated the compression of the thrombus against the vessel wall during deployment leading to partial flow restoration. During retrieval, the thrombus was retained by the stent struts even during the passage of vessel curvatures. CONCLUSIONS: The Solitaire FR is a safe and effective combined flow restoration and thrombectomy device in vivo. Partial flow restoration is achieved by thrombus compression immediately after deployment, but flow restoration decreases afterward until final retrieval results in maximal recanalization. PMID- 20966053 TI - Neuroform stent-assisted coiling of unruptured intracranial aneurysms: short- and midterm results from a single-center experience with 68 patients. AB - BACKGROUND AND PURPOSE: Intracranial stent placement assists in the coiling of wide-neck aneurysms and aids in reconstructing and protecting the parent artery. In this study, we analyze our experience in the use of the Neuroform system. MATERIALS AND METHODS: Records of patients treated with a Neuroform stent from June 2003 to September 2007 were retrieved from a data base for analysis of population characteristics, occurrence of complications, and acute and midterm angiographic results. RESULTS: Sixty-eight patients harboring 76 aneurysms located primarily in the anterior circulation were treated. There were 5 cases (6.6%) of clot formation after deployment (1 with a permanent neurologic deficit), 1 case of perioperative stent displacement with hemorrhage, and 5 cases (6.6%) of transient neurologic deficit due to thromboembolic events. The morbidity-mortality rate at discharge was 2.9%. One patient presented with a delayed in-stent thrombosis, and 3 others, with silent stenosis. Twenty-four aneurysms (31.6%) were completely occluded in the initial embolization. However, a marked increase in the occlusion rate was observed, with 44 of the 68 aneurysms (64.7%) examined at the 18-month follow-up and 26 of the 46 aneurysms (56.5%) examined in the 3-year follow-up presenting with complete occlusion. At the end of the study, a neck remnant was present in 6 aneurysms (13%) and a residual sac, in 7 (15.2%). Mean follow-up time was 25.7 months. CONCLUSIONS: The present series demonstrates the relative safety and feasibility of the Neuroform stent assisted coiling technique, which seems to provide better results over coiling alone for wide-neck aneurysms. Angiographic results improve with time due to progressive thrombosis of the aneurysm. PMID- 20966054 TI - Improved microsurgical creation of venous pouch arterial bifurcation aneurysms in rabbits. AB - BACKGROUND AND PURPOSE: The choice of the experimental aneurysm model is essential for valid embolization-device evaluations. So far, the use of the rabbit venous pouch arterial bifurcation aneurysm model has been limited by demanding microsurgery, low aneurysm patency rates, and high mortality. This study aimed to facilitate microsurgery and to reduce mortality by optimized peri /postoperative management. MATERIALS AND METHODS: Aneurysms were created in 16 New Zealand white rabbits under general intravenous anesthesia. Using modified microsurgical techniques, we sutured a jugular vein pouch into a bifurcation created between both CCAs. Aggressive anticoagulation (intraoperative intravenous: 1000-IU heparin, 10-mg acetylsalicylic acid/kg; postoperative subcutaneous: 14 days, 250-IU/kg /day heparin) and prolonged postoperative anesthesia (fentanyl patches: 12.5 MUg/h for 72 hours) were applied. Angiographic characteristics of created experimental aneurysms were assessed. RESULTS: The reduced number of interrupted sutures and aggressive anticoagulation caused no intra-/postoperative bleeding, resulting in 0% mortality. Four weeks postoperation, angiography showed patency in 14 of 16 aneurysms (87.5%) and Ohshima type B bifurcation geometry. Mean values of parent-artery diameters (2.3 mm), aneurysm lengths (7.9 mm), and neck widths (4.1 mm) resulted in a mean 1.9 aspect ratio. CONCLUSIONS: Compared with historical controls, the use of modified microsurgical techniques, aggressive anticoagulation, and anesthesia resulted in higher aneurysm patency rates and lower mortality rates in the venous pouch arterial bifurcation aneurysm model. Gross morphologic features of these aneurysms were similar to those of most human intracranial aneurysms. PMID- 20966055 TI - Stent-assisted coiling of complex middle cerebral artery aneurysms: initial and midterm results. AB - BACKGROUND AND PURPOSE: Clinical outcome and initial and midterm angiographic results of EVT of complex MCA aneurysms by using the stent-assisted coiling technique were retrospectively evaluated in our center where EVT of intracranial aneurysms is the first treatment option. MATERIALS AND METHODS: From November 2003 to October 2009, 49 patients (27 men, 22 women; mean age, 52 +/- 12 years) harboring 52 complex unruptured MCA aneurysms (11 ruptured previously and coiled but recanalized and 41 unruptured) were treated by EVT by using self-expandable intracranial stents. Procedural complications, clinical outcome, and initial and midterm angiographic results were evaluated. Initial treatment status and aneurysm sac size were tested as potential risk factors for recurrence. RESULTS: After successful stent deployment, coiling was performed in 50 aneurysms (96.2%) in 47 patients; however, 2 failures (3.8%) occurred in 2 patients. Ten intrastent clot formations (20%) observed on final control angiography induced 2 permanent moderate disabilities (GOS score = 2). Mortality and permanent neurologic morbidity were 0% and 4.3%, respectively. At a mean period of 14 +/- 9 months, among 48 aneurysms in 45 patients eligible for follow-up, 34 complete (71%) and 14 partial treatments (29%) were observed, 7 recurrences (14.6%) occurred, and 5 patients (10.4%) needed retreatment. No aneurysm bleeding or symptomatic intrastent stenosis was observed. Aneurysm sac size >=7 mm and incomplete initial treatment were associated with more recurrences without a statistically significant difference. CONCLUSIONS: For complex unruptured MCA aneurysms, EVT by using a self-expandable intracranial stent was feasible, safe, and durable and could be considered as the first-option treatment. PMID- 20966056 TI - Detection and classification of cranial dural arteriovenous fistulas using 4D-CT angiography: initial experience. AB - BACKGROUND AND PURPOSE: The criterion standard to diagnose and classify cranial DAVFs is DSA. Since this is invasive, relatively expensive and time-consuming, a noninvasive alternative is of interest. We aimed to evaluate the capabilities and pitfalls of 4D-CTA in a consecutive series of patients who presented with a newly diagnosed cranial DAVF, as demonstrated by conventional DSA. MATERIALS AND METHODS: Eleven patients were included in this study after biplane DSA demonstrated a cranial DAVF. They subsequently underwent 4D-CTA imaging by using a 320-detector CT scanner. DSA and 4D-CTA studies were independently read by 2 blinded observers, by using a standardized scoring sheet. 4D-CTA results were analyzed with DSA as the criterion standard. RESULTS: In 10 cases, there was full agreement between DSA and 4D-CTA regarding the Borden classification. However, in the remaining patient, a slow-filling DAVF with a low shunt volume was missed by both readers on 4D-CTA. In all 10 detected cases, >= 1 of the major contributing arteries could be identified with 4D-CTA. Although, by using DSA, the 2 observers identified additional arterial feeders in 7 and 8 cases, respectively, these discrepancies did not influence clinical decision making. CONCLUSIONS: Although novel 4D-CTA imaging may not rule out a small slow-flow DAVF, it appears to be a valuable new adjunct in the noninvasive diagnostic work-up, treatment planning, and follow-up of patients with cranial DAVFs. PMID- 20966057 TI - High-resolution MR neurography of diffuse peripheral nerve lesions. AB - High-resolution MR imaging of peripheral nerves is becoming more common and practical with the increasing availability of 3T magnets. There are multiple reports of MR imaging of peripheral nerves in compression and entrapment neuropathies. However, there is a relative paucity of literature on MRN appearance of diffuse peripheral nerve lesions. We attempted to highlight the salient imaging features of myriad diffuse peripheral nerve disorders and imaging techniques for MRN. Using clinical and pathologically proved relevant examples, we present the MRN appearance of various types of diffuse peripheral nerve lesions, such as traumatic, inflammatory, infectious, hereditary, radiation induced, neoplastic, and tumor variants. PMID- 20966059 TI - Contrast-enhanced angiographic cone-beam CT of cerebrovascular stents: experimental optimization and clinical application. AB - BACKGROUND AND PURPOSE: With modern imaging techniques, visualization of neurovascular stents remains challenging. We present a method for contrast enhanced C-arm CBCT that provides detailed and simultaneous visualization of neurovascular stents and host arteries. MATERIALS AND METHODS: CBCT was performed with a rotational angiography system by acquiring 620 projection frames over a 200 degrees arc at 80 kVp and a total of 260 mAs. A superselective intra arterial contrast injection protocol was optimized in swine experiments and implemented in 57 clinical examinations. High-resolution 3D reconstructions were evaluated by 3 blinded interventional neuroradiologists. Reviewers rated the images by answering questions related to both the quality of the stent and artery visualization and the clinical utility of the images. Raw agreement statistics, ICC, and kappa statistics were computed for the questionnaire results. RESULTS: Of 57 clinical evaluations, 5 were not evaluated due to the use of large balloon mounted stents (n = 4) and a failed contrast injection (n = 1). In 50 of 52 evaluated examinations, the reviewers agreed that simultaneous stent and vessel visualization was of diagnostic quality. There was strong agreement that stent vessel wall apposition could be assessed (kappa = 0.79). CBCT detected contrast filling defects (kappa = 0.85) and vascular calcification (kappa = 0.68). Artifacts resulting from the aneurysm coil mass impaired the delineation of adjacent structures (kappa = 0.72). CONCLUSIONS: We have developed a technique that enables simultaneous clinically useful imaging of neurovascular stents and their host arteries that is unobtainable with other current imaging modalities. Further improvements are required to reduce artifacts from large coil masses due to x-ray scattering. PMID- 20966060 TI - Artery or vein: to be or not to be? PMID- 20966061 TI - MR imaging texture analysis of the corpus callosum and thalamus in amnestic mild cognitive impairment and mild Alzheimer disease. AB - BACKGROUND AND PURPOSE: TA is a branch of image processing that seeks to reduce image information by extracting texture descriptors from the image. TA of MR images of anatomic structures in mild AD and aMCI is not well-studied. Our objective was to attempt to find differences among patients with aMCI and mild AD and normal-aging subjects, by using TA applied to the MR images of the CC and the thalami of these groups of subjects. MATERIALS AND METHODS: TA was applied to the MR images of 17 patients with aMCI, 16 patients with mild AD, and 16 normal-aging subjects. The TA approach was based on the GLCM. MR images were T1-weighted and were obtained in the sagittal and axial planes. The CC and thalami were manually segmented for each subject, and 44 texture parameters were computed for each of these structures. RESULTS: TA parameters showed differences among the 3 groups for the CC and thalamus. A pair-wise comparison among groups showed differences for AD-control and aMCI-AD for the CC; and for AD-control, aMCI-AD, and aMCI control for the thalamus. CONCLUSIONS: TA is a useful technique to aid in the detection of tissue alterations in MR images of mild AD and aMCI and has the potential to become a helpful tool in the diagnosis and understanding of these pathologies. PMID- 20966062 TI - Diffusion tensor group tractography of the corpus callosum in clinically isolated syndrome. AB - BACKGROUND AND PURPOSE: Many studies have observed atrophy and abnormal diffusion within the CC in MS. However, few studies have addressed whether such abnormalities appear at the earliest stage of MS, especially in CIS. In this study, we aimed to investigate the CC integrity and patterns of CC abnormalities in CIS with diffusion tensor group tractography. MATERIALS AND METHODS: First, probability maps of the entire CC and its subregions (genu, body, and splenium) were created from 19 healthy subjects. Then these probability maps were used to evaluate diffusion within the entire CC and its segments in 19 patients with CIS. Five indices, including the midsagittal CC area, FA, MD, lambda(1), and lambda(23), were used to characterize CC integrity. RESULTS: Significant differences were found between patients with CIS and healthy controls in the entire CC and its segments. For the entire CC, patients with CIS had a significantly lower midsagittal CC area and FA, higher MD and lambda(23), with a trend toward higher lambda(1). These 4 diffusion measures were correlated with T2 lesion volume. Moreover, abnormal white matter integrity was present in subregions of the CC; there was a robust significant increase in lambda(23) in the body and splenium and no difference in lambda(1) in the genu. CONCLUSIONS: Our results suggest that atrophy and abnormal diffusion inside the CC appear at the stage of CIS and the severity of damage in the genu is milder than that in the body and splenium. PMID- 20966063 TI - Final cerebral infarct volume is predictable by MR imaging at 1 week. AB - BACKGROUND AND PURPOSE: Stroke volume, an increasingly used end point in phase II trials, is considered stationary at least 30 days after the ictus. We investigated whether information conveyed by MR imaging measurements of the "final" infarct volume could be assessed as early as the subacute stage (days 3 6), rather than waiting for the chronic stage (days 30-45). MATERIALS AND METHODS: Ninety-five patients with middle cerebral artery stroke prospectively included in a multicenter study underwent MR imaging during the first 12 hours (MR imaging-1), between days 3 and 6 (MR imaging-2), and between days 30 and 45 (MR imaging-3). We first investigated the relationship between subacute (FLAIR-2) and chronic volumes (FLAIR-3), by using a linear regression model. We then tested the relationship between FLAIR volumes (either FLAIR-2 or FLAIR-3) and functional disability, measured by the mRS at the time of MR imaging-3, by using logistic regression. The performances of the models were assessed by using the AUC in ROC. RESULTS: A linear association between log FLAIR-2 and log FLAIR-3 volumes was observed. The proportion of FLAIR-3 variation, explained by FLAIR-2, was high (R(2) = 81%), without a covariate that improved this percentage. Both FLAIR-2 and FLAIR-3 were independent predictors of mRS (OR, 0.79 and 0.73; 95% CI, 0.64-0.97 and 0.56-0.96; P = .026 and .023). The performances of the models for the association between either FLAIR volume and mRS did not differ (AUC = 0.897 for FLAIR-2 and 0.888 for FLAIR-3). CONCLUSIONS: Stroke damage may be assessed by a subacute volume because subacute volume predicts the "true" final volume and provides the same clinical prognosis. PMID- 20966064 TI - Cerebral microhemorrhages detected by susceptibility-weighted imaging in amateur boxers. AB - BACKGROUND AND PURPOSE: SWI is a new technique for evaluating diffuse axonal injury associated with punctate hemorrhages. The aim of our study was to determine the prevalence of cerebral microhemorrhages in amateur boxers compared with nonboxers by using SWI and to evaluate the sensitivity of SWI compared with T2 FSE and T2*GE sequences. MATERIALS AND METHODS: We performed cranial MR imaging with a 1.5T scanner in 21 amateur boxers and 21 control subjects. The study protocol included conventional MR images, T2 FSE, T2*GE, and SWI sequences. The proportions of boxers and controls having CSP, DPVS, cerebral atrophy, cerebellar atrophy, ventricular dilation, PSWMD, and microhemorrhages were computed and were compared by using the chi(2) test of proportions. The relationship between microhemorrhages and boxing-related covariates was assessed by using the Wilcoxon rank sum test. The association between the categories was tested by using the Fisher exact test. RESULTS: Using SWI, microhemorrhages were found in 2 (9.52%) of 21 boxers. The microhemorrhages were not visible on T2 FSE or T2*GE images. The proportion of subjects with microhemorrhages did not differ significantly between the boxers and control subjects (chi(2) = 0.525, df = 1, P = .4688). The prevalence of CSP and DPVS was significantly higher in the boxers than in the control subjects. CONCLUSIONS: More microhemorrhages were detected in amateur boxers than in controls, but this difference was not statistically significant. PMID- 20966066 TI - Treatment of brain arteriovenous malformations by double arterial catheterization with simultaneous injection of Onyx: retrospective series of 17 patients. AB - BACKGROUND AND PURPOSE: The use of Onyx in the treatment of intracranial AVMs has increased the cure rate of endovascular embolization compared with the use of liquid adhesive agents. Inadvertent occlusion of the draining veins before the complete exclusion of the nidus constitutes a major risk of bleeding. We report a case series using the technique of double simultaneous arterial catheterization as an approach to achieve the complete exclusion of the nidus before reaching the venous drainage, through a more controlled hemodynamic filling. MATERIALS AND METHODS: Between April 2008 and November 2009, 17 patients with brain AVMs were treated by the DACT. The mean age of the patients was 32.7 years (range, 6-54 years), with 9 females and 8 males. The clinical onset was characterized by intracranial hemorrhage in 8 patients and by seizures in 7. The size of the AVMs ranged from 13 to 54 mm (average, 26.2 mm). The DACT was always used with the objective of curing the AVM. RESULTS: All 17 patients completed the EVT. The average number of sessions conducted was 1.4 (range, 1-3 sessions), with the average injection amount of 6.9 mL of Onyx (range, 2-25.2 mL). Sixteen AVMs (94.1%) were angiographically cured by embolization. Clinical complications occurred in 2 patients (11.7%); 1 of these was permanent (5.9%). No deaths were registered. CONCLUSIONS: This preliminary series shows that the DACT presents satisfactory results when used with curative intent. PMID- 20966065 TI - Global N-acetylaspartate declines even in benign multiple sclerosis. AB - BACKGROUND AND PURPOSE: Neuro-axonal damage is a well known sequelae of MS pathogeneses. Consequently, our aim was to test whether the ~20% of patients with MS exhibiting a clinically benign disease course also have minimal neural dysfunction as reflected by the global concentration of their MR imaging marker NAA. MATERIALS AND METHODS: Q(NAA) was obtained with nonlocalizing whole-head (1)H-MR spectroscopy in 43 patients with benign RRMS (30 women, 13 men; mean age, 44.7 +/- 7.3 years of age) with 21.0 +/- 4.4 years (range, 15-35 years) of disease duration from the first symptom and an EDSS score of 1.9 (range, 0-3). Q(NAA) was by divided by the brain volume (from MR imaging segmentation) to normalize it into WBNAA. All participants gave institutional review board approved written informed consent, and the study was HIPAA compliant. RESULTS: The patients' lesion load was 12.2 +/- 7.7 cm(3). Their 8.3 +/- 1.8 mmol/L WBNAA was 35% lower than that in controls (P < .001). Individual average loss rates (absolute loss compared with controls divided by disease duration) clustered around 0.22 +/- 0.09 mmol/L/year (1.7%/year, assuming monotonic decline). This rate could be extrapolated from that already reported for patients with RRMS of much shorter disease duration. WBNAA did not correlate with lesion load or EDSS. CONCLUSIONS: Normal WBNAA is not characteristic of benign MS and is not an early predictor of its course. These patients, therefore, probably benefit from successful compensation and sparing of eloquent regions. Because they may ultimately have a rapid decline once their brain plasticity is exhausted, they may benefit from treatment options offered to more affected patients. PMID- 20966067 TI - Effects of retraction of anterior teeth and initial soft tissue variables on lip changes in Japanese adults. AB - The aim of this study was to examine the effects of retraction of anterior teeth and the initial soft tissue profile variables on upper and lower lip changes in Japanese adults. Pre- and post-treatment cephalometric radiographs of 33 Japanese female adults (aged 23.0+/-5.0 years), with a Class II division 1 malocclusion, who had two or four first premolars extracted, were evaluated. Lateral cephalograms taken with the lips in a voluntary relaxed position were traced and compared. Nine linear and eight angular measurements were constructed for the hard tissue measurements and 16 linear and 2 angular for the soft tissue measurements. Stepwise multiple regression analysis revealed that the horizontal upper lip position could be explained by the position of the maxillary incisor cervical point and the occlusal plane to SN with a 54 percent contribution ratio, and horizontal lower lip position, maxillary incisor tip position, initial interlabial gap, and aesthetic line to the tip of lower lip with a 51 percent contribution ratio. All parameters employed explained the horizontal position of the upper and lower lip with higher than 96 percent confidence. While the horizontal positions could not be predicted by a limited number of parameters, the vertical positions of lips could be explained by three parameters with higher than 62 percent confidence. The predictability found in this study could be beneficial for orthodontists in treatment planning. PMID- 20966068 TI - Monomeric rhodopsin is sufficient for normal rhodopsin kinase (GRK1) phosphorylation and arrestin-1 binding. AB - G-protein-coupled receptor (GPCR) oligomerization has been observed in a wide variety of experimental contexts, but the functional significance of this phenomenon at different stages of the life cycle of class A GPCRs remains to be elucidated. Rhodopsin (Rh), a prototypical class A GPCR of visual transduction, is also capable of forming dimers and higher order oligomers. The recent demonstration that Rh monomer is sufficient to activate its cognate G protein, transducin, prompted us to test whether the same monomeric state is sufficient for rhodopsin phosphorylation and arrestin-1 binding. Here we show that monomeric active rhodopsin is phosphorylated by rhodopsin kinase (GRK1) as efficiently as rhodopsin in the native disc membrane. Monomeric phosphorylated light-activated Rh (P-Rh*) in nanodiscs binds arrestin-1 essentially as well as P-Rh* in native disc membranes. We also measured the affinity of arrestin-1 for P-Rh* in nanodiscs using a fluorescence-based assay and found that arrestin-1 interacts with monomeric P-Rh* with low nanomolar affinity and 1:1 stoichiometry, as previously determined in native disc membranes. Thus, similar to transducin activation, rhodopsin phosphorylation by GRK1 and high affinity arrestin-1 binding only requires a rhodopsin monomer. PMID- 20966069 TI - Albumin-based microbubbles bind up-regulated scavenger receptors following vascular injury. AB - We have shown previously that perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles bind to injured vascular tissue and can be detected with ultrasound imaging techniques. Prior studies have shown that scavenger receptors (SRs) are regulators of innate and adaptive immune responses and are involved in the progression of vascular disease such as atherosclerosis. In this study, we sought to determine the molecular mechanism of PESDA binding to balloon-injured vasculature. RT-PCR analysis of angioplastied aortas demonstrated a significantly (p <= 0.01) increased expression of SRs. Binding to SRs was confirmed using SR expressing CHO cells, and this binding was blocked by competitive inhibition with the SR-binding ligands oxidized LDL and malondialdehyde-acetaldehyde-modified LDL. Confocal imaging confirmed the co-localization of PESDA microbubbles to CD36, SRB-1, and Toll-like receptor 4, but not to monocytes/macrophages. This study demonstrates that PESDA binds to SRs and that this binding is in major part dependent upon the oxidized nature of PESDA microbubble shell proteins. The extent of SR mRNA expression was increased with injury and associated with microbubble retention as defined by scanning electron microscopy and immunohistochemistry. These findings clarify the mechanisms of how albumin-based microbubbles bind to injured and inflamed vasculature and further support the potential of this imaging technique to detect early vascular innate inflammatory pathophysiologic processes. PMID- 20966070 TI - Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assembly. AB - Innate immune receptors detect microbial pathogens and subsequently activate adaptive immune responses to combat pathogen invasion. MyD88 is a key adaptor molecule in both Toll-like receptor (TLR) and IL-1 receptor superfamily signaling pathways. This is illustrated by the fact that human individuals carrying rare, naturally occurring MYD88 point mutations suffer from reoccurring life threatening infections. Here we analyzed the functional properties of six reported non-synonymous single nucleotide polymorphisms of MYD88 in an in vitro cellular system. Two variants found in the MyD88 death domain, S34Y and R98C, showed severely reduced NF-kappaB activation due to reduced homo-oligomerization and IRAK4 interaction. Structural modeling highlights Ser-34 and Arg-98 as residues important for the assembly of the Myddosome, a death domain (DD) post receptor complex involving the DD of MyD88, IRAK4, and IRAK2 or IRAK1. Using S34Y and R98C as functional probes, our data show that MyD88 homo-oligomerization and IRAK4 interaction is modulated by the MyD88 TIR and IRAK4 kinase domain, demonstrating the functional importance of non-DD regions not observed in a recent Myddosome crystal structure. The differential interference of S34Y and R98C with some (IL-1 receptor, TLR2, TLR4, TLR5, and TLR7) but not all (TLR9) MyD88-dependent signaling pathways also suggests that receptor specificities exist at the level of the Myddosome. Given their detrimental effect on signaling, it is not surprising that our epidemiological analysis in several case-control studies confirms that S34Y and R98C are rare variants that may drastically contribute to susceptibility to infection in only few individuals. PMID- 20966071 TI - Phosphorylation of p50 NF-kappaB at a single serine residue by DNA-dependent protein kinase is critical for VCAM-1 expression upon TNF treatment. AB - The DNA binding activity of NF-kappaB is critical for VCAM-1 expression during inflammation. DNA-dependent protein kinase (DNA-PK) is thought to be involved in NF-kappaB activation. Here we show that DNA-PK is required for VCAM-1 expression in response to TNF. The phosphorylation and subsequent degradation of I kappaBalpha as well as the serine 536 phosphorylation and nuclear translocation of p65 NF-kappaB were insufficient for VCAM-1 expression in response to TNF. The requirement for p50 NF-kappaB in TNF-induced VCAM-1 expression may be associated with its interaction with and phosphorylation by DNA-PK, which appears to be dominant over the requirement for p65 NF-kappaB activation. p50 NF-kappaB binding to its consensus sequence increased its susceptibility to phosphorylation by DNA PK. Additionally, DNA-PK activity appeared to increase the association between p50/p50 and p50/p65 NF-kappaB dimers upon binding to DNA and after binding of p50 NF-kappaB to the VCAM-1 promoter. Analyses of the p50 NF-kappaB protein sequence revealed that both serine 20 and serine 227 at the amino terminus of the protein are putative sites for phosphorylation by DNA-PK. Mutation of serine 20 completely eliminated phosphorylation of p50 NF-kappaB by DNA-PK, suggesting that serine 20 is the only site in p50 NF-kappaB for phosphorylation by DNA-PK. Re establishing wild-type p50 NF-kappaB, but not its serine 20/alanine mutant, in p50 NF-kappaB(-/-) fibroblasts reversed VCAM-1 expression after TNF treatment, demonstrating the importance of the serine 20 phosphorylation site in the induction of VCAM-1 expression. Together, these results elucidate a novel mechanism for the involvement of DNA-PK in the positive regulation of p50 NF kappaB to drive VCAM-1 expression. PMID- 20966072 TI - Intrarenal renin angiotensin system revisited: role of megalin-dependent endocytosis along the proximal nephron. AB - The existence of a local renin angiotensin system (RAS) of the kidney has been established. Angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), angiotensin receptors, and high concentrations of luminal angiotensin II have been found in the proximal tubule. Although functional data have documented the relevance of a local RAS, the dualism between biosynthesis and endocytotic uptake of its components and their cellular processing has been incompletely understood. To resolve this, we have selectively analyzed their distribution, endocytosis, transcytosis, and biosynthesis in the proximal tubule. The presence of immunoreactive AGT, restricted to the early proximal tubule, was due to its retrieval from the ultrafiltrate and storage in endosomal and lysosomal compartments. Cellular uptake was demonstrated by autoradiography of radiolabeled AGT and depended on intact endocytosis. AGT was identified as a ligand of the multiple ligand-binding repeats of megalin. AGT biosynthesis was restricted to the proximal straight tubule, revealing substantial AGT mRNA expression. Transgenic AGT overexpression under the control of an endogenous promoter was also restricted to the late proximal tubule. Proximal handling of renin largely followed the patterns of AGT, whereas its local biosynthesis was not significant. Transcytotic transport of AGT in a proximal cell line revealed a 5% recovery rate after 1 h. ACE was expressed along late proximal brush-border membrane, whereas ACE2 was present along the entire segment. Surface expression of ACE and ACE2 differed as a function of endocytosis. Our data on the localization and cellular processing of RAS components provide new aspects of the functional concept of a "self-contained" renal RAS. PMID- 20966073 TI - Brain-specific Phgdh deletion reveals a pivotal role for L-serine biosynthesis in controlling the level of D-serine, an N-methyl-D-aspartate receptor co-agonist, in adult brain. AB - In mammalian brain, D-serine is synthesized from L-serine by serine racemase, and it functions as an obligatory co-agonist at the glycine modulatory site of N methyl-D-aspartate (NMDA)-selective glutamate receptors. Although diminution in D serine level has been implicated in NMDA receptor hypofunction, which is thought to occur in schizophrenia, the source of the precursor L-serine and its role in D serine metabolism in adult brain have yet to be determined. We investigated whether L-serine synthesized in brain via the phosphorylated pathway is essential for D-serine synthesis by generating mice with a conditional deletion of D-3 phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95). This enzyme catalyzes the first step in L-serine synthesis via the phosphorylated pathway. HPLC analysis of serine enantiomers demonstrated that both L- and D-serine levels were markedly decreased in the cerebral cortex and hippocampus of conditional knock-out mice, whereas the serine deficiency did not alter protein expression levels of serine racemase and NMDA receptor subunits in these regions. The present study provides definitive proof that L-serine-synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steady-state levels of D serine in adult brain. Furthermore, NMDA-evoked transcription of Arc, an immediate early gene, was diminished in the hippocampus of conditional knock-out mice. Thus, this study demonstrates that in mature neuronal circuits L-serine availability determines the rate of D-serine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus. PMID- 20966074 TI - Functional dissection of adenylate cyclase R, an inducer of spore encapsulation. AB - Cyclic AMP acting on protein kinase A controls sporulation and encystation in social and solitary amoebas. In Dictyostelium discoideum, adenylate cyclase R (ACR), is essential for spore encapsulation. In addition to its cyclase (AC) domain, ACR harbors seven transmembrane helices, a histidine kinase domain, and two receiver domains. We investigated the role of these domains in the regulation of AC activity. Expression of an ACR-YFP fusion protein in acr(-) cells rescued their sporulation defective phenotype and revealed that ACR is associated with the nuclear envelope and endoplasmic reticulum. Loss of the transmembrane helices (DeltaTM) caused a 60% reduction of AC activity, but DeltaTM-ACR still rescued the acr(-) phenotype. The isolated AC domain was properly expressed but inactive. Mutation of three essential ATP-binding residues in the histidine kinase domain did not affect the AC activity or phenotypic rescue. Mutation of the essential phosphoryl-accepting aspartate in receivers 1, 2, or both had only modest effects on AC activity and did not affect phenotypic rescue, indicating that AC activity is not critically regulated by phosphorelay. Remarkably, the dimerizing histidine phosphoacceptor subdomain, which in ACR lacks the canonical histidine for autophosphorylation, was essential for AC activity. Transformation of wild-type cells with an ACR allele (DeltaCRA) that is truncated after this domain inhibited AC activity of endogenous ACR and replicated the acr(-) phenotype. Combined with the observation that the isolated AC domain was inactive, the dominant-negative effect of DeltaCRA strongly suggests that the defunct phosphoacceptor domain acquired a novel role in enforcing dimerization of the AC domain. PMID- 20966075 TI - Imaging of mobile long-lived nanoplatforms in the live cell plasma membrane. AB - The plasma membrane has been hypothesized to contain nanoscopic lipid platforms, which are discussed in the context of "lipid rafts" or "membrane rafts." Based on biochemical and cell biological studies, rafts are believed to play a crucial role in many signaling processes. However, there is currently not much information on their size, shape, stability, surface density, composition, and heterogeneity. We present here a method that allows for the first time the direct imaging of nanoscopic long-lived platforms with raft-like properties diffusing in the live cell plasma membrane. Our method senses these platforms by their property to assemble a characteristic set of fluorescent marker proteins or lipids on a time scale of seconds. A special photobleaching protocol was used to reduce the surface density of labeled mobile platforms down to the level of well isolated diffraction-limited spots without altering the single spot brightness. The statistical distribution of probe molecules per platform was determined by single molecule brightness analysis. For demonstration, we used the consensus raft marker glycosylphosphatidylinositol-anchored monomeric GFP and the fluorescent lipid analog BODIPY-G(M1), which preferentially partitions into liquid-ordered phases. For both markers, we found cholesterol-dependent homo association in the plasma membrane of living CHO and Jurkat T cells in the resting state, thereby demonstrating the existence of small, mobile, long-lived platforms containing these probes. We further applied the technology to address structural changes in the plasma membrane during fever-type heat shock: at elevated temperatures, the glycosylphosphatidylinositol-anchored monomeric GFP homo-association disappeared, accompanied by an increase in the expression of the small heat shock protein Hsp27. PMID- 20966077 TI - Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia inducible factors: new link between hypoxia signaling and iron homeostasis. AB - Hepcidin is a liver-derived hormone with a key role in iron homeostasis. In addition to iron, it is regulated by inflammation and hypoxia, although mechanisms of hypoxic regulation remain unclear. In hepatocytes, hepcidin is induced by bone morphogenetic proteins (BMPs) through a receptor complex requiring hemojuvelin (HJV) as a co-receptor. Type II transmembrane serine proteinase (TMPRSS6) antagonizes hepcidin induction by BMPs by cleaving HJV from the cell membrane. Inactivating mutations in TMPRSS6 lead to elevated hepcidin levels and consequent iron deficiency anemia. Here we demonstrate that TMPRSS6 is up-regulated in hepatic cell lines by hypoxia and by other activators of hypoxia inducible factor (HIF). We show that TMPRSS6 expression is regulated by both HIF 1alpha and HIF-2alpha. This HIF-dependent up-regulation of TMPRSS6 increases membrane HJV shedding and decreases hepcidin promoter responsiveness to BMP signaling in hepatocytes. Our results reveal a potential role for TMPRSS6 in hepcidin regulation by hypoxia and provide a new molecular link between oxygen sensing and iron homeostasis. PMID- 20966076 TI - Roles of SIRT1 in the acute and restorative phases following induction of inflammation. AB - Endotoxin is a potent inducer of systemic inflammatory responses in human and rodents. Here, we show that in vivo endotoxin triggers a rapid and transient decline in ATP concentration in human peripheral blood leukocytes and murine peripheral blood leukocytes and liver, which is associated with a brief increase in expression of the autophagy indicator LC3-II. In both of these tissues, the ATP concentration reaches a nadir, and autophagy is induced between 2 and 4 h post-endotoxin infusion, and homeostasis is restored within 12 h. Mouse liver SIRT1 and AMP-activated protein kinase (AMPK) protein expression levels decline precipitously within 10 min and remain below detection levels for up to 12 h post endotoxin administration. In marked contrast, the expression of HIF-1alpha is induced within 90 min and remains elevated for up to 12 h. The ATP recovery is delayed, and the increases in both HIF-1alpha expression and autophagy are prolonged in endotoxin-challenged SIRT1 liver knock-out mice. Resveratrol prevents the decline in ATP concentration and SIRT1 expression, as well as the increase in HIF-1alpha expression and autophagy in liver of endotoxin-challenged wild type mice but not in SIRT1 liver knock-out mice. These results provide novel insight into the state of both cellular bioenergetics and metabolic networks during the acute phase of systemic inflammation and suggest a role for SIRT1 in acute metabolic decline, as well as the restoration of metabolic homeostasis during an inflammatory challenge. PMID- 20966078 TI - TGF-{beta}-induced MiR-491-5p expression promotes Par-3 degradation in rat proximal tubular epithelial cells. AB - Par-3 is a component of Par complex, which is critical for the integrity of tight junction. We previously reported that TGF-beta down-regulated Par-3 expression in rat proximal tubular epithelial cells, but the underlying mechanism remains unknown. In the present study, we demonstrated by a luciferase reporter assay that miR-491-5p down-regulated the luciferase activity through a binding site in the 3' UTR of Par-3. Overexpression of miR-491-5p dramatically decreased the expression of endogenous Par-3, disrupted tight junction, and resulted in decreased transepithelial resistance. Moreover, miR-491-5p expression was induced by TGF-beta1 through the MEK/p38 MAPK pathway. Importantly, miR-491-5p levels were increased significantly in a rat model of obstructive nephropathy, in parallel with decreased Par-3 levels. Taken together, we conclude that up regulation of miR-491-5p contributes to TGF-beta-regulated Par-3 expression. Our study uncovered a novel mechanism by which TGF-beta disrupts cell junction. PMID- 20966079 TI - Identification and characterization of an inhibitory metal ion-binding site in ferrochelatase. AB - Ferrochelatase catalyzes the insertion of ferrous iron into protoporphyrin IX to form heme. The severe metal ion substrate inhibition observed during in vitro studies of the purified enzyme is almost completely eliminated by mutation of an active site histidine residue (His-287, murine ferrochelatase numbering) to leucine and reduced over 2 orders of magnitude by mutation of a nearby conserved phenylalanine residue (Phe-283) to leucine. Elimination of substrate inhibition had no effect on the apparent V(max) for Ni(2+), but the apparent K(m) was increased 100-fold, indicating that the integrity of the inhibitory binding site is important for the enzyme to turn over substrates rapidly at low micromolar metal ion concentrations. The inhibitory site was observed to have a pK(a) value of 8.0, and this value was reduced to 7.5 by the F283L mutation and to 7.4 in a naturally occurring positional variant observed in most bacterial ferrochelatases, murine ferrochelatase H287C. A H287N variant was also found to be substrate-inhibited, but unlike the H287C variant, pH dependence of substrate inhibition was largely eliminated. The data indicate that the inhibitory metal ion-binding site is composed of multiple residues but primarily defined by His 287 and Phe-283 and is crucial for optimal activity at low metal ion concentrations. It is proposed that this binding site may be important for ferrous iron acquisition and desolvation in vivo. PMID- 20966080 TI - Cellular and molecular mechanisms of autosomal dominant form of progressive hearing loss, DFNA2. AB - Despite advances in identifying deafness genes, determination of the underlying cellular and functional mechanisms for auditory diseases remains a challenge. Mutations of the human K(+) channel hKv7.4 lead to post-lingual progressive hearing loss (DFNA2), which affects world-wide population with diverse racial backgrounds. Here, we have generated the spectrum of point mutations in the hKv7.4 that have been identified as diseased mutants. We report that expression of five point mutations in the pore region, namely L274H, W276S, L281S, G285C, and G296S, as well as the C-terminal mutant G321S in the heterologous expression system, yielded non-functional channels because of endoplasmic reticulum retention of the mutant channels. We mimicked the dominant diseased conditions by co-expressing the wild-type and mutant channels. As compared with expression of wild-type channel alone, the blend of wild-type and mutant channel subunits resulted in reduced currents. Moreover, the combinatorial ratios of wild type:mutant and the ensuing current magnitude could not be explained by the predictions of a tetrameric channel and a dominant negative effect of the mutant subunits. The results can be explained by the dependence of cell surface expression of the mutant on the wild-type subunit. Surprisingly, a transmembrane mutation F182L, which has been identified in a pre-lingual progressive hearing loss patient in Taiwan, yielded cell surface expression and functional features that were similar to that of the wild type, suggesting that this mutation may represent redundant polymorphism. Collectively, these findings provide traces of the cellular mechanisms for DFNA2. PMID- 20966081 TI - A Cys-loop mutation in the Caenorhabditis elegans nicotinic receptor subunit UNC 63 impairs but does not abolish channel function. AB - The nematode Caenorhabditis elegans is an established model organism for studying neurobiology. UNC-63 is a C. elegans nicotinic acetylcholine receptor (nAChR) alpha-subunit. It is an essential component of the levamisole-sensitive muscle nAChR (L-nAChR) and therefore plays an important role in cholinergic transmission at the nematode neuromuscular junction. Here, we show that worms with the unc 63(x26) allele, with its alphaC151Y mutation disrupting the Cys-loop, have deficient muscle function reflected by impaired swimming (thrashing). Single channel recordings from cultured muscle cells from the mutant strain showed a 100 fold reduced frequency of opening events and shorter channel openings of L-nAChRs compared with those of wild-type worms. Anti-UNC-63 antibody staining in both cultured adult muscle and embryonic cells showed that L-nAChRs were expressed at similar levels in the mutant and wild-type cells, suggesting that the functional changes in the receptor, rather than changes in expression, are the predominant effect of the mutation. The kinetic changes mimic those reported in patients with fast-channel congenital myasthenic syndromes. We show that pyridostigmine bromide and 3,4-diaminopyridine, which are drugs used to treat fast-channel congenital myasthenic syndromes, partially rescued the motility defect seen in unc-63(x26). The C. elegans unc-63(x26) mutant may therefore offer a useful model to assist in the development of therapies for syndromes produced by altered function of human nAChRs. PMID- 20966082 TI - Structural basis for hormone recognition by the Human CRFR2{alpha} G protein coupled receptor. AB - The mammalian corticotropin releasing factor (CRF)/urocortin (Ucn) peptide hormones include four structurally similar peptides, CRF, Ucn1, Ucn2, and Ucn3, that regulate stress responses, metabolism, and cardiovascular function by activating either of two related class B G protein-coupled receptors, CRFR1 and CRFR2. CRF and Ucn1 activate both receptors, whereas Ucn2 and Ucn3 are CRFR2 selective. The molecular basis for selectivity is unclear. Here, we show that the purified N-terminal extracellular domains (ECDs) of human CRFR1 and the CRFR2alpha isoform are sufficient to discriminate the peptides, and we present three crystal structures of the CRFR2alpha ECD bound to each of the Ucn peptides. The CRFR2alpha ECD forms the same fold observed for the CRFR1 and mouse CRFR2beta ECDs but contains a unique N-terminal alpha-helix formed by its pseudo signal peptide. The CRFR2alpha ECD peptide-binding site architecture is similar to that of CRFR1, and binding of the alpha-helical Ucn peptides closely resembles CRF binding to CRFR1. Comparing the electrostatic surface potentials of the ECDs suggests a charge compatibility mechanism for ligand discrimination involving a single amino acid difference in the receptors (CRFR1 Glu104/CRFR2alpha Pro-100) at a site proximate to peptide residue 35 (Arg in CRF/Ucn1, Ala in Ucn2/3). CRFR1 Glu-104 acts as a selectivity filter preventing Ucn2/3 binding because the nonpolar Ala-35 is incompatible with the negatively charged Glu-104. The structures explain the mechanisms of ligand recognition and discrimination and provide a molecular template for the rational design of therapeutic agents selectively targeting these receptors. PMID- 20966083 TI - FdC1, a novel ferredoxin protein capable of alternative electron partitioning, increases in conditions of acceptor limitation at photosystem I. AB - In higher plants, [2Fe-2S] ferredoxin (Fd) proteins are the unique electron acceptors from photosystem I (PSI). Fds are soluble, and distribute electrons to many enzymes, including Fd:NADP(H) reductase (FNR), for the photoreduction of NADP(+). In addition to well studied [2Fe-2S] Fd proteins, higher plants also possess genes for significantly different, as yet uncharacterized Fd proteins, with extended C termini (FdCs). Whether these FdC proteins function as photosynthetic electron transfer proteins is not known. We examined whether these proteins play a role as alternative electron acceptors at PSI, using quantitative RT-PCR to follow how their expression changes in response to acceptor limitation at PSI, in mutant Arabidopsis plants lacking 90-95% of photosynthetic [2Fe-2S] Fd. Expression of the gene encoding one FdC protein, FdC1, was identified as being strongly up-regulated. We confirmed that this protein was chloroplast localized and increased in abundance on PSI acceptor limitation. We purified the recombinant FdC1 protein, which exhibited a UV-visible spectrum consistent with a [2Fe-2S] cluster, confirmed by EPR analysis. Measurements of electron transfer show that FdC1 is capable of accepting electrons from PSI, but cannot support photoreduction of NADP(+). Whereas FdC1 was capable of electron transfer with FNR, redox potentiometry showed that it had a more positive redox potential than photosynthetic Fds by around 220 mV. These results indicate that FdC1 electron donation to FNR is prevented because it is thermodynamically unfavorable. Based on our data, we speculate that FdC1 has a specific function in conditions of acceptor limitation at PSI, and channels electrons away from NADP(+) photoreduction. PMID- 20966084 TI - DNA damage, DNA repair rates and mRNA expression levels of cell cycle genes (TP53, p21(CDKN1A), BCL2 and BAX) with respect to occupational exposure to styrene. AB - We studied the relationship between DNA damage, DNA repair rates and messenger RNA (mRNA) expression levels of cell cycle genes TP53, p21(CDKN1A), BCL2 and BAX in a group of 71 styrene-exposed workers and 51 control individuals. The exposure was assessed by measuring the concentration of styrene at workplace and in blood. Parameters of DNA damage [measured as single-strand breaks (SSBs) and endonuclease III-sensitive sites], gamma-irradiation-specific DNA repair rates and mRNA levels of studied genes were analyzed in peripheral blood lymphocytes. The workers were divided into low (<50 mg/m3) and high (>50 mg/m3) styrene exposure groups. We found negative correlations between mRNA expression of TP53, BCL2, BAX and styrene exposure (P < 0.001 for all parameters). In contrast, p21(CDKN1A) mRNA expression significantly increased with increasing styrene exposure (P = 0.001). SSBs and endonuclease III-sensitive sites increased with increasing mRNA levels of TP53 (P < 0.001 for both) and BCL2 (P = 0.038, P = 0.002, respectively), whereas the same parameters decreased with increasing mRNA levels of p21(CDKN1A) (P < 0.001, P = 0.007, respectively). gamma-Irradiation specific DNA repair rates increased with p21(CDKN1A) mRNA levels up to the low exposure level (P = 0.044). Our study suggests a possible relationship between styrene exposure, DNA damage and transcript levels of key cell cycle genes. PMID- 20966085 TI - Using extracellular polymeric substances (EPS)-producing cyanobacteria for the bioremediation of heavy metals: do cations compete for the EPS functional groups and also accumulate inside the cell? AB - Many cyanobacteria produce extracellular polymeric substances (EPS) mainly of polysaccharidic nature. These EPS can remain associated to the cell surface as sheaths, capsules and/or slimes, or be liberated into the surrounding environment as released polysaccharides (RPS). The ability of EPS-producing cyanobacteria to remove heavy metals from aqueous solutions has been widely reported in the literature, focusing mainly on the biotechnological potential. However, the knowledge of the effects of the metals in the cell's survival/growth is still scarce, particularly when they are simultaneously exposed to more than one metal. This work evaluated the effects of different concentrations of Cu(2+) and/or Pb(2+) in the growth/survival of Gloeothece sp. PCC 6909 and its sheathless mutant Gloeothece sp. CCY 9612. The results obtained clearly showed that both phenotypes are more severely affected by Cu(2+) than Pb(2+), and that the mutant is more sensitive to the former metal than the wild-type. Evident ultrastructural changes were also observed in the wild-type and mutant cells exposed to high levels (10 mg l(-1)) of Cu(2+). Moreover, in bi-metal systems, Pb(2+) was preferentially removed compared with Cu(2+), being the RPS of the mutant that is the most efficient polysaccharide fraction in metal removal. In these systems, the simultaneous presence of Cu(2+) and Pb(2+) caused a mutual inhibition in the adsorption of each metal. PMID- 20966086 TI - Variation in a surface-exposed region of the Mycoplasma pneumoniae P40 protein as a consequence of homologous DNA recombination between RepMP5 elements. AB - Mycoplasma pneumoniae is a human pathogen that causes a range of respiratory tract infections. The first step in infection is adherence of the bacteria to the respiratory epithelium. This step is mediated by a specialized organelle, which contains several proteins (cytadhesins) that have an important function in adherence. Two of these cytadhesins, P40 and P90, represent the proteolytic products from a single 130 kDa protein precursor, which is encoded by the MPN142 gene. Interestingly, MPN142 contains a repetitive DNA element, termed RepMP5, of which homologues are found at seven other loci within the M. pneumoniae genome. It has been hypothesized that these RepMP5 elements, which are similar but not identical in sequence, recombine with their counterpart within MPN142 and thereby provide a source of sequence variation for this gene. As this variation may give rise to amino acid changes within P40 and P90, the recombination between RepMP5 elements may constitute the basis of antigenic variation and, possibly, immune evasion by M. pneumoniae. To investigate the sequence variation of MPN142 in relation to inter-RepMP5 recombination, we determined the sequences of all RepMP5 elements in a collection of 25 strains. The results indicate that: (i) inter-RepMP5 recombination events have occurred in seven of the strains, and (ii) putative RepMP5 recombination events involving MPN142 have induced amino acid changes in a surface-exposed part of the P40 protein in two of the strains. We conclude that recombination between RepMP5 elements is a common phenomenon that may lead to sequence variation of MPN142 encoded proteins. PMID- 20966087 TI - The pobA gene of Burkholderia cenocepacia encodes a group I Sfp-type phosphopantetheinyltransferase required for biosynthesis of the siderophores ornibactin and pyochelin. AB - The opportunistic pathogen Burkholderia cenocepacia produces the siderophores ornibactin and pyochelin under iron-restricted conditions. Biosynthesis of both siderophores requires the involvement of non-ribosomal peptide synthetases (NRPSs). Using a transposon containing the lacZ reporter gene, two B. cenocepacia mutants were isolated which were deficient in siderophore production. Mutant IW10 was shown to produce normal amounts of ornibactin but only trace amounts of pyochelin, whereas synthesis of both siderophores was abolished in AHA27. Growth of AHA27, but not IW10, was inhibited under iron-restricted conditions. In both mutants, the transposon had integrated into the pobA gene, which encodes a polypeptide exhibiting similarity to the Sfp-type phosphopantetheinyltransferases (PPTases). These enzymes are responsible for activation of NRPSs by the covalent attachment of the 4'-phosphopantetheine (P-pant) moiety of coenzyme A. Previously characterized PPTase genes from other bacteria were shown to efficiently complement both mutants for siderophore production when provided in trans. The B. cenocepacia pobA gene was also able to efficiently complement an Escherichia coli entD mutant for production of the siderophore enterobactin. Using mutant IW10, in which the lacZ gene carried by the transposon is inserted in the same orientation as pobA, it was shown that pobA is not appreciably iron-regulated. Finally, we confirmed that Sfp-type bacterial PPTases can be subdivided into two distinct groups, and we present the amino acid signature sequences which characterize each of these groups. PMID- 20966088 TI - Mycoplasma gallisepticum and Mycoplasma synoviae express a cysteine protease CysP, which can cleave chicken IgG into Fab and Fc. AB - Major poultry pathogens M. gallisepticum and M. synoviae share a gene encoding a putative cysteine protease CysP similar to papain cysteine protease (C1A subfamily). Comparison of the cysP gene sequences of 18 M. synoviae and 10 M. gallisepticum strains sequenced in this study showed polymorphisms, including deletions. Seven M. synoviae strains, including the type strain WVU 1853, had a 39 bp deletion in the 3' end of the cysP gene. In the same cysP region, all M. gallisepticum strains showed a deletion of 66 bp. Immunoblot analysis with specific antibodies demonstrated that M. synoviae strains expressed CysP, which was approximately 65 kDa. Both M. synoviae and M. gallisepticum were able to digest chicken IgG (cIgG). Incubation of cIgG (~170 kDa) with M. synoviae or M. gallisepticum cells (~15 h at 37  degrees C) resulted in a papain-like cleavage pattern of cIgG and fragments corresponding to the antigen-binding fragment of IgG (Fab, ~45 kDa) and the crystallizable region fragment (Fc) of the IgG heavy chain (dimer of ~60 kDa). Iodoacetamide (50 mM) prevented cleavage of cIgG by both Mycoplasma species. Following site-directed mutagenesis (eight TGA codons were changed to TGG) the cysP gene of M. synoviae ULB 925 was expressed as a His-tagged protein in a cell-free system. Purified recombinant CysP (rCysP; ~67 kDa, pI~8) cleaved cIgG into Fab and Fc fragments. This indicates that CysP is responsible for the cIgG cleavage caused by M. synoviae and, probably, by M. gallisepticum. This is the first evidence to our knowledge that mycoplasmas have enzymes that can cleave the host IgG and indicates a novel strategy used by M. gallisepticum and M. synoviae for prolonged survival despite the antibody response of their host. PMID- 20966089 TI - Duplication of the chromosomal blaSHV-11 gene in a clinical hypermutable strain of Klebsiella pneumoniae. AB - In a collection of 110 clinical isolates of Klebsiella pneumoniae, a single strain, Kp593, was found to exhibit a mutator phenotype with a rifampicin mutation frequency 100-fold higher than the modal value for this species. Complementation experiments with the wild-type MutL, one of the main components of the methyl-directed mismatch repair system, allowed the mutator phenotype to be reversed. Sequencing revealed substitution of the conserved residue Lys307 to Arg and site-directed mutagenesis followed by complementation experiments confirmed the critical role of this mutation. The patient infected with Kp593 relapsed a month later and the strain isolated then, Kp869, was identical to Kp593, as verified by PFGE analysis. Phenotypically, Kp869 colonies were more mucoid than those of Kp593, probably due to increased capsule synthesis as shown by electron microscopy. In addition, Kp869 exhibited a 16-fold higher amoxicillin resistance level related to a 36.4 kb tandem duplication encompassing the chromosomal bla(SHV-11) gene, which was unstable in vitro. These data suggest that the mutator phenotype found in Kp593/Kp869 is associated with beneficial mutations conferring a selective advantage, such as increased virulence factor production and antibiotic resistance. The latter was due to resistance gene duplication, an event rarely described in natural isolates. This is the first description of the in vivo occurrence of gene duplication in a mutator background. PMID- 20966090 TI - Glutathione biosynthesis in the yeast pathogens Candida glabrata and Candida albicans: essential in C. glabrata, and essential for virulence in C. albicans. AB - Redox pathways play a key role in pathogenesis. Glutathione, a central molecule in redox homeostasis in yeasts, is an essential metabolite, but its requirements can be met either from endogenous biosynthesis or from the extracellular milieu. In this report we have examined the importance of glutathione biosynthesis in two major human opportunistic fungal pathogens, Candida albicans and Candida glabrata. As the genome sequence of C. glabrata had suggested the absence of glutathione transporters, we initially investigated exogenous glutathione utilization in C. glabrata by disruption of the MET15 gene, involved in methionine biosynthesis. We observed an organic sulphur auxotrophy in a C. glabrata met15Delta strain; however, unlike its Saccharomyces cerevisiae counterpart, the C. glabrata met15Delta strain was unable to grow on exogenous glutathione. This inability to grow on exogenous glutathione was demonstrated to be due to the lack of a functional glutathione transporter, despite the presence of a functional glutathione degradation machinery (the Dug pathway). In the absence of the ability to obtain glutathione from the extracellular medium, we examined and could demonstrate that gamma-glutamyl cysteine synthase, the first enzyme of glutathione biosynthesis, was essential in C. glabrata. Further, although gamma-glutamyl cysteine synthase has been reported to be non-essential in C. albicans, we report here for what is believed to be the first time that the enzyme is required for survival in human macrophages in vitro, as well as for virulence in a murine model of disseminated candidiasis. The essentiality of gamma-glutamyl cysteine synthase in C. glabrata, and its essentiality for virulence in C. albicans, make the enzyme a strong candidate for antifungal development. PMID- 20966092 TI - Polyamine biosynthesis and transport mechanisms are crucial for fitness and pathogenesis of Streptococcus pneumoniae. AB - Polyamines such as cadaverine, putrescine and spermidine are polycationic molecules that have pleiotropic effects on cells via their interaction with nucleic acids. Streptococcus pneumoniae (the pneumococcus) is a Gram-positive pathogen capable of causing pneumonia, septicaemia, otitis media and meningitis. Pneumococci have a polyamine transport operon (potABCD) responsible for the binding and transport of putrescine and spermidine, and can synthesize cadaverine and spermidine using their lysine decarboxylase (cad) and spermidine synthase (speE) enzymes. Previous studies from our laboratory have shown that an increase in PotD expression is seen following exposure to various stresses, while during infection, potD inactivation significantly attenuates pneumococcal virulence, and anti-PotD immune responses are protective in mice. In spite of their relative importance, not much is known about the global contribution of polyamine biosynthesis and transport pathways to pneumococcal disease. Mutants deficient in polyamine biosynthesis (DeltaspeE or Deltacad) or transport genes (DeltapotABCD) were constructed and were found to be attenuated in murine models of pneumococcal colonization and pneumonia, either alone or in competition with the wild-type strain. The DeltaspeE mutant was also attenuated during invasive disease, while the potABCD and cad genes seemed to be dispensable. HPLC analyses showed reduced intracellular polyamine levels in all mutant strains compared with wild-type bacteria. High-throughput proteomic analyses indicated reduced expression of growth, replication and virulence factors in mutant strains. Thus, polyamine biosynthesis and transport mechanisms are intricately linked to the fitness, survival and pathogenesis of the pneumococcus in host microenvironments, and may represent important targets for prophylactic and therapeutic interventions. PMID- 20966091 TI - TagA is a secreted protease of Vibrio cholerae that specifically cleaves mucin glycoproteins. AB - Vibrio cholerae is a human diarrhoeal pathogen that is a major cause of gastrointestinal disease and death worldwide. Pathogenic V. cholerae strains are characterized by the presence of a Vibrio pathogenicity island (VPI) that encodes virulence factors, including the toxin co-regulated pilus (TCP). TagA is encoded within the VPI and is positively co-regulated with cholera toxin and TCP. TagA is a sequelogue of the StcE mucinase of Escherichia coli O157 : H7. We investigated whether this sequence homology reflected a conserved enzymic substrate profile. TagA exhibited metalloprotease activity toward crude purified mucins, salivary mucin and LS174T goblet cell surface mucin. Like StcE, TagA did not cleave general protease substrates, but unlike StcE, TagA did not cleave the mucin-like serpin C1 esterase inhibitor. Both proteins cleaved the immune cell surface mucin CD43, but TagA demonstrated reduced enzymic efficiency relative to StcE. TagA was expressed and secreted by V. cholerae under ToxR-dependent conditions. A tagA deficient V. cholerae strain showed no defect in a model of in vitro attachment to the HEp-2 cell line; however, overexpression of a proteolytically inactive mutant, TagA(E433D), caused a significant increase in attachment. The increased attachment was reduced by pretreatment of epithelial monolayers with active TagA. Our results indicate that TagA is a mucinase and suggest that TagA may directly modify host cell surface molecules during V. cholerae infection. PMID- 20966093 TI - Transcriptional regulation, occurrence and putative role of the Pht family of Streptococcus pneumoniae. AB - Restricted to the genus Streptococcus, the Pht protein family comprises four members: PhtA, PhtB, PhtD and PhtE. This family has the potential to provide a protein candidate for incorporation in pneumococcal vaccines. Based on sequence analysis and on RT-PCR experiments, we show here that the pht genes are organized in tandem but that their expression, except that of phtD, is monocistronic. PhtD, PhtE, PhtB and PhtA are present in 100, 97, 81 and 62 % of the strains, respectively, and, by analysing its sequence conservation across 107 pneumococcal strains, we showed that PhtD displays very little variability. To analyse the physiological function of these proteins, several mutants were constructed. The quadruple Pht-deficient mutant was not able to grow in a poor culture medium, but the addition of Zn(2+) or Mn(2+) restored its growth capacity. Moreover, the phtD mRNA expression level increased when the culture medium was depleted in zinc. Therefore, we suggest that these proteins are zinc and manganese scavengers, and are able to store these metals and to release them when the bacterium faces an ion-restricted environment. The data also showed that this protein family, and more particularly PhtD, is a promising candidate to be incorporated into pneumococcal vaccines. PMID- 20966094 TI - Escherichia coli mhpR gene expression is regulated by catabolite repression mediated by the cAMP-CRP complex. AB - The expression of the mhp genes involved in the degradation of the aromatic compound 3-(3-hydroxyphenyl)propionic acid (3HPP) in Escherichia coli is dependent on the MhpR transcriptional activator at the Pa promoter. This catabolic promoter is also subject to catabolic repression in the presence of glucose mediated by the cAMP-CRP complex. The Pr promoter drives the MhpR independent expression of the regulatory gene. In vivo and in vitro experiments have shown that transcription from the Pr promoter is downregulated by the addition of glucose and this catabolic repression is also mediated by the cAMP CRP complex. The activation role of the cAMP-CRP regulatory system was further investigated by DNase I footprinting assays, which showed that the cAMP-CRP complex binds to the Pr promoter sequence, protecting a region centred at position -40.5, which allowed the classification of Pr as a class II CRP dependent promoter. Open complex formation at the Pr promoter is observed only when RNA polymerase and cAMP-CRP are present. Finally, by in vitro transcription assays we have demonstrated the absolute requirement of the cAMP-CRP complex for the activation of the Pr promoter. PMID- 20966095 TI - AbaA and WetA govern distinct stages of Aspergillus fumigatus development. AB - The opportunistic human pathogen Aspergillus fumigatus produces a massive number of asexual spores (conidia) as the primary means of dispersal, survival, genome protection and infection of hosts. In this report, we investigate the functions of two developmental regulators, AfuAbaA and AfuWetA, in A. fumigatus. The AfuabaA gene is predicted to encode an ATTS/TEA DNA-binding domain protein and is activated by AfuBrlA during the middle stage of A. fumigatus asexual development (conidiation). The deletion of AfuabaA results in the formation of aberrant conidiophores exhibiting reiterated cylinder-like terminal cells lacking spores. Furthermore, the absence of AfuabaA causes delayed autolysis and cell death, whereas the overexpression of AfuabaA accelerates these processes, indicating an additional role for AfuAbaA. The AfuwetA gene is sequentially activated by AfuAbaA in the late phase of conidiation. The deletion of AfuwetA causes the formation of defective spore walls and a lack of trehalose biogenesis, leading to a rapid loss of spore viability and reduced tolerance to various stresses. This is the first report to demonstrate that WetA is essential for trehalose biogenesis in conidia. Moreover, the absence of AfuwetA causes delayed germ-tube formation and reduced hyphal branching, suggesting a role of AfuWetA in the early phase of fungal growth. A genetic model depicting the regulation of conidiation in A. fumigatus is proposed. PMID- 20966096 TI - Deletion of the histone-like protein (Hlp) from Mycobacterium smegmatis results in increased sensitivity to UV exposure, freezing and isoniazid. AB - Adaptation to environmental stress is an important survival characteristic of any bacterial species. As a soil-dwelling saprophyte, Mycobacterium smegmatis is exposed to factors such as UV light and rounds of freezing and thawing that occur in temperate climates. Numerous studies in Escherichia coli have linked histone like proteins to stress resistance and adaptation. We hypothesized that the 'histone-like' protein Hlp might likewise be involved in the stress response of M. smegmatis. The hlp gene was inactivated and the M. smegmatis Deltahlp strain was found to be more susceptible to UV light and to the stress created by repeated cycles of freezing and thawing. In addition, loss of Hlp altered the colony morphology and allowed the organism to grow dispersed in the absence of a detergent, suggesting changes in the cell wall composition. As cell wall changes could affect permeability to certain antibiotics, the susceptibility of M. smegmatis Deltahlp to kanamycin, rifamipicin, ethambutol and isoniazid (INH) was tested. M. smegmatis Deltahlp was more susceptible to INH, but loss of Hlp did not affect susceptibility to the other antibiotics tested. This suggests that the increased sensitivity of M. smegmatis Deltahlp to INH was unlikely to be the result of alterations in cell permeability. PMID- 20966097 TI - Characterization of a broad-specificity non-haem iron N-demethylase from Pseudomonas putida CBB5 capable of utilizing several purine alkaloids as sole carbon and nitrogen source. AB - N-Demethylation of many xenobiotics and naturally occurring purine alkaloids such as caffeine and theobromine is primarily catalysed in higher organisms, ranging from fungi to mammals, by the well-studied membrane-associated cytochrome P450s. In contrast, there is no well-characterized enzyme for N-demethylation of purine alkaloids from bacteria, despite several reports on their utilization as sole source of carbon and nitrogen. Here, we provide what we believe to be the first detailed characterization of a purified N-demethylase from Pseudomonas putida CBB5. The soluble N-demethylase holoenzyme is composed of two components, a reductase component with cytochrome c reductase activity (Ccr) and a two-subunit N-demethylase component (Ndm). Ndm, with a native molecular mass of 240 kDa, is composed of NdmA (40 kDa) and NdmB (35 kDa). Ccr transfers reducing equivalents from NAD(P)H to Ndm, which catalyses an oxygen-dependent N demethylation of methylxanthines to xanthine, formaldehyde and water. Paraxanthine and 7-methylxanthine were determined to be the best substrates, with apparent K(m) and k(cat) values of 50.4+/-6.8 MUM and 16.2+/ 0.6 min(-1), and 63.8+/-7.5 MUM and 94.8+/-3.0 min(-1), respectively. Ndm also displayed activity towards caffeine, theobromine, theophylline and 3-methylxanthine, all of which are growth substrates for this organism. Ndm was deduced to be a Rieske [2Fe-2S]-domain-containing non-haem iron oxygenase based on (i) its distinct absorption spectrum and (ii) significant identity of the N-terminal sequences of NdmA and NdmB with the gene product of an uncharacterized caffeine demethylase in P. putida IF-3 and a hypothetical protein in Janthinobacterium sp. Marseille, both predicted to be Rieske non-haem iron oxygenases. PMID- 20966098 TI - Mortality of doctors in Taiwan. AB - BACKGROUND: Working in clinical practice involves exposure to many hazards, resulting in ongoing concerns regarding mortality in doctors when compared with the general public. AIMS: To evaluate the survival data of all Taiwanese doctors and to ascertain whether doctors experience premature mortality. METHODS: Death and census data from 1990 to 2006 were obtained for all practising doctors in Taiwan. Cause-specific standardized mortality ratios (SMRs) were calculated via the Life Table Analysis System using the general population of Taiwan as the reference. RESULTS: All the SMRs of different medical specialties were below 0.34. Doctors in Taiwan were found to be less likely to die from all causes, including suicide and drug abuse. The SMRs for suicide and drug abuse were generally below 0.50 [SMR = 0.14, 95% confidence interval (CI) 0.09-0.21 and SMR = 0.16, 95% CI 0.07-0.32, respectively]. CONCLUSIONS: The risks of all-cause and cause-specific mortality of doctors were found to be lower than those of the general population in Taiwan. PMID- 20966099 TI - Work-related stress case definitions and prevalence rates in national surveys. AB - BACKGROUND: There is concern about lack of consistency in the design of case definitions used to measure work-related stress in national workforce surveys and the implications of this for the reliability and validity of prevalence estimates as well as for developments in policy and practice on tackling work-related stress. AIMS: To examine associations between case definitions used for the measurement of work-related stress in nationally representative workforce surveys and the prevalence rates generated. METHODS: The study focused on 18 nationally representative workforce surveys conducted between 1995 and 2008 that involved British samples. The published report from each survey was scrutinized for evidence of the case definition used to measure work-related stress and the associated prevalence rate. RESULTS: Several types of case definition were identified that differed in terms of their theoretical basis, structure, and content. Each was associated with a unique range of prevalence rates. CONCLUSIONS: The results illustrate the challenge presented to the production of valid and reliable estimates of the scale of work-related stress by inconsistent case definition design. The imperative for theory-based consistency in the design of case definitions used for the measurement of work-related stress in national workforce surveys is highlighted. PMID- 20966100 TI - Nonrandom survival of gene conversions among yeast ribosomal proteins duplicated through genome doubling. AB - By comparing the patterns of evolution in the coding and upstream noncoding regions of yeast ribosomal protein (RP) genes duplicated in a genome duplication, we find that although nonsynonymous sites in the coding sequences show strong evidence for the fixation of recent gene conversion events, similar patterns are less evident among the synonymous positions and noncoding regulatory elements. This result suggests a potential explanation for the somewhat puzzling fact that duplicated RP genes are not functionally redundant despite their very high protein sequence identity. An analysis of the patterns of regulatory network evolution after genome duplication also indicates that the duplicated proteins have diverged considerably in expression despite their similar protein sequences. PMID- 20966101 TI - Musculoskeletal pain is associated with incident mobility disability in community dwelling elders. AB - BACKGROUND: Identifying mobility disability risk factors may facilitate development of interventions promoting functional independence in older persons. We tested the hypothesis that musculoskeletal pain is associated with first occurrence of severe mobility disability. METHODS: In a prospective observational study at 40 community-based sites, 759 older Catholic clergy in the Rush Religious Orders Study without baseline dementia, stroke, Parkinson's disease, or severe performance-based mobility disability (defined as gait speed less than or equal to 0.4 m/s) and at least one follow-up mobility evaluation were evaluated over a mean of 8.5 (SD = 3.8) years. All participants were queried about musculoskeletal pain in the year before baseline and underwent annual assessment of mobility. RESULTS: Using a proportional hazards model adjusted for age, sex, and education, the hazard for incident severe mobility disability was greater for participants reporting pain in the year before baseline (odds ratio = 1.47, 95% confidence interval = 1.17-1.85). Results were unchanged after adjusting for self reported mobility disability, gait speed, depressive symptoms, body mass index, physical activity, chronic medical conditions, and analgesic use. Compared with no report of musculoskeletal pain, musculoskeletal pain in one or two areas was associated with a 30% greater hazard for incident disability (odds ratio = 1.31, 95% confidence interval = 1.00-1.70). Musculoskeletal pain in three or more areas was associated with an 80% greater hazard for incident disability (odds ratio = 1.80, 95% confidence interval = 1.31-2.47). In participants without baseline self reported mobility disability (n = 486), musculoskeletal pain was associated with greater hazard for incident self-reported mobility disability (odds ratio = 1.38, 95% confidence interval = 1.11-1.73). CONCLUSION: In older persons, musculoskeletal pain is associated with incident mobility disability. PMID- 20966102 TI - Maximum shell size, growth rate, and maturation age correlate with longevity in bivalve molluscs. AB - Bivalve molluscs are newly discovered models of successful aging, and this invertebrate group includes Arctica islandica, with the longest metazoan life span. Despite an increasing biogerontological focus on bivalves, their life history traits in relation to maximum age are not as comprehensively understood as those in vertebrate model aging organisms. We explore the allometric scaling of longevity and the relationship between development schedules (time to maturity and growth rate) and longevity in the Bivalvia. Using a traditional nonphylogenetic approach and the phylogenetically independent contrasts method, the relationship among these life history parameters is analyzed. It is demonstrated that in bivalves, maximum shell size, development, and growth rates all associate with longevity. Our findings support the observations of life history patterns in mammals and fish. This is the first investigation into the relationship among longevity, size, and development schedules throughout this group, and the results strengthened by the control for phylogenetic independence. PMID- 20966103 TI - The functional ACTN3 577X variant increases the risk of falling in older females: results from two large independent cohort studies. AB - BACKGROUND: Falls among elderly people is a major issue in public health, causing debilitating outcomes including fracture. The identification of genetic risk factors for falling may provide a strategy for effectively targeting falls prevention programs. We investigated whether a common functional variant of skeletal muscle alpha-actinin-3 (ACTN3 p. R577X) previously associated with impairments in muscle strength, power, and physical functioning represents a risk factor for falls. METHODS: Case-control analysis was conducted using two large cohorts of Caucasian postmenopausal women--the North of Scotland Osteoporosis Study (n = 1,245) and the Aberdeen Prospective Osteoporosis Screening Study (n = 2,918)--for whom self-reported falls status and DNA samples were available. Cross sectional analysis of fallers versus nonfallers at baseline and follow-up was performed. In addition, individuals who reported having fallen at more than one timepoint (recurrent fallers) were compared with those who reported not falling at any timepoint. RESULTS: Association between R577X genotype and falls was identified and validated. Carriage of 577X (one or two copies) was significantly associated with a 33% (10%-61%) increased risk of falling, with the effect apparent at both baseline and follow-up assessments (meta-analysis p = .003 and p = .02, respectively). No significant effect on recurrent falls was observed. CONCLUSION: This study reports for the first time that the functional ACTN3 R577X genotype represents a genetic risk factor for falling in older females. PMID- 20966104 TI - Interactions between critical health system functions and HIV/AIDS, tuberculosis and malaria programmes. PMID- 20966105 TI - A conceptual and analytical approach to comparative analysis of country case studies: HIV and TB control programmes and health systems integration. AB - Attempts to comparatively analyse large-scale communicable disease control programmes have, for the most part, neglected the wider health system contexts within which the programmes lie. In addition, many evaluations of the integration of vertical disease control programmes into health systems have focused on single case studies or on a limited number of cases, or, when large numbers of cases were drawn upon, have been presented as a compendium of monographs rather than a systematic cross-national comparison. One reason for this may be that appropriate theories and tools for comparative health systems analysis are rare and difficult to formulate. In this paper we propose a conceptual framework and an analytical methodology which might be used to comparatively analyse a series of case studies that explore health systems, communicable diseases programmes and concepts of integration in order to make systematic comparisons to offer novel insights, to test new theories and to offer new hypotheses. We illustrate through a preliminary analysis how this framework can be applied to compare the impact of health systems integration and HIV and TB programmes in four countries in South East Asia that were the subject of cases studies. PMID- 20966106 TI - Integration of health systems and priority health interventions: a case study of the integration of HIV and TB control programmes into the general health system in Vietnam. AB - This case study on Vietnam aims to generate empirical evidence on the relative merits of integration of two priority health interventions, HIV/AIDS and tuberculosis (TB), into six functions of the wider health system: stewardship and governance, service delivery, demand generation, monitoring and evaluation, planning, and financing. Selective documentary reviews and 25 qualitative, semi structured interviews were conducted in early 2009 in Hanoi, Hai Duong province, Chih Linh district and Hoang Tien commune with informants from international, national and sub-national agencies steering or managing the HIV/AIDS and TB programmes and from health facilities providing HIV/AIDS and TB services. Data collected were collated and evaluated against 25 elements of integration. Each element of integration was ultimately classified as being 'fully/predominantly integrated', 'partially integrated', 'not or predominantly not integrated'. The results showed that none of the six programme functions was fully integrated into the general health care system as a whole. They were established either in parallel, notably at higher administrative levels, or were partially integrated. The study findings also revealed that little integration across all functional levels has occurred between the two programmes. Generally international agencies and sub-national domestic stakeholders supported more integration between vertical programmes (HIV and TB) and the general health systems, while national bodies responsible for HIV and TB favoured reinforcing a more vertical and thus less integrated approach. In the absence of shared assumptions and goals, this polarization of views may result in sub-optimal effectiveness and efficiency of each of the disease programmes as well as of HIV/TB interventions. PMID- 20966107 TI - Critical interactions between Global Fund-supported programmes and health systems: a case study in Lao People's Democratic Republic. AB - In Lao PDR, investment by the Global Fund to Fight AIDS, Tuberculosis and Malaria has played an important role in scaling up the response to HIV and tuberculosis (TB). As part of a series of case studies on how Global Fund-supported programmes interact with national health systems, we assessed the nature and extent of integration of the Global Fund portfolios within the national HIV and TB programmes, the integration of the HIV and TB programmes within the general health system, and system-wide effects of Global Fund support in Lao PDR. The study relied on a literature review and 35 interviews with key stakeholders using the Systemic Rapid Assessment Toolkit and thematic analysis. In Lao PDR, the HIV and TB programmes remain vertical and mostly weakly integrated with the general health system. However, Global Fund investments have extended the network of facilities delivering care at local level, resulting in greater integration with primary care and improved access for patients, particularly for TB. For HIV, as the prevalence remains low, services primarily target high-risk groups in urban areas. Less integrated functions include procurement and drug supply, and monitoring and evaluation. HIV and TB programmes are only starting to coordinate with each other. Global Fund-supported activities are generally integrated within the national disease programmes, except for monitoring and evaluation. Synergies of Global Fund support with the health system include improved access to services, institutional strengthening and capacity building, improved family planning (with wider condom distribution through HIV/AIDS social marketing programmes), and the delivery of add-on interventions, such as vaccinations and health education, alongside Global Fund-supported interventions at community level. Unintended consequences concern the lack of alignment between national stated priorities (maternal and child health) and the strong focus of external partners, such as the Global Fund, on financing communicable disease programmes. PMID- 20966108 TI - Health systems, communicable diseases and integration. AB - The HIV/AIDS, tuberculosis and malaria pandemics pose substantial challenges globally and to health systems in the countries they affect. This demands an institutional approach that can integrate disease control programmes within health and social care systems. Whilst integration is intuitively appealing, evidence of its benefits remains uncertain and evaluation is beset by lack of a common understanding of what it involves. The aim of this paper is to better define integration in health systems relevant to communicable disease control. We conducted a critical review of published literature on concepts, definitions, and analytical and methodological approaches to integration as applied to health system responses to communicable disease. We found that integration is understood and pursued in many ways in different health systems. We identified a variety of typologies that relate to three fundamental questions associated with integration: (1) why is integration a goal (that is, what are the driving forces for integration); (2) what structures and/or functions at different levels of health system are affected by integration (or the lack of); and (3) how does integration influence interactions between health system components or stakeholders. The frameworks identified were evaluated in terms of these questions, as well as the extent to which they took account of health system characteristics, the wider contextual environment in which health systems sit, and the roles of key stakeholders. We did not find any one framework that explicitly addressed all of these three questions and therefore propose an analytical framework to help address these questions, building upon existing frameworks and extending our conceptualization of the 'how' of integration to identify a continuum of interactions that extends from no interactions, to partial integration that includes linkage and coordination, and ultimately to integration. We hope that our framework may provide a basis for future evaluations of the integration of programmes and health systems in the development of sustainable and effective responses to communicable diseases. PMID- 20966109 TI - Critical interactions between Global Fund-supported programmes and health systems: a case study in Indonesia. AB - The Global Fund to Fight AIDS, Tuberculosis and Malaria has played an important role in financing the response to HIV/AIDS and tuberculosis (TB) in Indonesia. As part of a series of case studies, we assessed the nature and extent of integration of Global Fund portfolios into the national HIV and TB programmes, integration of the HIV and TB programmes within the general health system, and system-wide effects of Global Fund support on the health care system in Indonesia. The study relied on a literature review and interviews with 22 key informants using the Systemic Rapid Assessment Toolkit and thematic analysis. Global Fund programmes in Indonesia are highly vertical and centralized, in contrast with the decentralized nature of the Indonesian health system. Consequently, there is more integration of all functions at local levels than centrally. There is a high level of integration of planning of Global Fund HIV and TB portfolios into the National AIDS and TB programmes and some limited integration of these programmes with other disease programmes, through joint working groups. Other synergies include strengthening of stewardship and governance and increased staff recruitment encouraged by incentive payments and training. Monitoring and evaluation functions of the Global Fund programmes are not integrated with the disease programmes, with parallel indicators and reporting systems. System-wide effects include greater awareness of governance and stewardship in response to the temporary suspension of Global Fund funding in 2008, and increased awareness of the need to integrate programme planning, financing and service delivery. Global Fund investment has freed up resources for other programmes, particularly at local levels. However, this may hinder a robust exit strategy from Global Fund funding. Furthermore, Global Fund monetary incentives may result in staff shifting into HIV and TB programmes. PMID- 20966110 TI - Critical interactions between Global Fund-supported programmes and health systems: a case study in Papua New Guinea. AB - In Papua New Guinea, investment by the Global Fund to Fight AIDS, Tuberculosis and Malaria (the Global Fund) has played an important role in scaling up the response to HIV and tuberculosis (TB). As part of a series of case studies on how Global Fund-supported programmes interact with national health systems, we assessed the nature and extent of integration of the Global Fund portfolios within the national HIV and TB programmes, the integration of the HIV and TB programmes within the general health system, and system-wide effects of Global Fund support in Papua New Guinea. The study relied on a literature review and 30 interviews with key stakeholders using the Systemic Rapid Assessment Toolkit and thematic analysis. Global Fund-supported activities were found to be largely integrated, or at least coordinated, with the national HIV and TB programmes. However, this has reinforced the vertical nature of these programmes with respect to the general health system, with parallel systems established to meet the demands of programme scale-up and the performance-based nature of Global Fund investment in the weak health system context of Papua New Guinea. The more parallel functions include monitoring and evaluation, and procurement and supply chain systems, while human resources and infrastructure for service delivery are increasingly integrated at more local levels. Positive synergies of Global Fund support include engagement of civil-society partners, and a reliable supply of high-quality drugs which may have increased patient confidence in the health system. However, the severely limited and overburdened pool of human resources has been skewed towards the three diseases, both at management and service delivery levels. There is also concern surrounding the sustainability of the disease programmes, given their dependence on donors. Increasing Global Fund attention towards health system strengthening was viewed positively, but should acknowledge that system changes are slow, difficult to measure and require long term support. PMID- 20966111 TI - Critical interactions between Global Fund-supported programmes and health systems: a case study in Thailand. AB - As part of a series of case studies on the interactions between programmes supported by the Global Fund to Fight AIDS, Tuberculosis and Malaria and health systems, we assessed the extent of integration of national HIV, tuberculosis (TB) and malaria programmes with the general health system, the integration of the Global Fund-portfolios within the national disease programmes, and system-wide effects on the health system in Thailand. The study relied on a literature review and 34 interviews with key stakeholders using the Systemic Rapid Assessment Toolkit and thematic analysis. In Thailand, the HIV, TB and malaria programmes' structures and functions are well established in the general health care system, with the Department for Disease Control and the Ministry of Public Health's network of health providers at sub-national levels as the main responsible organizations for stewardship and governance, service delivery, monitoring and evaluation, planning, and to some extent, demand generation. Civil society groups are active in certain areas, particularly in demand generation for HIV/AIDS. Overall, the Global Fund-supported programmes were almost fully integrated and coordinated with the general health system. The extent of integration varied across disease portfolios because of different number of actors and the nature of programme activities. There were also specific requirements by Global Fund that limit integration for some health system functions namely financing and monitoring and evaluation. From the view of stakeholders in Thailand, the Global Fund has contributed significantly to the three diseases, particularly HIV/AIDS. Financial support from the early Global Fund rounds was particularly helpful to the disease programmes during the time of major structural change in the MoPH. It also promoted collaborative networks of stakeholders, especially civil societies. However, the impacts on the overall health system, which is relatively well developed, are seen as minimal. One major contribution is the establishment of a health service system for neglected population groups. No specific negative impacts on the health system were raised. PMID- 20966112 TI - System-wide effects of Global Fund investments in Nepal. AB - Nepal, with a concentrated HIV epidemic and high burden of tuberculosis (TB) and malaria, was perceived to have immensely benefited from grants by the Global Fund to Fight AIDS, Tuberculosis and Malaria in addressing the three diseases, amounting to total approved funding of US$80 million. This paper looks at the interaction and integration of Global Fund-supported programmes and national health systems. A mixed method 'case study' approach based on the Systemic Rapid Assessment Toolkit (SYSRA) was used to systematically analyse across the main health systems functional domains. The Country Coordinating Mechanism has been credited with providing the stewardship in attracting additional resources and providing oversight. The involvement of civil society for delivering key HIV and malaria interventions targeting high-risk groups was perceived to be highly beneficial. TB and malaria services were found to be well integrated into the public health care delivery system, while HIV services targeting at-risk groups were often delivered using parallel structures. Political instability, absence of continuity in leadership and sub-optimal investments in health were together perceived to have led to fragmentation of financing and planning activities, especially in HIV the programme. The demand for timely programmatic and financial reporting for donor-supported programmes has contributed to the creation of parallel monitoring and evaluation structures, with missed opportunities for strengthening and utilizing the national health management information systems. PMID- 20966113 TI - Rosmarinic acid antagonized 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in MES23.5 dopaminergic cells. AB - Rosmarinic acid (RA) is a naturally occurring polyphenolic compound found in various plant families. We previously reported that RA exerted protective effects against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity through antioxidative properties. In this study, we investigated whether RA could prevent effects of 1 methyl-4-phenylpyridinium (MPP(+))-induced insult in MES23.5 dopamineric cells. 1 Methyl-4-phenylpyridinium treatment decreased cell viability and dopamine content, as well as caused apoptotic morphological changes. 1-Methyl-4 phenylpyridinium-induced mitochondrial dysfunction, indicated by inhibition of activity associated with mitochondrial respiratory chain complex I, suggested mitochondrial transmembrane potential collapse and generation of reactive oxygen species. Decreased Bcl-2/Bax ratio and caspase 3 activation were also observed. Rosmarinic acid pretreatment restored the complex I activity of the mitochondrial respiratory chain and partially reversed the other damaging effects of MPP(+). Our results indicate that RA plays a neuroprotective role by ameliorating mitochondrial dysfunction against MPP(+)-induced cell apoptosis and suggest that RA has the potential to be considered an aid for prevention of Parkinson's disease. PMID- 20966114 TI - Determining epidermal disposition kinetics for use in an integrated nonanimal approach to skin sensitization risk assessment. AB - Development of risk assessment methods for skin sensitization in the absence of toxicological data generated in animals represents a major scientific and technical challenge. The first step in human skin sensitization induction is the transport of sensitizer from the applied dose on the skin surface to the epidermis, where innate immune activation occurs. Building on the previous development of a time course in vitro human skin permeation assay, new kinetic data for 10 sensitizers and 2 nonsensitizers are reported. Multicompartmental modeling has been applied to analyze the data and determine candidate dose parameters for use in integrated risk assessment methods: the area under the curve (AUC) and maximum concentration (C(max)) in the epidermis. A model with two skin compartments, representing the stratum corneum and viable skin (epidermis and dermis), was chosen following a formal model selection process. Estimates of the uncertainty, as well as average values of the epidermal disposition kinetics parameters, were made by fitting to the time course skin permeation data from individual skin donors. A potential reduced time course method is proposed based on two time points at 4 and 24 h, which gives results close to those from the full time course for the current data sets. The time course data presented in this work have been provided as a resource for development of predictive in silico skin permeation models. PMID- 20966115 TI - Accelerated evolution of CES7, a gene encoding a novel major urinary protein in the cat family. AB - Cauxin is a novel urinary protein recently identified in the domestic cat that regulates the excretion of felinine, a pheromone precursor involved in sociochemical communication and territorial marking of domestic and wild felids. Understanding the evolutionary history of cauxin may therefore illuminate molecular adaptations involved in the evolution of pheromone-based communication, recognition, and mate selection in wild animals. We sequenced the gene encoding cauxin, CES7, in 22 species representing all major felid lineages, and multiple outgroups and showed that it has undergone rapid evolutionary change preceding and during the diversification of the cat family. A comparison between feline cauxin and orthologous carboxylesterases from other mammalian lineages revealed evidence of strong positive Darwinian selection within and between several cat lineages, enriched at functionally important sites of the protein. The higher rate of radical amino acid replacements in small felids, coupled with the lack of felinine and extremely low levels of cauxin in the urine of the great cats (Panthera), correlates with functional divergence of this gene in Panthera, and its putative loss in the snow leopard. Expression studies found evidence for several alternatively spliced transcripts in testis and brain, suggesting additional roles in male reproductive fitness and behavior. Our work presents the first report of strong positive natural selection acting on a major urinary protein of nonrodent mammals, providing evidence for parallel selection pressure on the regulation of pheromones in different mammalian lineages, despite the use of different metabolic pathways. Our results imply that natural selection may drive rapid changes in the regulation of pheromones in urine among the different cat species, which in turn may influence social behavior, such as territorial marking and conspecific recognition, therefore serving as an important mechanism for the radiation of this group of mammals. PMID- 20966116 TI - Genetic diversity of the allodeterminant alr2 in Hydractinia symbiolongicarpus. AB - Hydractinia symbiolongicarpus, a colonial cnidarian (class Hydrozoa) epibiont on hermit crab shells, is well established as a model for genetic studies of allorecognition. Recently, two linked loci, allorecognition (alr) 1 and alr2, were identified by positional cloning and shown to be major determinants of histocompatibility. Both genes encode putative transmembrane proteins with hypervariable extracellular domains similar to immunoglobulin (Ig)-like domains. We sought to characterize the naturally occurring variation at the alr2 locus and to understand the origins of this molecular diversity. We examined full-length cDNA coding sequences derived from a sample of 21 field-collected colonies, including 18 chosen haphazardly and two laboratory reference strains. Of the 35 alleles recovered from the 18 unbiased samples, 34 encoded unique gene products. We identified two distinct structural classes of alleles that varied over a large central region of the gene but both possessed highly polymorphic extracellular domains I, similar to an Ig-like V-set domain. The discovery of structurally chimeric alleles provided evidence that interallelic recombination may contribute to alr2 variation. Comparisons of the genomic region encompassing alr2 from two field-derived haplotypes and one laboratory reference sequence revealed a history of structural variation at the haplotype level as well. Maintenance of large numbers of equally rare alleles in a natural population is a hallmark of negative frequency-dependent selection and is expected to produce high levels of heterozygosity. The observed alr2 allelic diversity is comparable with that found in immune recognition molecules such as human leukocyte antigens, B cell Igs, or natural killer cell Ig-like receptors. PMID- 20966117 TI - Transcriptional network structure has little effect on the rate of regulatory evolution in yeast. AB - Studies in evolutionary developmental biology suggest that the structure of genetic pathways may bias the fixation of natural variation toward particular nodes in these pathways. In an attempt to test this trend genome wide, we integrated several previously published data sets to examine whether the position of genes in the whole-genome transcriptional network of Saccharomyces cerevisiae is associated with the amount of cis-regulatory expression divergence between S. cerevisiae and its sibling species Saccharomyces paradoxus. We find little evidence for an association between connectivity and divergence in the global network that combines data from multiple conditions. However, relationships between connectivity and divergence are apparent in some of the smaller subnetworks. Despite a slight tendency for genes with more transcriptional interactions to show greater divergence, these differences explain no more than a small fraction of variation in evolutionary rates. These results suggest that the systems biology focus on large interactomes may miss some critical details of local interactions. More detailed experimental analysis will be needed to define the genetic pathways that control specific phenotypic traits and quantify the rate of regulatory changes at different points in these pathways. PMID- 20966118 TI - Acquired cytoresistance in the setting of hematopoietic cell transplantation. AB - BACKGROUND AND OBJECTIVES: Pre-existent renal insufficiency is a widely accepted risk factor for superimposed renal damage (e.g., due to ischemia or nephrotoxic drug administration). However, both experimental renal injury and surgical ablation of renal mass in rodents confer protection against superimposed renal insults (the so-called "acquired cytoresistance" state). This study addressed whether baseline renal function is associated with either increased or decreased susceptibility to renal injury in patients undergoing hematopoietic cell transplantation (HCT), a procedure that is widely recognized to induce acute or subacute renal damage. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Estimated GFRs (eGFRs; Modification of Diet in Renal Disease formula) were assessed at baseline and approximately 1 year after HCT in 1216 patients who were transplanted at the Fred Hutchinson Cancer Center between 1991 and 2002. The frequency of a renal functional decline (arbitrarily defined, a priori, as >=25% loss of baseline eGFR) and absolute reductions in eGFR (in ml/min) were calculated. RESULTS: Both the frequency and degree of post-HCT eGFR reductions directly and linearly correlated with baseline eGFRs (range, 25 to 135 ml/min). Thus, the higher the baseline eGFR, the greater the risk and severity of subsequent loss of renal function (P < 0.0001). CONCLUSIONS: These data indicate that reduced baseline renal function is not necessarily a risk factor for post HCT renal functional declines. Rather, these observations support the concept that "acquired cytoresistance," as seen in experimental animals, may, under selected circumstances, be expressed in the clinical arena. PMID- 20966119 TI - Equations to estimate creatinine excretion rate: the CKD epidemiology collaboration. AB - BACKGROUND AND OBJECTIVES: Creatinine excretion rate (CER) indicates timed urine collection accuracy. Although equations to estimate CER exist, their bias and precision are untested and none simultaneously include age, sex, race, and weight. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Participants (n = 2466) from three kidney disease trials were randomly allocated into equation development (2/3) and internal validation (1/3) data sets. CER served as the dependent variable in linear regression to develop new equations. Their stability was assessed within the internal validation data set. Among 987 individuals from three additional studies the equations were externally validated and compared with existing equations. RESULTS: Mean age was 46 years, 42% were women, and 9% were black. Age, sex, race, weight, and serum phosphorus improved model fit. Two equations were developed, with or without serum phosphorus. In external validation, the new equations showed little bias (mean difference [measured - estimated CER] -0.7% [95% confidence interval -2.5% to 1.0%] and 0.3% [95% confidence interval -2.6% to 3.1%], respectively) and moderate precision (estimated CER within 30% of measured CER among 79% [76% to 81%] and 81% [77% to 85%], respectively). Corresponding numbers within 15% were 51% [48% to 54%] and 54% [50% to 59%]). Compared with existing equations, the new equations had similar accuracy but showed less bias in individuals with high measured CER. CONCLUSIONS: CER can be estimated with commonly available variables with little bias and moderate precision, which may facilitate assessment of accuracy of timed urine collections. PMID- 20966120 TI - Hyperfiltration affects accuracy of creatinine eGFR measurement. AB - BACKGROUND AND OBJECTIVES: Surrogate markers such as creatinine, cystatin C (CysC), and beta trace protein (BTP) have been used to estimate GFR (eGFR). The accuracy of eGFR may be altered with hyperfiltration and differences in filtration fraction (FF). It is hypothesized that the accuracy of creatinine for eGFR may be affected by hyperfiltration and different effective renal plasma flow (ERPF). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 127 pediatric patients with various renal diseases underwent simultaneous measurements of GFR using 51Cr-EDTA renal scan and ERPF (131I-hippurate clearance) to calculate the FF (FF=GFR/ERPF). The eGFRs were calculated using the commonly used Schwartz (creatinine), Filler (CysC), and Benlamri (BTP) formulas. Agreement of the eGFRs with the measured isotope GFRs was assessed by Bland-Altman plots. Correlation analysis was performed using nonparametric tests to compare FF with eGFR-GFR. RESULTS: The 127 children at a median age (with 25th percentile, 75th percentile) of 11.9 (8.5, 14.9) years had a mean 51Cr EDTA-GFR of 100.6+/-32.1 ml/min per 1.73 m2 and a median 131I-hippurate clearance (ERPF) of 588 (398,739) ml/min per 1.73 m2. Mean FF was 17.7+/-4.5% with no correlation between the FF and the error (eGFR-GFR) for CysC and BTP eGFR, whereas there was a significant negative correlation between the error for Schwartz eGFR and FF. CONCLUSIONS: There is a significant negative correlation between the error for the Schwartz eGFR and the FF. CysC and BTP are not affected by differences in FF. PMID- 20966121 TI - The associations of social support and other psychosocial factors with mortality and quality of life in the dialysis outcomes and practice patterns study. AB - BACKGROUND AND OBJECTIVES: This study aimed to investigate the influence of social support and other psychosocial factors on mortality, adherence to medical care recommendations, and physical quality of life among hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data on 32,332 hemodialysis patients enrolled in the Dialysis Outcomes and Practice Patterns Study (1996 to 2008) in 12 countries were analyzed. Social support and other psychosocial factors related to ESRD and its treatment were measured by patient self-reports of health interference with social activities, isolation, feeling like a burden, and support from family and dialysis staff. Cox regression and logistic regression were used to examine associations of baseline social support and other psychosocial factors with all-cause mortality and with other measured outcomes at baseline, adjusting for potential confounders. RESULTS: Mortality was higher among patients reporting that their health interfered with social activities, were isolated, felt like a burden, and were dissatisfied with family support. Poorer family support and several psychosocial measures also were associated with lower adherence to the prescribed hemodialysis length and the recommended weight gain between sessions. Some international differences were observed. Poorer self reported social support and other psychosocial factors were associated with poor physical quality of life. CONCLUSIONS: Poorer social support and other psychosocial factors are associated with higher mortality risk, lower adherence to medical care, and poorer physical quality of life in hemodialysis patients. More research is needed to assess whether interventions to improve social support and other psychosocial factors will lengthen survival and enhance quality of life. PMID- 20966122 TI - FGF-23 as a predictor of renal outcome in diabetic nephropathy. AB - BACKGROUND AND OBJECTIVES: Fibroblast growth factor 23 (FGF-23) has emerged as a new factor in mineral metabolism in chronic kidney disease (CKD). An important regulator of phosphorus homeostasis, FGF-23 has been shown to independently predict CKD progression in nondiabetic renal disease. We analyzed the relation between FGF-23 and renal outcome in diabetic nephropathy (DN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: DN patients participating in a clinical trial (enalapril+placebo versus enalapril+losartan) had baseline data collected and were followed until June 2009 or until the primary outcome was reached. Four patients were lost to follow-up. The composite primary outcome was defined as death, doubling of serum creatinine, and/or dialysis need. RESULTS: At baseline, serum FGF-23 showed a significant association with serum creatinine, intact parathyroid hormone, proteinuria, urinary fractional excretion of phosphate, male sex, and race. Interestingly, FGF-23 was not related to calcium, phosphorus, 25OH vitamin D, or 24-hour urinary phosphorus. Mean follow-up time was 30.7+/-10 months. Cox regression showed that FGF-23 was an independent predictor of the primary outcome, even after adjustment for creatinine clearance and intact parathyroid hormone (10 pg/ml FGF-23 increase = hazard ratio, 1.09; 95% CI, 1.01 to 1.16, P=0.02). Finally, Kaplan-Meier analysis showed a significantly higher risk of the primary outcome in patients with FGF-23 values of >70 pg/ml. CONCLUSIONS: FGF-23 is a significant independent predictor of renal outcome in patients with macroalbuminuric DN. Further studies should clarify whether this relation is causal and whether FGF-23 should be a new therapeutic target for CKD prevention. PMID- 20966123 TI - Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. AB - Circulating permeability factors may be important in idiopathic nephrotic syndrome (INS) including focal segmental glomerulosclerosis (FSGS) and in recurrence after renal transplantation. Evidence for plasma factors includes posttransplant recurrence of proteinuria and its response to plasmapheresis or immunoadsorption and induction of proteinuria in experimental animals by infusion of patient plasma or its fractions. The authors and other investigators have used proteomic techniques to seek pathogenic molecules. The authors have recently proposed cardiotrophin-like cytokine-1 (CLC-1) as an active factor in FSGS. Other potential permeability factors include hemopexin and vascular permeability factor in minimal change nephrotic syndrome (MCNS) and soluble urokinase receptor in FSGS. In the authors' studies, in vitro plasma permeability activity is blocked by diverse substances that may decrease levels of active molecules or block the effects of circulating permeability factors. It has been shown that the simple sugar galactose blocks the effect of FSGS serum on albumin permeability in vitro and decreases permeability activity when administered to patients. Because identities of permeability factors and their mechanisms of action are not well defined, therapy of INS/FSGS is empiric. Corticosteroids are the mainstay of initial therapy whereas calcineurin inhibitors such as cyclosporine A (CsA) and immunosuppressive medications provide adjunctive therapy. Nonspecific therapies such as blocking the renin-angiotensin system and controlling blood pressure and plasma lipids may also diminish proteinuria and slow progression. Identification of molecules that initiate proteinuria and application of findings from in vitro studies may lead to development of new treatments to arrest progression and prevent recurrence after transplantation. PMID- 20966125 TI - ASNA-1 activity modulates sensitivity to cisplatin. AB - Cancer can be cured by platinum-based chemotherapy, but resistance is a major cause of treatment failure. Here we present the nematode Caenorhabditis elegans as a model to study interactions between the platinum drug cisplatin and signaling pathways in vivo. Null mutation in a single gene, asna-1, makes worms hypersensitive to cisplatin. The metalloregulated ATPase ASNA-1 promotes insulin secretion and membrane insertion of tail-anchored proteins. Using structural data from ASNA-1 homologues, we identify specific ASNA-1 mutants that are sensitive to cisplatin while still able to promote insulin signaling. Mutational analysis reveals that hypersensitivity of ASNA-1 mutants to cisplatin remains in absence of CEP-1/p53 or apoptosis. Human ASNA1 can substitute for the worm gene, indicating a conserved function. Cisplatin sensitivity is not affected by decreased insulin signaling in wild-type nematodes or restored insulin signaling in asna-1 mutants. These findings provide a functional insight into ASNA-1, demonstrate that C. elegans can be used to characterize cisplatin resistance mechanisms, and suggest that rationally designed drugs against ASNA-1 can sensitize cancer cells to cisplatin. PMID- 20966124 TI - Thrombotic microangiopathy and peritubular capillary C4d expression in renal allograft biopsies. AB - BACKGROUND AND OBJECTIVES: This study characterizes the pathologic and clinical relationships of thrombotic microangiopathy (TMA) to antibody-mediated rejection (AMR) in renal allograft biopsies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Consecutive renal allograft biopsies, routinely stained for C4d over a period of 51 months (n=1101), were reviewed. For comparative analysis of histology and clinical features, additional patients with TMA and peritubular capillary (PTC) C4d (n=5) were combined with those identified in the 51-month period of review (n=6). RESULTS: One hundred eighty-two of 1073 adequate biopsies from 563 allografts had PTC C4d in the study period. Six of 37 biopsies with TMA had PTC C4d (five at <=90 days and one at 213 days). Early (<=90 days) C4d+ biopsies (n=5) had more frequent TMA (11.9% C4d+ versus 3.4% C4d-; odds ratio, 3.84; P=0.03). Graft loss was significantly greater in an early C4d+TMA+ group (n=5 study+2 archival patients) than in C4d+ controls without TMA (n=21) (57% versus 9.5%; P=0.02). Early TMA+C4d+ biopsies had more severe glomerulopathy and less severe arteriolopathy than TMA+C4d- and had more frequent neutrophilic capillaritis than TMA-C4d+ biopsies. CONCLUSIONS: TMA was infrequent in this series of unselected, consecutive, renal allograft biopsies (3.4%). PTC C4d may be a significant risk factor for early TMA, and TMA is associated with glomerular thrombi and neutrophilic capillaritis. TMA in allografts with suspected AMR may portend a higher risk of graft loss. PMID- 20966126 TI - XMRV: a new virus in prostate cancer? AB - Several recent articles have reported the presence of a gammaretrovirus, termed "XMRV" (xenotropic murine leukemia virus-related virus) in prostate cancers (PCa). If confirmed, this could have enormous implications for the detection, prevention, and treatment of PCa. However, other articles report failure to detect XMRV in PCa. We tested nearly 800 PCa samples, using a combination of real time PCR and immunohistochemistry (IHC). The PCR reactions were simultaneously monitored for amplification of a single-copy human gene, to confirm the quality of the sample DNA and its suitability for PCR. Controls showed that the PCR assay could detect the XMRV in a single infected cell, even in the presence of a 10,000 fold excess of uninfected human cells. The IHC used 2 rabbit polyclonal antisera, each prepared against a purified murine leukemia virus (MLV) protein. Both antisera always stained XMRV-infected or -transfected cells, but never stained control cells. No evidence for XMRV in PCa was obtained in these experiments. We discuss possible explanations for the discrepancies in the results from different laboratories. It is possible that XMRV is not actually circulating in the human population; even if it is, the data do not seem to support a causal role for this virus in PCa. PMID- 20966127 TI - A multi-marker approach to predict incident CKD and microalbuminuria. AB - Traditional risk factors do not adequately identify individuals at risk for CKD. We related a multi-marker panel consisting of the following seven circulating biomarkers to the incidence of CKD and microalbuminuria (MA) in 2345 participants who attended the sixth Framingham Offspring Study examination (1995 to 1998): C reactive protein, aldosterone, renin, B-type natriuretic peptide (BNP), plasminogen-activator inhibitor type 1, fibrinogen, and homocysteine. We defined CKD at follow-up (2005 to 2008) as estimated GFR (eGFR) <60 ml/min per 1.73 m2; we defined MA as urine albumin-to-creatinine ratio >=25 (women) or 17 (men) mg/g on spot urine samples. We identified a parsimonious set of markers related to outcomes adjusting for standard risk factors and baseline renal function, and we assessed their incremental predictive utility. During a mean 9.5-year follow-up, 213 participants developed CKD and 186 developed MA. In multivariable logistic regression models, the multi-marker panel was associated with incident CKD (P < 0.001) and MA (P = 0.003). Serum homocysteine and aldosterone both were significantly associated with CKD incidence, and log-transformed aldosterone, BNP, and homocysteine were significantly associated with incident MA. Biomarkers improved risk prediction as measured by improvements in the c-statistics for both CKD and MA and by a 7% increase in net risk reclassification. In conclusion, circulating homocysteine, aldosterone, and BNP provide incremental information regarding risk for incident CKD and MA beyond traditional risk factors. PMID- 20966128 TI - Pendrin modulates ENaC function by changing luminal HCO3-. AB - The epithelial Na(+) channel, ENaC, and the Cl(-)/HCO(3)(-) exchanger, pendrin, mediate NaCl absorption within the cortical collecting duct and the connecting tubule. Although pendrin and ENaC localize to different cell types, ENaC subunit abundance and activity are lower in aldosterone-treated pendrin-null mice relative to wild-type mice. Because pendrin mediates HCO(3)(-) secretion, we asked if increasing distal delivery of HCO(3)(-) through a pendrin-independent mechanism "rescues" ENaC function in pendrin-null mice. We gave aldosterone and NaHCO(3) to increase pendrin-dependent HCO(3)(-) secretion within the connecting tubule and cortical collecting duct, or gave aldosterone and NaHCO(3) plus acetazolamide to increase luminal HCO(3)(-) concentration, [HCO(3)(-)], independent of pendrin. Following treatment with aldosterone and NaHCO(3), pendrin-null mice had lower urinary pH and [HCO(3)(-)] as well as lower renal ENaC abundance and function than wild-type mice. With the addition of acetazolamide, however, acid-base balance as well as ENaC subunit abundance and function was similar in pendrin-null and wild-type mice. We explored whether [HCO(3)(-)] directly alters ENaC abundance and function in cultured mouse principal cells (mpkCCD). Amiloride-sensitive current and ENaC abundance rose with increased [HCO(3)(-)] on the apical or the basolateral side, independent of the substituting anion. However, ENaC was more sensitive to changes in [HCO(3)( )] on the basolateral side of the monolayer. Moreover, increasing [HCO(3)(-)] on the apical and basolateral side of Xenopus kidney cells increased both ENaC channel density and channel activity. We conclude that pendrin modulates ENaC abundance and function, at least in part by increasing luminal [HCO(3)(-)] and/or pH. PMID- 20966129 TI - Smoking prevalence in the European Union: a comparison of national and transnational prevalence survey methods and results. AB - OBJECTIVES: To determine whether the European Commission Eurobarometer survey of 27 European Union (EU) member states produces reliable smoking prevalence estimates when compared to national prevalence survey data, and to identify approaches to standardising the measurement of smoking prevalence in the EU. METHODS: This was a direct comparison of questions, sampling methods and smoking prevalence estimates, between the 2006 Eurobarometer study and contemporaneous national surveys. All 27 EU member states were included. Participants were people surveyed in the 2006 Eurobarometer study and in various national surveys in the closest year to 2006 for which data were available. The main outcome measures were the mean and range of differences in prevalence estimates between the Eurobarometer and national surveys. RESULTS: Most national surveys used similar multistage sampling methods and involved sample sizes of 3000 or more, but the phrasing of the questions used to define smoking, the inclusion or exclusion of occasional smokers, the age ranges of participants and the frequency of national surveys varied substantially between countries. The Eurobarometer study used the same questions in all countries but in sample sizes of 1000, or in 3 countries, 500. Eurobarometer 2006 smoking prevalence estimates were on average 0.37 percentage points higher than those in national surveys, but with a 95% range from -10.49 to +11.23 percentage points. At the extremes, the equivalent national prevalence estimate for Slovakia was 13.0% higher and for the UK 10.0% lower than the Eurobarometer figure. CONCLUSIONS: Measurements of the prevalence of smoking, the biggest avoidable public health threat in the European Union, are highly discrepant within countries between national and European Commission survey estimates. Monitoring national smoking prevalence on a regular basis, using standardised methods in representative population samples, is an urgent priority for the EU. PMID- 20966131 TI - Tobacco control and the epidemiological framework. PMID- 20966130 TI - Covering their butts: responses to the cigarette litter problem. AB - BACKGROUND: Cigarette butt litter is a potential target of tobacco control. In addition to its toxicity and non-biodegradability, it can justify environmental regulation and policies that raise the price of tobacco and further denormalise its use. This paper examines how the tobacco industry has managed the cigarette butt litter issue and how the issue has been covered in the media. METHODS: We searched the Legacy Tobacco Documents Library (http://legacy.library.ucsf.edu/) using a snowball strategy. We analysed data from approximately 700 documents, dated 1959-2006, using an interpretive approach. We also searched two newspaper databases, Lexis/Nexis and Newsbank, and found 406 relevant articles, dated 1982 2009 which we analysed quantitatively and qualitatively. RESULTS: The tobacco industry monitored and developed strategies for dealing with the cigarette litter issue because it affected the social acceptability of smoking, created the potential for alliances between tobacco control and environmental advocates, and created a target for regulation. The industry developed anti-litter programs with Keep America Beautiful (KAB) and similar organisations. Media coverage focused on industry-acceptable solutions, such as volunteer clean-ups and installation of ashtrays; stories that mentioned KAB were also more frequently positive towards the tobacco industry. Among alternative approaches, clean outdoor air (COA) laws received the most media attention. CONCLUSIONS: Cigarette litter, like secondhand smoke, is the result of smoker behaviour and affects nonsmokers. The tobacco industry has tried and failed to mitigate the impact of cigarette litter. Tobacco control advocates should explore alliances with environmental groups and propose policy options that hold the industry accountable for cigarette waste. PMID- 20966132 TI - YouTube as a source of quitting smoking information. AB - OBJECTIVE: To conduct analyses to determine the extent to which YouTube videos posted specific to smoking cessation were actually about quitting smoking and if so, whether or not they portrayed evidence-based practices (EBPs). METHODS: In August 2008, researchers identified YouTube videos by search strategies, 'relevance' and 'view count' using the following three search terms: 'stop smoking', 'quit smoking' and 'smoking cessation (n=296 for full sample and n=191 for unique videos). RESULTS: Overall, almost 60% of videos contained a message about quitting smoking. Differences were found across search terms for videos about quitting smoking, with 'stop smoking' yielding the highest percentage (80.8%) of videos about quitting smoking. Almost half of the videos (48.9%) contained EBPs for cessation strategies; however, a significant portion contained either non--EBPs (28.4%) or both EBPs and non-EBPs (22.7%). The number of views per an individual video across the six categories ranged from a low of 8 in the 'relevance' strategy and 'smoking cessation' search term to a high of 1,247,540 in the 'view count' strategy and 'stop smoking' search term. Of the top three most viewed videos by strategy and search term, 66.7% included a specific mention of quitting smoking and, of these, the majority included EBPs. CONCLUSION: Results highlight the need to develop and upload videos containing EBPs both to increase the overall proportion of EBP videos in all categories, particularly in 'quit smoking' and 'stop smoking.' Research is needed to study whether YouTube videos influence knowledge, attitudes and behaviours regarding quitting smoking. PMID- 20966133 TI - Age verification cards fail to fully prevent minors from accessing tobacco products. AB - BACKGROUND: Proper age verification can prevent minors from accessing tobacco products. For this reason, electronic locking devices based on a proof-of age system utilising cards were installed in almost every tobacco vending machine across Japan and Germany to restrict sales to minors. OBJECTIVE: We aimed to clarify the associations between amount smoked by high school students and the usage of age verification cards by conducting a nationwide cross-sectional survey of students in Japan. METHODS: This survey was conducted in 2008. We asked high school students, aged 13-18 years, in Japan about their smoking behaviour, where they purchase cigarettes, if or if not they have used age verification cards, and if yes, how they obtained this card. RESULTS: As the amount smoked increased, the prevalence of purchasing cigarettes from vending machines also rose for both males and females. The percentage of those with experience of using an age verification card was also higher among those who smoked more. Somebody outside of family was the top source of obtaining cards. Surprisingly, around 5% of males and females belonging to the group with highest smoking levels applied for cards themselves. CONCLUSIONS: Age verification cards cannot fully prevent minors from accessing tobacco products. These findings suggest that a total ban of tobacco vending machines, not an age verification system, is needed to prevent sales to minors. PMID- 20966134 TI - Contraband cigarette consumption among adolescent daily smokers in Ontario, Canada. PMID- 20966135 TI - Effects of dissuasive packaging on young adult smokers. AB - BACKGROUND: Tobacco industry documents illustrate how packaging promotes smoking experimentation and reinforces existing smokers' behaviour. Plain packaging reduces the perceived attractiveness of smoking and creates an opportunity to introduce larger pictorial warnings that could promote cessation-linked behaviours. However, little is known about the effects such a combined policy measure would have on smokers' behaviour. METHODS: A 3 (warning size) *4 (branding level) plus control (completely plain pack) best-worst experiment was conducted via face-to-face interviews with 292 young adult smokers from a New Zealand provincial city. The Juster Scale was also used to estimate cessation linked behaviours among participants. RESULTS: Of the 13 options tested, respondents were significantly less likely to choose those featuring fewer branding elements or larger health warnings. Options that featured more branding elements were still preferred even when they also featured a 50% health warning, but were significantly less likely to be chosen when they featured a 75% warning. Comparison of a control pack representing the status quo (branded with 30% front of pack warning) and a plain pack (with a 75% warning) revealed the latter would be significantly more likely to elicit cessation-related behaviours. CONCLUSIONS: Plain packs that feature large graphic health warnings are significantly more likely to promote cessation among young adult smokers than fully or partially branded packs. The findings support the introduction of plain packaging and suggest use of unbranded package space to feature larger health warnings would further promote cessation. PMID- 20966136 TI - Workplace exposure to secondhand smoke and its association with respiratory symptoms--a cross-sectional study among workers in Shanghai. AB - OBJECTIVE: To describe workplace exposure to secondhand smoke (SHS) among different working populations in Shanghai; to identify any association between respiratory symptoms and SHS exposure in these workplaces. DESIGN: Cross sectional survey with a standardised questionnaire. SETTING: 150 worksites (including restaurants, shopping malls, hotels, hospitals, schools, kindergartens). SUBJECTS: 3530 workers. OUTCOME MEASURES: Prevalence of workers with workplace exposure to SHS; average time of exposure to SHS per day; proportion of workers reporting any respiratory and sensory symptoms. RESULTS: 13.3% of employees were covered by complete smoke-free policies. Restaurant employees had the highest level of exposure to SHS (67% exposed with 2.95+/-3.10 h of exposure on average per day) while kindergarten employees had the lowest level (0.5% exposed with 0.01+/-0.01 h of exposure per day). Compared with employees from kindergartens, non-smoking workers from restaurants and shopping malls reported a higher proportion of respiratory and sensory symptoms and were more likely to suffer from all eight respiratory and sensory symptoms (OR 1.8 8.9). The length of exposure to SHS each day was positively associated with all eight symptoms except runny nose. CONCLUSIONS: Workplace exposure to SHS is extensive in Shanghai and the implementation of the current municipal regulation does not provide adequate worker protection. There is an urgent need to establish 100% smoke-free legislation covering all workplaces and public places in Shanghai. PMID- 20966137 TI - Advisers vote against declaring dextromethorphan a controlled substance. PMID- 20966139 TI - International pharmacists group meets in Lisbon: New policy statement seeks to advance collaborative practice. PMID- 20966140 TI - Residencies matter, stakeholders say. PMID- 20966141 TI - Formation of a patient safety organization. PMID- 20966143 TI - Oral aloe vera for treatment of diabetes mellitus and dyslipidemia. PMID- 20966144 TI - Standard of care and novel treatments for chronic lymphocytic leukemia. AB - PURPOSE: The standard of care and novel treatments for chronic lymphocytic leukemia (CLL) are reviewed. SUMMARY: Recent advances in the treatment of CLL have dramatically changed the therapeutic landscape for both patients and health care professionals. The majority of conventional first-line therapies are noncurative and are only used to treat disease that is symptomatic or progressive and include chlorambucil, monotherapy with purine analogues, and combination chemotherapy. Immunotherapeutic agents such as rituximab and alemtuzumab may be indicated in select patient populations. However, because clinical trials have found that overall survival does not depend on the initial therapy, selection of first-line therapy should be based on patient-specific factors and the patient's goals for therapy with respect to response, survival, and symptom palliation. Progression-free survival time and time to treatment are critical endpoints for CLL treatment. An increasingly important endpoint is minimal residual disease (MRD), as it is considered to be the major cause of relapse in CLL. Finally, comparison of toxicities between different therapies is critical in CLL, as it is in other disease states. Several new agents are currently being evaluated for use in CLL, including alvocidib, oblimersen, and lumiliximab. CONCLUSION: Chemotherapy remains the mainstay of treatment for the majority of patients with CLL. The introduction of rituximab, alemtuzumab, and bendamustine has improved the current outlook for patients with CLL. As overall survival does not appear to depend on the initial therapy, treatment should be selected based on patient specific factors and goals. Challenges in CLL include determining when to initiate therapy, eradicating MRD, and managing therapeutic resistance. PMID- 20966145 TI - Extended use of a percutaneous left-ventricular assist device without a heparin based purge solution. AB - PURPOSE: The extended use of an Impella LP 2.5 percutaneous left-ventricular assist device (pVAD) without a heparin-based purge solution in a patient who developed cardiogenic shock after acute myocardial infarction (AMI) is described. SUMMARY: A 58-year-old Asian man with no history of cardiac disease, hypertension, or diabetes mellitus had an AMI and subsequent cardiogenic shock. He was started on dopamine and norepinephrine and transferred to a tertiary care center for rescue percutaneous coronary intervention (PCI). Given that his artery was patent with Thrombolysis In Myocardial Infarction 3 flow, PCI was not attempted. He had an ejection fraction of 25% and mid-distal anteroseptal akinesis. He was transferred to the intensive care unit on intra-aortic balloon pump (IABP) support. The patient's condition continued to deteriorate, and an Impella LP 2.5 pVAD was inserted for additional hemodynamic support and as a bridge to definitive revascularization. To reduce the potential for medication error and decrease the patient's bleeding risk, the purge solution was changed to 20% dextrose injection without heparin and continued at a rate of 15 mL/hr. The patient's hemodynamic values improved, and the pVAD and IABP were continued for the next five days. The patient was successfully anticoagulated with i.v. heparin throughout the remainder of pVAD support. While the patient did develop hemolytic anemia during his device support, there were no thrombotic or bleeding complications. CONCLUSION: An Impella LP 2.5 pVAD was used for 75 hours with a purge solution that contained no heparin. There were no thrombotic or bleeding complications. PMID- 20966146 TI - Rhabdomyolysis in a patient receiving ranolazine and simvastatin. AB - PURPOSE: A case of rhabdomyolysis occurring shortly after the addition of ranolazine to a stable simvastatin regimen is reported. SUMMARY: A 63-year-old Caucasian man with a history of hyperlipidemia and coronary artery disease arrived at an urgent care center with complaints of worsening bilateral lower extremity weakness over three days. He was admitted to a hospital within 24 hours. His other underlying medical conditions included congestive heart failure, chronic kidney disease, degenerative joint disease, and a history of stroke. Oral medications at the time of admission included furosemide 40 mg daily, clopidogrel 75 mg daily, hydralazine 50 mg three times daily, metoprolol 50 mg twice daily, isosorbide mononitrate 120 mg daily, omeprazole 20 mg daily, nitroglycerin tablets as needed for chest pain, simvastatin 80 mg daily, and the recent addition of ranolazine 500 mg daily. Laboratory tests revealed that the patient's serum creatinine (SCr) concentration was 3.9 mg/dL and his creatine kinase (CK) concentration was 31,989 units/L. Ranolazine and simvastatin were discontinued, and metoprolol, hydralazine, isosorbide mono-nitrate, and furosemide were continued via nasogastric tube, along with amlodipine 10 mg daily and omeprazole 40 mg daily. The patient's serum CK concentration remained above 10,400 units/L for four days. By day 7 of hospitalization, the patient's serum CK concentration was 715 units/L, and it was almost undetectable by hospital day 18 (24 units/L). The patient's SCr concentration remained at his baseline value of 2.2 mg/dL. CONCLUSION: A 63-year-old man with a history of chronic renal impairment on a stable dosage of simvastatin developed rhabdomyolysis after the addition of ranolazine to his medication regimen. PMID- 20966147 TI - Mental health stability in veterans with posttraumatic stress disorder receiving varenicline. AB - PURPOSE: The effects of varenicline treatment for smoking cessation on mental health (MH) stability in veterans with posttraumatic stress disorder (PTSD) was studied. METHODS: Data were collected by retrospective chart review at a Veterans Affairs medical center. Patients with PTSD who were prescribed varenicline for smoking cessation between May 2006 and July 2008 were included; all patients had failed previous attempts to quit using nicotine replacement therapy, bupropion, or both. The average numbers of encounters per month with MH professionals in a six-month baseline period before varenicline, during treatment, and after treatment were compared. The numbers of MH encounters were compared for patients with multiple MH disorders including major depressive disorder, schizophrenia, or bipolar disorder and those with PTSD alone. Patients who had completed a full course of varenicline therapy (4-12 weeks) without MH decompensation were surveyed to determine the rate of smoking cessation. RESULTS: Data were analyzed for 78 patients. MH encounters during varenicline therapy increased 29% over baseline. There was no significant difference in the numbers of encounters in the baseline and postvarenicline periods. MH decompensations were documented for 4 patients during varenicline therapy and 2 after completion of therapy. Before, during, and after varenicline, patients with multiple MH disorders had significantly more MH encounters than those with PTSD alone. Of the 42 patients in the follow-up survey, 19 (45%) said they refrained from smoking for 30 days and 13 (31%) for 90 days. CONCLUSION: Varenicline appeared to have destabilizing effects on MH in veterans with PTSD. PMID- 20966148 TI - Impact of health information technology on detection of potential adverse drug events at the ordering stage. AB - PURPOSE: The impact of implementing commercially available health care information technologies at hospitals in a large health system on the identification of potential adverse drug events (ADEs) at the medication ordering stage was studied. METHODS: All hospitals in the health system had implemented a clinical decision-support system (CDSS) consisting of a centralized clinical data repository, interfaces for reports, a results reviewer, and a package of ADE alert rules. Additional technology including computerized provider order entry (CPOE), an advanced CDSS, and evidence-based order sets was implemented in nine hospitals. ADE alerts at these hospitals were compared with alerts at nine hospitals without the advanced technology. A linear mixed-effects model was used in determining the mean response profile of six dependent variables over 28 total months for each experimental group. RESULTS: Overall, hospitals with CPOE and an advanced CDSS captured significantly more ADE alerts for pharmacist review; an average of 336 additional potential ADEs per month per hospital were reviewed. Pharmacists identified some 94% of the alerts as false positives. Alerts identified as potentially true positives were reviewed with physicians, and order changes were recommended. The number of true-positive alerts per 1000 admissions increased. CONCLUSION: The implementation of CPOE and advanced CDSS tools significantly increased the number of potential ADE alerts for pharmacist review and the number of true-positive ADE alerts identified per 1000 admissions. PMID- 20966149 TI - Frequency of and reasons for pharmacy residents breaching the National Matching Services applicant agreement. AB - PURPOSE: The frequency of and reasons for pharmacy residents breaching the National Matching Services (NMS) applicant agreement were evaluated. METHODS: An electronic survey was sent via e-mail to residency program directors of ASHP accredited postgraduate year 1 pharmacy residencies in the United States. The survey instrument was developed based on an initial pilot survey used to test the clarity and reliability of the questions. The primary objective of the survey was to determine the frequency with which pharmacy residents breach the NMS applicant agreement and fail to report to their assigned site. Characteristics of ASHP- accredited residency programs with residents who breached the NMS agreement and any punitive action taken on these individuals were also analyzed. RESULTS: Of the 636 surveys sent to residency program directors, 302 complete surveys were returned, yielding a response rate of 47.5%. Twenty-six respondents (8.6%) indicated that within the past five years, they had matched candidates who failed to report to their assigned site. Of these respondents, 13 (50%) reported the candidate to ASHP; 11 (44%) took no action. Respondents indicated that they would be comfortable reporting all candidates who breach the NMS agreement to ASHP and placing the candidates' information on a list accessible electronically only to residency program directors. CONCLUSION: Less than 10% of residency program directors reported having residency candidates who breached the NMS applicant agreement. The majority of these respondents indicated that these residents were not their first choices. The most common reason for candidate withdrawal was family obligation. PMID- 20966150 TI - Effect of emergency medicine pharmacists on medication-error reporting in an emergency department. AB - PURPOSE: The effect of an emergency medicine (EM) clinical pharmacist on medication-error reporting in an emergency department (ED) was studied. METHODS: The medication-error reports for patients seen at a university's ED between September 1, 2005, and February 28, 2009, were retrospectively reviewed. Errors reported before the addition of an EM pharmacist (from September 1, 2005, through February 28, 2006) were compared with those reported after the addition of two EM pharmacists (from September 1, 2008, through February 28, 2009). The severity of errors and the provider who reported the errors were characterized. RESULTS: A total of 402 medication errors were reported over the two time periods. Pharmacy personnel captured significantly more errors than did other health care personnel (94.5% versus 5.7%, p < 0.001). The addition of two EM pharmacists resulted in 14.8 times as many medication-error reports as were made when no EM pharmacist was in the ED. More errors that actually occurred were captured with two pharmacists providing care (95.7% versus 4.3%, p < 0.001). A majority of the errors documented were ordering errors (79.8%). Of these, 73.7% were captured after the addition of two EM pharmacists. Performance (40.0%) and knowledge (27.9%) deficits were the most common contributing factors to medication errors. CONCLUSION: During the study period after the addition of two EM pharmacists in the ED, 371 medication-error reports were completed, compared with 31 reports during the study period before the addition of the pharmacists. Pharmacy personnel reported the majority of medication errors during both study periods. PMID- 20966151 TI - Pharmacy practice model for academic medical centers. PMID- 20966152 TI - Lessons learned from a pharmacy practice model change at an academic medical center. AB - PURPOSE: The development and implementation of a new pharmacy practice model at an academic medical center are described. SUMMARY: Before the model change, decentralized pharmacists responsible for order entry and verification and clinical specialists were both present on the care units. Staff pharmacists were responsible for medication distribution and sterile product preparation. The decentralized pharmacists handling orders were not able to use their clinical training, the practice model was inefficient, and few clinical services were available during evenings and weekends. A task force representing all pharmacy department roles developed a process and guiding principles for the model change, collected data, and decided on a model. Teams consisting of decentralized pharmacists, decentralized pharmacy technicians, and team leaders now work together to meet patients' pharmacy needs and further departmental safety, quality, and cost-saving goals. Decentralized service hours have been expanded through operational efficiencies, including use of automation (e.g., computerized provider order entry, wireless computers on wheels used during rounds with physician teams). Nine clinical specialist positions were replaced by five team leader positions and four pharmacists functioning in decentralized roles. Additional staff pharmacist positions were shifted into decentralized roles, and the hospital was divided into areas served by teams including five to eight pharmacists. Technicians are directly responsible for medication distribution. No individual's job was eliminated. CONCLUSION: The new practice model allowed better alignment of staff with departmental goals, expanded pharmacy hours and services, more efficient medication distribution, improved employee engagement, and a staff succession plan. PMID- 20966153 TI - Targeting mitochondrial metabolism and machinery as a means to enhance photosynthesis. PMID- 20966154 TI - Leaf senescence is accompanied by an early disruption of the microtubule network in Arabidopsis. AB - The dynamic assembly and disassembly of microtubules (MTs) is essential for cell function. Although leaf senescence is a well-documented process, the role of the MT cytoskeleton during senescence in plants remains unknown. Here, we show that both natural leaf senescence and senescence of individually darkened Arabidopsis (Arabidopsis thaliana) leaves are accompanied by early degradation of the MT network in epidermis and mesophyll cells, whereas guard cells, which do not senesce, retain their MT network. Similarly, entirely darkened plants, which do not senesce, retain their MT network. While genes encoding the tubulin subunits and the bundling/stabilizing MT-associated proteins (MAPs) MAP65 and MAP70-1 were repressed in both natural senescence and dark-induced senescence, we found strong induction of the gene encoding the MT-destabilizing protein MAP18. However, induction of MAP18 gene expression was also observed in leaves from entirely darkened plants, showing that its expression is not sufficient to induce MT disassembly and is more likely to be part of a Ca(2+)-dependent signaling mechanism. Similarly, genes encoding the MT-severing protein katanin p60 and two of the four putative regulatory katanin p80s were repressed in the dark, but their expression did not correlate with degradation of the MT network during leaf senescence. Taken together, these results highlight the earliness of the degradation of the cortical MT array during leaf senescence and lead us to propose a model in which suppression of tubulin and MAP genes together with induction of MAP18 play key roles in MT disassembly during senescence. PMID- 20966155 TI - The problem with cell phones...or maybe not. PMID- 20966156 TI - Enriched environment improves motor function and increases neurotrophins in hemicerebellar lesioned rats. AB - BACKGROUND: Environmental enrichment (EE) defined as "a combination of complex inanimate and social stimulation" influences brain function and anatomy by enhancing sensory, cognitive, motor, and social stimulation. The beneficial effects of EE in the presence of brain damage have been partially attributed to upregulation of neurotrophins, proteins involved in neuronal survival and in activity-dependent plasticity. OBJECTIVE: The authors tested the hypothesis that EE may have advantageous effects on recovery of motor function after cerebellar damage, associated with changes in local neurotrophin production. METHODS: They performed a hemicerebellectomy in rats previously exposed to EE or reared in standard conditions. The time course of compensation of motor symptoms was analyzed in both lesioned groups. Then, the local production of the nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the spared hemicerebellum and other extracerebellar regions was evaluated. RESULTS: Long term exposure to EE accelerated the motor recovery in hemicerebellectomized rats and elicited an increase in NGF levels in the spared hemicerebellum, as compared with nonenriched lesioned and control rats. BDNF levels were higher in hemicerebellectomized rats but not influenced by EE. In the frontal cortex, both NGF and BDNF levels were upregulated in hemicerebellectomized enriched rats as compared with hemicerebellectomized nonenriched and control rats. CONCLUSIONS: This study suggests that the beneficial effects of EE on motor symptoms after cerebellar damage may be, at least partly, because of modulation of neurotrophic proteins involved in the regeneration processes. PMID- 20966158 TI - Computerized cognitive training in survivors of childhood cancer: a pilot study. AB - The objective of the current study was to pilot a computerized cognitive training program, Captain's Log, in a small sample of survivors of childhood cancer. A total of 9 survivors of acute lymphoblastic leukemia and brain tumors with attention and working memory deficits were enrolled in a home-based 12-week cognitive training program. Survivors returned for follow-up assessments postintervention and 3 months later. The intervention was associated with good feasibility and acceptability. Participants exhibited significant increases in working memory and decreases in parent-rated attention problems following the intervention. Findings indicate that home-based, computerized cognitive intervention is a promising intervention for survivors with cognitive late effects; however, further study is warranted with a larger sample. PMID- 20966159 TI - Pediatric oncology nurse and grief education: a telephone survey. AB - There has been an increased interest in the grief experiences of nurses. Unacknowledged, unaddressed compound grief can have devastating consequences on professional nurses and the patients and families under their care. A telephone survey was conducted using the current Children's Oncology Group institutions in the United States to ascertain what education and support is available to pediatric oncology nurses regarding professional grief. Three questions were asked of the person contacted at the participating institutions regarding grief education during orientation, grief education beyond orientation, and support mechanisms for staff experiencing professional grief. Out of the 176 eligible Children's Oncology Group institutions that were invited to participate in the survey, 78 institutions participated. The analysis of the results concluded that support for pediatric oncology nurses is often informal and sporadic and that education regarding professional grief is often nonexistent or very limited in its content. PMID- 20966157 TI - Motor cortex preactivation by standing facilitates word retrieval in aphasia. AB - BACKGROUND AND OBJECTIVES: A tight link between linguistic functions and activation of motor areas has been consistently reported, indicating that the 2 systems share functional neural resources. Few efforts have been made to explore whether this knowledge could aid the rehabilitation of aphasia. METHODS: The authors assessed whether preactivation of the leg motor cortex during standing, compared with sitting, can facilitate language production in patients with chronic aphasia. In a cross-over within-subject design, the authors assessed performance on a picture naming task and controlled for effects on processing speed and simple verbal reaction time. RESULTS: They found that standing compared with sitting had a beneficial effect on the number of semantic self-corrections that resulted in correct naming. In the absence of effects on motor or general processing speed, this points to a specific effect on lexical retrieval and selection. This was further corroborated by an error pattern analysis. Successful semantic self-corrections during standing were only found when there was already partial activation of the target semantic network-that is, when self-corrections were preceded by an incorrect but semantically associated naming response. DISCUSSION: These findings show that preactivation of the motor system, which extends beyond the intrinsic link between manual gestures and language, can facilitate lexical access in chronic aphasia and may open new directions in aphasia rehabilitation. PMID- 20966160 TI - System issues: challenges to intimate partner violence screening and intervention. AB - This ethnographic study examines the experiences of health care providers (HCPs) and advocates implementing intimate partner violence (IPV) screening and interventions in their health care organizations. Numerous policies and protocols have been developed to improve the response of HCPs to survivors of IPV. Typically studies have focused on HCPs with little attention to the role of organizations in providing care. The findings from this study highlight that even with IPV programs in place the organizational environment can contribute to suboptimal outcomes. Identified challenges included time constraints, organizational expectations for increased productivity, and dwindling organizational support and services for IPV. With the continuing debate regarding universal screening, this study illuminates the need for clinicians to have a supportive clinical environment and resources for IPV screening and intervention. PMID- 20966161 TI - Health professionals' estimation of cancer-related fatigue in children. AB - Many studies show that cancer-related fatigue is one of the most common symptoms experienced by children as a side effect of cancer therapy. This problem has grown considerably in recent years; the exact mechanisms underlying fatigue remain unclear. Therefore, assessing and managing this symptom can be problematic. This article describes the findings from a survey evaluating how health professionals (n = 56) at the Pediatric Oncology Centers in Izmir currently define and assess cancer-related fatigue. The results demonstrate that while the problems associated with fatigue are acknowledged, assessment tools are not widely used, and the majority of health professionals report that they would benefit from further education on the subject to assist in the care of patients. PMID- 20966162 TI - The role of E-mentorship in a virtual world for youth transplant recipients. AB - Because of geographic distances, many youth transplant recipients do not have the opportunity to meet and form relationships with peers who have undergone similar experiences. This article explores the role of E-mentorship in virtual environments. Most specifically, by analyzing data from a study conducted with the Zora virtual world with pediatric transplant recipients, suggestions and recommendations are given for conceiving the role of virtual mentors and allocating the needed resources. Zora is a graphical virtual world designed to create a community that offers psychoeducational support and the possibility of participating in virtual activities following a curriculum explicitly designed to address issues of school transition and medical adherence. Activities are designed to foster relationships, teach technological skills, and facilitate the formation of a support network of peers and mentors.This article addresses the research question, "What makes a successful E-mentorship model in virtual worlds for children with serious illnesses?" by looking at E-mentoring patterns such as time spent online, chat analysis, initiation of conversation, initiation of activities, and out-of-world contact. PMID- 20966163 TI - Clinician's perceptions of indicators of amenability to sex offender-specific treatment in juveniles. AB - Identifying and understanding the factors that predict treatment success is central to legal and clinical decision making about juveniles who commit sexual offenses. The current study surveyed 158 treatment providers who work with juvenile sexual offenders to explore empirically the construct of amenability as it relates to juvenile sex offender-specific treatment (SOST). Youths' unwillingness to alter deviant sexual interest/attitudes and unsupportive parenting were rated as strong indicators of poor SOST amenability, whereas the youths' motivation for change and belief in the efficacy of treatment, strong social support and positive attachments, and resilient personality traits were rated as strong indicators of good SOST amenability. Items distinctly rated as indicators of either poor or good treatment amenability (N = 48) were thematically grouped into internally consistent scales (alpha's ranging from .75 .87) reflecting several possible dimensions of amenability. PMID- 20966164 TI - Boundaries and dual relationships. AB - Ethical standards are core components of practice standards and codes of conduct for mental health practitioners. Practice standards and ethics related to boundaries are generally based on historical review, study of mental health services, and the impact of boundary crossing or boundary violations on clients receiving services. This article explores some common standards of ethical practice related to boundaries and dual or multiple relationships between mental health professionals and clients. The underlying conceptual basis for these standards and examples of questions encountered in clinical practice with sexual offenders are explored. PMID- 20966165 TI - Three decades of transplantation for chronic myeloid leukemia: what have we learned? AB - Last year marked 30 years of hematopoietic stem cell transplantation as a curative treatment of chronic myeloid leukemia (CML). Initially studies used stem cells from identical twins but techniques rapidly developed to use cells first from HLA-identical siblings and later unrelated donors. During the 1990s CML became the most frequent indication for allogeneic transplantation worldwide. This, together with the relative biologic homogeneity of CML in chronic phase, its responsiveness to graft-versus-leukemia effect and the ability to monitor low level residual disease placed CML at the forefront of research into different strategies of stem cell transplantation. The introduction of BCR-ABL1 tyrosine kinase inhibitors during the last decade resulted in long-term disease control in the majority of patients with CML. In those who fail to respond and/or develop intolerance to these agents, transplantation remains an effective therapeutic solution. The combination of tyrosine kinase inhibitors with transplantation is an exciting new strategy and it provides inspiration for similar approaches in other malignancies. PMID- 20966166 TI - NK-cell enteropathy: a benign NK-cell lymphoproliferative disease mimicking intestinal lymphoma: clinicopathologic features and follow-up in a unique case series. AB - Intestinal T-cell and natural killer (NK)-cell lymphomas are clinically aggressive and can be challenging to diagnose in small endoscopic biopsies. We describe 8 patients in whom atypical NK-cell lymphoproliferative lesions mimicked NK- or T-cell lymphoma. The patients (2 men; 6 women; ages 27-68 years) presented with vague gastrointestinal symptoms with lesions involving stomach, duodenum, small intestine, and colon. At endoscopy, the lesions exhibited superficial ulceration, edema, and hemorrhage. Biopsies revealed a mucosal infiltrate of atypical cells with an NK-cell phenotype (CD56(+)/TIA-1(+)/Granzyme B(+)/cCD3(+)), which displaced but did not invade the glandular epithelium. Epstein-Barr virus-encoded RNA in situ hybridization was negative, and T-cell receptor-gamma gene rearrangement showed no evidence of a clonal process. Based on an original diagnosis of lymphoma, 3 patients received aggressive chemotherapy followed by autologous bone marrow transplantation in 2. Five patients were followed without treatment. However, no patient developed progressive disease or died of lymphoma (median follow-up, 30 months). Repeat endoscopies in 6 of 8 patients showed persistence or recurrence of superficial gastrointestinal lesions. This unique entity mimics intestinal and NK-/T-cell lymphomas on endoscopic biopsies and can result in erroneous diagnosis, leading to aggressive chemotherapy. We propose the term "NK-cell enteropathy" for this syndrome of as yet unknown etiology. PMID- 20966167 TI - The platelet P2Y12 receptor for adenosine diphosphate: congenital and drug induced defects. AB - P2Y12, the G(i)-coupled platelet receptor for adenosine diphosphate (ADP), plays a central role in platelet function. Patients with congenital P2Y12 defects display a mild to moderate bleeding diathesis, characterized by mucocutaneous bleedings and excessive post-surgical and post-traumatic blood loss. Defects of P2Y12 should be suspected when ADP, even at high concentrations (>= 10 MUM), is unable to induce full, irreversible platelet aggregation. Tests that evaluate the degree of inhibition of adenylyl cyclase by ADP should be used to confirm the diagnosis. Drugs that inhibit P2Y12 are potent antithrombotic drugs, attesting the central role played by P2Y12 in platelet thrombus formation. Clopidogrel, the most widely used drug that inhibits P2Y12, is effective both in monotherapy and in combination with acetylsalicylic acid. The most important drawback of clopidogrel is its inability to inhibit adequately P2Y12-dependent platelet function in approximately one-third of patients who are therefore not protected from major cardiovascular events. New drugs, such as prasugrel and ticagrelor, which effectively inhibit P2Y12 in the majority of patients, proved to be more efficacious than clopdidogrel in preventing major cardiovascular events. Although they increase the incidence of major bleedings, the net clinical benefit is in favor of the new P2Y12 inhibitors. PMID- 20966168 TI - SIRT1 deficiency compromises mouse embryonic stem cell hematopoietic differentiation, and embryonic and adult hematopoiesis in the mouse. AB - SIRT1 is a founding member of a sirtuin family of 7 proteins and histone deacetylases. It is involved in cellular resistance to stress, metabolism, differentiation, aging, and tumor suppression. SIRT1(-/-) mice demonstrate embryonic and postnatal development defects. We examined hematopoietic and endothelial cell differentiation of SIRT1(-/-) mouse embryonic stem cells (ESCs) in vitro, and hematopoietic progenitors in SIRT1(+/+)(+/-), and (-/-) mice. SIRT1(-/-) ESCs formed fewer mature blast cell colonies. Replated SIRT1(-/-) blast colony-forming cells demonstrated defective hematopoietic potential. Endothelial cell production was unaltered, but there were defects in formation of a primitive vascular network from SIRT1(-/-)-derived embryoid bodies. Development of primitive and definitive progenitors derived from SIRT1(-/-) ESCs were also delayed and/or defective. Differentiation delay/defects were associated with delayed capacity to switch off Oct4, Nanog and Fgf5 expression, decreased beta-H1 globin, beta-major globin, and Scl gene expression, and reduced activation of Erk1/2. Ectopic expression of SIRT1 rescued SIRT1(-/-) ESC differentiation deficiencies. SIRT1(-/-) yolk sacs manifested fewer primitive erythroid precursors. SIRT1(-/-) and SIRT1(+/-) adult marrow had decreased numbers and cycling of hematopoietic progenitors, effects more apparent at 5%, than at 20%, oxygen tension, and these progenitors survived less well in vitro under conditions of delayed growth factor addition. This suggests a role for SIRT1 in ESC differentiation and mouse hematopoiesis. PMID- 20966169 TI - The interplay between tissue plasminogen activator domains and fibrin structures in the regulation of fibrinolysis: kinetic and microscopic studies. AB - Regulation of tissue-type plasminogen activator (tPA) depends on fibrin binding and fibrin structure. tPA structure/function relationships were investigated in fibrin formed by high or low thrombin concentrations to produce a fine mesh and small pores, or thick fibers and coarse structure, respectively. Kinetics studies were performed to investigate plasminogen activation and fibrinolysis in the 2 types of fibrin, using wild-type tPA (F-G-K1-K2-P, F and K2 binding), K1K1-tPA (F G-K1-K1-P, F binding), and delF-tPA (G-K1-K2-P, K2 binding). There was a trend of enzyme potency of tPA > K1K1-tPA > delF-tPA, highlighting the importance of the finger domain in regulating activity, but the differences were less apparent in fine fibrin. Fine fibrin was a better surface for plasminogen activation but more resistant to lysis. Scanning electron and confocal microscopy using orange fluorescent fibrin with green fluorescent protein-labeled tPA variants showed that tPA was strongly associated with agglomerates in coarse but not in fine fibrin. In later lytic stages, delF-tPA-green fluorescent protein diffused more rapidly through fibrin in contrast to full-length tPA, highlighting the importance of finger domain-agglomerate interactions. Thus, the regulation of fibrinolysis depends on the starting nature of fibrin fibers and complex dynamic interaction between tPA and fibrin structures that vary over time. PMID- 20966170 TI - Infusion of HLA-mismatched peripheral blood stem cells improves the outcome of chemotherapy for acute myeloid leukemia in elderly patients. AB - Treatment outcome of acute myeloid leukemia (AML) in elderly patients remains unsatisfactory. It has been shown that the infusion of granulocyte colony stimulating factor-mobilized donor peripheral blood stem cells (G-PBSCs) can enhance graft-versus-leukemia effects and speed hematopoietic recovery. Fifty eight AML patients aged 60-88 years were randomly assigned to receive induction chemotherapy with cytarabine and mitoxantrone (control group; n = 28) or it plus human leukocyte antigen-mismatched G-PBSCs (G-PBSC group; n = 30). Patients who achieved complete remission received another 2 cycles of postremission therapy with intermediate-dose cytarabine or it plus G-PBSCs. The complete remission rate was significantly higher in the G-PBSC group than in the control group (80.0% vs 42.8%; P = .006). The median recovery times of neutrophils and platelets were 11 days and 14.5 days, respectively, in the G-PBSC group and 16 days and 20 days, respectively, in the control group after chemotherapy. The 2-year probability of disease-free survival was significantly higher in the G-PBSC group than in the control group (38.9% vs 10.0%; P = .01). No graft-versus-host disease was observed in any patient. Persistent donor microchimerism was successfully detected in all of the 4 female patients. These results indicate that G-PBSCs in combination with conventional chemotherapy may provide a promising treatment method for AML in elderly patients. PMID- 20966171 TI - Transfusion and NHL risk: a meta-answer? PMID- 20966172 TI - Hemangioblasts: back to the future? PMID- 20966173 TI - Another miracle left in aspirin? PMID- 20966174 TI - To the heart of the APS puzzle. PMID- 20966175 TI - The silent war against CMV in CLL. PMID- 20966176 TI - Dual control: the HIF-2 regulator. PMID- 20966177 TI - Blind men and the APS. PMID- 20966178 TI - Autonomy and control in dyads: effects on interaction quality and joint creative performance. AB - Two studies examined interaction quality and joint performance on two creative tasks in unacquainted dyads primed for autonomy or control orientations. It was hypothesized that autonomy-primed dyads would interact more constructively, experience more positive mood, and engage the task more readily, and as a result these dyads would perform better. To test this, Study 1 primed orientation and explored verbal creative performance on the Remote Associates Task (RAT). In Study 2, dyads were primed with autonomy and control orientation and videotaped during two joint creative tasks, one verbal (RAT) and one nonverbal (charades). Videotapes were coded for behavioral indicators of closeness and task engagement. Results showed that autonomy-primed dyads felt closer, were more emotionally and cognitively attuned, provided empathy and encouragement to partners, and performed more effectively. The effects of primed autonomy on creative performance were mediated by interpersonal quality, mood, and joint engagement. PMID- 20966179 TI - Direct contact as a moderator of extended contact effects: cross-sectional and longitudinal impact on outgroup attitudes, behavioral intentions, and attitude certainty. AB - Cross-group friendships (the most effective form of direct contact) and extended contact (i.e., knowing ingroup members who have outgroup friends) constitute two of the most important means of improving outgroup attitudes. Using cross sectional and longitudinal samples from different intergroup contexts, this research demonstrates that extended contact is most effective when individuals live in segregated neighborhoods having only few, or no, direct friendships with outgroup members. Moreover, by including measures of attitudes and behavioral intentions the authors showed the broader impact of these forms of contact, and, by assessing attitude certainty as one dimension of attitude strength, they tested whether extended contact can lead not only to more positive but also to stronger outgroup orientations. Cross-sectional data showed that direct contact was more strongly related to attitude certainty than was extended contact, but longitudinal data showed both forms of contact affected attitude certainty in the long run. PMID- 20966180 TI - Pain management in spinal metastases: the role of percutaneous vertebral augmentation. AB - Recent technological advances combined with innovative interventional radiology techniques can now offer an alternative less invasive treatment option for many patients with malignant vertebral body infiltration. Percutaneous vertebral augmentation procedures offer less invasive but effective pain relief to many patients with symptomatic spinal metastatic disease. The procedures are image guided and involve the injection of polymethylmethacrylate bone cement into the effected vertebral body. This technique can also be combined with radiofrequency ablation, which may accelerate vertebral stability. In this review, we examine the recent literature surrounding this topic and provide an overview of these emerging techniques. PMID- 20966181 TI - Treatment of metastatic breast cancer: second line and beyond. AB - Increasing use of standard chemotherapy, especially anthracycline- and taxane based therapies, in early-stage breast cancer has led to a corresponding increase in heavily pretreated and/or treatment-resistant cases of metastatic breast cancer (MBC). Thus, second and later lines of MBC therapy frequently involve the clinically challenging picture of progressive disease and limited treatment options. While several prognostic factors have been identified to aid treatment selection in MBC patients, treatment is palliative and aimed at prolonging survival, controlling symptoms, and maximizing patients' quality of life. No globally accepted standard exists for meeting these goals, and treatment patterns vary according to region. The list of available agents for the treatment of MBC is increasing with newer chemotherapeutic agents and molecular-targeted therapies. Within recent years, several single-agent and combination chemotherapy regimens have been shown to improve progression-free survival and reduce symptoms of disease in clinical studies in patients with resistant and/or heavily pretreated MBC. However, at present, the demonstrated benefits of these medical interventions have usually not included extension of overall survival times. It is hoped that in the near future, ongoing refinements to treatment approaches used in second-line settings and beyond will allow meaningful improvements in symptom control and survival in MBC. PMID- 20966182 TI - Evaluation of interim PET response criteria in paediatric Hodgkin's lymphoma- results for dedicated assessment criteria in a blinded dual-centre read. AB - BACKGROUND: The aim of this study was to evaluate the use and reliability of the new positron emission tomography (PET)-based response criteria for interim positron emission tomography (iPET) in patients with paediatric Hodgkin's lymphoma (pHL). Particular emphasis was put on interobserver variability and on identification of a visual cut-off defining patients with very low risk for relapse. PATIENTS AND METHODS: The iPET scans of 39 pHL patients were evaluated in two independent centres by two PET-experienced specialists in nuclear medicine (blinded read, centre consensus) each. The iPET scans were interpreted using a 5 point scale and were compared with the outcome. Cohen's kappa-test (kappa) was used to analyse the interobserver agreement. RESULTS: Concordant ratings were assessed in 19 patients with iPET-negative findings, in 11 patients with iPET positive findings and in 2 patients with inconclusive ratings. A 'substantial agreement' between attended centres was achieved (kappa = 0.748). All patients suffering relapse were concordantly identified, taking mediastinal blood pool structures (MBPS) as visual cut-off between PET-positive and PET-negative findings, respectively. All pHL patients with uptake lower than or equal to MBPS remained in complete remission. CONCLUSION(S): The iPET interpretation assured low interobserver variability. High sensitivity for identification of pHL patients suffering relapse is achieved if [18F]-fluorodeoxyglucose uptake above the MBPS value is rated as a PET-positive finding. PMID- 20966183 TI - Metabolic syndrome and rare gynecological cancers in the metabolic syndrome and cancer project (Me-Can). AB - BACKGROUND: Risk factors for rare gynecological cancers are largely unknown. Initial research has indicated that the metabolic syndrome (MetS) or individual components could play a role. MATERIALS AND METHODS: The Metabolic syndrome and Cancer project cohort includes 288,834 women. During an average follow-up of 11 years, 82 vulvar, 26 vaginal and 43 other rare gynecological cancers were identified. Hazard ratios (HRs) were estimated fitting Cox proportional hazards regression models for tertiles and standardized z-scores [with a mean of 0 and a standard deviation (SD) of 1] of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and MetS. Risk estimates were corrected for random error in the measurement of metabolic factors. RESULTS: The MetS was associated with increased risk of vulvar [HR 1.78, 95% confidence interval (CI) 1.30-2.41) and vaginal cancer (HR 1.87, 95% CI 1.07-3.25). Among separate MetS components, 1 SD increase in BMI was associated with overall risk (HR 1.43, 95% CI 1.23-1.66), vulvar (HR 1.36, 95% CI 1.11-1.69) and vaginal cancer (HR 1.79, 95% CI 1.30 2.46). Blood glucose and triglyceride concentrations were associated with increased risk of vulvar cancer (HR 1.98, 95% CI 1.10-3.58 and HR 2.09, 95% CI 1.39-3.15, respectively). CONCLUSION: The results from this first prospective study on rare gynecological cancers suggest that the MetS and its individual components may play a role in the development of these tumors. PMID- 20966187 TI - Comparison of methods for assessing the impact of different disturbances and nutrient conditions upon functional characteristics of grassland communities. AB - BACKGROUND AND AIMS: Predicting the response of plant communities to variation in resources and disturbance is still a challenge, because findings depend on how ecological gradients are characterized and how grassland functional composition is assessed. Focusing on leaf dry matter content (LDMC), the efficacy of different methods for evaluating the best response of plant communities to either environmental or disturbance change is examined. METHODS: Data were collected on 69 grasslands located at four sites in the Pyrenees and Massif Central. N Ellenberg indices and plant nutrient content (Ni) were compared to assess fertility, and either LDMC (meas) measured or calculated from a trait database for which traits were measured under the same environmental conditions (db). Management regime (MR) was characterized in terms of categories (grazing, cutting) and plant height. KEY RESULTS: LDMCdb was positively correlated to LDMCmeas, but depended significantly on site temperature. N-Ellenberg and Ni were significantly correlated, and there was a significant effect of MR and temperature. LDMC responded to fertility, MR and temperature. Replacing MR by plant height in an REML analysis reduced the uncertainty of the LDMC prediction. LDMC was correlated to plant height at community level, whereas the correlation was weak at species level. Differences in LDMC between plant communities under any of the management regimes were significantly correlated to the standing herbage mass. CONCLUSION: The N-Ellenberg index is a better indicator of fertility than Ni which is short-term and environment-dependent. LDMC taken from a database allows plant trait variation due to species abundance (excluding variation due to trait plasticity in response to management) to be captured. So the former is better suited for assessing agricultural services that mainly depend on plant phenology and tissue composition. LDMC responded to defoliation regime in addition to fertility because plant height is roughly correlated with LDMC at plant community level. PMID- 20966186 TI - Phylogeny and biogeography of Allium (Amaryllidaceae: Allieae) based on nuclear ribosomal internal transcribed spacer and chloroplast rps16 sequences, focusing on the inclusion of species endemic to China. AB - BACKGROUND AND AIMS: The genus Allium comprises more than 800 species, placing it among the largest monocotyledonous genera. It is a variable group that is spread widely across the Holarctic region. Previous studies of Allium have been useful in identifying and assessing its evolutionary lineages. However, there are still many gaps in our knowledge of infrageneric taxonomy and evolution of Allium. Further understanding of its phylogeny and biogeography will be achieved only through continued phylogenetic studies, especially of those species endemic to China that have often been excluded from previous analyses. Earlier molecular studies have shown that Chinese Allium is not monophyletic, so the goal of the present study was to infer the phylogeny and biogeography of Allium and to provide a classification of Chinese Allium by placement of Chinese species in the context of the entire phylogeny. METHODS: Phylogenetic studies were based on sequence data of the nuclear ribosomal internal transcribed spacer (ITS) and chloroplast rps16 intron, analysed using parsimony and Bayesian approaches. Biogeographical patterns were conducted using statistical dispersal-vicariance analysis (S-DIVA). KEY RESULTS: Phylogenetic analyses indicate that Allium is monophyletic and consists of three major clades. Optimal reconstructions have favoured the ancestors of Amerallium, Anguinum, Vvedenskya, Porphyroprason and Melanocrommyum as originating in eastern Asia. CONCLUSIONS: Phylogenetic analyses reveal that Allium is monophyletic but that some subgenera are not. The large genetic distances imply that Allium is of ancient origin. Molecular data suggest that its evolution proceeded along three separate evolutionary lines. S-DIVA indicates that the ancestor of Amerallium, Anguinum, Vvedenskya, Porphyroprason and Melanocrommyum originated from eastern Asia and underwent different biogeographical pathways. A taxonomic synopsis of Chinese Allium at sectional level is given, which divides Chinese Allium into 13 subgenera and 34 sections. PMID- 20966188 TI - Serum uric acid level as a marker for mortality and acute kidney injury in patients with acute paraquat intoxication. AB - BACKGROUND: Paraquat (PQ) is a non-selective herbicide that generates reactive oxygen species (ROS) in vivo. Uric acid emerged as a marker of oxidative stress and may enhance ROS-mediated injury in acute PQ intoxication. Therefore, we investigated the association between uric acid levels and mortality and acute kidney injury (AKI) in the present study. METHODS: From January 2007 to December 2008, patients who arrived at our hospital with acute PQ intoxication (n = 513) were included in the study. Patients were divided into two groups (hyperuricaemia vs non-hyperuricaemia) based on uric acid levels. Mortality and AKI were analysed in reference to uric acid level. RESULTS: Patient mortality was higher in the hyperuricaemia group than the non-hyperuricaemia group (68.4% vs 38.3%, P < 0.05). The incidence of AKI and kidney failure was 64% and 43.3%, respectively. Hyperuricaemia increased the risk of mortality and kidney failure to 3.7- and 3.3 fold after adjustments for age, sex and the estimated amounts of PQ ingestion. Mean serum uric acid level was higher in death group than survival group and higher in kidney failure group than non-AKI group and non-failure group. CONCLUSIONS: Baseline serum uric acid level might be a good clinical marker for patients at risk of mortality and AKI after acute PQ intoxication. PMID- 20966189 TI - Adipose tissue-derived stem cells: can impure cell preparations give pure results? PMID- 20966192 TI - Microparticles initiate decompression-induced neutrophil activation and subsequent vascular injuries. AB - Progressive elevations in circulating annexin V-coated microparticles (MPs) derived from leukocytes, erythrocytes, platelets, and endothelial cells are found in mice subjected to increasing decompression stresses. Individual MPs exhibit surface markers from multiple cells. MPs expressing platelet surface markers, in particular, interact with circulating neutrophils, causing them to degranulate and leading to further MP production. MPs can be lysed by incubation with polyethylene glycol (PEG) telomere B surfactant, and the number of circulating MPs is reduced by infusion of mice with PEG or antibody to annexin V. Myeloperoxidase deposition and neutrophil sequestration in tissues occur in response to decompression, and the pattern differs among brain, omentum, psoas, and leg skeletal muscle. Both MP abatement strategies reduce decompression induced intravascular neutrophil activation, neutrophil sequestration, and tissue injury documented as elevations of vascular permeability and activated caspase-3. We conclude that MPs generated by decompression stresses precipitate neutrophil activation and vascular damage. PMID- 20966191 TI - Novel serum biomarkers for erythropoietin use in humans: a proteomic approach. AB - Erythropoietin (Epo) is produced primarily in the kidneys upon low blood oxygen availability and stimulates erythropoiesis in the bone marrow. Recombinant human Epo (rHuEpo), a drug developed to increase arterial oxygen content in patients, is also illicitly used by athletes to improve their endurance performance. Therefore, a robust and sensitive test to detect its abuse is needed. The aim of the present study was to investigate potential human serum biomarkers of Epo abuse employing a proteomic approach. Eight healthy male subjects were injected subcutaneously with rHuEpo (5,000 IU) every second day for a 16-day period. Serum was collected before starting the treatment regime and again at days 8 and 16 during the treatment period. Samples were homogenized and proteins separated by two-dimensional gel electrophoresis (2DE). Spots that changed significantly in response to rHuEpo treatment were identified by mass spectrometry. Both the number of reticulocytes and erythrocytes increased throughout the study, leading to a significant increase in hematocrit and hemoglobin content. In addition, transferrin levels increased but the percentage of iron bound to transferrin and ferritin levels decreased. Out of 97 serum proteins, seven were found to decrease significantly at day 16 compared with pre-Epo administration, and were identified as four isoforms of haptoglobin, two isoforms of transferrin, and a mixture of hemopexin and albumin. In support, total serum haptoglobin levels were found to be significantly decreased at both days 8 and 16. Thus a 2DE proteomic approach for discovery of novel markers of Epo action appears feasible. PMID- 20966190 TI - Maternal dietary tryptophan deficiency alters cardiorespiratory control in rat pups. AB - Malnutrition during pregnancy adversely affects postnatal forebrain development; its effect upon brain stem development is less certain. To evaluate the role of tryptophan [critical for serotonin (5-HT) synthesis] on brain stem 5-HT and the development of cardiorespiratory function, we fed dams a diet ~45% deficient in tryptophan during gestation and early postnatal life and studied cardiorespiratory variables in the developing pups. Deficient pups were of normal weight at postnatal day (P)5 but weighed less than control pups at P15 and P25 (P < 0.001) and had lower body temperatures at P15 (P < 0.001) and P25 (P < 0.05; females only). Oxygen consumption (Vo(2)) was unaffected. At P15, deficient pups had an altered breathing pattern and slower heart rates. At P25, they had significantly lower ventilation (Ve) and Ve-to-Vo(2) ratios in both air and 7% CO(2). The ventilatory response to CO(2) (% increase in Ve/Vo(2)) was significantly increased at P5 (males) and reduced at P15 and P25 (males and females). Deficient pups had 41-56% less medullary 5-HT (P < 0.01) compared with control pups, without a difference in 5-HT neuronal number. These data indicate important interactions between nutrition, brain stem physiology, and age that are potentially relevant to understanding 5-HT deficiency in the sudden infant death syndrome. PMID- 20966193 TI - Quadriceps metabolism during constant workrate cycling exercise in chronic obstructive pulmonary disease. AB - Impaired resting metabolism in peripheral muscles potentially contributes to exercise intolerance in chronic obstructive pulmonary disease (COPD). This study investigated the cytosolic energy metabolism of the quadriceps, from glycogen degradation to lactate accumulation, in exercising patients with COPD, in comparison to healthy controls. We measured, in 12 patients with COPD and 10 control subjects, resting and post-cycling exercise quadriceps levels of 1) energy substrates and end products of glycolysis (glycogen, glucose, pyruvate, and lactate) and intermediate markers of glycolysis (glucose-6-phosphate, glucose 1-phosphate, fructose-6-phosphate) and 2) the activity of key enzymes involved in the regulation of glycolysis (phosphofructokinase, lactate dehydrogenase). Exercise intensity (P < 0.01), duration (P = 0.049), and total work (P < 0.01) were reduced in patients with COPD. The variations in energy substrates and end products of glycolysis after cycling exercise were of similar magnitude in patients with COPD and controls. Glucose-6-phosphate (P = 0.036) and fructose-6 phosphate (P = 0.042) were significantly elevated in patients with COPD after exercise. Phosphofructokinase (P < 0.01) and lactate dehydrogenase (P = 0.02) activities were greater in COPD. Muscle glycogen utilization (P = 0.022) and lactate accumulation (P = 0.025) per unit of work were greater in COPD. We conclude that cycling exercise induced changes in quadriceps metabolism in patients with COPD that were of similar magnitude to those of healthy controls. These intramuscular events required a much lower exercise work load and time to occur in COPD. Our data suggest a greater reliance on glycolysis during exercise in COPD, which may contribute to exercise intolerance in COPD. PMID- 20966194 TI - Estradiol's beneficial effect on murine muscle function is independent of muscle activity. AB - Estradiol (E2) deficiency decreases muscle strength and wheel running in female mice. It is not known if the muscle weakness results directly from the loss of E2 or indirectly from mice becoming relatively inactive with presumably diminished muscle activity. The first aim of this study was to determine if cage activities of ovariectomized mice with and without E2 treatment differ. Ovariectomized mice were 19-46% less active than E2-replaced mice in terms of ambulation, jumping, and time spent being active (P <= 0.033). After E2-deficient mice were found to have low cage activities, the second aim was to determine if E2 is beneficial to muscle contractility, independent of physical activities by the mouse or its hindlimb muscles. Adult, female mice were ovariectomized or sham-operated and randomized to receive E2 or placebo and then subjected to conditions that should maintain physical and muscle activity at a constant low level. After 2 wk of hindlimb suspension or unilateral tibial nerve transection, muscle contractile function was assessed. Soleus muscles of hindlimb-suspended ovariectomized mice generated 31% lower normalized (relative to muscle contractile protein content) maximal isometric force than suspended mice with intact ovaries (P <= 0.049). Irrespective of whether the soleus muscle was innervated, muscles from ovariectomized mice generated ~20% lower absolute and normalized maximal isometric forces, as well as power, than E2-replaced mice (P <= 0.004). In conclusion, E2 affects muscle force generation, even when muscle activity is equalized. PMID- 20966195 TI - Movement of the human upper airway during inspiration with and without inspiratory resistive loading. AB - The electromyographic (EMG) activity of human upper airway muscles, particularly the genioglossus, has been widely measured, but the relationship between EMG activity and physical movement of the airway muscles remains unclear. We aimed to measure the motion of the soft tissues surrounding the airway during normal and loaded inspiration on the basis of the hypothesis that this motion would be affected by the addition of resistance to breathing during inspiration. Tagged MR imaging of seven healthy subjects was performed in a 3-T scanner. Tagged 8.6-mm spaced grids were used, and complementary spatial modulation of magnetization images were acquired beginning ~200 ms before inspiratory airflow. Deformation of tag line intersections was measured. The genioglossus moved anteriorly during normal and loaded inspiration, with less movement during loaded inspiration. The motion of tissues at the anterior border of the upper airway was nonuniform, with larger motions inferiorly. At the level of the soft palate, the lateral dimension of the airway decreased significantly during loaded inspiration (-0.15 +/- 0.09 and -0.48 +/- 0.09 mm during unloaded and loaded inspiration, respectively, P < 0.05). When resistance to inspiratory flow was added, genioglossus motion and lateral dimensions of the airway at the level of the soft palate decreased. Our results suggest that genioglossus motion begins early to dilate the airway prior to airflow and that inspiratory loading reduces the anterior motion of the genioglossus and increases the collapse of the lateral airway walls at the level of the soft palate. PMID- 20966196 TI - Effects of cross-education on the muscle after a period of unilateral limb immobilization using a shoulder sling and swathe. AB - The purpose of this study was to apply cross-education during 4 wk of unilateral limb immobilization using a shoulder sling and swathe to investigate the effects on muscle strength, muscle size, and muscle activation. Twenty-five right-handed participants were assigned to one of three groups as follows: the Immob + Train group wore a sling and swathe and strength trained (n = 8), the Immob group wore a sling and swathe and did not strength train (n = 8), and the Control group received no treatment (n = 9). Immobilization was applied to the nondominant (left) arm. Strength training consisted of maximal isometric elbow flexion and extension of the dominant (right) arm 3 days/wk. Torque (dynamometer), muscle thickness (ultrasound), maximal voluntary activation (interpolated twitch), and electromyography (EMG) were measured. The change in right biceps and triceps brachii muscle thickness [7.0 +/- 1.9 and 7.1 +/- 2.2% (SE), respectively] was greater for Immob + Train than Immob (0.4 +/- 1.2 and -1.9 +/- 1.7%) and Control (0.8 +/- 0.5 and 0.0 +/- 1.1%, P < 0.05). Left biceps and triceps brachii muscle thickness for Immob + Train (2.2 +/- 0.7 and 3.4 +/- 2.1%, respectively) was significantly different from Immob (-2.8 +/- 1.1 and -5.2 +/- 2.7%, respectively, P < 0.05). Right elbow flexion strength for Immob + Train (18.9 +/- 5.5%) was significantly different from Immob (-1.6 +/- 4.0%, P < 0.05). Right and left elbow extension strength for Immob + Train (68.1 +/- 25.9 and 32.2 +/- 9.0%, respectively) was significantly different from the respective limb of Immob (1.3 +/- 7.7 and -6.1 +/- 7.8%) and Control (4.7 +/- 4.7 and -0.2 +/- 4.5%, P < 0.05). Immobilization in a sling and swathe decreased strength and muscle size but had no effect on maximal voluntary activation or EMG. The cross-education effect on the immobilized limb was greater after elbow extension training. This study suggests that strength training the nonimmobilized limb benefits the immobilized limb for muscle size and strength. PMID- 20966197 TI - The effect of intermittent hypoxia on obstructive sleep apnea: beneficial or detrimental? PMID- 20966198 TI - Human SAP18 mediates assembly of a splicing regulatory multiprotein complex via its ubiquitin-like fold. AB - RNPS1, Acinus, and SAP18 form the apoptosis- and splicing-associated protein (ASAP) complex, which is also part of the exon junction complex. Whereas RNPS1 was originally identified as a general activator of mRNA processing, all three proteins have been found within functional spliceosomes. Both RNPS1 and Acinus contain typical motifs of splicing regulatory proteins including arginine/serine rich domains. Due to the absence of such structural features, however, a function of SAP18 in splicing regulation is completely unknown. Here we have investigated splicing regulatory activities of the ASAP components. Whereas a full-length Acinus isoform displayed only limited splicing regulatory activity, both RNPS1 and, surprisingly, SAP18 strongly modulated splicing regulation. Detailed mutational analysis and three-dimensional modeling data revealed that the ubiquitin-like fold of SAP18 was required for efficient splicing regulatory activity. Coimmunoprecipitation and immunofluorescence experiments demonstrated that SAP18 assembles a nuclear speckle-localized splicing regulatory multiprotein complex including RNPS1 and Acinus via its ubiquitin-like fold. Our results therefore suggest a novel function of SAP18 in splicing regulation. PMID- 20966199 TI - Mechanism of translational regulation by miR-2 from sites in the 5' untranslated region or the open reading frame. AB - MicroRNAs (miRs) commonly regulate translation from target mRNA 3' untranslated regions (UTRs). While effective miR-binding sites have also been identified in 5' untranslated regions (UTRs) or open reading frames (ORFs), the mechanism(s) of miR-mediated regulation from these sites has not been defined. Here, we systematically investigate how the position of miR-binding sites influences translational regulation and characterize their mechanistic basis. We show that specific translational regulation is elicited in vitro and in vivo not only from the 3'UTR, but equally effectively from six Drosophila miR-2-binding sites in the 5'UTR or the ORF. In all cases, miR-2 triggers mRNA deadenylation and inhibits translation initiation in a cap-dependent fashion. In contrast, single or dual miR-2-binding sites in the 5'UTR or the ORF yield rather inefficient or no regulation. This work represents the first demonstration that 5'UTR and ORF miR binding sites can function mechanistically similarly to the intensively investigated 3'UTR sites. Using single or dual binding sites, it also reveals a biological rationale for the high prevalence of miR regulatory sites in the 3'UTR. PMID- 20966200 TI - International workshop on environmental thoron and related issues. PMID- 20966201 TI - Preliminary assessment of thoron exposure in Canada. AB - Radon has been identified as the second leading cause of lung cancer after tobacco smoking. (222)Rn (radon gas) and (220)Rn (thoron gas) are the most common isotopes of radon. In this study, thoron exposure in Canada was assessed based on three community radon/thoron surveys conducted recently. It was confirmed that thoron was detectable in most homes and thoron progeny were present in every home surveyed. Results demonstrated that thoron concentrations varied more widely than radon. No clear correlation between (222)Rn and (220)Rn concentrations was observed in simultaneous measurements. It is estimated that thoron contributes to about 7 % of the radiation dose due to indoor radon exposure based on measurements in about 260 individual homes. Because indoor measurements and geological gamma-ray surveys did not support a reasonable association between (222)Rn and (220)Rn, thoron concentrations could not be predicted from widely available indoor radon information. In order to better assess thoron exposure in Canada and thoron risk to the Canadian population in various geographic locations, more thoron progeny measurements are required. PMID- 20966202 TI - Thoron measurements in Hungary. AB - In this study, several Hungarian dwellings and working places were surveyed using passive radon- and thoron-measuring devices (Radopot((r)) and Raduet((r))) from 2003 to 2008. The detectors were placed 15-30 cm from the wall throughout the 1- to 3-month period. In dwellings, the presence of thoron, ~100 Bq m(-3), was detected almost in all cases, ; however, in the cellars of these buildings, a value ~200 Bq m(-3) was typical. In the cases of manganese and bauxite mines, the concentration of thoron was mainly 200 and 500 Bq m(-3), respectively. In caves, it was 1000 Bq m(-3), whereas in the radon bath it was ~100 Bq m(-3). As in many cases, the ratio between thoron and radon concentrations was >0.25 and the dose contribution from thoron and its progeny was not negligible. Therefore, further investigation on the thoron progeny will be necessary for an accurate dose estimation. PMID- 20966203 TI - Collaborative investigations on thoron and radon in some rural communities of Balkans. AB - This paper deals with the results of the first-field use in the Balkans, i.e. Serbia and Republic of Srpska (Bosnia and Hercegovina), of a passive polycarbonate Mark II type and poliallyldiglycol carbonate (Cr-39) alpha track detectors sensitive to thoron as well as to radon. Both types of solid state nuclear track detectors were designed and supplied by National Institute of Radiological Sciences (NIRS), Chiba, Japan. The commercial names for these detectors which all have been field tested in Balkan rural communities are known as: UFO and RADUET passive discriminative radon/thoron detectors. No database of thoron and thoron progeny concentrations in dwellings in Serbia or Balkans region exist, and as a result, the level of exposure of the Serbian population to thoron and its progeny is unknown so far. PMID- 20966204 TI - Thoron and decay products, beyond UNSCEAR 2006 Annex E. AB - Uranium and thorium series radionuclides are present in all soils and rocks. Thus, radon and thoron, the radioactive noble gases originating in the uranium ((238)U) and thorium ((232)Th) decay chains is ubiquitous and everyone is exposed to both radon and thoron gases and their particulate radioactive decay products. As described in UNSCEAR Annex E (2006), radon and its decay products have been recognised for many years as a hazard to underground miners. More recently, the risks from exposure to residential radon have been demonstrated through residential case-control epidemiological studies. However, as discussed by UNSCEAR, exposures to thoron and its decay products have often been relatively ignored. Moreover, unlike radon the effects of exposure to thoron and its decay products are not available from epidemiology and thus, a dosimetric approach is required to assess risks. UNSCEAR continues to recommend the use of a dose conversion factor for thoron decay products of 40 nSv (Bq h m(-3))(-1). UNSCEAR Annex E suggests there is an emerging problem, namely, that the contribution of (220)Rn (thoron) gas to the (222)Rn (radon) gas measurement signal is not well known. Until recently, this has largely been ignored. This is an important consideration as measurements at work and homes are the basis for investigating lung cancer exposure-response relationships. Based on UNSCEAR Annex E, this paper provides an overview of the sources and levels of thoron and its associated decay products at home and work. In addition, this paper provides an overview of the thoron dosimetry considered by UNSCEAR Annex E and some recent results. PMID- 20966205 TI - A new passive radon-thoron discriminative measurement system. AB - A new passive radon-thoron discriminative measurement system has been developed for monitoring radon and thoron individually. It consists of a 'couple' of passive integrating devices with a CR39 nuclear track detector (NTD). The experimental prototype is based on the application of a new concept of NTD instrument developed at ENEA, named Alpha-PREM, acronym of piston radon exposure meter, which allows controlling the detector exposure with a patented sampling technique (Int. Eu. Pat. and US Pat.). The 'twin diffusion chambers system' was based on two A-PREM devices consisting of the standard device, named NTD-Rn, and a modified version, named NTD-Rn/Tn, which was set up to improve thoron sampling efficiency of the diffusion chamber, without changing the geometry and the start/stop function of the NTD-Rn device. Coupling devices fitted on each device allowed getting a system, which works as a double-chamber structure when deployed at the monitoring position. In this paper both technical and physical aspects are considered. PMID- 20966207 TI - The complexity of childhood development: variability in perspective. AB - The complexity of childhood development is exemplified in the variability of development that is seen across tasks and individuals. Furthermore, variability in performance is omnipresent within individuals across repetitions of a task and across individuals performing the same task. Previously, this variability was thought to reflect error of measurement or error of execution. On this account, variability reflects noise that should be filtered or averaged out of the data in order to reveal the "true" underlying characteristics of the performance. Although errors of measurement and execution indeed contribute to variability in movements, research in the last 2 decades has revealed characteristics of variability that are far more interesting than just noise. These characteristics can be deeply informative about underlying control processes and point to directions for clinical practice. This perspective article reviews different ways of characterizing variability, illustrates changes in variability as a result of development and learning, and discusses different theoretical perspectives on the role of variability that give clues about how to understand changes in variability and how to deal with variability in clinical settings. PMID- 20966208 TI - Variability in postural control during infancy: implications for development, assessment, and intervention. AB - Variability is commonly considered a key to typical motor development. However, multiple definitions and quantification systems have limited the clinical interpretation of variability and the translation of developmental research to assessment and intervention. The purposes of this perspective article are to highlight the importance of statistical variability and complexity in postural control during development and to describe implications for assessment and intervention during infancy and early childhood. Five tenets are proposed describing the role of variability in postural control to support movement experiences, exploration, and global development. Evidence for assessment and intervention focused on variability in postural control are introduced. PMID- 20966209 TI - Variation and variability: key words in human motor development. AB - This article reviews developmental processes in the human brain and basic principles underlying typical and atypical motor development. The Neuronal Group Selection Theory is used as theoretical frame of reference. Evidence is accumulating that abundance in cerebral connectivity is the neural basis of human behavioral variability (ie, the ability to select, from a large repertoire of behavioral solutions, the one most appropriate for a specific situation). Indeed, typical human motor development is characterized by variation and the development of adaptive variability. Atypical motor development is characterized by a limited variation (a limited repertoire of motor strategies) and a limited ability to vary motor behavior according to the specifics of the situation (ie, limited variability). Limitations in variation are related to structural anomalies in which disturbances of cortical connectivity may play a prominent role, whereas limitations in variability are present in virtually all children with atypical motor development. The possible applications of variation and variability in diagnostics in children with or at risk for a developmental motor disorder are discussed. PMID- 20966211 TI - Perspective on variability in the development of human action. AB - Humans are designed not only with variability but for variability. This article explores the important contribution of variability to successful human action. Human systems for action have abundant variability of tissues and processes. This plasticity provides for the necessary flexibility when humans encounter the metric and dynamic changes of growth, development, and adaptation of action across the life span. However, variability must have definable limits. The reduction of possible solutions to probable solutions and the reduction of variability appear to be common assumptions of most theories of human action. The lack of variability of action is a hindrance to the development of skilled, functional action, and excessive variability interferes with the production of automatic, dependable, and typical functional action. The lack of variability and excessive variability are hallmarks of the movement patterns produced by people across the life span following neurological insult. Active problem solving as therapy, with its inherent error as a part of the therapeutic process, is critical to the successful learning of functional actions. The role of the physical therapist is to create movement environments and provide personal and environmental constraints that elicit and support self-produced functional actions. PMID- 20966210 TI - Opportunities for early intervention based on theory, basic neuroscience, and clinical science. AB - Therapeutic approaches in the pediatric population have generally been less aggressive than those implemented for younger and older adults. Several factors contribute to this, starting with the challenge of engaging infants in the "goal" of therapy, their resistance to initiating behaviors that are uncomfortable or fatiguing, the desire to make therapy as functionally relevant as possible when many functional skills have yet to emerge, and residual history of outdated theoretical concepts. On the practical side of who will pay for this more aggressive approach, there is limited empirical evidence based on randomized controlled trials to convince third-party payers to fund more extensive services. This article outlines a theoretical perspective prominent in developmental science that argues not only for the importance of frequent bouts of functionally relevant activity on the self-organization of behavioral patterns, but also for the impact that should be expected from the use of rigorous interventions on underlying subsystems, such as neural organization, that support these outcomes. In order to propose some future opportunities for clinical research and application, examples from recent activity-based clinical studies are presented, along with theoretical principles, neuroscience, and other tissue science data concerning mechanisms that contribute to behavioral changes. One such opportunity is to increase the structured engagement of caregivers, guided by therapists, in administering well-defined activity intervention programs focused on the development of specific functional skills. Such an approach may be one of the few financially feasible options for generating sufficient therapy that adheres to principles for optimizing development of neuromotor control. PMID- 20966212 TI - A comparison of interventions for children with cerebral palsy to improve sitting postural control: a clinical trial. AB - BACKGROUND: The ability to sit independently is fundamental for function but delayed in infants with cerebral palsy (CP). Studies of interventions directed specifically toward sitting in infants with CP have not been reported. OBJECTIVE: The purpose of this study was to compare 2 interventions for improving sitting postural control in infants with CP. DESIGN: For this randomized longitudinal study, infants under 2 years of age and at risk for CP were recruited for intervention directed toward sitting independence. SETTING: The intervention was conducted at home or at an outpatient facility. PATIENTS AND INTERVENTION: Fifteen infants with typical development (mean age at entry = 5 months, SD = 0.5) were followed longitudinally as a comparison for postural variables. Thirty-five infants with delays in achieving sitting were recruited. Infants with delays were randomly assigned to receive a home program (1 time per week for 8 weeks; mean age = 15.5 months, SD = 7) or a perceptual-motor intervention (2 times per week for 8 weeks; mean age = 14.3 months, SD = 3). MEASUREMENTS: The primary outcome measure was center-of-pressure (COP) data, from which linear and nonlinear variables were extracted. The Gross Motor Function Measure (GMFM) sitting subsection was the clinical outcome measure. RESULTS: There was a main effect of time for the GMFM sitting subscale and for 2 of the COP variables. Interaction of group * time factors indicated significant differences between intervention groups on 2 COP measures, in favor of the group with perceptual-motor intervention. LIMITATIONS: The small number of infants limits the ability to generalize the findings. CONCLUSIONS: Although both groups made progress on the GMFM, the COP measures indicated an advantage for the group with perceptual-motor intervention. The COP measures appear sensitive for assessment of infant posture control and quantifying intervention response. PMID- 20966213 TI - Induction of the unfolded protein response after monocyte to macrophage differentiation augments cell survival in early atherosclerotic lesions. AB - Endoplasmic reticulum (ER) stress causes macrophage cell death within advanced atherosclerotic lesions, thereby contributing to necrotic core formation and increasing the risk of atherothrombotic disease. However, unlike in advanced lesions, the appearance of dead/apoptotic macrophages in early lesions is less prominent. Given that activation of the unfolded protein response (UPR) is detected in early lesion-resident macrophages and can enhance cell survival against ER stress, we investigated whether UPR activation occurs after monocyte to macrophage differentiation and confers a cytoprotective advantage to the macrophage. Human peripheral blood monocytes were treated with monocyte colony stimulating factor to induce macrophage differentiation, as assessed by changes in ultrastructure and scavenger receptor expression. UPR markers, including GRP78, GRP94, and spliced XBP-1, were induced after macrophage differentiation and occurred after a significant increase in de novo protein synthesis. UPR activation after differentiation reduced macrophage cell death by ER stress inducing agents. Further, GRP78 overexpression in macrophages was sufficient to reduce ER stress-induced cell death. Consistent with these in vitro findings, UPR activation was observed in viable lesion-resident macrophages from human carotid arteries and from the aortas of apoE(-/-) mice. However, no evidence of apoptosis was observed in early lesion-resident macrophages from the aortas of apoE(-/-) mice. Thus, our findings that UPR activation occurs during macrophage differentiation and is cytoprotective against ER stress-inducing agents suggest an important cellular mechanism for macrophage survival within early atherosclerotic lesions. PMID- 20966215 TI - Peripherally applied Abeta-containing inoculates induce cerebral beta amyloidosis. AB - The intracerebral injection of beta-amyloid-containing brain extracts can induce cerebral beta-amyloidosis and associated pathologies in susceptible hosts. We found that intraperitoneal inoculation with beta-amyloid-rich extracts induced beta-amyloidosis in the brains of beta-amyloid precursor protein transgenic mice after prolonged incubation times. PMID- 20966214 TI - Fate mapping analysis reveals that adult microglia derive from primitive macrophages. AB - Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders. PMID- 20966216 TI - Efficient atmospheric cleansing of oxidized organic trace gases by vegetation. AB - The biosphere is the major source and sink of nonmethane volatile organic compounds (VOCs) in the atmosphere. Gas-phase chemical reactions initiate the removal of these compounds from the atmosphere, which ultimately proceeds via deposition at the surface or direct oxidation to carbon monoxide or carbon dioxide. We performed ecosystem-scale flux measurements that show that the removal of oxygenated VOC via dry deposition is substantially larger than is currently assumed for deciduous ecosystems. Laboratory experiments indicate efficient enzymatic conversion and potential up-regulation of various stress related genes, leading to enhanced uptake rates as a response to ozone and methyl vinyl ketone exposure or mechanical wounding. A revised scheme for the uptake of oxygenated VOCs, incorporated into a global chemistry-transport model, predicts appreciable regional changes in annual dry deposition fluxes. PMID- 20966217 TI - Glacial silicic acid concentrations in the Southern Ocean. AB - Reconstruction of nutrient concentrations in the deep Southern Ocean has produced conflicting results. The cadmium/calcium (Cd/Ca) data set suggests little change in nutrient concentrations during the last glacial period, whereas the carbon isotope data set suggests that nutrient concentrations were higher. We determined the silicon isotope composition of sponge spicules from the Atlantic and Pacific sectors of the Southern Ocean and found higher silicic acid concentrations in the Pacific sector during the last glacial period. We propose that this increase results from changes in the stoichiometric uptake of silicic acid relative to nitrate and phosphate by diatoms, thus facilitating a redistribution of nutrients across the Pacific and Southern Oceans. Our results are consistent with the global Cd/Ca data set and support the silicic acid leakage hypothesis. PMID- 20966219 TI - An education that inspires. PMID- 20966220 TI - Environment. After red mud flood, scientists try to halt wave of fear and rumors. PMID- 20966218 TI - Kinetic scaffolding mediated by a phospholipase C-beta and Gq signaling complex. AB - Transmembrane signals initiated by a broad range of extracellular stimuli converge on nodes that regulate phospholipase C (PLC)-dependent inositol lipid hydrolysis for signal propagation. We describe how heterotrimeric guanine nucleotide-binding proteins (G proteins) activate PLC-betas and in turn are deactivated by these downstream effectors. The 2.7-angstrom structure of PLC beta3 bound to activated Galpha(q) reveals a conserved module found within PLC betas and other effectors optimized for rapid engagement of activated G proteins. The active site of PLC-beta3 in the complex is occluded by an intramolecular plug that is likely removed upon G protein-dependent anchoring and orientation of the lipase at membrane surfaces. A second domain of PLC-beta3 subsequently accelerates guanosine triphosphate hydrolysis by Galpha(q), causing the complex to dissociate and terminate signal propagation. Mutations within this domain dramatically delay signal termination in vitro and in vivo. Consequently, this work suggests a dynamic catch-and-release mechanism used to sharpen spatiotemporal signals mediated by diverse sensory inputs. PMID- 20966221 TI - Exoplanetary science. First Goldilocks exoplanet may not exist. PMID- 20966222 TI - Planetary science. How wet the moon? Just damp enough to be interesting. PMID- 20966223 TI - Animal science. Rinderpest, deadly for cattle, joins smallpox as a vanquished disease. PMID- 20966224 TI - China census. 1.3 billion divided by 6.5 million, and watch that floating decimal. PMID- 20966226 TI - Newsmaker interview: Hamid Ahmed and Samir Raouf. Iraq banks on peer review to rebuild its research base. Interview by Yudhijit Bhattacharjee. PMID- 20966227 TI - Archaeology. Reanalysis of French cave could deal setback to Neandertal smarts. PMID- 20966228 TI - Immune therapy steps up the attack. PMID- 20966229 TI - Astronomy. Radio astronomers take arms against a sea of signals. PMID- 20966231 TI - Who pays the price for shared social responsibility? PMID- 20966232 TI - Nuclear waste: Thorium's potential. PMID- 20966234 TI - Nuclear waste: progress with public engagement. PMID- 20966235 TI - Research funding. Politics and parthenotes. PMID- 20966236 TI - Developmental biology. Flipping the light switch. PMID- 20966237 TI - Chemistry. Creating ligands with multiple personalities. PMID- 20966238 TI - Structural biology. The flu's proton escort. PMID- 20966239 TI - Oceans. Chaos in the Gulf. PMID- 20966240 TI - Evolution. The long-term benefits of self-rejection. PMID- 20966241 TI - Epidemiology. Environment and disease risks. PMID- 20966242 TI - Detection of water in the LCROSS ejecta plume. AB - Several remote observations have indicated that water ice may be presented in permanently shadowed craters of the Moon. The Lunar Crater Observation and Sensing Satellite (LCROSS) mission was designed to provide direct evidence. On 9 October 2009, a spent Centaur rocket struck the persistently shadowed region within the lunar south pole crater Cabeus, ejecting debris, dust, and vapor. This material was observed by a second "shepherding" spacecraft, which carried nine instruments, including cameras, spectrometers, and a radiometer. Near-infrared absorbance attributed to water vapor and ice and ultraviolet emissions attributable to hydroxyl radicals support the presence of water in the debris. The maximum total water vapor and water ice within the instrument field of view was 155 +/- 12 kilograms. Given the estimated total excavated mass of regolith that reached sunlight, and hence was observable, the concentration of water ice in the regolith at the LCROSS impact site is estimated to be 5.6 +/- 2.9% by mass. In addition to water, spectral bands of a number of other volatile compounds were observed, including light hydrocarbons, sulfur-bearing species, and carbon dioxide. PMID- 20966243 TI - The LCROSS cratering experiment. AB - As its detached upper-stage launch vehicle collided with the surface, instruments on the trailing Lunar Crater Observation and Sensing Satellite (LCROSS) Shepherding Spacecraft monitored the impact and ejecta. The faint impact flash in visible wavelengths and thermal signature imaged in the mid-infrared together indicate a low-density surface layer. The evolving spectra reveal not only OH within sunlit ejecta but also other volatile species. As the Shepherding Spacecraft approached the surface, it imaged a 25- to-30-meter-diameter crater and evidence of a high-angle ballistic ejecta plume still in the process of returning to the surface--an evolution attributed to the nature of the impactor. PMID- 20966244 TI - LRO-LAMP observations of the LCROSS impact plume. AB - On 9 October 2009, the Lunar Crater Observation and Sensing Satellite (LCROSS) sent a kinetic impactor to strike Cabeus crater, on a mission to search for water ice and other volatiles expected to be trapped in lunar polar soils. The Lyman Alpha Mapping Project (LAMP) ultraviolet spectrograph onboard the Lunar Reconnaissance Orbiter (LRO) observed the plume generated by the LCROSS impact as far-ultraviolet emissions from the fluorescence of sunlight by molecular hydrogen and carbon monoxide, plus resonantly scattered sunlight from atomic mercury, with contributions from calcium and magnesium. The observed light curve is well simulated by the expansion of a vapor cloud at a temperature of ~1000 kelvin, containing ~570 kilograms (kg) of carbon monoxide, ~140 kg of molecular hydrogen, ~160 kg of calcium, ~120 kg of mercury, and ~40 kg of magnesium. PMID- 20966245 TI - Diviner Lunar Radiometer observations of the LCROSS impact. AB - The Lunar Reconnaissance Orbiter (LRO) Diviner instrument detected a thermal emission signature 90 seconds after the Lunar Crater Observation and Sensing Satellite (LCROSS) Centaur impact and on two subsequent orbits. The impact heated a region of 30 to 200 square meters to at least 950 kelvin, providing a sustained heat source for the sublimation of up to ~300 kilograms of water ice during the 4 minutes of LCROSS post-impact observations. Diviner visible observations constrain the mass of the sunlit ejecta column to be ~10(-6) to 10(-5) kilograms per square meter, which is consistent with LCROSS estimates used to derive the relative abundance of the ice within the regolith. PMID- 20966246 TI - Diviner Lunar Radiometer observations of cold traps in the Moon's south polar region. AB - Diviner Lunar Radiometer Experiment surface-temperature maps reveal the existence of widespread surface and near-surface cryogenic regions that extend beyond the boundaries of persistent shadow. The Lunar Crater Observation and Sensing Satellite (LCROSS) struck one of the coldest of these regions, where subsurface temperatures are estimated to be 38 kelvin. Large areas of the lunar polar regions are currently cold enough to cold-trap water ice as well as a range of both more volatile and less volatile species. The diverse mixture of water and high-volatility compounds detected in the LCROSS ejecta plume is strong evidence for the impact delivery and cold-trapping of volatiles derived from primitive outer solar system bodies. PMID- 20966247 TI - Hydrogen mapping of the lunar south pole using the LRO neutron detector experiment LEND. AB - Hydrogen has been inferred to occur in enhanced concentrations within permanently shadowed regions and, hence, the coldest areas of the lunar poles. The Lunar Crater Observation and Sensing Satellite (LCROSS) mission was designed to detect hydrogen-bearing volatiles directly. Neutron flux measurements of the Moon's south polar region from the Lunar Exploration Neutron Detector (LEND) on the Lunar Reconnaissance Orbiter (LRO) spacecraft were used to select the optimal impact site for LCROSS. LEND data show several regions where the epithermal neutron flux from the surface is suppressed, which is indicative of enhanced hydrogen content. These regions are not spatially coincident with permanently shadowed regions of the Moon. The LCROSS impact site inside the Cabeus crater demonstrates the highest hydrogen concentration in the lunar south polar region, corresponding to an estimated content of 0.5 to 4.0% water ice by weight, depending on the thickness of any overlying dry regolith layer. The distribution of hydrogen across the region is consistent with buried water ice from cometary impacts, hydrogen implantation from the solar wind, and/or other as yet unknown sources. PMID- 20966248 TI - Oscillatory mass transport in vapor-liquid-solid growth of sapphire nanowires. AB - In vapor-liquid-solid (VLS) growth, the liquid phase plays a pivotal role in mediating mass transport from the vapor source to the growth front of a nanowire. Such transport often takes place through the liquid phase. However, we observed by in situ transmission electron microscopy a different behavior for self catalytic VLS growth of sapphire nanowires. The growth occurs in a layer-by-layer fashion and is accomplished by interfacial diffusion of oxygen through the ordered liquid aluminum atoms. Oscillatory growth and dissolution reactions at the top rim of the nanowires occur and supply the oxygen required to grow a new (0006) sapphire layer. A periodic modulation of the VLS triple-junction configuration accompanies these oscillatory reactions. PMID- 20966249 TI - Species selection maintains self-incompatibility. AB - Identifying traits that affect rates of speciation and extinction and, hence, explain differences in species diversity among clades is a major goal of evolutionary biology. Detecting such traits is especially difficult when they undergo frequent transitions between states. Self-incompatibility, the ability of hermaphrodites to enforce outcrossing, is frequently lost in flowering plants, enabling self-fertilization. We show, however, that in the nightshade plant family (Solanaceae), species with functional self-incompatibility diversify at a significantly higher rate than those without it. The apparent short-term advantages of potentially self-fertilizing individuals are therefore offset by strong species selection, which favors obligate outcrossing. PMID- 20966250 TI - Two pairs of neurons in the central brain control Drosophila innate light preference. AB - Appropriate preferences for light or dark conditions can be crucial for an animal's survival. Innate light preferences are not static in some animals, including the fruit fly Drosophila melanogaster, which prefers darkness in the feeding larval stage but prefers light in adulthood. To elucidate the neural circuit underlying light preference, we examined the neurons involved in larval phototactic behavior by regulating neuronal functions. Modulating activity of two pairs of isomorphic neurons in the central brain switched the larval light preference between photophobic and photophilic. These neurons were found to be immediately downstream of pdf-expressing lateral neurons, which are innervated by larval photoreceptors. Our results revealed a neural mechanism that could enable the adjustment of animals' response strategies to environmental stimuli according to biological needs. PMID- 20966251 TI - Mechanisms of proton conduction and gating in influenza M2 proton channels from solid-state NMR. AB - The M2 protein of influenza viruses forms an acid-activated tetrameric proton channel. We used solid-state nuclear magnetic resonance spectroscopy to determine the structure and functional dynamics of the pH-sensing and proton-selective histidine-37 in M2 bound to a cholesterol-containing virus-envelope-mimetic membrane so as to better understand the proton conduction mechanism. In the high pH closed state, the four histidines form an edge-face pi-stacked structure, preventing the formation of a hydrogen-bonded water chain to conduct protons. In the low-pH conducting state, the imidazoliums hydrogen-bond extensively with water and undergo microsecond ring reorientations with an energy barrier greater than 59 kilojoules per mole. This barrier is consistent with the temperature dependence of proton conductivity, suggesting that histidine-37 dynamically shuttles protons into the virion. We propose a proton conduction mechanism in which ring-flip-assisted imidazole deprotonation is the rate-limiting step. PMID- 20966252 TI - Insight into the mechanism of the influenza A proton channel from a structure in a lipid bilayer. AB - The M2 protein from the influenza A virus, an acid-activated proton-selective channel, has been the subject of numerous conductance, structural, and computational studies. However, little is known at the atomic level about the heart of the functional mechanism for this tetrameric protein, a His(37)-Trp(41) cluster. We report the structure of the M2 conductance domain (residues 22 to 62) in a lipid bilayer, which displays the defining features of the native protein that have not been attainable from structures solubilized by detergents. We propose that the tetrameric His(37)-Trp(41) cluster guides protons through the channel by forming and breaking hydrogen bonds between adjacent pairs of histidines and through specific interactions of the histidines with the tryptophan gate. This mechanism explains the main observations on M2 proton conductance. PMID- 20966253 TI - Widespread divergence between incipient Anopheles gambiae species revealed by whole genome sequences. AB - The Afrotropical mosquito Anopheles gambiae sensu stricto, a major vector of malaria, is currently undergoing speciation into the M and S molecular forms. These forms have diverged in larval ecology and reproductive behavior through unknown genetic mechanisms, despite considerable levels of hybridization. Previous genome-wide scans using gene-based microarrays uncovered divergence between M and S that was largely confined to gene-poor pericentromeric regions, prompting a speciation-with-ongoing-gene-flow model that implicated only about 3% of the genome near centromeres in the speciation process. Here, based on the complete M and S genome sequences, we report widespread and heterogeneous genomic divergence inconsistent with appreciable levels of interform gene flow, suggesting a more advanced speciation process and greater challenges to identify genes critical to initiating that process. PMID- 20966254 TI - SNP genotyping defines complex gene-flow boundaries among African malaria vector mosquitoes. AB - Mosquitoes in the Anopheles gambiae complex show rapid ecological and behavioral diversification, traits that promote malaria transmission and complicate vector control efforts. A high-density, genome-wide mosquito SNP-genotyping array allowed mapping of genomic differentiation between populations and species that exhibit varying levels of reproductive isolation. Regions near centromeres or within polymorphic inversions exhibited the greatest genetic divergence, but divergence was also observed elsewhere in the genomes. Signals of natural selection within populations were overrepresented among genomic regions that are differentiated between populations, implying that differentiation is often driven by population-specific selective events. Complex genomic differentiation among speciating vector mosquito populations implies that tools for genome-wide monitoring of population structure will prove useful for the advancement of malaria eradication. PMID- 20966255 TI - ATM activation by oxidative stress. AB - The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells. PMID- 20966256 TI - The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression. AB - CD4(+)Foxp3(+) regulatory T (T(reg)) cells are important for maintaining immune tolerance. Understanding the molecular mechanism that regulates T(reg) differentiation will facilitate the development of effective therapeutic strategies against autoimmune diseases. We report here that the SUMO E3 ligase PIAS1 restricts the differentiation of natural T(reg) cells by maintaining a repressive chromatin state of the Foxp3 promoter. PIAS1 acts by binding to the Foxp3 promoter to recruit DNA methyltransferases and heterochromatin protein 1 for epigenetic modifications. Pias1 deletion caused promoter demethylation, reduced histone H3 methylation at Lys(9), and enhanced promoter accessibility. Consistently, Pias1(-/-) mice displayed an increased natural T(reg) cell population and were resistant to the development of experimental autoimmune encephalomyelitis. Our studies have identified an epigenetic mechanism that negatively regulates the differentiation of natural T(reg) cells. PMID- 20966257 TI - Serosurvey of Brucella spp. infection in the Kafue lechwe (Kobus leche kafuensis) of the Kafue flats in Zambia. AB - One of the diseases of veterinary and public health importance affecting the Kafue lechwe (Kobus leche kafuensis) on the Kafue flats is brucellosis, for which only scant information is available. During the 2003 (October), 2004 (December), and 2008 (July-December) hunting seasons in the Kafue flats, we conducted a study to determine the seroprevalence of Brucella spp. in the Kafue lechwe and to evaluate serologic tests for detection of Brucella spp. antibodies in lechwe. The Rose Bengal Test (RBT), competitive enzyme-linked immunosorbent assay (cELISA), and fluorescence polarization assay (FPA) were used. A total of 121 Kafue lechwe were hunted for disease investigations in 2003, 2004, and 2008 in the Kafue Flat Game Management Area. Of these, 21.6%, (95% confidence interval [CI]: 14.2-29.1%) had detectable antibodies to Brucella spp. The Kafue lechwe in Lochnivar National Park had higher antibody results than those in Blue Lagoon National Park (odds ratio=3.0; 95% CI: 0.94-9.4). Infection levels were similar in females (21.6%) and males (21.7%). Results were similar among RBT, FPA, cELISA tests, suggesting that these could effectively be used in diagnosing brucellosis in the Kafue lechwe. Our study demonstrates the presence of Brucella infections in the Kafue lechwe in two national parks located in the Kafue flats and further highlights the suitability of serologic assays for testing the Kafue lechwe. Because the Kafue lechwe is the most hunted wildlife species in Zambia, hunters need to be informed of the public health risk of Brucella spp. infection. PMID- 20966258 TI - Characterization of Mycoplasma isolated from an ibex (Capra ibex) suffering from keratoconjunctivitis in northern Italy. AB - In 2005 a Mycoplasma species was isolated from ocular-conjunctival swabs from an adult male Alpine ibex (Capra ibex) from the Valle d'Aosta Region, Northern Italy. The animal suffered from bilateral ocular discharge with diffuse inflammation, severe corneal involvement of the left eye and mild corneal opacity of the right eye. Histologic examination revealed a keratoconjunctivitis characterized by lymphocytic and plasmacellular infiltration. Laboratory investigations of the isolate included culture, transmission electron microscopy, PCR, and denaturing gradient gel electrophoresis, as well as DNA sequencing of the 16S rDNA gene. These tests identified the isolate as Mycoplasma mycoides subsp. capri large-colony serovar, an organism that has occasionally been associated with keratoconjunctivitis in goats. For a correct diagnosis, it is necessary to carry out laboratory investigations, as clinical cases of keratoconjunctivitis in wild ruminants are not always ascribable to Mycoplasma conjunctivae. PMID- 20966259 TI - Diagnosis, treatment, and outcome of eastern box turtles (Terrapene carolina carolina) presented to a wildlife clinic in Tennessee, USA, 1995-2007. AB - We performed a retrospective review of medical records for 574 eastern box turtles (Terrapene carolina carolina) that presented to the University of Tennessee College of Veterinary Medicine (UTCVM) wildlife clinic between 1995 and 2007. These cases were reviewed to document and investigate the presenting complaints, as identified by a good Samaritan, final diagnoses, treatment modalities, days in hospital, and final disposition. Presenting complaints were consistent with the final diagnoses in 81% of cases. Trauma was both the most common presentation and final diagnosis. Associations between final diagnosis and either environmental temperature or precipitation were not significant (P>0.05). However, precipitation had a statistically significant positive association (P<0.05) with aural abscessation. Approximately 5% (28/574) of the box turtles were evaluated for packed cell volume total protein and white blood cell count. No differences were observed between sick and healthy animals for any of these variables. Multiple treatment modalities were used in these cases and were often used in combination, rather than as individual therapies. The number of days spent in the hospital ranged from 0 to 66 days, with a median of 2 days. The wildlife clinic of UTCVM should continue to evaluate the health status of eastern box turtles. Our findings indicate that the high caseload, as well as case variety of eastern box turtles in eastern Tennessee, suggests potential use as a biomonitor for this species. PMID- 20966260 TI - Estimating chronic wasting disease effects on mule deer recruitment and population growth. AB - Chronic wasting disease (CWD), a prion disease of mule deer (Odocoileus hemionus), accelerates mortality and in so doing has the potential to influence population dynamics. Although effects on mule deer survival are clear, how CWD affects recruitment is less certain. We studied how prion infection influenced the number of offspring raised to weaning per adult (>=2 yr old) female mule deer and subsequently the estimated growth rate (lambda) of an infected deer herd. Infected and presumably uninfected radio-collared female deer were observed with their fawns in late summer (August-September) during three consecutive years (2006-2008) in the Table Mesa area of Boulder, Colorado, USA. We counted the number of fawns accompanying each female, then used a fully Bayesian model to estimate recruitment by infected and uninfected females and the effect of the disease on lambda. On average, infected females weaned 0.95 fawns (95% credible interval=0.56-1.43) whereas uninfected females weaned 1.34 fawns (95% credible interval=1.09-1.61); the probability that uninfected females weaned more fawns than infected females was 0.93). We used estimates of prevalence to weight recruitment and survival parameters in the transition matrix of a three-age, single-sex matrix model and then used the matrix to calculate effects of CWD on lambda. When effects of CWD on both survival and recruitment were included, the modeled lambda was 0.97 (95% credible interval = 0.82-1.09). Effects of disease on lambda were mediated almost entirely by elevated mortality of infected animals. We conclude that although CWD may affect mule deer recruitment, these effects seem to be sufficiently small that they can be omitted in estimating the influences of CWD on population growth rate. PMID- 20966261 TI - Serum biochemistry, serology, and parasitology of boreal caribou (Rangifer tarandus caribou) in the Northwest Territories, Canada. AB - Boreal caribou (Rangifer tarandus caribou) are an ecologically and culturally important wildlife species and now range almost exclusively in the boreal forests of Canada, including the Northwest Territories, northern Alberta, and British Columbia. Boreal caribou are threatened throughout their Canadian range because of direct and indirect natural and anthropogenic factors. In the Northwest Territories, however, they have a continuous range that overall has not yet been subjected to the same degree of anthropogenic habitat fragmentation and degradation that has occurred elsewhere in Canada. To monitor the health of boreal caribou populations and individuals, we collected blood from 104 adult, female boreal caribou captured between March 2003 and February 2006 and measured serum biochemical parameters. Serum creatinine was higher in pregnant than in nonpregnant caribou. Several biochemical parameters differed among years, but they tended to be similar to those reported for reindeer. Serum antibodies were found to an alphaherpesvirus, Toxoplasma gondii, and to the Mycobacterium avium subspecies paratuberculosis in 37.5, 2.9, and 1.3% of boreal caribou, respectively. Fecal samples were collected from 149 boreal caribou, and Cryptosporidium sp. oocysts, Giardia sp. cysts, trichostrongyle ova, dorsal spined nematode larvae, cestode ova, and Eimeria sp. were found. Trypanosoma sp. was detected in the blood of 72.1% of boreal caribou. Eimeria sp., Cryptosporidium sp., and Giardia sp. have not been previously reported in boreal caribou. PMID- 20966262 TI - Seasonal and demographic factors influencing gastrointestinal parasitism in ungulates of Etosha National Park. AB - Host-parasite dynamics can be strongly affected by seasonality and age-related host immune responses. We investigated how observed variation in the prevalence and intensity of parasite egg or oocyst shedding in four co-occurring ungulate species may reflect underlying seasonal variation in transmission and host immunity. This study was conducted July 2005-October 2006 in Etosha National Park, Namibia, using indices of parasitism recorded from 1,022 fecal samples collected from plains zebra (Equus quagga), springbok (Antidorcas marsupialis), blue wildebeest (Connochaetes taurinus), and gemsbok (Oryx gazella). The presence and intensity of strongyle nematodes, Strongyloides spp. and Eimeria spp. parasites, were strongly seasonal for most host-parasite combinations, with more hosts infected in the wet season than the dry season. Strongyle intensity in zebra was significantly lower in juveniles than adults, and in springbok hosts, Eimeria spp. intensity was significantly greater in juveniles than adults. These results provide evidence that acquired immunity is less protective against strongyle nematodes than Eimeria spp. infections. The seasonal patterns in parasitism further indicate that the long dry season may limit development and survival of parasite stages in the environment and, as a result, host contact and parasite transmission. PMID- 20966263 TI - Sarcoptic mange found in wolves in the Rocky Mountains in western United States. AB - We documented sarcoptic mange caused by mites (Sarcoptes scabiei) in 22 gray wolves (Canis lupus) in the northern Rocky Mountain states of Montana (n=16) and Wyoming (n=6), from 2002 through 2008. To our knowledge, this is the first report of sarcoptic mange in wolves in Montana or Wyoming in recent times. In addition to confirming sarcoptic mange, we recorded field observations of 40 wolves in Montana and 30 wolves in Wyoming displaying clinical signs of mange (i.e., alopecia, hyperkeratosis, and seborrhea). Therefore, we suspect sarcoptic mange may be more prevalent than we were able to confirm. PMID- 20966264 TI - Nematode larvae (order Spirurida) in gastric tissues of Australian anurans: a comparison between the introduced cane toad and sympatric native frogs. AB - The outcomes of host-parasite interactions depend heavily on the host's immune response, which, in turn, is governed by previous interactions between the host and parasite, both over the host's life time and over evolutionary time. In the case of species introductions, such as the cane toad (Bufo marinus) to Australia, parasites that are benign to native species of the introduced range may present a major challenge to the introduced species. Stomachs of introduced cane toads and seven species of sympatric native frogs were examined for parasites, and their pathology and biology were compared. Cane toads were host to eight species of third-stage spirurid larvae, six of which also occurred in the stomach wall of four native frog species. In general, encysted nematode larvae attained higher prevalence and species richness in introduced cane toads than in sympatric native frogs. This trend was largely explained by differences in body sizes: larger anurans were more likely to possess infections, and cane toads are inherently larger than native frogs. Encysted larvae in cane toad stomachs provoked a marked pathologic response. All larvae (physalopterine and Physocephalus spp.) were surrounded by concentric layers of dense, fibrous tissue, with considerable cellular infiltration characterized by lymphocytes and polymorphs. Many cysts were invaded by cells and exudate, which, in more advanced cases, became calcified. Some larvae appeared viable; most were in various stages of destruction, and some smaller Physocephalus spp. were mummified. Conversely, pathologic response observed in native frogs was minimal, with little fibrotic reaction surrounding the cysts, and no cellular infiltration. Presumably, the contrast in pathology between introduced and native hosts reflects the long evolutionary association between these nematode larvae and native frogs, whereas the recent exposure of introduced toads to these helminths provokes a severe reaction. PMID- 20966265 TI - Leptospirosis in free-ranging endangered European mink (Mustela lutreola) and other small carnivores (Mustelidae, Viverridae) from southwestern France. AB - To study the possible role of disease in the decline of endangered European mink (Mustela lutreola), we conducted a survey of antibody prevalence and renal carriage of pathogenic leptospira (Leptospira interrogans sensu lato) using serum and kidney samples collected from 1990 to 2007 from several free-ranging small carnivores and farmed American mink (Mustela vison) in southwestern France. An indirect microscopic agglutination test using a panel of 16 serovars belonging to 6 serogroups (Australis, Autumnalis, Icterohaemorrhagiae, Grippotyphosa, Panama, Sejroe) revealed antibodies in all species, with significant differences in antibody prevalences: 74% in European mink (n=99), 65.4% in European polecats (Mustela putorius, n=133), 86% in American mink (n=74), 89% in stone martens (Martes foina, n=19), 74% in pine martens (Martes martes, n=19), 35% in common genets (Genetta genetta, n=79), and 31% in farmed American mink (n=51). Serogroups Australis and Icterohaemorragiae were dominant in most free-ranging species; serogroup Grippotyphosa had high prevalences in European mink. Such high antibody prevalences have never been reported. They are probably related to the large number of known reservoirs, rats (Rattus spp.), muskrat (Ondatra zibethicus), and coypu (Myocastor coypu), in the study area. The polymerase chain reaction test specific for pathogenic leptospiral DNA detected renal carriage in 23% of 34 European mink, 22% of 18 polecats, and 15% of 33 free-ranging American mink, with no significant differences. Renal carriage shows that mustelids may shed leptospira for short periods, but their epidemiologic role is probably limited. High antibody prevalences suggest that the disease is unlikely to be highly pathogenic for these species; however, chronic forms of the disease (abortions, renal lesions) could reduce the reproductive success or life span of infected animals. Further studies on the pathogenicity of leptospirosis in these populations are needed to measure its impact on the population dynamics of these rodent predators. PMID- 20966266 TI - Infection dynamics of the lungworm Rhabdias pseudosphaerocephala in its natural host, the cane toad (Bufo marinus), and in novel hosts (native Australian frogs). AB - Host-parasite systems have often evolved over time, such that infection dynamics may become greatly modified from the time of initial contact of the host with the parasite. Biological invasions may be useful to clarify processes in the initial contact of hosts with parasites, and allow us to compare parasite uptake between the ancestral (coevolved) host and novel (noncoevolved) hosts. Cane toads (Bufo marinus) are spreading rapidly through tropical Australia, carrying with them a nematode lungworm (Rhabdias pseudosphaerocephala) congeneric with those found in Australian frogs. We investigated the dynamics of infections of the toad parasite by conducting histologic examinations of cane toads and three native Australian frogs (Litoria dahlii, Litoria nasuta, and Opisthodon ornatus) at 2, 6, and 10 days after experimental exposure to the toad lungworm. More worms were found in toads than in frogs, especially at longer periods postexposure. In toads, the infective larvae entered the skin and muscles within 2 days postexposure, passed into the coelom in 6 days, and reached the lungs at 10 days. In frogs, larvae were found in many organs rather than migrating to consistent target tissues; a few larvae reached the lungs of L. dahlii. Migratory larvae caused increasing inflammation (primarily granulomatous admixed with granulocytes then lymphocytes) through time, especially in frogs. Evolution has resulted in an enhanced ability of the lungworm to locate the target organ (the lungs) of the toad, and an increase in rates of parasite survival within this host. PMID- 20966267 TI - Coagulation profile and platelet parameters of the Arabian sand gazelle (Gazella subgutturosa marica): comparison with humans and camels. AB - During March 2009, we evaluated the hemostatic profile and platelet indices of 18 Arabian sand gazelles (Gazella subgutturosa marica) and compared the results with those from humans and camels (Camelus dromedarius). Gazelles and camels had shorter activated partial thromboplastin times, lower proconvertin and higher antihemophilic factor coagulation activity, and plasma fibrinogen levels than humans. Prothrombin time was longer in sand gazelles and shorter in camels than it was in humans. Plasma thromboplastin component, Stuart factor, and plasma thromboplastin antecedent were similar in gazelles, humans, and camels, whereas the platelet count of the sand gazelle was significantly higher than it was for camels and humans. PMID- 20966268 TI - Hematology and serum chemistry in stranded and wild-caught harbor seals in central California: reference intervals, predictors of survival, and parameters affecting blood variables. AB - Blood was collected from stranded harbor seal (Phoca vitulina) pups at admission (n=64) and release (n=45) from rehabilitation in 2007 and 2008 and from wild caught harbor seal pups, subadults, and adults (n=110) in 2004, 2007, and 2008. Blood values measured at the time of admission were not predictive of survival during rehabilitation. Mass was associated with survival until release, and all pups that died weighed less than 10 kg at the time of admission. Dohle bodies were observed in leukocytes from 15% to 22% of the pups in rehabilitation, but not in the wild pups. Thresholds (95% confidence intervals) among wild pups were less than those in the released pups for leukocytes, neutrophils, total cholesterol, alanine aminotransferase (ALT), glucose, phosphorus, sodium, potassium, total protein, albumin, and globulin; thresholds were greater in wild pups than in released pups for hemoglobin (HGB), hematocrit (HCT), and glucose. Thresholds among released pups were less than those in wild pups for HGB, HCT, mean cell volume, chloride, and creatine kinase; thresholds among released pups were greater than those in wild pups for neutrophils, platelets, total cholesterol, triglycerides, ALT, aspartate aminotransferase, sorbitol dehydrogenase, bilirubin, phosphorus, potassium, total protein, and albumin. Age, girth, and geographic location affected the blood variables from wild-caught pups; age class, geographic location, sex, and body condition affected the blood variables of wild-caught, subadult and adult harbor seals. PMID- 20966269 TI - Dermatitis in captive Wyoming toads (Bufo baxteri) associated with Fusarium spp. AB - From May 2007 to June 2008, 30 of 49 Wyoming toads (Bufo baxteri) kept at Omaha's Henry Doorly Zoo (Nebraska, USA) died showing clinical signs of ventral erythema, inappetance, lethargy, and delayed righting reflex. Treatment with antifungals and antibiotics was unsuccessful in all cases. Histopathologic analyses revealed dermatitis as the primary problem in 20 of 21 toads in which skin was examined. Fungal dermatitis was present in 17 toads, with hyphae approximately 1-3 MUm in diameter, and parallel cell walls and frequent septations. In 14 animals, the fungal dermatitis was the main pathologic lesion. Several species of bacteria were associated with all cases. A few animals tested positive for Ranavirus using polymerase chain reaction. Fusarium sp. was consistently cultured from skin, feces, kidneys, and from powdered food provided to crickets. Four isolates were identified as Fusarium proliferatum, Fusarium oxysporum, Fusarium solani, and Fusarium verticillioides, which suggested a secondary role of fungi. A specific underlying cause of disease could not be found, although the roles of humidity and Ranavirus infection are discussed, along with the well-known susceptibility of bufonids to fungal dermatitis. PMID- 20966270 TI - Total intravenous anesthesia with midazolam, ketamine, and xylazine or detomidine following induction with tiletamine, zolazepam, and xylazine in red deer (Cervus elaphus hippelaphus) undergoing surgery. AB - Sixteen captive female red deer were successfully anesthetized to surgically implant a telemetry system. The deer were immobilized with (mean+/-SD) 1.79+/ 0.29 mg/kg xylazine and 1.79+/-0.29 mg/kg tiletamine/zolazepam given intramuscularly with a dart gun. Anesthesia was maintained for 69+/-2 min using a total intravenous protocol with a catheter placed in the jugular vein. Group X received xylazine (0.5+/-0.055 mg/kg/hr) and group D, detomidine (2+/-0.22 MUg/kg/hr), both in combination with ketamine (2+/-0.02 mg/kg/hr) and midazolam (0.03+/-0.0033 mg/kg/hr), as a constant rate infusion. Anesthesia was reversed with 0.09+/-0.01 mg/kg atipamezole and 8.7+/-1.21 MUg/kg sarmazenil given intravenously in both groups. These drug combinations provided smooth induction, stable anesthesia for surgery, and rapid recovery. Respiratory depression and mild hypoxemia were seen, and we, therefore, recommend using supplemental intranasal oxygen. PMID- 20966271 TI - Comparison of chemical immobilization methods in wild foxes (Pseudalopex griseus and Pseudalopex culpaeus) in Chile. AB - We immobilized individuals of two species of free-ranging South American foxes, including 28 chilla foxes (Pseudalopex griseus; 13 males and 15 females) and five culpeo foxes (Pseudalopex culpaeus; four males and one female). Animals were trapped and chemically immobilized with ketamine and medetominide (K-M), ketamine and xylazine (K-X), or tiletamine-zolazepam (Z). Heart and respiratory rates, hemoglobin oxygen saturation (SpO2), rectal temperature, and palpebral and anal reflexes were measured at 5-min intervals. Data were analyzed to compare the effect of anesthetic combinations on induction and recovery times, body reflexes, and physiological variables over time. In both species, K-M gave the shortest induction time, followed by K-X and Z. Palpebral and anal reflexes in chilla foxes immobilized with K-M were maintained in more animals than those treated with either K-X or Z. Animals immobilized with Z had higher heart and respiratory rates than those immobilized with either of the other two combinations. Rectal temperature decreased over time for all combinations. Foxes immobilized with K-M maintained a higher SpO2 than those immobilized with either K-X or with Z. All anesthetic combinations were satisfactory in inducing rapid and safe immobilization of the species studied. The anesthetic plane and the effects on physiologic parameters were better in animals immobilized with K-M than with either K-X or Z, and we recommend this anesthetic combination for use in Chilean foxes. Nevertheless, all three drug combinations used were satisfactory in inducing rapid and relatively smooth anesthesia. PMID- 20966272 TI - Persistent organic pollutants in the blood of free-ranging sea otters (Enhydra lutris ssp.) in Alaska and California. AB - As part of tagging and ecologic research efforts in 1997 and 1998, apparently healthy sea otters of four age-sex classes in six locations in Alaska and three in California were sampled for persistent organic pollutants (POPs) and other chemicals of ecologic or environmental concern (COECs). Published techniques for the detection of POPs (specifically ?polychlorinated biphenyls [PCBs], ?DDTs, ?hexachlorocyclohexanes [HCHs], ?polycyclic aromatic hydrocarbons [PAHs], ?chlordanes [CHLs], hexachlorobenzene [HCB], dieldrin, and mirex) in the tissue of dead otters were modified for use with serum from live sea otters. Toxic equivalencies (TEQs) were calculated for POPs with proven bioactivity. Strong location effects were seen for most POPs and COECs; sea otters in California generally showed higher mean concentrations than those in Alaska. Differences in contaminant concentrations were detected among age and sex classes, with high levels frequently observed in subadults. Very high levels of ?DDT were detected in male sea otters in Elkhorn Slough, California, where strong freshwater outflow from agricultural areas occurs seasonally. All contaminants except mirex differed among Alaskan locations; only ?DDT, HCB, and chlorpyrifos differed within California. High levels of ?PCB (particularly larger, more persistent congeners) were detected at two locations in Alaska where associations between elevated PCBs and military activity have been established, while higher PCB levels were found at all three locations in California where no point source of PCBs has been identified. Although POP and COEC concentrations in blood may be less likely to reflect total body burden, concentrations in blood of healthy animals may be more biologically relevant and less influenced by state of nutrition or perimortem factors than other tissues routinely sampled. PMID- 20966273 TI - Heavy metal and selenium concentrations in liver tissue from wild American alligator (Alligator mississippiensis) livers near Charleston, South Carolina. AB - Liver samples from 33 wild American alligators (Alligator mississippiensis) livers from the Charleston, South Carolina, area were analyzed for arsenic (As), cadmium (Cd), cobalt (Co), chromium (Cr), mercury (Hg), nickel (Ni), lead (Pb), and selenium (Se) concentrations. Alligators are top predators and are considered a good biomonitoring species for various toxins, including heavy metals. Alligators from other areas in the US have shown high concentrations of mercury and other heavy metals, but the Charleston area, which is highly industrialized, has not been investigated. We found wide variation in hepatic heavy metal and selenium concentrations among alligators. Length and sex did not show a strong relationship with any metal based on statistical analysis. However, cluster analysis revealed three groupings of alligators based on liver metal concentrations. Alligators with low Se:Hg ratios also had high concentrations of Hg. Due to the wide variation in metal concentrations among individual alligators, we postulate that individual diet and microhabitat usage could be the cause for this variation. PMID- 20966274 TI - Mass mortality associated with koi herpesvirus in wild common carp in Canada. AB - Koi herpesvirus (KHV) was identified as being associated with more than one mortality event affecting common carp in Canada. The first was an extensive mortality event that occurred in 2007 in the Kawartha Lakes region, Ontario, affecting Lakes Scugog and Pigeon. Fish had branchial necrosis and hepatic vasculitis with an equivocal interstitial nephritis. Several fish also had branchial columnaris. Subsequent mortality events occurred in 2008 in additional bodies of water in south-central Ontario, such as Lake Katchewanooka and outside of Ontario in Lake Manitoba, Manitoba. Koi herpesvirus was detected in fish submitted for examination from all of these lakes by polymerase chain reaction (PCR), and sequence of the PCR product revealed 100% homology to KHV strains U and I. Real-time PCR analysis of KHV-infected wild carp revealed viral loads ranging from 6.02*10(1) to 2.4*10(6) copies MUg(-1) host DNA. This is the first report of KHV in Canada. PMID- 20966275 TI - Morbillivirus infection in a wild siberian tiger in the Russian Far East. AB - We report the first documented case of morbillivirus infection in a wild, free ranging Siberian tiger (Panthera tigris altaica). The tigress entered a small village in the Russian Far East in an ambulatory but stuporous state with no apparent recognition or fear of humans. Her condition progressed rapidly with neurological signs, anorexia, and ultimately death. Histologic lesions included vacuolated to malacic white matter in the brain stem, cerebellum, and thalamus, with associated lymphocytic meningoencephalitis. Large, intranuclear, eosinophilic inclusions were within regional astrocytes, and the brain lesions were immunohistochemically positive when stained for canine distemper viral antigen. Hematologic and blood chemistry results were consistent with overwhelming systemic infection and starvation. The animal also was antibody positive for canine distemper virus, feline panleukopenia, and feline coronavirus. PMID- 20966276 TI - Antimicrobial-resistant Salmonella isolated from Eurasian otters (Lutra lutra Linnaeus, 1758) in Portugal. AB - Eurasian otters (Lutra lutra Linnaeus, 1758) are present in a wide range of aquatic environments. Salmonella isolates have been obtained from otters at rehabilitation centers and in the wild and are sometimes associated with serious illnesses. Antimicrobial-resistant Salmonella were isolated from otter fecal samples collected in March 2006, September 2007, and March 2008 in two river basins in southern Portugal. From 67 samples tested, five were positive for Salmonella (7.58%). None of the isolates were susceptible to all antimicrobials tested, and all were resistant to multiple antimicrobials. Our results confirm the role of otters as potential carriers of Salmonella and the importance of environmental exposure to antimicrobial agents in selection for resistance in bacteria. PMID- 20966277 TI - A bighorn sheep die-off in southern Colorado involving a Pasteurellaceae strain that may have originated from syntopic cattle. AB - We investigated a pasteurellosis epizootic in free-ranging bighorn sheep (Ovis canadensis) wherein a Pasteurellaceae strain carried by syntopic cattle (Bos taurus) under severe winter conditions appeared to contribute to pneumonia in affected bighorns. Twenty-one moribund or dead bighorn sheep were found on the "Fossil Ridge" herd's winter range, Colorado, USA, between 13 December 2007 and 29 February 2008. Eight carcasses examined showed gross or microscopic evidence of acute to subacute fibrinous bronchopneumonia. All eight carcasses yielded at least one beta-hemolytic Mannheimia haemolytica biogroup 1(+/-(G)) strain, and seven also yielded a beta-hemolytic Bibersteinia trehalosi biogroup 4 (CDS) strain; evidence of Pasteurella multocida, Mycoplasma ovipneumoniae, and parainfluenza 3 and bovine respiratory syncytial viruses was also detected. Isolates of beta-hemolytic Manneimia haemolytica biogroup 1(G) from a bighorn carcass and a syntopic cow showed 99.5% similarity in genetic fingerprints; B. trehalosi biogroup 4(CDS) isolates were >=94.9% similar to an isolate from a nearby bighorn herd. Field and laboratory observations suggested that pneumonia in affected bighorns may have been caused by a combination of pathogens including two pathogenic Pasteurellaceae strains--one likely of cattle origin and one likely of bighorn origin--with infections in some cases perhaps exacerbated by other respiratory pathogens and severe weather conditions. Our and others' findings suggest that intimate interactions between wild sheep and cattle should be discouraged as part of a comprehensive approach to health management and conservation of North American wild sheep species. PMID- 20966278 TI - Monitoring for bovine viral diarrhea virus in Austrian red deer (Cervus elaphus elaphus) by using ear-notch samples. AB - During 2007-09, ear-notch samples from free-living (n=527) and farmed (n=237) Austrian red deer (Cervus elaphus elaphus) were tested for bovine viral diarrhea virus type 1 (BVDV-1) and type 2 (BVDV-2) by enzyme-linked immunosorbent assay and single-tube real-time reverse transcription PCR. Ear-notch samples were collected by applying modified ear tags from randomly selected hunter-harvested red deer and from individuals originating from deer holdings. All samples tested negative for BVDV-1 and BVDV-2. Results of this study show no evidence of persistently infected animals. They indicate further that BVDV is playing a minor role in free-living and farmed red deer in Austria. Ear-notch samples are an effective tool for in vivo and postmortem detection of BVDV in wildlife. This sample collection technique can be easily used in combination with tagging individual wild animals kept in captivity. PMID- 20966279 TI - Model study on the clinical signs and residue concentrations of sublethal carbofuran poisoning in birds. AB - The incidence of fatal poisoning of birds of prey caused by carbofuran has increased markedly in Hungary since 2007. An experimental model with broiler chickens was used to study clinical signs of sublethal carbofuran poisoning in birds and to measure the residue concentrations of carbamate in tissues after exposure. Eight chickens were treated with a carbofuran-containing insecticide orally by gastric tube at a single dose of 2.5 mg/kg body weight, and clinical signs of poisoning were observed. Gas chromatography was used to determine carbofuran concentrations in the blood, muscle, and liver samples, and in stomach contents. Poisoning was characterized by typical muscarinic and nicotinic clinical signs without mortality. Carbofuran in the stomach and edible tissues of acutely poisoned birds may lead to secondary poisoning of predators and may also present risks to human health. PMID- 20966280 TI - Mite-filled cyst on a Brown-headed Cowbird (Molothrus ater) in Florida, USA. AB - A large, partly pedunculated mass on the scapular area of a wild-caught captive Brown-headed Cowbird (Molothrus ater) consisted of a multiloculated keratin cyst inhabited by a new species of harpirhynchid mite (Harpirhynchus quasimodo). The mass did not interfere with flight or behavior. This is the first record of such an infestation of cowbirds in Florida. PMID- 20966281 TI - Influenza A viruses in American White Pelican (Pelecanus erythrorhynchos). AB - The role of many wild waterbird species in the ecology and epidemiology of avian influenza viruses (AIV) remains unclear. We report the first isolation of AIV from American White Pelicans (Pelecanus erythrorhynchos; Pelecaniformes) in North America. Two H13N9 AIVs were isolated from hatchling birds in breeding colonies in Minnesota, USA, during 2007 and 2008. Based on molecular sequencing of the hemagglutinin and neuraminidase genes, the 2008 virus was genetically related to AIVs previously isolated from gulls and shorebirds in North America. The 2007 isolate was most related to AIVs from Eurasian gulls and North American ducks, reflecting both global movement of these viruses and reassortment between viruses associated with duck and gull reservoirs. PMID- 20966282 TI - Health evaluation of western arctic King Eiders (Somateria spectabilis). AB - The western arctic population of King Eiders (Somateria spectabilis) has declined by >50% in recent years. A health assessment was conducted for adult King Eiders breeding on the north slope of Alaska, USA, to evaluate body condition (n=90, 2002-2006) and baseline biochemical and hematologic values (n=20-30, 2005-2006). Body condition for males and females was excellent. Total protein, calcium, alkaline phosphatase, amylase, and globulin were significantly higher in females than in males, likely because of differences in reproductive physiology. These baseline health data can be used to promote conservation of King Eiders and other closely related species of concern. PMID- 20966283 TI - Serologic evaluation of New Zealand sea lions for exposure to Brucella and Leptospira spp. AB - A serologic survey of anti-Brucella and antileptospiral antibodies was conducted on 147 adult, female New Zealand sea lions (Phocarctos hookeri). Most sea lions (n=138) were sampled at Sandy Bay, Enderby Island, Auckland Islands (50 degrees 30'S, 166 degrees 17'E), January 2000-March 2005. Nine were sampled at Otago, New Zealand (46 degrees 0'S, 170 degrees 40'E); four in April 2008 and five in March 2009. Serum from one of the Enderby Island females was weakly positive for antibodies to Brucella abortus using the competitive enzyme-linked immunosorbent assay, and one female had a low titer for Leptospira interrogans serovar pomona using the microscope agglutination test. All serum samples from Otago animals were negative. Brucellosis and leptospirosis are therefore considered unlikely to play a major role in population dynamics of these populations, and the low antibody prevalence of these agents suggests that they are an unlikely source of infection for humans, wildlife, or domestic species on mainland New Zealand. PMID- 20966284 TI - Salmonella Newport omphaloarteritis in a stranded killer whale (Orcinus orca) neonate. AB - Salmonella enterica serovar Newport (Salmonella Newport) was isolated from multiple tissues in a neonate killer whale (Orcinus orca) that stranded dead in 2005 along the central coast of California, USA. Necrotizing omphaloarteritis and omphalophlebitis was observed on histologic examination suggesting umbilical infection was the route of entry. Genetic analysis of skin samples indicated that the neonate had an offshore haplotype. Salmonellosis has rarely been identified in free-ranging marine mammals and the significance of Salmonella Newport infection to the health of free-ranging killer whales is currently unknown. PMID- 20966285 TI - Microfilariae infection in wild birds from the Brazilian cerrado. AB - We report the occurrence of microfilariae in wild birds of a cerrado area in northern Brazil (Tocantins State). Analyses of 166 passerine birds belonging to 46 species and 17 families captured between 2006 and 2008 revealed that 11 individuals (6.6%) were hosts for microfilariae. Two bird species, Formicivora grisea and Formicivora rufa (Thamnophilidae), were identified as hosts for microfilariae for the first time, and had high intensities of microfilaremia (65 and 107 in 100 microscopic fields, respectively). The prevalence and intensity of microfilariae described in the present study are among the highest reported for wild bird communities in the neotropics. PMID- 20966286 TI - Detection of rabies virus antibodies in Brazilian free-ranging wild carnivores. AB - Rabies virus is a pathogen of major concern in free-ranging wild carnivores in several regions of the world, but little is known about its circulation in Brazilian wild carnivores. Sera from 211 free-ranging wild carnivores, captured from 2000 to 2006 in four locations of two Brazilian biomes (Pantanal and Cerrado), were tested for rabies antibodies. Twenty-six individuals (12.3%) had neutralizing antibody titers >=0.10 IU/ml. The four sampled locations had antibody-positive animals, suggesting that Rabies virus circulates in all of these regions. Results underscore the risk posed by rabies for conservation of Brazilian carnivores and the possibility of the animals acting as reservoirs for the Rabies virus. PMID- 20966287 TI - Susceptibility of the common hamster (Cricetus cricetus) to Francisella tularensis and its effect on the epizootiology of tularemia in an area where both are endemic. AB - Francisella tularensis is a highly infectious zoonotic agent causing the disease tularemia. The common hamster (Cricetus cricetus) is considered a pest in eastern Europe, and believed to be a source of human tularemia infections. We examined the role of the common hamster in the natural cycle of tularemia using serologic methods on 900 hamsters and real-time polymerase chain reaction (PCR) on 100 hamsters in an endemic agricultural area. We collected 374 Ixodes acuminatus ticks from the hamsters and tested them by real-time PCR. All tests were negative. To examine clinical signs, pathology, and histopathology of acute tularemia infection similar to the natural infection, two hamsters were infected with a large dose of a wild strain of F. tularensis ssp. holarctica. After a short period of apathy, the animals died on the eighth and ninth days postinfection. The pathologic, histopathologic, and immunohistochemical examination contributed to the diagnosis of septicemia in both cases. Our results confirmed previous findings that common hamsters are highly sensitive to F. tularensis. We conclude that although septicemic hamsters may pose substantial risk to humans during tularemia outbreaks, hamsters in interepizootic periods do not act as a main reservoir of F. tularensis. PMID- 20966288 TI - Prevalence of neutralizing antibodies to West Nile virus in Eleonora's Falcons in the Canary Islands. AB - Birds are the major amplifying host for West Nile virus (WNV), a flavivirus that may affect humans and transmitted by bloodsucking vectors. Eleonora's Falcons (Falco eleonorae) migrate to the Canary Islands annually from WNV-endemic regions. To investigate the possible role of Eleonora's Falcons in the circulation of WNV, we measured WNV-specific antibodies in 81 falcons captured in 2006. None of the nestlings but 14.8% of the adults had WNV-neutralizing antibodies. RT-PCR did not detect flaviviruses in nonculicine ectoparasites (n=231) of the falcons. These findings suggest that WNV infection did not occur locally, but rather on the wintering grounds or during migration. PMID- 20966289 TI - Survival of captive and free-ranging Harlequin Ducks (Histrionicus histrionicus) following surgical liver biopsy. AB - We measured intra- and postoperative mortality rates of captive and free-ranging Harlequin Ducks (Histrionicus histrionicus) undergoing surgical liver biopsy sampling for determination of the induction of cytochrome P4501A, a biomarker of oil exposure. Liver biopsies were taken from and radio transmitters were implanted into 157 free-ranging Harlequin Ducks over three winters (55 in 2000, 55 in 2001, and 47 in 2002). No birds died during surgery, but seven (4.5%) died during recovery from anesthesia (three in 2001 and four in 2002). None of the deaths could be attributed directly to the liver biopsy. Four of the 150 (2.7%) birds that were released died in the 2 wk period after surgery. All post-release deaths occurred in 2001; no birds died after release in 2000 or 2002. No mortalities of 36 captive birds occurred during surgery or recovery or in the 2 wk period following surgery. Hemorrhage was a minor problem with one captive bird. Surgical liver biopsies appear to be a safe procedure, but anesthetic complications may occur with overwintering ducks. PMID- 20966290 TI - Parasites, primates, and ant-plants: clues to the life cycle of Controrchis spp. in black howler monkeys (Alouatta pigra) in southern Belize. AB - The purpose of this study was to investigate the prevalence, intensity, and possible transmission routes of the trematode, Controrchis spp. (Dicrocoeliidae), in a population of black howler monkeys (Alouatta pigra) near Monkey River, Belize. Alouatta pigra are arboreal primates that are typically folivorous and frugivorous. Controrchis is a dicrocoeliid trematode and, as such, should require a gastropod and an ant (Formicidae) intermediate host for transmission. From January to July 2005 and February 2006 to June 2007, we collected fecal samples and focal animal data from 18 individual primates in four social groups. Feces were stored in either 10% buffered formalin or 95% ethanol and examined using a double-centrifugation sugar-flotation technique. The prevalence of Controrchis spp. was 89%, and the mean intensity was 2.29 eggs per gram (epg), with a range of 1.00-6.57 epg. A general linear mixed model to examine the effect of sex, rainfall, and time spent feeding on various plant species, while controlling for individual and group identity, revealed that both group and the amount of time spent feeding on trumpet trees (Cecropia peltata) by individuals predicted the prevalence and intensity of Controrchis spp. infestation. Cecropia peltata has a mutualistic relationship with Azteca spp. ants and constitutes an important food source for A. pigra. Our findings provide strong, circumstantial evidence that A. pigra are infected with Controrchis spp. through the ingestion of metacercariae in Azteca spp. when feeding on C. peltata. Because C. peltata is a pioneer tree species and typically occurs in disturbed forests, results from this study suggest an important link between habitat disturbance and parasitism in a wild mammal. PMID- 20966291 TI - A comparative study of rabies virus isolates from hematophagous bats in Brazil. AB - The Brazilian chiropteran fauna consists of 167 species; of which, three are hematophagous: the common vampire bat (Desmodus rotundus), the white-winged vampire bat (Diaemus youngi), and the hairy-legged vampire bat (Diphylla ecaudata). The aim of this study was to describe the isolation of Rabies virus from common and hairy-legged vampire bats and to report the first comparative antigenic and genetic studies of isolates from these bats. Antigenic and genetic typing of both isolates identified them as antigenic variant 3 (AgV3), the variant frequently isolated from common vampire bats. Phylogenetic analysis showed 99.3% identity between the isolates. This is the first time since 1934 that Rabies virus has been isolated from hairy-legged vampire bats in Brazil. Our analysis provides evidence that the existence of rabies-positive isolates from hairy-legged vampire bats may be the result of an interspecific rabies transmission event from common vampire bats and suggests that roost cohabitation may occur. PMID- 20966292 TI - Captive rearing and release of Bar-headed Geese (Anser indicus) in China: a possible HPAI H5N1 virus infection route to wild birds. PMID- 20966295 TI - CT urography. PMID- 20966296 TI - Focal iodine defects on color-coded iodine perfusion maps of dual-energy pulmonary CT angiography images: a potential diagnostic pitfall. AB - OBJECTIVE: The purpose of this article is to systematically investigate focal iodine defects found in patients without other CT evidence for pulmonary embolism on color-coded iodine perfusion maps of dual-energy pulmonary CT angiography scans. SUBJECTS AND METHODS: Forty-three patients (mean age, 56.9 years; range, 29-88 years) who underwent pulmonary CT angiography using dual-energy CT from November 2007 to February 2008 but who had no pulmonary embolism were included in our study. Dark orange- or black-colored areas on color-coded iodine perfusion maps were interpreted as focal iodine defects. Two radiologists recorded the presence, location, and characteristics of the focal iodine defects in consensus and evaluated the examinations with regard to the causes of the focal iodine defects. RESULTS: Focal iodine defects were found in 41 patients (95%). The most commonly involved segments were the anterior segment of the right upper lobe (33/38, 86.8%), the apical segment of the right upper lobe (32/38, 84.2%), the medial segment of the right middle lobe (32/38, 84.2%), the apicoposterior segment of the left upper lobe (35/42, 83.3%), the superior and inferior lingular segments of the left upper lobe (23/42, 54.8%), and the medial-basal segment of the right lower lobe (11/32, 34.4%). Beam-hardening artifacts caused by contrast material in the superior vena cava accounted for nearly all defects in the apices of both upper lobes. Cardiac motion was the most common cause of defects in right middle lobe and left upper lobe lingular segments, and diaphragmatic motion was the most common cause in the lung bases. CONCLUSION: Knowledge of the focal iodine defects not related to pulmonary embolism leads to more accurate interpretation of dual-energy pulmonary CT angiography scans. PMID- 20966297 TI - Partially unroofed coronary sinus: MDCT and MRI findings. AB - OBJECTIVE: The purpose of this study was to analyze the MDCT and MRI findings in patients with unroofed coronary sinus syndrome. MATERIALS AND METHODS: This retrospective study included 11 patients with unroofed coronary sinus syndrome (10 adults, one child) without persistent left superior vena cava and one adult with communication of the left atrium and coronary sinus via an anomalous vein (unroofed coronary sinus variant). Four patients underwent contrast-enhanced ECG gated MDCT; six, MRI; and two patients, both CT and MRI. We also measured the coronary sinus on the CT scans of 28 adults with normal cardiac anatomy and 10 adults with persistent left superior vena cava and compared the measurements with those in the patients with unroofed coronary sinus syndrome. Seven patients underwent surgical treatment of unroofed coronary sinus syndrome. RESULTS: At echocardiography, unroofed coronary sinus syndrome was not clearly discriminated from atrial septal defect in two patients and was not suspected in three patients. CT and MRI showed that 11 patients had a defect in which the coronary sinus communicated with the left atrium and that the other patient had atresia of the coronary sinus orifice with an anomalous vein connecting the coronary sinus and left atrium. In patients with unroofed coronary sinus syndrome, the mean standardized diameter of the coronary sinus according to the patient's body surface area was 15 +/- 4 mm/m2, similar to that of the control group with persistent left superior vena cava (15 +/- 6 mm/m2; p = 0.97) and significantly greater than that of the group with normal cardiac anatomy (7 +/- 2 mm/m2; p < 0.0001). CONCLUSION: CT and MRI facilitate definite diagnosis of unroofed coronary sinus syndrome. PMID- 20966298 TI - Positive predictive value of CT urography in the evaluation of upper tract urothelial cancer. AB - OBJECTIVE: The purpose of this study was to determine the positive predictive value of CT urography in the diagnosis of upper tract urothelial malignancies. MATERIALS AND METHODS: Retrospective review of the records of patients who underwent 2,602 CT urographic examinations revealed that 81 (3%) examinations of 77 patients had findings suggesting upper tract urothelial cancer. Two radiologists in consensus categorized the findings as large masses (> 5 mm), small masses (<= 5 mm), or urothelial thickening. The positive predictive value of CT urography was determined with the findings at pathologic examination (n = 42), followup imaging (n = 29), or clinical follow-up alone (n = 5). One patient with insufficient follow-up information was excluded. The effects of age, sex, indication for examination, imaging appearance, and urine cytology were analyzed with the Fisher's exact test or Student's t test. Multivariate logistic regression analysis was used to generate a model for predicting the probability of the presence of upper tract urothelial cancer in patients with positive CT urographic examinations. RESULTS: The positive predictive value of CT urography for upper tract urothelial cancer was 53% (40/76) overall, 83% (29/35) for large masses, 0% (0/17) for small masses, and 46% (11/24) for urothelial thickening. Imaging appearance, urine cytology, and age were significant univariate predictors (p < 0.05) of the presence of upper tract urothelial cancer in patients with positive CT urographic examinations. The independent variables most likely associated with upper tract urothelial cancer were urine cytology (odds ratio, 60.0; 95% CI, 5.5-653.7) and imaging appearance (odds ratio, 24.4; 95% CI, 3.0-201.9) after adjusting for age and clinical indication. CONCLUSION: The positive predictive value of CT urography for upper tract urothelial cancer is moderate because benign findings mimic cancer. Positive findings on a CT urogram are more likely to indicate cancer in the setting of large masses or positive urine cytology. PMID- 20966299 TI - Utility of the apparent diffusion coefficient for distinguishing clear cell renal cell carcinoma of low and high nuclear grade. AB - OBJECTIVE: The purpose of our study was to assess the utility of the apparent diffusion coefficient (ADC) in distinguishing low-grade and high-grade clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: The cases of 57 patients with pathologically proven ccRCC who underwent preoperative MRI, including diffusion-weighted imaging, were retrospectively assessed. ADC values were obtained from ADC maps calculated using b-value combinations of 0 and 400 s/mm2 and of 0 and 800 s/mm2 (hereafter referred to as ADC-400 and ADC-800). Lesions were also evaluated for an array of conventional MRI features. A single expert uropathologist reviewed all slides to determine nuclear grade. The utility of ADC for detecting high-grade ccRCC, alone and in combination with conventional MRI features, was assessed using receiver operating characteristic (ROC) analysis and binary logistic regression. RESULTS: ADC-400 and ADC-800 were significantly lower among high-grade than among low-grade ccRCC (2.24 +/- 0.50 mm2/s vs 1.59 +/- 0.57 mm2/s for ADC-400, p < 0.001; 1.85 +/- 0.40 mm2/s vs 1.28 +/- 0.48 mm2/s for ADC 800; p < 0.001). The area under the ROC curve for identifying high-grade ccRCC using ADC-400 and ADC-800 was 0.801 and 0.824 respectively (p = 0.606), with optimal thresholds, sensitivity, and specificity as follows: ADC-400: 2.17 mm2/s, 88.5%, 64.5% and ADC-800: 1.20 mm2/s, 65.4%, 96.0%. Using multivariate logistic regression, only necrosis (p = 0.0229) and perinephric fat invasion (p = 0.0160) were retained among conventional imaging features as independent risk factors for high-grade ccRCC. The accuracy of the logistic regression model for predicting high-grade ccRCC was significantly improved by inclusion of either ADC-400 (p = 0.0143) or ADC-800 (p = 0.015). CONCLUSION: ADC is significantly lower in high grade ccRCC compared with low-grade ccRCC and increases the accuracy for detecting high-grade ccRCC compared with conventional MRI features alone. PMID- 20966300 TI - In vivo diffusion tensor imaging and tractography of human thigh muscles in healthy subjects. AB - OBJECTIVE: The aims of this study were to assess whether similar measurements of mean apparent diffusion coefficient and fractional anisotropy in muscles can be obtained with regions of interest drawn on cross-sectional diffusion tensor images and tractography and to assess whether water diffusivity in human thigh muscles is influenced by muscular compartment, age, and sex. SUBJECTS AND METHODS: Sixteen healthy volunteers (eight women, eight men) participated in this study. The right thigh of each subject was imaged with diffusion tensor imaging, and the mean apparent diffusion coefficient and fractional anisotropy values were calculated for each muscle of the quadriceps femoris and hamstrings. Fiber tracking was performed with a line propagation technique from the regions of interest drawn on cross-sectional diffusion tensor images. RESULTS: The water diffusivity parameters obtained with tractography did not differ significantly from those obtained with diffusion tensor imaging in the three regions of interest evaluated in each muscle. The mean apparent diffusion coefficient of women (1.80 * 10-3 mm2/s) was similar to that of men (1.79 * 10-3 mm2/s). Women and men had identical fractional anisotropy values (0.26). The fractional anisotropy value in young volunteers (0.27) was similar to that in older subjects (0.26). The hamstrings had a lower mean apparent diffusion coefficient (1.64 * 10 3 mm2/s) than the quadriceps femoris (1.91 * 10-3 mm2/s), but the quadriceps femoris had a significantly lower fractional anisotropy value (0.25) than the hamstrings (0.28). CONCLUSION: Our study showed that the water diffusivity values (mean apparent diffusion coefficient and fractional anisotropy) of the thigh muscles did not differ significantly with respect to sex or age of the subject. The quadriceps femoris and the hamstrings did have different mean apparent diffusion coefficient and fractional anisotropy values, which may reflect differences in hydration and muscular architecture. PMID- 20966301 TI - Verification bias in assessment of the utility of MRI in the diagnosis of cruciate ligament tears. AB - OBJECTIVE: The purpose of this study was to investigate the extent to which verification bias affects the sensitivity and specificity of MRI in the diagnosis of cruciate ligament tears. MATERIALS AND METHODS: Consecutively registered outpatients who underwent MRI evaluation of the knee were included in the study. The sensitivity and specificity of MRI were calculated for patients whose diagnosis was verified with arthroscopy. For patients who did not undergo arthroscopy, the effect of verification bias was estimated with global sensitivity analysis, a technique of graphic representation of whether a particular combination of sensitivity and specificity estimates is compatible with the observed data. RESULTS: Among the 356 patients included in the study, 82 patients (23%) had the MRI findings verified at arthroscopy. The sensitivity and specificity of MRI among patients who underwent arthroscopy were 38% and 90%. For patients whose disease status was not verified with arthroscopy, the influence of verification bias was estimated with global sensitivity analysis. The sensitivity of MRI ranged from 3% to 73%, and the specificity from 63% to 98%. The region comprising all possible combinations of sensitivity and specificity had a butterfly shape. The sensitivity and specificity pair estimated from cases verified with arthroscopy was included in this region. CONCLUSION: Verification bias did not greatly affect assessment of the diagnostic utility of MRI in the evaluation of cruciate ligament tears. The high specificity previously reported for MRI can be considered valid, but the sensitivity may not be as reliable. PMID- 20966302 TI - Ultrashort TE MRI: Usefulness after percutaneous vertebroplasty. AB - OBJECTIVE: The purpose of this study was to assess the feasibility of clinical 3 T ultrashort TE MRI for the visualization of bone cement after percutaneous vertebroplasty. CONCLUSION: Ultrashort TE MRI is useful for evaluating the volume of cement injected at percutaneous vertebroplasty and the presence of cement that has leaked into paraspinal soft tissues and disk spaces. PMID- 20966303 TI - Atypical MRI findings of Wernicke encephalopathy in alcoholic patients. PMID- 20966304 TI - Gossypiboma: stretched feces sign. PMID- 20966305 TI - HIV, HAART, and IRIS: tuberculosis versus malignancy. PMID- 20966306 TI - Postmortem imaging-guided biopsy as an adjuvant to minimally invasive autopsy with CT and postmortem angiography: a feasibility study. AB - OBJECTIVE: Although postmortem CT suffices for diagnosing most forms of traumatic death, the examination of natural death is, to date, very difficult and error prone. The introduction of postmortem angiography has led to improved radiologic diagnoses of natural deaths. Nevertheless, histologic changes to tissues, an important aspect in traditional examination procedures, remain obscure even with CT and CT angiography. For this reason, we examined the accuracy of a minimally invasive procedure (i.e., CT angiography combined with biopsy) in diagnosing major findings and the cause of death in natural deaths. MATERIALS AND METHODS: We examined 20 bodies in a minimally invasive fashion-namely, native CT, CT angiography, and biopsy-and compared the results to those obtained at subsequent autopsy and histologic analysis. RESULTS: Regarding the major findings and the cause of death, the minimally invasive examination showed almost identical results in 18 of 20 cases. In one case, the severity of a cardiac ischemia was underestimated; in another case, the iliopsoas muscles were not biopsied, thus missing the diagnosis of discoid muscle necrosis and therefore a death due to hypothermia. CONCLUSION: In light of increasing objections of the next of kin toward an autopsy and the necessity for medical examiners to assess the manner and cause of death, we think that the minimally invasive procedure described here may present a viable compromise in selected cases. PMID- 20966307 TI - Imaging of extraosseous myeloma: CT, PET/CT, and MRI features. AB - OBJECTIVE: A minority of patients with multiple myeloma have imaging findings of extraosseous involvement. Extraosseous myeloma may affect any organ and can mimic other malignancies. The objective of this article is to describe the clinical relevance of extraosseous myeloma and to present the diverse imaging findings of extraosseous myeloma. CONCLUSION: The presence of radiologically detectable extraosseous myeloma is associated with a poor prognosis and thus is an important factor in the initial workup and follow-up evaluation. PMID- 20966308 TI - Incidental thyroid nodules on chest CT: Review of the literature and management suggestions. AB - OBJECTIVE: This article will review the current literature regarding the detection of thyroid nodules with an emphasis on CT diagnosis. We will also discuss management strategies. CONCLUSION: With advances in cross-sectional imaging, the detection of incidental thyroid nodules has increased significantly. Detection of thyroid nodules is common on chest CT that is being performed for unrelated reasons. The workup of these nodules can be timeconsuming and expensive. PMID- 20966309 TI - Aortic valve and ascending thoracic aorta: Evaluation with isotropic MDCT. AB - OBJECTIVE: The purpose of this review is to show the range of abnormality involving the aortic valve and ascending thoracic aorta using 64- and 128-MDCT with 2D and 3D CT angiography. CONCLUSION: Ascending aorta abnormality can be complicated by secondary involvement or associated disease involving the aortic valve, coronary arteries, and heart. Interactive interrogation of high-quality isotropic volumes, with both 2D and 3D rendering tools, is essential to identify the full array of findings for best interpretative performance. PMID- 20966310 TI - Volume visualization of the ascending thoracic aorta using isotropic MDCT data: protocol optimization. AB - OBJECTIVE: The purpose of this article is to review in detail the optimization of data acquisition, reconstruction, and postprocessing for imaging the ascending aorta with 64- and dual-source 128-MDCT. CONCLUSION: Interpretative success necessitates careful adherence to protocols that maximize dataset resolution and relies on routine use of all of the postprocessing tools available to optimally evaluate the ascending aorta, aortic valve, heart, and coronary arteries. PMID- 20966311 TI - Late gadolinium-enhanced cardiovascular MRI at end-systole: feasibility study. AB - OBJECTIVE: The purpose of this article is to evaluate the image quality and infarct size of segmented late gadolinium-enhanced cardiovascular MRI at end systole, compared with middiastole, in patients with sinus rhythm (SR) and to compare the image quality of end-systole images in patients with atrial fibrillation (AFib) to that of end-systole and middiastole images in patients with SR. SUBJECTS AND METHODS: Study patients (n = 121) were distributed according to heart rate and rhythm: SR with low heart rate (<= 65 beats/minute), SR with intermediate heart rate (66-75 beats/minute), SR with high heart rate (>= 76 beats/minute), and AFib. Image quality was graded on a 5-point scale, where 4 equals optimal and 0 equals not assessable. Global infarct size (percentage of left ventricle [LV] myocardium) in patients with SR with myocardial infarction was quantified using a visual quantitative approach with a 5-point scale and a semiautomatic method. RESULTS: End-systole imaging had higher image quality than did middiastole imaging for patients with SR with high heart rate, whereas middiastole imaging had higher image quality than did end-systole imaging for patients with SR with low heart rate (p < 0.05 for patients with SR with low heart rate, p = 0.60 for patients with SR with intermediate heart rate, and p = 0.001 for patients with SR with high heart rate). The quality of end-systole imaging in patients with AFib was not significantly different from that in patients with SR (p = 0.40 vs SR middiastole imaging and p = 0.38 vs SR end systole imaging). The average difference of global infarct size was -0.3% and 0.2% of LV myocardium, and the limits of agreement were +/- 2.4% and +/- 3.3% of LV myocardium, for visual assessment and semiautomatic assessment, respectively. CONCLUSION: End-systole imaging can provide accurate diagnosis of myocardial infarction, comparable to middiastole imaging. The image quality of end-systole imaging is less susceptible to heart rate and rhythm compared with middiastole imaging. PMID- 20966312 TI - A prospective evaluation of dose reduction and image quality in chest CT using adaptive statistical iterative reconstruction. AB - OBJECTIVE: The purpose of this study was to compare the subjective image quality, image noise, and radiation dose of chest CT images reconstructed with a 30% blend of iterative reconstruction and 70% conventional filtered back projection (FBP) with those of images generated with 100% FBP. SUBJECTS AND METHODS: Clinically indicated chest CT examinations of 292 consecutively registered patients were prospectively alternately assigned to two scanners on which different reconstruction techniques were used: adaptive statistical iterative reconstruction (ASIR) blended with FBP and 100% FBP. Both acquisitions were performed with dose modulation (noise index, 25 for ASIR and 21 for FBP). Patient demographics and habitus were recorded. Two radiologists blinded to the reconstruction algorithm independently scored subjective image quality on a 3 point Likert scale and measured image noise and radiation dose. RESULTS: Compared with FBP images, ASIR images had significantly lower subjective image quality (p = 0.01), less image noise (p = 0.02), and less radiation dose (p < 0.0001). The CT dose index of the ASIR cohort (11.3 +/- 51) was significantly lower than that of the 100% FBP cohort (15.4 +/- 6.3) (p < 0.0001). Interobserver agreement on subjective image quality was excellent for both ASIR and FBP (Cronbach alpha, 0.92, p < 0.0001; Cronbach alpha, 0.85, p < 0.0001). CONCLUSION: In clinically indicated chest CT examinations, ASIR images had better image quality and less image noise at a lower radiation dose than images acquired with a conventional FBP reconstruction algorithm. PMID- 20966313 TI - Embryology and developmental defects of the interatrial septum. AB - OBJECTIVE: The various types of atrial septal defects (ASDs) can be differentiated on the basis of their imaging appearance on MDCT. CONCLUSION: It is fundamental for the cardiac imager to understand the embryologic development of the interatrial septum and the morphogenic differences of ASDs. PMID- 20966314 TI - Bridging the gap: Using CT colonography to improve colorectal cancer screening compliance. PMID- 20966315 TI - Feasibility of remote CT colonography at two rural Native American medical centers. AB - OBJECTIVE: Fort Defiance Indian Hospital and Tuba City Regional Health Care Center are two rural hospitals with limited availability of optical colonoscopy (OC) and other methods of colorectal cancer screening. Our goals were to determine whether adequate examinations could be obtained with remote supervision after brief onsite instruction and to share lessons learned in our experience with a remote CT colonography (CTC) screening program. MATERIALS AND METHODS: After brief onsite instruction, including performing a CTC examination on a volunteer to train the CT technologists, both sites began performing CTC using standard bowel preparation, fecal tagging, automatic insufflation, and low-dose technique. Studies were transferred to the University of Arizona Hospital for image quality assessment of stool, residual fluid, distention, and interpretation, with reports returned via the teleradiology information system. Clinical follow-up was performed on those patients referred for polypectomy or biopsy. RESULTS: Three hundred twenty-one subjects underwent CTC, including 280 individuals referred for screening examinations (87%). Ninety-two percent of subjects (295/321) had acceptable amounts of residual stool, 91% (293/321) had acceptable levels of fluid, and 92% (294/321) had acceptable distention. Fourteen percent (44/321) of CTC patients had polyps 6 mm or larger in size, with a positive predictive value of 41% for those who subsequently underwent colonoscopy polypectomy (11/27). CONCLUSIONS: CTC can be introduced to rural underserved communities, performed locally, and interpreted remotely with satisfactory performance, thereby increasing colorectal cancer screening capacity. Important aspects of implementation should include technologist training, referring physician education, careful attention to image transmission, and clearly defined methods of communication with patients and referring providers. PMID- 20966316 TI - CT colonography may improve colorectal cancer screening compliance. AB - OBJECTIVE: While colonoscopy is currently the preferred test for colorectal cancer (CRC) screening, the invasive and time-consuming characteristics of the test are often cited as reasons for noncompliance with screening. CT colonography (CTC) is a less invasive screening method that is comparable to colonoscopy for the detection of advanced neoplasia. The aim of this project was to assess patient preferences between colonoscopy and CTC in an open access system. MATERIALS AND METHODS: Two hundred fifty consecutive average-risk patients undergoing CRC screening completed a survey that assessed reasons for choosing CTC in lieu of colonoscopy, compliance with CRC screening if CTC was not offered, and which of the two tests they preferred. RESULTS: The most common reasons for undergoing CTC included convenience (33.6%), recommendation by referring provider (13.2%), and perceived safety (10.8%). Had CTC not been an available option, 91 of the 250 patients (36%) would have foregone CRC screening. Among the 57 patients who had experienced both procedures, 95% (n = 54) preferred CTC. CONCLUSION: These findings show the importance of providing CTC as an alternative screening option for CRC at our institution, which may increase CRC adherence screening rates. PMID- 20966317 TI - MDCT of giant gastric folds: differential diagnosis. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy of MDCT in the differentiation of diseases involving giant gastric folds and to identify the features most useful for predicting the presence of malignant gastric disease. MATERIALS AND METHODS: Blinded reviewers retrospectively analyzed 16-MDCT scans of 64 patients who had endoscopic findings of giant gastric folds. Thirty of these patients had histopathologic results showing scirrhous carcinoma; 15, large B-cell lymphoma; 14, acute gastric mucosal lesions; and five, Menetrier disease. Unenhanced transparent volume-rendered images were assessed to determine the morphologic features of the whole stomach. Contrast-enhanced images were used to analyze wall thickness, stratification, enhancement pattern, and perigastric conditions. We used the Cramer phi-prime correlation coefficient to calculate the overall diagnostic accuracy of MDCT in several gastric disorders. Scatterplot analysis was used for overall diagnostic score, and analysis of the receiver operator characteristic curves of the neighboring two diseases was used to locate the cutoff values for best diagnostic accuracy. We used exact logistic regression to identify which MDCT image features were most predictive of the presence of malignant gastric disease. RESULTS: The gastric wall was found to be significantly thicker in large B-cell lymphoma than in other disorders (p < 0.001). The overall diagnostic accuracy of MDCT in the four diseases was 100%. Loss of wall stratification was deemed the best MDCT predictor of the presence of malignancy. CONCLUSION: MDCT may be a reliable means of noninvasive diagnosis in the care of patients with endoscopically detected giant gastric folds and may be useful for differentiating benign from malignant disease. PMID- 20966318 TI - Biloma formation after radiofrequency ablation of hepatocellular carcinoma: incidence, imaging features, and clinical significance. AB - OBJECTIVE: The objective of our study was to evaluate the frequency, morphologic patterns, temporal changes, and clinical significance of biloma after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Between April 1999 and May 2008, 2,630 patients with HCC underwent a total of 3,284 sessions of RFA at our institution. We retrospectively reviewed all CT scans obtained before and after RFA in all patients. The frequency, morphologic patterns, temporal changes, and clinical course of biloma were studied at the thermal ablation zone after RFA. RESULTS: A total of 109 bilomas (3.3%, 109/3,284) developed after RFA in 104 patients in our series. The bilomas developed from 0 to 526 days (mean, 64 days) after RFA, and the mean follow-up period was 469 days (range, 0-2,703 days). The most common morphologic type of biloma was a crescent shape (42.2%). The mean size of the bilomas at initial presentation was 3.8 cm (range, 1.7-11 cm), and the mean size of the bilomas on the last follow-up CT scan was 2.8 cm (range, 0-6.3 cm). Fifty-three (48.6%) of the 109 bilomas resolved during follow-up at a mean interval of 286 days. In one patient, the biloma was considered a major complication because percutaneous drainage was required to manage the biloma with infection (0.9%, 1/109). No patient died of a biloma. CONCLUSION: The development of a biloma after percutaneous RFA in patients with HCC was not rare. However, in most cases they were a minor complication of no clinical significance. PMID- 20966319 TI - Oral contrast media for body CT: Comparison of diatrizoate sodium and iohexol for patient acceptance and bowel opacification. AB - OBJECTIVE: The purpose of the study was to determine whether a difference in patient preference exists between iohexol (Omnipaque) and diatrizoate sodium (Gastroview) as oral contrast medium for abdominal-pelvic CT. A secondary objective was to evaluate whether there are significant differences in bowel opacification and adverse effect profile for the two agents. SUBJECTS AND METHODS: From August 2007 through March 2009, 300 patients were enrolled in this prospective study after informed consent was obtained. Eligible patients were identified from those scheduled for outpatient abdominal-pelvic CT. Subjects were randomly assigned to receive one of two oral contrast agents in a double-blinded fashion. Subjects graded the taste using a 5-point scale, and data regarding demographics, total volume, and adverse effects were collected. A direct comparison of 30 mL of each of the two diluted agents in randomized order was then performed. CT images were graded for bowel opacification by two blinded abdominal radiologists. RESULTS: Of 287 subjects who expressed a preference, 233 patients (81%) preferred dilute iohexol compared with 54 patients (19%) who preferred dilute diatrizoate sodium (p < 0.001). Ten patients had no preference, and three patients did not complete the taste comparison study. No difference in bowel opacification was identified between the oral contrast agents (p = 0.27), nor was there a significant difference in adverse effects (p = 0.352). CONCLUSION: Patents preferred dilute iohexol over dilute diatrizoate sodium for oral contrast for abdominal-pelvic CT. There was no significant difference in bowel opacification or adverse effect profile. PMID- 20966320 TI - Differentiation between biliary cystic neoplasms and simple cysts of the liver: accuracy of CT. AB - OBJECTIVE: The objective of our study was to determine significant CT findings for the differentiation of biliary cystic neoplasms from simple hepatic cysts and to assess whether radiologists' performance for the differentiation is improved with the knowledge of significant CT criteria. MATERIALS AND METHODS: Review of surgical and pathologic records identified 25 patients with pathologically proven biliary cystic neoplasms (biliary cystadenomas [n = 8], biliary cystadenocarcinomas [n = 4]) or simple cysts [n = 13]). Two radiologists retrospectively reviewed CT images in consensus for the location, size, and outer margin of the lesion and for the presence of an internal septum, upstream bile duct dilatation, a transient hepatic attenuation difference (THAD), calcifications, a mural nodule, three or more other cysts, and a thick septum or outer wall. Individual CT findings considered significant for the differentiation were determined using univariate statistical analyses. Then, two successive review sessions for the differentiation between the two disease entities were independently performed by two other reviewers using a 4-point confidence scale. At the first session, no information was provided to reviewers for differentiation. At the second session, however, the reviewers were told of the results of univariate analyses. Radiologists' performance was evaluated using pairwise comparison of receiver operating characteristic (ROC) curves. RESULTS: The mean size of biliary cystic neoplasms (9.5 cm) was not significantly different from that of simple cysts (11.2 cm). The presence of upstream bile duct dilatation achieved the highest specificity (100%) for the differentiation of biliary cystic neoplasms from simple cysts, followed by THAD (84.6%), lesion location at the left lobe (76.9%), and coexistence of fewer than three other cysts (69.2%). The area under the curve of reviewers 1 and 2 significantly increased from 0.686 and 0.654 to 0.997 and 0.936, respectively, when the reviewers knew the information about the significant CT criteria (p = 0.003 and p = 0.008, respectively). CONCLUSION: Upstream bile duct dilatation, lesion location at the left hepatic lobe, fewer than three coexistent cysts, and THAD were found to be highly suggestive CT findings for the differentiation of biliary cystic neoplasms from simple hepatic cysts. Radiologists' performance was significantly improved with the knowledge of these highly suggestive CT criteria. PMID- 20966321 TI - Knowledge and attitudes of emergency department patients regarding radiation risk of CT: Effects of age, sex, race, education, insurance, body mass index, pain, and seriousness of illness. AB - OBJECTIVE: The purpose of this study was to assess knowledge and attitudes about radiation from CT among emergency department patients with symptoms prompting CT who were stratified on the basis of demographic variables, pain, and perceived illness. SUBJECTS AND METHODS: This survey study was based on three knowledge and three attitude questions asked of patients who underwent any CT examination from June 23 through July 31, 2008. Data were analyzed with chi-square for categoric data and the Student's t test or analysis of variance for continuous data. RESULTS: The survey was completed by 383 patients (mean age, 48 +/- 18 years; 60% women; 40% black; 52% white; 8% other race). In answering the three knowledge based questions, 79% and 83% of patients correctly estimated their risk of cancer from chest radiography and CT, respectively, as none, small, or very small. Patients who were white, more educated, and had lower pain scores were more likely to be correct. Only 34% of all patients correctly thought that CT gave more radiation than chest radiography; the more educated patients were more likely to be correct. In answering the three attitude questions, 74% of patients believed having their condition diagnosed with CT was more important than worrying about radiation. Patients preferred a better test with more radiation, although 68% wanted their physician to take the time to discuss the risk and benefits rather than using their judgment to order the best test. Privately insured patients preferred to have their condition diagnosed with CT rather than worry about radiation. Blacks and patients with less pain wanted the risks and benefits explained at the expense of time. Whites preferred a more definitive test at the expense of more radiation. CONCLUSION: Patients did not estimate the risk of development of cancer from their imaging examinations as high and were more concerned about having their condition diagnosed with CT than about the risk of future cancer. Knowledge and attitudes differed by age, race, education, insurance status, and pain level but not by sex, body mass index, or perceived seriousness of condition. PMID- 20966322 TI - The performance of outside readings by radiology practices. AB - OBJECTIVE: The purpose of our study was to determine how many radiology practices perform outside readings, what characteristics affect the prevalence and volume of outside readings, and how practices are paid for outside readings. MATERIALS AND METHODS: We analyzed data from the American College of Radiology's 2007 Survey of Radiologists, a stratified random sample e-mail and telephone survey. A total of 480 survey responses were evaluated; responses were weighted to make them representative of all U.S. radiology practices. We provide descriptive statistics and multivariable regression analysis results. RESULTS: Overall, 40% of radiology practices in the United States performed outside readings in 2007. Outside readings constituted an average of 11% of the workload of these practices and 4% of the total workload of radiologists in the United States. Other practice characteristics being equal, academic practices, government practices, radiology units of multispecialty groups, and small practices had particularly low odds of performing outside readings. If they did perform outside readings, then, other practice characteristics being equal, small practices, solo practices, radiology units of multispecialty groups, practices in the main cities of large metropolitan areas, and those in nonmetropolitan areas had, on average, a relatively large portion of their workload consisting of outside readings. By far, the most common methods of payment were directly billing for the professional component or receiving a flat fee per study. CONCLUSION: Outside readings were a common activity among radiology practices in 2007. There was substantial variability among practice types, sizes, and locations in whether practices performed outside readings and, if so, how much outside reading they did. PMID- 20966323 TI - Dual-source dual-energy CT with additional tin filtration: Dose and image quality evaluation in phantoms and in vivo. AB - OBJECTIVE: The objective of this study was to investigate the effect on radiation dose and image quality of the use of additional spectral filtration for dual energy CT using dual-source CT (DSCT). MATERIALS AND METHODS: A commercial DSCT scanner was modified by adding tin filtration to the high-kV tube, and radiation output and noise were measured in water phantoms. Dose values for equivalent image noise were compared between the dual-energy mode with and without tin filtration and the single-energy mode. To evaluate dual-energy CT material discrimination, the material-specific dual-energy ratio for calcium and that for iodine were determined using images of anthropomorphic phantoms. Data were additionally acquired from imaging a 38-kg pig and an 87-kg pig, and the noise of the linearly mixed images and virtual noncontrast images was compared between dual-energy modes. Finally, abdominal dual-energy CT images of two patients of similar sizes undergoing clinically indicated CT were compared. RESULTS: Adding tin filtration to the high-kV tube improved the dual-energy contrast between iodine and calcium as much as 290%. Data from our animal study showed that tin filtration had no effect on noise in the dual-energy CT mixed images but decreased noise by as much as 30% in the virtual noncontrast images. Virtual noncontrast images of patients acquired using 100 and 140 kV with added tin filtration had improved image quality relative to those generated using 80 and 140 kV without tin filtration. CONCLUSION: Tin filtration of the high-kV tube of a DSCT scanner increases the ability of dual-energy CT to discriminate between calcium and iodine without increasing dose relative to single-energy CT. Furthermore, the use of 100- and 140-kV tube potentials allows improved dual energy CT imaging of large patients. PMID- 20966324 TI - Radiation dose to the pediatric cardiac catheterization and intervention patient. AB - OBJECTIVE: The radiation dose from cardiac catheterization is particularly relevant when treating children because of their greater radiosensitivity compared with adults. Moreover, cardiac catheterization is being used increasingly for interventional radiology procedures, possibly resulting in higher patient radiation doses. This article reports the radiation doses and related factors, such as fluoroscopy time, for children who underwent cardiac catheterization and children who underwent other interventional radiology procedures. MATERIALS AND METHODS: We evaluated 239 consecutive patients who underwent cardiac catheterization (n = 205) or another interventional radiology procedure (n = 34) for which the dose-area product (DAP) was measured. The number of cine runs and fluoroscopic time for each procedure and the body mass index and body weight of each patient were recorded. We also used the double product combined with body weight, which is the weight- fluoroscopic time product. RESULTS: The average DAP +/- SD of cardiac catheterization and of an interventional radiology procedure was 1,702.6 +/- 2,110.1 cGy * cm2 and 2,242.2 +/- 2,509.4 cGy * cm2, respectively. The average fluoroscopic time +/- SD of cardiac catheterization and of an interventional radiology procedure was 24.1 +/- 16.8 minutes and 37.2 +/- 20.0 minutes. For children who underwent cardiac catheterization and those who underwent an interventional radiology procedure, a strong correlation was seen between the DAP and weight-fluoroscopic time product (cardiac catheterization, r = 0.906; interventional radiology procedure, r = 0.885) and a good correlation was detected between the DAP and weight (r = 0.819 and 0.895, respectively). CONCLUSION: There was a good correlation between the DAP and weight and between DAP and weight-fluoroscopic time product for children who underwent cardiac catheterization or an interventional radiology procedure. Therefore, body weight is important for determining radiation dose to children undergoing cardiac catheterization or an interventional radiology procedure. The normalized DAP (i.e., DAP divided by body weight), fluoroscopy time, and number of cine runs were greater in children who underwent an interventional radiology procedure than in those who underwent cardiac catheterization. Therefore, the radiation dose to children from interventional radiology procedures is a more critical issue. PMID- 20966325 TI - Semiautomated fluoroscopy radiation dose capture and reporting. AB - OBJECTIVE: This article describes a semiautomated system for the capture and reporting of fluoroscopic dose data in a large radiology department. By use of a novel Web-based interface, dose data are entered by technologists at the time of examination, and radiology reports are populated automatically. CONCLUSION: Dose data were successfully captured in 94% of 5,914 reports generated over the course of 6 months. Missing data were attributed to system malfunction (9.5%) and human error (90.5%) and could be reconstructed by quality control measurements in most instances. PMID- 20966326 TI - Whole-brain perfusion imaging with 320-MDCT scanner: Reducing radiation dose by increasing sampling interval. AB - OBJECTIVE: The purpose of this study was to investigate whether perfusion CT values obtained with a reduced-dose imaging protocol on a 320-MDCT scanner are similar to those obtained with a standard protocol. CONCLUSION: Similar perfusion values at one-half the radiation dose can be obtained with the alternative algorithm used in this study. PMID- 20966327 TI - MRI findings in psoriatic arthritis of the hands. AB - OBJECTIVE: The purpose of this essay is to provide a practical review of the spectrum of morphologic and functional MRI findings in psoriatic arthritis of the hand joints. CONCLUSION: The MRI findings of psoriatic arthritis include enthesitis, bone marrow edema, and periostitis accompanying articular or flexor tendon sheath synovitis in the early stage accompanied by destructive and proliferative bony changes, subluxation, and ankylosis in the late stage. PMID- 20966328 TI - MRI versus 131I whole-body scintigraphy for the detection of lymph node recurrences in differentiated thyroid carcinoma. AB - OBJECTIVE: The aim of this study was to compare the clinical usefulness of MRI and radioiodine (131I) whole-body scintigraphy for the detection of lymph node metastases in differentiated thyroid carcinoma (DTC). MATERIALS AND METHODS: After surgery and 131I therapy, 40 patients with DTC underwent 131I whole-body scintigraphy and MRI. Each patient was clinically suspected of having or already had evidence of nodal recurrences (confirmed by laboratory studies, cytologic analysis, or whole-body scintigraphy). Planar whole-body scintigraphy was done after administration of 111 MBq of 131I, and MRI was done using spin-echo T1- and T2-weighted imaging, T1-weighted spin-echo imaging with fat suppression, and STIR sequences. RESULTS: MRI detected nodal metastases as partly or entirely cystic and as heterogeneously enhanced on contrast-enhanced T1-weighted images. Hyperintense cystic areas appeared on T1- and T2-weighted images and STIR sequences in 57% of cases. Nodal metastases showed extracapsular spread in 24% of patients. MRI results were true-positive in 76%, true-negative in 90%, false negative in 24%, and false-positive in 11% of cases, whereas 131I whole-body scintigraphy results were true-positive in 71%, true-negative in 91%, and false negative in 29% of cases. There were no false-positive results of 131I whole-body scintigraphy. False-negative whole-body scintigraphy was induced by tumor dedifferentiation. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of MRI were 76.2%, 89.5%, 82.5%, 88.9%, and 77.3%, respectively, and the corresponding values for 131I whole-body scintigraphy were 71.4%, 100%, 85%, 100%, and 76%, respectively. CONCLUSION: Whole-body scintigraphy is more specific than MRI in the detection of nodal metastases in patients with DTC. The principal value of MRI is in non-iodine-avid recurrences and in evaluation of mediastinal foci. PMID- 20966329 TI - Assessment of therapy response in lung cancer with 18F-alpha-methyl tyrosine PET. AB - OBJECTIVE: PET with a novel tracer, L-[3-18F]-alpha-methyl tyrosine (18F-FMT), has been studied in lung cancer. We evaluated 18F-FMT PET for therapy response in comparison with 18F-FDG PET. SUBJECTS AND METHODS: Eighteen patients with lung cancer underwent PET studies with 18F-FMT and FDG before and after chemoradiotherapy. Uptake of tracers was measured by standardized uptake value (SUV) in the primary tumor and the mediastinal lymph node. The ratio of the lymph node maximum SUV (SUV(max)) to that of the primary tumor and the SUV(max) of the primary tumor itself were correlated with the survival time estimated by Kaplan Meier method. Metabolic response, as determined by the changes in the tracer uptake, was compared with Response Evaluation Criteria in Solid Tumors (RECIST) for therapy response. RESULTS: Agreement of therapeutic response evaluated by RECIST was noted in 10 (56%) of 18 patients evaluated with FDG PET and in 16 (89%) of 18 patients evaluated with 18F-FMT PET (p = 0.025). In nine patients with partial response, partial metabolic response was observed in eight (89%) by use of FDG PET and in nine (100%) by use of 18F-FMT PET. In nine patients with stable disease, stable metabolic disease was observed in two (22%) by use of FDG PET and in seven (78%) by use of 18F-FMT PET (p = 0.056). Fluorine-18-FMT PET revealed that the prognosis of the group with a lymph node-to-primary tumor SUV(max) ratio greater than or equal to 1 was significantly better than that in the group with a ratio of less than 1. CONCLUSION: Fluorine-18-FMT is a promising PET tracer for monitoring response to chemoradiotherapy and for predicting the prognosis of patients with lung cancer. PMID- 20966330 TI - Skeletal scintigraphy in pediatric sports medicine. AB - OBJECTIVE: Athletes can have pain derived from fractures or alternate pathology. Skeletal scintigraphy may detect abnormalities before anatomic imaging and provides a practical tool for whole-body imaging. However, study interpretation in children can be challenging. This pictorial essay describes a technique for pediatric skeletal scintigraphy and reviews findings commonly encountered in athletes. CONCLUSION: Skeletal scintigraphy complements anatomic findings in pediatric athletes. Familiarity with imaging technique and study interpretation can improve diagnosis. PMID- 20966331 TI - Semiautomated segmentation for volumetric analysis of intratumoral ethiodol uptake and subsequent tumor necrosis after chemoembolization. AB - OBJECTIVE: Linear measurements, such as those described by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, may be limited for assessment of response after transarterial chemoembolization (TACE). The purpose of this pilot study was to show intra- and interobserver reproducibility of volumetric measurements of Ethiodol (ethiodized oil) seen within tumor 24 hours after TACE and of necrotic and viable tumor 1 month after treatment. Volumetric measurements are compared with linear measurements and survival outcomes. MATERIALS AND METHODS: Between 2006 and 2009, 37 consecutive TACE procedures were performed in 27 patients with hepatic malignancies. CT images obtained 24 hours and 1 month after TACE were retrospectively analyzed. Three observers measured volumes twice. Intraoperator reproducibility was determined using Wilcoxon's signed rank test to assess whether the difference in each volumetric measurement approaches zero. The intraclass correlation coefficient (ICC) and Bland-Altman plots were used to determine interoperator reproducibility. Survival data were retrospectively obtained from the electronic medical record. RESULTS: Good intraobserver reproducibility and interobserver reproducibility (p > 0.05, ICC > 0.9, respectively) were shown for Ethiodol, whole tumor, and necrotic tumor volumes. The volume of Ethiodol correlated with subsequent necrotic tumor volume (p = 0.009), reduction in whole tumor volume (p = 0.004), and patient survival (p = 0.029). Kaplan-Meier curves suggest that Ethiodol accumulation in more than 50% of the tumor and a 10% or greater increase in the volume of necrotic tumor correlated with survival (p = 0.028 and 0.047, respectively). CONCLUSION: Semiautomated volumetric analysis can be performed with good intra- and interobserver reproducibility. The volume of Ethiodol accumulated in the tumor after TACE correlates with subsequent necrosis. These early measurements may predict survival outcomes. PMID- 20966332 TI - Long-term results of percutaneous radiologic gastrostomy and gastrojejunostomy in children with emphasis on technique: single or double gastropexy? AB - OBJECTIVE: The purpose of this article is to evaluate the safety and efficacy of radiologic gastrostomy and gastrojejunostomy in children, with an emphasis on the comparison of single and double gastropexy. MATERIALS AND METHODS: Between January 2000 and May 2009, a total of 91 percutaneous tubes (77 gastrostomies and 14 gastrojejunostomies) were placed in 90 patients. Patients' ages ranged from 4 months to 16.5 years. Gastropexy was performed in all cases. The first 50 children underwent double gastropexy, and 40 children underwent single gastropexy. In single gastropexy, two different punctures were performed each for the anchor and the tube. Differences in the incidence of major and minor complications and tube maintenance problems between the single- and double gastropexy groups were retrospectively analyzed by use of Fisher's exact test. RESULTS: The technical success rate was 100%. No procedure-related mortality or morbidity was detected. The overall major and minor complication rates were 4.4% and 16.7%, respectively. The mean follow-up period was 463 days. Twenty-nine tube maintenance problems were detected in 17 patients. There were four major complications (two cases of aspiration pneumonia and two site infections that required hospitalization). Minor complications occurred in 15 patients (nine localized site infections, two cases of gastroesophageal reflux, and four tube maintenance problems requiring secondary intervention). In total, 26 and 22 complications and tube maintenance problems occurred in the single- and double gastropexy groups, respectively. No statistically significant difference was detected between the two groups in terms of complications (p > 0.005). CONCLUSION: Radiologic gastrostomy and gastrojejunostomy are safe and effective methods for long-term nutritional support in children. Single gastropexy should be performed with two different punctures for each retention suture and the tube. PMID- 20966333 TI - Stabilization of mobile pulmonary nodules during radiofrequency ablation. AB - OBJECTIVE: Lung tumors can exhibit a high degree of mobility during insertion of radiofrequency applicators owing to both respiratory motion and the inherent characteristics of pulmonary parenchyma. The purpose of this report is to describe a technique used to secure lung tumors during insertion of a radiofrequency applicator. CONCLUSION: As experience with percutaneous imaging guided radiofrequency ablation increases, technical challenges become increasingly apparent. A technique whereby a mobile pulmonary tumor is anchored prior to placement of the ablation electrode is one method of overcoming such a challenge. PMID- 20966334 TI - Management of hypersplenism by partial splenic embolization with ethylene vinyl alcohol copolymer. AB - OBJECTIVE: Partial splenic embolization has been used for more than 20 years to manage thrombocytopenia secondary to hypersplenism. Both temporary and permanent embolic agents have been used without definition of an optimal agent. The purposes of this report are to describe the use of the Onyx nonadhesive liquid embolization system to treat three patients with severe hypersplenism precluding administration of systemic chemotherapy and to report on the hematologic response and clinical outcome after partial splenic embolization with this agent. CONCLUSION: The platelet counts of three patients treated by partial splenic embolization with the Onyx agent improved sufficiently for administration of systemic chemotherapy. In addition, severe postembolization syndrome, a common occurrence after partial splenic embolization, did not occur in our patient population. PMID- 20966335 TI - Vessel analysis on contrast-enhanced MRI of the breast: global or local vascularity? PMID- 20966336 TI - Contrast-enhanced MR angiography of the breast: Evaluation of ipsilateral increased vascularity and adjacent vessel sign in the characterization of breast lesions. AB - OBJECTIVE: The purpose of this study was to investigate the role of evaluation of breast vascularity with contrast-enhanced MR angiography in the differentiation of malignant from benign lesions. MATERIALS AND METHODS: Contrast-enhanced 3D MR angiograms of the breasts of 102 patients with unilateral and histopathologically confirmed breast lesions were evaluated retrospectively. All images were evaluated for both ipsilateral increased vascularity and adjacent vessel sign, and the values of these signs in the diagnosis of malignancy were assessed. RESULTS: Histopathologic analysis of 102 patients revealed 50 malignant and 52 benign results. In 31 of the 50 patients with breast cancer and in 11 of the 52 patients with benign lesions, ipsilateral breast vascularity was increased. The resulting sensitivity and specificity of ipsilateral increased vascularity were 62% and 79%. The adjacent vessel sign was present in 37 of the 50 patients with breast cancer and six of the 50 patients with benign lesions. The resulting sensitivity and specificity of the adjacent vessel sign were 74% and 89%. The overall accuracies of ipsilateral increased vascularity and the adjacent vessel sign were 71% and 81%. CONCLUSION: Both ipsilateral increased vascularity and the adjacent vessel sign were found to be associated with breast cancer in a significant percentage of patients. The adjacent vessel sign is more practical and generally applicable. There is a borderline significance in favor of the higher accuracy of the adjacent vessel sign in comparison with ipsilateral increased vascularity (p = 0.043). PMID- 20966337 TI - Stereotactic vacuum-assisted breast biopsy is not a therapeutic procedure even when all mammographically found calcifications are removed: analysis of 4,086 procedures. AB - OBJECTIVE: The purpose of our study was to assess whether in case of total removal of microcalcifications there is still residual tumor on the surgical specimen and, secondarily, to assess whether complete rather than partial excision of the imaging target with microcalcifications may result in increased diagnostic accuracy. MATERIALS AND METHODS: We retrospectively reviewed 4,086 stereotactic vacuum-assisted breast biopsy (VABB) procedures for microcalcifications and histologic findings to determine the frequency of malignancy, histologic underestimation, and complete removal of cancer. RESULTS: No residual microcalcifications on postbiopsy mammograms were seen in 1,594 of 4,047 (39.4%) procedures successfully completed: 351 of 1,594 lesions were malignant, 1,109 benign and 134 atypical. After partial removal of microcalcifications at VABB, the postsurgical specimen had infiltrating carcinoma in 130 of 566 cases (23%), whereas in case of total removal of microcalcifications, the underestimation occurred in 13 of 234 (5.5%) cases. The atypical ductal hyperplasia underestimation rate was 6.6% when the mammography target was completely removed and 38.7% when the target was only sampled. The percentage of lobular carcinoma in situ underestimation was the same for the two groups with partial and total removal of microcalcifications (21.2%). Among 1,016 VABB procedures with pathologic result of malignancy, 882 (86.6%) had residual cancer at surgery. In the group with complete removal of microcalcifications at VABB, residual cancer was found in 70% of cases. CONCLUSION: VABB may not be considered a therapeutic procedure, even in the case of complete removal of microcalcifications. However, a complete removal of microcalcifications may result in low rates of underestimation of malignancy and may consequently increase the diagnostic accuracy of the diagnostic procedure. PMID- 20966338 TI - Axillary ultrasound and fine-needle aspiration in the preoperative evaluation of the breast cancer patient: an algorithm based on tumor size and lymph node appearance. AB - OBJECTIVE: The objective of our study was to evaluate the utility of ultrasound guided fine-needle aspiration (FNA) of the axillary lymph nodes in breast cancer patients depending on the size of the primary tumor and the appearance of the lymph nodes. SUBJECTS AND METHODS: Data were collected about tumor size, lymph node appearance, and the results of ultrasound-guided FNA and axillary surgery of 224 patients with breast cancer undergoing 226 ultrasound-guided FNA. Lymph nodes were classified as benign if the cortex was even and measured < 3 mm, indeterminate if the cortex was even but measured >= 3 mm or measured < 3 mm but was focally thickened, and suspicious if the cortex was focally thickened and measured >= 3 mm or the fatty hilum was absent. The results of ultrasound-guided FNAs were analyzed by the sonographic appearance of the axillary lymph nodes and by the size of the primary tumor. The sensitivity and specificity of ultrasound guided FNA were calculated with axillary surgery as the reference standard. The sensitivity and specificity of axillary ultrasound to predict the ultrasound guided FNA result were calculated. RESULTS: Of the 224 patients, 51 patients (23%) had a positive ultrasound-guided FNA result, which yields an overall sensitivity of 59% and specificity of 100%. The sensitivity of ultrasound-guided FNA was 29% in patients with primary tumors <= 1 cm, 50% in patients with tumors > 1 to <= 2 cm, 69% in patients with tumors > 2 to <= 5 cm, and 100% in patients with tumors > 5 cm. The sensitivity of ultrasound-guided FNA in patients with normal-appearing lymph nodes was 11%; indeterminate lymph nodes, 44%; and suspicious lymph nodes, 93%. Sonographic characterization of lymph nodes as suspicious or indeterminate was 94% sensitive and 72% specific in predicting positive findings at ultrasound-guided FNA. CONCLUSION: Ultrasound-guided FNA of the axillary lymph nodes is most useful in the preoperative assessment of patients with large tumors (> 2 cm) or lymph nodes that appear abnormal. PMID- 20966339 TI - MRI appearances of uterine malignant mixed mullerian tumors. AB - OBJECTIVE: Uterine malignant mixed mullerian tumors (MMMTs) are rare aggressive tumors with a high incidence of lymphatic, peritoneal, and pulmonary metastases. Preoperative differentiation from endometrial adenocarcinoma would be beneficial because their prognoses differ. MATERIALS AND METHODS: We retrospectively reviewed MRI examinations of 51 histologically confirmed MMMTs. Tumor size, growth pattern, and imaging characteristics were recorded. Data were compared with MRI appearances of 73 endometrial adenocarcinomas. RESULTS: On T1-weighted images, MMMTs were predominantly isointense to myometrium (76%) and endometrium (71%), with heterogeneous texture in 33% of cases and hyperintense foci in 27% of cases. On T2-weighted images, 92% of MMMTs were hyperintense to myometrium and either hypointense (55%) or isointense (41%) to endometrium. In 12% of cases, large heterogeneous MMMTs obliterated uterine architecture and were aggressive in appearance, whereas in 88% of cases, the appearances were indistinguishable from those of endometrial adenocarcinoma. Significantly more MMMTs than endometrial adenocarcinomas had cervical invasion (p = 0.008) and nodal enlargement (p = 0.00008). Dynamic contrast-enhanced images (available for 19 of 51 patients) obtained at less than 1 minute after administration of contrast agent showed MMMT enhancement to be hypointense (42%; 5/12 patients) or isointense (33%; 4/12 patients) to myometrium; between 1 and 4 minutes after administration of contrast agent, tumors were hypointense (58%; 7/12 patients); and at more than 4 minutes after administration of contrast agent (n = 18), MMMTs were isointense in 56% of cases. This finding is significantly different from that for endometrial adenocarcinoma, where enhancement is less than that of myometrium in 90% of cases (p = 4 * 10-8). CONCLUSION: MMMTs do not have a pathognomonic MRI appearance. However, radiologic suspicion should increase in the presence of large heterogeneous infiltrative tumors or when tumoral enhancement equals or exceeds that of myometrium. PMID- 20966340 TI - Features of prospectively overlooked computer-aided detection marks on prior screening digital mammograms in women with breast cancer. AB - OBJECTIVE: The purpose of this article is to describe the features of prospectively overlooked computer-aided detection (CAD) marks on prior screening digital mammograms for women with breast cancer. SUBJECTS AND METHODS: A CAD system embedded in a digital mammography system was prospectively applied to 50,100 screening mammograms between December 2003 and December 2006. Each mammogram was originally interpreted by one of five radiologists using the CAD information. Seventy-five mammogram pairs of prior negative screening mammograms and subsequent mammograms of developed cancers were collected. Visible findings and their actionability were determined by three blinded radiologists. All CAD marks, both true-positive and false-positive, and the number of marked views for the visible findings on prior mammograms were analyzed. RESULTS: Of the 75 areas where cancer later developed, 61% (46/75) of mammograms had visible findings (21 masses, 17 microcalcifications, and eight masses with microcalcifications). Of these visible findings, 46% (21/46) were determined to be actionable, and 54% (25/46) were underthreshold. The CAD system had correctly depicted 74% (34/46) of the visible findings-52% (11/21) of masses, 94% (16/17) of microcalcifications, and 88% (7/8) of masses with microcalcifications. Actionable findings showed higher CAD sensitivity than did underthreshold findings (90% [19/21] vs 60% [15/25]; p = 0.04) and were more often marked on both views (58% [11/19] vs 27% [4/15]; p = 0.09). The average number of false-positive marks per case was 1.61. CONCLUSION: On prior screening digital mammograms, the CAD system had correctly marked 74% (34/46) of visible findings and 90% (19/21) of actionable findings. The actionable findings showed significantly higher CAD sensitivity and were marked on both mammographic views more often than the underthreshold findings were. PMID- 20966342 TI - The vanishing azygos lobe. PMID- 20966343 TI - Item response theory analyses of adult self-ratings of the ADHD symptoms in the Current Symptoms Scale. AB - The graded response model, which is based on item response theory, was used to evaluate the psychometric properties of adult self-ratings (N = 852) of the attention deficit/hyperactivity disorder inattention, hyperactivity, and impulsivity symptoms presented in the Current Symptoms Scale. This scale has four ordered response categories. The results for the discrimination parameters showed that all symptoms were generally good for discriminating their respective latent traits. For virtually all symptoms, their threshold values showed that they were especially good at representing the appropriate traits from around the mean trait level onward. The item information function values for most symptoms indicated reasonable reliability from approximately the mean trait level onward. All these findings are new and extend existing psychometric information for adult self ratings of the attention deficit/hyperactivity disorder symptoms in the Current Symptoms Scale. PMID- 20966344 TI - Analysis of WAIS-IV index score scatter using significant deviation from the mean index score. AB - The Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) does not include verbal IQ and performance IQ scores, as provided in previous editions of the scale; rather, this edition provides comparisons among four index scores, allowing analysis of an individual's WAIS-IV performance in more discrete domains of cognitive ability. To supplement the pairwise index score comparisons included in the WAIS-IV manuals, this article describes the use of the mean of the four index scores (the average index score) as a baseline for analyzing index score variability and as a method for identifying strengths and weaknesses within an individual's index score pattern. Davis's formula was used to calculate critical values for the identification of index scores with a statistically significant difference from the average index score. Subsequent analysis of the WAIS-IV normative sample indicates that variability in performance at the index score level is not uncommon in the general population. More than 70% of individuals in the normative sample have at least one index score that differs significantly from their mean index score. This variability in index score performance appears to have little relationship to age or gender, but it is strongly related to the full-scale IQ. PMID- 20966345 TI - Heart and soul physical activity program for African American women. AB - African American women are less physically active than White women and have a higher prevalence of inactivity-related diseases. Increased physical activity is known to reduce the risks for many chronic diseases. Positive health behavior changes have resulted from health promotion interventions conducted in African American churches. Eighteen midlife African American women participated in the Heart and Soul Physical Activity Program (HSPAP), a church-based physical activity intervention conceptualized in appraisal, belonging, tangible, and self esteem domains of social support. Feasibility of the HSPAP was tested by determining changes in time and intensity of physical activity and social support for physical activity from baseline to 6 weeks. Data analyses were conducted utilizing paired t tests. Significant increases in time spent in physical activity from a mean of 412 min/week at baseline to 552 min/week at 6 weeks were noted. Participants reported increases in social support for physical activity in the 6-week study. PMID- 20966346 TI - Natural patterns of change in poststroke depressive symptoms and function. AB - The objective of this study was to evaluate patterns of change in depressive symptoms and function in ischemic stroke patients 0 to 3 months poststroke. Twenty-three newly diagnosed ischemic stroke patients were enrolled in a study with nonrandomized prospective longitudinal design to assess function and depressive symptoms on admission, 2 weeks, 1 month, and 3 months poststroke in a tertiary care acute rehabilitation center in the Midwest. Participants' mean age was (69 +/- 11.9), Mini Mental State Exam (MMSE >= 23), and NIH Stroke Scale (M = 2.8, SD = +/- 2.3), and thus cognitively intact. Results suggest that the dominant pattern emerging for function (Functional Independence Measure) and depressive symptoms (Center for Epidemiologic Studies Depression Scale) showed significant improvement relative to baseline at 2 weeks poststroke and reached a plateau thereafter. The results may suggest that as stroke survivors gain independence in accomplishing activities of daily living, their moods improve as well. PMID- 20966347 TI - Sustaining engagement through work in postdisaster relief and reconstruction. AB - After the devastating 2008 earthquake in China, grass-roots government officials were the main local force in postquake relief and reconstruction. Like other survivors, many officials were severely bereaved. Their psychological well-being was at stake. We conducted 25 semistructured interviews to investigate sources of stress at work and their coping experiences. We coded interviews using the content analysis method. Misunderstandings and assaults from survivors, prolonged heavy workload, and grief and bereavement were major sources of stress at work. Finding meaning in the work, emotion regulation, and goal and time management were main coping strategies. The challenge and importance of the work, combined with support and recognition at work, fostered an empowering work environment. Few interviewees reported fatigue, whereas the majority displayed dedication to work, indicating a status of work engagement more than burnout among grass-roots officials. Implications of a meaning-oriented empowerment approach to stress management for disaster relief forces are drawn. PMID- 20966348 TI - Structurally conserved five nucleotide bulge determines the overall topology of the core domain of human telomerase RNA. AB - Telomerase is a unique ribonucleoprotein complex that catalyzes the addition of telomeric DNA repeats onto the 3' ends of linear chromosomes. All vertebrate telomerase RNAs contain a catalytically essential core domain that includes the template and a pseudoknot with extended helical subdomains. Within these helical regions is an asymmetric 5-nt internal bulge loop (J2a/b) flanked by helices (P2a and P2b) that is highly conserved in its location but not sequence. NMR structure determination reveals that J2a/b forms a defined S-shape and creates an ~90 degrees bend with a surprisingly low twist (~10 degrees ) between the flanking helices. A search of RNA structures revealed only one other example of a 5-nt bulge, from hepatitis C virus internal ribosome entry site, with a different sequence but the same structure. J2a/b is intrinsically flexible but the interhelical motions across the loop are remarkably restricted. Nucleotide substitutions in J2a/b that affect the bend angle, direction, and interhelical dynamics are correlated with telomerase activity. Based on the structures of P2ab (J2a/b and flanking helices), the conserved region of the pseudoknot (P2b/P3, previously determined) and the remaining helical segment (P2a.1-J2a.1 refined using residual dipolar couplings and the modeling program MC-Sym) we have calculated an NMR-based model of the full-length pseudoknot. The model and dynamics analysis show that J2a/b serves as a dominant structural and dynamical element in defining the overall topology of the core domain, and suggest that interhelical motions in P2ab facilitate nucleotide addition along the template and template translocation. PMID- 20966349 TI - Fossilized glycolipids reveal past oceanic N2 fixation by heterocystous cyanobacteria. AB - N(2)-fixing cyanobacteria play an essential role in sustaining primary productivity in contemporary oceans and freshwater systems. However, the significance of N(2)-fixing cyanobacteria in past nitrogen cycling is difficult to establish as their preservation potential is relatively poor and specific biological markers are presently lacking. Heterocystous N(2)-fixing cyanobacteria synthesize unique long-chain glycolipids in the cell envelope covering the heterocyst cell to protect the oxygen-sensitive nitrogenase enzyme. We found that these heterocyst glycolipids are remarkably well preserved in (ancient) lacustrine and marine sediments, unambiguously indicating the (past) presence of N(2)-fixing heterocystous cyanobacteria. Analysis of Pleistocene sediments of the eastern Mediterranean Sea showed that heterocystous cyanobacteria, likely as epiphytes in symbiosis with planktonic diatoms, were particularly abundant during deposition of sapropels. Eocene Arctic Ocean sediments deposited at a time of large Azolla blooms contained glycolipids typical for heterocystous cyanobacteria presently living in symbiosis with the freshwater fern Azolla, indicating that this symbiosis already existed in that time. Our study thus suggests that heterocystous cyanobacteria played a major role in adding "new" fixed nitrogen to surface waters in past stratified oceans. PMID- 20966350 TI - Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+ channel to maintain endothelial integrity. AB - Klotho is a circulating protein, and Klotho deficiency disturbs endothelial integrity, but the molecular mechanism is not fully clarified. We report that vascular endothelium in Klotho-deficient mice showed hyperpermeability with increased apoptosis and down-regulation of vascular endothelial (VE)-cadherin because of an increase in VEGF-mediated internal calcium concentration ([Ca(2+)]i) influx and hyperactivation of Ca(2+)-dependent proteases. Immunohistochemical analysis, the pull-down assay using Klotho-fixed agarose, and FRET confocal imaging confirmed that Klotho protein binds directly to VEGF receptor 2 (VEGFR-2) and endothelial, transient-receptor potential canonical Ca(2+) channel 1 (TRPC-1) and strengthens the association to promote their cointernalization. An in vitro mutagenesis study revealed that the second hydrolase domain of Klotho interacts with sixth and seventh Ig domains of VEGFR-2 and the third extracellular loop of TRPC-1. In Klotho-deficient endothelial cells, VEGF-mediated internalization of the VEGFR-2/TRPC-1 complex was impaired, and surface TRPC-1 expression increased 2.2-fold; these effects were reversed by supplementation of Klotho protein. VEGF-mediated elevation of [Ca(2+)]i was sustained at higher levels in an extracellular Ca(2+)-dependent manner, and normalization of TRCP-1 expression restored the abnormal [Ca(2+)]i handling. These findings provide evidence that Klotho protein is associated with VEGFR 2/TRPC-1 in causing cointernalization, thus regulating TRPC-1-mediated Ca(2+) entry to maintain endothelial integrity. PMID- 20966351 TI - Epigenetic regulation of promiscuous gene expression in thymic medullary epithelial cells. AB - Thymic central tolerance comprehensively imprints the T-cell receptor repertoire before T cells seed the periphery. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process by virtue of promiscuous expression of tissue restricted autoantigens. The molecular regulation of this unusual gene expression, in particular the involvement of epigenetic mechanisms is only poorly understood. By studying promiscuous expression of the mouse casein locus, we report that transcription of this locus proceeds from a delimited region ("entry site") to increasingly complex patterns along with mTEC maturation. Transcription of this region is preceded by promoter demethylation in immature mTECs followed upon mTEC maturation by acquisition of active histone marks and local locus decontraction. Moreover, analysis of two additional gene loci showed that promiscuous expression is transient in single mTECs. Transient gene expression could conceivably add to the local diversity of self-antigen display thus enhancing the efficacy of central tolerance. PMID- 20966352 TI - Age-related changes in vestibular evoked myogenic potentials using a modified blood pressure manometer feedback method. AB - PURPOSE: To collect age-specific vestibular evoked myogenic potential (VEMP) data and to characterize age-related differences in VEMP parameters using a modified blood pressure manometer (BPM) method of sternocleidomastoid (SCM) muscle monitoring. METHODS: VEMPs were recorded on healthy adults ranging in age from 23 to 84 years with no history of dizziness, neuromuscular pathologies, or cervical complaints. Participants were assigned to 3 groups using a nonprobability static group assignment based on their age. VEMP P1 and N1 latency, threshold, peak-to peak amplitude, and interamplitude difference (IAD) ratios were obtained at 130 dB SPL. RESULTS: Statistical differences were detected in peak-to-peak mean amplitude and threshold measures among groups. Post hoc analysis revealed that differences shown were between the young group and both older groups. No significant differences were noted in P1 and N1 latencies or IAD ratios. CONCLUSIONS: This study confirmed a significant decline in VEMP amplitude and increase in VEMP thresholds in healthy older persons. Normative age-related data may be necessary to properly interpret VEMP recordings in a clinical setting when evaluating aging populations. The BPM method utilized for controlling SCM muscle may be a valuable alternative to control SCM muscle contraction when electromyography equipment is not available. PMID- 20966353 TI - The impact of sudden hearing loss secondary to heroin overdose on fitting outcomes. AB - PURPOSE: There are few cases in the literature that report the auditory effects of heroin overdose. Follow-up and rehabilitation in these cases are unreported. In the case reported here, a 29-year-old woman presented with sudden bilateral sensorineural hearing loss subsequent to reported heroin overdose. She was fitted with binaural amplification and monitored over 3 months. METHOD: The Hearing Handicap Inventory for Adults-Screening version (HHIA-S), Expected Consequences of Hearing Aid Ownership (ECHO), and Satisfaction With Amplification in Daily Life (SADL) were administered after hearing aid fitting. These measures assessed the patient's perceptions of handicap as well as her expectations of and satisfaction with amplification. RESULTS: The patient's responses on the HHIA-S were higher than normative values at the time of the incident, indicating perceptions of greater handicap. Her perceptions of handicap decreased after having been fit with hearing aids. Responses on the SADL and ECHO were within normative values. CONCLUSION: This case provides a framework for managing the rehabilitation of this population. Audiologists need to understand their role in the careful monitoring of hearing rehabilitation and how they may help in determining complaints that may be hearing- or device-related versus those associated with the psychological symptoms experienced during the withdrawal period. PMID- 20966354 TI - Insulin receptor substrate regulation of phosphoinositide 3-kinase. AB - Insulin receptor substrates (IRS) serve as downstream messengers from activated cell surface receptors to numerous signaling pathway cascades. One of these pathways, phosphoinositide 3-kinase (PI3K), frequently displays aberrant function in the setting of cancer. IRS proteins are capable of both regulating and activating PI3K, depending on the cell of origin. As such, both prohost and protumor functions have been described for IRS proteins in human cancers. IRS proteins may eventually serve as biomarkers of PI3K activity, and serve a much needed role as a guide to using targeted pathway therapy. Additionally, IRS-1 could be indirectly targeted in lung cancer, by inhibiting neutrophil elastase, which functions to degrade IRS-1 in lung tumor cells, thereby generating PI3K hyperactivity. PMID- 20966356 TI - Government leadership needed for food fortification in sub saharan Africa. PMID- 20966355 TI - p27: a barometer of signaling deregulation and potential predictor of response to targeted therapies. AB - Phosphorylation of the cyclin-dependent kinase inhibitor p27 by upstream mitogenic signaling pathways regulates its stability, localization, and biological function. In human cancers, loss of the antiproliferative action of p27 can arise through reduced protein levels and/or cytoplasmic mislocalization, leading to increased cell proliferation and/or cell migration, respectively. Reduced p27 expression levels and p27 mislocalization have potential prognostic and therapeutic implications in various types of human cancers. This review highlights mechanisms of functional deregulation of p27 by oncogenic signaling that provide an important molecular rationale for pathway targeting in cancer treatment. PMID- 20966357 TI - Mental health promotion in a reformed health care system. PMID- 20966358 TI - Addressing mental health promotion in chronic disease prevention and health promotion. PMID- 20966359 TI - Stress associated with public health field research. PMID- 20966360 TI - Mental health promotion as a new goal in public mental health care: a randomized controlled trial of an intervention enhancing psychological flexibility. AB - OBJECTIVES: We assessed whether an intervention based on acceptance and commitment therapy (ACT) and mindfulness was successful in promoting positive mental health by enhancing psychological flexibility. METHODS: Participants were 93 adults with mild to moderate psychological distress. They were randomly assigned to the group intervention (n = 49) or to a waiting-list control group (n = 44). Participants completed measures before and after the intervention as well as 3 months later at follow-up to assess mental health in terms of emotional, psychological, and social well-being (Mental Health Continuum-Short Form) as well as psychological flexibility (i.e., acceptance of present experiences and value based behavior, Acceptance and Action Questionnaire-II). RESULTS: Regression analyses showed that compared with the participants on the waiting list, participants in the ACT and mindfulness intervention had greater emotional and psychological well-being after the intervention and also greater psychological flexibility at follow-up. Mediational analyses showed that the enhancement of psychological flexibility during the intervention mediated the effects of the intervention on positive mental health. CONCLUSIONS: The intervention is effective in improving positive mental health by stimulating skills of acceptance and value-based action. PMID- 20966361 TI - The structure of the genetic and environmental influences on mental well-being. AB - OBJECTIVES: We sought to investigate the structure of the genetic and environmental influences on 3 measures of mental well-being. METHODS: Analyses focused on the subsample of 349 monozygotic and 321 dizygotic same-sex twin pairs from a nationally representative sample of twins who completed self-report measures of emotional, psychological, and social well-being. RESULTS: The best fit model contained a common pathway to all 3 measures of well-being, no shared environmental effects, and 1 set of parameters for men and women. Heritability for the latent "mental well-being" factor was high (72%) and best indexed by psychological well-being. Moderate trait-specific genetic effects were seen for emotional and social well-being. Nonshared environmental effects for all measures were mostly trait specific. CONCLUSIONS: Genetic influences on the measures of mental well-being reflect a single, highly heritable genetic factor, although some trait-specific genetic influences were seen for emotional and social well being. Moderate proportions of environmental influences were also shared, but the majority of unique environment was trait-specific. PMID- 20966362 TI - "Dreadful to behold": frostbite on the 1910-1913 British Antarctic Expedition. PMID- 20966363 TI - Changes in mental well-being in the transition to late life: findings from MIDUS I and II. AB - The number of adults aged 65 years and older is increasing rapidly, creating public health challenges. We used data from the 1995 and 2005 national surveys of Midlife in the United States (MIDUS) to compare changes in mental well-being of participants (n = 1007) of 3 age cohorts (ages 45-54 years, 55-64 years, and 65 74 years in 1995). Older adults experienced a slight decline in mental well-being not seen among younger participants and not explained by demographic variables, physical ailments, mental illnesses, or chronic conditions. PMID- 20966364 TI - Change in level of positive mental health as a predictor of future risk of mental illness. AB - OBJECTIVES: We sought to describe the prevalence of mental health and illness, the stability of both diagnoses over time, and whether changes in mental health level predicted mental illness in a cohort group. METHODS: In 2009, we analyzed data from the 1995 and 2005 Midlife in the United States cross-sectional surveys (n = 1723), which measured positive mental health and 12-month mental disorders of major depressive episode, panic, and generalized anxiety disorders. RESULTS: Population prevalence of any of 3 mental disorders and levels of mental health appeared stable but were dynamic at the individual level. Fifty-two percent of the 17.5% of respondents with any mental illness in 2005 were new cases; one half of those languishing in 1995 improved in 2005, and one half of those flourishing in 1995 declined in 2005. Change in mental health was strongly predictive of prevalence and incidence (operationalized as a new, not necessarily a first, episode) of mental illness in 2005. CONCLUSIONS: Gains in mental health predicted declines in mental illness, supporting the call for public mental health promotion; losses of mental health predicted increases in mental illness, supporting the call for public mental health protection. PMID- 20966365 TI - Reductions in cigarette smoking and acute myocardial infarction mortality in Jefferson County, Texas. AB - After litigation against the tobacco industry ended in a settlement, the Texas legislature funded pilot projects to reduce tobacco use in selected areas of the state. Subsequent telephone surveys showed that well-funded activities were successful in reducing population rates of self-reported cigarette smoking. We present evidence that the reduction in smoking promptly led to lower rates of death from acute myocardial infarctions. PMID- 20966366 TI - Transforming the Nation's Health: next steps in mental health promotion. AB - The National Research Council and the Institute of Medicine have called for making the healthy mental, emotional, and behavioral development of young people a national priority. The Substance Abuse and Mental Health Services Administration (SAMHSA) in the US Department of Health and Human Services is uniquely positioned to help develop national mental health policies that promote mental health and prevent mental illnesses. In this article I describe the role of mental health in overall health, I make the case for a public health approach to mental health promotion and mental illness prevention, and I outline a strategy to promote individual, family, and community resilience. I also describe how SAMHSA works to achieve these goals. Ultimately, true health reform will not succeed without a comprehensive, committed focus on the mental health needs of all Americans. PMID- 20966367 TI - Consumer awareness of fast-food calorie information in New York City after implementation of a menu labeling regulation. AB - OBJECTIVES: We assessed consumer awareness of menu calorie information at fast food chains after the introduction of New York City's health code regulation requiring these chains to display food-item calories on menus and menu boards. METHODS: At 45 restaurants representing the 15 largest fast-food chains in the city, we conducted cross-sectional surveys 3 months before and 3 months after enforcement began. At both time points, customers were asked if they had seen calorie information and, if so, whether it had affected their purchase. Data were weighted to the number of city locations for each chain. RESULTS: We collected 1188 surveys pre-enforcement and 1229 surveys postenforcement. Before enforcement, 25% of customers reported seeing calorie information; postenforcement, this figure rose to 64% (P < .001; 38% and 72%, weighted). Among customers who saw calorie information postenforcement, 27% said they used the information, which represents a 2-fold increase in the percentage of customers making calorie-informed choices (10% vs 20%, weighted; P < .001). CONCLUSIONS: Posting calorie information on menu boards increases the number of people who see and use this information. Since enforcement of New York's calorie labeling regulation began, approximately 1 million New York adults have seen calorie information each day. PMID- 20966368 TI - Potential health impact of switching from car to public transportation when commuting to work. AB - We assessed humidity-corrected particulate matter (PM(2.5)) exposure and physical activity (using global positioning system monitors and diaries) among 18 people who commuted by car to Queens College, New York, New York, for 5 days, and then switched to commuting for the next 5 days via public transportation. The PM(2.5) differed little between car and public transportation commutes (1.41 MUg/M(3).min; P = .226). Commuting by public transportation rather than by car increased energy expenditure (+124 kcal/day; P < .001) equivalent to the loss of 1 pound of body fat per 6 weeks. PMID- 20966369 TI - Smoking characteristics of adults with selected lifetime mental illnesses: results from the 2007 National Health Interview Survey. AB - OBJECTIVES: We estimated smoking prevalence, frequency, intensity, and cessation attempts among US adults with selected diagnosed lifetime mental illnesses. METHODS: We used data from the 2007 National Health Interview Survey on 23 393 noninstitutionalized US adults to obtain age-adjusted estimates of smoking prevalence, frequency, intensity, and cessation attempts for adults screened as having serious psychological distress and persons self-reporting bipolar disorder, schizophrenia, attention deficit disorder or hyperactivity, dementia, or phobias or fears. RESULTS: The age-adjusted smoking prevalence of adults with mental illness or serious psychological distress ranged from 34.3% (phobias or fears) to 59.1% (schizophrenia) compared with 18.3% of adults with no such illness. Smoking prevalence increased with the number of comorbid mental illnesses. Cessation attempts among persons with diagnosed mental illness or serious psychological distress were comparable to attempts among adults without mental illnesses or distress; however, lower quit ratios were observed among adults with these diagnoses, indicating lower success in quitting. CONCLUSIONS: The prevalence of current smoking was higher among persons with mental illnesses than among adults without mental illnesses. Our findings stress the need for prevention and cessation efforts targeting adults with mental illnesses. PMID- 20966370 TI - Adding sexual orientation questions to statewide public health surveillance: New Mexico's experience. AB - We examined refusal rates for sensitive demographic questions to determine whether questions on sexual orientation are too sensitive for routine use on public health surveys. We compared the percentage of active refusals in New Mexico for a sexual orientation question and 6 other sensitive demographic questions. In 2007 and 2008, refusal rates for sexual orientation questions were similar to rates for questions on race/ethnicity and weight and significantly lower than rates for questions on household income. Perceptions that sexual orientation is too controversial a topic to be included on state surveys may be unfounded. PMID- 20966371 TI - Discrimination and adjustment among Chinese American adolescents: family conflict and family cohesion as vulnerability and protective factors. AB - OBJECTIVES: We examined racial/ethnic discrimination experiences of Chinese American adolescents to determine how discrimination is linked to poor adjustment (i.e., loneliness, anxiety, and somatization) and how the context of the family can buffer or exacerbate these links. METHODS: We collected survey data from 181 Chinese American adolescents and their parents in Northern California. We conducted hierarchical regression analyses to examine main effects and 2-way interactions of perceived discrimination with family conflict and family cohesion. RESULTS: Discrimination was related to poorer adjustment in terms of loneliness, anxiety, and somatization, but family conflict and cohesion modified these relations. Greater family conflict exacerbated the negative effects of discrimination, and greater family cohesion buffered the negative effects of discrimination. CONCLUSIONS: Our findings highlight the importance of identifying family-level moderators to help adolescents and their families handle experiences of discrimination. PMID- 20966372 TI - Improving the health and mental health of people living with HIV/AIDS: 12-month assessment of a behavioral intervention in Thailand. AB - OBJECTIVES: We examined findings from a randomized controlled intervention trial designed to improve the quality of life of people living with HIV in Thailand. METHODS: A total of 507 people living with HIV were recruited from 4 district hospitals in northern and northeastern Thailand and were randomized to an intervention group (n = 260) or a standard care group (n = 247). Computer assisted personal interviews were administered at baseline and at 6 and 12 months. RESULTS: At baseline, the characteristics of participants in the intervention and standard care conditions were comparable. The mixed-effects models used to assess the impact of the intervention revealed significant improvements in general health (B = 2.51; P = .001) and mental health (B = 1.57; P = .02) among participants in the intervention condition over 12 months and declines among those in the standard care condition. CONCLUSIONS: Our results demonstrate that a behavioral intervention was successful in improving the quality of life of people living with HIV. Such interventions must be performed in a systematic, collaborative manner to ensure their cultural relevance, sustainability, and overall success. PMID- 20966373 TI - Culturally sensitive collaborative treatment for depressed chinese americans in primary care. AB - OBJECTIVES: We examined the feasibility and effectiveness of using culturally sensitive collaborative treatment (CSCT) to improve recognition, engagement, and treatment of depressed Chinese Americans in primary care. METHODS: Chinese American patients in a primary care setting (n = 4228) were screened for depression. The primary study outcome was treatment engagement rate, and the secondary outcome was treatment response. RESULTS: Of the study participants, 296 (7%) screened positive for depression, 122 (41%) of whom presented for a psychiatric assessment; 104 (85%) were confirmed with major depressive disorder, and 100 (96%) of these patients were randomized into treatment involving either care management or usual care. Patients in the care management and usual care groups did not differ in terms of their outcomes. CSCT resulted in a nearly 7 fold increase in treatment rate among depressed patients in primary care. CONCLUSIONS: CSCT is both feasible and effective in improving recognition and treatment engagement of depressed Chinese Americans. Care management may have limited effects on depressed patients treated by psychiatrists, given that these patients tend to have favorable responses in general. PMID- 20966374 TI - Early childhood poverty, cumulative risk exposure, and body mass index trajectories through young adulthood. AB - OBJECTIVES: We assessed whether cumulative risk exposure underlies the relation between early childhood poverty and body mass index (BMI) trajectories. METHODS: We interviewed youths and their mothers in rural upstate New York (168 boys and 158 girls) from 1995 to 2006 when the youths were aged 9, 13, and 17 years. At each interview, we calculated their BMI-for-age percentile. RESULTS: Early childhood poverty predicted BMI growth trajectories from ages 9 to 17 years (b = 3.64; SE = 1.39; P < .01). Early childhood poverty also predicted changes in cumulative risk (b = 0.31; SE = 0.08; P < .001). Cumulative risk, in turn, predicted BMI trajectories (b = 2.41; SE = 0.75; P < .01). Finally, after we controlled for cumulative risk, the effect of early childhood poverty on BMI trajectories was no longer significant, indicating that cumulative risk exposure mediated the relation between early childhood poverty and BMI trajectories (b = 2.01; SE = 0.94). CONCLUSIONS: We show for the first time that early childhood poverty leads to accelerated weight gain over the course of childhood into early adulthood. Cumulative risk exposure during childhood accounts for much of this accelerated weight gain. PMID- 20966375 TI - Improving weight loss outcomes of community interventions by incorporating behavioral strategies. AB - OBJECTIVES: We examined whether adding behavioral weight loss strategies could improve the outcomes of a community weight loss campaign. METHODS: Shape Up RI is a 12-week, online, team-based program for health improvement in Rhode Island. In study 1, we randomly assigned participants to the standard Shape Up RI program or to the program plus video lessons on weight loss. In study 2, we randomly assigned participants to the standard program or to the program plus video lessons; daily self-monitoring of weight, eating, and exercise; and computer generated feedback. RESULTS: Adding video lessons alone (study 1) did not result in significantly improved weight loss (2.0 +/-2.8 kg vs 1.4 +/-2.9 kg; P = .15). However, when the video lessons were supplemented with self-monitoring and feedback (study 2), the average weight loss more than doubled (3.5 +/-3.8 kg vs 1.4 +/-2.7 kg; P < .01), and the proportion of individuals achieving a weight loss of 5% or more tripled (40.5% vs 13.2%; P < .01). Participants in study 2 submitted self-monitoring records on 78% of days, and adherence was significantly related to outcome. CONCLUSIONS: Adding behavioral strategies to community campaigns may improve weight loss outcomes with minimal additional cost. PMID- 20966376 TI - Comparative analysis of national legislation in support of the revised international health regulations: potential models for implementation in the United States. AB - In 2005, the World Health Organization adopted the revised International Health Regulations, or IHR (2005), to establish obligations for detecting and responding to public health emergencies of international concern. The success of the IHR (2005) rests on the ability of states to implement the objectives and to execute the regulations in a legal and politically acceptable manner. Implementation of the IHR (2005) may be challenging for federalist nations, where most public health regulatory power lies in local rather than in national governments. We examine the implementation strategies of 4 nations: Australia, Canada, Germany, and India. The methods currently being considered by these nations for executing the IHR (2005) are potentially applicable models for the United States to consider. PMID- 20966377 TI - Applying the chronic care model to homeless veterans: effect of a population approach to primary care on utilization and clinical outcomes. AB - OBJECTIVES: We compared a population-tailored approach to primary care for homeless veterans with a usual care approach. METHODS: We conducted a retrospective prolective cohort study of homeless veterans enrolled in a population-tailored primary care clinic matched to a historical sample in general internal medicine clinics. Overall, 177 patients were enrolled: 79 in the Homeless-Oriented Primary Care Clinic and 98 in general internal medicine primary care. RESULTS: Homeless-oriented primary care-enrolled patients had greater improvements in hypertension, diabetes, and lipid control, and primary care use was higher during the first 6 months (5.96 visits per person vs 1.63 for general internal medicine) but stabilized to comparable rates during the second 6 months (2.01 vs 1.31, respectively). Emergency department (ED) use was also higher (2.59 vs 1.89 visits), although with 40% lower odds for nonacute ED visits than for the general internal medicine group (95% confidence interval = 0.2, 0.8). Excluding substance abuse and mental health admissions, hospitalizations were reduced among the homeless veterans between the 2 periods (28.6% vs 10.8%; P < .01) compared with the general internal medicine group (48.2% vs 44.4%; P = .6; difference of differences, P < .01). CONCLUSIONS: Tailoring primary care to homeless veterans can decrease unnecessary ED use and medical admissions and improve chronic disease management. PMID- 20966378 TI - Mental health disorders, psychological distress, and suicidality in a diverse sample of lesbian, gay, bisexual, and transgender youths. AB - OBJECTIVES: We examined associations of race/ethnicity, gender, and sexual orientation with mental disorders among lesbian, gay, bisexual, and transgender (LGBT) youths. METHODS: We assessed mental disorders by administering a structured diagnostic interview to a community sample of 246 LGBT youths aged 16 to 20 years. Participants also completed the Brief Symptom Inventory 18 (BSI 18). RESULTS: One third of participants met criteria for any mental disorder, 17% for conduct disorder, 15% for major depression, and 9% for posttraumatic stress disorder. Anorexia and bulimia were rare. Lifetime suicide attempts were frequent (31%) but less so in the prior 12 months (7%). Few racial/ethnic and gender differences were statistically significant. Bisexually identified youths had lower prevalences of every diagnosis. The BSI 18 had high negative predictive power (90%) and low positive predictive power (25%) for major depression. CONCLUSIONS: LGBT youths had higher prevalences of mental disorder diagnoses than youths in national samples, but were similar to representative samples of urban, racial/ethnic minority youths. Suicide behaviors were similar to those among representative youth samples in the same geographic area. Questionnaires measuring psychological distress may overestimate depression prevalence among this population. PMID- 20966379 TI - The relationship of trauma to mental disorders among trafficked and sexually exploited girls and women. AB - OBJECTIVES: We explored the association between traumatic events and mental health among girls and women trafficked for sexual exploitation. METHODS: We used subscales of the Brief Symptom Inventory and Harvard Trauma Questionnaire to interview 204 trafficked girls and women in 7 posttrafficking service settings. Multivariate logistic regression models based on interview data were fitted for depression, anxiety, and posttraumatic stress disorder (PTSD) separately and adjusted for pretrafficking abuse to determine impact of trafficking-related trauma exposures. RESULTS: Injuries and sexual violence during trafficking were associated with higher levels of PTSD, depression, and anxiety. Sexual violence was associated with higher levels of PTSD (adjusted odds ratio [AOR] = 5.6; 95% confidence interval [CI] = 1.3, 25.4). More time in trafficking was associated with higher levels of depression and anxiety (AOR = 2.2; 95% CI = 1.1, 4.5). More time since trafficking was associated with lower levels of depression and anxiety but not of PTSD. CONCLUSIONS: Our findings inform the emerging field of mental health care for trafficked persons by highlighting the importance of assessing severity and duration of trafficking-related abuses and need for adequate recovery time. Therapies for anxiety, PTSD, and mood disorders in low-resource settings should be evaluated. PMID- 20966380 TI - Gender differences in mental health diagnoses among Iraq and Afghanistan veterans enrolled in veterans affairs health care. AB - OBJECTIVES: We examined gender differences in sociodemographic, military service, and mental health characteristics among Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans. We evaluated associations between these sociodemographic and service characteristics and depression and posttraumatic stress disorder (PTSD) diagnoses. METHODS: In a retrospective, cross-sectional study, we used univariate descriptive statistics and log binominal regression analyses of Department of Veterans Affairs (VA) administrative data on 329 049 OEF and OIF veterans seeking VA health care from April 1, 2002, through March 31, 2008. RESULTS: Female veterans were younger and more likely to be Black and to receive depression diagnoses than were male veterans, who were more frequently diagnosed with PTSD and alcohol use disorders. Older age was associated with a higher prevalence of PTSD and depression diagnoses among women but not among men. CONCLUSIONS: Consideration of gender differences among OEF and OIF veterans seeking health care at the VA will facilitate more targeted prevention and treatment services for these newly returning veterans. PMID- 20966381 TI - Lung volume measured during sequential swallowing in healthy young adults. AB - PURPOSE: Outcomes from studying the coordinative relationship between respiratory and swallow subsystems are inconsistent for sequential swallows, and the lung volume at the initiation of sequential swallowing remains undefined. The first goal of this study was to quantify the lung volume at initiation of sequential swallowing ingestion cycles and to identify the respiratory pattern(s) surrounding each sequential swallow ingestion cycle. The second goal was to compare these results with existing data for single swallows. METHOD: Twenty healthy young adults served as participants, 9 males and 11 females, between 19 and 28 years of age (M = 22 years of age). Participants completed 2 trials each of 100 mL of water self-delivered by cup and by straw. Calibrated respiratory inductance plethysmography, surface electromyography, and a contact throat microphone were used to detect respiratory parameters, identify swallow-related muscle contraction, and identify swallowing sounds, respectively. RESULTS: Significantly higher lung volume initiation for trials delivered by straw and more variable respiratory patterns surrounding cup and straw sequential swallowing ingestion cycles existed compared with single swallows. CONCLUSIONS: Results show that as the physiologic demands of swallowing deviate from single, small bolus swallows, the integration of the swallowing and respiratory systems change. This may reflect obligate differences in airway protection strategy and prolonged competition for respiratory resources. PMID- 20966382 TI - Fast mapping and word learning by preschoolers with specific language impairment in a supported learning context: effect of encoding cues, phonotactic probability, and object familiarity. AB - PURPOSE: To investigate whether phonological or semantic encoding cues improved the fast mapping or word learning performance of preschoolers with specific language impairment (SLI) or typical development (TD) and whether performance varied for words containing high- or low-frequency sublexical sequences that named familiar or unfamiliar objects. METHOD: Forty-two preschoolers with SLI, 42 preschoolers with TD matched for age and gender to the children with SLI, and 41 preschoolers with TD matched for expressive vocabulary and gender to the children with SLI learned words in a supported learning context. Fast mapping, word learning, and post-task performance were assessed. RESULTS: Encoding cues had no effect on fast mapping performance for any group or on the number of words children learned to comprehend. Encoding cues appeared to be detrimental to word production for children with TD. Across groups, a clear learning advantage was observed for words with low-frequency sequences and, to a lesser extent, words associated with an unfamiliar object. CONCLUSION: The results suggest that phonotactic probability and previous lexical knowledge affect word learning in similar ways for children with TD and SLI and that encoding cues were not beneficial for any group. PMID- 20966383 TI - Rhythmic versus phonemic interference in delayed auditory feedback. AB - PURPOSE: Delayed auditory feedback (DAF) of a speaker's voice disturbs normal speech production. Various traditional theories assume that the content of the delayed feedback signal interferes with the actual production of a particular speech unit (phonemic content hypothesis). The displaced rhythm hypothesis as an alternative explanation suggests that speech disturbances arise from a disruptive rhythm that is produced by the delayed speech signal. The present experimental study directly contrasted the role of rhythm and speech content in a DAF task using speech units as stimuli. METHOD: One hundred fifty-one participants read aloud 4 different sequences of double syllables that varied in phonemic content and rhythm while auditory feedback was either nondelayed or delayed by 200 or 400 ms. RESULTS: In line with previous studies, the authors found a peak of disturbances at a delay of about 200 ms, independent of speech rate. More important, the present results clearly support the displaced rhythm hypothesis. A speech rate dependency of this effect was also found. CONCLUSION: Rhythm seems to be a significant criterion of speech monitoring, and hence a mismatch between spoken words and auditory feedback realized by DAF induces obvious speech problems on rhythmic level regardless of phonemic discrepancy at the same time. PMID- 20966384 TI - Regional dialect variation in the vowel systems of typically developing children. AB - PURPOSE: To investigate regional dialect variation in the vowel systems of typically developing 8- to 12-year-old children. METHOD: Thirteen vowels in isolated h_d words were produced by 94 children and 93 adults (males and females). All participants spoke American English and were born and raised in 1 of 3 distinct dialect regions in the United States: western North Carolina (Southern dialect), central Ohio (Midland dialect), and southeastern Wisconsin (Northern Midwestern dialect). Acoustic analysis included formant frequencies (F1 and F2) measured at 5 equidistant time points in a vowel and formant movement (trajectory length). RESULTS: Children's productions showed many dialect-specific features comparable to those in adult speakers, both in terms of vowel dispersion patterns and formant movement. Different features were also found, including systemic vowel changes, significant monophthongization of selected vowels, and greater formant movement in diphthongs. CONCLUSIONS: The acoustic results provide evidence for regional distinctiveness in children's vowel systems. Children acquire not only the systemic relations among vowels but also their dialect specific patterns of formant dynamics. Directing attention to the regional variation in the production of American English vowels, this work may prove helpful in better understanding and interpreting the development of vowel categories and vowel systems in children. PMID- 20966385 TI - Fourier descriptor analysis and unification of voice range profile contours: method and applications. AB - PURPOSE: To describe a method for unified description, statistical modeling, and comparison of voice range profile (VRP) contours, even from diverse sources. METHOD: A morphologic modeling technique, which is based on Fourier descriptors (FDs), is applied to the VRP contour. The technique, which essentially involves resampling of the curve of the contour, is assessed and also is compared to density-based VRP averaging methods that use the overlap count. RESULTS: VRP contours can be usefully described and compared using FDs. The method also permits the visualization of the local covariation along the contour average. For example, the FD-based analysis shows that the population variance for ensembles of VRP contours is usually smallest at the upper left part of the VRP. To illustrate the method's advantages and possible further application, graphs are given that compare the averaged contours from different authors and recording devices--for normal, trained, and untrained male and female voices as well as for child voices. CONCLUSIONS: The proposed technique allows any VRP shape to be brought to the same uniform base. On this uniform base, VRP contours or contour elements coming from a variety of sources may be placed within the same graph for comparison and for statistical analysis. PMID- 20966386 TI - Examining continuity of early expressive vocabulary development: the generation R study. AB - PURPOSE: The authors investigated continuity and discontinuity of vocabulary skills in a population-based cohort in the Netherlands. METHOD: Mothers of 3,759 children completed the Dutch version of the MacArthur Short Form Vocabulary Checklist (Zink & Lejaegere, 2003) at 18 months and a Dutch translation of the Language Development Survey (Rescorla, 1989) at 30 months. At both ages, expressive vocabulary delay was defined as vocabulary scores <10th age- and gender-specific percentile. RESULTS: Of the children, 85.2% had normal vocabulary development at both ages, 6.2% were "late bloomers," 6.0% had late onset expressive vocabulary delay, and 2.6% had persistent expressive vocabulary delay. Word production and comprehension at 18 months explained 11.5% of the variance in 30-month vocabulary scores, with low birth weight, child age, gender and ethnicity, maternal age and education, and parenting stress explaining an additional 6.2%. Multinomial logistic regression was used to identify biological, demographic, and psychological factors associated with each of the vocabulary delay outcome groups relative to the typically developing group. CONCLUSIONS: Although multiple perinatal, demographic, and maternal psychosocial factors significantly predicted vocabulary skills at 30 months, positive predictive value and sensitivity were low. Future studies should address to what extent additional factors, such as brain maturation and genetic influences, can improve the prediction and understanding of continuity and discontinuity of language delay. PMID- 20966387 TI - The effects of age and infant hearing status on maternal use of prosodic cues for clause boundaries in speech. AB - PURPOSE: The present study examined the effects of age and hearing status of a child on maternal use of pitch change, preboundary vowel lengthening, and pause duration, all of which are prosodic cues correlated with clause boundaries in infant-directed speech. METHOD: Mothers' speech to infants with normal hearing (NH; n = 18), infants who are profoundly deaf with a cochlear implant (HI; n = 9), and an adult experimenter were recorded at 2 time periods separated by 6 months. NH infants were matched to HI infants by chronological age or hearing experience. Fundamental frequency of pre- and postboundary vowels, vowel duration, and pause duration between utterances was measured. RESULTS: Results demonstrated that mothers (a) exaggerated prosodic characteristics in infant directed speech regardless of infants' hearing status; (b) tailored preboundary vowel lengthening to infants' hearing experience rather than to chronological age; and (c) decreased exaggeration of pause duration over time. CONCLUSIONS: The results suggest that acoustic cues correlated with clause boundaries are available in maternal speech to HI infants. Their exaggeration relative to adult directed speech suggests that mothers' use of infant-directed speech is a natural behavior regardless of infant hearing status. Finally, mothers modify speech prosody according to their children's age and hearing experience. PMID- 20966388 TI - The influence of auditory acuity on acoustic variability and the use of motor equivalence during adaptation to a perturbation. AB - PURPOSE: The aim of this study was to relate speakers' auditory acuity for the sibilant contrast, their use of motor equivalent trading relationships in producing the sibilant /?/, and their produced acoustic distance between the sibilants /s/ and /?/. Specifically, the study tested the hypotheses that during adaptation to a perturbation of vocal-tract shape, high-acuity speakers use motor equivalence strategies to a greater extent than do low-acuity speakers in order to reach their smaller phonemic goal regions, and that high-acuity speakers produce greater acoustic distance between 2 sibilant phonemes than do low-acuity speakers. METHOD: Articulographic data from 7 German speakers adapting to a perturbation were analyzed for the use of motor equivalence. The speakers' produced acoustic distance between /s/ and /?/ was calculated. Auditory acuity was assessed for the same speakers. RESULTS: High-acuity speakers used motor equivalence to a greater extent when adapting to a perturbation than did low acuity speakers. Additionally, high-acuity speakers produced greater acoustic contrasts than did low-acuity-speakers. It was observed that speech rate had an influence on the use of motor equivalence: Slow speakers used motor equivalence to a lesser degree than did fast speakers. CONCLUSION: These results provide support for the mutual interdependence of speech perception and production. PMID- 20966389 TI - Prevalence and phenotype of childhood apraxia of speech in youth with galactosemia. AB - PURPOSE: In this article, the authors address the hypothesis that the severe and persistent speech disorder reported in persons with galactosemia meets contemporary diagnostic criteria for childhood apraxia of speech (CAS). A positive finding for CAS in this rare metabolic disorder has the potential to impact treatment of persons with galactosemia and inform explanatory perspectives on CAS in neurological, neurodevelopmental, and idiopathic contexts. METHOD: Thirty-three youth with galactosemia and significant prior or persistent speech sound disorder were assessed in their homes in 17 states. Participants completed a protocol yielding information on their cognitive, structural, sensorimotor, language, speech, prosody, and voice status and function. RESULTS: Eight of the 33 participants (24%) met contemporary diagnostic criteria for CAS. Two participants, 1 of whom was among the 8 with CAS, met criteria for ataxic or hyperkinetic dysarthria. Groupwise findings for the remaining 24 participants are consistent with a classification category termed Motor Speech Disorder-Not Otherwise Specified (Shriberg, Fourakis et al., 2010a). CONCLUSION: The authors estimate the prevalence of CAS in galactosemia at 18 per hundred-180 times the estimated risk for idiopathic CAS. Findings support the need to study risk factors for the high occurrence of motor speech disorders in galactosemia despite early compliant dietary management. PMID- 20966390 TI - Passive participle marking by African American English-speaking children reared in poverty. AB - PURPOSE: In this study, the authors examined the linguistic profile of African American English (AAE)-speaking children reared in poverty by focusing on their marking of passive participles and by comparing the results with the authors' previous study of homophonous forms of past tense (S. Pruitt & J. Oetting, 2009). METHOD: The data were from 45 five- to six-year-olds who spoke AAE and who participated in the authors' earlier study. Fifteen were classified as low-income (LSES); the others were classified as middle-income and served as either age- or language-matched controls. The data came from a probe that was designed by S. M. Redmond (2003), but it was modified to examine the morphological and phonological characteristics of AAE. RESULTS: Participle marking by all 3 groups was influenced by AAE phonology, but the LSES children marked the participles at lower rates than the controls. The LSES children's rates of participle marking were also lower than their rates of marking for homophonous forms of past tense. Unlike the children's rates of past-tense marking, their rates of participle marking were correlated to their vocabulary test scores. CONCLUSIONS: AAE speaking children reared in poverty present weaknesses in aspects of grammatical morphology that are related to their vocabulary weaknesses. PMID- 20966391 TI - Muscle-specific f-box only proteins facilitate bk channel beta(1) subunit downregulation in vascular smooth muscle cells of diabetes mellitus. AB - RATIONALE: activity of the large conductance Ca(2+)-activated K(+) (BK) channels is profoundly modulated by its beta(1) subunit (BK-beta(1)). However, BK-beta(1) expression is downregulated in diabetic vessels. The ubiquitin-proteasome system (UPS) is a major mechanism of intracellular protein degradation. Whether UPS participates in BK-beta(1) downregulation in diabetic vessels is unknown. OBJECTIVE: we hypothesize that UPS facilitates vascular BK-beta(1) degradation in diabetes. METHODS AND RESULTS: using patch clamp and molecular biological approaches, we found that BK-beta(1)-mediated channel activation and BK-beta(1) protein expression were reduced in aortas of streptozotocin-induced diabetic rats and in human coronary arterial smooth muscle cells (CASMCs) cultured in high glucose. This was accompanied by upregulation of F-box only protein (FBXO)-9 and FBXO-32 (atrogin-1), the key components of the Skp1-Cullin-F-box (SCF) type ubiquitin ligase complex. BK-beta(1) expression was suppressed by the FBXO activator doxorubicin but enhanced by FBXO-9 small interfering RNA or by the proteasome inhibitor MG-132. Cotransfection of atrogin-1 in HEK293 cells significantly reduced Flag-hSlo-beta(1) expression by 2.16-fold, compared with expression of Flag-hSlo-beta(1)V146A (a mutant without the PDZ-binding motif). After cotransfection with atrogin-1, the ubiquitination of Flag-hSlo-beta(1) was increased by 1.91-fold, compared with that of hSlo-beta(1)V146A, whereas cotransfection with atrogin-1DeltaF (a nonfunctional mutant without the F-box motif) had no effect. Moreover, inhibition of Akt signaling attenuated the phosphorylation of forkhead box O transcription factor (FOXO)-3a and enhanced atrogin-1 expression, which in turn suppressed BK-beta(1) protein levels in human CASMCs. CONCLUSIONS: downregulation of vascular BK-beta(1) expression in diabetes and in high-glucose culture conditions was associated with FOXO-3a/FBXO-dependent increase in BK-beta(1) degradation. PMID- 20966392 TI - In the RyR2(R4496C) mouse model of CPVT, beta-adrenergic stimulation induces Ca waves by increasing SR Ca content and not by decreasing the threshold for Ca waves. AB - RATIONALE: mutations of the ryanodine receptor (RyR) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). These mutations predispose to the generation of Ca waves and delayed afterdepolarizations during adrenergic stimulation. Ca waves occur when either sarcoplasmic reticulum (SR) Ca content is elevated above a threshold or the threshold is decreased. Which of these occurs in cardiac myocytes expressing CPVT mutations is unknown. OBJECTIVE: we tested whether the threshold SR Ca content is different between control and CPVT and how it relates to SR Ca content during beta-adrenergic stimulation. METHODS AND RESULTS: ventricular myocytes from the RyR2 R4496C(+/-) mouse model of CPVT and wild-type (WT) controls were voltage-clamped; diastolic SR Ca content was measured and compared with the Ca wave threshold. The results showed the following. (1) In 1 mmol/L [Ca(2+)](o), beta-adrenergic stimulation with isoproterenol (1MUmol/L) caused Ca waves only in R4496C. (2) SR Ca content and Ca wave threshold in R4496C were lower than those in WT. (3) beta-Adrenergic stimulation increased SR Ca content by a similar amount in both R4496C and WT. (4) beta-Adrenergic stimulation increased the threshold for Ca waves. (5) During beta-adrenergic stimulation in R4496C, but not WT, the increase of SR Ca was sufficient to reach threshold and produce Ca waves. CONCLUSIONS: in the R4496C CPVT model, the RyR is leaky, and this lowers both SR Ca content and the threshold for waves. beta-Adrenergic stimulation produces Ca waves by increasing SR Ca content and not by lowering threshold. PMID- 20966393 TI - A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse. AB - RATIONALE: coronary artery ligation to induce myocardial infarction (MI) in mice is typically performed by an invasive and time-consuming approach that requires ventilation and chest opening (classic method), often resulting in extensive tissue damage and high mortality. We developed a novel and rapid surgical method to induce MI that does not require ventilation. OBJECTIVE: the purpose of this study was to develop and comprehensively describe this method and directly compare it to the classic method. METHODS AND RESULTS: male C57/B6 mice were grouped into 4 groups: new method MI (MI-N) or sham (S-N) and classic method MI (MI-C) or sham (S-C). In the new method, heart was manually exposed without intubation through a small incision and MI was induced. In the classic method, MI was induced through a ventilated thoracotomy. Similar groups were used in an ischemia/reperfusion injury model. This novel MI procedure is rapid, with an average procedure time of 1.22 +/- 0.05 minutes, whereas the classic method requires 23.2 +/- 0.6 minutes per procedure. Surgical mortality was 3% in MI-N and 15.9% in MI-C. The rate of arrhythmia was significantly lower in MI-N. The postsurgical levels of tumor necrosis factor-alpha and myeloperoxidase were lower in new method, indicating less inflammation. Overall, 28-day post-MI survival rate was 68% with MI-N and 48% with MI-C. Importantly, there was no difference in infarct size or post-MI cardiac function between the methods. CONCLUSIONS: this new rapid method of MI in mice represents a more efficient and less damaging model of myocardial ischemic injury compared with the classic method. PMID- 20966394 TI - S100A12 in vascular smooth muscle accelerates vascular calcification in apolipoprotein E-null mice by activating an osteogenic gene regulatory program. AB - OBJECTIVE: The proinflammatory cytokine S100A12 is associated with coronary atherosclerotic plaque rupture. We previously generated transgenic mice with vascular smooth muscle-targeted expression of human S100A12 and found that these mice developed aortic aneurysmal dilation of the thoracic aorta. In the current study, we tested the hypothesis that S100A12 expressed in vascular smooth muscle in atherosclerosis-prone apolipoprotein E (ApoE)-null mice would accelerate atherosclerosis. METHODS AND RESULTS: ApoE-null mice with or without the S100A12 transgene were analyzed. We found a 1.4-fold increase in atherosclerotic plaque size and more specifically a large increase in calcified plaque area (45% versus 7% of innominate artery plaques and 18% versus 10% of aortic root plaques) in S100A12/ApoE-null mice compared with wild-type/ApoE-null littermates. Expression of bone morphogenic protein and other osteoblastic genes was increased in aorta and cultured vascular smooth muscle, and importantly, these changes in gene expression preceded the development of vascular calcification in S100A12/ApoE null mice. Accelerated atherosclerosis and vascular calcification were mediated, at least in part, by oxidative stress because inhibition of NADPH oxidase attenuated S100A12-mediated osteogenesis in cultured vascular smooth muscle cells. S100A12 transgenic mice in the wild-type background (ApoE+/+) showed minimal vascular calcification, suggesting that S100A12 requires a proinflammatory/proatherosclerotic environment to induce osteoblastic differentiation and vascular calcification. CONCLUSIONS: Vascular smooth muscle S100A12 accelerates atherosclerosis and augments atherosclerosis-triggered osteogenesis, reminiscent of features associated with plaque instability. PMID- 20966395 TI - The transcription factor Erg inhibits vascular inflammation by repressing NF kappaB activation and proinflammatory gene expression in endothelial cells. AB - OBJECTIVE: To test whether ETS-related gene (Erg) inhibits tumor necrosis factor (TNF)-alpha-dependent endothelial activation and inflammation. METHODS AND RESULTS: Endothelial activation underlies many vascular diseases, including atherosclerosis. Endothelial activation by proinflammatory cytokines decreases expression of the ETS transcription factor Erg. By using human umbilical vein endothelial cells (HUVECs), we showed that Erg overexpression by adenovirus (AdErg) repressed basal and TNF-alpha-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM), and interleukin 8 (IL-8). Erg inhibited TNF-alpha-dependent activation of the ICAM-1 promoter, nuclear factor (NF)-kappaB activity, and NF-kappaB p65 phosphorylation. Basal NF-kappaB activity was also inhibited by Erg overexpression. Chromatin immunoprecipitation showed that Erg binds to the ICAM-1 proximal promoter region, which contains 7 putative ETS binding sites. To test the anti-inflammatory role of Erg in vivo, we used a murine model of TNF-alpha-dependent acute inflammation. The injection of AdErg into the paw decreased TNF-alpha-induced inflammation compared with control. Finally, staining of human coronary plaques showed loss of Erg expression from the endothelium overlaying active plaque shoulders. CONCLUSIONS: We have identified a novel physiological anti-inflammatory pathway under the control of the transcription factor Erg; this pathway inhibits NF kappaB-dependent transcription and TNF-alpha-induced inflammation in vivo. These results suggest a novel approach to anti-inflammatory therapies. PMID- 20966396 TI - Toll-like receptor 9 signaling is critical for early experimental deep vein thrombosis resolution. AB - OBJECTIVE: Toll-like receptors (TLR) bridge innate immunity and host responses, including inflammation. Sterile inflammation such as a venous thrombus (Vt) may involve TLR signaling, including TLR9. METHODS AND RESULTS: TLR9 signaling on thrombus resolution was investigated using a mouse model of stasis Vt. Vt were significantly larger in TLR9-/- mice compared with wild-type (WT) at 2 and 8 days, despite a 2-fold increase in thrombus polymorphonucleic neutrophils at 2 days and monocytes at 8 days, whereas thrombus collagen and neovascularization was 55% and 37% less, respectively, at 8 days. Coincidently, decreased fibrinogen and increased thrombin-antithrombin complex were observed in TLR9-/- mouse thrombi. Vein wall interferon-alpha, interleukin-1alpha, and interleukin-2 were significantly reduced in TLR9-/- mice compared with WT. Thrombus cell death pathway markers were not significantly altered at 2 days, but caspase-1 was reduced in TLR9-/- thrombi at 8 days. MyD88 confers TLR9 intracellular signaling, but MyD88-/- mice had Vt resolution similar to that of WT. However, inhibition of the NOTCH ligand delta-like 4 was associated with larger Vt. Finally, stimulation with a TLR9 agonist was associated with smaller Vt. CONCLUSIONS: TLR9 signaling is integral for early and mid-Vt resolution through modulation of sterile inflammation, maintaining a TH1 milieu, and effects on the thrombosis pathway. PMID- 20966397 TI - The anti-inflammatory cytokine interleukin 19 is expressed by and angiogenic for human endothelial cells. AB - OBJECTIVE: To characterize the expression and function of interleukin (IL) 19, a recently described T-helper 2 anti-inflammatory IL, on endothelial cell (EC) pathophysiological features. METHODS AND RESULTS: The expression and effects of anti-inflammatory ILs on EC activation and development of angiogenesis are uncharacterized. We demonstrate by immunohistochemistry and immunoblot that IL-19 is expressed in inflamed, but not normal, human coronary endothelium and can be induced in cultured human ECs by serum and basic fibroblast growth factor. IL-19 is mitogenic and chemotactic, and it promotes EC spreading. IL-19 activates the signaling proteins STAT3, p44/42, and Rac1. In functional ex vivo studies, IL-19 promotes cordlike structure formation of cultured ECs and enhances microvessel sprouting in the mouse aortic ring assay. IL-19 induces tube formation in gelatinous protein (Matrigel) plugs in vivo. CONCLUSIONS: To our knowledge, these data are the first to report expression of the anti-inflammatory agent, IL-19, in ECs; and the first to indicate that IL-19 is mitogenic and chemotactic for ECs and can induce the angiogenic potential of ECs. PMID- 20966398 TI - Binding preferences for GPIHBP1, a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells. AB - OBJECTIVE: To define the ability of GPIHBP1 to bind other lipase family members and other apolipoproteins (apos) and lipoproteins. METHODS AND RESULTS: GPIHBP1, a GPI-anchored lymphocyte antigen (Ly)6 protein of capillary endothelial cells, binds lipoprotein lipase (LPL) avidly, but its ability to bind related lipase family members has never been evaluated. As judged by cell-based and cell-free binding assays, LPL binds to GPIHBP1, but other members of the lipase family do not. We also examined the binding of apoAV-phospholipid disks to GPIHBP1. ApoAV binds avidly to GPIHBP1-transfected cells; this binding requires GPIHBP1's amino terminal acidic domain and is independent of its cysteine-rich Ly6 domain (the latter domain is essential for LPL binding). GPIHBP1-transfected cells did not bind high-density lipoprotein. Chylomicrons bind avidly to GPIHBP1-transfected Chinese hamster ovary cells, but this binding is dependent on GPIHBP1's ability to bind LPL within the cell culture medium. CONCLUSIONS: GPIHBP1 binds LPL but does not bind other lipase family members. GPIHBP1 binds apoAV but does not bind apoAI or high-density lipoprotein. The ability of GPIHBP1-transfected Chinese hamster ovary cells to bind chylomicrons is mediated by LPL; chylomicron binding does not occur unless GPIHBP1 first captures LPL from the cell culture medium. PMID- 20966399 TI - Circulating fibroblast growth factor-23 is associated with fat mass and dyslipidemia in two independent cohorts of elderly individuals. AB - OBJECTIVE: Disturbances in mineral metabolism define an increased cardiovascular risk in patients with chronic kidney disease. Fibroblast growth factor-23 (FGF23) is a circulating regulator of phosphate and vitamin D metabolism and has recently been implicated as a putative pathogenic factor in cardiovascular disease. Because other members of the FGF family play a role in lipid and glucose metabolism, we hypothesized that FGF23 would associate with metabolic factors that predispose to an increased cardiovascular risk. The goal of this study was to investigate the relationship between FGF23 and metabolic cardiovascular risk factors in the community. METHODS AND RESULTS: Relationships between serum FGF23 and body mass index (BMI), waist circumference, waist-to-hip ratio, serum lipids, and fat mass were examined in 2 community-based, cross-sectional cohorts of elderly whites (Osteoporotic Fractures in Men Study: 964 men aged 75+/-3.2; Prospective Investigation of the Vasculature in Uppsala Seniors study: 946 men and women aged 70). In both cohorts, FGF23 associated negatively with high density lipoprotein and apolipoprotein A1 (7% to 21% decrease per 1-SD increase in log FGF23; P<0.01) and positively with triglycerides (11% to 14% per 1-SD increase in log FGF23; P<0.01). A 1-SD increase in log FGF23 was associated with a 7% to 20% increase in BMI, waist circumference, and waist-to-hip ratio and a 7% to 18% increase in trunk and total body fat mass (P<0.01) as determined by whole body dual x-ray absorptiometry. FGF23 levels were higher in subjects with the metabolic syndrome compared with those without (46.4 versus 41.2 pg/mL; P<0.05) and associated with an increased risk of having the metabolic syndrome (OR per 1 SD increase in log FGF23, 1.21; 95% CI, 1.04 to 1.40; P<0.05). CONCLUSIONS: We report for the first time on associations between circulating FGF23, fat mass, and adverse lipid metabolism resembling the metabolic syndrome, potentially representing a novel pathway(s) linking high FGF23 to an increased cardiovascular risk. PMID- 20966400 TI - From vessel sprouting to normalization: role of the prolyl hydroxylase domain protein/hypoxia-inducible factor oxygen-sensing machinery. AB - The accepted model of vessel branching distinguishes several endothelial cell fates. At the forefront of a vessel sprout, "tip cells" guide the sprouting vessel toward an angiogenic stimulus. Behind the tip, "stalk cells" proliferate to elongate the vessel branch and create a lumen. In mature vessels, endothelial cells acquire a streamlined shape to optimally conduct blood flow. For this purpose, endothelial cells switch to the "phalanx" cell fate, which is characterized by quiescent and nonproliferating cells aligned in a tight cobblestonelike layer. Vessel maturation also requires the recruitment of mural cells (ie, smooth muscle cells and pericytes). These cell fates are often altered in pathological conditions, most prominently during the formation of tumor vasculature. Given the essential role of hypoxia as the driving force for initiating angiogenesis, it is not surprising that the hypoxia-sensing machinery controls key steps in physiological and pathological angiogenesis. PMID- 20966401 TI - Macrophage, but not systemic, apolipoprotein E is necessary for macrophage reverse cholesterol transport in vivo. AB - OBJECTIVE: To assess the role of apolipoprotein (apo) E in macrophage reverse cholesterol transport (RCT) in vivo. METHODS AND RESULTS: ApoE exerts an antiatherosclerotic activity by regulating lipoprotein metabolism and promoting cell cholesterol efflux. We discriminated between macrophage and systemic apoE contribution using an assay of macrophage RCT in mice. The complete absence of apoE lead to an overall impairment of the process and, similarly, the absence of apoE exclusively in macrophages resulted in the reduction of cholesterol mobilization from macrophages to plasma, liver, and feces. Conversely, expression of apoE in macrophages is sufficient to promote normal RCT even in apoE-deficient mice. The mechanisms accounting for these results were investigated by evaluating the first step of RCT (ie, cholesterol efflux from cells). Macrophages isolated from apoE-deficient mice showed a reduced ability to release cholesterol into the culture medium, whereas the apoB-depleted plasma from apoE-deficient and healthy mice possessed a similar capacity to promote cellular lipid release from cultured macrophages. CONCLUSIONS: Our data demonstrate, for the first time to our knowledge, that apoE significantly contributes to macrophage RCT in vivo and that this role is fully attributable to apoE expressed in macrophages. PMID- 20966402 TI - Growth differentiation factor-15 and risk of recurrent events in patients stabilized after acute coronary syndrome: observations from PROVE IT-TIMI 22. AB - OBJECTIVE: To investigate growth differentiation factor (GDF)-15 at hospital discharge for assessment of the risk of death, recurrent myocardial infarction (MI), and congestive heart failure, and to determination of whether these risks can be modified by statins. METHODS AND RESULTS: GDF-15 is a transforming growth factor-beta-related cytokine induced in response to tissue injury. GDF-15 concentration is associated with all-cause mortality in patients with acute coronary syndrome (ACS). We measured GDF-15 in 3501 patients after ACS, treated with moderate or intensive statin therapy in PROVE IT-TIMI 22. By using established cutoff points, GDF-15 (<1200, 1200-1800, and >1800 ng/L) was associated with 2-year risk of death or MI (5.7%, 8.1%, and 15.1%, respectively; P<0.001), death (P<0.001), MI (P<0.001), and congestive heart failure (P<0.001). After adjustment for age, sex, body mass index, diabetes mellitus, hypertension, smoking, MI, qualifying event, renal function, B-type natriuretic peptide, and high-sensitivity C-reactive protein, GDF-15 was associated with the risk of death or MI (adjusted hazard ratio per ln increase GDF-15, 2.1 [95% CI, 1.6 to 2.9]; P<0.001), death (P<0.001), MI (P<0.001), and congestive heart failure (P<0.001). There was no significant interaction between GDF-15 and intensive statin therapy for the risk of death or MI (P=0.24 for the interaction). CONCLUSIONS: GDF-15 is associated with recurrent events after ACS, independent of clinical predictors, B type natriuretic peptide, and high-sensitivity C-reactive protein. This finding supports GDF-15 as a prognostic marker in ACS and investigation of other therapies that modify this risk. PMID- 20966403 TI - Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice. AB - OBJECTIVE: Atherosclerosis encompasses a conspicuously maladaptive inflammatory response that might involve innate immunity. Here, we compared the role of Toll like receptor 4 (TLR4) with that of TLR2 in intimal foam cell accumulation and inflammation in apolipoprotein E (ApoE) knockout (KO) mice in vivo and determined potential mechanisms of upstream activation and downstream action. METHODS AND RESULTS: We measured lipid accumulation and gene expression in the lesion-prone lesser curvature of the aortic arch. TLR4 deficiency reduced intimal lipid by ~75% in ApoE KO mice, despite unaltered total serum cholesterol and triglyceride levels, whereas TLR2 deficiency reduced it by ~45%. TLR4 deficiency prevented the increased interleukin-1alpha (IL-1alpha) and monocyte chemoattractant protein-1 mRNA levels seen within lesional tissue, and it also lowered serum IL-1alpha levels. Smooth muscle cells (SMC) were present within the intima of the lesser curvature of the aortic arch at this early lesion stage, and they enveloped and permeated nascent lesions, which consisted of focal clusters of foam cells. Cholesterol enrichment of SMC in vitro stimulated acyl-coenzyme A:cholesterol acyltransferase-1 mRNA expression, cytoplasmic cholesterol ester accumulation, and monocyte chemoattractant protein-1 mRNA and protein expression in a TLR4 dependent manner. CONCLUSIONS: TLR4 contributes to early-stage intimal foam cell accumulation at lesion-prone aortic sites in ApoE KO mice, as does TLR2 to a lesser extent. Intimal SMC surround and penetrate early lesions, where TLR4 signaling within them may influence lesion progression. PMID- 20966404 TI - Intravenous injection of apolipoprotein A-V reconstituted high-density lipoprotein decreases hypertriglyceridemia in apoav-/- mice and requires glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1. AB - OBJECTIVE: Apolipoprotein A-V (apoA-V), a minor protein associated with lipoproteins, has a major effect on triacylglycerol (TG) metabolism. We investigated whether apoA-V complexed with phospholipid in the form of a reconstituted high-density lipoprotein (rHDL) has potential utility as a therapeutic agent for treatment of hypertriglyceridemia (HTG) when delivered intravenously. METHODS AND RESULTS: Intravenous injection studies were performed in genetically engineered mouse models of severe HTG, including apoav-/- and gpihbp1-/- mice. Administration of apoA-V rHDL to hypertriglyceridemic apoav-/- mice resulted in a 60% reduction in plasma TG concentration after 4 hours. This decline can be attributed to enhanced catabolism/clearance of very-low-density lipoprotein (VLDL), where VLDL TG and cholesterol were reduced ~60%. ApoA-V that associated with VLDL after injection was also rapidly cleared. Site-specific mutations in the heparin-binding region of apoA-V (amino acids 186 to 227) attenuated apoA-V rHDL TG-lowering activity by 50%, suggesting that this sequence element is required for optimal TG-lowering activity in vivo. Unlike apoav-/- mice, injection of apoA-V rHDL into gpihbp1-/- mice had no effect on plasma TG levels, and apoA-V remained associated with plasma VLDL. CONCLUSIONS: Intravenously injected apoA-V rHDL significantly lowers plasma TG in an apoA-V deficient mouse model. Its intravenous administration may have therapeutic benefit in human subjects with severe HTG, especially in cases involving apoA-V variants associated with HTG. PMID- 20966405 TI - Impaired leg vasodilatory function after stroke: adaptations with treadmill exercise training. AB - BACKGROUND AND PURPOSE: Resting and reactive hyperemic leg blood flows are significantly reduced in the paretic compared with the nonparetic limb after disabling stroke. Our objective was to compare the effects of regular treadmill exercise (TM) with an active control regimen of supervised stretching (CONTROL) on peripheral hemodynamic function. METHODS: This intervention study used a randomized, controlled design, in which participants were randomized with stratification according to age and baseline walking capacity to ensure approximate balance between the 2 groups. Fifty-three chronic, ischemic stroke participants (29 TM and 24 CONTROL) with mild to moderate hemiparetic gait completed bilateral measurements of lower leg resting and reactive hyperemic blood flow using venous occlusion strain gauge plethysmography before and after the 6-month intervention period. Participants also underwent testing to track changes in peak aerobic fitness across time. RESULTS: Resting and reactive hyperemic blood flows were significantly reduced in the paretic compared with the nonparetic limb at baseline before any intervention (-28% and -34%, respectively, P<0.01). TM increased both resting and reactive hyperemic blood flow in the paretic limb by 25% compared with decreases in CONTROL (P<0.001, between groups). Similarly, nonparetic leg blood flow was significantly improved with TM compared with controls (P<0.001). Peak aerobic fitness improved by 18% in TM and decreased by 4% in CONTROL (P<0.01, between groups), and there was a significant relationship between blood flow change and peak fitness change for the group as a whole (r=.30, P<0.05). CONCLUSIONS: Peripheral hemodynamic function improves with regular aerobic exercise training after disabling stroke. PMID- 20966406 TI - Diversity of single small subcortical infarctions according to infarct location and parent artery disease: analysis of indicators for small vessel disease and atherosclerosis. AB - BACKGROUND AND PURPOSE: Single small subcortical infarctions (SSSIs), so-called lacunae, are typically caused by lipohyalinosis of a perforator artery. However, SSSIs can be caused by underlying large parent arterial disease or microatheroma of the proximal portion of a perforator artery. We sought to investigate whether indicators for small vessel disease (SVD) and atherosclerosis in patients with SSSI differ according to lesion location and the presence of parent artery disease. METHODS: We assessed 449 patients who had an SSSI (lesion diameter <= 20 mm) in the perforator territory of middle cerebral artery (n = 244), basilar artery (n= 141), and vertebral artery (n = 64) on diffusion-weighted imaging performed within 48 hours of stroke onset. We divided SSSI into 3 groups according to lesion location and the presence of parent artery disease: (1) SSSI with parent artery disease (SSSI+PAD); (2) proximal SSSI without PAD (pSSSI-PAD); and (3) distal SSSI without PAD (dSSSI-PAD). The prevalence of SVD indicators (leukoaraiosis and microbleeds) and atherosclerosis indicators (cerebral atherosclerosis and coronary heart disease) were compared among the groups. RESULTS: SSSI+PAD had the highest prevalence of atherosclerosis indicators and the lowest prevalence of SVD indicators, whereas dSSSI-PAD had the lowest prevalence of atherosclerosis indicators and the highest prevalence of SVD indicators. pSSSI-PAD showed intermediate features. Atherosclerosis indicators significantly increased and SVD indicators significantly decreased as the vascular territory became lower (from middle cerebral artery, basilar artery to vertebral artery). CONCLUSIONS: Differences in SVD and atherosclerosis indicators suggest that SSSI has a heterogeneous pathogenesis according to lesion location and the presence of PAD. PMID- 20966407 TI - Patient-level and hospital-level determinants of the quality of acute stroke care: a multilevel modeling approach. AB - BACKGROUND AND PURPOSE: Quality of care may be influenced by patient and hospital factors. Our goal was to use multilevel modeling to identify patient-level and hospital-level determinants of the quality of acute stroke care in a stroke registry. METHODS: During 2001 to 2002, data were collected for 4897 ischemic stroke and TIA admissions at 96 hospitals from 4 prototypes of the Paul Coverdell National Acute Stroke Registry. Duration of data collection varied between prototypes (range, 2-6 months). Compliance with 8 performance measures (recombinant tissue plasminogen activator treatment, antithrombotics < 24 hours, deep venous thrombosis prophylaxis, lipid testing, dysphagia screening, discharge antithrombotics, discharge anticoagulants, smoking cessation) was summarized in a composite opportunity score defined as the proportion of all needed care given. Multilevel linear regression analyses with hospital specified as a random effect were conducted. RESULTS: The average hospital composite score was 0.627. Hospitals accounted for a significant amount of variability (intraclass correlation = 0.18). Bed size was the only significant hospital-level variable; the mean composite score was 11% lower in small hospitals (<= 145 beds) compared with large hospitals (>= 500 beds). Significant patient-level variables included age, race, ambulatory status documentation, and neurologist involvement. However, these factors explained < 2.0% of the variability in care at the patient level. CONCLUSIONS: Multilevel modeling of registry data can help identify the relative importance of hospital-level and patient-level factors. Hospital-level factors accounted for 18% of total variation in the quality of care. Although the majority of variability in care occurred at the patient level, the model was able to explain only a small proportion. PMID- 20966408 TI - Hepatitis C virus infection and increased risk of cerebrovascular disease. AB - BACKGROUND AND PURPOSE: The association between hepatitis C virus (HCV) infection and cerebrovascular disease remains controversial. This study aimed to assess the risk of lethal cerebrovascular diseases associated with chronic HCV infection. METHODS: In this community-based prospective cohort study, 23 665 residents (aged 30 to 65 years) were enrolled in 1991 to 1992. They were personally interviewed using structured questionnaires and provided blood samples for various serological and biochemical tests at study entry. Serum HCV RNA level and HCV genotype were tested for participants seropositive for antibodies against HCV (anti-HCV). Deaths from cerebrovascular disease during follow-up were ascertained by computerized linkage with National Death Certification profiles from 1991 to 2008 (International Classification of Diseases, 9th Revision 430 to 438). Multivariate-adjusted hazard ratio with 95% CI was estimated for each risk predictor. RESULTS: There were 255 cerebrovascular deaths during 382 011 person years of follow-up. The cumulative risk of cerebrovascular deaths was 1.0% and 2.7% for seronegatives and seropositives of anti-HCV, respectively (P<0.001). The hazard ratio (95% CI) of cerebrovascular death was 2.18 (1.50 to 3.16) for anti HCV seropositives after adjustment for several conventional risk factors of cerebrovascular disease. Compared with participants seronegative for anti-HCV as the referent, the multivariate-adjusted hazard ratio (95% CI) was 1.40 (0.62 to 3.16), 2.36 (1.42 to 3.93), and 2.82 (1.25 to 6.37), respectively, for anti-HCV seropositive participants with undetectable, low, and high serum levels of HCV RNA (P<0.001 for trend). However, no significant association was observed between HCV genotype and cerebrovascular death. CONCLUSIONS: Chronic HCV infection is an independent risk predictor of cerebrovascular deaths showing a biological gradient of cerebrovascular mortality with increasing serum HCV RNA level. PMID- 20966409 TI - Cerebral oxygenation in preterm infants with germinal matrix-intraventricular hemorrhages. AB - BACKGROUND AND PURPOSE: Preterm infants are at risk of developing germinal matrix hemorrhages-intraventricular hemorrhages (GMH-IVH). Disturbances in cerebral perfusion are associated with GMH-IVH. Regional cerebral tissue oxygen saturation (r(c)SO2), measured with near-infrared spectroscopy, and fractional tissue oxygen extraction (FTOE) were calculated to obtain an indication of cerebral perfusion. Our objective was to determine whether r(c)SO2 and FTOE were associated with GMH IVH in preterm infants. METHODS: This case-control study included 17 preterm infants with Grade I to III GMH-IVH or periventricular hemorrhagic infarction (median gestational age, 29.4 weeks; range, 25.4 to 31.9 weeks; birth weight, 1260 g; range, 850 to 1840 g). Seventeen preterm infants without GMH-IVH, matched for gestational age and birth weight, served as control subjects (gestational age, 29.9 weeks; range, 26.0 to 31.6 weeks; birth weight, 1310 g; range, 730 to 1975 g). R(c)SO2 and transcutaneous arterial oxygen saturation were measured during 2 hours on Days 1 to 5, 8, and 15 after birth. FTOE was calculated as FTOE=(transcutaneous arterial oxygen saturation-r(c)SO2)/transcutaneous arterial oxygen saturation. RESULTS: Multilevel analyses showed that r(c)SO2 was lower and FTOE higher in infants with GMH-IVH on Days 1, 2, 3, 4, 5, 8, and 15. The largest difference occurred on Day 5 with r(c)SO2 median 64% in infants with GMH-IVH versus 77% in control subjects and FTOE median 0.30 versus 0.17. R(c)SO2 and FTOE were not affected by the grade of GMH-IVH. CONCLUSIONS: Preterm infants with GMH IVH had lower r(c)SO2 and higher FTOE during the first 2 weeks after birth irrespective of the grade of GMH-IVH. This suggests that cerebral perfusion is decreased persistently for 2 weeks in infants with GMH-IVH, even in the presence of mild hemorrhages. PMID- 20966410 TI - Genomewide linkage and peakwide association analyses of carotid plaque in Caribbean Hispanics. AB - BACKGROUND AND PURPOSE: Atherosclerosis is a complex subclinical cardiovascular disorder with a substantial genetic component. This study sought to identify genetic loci influencing carotid plaque in 2 independent samples. METHODS: B-mode ultrasound was performed to determine the presence and area of carotid plaque. Variance components analysis was used to test for linkage using 383 autosomal microsatellite markers in 1308 subjects from 100 Dominican families. Multiple linear and logistic regression models were used to investigate the association between plaque traits and 18,904 single nucleotide polymorphisms under the 1 logarithm of odds unit down regions of linkage peaks in an independent community based data set (N = 941, 41% Dominicans) from the Northern Manhattan Study. RESULTS: After adjustment for age, hypertension, diabetes mellitus, cigarette pack-years, body mass index, and waist-to-hip ratio, significant heritability was detected for plaque presence (h2 = 0.50 +/- 0.14, P < 0.0001) and plaque area (h2=0.17 +/- 0.04, P < 0.0001). Quantitative and dichotomous trait linkage analyses obtained similar results and identified 4 regions with multipoint logarithm of odds scores >= 2.00 on 7q36, 11p15, 14q32, and 15q23. In the association analysis of the 4 linkage peaks, several single nucleotide polymorphisms in or near SOX6, FSD2, AP3S2, EFTUD1, and MYOD1 were associated with carotid plaque traits with a nominal P <= 0.0005 in the Northern Manhattan Study data set and with a P <= 0.01 in Northern Manhattan Study Dominican subset. CONCLUSIONS: Carotid plaque has considerable heritability and may be influenced by loci on chromosomes 11p15, 14q32, and 15q23. The SOX6 gene within the bone morphogenic protein pathway could be a candidate for carotid plaque. Larger independent studies are needed to validate these findings. PMID- 20966411 TI - Psychosocial problems, quality of life, and functional independence among Indian stroke survivors. AB - BACKGROUND AND PURPOSE: Data regarding psychosocial problems and quality of life (QoL) among stroke survivors from developing countries are scarce. The purpose of this study is to examine QoL, anxiety, depression, and functional independence of stroke survivors and the relationship of these variables with stroke characteristics. METHODS: This was a prospective hospital-based study. Patients were interviewed after >= 1 month post stroke. World Health Organization QoL-BREF was used to assess QoL. Anxiety and depression measures were recorded using the Hospital Anxiety Depression Scale, and functional independence was evaluated using the Functional Independence Measure. Demography, stroke severity (measured by the National Institute of Health Stroke Scale), and stroke outcome (measured by the modified Rankin scale) were also documented. Univariate and multivariate analysis were completed using SPSS Statistics version 17.0 (SPSS, Inc, Chicago, Ill). RESULTS: One hundred sixty-two patients participated (men = 113, 69.8%); mean age was 54.3 +/- 12.9 years (range, 21-88 years). The mean duration of follow-up was 18.3 +/- 24.9 months (range, 1-180 months), and the mean National Institute of Health Stroke Scale score was 2.1 +/- 2.1 (range, 0-10). Presence of anxiety (odds ratio [OR] 0.20, CI 0.80-0.51, P=0.001), depression (OR 0.22, CI 0.10 to 0.47, P < 0.0001), and functional dependence in Functional Independence Measure (OR 3.56, CI 1.70 to 7.42, P = 0.001) were predictors of impaired QoL in the multivariate logistic regression analysis. Anxiety was seen in 39 patients (24%), and 60 patients (37%) had depression. Poor outcome predicted depression in logistic regression model (OR 4.40, CI 1.80 to 10.76, P = 0.001). Functionally dependent patients were more likely to be older (OR 0.94, CI 0.92 to 0.97, P = 0.001) and had severe stroke (OR 0.69, CI 0.53 to 0.88, P = 0.004). CONCLUSIONS: Presence of anxiety, depression, and functional dependence were associated with impaired QoL. There was low prevalence of anxiety and depression. Older age and stroke severity resulted in increased functional dependence. PMID- 20966412 TI - Sleep apnea in patients with transient ischemic attack and minor stroke: opportunity for risk reduction of recurrent stroke? AB - BACKGROUND AND PURPOSE: Patients with TIA and minor stroke are at high risk for recurrent stroke. Obstructive sleep apnea (OSA) may increase this risk. The objectives of our study were to determine the prevalence and severity of OSA and its clinical presentation in this population. METHODS: Patients who presented with TIA and minor stroke completed a questionnaire and nocturnal cardiopulmonary monitoring to diagnose OSA and associated nocturnal hypoxia. RESULTS: Sixty-six patients completed the study; 62% had OSA (respiratory disturbance index > 5). Forty-four percent of these patients had moderate or severe OSA (respiratory disturbance index > 15) that was associated with significant nocturnal hypoxia. Most patients did not have the typical clinical features of OSA, such as obesity and daytime sleepiness. CONCLUSIONS: Patients who experience TIA and minor stroke have a high prevalence of OSA and associated hypoxia. The atypical clinical presentation of OSA in this patient population may lead to under-recognition and treatment. Further studies are required to determine the impact of treating OSA on the risk of recurrent stroke. PMID- 20966413 TI - Age- and gender-specific prevalence of cardiovascular risk factors in 40,102 patients with first-ever ischemic stroke: a Nationwide Danish Study. AB - BACKGROUND AND PURPOSE: We describe the prevalence of cardiovascular risk factors at stroke onset in men and women of all ages. METHODS: A registry started in 2001, designed to register all hospitalized stroke patients in Denmark, now holds 40,102 patients with first-ever ischemic stroke. Patients underwent evaluation including stroke severity (Scandinavian Stroke Scale), CT, and cardiovascular risk factors: hypertension, atrial fibrillation, diabetes mellitus, intermittent arterial claudication, previous myocardial infarction, body mass index, smoking, and alcohol consumption. We estimated the independent effect of gender and age on prevalence of cardiovascular risk factors and calculated age and gender-specific prevalence rates for each risk factor. RESULTS: The register contained 47.9% women and 52.1% men. Men had more often diabetes mellitus, previous myocardial infarction, intermittent arterial claudication, and over the limit alcohol consumption. Women had more often hypertension and obesity. Atrial fibrillation and smoking were equally frequent in both genders. Age stratification revealed that the lifestyle cardiovascular risk factors smoking, alcohol, and obesity were more common in the younger patients with stroke (< 60 years), whereas prevalence of hypertension, diabetes mellitus, myocardial infarction, intermittent arterial claudication, and, in men, also atrial fibrillation decreases in the elderly (> 70 to 80 years), the decrease being generally more pronounced in men than in women. CONCLUSIONS: Cardiovascular risk factors were generally more prevalent in men. Lifestyle cardiovascular risk factors were more common in the young. Prevalence of hypertension, diabetes mellitus, coronary heart disease, and, in men, also atrial fibrillation go down after the age of 70 to 80 years. PMID- 20966414 TI - Functional occurrence of the interaction of tissue plasminogen activator with the NR1 Subunit of N-methyl-D-aspartate receptors during stroke. AB - BACKGROUND AND PURPOSE: Despite its fibrinolytic effect, tissue-type plasminogen activator (tPA) displays deleterious effects in the brain, including proexcitotoxicity, that can reduce the overall benefit from thrombolysis during stroke. We have proposed that tPA potentiates excitotoxicity by interacting with and cleaving the aminoterminal end of the NR1 subunit of N-methyl-d-aspartate receptors, leading to an increased calcium influx, Erk1/2 activation, and neurotoxicity. Because this mechanism is debated, our aim was to demonstrate its in vivo occurrence and relevance. Because tPA is released under ischemic conditions, we hypothesized that if it indeed processes NR1, then the released fragment should reactivate the immune system in animals that had been immunized long before with recombinant aminoterminal end of the NR1. This effect should be exacerbated in ischemic animals thrombolysed with recombinant tPA. METHODS: At a time when specific antibodies could not be detected any longer, mice previously vaccinated with recombinant aminoterminal end of the NR1 were subjected to thromboembolic stroke induced by injecting thrombin in the middle cerebral artery alone or with intravenous thrombolysis. RESULTS: Stroke performed 1 year after active immunization induced the reappearance of antibodies against the aminoterminal end of the NR1 in the plasma, an effect significantly increased when ischemia was followed by recombinant tPA-induced reperfusion. Moreover, immunization preventing the interaction of tPA with aminoterminal end of the NR1 reduced ischemic brain damages and extended the therapeutic window of tPA-induced thrombolysis. CONCLUSIONS: We demonstrate that the tPA-dependent interaction and cleavage of the NR1 subunit of N-methyl-d-aspartate receptors occurs in vivo after stroke and that this interaction is a relevant therapeutic target for stroke treatment. PMID- 20966415 TI - Enhanced detection of paroxysmal atrial fibrillation by early and prolonged continuous holter monitoring in patients with cerebral ischemia presenting in sinus rhythm. AB - BACKGROUND AND PURPOSE: Diagnosis of paroxysmal atrial fibrillation is difficult but highly relevant in patients presenting with cerebral ischemia yet free from atrial fibrillation on admission. Early initiation and prolongation of continuous Holter monitoring may improve diagnostic yield compared with the standard of care including a 24-hour Holter recording. METHODS: In the observational Find-AF trial (ISRCTN 46104198), consecutive patients presenting with symptoms of cerebral ischemia were included. Patients free from atrial fibrillation at presentation received 7-day Holter monitoring. RESULTS: Two hundred eighty-one patients were prospectively included. Forty-four (15.7%) had atrial fibrillation documented by routine electrocardiogram on admission. All remaining patients received Holter monitors at a median of 5.5 hours after presentation. In those 224 patients who received Holter monitors but had no previously known paroxysmal atrial fibrillation, the detection rate with early and prolonged (7 days) Holter monitoring (12.5%) was significantly higher than for any 24-hour (mean of 7 intervals: 4.8%, P = 0.015) or any 48-hour monitoring interval (mean of 6 intervals: 6.4%, P = 0.023). Of those 28 patients with new atrial fibrillation on Holter monitoring, 15 (6.7%) had been discharged without therapeutic anticoagulation after routine clinical care (ie, with data from 24-hour Holter monitoring only). Detection rates were 43.8% or 6.3% for short supraventricular runs of >= 10 beats or prolonged episodes (> 5 hours) of atrial fibrillation, respectively. Diagnostic yield appeared to be only slightly and not significantly increased during the first 3 days after the index event. CONCLUSIONS: Prolongation of Holter monitoring in patients with symptoms of cerebral ischemic events increases the rate of detection of paroxysmal atrial fibrillation up to Day 7, leading to a relevant change in therapy in a substantial number of patients. Early initiation of monitoring does not appear to be crucial. Hence, prolonged Holter monitoring (>= 7 days) should be considered for all patients with unexplained cerebral ischemia. PMID- 20966416 TI - Distinctive RNA expression profiles in blood associated with white matter hyperintensities in brain. AB - BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) are areas of high signal detected by T2 and fluid-attenuated inversion recovery sequences on brain MRI. Although associated with aging, cerebrovascular risk factors, and cognitive impairment, the pathogenesis of WMH remains unclear. Thus, RNA expression was assessed in the blood of individuals with and without extensive WMH to search for evidence of oxidative stress, inflammation, and other abnormalities described in WMH lesions in brain. METHODS: Subjects included 20 with extensive WMH (WMH+), 45% of whom had Alzheimer disease, and 18 with minimal WMH (WMH-), 44% of whom had Alzheimer disease. All subjects were clinically evaluated and underwent quantitative MRI. Total RNA from whole blood was processed on human whole genome Affymetrix HU133 Plus 2.0 microarrays. RNA expression was analyzed using an analysis of covariance. RESULTS: Two hundred forty-one genes were differentially regulated at +/- 1.2-fold difference (P < 0.005) in subjects with WMH+ as compared to WMH-, regardless of cognitive status and 50 genes were differentially regulated with +/- 1.5-fold difference (P < 0.005). Cluster and principal components analyses showed that the expression profiles for these genes distinguished WMH+ from WMH- subjects. Function analyses suggested that WMH specific genes were associated with oxidative stress, inflammation, detoxification, and hormone signaling, and included genes associated with oligodendrocyte proliferation, axon repair, long-term potentiation, and neurotransmission. CONCLUSIONS: The unique RNA expression profile in blood associated with WMH is consistent with roles of systemic oxidative stress and inflammation, as well as other potential processes in the pathogenesis or consequences of WMH. PMID- 20966417 TI - Identifying patients at high risk for stroke despite anticoagulation: a comparison of contemporary stroke risk stratification schemes in an anticoagulated atrial fibrillation cohort. AB - BACKGROUND AND PURPOSE: The risk of stroke in patients with atrial fibrillation (AF) is not homogeneous, and various clinical risk factors have informed the development of stroke risk stratification schemes (RSS). Among anticoagulated cohorts, the emphasis should be on the identification of patients who remain at high risk for stroke despite anticoagulation. METHODS: We investigated predictors of thromboembolism (TE) risk in an anticoagulated AF clinical trial cohort (n = 7329 subjects) and tested the predictive value of contemporary RSS in this cohort: CHADS2, Framingham, NICE 2006, American College of Cardiology/American Heart Association/European Society of Cardiology 2006, the 8th American College of Chest Physicians guidelines and the CHA2DS2-VASc schemes. RESULTS: On multivariate analysis, significant predictors of TE were stroke/TIA (hazard ratio [HR], 2.24; P < 0.001), age 75 years or older (HR, 1.77; P = 0.0002), coronary artery disease (HR, 1.52; P = 0.0047), and smoking (HR, 2.10; P = 0.0005), whereas reported alcohol use (HR, 0.70; P = 0.02) was protective. Comparison of contemporary RSS demonstrated variable classification of AF patients into risk strata, although c-statistics for TE were broadly similar among the RSS tested and varied between 0.575 (NICE 2006) and 0.647 (CHA2DS2-VASc). CHA2DS2-VASc classified 94.2% as being at high risk, whereas most other RSS categorized two thirds as being at high risk. Of the 184 TE events, 181 (98.4%) occurred in patients identified as being at high risk by the CHA2DS2-VASc schema. There was a stepwise increase in TE with increasing CHA2DS2-VASc score (P (trend) < 0.0001), which had the highest HR (3.75) among the tested schemes. The negative predictive value (ie, the percent categorized as "not high risk" actually being free from TE) for CHA2DS2-VASc was 99.5%. CONCLUSIONS: Coronary artery disease and smoking are additional risk factors for TE in anticoagulated AF patients, whereas alcohol use appears protective. Of the contemporary stroke RSS, the CHA2DS2-VASc scheme correctly identified the greatest proportion of AF patients at high risk, despite the similar predictive ability of most RSS evidenced by the c-statistic. PMID- 20966418 TI - Connective tissue growth factor is associated with a stable atherosclerotic plaque phenotype and is involved in plaque stabilization after stroke. AB - BACKGROUND AND PURPOSE: Carotid plaques remodel toward a more stable phenotype after stroke, but not after TIA. Connective tissue growth factor (CTGF) is involved in extracellular matrix production and is expressed in atherosclerotic plaques. We studied the role of CTGF in plaque remodeling after stroke and TIA. METHODS: Atherosclerotic plaques from carotid endarterectomy of asymptomatic patients (n = 16) and patients who experienced stroke (n = 15) or TIA (n = 33) were analyzed for CTGF levels, markers of plaque stability (collagen, smooth muscle cells, macrophage content, and lipid core), and levels of matrix metalloproteinase (MMP)-8, MMP-9, IL-4, IL-5, and IL-10. RESULTS: CTGF levels were higher in stroke patients compared to TIA patients. Plaques with a high level of CTGF revealed more collagen and smooth muscle cell content, whereas macrophage content and lipid core size were not different. The amount of CTGF was negatively associated with MMP-8 and MMP-9 activity and showed a positive correlation with the anti-inflammatory cytokines IL-4, IL-5, and IL-10. CONCLUSIONS: CTGF levels are associated with a more stable plaque phenotype. CTGF is increased in plaques after stroke compared to TIA, suggesting a role for CTGF in plaque stabilization after stroke. PMID- 20966419 TI - Lenticulostriate arterial lumina are normal in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a high-field in vivo MRI study. AB - BACKGROUND AND PURPOSE: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease. Although postmortem studies have demonstrated mural thickening in leptomeningeal arteries and lenticulostriate perforating arteries, it is unclear whether this also leads to luminal narrowing. High-field MRI scanners enable in vivo imaging of the lumen of the lenticulostriate arteries. The aim of this study is to examine the luminal diameters of lenticulostriate arteries in living patients with CADASIL and to investigate whether luminal narrowing is correlated with the number of lacunar infarcts in the basal ganglia. METHODS: Twenty-two NOTCH3 mutation carriers and 11 healthy control subjects were examined using high resolution 3-dimensional time-of-flight MR angiography imaging on a 7-T MRI scanner. Scans were analyzed for the presence of focal stenotic segments. The total number, length, and total cross-sectional area of lenticulostriate arteries were measured and compared between mutation carriers and control subjects. These measurements were correlated with age, disease duration, and number of lacunar infarcts in the basal ganglia. RESULTS: No stenotic segments were observed. No differences between mutation carriers and control subjects were found in total number of end branches (mutation carriers: mean, 14.6; control subjects: mean, 12.8), length of the lenticulostriate system, or total cross-sectional area of lenticulostriate artery lumina. Measurements of lenticulostriate artery lumina were not associated with lacunar infarct load in the basal ganglia area or with basal ganglia hyperintensities. CONCLUSIONS: Three-dimensional time-of-flight MR angiographic on 7 T showed no differences in luminal diameters of lenticulostriate arteries between patients with CADASIL and control subjects. PMID- 20966420 TI - An epidemiological survey of stroke in Lhasa, Tibet, China. AB - BACKGROUND AND PURPOSE: There have not been any new epidemiological studies related to stroke in Tibet for 20 years. This study aimed to collect stroke data from The City Staff Medical Insurance Registry in Lhasa, Tibet, to describe the incidence, clinical subtypes, and associated risk factors of stroke. METHODS: We used retrospective, population-based descriptive analysis of all urban and rural workers in the City Staff Medical Insurance Registry who were admitted to designated hospitals from October 2006 to October 2008. Stroke was defined by the International Classification of Disease (ICD)-10 coded from hospital records. RESULTS: Workers (81,298) were listed in the City Staff Medical Insurance Registry. Stroke patients (165) were included in the study, with 133 being first ever patients. The age-standardized incidence rate was 88.725/100,000 per year (95% CI, 72.228-105.221), and mortality rate was 25.941/100,000 per year (95% CI, 16.416-35.466). The case fatality rate was 21.82%. Seventeen of the 133 patients (12.8%) were < 45 years of age. Stroke incidence rate was higher in ethnic Han patients than ethnic Tibetan patients. The most common subtype was cerebral infarction, and the most important risk factor was hypertension. CONCLUSIONS: Since the last study 20 years ago in Lhasa, stroke remains the primary fatal disease for the elderly, and its occurrence at younger ages is higher in Lhasa than in other areas of China. However, the annual incidence rate and mortality rate have decreased. The annual incidence rate is at a similar level to that in other parts of China. The primary subtype of stroke in Lhasa is cerebral ischemia. PMID- 20966421 TI - Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the american heart association/american stroke association. AB - The aim of this updated statement is to provide comprehensive and timely evidence based recommendations on the prevention of ischemic stroke among survivors of ischemic stroke or transient ischemic attack. Evidence-based recommendations are included for the control of risk factors, interventional approaches for atherosclerotic disease, antithrombotic treatments for cardioembolism, and the use of antiplatelet agents for noncardioembolic stroke. Further recommendations are provided for the prevention of recurrent stroke in a variety of other specific circumstances, including arterial dissections; patent foramen ovale; hyperhomocysteinemia; hypercoagulable states; sickle cell disease; cerebral venous sinus thrombosis; stroke among women, particularly with regard to pregnancy and the use of postmenopausal hormones; the use of anticoagulation after cerebral hemorrhage; and special approaches to the implementation of guidelines and their use in high-risk populations. PMID- 20966422 TI - Normoxic expression of hypoxia-inducible factor 1 in rat Leydig cells in vivo and in vitro. AB - Hypoxia-inducible factors (HIF) are transcription factors that serve essential regulatory roles in cellular and molecular responses to oxygen debt. HIFs are composed of hypoxia-dependent alpha subunits (1alpha, 2alpha, 3alpha) and an oxygen-independent beta subunit. Previously we demonstrated that HIF-1, the master regulator of hypoxic responses, is expressed in the adult rat testis. We hypothesized that HIF-1 is involved in regulating responses to oxygen tension in the testis. Goals of this study were to determine if HIF-2alpha and HIF-3alpha are expressed in rat testis, identify testis cell types that express HIF-1alpha, and examine patterns of testicular HIF-1alpha protein expression under conditions of ischemia and hypoxia in vivo and in vitro. Reverse transcriptase polymerase chain reaction revealed that mRNA for Hif-1alpha, Hif-2alpha, and Hif-3alpha is expressed in the testis. The HIF-1alpha protein is the predominant subunit in testis. HIF-1alpha protein was abundant in normoxic testis, and its levels remained unchanged following ischemia created by surgically induced testicular torsion and reperfusion. Immunoblot and immunocytochemical experiments demonstrated that Leydig cells are the major source of HIF-1alpha in normoxic and hypoxic testes. To examine potential mechanisms of testicular HIF-1 stabilization, nuclear proteins from Leydig cells cultured in 5% or 21% oxygen, or cells cultured with H2O2, were analyzed by immunoblotting. Levels of HIF 1alpha were significantly diminished in 5% or 21% oxygen cultures compared with freshly isolated cells. Treating Leydig cells with H2O2 as a source of reactive oxygen species did not affect HIF-1alpha levels. High levels of constitutively expressed HIF-1alpha in normoxic Leydig cells suggest potentially unique roles for HIF-1 in Leydig cell responsiveness to oxygen. PMID- 20966423 TI - Protamine/DNA ratios and DNA damage in native and density gradient centrifuged sperm from infertile patients. AB - Protamines are the major nuclear proteins condensing DNA in the sperm nucleus. One of their proposed functions is the protection of the genetic message delivered by the sperm. To date, evidence of their involvement in DNA protection has been obtained by correlating the protamine P1/P2 ratio, protamine concentrations, or chromomycin A3 staining with DNA fragmentation. However, a correlation of the absolute protamine/DNA content with the DNA fragmentation in sperm from the same infertile patients as assessed with the comet assay has not been studied. Protamine/DNA ratios were calculated after protamine and DNA extraction, electrophoresis, and gel quantification of the protamines and DNA quantification in the sperm samples of 66 infertile patients before (native sample) and after a 2-step discontinuous PureSperm density gradient centrifuged (DGC) selection of the sperm. DNA fragmentation was assessed using the alkaline comet assay. In DGC sperm, the total protamine/DNA, P1/DNA, and P2/DNA ratios all correlated inversely with DNA damage in sperm from infertile patients. The detection of this inverse correlation between protamine/DNA ratios and DNA damage in DGC sperm adds support to the hypothesis that defective protamination is related to DNA damage in the clinically relevant subpopulation of sperm from infertile men. PMID- 20966424 TI - Differential proteomics leads to identification of domain-specific epididymal sperm proteins. AB - The alteration in the protein signatures of the testicular sperm during its epididymal sojourn makes it functionally competent for successful fertilization. The present study was undertaken to identify the proteins acquired on its 2 domains, that is, the head and the flagellum, during the epididymal transit using a differential proteomics approach. Testicular sperm proteome was compared with cauda epididymal sperm proteome in rat. The protein spots exclusively present in the cauda epididymal sperm proteome were searched in the cauda sperm head proteome and the cauda sperm flagella proteome, and a total of 335 spots were found by alignment and auto-matching of the gels, of which 140 could be identified by mass spectrometry. Database search revealed that of these 9 proteins were novels. Gene Ontology annotation revealed that the identified proteins were distributed across different cellular components and were primarily involved in metabolic processes. The study also provides information on the localization of these proteins on the sperm domains, which indirectly gives a clue about its putative function. Validation of 3 proteins, namely MMSDH, NDUFS1, and UQCRC2, using antibodies very elegantly demonstrates that the strategy has been very effective. This comprehensive data of domain-specific epididymal sperm proteins will be useful in development of newer targets for posttesticular contraception and diagnostic markers for infertility. PMID- 20966425 TI - Mechanisms of fertilization--a view from the study of gene-manipulated mice. AB - Recent gene knockout approaches have revealed that many of the factors previously considered to be important were largely dispensable in gene-knockout animals, and that previously unknown factors are emerging. Unexpectedly, sperm from 5 different gene-disrupted mouse lines (calmegin (Clgn), Adam1a, Adam2, Adam3, and Ace) all have defective zona-binding ability and oviduct-migrating ability. We have disrupted a new testis-specific molecular chaperone, calsperin (Calr3), which became the sixth gene sharing the same infertile phenotype. The relationships among these 6 factors are discussed. After zona penetration, sperm needs to fuse with eggs. We reported that sperm require IZUMO1 and eggs require CD9 for sperm-egg fusion. However, the distribution of IZUMO1 is not limited to the equatorial segment where it is believed the fusion takes place. Therefore, we produced a mouse line that lacks an equatorial segment-specific antigen, Spesp1. The Spesp1 +/- and -/- sperm showed a decreased fusing ability compared with wild type sperm, but the cause of the impaired fusion may not directly relate to the mechanism involving IZUMO1. In order to study the mechanism of fertilization, the visualization of sperm in vivo provides a powerful tool. We made a new transgenic mouse line that produces sperm with green fluorescent protein-tagged acrosome and DSRed2-tagged mitochondria. Studies of fertilization using gene-manipulated animals are described in the present review. PMID- 20966426 TI - Postnatal changes in the expression of claudin-11 in the testes and excurrent ducts of the domestic rabbit (Oryctolagus cuniculus domesticus). AB - We examined the expression of claudin-11 (CLDN11) in the testes and male reproductive tracts of rabbits. The rabbit CLDN11 cDNA sequences were nearly identical with human, mouse, and bovine CLDN11. The levels of CLDN11 mRNA and protein (22 kDa) were markedly increased in the testis during adult development. On postnatal day (PND) 10, CLDN11 was colocalized with ZO-1 at the lateral contacts between adjacent Sertoli cells and was perpendicular to the basal lamina. In adult testis on PND 180, CLDN11 was codistributed with ZO1, and the pattern of immunoreactivity consisted of wavy linear tracts parallel to the basal lamina, which was different according to the spermatogenic stage. These results suggest that CLDN11 participates in inter-Sertoli cell tight junctions (TJs) at the blood-testis barrier in adult rabbits. CLDN11 was also found in the basal regions of Sertoli cells adjacent to the basal lamina in adult testis, suggesting that CLDN11 also participates in the adhesion between Sertoli cells and the basal lamina. CLDN11 mRNA and protein expressions were decreased in the adult epididymis compared with those in immature animals. In adults, CLDN11 mRNA levels were relatively high in the efferent duct, followed by those in the vas deferens, proximal corpus, and distal cauda, although low levels were observed in the initial segment and caput. On PND 10, CLDN11 immunoreactivity was identified at the apicolateral contacts between adjacent epithelial cells in the epididymis and vas deferens. In adults, CLDN11 was found in the nonciliated cells in the efferent duct and at the lateral contacts in the epithelial cells in the epididymal segments. In the caput, CLDN11 was found at the apicolateral contacts between adjacent epithelial cells, but expression was weak to negligible in the corpus of the vas deferens. CLDN11 may play an important role in TJs and cell adhesion in immature rabbit excurrent duct epithelia. In adult rabbits, CLDN11 in efferent duct epithelium and epididymal epithelium may contribute to the specific environment for sperm maturation. PMID- 20966427 TI - Chromosomal abnormalities in 2 cases of testicular failure. AB - This study investigated the underlying chromosomal abnormalities of testicular failure using molecular cytogenetic analysis. We report 2 cases of rare genetic anomalies that resulted in hypogonadism. The first patient presented with severe hypogonadism. Chromosome analysis revealed a mosaic 46,X,r(Y) (p11.3q11.23)/45,X karyotype, with a ring Y chromosome. A Y chromosome microdeletion assay showed a deletion in the azoospermia factor a region. The second patient presented with infertility and nonobstructive azoospermia. Cytogenetic and fluorescent in situ hybridization analysis revealed a 47,XY,+mar.ish i(15) (D15Z1++,SNRPN2,PML2) karyotype, with a small supernumerary chromosome derived from chromosome 15. These results emphasize the need for molecular cytogenetic evaluation in patients with testicular failure before using advanced reproductive techniques. PMID- 20966428 TI - The cancer-HIV/AIDS treatment conundrum. PMID- 20966429 TI - Re: Performance of first mammography examination in women younger than 40 years. PMID- 20966430 TI - FDA to regulate direct-to-consumer genetic tests. PMID- 20966432 TI - Cancer in the developing world: Palliative care gains ground in developing countries. PMID- 20966433 TI - Evidence that Gsta4 modifies susceptibility to skin tumor development in mice and humans. AB - BACKGROUND: The incidence of nonmelanoma skin cancer (NMSC) is equivalent to that of all other cancers combined. Previously, we mapped the 12-O tetradecanoylphorbol-13-acetate (TPA) skin tumor promotion susceptibility locus, Psl1, to distal chromosome 9 in crosses of sensitive DBA/2 mice with relatively resistant C57BL/6 mice. Here, we used the mouse two-stage skin carcinogenesis model to identify the gene(s) responsible for the effects of Psl1. METHODS: Interval-specific congenic mouse strains (n >= 59 mice per strain) were used to more precisely map the Psl1 locus. Having identified glutathione S-transferase alpha4 (Gsta4) as a candidate tumor promotion susceptibility gene that mapped within the delimited region, we analyzed Gsta4-deficient mice (n = 62) for susceptibility to skin tumor promotion by TPA. We used quantitative polymerase chain reaction, western blotting, and immunohistochemistry to verify induction of Gsta4 in mouse epidermis following TPA treatment and biochemical assays to associate Gsta4 activity with tumor promotion susceptibility. In addition, single nucleotide polymorphisms (SNPs) in GSTA4 were analyzed in a case-control study of 414 NMSC patients and 450 control subjects to examine their association with human NMSC. Statistical analyses of tumor studies in mice were one-sided, whereas all other statistical analyses were two-sided. RESULTS: Analyses of congenic mice indicated that at least two loci, Psl1.1 and Psl1.2, map to distal chromosome 9 and confer susceptibility to skin tumor promotion by TPA. Gsta4 maps to Psl1.2 and was highly induced (mRNA and protein) in the epidermis of resistant C57BL/6 mice compared with that of sensitive DBA/2 mice following treatment with TPA. Gsta4 activity levels were also higher in the epidermis of C57BL/6 mice following treatment with TPA. Gsta4-deficient mice (C57BL/6.Gsta4(-/-) mice) were more sensitive to TPA skin tumor promotion (0.8 tumors per mouse vs 0.4 tumors per mouse in wild-type controls; difference = 0.4 tumors per mouse; 95% confidence interval = 0.1 to 0.7, P = .007). Furthermore, inheritance of polymorphisms in GSTA4 was associated with risk of human NMSC. Three SNPs were found to be independent predictors of NMSC risk. Two of these were associated with increased risk of NMSC (odds ratios [ORs] = 1.60 to 3.42), while the third was associated with decreased risk of NMSC (OR = 0.63). In addition, a fourth SNP was associated with decreased risk of basal cell carcinoma only (OR = 0.44). CONCLUSIONS: Gsta4/GSTA4 is a novel susceptibility gene for NMSC that affects risk in both mice and humans. PMID- 20966434 TI - What is esoteric healing? AB - Esoteric Healing is a type of energy healing that originated from the teachings of Djwhal Khul and Alice Bailey first published in the early 1950s. Esoteric Healing instructors and practitioners are located in more than 19 countries throughout the world. Nurses and nurse practitioners as well as other health professionals (e.g., psychologists and physicians) have integrated Esoteric Healing into their current practice and/or have a separate practice in Esoteric Healing. According to Dochterman and Bulechek, the nursing diagnosis "energy field, disturbed" is defined as a "disruption in the flow of energy surrounding a person's being." Esoteric Healing is proposed to assist a person in balancing her or his flow of energy. In this article, Esoteric Healing is defined, and the components of the energy field according to the teachings of Esoteric Healing are differentiated. The basic Esoteric Healing treatment procedure, treatment protocols, and indications for when Esoteric Healing may be an appropriate healing modality option are described. Finally, research on Esoteric Healing is addressed. PMID- 20966435 TI - Echocardiographic recognition of mitral valve involvement in primary aortic valve endocarditis. PMID- 20966436 TI - A systematic review and meta-analysis on the use of preemptive hemodynamic intervention to improve postoperative outcomes in moderate and high-risk surgical patients. AB - BACKGROUND: Complications from major surgery are undesirable, common, and potentially avoidable. The long-term consequences of short-term surgical complications have recently been recognized to have a profound influence on longevity and quality of life in survivors. In the past 30 years, there have been a number of studies conducted attempting to reduce surgical mortality and morbidity by deliberately and preemptively manipulating perioperative hemodynamics. Early studies had a high control-group mortality rate and were criticized for this as being unrepresentative of current practice and raised opposition to its implementation as routine care. We performed this review to update this body of literature and to examine the effect of changes in current practice and quality of care to see whether the conclusions from previous quantitative analyses of this field remain valid. METHODS: Randomized clinical trials evaluating the use of preemptive hemodynamic intervention to improve surgical outcome were identified using multiple methods. Electronic databases (MEDLINE, EMBASE, and the Cochrane Controlled Clinical Trials register) were screened for potential trials, reference lists of identified trials were examined, and additional sources were sought from experts and industry representatives. Identified studies that fulfilled the entry criteria were examined in full and subjected to quantifiable analysis, subgroup analysis, and sensitivity analysis where possible. RESULTS: There were 29 studies identified, 23 of which reported surgical complications. In total, the 29 trials involved 4805 patients with an overall mortality of 7.6%. The use of preemptive hemodynamic intervention significantly reduced mortality (pooled odds ratio [95% confidence interval] of 0.48 [0.33-0.78]; P = 0.0002) and surgical complications (odds ratio 0.43 [0.34-0.53]; P < 0.0001). Subgroup analysis showed significant reductions in mortality for studies using a pulmonary artery catheter, supranormal resuscitation targets, studies using cardiac index or oxygen delivery as goals, and the use of fluids and inotropes as opposed to fluids alone. By contrast, there was a significant reduction in morbidity for each of the 4 subgroups analyzed. CONCLUSION: The use of a preemptive strategy of hemodynamic monitoring and coupled therapy reduces surgical mortality and morbidity. PMID- 20966437 TI - Objective Structured Clinical Examination-based assessment of regional anesthesia skills: the Israeli National Board Examination in Anesthesiology experience. AB - Simulation techniques are increasingly being used in anesthesia training programs and to a lesser extent in evaluation of residents. We describe 7 years of experience with Objective Structured Clinical Examination-based regional anesthesia assessment in the Israeli National Board Examinations in Anesthesiology. We believe this is the first use of such mock scenarios for the assessment of regional anesthesia for the important purpose of national accreditation. During the study period, 308 candidates were examined in 1 of 8 different blocks. The total pass rate was 83%(257 of 308), ranging from 73% to 91%. The interrater correlation for total, critical, and global scores were 0.84, 0.88, and 0.75, respectively. Technological and cost constraints preclude actual assessment of regional anesthesia. However, testing formats that more closely reflect clinical practice are potentially valuable adjuncts to traditional examinations. PMID- 20966438 TI - Volatile anesthetics may not induce significant toxicity to human neuron-like cells. AB - BACKGROUND: In vitro experiments and in vivo animal studies suggest detrimental effects of volatile anesthetics including isoflurane on brain cells. It is not clear whether volatile anesthetics can cause human brain cell injury. METHODS: The SH-SY5Y cells, a human neuroblastoma cell line, were induced to differentiate into terminal neuron-like cells. These differentiated cells and the HCN-2 cells, a human cortical neuronal cell line, were exposed to 2% to 5% isoflurane, 6% sevoflurane, or 12% desflurane for 48 hours at 37 degrees C. Lactate dehydrogenase (LDH) release and the expression of caspase 3, synaptophysin, and drebrin were then measured. RESULTS: Exposure of the differentiated SH-SY5Y and HCN-2 cells to 2% to 4% isoflurane did not increase LDH release and the expression of caspase 3 whose activation leads to apoptosis. The expression of synaptophysin, a synaptic protein, and drebrin, a dendritic spine protein, in the differentiated SH-SY5Ycells was also not affected by 2% to 4% isoflurane. Exposure to 6% sevoflurane or 12% desflurane did not affect LDH release from differentiated SH-SY5Y cells. However, 5% isoflurane significantly increased LDH release from those cells. CONCLUSIONS: Our results suggest that volatile anesthetics at clinically relevant concentrations do not cause human neuron-like cell injury. Isoflurane also may not alter the quantity of dendritic spines and synapses in these human cells. PMID- 20966439 TI - Current-distance relationships for peripheral nerve stimulation localization. AB - BACKGROUND: Successful peripheral nerve blocks require accurate placement of the injection needle tip before local anesthetic application. In this investigation, we experimentally reconstructed polarity-dependent (anode and cathode) stimulation maps using ex vivo and in vivo animal models. METHODS: A novel ex vivo configuration (muscle-nerve composite) was first used to probe both cathodic and anodic stimulation characteristics. The electrophysiology (compound nerve action potential, CAP) of rat sciatic nerve was recorded at varying stimulation (monopolar electrode) distances and intensities. We repeated this methodology with an open dissection rat model that was more analogous to the clinical setting. Resultant data from the current sweeps were plotted as a 3-dimensional distance-stimulus-CAP map. These plots depict the minimum stimulation currents required for nerve activation and describe the expected electrophysiological outcomes as a function of distance and input stimulus intensity. The stimulation maps provide positional information relevant to clinical procedures such as nerve localization during regional anesthesia. RESULTS: Cathodic stimulation produced a complex biphasic electrophysiological response. The CAP amplitude (with fixed current) increased as the electrode moved closer towards the nerve, but decreased upon close proximity or nerve contact. This phenomenon was dependent upon stimulation intensity and was observed in both ex vivo and in vivo models. Anodic stimulation produced a monotonic relationship, with the CAP increasing with closer electrode-to-nerve distances. Minimum extraneural activation thresholds were found to be 0.34 +/- 0.11 mA (mean +/- sd) and 0.63 +/- 0.12 mA for cathode and anode stimulation, respectively. Intraneural thresholds were substantially lower, 0.12 +/- 0.03 mA and 0.32 +/- 0.09 mA, for cathode and anode, respectively. CONCLUSION: Cathodic stimulation may produce conduction block at close tip-to-nerve distances. In contrast, anodic stimulation elicited output characteristics that were predictable and more suitable for nerve localization. We believe anodic stimulation is a viable option at near-nerve distances, despite the increased current requirements. This hypothesis is a paradigm shift in stimulation nerve localization, which conventionally has been cathode based. The hypothesis should be clinically validated. PMID- 20966440 TI - The wolf is crying in the operating room: patient monitor and anesthesia workstation alarming patterns during cardiac surgery. AB - BACKGROUND: Vital sign monitors and ventilator/anesthesia workstations are equipped with multiple alarms to improve patient safety. A high number of false alarms can lead to a "crying wolf" phenomenon with consecutively ignored critical situations. Systematic data on alarm patterns and density in the perioperative phase are missing. Our objective of this study was to characterize the patterns of alarming of a commercially available patient monitor and a ventilator/anesthesia workstation during elective cardiac surgery. METHODS: We performed a prospective, observational study in 25 consecutive elective cardiac surgery patients. In all patients, identically fixed alarm settings were used. All incoming patient data and all alarms from the patient monitor and the anesthetic workstation were digitally recorded. Additionally, the anesthesia workplace was videotaped from 2 different angles to allow retrospective annotation and correlation of alarms with the clinical situation and assessment of the anesthesiologists' reaction to the alarms. RESULTS: Of the 8975 alarms, 7556 were hemodynamic alarms and 1419 were ventilatory alarms. For each procedure, 359 +/- 158 alarms were recorded, representing a mean density of alarms of 1.2/minute. CONCLUSION: Approximately 80% of the total 8975 alarms had no therapeutic consequences. Implementation of procedure-specific settings and optimization in artifact and technical alarm detection could improve patient surveillance and safety. PMID- 20966441 TI - Case report: intracranial placement of a nasotracheal tube in a patient with Goldenhar syndrome associated with cribriform plate agenesis. AB - We describe a case of inadvertent intracranial placement of a nasotracheal tube in a patient with an undiagnosed major congenital cranial anomaly (a variant of Goldenhar syndrome, which included absence of the cribriform plate). We believe that this is the first reported case in which this complication arose as a result of a congenital abnormality rather than traumatic or iatrogenic disruption of the skull base. We conclude that patients with known craniofacial abnormalities or associated syndromes scheduled for procedures involving planned nasotracheal intubation or nasogastric tube placement should undergo preoperative cranial imaging studies to verify an intact skull base. PMID- 20966442 TI - The effect of cross-training with adjustable airway model anatomies on laryngoscopy skill transfer. AB - BACKGROUND: A problem with learning endotracheal intubation on airway mannequins is poor transfer of direct laryngoscopy skills from model to patient. We developed an airway model with adjustable anatomic features and investigated whether practicing on a model with frequent adjustments improved laryngoscopy skills transfer. METHODS: Fifty-one paramedic students and 18 medical students with minimal previous experience practiced laryngoscopy 25 times with either the novel model with static features, the novel model with variable features, or a Laerdal Adult Intubation mannequin. For the variable group, the configuration changed after every 5 attempts. After training, all subjects performed 10 laryngoscopies on 2 new mannequins to test their competence at skills transfer. A mixed linear model analyzed various predictors of success as a binary outcome, including training group and change in laryngoscopy model. RESULTS: The odds ratio for success after a recent change in mannequin was 0.69 (0.49, 0.96 [95% confidence interval]). Compared with the Laerdal group, subjects with the static trainer did worse (odds ratio 0.46 [0.23, 0.94]), and subjects in the variable group were no different (0.74 [0.36, 1.52]). Change in laryngoscopy model decreased success rate by approximately 30% for all training groups. CONCLUSION: The results verify that proficiency on one model does not guarantee success on another. However, subjects who trained with a laryngoscopy mannequin in multiple configurations did not show better skill transfer than subjects practicing on fixed configuration airway models. PMID- 20966443 TI - Remifentanil decreases sevoflurane requirements to block autonomic hyperreflexia during transurethral litholapaxy in patients with high complete spinal cord injury. AB - BACKGROUND: An inhaled anesthetic concentration required to block autonomic hyperreflexia (AHR) is high enough to cause severe hypotension in patients with high spinal cord injury (SCI). We determined the effects of remifentanil on the sevoflurane requirement to block AHR in SCI. METHODS: The study involved 96 patients with chronic, complete SCI scheduled to undergo transurethral litholapaxy during general anesthesia. Anesthesia was induced with thiopental, and sevoflurane concentrations in 50% nitrous oxide were adjusted to maintain a bispectral index of 40 to 50. Whether the patient develops an AHR [an increase of systolic blood pressure (SBP) >20 to 40 mm Hg] was first examined by distending the bladder with glycine solution (the first trial). Patients who developed AHR were then allocated to receive no remifentanil infusion (control, n = 31), a target-controlled plasma concentration of 1 ng/mL (n = 25), or 3 ng/mL remifentanil (n = 24). After baseline hemodynamics had recovered, the target sevoflurane and remifentanil concentrations were maintained for at least 20 minutes and the procedure was resumed (the second trial). Each target sevoflurane concentration was determined by the up-and-down method based on changes (15% increase or more) of SBP in response to the bladder distension. SBP, heart rate, and bispectral index were measured before and during the bladder distension during the trials, and plasma concentrations of catecholamines during the first trial. RESULTS: Eighty-two (85.4%) of 96 patients developed AHR during the first trial, in which 2 were excluded because of hypotension (mean arterial blood pressure <50 mm Hg) developed during target-controlled drug administration. During the second trial, the end-tidal concentrations of sevoflurane to prevent AHR were reduced to 2.6% (95% confidence interval 2.5% to 2.8%, P < 0.01) and 2.2% (2.1% to 2.4%, P < 0.0001) in the groups receiving 1 and 3 ng/mL remifentanil, respectively, in comparison with 3.1% (2.9% to 3.3%) in the control. When considering minimum anesthetic concentration (MAC) values and the contribution of 50% nitrous oxide (0.48 MAC), the combined MAC values, expressed as multiples of MAC, were 2.27, 1.98, and 1.75 in the control, 1 ng/mL remifentanil, and 3 ng/mL remifentanil groups, respectively. CONCLUSIONS: Target controlled concentrations of 1 and 3 ng/mL remifentanil would reduce the requirement of sevoflurane combined with 50% nitrous oxide to block AHR by 16% and 29%, respectively, in SCI patients undergoing transurethral litholapaxy. PMID- 20966444 TI - A comparison of desflurane versus propofol: the effects on early postoperative lung function in overweight patients. AB - BACKGROUND: In this study, we evaluated the influence of propofol versus desflurane anesthesia in overweight patients on postoperative lung function and pulse oximetry values. METHODS: We prospectively studied 134 patients with body mass indices of 25 to 35 kg/m(2) undergoing minor peripheral surgery lasting 40 to 120 minutes. Patients were randomly assigned to receive propofol (total IV anesthesia) or desflurane anesthesia via a tracheal tube targeting bispectral index values of 40 to 60. Premedication, adjuvant drug usage, and ventilation were standardized. We measured oxyhemoglobin saturation and lung function preoperatively (baseline), and at 10 minutes, 0.5 hour, 2 hours, and 24 hours after tracheal extubation. All values were measured with the patient supine, in a 30 degrees head-up position. Changes from preoperative baseline values were first analyzed for the impact of body mass index and type of anesthesia using univariate methods, followed by linear regression and multivariate analysis of variance. RESULTS: Within the first 2 hours after surgery, the propofol group displayed lower oxyhemoglobin saturation (at 2 hours, mean +/- SD, 93.8% +/- 2.0% vs 94.6% +/- 2.1%; P < 0.007) and lung function (forced vital capacity, forced expiratory volume exhaled in 1 second [FEV(1)], peak expiratory flow, midexpiratory flow [MEF], forced inspiratory vital capacity, and peak inspiratory flow; between 11% and 20% larger reduction from baseline in the propofol group, all P < 0.001) compared with the desflurane group. Even 24 hours after surgery, FEV(1), peak expiratory flow, MEF, forced inspiratory vital capacity, and peak inspiratory flow were reduced more in the propofol group (all P < 0.01). At 2 hours after extubation, increasing obesity was associated with decreasing FEV(1) and MEF in patients anesthetized with propofol but not desflurane (P < 0.01). CONCLUSION: We conclude that, for superficial surgical procedures of up to 120 minutes, maintenance of anesthesia with propofol impairs early postoperative lung function and pulse oximetry values more than with desflurane. Furthermore, increasing obesity decreases pulmonary function at 2 hours after propofol anesthesia but not after desflurane anesthesia. PMID- 20966445 TI - The ABC of terms used in mathematical models of infectious diseases. AB - Mathematical models that incorporate a dynamic risk of infection figure prominently in the study of infectious diseases epidemiology as a tool to inform public health policy. In recent years, their use has expanded to address methodological questions, inform and validate study design and evaluate interventions. This glossary briefly highlights the applications of transmission dynamics modelling, explains different modelling methodologies and defines commonly encountered terms to provide an introductory and conceptual understanding of the vocabulary and frameworks used in the literature. PMID- 20966446 TI - Marital loss, mental health and the role of perceived social support: findings from six waves of an Australian population based panel study. AB - OBJECTIVES: To investigate the impact of transitions out of marriage (separation, widowhood) on the self reported mental health of men and women, and examine whether perceptions of social support play an intervening role. METHODS: The analysis used six waves (2001-06) of an Australian population based panel study, with an analytical sample of 3017 men and 3225 women. Mental health was measured using the MHI-5 scale scored 0-100 (alpha=0.97), with a higher score indicating better mental health. Perceptions of social support were measured using a 10-item scale ranging from 10 to 70 (alpha=0.79), with a higher score indicating higher perceived social support. A linear mixed model for longitudinal data was used, with lags for marital status, mental health and social support. RESULTS: After adjustment for social characteristics there was a decline in mental health for men who separated (-5.79 points) or widowed (-7.63 points), compared to men who remained married. Similar declines in mental health were found for women who separated (-6.65 points) or became widowed (-9.28 points). The inclusion of perceived social support in the models suggested a small mediation effect of social support for mental health with marital loss. Interactions between perceived social support and marital transitions showed a strong moderating effect for men who became widowed. No significant interactions were found for women. CONCLUSION: Marital loss significantly decreased mental health. Increasing, or maintaining, high levels of social support has the potential to improve widowed men's mental health immediately after the death of their spouse. PMID- 20966447 TI - A register-based study on excess suicide mortality among unemployed men and women during different levels of unemployment in Finland. AB - BACKGROUND: Suicide mortality is high among the unemployed, but the role of causation and selection models in producing employment status differences remains to be understood. This study analyses the association between unemployment and suicide during different levels of national unemployment adjusting for several factors that might explain or mediate the relationship. METHODS: The data comprised annual population-register and death-register information on 25-64-year old Finns at the beginning of each year in the period 1988-2003; thus, forming 16 separate follow-up cohorts. Experience of unemployment was measured at baseline and during the previous year for each cohort. Suicide was followed for 12 months after each baseline giving a total of 7388 suicides. RESULTS: Overall, age adjusted suicide mortality was two to three times higher among the unstably employed and almost fourfold among the long-term unemployed. Adjustment for social class and living arrangements had small effect on the HRs, but adjustment for household income per consumption unit decreased the differences by 13% and 31% among the long-term unemployed women and men, respectively. When the national unemployment level was high, excess suicide mortality among the unstably employed was lower than during low unemployment when those becoming unemployed might be more selected. No such differences were found among the long-term unemployed. CONCLUSION: Long-term unemployment seems to have causal effects on suicide, which may be partly mediated by low income. As the effect of unstable employment is lower during the recessionary stage of the economic cycle some part of the excess suicide among the unstably employed is likely to be attributable to selection into unemployment. PMID- 20966448 TI - Air pollution and mortality in New Zealand: cohort study. AB - BACKGROUND: Few cohort studies of the health effects of urban air pollution have been published. There is evidence, most consistently in studies with individual measurement of social factors, that more deprived populations are particularly sensitive to air pollution effects. METHODS: Records from the 1996 New Zealand census were anonymously and probabilistically linked to mortality data, creating a cohort study of the New Zealand population followed up for 3 years. There were 1.06 million adults living in urban areas for which data were available on all covariates. Estimates of exposure to air pollution (measured as particulate matter with an aerodynamic diameter less than 10 MUm, PM(10)) were available for census area units from a previous land use regression study. Logistic regression analyses were conducted to investigate associations between cause-specific mortality rates and average exposure to PM(10) in urban areas, with control for confounding by age, sex, ethnicity, social deprivation, income, education, smoking history and ambient temperature. RESULTS: The odds of all-cause mortality in adults (aged 30-74 years at census) increased by 7% per 10 MUg/m(3) increase in average PM(10) exposure (95% CI 3% to 10%) and 20% per 10 MUg/m(3) among Maori, but with wide CI (7% to 33%). Associations were stronger for respiratory and lung cancer deaths. CONCLUSIONS: An association of PM(10) with mortality is reported in a country with relatively low levels of air pollution. The major limitation of the study is the probable misclassification of PM(10) exposure. On balance, this means the strength of association was probably underestimated. The apparently greater association among Maori might be due to different levels of co morbidity. PMID- 20966449 TI - Mediocrity. PMID- 20966450 TI - The diabetic foot and ankle. PMID- 20966451 TI - Surgical management of diabetic foot and ankle infections. AB - Delayed treatment of any diabetic foot infection can lead to a limb- or life threatening scenario. Urgent and/or emergent surgery may be necessary in the early diagnosis of a severe diabetic foot infection that is followed by staged reconstructive procedures. This article provides the reader with a thorough understanding of the surgical management of severe diabetic foot infections and describes and guides treatment based on a rational schematic approach that identifies the anatomic location of the diabetic foot infection. PMID- 20966452 TI - Imaging of the diabetic foot diagnostic dilemmas. AB - Multiple diagnostic imaging modalities are available and beneficial for the evaluation of the diabetic foot. There is not yet "one best test" for sorting out the diagnostic dilemmas commonly encountered. The differentiation of cellulitis alone from underlying osteomyelitis and the early detection of abscesses remain important diagnostic goals. Equally important, differentiation of osteomyelitis and neuroarthropathy remains a difficult job. This is often compounded by postoperative diabetic foot states status after reconstruction. Diagnostic evaluation often involves multiple studies that are complementary and that include conventional radiography, computed tomography, nuclear medicine scintigraphy, magnetic resonance imaging, ultrasonography, and positron emission tomography. PMID- 20966453 TI - Abductor hallucis muscle flap and staged medial column arthrodesis for the chronic ulcerated charcot foot with concomitant osteomyelitis. AB - Midfoot ulceration is a common sequela of the diabetic Charcot rocker-bottom deformity. Because redundant soft tissue from a non- weight-bearing area is often scarce in this area of the foot, soft-tissue coverage may be challenging. Wound closure may be difficult to achieve with local wound care and off-loading techniques if the predisposing deformity that caused the ulceration is not addressed. In the same setting, surgical reconstruction is often feared when open wounds are present, given the potential for infection. Approaching these wounds with a rational stepwise and staged approach is prudent to eradicate the underlying infection and also to achieve durable wound closure and long-term deformity correction. The authors present the use of a local muscle flap and circular external fixation for closure of a recalcitrant Charcot plantar-medial midfoot ulceration and also discuss different adjunctive modalities to facilitate soft-tissue reconstruction in the diabetic foot. PMID- 20966454 TI - Factors associated with successful Chopart amputation in patients with diabetes: a systematic review. AB - Chopart amputations were first performed for treatment of a non-salvageable distal foot but became unfavorable because of the development of equinovarus contractures and ulcerations. The majority of below-knee amputations today occur in ambulatory patients with diabetes in which a Chopart amputation may be a viable option; however, the durability of the residual limb is questionable. The authors undertook a systematic review of electronic databases and other relevant sources to identify material relating to the factors associated with a successful Chopart amputation in ambulatory patients with diabetes. Studies were eligible for inclusion only if they consecutively enrolled ambulatory patients with diabetes who underwent a Chopart amputation, regardless of etiology, with or without any tendinous or osseous balancing performed and had a mean follow-up of >=12 months duration. Four studies involving 74 patients/feet were identified that met the inclusion criteria with a weighted mean follow-up of 21.1 months. The efficacy of tendinous and/or osseous balancing could not be assessed because of the lack of comparable techniques. However, review of the included studies supports that a residual functional limb can be maintained for >=12 months with the use of a properly fitting high-profile prosthetic device for lifelong ambulation. PMID- 20966455 TI - Off-label use and prescribing: what does it mean for the foot and ankle surgeon? AB - Drugs and medical devices obtain specific on-label indications for use by the Food and Drug Administration. Physicians are able to use such devices and drugs off label as part of the practice of medicine, but is this is good thing? This edition of In the Profession examines what it means to be off label in terms of regulations, clinical studies, industry marketing, and common areas of use. PMID- 20966456 TI - American Orthopaedic Foot and Ankle Society (AOFAS) 26th Annual Meeting. PMID- 20966457 TI - Rapid social network assessment for predicting HIV and STI risk among men attending bars and clubs in San Diego, California. AB - OBJECTIVES: To test the use of a rapid assessment tool to determine social network size, and to test whether social networks with a high density of HIV/sexually transmitted infection (STI) or substance using persons were independent predictors of HIV and STI status among men who have sex with men (MSM) using a rapid tool for collecting network information. METHODS: We interviewed 609 MSM from 14 bars in San Diego, California, USA, using an enhanced version of the Priorities for Local AIDS Control Efforts (PLACE) methodology. Social network size was assessed using a series of 19 questions of the form 'How many people do you know that have the name X?', where X included specific male and female names (eg, Keith), use illicit substances, and have HIV. Generalised linear models were used to estimate average and group-specific network sizes, and their association with HIV status, STI history and methamphetamine use. RESULTS: Despite possible errors in ascertaining network size, average reported network sizes were larger for larger groups. Those who reported having HIV infection or having past STI reported significantly more HIV infected and methamphetamine or popper using individuals in their social network. There was a dose-dependent effect of social network size of HIV infected individuals on self-reported HIV status, past STI and use of methamphetamine in the last 12 months, after controlling for age, ethnicity and numbers of sexual partners in the last year. CONCLUSIONS: Relatively simple measures of social networks are associated with HIV/STI risk, and may provide a useful tool for targeting HIV/STI surveillance and prevention. PMID- 20966458 TI - Will circumcision provide even more protection from HIV to women and men? New estimates of the population impact of circumcision interventions. AB - BACKGROUND: Mathematical modelling has indicated that expansion of male circumcision services in high HIV prevalence settings can substantially reduce population-level HIV transmission. However, these projections need revision to incorporate new data on the effect of male circumcision on the risk of acquiring and transmitting HIV. METHODS: Recent data on the effect of male circumcision during wound healing and the risk of HIV transmission to women were synthesised based on four trials of circumcision among adults and new observational data of HIV transmission rates in stable partnerships from men circumcised at younger ages. New estimates were generated for the impact of circumcision interventions in two mathematical models, representing the HIV epidemics in Zimbabwe and Kisumu, Kenya. The models did not capture the interaction between circumcision, HIV and other sexually transmitted infections. RESULTS: An increase in the risk of HIV acquisition and transmission during wound healing is unlikely to have a major impact of circumcision interventions. However, it was estimated that circumcision confers a 46% reduction in the rate of male-to-female HIV transmission. If this reduction begins 2 years after the procedure, the impact of circumcision is substantially enhanced and accelerated compared with previous projections with no such effect-increasing by 40% the infections averted by the intervention overall and doubling the number of infections averted among women. CONCLUSIONS: Communities, and especially women, may benefit much more from circumcision interventions than had previously been predicted, and these results provide an even greater imperative to increase scale-up of safe male circumcision services. PMID- 20966459 TI - ESHRE PGD Consortium/Embryology Special Interest Group--best practice guidelines for polar body and embryo biopsy for preimplantation genetic diagnosis/screening (PGD/PGS). AB - In 2005, the European Society for Human Reproduction and Embryology (ESHRE) Preimplantation Genetic Diagnosis (PGD) Consortium published a set of Guidelines for Best Practice to give information, support and guidance to potential, existing and fledgling PGD programmes (Thornhill AR, De Die-Smulders CE, Geraedts JP, Harper JC, Harton GL, Lavery SA, Moutou C, Robinson MD, Schmutzler AG, Scriven PN et al. ESHRE PGD Consortium best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS). Hum Reprod 2005;20:35-48.). The subsequent years have seen the introduction of a number of new technologies as well as the evolution of current techniques. Additionally, in light of ESHRE's recent advice on how practice guidelines should be written and formulated, the Consortium believed it was timely to revise and update the PGD guidelines. Rather than one document that covers all of PGD as in the original publication, these guidelines are separated into four new documents that apply to different aspects of a PGD programme; Organization of a PGD centre, fluorescence in situ hybridization-based testing, amplification-based testing and polar body and embryo biopsy for preimplantation genetic diagnosis/screening (PGD/PGS). Here we have updated the sections that pertain to embryology (including cryopreservation) and biopsy of embryos prior to PGD or PGS. Topics covered in this guideline include uses of embryo biopsy, laboratory issues relating to biopsy, timing of biopsy, biopsy procedure and cryopreserving biopsied embryos. PMID- 20966460 TI - ESHRE PGD consortium best practice guidelines for organization of a PGD centre for PGD/preimplantation genetic screening. AB - In 2005, the European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium published a set of Guidelines for Best Practice PGD to give information, support and guidance to potential, existing and fledgling PGD programmes. Subsequent years have seen the introduction of new technologies as well as the evolution of current techniques. Additionally, in light of recent advice from ESHRE on how practice guidelines should be written/formulated, the Consortium believed it was timely to update the PGD guidelines. Rather than one document that covers all of PGD, the new guidelines are separated into four documents, including one relating to organization of the PGD centre and three relating to the methods used: DNA amplification, fluorescence in situ hybridization and biopsy/embryology. Here, we have updated the sections on organization of the PGD centre. One area that has continued to expand is Transport PGD, in which patients are treated at one IVF centre, whereas their gametes/embryos are tested elsewhere, at an independent PGD centre. Transport PGD/preimplantation genetic screening (PGS) has a unique set of challenges with respect to the nature of the sample and the rapid turn-around time required. PGS is currently controversial. Opinions of laboratory specialists and clinicians interested in PGD and PGS have been taken into account here. Current evidence suggests that PGS at cleavage stages is ineffective, but whether PGS at the blastocyst stage or on polar bodies might show improved delivery rates is still unclear. Thus, in this revision, PGS has been included. This document should assist everyone interested in PGD/PGS in developing the best laboratory and clinical practice possible. PMID- 20966461 TI - ESHRE PGD consortium best practice guidelines for fluorescence in situ hybridization-based PGD. AB - In 2005, the European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium published a set of Guidelines for Best Practice PGD to give information, support and guidance to potential, existing and fledgling PGD programmes. The subsequent years have seen the introduction of new technologies as well as evolution of current techniques. Additionally, in light of recent advice from ESHRE on how practice guidelines should be written and formulated, the Consortium believed it was timely to revise and update the PGD guidelines. Rather than one document that covers all of PGD, the new guidelines are separated into four new documents that apply to different aspects of a PGD programme, i.e. organization of a PGD centre, fluorescence in situ hybridization (FISH)-based testing, amplification-based testing and polar body and embryo biopsy for PGD/preimplantation genetic screening (PGS). Here, we have updated the sections that pertain to FISH-based PGD. PGS has become a highly controversial technique. Opinions of laboratory specialists and clinicians interested in PGD and PGS have been taken into account here. Whereas some believe that PGS does not have a place in clinical medicine, others disagree; therefore, PGS has been included. This document should assist everyone interested in PGD/PGS in developing the best laboratory and clinical practice possible. Topics covered in this guideline include inclusion/exclusion criteria for FISH-based PGD testing, referrals and genetic counselling, preclinical validation of tests, FISH-based testing methods, spreading of cells for analysis, set-up of local IVF centre and transport PGD centres, quality control/ quality assurance and diagnostic confirmation of untransferred embryos. PMID- 20966462 TI - ESHRE PGD consortium best practice guidelines for amplification-based PGD. AB - In 2005, the European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium published a set of Guidelines for Best Practice PGD to give information, support and guidance to potential, existing and fledgling PGD programmes. The subsequent years have seen the introduction of a number of new technologies as well as the evolution of current techniques. Additionally, in light of recent advice from ESHRE on how practice guidelines should be written and formulated, the Consortium believed it was timely to revise and update the PGD guidelines. Rather than one document that covers all of PGD, as in the original publication, these guidelines are separated into four new documents that apply to different aspects of a PGD programme, i.e. Organization of a PGD centre, fluorescence in situ hybridization-based testing, Amplification-based testing and Polar Body and Embryo Biopsy for PGD/preimplantation genetic screening. Here, we have updated the sections that pertain to amplification-based PGD. Topics covered in this guideline include inclusion/exclusion criteria for amplification-based PGD testing, preclinical validation of tests, amplification-based testing methods, tubing of cells for analysis, set-up of local IVF centre and Transport PGD centres, quality control/quality assurance and diagnostic confirmation of untransferred embryos. PMID- 20966463 TI - Percutaneous intrasheath ultrasonographically guided first annular pulley release: anatomic study of a new technique. AB - OBJECTIVE: The purpose of this study was to define in volunteers a safe area for performing a percutaneous intrasheath first annular (A1) pulley release under ultrasonographic guidance in cadavers for the treatment of trigger fingers. METHODS: First, in 100 fingers of 10 volunteers, we used Doppler ultrasonography to determine the limits of the sectors enclosing structures at risk (arteries and tendons). From the synovial sheath's most volar point, we determined the relative position of the arterial walls and the distance to the flexor tendons. A scatterplot overlay of the arterial positions was digitally analyzed for determining the limits of the safe area. Second, we released the A1 pulley in 46 fingers from 5 cadavers, directing the edge of the cutting device toward our safe area from an intrasheath instrument position. The precision, safety, and efficacy of the release were evaluated by surgical exposure of the A1 and A2 pulleys and the neurovascular bundles. RESULTS: In our volunteers, we observed a volar safe area from +6.1 degrees to +180 degrees . Surgical precision was good in the cadavers, with no injuries to adjacent structures, a complete release in 44 fingers (95.7%), and an incomplete release of less than 1.6 mm in 2 fingers. CONCLUSIONS: This study determined a safe volar area for aiming surgical instruments from an intrasheath position for percutaneous ultrasonographically guided A1 pulley release. The technique can be performed safely in all fingers, but we suggest being cautious in the thumb and converting the surgery to an open procedure if ultrasonographic visualization is not optimal. PMID- 20966464 TI - Sonographically guided percutaneous first annular pulley release: cadaveric safety study of needle and knife techniques. AB - OBJECTIVE: The purpose of this study was to assess the safety of sonographically guided percutaneous finger and thumb first annular (A1) pulley releases performed using needle and hook knife techniques in an unembalmed cadaveric model. METHODS: A single operator completed 50 (40 fingers and 10 thumbs) sonographically guided percutaneous A1 pulley releases in unembalmed cadavers using previously described needle and hook knife techniques and simulated local anesthesia. Half of the fingers and thumbs were completed with each technique. An experienced observer blinded to the technique dissected each specimen and assessed for neurovascular, flexor tendon, and A2 pulley injury. Completeness of release was also recorded as a secondary outcome. RESULTS: No neurovascular or A2 pulley injury occurred in any digit, regardless of technique. No significant flexor tendon injury was seen in any digit, although minor surface scratches were visualized in 3 cases (6%; 2 knife and 1 needle). The hook knife technique was significantly more likely to result in a complete pulley release compared to the needle technique (22 of 25 [88%] versus 8 of 25 [32%]; P < .001). CONCLUSIONS: Sonographically guided percutaneous A1 pulley releases can be performed safely using previously described needle and hook knife techniques. The safety margin for thumb releases is less than that for finger releases, particularly with respect to the radial digital nerve. These cadaveric data support recently published clinical investigations recommending consideration of sonographically guided percutaneous A1 pulley release in the management of patients with a disabling trigger finger. PMID- 20966465 TI - Blood flow in the internal carotid artery with common carotid artery-occluding lesions in Takayasu arteritis. AB - OBJECTIVE: The purpose of this study was to investigate carotid artery hemodynamics and blood flow involving external carotid artery (ECA) and internal carotid artery (ICA) patency in patients with Takayasu arteritis (TA). METHODS: The common carotid artery (CCA), ECA, ICA, and vertebral artery (VA) were examined in 19 patients with TA involving ECA and ICA patency and in 19 healthy control participants. Bilateral carotid sonographic studies were performed with the use of 5- to 8-MHz linear transducers. RESULTS: Patency of the ECA and ICA was noted in 14 bilateral, 2 right-sided, and 3 left-sided CCA lesions. Flow in the ECA was retrograde, whereas flow in the ICA was directed cephalad and showed a low-frequency, damped waveform or even a veinlike waveform. The peak systolic velocity (PSV) of the ICA in the patients was significantly lower than that in the control participants (P < .001). A good correlation was observed in the PSV between the ECA and ICA (r = 0.77). The VA displayed normally directed flow, a significantly larger diameter, and a higher flow velocity (P < .001). CONCLUSIONS: Color duplex sonography can identify special features of TA with CCA occluding lesions and permit quantification of carotid artery flow velocities and VA diameters both efficiently and practically. PMID- 20966466 TI - First-trimester assessment of the nasal bones using the retronasal triangle view: a 3-dimensional sonographic study. AB - OBJECTIVE: The purpose of this study was to evaluate a new sonographic technique for identifying the nasal bones using the retronasal triangle view, ie, the coronal plane at which the palate and frontal processes of the maxilla are simultaneously visualized. METHODS: Three-dimensional (3D) volumes were acquired from women undergoing first-trimester sonographic screening for aneuploidy by 2 accredited operators. Those data sets in which the fetal face was clearly identified were selected for offline analysis by 2 other observers who were unaware of the sonographic or clinical findings. The nasal bones were classified as both present, only 1 present (right or left), or absent according to the presence or absence of 2 small paired echogenic linear structures at the upper tip of the retronasal triangle as determined by 3D navigation in the coronal plane and compared to those findings obtained by 3D navigation in the sagittal plane. Additional 3D data sets involving a subset of 4 first-trimester fetuses with trisomy 21 and absent nasal bones were also analyzed retrospectively and included randomly in the study group. RESULTS: A total of 110 3D data sets were analyzed, of which 86% were obtained transabdominally and 14% transvaginally. The quality of nasal bone identification was classified subjectively by the observers as good in 67% of cases, fair in 29%, and poor in 4%. The nasal bones were classified as at least 1 present in 106 of the cases (96%) and absent in 4 (4%), with complete agreement between observers in both the sagittal and coronal planes (kappa = 1). Discrimination between the right and left nasal bones was possible in 89% and 93% for observer A and in 96% and 96% for observer B by assessing the sagittal and coronal views, respectively (right nasal bone: kappa = 0.90 [95% confidence interval (CI), 0.79-1]; left nasal bone: kappa = 0.85 [95% CI, 0.60 0.99]). The nasal bones were not identified at the level of the retronasal triangle view in any of the fetuses with trisomy 21 and absent nasal bones. CONCLUSIONS: This study shows that the nasal bones can be confidently identified as paired echogenic structures located at the upper tip of the retronasal triangle. This coronal view of the fetal face offers the possibility of screening for the presence or absence of the nasal bones in the first trimester, especially when the standard midsagittal views of the fetal face are suboptimal because of fetal or maternal factors. Because both nasal bones can be evaluated simultaneously in the coronal plane, the retronasal triangle view may be advantageous over the conventional midsagittal view assessment, in which only 1 of the 2 nasal bones is evaluated. PMID- 20966467 TI - Frontomaxillary facial angle measurements in euploid Korean fetuses at 11 weeks' to 13 weeks 6 days' gestation. AB - OBJECTIVE: The purpose of this study was to evaluate the distribution of fetal frontomaxillary facial angles in a euploid Korean population at 11 weeks' to 13 weeks 6 days' gestation. METHODS: Three-dimensional volumes of the fetal head were obtained from women with low-risk singleton pregnancies at 11 weeks' to 13 weeks 6 days' gestation who consented to this prospective study. Only fetuses with either a normal karyotype confirmed by amniocentesis or no abnormalities after delivery were considered eligible for analysis and were characterized as euploid for the purposes of this study. Women with multiple pregnancies and those who were lost to follow-up and fetuses with abnormal karyotypes or anomalies diagnosed in utero or postnatally were excluded. The frontomaxillary facial angle was measured twice offline by a single examiner. Cases were categorized by crown rump length (CRL) in 10-mm intervals for analysis of the frontomaxillary facial angle. RESULTS: Among 375 enrolled cases, 158 were eligible for frontomaxillary facial angle analysis. The overall mean frontomaxillary facial angle +/- SD was 88.6 degrees +/- 9.7 degrees . The mean frontomaxillary facial angle for fetuses with a CRL of 40 to 49 mm (n = 35) was 93.7 degrees ; 50 to 59 mm (n = 53), 92.6 degrees ; 60 to 69 mm (n = 36), 85.3 degrees ; and 70 to 79 mm (n = 34), 81.0 degrees , showing an inverse relationship between the mean frontomaxillary facial angle and CRL (r = -0.5334; P < .0001). The proportion of cases with frontomaxillary facial angles of 85 degrees or greater was 60.8%, and that of cases with angles of 90 degrees or greater was 37.3%. CONCLUSIONS: Ethnic differences in frontomaxillary facial angle measurements should be considered when incorporating the frontomaxillary facial angle in fetal aneuploidy screening in the Korean population. PMID- 20966468 TI - Collaborative study on 4-dimensional echocardiography for the diagnosis of fetal heart defects: the COFEHD study. AB - OBJECTIVE: Congenital anomalies are the leading cause of infant mortality in the United States, and congenital heart defects (CHDs) are the most common type of birth defects. Recently, 4-dimensional ultrasonography (4DUS) with spatiotemporal image correlation (STIC) has been introduced for fetal echocardiography. Accumulating evidence indicates that 4DUS with STIC may facilitate the examination of the fetal heart. Our objectives were to determine the accuracy of 4DUS for the diagnosis of CHDs and the agreement among centers. METHODS: This study included 7 centers with expertise in 4D fetal echocardiography. Fetuses with and without confirmed heart defects were scanned between 18 and 26 weeks, and their volume data sets were uploaded onto a centralized file transfer protocol server. Intercenter agreement was determined using a kappa statistic for multiple raters. RESULTS: Ninety volume data sets were randomly selected for blinded analysis. Overall, the median (range) sensitivity, specificity, positive and negative predictive values, and false-positive and -negative rates for the identification of fetuses with CHDs were 93% (77%-100%), 96% (84%-100%), 96% (83% 100%), 93% (79%-100%), 4.8% (2.7%-25%), and 6.8% (5%-22%), respectively. The most frequent CHDs were conotruncal anomalies (36%). There was excellent intercenter agreement (kappa = 0.97). CONCLUSIONS: (1) Four-dimensional volume data sets can be remotely acquired and accurately interpreted by different centers. (2) Among centers with technical expertise, 4DUS is an accurate and reliable method for fetal echocardiography. PMID- 20966469 TI - Evaluation of sound speed for detection of liver fibrosis: prospective comparison with transient dynamic elastography and histology. AB - OBJECTIVE: The degree of liver fibrosis determines the prognosis and treatment of patients with chronic viral hepatitis. Transient elastography (TE) has been accepted as a noninvasive method for assessment of liver fibrosis. Sound velocity (SV) changes are also dependent on elastic properties of tissue. The aim of this pilot study was to evaluate whether SV estimation of liver tissue allows the determination of fibrosis stages in patients with chronic viral hepatitis. METHODS: Prospectively, 50 healthy volunteers and 149 patients received stiffness (TE, 50-Hz vibrator, 5-MHz array) and SV (conventional ultrasound, C5-2-MHz transducer) measurements. Eighty-four patients received representative liver biopsies. The estimated SV and stiffness were compared using liver biopsy as a reference (METAVIR fibrosis stage [F] scoring system [Hepatology 1996; 24:289 293]). Descriptive statistics, analysis of variance, receiver operating characteristic curve analysis, and box plot analysis as well as intra-operator and interoperator reproducibility analyses were performed. RESULTS: The SV ranged from 1540 to 1650 m/s. The mean SV +/- SD was significantly different between healthy volunteers (1559 +/- 11 m/s) and patients with F0-F3 (1575 +/- 21 mm/s) and F4 (1594 +/- 18 m/s) disease (P < .001). For detection of liver cirrhosis, the area under the receiver operating characteristic curve for SV was 0.80 (95% confidence interval, 0.69-0.89). With a cutoff value of 1589 m/s, the sensitivity, specificity, and positive and negative predictive values of SV for detection of liver cirrhosis were 82%, 76%, 70%, and 86%, respectively. Sound velocity measurements were reproducible (15%) and had acceptable operator independence (19%). CONCLUSIONS: The SV of liver tissue depends on the fibrosis stage. An SV of 1589 m/s or higher detects cirrhosis with high sensitivity. Therefore, SV measurement appears to be a promising new method for noninvasive quantification of liver fibrosis. PMID- 20966470 TI - Intratesticular isolated anechoic areas: prevalence, seminal profile, and longitudinal study. AB - OBJECTIVE: The aim of this study was to evaluate the prevalence of intratesticular isolated anechoic areas (ITIAAs) in a large population, the seminal profile, and follow-up of patients with ITIAAs. METHODS: A total of 2223 patients underwent an andrologic examination and scrotal sonography. In the patients with ITIAAs, a hormonal profile was obtained, and screening for neoplastic markers was performed. In selected cases, standard semen analysis was performed. Finally, a longitudinal study was initiated. RESULTS: The prevalence of ITIAAs was 2.7% (59 of 2223 cases). In 48 of 59 cases (81.4%), a single ITIAA was found, whereas in the other 11 cases (18.6%), multiple ITIAAs were detected. Among the 59 patients with ITIAAs, we observed concomitant epididymal anechoic areas (EAAs) in 25 (42.4% of cases), specifically in 19 of 48 cases with a single ITIAA and 6 of 11 cases with multiple ITIAAs. Regarding age, 91.5% (54 of 59 cases) of the ITIAAs were found in patients older than 30 years; concomitant EAAs were present in about 50% of the cases. In patients younger than 30 years, no EAAs were detected. The seminal profile showed reduced sperm motility percentages in the patients with ITIAAs and concomitant EAAs. The longitudinal study did not show any significant variation of ITIAA patterns; all neoplastic markers remained negative. CONCLUSIONS: An ITIAA is a pattern occasionally observed on sonography. The findings suggest that an ITIAA with a concomitant EAA could have a microtraumatic or inflammatory pathogenesis, whereas an ITIAA without a concomitant EAA in young patients could have a dysontogenetic origin. PMID- 20966471 TI - In vivo noninvasive temperature measurement by B-mode ultrasound imaging. AB - OBJECTIVE: This study investigated the use of ultrasound image analysis in quantifying temperature changes in tissue, both ex vivo and in vivo, undergoing local hyperthermia. METHODS: Temperature estimation is based on the thermal dependence of the acoustic speed in a heated medium. Because standard beam forming algorithms on clinical ultrasound scanners assume a constant acoustic speed, temperature-induced changes in acoustic speed produce apparent scatterer displacements in B-mode images. A cross-correlation algorithm computes axial speckle pattern displacement in B-mode images of heated tissue, and a theoretically derived temperature-displacement relationship is used to generate maps of temperature changes within the tissue. Validation experiments were performed on excised tissue and in murine subjects, wherein low-intensity ultrasound was used to thermally treat tissue for several minutes. Diagnostic temperature estimation was performed using a linear array ultrasound transducer, while a fine-wire thermocouple invasively measured the temperature change. RESULTS: Pearson correlations +/- SDs between the image-derived and thermocouple measured temperature changes were R2 = 0.923 +/- 0.066 for 4 thermal treatments of excised bovine muscle tissue and R2 = 0.917 +/- 0.036 for 4 treatments of in vivo murine tumor tissue. The average differences between the two temperature measurements were 0.87 degrees C +/- 0.72 degrees C for ex vivo studies and 0.97 degrees C +/- 0.55 degrees C for in vivo studies. Maps of the temperature change distribution in tissue were generated for each experiment. CONCLUSIONS: This study demonstrates that velocimetric measurement on B-mode images has potential to assess temperature changes noninvasively in clinical applications. PMID- 20966472 TI - Zero-crossing tracking technique for noninvasive ultrasonic temperature estimation. AB - OBJECTIVE: The purpose of this study was to investigate the feasibility of a zero crossing tracking (ZCT) technique for temperature estimation using ultrasound images. METHODS: The backscattered ultrasound radio frequency (RF) echo from a heated region experiences time shifts, which have been identified as causing a gross effect on sound speed changes and thermal expansion. The ZCT technique tracks the shifts in the zero-crossing instants between preheated and postheated A-lines to estimate the echo shifts caused by local temperature changes. Compared to the conventional cross-correlation (CCR) technique, ZCT does not require intensive computational loadings for correlation operations; hence, the computational efficiency could be improved. Phantom experiments were performed to compare the results of temperature estimation by using the ZCT and CCR techniques. RESULTS: The imaging probe was a commercial linear array, and a high intensity focused ultrasound transducer was used as a heating source. The acquired RF echo data were processed using the ZCT and CCR techniques. The estimation results of both techniques were similar. However, the ZCT technique yielded up to 7-fold better computational efficiency than the CCR technique. CONCLUSIONS: The ZCT technique has the ability to monitor temperature changes with superior processing speed. This method could be an alternative signal processing technique for ultrasonic temperature estimation. PMID- 20966473 TI - Cystic breast lesions: sonographic findings and clinical management. AB - OBJECTIVE: This article reviews basic sonographic findings for distinguishing cystic lesions of the breast. METHODS: We describe sonographic features of simple and complicated cysts in comparison with complex masses and intracystic carcinomas. RESULTS: We correlate cystic lesion appearances with histologic patterns and illustrate the diagnostic and therapeutic management of cystic breast lesions. CONCLUSIONS: Sonography is a useful tool in distinguishing simple cysts from complicated cysts and complex masses of the breast. PMID- 20966474 TI - Breast and scrotal sparganosis: sonographic findings and pathologic correlation. AB - OBJECTIVE: Sparganosis is caused by the tapeworm larva of the geneus Spirometra. Because sparganosis usually manifests as a migrating subcutaneous mass, sonography can play an important role in its diagnosis. METHODS: In this series, we investigated 4 cases of subcutaneous sparganosis and focused on the sonographic findings. Three of the cases involved the breast, and the other involved the scrotum, as confirmed by surgery. RESULTS: The characteristics of subcutaneous sparganosis included a poorly defined hyperechoic lesion with internal serpiginous tubular structures, anechoic serpiginous tubular structures with a surrounding hyperechoic lesion, and an elongated hyperechoic mass with a hypoechoic nodular lesion in the central portion. CONCLUSIONS: We suggest that a mass combined with a hypoechoic tubular structure should raise the suspicion of subcutaneous sparganosis. PMID- 20966475 TI - Noninvasive imaging of carotid arteries in stroke: emerging value of real-time high-resolution sonography in carotid occlusion due to cardiac embolism. AB - OBJECTIVE: Comprehension of the pathophysiologic characteristics of atherosclerosis has focused its attention on the study of dynamic and metabolic processes involving the vessel wall as possible causes of stroke. When compared with conventional radiologic techniques, sonography has the main advantage of being a real-time imaging modality. We report 2 acute stroke cases in which carotid sonography showed some dynamic features that could not be identified with computed tomography (CT) and magnetic resonance angiography (MRA). METHODS: Carotid sonography with high-resolution probes (9-14 MHz) was compared with CT and MRA findings showing carotid axis occlusion in 2 patients with acute stroke. RESULTS: In case 1, the internal carotid artery occlusion observed on CT and MRA was interpreted as a dissection on a clinical basis, but sonography showed a mobile embolus originating from the heart in the internal carotid artery. In case 2, the occlusion of the whole carotid axis observed on CT and MRA was instead related to a heart-originating embolus floating in the common carotid artery. CONCLUSIONS: The evaluation of dynamic aspects of atherosclerosis is fundamental to understanding the pathophysiologic characteristics of stroke. Sonography is fundamental in carotid artery imaging for its possibility of showing dynamic processes that could be misdiagnosed with "static" imaging. The correct identification of the pathophysiologic characteristics of stroke in these cases could have led to different diagnostic and therapeutic algorithms. PMID- 20966476 TI - Point-of-care sonographic diagnosis of abdominal wall venous thrombosis associated with inferior vena cava ligation and masquerading as cellulitis. PMID- 20966477 TI - An unusual cause of right heart failure in a patient with previous hysterectomy. PMID- 20966478 TI - Fetal extrahepatic vitelline vein aneurysm mimicking an umbilical vein varix. PMID- 20966479 TI - Prenatal diagnosis of cephalothoracopagus janiceps: sonographic-pathologic correlation. PMID- 20966480 TI - Hamartomatous polyp of the gallbladder with an associated choledochal cyst. PMID- 20966481 TI - Primary squamous cell carcinoma of the thyroid gland with eggshell calcification: sonographic and computed tomographic findings. PMID- 20966482 TI - Breast fibromatosis showing unusual sonographic features. PMID- 20966483 TI - Sinus of Valsalva rupture in a patient with a congenital ventricular septal defect. PMID- 20966484 TI - Telemedicine: a dream come true? PMID- 20966485 TI - Type 2 diabetes in younger adults: the emerging UK epidemic. AB - There is an emerging epidemic of type 2 diabetes (T2DM) in younger adults. They represent an extreme phenotype: likely to be obese, lead a sedentary lifestyle, have a strong family history of T2DM, be of black or minority ethnic origin, and come from less affluent socioeconomic groups. An accurate diagnosis of T2DM in younger adults, while essential to guide management, can be challenging even for the experienced diabetologist. Comorbidities such as hypertension, nephropathy and hyperlipidaemia are prevalent in this group, and, despite the lack of longitudinal data, they represent a very high risk group, with a need for aggressive management. This focused review of the epidemiology, aetiology, clinical outcomes, comorbidities and management of younger adults with T2DM will provide the non-specialist with up-to-date insight into the UK's emerging epidemic. PMID- 20966486 TI - Child safety week: (don't) strike while the iron's hot. PMID- 20966487 TI - Exploring how symptoms of attention-deficit/hyperactivity disorder are related to reading and mathematics performance: general genes, general environments. AB - Children with attention-deficit/hyperactivity disorder (ADHD) tend to perform more poorly on tests of reading and mathematical performance than their typical peers. Quantitative genetic analyses allow for a better understanding of the etiology of ADHD and reading and mathematics outcomes, by examining their common and unique genetic and environmental influences. Analyses were conducted on a sample 271 pairs of 10-year-old monozygotic and dizygotic twins drawn from the Western Reserve Reading and Mathematics Project. In general, the results suggested that the associations among ADHD symptoms, reading outcomes, and math outcomes were influenced by both general genetic and general shared-environment factors. The analyses also suggested significant independent genetic effects for ADHD symptoms. The results imply that differing etiological factors underlie the relationships among ADHD and reading and mathematics performance. It appears that both genetic and common family or school environments link ADHD with academic performance. PMID- 20966488 TI - Obesity prevention practices of elementary school nurses in Minnesota: findings from interviews with licensed school nurses. AB - Elementary schools are an optimal setting to provide obesity prevention interventions, yet little is known about the obesity prevention practices of elementary school nurses. The purpose of this study was to gain insight into current obesity-related school nursing practice in elementary schools in Minnesota, opinions regarding school nurse-led obesity prevention programs, and school nurses' interest in implementing obesity prevention programs. Semistructured interviews were conducted with key informants from 21 Minnesota school districts (urban = 7; suburban = 8; and rural = 6), who were licensed school nurses (LSNs). Findings indicated that LSNs provided some primary and secondary obesity prevention services. Key informants felt school nurses, administrators, and parents would be supportive of school-based, LSN-led obesity prevention efforts. Interest in increasing efforts was limited by time constraints, staffing, and resources. School nurses are well positioned to provide prevention services that will contribute to reducing childhood obesity. PMID- 20966490 TI - Is there harm in silence? PMID- 20966491 TI - Antenatal diagnosis of trisomy 18, harm and parental choice. AB - In this commentary I assess the possible harms to a fetus with trisomy 18 of continued life. I argue that, although there is good reason to avoid subjecting infants to major surgery and prolonged intensive care where there is little chance of benefit, doctors should support and engage honestly with parents who decide to continue their pregnancies. We should ensure that infants with trisomy 18 have access to high quality palliative care. PMID- 20966492 TI - He was my son, not a dying baby. PMID- 20966493 TI - Addict to win? A different approach to doping. AB - Traditionally the doping debate has been dominated by those who want to see doping forbidden (the prohibitionist view) and those who want to see it permitted (the ban abolitionist view). In this article, the authors analyse a third position starting from the assertion that doping use is a symptom of the paradigm of highly competitive elite sports, in the same way as addictions reflect current social paradigms in wider society. Based upon a conceptual distinction between occasional use, habitual use and addiction, and focusing on the physical and/or mental dependency caused by the addictive use of a certain drug, we argue that marihuana, stimulants and anabolic steroid abuse--the most frequently detected substances in doping tests--satisfies at least one, often both, of these conditions. A conclusion to be drawn from the authors' arguments is that the prohibitionist view is inappropriate for dealing with doping, as the severe sanctions attached to it will cut the doper off her/his social and professional environment, thereby risking reinforcing her/his addictive conduct. But the ban abolitionist view seems inappropriate as well. At first sight, it seems neither rational nor humane not to intervene when confronted with conduct which is highly harmful for the individual and upon which she has reduced or no control whatsoever. Instead the authors' proposal will be to contextualise dopers' conduct within sport healthcare and see it strictly in relation to each athlete's personal background. Developing preventive programmes--implemented through person tailored counselling and eventually treatment, rather than severe sanctions or the mere lifting of the ban--seems to be a more reasonable, and probably more efficient, way of conducting 'the war against doping'. PMID- 20966494 TI - [Role of Toll-like receptors in etiology of selected diseases of the skin]. AB - Toll-like receptors (TLR) play an important role in anti-infectious defense of organisms. So far in humans 10 receptors have been identified. They were classified into five different subfamilies according to their affinity to characteristic ligands. Every receptor has a similar structure (extracellular part, intramembrane part and cytoplasmic part), irrespective of a type of the ligands with which it reacts. Ligands are present on many cell types, including on those which make up the skin. That is why Toll-like receptors are an important part of the cutaneous, non-specific immunologic response. In the review problems associated with the structure and functions of Toll-like receptors are presented. Moreover, the latest information about the role of TLR in the etiology of some dermatoses (psoriasis, atopic dermatitis, acne vulgaris, rosacea, infections, systemic lupus erythematosus, mycosis fungoides) is discussed. In addition, therapeutic implications are described. PMID- 20966495 TI - [Mechanisms involved in the regulation of immune response in animal model of rheumatoid arthritis in mice (CIA)]. AB - Rheumatoid arthritis (RA) represents an example of the autoimmune disease. With a prevalence of 1% worldwide, the pathogenesis of RA is not clear yet. At present it is thought that the pathogenesis of RA results from an inflammatory response mediated by CD4+ Th1 cells that recognize unidentified antigens present in bone joints. Recently, there is a growing evidence for a role for Th17 lymphocytes in autoimmunity, including RA, suggesting that this population of helper cells may be more important in the pathogenesis of RA than Th1 cells. Thus far, treatment modalities for RA are limited, with the prevailing one acting nonspecifically on the immune system. However, such an approach results in a general immunosuppression and is accompanied by severe side-effects. There is a large demand for developing RA therapy that particularly targets pathogenic antigen specific T cells. Research on pathogenesis of the autoimmune diseases, and development of new drugs is now possible thanks to experimental animal models that mimic human diseases. Collagen-induced arthritis (CIA) in genetically susceptible strains of mice, rats, rabbits or rhesus monkeys has been used as an experimental model of RA, as it shares many histological and immunological features. The knowledge gained using this model allows to better understand the pathogenesis of RA and, consequently, to manipulate particular components of the immune system to develop efficient therapies. PMID- 20966496 TI - [Helicobacter spp. infections in chronic liver damage]. AB - Liver is a key organ responsible for organism's homeostasis. A proper function of this organ is crucial for detoxification of metabolic products and regulation of metabolic processes of macromolecules (proteins, lipids, carbohydrates). The most important infectious factors, leading to liver damage, are primary hepatotropic viruses, particularly those causing chronic inflammation of the organ (HBV, HCV, HDV), which may subsequently cause cirrhosis and/or primary hepatocellular carcinoma. There has been a growing interest in Helicobacter spp. liver infections as a potential factor promoting injury of the organ towards hepatocellular carcinoma. The association between hepatocellular carcinoma and the presence of Helicobacters in the liver has been well documented in animal models (Helicobacter hepaticus versus liver cancer in mice). Some reports also indicate similar association in humans, where the presence of Helicobacter antigens in patients with liver cancer is detected more often in comparison to healthy or chronically infected population. Although the molecular mechanisms underlying such a phenomenon are not well known, the knowledge on this subject has considerably increased during recent years. The review presents data on the association between the presence of Helicobacter spp. in the liver and injuries of the organ, as well as the role that is played by the bacteria in chronic liver diseases. PMID- 20966497 TI - [Pharmacological activation of tumor suppressor, wild-type p53 as a promising strategy to fight cancer]. AB - A powerful tumor suppressor--p53 protein is a transcription factor which plays a critical role in eliciting cellular responses to a variety of stress signals, including DNA damage, hypoxia and aberrant proliferative signals, such as oncogene activation. Since its discovery thirty one years ago, p53 has been connected to tumorigenesis as it accumulates in the transformed tumor cells. Cellular stress induces stabilization of p53 and promotes, depending on the stress level, cell cycle arrest or apoptosis in the irreversibly damaged cells. The p53 protein is found inactive in more than 50% of human tumors either by enhanced proteasomal degradation or due to the inactivating point mutations in its gene. Numerous data indicate that low molecular weight compounds, identified by molecular modeling or in the functional, cell-based assays, efficiently activate non-mutated p53 in cancer cells which in consequence leads to their elimination due to p53-dependent apoptosis. In this work we describe the structure and cellular function of p53 as well as the latest discoveries on the compounds with high anti-tumor activities aiming at reactivation of the tumor suppressor function of p53. PMID- 20966498 TI - [The role of stromal mast cells in the modification of CD4+CD25+Foxp3 regulatory T cells, Th17 lymphocytes and cytotoxic lymphocytes Tc1 in the development and progression of tumor]. AB - Despite the lack of direct evidence that immune surveillance cells protect against tumor development, indirect clinical observations and experimental studies indicate activity in the immune response against cancer cells of various origin. Little is known about the effects of the stromal tumor mast cell (MC) in the activity of immune cells, i.e. CD4+CD25+Foxp3+ regulatory T cells, Th17 lymphocytes, cytotoxic lymphocytes Tc1 and their mutual modulatory function and regulation of the antitumor immune response. Factors synthesized by stromal tumor mast cells including histamine, COX-2, CXCL8 (IL-8), VEGF, IL-6, TNF, iNOS, MMP 8, and MMP-9 may, on the one hand, directly affect the activity of T lymphocyte subpopulations, i.e. iTreg, Tc1, and Th17, and thus regulate immunological processes occurring in the vicinity of the tumor. On the other hand, through effects on angiogenesis, apoptosis, the cell cycle, secretion of cytokines and the expression of adhesion molecules, they may indirectly determine the progression of the neoplasm. Understanding the regulatory mechanisms occurring in the system: tumor stroma mast cell -> immune cells infiltrating the tumor (iTreg, Tc1, Th17 lymphocytes) -> expression of factors involved in angiogenesis, apoptosis, the cell cycle, and secretion of cytokines and adhesion molecules creates the future possibility of influencing the activation and regulation of selected proneoplastic and antineoplastic factors appearing in the neoplasm environment. Research on these mechanisms may be the beginning of a new approach to the fight against cancer growth and provide an opportunity to introduce new methods of treatment. The aim of this study was to present the current knowledge on the role of stromal tumor CD117+ mast cells and factors secreted by these cells in the activation of T lymphocyte subpopulations, i.e. CD4+CD25+Foxp3+ regulatory T cells, Th17 lymphocytes, and cytotoxic lymphocytes Tc1, as well as to present their impact on the degree of tumor invasiveness by regulating the synthesis of factors secreted by the lymphocyte subpopulations studied, e.g. IL 10 and TGF-beta (iTreg), IL-17A and IL-6 (Th17), IFN-gamma and IL-2 (Tc1). PMID- 20966499 TI - [Cells of the immune system in atherosclerosis--chosen data]. AB - Development of artherosclerosis is associated with participation of various cell types of the immune system such as: granulocytes, B and T lymphocytes, mast cells, dendritic cells and progenitor cells. Cytokines and growth factors have a great impact on activation of the atheromatous plaque. This pathological process results in increase of artery's tunic intima thickness, leading to coronary heart disease, myocardial infarction or stroke. It is suggested that a closer look at participation of the immune system cells in artherosclerosis may contribute to a change in the profile of therapy of this disease. PMID- 20966500 TI - [Gene polymorphisms of renin-angiotensin-aldosterone system components and the progression of chronic kidney diseases]. AB - The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathogenesis of hypertension as well as cardiovascular diseases and chronic kidney diseases. Among the most frequently studied RAAS gene polymorphisms are the angiotensin-converting enzyme insertion/deletion (I/D), angiotensinogen M235T and angiotensin II receptor type 1 A1166C polymorphisms. A significant correlation was found between the I/D polymorphism and cardiovascular morbidity and mortality rates. However, there was no significant correlation between I/D, M235T, A1166C polymorphism and arterial hypertension. The role of I/D polymorphism in the development and progression of chronic kidney disease is also non-conclusive. However, DD genotype has been identified as relevant for loss of renal function both in patients with IgA nephropathy and in patients of Asian origin with diabetic nephropathy. The relationship between RAAS gene polymorphism and transplanted kidney function has not been confirmed in large prospective and retrospective studies. CONCLUSION: there is no clear opinion concerning the influence of RAAS genotypes on the prevalence of post-transplant hypertension or erythrocytosis. Although a role of RAAS gene polymorphism in kidney function deterioration could not be ruled out, it is more likely that a variety of genetic and environmental factors influence the progression of chronic kidney diseases. PMID- 20966501 TI - [Rosacea]. AB - Rosacea is a chronic, inflammatory disease of the skin, usually localized on the face. The disease predominantly affects inhabitants of Northern and Western Europe and North America and is rarely found among other ethnic groups. The disease usually starts at the age of 20-30, with visible progression in the next decade of life and full clinical presentation at the age of 40-50. The pathogenesis of rosacea is heterogenic and not fully elucidated. The disease is associated with many different factors. The pathomechanism of the disease is complex and depends on: natural immunity, vascular disturbances, action of reactive oxygen species and proteolytic enzymes, UV radiation and infectious factors. The influence of environmental factors on natural, innate immunity can be responsible for different symptoms of the disease and can determine a type of treatment. At present rosacea is divided into 4 subtypes based on a type of clinical manifestations: erythematotelangiectatic, papulopustular, phymatous and ocular rosacea. The course of the disease is characterized by remissions and progressions. In most cases it is sufficient to use a topical, but sometimes even a systemic treatment. Every relapse to the disease is connected with progression of skin damage and aggravation of symptoms. Different topical and systemic ways of treatment are used but some of them are not accepted by FDA as a standard therapy of the disease. Except of the treatment also a proper care and life style are also important to control the disease. In the review the contemporary opinions on pathogenesis, clinical manifestations and therapeutic strategies were presented. PMID- 20966502 TI - [Anthocyanins as components of functional food for cardiovascular risk prevention]. AB - Epidemiologic studies suggest that the regular consumption of polyphenols, secondary metabolites of plants, is correlated with a decrease of the risk of cardiovascular disease, diabetes, arthritis and cancer. The most abundant flavonoid constituents of plants are anthocyanins--water-soluble, glycosylated, nonacetylated pigments. The profitable effects of these compounds may be partly attributed to their antioxidative and anti-inflammatory activity. The supplementation of anthocyanins or an anthocyanin-rich diet has been reported to significantly increase serum antioxidant potential. PMID- 20966503 TI - [The biological activity of lysosomotropic agents]. AB - Lysosomotropic agents have antitumor, antifungal and antimicrobial properties. These small, amphiphilic compounds, as weak bases, readily penetrate the lipid bilayer and diffuse into acidic subcellular compartments such as lysosomes or vacuoles. The mechanism of action of lysosomotropic compounds can be distinct, depending on their chemical structure and/or the kind of cells influenced. Our investigations of the influence of lysosomotropic agents on Saccharomyces cerevisiae have lead to a partial explanation of their mechanism of action. The amphiphilic character enables the compounds to penetrate the lipid bilayer and disturb its structure and functions and can inhibit the activity of plasma membrane H+ATPase. The accumulation of the compounds in yeast vacuoles, disrupting them and killing yeast cells, is another mechanism of action. Lysosomotropic agents can be substrates for ABC transporters in Saccharomyces cerevisiae cells. PMID- 20966504 TI - FLT3 internal tandem duplication and FLT3-D835 mutation in 80 AML patients categorized into cytogenetic risk groups. AB - BACKGROUND: Acute myeloid leukemia (AML) is a clonal disorder characterized by various genetic abnormalities and variable response to treatment. About 50% of patients with AML have no cytogenetic aberrations, presenting normal karyotype, and are categorized in the intermediate risk group. In this group detection of FLT3 mutations move a patient from the intermediate to the adverse risk group. MATERIAL/METHODS: Bone marrow from 80 AML patients was cultured to obtain chromosome slides and then karyotype. Simultaneously DNA was isolated from bone marrow and PCR reaction was conducted to test the FLT3 mutation status (ITD and D835). For statistical analysis Chi squared test was used. RESULTS: From the group of 80 AML patients seven were classified as a favorable risk group and FLT3/ITD was found only in one of these patients (14.28%), and FLT3/D835 in another one (14.28%). Fifteen patients showed a complex karyotype with more than three aberrations or with any aberration known as a poor prognosis. Among the adverse group FLT3/ITD was detected in three patients (20%) and D835 mutation in two other patients (13.33%). Among 58 patients with normal karyotype in GTG banding FLT3/ITD occurred in six cases (10.34%) and D835 mutation in two cases (3.45%). No significant difference was found among these three risk groups regarding presence or absence of FLT3/ITD and FLT/D835. DISCUSSION: Molecular characterization of mutations in several genes, such as FLT3, NPM1, MLL, CEBPA, in acute myeloid leukemia, especially in normal karyotype cases, could be another factor after cytogenetic analysis to stratify AML patients into different prognostic categories. PMID- 20966505 TI - [Prothrombotic aldosterone action--a new side of the hormone]. AB - Recent studies have focused on a new wave of interest in aldosterone due mainly to its growing profile as a local messenger in pathology of the cardiovascular system, rather than its hormonal action. In the last few years strong evidence for a correlation between raised aldosterone level and haemostasis disturbances leading to increased risk of cardiovascular events has been provided. It has been demonstrated that aldosterone contributes to endothelial dysfunction, fibrinolytic disorders and oxidative stress augmentation. It was also shown that chronic aldosterone treatment results in enhanced experimental arterial thrombosis. Our study in a venous model of thrombosis in normotensive rats confirmed that even a short-lasting increase in aldosterone level intensified thrombus formation. One-hour aldosterone infusion shortened bleeding time; increased platelet adhesion to collagen; reduced tissue factor, thrombin activatable fibrinolysis inhibitor, and plasminogen activator inhibitor; and increased plasminogen activator plasma level. A fall in plasma nitric oxide metabolite concentration with a decrease in aortic nitric oxide synthase mRNA level was also observed. Moreover, aldosterone increased hydrogen peroxide and malonyl dialdehyde plasma concentration and augmented NADPH oxidase and superoxide dismutase aortic expression. Therefore, the mechanism of aldosterone prothrombotic action is multiple and involves primary haemostasis activation, procoagulative and antifibrinolytic action, NO bioavailability impairment and oxidative stress augmentation. The effects of aldosterone were not fully abolished by mineralocorticoid receptor blockade, suggesting the involvement of alternative mechanisms in the prothrombotic aldosterone action. PMID- 20966506 TI - [Application of PCR techniques in toxicology]. AB - Molecular biology techniques have become widely used in toxicology, leading to the creation of a new science--molecular toxicology. The goal of molecular toxicology is to detect and study the changes induced by xenobiotics at the molecular level. The research scope of molecular toxicology includes examination of mutations in genomic DNA, differences in mRNA expression and study of genotype indicating individual sensitivity. The processes of activation and detoxification of xenobiotics, drugs and environmental carcinogens involve several enzymes (xenobiotic-metabolizing enzymes--XMEs). Most of the chemicals entering our bodies, regardless of whether they have medical, pathogenic or carcinogenic properties, require metabolic activation by phase I enzymes (cytochrome P-450). In the next process the phase I products are usually detoxified by phase II enzymes, mainly by epoxide hydrolase, glutathione transferase, N acetyltransferase or sulfotransferase. PCR techniques allow precise study of the effects of xenobiotics on cells and tissues by examining the level of activation of genes coding for phase I and II enzymes, or by testing the activity of other elements of the transcriptome. Studies of sensitivity of individual cells or tissues based on examination of mutation or gene polymorphism presence are also relevant. This paper presents the possibility of using various PCR techniques in toxicology and especially in the study of genetically determined sensitivity to xenobiotics. It also covers the possibilities of applying qPCR and qRT-PCR methods in the search for exposure biomarkers with particular emphasis on individual cytochrome P450 isoforms. Furthermore, it provides information about the possibility of implementing the differential display technique in the identification of new genes activated by toxic agents. PMID- 20966507 TI - [Akt kinase: a key regulator of metabolism and progression of tumors]. AB - The serine/threonine protein kinase Akt is a major transducer of the phosphoinositide 3-kinase pathway and plays a crucial role in regulation of cellular processes such as growth, metabolism, survival and proliferation. Mammalian cells are characterized by the expression of three different Akt isoforms (Akt1, Akt2, Akt3), encoded by distinct genes. Increased expression and activation of Akt observed in many human cancers is usually caused by amplification or mutation of Akt genes, amplification and activating mutation of the catalytic subunit of PI3K or deletion and mutations of phosphatidylinositol 3,4,5-triphosphate phosphatase--PTEN. Although activation of Akt alone is believed to be insufficient for tumorigenesis, it contributes to cancer progression by inhibiting apoptosis, promoting changes in metabolism and proliferation of cells and regulating their migration and invasion capabilities. Recent studies have provided evidence that depending on the cell type each specific Akt isoform may play a positive or negative role in cell migration and invasion. Akt is also involved in regulation of tumor angiogenesis. PMID- 20966508 TI - [RNA interference as a potential tool for diagnosis and therapy of some human diseases]. AB - RNA interference is one of the most important discoveries in the field of molecular biology. To date, many studies have been reported which suggest that RNA interference takes part in various biological processes essential for the development of many diseases. On the other hand, owing to its high specificity and efficiency, RNA interference has become a powerful tool in gene therapy. However, introduction of small interfering RNAs (siRNAs) to a target tissue requires overcoming some critical biological barriers. This, in turn, contributes to searching for new effective vectors, which should selectively penetrate the tissue and be able to exclude the innate immune response. This study provides a brief overview of the application of RNA interference in the diagnosis and therapy of some human diseases. PMID- 20966509 TI - [The role of AMP-activated protein kinase in regulation of skeletal muscle metabolism]. AB - AMP-activated protein kinase (AMPK) is a conserved, ubiquitously expressed eukaryotic enzyme that is activated in response to increasing AMP level. Regulation of AMPK activity in skeletal muscle is coordinated by contraction and phosphorylation by upstream kinases and a growing number of hormones and cytokines. Once activated, AMPK turns on catabolic, ATP-generating pathways, and turns off ATP-consuming metabolic processes such as biosynthesis and proliferation. Activation of AMPK promotes glucose uptake and fatty acid oxidation, and enhances glycogen storage capacity in skeletal muscle. Interestingly, increased glucose uptake in response to AMPK activation may occur in an insulin-independent manner. It has been confirmed that AMPK is an indirect molecular target of the antidiabetic drug metformin, and it is postulated that AMPK may be responsible for health benefits of exercise. Understanding of AMPK involving molecular pathways that govern skeletal muscle metabolism is of special interest and offers a unique possibility to find new physiological and/or pharmacological strategies that can improve insulin sensitivity. Here we review present knowledge on the physiological function of AMPK in muscle, and highlight its potential role in glucose homeostasis regulation. PMID- 20966510 TI - Physical illness in persons with schizophrenia--time for action. PMID- 20966511 TI - Genetics & hypertension. PMID- 20966512 TI - Zidovudine-induced anaemia in HIV/AIDS. PMID- 20966513 TI - Apolipoprotein E polymorphism in cerebrovascular & coronary heart diseases. AB - The role of apolipoprotein E (apo E) in lipid metabolism and cholesterol transport is well established. About 14 per cent of the variation in plasma cholesterol levels is attributed to polymorphisms in APO E gene (APO E). APO E consists of three common alleles, designated as epsilon2, epsilon3 and epsilon4 which code for E2, E3 and E4 proteins respectively resulting in three homozygous (E2/E2, E3/E3, E4/E4) and three heterozygous (E3/E2, E4/E2 and E4/E3) phenotypes. Different populations studied worldwide inherit variable frequencies of the APO E alleles and genotypes, with the most frequent allele being epsilon3.The epsilon4 allele has been consistently shown to be associated with Alzheimer's disease, coronary heart disease and cerebrovascular disorders. In this review, we have discussed the role of APO E polymorphisms in cerebrovascular and coronary heart diseases. The status of APO E polymorphisms and their disease associations in Asian Indians besides, other populations has also been discussed. Further, studies elucidating the pathophysiology of apo E deficiency conducted in knock out mice have been reviewed. PMID- 20966514 TI - Association of aldosterone synthase (CYP11B2 C-344T) gene polymorphism & susceptibility to essential hypertension in a south Indian Tamil population. AB - BACKGROUND & OBJECTIVE: Renin-angiotensin aldosterone system (RAAS) plays an important role in the regulation of blood pressure. Aldosterone, synthesized by aldosterone synthase in the adrenal cortex is encoded by the CYP11B2 gene. In this case-control study we examined the association between CYP11B2 C-344T polymorphism and essential hypertension in south Indian Tamil population. METHODS: The study was conducted in 406 hypertensive cases and 424 healthy controls from Tamil population. Genotyping was performed by PCR-restriction fragment length polymorphism method. Statistical analysis was performed by logistic regression analysis. RESULTS: The 344TT homozygous variant genotype (OR 1.8; 95% CI: 1.1-2.8; P=0.02) and T allele (P=0.007) were found to be significantly associated with hypertension. In gender based analysis, the risk was significantly higher in male hypertensives (OR-1.8; 95% CI: 1.0-3.6, P=0.05) but not in female subjects. INTERPRETATION & CONCLUSION: A significant association between CYP11B2 gene polymorphism and essential hypertension was observed and the risk was confined to male subjects in south Indian Tamil population. PMID- 20966515 TI - High incidence of zidovudine induced anaemia in HIV infected patients in eastern India. AB - BACKGROUND & OBJECTIVES: Zidovudine (ZDV) is the preferred nucleoside reverse transcriptase inhibitor in the first line antiretroviral regimen in India. It is known to be associated with life threatening toxicity like anaemia. This study was aimed at determining the prevalence of ZDV induced anaemia in HIV infected patients initiated on ZDV containing antiretroviral therapy regimen and also to find out the correlates, if any, for causing ZDV induced anaemia. METHODS: This retrospective study was carried in ART Centre, Sir Sunderlal Hospital, Banaras Hindu University, Varanasi between March 2005 to December 2007. HIV infected patients registered at ART Centre were treated according to guidelines of National AIDS Control Organization (NACO). Patients (n=1256) with haemoglobin (Hb)>8 g/dl were prescribed ZDV based antiretroviral therapy regimens. Patients developing anaemia (<8 g/dl) with other causes of anaemia excluded were recorded. Correlation of baseline characteristics (age, gender, haemoglobin levels, weight, CD(4) counts and WHO clinical stage) with risk of developing anaemia was also calculated. RESULTS: Two hundred three (16.2%) patients on ZDV regimen developed anaemia (<8 g%); 7.9 per cent (n=100) of these developed severe anaemia (<6.5 g%). Females were more prone to develop anaemia (P=0.026). Age, weight, WHO clinical stage and CD4 counts had no relation to development of anaemia. INTERPRETATION & CONCLUSION: High incidence of ZDV induced anaemia seen in this study indicates regular monitoring of patients, particularly women on ZDV based antiretroviral regimens. PMID- 20966516 TI - Comparison of HPLC & spectrophotometric methods for estimation of antiretroviral drug content in pharmaceutical products. AB - BACKGROUND & OBJECTIVES: Simple and reliable methods to estimate drugs in pharmaceutical products are needed. In most cases, antiretroviral drug estimations are performed using a HPLC method, requiring expensive equipment and trained technicians. A relatively simple and accurate method to estimate antiretroviral drugs in pharmaceutical preparations is by spectrophotometric method, which is cheap and simple to use as compared to HPLC. We undertook this study to standardise methods for estimation of nevirapine (NVP), lamivudine (3TC) and stavudine (d4T) in single tablets/capsules by HPLC and spectrophotometry and to compare the content of these drugs determined by both these methods. METHODS: Twenty tablets/capsules of NVP, 3TC and d4T each were analysed for their drug content by HPLC and spectrophotometric methods. Suitably diluted drug solutions were run on HPLC fitted with a C18 column using UV detection at ambient temperature. The absorbance of the diluted drug solutions were read in a spectrophotometer at 300, 285 and 270 nm for NVP, 3TC and d4T respectively. Pure powders of the drugs were used to prepare calibration standards of known drug concentrations, which was set up with each assay. RESULTS: The inter-day variation (%) of standards for NVP, 3TC and d4T ranged from 2.5 to 6.7, 2.1 to 7.7 and 6.2 to 7.7, respectively by HPLC. The corresponding values by spectrophotometric method were 2.7 to 4.7, 4.2 to 7.2 and 3.8 to 6.0. The per cent variation between the HPLC and spectrophotometric methods ranged from 0.45 to 4.49 per cent, 0 to 4.98 per cent and 0.35 to 8.73 per cent for NVP, 3TC and d4T,respectively. CONCLUSIONS: The contents of NVP, 3TC and d4T in the tablets estimated by HPLC and spectrophotometric methods were similar, and the variation in the amount of these drugs estimated by HPLC and spectrophotometric methods was below 10 per cent. This suggests that the spectrophotometric method is as accurate as the HPLC method for estimation of NVP, 3TC and d4T in tablet/capsule. Hence laboratories that do not have HPLC equipment can also undertake these drug estimations using spectrophotometer. PMID- 20966517 TI - Chandipura virus encephalitis outbreak among children in Nagpur division, Maharashtra, 2007. AB - BACKGROUND & OBJECTIVES: An outbreak of acute encephalitis syndrome (AES) among children from Nagpur division, Maharashtra was investigated to confirm the aetiology and to describe clinico-epidemiological features. METHODS: AES cases among children<15 yr, from Nagpur division, hospitalized between June-September 2007, were investigated. Serum and cerebrospinal fluid (CSF) were tested for IgM antibodies against Chandipura virus (CHPV) and Japanese encephalitis virus (JEV) and for CHPV RNA by RT-PCR. Partial N gene sequences were used for phylogenetic analysis. Virus isolations were attempted in rhabdomyosarcoma (RD) cell line. Sandflies were collected, pooled and tested for CHPV RNA by RT-PCR. RESULTS: A total of 78 AES cases were recorded in children<15 yr of age. Case fatality ratio was 43.6 per cent. Male to female ratio was 1:1.2. Chandipura (CHP) was confirmed in 39 cases. CHPV RNA was detected in both CSF and serum specimens of 2 cases and in serum of 22 cases. Phylogenetic analysis showed 99.98-100 per cent nucleotide identity in the sequences studied. Anti-CHPV IgM antibodies were detected in CSF of 2 cases and in serum of 8 cases. Seroconversion to anti-CHPV IgM antibodies was observed in 5 cases. Clinical manifestations of CHP cases (n=38) were fever (100%), convulsion (76.3%), altered sensorium (34.2%), headache (23.7%), vomiting (44.7%) and diarrhoea (23.7%). CHPV RNA was detected in one of two pools of sandflies from affected locality. INTERPRETATION & CONCLUSIONS: Chandipura virus was confirmed as the aetiological agent of this acute encephalitis outbreak with high case-fatality among children. PMID- 20966518 TI - Streptomycin induced protein expression analysis in Mycobacterium tuberculosis by two-dimensional gel electrophoresis & mass spectrometry. AB - BACKGROUND & OBJECTIVES: The resistance of Mycobacterium tuberculosis to streptomycin, a core drug for treatment of category II tuberculosis (TB) has posed a major challenge to the health providers as well as research workers worldwide and has severely compromised the therapeutic options. A significant proportion of streptomycin resistant M. tuberculosis isolates failed to show mutations in conventional targets like rpsL and rrs. Although efflux, permeability, etc. are also known to contribute, yet a substantial proportion of isolates remains resistant suggesting involvement of other unknown mechanism. A resistant isolate may show altered gene as well as protein expression under drug induced conditions and a whole cell proteome analysis under induced conditions might help in further understanding the mechanisms of drug resistance. The present study was therefore designed with the objective to identify proteins related to streptomycin resistance in M. tuberculosis isolate grown in presence and absence of streptomycin (SM). METHODS: A clinical isolate of M. tuberculosis from Mycobacterial Repository Centre at the Institute (NJIL & OMD), Agra was grown in Sauton's medium for 36 h with/without subinhibitory concentration of the drug (2 MUg/ml) and the cell lysate of isolates was prepared by sonication and centrifugation. Two-dimensional (2D) gel electrophoresis was employed to study the protein profile. The selected proteins were finally identified by MALDI-TOF mass spectrometry. RESULTS: Our study revealed eight inducible proteins (DnaK, fabG4, DNA-binding, hypothetical, two 14 kDa antigen and two 10 kDa chaperonin) that were upregulated in the presence of drug. INTERPRETATION & CONCLUSION: This preliminary study has thrown light on whether or not and how the resistant isolate responds to streptomycin at its non-toxic but sub-inhibitory concentration. An in-depth study of the upregulated proteins will give an insight into probable sites of drug action other than established primary sites. PMID- 20966519 TI - Pattern & correlates of neurocognitive dysfunction in Asian Indian adults with severe obstructive sleep apnoea. AB - BACKGROUND & OBJECTIVES: No published data are available on neurocognitive dysfunction in Asian Indians with obstructive sleep apnoea (OSA). We therefore, studied the pattern and correlates of neurocognitive dysfunction in Indian adults with severe OSA. METHODS: Fifty patients aged 25-65 yr with severe OSA (apnoea hypopnoea index>30) and 25 age, sex, and education level-matched normal controls were studied. Both groups were administered a standardized battery of neurocognitive tests. RESULTS: Patients with severe OSA had significantly impaired performance on tests of alertness, working memory, response inhibition, problem solving, and executive function. However, the difference in executive function between the groups disappeared after adjusting for delayed information processing. The test scores did not correlate with apnoea-hypopnoea index, arousal index, or Epworth sleepiness score. However, the percentage of time spent at <90 per cent oxygen saturation had a weak correlation with the number of stroop errors (Spearman's rho=0.64; P=0.033), number of trials required (rho=0.05; P=0.02), and perseverative errors on Wisconsin card sorting test (rho=0.36; P=0.02). INTERPRETATION & CONCLUSIONS: Our results suggested that delayed information processing rather than impaired abstract thinking was probably the cause of impaired performance on composite tests of neurocognitive function in patients with severe OSA. PMID- 20966520 TI - Effect of suicide gene therapy in combination with immunotherapy on antitumour immune response & tumour regression in a xenograft mouse model for head & neck squamous cell carcinoma. AB - BACKGROUND & OBJECTIVES: Prodrug activation strategy as well as immunotherapy have been widely used for cancer gene therapy. In the present study, using a head and neck squamous cell carcinoma (HNSCC) xenograft nude mouse model, we have investigated whether the two therapies in combination could improve tumour cell kill. We also investigated induction of immune effector cells viz., NK (DX5+) and DC (CD11c+) in vivo, post-combination gene therapy. METHODS: A retroviral vector producing cell line (PLTK47.1 VPC) carrying Herpes simplex virus thymidine kinase gene (HSVtk) was used for intratumoural injection into NT8e xenograft tumours followed by the prodrug ganciclovir (GCV). IL-2 plasmid DNA was injected intramuscularly. Immune cells were analyzed by flow-cytometry. Non parametric ANOVA was performed with Kruskal Wallis test. RESULTS: IL-2 could induce proliferation of both NK cells (DX5+) and dendritic cells (CD11c+) in vivo. Apoptosis was higher in combination therapy group as compared to HSVtk/GCV alone or IL-2 alone and was mediated through caspase-3 dependent pathway. Significant reduction in tumour volume was seen in all 3 treatment arms as compared to controls. INTERPRETATION & CONCLUSIONS: Combination of suicide gene therapy and immunotherapy leads to successful tumour regression in a HNSCC xenograft mouse model. Immunotherapy could help in a systemic long lived anti-tumour immune response which would prove powerful for the treatment of metastatic cancers, and also for minimal residual disease. The results of this study may form the basis for Phase 1 clinical trials. PMID- 20966521 TI - Prevalence of JAK2 V617F mutation in Indian patients with chronic myeloproliferative disorders. AB - BACKGROUND & OBJECTIVES: The Janus-associated Kinase-2 mutation JAK2 V617F in chronic myeloproliferative disorders (CMPDs) has been described as a frequent genetic event in majority of patients with polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Its frequency varies in different populations but there are no data from India. We therefore, looked for JAK2 V617F mutation in Indian patients with chronic myeloproliferative disorders. METHODS: Mutation screening for JAK2 V617F in patients with polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis was performed in 75 patients attending Haematology clinic in a tertiary care hospital in north India, by polymerase chain reaction and restriction enzyme-based assay. RESULTS: JAK2 V617F mutation was found in 51 of 75 cases (68%) of CMPD, 82 per cent in PV, 70 per cent in ET and 52 per cent of IMF. The presence of JAK2 V617F mutation was associated with a higher haemoglobin level (P<0.05), a higher white blood cell count (P<0.01) and higher age (P<0.05). INTERPRETATION & CONCLUSION: The JAK2 V617F mutation was detected in 86 per cent of patients with CMPD disorders. Peripheral blood mutation screening for JAK2 V617F can be incorporated into the initial evaluation of patients suspected to have CMPD. PMID- 20966522 TI - Growing up with the families of beta-thalassaemia major using an accelerated longitudinal design. AB - BACKGROUND & OBJECTIVES: It is difficult for a single investigator to study the psychosocial changes that occur over the life span of an individual affected with a chronic illness like beta-thalassaemia major. Therefore, a developmental epidemiological perspective is required to understand the chain of events and problems of psychological nature. We aimed to construct the picture of developmental epidemiology for psychosocial aspects in families of beta thalassaemia major patients attending a tertiary care hospital in north India. METHODS: The accelerated longitudinal design was used. The sample consisted of 100 children with beta-thalassaemia and their 150 parents, both groups were subdivided further so that each group represented the continuum of longitudinal course. The sampling was done for a period of 16 months from January 2004 to April 2005. RESULTS: Overall 54 per cent of children had significant psychopathology. Within the parents groups, 10 per cent had adjustment disorder, 33.3 per cent depressive disorder, and 10 per cent had anxiety disorder and 11 per cent somatoform disorder; 95 per cent of the parents of newly diagnosed children expressed feeling of dazed and shock, fear of death, hopelessness, separation anxiety and problems with their memory and concentration. There was significant difference only in the domain of psychological health in all the three groups of parents with respect to the quality of life. Among children, quality of life improved with their progression of illness. Growing up with beta thalassaemic family was analyzed. INTERPRETATION & CONCLUSIONS: The developmental epidemiological perspective was constructed in beta -thalassaemic children and their family using an accelerated longitudinal design. Such a design can test the hypothesized aetiological or developmental function of a targeted risk factor within a developmental path and may be used in studying the psychological impact of even other chronic illnesses over the life span of an individual for conceptual and holistic understanding. PMID- 20966523 TI - Inverse sampling to study disease burden of leprosy. AB - BACKGROUND & OBJECTIVES: Estimation of disease burden due to leprosy by conventional sampling procedure is difficult due to large sample size requirement. In such situation, inverse sampling procedure could be a choice. A pilot study was undertaken to study the feasibility of adopting inverse sampling procedure over conventional sampling in an endemic area of Uttar Pradesh, India. METHODS: Two community development blocks one with high endemic, namely, Fatehganj, and other low endemic, Ramnagar, in Bareilly district of Uttar Pradesh, India, were selected. The Inverse sampling was adopted in Fatehganj and conventional cluster sampling was used in Ramnagar. As per the design of inverse sampling, 25 new cases of leprosy were to be detected from a population that could provide the cases. Under conventional sampling, a sample of 44,000 subjects (population) was targeted for the survey. RESULTS: In Fatehganj, 25 new cases of leprosy were detected from a sample of 14734 individuals. In Ramnagar, a total of 63 new cases of leprosy were found after covering a sample of 44686 individuals. Both the techniques provided similar estimates. The precision obtained under inverse sampling was though less than that under conventional sampling but found to be more feasible and suitable for estimation of leprosy due to less population to be covered, time and cost. INTERPRETATION & CONCLUSION: Our findings showed reveals that inverse sampling was advantageous over conventional sampling and could be adopted for the large scale survey at national level. PMID- 20966524 TI - Anti-ulcer & antioxidant activities of Hedranthera barteri {(Hook F.) Pichon} with possible involvement of H+, K+ ATPase inhibitory activity. AB - BACKGROUND & OBJECTIVE: Hedranthera barteri (HB) is used in folk medicine as a vermifuge, laxative and an anti-inflammatory agent. The aim of this study was to evaluate the anti-ulcer and antioxidant properties of the dichloromethane fraction of HB root (DMHBR). METHODS: Anti-ulcerogenic activity was assessed in cold-restraint (CRU), aspirin (ASP), alcohol (AL), pyloric ligation (PL) induced gastric ulcer models in rats and histamine-induced duodenal ulcer (HST) in guinea pigs. The effect of DMHBR (100 mg/kg) on gastric juice for free and total acidity, peptic activity and mucin secretion, using the pylorus ligated model, were evaluated. The H+, K+-ATPase activity was assayed in gastric microsomes, spectrophotometrically. The in vitro anti-oxidant assays were explored through DPPH, nitric oxide, hydroxyl radical, superoxide anion scavenging assays. RESULTS: DMHBR reduced the incidence of ulcers in CRU (63.3%), PL (58.5%), ASP (52.7%), HST (75.0%) and AL (53.87%). Also, reductions were observed in the free acidity (49.4%), total acidity (45.8%) and peptic activity (32.9%) with increase in the mucin secretion by 81.6 per cent. DMHBR (60-100 MUg/ml) inhibited the H+,K+-ATPase activity with IC50 of 89.64 MUg/ml compared with omeprazole (10-50 MUg/ml ) with IC50 of 32.26 MUg/ml. DMHBR showed antioxidant activity with IC50 values of DPPH (397.69 MUg/ml), nitric oxide (475.88 MUg/ml), hydroxyl radical (244.22 MUg/ml) and superoxide anion radical (285.20 MUg/ml). INTERPRETATION & CONCLUSION: DMHBR showed anti-ulcer activity against experimentally-induced peptic ulcer models and exhibited both cytoprotective and anti-secretory property. It exhibited a proton pump inhibition activity and its anti-ulcer properties may be partly ascribed to its antioxidant activities. PMID- 20966525 TI - Introducing pentavalent vaccine in EPI in India: issues involved. PMID- 20966526 TI - Pentavalent & other new combination vaccines: solutions in search of problems. PMID- 20966527 TI - Maternal mortality trends in India: Has the policy of promoting institutional delivery paid off? PMID- 20966528 TI - Antibiotic use for febrile illness in rural paediatric population: questions? PMID- 20966529 TI - Misrepresenting data: deception or dogma? PMID- 20966532 TI - Molecularly imprinted nanoparticles with recognition properties towards a laminin H-Tyr-Ile-Gly-Ser-Arg-OH sequence for tissue engineering applications. AB - Nanotechnology is an emerging field that promises to revolutionize medicine and is increasingly used in tissue engineering applications. Our research group proposed for the first time molecular imprinting as a new nanotechnology for the creation of advanced synthetic support structures for cell adhesion and proliferation. The aim of this work was the synthesis and characterization of molecularly imprinted polymers with recognition properties towards a laminin peptide sequence and their application as functionalization structures in the development of bioactive materials. Nanoparticles with an average diameter of 200 nm were synthesized by precipitation polymerization of methacrylic acid in the presence of the template molecule and trimethylpropane trimethacrylate as the cross-linking agent. The imprinted nanoparticles showed good performance in terms of recognition capacity and selectivity. The cytotoxicity tests showed normal vitality of C2C12 myoblasts cultured in the medium that was put in contact with the imprinted polymers. After the deposition on the polymeric film surface, the imprinted particles maintained their specific recognition and rebinding behaviour, showing an even higher quantitative binding than free nanoparticles. Preliminary in vitro cell culture tests demonstrated the ability of functionalized materials to promote cell adhesion, proliferation and differentiation, suggesting that molecular imprinting can be used as an innovative functionalization technique. PMID- 20966530 TI - Stressor-responsive central nesfatin-1 activates corticotropin-releasing hormone, noradrenaline and serotonin neurons and evokes hypothalamic-pituitary-adrenal axis. AB - A recently discovered satiety molecule, nesfatin-1, is localized in neurons of the hypothalamus and brain stem and colocalized with stress-related substances, corticotropin-releasing hormone (CRH), oxytocin, proopiomelanocortin, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). Intracerebroventricular (icv) administration of nesfatin-1 produces fear-related behaviors and potentiates stressor-induced increases in plasma adrenocorticotropic hormone (ACTH) and corticosterone levels in rats. These findings suggest a link between nesfatin-1 and stress. In the present study, we aimed to further clarify the neuronal network by which nesfatin-1 could induce stress responses in rats. Restraint stress induced c-Fos expressions in nesfatin-1-immunoreactive neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, and in the nucleus of solitary tract (NTS), locus coeruleus (LC) and dorsal raphe nucleus (DR) in the brain stem, without altering plasma nesfatin-1 levels. Icv nesfatin-1 induced c-Fos expressions in the PVN, SON, NTS, LC, DR and median raphe nucleus, including PVN-CRH, NTS-NA, LC-NA and DR-5-HT neurons. Nesfatin-1 increased cytosolic Ca2+ concentration in the CRH-immunoreactive neurons isolated from PVN. Icv nesfatin-1 increased plasma ACTH and corticosterone levels. These results indicate that the central nesfatin-1 system is stimulated by stress and activates CRH, NA and 5-HT neurons and hypothalamic-pituitary-adrenal axis, evoking both central and peripheral stress responses. PMID- 20966533 TI - Microfibrous beta-TCP/collagen scaffolds mimic woven bone in structure and composition. AB - Woven bone, as the initial form of bone tissue, is always found in developing and repairing bone. It is thought of as a temporary scaffold for the deposition of osteogenic cells and the laying down of lamellar bone. Thus, we hypothesize that a matrix which resembles the architecture and components of woven bone can provide an osteoblastic microenvironment for bone cell growth and new bone formation. In this study, woven-bone-like beta-tricalcium phosphate (beta TCP)/collagen scaffolds were fabricated by sol-gel electrospinning and impregnating methods. Optimization studies on sol-gel synthesis and electrospinning process were conducted respectively to prepare pure beta-TCP fibers with dimensions close to mineralized collagen fibrils in woven bone. The collagen-coating layer prepared by impregnation had an adhesive role that held the beta-TCP fibers together, and resulted in rapid degradation and matrix mineralization in in vitro tests. MG63 osteoblast-like cells seeded on the resultant scaffolds showed three-dimensional (3D) morphologies, and merged into multicellular layers after 7 days culture. Cytotoxicity test further revealed that extracts from the resultant scaffolds could promote the proliferation of MG63 cells. Therefore, the woven-bone-like matrix that we constructed favored the attachment and proliferation of MG63 cells in three dimensions. It has great potential ability to shorten the time of formation of new bone. PMID- 20966534 TI - Preparation and biological evaluation of a fibroblast growth factor-2-apatite composite layer on polymeric material. AB - A polymeric percutaneous device with good biocompatibility and resistance to bacterial infection is required clinically. In this study, a fibroblast growth factor-2 (FGF-2)-hydroxyapatite (HAp) composite layer (FHAp layer) was formed on the surfaces of ethylene-vinyl alcohol copolymer (EVOH) specimens using a coating process in a supersaturated calcium phosphate solution supplemented with FGF-2. FGF-2 in the FHAp layer retained its biological activity to promote proliferation of fibroblasts. The EVOH specimens coated with HAp and FHAp layers were percutaneously implanted in the scalp of rats. Not only the HAp layer but also the FHAp layer showed good biocompatibility, and FGF-2 showed no harmful effects on the skin tissue responses to the implanted specimen as long as 14 d. No significantly higher infection resistance was verified for the FHAp layer over the HAp layer, although an FHAp layer coated on a metallic percutaneous device for bone fixation demonstrated higher resistance to bacterial infection over an HAp layer in the previous study. The efficacy of FHAp layers coated on percutaneous implants in resistance to bacterial infection depends on physical factors including fixation condition, stiffness and movement of implants. PMID- 20966535 TI - Synthesis, structural and in vitro studies of well-dispersed monomethoxy poly(ethylene glycol)-honokiol conjugate micelles. AB - Honokiol, an active principle extracted from Magnolia officinalis, has great potential as a cancer treatment. However, its poor water solubility greatly hampers its delivery to the tumor sites at an effective concentration. In this study, an amphiphilic polymer-drug conjugate was successfully prepared by condensation of low molecular weight monomethoxy-poly(ethylene glycol) (MPEG) 2000 with honokiol (HK) through an ester linkage to increase the hydrophilicity of honokiol. The MPEG-honokiol (MPEG-HK) conjugate prepared formed nano-sized micelles, with a mean particle size of less than 20 nm (MPEG-HK, 360 ug ml(-1)) in water, which could be well dispersed in water. The nanoparticles obtained were characterized by particle size distribution, morphology and zeta potential. The stability and hydrolysis profile of the polymeric pro-drug in phosphate-buffered saline (PBS) and plasma were also studied and the results showed that only 20% of the conjugated honokiol was released in 2.0 h in beagle dog plasma, while in PBS the time required to reach 20% of honokiol release was >200 h. Meanwhile, the inhibitory activity of the honokiol conjugate was found to be retained in vitro against LL/2 cell lines with an IC50 value of 10.7 ug ml(-1). These results suggest that the polymer-drug conjugate provides a potential new approach to hydrophobic drugs, such as honokiol, in formulation design. PMID- 20966536 TI - Frequency- and amplitude-transitioned waveforms mitigate the onset response in high-frequency nerve block. AB - High-frequency alternating currents (HFAC) have proven to be a reversible and rapid method of blocking peripheral nerve conduction, holding promise for treatment of disorders associated with undesirable neuronal activity. The delivery of HFAC is characterized by a transient period of neural firing at its inception, termed the 'onset response'. The onset response is minimized for higher frequencies and higher amplitudes, but requires larger currents. However, the complete block can be maintained at lower frequencies and amplitudes, using lower currents. In this in vivo study on whole mammalian peripheral nerves, we demonstrate a method to minimize the onset response by initiating the block using a stimulation paradigm with a high frequency and large amplitude, and then transitioning to a low-frequency and low-amplitude waveform, reducing the currents required to maintain the conduction block. In five of six animals, it was possible to transition from a 30 kHz to a 10 kHz waveform without inducing any transient neural firing. The minimum transition time was 0.03 s. Transition activity was minimized or eliminated with longer transition times. The results of this study show that this method is feasible for achieving a nerve block with minimal onset responses and current amplitude requirements. PMID- 20966537 TI - An indirect component in the evoked compound action potential of the vagal nerve. AB - The vagal nerve plays a vital role in the regulation of the cardiovascular system. It not only regulates the heart but also sends sensory information from the heart back to the brain. We hypothesize that the evoked vagal nerve compound action potential contains components that are indirect via the brain stem or coming via the neural network on the heart. In an experimental study of 15 pigs, we identified four components in the evoked compound action potentials. The fourth component was found to be an indirect component, which came from the periphery. The latency of the indirect component increased when heart rate and contractility were decreased by burst stimulation (P = 0.01; n = 7). When heart rate and contractility were increased by dobutamine administration, the latency of the indirect component decreased (P = 0.01; n = 9). This showed that the latency of the indirect component of the evoked compound action potentials may relate to the state of the cardiovascular system. PMID- 20966538 TI - A composite SWNT-collagen matrix: characterization and preliminary assessment as a conductive peripheral nerve regeneration matrix. AB - Unique in their structure and function, single-walled carbon nanotubes (SWNTs) have received significant attention due to their potential to create unique conductive materials. For neural applications, these conductive materials hold promise as they may enhance regenerative processes. However, like other nano scaled biomaterials it is important to have a comprehensive understanding how these materials interact with cell systems and how the biological system responds to their presence. These investigations aim to further our understanding of SWNT cell interactions by assessing the effect SWNT/collagen hydrogels have on PC12 neuronal-like cells seeded within and (independently) on top of the composite material. Two types of collagen hydrogels were prepared: (1) SWNTs dispersed directly within the collagen (SWNT/COL) and (2) albumin-coated SWNTs prepared using the surfactant 'sodium cholate' to improve dispersion (AL-SWNT/COL) and collagen alone serving as a control (COL). SWNT dispersion was significantly improved when using surfactant-assisted dispersion. The enhanced dispersion resulted in a stiffer, more conductive material with an increased collagen fiber diameter. Short-term cell interactions with PC12 cells and SWNT composites have shown a stimulatory effect on cell proliferation relative to plain collagen controls. In parallel to these results, p53 gene displayed normal expression levels, which indicates the absence of nanoparticle-induced DNA damage. In summary, these mechanically tunable SWNT-collagen scaffolds show the potential for enhanced electrical activity and have shown positive in vitro biocompatibility results offering further evidence that SWNT-based materials have an important role in promoting neuronal regeneration. PMID- 20966539 TI - TS gene polymorphisms are not good markers of response to 5-FU therapy in stage III colon cancer patients. AB - AIM: Although the predictive and prognostic value of thymidylate synthase (TS) expression and gene polymorphism in colon cancer has been widely studied, the results are inconclusive probably because of methodological differences. With this study, we aimed to elucidate the role of TS gene polymorphisms genotyping in therapy response in stage III colon carcinoma patients treated with 5-FU adjuvant chemotherapy. PATIENTS AND METHODS: 251 patients diagnosed with stage III colon carcinoma treated with surgery followed by 5-FU based adjuvant therapy were selected. The variable number of tandem repeats (VNTR) and the single nucleotide polymorphism (SNP) in the 5'-untranslated region of the TS gene were genotyped. RESULTS: There was a positive association between tumor T stage and the VNTR genotypes (p=0.05).In both univariate and multivariate survival analysis no effects of the studied polymorphisms on survival were found. However, there was an association between both polymorphisms and age. Among patients younger than 60 years, the patients homozygous for 2R seemed to have a better overall survival, whereas among the patients older than 67 this longer survival was seen by the carriers of other genotypes. CONCLUSION: We conclude that the TS VNTR and SNP do not predict response to 5-FU therapy in patients with stage III colon carcinoma. However, age appears to modify the effects of TS polymorphisms on survival. PMID- 20966540 TI - ESR1 amplification is rare in breast cancer and is associated with high grade and high proliferation: a multiplex ligation-dependent probe amplification study. AB - BACKGROUND: Expression of estrogen receptor alpha (ERalpha) is predictive for endocrine therapy response and an important prognostic factor in breast cancer. Overexpression of ERalpha can be caused by estrogen receptor 1 (ESR1) gene amplification and was originally reported to be a frequent event associated with a significantly longer survival for ER-positive women treated with adjuvant tamoxifen monotherapy, which was however questioned by subsequent studies. METHODS: This study aimed to reanalyze the frequency of ESR1 amplification by multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridisation (FISH), and to assess clinicopathologic correlations. MLPA was performed in a group of 135 breast cancer patients, and gains/amplifications were subjected to FISH. RESULTS: True ESR1 amplification by MLPA was rare (2%) and only 6% more patients showed a modest gain of ESR1. All MLPA-detected ESR1 amplifications and nearly all ESR1 gains were also FISH amplified and gained, but not all FISH amplifications/gains were MLPA amplified/gained, leading to an overall concordance of only 60% between both techniques. All 3 MLPA and FISH ESR1 amplified cases had high ERalpha expression, but there was no obvious correlation between ESR1 gain and ER status by IHC. ESR1 gains/amplifications were not associated with HER2 gain/amplification, but seemed to be associated with older age. Surprisingly, ESR1 gain/amplification was not associated with low grade as reported previously, but correlated with high grade and high proliferation. Furthermore, ESR1 gain/amplification by MLPA was not associated with nodal status or tumor size (pT status). CONCLUSIONS: ESR1 amplification as detected by MLPA is rare in breast cancer, and seems to be associated with high ERalpha expression, high age, high grade and high proliferation. This study confirms previous studies that showed differences in the ESR1 amplification frequencies detected by different techniques. PMID- 20966541 TI - p21/waf1 and smooth-muscle actin alpha expression in stromal fibroblasts of oral cancers. AB - BACKGROUND: Concerted alterations between stromal fibroblasts and neoplastic cells underline the carcinogenic process. Activation of alpha-smooth muscle actin (SMA) expression, a cytoskeleton protein normally expressed only in myoepithelial cells, is considered a landmark for the activation of stromal fibroblasts with little however being known regarding the mechanism governing the expression of SMA in the stroma. METHODS: We have evaluated by immunohistochemistry the expression of SMA in the stroma of oral malignant and pre-malignant lesions, in association with the expression of p53 and p21 tumor suppressors that were shown previously to be deregulated and/or mutated in stromal fibroblasts of various cancers. The effects of p21 knockdown in SMA expression and cell migration and the mRNA levels of endogenous p21 in fibroblasts co-cultured with cancer cells were also assessed. RESULTS: We found that both p21 and SMA expression was elevated in the stroma, but not the epithelium, of malignant as compared to pre malignant lesions. We also noted that the expression of both was positively correlated, implying that SMA expression may be regulated by p21. Consistently with this notion we found that siRNA-mediated p21 suppression resulted in the reduction of SMA levels and also inhibited cell migration. CONCLUSION: Our results show that p21 deregulation is associated with the activation of stromal fibroblasts of oral cancers by a mechanism that involves the stimulation of SMA expression. PMID- 20966542 TI - Immunohistochemical expression and localization of somatostatin receptor subtypes in androgen ablated prostate cancer. AB - OBJECTIVE: The aim was to examine the expression and localization of the five somatostatin receptors (termed SSTR1-5) in radical prostatectomies (RPs) from patients with prostatic adenocarcinoma (PCa) under complete androgen ablation (CAA) before operation. MATERIAL: The five SSTRs were evaluated in the epithelial, smooth muscle and endothelial cells of normal-looking epithelium (Nep), high-grade prostatic intraepithelial neoplasia (HGPIN) and PCa in 20 RPs with clinically detected PCa from patients under CAA. 20 RPs with clinically detected PCa from hormonally untreated patients were used as control group. RESULTS: Concerning the secretory cells (i) membrane staining was seen for SSTR3 and SSTR4; the mean percentages of positive cells, higher in SSTR3 than in SSTR4, decreased sharply in HGPIN and PCa compared with Nep; the mean percentages in the androgen ablated group were 30-90% lower than in the untreated; (ii) cytoplasmic staining was seen for all 5 SSTRs; the mean percentages of positive cells in Nep, HGPIN and PCa of the untreated group were similar, and in general as high as 80% or more; in the treated group, the Nep values were similar to those in the untreated, whereas the values in HGPIN and PCa were lower for SSTR1, 3 and 5, with a decrease of 30% for SSTR1; (iii) nuclear staining was seen with SSTR4 and SSTR5, the mean percentages for the former being much lower than for the latter; treatment affected both HGPIN and PCa, whose proportions of stained cells were 30 55% lower than in the untreated group. Cytoplasmic staining in the basal cells was seen for all 5 SSTRs, both in Nep and HGPIN. The values in the treated group were lower than in the other, the difference between the two group being in general comprised between 10 and 40%. Treatment did not affect SSTR staining in the smooth muscle and endothelial cells. CONCLUSIONS: The present study expands our knowledge on the expression and localization of the five SSTRs in the prostate following CAA. PMID- 20966543 TI - Glioblastomas with oligodendroglial component - common origin of the different histological parts and genetic subclassification. AB - BACKGROUND: Glioblastomas are the most common and most malignant brain tumors in adults. A small subgroup of glioblastomas contains areas with histological features of oligodendroglial differentiation (GBMO). Our objective was to genetically characterize the oligodendroglial and the astrocytic parts of GBMOs and correlate morphologic and genetic features with clinical data. METHODS: The oligodendroglial and the "classic" glioblastoma parts of 13 GBMO were analyzed separately by interphase fluorescence in situ hybridization (FISH) on paraffin sections using a custom probe set (regions 1p, 1q, 7q, 10q, 17p, 19q, cen18, 21q) and by comparative genomic hybridization (CGH) of microdissected paraffin embedded tumor tissue. RESULTS: We identified four distinct genetic subtypes in 13 GBMOs: an "astrocytic" subtype (9/13) characterized by +7/-10; an "oligodendroglial" subtype with -1p/-19q (1/13); an "intermediate" subtype showing +7/-1p (1/13), and an "other" subtype having none of the former aberrations typical for gliomas (2/13). The different histological tumor parts of GBMO revealed common genetic changes in all tumors and showed additional aberrations specific for each part. CONCLUSION: Our findings demonstrate the monoclonal origin of GBMO followed by the development of the astrocytic and oligodendroglial components. The diagnostic determination of the genetic signatures may allow for a better prognostication of the patients. PMID- 20966544 TI - Activating mutation (V617F) in the tyrosine kinase JAK2 is absent in locally confined or castration-resistant prostate cancer. AB - BACKGROUND: Transcription factor Stat5a/b is highly critical for the viability of human prostate cancer cells in vitro and for prostate tumor growth in vivo. Stat5 is constitutively active in clinical prostate cancers but not in the normal human prostate epithelium. Moreover, Stat5a/b activation in prostate cancer is associated with high histological grade of prostate cancer. However, the molecular mechanisms underlying constitutive activation of Stat5a/b in prostate cancer are unclear. The receptor-associated tyrosine kinase Jak2 is a known key activator of Stat5a/b in prostate cancer cells in response to ligand stimulation. Recently, a single gain-of-function point mutation of JAK2 was described in myeloproliferative diseases leading to constitutive Jak2 kinase activity, subsequent Stat5a/b activation and involvement of V617F Jak2 in the pathogenesis of myeloproliferative disorders. MATERIALS AND METHODS: We determined whether JAK2 undergoes the V617F activating mutation during clinical progression of human prostate cancer using a highly sensitive assay (amplification refractory mutation system) and a unique material of fresh specimens from organ-confined or castration-resistant prostate cancers. RESULTS: The JAK2 V617F mutation was not found in any of the normal or malignant prostate samples analyzed in this study. CONCLUSIONS: Future work should focus on determining the molecular mechanisms other than V617F mutation of Jak2 resulting in continuous Stat5 activation in clinical prostate cancers. PMID- 20966545 TI - Gene expression in oligodendroglial tumors. AB - BACKGROUND: Oligodendroglial tumors with 1p/19q loss are more likely to be chemosensitive and have longer survival than those with intact 1p/19q, but not all respond to chemotherapy, warranting investigation of the biological basis of chemosensitivity. METHODS: Gene expression profiling was performed using amplified antisense RNA from 28 oligodendroglial tumors treated with chemotherapy (26 serial stereotactic biopsy, 2 resection). Expression of differentially expressed genes was validated by real-time PCR. RESULTS: Unsupervised hierarchical clustering showed clustering of multiple samples from the same case in 14/17 cases and identified subgroups associated with tumor grade and 1p/19q status. 176 genes were differentially expressed, 164 being associated with 1p/19q loss (86% not on 1p or 19q). 94 genes differed between responders and non responders to chemotherapy; 12 were not associated with 1p/19q loss. Significant differential expression was confirmed in 11/13 selected genes. Novel genes associated with response to therapy included SSBP2, GFRA1, FAP and RASD1. IQGAP1, INA, TGIF1, NR2F2 and MYCBP were differentially expressed in oligodendroglial tumors with 1p/19q loss. CONCLUSION: Gene expression profiling using serial stereotactic biopsies indicated greater homogeneity within tumors than between tumors. Genes associated with 1p/19q status or response were identified warranting further elucidation of their role in oligodendroglial tumors. PMID- 20966546 TI - Deletion of chromosome 4q predicts outcome in stage II colon cancer patients. AB - BACKGROUND: Around 30% of all stage II colon cancer patients will relapse and die of their disease. At present no objective parameters to identify high-risk stage II colon cancer patients, who will benefit from adjuvant chemotherapy, have been established. With traditional histopathological features definition of high-risk stage II colon cancer patients is inaccurate. Therefore more objective and robust markers for prediction of relapse are needed. DNA copy number aberrations have proven to be robust prognostic markers, but have not yet been investigated for this specific group of patients. The aim of the present study was to identify chromosomal aberrations that can predict relapse of tumor in patients with stage II colon cancer. MATERIALS AND METHODS: DNA was isolated from 40 formaldehyde fixed paraffin embedded stage II colon cancer samples with extensive clinicopathological data. Samples were hybridized using Comparative Genomic Hybridization (CGH) arrays to determine DNA copy number changes and microsatellite stability was determined by PCR. To analyze differences between stage II colon cancer patients with and without relapse of tumor a Wilcoxon rank sum test was implemented with multiple testing correction. RESULTS: Stage II colon cancers of patients who had relapse of disease showed significantly more losses on chromosomes 4, 5, 15q, 17q and 18q. In the microsatellite stable (MSS) subgroup (n=28), only loss of chromosome 4q22.1-4q35.2 was significantly associated with disease relapse (p<0.05, FDR<0.15). No differences in clinicopathological characteristics between patients with and without relapse were observed. CONCLUSION: In the present series of MSS stage II colon cancer patients losses on 4q22.1-4q35.2 were associated with worse outcome and these genomic alterations may aid in selecting patients for adjuvant therapy. PMID- 20966547 TI - Automated analysis of protein expression and gene amplification within the same cells of paraffin-embedded tumour tissue. AB - BACKGROUND: The simultaneous detection of protein expression and gene copy number changes in patient samples, like paraffin-embedded tissue sections, is challenging since the procedures of immunohistochemistry (IHC) and Fluorescence in situ Hybridization (FISH) negatively influence each other which often results in suboptimal staining.Therefore, we developed a novel automated algorithm based on relocation which allows subsequent detection of protein content and gene copy number changes within the same cell. METHODS: Paraffin-embedded tissue sections of colorectal cancers were stained for CD133 expression. IHC images were acquired and image coordinates recorded. Slides were subsequently hybridized with fluorescently labeled DNA probes. FISH images were taken at the previously recorded positions allowing for direct comparison of protein expression and gene copy number signals within the same cells/tissue areas. Relocation, acquisition of the IHC and FISH images, and enumeration of FISH signals in the immunophenotyped tumour areas were done in an automated fashion. RESULTS: Automated FISH analysis was performed on 13 different colon cancer samples that had been stained for CD133; each sample was scored for MYC, ZNF217 and Chromosome 6 in CD133 positive and negative glands. From the 13 cases four (31%) showed amplification for the MYC oncogene and seven of 13 (54%) cases were amplified for ZNF217. There was no significant difference between CD133 positive tumour and CD133 negative tumour cells. CONCLUSION: The technique and algorithm presented here enables an easy and reproducible combination of IHC and FISH based on a novel automated algorithm using relocation and automated spot counting. PMID- 20966550 TI - A novel perspective for Alzheimer's disease: vitamin D receptor suppression by amyloid-beta and preventing the amyloid-beta induced alterations by vitamin D in cortical neurons. AB - Amyloid-beta (Abeta) is the core component of amyloid plaques of Alzheimer's disease (AD). The effects of Abeta include damage to neuronal plasma membrane, disruption of Ca(2+) homeostasis, and alterations of neurotrophic factor levels. The aim of this study was to determine the effects of Abeta treatment on vitamin D receptor (VDR), L-type voltage sensitive calcium channels A1C (LVSCC A1C), NGF, and observing the effects of vitamin D treatment on Abeta induced alterations in primary cortical neurons. As to the latter, we aimed to test the suggested neuroprotective role of vitamin D as a neglected neurosteroid. The expressions of VDR and LVSCC A1C were studied with qRT-PCR and Western blotting. NGF and cytotoxicity levels were determined by ELISA. Apoptotic cell death was investigated with caspase-3 protein expression by Western blotting. Our results showed that the Abeta triggers neurodegeneration not only by inducing LVSCC A1C expression and NGF levels and but also by dramatically suppressing VDR expression. Administration of vitamin D to this model protected neurons by preventing cytotoxicity and apoptosis, and also by downregulating LVSCC A1C and upregulating VDR. Additionally, vitamin D brought NGF expression to a state of equilibrium and did not show its apoptosis inducing effects. Consequently, prevention of Abeta toxicity which was one of the major component of AD type pathology by vitamin D treatment and understanding how Abeta effects vitamin D related pathways, might open up new frontiers in clarifying molecular mechanisms of neurodegeneration and provide basis for novel perspectives in both preventing and treating AD. PMID- 20966549 TI - Passive (amyloid-beta) immunotherapy attenuates monoaminergic axonal degeneration in the AbetaPPswe/PS1dE9 mice. AB - The role of amyloid-beta (Abeta in the neurodegeneration of Alzheimer's disease remains controversial, to a large extent because of the lack of robust neurodegeneration in mouse models of AD. To address this question, we examined the effects of Abeta antibodies in the recently described monoaminergic (MAergic) axonal degeneration in AbetaPPswe/PS1dE9 mice. To determine if Abeta accumulation is directly involved in degeneration of MAergic axons, we examined the effects of passive anti-Abeta antibody (7B6) administration on Abeta pathology and MAergic degeneration in AbetaPPswe/PS1dE9 mice. Injections of monoclonal antibody (mAb) 7B6 into mice (6 to 9 months of age) resulted in a modest reduction of Abeta load in the brains of AbetaPPswe/PS1dE9 mice. In addition, 7B6 treated AbetaPPswe/PS1dE9 mice had significantly higher densities of MAergic axons in both cortex and in hippocampus as compared to untreated mutant mice. For example, 7B6 treated mice showed almost 2-fold greater densities of serotonergic (5-HT) axons in the cortex compared to saline treated mice. Similar findings were observed in the catecholaminergic (TH) axons. Our results demonstrate that lowering of Abeta levels via passive Abeta immunotherapy ameliorates ongoing degenerative processes, supporting a causal link between Abeta and neurodegeneration. PMID- 20966551 TI - Hyperphosphorylated truncated protein tau induces caspase-3 independent apoptosis like pathway in the Alzheimer's disease cellular model. AB - Neurofibrillary degeneration and neuronal loss represent key pathological hallmarks of Alzheimer's disease (AD). It has been demonstrated that the decrease of total neuronal numbers correlates with the presence of neurofibrillary degeneration in AD brain. In order to unravel the mechanism leading to the cell death in AD, we developed a stably transfected human neuroblastoma cellular model with doxycycline-regulatable expression of AD truncated tau protein (AT tau, 151 391 4R). Cells expressing the longest tau isoform (Tau 40) were used as a control. We found that more than 80% of the total amount of AT tau and Tau 40 were phosphorylated. Strikingly, both AT tau and Tau 40 reduced the metabolic activity of the cells in a time-dependent manner (p < 0.0001) suggesting that tau overexpression slows down cell proliferation. However, AT tau showed significantly higher toxicity than Tau 40 (p < 0.0001), which indicates that truncation leads to a toxic gain of function. The analysis of the type of the cell death revealed the characteristic features of apoptosis such as cell shrinkage, nuclear, and DNA fragmentation. However, we did not find either the activation of executive caspase (caspase-3) or the caspase cleavage products (PARP and fodrin). These results show that posttranslationally modified truncated tau protein induces caspase-3-independent apoptosis-like programmed cell death, a phenomenon we term tauoptosis. PMID- 20966553 TI - New Delhi metallo-beta-lactamase 1: is there a need to worry? PMID- 20966552 TI - Automated detection of amyloid-beta-related cortical and subcortical signal changes in a transgenic model of Alzheimer's disease using high-field MRI. AB - In vivo imaging of amyloid-beta (Abeta) load as a biomarker of Alzheimer's disease (AD) would be of considerable clinical relevance for the early diagnosis and monitoring of treatment effects. Here, we investigated automated quantification of in vivo T2 relaxation time as a surrogate measure of plaque load in the brains of ten AbetaPP/PS1 transgenic mice (age 20 weeks) using in vivo MRI acquisitions on a 7T Bruker ClinScan magnet. AbetaPP/PS1 mice present with rapid-onset cerebral beta-amyloidosis, and were compared with eight age matched, wild-type control mice (C57Bl/6J) that do not develop Abeta-deposition in brain. Data were analyzed with a novel automated voxel-based analysis that allowed mapping the entire brain for significant signal changes. In AbetaPP/PS1 mice, we found a significant decrease in T2 relaxation times in the deeper neocortical layers, caudate-putamen, thalamus, hippocampus, and cerebellum compared to wildtype controls. These changes were in line with the histological distribution of cerebral Abeta plaques and activated microglia. Grey matter density did not differ between wild-type mice and AbetaPP/PS1 mice, consistent with a lack of neuronal loss in histological investigations. High-field MRI with automated mapping of T2 time changes may be a useful tool for the detection of plaque load in living transgenic animals, which may become relevant for the evaluation of amyloid lowering intervention effects in future studies. PMID- 20966554 TI - Hospital antibiogram: a necessity. AB - The hospital antibiogram is a periodic summary of antimicrobial susceptibilities of local bacterial isolates submitted to the hospital's clinical microbiology laboratory. Antibiograms are often used by clinicians to assess local susceptibility rates, as an aid in selecting empiric antibiotic therapy, and in monitoring resistance trends over time within an institution. Antibiograms can also used to compare susceptibility rates across institutions and track resistance trends. Some hospitals have adequate support from the computer department to be able to extract data from their reporting module. The WHONET software can be freely downloaded and used for analysis. Consensus guidelines have been developed by the Clinical and Laboratory Standards Institute (CLSI) to standardise methods used in constructing antibiograms. These guidelines can be incorporated into the WHONET software for analysis. Only the first isolate from the patient is to be included in the analysis. The analysis should be done on the basis of patient location and specimen type. The percentage susceptibility of the most frequently isolated bacteria should be presented in the antibiogram, preferably in a tabular form. The antibiogram must be printed or put up in the intranet for easy access to all clinicians. Antibiotic policy is one of the mandatory requirements for accreditation, and making an antibiogram is the first step before framing the antibiotic policy. The future of antibiograms would be the incorporation of patient related data to make information more reliable and for predicting outbreaks. PMID- 20966555 TI - Diagnosis of tuberculosis in an era of HIV pandemic: a review of current status and future prospects. AB - HIV and tuberculosis co-infection interact in fundamentally important ways. This interaction is evident patho-physiologically, clinically and epidemiologically. There are several differences between HIV-infected and HIV-uninfected patients with tuberculosis (TB) that have practical diagnostic implications. TB is more likely to be disseminated in nature and more difficult to diagnose by conventional diagnostic procedures as immunosuppression progresses. As TB rates continue to increase in HIV-endemic regions, improved diagnostic techniques merit consideration as TB-control strategies. There is a need to develop more user friendly techniques, which can be adapted for use in the high-burden and low income countries. This review focuses on the diagnostic challenges in HIV-TB co infection with an update on the current techniques and future prospects in an era of HIV pandemic. PMID- 20966556 TI - Study of HIV-1 subtypes in serodiscordant couples attending an integrated counselling and testing centre in Mumbai using heteroduplex mobility analysis and DNA sequencing. AB - AIMS: To determine the prevalent subtypes of HIV-1 in serodiscordant couples. SETTING: Integrated Counselling and Testing Centre (ICTC), Department of Microbiology. STUDY DESIGN: Prospective pilot study. PARTICIPANTS: Thirty HIV-1 serodiscordant couples. INCLUSION CRITERIA: a) Documentation of HIV-1 infection in one partner and seronegative status in the other, current history of continued unprotected sexual activity within the partnership, demonstration that they have been in a partnership for at least 1 year and are not currently on highly active antiretroviral therapy HAART; b) willingness of both partners to provide written informed consent including consent to continued couple counselling for 3 months. MATERIALS AND METHODS: HIV-1 subtyping was carried out by heteroduplex mobility analysis (HMA) by amplifying env region; and DNA sequencing by amplifying gag region. RESULTS: HIV-1 env gene was amplified successfully in 10/30 samples; gag gene, in 25/30 samples; and both env and gag gene were amplified successfully in 5/30 samples. HIV-1 subtype C was detected from 21 samples; subtype B, from 7; and subtype A, from 2. Sample from 1 positive partner was detected as subtype C by env HMA and subtype B by gag sequencing. CONCLUSION: HIV-1 subtype C was found to be the predominant subtype of HIV-1 in serodiscordant couples attending our ICTC, followed by HIV-1 subtype B and HIV-1 subtype A, respectively. DNA sequencing was found to be the most reliable method for determining the subtypes of HIV-1. PMID- 20966557 TI - Evaluation of Calypte AWARE HIV-1/2 OMT antibody test as a screening test in an Indian setting. AB - PURPOSE: Integrated counselling and testing centres (ICTC) provide counselling and blood testing facilities for HIV diagnosis. Oral fluid tests provide an alternative for people who do not want blood to be drawn. Also, it avoids the risk of occupational exposure. The goal of this study was to evaluate the utility of Calypte AWARE HIV-1/2 OMT antibody test as a screening test in an Indian setting. MATERIALS AND METHODS: A cross-sectional study was carried out after ethics committee approval in 250 adult ICTC clients. Blood was collected and tested from these clients for HIV diagnosis as per routine policy and the results were considered as the gold standard. Also, after another written informed consent, oral fluid was collected from the clients and tested for the presence of HIV antibodies. Twenty five clients who had and 25 clients who had not completed their secondary school education (Group A and Group B, respectively) were also asked to perform and interpret the test on their own and their findings and experiences were noted. RESULT: The sensitivity, specificity, PPV and NPV of the oral fluid antibody test were 100%, 98.51%, 94.11% and 100%, respectively. Seventy six percent of clients preferred oral fluid testing. Group B found it difficult to perform the test as compared to Group A and this difference was statistically significant (P <= 0.05). CONCLUSION: Oral fluid testing can be used as a screening test for HIV diagnosis; however, confirmation of reactive results by blood-based tests is a must. PMID- 20966558 TI - Molecular characterization of Chikungunya virus during an outbreak in South India. AB - INTRODUCTION: Re-emergence of Chikungunya is a major public health problem in the southern states of India. OBJECTIVES: This study was undertaken to investigate an outbreak of Chikungunya, in June-August 2008 using PCR and determine the prevalent genotypes of Chikungunya virus (CHIKV) associated with the outbreak. MATERIALS AND METHODS: Samples of blood were collected (in heparinized vacutainer tubes) from suspected patients of CHIKV infection from both Government Taluk Hospital in Kerala and a tertiary care hospital in Chennai, Tamil Nadu. A one step RT-PCR was carried out on a block thermo-cycler targeting the E2 gene that codes for the viral envelope protein. The amplicons were verified for 305 bp size by standard agarose gel electrophoresis. The PCR products were purified, sequenced, and compared with other CHIKV strains reported from different geographical regions. A phylogenetic tree was constructed using MEGA 4. RESULTS: Altogether 118 samples were collected from patients who presented with sudden onset of fever and/or joint pain, myalgia, and headache. CHIKV infection was confirmed by RT-PCR in 14 patients and all these cases were from Kerala. The positivity correlated with the early stage of the disease as all these patients had fever of less than seven days duration. The study isolates have been allotted the GenBank accession nos. GQ272368-GQ272381. Phylogenetic analysis of recent CHIKV isolates by partial sequencing of E2 region shows that isolates are closely related to strains from neighboring states and the African type. CONCLUSION: RT PCR is a useful technique for the early detection of CHIKV infection during outbreaks. Molecular characterization of the strains indicates that majority of the strains have originated from the Central/East African strains of CHIKV. PMID- 20966559 TI - Comparative evaluation of two polymerase chain reactions targeting different genomic regions to detect Mycobacterium tuberculosis in sputum. AB - PURPOSE: Tuberculosis remains an important health problem all over the world, especially in resource poor settings like India. The Ziehl-Neelsen (ZN) staining of sputum smear is still the method of choice in the diagnosis of tuberculosis in spite of its low sensitivity and specificity. This paper evaluates comparison of two different polymerase chain reaction (PCR) assays with sputum smear findings to detect Mycobacterium tuberculosis. MATERIALS AND METHODS: A total of 191 sputum samples were collected from 84 patients attending a tertiary care hospital, who were suspected of having pulmonary tuberculosis, were examined by PCR targeting two different genomic regions, namely, TRC 4 by non-nested format and IS6110 insertion element by nested format in comparison to ZN staining of sputum smears. RESULTS: Among the patients tested, 20.24% (Mid-p 95%CI: 31.5 52.4) were smear positive, 7.14% (Mid-p 95%CI: 2.94-14.26) were positive by TRC 4 PCR and 41.67% (Mid-p 95%CI: 12.7-29.8) were positive by IS6110 nested PCR (nPCR). The median age of overall positive cases was 42 years. Among the nPCR positives, the median for age of rural and peri-urban community was 46 and 32 years, respectively. The kappa coefficient between smear findings and TRC4 PCR findings was 0.27 and an agreement of 0.83 was observed (Z = 2.99; one-tailed P = 0.001). TRC 4 PCR picked two unique positives that were negative by smear and IS6110 nPCR. CONCLUSION: The non-nested TRC 4 PCR showed inability for accurate detection of M. tuberculosis in sputum samples. The study concluded that the nPCR targeting IS6110 is superior and more sensitive than TRC 4 PCR. PMID- 20966560 TI - Lateral flow assay for rapid differentiation of Mycobacterium tuberculosis complex and 97 species of mycobacteria other than tuberculosis grown in Lowenstein-Jensen and TK-SLC medium. AB - BACKGROUND: Mycobacterial antigen MPB64 is a secretory protein specific for Mycobacterium tuberculosis complex. A lateral flow immunochromatographic assay (ICA) is a method used for the rapid differentiation of M. tuberculosis complex. AIM: We aimed to evaluate the performance of ICA in rapid differentiation of M. tuberculosis complex from 97 Mycobacterium species other than tuberculosis (MOTT), which are grown in Lphiwenstein-Jensen and TK-selective (SLC) medium. MATERIALS AND METHODS: The study was performed in our laboratory between January 2009 and January 2010. A total of 394 isolates consisting of reference strains of 34 M. tuberculosis from World Health Organization (WHO) collection, 97 different MOTT bacilli, 7 Mycobacterium bovis BCG substrains and total 256 clinical Mycobacterium isolates were tested by ICA, which is based on anti-MPB64 monoclonal antibodies. All the strains were inoculated onto a TK-SLC (selective) medium and Lowenstein-Jensen medium. TK-SLC is a new rapid mycobacterial culture medium that indicates mycobacterial growth by colour change. RESULTS: The growth of mycobacterial strains was observed in 10-12 days on TK-SLC medium. ICA test was performed in 15 minutes. All strains belonging to M. tuberculosis complex group were found positive and all MOTT species were found negative on ICA slides. The results were confirmed with nucleic acid amplification by polymerase chain reaction (PCR) using primers specific for M. tuberculosis complex. CONCLUSION: With the additive effect of growth on TK-SLC medium in 10-12 days, the mycobacterial antigen MPB64 is a very useful and specific tool in rapid differentiation of M. tuberculosis and MOTT grown in culture. PMID- 20966561 TI - Serotype markers in a Streptococcus agalactiae strain collection from Zimbabwe. AB - OBJECTIVE: Group B streptococci (GBS) from Southern African areas have been less well characterized. Our objective was to study serotype and serovariant distribution of carrier GBS strains as part of a study of the epidemiology of GBS carriage in pregnant women from Zimbabwe. MATERIALS AND METHODS: We studied GBS isolated from 121 healthy pregnant women living in Harare and surrounding areas, Zimbabwe. Capsular polysaccharide (CPS) testing for serotype determination and surface-anchored protein testing for serosubtype determination were done by gene based serotyping (PCR), except for the proteins R3 and a novel protein called Z, which were detected by antibody-based methods. RESULTS: Strains of the CPS types Ia (15.7%), Ib (11.6%), II (8.3%), III (38.8%), V (24.0%) and NT (1.7%) were detected along with the strain-variable proteins Ciota (15.7% of isolates), Calpha (19.8%), Alp1 (epsilon-22.3%), Alp3 (5.0%), R4/Rib (46.3%), R3 (27.3%), Z (27.3%), and SAR5 (28.9%), which encodes the R5 protein. Up to four of the protein genes could be possessed or the gene product expressed by one and the same isolate. A total of 32 serovariants were detected. The findings assessed by us as most important were the very low prevalence of the gene Alp3 (Alp3--4.9%), high prevalence of R4 (Rib--46.2%), the proteins R3 (27.3%), Z (27.3%), and of SAR5 (R5--28.9%). The low prevalence of Alp3, notably in GBS type V strains, differed from findings with CPS type V GBS from non-African areas. Bacteria of the various CPS types showed distinct CPS/protein-marker associations. CONCLUSION: The results are of importance in relation to regional variations of GBS phenotypes and genotypes and thus, of importance in planning and research in the context of future vaccine formulations. PMID- 20966562 TI - Comparison of scpB gene and cfb gene polymerase chain reaction assays with culture on Islam medium to detect Group B Streptococcus in pregnancy. AB - PURPOSE: The purpose of the current study was to evaluate two low-costing PCR assays for rapid detection of Group B Streptococcus (GBS) in comparison to a pigment-based culture method. MATERIALS AND METHODS: One-hundred and fifty vaginal swabs were collected from pregnant women at 35-40 weeks of gestation. Vaginal swabs were inoculated in selective enrichment broth medium, and examined using Islam medium, cfb PCR and scpB PCR assays. The demographic data were analysed to identify independent predictors of GBS colonization (age and gravidity), with GBS status as the dependent variable. RESULTS: There was a significant association of age and gravidity with GBS colonization. GBS was detected in 25.3% of isolates by Islam medium, in 30.6% by using the cfb PCR assay and in 30% by using the scpB PCR assay. CONCLUSION: Older pregnant women (>=30 years) and multigravida (>3 pregnancies) are at higher risk of GBS colonization. Both scpB-gene and cfb-gene-based PCR methods are highly sensitive techniques (100% sensitivity) compared to culture method. However, the specificities of the scpB and cfb PCR assays were 93.75 and 92.85%, respectively. PMID- 20966563 TI - Diagnosis and follow-up of genital chlamydial infection by direct methods and by detection of serum IgG, IgA and secretory IgA. AB - PURPOSE: To determine the prevalence of Chlamydia trachomatis infection in a high risk population by direct and indirect methods and to evaluate the diagnosis of secretory immunoglobulin A (sIgA). PATIENTS AND METHODS: Urethral or endocervical specimens from 78 patients (48 females and 30 males) were examined by cell culture, direct fluorescence assay, PCR Cobas Amplicor (Roche Molecular Diagnostics), and sIgA was detected by the recombinant lipopolysaccharide (LPS) enzyme-linked immunoassay (rELISA). Serum from each patient was also obtained and analysed for the presence of IgG and IgA antibody by in-house microimmunofluorescence (MIF) and by the rELISA method (Medac, Hamburg, Germany). RESULTS: The overall C. trachomatis prevalence determined by direct methods was 28%. The detection of sIgA antibodies was significantly higher in the group of patients with a positive direct detection (50%) than in the group of negative direct detection (10.7%). The Chlamydia-specific IgA antibodies were detected by the rELISA in 40.9 and 53.6% of group I (positive direct detection) and group II patients (negative direct detection), respectively. The species-specific IgA antibodies were detected by the MIF method in 18.2 and 16.1% of group I and II patients, respectively. Chlamydia genus-specific IgG antibodies were detected by the rELISA in 86.4 and 83.9% of group I and group II patients and, C. trachomatis specific IgG were present in 81.8 and 73.2% of group I and group II patients, respectively, as assessed by the MIF test. CONCLUSION: Combining the positive direct methods and/or positive sIgA antibody results from cervical or urethral specimens had an indication of current C. trachomatis infection. PMID- 20966564 TI - Real-time polymerase chain reaction for rapid detection of genes encoding SHV extended-spectrum beta-lactamases. AB - PURPOSE: This study aimed to develop an improved method for the detection of bacterial SHV-type extended-spectrum beta-lactamases (ESBLs). MATERIALS AND METHODS: Our method was based on real-time polymerase chain reaction (PCR) in which the amplification of the product was monitored with a fluorescent probe. This method enabled the detection of bla SHV genes with high degrees of sensitivity and specificity. RESULTS: Based on ESBL phenotyping methods and bla gene DNA sequencing, we identified 240 bla genes from 662 Enterobacteriaceae isolated from clinical culture specimens. Of these 240 isolates, 26 had the bla SHV-28 genotype and three had the bla SHV-1 genotype. With our new real-time PCR assay, we detected 29 out of 29 bla SHV genes in ESBL-producing isolates. CONCLUSION: This method represents a powerful tool for epidemiological studies of SHV ESBLs. Furthermore, it has potential for use in diagnostic microbiology. PMID- 20966565 TI - Prevalence of virulence factors and antibiotic resistance in vancomycin-resistant Enterococcus faecium isolated from sewage and clinical samples in Iran. AB - PURPOSE: The purpose of the present study was to perform a molecular epidemiological survey by investigating the antibiotic resistance and the presence of known virulence factors in Enterococcus faecium isolates in Iran. The data collected from this study would allow us to control the spread and develop strategies for treatment of the enterococcal infections. MATERIALS AND METHODS: In this study, 156 vancomycin-sensitive E. faecium (VSEF; 58) and vancomycin resistant E. faecium (VREF; 98) samples were isolated from clinical specimen and sewage treatment plants (STPs). These isolates were screened for the presence of genes encoding for aggregation substance (asa1), cytolysin (cyl), enterococcal surface protein (esp), gelatinase (gelE) and hyaluronidase (hyl) by polymerase chain reaction (PCR). RESULTS: Although significantly different, the results showed the presence of hyl and esp genes in both clinical (41 and 75%, respectively) and sewage (3.2 and 41%, respectively) isolates. Sensitivity of all isolates to seven antibiotics was examined. The results of the clinical isolates showed that the majority of esp positive isolates were also resistant to vancomycin, ciprofloxacin and erythromycin. Furthermore, cyl, gelE and asa1 were not found in either clinical or STP isolates. Finally, we determined the distinct types of isolates using Pulse Field Gel Electrophoresis (PFGE), which confirmed that most of the isolates were clonally unrelated. CONCLUSION: Our results demonstrated that higher number of the clinical E. faecium isolates carried virulence genes than the isolates from STP. Finally, the lack of the genes in clinical and STP isolates confirmed that these genes do not transfer horizontally. PMID- 20966566 TI - Surveillance of device-associated infections at a teaching hospital in rural Gujarat--India. AB - PURPOSE: Surveillance of hospital-acquired infection (HAI), particularly device associated infection (DAI), helps in determining the infection rates, risk factors, and in planning the preventive strategies to ensure a quality healthcare in any hospital. The present study was carried out to know the prevalence of DAI in a tertiary care teaching hospital of rural Gujarat. MATERIALS AND METHODS: A prospective, site-specific surveillance of three common DAIs that is catheter associated urinary tract infection (CA-UTI), IV-catheter-related bloodstream infection (IV-CRBSI), and ventilator-associated pneumonia (VAP) was carried out between July 2007 and April 2008, in different wards/ICUs. A surveillance plan, with guidelines and responsibilities of nurses, clinicians and microbiologist was prepared. Infection surveillance form for each patient suspected to have DAI was filled. The most representative clinical sample, depending on the type of suspected DAI, was collected using standard aseptic techniques and processed for aerobes and facultative anaerobes. All the isolates were identified and antimicrobial sensitivity testing performed as per CLSI guidelines. An accurate record of total device days for each of the indwelling devices under surveillance was also maintained. Data, collected in the prescribed formats, were analysed on monthly basis; and then, compiled at the end of the study. Descriptive analysis of the data was done and DAI rate was expressed as number of DAI per 1000 device days. RESULTS: The overall infection rate for CA-UTI, IV-CRBSI, and VAP were found to be 0.6, 0.48, and 21.92 per 1000 device days, respectively. The organisms isolated were Staphylococcus aureus, CONS, Enterococci, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. CONCLUSIONS: Duration of indwelling devices was found to be the major risk-factor for acquiring DAIs. Low DAI rate might have been due to use of antibiotics, often prophylactic. Active surveillance is quite a tedious and time-consuming process; however the outcome is useful in prevention and control of DAIs. PMID- 20966567 TI - Utility of in vitro proton magnetic resonance spectroscopy in aetiological characterisation of brain abscesses. AB - PURPOSE: Brain abscesses often present an aetiological dilemma. Microscopy is insensitive and culture techniques are time consuming. Hence, a new rapid technique in vitro Proton Magnetic Resonance Spectroscopy (1HMRS) was evaluated for its usefulness in the identification of aetiology of brain abscesses. MATERIALS AND METHODS: A total of 39 pus specimens from brain abscesses were subjected to in vitro 1HMRS. These pus specimens were also processed by conventional culture methods. The spectral patterns generated by in vitro 1HMRS were further correlated with culture results. RESULTS: Pus specimens which showed the presence of anaerobes on culture revealed the presence of multiplet at 0.9 ppm (100%), lactate-lipid at 1.3 ppm (100%), acetate at 1.92 ppm (100%) and succinate at 2.4 ppm (75%). Pus specimens that revealed the presence of facultative anaerobes on culture showed a pattern B, i.e., the presence of lactate-lipid at 1.3 ppm (100%), acetate at 1.92 ppm (88.88%) along with the multiplet at 0.9 ppm (100%). Pattern C was seen in aerobic infection which showed the presence of lactate-lipid at 1.3 ppm (100%) along with the multiplet at 0.9 ppm. Pus from two tuberculous abscesses showed the complete absence of multiplet at 0.9 ppm. CONCLUSIONS: We observed in this study that it was possible to differentiate bacterial and tuberculous brain abscesses using in vitro 1HMRS. Further, it was also possible to distinguish between aerobic and anaerobic brain abscesses on the basis of spectral patterns. In vitro 1HMRS of fungal and actinomycotic brain abscess are also presented for its unusual spectra. PMID- 20966568 TI - IgG--indirect fluorescent antibody technique to detect seroprevalence of Toxoplasma gondii in immunocompetent and immunodeficient patients in southern districts of Tamil Nadu. AB - PURPOSE: The purpose of the study was to determine the prevalence of Toxoplasma antibodies in selected immunocompetent and immunodeficient patients in and around Tirunelveli District of Tamil Nadu. MATERIALS AND METHODS: This study was carried out from May 2006 to October 2007 in 175 immunodeficient and 175 immunocompetent patients. Serum samples were subjected into in-house IgG assay using indirect fluorescent antibody test (IFAT). RESULTS: Out of 350 patients tested by IgG IFAT, 41 (11.71%) had antibodies for Toxoplasma gondii with a mean IFA titre of 43.42 +/- 58.7 and the titre ranging from 1 : 16 to 1 : 256. Among the immunocompetent and immunodeficient groups, 19 patients (10.86%) and 22 patients (12.57%), respectively, had antibodies to T. gondii. Various risk factors associated within the study group was analysed and results were interpreted. CONCLUSIONS: The study has highlighted an overall seroprevalence of 11.71% with 12.57% in immunocompromised and 10.86% in immunocompetent patients respectively in a southern district, Tamil Nadu, which underlines the importance of screening of this parasite especially in the immunocompromised patients. PMID- 20966569 TI - Prevalence of hepatitis C virus genotypes and impact of T helper cytokines in achieving sustained virological response during combination therapy: a study from Central India. AB - Characterisation of host immune response to hepatitis C virus (HCV) genotypes may have an important prognostic and therapeutic implication. Genotype-3 was more prevalent in the examined cohort and demonstrated a significantly higher response to combination therapy than genotype-1. Sustained virological response (SVR) was 94.74% in genotype-3 and 45.45% in genotype-1. The patients who achieved SVR reported higher levels of circulating T helper 1 cytokines in comparison to subjects with no SVR in both the studied groups. Besides providing local prevalence, our study might also assist in understanding the host immune mechanisms involved to achieve SVR during combination therapy in chronic HCV patients. PMID- 20966570 TI - Evaluation of nitrate reductase assay for direct detection of drug resistance in Mycobacterium tuberculosis: rapid and inexpensive method for low-resource settings. AB - The aim of this study was to evaluate a nitrate reductase assay (NRA) for the direct detection of multidrug resistance (MDR) in Mycobacterium tuberculosis from 100 smear-positive sputum samples. The NRA results were compared with the reference proportion method for 100 sputum specimens for which comparable results were available. NRA results were obtained at day 7 for 61 specimens, results for 26 specimens were obtained at day 10, and the results for 13 specimens were obtained at day 14. Thus, 87% of NRA results were obtained in 10 days. NRA is a rapid, accurate, and cost-effective method for the detection of MDR in M. tuberculosis isolates as compared to the proportion method, which is time consuming. Therefore, NRA constitutes a useful tool for detection of tuberculosis drug resistance in low-resource countries with limited laboratory facilities due to its low-cost, ease of performance and lack of requirement of sophisticated equipment. PMID- 20966571 TI - Evaluation of BioFM liquid medium for culture of cerebrospinal fluid in tuberculous meningitis to identify Mycobacterium tuberculosis. AB - The present study was designed to evaluate the sensitivity and specificity of liquid culture medium (BioFM broth) for the diagnosis of tuberculous meningitis (TBM) in cerebrospinal fluid (CSF). CSF samples from 200 patients (TBM group = 150 and non-TBM group = 50) were tested for culture of Mycobacterium tuberculosis in BioFM liquid culture medium. Out of 150 TBM cases, 120 were found to be culture positive, indicating a sensitivity of 80% in BioFM broth within 2-3 weeks of inoculation. Positive cultures were also observed for CSF from 32 (64%) out of 50 non-TBM patients in BioFM liquid culture medium within 4 days of sample inoculation. Therefore, according to our study, BioFM broth system yielded 80% sensitivity [95% confidence interval (CI): 67-93%] and 36% specificity (95% CI: 57-98%) for TBM diagnosis. Our results indicate that although BioFM broth allows the detection of positive cultures within a shorter time, it has a high potential for contamination or for the coexistence of M. tuberculosis and non-tuberculous meningitis (NTM). This coexistence may go undetected or potentially lead to erroneous reporting of results. PMID- 20966572 TI - The effect of tigecycline and ertapenem against clinical isolates of Brucella melitensis detected by E-test on different media. AB - In this study, in vitro activity of tigecycline (TIG) and ertapenem (ERT) against clinical isolates of Brucella melitensis and the effect of different media on in vitro test results were investigated. The in vitro effects of TIG and ERT to 38 B. melitensis isolates were comparatively investigated in brucella agar and 5% sheep blood agar. MIC value of ERT was 0.032 MUg/mL in 23 of 38 and 20 of 38 isolates on blood and brucella agar, respectively. Minimum inhibitory concentration values of TIG were substantially different ranging between 0.064 0.25 MUg/mL on blood agar. However, MIC values of TIG were similar on brucella agar with 0.25 MUg/mL in 15 of 38 isolates and 0.5 MUg/mL in 10 of 38 isolates. In conclusion, although ERT and TIG were effective against B. melitensis isolates in vitro, further studies are needed in order to determine the use of these novel drugs in treatment of brucellosis. PMID- 20966573 TI - Mupirocin resistance in clinical isolates of staphylococci in a tertiary care centre in south India. AB - The present study was carried out to determine the rates of high-level and low level mupirocin resistance in Staphylococcus spp. (MuH and MuL) in southern India. A prospective study was carried out on Staphylococcus spp. isolated for a period of three months in the microbiology laboratory of an 800-bedded tertiary care hospital. One hundred sixty-seven non-duplicate Staphylococcus spp. isolated from different specimens were tested for mupirocin susceptibility using 5 and 200 MUg discs and by agar dilution. Rates of MuH were found to be two percent in methicillin-resistant Staphylococcus aureus (MRSA) and 28% in methicillin resistant coagulase-negative Staphylococcus spp. (MRCoNS). MuL strains may be still treated with mupirocin, while MuH strains require other treatment options for eradication, making prior screening and differentiation important. PMID- 20966574 TI - Comparison of isoelectric focusing and polymerase chain reaction for the detection of beta-lactamases. AB - Extended spectrum beta-lactamases (ESBLs) have been observed in virtually all the species of family Enterobacteriaceae. Threat posed by antibiotic resistance because of ESBLs is more serious as a number of technical problems are associated with the detection of these enzymes. Although a number of detection methods have been designed for ESBLs, every method has its own benefits and shortcomings as well. In earlier days, isoelectric focusing (IEF) was used as the gold standard for ESBL detection. This study was undertaken to compare IEF with polymerase chain reaction, a method which has been extensively used for ESBL detection these days. PMID- 20966575 TI - Nosocomial outbreak of septicaemia in neonatal intensive care unit due to extended spectrum beta-lactamase producing Klebsiella pneumoniae showing multiple mechanisms of drug resistance. AB - A total of 14 phenotypically similar clinical isolates of Klebsiella pneumoniae, resistant to multiple drugs including cefotaxime and ceftazidime, were isolated from blood of neonates admitted to neonatal intensive care unit (NICU) within a short span of 10 days. Alarmed at the possibility of occurrence of outbreak, a thorough investigation was done. Microbiological sampling of the NICU and labour room (LR) environment yielded 12 K. pneumoniae isolates. The presence of extended spectrum beta-lactamase (ESBL) in the clinical and environmental strains was detected by double-disk synergy test (DDST), CLSI phenotypic confirmatory disk diffusion test (PCDDT) and E-test ESBL strips. Amp-C screen (disk) test was done to determine Amp-C beta-lactamase production. 100% clinical strains, 57% NICU strains and 80% LR strains were ESBL positive. 57% clinical, 43% NICU and 20% LR strains were Amp-C screen positive. Polymerase chain reaction (PCR) of representative ESBL positive (10 clinical and 5 environmental) strains showed CTX gene and TEM and/or SHV gene in all. K. pneumoniae showing multiple mechanisms of drug resistance was responsible for the outbreak. PMID- 20966576 TI - Neonatal listeriosis: a case report from sub-Himalayas. AB - Perinatal listerial infection is the most common clinical syndrome caused by Listeria monocytogenes and includes abortion, still birth, neonatal sepsis, and meningitis. Reports of listeriosis from India are limited. Sub Himalayan . We report a case of neonatal listeriosis from Himachal Pradesh. A two-day-old full term male baby was referred from a peripheral hospital with fever listlessness, skin rash and non-acceptance of feed. Ceftriaxone was already started as an empirical therapy. Listeria monocytogenes was isolated from cerebrospinal fluid (CSF) and blood of the baby, and also from the genital tract of the mother. Unfortunately, the baby died before the preliminary report could be communicated. PMID- 20966577 TI - Isolation of Streptobacillus moniliformis from the blood of a child with acute lymphoblastic leukaemia. AB - This is an unusual report of isolation of Streptobacillus moniliformis from the blood of a male child with acute lymphoblastic leukaemia. No history of rat bite was there, but rats were present in the house. The possible source of infection may be food or water contaminated with rat excreta. Whether this bacteria can cause opportunistic infection in leukaemic patients, need to be evaluated further. PMID- 20966578 TI - A fatal case of empyema thoracis by Nocardia farcinica in an immunocompromised patient. AB - Empyema thoracis by Nocardia farcinica infection is uncommon. Here we report a rare and fatal infection in a 27-year-old HIV- seropositive male who presented with cough, expectoration, and breathlessness. Nocardia farcinica was isolated from sputum and pus from the pleural cavity. Confirmation of the isolate and minimum inhibitory concentrations (MIC) for various antibiotics was done at the Aerobic Actinomycetes Reference Laboratory, Centres for Disease Control and Prevention (CDC), Atlanta. Patient was treated with suitable antibiotics and antiretroviral drugs in spite of which he eventually succumbed to the disease. PMID- 20966579 TI - Microfilaria in malignant pleural effusion: an unusual association. AB - Lymphatic filariasis is common in tropical countries and is endemic in India. Filariasis presenting with pleural effusion is an unusual presentation. Malignancy in association of filarial pleural effusion is extremely rare. We report a case of a 60-year-old female who presented with chest pain, loss of weight and breathlessness for a few months. Pleural fluid examination revealed malignant cells, along with microfilaria of Wuchereria bancrofti. PMID- 20966580 TI - Human subcutaneous dirofilariasis in India: a report of three cases with brief review of literature. AB - Human subcutaneous dirofilariasis is a rare infection caused by filarial worms of the genus Dirofilaria. The parasites are transmitted to man by mosquitoes and the infection is manifested as subcutaneous nodules. Excision of the lesion is both diagnostic and therapeutic. Hereby we report three cases of human subcutaneous dirofilariasis. The worms were sent to our department for identification over a period of four years (2006-2009). Of these three patients, two men and one woman were between 15 and 45 years of age. In two cases, the infection manifested as a nodule on face, in one case near lower eyelid and in the other on the cheek, while in the third case as an itchy nodule on the abdomen. It is emphasized that both clinicians and microbiologists should have an increased awareness of this entity and include dirofilariasis in the differential diagnosis of patients presenting with subcutaneous nodules. PMID- 20966581 TI - Subcutaneous phaeohyphomycosis due to Exophiala spinifera in an immunocompromised host. AB - A case of phaeohyphomycosis presenting as multiple subcutaneous abscesses in a young lady with deteriorating liver function was reported here. The lesion started as a solitary abscess in the neck, mimicking tuberculous cold abscess and rapidly involved the face, chest, arms, and legs within six months with ulceration and discharge of thick brownish foul smelling pus. Potassium hydroxide mount of pus from various sites revealed septate dematiaceous hyphae and pseudohyphae. Culture yielded pure growth of Exophiala spinifera. Tissue debridement was done along with initiation of antifungal therapy with ketoconazole. As liver function deteriorated, antifungal therapy was withdrawn after seven days. Patient expired three weeks after admission due to hepatic failure. PMID- 20966582 TI - Oestrus ovis ophthalmomyiasis with keratitis. AB - A 35-year-old male patient presented with complaints of redness, swelling around the eyelids, watering, and irritation in the right eye. At presentation his best corrected visual acuity was 20/20 partial in the right eye. The tarsal conjunctiva of the upper eyelid showed injection with pseudomembrane. Underneath the pseudomembrane we noticed four motile larvae. The cornea showed an irregular cobweb-like mucous plaque adherent to the epithelium, with a clear stroma. The pseudomembrane was easily peeled-off under topical anaesthesia. The organisms were removed and identified as Oestrus ovis. Three days later the patient was comfortable and his visual acuity was 20/20 in the right eye. PMID- 20966583 TI - Allergic bronchopulmonary aspergillosis presenting with cavitary lesion and simulating a lung abscess. AB - A case of allergic bronchopulmonary aspergillosis (ABPA) is being described in a 52-year-old female patient who presented with a cavitary lesion on skiagram chest and simulating a lung abscess. Patient responded with the oral corticosteroid therapy with complete resolution of the initial radiographic abnormality. Despite various radiological presentations described in the literature, a lung abscess like presentation in ABPA is very rare and significant, because an early and correct diagnosis by the clinicians will help in early management of these cases to prevent the development of end-stage pulmonary fibrosis. PMID- 20966584 TI - Cutaneous histoplasmosis in AIDS. AB - A patient with human immunodeficiency virus (HIV) infection presented with multiple cutaneous lesions on upper extremities, trunk, face and with ulcers involving oral mucosa. Histoplasma capsulatum was isolated in culture from scrapings from both cutaneous as well as oral mucosal lesions. The patient responded well initially to the treatment with Amphotericin B followed by itraconazole; however, lesions recurred after three months with the further deterioration of immune status of the patient indicated by decline in CD4 counts. The same treatment was restarted and the patient is still being followed-up. PMID- 20966585 TI - Disseminated infection with Strongyloides stercoralis in a diabetic patient. AB - A 58-year-old male diabetic who was operated for carcinoma larynx 4 years back was admitted with exertional dyspnoea and bilateral leg swelling for the past 2 years. Over the last 2 months, there was a progressive worsening of symptoms. Echocardiography done 2 years back showed pericardial effusion. Echo done during the current admission also showed pericardial effusion with preserved left ventricular function; cytological examination of the pericardial fluid showed larvae of Strongyloides stercoralis. He was treated with antinematodal drugs. A follow-up echo done at discharge showed no pericardial effusion and the patient was completely asymptomatic. To our knowledge, this is the first reported case of Strongyloides pericardial effusion in a diabetic patient. PMID- 20966586 TI - Thyroid abscess due to Scedosporium apiospermum. AB - We report a case of thyroid abscess caused by Scedosporium apiospermum in a patient with cirrhosis of liver and autoimmune haemolytic anaemia. To date, there are no reports of isolation of this fungus from thyroid abscess. PMID- 20966587 TI - Cutting costs on mono-resistant tuberculosis diagnosis could eventually end up being more expensive. PMID- 20966588 TI - Displacement of dengue virus type 3 and type 2 by dengue virus type 1 in Delhi during 2008. PMID- 20966589 TI - Increasing levels of minimum inhibitory concentration vancomycin in methicillin resistant Staphylococcus aureus alarming bell for vancomycin abusers? PMID- 20966590 TI - Keratomycosis due to Scedosporium apiospermum. PMID- 20966591 TI - Carbapenem resistance in Acinetobacter baumannii isolated from blood of neonates with sepsis. PMID- 20966592 TI - Comparative study of blood culture and Staphylococcal coagglutination test in clinically suspected cases of enteric fever. PMID- 20966593 TI - Restraint stress induces connexin-43 translocation via alpha-adrenoceptors in rat heart. AB - BACKGROUND: Immobilization (IMO) confers emotional stress in animals and humans. It was recently reported that IMO in rats induced translocation of connexin-43 (Cx43) to gap junctions (GJs) and attenuated arrhythmogenesis with GJ inhibition, and Cx43 translocation in the ischemic heart was also shown. Few reports show the contribution of adrenoceptors to Cx43 upregulation in cardiomyocytes, but the involvement of adrenoceptors and ischemia in Cx43 translocation in IMO remains elusive. METHODS AND RESULTS: Male Sprague-Dawley rats underwent IMO and the ventricular distribution of Cx43 was examined by western blotting. IMO induced translocation of Cx43 to the GJ-enriched membrane fraction, with a peak at 60min. The IMO-induced Cx43 translocation was inhibited by pretreatment with the alpha(1)-adrenoceptor blockers, prazosin (1mg/kg, PO) and bunazosin (4mg/kg, PO), but not with either the beta(1)-blocker, metoprolol (10mg/kg, IP), or the beta(1+2)-blocker, propranolol (1mg/kg, PO). The translocation was inhibited by the nitric oxide, donor isosorbide dinitrate (100ug.kg(-1).min(-1), IV), possibly through sympathetic inhibition. Hypoxia inducible factor-1alpha was not redistributed by IMO. The beta-blockers, but not the alpha-blockers, inhibited the premature ventricular contractions (PVCs) induced by IMO. CONCLUSIONS: Translocation of Cx43 to the GJ-enriched fraction occurs via the alpha(1) adrenoceptor pathway, independently of ischemia. The beta-adrenoceptor pathway contributes to the inducing of PVCs in IMO. PMID- 20966594 TI - Vasodilator stress impairs the left ventricular function obtained with gated single-photon emission computed tomography in patients with known or suspected coronary artery disease. AB - BACKGROUND: Transient ischemic dilatation (TID) and post-stress dysfunction of the left ventricle (LV) are important markers of severe coronary artery disease (CAD). To clarify the effects of stressor type on TID and post-stress LV dysfunction, changes in LV measurements were compared between patients with exercise- or vasodilator-induced stress. METHODS AND RESULTS: The 689 patients referred for technetium-99m tetrofosmin myocardial perfusion imaging were included. Patients were stressed with either a vasodilator (n=236) or exercise (n=453). LV measurements were obtained with ECG-gated SPECT. LV end-diastolic and end-systolic volume indexes (LVEDVI, LVESVI) increased and LV ejection fraction (LVEF) decreased after stress in the vasodilator-stress group. Vasodilator-stress and the summed difference score (SDS) were independent variables that decreased LVEF after stress. Even in patients without reversible defects, vasodilator stress impaired LV function. There were no differences in the stress-to-rest ratios of LVEDVI (rEDV) and LVESVI (rESV) among patients with normal myocardial perfusion, fixed defects and reversible defects in the vasodilator-stress group, whereas in the exercise-stress group, rESV was significantly higher in the patients with reversible defects than in those without reversible defects. Within the vasodilator-stress group, neither rEDV nor rESV correlated with the SDS. CONCLUSIONS: Vasodilator-stress by itself decreases LVEF after stress. TID should be carefully interpreted when vasodilator-stress is used to detect severe CAD. PMID- 20966595 TI - Prevalence and clinical implication of complex atherosclerotic plaque in the descending thoracic aorta of Japanese patients assessed by transesophageal echocardiography. AB - BACKGROUND: Aging and westernization of lifestyle has accelerated the prevalence and severity of atherosclerotic cardiovascular diseases in the Japanese population. The aim of this study was to examine the prevalence of complex plaque formation in the descending thoracic aorta (DTA) as assessed by real-time 3 dimensional transesophageal echocardiography (3DTEE) and its relation to clinical factors. METHODS AND RESULTS: A prospective analysis of atherosclerotic plaque in the DTA of 350 consecutive patients who were clinically indicated for real-time 3DTEE was performed. Systematic assessment of the DTA plaques was performed using a biplane mode from the aorta at the level of the stomach to the aortic arch. When a large plaque (>4mm) was identified, detailed 3-dimensional (D) observations were performed using a 3D zoom mode. Complex plaque was defined as either mobile or an ulcer-like pouch in the DTA. Complex plaques were detected in 51 patients (15%), who were more advanced in age and had a higher prevalence of chronic kidney disease. A multivariate analysis revealed that the presence of complex plaque was an independent predictor of renal impairment. CONCLUSIONS: The prevalence of complex plaque was not low in the this Japanese study population. A close association between complex plaque and renal dysfunction raises the possibility that complex plaque in the DTA is a potential cause of renal dysfunction. PMID- 20966596 TI - Spontaneous development of left ventricular hypertrophy and diastolic dysfunction in mice lacking all nitric oxide synthases. AB - BACKGROUND: The role of the nitric oxide synthase (NOS) system in cardiac architecture and function remains unknown. This point was addressed in mice that lack all 3 NOS genes. METHODS AND RESULTS: Morphological, echocardiographic, and hemodynamic analyses were performed in wild-type (WT), singly nNOS(-/-), iNOS(-/ ), eNOS(-/-), and triply n/i/eNOS(-/-) mice. At 5 months of age, but not at 2 months of age, significant left ventricular (LV) hypertrophy was noted in n/i/eNOS(-/-) mice and to a lesser extent in eNOS(-/-) mice, but not in nNOS(-/-) or iNOS(-/-) mice, compared with WT mice. Importantly, significant LV diastolic dysfunction (as evaluated by echocardiographic E/A wave ratio and hemodynamic dP/dt and Tau), with preserved LV systolic function (as assessed by echocardiographic fractional shortening and hemodynamic +dP/dt), was noted only in n/i/eNOS(-/-) mice, and this was associated with enhanced LV end-diastolic pressure and increased lung wet weight, all of which are characteristics consistent with diastolic heart failure in humans. Finally, long-term oral treatment with an angiotensin II type 1 (AT(1)) receptor blocker, olmesartan, significantly prevented all these abnormalities of n/i/eNOS(-/-) mice. CONCLUSIONS: These results provide the first direct evidence that the complete disruption of all NOSs results in LV hypertrophy and diastolic dysfunction in mice in vivo through the AT(1) receptor pathway, demonstrating a pivotal role of the endogenous NOS system in maintaining cardiac homeostasis. PMID- 20966597 TI - Diagnostic value of adenosine-induced left ventricular diastolic dysfunction for detecting coronary artery restenosis in patients undergoing stent implantation by Stress ECG-gated myocardial perfusion SPECT. A pilot study. AB - BACKGROUND: Usefulness of diastolic dysfunction after adenosine stress for detecting coronary stenosis has not been defined. The diagnostic accuracy of a combination of myocardial perfusion and diastolic function, as defined by prolongation of time to peak-filling rate (TTPF)/R-R and myocardial perfusion alone for the detection of coronary restenosis, was evaluated. METHODS AND RESULTS: We used rest (201)Tl/ adenosine stress (99m)Tc-tetrofosmin myocardial perfusion singlephoton emission computed tomography (SPECT) in 70 patients. Patients were divided into the following 4 groups: 20 patients with normal SPECT without stent (Control group), 20 patients showing normal SPECT without coronary restenosis (Group 1), 16 patients showing significant coronary restenosis and myocardial ischemia (Group 2a) and 14 patients showing significant coronary restenosis without myocardial ischemia (Group 2b). The TTPF, which was calculated by quantitative gated SPECT (QGS)/R-R, was not different between after stress and at rest in Control group (0.18+/-0.02 vs 0.19+/-0.04, P=NS). The TTPF/R-R after stress was significantly lower than that at rest in Group 1 (0.17+/-0.02 vs 0.18+/-0.03, P<0.05), but TTPF/R-R after stress was significantly higher than that at rest in Groups 2a and 2b (0.22+/-0.03 vs 0.16+/-0.03, P<0.001 in Group 2a and 0.19+/-0.02 vs 0.16+/-0.02, P<0.001 in Group 2b, respectively). Diagnostic accuracy improved from 72% to 92% when prolongation of TTPF/R-R was taken into account (P<0.001). CONCLUSIONS: Diastolic dysfunction after stress was an accurate marker for detecting significant restenosis following stent implantation. PMID- 20966598 TI - Expression of chemokines, CXC chemokine ligand 10 (CXCL10) and CXCR3 in the inflamed islets of patients with recent-onset autoimmune type 1 diabetes. AB - The aim of this study is to present direct evidence for the involvement of CXC chemokine ligand 10 (CXCL10) and CXCR3 in human autoimmune type 1 diabetes. We examined five patients with recent-onset type 1 diabetes and five control subjects without diabetes. Islet cell antibodies or GAD antibodies or both were detected in all five patients. We used double-immunofluorescence to detect the expression of CXCL10 and CXCR3 (the receptor of CXCL10). CXCL10 was detected in the islets of all five patients. Almost all (84.2 +/- 10.3 %, mean +/- SD) CXCL10 positive cells were insulin-positive in the islet area. CXCL10-positive cells with glucagons, somatostatins or pancreatic polypeptides were not detected at all. CXCL10 expression was not seen in any islet without beta cells. CXCR3 was detected in the islet areas of all five patients. Almost all (80.3 +/- 13.4 %, mean +/- SD) CXCR3-positive cells were CD3-positive T cells. Our study showed that CXCL10 was expressed in the remaining beta cells, and the infiltrating T cells expressed CXCR3, in pancreatic islets of patients with recent-onset type 1 diabetes. The interaction of CXCL10 and CXCR3 would contribute to the selective destruction of beta cells in the development of type 1 diabetes. PMID- 20966599 TI - Prognostic effects of combined treatment with calcium channel blockers and statins in patients with coronary narrowing: from the Japanese Coronary Artery Disease study. AB - Calcium channel blockers (CCB) and statins are frequently prescribed for patients with coronary artery disease (CAD) complicated by hypertension and/or hypercholesterolemia. CCB have pleiotropic actions beyond their blood pressure lowering effect, while statins have pleiotropic actions beyond their cholesterol lowering effect. We assessed the hypothesis that combined treatment with CCB and statins has additional prognostic benefits resulting from potential additive or synergistic pleiotropic actions of both classes of drugs in the Japanese CAD (JCAD) study population. The JCAD study consisted of 13,812 patients with angiographically demonstrable significant coronary narrowing in at least 1 of 3 major coronary arteries who were followed-up for a mean of 2.7 years (follow-up rate, 88.4%). The primary endpoint of the present study was all cardiovascular events. We compared the event rate between patients receiving neither CCB nor statins and those receiving each drug alone or as a combination treatment using propensity score matching analysis. The rate of all events was 62.8 per 1,000 patient-years in the JCAD study. Kaplan-Meier analysis with the log-rank test showed no statistically significant difference in the event rate in each comparison. In conclusion, there may be no additional prognostic benefit beyond the blood-pressure-lowering and cholesterol-lowering effects in the combined treatment with CCB and statins for angiographically documented CAD patients. PMID- 20966600 TI - Comparison of platelet P2Y(12) ADP receptor-mediated pathway inhibition in triple versus dual antiplatelet therapy as assessed by VASP-phosphorylation in Japanese patients undergoing coronary stenting. AB - Despite wide interindividual variability in response to clopidogrel, platelet P2Y(12) ADP receptor inhibition in Japanese patients has not been fully studied using specific methodology. This study compared platelet P2Y(12) ADP receptor inhibition during treatment with clopidogrel versus clopidogrel plus cilostazol in patients undergoing coronary stenting. Forty-two patients in whom platelet function was measured within 2 months after coronary stenting were enrolled. All patients were treated with aspirin 100 or 200 mg/day, and were divided into a dual therapy group (aspirin plus clopidogrel 75 mg/day; n = 34) and a triple therapy group (aspirin plus clopidogrel 75 mg/day plus cilostazol 200 mg/day; n = 8). Vasodilator-stimulated phosphoprotein (VASP) phosphorylation analysis and 5 and 20 umol/L-induced maximal platelet aggregation were assessed. No differences were found in baseline characteristics except for a higher incidence of diabetes mellitus (DM) in the triple therapy group. Although there were no differences in platelet aggregation between the 2 groups, VASP index was significantly lower in the triple therapy group than in the dual therapy group (23.1 +/- 15.3% versus 51.2 +/- 19.9%; P = 0.001). The rate of low responsiveness to clopidogrel, defined by VASP index > 50%, was lower in the triple therapy group than in the dual therapy group (12.5% versus 55.9%; P = 0.047). Similarly, in DM patients the triple therapy group had a lower VASP index compared with the dual therapy group (23.1 +/- 15.3% versus 47.0 +/- 23.5%; P = 0.015).Clopidogrel plus cilostazol is more effective in inhibiting the platelet P2Y(12) ADP receptor pathway than clopidogrel alone. This may be useful for reducing clopidogrel resistance in Japanese patients. PMID- 20966601 TI - Imaging of subendocardial myocardial blood flow by dye-staining cardioscopy in patients with coronary artery disease. AB - This study was carried out to image subendocardial myocardial blood flow (SMBF) by dye-staining cardioscopy (DSC) in patients with coronary artery disease.In patients with epicardial coronary artery disease, SMBF plays a direct and critical role in determining the extent and severity of cardiac function and symptoms. If SMBF could be clinically imaged instantaneously, the effects of medical and interventional treatment on it can be directly evaluated. However, there are no clinically available methods for direct and real-time imaging of SMBF. Twenty-three patients [6 with chest pain syndrome (CPS); 3 with vasospastic angina pectoris (VSA); 9 with angina pectoris due to organic coronary stenosis (AP); 5 with old myocardial infarction OMI)] underwent DSC of the left ventricle by selective intracoronary injection of 1 mL of 2.5% Evans blue dye solution (EB). Five patients with acute myocardial infarction (AMI) underwent DSC before and after coronary stent deployment. The endocardial surface was stained diffusely blue with EB indicating normal blood flow in patients with CPS; stained in a patchy fashion indicating patchy blood flow in patients with VSA; and stained in a patchy fashion or not stained indicating patchy or no blood flow in those with AP and OMI. Myocardial staining with EB was observed after coronary stent deployment in all patients with AMI, indicating restoration of the SMBF. It is evident that SMBF could be imaged by DSC. This imaging modality is useful for the evaluation of therapies and accurate guidance of transendocardial therapies of the ischemic myocardium. PMID- 20966602 TI - Impact of statin therapy on renal function and long-term prognosis in acute coronary syndrome patients with chronic kidney disease. AB - A recent study showed that statins reduce cardiovascular events in stable coronary artery disease patients with chronic kidney disease (CKD). However, it remains unclear whether acute coronary syndrome (ACS) patients with CKD benefit from statins. A total of 501 patients with ACS who underwent successful percutaneous coronary intervention were investigated and CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/minute/1.73 m(2) at discharge. Three hundred and twenty-four of 501 patients (64.7%) had CKD and 173 patients (34.5%) received statins. The patients with CKD were older and had higher blood pressure than those without CKD. With a mean follow-up of 5.2 years, irrespective of treatment assignment, 74 patients with CKD experienced cardiac events (22.8%) in comparison to 25 without CKD (14.1%, HR 1.81; 95% CI 1.15-2.84, P = 0.0095). Cardiac events occurred in only 18 of the patients with CKD treated with statins (16.2%) and in 56 of those treated with CKD without statins (26.3%, HR 0.58; 95% CI 0.34-0.98, P = 0.039), whereas, no significant reduction of the events was observed in the patients without CKD treated with statins versus without having statins (P = 0.130). These data indicate that statin therapy reduces cardiac events in ACS patients with CKD. PMID- 20966603 TI - Benefit of revascularization in non-infarct-related artery in multivessel disease patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - This study compared the prognosis of ST-elevation myocardial infarction (STEMI) in patients with multivessel disease (MVD) with that of single vessel disease (SVD) and investigated the revascularization benefit of noninfarct-related artery (IRA) in MVD patients undergoing primary percutaneous coronary intervention (PCI). Between 2002 and 2009, 1278 patients with STEMI underwent primary PCI. Of these patients, 717 (56.1%) with SVD (only IRA obstruction) were placed in group A, while 561 (43.9%) with MVD (Group B) were further categorized into group 1 (PCI for IRA) and group 2 (staged PCI for IRA+non-IRA). The results demonstrated a lower degree of successful reperfusion in IRA and higher 30-day and 1-year cumulative mortality rates in group B (P < 0.001). While there was no difference in successful reperfusion in IRA between group 1 and group 2, the 30-day and one year cumulative mortality rates were higher in group 1. Multivariate analysis identified MVD as an independent predictor of 1-year mortality (P < 0.001). In conclusion, patients with subsequent PCI for MVD had better 30-day and 1-year outcomes than those with conservative treatment. PMID- 20966604 TI - Prognostic value of R-wave voltage in patients with anterior wall ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - The prognostic value of integrated R-wave voltages of precordial leads (V(1) V(6)) in patients with acute anterior wall ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) was investigated. Between July 2006 and October 2009, 292 patients with anterior wall STEMI with presentation < 12 hours underwent primary PCI. Thirty-four patients with electrocardiographic presentation of either complete right bundle branch block (BBB) or complete left BBB were categorized into group A, while the remaining 258 patients without BBB served as group B that was further subdivided into those with lower R-wave voltage (summation of V(1)-V(6) <= 1.7 mV) (group 1) and higher voltage (> 1.7 mV) (group 2) according to the ROC curve (sensitivity = 66.3%, specificity = 66%, P < 0.0001).While the procedural success rate was similar between groups A and B and groups 1 and 2, 30-day mortality was higher in group A than B (P <= 0.0001). Additionally, left ventricular ejection fraction (LVEF) was lower, whereas peak level of creatine phosphokinase (CPK), incidence of advanced congestive heart failure, and 30-day mortality were higher in group 1 than 2 (P < 0.01). Multivariate analysis revealed that lower R-wave voltage, multivessel disease, leukocyte count, peak CPK, and creatinine level were predictive of 30-day unfavorable clinical outcomes (all P < 0.01). R-wave voltage in precordial leads was a significant independent predictor of 30-day prognostic outcome in patients with anterior wall STEMI undergoing primary PCI. PMID- 20966605 TI - Relationship between the long-term preventive effect of combined treatment with antiarrhythmic drugs plus angiotensin-converting enzyme inhibitors and circadian variation in the onset of paroxysmal atrial fibrillation. AB - We examined the relationship between the efficacy of combined treatment with antiarrhythmic drugs (AAD) plus enalapril for maintaining sinus rhythm and circadian variation in the onset of paroxysmal AF.Three hundred and forty-four patients with paroxysmal AF (239 men, mean age, 69 +/- 11 years) who could be followed up >= 12 months were divided into 3 groups on the basis of circadian variation in the onset of AF: a diurnal group (7:00 AM-5:00 PM, n = 57), a nocturnal group (5:00 PM-7:00 AM, n = 108), and a mixed group (onset during both periods, n = 169). The maintenance rate of sinus rhythm during the follow-up period was compared between combined therapy (AAD plus enalapril) and AAD alone.In the diurnal group, the maintenance rates of sinus rhythm at 12, 36, 60, and 90 months were 100%, 100%, 100%, and 100%, respectively, for patients treated with AAD plus enalapril (n = 22) versus 97%, 91%, 89%, and 80% for patients treated with AAD alone (n = 35, P < 0.05). In the nocturnal group, the maintenance rates of sinus rhythm at 12, 36, 60, and 90 months were 96%, 96%, 96%, and 92%, respectively, in patients treated with AAD plus enalapril (n = 24) versus 100%, 100%, 100%, and 100% in patients treated with AAD alone (n = 84, P = NS). In the mixed group, maintenance rates of sinus rhythm at 12, 36, 60, and 90 months were 90%, 71%, 61%, and 57%, respectively, in patients treated with AAD plus enalapril (n = 49) versus 88%, 78%, 68%, and 61% in patients treated with AAD alone (n = 120, P = NS). Our findings suggest that the preventive efficacy of combined therapy with AAD plus enalapril is dependent on the timing of onset of paroxysmal AF, and this regimen seems to be most beneficial for the diurnal type of paroxysmal AF. PMID- 20966606 TI - Study design of SEASON registry: prospective Surveillance of cardiovascular Events in an Antiplatelet-treated arterioSclerosis Obliterans patients in JapaN )SEASON). AB - Antiplatelet therapy is widely performed for arteriosclerosis obliterans (ASO) to relieve ischemic symptoms and prevent cardiovascular events. However, the overall rate of cardiovascular events in patients with ASO under treatment with antiplatelet agents has not been fully investigated in Japan. The SEASON registry is a nationwide observational prospective cohort study designed to compile data from over 2,000 institutions across Japan, whose aims are to (1) understand the current status for the management of ASO and clarify the incidence of cardiovascular events in patients with ASO undergoing antiplatelet therapy, and (2) compare the effectiveness of sarpogrelate, a 5-HT(2A) receptor antagonist, in decreasing the event rate with those of other antiplatelet agents [UMIN ID: UMIN000003385]. The registry will recruit approximately 10,000 patients receiving antiplatelet therapy (8,000 patients for sarpogrelate and 2,000 for other antiplatelet agents), and the patients will be followed every 6 months during a two-year follow-up period. The investigators plan to report all cardiovascular events and exacerbations of ASO. Analysis focusing on the sarpogrelate-treated subgroup will also be performed. Exploratory analysis will be performed to determine the clinical characteristics of the patients and to elucidate the relationships between risk factors and cardiovascular events. The SEASON registry is the first attempt to create a nationwide database regarding the incidence of cardiovascular events in 10,000 ASO patients in Japan. In addition, it ultimately may enable us to conclude that sarpogrelate prevents cardiovascular events. Information on the severity and risk factors in ASO patients in the clinical settings will be applicable to epidemiological analysis. PMID- 20966607 TI - Utility of echocardiography versus BNP level for the prediction of pulmonary arterial pressure in patients with pulmonary arterial hypertension. AB - Recent advances in the treatment of pulmonary arterial hypertension provide a rational basis for earlier, noninvasive diagnosis of pulmonary arterial hypertension. However, the reliability of transthoracic echocardiography, plasma BNP levels, and other parameters for the diagnosis of pulmonary arterial hypertension remains unclear. Thus, the purpose of this study was to determine the utility of these modes of investigation for the prediction of pulmonary arterial pressure as compared with the current gold standard, Swan-Ganz catheterization. Among 46 PAH patients, 37 had connective tissue diseases, while the remainder had primary pulmonary arterial hypertension, chronic pulmonary thromboembolism, and interstitial pneumonitis. Systolic pulmonary arterial pressure calculated by transthoracic echocardiography was significantly correlated with systolic pulmonary arterial pressure measured using a Swan-Ganz catheter (r = 0.51, P < 0.01). Plasma BNP concentration did not correlate with systolic pulmonary arterial pressure (r = 0.10, NS) in the overall patient population. However, when we excluded left ventricular heart failure and left ventricular hypertrophy, BNP concentration was correlated with systolic pulmonary arterial pressure (r = 0.508, P < 0.05). Among other variables tested, ECG electrical axis was correlated with pulmonary arterial pressure (r = 0.46, P < 0.05) but uric acid, lactate dehydrogenase, %DLCO, enhanced IIp sound, and pulmonary artery enlargement on chest x-ray did not correlate with pulmonary arterial pressure. These data suggest that echocardiography is the noninvasive modality of choice for the assessment of pulmonary arterial hypertension. Plasma BNP level also predicts pulmonary arterial pressure, when left ventricular heart failure and cardiac hypertrophy are excluded. PMID- 20966608 TI - BAY 11-7082, a nuclear factor-kappaB inhibitor, reduces inflammation and apoptosis in a rat cardiac ischemia-reperfusion injury model. AB - Despite development of therapeutic modalities, myocardial ischemia-reperfusion (I/R) injury remains an important cause of cardiac dysfunction. Multiple strategies exist experimentally, but few are clinically available. Nuclear factor kappa-B (NF-kappaB) is a key transcription factor in the inflammatory response and is implicated in I/R injury. We hypothesized that the NFkappaB inhibitor BAY 11-7082 (BAY) would decrease the extent of injury after myocardial I/R. Hypoxia reoxygenation (H/R) was induced in rat neonatal cardiomyocytes with or without BAY pretreatment. NF-kappaB activation, vascular cell adhesion molecule (VCAM)-1, and monocyte chemoattractant protein (MCP)-1 were assayed by immunocytochemistry, Western blot or reverse transcriptase-polymerase chain reaction (RT-PCR). Sprague Dawley rats (n = 7) were administered BAY (130 ug/kg) and I/R was induced by ligation of the left anterior descending artery (LAD) for 30 minutes followed by reperfusion. Infarct size was analyzed after 24 hours. At 2 weeks, echocardiography was performed to evaluate ventricular function and hearts were analyzed for fibrosis and apoptosis. BAY treatment inhibited NF-kappaB p65 activation, as well as VCAM-1 and MCP-1 expression induced by H/R in cardiomyocytes. Compared with control rats, BAY pretreated rats showed reduced infarct size. Echocardiograms demonstrated preserved systolic function as a fractional shortening in the BAY+I/R group (P < 0.05). Fibrosis was reduced in the BAY+I/R group (P < 0.05) and apoptosis was also reduced in the BAY+I/R group (P < 0.05).In the rat myocardial I/R injury model, BAY significantly reduced the infarct size, and preserved myocardial function. These data demonstrate that a currently available and well-tolerated inhibitor of NF-kappaB can decrease the risk of myocardial injury associated with I/R. PMID- 20966609 TI - Electrical remodeling in fibrillating canine atrium: action potential alternans during rapid atrial pacing and late phase 3 early afterdepolarization after cessation of rapid atrial pacing. AB - Sustained atrial fibrillation (AF) was induced by atrial burst pacing, and monophasic action potentials (MAPs) were recorded. MAP alternans was observed at a cycle length (CL) of 167.5 +/- 28.2 msec before burst pacing and 201.3 +/- 40.2 msec after burst pacing. AF > 5 minutes duration was induced in 1 dog in the control condition but in all 8 dogs after burst pacing. The difference in RA MAPD(80) of the first spontaneous beat and steady-state sinus rhythm was significantly larger after atrial burst pacing than before atrial burst pacing (31.5 +/- 15.9 msec versus 8.2 +/- 9.0 msec) In 4 dogs, late phase 3 early after depolarization was observed after rapid atrial pacing. Rapid atrial pacing induced electrical remodeling includes APD alternans during rapid atrial pacing and also causes an increase in the MAPD of the initial several beats and the development of late phase 3 early afterdepolarizations after a sudden increase in CL. PMID- 20966610 TI - Year-long antihypertensive therapy with candesartan completely prevents development of cardiovascular organ injuries in spontaneously hypertensive rats. AB - Most previous studies have examined the effects of antihypertensive drugs in hypertensive animals for only a few months, and little information has been provided as to the protective effects of lifetime antihypertensive medication against cardiovascular organ injury. In this study, spontaneously hypertensive rats (SHR) were treated for 1 year with an angiotensin-II receptor antagonist (ARB) and the development of hypertensive organ injury was evaluated. Male 15 week-old SHR (n = 9) were given 25 mg/L candesartan (CS) in their drinking water for 1 year. Twelve SHR and 9 normotensive Wistar-Kyoto rats (WKY) were given normal tap water. Tail-cuff blood pressure was almost normalized by CS throughout 1 year (at 12-months: WKY 132 +/- 3, SHR 229 +/- 3, CS 137 +/- 4 mmHg). After 1 year, cardiac ventricular weight (SHR +33%, CS -2% versus WKY) and aortic thickness (SHR +34%, CS +4% versus WKY) in the CS-treated SHR rats were not different than those of WKY. Echocardiographic midwall fractional shortening (SHR -18%, CS -1% versus WKY) and left ventricular hydroxyproline content (SHR +47%, CS +11% versus WKY) were also improved by CS to the WKY level. With respect to kidney function, GFR (SHR -24%, CS +9% versus WKY) was preserved, proteinuria (SHR +312%, CS +12% versus WKY) was reduced, and the histological glomerular injury rate (SHR +186%, CS +6% versus WKY) was reduced by CS. These results suggest that long-term antihypertensive therapy with CS can completely prevent hypertensive cardiovascular and renal injuries in SHR. PMID- 20966611 TI - QT interval prolongation and torsade de pointes induced by propofol and hypoalbuminemia. AB - We report the case of a 70-year-old man presenting with the development of torsade de pointes (TDP) during infusion of propofol in the setting of severe hypoalbuminemia. TDP developed 15 hours after the beginning of a standard infusion of propofol, following the development of a prominent U wave and prolongation of the QTc interval. While the serum concentrations of electrolytes were within normal ranges, serum albumin as low as 1.4 mg/dL was observed. TDP disappeared during the infusion of isoproterenol, and QTc normalized after the discontinuation of propofol. We hypothesize that hypoalbuminemia increased the free fraction of propofol, causing marked QTc prolongation and TDP. PMID- 20966612 TI - Cardiac angiosarcoma diagnosed by transvenous endomyocardial biopsy with the aid of transesophageal echocardiography and intra-procedural consultation. AB - We report a case who had confirmed tumor cells in the biopsy specimens by transvenous endomyocardial biopsy with intra-procedural consultation and fast smear cytology. A 57-year-old female was admitted to our hospital because of shortness of breath and left back pain. Transthoracic echocardiography (TTE) and contrast-enhanced computed tomography (CT) scans demonstrated a large mass in the right atrium and multiple liver tumors thought to be due to spread of the disease. Coronary angiography showed the right coronary artery was involved in the mass. In order to confirm the histological diagnosis, we attempted transvenous endomyocardial tumor biopsy under fluoroscopic guidance. However, we failed to obtain adequate tissue material. Due to several risks associated with a surgical procedure such as an open surgical biopsy, transvenous endomyocardial tumor biopsy was again attempted with the aid of transesophageal echocardiography (TEE). Intra-procedural consultation and fast smear cytology enabled us to finish the procedure. Hematoxylin-eosin stained sections demonstrated spindle-shaped cells. Immunohistochemical stains of these cells were positive for anti-factor VIII antigen, CD31, and CD34. These findings indicated a definite diagnosis of angiosarcoma. Since there was no surgical indication for this tumor, the patient underwent chemotherapy with docetaxel and radiotherapy. Three months later, CT scans showed a reduction in the size of the cardiac tumor. PMID- 20966614 TI - Preliminary immunohistochemical study of natriuretic peptide receptor localization in canine and feline heart. AB - We examined the immunohistochemical distributions of natriuretic peptide receptor (NPR)-A, -B and -C that bind with natriuretic peptide hormones A, B and C in four healthy crossbreed young canine and feline cardiac tissues using specific antibodies against human antigens. Cross-immunoreactivities between antigens and antibodies were confirmed using western blot analysis. NPR-A and -C were expressed more strongly in dogs than cats. In both species, these expressions were stronger in the atria than the ventricles, with stronger expression in the left ventricles than the right. NPR-B was largely very weekly or undetected. In canine and feline cardiac tissues, the expressional distribution of NPR-A, -B, and -C closely matched with that of atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide as the ligands for corresponding receptors. PMID- 20966615 TI - Sarcoidosis--moving to the new standard of diagnosis? AB - In this article, the most recent literature data regarding the diagnosis of sarcoidosis have been reviewed. The diagnosis of sarcoidosis can be reliably established when there is a compatible clinical/radiological picture together with pathologic evidence of noncaseating epithelioid cell granulomas. Pathologic specimens can be obtained by conventional bronchoscopy with endobronchial, transbronchial lung biopsy, bronchoalveolar lavage, and recently introduced endoscopic ultrasound techniques (endoscopic ultrasound-guided fine-needle aspiration, EUS-FNA, and endobronchial ultrasound-guided transbronchial needle aspiration, EBUS-TBNA) or surgical procedures such as thoracotomy, thoracoscopy, and mediastinoscopy. The place and value of EBUS-TBNA or EUS-FNA in diagnosis of sarcoidosis are discussed. PMID- 20966616 TI - Constraints-controlled metastable dynamics of exercise-induced psychobiological adaptation. AB - A fundamental question in the theory of psychobiological adaptation and specifically of sports training is the problem of how adaptation to sports performance demands occurs as a consequence of systematic exercise. In this position paper, we review some results of our previous and current research conducted on several different levels of exercise-induced effects. Based on these results, we contend that the control of psychobiological systems during exercise is constraints based. Constraints direct the flow of behavioral changes on a rugged metastable landscape. Such adaptive behavior is soft-assembled, consisting of context-sensitive cooperative configurations of system components that dwell on different time scales. PMID- 20966617 TI - De novo erosive esophagitis in duodenal ulcer patients related to pre-existing reflux symptoms, smoking, and patient age, but not to Helicobacter pylori eradication: a one-year follow-up study. AB - It remains unclear whether the Helicobacter pylori eradication may cause or provoke gastroesophageal reflux disease. Therefore, we aimed to elucidate the role of H. pylori eradication and other factors in the development of erosive esophagitis in patients with duodenal ulcer. MATERIALS AND METHODS: We enrolled 183 H. pylori-positive duodenal ulcer patients without erosive esophagitis. Final endoscopy was performed 12 months later or in case if ulcer relapse was suspected. H. pylori was diagnosed by the urease test and histology if the results of at least one of the tests were positive. A total of 142 patients were assigned to the eradication treatment. The control group included 41 volunteers- 20-mg omeprazole b.i.d. for 4 weeks was administered. RESULTS: A total of 150 patients completed the study. Of the 119 patients, 70 (58.8%) were cured from H. pylori, and in 49 (41.2%) of patients, treatment of H. pylori was unsuccessful. All 31 controls remained H. pylori-positive. At the final endoscopy, erosive esophagitis was found in 19 (12.7%) patients. Erosive esophagitis developed in 8 (11.4%) successfully eradicated patients, in 9 (18.4%) unsuccessfully treated patients, and in 2 (6.5%) controls (P>0.05 comparing the groups). Multivariate logistic regression analysis revealed 3 factors at baseline, which were significant (P<0.05) in predicting the occurrence of erosive esophagitis: age more than 43 years (OR, 4.96; 95% CI, 1.47-16.71), nonerosive gastroesophageal reflux disease (OR, 3.96; 95% CI, 1.34-11.68), and smoking (OR, 3.17; 95% CI, 1.01-9.17). CONCLUSIONS: H. pylori eradication did not influence the incidence of erosive esophagitis in patients with duodenal ulcer during a one-year follow-up period. Pre-existing nonerosive gastroesophageal reflux disease, smoking, and older age are important predictors of de novo development of erosive esophagitis. PMID- 20966618 TI - Incidence and risk factors for early postoperative cognitive decline after coronary artery bypass grafting. AB - BACKGROUND. The aim of our study was to evaluate the incidence of early postoperative cognitive decline (POCD) and determine perioperative risk factors as well as the impact of asymptomatic cerebral vascular lesion on the development of neurocognitive complications. MATERIALS AND METHODS. A total of 127 consecutive adult patients undergoing on-pump coronary artery bypass grafting were studied. Neuropsychological testing was performed the day before surgery and 7-9 days after operation. Stepwise logistic regression analysis determined independent predictors of POCD. RESULTS. The incidence of postoperative cognitive decline was 46% (n=59). Patients in the POCD group were older (P=0.04) and had an increased prevalence of asymptomatic carotid artery stenosis (P=0.0001). POCD was associated with longer time in surgery (P=0.018), inotropic support intraoperativelly (P=0.02) and during postoperative period (P=0.008). Patients in the POCD group had an increased incidence of postoperative bleeding (P=0.037), delirium (P=0.016) and stayed in hospital for a longer period (P=0.007). Age of more than 65 years (OR, 2.7), asymptomatic carotid artery stenosis of more than 50% (OR, 26.89), duration of surgery of more than 4 hours (OR, 4.08), postoperative mechanical ventilation of more than 6 hours (OR, 3.33), and stay in an intensive care unit for more than 3 days (OR, 3.38) were significant independent predictors of cognitive decline. CONCLUSIONS. Increased age, preoperative prevalence of craniocervical atherosclerotic lesions, longer time in surgery, longer stay in an intensive care unit and mechanical ventilation time were found to be the risk factors for developing postoperative cognitive decline. PMID- 20966619 TI - The influence of thoracic epidural anesthesia on liver hemodynamics in patients under general anesthesia. AB - BACKGROUND AND OBJECTIVE: Hepatic hypoperfusion is regarded as an important factor in the pathophysiology of perioperative liver injury. Although thoracic epidural anesthesia is a widely used technique, limited data are available about the effects on hepatic blood flow with blockade restricted to thoracic segments in humans. The main objective of the present study was to investigate the effects of thoracic epidural anesthesia on hepatic blood flow under general anesthesia in humans. MATERIAL AND METHODS: In 40 patients under general anesthesia, we assessed hepatic blood flow using plasma disappearance rate of indocyanine green (PDRICG) as a simple noninvasive method before and after induction of thoracic epidural anesthesia. The epidural catheter was inserted at the Th7/8 or Th8/9, and 1% lidocaine at a mean (range) dose of 8 (6-10) mL was injected. Ephedrine bolus was given to patients who demonstrated a decrease in mean arterial blood pressure below 60 mm Hg after induction of thoracic epidural anesthesia (TEA-E group). Other patients did not receive any catecholamines during the study period (TEA group). Ten patients who did not undergo TEA served as controls (control group). RESULTS: In 7 patients, administration of ephedrine was necessary to avoid a decrease in mean arterial blood pressure below 60 mm Hg. Thus, the TEA-E group consisted of 7 patients and TEA group of 33. In the TEA group, thoracic epidural anesthesia was associated with a mean 2.3% min(-1) decrease in PDRICG (P<0.05). In the TEA-E group, all seven patients showed a 2.2% min(-1) decrease in PDRICG (P<0.05). Patients in the control group showed a mean 1.1% min(-1) increase in PDRICG (P<0.05). In contrast to hepatic blood flow, cardiac output was not affected by thoracic epidural anesthesia. CONCLUSIONS: In humans, thoracic epidural anesthesia is associated with a decrease in hepatic blood flow. Thoracic epidural anesthesia combined with ephedrine bolus was found to result in further decrease in hepatic blood flow. PMID- 20966620 TI - Ultrasonic measurement of ocular rectus muscle thickness in patients with Graves' ophthalmopathy. AB - The aim of this study was to evaluate changes in extraocular muscle thickness and to assess its correlation with the degree of proptosis in patients with Graves' ophthalmopathy (GO). MATERIAL AND METHODS: A total of 242 patients (207 females and 35 males) with Graves' ophthalmopathy were enrolled into the study (GO group). Their mean age was 53.83+/-14.49 years. In addition, we examined an age matched (53.51+/-12.79 years) control group of 40 healthy persons. All the participants underwent ophthalmological examination, including eye protrusion measurement and ultrasonographic evaluation of extraocular muscles thickness. RESULTS: The mean exophthalmos in the GO and control groups was 17.84+/-2.79 mm and 16.0+/-1.58 mm, respectively. The enlargement of inferior rectus muscle was recorded in 92.1% of patients, lateral rectus muscle in 81.2%, and medial rectus muscle in 50.8% (P<0.001). A significant correlation between exophthalmos and muscle thickness sum was found in the GO group (Spearman correlation coefficient, 0.515; P<0.0001). CONCLUSIONS: Graves' ophthalmopathy is more frequent in medium aged women than men. A significant enlargement of inferior, lateral, and medial straight muscles was noticed in the GO group. With increasing proptosis, the sum of the muscle thickness was increasing, and exophthalmos moderately correlated with muscle thickness sum. PMID- 20966621 TI - Colonic intussusception caused by colonic lipoma: a case report. AB - Intussusception is a pediatric condition that rarely presents in adults. Colonic lipomas 4 cm and more in diameter can cause colonic intussusception leading to emergency operation. Surgical resection of the involved segment must be the procedure of choice. We report a case of colonic intussusception caused by colonic lipoma in an adult. The patient underwent operation, and histopathological examination of the specimen confirmed the diagnosis of colonic submucosal lipoma. PMID- 20966622 TI - Associations of quality of sleep with lifestyle factors and profile of studies among Lithuanian students. AB - The objective of the study was to analyze associations among quality of sleep, profile of the studies, and lifestyle factors among the students of three different study profiles (medicine, economics, and law). MATERIAL AND METHODS: A total of 405 randomly selected students from the first and fourth years of studies from 4 different universities in Lithuania answered the standardized questionnaires consisting of two parts: 1) the Pittsburgh Sleep Quality Index (PSQI) for subjective evaluation of sleep quality; 2) the questionnaire about sleep and lifestyle habits and impact of poor sleep on the quality of life developed by the researchers. RESULTS: More than half (59.4%) of the students scored higher than 5 on the PSQI, which allowed suspecting sleep disorders. A significant difference in the frequency of poor sleepers was found regarding the profile of studies (P<0.05) showing the highest frequency of sleep disturbances among medical students. There was a significant correlation between quality of sleep and subjective evaluation of quality of life (P<0.01). Medical students experienced the highest impact of poor sleep on the quality of life (P=0.008). Students studying before going to sleep, spending more time studying, and having less leisure time had worse quality of sleep (P<0.01). A significant difference was found among three profiles of studies regarding the anxiety about studies (P<0.0005) and subjective estimation of success in studies (chi2=27.9, P<0.0005), showing the highest anxiety and worst satisfaction among students of medicine. CONCLUSIONS: The incidence of sleep problems is high among students in Lithuania, reaching 59.4%. Medical students have worse quality of sleep and worse impact of poor sleep on the quality of life compared to students of law and economics. A significant difference was found between medical students and their peers in other profiles of studies regarding their attitudes and habits related to studies: medical students spent more time for studying, were more anxious about studies and less satisfied with the results, studied more often before going to sleep. PMID- 20966623 TI - Pseudomonas aeruginosa bacteremia: resistance to antibiotics, risk factors, and patient mortality. AB - The aim of our study was to determine the prevalence of Pseudomonas aeruginosa bacteremia, risk factors, and outcome of patients treated at the Hospital of Kaunas University of Medicine. MATERIAL AND METHODS: All hospitalized patients with blood culture positive for Pseudomonas aeruginosa during the 5-year period were included. A retrospective data analysis was performed to evaluate patients' risk factors and mortality caused by P. aeruginosa bacteremia. RESULTS: A total of 47 (58.8%) bacteremia episodes occurred in an intensive care unit (ICU). A primary source of bacteremia was identified in 50 (62.5%) episodes. Overall mortality rate was 58.8%. Univariate risk factors analysis showed the factors, which significantly increased the risk of death: mechanical ventilation (13.67 times, P<0.001), patient hospitalization in the ICU (8.51 times, P<0.001), acute respiratory failure (8.44 times, P<0.001), infection site in the respiratory tract (4.93 times, P=0.003), and central vein catheter (4.44 times, P=0.002). Timely and appropriate treatment and surgery were significant protective factors for 30-day mortality (11.1 and 5.26 times, respectively; P=0.001). Meropenem resistant Pseudomonas aeruginosa strains caused bacteremia more frequently in patients older than 65 years than meropenem-sensitive strains (57.9%, n=11). All 19 patients with meropenem-resistant Pseudomonas aeruginosa bacteremia received inappropriate empirical antibiotic therapy. CONCLUSIONS: Treatment at the intensive care unit, mechanical ventilation, acute respiratory failure, source of infection in respiratory tract, and central vein catheter are the major risk factors associated with an increased mortality rate in patients with Pseudomonas aeruginosa bacteremia. The patients older than 65 years are at increased risk for bacteremia caused by carbapenem-resistant Pseudomonas aeruginosa strains. Carbapenems are not antibiotics of the choice of treatment for Pseudomonas aeruginosa bacteremia at the Hospital of Kaunas University of Medicine. PMID- 20966624 TI - [Modern approach to treatment of urinary incontinence]. AB - The number of persons having urinary incontinence is increasing with their age; the ratio of women to men with urinary incontinence aged up to 85 years is 2:1, and later the prevalence of this disorder becomes equal in both sexes. Urinary incontinence is a disease influencing the physical activities of persons, their emotional status, working capacity, and social communication. Patients having urination disorders also have psychological problems, feeling of inadequacy, worries about future, and discomfort due to potentially bad smell of urine. The major part of patients dodges to talk in public about existing problem; they are afraid to comment to the doctor about their complaints. Referring to the data of literature sources, there are some methods of treatment of urinary incontinence, which are applied in the clinical practice. After generalization and analysis of different methodologies of treatment, it was determined that in the primary stage of urinary incontinence, the conservative treatment methods are recommended; later, if the effects are not received, the surgical treatment methods are applied. PMID- 20966625 TI - HLA class II alleles and haplotypes in Lithuanian children with type 1 diabetes and healthy children (HLA and type 1 diabetes). AB - OBJECTIVE: Type 1 diabetes mellitus is a slowly progressive autoimmune disease. The genetic background of type 1 diabetes mellitus is polygenic with the major disease locus located in the human leukocytes antigen (HLA) region. High risk and protective alleles, haplotypes, and genotypes have been determined in Lithuanian children with type 1 diabetes mellitus and healthy children. MATERIAL AND METHODS: In this case-control study, 124 children with diabetes (55 males and 69 females; mean age, 9.2+/-3.9 years) were tested for HLA class II and compared with 78 healthy controls (43 males and 35 females; mean age, 10.8+/-3.4 years; range, 0-15 years). HLA DRB1, DQA1, and DQB1 alleles were genotyped using a polymerase chain reaction. RESULTS: T1D risk-associated haplotypes (DR4) DQA1*0301-DQB1*0302, (DR3)-DQA1*0501-DQB1*0201, and (DR1)-DQA1*0101-04-DQB1*0501 were more prevalent among children with diabetes than controls (50.0%, 41.1%, and 37.9% vs. 10.3%, 5.1%, and 24.4%, P<0.001). The haplotypes (DR4)-DQA1*0301 DQB1*0302 and (DR3)-DQA1*0501-DQB1*0201 increased T1D risk by 8.75 and 12.93 times, respectively (P<0.001). Protective haplotypes (DR2)-DQA1*0102-B1*0602, (DR11/12/13)-DQA1*05-DQB1*0301, and (DR13)-DQA1*0103-DQB1*0603 were significantly more prevalent among controls than children with diabetes (25.6%, 33.3%, 19.2% vs. 0%, 3.2%, 0%; P<0.001). These frequencies are quite similar to those from neighbor countries with varying incidence of type 1 diabetes mellitus. CONCLUSIONS: HLA class II haplotypes associated with type 1 diabetes mellitus positively or negatively were the same in Lithuanian children as in other European Caucasian populations. Differences in incidence and clinical manifestations of type 1 diabetes might be due to different environmental factors and/or lifestyle. PMID- 20966626 TI - Acute kidney injury in pediatric patients: experience of a single center during an 11-year period. AB - The aim of our study was to determine the causes of acute kidney injury (AKI) in children, to compare outcomes between two periods--1998-2003 and 2004-2008--and to evaluate the influence of new methods of renal replacement therapy on mortality. MATERIAL AND METHODS: A retrospective analysis of medical record data of all children treated for AKI at the Clinic of Children Diseases, Hospital of Kaunas University of Medicine, during the period of 1998-2008 was made. Both periods were compared regarding various variables. RESULTS: Of the 179 children with AKI, 75 (41.9%) were treated during 1998-2003 and 104 (58.1%) during 2004 2008. Primary glomerular disease and sepsis were the leading causes of AKI in both the periods. AKI without involvement of other organs was diagnosed for 106 (59.2%) children: for 42 (56.0%) children in the first period and 64 (61.5%) in the second. A total of 124 (69.3%) children were treated in a pediatric intensive care unit. Multiple organ dysfunction syndrome with AKI was diagnosed for 33 (44%) patients in the first period and for 40 (38.5%) in the second. A significant decrease in mortality among patients with multiple organ dysfunction syndrome during the second period was observed (78.8% vs. 37.5%). CONCLUSIONS: More than half of patients had secondary acute kidney injury of nonrenal origin. More than two-thirds (69.3%) of patients with AKI were treated in the pediatric intensive care unit. Multiple organ dysfunction syndrome was diagnosed for 40.8% of children with AKI. Renal replacement therapy was indicated for one-third of patients with AKI. A 2.5-fold decrease in mortality was observed in the second period as compared to the first one. PMID- 20966627 TI - Impact of hemodialysis dose and frequency on survival of patients on chronic hemodialysis in Lithuania during 1998-2005. AB - INTRODUCTION: The question of the targets of dialysis dosing remains controversial since the beginning of the long-term dialysis treatment era. It is still uncertain if higher dialysis dose is better. The aim of our study was to investigate issues of dialysis dose in Lithuania during the period of 1998-2005 and to determine associations between hemodialysis dose and survival of patients on chronic hemodialysis. MATERIAL AND METHODS: We analyzed data of all patients who started hemodialysis due to end-stage renal disease in Lithuania between January 1, 1998, and December 31, 2005. The information about hemodialysis frequency, duration, and adequacy (according to Kt/V) was obtained from medical documentation. The overall survival rate was estimated using the Kaplan-Meier method. Survival comparisons were made using the log-rank or Breslow tests. Univariate Cox proportional hazards analysis was used to select variables significantly associated with the risk of death; then these variables were included in multivariate Cox proportional hazards models. RESULTS: During the study period, from 2428 patients who started chronic hemodialysis, 58.5% of patients started hemodialysis three times a week. More than one-third (36.2%) of patients were dialyzed twice weekly, and 5.3% of patients started hemodialysis once weekly. Survival analysis revealed that patients dialyzed less than three times per week survived shorter than patients receiving a higher dialysis dose. Duration of HD session of <=8 hours per week was an independent risk factor for mortality. A higher mean Kt/V was associated with better survival of patients on chronic hemodialysis. CONCLUSIONS: Dialysis frequency and weekly duration of HD sessions were dependent on HD accessibility in Lithuania during the period of 1998-2005. Better survival of patients on chronic hemodialysis was associated with a higher hemodialysis dose. PMID- 20966628 TI - The influence of mean blood pressure on arterial stiffening and endothelial dysfunction in women with rheumatoid arthritis and systemic lupus erythematosus. AB - OBJECTIVE: To investigate the carotid-radial pulse wave velocity, augmentation index, and flow-mediated dilation of the brachial artery and factors possibly influencing them in women with rheumatoid arthritis and systemic lupus erythematosus. MATERIAL AND METHODS: A total of 63 women with rheumatoid arthritis, 31 with systemic lupus erythematosus, and 72 controls, aged 18-55 years, were examined. Parameters of arterial stiffness, augmentation index and carotid-radial pulse wave velocity, were obtained by applanation tonometry (Sphygmocor (v.7.01) AtCor Medical). Flow-mediated dilatation of the brachial artery, reflecting endothelial function was determined by ultrasound system (Logiq 7, General Electric). RESULTS: The groups of women with rheumatoid arthritis and systemic lupus erythematosus lupus differed from controls regarding augmentation index (P<0.001; P=0.008) and did not differ between each other. Women with systemic lupus erythematosus differed from controls regarding pulse wave velocity (P=0.018), while women with rheumatoid arthritis - did not. Flow mediated dilatation in both the groups of diseases was not different from controls. In rheumatoid arthritis patients, mean blood pressure was the main explanatory factor for augmentation index and pulse wave velocity; vessel diameter and high-density lipoprotein cholesterol - for flow-mediated dilatation. In women with systemic lupus erythematosus, pulse wave velocity was not related to any of the pending parameters; augmentation index was dependent on organ damage index, age, and mean blood pressure, and flow-mediated dilatation on vessel diameter, body mass index, and disease duration. CONCLUSIONS: The mean blood pressure was the major and the only one risk factor of arterial stiffening in rheumatoid arthritis, while the disease damage index played the most important role in the systemic lupus erythematosus group. The mean blood pressure in the systemic lupus erythematosus group was not as important as in the rheumatoid arthritis group, though may have a partial influence. PMID- 20966629 TI - The association between health-related quality of life and mortality among hemodialysis patients. AB - INTRODUCTION: Mortality rates for patients undergoing maintenance hemodialysis remain high. Published data regarding association between health-related quality of life (HRQOL) and mortality among hemodialysis patients are inconsistent. Very few data are published on the change in HRQOL over time as a predictor of mortality. The aim of this study was to assess whether HRQOL and change of it over time could be considered an independent predictor of mortality in hemodialysis patients. MATERIAL AND METHODS: This prospective observational study enrolled 183 patients undergoing maintenance hemodialysis. HRQOL was measured annually 2004-2008 using a generic Short Form 36 questionnaire. Physical component summary (PSC) and mental component summary (MSC) scores were calculated. The change of the patient's HRQOL over time was calculated as a difference between SF-36 scores of the first and the last HRQOL measurements. RESULTS: The median follow-up was 48 months (range, 1-72 months). Cutoff values for HRQOL predicting mortality for PSC score was >=35 and for MSC score was >=45. In the model adjusted for age, sex, dialysis months, creatinine, albumin and hemoglobin levels, mortality risk decreased by 0.96 (95% CI, 0.95-0.99) for 1 point increase in the baseline PSC score and decreased by 0.97 (95% CI, 0.95 0.98) for 1-point increase in the baseline MSC score. A 1-point decline in the PSC score (relative risk, 1.11; 95% CI, 1.008-1.221) and MSC score (relative risk, 1.07; 95% CI, 1.002-1.149) over the period of follow-up were associated with a significant additional increase in mortality. CONCLUSIONS: Both baseline HRQOL and decline of HRQOL are independent predictors of mortality in hemodialysis patients. PMID- 20966630 TI - Ten-year experience of kidney transplantation at the Hospital of Kaunas University of Medicine: demography, complications, graft and patient survival. AB - During 10 years, 163 cadaveric kidney transplantations were performed at the Hospital of Kaunas University of Medicine. The aim of this study was to analyze the first 10-year experience in kidney transplantation and to evaluate the most frequent early and late complications after transplantation, graft and patient survival, and impact of delayed graft function on graft survival. MATERIAL AND METHODS: A total of 159 patients were included into the study. Graft and patient survival was calculated at 1, 3, and 5 years after transplantation using the Kaplan-Meier method; graft function was also analyzed. RESULTS: Fifty-three patients (33.3%) in the early period and 72 (55.4%) in the late period had at least one episode of urinary tract infection. Less than half (47.2%) of patients had complications related to immunosuppressive treatment, mostly cytomegalovirus infection, in the late period. The risk of CMV reactivation was 3.98 times higher among recipients who received prophylaxis only with intravenous ganciclovir as compared to patients who received valganciclovir after a brief course of ganciclovir (OR, 3.98; 95% CI, 1.48-8.19; P=0.003). Delayed graft function was observed in 53 cases (33.3%); 37 (23.3%) grafts were lost. Graft and patient survival at 1, 3, and 5 years after transplantation was 85%, 82%, and 71% and 97%, 94%, and 94%, respectively. Graft survival at 1, 3, and 5 years was worse among patients with delayed graft function as compared to patients with good graft function (69%, 69%, 50% vs. 93%, 86%, 84%, respectively; P<0.05). CONCLUSIONS: Urinary tract infection was the most frequent complication after kidney transplantation. Reactivation of cytomegalovirus infection was present only in a quarter of our patients. The administration of valganciclovir was associated with a significantly lower incidence of CMV infection/disease. Graft and patient survival was sufficiently good. Delayed graft function was an independent risk factor for worse graft survival. PMID- 20966631 TI - Risk factors for cardiovascular hospitalization in hemodialysis patients. AB - The aim of this study was to evaluate the risk factors for cardiovascular hospitalization in hemodialysis patients. MATERIALS AND METHODS: A cross sectional cohort analysis of risk factors during one census month (November) and one-year follow-up for cardiovascular hospitalization rates during 5 consecutive years (2002-2006) in all end-stage renal disease patients hemodialyzed in Kaunas region was carried out. During the census month, we collected data on patient's age and sex, disability status, comorbidities, anemia control, malnutrition and inflammation, calcium-phosphorus metabolism, and patient's compliance with prescribed medications. We analyzed 559 patients during 1163 patient-years of observation. Patients were considered as new patients every year (1520 cases). Kaplan-Meier method and Cox regression analysis were used to evaluate time to first hospitalization. RESULTS: The mean number of cardiovascular hospitalizations was 0.31 per patient-year at risk, the total days of cardiovascular hospitalizations per patient-year at risk were 3.93, and the mean length of one hospitalization was 13.2+/-12.9 days. Cardiovascular diseases were the most frequent cause of hospitalization (25% of all hospitalizations). The relative risk of cardiovascular hospitalization increased by 1.03 for every year of age, by 1.7 for worse disability status, by 1.4 for nonadherence to medications, by 1.1 for every additional medication prescribed to the patient. Cardiovascular hospitalization risk was decreased by 0.99 with a 1-g/L rise in hemoglobin level. CONCLUSIONS: Older age, worse disability status, patient's noncompliance with medications, and higher number of medications used were associated with a higher risk for cardiovascular hospitalization. Higher hemoglobin level was associated with a lower risk for cardiovascular hospitalization. PMID- 20966632 TI - Vascular access for hemodialysis: creation, functioning, and complications (data of the Hospital of Kaunas University of Medicine). AB - BACKGROUND: There are no data about arteriovenous fistulas (AVF) formation, survival, and complications rate in patients with end-stage renal failure in Lithuania. MATERIAL AND METHODS: We analyzed the data of patients (N=272) with end-stage renal failure, dialyzed at the Hospital of Kaunas University of Medicine from January 1, 2000, until March 30, 2010, and identified 368 cases of AVF creation. The patients were divided into two groups: group 1 included the patients with an AVF that functioned for <15 months (n=138) and group 2 included patients with an AVF that functioned for >=15 months (n=171). RESULTS AND CONCLUSIONS: Less than half (47%) of the patients started planned hemodialysis and 51% of the patients started hemodialysis urgently. The mean time of AVF functioning was 15.43+/-8.67 months. Age, gender, the kidney disease, and time of AVF maturation had no influence on AVF functioning time. AVFs of the patients who started planned hemodialysis functioned longer as compared to AVFs of the patients who started hemodialysis urgently (P<0.05). Hospitalization time of the patients who started hemodialysis urgently was longer as compared that of the patients who had a matured AVF (37.63+/-20.55 days vs. 16.54+/-9.43 days). The first vascular access had better survival than repeated access. AVF survival in patients with ischemic brain vascular disease was worse than in patients without this comorbidity. PMID- 20966633 TI - The level of endotoxins in hemodialysis water and dialysate in Lithuanian hemodialysis centers. AB - The composition and quality of the dialysis fluid play an important role in the modulation of dialysis-related complications. During hemodialysis, patient's blood has a contact with dialysate through a semipermeable membrane. Bacterial endotoxins can pass through the membrane pores into the patient's blood and cause a silent chronic microinflammation. The aim of this study was to determine the level of endotoxins in hemodialysis water and dialysate in Lithuanian hemodialysis centers. Dialysis water (n=50) and dialysate (n=50) were collected from 91% (n=50) of all hemodialysis centers. The presence of bacterial endotoxins was evaluated using a sensitive Limulus amebocyte lysate test, which detects intact lipopolysaccharides. The level of endotoxins was lower than 0.25 EU/mL in 43 (86%) dialysis water samples and in 46 (92%) dialysate samples, and complied with the recommendations of the European Pharmacopoeia and the European Best Practice Guidelines for pure dialysis fluid. The dialysate of 39 (78%) Lithuanian hemodialysis centers complied with the definition of an ultrapure dialysis fluid. The water and dialysate were of insufficient quality in 14% and in 8% of Lithuanian hemodialysis centers, respectively, and this could be improved by the establishment of routine investigation of endotoxins. PMID- 20966634 TI - The usage of blood components in obstetrics. AB - Major obstetric hemorrhage remains the leading cause of maternal morbidity and mortality worldwide. Even though blood transfusion may be a life-saving procedure, an inappropriate usage of blood products in obstetric emergencies especially in cases of massive bleeding is associated with increased morbidity and risk of death. Thorough knowledge of the etiology, pathophysiology, and optimal therapeutic options of major obstetric hemorrhage may help to avoid lethal outcomes. There are evidence-based data about some risks related with transfusion of blood components: acute or delayed hemolytic, febrile, allergic reactions, transfusion-related acute lung injury, negative immunomodulative effect, transmission of infectious diseases, dissemination of cancer. This is why the indications for allogeneic blood transfusion are restricted, and new safer methods are being discovered to decrease the requirement for it. Red cell alloimmunization may develop in pregnancy; therefore, all pregnant women should pass screening for irregular antibodies. Antierythrocytic irregular antibodies may occur due to previous pregnancies or allogeneic red blood cell transfusions, and it is important for blood cross-matching in the future. Under certain circumstances, such as complicated maternal history, severe coagulation abnormalities, severe anemia, the preparation of cross-matched blood is necessary. There is evidence of very significant variation in the use of blood products (red cells, platelets, fresh frozen plasma, or cryoprecipitate) among clinicians in various medical institutions, and sometimes indications for transfusion are not correctly motivated. The transfusion of each single blood product must be performed only in case of evaluation of expected effect. The need for blood products and for their combination is necessary to estimate for each patient individually in case of obstetric emergencies either. Indications for transfusion of blood components in obstetrics are presented in order to improve the skills of doctors and to optimize therapeutic options in obstetric emergencies. PMID- 20966635 TI - Low-dose UVB irradiation stimulates matrix metalloproteinase-1 expression via a BLT2-linked pathway in HaCaT cells. AB - Skin exposure to low-dose ultraviolet B (UVB) light up-regulates the expression of matrix metalloproteinase-1 (MMP-1), thus contributing to premature skin aging (photo-aging). Although cyclooxygenase-2 (COX- 2) and its product, prostaglandin E(2) (PGE((2))), have been associated with UVB-induced signaling to MMP expression, very little are known about the roles of lipoxygenases and their products, especially leukotriene B((4)) (LTB((4))) and 12(S) hydroxyeicosatetraenoic acid (12(S)-HETE), in MMP-1 expression in skin keratinocytes. In the present study, we demonstrate that BLT2, a cell surface receptor for LTB((4)) and 12(S)-HETE, plays a critical role in UVB-mediated MMP-1 upregulation in human HaCaT keratinocytes. Moreover, our results demonstrated that BLT2-mediated MMP-1 upregulation occurs through a signaling pathway dependent on reactive oxygen species (ROS) production and the subsequent stimulation of ERK. Blockage of BLT2 via siRNA knockdown or with the BLT2 antagonist LY255283 completely abolished the up-regulated expression of MMP-1 induced by low-dose UVB irradiation. Finally, when HaCaT cells were transiently transfected with a BLT2 expression plasmid, MMP-1 expression was significantly enhanced, along with ERK phosphorylation, suggesting that BLT2 overexpression alone is sufficient for MMP-1 up-regulation. Together, our results suggest that the BLT2-ROS- ERK-linked cascade is a novel signaling mechanism for MMP-1 upregulation in low-dose UVB- irradiated keratinocytes and thus potentially contributes to photo-aging. PMID- 20966636 TI - Affective style and eating disorders: a field study. AB - Eating disorders (ED) are a heterogeneous group of problems related to restraint and/or overeating. It is proposed that individual differences in affective reactivity and moods (affective style) might be related to these behaviours. Variations in affective style are expressed by differing levels of sensitivity to the motivation systems of approach and avoidance. The present study tested whether a relation exists between ED and variations in the sensitivity of motivational systems as well as mood dispositions. A total of 2020 undergraduate students completed the Eating Disorder Diagnostic Scale (EDDS), the Behavioural Inhibition System and Behavioural Activation System Scales (BIS/BAS), and the Positive and Negative Affect Schedule (PANAS). The results showed a significant within- subject interaction of Alimentary group x Motivation (F=4.056; p<0.007). It was also observed that the Overeating group had lower levels of motivation asymmetry than the Normal (p<0.01) and Restrictive (p<0.005) groups and marginally lower levels than the Purgative group (p<0.07). The study results suggest mainly that the avoidance/inhibition motivational system is related to eating problems connected with overeating, including chronic alimentary restraint (chronic dieters). The theoretical and clinical implications of these findings are discussed. PMID- 20966638 TI - Current world literature. PMID- 20966641 TI - Bibliography. Biomarkers of outcomes of disease, treatment and complication. Current world literature. PMID- 20966640 TI - Biomarkers in immune reconstitution inflammatory syndrome: signals from pathogenesis. AB - PURPOSE OF REVIEW: Immune reconstitution inflammatory syndrome (IRIS) is the paradoxical worsening or unmasking of an infection or neoplasm in HIV-1-infected patients shortly after antiretroviral therapy (ART) initiation. New insights into the pathogenesis of IRIS may help identify biomarkers that could be useful in predicting or diagnosing IRIS. RECENT FINDINGS: Studies of immunopathogenesis have shown a signification activation of both innate and adaptive immune responses with elevation of plasma or serum chemokines and cytokines. Markers of inflammation such as C-reactive protein, interferon-inducible protein 10 or interferon gamma may be helpful as predictors of IRIS events. In addition, tuberculosis (TB)-associated IRIS is associated with a prominent Th1 response that can be heightened even prior to ART initiation in cases of unmasking TB, and may assist in early diagnosis. Large prospective studies are needed to elucidate the predictive and diagnostic value of IRIS biomarkers and advance them to the clinic. SUMMARY: Reversal of immunosuppression by ART leads to exaggerated pathogen-specific immune responses (known as IRIS) that appear to be primed prior to therapy. Inflammatory markers, chemokines and cytokines that signify innate and adaptive immune activation are biomarkers that could prove of clinical value after appropriate validation. PMID- 20966642 TI - Glutathione S-transferase M1, T1, and P1 polymorphisms and ovarian cancer risk: a meta-analysis. AB - INTRODUCTION: Cytosolic glutathione S-transferase (GST) comprises multiple isoenzymes that catalyze reactions between glutathione and lipophilic compounds with electrophilic centers, resulting in the neutralization of toxic compounds, xenobiotics, and products of oxidative stress. Several studies have examined whether GST polymorphisms (GSTM1 null/present genotype, GSTT1 null/present genotype, and GSTP1 Ile105Val) represent risk factors for ovarian cancer, as they all may denote reduced enzyme activity. This meta-analysis aimed to examine the associations between the aforementioned polymorphisms and ovarian cancer risk. METHODS: The MEDLINE database was searched up to September 2009 using the appropriate terms. Case-control studies with no mutually overlapping populations were selected. Pooled odds ratios (ORs) were appropriately derived from fixed effects or random-effects models. Meta-regression with publication year was also performed. RESULTS: Eight studies regarding GSTM1 null polymorphism status (2357 cases and 3044 controls), 6 studies concerning GSTT1 null polymorphism (1923 cases and 2759 controls), and 3 studies on GSTP1 Ile105Val were included in the meta-analysis. The GSTM1 null genotype was not associated with an increased risk for ovarian cancer (pooled OR, 1.031; 95% confidence interval, 0.867-1.226; random effects). The GSTT1 null genotype was not associated with an increased ovarian cancer risk (pooled OR, 0.934; 95% confidence interval, 0.804-1.086; random effects); similarly, no significant associations were demonstrated for GSTP1 Ile105Val. CONCLUSIONS: The examined GSTM1, GSTT1, and GSTP1 genotype polymorphisms do not seem to confer any additional risk for ovarian cancer. Given that the studies included in this meta-analysis involve mainly white populations, these results cannot be extrapolated on other populations, and additional data are needed for future race-specific analyses. PMID- 20966643 TI - LAPTM4B-35 overexpression is an independent prognostic marker in endometrial carcinoma. AB - BACKGROUND: Lysosomal protein transmembrane 4 beta-35 (LAPTM4B-35), a novel oncoprotein that belongs to the mammalian 4-tetratransmembrane spanning protein superfamily, has been implicated in oncogenesis and cancer progression in several solid malignances. However, the expression of LAPTM4B-35 and its role in endometrial cancer progression remain unknown. MATERIALS AND METHODS: We investigated the expression of the LAPTM4B-35 protein by immunohistochemistry in 30 normal endometrium specimens and 165 endometrial carcinomas and analyzed its correlation with various clinicopathologic features, including patient outcome. RESULTS: LAPTM4B-35 immunoreactivity was overexpressed in endometrial carcinoma cases compared with normal endometrium (P < 0.001). High LAPTM4B-35 expression was found in 117 (70.91%) of these 165 carcinomas and was positively correlated with the International Federation of Gynecology and Obstetrics stage, histological grade, depth of myometrial invasion, lymph node metastasis, lymph vascular space involvement, and recurrence, but not with age and histological type. Patients with high LAPTM4B-35 expression had significantly poorer overall survival and disease-free survival compared with patients with low expression of LAPTM4B-35 (P = 0.001 and P = 0.002, respectively). Multivariate analysis showed that high LAPTM4B-35 expression was an independent prognostic factor for both overall survival and disease-free survival of patients with endometrial carcinoma (both P = 0.005). CONCLUSIONS: These results showed that high LAPTM4B-35 expression was associated with progression and prognosis of endometrial carcinoma. PMID- 20966644 TI - The use of immunohistochemistry in the diagnosis of metastatic clear cell renal cell carcinoma: a review of PAX-8, PAX-2, hKIM-1, RCCma, and CD10. AB - The diagnosis of metastatic clear cell renal cell carcinoma may be difficult in some cases, particularly in the small image-guided biopsies that are becoming more common. As targeted therapies for renal cell carcinoma are now standard treatment, the recognition and diagnosis of renal cell carcinoma has become even more critical. Many adjunctive immunohistochemical markers of renal epithelial lineage such as CD10 and RCCma have been proposed as aids in the diagnosis of metastatic renal cell carcinoma, but low specificities often limit their utility. More recently described markers (PAX-2, PAX-8, human kidney injury molecule-1, hepatocyte nuclear factor-1-beta, and carbonic anhydrase-IX) offer the potential for greater sensitivity and specificity in this diagnostic setting; however, knowledge of their expected staining in other neoplasms and tissues is critical for appropriate use. In this review, we discuss the most widely used immunohistochemical markers of renal lineage with an emphasis on their sensitivity and specificity for metastatic clear cell renal cell carcinoma. Subsequently, we present a variety of organ-specific differential diagnostic scenarios in which metastatic clear cell renal cell carcinoma might be considered and we propose immunopanels for use in each situation. PMID- 20966645 TI - Human papillomavirus detection in head and neck squamous cell carcinomas. AB - Squamous cell carcinomas of the head and neck (HNSCC) are a frequent diagnosis in anatomic pathology practice. Tobacco use and heavy alcohol consumption are known risk factors for HNSCC but in other cases human papillomavirus (HPV) is linked to carcinogenesis. HPV proteins E6 and E7 promote oncogenesis by blocking the action of p53 and pRB, respectively. An absence of p53 mutations in addition to expression of p16 are part of the distinct molecular profile identified in the subset of HNSCCs because of HPV. Various methods are available for HPV detection but polymerase chain reaction and in situ hybridization techniques are commonly used. Both methods are amenable for testing formalin-fixed paraffin-embedded tissue that is a sample type readily available to the pathologist. HPV is detectable in approximately a quarter of all HNSCCs, and is particularly prevalent in the oropharynx in which the positivity rates approach 40%. A vast majority of HPV-related HNSCCs are owing to HPV type 16 with types 18, 31, and 33 accounting for almost all of the remaining cases. HPV-related HNSCCs are associated with better prognosis for both recurrence and survival. This group of tumors has also been shown to respond well to radiation treatment. As the clinical relevance of HPV in HNSCCs continues to emerge, anatomic pathologists are likely to receive increasing requests for testing. Herein, the authors review the biological and clinical aspects of HPV-associated HNSCC and review techniques for HPV detection. PMID- 20966646 TI - Immunohistology--past, present, and future. AB - The rapid development of immunohistochemistry, a morphology-based technique, has come about through refinements in detection systems and an increasing range of sensitive and specific antibodies that have allowed application of the technique to formalin-fixed, paraffin-embedded tissues. The introduction of heat-induced antigen retrieval has been a significant milestone to compliment these developments so that the immunohistochemistry is firmly entrenched as an indispensable adjunct to morphologic diagnosis. Although this ancillary stain was initially used in a qualitative manner, problems surrounding the many variables that influence antigen preservation in formalin-fixed, paraffin-embedded tissues were not a major issue and laboratories strived to optimize their staining protocols to the material they accessioned and processed. The advent of personalized medicine and targeted cancer treatment has imposed the need to quantitate the stain reaction product and has resulted in calls to standardize the process of immunostaining. A closer examination of the variables that influence the ability to show antigens in formalin-fixed, paraffin-embedded tissues revealed many important variables, particularly in the preanalytical phase of the assay, that are beyond the control of the accessioning laboratory. Although analytical factors have the potential to be standardized, the actions of many pivotal procedures including fixation and antigen retrieval are not completely understood. Postanalytical processes including threshold and cut-off values require consensus and standardization and it is clear that some of these goals can be achieved through the direction of national and international organizations associated with cancer diagnosis and treatment. With the ability to serve as a surrogate marker of many genetic abnormalities, immunohistochemistry enters a new era and the need to better understand some of the mechanisms fundamental to the technique become more pressing and the development of true quantitative assays is imperative. There is also an increasing appreciation that the technique highlights patterns of staining that reflect exquisite localization to organelles and tissue structures that are not appreciable in routine stains, adding a further dimension to morphologic diagnosis. PMID- 20966647 TI - Pineal tumors. AB - Pineal tumors are a rare and heterogeneous group of primary central nervous system neoplasms, including pineal parenchymal tumors (pineocytomas, pineal parenchymal tumors of intermediate differentiation, and pineoblastomas), germ cell tumors, and neuroepithelial tumors, such as astrocytomas, ependymomas, and papillary tumor of the pineal region. Their classification has evolved over time, with several updates incorporated into the most recent World Health Organization classification, published in 2007. This review highlights the most recent classification and grading scheme for pineal parenchymal tumors and discusses the newly recognized papillary tumor of the pineal region, including clinicopathologic features, differential diagnosis, and management options. PMID- 20966648 TI - Thyroid cancer of follicular cell origin in inherited tumor syndromes. AB - Well-differentiated thyroid cancer accounts for 95% of thyroid malignancies. In contrast to medullary thyroid carcinoma, in which about 25% are familial, only 5% of follicular cell-derived thyroid carcinomas are a component of a familial cancer syndrome. The familial follicular cell-derived tumors or nonmedullary thyroid carcinoma encompass a heterogeneous group of diseases, and are classified into 2 distinct groups: syndromic-associated tumors, occurring in syndromes in which nonmedullary thyroid carcinomas are the predominant tumor encountered, and nonsyndromic tumors, those occurring in tumor syndromes in which thyroid involvement is a minor component. The first group, syndromic-associated tumors, includes phosphase and tensin (PTEN)-hamartoma tumor syndrome/Cowden syndrome, familial adenomatous polyposis/Gardner syndrome, Carney complex type 1, Werner syndrome, and Pendred syndrome. Other syndromes, as McCune Albright syndrome, Peutz-Jeghers syndrome, and Ataxia-teleangiectasia syndrome may be associated with the development of follicular cell-derived tumors, but the link is less established than the above syndromes. The syndromic-associated tumors are the focus of this review. The second group of familial follicular cell-derived tumors syndromes or nonsyndromic tumors, in which nonmedullary thyroid carcinomas are the major findings, include pure familial papillary thyroid carcinoma, with or without oxyphilia, familial papillary thyroid carcinoma with papillary renal cell carcinoma, and familial papillary thyroid carcinoma with multinodular goiter. This review will discuss the clinical and pathological findings of the patients with familial syndrome-associated tumors: PTEN-hamartoma tumor syndrome/Cowden syndrome, familial adenomatous polyposis syndrome, Carney complex type 1, Werner syndrome, and Pendred syndrome. PMID- 20966649 TI - Recent trends in quality, patient safety, and error reduction in nongyn cytology. AB - This article reviews recent trends in nongyn cytology with an emphasis on error reduction, second opinion, and critical diagnosis. Compared with the surgical pathology literature, there is only a limited number of reports addressing these topics in nongyn cytology. Discussion of the error literature in nongyn cytology is presented with the intent to better identify error-prone cytology cases that could prompt intradepartmental consultation or an outside cytology expert's second opinion. The cytology second-opinion literature is also reviewed with the recommendation that interinstitutional second opinions add value to patient care. Last, the recent concept of critical value (critical diagnosis) in cytopathology is presented. All these initiatives promote patient safety, improve quality, decrease errors, and benefit patients. PMID- 20966652 TI - Epiphanies. PMID- 20966650 TI - Selected case from the Arkadi M. Rywlin International Pathology Slide Seminar: Sporadic lymphangioleiomyomatosis. AB - Lymphangioleiomyomatosis (LAM) is a systemic, progressive, and fatal condition affecting almost exclusively women in their reproductive years. LAM most often occurs as a sporadic disease, but also occurs in women with tuberous sclerosis complex (TSC) (syndromic LAM). There are no pathologic differences between sporadic and syndromic LAM. Sporadic LAM is a rare disease with prevalence of approximately 1 to 2 cases per million women in the United States and among populations of white descent, and is even rarer among Asian and African individuals. Syndromic LAM affects 4% to 5% of women with TSC. Sporadic LAM is often found also in association with renal angiomyolipoma, the most common sign of TSC, but LAM associated with angiomyolipoma does not define TSC. Although LAM is not diagnostic for TSC either in isolation or in association with angiomyolipoma, still it is considered by some researchers as an incomplete expression (forme fruste) of TSC. LAM may involve the lungs and the axial lymphatics and lymph nodes of the thorax and retroperitoneum. In sporadic LAM, thoracic, intraabdominal, and cervical lymph nodes can be involved with or without lung involvement. The diagnosis of LAM is often delayed. A case of LAM in a young lady, which was complicated with pleural and peritoneal chylous effusions, is presented. The diagnosis was first made on a retroperitoneal lymph node biopsy. The patient had a prolonged prior history of respiratory problems owing to lung involvement, and eventually died 2 years after diagnosis. Focus on the clinicopathologic diagnosis of TSC is also made. PMID- 20966655 TI - RE: Kesik et al: melatonin ameliorates doxorubicin-induced skin necrosis in rats. PMID- 20966658 TI - Risk stratification, risk adjustment, and other risks. PMID- 20966659 TI - Risk stratification index: an important advance in comparing health care apples to oranges. PMID- 20966661 TI - Broadly applicable risk stratification system for predicting duration of hospitalization and mortality. AB - BACKGROUND: Hospitals are increasingly required to publicly report outcomes, yet performance is best interpreted in the context of population and procedural risk. We sought to develop a risk-adjustment method using administrative claims data to assess both national-level and hospital-specific performance. METHODS: A total of 35,179,507 patient stay records from 2001-2006 Medicare Provider Analysis and Review (MEDPAR) files were randomly divided into development and validation sets. Risk stratification indices (RSIs) for length of stay and mortality endpoints were derived from aggregate risk associated with individual diagnostic and procedure codes. Performance of RSIs were tested prospectively on the validation database, as well as a single institution registry of 103,324 adult surgical patients, and compared with the Charlson comorbidity index, which was designed to predict 1-yr mortality. The primary outcome was the C statistic indicating the discriminatory power of alternative risk-adjustment methods for prediction of outcome measures. RESULTS: A single risk-stratification model predicted 30-day and 1-yr postdischarge mortality; separate risk-stratification models predicted length of stay and in-hospital mortality. The RSIs performed well on the national dataset (C statistics for median length of stay and 30-day mortality were 0.86 and 0.84). They performed significantly better than the Charlson comorbidity index on the Cleveland Clinic registry for all outcomes. The C statistics for the RSIs and Charlson comorbidity index were 0.89 versus 0.60 for median length of stay, 0.98 versus 0.65 for in-hospital mortality, 0.85 versus 0.76 for 30-day mortality, and 0.83 versus 0.77 for 1-yr mortality. Addition of demographic information only slightly improved performance of the RSI. CONCLUSION: RSI is a broadly applicable and robust system for assessing hospital length of stay and mortality for groups of surgical patients based solely on administrative data. PMID- 20966663 TI - Short-term memory impairment after isoflurane in mice is prevented by the alpha5 gamma-aminobutyric acid type A receptor inverse agonist L-655,708. AB - BACKGROUND: Memory blockade is an essential component of the anesthetic state. However, postanesthesia memory deficits represent an undesirable and poorly understood adverse effect. Inhibitory alpha5 subunit-containing gamma aminobutyric acid subtype A receptors (alpha5GABAA) are known to play a critical role in memory processes and are highly sensitive to positive modulation by anesthetics. We postulated that inhibiting the activity of alpha5GABAA receptors during isoflurane anesthesia would prevent memory deficits in the early postanesthesia period. METHODS: Mice were pretreated with L-655,708, an alpha5GABAA receptor-selective inverse agonist, or vehicle. They were then exposed to isoflurane for 1 h (1.3%, or 1 minimum alveolar concentration, or air oxygen control). Then, either 1 or 24 h later, mice were conditioned in fear associated contextual and cued learning paradigms. In addition, the effect of L 655,708 on the immobilizing dose of isoflurane was studied. Motor coordination, sedation, anxiety, and the concentration of isoflurane in the brain at 5 min, 1 h, and 24 h after isoflurane were also examined. RESULTS: Motor and sensory function recovered within minutes after termination of isoflurane administration. In contrast, a robust deficit in contextual fear memory persisted for at least 24 h. The alpha5GABAA receptor inverse agonist, L-655,708, completely prevented memory deficits without changing the immobilizing dose of isoflurane. Trace concentrations of isoflurane were measured in the brain 24 h after treatment. CONCLUSIONS: Memory deficits occurred long after the sedative, analgesic, and anxiolytic effects of isoflurane subsided. L-655,708 prevented memory deficit, suggesting that an isoflurane interaction at alpha5GABAA receptors contributes to memory impairment during the early postanesthesia period. PMID- 20966666 TI - Does erythrocyte blood transfusion prevent acute kidney injury? Propensity matched case control analysis. AB - BACKGROUND: Acute kidney injury is a common occurrence in intensive care unit patients with a reported incidence of 11-67% and is associated with an increased risk of death. In other patient populations, erythrocyte transfusion has been associated with increased risk of adverse outcomes including sepsis, multisystem organ dysfunction, and death. The purpose of this study was to determine the effect of erythrocyte transfusion on the development of acute kidney injury. METHODS: This was a retrospective analysis of prospectively collected data that used propensity matched transfused and nontransfused patients. Propensity matching was done using semiparsimonious logistic regression. McNemar test for nonindependent data sets was used to compare groups. RESULTS: Four hundred two patients from a trial on fluid management in patients with acute lung injury were matched. 38% of transfused patients had a rise in creatinine the day after transfusion compared with 33% of their nontransfused matches (P = 0.315). By day 7, creatinine had increased in 51% of transfused patients compared with 52% in nontransfused patients (P = 0.832). The incidences of renal risk, injury, and failure were 39 (19%), 27 (13%), and 11 (5%) in the transfused group and 38 (19%), 24 (12%), and 11 (5%) in the nontransfused group, P = 1.00, 0.785, and 1.00, respectively. CONCLUSIONS: Transfusion of erythrocytes to patients with acute lung injury had no effect on the development of acute kidney injury. PMID- 20966667 TI - Femoral nerve block improves analgesia outcomes after total knee arthroplasty: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Femoral nerve blockade (FNB) is a common method of analgesia for postoperative pain control after total knee arthroplasty. We conducted a systematic review to compare the analgesia outcomes in randomized controlled trials that compared FNB (with and without sciatic nerve block) with epidural and patient-controlled analgesia (PCA). METHODS: We identified 23 randomized controlled trials that compared FNB with PCA or epidural analgesia. These studies included 1,016 patients, 665 with FNB, 161 with epidural, and 190 with PCA alone. RESULTS: All 10 studies of single-shot FNB (SSFNB) used concurrent PCA opioids. SSFNB was found to reduce PCA morphine consumption at 24 h (-19.9 mg, 95% credible interval [CrI]: -35.2 to -4.6) and 48 h (-38.0 mg, 95% CrI: -56.0 to 19.7), pain scores with activity (but not at rest) at 24 and 48 h (-1.8 visual analog pain scale, 95% CrI: -3.3 to -0.02 at 24 h; -1.5 visual analog pain scale, 95% CrI: -2.9 to -0.02 at 48 h) and reduce the incidence of nausea (0.37 odds ratio, 95% CrI: 0.1 to 0.9) compared with PCA alone. SSFNB had similar morphine consumption and pain scores compared with SSFNB plus sciatic nerve block, and SSFNB plus continuous FNB. CONCLUSIONS: SSFNB or continuous FNB (plus PCA) was found to be superior to PCA alone for postoperative analgesia for patients having total knee arthroplasty. The impact of adding a sciatic block or continuous FNB to a SSFNB needs to be studied further. PMID- 20966668 TI - Risk factors for persistent postherniorrhaphy pain: unresolved. PMID- 20966669 TI - Neurotoxicity of anesthetic agents and the developing brain in rodents and primates: the time has come to focus on human beings. PMID- 20966672 TI - Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain: isoflurane or ischemia-reperfusion? PMID- 20966673 TI - Postoperative cognitive decline: the unsubstantiated phenotype. PMID- 20966675 TI - Permeability, osmosis, and edema. PMID- 20966677 TI - Effects of pterygium on ocular aberrations. AB - PURPOSE: To compare high-order aberration between the eyes with pterygium and normal fellow eyes. SETTING: Ophthalmic Research Center and Department of Ophthalmology Labbafinejad Medical Center Shahid Beheshti University of Medical Sciences Tehran, Iran. METHOD: This comparative cross-sectional study comprised 31 patients with unilateral pterygium. NIDEK OPD-Scan wavefront aberrometry was performed in all patients in both eyes. Then, aberometric parameters were compared between the eyes. RESULTS: Sixty-two eyes of 31 patients (23 men and 8 women) with a mean age of 42.5 +/- 5.9 years were included in the study. Root mean square (RMS) of total higher-order aberration increased statistically significantly in the involved eyes compared with normal fellow eyes (1.85 +/- 2.22 and 0.36 +/- 0.44 MUm; P = 0.001). All RMS of Zernike orders and all RMS of different aberrations were higher in the involved eyes group and were statistically significant except for spherical aberration. The most significant differences belonged to RMS of total trefoil (1.37 vs. 0.25 MUm) and RMS of total coma (0.37 vs. 0.14 MUm) (P = 0.0001). With decreasing the uninvolved optical zone (increasing the size of pterygium), RMS of all aberrations increased and the differences were statistically significant except for spherical aberration. CONCLUSION: Pterygium and its size have significant influence on high-order aberrations of the eye especially on measured total coma and total trefoil in compared with normal fellow eye. PMID- 20966678 TI - Femtosecond-assisted descemet stripping automated endothelial keratoplasty with fibrin glue-assisted sutureless posterior chamber lens implantation. AB - PURPOSE: We report a surgical technique for managing postsurgical aphakia with endothelial decompensation. The technique comprises femtosecond laser-assisted Descemet stripping automated endothelial keratoplasty (DSAEK) with fibrin glue assisted sutureless posterior chamber intraocular lens (IOL) implantation-"glued IOL". METHODS: Three eyes (of 3 patients) underwent the technique. The donor lenticules were created on a 60-kHz femtosecond laser platform (Intralase; Abott Medical Optics, Santa Ana, CA). Two partial-thickness scleral flaps and sclerotomies were made in host. After this, the Descemet was scored and stripped. A 3-piece 6.5-mm posterior chamber IOL was inserted, and its haptics were externalized through the sclerotomies. The haptics were then tucked into intrascleral pockets. The donor lenticule was inserted into the anterior chamber and unfolded. Air tamponade and pull suture manipulations were used to stabilize and center it. The partial-thickness scleral flaps were apposed with fibrin glue. RESULTS: The uncorrected and best-corrected visual acuities improved in all cases. There were no donor dislocations. The average donor endothelial cell loss was 27.7% at 6 months. CONCLUSIONS: Our series suggests that there is a benefit of glued IOL with DSAEK in such scenarios. It also has potential benefits as a combined procedure with DSAEK in comparison to anterior chamber IOL because it does not reduce the anterior chamber volume, does not require intact iris tissue, and unlike suture-fixated IOL, does not have knot slippage or pseudophakodonesis. PMID- 20966679 TI - Corneal neurotization: a novel technique for the anesthetic cornea: retraction. PMID- 20966681 TI - Predicting parametrial involvement in endometrial cancer: is this the end for radical hysterectomies in stage II endometrial cancers? PMID- 20966682 TI - Epidemiologic research using administrative databases: garbage in, garbage out. PMID- 20966683 TI - The "new" green journal web site: one-stop shopping. PMID- 20966684 TI - Does standardization of care through clinical guidelines improve outcomes and reduce medical liability? PMID- 20966685 TI - Evaluation of parametrial spread in endometrial carcinoma. AB - OBJECTIVE: To evaluate the detailed clinicopathologic characteristics of parametrial spread in uterine endometrial cancer. METHODS: We retrospectively identified 334 individuals with uterine endometrial cancer who had undergone radical hysterectomy between 1988 and 2007. Parametrial spread was determined by histopathological analysis of surgically resected specimens. RESULTS: Twenty eight (8.4%) individuals had histopathologically confirmed parametrial spread, and lymphatic or blood vessel invasion (22 cases) was the most frequently observed type of parametrial spread; direct invasion to parametrial connective tissue (five cases) or cardinal lymph node metastasis (four cases) were less frequently observed. Parametrial spread occurred not only in individuals with cervical involvement but also in individuals with more than half myometrial invasion, retroperitoneal (pelvic, paraaortic, or both), lymph node metastasis, ovarian metastasis, positive peritoneal cytology results, and lymphovascular space invasion. Twenty-six individuals (92.9%) with parametrial spread showed more than one of these histopathological factors (median number of factors 3, range 1-6); the other two individuals had lymphovascular space invasion alone. In 10 individuals with parametrial spread (35.7%), the condition recurred during the median follow-up period of 49 months, and initial recurrence was observed in the lung in six individuals (60.0%). Although the long-term prognosis for those with parametrial spread was significantly poorer than that of those without parametrial spread, both among all individuals (P<.001) and among individuals with International Federation of Gynecology and Obstetrics stage III (P<.05), multivariate analysis showed that parametrial spread was not an independent prognostic factor for uterine endometrial cancer. CONCLUSION: Parametrial spread cannot be predicted by cervical involvement alone but may be predicted by various lymphovascular space invasion-related histopathologic factors. Further, parametrial spread may not be an independent prognostic factor in individuals with uterine endometrial cancer. LEVEL OF EVIDENCE: III. PMID- 20966686 TI - Cervical stromal invasion predicting survival in endometrial cancer. AB - OBJECTIVE: To estimate the extent to which cervical stromal invasion would predict survival. METHODS: Cases of stage II endometrioid endometrial adenocarcinoma from three academic institutions were reviewed. A gynecologic pathologist reevaluated archived slides and measured the depth of cervical stromal invasion. Clinical data were abstracted and statistical analysis performed. RESULTS: Of 116 cases, 31 (27%) had gland involvement and 85 (73%) cervical stromal invasion. Cervical stromal invasion was categorized as the inner two thirds (n=59 [69%]) compared with the outer third (n=26 [31%]). Women with outer third cervical stromal invasion compared with those with inner two-thirds cervical stromal invasion were more likely to be aged at least 65 years (69% compared with 46%, P=.038), have at least 50% myometrial invasion (77% compared with 44%, P=.004), lymphvascular space invasion (46% compared with 20%, P=.016), and to have died (50% compared with 19%, P=.004). Overall survival for patients with no invasion and inner two-thirds cervical stromal invasion did not differ (106 compared with 146 months, P=.89). Survival for outer third cervical stromal invasion was 91 months (P=.021). Multivariable analysis found deep myometrial invasion (hazard ratio 3.1; confidence interval [CI], 1.2-8.2), lymphvascular space invasion (hazard ratio 3.2; CI 1.2-8.4), and outer third cervical stromal invasion (hazard ratio 2.8; CI 1.1-7.2) were independent predictors of death. CONCLUSION: Deep (outer third) cervical stromal invasion is an independent predictor of death in stage II endometrial cancers and these patients should receive radiation therapy. Superficial cervical stromal invasion did not increase risk of death and adjuvant radiation for this patient group may not be necessary. LEVEL OF EVIDENCE: III. PMID- 20966687 TI - The presence of human papillomavirus or p16 in six cases of retroperitoneal carcinoma. AB - OBJECTIVE: To describe six cases of unknown primary carcinoma of the retroperitoneum that were positive for human papillomavirus (HPV), a surrogate molecular marker for high-risk HPV (p16), or both. METHODS: Using the MD Anderson pathology database, females with confirmed HPV or p16 expression within retroperitoneal carcinomas of unknown primary were identified. Clinical data were collected by retrospective chart review. One pathologist reviewed all histology. Individuals with known primary were excluded. Data regarding individual demographics, presentation, Pap test history, pathology, HPV and p16 positivity, and outcome were analyzed using descriptive statistics. RESULTS: Six individuals were identified. The median age of the individuals was 43.5 years (range 27-54). Three malignancies (50%) were squamous and three (50%) were undifferentiated. Median follow-up was 12 months (range 6-48 months). Two of the six (33%) individuals had remote histories (more than 10 years) of abnormal Pap test results. All had normal gynecologic examination and Pap test results at diagnosis. Four tumors were HPV-positive (66%) and six were p16-positive (100%). All samples that were HPV-positive were also p16-positive. All individuals underwent treatment with chemotherapy, radiation, or both. One individual underwent initial attempt at resection that was unsuccessful. Two individuals are without evidence of disease, two have had progression of disease, and two have died of their disease. CONCLUSION: Pelvic masses of unknown primary may be HPV related despite normal cervical examinations. LEVEL OF EVIDENCE: III. PMID- 20966688 TI - Precursors for late preterm birth in singleton gestations. AB - OBJECTIVE: To characterize precursors for late preterm birth in singletons and incidences of neonatal morbidities and perinatal mortality by gestational age and precursor. METHODS: Using retrospective observational data, we compared 15,136 gestations born late preterm with 170,593 deliveries between 37 0/7 and 41 6/7 weeks. We defined the following categories of precursors for late preterm delivery: "spontaneous labor," "premature rupture of the membranes (preterm PROM)," "indicated" delivery, and "unknown." Incidences of neonatal morbidities were calculated according to category of precursor stratified by gestational age at delivery. Neonatal morbidities and mortality associated with potentially avoidable deliveries (eg, "soft" precursors or elective) were compared between late preterm births and neonates born at 37-40 weeks. RESULTS: Late preterm birth comprised 7.8% of all births and 65.7% of preterm births. Percentages of precursors were 29.8% spontaneous labor, 32.3% preterm PROM, 31.8% "indicated" (obstetric, maternal, or fetal condition), and 6.1% unknown. Different precursors for delivery were associated with varying incidences of neonatal morbidity. One in 15 neonates delivered late preterm for "soft" or elective precursors, and neonatal morbidity and mortality were increased compared with delivery at or after 37 weeks for these same indications. CONCLUSION: A significant number of late preterm births were potentially avoidable. Elective deliveries should be postponed until 39 weeks of gestation. LEVEL OF EVIDENCE: II. PMID- 20966689 TI - Leiomyomas at routine second-trimester ultrasound examination and adverse obstetric outcomes. AB - OBJECTIVE: To estimate the risk of adverse pregnancy outcomes associated with the presence of leiomyomas. METHODS: This was a retrospective cohort study of all consecutive singleton pregnancies from 1990 to 2007 undergoing routine second trimester fetal anatomic ultrasound survey. The presence or absence of leiomyomas was noted at second-trimester ultrasound examination. Primary and secondary obstetric outcomes were obtained as the individual progressed to delivery. Women with at least one leiomyoma at the time of second-trimester anatomic survey were compared with women without leiomyomas. Primary outcomes were intrauterine fetal death, breech presentation, placenta previa, cesarean delivery, placental abruption, preeclampsia, intrauterine fetal growth restriction, preterm premature rupture of membranes, and preterm birth. Univariable and multivariable analyses were performed. RESULTS: Of 72,373 women who underwent routine second-trimester anatomic survey, 64,047 women had complete obstetric follow-up data. The incidence of leiomyomas was 3.2% (n=2,058). Breech presentation (5.3% compared with 3.1%, adjusted odds ratio [OR] 1.5, 95% confidence interval [CI]1.3-1.9), placenta previa (1.4% compared with 0.5%, adjusted OR 2.2, 95% CI 1.5-3.2), cesarean delivery (33.1% compared with 24.2%, adjusted OR 1.2, 95% CI 1.1-1.4), placental abruption (1.4% compared with 0.7%, adjusted OR 2.1, 95% CI 1.4-3.0), preterm premature rupture of membranes (3.3% compared with 2.4%, adjusted OR 1.3, 95% CI 1.0-1.7), preterm birth less than 37 weeks (15.1% compared with 10.5%, adjusted OR 1.5, 95% CI 1.3-1.8), and less than 34 weeks (3.9% compared with 2.8%, adjusted OR 1.4, 95% CI 1.0-1.8), and intrauterine fetal death in women with a fetus with growth restriction (3.9% compared with 1.5%, adjusted OR 2.5, 95% CI 1.2-5.0) were significantly associated with the presence of leiomyomas. CONCLUSION: Women with leiomyomas are at low risk for obstetric complications compared with women without leiomyomas. LEVEL OF EVIDENCE: II. PMID- 20966690 TI - Depressive disorders during pregnancy: prevalence and risk factors in a large urban sample. AB - OBJECTIVE: To estimate the prevalence of major and minor depression, panic disorder, and suicidal ideation during pregnancy while also identifying factors independently associated with antenatal depressive disorders. METHODS: In this prospective study, participants were 1,888 women receiving ongoing prenatal care at a university obstetric clinic from January 2004 through January 2009. Prevalence of psychiatric disorders was measured using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria based on the Patient Health Questionnaire. Multiple logistic regression identified factors associated with probable major depressive disorder and any depressive disorder. RESULTS: Antenatal depressive disorders were present in 9.9% with 5.1% (97) meeting criteria for probable major depression and 4.8% (90) meeting criteria for probable minor depression. Panic disorder was present in 3.2% (61), and current suicidal ideation was reported by 2.6% (49). Among patients with probable major depression, 29.5% (28) reported current suicidal ideation. Psychosocial stress (odds ratio [OR], 1.29; 95% confidence interval [CI], 1.21-1.36), domestic violence (OR 3.45; 95% CI 1.46-8.12), chronic medical conditions (OR 3.05; 95% CI 1.63-5.69), and race (Asian: OR 5.81; 95% CI 2.55-13.23; or African American: OR 2.98; 95% CI 1.24-7.18) each significantly increased the odds of probable antepartum major depressive disorder, whereas older age (OR 0.92; 95% CI 0.88 0.97) decreased the odds. Factors associated with odds of any depression were similar overall except that Hispanic ethnicity (OR 2.50; 95% CI 1.09-5.72) also independently increased the odds of any depression. CONCLUSION: Antenatal major and minor depressive disorders are common and significantly associated with clinically relevant and identifiable risk factors. By understanding the high point prevalence and associated factors, clinicians can potentially improve the diagnosis and treatment rates of serious depressive disorders in pregnant women. LEVEL OF EVIDENCE: II. PMID- 20966691 TI - One-year follow-up of women with unfulfilled postpartum sterilization requests. AB - OBJECTIVE: To track outcomes of women in three cohorts-those who requested postpartum tubal ligation and received the procedure (postpartum tubal ligation [PPTL] YES), those who requested postpartum tubal ligation but did not receive the procedure (PPTL NO), and a control group (those who did not request postpartum tubal ligation)-for 1 year postpartum. METHODS: This was a record review evaluating women who delivered a liveborn singleton between December 2007 and May 2008 at the University of Texas San Antonio. Those in the case group were monitored until 1 year postdelivery. The primary outcome was pregnancy within 1 year of the index delivery among women in the control group compared with those in the PPTL NO group. Secondary outcomes included birth control requested at obstetric-admission discharge, attendance at a postpartum or other gynecology visit, contraceptive use between delivery and the postpartum visit, and request for contraception at the postpartum visit among the three cohorts. RESULTS: During the observation period, 429 of 1,460 women requested postpartum tubal ligation; 296 (69%) received the procedure and 133 (31%) did not. Within 1 year of the index delivery, 46.7% of women in the PPTL NO group became pregnant compared with 22.3% of those in the control group (P<.001). Attendance at the postpartum visit was lowest for women in the PPTL YES group (12.8%; P=.004) compared with the similarly low attendance among those in the PPTL NO (18.8%) and control groups (20.3%; P=.73). Women in the PPTL NO group and those in the control group selected similar methods of postpartum contraception at hospital discharge. CONCLUSION: Women who did not receive a requested postpartum tubal ligation were more likely to become pregnant within 1 year of delivery than were those in the control group (women not requesting permanent sterilization). LEVEL OF EVIDENCE: II. PMID- 20966692 TI - Postplacental or delayed insertion of the levonorgestrel intrauterine device after vaginal delivery: a randomized controlled trial. AB - OBJECTIVE: To estimate whether 6-month use of the levonorgestrel-releasing intrauterine device (IUD) would be higher when insertion occurred within 10 minutes of placental delivery compared with 6-8 weeks postpartum. METHODS: We enrolled pregnant women planning vaginal deliveries and desiring a postpartum levonorgestrel-releasing IUD. Patients were randomly assigned when admitted in labor to postplacental or delayed IUD insertion. The women followed up in person at 6-8 weeks and 6 months and were contacted by telephone at 3 months. Women were ineligible for a study IUD postenrollment for intrapartum events including infection, hemorrhage, and cesarean delivery; these women were contacted by phone at 3 and 6 months. Expelled IUDs were replaced per patient preference. RESULTS: Successful IUD placement occurred in 50 of 51 participants (98.0%) and 46 of 51 participants (90.2%) in the postplacental and delayed groups, respectively (P=.2). Expulsion within 6 months occurred in 12 of 50 (24.0%; 95% confidence interval [CI], 13.1-38.2) and two of 46 (4.4%; 95% CI 0.5-14.8) participants, respectively (P=.008). Intrauterine device use at 6 months was 43 of 51 (84.3%; 95% CI 71.4-93.0) and 39 of 51 (76.5%; 95% CI 62.5-87.2), respectively (P=.32). For ineligible patients, only 11 of 41 (26.8%) women were using IUDs at 6 months and two (4.9%) had become pregnant. CONCLUSION: Intrauterine device use 6 months after delivery is similar in women who have postpartum or scheduled delayed IUD placement through a study after replacement of expelled IUDs. Expulsions are significantly higher with postplacental compared with delayed IUD placement. Women asked to follow up with their own health care providers for delayed insertion are significantly less likely to receive an IUD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00476021. LEVEL OF EVIDENCE: I. PMID- 20966693 TI - Elective oophorectomy in the United States: trends and in-hospital complications, 1998-2006. AB - OBJECTIVES: To examine trends in rates of elective bilateral salpingo oophorectomy in the United States and to assess the association of perioperative complications with elective bilateral salpingo-oophorectomy. METHODS: This cross sectional study uses 1998-2006 data from the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, a nationally representative sample of inpatient hospitalizations. Analyses were limited to women aged 15 years or older at average risk for ovarian cancer who underwent hysterectomy for a benign gynecologic condition. Tests for trends in elective bilateral salpingo oophorectomy rates were performed using weighted least squares regression for two time periods, 1998 to 2001 and 2002 to 2006. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for risks of complications associated with elective bilateral salpingo-oophorectomy were estimated using logistic regression. RESULTS: During the period from 1998 to 2006, 39% of the 2,250,041 women who underwent hysterectomy for benign gynecologic indications had elective bilateral salpingo-oophorectomy (rate, 8.3 per 10,000). The elective bilateral salpingo oophorectomy rate increased from 7.8 per 10,000 in 1998 to 9.0 per 10,000 in 2001 (P trend <.05) and decreased from 9.0 per 10,000 in 2002 to 7.4 per 10,000 in 2006 (P trend <.05). The largest decline from 2002 to 2006 (20.3%) occurred among those aged 45 to 49 years. Compared with hysterectomy only, elective bilateral salpingo-oophorectomy was associated with an increased risk of complications when performed vaginally (OR 1.12; 95% CI 1.08-1.17) and a decreased risk of complications when performed abdominally (OR 0.91; 95% CI 0.89-0.94) or laparoscopically (OR 0.89; 95% CI 0.83-0.94). CONCLUSION: Elective bilateral salpingo-oophorectomy rates declined since 2002. However, the risks compared with the benefits of the procedure have not been clearly established. Prospective studies examining elective bilateral salpingo-oophorectomy with and without estrogen therapy are needed to guide practice patterns. LEVEL OF EVIDENCE: III. PMID- 20966694 TI - Lifetime risk of undergoing surgery for pelvic organ prolapse. AB - OBJECTIVE: To investigate the lifetime risk of first-time incident pelvic organ prolapse (POP) surgery with the intention of updating previous risk estimates that have been based on members of managed-care populations. METHODS: Age specific incidence rates of first-time prolapse surgery between 1981 and 2005 were calculated based on 44,728-incident cases. We estimated the lifetime risk as the cumulative incidence to age 85 years based on a life-table method and using the most recent cross-sectional incidence rates for the period 2001-2005. Age standardized rates by calendar year were also calculated to show the secular trend in prolapse surgery. RESULTS: The lifetime risk of surgery for POP in the general female population was 19% based on the most recent cross-sectional rates, a figure higher than the 11-12% reported from U.S. managed-care populations. CONCLUSION: There is a relatively high likelihood that a woman in Western Australia will undergo surgery for POP during her lifetime. If, as our results suggest, the burden of genital prolapse in general populations is higher than previously thought, there is justification for a stronger evidence base for prevention, early detection and intervention to reduce the personal and societal costs of these gynecological conditions. LEVEL OF EVIDENCE: II. PMID- 20966695 TI - The cavitated accessory uterine mass: a Mullerian anomaly in women with an otherwise normal uterus. AB - OBJECTIVE: To present clinical cases of women who had an accessory and cavitated noncommunicating uterine mass with functioning endometrium associated with a normal uterus, suggestive of a new type of Mullerian anomaly. METHODS: We report on five institutional cases: four cases of cavitated accessory uterine mass and a case of true adenomyoma. A review of the literature was performed by looking for these terms and others related in MEDLINE. RESULTS: Including ours, there are 18 cases in the literature showing an accessory cystic cavity lined by endometrioid epithelium with an otherwise normal uterus. Another 11 cases only partially fulfilled the inclusion criteria. All of the first cases were in young women presenting with severe dysmenorrhea (n=4). Generally, the tumor was located in the anterior wall of the uterus at the level of insertion of the round ligament. It presents a certain similarity with the cavitated true adenomyomas observed in older women in whom the endometrial lining of the cystic cavity is generally absent. For differential diagnosis with cavitated noncommunicating rudimentary uterine horns, hysterosalpingography showing a normal eutopic uterine cavity is decisive. CONCLUSION: Noncommunicating accessory uterine cavities and isolated cystic adenomyomas correspond to the same pathology: cavitated accessory uterine mass associated with an otherwise normal uterus. They present problems of differential diagnosis with true cavitated adenomyomas and cavitated rudimentary uterine horns. Accessory uterine mass could be caused by duplication and persistence of ductal Mullerian tissue in a critical area at the attachment level of the round ligament, possibly related to a gubernaculum dysfunction. LEVEL OF EVIDENCE: III. PMID- 20966696 TI - Within-population average ranges compared with Institute of Medicine recommendations for gestational weight gain. AB - OBJECTIVE: To compare the risk for pregnancy outcomes by gestational weight gain with the Institute of Medicine criteria and empirically established average ranges of gestational weight gain. METHODS: In a population-based data set comprising 678,560 singleton deliveries in Bavarian obstetric units from 2000 to 2007, we calculated the prevalence of adverse short-term pregnancy outcomes within the gestational weight-gain ranges recommended by the Institute of Medicine. We then compared these for gestational weight gain within data-based interquartile ranges (25th to 75th percentile) and interdecile ranges (10th to 90th percentile) of gestational weight gain by maternal weight category (underweight, normal weight, overweight, and obese). RESULTS: In underweight and normal-weight mothers, adherence to Institute of Medicine criteria was significantly associated with fewer preterm deliveries and small-for-gestational age births (prevalence [95% confidence interval] for preterm delivery in normal weight women: 5.33 [5.23-5.43] within Institute of Medicine criteria compared with 5.45 [5.36-5.54] in interquartile range). Overweight and obese mothers gaining weight within the Institute of Medicine recommendations had less preeclampsia and nonelective caesarean deliveries but had higher risks for gestational diabetes, small-for-gestational-age births, preterm delivery, and perinatal mortality compared with gestational weight gain within the respective interquartile ranges and interdecile ranges (prevalence for preterm delivery in overweight women: 8.14% [7.87-8.42] within Institute of Medicine criteria compared with 5.77% [5.60-5.93] in interquartile range). CONCLUSION: Although underweight and normal-weight women should be encouraged to aim for a gestational weight gain according to Institute of Medicine guidelines, different gestational weight gain recommendations in overweight and obese women might lessen some adverse short-term pregnancy outcomes. LEVEL OF EVIDENCE: II. PMID- 20966697 TI - Prepregnancy risk factors for antepartum stillbirth in the United States. AB - OBJECTIVE: To identify possible prepregnancy risk factors for antepartum stillbirth and to determine whether these factors identify women at higher risk for term stillbirth. METHODS: This retrospective cohort study of prepregnancy risk factors compared 712 singleton antepartum stillbirths with 174,097 singleton live births at or after 23 weeks of gestation. The risk of term antepartum stillbirth then was assessed in a subset of 155,629 singleton pregnancies. RESULTS: In adjusted multivariable analyses, African-American race, Hispanic ethnicity, maternal age 35 years or older, nulliparity, prepregnancy body mass index (BMI) 30 or higher, preexisting diabetes, chronic hypertension, smoking, and alcohol use were independently associated with stillbirth. Prior cesarean delivery and history of preterm birth were associated with increased stillbirth risk in multiparous women. The risk of a term stillbirth for women who were white, 25-29 years old, normal weight, multiparous, no chronic hypertension, and no preexisting diabetes was 0.8 per 1,000. Term stillbirth risk increased with the following conditions: preexisting diabetes (3.1 per 1,000), chronic hypertension (1.7 per 1,000), African-American race (1.8 per 1,000), maternal age 35 years or older (1.3 per 1,000), BMI 30 or higher (1 per 1,000), and nulliparity (0.9 per 1,000). CONCLUSION: There are multiple independent risk factors for antepartum stillbirth. However, the value of individual risk factors of race, parity, advanced maternal age (35-39 years old), and BMI to predict term stillbirth is poor. Our results do not support routine antenatal surveillance for any of these risk factors when present in isolation. LEVEL OF EVIDENCE: II. PMID- 20966698 TI - Length of the first stage of labor and associated perinatal outcomes in nulliparous women. AB - OBJECTIVE: To estimate whether length of the first stage of labor is associated with adverse maternal and neonatal outcomes. METHODS: This is a retrospective cohort study of nulliparous women with term, singleton gestations delivered in one academic center between 1990 and 2008. The length of the first stage was stratified into three subgroups: less than the 5th percentile, 5th to 95th percentile, and greater than the 95th percentile. Maternal and neonatal outcomes were compared using the chi test. Multivariable logistic regression models were used to control for confounders. RESULTS: Of the 10,661 nulliparous women meeting study criteria, the median (50th percentile) length of the first stage was 10.5 hours. Compared with women with a first stage between 2.8 and 30 hours (5th to 95th percentile thresholds), the risk of cesarean delivery was higher (6.1% compared with 13.5%; adjusted odds ratio [OR], 2.28, 95% confidence interval [CI], 1.92-2.72) in women with a first stage longer than 30 hours (greater than the 95th percentile). These women also had higher odds of chorioamnionitis (12.5% compared with 23.5%; adjusted OR, 1.58; 95% CI, 1.25-1.98) and neonatal admission to the neonatal intensive care unit (4.7% compared with 9.8%; adjusted OR, 1.53; 95% CI, 1.18-1.97) but no other associated adverse neonatal outcomes. CONCLUSION: Women with a prolonged first stage of labor have higher odds of cesarean delivery and chorioamnionitis, but their neonates are not at risk of increased morbidity. LEVEL OF EVIDENCE: II. PMID- 20966699 TI - Unplanned pregnancy in women with anorexia nervosa. AB - OBJECTIVE: To compare the frequency with which unplanned pregnancies occur in individuals with anorexia nervosa relative to women without eating disorders in the Norwegian Mother and Child Cohort Study. METHOD: In a sample of 62,060 women, 62 reported anorexia nervosa. Using data from a questionnaire completed by all participating mothers, we compared mother's age at birth and the frequency with which mothers reported their index pregnancy as being unplanned. RESULTS: Women with anorexia nervosa were younger (26.2 years, standard deviation 4.76) than women with no eating disorder (29.9 years, standard deviation 4.60) at the time of birth. Significantly more women with anorexia nervosa (50.0%) reported unplanned pregnancy than women in the referent group (18.9%). After adjustment for maternal age and infertility treatment, the relative risk of unplanned pregnancy in individuals with anorexia nervosa was 2.11 (95% confidence interval 1.64-2.72). Induced abortion was also significantly more common in women with anorexia nervosa than referent women (24.2% compared with 14.6%). CONCLUSION: The higher rate of unplanned pregnancy and abortion in women with anorexia nervosa is of clinical concern because absent or irregular menstruation may be misinterpreted as decreasing risk of pregnancy. LEVEL OF EVIDENCE: II. PMID- 20966700 TI - Comparative performance of the 2009 international Federation of gynecology and obstetrics' staging system for uterine corpus cancer. AB - OBJECTIVE: To perform a population-based analysis comparing the performance of the 1988 and 2009 International Federation of Gynecology and Obstetrics (FIGO) staging systems. METHODS: Women with endometrioid adenocarcinoma of the uterus treated between 1988 and 2006 and recorded in the Surveillance, Epidemiology, and End Results database were analyzed. Women were classified based on 1988 and 2009 FIGO staging systems. Major changes in the 2009 system include: 1) classification of patients with stage IA and IB tumors as stage IA; 2) elimination of stage IIA; and 3) stratification of stage IIIC into pelvic nodes only (IIIC1) or paraaortic nodal (IIIC2) involvement. Survival and use of adjuvant therapy were analyzed. RESULTS: A total of 81,902 women were identified. Based on the 1988 staging system, survival for stage IA was 90.7% (95% confidence interval [CI], 90-91%) compared with 88.9% (95% CI 88-89%) for IB tumors. In the 2009 system, survival was 89.6% (95% CI 89-90%) for stage IA and 77.6% (95% CI 76-79%) for stage IB. The survival for FIGO 1988 stage IIA was superior to stage IC, whereas in the 2009 system, survival for stage II was inferior to all stage I patients. The newly defined stage IIIC substages are prognostically different. Survival for stage IIIC1 was 57.0% (95% CI 54-60%) compared with 49.4% (95% CI 46-53%) for stage IIIC2. CONCLUSION: The 2009 FIGO staging system for uterine corpus cancer is highly prognostic. The reduction in stage I substages and the separation of stage III will further clarify important prognostic features. LEVEL OF EVIDENCE: III. PMID- 20966701 TI - Analysis of outcomes of microinvasive adenocarcinoma of the uterine cervix by treatment type. AB - OBJECTIVE: To estimate the risk of metastatic disease in microinvasive adenocarcinoma of the cervix in a large cohort. METHODS: Thirty-six cases were identified from the Mayo Clinic health information database, and 30 cases were identified using the University of Southern California gynecologic oncology patient database. Histopathology was reviewed by a single pathologist at each institution to confirm histologic subtype and grade of tumor, depth of invasion, linear extent of the tumor, the presence or absence of lymphovascular space invasion, margin status, parametrial involvement, and the presence of nodal metastasis. RESULTS: Fifty-two patients had stage IA1 cancers and 14 had stage IA2 cancers. Therapy ranged from cold knife conization to radical hysterectomy with lymphadenectomy. No parametrial involvement was noted in any of the patients who underwent parametrial resection. One patient with stage IA1 cancer had micrometastasis to a pelvic lymph node. No recurrences were noted with an average follow-up of 80 months. CONCLUSION: The management of microinvasive adenocarcinoma remains controversial, and radical therapy is applied more frequently to microinvasive adenocarcinoma than microinvasive squamous cell carcinoma of the cervix. The risk of extracervical disease is low and the risk of recurrence is not affected by the radicality of resection. Our data suggest that microinvasive adenocarcinoma is amenable to treatment with nonradical surgery. LEVEL OF EVIDENCE: III. PMID- 20966702 TI - Surveillance after treatment for cervical intraepithelial neoplasia: outcomes, costs, and cost-effectiveness. AB - OBJECTIVE: To estimate outcomes and costs of surveillance strategies after treatment for high-grade cervical intraepithelial neoplasia (CIN). METHODS: A hypothetical cohort of women was evaluated after treatment for CIN 2 or 3 using a Markov model incorporating data from a large study of women treated for CIN, systematic reviews of test accuracy, and individual preferences. Surveillance strategies included initial conventional or liquid-based cytology, human papillomavirus testing, or colposcopy 6 months after treatment, followed by annual or triennial cytology. Estimated outcomes included CIN, cervical cancer, cervical cancer deaths, life expectancy, costs, cost per life-year, and cost per quality-adjusted life-year. RESULTS: Conventional cytology at 6 and 12 months, followed by triennial cytology, was least costly. Compared with triennial cytology, annual cytology follow-up reduced expected cervical cancer deaths by 73% to 77% and had an average incremental cost per life-year gained of $69,000 to $81,000. For colposcopy followed by annual cytology, the incremental cost per life-year gained ranged from $70,000 to more than $1 million, depending on risk. Between-strategy differences in mean additional life expectancy per woman were less than 4 days; differences in mean incremental costs per woman were as high as $822. In the cost-utility analysis, colposcopy at 6 months followed by annual cytology had an incremental cost per quality-adjusted life-year of less than $5,500. Human papillomavirus testing or liquid-based cytology added little to no improvement to life-expectancy with higher costs. CONCLUSION: Annual conventional cytology surveillance reduced cervical cancers and cancer deaths compared with triennial cytology. For high risk of recurrence, a strategy of colposcopy at 6 months increased life expectancy and quality-adjusted life expectancy. Human papillomavirus testing and liquid-based cytology increased costs, but not effectiveness, compared with traditional approaches. PMID- 20966703 TI - Reproductive outcomes for survivors of childhood cancer. AB - Because of remarkable progress in therapy, long-term survival is expected for 80% of children and adolescents diagnosed with cancer. Infertility remains one of the most common and life-altering complications experienced by adults treated for cancer during childhood. Surgery, radiation, or chemotherapy that negatively affects any component of the hypothalamic-pituitary-gonadal axis may compromise reproductive outcomes in childhood cancer survivors. The risk of infertility is generally related to the tissues or organs involved in cancer and the specific type, dose, and combination of cytotoxic therapy. In addition to anticancer therapy, age at treatment, sex, and likely genetic factors influence the risk of permanent infertility. When possible, contemporary protocols limit cumulative doses of cytotoxic therapy in an effort to optimize reproductive potential. If sterilizing therapy is required for cancer control, then fertility preservation measures should be explored before initiation of therapy. For childhood cancer survivors who maintain fertility, health risks to offspring resulting from their cancer treatment are major concerns. Radiation affecting ovarian and uterine function has been linked to pregnancy complications, including spontaneous abortion, preterm labor, fetal malposition, and low birth weight. The risk of congenital malformations, genetic disorders, and cancer appears to be low, with the exception of cancer risk in offspring born to survivors with germline cancer predisposing mutations. This review summarizes research about cancer treatment factors affecting fertility and pregnancy outcomes of childhood cancer survivors. The data presented should facilitate the delivery of preventive counseling and age- and sex-appropriate interventions to optimize reproductive outcomes in childhood cancer survivors. PMID- 20966704 TI - "Miracle" extremely low birth weight neonates: examples of developmental plasticity. AB - Many extremely low birth weight (LBW) neonates now survive with intensive care. Their survival depends on fetal and neonatal adaptations of multiple organ systems, which represents a plasticity of development. Many extremely LBW neonates do not have severe lung immaturity, will breathe, and do not require surfactant treatment. The two clinically relevant modulators of this early lung maturation are antenatal corticosteroid treatments and fetal exposure to inflammation. Those same frequent fetal exposures also can mature the fetal innate immune system to become more proinflammatory. However, repeated fetal exposures to inflammatory mediators can blunt fetal inflammatory responses, which may minimize fetal injury. The brain of the extremely LBW neonate grows differently from that of the normal fetus such that brain volumes are different at term for the extremely LBW neonate and the term neonate. Regions of brain used to process information also differ from the child who was born very preterm and the child born at term. The adaptations that permit survival after very preterm birth may have adverse effects in later life. The biology of multiple organ system plasticities resulting from very preterm birth remains to be extensively explored. PMID- 20966705 TI - Recommendations for weight gain during pregnancy in the context of the obesity epidemic. AB - The Institute of Medicine and the National Research Council have issued new guidelines for gestational weight gain as well as recommendations for action and research that call for "a radical change in the care provided to women of childbearing age." For the first time, these guidelines consider the outcomes of both mother and child during and after delivery and the trade-offs between them. The recommendations call for women to begin pregnancy at a healthy weight and to gain within the guidelines, a goal not previously achieved. They also call for individualized preconceptional, prenatal, and postpartum care to help women attain a healthy weight, gain within the guidelines, and return to a healthy weight. Scientific evidence was inadequate to provide specific guidelines by obesity class or to support a public health recommendation to reduce the guidelines below 5-9 kg (11-20 lb) for obese women. PMID- 20966706 TI - The oncogenic potential of endometrial polyps: a systematic review and meta analysis. AB - OBJECTIVE: To systematically review and summarize the medical literature regarding the association of menopausal status, uterine bleeding, and polyp size and risk of malignancy among women undergoing polyp resection. DATA SOURCES: We supplemented a search of entries in electronic databases with references cited in original studies and review articles to identify studies assessing the risk of malignancy for patients undergoing polypectomy. Key word searches were performed using the words "endometrial polyp," "malignancy," "ultrasound," "saline sonohysterography," "hysteroscopy," and "histopathology." METHODS OF STUDY SELECTION: We evaluated abstracted data and performed quantitative analyses in observational studies assessing the effects of menopausal status, vaginal bleeding, and polyp size on the risk of malignancy in patients undergoing polyp resection (n=1,552). For each study with binary outcomes, relative risks with 95% confidence intervals (CIs) were calculated. Estimates of relative risk were calculated using fixed and random-effects models. Homogeneity was tested across the studies. Sensitivity analyses were performed to determine the effects of individual studies on the overall effect estimates. Publication bias was assessed using Egger test. TABULATION, INTEGRATION, AND RESULTS: Seventeen studies met inclusion criteria for this review. Among women found to have endometrial polyps, the prevalence of premalignant or malignant polyps was 5.42% (214 of 3,946) in postmenopausal women compared with 1.7% (68 of 3,997) in reproductive-aged women (relative risk 3.86; 95% CI 2.92-5.11). The prevalence of endometrial neoplasia within polyps in women with symptomatic bleeding was 4.15% (195 of 4,697) compared with 2.16% (85 of 3,941) for those without bleeding (relative risk 1.97; 95% CI 1.24-3.14). Among symptomatic postmenopausal women with endometrial polyps, 4.47% (88 of 1,968) had a malignant polyp in comparison to 1.51% (25 of 1,654) asymptomatic postmenopausal women (relative risk 3.36; 95% CI 1.45-7.80). CONCLUSION: Based on data from observational studies, both symptomatic vaginal bleeding and postmenopausal status in women with endometrial polyps are associated with an increased risk of endometrial malignancy. PMID- 20966707 TI - Hormonal contraceptives for contraception in overweight or obese women. AB - BACKGROUND: Obesity has reached epidemic proportions around the world. Metabolic changes in obesity and greater body mass may lead to reduced effectiveness of hormonal contraceptives, such as the skin patch, vaginal ring, implants, and injectables. We systematically reviewed the evidence on the effectiveness of hormonal contraceptives among overweight and obese women. OBJECTIVES: To examine the effectiveness of hormonal contraceptives in preventing unplanned pregnancies among women who are overweight or obese versus women of lower weight or body mass index (BMI). SEARCH STRATEGY: We searched MEDLINE, CENTRAL, POPLINE, EMBASE, ClinicalTrials.gov, and ICTRP. We also contacted investigators to identify other trials. SELECTION CRITERIA: All study designs were eligible. Any type of hormonal contraceptive could have been examined. The primary outcome was pregnancy. Overweight or obese women must have been identified by an analysis cutoff for weight or BMI (kg/m). DATA COLLECTION AND ANALYSIS: Data were abstracted by two authors; life-table rates were included where available. For dichotomous variables, we computed an odds ratio with 95% (CI). The main comparisons were between overweight or obese women of lower weight or BMI. MAIN RESULTS: We found 7 reports with data from 11 trials that included 39,531 women. One of three studies using BMI found a higher pregnancy risk for overweight or obese women. In the trial of two combination oral contraceptives, women with BMI >=25 had greater pregnancy risk compared to those with BMI <25 (OR 1.91; 95% CI 1.01 to 3.61). Among skin patch users, body weight was associated with pregnancy (reported P<.001) but BMI was not. Studies of a vaginal ring (never marketed) and a six-rod implant showed higher pregnancy rates for women weighing >=70 kg versus those weighing <70 kg (reported P values: 0.0013 and <0.05, respectively). However, two implant studies showed no trend by body weight, and trials of an injectable had no pregnancies. AUTHORS' CONCLUSION: Body weight addresses overall body size, while BMI generally reflects the amount of fat. Only one of three studies using BMI found a higher pregnancy risk for overweight women. The efficacy of implants and injectable contraceptives may be unaffected by body mass. The field could use trials of contraceptive methods with groups stratified by BMI. The current evidence on effectiveness by BMI is limited. However, the contraceptive methods examined here are still among the most effective when recommended regimen is followed. PMID- 20966713 TI - The new mammographic screening guidelines: what were they thinking? PMID- 20966714 TI - American Congress of Obstetricians and Gynecologists' grievance process. PMID- 20966715 TI - American congress of obstetricians and gynecologists' grievance process. PMID- 20966716 TI - No time for complacency: labor inductions, cesarean deliveries, and the definition of "term". PMID- 20966717 TI - Special requirements of electronic medical record systems in obstetrics and gynecology. PMID- 20966718 TI - Maternal outcome after conservative treatment of placenta accreta. PMID- 20966719 TI - Discordant blood chimerism in dizygotic monochorionic laser-treated twin-twin transfusion syndrome. PMID- 20966723 TI - From human papillomavirus to cervical cancer. PMID- 20966725 TI - Regionalization of care for obstetric hemorrhage and its effect on maternal mortality. PMID- 20966727 TI - Overlapping compared with end-to-end repair of third- and fourth-degree obstetric anal sphincter tears: a randomized controlled trial. PMID- 20966730 TI - Practice bulletin no. 116: Management of intrapartum fetal heart rate tracings. AB - Intrapartum electronic fetal monitoring (EFM) is used for most women who give birth in the United States. As such, clinicians are faced daily with the management of fetal heart rate (FHR) tracings. The purpose of this document is to provide obstetric care providers with a framework for evaluation and management of intrapartum EFM patterns based on the new three-tiered categorization. PMID- 20966731 TI - Committee opinion no. 471: Smoking cessation during pregnancy. AB - Smoking is the one of the most important modifiable causes of poor pregnancy outcomes in the United States, and is associated with maternal, fetal, and infant morbidity and mortality. The physical and psychologic addiction to cigarettes is powerful; however, the compassionate intervention of the obstetrician gynecologist can be the critical element in prenatal smoking cessation. An office based protocol that systematically identifies pregnant women who smoke and offers treatment or referral has been proved to increase quit rates. A short counseling session with pregnancy-specific educational materials and a referral to the smokers' quit line is an effective smoking cessation strategy. The 5A's is an office-based intervention developed to be used under the guidance of trained practitioners to help pregnant women quit smoking. Knowledge of the use of the 5A's, health care support systems, and pharmacotherapy add to the techniques providers can use to support perinatal smoking cessation. PMID- 20966732 TI - Committee opinion no. 472: Patient safety and the electronic health record. AB - The electronic health record (EHR) has the potential to improve the quality, safety, and efficiency of patient care when fully implemented, yet adoption of this tool has been slow. The advantages of the EHR include facilitating improved communication between health care providers; assisting with medication safety, tracking, and reporting; and promoting quality of care through optimized compliance with guidelines. Despite obstacles to widespread adoption and implementation, use of the EHR as a real-time, evidence-based support tool can help busy obstetrician-gynecologists improve the quality of the care they provide through improved care coordination, communication, and documentation. PMID- 20966733 TI - Treatment of the burn patient in primary care. PMID- 20966734 TI - MMP-2 and TIMP-2 in cutaneous melanoma: association with prognostic factors and description in cutaneous metastases. PMID- 20966736 TI - Traumatic ulcerative granuloma with stromal eosinophilia: a lesion with alarming histopathologic presentation and benign clinical course. AB - Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is a chronic, benign, self-limiting lesion of the oral mucosa. Clinically, the ulceration is characterized by the presence of indurated elevated borders and may resemble pyogenic granuloma or even squamous cell carcinoma of the mouth. Pathogenesis of the lesion is unclear. Although it had been suggested that TUGSE may represent a CD30+ lymphoproliferative disorder, this theory is currently not supported by evidence. We are presenting a classic example of TUGSE, its clinical course, differential diagnosis, and treatment. PMID- 20966737 TI - Value of Merkel cell polyomavirus DNA detection in routine pathology. PMID- 20966738 TI - What is extraocular cutaneous sebaceous carcinoma in situ? PMID- 20966739 TI - Postmortem orbital hemorrhage in the investigation of child abuse. PMID- 20966740 TI - Muscle stiffness in critical illness is not a form of rigor mortis. PMID- 20966741 TI - Sudden death during prolonged religious fasting. AB - Sickle cell trait (SCT) is estimated to occur in 6% to 10% of Africans, and the United Kingdom (UK) prevalence rate has been estimated at 3.2%. Although sudden death in sickle cell disease is well known, its occurrence in SCT is rare and requires extremes of physiological stress. We present a case of a 29-year-old black woman who died suddenly during a period of religious fasting. Her medical history was unremarkable, and there was no family history of sickle cell disease. At postmortem, she was found to be dehydrated, and macroscopically, the main abnormal findings were congested lungs and a small spleen. Histological examination revealed extensive vascular congestion with red blood cell sickling in both lungs, the liver, and the spleen. Electrophoresis on a postmortem blood sample confirmed the clinical suspicion that the patient was a carrier of SCT. The case highlights a novel scenario of SCT associated sudden death. We discuss the potential pathophysiological mechanisms that may have led to the patient's demise. We also remind pathologists to consider this diagnosis as potentially contributing to the cause of death in apparently fit young people of ethnic origin during episodes of physiological stress. PMID- 20966742 TI - Predicting and preventing chronic postsurgical pain and disability. PMID- 20966743 TI - Galactosylated alpha,beta-poly[(2-hydroxyethyl)-L-aspartamide]-bound doxorubicin: improved antitumor activity against hepatocellular carcinoma with reduced hepatotoxicity. AB - Galactosyl-terminated drug carriers are known to enhance drug accumulation in the liver, while possible accompanying hepatic toxicity is usually not clarified. This study developed a galactosyl-alpha,beta-poly[(2-hydroxyethyl)-L-aspartamide] doxorubicin conjugate (Gal-PHEA-DOX) and investigated its therapeutic efficacy and safety in orthotopic hepatocellular carcinoma-bearing mice. Gal-PHEA-DOX had a galactosylation degree of 7.5 mol% and a DOX content of 8.9 wt%. A biodistribution study showed that Gal-PHEA-DOX sustainedly circulated in the plasma and highly accumulated in hepatocarcinoma. Free drug liberated from Gal PHEA-DOX was relatively low in the liver and heart as compared with that of the DOX administration. The Gal-PHEA-DOX conjugate showed superior cytotoxicity against the hepatocellular carcinoma cell line HepG2 as compared with the nongalactosylated PHEA-DOX conjugate. Gal-PHEA-DOX exhibited comparable antitumor activity with PHEA-DOX in the S180-bearing mice, but more effective than PHEA-DOX or DOX in the Heps-bearing mice with negligible detrimental effect in the liver remnant. A systemic toxicity study showed that this conjugate did not show either cytotoxicity or hepatotoxicity at a relatively high dose, which would be harmful for free DOX. These results suggest that the Gal-PHEA-DOX conjugate has great potential for use in hepatocellular carcinoma chemotherapy because of its enhanced antitumor effect with reduced systemic toxicity including hepatotoxicity. PMID- 20966744 TI - Use of gated cardiac computed tomography angiography in the assessment of left ventricular assist device dysfunction. AB - The purpose of this study is to describe the utility and limitations of gated contrast-enhanced cardiac computed tomography angiography in assessing left ventricular assist device function. Computed tomography angiography (CTA) was used in 14 patients with left ventricular assist devices (LVADs) who had persistent heart failure symptoms, hemodynamic instability, or potential problems with LVAD flows. Retrospectively gated contrast-enhanced CTA was performed on 64 detector scanner, and the CTA images were postprocessed in multiple curved projections on TeraRecon workstation. This study describes the use of CTA to identify LVAD-related issues that altered clinical management and explores the role of CTA and other techniques in evaluating LVAD function. Six of 14 LVAD patients who demonstrated no abnormality on CTA remained stable with medical management. In the remaining eight patients, CTA was abnormal, including abnormalities specifically related to the LVAD cannula. As a result of findings detected by CTA, six patients underwent surgical intervention, including device exchange and heart transplant. Computed tomography angiography is a noninvasive method that enhances diagnostic evaluation of patients with suspected LVAD dysfunction and can lead to changes in patient management. PMID- 20966745 TI - Fibrin/hyaluronic acid composite hydrogels as appropriate scaffolds for in vivo artificial cartilage implantation. AB - Hydrogels prepared from a mixture of fibrin and high-molecular weight (MW) hyaluronic acid (HA) were found to be suitable scaffolds for chondrocyte seeding and pig knee cartilage regeneration. Collagen in the hydrogels is not necessary for the formation of biomechanically stable tissue. Regenerated cartilage showed very good biomechanical and histological properties only 6 months after implantation. Notably, the quality of the healing process was dependent on the initial chondrocyte concentration of the scaffolds. These experiments were performed according to good laboratory practice (GLP). PMID- 20966746 TI - Mosaic trisomy 11 in a fetus with bilateral renal agenesis: co-incidence or new association? AB - We report a fetus with mosaic trisomy 11 who also had bilateral renal agenesis. We describe the post-mortem examination findings in the fetus and cytogenetic analysis. There are no earlier reports of full trisomy 11, presumably because it is lethal and results in early spontaneous miscarriages. There is only one report published earlier in a fetus with mosaic trisomy 11. There have been a few case reports of trisomy 11 identified in pre-natal samples, where it was associated with normal outcome. Bilateral renal agenesis has not been reported earlier in association with mosaic nor non-mosaic trisomy 11. We describe this rare cytogenetic finding in a fetus with bilateral renal agenesis. We also discuss the issues around genetic counselling when this is encountered in clinical practice. PMID- 20966747 TI - Radiologic and hormonal evaluation of pituitary abnormalities in patients with Bardet-Biedl syndrome. AB - To describe the structural changes in the pituitary gland and accompanying pituitary hormonal problems in patients with Bardet-Biedl syndrome (BBS), 11 patients with BBS (median age: 12.8 years, range: 2.5-17.8 years; four boys and seven girls) have been examined for the anomalies of the pituitary region detected by MRI. Accompanying clinical, biochemical, and hormonal profiles concerning the pituitary function of the patients have also been investigated. We have found a high incidence of pituitary anomalies on MRI (63%) and a considerable percentage of hormonal derangements (45%) accompanying these. Among the structural pituitary abnormalities, tumoral changes (n=2), hypoplastic hypophysis, and/or sella (n=4) and rathke cleft cyst (n=2) were detected, whereas disturbances of the pituitary hormones such as growth hormone deficiency, hyperprolactinemia, hypogonadotrophic hypogonadism, and central precocious puberty accompanied the pituitary anomalies in these patients. Pituitary abnormalities and pituitary hormonal dysfunction are common findings and, therefore, should be included in the diagnostic criteria of BBS. PMID- 20966748 TI - Immunodeficiency secondary to anticytokine autoantibodies. AB - PURPOSE OF REVIEW: Anticytokine autoantibodies are an important and emerging mechanism of disease pathogenesis. We will review the clinical and laboratory features of syndromes in which immunodeficiency is caused by or associated with neutralizing anticytokine autoantibodies. RECENT FINDINGS: A growing number of patients have been described who demonstrate unique infectious phenotypes associated with neutralizing autoantibodies that target a particular cytokine known to participate in host defense against the offending organism. Examples include antigranulocyte macrophage-colony stimulating factor (GM-CSF) autoantibodies and pulmonary alveolar proteinosis; anti-interferon (IFN)-gamma autoantibodies and disseminated nontuberculous mycobacteria (NTM); anti interleukin-(IL)-6 autoantibodies and severe staphylococcal skin infection; anti IL-17A, anti-IL-17F, or anti-IL-22 autoantibodies in patients with mucocutaneous candidiasis in the setting of both the autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED) syndrome and in cases of thymoma. SUMMARY: Anticytokine autoantibodies have manifestations that are diverse, ranging from asymptomatic to life-threatening. These emerging and fascinating causes of acquired immunodeficiency may explain some previously idiopathic syndromes. PMID- 20966749 TI - Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency. AB - PURPOSE OF REVIEW: The present review describes the recent progress in the treatment of adenosine deaminase-deficient severe combined immunodeficiency (ADA SCID) using autologous gene-modified hematopoietic stem cells, comparing immune reconstitution with respect to allogeneic transplant and discussing differences with gene therapy for SCID-X1. RECENT FINDINGS: Since 2000, more than 30 ADA-SCID patients have been treated with gene therapy worldwide, with successful outcome in most cases, consisting of progressive immune reconstitution, efficient systemic detoxification, and long-term multilineage engraftment. Gene therapy resulted in restoration of thymic activity and T-cell functions, although the kinetic of reconstitution was slower compared with standard bone marrow transplant. Unlike allogeneic transplant from alternative donors, survival after gene therapy is excellent. In comparison with SCID-X1, ADA-SCID gene therapy presents a better safety profile and engraftment of multilineage transduced stem/progenitor cells, thanks to the use of nonmyeloablative preconditioning. New approaches using safer integrating vectors are being developed, which may lead to safer and effective gene therapy for ADA-SCID and other genetic disorders. SUMMARY: In the last decade, gene therapy has been developed as a successful and safe alternative strategy for patients affected by ADA-SCID lacking a compatible sibling donor. The application of innovative vector technology might further improve its efficacy and safety profile. PMID- 20966750 TI - Targeting the heparin-binding epidermal growth factor-like growth factor in ovarian cancer therapy. AB - PURPOSE OF REVIEW: Therapeutics targeting the ErbB protein family receptors have not always yielded favorable or successful results in present cancer therapy. This review discusses the possibility of the clinical adaptation of targeting against heparin-binding epidermal growth factor-like growth factor (HB-EGF), one of the ligands of the ErbB system, in ovarian cancer therapy. RECENT FINDINGS: We have previously described the results of studies concerning roles of HB-EGF in tumor formation in ovarian cancer. In brief, lisophosphatidic acid (LPA) and HB EGF are predominantly expressed in advanced ovarian cancer, and LPA-induced, a disintegrin and metalloprotease-mediated ectodomain shedding of HB-EGF was found to be critical to tumor formation. We also noted that exogenous expression of HB EGF enhanced tumor formation but inhibition blocked both extracellular signal related kinase and serine/threonine protein kinase activation. Finally we investigated the antitumor effects of CRM197 - a specific HB-EGF inhibitor - on ovarian cancer cells by evaluating human ovarian cancer cell proliferation. SUMMARY: We discuss alternative strategies to develop the chemotherapeutic agent based on targeting ErbB family ligands rather than their receptors. A phase I study of CRM197 for advanced ovarian cancer has already begun, which is the first approved trial of ErbB-ligand-targeted therapy. We also discuss clinical adaptations based on combination of CRM197 with other conventional chemotherapeutic agents. PMID- 20966751 TI - Women's health and health reform: implications of the Patient Protection and Affordable Care Act. AB - PURPOSE OF REVIEW: An overview of provisions in the 2010 health reform legislation with implications for women's health and obstetrician-gynecologists. RECENT FINDINGS: Between now and 2014, provisions of the Patient Protection and Affordable Care Act (ACA) will expand access to health coverage, primary care, and preventive services. Other provisions relate to federal abortion funding, medical liability, and disparities. SUMMARY: From a life-course perspective, ACA makes it feasible to link preconception, prenatal, family planning, and other care in a seamless continuum for women of childbearing age. Now is the time to implement a comprehensive well woman standard of care. PMID- 20966752 TI - Rheumatic diseases and pregnancy. AB - PURPOSE OF REVIEW: This review discusses how inflammatory rheumatic diseases [rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE)] of the mother can influence the course of pregnancy and the development of the fetus. Antirheumatic drug therapy of the mother and strategies to prevent fetal complications namely in SLE must be considered with care. RECENT FINDINGS: The current literature is presented discussing hypotheses about the immunologic mechanisms leading to amelioration or exacerbation of the rheumatic symptoms in rheumatoid arthritis and ankylosing spondylitis during pregnancy. In SLE, several recent studies have been published concerning fetal complications in the antiphospholipid syndrome and in Ro/SSA-positive and La/SSB-positive mothers and how to diagnose, treat, or prevent these. SUMMARY: Today, women with inflammatory rheumatic diseases are normally fertile and can be encouraged to become pregnant, when there is a stable and quiescent phase of the disease. This is in particular important for patients with SLE, although pregnancy outcome in SLE has improved over the last decades. Pregnancy in SLE is still a high-risk period during the disease course with the highest risk in women with active lupus nephritis. In contrast, women with rheumatoid arthritis develop amelioration of the rheumatic symptoms during the course of pregnancy in most cases; female ankylosing spondylitis patients are likely to show unaltered or aggravated symptoms of back pain and impaired function. PMID- 20966753 TI - Treatment of autoinflammatory syndromes. AB - PURPOSE OF REVIEW: Inherited autoinflammatory diseases are experiments in nature in which mutations of proteins playing a pivotal role in the regulation of the innate immunity lead to unprovoked episodes of inflammation. The understanding of the molecular pathways involved in these disorders has shed a new light on the pattern of activation and maintenance of the inflammatory response and disclosed new molecular therapeutic targets. In this review, we outline the more recent novelties in the treatment of autoinflammatory diseases and their possible implications for some multifactorial pediatric conditions. RECENT FINDINGS: Cryopyrin-associated periodic syndrome (CAPS) represents the prototype of autoinflammatory diseases. The study of the pathophysiological consequence of mutations of the cryopyrin gene (NLRP3) allowed the identification of the intracellular pathways thought to play a pivotal part in the activation and secretion of the potent inflammatory cytokine interleukin (IL)-1beta. The dramatic effect of IL-1 blockade in CAPS opens new perspectives for the treatment of other inherited and multifactorial inflammatory disorders. A number of IL-1 blockers are now available on the market. SUMMARY: Studies on the pathogenesis and treatment of inherited autoinflammatory diseases are also changing the approach to some multifactorial inflammatory conditions. PMID- 20966754 TI - Anti-IgE in the treatment of allergic disorders in pediatrics. AB - PURPOSE OF REVIEW: Neutralization of IgE antibodies is a conceptually new approach for the treatment of allergic diseases. This article reviews current concepts of anti-IgE therapy, with a focus on recent studies that provide insights into underlying mechanisms. Findings of the most recent clinical trials of anti-IgE in the treatment of allergic disorders are discussed. RECENT FINDINGS: Anti-IgE therapy in allergic asthma has been evaluated mostly in adults, but some studies have documented potential clinical efficacy in children and adolescent patients with moderate to severe uncontrolled asthma despite maximal conventional therapy. Pilot investigations have revealed some promising results regarding the use of anti-IgE in the treatment of other atopic diseases and as an adjunctive therapy in conjunction with allergen-specific immunotherapy. Recent work has provided novel insights into the kinetics of cellular responses to anti-IgE treatment and has identified significant anti-IgE effects on both basophils and dendritic cells, suggesting significant roles for these cells as effectors of IgE-mediated disease. SUMMARY: Studies of anti-IgE therapy have significantly advanced our understanding of IgE-mediated disease mechanisms and have demonstrated clinical efficacy in the treatment of allergic asthma in adults and children. Further studies are needed in children to evaluate long-term safety and to better define its potential use in allergic diseases other than asthma. PMID- 20966755 TI - Endocrine disruptors, travel-associated illness, and media violence: important health considerations for children and adolescents. AB - PURPOSE OF REVIEW: This article addresses three important topics that are part of contemporary life for children: endocrine disruptors, hazards of international travel, and the impact of media violence on children and adolescents. RECENT FINDINGS: Practitioners will learn about phthalates and Bisphenol-A as endocrine disruptors. In published studies, elevated phthalates were associated with an increase in pubertal gynecomastia and premature thelarche. Bisphenol-A was judged by the Food and Drug Administration as having some concern for potential effects on brain, behavior, and prostate gland in fetuses, infants, and young children: hence, the decision to take reasonable steps to reduce exposure of infants. In travel-related diseases, diarrheal disease (primarily Campylobacter and Salmonella), dermatologic conditions (animal bites), systemic febrile illness (malaria and dengue fever), and respiratory illnesses predominate. Children and adolescents spend more than 7 h using media per day. The degree to which media violence can be linked to behavior is not conclusive, but the prevention message for practitioners is important because parents can have an important mitigating effect. SUMMARY: Endocrine disruptors, travel-related diseases, and media violence are part of modern day life for our children. Pediatricians need to stay abreast of recent findings and have access to up-to-date resources to assist them in providing contemporary advice and guidance to patients and families. PMID- 20966756 TI - Nosological status of social phobia: contrasting classical and recent literature. AB - PURPOSE OF REVIEW: The aim of this review is to contrast classical and recent literature relating to social anxiety disorder in the context of its past, present and future position in classification systems. RECENT FINDINGS: Social phobia is common; it starts early and is chronic and disabling. It runs in families. Social phobia is frequently comorbid with other anxiety, mood and substance use disorders and it often precedes axis I disorders. Concerning neurobiology of social anxiety disorder research is sparse and the results are inconclusive. The data from research on genetics, early environment, temperamental features, cognitive processing, phenomenology and treatment response indicate significant overlap between social phobia and a number of other axis I and axis II disorders (avoidant personality disorder). SUMMARY: The review of the recent findings does not point to the existence of qualitative differences between social phobia and other anxiety and mood disorders. The results of recent research run against the current classification dividing anxiety and mood disorders into discrete categories and support the continuity among them. Taking into account conceptual issues of psychiatric classifications would promote subsequent research that could become a foundation for the development of psychiatric nosology. PMID- 20966757 TI - Quality of life and symptoms of depression in advanced heart failure patients and their partners. AB - PURPOSE OF REVIEW: To provide an overview of factors related to quality of life and symptoms of depression in heart failure patients and their partners. Furthermore, to give an overview of interventions that can be effective in improving their quality of life and decrease depressive symptoms. RECENT FINDINGS: Quality of life of patients with heart failure and their partners is poor compared with their age-matched peers from the general population and also compared with patients suffering from other chronic diseases. Furthermore, many heart failure patients are depressed. Depressive symptoms of patients and of their partners seem to be interrelated, making interventions complicated but needed. Although the number of studies that specifically target improvement of quality of life and depression in heart failure patients and their partners is still small, several interventions are known to improve quality of life, and these could be implemented in daily care. SUMMARY: This review considers demographic and clinical factors that are related to quality of life and depressive symptoms and addresses interventions that can contribute to improvement of quality of life of heart failure patients and their partners and decrease depressive symptoms. Education on self-care management and physical exercise are important elements of disease management programs. A multidisciplinary care approach including optimizing medical therapy and optimal symptom management is advised, focusing both on the patient and the caregiver. Treatment and care should not only focus on heart failure, but also address the consequences of co-morbidities and the side-effects of therapies. PMID- 20966758 TI - Decision making among older people with advanced heart failure as they transition to dependency and death. AB - PURPOSE OF REVIEW: This review critically considers recent research, identifying patient experiences of, and preferences for, participation in decision making during the end-of-life transition. RECENT FINDINGS: Clinicians typically experience significant difficulties in engaging older patients with advanced heart failure in discussions about palliative and end-of-life care and involving them in shared decision making. Advanced care planning is proposed as an approach to ensure greater patient involvement in end-of-life care management, although evidence regarding effective interventions in this area is limited. Policy initiatives and guidelines appear not to reflect clinical reality and healthcare professionals experience significant barriers in transferring the required knowledge and skills into their practice. The notion of transition itself as a process that healthcare professionals could use for assessment and management requires further research, but does offer more than just a focus on heart failure management at the end-of-life. SUMMARY: This review indicates a need to think carefully about how policy recommendations and guidance relating to patient participation in decision making at the end-of-life can be effectively implemented in practice. The need for continuity of involvement from key health workers is identified as very important in this regard. 'Transition' is also considered as a concept that may offer health professionals a different approach for assessment and management of heart failure patients over a longer period and means of integrating heart failure management with palliative care. PMID- 20966759 TI - Review of burn injury research for the year 2009. AB - Research in burn care for the calendar year 2009 was robust and diverse with >1400 research articles published on a wide range of topics. In this review, the authors highlight some innovative and potentially impactful research related to the overall care of burn- injured patients. The authors grouped articles according to the following categories: critical care, infection, inhalation injury, epidemiology, psychology, wound characterization and treatment, nutrition and metabolism, pain and itch management, burn reconstruction, and rehabilitation. They found that the holistic nature of burn care is reflected in the diverse research performed in 2009 throughout the world and that this research has provided important evidence that has improved or will improve burn care overall. PMID- 20966760 TI - CaMKII, the downstream hypertrophic signaling pathway in the heart: the 2009 Benedict R. Lucchesi Distinguished Lectureship Award. PMID- 20966761 TI - Bradykinin B2 receptor-dependent enhancement of enalapril-evoked hypotension in ethanol-fed female rats. AB - Our previous studies showed that chronic ethanol feeding attenuates centrally (clonidine) evoked and potentiates peripherally (hydralazine) evoked hypotension in female rats. In this study, we investigated whether chronic ethanol (8 weeks, 5% wt/vol) alters hemodynamic responses elicited by angiotensin-converting enzyme (ACE) inhibition (enalapril) in telemetered female rats. Given the intimate interaction between ACE and bradykinin, studies were extended to investigate the role of bradykinin receptor (B2R) in ethanol-enalapril interaction. Compared with pair-fed controls, ethanol-fed female rats exhibited (1) higher renal expressions of ACE and B2R proteins and angiotensin II levels and (2) lower blood pressure. Pharmacological inhibition of ACE and B2R supports functional role for the higher levels of these 2 proteins in ethanol-fed rats because enalapril (10 mg/kg, intraperitoneally) caused significantly greater hypotensive response in ethanol fed rats than in control rats. Further, blockade of B2R with bradyzide (2 mg/kg, intraperitoneally) abrogated the enhanced hypotensive effect of enalapril in ethanol-fed rats but had no effect on enalapril-evoked hypotension in control rats. Finally, enalapril enhancement of spontaneous baroreflex sensitivity (BRS) in control was absent in ethanol-fed rats. These findings demonstrate that chronic ethanol produces B2R-dependent enhancement of the hypotensive response elicited by enalapril and abrogates enalapril-evoked enhancement of spontaneous baroreflex response in female rats. PMID- 20966762 TI - S-nitrosylation Inhibits protein kinase C-mediated contraction in mouse aorta. AB - S-nitrosylation is a ubiquitous protein modification in redox-based signaling and forms S-nitrosothiol from nitric oxide (NO) on cysteine residues. Dysregulation of (S)NO signaling (nitrosative stress) leads to impairment of cellular function. Protein kinase C (PKC) is an important signaling protein that plays a role in the regulation of vascular function, and it is not known whether (S)NO affects PKC's role in vascular reactivity. We hypothesized that S-nitrosylation of PKC in vascular smooth muscle would inhibit its contractile activity. Aortic rings from male C57BL/6 mice were treated with auranofin or 1-chloro-2,4-dinitrobenzene (DNCB) as pharmacological tools, which lead to stabilize S-nitrosylation, and propylamine propylamine NONOate (PANOate) or S-nitrosocysteine (CysNO) as NO donors. Contractile responses of aorta to phorbol-12,13-dibutyrate, a PKC activator, were attenuated by auranofin, DNCB, PANOate, and CysNO. S nitrosylation of PKCalpha was increased by auranofin or DNCB and CysNO as compared with control protein. Augmented S-nitrosylation inhibited PKCalpha activity and subsequently downstream signal transduction. These data suggest that PKC is inactivated by S-nitrosylation, and this modification inhibits PKC dependent contractile responses. Because S-nitrosylation of PKC inhibits phosphorylation and activation of target proteins related to contraction, this posttranslational modification may be a key player in conditions of decreased vascular reactivity. PMID- 20966763 TI - High-carbohydrate high-fat diet-induced metabolic syndrome and cardiovascular remodeling in rats. AB - The prevalence of metabolic syndrome including central obesity, insulin resistance, impaired glucose tolerance, hypertension, and dyslipidemia is increasing. Development of adequate therapy for metabolic syndrome requires an animal model that mimics the human disease state. Therefore, we have characterized the metabolic, cardiovascular, hepatic, renal, and pancreatic changes in male Wistar rats (8-9 weeks old) fed on a high-carbohydrate, high-fat diet including condensed milk (39.5%), beef tallow (20%), and fructose (17.5%) together with 25% fructose in drinking water; control rats were fed a cornstarch diet. During 16 weeks on this diet, rats showed progressive increases in body weight, energy intake, abdominal fat deposition, and abdominal circumference along with impaired glucose tolerance, dyslipidemia, hyperinsulinemia, and increased plasma leptin and malondialdehyde concentrations. Cardiovascular signs included increased systolic blood pressure and endothelial dysfunction together with inflammation, fibrosis, hypertrophy, increased stiffness, and delayed repolarization in the left ventricle of the heart. The liver showed increased wet weight, fat deposition, inflammation, and fibrosis with increased plasma activity of liver enzymes. The kidneys showed inflammation and fibrosis, whereas the pancreas showed increased islet size. In comparison with other models of diabetes and obesity, this diet-induced model more closely mimics the changes observed in human metabolic syndrome. PMID- 20966764 TI - Effects of cocoa extract and dark chocolate on angiotensin-converting enzyme and nitric oxide in human endothelial cells and healthy volunteers--a nutrigenomics perspective. AB - Evidence suggests that cocoa from the bean of Theobroma cacao L. has beneficial effects on cardiovascular disease. The aim of this study was to investigate if cocoa extract and dark chocolate influence angiotensin-converting enzyme (ACE) and nitric oxide (NO) in human endothelial cells (in vitro) and in healthy volunteers (in vivo). ACE activity was analyzed with a commercial radioenzymatic assay and measured in human endothelial cells from umbilical veins (HUVEC) after 10 minutes of incubation with cocoa extract. NO was measured after 24 hours of incubation. ACE activity and NO were measured at baseline and after 30, 60, and 180 minutes in 16 healthy volunteers after a single intake of 75 g of dark chocolate containing 72% cocoa. Significant inhibition of ACE activity (P < 0.01) and significant increase of NO (P < 0.001) were seen in HUVEC. In the study subjects, a significant inhibition of ACE activity (mean 18%) 3 hours after intake of dark chocolate was seen, but no significant change in NO was seen. According to ACE genotype, significant inhibition of ACE activity was seen after 3 hours in individuals with genotype insertion/insertion and deletion/deletion (mean 21% and 28%, respectively). Data suggest that intake of dark chocolate containing high amount of cocoa inhibits ACE activity in vitro and in vivo. PMID- 20966766 TI - MicroRNA: redefining mechanisms in cardiovascular diseases. PMID- 20966765 TI - Mitochondria-targeted cardioprotection in aldosteronism. AB - Chronic aldosterone/salt treatment (ALDOST) is accompanied by an adverse structural remodeling of myocardium that includes multiple foci of microscopic scarring representing morphologic footprints of cardiomyocyte necrosis. Our previous studies suggested that signal-transducer-effector pathway leading to necrotic cell death during ALDOST includes intramitochondrial Ca overloading, together with an induction of oxidative stress and opening of the mitochondrial permeability transition pore (mPTP). To further validate this concept, we hypothesized that mitochondria-targeted interventions will prove to be cardioprotective. Accordingly, 8-week-old male Sprague-Dawley rats receiving 4 weeks ALDOST were cotreated with either quercetin, a flavonoid with mitochondrial antioxidant properties, or cyclosporine A (CsA), an mPTP inhibitor, and compared with ALDOST alone or untreated, age/sex-matched controls. We monitored mitochondrial free Ca and biomarkers of oxidative stress, including 8-isoprostane and H2O2 production; mPTP opening; total Ca in cardiac tissue; and collagen volume fraction to quantify replacement fibrosis, a biomarker of cardiomyocyte necrosis, and employed terminal deoxynucleotidyl transferase dUTP nick end labeling assay to address apoptosis in coronal sections of ventricular myocardium. Compared with controls, at 4 weeks ALDOST we found a marked increase in mitochondrial H2O2 production and 8-isoprostane levels, an increased propensity for mPTP opening, and greater concentrations of mitochondrial free [Ca]m and total tissue Ca, coupled with a 5-fold rise in collagen volume fraction without any terminal deoxynucleotidyl transferase dUTP nick end labeling-based evidence of cardiomyocyte apoptosis. Each of these pathophysiologic responses to ALDOST was prevented by quercetin or cyclosporine A cotreatment. Thus, mitochondria play a central role in initiating the cellular-subcellular mechanisms that lead to necrotic cell death and myocardial scarring. This destructive cycle can be interrupted and myocardium salvaged with its structure preserved by mitochondria-targeted cardioprotective strategies. PMID- 20966767 TI - Factors that influence electroconvulsive therapy referrals: a statewide survey of psychiatrists. AB - OBJECTIVE: This study sought to identify factors associated with patient treatment referral for electroconvulsive therapy (ECT) by psychiatrists practicing in Virginia. METHODS: Psychiatrists (N = 116) were surveyed regarding their knowledge about and attitudes toward ECT. We also inquired into other potential factors that might be associated with referral, such as distance from an ECT provider or availability of transportation. RESULTS: Most psychiatrists had a basic understanding of ECT, and most had a favorable opinion of ECT. However, a lesser degree of knowledge about ECT by psychiatrists correlated with both a less favorable view of ECT and with fewer referrals for treatment with ECT. In addition, physicians who viewed ECT as a "treatment of last resort" referred patients only sparingly. Factors that prevented even those physicians with favorable attitudes toward ECT from referring appropriate patients for ECT included patients' negative attitudes toward ECT, the logistics of arranging support and transportation, and financial constraints. CONCLUSIONS: Patient referral for ECT was associated with the treating physicians' and patients' knowledge and attitudes about ECT and with the presence of specific logistical barriers. Attention to these factors by treating physicians might enhance access to ECT treatment. PMID- 20966768 TI - Transient insight induction with electroconvulsive therapy in a patient with refractory schizophrenia: a case report and systematic literature review. AB - Anosognosia or lack of illness awareness is a clinical manifestation of both schizophrenia and right hemispheric lesions associated with stroke, neurodegeneration, or traumatic brain injury. It is thought to result from right hemispheric dysfunction or interhemispheric disequilibrium, which provides a neuroanatomical model for illness unawareness in schizophrenia. Lack of insight contributes to medication nonadherence and poor treatment outcomes and is often refractory to pharmacological and psychological interventions. We present the first report of transient illness awareness (<8 hours) after individual bilateral electroconvulsive therapy treatments in the case of a 39-year-old man with antipsychotic refractory schizophrenia. Electroencephalography demonstrated frontal slow wave activity with shifting frontotemporal predominance, which was concurrent with the patient's transient level of insight. A systematic review of the literature on electroconvulsive therapy-induced illness awareness in schizophrenia and psychotic disorders produced zero relevant results. Future research should focus on the prospective role of focal interventions, such as transcranial magnetic stimulation, in the development of a neurophysiological model for anosognosia reversal in schizophrenia that may, in turn, contribute to novel therapeutic developments targeting lack of illness awareness. PMID- 20966769 TI - An examination of mortality and other adverse events related to electroconvulsive therapy using a national adverse event report system. AB - BACKGROUND: : There is currently an incomplete understanding of adverse events related to electroconvulsive therapy (ECT) treatments. Much of the published literature is based either on a limited number of ECT providers or reports not representative of modern ECT practice. METHODS: : We searched the Veterans Affairs (VA) National Center for Patient Safety database for reports of adverse events related to ECT. The type and the cause of the events were determined and aggregated. The number of ECT treatments given in the VA was used to develop estimated rates of mortality associated with ECT. RESULTS: : There were no deaths associated with ECT reported in any VA hospital between 1999 and 2010. Based on the number of treatments given, we estimate the mortality rate associated with ECT as less than 1 death per 73,440 treatments. The most common reported adverse events related to ECT were injury to the mouth (including dental and tongue injury) and problems related to paralysis. CONCLUSIONS: : Based on this VA data, ECT may be safer than is widely reported. The reported adverse events were generally rare and typically minor in severity. Simple steps may possibly result in further enhancements to ECT safety. PMID- 20966770 TI - Long-term efficacy after acute augmentative repetitive transcranial magnetic stimulation in bipolar depression: a 1-year follow-up study. AB - BACKGROUND: : The efficacy of repetitive transcranial magnetic stimulation (rTMS) has been poorly investigated in the long-term. The present follow-up study was aimed to assess the long-term efficacy and the discontinuation effects of rTMS in a sample of depressed bipolar patients. METHODS: : After the completion of an acute trial with augmentative, low-frequency, navigated rTMS, 11 drug-resistant depressed bipolar subjects (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [Text Revision] criteria) entered a naturalistic follow up with monthly evaluations through the Hamilton Depression Rating Scale and the Young Mania Rating Scale. RESULTS: : After 1 year of follow-up, results showed that the achievement of remission after acute rTMS was predictive of maintenance of response at 1 year. On the other hand, the absence of acute rTMS response predicted the absence of subsequent response in the long-term. CONCLUSIONS: : This first report on the long-term discontinuation effects after acute rTMS suggests that immediate remission is predictive of sustained benefit after 1 year. Larger controlled studies are needed to confirm present preliminary findings. PMID- 20966771 TI - High-frequency prefrontal repetitive transcranial magnetic stimulation for the negative symptoms of schizophrenia: a case series. AB - OBJECTIVES: The negative symptoms of schizophrenia are difficult to treat and are predictors of poor outcome. New somatic treatments are needed to reverse these symptoms and improve function. One promising approach is repetitive transcranial magnetic stimulation (rTMS), although results to date have been mixed. This pilot study assessed higher doses of rTMS and assessed particular demographic factors that may influence treatment response. METHODS: Five patients with schizophrenia or schizoaffective disorder enrolled to receive 20 sessions of rTMS administered with a Magstim Super Rapid device (The Magstim Company Ltd, Wales, UK). Treatment was administered at 20 Hz for 2 seconds, intertrain interval of 28 seconds, and at 100% motor threshold to the left dorsolateral prefrontal cortex in an open label pilot study. Positive and Negative Syndrome Scale symptom assessments occurred at 2-week intervals during treatment and twice at 4-week intervals after termination. RESULTS: Treatments were well tolerated with no adverse events. One patient withdrew from the study in the setting of medication noncompliance. Of the patients who completed treatment, 2 had reductions in positive symptoms by 9% and 26%, maintained at 1 month. A third patient had a 14% reduction in negative symptoms at week 4, and a fourth patient had a 55% reduction at week 4. Negative symptom improvement was not related to depressive or extrapyramidal symptoms, which were unchanged with treatment. CONCLUSIONS: This pilot study of rTMS treatment for the negative symptoms of schizophrenia is promising with respect to safety and feasibility. The promising preliminary evidence for improvements in this open-label setting should be followed up with a randomized clinical trial to establish efficacy. Further work may explore the potential utility of rTMS for the otherwise largely untreatable negative symptoms, which account for so much of the morbidity of schizophrenia. PMID- 20966772 TI - Safe resumption of electroconvulsive therapy after non-ST segment elevation myocardial infarction. AB - We present the case of a 69-year-old woman with psychotic depression who suffered a non-ST segment elevation myocardial infarction at her first electroconvulsive therapy (ECT). Her course of ECT was resumed 19 days later, and she was able to complete it without further problems. Her depression remitted fully. We report the details of her cardiac management during subsequent treatment sessions and review the literature on cardiac adverse events with ECT. PMID- 20966773 TI - Deep repetitive transcranial magnetic stimulation associated with improved social functioning in a young woman with an autism spectrum disorder. AB - OBJECTIVES: There are currently no biomedical treatments targeting the core symptoms of autism spectrum disorders (ASDs). Considering evidence for cortical dysfunction in ASD, repetitive transcranial magnetic stimulation (rTMS) has been discussed as a potential therapeutic technique. METHODS: We describe the application of a new type of rTMS, deep rTMS, to the bilateral medial prefrontal cortex in a young woman with a high-functioning ASD. High-frequency rTMS was applied for 15 minutes each consecutive weekday for an 11-day period (9 treatments in total). Self-reported assessments were conducted before the first rTMS session, immediately after the last rTMS session, and 1-month after the last rTMS session. RESULTS: Self-reported assessments revealed a number of improvements after deep rTMS. These were primarily in the domain of social relating and interpersonal understanding and were corroborated by family members. CONCLUSIONS: Deep rTMS in ASD may serve to remediate aspects of cortical dysfunction (as standard rTMS seems to do in depression and schizophrenia) and provides a potential new avenue for the development of a biomedical treatment of impaired social relating in ASD. PMID- 20966774 TI - Cerebral air embolism as a complication of computed tomography-guided marking of the lung: depiction of air inflow route from a pulmonary vein to the left atrium. AB - Air embolism in the arterial system is a very rare but potentially fatal complication of percutaneous transthoracic needle biopsy or marking. We report a case of a patient with interstitial pneumonia associated with Sjogren syndrome, who presented with systemic arterial air embolism as a complication of computed tomography-guided marking of the lung. The air inflow route was depicted clearly on computed tomography from the peripheral pulmonary vein that crossed the needle pathway to the left atrium. PMID- 20966775 TI - A comparison of four versions of a computer-aided detection system for pulmonary nodules on chest radiographs. AB - PURPOSE: There are few computer-aided detection (CAD) systems that are available for the detection of nodules on chest radiographs. We evaluated the performance of a Food and Drug Administration-approved system and 3 of its subsequent versions to determine their potential to improve readers' accuracy. MATERIALS AND METHODS: We tested the performance of 4 generations of CAD software programs, RapidScreen 1.1 and OnGuard 3.0, 4.0, and 5.0 (Riverain Medical), for their ability to detect lung cancer on a sample of 100 patients with and 100 patients without nodules. Each proven nodule (computed tomography scan and/or pathology) was evaluated for its overall difficulty, size, density, shape, contour, and location. The sensitivity and number of false-positive (FP) marks were compared between the different versions; reasons for FP and false-negative marks were analyzed and compared. RESULTS: The newer versions have significantly improved overall sensitivity [62.5% (OnGuard 3.0), 62.5% (4.0), and 64.4% (5.0)] compared with the first version (44.2%). OnGuard 5.0 demonstrated sensitivity of 73.3% for moderately subtle lesions compared with very subtle lesions (20.0%). There was a significant reduction in the average number of FPs per image for each version (3.9 for 1.1, 3.3 for 3.0, 2.6 for 4.0, and 2.0 for 5.0). Rib and vessel crossings were the most common reasons for FPs. CONCLUSION: The latest version of CAD demonstrates good detection of moderately subtle lesions with a relatively low FP rate. PMID- 20966776 TI - Neonatal diabetes: current trends in diagnosis and management. AB - The purpose of this article is to describe diabetes diagnosed during the first 6 months of life. Neonatal diabetes, also known as congenital diabetes, presents a unique set of challenges for the pediatric healthcare provider. Neonatal diabetes is not type 1 diabetes. While the etiology of type 1 diabetes is multifactorial and includes genetic and environmental factors, neonatal diabetes is strictly a genetic condition. Management of children with neonatal diabetes, treatment of the disease, psychosocial considerations for the family, and nursing care required for this population are all included in this article. Unique issues related to the diagnosis of a genetic mutation resulting in a defect in the potassium channel are also discussed. PMID- 20966777 TI - Specialty care and the patient-centered medical home. AB - BACKGROUND: The medical home's success depends, in part, on the degree to which primary care physicians (PCPs) and specialists collaborate to create "medical neighborhoods" based on collective accountability. Such collaboration may require a new equilibrium in chronic disease care, with some of the routine follow-up currently provided by specialists reallocated to PCPs and their medical home teams. OBJECTIVES: To measure the care delivered by specialists for 7 chronic conditions, and to estimate the implications associated with reallocating half among the PCP workforce. RESEARCH DESIGN: Cross-sectional. SUBJECTS: Physicians from the 2007 National Ambulatory Medical Care Survey. MEASURES: We identified adult ambulatory visits for chronic obstructive pulmonary disease/asthma, low back pain, diabetes mellitus, coronary artery disease/congestive heart failure, chronic kidney disease, and depression. We calculated the time spent by specialists in direct and indirect care for established patients with these conditions. We summed individual physician estimates across specialists and converted the total into annual work weeks. After reducing this figure by half, we divided by the number of active PCPs. RESULTS: Most specialty visits (76.8%; 95% confidence interval [CI]: 73.6%-79.7%) were made by established patients. Specialists spent 552,844 (95% CI: 454,660-651,029) and 108,113 (95% CI: 86,103 130,122) cumulative work weeks providing direct and indirect follow-up care, respectively. Reallocating half of this care would generate 3.2 (95% CI: 2.6-3.8) additional work weeks for each PCP. CONCLUSIONS: The cumulative time spent by specialists in routine chronic disease follow-up is nontrivial. Reallocation of this care to PCP-directed medical homes may require multidimensional efforts to expand the primary care workforce. PMID- 20966778 TI - Systematic review: comparison of the quality of medical care in Veterans Affairs and non-Veterans Affairs settings. AB - BACKGROUND: The Veterans Health Administration, the nation's largest integrated delivery system, launched an organizational transformation in the mid 1990 s to improve the quality of its care. PURPOSE: To synthesize the evidence comparing the quality of medical and other nonsurgical care in Veterans Affairs (VA) and non-VA settings. DATA SOURCES: MEDLINE database and bibliographies of retrieved studies. STUDY SELECTION: Studies comparing the technical quality of nonsurgical care in VA and US non-VA settings published between 1990 and August 2009. DATA EXTRACTION: Two physicians independently reviewed 175 unique studies identified using the search strategy and abstracted data related to 6 domains of study quality. DATA SYNTHESIS: Thirty-six studies met the inclusion criteria. All 9 general comparative studies showed greater adherence to accepted processes of care or better health outcomes in the VA compared with care delivered outside the VA. Five studies of mortality following an acute coronary event found no clear survival differences between VA and non-VA settings. Three studies of care processes after an acute myocardial infarction found greater rates of evidence based drug therapy in VA, and 1 found lower use of clinically-appropriate angiography in the VA. Three studies of diabetes care processes demonstrated a performance advantage for the VA. Studies of hospital mortality found similar risk-adjusted mortality rates in VA and non-VA hospitals. LIMITATIONS: Most studies used decade-old data, assessed self-reported service use, or included only a few VA or non-VA sites. CONCLUSIONS: Studies that assessed recommended processes of care almost always demonstrated that the VA performed better than non-VA comparison groups. Studies that assessed risk-adjusted mortality generally found similar rates for patients in VA and non-VA settings. PMID- 20966779 TI - Access versus acculturation: identifying modifiable factors to promote cancer screening among Asian American women. AB - BACKGROUND: Asian Americans (AA) have the lowest rates of cancer screening of all ethnic groups. Reasons for these low rates of screening frequently include low acculturation levels. However, screening rates remain low for most AA populations despite differences in acculturation levels, suggesting presence of other important modifiers such as access barriers. OBJECTIVES: To compare the relative impact of access versus acculturation on breast and cervical cancer screening for AA subgroups. RESEARCH DESIGN: Multiple regressions models, controlling for sociodemographics, were developed for each AA subgroup. SUBJECTS: Women ages 18 and older from the 2003 California Health Interview Survey were included in this study. We included women with Chinese, Filipino, Japanese, Korean, South Asian, and Vietnamese origins. MEASURES: The dependent variables included clinical breast examination in the past year, mammogram in the past 2 years, and Pap test in the past 3 years. Independent variables included AA subgroup, access indicators, acculturation indicators, and other sociodemographics. RESULTS: Access explained more variation that acculturation alone in cancer screening for most AA women. The exceptions were in mammograms for Japanese, Koreans and South Asians and Pap test among Japanese. No insurance reduced the likelihood of clinical breast examination for immigrant Chinese and Filipinos, and no usual source of care reduced likelihood of Pap test for Japanese and South Asians compared with US born. CONCLUSIONS: Access indicators represent the ability to navigate the US health care system but have a differential impact on AA groups. These differences should be integrated into interventions designed to improve cancer screening rates. PMID- 20966780 TI - Accuracy of diagnostic mammography at facilities serving vulnerable women. AB - BACKGROUND: Breast cancer missed on diagnostic mammography may contribute to delayed diagnoses, whereas false-positive results may lead to unnecessary invasive procedures. Whether accuracy of diagnostic mammography at facilities serving vulnerable women differs from other facilities is unknown. OBJECTIVE: To compare the interpretive performance of diagnostic mammography at facilities serving vulnerable women to those serving nonvulnerable women. DESIGN: We examined 168,251 diagnostic mammograms performed at Breast Cancer Surveillance Consortium facilities from 1999 to 2005. We used hierarchical logistic regression to compare sensitivity, false positive rates, and cancer detection rates. SUBJECTS: Women aged between 40 and 80 years underwent diagnostic mammography to evaluate an abnormal screening mammogram or breast problem. MEASURES: Facilities were assigned vulnerability indices according to the populations served based on the proportion of mammograms performed on women with lower educational attainment, racial/ethnic minority status, limited household income, or rural residences. RESULTS: Sensitivity of diagnostic mammography did not vary significantly across vulnerability indices adjusted for patient-level characteristics, but false-positive rates for diagnostic mammography examinations to evaluate a breast problem were higher at facilities serving vulnerable women defined as those with lower educational attainment (odds ratio [OR], 1.39; 95% confidence interval [CI]: 1.08, 1.79); racial/ethnic minorities (OR, 1.32; 95% CI: 0.98, 1.76); limited income (OR, 1.34; 95% CI: 1.08, 1.66); and rural residence (OR, 1.55; 95% CI: 1.27, 1.88). CONCLUSIONS: Diagnostic mammography to evaluate a breast problem at facilities serving vulnerable women had higher false positive rates than at facilities serving nonvulnerable women. This may reflect concerns that vulnerable populations may be less likely to follow-up after abnormal diagnostic mammography or concerns that such populations have higher cancer prevalence. PMID- 20966781 TI - A decade of mortality reductions in major oncologic surgery: the impact of centralization and quality improvement. AB - BACKGROUND: For more than a decade, health policy groups have recommended concentrating care for certain high-risk oncologic procedures into high-volume centers. The degree to which practice patterns and outcomes have changed over that time period is unclear. OBJECTIVE: To evaluate temporal trends in the mortality and concentration of high-risk oncologic procedures. RESEARCH DESIGN: Retrospective cohort study using data from the Nationwide Inpatient Sample on 93,108 adult patients undergoing pancreatectomy, esophagectomy, gastrectomy, or major lung resection for organ-specific cancers from 1997 to 2006. The main outcome measure was in-hospital mortality. RESULTS: Risk- and volume-adjusted mortality decreased over time for all 4 procedures (P < 0.05). When hospitals were categorized into terciles of case volume, mortality gaps persisted between high- and low-volume centers in all procedures throughout the study period and did not significantly narrow over time. Patient volumes shifted toward high volume centers over time for all procedures (P <0.001), although at the end of the study period, low-volume centers still cared for one-quarter to one-third of patients undergoing each of the studied procedures. Most of the overall improvements in mortality were attributable to decreasing mortality within volume categories as opposed to the effects of care concentration. CONCLUSIONS: Modest concentration into higher-volume centers has taken place over the past decade, but improvements within volume categories have driven most of the generalized decreases in mortality. Significant outcome gaps between high- and low-volume centers still persist; further centralization may retain the potential to lower overall mortality. PMID- 20966782 TI - Positive and negative spillovers of the Health Disparities Collaboratives in federally qualified health centers: staff perceptions. AB - INTRODUCTION: Quality improvement (QI) interventions are usually evaluated for their intended effect; little is known about whether they generate significant positive or negative spillovers. METHODS: We mailed a 39-item self-administered survey to the 1256 staff at 135 federally qualified health centers (FQHC) implementing the Health Disparities Collaboratives (HDC), a large-scale QI collaborative intervention. We asked about the extent to which the HDC yielded improvements or detriments beyond its condition(s) of focus, particularly for non HDC aspects of patient care and FQHC function. RESULTS: Response rate was 68.7%. The HDC was perceived to improve non-HDC patient care and general FQHC functioning more often than it was regarded as diminishing them. In all, 45% of respondents indicated that the HDC improved the quality of care for chronic conditions not being emphasized by the HDC; 5% responded that the HDC diminished that quality. Seventy-five percent stated that the HDC improved care provided to patients with multiple chronic conditions; 4% signified that the HDC diminished it. Fifty-five percent of respondents indicated that the HDC improved their FQHC's ability to move patients through their center, and 80% indicated that the HDC improved their FQHC's QI plan as a whole; 8% and 2% indicated that the HDC diminished these, respectively. DISCUSSION: On balance, the HDC was perceived to yield more positive spillovers than negative ones. This QI intervention appears to have generated effects beyond its condition of focus; QI's unintended effects should be included in evaluations to develop a better understanding of QI's net impact. PMID- 20966783 TI - Rural residence is associated with delayed care entry and increased mortality among veterans with human immunodeficiency virus infection. AB - CONTEXT: Rural persons with human immunodeficiency virus (HIV) face many barriers to care, but little is known about rural-urban variation in HIV outcomes. OBJECTIVE: To determine the association between rural residence and HIV outcomes. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of mortality among persons initiating HIV care in Veterans Administration (VA) during 1998-2006, with mortality follow-up through 2008. Rural residence was determined using Rural Urban Commuting Area codes. We identified 8489 persons initiating HIV care in VA with no evidence of combination antiretroviral therapy (cART) use at care entry, of whom 705 (8.3%) were rural. OUTCOME MEASURE: All-cause mortality. RESULTS: At care entry, rural persons were less likely than urban persons to have drug use problems (10.6% vs. 19.5%, P < 0.001) or hepatitis C (34.3% vs. 41.2%, P = 0.001), but had more advanced HIV infection (median CD4: 186 vs. 246, P < 0.001). By 2 years after care entry, 5874 persons had initiated cART (528 rural [74.9%] and 5346 urban [68.7%], P = 0.001), and there were 1022 deaths (108 rural [15.3%] and 914 urban [11.7%], P = 0.004). The mortality hazard ratio for rural persons compared with urban was 1.34 (95% confidence interval: 1.05-1.69). The hazard ratio decreased to 1.18 (95% confidence interval: 0.93-1.50) after adjustment for HIV severity (CD4 and AIDS-defining illnesses) at care entry, and was 1.17 (95% confidence interval: 0.92-1.50) in a model adjusting for age, HIV severity at care entry, substance use, hepatitis B or C diagnoses, and cART initiation. CONCLUSIONS: Later entry into care drives increased mortality for rural compared with urban veterans with HIV. Future studies should explore the person, care system, and community-level determinants of late care entry for rural persons with HIV. PMID- 20966784 TI - How is medication prescribing ceased? A systematic review. AB - BACKGROUND: Medication prescribing is a complex process where the focus tends to be on starting new medication, changing a drug regimen, and continuing a drug regimen. On occasion, a prudent approach to prescribing may necessitate ending an ongoing course of medication, either because it should not have been started in the first place; because its continued use would cause harm; or because the medication is no longer effective. OBJECTIVE: To identify effective strategies for stopping pre-existing prescribing in situations where continued prescribing may no longer be clinically warranted. RESEARCH DESIGN: Systematic searches for English-language reports of experimental and quasi-experimental research were conducted in PubMed (1951-November 2009), EMBASE (1966-September 2008), and International Pharmaceutical Abstract b (1970-September 2008). A manual search for relevant review articles and a keyword search of a local database produced by a previous systematic search for prescribing influence and intervention research were also conducted. STUDY SELECTION AND DATA EXTRACTION: Following initial title screening for relevance 2 reviewers, using formal assessment and data extraction tools, independently assessed abstracts for relevance and full studies for quality before extracting data from studies selected for inclusion. RESULTS: Of 1306 articles reviewed, 12 were assessed to be of relevant, high-quality research. A variety of drugs were examined in the included studies with benzodiazepines the most common. Studies included in the review tested 9 different types of interventions. Effective interventions included patient mediated interventions, manual reminders to prescribers, educational materials given to patients, a face-to-face intervention with prescribers, and a case of regulatory intervention. Partially effective interventions included audit and feedback, electronic reminders, educational materials alone sent to prescribers, and distance communication combined with educational materials sent to prescribers. CONCLUSIONS: It appears possible to stop the prescribing of a variety of medications with a range of interventions. A common theme in effective interventions is the involvement of patients in the stopping process. However, prescribing at the level of individual patients was rarely reported, with data often aggregated to number of doses or number of drugs per unit population, attributing any reduction to cessation. Such studies are not measuring the actual required outcome (stopping prescribing), and this may reflect the broader ambiguity about when or why it might be important to end a prescription. Much more research is required into the process of stopping pre-existing prescribing, paying particular attention to improving the outcomes that are measured. PMID- 20966785 TI - Disparities in public use data availability for race, ethnic, and immigrant groups: national surveys for healthcare disparities research. AB - BACKGROUND: Disparities in healthcare coverage and access have a prominent place on the national health policy agenda. It is, therefore, essential to understand strengths and limitations of national surveys that provide annual or periodic data for population-based healthcare disparities research and monitoring. Importantly, publicly available data on healthcare coverage and access are needed for disparities populations defined by race, ethnicity, or immigrant group (REI). OBJECTIVE: To document public use data availability for REI groups, insurance coverage, and access to care measures in selected national surveys used for healthcare disparities research. DESIGN: We examined public use data for general population surveys that collect information on healthcare coverage and access on an annual or periodic basis for the nation. Data sources examined include the following: Current Population Survey, Survey of Income and Program Participation, National Health Interview Survey (NHIS), National Health and Nutrition Examining Survey, National Survey of Children's Health, Behavioral Risk Factor Surveillance System, and Medical Expenditure Panel Survey-Household Component. RESULTS: Although each survey has strengths for healthcare disparities research, there is no single survey that has detailed REI group identifiers, comprehensive measures of coverage and access, and geographic identifiers. CONCLUSIONS: Current Population Survey and NHIS have detailed REI identifiers. NHIS and Medical Expenditure Panel Survey-Household Component have comprehensive measures of coverage and access but are limited by smaller samples and no geography. Findings summarized in this article will assist with identifying existing data to examine healthcare coverage and access disparities and highlight areas for improvement in public use data availability. PMID- 20966786 TI - Xenon prevents inflammation-induced delayed pain hypersensitivity in rats. AB - Rats received an intraplantar carrageenan injection for inducing hind paw inflammation. After 1 h 45 min, they were exposed to medical air (air group), xenon 25% (Xe-25 group) or 50% (Xe-50 group) for 1 h 45 min. Mechanical nociceptive threshold was evaluated on experimental day and once daily for 1 week. Beyond the well-known antinociceptive effect of xenon, the delayed hyperalgesia observed for 4 days after carrageenan injection was strongly reduced in Xe-25 group and totally suppressed in Xe-50 group on the inflamed hind paw. Moreover, delayed hyperalgesia on the noninflamed hind paw was totally suppressed for both the xenon concentrations. These results show that xenon, beyond its antinociceptive effects, may be a fruitful therapeutic strategy to limit the development of pain sensitization after tissue injury. PMID- 20966787 TI - Muscle contraction force and fatigue: effects on mismatch negativity. AB - Muscle load can affect the performance of concurrent cognitive task. This effect is often explained by limited resources in the voluntary attention system. To examine whether earlier stages of cognitive information processing might be affected, we recorded the mismatch negativity component (MMN) of the auditory event-related brain potential before, during and after sustained handgrip at 7 and 30% of maximal voluntary contraction. MMN is an index of automatic detection of a deviating auditory event. MMN was not affected by force level. However, its amplitude at fronto-central sites decreased during the fatiguing 30% contraction, while it tended to increase during the light 7% work. Thus, muscle fatigue may affect auditory information processing at preattentive and preconscious stages, which could modify cognitive performance. PMID- 20966788 TI - Decreased BOLD responses in audiovisual processing. AB - Audiovisual processing was studied in a functional magnetic resonance imaging study using the McGurk effect. Perceptual responses and the brain activity patterns were measured as a function of audiovisual delay. In several cortical and subcortical brain areas, BOLD responses correlated negatively with the perception of the McGurk effect. No brain areas with positively correlated BOLD responses were found. This was unexpected as most studies of audiovisual integration use additivity and super additivity - that is, increased BOLD responses after audiovisual stimulation compared with auditory-only and visual only stimulation - as criteria for audiovisual integration. We argue that brain areas that show decreased BOLD responses that correlate with an integrated audiovisual percept should not be neglected from consideration as possibly involved in audiovisual integration. PMID- 20966789 TI - Preoperative communication to improve safety: a literature review. PMID- 20966790 TI - Lofty goals...yes, we can. PMID- 20966791 TI - Re: "Efficacy of adjuvant and neoadjuvant therapies for adult orbital sarcomas". PMID- 20966793 TI - Re: "Imiquimod 5% cream for the treatment of periocular basal cell carcinoma". PMID- 20966796 TI - Orbital nerve sheath myxoma: a case report. AB - A 72-year-old man was referred to the Service of Ophthalmology due to a 2-year history of ptosis and a painless mass in the lateral orbital margin of the right eye. Orbital MRI revealed a well-demarcated lesion in the superotemporal quadrant of the orbit. After surgical excision, histopathological examination led to the diagnosis of nerve sheath myxoma, a tumor composed of myxoid nodules separated by fibrous septa with spindle-shaped and stellate cells. Many of these cells were immunostained with antibodies to S-100 protein. This is the first case reported in the literature of such a tumor located in the orbit, and, though extremely rare, it should be considered in the differential diagnosis of orbital tumors. PMID- 20966797 TI - Prepuce mucosal graft for forniceal and conjunctival sac reconstruction in surgically intractable symblepharon. AB - A 12-year-old boy who had severe burns in the right eye from a firecracker injury 2 years previously was referred to our hospital with severe and recurrent symblepharon. The patient had received conjunctival sac reconstruction with amniotic membrane grafts twice at another hospital. A symblepharon lysis and conjunctival sac reconstruction with a mouth mucosal graft was performed. Eight months after surgery, he could not wear a prosthesis due to the recurrence of symblepharon. A prepuce mucosal graft obtained from circumcision was applied for forniceal and conjunctival sac reconstruction. One year postoperatively, the patient showed no recurrence of symblepharon and could comfortably wear a prosthesis. The prepuce is a useful alternative donor tissue in a male patient with no other available donor sites for conjunctival sac reconstruction. PMID- 20966798 TI - Primary eyelid leiomyoma. AB - A 10-year-old white male presented with a recurrent painful nodule of the left lateral lower eyelid margin with associated madarosis. The initial pathologic diagnosis at an outside institution was reported as chalazion. The lesion was re excised, and histopathologic examination with immunohistochemical evaluation confirmed the diagnosis of leiomyoma. This is the first reported case of primary leiomyoma originating in the eyelid. PMID- 20966799 TI - Dermabond as a hemostatic agent in chalazion excision in a hemophiliac. PMID- 20966800 TI - Cutaneous lupus erythematosus of the eyelid as a mimic of squamous epithelial malignancies: a clinicopathologic study of 9 cases. AB - PURPOSE: To describe 9 cases of chronic cutaneous lupus of the eyelid, its potential similarities with squamous epithelial malignancies, and clinical and histopathologic features that assist in distinguishing lupus from epidermal neoplasia. METHODS: The authors identified and reviewed 9 cases of cutaneous lupus involving the eyelid at their institutions since 1991. Published cases of cutaneous lupus involving the eyelid were identified using Ovid MEDLINE and PubMed and references within the articles. RESULTS: The average patient age at presentation was 52 years old (range 33-89) with a female-to-male ratio of 8:1. The right lower eyelid was the most commonly affected location, with 44% of the cases occurring at this site. Lesions had been present on average for 2.5 years prior to presentation (range 2-60 months). Lesions were clinically heterogeneous, ranging from macules to crusted shallow ulcers. In 44% of cases, the preoperative clinical diagnosis was that of either squamous cell carcinoma or basal cell carcinoma. The patients thought to have a skin malignancy were 10 years older at presentation, more likely to be male, and more likely to have ulcerative lesions with rapid onset when compared with the other lupus patients. CONCLUSIONS: A subset of patients with lupus (particularly discoid lupus) involving the eyelid have clinical features mimicking patients with squamous epithelial malignancy. In cases such as these, biopsies are critical for establishing the diagnosis and pursuing appropriate therapeutic approaches. PMID- 20966801 TI - A history of gonioscopy. AB - The first view of the iridocorneal angle in a living human occurred accidentally in the late 1800s. Lenses were first used to see the angle in 1914, but practical gonioscopy would not come into existence for many years as the slitlamp and lenses that could be used at the slitlamp were developed. This article reviews the history of gonioscopy. PMID- 20966802 TI - The 97.5th and 99.5th percentile of vertical cup disc ratio in the United States. AB - PURPOSE: The International Society of Geographical and Epidemiological Ophthalmology (ISGEO) suggests a case definition for the prevalence studies of glaucoma based on the 97.5th and 99.5th percentile of vertical optic cup distribution among the evaluated population. Although multiple studies evaluating the prevalence of glaucoma have been undertaken in the last 20 years, case definitions have varied, and data on the underlying population distribution are sparse. This study evaluates the population distribution of 97.5th and 99.5th percentile of vertical cup disc ratio (VCDR) and VCDR asymmetry (VCDRA) in the US population and its association with demographic characteristics, self-reported glaucoma, and visual field. METHODS: The National Health and Nutrition Examination Survey (NHANES) is a nationally representative sample of the US population, which during the years 2005 to 2008 collected frequency doubling technology screening fields and digital fundus photography. Accounting for the complex design of the NHANES population, estimates of the 97.5th and 99.5th percentile of VCDR and VCDRA were calculated, and national estimates of glaucoma prevalence were generated. Associations between disc characteristics, demographic variables, and self-reported glaucoma were explored. RESULTS: Approximately 2.11% (95% confidence interval, 1.55 to 2.67) of the US population older than 40 years has glaucoma based on ISGEO criteria. A much larger 5.13% (95% confidence interval, 4.43 to 5.85) of the US population older than 40 years self-reports having glaucoma. Based on the estimates from NHANES, 6.89% of the population has a VCDR or VCDRA >97.5th percentile in either eye or OU. For the at-risk population with VCDR/VCDRA above the 97.5th percentile, <20% reported having glaucoma, whereas for those at the 99.5th percentile, <50% reported having glaucoma. CONCLUSIONS: The prevalence of glaucoma from NHANES based on ISGEO criteria produces similar population estimated to other population-based studies. Self-reported glaucoma is ~2.4 times more common than what the prevalence estimates suggest. PMID- 20966803 TI - Modeling the patterns of visual field loss in glaucoma. AB - PURPOSE: A computer model was developed to test the assumption that diffuse neural loss can result in the field loss pattern characteristic of glaucoma. METHODS: The anterior visual pathways comprised the retinal ganglion cells, and their axons up to the optic nerve head (ONH) were modeled in a computer program. Axon resistance to stress was accounted for depending on the location on the ONH, taking into consideration the presence or absence of vessels in the area. Damage patterns were applied to the axons at the ONH, and the corresponding dendritic fields were removed accordingly. A visual field was extracted and represented on a gray scale after a predetermined stage of damage was reached. Two patterns of damage were considered, a diffuse damage produced by randomly removing fibers and an ordered anteroposterior elimination. RESULTS: Random damage never rendered a pattern loss. Ordered centrifugal fiber loss may produce a radial pattern more conspicuous when the vessels are endowed with a protective role. In both cases, scotomas tend to be detectable earlier in more peripheral locations, attributable to the increasing size of the receptive fields with eccentricity. CONCLUSIONS: The model shows that pattern loss typical of glaucoma cannot be solely the result of a random loss of fibers. Anteroposterior damage of the ONH can explain radial progression of scotomas if a protective role is introduced for the central vessels. PMID- 20966804 TI - Perimetric indices as predictors of future glaucomatous functional change. AB - PURPOSE: To evaluate the use of global indices summarizing the current status of a patient's visual field as predictors of their future rate of change. METHODS: Ninety-five subjects with early or suspected glaucoma were studied, of whom 50 exhibited glaucomatous optic neuropathy (GON) at baseline. Subjects underwent seven annual visual field tests. Results from the first test in the sequence were used to predict their subsequent rate of change. Two global indices were considered: mean deviation (MD) and pattern standard deviation (PSD). RESULTS: Using multiple linear regression, baseline MD predicted subsequent slope of MD significantly better than baseline PSD predicted subsequent slope of PSD (p = 0.017). Using multiple logistic regression, a worse initial MD was predictive of being in the worst tertile for subsequent change in MD (pseudo-R2 = 0.33 for subjects with GON at baseline and 0.31 for those without). Worse initial PSD was not predictive of being in the worst tertile for subsequent change in PSD (pseudo R2 = 0.09 with GON at baseline, 0.10 without). CONCLUSIONS: Among patients with otherwise similar clinical profiles, a worse visual field at baseline, as measured by the global index MD, is predictive of a more rapid future rate of change. This should be taken into account when clinical decisions are made concerning management of patients who already have some visual field damage at presentation. PMID- 20966805 TI - Comparison of functional and nonfunctional neuroendocrine tumors in the pancreas and peripancreatic region. AB - OBJECTIVE: To present our experience of 93 neuroendocrine tumors (NETs) in the pancreas and peripancreatic region, with emphasis on how resectability affects long-term survival and the impact of functional status on the survival outcome. METHODS: Ninety-three patients with NETs in the pancreas and peripancreatic region were included to compare the clinical features between functional and nonfunctional NETs. Prognostic factors were determined by univariate and multivariate analyses. RESULTS: There were 39 functional (41.9%) and 54 nonfunctional NETs (58.1%). According to World Health Organization (WHO) tumor categories, there were 57 well-differentiated tumors (61.3%), 26 well differentiated carcinomas (28%), and 10 poorly differentiated carcinomas (10.8%). Univariate analysis showed that functional status of the tumor, tumor stage, lymph node status, and pathological classification were prognostic factors for both disease-free survival and disease-specific survival. Resectability did not influence the survival outcome, with the resectable and unresectable groups demonstrating a 5-year disease-specific survival of 86.4% and 65.6%, respectively (P = 0.210). Only the WHO pathological classification was an independent prognostic factor after multivariate analysis. CONCLUSIONS: Irresectability does not necessarily preclude long-term survival for both functional and nonfunctional NETs. It is the WHO pathological classification, instead of hormonal functional status, that is an independent prognostic factor and has impact on the survival outcome. PMID- 20966806 TI - Functional capacity of human islets after long-distance shipment and encapsulation. AB - OBJECTIVE: Human islets produced at an isolation center are shipped to researchers, usually taking short periods to arrive at their destination. In this study, we investigated whether human islets after long-distance shipment across the Pacific Ocean for 2 to 3 days and encapsulation could maintain their functionality. METHODS: Human islets were encapsulated in alginate and viability assessed using carboxyfluorescein diacetate and propidium iodide. Stimulation index after static glucose incubation was calculated. Streptozotocin-induced diabetic nonobese diabetic/severe combined immunodeficient mice were transplanted with 3000, 2000, or 1000 islet equivalents of nonencapsulated and encapsulated islets and glucose levels monitored. When levels were normal, the graft was retrieved and assessed. RESULTS: Viability of human islets was unaltered after long-distance shipment with a retrieval rate of 88.3% +/- 1.9%. After encapsulation, the viability was unchanged (before encapsulation 86.1% +/- 0.7% vs after encapsulation 80.8 +/- 0.7%) at 11 days after isolation. Function in vitro of nonencapsulated and encapsulated islets was unaffected with a stimulation index of 2.2 and 1.9, respectively. Euglycemia was achieved in 100% mice receiving 2000 and 3000 islet equivalents of nonencapsulated and encapsulated islets, respectively. Capsules retrieved after transplantation was intact, free floating, and contained viable islets. CONCLUSION: Human islets can be shipped safely for long distances without compromising viability and function even after encapsulation and culture. PMID- 20966807 TI - Adjunctive continuous high-volume hemofiltration in patients with acute severe pancreatitis: a prospective nonrandomized study. AB - OBJECTIVES: To evaluate the efficacy of adjunctive continuous high-volume hemofiltration (HVHF) in patients with severe acute pancreatitis. METHODS: Seventy-five patients admitted to the intensive care unit for severe acute pancreatitis from July 2006 to May 2009 were given informed consent and were followed prospectively. Patients were divided into 4 groups according to whether they accepted continuous HVHF (42 vs 33) and if they showed signs of acute kidney injury. RESULTS: Patients of the 4 groups were comparable at baseline. The 28-day survival rate was higher in patients who accepted HVHF (81% vs 57.6%, P=0.026), especially in those without acute kidney injury (95% vs 66.7, P=0.026). Furthermore, after 72 hours of therapy, the patients who accepted HVHF had significantly better Acute Physiology and Chronic Health Evaluation II scores (16.8+/-4.37 vs 13.39+/-3.17; P<0.05), body temperature (38.2 degrees C+/-1.01 degrees C vs 37.73 degrees C+/-0.95 degrees C; P<0.05), urine volume (1186+/-841 mL vs 2381+/-2462 mL; P<0.05), and base excess (-6.3+/-4.5 vs 0.64+/-3.4; P<0.05). However, the improvement in patients who did not accept HVHF was not so obviously. CONCLUSION: High-volume hemofiltration was associated with improved clinical outcome in acute pancreatitis patients, and should be initiated before kidney injury appearance. PMID- 20966808 TI - Reinforcement of pancreticojejunostomy using polyglycolic acid mesh and fibrin glue sealant. AB - OBJECTIVES: To examine whether pressure-tight reinforcement of pancreaticojejunostomy (PJ) using polyglycolic acid (PGA) mesh and fibrin glue sealant can reduce the incidence of postoperative pancreatic fistula (POPF). METHODS: The study population included 128 consecutive patients who underwent pancreaticoduodenectomy between September 2006 and January 2010. Postoperative mortality and morbidity among 50 patients who underwent reinforcement of PJ anastomosis using PGA mesh and fibrin glue were compared with 78 patients (historical controls). RESULTS: The 2 groups demonstrated no significant differences in frequencies of overall or septic complications, reoperation, or in hospital death. No significant difference in the frequency of POPF, delayed gastric emptying, or intra-abdominal abscess was found between groups. There was no difference between the 2 groups in the number of necessary interventions, and no bleeding complications or POPF-related mortality occurred. The median length of postoperative in-hospital stay between the 2 groups was similar: 13 days (range, 8-101 days) versus 14 days (range, 8-61 days). Similar findings were observed in a subgroup analysis consisting of patients with a pancreatic duct diameter smaller than 3 mm. CONCLUSION: This retrospective single-center study showed that reinforcement of PJ anastomosis using PGA mesh and fibrin glue provided no significant benefit in reducing the frequency of POPF. PMID- 20966809 TI - Comparison of autoanalyzer and back titration for measurement of bicarbonate concentration in endoscopically collected pancreatic fluid. AB - OBJECTIVES: In secretin-stimulated pancreatic function testing, the standard technique for bicarbonate measurement is back titration (BT). Chemistry autoanalyzers (AAs) automate bicarbonate measurement and are universally available; however, this method has not been validated in pancreatic fluid. The aims of the study were (1) to compare the AA and BT for measurement of bicarbonate in pancreatic fluid and (2) to determine the effects of variable conditions on bicarbonate concentration. METHODS: Pancreatic fluid samples were analyzed for bicarbonate concentration using both BT and AA. Additional experiments were conducted to determine the effect of different sample conditions. RESULTS: The results obtained by BT and AA were highly concordant (Lin concordance coefficient, 0.96). An AA cutpoint of 84 mM optimized sensitivity (91.1%) and specificity (94.1%) compared with the BT reference standard. Blood contamination spuriously increased the bicarbonate, an effect that was eliminated by centrifugation. The bicarbonate levels were not significantly affected by delayed analysis, storage condition, nitrogen gas treatment, or the addition of mineral oil or protease inhibitors. CONCLUSIONS: The bicarbonate concentrations obtained by AA are highly concordant with those obtained by BT. Secretin pancreatic function testing fluid analysis may now be performed in any hospital. PMID- 20966810 TI - Superoxide dismutase and nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase polymorphisms and pancreatic cancer risk. AB - OBJECTIVES: Pancreatic carcinoma etiology and molecular pathogenesis is weakly understood. According to the assumption that genetic variation in carcinogen metabolism further modifies the risk of exposure-related cancers, an association of functional polymorphisms in oxidative stress-modifying genes superoxide dismutase 2 (SOD2 [Ala16Val, rs4880]), SOD3 (Arg231Gly, rs1799895), nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase (NQO1 [Pro187Ser, rs1800566], and NQO2 (Phe47Leu, rs1143684) with pancreatic cancer risk was studied. METHODS: Polymorphisms were studied by allelic discrimination. RESULTS: In a hospital-based case-control study on 500 individuals (235 cases and 265 controls) of Czech white origin, SOD2, SOD3, NQO1, and NQO2 polymorphisms showed no significant association with pancreatic cancer risk. Major lifestyle factors such as smoking and alcohol, coffee, or tea consumption did not modify the effect of the studied polymorphisms. CONCLUSIONS: The first European study of the SOD2, SOD3, NQO1, and NQO2 roles in pancreatic cancer etiology did not find significant associations. Despite this observation, other populations with different lifestyle(s) may be at risk and should be further studied. PMID- 20966811 TI - Diagnostic performance of cyst fluid carcinoembryonic antigen and amylase in histologically confirmed pancreatic cysts. AB - OBJECTIVES: The objective of this study was to evaluate and validate cyst fluid carcinoembyronic antigen (CEA) and amylase in differentiating (1) nonmucinous from mucinous pancreatic cystic lesions (PCLs), (2) benign mucinous from malignant mucinous PCLs, and (3) pseudocysts from nonpseudocysts (amylase only). METHODS: A retrospective analysis of patients with histologically confirmed PCLs from February 1996 to April 2007 was performed. Cyst fluid CEA (n=124) and/or amylase (n=91) were measured and correlated to cyst type. RESULTS: Carcinoembyronic antigen levels (P=0.0001), but not amylase, were higher in mucinous versus nonmucinous cysts. The sensitivity, specificity, and diagnostic accuracy of CEA 200 ng/mL or greater for the diagnosis of mucinous PCLs were 60%, 93%, and 72%, respectively. Carcinoembyronic antigen levels did not differentiate benign from malignant mucinous cysts. Whereas amylase levels were higher in pseudocysts than nonpseudocysts (P=0.009), 54% of noninflammatory PCLs had a level greater than 250 IU/L, including mucinous cystic neoplasms (median, 6800 IU/L; interquartile range, 70-25,295 IU/L). Malignant mucinous cysts had lower amylase levels than benign mucinous cysts (P=0.0008). CONCLUSIONS: Cyst fluid CEA and amylase levels are suggestive but not diagnostic in differentiating PCLs. Unlike CEA, amylase may help differentiate benign from malignant mucinous cysts. Novel biomarkers are needed. PMID- 20966812 TI - Macrolane for breast enhancement: 12-month follow-up. AB - BACKGROUND: Stabilized hyaluronic acid-based gel of nonanimal origin (NASHA-based gel) is well established for use in aesthetic facial procedures. A new formulation (Macrolane VRF30, Q-Med AB, Uppsala, Sweden) may be suitable for patients seeking breast enhancement. The aim of this study was to develop a reproducible technique for injecting NASHA-based gel posterior to the mammary gland (subglandular injection) and to assess treatment safety and efficacy. The feasibility of dual-plane submuscular injection was also explored. METHODS: Nonpregnant, nonbreastfeeding women with small breasts were recruited for this open-label, noncomparative study. Patients were treated in groups of four to enable step-wise revision of the injection technique. Safety and efficacy assessments (12-month follow-up) included adverse event reporting and the Global Aesthetic Improvement Scale, respectively. RESULTS: Twenty-four women (mean age, 37 years) were recruited, 20 of whom underwent subglandular injection. A reproducible injection technique was successfully developed that could be performed under local anesthesia. High subject improvement rates for breast appearance (38 of 46 breasts; 83 percent) were observed for at least 6 months after treatment. At 12 months, 69 percent of breasts were still considered improved. Similar trends were observed with patient satisfaction levels. NASHA based gel was generally well tolerated, with no inflammatory reactions or serious adverse events. Capsular contracture was the most commonly reported adverse event. CONCLUSION: NASHA-based gel is a new option for patients who desire aesthetic improvement of the breast but who do not want to undergo surgery. Further studies to confirm these findings in larger numbers of patients are warranted. PMID- 20966813 TI - Primary septoplasty in the repair of unilateral complete cleft lip and palate. AB - BACKGROUND: The purpose of this study was to assess and compare nasal symmetry in patients who underwent correction of a complete unilateral cleft lip using the Afroze incision without and with primary septoplasty using a standardized two dimensional photographic analysis. METHODS: A prospective cohort study of 190 consecutive patients with complete unilateral cleft lip and alveolus with cleft palate treated with or without septoplasty using the Afroze incision technique was conducted at a high-volume center. Eighty-two patients operated on without primary septoplasty and 76 patients operated on with primary septoplasty were evaluated. Nasal symmetry was compared between patients using two-dimensional photographic analysis. Ratios between the cleft side and the non-cleft side for five parameters were used to assess symmetry: alar base-to-interpupillary line distance, columella-to-Cupid's bow distance, nostril gap area, nostril width, and nostril height. The Mann-Whitney U test was used to calculate differences between the two groups. RESULTS: Patients operated on with primary septoplasty showed more nasal symmetry compared with patients operated on without septoplasty. This difference was statistically significant for columella-to-Cupid's bow distance, nostril gap area, and nostril height (p = 0.008, p < 0.001, and p < 0.001, respectively) and for the distance between alar base and the alar base-to interpupillary line distance (p = 0.145) the difference was present but not statistically significant. For nostril width, no difference was found (p = 0.850). CONCLUSION: Patients treated with primary septoplasty showed better results in terms of nasal symmetry when analyzed using two-dimensional photographic analyses. PMID- 20966814 TI - Outcome analysis in 93 facial rejuvenation patients treated with a deep-plane face lift. AB - BACKGROUND: This prospective study assessed outcomes in patients undergoing a deep-plane face lift and other simultaneous facial cosmetic procedures. It is the first prospective outcome study to assess and compare these patients and provide data on patient satisfaction and quality of life-the most important determinants of surgical success. METHODS: From 2002 to 2007, in-person interviews were conducted with 93 patients who attended a follow-up appointment at least 1 month after surgery from a total of 122 consecutive patients treated with a deep-plane face lift and other facial rejuvenation procedures (response rate, 76 percent). Questions were asked in six categories: patient data, indications, recovery, results, complications, and psychological effects. Responses were analyzed in four groups: face lift alone; face lift and blepharoplasties; face lift and forehead lift; and face lift, blepharoplasties, and endoscopic forehead lift. RESULTS: The average subjective reduction in apparent age was 11.9 years (range, 0 to 27.5 years). Seventy-seven patients (82.8 percent) reported an improvement in self-esteem, and 64 patients (69.6 percent) reported an improved quality of life. There was no significant correlation between result rating and procedure groups, age, gender, smoking history, previous face lift, body mass index, or the occurrence of a complication. CONCLUSIONS: Despite a significant recovery period, patient satisfaction was high, with 96.7 percent of patients reporting a more youthful appearance after surgery. Scar dissatisfaction was rare (2.2 percent). With proper patient preparation and education, facial rejuvenation effectively meets patient expectations. These findings support the recommendation of surgical facial rejuvenation to patients who wish to look younger. PMID- 20966815 TI - Radial nerve injuries and outcomes: our experience. AB - BACKGROUND: The purpose of this study was to evaluate retrospectively the patients who had undergone radial nerve reconstruction. METHODS: The medical charts of 35 patients with radial nerve lesions and 13 patients with superficial radial nerve lesions who underwent surgical exploration and repair in the authors' center were reviewed. The outcomes were analyzed in relation to various factors, such as age at injury, denervation time, level of injury, length of nerve graft, and type of reconstruction. RESULTS: With regard to the radial nerve, good and excellent motor results were seen in 27 of 35 cases (77.14 percent). Postoperative lateral pinch and grip strength of the affected side were equal to 75.49 percent and 76.42 percent of those of the nonaffected side, respectively. Patient age, level of injury, denervation time, associated nerve injuries, length of nerve graft, and type of surgical reconstruction significantly influenced the functional outcome. For the superficial radial nerve, good and excellent sensory results were seen in 10 of 13 cases (76.92 percent). Postoperatively, pain scores were graded as excellent in 69.23 percent and as good in 23.07 percent of patients. CONCLUSIONS: Better functional results were achieved in younger patients, with denervation time of 3 months or less, in lesions in continuity, in patients without associated nerve injuries, in distal lesions, with neurolysis, and with nerve grafts less than or equal to 5 cm long. Functional outcomes following microsurgical repair of radial nerve injuries are encouraging and should be pursued. PMID- 20966816 TI - Quality of innervation in sensate medial plantar flaps for heel reconstruction. AB - BACKGROUND: Reconstruction of the heel represents a difficult challenge for surgeons, given the demand for thick, durable skin capable of withstanding both pressure and shear. The authors describe the use of a sensate medial plantar flap for heel reconstruction in three patients and document the long-term retention of sensation compared with the contralateral uninjured heel and corresponding donor site. METHODS: A medial plantar flap was harvested to include the branch of the medial plantar nerve to the instep to preserve innervation. Sharp pain, light and deep pressure, vibration, cold temperature, and static and dynamic two-point discrimination were examined between 6 months and 1 year after surgery. RESULTS: Sharp pain, vibration, and deep pressure sensation were present equally in the medial plantar flap, contralateral heel, and contralateral instep. Cold perception, light pressure, and static two-point and dynamic two-point discrimination were significantly less in the normal contralateral heel when compared with the heel reconstructed by the innervated flap. There were no significant differences in sensation between the medial plantar flap and the contralateral instep. CONCLUSIONS: The medial plantar flap is capable of providing durable, sensate coverage of plantar hindfoot defects with minimal donor-site morbidity. Furthermore, that sensation remains identical to that of the instep donor site and superior to that of the normal heel pad. PMID- 20966817 TI - Outcomes of partial vaginal reconstruction with pedicled flaps following oncologic resection. AB - BACKGROUND: Immediate flap reconstruction for partial vaginal resection is often performed with resection of colorectal, gynecologic, and urologic malignancies. Surgical and functional outcomes have not been well described. The aim of the authors' study was to identify factors associated with improved outcomes in patients undergoing immediate flap reconstruction for partial vaginal resection. METHODS: The authors reviewed all consecutive partial vaginal resections with immediate flap reconstruction at their institution between 2000 and 2009. Patient, treatment, and outcome data were collected and retrospectively analyzed. Logistic regression was used to evaluate predictive factors associated with complications. RESULTS: Seventy-two women were included in the study. Mean follow up was 32 months (range, 1 to 93 months). The most common pathology was rectal adenocarcinoma (63 percent); 89 percent of patients underwent preoperative radiotherapy and 87 percent preoperative chemotherapy. Most vaginal defects were located posteriorly (72 percent) and reconstructed with vertical rectus abdominis myocutaneous flaps (87 percent). Readmission or reoperation was required in 8 percent of patients. Complications were higher in patients who received preoperative radiotherapy than in those who did not (66 versus 25 percent) and who had posterior defects rather than anterior defects (66 versus 30 percent). Patients experiencing postoperative complications had higher preoperative radiation doses (p = 0.014). Of 24 patients with available postoperative sexual function data, 68 percent reported successful penile-vaginal intercourse. CONCLUSIONS: Immediate flap reconstruction for partial vaginal resection has a high incidence of minor complications. Preoperative radiotherapy is associated with increased complications. Most patients able to practice penile-vaginal intercourse preoperatively also could postoperatively. For patients undergoing pelvic oncologic resection, immediate flap reconstruction for partial vaginal resection should be considered; however, counseling on relevant risks and functional outcomes is vital. PMID- 20966818 TI - Does previous chest wall irradiation increase vascular complications in free autologous breast reconstruction? AB - BACKGROUND: Prior radiation therapy to the chest, in theory, has a detrimental impact on the recipient vessels in breast reconstruction and may impact microvascular success. The purpose of this study was to determine whether prereconstruction radiation therapy affects the rate of vascular complications in free flap breast reconstruction. METHODS: This was a retrospective review of free flap breast reconstruction performed between 2005 and 2009 by the senior authors. In addition to medical and surgical history, vascular complications were recorded, including intraoperative and postoperative thromboses and technical difficulties resulting in a variation of the standard approach. RESULTS: In total, 226 flaps were placed into an irradiated field, whereas 799 were transposed into a radiation-naive defect. Vascular complications as a whole were more prevalent in the irradiated group (9.6 percent versus 17.3 percent; p = 0.001). In regression modeling, radiation therapy was identified as an independent risk factor (odds ratio, 1.68; 95 percent confidence interval, 1.04 to 2.70). In subanalysis, there is a significantly higher rate of intraoperative vascular complications (7.6 percent versus 14.2 percent; p = 0.003), although individual outcomes did not reach formal significance. Previous irradiation had no effect on delayed vascular complications, flap loss, fat necrosis, infection, skin flap necrosis, hematoma, seroma, or delayed wound healing. CONCLUSIONS: Prereconstruction radiation therapy increases the rate of vascular complications in free flap breast reconstruction, the majority of which appear intraoperatively. Although radiation does not hinder the overall success of reconstruction or contribute to postoperative complications, surgeons should be aware that working in a previously irradiated field carries additional technical risk. PMID- 20966819 TI - The influence of low and high pressure levels during negative-pressure wound therapy on wound contraction and fluid evacuation. AB - BACKGROUND: Negative-pressure wound therapy promotes healing by drainage of excessive fluid and debris and by mechanical deformation of the wound. The most commonly used negative pressure, -125 mmHg, may cause pain and ischemia, and the pressure often needs to be reduced. The aim of the present study was to examine wound contraction and fluid removal at different levels of negative pressure. METHODS: Peripheral wounds were created in 70-kg pigs. The immediate effects of negative-pressure wound therapy (-10 to -175 mmHg) on wound contraction and fluid removal were studied in eight pigs. The long-term effects on wound contraction were studied in eight additional pigs during 72 hours of negative-pressure wound therapy at -75 mmHg. RESULTS: Wound contraction and fluid removal increased gradually with increasing levels of negative pressure until reaching a steady state. Maximum wound contraction was observed at -75 mmHg. When negative-pressure wound therapy was discontinued, after 72 hours of therapy, the wound surface area was smaller than before therapy. Maximum wound fluid removal was observed at -125 mmHg. CONCLUSIONS: Negative-pressure wound therapy facilitates drainage of wound fluid and exudates and results in mechanical deformation of the wound edge tissue, which is known to stimulate granulation tissue formation. Maximum wound contraction is achieved already at -75 mmHg, and this may be a suitable pressure for most wounds. In wounds with large volumes of exudate, higher pressure levels may be needed for the initial treatment period. PMID- 20966820 TI - Five-year outcome of surgical treatment of migraine headaches. AB - BACKGROUND: This study was designed to assess the long-term efficacy of surgical deactivation of migraine headache trigger sites. METHODS: One hundred twenty-five volunteers were randomly assigned to the treatment (n = 100) or control group (n = 25) after examination by the team neurologist to ensure a diagnosis of migraine headache. Patients were asked to complete the Medical Outcomes Study 36-Item Short Form Health Survey, Migraine-Specific Quality of Life, and Migraine Disability Assessment questionnaires before treatment and at 12- and 60-month postoperative follow-up. The treatment group received botulinum toxin to confirm the trigger sites; controls received saline injections. Treated patients underwent surgical deactivation of trigger site(s). Results were analyzed at 1 year (previously published) and 5 years postoperatively (the subject of this report). RESULTS: Eighty-nine of 100 patients in the treatment group underwent surgery, and 79 were followed for 5 years. Ten patients underwent deactivation of additional (different) trigger sites during the follow-up period and were not included in the data analysis. The final outcome with or without inclusion of these 10 patients was not statistically different. Sixty-one (88 percent) of 69 patients have experienced a positive response to the surgery after 5 years. Twenty (29 percent) reported complete elimination of migraine headache, 41 (59 percent) noticed a significant decrease, and eight (12 percent) experienced no significant change. When compared with the baseline values, all measured variables at 60 months improved significantly (p < 0.0001). CONCLUSION: Based on the 5-year follow-up data, there is strong evidence that surgical manipulation of one or more migraine trigger sites can successfully eliminate or reduce the frequency, duration, and intensity of migraine headache in a lasting manner. PMID- 20966821 TI - Retinal pigment epitheliopathy, macular telangiectasis, and intraretinal crystal deposits in HIV-positive patients receiving ritonavir. AB - PURPOSE: The purpose of this study was to describe the occurrence of a retinal pigment epitheliopathy associated with macular telangiectasis and intraretinal crystal deposits in three human immunodeficiency virus-positive patients receiving long-term ritonavir as part of highly active antiretroviral therapy. METHODS: The patient's records were reviewed. RESULTS: The CD4 T-cell counts at presentation were 163 cells per microliter, 464 cells per microliter, and 349 cells per microliter, and viral loads were undetectable in all patients. None of the patients had a concurrent AIDS-defining illness. Other significant medical history included hyperlipidemia in one patient and a remote history of lymphoma and tuberculosis in a second patient. Initial visual acuity ranged from 20/32 to 20/400, with a median of 20/150. Anterior segment examination and intraocular pressures were normal in all eyes. Posterior segment examination revealed bilateral macular retinal pigment epitheliopathy with intraretinal crystalline deposits. No hemorrhage or cotton wool spots were seen consistent with human immunodeficiency virus retinopathy, and there was no evidence of previous or active cystomegalovirus retinitis. Fluorescein angiography revealed parafoveal telangiectasis with late leakage in two of the three patients. Optical coherence tomography showed thickening of the macula in three eyes and inner foveal cysts in two eyes. Autofluorescence performed on one patient revealed complete loss of normal retinal pigment epithelium autofluorescence corresponding to the area of retinal pigment epitheliopathy bilaterally. The only medicine common to all 3 patients was ritonavir, and the duration of ritonavir therapy before presentation was 19 months in one patient, 30 months in the second patient, and 5 years in the third patient. CONCLUSION: Retinal changes characterized by retinal pigment epitheliopathy, parafoveal telangiectasias, and intraretinal crystal deposits occurred in three human immunodeficiency virus-positive patients on long-term ritonavir as part of highly active antiretroviral therapy. PMID- 20966822 TI - Acquired vitelliform detachment in patients with subretinal drusenoid deposits (reticular pseudodrusen). AB - PURPOSE: To report a recently observed association of macular vitelliform detachment and subretinal drusenoid deposits (reticular pseudodrusen). METHODS: Clinical and multimodal imaging data of patients with acquired vitelliform lesions in association with subretinal drusenoid deposits were reviewed. Acquired vitelliform lesions were defined as subretinal accumulations of yellow material that developed in adulthood. Subretinal drusenoid deposits were diagnosed as being present if there were drusen-like accumulations that colocalized with aggregates of subretinal material as seen by multimodal imaging including spectral-domain optical coherence tomography, autofluorescence, and near-infrared imaging. RESULTS: Seven eyes of 6 patients with a mean age of 85 years, all of whom were white, were found to have vitelliform material in association with subretinal drusenoid deposits. The median visual acuity was 20/30. The vitelliform material was hyperautofluorescent and was in all eyes located in the subretinal space between the inner segment/outer segment junction and the retinal pigment epithelium. This material had the same color, autofluorescence, and optical coherence tomographic characteristics as the vitelliform material seen in association with cuticular drusen. CONCLUSION: Acquired vitelliform lesions can occur in association with subretinal drusenoid deposits. Subretinal drusenoid deposits might be mistaken for cuticular drusen because of their similar appearance in color fundus photography but can be easily distinguished with multimodal imaging because they lie above the retinal pigment epithelium. Subretinal drusenoid deposits may reflect abnormalities in the function of the retinal pigment epithelium and their presence may interfere with photoreceptor outer segment turnover, leading to an accumulation of vitelliform material. PMID- 20966823 TI - The use of carbonic anhydrase inhibitors in the retreatment of cystic macular lesions in retinitis pigmentosa and X-linked retinoschisis. AB - PURPOSE: The purpose of this study was to determine if carbonic anhydrase inhibitors can restore their efficacy after a period of discontinued use in patients with cystic foveal lesions who demonstrated subsequent worsening in the extent of their foveal cysts after initially exhibiting a favorable response to treatment. METHODS: Retrospective chart review was conducted on all patients with retinitis pigmentosa or X-linked retinoschisis who were either currently on treatment or had been treated with carbonic anhydrase inhibitors for cystic macular lesions. A total of three patients were included in the study. RESULTS: All three patients exhibited a recurrence of their cystic macular lesions while on treatment with carbonic anhydrase inhibitors. After discontinuing treatment for a period of 1 month to 6 months, all patients showed a favorable response to retreatment as monitored with optical coherence tomography scans. CONCLUSION: The present study shows that patients who show signs of recurring macular cysts while still on treatment can have a favorable response when treatment is reinstated after a period of discontinued use of a carbonic anhydrase inhibitor. PMID- 20966824 TI - Adjunctive use of a novel releasable suture technique in transconjunctival vitrectomy. AB - PURPOSE: The purpose of this study was to determine the merits of a transconjunctival vitrectomy with the releasable suture technique in a large series of 20-gauge, 23-gauge, and hybrid trocar vitrectomy and to assess its effectiveness in minimizing the occurrence of incompetent wound closures. METHODS: One hundred and one patients, with a variety of vitreoretinal disorders, and totaling 125 eyes, were enrolled. Each entry site wound was closed, with the releasable suture technique using 8-0 nylon. Postoperatively, sutures were released under a slit lamp at the office a mean 22.9 hours after surgery. In addition to the usual intraoperative and postoperative identification of complications, preoperative and postoperative intraocular pressures were monitored. RESULTS: The full results from all 337 sclerotomies (206, 20 gauge; and 131, 23 gauge) were assessed. It was observed that there were no significant differences between preoperative and postoperative intraocular pressure measurements (P > 0.05); no eyes required fluid or gas supplements, there was no significant wound leakage or hypotony; and no significant complications occurred, such as endophthalmitis or choroidal detachment. CONCLUSION: These results indicate that transconjunctival vitrectomy with releasable sutures, including those conducted with larger instrument trocar systems, offer patients excellent chances for a favorable outcome without incidences of postoperative wound leakage or hypotony. PMID- 20966825 TI - Combined therapy: photodynamic therapy and bevacizumab to treat myopic neovascular membranes. One-year follow-up. AB - PURPOSE: The purpose of this study was to evaluate whether combined customized photodynamic therapy (PDT) and bevacizumab in myopic choroidal neovascularization can improve vision and whether it is possible to decrease the frequency and number of intravitreal antiangiogenic injections. METHODS: A prospective, consecutive, noncomparative, interventional case series of 36 patients with myopic choroidal neovascularization, treated with an initial dose of PDT and intravitreal bevacizumab 48 hours to 60 hours afterward. Retreatments were carried out as required with monthly bevacizumab and PDT every 3 months if there were relapses. Follow-up lasted 1 year in all cases. RESULTS: The mean best corrected visual acuity increased from 44 letters before the initial treatment to 59.5 letters at the 12-month follow-up (P < 0.01). Compared with initial vision, 94.5% of the eyes had the same or better vision and 5.5% lost fewer than 6 lines of vision. The mean number of PDT treatments was 1.1 per patient, and the mean number of bevacizumab injections was 1.5 per patient. Only 1 initial treatment with PDT + bevacizumab was necessary in 28 cases (77.8%). CONCLUSION: Combined personalized PDT + bevacizumab therapy makes it possible to obtain visual results similar to those obtained in monotherapy studies but with fewer intravitreal injections. It appears to be an interesting option for this type of patient. PMID- 20966826 TI - Multimodal fundus imaging of pseudoxanthoma elasticum. AB - PURPOSE: To investigate spectral domain optical coherence tomography and autofluorescence findings in eyes with pseudoxanthoma elasticum. METHODS: A retrospective analysis of visual acuity, spectral domain optical coherence tomography, and autofluorescence findings of consecutive patients with pseudoxanthoma elasticum was performed. The spectral domain optical coherence tomography was evaluated for retinal architecture, subretinal accumulations, and photoreceptor layer thickness. Autofluorescence and near-infrared reflectance images were reviewed for correlative findings. RESULTS: There were 21 patients (42 eyes) with pseudoxanthoma elasticum with a mean age of 56.1 +/- 12.4 years. Subretinal fluid was found in 14 eyes, 7 of which had no signs of choroidal neovascularization. In six of the seven eyes with a history of choroidal neovascularization controlled with antivascular endothelial growth factor injections, there were areas of subretinal fluid that were not contiguous with the choroidal neovascularization and did not seem responsive to antivascular endothelial growth factor injections. Two types of formed material were observed in the subretinal space and outer retina. The first was hypoautofluorescent deposits above the retinal pigment epithelium resembling subretinal drusenoid deposits (reticular pseudodrusen). The second was yellow to brown hyperautofluorescent aggregates in the subretinal space and outer retina similar to those seen in pattern dystrophies and was found in 19 eyes. There was an apparent association between the presence of subretinal fluid and pattern dystrophy-like findings. CONCLUSION: Subretinal fluid in patients with pseudoxanthoma elasticum is not always indicative of active leakage from underlying choroidal neovascularization and can be resistant to antivascular endothelial growth factor injections. This fluid is associated with pattern dystrophy-like findings and may indicate abnormal retinal pigment epithelial function. PMID- 20966827 TI - The geography of heterosexual partnerships in Baltimore city adults. AB - BACKGROUND: Human immunodeficiency virus/sexually transmitted disease (HIV/STD) risk is determined in part by sexual network characteristics, which include spatial parameters. Geography and proximity of partner selection are important factors, which may explain neighborhood-level differences in HIV/STD morbidity. To study the effects of neighborhood factors on HIV/STD transmission in high density urban areas, the geography of partner selection must be understood. METHODS: The Baltimore site of the National HIV Behavioral Surveillance system surveyed adults reporting one or more heterosexual partnerships. Spatial assortativity was defined as both partners residing in the same or adjacent census tracts and based on participant report. HIV core areas were defined as the census tracts in the top quartile for standardized HIV/AIDS case rates. RESULTS: Participants (n = 307) provided data on 776 recent sexual partnerships, and geographic information were obtained for 510 partnerships (66%). Almost half (47%) reported choosing spatially assortative partners. Participants who lived in high HIV-prevalence areas were more likely to choose spatially assortative partners than residents of lower prevalence areas after adjusting for partnership type, gender, and number of partners. Although this population exhibited assortative mixing in all types of partnerships, racial and age assortativities were not associated with choosing spatially assortative partners. CONCLUSIONS: Over 15 years ago, STD clinic patients in Baltimore were found to seek partners within close proximity. We confirm these results in a non-STD clinic population, indicating a continuing need for neighborhood approaches to intervention programs in urban areas. PMID- 20966828 TI - Human papillomavirus infection and cytologic abnormalities of the anus and cervix among HIV-infected women in the study to understand the natural history of HIV/AIDS in the era of effective therapy (the SUN study). AB - BACKGROUND: Human papillomavirus (HPV) infection of the cervix and related abnormal cervical cytology in HIV-infected women has been well described. Little is known about anal HPV infection in HIV-infected women. METHODS: The SUN Study is a prospective cohort study of 700 HIV-infected patients including 167 women. At baseline, patients completed a behavioral questionnaire and provided, among other samples, cervical and anal swabs for HPV detection and genotyping and for cytologic examination. Here, we present the available baseline data on the 167 women in the SUN study. RESULTS: Baseline results were available for 120 women (median age: 38 years, 57% non-Hispanic black, median CD4 cell count 444.5 cells/mm3), of whom, 77% were taking antiretroviral therapy. The prevalences in the anus and cervix of any HPV were 90% and 83%, respectively (P = 0.039), and of high-risk (HR) types 85% and 70%, respectively, (P = 0.001). There was no significant difference in the prevalences of abnormal cytology between the anus and cervix: 38% and 33%, respectively (P = 0.217). Although the presence of abnormal cervical cytology was associated with the presence of abnormal anal cytology (relative risk: 1.7, P = 0.024), its sensitivity (52.5%) and positive predictive value positive (45.6%) for identifying women with abnormal anal cytology were poor. A history of anal sex was not associated with anal HPV infection or abnormal anal cytology. CONCLUSIONS: In this cohort of HIV-infected women, anal HPV infection was more prevalent and diverse than cervical HPV infection. Anal cytologic abnormalities were as prevalent as cervical cytologic abnormalities, and although abnormal cervical cytology was predictive of abnormal anal cytology, results were not highly concordant. These data support the need for studies of anal cytologic screening of HIV-infected women. PMID- 20966829 TI - Characteristics of women reporting multiple recent sex partners presenting to a sexually transmitted disease clinic for care. AB - BACKGROUND: Sexually transmitted disease (STD) clinic attendees are considered to be at higher risk of sexually transmitted infections (STIs) than the general population. However, little is known about STD clinic subpopulations and their unique risks for STI's. The goal of this project was to begin to characterize an important STD clinic subpopulation, the small proportion of women reporting a recent history of multiple sex partners. METHODS: Screening of electronic medical records from 2007 identified 347 (7%) women with >=4 partners in the last 12 months. Records for women with >=4 sex partners were matched with women reporting 1 sex partner in the last 12 months. Demographic, sexual history, STI history, and laboratory diagnosis(es) were extracted from the electronic medical record and compared using a case-control study design. RESULTS: Approximately 5000 women presented to our STD clinic in 2007; 7.0% reported>=4 sex partners. Women with >=4 sex partners were less often black and on average younger than women with single partners (Median age, 24 vs. 29). They reported more nonvaginal sex, more same-sex contacts, but more consistent condom use than women with single partners. Dyspareunia, genital lesions, abdominal pain, and skin findings were more commonly reported by women with >=4 sex partners. Women with multiple partners were also more likely to report ever having had >=3 STI's and were more likely to report a history of gonorrhea or syphilis. They were also more likely to be diagnosed at presentation with chlamydia, gonorrhea, or syphilis. CONCLUSION: Women reporting multiple sex partners are an important minority among STD clinic attendees. Understanding the antecedents to high risk sexual behavior as determined by partner number is an important step in reducing STI's in this group. PMID- 20966830 TI - Determining the impact of text messaging for sexual health promotion to young people. AB - BACKGROUND: The use of new technologies, such as mobile phones and internet, has increased dramatically in recent years. Text messages offer a novel method of sexual health promotion to young people who are the greatest users of new technology and are also at high risk of sexually transmitted infections (STIs). METHODS: In January 2008, young people aged between 16 and 29 years were recruited from a music festival in Melbourne, Australia. They completed a short survey and were asked to provide their mobile phone numbers. Participants received fortnightly short messaging service (SMS) relating to sexual health for 4 months, and then completed an online follow-up survey. Survey data were weighted to account for those lost to follow-up. McNemar's test was used to compare changes in survey responses. RESULTS: A total of 1771 participants were included in analysis as they were sexually active and provided a valid mobile phone number at baseline. In all, 18% (319/1771) withdrew from receiving the SMS during the broadcast period and 40% (587/1452) completed the follow-up survey. The majority reported on the follow-up survey that they found the SMS entertaining (80%), informative (68%), and they showed the SMS to others (73%). Weighted analyses found a significant increase in knowledge (P < 0.01) and STI testing (P < 0.05) over time in both males and females. CONCLUSION: The findings indicate that SMS appear to be a feasible, popular, and effective method of sexual health promotion to young people with a relatively low withdrawal rate, positive feedback, and an observed improvement in sexual health knowledge and STI testing. PMID- 20966832 TI - Impact of substance abuse on access to renal transplantation. AB - BACKGROUND: With an ever-increasing demand for kidneys and limited supply pool, it is essential to understand the balance between utility and equity in transplant access. The goal of this project was to evaluate the association between recipient's substance abuse and renal transplant access in patients with end-stage renal disease (ESRD). METHODS: We used data from the United States Renal Data System. The primary variables of interest were abuse of alcohol, tobacco, or illicit drugs based on information from Centers for Medicare & Medicaid Services form 2728. We analyzed three outcomes in Cox model: (1) being placed on the waiting list for renal transplantation or transplanted (whichever occurred first); (2) first transplant in patients who were placed on the waiting list; and (3) graft loss or mortality after transplant. In addition, we performed subgroup analysis based on age, race, sex, diabetic status, and donor type. RESULTS: We analyzed 1,077,699 patients (age of ESRD onset 62.9+/-15.5 years, 54.1% males, 64.2% white, and 29.7% African American). When compared with those with no substance abuse, abusing all three substances was associated with reduced transplant access (hazard ratio 0.39, P<0.001 for wait listing/transplant; hazard ratio 0.67, P=0.019 for transplant). This trend was similar in most subgroups studied. CONCLUSION: We demonstrated that patients with ESRD abusing or dependent on tobacco, alcohol, or illicit drugs are less likely to be placed on the waiting list for kidney transplant; and once on the list are less likely to be transplanted. The possible utility justifications for such disparity and potential interventions are discussed. PMID- 20966841 TI - Elder abuse and the community nurse: supporting the patient. AB - This article explains what elder abuse is. It details difficulties in definitions, terminology and the challenges which community nurses face when addressing elder abuse. Guidelines are given which enable clarity regarding elder abuse in the home and the discussion highlights issues specific to elder abuse in the home. This article also includes a review of the role of the community nurse in primary prevention as well as secondary and tertiary care. PMID- 20966842 TI - Managing quality of life in the older person with a stoma. AB - Undergoing surgery and having the formation of a stoma may be required for a number of reasons and how a patient accepts their new body image and changes to their lifestyle can be greatly determined by the support and care they receive from their stoma nurse and other health professionals involved in their recovery after stoma formation. Preparing a patient pre-operatively and taking time to listen to their individual needs will enhance their perception of living with a stoma and accepting their stoma, thus not negatively impacting on what they perceive to be their quality of life. Acknowledging the quality of life of an individual and taking measures to maintain a person's quality of life at an early stage within the surgical pathway will have a positive impact on a patient's recovery from surgery and ability to cope with the daily routine involved when living with a stoma. Nurses need to understand what their patient perceives as a good quality of life and how to alter any negative factors that may inhibit a patient's ability to care for and accept their stoma. PMID- 20966843 TI - Implementing KSF competency testing in primary care. Part 1: developing an appraisal tool. AB - The delivery of an effective community nursing workforce relies on competent staff. Commissioners will need to be assured that their providers employ competent, efficient staff who give value for money. The Knowledge and Skills Framework (KSF) was introduced as part of Agenda for Change to identify the competences required, but competency testing using the KSF has not been fully implemented across the UK, and measuring competency, using the KSF indicators, still leaves much room for variation and a non-standardized approach. In the first of this two-part article, the authors discuss the process through which the provider services of one London PCT developed standardized competences using the KSF which were linked to staff performance and which provided clear areas for individual development. PMID- 20966844 TI - Mycobacterium tuberculosis: implications for district nurses. AB - Despite the belief of many health professionals, tuberculosis is not a disease of the past but is on the increase (Department of Health (DH), 2004) and the UK has seen a year on year increase in the number of new cases (Health Protection Agency, 2008). The DH have made a number of recommendations to combat this increase and one of those recommendations is to raise awareness among health staff (2004). This review has set out to examine district nurses' knowledge about tuberculosis and the consequences of poor knowledge. Five themes emerged from the literature search with the most prominent being the subject of adherence and how this could be addressed. The review has identified that district nurses should have a greater knowledge of tuberculosis and patient treatment could be improved by the nurse having a better understanding about tuberculosis care. PMID- 20966845 TI - What does the future hold for people with long-term health conditions? PMID- 20966846 TI - An investigation of the role nurses play in Norwegian home care. AB - Registered nurses' (RNs') role in Norwegian home care services exists in a state of flux owing to the early discharge of patients from hospitals, more time consuming and complex care for young patients, and a growing number of older care recipients. The aim of this study was to investigate the RN role through an integrative research review, with a focus on nursing activities and competence. This study found that RNs and assistant nurses often perform the same tasks, providing assistance with personal hygiene, medication and wound management. The change towards more medicalized and complex home care entails that requirements pertaining to RNs' competence, the allocation of RNs' time and skills to those in most need of nursing care, and the assignment of assistant nurses to lower care levels activities must be delineated. Norwegian home care must examine how care activities can be better allocated between RNs, social educators, assistant nurses, and informal care-givers. PMID- 20966847 TI - Liberating the NHS; commissioning, outsourcing and a new politics debate. AB - In the short months following the result of the UK 2010 General election, a new Government White Paper has been released entitled: Equity and Excellence: Liberating the NHS (Department of Health (DH), 2010a). It strives to distance itself from previous health-care proposals (DH, 2009), yet if the initiatives of this latest paper are combined against previous initiatives, also using high impact declarative terms, such as competition and choice, it is clear that little has changed and more important principles than saving money are at risk. PMID- 20966848 TI - Right Nurse, Right Skills: quality before quantity. PMID- 20966849 TI - Safeguarding research subjects who lack decision-making capacity. AB - In keeping with the Declaration of Helsinki, health-care research generally requires the informed consent of those who participate in the study. This approach upholds the autonomy of the participants but restricts research to subjects who have decision-making capacity. In order that people who lack decision making capacity can benefit from properly conducted research, the Mental Capacity Act 2005 introduced safeguards that enable researchers to investigate the care and treatment of people with incapacity while protecting this vulnerable patient group. This article outlines the requirements that must be met when conducting research with subjects who lack decision-making capacity. PMID- 20966850 TI - Importance of workplace. PMID- 20966856 TI - Planning for the rising costs of education. PMID- 20966857 TI - Short back and sides. AB - The recently published NHS White Paper, Equity and Excellence: Liberating the NHS (Department of Health (DH), 2010), sets out one of the biggest shake-ups of the country's health system since the NHS was established over 60 years ago. It introduces four main topics to enact this change: Liberating the NHS Putting patients and the public first Improving healthcare outcomes Autonomy, accountability and democratic legitimacy Cutting bureaucracy and improving efficiency. PMID- 20966858 TI - Oil on troubled waters: emollients and eczema. AB - While most of us will have suffered from episodes of dry skin (xerosis) at some stage in our lives, this is usually confined to the occasional mildly annoying episode. However, for others, particularly those with eczema, this forms part of a chronic, very distressing situation that often has a significant impact on their quality of life. Despite the fact that many children and adults have eczema, it is still often considered to be a minor skin condition that children will 'grow out of'. However, an increased research focus towards examining the impact of eczema on the individual has shown that eczema is anything but a minor problem. PMID- 20966859 TI - Psoriasis: the burden of disease and treatment. AB - We've all met them: the patient with chronic disease that simply will not help themselves. Why don't they listen to us? Why, when it's clear they understand the principles, do they seem to do everything in their power to make life difficult for themselves-and, in turn, for us? Of course, as enlightened nurses we take the trouble to understand the individual, and learn that their failure to follow a treatment programme is connected to their feelings about their disease and their body. If they ignore the answer they are also ignoring the problem and, in some way, they are taking control of their situation, making choices and asserting themselves. PMID- 20966860 TI - Effective evidence-based catheter management: an update. AB - Every year over one million urinary catheters are inserted in NHS hospitals. Each of these has the potential to harm. Urinary catheters can lead to trauma and increase the risks of infection and bladder dysfunction. Urinary catheterization can have catastrophic effects on the bladder and a person's ability to regain continence in the future (Patel and Arya, 2001). Approximately 25% of urinary catheterizations are not clinically necessary. Certain groups of people, such as older people, are at a greater risk of unnecessary catheterization and its associated risks. This article explores the clinical indications for urinary catheterization, the importance of appropriate product selection, and acting to reduce the risk of infection. PMID- 20966861 TI - Offering patients a choice of urinary catheter drainage system. AB - The aim of this article is to promote understanding of the benefits, assessment process and suitability of catheter valves, as a form of urinary drainage for patients. A literature review on the benefits of catheter valves provides the opportunity for an in-depth discussion that compares and contrasts different urinary drainage systems. On the evidence of the literature review, all patients require a holistic assessment which considers a number of factors, and provides the nurse with the essential objective data to ascertain the suitability of the catheter valve. These data can be transferred into an easy step-by-step algorithm to help guide the nurse in making the decision, with the patient, on the most appropriate urinary catheter drainage system. PMID- 20966862 TI - The ostomy skin tool: tracking peristomal skin changes. AB - The Ostomy Skin Tool is a standardized measuring instrument for assessing the extent and severity of peristomal skin change in terms of discolouration (D), erosion (E), and tissue overgrowth (T) (DET). The reliability and validity of this tool has been determined in a previous study. The purpose of this article is to highlight the study's most important findings, and to demonstrate the usefulness of the DET score by evaluating three examples of peristomal skin changes. Additionally, a simplified categorical severity scale (defining 'mild', 'moderate', and 'severe' conditions) is introduced that may improve clinical interpretation of the DET score. It is reasonable to conclude that the DET score may empower the ostomy care nurse with an evidence-based platform to make qualified decisions on evaluation and treatment of peristomal skin disorders. PMID- 20966863 TI - Self-helplessness in arthritis: an important but overlooked index. AB - The recent introduction of patient-reported outcome measures (PROMs) assessment into rheumatology practice has changed the way patients suffering from inflammatory arthritis are assessed. This article describes a cross-sectional study of 102 rheumatoid arthritis (RA) patients that was undertaken to evaluate the construct of helplessness in patients with RA, its correlation with other disease activity parameters, and its sensitivity to change following biologic therapy. The study also set out to explore the possibility of including a self helplessness measurement, using the modified Rheumatology Attitude Index (mRAI), as part of the holistic patient assessment in standard clinical practice. Assessment of self-helplessness was shown to be significantly correlated with both psychological as well as functional status measures. The mRAI index is a highly useful and predictive tool for clinical use that is responsive to change in the patients' clinical condition. As part of the PROMs questionnaire, this scale can be applied in a manner similar to other indicators of disease activity status, and is as easy to administer and interpret in standard clinical practice. PMID- 20966864 TI - Medullary sponge kidney: causes and treatments. AB - Medullary sponge kidney is a little known and little understood disease. A patient with a medullary sponge kidney may undergo decades of suffering in the form of infections and pain before any diagnosis is even made. When a diagnosis is made, it is more than likely to be an incidental finding from a test for another problem. However, on diagnosis there are a number of options available to treat this condition. These include non-invasive treatments such as drug therapy, diet or extracorporeal shock wave lithotripsy, to invasive therapies such as percutaneous nephrolithotomy, ureteroscopy and more advanced surgery. The aim of this article is to highlight this little known condition, outline the effects, and discuss the treatment options available to patients. PMID- 20966865 TI - The developing role of children's nurses in community palliative care. AB - This article addresses some of the contemporary issues in relation to providing palliative care for children in Ireland, particularly focusing on the creation of the specialist palliative care nursing outreach posts. The recent publication of an Irish national policy on palliative care for children with life-limiting illness is welcome news for paediatric nurses in Ireland. Children are valued members of society and have a right to receive quality health care and support appropriate to meet both children and the families' precise needs. However, community services for children with life-limiting illnesses remain inadequate, with many parents and families struggling to provide palliative care for children in the home. Currently, community nurses, who are not always registered children's nurses, are providing palliative care for children at the end of life. These nurses may not fully understand the specific needs of critically or chronically ill children and their families. In addition, there are no specific palliative care educational programmes in Ireland with regard to end-of-life care for children. The challenges of providing palliative care to children and their families in relation to symptom control, controversial ethical and legal issues, and emotional and practical support, mean that advanced knowledge is required in order to progress the agenda and thus provide excellence in children's palliative care in Ireland. It is important that the agenda is moved forward so that children and their families requiring palliative care and nursing support do not suffer from a lack of professional provision for their needs. PMID- 20966866 TI - Can the NICE quality standards help drive NHS improvements? AB - Professor Alan Glasper examines the implications of the NICE quality standards, which are designed, in part, to support health professionals such as nurses in making informed, evidence-based care decisions in the best interests of patients. PMID- 20966867 TI - Progress in making the NHS safer and dealing with complaints. AB - Two national organizations concerned with patient safety-the National Patient Safety Agency and the Parliamentary and Health Service Ombudsman-have recently published their annual reports. The publications reveal important insights into how the NHS is currently dealing with the issue of patient safety, and complaints brought against the NHS by patients. PMID- 20966868 TI - Advance directives and personality-changing illness. AB - An advance decision (AD) to refuse treatment allows an individual to express his/her wishes regarding future treatment in the event of losing capacity to make decisions. Relevant and applicable ADs are legally binding, even when refusal of the specfied treatment will lead to the patient's death; but health professionals are required under the Mental Capacity Act to consider a number of factors in deciding whether a patient's AD should be followed. The decision for the health professional is not always clear-cut. For example, what happens when Alzheimer's changes an indivdual's personality so much that they seem to be a different person: does their previous decision still stand? This article examines the criteria to be considered in such a case, and highlights the wider principles to be followed in making any decision on whether to follow an individual's instruction to refuse treatment. PMID- 20966869 TI - The death of Florence Nightingale: BJN 100 years ago. AB - This August marks the centenary of the death of Florence Nightingale, who died at 2 o'clock on Saturday 13 August 1910 at her home, 10 South Street, Park Lane, London. The following are some snippets which appeared in the BJN of the 20 and 27 August 1910. It was not until the announcement of her death in the morning papers of Monday 15 August that the country heard about Nightingale's death. In her last hours she was attended by Sir Thomas Barlow and two nurses from the Nursing Sisters' Institution, Devonshire Square, founded by Mrs Elizabeth Fry in 1840. PMID- 20966870 TI - Time to retire...or carry on nursing? AB - Plans to scrap the default retirement age (DRA) have met with strong criticism from business groups and fears that the Government have rushed the proposals through without proper consultation. For nurses it means that, from next October, employers will be unable to automatically lay off staff when they reach the age of 65 years. Although the DRA will be scrapped in October the real effects will not be felt until April onwards, as employers must give 6 months' notice to staff that they want to retire. PMID- 20966871 TI - Anthraquinones with antiplasmodial activity from the roots of Rennellia elliptica Korth. (Rubiaceae). AB - Dichloromethane root extract of Rennellia elliptica Korth. showed strong inhibition of Plasmodium falciparum growth in vitro with an IC50 value of 4.04 ug/mL. A phytochemical study of the dichloromethane root extract has led to the isolation and characterization of a new anthraquinone, 1,2-dimethoxy-6-methyl 9,10-anthraquinone (1), and ten known anthraquinones: 1-hydroxy-2-methoxy-6 methyl-9,10-anthraquinone (2), nordamnacanthal (3), 2-formyl-3-hydroxy-9,10 anthraquinone (4), damnacanthal (5), lucidin-omega-methyl ether (6), 3-hydroxy-2 methyl-9,10-anthraquinone (7), rubiadin (8), 3-hydroxy-2-methoxy-6-methyl-9,10 anthraquinone (9), rubiadin-1-methyl ether (10) and 3-hydroxy-2-hydroxymethyl 9,10-anthraquinone (11). Structural elucidation of all compounds was accomplished by modern spectroscopic methods, notably 1D and 2D NMR, IR, UV and HREIMS. The new anthraquinone 1, 2-formyl-3-hydroxy-9,10-anthraquinone (4) and 3-hydroxy-2 methyl-9,10-anthraquinone (7) possess strong antiplasmodial activity, with IC50 values of 1.10, 0.63 and 0.34 uM, respectively. PMID- 20966872 TI - Efficient microwave-assisted synthesis of 5-deazaflavine derivatives. AB - A series of pyrimido[4,5-b]quinolines (5-deazaflavines), were synthesized by microwave assisted intramolecular cyclization. The N4-substituted-2,4-diamino-6 chloro-pyrimidine-5-carbaldehydes, were prepared by selective monoamination of 2 amino-4,6-dichloropyrimidine-5-carbaldehyde with aliphatic and aromatic amines. PMID- 20966873 TI - Protecting groups in carbohydrate chemistry: influence on stereoselectivity of glycosylations. AB - Saccharides are polyhydroxy compounds, and their synthesis requires complex protecting group manipulations. Protecting groups are usually used to temporarily mask a functional group which may interfere with a certain reaction, but protecting groups in carbohydrate chemistry do more than protecting groups usually do. Particularly, protecting groups can participate in reactions directly or indirectly, thus affecting the stereochemical outcomes, which is important for synthesis of oligosaccharides. Herein we present an overview of recent advances in protecting groups influencing stereoselectivity in glycosylation reactions, including participating protecting groups, and conformation-constraining protecting groups in general. PMID- 20966874 TI - The Nrf2 system as a potential target for the development of indirect antioxidants. AB - Oxidative stress causes damage to multiple cellular components such as DNA, proteins, and lipids, and is implicated in various human diseases including cancer, neurodegeneration, inflammatory diseases, and aging. In response to oxidative attack, cells have developed an antioxidant defense system to maintain cellular redox homeostasis and to protect cells from damage. The thiol-containing small molecules (e.g. glutathione), reactive oxygen species-inactivating enzymes (e.g. glutathione peroxidase), and phase 2 detoxifying enzymes (e.g. NAD(P)H: quinine oxidoreductase 1 and glutathione-S-transferases) are members of this antioxidant system. NF-E2-related factor 2 (Nrf2) is a CNC-bZIP transcription factor which regulates the basal and inducible expression of a wide array of antioxidant genes. Following dissociation from the cytosolic protein Keap1, a scaffolding protein which binds Nrf2 and Cul3 ubiquitin ligase for proteasome degradation, Nrf2 rapidly accumulates in the nucleus and transactivates the antioxidant response element in the promoter region of many antioxidant genes. The critical role of Nrf2 has been demonstrated by various animal studies showing that mice with a targeted disruption of the nrf2 gene are prone to develop lesions in response to environmental toxicants/carcinogens, drugs, and inflammatory insults. In this review, we discuss the role of the Nrf2 system, with particular focus on Nrf2-controlled target genes and the potential pleiotropic effects of Nrf2 activation of indirect antioxidants. PMID- 20966875 TI - Antioxidant-prooxidant properties of a new organoselenium compound library. AB - The present study describes the biological evaluation of a library of 59 organo selenium compounds as superoxide (O2-) generators and cytotoxic agents in human prostate cancer cells (PC-3) and in breast adenocarcinoma (MCF-7). In order to corroborate that the biological activity for selenium compounds depends on the chemical form, a broad structural variety is presented. These structures include selenocyanates, diselenides, selenoalkyl functional moieties and eight newly synthesized symmetrically substituted dithioselenites and selenylureas. Eleven of the derivatives tested showed high levels of superoxide generation in vitro via oxidation of reduced glutathione (GSH) and nine of them were more catalytic than the reference compound, diselenodipropionic acid. Eighteen of the library compounds inhibited cell growth more than or similar to reference chemotherapeutic drugs in PC-3 and eleven were more potent cytotoxic agents than etoposide in the MCF-7 cell line. Considering both parameters (superoxide generation and cell cytotoxicity) compounds B1, C6 and C9 displayed the best therapeutic profiles. Considering that many diselenide compounds can generate superoxide (O2-) in vitro via oxidation of GSH and other thiols, the analogue B1, that contains a diselenide moiety, was selected for a preliminary mechanistic investigation, which revealed that B1 has apoptogenic effects similar to camptothecin mediated by reactive oxygen species (ROS) in lymphocytic leukemia cells (CCRF-CEM) and affected the MCF-7 cell-cycle in G2/M and S-phases. PMID- 20966877 TI - Tetrabutylammonium bromide media aza-Michael addition of 1,2,3,6 tetrahydrophthalimide to symmetrical fumaric esters and acrylic esters under solvent-free conditions. AB - The aza-Michael addition of 1,2,3,6-tetrahydrophthalimide with symmetrical fumaric esters has been performed efficiently in a solvent-free system at 100 degrees C and using 1,4-diazabicyclo[2.2.2]octane (DABCO) as a base in the presence of tetrabutylammonium bromide (TBAB). The products were obtained in good to high yields within 2.5-7.0 h. This reaction worked well on linear alkyl fumarates and was not effective with nonlinear alkyl fumarates. Although the reaction was also applicable to acrylates such as n-butyl acrylate, methacrylates and crotonates were not suitable Michael acceptors for this reaction. PMID- 20966878 TI - Chemometric studies on natural products as potential inhibitors of the NADH oxidase from Trypanosoma cruzi using the VolSurf approach. AB - Natural products have widespread biological activities, including inhibition of mitochondrial enzyme systems. Some of these activities, for example cytotoxicity, may be the result of alteration of cellular bioenergetics. Based on previous computer-aided drug design (CADD) studies and considering reported data on structure-activity relationships (SAR), an assumption regarding the mechanism of action of natural products against parasitic infections involves the NADH-oxidase inhibition. In this study, chemometric tools, such as: Principal Component Analysis (PCA), Consensus PCA (CPCA), and partial least squares regression (PLS), were applied to a set of forty natural compounds, acting as NADH-oxidase inhibitors. The calculations were performed using the VolSurf+ program. The formalisms employed generated good exploratory and predictive results. The independent variables or descriptors having a hydrophobic profile were strongly correlated to the biological data. PMID- 20966879 TI - Synthesis, gastroprotective effect and cytotoxicity of new amino acid diterpene monoamides and diamides. AB - Following our studies on the gastroprotective effect and cytotoxicity of terpene derivatives, new amides were prepared from the diterpene 8(17)-labden-15,19-dioic acid (junicedric acid) and its 8(9)-en isomer with C-protected amino acids (amino acid esters). The new compounds were evaluated for their gastroprotective effect in the ethanol/HCl-induced gastric lesions model in mice, as well as for cytotoxicity using the following human cell lines: normal lung fibroblasts (MRC 5), gastric adenocarcinoma cells (AGS) and liver hepatocellular carcinoma (Hep G2). A dose-response experiment showed that at 25 mg/kg the C-15 leucyl and C 15,19-dileucylester amides of junicedric acid reduced gastric lesions by about 65.6 and 49.6%, respectively, with an effect comparable to lansoprazole at 20 mg/kg (79.3% lesion reduction). The comparison of the gastroprotective effect of 18 new amino acid ester amides was carried out at a single oral dose of 25 mg/kg. Several compounds presented a strong gastroprotective effect, reducing gastric lesions in the 70.9-87.8% range. The diprolyl derivative of junicedric acid, the most active product of this study (87.8% lesion reduction at 25 mg/kg) presented a cytotoxicity value comparable with that of the reference compound lansoprazole. The structure-activity relationships are discussed. PMID- 20966876 TI - Plant phenolics: extraction, analysis and their antioxidant and anticancer properties. AB - Phenolics are broadly distributed in the plant kingdom and are the most abundant secondary metabolites of plants. Plant polyphenols have drawn increasing attention due to their potent antioxidant properties and their marked effects in the prevention of various oxidative stress associated diseases such as cancer. In the last few years, the identification and development of phenolic compounds or extracts from different plants has become a major area of health- and medical related research. This review provides an updated and comprehensive overview on phenolic extraction, purification, analysis and quantification as well as their antioxidant properties. Furthermore, the anticancer effects of phenolics in-vitro and in-vivo animal models are viewed, including recent human intervention studies. Finally, possible mechanisms of action involving antioxidant and pro oxidant activity as well as interference with cellular functions are discussed. PMID- 20966880 TI - Antibacterial activity of phytochemicals isolated from Atractylodes japonica against methicillin-resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has been emerging worldwide as one of the most important problems in communities and hospitals. Therefore, new agents are needed to treat acute oral infections from MRSA. In this study, antibacterial compounds from the roots of Atractylodes japonica (A. japonica) were isolated and characterized. The compounds were isolated from the root extracts using HPLC-piloted activity-guided fractionations. Four A. japonica compounds were isolated and identified as atractylenolide III (1), atractylenolide I (2), diacetylatractylodiol [(6E,12E)-tetradeca-6,12-diene-8,10 diyne-1,3-diol diacetate, TDEYA, 3). and (6E,12E)-tetradecadiene-8,10-diyne-1,3 diol (TDEA, 4), which was obtained by hydrolysis of TDEYA. The minimum inhibitory concentrations (MICs) was determined in the setting of clinical MRSA isolates. Compound 4 showed anti-MRSA activity with a MIC value of 4-32 MUg/mL. The overall results provide promising baseline information for the potential use of the extract of A. japonica as well as some of the isolated compounds in the treatment of bacterial infections. PMID- 20966881 TI - The pharmacological effects of morroniside and loganin isolated from Liuweidihuang Wan, on MC3T3-E1 cells. AB - Liuweidihuang wan (LW), initially a well-known formula for curing "wu chi wu ruan", is commonly used nowadays for clinical treatment of postmenopausal osteoporosis (PO), but the identity of the effective substance(s) remains unclear. The present study was designed to evaluate the effects of morroniside and loganin isolated from LW on the proliferation, differentiation and apoptosis of MC3T3-E1 cells, as well as the possible mechanism of action. Morroniside and loganin had no effects on the proliferation of MC3T3-E1 cells, but both susbtances could improve the activity of alkaline phosphatase (ALP), and increase the contents of collagen type I and osteocalcin. Simultaneously, the mRNA expression of caspase-3, capase-9, RANKL was down-regulated and that of bcl-2 was up-regulated, which partially explains the anti-osteoporosis mechanism in MC3T3 E1 cells. In conclusion, morroniside and loganin may directly promote the differentiation and inhibit the apoptosis of MC3T3-E1 cells, and accordingly indirectly reduce bone resorption, which makes them promising natural drugs leads for treating PO in the near future. PMID- 20966882 TI - Evaluation on anti-hepatitis viral activity of Vitis vinifer L. AB - Suosuo grape (Vitis vinifer L) is traditionally used as a therapeutic agent for measles and hepatitis by the ethnic Uighurs. This work aimed to investigate the anti-HBV effect of total triterpene (VTT), total flavonoids (VTF) and total polysaccharides (VTP) from Suosuo grape, and their synergistic effects were also tested. The viral antigens of cellular secretion, HBsAg and HBeAg, were determined by enzyme linked immunosorbent assay (ELISA).The quantity of HBV-DNA released in the supernatant was assayed by real-time PCR. It was found that it effectively suppressed the secretion of HBsAg and HBeAg from HepG2.2.15 cells in a dose-dependent manner, as well as the HBV DNA. The results of orthogonal design experiment showed that the combination of VTT 20 MUg/mL, VTF 50 MUg/mL and VTP 50 MUg/mL had the best optimistic inhibitory effects on HBeAg secretion. PMID- 20966883 TI - Prenylated xanthones from the bark of Garcinia xanthochymus and their 1,1 diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities. AB - Garcinia xanthochymus has been widely used in traditional Chinese medicine for expelling worms and removing food toxins. Bioassay-guided fractionation of an EtOAc-soluble extract of G. xanthochymus stem bark led to the isolation of six new xanthones. Their structures were elucidated by spectroscopic methods, especially 2D-NMR techniques. Free-radical-scavenging activities of the isolated compounds were elucidated through DPPH method. Most of the isolated compounds showed considerable free radical scavenging activity on DPPH assay. Compound 1 exhibited effective antioxidant scavenging activity against DPPH radical with an IC50 value of 19.64 MUM, and compound 6 showed the lowest activity among all the tested molecules, with an IC50 value of 66.88 MUM. These findings support the notion that the plant genus Garcinia is a good source of bioactive compounds. PMID- 20966884 TI - Creation of a databank for content of antioxidants in food products by an amperometric method. AB - Oxidative stress, i.e. excessive content of reactionary, oxygen, and nitrogen compounds (ROAC), including free radicals, is one of the causes of various dangerous diseases as well as premature aging. The adverse effect of free radicals can be neutralized by antioxidants. In order to carry out antioxidant therapy, one needs to know the contents of antioxidants in food products. We have created the databank for the contents of antioxidants in 1,140 food products, beverages, etc. Apart from water-soluble antioxidants, fat-soluble antioxidants in dairy and fish products, cacao, chocolate, nuts etc. were determined for the first time using an amperometric method. PMID- 20966886 TI - The role of the oncologist in the management of VTE. PMID- 20966885 TI - One-pot synthesis of 2,3,4-triarylquinolines via suzuki-miyaura cross-coupling of 2-aryl-4-chloro-3-iodoquinolines with arylboronic acids. AB - Palladium-catalyzed Suzuki cross-coupling of 2-aryl-4-chloro-3-iodoquinolines with excess arylboronic acids (2.5 equiv.) in the presence of tricyclohexylphosphine afforded the 2,3,4-triarylquinolines in one-pot operation. The incipient 2,3-diaryl-4-chloroquinolines were also prepared and transformed to the primary 4-amino-2,3-diarylquinolines and 2,3-diarylquinolin-4(1H)-ones. PMID- 20966887 TI - First-line treatment of elderly multiple myeloma patients. PMID- 20966888 TI - Effects of vitamin D in colorectal cancer. PMID- 20966889 TI - Update on CYP2D6 and its impact on tamoxifen therapy. PMID- 20966890 TI - Disease state awareness in sarcoma. PMID- 20966891 TI - Early cervical neoplasia: advances in screening and treatment modalities. AB - Cervical cancer is one of the most common causes of cancer in women worldwide. However, improvements in screening programs and treatment modalities have significantly reduced the morbidity and mortality of this disease. The discovery that infection with the human papillomavirus is a crucial part of the causative pathway in cervical cancer pathogenesis has revolutionized screening and prompted investigations into alternatives to traditional cytologic evaluation, which may be useful in low-resource settings. Concomitant with improved screening has been a shift towards greater detection of both preinvasive and early-stage neoplastic disease. Earlier detection not only allows for surgical management of disease, with the avoidance of chemotherapy and radiation, but also the possibility of fertility preservation. As surgical technologies advance to encompass minimally invasive procedures, interventions for early-stage cervical cancer are becoming increasingly effective in disease eradication while permitting patients to maintain their quality of life. PMID- 20966892 TI - Preclinical and clinical activity of ATP mimetic JAK2 inhibitors. AB - The discovery of a common Janus kinase 2 (JAK2) point mutation, JAK2V617F, in myeloproliferative neoplasms has generated enormous interest in the development and therapeutic use of small molecule JAK2 inhibitor-targeted therapy in these diseases. A handful of compounds are currently in clinical development in primary myelofibrosis or post-polycythemia vera (PV)/essential thrombocythemia (ET) myelofibrosis. To date, clinical benefit has been demonstrated in terms of reduction of splenomegaly, improvement in constitutional symptoms, and control of leukocytosis. Some of the drugs have also been evaluated in PV and ET, with demonstrated activity against erythrocytosis, thrombocytosis, pruritus, and splenomegaly. However, drug effect on bone marrow fibrosis or JAK2 allele burden has been modest so far. Regardless, it is important to keep in mind that current anti-JAK2 treatment trials constitute only the beginning of many upcoming similar clinical trials, and that it is premature to make generalizations or any form of comparative conclusions regarding drug activity or toxicity. PMID- 20966893 TI - Deafness and blindness as a presentation of colorectal meningeal carcinomatosis. PMID- 20966894 TI - Visual and hearing loss due to colorectal meningeal carcinomatosis: a case-based review. PMID- 20966895 TI - Drivers aged 16 or 17 years involved in fatal crashes --- United States, 2004 2008. AB - Motor vehicle crashes are the leading cause of death among teens in the United States, accounting for approximately one third of deaths in this age group. Crash risk is highest during the first years of independent driving. To characterize trends in fatal crashes involving drivers aged 16 or 17 years, CDC analyzed data from the Fatality Analysis Report System (FARS) for 2004-2008. This report summarizes the results of that analysis, which indicated that, during 2004-2008, a total of 9,644 passenger vehicle drivers aged 16 or 17 years were involved in fatal crashes. During that period, the annual population-based rate for drivers aged 16 or 17 years involved in fatal crashes declined 38%, from 27.1 per 100,000 population in 2004 to 16.7 in 2008. By state, 5-year annualized rates for drivers aged 16 or 17 years involved in fatal crashes ranged from 9.7 per 100,000 population in New Jersey and New York to 59.6 in Wyoming. To further reduce fatal crashes involving young drivers, states should periodically reexamine and update graduated driver licensing (GDL) programs, and communities should vigorously enforce laws on minimum legal drinking age, blood alcohol concentration (BAC), and safety belt use, all of which can reduce the number of fatal crashes among young drivers. PMID- 20966896 TI - HIV transmission through transfusion --- Missouri and Colorado, 2008. AB - Transmission of human immunodeficiency virus (HIV) through transfusion of contaminated blood components was documented in the United States in 1982. Since then, the risk for transfusion-transmitted HIV infection has been almost eliminated by the use of questionnaires to exclude donors at higher risk for HIV infection and the use of highly sensitive laboratory screening tests to identify infected blood donations. The risk for acquiring HIV infection through blood transfusion today is estimated conservatively to be one in 1.5 million, based on 2007-2008 data. This report describes the first U.S. case of transfusion transmitted HIV infection reported to CDC since 2002. A blood center in Missouri discovered that blood components from a donation in November 2008 tested positive for HIV infection. A lookback investigation determined that this donor had last donated in June 2008, at which time he incorrectly reported no HIV risk factors and his donation tested negative for the presence of HIV. One of the two recipients of blood components from this donation, a patient undergoing kidney transplantation, was found to be HIV infected, and an investigation determined that the patient's infection was acquired from the donor's blood products. Even though such transmissions are rare, health-care providers should consider the possibility of transfusion-transmitted HIV in HIV-infected transfusion recipients with no other risk factors. PMID- 20966897 TI - State medicaid coverage for tobacco-dependence treatments --- United States, 2009. AB - Medicaid enrollees have nearly twice the smoking rates (37%) of the general adult population (21%), and smoking-related medical costs are responsible for 11% of Medicaid expenditures. In 2008, the Public Health Service released clinical practice guidelines recommending comprehensive coverage of effective tobacco dependence medications and counseling by health insurers. Healthy People 2010 established a clear objective for Medicaid programs to cover all Food and Drug Administration--approved medications and counseling for tobacco cessation. To monitor progress toward that objective, the Center for Health and Public Policy Studies at the University of California, Berkeley, in collaboration with CDC, surveyed Medicaid programs in the 50 states and the District of Columbia (DC) to document their 2009 tobacco-dependence treatment coverage and found that 47 programs offered coverage. Only eight state programs offered coverage of all recommended pharmacotherapy and counseling for all Medicaid enrollees, and 16 programs reported coverage for fee-for-service enrollees that differed from that provided for Medicaid managed-care enrollees. Among the 33 programs that covered at least one combination therapy, the nicotine patch plus bupropion slow release (SR) was the one combination covered by all. The Affordable Care Act mandates Medicaid coverage of tobacco-dependence treatments for pregnant women, beginning October 1, 2010. Coverage of pharmacotherapy for all Medicaid enrollees will be enhanced by January 2014, when states no longer may exclude tobacco-dependence cessation drugs from covered benefits. Monitoring the extent to which Medicaid programs place limitations on these treatments can help in evaluating accessibility of tobacco-dependence treatments to Medicaid enrollees. PMID- 20966898 TI - P values: use and misuse in medical literature. AB - P values are widely used in the medical literature but many authors, reviewers, and readers are unfamiliar with a valid definition of a P value, let alone how to interpret one correctly. Popular explanations such as "the probability that study results are due to chance" are wrong in a variety of ways and can lead to substantial errors in evaluating the evidence from research studies. Belief that "statistical significance" can alone discriminate between truth and falsehood borders on magical thinking. The article points out how to better interpret P values by avoiding common errors. Statistical analyses and P values are important tools in evidence-based medicine, but have to be used cautiously and with better understanding. PMID- 20966899 TI - Interplay between miR-155, AT1R A1166C polymorphism, and AT1R expression in young untreated hypertensives. AB - BACKGROUND: A silent polymorphism (+1166 A/C single-nucleotide polymorphism) localized in the 3'-UTR (untranslated region) of the human angiotensin II type-1 receptor (AT1R) has been associated with hypertension and cardiovascular complications. The +1166 A/C is recognized by a specific microRNA-155 (miR-155), which is base-pairing complementary with the +1166 A-allele but not with the mutant +1166 C allele. Aim of our study was to investigate the interplay between miR-155 and AT1R protein expression. METHODS: Sixty-four subjects were selected for the +1166 A/C from the cohort of hypertensives (n = 573) of the Hypertension and Ambulatory Recording Venetia Study (HARVEST): 25 were homozygous for the 1166 A allele, 20 heterozygous, and 19 homozygous for the 1166 C allele. RESULTS: miR 155 expression was significantly decreased in subjects with CC genotype in comparison to AA and AC genotype. AT1R protein expression was significantly increased in the CC group in comparison to AA and AC (P < 0.01) although AT1R mRNA expression was not significantly different in the three groups. AT1R protein expression was positively correlated with systolic and diastolic blood pressure and negatively correlated with miR-155 expression level. Plasma transforming growth factor-beta1 (TGF-beta1) may have a modulator role in the interplay between miR-155 and AT1R protein expression as it was correlated negatively with miR-155 expression and positively with AT1R protein expression in subjects with CC genotype. CONCLUSION: The interplay between miR-155 expression, +1166C polymorphism, and AT1R protein expression may have a role in the regulation of blood pressure. PMID- 20966900 TI - Cognitive-behavioral treatment of nonalcoholic Fatty liver disease: a propensity score-adjusted observational study. AB - The effectiveness of cognitive-behavior treatment (CBT) in nonalcoholic fatty liver disease (NAFLD), largely related to overweight/obesity and considered the hepatic expression of the metabolic syndrome (MS), has so far been tested in very limited samples. In a tertiary referral center, consecutively observed NAFLD subjects were offered a CBT program aimed at weight loss and increased physical activity, based on 13 group sessions; 68 cases entered the treatment protocol, those who refused (n = 82) were given recommendations for diet and physical activity. Treatment goals (weight loss >=7% initial body weight, normalization of liver enzymes, and improved parameters of MS) were tested by logistic regression at 6 months (all cases) and at 2 years, both on intention-to-treat and in completers (Diet, 78; CBT, 65). The results were adjusted for the propensity score of attending the CBT program, based on civil, anthropometric and clinical variables. At baseline the CBT group had a larger prevalence of obesity and more severe insulin resistance (homeostasis model assessment (HOMA)). At follow-up, CBT was associated with a higher probability of weight loss and normal liver enzymes (6-month: odds ratio (OR), 2.56; 95% confidence interval (CI), 1.15-5.69; 2-year intention-to-treat: OR, 3.57, 95% CI, 1.59-8.00), after adjustment for propensity and changes in body weight. A similar trend was observed in the outcome goals of insulin resistance and the score of MS, which were both reduced. In conclusion, subjects with NAFLD participating in a CBT program significantly improve their general and liver parameters. The beneficial effects are largely maintained at 2-year follow-up, in keeping with the lifestyle-related pathogenesis of disease. PMID- 20966901 TI - A solid high-protein meal evokes stronger hunger suppression than a liquefied high-protein meal. AB - Hunger is a potential problem for compliance with an energy-restricted diet. Relatively high-protein meal-replacement products have been shown to diminish this problem; they are available as liquid and solid meals, yet their physical state can affect hunger suppression. The objective was to investigate the differences in appetite profile and physiological parameters after consumption of a single-macronutrient, subject-specific, high-protein meal in liquefied vs. solid form, controlled for energy density, weight, and volume. Ten male subjects (age: 21.1 +/- 3.9 years; BMI: 22.4 +/- 1.2 kg/m2) were offered lunch subject specifically as 15% of daily energy requirement (DER), consisting of solid (steamed chicken breast + 750 ml water) or liquefied protein (steamed chicken breast blended in 500 ml water + 250 ml water). Appetite profiles, insulin, glucose, and ghrelin were measured over 3 h. Comparing the solid vs. liquefied condition, oral exposure time did not differ between conditions (19.2 +/- 0.4 and 18.8 +/- 0.6 min, respectively; P = 0.13). Area under the curve (AUC) effects were observed for thirst; statistically significant condition * time interactions and statistically significant differences at several time points were observed for desire to eat (condition * time P < 0.05; 31 +/- 6 mm vs. 53 +/- 8 mm; P < 0.04 at 115 min) and thirst (condition * time P < 0.01; 27 +/- 8 mm vs. 41 +/- 8 mm; P < 0.05 at 30 min and 23 +/- 6 mm vs. 41 +/- 8 mm; P < 0.02 at 70 min) to be lower, while hunger suppression (79 +/- 3 mm and 52 +/- 10 mm; P < 0.03 at 20 min and 61 +/- 7 mm and 44 +/- 8 mm; P < 0.03 at 115 min) was higher in the solid condition. Glucose, insulin, and ghrelin concentration curves were similar for both conditions. In conclusion, solid protein evokes a stronger suppression of hunger and desire to eat than liquefied protein. PMID- 20966902 TI - Genome-wide association study of anthropometric traits and evidence of interactions with age and study year in Filipino women. AB - Increased values of multiple adiposity-related anthropometric traits are important risk factors for many common complex diseases. We performed a genome wide association (GWA) study for four quantitative traits related to body size and adiposity (BMI, weight, waist circumference, and height) in a cohort of 1,792 adult Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). This is the first GWA study of anthropometric traits in Filipinos, a population experiencing a rapid transition into a more obesogenic environment. In addition to identifying suggestive evidence of additional single-nucleotide polymorphism (SNP) association signals (P < 10(-5)), we replicated (P < 0.05, same direction of additive effect) associations previously reported in European populations of both BMI and weight with MC4R and FTO, of BMI with BDNF, and of height with EFEMP1, ZBTB38, and NPPC, but none with waist circumference. We also replicated loci reported in Japanese or Korean populations as associated with BMI (OTOL1) and height (HIST1H1PS2, C14orf145, GPC5). A difference in local linkage disequilibrium (LD) between European and Asian populations suggests a narrowed association region for BDNF, while still including a proposed functional nonsynonymous amino acid substitution variant (rs6265, Val66Met). Finally, we observed significant evidence (P < 0.0042) for age-by-genotype interactions influencing BMI for rs17782313 (MC4R) and rs9939609 (FTO), and for a study year by-genotype interaction for rs4923461 (BDNF). Our results show that several genetic risk factors are associated with anthropometric traits in Filipinos and provide further insight into the effects of BDNF, FTO, and MC4R on BMI. PMID- 20966903 TI - Body fat measured by a near-infrared interactance device as a predictor of cardiovascular events: the FINRISK'92 cohort. AB - We evaluated how body fat percentage, measured by a portable near-infrared interactance (NIR) device predicts cardiovascular (CVD), coronary heart disease (CHD), and ischemic stroke events in a prospective population-based survey. The study population consisted of 2,842 men and 3,196 women, who participated in the FINRISK'92 survey. Obesity was assessed with BMI, waist circumference, and waist to-hip ratio (WHR) and body fat percentage measured with an NIR. Mean length of follow-up was 9 years and 3 months. In Cox proportional hazards regression analyses for men, BMI, waist circumference, and WHR as well as body fat percentage were predictors of a CVD event when adjusted for age and for major risk factors. Hazard ratio (HR) per 1 s.d. was 1.27 (95% confidence interval: 1.10-1.48) for body fat percentage, 1.30 (1.16-1.46) for BMI, and 1.31 (1.16 1.50) for waist circumference. Among women, the body fat lost its predictive power in a fully adjusted model. Body fat percentage, BMI, waist circumference, and WHR were predictors of a CHD event both among men and women, whereas body fat percentage did not predict ischemic stroke among either gender. We observed that body fat percentage measured by an NIR device was a significant predictor of CVD and CHD events among men and women, but in our population-based survey, it did not provide any additional predictive power over and above the simpler measures, such as BMI or WHR. PMID- 20966904 TI - Lack of association of CD36 SNPs with early onset obesity: a meta-analysis in 9,973 European subjects. AB - A recent study suggested that four CD36 polymorphisms (namely rs3211867, rs3211883, rs3211908, and rs1527483) were associated with an increased risk of obesity, an increased BMI and percentage of body fat in European adolescents. We first attempted to confirm these results in three independent case-control genome wide association studies (GWAS) data totaling 3,509 subjects of French and German origin, but we were unable to find any association of these variants with early onset obesity risk. We then genotyped the four CD36 single-nucleotide polymorphisms (SNPs) in a large population-based study of 4,667 Finnish subjects and we did not replicate any of the recently reported associations with BMI. By combining all available data in a meta-analysis (N = 9,973), we found no evidence for an association of the reported four variants in CD36 with increased obesity risk or increased BMI (0.07 <= P values <= 0.93). Finally, we assessed the contribution of the full CD36 locus gene variation to obesity risk in 3,509 subjects and we did not detect any significant association with obesity after correction for multiple testing. In summary, we were unable to confirm the recently reported association of variants in CD36 with early onset obesity in populations of European ancestry. PMID- 20966905 TI - Melanocortin-4 receptor gene mutations in a Dutch cohort of obese children. AB - The most common monogenic form of obesity is caused by mutations in the gene encoding the melanocortin-4 receptor (MC4R). We have screened the MC4R coding sequence in 291 patients of a Dutch outpatient pediatric obesity clinic. We analyzed the minimal promoter region of the gene in a random subgroup of 217 children. Our aims were (i) to determine the frequency of MC4R mutations in a cohort of Dutch clinically obese children and (ii) to search for mutations in the promoter of the gene. Eleven MC4R coding variants were detected. Five children had mutations that have been shown to affect receptor function by other research groups (p.Y35X, p.I251fs, p.G231S). These children did not have earlier onset of obesity or higher BMI-SDS than the remainder of the cohort. One child had a novel nonsynonymous coding mutation (p.L304F). This variant showed a markedly decreased cell surface expression in in vitro experiments and is thus expected to be pathogenic. We detected 12 variants in the MC4R flanking regions. Five of these were not previously described (c.-1101C>T, c.-705A>T, c.-461A>G, c.-312T>C, c. 213A>G). We investigated these mutations by family studies and a bioinformatic approach. We conclude that rare heterozygous mutations in the coding sequence of MC4R account for some severe obesity cases in the Dutch population. These patients are difficult to recognize in a clinical setting. We generated a list of all MC4R variants that were described in the literature so far, which can aid the interpretation of mutations found in a diagnostic setting. PMID- 20966906 TI - Leptin is inversely associated with lung function in African Americans, independent of adiposity: the Jackson Heart Study. AB - Leptin, a 16-kDa protein, has proinflammatory properties and has been linked to respiratory physiological responses in majority white populations. Little is known, however, about the relationship of leptin with lung function in nonwhites. Cross-sectional associations of circulating serum leptin concentrations with forced expiratory volume in 1 s (FEV(1)), FEV in 6 s (FEV(6)), and vital capacity (FVC), assessed by spirometry, were examined in 4,679 African-American men and women participants (54.3 +/- 12.4 years; 62.7% women) in the Jackson Heart Study (JHS). The independent association of leptin was examined in relation to FEV(1), FEV(6), and FVC% predicted after adjustment for age, education, smoking status, pack-years of cigarette smoking, respiratory medication use, and menopausal status in women; additional adjustment included total body weight, waist circumference, and BMI. Serum leptin was inversely related to FEV(1), FEV(6), and FVC% predicted values in men. A dose-response relationship was observed with men in the highest leptin quartile having a significantly lower lung function compared to men in the lower leptin quartile. BMI significantly modified this relationship in women: leptin was most consistently associated with lung function in obese women, less consistent in overweight women, and absent in normal-weight women. Serum leptin concentration was strongly, inversely, and independently associated with lung function in African Americans, especially African-American men and obese women. PMID- 20966908 TI - Novel electrocardiographic parameters of altered repolarization in uncomplicated overweight and obesity. AB - In addition to well-known electrocardiographic measurements, as QT, QT dispersion, and QT apex dispersion, new parameters such as Tpeak-Tend, Tpeak-Tend dispersion, and Tpeak-Tend/QT ratio have been recently introduced as indexes of increased arrhythmic risk. The aim of the present study was to test, in overweight and obese subjects not affected by conditions of comorbidity, the aforementioned markers of ventricular repolarization. We studied 60 athletic subjects with normal body weight (21 females and 39 males, BMI between 19 and 24, mean BMI 22.0 +/- 2.0 kg/m(2), aged 14-64 years, mean age 32 +/- 13.59) and 60 sedentary and overweight/obese subjects (34 overweight and 26 obese, 22 females, and 38 males, BMI between 26 and 55, mean BMI 30.7 +/- 5.7 kg/m(2), aged 14-64, mean age 38 +/- 14.49). Each subject underwent anthropometric measurements and a 12-lead electrocardiogram, from which the following different parameters were calculated: QT, corrected QT, QT dispersion, QT apex dispersion, Tpeak-Tend, Tpeak-Tend dispersion and Tpeak-Tend/QT ratio were calculated. The aforementioned repolarization markers resulted, respectively: 340.2 +/- 25.1, 373.8 +/- 25.9, 29 +/- 16.2, 23.5 +/- 14.6, 87.3 +/- 12.8, 26.5 +/- 16.8, and 0.22 +/- 0.03 ms in control subjects and 362.5 +/- 28.5, 397.4 +/- 35.4, 34.5 +/- 16.8, 30.7 +/- 16.3, 90.5 +/- 15.2, 27 +/- 17.1, and 0.22 +/- 0.04 ms in overweight/obese subjects. Neither uncomplicated obesity nor overweight were associated with a statistically significant difference in QT dispersion, QT apex dispersion, Tpeak Tend, Tpeak-Tend dispersion, and Tpeak-Tend/QT ratio; QT and corrected QT were the only parameters that showed statistically significant variations between normal weight and overweight/obese subjects. PMID- 20966907 TI - Parent-only treatment for childhood obesity: a randomized controlled trial. AB - Parent-only (PO) treatments for childhood obesity are feasible, more cost effective and potentially easier to disseminate. The objective of this study was to determine whether a PO treatment is not inferior to a parent + child (PC) treatment for childhood obesity. Eighty parent-child dyads with an 8-12 year old overweight or obese child (>85th BMI-P) were recruited and randomized into PO or PC treatment for childhood obesity. Parents or parent-child dyads attended 5 month treatment groups. Child and parent body size, child caloric intake, and child physical activity were assessed at baseline, post-treatment, and 6-months follow-up. Noninferiority testing using mixed linear models was used to compare PO treatment with PC treatment. Results showed that the PO group was not inferior to the PC group in terms of child weight loss. Results also showed that the PO group was not inferior to the PC group in terms of parent weight loss and child physical activity, but not child caloric intake. This study suggests that a PO treatment could provide similar results to PC in child weight loss and other relevant outcomes, and potentially could be more cost-effective and easier to disseminate. Although further research is needed, this study suggests that PO groups are a viable method for providing childhood obesity treatment. PMID- 20966909 TI - Eating frequency is associated with energy intake but not obesity in midlife women. AB - Midlife women tend to gain weight with age, thus increasing risk of chronic disease. The purpose of this study was to examine associations between overweight/obesity and behavioral factors, including eating frequency, in a cross sectional national sample of midlife women (n = 1,099) (mean age = 49.7 years, and BMI = 27.7 kg/m2). Eating behaviors and food and nutrient intakes were based on a mailed 1-day food record. BMI was calculated from self-reported height and weight, and level of physical activity was assessed by self-reported questionnaire. After exclusion of low-energy reporters (32% of sample), eating frequency was not associated with overweight/obesity (P > 0.05) and was not different between BMI groups (normal, 5.21 +/- 1.79; overweight, 5.16 +/- 1.74; obese, 5.12 +/- 1.68, P = 0.769). Adjusted logistic regression showed that eating frequency, snacking frequency, breakfast consumption, eating after 10 PM and consuming meals with children or other adults were not significantly associated with overweight/obesity. Total energy intake increased as eating frequency increased in all BMI groups, however, obese women had greater energy intake compared to normal weight women who consumed the same number of meals and snacks. Intake of fruit and vegetables, whole grains, dietary fiber, dairy, and added sugars also increased as eating frequency increased. While eating frequency was not associated with overweight/obesity, it was associated with energy intake. Thus, addressing total energy intake rather than eating frequency may be more appropriate to prevent weight gain among midlife women. PMID- 20966910 TI - The differential prevalence of obesity and related behaviors in two- vs. four year colleges. AB - The objective of this study was to determine whether obesity prevalence and weight-related behaviors (e.g., diet, physical activity) differ among students enrolled in 2-year community/technical colleges and those attending 4-year colleges/universities. This information could inform the development of intervention strategies. Through an existing surveillance system of Minnesota postsecondary education institutions, survey data were collected from 16,539 students from 27 campuses (14 two-year college campuses, 13 four-year college/university campuses; 2007-2008), including self-reported physical activity, media use, dietary patterns, weight control behaviors, height, and weight. Unadjusted analyses indicated that students enrolled in 2-year colleges, particularly females, had a higher prevalence of overweight/obesity, lower levels of physical activity, more television viewing, higher intakes of soda, fast food, and diet pills compared to students attending 4-year colleges (P < 0.05). Females attending 4-year colleges were more likely to engage in certain unhealthy weight control behaviors (taking diet pills, binge eating, self-induced vomiting) compared to females attending 2-year institutions. Among male students there were fewer differences between 2-year and 4-year colleges. Controlling for sociodemographic factors (e.g., race/ethnicity, age), most disparities in prevalence estimates remained, though many were attenuated. Overall, few young adults engage in weight-related behaviors consistent with national recommendations. Two-year college students may represent a particularly at-risk group. Disparities between 2- and 4-year college students exist beyond the sociodemographic differences in these populations. Effective weight-related interventions are needed for young adults, particularly females attending 2-year colleges and all males attending postsecondary institutions. PMID- 20966911 TI - Subclinical regional left ventricular dysfunction in obese patients with and without hypertension or hypertrophy. AB - We investigated the impact of obesity on the abnormalities of systolic and diastolic regional left ventricular (LV) function in patients with or without hypertension or hypertrophy, and without heart failure. We studied 120 individuals divided into 6 groups of 20 patients (42 +/- 6 years, 60 females) using standard and pulsed-wave tissue Doppler imaging (TDI) echocardiography, and heterogeneity index (HI): nonobese (I: no hypertension, no hypertrophy, control group; II: hypertension, no hypertrophy; III: hypertension and hypertrophy) and obese (IV: no hypertension, no hypertrophy; V: hypertension, no hypertrophy; VI: hypertension and hypertrophy). The criterion for obesity was BMI >=30 kg/m2, for hypertension was blood pressure >= 140/90 mm Hg, for hypertrophy in nonobese was LV mass/body surface area (BSA) >134 g/m(2) (men) and >110 mg/m2 (women), and in obese was LV mass/height(2.7) >50 (men) and >40 (women). Obese groups had normal LV ejection fraction compared with nonobese groups, but decreased longitudinal and radial systolic myocardial peak velocities (S'), and early diastolic myocardial peak velocity (E'). Also, a great variability of E' and late diastolic myocardial peak velocity (A') from the longitudinal basal region was observed in obese groups (E'basal nonobese: 11 +/- 7 vs. obese 19 +/- 11, P < 0.001, A'basal nonobese: 7 +/- 4 vs. obese 11 +/- 7, P < 0.001). Our findings were more evident when comparing groups IV with V and VI, with the latter having concentric hypertrophy and obvious segmental systolic and diastolic dysfunctions. Subclinical myocardial alterations and increased variability of the velocities were observed in obese groups, especially with hypertension and hypertrophy, reflecting impaired regional LV relaxation, segmental atrial, and systolic dysfunctions. PMID- 20966912 TI - Associations of smoking cessation with visceral fat area and prevalence of metabolic syndrome in men: the Hitachi health study. AB - Weight gain after smoking cessation may deteriorate metabolic risk profiles, including that for metabolic syndrome. How risk profiles change according to the duration of smoking cessation and whether the visceral fat area (VFA) or the subcutaneous fat area (SFA) contributes to these changes remains uncertain. The subjects comprised 5,697 Japanese men who underwent an abdominal computed tomography examination during a health check-up. Using never smokers as a reference group, the odds ratios of having metabolic syndrome and its components, defined using the National Cholesterol Education Program Adult Treatment Panel IIIcriteria, were calculated for each smoking category with adjustments for age, alcohol drinking, and physical activity (model 1) using a logistic regression analysis. Additional adjustments were also made for either VFA (model 2) or SFA (model 3). Current smokers had the lowest VFA (120.4 cm2) whereas ex-smokers (124.0-132.0 cm2) had a higher VFA than nonsmokers (123.1 cm2). Among the ex smokers, VFA tended to decrease with increasing years of smoking cessation. In model 1, the odds ratios of having metabolic syndrome for current smokers and ex smokers with smoking cessation for <= 4, 5-9, 10-14, and >= 15 years were 1.02, 1.33, 1.36, 1.40, and 1.09, respectively. The elevated odds ratios among ex smokers (<= 14 years) were reduced by 35-55.6% after further adjustment for VFA but not for SFA. Smoking cessation is associated with a deterioration of the metabolic risk profile, which can be ascribed, at least in part, to an increase in VFA not SFA. PMID- 20966913 TI - The nature of the ingested protein has no effect on lean body mass during energy restriction in overweight rats. AB - Severe energy restriction in obesity not only leads to fat mass loss but also to lean mass loss. The aim of this study was to compare the capacity of casein, a slowly digested protein, and milk soluble proteins (MSP; rapidly digested) to limit the loss of lean mass induced by energy restriction. Obesity was first induced in male Wistar rats by a 5-week feeding with a high-fat high-sucrose diet. The impact of energy restriction was then studied with high-protein (32%) diets containing either casein, MSP, or a 50/50 mixture of both proteins for 3 weeks (n = 10 per group). Food intake, body weight, nitrogen balance, creatinine, and 3-methyl-histidine excretion were measured during energy restriction. Then, tissue weights, plasma metabolic parameters (amino acids, glucose, insulin, cholesterol, triglycerides), and in vivo liver and extensor digitorum longus (EDL) muscle protein synthesis rates were measured in postabsorptive state at the end of the experimental period. Although significant differences relevant to protein metabolism were observed between groups (protein intake, plasma amino acid concentrations, fecal nitrogen excretion, muscle protein synthesis rates), week per week, there were no significant differences in nitrogen balance whatever the protein used. In conclusion, our results show that in young overweight energy restricted rats, using a high-protein diet, the nature of protein intake has no influence on body protein retention. PMID- 20966914 TI - Treating type 2 diabetes mellitus with sleeve gastrectomy in obese patients. PMID- 20966915 TI - Variants in the CD36 gene locus determine whole-body adiposity, but have no independent effect on insulin sensitivity. AB - CD36 variants have been associated with type 2 diabetes, features of the metabolic syndrome, and alterations in lipid metabolism. In contrast, the effect of single-nucleotide polymorphisms (SNPs) in CD36 on insulin resistance is controversial in literature. Therefore, we investigated whether genetic variation within the CD36 gene locus affects insulin resistance in a well-phenotyped cohort of white European subjects at increased risk for type 2 diabetes. We genotyped 1,790 subjects (1,174 women, 616 men) for six SNPs tagging 100% of common variants (minor allele frequency >=0.05) within the CD36 gene locus with an r2 >= 0.8. All subjects underwent an oral glucose tolerance test (OGTT) and a subset additionally a hyperinsulinemic-euglycemic clamp (n = 523). Ectopic hepatic lipids (n = 346) were assessed by magnetic resonance spectroscopy. After appropriate adjustment and Bonferroni correction for multiple comparisons, the four CD36 SNPs rs9784998, rs3211883, rs3211908, and rs3211956 significantly associated with BMI and rs3211883 and rs3211908 significantly associated with waist circumference (all P < 0.0042). In contrast, CD36 SNPs rs3211816 and rs3211960 were not associated with measures of adiposity (all P >= 0.11). No reliable association was detected between the six CD36 SNPs and insulin sensitivity or ectopic hepatic lipid accumulation after adjustment for age, gender, and BMI. In the long run, genetic variation within the CD36 locus may contribute to metabolic disease via its effect on body adiposity, but not via an independent effect on insulin sensitivity. PMID- 20966916 TI - Chronic optical access through a polished and reinforced thinned skull. AB - We present a method to form an optical window in the mouse skull that spans millimeters and is stable for months without causing brain inflammation. This enabled us to repeatedly image blood flow in cortical capillaries of awake mice and determine long-range correlations in speed. We also repeatedly imaged dendritic spines, microglia and angioarchitecture, as well as used illumination to drive motor output via optogenetics and induce microstrokes via photosensitizers. PMID- 20966918 TI - Linking Alzheimer's disease to insulin resistance: the FoxO response to oxidative stress. AB - Oxidative stress is an important determinant not only in the pathogenesis of Alzheimer's disease (AD), but also in insulin resistance (InsRes) and diabetic complications. Forkhead box class O (FoxO) transcription factors are involved in both insulin action and the cellular response to oxidative stress, thereby providing a potential integrative link between AD and InsRes. For example, the expression of intra- and extracellular antioxidant enzymes, such as manganese superoxide dismutase and selenoprotein P, is regulated by FoxO proteins, as is the expression of important hepatic enzymes of gluconeogenesis. Here, we review the molecular mechanisms involved in the pathogenesis of AD and InsRes and discuss the function of FoxO proteins in these processes. Both InsRes and oxidative stress may promote the transcriptional activity of FoxO proteins, resulting in hyperglycaemia and a further increased production of reactive oxygen species (ROS). The consecutive activation of c-Jun N-terminal kinases and inhibition of Wingless (Wnt) signalling may result in the formation of beta amyloid plaques and tau protein phosphorylation. Wnt inhibition may also result in a sustained activation of FoxO proteins with induction of apoptosis and neuronal loss, thereby completing a vicious circle from oxidative stress, InsRes and hyperglycaemia back to the formation of ROS and consecutive neurodegeneration. In view of their central function in this model, FoxO proteins may provide a potential molecular target for the treatment of both InsRes and AD. PMID- 20966920 TI - The renin-angiotensin system and cancer: old dog, new tricks. AB - For cancers to develop, sustain and spread, the appropriation of key homeostatic physiological systems that influence cell growth, migration and death, as well as inflammation and the expansion of vascular networks are required. There is accumulating molecular and in vivo evidence to indicate that the expression and actions of the renin-angiotensin system (RAS) influence malignancy and also predict that RAS inhibitors, which are currently used to treat hypertension and cardiovascular disease, might augment cancer therapies. To appreciate this potential hegemony of the RAS in cancer, an expanded comprehension of the cellular actions of this system is needed, as well as a greater focus on translational and in vivo research. PMID- 20966924 TI - Awesome allotropy. PMID- 20966922 TI - Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. AB - The fusion oncogene, promyelocytic leukaemia (PML)-retinoic acid receptor-alpha (RARA), initiates acute promyelocytic leukaemia (APL) through both a block to differentiation and increased self-renewal of leukaemic progenitor cells. The current standard of care is retinoic acid (RA) and chemotherapy, but arsenic trioxide also cures many patients with APL, and an RA plus arsenic trioxide combination cures most patients. This Review discusses the recent evidence that reveals surprising new insights into how RA and arsenic trioxide cure this leukaemia, by targeting PML-RARalpha for degradation. Drug-triggered oncoprotein degradation may be a strategy that is applicable to many cancers. PMID- 20966921 TI - Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. AB - Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) was first recognized in 2004 as a distinct, clinically relevant molecular subset of lung cancer. The disease has been the subject of intensive research at both the basic scientific and clinical levels, becoming a paradigm for how to understand and treat oncogene-driven carcinomas. Although patients with EGFR mutant tumours have increased sensitivity to tyrosine kinase inhibitors (TKIs), primary and acquired resistance to these agents remains a major clinical problem. This Review summarizes recent developments aimed at treating and ultimately curing the disease. PMID- 20966925 TI - The era of carbon allotropes. PMID- 20966923 TI - Walls around tumours - why plants do not develop cancer. AB - In plants, as in animals, most cells that constitute the organism limit their reproductive potential in order to provide collective support for the immortal germ line. And, as in animals, the mechanisms that restrict the proliferation of somatic cells in plants can fail, leading to tumours. There are intriguing similarities in tumorigenesis between plants and animals, including the involvement of the retinoblastoma pathway as well as overlap with mechanisms that are used for stem cell maintenance. However, plant tumours are less frequent and are not as lethal as those in animals. We argue that fundamental differences between plant and animal development make it much more difficult for individual plant cells to escape communal controls. PMID- 20966926 TI - Green carbon as a bridge to renewable energy. PMID- 20966927 TI - Simply carbon. Interview by Alison Stoddart. PMID- 20966929 TI - Flexible electronics: tiny lamps to illuminate the body. PMID- 20966930 TI - Oxide electronics: Upward mobility rocks! PMID- 20966931 TI - Material witness: Beanbag robotics. PMID- 20966932 TI - Organic semiconductors: A little energy goes a long way. PMID- 20966933 TI - Nanoparticle assembly: made to order. PMID- 20966934 TI - Sequential gene expression profiling during treatment for identification of predictive markers and novel therapeutic targets in chronic lymphocytic leukemia. PMID- 20966939 TI - Single-molecule kinetics: Caught in the act. PMID- 20966935 TI - Follicular dendritic cell-induced microRNA-mediated upregulation of PRDM1 and downregulation of BCL-6 in non-Hodgkin's B-cell lymphomas. AB - B-cell lymphoma 6 (BCL6) and PR domain containing 1 (PRDM1) are considered as master regulators for germinal center (GC) formation and terminal B-cell differentiation. Dysregulation of BCL6 and PRDM1 has been associated with lymphomagenesis. Here, we show for the first time that direct cell-cell contact between follicular dendritic cells (FDC) and B-lymphocytes, by influencing the expression of a set of microRNAs (miRNAs), regulates the expression of BCL6 and PRDM1. We identify that, on cell adhesion to FDC, FDC induces upregulation of PRDM1 expression through downregulation of miR-9 and let-7 families and induces downregulation of BCL-6 through upregulation of miR-30 family in B-lymphocytes and lymphoma cells. We further demonstrate that the miR-30 family directly controls BCL-6 expression and miR-9-1 and let-7a directly control PRDM-1 expression through targeting their 3'UTR, mediating the FDC effect. Our studies define a novel regulatory mechanism in which the FDC, through induction of miRNAs in B-lymphocytes, orchestrates the regulation of transcription factors, promotes germinal center B-cell survival and differentiation. Dysregulation of miRNAs may interfere with B-cell survival and maturation, thus representing a novel molecular mechanism, as well as a potential therapeutic target in B-cell lymphomas. PMID- 20966940 TI - Molecular binding: Under water's influence. PMID- 20966941 TI - Enzyme dynamics: Control of active-site compression. PMID- 20966942 TI - Metal-organic frameworks: Model, make, measure. PMID- 20966943 TI - Micromechanics: Enzymatic actuators. PMID- 20966944 TI - Carbon allotropes: On the road to carbyne. PMID- 20966946 TI - Porous organic molecules. AB - Most synthetic materials that show molecular-scale porosity consist of one-, two- or three-dimensional networks. Porous metal-organic frameworks in particular have attracted a lot of recent attention. By contrast, discrete molecules tend to pack efficiently in the solid state, leaving as little empty space as possible, which leads to non-porous materials. This Perspective discusses recent developments with discrete organic molecules that are porous in the solid state. Such molecules, which may be either crystalline or amorphous, can be categorized as either intrinsically porous (containing permanent covalent cavities) or extrinsically porous (inefficiently packed). We focus on the possible advantages of organic molecules over inorganic or hybrid systems in terms of molecular solubility, choice of components and functionalities, and structural mobility and responsiveness in non-covalent extended solids. We also highlight the potential for 'undiscovered' porous systems among the large number of cage-like organic molecules that are already known. PMID- 20966947 TI - A primary hydrogen-deuterium isotope effect observed at the single-molecule level. AB - The covalent chemistry of reactants tethered within a single protein pore can be monitored by observing the time-dependence of ionic current flow through the pore, which responds to bond making and breaking in individual reactant molecules. Here we use this 'nanoreactor' approach to examine the reaction of a quinone with a thiol to form a substituted hydroquinone by reductive 1,4-Michael addition. Remarkably, a primary hydrogen-deuterium isotope effect is readily detected at the single-molecule level during prototropic rearrangement of an initial adduct. The observation of individual reaction intermediates allows the measurement of an isotope effect whether or not the step involved is rate limiting, which would not be the case in an ensemble measurement. PMID- 20966948 TI - Photoelectrochemical complexes for solar energy conversion that chemically and autonomously regenerate. AB - Naturally occurring photosynthetic systems use elaborate pathways of self-repair to limit the impact of photo-damage. Here, we demonstrate a complex consisting of two recombinant proteins, phospholipids and a carbon nanotube that mimics this process. The components self-assemble into a configuration in which an array of lipid bilayers aggregate on the surface of the carbon nanotube, creating a platform for the attachment of light-converting proteins. The system can disassemble upon the addition of a surfactant and reassemble upon its removal over an indefinite number of cycles. The assembly is thermodynamically metastable and can only transition reversibly if the rate of surfactant removal exceeds a threshold value. Only in the assembled state do the complexes exhibit photoelectrochemical activity. We demonstrate a regeneration cycle that uses surfactant to switch between assembled and disassembled states, resulting in an increased photoconversion efficiency of more than 300% over 168 hours and an indefinite extension of the system lifetime. PMID- 20966949 TI - N-silyl oxyketene imines are underused yet highly versatile reagents for catalytic asymmetric synthesis. AB - The reactions of acyl anion equivalents (d1 synthons) with carbonyl electrophiles allow for the construction of a wide range of molecules useful for the synthesis of biologically active compounds, natural products and chiral ligands. Despite their utility, significant challenges still exist for developing catalytic, enantioselective variants of these reactions. For example, the asymmetric benzoin process, arguably the most characteristic reaction of d synthetic equivalents, finds no general solution for reactions involving aliphatic acyl anions. In this Article, we introduce a new class of stable, isolable silyl ketene imines derived from protected cyanohydrins. These nucleophiles serve as acyl anion equivalents in Lewis base catalysed aldol addition reactions and allow for the preparation of cross-benzoin and glycolate-aldol products in high yield and with exceptional diastereo- and enantioselectivities. PMID- 20966950 TI - De novo synthesis of a metal-organic framework material featuring ultrahigh surface area and gas storage capacities. AB - Metal-organic frameworks--a class of porous hybrid materials built from metal ions and organic bridges--have recently shown great promise for a wide variety of applications. The large choice of building blocks means that the structures and pore characteristics of the metal-organic frameworks can be tuned relatively easily. However, despite much research, it remains challenging to prepare frameworks specifically tailored for particular applications. Here, we have used computational modelling to design and predictively characterize a metal-organic framework (NU-100) with a particularly high surface area. Subsequent experimental synthesis yielded a material, matching the calculated structure, with a high BET surface area (6,143 m(2) g(-1)). Furthermore, sorption measurements revealed that the material had high storage capacities for hydrogen (164 mg g(-1)) and carbon dioxide (2,315 mg g(-1))--gases of high importance in the contexts of clean energy and climate alteration, respectively--in excellent agreement with predictions from modelling. PMID- 20966951 TI - Synthesis of glycine-containing complexes in impacts of comets on early Earth. AB - Delivery of prebiotic compounds to early Earth from an impacting comet is thought to be an unlikely mechanism for the origins of life because of unfavourable chemical conditions on the planet and the high heat from impact. In contrast, we find that impact-induced shock compression of cometary ices followed by expansion to ambient conditions can produce complexes that resemble the amino acid glycine. Our ab initio molecular dynamics simulations show that shock waves drive the synthesis of transient C-N bonded oligomers at extreme pressures and temperatures. On post impact quenching to lower pressures, the oligomers break apart to form a metastable glycine-containing complex. We show that impact from cometary ice could possibly yield amino acids by a synthetic route independent of the pre-existing atmospheric conditions and materials on the planet. PMID- 20966952 TI - The maximum pentagon separation rule provides a guideline for the structures of endohedral metallofullerenes. AB - Fullerenes tend to follow the isolated pentagon rule, which requires that each of the 12 pentagons is surrounded only by hexagons. Over the past decade many violations to this rule were reported for endohedral fullerenes. Based on the ionic model M(3)N(6+)@C(2n)(6-) and the orbital energies of the isolated cages, in 2005 we formulated a molecular orbital rule to identify the most suitable hosting cages in endohedral metallofullerenes. Now, we give physical support to the orbital rule, and we propose the maximum pentagon separation rule, which can be applied to either isolated pentagon rule cages or to non-isolated pentagon rule cages with the same number of adjacent pentagon pairs. The maximum pentagon separation rule can be formulated as 'The electron transfer from the internal cluster to the fullerene host preferentially adds electrons to the pentagons; therefore, the most suitable carbon cages are those with the largest separations among the 12 pentagons'. PMID- 20966953 TI - Recognition-mediated activation of therapeutic gold nanoparticles inside living cells. AB - Supramolecular chemistry provides a versatile tool for the organization of molecular systems into functional structures and the actuation of these assemblies for applications through the reversible association between complementary components. Use of this methodology in living systems, however, represents a significant challenge owing to the chemical complexity of cellular environments and lack of selectivity of conventional supramolecular interactions. Herein, we present a host-guest system featuring diaminohexane-terminated gold nanoparticles (AuNP-NH(2)) and complementary cucurbit[7]uril (CB[7]). In this system, threading of CB[7] on the particle surface reduces the cytotoxicity of AuNP-NH(2) through sequestration of the particle in endosomes. Intracellular triggering of the therapeutic effect of AuNP-NH(2) was then achieved through the administration of 1-adamantylamine (ADA), removing CB[7] from the nanoparticle surface, causing the endosomal release and concomitant in situ cytotoxicity of AuNP-NH(2). This supramolecular strategy for intracellular activation provides a new tool for potential therapeutic applications. PMID- 20966954 TI - Synthesis of polyynes to model the sp-carbon allotrope carbyne. AB - Carbyne is an allotrope of carbon composed of sp-hybridized carbon atoms. Although its formation in the laboratory is suggested, no well-defined sample is described. Interest in carbyne and its potential properties remains intense because of, at least in part, technological breakthroughs offered by other carbon allotropes, such as fullerenes, carbon nanotubes and graphene. Here, we describe the synthesis of a series of conjugated polyynes as models for carbyne. The longest of the series consists of 44 contiguous acetylenic carbons, and it maintains a framework clearly composed of alternating single and triple bonds. Spectroscopic analyses for these polyynes reveal a distinct trend towards a finite gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital for carbyne, which is estimated to be ~485 nm (~2.56 eV). Even the longest members of this series of polyynes are not particularly sensitive to light, moisture or oxygen, and they can be handled and characterized under normal laboratory conditions. PMID- 20966955 TI - Direct enantio-convergent transformation of racemic substrates without racemization or symmetrization. AB - Asymmetric reactions that transform racemic mixtures into enantio-enriched products are in high demand, but classical kinetic resolution produces enantiopure compounds in <50% yield even in an ideal case. Many deracemization processes have thus been developed including dynamic kinetic resolution and dynamic kinetic asymmetric transformation, which can provide enantio-enriched products even after complete conversion of the racemic starting materials. However, these dynamic processes require racemization or symmetrization of the substrates or intermediates. We demonstrate a direct chemical enantio-convergent transformation without a racemization or symmetrization process. Copper(I) catalysed asymmetric allylic substitution of a racemic allylic ether afforded a single enantiomer of an alpha-chiral allylboronate with complete conversion and high enantioselectivity (up to 98% enantiomeric excess). One enantiomer of the substrate undergoes an anti-S(N)2'-type reaction whereas the other enantiomer reacts via a syn-S(N)2' pathway. The products, which cannot be prepared by dynamic procedures, have been used to construct all-carbon quaternary stereocentres. PMID- 20966956 TI - Spectroscopic visualization of sound-induced liquid vibrations using a supramolecular nanofibre. AB - The question of whether sound vibration of a medium can bring about any kind of molecular or macromolecular events is a long-standing scientific controversy. Although it is known that ultrasonic vibrations with frequencies of more than 1 MHz are able to align certain macromolecules in solution, no effect has yet been reported with audible sound, the frequency of which is much lower (20-20,000 Hz). Here, we report on the design of a supramolecular nanofibre that in solution becomes preferentially aligned parallel to the propagation direction of audible sound. This phenomenon can be used to spectroscopically visualize sound-induced vibrations in liquids and may find application in a wide range of vibration sensing technologies. PMID- 20966957 TI - A bidentate Lewis acid with a telluronium ion as an anion-binding site. AB - The search for receptors that can selectively capture small and potentially toxic anions in protic media has sparked a renewed interest in the synthesis and anion binding properties of polydentate Lewis acids. Seeking new paradigms to enhance the anion affinities of such systems, we synthesized a bidentate Lewis acid that contains a boryl and a telluronium moiety as Lewis acidic sites. Anion complexation studies indicate that this telluronium borane displays a high affinity for fluoride in methanol. Structural and computational studies show that the unusual fluoride affinity of this bidentate telluronium borane can be correlated with the formation of a B-F -> Te chelate motif supported by a strong lone-pair(F) -> sigma*(Te-C) donor-acceptor interaction. These results, which illustrate the viability of heavier chalcogenium centres as anion-binding sites, allow us to introduce a novel strategy for the design of polydentate Lewis acids with enhanced anion affinities. PMID- 20966958 TI - Catalytic enantioselective syn hydration of enones in water using a DNA-based catalyst. AB - The enantioselective addition of water to olefins in an aqueous environment is a common transformation in biological systems, but was beyond the ability of synthetic chemists. Here, we present the first examples of a non-enzymatic catalytic enantioselective hydration of enones, for which we used a catalyst that comprises a copper complex, based on an achiral ligand, non-covalently bound to (deoxy)ribonucleic acid, which is the only source of chirality present under the reaction conditions. The chiral beta-hydroxy ketone product was obtained in up to 82% enantiomeric excess. Deuterium-labelling studies demonstrated that the reaction is diastereospecific, with only the syn hydration product formed. So far, this diastereospecific and enantioselective reaction had no equivalent in conventional homogeneous catalysis. PMID- 20966959 TI - Neglected neptunium. AB - Jim Ibers talks about neptunium, an element that has remained largely unnoticed despite the flurry of activity devoted to its neighbours in the periodic table, uranium and plutonium. PMID- 20966960 TI - Caspase-3-dependent export of TCTP: a novel pathway for antiapoptotic intercellular communication. AB - The apoptotic program incorporates a paracrine component of importance in fostering tissue repair at sites of apoptotic cell deletion. As this paracrine pathway likely bears special importance in maladaptive intercellular communication leading to vascular remodeling, we aimed at further defining the mediators produced by apoptotic endothelial cells (EC), using comparative and functional proteomics. Apoptotic EC were found to release nanovesicles displaying ultrastructural characteristics, protein markers and functional activity that differed from apoptotic blebs. Tumor susceptibility gene 101 and translationally controlled tumor protein (TCTP) were identified in nanovesicle fractions purified from medium conditioned by apoptotic EC and absent from purified apoptotic blebs. Immunogold labeling identified TCTP on the surface of nanovesicles purified from medium conditioned by apoptotic EC and within multivesicular blebs in apoptotic EC. These nanovesicles induced an extracellular signal-regulated kinases 1/2 (ERK 1/2)-dependent antiapoptotic phenotype in vascular smooth muscle cells (VSMC), whereas apoptotic blebs did not display antiapoptotic activity on VSMC. Caspase-3 biochemical inhibition and caspase-3 RNA interference in EC submitted to a proapoptotic stimulus inhibited the release of nanovesicles. Also, TCTP siRNAs in EC attenuated the antiapoptotic activity of purified nanovesicles on VSMC. Collectively, these results identify TCTP-bearing nanovesicles as a novel component of the paracrine apoptotic program of potential importance in vascular repair. PMID- 20966961 TI - Regulation of PIDD auto-proteolysis and activity by the molecular chaperone Hsp90. AB - In response to DNA damage, p53-induced protein with a death domain (PIDD) forms a complex called the PIDDosome, which either consists of PIDD, RIP-associated protein with a death domain and caspase-2, forming a platform for the activation of caspase-2, or contains PIDD, RIP1 and NEMO, important for NF-kappaB activation. PIDDosome activation is dependent on auto-processing of PIDD at two different sites, generating the fragments PIDD-C and PIDD-CC. Despite constitutive cleavage, endogenous PIDD remains inactive. In this study, we screened for novel PIDD regulators and identified heat shock protein 90 (Hsp90) as a major effector in both PIDD protein maturation and activation. Hsp90, together with p23, binds PIDD and inhibition of Hsp90 activity with geldanamycin efficiently disrupts this association and impairs PIDD auto-processing. Consequently, both PIDD-mediated NF-kappaB and caspase-2 activation are abrogated. Interestingly, PIDDosome formation itself is associated with Hsp90 release. Characterisation of cytoplasmic and nuclear pools of PIDD showed that active PIDD accumulates in the nucleus and that only cytoplasmic PIDD is bound to Hsp90. Finally, heat shock induces Hsp90 release from PIDD and PIDD nuclear translocation. Thus, Hsp90 has a major role in controlling PIDD functional activity. PMID- 20966962 TI - The DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage. AB - Apaf1 is a key regulator of the mitochondrial intrinsic pathway of apoptosis, as it activates executioner caspases by forming the apoptotic machinery apoptosome. Its genetic regulation and its post-translational modification are crucial under the various conditions where apoptosis occurs. Here we describe Ku70/86, a mediator of non-homologous end-joining pathway of DNA repair, as a novel regulator of Apaf1 transcription. Through analysing different Apaf1 promoter mutants, we identified an element repressing the Apaf1 promoter. We demonstrated that Ku70/86 is a nuclear factor able to bind this repressing element and downregulating Apaf1 transcription. We also found that Ku70/86 interaction with Apaf1 promoter is dynamically modulated upon DNA damage. The effect of this binding is a downregulation of Apaf1 expression immediately following the damage to DNA; conversely, we observed Apaf1 upregulation and apoptosis activation when Ku70/86 unleashes the Apaf1-repressing element. Therefore, besides regulating DNA repair, our results suggest that Ku70/86 binds to the Apaf1 promoter and represses its activity. This may help to inhibit the apoptosome pathway of cell death and contribute to regulate cell survival. PMID- 20966963 TI - Prostaglandins antagonistically control Bax activation during apoptosis. AB - The Bax protein (Bcl-2-associated X protein) is pivotal for the apoptotic process. Bax, which resides in an inactive form in the cytosol of healthy cells, is activated during the early stages of apoptosis and becomes associated with mitochondria through poorly understood mechanisms. In this study, we show that a family of bioactive lipids, namely prostaglandins, regulates Bax-dependent apoptosis. The prostaglandin E(2) (PGE(2)) or its derivative PGA(2) binds to Bax, induces its change of conformation, and thereby triggers apoptosis. A cysteine present in the loop between the two transmembrane alpha-helices of Bax, Cys126 is critical for its activation. PGD(2) inhibits PGE(2) binding to Bax and PGE(2) induced apoptosis, as well as cell death induced by staurosporine and UV-B in various cell lines. This result is consistent with the fact that apoptosis is accompanied during these treatments by an increase in PGE(2). This process is distinct, yet cooperative, from that involving the BH3-only protein Bid. Our results establish that the PGE(2)/PGD(2) balance is involved in a new early mechanism of control in the activation of Bax during apoptosis. PMID- 20966965 TI - Stem cells: dividing with symmetry. PMID- 20966964 TI - Drosophila Ndfip is a novel regulator of Notch signaling. AB - In the Drosophila wing, the Nedd4 ubiquitin ligases (E3s), dNedd4 and Su(dx), are important negative regulators of Notch signaling; they ubiquitinate Notch, promoting its endocytosis and turnover. Here, we show that Drosophila Nedd4 family interacting protein (dNdfip) interacts with the Drosophila Nedd4-like E3s. dNdfip expression dramatically enhances dNedd4 and Su(dx)-mediated wing phenotypes and further disrupts Notch signaling. dNdfip colocalizes with Notch in wing imaginal discs and with the late endosomal marker Rab7 in cultured cells. In addition, dNdfip expression in the wing leads to ectopic Notch signaling. Supporting this, expression of dNdfip suppressed Notch(+/-) wing phenotype and knockdown of dNdfip enhanced the Notch(+/-) wing phenotype. The increase in Notch activity by dNdfip is ligand independent as dNdfip expression also suppressed deltex RNAi and Serrate(+/-) wing phenotypes. The opposing effects of dNdfip expression on Notch signaling and its late endosomal localization support a model whereby dNdfip promotes localization of Notch to the limiting membrane of late endosomes allowing for activation, similar to the model previously shown with ectopic Deltex expression. When dNedd4 or Su(dx) are also present, dNdfip promotes their activity in Notch ubiquitination and internalization to the lysosomal lumen for degradation. PMID- 20966966 TI - Checking out the neighbourhood. PMID- 20966967 TI - Cell cycle: cycling through acetylation. PMID- 20966969 TI - TRAPP complexes in membrane traffic: convergence through a common Rab. AB - Transport protein particle (TRAPP; also known as trafficking protein particle), a multimeric guanine nucleotide-exchange factor for the yeast GTPase Ypt1 and its mammalian homologue, RAB1, regulates multiple membrane trafficking pathways. TRAPP complexes exist in three forms, each of which activates Ypt1 or RAB1 through a common core of subunits and regulates complex localization through distinct subunits. Whereas TRAPPI and TRAPPII tether coated vesicles during endoplasmic reticulum to Golgi and intra-Golgi traffic, respectively, TRAPPIII has recently been shown to be required for autophagy. These advances illustrate how the TRAPP complexes link Ypt1 and RAB1 activation to distinct membrane tethering events. PMID- 20966970 TI - Clocks not winding down: unravelling circadian networks. AB - An intrinsic clock enables an organism to anticipate environmental changes and use energy sources more efficiently, thereby conferring an adaptive advantage. Having an intrinsic clock to orchestrate rhythms is also important for human health. The use of systems biology approaches has advanced our understanding of mechanistic features of circadian oscillators over the past decade. The field is now in a position to develop a multiscale view of circadian systems, from the molecular level to the intact organism, and to apply this information for the development of new therapeutic strategies or for enhancing agricultural productivity in crops. PMID- 20966972 TI - Endogenous endophthalmitis: 10-year experience at a tertiary referral centre. AB - PURPOSE: Endogenous endophthalmitis (EE) is a sight-threatening emergency and the aetiology is often multifactorial. Delayed diagnosis may exacerbate the poor visual prognosis. We describe the management and visual outcomes of EE presenting to a tertiary referral centre. PATIENTS AND METHODS: A prospective consecutive case series of 64 patients presenting with presumed EE from 1997 to 2007 to the Royal Victorian Eye and Ear Hospital were included. All data were collected in a standardized manner. Outcome measures included: visual acuity, microbial profiles, and vitrectomy rate. RESULTS: In total, 64 cases of EE were identified over the study period with a mean age of 57.5 years, and 53.5% were male. Presenting acuities ranged from Snellen 6/6 to no perception of light (NPL). Identifiable risk factors were present in 78.1%, with the majority related to intravenous drug abuse. A 64.1% culture positivity rate was recorded. A vitrectomy rate of 57, 56, and 21% was recorded in documented bacterial, fungal, and no growth cases, respectively. Final Snellen acuities ranged from 6/6 to NPL. A total of 5 out of 64 eyes were enucleated, of which 3 identified Klebsiella species. Better visual outcome was documented in fungal cases. CONCLUSION: EE is a serious ocular condition and has a varied aetiology. Visual outcomes are often poor, irrespective of the method of management. Fungal aetiology often confers a better prognosis, and vitrectomy is advocated for bacterial proven cases. PMID- 20966971 TI - The FERM domain: organizing the structure and function of FAK. AB - Focal adhesion kinase (FAK) is a scaffold and tyrosine kinase protein that binds to itself and cellular partners through its four-point-one, ezrin, radixin, moesin (FERM) domain. Recent structural work reveals that regulatory protein partners convert auto-inhibited FAK into its active state by binding to its FERM domain. Further, the identity of FAK FERM domain-interacting proteins yields clues as to how FAK coordinates diverse cellular responses, including cell adhesion, polarization, migration, survival and death, and suggests that FERM domains might mediate information transfer between the cell cortex and nucleus. Importantly, the FAK FERM domain might act as a paradigm for the actions of other FERM domain-containing proteins. PMID- 20966973 TI - The Carmarthenshire Glaucoma Referral Refinement Scheme, a safe and efficient screening service. AB - AIM: It has been previously shown that community refinement of glaucoma referrals is an efficient way to investigate and treat glaucoma suspects. The potential for false negatives has not been explored previously and we describe a scheme in which effort has been made to both assess and control for this, and report on its success. METHODS: Trained optometrists were recruited to examine and investigate the patients referred with suspected glaucoma, with a view to decreasing false positive rates in accordance with an agreed protocol. The randomly selected notes of 100 patients referred onward to the Hospital Eye Service (HES) by trained, accredited optometrists, and the notes and optic disc images of 100 randomly selected patients retained in the community were examined in order to determine the efficiency and safety of the scheme. RESULTS: The scheme resulted in a 53% reduction in the total number of referrals to HES with a cost saving of L117 per patient. Analysis of patients referred resulted in a diagnosis of glaucoma or retention of patients in HES with suspected glaucoma in 83% and a good correlation between the hospital and optometric measurements. Analysis of notes and optic nerve images of patients not referred indicated no compromise on patient safety. CONCLUSION: This study suggests that suspected glaucoma can be successfully refined in the community with benefits to both the patient and the hospital. We also suggest that such a scheme may be safe as well as cost effective, a conclusion that has not as yet been reached by any other study. PMID- 20966974 TI - Cystic macular oedema on spectral-domain optical coherence tomography in choroideremia patients without cystic changes on fundus examination. AB - PURPOSE: To determine the prevalence of cystic macular oedema (CME) in patients with choroideremia (CHM) by using spectral-domain optical coherence tomography (SD-OCT). METHODS: A total 16 patients affected with CHM were enrolled in the study. All patients underwent a complete eye examination. SD-OCT was performed using an OPKO spectral-domain OCT/SLO instrument. RESULTS: The average age of the study patients was 44.0 +/- 16.0 years (range, 13-63 years). Out of the 16 patients with CHM, 10 patients (62.5%) showed a degree of CME on SD-OCT testing in at least one eye, and 8 patients (50%) showed CME in both eyes. CONCLUSIONS: Because of its notable prevalence, it would seem prudent to screen CHM patients by SD-OCT for the possible presence of CME and to identify those amenable to future treatment strategies for their macular oedema. PMID- 20966976 TI - Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies. AB - Three decades of p53 research have led to many advances in understanding the basic biology of normal and cancer cells. Nonetheless, the detailed functions of p53 in normal cells, and even more so in cancer cells, remain obscure. A major breakthrough is the realization that mutant p53 has a life of its own: it contributes to cancer not only through loss of activity, but also through gain of specific 'mutant functions'. This new focus on mutant p53 is the rationale behind the meeting series dedicated to advances on mutant p53 biology. This review provides an overview of results presented at the Fourth International Workshop on Mutant p53, held in Akko, Israel in March 2009. New roles and functions of p53 relevant for tumor suppressions were presented, including the regulation of microRNAs networks, the modulation of cell-stroma interactions and the induction of senescence. A main focus of the meeting was the rapidly growing body of knowledge on autonomous properties of mutant p53 and on their oncogenic 'gain of function' impact. Importantly, the meeting highlighted that, 30 years after p53 discovery, research on mutant p53 is entering the clinical and translational era. Two major steps forward in this respect are a better understanding of the active mechanism of small drugs targeting mutant p53 in tumor cells and an improved definition of the prognostic and predictive value of mutant p53 in human cancer. PMID- 20966975 TI - Short-term changes of visual hallucinations after intravitreal injection of ranibizumab in neovascular age-related macular degeneration. PMID- 20966977 TI - International imperatives. PMID- 20966978 TI - Desperately patronising. PMID- 20966980 TI - Nirvana impediment. PMID- 20966989 TI - Grand tour takes place at dental academy. PMID- 20966981 TI - Herbal history. PMID- 20966992 TI - Registrar earns Fellowship to research HPV. PMID- 20966995 TI - California achieves 58% water fluoridation. PMID- 20966996 TI - Ethical sourcing of dental instruments and materials. AB - There is evidence that dental instruments and materials are being manufactured in the developing world under poor labour conditions. It is suggested that the level of awareness of the dental team with regard to this is raised and that a culture of greater inquiry into the sourcing of instruments and materials is developed. PMID- 20966997 TI - Risk management in clinical practice. Part 7. Dento-legal aspects of orthodontic practice. AB - Orthodontic treatment, like any aspect of general dentistry, exposes the clinician to the risk of malpractice and litigation. While for orthodontists this issue has not been a major concern over the last century, risk management has, over the last decade, become a significant issue in orthodontic practice. The patient-orthodontist contact may be classified into pre-treatment, active treatment and post-treatment periods. Risk management issues pertinent to each time period are discussed in this article with the intention of increasing the clinician's awareness of potential problems. Armed with this knowledge the overriding message for the clinician is to practise orthodontics with the philosophy of prevention and avoidance. To the best of your ability, avoid giving patients a reason to institute legal proceedings. PMID- 20966998 TI - Osteomyelitis presenting in two patients: a challenging disease to manage. AB - Chronic osteomyelitis of the jaw is a rare entity in the healthy population of the developed world. It is normally associated with radiation and bisphosphonates ingestion and occurs in immunosuppressed individuals such as alcoholics or diabetics. Two cases are reported of chronic osteomyelitis in healthy individuals with no adverse medical conditions. The management of these cases are described. PMID- 20966999 TI - Application of teledentistry in oral medicine in a community dental service, N. Ireland. AB - Currently, patients with oral medicine conditions from all areas of Northern Ireland are referred by dentists and doctors to a small number of specialist services: predominantly, the Regional Oral Medicine Consultant at the School of Dentistry, Belfast. On receipt of the referral the consultant makes an assessment of the urgency of the case and the patient is placed on a waiting list. Until the recent implementation of waiting list initiatives (Elective Access Protocol, Department of Health, N. Ireland, 2006), patients remained on the waiting list for long periods of time. Analysis of these patient profiles highlights that many need both multiple treatment and review appointments of their chronic conditions, and consequently remain in the hospital system for significant periods of time. This increases the waiting time for these services. The idea of using teledentistry to triage referrals, and its potential as a tool to support locally based treatment, poses an alternative approach to the management of oral medicine referrals. It may be of particular interest to practitioners in rural locations where distance from the regional centre is significant. In 2005, to test this theory, a prototype teledentistry system was set up as part of a service improvement scheme by the Community Dental Service of the Homefirst Legacy Trust (now Northern Trust) in partnership with the Oral Medicine Department at the School of Dentistry, Royal Group of Hospitals Legacy Trust (now Belfast Trust). This paper describes the feasibility study. PMID- 20967004 TI - Summary of: estimating age and the likelihood of having attained 18 years of age using mandibular third molars. PMID- 20967005 TI - Summary of: a pilot study of bioaerosol reduction using an air cleaning system during dental procedures. PMID- 20967026 TI - Crucial function of histone deacetylase 1 for differentiation of teratomas in mice and humans. AB - Histone deacetylase (HDAC) inhibitors induce cell cycle arrest, differentiation or apoptosis in tumour cells and are, therefore, promising anti-cancer reagents. However, the specific HDAC isoforms that mediate these effects are not yet identified. To explore the role of HDAC1 in tumourigenesis and tumour proliferation, we established an experimental teratoma model using wild-type and HDAC1-deficient embryonic stem cells. HDAC1-deficient teratomas showed no significant difference in size compared with wild-type teratomas. Surprisingly, loss of HDAC1 was not only linked to increased apoptosis, but also to significantly enhanced proliferation. Epithelial structures showed reduced differentiation as monitored by Oct3/4 expression and changed E-cadherin localization and displayed up-regulated expression of SNAIL1, a regulator of epithelial cell plasticity. Increased levels of the transcriptional regulator SNAIL1 are crucial for enhanced proliferation and reduced differentiation of HDAC1-deficient teratoma. Importantly, the analysis of human teratomas revealed a similar link between loss of HDAC1 and enhanced tumour malignancy. These findings reveal a novel role for HDAC1 in the control of tumour proliferation and identify HDAC1 as potential marker for benign teratomas. PMID- 20967027 TI - Conformational flexibility of RNA polymerase III during transcriptional elongation. AB - RNA polymerase (Pol) III is responsible for the transcription of genes encoding small RNAs, including tRNA, 5S rRNA and U6 RNA. Here, we report the electron cryomicroscopy structures of yeast Pol III at 9.9 A resolution and its elongation complex at 16.5 A resolution. Particle sub-classification reveals prominent EM densities for the two Pol III-specific subcomplexes, C31/C82/C34 and C37/C53, that can be interpreted using homology models. While the winged-helix-containing C31/C82/C34 subcomplex initiates transcription from one side of the DNA-binding cleft, the C37/C53 subcomplex accesses the transcription bubble from the opposite side of this cleft. The transcribing Pol III enzyme structure not only shows the complete incoming DNA duplex, but also reveals the exit path of newly synthesized RNA. During transcriptional elongation, the Pol III-specific subcomplexes tightly enclose the incoming DNA duplex, which likely increases processivity and provides structural insights into the conformational switch between Pol III-mediated initiation and elongation. PMID- 20967029 TI - [Are you Facebook friend with Tidsskriftet?]. PMID- 20967028 TI - Directed differentiation of human embryonic stem cells toward chondrocytes. AB - We report a chemically defined, efficient, scalable and reproducible protocol for differentiation of human embryonic stem cells (hESCs) toward chondrocytes. HESCs are directed through intermediate developmental stages using substrates of known matrix proteins and chemically defined media supplemented with exogenous growth factors. Gene expression analysis suggests that the hESCs progress through primitive streak or mesendoderm to mesoderm, before differentiating into a chondrocytic culture comprising cell aggregates. At this final stage, 74% (HUES1 cells) and up to 95-97% (HUES7 and HUES8 cells) express the chondrogenic transcription factor SOX9. The cell aggregates also express cell surface CD44 and aggrecan and deposit a sulfated glycosaminoglycan and cartilage-specific collagen II matrix, but show very low or no expression of genes and proteins associated with nontarget cell types. Our protocol should facilitate studies of chondrocyte differentiation and of cell replacement therapies for cartilage repair. PMID- 20967030 TI - Use of antibiotics gives cause for concern. PMID- 20967032 TI - [How long shall one wait for hip fracture surgery?]. PMID- 20967033 TI - [Colorectal cancer screening]. PMID- 20967034 TI - [Colorectal cancer screening--at last discussed!]. PMID- 20967035 TI - [Extensive fractures following seizures]. PMID- 20967036 TI - [Irresponsibly about the merger process in the editorial]. PMID- 20967037 TI - [Meaningless about whiplash injuries]. PMID- 20967038 TI - [Deficient hearing rehabilitation in Norway]. PMID- 20967039 TI - [Physicians who become hospital chief executives]. PMID- 20967040 TI - [Overactive pelvic floor syndrome]. AB - BACKGROUND: The etiology of the overactive pelvic floor syndrome is not fully understood and no gold standards are available for diagnosis or treatment. The article presents an overview of literature, and discusses diagnostics and treatment. MATERIAL AND METHODS: Literature was identified through a non systematic search in PubMed, and discussed in light of the authors' clinical experience with the patient group. RESULTS: The main symptoms of overactive pelvic floor syndrome are pain and defecation difficulties; the latter often leads to chronic constipation. Other symptoms depend on which parts of the pelvic floor that are most affected. Pain is often chronic and ranges from mild to severe; it is aggravated by micturition, sexual intercourse, orgasm, defecation and sitting on hard surfaces, and reduces the ability to work and quality of life in general. Injection of Botulinum toxin in the pelvic floor muscles seems to alleviate pain in many patients. Physiotherapy of the pelvic floor and treatment offered by pain clinics can also be useful. INTERPRETATION: A close cooperation between gastroenterologists, surgeons, urologists, gynecologists, neurologists, physiotherapists and possibly pain clinics is important to improve the situation for these patients. PMID- 20967041 TI - [Use of fluoroquinolones in nursing homes]. AB - BACKGROUND: In Norway, a substantial increase in the use of fluoroquinolones (in the last years) has occurred in parallel with a disconcertering increase in ciprofloxacin resistant E. Coli bacteria. Elderly patients (over 70 years) use most antibiotics. The purpose of this study is to investigate prescribing of fluoroquinolone in nursing homes within a Norwegian municipality. MATERIAL AND METHODS: Clinical information was recorded for nursing home patients treated with fluoroquinolone in Arendal municipality in the period 01.12.06-31.11.07. RESULTS: 94 courses of ciprofloxacin were prescribed for 78 patients. No patients were treated with ofloxacine. Urinary tract infection was the most common indication for patients both in long- term (78%) and short term (40%) wards. In short-term wards, respiratory tract infection was also a common indication for prescribing ciprofloxacin (37%), but not in long- term wards (4%). 44 infections (47%) were verified by microbiology culture. 12 infections were caused by a bacterium susceptible only to ciprofloxacin. INTERPRETATION: Ciprofloxacin was used in a large proportion of the patients in cases when another antibiotic should have been the first choice according to Norwegian national guidelines. Results of microbiology culture showed that most pathogens were susceptible to antibiotics with a narrower spectrum than ciprofloxacin. PMID- 20967042 TI - [A 40ish man with weight loss and scrotum edema]. PMID- 20967043 TI - [Some diseases will come back]. PMID- 20967044 TI - [Economic incentives and treatment quality]. PMID- 20967045 TI - [Edvard Munch and Spanish flu]. PMID- 20967047 TI - [Maternal health and health care aid]. PMID- 20967049 TI - Quantum imaging and inverse scattering. AB - We consider the inverse scattering problem that arises in two-photon quantum imaging with interferometric measurements. We show that the two-point correlation function of the field contains information about the scattering medium at a spatial frequency of twice the Rayleigh bandwidth. The linearized inverse problem, however, yields reconstructions with a resolution of lambda/2, where lambda is the wavelength of light. PMID- 20967050 TI - In situ spatial mapping of Gouy phase slip for high-detail attosecond pump-probe measurements. AB - Attosecond pump-probe experiments routinely utilize extreme ultraviolet (XUV) and IR fields, with relative phase being the variable parameter. However, the Gouy phase slip between the focused IR and XUV pulses inevitably leads to a certain amount of phase averaging and loss of accuracy. By using ion imaging, we establish a one-to-one mapping between the local phase slip and the spatial coordinates of the focal volume, thus performing in situ characterization of the Gouy phase of a complex beam and its role in ionization of He and Xe. We demonstrate that spatially discriminated ion imaging enhances the contrast of a phase-dependent XUV+IR ionization signal. We utilize our technique to unmask a weak ionization asymmetry, thus opening pathways for further high-precision attosecond studies. PMID- 20967051 TI - Intraoperative spectral domain optical coherence tomography for vitreoretinal surgery. AB - We demonstrate in vivo human retinal imaging using an intraoperative microscope mounted optical coherence tomography system (MMOCT). Our optomechanical design adapts an Oculus Binocular Indirect Ophthalmo Microscope (BIOM3), suspended from a Leica ophthalmic surgical microscope, with spectral domain optical coherence tomography (SD-OCT) scanning and relay optics. The MMOCT enables wide-field noncontact real-time cross-sectional imaging of retinal structure, allowing for SD-OCT augmented intrasurgical microscopy for intraocular visualization. We experimentally quantify the axial and lateral resolution of the MMOCT and demonstrate fundus imaging at a 20Hz frame rate. PMID- 20967052 TI - Strong enhancement of magnetic dipole emission in a multilevel electronic system. AB - The Purcell effect is commonly used to increase light emission by enhancing the radiative decay of electric dipole transitions. In this Letter, we demonstrate that the opposite effect, namely, the inhibition of electric dipole transitions, can be used to strongly enhance light emission via magnetic dipole transitions. Specifically, by exploiting the differing symmetries of competitive electric and magnetic dipole transitions in trivalent europium, we demonstrate a fourfold enhancement of the far-field emission from the (5)D(0)->(7)F(1) magnetic dipole transition in trivalent europium. We show that this strong enhancement is well predicted by a three-level model that couples the individual Purcell enhancement factors of competitive transitions from the same excited state. PMID- 20967053 TI - Multiple-trap laser tweezers Raman spectroscopy for simultaneous monitoring of the biological dynamics of multiple individual cells. AB - We report the development of a multiple-trap laser tweezers Raman spectroscopy (LTRS) array for simultaneously acquiring Raman spectra of individual cells in physiological environments. This LTRS-array technique was also combined with phase contrast and fluorescence microscopy, allowing measurement of Raman spectra, refractility, and fluorescence images of individual cells with a temporal resolution of ~5 s. As a demonstration, we used this technique to monitor multiple Bacillus cereus spores germinating in a nutrient medium for up to 90min and observed the kinetics of dipicolinic acid release and uptake of nucleic acid-binding stain molecules during spore germination. PMID- 20967054 TI - Chalcogenide glass waveguides integrated with quantum cascade lasers for on-chip mid-IR photonic circuits. AB - We demonstrate on-chip hybrid integration of chalcogenide glass waveguides and quantum cascade lasers (QCLs). Integration is achieved using an additive solution casting and molding method to directly form As(2)S(3) strip waveguides on an existing QCL chip. Integrated As(2)S(3) strip waveguides constructed in this manner display strong optical confinement and guiding around 90 degrees bends, with a NA of 0.24 and bend loss of 12.9dB at a 1mm radius (lambda=4.8MUm). PMID- 20967055 TI - Tunable broadband isolator based on electro-optically induced linear gratings in a nonlinear photonic crystal. AB - We theoretically propose a broadband optical isolator based on second-harmonic generation in a one-dimensional quadratic nonlinear photonic crystal (NPC) with an embedded defect. An external electric field along the z axis is applied to modulate the NPC refractive index periodically. Complete optical isolation always could be reached with the help of an external field. Influences of the defect position and thickness are discussed. The spectral and power tolerances of the isolator also have been investigated and show high contrast within a wide wavelength range at different power levels. PMID- 20967056 TI - Toward a UV-visible-near-infrared hyperspectral imaging platform for fast multiplex reflection spectroscopy. AB - A reflection hyperspectral imaging system covering a 350-1000nm spectral range is realized by a UV-visible-near-IR Fourier transform imaging spectrometer. The system has a simple design and good spectral and spatial resolving performance. Accurate and fast microspectroscopic measurement results on novel colloidal crystal beads demonstrate the system has practical potential for high-throughput molecular multiplex assays. PMID- 20967057 TI - Study of the interference effects in an optical cavity for organic light-emitting diode applications. AB - The interference effects generated in a bottom-emitting electroluminescent device fabricated on a polymer underlayer introduced with the aim of improving the anode roughness have been studied. The analysis of the interference fringes at different detection angles and the spatial coherence demonstrates that this phenomenon is due to multiple internal reflections that propagate in the polymer layer. This effect can be eliminated by modifying the polymer thickness and the incidence angle of the electromagnetic radiation at the anode-polymer interface. Inkjet etching technology is adopted for microcavities-shaped polymer structuring to destroy the resonator effect of the optical cavity. PMID- 20967058 TI - High spatial resolution ellipsometer for characterization of epitaxial graphene. AB - An ellipsometer with 3MUm*5MUm spot size constructed with a single focusing and imaging element is used to measure the layer number of exfoliated graphene on glass and expitaxial graphene on SiC. Ellipsometric sensitivity to graphene layer number increases with decreasing layer number and decreasing substrate refractive index. Single-atomic-layer sensitivity has been achieved. High spatial resolution imaging and ellipsometry is useful for rapid characterization of epitaxially grown graphene films. PMID- 20967059 TI - Thresholdless surface solitons. AB - We report on the existence of nonlinear surface waves that, on the one hand, do not require the threshold energy flow for their excitation, and, on the other hand, extend into media at both sides of the interface at low powers, i.e., cannot be reduced to the conventional Tamm states. Such waves can be excited if the refractive index in at least one of the materials forming the interface is periodically modulated, with properly selected modulation depth and frequency. Thresholdless surface solitons can be stable in the entire existence domain. PMID- 20967060 TI - Enhancement of third-harmonic generation in nonlocal spatial solitons. AB - We report on the observation of Type I third-harmonic generation induced by a train of femtosecond laser pulses in nematic liquid crystals. We find that as the average power of the train is increased, the frequency conversion process is enhanced as a consequence of the tight confinement of the pulses into a nonlocal spatial soliton. PMID- 20967061 TI - Tomographic molecular imaging of x-ray-excitable nanoparticles. AB - X-ray luminescence computed tomography (XLCT) is proposed as a new dual molecular/anatomical imaging modality. XLCT is based on the selective excitation and optical detection of x-ray-excitable nanoparticles. As a proof of concept, we built a prototype XLCT system and imaged near-IR-emitting Gd(2)O(2)S:Eu phosphors in various phantoms. Imaging in an optically diffusive medium shows that imaging performance is not affected by optical scatter; furthermore, the linear response of the reconstructed images suggests that XLCT is capable of quantitative imaging. PMID- 20967062 TI - Thermal emission of macroporous silicon chirped photonic crystals. AB - In this Letter we report on the thermal properties of macroporous silicon photonic crystals with the unit cell gradually varied along the pore axis. We show experimentally that arbitrarily large omnidirectional total-reflectance bands can be produced with such structures. We also demonstrate that those bands can be effectively used to reduce thermal radiation in large spectral bands. PMID- 20967063 TI - Thermal nonlinear effects in hybrid silica/polymer microdisks. AB - The linear and thermal nonlinear spectral responses of silica and hybrid silica/polymer microdisk resonators are investigated. Both types of resonators can be fabricated using the same technological procedure with only slight modification. An extra polymer layer results in opposite sign of the nonlinear thermal optical response of the hybrid microdisks compared to the pure silica ones, which can be explained by the different thermorefractive coefficients of silica and polymer. A full compensation of eigen frequency shift, caused by thermal nonlinearity, has been demonstrated experimentally. PMID- 20967064 TI - C- and L-band tunable fiber ring laser using a two-taper Mach-Zehnder interferometer filter. AB - A stable C- and L-band tunable fiber ring laser, using a two-taper Mach-Zehnder interferometer (MZI) as a filter, is proposed and demonstrated experimentally. One of the two taper waists is mechanically bent to tune the laser wavelength. Being amplified by an L-band erbium-doped fiber amplifier and an erbium-doped fiber, respectively, the fiber ring laser has a full L-band (1564-1605nm) and C band (1550-1565nm) tuning range with a side-mode suppression ratio as high as 50dB. The laser linewidth and the minimum tuning step are related to the MZI's cavity length. It was also found that thermal annealing relieved the internal stresses of the tapers and greatly improved the laser performance. PMID- 20967065 TI - Tunable optical-path correlator for distributed strain or temperature-sensing application. AB - Based on a cavity-length tunable fiber-loop resonator, a multibeam optical path difference is generated. It can be used to match and correlate the reflective signals from the partial reflective ends of each sensing fiber gauge. The correlation signals correspond to the sensing gauge lengths, and the shift of the correlation peak is related with the fiber sensing gauge elongation caused by strain or temperature. Therefore, it can be used to measure distributed strain or deformation for smart structural monitoring. PMID- 20967066 TI - Single-mode low-loss optical fibers for long-wave infrared transmission. AB - In this Letter, we report single-mode fibers made of chalcogenide glasses with low loss in the 5-12MUm range. Glasses from the Ge-As-Te-Se system were optimized to prevent nucleation and to exhibit low density of charge carriers. Single-mode fibers were obtained through the rod-in-tube method by substituting 2% Te/Se between the core and cladding glasses. The resulting single-mode fibers had a core diameter of 30MUm and exhibited losses of ~6 dB/m at 10.6MUm, and as low as 3-4dB/m in the 6-10MUm range. PMID- 20967067 TI - Resolution improvement in optical projection tomography by the focal scanning method. AB - Optical projection tomography (OPT) requires the depth of field (DOF) of the lens to cover at least half of the sample. There is a trade-off between obtaining high resolution with a high-NA lens and obtaining large DOF with a low-NA lens. The DOF of a high-NA objective lens can be extended by scanning its focal plane through the sample. We call this extended DOF image a "pseudoprojection." Images reconstructed from these pseudoprojections have isometric resolution, which can be the same as the lateral resolution of the high-NA objective. The focal scanning method produces an over 10* improvement in OPT resolution. PMID- 20967068 TI - Analytical extraction of the recombination zone location in organic light emitting diodes from emission pattern extrema. AB - We present an analytical method for extracting the recombination zone location from emission patterns produced by organic LEDs (OLEDs). The method is based on derivation of the closed-form expressions for OLED-radiated power developed in previous work and formulation of the analytical relations between the emitter position and the pattern extrema. The results are confirmed to be in good agreement with reported optical measurements. The resultant formulae offer insight regarding the dominant physical processes in the device and can be utilized to assess or verify the location of the recombination zone, a very important parameter in the optimization process of OLED efficiency, from standard optical measurements, otherwise a very difficult task to achieve. PMID- 20967069 TI - Blind frequency-resolved optical-gating pulse characterization for quantitative differential multiphoton microscopy. AB - We use a unique multifocal multiphoton microscope to directly characterize the pulse in the focal plane of a high-NA objective using second-harmonic generation frequency-resolved optical gating (FROG). Because of the nature of the optical setup, femtosecond laser pulses of orthogonal polarization states are generated in the focal plane, each acquiring a different spectral dispersion. By applying an additional constraint on the phase extraction algorithm, we simultaneously extract both the gate and probe pulses from a single spectrogram with a FROG error of 0.016. PMID- 20967070 TI - Warm-white light-emitting diodes integrated with colloidal quantum dots for high luminous efficacy and color rendering. AB - Warm-white LEDs (WLEDs) with high spectral quality and efficiency are required for lighting applications, but current experimental performances are limited. We report on nanocrystal quantum dot (NQD) hybridized WLEDs with high performance that exhibit a high luminous efficacy of optical radiation exceeding 350lm/W(opt) and a high color rendering index close to 90 at a low correlated color temperature <3000K. These spectrally engineered WLEDs are obtained using a combination of CdSe/ZnS core/shell NQD nanophosphors integrated on blue InGaN/GaN LEDs. PMID- 20967071 TI - Single-photon generation by correlated loss in a three-core optical fiber. AB - We demonstrate that by an asymmetric coupling of two nonlinear waveguiding cores to the third strongly absorptive core, it is possible to realize single-photon generation on demand from an input coherent state. This three-core fiber setup can also be implemented for achieving strong photon-number squeezing even for large losses in side cores. PMID- 20967072 TI - Optical absorption enhancement in disordered vertical silicon nanowire arrays for photovoltaic applications. AB - Optical properties are numerically investigated for vertically aligned silicon nanowire arrays with three types of structural randomness, i.e., random position, diameter, and length. Nanowire arrays with random position show slight absorption enhancement, while those with random diameter or length show significant absorption enhancement, which is attributed to the stronger optical scattering in a random structure. Our results indicate that structural randomness in vertical nanowire arrays will not destroy but rather can further enhance optical absorption compared to ordered nanowire arrays. PMID- 20967073 TI - Thermal unbalance by an amplified spontaneous emission absorber in an Nd:YAG thin disk laser. AB - We investigate heat generation in a Nd:YAG thin-disk laser composite with an undoped anti-amplified spontaneous emission (ASE) cap and a side ASE absorber under lasing and nonlasing conditions. The heat load unbalance in three different regions induces a large transverse temperature inhomogeneity under the nonlasing condition. The additional heat fraction generated by the concentration quenching is observed. PMID- 20967074 TI - Purcell factor and superradiance in Si-patterned waveguides. AB - Numerical modeling of slotted photonic crystal Si waveguides is reported. Employing multiple slots in a single waveguide, we obtained large Purcell enhancements for a large ensemble of emitters coupled with the same optical mode. This allows observation of peculiar physical phenomena, such as anisotropic bandgap superradiance. PMID- 20967075 TI - Laser optoacoustic spectroscopy of gold nanorods within a highly scattering medium. AB - We describe a spectroscopic comparative analysis based on the optoacoustic technique over the wavelength range from 410nm to 1000nm using a Q-switched Nd:YAG pumped optical parametric oscillator tunable source on a gold nanostructure solution located within a highly scattering medium. The advantages of this method over standard spectroscopy techniques are the possibility to localize and monitor the spectroscopic response of absorbing materials located within turbid media. The operation is confirmed using a comparative analysis with the spectroscopic results obtained from a reference measurement scheme, based on a highly sensitive collimated optical transmission setup in parallel and under the same experimental conditions as the optoacoustic technique. PMID- 20967076 TI - Digital self-referencing quantitative phase microscopy by wavefront folding in holographic image reconstruction. AB - A completely numerical method, named digital self-referencing holography, is described to easily accomplish a quantitative phase microscopy for microfluidic devices by a digital holographic microscope. The approach works through an appropriate numerical manipulation of the retrieved complex wavefront. The self referencing is obtained by folding the retrieved wavefront in the image plane. The folding operation allows us to obtain the correct phase map by subtracting from the complex region of interest a flat area outside the microfluidic channel. To demonstrate the effectiveness of the method, quantitative phase maps of bovine spermatozoa and in vitro cells are retrieved. PMID- 20967077 TI - Practical non-Poissonian light source for passive decoy state quantum key distribution. AB - Passive decoy state quantum key distribution (QKD) has enormous potential in high speed applications. In this Letter, an intrinsic-stable non-Poissonian light source was implemented with Faraday mirrors and could be a crucial element in realizing passive decoy state QKD. The stable g((2))(0) was obtained through a Hanbury Brown-Twiss experiment, and the results fit well with the theoretical value according to Curty et al.'s theory [Opt. Lett.34, 3238 (2009)]. PMID- 20967078 TI - Maxwell fish-eye and Eaton lenses emulated by microdroplets. AB - Despite strong experimental and theoretical evidence supporting superresolution imaging based on microlenses, the imaging mechanisms involved are not well understood. Based on the transformation optics approach, we demonstrate that a microlens may act as a two-dimensional fish-eye or an inverted Eaton lens. An asymmetric inverted Eaton lens may exhibit considerable image magnification, which has been confirmed experimentally. PMID- 20967079 TI - Holographic projector using one lens. AB - It is shown that the lens count in a Fourier holographic projector can be reduced by encoding the equivalent lens power in sets of Fresnel holograms. By using appropriately calculated Fresnel holograms in a reflective configuration to effectively share a lens between the beam-expansion and demagnification stages of a holographic projector, a reduction in lens count from four to one is demonstrated. PMID- 20967080 TI - Enhanced light absorption of TiO(2) in the near-ultraviolet band by Au nanoparticles. AB - We propose a scheme to enhance near-UV band absorption of a rutile TiO(2) nanoparticle by placing Au nanoparticles in its neighborhood. The discrete-dipole approximation method was employed to calculate the absorption spectrum of pure rutile TiO(2) and that of TiO(2) mixed with Au nanoparticles. The results indicate that pure rutile TiO(2) has its maximum absorption located in the deep UV band. With the existence of Au nanoparticles, a significant light harvesting effect occurs, and this maximum shifts to the near-UV band, where usual excitation wavelength falls. PMID- 20967081 TI - Negative radiation pressure on gain medium structures. AB - We demonstrate negative radiation pressure on gain medium structures, such that light amplification may cause a nanoscale body to be pulled toward a light source. Optically large gain medium structures, such as slabs and spheres, as well as deep subwavelength bodies, may experience this phenomenon. The threshold gain for radiation pressure reversal is obtained analytically for Rayleigh spheres, thin cylinders, and thin slabs. This threshold vanishes when the gain medium structure is surrounded by a medium with a matched refractive index, thus eliminating the positive scattering forces. PMID- 20967082 TI - Hybrid waveguide-plasmon resonances in gold pillar arrays on top of a dielectric waveguide. AB - We propose a hybrid waveguide-plasmon system consisting of gold pillar arrays on top of a dielectric waveguide. The formation of extraordinary transmissions induced by the hybrid waveguide-plasmon resonances is investigated by rigorous coupled-wave analysis. The characteristics of the hybrid resonances can be predicted by introducing the photonic crystal slab theory. Extremely narrow absorption peaks and the electromagnetically induced transparency-like optical property are demonstrated in our hybrid system. PMID- 20967083 TI - Approximation of the Fraunhofer diffraction peak, produced by particles of arbitrary shape. AB - A simple analytical formula is developed to describe light diffraction by chaotically oriented particles of arbitrary shape. The formula expresses the angular pattern through three well-defined microphysical characteristics of an ensemble: the average cross-sectional area, the average area squared, and the average length of the contour bordering the particle projection. PMID- 20967084 TI - Delayed optical images through coupled-resonator-induced transparency. AB - We propagated transverse two-dimensional images encoded on optical pulses through a frequency window of a coupled-image-resonator-induced transparency. The optical images are stored and delayed by 10.6ns, reflecting the tunable dispersion of the coupled resonator. The k-space bandwidth of the amplitude transfer function of the system is discussed in the presence of the off-resonance Fano interference effect between the two resonators. PMID- 20967085 TI - Materials processing with a tightly focused femtosecond laser vortex pulse. AB - In this Letter we present the first (to our knowledge) demonstration of material modification using tightly focused single femtosecond laser vortex pulses. Double charge femtosecond vortices were synthesized with a polarization-singularity beam converter based on light propagation in a uniaxial anisotropic medium and then focused using moderate- and high-NA optics (viz., NA=0.45 and 0.9) to ablate fused silica and soda-lime glass. By controlling the pulse energy, we consistently machine micrometer-size ring-shaped structures with <100nm uniform groove thickness. PMID- 20967086 TI - Evidence of Autler-Townes splitting in high-order nonlinear processes. AB - We demonstrate Autler-Townes (AT) splitting of four-wave mixing in an electromagnetically induced transparency window, which results from the destructive interference between a three-photon process and a five-photon process. The primary and secondary AT splittings are achieved via induced atomic coherence in a four-level Y-type atomic system. Theoretical calculations fit well with the experimentally measured results. Such controlled multichannel splitting of nonlinear optical signals can have potential applications in optical communication and quantum information processing. PMID- 20967087 TI - Polarization synthesis by computer-generated holography using orthogonally polarized and correlated speckle patterns. AB - An interlaced polarization computer-generated hologram (PCGH) is designed to produce specific irradiance and polarization states in the image plane. The PCGH produces a tangentially polarized annular pattern with correlated speckle, which is achieved by a novel application of the diffuser optimization method. Alternating columns of orthogonal linear polarizations illuminate an interlaced PCGH, producing a ratio of polarization of 88% measured on a fabricated sample. The demonstrated technique can be applied to designs for arbitrary irradiance and polarization states in the image plane. PMID- 20967088 TI - Dual plane in-line digital holographic microscopy. AB - We report a dual plane in-line digital holographic microscopy technique that exploits the method of subtraction of average intensity of the entire hologram to suppress the zero-order diffracted wave. Two interferograms are recorded at different planes to eliminate the conjugate image. The experimental results demonstrate successful reconstruction of phase objects as well as of amplitude objects. The two interferograms can be recorded simultaneously, using two CCD or CMOS sensors, in order to increase the acquisition rate. This enhanced acquisition rate, together with the improved reconstruction capability of the proposed method, may find applications in biomedical research for visualization of rapid dynamic processes at the cellular level. PMID- 20967089 TI - Measuring the spatial polarization distribution of multimode beams emerging from passive step-index large-mode-area fibers. AB - We measure the polarization state of each guided transversal mode propagating in step-index large-mode-area fibers (V~4) using a correlation-filter based measurement technique in combination with a Stokes parameter measurement. The entire emerging beam, expressed in terms of a phase-dependent superposition of linearly polarized modes, demonstrates spatially varying polarization properties. By knowing the information about modal amplitudes and phase differences, full information about the optical field is available. PMID- 20967090 TI - In vivo Fourier-domain full-field OCT of the human retina with 1.5 million A lines/s. AB - In vivo full-field (FF) optical coherence tomography (OCT) images of human retina are presented by using a rapidly tunable laser source in combination with an ultra-high-speed camera. Fourier-domain FF-OCT provided a way to increase the speed of retinal imaging by parallel acquisition of A-scans. Reduced contrast caused by cross talk was observed only below the retinal pigment epithelium. With a 100Hz sweep rate, FF-OCT was fast enough to acquire OCT images with acceptable motion artifacts. FF-OCT allows ultrafast retinal imaging, boosting image speed by a lack of moving parts and a considerably higher irradiation power. PMID- 20967091 TI - Yb,Na:PbF(2): a potential new high-power laser material. AB - Yb:PbF(2) and Yb,Na:PbF(2) laser crystals are grown by the Bridgman method. Room temperature absorption, photoluminescence spectra, and fluorescence lifetimes of Yb(3+) ions in the crystals have been investigated. Experimental results show that Na(+) ions codoping with Yb(3+) as charge compensators can suppress the deoxidization of Yb(3+) to Yb(2+). The result of diode-pumped laser operation of a Yb,Na:PbF(2) single crystal is reported for the first time to the best of our knowledge . With a 1mol.%Yb(3+)-doped sample, we obtained 2.37W output power at 1056nm for 17.9W of incident power at 978nm. PMID- 20967092 TI - Resonance splitting in gyrotropic ring resonators. AB - We present the theoretical concept of an optical isolator based on resonance splitting in a silicon ring resonator covered with a magneto-optical polymer cladding. For this task, a perturbation method is derived for the modes in the cylindrical coordinate system. A polymer magneto-optical cladding causing a 0.01 amplitude of the off-diagonal element of the dielectric tensor is assumed. It is shown that the derived resonance splitting of the clockwise and counterclockwise modes increases for smaller ring radii. For the ring with a radius of approximately 1.5MUm, a 29GHz splitting is demonstrated. An integrated optical isolator with a 10MUm geometrical footprint is proposed based on a critically coupled ring resonator. PMID- 20967093 TI - Partial-coherence method to model experimental free-electron laser pulse statistics. AB - A general numerical approach is described that allows obtaining model sets of temporal pulse shapes of free-electron lasers (FELs) operating in the self amplified spontaneous emission mode. Based on a random partial-coherence approach, sets of pulse shapes can be calculated that satisfy statistical criteria of FEL light predicted by established FEL theory. Importantly, the numerically retrieved sets of pulses reproduce the experimentally accessible FEL light characteristics as measured at the Free-electron LASer at Hamburg (FLASH), such as the average spectrum, single-shot spectral shape, and pulse duration. The high-precision agreement with the experimental average spectral shape, without further knowledge of FEL machine parameters, makes this approach a convenient tool for the analysis and theoretical modeling of nonlinear optical or pump-probe experiments with FEL light. PMID- 20967094 TI - Dispersion-based pulse shaping for multiplexed two-photon fluorescence microscopy. AB - We demonstrate selective two-photon excited fluorescence microscopy with shaped pulses produced with a simple yet efficient scheme based on dispersive optical components. The pulse train from a broadband oscillator is split into two subtrains that are sent through different amounts of glass. Beam recombination results in pulse-shape switching at a rate of 150MHz. Time-resolved photon counting detection then provides two simultaneous images resulting from selective two-photon excitation, as demonstrated in a live embryo. Although less versatile than programmable pulse-shaping devices, this novel arrangement significantly improves the performance of selective microscopy using broadband shaped pulses while simplifying the experimental setup. PMID- 20967095 TI - Multimodal nonlinear optical polarizing microscopy of long-range molecular order in liquid crystals. AB - We demonstrate orientation-sensitive multimodal nonlinear optical polarizing microscopy capable of probing orientational, polar, and biaxial features of mesomorphic ordering in soft matter. This technique achieves simultaneous imaging in broadband coherent anti-Stokes Raman scattering, multiphoton excitation fluorescence, and multiharmonic generation polarizing microscopy modes and is based on the use of a single femtosecond laser and a photonic crystal fiber as sources of the probing light. We show the viability of this technique for mapping of three-dimensional patterns of molecular orientations and show that images obtained in different microscopy modes are consistent with each other. PMID- 20967096 TI - Sub-50 nm patterning by immersion interference lithography using a Littrow prism as a Lloyd's interferometer. AB - We present a simple setup that combines immersion lithography with a Lloyd's mirror interferometer. Aiming for smaller structure sizes, we have replaced the usual Lloyd's interferometer by a triangular Littrow prism with one metal-coated side, which acts as a mirror. Because of the higher refractive index of the prism, the wavelength and, thus, the attainable structure sizes, are decreased significantly. Using a laser with a wavelength of 244nm, we could produce line patterns with a period of less than 100nm and a width of 45nm. The introduced setup retains all the advantages of a Lloyd's mirror interferometer, in particular the flexibility in periodicity. PMID- 20967097 TI - Laser cooling with a single laser beam and a planar diffractor. AB - A planar triplet of diffraction gratings is used to transform a single laser beam into a four-beam tetrahedral magneto-optical trap. This "flat" pyramid diffractor geometry is ideal for future microfabrication. We demonstrate the technique by trapping and subsequently sub-Doppler cooling (87)Rb atoms to 30 MUK. PMID- 20967098 TI - Scintillation of Airy beam arrays in atmospheric turbulence. AB - We investigate the scintillation properties of Airy beam arrays in atmospheric turbulence. By utilizing the "self-bending" propagation property of Airy beams, the constituent beamlets propagate through relatively independent regions of turbulence but still largely overlap at the on-axis detector. Through numeric simulations, it is shown that the scintillation of an Airy beam array is significantly reduced and close to the theoretical minimum. PMID- 20967099 TI - High-energy femtosecond fiber laser at 976 nm. AB - We report on a passively mode-locked fiber laser emitting around 976nm. The self starting mode locking is achieved in an unidirectional ring cavity by means of nonlinear polarization evolution. Stable single-pulse operation is observed for 480mW of average output power. This all-normal dispersion laser generates naturally chirped pulses with 1ps duration. The repetition rate is 40.6MHz, resulting in 12nJ pulse energy. External compression using bulk grating shortens the pulse duration down to 286fs. PMID- 20967100 TI - Athermal performance in high-Q polymer-clad silicon microdisk resonators. AB - We present a method for eliminating the temperature dependence of the resonance wavelength in high-Q silicon-based microdisk resonators by using a polymer cladding with a negative thermo-optic coefficient. Design requirements for athermal performance are derived based on theory and simulation, and their validity is experimentally verified. PMID- 20967101 TI - Analytic solution of flat-top Gaussian and Laguerre-Gaussian laser field components. AB - We generalized the nonparaxial field components of Laguerre-Gaussian and flattened Gaussian beams obtained using the angular spectrum method to include symmetric radial and angular expansions and simplified them using an approximate evaluation of the integral equations for the field components. These field components possess series expressions in orders of a natural expansion parameter, which clarifies the physical interpretation of the series expansion. A connection between Laguerre-Gaussian and flat-top Gaussian profiles is obtained. PMID- 20967102 TI - Wavelength-tunable optical parametric regenerator. AB - We designed a wavelength-tunable optical parametric regenerator, where functions of reamplification, reshaping, and wavelength conversion are incorporated into a highly nonlinear fiber component. The uniform power transfer functions and negative penalties over a 20nm input wavelength range are experimentally demonstrated. PMID- 20967103 TI - Simulations of petawatt-class few-cycle optical-parametric chirped-pulse amplification, including nonlinear refractive index effects. AB - We present three-dimensional simulations of optical-parametric chirped-pulse amplification stages for a few-cycle petawatt-class laser. The simulations take into account the effects of depletion, diffraction, walk-off, quantum noise, and the nonlinear refractive index (n(2)). In the absence of n(2) effects, we show these stages can generate 3.67J pulses supporting 4fs transform-limited pulse durations. Adding the nonlinear refractive index to the simulation, the energy output is reduced by ~11% and the bandwidth narrows by ~129nm, increasing the Fourier limit by ~17.5%. PMID- 20967104 TI - Facet-embedded thin-film III-V edge-emitting lasers integrated with SU-8 waveguides on silicon. AB - A thin-film InGaAs/GaAs edge-emitting single-quantum-well laser has been integrated with a tapered multimode SU-8 waveguide onto an Si substrate. The SU-8 waveguide is passively aligned to the laser using mask-based photolithography, mimicking electrical interconnection in Si complementary metal-oxide semiconductor, and overlaps one facet of the thin-film laser for coupling power from the laser to the waveguide. Injected threshold current densities of 260A/cm(2) are measured with the reduced reflectivity of the embedded laser facet while improving single mode coupling efficiency, which is theoretically simulated to be 77%. PMID- 20967105 TI - Compact chip-scale filter based on curved waveguide Bragg gratings. AB - We propose a method for miniaturization of filters based on curved waveguide Bragg gratings, so that long structures can be packed into a small area on a chip. This eliminates the stitching errors introduced in the fabrication process, which compromise the performance of long Bragg gratings. Our approach relies on cascading curved waveguide Bragg gratings with the same radius of curvature. An analytical model for the analysis of these devices was developed, and a filter based on this model was designed and fabricated in a silicon on insulator platform. The filter had a total length of 920MUm, occupied an area of 190MUm*114MUm, and exhibited a stop band of 1.7nm at 1.55MUm and an extinction ratio larger than 23dB. PMID- 20967106 TI - High-gain fiber, optical-parametric, chirped-pulse amplification of femtosecond pulses at 1 MUm. AB - Fiber-based optical-parametric chirped-pulse amplification is reported at 1MUm in a microstructured fiber in the femtosecond regime. The signal has been highly stretched by an Offner triplet and then amplified with an all-fiber, pulsed-pump, fiber optical-parametric amplifier. More than 30dB gain has been achieved over 8.3nm, and the amplified signal has been recompressed. PMID- 20967107 TI - Generation of correlated photons in hydrogenated amorphous-silicon waveguides. AB - We report the first (to our knowledge) observation of correlated photon emission in hydrogenated amorphous-silicon waveguides. We compare this to photon generation in crystalline silicon waveguides with the same geometry. In particular, we show that amorphous silicon has a higher nonlinearity and competes with crystalline silicon in spite of higher loss. PMID- 20967108 TI - Widely tunable mid-IR difference-frequency generation based on fiber lasers. AB - A wide tuning technique for mid-IR difference-frequency generation (DFG) with uniform grating periodically poled LiNbO(3) (PPLN) is presented. Based on the dispersion property of the PPLN, the quasi-phase matching (QPM) band for the pump can evolve to two separate bands, and the spacing between them can be increased with the decrease of the crystal temperature. Two such separate QPM bands can be used for increasing the idler tuning range when the crystal temperature is set to adapt the pump tuning. With the technique, an idler tuning range of 690nm is experimentally achieved with fiber laser fundamental lights. PMID- 20967109 TI - Dark-field optical coherence microscopy. AB - Dark-field illumination is known to enhance scattering contrast in optical microscopy. We combined this concept with Fourier domain optical coherence microscopy (OCM). The detection and illumination paths are decoupled, and only the scattered light originating from the sample generates the tomogram signal, whereas any specular reflection is highly suppressed. We analyze and discuss this dark-field OCM concept and present its superior imaging quality on live cell samples. PMID- 20967110 TI - Generation of 2.5 MUJ vacuum ultraviolet pulses with sub-50 fs duration by noncollinear four-wave mixing in argon. AB - Generation of sub-50fs vacuum UV pulses with more than 2.5MUJ energy at a 1kHz repetition rate is reported. The pulses at 160nm are produced using noncollinear difference-frequency four-wave mixing between the fundamental and third harmonics of an amplified Ti:sapphire laser in argon. While the pulse duration is maintained by increasing the phase-matching pressure, noncollinear interaction improves the conversion efficiency by 1 order of magnitude in comparison with the previous results in collinear geometry. PMID- 20967111 TI - Extending the detection range of optical vortices by Dammann vortex gratings. AB - We report a 2D static binary phase Dammann vortex grating that combines the features of a conventional vortex grating and a Dammann grating. This grating uniformly distributes energies among the diffraction orders, so the low efficiency problem at higher diffraction orders of conventional vortex gratings is resolved and the detection range of the optical vortices (OVs) is greatly increased. Experimental results of OV detection using a fabricated 5*5 Dammann vortex grating are given, and the topological charge detection range from -12 to +12 is achieved. The potential applications of such gratings include transmitting, receiving, and multiplexing OV beams in optical communication systems. PMID- 20967112 TI - Chaos in the pulse spacing of passive Q-switched all-solid-state lasers. AB - We report the experimental and theoretical verification that, in a diode-pumped Nd:YAG+Cr:YAGQ-switched laser, the instabilities in the pulse spacing ("jitter") are ruled by low-dimensional deterministic chaos. From our experimental time series, we determine the embedding and fractal dimensions of the attractor, as well as the values of the Lyapunov exponents. We also present a simplified theoretical description in terms of a map of the same universality class as the logistic map, which explains the bifurcations' cascade and the period-three window of stability observed. The achieved characterization of the dynamics and its main parameters opens a door to effective ways to reduce the jitter, which is of practical interest, through mechanisms of control of chaos. Conversely, the difficulty in the prediction of the interpulse spacing makes this system attractive for high power, robust FM chaotic laser cryptography in free-space propagation. PMID- 20967113 TI - Plasmonics-based spatially activated light microscopy for super-resolution imaging of molecular fluorescence. AB - In this Letter, we explore plasmonics-based spatially activated light microscopy (PSALM) for sub-diffraction-limited imaging of biomolecules. PSALM is based on the spatially switched activation of local amplified electromagnetic hot spots under multiple light incidence conditions. The hot spots are associated with surface plasmons that are excited and localized by surface nanostructures. The feasibility of the concept was demonstrated by imaging fluorescent nanobeads on a two-dimensional gold nanograting of a 100-nm-wide grating ridge, the size of which is the measure of the imaging resolution. The result confirms the performance of PSALM for imaging nanobeads at a resolution below the conventional diffraction limit. PMID- 20967114 TI - Switching of liquid-crystal devices between reflective and transmissive modes using long-pitch cholesteric liquid crystals. AB - We propose liquid-crystal (LC) devices capable of switching between reflective and transmissive modes using the scattering and transparent states of long-pitch cholesteric LCs (CLCs). Two different device configurations can be realized by changing the location of a CLC layer. Low-power operation without the parallax problem can be achieved using the bistable switching of CLCs. We believe that the proposed devices are potential candidates for highly efficient transflective displays. PMID- 20967115 TI - Analytical solutions of the simplified spherical harmonics equations. AB - We derived analytical solutions of the simplified spherical harmonics equations, an approximation of the radiative transfer equation, for infinitely extended scattering media. The derived equations are simple (sum of exponential functions) and quickly evaluated. We compared the solutions with Monte Carlo simulations in the steady-state and time domains and found much better agreement compared to solutions of the diffusion equation, especially for large absorption coefficients, short time values, and small distances from the source. PMID- 20967116 TI - Ultrafast acoustics in the middle UV range: coherent phonons at higher frequencies and in smaller objects. AB - We show that the propagation of coherent acoustic phonons generated by femtosecond optical excitation can be clearly resolved using a probe laser in the middle UV (MUV) range. The MUV probe is easily produced from a high-repetition rate femtosecond laser and a homemade frequency tripler. We present various experimental results that demonstrate efficient and high frequency detection of acoustic phonons. Thus, we show that the MUV range offers a unique way to reach higher frequencies and probe smaller objects in ultrafast acoustics. PMID- 20967117 TI - Multicrystal, continuous-wave, single-pass second-harmonic generation with 56% efficiency. AB - We report a simple and compact implementation for single-pass second-harmonic generation (SP-SHG) of cw laser radiation, based on a cascaded multicrystal (MC) scheme, that can provide the highest conversion efficiency at any given fundamental power. By deploying a suitable number of identical 30-mm-long MgO:sPPLT crystals in a cascade and a 30W cw Yb-fiber laser at 1064nm as the fundamental source, we demonstrate SP-SHG into the green with a conversion efficiency as high as 56% in the low-power as well as the high-power regime, providing 5.6W of green output for 10W and 13W of green output for 25.1W of input pump power. The MC scheme permits substantial increase in cw SP-SHG efficiency compared to the conventional single-crystal scheme without compromising performance with regard to power stability and beam quality. PMID- 20967118 TI - Fiber optical parametric oscillator for sub-50 fs pulse generation: optimization of fiber length. AB - We demonstrate generation of 48fs pulses with linear chirp using a short (27mm) fiber optical parametric oscillator (FOPO), which is synchronously pumped by a mode-locked ytterbium-doped fiber laser. We also study the pulse quality for both the short- and long-wavelength operation where the fiber length inside of the oscillator varies from 17 to 61mm. The optimal pulse duration is observed only in the short-wavelength operation. Furthermore, we model the FOPO system as a single pass parametric amplifier including dispersive pulse broadening and walk-off between the pump and output. The optimal condition arises from the minimization of the walk-off and dispersion. When walk-off is large, the parametric amplification process is most efficient over some reduced effective fiber length, leading to an upper limit in the amount of the observed pulse broadening. PMID- 20967119 TI - Resolution improvement of digital holographic images based on angular multiplexing with incoherent beams in orthogonal polarization states. AB - We present a method to improve the resolution of digital holographic images based on angular multiplexing with incoherent beams from two orthogonal polarized components of natural light. Two incoherent subholograms are synchronously recorded by two pairs of incoherent object waves and reference waves with orthogonal polarization states, in which the object is illuminated by two incoherent beams from different directions. The increase in resolution is obtained through phase correction and superposition of two reconstructed object waves. Experimental results show that the resolution and quality of the reconstructed image can be effectively improved. PMID- 20967120 TI - Complete characterization of quantum-limited timing jitter in passively mode locked fiber lasers. AB - We characterize the timing jitter of passively mode-locked, femtosecond, erbium fiber lasers with unprecedented resolution, enabling the observation of quantum origin timing jitter up to the Nyquist frequency. For a pair of nearly identical 79.4MHz dispersion-managed lasers with an output pulse energy of 450pJ, the high frequency jitter was found to be 2.6fs [10kHz, 39.7MHz]. The results agree well with theoretical noise models over more than three decades, extending to the Nyquist frequency. It is also found that unexpected noise may occur if care is not taken in optimizing the mode-locked state. PMID- 20967122 TI - Fringe-pattern denoising based on discrete topological analysis. AB - We present an effective way to solve the denoising problem of fringe patterns in optics interferometry. The proposed method is based on the topological analysis of an appropriate cost function. To overcome the blurring drawback of the linear diffusion approach, the linear diffusion coefficient at each edge is perturbed successively. The total variation of a discrete cost function can be taken as an indicator function to pick out the most suitable edges of pixels at which the diffusion coefficients are to be perturbed. Then, a filtered image can be obtained by using selected diffusion coefficients associated to the edges. We demonstrate the performance of the proposed method via application to numerically simulated and experimentally obtained fringe patterns. PMID- 20967123 TI - Raman fiber laser pumped by a semiconductor disk laser and mode locked by a semiconductor saturable absorber mirror. AB - A 1.6um mode-locked Raman fiber laser pumped by a 1480nm semiconductor disk laser is demonstrated. Watt-level core pumping of the single-mode fiber Raman lasers with low-noise disk lasers together with semiconductor saturable absorber mirror mode locking represents a highly practical solution for short-pulse operation. PMID- 20967124 TI - Coupled-mode approach to surface plasmon polaritons in nonlinear periodic structures. AB - We present a coupled-mode theory describing light propagation in an array of nonlinear plasmonic waveguides. Our model predicts a two-band dependence of the propagation constant versus transverse quasi-momentum and existence of discrete and gap plasmon solitons. PMID- 20967125 TI - Universal description of geometric phases in higher-order optical modes bearing orbital angular momentum. AB - We study geometric phases that arise from (cyclic) transformations of the transverse spatial structure of paraxial optical modes. Our approach involves bosonic ladder operators that, in the spirit of the quantum-mechanical harmonic oscillator, generate sets of transverse optical modes. It applies to modes of all orders in a very natural way and provides a universal geometric interpretation of the phase shifts acquired by nonastigmatic modes under typical experimental conditions. PMID- 20967126 TI - Odorant receptor (Or) genes: polymorphism and divergence in the D. melanogaster and D. pseudoobscura lineages. AB - BACKGROUND: In insects, like in most invertebrates, olfaction is the principal sensory modality, which provides animals with essential information for survival and reproduction. Odorant receptors are involved in this response, mediating interactions between an individual and its environment, as well as between individuals of the same or different species. The adaptive importance of odorant receptors renders them good candidates for having their variation shaped by natural selection. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed nucleotide variation in a subset of eight Or genes located on the 3L chromosomal arm of Drosophila melanogaster in a derived population of this species and also in a population of Drosophila pseudoobscura. Some heterogeneity in the silent polymorphism to divergence ratio was detected in the D. melanogaster/D. simulans comparison, with a single gene (Or67b) contributing ~37% to the test statistic. However, no other signals of a very recent selective event were detected at this gene. In contrast, at the speciation timescale, the MK test uncovered the footprint of positive selection driving the evolution of two of the encoded proteins in both D. melanogaster--OR65c and OR67a--and D. pseudoobscura--OR65b1 and OR67c. CONCLUSIONS: The powerful polymorphism/divergence approach provided evidence for adaptive evolution at a rather high proportion of the Or genes studied after relatively recent speciation events. It did not provide, however, clear evidence for very recent selective events in either D. melanogaster or D. pseudoobscura. PMID- 20967127 TI - Progranulin is neurotrophic in vivo and protects against a mutant TDP-43 induced axonopathy. AB - Mislocalization, aberrant processing and aggregation of TAR DNA-binding protein 43 (TDP-43) is found in the neurons affected by two related diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal lobe dementia (FTLD). These TDP-43 abnormalities are seen when TDP-43 is mutated, such as in familial ALS, but also in FTLD, caused by null mutations in the progranulin gene. They are also found in many patients with sporadic ALS and FTLD, conditions in which only wild type TDP 43 is present. The common pathological hallmarks and symptomatic cross over between the two diseases suggest that TDP-43 and progranulin may be mechanistically linked. In this study we aimed to address this link by establishing whether overexpression of mutant TDP-43 or knock-down of progranulin in zebrafish embryos results in motor neuron phenotypes and whether human progranulin is neuroprotective against such phenotypes. Mutant TDP-43 (A315T mutation) induced a motor axonopathy characterized by short axonal outgrowth and aberrant branching, similar, but more severe, than that induced by mutant SOD1. Knockdown of the two zebrafish progranulin genes, grna and grnb, produced a substantial decrease in axonal length, with knockdown of grna alone producing a greater decrease in axonal length than grnb. Progranulin overexpression rescued the axonopathy induced by progranulin knockdown. Interestingly, progranulin also rescued the mutant TDP-43 induced axonopathy, whilst it failed to affect the mutant SOD1-induced phenotype. TDP-43 was found to be nuclear in all conditions described. The findings described here demonstrate that progranulin is neuroprotective in vivo and may have therapeutic potential for at least some forms of motor neuron degeneration. PMID- 20967128 TI - Machine learning methods for prediction of CDK-inhibitors. AB - Progression through the cell cycle involves the coordinated activities of a suite of cyclin/cyclin-dependent kinase (CDK) complexes. The activities of the complexes are regulated by CDK inhibitors (CDKIs). Apart from its role as cell cycle regulators, CDKIs are involved in apoptosis, transcriptional regulation, cell fate determination, cell migration and cytoskeletal dynamics. As the complexes perform crucial and diverse functions, these are important drug targets for tumour and stem cell therapeutic interventions. However, CDKIs are represented by proteins with considerable sequence heterogeneity and may fail to be identified by simple similarity search methods. In this work we have evaluated and developed machine learning methods for identification of CDKIs. We used different compositional features and evolutionary information in the form of PSSMs, from CDKIs and non-CDKIs for generating SVM and ANN classifiers. In the first stage, both the ANN and SVM models were evaluated using Leave-One-Out Cross Validation and in the second stage these were tested on independent data sets. The PSSM-based SVM model emerged as the best classifier in both the stages and is publicly available through a user-friendly web interface at http://bioinfo.icgeb.res.in/cdkipred. PMID- 20967129 TI - Platelet serotonin level predicts survival in amyotrophic lateral sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease involving upper and lower motor neurons loss. Clinical features are highly variable among patients and there are currently few known disease-modifying factors underlying this heterogeneity. Serotonin is involved in a range of functions altered in ALS, including motor neuron excitability and energy metabolism. However, whether serotoninergic activity represents a disease modifier of ALS natural history remains unknown. METHODOLOGY: Platelet and plasma unconjugated concentrations of serotonin and plasma 5-HIAA, the major serotonin metabolite, levels were measured using HPLC with coulometric detection in a cohort of 85 patients with ALS all followed-up until death and compared to a control group of 29 subjects. PRINCIPAL FINDINGS: Platelet serotonin levels were significantly decreased in ALS patients. Platelet serotonin levels did not correlate with disease duration but were positively correlated with survival of the patients. Univariate Cox model analysis showed a 57% decreased risk of death for patients with platelet serotonin levels in the normal range relative to patients with abnormally low platelet serotonin (p = 0.0195). This protective effect remained significant after adjustment with age, gender or site of onset in multivariate analysis. Plasma unconjugated serotonin and 5-HIAA levels were unchanged in ALS patients compared to controls and did not correlate with clinical parameters. CONCLUSIONS/SIGNIFICANCE: The positive correlation between platelet serotonin levels and survival strongly suggests that serotonin influences the course of ALS disease. PMID- 20967130 TI - Immunomodulation targeting abnormal protein conformation reduces pathology in a mouse model of Alzheimer's disease. AB - Many neurodegenerative diseases are characterized by the conformational change of normal self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high beta-sheet content and resistance to degradation. The most common is Alzheimer's disease (AD) where the normal soluble amyloid beta (sAbeta) peptide is converted into highly toxic oligomeric Abeta and fibrillar Abeta that deposits as neuritic plaques and congophilic angiopathy. Currently, there is no highly effective treatment for AD, but immunotherapy is emerging as a potential disease modifying intervention. A major problem with most active and passive immunization approaches for AD is that both the normal sAbeta and pathogenic forms are equally targeted with the potential of autoimmune inflammation. In order to avoid this pitfall, we have developed a novel immunomodulatory method that specifically targets the pathological conformations, by immunizing with polymerized British amyloidosis (pABri) related peptide which has no sequence homology to Abeta or other human proteins. We show that the pABri peptide through conformational mimicry induces a humoral immune response not only to the toxic Abeta in APP/PS1 AD transgenic mice but also to paired helical filaments as shown on AD human tissue samples. Treated APP/PS1 mice had a cognitive benefit compared to controls (p<0.0001), associated with a reduction in the amyloid burden (p = 0.0001) and Abeta40/42 levels, as well as reduced Abeta oligomer levels. This type of immunomodulation has the potential to be a universal beta-sheet disrupter, which could be useful for the prevention or treatment of a wide range of neurodegenerative diseases. PMID- 20967132 TI - A Micro-fabricated Hydrogen Storage Module with Sub-atmospheric Activation and Durability in Air Exposure. AB - The objective of this work was to develop a hydrogen storage module for onboard electrical power sources suitable for use in micro power systems and micro electro-mechanical systems (MEMS). Hydrogen storage materials were developed as thin-film inks to be compatible with an integrated manufacturing process. Important design aspects were (a) ready activation at sub-atmospheric hydrogen pressure and room temperature and (b) durability, i.e. capable of hundreds of absorption/desorption cycles and resistance to deactivation on exposure to air. Inks with palladium-treated intermetallic hydrogen storage alloys were developed and are shown here to be compatible with a thin-film micro-fabrication process. These hydrogen storage modules absorb hydrogen readily at atmospheric pressure, and the absorption/desorption rates remained fast even after the ink was exposed to air for 47 weeks. PMID- 20967133 TI - Older Adults Talk Technology: Technology Usage and Attitudes. AB - Older adults (n = 113) participated in focus groups discussing their use of and attitudes about technology in the context of their home, work, and healthcare. Participants reported using a wide variety of technology items, particularly in their homes. Positive attitudes (i.e., likes) outnumbered negative attitudes (i.e., dislikes), suggesting that older adults perceive the benefits of technology use to outweigh the costs of such use. Positive attitudes were most frequently related to how the technology supported activities, enhanced convenience, and contained useful features. Negative attitudes were most frequently associated with technology creating inconveniences, unhelpful features, as well as security and reliability concerns. Given that older adults reported more positive than negative attitudes about the technologies they use, these results contradict stereotypes that older adults are afraid or unwilling to use technology. These findings also highlight the importance of perceived benefits of use and ease of use for models of technology acceptance. Emphasizing the benefits of technology in education and training programs may increase future technology adoption. PMID- 20967131 TI - The role of microglia in synaptic stripping and synaptic degeneration: a revised perspective. AB - Chronic neurodegenerative diseases of the CNS (central nervous system) are characterized by the loss of neurons. There is, however, growing evidence to show that an early stage of this process involves degeneration of presynaptic terminals prior to the loss of the cell body. Synaptic plasticity in CNS pathology has been associated with microglia and the phenomenon of synaptic stripping. We review here the evidence for the involvement of microglia in synaptic stripping and synapse degeneration and we conclude that this is a case of guilt by association. In disease models of chronic neurodegeneration, there is no evidence that microglia play an active role in either synaptic stripping or synapse degeneration, but the degeneration of the synapse and the envelopment of a degenerating terminal appears to be a neuron autonomous event. We highlight here some of the gaps in our understanding of synapse degeneration in chronic neurodegenerative disease. PMID- 20967134 TI - Influenza Transmission in Preschools: Modulation by contact landscapes and interventions. AB - Epidemiologic data suggest that schools and daycare facilities likely play a major role in the dissemination of influenza. Pathogen transmission within such small, inhomogenously mixed populations is difficult to model using traditional approaches. We developed simulation based mathematical tool to investigate the effects of social contact networks on pathogen dissemination in a setting analogous to a daycare center or grade school. Here we show that interventions that decrease mixing within child care facilities, including limiting the size of social clusters, reducing the contact frequency between social clusters, and eliminating large gatherings, could diminish pathogen dissemination. Moreover, these measures may amplify the effectiveness of vaccination or antiviral prophylaxis, even if the vaccine is not uniformly effective or antiviral compliance is incomplete. Similar considerations should apply to other small, imperfectly mixed populations, such as offices and schools. PMID- 20967135 TI - Developing Effective P-20 Partnerships to Benefit Chicano/Latino Students and Families. AB - To consider how interdisciplinary P-20 partnerships increase college-going rates among Chicano/Latino youth, the authors highlight evidence from the Educational Partnership Center (EPC) at the University of California, Santa Cruz, a P-20 partnership that builds academic achievement and college and career pathways. Three elements advance EPC effectiveness: collaborative governance structures sustaining shared vision, mission, and goals; innovating with data-driven decision-making; and complementary theories aligning goals from childhood through college to careers. Three studies, guided by these theories, illuminate such effectiveness. PMID- 20967136 TI - Strategies Used by Gay and Bisexual Young Men to Cope with Heterosexism. AB - Although the pervasiveness of heterosexism in the lives of gay and bisexual youth is well established, little is known about the strategies these youth use to cope with stigma and discrimination based on their sexual minority status. In this qualitative study, the authors present findings and implications for clinical practice based on interviews with 43 gay and bisexual young men. Respondents' coping strategies are discussed in relation to current theory and research on coping with stigma, as well as the emerging field of emotion regulation. The narratives from the current study suggest that the emotion regulation paradigm is well suited to understanding the functions of strategies for coping with heterosexism and similar types of stigma. PMID- 20967138 TI - Decontamination of Bacillus anthracis Spores: Evaluation of Various Disinfectants. AB - The present study compares the efficacy of various disinfectants against Bacillus anthracis spores. While Bleach Rite((r)) and 10% bleach reduce spore numbers by 90% within 10 minutes, a long contact time is required for complete disinfection. By contrast, although SporGon((r)) did not initially reduce the number of spores as quickly as Bleach Rite or 10% bleach, shorter contact times were required for complete eradication of viable spores. PMID- 20967137 TI - Kinetics of DNA and RNA Hybridization in Serum and Serum-SDS. AB - Cancer is recognized as a serious health challenge both in the United States and throughout the world. While early detection and diagnosis of cancer leads to decreased mortality rates, current screening methods require significant time and costly equipment. Recently, increased levels of certain micro-ribonucleic acids (miRNAs) in the blood have been linked to the presence of cancer. While blood based biomarkers have been used for years in cancer detection, studies analyzing trace amounts of miRNAs in blood and serum samples are just beginning. Recent developments in deoxyribonucleic acid (DNA) nanotechnology and DNA computing have shown that it is possible to construct nucleic-acid-based chemical networks that accept miRNAs as inputs, perform Boolean logic functions on those inputs, and generate as an output a large number of DNA strands that can readily be detected. Since miRNAs occur in blood in low abundance, these networks would allow for amplification without using polymerase chain reaction. In this study, we report initial progress in the development of a DNA-based cross-catalytic network engineered to amplify specific cancer-related miRNAs. Subcomponents of the DNA network were tested individually, and their operation in serum, as well as a mixture of serum with sodium dodecyl sulfate, is demonstrated. Preliminary simulations of the full cross-catalytic network indicate successful operation. PMID- 20967139 TI - To be an immigrant and a patient in Sweden: A study with an individualised perspective. AB - The aim is to describe how experiences of being an immigrant can influence the situation when becoming a patient in Swedish health care. A hermeneutic approach was used. Sixteen persons born in non-Nordic countries were interviewed. The data was analysed with an empirical hermeneutical method. The findings indicate that positive experiences (i.e., establishing oneself in a new home country) enhance the possibilities of taking part in caring situations and vice versa. Hence, there is a need for individually adapted care that takes one's whole life situation into consideration. Consequently, it is suggested that the concept, "cultural competence" merely serves the purpose of illuminating caregivers' need for categorisation. It does not illuminate individual needs in a caring situation. PMID- 20967140 TI - Feeling confident in burdensome yet enriching care: Community nurses describe the care of patients with hard-to-heal wounds. AB - Treating patients with hard-to-heal wounds is a complex task that requires a holistic view. Therefore this study focuses on the nurse's perspective with the aim on describing how community nurses experience the phenomenon the care of patients with hard-to-heal wounds. The method used was a reflective lifeworld approach. Seven qualitative interviews with community nurses were conducted. The findings show a tension between enriching and burdensome care. In this tension, the nurses try to find energy to reach harmony in their work through reflection, acceptance, and distance. This is further described by the constituents: "taking responsibility," "showing respect for the whole person," "being confident in order to offer confidence," "seeing time and place as important." The discussion highlights the importance for a nurse to find how to give ideal care in one's duty but not beyond it. As a consequence the concept "compliance" needs to be challenged in order to promote confidence and mutual trust between nurses and patients. Confidence can be seen as a key, both for nurses and patients, and is dependent on good inter-professional cooperation, competence, and closure. PMID- 20967142 TI - Clinical implications of ambulatory and home blood pressure monitoring. AB - Because blood pressure (BP) is an ever changing hemodynamic phenomenon, a BP value, once measured at a physician's office (Office BP), is often unrepresentative of an individual's true BP status. Both ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM) provide more accurate and reproducible estimate of BP, and produce stronger predictive ability for cardiovascular outcome than conventional office BP. Two BP measuring techniques, ABPM and HBPM have been widely in clinical use for the detection and management of hypertension. However, they have different advantages and limitations in practice. At present, it has become crucial to understand the characteristics and clinical implications of these BP measuring techniques for those responsible for the care of hypertensive patients. PMID- 20967141 TI - Health inequalities among older men and women in Africa and Asia: evidence from eight Health and Demographic Surveillance System sites in the INDEPTH WHO-SAGE Study. AB - BACKGROUND: Declining rates of fertility and mortality are driving demographic transition in all regions of the world, leading to global population ageing and consequently changing patterns of global morbidity and mortality. Understanding sex-related health differences, recognising groups at risk of poor health and identifying determinants of poor health are therefore very important for both improving health trajectories and planning for the health needs of ageing populations. OBJECTIVES: To determine the extent to which demographic and socio economic factors impact upon measures of health in older populations in Africa and Asia; to examine sex differences in health and further explain how these differences can be attributed to demographic and socio-economic determinants. METHODS: A total of 46,269 individuals aged 50 years and over in eight Health and Demographic Surveillance System (HDSS) sites within the INDEPTH Network were studied during 2006-2007 using an abbreviated version of the WHO Study on global AGEing and adult health (SAGE) Wave I instrument. The survey data were then linked to longitudinal HDSS background information. A health score was calculated based on self-reported health derived from eight health domains. Multivariable regression and post-regression decomposition provide ways of measuring and explaining the health score gap between men and women. RESULTS: Older men have better self-reported health than older women. Differences in household socio economic levels, age, education levels, marital status and living arrangements explained from about 82% and 71% of the gaps in health score observed between men and women in South Africa and Kenya, respectively, to almost nothing in Bangladesh. Different health domains contributed differently to the overall health scores for men and women in each country. CONCLUSION: This study confirmed the existence of sex differences in self-reported health in low- and middle income countries even after adjustments for differences in demographic and socio economic factors. A decomposition analysis suggested that sex differences in health differed across the HDSS sites, with the greatest level of inequality found in Bangladesh. The analysis showed considerable variation in how differences in socio-demographic and economic characteristics explained the gaps in self-reported health observed between older men and women in African and Asian settings. The overall health score was a robust indicator of health, with two domains, pain and sleep/energy, contributing consistently across the HDSS sites. Further studies are warranted to understand other significant individual and contextual determinants to which these sex differences in health can be attributed. This will lay a foundation for a more evidence-based approach to resource allocation, and to developing health promotion programmes for older men and women in these settings. PMID- 20967143 TI - Coronary computed tomography angiography for screening of an asymptomatic population: too much or too soon? PMID- 20967144 TI - Subclinical coronary artery disease as detected by coronary computed tomography angiography in an asymptomatic population. AB - BACKGROUND AND OBJECTIVES: Primary prevention of coronary artery disease (CAD) has become a public health issue, according to increasing awareness of the substantial risks posed by asymptomatic atherosclerosis. The aims of this study were to determine the prevalence and characteristics of subclinical CAD using coronary computed tomography angiography (CCTA), and to evaluate the role of this advanced technology in identifying subclinical CAD in asymptomatic Korean individuals, compared with conventional risk stratification. SUBJECTS AND METHODS: We enrolled 4,320 consecutive asymptomatic individuals (61% males, aged 50+/-9 years), who underwent 64-slice CCTA during a routine health check. RESULTS: Coronary artery plaques were present in 1,053 (24%) individuals. Significant stenosis (diameter stenosis >=50%) was identified in 139 (3%) subjects, and most of the significant lesions (87%) were located in the left anterior descending artery. CCTA revealed noncalcified plaques in 5% of subjects with a coronary calcium score of zero (n=801). Although 25% (n=10) of those with noncalcified plaque had significant stenosis, most of them (90%) were classified into low- or moderate-risk groups according to National Cholesterol Education Program risk stratification guidelines. In a young population (age <=55 years for males, <=65 years for females), 30% of subjects with significant stenosis were classified into a low-risk group and 60% had low (0 to 100) calcium scores. CONCLUSION: Subclinical CAD in asymptomatic individuals cannot be ignored for its considerable prevalence, CCTA may be helpful in identifying at-risk subclinical CAD in a noninvasive manner, especially in the young and traditionally low-risk population. PMID- 20967145 TI - A transthoracic echocardiographic follow-up study after catheter ablation of atrial fibrillation: can we detect pulmonary vein stenosis by transthoracic echocardiography? AB - BACKGROUND AND OBJECTIVES: While pulmonary vein isolation (PVI) is an effective curative procedure for patients with atrial fibrillation (AF), pulmonary vein (PV) stenosis is a potential complication which may lead to symptoms that are often unrecognized. The aim of this study was to compare differences between ablation sites in pulmonary venous flow (PVF) measured by transthoracic Doppler echocardiography (TTE) before and after PVI. SUBJECTS AND METHODS: ONE HUNDRED FIVE PATIENTS (M : F=64 : 41; mean age 56+/-10 years) with paroxysmal AF (n=78) or chronic, persistent AF (n=27) were enrolled. PVI strategies consisted of ostial ablation (n=75; OA group) and antral ablation using an electroanatomic mapping system (n=30; AA group). The ostial diameter was estimated by magnetic resonance imaging (MRI) in patients with PVF >=110 cm/sec by TTE after PVI. RESULTS: No patient complained of PV stenosis-related symptoms. Changes in mean peak right PV systolic (-6.7+/-28.1 vs. 10.9+/-25.9 cm/sec, p=0.038) and diastolic (-4.1+/-17.0 vs. 9.9+/-25.9 cm/sec, p=0.021) flow velocities were lower in the AA group than in the OA group. Although the change in mean peak systolic flow velocity of the left PV before and after PVI in the AA group was significantly lower than the change in the OA group (-13.4+/-25.1 vs. 9.2+/-22.3 cm/sec, p=0.016), there was no difference in peak diastolic flow velocity. Two patients in the OA group had high PVF velocities (118 cm/sec and 133 cm/sec) on TTE, and their maximum PV stenoses measured by MRI were 62.5% and 50.0%, respectively. CONCLUSION: PV stenosis after PVI could be detected by TTE, and PVI by antral ablation using an electroanatomic mapping system might be safer and more useful for the prevention of PV stenosis. PMID- 20967146 TI - Right ventricular remodeling determines tricuspid valve geometry and the severity of functional tricuspid regurgitation: a real-time 3-dimensional echocardiography study. AB - BACKGROUND AND OBJECTIVES: Right ventricle (RV) remodeling can determine tricuspid valve (TV) geometry and the severity of functional tricuspid regurgitation (TR). SUBJECTS AND METHODS: In 53 patients with various degrees of functional TR and in sinus rhythm, RV and TV geometries were analyzed using real time 3-dimensional echocardiography, including tenting angles of 3 leaflets, septal-lateral and antero-posterior tricuspid annulus diameters and inlet RV dimensions, mid-RV septal-lateral dimension, and the distance between annulus and apex. A mid-systole frame when the TV tenting is smallest was selected for the analysis. RV end-diastolic and end-systolic volumes were measured. The severity of functional TR was determined by distal jet area. RESULTS: TR distal jet area was mainly determined by septal-lateral annulus diameter (p<0.001) RV inlet dimension (p=0.015), RV end-systolic volume (p=0.010), septal (p=0.019), and anterior leaflet tenting angles (p=0.045) by multiple stepwise linear regression analysis. Leaflet tenting angles were mainly determined by septal-lateral RV inlet dimension. Septal-lateral annulus diameter was determined by septal-lateral RV inlet dimension (p<0.001) and mid RV dimension (p=0.033), whereas antero posterior annulus diameter was determined by antero-posterior RV inlet dimension (p<0.001). CONCLUSION: Functional TR severity is determined by septal-lateral annulus and RV dilation, and tenting of septal and anterior leaflets. TV leaflet tenting is mainly determined by septal-lateral RV inlet dilation, and tricuspid annulus dilation is closely linked with inlet RV dilation. PMID- 20967147 TI - Exercise training improves age-related myocardial metabolic derangement: proton magnetic resonance spectroscopy study in the rat model. AB - BACKGROUND AND OBJECTIVES: The objective of this study was to determine whether long-term exercise training will improve age-related cardiac metabolic derangement using proton magnetic resonance (MR) spectroscopy. MATERIALS AND METHODS: Young and old male Fischer 344 rats were assigned to sedentary controls groups {young control (YC) group-3 months of age: YC, n=10; old control (OC) group-22 months of age: OC, n=10}, and an exercise training group (OT, n=5). After 12-week of treadmill exercise training, MR spectroscopy at 4.7 T was performed to assess myocardial energy metabolism: measurements of myocardial creatine-to-water ratio (Scr/Sw) were performed using the XWIN-NMR software. RESULTS: Exercise capacity was 14.7 minutes greater in OT than that in OC (20.1+/ 1.9 minutes in OT, 5.4+/-2.3 minutes in OC; p<0.001). The 12-week exercise training rendered the old rats a maximum exercise capacity matching that of untrained YC rats (17.9+/-1.5 minutes in YC, 20.1+/-1.9 minutes in OT; p>0.05). The creatine-to-water ratios in the interventricular septa of YC did not differ significantly from that of OT (0.00131+/-0.00025 vs. 0.00127+/-0.00031; p=0.37). However, OC showed significant reduction in creatine-to-water ratio compared to OT (0.00096+/-0.00025 vs. 0.00127+/-0.00031; p<0.001). Mean total creatine concentrations in the myocardium were similar between YC and OT (13.3+/-3.6 vs. 11.5+/-4.1 mmol/kg wet weight; p=0.29). In contrast, the mean total creatine concentration of OC was significantly reduced compared to OT (6.8+/-3.2 vs. 11.5+/-4.1 mmol/kg wet weight; p=0.03). CONCLUSION: Our findings suggest that long-term exercise training in old rats induced prevention of age-related deterioration in myocardial metabolism. PMID- 20967148 TI - Gene expression of endothelin-1 and endothelin receptor a on monocrotaline induced pulmonary hypertension in rats after bosentan treatment. AB - BACKGROUND AND OBJECTIVES: Endothelin (ET)-1, a potent endothelium-derived vasoconstrictor peptide, has a potential pathophysiologic role in pulmonary hypertension. Bosentan, a dual ET receptor (ET(A)/ET(B)) antagonist, is efficacious in treatment of pulmonary hypertension. The objectives of this study were to investigate the expression of ET-1 and ET receptor A (ERA) genes and to evaluate the effect of bosentan in monocrotaline (MCT)-induced pulmonary hypertension. MATERIALS AND METHODS: Four-week-old male Sprague-Dawley rats were treated as follows: control (n=36), subcutaneous (sc) injection of saline; MCT (n=36), sc injection of MCT (60 mg/kg); and bosentan (n=36), sc injection of MCT (60 mg/kg) plus 25 mg/kg/day bosentan orally. RESULTS: Serum ET-1 concentrations in the MCT group were higher than the control group on day 28 and 42. Quantitative analysis of peripheral pulmonary arteries revealed that the increase in medial wall thickness after MCT injection was significantly attenuated in the bosentan group on day 28 and 42. In addition, the increase in the number of intra acinar muscular arteries after MCT injection was reduced by bosentan on day 14, 28 and 42. The levels of ET-1 and ERA gene expression were significantly increased in the MCT group compared with control group on day 5, and bosentan decreased the expression of ET-1 on day 5. CONCLUSION: ET-1 contributes to the progression of cardiopulmonary pathology in rats with MCT-induced pulmonary hypertension. Administration of bosentan reduced ET-1 gene expression in MCT induced pulmonary hypertension in rats. PMID- 20967149 TI - An extremely rare variety of anomalous coronary artery: right coronary artery originating from the distal left circumflex artery. AB - A single coronary artery (SCA) is a rare congenital anomaly of the coronary circulation, which is often associated with myocardial ischemia and other congenital cardiac anomalies. A 77-year-old woman visited our hospital complaining of typical chest pain. Coronary angiography revealed an isolated SCA. The right coronary artery did not originate from the aorta, but instead emerged from the distal left circumflex artery, with significant stenosis at the proximal portion of the left anterior descending artery. A stent was successfully implanted at the culprit lesion. There was no perfusion defect detected by a cardiac SPECT study. PMID- 20967150 TI - Long journey of sclerosant from the esophagus to the right atrium. AB - A 34-year-old man, who had been treated with an endoscopic injection of a mixture of n-butyl-2-cyanoacrylate (Histoacryl) and Lipiodol for control of variceal bleeding 6 months previously, presented with an intracardiac mass in the right atrium (RA). Two-dimensional echocardiography revealed an intracardiac mass in the RA that appeared to extend from the inferior vena cava. The origin of the sclerosant was traced by computed tomography (CT). This is a very rare case in which the sclerosant migration route was demonstrated by CT scan. The findings of this case suggest that the systemic migration of sclerosant into an intracardiac chamber should be considered in patients with an intracardiac mass, especially with a history of previous sclerotherapy for variceal bleeding. PMID- 20967151 TI - Mechanical circulatory support to control medically intractable arrhythmias in pediatric patients after cardiac surgery. AB - Postoperative intractable arrhythmia can result in high morbidity and mortality. This report describes our experiences using mechanical circulatory support (MCS) to control medically intractable arrhythmias in three pediatric patients with congenital heart disease (CHD), after palliative or total corrective open-heart surgery. PMID- 20967152 TI - A case of guide wire fracture with remnant filaments in the left anterior descending coronary artery and aorta. AB - Guide wire fractures during percutaneous coronary intervention (PCI) are very rare, but when they do occur they may lead to life-threatening complications, such as embolization, thrombus formation and perforation. In cases when percutaneous retrieval has failed, surgical extraction of the remnant fragments is recommended. We present a case of remnant guide wire filaments that remained in place without complications, over a one-year clinical follow up period. PMID- 20967154 TI - The effect of high-dose valsartan on left ventricular function following primary percutaneous coronary intervention. PMID- 20967153 TI - Evaluation of Cardiac Function by Transthoracic Echocardiography in Subjects with ST-Segment Elevation Myocardial Infarction Following Primary Percutaneous Coronary Intervention according to Valsartan Dose: The Valsartan One Center Trial. AB - BACKGROUND: The aim of this study was to evaluate the mid-term changes in cardiac function by transthoracic echocardiogram (TTE) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) according to valsartan dose. METHODS: Between April 2006 and February 2009, 78 subjects (mean age: 57 +/- 12 years, M : F = 74 : 4) with STEMI who underwent primary PCI were enrolled. Fifty three patients received low dose valsartan (40 or 80 mg) and 25 patients received high dose valsartan (160 or 320 mg). Follow-up TTE was done approximately 2 years later. We evaluated the changes in left ventricular (LV) function between initial and final TTE after primary PCI and compared the changes between low and high dose valsartan group. RESULTS: The mean follow-up TTE duration was 24 +/- 8 months. Deceleration time (188.6 +/- 56.3 msec vs. 221.5 +/- 71.3 msec, p = 0.01), E/e' (12.24 +/- 5.2 vs. 10.1 +/- 4.9, p = 0.002), ejection fraction (52.7 +/- 8% vs. 55.2 +/- 8.4%, p < 0.01), and wall motion score index (1.45 +/- 0.30 vs. 1.33 +/- 0.32, p < 0.01) showed significant changes during the follow-up period. Wall motion improvement in injured myocardial segments was more frequently observed in the high-dose valsartan group compared to the low-dose group [18/25 (72%) vs. 24/53 (43.7%), p = 0.03]. There was no significant difference in the changes in cardiac dimensions and function between the low and high dose valsartan group. CONCLUSION: In patients with STEMI who undergoing primary PCI, high-dose valsartan treatment may be more helpful than low-dose in improving wall motion in the injured myocardium. PMID- 20967155 TI - Relation of anemia to echocardiographically estimated left ventricular filling pressure in hypertensive patients over 50 year-old. AB - BACKGROUND: Anemia is associated with worse long term outcomes in heart failure. However, there is little evidence on the effect of low hemoglobin level to the left ventricular (LV) structure and diastolic function in hypertensive patients. This study assessed the relationship of hemoglobin level to LV filling pressure in elderly hypertensive patients. METHODS: From January 2005 to January 2009, 200 newly diagnosed hypertensive patients over 50 years old (mean age 60 +/- 6 years, 116 women) were analyzed. The clinical parameters and comprehensive echocardiographic data were obtained. The patients with and without anemia were compared. RESULTS: There were significant differences between the anemic and non anemic groups in the LV mass index (115.27 +/- 34.95 vs. 103.75 +/- 28.21 g/m(2)), left atrial (LA) volume index (29.31 +/- 10.74 vs. 24.99 +/- 7.43 mL/m(2)), and E/E' (11.92 +/- 4.34 vs. 9.37 +/- 2.51). Chronic renal failure was more prevalent in anemic group. On multivariate logistic analysis, anemia was significantly correlated with high LV filling pressure, reflected by E/E', even after controlling for LV mass index and LA volume index. Furthermore, E/E' was significantly correlated with the hemoglobin level (R(2) = 0.093, p < 0.001). CONCLUSION: In newly-diagnosed hypertensive patients over 50 years old, the presence of anemia was significantly associated with elevated LV filling pressure and LV structural changes. And the hemoglobin level was negatively correlated with noninvasively estimated LV filling pressure. PMID- 20967156 TI - Targeted ultrasound imaging of apoptosis with annexin a5 microbubbles in acute Doxorubicin-induced cardiotoxicity. AB - BACKGROUND: The aim of this study was to assess the feasibility of targeted ultrasound imaging on apoptosis with annexin A5 microbubbles (A5MB) in acute doxorubicin-induced cardiotoxicity. METHODS: Avidinated and octafluoropropan filled phospholipid microbubbles were conjugated with biotinylated annexin A5. To confirm the specific binding of A5MB, flow cytometry was performed with hydrogen peroxide induced apoptosis in rat aorta smooth muscle cells incubated with fluorescein-5-isothiocyanate (FITC) labeled annexin A5 and A5MB. Adult male rats were injected intraperitoneally with 5 mg/kg doxorubicin weekly for 3 weeks (n = 5). Control rats were injected with normal saline (n = 5). At 24 hours after the final treatment, triggering imaging was performed 15 min after an intravenous bolus injection of A5MB for washout of freely circulating microbubbles. After echocardiography, the heart was isolated for histological detection of apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. RESULTS: In the in vitro tests, fluorescence intensity was low for healthy cells and high for apoptotic cells when incubated with FITC-labeled annexin A5 and A5MB. Rats treated with doxorubicin showed significant contrast opacification of the myocardium on contrast echocardiography using A5MB. However, no opacification was observed in control rats. Apoptosis was confirmed by TUNEL assay in doxorubicin treated rats. CONCLUSION: Acute doxorubicin-induced cardiomyopathy based on early apoptosis can be assessed and imaged with targeted ultrasound imaging using A5MB in rats. PMID- 20967157 TI - A Case with Upper Extremity Deep Vein Thrombosis after in vitro Fertilization. AB - Deep vein thrombosis (DVT) is a predisposing condition of pulmonary embolism which can be fatal. Usually, DVT is found in the lower extremities. However, DVT can be occurred in the upper extremities. The usual predisposing conditions of the upper extremity DVT include insertion of central venous catheters and pacemaker wires. Here, we report a case of upper extremity DVT after in vitro fertilization and embryo transfer. The patient was successfully controlled with subcutaneous administration of low molecular weight heparin. PMID- 20967158 TI - A Case of Acute ST-Segment Elevation Myocardial Infarction Mimicking Stress Induced Cardiomyopathy; Demonstration of Typical Echocardiographic Finding Correlated with Unusual Distribution of Left Anterior Descending Coronary Artery. AB - Stress-induced cardiomyopathy (SCMP) is diagnosed in 1-2% of patients presenting with symptoms suggestive of acute coronary syndrome. Because of sharing many common clinical features with SCMP, acute ST-segment elevation myocardial infarction (STEMI) can be misdiagnosed as SCMP. However, it can be associated with fatal outcome of the patient. Also, diagnosis of SCMP seems to be always challenging to clinicians, especially in the decision of taking coronary angiography which is still invasive and even risky. Here, we present a case with acute STEMI mimicking SCMP as a result of anatomical variation of coronary circulation. In this patient, prompt and early coronary angiography and stent implantation was very helpful. PMID- 20967159 TI - A rare case with primary undifferentiated carcinoma of pericardium. AB - A primary pericardial tumor is very rare. A 77-year-old woman was admitted to our hospital with chief complaint of exertional dyspnea due to large amount of pericardial effusion. She was finally diagnosed as pericardial undifferentiated carcinoma without definite histopathologial, immunochemistry feature. Despite palliative radiation therapy, the patient died of multiple organ failure. The prognosis of primary pericardial undifferentiated carcinoma is known to be very poor, especially in old people. PMID- 20967160 TI - Cardiovascular Behcet's Disease Presenting as a Subepicardial Hematoma: An Uneventful 2-Year Clinical Course. AB - Cardiovascular involvement in Behcet's disease is not uncommon and could be life threatening. We describe here a 28-year-old man, who developed sudden onset chest pain during warfarinization due to deep vein thrombosis. Echocardiography and computed tomography showed a 60*60 mm-sized hematoma in the pericardial space compressing the right heart. Coronary angiography showed totally occluded proximal right coronary artery. The hematoma was located at the subepicardial plane of the right atrium on surgical view and successfully evacuated. Follow-up echocardiography revealed complete resolution of the hematoma. He is doing well for 24 months after surgery. PMID- 20967161 TI - Two cases of incidentally diagnosed idiopathic left atrial appendage ostial stenosis. AB - We report here on 2 cases of idiopathic left atrial appendage ostial stenosis (LAA), and this rare finding was detected on transesophageal echocardiography. Its clinical implication is still unknown, given the small number of reported cases. Incompletely ligated LAA has characteristics similar to those observed in idiopathic LAA ostial stenosis, including the narrowed orifice, the small LAA cavity and the accelerated blood flow across the stenotic area. Since the incompletely ligated LAA has been reported to be complicated with thromboembolic events, we can assumed that the patients with idiopathic LAA ostial stenosis have a higher risk of thromboembolism than those with a normal LAA structure. PMID- 20967162 TI - Old blood, new blood or better stored blood? PMID- 20967164 TI - Platelet gel in the treatment of cutaneous ulcers: the experience of the Immunohaematology and Transfusion Centre of Parma. AB - BACKGROUND: Platelet gel is being ever more frequently used to promote healing of cutaneous ulcers. However, the factors that determine the often variable clinical outcome of this procedure are still incompletely understood. AIMS: The aims of this study were to demonstrate that platelet gel, even when obtained under strictly controlled conditions, produces highly variable outcomes in patients with cutaneous ulcers and to propose a method for in vitro standardisation of the biological properties of platelet gel. MATERIAL AND METHODS.: Patients were enrolled on the basis of a pre-defined protocol. Platelet concentrate was produced with standard methods, with a variability in platelet count among the different samples of less than 10%. The platelet gel for clinical use was obtained, under strictly standardized conditions, by adding thrombin and calcium gluconate to the concentrates. For in vitro studies, platelet gel, obtained from platelet-rich plasma from four donors, was frozen and thawed twice so as to increase gel contraction. The supernatant was used to modify cell proliferation, protein synthesis, and the expression of selected genes in cultures of human diploid fibroblasts. RESULTS: Seventeen patients (aged 44-78 years) with ulcers (4 diabetic, 11 vascular, 1 post-traumatic, 1 decubitus) were treated with platelet gel (4 autologous, 13 homologous). Complete re-epithelialisation of four ulcers (1 diabetic, 1 post-traumatic, 2 vascular) was obtained after applications of platelet gel (2 autologous, 2 homologous); in 11 other cases there was a greater than 50% reduction in the size of the ulcer. Two patients had no benefit. The supernatant of the platelet gel was able to promote dose-dependent proliferation and changes in gene expression as well as in metabolic activities related to protein synthesis. CONCLUSIONS: Although the use of platelet gel in the treatment of cutaneous ulcers is increasing, and conditions for its production are better standardised, very considerable variability of clinical outcomes is still observed, even within single centres, suggesting that there are differences in biological properties of platelet concentrates from individual patients which cannot be readily controlled with current techniques. The biological effects of the platelet gel supernatant described in this article may provide the basis for a simple biological validation of platelet preparations before their clinical use, so as to reduce this potentially important source of variability. PMID- 20967163 TI - Anaerobic storage of red blood cells. PMID- 20967165 TI - In vitro effects of anthocyanin extracts from Justicia secunda Vahl on the solubility of haemoglobin S and membrane stability of sickle erythrocytes. AB - BACKGROUND: Sickle cell disease or drepanocytosis is caused by the polymerisation of abnormal haemoglobin S when oxygen tension decreases. This lead to the changes in the shape of red blood cells and anaemia. It has also been postulated that the red cells of patients with sickle cell disease contain a higher than normal concentration of calcium ions. These ions are bound to membrane proteins resulting in dehydration and loss of red blood cell deformability and cell-to cell adherence. Anthocyanins extracted from some Congolese plants used in traditional medicine against sickle cell disease have recently been shown to have anti-sickling activity in vitro. Justicia secunda is a plant used in Congo by Jehovah's Witnesses, well known for their refusal of blood transfusions, against anaemia. MATERIALS AND METHODS: Emmel, Itano and osmotic fragility tests were used to test the effect of anthocyanin extracts from Justicia secunda leaves on haemoglobin S solubility and sickle cell membrane stability. RESULTS: Anthocyanins from Justicia secunda were found to possess anti-sickling activity. Treated SS red blood cells recovered a normal, classical biconcave form with a radius of 3.3+/-0.3 MUm, similar to that of normal erythrocytes. The solubility of deoxyhaemoglobin S increased and the osmotic fragility of drepanocytes decreased upon treatment with anthocyanin extracts. CONCLUSION: These findings suggest that anthocyanin extracts play a role in both stabilising the red blood cell membrane and inhibiting polymerisation of haemoglobin S. This provides a possible molecular basis for earlier reports on the anti-sickling properties of anthocyanins from some Congolese plants and their use in the management of sickle cell disease by Congolese traditional healers. PMID- 20967166 TI - Platelet gel for the treatment of traumatic loss of finger substance. AB - BACKGROUND: Autologous or allogenic platelet gel is a blood component that exploits the effects of the cytokines contained in platelet alpha granules to stimulate repair processes. The properties of platelet gel were first tested on chronic ulcers to accelerate healing and later in orthopaedic, dental, vascular and cardiothoracic surgery. In our centre, we have been using platelet gel for 5 years, first for surgical patients with difficult wounds, then for orthopaedic patients undergoing osteosynthesis surgery and patients with ulcers not responding to traditional therapies. Subsequently we decided to extend the use of platelet gel also to amputations or traumatic loss of tissue of fingers. MATERIALS AND METHODS: In this article we present the results obtained over 5 years concerning 115 patients with finger amputations or wounds treated with platelet gel in our Service of Transfusion Medicine. Platelets were obtained fom allogeneic buffy coats (10 mL) and the gel was produced by adding thrombin to concentrated platelets. The decision to use homologous platelet gel was based on its limited cost, ease of preparation, almost unlimited availability, the fact that the number of platelets that can be collected is much higher than the therapeutic range and so able to replace the losses due to secondary medication, and last, but not least, it causes no discomfort to patients. The safety of the product was ensured by virology tests including molecular biology studies. RESULTS: The recovery of soft tissue in all patients ranged from 80 to 100%; the median time for this recovery was 3 weeks (range, 10 days - 6 weeks). Approximately 60% of the patients complained of local hypoaesthesia for some weeks; 30% of the patients developed hyperaesthesia, which resolved completely within 6-8 weeks from starting treatment. Loss of bone tissue represented an obstacle to total tissue recovery, but the aesthetic results were satisfactory in nearly all cases. CONCLUSION: All patients showed good compliance, both because of the low frequency of medications (at most, twice a week) and because of the painless platelet gel applications. The only negative aspect was abnormal nail growth in a case of distal partial amputation of a finger. In conclusion, we believe that platelet gel can be very useful in patients with traumatic or surgical loss of finger tissue, since it can resolve critical situations thus avoiding amputation of residual tissue and compromised joint function. PMID- 20967167 TI - Effects of storage time and leucocyte burden of packed and buffy-coat depleted red blood cell units on red cell storage lesion. AB - BACKGROUND: The red cell storage lesion (RCSL) comprises the biochemical and biomechanical changes that take place during red blood cell (RBC) storage, reducing the survival and function of these cells. Contaminating white blood cells have been major contributors to the RCSL. Markers of RCSL, such as CD47 and phosphatidylserine (PS), on RBC are attracting more attention. The aim of this study was to elucidate the effects of storage time and buffy-coat removal on CD47 and PS expression on RBC. Potassium and free haemoglobin levels in the supernatant plasma were also assessed. MATERIALS AND METHODS: Forty-three red cell concentrates were divided into two groups [Group 1: packed red cells (n=22); Group 2: red cell units from which the buffy-coat had been removed (n=21)] and samples were collected on days 1, 14 and 28. Flow cytometry was used to monitor changes of CD47 and PS expression on RBC over times. Supernatant potassium was measured and percent of haemolysis calculated. RESULTS: A significant, progressive decrease in RBC CD47 expression during storage was observed in both groups. The decrease in RBC CD47 expression was significantly less in the buffy coat-removed group of units than in the other group. The percentage of annexin V positive cells increased significantly in both groups. Buffy-coat depleted components showed less expression of PS only in the early samples. There were significant, progressive increases in percentage of haemolysis and supernatant potassium during storage in both groups. CONCLUSION: RBC stored for more than 14 days exhibited reduced CD47 and increased PS. Buffy coat removal reduced the loss of CD47, but had no impact on plasma haemoglobin, potassium or RBC PS exposure. PMID- 20967168 TI - Imbalance in A2 and A2B phenotype frequency of ABO group in South India. AB - BACKGROUND: The heterogeneity of A and B alleles results in weak variants of these antigens. Subgroups of A differ from each other quantitatively and qualitatively. The expected frequencies of A1 and A2 subtypes will be in Hardy Weinberg equilibrium for the Mendelian inheritance of the allelic A1 and A2 genes. The frequency of A subgroups in the population from south India is not known. The aim of our study was to study the frequency of A subtypes and the prevalence of anti-A1 antibody among this population. METHODS: Over a period of 3 years, patients' blood group was typed using a standard tube technique. Anti-A1 lectin studies were done for all patients with groups A and AB. Based on serological reactivity the samples were classified into A1/A1B, A2/A2B and weak A subgroups. The prevalence of A subgroups was determined. The significance of differences in proportions was analysed using the chi-square test. RESULTS: A total of 40,113 patients' samples were typed for ABO, Rh group and A subgroups in our blood bank attached to a tertiary care hospital. Among 10,325 group A samples, 98.14% classified as A1, 1.07% as A2, and 0.01% as weak A; the remaining group A samples were from neonates and reacted poorly with anti A1-lectin. The majority of AB samples (n=2,667) were of A1B type (89.28%). However, the proportion of A2B (8.99%) among AB samples was significantly higher than that of A(2) in group A samples (p < 0.0001). The prevalence of anti-A(1) antibodies among A2 and A2B samples was 1.8% and 3.75%, respectively, and none of them showed reactivity at 37 degrees C. CONCLUSION: The results of our study show a significantly higher proportion of A2B subtypes than A2 subgroups. A similar imbalance is seen in blacks and Japanese. The incidence of anti-A1 antibodies is also higher among A2B patients. PMID- 20967169 TI - Determining the volume of blood required for the correction of foetal anaemia by intrauterine transfusion during pregnancies of Rh isoimmunised women. AB - BACKGROUND: Severe anaemic foetuses of Rhesus (Rh) isoimmunised mothers are usually treated by intrauterine transfusion (IUT). It is helpful to determine the volume of blood necessary to raise the concentration of haemoglobin by 1.0 g/dL in response to intrauterine transfusions. METHODS: In this cross-sectional, observational study we evaluated 107 first IUT for the correction of anaemia caused by haemolysis triggered by maternal Rh immunisation. The concentration of foetal haemoglobin was determined in umbilical cord blood before and after the IUT. The variation in foetal concentration of haemoglobin after transfusion was compared between groups of hydropic and non-hydropic foetuses, between groups of foetuses with different degrees of anaemia and with groups of gestational age less than or more than 28 weeks. The t-test for averages and ANOVA were used to compare average differences among the groups. p values less than 0.05 were considered statistically significant. RESULTS: Fifty-five (61.4%) foetuses were found to be anaemic while hydrops was observed in 40 (44%) at the time of the IUT. The volume of red blood cell concentrate infused varied from 5 to 90 mL, with 11.2+/-1.5 mL being necessary to raise the circulating concentration of haemoglobin by 1.0 g/dL. The foetal response was not influenced significantly by either the degree of foetal anaemia (p=0.56) or the presence of hydrops (p=0.17). The foetuses with a gestational age of 28 weeks or less required a smaller volume of red blood cell concentrate than those with a gestational age of more than 28 weeks (9.3+/-5.4 mL and 13.4+/-4.8 mL, respectively; p<0.0001) in order to raise their concentration of circulating haemoglobin by 1.0 g/dL. CONCLUSION: The volume of red blood cell concentrate necessary to correct anaemia in pregnancies complicated by Rh isoimmunisation must be considered carefully, since the response to the infusion of blood is peculiar in extremely premature infants. Hydrops and the degree of anaemia were not determinants of the change in the final concentration of circulating haemoglobin following the blood transfusion. PMID- 20967170 TI - Gender differences in giving blood: a review of the literature. AB - BACKGROUND: An overview of European blood donors shows that the distribution of men and women donors is similar in many countries, with Italy being an exception in that women account for only 30% of donors. Gender medicine is a key issue in this context, even though gender studies are very limited in the transfusion field, whether considered broadly or with specific regards to the selection, management and retention of donors. It, therefore, seemed important to compare the presence of women among blood donors in different European countries and examine the roles that gender is reported to play in the donation of blood in order to identify possible implications for communication with and management of the donor. METHODS: To determine the proportion of women among donors in European countries, data were collected from annual reports or documents available on the websites of national associations; furthermore, all papers related to giving blood published in the five main journals in the sector (Transfusion, Vox Sanguinis, Transfusion and Apheresis Science, Transfusion Medicine, Blood Transfusion) were considered; about 80 publications were selected and the gender variable was examined. RESULTS: The published studies showed that gender plays key roles in the motivation to give blood (women being more altruistic, men being more individualistic) and in adverse reactions, which was a particularly critical problem leading to fewer women become regular donors. A few aspects specific to the management of donors in Italy also emerged. DISCUSSION: Gender seems to play an important role in the aspects studied and does, therefore, merit further consideration in relation to strategies to recruit donors and the management of critical events during donation. PMID- 20967171 TI - Plasma-derived versus recombinant factor VIII concentrates for the treatment of haemophilia A: plasma-derived is better. PMID- 20967173 TI - Occult hepatitis B in blood donors: a description of two cases. PMID- 20967172 TI - Plasma-derived versus recombinant Factor VIII concentrates for the treatment of haemophilia A: recombinant is better. PMID- 20967174 TI - Red cell exchange is not effective for patients with sickle cell anaemia and coexisting warm autoantibody haemolysis. PMID- 20967176 TI - Future challenges in the use of magnetic resonance imaging for the diagnosis of iron overload. PMID- 20967175 TI - Frequency and type of newly diagnosed haemoglobin variants in Northern Italy. PMID- 20967178 TI - Mycetoma clinically masquerading as squamous cell carcinoma: case report and literature review. AB - Mycetoma is a chronic and progressive subcutaneous granulomatous infection characterized by painless swelling and tumefaction, draining sinus tracts, and purulent discharge. The term eumycetoma is used to describe an infection caused by fungi, while an actinomycetoma is used to describe an infection caused by filamentous bacteria. An accurate identification of the pathogen plays a vital role in the treatment plan as well as a positive outcome for the patient. In this report, we present an elderly white female with an initial presentation of mycetoma masquerading as a squamous cell carcinoma. We also review microbiology, diagnostic modalities, and treatment for mycetoma. PMID- 20967179 TI - Treatment of scalp and facial seborrheic dermatitis with desonide hydrogel 0.05%. AB - BACKGROUND: Desonide is a low-potency corticosteroid recently formulated in a novel aqueous gel (hydrogel) formulation. Currently US Food and Drug Administration approved for use in the treatment of mild-to-moderate atopic dermatitis, this hydrogel formulation may offer aesthetic advantages over traditional vehicles. OBJECTIVE: To conduct a pilot study evaluating efficacy, tolerability, and patient preference of desonide hydrogel 0.05% for the treatment of scalp and facial seborrheic dermatitis. METHODS: Subjects treated affected areas on the face or scalp twice daily for four weeks. Evaluations of pruritus, target area scaling, induration and erythema; static global assessments; and photography were conducted. RESULTS: Ten subjects aged 13 to 73 years with mild scalp or facial seborrheic dermatitis completed the study. Statistically significant reductions in pruritus, target area scaling, erythema, and induration, and significant improvements in static global assessments were demonstrated over Baseline (all P<0.05). CONCLUSION: Desonide hydrogel 0.05% may provide an effective, well-tolerated, and cosmetically elegant treatment option for scalp and facial seborrheic dermatitis. PMID- 20967180 TI - Increasing patient adherence in antifungal infection treatment: once-daily dosing of sertaconazole. AB - Adherence to treatment is an important issue in all areas of clinical medicine, including dermatology. Consequences of poor compliance include reduced treatment benefits, biased assessments of treatment efficacy, increased healthcare costs, and in some cases even death. To date, even the most effective interventions in patients' habits have not led to large improvements in either adherence or treatment outcome. New objective electronic measures permit unbiased reporting of actual adherence to therapy regimens and have revealed that nonadherence is more pervasive than had been suspected, usually occurring when patients omit or delay a dose. In dermatology, adherence to therapy for dermatomycosis is known to decrease with the duration of treatment and the number of applications required each day, particularly once symptoms have disappeared. Simpler dosing regimens are sought for the treatment of cutaneous fungal infections. Sertaconazole, an imidazole antifungal, has pharmacokinetics that are considered favorable for once daily antimycotic therapy. It is hypothesized that its prolonged dermal retention may translate into the need for less frequent application for successful treatment in clinical practice. PMID- 20967181 TI - Therapeutic and Aesthetic Uses of Photodynamic Therapy Part five of a five-part series: ALA-PDT and MAL-PDT What Makes Them Different. AB - The use of photodynamic therapy has increased dramatically over the past several years. More clinicians are utilizing this therapy and additional indications for its use have become available. The photosensitizers that are utilized for this therapy differ and have been used differently over the past 10 years of our experience with photodynamic therapy. This manuscript examines the photosensitizers and the differences between them as well as reviews the literature on photosensitizers. PMID- 20967182 TI - Teens and tanning knowledge and attitudes. AB - BACKGROUND: The incidence of skin cancer, including melanoma, continues to increase. Teenagers are especially vulnerable, as are young females. The incidence of melanoma among young women in their twenties and thirties has begun to increase again. These young people are also the population that frequent tanning salons. OBJECTIVE: This voluntary, anonymous, New York University, Institutional Review Board-approved survey was given to students in grades 9 through 12 to ascertain their understanding of what causes skin cancers and the dangers of excessive sun exposure and tanning salons. METHODS AND MATERIALS: An Institutional Review Board-approved, 22-question survey was administered anonymously to more than 450 students with 368 returned responses. The survey was administered to students in grades 9 through 12 at two high schools in New York and New Jersey. RESULTS: More than 80 percent of students view movie stars as tan and almost 60 percent see "tan" people as better looking. In addition, more than 90 percent believe that a tan does not prevent further damage to the skin (as opposed to the customary belief that a "base" tan can protect against extreme sun exposures, such as when on a tropical vacation). There appears to be a disconnect between knowledge and sun tanning behaviors. Most teenagers still believe that tans are attractive and teenage girls continue to use tanning salons and tan naturally. We need to address the connection between sun tanning in youth and skin cancers years later. Legislation to limit access of tanning salons to teenagers needs to be enacted. PMID- 20967183 TI - Review of intravenous immunoglobulin in the treatment of stevens-johnson syndrome and toxic epidermal necrolysis. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and serious cutaneous adverse reactions. There is controversy over the use of intravenous immunoglobulin (IVIG) in the treatment of SJS or TEN. The lack of randomized controlled trials to assess the benefits and risks of IVIG is due to its low prevalence and the high mortality rate associated with these cutaneous adverse reactions, especially in TEN. This article reviews published literature on case series that either supports or refutes the use of IVIG in the treatment of SJS or TEN. PMID- 20967184 TI - Demodex dermatitis: a retrospective analysis of clinical diagnosis and successful treatment with topical crotamiton. AB - Given the reported common occurrence of Demodex dermatitis in the general population, Demodex dermatitis-considered as a separate condition from rosacea and seborrheic dermatitis-was evaluated in a retrospective case analysis. PMID- 20967185 TI - Rosacea, reactive oxygen species, and azelaic Acid. AB - Rosacea is a common skin condition thought to be primarily an inflammatory disorder. Neutrophils, in particular, have been implicated in the inflammation associated with rosacea and mediate many of their effects through the release of reactive oxygen species. Recently, the role of reactive oxygen species in the pathophysiology of rosacea has been recognized. Many effective agents for rosacea, including topical azelaic acid and topical metronidazole, have anti inflammatory properties. in-vitro models have demonstrated the potent antioxidant effects of azelaic acid, providing a potential mechanistic explanation for its efficacy in the treatment of rosacea. PMID- 20967186 TI - Therapeutic and Aesthetic Uses of Photodynamic Therapy Part five of a five-part series: ALA-PDT in Clinical Practice How One Clinician Performs This Procedure. AB - The use of 5-aminolevulinic acid-photodynamic therapy in clinical practice is an individual determination based on experiences learned from clinicians and from personal experience. This manuscript reviews how one clinician approaches patients interested in having photodynamic therapy. It covers all practical aspects of the treatment process and reviews how photodynamic therapy can be utilized in your clinical practice. PMID- 20967187 TI - Practical uses of botanicals in skin care. AB - Cosmeceuticals are the fastest growing sector of the cosmetic industry, and the future of antiaging cosmeceuticals in particular is very promising. Botanical extracts that support the health, texture, and integrity of the skin, hair, and nails are widely used in cosmetic formulations. They form the largest category of cosmeceutical additives found in the marketplace today due to the rising consumer interest and demand for natural products. Various plant extracts that formed the basis of medical treatments in ancient civilizations and many traditional cultures are still used today in cleansers, moisturizers, astringents, and many other skin care products. New botanical skin care treatments are emerging, presenting dermatologists and their patients the challenge of understanding the science behind these cosmeceuticals. Thus, dermatologists must have a working knowledge of these botanicals and keep up with how they evolve to provide optimal medical care and answer patient questions. The most popular botanicals commonly incorporated into skin care protocols are discussed. PMID- 20967188 TI - Unusual documentation of the transformation of a nevus into malignant melanoma. AB - It is well documented that congenital nevi have a statistical chance of becoming malignant; however, it is unusual to actually follow the progression of such an event. A 48-year-old man photographically documented changes in his own nevus, which was present at birth, over a period of six months. Seeing this evolution in one lesion is interesting. Emphasis must not only be placed upon the importance of early diagnosis, but also on the expeditious removal of suspicious nevi and treatment. PMID- 20967189 TI - Weight-based Dosing and Extended-release Formulation of Minocycline Tablets: Is There Clinical Significance? PMID- 20967190 TI - Laser classification systems. PMID- 20967191 TI - Immunophenotypic diagnosis of primary cutaneous lymphomas: a review for the practicing dermatologist. AB - The application of CD markers to medicine has advanced our understanding of several dermatological diseases, most notably primary cutaneous lymphomas. CD markers are monoclonal antibodies that target cell surface molecules on leukocytes and antigens from other cells. T-cell processes are typically CD3+, CD20-, CD45+ while B-cell processes are typically CD3-, CD20+, and CD45+. Other CD markers are used to further delineate cutaneous lymphomas. Although an imperfect system, CD markers empower dermatologists to synthesize immunophenotyping with clinical findings and formulate an appropriate diagnosis. PMID- 20967192 TI - Absence of Degradation of Tretinoin When Benzoyl Peroxide is Combined with an Optimized Formulation of Tretinoin Gel (0.05%). AB - BACKGROUND: Clinicians have been reluctant to prescribe benzoyl peroxide concurrently with topical tretinoin due to a belief that the benzoyl peroxide may cause oxidation and degradation of the tretinoin molecule, thereby reducing its effectiveness. However, benzoyl peroxide-induced degradation of tretinoin may not necessarily apply to all topical tretinoin formulations. OBJECTIVE: To evaluate the potential for benzoyl peroxide-induced degradation of an optimized aqueous gel formulation of tretinoin (0.05%). METHODS: Tretinoin gel (0.05%) and benzoyl peroxide gel (6.26% premix concentration to produce 5% benzoyl peroxide in a fixed combination clindamycin product) were mixed together (1:1) at 32oC and samples assayed after 1, 2, 3, 5, and 7 hours. Each sample was analyzed for tretinoin (expressed as % tretinoin remaining) and its degradation product content. RESULTS: No loss of tretinoin was observed over the seven-hour time period. When tretinoin gel (0.05%) was combined with benzoyl peroxide, 100 percent of the initial tretinoin concentration remained after seven hours. There was no increase in the degradation products of tretinoin. CONCLUSIONS: There was no benzoyl peroxide-induced degradation of tretinoin when the optimized formulation of tretinoin gel (0.05%) was admixed with benzoyl peroxide gel (6.26%). Although the direct clinical significance of these results is unknown, clinicians may feel comfortable using this particular combination concurrently without concerns about tretinoin oxidation and degradation. PMID- 20967193 TI - Contact allergens in a pediatric population: association with atopic dermatitis and comparison with other north american referral centers. AB - OBJECTIVE: The authors aimed to retrospectively identify associations between allergen sensitization frequencies and specific comorbidities in a patient population in Miami, Florida, tested between November 2004 and July 2006 with a pediatric standard series and to compare their findings to recent pediatric and adult patch testing data published by other North American referral centers. DESIGN: The authors performed a retrospective chart review evaluating the most common, clinically relevant contact allergens against the frequency of specific comorbidities, such as atopic dermatitis. The results were compared with the patch testing data from the Ottawan Contact Dermatitis Group's 1996-2006 study, the North American Contact Dermatitis Group 2001-2004 study, and the Mayo Clinic 1998-2000 study and the 2000-2006 study. SETTING: University of Miami, Miami, Florida. PARTICIPANTS: Sixty-nine Miami children and adolescents between age six months and 18 years, having been referred for comprehensive patch testing. MEASUREMENTS: The frequency of positive patch test reactions and clinical relevance was evaluated against the frequency of comorbidities. RESULTS: Forty five patients met all the inclusion criteria. Of these, 95.6 percent (43 patients) had at least one positive patch test reaction, with 76.7 percent of them having a personal history of atopic dermatitis. The most common pediatric allergens were found to significantly overlap with those of other North American referral centers. CONCLUSIONS: Allergic contact dermatitis is prevalent in atopic dermatitis; however, the authors were not able to demonstrate a statistically significant association, as the majority of patients referred had atopic dermatitis, and thus the control group was inadequate. Furthermore, allergens at the Miami center paralleled those seen at different centers within North America. PMID- 20967194 TI - Allergic Contact Dermatitis: Patch Testing Beyond the TRUE Test. AB - Epicutaneous patch testing is the gold standard method for the diagnosis of allergic contact dermatitis. Despite this knowledge, many clinical dermatologists do not offer patch testing in their offices or offer testing with only a limited number of allergens. Introduced in 1995, the Thin-Layer Rapid Use Epicutaneous Test originally contained 23 allergens and one control. In 2007, five additional allergens were added. This United States Food and Drug Administration-approved patch testing system made patch testing more convenient, and after its introduction, more dermatologists offered patch testing services. However, the number of allergens in the Thin-Layer Rapid Use Epicutaneous Test remains relatively low. Every two years, the North American Contact Dermatitis Group collects and reports the data from patch testing among its members to a standardized series of allergens. In 2005-2006, the Group used a series of 65 allergens. Of the top 30 allergens reported in 2005-2006, 10 were not included in the Thin-Layer Rapid Use Epicutaneous Test. Knowledge of and testing for additional allergens such as these may increase patch testing yield. PMID- 20967195 TI - Coal tar 2% foam in combination with a superpotent corticosteroid foam for plaque psoriasis: case report and clinical implications. AB - Psoriasis is a chronic, inflammatory, immune-mediated, multi-system disease that is treated with a variety of medicines, including topical corticosteroids and, historically, coal tar. In this case, the authors evaluated whether combination therapy with coal tar foam 2% and a topical corticosteroid would induce a remission and maintain clearance of plaque-type psoriasis over an eight-week period. A 59-year-old Caucasian woman with plaque psoriasis of her elbows presented to the authors' dermatology clinic and was treated with clobetasol propionate 0.05% emollient foam in combination with coal tar 2% foam twice daily to her elbows for two weeks. After two weeks, the patient was switched to a maintenance regimen of twice-daily coal tar 2% foam during the week and twice daily application of the corticosteroid on the weekends. The patient exhibited very favorable clearance of her plaque psoriasis on this regimen at her eight week follow-up visit. In this case, the combination of coal tar 2% foam and clobetasol propionate 0.05% emollient foam twice daily was used effectively to induce remission of localized plaque psoriasis followed by an efficacious maintenance regimen, which incorporated intermittent therapy with both topical agents. PMID- 20967196 TI - CD8+ Pagetoid Reticulosis Presenting as a Solitary Foot Plaque in a Young Woman. AB - BACKGROUND: Pagetoid reticulosis is a rare variant of mycosis fungoides. This rare condition typically presents as a solitary plaque located on the extremities with an indolent clinical course (Woringer-Kolopp disease) or as a more generalized presentation with diffuse cutaneous involvement and a more aggressive clinical course (Ketron-Goodman disease). PURPOSE: To review the cutaneous manifestations, pathology, and treatment of localized pagetoid reticulosis. METHODS: The authors describe a 24-year-old woman with a slowly enlarging, localized plaque of seven months duration, representing the localized form of pagetoid reticulosis with CD8+ immunophenotype. RESULTS: The histological, immunohistochemical, and clinical features of the patient's skin lesion were characteristic for a diagnosis of Woringer-Kolopp disease. Systemic work-up for lymphoma was negative. CONCLUSION: Woringer-Kolopp disease is most commonly seen in middle-aged men as a solitary lesion of the extremities, and it should always be considered in the differential diagnosis when a patient presents with such a lesion. A histological analysis demonstrated atypical lymphocytes preferentially localized to the epidermis with a CD4+, CD8+, or CD4-/CD8- phenotype. The treatment of choice for a solitary lesion may be localized radiation therapy, but newer therapies, such as bexarotene, may warrant further investigation. PMID- 20967197 TI - Neural coding of movement direction in the healthy human brain. AB - Neurophysiological studies in monkeys show that activity of neurons in primary cortex (M1), pre-motor cortex (PMC), and cerebellum varies systematically with the direction of reaching movements. These neurons exhibit preferred direction tuning, where the level of neural activity is highest when movements are made in the preferred direction (PD), and gets progressively lower as movements are made at increasing degrees of offset from the PD. Using a functional magnetic resonance imaging adaptation (fMRI-A) paradigm, we show that PD coding does exist in regions of the human motor system that are homologous to those observed in non human primates. Consistent with predictions of the PD model, we show adaptation (i.e., a lower level) of the blood oxygen level dependent (BOLD) time-course signal in M1, PMC, SMA, and cerebellum when consecutive wrist movements were made in the same direction (0 degrees offset) relative to movements offset by 90 degrees or 180 degrees . The BOLD signal in dorsolateral prefrontal cortex adapted equally in all movement offset conditions, mitigating against the possibility that the present results are the consequence of differential task complexity or attention to action in each movement offset condition. PMID- 20967198 TI - Lipidomics analysis reveals efficient storage of hepatic triacylglycerides enriched in unsaturated fatty acids after one bout of exercise in mice. AB - BACKGROUND: Endurance exercise induces lipolysis, increases circulating concentrations of free fatty acids (FFA) and the uptake and oxidation of fatty acids in the working muscle. Less is known about the regulation of lipid metabolism in the liver during and post-exercise. METHODOLOGY/PRINCIPAL FINDINGS: We performed an ultra fast liquid chromatography-mass spectrometry (UFLC-MS) based lipidomics analysis of liver tissue samples obtained from C57Bl/6J mice immediately after a 60 min treadmill run of moderate intensity, and after 3 h of recovery. The PLS-DA scores plot for 115 quantified lipid molecular species revealed a clear separation of the hepatic lipid profile of sedentary from recovering mice, but not from mice immediately after running. 21 lipid species were considered to be most responsible for the difference in the hepatic lipid profiles, including 17 triacylglycerides (TG), one lysophosphatidylcholine (LPC) and three phosphatidylcholines (PC). TG species were found to be more abundant in the recovery phase, while PC species were decreased. The degree of accumulation of individual TG species correlated well with the amount of theoretical energy stored whereas no increase was found for TG species containing only saturated or one monounsaturated fatty acid. Total liver TG content as assayed by an enzymatic method was increased to 163% in the recovery phase, while it was significantly decreased in skeletal muscle by the exercise bout and remained less in the recovery phase. Results from fasted and refed mice indicate that fasting-induced lipolysis was associated with a pronounced accumulation of hepatic TG, which is reversed by refeeding for 5 h. Thus food intake per se did not elevate hepatic TG. CONCLUSION: These data indicate that high availability of FFA induced by endurance exercise or fasting resulted in a transient hepatic TG accumulation, while muscle TG content was decreased during exercise presumably due to increased muscle fatty acid oxidation. PMID- 20967199 TI - Increased immune complexes of hypocretin autoantibodies in narcolepsy. AB - BACKGROUND: Hypocretin peptides participate in the regulation of sleep-wake cycle while deficiency in hypocretin signaling and loss of hypocretin neurons are causative for narcolepsy-cataplexy. However, the mechanism responsible for alteration of the hypocretin system in narcolepsy-cataplexy and its relevance to other central hypersomnias remain unknown. Here we studied whether central hypersomnias can be associated with autoantibodies reacting with hypocretin-1 peptide present as immune complexes. METHODOLOGY: Serum levels of free and dissociated (total) autoantibodies reacting with hypocretin-1 peptide were measured by enzyme-linked immunosorbent assay and analyzed with regard to clinical parameters in 82 subjects with narcolepsy-cataplexy, narcolepsy without cataplexy or idiopathic hypersomnia and were compared to 25 healthy controls. PRINCIPAL FINDINGS: Serum levels of total but not free IgG autoantibodies against hypocretin-1 were increased in narcolepsy-cataplexy. Increased levels of complexed IgG autoantibodies against hypocretin-1 were found in all patients groups with a further increase in narcolepsy-cataplexy. Levels of total IgM hypocretin-1 autoantibodies were also elevated in all groups of patients. Increased levels of anti-idiotypic IgM autoantibodies reacting with hypocretin-1 IgG autoantibodies affinity purified from sera of subjects with narcolepsy cataplexy were found in all three groups of patients. Disease duration correlated negatively with serum levels of hypocretin-1 IgG and IgM autoantibodies and with anti-idiotypic IgM autoantibodies. CONCLUSION: Central hypersomnias and particularly narcolepsy-cataplexy are characterized by higher serum levels of autoantibodies directed against hypocretin-1 which are present as immune complexes most likely with anti-idiotypic autoantibodies suggesting their relevance to the mechanism of sleep-wake cycle regulation. PMID- 20967200 TI - Viewing pictures of a romantic partner reduces experimental pain: involvement of neural reward systems. AB - The early stages of a new romantic relationship are characterized by intense feelings of euphoria, well-being, and preoccupation with the romantic partner. Neuroimaging research has linked those feelings to activation of reward systems in the human brain. The results of those studies may be relevant to pain management in humans, as basic animal research has shown that pharmacologic activation of reward systems can substantially reduce pain. Indeed, viewing pictures of a romantic partner was recently demonstrated to reduce experimental thermal pain. We hypothesized that pain relief evoked by viewing pictures of a romantic partner would be associated with neural activations in reward-processing centers. In this functional magnetic resonance imaging (fMRI) study, we examined fifteen individuals in the first nine months of a new, romantic relationship. Participants completed three tasks under periods of moderate and high thermal pain: 1) viewing pictures of their romantic partner, 2) viewing pictures of an equally attractive and familiar acquaintance, and 3) a word-association distraction task previously demonstrated to reduce pain. The partner and distraction tasks both significantly reduced self-reported pain, although only the partner task was associated with activation of reward systems. Greater analgesia while viewing pictures of a romantic partner was associated with increased activity in several reward-processing regions, including the caudate head, nucleus accumbens, lateral orbitofrontal cortex, amygdala, and dorsolateral prefrontal cortex--regions not associated with distraction-induced analgesia. The results suggest that the activation of neural reward systems via non pharmacologic means can reduce the experience of pain. PMID- 20967201 TI - Two lamprey Hedgehog genes share non-coding regulatory sequences and expression patterns with gnathostome Hedgehogs. AB - Hedgehog (Hh) genes play major roles in animal development and studies of their evolution, expression and function point to major differences among chordates. Here we focused on Hh genes in lampreys in order to characterize the evolution of Hh signalling at the emergence of vertebrates. Screening of a cosmid library of the river lamprey Lampetra fluviatilis and searching the preliminary genome assembly of the sea lamprey Petromyzon marinus indicate that lampreys have two Hh genes, named Hha and Hhb. Phylogenetic analyses suggest that Hha and Hhb are lamprey-specific paralogs closely related to Sonic/Indian Hh genes. Expression analysis indicates that Hha and Hhb are expressed in a Sonic Hh-like pattern. The two transcripts are expressed in largely overlapping but not identical domains in the lamprey embryonic brain, including a newly-described expression domain in the nasohypophyseal placode. Global alignments of genomic sequences and local alignment with known gnathostome regulatory motifs show that lamprey Hhs share conserved non-coding elements (CNE) with gnathostome Hhs albeit with sequences that have significantly diverged and dispersed. Functional assays using zebrafish embryos demonstrate gnathostome-like midline enhancer activity for CNEs contained in intron2. We conclude that lamprey Hh genes are gnathostome Shh-like in terms of expression and regulation. In addition, they show some lamprey-specific features, including duplication and structural (but not functional) changes in the intronic/regulatory sequences. PMID- 20967202 TI - Ancient geographical gaps and paleo-climate shape the phylogeography of an endemic bird in the sky islands of southern India. AB - BACKGROUND: Sky islands, formed by the highest reaches of mountain tracts physically isolated from one another, represent one of the biodiversity-rich regions of the world. Comparative studies of geographically isolated populations on such islands can provide valuable insights into the biogeography and evolution of species on these islands. The Western Ghats mountains of southern India form a sky island system, where the relationship between the island structure and the evolution of its species remains virtually unknown despite a few population genetic studies. METHODS AND PRINCIPAL FINDINGS: We investigated how ancient geographic gaps and glacial cycles have partitioned genetic variation in modern populations of a threatened endemic bird, the White-bellied Shortwing Brachypteryx major, across the montane Shola forests on these islands and also inferred its evolutionary history. We used bayesian and maximum likelihood-based phylogenetic and population-genetic analyses on data from three mitochondrial markers and one nuclear marker (totally 2594 bp) obtained from 33 White-bellied Shortwing individuals across five islands. Genetic differentiation between populations of the species correlated with the locations of deep valleys in the Western Ghats but not with geographical distance between these populations. All populations revealed demographic histories consistent with population founding and expansion during the Last Glacial Maximum. Given the level of genetic differentiation north and south of the Palghat Gap, we suggest that these populations be considered two different taxonomic species. CONCLUSIONS AND SIGNIFICANCE: Our results show that the physiography and paleo-climate of this region historically resulted in multiple glacial refugia that may have subsequently driven the evolutionary history and current population structure of this bird. The first avian genetic study from this biodiversity hotspot, our results provide insights into processes that may have impacted the speciation and evolution of the endemic fauna of this region. PMID- 20967203 TI - Task-related effects on the temporal and spatial dynamics of resting-state functional connectivity in the default network. AB - Recent evidence points to two potentially fundamental aspects of the default network (DN), which have been relatively understudied. One is the temporal nature of the functional interactions among nodes of the network in the resting-state, usually assumed to be static. The second is possible influences of previous brain states on the spatial patterns (i.e., the brain regions involved) of functional connectivity (FC) in the DN at rest. The goal of the current study was to investigate modulations in both the spatial and temporal domains. We compared the resting-state FC of the DN in two runs that were separated by a 45 minute interval containing cognitive task execution. We used partial least squares (PLS), which allowed us to identify FC spatiotemporal patterns in the two runs and to determine differences between them. Our results revealed two primary modes of FC, assessed using a posterior cingulate seed--a robust correlation among DN regions that is stable both spatially and temporally, and a second pattern that is reduced in spatial extent and more variable temporally after cognitive tasks, showing switching between connectivity with certain DN regions and connectivity with other areas, including some task-related regions. Therefore, the DN seems to exhibit two simultaneous FC dynamics at rest. The first is spatially invariant and insensitive to previous brain states, suggesting that the DN maintains some temporally stable functional connections. The second dynamic is more variable and is seen more strongly when the resting-state follows a period of task execution, suggesting an after-effect of the cognitive activity engaged during task that carries over into resting-state periods. PMID- 20967204 TI - Seasonal changes in bacterial and archaeal gene expression patterns across salinity gradients in the Columbia River coastal margin. AB - Through their metabolic activities, microbial populations mediate the impact of high gradient regions on ecological function and productivity of the highly dynamic Columbia River coastal margin (CRCM). A 2226-probe oligonucleotide DNA microarray was developed to investigate expression patterns for microbial genes involved in nitrogen and carbon metabolism in the CRCM. Initial experiments with the environmental microarrays were directed toward validation of the platform and yielded high reproducibility in multiple tests. Bioinformatic and experimental validation also indicated that >85% of the microarray probes were specific for their corresponding target genes and for a few homologs within the same microbial family. The validated probe set was used to query gene expression responses by microbial assemblages to environmental variability. Sixty-four samples from the river, estuary, plume, and adjacent ocean were collected in different seasons and analyzed to correlate the measured variability in chemical, physical and biological water parameters to differences in global gene expression profiles. The method produced robust seasonal profiles corresponding to pre-freshet spring (April) and late summer (August). Overall relative gene expression was high in both seasons and was consistent with high microbial abundance measured by total RNA, heterotrophic bacterial production, and chlorophyll a. Both seasonal patterns involved large numbers of genes that were highly expressed relative to background, yet each produced very different gene expression profiles. April patterns revealed high differential gene expression in the coastal margin samples (estuary, plume and adjacent ocean) relative to freshwater, while little differential gene expression was observed along the river-to-ocean transition in August. Microbial gene expression profiles appeared to relate, in part, to seasonal differences in nutrient availability and potential resource competition. Furthermore, our results suggest that highly-active particle-attached microbiota in the Columbia River water column may perform dissimilatory nitrate reduction (both dentrification and DNRA) within anoxic particle microniches. PMID- 20967205 TI - Anthrax lethal toxin suppresses murine cardiomyocyte contractile function and intracellular Ca2+ handling via a NADPH oxidase-dependent mechanism. AB - OBJECTIVES: Anthrax infection is associated with devastating cardiovascular sequelae, suggesting unfavorable cardiovascular effects of toxins originated from Bacillus anthracis namely lethal and edema toxins. This study was designed to examine the direct effect of lethal toxins on cardiomyocyte contractile and intracellular Ca(2+) properties. METHODS: Murine cardiomyocyte contractile function and intracellular Ca(2+) handling were evaluated including peak shortening (PS), maximal velocity of shortening/ relengthening (+/- dL/dt), time to-PS (TPS), time-to-90% relengthening (TR(90)), intracellular Ca(2+) rise measured as fura-2 fluorescent intensity (DeltaFFI), and intracellular Ca(2+) decay rate. Stress signaling and Ca(2+) regulatory proteins were assessed using Western blot analysis. RESULTS: In vitro exposure to a lethal toxin (0.05-50 nM) elicited a concentration-dependent depression on cardiomyocyte contractile and intracellular Ca(2+) properties (PS, +/- dL/dt, DeltaFFI), along with prolonged duration of contraction and intracellular Ca(2+) decay, the effects of which were nullified by the NADPH oxidase inhibitor apocynin. The lethal toxin significantly enhanced superoxide production and cell death, which were reversed by apocynin. In vivo lethal toxin exposure exerted similar time-dependent cardiomyocyte mechanical and intracellular Ca(2+) responses. Stress signaling cascades including MEK1/2, p38, ERK and JNK were unaffected by in vitro lethal toxins whereas they were significantly altered by in vivo lethal toxins. Ca(2+) regulatory proteins SERCA2a and phospholamban were also differentially regulated by in vitro and in vivo lethal toxins. Autophagy was drastically triggered although ER stress was minimally affected following lethal toxin exposure. CONCLUSIONS: Our findings indicate that lethal toxins directly compromised murine cardiomyocyte contractile function and intracellular Ca(2+) through a NADPH oxidase-dependent mechanism. PMID- 20967206 TI - Interplant communication of tomato plants through underground common mycorrhizal networks. AB - Plants can defend themselves to pathogen and herbivore attack by responding to chemical signals that are emitted by attacked plants. It is well established that such signals can be transferred through the air. In theory, plants can also communicate with each other through underground common mycorrhizal networks (CMNs) that interconnect roots of multiple plants. However, until now research focused on plant-to-plant carbon nutrient movement and there is no evidence that defense signals can be exchanged through such mycorrhizal hyphal networks. Here, we show that CMNs mediate plant-plant communication between healthy plants and pathogen-infected tomato plants (Lycopersicon esculentum Mill.). After establishment of CMNs with the arbuscular mycorrhizal fungus Glomus mosseae between tomato plants, inoculation of 'donor' plants with the pathogen Alternaria solani led to increases in disease resistance and activities of the putative defensive enzymes, peroxidase, polyphenol oxidase, chitinase, beta-1,3-glucanase, phenylalanine ammonia-lyase and lipoxygenase in healthy neighbouring 'receiver' plants. The uninfected 'receiver' plants also activated six defence-related genes when CMNs connected 'donor' plants challenged with A. solani. This finding indicates that CMNs may function as a plant-plant underground communication conduit whereby disease resistance and induced defence signals can be transferred between the healthy and pathogen-infected neighbouring plants, suggesting that plants can 'eavesdrop' on defence signals from the pathogen-challenged neighbours through CMNs to activate defences before being attacked themselves. PMID- 20967207 TI - Convergence of Rad6/Rad18 and Fanconi anemia tumor suppressor pathways upon DNA damage. AB - Extremely high cancer incidence associated with patients with Fanconi anemia (FA) suggests the importance of the FA signaling pathway in the suppression of non-FA human tumor development. Indeed, we found that an impaired FA signaling pathway substantially contributes to the development of non-FA human tumors. However, the mechanisms underlying the function of the FA pathway remain less understood. Using RNA interfering approach in combining with cell proliferation and reporter assays, we showed that the function of FA signaling pathway is at least partly mediated through coupling with hRad6/hRad18 signaling (HHR6 pathway). We previously reported that FANCD2 monoubiquitination, a hallmark of the FA pathway activation, can be regulated by HHR6. Here we found that hRad18 can also regulate activation of the FA pathway. More importantly, we found that FANCD2 is capable of modulating activity of DNA translesion synthesis polymerase eta, an effector of HHR6 pathway. These results provide novel insights into how the FA pathway is intertwined with HHR6 pathway to maintain chromosomal stability and suppress the development of human cancer, representing an important conceptual advance in the field of FA cancer research. PMID- 20967208 TI - Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer. AB - BACKGROUND: We previously identified an association between a mismatch repair gene, MLH1, promoter SNP (rs1800734) and microsatellite unstable (MSI-H) colorectal cancers (CRCs) in two samples. The current study expanded on this finding as we explored the genetic basis of DNA methylation in this region of chromosome 3. We hypothesized that specific polymorphisms in the MLH1 gene region predispose it to DNA methylation, resulting in the loss of MLH1 gene expression, mismatch-repair function, and consequently to genome-wide microsatellite instability. METHODOLOGY/PRINCIPAL FINDINGS: We first tested our hypothesis in one sample from Ontario (901 cases, 1,097 controls) and replicated major findings in two additional samples from Newfoundland and Labrador (479 cases, 336 controls) and from Seattle (591 cases, 629 controls). Logistic regression was used to test for association between SNPs in the region of MLH1 and CRC, MSI-H CRC, MLH1 gene expression in CRC, and DNA methylation in CRC. The association between rs1800734 and MSI-H CRCs, previously reported in Ontario and Newfoundland, was replicated in the Seattle sample. Two additional SNPs, in strong linkage disequilibrium with rs1800734, showed strong associations with MLH1 promoter methylation, loss of MLH1 protein, and MSI-H CRC in all three samples. The logistic regression model of MSI-H CRC that included MLH1-promoter methylation status and MLH1 immunohistochemistry status fit most parsimoniously in all three samples combined. When rs1800734 was added to this model, its effect was not statistically significant (P-value = 0.72 vs. 2.3*10(-4) when the SNP was examined alone). CONCLUSIONS/SIGNIFICANCE: The observed association of rs1800734 with MSI-H CRC occurs through its effect on the MLH1 promoter methylation, MLH1 IHC deficiency, or both. PMID- 20967209 TI - Genetic admixture and population substructure in Guanacaste Costa Rica. AB - The population of Costa Rica (CR) represents an admixture of major continental populations. An investigation of the CR population structure would provide an important foundation for mapping genetic variants underlying common diseases and traits. We conducted an analysis of 1,301 women from the Guanacaste region of CR using 27,904 single nucleotide polymorphisms (SNPs) genotyped on a custom Illumina InfiniumII iSelect chip. The program STRUCTURE was used to compare the CR Guanacaste sample with four continental reference samples, including HapMap Europeans (CEU), East Asians (JPT+CHB), West African Yoruba (YRI), as well as Native Americans (NA) from the Illumina iControl database. Our results show that the CR Guanacaste sample comprises a three-way admixture estimated to be 43% European, 38% Native American and 15% West African. An estimated 4% residual Asian ancestry may be within the error range. Results from principal components analysis reveal a correlation between genetic and geographic distance. The magnitude of linkage disequilibrium (LD) measured by the number of tagging SNPs required to cover the same region in the genome in the CR Guanacaste sample appeared to be weaker than that observed in CEU, JPT+CHB and NA reference samples but stronger than that of the HapMap YRI sample. Based on the clustering pattern observed in both STRUCTURE and principal components analysis, two subpopulations were identified that differ by approximately 20% in LD block size averaged over all LD blocks identified by Haploview. We also show in a simulated association study conducted within the two subpopulations, that the failure to account for population stratification (PS) could lead to a noticeable inflation in the false positive rate. However, we further demonstrate that existing PS adjustment approaches can reduce the inflation to an acceptable level for gene discovery. PMID- 20967210 TI - The signaller's dilemma: a cost-benefit analysis of public and private communication. AB - BACKGROUND: Understanding the diversity of animal signals requires knowledge of factors which may influence the different stages of communication, from the production of a signal by the sender up to the detection, identification and final decision-making in the receiver. Yet, many studies on signalling systems focus exclusively on the sender, and often ignore the receiver side and the ecological conditions under which signals evolve. METHODOLOGY/PRINCIPAL FINDINGS: We study a neotropical katydid which uses airborne sound for long distance communication, but also an alternative form of private signalling through substrate vibration. We quantified the strength of predation by bats which eavesdrop on the airborne sound signal, by analysing insect remains at roosts of a bat family. Males do not arbitrarily use one or the other channel for communication, but spend more time with private signalling under full moon conditions, when the nocturnal rainforest favours predation by visually hunting predators. Measurements of metabolic CO(2)-production rate indicate that the energy necessary for signalling increases 3-fold in full moon nights when private signalling is favoured. The background noise level for the airborne sound channel can amount to 70 dB SPL, whereas it is low in the vibration channel in the low frequency range of the vibration signal. The active space of the airborne sound signal varies between 22 and 35 meters, contrasting with about 4 meters with the vibration signal transmitted on the insect's favourite roost plant. Signal perception was studied using neurophysiological methods under outdoor conditions, which is more reliable for the private mode of communication. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate the complex effects of ecological conditions, such as predation, nocturnal ambient light levels, and masking noise levels on the performance of receivers in detecting mating signals, and that the net advantage or disadvantage of a mode of communication strongly depends on these conditions. PMID- 20967211 TI - Genome-wide patterns of gene expression during aging in the African malaria vector Anopheles gambiae. AB - The primary means of reducing malaria transmission is through reduction in longevity in days of the adult female stage of the Anopheles vector. However, assessing chronological age is limited to crude physiologic methods which categorize the females binomially as either very young (nulliparous) or not very young (parous). Yet the epidemiologically relevant reduction in life span falls within the latter category. Age-grading methods that delineate chronological age, using accurate molecular surrogates based upon gene expression profiles, will allow quantification of the longevity-reducing effects of vector control tools aimed at the adult, female mosquito. In this study, microarray analyses of gene expression profiles in the African malaria vector Anopheles gambiae were conducted during natural senescence of females in laboratory conditions. Results showed that detoxification-related and stress-responsive genes were up-regulated as mosquitoes aged. A total of 276 transcripts had age-dependent expression, independently of blood feeding and egg laying events. Expression of 112 (40.6%) of these transcripts increased or decreased monotonically with increasing chronologic age. Seven candidate genes for practical age assessment were tested by quantitative gene amplification in the An. gambiae G3 strain in a laboratory experiment and the Mbita strain in field enclosures set up in western Kenya under conditions closely resembling natural ones. Results were similar between experiments, indicating that senescence is marked by changes in gene expression and that chronological age can be gauged accurately and repeatedly with this method. These results indicate that the method may be suitable for accurate gauging of the age in days of field-caught, female An. gambiae. PMID- 20967212 TI - Modulators of cytoskeletal reorganization in CA1 hippocampal neurons show increased expression in patients at mid-stage Alzheimer's disease. AB - During the progression of Alzheimer's disease (AD), hippocampal neurons undergo cytoskeletal reorganization, resulting in degenerative as well as regenerative changes. As neurofibrillary tangles form and dystrophic neurites appear, sprouting neuronal processes with growth cones emerge. Actin and tubulin are indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli. We have previously shown that actin capping protein beta2 subunit, Capzb2, binds tubulin and, in the presence of tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons resulted in short, dystrophic neurites, seen in neurodegenerative diseases including AD. Here we demonstrate the statistically significant increase in the Capzb2 expression in the postmortem hippocampi in persons at mid-stage, Braak and Braak stage (BB) III IV, non-familial AD in comparison to controls. The dynamics of Capzb2 expression in progressive AD stages cannot be attributed to reactive astrocytosis. Moreover, the increased expression of Capzb2 mRNA in CA1 pyramidal neurons in AD BB III-IV is accompanied by an increased mRNA expression of brain derived neurotrophic factor (BDNF) receptor tyrosine kinase B (TrkB), mediator of synaptic plasticity in hippocampal neurons. Thus, the up-regulation of Capzb2 and TrkB may reflect cytoskeletal reorganization and/or regenerative response occurring in hippocampal CA1 neurons at a specific stage of AD progression. PMID- 20967213 TI - Diversity promotes temporal stability across levels of ecosystem organization in experimental grasslands. AB - The diversity-stability hypothesis states that current losses of biodiversity can impair the ability of an ecosystem to dampen the effect of environmental perturbations on its functioning. Using data from a long-term and comprehensive biodiversity experiment, we quantified the temporal stability of 42 variables characterizing twelve ecological functions in managed grassland plots varying in plant species richness. We demonstrate that diversity increases stability i) across trophic levels (producer, consumer), ii) at both the system (community, ecosystem) and the component levels (population, functional group, phylogenetic clade), and iii) primarily for aboveground rather than belowground processes. Temporal synchronization across studied variables was mostly unaffected with increasing species richness. This study provides the strongest empirical support so far that diversity promotes stability across different ecological functions and levels of ecosystem organization in grasslands. PMID- 20967214 TI - Why are there social gradients in preventative health behavior? A perspective from behavioral ecology. AB - BACKGROUND: Within affluent populations, there are marked socioeconomic gradients in health behavior, with people of lower socioeconomic position smoking more, exercising less, having poorer diets, complying less well with therapy, using medical services less, ignoring health and safety advice more, and being less health-conscious overall, than their more affluent peers. Whilst the proximate mechanisms underlying these behavioral differences have been investigated, the ultimate causes have not. METHODOLOGY/PRINCIPAL FINDINGS: This paper presents a theoretical model of why socioeconomic gradients in health behavior might be found. I conjecture that lower socioeconomic position is associated with greater exposure to extrinsic mortality risks (that is, risks that cannot be mitigated through behavior), and that health behavior competes for people's time and energy against other activities which contribute to their fitness. Under these two assumptions, the model shows that the optimal amount of health behavior to perform is indeed less for people of lower socioeconomic position. CONCLUSIONS/SIGNIFICANCE: The model predicts an exacerbatory dynamic of poverty, whereby the greater exposure of poor people to unavoidable harms engenders a disinvestment in health behavior, resulting in a final inequality in health outcomes which is greater than the initial inequality in material conditions. I discuss the assumptions of the model, and its implications for strategies for the reduction of health inequalities. PMID- 20967215 TI - Fibulin-1 is increased in asthma--a novel mediator of airway remodeling? AB - BACKGROUND: The extracellular matrix is a dynamic and complex network of macromolecules responsible for maintaining and influencing cellular functions of the airway. The role of fibronectin, an extracellular matrix protein, is well documented in asthma. However, the expression and function of fibulin-1, a secreted glycoprotein which interacts with fibronectin, has not been reported. Fibulin-1 is widely expressed in basement membranes in many organs including the lung. There are four isoforms in humans (A-D) of which fibulin-1C and 1D predominate. The objective of this study was to study the expression of fibulin-1 in volunteers with and without asthma, and to examine its function in vitro. METHODOLOGY/PRINCIPAL FINDINGS: We used immunohistochemistry and dot-blots to examine fibulin-1 levels in bronchial biopsies, bronchoalveolar lavage fluid and serum. Real-time PCR for fibulin-1C and 1D, and ELISA and western blotting for fibulin-1 were used to study the levels in airway smooth muscle cells. The function of fibulin-1C was determined by assessing its role, using an antisense oligonucleotide, in cell proliferation, migration and wound healing. A murine model of airway hyperresponsiveness (AHR) was used to explore the biological significance of fibulin-1. Levels of fibulin-1 were significantly increased in the serum and bronchoalveolar lavage fluid of 21 asthmatics compared with 11 healthy volunteers. In addition fibulin-1 was increased in asthma derived airway smooth muscle cells and fibulin-1C contributed to the enhanced proliferation and wound repair in these cells. These features were reversed when fibulin-1C was suppressed using an antisense oligomer. In a mouse model of AHR, treatment with an AO inhibited the development of AHR to methacholine. CONCLUSIONS: Our data collectively suggest fibulin-1C may be worthy of further investigation as a target for airway remodeling in asthma. PMID- 20967216 TI - Cortical representation of lateralized grasping in chimpanzees (Pan troglodytes): a combined MRI and PET study. AB - Functional imaging studies in humans have localized the motor-hand region to a neuroanatomical landmark call the KNOB within the precentral gyrus. It has also been reported that the KNOB is larger in the hemisphere contralateral to an individual's preferred hand, and therefore may represent the neural substrate for handedness. The KNOB has also been neuronatomically described in chimpanzees and other great apes and is similarly associated with handedness. However, whether the chimpanzee KNOB represents the hand region is unclear from the extant literature. Here, we used PET to quantify neural metabolic activity in chimpanzees when engaged in unilateral reach-and-grasping responses and found significantly lateralized activation of the KNOB region in the hemisphere contralateral to the hand used by the chimpanzees. We subsequently constructed a probabilistic map of the KNOB region in chimpanzees in order to assess the overlap in consistency in the anatomical landmarks of the KNOB with the functional maps generated from the PET analysis. We found significant overlap in the anatomical and functional voxels comprising the KNOB region, suggesting that the KNOB does correspond to the hand region in chimpanzees. Lastly, from the probabilistic maps, we compared right- and left-handed chimpanzees on lateralization in grey and white matter within the KNOB region and found that asymmetries in white matter of the KNOB region were larger in the hemisphere contralateral to the preferred hand. These results suggest that neuroanatomical asymmetries in the KNOB likely reflect changes in connectivity in primary motor cortex that are experience dependent in chimpanzees and possibly humans. PMID- 20967217 TI - Increased anion channel activity is an unavoidable event in ozone-induced programmed cell death. AB - BACKGROUND: Ozone is a major secondary air pollutant often reaching high concentrations in urban areas under strong daylight, high temperature and stagnant high-pressure systems. Ozone in the troposphere is a pollutant that is harmful to the plant. PRINCIPAL FINDINGS: By exposing cells to a strong pulse of ozonized air, an acute cell death was observed in suspension cells of Arabidopsis thaliana used as a model. We demonstrated that O(3) treatment induced the activation of a plasma membrane anion channel that is an early prerequisite of O(3)-induced cell death in A. thaliana. Our data further suggest interplay of anion channel activation with well known plant responses to O(3), Ca(2+) influx and NADPH-oxidase generated reactive oxygen species (ROS) in mediating the oxidative cell death. This interplay might be fuelled by several mechanisms in addition to the direct ROS generation by O(3); namely, H(2)O(2) generation by salicylic and abscisic acids. Anion channel activation was also shown to promote the accumulation of transcripts encoding vacuolar processing enzymes, a family of proteases previously reported to contribute to the disruption of vacuole integrity observed during programmed cell death. SIGNIFICANCE: Collectively, our data indicate that anion efflux is an early key component of morphological and biochemical events leading to O(3)-induced programmed cell death. Because ion channels and more specifically anion channels assume a crucial position in cells, an understanding about the underlying role(s) for ion channels in the signalling pathway leading to programmed cell death is a subject that warrants future investigation. PMID- 20967218 TI - Phosphatidylinositol 5-phosphate links dehydration stress to the activity of ARABIDOPSIS TRITHORAX-LIKE factor ATX1. AB - BACKGROUND: Changes in gene expression enable organisms to respond to environmental stress. Levels of cellular lipid second messengers, such as the phosphoinositide PtdIns5P, change in response to a variety of stresses and can modulate the localization, conformation and activity of a number of intracellular proteins. The plant trithorax factor (ATX1) tri-methylates the lysine 4 residue of histone H3 (H3K4me3) at gene coding sequences, which positively correlates with gene transcription. Microarray analysis has identified a target gene (WRKY70) that is regulated by both ATX1 and by the exogenous addition of PtdIns5P in Arabidopsis. Interestingly, ATX1 contains a PtdIns5P interaction domain (PHD finger) and thus, phosphoinositide signaling, may link environmental stress to changes in gene transcription. PRINCIPAL FINDINGS: Using the plant Arabidopsis as a model system, we demonstrate a link between PtdIns5P and the activity of the chromatin modifier ATX1 in response to dehydration stress. We show for the first time that dehydration leads to an increase in cellular PtdIns5P in Arabidopsis. The Arabidopsis homolog of myotubularin (AtMTM1) is capable of generating PtdIns5P and here, we show that AtMTM1 is essential for the induced increase in PtdIns5P upon dehydration. Furthermore, we demonstrate that the ATX1-dependent gene, WRKY70, is downregulated during dehydration and that lowered transcript levels are accompanied by a drastic reduction in H3K4me3 of its nucleosomes. We follow changes in WRKY70 nucleosomal K4 methylation as a model to study ATX1 activity at chromatin during dehydration stress. We found that during dehydration stress, the physical presence of ATX1 at the WRKY70 locus was diminished and that ATX1 depletion resulted from it being retained in the cytoplasm when PtdIns5P was elevated. The PHD of ATX1 and catalytically active AtMTM1 are required for the cytoplasmic localization of ATX1. CONCLUSIONS/SIGNIFICANCE: The novelty of the manuscript is in the discovery of a mechanistic link between a chromatin modifying activity (ATX1) and a lipid (PtdIns5P) synthesis in a signaling pathway that ultimately results in altered expression of ATX1 dependent genes downregulated in response to dehydration stress. PMID- 20967219 TI - The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine. AB - BACKGROUND: Microseminoprotein-beta (MSMB) regulates apoptosis and using genome wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk. METHODOLOGY/PRINCIPAL FINDINGS: MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate. CONCLUSIONS: These data show that some high risk alleles discovered using genome wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring. PMID- 20967220 TI - Individual differences in AMY1 gene copy number, salivary alpha-amylase levels, and the perception of oral starch. AB - BACKGROUND: The digestion of dietary starch in humans is initiated by salivary alpha-amylase, an endo-enzyme that hydrolyzes starch into maltose, maltotriose and larger oligosaccharides. Salivary amylase accounts for 40 to 50% of protein in human saliva and rapidly alters the physical properties of starch. Importantly, the quantity and enzymatic activity of salivary amylase show significant individual variation. However, linking variation in salivary amylase levels with the oral perception of starch has proven difficult. Furthermore, the relationship between copy number variations (CNVs) in the AMY1 gene, which influence salivary amylase levels, and starch viscosity perception has not been explored. PRINCIPAL FINDINGS: Here we demonstrate that saliva containing high levels of amylase has sufficient activity to rapidly hydrolyze a viscous starch solution in vitro. Furthermore, we show with time-intensity ratings, which track the digestion of starch during oral manipulation, that individuals with high amylase levels report faster and more significant decreases in perceived starch viscosity than people with low salivary amylase levels. Finally, we demonstrate that AMY1 CNVs predict an individual's amount and activity of salivary amylase and thereby, ultimately determine their perceived rate of oral starch viscosity thinning. CONCLUSIONS: By linking genetic variation and its consequent salivary enzymatic differences to the perceptual sequellae of these variations, we show that AMY1 copy number relates to salivary amylase concentration and enzymatic activity level, which, in turn, account for individual variation in the oral perception of starch viscosity. The profound individual differences in salivary amylase levels and salivary activity may contribute significantly to individual differences in dietary starch intake and, consequently, to overall nutritional status. PMID- 20967221 TI - AGT M235T genotype/anxiety interaction and gender in the HyperGEN study. AB - BACKGROUND: Both anxiety and elevated heart rate (HR) have been implicated in the development of hypertension. The HyperGen cohort, consisting of siblings with severe and mild hypertension, an age-matched random sample of persons from the same base populations, and unmedicated adult offspring of the hypertensive siblings (N = 1,002 men and 987 women), was analyzed for an association of the angiotenisinogen AGTM235T genotype (TT, MT, MM) with an endophenotype, heart rate (HR) in high and low anxious groups. METHODOLOGY: The interaction of AGTM genotype with anxiety, which has been independently associated with hypertension, was investigated adjusting for age, hypertension status, smoking, alcohol consumption, beta blocker medication, body mass index, physical activity and hours of television viewing (sedentary life style). PRINCIPAL FINDINGS: Although there was no main effect of genotype on HR in men or women, high anxious men with the TT genotype had high HR, whereas high anxious men with the MM genotype had low HR. In women, HR was inversely associated with anxiety but there was no interaction with genotype. CONCLUSION/SIGNIFICANCE: The results suggest that high anxiety in men with the TT genotype may increase risk for hypertension whereas the MM genotype may be protective in high anxious men. This type of gene x environment interaction may be one reason why genome wide association studies sometimes fail to replicate. The locus may be important only in combination with certain environmental factors. PMID- 20967222 TI - Automated extraction improves multiplex molecular detection of infection in septic patients. AB - Sepsis is one of the leading causes of morbidity and mortality in hospitalized patients worldwide. Molecular technologies for rapid detection of microorganisms in patients with sepsis have only recently become available. LightCycler SeptiFast test M(grade) (Roche Diagnostics GmbH) is a multiplex PCR analysis able to detect DNA of the 25 most frequent pathogens in bloodstream infections. The time and labor saved while avoiding excessive laboratory manipulation is the rationale for selecting the automated MagNA Pure compact nucleic acid isolation kit-I (Roche Applied Science, GmbH) as an alternative to conventional SeptiFast extraction. For the purposes of this study, we evaluate extraction in order to demonstrate the feasibility of automation. Finally, a prospective observational study was done using 106 clinical samples obtained from 76 patients in our ICU. Both extraction methods were used in parallel to test the samples. When molecular detection test results using both manual and automated extraction were compared with the data from blood cultures obtained at the same time, the results show that SeptiFast with the alternative MagNA Pure compact extraction not only shortens the complete workflow to 3.57 hrs., but also increases sensitivity of the molecular assay for detecting infection as defined by positive blood culture confirmation. PMID- 20967223 TI - Bile acid-induced virulence gene expression of Vibrio parahaemolyticus reveals a novel therapeutic potential for bile acid sequestrants. AB - Vibrio parahaemolyticus, a bacterial pathogen, causes human gastroenteritis. A type III secretion system (T3SS2) encoded in pathogenicity island (Vp-PAI) is the main contributor to enterotoxicity and expression of Vp-PAI encoded genes is regulated by two transcriptional regulators, VtrA and VtrB. However, a host derived inducer for the Vp-PAI genes has not been identified. Here, we demonstrate that bile induces production of T3SS2-related proteins under osmotic conditions equivalent to those in the intestinal lumen. We also show that bile induces vtrA-mediated vtrB transcription. Transcriptome analysis of bile responsive genes revealed that bile strongly induces expression of Vp-PAI genes in a vtrA-dependent manner. The inducing activity of bile was diminished by treatment with bile acid sequestrant cholestyramine. Finally, we demonstrate an in vivo protective effect of cholestyramine on enterotoxicity and show that similar protection is observed in infection with a different type of V. parahaemolyticus or with non-O1/non-O139 V. cholerae strains of vibrios carrying the same kind of T3SS. In summary, these results provide an insight into how bacteria, through the ingenious action of Vp-PAI genes, can take advantage of an otherwise hostile host environment. The results also reveal a new therapeutic potential for widely used bile acid sequestrants in enteric bacterial infections. PMID- 20967224 TI - A novel secretory poly-cysteine and histidine-tailed metalloprotein (Ts-PCHTP) from Trichinella spiralis (Nematoda). AB - BACKGROUND: Trichinella spiralis is an unusual parasitic intracellular nematode causing dedifferentiation of the host myofiber. Trichinella proteomic analyses have identified proteins that act at the interface between the parasite and the host and are probably important for the infection and pathogenesis. Many parasitic proteins, including a number of metalloproteins are unique for the nematodes and trichinellids and therefore present good targets for future therapeutic developments. Furthermore, detailed information on such proteins and their function in the nematode organism would provide better understanding of the parasite-host interactions. METHODOLOGY/PRINCIPAL FINDINGS: In this study we report the identification, biochemical characterization and localization of a novel poly-cysteine and histidine-tailed metalloprotein (Ts-PCHTP). The native Ts PCHTP was purified from T. spiralis muscle larvae that were isolated from infected rats as a model system. The sequence analysis showed no homology with other proteins. Two unique poly-cysteine domains were found in the amino acid sequence of Ts-PCHTP. This protein is also the first reported natural histidine tailed protein. It was suggested that Ts-PCHTP has metal binding properties. Total Reflection X-ray Fluorescence (TXRF) assay revealed that it binds significant concentrations of iron, nickel and zinc at protein:metal ratio of about 1:2. Immunohistochemical analysis showed that the Ts-PCHTP is localized in the cuticle and in all tissues of the larvae, but that it is not excreted outside the parasite. CONCLUSIONS/SIGNIFICANCE: Our data suggest that Ts-PCHTP is the first described member of a novel nematode poly-cysteine protein family and its function could be metal storage and/or transport. Since this protein family is unique for parasites from Superfamily Trichinelloidea its potential applications in diagnostics and treatment could be exploited in future. PMID- 20967225 TI - Inhibition of the liver enriched protein FOXA2 recovers HNF6 activity in human colon carcinoma and liver hepatoma cells. AB - Recently, we demonstrated that the transcription factors HNF6 and FOXA2 function as key regulators in human colorectal liver metastases. To better understand their proposed inhibitory crosstalk, the consequences of functional knockdown of FOXA2 on HNF6 and C/EBPalpha activity were investigated in the human colon Caco-2 and HepG2 carcinoma cell lines. Specifically, siRNA-mediated gene silencing of FOXA2 repressed transcript expression by >80%. This resulted in a statistically significant 6-, 3-, 4-, and 8-fold increase in mRNA expression of HNF6 and of genes targeted by this transcription factor, e.g., HSP105B, CYP51, and C/EBPalpha, as determined by qRT-PCR. Thus, functional knockdown of FOXA2 recovered HNF6 activity. Furthermore, with nuclear extracts of Caco-2 cells no HNF6 DNA binding was observed, but expression of HNF1alpha, FOXA2, FOXA3, and HNF4alpha protein was abundant. We therefore transfected a plasmid encoding HNF6 into Caco-2 cells but also employed a retroviral vector to transfect HNF6 into HepG2 cells. This resulted in HNF6 protein expression with DNA binding activity being recovered as determined by EMSA band shift assays. Furthermore, by flow cytometry the consequences of HNF6 expression on cell cycle regulation in transfected cells was studied. Essentially, HNF6 inhibited cell cycle progression in the G2/M and G1 phase in Caco-2 and HepG2 cell lines, respectively. Here, proliferation was reduced by 80% and 50% in Caco-2 and HepG2 cells, respectively, as determined by the BrdU labeling assay. Therefore functional knockdown of FOXA2 recovered HNF6 activity and inhibited growth of tumor-cells and may possibly represent a novel therapeutic target in primary and secondary liver malignancies. PMID- 20967226 TI - New copy number variations in schizophrenia. AB - Genome-wide screenings for copy number variations (CNVs) in patients with schizophrenia have demonstrated the presence of several CNVs that increase the risk of developing the disease and a growing number of large rare CNVs; the contribution of these rare CNVs to schizophrenia remains unknown. Using Affymetrix 6.0 arrays, we undertook a systematic search for CNVs in 172 patients with schizophrenia and 160 healthy controls, all of Italian origin, with the aim of confirming previously identified loci and identifying novel schizophrenia susceptibility genes. We found five patients with a CNV occurring in one of the regions most convincingly implicated as risk factors for schizophrenia: NRXN1 and the 16p13.1 regions were found to be deleted in single patients and 15q11.2 in 2 patients, whereas the 15q13.3 region was duplicated in one patient. Furthermore, we found three distinct patients with CNVs in 2q12.2, 3q29 and 17p12 loci, respectively. These loci were previously reported to be deleted or duplicated in patients with schizophrenia but were never formally associated with the disease. We found 5 large CNVs (>900 kb) in 4q32, 5q14.3, 8q23.3, 11q25 and 17q12 in five different patients that could include some new candidate schizophrenia susceptibility genes. In conclusion, the identification of previously reported CNVs and of new, rare, large CNVs further supports a model of schizophrenia that includes the effect of multiple, rare, highly penetrant variants. PMID- 20967227 TI - Influence of microbial biofilms on the preservation of primary soft tissue in fossil and extant archosaurs. AB - BACKGROUND: Mineralized and permineralized bone is the most common form of fossilization in the vertebrate record. Preservation of gross soft tissues is extremely rare, but recent studies have suggested that primary soft tissues and biomolecules are more commonly preserved within preserved bones than had been presumed. Some of these claims have been challenged, with presentation of evidence suggesting that some of the structures are microbial artifacts, not primary soft tissues. The identification of biomolecules in fossil vertebrate extracts from a specimen of Brachylophosaurus canadensis has shown the interpretation of preserved organic remains as microbial biofilm to be highly unlikely. These discussions also propose a variety of potential mechanisms that would permit the preservation of soft-tissues in vertebrate fossils over geologic time. METHODOLOGY/PRINCIPAL FINDINGS: This study experimentally examines the role of microbial biofilms in soft-tissue preservation in vertebrate fossils by quantitatively establishing the growth and morphology of biofilms on extant archosaur bone. These results are microscopically and morphologically compared with soft-tissue extracts from vertebrate fossils from the Hell Creek Formation of southeastern Montana (Latest Maastrichtian) in order to investigate the potential role of microbial biofilms on the preservation of fossil bone and bound organic matter in a variety of taphonomic settings. Based on these analyses, we highlight a mechanism whereby this bound organic matter may be preserved. CONCLUSIONS/SIGNIFICANCE: Results of the study indicate that the crystallization of microbial biofilms on decomposing organic matter within vertebrate bone in early taphonomic stages may contribute to the preservation of primary soft tissues deeper in the bone structure. PMID- 20967228 TI - Tissue transglutaminase promotes drug resistance and invasion by inducing mesenchymal transition in mammary epithelial cells. AB - Recent observations that aberrant expression of tissue transglutaminase (TG2) promotes growth, survival, and metastasis of multiple tumor types is of great significance and could yield novel therapeutic targets for improved patient outcomes. To accomplish this, a clear understanding of how TG2 contributes to these phenotypes is essential. Using mammary epithelial cell lines (MCF10A, MCF12A, MCF7 and MCF7/RT) as a model system, we determined the impact of TG2 expression on cell growth, cell survival, invasion, and differentiation. Our results show that TG2 expression promotes drug resistance and invasive functions by inducing epithelial-mesenchymal transition (EMT). Thus, TG2 expression supported anchorage-independent growth of mammary epithelial cells in soft-agar, disrupted the apical-basal polarity, and resulted in disorganized acini structures when grown in 3D-culture. At molecular level, TG2 expression resulted in loss of E-cadherin and increased the expression of various transcriptional repressors (Snail1, Zeb1, Zeb2 and Twist1). Tumor growth factor-beta (TGF-beta) failed to induce EMT in cells lacking TG2 expression, suggesting that TG2 is a downstream effector of TGF-beta-induced EMT. Moreover, TG2 expression induced stem cell-like phenotype in mammary epithelial cells as revealed by enrichment of CD44(+)/CD24(-/low) cell populations. Overall, our studies show that aberrant expression of TG2 is sufficient for inducing EMT in epithelial cells and establish a strong link between TG2 expression and progression of metastatic breast disease. PMID- 20967229 TI - Checkpoint-dependent and -independent roles of Swi3 in replication fork recovery and sister chromatid cohesion in fission yeast. AB - Multiple genome maintenance processes are coordinated at the replication fork to preserve genomic integrity. How eukaryotic cells accomplish such a coordination is unknown. Swi1 and Swi3 form the replication fork protection complex and are involved in various processes including stabilization of replication forks, activation of the Cds1 checkpoint kinase and establishment of sister chromatid cohesion in fission yeast. However, the mechanisms by which the Swi1-Swi3 complex achieves and coordinates these tasks are not well understood. Here, we describe the identification of separation-of-function mutants of Swi3, aimed at dissecting the molecular pathways that require Swi1-Swi3. Unlike swi3 deletion mutants, the separation-of-function mutants were not sensitive to agents that stall replication forks. However, they were highly sensitive to camptothecin that induces replication fork breakage. In addition, these mutants were defective in replication fork regeneration and sister chromatid cohesion. Interestingly, unlike swi3-deleted cell, the separation-of-functions mutants were proficient in the activation of the replication checkpoint, but their fork regeneration defects were more severe than those of checkpoint mutants including cds1Delta, chk1Delta and rad3Delta. These results suggest that, while Swi3 mediates full activation of the replication checkpoint in response to stalled replication forks, Swi3 activates a checkpoint-independent pathway to facilitate recovery of collapsed replication forks and the establishment of sister chromatid cohesion. Thus, our separation-of-function alleles provide new insight into understanding the multiple roles of Swi1-Swi3 in fork protection during DNA replication, and into understanding how replication forks are maintained in response to different genotoxic agents. PMID- 20967230 TI - Ask a biologist: bringing science to the public. PMID- 20967231 TI - Genome-wide analysis of light- and temperature-entrained circadian transcripts in Caenorhabditis elegans. AB - Most organisms have an endogenous circadian clock that is synchronized to environmental signals such as light and temperature. Although circadian rhythms have been described in the nematode Caenorhabditis elegans at the behavioral level, these rhythms appear to be relatively non-robust. Moreover, in contrast to other animal models, no circadian transcriptional rhythms have been identified. Thus, whether this organism contains a bona fide circadian clock remains an open question. Here we use genome-wide expression profiling experiments to identify light- and temperature-entrained oscillating transcripts in C. elegans. These transcripts exhibit rhythmic expression with temperature-compensated 24-h periods. In addition, their expression is sustained under constant conditions, suggesting that they are under circadian regulation. Light and temperature cycles strongly drive gene expression and appear to entrain largely nonoverlapping gene sets. We show that mutations in a cyclic nucleotide-gated channel required for sensory transduction abolish both light- and temperature-entrained gene expression, implying that environmental cues act cell nonautonomously to entrain circadian rhythms. Together, these findings demonstrate circadian-regulated transcriptional rhythms in C. elegans and suggest that further analyses in this organism will provide new information about the evolution and function of this biological clock. PMID- 20967232 TI - Subtle alterations in PCNA-partner interactions severely impair DNA replication and repair. AB - The robustness of complex biological processes in the face of environmental and genetic perturbations is a key biological trait. However, while robustness has been extensively studied, little is known regarding the fragility of biological processes. Here, we have examined the susceptibility of DNA replication and repair processes mediated by the proliferating cell nuclear antigen (PCNA). Using protein directed evolution, biochemical, and genetic approaches, we have generated and characterized PCNA mutants with increased affinity for several key partners of the PCNA-partner network. We found that increases in PCNA-partner interaction affinities led to severe in vivo phenotypic defects. Surprisingly, such defects are much more severe than those induced by complete abolishment of the respective interactions. Thus, the subtle and tunable nature of these affinity perturbations produced different phenotypic effects than realized with traditional "on-off" analysis using gene knockouts. Our findings indicate that biological systems can be robust to one set of perturbations yet fragile to others. PMID- 20967233 TI - Day and night: circadian rhythms in worms. PMID- 20967234 TI - Oral ondansetron administration in emergency departments to children with gastroenteritis: an economic analysis. AB - BACKGROUND: The use of antiemetics for children with vomiting is one of the most controversial decisions in the treatment of gastroenteritis in developed countries. Ondansetron, a selective serotonin receptor antagonist, has been found to be effective in improving the success of oral rehydration therapy. However, North American and European clinical practice guidelines continue to recommend against its use, stating that evidence of cost savings would be required to support ondansetron administration. Thus, an economic analysis of the emergency department administration of ondansetron was conducted. The primary objective was to conduct a cost analysis of the routine administration of ondansetron in both the United States and Canada. METHODS AND FINDINGS: A cost analysis evaluated oral ondansetron administration to children presenting to emergency departments with vomiting and dehydration secondary to gastroenteritis from a societal and health care payer's perspective in both the US and Canada. A decision tree was developed that incorporated the frequency of vomiting, intravenous insertion, hospitalization, and emergency department revisits. Estimates of the monetary costs associated with ondansetron use, intravenous rehydration, and hospitalization were derived from administrative databases or emergency department use. The economic burden in children administered ondansetron plus oral rehydration therapy was compared to those not administered ondansetron employing deterministic and probabilistic simulations. We estimated the costs or savings to society and health care payers associated with the routine administration of ondansetron. Sensitivity analyses considered variations in costs, treatment effects, and exchange rates. In the US the administration of ondansetron to eligible children would prevent approximately 29,246 intravenous insertions and 7,220 hospitalizations annually. At the current average wholesale price, its routine administration to eligible children would annually save society US$65.6 million (US$49.1-US$81.1) and health care payers US$61.1 million (US$46.2-US$76.3). In Canada the administration of ondansetron to eligible children would prevent 4,065 intravenous insertions and 1,003 hospitalizations annually. Its routine administration would annually save society CDN$1.72 million (CDN$1.15-CDN$1.89) and the health care system CDN$1.18 million (CDN$0.88 CDN$1.41). CONCLUSIONS: In countries where intravenous rehydration is often employed, the emergency department administration of oral ondansetron to children with dehydration and vomiting secondary to gastroenteritis results in significant monetary savings compared to a no-ondansetron policy. Please see later in the article for the Editors' Summary. PMID- 20967235 TI - Prenatal treatment for serious neurological sequelae of congenital toxoplasmosis: an observational prospective cohort study. AB - BACKGROUND: The effectiveness of prenatal treatment to prevent serious neurological sequelae (SNSD) of congenital toxoplasmosis is not known. METHODS AND FINDINGS: Congenital toxoplasmosis was prospectively identified by universal prenatal or neonatal screening in 14 European centres and children were followed for a median of 4 years. We evaluated determinants of postnatal death or SNSD defined by one or more of functional neurological abnormalities, severe bilateral visual impairment, or pregnancy termination for confirmed congenital toxoplasmosis. Two-thirds of the cohort received prenatal treatment (189/293; 65%). 23/293 (8%) fetuses developed SNSD of which nine were pregnancy terminations. Prenatal treatment reduced the risk of SNSD. The odds ratio for prenatal treatment, adjusted for gestational age at maternal seroconversion, was 0.24 (95% Bayesian credible intervals 0.07-0.71). This effect was robust to most sensitivity analyses. The number of infected fetuses needed to be treated to prevent one case of SNSD was three (95% Bayesian credible intervals 2-15) after maternal seroconversion at 10 weeks, and 18 (9-75) at 30 weeks of gestation. Pyrimethamine-sulphonamide treatment did not reduce SNSD compared with spiramycin alone (adjusted odds ratio 0.78, 0.21-2.95). The proportion of live-born infants with intracranial lesions detected postnatally who developed SNSD was 31.0% (17.0%-38.1%). CONCLUSION: The finding that prenatal treatment reduced the risk of SNSD in infected fetuses should be interpreted with caution because of the low number of SNSD cases and uncertainty about the timing of maternal seroconversion. As these are observational data, policy decisions about screening require further evidence from a randomized trial of prenatal screening and from cost effectiveness analyses that take into account the incidence and prevalence of maternal infection. Please see later in the article for the Editors' Summary. PMID- 20967236 TI - Nuclear fission without microtubules--a return to the past? PMID- 20967237 TI - Fission yeast cells undergo nuclear division in the absence of spindle microtubules. AB - Mitosis in eukaryotic cells employs spindle microtubules to drive accurate chromosome segregation at cell division. Cells lacking spindle microtubules arrest in mitosis due to a spindle checkpoint that delays mitotic progression until all chromosomes have achieved stable bipolar attachment to spindle microtubules. In fission yeast, mitosis occurs within an intact nuclear membrane with the mitotic spindle elongating between the spindle pole bodies. We show here that in fission yeast interference with mitotic spindle formation delays mitosis only briefly and cells proceed to an unusual nuclear division process we term nuclear fission, during which cells perform some chromosome segregation and efficiently enter S-phase of the next cell cycle. Nuclear fission is blocked if spindle pole body maturation or sister chromatid separation cannot take place or if actin polymerization is inhibited. We suggest that this process exhibits vestiges of a primitive nuclear division process independent of spindle microtubules, possibly reflecting an evolutionary intermediate state between bacterial and Archeal chromosome segregation where the nucleoid divides without a spindle and a microtubule spindle-based eukaryotic mitosis. PMID- 20967238 TI - Genome-wide analyses reveal a role for peptide hormones in planarian germline development. AB - Bioactive peptides (i.e., neuropeptides or peptide hormones) represent the largest class of cell-cell signaling molecules in metazoans and are potent regulators of neural and physiological function. In vertebrates, peptide hormones play an integral role in endocrine signaling between the brain and the gonads that controls reproductive development, yet few of these molecules have been shown to influence reproductive development in invertebrates. Here, we define a role for peptide hormones in controlling reproductive physiology of the model flatworm, the planarian Schmidtea mediterranea. Based on our observation that defective neuropeptide processing results in defects in reproductive system development, we employed peptidomic and functional genomic approaches to characterize the planarian peptide hormone complement, identifying 51 prohormone genes and validating 142 peptides biochemically. Comprehensive in situ hybridization analyses of prohormone gene expression revealed the unanticipated complexity of the flatworm nervous system and identified a prohormone specifically expressed in the nervous system of sexually reproducing planarians. We show that this member of the neuropeptide Y superfamily is required for the maintenance of mature reproductive organs and differentiated germ cells in the testes. Additionally, comparative analyses of our biochemically validated prohormones with the genomes of the parasitic flatworms Schistosoma mansoni and Schistosoma japonicum identified new schistosome prohormones and validated half of all predicted peptide-encoding genes in these parasites. These studies describe the peptide hormone complement of a flatworm on a genome-wide scale and reveal a previously uncharacterized role for peptide hormones in flatworm reproduction. Furthermore, they suggest new opportunities for using planarians as free-living models for understanding the reproductive biology of flatworm parasites. PMID- 20967240 TI - Being more realistic about the public health impact of genomic medicine. PMID- 20967239 TI - Emergence of noise-induced oscillations in the central circadian pacemaker. AB - Bmal1 is an essential transcriptional activator within the mammalian circadian clock. We report here that the suprachiasmatic nucleus (SCN) of Bmal1-null mutant mice, unexpectedly, generates stochastic oscillations with periods that overlap the circadian range. Dissociated SCN neurons expressed fluctuating levels of PER2 detected by bioluminescence imaging but could not generate circadian oscillations intrinsically. Inhibition of intercellular communication or cyclic-AMP signaling in SCN slices, which provide a positive feed-forward signal to drive the intracellular negative feedback loop, abolished the stochastic oscillations. Propagation of this feed-forward signal between SCN neurons then promotes quasi circadian oscillations that arise as an emergent property of the SCN network. Experimental analysis and mathematical modeling argue that both intercellular coupling and molecular noise are required for the stochastic rhythms, providing a novel biological example of noise-induced oscillations. The emergence of stochastic circadian oscillations from the SCN network in the absence of cell autonomous circadian oscillatory function highlights a previously unrecognized level of circadian organization. PMID- 20967241 TI - Production and characterisation of a neutralising chimeric antibody against botulinum neurotoxin A. AB - Botulinum neurotoxins, produced by Clostridium botulinum bacteria, are the causative agent of botulism. This disease only affects a few hundred people each year, thus ranking it among the orphan diseases. However, botulinum toxin type A (BoNT/A) is the most potent toxin known to man. Due to their potency and ease of production, these toxins were classified by the Centers for Disease Control and Prevention (CDC) as Category A biothreat agents. For several biothreat agents, like BoNT/A, passive immunotherapy remains the only possible effective treatment allowing in vivo neutralization, despite possible major side effects. Recently, several mouse monoclonal antibodies directed against a recombinant fragment of BoNT/A were produced in our laboratory and most efficiently neutralised the neurotoxin. In the present work, the most powerful one, TA12, was selected for chimerisation. The variable regions of this antibody were thus cloned and fused with the constant counterparts of human IgG1 (kappa light and gamma 1 heavy chains). Chimeric antibody production was evaluated in mammalian myeloma cells (SP2/0-Ag14) and insect cells (Sf9). After purifying the recombinant antibody by affinity chromatography, the biochemical properties of chimeric and mouse antibody were compared. Both have the same very low affinity constant (close to 10 pM) and the chimeric antibody exhibited a similar capacity to its parent counterpart in neutralising the toxin in vivo. Its strong affinity and high neutralising potency make this chimeric antibody interesting for immunotherapy treatment in humans in cases of poisoning, particularly as there is a probable limitation of the immunological side effects observed with classical polyclonal antisera from heterologous species. PMID- 20967242 TI - Computer therapy for the anxiety and depressive disorders is effective, acceptable and practical health care: a meta-analysis. AB - BACKGROUND: Depression and anxiety disorders are common and treatable with cognitive behavior therapy (CBT), but access to this therapy is limited. OBJECTIVE: Review evidence that computerized CBT for the anxiety and depressive disorders is acceptable to patients and effective in the short and longer term. METHOD: Systematic reviews and data bases were searched for randomized controlled trials of computerized cognitive behavior therapy versus a treatment or control condition in people who met diagnostic criteria for major depression, panic disorder, social phobia or generalized anxiety disorder. Number randomized, superiority of treatment versus control (Hedges g) on primary outcome measure, risk of bias, length of follow up, patient adherence and satisfaction were extracted. PRINCIPAL FINDINGS: 22 studies of comparisons with a control group were identified. The mean effect size superiority was 0.88 (NNT 2.13), and the benefit was evident across all four disorders. Improvement from computerized CBT was maintained for a median of 26 weeks follow-up. Acceptability, as indicated by adherence and satisfaction, was good. Research probity was good and bias risk low. Effect sizes were non-significantly higher in comparisons with waitlist than with active treatment control conditions. Five studies comparing computerized CBT with traditional face-to-face CBT were identified, and both modes of treatment appeared equally beneficial. CONCLUSIONS: Computerized CBT for anxiety and depressive disorders, especially via the internet, has the capacity to provide effective acceptable and practical health care for those who might otherwise remain untreated. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000030077. PMID- 20967243 TI - Thermal stability of the human immunodeficiency virus type 1 (HIV-1) receptors, CD4 and CXCR4, reconstituted in proteoliposomes. AB - BACKGROUND: The entry of human immunodeficiency virus (HIV-1) into host cells involves the interaction of the viral exterior envelope glycoprotein, gp120, and receptors on the target cell. The HIV-1 receptors are CD4 and one of two chemokine receptors, CCR5 or CXCR4. METHODOLOGY/PRINCIPAL FINDINGS: We created proteoliposomes that contain CD4, the primary HIV-1 receptor, and one of the coreceptors, CXCR4. Antibodies against CD4 and CXCR4 specifically bound the proteoliposomes. CXCL12, the natural ligand for CXCR4, and the small-molecule CXCR4 antagonist, AMD3100, bound the proteoliposomes with affinities close to those associated with the binding of these molecules to cells expressing CXCR4 and CD4. The HIV-1 gp120 exterior envelope glycoprotein bound tightly to proteoliposomes expressing only CD4 and, in the presence of soluble CD4, bound weakly to proteoliposomes expressing only CXCR4. The thermal stability of CD4 and CXCR4 inserted into liposomes was examined. Thermal denaturation of CXCR4 followed second-order kinetics, with an activation energy (E(a)) of 269 kJ/mol (64.3 kcal/mol) and an inactivation temperature (T(i)) of 56 degrees C. Thermal inactivation of CD4 exhibited a reaction order of 1.3, an E(a) of 278 kJ/mol (66.5 kcal/mol), and a T(i) of 52.2 degrees C. The second-order denaturation kinetics of CXCR4 is unusual among G protein-coupled receptors, and may result from dimeric interactions between CXCR4 molecules. CONCLUSIONS/SIGNIFICANCE: Our studies with proteoliposomes containing the native HIV-1 receptors allowed an examination of the binding of biologically important ligands and revealed the higher-order denaturation kinetics of these receptors. CD4/CXCR4-proteoliposomes may be useful for the study of virus-target cell interactions and for the identification of inhibitors. PMID- 20967244 TI - Tiny sea anemone from the Lower Cambrian of China. AB - BACKGROUND: Abundant fossils from the Ediacaran and Cambrian showing cnidarian grade grossly suggest that cnidarian diversification occurred earlier than that of other eumetazoans. However, fossils of possible soft-bodied polyps are scanty and modern corals are dated back only to the Middle Triassic, although molecular phylogenetic results support the idea that anthozoans represent the first major branch of the Cnidaria. Because of difficulties in taxonomic assignments owing to imperfect preservation of fossil cnidarian candidates, little is known about forms ancestral to those of living groups. METHODS AND FINDINGS: We have analyzed the soft-bodied polypoid microfossils Eolympia pediculata gen. et sp. nov. from the lowest Cambrian Kuanchuanpu Formation in southern China by scanning electron microscopy and computer-aided microtomography after isolating fossils from sedimentary rocks by acetic acid maceration. The fossils, about a half mm in body size, are preserved with 18 mesenteries including directives bilaterally arranged, 18 tentacles and a stalk-like pedicle. The pedicle suggests a sexual life cycle, while asexual reproduction by transverse fission also is inferred by circumferential grooves on the body column. CONCLUSIONS: The features found in the present fossils fall within the morphological spectrum of modern Hexacorallia excluding Ceriantharia, and thus Eolympia pediculata could be a stem member for this group. The fossils also demonstrate that basic features characterizing modern hexacorallians such as bilateral symmetry and the reproductive system have deep roots in the Early Cambrian. PMID- 20967245 TI - Cytochrome P450 reductase: a harbinger of diffusible reduced oxygen species. AB - The bi-enzymatic system of cytochrome P450 (CYP, a hemoprotein) and cytochrome P450 reductase (CPR, a diflavoenzyme) mediate the redox metabolism of diverse indigenous and xenobiotic molecules in various cellular and organ systems, using oxygen and NADPH. Curiously, when a 1:1 ratio is seen to be optimal for metabolism, the ubiquitous CYP:CPR distribution ratio is 10 to 100:1 or higher. Further, the NADPH equivalents consumed in these in vitro or in situ assemblies usually far exceeded the amount of substrate metabolized. We aimed to find the rationale to explain for these two oddities. We report here that CPR is capable of activating molecular oxygen on its own merit, generating diffusible reduced oxygen species (DROS). Also, in the first instance for a flavoprotein, CPR is shown to deplete peroxide via diffusible radical mediated process, thereby leading to the formation of water (but without significant evolution of oxygen). We also quantitatively demonstrate that the rate of oxygen activation and peroxide depletion by CPR accounts for the major reactivity in the CYP+CPR mixture. We show unambiguously that CPR is able to regulate the concentration of diffusible reduced oxygen species in the reaction milieu. These findings point out that CPR mediated processes are bound to be energetically 'wasteful' and potentially 'hazardous' owing to the unavoidable nature of the CPR to generate and deplete DROS. Hence, we can understand that CPR is distributed at low densities in cells. Some of the activities that were primarily attributed to the heme-center of CYP are now established to be a facet of the flavins of CPR. The current approach of modeling drugs to minimize "uncoupling" on the basis of erstwhile hypothesis stands questionable, considering the ideas brought forth in this work. PMID- 20967246 TI - Dynamics of the Drosophila circadian clock: theoretical anti-jitter network and controlled chaos. AB - BACKGROUND: Electronic clocks exhibit undesirable jitter or time variations in periodic signals. The circadian clocks of humans, some animals, and plants consist of oscillating molecular networks with peak-to-peak time of approximately 24 hours. Clockwork orange (CWO) is a transcriptional repressor of Drosophila direct target genes. METHODOLOGY/PRINCIPAL FINDINGS: Theory and data from a model of the Drosophila circadian clock support the idea that CWO controls anti-jitter negative circuits that stabilize peak-to-peak time in light-dark cycles (LD). The orbit is confined to chaotic attractors in both LD and dark cycles and is almost periodic in LD; furthermore, CWO diminishes the Euclidean dimension of the chaotic attractor in LD. Light resets the clock each day by restricting each molecular peak to the proximity of a prescribed time. CONCLUSIONS/SIGNIFICANCE: The theoretical results suggest that chaos plays a central role in the dynamics of the Drosophila circadian clock and that a single molecule, CWO, may sense jitter and repress it by its negative loops. PMID- 20967247 TI - Transitions between central and peripheral vision create spatial/temporal distortions: a hypothesis concerning the perceived break of the curveball. AB - BACKGROUND: The human visual system does not treat all parts of an image equally: the central segments of an image, which fall on the fovea, are processed with a higher resolution than the segments that fall in the visual periphery. Even though the differences between foveal and peripheral resolution are large, these differences do not usually disrupt our perception of seamless visual space. Here we examine a motion stimulus in which the shift from foveal to peripheral viewing creates a dramatic spatial/temporal discontinuity. METHODOLOGY/PRINCIPAL FINDINGS: The stimulus consists of a descending disk (global motion) with an internal moving grating (local motion). When observers view the disk centrally, they perceive both global and local motion (i.e., observers see the disk's vertical descent and the internal spinning). When observers view the disk peripherally, the internal portion appears stationary, and the disk appears to descend at an angle. The angle of perceived descent increases as the observer views the stimulus from further in the periphery. We examine the first- and second-order information content in the display with the use of a three dimensional Fourier analysis and show how our results can be used to describe perceived spatial/temporal discontinuities in real-world situations. CONCLUSIONS/SIGNIFICANCE: The perceived shift of the disk's direction in the periphery is consistent with a model in which foveal processing separates first- and second-order motion information while peripheral processing integrates first- and second-order motion information. We argue that the perceived distortion may influence real-world visual observations. To this end, we present a hypothesis and analysis of the perception of the curveball and rising fastball in the sport of baseball. The curveball is a physically measurable phenomenon: the imbalance of forces created by the ball's spin causes the ball to deviate from a straight line and to follow a smooth parabolic path. However, the curveball is also a perceptual puzzle because batters often report that the flight of the ball undergoes a dramatic and nearly discontinuous shift in position as the ball nears home plate. We suggest that the perception of a discontinuous shift in position results from differences between foveal and peripheral processing. PMID- 20967248 TI - Rapid and highly sensitive detection of malaria-infected erythrocytes using a cell microarray chip. AB - BACKGROUND: Malaria is one of the major human infectious diseases in many endemic countries. For prevention of the spread of malaria, it is necessary to develop an early, sensitive, accurate and conventional diagnosis system. METHODS AND FINDINGS: A cell microarray chip was used to detect for malaria-infected erythrocytes. The chip, with 20,944 microchambers (105 um width and 50 um depth), was made from polystyrene, and the formation of monolayers of erythrocytes in the microchambers was observed. Cultured Plasmodium falciparum strain 3D7 was used to examine the potential of the cell microarray chip for malaria diagnosis. An erythrocyte suspension in a nuclear staining dye, SYTO 59, was dispersed on the chip surface, followed by 10 min standing to allow the erythrocytes to settle down into the microchambers. About 130 erythrocytes were accommodated in each microchamber, there being over 2,700,000 erythrocytes in total on a chip. A microarray scanner was employed to detect any fluorescence-positive erythrocytes within 5 min, and 0.0001% parasitemia could be detected. To examine the contamination by leukocytes of purified erythrocytes from human blood, 20 ul of whole blood was mixed with 10 ml of RPMI 1640, and the mixture was passed through a leukocyte isolation filter. The eluted portion was centrifuged at 1,000*g for 2 min, and the pellet was dispersed in 1.0 ml of medium. SYTO 59 was added to the erythrocyte suspension, followed by analysis on a cell microarray chip. Similar accommodation of cells in the microchambers was observed. The number of contaminating leukocytes was less than 1 on a cell microarray chip. CONCLUSION: The potential of the cell microarray chip for the detection of malaria-infected erythrocytes was shown, it offering 10-100 times higher sensitivity than that of conventional light microscopy and easy operation in 15 min with purified erythrocytes. PMID- 20967249 TI - Multiple routes and milestones in the folding of HIV-1 protease monomer. AB - Proteins fold on a time scale incompatible with a mechanism of random search in conformational space thus indicating that somehow they are guided to the native state through a funneled energetic landscape. At the same time the heterogeneous kinetics suggests the existence of several different folding routes. Here we propose a scenario for the folding mechanism of the monomer of HIV-1 protease in which multiple pathways and milestone events coexist. A variety of computational approaches supports this picture. These include very long all-atom molecular dynamics simulations in explicit solvent, an analysis of the network of clusters found in multiple high-temperature unfolding simulations and a complete characterization of free-energy surfaces carried out using a structure-based potential at atomistic resolution and a combination of metadynamics and parallel tempering. Our results confirm that the monomer in solution is stable toward unfolding and show that at least two unfolding pathways exist. In our scenario, the formation of a hydrophobic core is a milestone in the folding process which must occur along all the routes that lead this protein towards its native state. Furthermore, the ensemble of folding pathways proposed here substantiates a rational drug design strategy based on inhibiting the folding of HIV-1 protease. PMID- 20967250 TI - Influences of forest structure, climate and species composition on tree mortality across the eastern US. AB - Few studies have quantified regional variation in tree mortality, or explored whether species compositional changes or within-species variation are responsible for regional patterns, despite the fact that mortality has direct effects on the dynamics of woody biomass, species composition, stand structure, wood production and forest response to climate change. Using bayesian analysis of over 430,000 tree records from a large eastern US forest database we characterised tree mortality as a function of climate, soils, species and size (stem diameter). We found (1) mortality is U-shaped vs. stem diameter for all 21 species examined; (2) mortality is hump-shaped vs. plot basal area for most species; (3) geographical variation in mortality is substantial, and correlated with several environmental factors; and (4) individual species vary substantially from the combined average in the nature and magnitude of their mortality responses to environmental variation. Regional variation in mortality is therefore the product of variation in species composition combined with highly varied mortality environment correlations within species. The results imply that variation in mortality is a crucial part of variation in the forest carbon cycle, such that including this variation in models of the global carbon cycle could significantly narrow uncertainty in climate change predictions. PMID- 20967251 TI - Chloroquine clinical failures in P. falciparum malaria are associated with mutant Pfmdr-1, not Pfcrt in Madagascar. AB - Molecular studies have demonstrated that mutations in the Plasmodium falciparum chloroquine resistance transporter gene (Pfcrt) play a major role in chloroquine resistance, while mutations in P. falciparum multidrug resistance gene (Pfmdr-1) act as modulator. In Madagascar, the high rate of chloroquine treatment failure (44%) appears disconnected from the overall level of in vitro CQ susceptibility (prevalence of CQ-resistant parasites <5%) or Pfcrt mutant isolates (<1%), strongly contrasting with sub-Saharan African countries. Previous studies showed a high frequency of Pfmdr-1 mutant parasites (>60% of isolates), but did not explore their association with P. falciparum chloroquine resistance. To document the association of Pfmdr-1 alleles with chloroquine resistance in Madagascar, 249 P. falciparum samples collected from patients enrolled in a chloroquine in vivo efficacy study were genotyped in Pfcrt/Pfmdr-1 genes as well as the estimation of the Pfmdr-1 copy number. Except 2 isolates, all samples displayed a wild-type Pfcrt allele without Pfmdr-1 amplification. Chloroquine treatment failures were significantly associated with Pfmdr-1 86Y mutant codon (OR = 4.6). The cumulative incidence of recurrence of patients carrying the Pfmdr-1 86Y mutation at day 0 (21 days) was shorter than patients carrying Pfmdr-1 86N wild type codon (28 days). In an independent set of 90 selected isolates, in vitro susceptibility to chloroquine was not associated with Pfmdr-1 polymorphisms. Analysis of two microsatellites flanking Pfmdr-1 allele showed that mutations occurred on multiple genetic backgrounds. In Madagascar, Pfmdr-1 polymorphism is associated with late chloroquine clinical failures and unrelated with in vitro susceptibility or Pfcrt genotype. These results highlight the limits of the current in vitro tests routinely used to monitor CQ drug resistance in this unique context. Gaining insight about the mechanisms that regulate polymorphism in Pfmdr1 remains important, particularly regarding the evolution and spread of Pfmdr-1 alleles in P. falciparum populations under changing drug pressure which may have important consequences in terms of antimalarial use management. PMID- 20967252 TI - Do scientific advancements lean on the shoulders of giants? A bibliometric investigation of the Ortega hypothesis. AB - BACKGROUND: In contrast to Newton's well-known aphorism that he had been able "to see further only by standing on the shoulders of giants," one attributes to the Spanish philosopher Ortega y Gasset the hypothesis saying that top-level research cannot be successful without a mass of medium researchers on which the top rests comparable to an iceberg. METHODOLOGY/PRINCIPAL FINDINGS: The Ortega hypothesis predicts that highly-cited papers and medium-cited (or lowly-cited) papers would equally refer to papers with a medium impact. The Newton hypothesis would be supported if the top-level research more frequently cites previously highly-cited work than that medium-level research cites highly-cited work. Our analysis is based on (i) all articles and proceedings papers which were published in 2003 in the life sciences, health sciences, physical sciences, and social sciences, and (ii) all articles and proceeding papers which were cited within these publications. The results show that highly-cited work in all scientific fields more frequently cites previously highly-cited papers than that medium-cited work cites highly-cited work. CONCLUSIONS/SIGNIFICANCE: We demonstrate that papers contributing to the scientific progress in a field lean to a larger extent on previously important contributions than papers contributing little. These findings support the Newton hypothesis and call into question the Ortega hypothesis (given our usage of citation counts as a proxy for impact). PMID- 20967253 TI - Opposite associations of trunk and leg fat depots with plasma ferritin levels in middle-aged and older Chinese men and women. AB - BACKGROUND: Few data have been published on the associations of ferritin with trunk and leg fat depots. We aimed to investigate these associations in a Chinese population. METHODOLOGY: Trunk fat mass and leg fat mass were determined in a cross-sectional sample of 1,150 Chinese (479 men and 671 women) aged 50-70 years by dual-energy X-ray absorptiometry scan. Fasting plasma ferritin was measured. PRINCIPAL FINDINGS: Plasma ferritin was positively correlated with waist circumference, waist-to-hip ratio, total body fat and trunk fat mass, but inversely correlated with leg fat mass in men (r = 0.16, 0.26, 0.19, 0.22 and 0.12, respectively, all P<0.05) and women (r = 0.16, 0.16, 0.08, 0.17 and -0.12, respectively, all P<0.05). Multivariate regression analysis showed that ferritin levels increased with larger trunk fat mass (beta = 0.33 +/- 0.08 for men and beta = 0.21 +/- 0.05 for women, both P<0.001) while decreased with larger leg fat mass (beta = -0.12 +/- 0.09, P = 0.15 for men; and beta = -0.14 +/- 0.05, P = 0.005 for women). Moreover, plasma ferritin levels decreased with increasing tertile of leg fat mass among each tertile of trunk fat mass. CONCLUSION: This is the first study to report the opposite associations of trunk and leg fat depots with plasma ferritin levels. PMID- 20967254 TI - Towards a rational screening strategy for albuminuria: results from the unreferred renal insufficiency trial. AB - BACKGROUND: There remains debate about the screening strategies for albuminuria. This study evaluated whether a screening strategy in an apparently healthy population based on basic clinical and biochemical parameters could be more effective than a strategy where screening for albuminuria is performed unselectively. METHODOLOGY/PRINCIPAL FINDINGS: The Unreferred Renal Insufficiency (URI) Study is a cross-sectional study on the prevalence of metabolic risk factors in Belgian workers, volunteering to be screened during a routine yearly occupational check-up. Subjects (n = 295) with treated hypertension, known diabetes, treated dyslipidaemia, cardiovascular and renal disease were excluded. Among 1,191 apparently healthy subjects, 23% had unknown hypertension, 13% had impaired glucose tolerance, 15.4% had normoalbuminuria, 4.2% had microalbuminuria and 0.4% had macroalbuminuria. Subjects with resting heart rate >=85 bpm, plasma glucose >=5.6 mmol/L and blood pressure >=140/90 mmHg were associated with albuminuria of any degree. A strategy where only subjects with at least one of these risk factors (n = 431) were screened for albuminuria, would identify all subjects with macroalbuminuria (5/5), 64% of those with microalbuminuria (32/50), and less than half of those with normoalbuminuria (81/183). An alternative strategy whereby subjects were first screened for presence of albuminuria, and additional cardiovascular risk factors were only measured in subjects positive for albuminuria (n = 238), would identify only 27% (118/431) of the subjects with additional and potentially modifiable cardiovascular risk factors. On the other hand, half of the subjects in this study with albuminuria (120/238, of which 102 had normoalbuminuria), had no additional cardiovascular risk factor at all. CONCLUSIONS: Screening an apparently healthy population directly for albuminuria will result in a high percentage of false positives, mostly measured in the normal range. Screening for microalbuminuria and macroalbuminuria based on presence of additional, potentially modifiable risk factors appears to be more beneficial. Trial registration 2006 NCT00365911. PMID- 20967255 TI - Neuroanatomical study of the A11 diencephalospinal pathway in the non-human primate. AB - BACKGROUND: The A11 diencephalospinal pathway is crucial for sensorimotor integration and pain control at the spinal cord level. When disrupted, it is thought to be involved in numerous painful conditions such as restless legs syndrome and migraine. Its anatomical organization, however, remains largely unknown in the non-human primate (NHP). We therefore characterized the anatomy of this pathway in the NHP. METHODS AND FINDINGS: In situ hybridization of spinal dopamine receptors showed that D1 receptor mRNA is absent while D2 and D5 receptor mRNAs are mainly expressed in the dorsal horn and D3 receptor mRNA in both the dorsal and ventral horns. Unilateral injections of the retrograde tracer Fluoro-Gold (FG) into the cervical spinal enlargement labeled A11 hypothalamic neurons quasi-exclusively among dopamine areas. Detailed immunohistochemical analysis suggested that these FG-labeled A11 neurons are tyrosine hydroxylase positive but dopa-decarboxylase and dopamine transporter-negative, suggestive of a L-DOPAergic nucleus. Stereological cell count of A11 neurons revealed that this group is composed by 4002+/-501 neurons per side. A 1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine (MPTP) intoxication with subsequent development of a parkinsonian syndrome produced a 50% neuronal cell loss in the A11 group. CONCLUSION: The diencephalic A11 area could be the major source of L-DOPA in the NHP spinal cord, where it may play a role in the modulation of sensorimotor integration through D2 and D3 receptors either directly or indirectly via dopamine formation in spinal dopa-decarboxylase-positives cells. PMID- 20967256 TI - Cooperation, norms, and revolutions: a unified game-theoretical approach. AB - BACKGROUND: Cooperation is of utmost importance to society as a whole, but is often challenged by individual self-interests. While game theory has studied this problem extensively, there is little work on interactions within and across groups with different preferences or beliefs. Yet, people from different social or cultural backgrounds often meet and interact. This can yield conflict, since behavior that is considered cooperative by one population might be perceived as non-cooperative from the viewpoint of another. METHODOLOGY AND PRINCIPAL FINDINGS: To understand the dynamics and outcome of the competitive interactions within and between groups, we study game-dynamical replicator equations for multiple populations with incompatible interests and different power (be this due to different population sizes, material resources, social capital, or other factors). These equations allow us to address various important questions: For example, can cooperation in the prisoner's dilemma be promoted, when two interacting groups have different preferences? Under what conditions can costly punishment, or other mechanisms, foster the evolution of norms? When does cooperation fail, leading to antagonistic behavior, conflict, or even revolutions? And what incentives are needed to reach peaceful agreements between groups with conflicting interests? CONCLUSIONS AND SIGNIFICANCE: Our detailed quantitative analysis reveals a large variety of interesting results, which are relevant for society, law and economics, and have implications for the evolution of language and culture as well. PMID- 20967258 TI - Genomic signature-based identification of influenza A viruses using RT PCR/electro-spray ionization mass spectrometry (ESI-MS) technology. AB - BACKGROUND: The emergence and rapid spread of the 2009 H1N1 pandemic influenza A virus (H1N1pdm) in humans highlights the importance of enhancing the capability of existing influenza surveillance systems with tools for rapid identification of emerging and re-emerging viruses. One of the new approaches is the RT-PCR electrospray ionization mass spectrometry (RT-PCR/ESI-MS) technology, which is based on analysis of base composition (BC) of RT-PCR amplicons from influenza "core" genes. Combination of the BC signatures represents a "genomic print" of an influenza A virus. METHODOLOGY/PRINCIPAL FINDINGS: Here, 757 samples collected between 2006 and 2009 were tested, including 302 seasonal H1N1, 171 H3N2, 7 swine triple reassortants, and 277 H1N1pdm viruses. Of the 277 H1N1pdm samples, 209 were clinical specimens (throat, nasal and nasopharyngeal swabs, nasal washes, blood and sputum). BC signatures for the clinical specimen from one of the first cases of the 2009 pandemic, A/California/04/2009, confirmed it as an unusual, previously unrecognized influenza A virus, with "core" genes related to viruses of avian, human and swine origins. Subsequent analysis of additional 276 H1N1pdm samples revealed that they shared the genomic print of A/California/04/2009, which differed from those of North American swine triple reassortant viruses, seasonal H1N1 and H3N2 and other viruses tested. Moreover, this assay allowed distinction between "core" genes of co-circulating groups of seasonal H1N1, such as clades 2B, 2C, and their reassortants with dual antiviral resistance to adamantanes and oseltamivir. CONCLUSIONS/SIGNIFICANCE: The RT-PCR/ESI-MS assay is a broad range influenza identification tool that can be used directly on clinical specimens for rapid and accurate detection of influenza virus genes. The assay differentiates the H1N1pdm from seasonal and other nonhuman hosts viruses. Although not a diagnostic tool, this assay demonstrates its usefulness and robustness in influenza virus surveillance and detection of novel and unusual viruses with previously unseen genomic prints. PMID- 20967259 TI - MicroRNA discovery and analysis of pinewood nematode Bursaphelenchus xylophilus by deep sequencing. AB - BACKGROUND: MicroRNAs (miRNAs) are considered to be very important in regulating the growth, development, behavior and stress response in animals and plants in post-transcriptional gene regulation. Pinewood nematode, Bursaphelenchus xylophilus, is an important invasive plant parasitic nematode in Asia. To have a comprehensive knowledge about miRNAs of the nematode is necessary for further in depth study on roles of miRNAs in the ecological adaptation of the invasive species. METHODS AND FINDINGS: Five small RNA libraries were constructed and sequenced by Illumina/Solexa deep-sequencing technology. A total of 810 miRNA candidates (49 conserved and 761 novel) were predicted by a computational pipeline, of which 57 miRNAs (20 conserved and 37 novel) encoded by 53 miRNA precursors were identified by experimental methods. Ten novel miRNAs were considered to be species-specific miRNAs of B. xylophilus. Comparison of expression profiles of miRNAs in the five small RNA libraries showed that many miRNAs exhibited obviously different expression levels in the third-stage dispersal juvenile and at a cold-stressed status. Most of the miRNAs exhibited obviously down-regulated expression in the dispersal stage. But differences among the three geographic libraries were not prominent. A total of 979 genes were predicted to be targets of these authentic miRNAs. Among them, seven heat shock protein genes were targeted by 14 miRNAs, and six FMRFamide-like neuropeptides genes were targeted by 17 miRNAs. A real-time quantitative polymerase chain reaction was used to quantify the mRNA expression levels of target genes. CONCLUSIONS: Basing on the fact that a negative correlation existed between the expression profiles of miRNAs and the mRNA expression profiles of their target genes (hsp, flp) by comparing those of the nematodes at a cold stressed status and a normal status, we suggested that miRNAs might participate in ecological adaptation and behavior regulation of the nematode. This is the first description of miRNAs in plant parasitic nematodes. The results provide a useful resource for further in-depth study on molecular regulation and evolution of miRNAs in plant parasitic nematodes. PMID- 20967260 TI - Brn2 is a transcription factor regulating keratinocyte differentiation with a possible role in the pathogenesis of lichen planus. AB - Terminal differentiation of skin keratinocytes is a vertically directed multi step process that is tightly controlled by the sequential expression of a variety of genes. In this study, we investigated the role of the POU domain-containing transcription factor Brn2 in keratinocyte differentiation. Immunohistochemical analysis showed that Brn2 is expressed primarily in the upper granular layer. Consistent with its epidermal localization, Brn2 expression was highly induced at 14 days after calcium treatment of cultured normal human epidermal keratinocytes. When Brn2 was overexpressed by adenoviral transduction, Brn2 led to increased expression of the differentiation-related genes involucrin, filaggrin, and loricrin in addition to inhibition of their proliferation. Chromatin immunoprecipitation demonstrated that Brn2 bound to the promoter regions of these differentiation-related genes. We injected the purified Brn2 adenovirus into rat skin, which led to a thickened epidermis with increased amounts of differentiation related markers. The histopathologic features of adenovirus-Brn2 injected skin tissues looked similar to the features of lichen planus, a human skin disease showing chronic inflammation and well-differentiated epidermal changes. Moreover, Brn2 is shown to be expressed in almost all cell nuclei of the thickened epidermis of lichen planus, and Brn2 also attracts T lymphocytes. Our results demonstrate that Brn2 is probably a transcriptional factor playing an important role in keratinocyte differentiation and probably also in the pathogenesis of lichen planus lesions. PMID- 20967261 TI - Renal transplant immunosuppression impairs natural killer cell function in vitro and in vivo. AB - BACKGROUND: Despite an increasing awareness of the importance of innate immunity, the roles of natural killer (NK) cells in transplant rejection and antiviral and cancer immunity during immunosuppression have not been clearly defined. METHODS: To address this issue we have developed a quantitative assay of NK cell function that can be used on clinical samples and have studied the influence of immunosuppression on NK cell function. NK cell degranulation and intracellular interferon (IFN)-gamma production were determined by flow cytometry of peripheral blood samples. RESULTS: Overnight ex vivo treatment of peripheral blood cells from healthy controls with ciclosporin or tacrolimus inhibited NK cell degranulation and IFN-gamma production in a dose-dependent manner. A similar impairment of function was seen in NK cells from patients treated in vivo with calcineurin inhibitors. In the early post-transplant period, there was a variable reduction of NK cell counts after treatment with alemtuzumab and basiliximab. CONCLUSIONS: The functional inhibition of NK cells in early transplant patients coincides with the period of maximum susceptibility to viral infections. The ability to assay NK cell function in clinical samples allows assessment of the impact of immunosuppression on these effector cells. This information may be helpful in guiding the titration of immunosuppression in the clinical setting. PMID- 20967263 TI - Treating viral exacerbations of chronic obstructive pulmonary disease: insights from a mouse model of cigarette smoke and H1N1 influenza infection. AB - BACKGROUND: Chronic obstructive pulmonary disease is a progressive lung disease that is punctuated by periods of exacerbations (worsening of symptoms) that are attributable to viral infections. While rhinoviruses are most commonly isolated viruses during episodes of exacerbation, influenza viruses have the potential to become even more problematic with the increased likelihood of an epidemic. METHODOLOGY AND PRINCIPAL FINDINGS: This study examined the impact of current and potential pharmacological targets namely the systemic corticosteroid dexamethasone and the peroxisome proliferator-activated receptor-gamma agonist pioglitazone on the outcome of infection in smoke-exposed mice. C57BL/6 mice were exposed to room air or cigarette smoke for 4 days and subsequently inoculated with an H1N1 influenza A virus. Interventions were delivered daily during the course of infection. We show that smoke-exposed mice have an exacerbated inflammatory response following infection. While smoke exposure did not compromise viral clearance, precision cut lung slices from smoke-exposed mice showed greater expression of CC (MCP-1, -3), and CXC (KC, MIP-2, GCP-2) chemokines compared to controls when stimulated with a viral mimic or influenza A virus. While dexamethasone treatment partially attenuated the inflammatory response in the broncho-alveolar lavage of smoke-exposed, virally-infected animals, viral-induced neutrophilia was steroid insensitive. In contrast to controls, dexamethasone-treated smoke-exposed influenza-infected mice had a worsened health status. Pioglitazone treatment of virally-infected smoke-exposed mice proved more efficacious than the steroid intervention. Further mechanistic evaluation revealed that a deficiency in CCR2 did not improve the inflammatory outcome in smoke-exposed, virally-infected animals. CONCLUSIONS AND SIGNIFICANCE: This animal model of cigarette smoke and H1N1 influenza infection demonstrates that smoke-exposed animals are differentially primed to respond to viral insult. While providing a platform to test pharmacological interventions, this model demonstrates that treating viral exacerbations with alternative anti-inflammatory drugs, such as PPAR-gamma agonists should be further explored since they showed greater efficacy than systemic corticosteroids. PMID- 20967264 TI - Tumor necrosis factor-alpha regulates distinct molecular pathways and gene networks in cultured skeletal muscle cells. AB - BACKGROUND: Skeletal muscle wasting is a debilitating consequence of large number of disease states and conditions. Tumor necrosis factor-alpha (TNF-alpha) is one of the most important muscle-wasting cytokine, elevated levels of which cause significant muscular abnormalities. However, the underpinning molecular mechanisms by which TNF-alpha causes skeletal muscle wasting are less well understood. METHODOLOGY/PRINCIPAL FINDINGS: We have used microarray, quantitative real-time PCR (QRT-PCR), Western blot, and bioinformatics tools to study the effects of TNF-alpha on various molecular pathways and gene networks in C2C12 cells (a mouse myoblastic cell line). Microarray analyses of C2C12 myotubes treated with TNF-alpha (10 ng/ml) for 18h showed differential expression of a number of genes involved in distinct molecular pathways. The genes involved in nuclear factor-kappa B (NF-kappaB) signaling, 26s proteasome pathway, Notch1 signaling, and chemokine networks are the most important ones affected by TNF alpha. The expression of some of the genes in microarray dataset showed good correlation in independent QRT-PCR and Western blot assays. Analysis of TNF treated myotubes showed that TNF-alpha augments the activity of both canonical and alternative NF-kappaB signaling pathways in myotubes. Bioinformatics analyses of microarray dataset revealed that TNF-alpha affects the activity of several important pathways including those involved in oxidative stress, hepatic fibrosis, mitochondrial dysfunction, cholesterol biosynthesis, and TGF-beta signaling. Furthermore, TNF-alpha was found to affect the gene networks related to drug metabolism, cell cycle, cancer, neurological disease, organismal injury, and abnormalities in myotubes. CONCLUSIONS: TNF-alpha regulates the expression of multiple genes involved in various toxic pathways which may be responsible for TNF-induced muscle loss in catabolic conditions. Our study suggests that TNF alpha activates both canonical and alternative NF-kappaB signaling pathways in a time-dependent manner in skeletal muscle cells. The study provides novel insight into the mechanisms of action of TNF-alpha in skeletal muscle cells. PMID- 20967265 TI - Silkworm coatomers and their role in tube expansion of posterior silkgland. AB - BACKGROUND: Coat protein complex I (COPI) vesicles, coated by seven coatomer subunits, are mainly responsible for Golgi-to-ER transport. Silkworm posterior silkgland (PSG), a highly differentiated secretory tissue, secretes fibroin for silk production, but many physiological processes in the PSG cells await further investigation. METHODOLOGY/PRINCIPAL FINDINGS: Here, to investigate the role of silkworm COPI, we cloned six silkworm COPI subunits (alpha, beta, beta', delta, epsilon, and zeta-COP), determined their peak expression in day 2 in fifth-instar PSG, and visualized the localization of COPI, as a coat complex, with cis-Golgi. By dsRNA injection into silkworm larvae, we suppressed the expression of alpha-, beta'- and gamma-COP, and demonstrated that COPI subunits were required for PSG tube expansion. Knockdown of alpha-COP disrupted the integrity of Golgi apparatus and led to a narrower glandular lumen of the PSG, suggesting that silkworm COPI is essential for PSG tube expansion. CONCLUSIONS/SIGNIFICANCE: The initial characterization reveals the essential roles of silkworm COPI in PSG. Although silkworm COPI resembles the previously characterized coatomers in other organisms, some surprising findings require further investigation. Therefore, our results suggest the silkworm as a model for studying intracellular transport, and would facilitate the establishment of silkworm PSG as an efficient bioreactor. PMID- 20967262 TI - Expression of conjoined genes: another mechanism for gene regulation in eukaryotes. AB - From the ENCODE project, it is realized that almost every base of the entire human genome is transcribed. One class of transcripts resulting from this arises from the conjoined gene, which is formed by combining the exons of two or more distinct (parent) genes lying on the same strand of a chromosome. Only a very limited number of such genes are known, and the definition and terminologies used for them are highly variable in the public databases. In this work, we have computationally identified and manually curated 751 conjoined genes (CGs) in the human genome that are supported by at least one mRNA or EST sequence available in the NCBI database. 353 representative CGs, of which 291 (82%) could be confirmed, were subjected to experimental validation using RT-PCR and sequencing methods. We speculate that these genes are arising out of novel functional requirements and are not merely artifacts of transcription, since more than 70% of them are conserved in other vertebrate genomes. The unique splicing patterns exhibited by CGs reveal their possible roles in protein evolution or gene regulation. Novel CGs, for which no transcript is available, could be identified in 80% of randomly selected potential CG forming regions, indicating that their formation is a routine process. Formation of CGs is not only limited to human, as we have also identified 270 CGs in mouse and 227 in drosophila using our approach. Additionally, we propose a novel mechanism for the formation of CGs. Finally, we developed a database, ConjoinG, which contains detailed information about all the CGs (800 in total) identified in the human genome. In summary, our findings reveal new insights about the functionality of CGs in terms of another possible mechanism for gene regulation and genomic evolution and the mechanism leading to their formation. PMID- 20967266 TI - Reduced satellite cell numbers and myogenic capacity in aging can be alleviated by endurance exercise. AB - BACKGROUND: Muscle regeneration depends on satellite cells, myogenic stem cells that reside on the myofiber surface. Reduced numbers and/or decreased myogenic aptitude of these cells may impede proper maintenance and contribute to the age associated decline in muscle mass and repair capacity. Endurance exercise was shown to improve muscle performance; however, the direct impact on satellite cells in aging was not yet thoroughly determined. Here, we focused on characterizing the effect of moderate-intensity endurance exercise on satellite cell, as possible means to attenuate adverse effects of aging. Young and old rats of both genders underwent 13 weeks of treadmill-running or remained sedentary. METHODOLOGY: Gastrocnemius muscles were assessed for the effect of age, gender and exercise on satellite-cell numbers and myogenic capacity. Satellite cells were identified in freshly isolated myofibers based on Pax7 immunostaining (i.e., ex-vivo). The capacity of individual myofiber-associated cells to produce myogenic progeny was determined in clonal assays (in-vitro). We show an age associated decrease in satellite-cell numbers and in the percent of myogenic clones in old sedentary rats. Upon exercise, there was an increase in myofibers that contain higher numbers of satellite cells in both young and old rats, and an increase in the percent of myogenic clones derived from old rats. Changes at the satellite cell level in old rats were accompanied with positive effects on the lean-to-fat Gast muscle composition and on spontaneous locomotion levels. The significance of these data is that they suggest that the endurance exercise mediated boost in both satellite numbers and myogenic properties may improve myofiber maintenance in aging. PMID- 20967268 TI - Genipin-induced inhibition of uncoupling protein-2 sensitizes drug-resistant cancer cells to cytotoxic agents. AB - Uncoupling protein-2 (UCP2) is known to suppress mitochondrial reactive oxygen species (ROS) production and is employed by drug-resistant cancer cells to mitigate oxidative stress. Using the drug-sensitive HL-60 cells and the drug resistant MX2 subline as model systems, we show that genipin, a UCP2 inhibitor, sensitizes drug-resistant cells to cytotoxic agents. Increased MX2 cell death was observed upon co-treatment with genipin and different doses of menadione, doxorubicin, and epirubicin. DCFH-DA fluorimetry revealed that the increase in MX2 cell death was accompanied by enhanced cellular ROS levels. The drug-induced increase in ROS was linked to genipin-mediated inhibition of mitochondrial proton leak. State 4 and resting cellular respiratory rates were higher in the MX2 cells in comparison to the HL-60 cells, and the increased respiration was readily suppressed by genipin in the MX2 cells. UCP2 accounted for a remarkable 37% of the resting cellular oxygen consumption indicating that the MX2 cells are functionally reliant on this protein. Higher amounts of UCP2 protein were detected in the MX2 versus the HL-60 mitochondria. The observed effects of genipin were absent in the HL-60 cells pointing to the selectivity of this natural product for drug-resistant cells. The specificity of genipin for UCP2 was confirmed using CHO cells stably expressing UCP2 in which genipin induced an ~22% decrease in state 4 respiration. These effects were absent in empty vector CHO cells expressing no UCP2. Thus, the chemical inhibition of UCP2 with genipin sensitizes multidrug-resistant cancer cells to cytotoxic agents. PMID- 20967267 TI - Abnormalities in oxygen sensing define early and late onset preeclampsia as distinct pathologies. AB - BACKGROUND: The pathogenesis of preeclampsia, a serious pregnancy disorder, is still elusive and its treatment empirical. Hypoxia Inducible Factor-1 (HIF-1) is crucial for placental development and early detection of aberrant regulatory mechanisms of HIF-1 could impact on the diagnosis and management of preeclampsia. HIF-1alpha stability is controlled by O(2)-sensing enzymes including prolyl hydroxylases (PHDs), Factor Inhibiting HIF (FIH), and E3 ligases Seven In Absentia Homologues (SIAHs). Here we investigated early- (E-PE) and late-onset (L PE) human preeclamptic placentae and their ability to sense changes in oxygen tension occurring during normal placental development. METHODS AND FINDINGS: Expression of PHD2, FIH and SIAHs were significantly down-regulated in E-PE compared to control and L-PE placentae, while HIF-1alpha levels were increased. PHD3 expression was increased due to decreased FIH levels as demonstrated by siRNA FIH knockdown experiments in trophoblastic JEG-3 cells. E-PE tissues had markedly diminished HIF-1alpha hydroxylation at proline residues 402 and 564 as assessed with monoclonal antibodies raised against hydroxylated HIF-1alpha P402 or P564, suggesting regulation by PHD2 and not PHD3. Culturing villous explants under varying oxygen tensions revealed that E-PE, but not L-PE, placentae were unable to regulate HIF-1alpha levels because PHD2, FIH and SIAHs did not sense a hypoxic environment. CONCLUSION: Disruption of oxygen sensing in E-PE vs. L-PE and control placentae is the first molecular evidence of the existence of two distinct preeclamptic diseases and the unique molecular O(2)-sensing signature of E-PE placentae may be of diagnostic value when assessing high risk pregnancies and their severity. PMID- 20967269 TI - Prediction of optimal folding routes of proteins that satisfy the principle of lowest entropy loss: dynamic contact maps and optimal control. AB - An optimization model is introduced in which proteins try to evade high energy regions of the folding landscape, and prefer low entropy loss routes during folding. We make use of the framework of optimal control whose convenient solution provides practical and useful insight into the sequence of events during folding. We assume that the native state is available. As the protein folds, it makes different set of contacts at different folding steps. The dynamic contact map is constructed from these contacts. The topology of the dynamic contact map changes during the course of folding and this information is utilized in the dynamic optimization model. The solution is obtained using the optimal control theory. We show that the optimal solution can be cast into the form of a Gaussian Network that governs the optimal folding dynamics. Simulation results on three examples (CI2, Sso7d and Villin) show that folding starts by the formation of local clusters. Non-local clusters generally require the formation of several local clusters. Non-local clusters form cooperatively and not sequentially. We also observe that the optimal controller prefers "zipping" or small loop closure steps during folding. The folding routes predicted by the proposed method bear strong resemblance to the results in the literature. PMID- 20967270 TI - Representation of global and national conservation priorities by Colombia's Protected Area Network. AB - BACKGROUND: How do national-level actions overlap with global priorities for conservation? Answering this question is especially important in countries with high and unique biological diversity like Colombia. Global biodiversity schemes provide conservation guidance at a large scale, while national governments gazette land for protection based on a combination of criteria at regional or local scales. Information on how a protected area network represents global and national conservation priorities is crucial for finding gaps in coverage and for future expansion of the system. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the agreement of Colombia's protected area network with global conservation priorities, and the extent to which the network reflects the country's biomes, species richness, and common environmental and physical conditions. We used this information to identify priority biomes for conservation. We find the dominant strategy in Colombia has been a proactive one, allocating the highest proportion of protected land on intact, difficult to access and species rich areas like the Amazon. Threatened and unique areas are disproportionately absent from Colombia's protected lands. We highlight six biomes in Colombia as conservation priorities that should be considered in any future expansion of Colombia's protected area network. Two of these biomes have less than 3% of their area protected and more than 70% of their area transformed for human use. One has less than 3% protected and high numbers of threatened vertebrates. Three biomes fall in both categories. CONCLUSIONS: Expansion of Colombia's Protected Area Network should consider the current representativeness of the network. We indicate six priority biomes that can contribute to improving the representation of threatened species and biomes in Colombia. PMID- 20967271 TI - Profound depletion of HIV-1 transcription in patients initiating antiretroviral therapy during acute infection. AB - BACKGROUND: Although combination antiretroviral therapy (cART) initiated in the acute phase of HIV-1 infection may prevent expansion of the latent reservoir, its benefits remain controversial. In the current study, HIV-1 RNA transcription patterns in peripheral blood mononuclear cells (PBMC) were monitored during acute cART to assess the effect of early treatment on cellular viral reservoirs. METHODOLOGY/PRINCIPAL FINDINGS: Acutely HIV-1 infected patients (n = 24) were treated within 3-15 weeks after infection. Patients elected to cease treatment after >=1 year of therapy. HIV-1 DNA (vDNA), HIV-1 RNA species expressed both in latently and productively infected cells, unspliced (UsRNA), multiply spliced (MsRNA-tatrev; MsRNA-nef), and PBMC-associated extracellular virion RNA (vRex), expressed specifically by productively infected cells, were quantified in PBMC by patient matched real-time PCR prior, during and post cART. In a matched control group of patients on successful cART started during chronic infection (n = 15), UsRNA in PBMC and vDNA were measured cross-sectionally. In contrast to previous reports, PBMC-associated HIV-1 RNAs declined to predominantly undetectable levels on cART. After cART cessation, UsRNA, vRex, and MsRNA-tatrev rebounded to levels not significantly different to those at baseline (p>0.1). In contrast, MsRNA-nef remained significantly lower as compared to pretreatment (p = 0.015). UsRNA expressed at the highest levels of all viral RNAs, was detectable on cART in 42% of patients with cART initiated during acute infection as opposed to 87% of patients on cART initiated during chronic infection (Fisher's exact test; p = 0.008). Accordingly, UsRNA levels were 105-fold lower in the acute as compared to the chronic group. CONCLUSION: Early intervention resulted in profound depletion of PBMC expressing HIV-1 RNA. This is contrary to chronically infected patients who predominantly showed continuous UsRNA expression on cART. Thus, antiretroviral treatment initiated during the acute phase of infection prevented establishment or expansion of long-lived transcriptionally active viral cellular reservoirs in peripheral blood. PMID- 20967272 TI - T regulatory cells in cord blood--FOXP3 demethylation as reliable quantitative marker. AB - BACKGROUND: Regulatory T-cells (Tregs), characterized as CD4+CD25(hi) T-cells expressing FOXP3, play a crucial role in controlling healthy immune development during early immune maturation. Recently, FOXP3 demethylation was suggested to be a novel marker for natural Tregs in adults. In cord blood, the role and function of Tregs and its demethylation is poorly understood. We assessed FOXP3 demethylation in cord blood in relation to previously used Treg markers such as CD4+CD25(hi), FOXP3 mRNA, protein expression, and suppressive Treg function. METHODOLOGY: Cord blood mononuclear cells (CBMC) were isolated from 70 healthy neonates, stimulated for 3 days with the microbial stimulus lipid A (LpA), and allergen Dermatophagoides pteronyssinus (Derp1). Tregs (CD4+CD25(hi), intracellular, mRNA FOXP3 expression, isolated cells), DNA methylation of the FOXP3-locus and suppressive Treg function were assessed. PRINCIPAL FINDINGS: Demethylation of FOXP3 in whole blood was specific for isolated CD4+CD25(hi) Tregs. Demethylation of FOXP3 was positively correlated with unstimulated and LpA stimulated FOXP3 mRNA-expression (p<=0.05), and CD4+CD25(hi) T-cells (p<=0.03). Importantly, increased FOXP3 demethylation correlated with more efficient suppressive capacity of Tregs (r = 0.72, p = 0.005). Furthermore, FOXP3 demethylation was positively correlated with Th2 cytokines (IL-5, IL-13) following LpA-stimulation (p = 0.006/0.04), with Th2 and IL-17 following Derp1+LpA-stimulations (p<=0.009), but not Th1 cytokines (IFN-gamma). CONCLUSIONS: FOXP3 demethylation reliable quantifies Tregs in cord blood. FOXP3 demethylation corresponds well with the suppressive potential of Tregs. The resulting strict correlation with functionally suppressive Tregs and the relative ease of measurement render it into a valuable novel marker for large field studies assessing Tregs as qualitative marker indicative of functional activity. PMID- 20967273 TI - Yokukansan inhibits neuronal death during ER stress by regulating the unfolded protein response. AB - BACKGROUND: Recently, several studies have reported Yokukansan (Tsumura TJ-54), a traditional Japanese medicine, as a potential new drug for the treatment of Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress is known to play an important role in the pathogenesis of AD, particularly in neuronal death. Therefore, we examined the effect of Yokukansan on ER stress-induced neurotoxicity and on familial AD-linked presenilin-1 mutation-associated cell death. METHODS: We employed the WST-1 assay and monitored morphological changes to evaluate cell viability following Yokukansan treatment or treatment with its components. Western blotting and PCR were used to observe the expression levels of GRP78/BiP, caspase-4 and C/EBP homologous protein. RESULTS: Yokukansan inhibited neuronal death during ER stress, with Cnidii Rhizoma (Senkyu), a component of Yokukansan, being particularly effective. We also showed that Yokukansan and Senkyu affect the unfolded protein response following ER stress and that these drugs inhibit the activation of caspase-4, resulting in the inhibition of ER stress-induced neuronal death. Furthermore, we found that the protective effect of Yokukansan and Senkyu against ER stress could be attributed to the ferulic acid content of these two drugs. CONCLUSIONS: Our results indicate that Yokukansan, Senkyu and ferulic acid are protective against ER stress-induced neuronal cell death and may provide a possible new treatment for AD. PMID- 20967274 TI - Gender difference of alanine aminotransferase elevation may be associated with higher hemoglobin levels among male adolescents. AB - BACKGROUND: To explore the gender difference of ALT elevation and its association with high hemoglobin levels. METHODS: A cross-sectional study of 3547 adolescents (2005 females, mean age of 16.5?.3 years) who were negative for hepatitis B surface antigen received health checkups in 2006. Body mass index (BMI), levels of hemoglobin, ALT and cholesterol were measured. ALT >42 U/L was defined as elevated ALT. Elevated ALT levels were detected in 112 of the 3547 participants (3.3%), more prevalent in males than in females (5.4% vs. 1.4%, p<0.001). Hemoglobin levels had a significant linear correlation with ALT levels in both genders. Abnormal ALT started to occur if hemoglobin >11 g/dl in females or >13.5 g/dl in males, but the cumulative cases of elevated ALT increased more quickly in males. Proportion of elevated ALT increased as either the BMI or hemoglobin level rise, more apparent in male adolescents. Logistic regression modeling showed odds ratio (95% confidence interval) were 24.7 (15.0-40.6) for BMI >=27 kg/m(2); 5.5 (2.9-10.4) for BMI 24-27 kg/m(2); 2.7 (1.3-5.5) for Q5 (top 20th percentile) hemoglobin level; and 2.6 (1.6-4.1) for male gender. Further separately fitting the logistic models for two genders, the significance of Q5 hemoglobin level only appeared in the males. CONCLUSIONS: High hemoglobin level is a significant risk factor of ALT elevation after control hepatitis B, obesity and gender. Males have greater risk of abnormal liver function which may be associated with higher hemoglobin levels. PMID- 20967275 TI - Effect of smoking on circulating angiogenic factors in high risk pregnancies. AB - OBJECTIVE: Changes in maternal concentrations of the anti-angiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng), and the pro-angiogenic placental growth factor (PlGF) precede the development of preeclampsia in healthy women. The risk of preeclampsia is reduced in women who smoke during pregnancy. The objective of this study was to investigate whether smoking affects concentrations of angiogenic factors (sFlt1, PlGF, and sEng) in women at high risk for developing preeclampsia. STUDY DESIGN: We performed a secondary analysis of serum samples from 993 high-risk women (chronic hypertension, diabetes, multifetal gestation, and previous preeclampsia) in a preeclampsia prevention trial. sFlt1, sEng and PlGF were measured in serum samples obtained at study entry, which was prior to initiation of aspirin (median 19.0 weeks' [interquartile range of 16.0-22.6 weeks']). Smoking status was determined by self-report. RESULTS: sFlt1 was not significantly different in smokers from any high-risk groups compared to their nonsmoking counterparts. PlGF was higher among smokers compared to nonsmokers among diabetic women (142.7 [77.4 337.3] vs 95.9 [48.5-180.7] pg/ml, p = 0.005) and women with a history of preeclampsia (252.2 [137.1-486.0] vs 152.2 [73.6-253.7] pg/ml, p = 0.001). sEng was lower in smokers with multifetal gestations (5.8 [4.6-6.5] vs 6.8 [5.5-8.7] ng/ml, p = 0.002) and trended lower among smokers with diabetes (4.9 [3.8-5.6] vs 5.3 [4.3-6.3] ng/ml, p = 0.05). Smoking was not associated with a lower incidence of preeclampsia in any of these groups. CONCLUSIONS: In certain high-risk groups, smoking is associated with changes in the concentrations of these factors towards a pro-angiogenic direction during early pregnancy; however, there was no apparent association between smoking and the development of preeclampsia in our cohort. PMID- 20967277 TI - Memory for self-performed actions in individuals with Asperger syndrome. AB - Memory for action is enhanced if individuals are allowed to perform the corresponding movements, compared to when they simply listen to them (enactment effect). Previous studies have shown that individuals with Autism Spectrum Disorders (ASD) have difficulties with processes involving the self, such as autobiographical memories and self performed actions. The present study aimed at assessing memory for action in Asperger Syndrome (AS). We investigated whether adults with AS would benefit from the enactment effect when recalling a list of previously performed items vs. items that were only visually and verbally experienced through three experimental tasks (Free Recall, Old/New Recognition and Source Memory). The results showed that while performance on Recognition and Source Memory tasks was preserved in individuals with AS, the enactment effect for self-performed actions was not consistently present, as revealed by the lower number of performed actions being recalled on the Free Recall test, as compared to adults with typical development. Subtle difficulties in encoding specific motor and proprioceptive signals during action execution in individuals with AS might affect retrieval of relevant personal episodic information. These disturbances might be associated to an impaired action monitoring system. PMID- 20967276 TI - Octopamine neuromodulatory effects on a social behavior decision-making network in Drosophila males. AB - Situations requiring rapid decision-making in response to dynamic environmental demands occur repeatedly in natural environments. Neuromodulation can offer important flexibility to the output of neural networks in coping with changing conditions, but the contribution of individual neuromodulatory neurons in social behavior networks remains relatively unknown. Here we manipulate the Drosophila octopaminergic system and assay changes in adult male decision-making in courtship and aggression paradigms. When the functional state of OA neural circuits is enhanced, males exhibit elevated courtship behavior towards other males in both behavioral contexts. Eliminating the expression of the male form of the neural sex determination factor, Fruitless (Fru(M)), in three OA suboesophageal ganglia (SOG) neurons also leads to increased male-male courtship behavior in these same contexts. We analyzed the fine anatomical structure through confocal examination of labeled single neurons to determine the arborization patterns of each of the three Fru(M)-positive OA SOG neurons. These neurons send processes that display mirror symmetric, widely distributed arbors of endings within brain regions including the ventrolateral protocerebra, the SOG and the peri-esophageal complex. The results suggest that a small subset of OA neurons have the potential to provide male selective modulation of behavior at a single neuron level. PMID- 20967279 TI - Characteristics and programme-defined treatment outcomes among childhood tuberculosis (TB) patients under the national TB programme in Delhi. AB - BACKGROUND: Childhood tuberculosis (TB) patients under India's Revised National TB Control Programme (RNTCP) are managed using diagnostic algorithms and directly observed treatment with intermittent thrice-weekly short-course treatment regimens for 6-8 months. The assignment into pre-treatment weight bands leads to drug doses (milligram per kilogram) that are lower than current World Health Organization (WHO) guidelines for some patients. OBJECTIVES: The main aim of our study was to describe the baseline characteristics and treatment outcomes reported under RNTCP for registered childhood (age <15 years) TB patients in Delhi. Additionally, we compared the reported programmatic treatment completion rates between children treated as per WHO recommended anti-TB drug doses with those children treated with anti-TB drug doses below that recommended in WHO guidelines. METHODS: For this cross-sectional retrospective study, we reviewed programme records of all 1089 TB patients aged <15 years registered for TB treatment from January to June, 2008 in 6 randomly selected districts of Delhi. WHO disease classification and treatment outcome definitions are used by RNTCP, and these were extracted as reported in programme records. RESULTS AND CONCLUSIONS: Among 1074 patients with records available, 651 (61%) were females, 122 (11%) were <5 years of age, 1000 (93%) were new cases, and 680 (63%) had extra-pulmonary TB (EP-TB)--most commonly peripheral lymph node disease [310 (46%)]. Among 394 pulmonary TB (PTB) cases, 165 (42%) were sputum smear-positive. The overall reported treatment completion rate was 95%. Similar reported treatment completion rates were found in all subgroups assessed, including those patients whose drug dosages were lower than that currently recommended by WHO. Further studies are needed to assess the reasons for the low proportion of under 5 years of age TB case notifications, address challenges in reaching all childhood TB patients by RNTCP, the accuracy of diagnosis, and the clinical validity of reported programme defined treatment completion. PMID- 20967278 TI - Molecular immune responses to aerosol challenge with Francisella tularensis in mice inoculated with live vaccine candidates of varying efficacy. AB - BACKGROUND: Francisella tularensis is a facultative intracellular bacterial pathogen and the etiological agent of tularemia. The subspecies F. tularensis tularensis is especially virulent for humans when inhaled and respiratory tularemia is associated with high mortality if not promptly treated. A live vaccine strain (LVS) derived from the less virulent holarctica subspecies confers incomplete protection against aerosol challenge with subsp. tularensis. Moreover, correlates of protection have not been established for LVS. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we compare molecular immune responses elicited by LVS and two defined deletion mutants of clinical subsp. tularensis strain, SCHU S4, that confer enhanced protection in a mouse model. BALB/c mice were immunized intradermally then challenged with an aerosol of SCHU S4 six weeks later. Changes in the levels of a selected panel of cytokines and chemokines were examined in the lungs, spleens, and sera of vaccinated and challenged mice. Mostly, increased cytokine and chemokine levels correlated with increased bacterial burden. However, after adjusting for this variable, immunization with either of the two Schu S4 mutants resulted in higher levels of several pulmonary cytokines, versus those resulting after LVS immunization, including IL-17. Moreover, treatment of mice immunized with DeltaclpB with anti-IL-17 antibodies post-challenge enhanced lung infection. CONCLUSIONS/SIGNIFICANCE: This is the first report characterizing local and systemic cytokine and chemokine responses in mice immunized with vaccines with different efficacies against aerosol challenge with virulent F. tularensis subsp. tularensis. It shows that increases in the levels of most of these immunomodulators, including those known to be critical for protective immunity, do not superficially correlate with protection unless adjusted for the effects of bacterial burden. Additionally, several cytokines were selectively suppressed in the lungs of naive mice, suggesting that one mechanism of vaccine action is to overcome this pathogen-induced immunosuppression. PMID- 20967280 TI - Situational awareness and health protective responses to pandemic influenza A (H1N1) in Hong Kong: a cross-sectional study. AB - BACKGROUND: Whether information sources influence health protective behaviours during influenza pandemics or other emerging infectious disease epidemics is uncertain. METHODOLOGY: Data from cross-sectional telephone interviews of 1,001 Hong Kong adults in June, 2009 were tested against theory and data-derived hypothesized associations between trust in (formal/informal) information, understanding, self-efficacy, perceived susceptibility and worry, and hand hygiene and social distancing using Structural Equation Modelling with multigroup comparisons. PRINCIPAL FINDINGS: Trust in formal (government/media) information about influenza was associated with greater reported understanding of A/H1N1 cause (beta = 0.36) and A/H1N1 prevention self-efficacy (beta = 0.25), which in turn were associated with more hand hygiene (beta = 0.19 and beta = 0.23, respectively). Trust in informal (interpersonal) information was negatively associated with perceived personal A/H1N1 susceptibility (beta = -0.21), which was negatively associated with perceived self-efficacy (beta = -0.42) but positively associated with influenza worry (beta = 0.44). Trust in informal information was positively associated with influenza worry (beta = 0.16) which was in turn associated with greater social distancing (beta = 0.36). Multigroup comparisons showed gender differences regarding paths from trust in formal information to understanding of A/H1N1 cause, trust in informal information to understanding of A/H1N1 cause, and understanding of A/H1N1 cause to perceived self-efficacy. CONCLUSIONS/SIGNIFICANCE: Trust in government/media information was more strongly associated with greater self-efficacy and handwashing, whereas trust in informal information was strongly associated with perceived health threat and avoidance behaviour. Risk communication should consider the effect of gender differences. PMID- 20967281 TI - Novel HTS strategy identifies TRAIL-sensitizing compounds acting specifically through the caspase-8 apoptotic axis. AB - Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is potentially a very important therapeutic as it shows selectivity for inducing apoptosis in cancer cells whilst normal cells are refractory. TRAIL binding to its cognate receptors, Death Receptors-4 and -5, leads to recruitment of caspase-8 and classical activation of downstream effector caspases, leading to apoptosis. As with many drugs however, TRAIL's usefulness is limited by resistance, either innate or acquired. We describe here the development of a novel 384-well high throughput screening (HTS) strategy for identifying potential TRAIL-sensitizing agents that act solely in a caspase-8 dependent manner. By utilizing a TRAIL resistant cell line lacking caspase-8 (NB7) compared to the same cells reconstituted with the wild-type protein, or with a catalytically inactive point mutant of caspase-8, we are able to identify compounds that act specifically through the caspase-8 axis, rather than through general toxicity. In addition, false positive hits can easily be "weeded out" in this assay due to their activity in cells lacking caspase-8-inducible activity. Screening of the library of pharmacologically active compounds (LOPAC) was performed as both proof-of concept and to discover potential unknown TRAIL sensitizers whose mechanism is caspase-8 mediated. We identified known TRAIL sensitizers from the library and identified new compounds that appear to sensitize specifically through caspase-8. In sum, we demonstrate proof-of-concept and discovery of novel compounds with a screening strategy optimized for the detection of caspase-8 pathway-specific TRAIL sensitizers. This screen was performed in the 384-well format, but could easily be further miniaturized, allows easy identification of artifactual false positives, and is highly scalable to accommodate diverse libraries. PMID- 20967282 TI - Congenital sensorineural deafness in Australian stumpy-tail cattle dogs is an autosomal recessive trait that maps to CFA10. AB - BACKGROUND: Congenital sensorineural deafness is an inherited condition found in many dog breeds, including Australian Stumpy-tail Cattle Dogs (ASCD). This deafness is evident in young pups and may affect one ear (unilateral) or both ears (bilateral). The genetic locus/loci involved is unknown for all dog breeds. The aims of this study were to determine incidence, inheritance mechanism, and possible association of congenital sensorineural deafness with coat colour in ASCD and to identify the genetic locus underpinning this disease. METHODOLOGY/PRINCIPAL FINDINGS: A total of 315 ASCD were tested for sensorineural deafness using the brain stem auditory evoked response (BAER) test. Disease penetrance was estimated directly, using the ratio of unilaterally to bilaterally deaf dogs, and segregation analysis was performed using Mendel. A complete genome screen was undertaken using 325 microsatellites spread throughout the genome, on a pedigree of 50 BAER tested ASCD in which deafness was segregating. Fifty-six dogs (17.8%) were deaf, with 17 bilaterally and 39 unilaterally deaf. Unilaterally deaf dogs showed no significant left/right bias (p = 0.19) and no significant difference was observed in frequencies between the sexes (p = 0.18). Penetrance of deafness was estimated as 0.72. Testing the association of red/blue coat colour and deafness without accounting for pedigree structure showed that red dogs were 1.8 times more likely to be deaf (p = 0.045). The within family association between red/blue coat colour and deafness was strongly significant (p = 0.00036), with red coat colour segregating more frequently with deafness (COR = 0.48). The relationship between deafness and coat speckling approached significance (p = 0.07), with the lack of statistical significance possibly due to only four families co-segregating for both deafness and speckling. The deafness phenotype was mapped to CFA10 (maximum linkage peak on CFA10 -log10 p value = 3.64), as was both coat colour and speckling. Fine mapping was then performed on 45 of these 50 dogs and a further 48 dogs (n = 93). Sequencing candidate gene Sox10 in 6 hearing ASCD, 2 unilaterally deaf ASCD and 2 bilaterally deaf ASCD did not reveal any disease-associated mutations. CONCLUSIONS: Deafness in ASCD is an incompletely penetrant autosomal recessive inherited disease that maps to CFA10. PMID- 20967283 TI - Age and diet affect gene expression profiles in canine liver tissue. AB - BACKGROUND: The liver plays a central role in nutrient and xenobiotic metabolism, but its functionality declines with age. Senior dogs suffer from many of the chronic hepatic diseases as elderly humans, with age-related alterations in liver function influenced by diet. However, a large-scale molecular analysis of the liver tissue as affected by age and diet has not been reported in dogs. METHODOLOGY/PRINCIPAL FINDINGS: Liver tissue samples were collected from six senior (12-year old) and six young adult (1-year old) female beagles fed an animal protein-based diet (APB) or a plant protein-based diet (PPB) for 12 months. Total RNA in the liver tissue was extracted and hybridized to Affymetrix GeneChip(r) Canine Genome Arrays. Using a 2.0-fold cutoff and false discovery rate <0.10, our results indicated that expression of 234 genes was altered by age, while 137 genes were differentially expressed by diet. Based on functional classification, genes affected by age and/or diet were involved in cellular development, nutrient metabolism, and signal transduction. In general, gene expression suggested that senior dogs had an increased risk of the progression of liver disease and dysfunction, as observed in aged humans and rodents. In particular for aged liver, genes related to inflammation, oxidative stress, and glycolysis were up-regulated, whereas genes related to regeneration, xenobiotic metabolism, and cholesterol trafficking were down-regulated. Diet-associated changes in gene expression were more common in young adult dogs (33 genes) as compared to senior dogs (3 genes). CONCLUSION: Our results provide molecular insight pertaining to the aged canine liver and its predisposition to disease and abnormalities. Therefore, our data may aid in future research pertaining to age associated alterations in hepatic function or identification of potential targets for nutritional management as a means to decrease incidence of age-dependent liver dysfunction. PMID- 20967284 TI - Neural correlates of face and object perception in an awake chimpanzee (Pan troglodytes) examined by scalp-surface event-related potentials. AB - BACKGROUND: The neural system of our closest living relative, the chimpanzee, is a topic of increasing research interest. However, electrophysiological examinations of neural activity during visual processing in awake chimpanzees are currently lacking. METHODOLOGY/PRINCIPAL FINDINGS: In the present report, skin surface event-related brain potentials (ERPs) were measured while a fully awake chimpanzee observed photographs of faces and objects in two experiments. In Experiment 1, human faces and stimuli composed of scrambled face images were displayed. In Experiment 2, three types of pictures (faces, flowers, and cars) were presented. The waveforms evoked by face stimuli were distinguished from other stimulus types, as reflected by an enhanced early positivity appearing before 200 ms post stimulus, and an enhanced late negativity after 200 ms, around posterior and occipito-temporal sites. Face-sensitive activity was clearly observed in both experiments. However, in contrast to the robustly observed face evoked N170 component in humans, we found that faces did not elicit a peak in the latency range of 150-200 ms in either experiment. CONCLUSIONS/SIGNIFICANCE: Although this pilot study examined a single subject and requires further examination, the observed scalp voltage patterns suggest that selective processing of faces in the chimpanzee brain can be detected by recording surface ERPs. In addition, this non-invasive method for examining an awake chimpanzee can be used to extend our knowledge of the characteristics of visual cognition in other primate species. PMID- 20967285 TI - Changed genome heterochromatinization upon prolonged activation of the Raf/ERK signaling pathway. AB - The Raf/ERK (Extracellular Signal Regulated Kinase) signal transduction pathway controls numerous cellular processes, including growth, differentiation, cellular transformation and senescence. ERK activation is thought to involve complex spatial and temporal regulation, to achieve a high degree of specificity, though precisely how this is achieved remains to be confirmed. We report here that prolonged activation of a conditional form of c-Raf-1 (BXB-ER) leads to profound changes in the level and distribution of a heterochromatic histone mark. In mouse fibroblasts, the heterochromatic trimethylation of lysine 9 in histone H3 (H3K9Me3) is normally confined to pericentromeric regions. However, following ERK activation a genome-wide redistribution of H3K9Me3 correlates with loss of the histone modification from chromocentres and the appearance of numerous punctuate sites throughout the interphase nucleus. These epigenetic changes during interphase correlate with altered chromosome structure during mitosis, where robust H3K9Me3 signals appear within telomeric heterochromatin. This pattern of heterochromatinization is distinct from previously described oncogene induced senescence associated heterochromatin foci (SAHF), which are excluded from telomeres. The H3K9Me3 histone mark is known to bind the major heterochromatin protein HP1 and we show that the alterations in the distribution of this histone epistate correlate with redistribution of HP1beta throughout the nucleus. Interestingly while ERK activation is fully reversible, the observed chromatin changes induced by epigenetic modifications are not reversible once established. We describe for the first time a link from prolonged ERK activation to stable changes in genome organization through redistribution of heterochromatic domains involving the telomeres. These epigenetic changes provide a possible mechanism through which prolonged activation of Raf/ERK can lead to growth arrest or the induction of differentiation, senescence and cancer. PMID- 20967286 TI - Biochemical properties of a novel cysteine protease of Plasmodium vivax, vivapain 4. AB - BACKGROUND: Multiple cysteine proteases of malaria parasites are required for maintenance of parasite metabolic homeostasis and egress from the host erythrocyte. In Plasmodium falciparum these proteases appear to mediate the processing of hemoglobin and aspartic proteases (plasmepsins) in the acidic food vacuole and the hydrolysis of erythrocyte structural proteins at neutral pH. Two cysteine proteases, vivapain (VX)-2 and VX-3 have been characterized in P. vivax, but comprehensive studies of P. vivax cysteine proteases remain elusive. FINDINGS: We characterized a novel cysteine protease of P. vivax, VX-4, of which orthologs appears to have evolved differentially in primate plasmodia with strong cladistic affinity toward those of rodent Plasmodium. Recombinant VX-4 demonstrated dual substrate specificity depending on the surrounding micro environmental pH. Its hydrolyzing activity against benzyloxycarbonyl-Leu-Arg-4 methyl-coumaryl-7-amide (Z-Leu-Arg-MCA) and Z-Phe-Arg-MCA was highest at acidic pH (5.5), whereas that against Z-Arg-Arg-MCA was maximal at neutral pH (6.5-7.5). VX-4 preferred positively charged amino acids and Gln at the P1 position, with less strict specificity at P3 and P4. P2 preferences depended on pH (Leu at pH 5.5 and Arg at pH 7.5). Three amino acids that delineate the S2 pocket were substituted in VX-4 compared to VX-2 and VX-3 (Ala90, Gly157 and Glu180). Replacement of Glu180 abolished activity against Z-Arg-Arg-MCA at neutral pH, indicating the importance of this amino acid in the pH-dependent substrate preference. VX-4 was localized in the food vacuoles and cytoplasm of the erythrocytic stage of P. vivax. VX-4 showed maximal activity against actin at neutral pH, and that against P. vivax plasmepsin 4 and hemoglobin was detected at neutral/acidic and acidic pH, respectively. CONCLUSION: VX-4 demonstrates pH dependent substrate switching, which might offer an efficient mechanism for the specific cleavage of different substrates in different intracellular environments. VX-4 might function as a hemoglobinase in the acidic parasite food vacuole, a maturase of P. vivax plasmepsin 4 at neutral or acidic pH, and a cytoskeleton-degrading protease in the neutral erythrocyte cytosol. PMID- 20967287 TI - Systemic FasL and TRAIL neutralisation reduce leishmaniasis induced skin ulceration. AB - Cutaneous leishmaniasis (CL) is caused by Leishmania infection of dermal macrophages and is associated with chronic inflammation of the skin. L. aethiopica infection displays two clinical manifestations, firstly ulcerative disease, correlated to a relatively low parasite load in the skin, and secondly non-ulcerative disease in which massive parasite infiltration of the dermis occurs in the absence of ulceration of epidermis. Skin ulceration is linked to a vigorous local inflammatory response within the skin towards infected macrophages. Fas ligand (FasL) and Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) expressing cells are present in dermis in ulcerative CL and both death ligands cause apoptosis of keratinocytes in the context of Leishmania infection. In the present report we show a differential expression of FasL and TRAIL in ulcerative and non-ulcerative disease caused by L. aethiopica. In vitro experiments confirmed direct FasL- and TRAIL-induced killing of human keratinocytes in the context of Leishmania-induced inflammatory microenvironment. Systemic neutralisation of FasL and TRAIL reduced ulceration in a model of murine Leishmania infection with no effect on parasitic loads or dissemination. Interestingly, FasL neutralisation reduced neutrophil infiltration into the skin during established infection, suggesting an additional proinflammatory role of FasL in addition to direct keratinocyte killing in the context of parasite induced skin inflammation. FasL signalling resulting in recruitment of activated neutrophils into dermis may lead to destruction of the basal membrane and thus allow direct FasL mediated killing of exposed keratinocytes in vivo. Based on our results we suggest that therapeutic inhibition of FasL and TRAIL could limit skin pathology during CL. PMID- 20967288 TI - CD8+ T cells as a source of IFN-gamma production in human cutaneous leishmaniasis. AB - BACKGROUND: In human leishmaniasis Th1/Th2 dichotomy similar to murine model is not clearly defined and surrogate marker(s) of protection is not yet known. In this study, Th1/Th2 cytokines (IL-5, IL-10, IL-13 and IFN-gamma) profile induced by purified CD4(+)/CD8(+) T cells in response to Leishmania antigens were assessed at transcript and protein levels in 14 volunteers with a history of self healing cutaneous leishmaniasis (HCL) and compared with 18 healthy control volunteers. METHODOLOGY/PRINCIPAL FINDINGS: CD4(+)/CD8(+)/CD14(+) cells were purified from peripheral blood using magnetic beads; CD4(+)/CD8(+) T cells were co-cultured with autologous CD14(+) monocytes in the presence of soluble Leishmania antigens (SLA). Stimulation of either CD4(+) T cells or CD8(+) T cells of HCL volunteers with SLA induced a significantly (P<0.05) higher IFN-gamma production compared with the cells of controls. Upregulation of IFN-gamma gene expression in CD4(+) cells (P<0.001) and CD8(+) cells (P = 0.006) of HCL volunteers was significantly more than that of controls. Significantly (P<0.05) higher fold-expression of IFN-gamma gene was seen in CD4(+) cells than in CD8(+) cells. In HCL volunteers a significantly (P = 0.014) higher number of CD4(+) cells were positive for intracellular IFN-gamma production than CD8(+) cells. CONCLUSIONS/SIGNIFICANCE: Collectively, the volunteers have shown maintenance of specific long-term immune responses characterized by a strong reaction to leishmanin skin test and IFN-gamma production. The dominant IFN-gamma response was the result of expansion of both CD4(+) and CD8(+) T cells. The results suggested that immune response in protected individuals with a history of zoonotic cutaneous leishmaniasis (ZCL) due to L. major is mediated not only through the expansion of antigen-specific IFN-gamma producing CD4(+) Th1 cells, but also through IFN-gamma producing CD8(+) T cells. PMID- 20967289 TI - Coinfection with different Trypanosoma cruzi strains interferes with the host immune response to infection. AB - A century after the discovery of Trypanosoma cruzi in a child living in Lassance, Minas Gerais, Brazil in 1909, many uncertainties remain with respect to factors determining the pathogenesis of Chagas disease (CD). Herein, we simultaneously investigate the contribution of both host and parasite factors during acute phase of infection in BALB/c mice infected with the JG and/or CL Brener T. cruzi strains. JG single infected mice presented reduced parasitemia and heart parasitism, no mortality, levels of pro-inflammatory mediators (TNF-alpha, CCL2, IL-6 and IFN-gamma) similar to those found among naive animals and no clinical manifestations of disease. On the other hand, CL Brener single infected mice presented higher parasitemia and heart parasitism, as well as an increased systemic release of pro-inflammatory mediators and higher mortality probably due to a toxic shock-like systemic inflammatory response. Interestingly, coinfection with JG and CL Brener strains resulted in intermediate parasitemia, heart parasitism and mortality. This was accompanied by an increase in the systemic release of IL-10 with a parallel increase in the number of MAC-3(+) and CD4(+) T spleen cells expressing IL-10. Therefore, the endogenous production of IL-10 elicited by coinfection seems to be crucial to counterregulate the potentially lethal effects triggered by systemic release of pro-inflammatory mediators induced by CL Brener single infection. In conclusion, our results suggest that the composition of the infecting parasite population plays a role in the host response to T. cruzi in determining the severity of the disease in experimentally infected BALB/c mice. The combination of JG and CL Brener was able to trigger both protective inflammatory immunity and regulatory immune mechanisms that attenuate damage caused by inflammation and disease severity in BALB/c mice. PMID- 20967291 TI - Inference of surface membrane factors of HIV-1 infection through functional interaction networks. AB - BACKGROUND: HIV infection affects the populations of T helper cells, dendritic cells and macrophages. Moreover, it has a serious impact on the central nervous system. It is yet not clear whether this list is complete and why specifically those cell types are affected. To address this question, we have developed a method to identify cellular surface proteins that permit, mediate or enhance HIV infection in different cell/tissue types in HIV-infected individuals. Receptors associated with HIV infection share common functions and domains and are involved in similar cellular processes. These properties are exploited by bioinformatics techniques to predict novel cell surface proteins that potentially interact with HIV. METHODOLOGY/PRINCIPAL FINDINGS: We compiled a set of surface membrane proteins (SMP) that are known to interact with HIV. This set is extended by proteins that have direct interaction and share functional similarity. This resulted in a comprehensive network around the initial SMP set. Using network centrality analysis we predict novel surface membrane factors from the annotated network. We identify 21 surface membrane factors, among which three have confirmed functions in HIV infection, seven have been identified by at least two other studies, and eleven are novel predictions and thus excellent targets for experimental investigation. CONCLUSIONS: Determining to what extent HIV can interact with human SMPs is an important step towards understanding patient specific disease progression. Using various bioinformatics techniques, we generate a set of surface membrane factors that constitutes a well-founded starting point for experimental testing of cell/tissue susceptibility of different HIV strains as well as for cohort studies evaluating patient specific disease progression. PMID- 20967295 TI - Dalfampridine in multiple sclerosis. AB - Dalfampridine (4-aminopyridine or 4-AP) is a potassium channel blocker that is historically known in the literature as fampridine (INN). This review begins with an outline of the pharmacology and pharmacokinetics. Early clinical trials are highlighted, followed by a review of the more recent phase II and III placebo controlled clinical trials that have examined dalfampridine in multiple sclerosis patients. In these trials, extended-release dalfampridine was shown to result in an average 25% increase in the walking speed in more than one-third of the patients who received the drug and met the prescribed criteria for consistent responders. The safety profile of dalfampridine is also reviewed, with a focus on the risk for epileptic seizures as an adverse effect. PMID- 20967294 TI - Catalytic mechanism of cellulose degradation by a cellobiohydrolase, CelS. AB - The hydrolysis of cellulose is the bottleneck in cellulosic ethanol production. The cellobiohydrolase CelS from Clostridium thermocellum catalyzes the hydrolysis of cello-oligosaccharides via inversion of the anomeric carbon. Here, to examine key features of the CelS-catalyzed reaction, QM/MM (SCCDFTB/MM) simulations are performed. The calculated free energy profile for the reaction possesses a 19 kcal/mol barrier. The results confirm the role of active site residue Glu87 as the general acid catalyst in the cleavage reaction and show that Asp255 may act as the general base. A feasible position in the reactant state of the water molecule responsible for nucleophilic attack is identified. Sugar ring distortion as the reaction progresses is quantified. The results provide a computational approach that may complement the experimental design of more efficient enzymes for biofuel production. PMID- 20967296 TI - Eribulin mesilate, a halichondrin B analogue, in the treatment of breast cancer. AB - Eisai is developing eribulin mesilate (E-7389), a synthetic macrocyclic ketone analogue of the tubulin inhibitor halichondrin B, for the treatment of a variety of solid tumors that include but are not limited to breast and lung cancer. In this context, eribulin is in phase III clinical trials in breast cancer; however, it has also progressed to phase II for nonsmall cell lung cancer, soft tissue sarcomas, pancreatic, prostate, head and neck cancer, bladder and ovarian and related gynecological tumors. Eribulin has shown synergistic in vitro antiproliferative activity in combination with the breast cancer drugs gemcitabine, epirubicin, trastuzumab, docetaxel and vinorelbine. Clinical trials have established efficacy, safety and a distinct survival advantage of 2.5 months with eribulin as compared to other treatments of physician's choice in metastatic breast cancer patients with heavy pretreatment and taxane resistance. It has a manageable side effect profile, consisting mostly of neutropenia and fatigue, with distinct tolerance at full doses in renal dysfunction, a lower incidence of peripheral neuropathy, minimal chances of drug-drug interactions and hypersensitivity. It appears to be a suitable candidate for third-line monotherapy and beyond for locally advanced and metastatic breast cancer. This review will focus on published and peer-reviewed data on breast cancer. PMID- 20967297 TI - Ulipristal acetate for emergency contraception. AB - Ulipristal acetate is a progesterone receptor modulator. As an emergency contraceptive, a 30-mg micronized formulation is effective for use up to 120 h from unprotected sexual intercourse. Ulipristal acetate acts as an antagonist of the progesterone receptor at the transcriptional level and a competitive antagonist of glucocorticoid receptor function. In contrast to other contraceptives, it has little effect on sex hormone-binding globulin. Although a single small study demonstrated some potential endometrial effects after ulipristal acetate administration, the clinical relevance of these findings is unclear. The incidence of adverse events in clinical trials for emergency contraception has typically been minimal, with one study showing a higher than expected incidence of nausea upon ulipristal acetate use. Ulipristal acetate, like other emergency contraceptive products, can lengthen the time to the next expected menstruation. Ulipristal acetate may have several advantages over currently approved emergency contraceptives. When compared to levonorgestrel, ulipristal acetate maintains its efficacy for a full 120 h, whereas levonorgestrel formulations have declining efficacy over that time frame. Moreover, although the copper intrauterine device (IUD) is highly effective as an emergency contraceptive, accessibility is an issue since the IUD requires a skilled provider for insertion. PMID- 20967298 TI - Biological markers in schizophrenia: An update. AB - Biological markers are quantitative measures that allow clinicians to diagnose and assess the disease process, monitor response to treatment and may, to some extent, assist with prognostic assessments (1). Biological markers can modify the way clinicians approach, treat and care for patients. This has significant diagnostic and treatment-related implications, especially for chronic disabling disorders with complex etiopathogenesis, such as schizophrenia. Years of research have yielded a variety of relatively consistent findings in different domains including neuroanatomy, functional and molecular neuroimaging, neurophysiology, genetics and biochemistry. These attributes can complement clinical findings with improved diagnostic validity, and to some extent, assist the clinician in early initiation of efficacious treatment and predicting prognosis. On the contrary, many of these potential biological markers may require expensive testing and enhanced technological expertise. Considering the issues with sensitivity and specificity and an overlap with other neuropsychiatric disorders, their role in routine clinical care continues to be ambiguous. PMID- 20967299 TI - Botulinum toxin type A: Exploring new indications. AB - The use of botulinum toxin has expanded in the last five years to include traditional neurological use against dystonia and spasticity, as well as the emerging use for headache, pain, neuropathy, myofascial pain, joint arthritis, otolaryngology, gastroenterology and genitourinary disorders. This review will focus on these emerging uses of botulinum toxin as reported in recent literature. The exploratory use of botulinum toxin for cervical dystonia, blepharospasm and spasticity in small trials and case reports, has led to its detailed study in larger placebo-controlled clinical trials. Although the use of botulinum toxin for new indications may benefit a specific subset of patients with refractory pain and disability, the reader must realize that this is an emerging area, generally limited by a lack of large, placebo-controlled studies. PMID- 20967300 TI - Vandetanib: An overview of its clinical development in NSCLC and other tumors. AB - Vandetanib is an oral inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), epidermal growth factor receptor (EGFR) and Ret tyrosine kinases involved in tumor growth, progression and angiogenesis. Phase I studies indicated that the recommended dose of vandetanib as a single agent is 300 mg/day. Rash, diarrhea, hypertension and asymptomatic Q-Tc prolongation were the most common adverse events. Four randomized phase III clinical trials evaluated the efficacy of vandetanib in non-small cell lung cancer (NSCLC) in combination with docetaxel (ZODIAC), pemetrexed (ZEAL) or as a single agent (ZEST and ZEPHYR). Only the ZODIAC trial met its primary endpoint (progression-free survival [PFS]), while no study showed an advantage in overall survival with vandetanib. No significant antitumor activity has been observed in small cell lung cancer, advanced ovarian, colorectal, breast, prostate cancer and multiple myeloma. In advanced metastatic medullary thyroid cancer, one randomized phase III clinical trial has demonstrated that vandetanib can significantly improve response rate, PFS and time to worsening of pain. Several key questions remain to be addressed regarding the identification of clinical or molecular biomarkers predictive of response, the choice of the optimal dose or schedule of vandetanib and the safety of long term administration. The results of ongoing trials in untreated patients with advanced NSCLC and other tumors should better define the optimal clinical application of vandetanib. PMID- 20967301 TI - A report from the 46th Annual Meeting of the American Society of Clinical Oncology (June 4-8, 2010 - Chicago, Illinois, USA). AB - A large anticancer armamentarium is available for treating patients with solid and hematological malignancies, but currently available therapies for cancer have many limitations in terms of curing the disease. Fighting for new therapies is thus essential, as is getting first-hand information on new therapies as they become available. The annual meeting of the American Society of Clinical Oncology (ASCO) helps serve that purpose by spreading knowledge on new treatments and new targets for intervention. To supplement ASCO's efforts and for the benefit of our users and readers, this report will offer a glimpse of what this year's meeting was like, giving special attention to currently available therapies and investigational drugs in development, the anticancer activity of which was reported during the meeting in Chicago. PMID- 20967302 TI - Classification and treatment of the anterior maxillary dentition affected by dental erosion: the ACE classification. AB - Erosive tooth wear is a serious problem with very costly consequences. Intercepting patients at the initial stages of the disease is critical to avoid significant irreversible damages to their dentition and to benefit from still favorable conditions when it comes to clinical performance of the restorative measures proposed. In this article, a new classification is proposed to quantify the severity of the dental destruction and to guide clinicians and patients in the therapeutic decision-making process. The classification is based on several parameters relevant for both the selection of treatment and the assessment of the prognosis, such as dentin exposure in the palatal tooth contact areas, alterations at the level of the incisal edges, and ultimately, loss of pulp vitality. PMID- 20967303 TI - A technique to identify and reconstruct the cementoenamel junction level using combined periodontal and restorative treatment of gingival recession. A prospective clinical study. AB - Gingival recession is often associated with abrasion in the cervical area with an unidentifiable cementoenamel junction (CEJ). This condition complicates the diagnosis and treatment of gingival recession. The aim of this study was to propose a technique to identify the CEJ level for planning periodontal and restorative treatment of the recession. The CEJ of a contralateral homologous tooth or adjacent teeth was used to replicate the lost CEJ at the treated tooth. Reconstruction of the CEJ using composite resin and a coronally advanced flap, with or without a connective tissue graft, was performed for 25 recessions in 12 patients. After 2 years, 20 defects (80%) showed complete root coverage with a significant recession reduction (2.4 mm, P < .0001). PMID- 20967304 TI - Reconstruction of an atrophied posterior mandible with the inlay technique and inorganic bovine bone block: a case report. AB - A 53-year-old woman underwent bilateral reconstruction of her severely atrophic posterior mandible using inlay inorganic bovine bone block grafting. Four months later, a bone specimen was taken for histologic evaluation and eight dental implants were placed. These implants were loaded with a provisional prosthesis after another 4 months. When the definitive prosthesis was inserted 8 months postsurgery, all implants were osseointegrated. Histologic analysis showed that the grafted bone was lined with newly formed bone. The results indicate that inorganic bovine bone blocks might serve as an alternative to autogenous grafting for posterior mandibular augmentation using the inlay technique. PMID- 20967305 TI - Use of the tunnel technique and an acellular dermal matrix in the treatment of multiple adjacent teeth with gingival recession in the esthetic zone. AB - The proper management of gingival recession is critical to the establishment of a natural-appearing soft tissue architecture. Subepithelial connective tissue grafts have been considered the "gold standard" but are limited by the availability of palatal donor tissue. Tunnel techniques have improved the esthetic results of connective tissue grafting. Acellular dermal matrices have been successful in the treatment of gingival recession and are not limited by the palatal anatomy. The aim of this report is to describe the application of the tunnel technique, with use of an acellular dermal matrix, in the correction of gingival recession affecting multiple adjacent teeth in the esthetic zone. PMID- 20967306 TI - Bone remodeling around implants placed in fresh extraction sockets. AB - The aim of the present experimental study was to evaluate the physiologic bone remodeling in beagle dogs following the placement of small-diameter (3.25 mm) implants in fresh extraction sites. Five 1-year-old beagle dogs that weighed approximately 10 to 13 kg each were used in this study. The third and fourth premolars (P3, P4) were used as experimental teeth, which were hemisected using a fissure bur; the distal roots were removed carefully using forceps. Implants (3.25-mm wide, 10- or 11.5-mm long) were placed in the fresh extraction sockets with the neck of the implant at the level of the buccal bone crest. The dogs were subsequently put to sleep according to the following schedule: one dog 15 days after implant placement, two dogs after 1 month, and the remaining two dogs after 3 months. The distance from the implant shoulder to the bone wall crest was measured at both the buccal and lingual sites. The width of the buccolingual bone crest was measured using a caliper. Assessments were made immediately after root extraction and at 2, 4, and 12 weeks after implant placement. The mean width of the buccolingual bone crest was 4.5 +/- 0.5 mm at the time of root extraction. Subsequently, at 2, 4, and 12 weeks after implant placement, the buccolingual bone width was 4.1 +/- 0.5 mm, 3.7 +/- 0.3 mm, and 3.5 +/- 0.7 mm, respectively. Two weeks after implant placement, the lingual bone crest was measured at 0.2 +/- 0.3 mm from the implant shoulder, while the buccal bone crest was 0.3 +/- 0.3 mm. After 4 weeks of healing, the mean distance from the implant shoulder to the lingual bone crest was 0.1 +/- 0.9 mm, compared to 0.4 +/- 0.9 mm for the buccal bone crest. After 12 weeks of healing, the bone crest at the lingual sites was 0.3 +/- 0.5 mm from the implant shoulder, compared to 0.8 +/- 0.3 mm at the buccal sites. The findings from this study show that although vertical bone remodeling was indeed observed, the mean vertical buccal bone resorption was 0.5 mm. It might be suggested, therefore, that the implant position along the lingual wall and the use of implants with a narrow diameter in relation to the extraction socket width play a key role in reducing the rate of vertical bone resorption at the buccal aspect of implants placed in fresh extraction sockets. PMID- 20967307 TI - Evaluation of peri-implant marginal bone loss using modified abutment connections at various crestal level placements. AB - The purpose of this study was to evaluate crestal bone loss around 282 two-piece implants with straight (n = 193) and platform-switched (n = 89) abutment connections after placement at various crestal levels. Implants were assigned into two groups according to straight and platform-switched abutment connections. Each group was further subdivided into three groups depending on the location (supracrestal, crestal, or subcrestal) of the implant cervical platform. Linear measurements of bone resorption were made from the implant's platform to the first point of bone-to-implant contact at the time of implant placement and 2 years postrestoration. Data were statistically analyzed. Statistically significant differences were found between subgroups in both straight and platform-switched categories. The only nonstatistically significant difference (P = .341) arose when comparing the supra- and subcrestal locations in the straight abutment connection group. The platform-switched group exhibited significantly less bone loss (P = .046) only in subcrestal locations. The platform-switched concept was not beneficial during the overall comparison, but it was for the subcrestal location of the abutment connection. Crestal placement of the implant abutment connection resulted in higher marginal bone resorption in both straight and platform-switched abutments. PMID- 20967308 TI - Progressive root resorption associated with the treatment of deep gingival recession. A clinical case. AB - This case report presents an unusual complication, cervical root resorption, after a conventional connective tissue grafting procedure and tetracycline root conditioning. The recession was 7 mm high, with 0.5 mm of keratinized tissue present, a 2-mm probing depth, and was classified as Miller Class III. The clinical result was satisfactory and 5 mm of root coverage was achieved. However, after 20 months, cervical resorption was diagnosed. It is suggested that tetracycline root conditioning may cause root resorption in long-term evaluations. There is also a possibility of root resorption occurring in 1-year postoperative controls. Other factors will be discussed in relation to this negative clinical result. PMID- 20967309 TI - Computer-aided implant placement in the reconstruction of a severely resorbed maxilla-a 5-year clinical study. AB - Many studies have shown success with implants placed in grafted bone, and there is an emerging desire to simplify the treatment process by placing implants via a flapless approach using navigation or computer-aided design/computer-assisted manufacture techniques. This paper reports a preliminary study of laboratory and clinical procedures that may enable flapless implant placement in patients treated previously with extensive onlay grafting of the severely resorbed maxilla, thereby avoiding secondary exposure of the grafted site. Six patients received 39 implants, with a cumulative survival rate of 97.7% over an average of 48.8 months; all prosthetic reconstructions are successful to date. PMID- 20967310 TI - Immediate restoration of single implants placed immediately after implant removal. A case report. AB - The purpose of this case report is to describe the treatment of implants placed in fresh extraction sockets and immediately restored in cases of failure. A healthy 58-year-old nonsmoking man was referred for an implant that had lost osseointegration because of infection. The prosthesis showed slight mobility. It was therefore decided to remove the implant and replace it with a new one immediately. Since the patient refused to wear a provisional removable prosthesis, the possibility of applying an immediate loading protocol was discussed. The failed implant was removed carefully and the residual extraction socket was thoroughly debrided. Subsequently, the new implant was placed with a sterile surgical technique, as described by the manufacturer. The inserted implant had a titanium plasma-sprayed surface. Immediately following implant placement and with the patient still under local anesthesia, the initial restorative treatment began. The patient was placed on a strict follow-up regimen until soft tissue healing was complete. Subsequent follow-up examinations were performed after 12 months. At each recall, the patient underwent a thorough clinical and radiographic evaluation. The healing period proceeded smoothly. At the end of the follow-up period, the implant was asymptomatic, immobile, and osseointegrated. No peri-implant bony defects were observed on probing. The results of the present case report seem to suggest that implants placed in fresh extraction sockets and restored immediately might provide a valid treatment option for the treatment of failed implants. PMID- 20967311 TI - Simulation of liquid imidazole using a high-rank quantum topological electrostatic potential. AB - Rigid body molecular dynamics simulations were carried out on pure liquid imidazole at four different temperatures and at 1 atm. Imidazole, which is important both in life science and materials science, is one of the simplest molecules to possess both a lone pair and a pi system. These two features are known to benefit from multipolar electrostatics. Here the electrostatic interaction is governed by atomic multipole moments obtained from topologically partitioned ab initio electron densities. The non-electrostatic terms are modeled with Lennard-Jones parameters adjusted to fit the experimental liquid density. All sigma values are incrementally increased by one single scaling factor. We report on how the presence of multipolar electrostatics influences the local structure, dynamics and thermodynamics of the liquid compared to electrostatics by atomic point charges. The point charge force field exaggerates the number of pi-stacked dimers in the liquid, and underestimates the number of hydrogen-bonded dimers. The effect of the temperature on the local structure of liquid imidazole was analysed using radial and spatial distribution functions. PMID- 20967312 TI - Multidimensional steric effect for the XeF* (B, C) formation in the oriented Xe* ((3)P(2), M(J) = 2) + oriented NF(3) reaction. AB - Steric effect for the XeF* (B, C) formations in the oriented Xe* ((3)P(2), M(J) = 2) + oriented NF(3) reaction has been observed as a function of the mutual configuration between the molecular orientation and the atomic orientation in the collision frame. Molecular steric opacity function has been determined as a function of the atomic orbital alignment (L(Z)') in the collision frame. The larger reactivity at the side with the smaller reactivity at the molecular axis direction is observed for the XeF* (B, C) channels at each atomic orbital alignment. A good correlation between the shape of the molecular steric opacity function and the molecular geometry of NF(3) is recognized. The L(Z)' selectivity in the molecular steric opacity function is different between the XeF* (B, C) channels; in the sideways direction, the XeF* (B) channel is favorable at L(Z)' = 0, while the XeF* (C) channel is favorable at |L(Z)'| = 1. In contrast, at the molecular axis direction, the XeF* (B) channel is favorable at |L(Z)'| = 1, while the XeF* (C) channel is favorable at L(Z)' = 0. We propose the collision-induced harpoon mechanism for the XeF* (B, C) formation in the Xe* ((3)P(2)) + NF(3) reaction. PMID- 20967313 TI - Uranyl nitrate complex extraction into TBP/dodecane organic solutions: a molecular dynamics study. AB - Liquid-liquid extraction of uranyl is studied by conducting atomistic molecular dynamics simulation using quantum chemistry calibrated force fields via restrained electrostatic potential fitting of atomic forces. The simulations depict the migration of uranyl nitrate complexes from the aqueous-organic interface into the tri-n-butyl phosphate (TBP)/dodecane organic phase, in the form of UO(2)(NO(3))(2).H(2)O.2TBP and UO(2)(NO(3))(2).3TBP. The migration process is characterized by the gradual breaking of all the hydrogen bonds between the complex and the water molecules at the interface. Moreover, our simulation results suggest that the experimentally observed complex UO(2)(NO(3))(2).2TBP is formed after the migration of the aforementioned complexes into the organic phase by means of a reorganization of the nitrate binding mode from mono to bidentate which removes the excess oxygen atoms bound to uranyl. PMID- 20967314 TI - Molecular modeling of the human serotonin(1A) receptor: role of membrane cholesterol in ligand binding of the receptor. AB - Serotonin(1A) receptors are important neurotransmitter receptors and belong to the superfamily of G-protein coupled receptors (GPCRs). Although it is an important drug target, the crystal structure of the serotonin(1A) receptor has not been solved yet. Earlier homology models of the serotonin(1A) receptor were generated using rhodopsin as a template. We have used two recent crystal structures of the human beta(2)-adrenergic receptor, one of which shows specific cholesterol binding site(s), as templates to model the human serotonin(1A) receptor. Since the sequence similarity between the serotonin(1A) receptor and beta(2)-adrenergic receptor is considerably higher than the similarity between the serotonin(1A) receptor and rhodopsin, our model is more reliable. Based on these templates, we generated models of the serotonin(1A) receptor in the absence and presence of cholesterol. The receptor model appears more compact in the presence of cholesterol. We validated the stability of 'compactness' using coarse grain MD simulation. Importantly, all ligands exhibit higher binding energies when docked to the receptor in the presence of cholesterol, thereby implying that membrane cholesterol facilitates ligand binding to the serotonin(1A) receptor. To the best of our knowledge, this is one of the first reports in which lipid specific receptor conformations have been modeled by homology modeling. PMID- 20967315 TI - Mass spectrometry at the interface of proteomics and genomics. AB - With the onset of modern DNA sequencing technologies, genomics is experiencing a revolution in terms of quantity and quality of sequencing data. Rapidly growing numbers of sequenced genomes and metagenomes present a tremendous challenge for bioinformatics tools that predict protein-coding regions. Experimental evidence of expressed genomic regions, both at the RNA and protein level, is becoming invaluable for genome annotation and training of gene prediction algorithms. Evidence of gene expression at the protein level using mass spectrometry-based proteomics is increasingly used in refinement of raw genome sequencing data. In a typical "proteogenomics" experiment, the whole proteome of an organism is extracted, digested into peptides and measured by a mass spectrometer. The peptide fragmentation spectra are identified by searching against a six-frame translation of the raw genomic assembly, thus enabling the identification of hitherto unpredicted protein-coding genomic regions. Application of mass spectrometry to genome annotation presents a range of challenges to the standard workflows in proteomics, especially in terms of proteome coverage and database search strategies. Here we provide an overview of the field and argue that the latest mass spectrometry technologies that enable high mass accuracy at high acquisition rates will prove to be especially well suited for proteogenomics applications. PMID- 20967316 TI - Nanosensors: towards morphological control of gas sensing activity. SnO2, In2O3, ZnO and WO3 case studies. AB - Anisotropy is a basic property of single crystals. Dissimilar facets/surfaces have different geometric and electronic structure that results in dissimilar functional properties. Several case studies unambiguously demonstrated that the gas sensing activity of metal oxides is determined by the nature of surfaces exposed to ambient gas. Accordingly, a control over crystal morphology, i.e. over the angular relationships, size and shape of faces in a crystal, is required for the development of better sensors with increased selectivity and sensitivity in the chemical determination of gases. The first step toward this nanomorphological control of the gas sensing properties is the design and synthesis of well-defined nanocrystals which are uniform in size, shape and surface structure. These materials possess the planes of the symmetrical set {hkl} and must therefore behave identically in chemical reactions and adsorption processes. Because of these characteristics, the form-controlled nanocrystals are ideal candidates for fundamental studies of mechanisms of gas sensing which should involve (i) gas sensing measurements on specific surfaces, (ii) their atomistic/quantum chemical modelling and (ii) spectroscopic information obtained on same surfaces under operation conditions of sensors. PMID- 20967317 TI - (S)-stereoisomer of telomestatin as a potent G-quadruplex binder and telomerase inhibitor. AB - Total synthesis of the (S)-stereoisomer of telomestatin (1) was accomplished. (S) Telomestatin exhibited potency four times that of the natural product, (R) telomestatin, which was the most potent telomerase inhibitor previously reported. In the circular dichroism spectral analysis of the complexes possessing randomly structured single-stranded d[TTAGGG](4) oligonucleotide, (S)-telomestatin, like (R)-telomestatin, induced an antiparallel G-quadruplex structure. The melting temperature (T(m)) value of the (S)-isomer complex was greater than that of the (R)-telomestatin complex. Therefore, it is concluded that the stereochemistry of the thiazoline of telomestatin is important to the binding ability of a G quadruplex binder, and (S)-telomestatin as a G-quadruplex binder is more potent than the natural product. PMID- 20967318 TI - Oxidative desulfurization-fluorination of thioethers. Application for the synthesis of fluorinated nitrogen containing building blocks. AB - An oxidative desulfurization-fluorination protocol has been used to synthesize (2S)-2-(difluoromethyl)-N-tosylpyrrolidine (6a) and (2S)-2-(trifluoromethyl)-N tosylpyrrolidine (7a) from the (2S)-prolinol-derived (2S)-2-(4 chlorophenylthiomethyl)-N-tosylpyrrolidine (9) or (2S)-2-(dithian-2-yl)-N tosylpyrrolidine (5). Efforts to prepare 3,3-difluoroalanine similarly from an N protected S-aryl-cysteine ester 17 gave only traces of the target compound 18. Instead, an unique N-(alpha,alpha-difluorobenzyl)-N-alpha',alpha'-dibromoglycine ester 19 was formed by an unprecedented sequence of reaction steps. A plausible mechanism is suggested involving a sulfur-assisted deoxygenation-difluorination of an imino oxygen and a haloform reaction like carbon-carbon bond fission as key steps. Efforts to prepare (2S)-2-(fluoromethyl)-N-tosylpyrrolidine (12) from (2S) N-tosylprolinol (3) by treatment with FluoleadTM (1-tert-butyl-4 trifluorosulfanyl-3,5-dimethylbenzene) gave only 5% of the target compound, but 95% of (3R)-3-fluoro-N-tosylpiperidine (11a) by ring enlargement. PMID- 20967319 TI - Exo/endo selectivity-control in Lewis-acid catalyzed tandem heterocyclization/formal [4+3] cycloaddition: synthesis of polyheterocycles from 2-(1-alkynyl)-2-alken-1-ones and 1,3-diphenylisobenzofuran. AB - A novel catalytic exo/endo selectivity-controllable tandem heterocyclization/formal [4+3] cycloaddition was developed, which provides rapid, efficient and stereoselective access to highly fused polyheterocycles from readily available 2-(1-alkynyl)-2-alken-1-ones and 1,3-diphenylisobenzofuran under mild conditions. PMID- 20967320 TI - Selective reduction of a Pd pincer PCP complex to well-defined Pd(0) species. AB - Well-defined dimeric or polymeric Pd(0) complexes [Pd(MU-(iPr)PCHP)](n) (n = 2 or infinity) containing the bridging ligand alpha,alpha'-bis(diisopropylphosphino)-m xylene ((iPr)PCHP) are produced under mild conditions when the cyclometallated PCP pincer complex ((iPr)PCP)Pd-OH reacts with methanol or isopropanol. PMID- 20967321 TI - Enzyme-assisted binary probe for sensitive detection of RNA and DNA. AB - The new enzyme-assisted assay for DNA/RNA detection provides real-time fluorescent signal readout along with low limit of detection and high discrimination power toward a single-base substitution. Requiring only two new unmodified DNA oligonucleotides for the detection of each new analyte, the assay is an efficient tool for low-cost analysis of multiple analytes. PMID- 20967322 TI - Microfluidics for bacterial chemotaxis. AB - Microfluidics is revolutionizing the way we study the motile behavior of cells, by enabling observations at high spatial and temporal resolution in carefully controlled microenvironments. An important class of such behavior is bacterial chemotaxis, which plays a fundamental role in a broad range of processes, including disease pathogenesis, biofilm formation, bioremediation, and even carbon cycling in the ocean. In biophysical research, bacterial chemotaxis represents a powerful model system to understand how cells and organisms sense and respond to gradients. Using microfluidics to study chemotaxis of free swimming bacteria presents experimental challenges that are distinct from those arising in chemotaxis studies of surface-adherent cells. Recently, these challenges have been met by the development of advanced microdevices, able to generate flow-free, steady gradients of arbitrary shape. Much attention to date has been focused on tool development. Yet, we are now at an exciting turning point where science begins to balance technology. Indeed, recent microfluidic studies provided new insights on both the mechanisms governing bacterial gradient sensing (e.g. tuning of response sensitivity, discrimination between conflicting gradients) and the large-scale consequences of chemotaxis (e.g. in the oceans). Here we outline the principles underlying recently proposed gradient generators for bacterial chemotaxis, illustrate the advantage of the microfluidic approach through selected examples, and identify a broader set of scientific questions that may now be addressed with this rapidly developing technology. The latest generation of microfluidic gradient generators, in particular, holds appeal for both biophysicists seeking to unravel the fundamental mechanisms of bacterial chemotaxis, and ecologists wishing to model chemotaxis in realistic environments. Time is ripe for a deeper integration between technology and biology in fully bringing to bear microfluidics on studies of this fascinating microbial behavior. PMID- 20967323 TI - MALDI-TOF mass spectrometry proteomic phenotyping of clinically relevant fungi. AB - Proteomics is particularly suitable for characterising human pathogens with high life cycle complexity, such as fungi. Protein content and expression levels may be affected by growth states and life cycle morphs and correlate to species and strain variation. Identification and typing of fungi by conventional methods are often difficult, time-consuming and frequently, for unusual species, inconclusive. Proteomic phenotypes from MALDI-TOF MS were employed as analytical and typing expression profiling of yeast, yeast-like species and strain variants in order to achieve a microbial proteomics population study. Spectra from 303 clinical isolates were generated and processed by standard pattern matching with a MALDI-TOF Biotyper (MT). Identifications (IDs) were compared to a reference biochemical-based system (Vitek-2) and, when discordant, MT IDs were verified with genotyping IDs, obtained by sequencing the 25-28S rRNA hypervariable D2 region. Spectra were converted into virtual gel-like formats, and hierarchical clustering analysis was performed for 274 Candida profiles to investigate species and strain typing correlation. MT provided 257/303 IDs consistent with Vitek-2 ones. However, amongst 26/303 discordant MT IDs, only 5 appeared "true". No MT identification was achieved for 20/303 isolates for incompleteness of database species variants. Candida spectra clustering agreed with identified species and topology of Candida albicans and Candida parapsilosis specific dendrograms. MT IDs show a high analytical performance and profiling heterogeneity which seems to complement or even outclass existing typing tools. This variability reflects the high biological complexity of yeasts and may be properly exploited to provide epidemiological tracing and infection dispersion patterns. PMID- 20967324 TI - Sensing with fluorescent nanoparticles. AB - Fluorescent chemosensors are chemical systems that can detect and signal the presence of selected analytes through variations in their fluorescence emission. Their peculiar properties make them arguably one of the most useful tools that chemistry has provided to biomedical research, enabling the intracellular monitoring of many different species for medical and biological purposes. In its simplest design, a fluorescent chemosensor is composed of a fluorescent dye and a receptor, with a built-in transduction mechanism that converts recognition events into variations of the emission properties of the fluorescent dye. As soon as fluorescent nanoparticles became available, several applications in the field of sensing were explored. Nanoparticles have been used not only as better-performing substitutes of traditional dyes but also as multivalent scaffolds for the realization of supramolecular assemblies, while their high surface to volume ratio allows for distinct spatial domains (bulk, external surface, pores and shells) to be functionalized to a comparable extent with different organic species. Over the last few years, nanoparticles proved to be versatile synthetic platforms for the implementation of new sensing schemes. PMID- 20967325 TI - Direct aromatic-ring amination by aqueous ammonia with a platinum loaded titanium oxide photocatalyst. AB - Active species generated from aqueous ammonia with a platinum-loaded titanium oxide photocatalyst can selectively aminate the aromatic ring of benzene and some substituted benzenes. PMID- 20967326 TI - Selective internuclear coupling estimation in the solid-state NMR of multiple spin systems. AB - A new solid-state NMR method is presented for estimating homonuclear dipole dipole couplings for selected groups of nuclear spins in a multiple-spin coupled network. The methodology combines off-magic-angle spinning, frequency selective spin echoes, and multiple quantum filtering. The new method is insensitive to incoherent relaxation effects and may be used to estimate weak couplings. Internuclear (13)C-(13)C couplings are estimated in uniformly (13)C-labelled l Histidine.HCl.H(2)O. Weak intermolecular couplings between (13)C nuclei separated by distances exceeding 6 A are estimated. PMID- 20967327 TI - Phosphite copper(I) trifluoroacetates [((RO)3P)mCuO2CCF3] (m = 1, 2, 3): synthesis, solid state structures and their potential use as CVD precursors. AB - Metal-organics [((RO)(3)P)(m)CuO(2)CCF(3)] (R = CH(3): 11a, m = 1; 11b, m = 2; 11c, m = 3. R = CH(2)CH(3): 12a, m = 1; 12b, m = 2; 12c, m = 3. R = CH(2)CF(3): 13a, m = 1; 13b, m = 2; 13c, m = 3) are either accessible by the reaction of [((RO)(3)P)(m)CuCl] (R = CH(3): 5a, m = 1; 5b, m = 2; 5c, m = 3. R = CH(2)CH(3): 6a, m = 1; 6b, m = 2; 6c, m = 3) with [KO(2)CCF(3)] (7), or treatment of [Cu(2)O] (8) with HO(2)CCF(3) (9) and P(OR)(3) (2, R = CH(3); 3, R = CH(2)CH(3); 4, R = CH(2)CF(3)). (31)P{(1)H} NMR spectra [((CH(3)O)(3)P)(m)CuO(2)CCF(3)] (m = 1, 1.5, 2, 2.5, 3, 3.5, and 4) have been studied at 25 and -80 degrees C showing phosphite ligand exchange in solution. The molecular structures of 11a and 13a 13c in the solid state are reported. Complexes 11a and 13a are tetramers featuring MU-eta(2)(1kappaO:2kappaO')- and MU(3) eta(2)(1kappaO:2kappaO':3kappaO')-(11a) or MU(3) eta(2)(1kappaO:2kappaO':3kappaO')-bonded O(2)CCF(3) ligands (13a) with the Cu(I) ions being part of CuPO(2) and CuPO(3) units (11a), while in 13a solely a CuPO(3) moiety is present. Skeletal isomerism of 11a vs. 13a is discussed. Compound 13b is dimeric ({CuP(2)O(2)}(2)) with pseudo-tetrahedral Cu environments and MU eta(2)(1kappaO:2kappaO')O(2)CCF(3) functionalities. In monomeric 13c the O(2)CCF(3) ligand is eta(1)(kappaO)-bonded to a tetra-coordinated Cu(i) ion. The thermal solid state properties of 11, 12 and 13 were studied by Thermo Gravimetry (TG). These complexes decompose by phosphite elimination, decarboxylation and dealkylation. Hot-wall Chemical Vapour Deposition (CVD) experiments were carried out at 380 degrees C using 11c as precursor for the deposition of copper onto pieces of TiN-coated oxidized silicon substrates. Copper layers of high purity were obtained with grain sizes between 200-1200 nm. PMID- 20967328 TI - Reactivity of the bifunctional ambiphilic molecule 8-(dimesitylboryl)quinoline: hydrolysis and coordination to Cu(I), Ag(I) and Pd(II). AB - The ambiphilic molecule 8-(dimesitylboryl)quinoline (1) was synthesized by treatment of 8-bromoquinoline or 8-iodoquinoline with n-BuLi followed by dimesitylboronfluoride. Hydrolysis of 1 is unusually rapid compared to bulky triorganoboranes with the sequential loss of mesitylene and formation of mesityl(quinolin-8-yl)borinic acid (2) and 8-quinoline boronic acid dimer (3). Cooperativity within the bifunctional ambiphilic site leads to water activation and protodeboronation of the B-C(Mes) bonds. Blocking of the ambiphilic site of 1 by methylation of the quinoline nitrogen atom leads to an air-stable N-methyl quinolinium salt. Coordination complexes were formed by reaction of 1 with CuCl, Ag(OTf), and PdCl(2)(PhCN)(2) with coordination of the quinolinyl nitrogen to the metal ion. The Cu(I) and Ag(I) centers are stabilized by eta(3) BC(ipso)C(ortho)pi-interaction. The isolated Pd(II) complex is a product of cyclometalation, resulting from elimination of HCl upon deprotonation of the ortho-methyl group of nearby mesityl. The bonding in 7 could be understood as a 16-electron Pd complex that features an anionic eta(3)-C(ipso)-C(ortho)-C(benzyl) allylic ligand fragment plus a Pd->B bond, or an eta(4)-BC(ipso)-C(ortho) C(benzyl) boratabutadiene anion fragment. PMID- 20967329 TI - Bioconjugate functionalization of thermally carbonized porous silicon using a radical coupling reaction. AB - The high stability of Salonen's thermally carbonized porous silicon (TCPSi) has attracted attention for environmental and biochemical sensing applications, where corrosion-induced zero point drift of porous silicon-based sensor elements has historically been a significant problem. Prepared by the high temperature reaction of porous silicon with acetylene gas, the stability of this silicon carbide-like material also poses a challenge--many sensor applications require a functionalized surface, and the low reactivity of TCPSi has limited the ability to chemically modify its surface. This work presents a simple reaction to modify the surface of TCPSi with an alkyl carboxylate. The method involves radical coupling of a dicarboxylic acid (sebacic acid) to the TCPSi surface using a benzoyl peroxide initiator. The grafted carboxylic acid species provides a route for bioconjugate chemical modification, demonstrated in this work by coupling propylamine to the surface carboxylic acid group through the intermediacy of pentafluorophenol and 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC). The stability of the carbonized porous Si surface, both before and after chemical modification, is tested in phosphate buffered saline solution and found to be superior to either hydrosilylated (with undecylenic acid) or thermally oxidized porous Si surfaces. PMID- 20967330 TI - A new approach to internal Lewis pairs featuring a phosphenium acid and a pyridine base. AB - A bis(imino)acenaphthene (BIAN) ligand containing a pendant Lewis base has been used as a new framework to support a N-heterocyclic phosphenium cation (NHP). Reactivity studies demonstrate the ability of the ligand to act as a Lewis base, while the phosphorus centre provides a Lewis acidic site, giving new opportunities in NHP chemistry. PMID- 20967331 TI - High-throughput 3D spheroid culture and drug testing using a 384 hanging drop array. AB - Culture of cells as three-dimensional (3D) aggregates can enhance in vitro tests for basic biological research as well as for therapeutics development. Such 3D culture models, however, are often more complicated, cumbersome, and expensive than two-dimensional (2D) cultures. This paper describes a 384-well format hanging drop culture plate that makes spheroid formation, culture, and subsequent drug testing on the obtained 3D cellular constructs as straightforward to perform and adapt to existing high-throughput screening (HTS) instruments as conventional 2D cultures. Using this platform, we show that drugs with different modes of action produce distinct responses in the physiological 3D cell spheroids compared to conventional 2D cell monolayers. Specifically, the anticancer drug 5 fluorouracil (5-FU) has higher anti-proliferative effects on 2D cultures whereas the hypoxia activated drug commonly referred to as tirapazamine (TPZ) are more effective against 3D cultures. The multiplexed 3D hanging drop culture and testing plate provides an efficient way to obtain biological insights that are often lost in 2D platforms. PMID- 20967332 TI - The time domain in co-stained cell imaging: time-resolved emission imaging microscopy using a protonatable luminescent iridium complex. AB - The intense luminescence of the new complex Ir(ppy)(2)(pybz) (1) within the cytoplasm of live cells can be discriminated from the fluorescence of an organic stain, solely on the basis of the emission timescale {pybzH = 2-pyridyl benzimidazole}. The protonated form of 1 displays red-shifted emission, and may be implicated in a superior uptake compared to Ir(ppy)(3). PMID- 20967333 TI - Iron-catalyzed synthesis of glycine derivatives via carbon-nitrogen bond cleavage using diazoacetate. AB - Treatment of tertiary amines with diazoacetate in the presence of a catalytic amount of an iron salt, FeCl(3), in ethanol gave glycine derivatives. In this reaction, a carbon-nitrogen single bond of the amine was cleaved. PMID- 20967334 TI - Cu(I) complexes based on cis, cis-1,3,5-tris(arylideneamino)cyclohexane ligands: synthesis, structure and CO binding. AB - A new series of sterically bulky, facially coordinating N(3)-donor tach-based ligands (tach; cis,cis-1,3,5-triaminocyclohexane) [2.1; cis,cis-1,3,5-tris(2,4 dimethylbenzylideneamino)cyclohexane, 4.1; cis,cis-1,3,5 tris(pentamethylbenzylideneamino)cyclohexane, 5.1; cis,cis-1,3,5-tris(2,6 dimethoxybenzylideneamino)cyclohexane, 6.1; cis,cis-1,3,5 tris(pentafluorobenzylideneamino)cyclohexane, 7.1; cis,cis-1,3,5-tris(3,5 bis(ditrifluoromethyl)benzylideneamino)cyclohexane, 8.1; cis,cis-1,3,5-tris(2 trifluoromethylbenzylideneamino)cyclohexane, 9.1; cis,cis-1,3,5-tris(2 methoxybenzylideneamino)cyclohexane] have been obtained from the condensation of tach with three equivalents of the appropriate substituted benzaldehyde. Reaction with [Cu(NCCH(3))(4)]PF(6) gives Cu(I) complexes of tach-based ligands {2.2-9.2, eg; 2.2; [Cu(2.1)(NCCH(3))]PF(6)}. Displacement of the acetonitrile ligand by CO was achieved successfully for all the Cu(I) complexes of tach-based ligands and the resulting complexes have been shown to bind carbon monoxide {2.3-9.3, eg; 2.3; [Cu(2.1)(CO)]PF(6)}. The X-ray single crystal structures of 5.1, 8.1, 9.1, 3.2, 7.2, 8.2, 9.2, 3.3, 5.3 and 6.3 have been determined. PMID- 20967335 TI - Electrochemistry in nanoscopic volumes. AB - Exploration of electrochemical properties in ultrasmall volumes is still an emerging area. It is not only of great importance for the fundamental research, but also endowed with practical significance in the area of bioanalysis and medicine. Microelectrodes with superior electrochemical characteristics and versatile configurations are suitable tools for the investigation in confined geometries, and remarkable progress involving both preparation methods and theoretical interpretation has been made during the last few decades. Despite this success, electrochemical studies in nanoscopic volumes are still highly challenging due to the less predictable situations in very limited spatial and temporal domains, as well as difficulty in micromanipulation at the nanoscale. In this mini-review, we will summarize the main strategies for this topic, briefly look through the recent advances, and specifically introduce the design and application of a new kind of on-chip ultrasmall electrochemical cells based on micro- and nanogap electrodes, which are prepared by photolithographic method with volume ranging from femtolitre to attolitre. Finally, the limits of current systems and the future perspectives of this field are discussed. PMID- 20967336 TI - DNA-mediated site-specific deposition of gold nanoparticles on silicon wafers. AB - We report a method for the site-specific deposition of gold nanoparticles, as programmed by DNA sequences immobilized on the surface of silicon oxide-coated silicon wafers. After optimization of surface chemistries, selectivities of between 8:1 and 118:1 were achieved for the DNA-based sorting of populations of gold nanoparticle of 15 nm and 60 nm diameter from a common suspension via oligonucleotide duplex formation. PMID- 20967337 TI - Synthesis and characterisation of polymeric materials consisting of {Fe2(CO)5} unit and their relevance to the diiron sub-unit of [FeFe]-hydrogenase. AB - By using "click" chemistry between a diazide and a diiron model complex armed with two alkynyl groups, two polymeric diiron complexes (Poly-Py and Poly-Ph) were prepared. The two polymeric complexes were investigated using infrared spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermal gravimetric analysis (TGA), Mossbauer spectroscopy, and cyclic voltammetry (Poly-Py only, due to the insolubility of Poly-Ph). To probe the coordinating mode of the diiron units in the two polymeric complexes, two control complexes (3 and 4) were also synthesised using a monoazide. Complexes 3 and 4 were well characterised and the latter was further crystallographically analysed. It turns out that in both complexes (3 and 4) and the two polymeric diiron complexes, one of the two iron atoms in the diiron unit coordinates with one of the triazole N atoms. Our results revealed that both morphologies and properties of Poly-Py and Poly-Ph are significantly affected by the organic moiety of the diazide. Compared to the protonating behaviour of the complexes 3 and 4, Poly-Py exhibited proton resistance. In electrochemical reduction, potentials for the reduction of the diiron units in Poly-Py and hence its catalytic reduction of proton in acetic acid-DMF shifted by over 400 mV compared to those for complexes 3 and 4. It is likely that the polymeric nature of Poly-Py offers the diiron units a "protective" environment in an acidic medium and more positive reduction potential. PMID- 20967338 TI - Generation of core-shell microcapsules with three-dimensional focusing device for efficient formation of cell spheroid. AB - We present a microfluidic device generating three-dimensional (3D) coaxial flow by the addition of a simple hillock to produce an alginate core-shell microcapsule for the efficient formation of a cell spheroid. A hillock tapered at downstream of the two-dimensional focusing channel enables outside flow to enclose the core flow. The aqueous solution in the core flow was focused and surrounded by 1.8% alginate solution to be solidified as a shell. The double layered coaxial flow (aqueous phase) was broken up into a droplet by the shear flow of oleic acid (oil phase) containing calcium chloride for the polymerization of the alginate shell. The droplet generated from the laminar coaxial flow maintained a double-layer structure and gelation of the alginate solution made a core-shell microcapsule. The shell-thickness of the microcapsule was adjusted from 8-21 MUm by the variation of two aqueous flow rates. The inner shape of the shell was almost spherical when the ratio of the water-glycol mixture in the core flow exceeded 20%. The microcapsule was used to form a spheroid of embryonic carcinoma cells (embryoid body; EB) by injecting a cell suspension into the core flow. The cells inside the microcapsule aggregated into an EB within 2 days and the EB formation rate was more than 80% with strong compaction. The microcapsule formed single spherical EBs without small satellite clusters or a bumpy shape as observed in solid microbeads. The microfluidic chip for encapsulation of cells could generate a number of EBs with high rate of EB formation when compared with the conventional hanging drop method. The core-shell microcapsule generated by 3D focusing in the microchannel was effective in forming large number of spherical cell clusters and the encapsulation of cells in the microcapsule is expected to be useful in the transplantation of islet cells or cancer stem cell enrichment. PMID- 20967339 TI - Synthesis of core-shell gold coated magnetic nanoparticles and their interaction with thiolated DNA. AB - Core-shell magnetic nanoparticles have received significant attention recently and are actively investigated owing to their large potential for a variety of applications. Here, the synthesis and characterization of bimetallic nanoparticles containing a magnetic core and a gold shell are discussed. The gold shell facilitates, for example, the conjugation of thiolated biological molecules to the surface of the nanoparticles. The composite nanoparticles were produced by the reduction of a gold salt on the surface of pre-formed cobalt or magnetite nanoparticles. The synthesized nanoparticles were characterized using ultraviolet visible absorption spectroscopy, transmission electron microscopy, energy dispersion X-ray spectroscopy, X-ray diffraction and super-conducting quantum interference device magnetometry. The spectrographic data revealed the simultaneous presence of cobalt and gold in 5.6+/-0.8 nm alloy nanoparticles, and demonstrated the presence of distinct magnetite and gold phases in 9.2+/-1.3 nm core-shell magnetic nanoparticles. The cobalt-gold nanoparticles were of similar size to the cobalt seed, while the magnetite-gold nanoparticles were significantly larger than the magnetic seeds, indicating that different processes are responsible for the addition of the gold shell. The effect on the magnetic properties by adding a layer of gold to the cobalt and magnetite nanoparticles was studied. The functionalization of the magnetic nanoparticles is demonstrated through the conjugation of thiolated DNA to the gold shell. PMID- 20967341 TI - Combining synchrotron-based X-ray techniques with vibrational spectroscopies for the in situ study of heterogeneous catalysts: a view from a bridge. AB - The advantages, challenges, and future possibilities for combining synchrotron based X-ray techniques with vibrational spectroscopies are considered in this critical review. Particular emphasis is given to (1) quantifying structure and structural change--on a wide range of length scales--in working heterogeneous catalytic systems; (2) relating that change to chemical speciation occurring at the surface of the catalyst; and (3) determining how such change relates to the overall function of the catalyst material. We will consider those resources that exist today and suggest some possible future directions yet to be ventured into or demonstrated. Lastly, we will consider how the catalysis community interacts with, and uses the resources offered by, modern synchrotron radiation facilities and whether this current relationship provides the best and most inclusive means for the exploitation of these resources in this field of research (83 references). PMID- 20967340 TI - What site-directed labeling studies tell us about the mechanism of rhodopsin activation and G-protein binding. AB - Rhodopsin is the photoreceptor protein responsible for dim-light vision in mammals. Due to extensive biophysical, structural and computational analysis of this membrane protein, it is presently the best understood G-protein coupled receptor (GPCR). Here I briefly review one approach that has been extensively used to identify dynamic and structural changes in rhodopsin--the use of site directed labeling methods (SDL) coupled with electron paramagnetic resonance (EPR) and fluorescence spectroscopy. These SDL studies involve introducing individual cysteine residues into the receptor, then labeling them with cysteine reactive probes for subsequent analysis by the appropriate spectroscopy. I will give a brief overview of how SDL methods are carried out and how the data is analyzed. Then, I will discuss how SDL studies were carried out on rhodopsin, and how they were used to identify a key structural change that occurs in rhodopsin upon activation--movement of transmembrane helix 6 (TM6). I will also briefly discuss how the SDL studies of rhodopsin compare with SDL studies of other GPCRs, and compare the SDL data with early and recent crystal structures of rhodopsin. Finally, I will discuss why the TM6 movement is required for rhodopsin to couple with the G-protein transducin, and speculate how this mechanism might be a universal method used by all GPCRs to bind G-proteins and perhaps other proteins involved in visual signal transduction, such as arrestin and rhodopsin kinase. PMID- 20967342 TI - New strategy for drastic enhancement of selectivity via chemical modification of counter anions in ionic liquid polymer phase. AB - A new strategy for the design of a new chromatographic stationary phase via simple modifications of the counter anions in poly(ionic liquid)-grafted silica phase based on ionic self-assembly technology is proposed. The phase with methyl orange dye as counter anions exhibits ultra-high selectivity towards shape constrained isomers. PMID- 20967343 TI - Pd2L2 metallacycles as molecular containers for small molecules. AB - M(2)L(2) type metallacyclic complexes, [Pd(2)(L1)(2)Cl(4)].1.5CH(2)Cl(2) (1), [Pd(2)(L1)(2)Cl(4)].2CHCl(3) (2), [Pd(2)(L2)(2)Cl(4)].2CH(2)Cl(2).2CH(3)CN (3), [Pd(2)(L2)(2)Cl(4)].2CHCl(3).2CH(3)CN (4) and [Pd(2)(L3)(2)Cl(4)].CH(2)Cl(2).2CH(3)CN (5), have been prepared from three semi rigid benzimidazol or benzotriazol ligands, 1,4-bis(benzimidazol-1-ylmethyl) 2,3,5,6-tetramethylbenzene (L1), 1,4-bis(5,6-dimethylbenzimidazol-1-ylmethyl) 2,3,5,6-tetramethylbenzene (L2) and 1,4-bis(benzotriazol-1-ylmethyl)-2,3,5,6 tetramethylbenzene (L3). All the complexes were structurally characterized by single-crystal X-ray diffraction and the phase purity was confirmed by powder X ray diffraction (PXRD) measurements. The solution structure of representative complex 1 was studied by (1)H NMR titration and ESI mass spectroscopy. The thermal stability and guest-exchange properties of 1, 3 and 4 were investigated, revealing that the Pd(2)L(2) metallacycles can act as a selective receptor for CH(2)Cl(2) or CHCl(3) guest molecules. The catalytic activity of 1 in Suzuki Miyaura coupling reaction was also studied and 1 could be recycled at least 5 times under heterogeneous conditions, indicative of a potential self-supported catalyst. PMID- 20967344 TI - Polymer-assisted preparation of nanoscale films of thermoelectric PbSe and PbTe and of lead chalcogenide-polymer composite films. AB - Polymer films of polyethyleneoxide (PEO) or poly(L-lactide) (PLLA) containing a single-source precursor for either PbSe or PbTe were used to produce films of nanoparticles of these thermoelectric materials. The monomeric homoleptic chalcogenolates lead(II) bis-(2,4,6-trifluoromethylphenylselenolate) Pb[SeC(6)H(2)(CF(3))(3)](2) and lead(II) bis-[tris(trimethylsilyl)silyl tellurolate] Pb[TeSi(SiMe(3))(3)](2) were used as single-source precursors for the thermolytic formation of the lead chalcogenides. The thickness and the quality of as-obtained thin films depended decisively on the spin-coating conditions, on the polymer, on the precursor concentration in the composite film before thermolysis and on the annealing time. Thin layers of particles of 30-50 nm size and high crystallinity were obtained. They were characterized by X-ray diffraction, thermal analysis and electron microscopy. PMID- 20967345 TI - Investigation of the influence of high-risk human papillomavirus on the biochemical composition of cervical cancer cells using vibrational spectroscopy. AB - The main aetiology of cervical cancer is infection with high-risk human papillomavirus (HPV). Cervical cancer is almost 100% curable if detected in the early stages. Thus, information about the presence and levels of HPV in patient samples has high clinical value. As current screening methods, such as the Pap smear test, are highly subjective and in many cases show low sensitivity and specificity, new supportive techniques are desirable to improve the quality of cervical cancer screening. In this study, vibrational spectroscopic techniques (Raman and Fourier Transform Infra Red absorption) have been applied to the investigation of four cervical cancer cell lines: HPV negative C33A, HPV-18 positive HeLa with 20-50 integrated HPV copies per cell, HPV-16 positive SiHa with 1-2 integrated HPV strands per cell and HPV-16 positive CaSki containing 60 600 integrated HPV copies per cell. Results show that vibrational spectroscopic techniques can discriminate between the cell lines and elucidate cellular differences originating from proteins, nucleic acids and lipids. Similarities between C33A and SiHa cells were exhibited in the Raman and infrared spectra and were confirmed by Principal Component Analysis (PCA). Analysis of the biochemical composition of the investigated cells, with the aid of PCA, showed a clear discrimination between the C33A-SiHa group and HeLa and CaSki cell lines indicating the potential of vibrational spectroscopic techniques as a support to current methods for cervical cancer screening. PMID- 20967346 TI - Comparing dendritic with linear esterase peptides by screening SPOT arrays for catalysis. AB - Fluorescence screening of a 96-membered SPOT library of histidine containing dendritic and linear peptides revealed the remarkable esterolytic activity of short histidine oligomers that show catalytic proficiencies within one order of magnitude of histidine-containing esterase peptide dendrimers. PMID- 20967347 TI - Solid phase total synthesis of the 3-amino-6-hydroxy-2-piperidone (Ahp) cyclodepsipeptide and protease inhibitor Symplocamide A. AB - The solid phase total synthesis of the marine cyanobacterial Ahp cyclodepsipeptide Symplocamide A is reported as a model for a general route for the synthesis of tailor-made non-covalent serine protease inhibitors. PMID- 20967348 TI - New metal-coordination-inhibited charge transfer emission for terfluorenes: highly sensitive and selective detection for Hg2+ with ratiometric "turn-on" fluorescence response. AB - Two terfluorenes TFOH and TFN exhibit high sensitivity and selectivity for the detection of Hg(2+) with ratiometric fluorescence response. The sensory mechanism is attributed to a new metal-coordination-inhibited spiroconjugation-like charge transfer emission. PMID- 20967349 TI - Structural diversity through ligand flexibility: two novel metal-organic nets via ligand-to-ligand cross-linking of "paddlewheels". AB - Solvothermal reaction of a partially flexible ligand, H(4)L, and Cu(NO(3))(2).2.5H(2)O afforded two cross-linked Kagome lattices of formula [Cu(2)(L)](n): an acs net sustained by novel trigonal prismatic supermolecular building blocks (SBBs) and the first example of a partially pillared Kagome net. PMID- 20967350 TI - Flowerlike supramolecular architectures assembled from C60 equipped with a pyridine substituent. AB - Fullerene (C(60))-rich and photoconductive flowerlike supramolecular assembly was constructed from self-organization of pyridine substituted C(60) by a facile drop casting method. PMID- 20967351 TI - Homospin single-chain magnet with 1D ferromagnetic azido-cobalt Ising-type chain. AB - A new 2D coordination polymer with an azide-bridged 1D homospin chain is synthesized, which shows slow magnetic relaxation and step hysteresis loop, and is ascribed to be a typical Ising-type single-chain magnet. PMID- 20967352 TI - Diameter dependent electron transfer in supramolecular nanohybrids of (6,5)- or (7,6)-enriched semiconducting SWCNT as donors and fullerene as acceptor. AB - Diameter dependent electron donor behavior of (6,5)- and (7,6)-enriched semiconducting SWCNT is proved by constructing supramolecular nanohybrids with pyrene functionalized electron acceptor, fullerene, and the subsequent photocatalytic/ photoelectrochemical processes. PMID- 20967353 TI - Dynamic response of chlorine atoms on a RuO(2)(110) model catalyst surface. AB - The dynamic behavior of surface accommodated chlorine atoms on RuO(2)(110) was studied by a variety of experimental methods including high resolution core level shift, thermal desorption-, and in situ infrared spectroscopy as well as in situ surface X-ray diffraction in combination with state-of-the-art density functional theory calculations. On the chlorinated RuO(2)(110) surface the undercoordinated oxygen atoms have been selectively replaced by chlorine. These strongly bound surface chlorine atoms shift from bridging to on-top sites when the sample is annealed in oxygen, while the reverse shift of Cl from on-top into bridge positions is observed during CO exposure; the vacant bridge position is then occupied by either chlorine or CO. For the CO oxidation reaction over chlorinated RuO(2)(110), the reactant induced site switching of chlorine causes a site blocking of the catalytically active one-fold coordinatively unsaturated (1f-cus) Ru sites. This site blocking reduces the number of active sites and, even more important, on-top Cl blocks the free migration of the adsorbed reactants along the one-dimensional 1f-cus Ru rows, thus leading to a loss of catalytic activity. PMID- 20967354 TI - Fast synthesis of nanocrystalline Mg2Si by microwave heating: a new route to nano structured thermoelectric materials. AB - The ultra fast synthesis of nanocrystalline Mg(2)Si was carried out using microwave radiation. The elemental precursors were first milled together under dry conditions to get fine particles. The resulting mixture of powders of Mg and Si was cold pressed before being heated by microwave irradiation. Precursors and products were analyzed by X-ray diffraction and scanning electron microscopy. The high energy ball milling parameters utilized to prepare the reactive powders have quite an influence on the behavior of the mixture under irradiation. Moreover, SEM imaging demonstrates that the power and time of irradiation are crucial for the grain growth of the Mg(2)Si and must be adequately controlled in order to avoid the decomposition of the phase. Our results show that we successfully managed to easily and quickly synthesize homogeneous nanocrystalline Mg(2)Si with particle size smaller than 100 nm using a microwave power of only 175 W for two minutes on powders ball milled for two hours. PMID- 20967355 TI - Pd-catalyzed 5-endo-trig-type cyclization of beta,gamma-unsaturated carbonyl compounds: an efficient ring closing reaction to give gamma-butenolides and 3 pyrrolin-2-ones. AB - The 5-endo-trig-type cyclization has been performed using a Pd-bis(isoxazoline) catalyst. The present cyclization of beta,gamma-unsaturated carbonyl compounds gave gamma-butenolides and 3-pyrrolin-2-ones in good to excellent yields. PMID- 20967356 TI - Polypyrrole self-organized nanopore arrays formed by controlled electropolymerization in TiO2 nanotube template. AB - A new concept for formation of nanostructured intrinsically conducting polymers (ICP) is demonstrated. Polypyrrole can be electropolymerized from an ionic surfactant-solution in TiO(2) nanotube framework to form a geometrical structure of self-organized nanopore arrays. Polymerization is initialized selectively in the space between nanotube walls forming a mechanically stable polymer network with controlled wall thickness from 40 to 10 nm. Such robust polymer nanostructures are very promising for application in electrochemical systems of limited charge carrier diffusion length. PMID- 20967357 TI - Activation of dihydrogen by non-metal systems. AB - This feature article reviews advances in the metal-free activation of hydrogen and the utilization of these and related systems in catalytic hydrogenations. PMID- 20967358 TI - Two cationic metal-organic frameworks based on cadmium and alpha,omega alkanedisulfonate anions and their photoluminescent properties. AB - We have successfully synthesized three cadmium-based metal-organic frameworks by utilizing two separate organic linkers to direct the structure. The first material is a three-dimensional neutral framework based on 2D cadmium ethanedisulfonate layers pillared by a 4,4'-bipyridine linker. The other two materials are 3D cationic frameworks and are the first with propanedisulfonate and butanedisulfonate as extraframework charge balancing anions. Both structures occupy a high symmetry hexagonal crystal system where Cd-bipy chains are arranged into three crystallographically distinct layers that stack spirally along [001]. The framework is stabilized by alkanesulfonate anions that are electrostatically and hydrogen bonded to the framework. Each material was characterized by single crystal and powder X-ray diffraction. The thermal and luminescent properties were also investigated by thermogravimetric analysis and photoluminescence spectroscopy, respectively. All three materials exhibit high thermal stability to above 300 degrees C and efficient blue emissive photoluminescence centered at 425 nm to 450 nm upon 350 nm excitation. PMID- 20967359 TI - Biotin as acylating agent in the Friedel-Crafts reaction. Avidin affinity of biotinyl derivatives of ferrocene, ruthenocene and pyrene and fluorescence properties of 1-biotinylpyrene. AB - (D)-Biotin was used for Friedel-Crafts acylation of electron-rich aromatic molecules--ferrocene, ruthenocene and pyrene. The reaction carried out in the presence of trifluoroacetic anhydride and trifluoromethanesulfonic acid afforded the corresponding biotinylarenes in moderate yields. These compounds, although lacking an amide bond, exhibited high affinity for avidin, with the ability to displace 2-(4'-hydroxyphenylazo)-benzoic acid (HABA) in its complex with avidin. Their affinity for avidin was determined by a solid-phase competitive enzymatic assay, which gave IC(50) values in the range of 33-58 nM (under the same conditions biotin showed IC(50) = 24 +/- 7 nM). 1-Biotinylpyrene (1c) excited at 355 nm displayed fluorescence emission in aqueous solutions with lambda(max) = 461 nm. The fluorescence maximum was shifted to 425 nm upon binding of 1c to avidin. Formation of the avidin-1c complex was also evidenced by quenching of the fluorescence from the protein tryptophan residues (342 nm) and appearance of the emission band of the avidin-bound 1c at 430 nm as a result of a Forster resonance energy transfer (FRET) phenomenon. PMID- 20967360 TI - Microwave and flow syntheses of Pseudomonas quinolone signal (PQS) and analogues. AB - Expedient syntheses of Pseudomonas quinolone signal (PQS) and related structural analogues using microwave and flow methods are reported. PMID- 20967361 TI - Self-lubricating nanoparticles: self-organization into 3D-superlattices during a fast drying process. AB - Fluorinated tetraethylene glycol-stabilized Au nanoparticles (FTEG-AuNPs) were well-dispersed in general polar organic solvents, such as methanol (MeOH) and THF. The cast film of FTEG-AuNPs on a TEM grid and a glass substrate was found to form a highly ordered 3D-superlattice assembly, whereas tetraethylene glycol stabilized AuNPs (TEG-AuNPs) provide an amorphous AuNP aggregation. These data indicate that the fluorine feature on the surface of the FTEG-AuNPs is critical for the nanostructured assembly. PMID- 20967362 TI - Carbazole endcapped heterofluorenes as host materials: theoretical study of their structural, electronic, and optical properties. AB - By mimicking the molecular structure of 4,4'-bis(N-carbazolyl)-2,2'-biphenyl (CBP), which is a widely used host material, a new series of host molecules (carbazole-endcapped heterofluorenes, CzHFs) were designed by linking the hole transporting carbazole to the core heterofluorene molecules in either meta or para positions of the heterofluorene. The aromatic cores considered in this study are biphenyl, fluorene, silafluorenes, germafluorenes, carbazole, phosphafluorene, oxygafluorene, and sulfurafluorene. To reveal their molecular structures, optoelectronic properties and structure-property relationships of the proposed host materials, an in-depth theoretical investigation was elaborated via quantum chemical calculations. The electronic structures in the ground states, cationic and anionic states, and lowest triplet states of these designed molecules have been studied with emphasis on the highest occupied molecular orbitals (HOMOs), the lowest unoccupied molecular orbitals (LUMOs), energy gaps (E(g)), triplet energy gaps ((3)E(g)), as well as some other electronic properties including ionization potentials (IPs), electron affinities (EAs), reorganization energies (lambda), triplet exciton generation fraction (chi(T)), spin density distributions (SD), and absorption spectra. These photoelectronic properties can be tuned by chemical modifications of the heteroatom and the carbazole substitution at different positions. This study provides theoretical insights into the nature of host molecules, and shows that the designed CzHFs can meet the requirements of the host materials for triplet emitters. PMID- 20967363 TI - The coordination chemistry of the proton. AB - It is well known that an acidic hydrogen atom can form hydrogen bonds to a hydrogen bond acceptor, a Lewis base. It is considerably less known that the proton can coordinate two or more atoms conveniently in bonding modes that cannot be described as hydrogen bonding. Agostic interactions, bridging hydrides, 3 centre-2-electron bonds in boranes, bifurcated hydrogen atoms, they are all elements of the coordination chemistry of the proton and, of course, the hydrogen bond comes in more than one facette as well. PMID- 20967364 TI - Effect of dibenzopyrene measurement on assessing air quality in Beijing air and possible implications for human health. AB - Size fractionated particulate matter (PM) was collected in summer and winter from Beijing, China for the characterization of an expanded list of PAHs and evaluation of air pollution metrics. Summertime SigmaPAHs on PM was 14.6 +/- 29(PM 1.5), 0.88 +/- 0.49(PM 1.5-7.2) and 0.29 +/- 0.076(PM 7.2) ng m(-3) air while wintertime concentrations were 493 +/- 206(PM 1.5), 26.7 +/- 14(PM 1.5-7.2) and 5.3 +/- 2.5(PM 7.2) ng m(-3) air. Greater than 90% of the carcinogenic PAHs were concentrated on PM(1.5). Dibenzopyrene isomers made up a significant portion (~30%) of the total carcinogenic PAH load during the winter. To our knowledge, this is the first report of dibenzopyrenes in the Beijing atmosphere and among the few studies that report these highly potent PAHs in ambient particulate matter. Lifetime risk calculations indicated that 1 out of 10,000 to over 6 out of 100 Beijing residents may have an increased risk of lung cancer due to PAH concentration. Over half of the lifetime risk was attributed to Sigmadibenzopyrenes. The World Health Organization and Chinese daily PM(10) standard was exceeded on each day of the study, however, PAH limits were only exceeded during the winter. The outcomes of the air pollution metrics were highly dependent on the individual PAHs measured and seasonal variation. PMID- 20967365 TI - A tiered procedure for assessing the formation of biotransformation products of pharmaceuticals and biocides during activated sludge treatment. AB - Upon partial degradation of polar organic micropollutants during activated sludge treatment, transformation products (TPs) may be formed that enter the aquatic environment in the treated effluent. However, TPs are rarely considered in prospective environmental risk assessments of wastewater-relevant compound classes such as pharmaceuticals and biocides. Here, we suggest and evaluate a tiered procedure, which includes a fast initial screening step based on high resolution tandem mass spectrometry (HR-MS/MS) and a subsequent confirmatory quantitative analysis, that should facilitate consideration of TPs formed during activated sludge treatment in the exposure assessment of micropollutants. At the first tier, potential biotransformation product structures of seven pharmaceuticals (atenolol, bezafibrate, ketoprofen, metoprolol, ranitidine, valsartan, and venlafaxine) and one biocide (carbendazim) were assembled using computer-based biotransformation pathway prediction and known human metabolites. These target structures were screened for in sludge-seeded batch reactors using HR-MS/MS. The 12 TPs found to form in the batch experiments were then searched for in the effluents of two full-scale, municipal wastewater treatment plants (WWTPs) to confirm the environmental representativeness of this first tier. At the second tier, experiments with the same sludge-seeded batch reactors were carried out to acquire kinetic data for major TPs that were then used as input parameters into a cascaded steady-state completely-stirred tank reactor (CSTR) model for predicting TP effluent concentrations. Predicted effluent concentrations of four parent compounds and their three major TPs were corroborated by comparison to 3-day average influent and secondary effluent mass flows from one municipal WWTP. CSTR model-predicted secondary effluent mass flows agreed within a factor of two with measured mass flows and confidence intervals of predicted and measured mass flows overlapped in all cases. The observed agreement suggests that the combination of batch-determined transformation kinetics with a simple WWTP model may be suitable for estimating aquatic exposure to TPs formed during activated sludge treatment. Overall, we recommend the tiered procedure as a realistic and cost-effective approach to include consideration of TPs of wastewater-relevant compounds into exposure assessment in the context of prospective chemical risk assessment. PMID- 20967366 TI - Understanding the mechanism of non-polar Diels-Alder reactions. A comparative ELF analysis of concerted and stepwise diradical mechanisms. AB - The electron-reorganization along the concerted and stepwise pathways associated with the non-polar Diels-Alder reaction between cyclopentadiene (Cp, 1) and ethylene (2) has been studied using the topological analysis of the electron localization function (ELF) at the B3LYP/6-31G(d) level of theory. ELF results for the concerted mechanism stresses that the electron-reorganization demanded on the diene and ethylene reagents to reach two pseudo-diradical structures is responsible for the high activation energy. A comparative ELF analysis of some relevant points of the non-polar Diels-Alder reaction between Cp and styrene (10) suggests that these concerted mechanisms do not have a pericyclic electron reorganization. PMID- 20967367 TI - [Fe(II)LSCo(III)LS]2 <=> [Fe(III)LSCo(II)HS]2 photoinduced conversion in a cyanide-bridged heterobimetallic molecular square. AB - The self-assembly of [Fe(III){B(pz)(4)}(CN)(3)](-) and [Co(II)(bik)(2)(S)(2)](2+) affords the diamagnetic cyanide-bridged [Fe(II)(LS)Co(III)(LS)](2) molecular square which is converted into the corresponding magnetic [Fe(III)(LS)Co(II)(HS)](2) species under light irradiation at relatively low temperatures. PMID- 20967368 TI - Application of PET deprotection for orthogonal photocontrol of aqueous solution viscosity. AB - Photorelease and photoisomerization of trans-cinnamic acid in aqueous CTAB solutions induces a bulk solution viscosity increase and decrease, respectively, triggered by orthogonal irradiation wavelengths. PMID- 20967369 TI - Two luminescent enantiomorphic 3D metal-organic frameworks with 3D homochiral double helices. AB - Two enantiomorphic Cd(II) coordination polymers with three-dimensional homochiral double helices have been assembled respectively from two tripodal enantiopure amino acid derivatives, which exhibit (3,4)-connected (6(3))(6(3).10(3)) topology and strong purple fluorescence. PMID- 20967370 TI - Synthesis of mesoporous PtCu film modified with Ru submonolayer as catalyst for methanol electrooxidation. AB - A mesoporous PtCu catalyst modified with a Ru submonolayer is successfully synthesized by a facile electrochemical process of electrodeposition, dealloying and Ru underpotential deposition. The material has a large specific surface area comparable to nanoparticles (11 m(2) g(-1)) and exhibits a promising catalyst activity for the methanol oxidation reaction. PMID- 20967371 TI - Exploring the physicoelectrochemical properties of graphene. AB - Convincing evidence is presented demonstrating that the electro-catalytic nature of graphene resides in electron transfer from the edge of graphene which structurally resembles the behaviour of edge plane (rather than basal plane) of highly ordered pyrolytic graphite. The impact of surfactants intrinsic to graphene on the electrochemical response is highlighted. PMID- 20967372 TI - Where on Earth has our water come from? AB - The presence of water in the Earth has long been an enigma. However, computer modelling techniques have shown that the adsorption of water onto the fractal surfaces of interplanetary dust particles, which are present in the planetary accretion disk, is sufficiently strong to provide a viable origin of terrestrial water. PMID- 20967373 TI - Droplet microfluidics: recent developments and future applications. AB - We report recent advances in the field of droplet-based microfluidics. Specifically, we highlight the unique features of such platforms for high throughput experimentation; describe functional components that afford complex analytical processing and report on applications in synthesis, high-throughput screening, cell biology and synthetic and systems biology. Issues including the integration of high-information content detection methods, long term droplet stability and opportunities for large scale and intelligent biological experimentation are also discussed. PMID- 20967374 TI - Direct observation of macropore self-formation in hierarchically structured metal oxides. AB - The current work presents an unprecedented direct observation of macropore formation in the spontaneous self-assembly process to obtain hierarchical meso/macroporous metal oxides made possible with the help of an unusual titanium alkoxide. PMID- 20967375 TI - Supramolecular surface-confined architectures created by self-assembly of triangular phenylene-ethynylene macrocycles via van der Waals interaction. AB - At the liquid/graphite interface triangular and rhombic phenylene-ethynylene macrocycles substituted by alkyl chains self-assemble to form porous two dimensional (2D) molecular networks of honeycomb and Kagome types, respectively, or close-packed non-porous structures via alkyl chain interdigitation as the directional intermolecular linkages. Factors that affect the formation of the 2D molecular networks, such as alkyl chain length, solvent, solute concentration, and co-adsorption of guest molecules, were elucidated through a systematic study. For the porous networks, various molecules and molecular clusters were adsorbed in the pores reflecting the size and shape complementarity, exploring a new field of 2D host-guest chemistry. PMID- 20967376 TI - Decoration of nitrogen vacancies by oxygen atoms in boron nitride nanotubes. AB - Decoration of nitrogen vacancies by oxygen atoms has been studied by near-edge X ray absorption fine structure (NEXAFS) around B K-edge in several boron nitride (BN) structures, including bamboo-like and multi-walled BN nanotubes. Breaking of B-N bonds and formation of nitrogen vacancies under low-energy ion bombardment reduces oxidation resistance of BN structures and promotes an efficient oxygen healing mechanism, in full agreement with some recent theoretical predictions. The formation of mixed O-B-N and B-O bonds is clearly identified by well-resolved peaks in NEXAFS spectra of excited boron atoms. PMID- 20967377 TI - A suggested periodic table up to Z<= 172, based on Dirac-Fock calculations on atoms and ions. AB - Extended Average Level (EAL) Dirac-Fock calculations on atoms and ions agree with earlier work in that a rough shell-filling order for the elements 119-172 is 8s < 5g<= 8p(1/2) < 6f < 7d < 9s < 9p(1/2) < 8p(3/2). The present Periodic Table develops further that of Fricke, Greiner and Waber [Theor. Chim. Acta 1971, 21, 235] by formally assigning the elements 121-164 to (nlj) slots on the basis of the electron configurations of their ions. Simple estimates are made for likely maximum oxidation states, i, of these elements M in their MX(i) compounds, such as i = 6 for UF(6). Particularly high i are predicted for the 6f elements. PMID- 20967378 TI - Coordination chemistry of Si5Cl10 with organocyanides. AB - Organocyanides readily coordinate to decachlorocyclopentasilane (Si(5)Cl(10)) to form "inverse sandwich" compounds 1-3 with a planar Si(5) ring. The products were isolated in high yield and fully characterized by elemental analysis, multinuclear NMR, IR and UV-Vis spectroscopy. While the spectroscopic data suggests the presence of a fairly weak interaction between the Si(5) ring and the coordinative organocyanide ligands, single-crystal X-ray diffraction studies of compound 1 and 2 show MU(5)-coordination of the apical cyano nitrogen atoms to the silicon atoms in the Si(5) ring. Distances between silicon atoms and nitrogen atoms are significantly shorter than a Si-N van der Waals bond but longer than the sum of their covalent radii. Multiple interactions between the cyano groups and equatorial Cl atoms, and intermolecular interactions were observed in the solid state for both compounds 1 and 2. PMID- 20967379 TI - Overview of single-cell analyses: microdevices and applications. AB - Numerous microdevices developed for single-cell analyses have been presented in the last decades. Practical usefulness in biological and clinical settings has become an important focus during the development and implementation of new structures and assays. Single-cell analysis has been applied in intracellular research, gene- and protein content and expression, PCR, cell culture and division, clone formation, differentiation, morphology, lysis, separation, sorting, cytotoxicity and fluorescence screens, antibody secretion, etc. as discussed here along with brief descriptions of the technical devices used for the studies, e.g. well-, trap-, pattern-, and droplet-based structures. This review aims to serve as an overview of available techniques for single-cell analysis by describing the different biological single-cell assays that have been performed to date and how each individual application requires a particular device design. PMID- 20967380 TI - Functional integration of DNA purification and concentration into a real time micro-PCR chip. AB - Microfluidic devices for on-chip amplification of DNA from various biological and environmental samples have gained extensive attention over the past decades with many applications including molecular diagnostics of disease, food safety and biological warfare testing. But the integration of sample preparation functions into the chip remains a major hurdle for practical application of the chip-based diagnostic system. We present a PCR-based molecular diagnostic device comprised of a microfabricated chip and a centrifugal force assisted liquid handling tube (CLHT) that is designed to carry out concentration and purification of DNA and subsequent amplification of the target gene in a single chip. The reaction chamber of the chip contains an array of pillar structures to increase the surface area for capturing DNA from a raw sample of macro volume in the presence of kosmotropic agents. The CLHT was designed to provide an effective interface between sample preparation and the microfluidic PCR chip. We have characterized the effect of various fluidic parameters including DNA capture, amplification efficiency and centrifugal pressure generated upon varying sample volume. We also evaluated the performance of this system for quantitative detection of E. coli O157:H7. From the samples containing 10(1) to 10(4) cells per mL, the C(T) value linearly increased from 25.1 to 34.8 with an R(2) value greater than 0.98. With the effectiveness and simplicity of operation, this system will provide an effective interface between macro and micro systems and bridge chip-based molecular diagnosis with practical applications. PMID- 20967381 TI - Which CIDE are you on? Apoptosis and energy metabolism. AB - Around 1998, cell death-inducing DNA fragmentation factor-alpha (DFFA)-like effector (CIDE) proteins including CIDEA, CIDEB and CIDEC/fat specific protein 27 (Fsp27) were first identified by their sequence homology with the N-terminal domain of the DNA fragmentation factor (DFF). Indeed, in vitro analysis revealed that all three CIDE proteins are involved in apoptosis. However, recent gene targeting studies have provided novel insights into the physiological function of CIDE proteins. Mice deficient in each CIDE protein exhibit lean phenotypes, a reduction of lipid droplet size in white adipose tissue and increased metabolic rate. Thus, all CIDE proteins play an important role in energy metabolism and lipid droplet formation. More recently, a glycoproteomics approach has shown that post-translational regulation of CIDE proteins via glycosylation modulates transforming growth factor (TGF)-beta 1-dependent apoptosis. Another recent study using mouse embryonic fibroblasts derived from CIDEA-deficient mice revealed that 5'AMP-activated protein kinase (AMPK) activity is regulated by CIDEA-mediated ubiquitin-dependent proteasomal degradation via a protein interaction with the AMPK beta subunit. Even after a decade of study, the physiological roles of CIDE proteins have still not been completely elucidated. This review aims to shed light on the novel functions of CIDE proteins and their physiological roles. PMID- 20967382 TI - A mathematical analysis of nuclear intensity dynamics for Mig1-GFP under consideration of bleaching effects and background noise in Saccharomyces cerevisiae. AB - Fluorescence microscopy is an imaging technique that provides insights into signal transduction pathways through the generation of quantitative data, such as the spatiotemporal distribution of GFP-tagged proteins in signaling pathways. The data acquired are, however, usually a composition of both the GFP-tagged proteins of interest and of an autofluorescent background, which both undergo photobleaching during imaging. We here present a mathematical model based on ordinary differential equations that successfully describes the shuttling of intracellular Mig1-GFP under changing environmental conditions regarding glucose concentration. Our analysis separates the different bleaching rates of Mig1-GFP and background, and the background-to-Mig1-GFP ratio. By applying our model to experimental data, we can thus extract the Mig1-GFP signal from the overall acquired signal and investigate the influence of kinase and phosphatase on Mig1. We found a stronger regulation of Mig1 through its kinase than through its phosphatase when controlled by the glucose concentration, with a constant (de)phosphorylation rate independent of the glucose concentration. By replacing the term for decreasing excited Mig1-GFP concentration with a constant, we were able to reconstruct the dynamics of Mig1-GFP, as it would occur without bleaching and background noise. Our model effectively demonstrates how data, acquired with an optical microscope, can be processed and used for a systems biology analysis of signal transduction pathways. PMID- 20967383 TI - Nanomaterial surface chemistry design for advancements in capillary electrophoresis modes. AB - Tailored surface chemistry impacts nanomaterial function and stability in applications including in various capillary electrophoresis (CE) modes. Although colloidal nanoparticles were first integrated as colouring agents in artwork and pottery over 2000 years ago, recent developments in nanoparticle synthesis and surface modification increased their usefulness and incorporation in separation science. For instance, precise control of surface chemistry is critically important in modulating nanoparticle functionality and stability in dynamic environments. Herein, recent developments in nanomaterial pseudostationary and stationary phases will be summarized. First, nanomaterial core and surface chemistry compositions will be classified. Next, characterization methods will be described and related to nanomaterial function in various CE modes. Third, methods and implications of nanomaterial incorporation into CE will be discussed. Finally, nanoparticle-specific mechanisms likely involved in CE will be related to nanomaterial surface chemistry. Better understanding of surface chemistry will improve nanoparticle design for the integration into separation techniques. PMID- 20967384 TI - Diabetes induces compositional, structural and functional alterations on rat skeletal soleus muscle revealed by FTIR spectroscopy: a comparative study with EDL muscle. AB - Diabetes Mellitus (DM) is a metabolic disorder, characterized by abnormally high blood glucose levels due to decreased secretion or effectiveness in function of insulin. Having a role in carbohydrate and lipid metabolism, skeletal muscle is affected by the absence of insulin in diabetic conditions. This current study reports the application of Fourier transform infrared (FTIR) spectroscopy in the determination of macromolecular alterations in streptozotocin (STZ)-induced diabetic rat skeletal Soleus (SOL) muscles, which highlight the promise of this technique in medical research. The results revealed that DM induced several alterations in macromolecular content and structure of slow-contracting SOL muscles. In diabetic SOL muscles, a decrease in the content of lipids, proteins and nucleic acids together with an increase in lipid order was observed. The decrease in the level of unsaturation and acyl chain length of lipids demonstrated the increased lipid peroxidation in DM. There were alterations in protein secondary structure in DM with a decrease in alpha-helix and beta-sheet content of proteins, whereas the content of aggregated beta-strands increased, which is generally seen when proteins denature. Besides, the integrity of collagen molecules was found to be decreased, demonstrating the alterations in its triple helical structure in diabetic muscles. Furthermore, the same alterations mentioned above were also observed in diabetic fast-contracting Extensor Digitorum Longus (EDL) muscles. However, having a high content of mitochondria and relying on an oxidative pathway, SOL muscle was found to be more affected by DM. PMID- 20967385 TI - Homoleptic imidazolate frameworks [Sr(1-x)Eu(x)(Im)2]--hybrid materials with efficient and tuneable luminescence. AB - Homoleptic frameworks of the formula [Sr(1-x)Eu(x)(Im)(2)] (1) (x = 0.01-1.0; Im( ) = imidazolate anion, C(3)H(3)N(2)(-)) are hybrid materials that exhibit an intensive green luminescence. Tuning of both emission wavelength and quantum yield is achieved by europium/strontium substitution so that a QE of 80% is reached at a Eu content of 5%. Even 100% pure europium imidazolate still shows 60% absolute quantum efficiency. Substitution of Sr/Eu shows that doping with metal cations can also be utilized for coordination compounds to optimize materials properties. The emission is finely tuneable in the region 495-508 nm via variation of the europium content. The series of frameworks [Sr(1 x)Eu(x)(Im)(2)] presents dense MOFs with the highest quantum yields reported for MOFs so far. PMID- 20967386 TI - Zn-porphyrin/Zn-phthalocyanine dendron for SWNT functionalisation. AB - SWNT-porphyrin/phthalocyanine conjugates are described and fully characterised; their optical and electrochemical properties are investigated. PMID- 20967387 TI - Selective labeling of polypeptides using protein farnesyltransferase via rapid oxime ligation. AB - An aldehyde-containing alternative substrate for protein farnesyltransferase was prepared and shown to be enzymatically incorporated into a peptide and a protein. The protein was subsequently immobilized onto aminooxy-functionalized agarose beads or labeled with a fluorophore. This method for protein modification provides an alternative to the commonly employed Cu(I)-catalyzed click reaction. PMID- 20967388 TI - Influence of surface plasmon resonance on the emission intermittency of photoluminescence from gold nano-sea-urchins. AB - The effect of surface plasmon resonance (SPR) on the blinking emission of photoluminescence from noble metal nanostructures still requires further investigation in quantum mechanics and limits their applications. We investigate one photon luminescent emission intermittency of noble metal nanostructures with differently sized sea-urchin-shaped nanoparticles, known as nano-sea-urchins (NSUs). The probability of the "on" process in one photon luminescent emission intermittency of NSUs increases due to the strong electric field of SPR. This mechanism is explained by the reaction potential threshold model we propose here. Furthermore, the ameliorated photoluminescence of NSUs is strong enough to excite waterweed bioluminescence and can act as an in vivo bio-light emitting device, which has potential applications in cytotoxicity, bio-imaging and bio-labeling. PMID- 20967389 TI - Ligand-assisted fabrication of hollow CdSe nanospheres via Ostwald ripening and their microwave absorption properties. AB - Hollow CdSe nanospheres were successfully synthesized by a ligand-assisted solvothermal method based on an Ostwald ripening mechanism. The hollow CdSe nanospheres were synthesized in benzyl alcohol under solvothermal conditions using Cd(Ac)2 and Se as the precursors, and tryptophan as a ligand. The resulting hollow structures consisted of small nanocrystallite building blocks. More importantly, the hollow CdSe nanospheres could be used as an excellent microwave absorber for cm- and mm-wave absorption, depending on the thickness of the absorber. PMID- 20967390 TI - 1,4-Addition of silicon dienoates to alpha,beta-unsaturated aldehydes catalyzed by in situ-generated silicon Lewis acid. AB - In situ-generated silyl methide species (R(3)Si-CTf(2)R') effectively catalyzed the reaction of beta-substituted alpha,beta-unsaturated aldehydes with silicon dienoates such as 3-bromo-2-TESO-furan to give the corresponding gamma-adducts with excellent 1,4-selectivity and good anti selectivity. PMID- 20967391 TI - Chemical imaging of articular cartilage sections with Raman mapping, employing uni- and multi-variate methods for data analysis. AB - Raman mapping in combination with uni- and multi-variate methods of data analysis is applied to articular cartilage samples. Main differences in biochemical composition and collagen fibers orientation between superficial, middle and deep zone of the tissue are readily observed in the samples. Collagen, non-collagenous proteins, proteoglycans and nucleic acids can be distinguished on the basis of their different spectral characteristics, and their relative abundance can be mapped in the label-free tissue samples, at so high a resolution as to permit the analysis at the level of single cells. Differences between territorial and inter territorial matrix, as well as inhomogeneities in the inter-territorial matrix, are properly identified. Multivariate methods of data analysis prove to be complementary to the univariate approach. In particular, our partial least squares regression model gives a semiquantitative mapping of the biochemical constituents in agreement with average composition found in the literature. The combination of hierarchical and fuzzy cluster analysis succeeds in detecting variations between different regions of the extra-cellular matrix. Because of its characteristics as an imaging technique, Raman mapping could be a promising tool for studying biochemical changes in cartilage occurring during aging or osteoarthritis. PMID- 20967392 TI - A bis-salicylaldoximato-copper(II) receptor for selective sulfate uptake. AB - The preferential uptake of sulfate over the industrially important anions, chloride and nitrate and structurally similar dihydrogen phosphate has been achieved in aqueous media with a dicopper salicylaldoxime complex. PMID- 20967393 TI - Supramolecular gel chemistry: developments over the last decade. AB - This highlight gives a brief flavour of the development of gels derived from low molecular weight gelators broadly in the first decade of the 2000's. A particular theme is the emergence of switchable gels and increasing hi-tech niche application areas. Control and exploitation of supramolecular gels forms a huge part of the grand challenge of directed assembly of extended structures with targeted properties. PMID- 20967394 TI - Mercury in rivers in NW England: from rural headwaters to the heartlands of the historic industrial base. AB - Total mercury (T-Hg) concentrations in rivers are described across a rural to urban/industrial and agricultural landscape gradient in NW England. T-Hg ranges between 0.2 and 230 ng L(-1). The regional median was 3.6 ng L(-1) with individual river medians ranging between 1.9 and 8.3 ng L(-1). Median T-Hg concentrations were sometimes moderately higher for the lowland areas and at higher flows. Our estimates suggest that the Ribble estuary receives 9.2 kg y(-1) and the Wyre estuary 0.7 kg y(-1). In order to examine regional inputs from urban/industrial components, regression analysis was undertaken by comparing three types of hydrochemical signature: suspended sediments (SS), which provide a measure of the particulate component, dissolved organic carbon (DOC) that provides an indication of humic/fulvic acids that are part of the organic colloids and strong chelating agents, and boron a marker of sewage effluents and population density. The results show high positive relationships of T-Hg with both SS and DOC, but no relationship with the urban/industrial signal. The regression analysis with T-Hg indicated on average a gradient of 0.33 ng mg(-1) for DOC and 0.2 ng mg(-1) for SS. They indicate the primary importance of a diffuse source of T-Hg. For the upland areas and cleaner river systems, the linkages between T-Hg and DOC were particularly strong, while for the lowland areas, the linkage with SS proved stronger. Analysis of a latter subset of data that partition the SS into organic and inorganic fractions indicated that the T Hg was primarily linked with the organic fraction. Indeed, multiple regression of T-Hg with DOC and POM reveals gradients similar to other parts of the World. PMID- 20967395 TI - One-step formation of multiple emulsions in microfluidics. AB - We present a robust way to create multiple emulsions with controllable shell thicknesses that can vary over a wide range. We use a microfluidic device to create a coaxial jet of immiscible fluids; using a dripping instability, we break the jet into multiple emulsions. By controlling the thickness of each layer of the jet, we adjust the thicknesses of the shells of the multiple emulsions. The same method is also effective in creating monodisperse emulsions from fluids that cannot otherwise be controllably emulsified, such as, for example, viscoelastic fluids. PMID- 20967396 TI - Aptamer sandwich-based carbon nanotube sensors for single-carbon-atomic resolution detection of non-polar small molecular species. AB - A portable sensor platform for the detection of small molecular species is crucial for the on-site monitoring of environmental pollutants, food toxicants, and disease-related metabolites. However, it is still extremely difficult to find highly selective and sensitive sensor platforms for general small molecular detection. Herein, we report aptamer sandwich-based carbon nanotube sensor strategy for small molecular detection, where aptamers were utilized to capture target molecules as well as to enhance the sensor signals. We successfully demonstrated the detection of non-polar bisphenol A molecules with a 1 pM sensitivity. Significantly, our sensors were able to distinguish between similar small molecular species with single-carbon-atomic resolution. Furthermore, using the additional biotin modification on labeling aptamer, we enhanced the detection limit of our sensors down to 10 fM. This strategy allowed us to detect non-polar small molecular species using carbon nanotube transistors, thus overcoming the fundamental limitation of field effect transistor-based sensors. Considering the extensive applications of sandwich assay for the detection of rather large biomolecules, our results should open up completely new dimension in small molecular detection technology and should enable a broad range of applications such as environmental protection and food safety. PMID- 20967397 TI - Evaluation of a gas sensor array and pattern recognition for the identification of bladder cancer from urine headspace. AB - Previous studies have indicated that volatile compounds specific to bladder cancer may exist in urine headspace, raising the possibility that headspace analysis could be used for diagnosis of this particular cancer. In this paper, we evaluate the use of a commercially available gas sensor array coupled with a specifically designed pattern recognition algorithm for this purpose. The best diagnostic performance that we were able to obtain with independent test data provided by healthy volunteers and bladder cancer patients was 70% overall accuracy (70% sensitivity and 70% specificity). When the data of patients suffering from other non-cancerous urological diseases were added to those of the healthy controls, the classification accuracy fell to 65% with 60% sensitivity and 67% specificity. While this is not sufficient for a diagnostic test, it is significantly better than random chance, leading us to conclude that there is useful information in the urine headspace but that a more informative analytical technique, such as mass spectrometry, is required if this is to be exploited fully. PMID- 20967398 TI - Preparation and electrical properties of Ca-doped La(2)NiO(4+delta) cathode materials for IT-SOFC. AB - Ca-doped La(2)NiO(4+delta) is synthesized via the nitrate-citrate route. The effects of Ca substitution for La on the sinterability, lattice structure and electrical properties of La(2)NiO(4+delta) are investigated. Ca-doping is unfavorable for the densification process of La(2-x)Ca(x)NiO(4+delta) materials. The introduction of Ca leads to the elongation of the La-O(2) bond length, which provides more space for the migration of oxygen ion in La(2)O(2) rock salt layers. The substitution of Ca increases remarkably the electronic conductivity of La(2-x)Ca(x)NiO(4+delta). With increasing Ca-doping level, both the excess oxygen concentration and the activation energy of oxygen ion migration decrease, resulting in an optimization where a highest ionic conductivity is presented. Ca doping is charge compensated by the oxidation of Ni(2+) to Ni(3+) and the desorption of excess oxygen. The substitution of Ca enhances the structural stability of La(2)NiO(4+delta) material at high temperatures and renders the material a good thermal cycleability. La(1.7)Ca(0.3)NiO(4+delta) exhibits an excellent chemical compatibility with CGO electrolyte. La(2-x)Ca(x)NiO(4+delta) is a promising cathode alternative for solid oxide fuel cells. PMID- 20967399 TI - Encapsulated nano-heat-sinks for thermal management of heterogeneous chemical reactions. AB - This paper describes a new way to control temperatures of heterogeneous exothermic reactions such as heterogeneous catalytic reaction and polymerization by using encapsulated nanoparticles of phase change materials as thermally functional additives. Silica-encapsulated indium nanoparticles and silica encapsulated paraffin nanoparticles are used to absorb heat released in catalytic reaction and to mitigate gel effect of polymerization, respectively. The local hot spots that are induced by non-homogenous catalyst packing, reactant concentration fluctuation, and abrupt change of polymerization rate lead to solid to liquid phase change of nanoparticle cores so as to avoid thermal runaway by converting energies from exothermic reactions to latent heat of fusion. By quenching local hot spots at initial stage, reaction rates do not rise significantly because the thermal energy produced in reaction is isothermally removed. Nanoparticles of phase change materials will open a new dimension for thermal management of exothermic reactions to quench local hot spots, prevent thermal runaway of reaction, and change product distribution. PMID- 20967400 TI - Treatments for stroke prevention in atrial fibrillation: a network meta-analysis and indirect comparisons versus dabigatran etexilate. AB - Patients with atrial fibrillation at moderate to high risk of stroke are not always anticoagulated despite a lack of contraindications to vitamin K antagonists (VKAs) like warfarin. These patients are treated with aspirin, aspirin-clopidogrel combination therapy or even receive no thromboprophylaxis. The oral direct thrombin inhibitor, dabigatran etexilate 150 mg BID and 110 mg BID, might represent an alternative for these patients; however, no head-to-head clinical trial data exist versus these alternative treatments. A network meta analysis (NMA) was performed to indirectly compare dabigatran etexilate with antiplatelets and placebo. Compared with placebo, dabigatran etexilate 150 mg BID was estimated to significantly reduce the risk of any stroke (ischaemic and haemorrhagic) by 75% (relative risk [RR] 0.25; 95% confidence interval [CI] 0.12 0.51), ischaemic stroke by 77% (RR 0.23; 95% CI 0.14-0.38), systemic embolism by 83% (RR 0.17; 95% CI 0.05-0.50) and mortality by 36% (RR 0.64; 95% CI 0.45-0.91). Dabigatran etexilate 150 mg BID was estimated to significantly reduce the risk of any stroke compared with aspirin monotherapy by 63% (RR 0.37; 95% CI 0.20-0.69) and aspirin plus clopidogrel by 61% (RR 0.39; 95% CI 0.21-0.72). Trends toward reduced risk with both dabigatran etexilate regimens were found for most clinical outcomes. Relative risk estimates of dabigatran etexilate versus adjusted-dose VKAs within the NMA were consistent with results from the head-to-head randomised trial of these two strategies. Indirect evidence suggests treatment with dabigatran etexilate offers benefit for the prevention of stroke, systemic embolism and mortality over antiplatelets and placebo. There was no indication of increased intracranial or extracranial haemorrhage with dabigatran etexilate compared to antiplatelet agents. PMID- 20967402 TI - Retrieval of displaced coil using a Solitaire((r)) stent. PMID- 20967401 TI - [Stem and progenitor cell-based therapy approaches: current developments on treatment of acute myocardial infarction and chronic ischemic cardiomyopathy]. AB - Percutaneous coronary intervention (PCI) for coronary revascularization in conjunction with an optimized pharmacological treatment can reduce adverse left ventricular remodeling and dysfunction in patients with acute myocardial infarction. Despite these modern therapeutic strategies a significant number of these patients continue to develop adverse cardiac remodeling and LV dysfunction which is associated with a poor prognosis. Stem and progenitor cell-based approaches for treatment of acute myocardial infarction and chronic ischemic cardiomyopathy are an interesting direction of current experimental and clinical research. The current review article provides a summary of recent developments of cell-based therapies of ischemic heart disease, including the assessment of the repair and regeneration capacity of different stem and progenitor cell populations. In addition the advantages and disadvantages of different modes of cell application and potential strategies for the improvement of stem and progenitor cell function for their use in cell-based cardiovascular therapies will be described. PMID- 20967404 TI - [Vaccinations with atopic dermatitis and other chronic inflammatory skin diseases]. AB - One of the most effective preventive measures in medicine is vaccination for avoidance of vaccination preventable diseases. If higher vaccination rates could be achieved individual pathogens could be eliminated and even made extinct. Vaccination is not obligatory in Germany. In previous decades many diseases which were preventable by vaccination have become rare. Being unaware of the course of the disease, the willingness to be vaccinated decreases and doubts about vaccination increase. If atopic dermatitis or allergy is known, the doctor performing the vaccination and also the dermatologist are often asked questions on the indications, performing standard vaccination and the vaccination schedule. This review article is intended to supply dermatologists with answers to frequently asked questions on indications and performing standard vaccinations in connection with atopic dermatitis, allergies and chronic inflammatory skin diseases. Although patients often have uncertainties and doubts, undesirable severe medicinal effects are rare even for patients with atopic dermatitis. PMID- 20967403 TI - [Do opioids induce hyperalgesia?]. AB - Opioids are the most potent drugs for treatment of acute and chronic pain. However, accumulating evidence suggests that opioids may paradoxically also enhance pain, often referred to as opioid-induced hyperalgesia. Opioid-induced hyperalgesia is defined as an increased sensitivity to pain or a decreased pain threshold in response to opioid therapy. Several mechanisms have been proposed to support opioid-induced hyperalgesia. However, it remains unclear whether opioid induced hyperalgesia develops during continuous chronic application of opioids or on their withdrawal. This review provides a comprehensive summary of clinical research concerning opioid-induced hyperalgesia and the molecular mechanisms of opioid withdrawal and opioid tolerance and other potential mechanisms which might induce hyperalgesia during opioid therapy will be discussed. The status quo of our knowledge will be summarized and the clinical relevance of opioid-induced hyperalgesia will be discussed. PMID- 20967405 TI - [Standards and pitfalls of in-vitro diagnostics of Hymenoptera venom allergy]. AB - In patients with a history of anaphylactic sting reactions, in-vitro tests are performed in order to demonstrate venom sensitization to the causative venom. Measurement of specific IgE-antibodies (sIgE) to the natural composite venom represents the standard in-vitro method to demonstrate venom sensitization. If sensitization to the composite venom cannot be demonstrated, one may determine sIgE to recombinant allergen compounds, in order to demonstrate sensitization to molecular venom allergens. Moreover, several cellular tests are available to confirm venom sensitization. Herein basophils, which carry cell-bound sIgE, can be used to produce a confirmatory response upon incubation with venom allergens. Reactions to both honey bee and vespid venom may either indicate true double sensitization or cross sensitization. The identification of antibodies cross reacting to venoms and to other allergen sources does not exclude clinical relevance. Elevated baseline serum tryptase is a risk factor for severe systemic reactions after a field sting and during venom immunotherapy (VIT), the latter in particular for VIT with vespid venom. Serum tryptase measurement should, therefore, be included into routine diagnostics of venom allergy. The measurement of IgG-antibodies specific to venom is not recommended for routine work-up. None of the mentioned in-vitro tests, which may be used before, during or after VIT, allow, however, a precise prognosis with respect to future sting reactions, or to side effects and to the efficacy of VIT, respectively. To validate the reason for a VIT, one should also consider patient history and results of other tests. PMID- 20967406 TI - [The risks of autogenous cartilage grafting in laryngotracheal reconstruction in adults]. AB - BACKGROUND: Laryngotracheal reconstruction with autogenous rib cartilage graft has become a well established surgical method for the repair of subglottic and glottic laryngotracheal stenoses in infants and children. There are far fewer reports on the application of this method in adult patients. In particular, detailed observations of the healing behaviour of autogenous adult rib cartilage grafts are lacking. MATERIAL AND METHOD: The course of disease in five adult female patients (age 25-47 years) who underwent one- or two-stage laryngotracheal reconstruction with rib cartilage grafts are reported. RESULTS: Primary healing was observed in the youngest patient (25 years) only. In the other four patients the cartilage graft had to be partly removed 4-6 weeks postoperatively due to partial necrosis, followed by open wound treatment. As a result of these measures a sufficiently large laryngotracheal lumen could be achieved in all cases. DISCUSSION: Partial ossification of the adult rib cartilage was considered the reason for the observed healing difficulties. Endoscopic follow-up showed that epithelialization of the free endolaryngeal surface of the cartilage graft, i.e. graft healing, takes at least 3 months. Therefore, close endoscopic follow-up during this period appears indispensable. PMID- 20967407 TI - [Multimodality therapy for lung cancer]. AB - The primary treatment of lung cancer depends on tumor stage. In case of lung cancer in clinical stage I to IIb and T3N1 surgical treatment is recommended. The use of adjuvant chemotherapy is indicated in stage II and IIIa. In case of limited N2-disease trimodality therapy with chemo- or radiochemotherapy followed by surgery and eventual adjuvant radiotherapy leads to five year survival rate of about 20-40. Non resectable or extended mediastinal lymph node metastases are an indication for definite combined radiochemotherapy. Secondary resection may be evaluated in experienced centers. If the tumor has infiltrated the mediastinum or the upper sulcus (T3/4) or in case of solitary metastasis an individual trimodal treatment plan has to be elaborated. Also for small cell lung cancer surgery combined with chemotherapy can be applied in stage I and II, else and especially in stage III radiochemotherapy should be applied. Additional prophylactic cranial irradiation is used. The majority of lung cancer patients suffers from metastatic disease. The value of systemic chemotherapy is limited with significant, but small improvement in overall survival. Also treatment with the new molecularly targeted drugs does not result in a breakthrough in unselected patient cohorts. Recently, substantial progress could be achieved by personalized treatment approaches for patients harbouring special genetic alterations. PMID- 20967408 TI - [Multimodality therapy of colorectal cancer]. AB - Adjuvant chemotherapy for resected stage III colon cancer is indicated for all patients, including elderly patients >70 years. In general, adjuvant oxaliplatin fluoropyrimidine chemotherapy should be started within 6 weeks after tumor resection and should be given for a period of 6 months. However, patients aged >70 should receive fluoropyrimidine mono-chemotherapy. This mono-therapy, but not an oxaliplatin-based combination, can also be considered for patients with standard risk stage II tumors without microsatellite instability. In stage II patients with a high risk constellation adjuvant oxaliplatin-fluoropyrimidine combination therapy should be considered. Patients with stage II and III rectal cancer require neoadjuvant radiochemotherapy with fluoropyrimidine followed by adjuvant fluoropyrimidine treatment. There is no role for the use of VEGF- or EGFR-antibodies in the adjuvant therapy of colon cancer or in neoadjuvant therapy of rectal cancer. The prognosis of patients with primary resectable colorectal liver metastases may be improved by adjuvant or perioperative chemotherapy, while neoadjuvant systemic chemotherapy frequently facilitates potential curative resection of initially non-resectable liver metastases. PMID- 20967409 TI - [Interdisciplinary psychiatry]. PMID- 20967411 TI - [The spinal column in focus: imaging diagnostics from trauma via tumors to degeneration]. PMID- 20967410 TI - [Prevalence and clinical significance of incidental cardiac findings in non-ECG gated chest CT scans]. AB - BACKGROUND: The purpose of this study was to evaluate the prevalence and clinical significance of incidental cardiac findings in non-ECG-gated chest CT. PATIENTS AND METHODS: Non-ECG-gated chest CT examinations of 300 patients were retrospectively analyzed for incidental cardiac findings. Subsequently, these findings were evaluated for their clinical relevance by a cardiologist. RESULTS: A total of 107 out of 300 examined patients had 174 incidental cardiac findings including coronary calcification (90), aortic/mitral valve calcification (42), iatrogenic changes (23), pericardial effusion (6), dilatation of the heart (4), myocardial changes (3), thrombus in the left ventricle (2), constrictive pericarditis (2) and atrial myxoma (1). Of the cardiac findings 51% were described in the written report and in 53 out of the 107 patients the cardiac findings were unknown. Newly detected incidental findings from 8 patients were rated as clinically significant: pericardial effusion (4), constrictive pericarditis (1), thrombus in the left ventricle (1), atrial myxoma (1) and dilatation of the heart (1). CONCLUSION: Incidental cardiac findings are frequent in non-ECG-gated chest CT and may have a high clinical relevance. PMID- 20967412 TI - [Biochemical magnetic resonance imaging of intervertebral discs and facet joints]. AB - The limited specificity of standard magnetic resonance imaging (MRI) in patients with low back pain encourages the development of new imaging techniques. Quantitative MR methods have the potential to assess biochemical changes of spinal structures in vivo. Early diagnosis of intervertebral disc and facet joint changes in young to middle aged patients allows the use of a specific therapy and preventative measures. Potential techniques are T2 and T2* mapping, diffusion weighted imaging, magnetization transfer imaging, T1rho mapping, sodium imaging and MR spectroscopy. Well designed longitudinal therapy studies, which assess biochemical and clinical parameters, are necessary. High-field MR systems (3 Tesla) are needed for high resolution biochemical MRI and clinically reasonable scan times. PMID- 20967413 TI - [Imaging of non-traumatic spinal diseases in children]. AB - Pain is also the main symptom of spinal diseases in children. The younger the child, the more frequently organic causes are to be found, whereas in adolescents functional dorsalgia and lumbalgia are ubiquitous. Apart from the neonatal period, where ultrasound is used as the primary method for investigation of closed spinal dysraphia, radiography is still considered to be the first choice examination, which nevertheless should only be carried out after a thorough anamnesis and clinical examination. For targeted follow-up and especially exclusion of neoplasms, MRI is the method of choice in most cases. Computed tomography (CT) plays an important role preoperatively and postoperatively in corrective spine surgery and together with scintigraphy in the diagnostics of spondylolysis and some tumors such as osteoid osteoma. Important is the care of children with hereditary spinal malformations, especially dysraphias where the entire CNS may be affected as with the common association of myelomeningocele and Chiari II malformation with hydrocephalus and hydromyalia. PMID- 20967414 TI - [Tips, tricks and pitfalls in the diagnostic imaging of traumatic spinal cord injuries]. AB - Over the last several decades the survival rate for acute spinal cord lesions has improved, which has resulted in an increased number of chronic spinal cord injuries. Magnetic resonance imaging (MRI) plays an essential role in imaging of the spinal cord, as it allows a detailed depiction of neural structures. However, the correct radiologic diagnosis is often complicated by the multitude of differential diagnoses. This article provides tips and tricks to achieve an accurate imaging report and details potential pitfalls in the interpretation of MR images. Acute spinal cord injuries show different characteristics which range from edema to intramedullary bleeding and to transsection. The spectrum of chronic spinal cord injuries encompasses myelomalacia, syrinx, cystic myelopathia and myeloatrophy. In addition to typical morphological features this article concentrates on the pathogenesis of injury patterns, on the use of appropriate contrast-enhanced MR sequences and on new MR techniques for the differentiation of individual pathologies. PMID- 20967415 TI - [Who is who revisited: spinal trauma]. AB - The ideal classification of spinal trauma does not yet exist, primarily because the combination of morphological, biomechanical and clinical parameters in one single nomenclature has proved impossible. For radiologists and surgeons who work closely together, only a few classifications of injury patterns have been shown to be useful enough to provide rapid and stable therapy decisions. Many classifications are too complex to be practical for day-to-day practice, such as the Magerl classification, which has been adopted by the Arbeitsgemeinschaft fur Osteosynthesefragen (AO). Not least because of this classification difficulty, eponyms and synonyms are widely used to describe trauma of the spine, comparable to the number of terms used to describe fractures of the upper and lower limbs. The members of trauma teams should be aware of the definitions of these terms as well as the strengths and limitations of the existing classifications of spinal trauma. PMID- 20967416 TI - [Imaging of demyelinating and neoplastic diseases of the spinal cord]. AB - The clinical symptoms of myelopathy are variable and non-specific. Demyelinating as well as neoplastic spinal cord diseases can cause paresthesia, progressive sensomotoric deficits and bowel and bladder dysfunction. Imaging of the spine, especially with magnetic resonance imaging (MRI), is an essential component in the diagnostic assessment of myelopathy and makes a substantial contribution to achieving the correct diagnosis. Although intramedullary neoplasms are far less common than demyelinating spinal cord diseases, radiologists should be familiar with the three most common entities, astrocytoma, ependymoma and hemangioblastoma, which represent over 70% of all spinal cord neoplasms. An early diagnosis and therapy is essential with neoplastic and demyelinating spinal cord diseases to hold residual neurological deficits as low as possible. PMID- 20967417 TI - Trace metal bioaccumulation by soft-bottom polychaetes (Annelida) of Sundarban Mangrove Wetland, India and their potential use as contamination indicator. AB - Bioaccumulation of trace metals in four soft-bottom polychaetes along with the host sediments was recorded from the intertidal regions of Indian Sundarban mangrove wetland. The enrichment of Mn (maximum 730 mg kg-1) and Zn (maximum 320 mg kg-1) was recorded for all the polychaetes followed by Cr, Cu, As, Co, Ni and Pb, showing sharp variations between the species. However, concentrations of Sn and Hg were very low with small variations between the species. An overall high bioconcentration factor (BCF) was recorded in the capitellid worm Mastobranchus indicus. The results of the investigation indicate the possibility of developing a standard test protocol for bioaccumulation by polychaetous annelids. PMID- 20967418 TI - Sonographic appearance of transobturator slings: implications for function and dysfunction. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to determine associations between the ultrasonic appearance of Monarc suburethral slings and postoperative bladder symptoms at an average follow-up time of 11 months. METHODS: A prospective clinical audit was conducted on 98 patients after Monarc suburethral sling. The assessment included pelvic floor ultrasound to determine the gap between the sling and symphysis pubis, the angle formed by cranial and caudal ends of the sling at rest and on Valsalva, and the location of the sling relative to the urethra. RESULTS: Patients who reported postoperative stress incontinence (SI) or urge incontinence (UI) had a significantly wider gap between the symphysis pubis and sling (P = 0.032 and P = 0.006, respectively). CONCLUSIONS: A narrower gap between the tape and symphysis pubis is associated with both SI and UI cure. Tighter transobturator sling placement seems to be advantageous for the cure of both SI and UI. PMID- 20967419 TI - Sacrocolpopexy may cause difficult defecation by inhibiting the external opening out mechanism. PMID- 20967420 TI - Dopaminergic drugs and the risk of hip or femur fracture: a population-based case control study. AB - SUMMARY: The effect of dopaminergic medication on the risk of hip/femur fractures is not clear. Our results showed a nearly twofold increased risk of hip/femur fractures in current dopaminergic drug users. Concomitant use of antidepressants further increased this risk. Fracture risk assessment may be warranted in elderly users of dopaminergic drugs. INTRODUCTION: Dopaminergic drugs, often used in the treatment of Parkinson's disease, have several pharmacological effects that may increase or decrease the risk of falling and fractures. Thus, the effect of dopaminergic medication on the risk of hip/femur fractures is not clear. The objective of the study was to examine the effect of dopaminergic medication and concomitant use of psychotropics on the risk of hip/femur fractures taking into account the timing of dopaminergic drug use. METHODS: A population-based case control study in the PHARMO database was conducted for the period 1991 to 2002. Cases were patients aged 18 years and older with a first hip or femur fracture and matched to four control patients by year of birth, sex and geographical region. RESULTS: The study population included 6,763 cases and 26,341 controls. Current use of dopaminergic drugs (1-30 days before the index date) was associated with an increased risk of hip/femur fractures compared to never use (OR(adj) 1.76, 95% CI = 1.39-2.22), but this excess risk rapidly dropped to baseline levels when treatment had been discontinued >1 year ago. Concomitant use of antidepressants among current dopaminergic drug users further increased the risk of hip/femur fractures (OR(adj) 3.51, 95% CI = 2.10-5.87) while there was no additional risk with concomitant use of other psychotropics. CONCLUSIONS: Although the observed association between dopaminergic drugs and fracture risk may not be entirely causal, due to absence of information on the (severity of the) underlying disease, fracture risk assessment may be warranted in elderly users of dopaminergic drugs. PMID- 20967421 TI - Quantitative genetic study of the circulating osteopontin in community-selected families. AB - The study assessed contribution of genetic factors to variability of osteopontin (OPN) levels. Evidence of association of OPN levels with polymorphisms in its structural gene and integrin-binding sialoprotein gene loci was obtained. The results motivate research of OPN-related proteins and genes with respect to biomineralization and other biological processes. INTRODUCTION: OPN is a major phosphoprotein in bone, which plays key role in regulation of bone mineralization process. It is considered as a promising biomarker for osteoarthritis and osteoporosis, and various other pathological conditions. However, the contribution of genetics and other confounding factors to OPN circulating levels variation in general population has never been specifically determined. The main aims of the present study included (1) evaluation of the putative genetic and familial factors' effect on OPN variability and (2) testing the hypothesis that OPN plasma levels are associated with the genetic polymorphisms in its structural gene locus (SPP1) and in integrin-binding sialoprotein gene locus (IBSP). METHODS: To address these questions, we used a family-based sample of 925 apparently healthy Caucasian individuals. Association of OPN levels with three SNPs in each of the two selected gene loci was explored using pedigree disequilibrium tests. RESULTS: Some 58% and 13% of the OPN levels variability were attributable to genetic factors and common spouse environment, respectively. Three SNPs showed nominally significant association with OPN (p < 0.05). Of these, rs2616262 linked to IBSP promoter region remained significant after correction for multiple testing (p = 0.003). Significant association of this SNP and rs10516799 (distal segment of SPP1) with OPN was confirmed in several statistical tests. Using a special modification of variance component analysis, we examined gene-gene and gene-sex interaction effects, but found non-significant confirmation for these hypotheses. CONCLUSIONS: Further studies are required to confirm the observed results and to explore the underlying molecular and physiological mechanisms. PMID- 20967422 TI - Construction and validation of a simplified fracture risk assessment tool for Canadian women and men: results from the CaMos and Manitoba cohorts. AB - A procedure for creating a simplified version of fracture risk assessment tool (FRAX(r)) is described. Calibration, fracture prediction, and concordance were compared with the full FRAX tool using two large, complementary Canadian datasets. INTRODUCTION: The Canadian Association of Radiologists and Osteoporosis Canada (CAROC) system for fracture risk assessment is based upon sex, age, bone mineral density (BMD), prior fragility fracture, and glucocorticoid use. CAROC does not require computer or web access, and categorizes 10-year major osteoporotic fracture risk as low (<10%), moderate (10-20%), or high (>20%). METHODS: Basal CAROC fracture risk tables (by age, sex, and femoral neck BMD) were constructed from Canadian FRAX probabilities for major osteoporotic fractures (adjusted for prevalent clinical risk factors). We assessed categorization and fracture prediction with the updated CAROC system in the CaMos and Manitoba BMD cohorts. RESULTS: The new CAROC system demonstrated high concordance with the Canadian FRAX tool for risk category in both the CaMos and Manitoba cohorts (89% and 88%). Ten-year fracture outcomes in CaMos and Manitoba BMD cohorts showed good discrimination and calibration for both CAROC (6.1-6.5% in low-risk, 13.5-14.6% in moderate-risk, and 22.3-29.1% in high-risk individuals) and FRAX (6.1-6.6% in low-risk, 14.4-16.1% in moderate-risk, and 23.4-31.0% in high-risk individuals). Reclassification from the CAROC risk category to a different risk category under FRAX occurred in <5% for low-risk, 20 24% for moderate-risk, and 27-30% for high-risk individuals. Reclassified individuals had 10-year fracture outcomes that were still within or close to the original nominal-risk range.. CONCLUSION: The new CAROC system is well calibrated to the Canadian population and shows a high degree of concordance with the Canadian FRAX tool. The CAROC system provides s a simple alternative when it is not feasible to use the full Canadian FRAX tool. PMID- 20967423 TI - Bone mass in male and female children and adolescents with Down syndrome. AB - SUMMARY: Children and adolescents with Down syndrome (DS) have lower levels of bone mass compared with youths without DS. Their sexual dimorphism in bone mass also differs from that observed in children and adolescents without Down syndrome. INTRODUCTION: This study aimed to compare bone mass and sexual dimorphism in bone mass between male and female youths with DS and age- and sex matched controls without DS. METHODS: Bone mineral density (BMD), volumetric BMD, bone mineral apparent density (BMAD), BMD/height (BMDH), and total lean mass were measured or calculated from DXA. Thirty-two youths (15 females) with DS and 32 youths (13 females) without DS participated in the study. RESULTS: ANOVA tests showed lower BMAD and BMDH in females with DS compared with females without DS. ANCOVA tests revealed lower BMD in the whole body of males and females as well as BMD in the hip region of the females with DS compared with their counterparts without DS. Within the group with DS, females had greater lumbar spine BMD than the males. CONCLUSIONS: The low values of BMD and related parameters, together with the differences in the sexual dimorphism, indicate a non-standard bone development in this specific population of children and adolescents with DS. PMID- 20967424 TI - Parental smoking during pregnancy and offspring bone mass at age 10 years: findings from a prospective birth cohort. AB - We investigated an intrauterine influence of maternal smoking during pregnancy on childhood bone mass. Daughters, but not sons, of mothers who smoked had higher bone mass at age 10years. This appears to be due to familial factors related to parental smoking influencing increased offspring adiposity rather than a direct intrauterine effect. INTRODUCTION: Neonatal studies have demonstrated an adverse relationship between maternal smoking in pregnancy and foetal bone mineral accrual. We aimed to investigate an intrauterine influence of maternal smoking during pregnancy on offspring bone mass at mean age 9.9 years. METHODS: We compared associations of maternal and paternal smoking in pregnancy with offspring total body less head (TBLH) and spine bone mineral content (BMC), bone area (BA), bone mineral density (BMD) and area-adjusted BMC (ABMC) in 7,121 children in the Avon Longitudinal Study of Parents and Children. RESULTS: Maternal smoking in any trimester was associated with increased TBLH BMC, BA and BMD in girls (mean difference [95% CI] (sex-specific SD scores), 0.13 [0.05 0.22], 0.13 [0.04-0.21], 0.13 [0.04-0.22], respectively) but not boys (0.01 [ 0.07-0.09], 0.00 [-0.08-0.08], 0.04 [-0.05-0.12]), and also with spine BMC, BA and BMD in girls (0.13 [0.03-0.23], 0.12 [0.03-0.22], 0.10 [0.00-0.21]) but not boys (0.03 [-0.06-0.12], 0.00 [-0.09-0.09], 0.05 [-0.04-0.14]), but not with ABMC. Paternal smoking associations were similar, with no statistical evidence for a difference between maternal and paternal effects. Maternal associations increased on adjustment for offspring birth weight and gestational age, but attenuated to the null after adjustment for current height and weight. CONCLUSIONS: We found little evidence that maternal smoking was related to bone mass in boys. In girls, maternal smoking associations were similar to those of paternal smoking, suggesting that these were attributable to shared familial characteristics, not intrauterine mechanisms. PMID- 20967425 TI - Exercise prescription after fragility fracture in older adults: a scoping review. AB - The purpose of this study is to identify and chart research literature on safety, efficacy, or effectiveness of exercise prescription following fracture in older adults. We conducted a systematic, research-user-informed, scoping review. The population of interest was adults aged >=45 years with any fracture. "Exercise prescription" included post-fracture therapeutic exercise, physical activity, or rehabilitation interventions. Eligible designs included knowledge synthesis studies, primary interventional studies, and observational studies. Trained reviewers independently evaluated citations for inclusion. A total of 9,415 citations were reviewed with 134 citations (119 unique studies) identified: 13 knowledge syntheses, 95 randomized or controlled clinical trials, and 11 "other" designs, representing 74 articles on lower extremity fractures, 34 on upper extremity, eight on vertebral, and three on mixed body region fractures. Exercise prescription characteristics were often missing or poorly described. Six general categories emerged describing exercise prescription characteristics: timing post fracture, person prescribing, program design, functional focus, exercise script parameters, and co-interventions. Upper extremity and ankle fracture studies focused on fracture healing or structural impairment outcomes, whereas hip fracture studies focused more on activity limitation outcomes. The variety of different outcome measures used made pooling or comparison of outcomes difficult. There was insufficient information to identify evidence-informed parameters for safe and effective exercise prescription for older adults following fracture. Key gaps in the literature include limited numbers of studies on exercise prescription following vertebral fracture, poor delineation of effectiveness of different strategies for early post-fracture mobilization following upper extremity fracture, and inconsistent details of exercise prescription characteristics after lower extremity fracture. PMID- 20967427 TI - Nanomaterials for improved analytical processes. PMID- 20967428 TI - Authenticity and provenance studies of copper-bearing andesines using Cu isotope ratios and element analysis by fs-LA-MC-ICPMS and ns-LA-ICPMS. AB - Whereas colored andesine/labradorite had been thought unique to the North American continent, red andesine supposedly coming from the Democratic Republic of the Congo (DR Congo), Mongolia, and Tibet has been on the market for the last 10 years. After red Mongolian andesine was proven to be Cu-diffused by heat treatment from colorless andesine starting material, efforts were taken to distinguish minerals sold as Tibetan and Mongolian andesine. Using nanosecond laser ablation-inductively coupled plasma mass spectrometry (ICPMS), the main and trace element composition of andesines from different origins was determined. Mexican, Oregon, and Asian samples were clearly distinguishable by their main element content (CaO, SiO(2) Na(2)O, and K(2)O), whereas the composition of Mongolian, Tibetan, and DR Congo material was within the same range. Since the Li concentration was shown to be correlated with the Cu concentration, the formerly proposed differentiation by the Ba/Sr vs. Ba/Li ratio does not distinguish between samples from Tibet and Mongolia, but only between red and colorless material. Using femtosecond laser ablation multi-collector ICPMS in high resolution mode, laboratory diffused samples showed variations up to 30/00 for (65)Cu/(63)Cu within one mineral due to the diffusion process. Ar isotope ratio measurements proved that heat treatment will reduce the amount of radiogenic (40)Ar in the samples significantly. Only low levels of radiogenic Ar were found in samples collected on-site in both mine locations in Tibet. Together with a high intra-sample variability of the Cu isotope ratio, andesine samples labeled as coming from Tibet are most probably Cu-diffused, using initially colorless Mongolian andesines as starting material. Therefore, at the moment, the only reliable source of colored andesine/labradorite remains the state of Oregon. PMID- 20967429 TI - DC insulator dielectrophoretic applications in microdevice technology: a review. AB - Dielectrophoresis is a noninvasive, nondestructive, inexpensive, and fast technique for the manipulation of bioparticles. Recent advances in the field of dielectrophoresis (DEP) have resulted in new approaches for characterizing the behavior of particles and cells using direct current (DC) electric fields. In such approaches, spatial nonuniformities are created in the channel by embedding insulating obstacles in the channel or flow field in order to perform separation or trapping. This emerging field of dielectrophoresis is commonly termed DC insulator dielectrophoresis (DC-iDEP), insulator-based dielectrophoresis (iDEP), or electrodeless dielectrophoresis (eDEP). In many microdevices, this form of dielectrophoresis has advantages over traditional AC-DEP, including single material microfabrication, remotely positioned electrodes, and reduced fouling of the test region. DC-iDEP applications have included disease detection, separation of cancerous cells from normal cells, and separation of live from dead bacteria. However, there is a need for a critical report to integrate these important research findings. The aim of this review is to provide an overview of the current state-of-art technology in the field of DC-iDEP for the separation and trapping of inert particles and cells. In this article, a review of the concepts and theory leading to the manipulation of particles via DC-iDEP is given, and insulating obstacle geometry designs and the characterization of device performance are discussed. This review compiles and compares the significant findings obtained by researchers in handling and manipulating particles. PMID- 20967430 TI - Size-exclusion chromatography (SEC) of branched polymers and polysaccharides. AB - Branched polymers are among the most important polymers, ranging from polyolefins to polysaccharides. Branching plays a key role in the chain dynamics. It is thus very important for application properties such as mechanical and adhesive properties and digestibility. It also plays a key role in viscous properties, and thus in the mechanism of the separation of these polymers in size-exclusion chromatography (SEC). Critically reviewing the literature, particularly on SEC of polyolefins, polyacrylates and starch, we discuss common pitfalls but also highlight some unexplored possibilities to characterize branched polymers. The presence of a few long-chain branches has been shown to lead to a poor separation in SEC, as evidenced by multiple-detection SEC or multidimensional liquid chromatography. The local dispersity can be large in that case, and the accuracy of molecular weight determination achieved by current methods is poor, although hydrodynamic volume distributions offer alternatives. In contrast, highly branched polymers do not suffer from this extensive incomplete separation in terms of molecular weight. PMID- 20967431 TI - Muscle changes can account for bone loss after botulinum toxin injection. AB - Studies to date have assumed that botulinum toxin type A (BTX) affects bone indirectly, through its action on muscle. We hypothesized that BTX has no discernable effect on bone morphometry, independent of its effect on muscle. Therefore, we investigated whether BTX had an additional effect on bone when combined with tenotomy compared to tenotomy in isolation. Female BALB/c mice (n = 73) underwent one of the following procedures in the left leg: BTX injection and Achilles tenotomy (BTX-TEN), BTX injection and sham surgery (BTX-sham), Achilles tenotomy (TEN), or sham surgery (sham). BTX groups were injected with 20 MUL of BTX (1 U/100 g) in the posterior lower hindlimb. At 4 weeks, muscle cross sectional area (MCSA) and tibial bone morphometry were assessed using micro-CT. Each treatment, other than sham, resulted in significant muscle and bone loss (P < 0.05). BTX-TEN experienced the greatest muscle loss (23-45% lower than other groups) and bone loss (20-30% lower bone volume fraction than other groups). BTX sham had significantly lower MCSA and bone volume fraction than TEN and sham. After adjusting for differences in MCSA, there were no significant between-group differences in bone properties. We found that BTX injection resulted in more adverse muscle and bone effects than tenotomy and that effects were amplified when the procedures were combined. However, between-group differences in bone could be accounted for by MCSA. We conclude that any independent effect of BTX on bone morphometry is likely small or negligible compared with the effect on muscle. PMID- 20967432 TI - Ordnance gelatine as an in vitro tissue simulation scaffold for extracorporeal shock wave lithotripsy. AB - In vitro shock wave lithotripsy (SWL) research is typically performed utilizing wet coupling lithotriptors with a mesh basket model. This model does not take into account shock wave energy attenuation through tissue. Models using dry coupling lithotriptors rely on immersion chambers and face similar limitations. Ordnance gelatin (OG) displays strength and viscous properties similar to human tissue and is therefore widely used for ballistic tissue injury research. We present our initial experience using an OG tissue simulating scaffold for dry coupling SWL research. Using 10% OG prepared in a disc-shaped mold (five stone wells/gel), we tested the model using a Modulith SLX-F2 lithotriptor and artificial stone phantoms. Following a test of concept run on an empty gel mold and a material integrity check for leakage, we shocked 60 stones (30 narrow focus [NF], 30 wide focus [WF]) in human pooled urine. Half were shocked using gels containing open-ended wells with the remainder closed-ended wells. Fragmentation coefficients (FC) were calculated across both foci and gel models. All gels successfully completed 5,000 shocks (1,000/well) without loss of gel integrity or fluid leakage. The mean FC using open-ended wells was 77.9 +/- 7.6% NF and 74.4 +/- 4.8% WF, and for closed wells 75.9 +/- 8.0% NF and 67.1 +/- 3.5% WF. The total model cost including the preparation of gels and begostones was assessed at approximately $1 per stone (Canadian). Ordnance gel serves as an excellent surrogate tissue shockwave scaffold providing an easily manufactured, reproducible and inexpensive model for dry coupling SWL research. PMID- 20967433 TI - Epidemiologic insights into pediatric kidney stone disease. AB - The epidemiology of pediatric kidney stone has not yet been as rigorously defined as that of adult kidney stone disease. Herein, we review our recent epidemiologic works characterizing pediatric stone disease using the Kids' Inpatient Database (KID). Specifically we investigated the age and gender distribution of pediatric kidney stone disease, changes in disease prevalence over time, and medical comorbidities associated with this disorder. We identified patients by International Classification of Disease 9th Edition (ICD-9) codes for renal and ureteral calculi as the primary diagnosis. Medical comorbidities were identified using specific comorbidity software. Statistical comparisons between children with and without stone disease were performed. In the first decade of life, stone disease was more prevalent among males than females; however, in the second decade of life females were more commonly affected. Of note, there was a significant increase in treated stone disease across both genders between 1997 and 2003. We also found that the risk of kidney stone diagnosis in children younger than 6 years of age was significantly associated with hypertension and diabetes mellitus. The gender distribution among pediatric stone formers varies significantly by age, although overall females have a greater prevalence than males. There is also a strong association of stone disease and both diabetes and hypertension, although this was only observed in children less than 6 years of age. Taken all together, these findings suggest that urolithiasis in the young child is a complex systemic disease process. PMID- 20967434 TI - Micro-computed tomography for analysis of urinary calculi. AB - Micro-computed tomographic (micro CT) imaging has become an important tool for the study of urinary stones. The method involves the collection of a series of X ray pictures of the stone as it is rotated, and the internal structure of the stone is computationally reconstructed from these pictures. The entire process takes from 30 min to an hour with present technology. Resulting images of the stone provide unprecedented detail of the mineral composition and its morphological arrangement within the stone. For smaller stones, reconstructions can easily have voxel sizes of <5 MUm, making this a truly microscopic view of the stone. The micro CT reconstructions can be viewed with any of a number of existing methods for visualizing the structure of both the surface and internal features of the stone. Because the entire process is non-destructive, traditional analysis methods--such as dissection and spectroscopic examination of portions of the stones--can also be performed. Micro CT adds value to traditional methods by identifying regions of the stone to be analyzed, and also with its ability to scan a cluster of stones or stone fragments at once. Finally, micro CT has become a powerful tool to help investigate events in stone formation that distinguish different kinds of stone disease. PMID- 20967435 TI - Percutaneous nephrolithotomy for complex caliceal and staghorn stones in patients with solitary kidney. AB - Treatment of patients with solitary kidney having complex stones is one of the most challenging problem in urology. We present our experience with percutaneous nephrolithotomy (PCNL) in treating 16 patients with staghorn stones in a solitary kidney to determine long-term renal functional results. We retrospectively reviewed the records of 16 patients with complex caliceal or staghorn stones in a solitary kidney treated with PCNL. Demographic data, number and location of accesses, hemoglobin values, stone analyses, and complications were studied. Serum creatinine, glomerular filtration rate (GFR), systolic and diastolic blood pressure, new onset hypertension, and kidney morphology were determined preoperatively and postoperatively at 1 month and 1 year. Male to female ratio was 14:2 and mean age was 49.6 years (range 31-55). Of these, 10 (62.5%) patients required a single tract, while 6 (37.5%) required multiple tracts. The calculi were extracted or fragmented successfully in 13 (81.3%) patients and complete stone clearance was achieved after the first stage. In two patients with residual calculi, a double-J catheter was inserted and extracorporeal shock wave lithotripsy (SWL) was performed. There were no significant intraoperative problems except in one patient, who had bleeding from an infundibular tear attributable to torquing. During the 1-year study period, none of the patients progressed to end-stage renal disease requiring dialysis. We demonstrated a significant improvement in creatinine and GFR levels from preoperatively to 1 year follow-up. The number of patients with hypertension before PCNL was 5 and by the end of follow-up there was no new onset hypertension. The demonstrated effectiveness, small number of complications at short-term, not any poorly effect on renal function and blood pressure at the long-term follow-up confirm that PCNL is not only effective but is also safe in the solitary kidney with staghorn calculi. PMID- 20967436 TI - Composition and morphology of phosphate stones and their relation with etiology. AB - Calcium phosphate (CaP) stones account for about 15% of all urinary stones, with a marked female preponderance, and reflect a wide diversity of etiology. Variation of the relative prevalence of CaP urolithiasis over time is disputed, and relevance of CaP stone analysis for etiologic diagnosis is underestimated or even negated. Based on the analysis of more than 50,000 stones over the past three decades, we evaluated the changes in the relative proportion of CaP stones between 1980-1989 (period 1) and 2000-2009 (period 2). In addition, using morphologic examination combined with Fourier-transform infrared analysis, we assessed the associations between CaP stone analysis and etiopathogenic factors. Between periods 1 and 2, the overall proportion of struvite-free stones remained essentially unchanged (11.6 vs. 11.1%), with a decreasing proportion of carbapatite stones (10.6 vs. 8.4%, p < 0.001) and a rising proportion of brushite stones (0.8 vs. 2.2%, p < 0.001). Hypercalciuria was associated with 87% of brushite, and 60% of carbapatite stones. Urinary tract infection was associated with presence of minor amounts of struvite and/or with a carbonation rate of carbapatite > 15%. In CaP stones associated with primary hyperparathyroidism, the main component was carbapatite in 66.9% and brushite in 29.1% of cases. Distal renal tubular acidosis was always associated with carbapatite stones exhibiting a peculiar, virtually pathognomonic, morphology. In conclusion, comprehensive analysis of stones involving morphologic examination is of clinical relevance for improved etiologic evaluation of patients with CaP urolithiasis. PMID- 20967437 TI - Novel ultrasound method to reposition kidney stones. AB - The success of surgical management of lower pole stones is principally dependent on stone fragmentation and residual stone clearance. Choice of surgical method depends on stone size, yet all methods are subjected to post-surgical complications resulting from residual stone fragments. Here we present a novel method and device to reposition kidney stones using ultrasound radiation force delivered by focused ultrasound and guided by ultrasound imaging. The device couples a commercial imaging array with a focused annular array transducer. Feasibility of repositioning stones was investigated by implanting artificial and human stones into a kidney-mimicking phantom that simulated a lower pole and collecting system. During experiment, stones were located by ultrasound imaging and repositioned by delivering short bursts of focused ultrasound. Stone motion was concurrently monitored by fluoroscopy, ultrasound imaging, and video photography, from which displacement and velocity were estimated. Stones were seen to move immediately after delivering focused ultrasound and successfully repositioned from the lower pole to the collecting system. Estimated velocities were on the order of 1 cm/s. This in vitro study demonstrates a promising modality to facilitate spontaneous clearance of kidney stones and increased clearance of residual stone fragments after surgical management. PMID- 20967438 TI - In vitro evaluation of the Lithoclast Ultra Vario combination lithotrite. AB - Rigid intracorporeal lithotrites can be invaluable in the removal of large stone burdens during percutaneous nephrolithotomy. One such device, the Lithoclast Ultra Vario (LUV) has an outer ultrasound probe and inner pneumatic-ballistic probe. The ballistic probe can be advanced or retracted and run at 1-12 Hz. Since it can be difficult to predict optimal settings with any new device, we asked if in vitro testing could give insight into how best to operate this lithotrite. We tested the LUV under hands-free conditions that simulate treatment of fixed stones and freely movable stones. A fixed-stone test system measured the time to penetrate a gypsum model stone placed atop the probe and a movable-stone system determined time for comminution of a stone within a confined space. In addition, the time to evacuate 2-mm stone particles was measured. For hands-on testing, model stones were placed in a plastic dish submerged in water and the time to comminution was measured. Penetration time of fixed stones was faster with the ballistic probe extended 2.5 mm than when retracted (5.30 +/- 0.85 vs. 8.75 +/- 1.07 s, p < 0.0001). Comminution of free stones was faster with the ballistic probe retracted than when it was extended 1 mm or 2.5 mm (9.7 +/- 0.9, 13.8 +/- 1.3, 23.7 +/- 3.2 s, p < 0.0001). In hands-on testing, extending the ballistic probe substantially reduced the efficiency of comminution (36.7 +/- 6.4 vs. 131.3 +/- 15.3 s, p < 0.0001). Clearance of fragments was considerably faster when the pneumatic-ballistic rate was 12 Hz compared to 1 Hz (12.3 +/- 1.1 vs. 28.3 +/- 2.2 s, p < 0.0001). These in vitro findings suggest ways to take advantage of the positive features while minimizing potential limitations of this lithotrite. Extending the ballistic probe is an advantage when the stone is immobile, as would be the case in treating a large stone that can be isolated against the wall of the pelvicalyceal system, but is a distinct disadvantage--due to retropulsion- when the stone is free to move. Operation of the LUV at fast ballistic rate significantly improved its ability to aspirate stone fragments. PMID- 20967439 TI - Analysis of mixed stones is prone to error: a study with US laboratories using micro CT for verification of sample content. AB - This project sought to test the ability of commercial stone analysis laboratories to correctly analyze urinary stones. Human stone specimens were cleaved into pieces, and the pieces of each specimen were verified as being similar using micro-computed tomography (micro CT), a non-destructive method. Thus, similar specimens from 25 stones were sent to five laboratories, and a sixth piece was kept for analysis in our laboratory using Fourier-transform infrared spectroscopy (FT-IR). The results showed that laboratories were very good at analyzing pure specimens, but with mixed specimens the accuracy and consistency varied. In six stones containing apatite, a mineral easily identified using micro CT, apatite was missed 20% of the time. Struvite content in the specimens was inconsistently reported, with laboratories differing in their reports of the presence of struvite in six of the 25 stones (24%). A mixed stone containing atazanavir was not reported by any of the laboratories as containing that drug. Nomenclature differed among the laboratories, especially with regard to apatite, which was variously reported as hydroxyapatite, carbonate apatite, or as apatite with calcium carbonate. One laboratory reported protein in every stone, while for all others protein was reported in only one stone. We conclude that physicians need to be aware that reports on mixed stones, which represent >90% of all calculi, can be erroneous. It is likely that supplying a greater amount of stone material will assist a laboratory in making a correct analysis of mixed stones. Also, standardization of nomenclature could assist in analysis reproducibility, but this remains to be tested. PMID- 20967440 TI - Preliminary feasibility study of FTIR microscopic mapping system for the rapid detection of the composited components of prostatic calculi. AB - Awareness of the chemical composition of prostatic calculi is of great importance for pathogenesis of prostatic lithiasis, the feasibility of FTIR microspectroscopic mapping system used for rapidly screening and detecting the real composited components of prostatic calculi in a short time was initially evaluated. Prostatic calculi were retrieved during transurethral resection of the prostate from nine patients diagnosed having benign prostatic hyperplasia with lower urinary tract symptoms. The level of serum prostatic-specific antigen was within 0-12.63 ng/ml. The calculi samples were examined and compared using FTIR microspectroscopic mapping system, or the traditional FTIR and Raman microspectroscopies. The traditional FTIR microspectroscopic results indicate that nine calculi samples mainly consisted of carbonated HA (hydroxyapatite), but calcium oxalate (undifferentiated) might be also detected in some samples. However, Raman spectral results could detect three components, HA, COM (calcium oxalate monohydrate) or COD (calcium oxalate dihydrate) separated in nine samples. Different compositions in the prostatic calculi were obtained by both spectroscopic detections with manual single-point random analysis implying that both manually traditional methods were failed to provide the real chemical composition of the prostatic calculi in a short time. The FTIR microscopic mapping system via point-by-point mapping analysis evidenced that it could rapidly detect all the complicated components distributed within the prostatic calculi rather than uncertain components detected by traditional FTIR or Raman microspectroscopy. More studies should be carried out in future. This preliminary result suggests that the FTIR mapping better characterizes the stone composition over single-point FTIR and Raman microscopic analysis in prostatic calculi. PMID- 20967441 TI - Antiplatelet versus anticoagulation therapy after extracardiac conduit Fontan: a systematic review and meta-analysis. AB - The benefits of prophylactic anticoagulation or antiplatelet therapy for patients undergoing extracardiac conduit (ECC) Fontan procedure still are a matter of debate. Through a systematic review and meta-analysis, this study aimed to determine the incidence of thromboembolism among patients undergoing ECC Fontan who received anticoagulation or antiplatelet therapy. Until February 2010, MEDLINE studies describing the incidence of thromboembolic events after ECC Fontan were reviewed. Information on type of drugs and clinical outcome was extracted. The 20 studies analyzed involved 1,075 patients: 220 (20.4%) in the antiplatelet group and 855 (79.5%) in the anticoagulation group. The mean follow up period ranged from 2 to 144 months. The overall thromboembolism rate was 5.2% (95% confidence interval [CI], 3.8-7%; I(2) = 0%; p(het) = 0.32). The effect of different therapeutic strategies on the occurrence of thromboembolic and bleeding events was analyzed. Interestingly, the anticoagulation therapy compared with the antiplatelet therapy was not associated with a significant reduction in the incidence of overall thromboembolic complications (5% vs 4.5%, respectively; I(2) = 0%; p(het) = 0.80). Only two cases of bleeding were observed among patients receiving anticoagulant therapy at the time of the event. For patients undergoing ECC Fontan, the rate of thromboembolic and bleeding events associated with antiplatelet therapy is similar to that associated with anticoagulation therapy. PMID- 20967442 TI - Mechanisms of degradation of DNA standards for calibration function during storage. AB - Establishment of molecular diagnostics offering quantitative technology is directly associated with real-time polymerase chain reaction (PCR). This rapid, accurate and sensitive method requires careful execution, including reliable calibration standards. The storage of such standards is crucial to prevent nucleic acid decay and to ensure stable results using real-time PCR. In this study, a broad investigation of possible causes of DNA degradation during storage was performed, including GC-content of the fragments, long-term storage, rapid freeze-and-thaw experiments, genomic DNA and short DNA fragments of different species, the influence of shear stress and the effect of nuclease remaining after DNA isolation. Several known chemical DNA degradation mechanisms have been matched with the experimental data through a process of elimination. Protocols for practical application, as well as a theoretical model describing the underlying mechanisms of deviation of real-time PCR results due to decay of standard DNA, have been developed. Primary amines in the buffer composition, which enhance depurination of the DNA helix, and shear stress due to ice crystal formation, could be identified as major sources of interaction. This results in degradation of the standard DNA, as well as in the probability of occurrence of mismatches affecting real-time PCR performance. PMID- 20967443 TI - The effects of muscle exercise and bed rest on [18F]methylcholine PET/CT. AB - PURPOSE: This study evaluated the impact of limited and strenuous physical exercise on [(18)F]methylcholine uptake in muscle. METHODS: Ten consecutive patients participated, three of whom had strict bed rest, three were allowed to walk around and four performed strenuous single arm exercise by lifting a 7.5-kg weight. [(18)F]Methylcholine uptake was measured in the biceps and gluteus muscles on both sides. RESULTS: Strenuous exercise resulted in a 202% increase in [(18)F]methylcholine uptake in the activated biceps muscle as well as a 112% increase in muscle groups used to retain body position. This resulted in asymmetrical images that were visually less easy to interpret. In walking patients there was a more limited increase in biceps (45%) and gluteus (74%) muscle uptake, without visually recognizable differences. CONCLUSION: Strenuous exercise may result in a considerable increase in [(18)F]methylcholine uptake in muscle and should be avoided prior to imaging. Strict bed rest does not seem to be required. Tracer injection while resting on the scanner remains a safe approach. PMID- 20967444 TI - The influence of agroforestry and other land-use types on the persistence of a Sumatran tiger (Panthera tigris sumatrae) population: an individual-based model approach. AB - The importance of preserving both protected areas and their surrounding landscapes as one of the major conservation strategies for tigers has received attention over recent decades. However, the mechanism of how land-use surrounding protected areas affects the dynamics of tiger populations is poorly understood. We developed Panthera Population Persistence (PPP)--an individual-based model--to investigate the potential mechanism of the Sumatran tiger population dynamics in a protected area and under different land-use scenarios surrounding the reserve. We tested three main landscape compositions (single, combined and real land-uses of Tesso-Nilo National Park and its surrounding area) on the probability of and time to extinction of the Sumatran tiger over 20 years in Central Sumatra. The model successfully explains the mechanisms behind the population response of tigers under different habitat landscape compositions. Feeding and mating behaviours of tigers are key factors, which determined population persistence in a heterogeneous landscape. All single land-use scenarios resulted in tiger extinction but had a different probability of extinction within 20 years. If tropical forest was combined with other land-use types, the probability of extinction was smaller. The presence of agroforesty and logging concessions adjacent to protected areas encouraged the survival of tiger populations. However, with the real land-use scenario of Tesso-Nilo National Park, tigers could not survive for more than 10 years. Promoting the practice of agroforestry systems surrounding the park is probably the most reasonable way to steer land use surrounding the Tesso-Nilo National Park to support tiger conservation. PMID- 20967445 TI - Redefining conversion in laparoscopic colectomy and its influence on outcomes: analysis of 418 cases from a single institution. AB - BACKGROUND: The reported rates of conversion in laparoscopic colectomy are varied. The incidence of conversion is not, however, well defined. The aim of the present study is to redefine conversion and to analyze differences in outcome. METHODS: Treatment parameters of a total of 418 consecutive patients who underwent laparoscopic colonic resection from 2005 to 2007 were analyzed. Treatment was classified as laparoscopic colonic resection, laparoscopy-assisted colonic resection (lap-assisted), and laparoscopic conversion. RESULTS: There were significant differences in median operating time between laparoscopic colonic resection, lap-assisted, and laparoscopic conversion (125 min, 160 min, and 140 min; p = 0.0001); median hospital length of stay was significantly different (laparoscopic, 5.0 days, versus lap-assisted, 6.0 days, versus laparoscopic conversion, 6.5 days; p = 0.0001); and median incision length was also noted to vary significantly (laparoscopic, 5.0 cm, lap-assisted, 8.0 cm, and conversion, 12.0 cm; p = 0.00001). Multivariate analysis reveals that older age (Odds Ratio [OR] = 1.07, 95% Confidence Interval [CI] = 1.02-1.12), higher Body Mass Index ([BMI], OR = 1.15, 95% CI = 1.03-1.29), and pT stage were significant factors affecting conversion. Disease-free survival for cancers was not influenced by conversion (p = 0.653). The overall complication rate was 16.7% and was significantly increased in lap-assisted cases and in conversion cases (26% versus 13%; p = 0.003). CONCLUSIONS: A consistent definition for conversion in laparoscopic colonic resection is required. Our proposed definitions may provide a solution. The definition of lap-assisted as a separate entity serves as a bridge between laparoscopy and full conversion. Risk factors of age, BMI, and advanced tumor stage are conversion predictors and are associated with increased hospital stay and postoperative morbidity. PMID- 20967446 TI - Defining the position of the deep inguinal ring using findings at laparoscopic inguinal hernia repair. AB - PURPOSE: We aim to establish the surface marking of the deep inguinal ring by laparoscopy and investigate if the patient's build influences it. METHODS: Sixty consecutive patients undergoing laparoscopic hernia repairs were studied. The bony landmarks, anterior-superior iliac spine (ASIS) and pubic tubercle (PT), and the two traditional landmarks, the mid-inguinal point (MIP) and midpoint of inguinal ligament (MPIL), were marked on the anaesthetized patient before the surgery. The deep ring was located by indenting the surface until laparoscopy shows the deep ring being occluded. RESULTS: The true surface marking of the deep ring was found to lie at a mean distance of 9.6 mm medial to the MPIL landmark and 4.5 mm lateral to the MIP, approximately one-third of the distance from the MIP to the MPIL. Multivariate analysis confirmed that age, gender, race, BMI or pelvic habitus did not vary it. CONCLUSIONS: The deep ring is located under a point just lateral to the MIP, which is the midpoint of a line drawn joining the ASIS and pubic symphysis. This should be taught to future generations of medical students as the point to apply occluding pressure to differentiate clinically between direct and indirect inguinal hernias. PMID- 20967447 TI - Characterization of novel alleles of toxin co-regulated pilus A gene (tcpA) from environmental isolates of Vibrio cholerae. AB - Vibrio cholerae is causative agent of life threatening diarrheal disease, cholera. The toxin co-regulated pilus (TCP) is a critical colonization factor of V. cholerae and it also serves as receptor for CTXF. In this study, we describe nucleotide sequence of four novel alleles of tcpA gene from toxigenic and non toxigenic V. cholerae isolated from environmental sources. The phylogenetic analysis of tcpA revealed that it is related to tcpA of newly emerged O1 strain and unrelated to tcpA of wild type (classical and El Tor strains). All strains showed variant tcpA and also harbored intact Vibrio Pathogenicity Island (VPI). The expression of all variant alleles was demonstrated by RT-PCR. PMID- 20967448 TI - Unprecedented enhancement of transient gene expression from minimal cassettes using a double terminator. AB - The potential of using vector-free minimal gene cassettes (MGCs) with a double terminator for the enhancement and stabilization of transgene expression was tested in sugarcane biolistic transformation. The MGC system used consisted of the enhanced yellow fluorescent protein (EYFP) reporter gene driven by the maize ubiquitin-1 (Ubi) promoter and a single or double terminator from nopaline synthase (Tnos) or/and Cauliflower mosaic virus 35S (35ST). Transient EYFP expression from Tnos or 35ST single terminator MGC was very low and unstable, typically peaking early (8-16 h) and diminishing rapidly (48-72 h) after bombardment. Addition of a ~260 bp vector sequence (VS) to the single MGC downstream of Tnos (Tnos + VS) or 35ST (35ST + VS) enhanced EYFP expression by 1.25- to 25-fold. However, a much more significant increase in EYFP expression was achieved when the VS in 35ST + VS was replaced by Tnos to generate a 35ST Tnos double terminator MGC, reaching its maximum at 24 h post-bombardment. The enhanced EYFP expression from the double terminator MGC was maintained for a long period of time (168 h), resulting in an overall increase of 5- to 65-fold and 10- to 160-fold as compared to the 35ST and Tnos single terminator MGCs, respectively. The efficiency of the double terminator MGC in enhancing EYFP expression was also demonstrated in sorghum and tobacco, suggesting that the underlying mechanism is highly conserved among monocots and dicots. Our results also suggest the involvement of posttranscriptional gene silencing in the reduced and unstable transgene expression from single terminator MGCs in plants. PMID- 20967449 TI - PR-1 gene family of grapevine: a uniquely duplicated PR-1 gene from a Vitis interspecific hybrid confers high level resistance to bacterial disease in transgenic tobacco. AB - A functional contribution of pathogenesis-related 1 (PR-1) proteins to host defense has been established. However, systematic investigation of the PR-1 gene family in grapevine (Vitis spp.) has not been conducted previously. Through mining genomic databases, we identified 21 PR-1 genes from the Vitis vinifera genome. Polypeptides encoded by putative PR-1 genes had a signal sequence of about 25 residues and a mature protein of 10.9-29 kDa in size. PR-1 mature proteins contained a highly conserved six-cysteine motif and pI values ranging from 4.6 to 9. A major cluster with 14 PR-1 genes was mapped to a 280-kb region on chromosome 3. One particular PR-1 gene within the cluster encoding a basic type isoform (pI 7.77), herein named VvPR1b1, was isolated from various genotypes of grapevine (Vitis spp.) for functional studies. Sequence analysis of PCR amplified DNA revealed that all genotypes contained a single VvPR1b1 gene except for a broad-spectrum bacterial and fungal disease resistant Florida bunch grape hybrid, 'BN5-4', from which seven different homologues were identified. Duplication of VvPR1b1-related genes encoding acidic-type PR-1 isoforms was also observed among several genotypes. However, transgenic expression analysis of grapevine PR-1 genes under strong constitutive promoters in transgenic tobacco revealed that only the basic-type VvPR1b1 gene duplicated in 'BN5-4' was capable of conferring high level resistance to bacterial disease caused by Pseudomonas syringae pv. tabaci. PMID- 20967450 TI - Response properties of visual neurons in the turtle nucleus isthmi. AB - The optic tectum holds a central position in the tectofugal pathway of non mammalian species and is reciprocally connected with the nucleus isthmi. Here, we recorded from individual nucleus isthmi pars parvocellularis (Ipc) neurons in the turtle eye-attached whole-brain preparation in response to a range of computer generated visual stimuli. Ipc neurons responded to a variety of moving or flashing stimuli as long as those stimuli were small. When mapped with a moving spot, the excitatory receptive field was of circular Gaussian shape with an average half-width of less than 3 degrees . We found no evidence for directional sensitivity. For moving spots of varying sizes, the measured Ipc response-size profile was reproduced by the linear Difference-of-Gaussian model, which is consistent with the superposition of a narrow excitatory center and an inhibitory surround. Intracellular Ipc recordings revealed a strong inhibitory connection from the nucleus isthmi pars magnocellularis (Imc), which has the anatomical feature to provide a broad inhibitory projection. The recorded Ipc response properties, together with the modulatory role of the Ipc in tectal visual processing, suggest that the columns of Ipc axon terminals in turtle optic tectum bias tectal visual responses to small dark changing features in visual scenes. PMID- 20967451 TI - [Palliative medicine]. PMID- 20967452 TI - [Reliability of the PRISCUS-PAQ. Questionnaire to assess physical activity of persons aged 70 years and older]. AB - A questionnaire (Q) to measure physical activity (PA) of persons >=70 years for epidemiological research is lacking. The aim was to develop the PRISCUS-PAQ and test the reliability in community-dwelling people (>=70 years). Validated PA questionnaires were translated and adapted to design the PRISCUS-PAQ. Its test retest reliability for 91 randomly selected people (36% men) aged 70-98 (76+/-5) years ranged from 0.47 (walking) to 0.82 (riding a bicycle). The overall activity score was 0.59 as determined by the intraclass correlation coefficient (ICC). Recording of general activities, e.g., housework (ICC=0.59), was in general less reliable than athletic activities, e.g., gymnastics (ICC=0.76). The PRISCUS-PAQ, which is a short instrument with acceptable reliability to collect the physical activity of the elderly in a telephone interview, will be used to collect data in a large cohort of older people in the German research consortium PRISCUS. PMID- 20967453 TI - Left ventricular dilation in toll-like receptor 2 deficient mice after myocardial ischemia/reperfusion through defective scar formation. AB - Restoration of myocardial blood flow after ischemia triggers an inflammatory response involving toll-like receptors (TLRs). TLR2(-/-)-mice show short-term advantages upon reperfusion injury as compared with WT controls. Accordingly, it has been shown that transient TLR2-blockade prior to reperfusion is associated with improved left-ventricular performance after myocardial scar formation. We present here adverse myocardial remodeling due to a chronic lack of TLR2 expression. Myocardial ischemia/reperfusion (MI/R) was surgically induced in C3HeN-mice by ligation of the left anterior descending coronary artery for 20 min, followed by 24 h or 28 days of reperfusion. TLR2(-/-)-mice and TLR2-Ab treated (T2.5) WT-mice displayed a reduction of infarct size, plasma troponin T concentrations, and leukocyte infiltration as compared with untreated controls after 24 h of reperfusion. After 28 days, however, magnetic resonance imaging revealed a marked left ventricular dilation in TLR2(-/-)-animals, which was associated with pronounced matrix remodeling characterized by reduced collagen and decorin density in the infarct scar. Our data show adverse effects on myocardial remodeling in TLR2(-/-)-mice. Although interception with TLR2 signaling is a promising concept for the prevention of reperfusion injury after myocardial ischemia, these data give cause for serious concern with respect to the time-point and duration of the potential treatment. PMID- 20967454 TI - Epithelioid cotyledonoid dissecting leiomyoma: a case report and review of the literature. AB - A 63-year-old mother of two, presented with blood-stained vaginal discharge and right sided lower abdominal pain. A MRI examination confirmed a right parametrial mass, abutting the lateral margin of the uterus and the patient had a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Histological examination diagnosed a cotyledonoid leiomyoma, but with a new epithelioid variant. Cotyledonoid leiomyom's usually have a large, fungating appearance and demonstrate apparent widespread infiltrative growth and extension into the pelvic cavity, broad ligament and retroperitoneal space which may raise significant concern about the possibility of a malignant neoplasm. As these tumours are rare and infrequently encountered, it is imperative that clinicians be aware of this entity as they may pose a significant diagnostic and management challenge when encountered. Awareness of this newly described epithelioid cell variant of cotyledonoid dissecting leiomyoma is necessary for an accurate diagnosis and to facilitate appropriate management decisions at the time of surgery. This new variant further emphasizes the need for meticulous histopathological assessment which should be undertaken to circumvent misdiagnosis. This has direct clinical relevance to all operating gynaecologists and may have implications for litigation because patients may be inappropriately and inadvertently over-treated for an essentially benign condition. PMID- 20967455 TI - Development of the nine X-STR loci typing system and genetic analysis in three nationality populations from China. AB - This study is to develop a new multiplex polymerase chain reaction (PCR) system that simultaneously amplifies the nine X-chromosome short tandem repeats loci in the same PCR reaction, and to explore their polymorphism and mutation rate among three nationality populations from China. These loci included DXS6854, DXS9902, DXS6809, GATA172D05, HPRTB, DXS7423, DXS6807, DXS8378, and DXS8377. The samples of 890 (484 males and 406 females) unrelated individuals from Guangdong Han population, Xinjiang Uigur, and Inner-Mongolia Mongol were successfully analyzed using this multiplex system. The allele frequencies and mutation rates of the nine loci were investigated, and the comparison of allele frequency distribution among different populations was performed. There were 87 alleles for all the loci, and six to 18 alleles for each locus observed by our new multiplex PCR system. Polymorphism information content was 0.4998-0.9101, and power of discrimination in females was 0.6518-0.9846. Five cases with mutation of above loci were detected in 5,310 meioses. Pair-wise comparisons of allele frequencies distribution showed significant differences for most loci among different populations. Our results indicate that this multiplex system is very useful for identification analysis, and that the information about polymorphism and mutation rate is necessary for forensic application in three nationality populations from China. PMID- 20967456 TI - Development of a second retinal artery macroaneurysm within a few months. PMID- 20967457 TI - Response to the letter of M. Brugnoli. PMID- 20967459 TI - Dwarf apple MbDREB1 enhances plant tolerance to low temperature, drought, and salt stress via both ABA-dependent and ABA-independent pathways. AB - In higher plants, DREB1/CBF-type transcription factors play an important role in tolerance to low temperatures, drought, and high-salt stress. These transcription factors bind to CRT/DRE elements in promoter regions of target genes, regulating their expression. In this study, we cloned and characterized a novel gene encoding a DREB1 transcription factor from dwarf apple, Malus baccata (GenBank accession number: EF582842). Expression of MbDREB1 was induced by cold, drought, and salt stress, and also in response to exogenous ABA. Subcellular localization analyses revealed that MbDREB1 localizes in the nucleus. A yeast activity assay demonstrated that the MbDREB1 gene encodes a transcription activator, which specifically binds to DRE/CRT elements. Compared with wild-type plants, transgenic Arabidopsis overexpressing MbDREB1 showed increased tolerance to low temperature, drought, and salt stresses. Analysis of the MbDREB1 promoter revealed an ABA-responsive element (ABRE), an inducer of CBF expression 1 (ICE1) like binding site, two MYB recognition sites, and three stress-inducible GT-1 boxes. GUS activities driven by the MbDREB1 promoter in transgenic Arabidopsis increased in response to ABA, cold temperature, drought, and salt treatments. Interestingly, the expression of both ABA-independent and ABA-dependent stress induced genes (COR15a and rd29B, respectively) was activated under normal growth conditions in Arabidopsis overexpressing MbDREB1. These results suggest that MbDREB1 functions as a transcription factor and increases plant tolerance to low temperature, drought, and salt stress via both ABA-dependent and ABA-independent pathways. PMID- 20967458 TI - Effect of lemon verbena supplementation on muscular damage markers, proinflammatory cytokines release and neutrophils' oxidative stress in chronic exercise. AB - Intense exercise is directly related to muscular damage and oxidative stress due to excessive reactive oxygen species (ROS) in both, plasma and white blood cells. Nevertheless, exercise-derived ROS are essential to regulate cellular adaptation to exercise. Studies on antioxidant supplements have provided controversial results. The purpose of this study was to determine the effect of moderate antioxidant supplementation (lemon verbena extract) in healthy male volunteers that followed a 90-min running eccentric exercise protocol for 21 days. Antioxidant enzymes activities and oxidative stress markers were measured in neutrophils. Besides, inflammatory cytokines and muscular damage were determined in whole blood and serum samples, respectively. Intense running exercise for 21 days induced antioxidant response in neutrophils of trained male through the increase of the antioxidant enzymes catalase, glutathione peroxidase and glutathione reductase. Supplementation with moderate levels of an antioxidant lemon verbena extract did not block this cellular adaptive response and also reduced exercise-induced oxidative damage of proteins and lipids in neutrophils and decreased myeloperoxidase activity. Moreover, lemon verbena supplementation maintained or decreased the level of serum transaminases activity indicating a protection of muscular tissue. Exercise induced a decrease of interleukin-6 and interleukin-1beta levels after 21 days measured in basal conditions, which was not inhibited by antioxidant supplementation. Therefore, moderate antioxidant supplementation with lemon verbena extract protects neutrophils against oxidative damage, decreases the signs of muscular damage in chronic running exercise without blocking the cellular adaptation to exercise. PMID- 20967460 TI - Bacteriocin-like substance from Bacillus amyloliquefaciens shows remarkable inhibition of Acanthamoeba polyphaga. AB - The effectiveness of a bacteriocin-like substance (BLS) produced by Bacillus amyloliquefaciens was tested against Acanthamoeba polyphaga strains, and its cytotoxic potential on Vero cells was investigated. Amebicidal activity of the purified BLS was tested by plate bioassays with concentrations ranging from 12.5 to 6,400 AU mL(-1). Damage to A. pholyphaga cells was monitored using an inverted microscope and counted in a Fuchs-Rosenthal chamber after 24, 48, and 72 h. According to the results obtained, the BLS showed remarkable amebicidal and amebostatic effect on A. polyphaga and showed no cytotoxicity on the Vero cells. These results may have great relevance in the development of new acanthamoebicidal compounds. PMID- 20967426 TI - Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson's, Huntington's, Alzheimer's, prions, bactericides, chemical toxicology and others as examples. AB - Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-kappaB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions. PMID- 20967461 TI - Polymorphisms in the 18S rDNA gene of Cystoisospora belli and clinical features of cystoisosporosis in HIV-infected patients. AB - Intraspecific variability among Cystoisospora belli isolates and its clinical implications in human cystoisosporosis have not been established. In this study, the restriction fragment length polymorphisms in a 1.8-kb amplicon of the small subunit ribosomal DNA (SSU rDNA) of the parasite was investigated in 20 C. belli positive stool samples obtained from 15 HIV-infected patients. Diarrheic syndrome was observed in all patients with cystoisosporosis and the number of diarrheic episodes per patient during hospitalization ranged from 1 to 26 (mean of 9.64 +/- 9.30), with a mean duration of 2 to 12 days (mean of 5.90 +/- 3 days). Three restriction profiles (RF) were generated with MboII digestion, which were named RFI, RFII, and RFIII. Two isolates obtained from a patient with extraintestinal cystoisosporosis showed distinct restriction profiles with MboII. This study demonstrates that patients can be infected with different C. belli genotypes, and this information may be useful for identifying new C. belli genotypes infecting humans. PMID- 20967462 TI - Contribution to the knowledge of Culicoides (Diptera: Ceratopogonidae) host preferences in France. AB - Knowledge on host-feeding pattern of blood-sucking insects helps to understand the epidemiology of a vector-born disease. We determined blood meal origin from blood-fed Culicoides thanks to molecular techniques. A set of primers was used to selectively amplify segment of vertebrates' prepronociceptin gene from abdomen of engorged Culicoides (Diptera: Ceratopogonidae). Vertebrate DNA was successfully amplified in 91% of blood-fed Culicoides assayed. Direct sequencing and comparison of resultant sequences with sequences in GenBank, using BLAST, lead to the specific identification of the host in 100% of the cases. A total of 157 blood-fed females belonging to 13 different Culicoides' species were captured thanks to light traps in different areas of France between 2008 and 2009. Blood meal origin was determined for 143 blood-fed midges: 59 Culicoides obsoletus, 18 Culicoides dewulfi, 16 Culicoides scoticus, 11 Culicoides chiopterus, 10 Culicoides lupicaris, 1 Culicoides pulicaris, 8 Culicoides punctatus, 10 Culicoides pallidicornis, 3 Culicoides achrayi, 2 Culicoides furcillatus, 3 Culicoides brunnicans, 1 Culicoides picturatus and 1 Culicoides poperinghensis. The predominant species in our study belong to the C. obsoletus complex; they are considered as putative vectors of Bluetongue virus in the north of Europe. C. chiopterus sampled fed only on cattle, while blood meal origin of C. dewulfi, C. obsoletus and C. scoticus was diversified. In our sampling, we found that midges were fed mainly on cattle (54%), rabbits (20%), horses (17%), sheep (4%), pigs or wild boars (4%) and human (1%). Cattle DNA was found in at least 11 different species of Culicoides assayed. PMID- 20967463 TI - Development of high-resolution melting (HRM) analysis for population studies of Fascioloides magna (Trematoda: Fasciolidae), the giant liver fluke of ruminants. AB - The high-resolution melting (HRM) technique was successfully optimized as fast and effective method for population study of digenetic fluke, Fascioloides magna (Trematoda: Fasciolidae), originally North American liver parasite of free-living and domestic ruminants. Previously selected variable region (439 bp) of mitochondrial cytochrome c oxidase subunit I (cox1) of 249 fluke individuals from enzootic European and North American regions were sequenced and mutually compared. The sequence analysis of partial cox1 revealed presence of seven structurally different haplotypes. Based on the sequence structure and alignments of six of them (Ha1-Ha6), three internal probes were designed and applied in HRM based haplotype determination of all F. magna specimens. HRM analysis, performed with three designed probes, resulted in classification of samples into the seven haplogroups, equally with their assortment according to the sequence analysis. The representative of the haplotype, which was not involved in probe design (Ha7), was characterized by a unique melting curve shape as well. This provided an evidence of optimally settled conditions in HRM assay and indicated a probability of successful discrimination of novel haplotypes in future population studies on F. magna. The successful optimization of HRM method stands for an opportunity of detection of genetically unknown North American variants of F. magna and promises its application as fast and cheap screening technique for phylogeography studies of the giant liver fluke on its original continent. PMID- 20967464 TI - Development of cellular immune response of mice to infection with low doses of Trichinella spiralis, Trichinella britovi and Trichinella pseudospiralis larvae. AB - The murine cellular immune response to the infection with ten larvae of encapsulating (Trichinella spiralis, Trichinella britovi) and non-encapsulating species (Trichinella pseudospiralis) was studied. Both T. spiralis and T. britovi stimulated the proliferation of splenic T and B lymphocytes during the intestinal phase of infection, but T. spiralis activated the proliferative response also at the muscle phase, particularly in B cells. Non-encapsulating T. pseudospiralis stimulated the proliferation of T and B cells only on day 10 post-infection (p.i.) and later at the muscle phase. The numbers of splenic CD4 and CD8 T cells of T. spiralis infected mice were significantly increased till day 10 p.i., i.e., at the intestinal phase, and then at the late muscle phase, on day 60 p.i. T. britovi infection increased the CD4 and CD8 T cell numbers only on day 30 p.i. Decreased numbers of CD4 and CD8 T cells after T. pseudospiralis infection suggest a suppression of cellular immunity. Both encapsulating Trichinella species induced the Th2 response (cytokines interleukin-5 (IL-5) and interleukin 10) at the intestinal phase and the Th2 dominant response at the advanced muscle phase. Interferon-gamma (IFN-gamma) production (Th1 type) started to increase with migrating newborn larvae from day 15 p.i. till the end of the experiment. IL 5 production was suppressed during the intestinal phase of T. pseudospiralis infection. The immune response to T. pseudospiralis was directed more to the Th1 response at the muscle phase, the high IFN-gamma production was found on day 10 p.i. and it peaked on days 45 and 60 p.i. PMID- 20967465 TI - A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome. AB - Warburg Micro syndrome and Martsolf syndrome are clinically overlapping autosomal recessive conditions characterized by congenital cataracts, microphthalmia, postnatal microcephaly, and developmental delay. The neurodevelopmental and ophthalmological phenotype is more severe in Warburg Micro syndrome in which cerebral malformations and severe motor and mental retardation are common. While biallelic loss-of-function mutations in RAB3GAP1 are present in the majority of patients with Warburg Micro syndrome; a hypomorphic homozygous splicing mutation of RAB3GAP2 has been reported in a single family with Martsolf syndrome. Here, we report a novel homozygous RAB3GAP2 small in-frame deletion, c.499_507delTTCTACACT (p.Phe167_Thr169del) that causes Warburg Micro syndrome in a girl from a consanguineous Turkish family presenting with congenital cataracts, microphthalmia, absent visually evoked potentials, microcephaly, polymicrogyria, hypoplasia of the corpus callosum, and severe developmental delay. No RAB3GAP2 mutations were detected in ten additional unrelated patients with RAB3GAP1 negative Warburg Micro syndrome, consistent with further genetic heterogeneity. In conclusion, we provide evidence that RAB3GAP2 mutations are not specific to Martsolf syndrome. Rather, our findings suggest that loss-of-function mutations of RAB3GAP1 as well as functionally severe RAB3GAP2 mutations cause Warburg Micro syndrome while hypomorphic RAB3GAP2 mutations can result in the milder Martsolf phenotype. Thus, a phenotypic severity gradient may exist in the RAB3GAP associated disease continuum (the "Warburg-Martsolf syndrome") which is presumably determined by the mutant gene and the nature of the mutation. PMID- 20967466 TI - Effects of human full-length amelogenin on the proliferation of human mesenchymal stem cells derived from bone marrow. AB - Amelogenins are enamel matrix proteins that play a crucial role in enamel formation. Recent studies have revealed that amelogenins also have cell signaling properties. Although amelogenins had been described as specific products of ameloblasts, recent research has demonstrated their expression in bone marrow stromal cells. In this study, we examined the effect of recombinant human full length amelogenin (rh174) on the proliferation of human mesenchymal stem cells (MSCs) derived from bone marrow and characterized the associated changes in intracellular signaling pathways. MSCs were treated with rh174 ranging in dose from 0 to 1,000 ng/ml. Cell proliferative activity was analyzed by bromodeoxyuridine (BrdU) immunoassay. The expression of lysosomal-associated membrane protein 1 (LAMP1), a possible amelogenin receptor, in MSCs was analyzed. Anti-LAMP1 antibody was used to block the binding of rh174 to LAMP1. The MAPK-ERK pathway was examined by Cellular Activation of Signaling ELISA (CASE) kit and western blot analysis. A specific MAPK inhibitor, U0126, was used to block ERK activity. It was shown that rh174 increased the proliferation of MSCs and MAPK ERK activity. The MSC proliferation and MAPK-ERK activity enhanced by rh174 were reduced by the addition of anti-LAMP1 antibody. Additionally, the increased proliferation of MSCs induced by rh174 was inhibited in the presence of U0126. In conclusion, it is demonstrated that rh174 increases the proliferation of MSCs by interaction with LAMP1 through the MAPK-ERK signaling pathway, indicating the possibility of MSC application to tissue regeneration in the orofacial region. PMID- 20967467 TI - Localization of NK1 receptors and roles of substance-P in subepithelial fibroblasts of rat intestinal villi. AB - Subepithelial fibroblasts of the intestinal villi, which form a contractile cellular network beneath the epithelium, are in close contact with epithelial cells, nerve varicosities, capillaries, smooth muscles and immune cells, and secrete extracellular matrix molecules, growth factors and cytokines, etc. Cultured subepithelial fibroblasts of the rat duodenal villi display various receptors such as endothelins, ATP, substance-P and bradykinin, and release ATP in response to mechanical stimulation. In this study, the presence of functional NK1 receptors (NK1R) was pharmacologically confirmed in primary culture by Ca(2+) measurement, and the effects of substance-P were measured in an acute preparation of epithelium-free duodenal villi from 2- to 3-week-old rats using a two-photon laser microscope. Substance-P elicited an increase in the intracellular Ca(2+) concentration and contraction of the subepithelial fibroblasts in culture and the isolated villi. The localization of NK1R and substance-P in the villi was examined by light and electron microscopic immunohistochemistry. NK1R-like immunoreactivity was intensely localized on the plasma membrane of villous subepithelial fibroblasts in 10-day- to 4-week-old rats and mice and was decreased or absent in adulthood. The pericryptal fibroblasts of the small and large intestine were NK1R immuno-negative. These villous subepithelial fibroblasts form synapse-like structures with both substance-P-immunopositive and -immunonegative nerve varicosities. Here, we propose that the mutual interaction between villous subepithelial fibroblasts and afferent neurons via substance-P and ATP plays important roles in the maturation of the structure and function of the small intestine. PMID- 20967468 TI - Carbon dioxide balneotherapy and cardiovascular disease. AB - Carbon dioxide (CO(2)) balneotherapy is a kind of remedy with a wide spectrum of applications which have been used since the Middle Ages. However, its potential use as an adjuvant therapeutic option in patients with cardiovascular disease is not yet fully clarified. We performed a thorough review of MEDLINE Database, EMBASE, ISI WEB of Knowledge, COCHRANE database and sites funded by balneotherapy centers across Europe in order to recognize relevant studies and aggregate evidence supporting the use of CO(2) baths in various cardiovascular diseases. The three main effects of CO(2) hydrotherapy during whole body or partial immersion, including decline in core temperature, an increase in cutaneous blood flow, and an elevation of the score on thermal sensation, are analyzed on a pathophysiology basis. Additionally, the indications and contra-indications of the method are presented in an evidence-based way, while the need for new methodologically sufficient studies examining the use of CO(2) baths in other cardiovascular substrates is discussed. PMID- 20967469 TI - Balneoprevention: new approaches. AB - The present study outlines a strategy for studying application of balneotreatment in preventive medicine (balneoprevention). Prophylactic use of spa treatment and mineral water consumption can be studied using epidemiological methods in the involved population. Calculated toxicological risk of balneological treatment can be decreased by performing a complete chemical analysis (including high performance organic analyses) and specific toxicity tests of medicinal water and mud (peloid) samples. PMID- 20967470 TI - Nutritional status of patients with locally advanced pancreatic cancer: a pilot study. AB - PURPOSE: Nutritional status may influence quality of life and prognosis among pancreatic cancer patients, yet few studies describe measures of nutritional status during treatment. We evaluated the nutritional status of locally advanced pancreatic cancer (LAPC) patients undergoing chemoradiotherapy who received baseline nutritional assessment and counseling. METHODS: Fourteen newly diagnosed LAPC patients enrolled in phase I/II trials of capecitabine with concomitant radiotherapy were assessed for baseline clinical nutrition measures (body mass index, albumin, weight loss, total energy, and protein intake). Participants completed the Anorexia/Cachexia Subscale (A/CS) questionnaire at baseline and during the 6 weeks of treatment. We evaluated associations between baseline characteristics and subsequent A/CS scores with linear regression and changes in A/CS were assessed with the paired t test. RESULTS: We observed a statistically significant increase in mean A/CS between baseline [24.9, standard deviation (SD) = 9.7] and end of treatment (29.9, SD = 6.2). Controlling for baseline A/CS score, only weight loss greater than 5% of body weight over 1 month was associated with A/CS scores at 6 weeks (beta = 10.558, standard error = 3.307, p value = 0.009) and mean A/CS scores during the last 3 weeks of treatment (beta = 12.739, standard error = 2.251, p value = 0.001). CONCLUSIONS: After 6 weeks of chemoradiotherapy, LAPC patients reported a statistically significant improvement in appetite and weight concerns. Increases in AC/S scores were associated with higher baseline A/CS scores and weight loss of 5% or more during 1 month. Further research is needed to determine the impact of nutritional support during treatment, as improvements in this domain may impact LAPC patients' overall quality of life. PMID- 20967471 TI - Surgical treatment of cervical kyphosis. AB - Cervical kyphosis is an uncommon but potentially debilitating and challenging condition. We reviewed the etiology, presentation, clinical and radiological evaluation, and treatment of cervical kyphosis. Based on the current controversy as to the ideal mode of surgical management, we paid particular attention to the available surgical strategies. There are three approaches for cervical kyphosis: the anterior, posterior or combined procedures. The principal indication for the posterior strategy is a flexible kyphosis or kyphosis caused by ankylosing spondylitis. The main point of debate is between the choice of the anterior or the combined strategy. The two strategies were compared with regard to clinical outcome, correction of deformity, rate of fusion, complications, revision surgery, and mortality. The combined strategy appears to result in a greater degree of correction than the anterior-alone strategy, and it is more likely to improve the cervical alignment to achieve a lordosis. However, the procedure carries a higher rate of postoperative neurological deterioration, complications, revision surgery, and mortality. Although the anterior-alone strategy achieves a smaller reduction of cervical kyphosis, it has a lower rate of postoperative neurological deterioration, complications, revision surgery, and mortality. We recommend that the surgical treatment of cervical kyphosis should be planned on an individual basis. A multicenter, prospective, randomized controlled study would be necessary to determine the ideal mode of treatment for complex cervical kyphosis. PMID- 20967472 TI - What can Drosophila teach us about iron-accumulation neurodegenerative disorders? AB - The present review focuses on the development and use of Drosophila for modeling neurodegenerative disorders that involve iron accumulation, in particular Friedrich's Ataxia (FRDA) and Neurodegeneration with Iron accumulation (NBIA). Several Drosophila models of such disorders have been introduced successfully in the last few years. Here we review these models and note on the feasibility and advantages of using fly models for understanding the molecular and cellular bases of these devastating diseases. PMID- 20967473 TI - The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis. AB - Tofisopam is a member of the 2,3-benzodiazepine compound family which is marketed for the treatment of anxiety in some European countries. In contrast to classical 1,4-benzodiazepines, the compound does not bind to the benzodiazepine binding site of the gamma-aminobutyric acid receptor and its psychopharmacological profile differs from such compounds. In addition to anxiolytic properties, antipsychotic effects are reported. We now show that tofisopam, 50 mg/kg intraperitoneally (i.p.), administered in parallel to repeated doses of dizocilpine 0.2 mg/kg i.p. can ameliorate dizocilpine-induced prolongation of immobility, which is considered to be a model of negative symptoms of psychosis. We further show that tofisopam acts as an isoenzyme-selective inhibitor of phosphodiesterases (PDEs) with highest affinity to PDE-4A1 (0.42 MUM) followed by PDE-10A1 (0.92 MUM), PDE-3 (1.98 MUM) and PDE-2A3 (2.11 MUM). The data indicate that tofisopam is an interesting candidate for the adjuvant treatment of psychosis with focus on negative symptoms. Combined partial inhibition of PDE-4 and PDE-10 as well as PDE-2 may be the underlying mechanism to this activity. Due to the good safety profile of tofisopam as evident from long-term use of this agent in patients, it may be concluded that dual or triple inhibition of PDE isoenzymes with additive or synergistic effects may be an interesting approach to pharmacological activity, resulting in active compounds with beneficial safety profile. Dose-limiting side effects such as emesis induced by selective inhibition of PDE-4 may be prevented by such strategies. PMID- 20967474 TI - First report on the phylogeny of bovine norovirus in Turkey. AB - Bovine norovirus (BoNoV) is an important cause of diarrhea in calves and has been reported in several countries. The aims of this study were to investigate for the first time the presence of norovirus in Turkish calves by real-time reverse transcription-polymerase chain reaction (qRT-PCR) and to determine the phylogeny of any circulating strains. Fecal samples from 70 diarrheic calves were collected and analysed by SYBR Green qRT-PCR. BoNoV was detected in fecal samples from six calves. The capsid gene was partially sequenced, and phylogenetic analysis was performed. This showed that the six Turkish BoNoVs clustered with the GIII-2 prototype. PMID- 20967475 TI - Substitution of aspartic acid with glutamic acid at position 67 of the BRCA1 RING domain retains ubiquitin ligase activity and zinc(II) binding with a reduced transition temperature. AB - Breast cancer susceptibility protein 1 (BRCA1) participates in genomic integrity maintenance through DNA repair, cell cycle checkpoint, protein ubiquitination, and transcriptional regulation. The N-terminus of BRCA1 contains a RING domain which forms two Zn(2+) binding sites in an interleaved fashion. A number of deleterious BRCA1 missense mutations, which predispose an individual to a subset of hereditary breast and ovarian cancers, have been identified in the RING domain. Disruption of Zn(2+) binding sites and protein structure results in the inactivation of BRCA1 tumor suppression function. An unprecedented D67E BRCA1 mutation, identified in Thai familial breast cancer patients, is located in the vicinity of Zn(2+) binding site II, and its pathogenic significance remains elusive. The present study revealed that the D67E BRCA1 RING protein assumes a preformed structure in the absence of Zn(2+). The Zn(2+)-bound mutant protein was more folded, resulting in enhanced proteolytic resistance and dimerization. This indicated that the mutation retained Zn(2+) binding, and barely perturbed the native global structure of the BRCA1 RING domain. The complex between D67E BRCA1 and BARD1 RING domains exhibited a substantial ubiquitin ligase activity compared with a defective complex containing the C61G BRCA1 mutation. However, the D67E mutation was slightly less stable toward thermal denaturation. This implies that the D67E mutation might be a neutral or mild cancer-risk modifier of other defective mechanisms underlying BRCA1-mutation-related breast cancer. PMID- 20967476 TI - Wound healing following regenerative procedures in furcation degree III defects: histomorphometric outcomes. AB - Degree III furcation involvements were surgically created at four first molars in each of three monkeys. Following 6 weeks of healing, full-thickness flaps were elevated. Following 24% EDTA gel conditioning, the defects were treated with one of the following: (1) enamel matrix proteins (EMD), (2) guided tissue regeneration (GTR) or (3) a combination EMD and GTR. The control defects did not receive any treatment. After 5 months of healing, the animals were sacrificed. Three 8 MUm thick histological central sections, 100 MUm apart, were used for histomorphometric analysis in six zones of each tooth either within the furcation area or on the pristine external surface of the root. In all specimens, new cementum with inserting collagen fibres was formed. Following GTR or GTR + EMD, cementum was formed up to and including the furcation fornix indicating complete regeneration on the defect periphery. Periodontal ligament fibres were less in all four modalities compared to pristine tissues. In the teeth treated with GTR and GTR + EMD a higher volume of bone and periodontal ligament tissues was observed compared to EMD. After 5 months of healing, regenerated tissues presented quantitative differences from the pristine tissues. In the two modalities where GTR alone or combined with EMD was used, the regenerated tissues differed in quantity from the EMD-treated sites. PMID- 20967477 TI - Effects of disease modifying treatments on cognitive dysfunction in multiple sclerosis. AB - Cognitive dysfunctions are frequent in multiple sclerosis and have a negative impact on employment and quality of life. Pathophysiology of impaired mental activities is probably multifactorial including sensory deafferentation, lesion related disconnection of associative areas (cortico-cortical and cortico thalamic), involvement of normal appearing white and gray matter, and direct effects of products of inflammation. Available immunomodulatory treatments for multiple sclerosis may have a role in MS-related cognitive dysfunction because they positively impact some of the pathogenetic studies. Pivotal phase III clinical trials have effectively shown some benefit, confirmed by some post marketing studies. However, results of these studies must be interpreted with great caution because many methodological problems may undermine the quality of the studies. PMID- 20967478 TI - A case of reversible posterior leukoencephalopathy syndrome with acute hypotension. AB - Reversible posterior leukoencephalopathy syndrome (RPLS) is theoretically associated with hypertensive encephalopathy because the most patients demonstrate abrupt increasing of blood pressure (BP). A 59-year-old woman, who had undergone cholecystectomy 4 days before, complained of a headache and rapidly progressing visual disturbance. Her BP was postoperatively controlled at around 150/80, but her BP was 89/46 when she noticed her symptoms. Magnetic resonance imaging showed vasogenic edema in bilateral occipital and right parietal lobes, and intracranial magnetic resonance angiography revealed bilateral diffuse peripheral vasoconstriction. After discontinuing ropivacaine administration via epidural catheter, her BP rose to 114/62 and her symptoms completely disappeared within a few days. Except for hypotension, the clinical course and the radiological evidences in our case were consistent with RPLE. This case supports another hypothesis of RPLS mechanism that arterial endothelial injury by toxic drug effect results in transudation of fluid from blood vessels causing vasogenic brain edema. PMID- 20967479 TI - Species identification of staphylococci by amplification and sequencing of the tuf gene compared to the gap gene and by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. AB - Staphylococcal species, notably, coagulase-negative staphylococci (CoNS), are frequently misidentified using phenotypic methods. The partial nucleotide sequences of the tuf and gap genes were determined in 47 reference strains to assess their suitability, practicability, and discriminatory power as target molecules for staphylococcal identification. The partial tuf gene sequence was selected and further assessed with a collection of 186 strains, including 35 species and subspecies. Then, to evaluate the efficacy of this genotyping method versus the technology of matrix-assisted laser desorption ionization time-of flight mass spectrometry (MALDI-TOF-MS), the 186 strains were identified using MALDI-TOF-MS (Axima(r) Shimadzu) coupled to the SARAMIS(r) database (AnagnosTec). The French National Reference Center for Staphylococci identification method was used as a reference. One hundred and eighty-four strains (98.9%) were correctly identified by tuf gene sequencing. Only one strain was misidentified and one was unidentified. MALDI-TOF-MS identified correctly 138 isolates (74.2%). Four strains were misidentified, 39 were unidentified, five were identified at the group (hominis/warneri) level, and one strain was identified at the genus level. These results confirm the value of MALDI-TOF-MS identification for common species in clinical laboratory practice and the value of the partial tuf gene sequence for the identification of all staphylococcal species as required in a reference laboratory. PMID- 20967480 TI - Non-specific laboratory test indicators of severity in hospitalized adults with swine influenza (H1N1) pneumonia. PMID- 20967481 TI - Colorectal gastrointestinal stromal tumor. AB - Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm arising in the digestive tract, with an estimated prevalence of 15-20 per 1,000,000. GISTs are related to the interstitial cells of Cajal and are characterized by constitutive over-expression of the transmembrane tyrosine kinase receptor KIT. This is produced by a patognomonic mutation of the proto oncogene c-kit that occurs in up to 90% of cases. Exon 11 is affected most frequently; exons 9 and 13 are less commonly involved. One-third of GISTs lacking KIT mutations exhibits alternative activating mutations in the PDGFRalpha gene. Colorectal GISTs represent about 5-10% of the cases, mainly located in the rectum that is the third common site. Benign GISTs are more common, but many tumors are of uncertain malignant potential; tumor size and rate of mitosis are still the most reliable criteria for assessing the risk of an aggressive behavior. Surgery is the first-line treatment for resectable non-metastatic colorectal GIST. Standard oncologic resection is inappropriate because skip metastases and lymphatic spread are rarely reported. Segmental colectomy with negative margins is recommended, and local excision is oncologically adequate in highly selected rectal tumors. Radical surgery alone is not always curative especially in high risk GISTs, and half of patients develops local recurrences or distant metastases after R0 operation. Medical therapeutic strategies have rapidly evolved after the introduction of targeted molecular therapy. Efficacy and safety of imatinib mesylate was first demonstrated in patients with metastatic and unresectable disease. Adjuvant and neoadjuvant use of imatinib are promising therapeutic options to improve the outcome of surgery to downstage unresectable lesions and to allow less extensive resections. PMID- 20967482 TI - Health care costs and their predictors of inflammatory bowel diseases in Germany. AB - OBJECTIVES: Detailed cost studies of inflammatory bowel diseases (IBD) for Germany are limited. Aim of this study was to collect resource-use data related to IBD via a cross-sectional study, to quantify these from the perspective of the Statutory Health Insurance (SHI) and to identify cost-driving factors. METHODS: Patients with Crohn's disease (CD) or ulcerative colitis (UC) from 24 gastroenterological specialists' practices and two hospitals were enrolled in an internet-based database between March 2006 and July 2007. Outpatient services, inpatient visits as well as medication usage were recorded and evaluated from the perspective of the SHI for 2007. Disease severity was measured by the Crohn's Disease Activity Index (CDAI) and the Colitis Activity Index (CAI), respectively. Extensive statistical analyses including generalized linear modeling (gamma model with the log link) to identify cost-driving factors were performed. RESULTS: Data from 1,030 patients with IBD (CD: 511; UC: 519) were collected. On average a patient with CD incurs annual costs of EUR 3,767 (+/- 5,895 (SD)) (among those 68.5% medication; 20.5% inpatient) and an average patient with UC incurs EUR 2,478 (+/- 4,591) (74% medication; 10% inpatient), whereas 10% of the patient with IBD account for 49% (CD: 50%; UC: 46%) of the costs. The regression analysis showed that especially the use of TNF-alpha-inhibitors, inpatient stays, gender as well as the severity status has a significant influence on costs. Further disease-specific impact factors were identified. CONCLUSIONS: This is the first study to calculate costs due to CD and UC from the perspective of the SHI in Germany and to identify cost-driving factors. It confirms a high economic burden of IBD to payers and society. PMID- 20967483 TI - In vitro investigation and biomechanical modeling of the effects of PLF-68 on osteoarthritis in a three-dimensional model. AB - In this study, it was hypothesized that Pluronic F-68 (PLF-68) increases matrix synthesis of osteoarthritis (OA) chondrocytes in addition to its well-documented cell survival effect. To test this hypothesis, rat articular chondrocytes were embedded in agarose discs and were exposed to 5-azacytidine (Aza-C) to induce OA like alterations. Chondrocytes were then treated with PLF-68 (8 and 12 mg/ml) for 10 days. Aza-C-exposed and PLF-68-untreated chondrocytes and Aza-C-unexposed and PLF-68-untreated chondrocytes were used as negative and positive control groups, respectively. Dynamic hydrostatic pressure (max 0.2 MPa, 0.1 Hz) was applied to discs for 30 min/day (5 days/week). Cell viability, collagen and proteoglycan deposition in discs were determined. Unconfined compression stress relaxation tests were performed to determine peak stress and material parameters of discs- namely spring constants (k (1) and k (2)), damping coefficient (eta), instantaneous modulus (E (0)) and relaxed modulus (E (infinity)) using Kelvin model to evaluate the functional coherence of the matrix. PLF-68 treatment significantly increased the collagen deposition in discs and viability of OA-like chondrocytes. A dose-dependent increase was also observed for elastic stiffness parameters (k (1), k (2), E (0) and E (infinity)). Same positive effect of PLF-68 was not observed for proteoglycan deposition. However, dose-dependent increase in eta suggests that PLF-68 treatment resulted with the deposition of functional matrix. This is the first study which reports that PLF-68 has also positive effect on collagen synthesis of OA cells. As a conclusion, our results suggest that PLF-68 has a potential for recovery from OA-like alterations, which should be further analyzed. PMID- 20967484 TI - A phase II study of cell cycle inhibitor UCN-01 in patients with metastatic melanoma: a California Cancer Consortium trial. AB - BACKGROUND: Genetic abnormalities in cell cycle control are common in malignant melanoma. UCN-01 (7-hydroxystaurosporine) is an investigational agent that exhibits antitumor activity by perturbing the cancer cell cycle. A patient with advanced melanoma experienced a partial response in a phase I trial of single agent UCN-01. We sought to determine the activity of UCN-01 against refractory metastatic melanoma in a phase II study. Patients and methods Patients with advanced melanoma received UCN-01 at 90 mg/m(2) over 3 h on cycle 1, reduced to 45 mg/m(2) over 3 h for subsequent cycles, every 21 days. Primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A two-stage (17 + 16), single arm phase II design was employed. A true response rate of >= 20% (i.e., at least one responder in the first stage, or at least four responders overall) was to be considered promising for further development of UCN-01 in this setting. Results Seventeen patients were accrued in the first stage. One patient was inevaluable for response. Four (24%) patients had stable disease, and 12 (71%) had disease progression. As there were no responders in the first stage, the study was closed to further accrual. Median PFS was 1.3 months (95% CI, 1.2-3.0) while median OS was 7.3 months (95% CI, 3.4-18.4). One-year and two year OS rates were 41% and 12%, respectively. A median of two cycles were delivered (range, 1-18). Grade 3 treatment-related toxicities include hyperglycemia (N = 2), fatigue (N = 1), and diarrhea (N = 1). One patient experienced grade 4 creatinine elevation and grade 4 anemia possibly due to UCN-01. No dose modification was required as these patients had disease progression. Conclusion Although well tolerated, UCN-01 as a single agent did not have sufficient clinical activity to warrant further study in refractory melanoma. PMID- 20967485 TI - Eyelid and conjunctival paracoccidioidomycosis simulating carcinoma. AB - Paracoccidioidomycosis (PCM) is the most prevalent systemic mycosis in immunocompetent individuals in Brazil. Ocular infection by PCM is rare; however, when infection does occur, the most common ocular sites involved are eyelid and conjunctiva. A 68-year-old white male presented with a 2-month history of a painless, ulcerated, infiltrative and diffuse whitish lesion located on the right inferior eyelid. A clinical diagnosis of malignant tumor, possibly squamous cell carcinoma, was made. The histopathologic examination showed a hyperplastic epithelium with inflammatory infiltrate of lymphocytes, plasma cells, neutrophils and histiocytes. Large numbers of giant cells were also present. Periodic acid Schiff and Grocott (silver methenamine) stains showed several large round structures with peripheral lateral small budding cells that resembled a "ship's wheel". No multinucleated fungi were seen. The fungi varied in size and small forms were round and single fungal structures. A diagnosis of paracoccidioidomycosis was made PCM eyelid infection is rare and can simulate carcinoma both clinically and histopathologically. PMID- 20967487 TI - Ixodid ticks in Bosnia and Herzegovina. AB - Ticks of the Ixodidae family represent an enormous threat to human and animal health. From January to December 2004, a total of 10,050 ixodid ticks were collected from 26 areas in Bosnia and Herzegovina and determined to the species level. Ticks were collected from dogs, sheep, cows, goats, rodents, humans and plants. Ixodes ricinus was the most prevalent species, followed by Dermacentor marginatus marginatus, Rhipicephalus bursa, Hyalomma marginatum marginatum, Rhipicephalus sanguineus, Haemaphysalis punctata, Dermacentor reticulatus and Ixodes hexagonus. PMID- 20967489 TI - Polymeric biomaterials for gene and drug delivery. PMID- 20967488 TI - Differential expression of tartrate-resistant acid phosphatase isoforms 5a and 5b by tumor and stromal cells in human metastatic bone disease. AB - Tartrate-resistant acid phosphatase (TRAP) exists in human serum as two major isoforms, monomeric 5a and proteolytically processed enzymatically active 5b. The 5b isoform is secreted by osteoclasts and has recently been advocated as a serum marker for bone metastasis in breast cancer patients. The 5a isoform, on the other hand, is not bone-derived and has been proposed to be a marker of activated macrophages and chronic inflammation. In this study, expression of TRAP protein and enzymatic activity in bone metastases from different primary sites was examined. TRAP activity was high in bone metastases from prostate cancer, intermediate in breast cancer, and low in lung and kidney cancers. The partially purified TRAP from breast cancer bone metastasis samples exhibited the enzymatic characteristics of purple acid phosphatase. Both 5a and 5b isoforms were expressed in bone metastases of different histogenetic origins, i.e. prostate, breast, lung and kidney, and also a novel previously unreported 42 kDa variant of the TRAP 5a isoform was identified in bone metastases. This novel TRAP 5a isoform was absent in human bone, indicating that the 42 kDa variant is specific to metastatic cancer tissue. Immunohistochemistry revealed that metastatic cancer cells were the predominant source of TRAP 5a, whereas tumor-associated macrophages and occasionally multinucleated giant cells in the tumor stroma preferentially expressed the proteolytically processed TRAP 5b variant. Our results indicate the presence of a previously unstudied variant of monomeric TRAP 5a in cancer cells, which may have functional and diagnostic implications. Moreover, the presence of TRAP-positive macrophages in bone metastases could, together with cancer cells and osteoclasts, contribute to the elevated levels of serum TRAP activity observed in patients with bone metastases. PMID- 20967490 TI - The use of disaccharides in inhibiting enzymatic activity loss and secondary structure changes in freeze-dried beta-galactosidase during storage. AB - PURPOSE: The purpose of this study is to show how disaccharides differ in their ability to protect lyophilized beta-galactosidase from enzymatic activity loss and secondary structure changes during storage. METHODS: beta-galactosidase was lyophilized with trehalose, sucrose, cellobiose or melibiose at 2:1, 20:1 and 40:1 excipient/protein weight ratios, and stored up to 90 days at 45 degrees C. Protein enzymatic activity was studied using o-nitrophenyl-beta-D galactopyranoside cleavage test, and its secondary structure in lyophilizates analyzed using Fourier transform infrared spectroscopy. The crystallization tendencies, glass transition temperatures and water contents of lyophilizates were evaluated using x-ray powder diffractometry, differential scanning calorimetry and thermogravimetry, respectively. RESULTS: The enzymatic activity of beta-galactosidase decreased more slowly in lyophilizates containing trehalose or melibiose at 2:1 excipient/protein weight ratio when compared to those containing sucrose or cellobiose. Similar behavior was observed when analyzing the protein's secondary structure in lyophilizates. In 20:1 and 40:1 excipient/protein weight ratio lyophilizates the decrease of enzymatic activity was less dependent on the excipient, but activity was always amongst the highest in melibiose lyophilizates. CONCLUSIONS: Melibiose was shown to be effective in protecting lyophilized beta-galactosidase during storage. The protein secondary structure was shown to change at comparable rate in lyophilizates as its enzymatic activity after rehydration. PMID- 20967491 TI - The rule of five for non-oral routes of drug delivery: ophthalmic, inhalation and transdermal. AB - The Rule of Five predicts suitability of drug candidates, but was developed primarily using orally administered drugs. Here, we test whether the Rule of Five predicts drugs for delivery via non-oral routes, specifically ophthalmic, inhalation and transdermal. We assessed 111 drugs approved by FDA for those routes of administration and found that >98% of current non-oral drugs have physicochemical properties within the limits of the Rule of Five. However, given the inherent bias in the dataset, this analysis was not able to assess whether drugs with properties outside those limits are poor candidates. Indeed, further analysis indicates that drugs well outside the Rule of Five limits, including hydrophilic macromolecules, can be delivered by inhalation. In contrast, drugs currently administered across skin fall within more stringent limits than predicted by the Rule of Five, but new transdermal delivery technologies may make these constraints obsolete by dramatically increasing skin permeability. The Rule of Five does appear to apply well to ophthalmic delivery. We conclude that although current non-oral drugs mostly have physicochemical properties within the Rule of Five thresholds, the Rule of Five should not be used to predict non-oral drug candidates, especially for inhalation and transdermal routes. PMID- 20967492 TI - Accumulation of phenylpropanoid and sesquiterpenoid volatiles in male rectal pheromonal glands of the guava fruit fly, Bactrocera correcta. AB - The guava fruit fly, Bactrocera correcta, is widely distributed in Thailand and other surrounding Southeast Asian countries, and, like the closely related sympatric species, the oriental fruit fly, B. dorsalis, infests various fruits, including guava, peach, and mango. Males of both B. correcta and B. dorsalis are strongly attracted to, and compulsively feed on, methyl eugenol (ME). Bactrocera dorsalis males fed on ME sequester its metabolite phenylpropanoids, (E)-coniferyl alcohol and 2-allyl-4,5-dimethoxyphenol, in the rectal pheromone gland. In contrast, B. correcta males fed on ME sequester two different metabolites, (Z) coniferyl alcohol (ZCF) and (Z)-3,4-dimethoxycinnamyl alcohol (DMC), in the rectal gland. Examination of the temporal changes of ME metabolites in B. correcta male rectal glands revealed that the total of ZCF and DMC was as high as 100 MUg/male at 24 hr after ME feeding. ZCF and DMC were detected in a large proportion of wild B. correcta males captured at various sites in Thailand. Since B. correcta and B. dorsalis are sympatric species in Thailand, these two different subsets of rectal phenylpropanoids could play a role to avoid interbreeding between the species. Further survey of wild flies in Thailand revealed that a large proportion of males of B. correcta store large quantities (over 250 MUg/gland) of sesquiterpene hydrocarbons, including beta-caryophyllene, alpha-humulene, and alloaromadendrene in the rectal gland in addition to, or instead of, ZCF and DMC. Laboratory-reared males also sequestered beta caryophyllene and alpha-humulene, along with ZCF and DMC, when the sesquiterpenes were artificially supplied together with ME. A field test demonstrated that a mixture (1:1) of beta-caryophyllene and alpha-humulene attracted male B. correcta, albeit in smaller numbers than in traps baited with ME. The sequestration of sesquiterpenes, in addition to the different ME metabolites in the pheromone gland in B. correcta males, contrasts with the situation in B. dorsalis males, suggesting a potential role in intra and/or inter-specific interactions between these sympatric species. PMID- 20967493 TI - "I kiss them because I love them": the emergence of heterosexual men kissing in British institutes of education. AB - In this article, we combined data from 145 interviews and three ethnographic investigations of heterosexual male students in the U.K. from multiple educational settings. Our results indicate that 89% have, at some point, kissed another male on the lips which they reported as being non-sexual: a means of expressing platonic affection among heterosexual friends. Moreover, 37% also reported engaging in sustained same-sex kissing, something they construed as non sexual and non-homosexual. Although the students in our study understood that this type of kissing remains somewhat culturally symbolized as a taboo sexual behavior, they nonetheless reconstructed it, making it compatible with heteromasculinity by recoding it as homosocial. We hypothesize that both these types of kissing behaviors are increasingly permissible due to rapidly decreasing levels of cultural homophobia. Furthermore, we argue that there has been a loosening of the restricted physical and emotional boundaries of traditional heteromasculinity in these educational settings, something which may also gradually assist in the erosion of prevailing heterosexual hegemony. PMID- 20967494 TI - The association between sexual motives and sexual satisfaction: gender differences and categorical comparisons. AB - Past research suggests that sexual satisfaction may be partially dependent on sexual motives (the reasons people have sex). The primary goal of this study was to determine which of a wide range of empirically derived sexual motives were related to sexual satisfaction, and whether gender differences existed in these relationships. Examining data from 544 undergraduate participants (93 men, 451 women), we found that certain types of motives predicted levels of sexual satisfaction for both genders. However, a greater number of motive categories were related to satisfaction for women than for men, and sexual motives were a more consistent predictor of satisfaction in general for women than for men. We also found that empirical categories of motives predicted more variance in satisfaction ratings than did previously used theoretical categories. These findings suggest that a wide range of sexual motives are related to sexual satisfaction, that these connections may be moderated by gender, and that empirically-constructed categories of motives may be the most effective tool for studying this link. PMID- 20967495 TI - Mixed method designs in implementation research. AB - This paper describes the application of mixed method designs in implementation research in 22 mental health services research studies published in peer-reviewed journals over the last 5 years. Our analyses revealed 7 different structural arrangements of qualitative and quantitative methods, 5 different functions of mixed methods, and 3 different ways of linking quantitative and qualitative data together. Complexity of design was associated with number of aims or objectives, study context, and phase of implementation examined. The findings provide suggestions for the use of mixed method designs in implementation research. PMID- 20967496 TI - Do changes in cigarette design influence the rise in adenocarcinoma of the lung? AB - BACKGROUND: Incidence rates for adenocarcinoma of the lung are increasing and are higher in the United States than in many other developed countries. We examine whether these trends may be associated with changes in cigarette design. METHODS: Lung cancer risk equations based on observations during 1960-1972 from the American Cancer Society Cancer Prevention Study I are applied to 5-year birth cohort-specific estimates of changes in smoking behaviors to predict birth cohort specific rates of squamous cell carcinoma and adenocarcinoma of the lung among US White men for the period 1973-2000. These expected rates are compared to observed rates for the same birth cohorts of White men in the US Surveillance, Epidemiology and End Results (SEER) data. RESULTS: Changes in smoking behaviors over the past several decades adequately explain the changes in squamous cell carcinoma rates observed in the SEER data. However, predicted rates for adenocarcinoma do not match the observed SEER data without inclusion of a term increasing the risk for adenocarcinoma with the duration of smoking after 1965. CONCLUSION: The risk of developing squamous cell carcinoma from smoking appears to have remained stable in the United States over the past several decades; however, the risk of adenocarcinoma has increased substantially in a pattern temporally associated with changes in cigarette design. PMID- 20967498 TI - Williopsis saturnus yeast killer toxin does not kill Streptococcus pneumoniae. AB - Streptococcus pneumoniae is an important human bacterial pathogen, and the increase in antibiotic resistance demands the development of new antimicrobial compounds. Several reports have suggested that yeast killer toxins show activity against bacteria and we therefore investigated the activity of K9 killer toxin from the yeast Williopsis saturnus var. mrakii NCYC 500 against S. pneumoniae. However, no inhibition of bacterial growth was observed with concentrated K9 preparations in agar diffusion assays and in liquid culture. Although cell morphology was slightly affected by K9 treatment, no effect on cellular viability was detectable, and K9 had no stimulatory effect on cell lysis induced by beta lactams or Triton X-100. This indicated that K9 did not contribute to cell wall damage. Moreover, flow cytometry was used as a sensitive assessment of integrity of cells exposed to killer toxin. No significant damage of S. pneumoniae cells was evident, although minor changes in fluorescence suggested that K9 killer toxin may interact with bacterial surface components. PMID- 20967497 TI - Spontaneous in vitro maturation and artificial activation of human germinal vesicle oocytes recovered from stimulated cycles. AB - PURPOSE: To define germinal vesicles (GV) by morphometric and morphologic examination and by chromatin compaction and to assess their spontaneous nuclear and cytoplasmic competence. MATERIALS: 131 GV were cultured for 42.7 +/- 2.4 h. Nuclear maturation was evaluated at four time points. Sixty-seven in vitro and twenty-five in vivo metaphase II (MII) were activated. Parthenotes with 2 PB and one pronucleus (NA) were studied for ploidy. RESULTS: A total of 74.8% GV matured to MII: 55% at 21.4 +/- 2.4 h and 47.3% in the following 24 h. Artificial activation induced NA in 79.2% of in vivo-MII and in 22.4% of in vitro-MII. All NA were haploid. CONCLUSIONS: GV spontaneously mature at the nuclear level. Their NA are haploid, but their cytoplasmic competence is compromised. Variables were not found to be predictors of oocyte competence, probably due to our population being homogeneous with respect to most of the variables studied. PMID- 20967499 TI - Five new species of yeasts from fresh water and marine habitats in the Florida Everglades. AB - Yeast populations in the Shark River Slough of the Florida Everglades, USA, were examined during a 3-year period (2002-2005) at six locations ranging from fresh water marshes to marine mangroves. Seventy-four described species (33 ascomycetes and 41 basidiomycetes) and an approximately equal number of undescribed species were isolated during the course of the investigation. Serious human pathogens, such as Candida tropicalis, were not observed, which indicates that their presence in coastal waters is due to sources of pollution. Some of the observed species were widespread throughout the fresh water and marine habitats, whereas others appeared to be habitat restricted. Species occurrence ranged from prevalent to rare. Five representative unknown species were selected for formal description. The five species comprise two ascomycetes: Candida sharkiensis sp. nov. (CBS 11368(T)) and Candida rhizophoriensis sp. nov. (CBS 11402(T)) (Saccharomycetales, Metschnikowiaceae), and three basidiomycetes: Rhodotorula cladiensis sp. nov. (CBS 10878(T)) in the Sakaguchia clade (Cystobasidiomycetes), Rhodotorula evergladiensis sp. nov. (CBS 10880(T)) in the Rhodosporidium toruloides clade (Microbotryomycetes, Sporidiobolales) and Cryptococcus mangaliensis sp. nov. (CBS 10870(T)) in the Bulleromyces clade (Agaricomycotina, Tremellales). PMID- 20967500 TI - The placement of skin surface markers for non-invasive measurement of scapular kinematics affects accuracy and reliability. AB - Abnormal scapular movement is widely believed to be an important factor in clinical pathology of the shoulder joint complex. Validated non-invasive techniques for measuring scapular movement have been developed, but the effect of marker placement on accuracy is unknown. The objective of this study was to determine the accuracy and reliability of different groupings of markers to achieve the best accuracy and reliability for measuring scapular kinematics. Eight healthy young adult subjects were recruited. An optoelectronic marker grid was applied to the skin overlying the scapula. Two bone pins with optoelectronic marker carriers were inserted into the scapula. The accuracy of six surface marker configurations was determined by comparing the measured kinematics with scapular bone pins (the gold standard). Four humeral movements were tested: glenohumeral abduction, glenohumeral horizontal adduction, hand behind back, and forward reaching. All three rotations had a significant difference in the accuracy of the patches (p = 0.04 to p < 0.0001). For posterior tipping there was a significant effect of movement (p = 0.003) and a significant interaction (p < 0.0001). There was also a significant interaction for external rotation (p = 0.001). The marker grouping with the largest cranio-caudal spread had the highest accuracy for measuring posterior tilting (RMS 1.9 degrees ). Markers closer to the scapular spine were more accurate for tracking external rotation (RMS 2.0 degrees ) while an intermediate grouping of markers were most accurate for quantifying upward rotation (RMS 1.9 degrees ). The reliability between days ranged between 3.8 degrees and 7.5 degrees (based on RMS difference between trials) and there was a significant interaction between patch and movement (p < 0.0001). Intraclass correlation coefficients show moderate to good agreement for most arm movements and scapular rotations. Thus, there exists distinct optimal configurations of non-invasive marker locations for accurately measuring scapular kinematics. PMID- 20967501 TI - A review of the ultrastructural features of superficial candidiasis. AB - Commensal yeast Candida causes opportunistic infections ranging from superficial lesions to disseminated mycoses in compromised patients. Superficial candidiasis, the commonest form of candidal infections, primarily affects the mucosa and the skin where Candida lives as a commensal. Conversion of candidal commensalism into opportunism at the fungal-epithelial interface is still ill-defined. Nevertheless, fungal virulence mechanisms such as adhesion to epithelia, morphogenesis, production of secretory hydrolytic enzymes, and phenotypic switching are thought to contribute in the process of pathogenesis. On the other hand, host responses in terms of immunity and local epithelial responses are actively involved in resisting the fungal challenge at the advancing front of the infection. Ultrastructural investigations using electron microscopy along with immunohistochemistry, cytochemistry, etc. have helped better viewing of Candida host interactions. Thus, studies on the ultrastructure of superficial candidiasis have revealed a number of fungal behaviors and associated host responses such as adhesion, morphogenesis (hyphae and appresoria formation), thigmotropism, production and distribution of extracellular enzymes, phagocytosis, and epithelial changes. The purpose of this review is to sum up most of the ultrastructural findings of Candida-host interactions and to delineate the important pathological processes underlying superficial candidiasis. PMID- 20967502 TI - Inherited germline TP53 mutation encodes a protein with an aberrant C-terminal motif in a case of pediatric adrenocortical tumor. AB - Childhood adrenocortical tumor (ACT), a very rare malignancy, has an annual worldwide incidence of about 0.3 per million children younger than 15 years. The association between inherited germline mutations of the TP53 gene and an increased predisposition to ACT was described in the context of the Li-Fraumeni syndrome. In fact, about two-thirds of children with ACT have a TP53 mutation. However, less than 10% of pediatric ACT cases occur in Li-Fraumeni syndrome, suggesting that inherited low-penetrance TP53 mutations play an important role in pediatric adrenal cortex tumorigenesis. We identified a novel inherited germline TP53 mutation affecting the acceptor splice site at intron 10 in a child with an ACT and no family history of cancer. The lack of family history of cancer and previous information about the carcinogenic potential of the mutation led us to further characterize it. Bioinformatics analysis showed that the non-natural and highly hydrophobic C-terminal segment of the frame-shifted mutant p53 protein may disrupt its tumor suppressor function by causing misfolding and aggregation. Our findings highlight the clinical and genetic counseling dilemmas that arise when an inherited TP53 mutation is found in a child with ACT without relatives with Li Fraumeni-component tumors. PMID- 20967503 TI - Distal pancreatectomy combined with celiac axis resection in treatment of carcinoma of the body/tail of the pancreas: proceed with caution. PMID- 20967505 TI - Overdose prevention and naloxone prescription for opioid users in San Francisco. AB - Opiate overdose is a significant cause of mortality among injection drug users (IDUs) in the United States (US). Opiate overdose can be reversed by administering naloxone, an opiate antagonist. Among IDUs, prevalence of witnessing overdose events is high, and the provision of take-home naloxone to IDUs can be an important intervention to reduce the number of overdose fatalities. The Drug Overdose Prevention and Education (DOPE) Project was the first naloxone prescription program (NPP) established in partnership with a county health department (San Francisco Department of Public Health), and is one of the longest running NPPs in the USA. From September 2003 to December 2009, 1,942 individuals were trained and prescribed naloxone through the DOPE Project, of whom 24% returned to receive a naloxone refill, and 11% reported using naloxone during an overdose event. Of 399 overdose events where naloxone was used, participants reported that 89% were reversed. In addition, 83% of participants who reported overdose reversal attributed the reversal to their administration of naloxone, and fewer than 1% reported serious adverse effects. Findings from the DOPE Project add to a growing body of research that suggests that IDUs at high risk of witnessing overdose events are willing to be trained on overdose response strategies and use take-home naloxone during overdose events to prevent deaths. PMID- 20967504 TI - Evaluation of hexachlorocyclohexane contamination from the last lindane production plant operating in India. AB - PURPOSE: alpha-Hexachlorocyclohexane (HCH), beta-HCH, and lindane (gamma-HCH) were listed as persistent organic pollutants by the Stockholm Convention in 2009 and hence must be phased out and their wastes/stockpiles eliminated. At the last operating lindane manufacturing unit, we conducted a preliminary evaluation of HCH contamination levels in soil and water samples collected around the production area and the vicinity of a major dumpsite to inform the design of processes for an appropriate implementation of the Convention. METHODS: Soil and water samples on and around the production site and a major waste dumpsite were measured for HCH levels. RESULTS: All soil samples taken at the lindane production facility and dumpsite and in their vicinity were contaminated with an isomer pattern characteristic of HCH production waste. At the dumpsite surface samples contained up to 450 g kg(-1) Sigma HCH suggesting that the waste HCH isomers were simply dumped at this location. Ground water in the vicinity and river water was found to be contaminated with 0.2 to 0.4 mg l(-1) of HCH waste isomers. The total quantity of deposited HCH wastes from the lindane production unit was estimated at between 36,000 and 54,000 t. CONCLUSIONS: The contamination levels in ground and river water suggest significant run-off from the dumped HCH wastes and contamination of drinking water resources. The extent of dumping urgently needs to be assessed regarding the risks to human and ecosystem health. A plan for securing the waste isomers needs to be developed and implemented together with a plan for their final elimination. As part of the assessment, any polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/PCDF) generated during HCH recycling operations need to be monitored. PMID- 20967506 TI - Assessing the quality of clinical teachers. PMID- 20967507 TI - Splenic artery pseudoaneurysm complicating pancreatitis. PMID- 20967509 TI - Gut feelings as a third track in general practitioners' diagnostic reasoning. AB - BACKGROUND: General practitioners (GPs) are often faced with complicated, vague problems in situations of uncertainty that they have to solve at short notice. In such situations, gut feelings seem to play a substantial role in their diagnostic process. Qualitative research distinguished a sense of alarm and a sense of reassurance. However, not every GP trusted their gut feelings, since a scientific explanation is lacking. OBJECTIVE: This paper explains how gut feelings arise and function in GPs' diagnostic reasoning. APPROACH: The paper reviews literature from medical, psychological and neuroscientific perspectives. CONCLUSIONS: Gut feelings in general practice are based on the interaction between patient information and a GP's knowledge and experience. This is visualized in a knowledge-based model of GPs' diagnostic reasoning emphasizing that this complex task combines analytical and non-analytical cognitive processes. The model integrates the two well-known diagnostic reasoning tracks of medical decision making and medical problem-solving, and adds gut feelings as a third track. Analytical and non-analytical diagnostic reasoning interacts continuously, and GPs use elements of all three tracks, depending on the task and the situation. In this dual process theory, gut feelings emerge as a consequence of non-analytical processing of the available information and knowledge, either reassuring GPs or alerting them that something is wrong and action is required. The role of affect as a heuristic within the physician's knowledge network explains how gut feelings may help GPs to navigate in a mostly efficient way in the often complex and uncertain diagnostic situations of general practice. Emotion research and neuroscientific data support the unmistakable role of affect in the process of making decisions and explain the bodily sensation of gut feelings.The implications for health care practice and medical education are discussed. PMID- 20967510 TI - A case-control study of laparoscopy-assisted and open distal gastrectomy for advanced gastric cancer. AB - BACKGROUND: The application of laparoscopy-assisted gastric surgery has been increasing rapidly for the treatment of early gastric cancer. However, there were few reports of laparoscopic surgery in the management of advanced gastric cancer (AGC), especially with T3 depth of invasion. The aim of this study was to compare the technical feasibility and oncologic efficacy of laparoscopy-assisted distal gastrectomy (LADG) versus open distal gastrectomy (ODG) for advanced gastric cancer. METHODS: A retrospective case-control study was performed comparing LADG and ODG for AGC. Thirty-five consecutive patients with AGC undergoing LADG between August 2005 and December 2007 were enrolled and these patients were compared with 35 AGC patients undergoing ODG during the same period. RESULTS: Forty-two (60.0%) patients were T3 in terms of depth of invasion. Tumor location and histology were similar between the two groups. Operation time was significantly longer in the LADG group than in the ODG group. Estimated blood loss was significantly less in the LADG group. Hospital length of stay after LADG was significantly shorter than in the open group. Postoperative pain was significantly lower for laparoscopic patients. There were no significant differences in postoperative early and late complication and in the number of lymph nodes retrieved between the two groups, and the cumulative survival of the two groups was similar. CONCLUSION: Our data indicate that LADG for AGC, mostly with T3 depth of invasion, yields good oncologic outcomes including the similar early and late complication and the cumulative survival between the two groups after 50 months of follow-up. To be accepted as a choice treatment for advanced distal gastric cancer, well-designed prospective trial to assess long-term outcomes is necessary. PMID- 20967511 TI - H2S protects hippocampal neurons from anoxia-reoxygenation through cAMP-mediated PI3K/Akt/p70S6K cell-survival signaling pathways. AB - The study aims to investigate the effect of hydrogen sulfide (H(2)S) on the phosphatidylinositol 3-kinase (PI3K)/Akt/p70 ribosomal S6 kinase (p70S6K) signal transduction pathway after oxygen glucose deprivation/reoxygenation (OGD/R) in the rat hippocampus. Newborn Wister rats were decapitated under anesthesia, and hippocampal tissue was dissected. Cells were plated at 1.0 * 10(5) cells/mL on polylysine-treated 96-well and 6-well plates. After 7 days in culture, cells were randomly assigned to six groups: control, OGD/R, sodium hydrosulfide (NaHS) following OGD/R, NaHS/triciribine following OGD/R, NaHS/rapamycin following OGD/R, and NaHS/triciribine/rapamycin following OGD/R. Neuronal purity and cell viability were assessed in each group, as well as apoptosis and expression of cyclic adenosine 3', 5'-monophosphate (cAMP), PI3K, Akt, and p70S6K. NaHS enhanced cAMP concentration and expression of PI3K, Akt, and p70S6K. In addition, neuronal viability was increased and apoptotic neuronal numbers decreased (P<0.01). Triciribine inhibited Akt and p70S6K, as well as decreased cell survival and viability compared with the NaHS group (P<0.05 or P<0.01). Rapamycin resulted in decreased p70S6K expression and neuronal viability, as well as increased number of apoptotic neurons compared with the NaHS group (P<0.05 or P<0.01). H(2)S acted via cAMP-mediated PI3K/Akt/p70S6K signal transduction pathways to inhibit hippocampal neuronal apoptosis and protect neurons from OGD/R induced injury. PMID- 20967512 TI - Cardiac risk associated with the receipt of anthracycline and trastuzumab in a large nationwide cohort of older women with breast cancer, 1998-2005. AB - To determine the risk of cardiotoxicities in association with trastuzumab with/without anthracycline-containing chemotherapy in a large nationwide population-based cohort of patients with breast cancer. We studied 47,806 women with breast cancer ages >= 65 in 1998-2005 from 16 cancer registries in the Surveillance, Epidemiology and End Results (SEER)-Medicare data and 16,092 cases matched with equal number of controls on the propensity of receiving chemotherapy or trastuzumab. Cumulative incidence of congestive heart failure in year-1 was 5.5% for patients receiving anthracycline and trastuzumab and 3.2% for those receiving anthracycline without trastuzumab. The cumulative incidence of congestive heart failure in year-5 was 15.5 and 9.1%, respectively. Compared to those without chemotherapy and trastuzumab, patients treated with anthracycline containing chemotherapy and no trastuzumab were 19% significantly more likely to develop congestive heart failure (hazard ratio = 1.19, 95% CI = 1.05-1.34), whereas those receiving trastuzumab without anthracycline and those receiving both trastuzumab and anthracycline were 1.97 and 2.37 times more likely to develop congestive heart failure after adjusting for patient and tumor characteristics. Concurrent or sequential use of anthracycline and trastuzumab was associated with a greater risk of congestive heart failure and cardiomyopathy. Carefully monitoring cardiac functions in patients receiving anthracycline and trastuzumab is warranted. PMID- 20967513 TI - Primary gastric Hodgkin lymphoma and metachronous early gastric carcinoma: a case report. AB - Primary Gastric Hodgkin lymphoma is seen very rarely. Primary gastric Hodgkin lymphoma and gastric carcinoma in same patient is very very rare entity. Almost all of the primary gastric lymphoma cases are non-Hodgkin lymphoma type. We report the case of 45-year-old man with 3-month history of abdominal pain and weight loss. Upper gastrointestinal endoscopic examination revealed an ulcerated polypoid mass on greater curve of stomach and histopathological examination of biopsy showed adenocarcinoma. After near total gastrectomy, gastric Hodgkin lymphoma diagnosis was made, and postoperative 4 courses of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) regimen were administered, and then total 3,600 cGy radiotherapy was delivered. After 7 years, during control examination, early gastric carcinoma was diagnosed. Our case is very rare entity of gastric Hodgkin lymphoma and metachronous gastric carcinoma. This case also shows the importance of follow-up of patients not only for the relapse of primary disease but also for the development of secondary malignancy which can be diagnosed at early curable stage. PMID- 20967514 TI - Short-term outcomes of cetuximab combined with standard chemotherapy as first line setting for Chinese patients with non-small cell lung cancer: a report of 12 cases. AB - Cetuximab combined with chemotherapy has been used to treat Non-small cell lung cancer (NSCLC) in recent years, however, the data from China was rare. This study was to summarize our experiences in treating NSCLC patients with cetuximab in the first line setting. From October 1st 2006 to Jun 30th 2010, twelve NSCLC patients were treated with cetuximab combined standard chemotherapy as first line setting in Sun Yat-sen University Cancer Center entered the study and the short-term efficacy and safety were analyzed. A total of 132 cycles of cetuximab treatment, with a median of nine cycles in the whole group were administered. The ORR was 41.7% (5/12), DCR was 83.3% (10/12), median TTP was 5.5 months (2-23), and median OS was 9 months (2-48) in the whole group. There were 75% (9/12) patients occurred acne-like rash within first 3 weeks, their ORR was 55.6% (5/9), DCR was 100% (9/9), however, ORR and DCR in patients who didn't occurred acne-like rash within first 3 weeks were 0 and 33.3% (1/3), the difference ORR between two group was insignificant (P = 0.091), however, DCR was significant different (P = 0.007). There no treatment-associated death and no cetuximab-associated discontinuation. The incidence of acne-like rash was 83.3% (10/12) and 75% (9/12) occurred within first 3 weeks, there were eight patients suffered side effects associated with chemotherapy. So we can draw a conclusion that the short-term outcome of cetuximab application in first line setting for patients with NSCLC were promising since the higher ORR and DCR, especially those occurred acne-like rash within the first 3 weeks, and the addition of cetuximab in this population was safe. PMID- 20967515 TI - Childhood rickettsiosis. AB - Rickesttsial diseases are a group of diseases caused by obligate intracellular gram negative bacilli and transmitted to man by arthropod vectors (except Q fever). It is increasingly realised that rickesttsial diseases are underdiagnosed. It is now well documented that rickettsial disease is prevalent all over India, in pockets. The hallmark of rickettsial infection is microvasculitis, causing microinfarcts in various organs. Usually the patients present with classical triad of Fever, Headache & Rash. Apart from this, pain in legs, oedema, Gastro-intestinal symptoms, hepato-splenomegaly, anaemia, necrotic rash, gangrene of digits, toes, earlobes, scrotum, painless eschar and lymphadenopathy are other manifestations. Complications include encephalitis, ARDS, pneumonia, Myocarditis, Renal failure and Vascular collapse. Endocarditis is seen in Q fever. Gold standard test for confirmation of diagnosis is I.F.A. Weil felix test is widely available but unacceptable for accurate diagnosis. Weil Felix test can be used in developing countries where other tests are not available. ELISA Should be preferred and is now available in India. The drug of choice for all age group is doxycycline. Rickettsia are potentially dangerous pathogens and unfortunately, specific serological tests are available in only a few specialized laboratories. Hence, it is imperative to have a high index of suspicion for Rickettsial diseases and make a clinical diagnosis based on prudent history taking and appropriate physical findings. A therapeutic trial with a specific agent in these patients is justified because a delay in initiating treatment may prove fatal. A rapid and favorable response is suggestive of a correct diagnosis. PMID- 20967516 TI - Mitochondrial biogenesis and fragmentation as regulators of muscle protein degradation. AB - Mitochondria form a dynamic network that rapidly adapts to cellular energy demand. This adaptation is particularly important in skeletal muscle because of its high metabolic rate. Indeed, muscle energy level is one of the cellular checkpoints that lead either to sustained protein synthesis and growth or protein breakdown and atrophy. Mitochondrial function is affected by changes in shape, number, and localization. The dynamics that control the mitochondrial network, such as biogenesis and fusion, or fragmentation and fission, ultimately affect the signaling pathways that regulate muscle mass. Regular exercise and healthy muscles are important players in the metabolic control of human body. Indeed, a sedentary lifestyle is detrimental for muscle function and is one of the major causes of metabolic disorders such as obesity and diabetes. This article reviews the rapid progress made in the past few years regarding the role of mitochondria in the control of proteolytic systems and in the loss of muscle mass and function. PMID- 20967517 TI - Coexistence of chronic myeloid leukemia and pulmonary plasmacytoma mimicking primary lung cancer. AB - A 61-year-old man was diagnosed with the simultaneous occurrence of chronic myeloid leukemia (CML) and infiltrative intrathoracic plasmacytoma, radiologically mimicking bronchogenic carcinoma. Following the administration of imatinib mesylate (IM; 400 mg/day), both hematologic and partial cytogenetic remission of CML were achieved. However, the pulmonary plasmacytoma was persistently aggravated. High-dose dexamethasone was added to the IM therapy because the patient refused radiotherapy to control the aggravated pulmonary plasmacytoma. Finally, he died due to pneumonia and multi-organ failure during concurrent administration of IM and high-dose dexamethasone. PMID- 20967518 TI - A nonradiation-containing, intermediate-dose methotrexate regimen for elderly patients with primary central nervous system lymphoma. AB - To assess the efficacy, acute toxicity, and delayed neurotoxicity of intermediate dose methotrexate (MTX)-containing chemotherapy without whole-brain radiotherapy in the treatment of elderly patients with primary central nervous system lymphoma (PCNSL), we conducted a retrospective analysis of elderly patients (N = 17; median age 67) with newly diagnosed PCNSL who were treated with chemotherapy alone at Tsukuba University Hospital from January 2005 to December 2009. Induction therapy consisted of intravenous intermediate-dose MTX (1 g/m2), ranimustine, procarbazine, methylprednisolone, and intrathecal MTX and cytarabine. Patients who achieved complete response (CR) or partial response (PR) received 5 cycles of maintenance therapy every 6 weeks. All patients in this study achieved CR or PR and received maintenance therapy. Overall survival (OS) and progression-free survival (PFS) were 100 and 80% at 1 year, and 61 and 43% at 2 years, respectively. The median OS and PFS were 36 and 20 months, respectively. Delayed neurotoxicity did not develop in any patient before lymphoma progression. In terms of response rate, OS, and PFS, the nonradiation-containing, intermediate dose MTX-containing protocol used in elderly Japanese patients was comparable to previous protocols that consisted of more intensive chemotherapy. Acute and delayed toxicities were manageable and quality of life was maintained until progression. PMID- 20967519 TI - Anti-inflammatory/Anti-oxidative stress activities and differential regulation of Nrf2-mediated genes by non-polar fractions of tea Chrysanthemum zawadskii and licorice Glycyrrhiza uralensis. AB - Accumulating evidence from epidemiological studies indicates that chronic inflammation and oxidative stress play critical roles in neoplastic development. The aim of this study was to investigate the anti-inflammatory, anti-oxidative stress activities, and differential regulation of Nrf2-mediated genes by tea Chrysanthemum zawadskii (CZ) and licorice Glycyrrhiza uralensis (LE) extracts. The anti-inflammatory and anti-oxidative stress activities of hexane/ethanol extracts of CZ and LE were investigated using in vitro and in vivo approaches, including quantitative real-time PCR (qPCR) and microarray. Additionally, the role of the transcriptional factor Nrf2 (nuclear erythroid-related factor 2) signaling pathways was examined. Our results show that CZ and LE extracts exhibited potent anti-inflammatory activities by suppressing the mRNA and protein expression levels of pro-inflammatory biomarkers IL-1beta, IL-6, COX-2 and iNOS in LPS-stimulated murine RAW 264.7 macrophage cells. CZ and LE also significantly suppressed the NO production of LPS-stimulated RAW 264.7 cells. Additionally, CZ and LE suppressed the NF-kappaB luciferase activity in human HT-29 colon cancer cells. Both extracts also showed strong Nrf2-mediated antioxidant/Phase II detoxifying enzymes induction. CZ and LE induced NQO1, Nrf2, and UGT and antioxidant response element (ARE)-luciferase activity in human hepatoma HepG2 C8 cells. Using Nrf2 knockout [Nrf2 (-/-)] and Nrf2 wild-type (+/+) mice, LE and CZ showed Nrf2-dependent transactivation of Nrf2-mediated antioxidant and phase II detoxifying genes. In summary, CZ and LE possess strong inhibitory effects against NF-kappaB-mediated inflammatory as well as strong activation of the Nrf2 ARE-anti-oxidative stress signaling pathways, which would contribute to their overall health promoting pharmacological effects against diseases including cancer. PMID- 20967520 TI - Paracellular tightness and claudin-5 expression is increased in the BCEC/astrocyte blood-brain barrier model by increasing media buffer capacity during growth. AB - Most attempts to develop in vitro models of the blood-brain barrier (BBB) have resulted in models with low transendothelial electrical resistances (TEER), as compared to the native endothelium. The aim of the present study was to investigate the impact of culture pH and buffer concentration on paracellular tightness of an established in vitro model of the BBB consisting of bovine brain capillary endothelial cells (BCEC) co-cultured with rat astrocytes. BCEC and rat astrocytes were isolated and co-cultured using astrocyte-conditioned media with cAMP increasing agonists and dexamethasone. The co-culture had average TEER values from 261 +/- 26 Omega cm2 to 760 +/- 46 Omega cm2 dependent on BCEC isolation batches. Furthermore, mRNA of occludin, claudin-1, claudin-5, JAM-1, and ZO-1 were detected. Increased buffer concentration by addition of HEPES, MOPS, or TES to the media during differentiation increased the TEER up to 1,638 +/- 256 Omega cm2 independent of the type of buffer. This correlated with increased expression of claudin-5, while expression of the other tight junction proteins remained unchanged. Thus, we show for the first time that increased buffer capacity of the medium during differentiation significantly increases tightness of the BCEC/astrocyte in vitro BBB model. This regulation may be mediated by increased claudin-5 expression. The observations have practical implications for generating tighter BBB cell culture models, and may also have physiological implications, if similar sensitivity to pH-changes can be demonstrated in vivo. PMID- 20967521 TI - Prediction of exposure-response relationships to support first-in-human study design. AB - In drug development, phase 1 first-in-human studies represent a major milestone as the drug moves from preclinical discovery to clinical development activities. The safety of human subjects is paramount to the conduct of these studies and regulatory considerations guide activities. Forces of evolution on the pharmaceutical industry are re-shaping the first-in-human dose selection strategy. Namely, high attrition rates in part due to lack of efficacy have led to the re-organization of research and development organizations around the umbrella of translational research. Translational research strives to bring basic research advances into the clinic and support the reverse transfer of information to enhance compound selection strategies. Pharmacokinetic/pharmacodynamic (PK/PD) modeling holds a unique position in translational research by attempting to integrate diverse sets of information. PK/PD modeling has demonstrated utility in dose selection and trial design for later stages of drug development and is now being employed with greater prevalence in the translational research setting to manage risk (i.e., oncology and inflammation/immunology). Moving from empirical E (max) models to more mechanistic representations of the biological system, a higher fidelity of human predictions is expected. Strategies that have proven useful for PK predictions are being applied to PK/PD predictions. This review article examines examples of the application of PK/PD modeling in establishing target concentrations for supporting first-in-human study design. PMID- 20967522 TI - Are cutaneous microdialysis cytokine findings supported by end point biopsy immunohistochemistry findings? AB - Insertion of a cutaneous microdialysis catheter into normal dermis has been shown to induce the production of IL1b, IL6 and IL8 in an innate response to minimal trauma. In the present study, skin biopsy for immunohistochemistry has been performed at the site of the microdialysis catheter to compare the findings with that of the microdialysis findings 24 h after insertion. Of the three named cytokines, concordance between the two investigated technologies was highest for IL8 (100%) followed by IL6 (70%) and IL1b (50%). For seven other pro-inflammatory and T cell-relevant cytokines studied, concordance ranged between 50% and 80%. The total number of positive (microdialysis or immunofluorescence) findings was similar between the two methodologies. Technical and biological phenomenon can explain the differences. We conclude that both methodologies illustrate important features of tissue biology and that a combination of the two methods in clinical research can provide the chronology of soluble mediator participation and the more classic, but also more invasive, biopsy-based methodology at a point which constitutes the end of the observation period. We conclude further that at the 24 h time period here studied, microdialysis catheters are still functional and thus capable of producing relevant data which can be corroborated and extended by the "end point biopsy". PMID- 20967523 TI - Selective histopathology in cholecystectomy for gallstone disease. PMID- 20967525 TI - [Statutes of the German Society for Pathology inc]. PMID- 20967526 TI - [Superiority of Toupet compared to Nissen fundoplication: New evidence level from meta-analysis]. PMID- 20967527 TI - [Hemoptysis as the first sign of ruptured thoracic aorta]. AB - Acute aortic rupture is associated with a high mortality. The leading symptoms are chest pain, dyspnea and hemodynamic instability as well as hemoptysis. In the current case report a patient with known coronary artery disease and prior coronary artery bypass surgery presented with hemoptysis. He was initially treated for a presumed gastroenterological disorder. The chest X-ray delineated a structure suggestive of aortic rupture and this diagnosis was confirmed by computed tomography. Emergency treatment was performed by implantation of an endovascular stent prosthesis. This procedure is currently regarded the standard treatment of rupture of the descending thoracic aorta. We conclude our case report with a discussion of epidemiology, symptoms, pathogenesis and therapy of this clinically dramatic disease. PMID- 20967528 TI - [Certified breast centers in Germany : How much is plastic surgery involved?]. AB - INTRODUCTION: This study was designed to assess the degree of cooperation between plastic surgeons and gynecologists in certified breast centers in Germany. The rate of breast reconstruction after mastectomy remains low at 8-13%. In certified breast centers plastic surgeons are often not members of the team. METHODS: A total of 220 hospitals affiliated to the West German Breast Center (WBC) were contacted in 2007 and 80 breast centers and hospitals returned the questionnaire. This study is based on the data of approximately 24,000 patients. RESULTS: At the time of the investigation 60 out of the 80 hospitals (75%) were certified breast centers. Many different criteria have been applied for certified breast centers: the state of Nordrhein-Westfalen, the DKG/DGS (German Cancer Society/German Society of Senology), EUSOMA and others. In 8 hospitals (10%) a plastic surgeon was part of the team in the breast center. Most breast centers (44 out of 80) function with 3-4 attending specialists for breast surgery. DISCUSSION: The cooperation between gynecologists and plastic surgeons within a breast center can be strengthened. A microsurgical breast augmentation is not the ideal solution for every patient with a mastectomy but every patient has the right to obtain complete information about the whole spectrum of breast reconstruction including microsurgical free flap reconstruction. PMID- 20967529 TI - [Sleeve gastrectomy in the treatment of morbid obesity. Study results and first experiences with the transvaginal hybrid NOTES technique]. AB - BACKGROUND: Surgery for morbid obesity is also becoming more important in Germany. Besides standard procedures such as the Roux-en-Y (RNY) bypass, sleeve gastrectomy seems to be a new option which is mainly related to gastric restriction, neurohumoral changes and other unknown factors. The results of sleeve gastrectomy have to be compared with other established procedures such as the RNY bypass according the complication rate, weight loss and improvement of weight-related comorbidities such as diabetes and hypertension. PATIENTS AND METHODS: Between May 2008 and August 2009 sleeve gastrectomy was performed in a total of 200 patients (136 female and 64 male) with an obesity grade II-III. The average age of the patients was 43 years (range 21-72 years) and the average BMI 47.9 kg/m(2) (range 35.5-75.3 kg/m(2)). Of the patients 70 (35%) were diabetics and 96 (48%) suffered from hypertension. In 14 cases the operation was planned using the transvaginal assisted (hybrid NOTES) technique. RESULTS: Laparoscopic sleeve gastrectomy was possible in all patients. Of the patients 3 (1.5%) suffered from postoperative complications, such as leakage from the suture line in 2 (1%) cases and in 1 case (0.5%) with hemorrhaging from the abdominal wall and subsequent pulmonary embolism resulting in a mortality rate of 1% (2 cases). In the 197 cases without complications the mean hospital stay was 3.5 days (range 2-9 days). Using the transvaginal technique the number of trocars could be reduced by 1-2 and in all cases the resected stomach was retrieved transvaginally. No complications occurred due to the vaginal access. Antidiabetic medication was stopped 3 months after the operation in 45 (64%) out of 70 diabetics and the need for antihypertension drugs was also reduced. The mean weight loss after 3, 6 and 12 months was 27.3%, 41% and 58%, respectively. CONCLUSIONS: Sleeve gastrectomy seems to be an effective surgical option for the treatment of morbid obesity with a low complication rate. During the first year after the operation weight loss was excellent and weight-related comorbidities such as diabetes and hypertension improved significantly. The transvaginal hybrid NOTES technique can be performed but there is still need for additional trocars through the abdominal wall. Long-term results with respect to a durable weight loss and obesity-associated comorbidities are still lacking. The results of sleeve gastrectomy are at present comparable to those of a RNY bypass. PMID- 20967530 TI - [MBA further education options]. PMID- 20967531 TI - [Stoma prolapse and stoma retraction]. AB - Prolapse and retraction of an intestinal stoma are postoperative complications which severely decrease the quality of life of patients and in some cases lead to an operative revision. Both entities should be treated with sophisticated care by specialized stoma therapists in the early phase in order to prevent secondary problems such as dermal ulceration. However, in case of additional problems, such as ileus, bleeding, incarceration or impossibility of adequate stoma care, an operative revision is indicated. It remains an individual decision whether a local or a transabdominal revision of the stoma is necessary.At present the level of information and the number of well designed studies dealing with prolapse or retraction of a stoma are unsatisfactory and there are merely studies which report on prolapse and retraction as an incidental finding rather than primarily focusing on these problems. In addition there is a lack of clear cut definitions for both entities which would allow a comparison of data obtained in different studies.There is clearly a demand for a structured scientific clarification as the occurrence of stomal retraction or prolapse may present psychological and medical problems for the patients and therefore needs to be treated, conservatively and/or operatively, by both stoma specialists and surgeons. PMID- 20967532 TI - [Diagnosis and definition of anastomotic leakage from the radiologist's perspective]. AB - Anastomotic leakage is a typical complication in gastrointestinal surgery. The frequency of occurrence and symptoms depend on the location of the intervention in the gastrointestinal tract. Consensus definitions have been published for bile leakage, pancreatic fistulas and colorectal leakage but there is still no overall standard classification for anastomotic leakage after surgical intervention in the gastrointestinal tract. Hence, there are also no standard guidelines for a diagnostic algorithm. Radiological techniques for the diagnosis of an anastomotic leakage include sonography, X-ray, fluoroscopy and computed tomography (CT). Percutaneous transhepatic cholangiography (PTC) could be helpful for the diagnosis of a leakage of a biliary enteric anastomosis. Magnetic resonance imaging (MRI) plays a subordinate role in the diagnosis of anastomotic leakage. PMID- 20967533 TI - [Convention of holders of university-chairs in trauma surgery: key points on terms of reference for trauma surgery in universities--structural considerations on healthcare, research and teaching]. PMID- 20967534 TI - [What's new for prevention of thromboembolism in trauma surgery?]. PMID- 20967535 TI - Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse. AB - AIMS/HYPOTHESIS: Substantial evidence suggests a link between elevated inflammation and development of insulin resistance. Toll-like receptor 2 (TLR2) recognises a large number of lipid-containing molecules and transduces inflammatory signalling in a variety of cell types, including insulin-responsive cells. Considering the contribution of the fatty acid composition in TLR2 depedent signalling, we hypothesised that the inflammatory signals transduced by TLR2 contribute to insulin resistance. METHODS: Mice deficient in TLR2 were used to investigate the in vivo roles of TLR2 in initiating and maintaining inflammation-associated insulin resistance and energy homeostasis. RESULTS: We first recapitulated the observation with elevated expression of TLR2 and inflammatory cytokines in white adipose tissue and liver of ob/ob mice. Aged or high-fat-fed TLR2-deficient mice were protected from obesity and adipocyte hypertrophy compared with wild-type mice. Moreover, mice lacking TLR2 exhibited improved glucose tolerance and insulin sensitivity regardless of feeding them regular chow or a high-fat diet. This is accompanied by reductions in expression of inflammatory cytokines and activation of extracellular signal-regulated kinase (ERK) in a liver-specific manner. The attenuated hepatic inflammatory cytokine expression and related signalling are correlated with increased insulin action specifically in the liver in TLR2-deficient mice, reflected by increased insulin stimulated protein kinase B (Akt) phosphorylation and IRS1 tyrosine phosphorylation and increased insulin-suppressed hepatocyte glucose production. CONCLUSIONS/INTERPRETATION: The absence of TLR2 attenuates local inflammatory cytokine expression and related signalling and increases insulin action specifically in the liver. Thus, our work has identified TLR2 as a key mediator of hepatic inflammation-related signalling and insulin resistance. PMID- 20967536 TI - Starvation/stationary-phase survival of Rhodococcus erythropolis SQ1: a physiological and genetic analysis. AB - The adaptation of Rhodocccus erythropolis SQ1 to energy and carbon starvation was investigated in terms of both the capacity to survive starvation and the contribution of a nutrient-induced stationary phase to cross-protection to other types of environmental stress. It was found that R. erythropolis SQ1 survives for at least 43 days in LB and distilled water, and 65 days in chemically defined medium (CDM) containing high (1%) or low (0.1%) glucose. Furthermore, early stationary-phase R. erythropolis SQ1 grown in CDM 0.1% exhibited enhanced resistance to heat and oxidative stress compared with exponential-phase cells. A second objective of this study was to identify genetic elements involved in starvation/stationary-phase survival. A mutant bank of R. erythropolis SQ1 generated by random transposon insertion mutagenesis was screened; four mutants lost culturability when grown in CDM 1%. No drop in culturability was observed when these mutants were grown in CDM 0.1%. The DNA flanking transposon insertion could be recovered from three mutants. Transposon insertions were found in uvrB (UvrB, part of the DNA excision repair mechanism), between a putative guaB gene and another guaB-like gene, and between a gene encoding a putative phosphoglycerate mutase and putative thioredoxin/cytochrome c biogenesis genes. This represents a first study of the starvation/stationary-phase survival response of Rhodococcus, an organism of immense significance in environmental bioremediation and a number of industrial processes. PMID- 20967537 TI - Effects of hand termination and accuracy constraint on eye-hand coordination during sequential two-segment movements. AB - The purpose of this study was to examine the effects of accuracy constraints and termination requirements of hand movement on eye-hand coordination. Healthy adults performed two-segment eye and hand aiming movements to predetermined stationary targets. While two-segment eye movements were made to the first and second targets for all conditions, hand movements were varied across conditions. The first segment had two target sizes to alter accuracy constraints. There were three hand movement types with different termination requirements: (1) stop both at the first and at the second targets, (2) stop at the first target and discontinue, and (3) move through the first target and discontinue. The results showed that the initiation of saccades was moderately correlated with the initiation of hand movements, and both initiations changed in a similar fashion depending on various hand termination requirements. Amplitude of primary saccades and frequency of corrective saccades during the first segment were affected by the combined effects of accuracy constraints and hand termination requirements. These results suggest that the planning and execution of saccades are based in part on global task constraints related to the accuracy and termination demands of hand movements over the two segments. During the transition from the first to the second segment, the gaze was held on the first target until shortly after the pointing to that target was terminated, showing gaze anchoring. The gaze anchoring was prolonged due to the increased accuracy constraint of that target or by including pointing to the second target. However, the gaze anchoring was broken prior to the completion of pointing when the accuracy constraint was reduced and pointing to the second target was excluded. The observed modifications of gaze anchoring imply that the oculomotor system is functionally obligated to fixate a gaze to a pointing target only to the extent that successful completion of a pointing task is ensured by the actual completion or by a predictive assessment of pointing termination. PMID- 20967539 TI - Caffey disease. PMID- 20967538 TI - Two forms of touch perception in the human brain. AB - We compared the judgment of distance between two simultaneous tactile stimuli applied to different body parts, with judgment of intensity of skin contact of the very same stimulation. Results on normal subjects showed that both tasks bilaterally activate parietal and frontal areas. However, the evaluation of distances on the body surface selectively activated the angular gyrus and the temporo-parieto-occipital junction in the right hemisphere. The different involvement of the brain areas in the two tactile tasks is interpreted as the need for using a Mental Body Representation (MBR) in the distance task, while the judgment of the intensity of skin deflection can be performed without the mediation of the MBR. The present study suggests that the cognitive processes underlying the two tasks are supported by partially different brain networks. In particular, our results show that metric spatial evaluation is lateralized to the right hemisphere. PMID- 20967540 TI - Hepatobiliary and pancreatic imaging in children-techniques and an overview of non-neoplastic disease entities. AB - Imaging plays a major role in the diagnostic work-up of children with hepatobiliary or pancreatic diseases. It consists mainly of US, CT and MRI, with US and MRI being the preferred imaging modalities because of the lack of ionizing radiation. In this review the technique of US, CT and MRI in children will be addressed, followed by a comprehensive overview of the imaging characteristics of several hepatobiliary and pancreatic disease entities most common in the paediatric age group. PMID- 20967541 TI - The positive color Doppler sign post biopsy: effectiveness of US-directed compression in achieving hemostasis. AB - BACKGROUND: Percutaneous biopsies of soft-tissue organs are frequently performed using US guidance. US permits visualization of blood flow on color Doppler imaging. OBJECTIVE: To report the presence of color Doppler signal (positive color Doppler sign) along the biopsy tract after percutaneous needle biopsy of the liver and kidney as an indication of bleeding and to describe US-guided hemostasis. MATERIALS AND METHODS: A case-control study of US-guided liver and kidney biopsies performed between January 2005 and September 2009 was undertaken. All pediatric patients with a positive color Doppler sign along the biopsy tract were included. Controls consisted of patients in whom no color Doppler sign was identified. RESULTS: Fifty-three cases with positive color Doppler sign were identified. One hundred and six matched controls were selected. The average compression time was 9.2 min in kidney and 8.4 min in liver cases. US-guided compression achieved cessation of the positive color Doppler sign in all cases. There was no significant difference between the mean pre- and post-procedure hemoglobin and platelet levels between kidney cases and controls (P=0.68 and P=0.63, respectively) and between liver cases and controls (P=0.45 and P=0.80). CONCLUSION: Color Doppler US can detect bleeding post percutaneous liver and kidney biopsies. US-guided compression is effective in obliterating the color Doppler signal and achieving appropriate hemostasis. PMID- 20967543 TI - Comment on Memisoglu et al.: Does the technique of lateral cross-wiring (Dorgan's technique) reduce iatrogenic ulnar nerve injury? PMID- 20967542 TI - Isoforms of the nonclassical class I MHC antigen H2-Q5 are enriched in brain and encode Qdm peptide. AB - Although the human nonclassical class Ib major histocompatibility complex (Mhc) locus, HLA-G, is known to act as an immune suppressor in immune-privileged sites, little is currently known regarding participation of the rodent class Ib Mhc in similar pathways. Here, we investigated the expression properties of the mouse nonclassical Mhc H2-Q5(k) gene, previously detected in tumors and tissues associated with pregnancy. We find that H2-Q5(k) is alternatively spliced into multiple novel isoforms in a wide panel of C3H tissues. Unlike other known class I MHC, it is most highly transcribed in the brain, where the classical class Ia Mhc products are scarce. The truncated isoforms are selectively enriched in sites of immune privilege and are translated into cell surface proteins in neural crest derived transfected cells. Furthermore, we present data supporting a model whereby Q5(k) isoforms serve an immune-protective role by donating their Qdm leader peptide to Qa-1, in a pathway homologous to the HLA-G leader fragment binding HLA-E and inhibiting CD94/NKG2A-positive cytotoxic cells. In addition, we report a previously unknown homolog of H2-Q5(k) in the C57BL/6 mouse, which encodes Qdm, but is transcribed solely into noncanonical isoforms. Collectively, these studies demonstrate that H2-Q5(k), and its homologous class I-like H2(b) gene may play tissue-specific roles in regulating immune surveillance. PMID- 20967544 TI - Is there any impact of plasma M30 and M65 levels on progression-free survival of patients with advanced gastric cancer? AB - PURPOSE: M30 and M65 are different circulating fragments of cytokeratin 18. They release during apoptotic cell death, so it is believed that they reflect cell death of epithelial tumors. The aim of this study was to determine the prognostic value of plasma M30 and M65 levels in predicting of survival for patients with advanced gastric cancer compare with healthy controls. METHODS: Thirty-four patients with advanced gastric cancer and thirty-two healthy controls were included. Plasma M30 and M65 values were measured by quantitative ELISA method. RESULTS: The median age of patients and control groups was 60 and 56 years, respectively. No difference was detected between patient and control groups with respect to plasma median M30 values (390.4 vs. 270.7 U/l, respectively, P = 0.10). The median plasma M65 values of patients were significantly higher than those of control group (1232.1 vs. 580.1 U/l, P < 0.001). The best cut-off values for plasma M30 and M65 for predicting progression-free survival (PFS) were 277.7 and 1434.9 U/l in ROC analysis. The patients whose plasma M30 values were higher than 277.7 U/l had worse PFS than patients with plasma M30 value <277.7 U/l (8.9 vs. 11.2, respectively, P = 0.01). The median PFS of patients whose M65 levels lower than or equal to 1434.9 U/l was better than that of patients whose M65 levels were >1434.9 U/l (12.4 vs. 10.4, respectively, P = 0.04). But plasma M30 and M65 level in patient group were not found to be an important prognostic factor for PFS in the multivariate analysis. CONCLUSIONS: These results showed that plasma M65 values were significantly elevated in patients with advanced gastric cancer compared to healthy people. Moreover, both increased plasma M30 and M65 levels can predict PFS in patients with gastric cancer. PMID- 20967545 TI - A novel locus on proximal chromosome 18 associated with agenesis of the corpus callosum in mice. AB - Agenesis of the corpus callosum (ACC) is a congenital abnormality of the brain structure. We have produced transgenic mice expressing both reverse tetracycline controlled transactivator (rtTA) and transcriptional silencer (tTS) ubiquitously. Although the transgene products do not affect development of the mouse brain, one of the founder lines, TAS, showed ACC, suggesting transgenic disruption of endogenous gene(s). To identify the causative gene and its role in ACC, we performed pathological investigations of the brain and chromosomal mapping of foreign genes in TAS mice. Sixty-two percent of the heterozygous TAS mice showed ACC accompanied with formation of Probst bundles, as seen in human. Complete penetrance of ACC was observed in homozygous TAS mice. Furthermore, homozygous TAS fetuses revealed that ACC is a congenital anomaly. Moreover, axons of the corpus callosum were not repelled by the midline glial structures in TAS mice. These findings suggested that the causative gene for ACC is involved in critical steps in corpus callosum development. Multiple FISH analyses were performed to determine the site of transgene insertion. On 1-color FISH analyses, rtTA and tTS were detected on the A/B region of chromosome 18, suggesting cointegration of the transgenes. On 2-color FISH analyses, tTS signal was observed in a region from 9.3 to 16.9 Mb on chromosome 18. The TAS mice may serve as a useful model to identify a novel gene regulating corpus callosum development and to gain a new insight into molecular genetics of ACC. PMID- 20967546 TI - Effects of a surface matching articular resurfacing device on tibiofemoral contact pressure: results from continuous dynamic flexion-extension cycles. AB - INTRODUCTION: The application of a defect-size metal implant for the treatment of focal articular cartilage lesions of the femoral condyle is of potential concern resulting in cartilage damage to opposing biological structures. This in vitro study aims to determine the tibiofemoral contact pressure with a contoured articular partial femoral resurfacing device under continuous dynamic pressure loads. METHODS: Peak and area contact pressures were determined in eight fresh frozen cadaveric specimens using a pressure-sensitive sensor placed in the medial compartment above the menisci. All knees were tested in the untreated condition and after implantation of the prosthetic device in the weight-bearing area of the medial femoral condyle. A robotic knee simulator was used to test each knee under continuous pressure load for 400 s during 40 dynamic knee bending cycles (5 degrees -45 degrees flexion) with body weight ground reaction force (GRF). The GRF was adjusted to the living body weight of the cadaver donor and maintained throughout all cycles. RESULTS: Comparison of the untreated condition to focal inlay resurfacing showed no statistically significant differences (P <= 0.05) between all testing conditions. The average maximum peak contact pressure across all 40 flexion cycles increased by 5.1% after resurfacing compared to the untreated knees. The average area contact pressure essentially stayed the same (+0.9%). CONCLUSION: The data suggest that resurfacing with the contoured articular prosthetic device does not pose any immediate deleterious effects to the opposing surfaces based on peak and area contact pressure in a continuous dynamic in vitro application. However, long-term in vivo effects remain to be evaluated. PMID- 20967547 TI - How to evaluate the quality of fracture reduction and fixation of the wrist and ankle in clinical practice: a Delphi consensus. AB - METHOD: A Delphi study was conducted to obtain consensus on the most important criteria for the radiological evaluation of the reduction and fixation of the wrist and ankle. The Delphi study consisted of a bipartite online questionnaire, focusing on the interpretation of radiographs and CT scans of the wrist and the ankle. Questions addressed imaging techniques, aspects of the anatomy and fracture reduction and fixation. Agreement was expressed as the percentage of respondents with similar answers. Consensus was defined as an agreement of at least 90%. RESULTS: In three Delphi rounds, respectively, 64, 74 and 62 specialists, consisting of radiologists, trauma and orthopaedic surgeons from the Netherlands responded. After three Delphi rounds, consensus was reached for three out of 14 (21%) imaging techniques proposed, 11 out of the 13 (85%) anatomical aspects and 13 of the 22 (59%) items for the fracture reduction and fixation. This Delphi consensus differs from existing scoring protocols in terms of the greater number of anatomical aspects and aspects of fracture fixation requiring evaluation and is more suitable in clinical practice due to a lower emphasis on measurements. PMID- 20967548 TI - Treatment of distal clavicle fracture: a systematic review of treatment modalities in 425 fractures. AB - The Neer type II distal clavicle fracture is notorious for its high nonunion rate, and surgical treatment is usually recommended. We reviewed articles from January 1990 to September 2009, and among them, 425 cases from 21 studies were included. According to the 425 cases in the literature, sixty patients were treated nonsurgically and 365 surgically. From 365 patients who were treated surgically, 105 were identified as receiving the coracoclavicular stabilization, 162 hook plate, 42 intramedullary fixation, 16 interfragmentary fixation, and 40 K-wire plus tension band wiring. The nonsurgical treatment resulted in 20 (33.3%) nonunions and 4 (6.7%) other complications. The surgical treatment resulted in 6 (1.6%) nonunions, 81 (22.2%) complications other than nonunion. The nonunion rate was significantly high with nonsurgical treatment (p < 0.001), and the complication rate was statistically high with surgery (p = 0.002). With surgical treatment, the nonunion rate was not significantly different among the modalities (p = 0.391). The complication rate was significantly higher in cases of the hook plate (40.7%) and the K-wire plus tension band wiring (20.0%) than those of the coracoclavicular stabilization (4.8%), the intramedullary (2.4%) and the interfragmentary fixation (6.3%). For the nonsurgical treatment, the functional outcomes were generally acceptable despite the high nonunion rate. The nonsurgical treatment could be considered as the first line treatment after sufficient counsel with the patient. The nonunion rate is high, however, the functional outcome is acceptable in most of the cases with nonunion. If the surgical treatment is considered, the intramedullary screw fixation, CC stabilization and interfragmentary fixation would be preferred because of their low complication rate. PMID- 20967550 TI - Fasciculations and cramps: how benign? Report of four cases progressing to ALS. AB - Clinical diagnosis of amyotrophic lateral sclerosis (ALS) in patients presenting with cramps and fasciculations may not be evident at the first consultation. Sequential reviews, clinical and neurophysiological, form an important part of clinical practice in such cases. Recent attempts to delineate a more benign group with cramps and fasciculations have lacked information on the long term profile, both clinical and neurophysiological. Four patients who were initially diagnosed as suffering from benign cramps and fasciculations, but who subsequently progressed to ALS, are described. We propose that a diagnosis of benign cramps and fasciculations should not be considered secure without a minimum follow up of 4-5 years. PMID- 20967551 TI - Osteopontin predicts long-term functional outcome among ischemic stroke patients. AB - Osteopontin (OPN) is a multifunctional protein which has shown neuroprotective properties in animal models of cerebral ischemia. Nevertheless, its role in acute human stroke has not yet been established. Therefore, we aimed to determine human serum OPN level during acute ischemic stroke and its relationship with patient outcome. We measured OPN levels in 178 consecutive patients with a middle cerebral artery (MCA) occlusion who received fibrinolytic therapy and in 40 control subjects. OPN level was determined by an enzyme-linked immunosorbent assay (ELISA). Bad functional outcome was defined by modified Rankin Scale (mRS) score >2 at 3 months after stroke onset. A logistic regression analysis was performed to determine factors that could be independently associated with poor prognosis. OPN levels among stroke patients did not differ from the controls' OPN levels (16.65 vs. 17.83 ng/mL, p = 0.404). Interestingly, OPN level was increased among those patients who showed worse prognosis at 3 months (19.96 vs. 15.48 ng/mL, p = 0.040). In a logistic regression model, an OPN level >27.22 ng/mL was found to be an independent factor for a bad outcome (OR 5.01, 95% CI 1.60-15.72, p = 0.006) after adjusting for potential confounders. Those patients showing higher OPN levels before tPA administration displayed a worse prognosis compared to those with lower OPN levels. Further research is necessary to elucidate the role of OPN in ischemic stroke pathophysiology and validate OPN as a useful tool to predict long-term stroke outcome. PMID- 20967552 TI - Oncomodulation by human cytomegalovirus: novel clinical findings open new roads. AB - The question whether human cytomegalovirus may affect cancer diseases has been discussed (very controversially) for decades. There are convinced believers and strict opponents of the idea that HCMV might be able to play a role in the course of cancer diseases. In parallel, the number of published reports on the topic is growing. Recently published and presented (Ranganathan P, Clark P, Kuo JS, Salamat S, Kalejta RF. A Survey of Human Cytomegalovirus Genomic Loci Present in Glioblastoma Multiforme Tissue Samples. 35th Annual International Herpes Workshop, Salt Lake City, 2010) data on HCMV detection in glioblastoma tissues and colocalisation of HCMV proteins with cellular proteins known to be relevant for glioblastoma progression motivated us to recapitulate the current state of evidence. PMID- 20967553 TI - Intradialytic hypotension. AB - Intradialytic hypotension (IDH) is common in children during conventional, 4 hour haemodialysis (HD) sessions. The declining blood pressure (BP) was originally believed to be caused by ultrafiltration (UF) and priming of the HD circuit, however emerging data now supports a multifactorial aetiology. Therefore strategies to improve haemodynamic stability need to be diverse and address specific patient requirements or risks. In the treatment of IDH immediate action is required to stop or reduce the severity of symptoms that may precede or follow. Typically UF is slowed or stopped, a fluid bolus is given and in resistant cases the HD session is prematurely discontinued. Patients complete their treatment under-dialysed and volume expanded. Chronically, repeated episodes of IDH cause devastating, multi-system morbidity with an increased risk of mortality. This had provided the impetus for more haemodynamically friendly dialysis prescriptions that attenuate the risk of IDH. During pediatric HD several preventative strategies have been tested but with variable success. Of these, dialysate sodium profiling, UF guided by relative blood volume (RBV) algorithms, cooling and intradialytic mannitol appear to be the most effective. However in refractory cases one may be left with no option but to switch dialysis modality to haemodiafiltration (HDF) or more frequent or prolonged HD regimens. PMID- 20967554 TI - Older women, breast cancer, and social support. AB - INTRODUCTION: One in ten women over the age of 65 will develop breast cancer. Despite this high incidence of breast cancer among older women, social support for them is often inadequate. This paper describes a qualitative study of the impact of a breast cancer diagnosis on older women from racially/ethnically diverse populations and their subsequent need for social support. METHODS: Forty seven older African American, Asian American, Caucasian and Latina women between the ages of 65 to 83 participated in a larger study examining the impact of breast cancer on women from racially/ethnically diverse populations and the meaning and nature of social support. The women completed an in-depth qualitative interview on the psychosocial impact of breast cancer and the meaning and nature of social support. RESULTS AND CONCLUSION: The results indicate that there are variations in reactions to a breast cancer diagnosis among older women, and that these reactions impact their experiences with seeking social support at diagnosis and during treatment. Respondents were concerned about their aging bodies, potential dependency on others, and loss of autonomy. At the same time, the severity of cancer treatment and existing co-morbidities often meant they needed to learn to receive support, and to reach out if they had no support. The implications of these findings underscore the older cancer patient's need to strengthen her supportive networks at the time of diagnosis, during treatment, and post-treatment. PMID- 20967555 TI - Cost and effectiveness of reduced-intensity and conventional allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome. AB - GOALS OF WORK: Allogeneic stem cell transplantation with a reduced-intensity regimen (RIST) has been evaluated mostly in terms of its clinical benefit, and the pharmacoeconomic aspects of this procedure remain unclear. We compared the cost and effectiveness of RIST with those of stem cell transplantation using a conventional myeloablative regimen (CST). PATIENTS AND METHODS: Fifty consecutive patients who underwent transplantation for myeloid malignancy were included. Life years and medical costs during the entire treatment course for up to 2 years after transplantation were evaluated, and cost-effectiveness was assessed from the payer's perspective. MAIN RESULTS: Of these 50 cases, 35 were treated with CST and 15 were treated with RIST. The mean survival time was 1.5 years in CST and 1.2 years in RIST, while the mean total cost per patient within the first 2 years was $29,630 for CST and $29,466 for RIST, with no significant difference. The duration of total hospitalization was shorter in RIST than in CST; then, the cost for hospitalization represented a lower proportion of the total cost in RIST (49% of total cost) than in CST (63%). In contrast, the cost related to the conditioning regimen was significantly higher in RIST than in CST. CONCLUSIONS: This result suggests that the increased cost of the conditioning regimen offsets the reduced cost of hospitalization in RIST. Although some differences were observed in the details of the cost, the total cost and mean survival were comparable between CST and RIST, and this result was confirmed by a probabilistic sensitivity analysis. PMID- 20967556 TI - Alcohol drinking patterns and the risk of fatty liver in Japanese men. AB - BACKGROUND: Alcohol is considered to be a major cause of fatty liver (FL). In contrast, however, recent investigations have suggested that moderate alcohol consumption is protective against FL. To clarify the role of alcohol consumption in FL development, we examined the association between drinking patterns and FL prevalence. METHODS: We enrolled 9,886 male participants at regular medical health checks. Each subject's history of alcohol consumption was determined by questionnaire. The subjects were classified according to alcohol consumption as non-, light, moderate, and heavy drinkers (0, <20, 20-59, and >=60 g/day, respectively). FL was defined by ultrasonography. Independent predictors of FL were determined by logistic regression analysis. RESULTS: The prevalence of FL displayed a "U-shaped curve" across the categories of daily alcohol consumption (non-, 44.7%; light, 39.3%; moderate, 35.9%; heavy drinkers, 40.1%; P < 0.001). The prevalence of FL was associated positively with body mass index and other obesity-related diseases and inversely with alcohol consumption (light, odds ratio [OR] 0.71, 95% confidence interval [CI] 0.59-0.86; moderate, OR 0.55, CI 0.45-0.67; heavy, OR 0.44, CI 0.32-0.62) as determined by multivariate analysis after adjusting for potential confounding variables. In addition, examination of drinking patterns (frequency and volume) revealed that the prevalence of FL was inversely associated with the frequency of alcohol consumption (>=21 days/month) (OR 0.62, CI 0.53-0.71) but not with the volume of alcohol consumed. CONCLUSIONS: Our observations suggest that alcohol consumption plays a protective role against FL in men, and consistent alcohol consumption may contribute to this favorable effect. PMID- 20967558 TI - Enzymatic repair of Amadori products. AB - Protein deglycation, a new form of protein repair, involves several enzymes. Fructosamine-3-kinase (FN3K), an enzyme found in mammals and birds, phosphorylates fructosamines on the third carbon of their sugar moiety, making them unstable and causing them to detach from proteins. This enzyme acts particularly well on fructose-epsilon-lysine, both in free form and in the accessible regions of proteins. Mice deficient in FN3K accumulate protein-bound fructosamines and free fructoselysine, indicating that the deglycation mechanism initiated by FN3K is operative in vivo. Mammals and birds also have an enzyme designated 'FN3K-related protein' (FN3KRP), which shares ~ 65% sequence identity with FN3K. Unlike FN3K, FN3KRP does not phosphorylate fructosamines, but acts on ribulosamines and erythrulosamines. As with FN3K, the third carbon is phosphorylated and this leads to destabilization of the ketoamines. Experiments with intact erythrocytes indicate that FN3KRP is also a protein-repair enzyme. Its physiological substrates are most likely formed from ribose 5-phosphate and erythrose 4-phosphate, which give rise to ketoamine 5- or 4-phosphates. The latter are dephosphorylated by 'low-molecular-weight protein-tyrosine-phosphatase A' (LMW-PTP-A) before FN3KRP transfers a phosphate on the third carbon. The specificity of FN3K homologues present in plants and bacteria is similar to that of mammalian FN3KRP, suggesting that deglycation of ribulosamines and/or erythrulosamines is an ancient mechanism. Mammalian cells contain also a phosphatase acting on fructosamine 6-phosphates, which result from the reaction of proteins with glucose 6-phosphate. PMID- 20967557 TI - Changes in gastric mucosal patterns seen by magnifying NBI during H. pylori eradication. AB - BACKGROUND: Magnifying narrow-band imaging (NBI) endoscopy visualizes superficial gastric mucosal and capillary patterns. We aimed to investigate changes in gastric mucosal patterns seen by magnifying NBI endoscopy after Helicobacter pylori eradication. METHODS: Gastric mucosal patterns in non-pathological gastric corpus were observed by magnifying NBI endoscopy before and 12 weeks after H. pylori eradication in thirty patients. By using paired photographs of each case, changes in NBI mucosal patterns during H. pylori eradication were judged in a consensus manner by three blinded endoscopists. RESULTS: At 12 weeks after H. pylori eradication, 20 of 24 subjects who had been successfully treated showed remarkable changes in gastric mucosal patterns (sensitivity 83.3%, specificity 100%). In the specimens from these subjects, the patterns of enlarged or elongated pits were improved to small oval or pinhole-like round pits, and the density of fine irregular vessels was decreased. Histological assessment showed alleviation of chronic inflammation in all subjects (p < 0.0001), while such a change was not observed for four subjects showing severe gastric atrophy and intestinal metaplasia. When the subjects were divided according to the presence of severe gastric atrophy, the diagnostic efficacy of magnifying NBI for predicting the results of H. pylori eradication was excellent in subjects without severe gastric atrophy and intestinal metaplasia (sensitivity and specificity, 100%). However, no change in the NBI mucosal pattern was observed in subjects with severe gastric atrophy and intestinal metaplasia, regardless of the H. pylori eradication result. CONCLUSIONS: At least in subjects without severe gastric atrophy or intestinal metaplasia, successful H. pylori eradication treatment shows improvements in gastric mucosal patterns with the use of magnifying NBI endoscopy early after successful treatment. PMID- 20967559 TI - Triostin A derived hybrid for simultaneous DNA binding and metal coordination. AB - The natural product triostin A is known as an antibiotic based on specific DNA recognition. Structurally, a bicyclic depsipeptide backbone provides a well defined scaffold preorganizing the recognition motifs for bisintercalation. Replacing the intercalating quinoxaline moieties of triostin A by nucleobases results in a potential major groove binder. The functionalization of this DNA binding triostin A analog with a metal binding ligand system is reported, thereby generating a hybrid molecule with DNA binding and metal coordinating capability. Transition metal ions can be placed in close proximity to dsDNA by means of non covalent interactions. The synthesis of the nucleobase-modified triostin A analog is described containing a propargylglycine for later attachment of the ligand by click-chemistry. As ligand, two [1,4,7]triazacyclononane rings were bridged by a phenol. Formation of the proposed binuclear zinc complex was confirmed for the ligand and the triostin A analog/ligand construct by high-resolution mass spectrometry. The complex as well as the respective hybrid led to stabilization of dsDNA, thus implying that metal complexation and DNA binding are independent processes. PMID- 20967560 TI - Angioedema triggered by pulp extirpation--a case report. AB - BACKGROUND: C1-esterase inhibitor deficiency results in episodes of non-allergic edema of parts of the body. Edema of the face may be triggered by dental therapy. CASE REPORT: We report a case of C1-esterase inhibitor deficiency which was detected in a 42-year-old woman. The patient was completely unaware that she had this disorder or of any related family history, and the patient developed an intense facial angioedema after pulp extirpation of lower premolar tooth. DISCUSSION: In this case, the diagnosis of angioedema due to C1-esterase inhibitor deficiency was established at a later stage. The differing causes of C1 esterase inhibitor deficiency are briefly discussed and the treatment modalities outlined. PMID- 20967561 TI - The effect of a selective octopamine antagonist, epinastine, on pharyngeal pumping in Caenorhabditis elegans. AB - This paper investigates the effect of epinastine, a selective octopamine antagonist in invertebrates, in Caenorhabditis elegans. Specifically, its ability to block the inhibitory action of octopamine on C. elegans-isolated pharynx was assayed. Isolated pharynxes were stimulated to pump by the addition of 500 nM 5 hydroxytryptamine (5-HT) (113 +/- 2 per 30 s, n = 15). Octopamine inhibited the 5 HT-induced pumping in a concentration-dependent manner (threshold 1-5 MUM) with a 61 +/- 11% inhibition with 50 MUM (n = 5). Epinastine (0.1 MUM) antagonized the inhibitory response to octopamine (P < 0.001; n = 15). Tyramine also inhibited pharyngeal pumping induced by 5-HT but was less potent than octopamine. Tyramine, 50 MUM to 1 mM, gave a transient inhibition e.g. of 40 +/- 5% at 50 MUM (n = 5). A higher (10 MUM) concentration of epinastine was required to block the tryamine response compared with octopamine. It is concluded that epinastine selectively antagonizes the effect of octopamine on C. elegans pharynx. Further studies are required to test its selectivity for octopamine in other tissues and other nematodes. PMID- 20967562 TI - Signalling pathways involved in ribonuclease-7 expression. AB - Antimicrobial peptides are host defence molecules that play a potential role in preventing infection at the epithelial surfaces. Ribonuclease (RNase)-7 has been shown to possess a broad spectrum of microbicidal activity against various pathogens. Here, we demonstrate that RNase-7 protein is localised to the superficial layers of ocular surface cells and increased in response to interleukin (IL)-1beta, suggesting an active role during inflammation related to ocular surface infection. Signal transduction pathways involved in RNase-7 expression are unknown. Involvement of transforming growth factor beta-activated kinase-1 (TAK-1) activated nuclear factor kappa B (NF-kappaB) and mitogen activated protein kinase (MAPK) pathway molecules [c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38] were studied because of their importance in infection and inflammation. Blocking the MAPKs resulted in inhibition of RNase-7 expression in response to IL-1beta. However, RNase-7 induction by IL-1beta was not affected by inhibiting the NF-kappaB signalling pathway. In conclusion, our results indicate that RNase-7 expression is specifically mediated via MAPKs but not NF-kappaB signalling pathways. PMID- 20967564 TI - The expression of TGF-beta3 for epithelial-mesenchyme transdifferentiated MEE in palatogenesis. AB - The fate of the palatal medial edge epithelial (MEE) cells undergoes programming cell death, migration, and epithelial-mesenchymal transdifferentiation (EMT) coincident with the process of palatal fusion and disappearance of MEE. Mesenchymal cells in the palate have both cranial neural crest (CNC) and non-CNC origins. The objectives of this study were to identify the populations of palatal mesenchymal cells using beta-galactosidase (beta-gal) and DiI cell lineage markers, and to determine whether MEE-derived cells continued to express transforming growth factor-beta3 (TGF-beta3) and transforming growth factor-beta type III receptor (TbetaR-III), which were specific for MEE. A model has been developed using Wnt1 tissue specific expression of Cre-recombinase to activate beta-gal solely in the CNC. The expressions of TGF-beta3 and TbetaR-III in MEE were temporally correlated with critical events in palatogenesis. Three cell populations could be distinguished in the palatal mesenchymal CNC-derived, non CNC derived and MEE-derived. After fusion, beta-gal- and DiI+ mesenchymal cells continued to express TGF-beta3, however TbetaR-III was expressed only in the epithelial MEE, as well as keratin expression. In addition, we performed laser capture microdissection to identify mRNA expression of isolated DiI+ MEE cells. Both epithelial and transdifferentiated MEE have expressed TGF-beta3, however, TbetaR-III was only expressed in epithelium. Extracellular matrix, especially MMP13 has been expressed coincident with fused stage which can be strongly associated with TGF-beta3. These results demonstrate that combining a heritable marker and a cell lineage dye can distinguish different populations of mesenchymal cells in the developing palate. Furthermore, TGF-beta3 and MMP13 could be strongly associated with EMT in palatogenesis. PMID- 20967565 TI - The role of epidermal growth factor in the healing tympanic membrane following perforation in rats. AB - Epidermal Growth Factor (EGF) has been identified as playing a critical role in the wound healing process. The objective of this study is to investigate the role that EGF plays in rat tympanic membrane (TM) wound healing using two techniques, microarray and immunohistochemistry. The tympanic membranes of rats were perforated using a sterile needle and sacrificed at time points during 2 weeks following perforation. The normalized signal intensities at the time points for EGF and associated genes are presented. The rat EGF mRNA did not change significantly between time points. Five associated proteins, including heparin binding EGF-like growth factor were found to be differentially expressed above a two fold threshold at 12 h following perforation. EGF staining was found at low levels in the uninjured TM. Levels of EGF staining increased at 24 h in the basal keratinocyte layer, became diffusely elevated in the specimen at 36 h, before a second peak in staining of the keratinocyte layer at Day 4. The staining of EGF corresponds to its multiple roles in TM wound healing. PMID- 20967566 TI - Aggression, digit ratio and variation in androgen receptor and monoamine oxidase a genes in men. AB - Variation in prenatal exposure to androgens is thought to be responsible for some of the individual differences in aggressive behavior among adults. A putative indicator of prenatal testosterone exposure, 2D:4D (the index to ring finger length) ratios have shown a weak correlation with aggression. Variation in sensitivity of the androgen receptor, resulting from polymorphism in the AR gene, is also thought to influence the relative expression of sexually dimorphic traits within each sex, including aggressive behavior and 2D:4D. Here we examine variation in aggression, 2D:4D, and polymorphism in the AR and MAO-A genes in a sample of 188 men. We find no evidence of AR gene influence on right hand 2D:4D, and a weak trend towards more feminine-typical left hand 2D:4D in men with more sensitive androgen receptors. Men with more sensitive androgen receptors tended to score lower on many of the subscales of the Aggression Questionnaire and Indirect Aggression Questionnaire. We found no influence of MAO-A allele on either digit ratio or aggressive behavior. We conclude that more masculine typical 2D:4D does not reflect greater sensitivity to testosterone through variation in this locus on the AR gene, and that AR alleles conferring greater sensitivity to testosterone are associated with lower, not higher propensity to aggression. PMID- 20967563 TI - The Generation R Study: design and cohort update 2010. AB - The Generation R Study is a population-based prospective cohort study from fetal life until young adulthood. The study is designed to identify early environmental and genetic causes of normal and abnormal growth, development and health during fetal life, childhood and adulthood. The study focuses on four primary areas of research: (1) growth and physical development; (2) behavioural and cognitive development; (3) diseases in childhood; and (4) health and healthcare for pregnant women and children. In total, 9,778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. General follow-up rates until the age of 4 years exceed 75%. Data collection in mothers, fathers and preschool children included questionnaires, detailed physical and ultrasound examinations, behavioural observations, and biological samples. A genome wide association screen is available in the participating children. Regular detailed hands on assessment are performed from the age of 5 years onwards. Eventually, results forthcoming from the Generation R Study have to contribute to the development of strategies for optimizing health and healthcare for pregnant women and children. PMID- 20967567 TI - Risk assessment of the introduction of Rift Valley fever from the Horn of Africa to Yemen via legal trade of small ruminants. AB - Rift Valley fever (RVF) is a mosquito-borne viral zoonosis of increasing global importance. Occurring since 1930 across Africa, it was detected for the first time in Saudi Arabia and Yemen in September 2000, leading to human deaths and major losses in livestock populations. Assuming the virus has not survived in Yemen or has been circulating at a low level, authors qualitatively assessed the likelihood of "re-introduction" of RVF into Yemen through the legal importation of small ruminants from the Horn of Africa. The overall probability of introduction was assessed very low to medium, increasing during festival periods and higher when considering a direct transmission exposure as compared to a vectorial transmission exposure. The uncertainty was considered to be medium underlining important gaps in information that need to be fulfilled in the region. Options to reduce the risk are proposed and discussed, including possible improvements of the current Yemeni quarantine system. PMID- 20967568 TI - Tick loads in cattle raised on sweet and sour rangelands in the low-input farming areas of South Africa. AB - The objective of this study was to compare tick loads and prevalence in Nguni and non-descript cattle in the sweet (palatable throughout the year) and sour (palatable only in the rainy season) communal rangelands of the Eastern Cape Province, South Africa. Engorged adult female ixodid ticks were collected and identified seasonally from 144 cattle raised on sweet and sour rangelands from August 2007 to April 2008. Three tick species were identified in the sweet and sour rangelands namely Rhipicephalus appendiculatus, Rhipicephalus (Boophilus) decoloratus, and Rhipicephalus evertsi evertsi with prevalences of 71.1%, 29.2%, and 40.2%, respectively. Hyalomma species (19.0%) occurred only in the sour rangeland. Higher tick counts were recorded in the hot-wet season than in the cool-dry season (P < 0.05). Cattle in the sweet rangeland had significantly lower tick loads than those in the sour rangeland in all the seasons except the hot-dry season. The Nguni breed had lower (P < 0.05) tick loads of R. appendiculatus in the hot-wet and post-rainy season and Hyalomma species in all seasons than the non-descript cattle. The use of a tick-resistant Nguni breed in the integrated control of ticks on cattle in the communal areas of South Africa is recommended. PMID- 20967569 TI - The presence, characterization and prognosis of coronary plaques among patients with zero coronary calcium scores. AB - Patients with coronary artery calcium (CAC) scores of zero are generally considered not to have atherosclerosis. Recent studies involving computed tomography coronary angiography (CTCA) challenge this assumption. This goal of the present study is to assess the frequency, morphology, location, and the prognosis of patients with plaque detected on CTCA and zero CAC. 1,119 patients (51 +/- 12 years, 52% male) with a zero CAC score during CTCA study were retrospectively identified. The CTCA studies were assessed for the presence, morphology, location and severity of all coronary plaques. All-cause mortality was assessed. The prevalence of coronary plaque was 13% (147 patients). Among the 212 plaques identified 154 (73%) were non-calcified, 28 (13%) were calcified, and 30 (14%) were of mixed morphology. Notably, >=70% stenosis was noted among only 0.4% of all patients. ROC analysis revealed that coronary artery disease risk factors did not add to the prediction of plaque among our patients. Over a mean follow-up of 2.5 +/- 0.6 years there were 4 deaths (0.4%), all in patients without coronary plaque on CTCA. The presence of coronary plaque is not uncommon among patients with zero CAC scores. These plaques were rarely associated with hemodynamically significant stenoses and were associated with an excellent prognosis. Clinical factors do not appear to be useful in predicting which patients with zero CAC scores have undetected coronary plaque. PMID- 20967570 TI - Using a generic measure of quality of life in patients with obstructive sleep apnea. AB - PURPOSE: To evaluate the utility of a Multicultural Quality of Life Index (MQLI) in patients with Obstructive Sleep Apnea-Hypopnea (OSAH). METHODS: Physical examination, MQLI and the Epworth Sleepiness Scale (ESS) were applied to participants. In addition, a polysomnography or a respiratory polygraphy was carried out. RESULTS: A total of 221 patients participated, 186 (84%) males, mean age 48.8 +/- 11.8 years. The MQLI scores 7were .73 +/- 1.45 and the ESS 9.9 +/- 5.2. A total of 188 (85%) patients had OSAH: 40 (21%) mild, 43 (23%) moderate, and 105 (56%) severe. The average time to answer the MQLI was 3.5 min. Cronbach's alpha index was 0.930. MQLI score in patients with and without OSAH was 7.73 versus 7.75 (p = 0.949); and by severity: non-OSAH 7.75, mild 8.04, moderate 8.14, and severe 7.44 (p = 0.023). There was a slight correlation between MQLI score and Apnea-Hypopnea Index in total population, but it disappeared when we analyzed by severity. MQLI and ESS correlation was R = -0.3256 (p < 0.0001). CONCLUSIONS: The MQLI has limitations in identifying quality of life (QOL) alterations and a poor correlation with severity in OSAH patients. The MQLI quantifies QOL in a general way. We recommend supplementing the QOL evaluation with disease-specific instruments. PMID- 20967571 TI - Mandibular exercises improve mandibular advancement device therapy for obstructive sleep apnea. AB - RATIONALE: Temporomandibular disorder (TMD) has been the most common contraindication for mandibular advancement device (MAD) as a treatment for obstructive sleep apnea syndrome (OSAS). Exercising the mandible is a recommended form of therapy for TMD. OBJECTIVES: To assess the efficacy of mandibular exercises in the control of pain, changes of quality of life and to assess the impact of MAD compliance in OSAS patients with previously diagnosed TMD. METHODS: A blind, randomized, and controlled trial was used to evaluate 29 OSAS patients with TMDs were divided in two groups: the exercise support therapy (ST) and placebo therapy (PT), who were evaluated prior to and 120 days after MAD treatment. Treatment outcomes were measured using the Fletcher and Luckett sleep questionnaire, Epworth sleepiness scale, SF-36 inventory of quality of life, polysomnography, diary of MAD usage, and the research diagnostic criteria for TMD. MEASUREMENTS AND MAIN RESULTS: ST group showed significant improvement in their sleep quality and life quality when compared to the PT group (p < 0.05). Higher number of patients with persistent pain was observed in the PT group (p = 0.01). There was a reduction of pain intensity in the ST group, but not in the PT group (p < 0.05). Higher MAD compliance was observed in the ST group (p < 0.05). CONCLUSIONS: Mandibular exercises enable patients with TMD to use MAD; exercises were found to be effective in reducing pain and increasing MAD compliance and produced a significant improvement in the quality of life and quality of sleep. PMID- 20967573 TI - Non-functioning pancreatic neuroendocrine tumors--a case report and review of literature. AB - PURPOSE: Neuroendocrine tumors of pancreas (PNET) are rare pancreatic neoplasms comprising 1-2% of all pancreatic tumors. The overall prognosis and long-term survival for PNET patients is far better than for patients with exocrine pancreatic cancer. PNETs are classified as functional or nonfunctional based on the presence or absence of a specific clinical syndrome associated with hormone oversecretion. METHODS: We present the case of a 36-year-old female with epigastric and right upper quadrant abdominal pain for 3 months associated with decreased appetite, early satiety and a 20-lb weight loss. On examination, she was cachectic with hepatomegaly. RESULTS: Laboratory assays showed elevated liver and pancreatic enzymes. On computed tomography (CT) scan of the abdomen and pelvis, there was a low-attenuation mass in the distal pancreatic tail measuring 4.7 * 2.4 cm with multiple liver masses, omental implants, left ovarian mass, and a small amount of ascites. CT-guided liver biopsy on pathology was consistent with a well-differentiated pancreatic neuroendocrine carcinoma with metastasis to the liver. Assays for biomarkers of pancreatic neuroendocrine tumors showed an elevated chromogranin A with normal to non-specific elevations of the rest. CONCLUSIONS: The patient and her family declined palliative chemoembolization of the liver lesions or palliative chemotherapy and desired home hospice. We describe here the presentation and course of the case as well as a literature review of PNET with particular emphasis on nonfunctioning PNETs. PMID- 20967574 TI - Chemical shift assignments of a minimal Rna14p/Rna15p heterodimer from the yeast cleavage factor IA complex. AB - The two yeast proteins Rna14p and Rna15p form part of the cleavage/polyadenylation factor IA (CF IA) complex that is involved in the 3' processing of pre-mRNA. Association of the two proteins is mediated by a small C terminal peptide from Rna14p and a region in Rna15p that corresponds to the hinge domain first identified within the human orthologue. Here I report the (1)H, (13)C and (15)N spectral assignments for a bacterially co-expressed heterodimer of Rna14p/Rna15p. Further analysis of secondary chemical shifts reveals that both peptides are predominantly alpha-helical within the complex. PMID- 20967575 TI - Unilateral cerebellar hypoplasia with different clinical features. AB - Unilateral cerebellar hypoplasia (UCH) is a rare pathological condition characterized by the loss of volume in cerebellar hemispheres ranging from mild asymptomatic to severe symptomatic cases. As the designation of UCH remains problematic, the underlying etiopathogenesis also lacks explanation. We investigated the patients admitted to Departments of Child Neurology, Neurology, and Genetics between the years 1992 and 2010 and detected 12 patients with unilateral cerebellar volume loss, with the exclusion of all other cerebellar pathologies. The ages of patients ranged between 6 months to 55 years. Five patients had a delay in developmental milestones, and one of these was diagnosed with neurofibromatosis type 1. Two patients had epileptic seizures, one patient had peripheral facial paralysis as a component of Moebius syndrome, and four patients were incidentally diagnosed during etiological work-up for headache. The clinical outcomes of patients varied from healthy subjects to marked developmental impairment. Radiologically, five patients had severe disproportionate UCH, six had moderate disproportionate, and one had mild proportionate UCH. Cerebellar peduncles were affected in all, and vermis was partly hypoplastic in eight patients. Brainstem was involved in four patients, and seven patients showed involvement of white matter and/or corpus callosum. Imaging features supported that patients with severe disproportionate UCH also displayed additional cerebral and commissural changes, which were related to ischemic or vascular injuries, implying a prenatally acquired disruption. In the presence of such a wide spectrum of clinical and radiological features, a prenatally acquired lesion and, thus, a disruption seem to be more explanatory rather than a primary developmental process or malformation in the etiopathogenesis of unilateral cerebellar hypoplasia. PMID- 20967576 TI - Brain region-specific changes in oxidative stress and neurotrophin levels in autism spectrum disorders (ASD). AB - Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by social and language deficits, stereotypic behavior, and abnormalities in motor functions. The particular set of behavioral impairments expressed in any given individual is variable across the spectrum. These behavioral abnormalities are consistent with our current understanding of the neuropathology of ASD which suggests abnormalities in the amygdala, temporal and frontal cortexes, hippocampus, and cerebellum. However, regions unrelated to these behavioral deficits appear largely intact. Both genetic predisposition and environmental toxins and toxicants have been implicated in the etiology of autism; the impact of these environmental triggers is associated with increases in oxidative stress, and is further exacerbated when combined with genetic susceptibility. We have previously reported increased levels of 3-nitrotyrosine (3-NT), a marker of oxidative stress, in ASD cerebella. We have also shown that this increase was associated with an elevation in neurotrophin-3 (NT-3) levels. The objectives of the current study were to determine whether the increase in oxidative stress in ASD is brain region-specific, to identify the specific brain regions affected by oxidative stress, and to compare brain region-specific NT-3 expression between ASD and control cases. The levels of 3-NT and NT-3 were measured with specific ELISAs in individual brain regions of two autistic and age and postmortem interval (PMI)--matched control donors. In the control brain, the levels of 3-NT were uniformly low in all brain regions examined ranging from 1.6 to 12.0 pmol/g. On the other hand, there was a great variation in 3-NT levels between individual brain regions of the autistic brains ranging from 1.7 to 281.2 pmol/g. The particular brain regions with the increased 3-NT and the magnitude of the increase were both different in the two autistic cases. In the older autistic case, the brain regions with highest levels of 3-NT included the orbitofrontal cortex (214.5 pmol/g), Wernicke's area (171.7 pmol/g), cerebellar vermis (81.2 pmol/g), cerebellar hemisphere (37.2 pmol/g), and pons (13.6 pmol/g); these brain areas are associated with the speech processing, sensory and motor coordination, emotional and social behavior, and memory. Brain regions that showed 3-NT increase in both autistic cases included the cerebellar hemispheres and putamen. Consistent with our earlier report, we found an increase in NT-3 levels in the cerebellar hemisphere in both autistic cases. We also detected an increase in NT 3 level in the dorsolateral prefrontal cortex (BA46) in the older autistic case and in the Wernicke's area and cingulate gyrus in the younger case. These preliminary results reveal, for the first time, brain region-specific changes in oxidative stress marker 3-NT and neurotrophin-3 levels in ASD. PMID- 20967577 TI - Cerebellar zones: a personal history. AB - Cerebellar zones were there, of course, before anyone noticed them. Their history is that of young people, unhindered by preconceived ideas, who followed up their observations with available or new techniques. In the 1960s of the last century, the circumstances were fortunate because three groups, in Leiden, Lund, and Bristol, using different approaches, stumbled on the same zonal pattern in the cerebellum of the cat. In Leiden, the Haggqvist myelin stain divulged the compartments in the cerebellar white matter that channel the afferent and efferent connections of the zones. In Lund, the spino-olivocerebellar pathways activated from individual spinal funiculi revealed the zonal pattern. In Bristol, charting the axon reflex of olivocerebellar climbing fibers on the surface of the cerebellum resulted in a very similar zonal map. The history of the zones is one of accidents and purposeful pursuit. The technicians, librarians, animal caretakers, students, secretaries, and medical illustrators who made it possible remain unnamed, but their contributions certainly should be acknowledged. PMID- 20967578 TI - 1,2,5,6,9,10-alphaHexabromocyclododecane (HBCD) impairs thyroid hormone-induced dendrite arborization of Purkinje cells and suppresses thyroid hormone receptor mediated transcription. AB - 1,2,5,6,9,10-alphaHexabromocyclododecane (HBCD) is a nonaromatic, brominated cyclic alkane used as an additive flame retardant. It bioaccumulates, persists in the environment, and has been detected in humans and wildlife. Its developmental neurotoxicity is of great concern. We investigated the effect of HBCD on thyroid hormone (TH) receptor (TR)-mediated transcription using transient transfection based reporter gene assays and found that a low-dose (10(-10) M) HBCD suppressed TR-mediated transcription. We further examined the effect of HBCD on interaction of TR with TH response element (TRE) and found a partial dissociation of TR from TRE. HBCD did not dissociate steroid receptor coactivator-1 from TR in the presence of TH; neither did it recruit corepressors (N-CoR and SMRT) to TR in the absence of TH. Furthermore, low-dose HBCD (10(-10) M) significantly suppressed TH induced dendrite arborization of Purkinje cells in primary cerebellar culture derived from newborn rat. These results show that low-dose HBCD can potentially disrupt TR-mediated transactivation and impairs Purkinje cell dendritogenesis, suggesting that HBCD can interfere with TH action in target organs, including the developing brain. PMID- 20967579 TI - Contemporary approaches to Alzheimer's disease and frontotemporal dementia. AB - Alzheimer's disease and frontotemporal dementia are two of the most common neurodegenerative dementias. Here, we review the clinical presentation, genetic causes, typical neuropathology, and current treatments for these disorders. We then review molecules involved in their pathogenesis and protocols for working with these species and conclude with a discussion of experimental systems and outcome measures for studying these disorders. PMID- 20967580 TI - Preparing synthetic Abeta in different aggregation states. AB - This chapter outlines protocols that produce homogenous preparations of oligomeric and fibrillar amyloid-beta peptide (Abeta). While there are several isoforms of this peptide, the 42 amino acid form is the focus because of its genetic and pathological link to Alzheimer's disease (AD). Past decades of AD research highlight the dependence of Abeta42 function on its structural assembly state. Biochemical, cellular and in vivo studies of Abeta42 usually begin with purified peptide obtained by chemical synthesis or recombinant expression. The initial steps to solubilize and prepare these purified dry peptide stocks are critical to controlling the structural assembly of Abeta. To develop homogenous Abeta42 assemblies, we initially monomerize the peptide, erasing any "structural history" that could seed aggregation, by using a strong solvent. It is this starting material that has allowed us to define and optimize conditions that consistently produce homogenous solutions of soluble oligomeric and fibrillar Abeta42 assemblies. These preparations have been developed and characterized by using atomic force microscopy (AFM) to identify the structurally discrete species formed by Abeta42 under specific solution conditions. These preparations have been used extensively to demonstrate a variety of functional differences between oligomeric and fibrillar Abeta42. We also present a protocol for fluorescently labeling oligomeric Abeta42 that does not affect structure, as measured by AFM, or function, as measured by a cellular uptake assay. These reagents are critical experimental tools that allow for defining specific structure/function connections. PMID- 20967581 TI - Isolation of low-n amyloid beta-protein oligomers from cultured cells, CSF, and brain. AB - Recent data suggest that soluble, non-fibrillar assemblies of the amyloid beta protein (Abeta) may mediate the synaptic deficits that characterize the early stages of Alzheimer's disease. Consequently, much effort has been expended in isolating and studying a variety of different Abeta assemblies. Here, we describe the use of immunoprecipitation/western blotting and size exclusion chromatography/western blotting to characterize Abeta present in conditioned medium from cultured cells, human cerebrospinal fluid, and human cortex extracted with aqueous buffer, detergent, and formic acid. PMID- 20967582 TI - Detecting abeta*56 oligomers in brain tissues. AB - Since its original description in 1906 by Dr Alois Alzheimer, amyloid plaques and neurofibrillary tangles have remained the hypothetical cause of Alzheimer's disease. However, plaque burden poorly predicts cognitive status in humans, which led several groups to investigate the possibility that soluble species of amyloid beta (Abeta) peptides could be playing an important pathological function in the aging brain. Through a multistep fractionation protocol, we identified a 56 kDa oligomer of Abeta, termed Abeta*56, the amount of which correlates with cognitive impairment. Here, we describe our biochemical approach to isolate this oligomeric Abeta species in brain tissue of transgenic mouse models of AD. PMID- 20967583 TI - Assessing Abeta aggregation state by atomic force microscopy. AB - There has been a growing recognition of a wide variety of diseases commonly referred to as conformational diseases, which share the feature of specific disease-related proteins adopting nonnative conformation that promote their ordered aggregation and deposition on surfaces. Due to the nanoscale dimensions and the varied morphology of such aggregates, atomic force microscopy (AFM) has emerged as an ideal tool for distinguishing structural features of the numerous potential aggregate forms, ranging from small globular oligomers to large mature amyloid fibrils. Beyond the ability to morphologically distinguish aggregate forms, AFM also can dynamically track the aggregation process due to its unique ability to be operated not only in air (ex situ), but also in solution (in situ). This feature provides for tracking the fate of individual aggregates over time. This chapter describes the use of AFM in characterizing the aggregation of the amyloid-beta peptide (Abeta), which is hypothesized to play a key role in Alzheimer's disease (AD), a late-onset neurodegenerative conformational disease. PMID- 20967584 TI - Measuring APP carboxy-terminal fragments. AB - The accumulation of the amyloid-beta (Abeta) peptide in the form of insoluble fibrillar deposits and soluble oligomeric aggregates is widely believed to play a causal role in Alzheimer's disease (AD). Proteolytic cleavage of APP by the beta site APP cleaving enzyme (BACE1) near the C-terminus results in the formation of the APP C-terminal fragment (CTF) C99, a substrate for subsequent cleavage by gamma-secretase to generate Abeta. Alternatively, APP cleavage by alpha-secretase to generate the APP CTF C83 occurs within the Abeta region, precluding its formation. Therefore, modulation of beta- and/or gamma-secretase activity represents important therapeutic targets. Transgenic mice overexpressing human APP generate detectable levels of APP CTFs and Abeta. We have shown that highly sensitive and specific methods for determining levels of APP CTFs and Abeta are useful for understanding how genetic manipulation of APP processing impacts Abeta generation and accumulation. PMID- 20967585 TI - Detection of APP intracellular domain in brain tissue. AB - The cleavage of amyloid precursor protein (APP) by gamma-secretase produces Abeta peptides, which are prominent features in Alzheimer's disease and have been extensively studied. By contrast, APP intracellular domain (AICD), also a product of this cleavage event, has received little or no investigative attention. A major reason for this is that AICD is generally not detected in tissue lysates and, therefore, is neglected as a non-relevant product of APP metabolism. However, recent studies have shown that AICD regulates a number of important cellular events. Furthermore, we found that contrary to previous assertions, AICD can be detected in brain lysates using Western blotting if an antigen retrieval protocol is employed. Here we describe the protocol for AICD detection and note the biological relevance of AICD in physiological and pathological conditions. PMID- 20967586 TI - Cell-based assays for regulators of tau biology. AB - Understanding the molecular mechanisms of Alzheimer's disease (AD) is a challenging endeavor, namely, due to the fact that the disease only occurs in the central nervous system of elderly humans. Thus, model systems simply do not accurately portray this cellular landscape. While we cannot ask many mechanistic questions using the human brain as our test subject, cell culture techniques that have emerged at least provide us with the ability to pose fundamental biochemical questions, which may ultimately lead to translational outcomes for AD. In particular, the intracellular microtubule-associated protein tau that accumulates in AD is found in normal cells. Manipulating these cells may allow us to address basic questions about tau biology that would provide novel therapeutic strategies down the road. Here, we describe several techniques to explore tau cell biology using the Odyssey((r)) Infrared Imaging system (Odyssey system) from LI-COR Biosciences. We provide a detailed protocol on how to perform a scalable drug screening assay called the In-Cell Western and follow-up these screens with standard Western analysis to confirm whether "hits" are valid by more traditional means. We provide some tips on where mistakes are most likely to occur, and we interpret our standard Western data, providing some estimation as to the composition of the banding pattern that is typical for this enigmatic protein. PMID- 20967587 TI - Split GFP complementation assay for quantitative measurement of tau aggregation in situ. AB - A primary pathological hallmark of Alzheimer disease brain is the presence of neurofibrillary tangles, which are highly aggregated and insoluble accumulations of the microtubule-associated protein tau. Although it is becoming increasingly apparent that the mature neurofibrillary tangles are not the toxic species, intermediates between soluble tau and the neurofibrillary tangles likely play key roles in the neurodegenerative process. Therefore, it is critically important to be able to quantitatively monitor the process of tau aggregation in living cells in order to understand the evolution of tau from its physiological to its pathological forms. To detect and quantitate the aggregation of tau in cells, we established a split green fluorescent protein (GFP) complementation assay. In this assay, GFP is separated into two spontaneously associating fragments that form the fluorescent fluorophore. The smaller GFP fragment, GFP(11), is fused to tau and coexpressed in cells with the larger fragment GFP(1-10) leading to the association and reconstitution of the active fluorophore. However, if tau becomes partitioned into aggregates, the GFP(11) tag will be less accessible for interactions with GFP(1-10) resulting in a decrease in GFP complementation and fluorescence which can be monitored either using fluorescence microscopy or with a fluorescence plate reader. Thus, this assay is a valuable tool for measuring tau aggregation in living cells and evaluating -factors that modulate this process. PMID- 20967588 TI - Apolipoprotein E expression and purification. AB - Since the discovery of the association of apolipoprotein E (apoE) 4 with Alzheimer's disease 17 years ago, numerous in vitro experiments with the apoE isoforms (apoE2, apoE3, and apoE4) have been performed to try to understand the basis for this association. The majority of these studies used commercial sources for apoE, but some used recombinant protein. In either case, these studies were most often conducted without considering the ramifications of the structural and biophysical differences among the three isoforms or without adequate quality control of the preparations. Here, we present a protocol for producing recombinant apoE that we have used successfully in our laboratory for the last 20 years. We also review the considerations that are critical for obtaining reliable and interpretable results with the end product. PMID- 20967589 TI - Abeta toxicity in primary cultured neurons. AB - The aggregation of beta-amyloid (Abeta) into soluble oligomers is considered an early event in Alzheimer's disease. Furthermore, the presence of these aggregates seems to lead to neurodegeneration in the context of this disease. However, the mechanisms underlying Abeta-induced neurotoxicity are not completely understood. Primary cultures of pyramidal neurons have proven to be an excellent model system for the study of such mechanisms. These cultures provide a homogenous population of neurons that extend and differentiate axons and dendrites and that establish functional synapses among them. In addition, the neurotoxic effects of preaggregated Abeta can be easily analyzed both morphologically and biochemically. Here, we describe in detail the materials and methods used for the preparation and maintenance of primary cultures of hippocampal pyramidal neurons, as well as for the aggregation of and treatment with Abeta. PMID- 20967590 TI - Manipulation of gene expression in the central nervous system with lentiviral vectors. AB - Viral vector-mediated gene transfer is widely used to manipulate gene expression (overexpression or knock down) in cultures and in different tissues of animals. Vectors based on lentiviruses have particularly useful features. Lentiviral vectors mediate gene transfer into any neuronal cell types and induce sustained expression without significant immune responses after delivery into the nervous system. Lentivirus-mediated expression of therapeutic genes has led to long-term treatment of animal models of neurological disorders, such as spinal injury, Parkinson's disease, Huntington's disease, and Alzheimer's disease. Here, we describe the preparation and purification of lentiviral vectors and methods of lentiviral infection in primary neural cultures and in brain regions of interest by stereotaxic injection. PMID- 20967591 TI - Selecting a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease and cause of dementia. Significant strides toward understanding and developing therapies for AD have been supported by the use of transgenic mouse models of AD. Over the last two decades, a number of mouse models have been created to recapitulate the major neuropathological hallmarks of the disease, namely amyloid plaques and neurofibrillary tangles. These mice recapitulate many, although not all, of the key features of AD, and have been widely used in AD research. At the present time, there are numerous types of transgenic mice available for the study of AD, many of which have been characterized to some extent in terms of neuronal, neuropathological, and/or behavioral abnormalities. This repository of transgenic mice offers a wealth of opportunity to investigate the cellular mechanisms underlying AD, and the choice of mouse model for research should be guided by the specific questions to be answered. We provide here some considerations for selecting a mouse model of AD best suited to particular lines of investigation. PMID- 20967592 TI - Monitoring spatial learning and memory in Alzheimer's disease mouse models using the Morris Water Maze. AB - Mouse models of Alzheimer's Disease are essential for understanding how pathological cascades alter neural circuitry and eventually disrupt cognitive function. A key prerequisite for the use of such models, therefore, is the ability to accurately and reliably measure cognitive function. The Morris Water Maze has emerged in the field as the standard test for assessing spatial cognition. There are many variations on the exact procedures and types of analysis that can be done within the framework of this test. We detail a procedure, with variations, that can be used to robustly detect cognitive deficits in Alzheimer's Disease mouse models as well as factors that ameliorate those deficits. PMID- 20967593 TI - Step-by-step in situ hybridization method for localizing gene expression changes in the brain. AB - RNA in situ hybridization is a powerful technique for examining gene expression in specific cell populations. This method is particularly useful in the central nervous system with its high cellular diversity and dynamic gene expression regulation associated with development, plasticity, neuronal activity, aging, and disease. Standard quantitative techniques such as Western blotting and real-time PCR allow the detection of altered gene or protein expression but provide no information about their cellular source or possible alterations in expression patterns. Here, we describe a step-by-step RNA in situ hybridization method on adult and embryonic brain sections for quantitative neuroscience. We include fully detailed protocols for RNase-free material preparation, perfusion, fixation, sectioning, selection of expressed sequence tag cDNA clones, linearization of cDNA, synthesis of digoxigenin-labeled RNA probes (riboprobes), in situ hybridization on floating and mounted sections, nonradioactive immunohistochemical detection of riboprobes for light and fluorescence microscopy, and double labeling. We also include useful information about quality control steps, key online sites, commercially available products, stock solutions, and storage. Finally, we provide examples of the utility of this approach in understanding the neuropathogenesis of Alzheimer's disease. With virtually all genomic coding sequences cloned or being cloned into cDNA plasmids, this technique has become highly accessible to explore gene expression profiles at the cellular and brain region level. PMID- 20967594 TI - Real-time visualization of axonal transport in neurons. AB - The normal function of neurons depends on the integrity of microtubule-dependent transport of cellular materials and organelles to/from their cell bodies or axon terminus. In this chapter, we describe the design and implementation of a fluorescence imaging method to visualize axonal transport in neurons directly. We combine a pseudo total internal reflection microscopy, quantum dot fluorescence labeling, microfluidic neuronal culture chamber, and single molecule detection methods to achieve a high spatial and temporal resolution in tracking nerve growth factor transport in dorsal root ganglia neurons. PMID- 20967595 TI - Quantifying biomarkers of cognitive dysfunction and neuronal network hyperexcitability in mouse models of Alzheimer's disease: depletion of calcium dependent proteins and inhibitory hippocampal remodeling. AB - High levels of Abeta impair neuronal function at least in part by disrupting normal synaptic transmission and causing dysfunction of neural networks. This network dysfunction includes abnormal synchronization of neuronal activity resulting in epileptiform activity. Over time, this aberrant network activity can lead to the depletion of calcium-dependent proteins, such as calbindin, Fos, and Arc, and compensatory inhibitory remodeling of hippocampal circuits, including GABAergic sprouting and ectopic expression of the inhibitory neuropeptide Y (NPY) in dentate granule cells. Here we present detailed protocols for detecting and quantifying these alterations in mouse models of Alzheimer's disease (AD) by immunohistochemistry. These methods are useful as surrogate measures for detecting chronic aberrant network activity in models of AD and epilepsy. In addition, since we have found that the severity of these changes relates to the degree of Abeta-dependent cognitive impairments, the protocols are useful for quantifying biomarkers of cognitive impairment in mouse models of AD. PMID- 20967596 TI - Epigenetic changes in the brain: measuring global histone modifications. AB - Recent years have witnessed an explosion of research on the role of epigenetic modifications, such as DNA methylation and histone protein acetylation and phosphorylation, in neuroscience. These changes exert control over gene expression and have been shown to play important roles in a variety of neural processes, including learning and memory. We and others have also recently shown that epigenetic changes may contribute to neurodegenerative disorders, such as Alzheimer's disease. Western blot analysis with antibodies raised against specific histone modifications is a relatively simple technique able to reveal the type, location, and degree of histone posttranslational modifications produced by an experimental manipulation. Here we provide a step-by-step protocol for isolating histone proteins from tissue and measuring these posttranslational modifications. PMID- 20967597 TI - Setup of a PCR laboratory. AB - PCR represents an extremely powerful and central molecular biology method. At the heart of its power is the exquisite sensitivity offered: single molecule detection in certain contexts. However, with great power comes great responsibility. Contamination of reagents or test samples with amplifiable material, such as previous reaction products, can be crippling to scientists applying PCR protocols. Prevention of PCR contamination is far and away preferred over eradication. This chapter sets out to offer guidance as to how to use PCR while minimising contamination problems. PMID- 20967598 TI - Long-range PCR with a DNA polymerase fusion. AB - Proofreading DNA polymerase fusions offer several advantages for long-range PCR, including faster run times and higher fidelity compared with Taq-based enzymes. However, their use so far has been limited to amplification of small to mid-range targets. In this article, we present a modified protocol for using a DNA polymerase fusion to amplify genomic targets exceeding 20 kb in length. This procedure overcomes several limitations of Taq blends, which up until recently, were the only option for long-range PCR. With a proofreading DNA polymerase fusion, high-molecular-weight amplicon can be generated and analyzed in a single day, and a significant proportion is expected to be error-free. PMID- 20967599 TI - Isolation of genomic insertion sites of proviruses using Splinkerette-PCR-based procedures. AB - The availability of whole genomic sequences provides a great framework for biologists to address a broad range of scientific questions. However, functions of most mammalian genes remain obscure. The forward genetics strategy of insertional mutagenesis uses DNA mutagens such as retroviruses and transposable elements; this strategy represents a powerful approach to functional genomics. A variety of methods to uncover insertion sites have been described. This chapter details SplinkTA-PCR and SplinkBlunt-PCR, modified from splinkerette-PCR, for mapping chromosomally the insertion sites of a murine leukemia virus that causes leukemia in the BXH-2 strain of mice. These protocols are easy to use, reliable, and efficient. PMID- 20967600 TI - Lariat-dependent nested PCR for flanking sequence determination. AB - Methods detailed in this chapter relate to the use of Lariat-dependent Nested (LaNe) PCR to characterize unknown RNA or DNA sequence flanking known regions. A multitude of approaches designed to determine flanking sequences have been described in the literature. Variously, problems related to these approaches include lack of resolution or failure, depending on experimental context, and complex handling. LaNe-based methods are designed to harness "two-sided" gene specific PCR with the option of nesting but without the requirement for inefficient and involved enzyme preprocessing steps. PMID- 20967601 TI - CODEHOP PCR and CODEHOP PCR primer design. AB - While PCR primer design for the amplification of known sequences is usually quite straightforward, the design, and successful application of primers aimed at the detection of as yet unknown genes is often not. The search for genes that are presumed to be distantly related to a known gene sequence, such as homologous genes in different species, paralogs in the same genome, or novel pathogens in diverse hosts, often turns into the proverbial search for the needle in the haystack. PCR-based methods commonly used to address this issue involve the use of either consensus primers or degenerate primers, both of which have significant shortcomings regarding sensitivity and specificity. We have developed a novel primer design approach that diminishes these shortcomings and instead takes advantage of the strengths of both consensus and degenerate primer designs, by combining the two concepts into a Consensus-Degenerate Hybrid Oligonucleotide Primer (CODEHOP) approach. CODEHOP PCR primers contain a relatively short degenerate 3' core and a 5' nondegenerate clamp. The 3' degenerate core consists of a pool of primers containing all possible codons for a 3-4 aminoacid motif that is highly conserved in multiply aligned sequences from known members of a protein family. Each primer in the pool also contains a single 5' nondegenerate nucleotide sequence derived from a codon consensus across the aligned aminoacid sequences flanking the conserved motif. During the initial PCR amplification cycles, the degenerate core is responsible for specific binding to sequences encoding the conserved aminoacid motif. The longer consensus clamp region serves to stabilize the primer and allows the participation of all primers in the pool in the efficient amplification of products during later PCR cycles. We have developed an interactive web site and algorithm (iCODEHOP) for designing CODEHOP PCR primers from multiply aligned protein sequences, which is freely available online. Here, we describe the workflow of a typical CODEHOP PCR assay design and optimization and give a specific implementation example along with "best practice" advice. PMID- 20967602 TI - Sequencing of difficult DNA Regions by SAM sequencing. AB - Nucleotide analogues are used increasingly in medicine and biotechnology to effect DNA sequence change, principally via clastogenic and transcriptional effects. This article, however, discusses the use of mutagenic nucleotide analogues to improve the sequencing of recalcitrant and repetitive DNA motifs. Guidance in the technical and practical approaches that support use of this approach with different DNA sequencing technologies is provided, including for high-throughput technologies. PMID- 20967603 TI - A global single-cell cDNA amplification method for quantitative microarray analysis. AB - We describe here a protocol to faithfully amplify global cDNAs from single cells. The amplified cDNAs retain their sense-antisense orientation and can be easily applied to template preparation for quantitative high-density oligonucleotide microarray analyses. The amplification protocol comprises (1) lysis of a single cell in a tube without purification, (2) first-strand cDNA synthesis with the first primer tailed with oligo dT, (3) elimination of the unreacted first primer, (4) poly (dA) tailing of the cDNA, (5) second-strand cDNA synthesis with the second primer tailed with oligo dT, and (6) 20-cycle, directional PCR with the two primers. To prepare the template for the isothermal linear amplification with T7 RNA polymerase to synthesize labeled cRNAs for microarray hybridization, the promoter sequence is added to the cDNA with another round of PCR. The promoter tagged cDNA is purified with gel electrophoresis and amplified with one final cycle of PCR. PMID- 20967604 TI - Quantitation of microRNAs by real-time RT-qPCR. AB - MicroRNAs (miRNAs) are ~22 nucleotide regulatory RNA molecules that play important roles in controlling developmental and physiological processes in animals and plants. Measuring the level of miRNA expression is a critical step in methods that study the regulation of biological functions and that use miRNA profiles as diagnostic markers for cancer and other diseases. Even though the quantitation of these small miRNA molecules by RT-qPCR is challenging because of their short length and sequence similarity, a number of quantitative RT-qPCR based miRNA quantitation methods have been introduced since 2004. The most commonly used methods are stem-loop reverse transcription (RT)-based TaqMan((r)) MicroRNA assays and arrays. The high sensitivity and specificity, large dynamic range, and simple work flow of TaqMan((r)) MicroRNA assays and arrays have made TaqMan analysis the method of choice for miRNA expression profiling and follow-up validation. Other methods such as poly (A) tailing-based and direct RT-based SYBR miRNA assays are also discussed in this chapter. PMID- 20967605 TI - High-throughput SuperSAGE. AB - SuperSAGE is a method of digital gene expression profiling that allows isolation of 26-bp tag fragments from expressed transcripts. Combined with the ultrahigh throughput sequencing technologies, SuperSAGE enables analysis of millions of transcripts with lower cost and reduced effort and time. In this chapter, we present an updated protocol for this High-throughput SuperSAGE method with a special emphasis on the technique of library multiplexing. PMID- 20967606 TI - Deep cap analysis of gene expression. AB - The cap analysis of gene expression (CAGE) technology has been established to detect transcriptional starting sites (TSSs) and expression levels by utilizing 5' cDNA tags and PCR. It has been reported that the amount of templates is proportional to the amplification efficiency of PCR. CAGE has been used as a key technique for analyzing promoter activity and finding new transcripts including alternative spliced products and noncoding transcripts. Here, we introduce more powerful tools such as deepCAGE, which can be utilized for high-throughput next generation sequencing technology. DeepCAGE can produce much deeper transcriptome datasets and can reveal more details of the regulatory network. PMID- 20967608 TI - PAP-LMPCR: an improved, sequence-selective method for the in vivo analysis of transcription factor occupancy and chromatin fine structure. AB - In vivo footprinting and ligation-mediated PCR (LMPCR) are well-established methods for the examination of the chromatin structure of eukaryotic genes. Here, we describe an improved method (pyrophosphorolysis activated polymerization LMPCR or PAP-LMPCR) that overcomes the shortfalls of previous methods by being capable of reading through sequences that up to now were refractory to this type of analysis. This includes dinucleotide repeat sequences or GC-rich regions. We also describe conditions capable of distinguishing between different alleles, thus enabling the simultaneous analysis of monoallelically expressed genes without having to employ interspecies hybrids. PMID- 20967607 TI - Linking emulsion PCR haplotype analysis. AB - The experimental measurement of haplotype requires the determination of two or more genotypes on the same DNA molecule. Because such measurements are much more complicated than measurements of genotypes, haplotypes are typically inferred using population data for linkage disequilibrium between the markers of interest. We have developed a method for molecular haplotyping, linking emulsion PCR (LE PCR), and have demonstrated that the method is sufficiently robust to determine haplotypes for multiple markers in a population setting. LE-PCR uses emulsion PCR to isolate single template molecules for simultaneous PCR of widely spaced markers and uses linking PCR to fuse these amplicons into one short amplicon, which maintains the phase of the markers. LE-PCR is illustrated for polymorphisms in human paraoxonase 1 (PON1) that have been shown to affect transcriptional activity and substrate specificity in the detoxification of organophosphates. PMID- 20967609 TI - The many faces of MLPA. AB - Multiplex Ligation-dependent Probe Amplification (MLPA) is a PCR-based technique that was developed for identifying deletions and duplications in genomic DNA. The simplicity and sensitivity of this approach has led to it being implemented in many laboratories around the world. Since the original publication, there have been several variants of MLPA described, allowing the quantitative analysis of mRNA transcript levels, CpG methylation, complex genomic regions, and DNaseI hypersensitive sites. This chapter outlines the basic MLPA protocol, describes the different modifications and applications that have been published, and discusses the critical points during each of the steps. PMID- 20967610 TI - Assessing gene-specific methylation using HRM-based analysis. AB - As DNA methylation analysis enters the mainstream of biomedical research, there is increasing interest in methodologies that can be used for rapid analysis of a wide variety of biological and clinical samples. The methods that have been commonly used for methylation analysis are usually time-consuming and require multiple steps. The methylation-sensitive high-resolution melting (MS-HRM) assay is an in-tube assay which was developed to assess promoter methylation in sodium bisulphite-modified DNA and is particularly useful for assessing methylation in short fragments of DNA derived from formalin-fixed paraffin-embedded biopsies. PMID- 20967611 TI - Alu PCR. AB - Alu PCR is a rapid and easy-to-perform "DNA fingerprinting" technique based on the simultaneous analysis of many genomic loci flanked by Alu repetitive elements, which allows the detection of genetic polymorphisms and mutations in human and primate genomes. In the protocol described in the present chapter, two fluorochrome-labelled primers complementary to Alu sequences are used to perform the PCR, and the amplification products are then analysed by capillary electrophoresis. The resulting -complex electrophoretic pattern may show sample to-sample variability due to insertion, deletion, or sequence change of Alu retrotransposons, or caused by length variation of the sequence interposed between two Alus. PMID- 20967612 TI - Asynchronous PCR. AB - Asynchronous PCR (aPCR) is a new PCR method that directs an ordered and sequential amplification of the + and - strands of DNA amplicons. There are several unique characteristics of aPCR that generate new application opportunities. The melting temperature (Tm) of the forward and reverse aPCR primers differ by at least 15 degrees C. The concentration of the lower Tm primer is reduced from 900 to 100 nM, thereby allowing for asynchronous or asymmetric strand-specific amplification. Furthermore, unique thermocycling parameter strategy dictates the + and - strand amplification cue. Each aPCR cycle includes two annealing and extension steps. Sequential annealing and extension of forward and reverse primers during each cycle produce transient single-stranded DNA (ssDNA) amplicons which help hybridization-based probes such as peptide nucleic acid (PNA) bind to the target sequences more effectively. This new method can be used in real-time quantitative PCR (qPCR) for gene expression analyses as well as production of robust ssDNA targets for microarray and other hybridization-based applications. PMID- 20967613 TI - Novel applications of PCR through the use of DNA substrates. AB - The ability to amplify genetic material using PCR has transformed the field of diagnostics. Now any organism can be detected by identifying the presence of specific nucleic acids. However, there still remain areas in which traditional PCR cannot easily be applied. In this chapter, we describe a different flavour of PCR in which an enzyme acts on a DNA substrate to convert it into a DNA product that can be detected by PCR. This opens up new areas for the application of the PCR technique and we will show how the technique can be used to detect immunoconjugates, bacterial drug resistance, and bacterial contamination. PMID- 20967614 TI - Enhanced solid phase PCR for increased loading of amplicon onto solid support. AB - The loading of amplicons onto solid supports such as beads during multiplex PCR or emulsion PCR conventionally has been performed by use of Solid Phase PCR or asymmetric Solid Phase PCR. These approaches are restrictive with respect to amplification efficiency and degree of amplicon loading. This chapter details Enhanced Solid Phase PCR principles and methodologies to enable higher amplicon loading in the context of uncompromised amplification efficiency. PMID- 20967615 TI - Application of blocking oligonucleotides to improve signal-to-noise ratio in a PCR. AB - "Universal" or group-specific PCR primers have a tendency to predominately hybridise with the common sequences in samples with mixed templates. The result is that the rarer sequences are seldom retrieved by cloning or sequencing. The use of a blocking oligonucleotide (oligo) designed to specifically prevent amplification of dominant or unwanted DNA templates is an easy way to improve the amplification of rarer sequences. Here, we describe the different types of blocking principles and the different types of blocking oligos and give guidelines and examples of their application. PMID- 20967616 TI - Asymmetric overlap extension PCR method for site-directed mutagenesis. AB - Overlap extension PCR (OE-PCR) has been widely used in site-directed mutagenesis. The original OE-PCR included two rounds of PCRs and required tedious steps to purify the first-round PCR product. By combining asymmetric PCR and overlap extension, a novel asymmetric overlap extension PCR (AOE-PCR) method has been developed. This method consists of two separate asymmetric PCRs of around 30 cycles and a single cycle of annealing and extension after directly mixing the first-round PCR products. AOE-PCR eliminates intermediate purification steps and amplification of wild-type template and requires fewer PCR cycles, and is, therefore, a much simpler and faster and more efficient site-directed mutagenesis method than the original OE-PCR approach. PMID- 20967617 TI - Ribosome display: a technology for selecting and evolving proteins from large libraries. AB - The selection and concomitant affinity maturation of proteins to bind to user defined target molecules have become a key technology in biochemical research, diagnostics, and therapy. One of the most potent selection technologies for such applications is ribosome display. It works entirely in vitro, and this has two important consequences. First, since no transformation of any cells is required, libraries with much greater diversity can be handled than with most other techniques. Second, since a library does not have to be cloned and transformed, it is very convenient to introduce random errors in the library by PCR-based methods and select improved binders. Thus, a true directed evolution, an iteration between randomization and selection over several generations, can be conveniently carried out, e.g., for affinity maturation. Ribosome display has been used successfully for the selection of antibody fragments and other binding proteins, such as Designed Ankyrin Repeat Proteins (DARPins). PMID- 20967618 TI - GLOBE: Analysis of DNA-protein interaction analysis. AB - Emulsion PCR, a hyper, multi, parallel PCR in water-phase droplets in water-in oil (w/o) emulsion, can be used to make a genetic l ibrary on beads (GLOBE). In GLOBE, we have developed a novel high-throughput screening system for the analysis of the recognition sequences of DNA-binding proteins, which can be prepared by using either an in vivo or an in vitro protein synthesis system. The system can contribute to the low-cost comprehensive analysis of transcription factor-binding regions. PMID- 20967619 TI - PCR DNA-array profiling of DNA-binding transcription factor activities in adult mouse tissues. AB - Differential gene expression is tightly controlled by transcription factors (TFs), which bind close to target genes and interact together to activate and coregulate transcription. Bioinformatics analysis of published genome-wide gene expression data has allowed the development of comprehensive models of TFs likely to be active in particular tissues (signature TFs); however, the predicted activities of many of the TFs have not been experimentally confirmed. Here, we describe methods for the parallel analysis of the activities of more than 200 transcription factor proteins, using an advanced oligonucleotide array-based transcription factor assay (OATFA) platform, to assay TF activities in mice. The system uses a PCR-based system to translate cellular levels of target DNA-TF complex into a dye-tagged DNA signal, which is read by the developed microarray. The PCR step introduces semiquantitative amplification of the represented TF binding sequences. Experimental OATFA findings can identify many TF activities, which bioinformatics profiling does not predict. Newly identified TF activities can be confirmed by antibody-ELISA against active TFs. The PCR-based OATFA microarray analysis is a comprehensive method that can be used to reveal transcriptional systems and pathways which may function in different mammalian tissues and cells. PMID- 20967620 TI - Nucleotide exchange and excision technology DNA shuffling and directed evolution. AB - Remarkable success in optimizing complex properties within DNA and proteins has been achieved by directed evolution. In contrast to various random mutagenesis methods and high-throughput selection methods, the number of available DNA shuffling procedures is limited, and protocols are often difficult to adjust. The strength of the nucleotide exchange and excision technology (NExT) DNA shuffling described here is the robust, efficient, and easily controllable DNA fragmentation step based on random incorporation of the so-called 'exchange nucleotides' by PCR. The exchange nucleotides are removed enzymatically, followed by chemical cleavage of the DNA backbone. The oligonucleotide pool is reassembled into full-length genes by internal primer extension, and the recombined gene library is amplified by standard PCR. The technique has been demonstrated by shuffling a defined gene library of chloramphenicol acetyltransferase variants using uridine as fragmentation defining exchange nucleotide. Substituting 33% of the dTTP with dUTP in the incorporation PCR resulted in shuffled clones with an average parental fragment size of 86 bases and revealed a mutation rate of only 0.1%. Additionally, a computer program (NExTProg) has been developed that predicts the fragment size distribution depending on the relative amount of the exchange nucleotide. PMID- 20967621 TI - RNA and DNA microarrays. AB - The development of microarray technology has revolutionized RNA and deoxyribonucleic acid (DNA) research. In contrast with traditional biological assays, microarrays allow the simultaneous measurement of tens of thousands of messenger RNA (mRNA) transcripts for gene expression or of genomic DNA fragments for copy number variation analysis. Over the past decade, genome-wide RNA or DNA microarray analysis has become an essential component of biology and biomedical research. The successful use of microarrays requires attention to unique issues of experimental design and execution. This chapter provides an overview of the methodology and applications of RNA and DNA microarrays in various areas of biological research. PMID- 20967622 TI - Aptamer arrays. AB - In less than 40 years, aptamers have consolidated their role in biosensor development. Chemically related to nucleic acid probes, production of aptamers against targets of various sizes and compositions places them as ideal capture elements, alternative to more consolidated molecules such as antibodies. Thanks to their chemical simplicity and production, as well as their unique characteristics, aptamers have been successfully integrated in several innovative approaches. The incorporation of aptamers into the existing microarray technologies has lead to the reporting of various detection strategies, including direct fluorescence detection of fluorescent reporters, fluorescence anisotropy, FRET, SPR imaging, and electrochemical detection. PMID- 20967623 TI - Oligonucleotide microarrays for identification of microbial pathogens and detection of their virulence-associated or drug-resistance determinants. AB - Microarrays are spatially ordered arrays with ligands chemically immobilized in discrete spots on a solid matrix, usually a microscope slide. Microarrays are a high-throughput large-scale screening system enabling simultaneous identification of a large number of labeled target molecules (up to several hundred thousand) that bind specifically to the immobilized ligands of the array. DNA microarrays represent a promising tool for clinical, environmental, and industrial microbiology since the technology allows relatively rapid identification of large number of genetic determinants simultaneously, providing detailed genomic level information regarding the pathogen species, including identification of their virulence-associated factors and the presence of antibiotic resistance genes. In this chapter, we describe key aspects and methodologies important for the development and use of DNA microarrays for microbial diagnostics. PMID- 20967624 TI - Protein microarrays printed from DNA microarrays. AB - Protein arrays are miniaturised and highly parallelised formats of interaction based functional protein assays. Major bottlenecks in protein microarraying are the limited availability and high cost of purified, functional proteins for immobilisation and the limited stability of immobilised proteins in their functional state. In contrast, protein-coding DNA is readily available by PCR, and DNA arrays can be stored over prolonged times without deterioration. This chapter presents a method for the rapid and economical "printing" of replicate protein microarrays directly from a single DNA array template using cell-free protein synthesis, termed "DNA array to protein array," DAPA. The procedure is a truly enabling technology, making customised protein microarrays affordable for laboratories with no access to routine microarray spotting. The experimental effort involved for the printing of a protein array from the template DNA array is comparable to the assembly of a Western blot. PMID- 20967625 TI - Lithographically defined two- and three-dimensional tissue microarrays. AB - Traditional methods to study normal and pathological development of tissues have been limited by -difficulties in controlling experimental conditions and quantifying biological processes of interest. Here we describe methods to create microarrays of engineered tissues that enable controlled and quantitative investigations. Using soft lithography-based techniques, extracellular matrix proteins can be microcontact printed or micromolded to make two- and three dimensional micropatterned scaffolds. The ultimate form and resulting properties of the tissue construct are dictated by the geometry of the patterned extracellular matrix components. This chapter describes elastomeric stamp fabrication, microcontact printing and micromolding of extracellular matrix proteins, cell culture in micropatterned substrata, and quantitative immunofluorescence analysis of micropatterned tissues. PMID- 20967626 TI - Ratiometric lectin microarray analysis of the mammalian cell surface glycome. AB - The mammalian cell surface is rich with carbohydrate polymers involved in a diversity of biological recognition events. Dynamic alterations of surface glycans mediate cell-cell communication in the immune system and host specificity of bacterial and viral pathogens. In addition, altered surface glycosylation has been implicated in disease progression of many cancers and may serve as important new targets for therapeutics. Despite the importance of glycosylation, the systematic analysis of sugars, i.e., glycomics, has lagged behind the well studied disciplines of genomics and proteomics. This deficiency is due in part to the unique analytical challenges presented by glycans and the overwhelming diversity of sugars in nature. New microarray technologies have provided a high throughput methods with which to probe the glycome. Our laboratory has pioneered a shown ratiometric two-color lectin microarray method that rapidly evaluates differences in the glycosylation of mammalian cells. Herein, we present a detailed protocol of our lectin microarray methodology for the differential analysis of mammalian glycomes. PMID- 20967627 TI - Cell microarrays based on hydrogel microstructures for the application to cell based biosensor. AB - Cell-based biosensors constitute a promising field that has numerous applications ranging from pharmaceutical screening to detection of pathogen and toxicant. The trends toward miniaturization of cell-based biosensor continue to spur development of cell microarray integrated into microfluidic devices. For cell based biosensors to be useful for larger applications, several technical goals must be realized. First, the cell-patterning method used to generate multi phenotypic array can accommodate multiple cell lines without major losses of cell viability, maintain total isolation of each cell phenotype, provide for the adequate mass transfer of dissolved gases and nutrients, and easy enough to allow for mass production. Second, cells on microarray must be cultured in three dimensional environment as they do in real tissue to obtain accurate response of cells against target analyte. Third, physiological status of micropatterned cells must be monitored non-invasively. As one solution to satisfy these requirements, we prepare cell microarrays using microfabricated poly(ethylene glycol)(PEG) hydrogel. Arrays of hydrogel microstructures encapsulating one or more different cell phenotypes can be fabricated using photolithography or photoreaction injection molding, and can be incorporated within microfluidic network. Finally, we demonstrate the potential application of cell-containing hydrogel microarrays for toxin detection by monitoring toxin-induced change of cell viability and intercellular enzymatic reaction. PMID- 20967628 TI - Fabrication of bacteria and virus microarrays based on polymeric capillary force lithography. AB - There is a growing interest on the fabrication of bacteria and virus microarray owing to their great potential in many biological applications ranging from diagnostic devices to advanced platforms for fundamental studies on molecular biology. Over the past decade, a number of studies with regard to the biomolecular patterning have been presented. Capillary force lithography (CFL) for polymeric thin films can provide well-ordered microarray structures over a large area in a facile and cost-efficient way while maintaining its biocompatibility during a process. Patterned polymeric structures can be utilized either to physical barriers for the confinement of bacteria or to physicochemical template for the subsequent binding of viruses. In this chapter, we have shown that the patterned structures of poly(ethylene glycol) (PEG) containing polymer enables a selective binding of Escherichia coli, leading to a physically guided microarray of bacteria. Additionally, we demonstrate the fabrication of virus microarray of M13 viruses via electrostatic interactions with a prepatterned microstructure of polyelectrolyte multilayers. PMID- 20967629 TI - 3D polymer scaffold arrays. AB - We have developed a combinatorial platform for fabricating tissue scaffold arrays that can be used for screening cell-material interactions. Traditional research involves preparing samples one at a time for characterization and testing. Combinatorial and high-throughput (CHT) methods lower the cost of research by reducing the amount of time and material required for experiments by combining many samples into miniaturized specimens. In order to help accelerate biomaterials research, many new CHT methods have been developed for screening cell-material interactions where materials are presented to cells as a 2D film or surface. However, biomaterials are frequently used to fabricate 3D scaffolds, cells exist in vivo in a 3D environment and cells cultured in a 3D environment in vitro typically behave more physiologically than those cultured on a 2D surface. Thus, we have developed a platform for fabricating tissue scaffold libraries where biomaterials can be presented to cells in a 3D format. PMID- 20967630 TI - PDMS microfluidic capillary systems for patterning proteins on surfaces and performing miniaturized immunoassays. AB - In this chapter, we describe the fabrication and use of microfluidic capillary systems (CSs) made in soft, transparent polydimethylsiloxane (PDMS). Sixteen microfluidic CSs, each containing a loading pad, a microchannel, and a capillary pump are engraved in a single PDMS chip. The CSs are used for two applications, firstly to pattern fibronectin on glass surfaces to locally control the adhesion of cultured cells to the substrate, and secondly to carry out multiplexed miniaturized immunoassays. PMID- 20967631 TI - Merging photolithography and robotic protein printing to create cellular microarrays. AB - Photolithographic patterning of proteins on surfaces has been used extensively in the past to define cell adhesion domains with micrometer-scale resolution. However, photolithographic patterning is not amenable to depositing several different proteins on the same surface. We propose to merge photolithography with robotic printing of proteins in order to create arrays of protein spots (~300-500 MUm diameters) with encoded micrometer-scale cell adhesive domains. This method for biointerface design can employ standard positive tone resist lithography to create temporary stencils for printing of protein arrays. Alternatively, nonfouling poly(ethylene glycol) hydrogels can be micropatterned on top of protein spots. In both cases, cells become adherent on the underlying protein domains, but on-the-spot distribution of cells is defined by the photolithographic pattern. The ability to define multiple cell-substrate and cell cell interaction scenarios on the same surface is applicable to high-throughput screening of the microenvironment components required for cellular differentiation, for example, for guiding stem cells toward the desired tissue type. PMID- 20967632 TI - Generation of protein and cell microarrays on functionalized surfaces. AB - The technique of selective immobilization of biomolecules in defined positions or areas using a simple procedure is essential for various applications such as biosensors, biochips, biomedical microdevices, and tissue engineering. For the generation of biomolecule microarrays, it is necessary to develop a functional surface retaining protein functionality and cell viability, and an efficient patterning tool having flexibility of size and shape. In this chapter, we have presented the simple tools of protein and cell microarray based on functionalized surface such as a spotting method with improvement of protein functionality, a functionalized silicon-based surface using photolithography, and an orthogonally polyelectrolyte-coated surface based on soft-lithography. PMID- 20967633 TI - Microprinting of liver micro-organ for drug metabolism study. AB - In their normal in vivo matrix milieu, tissues assume complex well-organized 3D architectures. Therefore, a primary aim in the tissue engineering design process is to fabricate an optimal analog of the in vivo scenario, in which the precise configuration and composition of cells and bioactive matrix components can establish the well-defined biomimetic microenvironments that promote cell-cell and cell-matrix interactions. With the advent and refinements in microfabricated systems which can present physical and chemical cues to cells in a controllable and reproducible fashion unrealizable with conventional tissue culture, high fidelity, high-throughput in vitro models are achieved. The convergence of solid freeform fabrication (SFF) technologies, namely microprinting, along with microfabrication techniques, a 3D microprinted micro-organ, can serve as an in vitro platform for cell culture, drug screening, or to elicit further biological insights. This chapter firstly details the principles, methods, and applications that undergird the fabrication process development and adaptation of microfluidic devices for the creation of a drug screening model. This model involves the combinatorial setup of an automated syringe-based, layered direct cell writing microprinting process with soft lithographic micropatterning techniques to fabricate a microscale in vitro device housing a chamber of microprinted 3D micro organ that biomimics the cell's natural microenvironment for enhanced performance and functionality. In order to assess the structural formability and biological feasibility of such a micro-organ, 3D cell-encapsulated hydrogel-based tissue constructs are microprinted reproducibly in defined design patterns and biologically characterized for both viability and cell-specific function. Another key facet of the in vivo microenvironment that is recapitulated with the in vitro system is the necessary dynamic perfusion of the 3D microscale liver analog with cells probed for their collective drug metabolic function and suitability as a drug metabolism model. PMID- 20967634 TI - Microcontact printing. AB - Microcontact printing (MUCP) is a useful technique for transferring certain molecules onto surfaces with high spatial resolution using elastomeric stamps. The stamp for MUCP is fabricated by replica molding from a master made by microlithography. After wetting with a type of material as an "ink," the stamp comes into contact with the substrate. The ink is selectively transferred onto parts of the substrate wherever the stamp makes direct contact, to generate patterns and structures with designated features. Self-assembled monolayers (SAMs) and MUCP are useful in many different fields, e.g., in the studies of protein adsorption, cell attachment, and in the construction of sensors. PMID- 20967635 TI - Micromolding for the fabrication of biological microarrays. AB - The PRINT((r)) (pattern replication in non-wetting templates) process has been developed as a simple, gentle way to pattern films or generate discrete particles in arrays out of either pure biological materials or biomolecules encapsulated within polymeric materials. Patterned films and particle arrays can be fabricated in a wide array of sizes and shapes using Fluorocur((r)) (a UV-curable perfluoropolyether polymer) from the nanometer to micron scale. PMID- 20967636 TI - Progress report on microstructured surfaces based on chemical vapor deposition. AB - This book chapter discusses recent advances in the fabrication of microscale surface patterns using chemical vapor deposition polymerization. Reactive poly(p xylylene) (PPX) coatings are useful for their ability to immobilize specific biomolecules, as determined by the PPX functional group. PPXs can either be modified postdeposition, or they can be patterned onto a substrate in situ. Specific methods discussed in this progress report include microcontact printing, vapor-assisted micropatterning in replica structures, projection lithography based patterning, and selective polymer deposition. PMID- 20967637 TI - Methods for forming human microvascular tubes in vitro and measuring their macromolecular permeability. AB - This chapter describes a protocol for forming open endothelial tubes in vitro and quantifying their permeability to macromolecules. These tubes consist of confluent monolayers of human microvascular endothelial cells in perfused microfluidic collagen gels. The cylindrical geometry of the tubes mimics the shape of microvessels in vivo; it allows simultaneous and/or repeated measurements of permeability coefficients and detection of focal leaks. We have used these in vitro models to test the effects of agonists on microvascular permeability and are developing arrays of microvascular tubes to enable large scale testing. PMID- 20967638 TI - Microarray bioinformatics. AB - Bioinformatics has become an increasingly important tool for molecular biologists, especially for the analysis of microarray data. Microarrays can produce vast amounts of information requiring a series of consecutive analyses to render the data interpretable. The direct output of microarrays cannot be directly interpreted to show differences in settings, conditions of samples, or time points. To make microarray experiments interpretable, it is necessary that a series of algorithms and approaches be applied. After normalization of generated data, which is necessary to make a comparison feasible, significance analysis, clustering of samples and biological compounds of interest and visualization are generally performed. This chapter will focus on providing a basic understanding of the generally approaches and algorithms currently employed in microarray bioinformatics. PMID- 20967639 TI - The mediating effect of perceived burdensomeness on the relation between depressive symptoms and suicide ideation in a community sample of older adults. AB - OBJECTIVES: Suicide is a prevalent problem in older adults. One of the best predictors of suicide in older adults is suicide ideation; suicide ideation has been frequently associated with depression. However, suicide ideation is not always present when an older adult is depressed and is sometimes present when an older adult is not depressed. Perceived burdensomeness, a recently proposed risk factor [Joiner Jr, T.E. (2005)], has been linked to suicide ideation in depressed samples and in older adults. Thus, perceived burdensomeness may be the necessary risk factor for suicide ideation. METHOD: The Geriatric Suicide Ideation Scale (GSIS; [Heisel et al. (2006)]), Center for Epidemiologic Studies Depression (CES D; [Radloff, L.S. (1977)]) scale, and Suicide Cognitions Scale (SCS; [Rudd, M.D., Schmitz, B., McClenen, R., Joiner, T., Elkins, G., & Claassen, C.A. (n.d.)]) were completed by a community sample of older adults recruited from primary care clinics (n = 106). A regression analysis was conducted following Baron and Kenny's [1986] guidelines to test the hypothesis that perceived burdensomeness (measured by the SCS perceived burdensomeness subscale) mediates the relation between depression (assessed with the CES-D) and suicide ideation (measured by the GSIS suicide ideation subscale) in older adults. RESULTS: Perceived burdensomeness mediated the relation between depression and suicide ideation, accounting for 68.3% of the variance in suicide ideation. CONCLUSION: Perceived burdensomeness may explain the relation between depression and suicide ideation. Clinicians seeing older adults should assess for depression and perceived burdensomeness when determining suicide risk. Future research directions include treatment studies for perceived burdensomeness as a way to reduce suicide ideation. PMID- 20967640 TI - Investigation of tissue-specific human orthologous alternative splice events in pig. AB - Alternative splicing of pre-mRNA can contribute to differences between tissues or cells either by regulating gene expression or creating proteins with various functions encoded by one gene. The number of investigated alternative splice events in pig has so far been limited. In this study we have investigated alternative splice events detected in humans, in orthologous pig genes. A total of 17 genes with predicted exon skipping events were selected for further studies. The splice events for the selected genes were experimentally verified using real-time quantitative PCR analysis (qPCR) with splice-specific primers in 19 different tissues. The same splice variants as reported in humans were detected in 15 orthologous pig genes, however, the expression pattern predicted in the in silico analyses was only experimentally verified in a few cases. The results support the findings that splice events resulting in preservation of open reading frame are indicative of a functional significance of the splice variants of the gene. PMID- 20967642 TI - Phylogenetic analysis of different breeds of domestic chickens in selected area of Peninsular Malaysia inferred from partial cytochrome b gene information and RAPD markers. AB - The present investigation was carried out in an attempt to study the phylogenetic analysis of different breeds of domestic chickens in Peninsular Malaysia inferred from partial cytochrome b gene information and random amplified polymorphic DNA (RAPD) markers. Phylogenetic analysis using both neighbor-joining (NJ) and maximum parsimony (MP) methods produced three clusters that encompassed Type-I village chickens, the red jungle fowl subspecies and the Japanese Chunky broilers. The phylogenetic analysis also revealed that majority of the Malaysian commercial chickens were randomly assembled with the Type-II village chickens. In RAPD assay, phylogenetic analysis using neighbor-joining produced six clusters that were completely distinguished based on the locality of chickens. High levels of genetic variations were observed among the village chickens, the commercial broilers, and between the commercial broilers and layer chickens. In this study, it was found that Type-I village chickens could be distinguished from the commercial chickens and Type-II village chickens at the position of the 27th nucleotide of the 351 bp cytochrome b gene. This study also revealed that RAPD markers were unable to differentiate the type of chickens, but it showed the effectiveness of RAPD in evaluating the genetic variation and the genetic relationships between chicken lines and populations. PMID- 20967643 TI - The effect of a mutation in the 3-UTR region of the HMGCR gene on cholesterol in Beijing-you chickens. AB - The 3-hydroxyl-3-methylglutaryl Coenzyme A reductase (HMGCR) gene was examined for polymorphisms in Beijing-you chickens. A "T" base insert was detected at nucleotide 2749 of the 3-UTR region of the HMGCR gene and was used as the basis for distinguishing a B allele, distinct from the A. Serum and muscle contents of total cholesterol. LDL-cholesterol in serum was significantly lower in AB birds and lowest in BB birds. Real-time PCR showed that the same trends across genotypes occurred in an abundance of HMGCR transcripts in liver, but there was no difference in contents of HMGCR mRNA in breast or thigh muscles. Hepatic expression and serum LDL-cholesterol were meaningfully correlated (partial, with total serum cholesterol held constant, r = 0.923). In muscle, similar genotypic differences were found for the abundance of the LDL receptor (LDLR) transcript. Cholesterol content in breast muscle related to LDLR expression (partial correlation with serum LDL-cholesterol held constant, r = 0.719); the equivalent partial correlation in thigh muscle was not significant. The results indicated that the B allele significantly reduces hepatic abundance of HMGCR transcripts, probably accounting for genotypic differences in serum cholesterol. In muscle, the cholesterol content appeared to reflect differences in LDLR expression with apparent mechanistic differences between breast and thigh. PMID- 20967644 TI - Exon 1 polymorphisms in the equine CSN3 gene: SNPs distribution analysis in Murgese horse breed. AB - The aim of this study was to assess genetic polymorphism at two loci in the exon 1 of the CSN3 gene in Murgese horse breed by PCR-RFLP analysis. The overall frequencies of alleles A and G at c.-66A > G locus were 0.80 and 0.20, respectively, and no GG animals were found in the population. At the c.-36C > A locus allelic frequencies were 0.74 and 0.26 for allele C and A, respectively, and no AA animals were detected. Population genetic indexes, namely gene heterozygosity, gene homozygosity, effective allele numbers, fixation index, and polymorphism information index were calculated. Combined genotypic frequencies and possible haplotypes frequencies were also reported. Only three out of nine possible genotypic combinations were found in the studied population. The most frequent genotype was AACC (0.49) while the frequency of AGCA was 0.40. Only five animals were genotyped as AACA (11%). Consequently, the most frequent haplotype in the population was AC (0.744), followed by GA (0.200) and AA (0.056). PMID- 20967645 TI - High concordance of bovine single nucleotide polymorphism genotypes generated using two independent genotyping strategies. AB - Single nucleotide polymorphisms (SNPs) represent the most common form of DNA sequence variation in mammalian livestock genomes. While the past decade has witnessed major advances in SNP genotyping technologies, genotyping errors caused, in part, by the biochemistry underlying the genotyping platform used, can occur. These errors can distort project results and conclusions and can result in incorrect decisions in animal management and breeding programs; hence, SNP genotype calls must be accurate and reliable. In this study, 263 Bos spp. samples were genotyped commercially for a total of 16 SNPs. Of the total possible 4,208 SNP genotypes, 4,179 SNP genotypes were generated, yielding a genotype call rate of 99.31% (standard deviation +/- 0.93%). Between 110 and 263 samples were subsequently re-genotyped by us for all 16 markers using a custom-designed SNP genotyping platform, and of the possible 3,819 genotypes a total of 3,768 genotypes were generated (98.70% genotype call rate, SD +/- 1.89%). A total of 3,744 duplicate genotypes were generated for both genotyping platforms, and comparison of the genotype calls for both methods revealed 3,741 concordant SNP genotype call rates (99.92% SNP genotype concordance rate). These data indicate that both genotyping methods used can provide livestock geneticists with reliable, reproducible SNP genotypic data for in-depth statistical analysis. PMID- 20967646 TI - Effect of biofouling on anodized and sol-gel treated titanium surfaces: a comparative study. AB - Anodization and sol-gel treatments of titanium (Ti) were evaluated as biofilm control measures on surfaces exposed to seawater exposed to ultraviolet light. Anodized and sol-gel treated specimens were characterized using Raman spectroscopy to confirm the presence of TiO(2). The single anatase phase was observed at the anodized surfaces whereas the anatase/rutile mixed phase was detected on the sol-gel coated surfaces. After exposure of the specimens to seawater, biofilms were characterized by total viable counts, and epifluorescence and Raman microscopy. These techniques confirmed the reduction in biofilm formation on both the anodized and sol-gel coated Ti specimens compared to the untreated specimens. Biofilm control by anodization was found to be more effective than by sol-gel treatment of the specimens. The higher particle size and the inhomogeneity at the sol-gel coated surfaces produced less effective biofilm control. PMID- 20967647 TI - Rights and representations: querying the male-to-male sexual subject in India. AB - Same-sex sexualities in India have been portrayed in research and activism as socially marginal and minoritarian. Whilst proceeding from a commitment to the political utility of such a view, this paper questions such a standpoint. Drawing on ethnographic research conducted in different sites, the paper considers male to-male sexualities as enacted and implicated in the production of ostensibly heteronormative spaces. This, in turn, raises questions about the representation of the queer or same-sex sexual subject in law and HIV prevention, especially in the context of post-colonial perspectives on sexuality. PMID- 20967641 TI - Generation and analysis of ESTs from the grass carp, Ctenopharyngodon idellus. AB - Grass carp, Ctenopharyngodon idellus (Valenciennes, 1844), is an economically important species widely cultured in the world, but its genome research resources are largely lacking. The objectives of this study were to construct normalized cDNA libraries for efficient EST analysis, to generate ESTs from these libraries, and to identify EST-related molecular markers such as microsatellites and single nucleotide polymorphisms (SNPs) for genetic analysis of this species. A total of 6,269 ESTs were generated representing 4,815 unique sequences, from which 105 putative microsatellites and 5,228 SNPs were identified. These genome resources provide the material basis for future genetic and functional analyses in this species. PMID- 20967650 TI - (Not) talking about sex: couple reports of sexual discussion and expression in Bangalore, India. AB - Adolescent marriage is common in India, placing young women at risk of HIV, early pregnancy and poor birth outcomes. Young women's capacity to express their sexual desires is central to negotiating safe and mutually consensual sexuality. Men, too, play an important role in shaping women's sexual and reproductive health outcomes, but little research has examined how men influence women's sexual expression. Using paired husband and wife data, this paper reports on a preliminary investigation into the patterns of and concurrence between women's sexual expression and their husbands' attitudes about it, as well as the influence of men's approval of their wives' sexual expression on women's actual expression of sexual desire. The results suggest that, among this sample, men are more open to sexual expression than their wives and that, for women, expressing desire not to have sex is far more common than expressing desire to have sex. Further, men's approval of sexual expression from wives appears to positively influence women's actual expression. These findings suggest that men may be resources for women to draw upon as they negotiate sexuality in adolescence and early adulthood. PMID- 20967649 TI - Reasons for non-use of condoms among men who have sex with men: a comparison of receptive and insertive role in sex and online and offline meeting venue. AB - This study examined reasons for non-use of condoms among an online survey sample of 462 non-condom using men who have sex with men to: (1) identify major domains, themes and categories encompassing reasons for non-use of condoms and (2) examine whether reasons varied by role-in-sex (insertive or receptive) and meeting venue (online or offline). A thematic analysis was completed on participant responses to an open-ended question about reasons for non-condom use. Preference for not using condoms and contextual factors were the top two reasons given for not using condoms, followed by a reasoned judgment based on risk assessment, relationship status and interpersonal communication. No major differences were found between men who reported non-condom use at last receptive and insertive anal intercourse. By contrast when meeting online, men were more likely to report reasons for non condom use that corresponded to individual preference and mutual agreement not to use condoms. When meeting offline, men were more likely to cite reasons related to context and relationships. In developing HIV-prevention interventions for this population, researchers should address both venues separately, as reasons why men engage in non-use of condoms appear to differ. PMID- 20967651 TI - Structure and agency: reflections from an exploratory study of Vancouver indoor sex workers. AB - Sex work research continues to be characterised by debates around decriminalization. Central to these debates are claims about the agency of those involved in the sex trade. Some researchers argue that individuals involved in the sex trade are victims of structural and interpersonal constraint, whilst others depict them as workers exercising choice. Drawing on structure-agency theory, a review of legal and media accounts of the sex trade and qualitative interviews with 21 indoor sex workers in Vancouver, Canada, we argue that both of these perspectives are insufficient. Rather than reducing the sex trade to part of a binary, we suggest that it is necessary to analyse sex work through the complex interplay of both structure and agency. Specifically, structural analyses undercover the numerous ways that sex workers are controlled, observed and influenced whilst agency perspectives elicit the means that sex workers continue to exercise control in spite of disadvantage. While we do not finalise decriminalisation debates, we do critique current Canadian laws for the lack of responsiveness to the lives of sex workers and their exploitative and contradictory stance on sex work. PMID- 20967653 TI - Higher mental stimulation at work is associated with improved cognitive functioning in both young and older workers. AB - The study examined whether mental stimulation received in the workplace positively affects cognitive functioning and rate of cognitive change. Data taken from the VISAT (ageing, health and work) longitudinal study concerned 3237 workers who were seen three times (in 1996, 2001 and 2006) and who were aged between 32 and 62 years at baseline. Measures of cognitive stimulation both at work and outside work were available at baseline. Cognitive efficiency was assessed on the three occasions through episodic verbal memory, attention and processing speed tests. Greater cognitive stimulation (at work and outside work) was associated with higher levels of cognitive functioning and a more favourable change over the 10-year follow-up. These results were obtained after adjustment for age, education, sex and a variety of medical, physical and psychosocial confounders. The study thus supports the hypothesis that exposure to jobs that are mentally demanding and that offer learning opportunities increases the level of cognitive functioning and possibly attenuates age-related decline. STATEMENT OF RELEVANCE: The effect of occupational activity on cognitive functioning is under-researched. This paper reports results from a substantive longitudinal study, with findings indicating that exposure to jobs that are mentally demanding are beneficial in increasing levels of cognitive functioning and possibly attenuating age-related decline. PMID- 20967654 TI - Patient source of learning about health technologies and ratings of trust in technologies used in their care. AB - In order to design effective health technologies and systems, it is important to understand how patients learn and make decisions about health technologies used in their care. The objective of this study was to examine patients' source of learning about technologies used in their care and how the source related to their trust in the technology was used. Individual face-to-face and telephone interviews were conducted with 24 patients. Altogether, 13 unique sources of information about technology were identified and three major themes emerged: outside of the work system vs. inside the work system; when the health information was provided; the medium used. Patients used multiple sources outside of the healthcare work system to learn about technologies that will be used in their care. Results showed a relationship between learning about technologies from web sources and trust in technologies but no relationship between learning about technologies from healthcare providers and trust in technologies. STATEMENT OF RELEVANCE: The value of considering human attitudes about elements in health systems has been illustrated. This research shows a relationship between patient attitudes about medical technologies used in their care and healthcare work system design. Results show that patient attitudes are formed about technologies used in their care by sources within and outside of the sociotechnical work system. PMID- 20967655 TI - A multi-level approach of evaluating crew resource management training: a laboratory-based study examining communication skills as a function of team congruence. AB - The article proposes a multi-level approach for evaluating communication skills training (CST) as an important element of crew resource management (CRM) training. Within this methodological framework, the present work examined the effectiveness of CST in matching or mismatching team compositions with regard to hierarchical status and competence. There is little experimental research that evaluated the effectiveness of CRM training at multiple levels (i.e. reaction, learning, behaviour) and in teams composed of members of different status and competence. An experiment with a two (CST: with vs. without) by two (competence/hierarchical status: congruent vs. incongruent) design was carried out. A total of 64 participants were trained for 2.5 h on a simulated process control environment, with the experimental group being given 45 min of training on receptiveness and influencing skills. Prior to the 1-h experimental session, participants were assigned to two-person teams. The results showed overall support for the use of such a multi-level approach of training evaluation. Stronger positive effects of CST were found for subjective measures than for objective performance measures. STATEMENT OF RELEVANCE: This work provides some guidance for the use of a multi-level evaluation of CRM training. It also emphasises the need to collect objective performance data for training evaluation in addition to subjective measures with a view to gain a more accurate picture of the benefits of such training approaches. PMID- 20967656 TI - Effects of sign characteristics and training methods on safety sign training effectiveness. AB - This study investigated whether or not training methods affected the effectiveness of symbol training and if there were any relationships between sign symbol characteristics and training effectiveness. Altogether, 26 Mainland China industrial safety signs were used and 60 participants were randomly assigned into four equal-sized groups of control, paired-associate learning, recall training and recognition training. The result was that participants from all the training groups showed significantly greater improvement in comprehension performance than those in the control group, indicating that the training methods improved comprehension of the meaning of safety signs. Participants from the recall training group performed better in the post-training test than those from other training groups. It seems that the recall task elicited a deeper level of learning than the recognition task and that questioning and feedback had a positive effect on training effectiveness. The results also showed that sign characteristics had no significant influence on training effectiveness. It was concluded that recall training is more effective in enhancing comprehension of industrial safety signs than paired-associate learning or recognition training. The findings of this study provide a basis for useful guidelines for designing symbol-training programmes and for designing more user-friendly safety signs. STATEMENT OF RELEVANCE: The present study shows that recall training was more effective in improving comprehension of industrial safety signs than paired associate learning or recognition training and cognitive sign features did not influence training effectiveness. They provide a basis for useful guidelines for designing symbol-training programmes and for designing more user-friendly safety signs. PMID- 20967657 TI - Influence of three principles of pacing on the temporal organisation of work during cyclic assembly and disassembly tasks. AB - A study was conducted to investigate the influence of different approaches to arranging the pace and temporal organisation of repetitive assembly and disassembly tasks on both average performance and its variability and to compare assembly and disassembly times derived with psychophysical methods to a more traditional methods-time measurement (MTM) approach. The conditions studied were a traditional assembly line arrangement, where assemblies were started at a pace of 110 MTM (repeated on two occasions), a batch condition, where subjects were required to complete 36 assemblies within the total amount of time allowed at 110, MTM and a psychophysical condition, where subjects were allowed to choose their pace (repeated on two occasions). Overall, the results suggest that the mean time spent working in each cycle (the 'on-time') remained fairly constant across conditions, while the idle 'off-time' in between on-times was shorter and of less varied duration in the more autonomous batch and psychophysical conditions. During the second psychophysical (self-paced) condition, subjects completed a significantly higher number of assemblies than during the 110 MTM line condition. The higher pace was achieved through reduction in mean off-times and the potential implications for musculoskeletal risk are discussed. STATEMENT OF RELEVANCE: Higher levels of autonomy over work pace, which intuitively would be beneficial from an ergonomics standpoint, actually led to subjects selecting to organise work such that off-times (idle times) were reduced. In contrast, active 'on' times were not affected much by autonomy. These results point to a reason that piecework would be associated with increased risk for musculoskeletal disorders. PMID- 20967658 TI - The effect of load weight on balance control during lateral box transfers. AB - Few studies have endeavoured to measure balance control during manual material handling. This study examined the effects of load weight during a stationary manual material handling task. In total, 36 healthy participants completed 180 degrees lateral transfer tasks of a loaded (5% of body weight) and an unloaded box. The projection of the centre of mass onto the base of support, as measured via a passive-marker 3-D motion analysis system, was used to quantify balance control. Muscle activities of lower extremity muscles were also measured. When moving the loaded box, individuals ventured >= 1 cm closer to the edges of the base of support and increased centre of mass movement up to 14%. In addition, muscle electromyographic activity on both sides of the shank increased. In summary, during loaded configurations, vulnerability to loss of balance was increased and individuals appeared to adapt by increasing co-contraction of the shank muscles suggesting increased ankle stiffness. STATEMENT OF RELEVANCE: Industries requiring manual material handling have a particularly high rate of injuries due to falls. This study suggests that larger load weights during lateral material handling tasks adversely affect balance control and may create a vulnerability to imbalance throughout the entire manoeuvre. PMID- 20967659 TI - The development of a model to predict the effects of worker and task factors on foot placements in manual material handling tasks. AB - Accurate prediction of foot placements in relation to hand locations during manual materials handling tasks is critical for prospective biomechanical analysis. To address this need, the effects of lifting task conditions and anthropometric variables on foot placements were studied in a laboratory experiment. In total, 20 men and women performed two-handed object transfers that required them to walk to a shelf, lift an object from the shelf at waist height and carry the object to a variety of locations. Five different changes in the direction of progression following the object pickup were used, ranging from 45 degrees to 180 degrees relative to the approach direction. Object weights of 1.0 kg, 4.5 kg, 13.6 kg were used. Whole-body motions were recorded using a 3-D optical retro-reflective marker-based camera system. A new parametric system for describing foot placements, the Quantitative Transition Classification System, was developed to facilitate the parameterisation of foot placement data. Foot placements chosen by the subjects during the transfer tasks appeared to facilitate a change in the whole-body direction of progression, in addition to aiding in performing the lift. Further analysis revealed that five different stepping behaviours accounted for 71% of the stepping patterns observed. More specifically, the most frequently observed behaviour revealed that the orientation of the lead foot during the actual lifting task was primarily affected by the amount of turn angle required after the lift (R(2) = 0.53). One surprising result was that the object mass (scaled by participant body mass) was not found to significantly affect any of the individual step placement parameters. Regression models were developed to predict the most prevalent step placements and are included in this paper to facilitate more accurate human motion simulations and ergonomics analyses of manual material lifting tasks. STATEMENT OF RELEVANCE: This study proposes a method for parameterising the steps (foot placements) associated with manual material handling tasks. The influence of task conditions and subject anthropometry on the foot placements of the most frequently observed stepping pattern during a laboratory study is discussed. For prospective postural analyses conducted using digital human models, accurate prediction of the foot placements is critical to realistic postural analyses and improved biomechanical job evaluations. PMID- 20967660 TI - Whole body vibration exposures in forklift operators: comparison of a mechanical and air suspension seat. AB - Using a repeated measures design, this study compared differences in whole body vibration (WBV) exposures when 12 forklift operators drove the same forklift with a mechanical suspension and an air suspension seat. A portable PDA-based WBV data acquisition system collected and analysed time-weighted and raw WBV data per ISO 2631-1 and 2631-5 WBV measurement standards. Tri-axial measurements of weighted vibration (A(w)), crest factor, vibration dose values, time-weighted average peak, raw (+) peak, raw (-) peak and static compression dose (S(ed)) were compared between seats. There were significant differences in z-axis WBV exposures with the air suspension seat, yielding lower WBV exposures. In addition, there were differences between seats in how they attenuated WBV exposures based on the driver's weight. In the mechanical suspension seat, WBV exposures were weight-dependent, with lighter drivers having higher WBV exposures, whereas with the air suspension seat, the same trends were not as prevalent. STATEMENT OF RELEVANCE: This study contributes to the understanding of how different seat suspensions can influence WBV transmission and how some components of vibration transmission are dependent on the weight of the driver. Additional systematic studies are needed to quantify how various factors can influence WBV exposures. PMID- 20967661 TI - Relationship between aerobic capacity, injury risk and tenure for new-hire delivery drivers. AB - Over a 2-year study period, aerobic capacity was measured at time of hire for 1419 delivery drivers. Injury experience and tenure were then monitored for these new-hires during that same period. Number of strain injuries, time to first strain and time to termination were regressed on aerobic capacity adjusting for tenure. Statistically significant, monotonically changing relationships were found for all three outcome variables. A unit increase in aerobic capacity was predicted to result in a 3.7% decrease in injury rate and a 1.1% decrease in risk of termination. When age was included in the model for time to termination, aerobic capacity was no longer a significant predictor. The findings regarding injury experience and aerobic capacity support National Institute for Occupational Safety and Health recommendations that individuals should work at no more than 21-30% of their aerobic capacity. STATEMENT OF RELEVANCE: Knowledge of the nature of the relationship between aerobic capacity, injury experience and retention allows the ergonomist to determine whether there is a point of diminishing returns in intervention effectiveness for higher levels of aerobic capacity. PMID- 20967662 TI - Migrants and the key role that they play in what has been termed the age of migration. PMID- 20967663 TI - Saturated and aromatic mineral oil hydrocarbons from paperboard food packaging: estimation of long-term migration from contents in the paperboard and data on boxes from the market. AB - In the absence of a functional barrier, mineral oil hydrocarbons from printing inks and recycled fibres tend to migrate from paper-based food-packaging materials through the gas phase into dry food. Concentrations easily far exceed the limit derived from the acceptable daily intake (ADI) of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Since the estimation of long-term migration into the food by testing at 40 degrees C for 10 days is difficult, it seems preferable (and easier) to use the mineral oil content in the paperboard. Evaporation experiments showed that hydrocarbons eluted up to about n-C24 are sufficiently volatile for relevant migration into dry food: in worst-case situations, about 80% migrate into the packed food. The extraction of the paperboard was optimised to give good recovery of the relevant hydrocarbons, but to discriminate against those of high molecular mass which tend to disturb gas chromatographic analysis in on-line coupled normal phase HPLC-GC-FID. Even though some of the relevant hydrocarbons had already evaporated, the average concentration of < C24 mineral oil saturated hydrocarbons (MOSH) in the paperboard boxes of 102 products from the Swiss and Italian market was 626 mg kg 1. Nearly 15% of investigated boxes still contained more than 1000 mg kg-1 < C24 MOSH up to over 3000 mg kg-1 (maximum = 3500 mg kg-1). This amount of MOSH in the board have the potential of contaminating the packed food at a level exceeding the limit, derived from the JECFA ADI, hundreds of times. PMID- 20967664 TI - Pyrrolizidine alkaloids in food: downstream contamination in the food chain caused by honey and pollen. AB - In recent years, there has been a steadily growing number of published data on pyrrolizidine alkaloids (PAs) in honey and pollen. This raises the question whether honey and/or pollen used as ingredients in food processing might provoke a downstream contamination in the food chain. Here we addressed two different facets in connection with PAs in honey and pollen. First, we analysed the PA content of several food types such as mead (n = 19), candy (n = 10), fennel honey (n = 9), soft drinks (n = 5), power bars and cereals (n = 7), jelly babies (n = 3), baby food (n = 3), supplements (n = 3) and fruit sauce (n = 1) that contained honey as an ingredient in the range of 5% to approximately 37%. Eight out of 60 retail samples were tested as being PA-positive, corresponding to 13%. Positive samples were found in mead, candy and fennel honey, and the average PA content was calculated to be 0.10 ug g(-1) retronecine equivalents (ranging from 0.010 to 0.484 ug g(-1)). Furthermore, we investigated the question whether and how PAs from PA pollen are transferred from pollen into honey. We conducted model experiments with floral pollen of Senecio vernalis and PA free honey and tested the influence of the quantity of PA pollen, contact time and a simulated honey filtration on the final PA content of honey. It could clearly be demonstrated that the PA content of honey was directly proportional to the amount of PA pollen in honey and that the transfer of PAs from pollen to honey was a rather quick process. Consequently, PA pollen represents a major source for the observed PA content in honey. On the other hand, a good portion remains in the pollen. This fraction is not detected by the common analytical methods, but will be ingested, and it represents an unknown amount of 'hidden' PAs. In addition, the results showed that a technically and legally possible honey filtration (including the removal of all pollen) would not be an option to reduce the PA level of the final product significantly. PMID- 20967667 TI - Parameter optimization of the fungicide (Vapam) sorption onto soil modified with clinoptilolite by Taguchi method. AB - This study employs the Taguchi optimization methodology to optimize the effective parameters for the pesticide (Vapam) sorption onto soil modified with natural zeolite (clinoptilolite). The experimental factors and their ranges chosen for determination of the effective parameters were: initial Vapam concentration (0.4 1.6 mg/L), initial pH of the pesticide solution (2-12), the percentage of clinoptilolite in the modified soil (0-6 %), temperature (15-35 degrees C) and shaking time (2-24 h). The orthogonal array (OA) L(16) and the bigger the better response category of the Taguchi method were selected to determine the optimum conditions: initial Vapam concentration (1.2 mg/L), initial pH of the pesticide solution (2), the percentage of clinoptilolite in the modified soil (4 %), temperature (15 degrees C) and shaking time (2 h). The results showed that in comparison with other parameters, the initial Vapam concentration was the most effective one for the sorption of this pesticide onto soil, modified with clinoptilolite. Moreover, after determining the optimum levels of the sorption process parameters, confirmation experiments were performed to prove the effectiveness of the Taguchi's experimental design methodology. PMID- 20967668 TI - Occupational exposure to polycyclic aromatic hydrocarbons in airborne particulate matter: validation and application of a gas chromatography-mass spectrometry analytical method. AB - This study concerns the validation of an analytical method for the measurement of occupational exposure to trace levels of polycyclic aromatic hydrocarbons (PAHs) in airborne particulate matter (APM). Personal exposure to selected PAHs of five workers occupationally exposed to urban pollution in Rome, Italy, was evaluated. The samples were collected over 10 days evenly distributed during winter and summer of 2008. Polycyclic aromatic hydrocarbons were collected by a sampling pump and trapped in polytetrafluoroethylene filters; ultrasonic extraction was applied to extract PAH species from the matrix with toluene, and the concentrated extract was quantitatively analyzed by GC/MS. The analytical method was optimized and validated using a standard reference material of urban dust (SRM 1649a). Detection limits ranged from 0.8 ng per sample for indeno [1,2,3-cd] pyrene to 20.4 ng for sample for anthracene. Experimental results of the 50 personal samples collected showed that phenanthrene was the predominant polycyclic aromatic hydrocarbon [95% CI (32.42-41.13 ng m(-3))]; the highest benzo[a]pyrene concentration was 2.58 ng m(-3), approximately 2-fold higher than European annual target values (1 ng m(-3)). Seasonal variations of personal exposure to selected PAHs suggested higher emissions and reduced atmospheric reactivity of PAH compounds in winter. The analytical method was a suitable procedure for the determination of 13 of the 16 priority PAHs in APM personal samples and can be considered a useful tool to evaluate occupational exposure to low PAH levels. PMID- 20967669 TI - Differential gaze behavior towards sexually preferred and non-preferred human figures. AB - The gaze pattern associated with image exploration is a sensitive index of our attention, motivation, and preference. To examine whether an individual's gaze behavior can reflect his or her sexual interest, this study compared gaze patterns of young heterosexual men and women (M = 19.94 years, SD = 1.05) while they viewed photographs of plain-clothed male and female figures aged from birth to 60 years old. The analysis revealed a clear gender difference in viewing sexually preferred figure images. Men displayed a distinctive gaze pattern only when viewing 20-year-old female images, with more fixations and longer viewing times dedicated to the upper body and waist-hip regions. Women also directed more attention at the upper body on female images in comparison to male images, but this difference was not age-specific. Analysis of local image salience revealed that observers' eye-scanning strategies could not be accounted for by low-level processes, such as analyzing local image contrast and structure, but were associated with attractiveness judgments. The results suggest that the difference in cognitive processing of sexually preferred and non-preferred figures can be manifested in gaze patterns associated with figure viewing. Thus, eye-tracking holds promise as a potential sensitive measure for sexual preference, particularly in men. PMID- 20967670 TI - Effect of a concentric warm-up exercise on eccentrically induced soreness and loss of function of the elbow flexor muscles. AB - The aim of this study was to examine the effect of concentric warm-up exercise on eccentrically induced changes in muscle strength, range of motion, and soreness of the elbow flexors. Ten resistance-exercise naive participants performed intermittent incremental eccentric actions (42 in total) of the elbow flexor muscles of each arm to induce muscle damage. The arms of each participant were randomly assigned either to a pre-eccentric exercise warm-up involving intermittent concentric exercise (warm-up) or no prior exercise (control). Strength, range of motion, and ratings of soreness were recorded before and 1, 2, 3, 4, and 7 days after exercise. Strength, range of motion, and soreness during muscular movements changed over time (P at most 0.01; Cohen's d at least 0.51, medium). There was an interaction (P < 0.001) for strength, showing a smaller reduction after exercise for warm-up than control (P < 0.001, d = 2.44, large effect). The decreased range of motion was less for warm-up than control for the arm while extended (P < 0.001), flexed (P = 0.002), and relaxed (P = 0.004). Muscle soreness was reduced for the warm-up group, while the muscle was flexed, extended, and relaxed compared with control (P < 0.001). The results demonstrate that a concentric warm-up exercise attenuates the reduction in loss of strength, range of motion, and muscle soreness after eccentric-exercise-induced muscle damage and might allow higher intensities of training to be performed. PMID- 20967671 TI - Landing techniques in volleyball. AB - Knee injuries such as anterior cruciate ligament lesions and patellar tendonitis are very frequent in volleyball, and are often attributed to micro traumas that occur during the landing phase of airborne actions. The aim of the present study was to compare different jumping activities during official men's and women's volleyball games. Twelve top-level matches from the Italian men's and women's professional leagues were analysed. The jumps performed during the games were classified according to the landing technique used by the player (left or right foot or both feet together), court position, and ball trajectory. Chi-square analyses were performed to detect differences in landing techniques between the sexes, court positions, and trajectories when serving, attacking, blocking, and setting. Significant differences (P < 0.05) were found between the sexes for block, set, and spike but not for the jump serve. The frequency of landings on one foot was related to court position and the trajectory of the sets: when spiking faster sets, the players were more likely to use a one-footed landing. The present results should help coaches and physiotherapists to devise appropriate training and prevention programmes, and reveal the need for further detailed biomechanical investigations of the relationships between landings and knee injuries. PMID- 20967672 TI - Parallel assessment of nutrition and activity in athletes: validation against doubly labelled water, 24-h urea excretion, and indirect calorimetry. AB - The assessment of nutrition and activity in athletes requires accurate and precise methods. The aim of this study was to validate a protocol for parallel assessment of diet and exercise against doubly labelled water, 24-h urea excretion, and respiratory gas exchange. The participants were 14 male triathletes under normal training conditions. Energy intake and doubly labelled water were weakly associated with each other (r = 0.69, standard error of estimate [SEE] = 304 kcal x day(-1)). Protein intake was strongly correlated with 24-h urea (r = 0.89) but showed considerable individual variation (SEE = 0.34 g kg(-1) x day(-1)). Total energy expenditure based on recorded activities was highly correlated with doubly labelled water (r = 0.95, SEE = 195 kcal x day(-1)) but was proportionally biased. During running and cycling, estimated exercise energy expenditure was highly correlated with gas exchange (running: r = 0.89, SEE = 1.6 kcal x min(-1); cycling: r = 0.95, SEE = 1.4 kcal x min(-1)). High exercise energy expenditure was slightly underestimated during running. For nutrition data, variations appear too large for precise measurements in individual athletes, which is a common problem of dietary assessment methods. Despite the high correlations of total energy expenditure and exercise energy expenditure with reference methods, a correction for systematic errors is necessary for the valid estimation of energetic requirements in individual athletes. PMID- 20967673 TI - Reliability and construct validity of soccer skills tests that measure passing, shooting, and dribbling. AB - In this study, we examined the reliability and construct validity of new soccer skills tests. Twenty soccer players (10 professional and 10 recreational) repeated trials of passing, shooting, and dribbling skills on different days. Passing and shooting skills required players to kick a moving ball, delivered at constant speed, towards one of four randomly determined targets. Dribbling required players to negotiate seven cones over 20 m. Each trial consisted of 28 passes, 8 shots, and 10 dribbles. Ball speed, precision, and success were determined for all tests using video analysis. Systematic bias was small (<9% in all measures) and all outcome measures were similar between trials. Test-retest reliability statistics were as follows: ball speed (passing, shooting, dribbling; coefficient of variation [CV]: 6.5%, 6.9%, 2.4%; ratio limits of agreement [RLOA]: 0.958 *// 1.091, 0.990 *// 1.107, 0.993 *// 1.039), precision (passing, shooting, dribbling; CV: 10.0%, 23.5%, 4.6%; RLOA: 0.956 *// 1.147, 1.030 *// 1.356, 1.000 *// 1.068), and success (passing, shooting, dribbling; CV: 11.7%, 14.4%, 2.2%; RLOA: 1.017 *// 1.191, 0.913 *// 1.265, 0.996 *// 1.035). Professional players performed better than recreational players in at least one outcome measure for all skills. These findings demonstrate the reliability and validity of new soccer skill protocols. PMID- 20967674 TI - Motion analysis of match-play in elite U12 to U16 age-group soccer players. AB - The aim of this study was to quantify the motion demands of match-play in elite U12 to U16 age-group soccer players. Altogether, 112 players from two professional soccer clubs at five age-group levels (U12-U16) were monitored during competitive matches (n = 14) using a 5 Hz non-differential global positioning system (NdGPS). Velocity thresholds were normalized for each age group using the mean squad times for a flying 10 m sprint test as a reference point. Match performance was reported as total distance, high-intensity distance, very high-intensity distance, and sprint distance. Data were reported both in absolute (m) and relative (m . min(-1)) terms due to a rolling substitute policy. The U15 (1.35 +/- 0.09 s) and U16 (1.31 +/- 0.06 s) players were significantly quicker than the U12 (1.58 +/- 0.10 s), U13 (1.52 +/- 0.07 s), and U14 (1.51 +/- 0.08 s) players in the flying 10 m sprint test (P < 0.001). The U16 age-group covered significantly more absolute total distance (U16 > U12, U13, U14), high intensity distance (U16 > U12, U13, U14, U15), very high-intensity distance (U16 > U12, U13), and sprint distance (U16 > U12, U13) than their younger counterparts (P < 0.05). When the data are considered relative to match exposure, few differences are apparent. Training prescription for youth soccer players should consider the specific demands of competitive match-play in each age-group. PMID- 20967675 TI - Ovarian susceptibility to benzo[a]pyrene: tissue burden of metabolites and DNA adducts in F-344 rats. AB - Exposure to environmental toxicants has been implicated as one of the causative factors for infertility in mammals. The objective of this study was to determine the amount of ingested benzo[a]pyrene (BaP), an environmental toxicant that reaches the reproductive tissues (internal dose) subsequent to a single acute exposure. Toward this end, the concentrations of BaP reactive metabolites and BaP DNA adducts were measured throughout the course of BaP's residence in the body. Ten-week-old female Fischer-344 rats weighing approximately 220 g were administered 5 mg BaP/kg body weight orally. 1, 7, 14, 2,1 and 28 d post BaP exposure, BaP parent compound and metabolites from plasma, ovaries, and liver tissues were extracted using liquid-liquid extraction. The extracts were analyzed by reverse-phase highperformance liquid chromatography (HPLC). DNA was isolated and analyzed for BaP-induced DNA adducts by (32)P-postlabeling method. The BaP total metabolite concentrations in plasma, ovaries, and liver showed a gradual decrease from d 1 to 28 post BaP administration. The BaP-DNA adducts concentrations in ovaries and liver tissues from the treatment group demonstrated a trend similar to that observed for metabolites. Ovaries showed greater concentrations of DNA adducts compared to liver. However, with an increase in time post cessation of exposure, the adduct concentrations in liver tissue started declining rapidly, from d 1 to 28. For ovaries, the adduct concentrations demonstrated a significant decline from d 1 to 7 and a gradual fall thereafter. A concordance between BaP reactive metabolite levels and adduct concentrations indicates that the bioavailability of reactive metabolites determines the binding with DNA and consequently the formation and persistence of adducts in an acute exposure regimen. PMID- 20967676 TI - Probabilistic human health risk assessment for quarterly exposure to high chloroform concentrations in drinking-water distribution network of the Province of Quebec, Canada. AB - Because quarterly concentrations of total trihalomethanes (THM) exceeding the 80 MUg/L guideline are often tolerated by the public health authorities of the Province of Quebec (Canada), this study examined whether quarterly episodes of high concentrations of THM may pose a risk to the health of its population. Using Monte Carlo simulations, a probabilistic risk assessment was performed for infants (0-<6 mo), toddlers (6 mo-<5 yr) and adults (>=20 yr). Multiroute exposure including ingestion of drinking water as well as inhalation and dermal exposure while showering or bathing was considered. The resulting absorbed doses were compared to short-term reference values for chloroform, used as surrogate for THM, by calculating risk quotients (RQ). On the basis of THM concentrations values in Quebec's drinking water distribution systems during the months of July to October and exceeding the guideline value (>80 MUg/L), the 95th percentile value of RQ were 0.65, 0.46, and 0.24 for infants, toddlers, and adults, respectively. Back-calculation allowed determining that a chloroform concentration of 330 MUg/L would result in RQ <= 1 for 99% of infants, the subgroup considered the most susceptible among the general population. Overall, this study showed that episodes of high THM concentration encountered in Quebec drinking-water distribution network need not be considered as an immediate health concern for the general population. However, these results should not be interpreted as an authorization to exceed the 80 MUg/L standard but rather as a risk management tool for public health authorities. PMID- 20967677 TI - Changes in plasma retinol of American kestrels (Falco sparverius) in response to dietary or in ovo exposure to environmentally relevant concentrations of a penta brominated diphenyl ether mixture, DE-71. AB - Polybrominated diphenyl ethers (PBDE) are ubiquitous, lipophilic, and bioaccumulative brominated flame retardants. Plasma retinol concentrations of captive adult American kestrels were assessed at the beginning of the breeding season following 3 wk of daily dietary exposure to vehicle (control), low (0.3 ng/g wet weight [ww]), or high (1.6 ng/g ww) concentrations of DE-71 and in their 25-d-old nestlings following embryonic exposure by maternal deposition to environmentally relevant low (291 +/- 48 ng/g ww) or high (1111 +/- 160 ng/g ww) sum (Sigma) PBDE concentrations. Unexpectedly, low in ovo concentrations of total alpha-hexabromocyclododecane (HBCD) were detected. Plasma retinol concentrations of adult males exposed to higher DE-71 concentrations were negatively correlated with in ovo SigmaPBDE, BDE-100, and HBCD levels. Maternal (13%) and nestling (11%) retinol levels were lower in the low-exposure group compared to respective controls, and biologically significant since their retinol levels were correlated with hatching success and growth, respectively. Maternal retinol levels were also correlated with BDE-153. The underlying mechanisms may involve (1) PBDE exposure, hydroxylated (OH-) metabolites, and subsequent changes in retinol mobilization; (2) decreased maternal food consumption; and (3) reduced maternal retinol yolk deposits. The apparent lack of retinol changes in the high-exposure kestrel may reflect compensation occurring, either by increased mobilization and transportation of retinol, and/or higher food consumption in these birds. When highly mobile as evidenced during reproduction or development, retinol concentrations of adult and nestling kestrels are sensitive to environmentally relevant PBDE and HBCD levels. PMID- 20967679 TI - The effect of a multicomponent dual-modality exercise program targeting osteoporosis on bone health status and physical function capacity of postmenopausal women. AB - PURPOSE: Exercise is important for the prevention of osteoporosis and the reduction of fracture risk because it improves muscle mass and strength, besides improving balance. We evaluated the effect of a specific exercise program on bone mass and quality and physical function capacity in postmenopausal women with low bone mineral density. METHODS: Participants (N = 125) underwent a bone mass (Dual X-ray Absorptiometry), bone quality (osteosonography), and physical functional capacity assessment. Fifty-eight of them took part in an 11-month exercise program (E), that included a multicomponent (strength, aerobic capacity, balance, joint mobility) dual-modality (on ground and in the water; alternating group and home-based exercise periods) exercise regimen. The others represented a control group (C) that did not exercise. After the exercise program all participants were reevaluated. RESULTS: After the training program: femoral neck T-score significantly improved in E; C significantly decreased all bone quality (osteosonography) parameters, whereas E showed no differences; E significantly improved all the physical function capacity parameters, while most of them decreased or did not change in C. CONCLUSIONS: A specific exercise program targeting osteoporosis improves physical function capacity, reduces physiological bone loss, and maintains bone quality in low bone mineral density postmenopausal women. PMID- 20967681 TI - Comparative use of complementary medicine, allied health, and manual therapies by middle-aged and older Australian women. AB - We compared use of Complementary and Alternative Medicines (CAM) and therapies, Allied Health interventions (AH), and Manual Therapies (MT) in middle-aged and older Australian women. Cross-sectional data from the 2007 phase of the Longitudinal study of Aging in Women (LAW study) was analyzed. Self-reported 12 month usage patterns of CAM, AH, and MT were determined by mailed questionnaire. Results revealed that 56.2% of the middle-aged group, and 55.0% of the older group used CAM, AH, and MT services in the previous 12 months (a nonsignificant difference). In contrast, there was a highly significant difference between the overall use of CAM products by middle-aged women (88.2%) and older women (67.7%: p = .002). PMID- 20967680 TI - Exercise self-regulation among older women participating in a heart disease management intervention. AB - Using behavioral self-regulation processes may facilitate exercise among older women with heart disease. Data from women in a heart disease-management program (n = 658, mean 73 years), was used to explore associations among exercise self regulation components (i.e., choosing to improve exercise and observing, judging, and reacting to one's behavior) and exercise capacity. General linear models showed that choosing exercise predicted higher exercise self-regulation scores postprogram and 8 months later. In turn, these scores predicted greater improvements in exercise capacity concurrently and 8 months later. Interaction analyses revealed that the effect of self-regulation on exercise capacity was stronger among women who chose to work on exercise. PMID- 20967682 TI - Aging and sexuality: how much do gynecologists know and care? AB - Enhanced knowledge and healthy attitudes toward aging sexuality can help promote the perception that full sexual expression is part of the entire extent of adulthood. We sought to determine gynecologists' knowledge and attitude regarding sexuality in older women. A total of 141 gynecologists in five hospitals responded to the survey: Aging Sexual Attitude and Knowledge Scale (ASKAS). No correlation was found between respondents' knowledge and attitude (r = .06, p = .54); no correlation found between respondents' age and knowledge (r = .20, p = .02), but 20% of the variance in attitude could be explained by age (beta 0.20, p = .02). Neither gender, ethnicity, level of training, nor hospital location demonstrated a significant correlation to either knowledge or attitude scores. PMID- 20967683 TI - The perception of menopause among Turkish women. AB - The perception of menopause, menopausal attitudes, and problems faced during this period vary from one society to another. This study was conducted in order to determine the symptoms and perception of menopause, as well as factors affecting and influencing this perception. This study was made with the help of 300 women in menopause who applied to Akdeniz University Research and Application Hospital in January 2007. The study used sociodemographic data from a descriptive survey form. The data were collected by researchers in face-to-face interviews. The mean menopause age of participating women was x = 45.75 +/- 4.7. A total of 41.3% of the women had primary education, and 62% of the women also had one or two children. There was a significant relationship between attitudes toward menopause and a woman's age, educational status, number of children, duration of living with spouse, satisfaction with marriage, menopausal age, menopause duration, and sexual intercourse after the menopausal period. The most important aspect of polyclinic services related to menopause is to increase and maintain women's quality of life. In this context, education modules should be developed to help couples perceive menopause in a more positive way. PMID- 20967684 TI - Advance care planning by unmarried women of different sexual orientations: the importance of social support. AB - We examined social support as a facilitator of advance care planning in unmarried women of different sexual orientations. Survey participants consisted of 215 women, 90 who reported a preference for partnering with women (WPW) and 125 for partnering with men (WPM). Our findings indicate that the association between social support and advance care planning was mixed. Specifically, social support had no significant impact on executing a will for either WPW or WPM. Among WPW, naming a health-care proxy was associated with reporting a partner who provided social support. For WPM, having a partner for social support was not associated with naming a health-care proxy. These insights help in the understanding of women's advance care planning. PMID- 20967687 TI - The diagnostic accuracy of an incidental memory modification of the Boston Naming Test (memo-BNT) in differentiating between normal aging and mild Alzheimer's disease. AB - Early Alzheimer's disease (AD) is associated with deficits in episodic memory. Semantic memory and naming have also been found to be affected, although to a lesser degree than episodic memory. Most episodic memory tests used in clinical settings assess intentional memory. The aim of the present paper was to present an incidental memory modification of the Boston Naming Test (memo-BNT) and to study the diagnostic accuracy of the BNT and the memo-BNT in differentiating between healthy old controls and AD patients. There were three groups in the study: 22 young controls (mean age 21.7), 23 normally aged old controls (mean age 70.6), and 23 patients with mild AD (mean age 74.0). There were no differences in the memo-BNT test scores between the old and young control participants. There were, however, significant differences between the AD patients and both control groups in several of the memo-BNT measures. Incidental free recall was the best measure in discriminating between the healthy aged controls and the AD patients (AUC = .939) and it had a better diagnostic accuracy than naming (AUC = 880). The results indicate that the memo-BNT could be used in clinical settings especially to differentiate between normal aging and mild AD. PMID- 20967688 TI - Cognitive change on the repeatable battery of neuropsychological status (RBANS) in Parkinson's disease with and without bilateral subthalamic nucleus deep brain stimulation surgery. AB - Cognitive change following bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) surgery in those with Parkinson's disease (PD) has led to equivocal results. The current study applied a standardized regression-based (SRB) method based on 20 medically managed PD patients and 20 STN DBS PD surgical patients who were administered the Repeatable Battery of Neuropsychological Status (RBANS). Of the medically managed PD participants, 94% remained stable compared to 73% of the DBS group. In the DBS group cognitive change was noted on the Total scale and the Immediate Memory Index. A secondary analysis also revealed reliable change on several subtest scores. Although preliminary, the current study provides change parameters for post DBS surgery on this brief battery. PMID- 20967689 TI - Embodiment of motor skills when observing expert and novice athletes. AB - If people are shown a dynamic movie of an action such as kicking a soccer ball or hitting a tennis ball, they will respond to it faster if it requires the same effector. This standard congruency effect was reported to reverse when participants viewed static images of famous athletes not actually performing an action. It was suggested that the congruent response was inhibited because of a social contrast effect, based on an implied action, whereby responders viewed themselves as comparatively worse than the professional athlete. The present study recorded hand and foot responses when identifying static images of both famous and novice athletes in soccer and tennis. The action was either explicit or implied. In Experiment 1, a standard congruency effect was found for all images. In Experiment 2, when a response was based on the identity of the athlete rather than their expertise, the standard congruency effect was enhanced for images of novice athletes, but was eliminated for experts, suggesting a social contrast effect. Our study is the first to show that embodiment effects can be seen for implied and explicit action images of both novices and experts, and that static images are capable of eliciting priming effects associated with sport relevant effector pairings. PMID- 20967690 TI - [Attachment and somatoform disorders: low coherence and unresolved states of mind related to chronic pain]. AB - Although attachment theory has become an influential approach used for the study of mental disorders, hitherto little has been known about the relation of attachment to somatoform disorders. In this study 15 patients with a somatoform pain disorder were compared with 15 non-clinical control participants. Attachment representations were measured by the Adult Attachment Interview (AAI). Compared to the control group, the patient group describes parental behavior as less loving and more rejecting, expresses more anger towards the mother, shows more signs of unresolved loss and trauma, and their interviews are markedly less coherent. None of the patients is classified as secure; the majority falls within the unresolved category. The findings of this study can contribute to a better understanding of the often described adversities in the therapeutic alliance with these patients. PMID- 20967691 TI - [New knowledge about vitamin D balance--not only a "bone vitamin"]. PMID- 20967695 TI - Evaluation of TFAM and FABP4 gene polymorphisms in three lines of Nellore cattle selected for growth. AB - We analyzed the polymorphisms TFAM HaeIII, TFAM MboI and FABP4 MspA1I in three Nellore lines selected for growth in order to evaluate how selection affects the frequencies of these polymorphisms and evaluate their association with growth and carcass traits in Zebu cattle. Birth, weaning and yearling weights, rump height, longissimus muscle area, backfat thickness, and rump fat thickness were analyzed. The sample was constituted of animals from two lines selected for yearling weight (NeS and NeT), and a control line (NeC), established in 1980, at the Sao Paulo Instituto de Zootecnia. Two hundred and seventy-two heifers were genotyped for TFAM gene SNPs, and 325 heifers were genotyped for the FABP4 SNP. High frequencies were observed for the alleles A (TFAM HaeIII), C (TFAM MboI) and C (FABP4 MspA1I). Significant differences in allele frequencies between NeS and NeT were observed for the TFAM HaeIII, and between the line NeT and lines NeC and NeS for the FABP4 MspA1I SNP. Five haplotypes were observed for the two polymorphisms in the TFAM gene, haplotype AACC being the most frequent. None of the markers separately or according to haplotype was significantly associated with the growth and carcass traits. The low frequencies of alleles that are associated with high marbling scores and thick subcutaneous fat in taurine breeds might explain the low means for these traits in Nellore cattle. PMID- 20967696 TI - Metagenomic study of single-nucleotide polymorphism within candidate genes associated with type 2 diabetes in an Indian population. AB - A population-based study was undertaken to evaluate linkage between single nucleotide polymorphisms known as risk factors and type 2 diabetes in an Indian population. The study population was comprised of 40 normal glucose-tolerant individuals (21 males and 19 females) and 40 type 2 diabetes patients (21 males and 19 females). The genes and their corresponding single-nucleotide polymorphisms that we screened were VDR (rs 731236 and rs 1544410), IL-6 (rs 1800795), TCF7L2 (rs 7903146) and TNF-alpha (rs 1800629). The risk alleles were more frequent in the subjects with type 2 diabetes, except for the TNF-alpha gene, which was very infrequent in the population; the normal allele occurred at high and similar frequencies in both normal and diabetic individuals. PMID- 20967697 TI - Development of two multiplex mini-sequencing panels of ancestry informative SNPs for studies in Latin Americans: an application to populations of the State of Minas Gerais (Brazil). AB - Admixture occurs when individuals from parental populations that have been isolated for hundreds of generations form a new hybrid population. Currently, interest in measuring biogeographic ancestry has spread from anthropology to forensic sciences, direct-to-consumers personal genomics, and civil rights issues of minorities, and it is critical for genetic epidemiology studies of admixed populations. Markers with highly differentiated frequencies among human populations are informative of ancestry and are called ancestry informative markers (AIMs). For tri-hybrid Latin American populations, ancestry information is required for Africans, Europeans and Native Americans. We developed two multiplex panels of AIMs (for 14 SNPs) to be genotyped by two mini-sequencing reactions, suitable for investigators of medium-small laboratories to estimate admixture of Latin American populations. We tested the performance of these AIMs by comparing results obtained with our 14 AIMs with those obtained using 108 AIMs genotyped in the same individuals, for which DNA samples is available for other investigators. We emphasize that this type of comparison should be made when new admixture/population structure panels are developed. At the population level, our 14 AIMs were useful to estimate European admixture, though they overestimated African admixture and underestimated Native American admixture. Combined with more AIMs, our panel could be used to infer individual admixture. We used our panel to infer the pattern of admixture in two urban populations (Montes Claros and Manhuacu) of the State of Minas Gerais (southeastern Brazil), obtaining a snapshot of their genetic structure in the context of their demographic history. PMID- 20967698 TI - Effects of Thai black sticky rice extract on oxidative stress and lipid metabolism gene expression in HepG2 cells. AB - Anthocyanins, which are found in some food, including Thai black sticky rice, are reported to have health-promoting properties. Oxidative stress plays a major role in the pathogenesis of many degenerative diseases induced by free radicals, such as cardiovascular disease, stroke and cancer. We evaluated the anthocyanin-rich extract (ARE) from Thai black sticky rice for antioxidative and antihyperlipidemic effects on HepG2 cells. Cell viability was investigated with the neutral red assay and the MTT assay, and oxidative stress was determined by the DCFH-DA assay. RT-PCR was used to evaluate the effect of ARE on LDLR, HMG CoAR, PPAR (alpha1,gamma) and LXRa gene expression. We found that ARE at high doses (>= 800 mg/L) induces cytotoxicity. However, at 600-1000 mg/L it reduced intracellular oxidative stress (P < 0.05) in a dose-dependent manner, and at 200 mg/L it significantly enhanced the expression of the LDLR gene in HepG2 cells. We concluded that ARE can be beneficial for health promotion by reducing oxidative stress and enhancing LDL clearance, regulating LDLR production on the cell surface membrane, thereby maintaining lipid homeostasis. PMID- 20967699 TI - Meiotic behavior as a selection tool in silage corn breeding. AB - In breeding programs, commercial hybrids are frequently used as a source of inbred lines to obtain new hybrids. Considering that maize production is dependent on viable gametes, the selection of populations to obtain inbred lines with high meiotic stability could contribute to the formation of new silage corn hybrids adapted to specific region. We evaluated the meiotic stability of five commercial hybrids of silage corn used in southern Brazil with conventional squashing methods. All of them showed meiotic abnormalities. Some abnormalities, such as abnormal chromosome segregation and absence of cytokinesis, occurred in all the genotypes, while others, including cytomixis and abnormal spindle orientation, were found only in some genotypes. The hybrid SG6010 had the lowest mean frequency of abnormal cells (21.27%); the highest frequency was found in the hybrid P30K64 (44.43%). However, the frequency of abnormal meiotic products was much lower in most genotypes, ranging from 7.63% in the hybrid CD304 to 43.86% in Garra. Taking into account the percentage of abnormal meiotic products and, hence, meiotic stability, only the hybrids CD304, P30K64, SG6010, and P30F53 are recommended to be retained in the breeding program to obtain inbred lines to create new hybrids. PMID- 20967700 TI - Virtual histology intravascular ultrasound evaluation of the left anterior descending coronary artery in patients with transient left ventricular ballooning syndrome. AB - BACKGROUND: transient left ventricular ballooning syndrome (TLVBS) has been recently recognised as an acute disease mimicking myocardial infarction. AIM: we used greyscale and virtual histology (VH) intravascular ultrasound (IVUS) to study the presence and characteristics of atherosclerotic plaque in the left anterior descending (LAD) artery in patients with TLVBS. METHODS: the study population consisted of 14 consecutive patients with a TLVBS diagnosis based on typical symptoms and balloon-like left ventricle abnormalities. The IVUS imaging and analysis included at least the mid and proximal segments of each LAD. Virtual histology (VH)-IVUS analysis colour-coded plaque as calcific, fibrotic, fibrofatty, and necrotic core; VH-IVUS-derived thin-cap fibroatheroma (TCFA) and high-risk plaques were identified. RESULTS: the total length of the IVUS-analysed LAD averaged 55 +/- 14 mm. Greyscale analysis revealed a mean plaque burden of 28.9 +/- 11%. There were 7 ruptured plaques; these were present in mid-segments of the LAD in 3 patients, and in the proximal segment in 4 patients. The VH-TCFAs were found in 8 patients, while the remaining 6 patients had a necrotic core > 25%. The average number of VH-TCFAs was 4.8 +/- 2.9 per patient. Combining greyscale and VH-IVUS data, 8 patients had either a ruptured plaque or a VH-TCFA, while the other 6 patients had a necrotic core > 25%. The distance from the coronary ostium to the cross-sections with a VH-TFCA was 20 +/- 2.8 mm. CONCLUSIONS: vulnerable plaques are observed in patients with TLVBS. Our findings support the hypothesis that TLVBS may be related to the natural course of atherosclerotic plaque development. Further study into the relations between vulnerable plaque surface, platelet activity and subsequent thrombus formation is needed in this population. PMID- 20967701 TI - [Editorial comment: Tako-tsubo syndrome - another form of acute coronary syndrome?]. PMID- 20967702 TI - Circulating endothelial cells in coronary artery disease. AB - BACKGROUND: endothelial damage and dysfunction play a crucial role in the pathophysiology of coronary artery disease (CAD). The quantification of circulating endothelial cells (CEC) in the peripheral blood is a novel method for assessing endothelial damage. AIM: to evaluate the possible diagnostic use of single quantification of CEC in peripheral blood by flow cytometry in patients with CAD. METHODS: we examined 48 patients with CAD, including 23 patients with acute myocardial infarction (AMI) and 25 patients with stable angina (SA). The control group consisted of 20 healthy subjects without symptoms of CAD. The CEC count was evaluated by flow cytometry using antibodies against CD31, CD146, and CD45. Plasma biochemical markers of endothelial damage (von Willebrand Factor [vWF], thrombomodulin [TM]) were measured by ELISA. Serum concentrations of troponin I (TnI) and lipid parameters were also included in the statistical analysis. RESULTS: A significant increase in the CEC count was found in patients with AMI compared to the control group (p < 0.05) and SA patients (p < 0.05). However, no difference was found in the CEC count between patients with SA and the control group. Increased vWF activity was found in both groups of CAD patients compared to the control group (AMI: p < 0.001, SA: p , 0.01), and vWF activity was significantly higher in AMI patients compared to SA patients (p < 0.001). Thrombomodulin concentration did not differ significantly between any patient groups and the control group. The CEC count correlated positively with vWF activity (r = 0.3852, p < 0.05) and the atherogenic index TC/HDL-C (r = 0.3844, p < 0.05) in all patients with CAD (AMI + SA). The sensitivity of CEC count for the diagnosis of an acute coronary syndrome was lower than that of TnI level on admission (39% vs 69%). CONCLUSIONS: we confirmed that CEC count in peripheral blood can be determined by flow cytometry in CAD patients with both AMI and SA. The CEC count in AMI was increased in comparison to healthy subjects and SA patients in one third of all cases. To determine whether CEC count could be used to improve the diagnosis of an acute coronary syndrome in patients with CAD, additional studies in larger patient groups would be required. PMID- 20967703 TI - [Editorial comment: In search of a clinically useful method for assessing vascular endothelial function]. PMID- 20967704 TI - ST elevation in the lead aVR during exercise treadmill testing may indicate left main coronary artery disease. AB - BACKGROUND: exercise treadmill testing (ETT) is the most widely used method for evaluating patients with coronary artery disease. Predicting the left main coronary artery (LMCA) disease before invasive procedures is very important in risk assessment because of its severe clinical outcome. AIM: To examine whether ST elevation in lead aVR during ETT may suggest LMCA disease since the lead aVR is the reciprocal lead of LMCA. METHODS: in this study, 61 patients with positive ETT were included. The study group consisted of 21 patients with ST elevation in lead aVR. Forty patients, also having positive ETT, but without ST elevation in lead aVR comprised the control group. All patients underwent coronary angiography. RESULTS: coronary angiography in the study group revealed significant LMCA stenosis in 16 (76%) patients, whereas LMCA disease was present in only 3 (8%) patients from the control group. There was no significant coronary artery stenosis in 5 patients in the study group and 12 patients in the control group. Of the 16 patients who had LMCA stenosis, 9 had isolated LMCA disease and 7 had additional stenotic lesions in LAD or circumflex coronary arteries. The sensitivity and specificity of ST segment elevation in lead aVR during ETT was 84% and 88%, respectively. The values of positive and negative predictive value of this finding in diagnosing the presence of LMCA were 76% and 93%, respectively. CONCLUSIONS: ST segment elevation in lead aVR during ETT may point to a high probability of the presence of LMCA disease. PMID- 20967705 TI - [Editorial comment: Stress ST-segment elevation in the aVR lead in patients with significant left coronary artery stenosis]. PMID- 20967706 TI - Percutaneous peripheral interventions in patients with multivessel coronary artery disease. AB - BACKGROUND: coronary artery disease (CAD) is often accompanied by peripheral artery disease. There are patients who are disqualified from surgical approach in the treatment of limb ischaemia due to many comorbidities including severe CAD. AIM: to examine whether multilevel intervention (peripheral and coronary) in patients with multi-vessel CAD (MVD) carries a higher in-hospital and long-term risk in comparison to patients with a single vessel disease (SVD). METHODS: data on consecutive patients with peripheral artery disease and CAD (acute coronary syndrome) were gathered in our department from January 2003 till June 2009. All patients included in the study had peripheral and coronary angioplasty performed during the same index hospital stay. Patients were divided into two groups: those with SVD and those with MVD in coronary angiography. RESULTS: there were 116 patients included in the study - 56 patients in the SVD group and 60 patients in the MVD group. The frequency of major adverse cerebrovascular and cardiac events during long-term follow up tended to be higher in patients with MVD, however the difference did not reach statistical significance (MVD vs SVD: 13.3% vs 3.6%, p = 0.061). There were significantly more major adverse peripheral events such as repeat percutaneous transluminal angioplasty, stroke/transient ischaemic attack and lower limb amputation in the MVD group than in the SVD patients (20% vs 1.8%, p = 0.002). CONCLUSIONS: percutaneous angioplasty of lower limb arteries in patients with MVD seems to be an effective and relatively safe method of treatment of patients with disseminated atherosclerosis and an alternative to surgical treatment. PMID- 20967707 TI - [Time for consensus]. PMID- 20967708 TI - Immediate and 6-month outcomes of transapical and transfemoral Edwards-Sapien prosthesis implantation in patients with aortic stenosis. AB - BACKGROUND: severe symptomatic aortic valve stenosis is an unequivocal indication for surgical valve replacement, assuring symptoms relief and increasing survival. About one third of elderly patients is not being operated due to, among others, high peri-procedural risk and comorbidities. Transcatheter aortic valve implantation (TAVI) has recently become a valuable therapeutic option for these patients. AIM: to present early results of first TAVI Edwards-Sapien procedures in our hospital, performed in symptomatic patients with high operational risk or other contraindications for conventional surgery, as well as the results of 6 month follow-up. METHOD: twelve patients referred for TAVI were included in the analysis. The valve was implanted in 11 patients and in 1 patient the procedure was finished with aortic valve valvuloplasty. Eight (72.7%) patients underwent transapical (TA) and 3 (27.3%) patients transfemoral (TF) TAVI. Seven (63.6%) 26 mm valves and 4 (34.4%) 23 mm valves were implanted. RESULTS: the efficacy of the procedure was 92%: 100% in the TA group, and 75% in the TF group. During the procedure 1 patient developed ventricular fibrillation. Atrial fibrillation and right ventricle perforation by the endocavitary electrode was observed in another patient. Prolonged wound healing occurred in 4 patients and contrast-induced renal failure occurred in 2 patients. There were no deaths at 30-days. Two patients had a pacemaker implanted during hospitalisation. A significant improvement of echocardiographic parameters was observed: maximum gradient across the aortic valve was 104.4 +/- 23.9 mm Hg before vs 25.2 +/- 6.1 mm Hg after the intervention, p = 0.000001, mean gradient - 63.8 +/- 18.3 vs 12.7 +/- 3.7 mm Hg, p = 0.000004, and valvular surface - 0.7 +/- 0.2 vs 1.5 +/- 0.2 cm2, p = 0.000106, respectively. During the 6-month follow-up period 1 patient died of multiorgan failure and 6 patients required another hospitalisation. After 6 months an improvement in physical capacity was observed in all but one patients (NYHA II - 9 patients, NYHA III - 1 patient). CONCLUSIONS: 1. The authors' initial experiences with TAVI Edwards-Sapien procedure confirm its efficacy and safety in patients with symptomatic aortic stenosis and high surgical risk. 2. Echocardiographic parameters of the implanted valves, assessed during hospitalisation and 6 month later, are satisfactory. 3. Due to the risk of complications, patients require careful observation in the postoperative period and during short-term follow-up. PMID- 20967709 TI - [Editorial comment: Aortic valve stenosis - new challenges for interventional cardiology]. PMID- 20967710 TI - Quality of life and depression in patients with different patterns of atrial fibrillation. AB - BACKGROUND: atrial fibrillation (AF) is difficult to cure and significantly affects quality of life was well as emotional status of patients. AIM: to evaluate quality of life and depression level in patients with various patterns of AF. METHODS: we studied 150 consecutive patients with AF aged 35-83 years, including 61 patients with paroxysmal AF, 46 patients with persistent AF, and 43 patients with permanent AF. The control group included 70 healthy persons (mean age: 55.5 +/- 14.5 years). Quality of life was estimated using the Nottingham Health Profile questionnaire. Risk of depression occurrence was estimated using the Beck Depression Inventory scale. Physical abilities, energy level, pain, emotional reactions, sleep, social isolation, problems with work, family life and sexual life were analysed. RESULTS: the mean age of patients with paroxysmal AF was higher in comparison to patients with permanent AF (68.4 +/- 9.4 vs 62.0 +/- 9.2 years, p < 0.05). In patients with all AF forms, the prevalence of symptoms indicating depression was significantly higher in comparison with control group (paroxysmal AF: 10.8 +/- 5.8%, persistent AF: 10.0 +/- 6.4%, permanent AF: 10.1 +/- 7.2% vs 5.7 +/- 5.8% in controls, p < 0.01). The level of depression was higher in women regardless of AF form (p < 0.005). Patients with paroxysmal and permanent AF had lower scores of emotional reactions (p < 0.05) and social isolation (p < 0.05) in comparison with the control group. All patients with AF had lower scores of energy level in comparison with the control group (paroxysmal AF: 1.2 +/- 0.2, persistent AF: 1.1 +/- 0.2, permanent AF: 1.2 +/- 0.2 vs 0.5 +/- 0.1 in controls, p < 0.005). Patients with paroxysmal, persistent and permanent AF had greater degree of activity limitations than the control group (1.8 +/- 0.2, 1.7 +/- 0.3, 2.1 +/- 0.3, respectively, vs 1.0 +/- 0.2, p < 0.005). Limitations of work were detected in 28.6-35.9% of patients with various forms of AF, sex life disturbances in 23.8-33.9% of patients, and family life problems in 10.3-21.4% of patients. The lowest results of these scores were noted in patients with paroxysmal AF. CONCLUSIONS: atrial fibrillation, independently of its form, has substantial impact on the risk of depression occurrence. Patients with paroxysmal and permanent AF had lower self-evaluation of their energy level. In all studied groups of AF patients, the arrhythmia significantly limited quality of life, especially sexual life as well as professional and home activity. PMID- 20967711 TI - [Acute intermediate-risk pulmonary embolism with right-sided free-floating intracardiac thrombus, systemic inflammatory reaction syndrome, multiple organ dysfunction syndrome, disseminated intravascular coagulation and acute ischaemia of a limb]. AB - A case of a 64 year-old woman admitted to ICCU because of severe dyspnoea and oedema of left lower limb is presented. We diagnosed coincidence of acute pulmonary embolism with right-sided free-floating heart thrombi, systemic inflammatory reaction syndrome, multiple organ dysfunction syndrome, disseminated intravascular coagulation and acute ischaemia of the right lower limb. Due to atypical clinical presentation therapeutic strategies were discussed with ZATPOL registry coordinator. The patient was treated pharmacologically, underwent cardiosurgical evacuation of right-sided intracardiac thrombus and lower limb amputation. At follow up visit 6 months after discharge from hospital she was in good general condition with no complaints. PMID- 20967712 TI - [Right atrial tumour and right ventricular failure - diagnostic role of echocardiography and cardiovascular magnetic resonance]. AB - A case of a 66 year-old female with advanced right ventricular failure is described. Echocardiography and MRI revealed the presence of right atrial tumour. The patient underwent successful surgery and histological examination revealed lymphoma. PMID- 20967713 TI - [Cardiac tamponade of unknown aetiology in a dialyzed patient]. AB - A case of a 58 year-old male with renal failure and recurrent cardiac tamponade is presented. In spite of extensive work-up, aetiology of pericardial effusion remained unknown. Diagnostic difficulties in this setting are discussed. PMID- 20967715 TI - Computed tomography angiography for visualisation of distal coronary arteries and selection for surgical revascularisation in a patient with acute myocardial infarction. AB - Patients with symptomatic multivessel coronary artery disease rejected for coronary revascularisation have adverse prognosis. We describe a 61 year-old male with non-ST-elevation myocardial infarction who was considered unsuitable for coronary revascularisation based on the conventional angiography findings. Unlike conventional angiography, computed tomography angiography visualised distal coronary segments and the patient underwent successful coronary artery bypass grafting. PMID- 20967717 TI - [The role of tissue factor and tissue factor pathway inhibitor in blood coagulation and in thrombotic complications]. PMID- 20967718 TI - [Cardiac stem cells]. PMID- 20967719 TI - [Influenza and cardiovascular diseases]. PMID- 20967720 TI - [Myocardial infarction or pericarditis?]. PMID- 20967722 TI - Congenitally corrected transposition of the great arteries and participation in competitive sport. AB - Congenitally corrected transposition of the great arteries is a rare anomaly, where the systemic circulation is supported by the morphological right ventricle. We present a 43 year-old asymptomatic male, a former competitive short-distance runner, with recently diagnosed congenitally corrected transposition of the great arteries. To our knowledge this is the first report of such a case. PMID- 20967723 TI - Treatment strategies for coronary lesions in Takayasu arteritis patients - case report and review of the literature. AB - Takayasu arteritis is type of vasculitis that usually affects the aorta and its major branches. While coronary involvement is seen infrequently, treatment strategy is less clear. Here, we report a case of a 45 year-old woman with Takayasu arteritis who underwent a Y-graft coronary bypass surgery four years previously. We present the long-term follow-up this patient, with a literature review. and we discuss treatment strategies. PMID- 20967725 TI - Syncope cluster in a patient with vasovagal history. AB - We report a case of a 55 year-old man with a history of vasovagal syncope who experienced six unexpected syncopal events over the course of two hours. Two of these occurred in the supine position during ECG monitoring, which showed a long lasting sinus pause. Before the last syncopal episode, the ECG recording was started at the moment when the patient had the recurrence of presyncopal symptoms. Recordings showed sinus rhythm slowing for 12 s and then sinus arrest lasting for 29 s. A thorough clinical examination revealed no relevant abnormalities. The patient was treated with a permanent pacemaker implantation. PMID- 20967726 TI - [Commentary to the article: Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomized controlled trials. Lancet Oncology, 2010; DOI:10.1016/S1470-2045(10)70106-6]. PMID- 20967727 TI - [Comment to article "Szczeki" w oceanie sartanow]. PMID- 20967728 TI - Takayasu's arteriopathy with associated occlusion of right coronary artery, brachiocephalic trunk and left subclavian artery and aortic regurgitation. Cardiovascular approach leading to a successful outcome - a case presentation. AB - In a 37 year-old woman with Takayasu's arteriopathy angiography revealed occlusion of right coronary artery (RCA), brachiocephalic trunk and left carotid artery (LCA), as well as aortic regurgitation. She underwent a complex cardiovascular surgery consisting of aortic valve implantation, RCA grafting and implantation of vascular bifurcated graft anastomosed between ascending aorta and brachiocephalic trunk and LCA. The multi-slice computed tomography performed two weeks after the operation revealed preserved grafts patency. PMID- 20967729 TI - Takayasu arteriopathy - rare, but worth remembering the disease. PMID- 20967730 TI - [Treatment of pulmonary hypertension in 2010. News from the International Conference on Pulmonary Circulation, Prague, 2(nd)-5(th) June 2010]. PMID- 20967731 TI - [14(th) International congress of the Polish Cardiac Society - president's view]. PMID- 20967732 TI - [Kardiologia Polska (Polish Heart Journal) - annual report]. PMID- 20967733 TI - [European Society of Cardiology Congress - Stockholm 2010]. PMID- 20967735 TI - Metabolic profiling of Escherichia coli by ion mobility-mass spectrometry with MALDI ion source. AB - Comprehensive metabolome analysis using mass spectrometry (MS) often results in a complex mass spectrum and difficult data analysis resulting from the signals of numerous small molecules in the metabolome. In addition, MS alone has difficulty measuring isobars and chiral, conformational and structural isomers. When a matrix-assisted laser desorption ionization (MALDI) source is added, the difficulty and complexity are further increased. Signal interference between analyte signals and matrix ion signals produced by MALDI in the low mass region (<1500 Da) cause detection and/or identification of metabolites difficult by MS alone. However, ion mobility spectrometry (IMS) coupled with MS (IM-MS) provides a rapid analytical tool for measuring subtle structural differences in chemicals. IMS separates gas-phase ions based on their size-to-charge ratio. This study, for the first time, reports the application of MALDI to the measurement of small molecules in a biological matrix by ion mobility-time of flight mass spectrometry (IM-TOFMS) and demonstrates the advantage of ion-signal dispersion in the second dimension. Qualitative comparisons between metabolic profiling of the Escherichia coli metabolome by MALDI-TOFMS, MALDI-IM-TOFMS and electrospray ionization (ESI) IM-TOFMS are reported. Results demonstrate that mobility separation prior to mass analysis increases peak-capacity through added dimensionality in measurement. Mobility separation also allows detection of metabolites in the matrix-ion dominated low-mass range (m/z < 1500 Da) by separating matrix signals from non matrix signals in mobility space. PMID- 20967736 TI - Investigation of the pyrolysis products of methionine-enkephalin-Arg-Gly-Leu using liquid chromatography-tandem mass spectrometry. AB - Low-temperature pyrolysis of methionine-enkephalin-Arg-Gly-Leu has been carried out and the non-volatile residues have been analyzed. The fragments were separated and characterized by LC-UV/Vis-MS/MS. Two major types of pyrolysis products were identified by matching the experimental results with a theoretical list that contains the expected fragments. These products were mainly composed of cyclic oligopeptides and linear fragments produced from the peptide backbone. These fragments have preserved the sequence of amino acids in the peptide. In some cases, a complete or partial loss of an amino-acid side group was observed. Tandem mass spectrometry and cyanogen bromide cleavage experiments were used to confirm the nature of the cyclic and linear pyrolysates, in addition to chromatographic and mass spectrometric data of actual standard synthetic cyclic peptides. PMID- 20967737 TI - Phase I and II metabolites of speciogynine, a diastereomer of the main Kratom alkaloid mitragynine, identified in rat and human urine by liquid chromatography coupled to low- and high-resolution linear ion trap mass spectrometry. AB - Mitragyna speciosa (Kratom in Thai), a Thai medical plant, is misused as herbal drug of abuse. Besides the most abundant alkaloids mitragynine (MG) and paynantheine (PAY), several other alkaloids were isolated from Kratom leaves, among them the third abundant alkaloid is speciogynine (SG), a diastereomer of MG. The aim of this present study was to identify the phase I and II metabolites of SG in rat urine after the administration of a rather high dose of the pure alkaloid and then to confirm these findings using human urine samples after Kratom use. The applied liquid chromatography coupled to low- and high-resolution mass spectrometry (LC-HRMS-MS) provided detailed information on the structure in the MS(n) mode particularly with high resolution. For the analysis of the human samples, the LC separation had to be improved markedly allowing the separation of SG and its metabolites from its diastereomer MG and its metabolites. In analogy to MG, besides SG, nine phase I and eight phase II metabolites could be identified in rat urine, but only three phase I and five phase II metabolites in human urine. These differences may be caused by the lower SG dose applied by the user of Kratom preparations. SG and its metabolites could be differentiated in the human samples from the diastereomeric MG and its metabolites comparing the different retention times determined after application of the single alkaloids to rats. In addition, some differences in MS(2) and/or MS(3) spectra of the corresponding diastereomers were observed. PMID- 20967738 TI - Tandem mass spectrometry of silver-adducted ferrocenyl catalyst complexes. AB - Ferrocene is a popular template in material science due to its exceptional characteristics that offer the ability to optimize the selectivity and activity of catalysts by the addition of carefully selected substituents. In combinatorial catalyst development, the high susceptibility to electrophilic substitution reactions offers the opportunity for the rapid introduction of molecular diversity. Mass spectrometry (MS)-based continuous-flow systems can be applied to rapidly evaluate catalyst performance as well as to (provisionally) identify the introduced catalyst complexes. Herein, we describe the fragmentation characteristics of the [ferrocenyl bidentate + Ag](+) catalyst complexes in dedicated (high-resolution) MS(n) experiments. The investigation of the fragmentation patterns of a selected number of catalyst classes is accompanied with a density functional theory investigation of fragmentation intermediates in order to assess the viability of a selected fragmentation mechanism. PMID- 20967739 TI - Energy-dependent dissociation of benzylpyridinium ions in an ion-trap mass spectrometer. AB - Benzylpyridinium ions, generated via electrospray ionization of dilute solutions of their salts in acetonitrile/water, are probed by collisional activation in an ion-trap mass spectrometer. From the breakdown diagrams obtained, phenomenological appearance energies of the fragment ions are derived. Comparison of the appearance energies with calculated reaction endothermicities shows a reasonably good correlation for this particular class of compounds. In addition, the data indirectly indicate that at threshold the dissociation of almost all of the benzylpyridinium ions under study leads to the corresponding benzylium ions, rather than the tropylium isomers. Substituent effects on the fragmentation for a series of benzylpyridinium ions demonstrate that neither mass effects nor differences in density of states seriously affect the energetics derived from the ion-trap experiments. PMID- 20967740 TI - Safe use of radioisotopes. AB - The pursuit of scientific knowledge has been considerably advanced by the use of biochemical molecules that incorporate radioisotopes at specific sites. The fate of these labeled molecules, and/or the radiolabeled products that result from biochemical reactions in which the parent molecule was involved, can be traced using a variety of instruments that detect radioactivity. This appendix begins with a discussion of the principles of radioactivity in order to provide the reader/user with knowledge on which to base a common sense approach to the safe use of isotopes. The characteristics of isotopes most commonly used in a molecular biology laboratory are then detailed, as well as the safety precautions and monitoring methods peculiar to each one. Detection and imaging methods used in experimental analysis are reviewed. Finally, an outline of an orderly response to a spill of radioactive material is presented. PMID- 20967741 TI - Neutral red uptake cytotoxicity tests for estimating starting doses for acute oral toxicity tests. AB - In vitro cytotoxicity assays can be used as alternative toxicity tests to reduce the total number of animals needed for acute oral toxicity tests. This unit describes two methods for determining the in vitro cytotoxicity of test substances using neutral red uptake (NRU) and using the in vitro data to determine starting doses for in vivo acute oral systemic toxicity tests, e.g., the up-and-down procedure or the acute toxic class method. The use of the NRU methods to determine starting doses for acute oral toxicity tests may reduce the number of animals required, and for relatively toxic substances, this approach may also reduce the number of animals that die or require humane euthanasia due to severe toxicity. An interlaboratory validation study has demonstrated that the methods are useful and reproducible for these purposes. Two standardized protocols provide details for performing NRU tests with rodent and human cells. PMID- 20967742 TI - CFU-MK assay for acute thrombocytopenia. AB - In this unit, protocols to culture human platelet progenitors (Colony Forming Unit-Megakaryocyte; CFU-M) with or without toxicants are described. Platelet progenitors are obtained from human umbilical cord blood. After separation of mononuclear cells, the cell suspension can be cryopreserved or plated immediately. Megakaryocytes are identified by immunocytochemistry. Test chemicals are added to the culture medium before cells are plated. Megakaryocytes are scored after 12 days of culture. IC(10), IC(50) and IC(90) can be calculated by comparison to control cultures. A predictive model is proposed to evaluate the hazard of thrombocytopenia induced by chemicals. When IC(50) and IC(90) are below C(max) in humans, the likelihood of thrombocytopenia is strong. PMID- 20967743 TI - Overview of gastrointestinal toxicology. AB - The gastrointestinal (GI) tract has the unique feature of having a huge area for exposure to potentially harmful agents, including concentrated acid, food, chemicals, and pathogens. Research over the past decades has identified some of the key events that are involved in mucosal damage and defense. The enteric nervous system, immune system, and a variety of endocrine and paracrine mediators act in concert to endure mucosal barrier integrity and gut homeostasis. Disruptors of mucosal defense mechanisms include drugs, food allergens and contaminants, metals, chemicals, radiation, and pathogens. A variety of animal experimental models have been set up to detect possible deleterious effects to the GI tract and the potential risk in humans. PMID- 20967744 TI - Methods to measure gastric mucosal lesions in the rat. AB - The maintenance of gastric mucosal integrity is ensured by a dynamic balance between protective and noxious factors. The gastric mucosa has multiple protective mechanisms that allow the mucosa to withstand frequent exposure to potentially damaging agents such as acid and peptic secretions, bacterial products, ingested food, alcoholic beverages, and certain drugs. The imbalance between defensive and aggressive factors is at the basis of the formation of erosions/lesions or ulcerations of the gastric mucosa. The difference between an erosion/lesion and ulceration is that the former is confined to the mucosa, while an ulceration penetrates to the muscularis mucosae. This unit presents two models of acute mucosal lesions induced in the rat by gastrotoxic agents acting through different mechanisms of action. The protocols explain how to measure gastric mucosal lesions by microscopic examination of the stomach by light microscopy and by scanning electron microscopy. PMID- 20967745 TI - Assessment of enteral bacteria. AB - The disruption of intestinal barrier leads to the penetration of noxious luminal compounds into the gut wall, causing further damage. This unit describes the assessment of enteric bacteria translocation into the intestinal wall of rats, an established method for the evaluation of bowel damage to the mucosal epithelial barrier. The Basic Protocol provided in the present unit describes collection and preparation of small intestine sample, performing of sample serial dilutions for bacterial culture, performing of the culture of aerobic and anaerobic bacteria on petri dishes, incubation of the cultured plates, and counting of bacterial colonies. The Support Protocols describes the procedures for the preparation of petri dishes for the culture, using different employable media for aerobes or anaerobes. The Alternate Protocol describes the use of the "inclusion method," suitable for the culture of anaerobic bacteria. PMID- 20967746 TI - Assessment of ischemic vascular damage. AB - This protocol describes a model convenient for acute experiments in anesthetized rats, performed by selective occlusion of the superior mesenteric artery. Such a model provides a means for assessing the role played by various pathophysiological mechanisms in the development of intestinal ischemic injury. It is especially suitable for studying different treatments, mainly pharmacological ones, to help cope with this problem in clinical practice. In the form of support protocols, this unit includes functional vascular and chemiluminescence studies, determination of vascular permeability and myeloperoxidase activity, transit time, and mortality. PMID- 20967747 TI - Measurement of gastric acid secretion in the anaesthetized rat. AB - The protocols described in this unit are designed to assess the effects of substances on gastric acid secretion by the rat stomach, with the animal under general anesthesia. Both stimulatory and inhibitory effects of compounds can be evaluated and specific mechanisms of action can also be investigated. Acid secretion is induced by substances that directly activate parietal cell receptors (histamine and bethanechol), by indirect stimuli, like 2-deoxy-D-glucose, by electrical stimulation of vagal nerves, or by the peptide pentagastrin. Reference antisecretory drugs are represented by histamine H(2) receptor antagonists and proton pump inhibitors. This model allows the evaluation of complete dose response curves together with a time-course of the secretory/antisecretory effects. Indirect effects involving activation or inhibition of vagal pathways are evaluated in intact animals by means of electrical vagal stimulation or in vagotomized animals. PMID- 20967748 TI - Endogenous gastric mediators: patho-physiological role and measurements. AB - The protocols described in this unit are designed to present the major endogenous gastric mediators involved in the control of gastric acid secretion, namely gastrin and histamine, and in the regulation of gastric motility, which include motilin and ghrelin, under physiological and pathological conditions. The measurement of these mediators in plasma or serum of humans and animals by radioimmunoassay are described and their pathophysiological role is discussed. PMID- 20967749 TI - Measurement of small intestinal damage. AB - Many animal models have been devised for investigating the pathogenesis of intestinal lesions and for screening drugs for the treatment of intestinal ulcers in humans. Recently, particular attention has been focused on NSAID-induced intestinal lesions as a result of the development of the capsule endoscope and double-balloon endoscope. Ischemic enteritis, one of the most dramatic abdominal emergencies, is known to cause severe damage to the small intestine by a significant decrease of arterial blood flow in the small intestine. In this unit, two animal models for small intestinal damage induced by NSAIDs or intestinal ischemia are described. Also included are methods for lesion induction and evaluation of the damage as well as the measurement of pathogenic functional and biochemical changes. PMID- 20967750 TI - Generation of stable, high-producing CHO cell lines by lentiviral vector-mediated gene transfer in serum-free suspension culture. AB - Lentivirus-derived vectors (LVs) were studied for the generation of stable recombinant Chinese hamster ovary (CHO) cell lines. Stable pools and clones expressing the enhanced green fluorescent protein (eGFP) were selected via fluorescence-activated cell sorting (FACS). For comparison, cell pools and cell lines were also generated by transfection, using the LV transfer plasmid alone. The level and stability of eGFP expression was greater in LV-transduced cell lines and pools than in those established by transfection. CHO cells were also infected at two different multiplicities of infection with an LV co-expressing eGFP and a tumor necrosis factor receptor:Fc fusion protein (TNFR:Fc). At 2-day post-infection, clonal cell lines with high eGFP-specific fluorescence were recovered by FACS. These clones co-expressed TNFR:Fc with yields of 50-250 mg/L in 4-day cultures. The recovered cell lines maintained stable expression over 3 months in serum-free suspension culture without selection. In conclusion, LV mediated gene transfer provided an efficient alternative to plasmid transfection for the generation of stable and high-producing recombinant cell lines. PMID- 20967751 TI - Purification of monomeric mAb from associated aggregates using selective desorption chromatography in hydroxyapatite systems. AB - Selective desorption on ceramic hydroxyapatite (CHT) was implemented for the purification of monomeric monoclonal antibody (mAb) from associated aggregates and other post-protein A step impurities. A robotic liquid handling system was employed to carry out a parallel batch screen of selective desorbents on a post protein A step mAb mixture. The effect of different phosphate concentrations was also investigated. Selective batch separations were achieved between monomeric mAb and associated aggregates/impurities. The batch screen results also established optimal mobile phase conditions for each selective desorbent. These initial batch results were then used to guide column separations, and baseline separation of monomeric mAb from associated aggregates and impurities was achieved, validating the screening results. Selective desorption also resulted in improved separations on CHT, with 100% yield of pure monomeric mAb as compared to 61% and 79%, respectively, for conventional linear and step gradient operations. This proof of concept study demonstrates selective desorption on CHT as an effective separation technique for the purification of monomeric mAb from associated aggregates and other post-protein A step impurities in a single process step. PMID- 20967752 TI - A unique phenotypic modification of Lactococcus lactis cultivated in a Couette bioreactor. AB - Batch cultures of Lactococcus lactis NCDO 2118 and IL 1403 were performed in a Couette bioreactor operated in the modulated wavy vortex flow and the turbulent regimes. This study provides an overall analysis taking into account both mechanical stress and mixing in a Couette bioreactor. A unique phenotypic aspect has been proved to occur only in the modulated wavy vortex flow regime for the two studied strains, namely that the cells become entrapped in a filamentous form. No change in the metabolic behavior of the cells has been observed. The polymeric matrix has been microscopically observed through FISH and fluorescent lectin binding, showing cells entrapped in a glycoconjugate matrix. All hypotheses regarding insufficient mixing as a cause of this phenotype have been discarded, leading to the conclusion that this particular phenotypic feature is essentially due a combined effect of mechanical stress and flow structure. Particle size measurement during the fermentation course indicates that formation of filamentous form results from a continuous aggregation started in the early stages of the cultivation. According to our results a minimum shear is required to induce the ability for cells to aggregate. Then, it appears that both flow structure and mechanical stress (shear) are responsible for the appearance of such a filamentous form. As far as the authors know, this is the first experimental evidence of a bio polymerization induced by the flow structure. PMID- 20967753 TI - Genome-scale modeling and in silico analysis of ethanologenic bacteria Zymomonas mobilis. AB - Bioethanol has been recognized as a potential alternative energy source. Among various ethanol-producing microbes, Zymomonas mobilis has acquired special attention due to its higher ethanol yield and tolerance. However, cellular metabolism in Z. mobilis remains unclear, hindering its practical application for bioethanol production. To elucidate such physiological characteristics, we reconstructed and validated a genome-scale metabolic network (iZM363) of Z. mobilis ATCC31821 (ZM4) based on its annotated genome and biochemical information. The phenotypic behaviors and metabolic states predicted by our genome-scale model were highly consistent with the experimental observations of Z. mobilis ZM4 strain growing on glucose as well as NMR-measured intracellular fluxes of an engineered strain utilizing glucose, fructose, and xylose. Subsequent comparative analysis with Escherichia coli and Saccharomyces cerevisiae as well as gene essentiality and flux coupling analyses have also confirmed the functional role of pdc and adh genes in the ethanologenic activity of Z. mobilis, thus leading to better understanding of this natural ethanol producer. In future, the current model could be employed to identify potential cell engineering targets, thereby enhancing the productivity of ethanol in Z. mobilis. PMID- 20967754 TI - On particle ionization/enrichment of multifunctional nanoprobes: washing/separation-free, acceleration and enrichment of microwave-assisted tryptic digestion of proteins via bare TiO2 nanoparticles in ESI-MS and comparing to MALDI-MS. AB - A simple, rapid, straightforward and washing/separation free of in-solution digestion method for microwave-assisted tryptic digestion of proteins (cytochrome c, lysozyme and myoglobin) using bare TiO(2) nanoparticles (NPs) prepared in aqueous solution to serve as multifunctional nanoprobes in electrospray ionization mass spectrometry (ESI-MS) was demonstrated. The current approach is termed as 'on particle ionization/enrichment (OPIE)' and it can be applied in ESI MS, atmospheric pressure-matrix-assisted laser desorption/ionization mass spectrometry (AP-MALDI-MS) and matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MALDI-TOF-MS). The bare TiO(2) NPs can assist, accelerate and effectively enhance the digestion efficiency, sequence coverage and detection sensitivity of peptides for the microwave-assisted tryptic digestion of proteins in ESI-MS. The reason is attributed to the fact that proteins or partially digested proteins are easily attracted or concentrated onto the surface of TiO(2) NPs, resulting in higher efficiency of digestion reactions in the microwave experiments. Besides, the TiO(2) NPs could act as a microwave absorber to accelerate and enrich the protein fragments in a short period of time (40-60 s) from the microwave experiments in ESI-MS. Furthermore, the bare TiO(2) NPs prepared in aqueous solution exhibit high adsorption capability toward the protein fragments (peptides); thus, the OPIE approach for detecting the digested protein fragments via ESI and MALDI ionization could be achieved. The current technique is also a washing and separation-free technique for accelerating and enriching microwave-assisted tryptic digestion of proteins in the ESI-MS and MALDI-MS. It exhibits potential to be widely applied to biotechnology and proteome research in the near future. PMID- 20967755 TI - Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease. AB - The diagnosis of Wilson disease (WD) is challenging, especially in children. Early detection is desirable in order to avoid dramatic disease progression. The aim of our study was to re-evaluate in WD children with mild liver disease the conventional diagnostic criteria and the WD scoring system proposed by an international consensus in 2001. Forty children with WD (26 boys and 14 girls, age range = 1.1-20.9 years) and 58 age-matched and sex-matched patients with a liver disease other than WD were evaluated. Both groups were symptom-free and had elevated aminotransferases as predominant signs of liver disease. In all WD patients, the diagnosis was supported by molecular analysis, the liver copper content, or both. A receiver operating characteristic (ROC) analysis of ceruloplasmin at the cutoff value of 20 mg/dL showed a sensitivity of 95% [95% confidence interval (CI) = 83%-99.4%] and a specificity of 84.5% (95% CI = 72.6% 92.6%). The optimal basal urinary copper diagnostic cutoff value was found to be 40 MUg/24 hours (sensitivity = 78.9%, 95% CI = 62.7%-90.4%; specificity = 87.9%, 95% CI = 76.7%-95%). Urinary copper values after penicillamine challenge did not significantly differ between WD patients and control subjects, and the ROC analysis showed a sensitivity of only 12%. The WD scoring system was proved to have positive and negative predictive values of 93% and 91.6%, respectively. CONCLUSION: Urinary copper excretion greater than 40 MUg/24 hours is suggestive of WD in asymptomatic children, whereas the penicillamine challenge test does not have a diagnostic role in this subset of patients. The WD scoring system provides good diagnostic accuracy. PMID- 20967756 TI - MicroRNA silencing of tumor suppressor DLC-1 promotes efficient hepatitis C virus replication in primary human hepatocytes. AB - MicroRNAs (miRNAs) are approximately 22-nucleotide noncoding RNAs that constitute silencers of target gene expression. Aberrant expression of miRNA has been linked to a variety of cancers, including hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) infection is considered a major cause of chronic liver disease and HCC, although the mechanism of virus infection-associated hepatocarcinogenesis remains unclear. We report a direct role of miRNAs induced in HCV-infected primary human hepatocytes that target the tumor suppressor gene DLC-1 (a Rho GTPase-activating protein), which is frequently deleted in HCC, and other solid human tumors. MicroRNA miR-141 that targets DLC-1 was accentuated in cells infected with HCV genotypes 1a, 1b, and 2a. We present several lines of evidence that efficient HCV replication requires miR-141-mediated suppression of DLC-1. An increase in miR-141 correlated with the inhibition of DLC-1 protein in HCV infected cells. Depletion of miR-141 with oligonucleotides complementary to the miRNAs inhibited virus replication, whereas artificially increased levels of intracellular miR-141 enhanced HCV replication. HCV-infected hepatocytes showed enhanced cell proliferation that can be countered by overexpression of DLC-1. CONCLUSION: The collective results of this study suggest a novel mechanism of HCV infection-associated miRNA-mediated regulation of a tumor suppressor protein that has the ability to influence cell proliferation and HCV infection-mediated liver cancer. PMID- 20967757 TI - C-reactive protein impairs hepatic insulin sensitivity and insulin signaling in rats: role of mitogen-activated protein kinases. AB - Plasma C-reactive protein (CRP) concentration is increased in the metabolic syndrome, which consists of a cluster of cardiovascular disease risk factors, including insulin resistance. It is not known, however, whether CRP is merely a marker of accompanying inflammation or whether it contributes causally to insulin resistance. The objective of this study is to investigate the role that CRP may play in the development of insulin resistance. We examined the effect of single dose intravenous administration of purified human (h)CRP on insulin sensitivity in Sprague-Dawley rats using the euglycemic, hyperinsulinemic clamp technique. hCRP was associated with impaired insulin suppression of endogenous glucose production with no reduction in peripheral tissue glucose uptake, suggesting that hCRP mediated insulin resistance in the liver but not extrahepatic tissues. We further assessed components of the insulin signaling pathway and mitogen activated protein kinases (MAPKs) in the liver. Liver tissues derived from hCRP treated rats showed reduced insulin-stimulated insulin receptor substrate (IRS) tyrosine phosphorylation, IRS/phosphatidylinositol 3-kinase (PI3K) association, and Akt phosphorylation, consistent with hCRP-induced impairment of hepatic insulin signaling. Furthermore, hCRP enhanced phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK as well as IRS-1 Ser(612) . Finally, we observed in primary cultured rat hepatocytes that U0126 (a selective inhibitor of MAPK/ERK kinase1/2) corrected hCRP-induced impairment of insulin signaling. CONCLUSIONS: hCRP plays an active role in inducing hepatic insulin resistance in the rat, at least in part by activating ERK1/2, with downstream impairment in the insulin signaling pathway. PMID- 20967759 TI - Repeated radiofrequency ablation for management of patients with cirrhosis with small hepatocellular carcinomas: a long-term cohort study. AB - In most patients with cirrhosis, successful percutaneous ablation or surgical resection of hepatocellular carcinoma (HCC) is followed by recurrence. Radiofrequency ablation (RFA) has proven effective for treating HCC nodules, but its repeatability in managing recurrences and the impact of this approach on survival has not been evaluated. To this end, we retrospectively analyzed a prospective series of 706 patients with cirrhosis (Child-Pugh class <= B7) who underwent RFA for 859 HCC <= 35 mm in diameter (1-2 per patient). The results of RFA were classified as complete responses (CRs) or treatment failures. CRs were obtained in 849 nodules (98.8%) and 696 patients (98.5%). During follow-up (median, 29 months), 465 (66.8%) of the 696 patients with CRs experienced a first recurrence at an incidence rate of 41 per 100 person-years (local recurrence 6.2; nonlocal 35). Cumulative incidences of first recurrence at 3 and 5 years were 70.8% and 81.7%, respectively. RFA was repeated in 323 (69.4%) of the 465 patients with first recurrence, restoring disease-free status in 318 (98.4%) cases. Subsequently, RFA was repeated in 147 (65.9%) of the 223 patients who developed a second recurrence after CR of the first, restoring disease-free status in 145 (98.6%) cases. Overall, there were 877 episodes of recurrence (1-8 per patient); 577 (65.8%) of these underwent RFA that achieved CRs in 557 (96.5%) cases. No procedure-related deaths occurred in 1,921 RFA sessions. Estimated 3- and 5-year overall and disease-free (after repeated RFAs) survival rates were 67.0% and 40.1% and 68.0 and 38.0%, respectively. CONCLUSION: RFA is safe and effective for managing HCC in patients with cirrhosis, and its high repeatability makes it particularly valuable for controlling intrahepatic recurrences. PMID- 20967758 TI - Adipose triglyceride lipase is a major hepatic lipase that regulates triacylglycerol turnover and fatty acid signaling and partitioning. AB - Despite advances in our understanding of the ways in which nutrient oversupply and triacylglycerol (TAG) anabolism contribute to hepatic steatosis, little is known about the lipases responsible for regulating hepatic TAG turnover. Recent studies have identified adipose triglyceride lipase (ATGL) as a major lipase in adipose tissue, although its role in the liver is largely unknown. Thus, we tested the contribution of ATGL to hepatic lipid metabolism and signaling. Adenovirus-mediated knockdown of hepatic ATGL resulted in steatosis in mice and decreased hydrolysis of TAG in primary hepatocyte cultures and in vitro assays. In addition to altering TAG hydrolysis, ATGL was shown to play a significant role in partitioning hydrolyzed fatty acids between metabolic pathways. Although ATGL gain and loss of function did not alter hepatic TAG secretion, fatty acid oxidation was increased by ATGL overexpression and decreased by ATGL knockdown. The effects on fatty acid oxidation coincided with decreased expression of peroxisome proliferator-activated receptor alpha (PPAR-alpha) and its target genes in mice with suppressed hepatic ATGL expression. However, PPAR-alpha agonism was unable to normalize the effects of ATGL knockdown on PPAR-alpha target gene expression, and this suggests that ATGL influences PPAR-alpha activity independently of ligand-induced activation. CONCLUSION: Taken together, these data show that ATGL is a major hepatic TAG lipase that plays an integral role in fatty acid partitioning and signaling to control energy metabolism. PMID- 20967760 TI - Disruption of the 12/15-lipoxygenase gene (Alox15) protects hyperlipidemic mice from nonalcoholic fatty liver disease. AB - We have shown that Alox15, the gene encoding for 12/15-lipoxygenase (12/15-LO), is markedly up-regulated in livers from apolipoprotein E-deficient (ApoE(-/-)) mice, which spontaneously develop nonalcoholic fatty liver disease secondary to hyperlipidemia. In the current study, we used ApoE(-/-) mice with a targeted disruption of the Alox15 gene to assess the role of 12/15-LO in the development and progression of hepatic steatosis and inflammation. Compared with ApoE(-/-) mice, which exhibited extensive hepatic lipid accumulation and exacerbated inflammatory injury, ApoE/12/15-LO double-knockout (ApoE(-/-)/12/15-LO(-/-)) mice showed reduced serum alanine aminotransferase levels; decreased hepatic steatosis, inflammation, and macrophage infiltration; and decreased fatty acid synthase, tumor necrosis factor alpha (TNFalpha), monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-18, and IL-6 expression. Remarkably, disruption of Alox15 attenuated glucose intolerance and high-fat diet-induced insulin resistance, up-regulated insulin receptor substrate-2, and exerted opposite effects on hepatic c-Jun amino-terminal kinase and adenosine monophosphate-activated protein kinase phosphorylation, known negative and positive regulators of insulin signaling, respectively. In adipose tissue, the absence of Alox15 induced significant reductions in the expression of the proinflammatory and insulin-resistant adipokines MCP-1, TNFalpha, and resistin while increasing the expression of glucose transporter-4. Interestingly, compared with ApoE(-/-) mice, which exhibited increased hepatic caspase-3 staining, ApoE( /-)/12/15-LO(-/-) mice showed attenuated hepatocellular injury. Consistent with this finding, hepatocytes isolated from ApoE(-/-) mice were more vulnerable to TNFalpha-induced programmed cell death, an effect that was not observed in hepatocytes carrying a targeted disruption of the Alox15 gene. CONCLUSION: Collectively, our data suggest a potentially relevant mechanism linking 12/15-LO to the promotion of hepatic steatosis, insulin resistance, and inflammation in experimental liver disease of metabolic origin. PMID- 20967761 TI - Measuring the cost of hospital adverse patient safety events. AB - This paper estimates the excess cost of hospital inpatient care due to adverse safety events in the U.S. Department of Veterans Affairs (VA) hospitals during fiscal year 2007. We measured adverse events according to the Patient Safety Indicator (PSI) algorithms of the Agency for Healthcare Research and Quality. Patient level cost regression analyses were performed using generalized linear modeling techniques. Accounting for the heavily skewed distribution of costs among patients having adverse safety events, results suggested that the excess cost of nine different PSIs for VA patients are much higher than previously estimated. We tested sensitivity of results to whether costs were measured by VA's Decision Support System (DSS) that uses local costs of specific inputs, or by the average costing system developed by VA's Health Economics Resource Center. DSS costing appeared to better characterize the high cost patients. PMID- 20967762 TI - The perils with the misuse of predictive power. AB - In early drug development, especially when studying new mechanisms of action or in new disease areas, little is known about the targeted or anticipated treatment effect or variability estimates. Adaptive designs that allow for early stopping but also use interim data to adapt the sample size have been proposed as a practical way of dealing with these uncertainties. Predictive power and conditional power are two commonly mentioned techniques that allow predictions of what will happen at the end of the trial based on the interim data. Decisions about stopping or continuing the trial can then be based on these predictions. However, unless the user of these statistics has a deep understanding of their characteristics important pitfalls may be encountered, especially with the use of predictive power. The aim of this paper is to highlight these potential pitfalls. It is critical that statisticians understand the fundamental differences between predictive power and conditional power as they can have dramatic effects on decision making at the interim stage, especially if used to re-evaluate the sample size. The use of predictive power can lead to much larger sample sizes than either conditional power or standard sample size calculations. One crucial difference is that predictive power takes account of all uncertainty, parts of which are ignored by standard sample size calculations and conditional power. By comparing the characteristics of each of these statistics we highlight important characteristics of predictive power that experimenters need to be aware of when using this approach. PMID- 20967763 TI - A technique combining trifluoroacetyl derivatization and gas chromatography-mass spectrometry to distinguish methamphetamine and its 4-substituted analogs. PMID- 20967764 TI - Incidence of urinary tract infection in patients with type 2 diabetes. Experience from adverse event reporting in clinical trials. AB - PURPOSE: Diabetes mellitus has long been widely considered to be associated with an increased risk of urinary tract infection (UTI), but information on incidence rates are scarce and risk factor data have been conflicting. The aim was to estimate UTI incidence and evaluate potential risk factors for UTI in patients with type 2 diabetes included in recent clinical trials. METHODS: Type 2 diabetes patients from 10 AstraZeneca phase III diabetes clinical trials (n=6016, mean 57.4 years, 50.7% female) conducted during 2004-2007 were included. Patients free of UTI at baseline were followed for up to 6 months after inclusion in the trials. UTI was considered present if any term sorting under the MedDRA high level term "UTIs" was recorded as an adverse event. RESULTS: In all, 142 patients had an adverse event for UTI, corresponding to an incidence of 59.5/1000 person years for all patients (91.5/1000 in women, 28.2/1000 in men) and a cumulative incidence of 2% during 6 months. Female gender was associated with an increased incidence [relative risk (RR) 3.4; 95% confidence interval (CI) 2.3-5.1] and also higher age (RR 2.5 [95% CI 1.4-4.8] for ages >= 70 years vs. 40-49 years). No increased incidence was associated with body mass index (25-29, 30+ vs. <25 kg/m(2) ), HbA1c (<8% vs. >8%), race (Black, Oriental vs. Caucasian) or drug treatment (study drug, comparator vs. placebo). A history of immune system disorder conveyed a twofold higher risk for UTI. CONCLUSION: UTI is common among female patients with type 2 diabetes and older patients of both genders. PMID- 20967765 TI - Innovative applications are welcome. PMID- 20967766 TI - A novel high-resolution chipCE assay for rapid detection of EGFR gene mutations and amplifications in lung cancer therapy by a combination of fragment analysis, denaturing CE and MLPA. AB - There is a growing interest in evaluating molecular markers as predictors of response to new generation of targeted cancer therapies. One of such areas is biological therapy targeting epidermal growth factor receptor gene (EGFR) in lung cancer. The testing of tumor tissue is focused on specific EGFR mutations and EGFR gene amplification, since tumors exhibiting positivity of either of the two marker types are highly sensitive towards the treatment. Although traditional methods of DNA sequencing and fluorescence in situ hybridization are still in use for the detection of EGFR mutations and gene amplification, respectively, there is a need for new dedicated techniques with the primary emphasis on simplicity, sensitivity, speed and cost effectiveness. The main purpose of this work was to integrate diverse assays for both EGFR tests onto a single platform to eliminate the need for different instruments and separate processing. We demonstrate a chip capillary electrophoresis (chipCE) application for EGFR mutation detection by a combination of fragment analysis and denaturing CE along with multiplex ligation dependent probe amplification (MLPA) for evaluation of EGFR amplification. All separations are carried out in denaturing sieving polymer on a modified Bioanalyzer 2100 chipCE instrument running at temperatures of up to 65 degrees C. The main strength of the resulting high-resolution chipCE application is in its simplicity, speed of analysis and minimal amount of sample required for complete testing of EGFR status. Such an approach could potentially fit medium throughput laboratories providing molecular pathology services for clinical oncologists with fast turnaround times and limited consumption of tissue material. PMID- 20967767 TI - Global analysis of single nucleotide polymorphisms in the exons of human deoxyribonuclease I-like 1 and 2 genes. AB - Several SNPs in the deoxyribonuclease I-like 1 (DNase 1L1) and DNase 1L2 were investigated. In the present study, the genotype distributions of three synonymous SNPs (V59V, rs1050095; P67P, rs1130929; A277A, rs17849495) in the DNase 1L1 gene and four non-synonymous SNPs, V122I (rs34952165), Q170H (rs6643670), and D227A (rs5987256) in the DNase 1L1 gene, as well as D197A (rs62621282) in the DNase 1L2 gene were investigated in 13 populations. In all the populations, no variation was found in four SNPs (V59V, Q170H, D227A, and A277A) in DNASE1L1 or in D197A in DNASE1L2. As for V122I, only the German population showed a low degree of polymorphism. The SNP V122I in DNASE1L1 was monoallelic for the G-allele in all of the Asian and African populations examined, with no polymorphism being evident. Since the A-allele in SNP V122I was distributed in only the Caucasian populations, not in the other ethnic groups, it was confirmed that the A-allele in SNP V122I was Caucasian-specific. On the other hand, only P67P in DNASE1L1 was polymorphic among three synonymous SNPs. The effect of nucleotide substitution corresponding to polymorphic SNP P67P on DNase 1L1 activity was examined: the corresponding nucleotide substitution in polymorphic SNP P67P has little effect on the DNase activity. PMID- 20967768 TI - Comparison of protein precipitation methods for various rat brain structures prior to proteomic analysis. AB - Sample preparation is a fundamental step in proteomic methodologies. The quality of the results from a proteomic experiment is dependent on the nature of the sample and the properties of the proteins. In this study, various pre-treatment methods were compared by proteomic analysis; we analysed various rat brain structures after chloroform/methanol, acetone, TCA/acetone and TCA protein precipitation procedures. The protein content of the supernatant was also examined by 2-DE. We found that for four of the rat brain structures, precipitation with chloroform/methanol and acetone delivered the highest protein recovery for top-down proteomic analysis; however, TCA precipitation resulted in good protein separation and the highest number of protein spots in 2-DE. Moreover, TCA precipitation also gave high efficiency of protein recovery if prior sonication procedure was performed. PMID- 20967769 TI - Miniature flowing atmospheric-pressure afterglow ion source for facile interfacing of CE with MS. AB - Here, we present a miniaturized version of the flowing atmospheric-pressure afterglow (miniFAPA) ion source and use it for sheathless coupling of CE with MS. The simple design of the CE-miniFAPA-MS interface makes it easy to separate the electric potentials used for CE and for ionization. A pneumatically assisted nebulization of the CE effluent transfers the analytes from the liquid phase into the gas phase before they are ionized by interacting with reactive species produced by the FAPA. An important advantage of this interface is its high stability during operation: optimization of five different parameters indicated that the interface is not sensitive to minor deviations from the optimum values. Other advantages include ease of construction and maintenance, as well as relatively low cost. Samples with complex matrices, such as yeast extract, soil extract and urine, spiked with the test compounds, were successfully analyzed using the CE-miniFAPA-MS setup. PMID- 20967770 TI - Novel and highly sensitive mixed-polymeric electrokinetic chromatography system for determination of contaminants and impurities of heparin samples. AB - A mixed-polymeric electrokinetic chromatography system has been developed for the simultaneous determination of a contaminant like oversulfated condroitin sulfate (OSCS) and impurities expressed as dermatan (Der) in heparin (Hep) samples. The EKC system consisted of 0.5% w/v polymeric beta-CD, 0.4% w/v tetronic((r)) 1107 and 400 mM tris-phosphate buffer at pH 3.5. The optimized electrophoretic conditions included the use of an uncoated-silica capillary of 50 cm of total length and 75 MUm id, an applied voltage of -7 kV, a temperature of 30 degrees C and 200 nm UV-detection. The highly sensitive method developed showed low values of LOD, 0.07% w/w (0.07 MUg/mL) (OSCS) and 0.1% w/w (0.1 MUg/mL) (Der), and values of LOQ 0.2% w/w (0.2 MUg/mL) (OSCS) and 0.3% w/w (0.3 MUg/mL) (Der) with a concentration level of Hep sample as low as 0.1 mg/mL. Additional parameters of validation such as specificity, linearity, accuracy, and robustness were evaluated according to international guidelines. Owing to its simplicity, high sensitivity, and reliability, the proposed method can be an advantageous alternative to the traditional methodologies for the analysis of Hep in raw material and specially in finished products because of the low amounts of Hep sample required. PMID- 20967773 TI - Ectopic osteochondral formation of biomimetic porous PVA-n-HA/PA6 bilayered scaffold and BMSCs construct in rabbit. AB - In this work, the novel poly vinyl alcohol/gelatin-nano-hydroxyapatite/polyamide6 (PVA-n-HA/PA6) bilayered scaffold with biomimetic properties for articular cartilage and subchondral bone is developed. Furthermore, when these osteochondral scaffolds were seeded with induced bone mesenchymal stem cells (BMSCs) and implanted at ectopic sites, showed the potential for an engineered cartilage tissue and the corresponding subchondral bone. BMSCs were expanded in vitro and induced to chondrogenic or osteogenic potential by culturing in suitable media for 14 days. Subsequently, these induced cells were seeded into PVA-n-HA/PA6 separately, and the constructs were implanted into the rabbit muscle pouch for upto 12 weeks. Ectopic neocartilage formation in the PVA layer and reconstitution of the subchondral bone which remained confined within the n HA/PA6 layer with the alteration of the cellular phenotype were identified with Masson's trichrome stain. Simultaneously, the RT-PCR results confirmed the expression of specific extracellular matrix (ECM) markers for cartilaginous tissue, such as collagen type II (Col-II), or alternatively, markers for osteoid tissue, such as collagen type I (Col-I) at the corresponding layers. During ectopic implantation, the underlying subchondral bone layer was completely integrated with the cartilage layer. The result from the ectopic osteochondral scaffolds implantation suggests that PVA-n-HA/PA6 with induced BMSCs is a possible substitute with potential in cartilage repair strategies. PMID- 20967774 TI - Prevention of abdominal adhesion formation by thermosensitive PECE-hydrogel in a rat uterine horn model. AB - In this work, we investigated the efficacy of PECE-hydrogel in preventing postsurgical peritoneal adhesions in the rat uterine horn model. Standardized surgical traumas were applied to the peritoneum of the abdominal wall and the uterine horns. PECE hydrogel was applied to the two wound surfaces. Animals were euthanized at different times after surgery, and the gross necropsy findings were documented. Adhesion formation was assessed according to adhesion extent and adhesion severity, and the hydrogel degradation and healing of peritoneal wounds were observed. The remesothelialization was dynamically observed by scanning electron microscope. The results showed that none of the animals in the hydrogel treated group (n = 12) developed adhesion. In contrast, all untreated animals (n = 12) had adhesions that could only be separated by sharp dissection (p < 0.001). The hydrogel could adhere to the peritoneal wounds and gradually disappear from the wounds within 7-9 days and transformed into viscous fluid being completely absorbed within 12 days. The injured parietal and visceral peritoneum was remesothelialized in about 7 and 9 days, respectively. This work confirmed that PECE hydrogel holds promise as a novel absorbable biomaterial for the reduction of postoperative adhesions after laparotomy. PMID- 20967775 TI - Study on the influence of cross-sectional area and zeta potential on separation for hybrid-chip-based capillary electrophoresis using 3-D simulations. AB - Hybrid chips combing microchips with capillaries have displayed particular advantages in achieving UV-vis and mass spectroscopic detection. In this work, systematic 3-D numerical simulations have been carried out to explore the influence of junction interface cross-sectional area and zeta-potential distribution on sample band broadening in hybrid-chip electrophoresis separation. In this case, the ratio of cross-sectional area of chip to capillary channel (S(ratio) ) is used as the parameter of the variation in junction interface cross sectional area. Theoretical simulations demonstrated that the decrease of the S(ratio) would increase the separation efficiency in the hybrid-chip-based CE with uniform zeta-potential distribution. zeta-potential distribution along the axial direction of the channel also affects mass transport in hybrid-chip-based CE. Therefore, the effect of zeta-potential distribution has been considered in the 3-D simulation. Theoretical simulation results reveal that zeta-potential distribution rather than the interface cross-sectional area variation (S(ratio) ) controls the sample band broadening and manipulates sample separation efficiency in the hybrid-chip-based CE with non-uniform zeta-potential distribution. Both the theoretical simulations and experimental results show that optimal hybrid chip CE separation efficiency can be achieved at S(ratio) =1. PMID- 20967776 TI - A new gravity-driven microfluidic-based electrochemical assay coupled to magnetic beads for nucleic acid detection. AB - In this work, the characterisation and the optimisation of hybridisation assays based on a novel, rapid and sensitive micro-analytical, gravity-driven, flow device is reported. This device combines a special chip containing eight polymer microchannels, with a portable, computer-controlled instrument. The device is used as a platform for affinity experiments using oligonucleotide-modified paramagnetic particles. In our approach, both hybridisation and labelling events are performed on streptavidin-coated paramagnetic microparticles functionalized with a biotinylated capture probe. Modified particles, introduced in the microchannel inlet of the chip, accumulate near the electrode surface by virtue of a magnetic holder. After hybridisation with the complementary sequence, the hybrid is labelled with an alkaline phosphatase conjugate. The electrochemical substrate for alkaline phosphatase revelation is p-aminophenyl phosphate. Solutions and reagents are sequentially passed through the microchannels, until enzyme substrate is added for in situ signal detection. Upon readout, the magnet array is flipped away, beads are removed by addition of regeneration buffer, and the so-regenerated chip is ready for further analysis. This protocol has been applied to the analytical detection of specific DNA sequences of Legionella pneumophila, with an RSD=8.5% and a detection limit of 0.33 nM. PMID- 20967777 TI - Multifunctional protein processing chip with integrated digestion, solid-phase extraction, separation and electrospray. AB - We describe a microfluidic device in which integrated tryptic digestion, SPE, CE separation and electrospray ionization for MS are performed. The chip comprised of 10 * 30 MUm channels for CE, and two serially connected 150 MUm deep, 800 MUm wide channels packed with 40 to 60 MUm diameter beads, loaded with either immobilized trypsin, reversed-phase packing or both. On-chip digestion of cytochrome c using the trypsin bed showed complete consumption of the protein in 3 min, in contrast to the 2 h required for conventional solution phase tryptic digestion. SPE of 0.25 MUg/mL solutions of the peptides leu-enkephalin, angiotensin II and LHRH gave concentration enhancements in the range of 4.4-12, for a ten times nominal volume ratio. A 100 nM cytochrome c sample concentrated 13.3 times on-chip gave a sequence coverage of 85.6%, with recovery values ranging from 41.2 to 106%. The same sample run without SPE showed only five fragment peaks and a sequence coverage of 41.3%. When both on-chip digestion and SPE (13.3 volume ratio concentration enhancement) were performed on 200 nM cytochrome c samples, a sequence coverage of 76.0% and recovery values of 21-105% were observed. Performing on-chip digestion alone on the same sample gave only one significant fragment peak. The above digestion/peptide concentration step was compared to on-chip protein concentration by SPE followed by on-chip digestion with solution phase trypsin. Both procedures gave similar recovery results; however, much larger trypsin autodigestion interference in the latter approach was apparent. PMID- 20967778 TI - Collision of a long DNA molecule with an isolated nanowire. AB - We provide an experimental test of the universal behavior arising in simulations of the electrophoretic collision of a long DNA molecule with an isolated, thin post. Our experiments take advantage of a robust protocol to embed matrices of circa 100 nm radius ZnO nanowires in a microfluidic channel. The density and height of the nanowires are easily controlled by the seeding and growth conditions. Single-molecule videomicroscopy of lambda-DNA electrophoresis in a sparse nanowire array shows that the average holdup time decays exponentially with the impact parameter, in agreement with simulations. Only at the largest electric field studied here does the hooking probability approach that for an infinitesimally thin post. PMID- 20967779 TI - Analysis of carbonaceous biomarkers with the Mars Organic Analyzer microchip capillary electrophoresis system: aldehydes and ketones. AB - A microchip CE method is developed for the analysis of two oxidized forms of carbon, aldehydes and ketones, with the Mars Organic Analyzer (MOA). Fluorescent derivitization is achieved in ~ 15 min by hydrazone formation with Cascade Blue hydrazide in 30 mM borate pH 5-6. The microchip CE separation and analysis method is optimized via separation in 30 mM borate buffer, pH 9.5, at 20 degrees C. A carbonyl standard consisting of ten aldehydes and ketones found in extraterrestrial matter is successfully separated; the resulting LOD depends on the reactivity of the compound and range from 70 pM for formaldehyde to 2 MUM for benzophenone. To explore the utility of this method for analyzing complex samples, analyses of several fermented beverages are conducted, identifying ten aldehydes and ketones ranging from 30 nM to 5 mM. A Martian regolith simulant sample, consisting of a basalt matrix spiked with soluble ions and acetone, is designed and analyzed, but acetone is found to have a limited detectable lifetime under simulant Martian conditions. This work establishes the capability of the MOA for studying aldehydes and ketones, a critical class of oxidized organic molecules of interest in planetary and in terrestrial environmental and health studies. PMID- 20967780 TI - The polypeptide tunnel exit of the mitochondrial ribosome is tailored to meet the specific requirements of the organelle. AB - The ribosomal polypeptide tunnel exit is the site where a variety of factors interact with newly synthesized proteins to guide them through the early steps of their biogenesis. In mitochondrial ribosomes, this site has been considerably modified in the course of evolution. In contrast to all other translation systems, mitochondrial ribosomes are responsible for the synthesis of only a few hydrophobic membrane proteins that are essential subunits of the mitochondrial respiratory chain. Membrane insertion of these proteins occurs co-translationally and is connected to a sophisticated assembly process that not only includes the assembly of the different subunits but also the acquisition of redox co-factors. Here, we describe how mitochondrial translation is organized in the context of respiratory chain assembly and speculate how alteration of the ribosomal tunnel exit might allow the establishment of a subset of specialized ribosomes that individually organize the early steps in the biogenesis of distinct mitochondrially-encoded proteins. PMID- 20967782 TI - Pathogenesis of CADASIL: transgenic and knock-out mice to probe function and dysfunction of the mutated gene, Notch3, in the cerebrovasculature. AB - Small vessel diseases (SVDs) of the brain are the leading cause of vascular cognitive impairment and a major contributor to stroke in the human adult, however, their pathogenesis is poorly understood. Dominant mutations in NOTCH3 cause CADASIL, one of the most prevalent inherited cerebral SVDs. The disease gene encodes a transmembrane receptor primarily expressed in smooth muscle cells of small arteries and pericytes of brain capillaries. Pathogenic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, leading to its abnormal accumulation in the vessels of patients. Mice lacking NOTCH3 have revealed a critical role for NOTCH3 in the elaboration of small arteries. Despite being incomplete disease models, transgenic mice expressing CADASIL-associated NOTCH3 mutations, have provided important insights into specific aspects of CADASIL pathogenesis, including the functional significance of disease-linked mutations and the earliest pathological events that initiate brain lesions. In this paper, I provide a critical overview of these studies. Moreover, I discuss future directions and further work that needs to be done. PMID- 20967781 TI - Meiotic versus mitotic recombination: two different routes for double-strand break repair: the different functions of meiotic versus mitotic DSB repair are reflected in different pathway usage and different outcomes. AB - Studies in the yeast Saccharomyces cerevisiae have validated the major features of the double-strand break repair (DSBR) model as an accurate representation of the pathway through which meiotic crossovers (COs) are produced. This success has led to this model being invoked to explain double-strand break (DSB) repair in other contexts. However, most non-crossover (NCO) recombinants generated during S. cerevisiae meiosis do not arise via a DSBR pathway. Furthermore, it is becoming increasingly clear that DSBR is a minor pathway for recombinational repair of DSBs that occur in mitotically-proliferating cells and that the synthesis-dependent strand annealing (SDSA) model appears to describe mitotic DSB repair more accurately. Fundamental dissimilarities between meiotic and mitotic recombination are not unexpected, since meiotic recombination serves a very different purpose (accurate chromosome segregation, which requires COs) than mitotic recombination (repair of DNA damage, which typically generates NCOs). PMID- 20967783 TI - The scientific importance of asking questions at meetings: why virtual debate is not enough. PMID- 20967784 TI - Antimicrobial resistance, integrons and plasmid replicon typing in multiresistant clinical Escherichia coli strains from Enugu State, Nigeria. AB - Eleven multiresistant Escherichia coli strains of animal and human origin were assayed for the presence of antimicrobial resistance genes, integrons and associated gene cassettes, as well as plasmid content. Ciprofloxacin-resistant strains were screened for amino acid changes in GyrA and ParC proteins. The E. coli strains were found to harbor a variety of genes including cmlA, aac (3)-II, aac (3)-IV, aadA, strA-strB, tet (A), tet (B), bla(TEM), sul1, sul2 and sul3. Four of the eight int I1-positive strains were also positive for qacE Delta1 sul1 region and the following gene cassettes were detected: dfrA7, dfrA12 + orfF + aadA2 and bla(OXA1)+ aadA1. Five strains contained class 1 integrons lacking the qacE Delta1 -sul1 region and they showed a single type of gene cassette arrangement (estX + psp + aadA2 + cmlA + aadA1 + qacH + IS440 + sul3). The two int I2-positive strains carried the same type of gene cassette arrangement (dfrA1 + sat + aadA1). The seven ciprofloxacin-resistant E. coli strains exhibited a Ser 83-Leu substitution in GyrA protein and a Ser-80-Ile substitution in ParC protein; six of these strains presented an additional substitution in GyrA (Asp 87-Gly or Asp-87-Asn) and one strain in ParC (Glu-84-Gly). Eight different plasmid-replicon-types were detected among the 11 E. coli strains, IncF being the most frequent one detected, found in nine strains; other plasmid replicon types detected were IncX, IncI1, IncY, IncW, IncFIC, IncB/O, and IncK. Antimicrobial resistance in the E. coli strains studied was mediated by a variety of genes, some of them included in integrons, as well as by mutations gyr A and par C genes. PMID- 20967785 TI - Augmented adherence and internalization of group A Streptococcus pyogenes to influenza A virus infected MDCK cells. AB - Respiratory tract infections are one of the leading causes of morbidity and mortality. There is considerable epidemiologic evidence that infection with respiratory viruses increases the incidence and severity of secondary bacterial complications. However, very limited number of studies were concerned with the mechanism behind such synergy. In this context, our study aimed to explore the interaction between Group A Streptococcus pyogenes (GAS) and Influenza A virus (IAV). Our results revealed that the GAS adherence and internalization into Madin Darby canine kidney (MDCK) cells markedly increased after IAV infection. When M6 protein defective mutant of GAS was used, the virus enhanced adherence and internalization was nearly abolished indicating the involvement of M protein binding sites on the MDCK cell surface. Interestingly, the modulation of some O linked glycolproteins as well as sialic acid, mucin and fibrinogen-like residues on the surface of MDCK cells contributed to augmented bacterial adherence and/or internalization. In the same way, qRT-PCR experiments showed an overexpression of the membrane associated mucin (MUC1) on the surface of the MDCK cells after IAV infection. Altogether, the present study revealed that IAV infection augments the adherence and internalization of GAS to MDCK cells via modulation of membrane associated O-linked glycoproteins, fibrinogen, sialic acid residues and the mucin, MUC1 on the surface of MDCK cell. PMID- 20967786 TI - Metamorphosis of Borrelia burgdorferi organisms--RNA, lipid and protein composition in context with the spirochetes' shape. AB - Borrelia burgdorferi, the agent of Lyme borreliosis, has the ability to undergo morphological transformation from a motile spirochetal to non-motile spherical shape when it encounters unfavorable conditions. However, little information is available on the mechanism that enables the bacterium to change its shape and whether major components of the cells--nucleic acids, proteins, lipids--are possibly modified during the process. Deducing from investigations utilizing electron microscopy, it seems that shape alteration begins with membrane budding followed by folding of the protoplasmatic cylinder inside the outer surface membrane. Scanning electron microscopy confirmed that a deficiency in producing functioning periplasmic flagella did not hinder sphere formation. Further, it was shown that the spirochetes' and spheres' lipid compositions were indistinguishable. Neither phosphatidylcholine nor phosphatidylglycerol were altered by the structural transformation. In addition, no changes in differential protein expression were detected during this process. However, minimal degradation of RNA and a reduced antigen-antibody binding activity were observed with advanced age of the spheres. The results of our comparisons and the failure to generate mutants lacking the ability to convert to spheres suggest that the metamorphosis of B. burgdorferi results in a conditional reconstruction of the outer membrane. The spheres, which appear to be more resistant to unfavorable conditions and exhibit reduced immune reactivity when compared to spirochetes, might allow the B. burgdorferi to escape complete clearance and possibly ensure long-term survival in the host. PMID- 20967787 TI - Molecular typing of Epidermophyton floccosum isolated from patients with dermatophytosis by RAPD-PCR. AB - We evaluated the ability of randomly amplified polymorphic DNA (RAPD) to type Epidermophyton floccosum isolates recovered from patients with dermatophytosis originating from different regions of Iran. A total of 13 clinical isolates of E. floccosum obtained from Iranian patients were analyzed by RAPD with 7 arbitrary primers (OPN16, OPD18' OPU15, OPX19, R28, OPA04 and OPAA17). Among the applied primers, OPN16 produced banding patterns from all the isolates. In addition, some of the isolates had very close relation. The phenon line which represented the mean similarities was at the value of 73%. At this level, 4 groups were characterized. Two isolates of a patient had different molecular patterns, suggesting infection transmission from different sources in the case of a single patient. RAPD-PCR provided a rapid and practical tool for identification of E. floccosum isolates, which was independent of morphological characteristics, and enhanced laboratory diagnosis of dermatophytosis. PMID- 20967788 TI - Mode of action of plantaricin MG, a bacteriocin active against Salmonella typhimurium. AB - Plantaricin MG is a 2,180-Da bacteriocin produced by Lactobacillus plantarum KLDS1.0391, which was isolated from Chinese traditional fermented cream. Plantaricin MG showed a broad inhibitory activity against not only Gram-positive bacteria but also Gram-negative bacteria including Listeria monocytogenes and Salmonella typhimurium. The mode of action of plantaricin MG on S. typhimurium was reported in this article. The addition of plantaricin MG to energized cells of S. typhimurium dissipated both, the transmembrane potential (Deltapsi) and the pH gradient (DeltapH). Energized membrane, obtained after the addition of glucose, was more susceptible to plantaricin MG action, leading to the release of intracellular K(+)ions, inorganic phosphate, ATP and UV-absorbing materials. These data suggest that the presence of a proton motive force promotes the interaction of plantaricin MG with the cytoplasmic membrane of energized cells, leading to pores formation which allows the efflux of ions, thereby ensuring efficient killing of target bacteria. PMID- 20967789 TI - Identification of blaOXA-128 and blaOXA-129, two novel OXA-type extended-spectrum beta-lactamases in Pseudomonas aeruginosa, in Hunan Province, China. AB - We collected 97 non-repetitive carbapenemases-sensitive clinical isolates of Pseudomonas aeruginosa in Human Province, China, during the period of October 2006 to January 2007. From these isolates, we identified two novel oxacillin hydrolysing (OXA) type extended-spectrum-beta-lactamases (ESBLs): bla OXA-128 and bla OXA-129, which contain the mutations of I89V from bla OXA-56 and K134N from bla OXA-10, respectively. Clinical isolates containing either bla OXA-128 or bla OXA-129 show resistance to cephamycin-class antibiotics but sensitive to carbapenem-class antibiotics. The occurrence of novel OXA-type lactamases suggests a regional prevalent pattern of ESBLs Pseudomonas aeruginosa in this area. PMID- 20967790 TI - Effect of sub-lethal doses of vancomycin and oxacillin on biofilm formation by vancomycin intermediate resistant Staphylococcus aureus. AB - Biofilms are means of protection to bacteria against antibiotics and antibodies. Catheters and others tube devices used by patients are prone to accumulation of thick layers of biofilms as hiding place for etiologic agents, resulting in substantial morbidity and mortality. Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of hospital-acquired infections. Vancomycin remains the only treatment of choice for MRSA infections. In the present study a vancomycin resistant S. aureus (VRSA) (Labeled as CP2) was isolated from the blood of a post operative cardiac patient. It harbors a plasmid which carry vanA gene and exhibited low-level vancomycin resistance (MIC 16 MUg/ml), high level of oxacillin/methicillin resistance (MIC 500 MUg/ml) and was sensitive to teicoplanin. CP2 also found to carry icaA gene on its chromosome. This strain exhibited resistance to triton-X100 induced autolysis under sub-inhibitory concentration of vancomycin and produced some extracellular matrix material that surrounding the cells. These characteristic features have warranted us to study the biofilm formation by CP2 on biomedical indwellings in presence of vancomycin and oxacillin. Our findings suggest that sub-lethal dose of vancomycin induced the biofilm formation by CP2 on nylon and silicon indwellings whereas oxacillin facilitated the biofilm formation on glass surfaces exclusively. This implicates that not only the antibiotics but also the indwelling material influences biofilm formation. Therefore, these implants serve as potential surfaces for bacterial adhesion that lead to biofilm formation, thus provide hiding places for pathogens from the actions of antimicrobials. PMID- 20967791 TI - Survival and adherence of antimicrobial peptide ST4SA, produced by Enterococcus mundtii, at conditions found in the human gastro-intestinal tract. AB - The probiotic strain Enterococcus mundtii ST4SA, isolated from soy beans, produces a broad-spectrum antimicrobial peptide. The aim of this study was to determine if peptide ST4SA could withstand conditions simulating those found in the gastro-intestinal tract (GIT). Antimicrobial activity of peptide ST4SA has been monitored by growth inhibition of Enterococcus faecium on plates and leakage of beta-galactosidase from damaged cells. The ability of peptide ST4SA to adhere to target cells, which is the first step in cell destruction, has been determined by calculating the percentage of active peptide that remained in the cell-free supernatant. Seventy-five percent of peptide ST4SA adhered to E. faecium HKLHS at 37 degrees C, 88% adhered to the cells at pH 8.0 and 10.0, and 75% adhered to the cells at pH 4.0 and 6.0 at 37 degrees C. Complete adherence of peptide ST4SA to E. faecium HKLHS was recorded in the presence of 3.0%, 5.0% and 10.0% (v/v) pancreatic juice, 0.3%, 0.5% and 1.0% (v/v) oxbile and 1% (w/v) NaCl, MgCl(2) and KCl. Peptide ST4SA survived conditions associated with the GIT and may be used to prevent or retard the growth of intestinal microbiota. PMID- 20967792 TI - 31P NMR of phospholipid metabolites in prostate cancer and benign prostatic hyperplasia. AB - (1)H MRSI in vivo is increasingly being used to diagnose prostate cancer noninvasively by measurement of the resonance from choline-containing phospholipid metabolites. Although (31) P NMR in vivo or in vitro is potentially an excellent method for probing the phospholipid metabolites prominent in prostate cancer, it has been little used recently. Here, we report an in vitro (31)P NMR comparison of prostate cancer and benign prostatic hyperplasia, focusing on the levels of the major phospholipid metabolites. Unlike phosphocholine and glycerophosphocholine, phosphoethanolamine and glycerophosphoethanolamine (and their ratio) were significantly different between cancer and benign prostatic hyperplasia. The high level of phosphoethanolamine+glycerophosphoethanolamine relative to phosphocholine+glycerophosphocholine suggests that the former may be significant contributors to the "total choline" resonance observed by (1)H MRSI in vivo. PMID- 20967793 TI - Realistic simulation of cardiac magnetic resonance studies modeling anatomical variability, trabeculae, and papillary muscles. AB - Simulated magnetic resonance imaging brain studies have been generated for over a decade. Despite their useful potential, simulated cardiac studies are only emerging. This article focuses on the realistic simulation of cardiac magnetic resonance imaging datasets. The methodology is based on the XCAT phantom, which is modified to increase realism of the simulated images. Modifications include the modeling of trabeculae and papillary muscles based on clinical measurements and published data. To develop and evaluate our approach, the clinical database included 40 patients for anatomical measurements, 10 patients for papillary muscle modeling, and 10 patients for local gray value statistics. The virtual database consisted of 40 digital voxel phantoms. Histograms from different tissues were obtained from the real datasets and compared with histograms of the simulated datasets with the Chi-square dissimilarity metric (chi(2)) and Kullback Leibler divergence. For the original phantom, chi(2) values averaged 0.65 +/- 0.06 and Kullboek-Leibler values averaged 0.69 +/- 0.38. For the modified phantom, chi(2) values averaged 0.34 +/- 0.12 and Kullboek-Leibler values averaged 0.32 +/- 0.15. The proposed approach demonstrated a noticeable improvement of the local appearance of the simulated images with respect to the ones obtained originally. PMID- 20967794 TI - Characterization of a new solvate of risedronate. AB - Three new forms of the osteoporosis drug sodium risedronate, sodium [1-hydroxy-2 (3-pyridinyl)ethylidene]bisphosphonate, were identified and designated as the J, K, and M phases. Form J is an acetic acid disolvate with the chemical composition Na(+) [C(7) H(10) NO(7) P(2)](-) . 2CH(3) COOH, as determined by single-crystal structure analysis. This novel solvate is easily formed by the recrystallization of sodium risedronate from acetic acid. Dissolution of the new disolvate was characterized in distilled water, a compendial buffer, simulated gastric fluid sine pepsin (pH 1.2), and a biorelevant buffer system FaSSIF-V2 (pH 6.8). It was demonstrated that solubility of the disolvate in physiological buffers differed significantly from that of the original molecule, with delayed dissolution under simulated esophageal and gastric conditions, but rapid and complete dissolution under simulated intestinal conditions. These studies suggest that through the generation of novel solvates, the biopharmaceutical properties of poorly soluble drug candidates can be improved. PMID- 20967795 TI - Graphene quantum sheets: a new material for spintronic applications. PMID- 20967797 TI - Reconstructing the differentiation niche of embryonic stem cells using biomaterials. AB - The biochemical cues and topographical architecture of the extracellular environment extensively influence ES cell fate. The microenvironment surrounding the developing embryo presents these instructive cues in a complex and interactive manner in order to guide cell fate decisions. Current stem cell research aims to reconstruct this multifaceted embryonic niche to recapitulate development in vitro. This review focuses on 2D and 3D differentiation niches created from natural and synthetic biomaterials to guide the differentiation of ES cells toward specific lineages. Biomaterials engineered to present specific physical constraints are also reviewed for their role in differentiation. PMID- 20967796 TI - Notch signalling in T-cell lymphoblastic leukaemia/lymphoma and other haematological malignancies. AB - Notch receptors participate in a highly conserved signalling pathway that regulates normal development and tissue homeostasis in a context- and dose dependent manner. Deregulated Notch signalling has been implicated in many diseases, but the clearest example of a pathogenic role is found in T-cell lymphoblastic leukaemia/lymphoma (T-LL), in which the majority of human and murine tumours have acquired mutations that lead to aberrant increases in Notch1 signalling. Remarkably, it appears that the selective pressure for Notch mutations is virtually unique among cancers to T-LL, presumably reflecting a special context-dependent role for Notch in normal T-cell progenitors. Nevertheless, there are some recent reports suggesting that Notch signalling has subtle, yet important roles in other forms of haematological malignancy as well. Here, we review the role of Notch signalling in various blood cancers, focusing on T-LL with an eye towards targeted therapeutics. PMID- 20967799 TI - An active intracellular device to prevent lethal disease outcomes in virus infected bacterial cells. AB - Synthetic biology includes an effort to logically control cellular behavior. One long-term goal is to implement medical interventions inside living cells, creating intracellular "disease fighters"; one may imagine a system that detects viral infection and responds to halt the spread of the virus. Here, we explore a system designed to display some of the qualitative features that such disease prevention systems should have, while not claiming that the system itself has any medical application. An intracellular disease prevention mechanism should: lie dormant in the absence of the disease state; detect the onset of a lethal disease pathway; respond to halt or mitigate the disease's effects; and be subject to external deactivation when required. We have created a device that displays these properties, in the highly simplified case of a bacterial viral disease. Our system detects the onset of the lytic phase of bacteriophage lambda in Escherichia coli, responds by preventing this lethal pathway from being followed, and is deactivated by a temperature shift. We have formulated a mathematical model of the engineered system, using parameters obtained from the literature and by local experimental measurement, and shown that the model captures the essential experimental behavior of the system in most parameter regimes. PMID- 20967800 TI - A new bioproduction route for a novel antimicrobial peptide. AB - Beta defensins are antimicrobial peptides (AMPs) with a broad spectrum antimicrobial behavior against pathogens while having minimal tendency to incur pathogen resistance. Human beta-defensin 28 (hBD28) is a strongly cationic AMP and hence hypothesized to be highly effective in permeabilizing negatively charged pathogen membranes. However, the scarcity of hBD28 in vivo has impeded detailed structure and antimicrobial studies of hBD28. Chemical synthesis of hBD28 rendered extremely poor yields due to inefficient cysteine oxidation. In this study, a rapid and scalable production route to produce bioactive hBD28 in Escherichia coli (E. coli) is reported. The design of a dual fusion tag expression construct was pivotal in enhancing soluble expression and easing purification of hBD28. The final hBD28 (purity >95%) displayed significant antimicrobial activity against E. coli K12 and showed dose-dependent killing kinetics. Circular dichroism spectroscopy confirmed the presence of both beta sheet and alpha-helix conformations in the secondary structure of hBD28. PMID- 20967801 TI - Continuous supercritical emulsions extraction: a new technology for biopolymer microparticles production. AB - Supercritical emulsion extraction (SEE) was recently proposed for the production of biopolymer microparticles starting from oil-in-water emulsions. This technology can improve the product quality because of the fast and selective extraction of the dispersed oily phase by using supercritical carbon dioxide (SC CO(2) ). However, until now, SEE was proposed in batch configuration, sharing with the traditional processes an intrinsically discontinuous operation and problems of batches reproducibility and process yield. In this study, by using a countercurrent packed column, the SEE process was proposed in a continuous operating mode (SEE-CM) for the production of poly-lactic-co-glycolic acid (PLGA) microparticles. The new process design takes advantage of the large contact area between the SC-CO(2) and emulsion allowing the production of PLGA microparticles with controlled and narrow size distributions in only few minutes. SEE-CM operating parameters such as pressure, temperature, and flow rate ratios were analyzed and the process efficiency in terms of recovered material and its size distribution compared with SEE (batch mode operation) and conventional evaporation technology. PLGA microparticles showed a mean particle size between 1 3 um (depending on the droplet sizes) with a SD that was always smaller than that associated with particles produced by discontinuous processes. Single and double emulsions were successfully treated and the microparticles physico-chemical properties showed no morphological and structural differences between the SEE-CM produced microparticles and the ones obtained by conventional evaporation technology. PMID- 20967802 TI - Economic comparison of multiple techniques for recovering leaf protein in biomass processing. AB - Leaf protein concentrates (LPC) can be used as a valuable co-product to cellulosic biofuel production and can also mitigate the food versus fuel controversy. Two major approaches have been considered for LPC production: a well characterized mechanical pressing method and a less studied method involving aqueous extraction with recovery using ultrafiltration. Experimental results with switchgrass extracts show low protein recovery after filtration, particularly if protein is recovered after cellulose hydrolysis. Economic modeling suggests that aqueous extraction costs less than mechanical pressing, but due to lower protein yields and lower quality, overall profit is higher for mechanical pressing versus aqueous extraction ($26/Mg feedstock vs. $14/Mg). If modest improvements can be made in extraction yields, filtration recovery, and protein quality, then the profitability of the aqueous extraction approach can be increased to $37/Mg feedstock. This study suggests that aqueous extraction is a viable alternative for LPC co-production in a biorefinery if key improvements can be made in the process. PMID- 20967803 TI - Cellulose solvent-based biomass pretreatment breaks highly ordered hydrogen bonds in cellulose fibers of switchgrass. AB - The switchgrass (SG) samples pretreated by cellulose solvent- and organic solvent based lignocellulose fractionation were characterized by enzymatic hydrolysis, substrate accessibility assay, scanning electron microscopy, X-ray diffraction (XRD), cross polarization/magic angle spinning (CP/MAS) (13)C nuclear magnetic resonance (NMR), and Fourier transform infrared spectroscopy (FTIR). Glucan digestibility of the pretreated SG was 89% at hour 36 at one filter paper unit of cellulase per gram of glucan. Crystallinity index (CrI) of pure cellulosic materials and SG before and after cellulose solvent-based pretreatment were determined by XRD and NMR. CrI values varied greatly depending on measurement techniques, calculation approaches, and sample drying conditions, suggesting that the effects of CrI data obtained from dried samples on enzymatic hydrolysis of hydrated cellulosic materials should be interpreted with caution. Fast hydrolysis rates and high glucan digestibilities for pretreated SG were mainly attributed to a 16.3-fold increase in cellulose accessibility to cellulase from 0.49 to 8.0 m(2)/g biomass, because the highly ordered hydrogen-bonding networks in cellulose fibers of biomass were broken through cellulose dissolution in a cellulose solvent, as evidenced by CP/MAS (13)C-NMR and FTIR. PMID- 20967805 TI - Dual effect of halides in the Stille reaction: in situ halide metathesis and catalyst stabilization. AB - Halide anions can increase or decrease the transmetallation rate of the Stille reaction through in situ halide metathesis. Although the influence of the halogen present in oxidative addition complexes on the transmetallation rate with organostannanes was already known, the application of in situ halide metathesis to accelerate cross-coupling reactions with organometallic reagents is not described in the literature yet. In addition a second unprecedented role of halides was discovered. Halide anions stabilize the [Pd(0)(L)(2)] catalyst in Stille reactions, by means of [Pd(0)X(L)(2)](-) formation (X=Cl, I), hereby preventing its leaching from the catalytic cycle. Both arene (iodobenzene) and azaheteroarene (2-halopyridine, halopyrazine, 2-halopyrimidine) substrates were used. PMID- 20967804 TI - Hydrophobic polycationic coatings disinfect poliovirus and rotavirus solutions. AB - Coating surfaces with N-alkylated polyethylenimines (PEIs), namely branched N,N hexyl,methyl-PEI via covalent attachment to glass or linear N,N-dodecyl,methyl PEI by physical deposition ("painting") onto polyethylene, enables the resultant materials to quickly and efficiently disinfect aqueous solutions of (non enveloped) poliovirus and rotavirus. PMID- 20967806 TI - Ternary heterostructured nanoparticle tubes: a dual catalyst and its synergistic enhancement effects for O2/H2O2 reduction. PMID- 20967807 TI - [Cp2Ti(III)(NCy)2C-Ti(III)Cp2]: a transient titanocene carbene complex? PMID- 20967808 TI - A metal-ion-driven supramolecular chirality pendulum. PMID- 20967809 TI - NHC-catalyzed Michael addition to alpha,beta-unsaturated aldehydes by redox activation. PMID- 20967811 TI - Change of direction: enantioselective CuH-catalyzed 1,2-reduction of alpha,beta unsaturated ketones. PMID- 20967812 TI - Cyclic voltammetry in the absence of excess supporting electrolyte offers extra kinetic and mechanistic insights: comproportionation of anthraquinone and the anthraquinone dianion in acetonitrile. PMID- 20967810 TI - Oxaziridine-mediated oxyamination of indoles: an approach to 3-aminoindoles and enantiomerically enriched 3-aminopyrroloindolines. PMID- 20967813 TI - Effective chirogenesis in a bis(metallosalphen) complex through host-guest binding with carboxylic acids. PMID- 20967814 TI - A compound with a Si-C triple bond. PMID- 20967816 TI - Nobel Prizes 2010: Richard F. Heck / Ei-ichi Negishi / Akira Suzuki. PMID- 20967815 TI - Synthesis of (+/-)-merrilactone A and (+/-)-anislactone A. PMID- 20967817 TI - Bioorthogonal small-molecule ligands for PARP1 imaging in living cells. PMID- 20967818 TI - Asborin inhibits Aldo/Keto reductase 1A1. AB - Asborin is the carbaborane analogue of aspirin. Replacement of the phenyl ring in aspirin by ortho-carbaborane was found to change the pharmacological profile of the compound remarkably. Unlike aspirin, asborin cannot selectively acetylate a single serine residue in the active site of cyclooxygenase, and as a result inhibitory potency is reduced. Activation of the acetyl group and the presence of the hydrophobic and bulky cluster therefore did not meet the requirements for cyclooxygenase inhibition. Both features, however, match perfectly for inhibition of the aldo/keto reductase family. Herein, we describe the identification of aldo/keto reductase (AKR) 1A1 as an enzymatic target of asborin, which is inhibited in the low micromolar range. The detailed mode of inhibition was studied and is discussed with respect to the cluster properties. The results shed light on how ortho-carbaborane can be used as a drug synthon, as well as on the development of carbaborane-based inhibitors of other aldo/keto reductases. PMID- 20967819 TI - Polycyclic N-benzamido imides with potent activity against vaccinia virus. AB - The synthesis and antiviral activity of a series of novel polycyclic analogues of the orthopoxvirus egress inhibitor tecovirimat (ST-246) is presented. Several of these compounds display sub-micromolar activity against vaccinia virus, and were more potent than cidofovir (CDV). The more active compounds were about 10-fold more active than CDV, with minimum cytotoxic concentrations above 100 MUM. Chemical manipulations of the two carbon-carbon double bonds present in the compounds were carried out to further explore the structure-activity relationships of these new polycyclic imides. Hydrogenation of the two carbon carbon double bonds decreases antiviral activity, whereas either cyclopropanation or epoxidation of the double bonds fully eliminates the antiviral activity. PMID- 20967820 TI - Switching the regioselectivity in cycloaddition-retro-electrocyclizations between donor-activated alkynes and the electron-accepting olefins TCNE and TCNQ. PMID- 20967821 TI - Supramolecular synthons in designing low molecular mass gelling agents: L-amino acid methyl ester cinnamate salts and their anti-solvent-induced instant gelation. AB - Easy access to a class of chiral gelators has been achieved by exploiting primary ammonium monocarboxylate (PAM), a supramolecular synthon. A combinatorial library comprising of 16 salts, derived from 5 L-amino acid methyl esters and 4 cinnamic acid derivatives, has been prepared and scanned for gelation. Remarkably, 14 out of 16 salts prepared (87.5 % of the salts) show moderate to good gelation abilities with various solvents, including commercial fuels, such as petrol. Anti solvent induced instant gelation at room temperature has been achieved in all the gelator salts, indicating that the gelation process is indeed an aborted crystallization phenomenon. Rheology, optical and scanning electron microscopy, small angle neutron scattering, and X-ray powder diffraction have been used to characterize the gels. A structure-property correlation has been attempted, based on these data, in addition to the single-crystal structures of 5 gelator salts. Analysis of the FT-IR and (1)H NMR spectroscopy data reveals that some of these salts can be used as supramolecular containers for the slow release of certain pest sex pheromones. The present study clearly demonstrates the merit of crystal engineering and the supramolecular synthon approach in designing new materials with multiple properties. PMID- 20967822 TI - Iridium-catalyzed asymmetric hydrogenation of unfunctionalized, trialkyl substituted olefins. AB - Chiral iridium complexes with bicyclic pyridine-based N,P ligands have emerged as efficient catalysts for the enantioselective hydrogenation of unfunctionalized trialkyl-substituted olefins. Optimization of the reaction conditions by variation of the solvent, pressure, and temperature led to enantiomeric excesses of up to 99%. Three pure alkenes, (E)-2-cyclohexyl-2-butene and (E)- and (Z)-3,4 dimethyl-2-pentene were converted into the corresponding chiral alkanes with 97%, 94%, and 93% ee, respectively. Hydrogenation of the three C=C bonds of both alpha and gamma-tocotrienyl acetate led to alpha- and gamma-tocopheryl acetate with very high diastereoselectivity. The same catalysts were successfully applied in the hydrogenation of trisubstituted alkenes with a carboxylic ester or a keto group in the gamma position. This reaction was used as a key step in a highly enantioselective synthesis of the pheromone of the caddisfly Hesperophylax occidentalis. The hydrogenation of a structurally analogous allylic alcohol also gave high enantioselectivities. PMID- 20967823 TI - Gelling process differences in reverse emulsion, in situ gelling polymeric materials for intracranial aneurysm embolization, formulated with injectable contrast agents. AB - The use of liquid-to-solid curing materials for brain aneurysm embolization has become increasingly attractive, as liquid embolics can be delivered noninvasively and can potentially achieve a higher degree of aneurysm volume occlusion. This study was aimed at characterizing differences in the gelling process of a reverse emulsion, crosslinking polymer system formulated with different types of injectable contrast agents. The polymeric system consists of poly(propylene glycol) diacrylate (PPODA) and pentaerythritol tetrakis(3-mercaptopropionate) (QT). These monomers undergo Michael-type addition upon initiation by a basic, aqueous solution. ConrayTM and OmnipaqueTM 300, commercially available contrast agents, were pH-adjusted to basic conditions and used as initiating solutions with the PPODA-QT system. Material characteristics were identified through rheology and scanning electron microscopy (SEM). Results showed that Conray- and Omnipaque-formulated materials progress through the gelling process uniquely, evidenced by distinctly different viscosity profiles and droplet distributions. These results indicate that Conray is more miscible with the PPODA-QT organic phase. Greater solubility in the organic phase allows Conray-formulated gels to have faster and more widespread reaction initiation kinetics when Conray and Omnipaque have the same pH. Omnipaque-formulated gels require a higher pH for the material to solidify in a time frame comparable to Conray-formulated gels. This discrepancy arises because the majority of reaction initiation sites in Omnipaque formulated gels occur at phase boundaries via hydroxide ion flux from emulsified droplets rather than from hydroxide ions that are solubilized and integrated within the PPODA-QT organic phase. PMID- 20967824 TI - Activation of the endotoxin/toll-like receptor 4 pathway: the way to go from nonalcoholic steatohepatitis up to hepatocellular carcinoma. PMID- 20967825 TI - Positron emission tomography scan for a hepatic mass. PMID- 20967826 TI - Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. AB - Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis. Recently, we showed that NASH-related cirrhosis is associated with Hedgehog (Hh) pathway activation. The gene encoding osteopontin (OPN), a profibrogenic extracellular matrix protein and cytokine, is a direct transcriptional target of the Hh pathway. Thus, we hypothesize that Hh signaling induces OPN to promote liver fibrosis in NASH. Hepatic OPN expression and liver fibrosis were analyzed in wild type (WT) mice, Patched-deficient (Ptc(+/-) ) (overly active Hh signaling) mice, and OPN-deficient mice before and after feeding methionine and choline-deficient (MCD) diets to induce NASH-related fibrosis. Hepatic OPN was also quantified in human NASH and nondiseased livers. Hh signaling was manipulated in cultured liver cells to assess direct effects on OPN expression, and hepatic stellate cells (HSCs) were cultured in medium with different OPN activities to determine effects on HSC phenotype. When fed MCD diets, Ptc(+/-) mice expressed more OPN and developed worse liver fibrosis (P < 0.05) than WT mice, whereas OPN-deficient mice exhibited reduced fibrosis (P < 0.05). In NASH patients, OPN was significantly up-regulated and correlated with Hh pathway activity and fibrosis stage. During NASH, ductular cells strongly expressed OPN. In cultured HSCs, SAG (an Hh agonist) up-regulated, whereas cyclopamine (an Hh antagonist) repressed OPN expression (P < 0.005). Cholangiocyte-derived OPN and recombinant OPN promoted fibrogenic responses in HSCs (P < 0.05); neutralizing OPN with RNA aptamers attenuated this (P < 0.05). CONCLUSION: OPN is Hh-regulated and directly promotes profibrogenic responses. OPN induction correlates with Hh pathway activity and fibrosis stage. Therefore, OPN inhibition may be beneficial in NASH. PMID- 20967827 TI - Outcome of laparoscopic duodenal switch for morbid obesity. AB - BACKGROUND: The aim of this study was to determine the safety and efficacy of laparoscopic duodenal switch (LDS) as a treatment option in a selected group of patients with morbid obesity. METHODS: This retrospective analysis of a prospective database assessed the frequency of all complications and alterations in weight, body mass index (BMI), co-morbidity and quality of life. RESULTS: One hundred and twenty-one patients underwent LDS between April 2003 and March 2009. Median preoperative weight was 160 kg and median BMI 55 kg/m(2). All procedures were performed laparoscopically. The in-hospital mortality rate was zero. No ileoduodenal anastomotic stenosis was encountered. There were four clinical leaks (3.3 per cent) managed by laparoscopic drainage and placement of a feeding jejunostomy. Median percentage excess weight loss was 75 per cent at 12 months and 90 per cent at 24 months. Thirty-six of 40 diabetic patients had complete resolution of diabetes within 1 year. There were significant improvements in other obesity-related co-morbidity. Only a few patients developed postoperative protein deficiency, and fat-soluble vitamin deficiencies were easily managed with oral supplementation. CONCLUSION: The LDS procedure is a safe and effective treatment for morbid obesity and its associated co-morbidity in selected patients. PMID- 20967828 TI - Liver regeneration is impaired in lipodystrophic fatty liver dystrophy mice. AB - We previously reported that mice subjected to partial hepatectomy exhibit rapid development of hypoglycemia followed by transient accumulation of fat in the early regenerating liver. We also showed that disrupting these metabolic alterations results in impaired liver regeneration. The studies reported here were undertaken to further characterize and investigate the functional importance of changes in systemic adipose metabolism during normal liver regeneration. The results showed that a systemic catabolic response is induced in each of two distinct, commonly used experimental models of liver regeneration (partial hepatectomy and carbon tetrachloride treatment), and that this response occurs in proportion to the degree of induced hepatic insufficiency. Together, these observations suggest that catabolism of systemic adipose stores may be essential for normal liver regeneration. To test this possibility, we investigated the hepatic regenerative response in fatty liver dystrophy (fld) mice, which exhibit partial lipodystrophy and have diminished peripheral adipose stores. The results showed that the development of hypoglycemia and hepatic accumulation of fat was attenuated and liver regeneration was impaired following partial hepatectomy in these animals. The fld mice also exhibited increased hepatic p21 expression and diminished plasma levels of the adipose-derived hormones adiponectin and leptin, which have each been implicated as regulators of liver regeneration. CONCLUSION: These data suggest that the hypoglycemia that develops after partial hepatectomy induces systemic lipolysis followed by accumulation of fat derived from peripheral stores in the early regenerating liver, and that these events may be essential for initiation of normal liver regeneration. PMID- 20967829 TI - Motor patterns of distal hind limb muscles in walking turtles: Implications for models of limb bone loading. AB - Previous studies of limb bone loading in walking turtles indicate that the ground reaction force exerts a flexor moment at the ankle during stance, requiring extensor muscle activity to maintain joint equilibrium. Of four proposed ankle extensors in turtles, two (gastrocnemius medialis, pronator profundus) originate on the tibia and fibula, respectively, while the other two (flexor digitorum longus, gastrocnemius lateralis) originate from the distal femur, crossing the flexor aspect of the knee and potentially eliciting compensatory forces from antagonist knee extensor muscles that could contribute to femoral stress. Published bone stress models assume all four proposed ankle extensors are active during stance in turtles. However, if only the ankle extensors that cross the knee were active then femoral stresses might be higher than predicted by published models, whereas if only extensors that do not cross the knee were active then femoral stresses might be lower than predicted. We analyzed synchronized footfall and electromyographic activity patterns in slider turtles (Trachemys scripta) and found that all four proposed ankle extensors were active during at least part of stance phase in most individuals, corroborating bone stress models. However, activation patterns were complex, with multiple bursts in many ankle extensors that frequently persisted into swing phase. In addition, two hypothesized ankle flexors (tibialis anterior, extensor digitorum communis) were frequently active during stance. This might increase the joint moment that ankle extensors must counter, elevating the forces they transfer across the knee joint and, thereby, raising femoral stress. Recognition of these activity patterns may help reconcile differences between evaluations of loads on turtle limbs based on force platform versus in vivo strain studies. Moreover, while some variation in motor patterns for the distal hind limbs of turtles may reflect functional compartmentalization of muscles, it may also indicate flexibility in the control of their limb movements. PMID- 20967830 TI - Interspecific variation of ontogeny and skull shape among porpoises (Phocoenidae). AB - All extant members of Phocoenidae (porpoises) have been characterized as pedomorphic based on skeletal characters. To investigate the ontogenetic background for pedomorphosis and assess interspecific differences in ontogeny among phocoenids, samples of the six extant species were compared in terms of development of both epiphyseal and cranial suture fusion. Across all species, full maturity of the vertebral column was rare. Vertebral epiphyseal development did not progress so far in most Phocoena phocoena as in Phocoenoides dalli and Phocoena dioptrica. P. phocoena, Phocoena spinipinnis, Ph. dalli, and P. dioptrica, for which large series were available, were further compared in terms of ontogeny of cranial shape by three-dimensional geometric morphometrics. Ph. dalli and P. dioptrica generally showed further development of cranial sutures than the other species. Postnatal skull shape development was similar for all species studied; the majority of interspecific shape differences are present at parturition. Smaller species had a higher rate of shape development relative to growth in size than Ph. dalli and P. dioptrica, but they still showed less allometric development due to less postnatal growth. Interspecific shape differences indicate phylogenetic relationships similar to that proposed based on morphology or convergent evolution of the two pelagic species, Ph. dalli and P. dioptrica, under the scenarios suggested by recent molecular studies. A shape trend coinciding with habitat preference was detected; in species with pelagic preference the position and orientation of the foramen magnum aligned the skull with the vertebral column; the rostrum showed less ventral inclination, and the facial region was larger and more concave in lateral aspect. PMID- 20967831 TI - Magnetic resonance microscopy of the barramundi (Lates calcarifer) brain. AB - Magnetic resonance imaging (MRI) is an established technique for morphological imaging of the central nervous system. Despite its prevalent use in a range of taxa, few studies exist on the brains of teleosts. In this study, we present a detailed analysis of a teleost brain using high-resolution MRI. Images were acquired from a Bruker 16.4 T vertical magnet with a three-dimensional flash T(2)*-weighted image sequence. High contrast was obtained using Magnevist(r) and the following imaging parameters: a flip angle of 30 degrees , a repetition time of 50 ms, an echo time of 14 ms, and an image matrix of 1024 * 400 * 400. The resulting isotropic resolution of 30 MUm allowed us to thoroughly describe the architecture of the barramundi (Lates calcarifer) brain, including descriptions of nuclei, fiber tracts, and cellular layers. A good correspondence, both in contrast and morphology, was found between magnetic resonance images and Nissl stained brain sections, allowing for an analysis of the benefits and drawbacks of MRI and conventional histology. PMID- 20967832 TI - Seasonal flexibility in organ size in the Andean lizard Liolaemus moradoensis. AB - The understanding of animal functioning in fluctuating environments is a major goal of physiological and evolutionary ecology. In temperate terrestrial habitats, one of the most pervasive changes in environmental conditions is that associated with the seasonal change along the year. In this study, we describe the pattern of seasonal variation in the size of nine internal organs in the lizard Liolaemus moradoensis from the Andes Mountains of Central Chile. We observed that the size of digestive organs was greater during summer in comparison to other seasons. Dry masses of liver and fat bodies reached maximum values during summer and minimum during spring. We suspect that lowest spring values are related with build-up costs of energetically expensive organs (e.g., digestive, muscle mass) at the end of the hibernation period. Dry mass of the heart and lungs did not show a clear pattern of variation, suggesting that cardiac and pulmonary performance were maintained throughout the year. The dry mass of kidneys was greater during winter than during summer, a result observed in other hibernating lizards but for which there is no clear explanation. Finally, the dry mass of testes showed a maximum value during autumn and a progressive reduction toward summer, indicating that reproduction occurs during autumn. When represented in a bivariate space, acquisition (digestive), distribution (heart, lungs and kidneys), storage (liver and fat bodies), and expenditure (testes) organs generate four clusters. In general terms, observed seasonal pattern of change in organ size is in agreement with those reported for other lizard species that inhabit highly fluctuating environments. PMID- 20967833 TI - Three-dimensional tracking and temporal analysis of liposomal transport in live cells using bright-field imaging. AB - Gold nanoparticles (AuNPs) confined in liposomes of diameters around 200 nm produce strong scattering signal owing to surface plasmon resonance, and therefore bright-field optical tracking of the AuNP-encapsulating liposomes can be conducted in living cells. Using an optical profiling technique called noninterferometric wide-field optical profilometry and a bright-field tracking algorithm, the polynomial-fit Gaussian weight method, we analyze three dimensional (3D) motion of such liposomes in living fibroblasts. The positioning accuracy in three dimensions is nearly 20 nm. We tag the liposome membranes with fibroblast growth factor-1 and reveal the intracellular transportation processes toward or away from the nucleus. On the basis of a temporal analysis of the intracellular 3D trajectories of AuNP-encapsulating liposomes, we identify directed and diffusive motions in the transportation processes. PMID- 20967834 TI - Cardiorespiratory measurements during field tests in CF: use of an ambulatory monitoring system. AB - Respiratory inductive plethysmography (e.g., LifeShirt) may offer in-depth study of the cardiorespiratory responses during field exercise tests. The aims of this study were to assess the reliability, discriminate validity, and responsiveness of cardiorespiratory measurements recorded by the LifeShirt during field exercise tests in adults with CF. To assess reliability and discriminate validity, participants with CF and stable lung disease and healthy participants performed the 6-Minute Walk Test (6MWT) and Modified Shuttle Test (MST) on two occasions. To assess responsiveness, participants with CF experiencing an exacerbation performed the 6MWT at the start and end of an admission for intravenous antibiotics. The LifeShirt was worn during all exercise tests. Reliability and discriminate validity were assessed in 18 participants with CF (mean (SD) age: 26 (10) years; FEV1 %predicted: 69.2 (23)%) and 18 healthy participants (age: 24 (5) years, FEV1 % predicted: 92 (8)%). There was no difference in 6MWT and MST performance between days and reliability of cardiorespiratory measures was acceptable (bias: P > 0.05; CV < 10%). Participants with CF demonstrated a significantly greater response to exercise (e.g., ventilation, respiratory rate) compared to healthy participants indicating discriminate validity. Responsiveness was assessed in 12 participants with CF: clinical measurements and 6MWT performance improved (61 (81) min; P < 0.05) however, cardiorespiratory measurements recorded by the LifeShirt remained the same (bias: P > 0.05; CV < 10%). This study provides evidence that cardiorespiratory responses can be measured non-invasively during field exercise tests in adults with CF. Reliability and discriminate validity of key cardiorespiratory measurements recorded by the LifeShirt were demonstrated. Some information on responsiveness is reported. PMID- 20967835 TI - Treatment of pediatric pulmonary hypertension with simvastatin: an observational study. AB - BACKGROUND: Animal studies and an adult human case series suggest that statins may have a role in the treatment of pulmonary hypertension. We reviewed the results of empirical therapy for children at Primary Children's Medical Center to determine whether simvastatin had a favorable effect on non-invasive estimates of pulmonary arterial pressure. MATERIALS AND METHODS: The medical records of children with pulmonary hypertension who were treated with simvastatin were reviewed. Mean measurements of the gradient of tricuspid valve regurgitation before and after treatment were compared by a paired t-test. A favorable response to simvastatin was defined as a 20% decrease in the average measurement of the gradient of tricuspid valve regurgitation or a 20% decrease in right ventricular anterior wall thickness when tricuspid valve regurgitation resolved during treatment. Potential factors associated with a favorable response to simvastatin were identified with a Fisher exact test. RESULTS: Twelve children, 4-15 years of age, had adequate Doppler velocity waveforms to reliably measure gradients of tricuspid valve regurgitation during a period of 1 year before treatment. Eleven patients had gradients of tricuspid valve regurgitation that could be measured during a period of 1 year after treatment. Patients were treated with simvastatin 0.09-0.28 mg/kg/day. Collectively, there was no difference between the average measurements of the gradient of tricuspid valve regurgitation before and after treatment (66 +/- 21 mmHg vs. 63 +/- 28 mmHg). Three of the five patients with clinical findings consistent with alveolar hypoxia and none of the seven patients without clinical findings consistent with alveolar hypoxia had a favorable response to treatment with simvastatin (P = 0.05). CONCLUSION: Simvastatin may decrease pulmonary arterial pressure in a subset of patients with pulmonary hypertension. PMID- 20967836 TI - Gastro-esophageal reflux in early childhood wheezers. AB - Wheezing is common among infants and young children due to peculiar anatomical and physiological properties of their lungs. Gastro-oesophageal reflux (GER) has been incriminated as one of the cause of non-asthmatic wheezing in this age group. The present study evaluates the magnitude of GER and its causal relationship with wheezing in early childhood. All recurrent and persistent wheezers (under two years) were investigated for GER and treated medically where tests were positive. The subjects were further profiled to identify any predictors for GER. Sixty-seven children of less than 2 years age with recurrent or persistent wheezing were evaluated for GER. Mean age of the study subjects at enrolment was 10.8 months and at onset of wheezing was 7.1 (+/- 3.8 S.D) months. Asthma and wheeze associated lower respiratory tract infection (WALRI) was diagnosed in about 1/3 each of the patients studied. GER studies were positive in over one-third (25/67) of cases. Forty-two percent of children who wheezed by 1 year of age had a positive GER study. Interestingly, nearly half (12/25) of the patients with an abnormal study did not have any clinical suggestion of regurgitation ("silent" GERs). The severity of wheezing was higher among those who had GER versus those who did not (p <= 0.048; OR: 3.2). However, only 32% patients showed significant response to anti reflux treatment alone while others had partial response. GER, therefore, is an important cause for recurrent wheezing among children less than 2 years of age, either singularly or as a co morbidity. The study findings justify investigations for GER among early wheezers; particularly for those who have onset of symptoms by 12 months of age or those who have severe disease. PMID- 20967837 TI - The study of phase separation in amorphous freeze-dried systems, part 2: investigation of Raman mapping as a tool for studying amorphous phase separation in freeze-dried protein formulations. AB - Phase separation in amorphous freeze-dried proteins systems is speculated to occur, but limitations in methods of detection have hindered progress in identifying and studying this phenomenon. We present here preliminary results obtained on model two-component protein-stabilizer systems that illustrate the potential of a novel confocal Raman mapping technique in detecting phase separation in protein-containing formulations. The Raman technique detected the presence of phase separation in Ficoll/bovine serum albumin (BSA) samples at ratios of 1:2 to 2:1 and in trehalose/lysozyme samples at weight ratios of 1:1 and 3:1. A model physical mixture of Ficoll and BSA was used as a positive control to illustrate extreme phase separation. The results suggest that Raman mapping of freeze-dried protein systems offers a means of identifying phase separation in susceptible formulations. Contrary to the use of differential scanning calorimetry, Raman does not rely upon a change in heat capacity. This is a strong advantage over calorimetry, which is not capable of detecting phase separation in systems that result in at least one protein-rich phase because of the weak change in heat capacity and the broad temperature range associated with the glass transition temperature in these systems. PMID- 20967838 TI - Impact of age and gender on adherence to infection control guidelines and medical regimens in cystic fibrosis. AB - RATIONALE: The goal of the present research was to examine the impact of age and gender on adherence to both infection control (IC) guidelines and traditional medical treatments in a cystic fibrosis (CF) population. Adherence behaviors are consistently suboptimal in chronic illness populations, particularly pulmonary diseases; understanding the factors related to adherence behaviors in CF can aid in the development of interventions to promote adherence. METHOD: Participants consisted of 74 individuals with CF ages 9 years and above. Participants were asked to complete questionnaires designed to assess demographic data, treatment adherence, and health beliefs. RESULTS: With respect to IC guidelines, chi-square analyses revealed significant age differences in adherence behaviors such that the young adult subsample was least adherent to IC (chi2 = 15.10, df = 6, P = 0.020). Next, a 4 (age: child, adolescent, young adult, adult) * 2 (gender) completely between subjects analysis of variance (ANOVA) was conducted on medical treatment adherence. There was a significant main effect for age [F(3, 65) = 2.940, P = 0.040, etaP2 = 0.119] indicating that the adolescent subsample had the most adherence challenges. Gender was nonsignificant across both adherence types. CONCLUSIONS: Study findings are suggestive of age-related differences in adherence behaviors across both IC and medical regimens and support the use of developmentally sensitive approaches to assessment and interventions addressing adherence. PMID- 20967839 TI - Helmet-delivered heliox-CPAP in severe upper airway obstruction caused by PHACES syndrome. AB - We present the case of a 4-month-old girl with PHACES syndrome and severe upper respiratory airway obstruction secondary to multiple subglottic and tracheal hemangiomas effectively treated with heliox-CPAP delivered by helmet (HH-CPAP). PMID- 20967840 TI - Socioeconomic status and risk of hospitalization among individuals with cystic fibrosis in Ontario, Canada. AB - BACKGROUND: Socioeconomic status (SES) is a strong predictor of outcomes in cystic fibrosis (CF); however, there are no published studies evaluating this relationship in Canadians with CF. The objective of this study was to assess the effect of SES on annual hospitalization rates in a large cohort of pediatric and adult CF subjects under a universal health care system. METHODS: A population based longitudinal study was completed in Ontario from 1993 to 2002 using a comprehensive CF registry containing patient-level data, linked to provincial health care administrative databases. Income quintiles were derived at the neighborhood level using postal code information and Statistics Canada census data. The effect of income quintile on the annual hospitalization rate for respiratory-related illness was estimated by Poisson regression using generalized estimating equations, and was expressed as a rate ratio (RR) and 95% confidence interval (CI). The analysis was adjusted for age, sex, lung function, nutritional status, the presence of diabetes, area of residence, and distance between the subject's residence and the reporting CF centre. RESULTS: A total of 1,174 participants over the age of 6 years contributed 8,444 patient-years of data. No statistically significant differences in annual hospitalization rates for respiratory-related causes were found between the lowest and highest income quintiles (adjusted RR 1.17 [95% CI 0.96-1.43]). The effect of income quintile remained non-significant across a majority of markers of CF disease severity and across a range of subgroups. CONCLUSIONS: After adjusting for important covariates, no SES-disparities in hospitalization rates were found in a large Canadian pediatric and adult CF cohort. It may be the distinctive combination of universal health care, a national network of specialty CF clinics, and drug and travel coverage available in Ontario that results in similar hospitalization rates regardless of SES. PMID- 20967841 TI - Pulmonary function impairment after trachea-esophageal fistula: a minor role for gastro-esophageal reflux disease. AB - BACKGROUND: Long-term impairment of pulmonary function in trachea-esophageal fistula (TEF) patients is, at least in part, commonly ascribed to gastro esophageal reflux disease (GERD). The objective of this study was to examine the independent effects of the underlying condition and GERD on cardiopulmonary function. METHODS: Cardiopulmonary function of TEF patients, who had (severe) GERD (s-GERD) requiring antireflux surgery (TEF + GERD, n = 11) and TEF patients who did not have s-GERD (group TEF-GERD, n = 20) were compared with control patients who had isolated s-GERD requiring antireflux surgery (group GERD, n = 13). All patients performed spirometry, lung volume measurements, measurement of diffusion capacity and maximal cardiopulmonary exercise testing (CPET). RESULTS: Mean age of the participants was 13.8 +/- 2.7 (group TEF + GERD). 13.2 +/- 2.9 (group TEF-GERD), and 14.7 +/- 1.5 years (group GERD). FVC and TLC were significantly lower in patients with TEF (with and without s-GERD) when compared to patients with isolated s-GERD. Most pulmonary function parameters were similarly affected in both TEF groups, but FEV(1) was lower in the TEF + GERD group than in the TEF-GERD group. Cardiopulmonary exercise parameters were similar in all groups. CONCLUSIONS: TEF patients had restrictive lung function impairment when compared to patients with isolated s-GERD. This difference may be due to several causes, including thoracotomy. FEV(1) was lower in TEF + GERD when compared to TEF-GERD indicating that GERD may affect large airway function in TEF patients. Other differences between TEF patients with and without s-GERD were not significant, suggesting only a minor role for GERD. PMID- 20967842 TI - Obesity and obstructive sleep apnea syndrome in children: a tale of inflammatory cascades. AB - Obesity has emerged as one of the most prevalent diseases in the western hemisphere, and its prevalence continues to increase. Obese children are at increased risk for several disorders, particularly affecting the cardiovascular and metabolic systems. The mechanisms leading to obesity-related morbidities are likely multifactorial, and include activation of inflammatory pathways ultimately leading to end-organ injury. Furthermore, the concurrent presence of obesity and other diseases facilitated by increased fat deposition poses a theoretical risk of accentuating obesity-related complications. One of the conditions whose prevalence is increased by obesity in childhood is the obstructive sleep apnea syndrome (OSAS). OSAS in non-obese children may lead to co-morbidities that are not only remarkably similar to those associated with obesity but recruit similar inflammatory mechanisms as those activated by obesity, suggesting that the two disorders may amplify each other and synergistically augment the magnitude of their respective adverse consequences. The objective of this review is to critically review the effects of both obesity and OSAS in inducing systemic inflammation in children and will examine the latest evidence pertaining to the up-regulation of specific inflammatory mediators. PMID- 20967844 TI - Re: Lum S, Hoo AF, Hulskamp G, Wade A, Stocks J. Potential misinterpretation of infant lung function unless prospective healthy controls are studied. Pediatr pulmonol 2010;45:906-913. PMID- 20967845 TI - Pulmonary exacerbations are associated with subsequent FEV1 decline in both adults and children with cystic fibrosis. AB - BACKGROUND: Patients with cystic fibrosis (CF) frequently experience pulmonary exacerbations that may lead to a faster subsequent decline in pulmonary function; however, this relationship has not been clearly established. The purpose of this study was to determine the association between the frequency of pulmonary exacerbations and subsequent forced expiratory volume in 1 sec (FEV(1) ) decline in adults and children with CF. METHODS: Cohort study of subjects followed in the Cystic Fibrosis Foundation Patient Registry from 2003 through 2006. Mixed effects modeling was used to estimate differences in rates of decline in FEV(1) in 2004 2006 for patients with 0, 1, 2, or 3+ pulmonary exacerbation(s) in 2003. RESULTS: Of 8,490 subjects who met inclusion criteria, 60% had 0 exacerbations, 23% had 1, 10% had 2, and 7% had 3+ exacerbations in 2003. Compared to children with no pulmonary exacerbations in 2003, children with one or more exacerbations experienced a significantly (P < 0.001) greater rate of FEV(1) decline in 2004 2006. In contrast, among adults, only those with 3+ exacerbations in 2003 had a significantly (P = 0.01) greater rate of FEV(1) decline in 2004-2006 than those with no exacerbations in 2003. CONCLUSIONS: There is a strong association between the frequency of pulmonary exacerbations and subsequent decline in pulmonary function. In adults, having 3+ exacerbations, and among children, having any exacerbations is associated with a greater rate of decline in the ensuing 3 years. Improved prevention, identification, and treatment of pulmonary exacerbations are likely to have long-term benefits for patients with CF, especially children. PMID- 20967843 TI - Modulatory effect of the SLC9A3 gene on susceptibility to infections and pulmonary function in children with cystic fibrosis. AB - In cystic fibrosis (CF), CFTR dysfunction leads to salt and water imbalance across airway epithelia, depleted surface liquid layer, and impaired mucociliary clearance. This provides optimal conditions for chronic bacterial infections leading to excessive inflammation and progressive obstructive lung disease. We hypothesized that other epithelial channels affecting salt balance across the airways may play a role in the susceptibility to bacterial infections and modulate severity of CF lung disease. The SLC9A3 gene encoding a Na(+) /H(+) exchanger was demonstrated to be a modifier intestinal disease in a murine model of CF. We examined the potential role of SLC9A3 as a modifier of CF lung disease severity. We analyzed 11 SLC9A3 gene variants for association with age of first Pseudomonas aeruginosa infection and lung function in children with CF. The T allele of an intronic variant in the SLC9A3 gene (rs4957061) was significantly (P = 0.02) associated with earlier acquisition of Pseudomonas infection in a cohort of 1,004 pediatric patients. Analysis of lung function in a subset of these patients (752) revealed that patients homozygous for the T allele had substantially reduced lung function and accelerated rate of decline. Although the functional basis for the modulatory effects of this SLC9A3 variant on CF lung disease remains to be elucidated, altered function of the Na(+) /H(+) exchanger may further deplete the airway liquid surface, thereby enhancing susceptibility to Pseudomonas infections and worsening the severity of lung disease. PMID- 20967846 TI - Methacholine-induced lung function changes measured with infant body plethysmography. AB - Several techniques have been applied to measure airway responsiveness (AR) in infants, but there are limited data on lung function changes measured by body plethysmography during induced bronchoconstriction. The aim of this study was to compare changes in maximum forced expiratory flow measured at functional residual capacity (V'(maxFRC)) by rapid thoracoabdominal compression (RTC) technique with plethysmographic measurements of specific airway conductance (sG(aw) ), and to investigate whether changes in functional residual capacity (FRC) occur during methacholine-induced bronchoconstriction in infants. We examined 94 infants with recurrent airway symptoms using methacholine airway challenge test including RTC and plethysmographic measurements. A significant association between changes in V'(maxFRC) and sG(aw) (r = 0.30; P = 0.004) was observed, but after adjustments with baseline variability the changes in V'(maxFRC) were greater and showed a closer association with changes in oxygen saturation. At the point of maximal airway obstruction, there was a poor agreement between V'(maxFRC) and sG(aw) to indicate a significant methacholine-induced bronchoconstriction. Airway challenge was also associated with a significant increase in FRC (P < 0.001), with decreasing V'(maxFRC). We conclude that in infants undergoing airway challenge with methacholine, plethysmographic measurements of sG(aw) correlate with the changes in V(maxFRC), but the agreement is poor and the methods cannot be used interchangeably. V(maxFRC) is also more sensitive to detect airway obstruction than sG(aw). However, methacholine-induced bronchoconstriction was associated with significant increases in FRC, which may affect the validity of V(maxFRC) measurements during the test. PMID- 20967847 TI - Cognitive limitations associated with tamoxifen and aromatase inhibitors in employed breast cancer survivors. AB - OBJECTIVES: Previous research has suggested that endocrine therapy is associated with cognitive limitations in breast cancer survivors (BCS); this study examined the relationship in employed BCS, an average of three years post-primary treatment. METHODS: 77 BCS with past or current exposure to tamoxifen or aromatase inhibitors and 56 BCS with no history of endocrine therapy completed self-report measures of cognitive function, anxiety, depression, and fatigue as well as an online neurocognitive battery. RESULTS: Exposure to endocrine therapy was not related to scores on the objective measures, but moderately related to perceived attentional problems at work (beta = -0.20; CI(0.95) = -2.75, -0.25) and perceived cognitive functioning in overall life (beta = 0.17; CI(0.95) = 0.33, 11.47) in excess of what could be explained by symptom burden measures. No differences were reported between groups on symptom burden measures. Symptoms of physical fatigue, depression, and anxiety were positively associated with self report of general cognitive limitations (R(2) change range: 0.28-0.37), and symptoms of depression and anxiety were positively associated with perceived cognitive limitations at work (R(2) change range: 0.21-0.28). DISCUSSION: Symptoms of depression, anxiety, and fatigue should be screened for and treated in BCS, as an approach to mitigating perceived cognitive limitations. However, healthcare providers should be aware that cognitive limitations exist in excess of what can be associated with symptom burden, and may be related to endocrine therapy and other cancer treatments. PMID- 20967848 TI - Social support and survival in young women with breast carcinoma. AB - PURPOSE: Although previous evidence has shown increased likelihood for survival in cancer patients who have social support, little is known about changes in social support during illness and their impact on survival. This study examines the relationship between social support and survival among women diagnosed with breast carcinoma, specifically assessing the effect of network size and changes in social contact post-diagnosis. METHODS: A population-based sample of 584 women was followed for up to 12.5 years (median follow-up = 10.3 years). The mean age at diagnosis was 44 years, 81% were married, and 29% were racial/ethnic minorities. Cox regression analysis was used to estimate survival as a function of social support (changes in social contact and the size of social support), disease severity, treatment, health status, and socio-demographic factors. RESULTS: Fifty-four percent of the women had local and 44% had regional stage disease. About 53% underwent mastectomy, 68% received chemotherapy, and 55% had radiation. Regression results showed that disease stage, estrogen receptor status, and mastectomy were associated with greater risk of dying. Although network size was not related to survival, increased contact with friends/family post-diagnosis was associated with lower risk of death, with a hazard ratio of 0.31 (95% CI, 0.17-0.57). CONCLUSION: Findings from this study have identified an important aspect of a woman's social network that impacts survival. An increase in the amount of social contact, representing greater social support, may increase the likelihood of the women's survival by enhancing their coping skills, providing emotional support, and expanding opportunities for information-sharing. PMID- 20967849 TI - When peer support may be most beneficial: the relationship between upward comparison and perceived threat. AB - OBJECTIVE: Currently, the mechanism by which dyadic peer support programs may facilitate positive psychological adjustment for cancer patients is unclear. This study utilized social comparison theory to examine the effects of peer support on the psychological adjustment of women with breast cancer. METHODS: A cross sectional survey of 251 recently diagnosed breast cancer patients (52% response), who had received a dyadic peer support intervention, was undertaken assessing anxiety, depression, perceived threat, and upward comparison. RESULTS: Perceived cancer threat significantly moderated the relationship between positive upward comparison and depression levels (p = 0.017). Women who engaged in upward comparisons and who perceived their diagnosis to be more threatening had lower depression levels than women who were less threatened. CONCLUSIONS: Peer support services that provide support from cancer survivors may be especially beneficial for people who appraise their cancer diagnosis as more threatening. The application of theoretical models to future evaluation designs will further increase understanding of the psychological mechanisms involved in the effects of peer support and inform program development. PMID- 20967850 TI - Benefit of gluten-free diet in idiopathic pulmonary hemosiderosis in association with celiac disease. AB - Lane-Hamilton syndrome refers to the uncommon co-occurrence of idiopathic pulmonary hemosiderosis and celiac disease (CD). Three children aged between 7 and 14 years with IPH were detected to have co-existing non-diarrheal CD. Institution of gluten-free diet in each of the three children resulted in amelioration of the pulmonary symptoms along with improvement of anthropometric parameters and hemoglobin over a short-term follow-up period of 8-17 months. Inhaled/oral steroids and immunosuppressants could be weaned off after dietary exclusion therapy in each of the three children. Gluten free diet should be instituted in all patients diagnosed with Lane-Hamilton syndrome. It ameliorates both the pulmonary as well as the intestinal symptoms although the precise mechanism of the pulmonary response is as yet unclear. PMID- 20967852 TI - Infection with an intestinal helminth parasite reduces Freund's complete adjuvant induced monoarthritis in mice. AB - OBJECTIVE: Assessment of infection with helminth parasites in murine models of disease could identify antiinflammatory mechanisms that translate into treatments for arthritic disease. The aim of this study was to test the ability of infection with the tapeworm Hymenolepis diminuta to ameliorate Freund's complete adjuvant (CFA)-induced monoarthritis in mice. METHODS: Mice received CFA with or without H diminuta, and knee swelling, pain, and measures of inflammation were assessed. RESULTS: Injection of CFA resulted in rapid (within 24 hours) and sustained (lasting 20 days) knee swelling, a decreased pain threshold, increased blood flow to the knee, and increased production of tumor necrosis factor alpha and interleukin-12p40 (IL-12p40). In mice that were infected with H diminuta 8 days prior to receiving CFA, the severity of arthritis was reduced as assessed by these indices of inflammation and infection 2 days after CFA injection and resulted in more rapid resolution of knee swelling. This antiarthritic effect required a viable infection and was dependent on adaptive immunity, because infection with H diminuta did not protect mice lacking T cells and B cells or the IL-4 receptor alpha chain from CFA-induced inflammation. Interleukin-10 was of prime importance in the antiarthritic effect, because IL-10-knockout mice were not protected by infection, the antiarthritic effect was ablated by use of neutralizing IL-10 antibodies, and transfer of CD4+ cells from infected wild-type mice but not IL-10-knockout mice significantly reduced CFA-induced knee swelling. CONCLUSION: In mice, the adaptive immune response to infection with H diminuta involves mobilization of IL-10, which has the concomitant advantage of dampening the innate immune responses that drive CFA-induced joint inflammation. PMID- 20967854 TI - Classification of rheumatoid arthritis: comparison of the 1987 American College of Rheumatology criteria and the 2010 American College of Rheumatology/European League Against Rheumatism criteria. AB - OBJECTIVE: New criteria to classify rheumatoid arthritis (RA) have been derived in order to increase the specificity and sensitivity for early RA compared with the 1987 American College of Rheumatology (ACR) criteria. The aim of this study was to evaluate differences in classification between the 1987 ACR criteria and the 2010 ACR/European League Against Rheumatism (EULAR) criteria in an early arthritis cohort and to determine the test characteristics of the 2010 ACR/EULAR criteria. METHODS: A total of 2,258 patients with early arthritis included in the Leiden Early Arthritis Clinic cohort were studied. Fulfillment of the 1987 and 2010 criteria for the classification of RA was determined at baseline. The diagnosis of each patient at 1 year was assessed. The sensitivity and specificity of the 2010 criteria were determined using the following outcome measures: initiation of methotrexate therapy or any disease-modifying antirheumatic drug (DMARD) therapy during the first year of followup and having persistent arthritis during 5 years of followup. RESULTS: At their first presentation, 1,099 patients fulfilled the 2010 criteria, and 726 patients fulfilled the 1987 criteria for RA. Eighty-two of the 726 patients fulfilling the 1987 criteria did not fulfill the 2010 criteria. Sixty-eight percent of the patients who fulfilled the 1987 criteria during the first year of disease but not at baseline did fulfill the 2010 criteria at baseline. In 18% of patients, use of the 2010 classification criteria also led to a revoked classification at 1 year. The sensitivity and specificity of the 2010 criteria were 0.84 and 0.60, respectively, with methotrexate therapy as the outcome and 0.74 and 0.74, respectively, with DMARD therapy as the outcome. With persistent arthritis as the outcome, the sensitivity and specificity of the 2010 criteria were 0.71 and 0.65, respectively. CONCLUSION: Compared with the 1987 criteria, the 2010 criteria classify more patients with RA and at an earlier phase of the disease. The discriminative ability of the 2010 criteria is acceptable. PMID- 20967853 TI - Selective ERK activation differentiates mouse and human tolerogenic dendritic cells, expands antigen-specific regulatory T cells, and suppresses experimental inflammatory arthritis. AB - OBJECTIVE: Most therapeutic treatments for autoimmune arthritis rely on immunosuppressive drugs, which have side effects. Although a previous study by our group showed that specific ERK activation suppressed immune responses, its application in a therapeutic setting has never been tested. The aim of the present study was to define the ERK-dependent immunosuppressive mechanisms and to apply selective ERK activation for the treatment of experimental inflammatory arthritis. METHODS: A constitutively active ERK activator was coexpressed with a model antigen using lentivectors. Immunosuppressive mechanisms were characterized at the level of dendritic cell (DC) function, differentiation of antigen-specific Treg cells, and inhibition of inflammatory T cells. Administration of the ERK activator with antigen as a strategy to suppress inflammatory arthritis was tested in an experimental mouse model. RESULTS: Selective ERK activation induced mouse and human DCs to secrete bioactive transforming growth factor beta, a process required for suppression of T cell responses and differentiation of antigen-specific Treg cells. Treg cells strongly proliferated after antigen reencounter in inflammatory conditions, and these cells exhibited antigen dependent suppressive activities. Inflammatory arthritis was effectively inhibited through antigen-specific mechanisms. Importantly, this strategy did not rely on identification of the initiating arthritogenic antigen. Equivalent mechanisms were demonstrated in human monocyte-derived DCs, setting the scene for a possible rapid translation of this approach to patients with rheumatoid arthritis. CONCLUSION: This strategy of selective ERK activation resulted in an effective therapeutic protocol, with substantial advantages over DC or T cell vaccination. PMID- 20967855 TI - A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis. AB - OBJECTIVE: The UPAR gene encodes a pleiotropic receptor (urokinase-type plasminogen activator receptor [uPAR]) involved in fibrosis, immunity, angiogenesis, and vascular remodeling. Previous studies have implicated uPAR in systemic sclerosis (SSc) vasculopathy and impaired angiogenesis. We undertook this study to investigate whether UPAR gene promoter polymorphisms might be associated with SSc phenotypes in the European Caucasian population. METHODS: We studied a total population of 1,339 individuals. The Italian discovery cohort comprised 388 SSc patients and 391 healthy controls. The French replication cohort consisted of 344 SSc patients and 216 healthy controls. The UPAR rs344781 and rs4251805 single-nucleotide polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS: In the Italian cohort, the rs344781 G allele was associated with SSc-related digital ulceration (odds ratio [OR] 1.39), pulmonary arterial hypertension (PAH) (OR 1.81), anticentromere antibody (ACA) positivity (OR 1.45), and limited cutaneous SSc (lcSSc) (OR 1.37). The rs344781 GG genotype was associated with SSc-related (OR 3.79), ACA-positive SSc (OR 2.17), and lcSSc (OR 1.96). Allelic and genotypic associations with SSc-related digital ulceration and ACA-positive SSc were replicated in the French sample. Combined analyses showed an association of the rs344781 G allele and GG genotype with SSc-related digital ulceration (allele OR 1.41, genotype OR 2.15), SSc-related PAH (allele OR 1.65, genotype OR 3.16), ACA positive SSc (allele OR 1.47, genotype OR 2.40), and lcSSc (allele OR 1.34, genotype OR 1.77). In a multivariate logistic regression analysis model including the above associated phenotypes of SSc patients, the rs344781 GG genotype remained an independent risk factor for SSc-related digital ulceration (OR 1.96) and SSc-related PAH (OR 2.68). CONCLUSION: The UPAR rs344781 gene variant is associated with the SSc vascular phenotype. PMID- 20967856 TI - When anti-CCR2 treatment for arthritis strikes out. PMID- 20967857 TI - Reduced frequency and severity of infusion-related adverse events after change in ofatumumab infusion regimen: comment on the article by Ostergaard et al. PMID- 20967858 TI - The emerging role of interleukin-1beta in autoinflammatory diseases. PMID- 20967859 TI - Ablation of the Ccr2 gene exacerbates polyarthritis in interleukin-1 receptor antagonist-deficient mice. AB - OBJECTIVE: The pathogenesis of rheumatoid arthritis (RA) involves cytokines and chemokines. Given the role of intraarticular macrophage infiltration in RA, this study was undertaken to address the pathogenic role of CCR2, a chemokine receptor that is abundantly expressed by macrophages, in Il1rn-deficient mice, a mouse model of RA. METHODS: Il1rn-deficient and Il1rn and Ccr2-double-deficient mice were subjected to clinical assessment of arthritis and histologic examination. Bone mineral density was measured with computed tomography. The types of cells infiltrating joints were determined by immunohistochemical analysis and flow cytometric analysis. Osteoclasts in joints were quantified after tartrate resistant acid phosphatase staining. Cytokine and chemokine levels were measured by enzyme-linked immunosorbent assay and multiplex suspension array assay. The expression patterns of chemokines and osteoclastogenic factors were determined by double-color immunofluorescence analysis. Anti-mouse CXCR2 antibody was injected into Il1rn and Ccr2-double-deficient mice for blocking experiments. RESULTS: Ablation of the Ccr2 gene actually exacerbated arthritis and intraarticular osteoclastogenesis, while it enhanced intraarticular neutrophil but not macrophage accumulation in Il1rn-deficient mice. Infiltrated neutrophils expressed the osteoclastogenic factors RANKL and ADAM-8, thereby augmenting intraarticular osteoclastogenesis in Il1rn and Ccr2-double-deficient mice. Moreover, the double-deficient mice exhibited enhanced expression of the neutrophilic chemokines keratinocyte chemoattractant and macrophage inflammatory protein 2 (MIP-2), compared with Il1rn-deficient mice. Finally, neutralizing antibodies to CXCR2, the receptor for keratinocyte chemoattractant and MIP-2, dramatically attenuated arthritis in Il1rn and Ccr2-double-deficient mice. CONCLUSION: Our findings indicate that CCR2-mediated signals can modulate arthritis in Il1rn-deficient mice by negatively regulating neutrophil infiltration. PMID- 20967860 TI - The incidence of gastrointestinal perforations among rheumatoid arthritis patients. AB - OBJECTIVE: Gastrointestinal (GI) perforation has emerged as a novel safety concern in relation to medications used to treat rheumatoid arthritis (RA). This study was undertaken to characterize the incidence and risk factors for GI perforation in RA patients. METHODS: Using administrative databases of a large US health plan, we identified RA patients treated with biologic agents, methotrexate (MTX), oral glucocorticoids, and nonsteroidal antiinflammatory drugs (NSAIDs). Additional risk factors we evaluated included diverticulitis. Hospitalization with GI perforation was identified using a validated algorithm. Incidence rates and risk factors were evaluated using Cox proportional hazards models. RESULTS: Among 40,841 RA patients, 37 hospitalizations with GI perforation were identified. The rate of GI perforation among patients currently being treated with biologic agents who were also receiving oral glucocorticoids was higher (1.12 per 1,000 person-years [95% confidence interval (95% CI) 0.50-2.49]) than for patients being treated with biologic agents who were not also receiving glucocorticoids (0.47 per 1,000 person-years [95% CI 0.22-0.98]) or for patients being treated with MTX who were also receiving glucocorticoids (0.87 per 1,000 person-years [95% CI 0.36-2.10]). Neither biologic agents nor MTX was significantly associated with GI perforation, in contrast to current treatment with glucocorticoids and NSAIDs together (hazard ratio 4.7 [95% CI 1.9-12.0]) or glucocorticoids alone (hazard ratio 2.8 [95% CI 1.3-6.1]). Diverticulitis also was a strong risk factor (hazard ratio 9.1 [95% CI 3.1-26.4]). Seventy percent of patients with GI perforation received glucocorticoids, had antecedent diverticulitis, or both. CONCLUSION: GI perforation is an uncommon but serious adverse event among RA patients. Because a majority of patients with GI perforation were being treated with glucocorticoids or had previously experienced diverticulitis, these individuals should be considered at higher risk. PMID- 20967861 TI - Therapeutic potential of anti-interleukin-17A aptamer: suppression of interleukin 17A signaling and attenuation of autoimmunity in two mouse models. AB - OBJECTIVE: The proinflammatory cytokine interleukin-17A (IL-17A) is produced primarily by the CD4+ T cell subset called Th17 cells, which is involved in host defense, inflammation, and autoimmune disorders. This study was undertaken to investigate the effect of a high-affinity RNA molecule, called an aptamer, against human IL-17A on IL-17A-induced signal transduction in vitro and its anti autoimmune efficacy in vivo in 2 mouse models of inflammation. METHODS: By screening a large library of nuclease-resistant RNA oligonucleotides, we selected an RNA aptamer, Apt21-2, that binds human and mouse IL-17 and blocks the interaction between IL-17A and its receptor. The inhibition of IL-17A-mediated phosphorylation and marker protein production was analyzed in human and mouse cells. Mice with glucose-6-phosphate isomerase (GPI)-induced rheumatoid arthritis and myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis were used to assess efficacy. RESULTS: Apt21-2 prevented efficient phosphorylation of the IL-17A signaling factors IkappaB and JNK and inhibited the production of IL-6 in human and mouse cells. A PEGylated form of Apt21-2 (PEG21-2idT) exhibited a 50% inhibition concentration (IC(50) ) in the range of 1-2 nM and 70-80 nM in human and mouse cells, respectively. When administered immediately after immunization with GPI or MOG, PEG21-2idT inhibited in a dose-dependent manner the development of arthritic or neurologic symptoms. Significantly, PEG21-2idT slowed the progression of arthritis when administered after the onset of GPI-induced arthritis. CONCLUSION: Our findings indicate that the chemically processed anti-IL-17A aptamer PEG21-2idT inhibits the actions of IL-17A as well as the development of autoimmunity in 2 mouse models of inflammation. These results offer for the first time an aptamer-based therapeutic approach to the treatment of Th17 cell-mediated autoimmune disorders. PMID- 20967862 TI - Prospective validation of the prognostic value of elevated serum vascular endothelial growth factor in patients with nasopharyngeal carcinoma: more distant metastases and shorter overall survival after treatment. AB - BACKGROUND: The purpose of this prospective study was to investigate the prognostic value of serum vascular endothelial growth factor (sVEGF) in patients with nasopharyngeal carcinoma (NPC). METHODS: sVEGF was prospectively detected in 306 patients with NPC with enzyme-linked immunosorbent assay before treatment. The correlations between sVEGF and the survival of these patients were evaluated. RESULTS: Patients were followed for at least 36 months. The mean sVEGF was 387.0 ng/L. sVEGF showed no difference in sex, age, and local recurrence. However, sVEGF was positively associated with histology, TNM classification, distant metastasis, and overall survival (OS; p < .05). The 4-year OS and distant metastasis-free survival (DMFS) of the high-sVEGF versus low-sVEGF groups were 68% versus 86% and 70% versus 89%, respectively (p < .05). Stratified analysis showed that patients with stage IV(a,b) , T(4) , N(1) , or N(positive) disease with high VEGF levels had worse 4-year OS and 4-year DMFS than those with low VEGF levels (p < .05). Multifactorial Cox regression confirmed sVEGF was among the independent prognostic factors. CONCLUSION: Elevation of sVEGF in patients with NPC predicts more posttreatment distant metastases and shorter OS and can be used as an independent poor prognostic indicator. PMID- 20967863 TI - Vascular endothelial growth factor and vascular endothelial growth factor receptor-2 tumor expression in patients with advanced laryngeal cancer after induction chemotherapy for organ preservation. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) expression seems to be associated with worse overall survival in patients with head and neck squamous cell carcinoma. The purposes of this study were to assess the prognostic values of the immunohistochemical expression of VEGF and vascular endothelial growth factor receptor-2 (VEGFR-2) in a cohort of patients with operable advanced laryngeal cancer who had been treated with induction chemotherapy. METHODS: VEGF and VEGFR-2 expression in the malignant cells was quantified by an enzyme immunosorbent assay in a retrospective series. RESULTS: Fifty-nine patients were included in this study. We found moderate to high VEGF expression in 61% of patients and none to low expression in 39%. VEGFR-2 expression was moderate to high in 58% of patients and was none to low in 42%. The probability of a complete response to induction chemotherapy was significantly higher in patients with none to low VEGF expression (74% vs 40%; p = .02). CONCLUSION: VEGF expression seems to be a significant predictor of complete response to induction chemotherapy. PMID- 20967864 TI - Long-term follow-up of 44 patients with adenocarcinoma of the nasal cavity and sinuses primarily treated with endoscopic resection followed by radiotherapy. AB - BACKGROUND: Endoscopic resection followed by radiotherapy as primary treatment for adenocarcinoma of the sinuses is emerging as an alternative to open resection. METHODS: A total of 44 patients primarily treated by an endoscopic approach followed by radiotherapy from 1992 to 2004 seen at our ENT-Department were analyzed for outcome and prognostic factors. RESULTS: Median follow-up was 61 months. Median follow-up of the patients alive at the end of the follow-up period was 100 months. For the 5-year follow-up, the overall survival, disease specific survival, and recurrence-free survival were 63% (+/-7% SE), 82% (+/-6), and 60% (+/-8%), respectively. The overall survival, disease-specific survival, and recurrence-free survival after 100 months of follow-up were 53% (+/-8%), 72% (+/-9%), and 54% (+/-9%), respectively. Four factors significantly influenced the disease-specific survival. CONCLUSION: This study of a homogeneous cohort of patients with sinonasal adenocarcinoma treated by endoscopic resection and radiotherapy confirms that endoscopic resection is a valid alternative to open resection. PMID- 20967865 TI - Surgical salvage of persistent or recurrent nasopharyngeal carcinoma with maxillary swing approach - Critical appraisal after 2 decades. AB - BACKGROUND: The purpose of this study was to report on our experience on salvage nasopharyngectomy using the maxillary swing approach for persistent or recurrent nasopharyngeal carcinoma after primary treatment. METHODS: Over the past 2 decades, we have performed salvage nasopharyngectomies for 246 patients. Thirty seven patients (15%) had persistent disease and 209 (85%) had recurrent tumors. RESULTS: All patients survived the operation with minimal morbidity. Negative resection margins were achieved in 191 patients (78%), and 55 patients (22%) had microscopic residual disease. The median follow-up was 38 months. The 5-year actuarial control of disease in the nasopharynx was 74%. The 5-year disease-free survival was 56%. Cox regression model identified the negative resection margin and the size of the tumor as 2 independent factors that affected local control of disease and survival. CONCLUSION: Maxillary swing nasopharyngectomy is an effective salvage procedure for a small, persistent, or recurrent tumor in the nasopharynx after primary therapy. PMID- 20967866 TI - Oncologic and functional results after transhyoid surgical approach for cancer of the base of tongue. AB - BACKGROUND: The optimal treatment for base of tongue cancer remains unclear, especially in advanced stages. METHODS: We retrospectively review 84 previously untreated patients that underwent a transhyoid resection of a base of tongue carcinoma. Sixty-four patients (76%) underwent postoperative radiotherapy. RESULTS: Five patients had stage II disease, 6 had stage III, 58 had stage IVA, and 15 had stage IVB. The overall recurrence rate was 68%. Five-year disease specific survival rates by stage were 100%, 67%, 27%, and 8% for stage II to IVB, respectively (p = .0007). Multivariate analysis showed that the presence of lymph node metastases was an independent predictor of reduced disease-specific survival rates (p = .02). All patients maintained an intelligible voice, and oral alimentation was successfully recovered in 97.5% of them. CONCLUSIONS: The transhyoid approach allowed adequate resection of base of tongue cancers with low morbidity and acceptable functional results, but the oncologic outcomes in advanced stages are poor. Head Neck, 2011. PMID- 20967867 TI - Antitumor activity of enzastaurin as radiation sensitizer in head and neck squamous cell carcinoma. AB - BACKGROUND: The antitumor effect of enzastaurin, a specific protein kinase C beta (PKC-beta) inhibitor, was tested on head and neck squamous cell carcinoma (HNSCC) cell lines, as well as HNSCC xenograft model. METHODS: HNSCC cell lines and xenograft were treated with enzastaurin alone or in combination with radiation to evaluate its antitumor effect. Annexin V-FITC staining and Western blot were done to analyze enzastaurin-induced changes in apoptosis and the PIK3/AKTAKT signal transduction pathway. RESULTS: Enzastaurin showed strong antitumor activity either alone or in combination with radiation both in HNSCC cell lines and in xenograft, with a corresponding reduction in the expression of key radioresponsive proteins. CONCLUSION: Enzastaurin can inhibit tumor growth and improve the efficacy of radiation for HNSCC both in vitro and in vivo. This suggests that enzastaurin may represent a better strategy for the treatment of HNSCC patients, either as a monotherapy or as a radiosensitizer. PMID- 20967868 TI - Lean body mass gain in patients with head and neck squamous cell cancer treated perioperatively with a protein- and energy-dense nutritional supplement containing eicosapentaenoic acid. AB - BACKGROUND: Cancer-associated weight loss may be mediated by an inflammatory response to cancer. Eicosapentaenoic acid (EPA) may suppress this response. METHODS: Beginning no later than 2 weeks before surgery, patients with head and neck cancer and with weight loss, who were undergoing major resection with curative intent consumed a protein- and energy-dense nutritional supplement containing EPA from fish oil, in addition to usual diet or tube feed. RESULTS: Thirty-one subjects consumed an average of 1.8 containers/day before surgery and 1.5/day during hospitalization (per container: 300 kilocalories, 16 grams (g) protein, 1.08 g EPA). Seventy percent of subjects maintained or gained weight before hospital admission. Mean weight gain was 0.71 kg at admission and 0.66 kg at discharge. At discharge lean body mass increased by 3.20 kg (p < .001) and fat decreased by 3.19 kg (p < .001). CONCLUSIONS: An EPA-containing protein- and energy-dense nutritional supplement may help increase perioperative lean body mass in patients with head and neck cancer-related weight loss. PMID- 20967869 TI - Survival of patients with palliative head and neck cancer. AB - BACKGROUND: The purpose of this study was to describe patient characteristics and prognostic factors for survival in the palliative stage of patients with head and neck cancer. METHODS: Since November 2003, all patients with palliative head and neck cancer treated in our hospital have been recorded in a central database. In total, 262 deceased patients were included in this retrospective study. RESULTS: The reasons for palliation were inoperability, distant metastases, refusal of curative treatment, or poor condition. The mean palliative phase lasted 5.3 months for patients with squamous cell carcinomas. Involvement of a specialized nurse was significantly related with the number of admissions and place of dying. Multivariate analysis showed comorbidity and treatment to be independent predictors of survival in the palliative phase. CONCLUSION: Comorbidity and palliative interventions are possible prognostic factors for survival. The involvement of a specialized nurse might be associated with an improved quality of life. PMID- 20967870 TI - Mastication in patients treated for malignancies in tongue and/or floor of mouth: A 1-year prospective study. AB - BACKGROUND: People confronted with oral cancer run a high risk of deteriorated masticatory performance. Reduced masticatory function may affect quality of life and food choice. An altered food choice may result in lower intakes for key nutrients and weight loss. METHODS: Dental state, bite force, and masticatory performance were determined in a group of 45 patients with squamous cell carcinoma of the tongue and/or floor of mouth. Measurements were performed before surgery and at various moments after surgery and/or radiotherapy. RESULTS: Surgical intervention had a large negative impact on oral function. Radiotherapy further worsened oral function. Also, the recovery of oral function 1 year after surgery was less prominent for the surgery-radiotherapy group than for the surgery group. CONCLUSION: Objective determination of oral function 1 year after surgery showed that patients treated for malignancies in the tongue and/or floor of mouth had significantly deteriorated masticatory performance, bite force, and dental state. PMID- 20967871 TI - Expression of inhibitor of apoptosis family proteins in human oral squamous cell carcinogenesis. AB - BACKGROUND: The purpose of this study was to determine inhibitor of apoptosis (IAP) expression, its relationship with p53, and epigenetic change in oral carcinogenesis that remain to be elucidated. METHODS: We measured IAP and p53 expression in 44 oral potentially malignant disorders and their corresponding malignant-transformed oral squamous cell carcinomas (OSCCs), and in 44 other non transformed oral potentially malignant disorders. IAP and p53 expression in 10 fresh OSCCs, together with epigenetic change of their mutation, were also determined. RESULTS: Normal mucosa did not express IAP/mutated p53. Oral potentially malignant disorders that underwent transformation exhibited high IAPs (>90%) and less-consistent mutated-p53 (34%) expression, whereas transformed OSCCs exhibited high IAP and mutated-p53 expression. Fresh OSCCs exhibited 80% to 100% IAP mRNA expression and 50% protein, mRNA, and p53 mutation expression. Normal tissues revealed DNA methylation of IAP, whereas cancerous tissues overexpressing IAP exhibited hypomethylation. CONCLUSION: This study showed that IAP expression is an early event in oral carcinogenesis and that epigenetic and genetic pathways are associated with IAP expression in OSCC. PMID- 20967872 TI - Determinants of head and neck cancer survival by race. AB - BACKGROUND: Several factors contribute to the documented racial disparity in head and neck cancer, among which are socioeconomic status, access to care, and biologic factors. METHODS: Clinical characteristics of 87 African-American patients with head and neck cancer and a random sample of 261 white patients matched on age and smoking dose were associated with outcome. RESULTS: Black patients with cancers of the oral cavity and larynx were more likely diagnosed with advanced stages than whites, after adjusting for socioeconomic and insurance status and other confounding factors. There was a significant difference in relapse-free survival between blacks and whites with tumors of the larynx (hazard ratio [HR] = 3.36, 95% confidence interval [CI]: 1.62-7.00), but not with tumors of the oral cavity or pharynx. CONCLUSIONS: Differences in disease outcome may be attributed to a combination of tumor stage, socioeconomic status, and access to health care. The inclusion of biologic markers such as human papillomavirus (HPV) status is needed in future studies to further evaluate racial disparities in head and neck cancer outcomes. PMID- 20967873 TI - Limitations and complications of endoscopic surgery for treatment for sinonasal inverted papilloma: a reassessment after 212 cases. AB - BACKGROUND: The purpose of this study was to define the optimal surgical strategy for sinonasal inverted papilloma in relation to the site of origin and tumor extent. METHODS: Retrospective analysis of patients affected by inverted papilloma treated by purely endoscopic or combined approaches at the Department of Otorhinolaryngology of the University of Brescia and Pavia-Varese from November 1991 to December 2007. RESULTS: Two hundred twelve patients were considered eligible for this study. An exclusive endoscopic approach was performed in 198 patients (93.4%); the remaining 14 patients (6.6%) underwent an endoscopic approach combined with an osteoplastic frontal flap. Follow-up ranged from 24 to 192 months (mean, 53.8 months). A single recurrence was observed in 12 patients (5.7%). Twenty complications (9.4%) were observed. CONCLUSION: Endoscopic surgery is the first choice in the treatment of inverted papilloma; only lesions with extensive involvement of frontal sinus and/or supraorbital cell may require a combined approach. A minimum follow-up of 5 years is recommended. PMID- 20967874 TI - Lymph node ratio as an independent prognostic factor in oral squamous cell carcinoma. AB - BACKGROUND: We aimed to validate the lymph node ratio (LNR) as an independent prognostic factor in oral squamous cell carcinoma (OSCC) and compare its utility with the current nodal staging system. METHODS: We conducted a retrospective analysis of 313 patients with OSCC undergoing neck dissection. The LNR was adjusted by relevant covariates in a multivariable Cox regression model. RESULTS: LNR displaced conventional nodal staging and was shown to be an independent predictor of regional failure (p = .020), disease-specific (p = .003) and overall survival (p = .001). Patients with an LNR of 2.5% to 7.5%, 7.5% to 20%, and >20% had 2.6, 3.7, and 4.4 times the risk of death from OSCC, respectively, when compared with patients with an LNR <2.5%. CONCLUSIONS: The LNR is an independent prognostic factor in OSCC and may be used in conjunction with the current TNM staging to enable better risk stratification and selection for adjuvant therapy. PMID- 20967876 TI - Biological applications of gold nanorods. AB - Gold nanoparticles have been used as an additive for aesthetic purposes for centuries. However, only in the last decade scientists have begun to understand the fundamental concepts that explain the fascinating optical properties nanoscale particles possess. Gold nanoparticles may be tuned to absorb and scatter light in the visible to near-infrared region of the electromagnetic spectrum. These properties result from the collective oscillations of electrons along the metal surface and can be altered by changing the particles' shape, size, or environment. Gold nanoparticles having a rod-like morphology are of particular interest because of their anisotropic shape. The absorption profile of gold nanorods includes two absorption bands: one due to light absorbed along the short axis (transverse) and the other due to absorption along the long axis (longitudinal). As the rod length increases, so does the longitudinal band red shift together with an increase in the extinction coefficient. As a result of this optical control and sensitivity to changes in local environment, gold nanorods are useful materials for sensing, photothermal therapy, and imaging. This article highlights established and emerging applications of gold nanorods as a platform for viable biological tools. PMID- 20967875 TI - Nanoparticles as magnetic resonance imaging contrast agents for vascular and cardiac diseases. AB - Advances in nanoparticle contrast agents for molecular imaging have made magnetic resonance imaging a promising modality for noninvasive visualization and assessment of vascular and cardiac disease processes. This review provides a description of the various nanoparticles exploited for imaging cardiovascular targets. Nanoparticle probes detecting inflammation, apoptosis, extracellular matrix, and angiogenesis may provide tools for assessing the risk of progressive vascular dysfunction and heart failure. The utility of nanoparticles as multimodal probes and/or theranostic agents has also been investigated. Although clinical application of these nanoparticles is largely unexplored, the potential for enhancing disease diagnosis and treatment is considerable. PMID- 20967877 TI - Endoscopic ultrasound-guided fine-needle aspiration of intrathoracic and intra abdominal spindle cell and mesenchymal lesions. AB - BACKGROUND: The role of endoscopic ultrasound-guided fine-needle aspiration (EUS FNA) in the evaluation of spindle cell and mesenchymal lesions is unclear. This study reviews the use of EUS-FNA in diagnosing intrathoracic and intra-abdominal spindle and mesenchymal cell lesions at an academic institution. METHODS: All EUS FNA specimens with a significant spindle or mesenchymal cell component were retrieved. Follow-up was comprised of clinical correlation, chart review, or evaluation of subsequent tissue specimens, including FNAs, biopsies, and/or surgical resections. Lesions were categorized as either inflammatory/reactive or neoplastic. RESULTS: Forty-four EUS-FNA specimens were retrieved from 39 patients (21 men and 18 women with a median age of 61 years [range, 20-88 years]). Anatomic sites included 19 lymph node specimens, 15 gastrointestinal tract specimens, 7 pancreatic specimens, and 4 other anatomic site specimens. Twenty two cases were inflammatory/reactive lesions, including 17 granulomatous lesions and 5 cases of chronic pancreatitis. Twenty-two cases were neoplastic, including 14 gastrointestinal stromal tumors, 2 smooth muscle tumors, 2 sarcomatoid carcinomas, 2 melanomas, 1 sarcoma, and 1 solitary fibrous tumor. A specific cytologic diagnosis was rendered in 30 cases (81%). Immunocytochemistry was performed on 21 neoplastic cases and contributed to the differential diagnosis in 18 cases. No false-positive findings were encountered. Three false-negative results were identified and were attributed to sampling error. CONCLUSIONS: Spindle cell neoplasms are rarely encountered on EUS-FNA. The differential diagnosis encompasses a wide variety of benign and neoplastic entities. Correlation of cytomorphology and ancillary studies yields a high diagnostic accuracy of spindle cell and mesenchymal lesions on EUS-FNA. PMID- 20967878 TI - Molecular characterization of AML with ins(21;8)(q22;q22q22) reveals similarity to t(8;21) AML. AB - In acute myeloid leukemia (AML), nonrandom clonal chromosome aberrations are detectable in ~ 55% of adult cases. Translocation t(8;21)(q22;q22) resulting in the 5'RUNX1/3'RUNX1T1 fusion gene occurs in ~ 8% of AML cases. Also, ins(8;21) and ins(21;8) have been described that show a broad heterogeneity at the molecular level with inserted fragment sizes ranging from 2.4 to 44 Mb. Microarray-based comparative genomic hybridization (arrayCGH) in 49 intermediate risk AML and RT-PCR-based screening in 532 AML cases allowed the detection of ins(21;8)/ins(8;21) in three cases; arrayCGH and subsequent RT-PCR revealed an ~ 0.5 Mb sized inserted fragment generating the 5'RUNX1/3'RUNX1T1 fusion gene in one case with a submicroscopic ins(21;8)(q22;q22q22) whereas the other two cases were identified by banding analysis and RT-PCR, respectively. Gene expression profiling (GEP) and a detailed review of the literature highlighted similar biological features of AML cases with ins(21;8)/ins(8;21) and t(8;21)(q22;q22). Our study demonstrates the potential of high-resolution array-based analysis and GEP and provides further evidence that AML with insertions generating the 5'RUNX1/3'RUNX1T1 fusion not only biologically resemble the t(8;21)(q22;q22) AML subgroup, but might also share its prognostically favorable clinical behavior. Thus, similar treatment options should be considered in these patients. PMID- 20967879 TI - Stable isotope ratio profiling of testosterone preparations. AB - Gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) is the preferred method of confirming the administration of exogenous testosterone by athletes. This relies on synthetic testosterone preparations being depleted in (13) C compared to natural testosterone. There is concern, however, about the existence of synthetic testosterone products that are unexpectedly (13) C enriched and which may allow athletes to circumvent the current GC-C-IRMS test. Further to the reported studies of legitimate pharmaceutical-grade testosterone products, a detailed analysis of seized materials from border-level seizures was required to obtain intelligence concerning trends in 'black market' testosterone manufacture and distribution. The sample set collected for this study between 2006 and 2009 inclusive provided a delta(13) C range (n = 266) of -22.90/00 to 32.60/00 with mean and median values of -28.40/00 and -28.60/00, respectively. Within this distribution there were 24 samples (9%) confirmed to have delta(13) C values in the range reported for endogenous urinary steroid metabolites (>= 25.80/00). The benefit of delta(13) C profiling for testosterone preparations was demonstrated by the ability to identify specific seized products that can be target tested for future intelligence purposes. In addition, the potential of stable hydrogen isotope ratio ((2) H/(1) H; delta(2) H) discrimination to complement delta(13) C analysis was investigated. Methodologies for the determination of delta(2) H values by gas chromatography-thermal conversion isotope ratio mass spectrometry (GC-TC-IRMS) were developed to provide a delta(2) H range (n = 173) of -1770/00 to -2680/00 with mean and median values of -2310/00 and -2340/00, respectively. PMID- 20967880 TI - Influence of cell-internalization on relaxometric, optical and compositional properties of targeted paramagnetic quantum dot micelles. AB - Quantum dot micelles (pQDs) with a paramagnetic coating are promising nanoparticles for bimodal molecular imaging. Their bright fluorescence allows for optical detection, while their Gd payload enables visualization with contrast enhanced MRI. A popular approach in molecular MRI is the targeting of abundantly expressed cell surface receptors. Ligand-receptor binding often results in cell internalization of the targeted contrast agent. The interpretation of molecular imaging with pQDs therefore requires knowledge about the consequences of cellular internalization for their relaxometric, optical and compositional properties. To study these, Cd-containing core-shell-shell QDs coated with a monolayer of lipids, of which 50 mol% was a Gd-containing lipid, were incubated with human umbilical vein-derived endothelial cells (HUVECs) for up to 24 h. alpha(nu) beta(3)-integrin targeted (RGD) and non-targeted (NT) pQDs were compared. pQDs uptake was monitored by fluorescence microscopy, FACS, ICP-MS, relaxometry and MRI. Cell-associated pQDs displayed longitudinal relaxation rates and fluorescent intensities which were linear with the cell-associated Gd and Cd concentrations, implying that the Gd and Cd uptake by HUVECs can be quantified using relaxometric and optical measurements, respectively. However, the Gd-to-Cd molar ratio in pellets of pQD-incubated cells was consistently higher than the Gd-to-Cd molar ratio of the pQDs as prepared. It is proposed that this increase in Gd-to-Cd molar ratio was due to non-specific lipid-transfer between the pQDs and the cellular membranes. These findings show that, in the case of contrast agents that are formed by non-covalent interactions, experimental procedures are needed with which representative components of the probes can be monitored. PMID- 20967881 TI - Astrocyte reactivity to unconjugated bilirubin requires TNF-alpha and IL-1beta receptor signaling pathways. AB - Jaundice and sepsis are common neonatal conditions that can lead to neurodevelopment sequelae, namely if present at the same time. We have reported that tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta are produced by cultured neurons and mainly by glial cells exposed to unconjugated bilirubin (UCB). The effects of these cytokines are mediated by cell surface receptors through a nuclear factor (NF)-kappaB-dependent pathway that we have showed to be activated by UCB. The present study was designed to evaluate the role of TNF alpha and IL-1beta signaling on astrocyte reactivity to UCB in rat cortical astrocytes. Exposure of astrocytes to UCB increased the expression of both TNF alpha receptor (TNFR)1 and IL-1beta receptor (IL-1R)1, but not TNFR2, as well as their activation, observed by augmented binding of receptors' molecular adaptors, TRAF2 and TRAF6, respectively. Silencing of TNFR1, using siRNA technology, or blockade of IL-1beta cascade, using its endogenous antagonist, IL-1 receptor antagonist (IL-1ra), prevented UCB-induced cytokine release and NF-kappaB activation. Interestingly, lack of TNF-alpha signal transduction reduced UCB induced cell death for short periods of incubation, although an increase was observed after extended exposure; in contrast, inhibition of IL-1beta cascade produced a sustained blockade of astrocyte injury by UCB. Together, our data show that inflammatory pathways are activated during in vitro exposure of rat cortical astrocytes to UCB and that this activation is prolonged in time. This supports the concept that inflammatory pathways play a role in brain damage by UCB, and that they may represent important pharmacological targets. PMID- 20967882 TI - Evidence of hypothalamic degeneration in the anorectic anx/anx mouse. AB - Mice homozygous for the anorexia (anx) mutation are characterized by poor food intake and death by three to five weeks after birth. By P21 these mice display lower density of hypothalamic neuropeptides, including Agouti gene-related protein (AGRP). The AGRP/neuropeptide Y (NPY) system of the anx/anx mice develops normally until postnatal day (P) 12, then the normal increase in fiber density ceases, in some areas even distinctly decreases. This overlaps with activation of microglia, indicating an inflammatory and/or degenerative process. Here we studied, by in situ hybridization and immunohistochemistry (IHC), the expression of major histocompatibility complex (MHC) class I-related molecules and markers for cellular reactivity in hypothalamus of anx/anx mice. MHC class I transcript and -related proteins were found in arcuate nucleus (Arc), presumably both in neurons and glia, the latter also in areas innervated by AGRP (NPY) neurons. In the anx/anx hypothalamus, using TUNEL labeling, significantly higher number of apoptotic cells were found compared with +/+ mice, and active caspase 6 immunoreactivity was detected in degenerating NPY-fibers as well as signs of "microglia-associated cell death". In addition, Y1 receptor-labeled processes and soma of pro-opiomelanocortin (POMC) neurons, were markedly decreased at P21. These results support the hypothesis of degeneration of hypothalamic arcuate neuron populations in the anx/anx mice, whereby the AGRP system may be first affected, the changes in the POMC system being secondary in this process. PMID- 20967883 TI - Ectopic release sites lack fast vesicle recycling mechanisms, causing long-term depression of neuron-glial transmission in rat cerebellum. AB - Classical synaptic transmission occurs at active zones within the synaptic cleft, but increasing evidence suggests that vesicle fusion can also occur outside of these zones, releasing transmitter directly into the extrasynaptic space. The role of such "ectopic" release is unclear, but in the cerebellar molecular layer it is thought to guide the processes of Bergmann glia toward synaptic terminals through activation of glial alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) receptors. Once surrounding the terminal, the glial process is presumed to limit spillover of neurotransmitter between synapses by rapid uptake of glutamate. We have previously reported that this route for neuron-glial transmission exhibits long-term depression following repetitive stimulation at frequencies in the 0.1-1 Hz range, in ex vivo slices from rat cerebellum. Here, we present evidence that LTD arises because ectopic sites lack the fast recycling mechanisms that operate at the active zone. Consequently, ectopic vesicles constitute an exhaustible pool that is depleted at normal synaptic firing rates and only recovers slowly. This effect is cumulative, meaning that the strength of ectopic transmission provides a read-out of the average frequency of presynaptic firing over several minutes. Glial processes are therefore likely to interact most closely with terminals that fire infrequently; conditions that may promote elimination of, rather than support for, the connection. PMID- 20967884 TI - Response of transcription factor NFATc3 to excitotoxic and traumatic brain insults: identification of a subpopulation of reactive astrocytes. AB - Astrocytes react to brain injury triggering neuroinflammatory processes that determine the degree of neuronal damage. However, the signaling events associated to astrocyte activation remain largely undefined. The nuclear factor of activated T-cells (NFAT) is a transcription factor family implicated in activation of immune cells. We previously characterized the expression of NFAT isoforms in cultured astrocytes, and NFAT activation in response to mechanical lesion. Here we analyze NFATc3 in two mouse models of inflammatory brain damage: hippocampal excitotoxicity induced by intracerebral kainic acid (KA) injection and cortical mechanical lesion. Immunofluorescence results demonstrated that NFATc3 is specifically induced in a subset of reactive astrocytes, and not in microglia or neurons. In KA-treated brains, NFATc3 expression is transient and NFATc3-positive astrocytes concentrate around damaged neurons in areas CA3 and CA1. Complementary Western blot and RT-PCR analysis revealed an NFAT-dependent induction of RCAN1-4 and COX-2 in hippocampus as soon as 6 h after KA exposure, indicating that NFAT activation precedes NFATc3 over-expression. Moreover, activation of NFAT by ATP increased NFATc3 mRNA levels in astrocyte cultures, suggesting that NFATc3 expression is controlled through an auto-regulatory loop. Meanwhile, stab wound enhanced NFATc3 expression specifically in a subclass of reactive astrocytes confined within the proximal layer of the glial scar, and GFAP immunoreactivity was attenuated in NFATc3-expressing astrocytes. In conclusion, our work establishes NFATc3 as a marker of activation for a specific population of astrocytes in response to brain damage, which may have consequences for neuronal survival. PMID- 20967885 TI - Modulation of adult hippocampal neurogenesis during myelin-directed autoimmune neuroinflammation. AB - In chronic autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) clinical signs of cognitive dysfunction have been associated with structural changes in the hippocampus. Moreover, experimental studies indicate that inflammatory responses within the CNS modulate the homeostasis of newborn cells in the adult dentate gyrus (DG). However, it remained open whether such changes happen regardless of the primary immunological target or whether a CNS antigen-directed T lymphocyte-mediated autoimmune response may exert a specific impact. We therefore induced experimental autoimmune encephalomyelitis (EAE), a common model of MS serving as a paradigm for a CNS-specific immune response, by immunizing C57BL/6 mice with encephalitogenic myelin oligodendrocyte glycoprotein (MOG) p35-55. In EAE animals, we found enhanced de novo generation and survival of doublecortin (DCX) positive immature neurons when compared with controls immunized with CNS irrelevant antigen (ovalbumine). However, despite activation of neurogenesis, we observed a reduced capacity of these cells to generate mature neurons. Moreover, the high number of newly born cells retained the expression of the glial marker GFAP. These effects were associated with downregulation of pro-neurogenic factors Neurogenin1 and Neurogenin2 and dysregulation of Notch, beta-catenin, Sonic Hedgehog (Shh) signaling as suggested by altered gene expression of effector molecules. Thus, a CNS antigen-specific immune response leads to an aberrant differentiation of neural precursors associated with dysbalance of signaling pathways relevant for adult hippocampal neurogenesis. These results may further extend our understanding of disturbed regeneration in the course of chronic inflammatory CNS diseases such as MS. PMID- 20967886 TI - PKC-dependent inhibition of CA2+-dependent exocytosis from astrocytes. AB - Astrocytes release various bioactive substances via Ca(2+) - and soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent exocytosis; however the regulatory mechanisms of glial exocytosis are still poorly understood. In the present study, we investigated the effect of protein kinase C (PKC) on exocytosis in glial cells using primary cultured astrocytes and clonal rat glioma C6 cells. Mass spectrometry and Western blot analysis using phospho-specific antibodies revealed that phorbol 12-myristate 13-acetate (PMA) treatment induced the phosphorylation of synaptosomal-associated protein of 23 kDa (SNAP-23) on Ser(95), Ser(120), and Ser(160) in cultured astrocytes and C6 cells. Phosphorylation at these sites was suppressed by treatment with the PKC inhibitor, bisindolylmaleimide I (BIS). In contrast, Ser(110) of SNAP-23 was constitutively phosphorylated in these cells and was dephosphorylated in a PKC dependent manner. Exogenously expressed human growth hormone (hGH) accumulated in cytoplasmic granular structures in cultured astrocytes, and its release after ATP treatment was Ca(2+) - and SNARE-dependent. PMA treatment suppressed the ATP induced hGH release from astrocytes and this inhibition was reversed by BIS. We also observed PMA-dependent suppression and an attenuation of that suppression by BIS in ionomycin-induced hGH release from C6 cells. These results suggest that intracellular activation of PKC suppresses Ca(2+) - and SNARE-dependent exocytosis in astroglial cells. PMID- 20967888 TI - Comparative effects of doxercalciferol (1alpha-hydroxyvitamin D2) versus calcitriol (1alpha,25-dihydroxyvitamin D3) on the expression of transporters and enzymes in the rat in vivo. AB - Effects of 1.28 nmol/kg doxercalciferol [1alpha(OH)D2], a synthetic vitamin D2 analog that undergoes metabolic activation to 1alpha,25-dihydroxyvitamin D2, the naturally occurring, biologically active form of vitamin D2, on rat transporters and enzymes were compared with those of 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3, active form of vitamin D3; 4.8 and 6.4 nmol/kg] given on alternate days intraperitoneally for 8 days. Changes were mostly confined to the intestine and kidney where the vitamin D receptor (VDR) was highly expressed: increased intestinal Cyp24 and Cyp3a1 messenger RNA (mRNA) and a modest elevation of apical sodium-dependent bile salt transporter (Asbt) and P-glycoprotein (P-gp) protein; increased renal VDR, Cyp24, Cyp3a9, Mdr1a, and Asbt mRNA, as well as Asbt and P gp protein expression; and decreased renal PepT1 and Oat1 mRNA expression. In comparison, 1alpha(OH)D2 treatment exerted a greater effect than 1,25(OH)2D3 on Cyp3a and Cyp24 mRNA. However, the farnesoid X receptor -related repressive effects on liver Cyp7a1 were absent because intestinal Asbt, FGF15 and portal bile acid concentrations were unchanged. Rats on the alternate day regimen showed milder changes and lessened signs of hypercalcemia and weight loss compared with rats receiving daily injections (similar or greater amounts of 0.64-2.56 nmol/kg daily *4) described in previous reports, showing that the protracted pretreatment regimen was associated with milder inductive and lesser toxic effects in vivo. PMID- 20967887 TI - WNT signaling in activated microglia is proinflammatory. AB - Microglia activation is central to the neuroinflammation associated with neurological and neurodegenerative diseases, particularly because activated microglia are often a source of proinflammatory cytokines. Despite decade-long research, the molecular cascade of proinflammatory transformation of microglia in vivo remains largely elusive. Here, we report increased beta-catenin expression, a central intracellular component of WNT signaling, in microglia undergoing a proinflammatory morphogenic transformation under pathogenic conditions associated with neuroinflammation such as Alzheimer's disease. We substantiate disease associated beta-catenin signaling in microglia in vivo by showing age-dependent beta-catenin accumulation in mice with Alzheimer's-like pathology (APdE9). In cultured mouse microglia expressing the WNT receptors Frizzled FZD(4,5,7,8) and LDL receptor-related protein 5/6 (LRP5/6), we find that WNT-3A can stabilize beta catenin. WNT-3A dose dependently induces LRP6 phosphorylation with downstream activation of disheveled, beta-catenin stabilization, and nuclear import. Gene expression profiling reveals that WNT-3A stimulation specifically increases the expression of proinflammatory immune response genes in microglia and exacerbates the release of de novo IL-6, IL-12, and tumor necrosis factor alpha. In summary, our data suggest that the WNT family of lipoglycoproteins can instruct proinflammatory microglia transformation and emphasize the pathogenic significance of beta-catenin-signaling networks in this cell type. PMID- 20967889 TI - Drug metabolism in the horse: a review. AB - A detailed understanding of equine drug metabolism is important for detection of drug abuse in horseracing and also in veterinary drug development and practice. To date, however, no comprehensive review of equine drug metabolism has been published. The majority of literature regarding equine drug metabolite profiles is derived from sports drug detection research and is generally targeted at detecting marker metabolites of drug abuse. However, the bulk of the literature on equine drug metabolism enzymology is derived from veterinary studies aimed at determining the molecular basis of metabolism. In this article, the phase 1 and 2 metabolisms of seven of the most important classes of drugs monitored in horseracing are reviewed, including: anabolic-androgenic steroids (AAS), beta2 agonists, stimulants, sedatives/tranquilizers, local anesthetics, non-steroidal anti-inflammatory analgesics (NSAIDS)/cyclooxygenase-2 (COX-2) inhibitors, and opioid analgesics. A summary of the literature relating to the enzymology of drug metabolism in this species is also be presented. The future of equine drug metabolism in the area of doping research will be influenced by several factors, including: a possible move towards the increased use of blood and other alternative testing matrices; the development of assays based on intact drug conjugates; the increasing threat of 'designer' and herbal- based products; advances in the use of in vitro technologies; the increased use of liquid chromatography/high-resolution mass spectrometry; and the possibility of screening using 'omics' approaches. Also, the recent cloning of a range of equine cytochrome P450 (CYP) enzymes opens up the potential for carrying out more detailed mechanistic pharmacological and toxicological veterinary studies. PMID- 20967890 TI - Characterization of in vitro generated metabolites of the selective androgen receptor modulators S-22 and S-23 and in vivo comparison to post-administration canine urine specimens. AB - Selective androgen receptor modulators (SARMs) have great therapeutic potential in various diseases including cancer cachexia, sarcopenia, and osteoporosis, and the number of drug candidates has been growing over the last decade. The SARM drug candidates S-22 and S-23 belong to one of the most advanced groups of androgen receptor modulators and are based on an arylpropionamide-derived core structure. Due to their anabolic effects, SARMs have been prohibited in elite sports and have been a subject of sports drug testing programmes since January 2008. Consequently, the structure of analytically useful urinary metabolites should be elucidated to provide targets for sensitive and retrospective analysis. In the present study, the phase-I and -II metabolism of S-22 and S-23 was simulated using hepatic human enzymes, and resulting metabolites were characterized by means of state-of-the-art mass spectrometric approaches employing high resolution/high accuracy Orbitrap mass spectrometry. Subsequently, the newly defined target compounds including the glucuronic acid conjugates of S 22 and S-23, their corresponding monohydroxylated and bishydroxylated analogs, as well as their B-ring depleted counterparts were implemented into an existing routine doping control procedure, which was examined for its specificity for the added substances. In order to obtain proof-of-concept data for authentic urine specimens, canine urine samples collected up to 72 h after oral administration of S-22 to dogs were analyzed using the established approach outlining the capability of the presented assay to detect the glucuronide of S-22 as well as the B-ring-depleted metabolite (M3) in all samples following therapeutic (31.4 ug/kg) dosing. Finally, M3 was chemically synthesized, characterized by nuclear magnetic resonance spectroscopy and high resolution/high accuracy mass spectrometry, and chosen as primary target for future doping control analyses. PMID- 20967891 TI - Eliciting willingness to pay in obstetrics: comparing a direct and an indirect valuation method for complex health outcomes. AB - OBJECTIVE: To compare direct and indirect willingness to pay (WTP) elicitation methods in terms of feasibility, reliability, and comparability. The application is obstetrics, where always both a mother's and a child's health are at stake. METHODS: An open-ended contingent valuation method (CVM) as a direct WTP elicitation method, and the discrete choice experiment (DCE) as an indirect WTP elicitation method. Vignettes to be valued were based on clinical patient data. Participants were 88 laypersons who received their questionnaires by postal mail. RESULTS: The DCE task was completed faster (p=0.006) and was regarded easier (p<0.001) than the CVM task. Test-retest for CVM was substantial (ICC=0.76), and for DCE moderate (k=0.49). Female sex (p<0.001), age>=50 years (p=0.013), higher income (p<0.001), and higher education (p<0.001) were associated with higher WTP. Correlation between CVM and DCE was 0.79 (Kendall's Tau-b; p<0.001). The implied WTP as derived with DCE was between 2.3 and 10.2 times higher than with CVM. The relationship between the WTPs was linear. CONCLUSION: It is yet unclear what lies behind the numbers of DCE. DCE has no methodological benefits over the conventional CVM when eliciting WTP for complex health outcomes in obstetrics. PMID- 20967892 TI - Review of the statistical analysis of the dog telemetry study. AB - In 2008, the PSI Toxicology Special Interest Group met to discuss the design and analysis of dog telemetry studies. The dog telemetry study is one component of the integrated cardiovascular assessment required by regulatory bodies. Although there are guidelines for these studies, little is said about the statistical analysis. With parameters of interest measured continually over time, in studies typically involving four dogs, the analysis is not straightforward. This has led to many different types of analysis being proposed in the literature, with many different methods applied within the pharmaceutical industry itself. This paper summarizes the PSI Toxicology group's discussions and recommendations around these issues. PMID- 20967893 TI - A course for clinical trial personnel in clinical study designs, randomization, allocation schedules, and interactive response systems. AB - This continuing education course for professionals involved in all areas of clinical trials integrates concepts related to the role of randomization in the scientific process. The course includes two interactive lecture and discussion sections and a workshop practicum. The first interactive lecture introduces basic clinical trial issues and statistical principles such as bias, blinding, randomization, control groups, and the importance of formulating clear and discriminating clinical and statistical hypotheses. It then focuses on the most commonly used clinical study designs and the corresponding patient randomization schemes. The second interactive lecture focuses on the implementation of randomization of patients and drug supply through allocation and component ID schedules. The workshop practicum, conducted in small groups, enables students to apply the lecture concepts to real clinical studies. Flexibility was built into the workshop practicum materials to allow the course content to be customized to specific audiences, and the interactive lecture sessions can be stretched to cover more advanced topics according to class interest and time availability. PMID- 20967894 TI - Naked DNA delivery to whole pig cardiac tissue by coronary sinus retrograde injection employing non-invasive catheterization. AB - BACKGROUND: Hydrodynamic injection has demonstrated to be very efficient in the liver of small animals, although this procedure must be translated to the clinical practice in a milder but no less efficient way. The present study evaluates the capacity of non-invasive interventional catheterization as a procedure for naked DNA delivery to the heart in large animals. METHODS: Two catheters were placed in the coronary sinus: one of them to block blood circulation and the other to retrogradely inject 50 ml of a saline solution of DNA (20 ug/ml) containing the enhanced green fluorescent protein (EGFP) gene, at a flow rate of 5 ml/s. RESULTS: The results obtained show that EGFP protein, identified by immunohistochemistry, was present and widely distributed throughout the atrial and ventricular cardiac tissue. This observation agrees with the efficiency of EGFP gene delivery resulting in 1-200 EGFP gene copies per endogenous haploid genome. However, the transcription efficiency of the exogenous EGFP gene was at a ratio of 0.2-10 copies with respect to the endogenous GAPDH gene, suggesting that optimized gene constructs for expression in cardiac tissue could increase the final efficacy of gene transfer. CONCLUSIONS: We conclude that the retrovenous injection of naked DNA in the coronary sinus employing the catheterization technique is an easy and probably safe method for whole cardiac gene transfer. PMID- 20967895 TI - Chlorophenol stress affects aromatic amino acid biosynthesis-a genome-wide study. AB - Chlorophenols are a class of chemicals commonly used in preservatives, disinfectants, algaecides, herbicides and pesticides. However, there is a growing evidence that these compounds are a threat to human health. This is alarming as many chlorophenols are common pollutants found in the global environment at potentially biohazardous levels. Despite chlorophenols being abundant, widely used and poisonous, we know relatively little about their mechanism of toxicity in eukaryotes. Thus, we performed genome-wide growth screens using Saccharomyces cerevisiae to understand the molecular basis of chlorophenol toxicity. Of ~4850 single gene knockout strains tested, 393 mutants showed growth sensitivity to treatment with 4-chlorophenol (4-CP), 2,4-dichlorophenol (2,4-DCP) or pentachlorophenol (PCP). Only eight mutants showed growth hypersensitivity to all the three treatments and harboured deletions in genes important for aromatic amino acid biosynthesis (ARO1, ARO7) or mitochondrial protein synthesis and respiration (ATP5, ISA1, RML2, GET2, SLS1, MRPL38). PMID- 20967896 TI - Hydration preferences for Mn4Ca cluster models of photosystem II: location of potential substrate-water binding sites. AB - Density functional theory calculations are reported on a set of three model structures of the Mn(4)Ca cluster in the water-oxidizing complex of Photosystem II (PSII), which share the structural formula [CaMn(4)C(9)H(10)N(2)O(16)](q+).(H(2)O)(n) (q=-1, 0, 1, 2, 3; n=0-7). In these calculations we have explored the preferred hydration sites of the Mn(4)Ca cluster across five overall oxidation states (S(0) to S(4)) and all feasible magnetic-coupling arrangements to identify the most likely substrate-water binding sites. We have also explored charge-compensated structures in which the overall charge on the cluster is maintained at q=0 or +1, which is consistent with the experimental data on sequential proton loss in the real system. The three model structures have skeletal arrangements that are strongly reminiscent, in their relative metal-atom positions, of the 2.9-, 3.7-, and 3.5 A-resolution crystal structures, respectively, whereas the charge states encompassed in our study correspond to an assignment of (Mn(III))(3)Mn(II) for S(0) and up to (Mn(IV))(3)Mn(III) for S(4). The three models differ principally in terms of the spatial relationship between one Mn (Mn(4)) and a generally robust Mn(3)Ca tetrahedron that contains Mn(1), Mn(2), and Mn(3). Oxidation-state distributions across the four manganese atoms, in most of the explored charge states, are dependent on details of the cluster geometry, on the extent of assumed hydration of the clusters, and in some instances on the imposed magnetic-coupling between adjacent Mn atoms. The strongest water-binding sites are generally those on Mn(4) and Ca. However, one structure type displays a high-affinity binding site between Ca and Mn(3), the S-state-dependent binding-energy pattern of which is most consistent with the substrate water-exchange kinetics observed in functional PSII. This structure type also permits another water molecule to access the cluster in a manner consistent with the substrate-water interaction with the Mn cluster, seen in electron spin-echo envelope modulation (ESEEM) studies of the functional enzyme in the S(0) and S(2) states. It also rationalizes the significant differences in hydrogen-bonding interactions of the substrate water observed in the FTIR measurements of the S(1) and S(2) states. We suggest that these two water-binding sites, which are molecularly close, model the actual substrate-binding sites in the enzyme. PMID- 20967897 TI - Endogenous arene hydroxylation promoted by copper(I) cluster helicates. AB - A novel neutral triple-stranded hexanuclear copper(I) cluster helicate [Cu(I)(6)L(3)].2CH(3)CN derived from a thiosemicarbazone ligand could be synthesized and crystallographically characterized. The MALDI mass spectrum of this complex suggests that the tetranuclear copper(I) cluster helicate [Cu(I)(4)L(2)] is also present in solution. These copper(I) cluster helicates are capable, in the presence of O(2), of hydroxylating the arene linker of their supporting ligand strands. The resulting dinuclear complex [Cu(II)(2)L'(OH)] is formed by two copper(II) centers, a new ligand arising from the hydroxylation reaction, and one hydroxide group. The magnetic investigation of this compound shows a strong antiferromagnetic coupling between the two Cu(II) centers. The kinetic studies for the hydroxylation process show values of DeltaH(?)=-70 kJ mol(-1), similar to those mediated by the tyrosinase enzymes. PMID- 20967898 TI - Preparation and investigation of vitamin B6-derived aminopyridinol antioxidants. AB - 3-Pyridinols bearing amine substitution para to the hydroxylic moiety have previously been shown to inhibit lipid peroxidation more effectively than typical phenolic antioxidants, for example, alpha-tocopherol. We report here high yielding, large-scale syntheses of mono- and bicyclic aminopyridinols from pyridoxine hydrochloride (i.e., vitamin B(6)). This approach provides straightforward, scaleable access to novel, potent, molecular scaffolds whose antioxidant properties have been investigated in homogeneous solutions and in liposomal vesicles. These molecular aggregates mimic cell membranes that are the targets of oxidative damage in vivo. PMID- 20967899 TI - Reversible DNA condensation induced by a tetranuclear nickel(II) complex. AB - DNA condensing agents play a critical role in gene therapy. A tetranuclear nickel(II) complex, [Ni(II)(4)(L-2H)(H(2)O)(6)(CH(3)CH(2)OH)(2)].6NO(3) (L=3,3',5,5'-tetrakis{[(2-hydroxyethyl)(pyridin-2-ylmethyl)amino]methyl}biphenyl 4,4'-diol), has been synthesized as a nonviral vector to induce DNA condensation. X-ray crystallographic data indicate that the complex crystallizes in the monoclinic system with space group P2(1)/n, a=10.291(9), b=24.15(2), c=13.896(11) A, and beta=98.175(13) degrees . The DNA condensation induced by the complex has been investigated by means of UV/Vis spectroscopy, fluorescence spectroscopy, circular dichroism spectroscopy, dynamic light scattering, atomic force microscopy, gel electrophoresis assay, and zeta potential analysis. The complex interacts strongly with DNA through electrostatic attraction and induces its condensation into globular nanoparticles at low concentration. The release of DNA from its compact state has been achieved using the chelator ethylenediaminetetraacetic acid (EDTA) for the first time. Other essential properties, such as DNA cleavage inactivity and biocompatibility, have also been examined in vitro. In general, the complex satisfies the requirements of a gene vector in all of these respects. PMID- 20967900 TI - IFDAT-International forum for drug and alcohol testing, 12-14 April 2010, Barcelona, Spain. AB - The second programme of its kind globally, the highly successful, collaborative, productive and energizing IFDAT-International Forum for Drug and Alcohol Testing, was held in Barcelona, Spain, from 12-14 April. IFDAT was attended by over 100 delegates, conference sponsors and exhibitors from the international workplace drug and alcohol testing industry. Representing over 20 countries, the delegate professionals, speakers, and presenters included employers, service agents, an international publisher, and workplace testing suppliers. The purpose of the forum was to exchange knowledge, learn about new technology, and support the evolution and growth of the emerging international workplace drug and alcohol testing industry. This purpose was accomplished. Delegates from around the globe exchanged their experiences and thoughts about effective workplace drug testing programmes over two days of intensive presentations and panel discussions. The presenters and panelists included drug and alcohol testing professionals, authorities, and intellectuals from around the world. IFDAT conferences are planned for every 18 months, and the next Forum, to be held in Houston, Texas, USA is in the planning process for 2011. PMID- 20967901 TI - The aromatic carbon-carbon ipso-substitution reaction. AB - The aim of this review is to illustrate what we have dubbed an aromatic carbon carbon ipso-substitution reaction in which a new Ar-C bond is formed at the expense of another Ar-C bond. The potentiality of several C-based leaving groups including alkyl, carbinol, CN, COOH, and carbonyl groups in arylation reactions will be illustrated accordingly for the preparation of biphenyl-, vinyl-, alkynyl , and alkyl-substituted aromatics. PMID- 20967902 TI - A lutetium allyl complex that bears a pyridyl-functionalized cyclopentadienyl ligand: dual catalysis on highly syndiospecific and cis-1,4-selective (co)polymerizations of styrene and butadiene. AB - A novel linked-half-sandwich lutetium-bis(allyl) complex [(C(5)Me(4) C(5)H(4)N)Lu(eta(3)-C(3)H(5))(2)] (1) attached by a pyridyl-functionalized cyclopentadienyl ligand was synthesized and fully characterized. Complex 1 in combination with [Ph(3)C][B(C(6)F(5))(4)] exhibited unprecedented dual catalysis with outstanding activities in highly syndiotactic (rrrr>99%) styrene polymerization and distinguished cis-1,4-selective (99%) butadiene polymerization, respectively. Strikingly, this catalyst system exhibited remarkable activity (396 kg copolymer (mol(Lu) h)(-1)) for the copolymerization of butadiene and styrene. Irrespective of whether the monomers were fed in concurrent mode or sequential addition of butadiene followed by styrene, diblock copolymers were obtained exclusively, which was confirmed by a kinetics investigation of monomer conversion of copolymerization with time. In the copolymers, the styrene incorporation rate varied from 4.7 to 85.4 mol%, whereas the polybutadiene (PBD) block was highly cis-1,4-regulated (95%) and the polystyrene segment remained purely syndiotactic (rrrr>99%). Correspondingly, the copolymers exhibited glass transition temperatures (T(g)) around -107 degrees C and melting points (T(m)) around 268 degrees C; typical values for diblock microstructures. Such copolymers cannot be accessed by any other methods known to date. X-ray powder diffraction analysis of these diblock copolymers showed that the crystallizable syndiotactic polystyrene (syn-PS) block was in the toluene delta clathrate form. The AFM micrographs of diblock copolymer showed a remarkable phase-separation morphology of the cis-1,4-PBD block and syn-PS block. This represents the first example of a lutetium-based catalyst showing both high activity and selectivity for the (co)polymerization of styrene and butadiene. PMID- 20967903 TI - On the trimerization of cyanoacetylene: mechanism of formation of tricyanobenzene isomers and laboratory detection of their radio spectra. AB - In support of a deeper understanding of the chemistry of cyanoacetylene--a known constituent of planetary atmospheres and interstellar space--theoretical and experimental studies address the chemical mechanism of dimerization and trimerization, and provide high-resolution rotational spectra of two of the trimeric products, 1,2,3- and 1,2,4-tricyanobenzene. Analysis of the rotational spectra is particularly challenging because of quadrupolar coupling from three (14)N nuclei. The laboratory rotational spectra provide the basis for future searches for these polar aromatic compounds in interstellar space by radio astronomy. PMID- 20967904 TI - Oligo-m-phenyleneoxalamide copper(II) mesocates as electro-switchable ferromagnetic metal-organic wires. AB - Double-stranded copper(II) string complexes of varying nuclearity, from di- to tetranuclear species, have been prepared by the Cu(II)-mediated self-assembly of a novel family of linear homo- and heteropolytopic ligands that contain two outer oxamato and either zero (1 b), one (2 b), or two (3 b) inner oxamidato donor groups separated by rigid 2-methyl-1,3-phenylene spacers. The X-ray crystal structures of these Cu(II) (n) complexes (n=2 (1 d), 3 (2 d), and 4 (3 d)) show a linear array of metal atoms with an overall twisted coordination geometry for both the outer CuN(2)O(2) and inner CuN(4) chromophores. Two such nonplanar all syn bridging ligands 1 b-3 b in an anti arrangement clamp around the metal centers with alternating M and P helical chiralities to afford an overall double meso-helicate-type architecture for 1 d-3 d. Variable-temperature (2.0-300 K) magnetic susceptibility and variable-field (0-5.0 T) magnetization measurements for 1 d-3 d show the occurrence of S=nS(Cu) (n=2-4) high-spin ground states that arise from the moderate ferromagnetic coupling between the unpaired electrons of the linearly disposed Cu(II) ions (S(Cu)=1/2) through the two anti m phenylenediamidate-type bridges (J values in the range of +15.0 to 16.8 cm(-1)). Density functional theory (DFT) calculations for 1 d-3 d evidence a sign alternation of the spin density in the meta-substituted phenylene spacers in agreement with a spin polarization exchange mechanism along the linear metal array with overall intermetallic distances between terminal metal centers in the range of 0.7-2.2 nm. Cyclic voltammetry (CV) and rotating-disk electrode (RDE) electrochemical measurements for 1 d-3 d show several reversible or quasireversible one- or two-electron steps that involve the consecutive metal centered oxidation of the inner and outer Cu(II) ions (S(Cu)=1/2) to diamagnetic Cu(III) ones (S(Cu)=0) at relatively low formal potentials (E values in the range of +0.14 to 0.25 V and of +0.43 to 0.67 V vs. SCE, respectively). Further developments may be envisaged for this family of oligo-m-phenyleneoxalamide copper(II) double mesocates as electroswitchable ferromagnetic 'metal-organic wires' (MOWs) on the basis of their unique ferromagnetic and multicenter redox behaviors. PMID- 20967905 TI - Silver pyrazolates as coordination-polymer luminescent metallomesogens. AB - Silver pyrazolates with columnar liquid-crystal phases that are stable at room temperature have been prepared by reaction of silver nitrate with 3,5 diarylpyrazolates. The complexes consist of open-chain oligomers, despite the fact that the most common structural type for homoleptic coinage metal pyrazolates is the trimeric metallacycle [M(MU-pz)](3). The special characteristics of silver in forming reversible metal-ligand bonds in solution, evidenced experimentally, leads to supramolecular organizations in which the silver cations promote self-organization of the nonmesomorphic pyrazolates into helical 1D polymers that exhibit columnar mesophases. The materials are readily soluble in common organic solvents and are liquid-crystalline over a broader temperature range than their gold counterparts, which are known to form discrete cyclic trinuclear species. Thin films of the silver complexes show luminescence at room temperature. The compounds described here are the first examples of luminescent metallomesogens formed by a main-chain coordination polymer. PMID- 20967906 TI - The dynamic chemistry of molecular borromean rings and Solomon knots. AB - The dynamic solution equilibria between molecular Borromean rings (BRs) and Solomon knots (SKs), assembled from transition metal-templated macrocycles, consisting of exo-bidentate bipyridyl and endo-tridentate diiminopyridyl ligands, have been examined with respect to the choice of the metal template and reaction conditions employed in the synthesis of the metalated BRs, otherwise known as Borromeates. Three new Borromeates, their syntheses templated by Cu(II), Co(II), and Mn(II), have been characterized extensively (two by X-ray crystallography) to the extent that the metal centers in the assemblies have been shown to be distanced sufficiently from each other not to communicate. The solid-state structure of the Co(II)-Borromeate reveals that six MeOH molecules, arranged in a [O--H...O] hydrogen bonded, chair-like conformation, are located within its oxophilic central cavity. When a mixture of Cu(II) and Zn(II) is used as the source of templation, there exists a dynamic equilibrium, in MeOH at room temperature, between a mixed-metal BR and a SK, from which the latter has been fractionally crystallized. By employing appropriate synthetic protocols with Zn(II) or Cd(II) as the template, significant amounts of SKs are formed alongside BRs. Modified crystallization conditions resulted in the isolation of both an all zinc BR and an all-zinc SK, crystals of which can be separated manually, leading to the full characterization of the all-zinc SK by (1)H NMR spectroscopy and X ray crystallography. This doubly interlocked [2]catenate has been identified retrospectively in recorded spectra, where it was attributed previously to a Borromeate with a Zn(II) cation coordinated to the oxophilic interior walls of the ensemble. Interestingly, these Zn(II)-templated assemblies do not interconvert in MeOH at room temperature, indicating the significant influence of both the metal template and solvent on the solution equilibria. It would also appear that d(10) metal ions favor SK formation-no evidence of Cu(II)-, Co(II)-, or Mn(II)-templated SKs has been found, yet a 1:0.9 ratio of BR:SK has been identified by (1)H NMR spectroscopy when Cd(II) is used as the template. PMID- 20967907 TI - Luminescent cyclometalated dialkynylgold(III) complexes of 2-phenylpyridine-type derivatives with readily tunable emission properties. AB - A novel class of luminescent dialkynylgold(III) complexes containing various phenylpyridine and phenylisoquinoline-type bidentate ligands has been successfully synthesized and characterized. The structures of some of them have also been determined by X-ray crystallography. Electrochemical studies demonstrate the presence of a ligand-centered reduction originating from the cyclometalating C^N ligand, whereas the first oxidation wave is associated with an alkynyl ligand-centered oxidation. The electronic absorption and photoluminescence properties of the complexes have also been investigated. In dichloromethane solution at room temperature, the low-energy absorption bands are assigned as the metal-perturbed pi-pi* intraligand (IL) transition of the cyclometalating C^N ligand, with mixing of charge-transfer character from the aryl ring to the pyridine or isoquinoline moieties of the cyclometalating C^N ligand. The low-energy emission bands of the complexes in fluid solution at room temperature are ascribed to originate from the metal-perturbed pi-pi* IL transition of the cyclometalatng C^N ligand. For complex 4 that contains an electron-rich amino substituent on the alkynyl ligand, a structureless emission band, instead of one with vibronic structures as in the other complexes, was observed, which was assigned as being derived from an excited state of a [pi(C=CC(6) H(4) NH(2) )->pi*(C^N)] ligand-to-ligand charge-transfer (LLCT) transition. PMID- 20967908 TI - Modulation of photoswitching profiles by 10,11-dialkoxymethyl substituents in c(2)-symmetric dibenzosuberane-based helicenes. AB - A series of C(2)-symmetric, 10,11-disubstituted dibenzosuberane (DBS)-based helicenes 6 a-c with a common 7-bromo-alpha-tetralin-based bottom fragment were synthesized. Their absolute stereochemistry was determined to be 10R,11R,P after reductive desulfurization of the corresponding (10R,11R,1'S)-episulfides with complete stereospecificity. Photoisomerization of the diastereomerically pure (P) 6 c in hexane led to virtually exclusive formation of the opposite M-form diastereomer (P/M', <1:>99) at 290 nm. The preferential return of (M')-6 c to (P) 6 c was also achieved with high selectivity (P/M', 90:10) at 330 nm. Molecular simulations of (P)-6 c and (M')-6 c with both DBS conformations suggest that the selectivities of photoswitching are controlled by the conformation of the top DBS template as evidenced by their (1)H NMR spectra. Doping 6 c into a nematic liquid crystal (E7) led to a cholesteric mesophase with modulated pitches, reversible helical senses, and with a switch memory of ternary logic. PMID- 20967909 TI - Strategy towards olefin carbohydroxylation: transmetalation of 2-rhodaoxetanes with organoboron nucleophiles. PMID- 20967910 TI - High gas sorption and metal-ion exchange of microporous metal-organic frameworks with incorporated imide groups. AB - Metal-organic frameworks (MOFs), {[Cu(2)(bdcppi)(dmf)(2)].10DMF.2H(2)O}(n) (SNU 50) and {[Zn(2)(bdcppi)(dmf)(3)].6DMF.4H(2)O}(n) (SNU-51), have been prepared by the solvothermal reactions of N,N'-bis(3,5-dicarboxyphenyl)pyromellitic diimide (H(4)BDCPPI) with Cu(NO(3))(2) and Zn(NO(3))(2), respectively. Framework SNU-50 has an NbO-type net structure, whereas SNU-51 has a PtS-type net structure. Desolvated solid [Cu(2)(bdcppi)](n) (SNU-50'), which was prepared by guest exchange of SNU-50 with acetone followed by evacuation at 170 degrees C, adsorbs high amounts of N(2), H(2), O(2), CO(2), and CH(4) gases due to the presence of a vacant coordination site at every metal ion, and to the presence of imide groups in the ligand. The Langmuir surface area is 2450 m(2) g(-1). It adsorbs H(2) gas up to 2.10 wt% at 1 atm and 77 K, with zero coverage isosteric heat of 7.1 kJ mol(-1), up to a total of 7.85 wt% at 77 K and 60 bar. Its CO(2) and CH(4) adsorption capacities at 298 K are 77 wt% at 55 bar and 17 wt% at 60 bar, respectively. Of particular note is the O(2) adsorption capacity of SNU-50' (118 wt% at 77 K and 0.2 atm), which is the highest reported so far for any MOF. By metal-ion exchange of SNU-51 with Cu(II), {[Cu(2)(bdcppi)(dmf)(3)].7DMF.5H(2)O}(n) (SNU-51-Cu(DMF)) with a PtS-type net was prepared, which could not be synthesized by a direct solvothermal reaction. PMID- 20967911 TI - Versatile anion-pi interactions between halides and a conformationally rigid bis(tetraoxacalix[2]arene[2]triazine) cage and their directing effect on molecular assembly. PMID- 20967912 TI - Organic light-emitting diodes from symmetrical and unsymmetrical pi-extended tetraoxa[8]circulenes. PMID- 20967913 TI - Total synthesis of nominal banyaside B: structural revision of the glycosylation site. PMID- 20967914 TI - On the intrinsic photophysics of fluorescein. PMID- 20967915 TI - Ionic-liquid-tethered nanoparticles: hybrid electrolytes. PMID- 20967916 TI - Where is the heavy-atom effect? Role of the central ligand in tetragold(I) ethynyl complexes. PMID- 20967917 TI - Copper(II)-catalyzed meta-selective direct arylation of alpha-aryl carbonyl compounds. PMID- 20967918 TI - Hollow ferrocenyl coordination polymer microspheres with micropores in shells prepared by Ostwald ripening. PMID- 20967919 TI - Antibody formation and mannose-6-phosphate receptor expression impact the efficacy of muscle-specific transgene expression in murine Pompe disease. AB - BACKGROUND: Lysosomal storage disorders such as Pompe disease can be more effectively treated, if immune tolerance to enzyme or gene replacement therapy can be achieved. Alternatively, immune responses against acid alpha-glucosidase (GAA) might be evaded in Pompe disease through muscle-specific expression of GAA with adeno-associated virus (AAV) vectors. METHODS: An AAV vector containing the MHCK7 regulatory cassette to drive muscle-specific GAA expression was administered to GAA knockout (KO) mice, immune tolerant GAA-KO mice and mannose-6 phosphate deficient GAA-KO mice. GAA activity and glycogen content were analyzed in striated muscle to determine biochemical efficacy. RESULTS: The biochemical efficacy from GAA expression was slightly reduced in GAA-KO mice, as demonstrated by higher residual glycogen content in skeletal muscles. Next, immune tolerance to GAA was induced in GAA-KO mice by co-administration of a second AAV vector encoding liver-specific GAA along with the AAV vector encoding muscle-specific GAA. Antibody formation was prevented by liver-specific GAA, and the biochemical efficacy of GAA expression was improved in the absence of antibodies, as demonstrated by significantly reduced glycogen content in the diaphragm. Efficacy was reduced in old GAA-KO mice despite the absence of antibodies. The greatest impact upon gene therapy was observed in GAA-KO mice lacking the mannose-6 phosphate receptor in muscle. The clearance of stored glycogen was markedly impaired despite high GAA expression in receptor-deficient Pompe disease mice. CONCLUSIONS: Overall, antibody formation had a subtle effect upon efficacy, whereas the absence of mannose-6-phosphate receptors markedly impaired muscle targeted gene therapy in murine Pompe disease. PMID- 20967920 TI - Study of dyadic communication in couples managing prostate cancer: a longitudinal perspective. AB - OBJECTIVE: Cancer patients and partners often report inadequate communication about illness-related issues, although it is essential for mutual support and informal caregiving. This study examined the patterns of change in dyadic communication between patients with prostate cancer and their partners, and also determined if certain factors affected their communication over time. METHOD: Using multilevel modeling, this study analyzed longitudinal data obtained from a randomized clinical trial with prostate cancer patients and their partners, to examine their communication over time. Patients and partners (N=134 pairs) from the usual-care control group independently completed baseline demographic assessment and measures of social support, uncertainty, symptom distress, and dyadic communication at baseline, and 4-, 8-, and 12-month follow-ups. RESULTS: The results indicated that (1) patients and partners reported similar levels of open communication at the time of diagnosis. Communication reported by patients and partners decreased over time in a similar trend, regardless of phase of illness; (2) phase of illness affected couples' open communication at diagnosis but not patterns of change over time; and (3) couples' perceived communication increased as they reported more social support, less uncertainty, and fewer hormonal symptoms in patients. Couples' demographic factors and general symptoms, and patients' prostate cancer-specific symptoms did not affect their levels of open communication. CONCLUSIONS: Perceived open communication between prostate cancer patients and partners over time is affected by certain baseline and time varying psychosocial and cancer-related factors. The results provide empirical evidence that may guide the development of strategies to facilitate couples' interaction and mutual support during survivorship. PMID- 20967921 TI - Optimization-based metabolic control analysis. AB - In this work, a novel optimization-based metabolic control analysis (OMCA) method is introduced for reducing data requirement for metabolic control analysis (MCA). It is postulated that using the optimal control approach, the fluxes in a metabolic network are correlated to metabolite concentrations and enzyme activities as a state-feedback control system that is optimal with respect to a homeostasis objective. It is then shown that the optimal feedback gains are directly related to the elasticity coefficients (ECs) of MCA. This approach requires determination of the relative "importance" of metabolites and fluxes for the system, which is possible with significantly reduced experimental data, as compared with typical MCA requirements. The OMCA approach is applied to a top down control model of glycolysis in hepatocytes. It is statistically demonstrated that the OMCA model is capable of predicting the ECs observed experimentally with few exceptions. Further, an OMCA-based model reconciliation study shows that the modification of four assumed stoichiometric coefficients in the model can explain most of the discrepancies, with the exception of elasticities with respect to the NADH/NAD ratio. PMID- 20967923 TI - Thinking about it: thoughts about health and valuing QALYs. AB - When valuing health states (e.g., for use in the assessment of health technologies), health economists often ask respondents how many years of life in poor health they would be willing to trade-off in order to live in full health. Problems with preferences of this kind have led to calls for the use of more direct measures of the utility associated with experiencing a health state. The fact remains, however, that individuals are often willing to make large sacrifices in life expectancy to alleviate conditions for which there appears to be a considerable degree of hedonic adaptation. The purpose of this study is to investigate this important discrepancy in more detail. Data from 1173 internet and telephone surveys in the United States suggest that time trade-off responses are related to the frequency and intensity of negative thoughts about health in ways that may not be very well captured by any of the proposed valuation methods. PMID- 20967922 TI - Transport and binding characterization of a novel hybrid particle impregnated membrane material for bioseparations. AB - The transport and binding properties of a novel hybrid particle-nonwoven membrane medium are described. In this construct, a polymeric chromatographic resin is entrapped between two layers of a nonwoven polypropylene membrane. The membrane supported resin medium offers the advantage of increased interstitial pore diameter to allow passage of cells and other debris in the feed, while providing sufficiently high surface area for product capture within the resin particles. Columns packed with PIM displayed excellent flow distribution and had interstitial porosities of 0.48 +/- 0.01, 25-60% larger than those typical of a packed bed. These columns were able to pass over 95% of E. coli cells and human red blood cell concentrate in 30 column volumes while maintaining a pressure drop significantly lower than that of a packed bed with a similar amount of resin. The dynamic binding capacity of bovine serum albumin (BSA) to the chromatographic resin entrapped in the PIM packed column was essentially the same as that observed with the same volume of resin in a packed bed. The General Rate (GR) model of chromatography was used to analyze experiments indicating the breakthrough behavior of the PIM columns is predictable, and very similar to those of a normal packed bed. These results suggest that PIM constructs can be designed to process viscous mobile phases containing particulates while retaining the desirable binding characteristics of the embedded chromatographic resin and could find uses in adsorption separation processes from complex feed streams such as whole blood, cell culture, and food processing. PMID- 20967925 TI - [The blood circulating in the body is distributed by a richly branched vasculature to tissues and organs]. PMID- 20967927 TI - [Return to the pre-Semmelweis-age - MRSA, NDM-1 and what is to come?]. PMID- 20967928 TI - [Treatment of Ebola infection with siRNA.]. PMID- 20967930 TI - [PAH and many other indications. Old and new endothelin receptor antagonists.]. PMID- 20967931 TI - [Effects, side effects and interactions. Endothelin and endothelin receptor antagonists]. PMID- 20967932 TI - [Causes of selectivity, activation and inhibition. Molecular mechanisms of endothelin-receptor recognition]. PMID- 20967933 TI - [Therapy according to current guidelines. Practical management of pulmonary arterial hypertension.]. PMID- 20967934 TI - [The ideal dosage form for clinical study. Bosentan in pediatric patients]. PMID- 20967935 TI - ["Second opinion procedures" piggy bank or quality instrument? New scheme for regulation of specific drugs]. PMID- 20967936 TI - [Help from support groups. Pulmonary hypertension from patient's viewpoint]. PMID- 20967937 TI - [Ingredients with vasodilator effect. Effect of green tea on the formation of endothelin-1]. PMID- 20967939 TI - [Announcement. Innovation Award in Medical / Pharmaceutical Chemistry]. PMID- 20967945 TI - The relationship between gastroesophageal reflux and cough in children with chronic unexplained cough using combined impedance-pH-manometry recordings. AB - INTRODUCTION: Assessment of the reflux-cough association in children is challenging. Esophageal (impedance) pH recording is sensitive to recognize reflux. However, cough recorded by an event marker, possibly lacks accuracy. We aimed to study the exact time relationship between reflux and cough in children with chronic cough. METHODS: Twenty-six children (12 boys; 1-10.5 years) with chronic unexplained cough underwent ambulatory impedance-pH-manometry recordings. Manometry was used for precise cough recognition. Reflux was assessed with impedance-pH monitoring and defined as acid (pH <4), weakly acidic (WA) (pH 4-7), weakly alkaline (WALK) (pH >=7), or acid only (pH <4 for >=4 sec without impedance pattern). Cough was considered "induced by" reflux, if it started <=2 min after reflux. The Symptom Association Probability (SAP) was calculated and considered positive if >95%. Cough-induced reflux if it occurred 30 sec before the reflux event. RESULTS: Impedance-pH detected 30 (21-52) reflux episodes/patient (55.2% acid, 41.5% WA, and 3.3% WALK). Additionally 59 acid only events were identified [1 (0-21)/patient]. Manometry detected 47 (5-203) cough bursts/patient. Reflux-cough was found in 22/26 patients. Ten patients had a +SAP for reflux-cough (one acid, six WA, and three acid + WA gastroesophageal reflux [GER]), of which nine had a normal acid exposure. Six out of 10 patients with +SAP using manometry had a +SAP using the event marker. Cough-reflux was detected in 19 patients [3 (0-7)/patient]. Only a small fraction of the esophageal acid exposure [9.6 (0.4-31.8%)] was secondary to cough. CONCLUSION: Both acid and WA GER may precede cough in children with unexplained cough, but cough does not induce GER. Objective cough recording improves symptom association analysis. PMID- 20967946 TI - [Expression of cannabinoid receptor I during mice skin incised wound healing course]. AB - OBJECTIVE: To investigate the expression of cannabinoid receptor I (CB1R) during mice skin incised wound healing course and time-dependent changes of CB1R in wound age determination. METHODS: The changes of CBIR expression in skin incised wound were detected by immunohistochemistry and Western blotting. RESULTS: The control group showed a low expression of CB1R detected mainly in epidermis, hair follicles, sebaceous gland and dermomuscular layer. CB1R expression was undetectable in neutrophils in the wound specimens from 6h to 12h post-injury. CB1R positive cells were mostly mononuclear cells (MNCs) and fibroblastic cells (FBCs) from 1 d to 5 d post-injury. CB1R positive cells were mostly FBCs from 7 d to 14d post-injury. The ratio of the CB1R positive cells increased gradually in the wound specimens from 6 h to 3 d post-injury, reached peak level at 5 d, and then decreased gradually from 7d to 14 d post-injury. The positive bands of CB1R were observed in all time points of the wound healing course by Western blotting. The expression peak showed at 5 d post-injury. CONCLUSION: CB1R is activated during the wound healing course. The expression of CB1R is found in mononuclear cells, which could be involved in inflammation reaction. CBIR is observed in fibroblastic cells, which could participate in the wound healing. CB1R may be a potentially useful marker for determination of wound healing age. PMID- 20967947 TI - [Expression of microtubule associated protein-2 mRNA after cerebral contusion]. AB - OBJECTIVE: To explore the mRNA expression of microtubule associated protein-2 (MAP-2) after cerebral contusion, and to investigate its relationship with post injury interval in a rat model of cerebral contusion. METHODS: Based on Feeney's model of cerebral contusion, the time-dependent changes of MAP-2 mRNA were detected by real-time PCR method in different groups. RESULTS: MAP-2 mRNA showed a lower expression in the brain of the control group. The expression of MAP-2 mRNA decreased 1 h post-injury, and reached the lowest level at 6 h, and the expression of MAP-2 mRNA gradually increased in the focus of the cerebral contusion from 12h to 14d after contusion, which kept a high level up to 14 d post-injury. CONCLUSION: The time-dependent changes of MAP-2 mRNA expression may be a new method for estimating the wound age of cerebral contusion in forensic practice. PMID- 20967948 TI - [DNA degradation of porcine retinal cells for estimation of postmortem interval]. AB - OBJECTIVE: To investigate DNA degradation of porcine retinal cells by single cell gel electrophoresis (SCGE) for estimation of postmortem interval (PMI). METHODS: Degradation of retinal cells was observed by SCGE at 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24h after death respectively, under the environmental conditions of being kept in dark place as well as a controlled temperature of (15 +/- 2) degrees C and humidity of (50 +/- 5)%. The comet pictures were captured by fluorescence microscope and analyzed by single cell gel electrophoresis (IMI 1.0). RESULTS: From 2h to 24h postmortem, the degree of degradation of retinal DNA increased with the prolongation of PMI. The postmortem regression functions of head DNA%, L(T)/L(H), I(T)/I(H) were y = 92.227-5.188 x + 0.019 x2 + 0.001 x3 (R2 = 0.971), y = 0.035e(0.191x) (R2 = 0.947), y = 0.099e(0.264x) (R2 = 0.955), respectively. CONCLUSION: The examination of retinal cell DNA degradation by SCGE is useful for estimating PMI. PMID- 20967949 TI - [Succession of sarcosaphagous insects at summer and autumn in Shijiazhuang area]. AB - OBJECTIVE: To study the succession of sarcosaphagous insects and their regular activity on carcass in Shijiazhuang area. METHODS: Nine rabbits were sacrificed and placed at the same site during June to September in 2007-2009. The common species of sarcosaphagous insects were observed. RESULTS: Nine main species could be identified belonging to 3 families and 4 genera from Diptera, including Musca domestica (Linnaeus), Muscina stabulans (Fall en), Hydrotaea (Ophyra) capensis (Wiedemann), Hydrotaea (Ophyra) spinigera (Stein), Lucilia sericata (Meigen), Chrysomya megacephala (Fabricius), Boerttcherisca Peregrina (Robineau-Desvoidy), Parasarcophaga crassipalpi (Macquart) and Helicophagella melanura (Meigen). Eleven main species belonging to 4 families from Coleoptera include Nicrophorus concolor (Kraatz), Silpha carinata(Herbst), Nicrophorus fossor (Eneshas), Ptomascopus morio (Kraatz), Eusilpha bicolor (Fairmaire), Scarabaeus rugosus (Hausmann), Harpalus rufipes (DeGeer), Dolichus halensis (Schaller), Goncephalum pusillum (Fabricius), Cafius seminitens (Horn) and Aleochara pacifica (Casey). Two main species from 2 families were Tetramorium caespitum (Linnaeus) and Vespa velutina(Lepeletier). CONCLUSION: It is evident that the succession of sarcosaphagous flies in Shijiazhuang with its unique geographical features. It may be used for estimating postmortem interval in Shijiazhuang area. PMID- 20967950 TI - [Determination of acid-resistant silicic particles in lung by micro-XRF and its application in diagnosis of drowning]. AB - OBJECTIVE: Using microbeam X-ray fluorescence (Micro-XRF) analyzer for determination of acid-resistant silicic particles in lung, and to explore its potential application in diagnosis of drowning. METHODS: Thirty two white rabbits were divided randomly into drowning group (n=12), post-mortem immersion group (n=10) and control group (n=10). Lungs and water sample were collected for determination of area concentration of acid-resistant silicic particles using Micro-XRF method. RESULTS: The area concentration of acid-resistant silicic particles for the drowning water sample was 4.4 mm2/mL. For the lungs of drowning group, the post-mortem immersion group and the control group, the determined average values were (25.30 +/- 10.95) mm2/g, (1.68 +/- 0.63) mm2/g and (1.65 +/- 0.85) mm2/g, respectively, with a statistically significant difference between the drowning group and the other two groups. CONCLUSION: The area concentration of acid-resistant silicic particles in lungs may be used as an indicator of drowning. The method is highly sensitive and rapid. It provides a potential application in drowning diagnosis. PMID- 20967951 TI - [Effects of triptolide on hypothalamic-pituitary-adrenal axis of rats]. AB - OBJECTIVE: To observe the effects of triptolide on the hypothalamic-pituitary adrenal axis (HPAA) of rats in light of morphological and functional changes. METHODS: Thirty Sprague-Dawley (SD) male rats were randomized into 3 groups and given 2% propylene glycol, mixture of propylene glycol and prednisone acetate or compounds of propylene glycol and triptolide by gavage, respectively, for consecutive 7 weeks. Determination in the 3 groups was conducted concerning the contents of blood plasma cortisol (COR), adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) besides measurement of the rats' body weight, coefficient of the adrenal gland and observation of the histopathological changes in fascicular zone of adrenal cortex. Immunohistochemical staining technique was used to detect the expression of ACTH in pituitary in the 3 groups. RESULTS: (1) The content of COR in the groups of triptolide and prednisone acetate appeared lower and serum ACTH showed no significant difference, but CRH in the group of triptolide was augmented as compared with the control group (P < 0.05). (2) The rats' weight in the groups of triptolide and prednisone acetate was declined, and yet, the coefficient of the adrenal gland remained no significant change in comparison with the controls. HE staining and electron microscopy examination revealed thinned and constricted zona fasciculata in adrenal gland in the rats of triptolide and prednisone acetate, with hypofunction. ACTH expression in the group of triptolide was higher than that of the control group (P < 0.05). CONCLUSION: Morphologically and functionally, the findings suggest that long-term use of triptolide may result in atrophied cortex and hypofunction of the adrenal gland, leading to augmented production and secretion of CRH and ACTH from respective hypothalamic and pituitary. PMID- 20967952 TI - [Decomposition kinetics of bupivacaine in biological specimens]. AB - OBJECTIVE: To study on the decomposition kinetics of bupivacaine in brain, blood and urine, which were collected from dogs executed by bupivacaine and stored in different conditions. METHODS: Dogs were given arachnoid cavity anesthesia with bupivacaine. Then the brain, blood and urine were collected and divided equally to three groups stored in 20, 4 and -20 degrees C respectively. The concentrations of bupivacaine at different days were determined by the GC. The equation and half-time period of decomposition kinetics were imitated and calculated with WinNolin program. RESULTS: The decomposition kinetics of bupivacaine in the dogs' brain, blood and urine were fit to the first order kinetics. The common equation was lgC = lgCo-kt/2.303 and k was the decomposition constant of first order reaction. CONCLUSION: Bupivacaine in the brain, blood and urine specimens were found to be decomposed at various environments for storage. The higher temperature for storage, the faster of decomposition reaction. PMID- 20967953 TI - [Determination of ethyl glucuronide in blood and urine by LC-MS/MS]. AB - OBJECTIVE: To develop a method for determining ethyl glucuronide (EtG) in blood and urine by liquid chromatograph coupled with tandem mass spectrometer (LC MS/MS). METHODS: After blood and urine de-proteined by acetonitrile, the supernate obtained from a centrifuge was analyzed by LC-MS/MS. RESULTS: Determination limit of EtG in both blood and urine was 0.05 pg/mL, with a linear range of 0.10-5.00 microg/mL (r > 0.999). Accuracy in both matrixes was 95%-109%. Inter- and intra-day RSD were less than 12%. The method showed an excellent performance when it was used to analyze authentic blood and urine samples for EtG. CONCLUSION: The method is capable for blood and urine EtG analysis. PMID- 20967954 TI - [Disability evaluation of 204 cases of children with brain injury in road traffic accidents]. AB - OBJECTIVE: To study the types, characteristics and common complications as well as disability assessment for the children with craniocerebral injury in the road traffic accidents. METHODS: Data from 204 cases of children with cranio-injury in road traffic accidents were collected and were statistically analyzed according to the location injured, complication, the type of complication and the severity of disability. RESULTS: There were 64 cases of simple diffuse primary craniocerebral injury, 80 cases of simple local primary cranio-injury, 24 cases of diffuse secondary craniocerebral injury and 36 cases of local secondary cranio injury. The main complications included traumatic epilepsy (14, 6.9%), traumatic cerebral infarction (9, 4.4%), traumatic hydrocephalus (7, 3.4%) and traumatic mental disorder (5, 2.5%). CONCLUSION: Among the children with cranio-injury due to road traffic accidents, simple primary cranio-injury was the most common result, whereas the traumatic epilepsy and traumatic cerebral infarction were the major types of complications. The assessment criteria for body impairment of the children with craniocerebral injury in the road traffic accidents should be broadened accordingly, with addition of certain specific items for children. PMID- 20967955 TI - [Analysis of 51 cases of medical disputes in death after percutaneous coronary intervention]. AB - OBJECTIVE: To investigate the causes and features of medical disputes in percutaneous coronary intervention (PCI) in the cardiology and to provide references for forensic expert testimony and medical disputes prevention. METHODS: Fifty one disputed fatal cases in PCI were analyzed in terms of the cause of death, informed consent and medical operations retrospectively. RESULTS: Thirty five cases were due to medical negligence, 28 due to defect technical operation, 2 due to mistake medical management and 5 due to both defect technical operation and mistake medical management. CONCLUSION: The causes of PCI medical negligence are defect medical operation, violate medical disciplines and insufficiency of informed consent. PMID- 20967956 TI - [Application of multiple polymorphism genetic markers in determination of half sibling sharing a same mother]. AB - OBJECTIVE: Determination strategies for half sibling sharing a same mother were investigated through the detection of autosomal and X-chromosomal STR (X-STR) loci and polymorphisms on hypervariable (HV) region of mitochondrial DNA (mtDNA). METHODS: Genomic DNA were extracted from blood stain samples of the 3 full siblings and one dubious half sibling sharing the same mother with them. Fifteen autosomal STR loci were genotyped by Sinofiler kit, and 19 X-STR loci were genotyped by Mentype Argus X-8 kit and 16 plex in-house system. Polymorphisms of mtDNA HV-I and HV-II were also detected with sequencing technology. RESULTS: Full sibling relationship between the dubious half sibling and each of the 3 full siblings were excluded based on the results of autosomal STR genotyping and calculation of full sibling index (FSI) and half sibling index (HIS). Results of sequencing for mtDNA HV-I and HV-II showed that all of the 4 samples came from a same maternal line. X-STR genotyping results determined that the dubious half sibling shared a same mother with the 3 full siblings. CONCLUSION: It is reliable to combine three different genotyping technologies including autosomal STR, X-STR and sequencing of mtDNA HV-I and HV-II for determination of half sibling sharing a same mother. PMID- 20967957 TI - [Construction and application of fluorescence labeled multiplex typing system for 3 new miniSTR loci]. AB - OBJECTIVE: To establish a miniSTR multiplex set including three STR loci unlinked from the CODIS loci: D1S1676, D6S1274 and D17S1299, to generate amplified fragment less than 115 bp in size and to study the genotype of degraded DNA samples. METHODS: After amplification with different fluorescence labeled primers, the amplified products from 100 unrelated individual and 2 highly degraded specimens were analyzed by 310 Genetic Analyzer. RESULTS: Three miniSTR loci were determined by fluorescence-labeled multiplex-PCR technique. Each locus was successfully genotyped in all 100 samples. In D1S1676, D6S1274 and D17S1299 loci, 9, 9, 7 alleles and 27, 23, 18 genotypes were observed respectively. The distribution of genotype for three miniSTR loci in Chengdu Han population was in accordance with Hardy-Weinberg equilibrium. The combined exclusion probability and the combined discrimination power of the three STR loci in Chengdu Han population were 0.9991 and 0.9160 respectively. CONCLUSION: This miniSTR multiplex set could be used in individual identification and paternity test. It also provides a new method in the analysis of degraded DNA sample. PMID- 20967958 TI - [Application of direct amplification with PowerPlex 16 HS system for detection of DNA in conventional evidence materials]. AB - OBJECTIVE: To study the effectiveness of direct amplification with PowerPlex 16 HS system for DNA detection in three conventional materials: fresh blood, oral swab, and cigarette butt. METHODS: The genetic data of 11 samples of fresh blood, 10 samples of oral swab and 10 samples of cigarette butts were analyzed with PowerPlex 16 HS kit. The result was statistically analyzed. RESULTS: Success rate of whole genetic map test in fresh blood and oral swab samples was 100%. Success rate in cigarette butt samples was 90%. CONCLUSION: Direct amplification with PowerPlex 16 HS system is effective method to three types of conventional evidence material including fresh blood, oral swab and cigarette butt. PMID- 20967959 TI - [Advances on study of Lucilia species in estimating postmortem interval in forensic medicine]. AB - Sarcosaphagous insects are very important to investigate some criminal cases. They are significant useful in estimating post-mortem interval (PMI) and corpse transfer post-mortem. Lucilia are very common sarcosaphagous insects. They like sunshine and are usually the earliest to touch the cadaver. These characteristics and others such as the stages of their larvae development can offer good evidences for criminal case investigation. This paper summarizes details of their application for estimating postmortem interval in recent years and reviews the methods to identify species and to determine the age of adult Lucilia with molecular biology and entomological morphology. PMID- 20967960 TI - [Forensic appraisal of subarachnoid hemorrhage]. AB - Subarachnoid hemorrhage (SAH) can be classified as traumatic SAH or spontaneous SAH based on etiology. The traumatic SAH is the common manifestation of head injury and difficult to make a diagnosis in forensic investigation. Based on practical experiences of forensic investigation and relevant references, the main points (SAH identification, examination, death mechanism) were summarized in this article. For the understanding, we try to classify the traumatic SAH into three subtypes: brain injury associated SAH, traumatic rupture of basal cerebral vessels SAH and traumatic focal SAH. PMID- 20967961 TI - [Advancement of methanol poisoning mechanism research]. AB - The methanol poisoning by oral intake or skin contact occurs occasionally, which may have serious consequences including blindness and/or death. Methanol and its metabolites, formaldehyde and formic acid, are associated with metabolic acidosis, visual dysfunction and neurological symptoms. At present, the mechanism of methanol poisoning primarily focuses on the cell hypoxia, the alteration of structure and biological activity induced by free radical and lactic acid. Meanwhile, methanol poisoning causes changes in the balance between the production of free radicals and antioxidant capacity and in the proteases protease inhibitors system, which lead to a series of disturbances. PMID- 20967962 TI - [Circumferential pulmonary vein isolation with the cryoballoon technique]. AB - We present a clinical case on cryoballoon ablation of paroxysmal atrial fibrillation. This is a report of the first case performed at our center using this new technology. PMID- 20967963 TI - [Pheocromocytoma with negative MIBG]. AB - Pheochomocytomas are catecholamine-releasing tumors derived from chromaffin cells. These kind of tumors occur in less than 1% of the patients evaluated for hypertension. The authors present a case of pheochomocytoma difficult to localize because MIBG scintigraphy was negative and elaborate a review about that subject. PMID- 20967964 TI - [Cardiomyopathy: first clinical manifestation of a pheochromocytoma--case report]. AB - Stress cardiomyopathy clinical presentation mimics an acute coronary syndrome. It is characterized by left ventricular multi-segmental commitment, absence of significant coronary artery disease and by the complete resolution of all the findings. Its pathophysiology is not yet clear, but the main theory suggests a catecholamine-mediated cardiotoxicity mechanism. Pheochromocytoma is a neuroendocrine tumor producer of catecholamines with several cardiovascular manifestations. We report a case of stress cardiomyopathy that was the first clinical manifestation of an unknown pheochromocytoma. PMID- 20967965 TI - [The morbidity with temporary disability among workers of petrochemical industry]. AB - The article deals with the data on morbidity with temporary disability among workers producing rubber and mechanical rubber articles in petrochemical industry. The leading place in the structure of morbidity is taken by the diseases of nervous and cardiovascular systems, liver, gastrointestinal tract, respiratory system and thyroid gland. PMID- 20967966 TI - [The characteristics of medical activities in families fostering disabled children]. AB - The characteristics of medical activities in families fostering disabled children are given. The assessment is implemented according the system of specific indicators developed by the authors to determine corresponding social hygienic, medical organizational and social psychological factors. The analysis of medical activities indicators is carried out to reveal the groups of higher medical social risk and to establish the requirements in different types of medical care. PMID- 20967967 TI - [The medical support of adolescents]. AB - The detailed analysis of the level and structure of adolescents? morbidity, the structure of causes of restrictions of youth fitness to military service is presented. The article also includes the data on the rate of gynecological disorders, the structure of extra gynecological pathology impacting the possibilities to implement the reproductive function on girls. The major measures to enhance the diagnostic and curative and health-improving care of adolescents are substantiated and developed. The techniques of calculating the additional volumes of medical care and the limits of their financing are presented. PMID- 20967968 TI - [The provision of quality and security of medical care on the basis of standardization of medical nurse activities in counseling diagnostic center]. AB - The enhancement of curative diagnostic process and the increase of its quality depend not only on the management, but on the reasonable implementation of high tech new technologies. Nowadays, the evidence-based medical nursing practice represents an actively developing direction of medical nurse business. The State Novosibirsk oblast diagnostic center has developed the standards of nurse activities targeted to decrease the duplication in work, the provision of personnel and patient security. The audit of implementation of standards and the monitoring of nursing process permit to timely input the adjustments to the provision of quality of medical nurse care. PMID- 20967969 TI - [The systematic approaches to population health promotion in the subject of the Russian Federation]. AB - The development of population health promotion system in the subject of the Russian Federation permits to increase the effectiveness of activities concerning health promotion, prevention and organization of healthy life-style and provision of medical care. PMID- 20967970 TI - [The theoretical characteristics of the organization of the system of consultative medical care]. AB - In the Russian Federation, nowadays, there is no normative legal definition of the concept of medical care and subsequent definition of its structural types, including "the consultative medical care". The definition of this concept and its legal consolidation provide the normative legal base for structural development of comprehensive system of medical consultative care which will embrace both previous forms of medical and paramedical activities and new forms conditioned by scientific and technical progress and social evolution of society. PMID- 20967971 TI - [The diseases of circulatory system and the characteristics of organization of curative preventive care in the Republic of Dagestan]. AB - The analysis of the circulatory system diseases morbidity and its mortality in the Republic of Dagestan is presented. The recommendations on the reformation of medical care in the Republic are presented. PMID- 20967972 TI - [The medical care to patients with diet behavior disorders in case of obesity]. AB - The article deals with the results of the study applied to 304 patients with exogenic constitutional obesity during their reception. The Danish questionnaire DEBQ related to the issues of diet behavior was applied. The study revealed significant motivations of women to visit their physician with the purpose of weight adjustment: health problems (75%), need to obtain quick promotion (37%), self-affirmation (26%), to keep girlfriend, mother, colleague company (4%), curiosity (3%). The programs of prevention and rehabilitation are developed for patients with overweight and obesity to take into account the type of diet behavior and factors to increase the patients. PMID- 20967973 TI - [The stomatological care of disabled patients in the conditions of urban polyclinic]. AB - The article deals with the issues of providing stomatological care to disabled persons. The organization of stomatological care in the urban stomatological polyclinic is presented. The elder patients who received dental care in the orthopedic department were in sound majority. The conditions and organization of stomatological care to disabled patients dictate the necessity to apply the measures of social implementation as regarded the provision of stomatologic services including preventive, curative, diagnostic, rehabilitative, prosthetic and orthopaedic care. PMID- 20967974 TI - [The supplementary professional education in the field of social health care]. AB - The results of study of psychological educational basis of the training of professionals in the field of social health to work in rural areas are presented. PMID- 20967975 TI - [At the origins of preventive medicine in the Tambovskaya oblast]. AB - The article analyzes the stages of becoming of preventive medicine in Tambovskaya oblast. The regional characteristics of development of actual public health system are exposed. The focus is made on the studying of regional experience of implementing the informational and educational technologies in the formation of healthy life-style among youth generation. PMID- 20967976 TI - [The organization of maternity and child care in the Buryat-Mongolskaya ASSR during the Great Patriotic War]. AB - In Ulan-Ude, in 1942, the mortality of children at the age from 0 to 15 years consisted 64% of total numbers of died persons. The main causes of children mortality during all the war were tuberculosis, pneumonia, toxic dyspepsia and diarrhea. In October 1942, the government adopted a special decree obligated Narcomzdrav of the USSR to re-establish the system of maternity and child care existed before the war. The focus was made on the district principle of functioning of women and children consultations and polyclinics and to take measures to enhance the children diet and food vitaminization. In Buryat Mongolskaya ASSR, during the war period, no epidemics of infectious diseases were allowed. In this difficult period of life the first multifield children hospital and municipal infection hospital with children beds were established and functioned with success. PMID- 20967977 TI - [Clinical and urodynamic rationale of the overactive bladder neurophysiological model]. AB - The analysis of 58 cases of overactive bladder has shown that detrusor activity is not linked with clinical symptoms but is caused by supra segmentary lesion of the nervous system. The clinical picture of overactive bladder fits the proposed neurophysiological model where ischemic damage of the association neuron located in the lumbar spinal marrow triggers miction disorders leading to preganglionary detrusor denervation. Combined therapy with alpha1-adrenoblocker and M cholinolytic is pathogenetically sound. Trospium chloride (spasmex) was used for long-term treatment of the patients as it produces minimal number of side effects and enables dose and schedule variation. PMID- 20967978 TI - [Treatment of overactive bladder in women with vitaprost forte]. AB - We treated 40 women aged 49-80 years (mean age 63.6 +/- 1.5 years) with overactive bladder (OB). All the patients used suppositoria vitaprost forte once a day before going to bed for 30 days. Miction was assessed before treatment, on treatment day 15 and 30, 30 days after the treatment course. The patients responded to questionnaires on disturbance and discomfort because of miction disorders and kept diary records on miction 3 days before visit to a doctor. The treatment lowered the number of imperative urges by 46%, episodes of urgent incontinence--by 69%. Dyscomfort due to imperative symptoms reduced 2.1-fold, anxiety--by 70%, effects of bladder symptoms on everyday life--by 48%. Satisfaction with treatment results reached 74%. One month after vitaprost forte treatment the subjective and objective miction improvement continued. After the treatment we observed a 20-40% increase in bladder capacity in different urges. This is explained by reduced detrusor ischemia which plays an important role in OB pathogenesis. PMID- 20967979 TI - [Combined treatment of chronic cystitis in postmenopausal women with application of AMUS-01-INTRAMAG device and rectomassager attachment]. AB - Sixty eight postmenopausal women with chronic recurrent cystitis received local antibacterial treatment consisting in bladder ionophoresis and vaginal exposure to estrogens and vibromagnetic action of RECTOMASSAGER attachment and AMUS-01 INTRAMAG device. This local treatment proved superior to systemic one as 1-year follow-up registered a 3.1-fold reduction in recurrence rate vs control patients. PMID- 20967980 TI - [Surgical tactics in acute epididymitis in children]. AB - Differentiated surgical policy was applied in the treatment of 147 children aged under 18 years with acute epididymitis. Basing on laboratory, clinical and ultrasound characteristics, three treatment methods were used: conservative treatment, puncture of the scrotum, revision of the scrotum. Puncture treatment of acute epididymitis appeared effective in accurate diagnosis of indications for this therapy and due performance. Ultrasound potential is shown in differential diagnosis in acute scrotum syndrome. PMID- 20967981 TI - [Choice of treatment of erectile dysfunction associated with hypogonadism]. AB - A study was made in the urological clinic of I.M. Sechenov Moscow Medical Academy with participation of 96 patients (mean age 48.24 +/- 9.19 years) with erectile dysfunction (ED) associated with hypogonadism. The patients were divided into three groups. Group 1 (n = 30) received 1 intramuscular injection of testosterone undecanoate. Group 2 (n = 34) received on-demand monotherapy with vardenafil for 6 weeks. Group 3 (n = 32) received combined treatment with the above modalities in the same doses and duration. Before and 6 weeks after treatment the patients responded to IIEF-5 questionnaire. All the patients showed a significant improvement of the erectile function. Overall AMS score after the treatment rose more in patients of groups 1 and 3 (p < 0.001). In group 2 the changes were weaker but significant (p = 0.005). The domain of psychological AMS symptoms reduced insignificantly after treatment in group 2 (p = 0.535), but significantly in groups 1 and 3, respectively (p = 0.013 vs p = 0.001). Androgenic deficiency regressed in groups 1 and 3 but enhanced in group 2 (p = 0.001). Domain of sexual symptoms of the AMS scale reduced more significantly in patients of groups 2 and 3 (p < 0.001). Percentage of patients satisfied with the treatment results was 68.85, 70,6 and 90,6% in groups 1, 2 and 3, respectively. Thus, combined treatment of erectile dysfunction in patients with hypogonadism (parenteral testosterone undecanoate and vardenafil) is more effective than monotherapy with androgen-containing drugs or inhibitors of phosphodiesterase of type 5. PMID- 20967982 TI - [Treatment of prostatic adenoma]. AB - We used lymphotropic therapy in addition to standard treatment in 116 of 232 patients with benign prostatic hyperplasia. The effect was evaluated in the course of treatment and followed up for a year. Improvement in general condition of the patients, symptoms of infravesical obstruction, size of the prostate, urinary flow rate demonstrated high efficacy of lymphotropic therapy leading to a higher rate of persistent remission and higher quality of life. PMID- 20967983 TI - [Urination disorders in patients with spinal and spinal cord trauma]. PMID- 20967984 TI - [Standardization of the laboratory test for PSA]. PMID- 20967985 TI - [Percutaneous nephrolithotripsy in supine position in a patient with incomplete osteogenesis]. PMID- 20967986 TI - [Neuroimmunoendocrinal markers in diagnosis and prognosis of a prostatic cancer surpine]. PMID- 20967987 TI - [Therapy of erectile dysfunction after radical prostatectomy]. PMID- 20967988 TI - [Management of urological patients with HIV infection]. AB - The analysis of urological care for HIV infected patients treated in Moscow city clinical hospital N 47 covers 12-year trends in hospitalization of HIV-infected urological patients, their nosological distribution, statistics of surgical outcomes. The highest efficacy of empiric antibacterial therapy of acute pyelonephritis in HIV-infected patients was seen in combined administration of fluorofloxacin of the second generation (ofloxacin) and nitroimidasol (metronidasol). Specific features of pharmacokinetics and interaction of antiretroviral drugs with medicines used in urological practice are analysed. PMID- 20967989 TI - [First experience with outpatient shock-wave lithotripsy]. AB - Clinical experience with administration of extracorporeal shock wave lithotripsy (ESWL) in an outpatient clinic demonstrates feasibility of urolith fragmentation in some patients using certain lithotriptors. Concrements can be removed from about 97.0% patients without their hospitalization. PMID- 20967990 TI - [Quality of life in patients with urolithiasis depending on methods of drainage of the upper urinary tract]. AB - A sociological study was made of quality of life of 60 patients with nephrostomic drainage and 71 patients with an ureteral stent according to standard international questionnaires SF-36 and EORTC QLQ-C30, version 3.0. It was found that both internal and external drain significantly aggravate quality of life in the same degree. Younger patients of both groups suffered less. Quality of life was higher in both groups in drainage duration up to 1 month (p < 0.05), in 1 to 6 month draining quality of life is worse in both groups. Internal drainage is worse tolerated by males aged 25-44 years and elderly women aged 60-75 years, especially in long-term drain (over 6 months). Internal drainage is worse tolerated by elderly females (60-75 years of age) and senile women (over 75 years) in 6 month and longer drainage. The study of large number of patients revealed significant differences in quality of life in patients with nephrostomic drain and ureteral stent. PMID- 20967991 TI - [Current status of antibiotic resistance of pyelonephritis causing pathogens]. AB - The article gives the analysis of frequent clinical situations arising in empiric therapy of pyelonephritis alone and accompanied with other severe diseases such as decompensated diabetes mellitus, chronic renal insufficiency, HIV infection. The choice of antibacterial drugs for empiric therapy of pyelonephritis is based on the results of the tests for antibiotic resistance of pyelonephritis causing agents, pharmacokinetic and pharmacodynamic studies. Present-day standards and recommendations of leading centers of pyelonephritis empiric therapy are reviewed. PMID- 20967992 TI - [Biological aspects of choice of the intestinal segment for the cystoplasty]. AB - Contractile activity of the iliac and sigmoid intestines versus detrusor activity, reabsorption and secretory activity of the iliac and sigmoid intestinal mucosa in contact with urine were studied in 30 rats. It was found that isolated segments of the iliac and sigmoid intestines have spontaneous contractile activity (stronger in the iliac intestine) while bladder segment contracted only in response to electric stimulation. A contraction-stimulating effect of acetylcholine and a relaxing effect of noradrenaline in experiments with the iliac intestine were close to their effects on the detrusor. The sigmoid intestine responded weaker to the above mediators. The iliac mucosa actively reabsorbed urinary urea, creatinin, glucose causing elevation of their concentrations in blood as well as K, Na, Ca, CI, P and secreted protein in urine leading to hypoproteinemia. The sigmoid mucosa showed weaker metabolic activity. The results of the study demonstrate importance of consideration of biological properties of different intestinal regions for choice of a cystoplasty method after cystectomy. PMID- 20967993 TI - [Treatment of overactive urinary bladder with imperative urinary incontinence in women]. AB - The clinic at the nephrology and urology chair of the State Altai Medical University admitted 40 females aged 20-74 years with overactive bladder (OAB) symptoms and imperative urinary incontinence (IUI) in 2008-2009. The patients were divided into two groups: 20 patients of group 1 received an anticholinesterase drug solifenacin (vesikar) in a dose 5 mg/day; 20 patients of group 2 received combined treatment. The course of treatment lasted for 1-3 months. As shown by the voiding diary and uroflowmetry, vesikar noticeably reduced or eliminated the rate and intensity of imperative voiding. Urodynamic parameters also changed positively. The treatment prolonged voiding time and volume, lowered Qmax. The effect was persistent. PMID- 20967994 TI - [Surgical treatment of paraurethral cysts in women]. AB - We operated 29 patients aged 16-54 (mean age 35.4 years) with paraurethral cysts. Of them, 26 (89.6%) patients had skin cysts, 3 (10.4%) patients had Hartner cysts. The size of the cysts varied from 1.2 to 6 cm in case of skin cysts and from 4 to 8 cm in Hartner cysts. The paraurethral cysts were detected at vaginal examination. The diagnosis was confirmed at ultrasound examination. The operations were performed under general anesthesia in 23 and under local anesthesia in 6 women. Normal urination restored in 27 patients within 4 postoperative days. Postoperative cystitis developed in 2 patients with an abscess. No malignancy was found at histological examination. Paraurethral cysts are treated by single-stage surgery or resection and destruction of the cystous capsule with subsequent suturing on the vaginal wall. PMID- 20967995 TI - [Awareness of the patients about detection of prostatic cancer]. AB - We introduced an original simple anonymous questionnaire for urological patients in Moscow and Omsk outpatient clinics and hospitals. A total of 580 patients aged between 40 and 70 years (mean age 61.48 years) responded from February to June 2008. The questions concerned PSA test. In Omsk more men were tested for PSA: 77% against 67 in Moscow. Men with higher education made PSA test more often (88 and 60%, respectively). Only 31% responders know why PSA test is made. Of men over 70 years of age in Moscow, 43% responders made PSA test for the first time at the age from 60 to 69 years, the rest patients made it at the age 70 years and older. In Omsk, 88% responders made PSA test at the age of 70 and older. In men aged 40 49 years a mean IPSS point was 4, QOL--3. The highest IPSS (20 points) and QOL (4 points) were registered in men over 70. Among the responders over 70 years old, 38% were sexually active. The results of our questionnaire survey demonstrate that age of the patients who undergo PSA test in Moscow and Omsk is over 70. Quality of life is not adequately understandable for elderly questionnaire responders and should be simplified. Regular check-ups are effective for early detection of prostatic cancer and other diseases. PMID- 20967996 TI - [Current opportunities of pharmacotherapy of prostatic adenoma]. PMID- 20967997 TI - [Ureteral diverticulum]. AB - The article reports a case of congenital ureteral diverticulum found by chance at dynamic IVU with fluoroscopy. The diagnosis was confirmed at non-contrast MR tomography, CT and repeated target ultrasonography using color Doppler mapping and 3D. This is the first description in the Russian literature of ultrasound, IVU with fluoroscopy and non-contrast MR urography findings before and after intravenous injection of 2.0 ml lasix on MR tomograph in ureteral diverticulum. PMID- 20967998 TI - [Diagnosis and treatment of urinary incontinence and prolapse of the pelvic organs in women]. PMID- 20967999 TI - [Anti-radical activity and oxidative stability of oils manufactured from flax, sesame and silybum seeds]. AB - Comparative analysis of oils, prepared from flax, sesame and silybum seed composition, and adequate oil blends, prepared by mixing flax oil, sesame oil and silybum oil was performed. Antiradical activity was evaluated for the oils, both for their methanol-soluble phase and the fraction insoluble in methanol. DPPH radical scavenging activity expressed in Trolox equivalent antioxidant capacity. Oxidative stability during 6-month store was evaluated by peroxide value and dienic conjugates content. Oils from seed composition show the more high antiradical activity and oxidative stability than adequate oil blends. A significant correlation was found between antiradical activity and gamma-/alpha tocopherol ratio in oils. PMID- 20968000 TI - [The influence of finely-ground vivarium feed on structural and functional condition of the liver hepatocytes in rats]. AB - It was determined that a long-lasting consumption of a finely-growing feed vivarium even in the early postnatal period (60 days) causes certain changes in liver hepatocytes in rats. There takes place nucleous area and cell cytoplasm diminishing, accompanied by a decrease of albumines' synthesis level. In the later postnatal period (120 days) the hepatocytes' nucleus and cytoplasm area drastically increases, which is accompanied by the increase of albumine content in blood up to reference values. During the following period of the natal development (120-180 days) the levels as on the 128th day of the animals' development. In such a case the nucleous area slightly diminishes. PMID- 20968001 TI - [Contents of flavonoids, tannins and fiber in some species of vegetative tea]. AB - The content of some biologically active substances such as flavonoids, tannins and soluble dietary fiber in various types of vegetative tea was analyzed. The results are shown that the content of flavonoids ranges from 0.28 to 9.87%, tannins--from 0.91 to 7.07% and soluble dietary fiber 0.37 up to 14.7%. PMID- 20968002 TI - [Toxicological and hygiene characterization of titanium dioxide nanoparticles introduced to the gastrointestinal tract of rats. Communication 1. Integral, biochemical and hematologic indices, small intestinal macromolecule absorption, DNA damage]. AB - Water suspensions of titanium dioxide nanoparticles were introduced intragastrically to growing male Wistar rats daily for 28 days. The data obtained revealed the presence of toxic risks related to said nanomaterials action and demonstrate the necessity of sanitary regulation of titanium dioxide nanoparticles used in food contact materials, cosmetics and other commodity. PMID- 20968003 TI - [Using dietary supplement containing dietary fiber, fermented wine yeasts, vitamins and minerals, under the influence of dust-gas mixture. The experiments on laboratory animals]. AB - In chronic experiment in rats pro for show, what of food biologically active "Rekitsen-RD", promotes increase of efficiency of mechanisms of detoxication, antioxidant activity and immune protection of an organism. PMID- 20968004 TI - [Model experiments on sorption properties of beet-root fiber]. AB - Model experiments provided results of determining sorbate properties of beet-root fiber in respect of copper, plumbum and zinc in diary foods. It was determined that this fiber makes possible the absorbing of the above mentioned heavy metal, which increases the hygienic safety of the studied diary foods. PMID- 20968005 TI - [Content of heavy metals in various kinds of loose-leaf tea]. AB - The content of heavy metals--lead, cadmium, mercury, arsenicum was studied in 7 kinds of tea. Lead was detected practically in all studied kinds of tea, except for self-drinking long-lenved tea Sri-Lanka, cadmium was detected in Chinese Green coarse-grained tea, arsenicum was detected in all kinds of tea. However heavy metals content in all studied kinds of tea doesn't exceed their maximum allowable concentration. PMID- 20968006 TI - [Dietary fiber and nutritional support in pediatrics: current understanding]. AB - The article summarizes the materials on the use of dietary fiber (DF) in the diet of children of different ages. According to the few studies that DF used in children's diets, play an important role in the prevention and treatment of obesity and in lowering serum cholesterol, which reduces the risk of children of cardiovascular disease. Given that children and adolescents consume food insufficient number of DF should be encouraged to increase in baby food for their consumption at the expense of fruit, vegetables and products prepared from cereals. A number of recommendations on the level of consumption of DF children and adolescents of all ages. PMID- 20968007 TI - [Determination of melamine in milk and milk-containing products by capillary zone electrophoresis]. AB - For determination of melamine methods of reversed phase and ion-pair high performance liquid chromatography, and also immune-enzyme analysis are used. The purpose of our work was working out of a technique of determination melamine in milk and lactiferous products method CZE. As a result of researches determination conditions melamine in foodstuff by method CZE (sensitivity from 0.8-1.0 mg/l) are developed, and also conditions of its isolation from objects of research are adapted. PMID- 20968008 TI - [Effect of vitamin beverages on vitamin sufficiency of the workers of Pskov Hydroelectric Power-Plant]. AB - The research of influence of vitamin complexes in the form of a drink or kissel on vitamin sufficiency of working persons has been carried out. Long inclusion (6,5 months) in a diet of vitamin drinks containing about 80% from recommended daily consumption of vitamins, was accompanied by trustworthy improvement of vitamins C and B6 sufficiency and prevention of seasonal deterioration of beta carotene status. As initially surveyed have been well provided with vitamins A and E, their blood serum level increase had not occurred. PMID- 20968009 TI - [Vitamin D level in the indigenous populations of Russia European North]. AB - The aim of our research was to investigate the level of 25-OH vitamin D3 in blood plasma of indigenous inhabitants of Russia European North. The study showed that there was wide spreading of vitamin D deficiency among northerners especially in teenager. The significant reduction of level of 25-OH vitamin D3 was revealed in the inhabitants of Far North in March. PMID- 20968010 TI - [Principles of optimal nutrition of sportsmen in various kinds of sport]. AB - Basic principles of optimal nutrition of sportsmen in various kinds of sport are formulated. Their diet must be well-balanced in terms of all nutrients and contain essential vitamins and minerals. There is outlined an indispensable content of the basic nutrients in sportsmen's daily diet: proteins, fats, carbohydrates, as well as vitamins and minerals. PMID- 20968011 TI - [Effect of iron-containing supplements on the level of iron, copper, and manganese in young sportsmen]. AB - In was defined that 2-week intake by senior school pupils of iron-containing supplements combined with an ascorbic acid was followed by a significant increase of iron concentration in plasma and formal blood elements, hemoglobin and erythrocytes level, increase of vitamin C provision and physical performance efficiency at simultaneous decrease of copper and manganese content in blood plasma. PMID- 20968012 TI - [The Ural Center for Neutron Therapy: results and perspectives in the treatment of head and neck neoplasms]. PMID- 20968013 TI - [Cancer of hormone-dependent tissues and problems of comorbidity (cardiovascular diseases, stroke, osteoporosis)]. PMID- 20968015 TI - [Five-year survival of breast cancer patients in the Republic of Daghestan]. PMID- 20968014 TI - [Selective serotonin reuptake inhibitors and mammary pathologies]. PMID- 20968016 TI - [Gastric cancer morbidity in the Republic of Uzbekistan]. PMID- 20968017 TI - [Prophylaxis of early radiation injuries to intact tissues following exposure to combined photon-neutron radiotherapy for malignant head and neck tumors]. AB - Our data are presented on comparison of early- and late-response and complications in 320 patients with head and neck tumors after combined photon neutron radiotherapy (CPNT) alone or in conjunction with cisplatin. Laser therapy via the LGN-222 quartz installation alternating with irradiation sessions was used to prevent and palliate radiation injuries. As a result, the incidence of acute (grade I-II) reactions was significantly lowered and severe fast-neutron induced complications were avoided. Grade I (RTOG) skin and mucous membrane injuries were rarer in the main group receiving laser therapy (2.47%) as compared with controls (8.93%) (p < or = 0.02). Grade II injuries totaled 11.6% as compared with 5.57% in control (p < or = 0.02). No damage to skin and mucous membranes in grade III-IV (RTOG) was reported. Use of cisplatin was followed by a rise in frequency of both focal (90%) and diffuse (10%) film-coated membrane epithelite (p < or = 0.02). However, radiation-related response was aborted within 10-14 days after treatment in all cases. Our procedure may be used as a method of choice in prophylaxis of severe tissue damage and CPNT-induced complications. PMID- 20968018 TI - [Role of fast neutrons in the treatment of soft tissue sarcoma]. AB - The report deals with our data on evaluation of combined photon-neutron radiotherapy (CPNT) received by 33 patients with soft tissue sarcoma at the Clinic of the Urals Neutron Therapy Center. Follow-up ranged 10-80 months (median -68 months). Complete response was reported in 100% (control--45%). All the patients survived 12 months after treatment (control--85%); 5-year survival was 42 and 22%, respectively. Our modality appeared to be the only means of ionizing radiation dose dispensation in cases of early relapse after photon therapy when there was a glimmer of hope of stabilization. PMID- 20968019 TI - [Long-term results of combined photon-neutron radiotherapy for malignant salivary gland tumors at the Ural Neutron Therapy Center]. AB - An evaluation of combined photon-neutron radiotherapy (CPNT) of malignant tumors of the salivary gland (31) is presented. Overall 1-year survival was 100%, 2 years--95%, 3 years--65%, 4 years--57% and 5 years--47%. Radiation-related injury incidence did not vary dramatically: CPNT--15%, photon therapy--11%. Most relapse occurred within the first 24 months. PMID- 20968020 TI - [Radionuclide visualization of lymphatic flow from primary breast cancer]. AB - Our study was concerned with evaluation of patterns of lymph flow from primary breast cancer. Radionuclide scintigraphy (RS) of lymph nodes was performed in 92 patients. Scinitigraphic images were obtained 30-60 and 240-360 min after intratumoral injection of 75-150 MBq (0,5-1 vl) of 99mTc nanocolloids. The pool sites of the radiodrug collection were as follows: axillary (Ax), sub supraclavicular (SSCL) and internal mammary (IM). Imaging proved effective in 86 cases. No drug transport was recorded in 5 cases; 4 of them revealed macroscopic metaststases to the lymph nodes. External involvement of the axillary lymph nodes was visualized in 51 patients out of 52 while in 26 it occurred on the axillary site only. In another 25 patients, images of lymph nodes were obtained on 2 or 3 sites: drainage Ax+SSCL (12;23.1%), Ax+IM (6;11.6%) and Ax+SSCL+IM (7;13.4%). In patients with tumors in internal quadrants (34), the lymph flow patterns were as follows: Ax (12;35.3%), IM (2;5.8%), Ax+SSCL (8;23.5%), Ax+IM+SSCL (5;14.7%). Hence, the efficacy of lymph node visualization after intratumoral injection of nanocolloids was 98%. Visualization on Ax sites was further confirmed by lymph flow to SSCL and IM (29.1%) and (35.9%), respectively. The likelihood of lymph flow to IM is significantly higher in patients with internal localization of breast cancer (37.1%) but it is not negligible (22.9%) in cases of external quadrants. PMID- 20968021 TI - [New prognostic factors in the treatment of patients with stage-III Hodgkin's disease]. AB - Our data are presented on evaluation of chemoradiotherapy of 365 patients with stage III Hodgkin's disease. Patients with stage IIIA tumors revealed the following significant differences of overall and relapse-free survival (p < or = 0.00001): 15-year overall survival (nodular sclerosis G1) - 95% vs.G2 - 45%; 15 year relapse-free survival: G1 - 86%, G2 - 32%. In stage IIIB group, overall survival (50%) was significantly lower as compared with 70%. Involvement foci significantly regressed by less than 75% (p = 0.044) after 2-4 cycles of preliminary combination chemotherapy. Our results suggest that differentiated criteria be used for prognosis of stage III Hodgkin's disease treatment. PMID- 20968022 TI - [Variation of mortality risk among cancer patients and individualized therapy]. AB - To investigate the deviation of survival curves from monotonous shape, 17 curves for 6 most common cancer sites of 87,205 patients (aged 30-89) were selected from The U.S. Surveillance, Epidemiology and End Results (SEER) Register database. The curves were analyzed using monotonous exponential and harmonic functions which allowed a corresponding estimation of quasi-sinusoidal disturbances of monthly death hazard. Detectable fluctuations of the latter were established in the 0-40- month life span zone depending on tumor site and age at diagnosis. PMID- 20968023 TI - [Infantile myofibroma and myofibromatosis: clinical and morphologic assessment of eighteen cases]. AB - Infantile myofibroma (myofibromatosis) (IM) is a mesenchymal tumor of soft tissues of the head, extremities and trunk. It is characterized by relapse-free infiltrative growth. It consists of neoplastic myofibroblasts at varying stage of cell differentiation which form multi-structured tumor zones. IM's morphological differentiated diagnosis is established vis-a-vis other varieties of tumor and reactive nodular structures of fibroblasts, primarily, infantile hemangiopericytomas and desmoid fibromatosis. Immunohistological and ultrastructural examination of tumor is required for making correct diagnosis of IM. PMID- 20968024 TI - [Criteria for the effectiveness of interleukin-2 immunotherapy in a spontaneous murine mammary tumor model]. AB - A novel approach is suggested to identify more homogenous subgroups involved in the follow-up of growth of spontaneous mammary tumors in mice (116, history-based analysis). That depends on subclinical period (preneoplastic and non-invasive stages of tumor growth) as well as rate of growth after clinical manifestation. An analysis of tumor growth rate versus survival of experimental and control animals after primary diagnosis and clinical manifestation of tumor showed that following a single peritumoral 2.5 x 10(6) IU IL-2 treatment tumor growth slowed down (n = 29; p < or = 0.05) while survival tended to improve. Originally fast growing tumors without significant subclinical stage continued to grow but slowly. Females with such tumors survived longer than untreated controls without showing, however, any improvement on that parameter. PMID- 20968025 TI - [Evolution and perspectives in the surgical treatment of ovarian cancer]. AB - Owing to its anatomo-topographic features, ovarian carcinoma starts to disseminate at early stages. Views on surgical treatment are divided between radical removal of all metastatic tissues, and operation "within reasonable limits of safety". Volume of surgery is discussed on the basis of the available literature and our own data with due consideration of patterns of tumor dissemination and recurrence and a complex of intraperitoneal factors. Potential of nanotechnologies and, in particular, photodynamic therapy of relapsing canceromatosis of the peritoneum is discussed. PMID- 20968026 TI - [A method for forming a urinary bladder from the sigmoid after radical cystectomy in patients with bladder cancer]. AB - A procedure was evolved and tested for forming a urinary bladder from the sigmoid in the course of radical cystectomy carried out for invasive bladder cancer (20). A sigmo-sigmoid anastomosis ("end-to-side") was used by means of an apparatus suture. PMID- 20968027 TI - [Statistics of kidney tumors in St. Petersburg, Russia, in the years 1999-2008, based on surgical material]. PMID- 20968028 TI - [Synchronous Merkel cell skin cancer and breast cancer]. PMID- 20968029 TI - [Histogenesis of lung cancer]. PMID- 20968030 TI - [Local anesthesia for biopsy of the prostate]. PMID- 20968031 TI - [Significance of the number of biopsy specimens from the prostate gland for adequate clinical appraisal of neoplasia]. PMID- 20968032 TI - [World-wide fame of the science and pride of the Ukrainian people--Platon Hryhorovych Kostiuk]. PMID- 20968033 TI - [Calcium ions in cell nucleus]. PMID- 20968034 TI - [Increased expression of voltage-dependent anion channel and adenine nucleotide translocase and the sensitivity of calcium-induced mitochondrial permeability transition opening pore in the old rat heart]. AB - We investigated mRNA and protein expression of voltage-dependent anion channel (VDAC), mRNA adenine nucleotide translocase (ANT) as well as the sensitivity of the mitochondrial permeability transition pore opening (MPTP) to Ca2+ in the adult and old rat heart. It was shown that in the old rats hearts VDAC mRNA expression increased by 1.7 (p < 0.05) times and mRNA ANT expression increased by 1.8 (p < 0.05) times in comparison with adult animals. The Western Blot analysis showed that the level of VDAC protein expression in the old rat hearts also significantly increased compared with adult animals. In the hearts of old rats, the sensitivity of MPTP opening to calcium (10(-7)-10(-4) mol/l) determined by mitochondria swelling, increased two-fold (p < 0.05). Therefore, an increased VDAC and ANT expression, as the main structural functional components of the MPTP, and an increased sensitivity of MPTP opening to Ca2+ caused an increase in the permeability of mitochondrial membranes in aging. Each of these factors may contribute to alterations in mitochondrial barrier properties and lead to mitochondrial dysfunction. PMID- 20968035 TI - [Characteristics of sensory neurotransmission in co-culture of neurons from the dorsal root ganglion and dorsal horn spinal cord in rats]. AB - We examined properties of chemical neurotransmission at the level of primary afferent inputs into spinal cord with the new easy-to-use in vitro model of contiguously-cultivated dissociated both the dorsal root ganglion neurons (DRG) and the dorsal horn spinal cord neurons (DHSC) from newborn rats. The results of our studies showed the presence of excitatory and inhibitory DRG neurons synapses on the cells of DHSC. The excitatory afferent signaling in such synapses was mediated by presynaptic release of glutamate and a following activation of both NMDA- and non-NMDA-receptor subclasses. In these cases the activation of non-NMDA receptors makes a main contribution to realization of excitatory postsynaptic effects. Either glycine- or GABA-ergic DRG neurons were involved in transmission of inhibitory signals to the DHSC neurons. However, in vast majority of examined neuronal pairs the inhibitory synaptic transmission was mediated by presynaptic release of glycine. As distinct from the previous similar methods, an in vitro model of co-culture of both the DRG and the DHSC neurons proposed here allows to use comprehensively modem technical approaches for examination of the transmission of somatosensory information from the periphery to the CNS. The described model could be acceptable for detailed investigation of specific properties of primary afferent synapses. PMID- 20968036 TI - [Effects of ubiquitin gene silencing in anoxia-reoxygenation of cultured cardiomyocytes]. AB - Ubiquitin-dependent proteasomal proteolysis is crucialin the turnover of cardiomyocytes functional proteins (actin, myosin, ion channels at. al.), therefore, investigation of cell death after ubiquitin (UBB) gene silencing using RNA interference and anoxia-reoxygenation (AR) modeling appears to be attractive. Cardiomyocytes were transfected by siRNA to ubiquitin gene using electroporation procedure, and then primary culture was treated by 30 min of anoxia and 60 min of reoxygenation. The number of living, necrotic and apoptotic cardiomyocytes was determined by fluorescence microscopy. The level of UBB and proteasome subunits beta5 (PSMB5) and beta9 (PSMB9) mRNA expression was estimated by real-time PCR. It was shown that UBB mRNA expression was increased by 2.1 times after AR modelling (P < 0.05). Small interference RNA injection in cell culture decreased ubiquitin, PSMB5 and PSMB9 expression by 2.4 (P < 0.05), 1.3 (P > 0.05) and 1.6 (P < 0.05) times, respectively, compared with control (scrambled siRNA introduction). At the same time, the number of living cardiomyocytes decreased to 70.26 +/- 1.54%, P<0.05, and the level of necrotic cells, apoptotic cells and cells with signs of autophagy augmented by 25.92 +/- 1.52%, (P = 0.38), 4.32 +/- 0.53% (P = 0.15) and 38.2 +/- 3.81% (P = 0.001), respectively. Ubiquitin silencing after AR (30 min/l h) increased the number of living cells by 3.7% and decreased the number of necrotic cells by 4.7% and did not alter the apoptotic and autophagic cells populations. The data obtained indicate that ubiquitin gene silencing, mRNA expression of which augmented during AR, induces necrotic and autophagic death of intact neonatal cardiomyocytes in culture, but enhances the AR resistance of these cells to some extent. PMID- 20968037 TI - [Changes of vascular reactivity and reactive oxygen species in conditions of varying duration of permanent stay in the alienation zone in mice]. AB - Peculiarities of changes in the vascular reactivity and in the content of reactive forms of oxygen and stable metabolites of nitric oxide (NO) were studied in the aorta preparations of C57BL/6 and BALB/c mice of the two age groups (6 and 18 mo.), which were born and permanently kept in the Chernobyl alienation zone. The results obtained showed a disturbance of acetylcholine-induced endothelium dependent reactions of relaxation of smooth muscles of the thoracic aorta. A lower level of NO synthesis and lower level of oxidative arginase metabolism of arginine corresponded to a higher degree of damage of endothelium-dependent reactions of relaxation of the thoracic aorta smooth muscles. A decrease of NO synthesis in conditions of permanent effects of low doses of radiation was conditioned by an increase of generation of reactive forms of oxygen, namely, superoxide and hydroxyl radicals, which might be formed in mitochondria. In conditions of permanent effects of low doses of radiation a lesser level of protein nitrosothilation, same as lesser one of generation of OH-radical, corresponded to a higher level of damage of endothelium-dependent reactions. PMID- 20968038 TI - [The vasodilation effects of flokalin, a fluorine-containing K(ATP) channel opener]. AB - In experiments on anesthetized dogs it was shown that the amplitude and duration of hypotensive effect of flocalin, a fluorine-containing pinacidil analogue, were dose-dependent and similar to those evoked by the known ATP-sensitive potassium channel opener pinacidil. However, flocalin appeared to be 3.5 times less toxic than pinacidil. Registration of systemic arterial pressure (SAP) has shown that following intravenous introduction of the threshold dose of flocalin (0.05 mg/ kg) the dilatation lasts around three minutes with the amplitude 9.52% +/- 2.01% (n=7, P < 0.05). Introduction of flocalin in a dose 0.5 mg/kg and above reduced SAP on more than 37%. Flocalin at 0.5, 0.75, 1.0 and 1.5 mg/kg reduced SAP by 42.07 +/- 6.18 (n=5, P < 0.05); 44.22 +/- 4.87 (n=3, P < 0.05); 44.3 +/- 4.59 (n=5, P < 0.05) and 66.28 +/- 3.15 mm Hg (n=3, P < 0.05), accordingly. Intravenous introduction of high doses of flocalin (0.75-1.5 mg/kgs) quite often reduced SAP to 40-50 mm Hg. However, such dangerous reduction in arterial pressure was comparatively short and lasted not more than 15 minutes, and then (usually within an hour) SAP gradually restored. Introduction of flocalin in hip artery, while measuring the perfusion pressure, produced practically similar results. In our opinion, the optimal cardioprotective doses of flocalin were 0.1 and 0.2 mg/kg. In experiments with acute ischemia and reperfusion of myocardium, preischemic introduction of flocalin at 0.1 and 0.2 mg/kg reduced an infarct size of myocardium by 37-40% and reduced SAP within first 5 and 25 minutes, accordingly. PMID- 20968039 TI - [Expression of proteasome subunits PSMB5 and PSMB9 mRNA in hippocampal neurons in experimental diabetes mellitus: link with apoptosis and necrosis]. AB - There is a huge body of evidence showing that long-termed diabetes mellitus is followed with hippocampal dysfunction. The goal of this work was to investigate the expression of proteasome subunits PSMB5 and PSMB9 mRNA in CA1, CA2 and CA3 areas of hippocampus in parallel with processes of cell death (apoptosis and necrosis) in development dynamics of streptozotocine-induced diabetes. We have studied hippocampal neurons using chromatine dye Hoechst-33342 and immunohistochemical detection of apoptotic cell death marker caspase-3. At day 3 and 7 after injection of streptozotocine we have performed visualization of caspase-3-immunopositive neurons showing signs of neurodegeneration in hippocampal sections using confocal microscope Olympus FV1000. The rate of proteasome subunits PSMB5 and PSMB9 mRNA expression was determined with RT-PCR. The results indicated elevation of PSMB9 mRNA content (from 4807 +/- 0.392 arbU up to 20,023 +/- 4949 arbU on day 3 and up to 20,253 +/- 5141 arbU on day 7). A maximal number of cells with signs of chromatin condensation was observed at day 3 and day 7 in CA2 and CA3 area (11.51% and 12.49% respectively). That indicates an intensification of proapoptotic processes. Summarizing the results presented above we can conclude that during the first week of diabetes mellitus development, hippocampal cells undergo the process of impairment and degeneration. PMID- 20968040 TI - [The role of mitochondria in NO-dependent regulation of Na+, K+ -ATP activity in the rat aorta]. AB - In experiments in vivo we studied the interaction between two ion-transporting mechanisms of cardiovascular system--Na+, K+ -ATPase of rat aorta and Ca2+ uptake system of mitochondria in short-term response to different doses of NO donor, nitroglycerine (NG). The activity of the Na+, K+ -ATPase was determined in rat aorta, and mitochondrial uptake of Ca2+ was studied in rat heart mitochondria assuming that metabolism induced by NO in cardiac mitochondria is similar to that in rat aortic mitochondria. The data show a coordinated dose-dependent action of NG on Na+, K+ -ATPase activity as well as Ca2+ -uptake in mitochondria. An activation of Na+, K+ -ATPase by low dose of NG (0.25 mg/kg body weight) is accompanied by the activation of Ca2+ -uptake in mitochondria as a result of inhibition of permeability transition pore. However, further increase of the dose of the drug leads to reciprocal changes of studied parameters: the decrease in Na+ -pump activity below the control level and the increase of Ca2+ -uptake in mitochondria with a peak at 1.0 mg/kg NG, which takes place in parallel with the dramatic rise in the level of ROS and RNS together with their toxic products, nitrosothiols (NT) and free iron (Fe2+) content in mitochondria. Strong correlation between Ca2+ -uptake and Fe2+ -release, Fe2+ -release and OH-radical formation, the rise in OH-radical level and the decrease of that of H2O2 and mitochondrial NT together with the inhibition of Na+, K+ -ATPase favor a hypothesis that oxidative stress in rat aorta is of mitochondrial origin due to an enhanced uptake of Ca2+ into mitochondrial matrix, Fe2+ deliverance and manifold increase in OH-radical formation from decomposition of hydroperoxide in Haber-Weiss reaction and the decomposition of mitochondrial NT via formation of peroxynitrite, both catalysed by Fe2+, with subsequent release of *OH-radical. Effective abolition of Na+, K+ -ATPase inhibition by potent antioxidant melatonine gives the evidence of the oxidative nature of Na+, K+ -ATPase inhibition by nitric oxide in rat aorta. PMID- 20968041 TI - [Laminar distribution of the active spinal cord neurons during the feeding related stereotyped movements in the rat]. AB - The comparative study of expression of early c-fos-gene (marker of neuronal activation) and NADPH-diaphorase reactivity (NADPH-dr) was performed in the cervical spinal cord of rats in the control (intact) animal, in the state of starvation and after realization of long-lasting (repeated 4 to 12 times per minute for 30 min) motivated stereotyped food-procuring forelimb movements. In comparison with control rats; in the starving rats or rats showed forelimb movement to reach-to-grasp the food, the number of Fos-immunoreactive (Fos-ir) cells in the dorsal and ventral horns of a 40-microm-thick slice was significantly greater (P < 0.05). The number of Fosir neurons in the starving state clearly exceeded that in the most layers after realization of movements. Increase of Fos immunoreactivity in the superficial (2i, 3) and deeper (4, 5) layers of the dorsal horn was initiated, evidently, by signals from peripheral and supraspinal structures. We also found labelled cells within layers 6-8, and 9 demonstrating the activity of interneurons and motoneurons directly involved into generation of operant forelimb movements. According to our data, high density of NADPH-dr/NO-generating neurons in the C6/C7 segments are observed in the substance gelatinosa (layer 2i) and layers 7 and 10. NADPH-dr cells and Fos-ir neurons were intermixed within the layers but did not demonstrate double labelling. It is possible to suggest that NADPH-dr/NO-generating cells of the spinal cord did not operate under realization of the studied operant reflexes, which did not include nociceptive component. PMID- 20968042 TI - [Effect of NF-kappaB activation inhibitor curcumin on the oogenesis and follicular cell death in immune ovarian failure in mice]. AB - In experiments on CBA mice, we studied the influence of an inhibitor of nuclear transcription factor kappaB activation curcumin, obtained from Curcuma longa, on the meiotic maturation of oocytes and apoptotic and necrotic death of follicular cells at immune ovary failure induced by immunization of animals with allogenic ovarian extracts. NF-kappaB plays a pivotal role in the induction of genes encoding pro-inflammatory factors (cytokines, adhesion molecules, inducible NO synthase and cyclooxygenase) and in regulation of cell proliferation and death. It has been shown that immunization of mice increased the death of follicular cells through anapoptotic and necrotic pathways, which led to inflammatory response (according to blood leukogram and impairment the oocyte meiotic maturation at metaphase I and II). Intragastric administration of curcumin (Sigma, USA, 2 mg of the mouse weight, four times a week during the period of immunization) reduced the number of the follicular cells died through apoptotic and especially necrotic pathway. Curcumin attenuated an inflammatory response and improved the meiotic maturation of oocytes impaired under experimental immune ovarian failure in mice. PMID- 20968043 TI - [Effect of long-term monosodium glutamate administration on structure and functional state of the stomach and body weight in rats]. AB - The influence of prolonged administration of monosodium glutamate (MSG) on basal gastric acid secretion, body weight and gastric mucosa in rats was studied. We found that 10-, 20-, 30-days feeding by MSG in doses 15 to 30 mg/kg (equivalent to I and 2 g/person) leads to erosive and ulcerative lesions of the gastric mucosa and an increased secretion of hydrochloric acid and an increased body weight. It is concluded that the stimulating effect of MSG on the basal secretion of hydrochloric acid in the stomach may be implicated in the pathogenesis of a number of acid-dependent diseases. An excessive consumption of MSG can cause a "Chinese Restaurant Syndrome" and gastritis, gastric and duodenal ulcers. Therefore, the maximum dose of MSG should be reconsidered taking into account its influence on the secretory capacity of the stomach. We also conclude that prolonged, excessive and systemic consumption of MSG causes obesity. PMID- 20968044 TI - [The pathways of taurine influences on gastric secretion]. AB - In chronic experiments with dogs with gastric fistulas the influence of amino acid taurine on the gastric secretion was investigated. We showed that taurine did not cause acid gastric secretion out of digestion, but increased the gastric secretion stimulated by histamine, increased the contents of gastric acid and pepsine in gastric secretes. When administered either 15 minutes or two hours prior histamine injection, taurine affected the Na+ and K+ concentrations in gastric juice. The greatest changes in the basic indices of gastric secretion were observed 14 hours after administration of taurine. In these experiments the contents of total proteins and components of adenile system in gastric secretes was increased also. Blockade of cholinoreceptors by atropine, benzohexonium and IEM-1678 decreased the effects of taurine on gastric secretion stimulated by histamine. Blockade of a-adrenoreceptors by phentolamine did not prevent the taurine-induced effects on histamine-stimulated gastric secretion. It is established that under conditions of the blockade of beta-adrenoreceptors by obsidane, taurine does not manifest entirely its potentiating influence on the gastric secretion stimulating by histamine. The data obtained indicate that taurine affects gastric secretion stimulated by histamine and realization of this effect occurs through M- and N-cholino- and B-adrenoreceptors. PMID- 20968045 TI - [The effect of initial hormonal status of recipient animals on morphological state and endocrine function of ovarian tissue transplant]. AB - The aim of investigation was a comparative analysis of morphofunctional characteristics of allografts of mature ovarian tissue and neonatal ovary depending on initial hormonal status of recipient animals. Rats' mature ovarian tissue and neonatal ovary were transplanted under renal capsule simultaneously with ovariectomy and 2 months later. Data analysis indicated that the development of ovarian tissue transplant was determined by its maturity and initial hormonal status of recipient. Mature ovarian tissue transplants preserve morphology and endocrine function to the 60th day after transplantation to the recipient animals with the initial hormonal status that corresponds to the norm. Neonatal ovary transplants are developed to the mature stage following transplantation to recipients with hormonal status that corresponded to the ovariectomized animals, that is, low concentration of sex hormones and an increased level of follicle stimulating hormone. PMID- 20968046 TI - [Alteration of calcium signaling as one of the mechanisms of Alzheimer's disease and diabetic polyneuropathy]. AB - This review is devoted to the action of amyloid-beta peptide on the functional activity of intracellular and plasmalemmal calcium-regulated structures in cultured hyppocampal neurons: mitochondria and voltage-gated calcium channels. A comparative analysis of relative changes of plasmalemmal structures in such neurodegenerative diseases as Alzheimer's illness and diabetic neuropathy has been made. PMID- 20968047 TI - [The materials of International Conference "Biological Effects of Small Doses of Ionizing Irradiation and Radioactive Pollution of Environment (BIORAD-2009)" (Syktyvkar, 28 September-1 October, 2009)]. PMID- 20968048 TI - [Biological effects of chronic radiation exposure on plant populations]. AB - The findings from long-term field studies on biological effects in plant populations inhabiting radioactively contaminated territories contrast in levels and compositions of dose-forming radionuclides are presented. Plant populations developing under radioactive impact show enhanced frequencies of gene and chromosome mutations, and their reproductive potential is inferior to reference populations. Even relatively low levels of technogenic impact are able to increase genetic diversity and destroy regularities inherent for intact populations. Chronic radiation exposure from a certain level appears to be an ecological factor changing genetic structure of wild populations. Data presented indicate the presence of adaptation processes in plant populations in territories with technogenic impact. Under ecological stress, there are selection processes for resistance improvement in plant populations. But an appearance and rate of this process can essentially differ in dependence on radioecological conditions. PMID- 20968049 TI - [The assessment of no adverse effect doses for plant populations chronically exposed to radionuclides of uranium and thorium decay series]. AB - Dose rates cause no adverse effects on natural populations of Pinus sylvestris L. and Vicia cracca L. inhabiting territories contaminated by uranium mill tailings and radium production wastes (Vodny settlement, Komi Republic) were determined. A significant increase in embryonic lethal mutation frequency in V. cracca legumes and decrease in seedlings survival rate as compared with control values were registered at dose rate equal to 1.67 mGy/day, that is 280 times higher than the one calculated for the reference site. The adverse effects in P. sylvestris expressed in increased frequency of chromosome aberrations in meristematic root tips and decreased reproductive capacity of seeds were determined at absorbed dose rate equal to 0.083 mGy/day. Data obtained show that the decrease in plant reproductive capacity in case of chronic exposure of radionuclides of uranium and thorium decay series can observe at lower weighted absorbed dose rates than in case of environmental contamination by artificial radionuclides. PMID- 20968050 TI - [Comparative morphological analysis of peripheral endocrine glands in small mammals inhabiting areas with high levels of radioactive pollutants and exposed to chronic irradiation in laboratory experiments]. AB - The comparative study of cellular-tissue reactions in endocrine organs (thyroid and suprarenal glands, ovary) of rodents exposed to radiation in natural conditions (Radium station in Komi Republic and 30-km zone of Chernobyl APP) and experimental conditions modeling the chronic exposure has been conducted. There is evidence that chronic irradiation in low doses causes morphological disorders in different levels of structural organization (cellular-tissue, organism and population levels). The experimental results showed that observed variations in thyroid, suprarenal glands and ovary by morphometric parameters reflect the natural changes in their functional activity (within the physiological limits). These changes are directed at the homeostasis maintenance in changed conditions and have a compensatory and adaptation character. The effects of low dose radiation influence with combination of other agents may be amplified at the cellular-tissue reactions level. In comparison with experimental results, the natural conditions (high level of radioactivity with alpha- and beta-emitters, high natural radionuclides, toxic elements and extreme climatic factors) induce more expressed changes as a significant increasing of chromosomal and genes mutations in cells, destructive processes in organs of endocrine system and disorders of reproductive functions. PMID- 20968051 TI - [Polonium-210 in fishes from the Black Sea]. AB - The specific activity of naturally occurring radionuclide 210Po in main species of the Black Sea fishes and some their organs were used for the calculation of absorbed and equivalent dose rates. The values of the dose in investigated fish depend on their ecological belonging. Maximum values of equivalent dose rates for viscera and, first of all, liver exceed such for the whole body of fishes. But they are significantly lower than the dose rate limit recommended by IAEA for the protection of aquatic organisms from ionizing radiation. PMID- 20968052 TI - [The adaptive strategy of rodent populations living in conditions of radioactive and chemical environmental pollution]. AB - The comparative analysis of demographic, morphological and physiological processes in mouselike rodents in pollution zones (90Sr + 90Y, 137Cs) on East Ural radioactive track (EURT) and (Cu + Cd + Pb + Zn + SO2) on a site near copper smelting factory is carried out. The direct (not mediated) defeat of animals by an irradiation leads to inherited adaptation (density preservation, tolerance increase to pollution, migration decrease and so forth). The mediated defeat of animals at pollution by metals influences animals as a result of degradation of a vegetative cover, reducing a forage reserve, shelters and reproduction places. Population is decreasing, migration is increasing. Hence, population reacts onto direct defeat of animals or on inhabitancy locuses degradation, id est unspecifically, without dependence from the physical and chemical nature of pollution. PMID- 20968053 TI - [Remote effects in plant populations from zones of radiation and chemical pollution]. AB - A comparative research of dandelion seed progeny from the coenopopulations growing for a long time in a gradient of radioactive (zone of the East-Ural radioactive trace--EURT) or chemical (zone exposure Nizhny Tagil Metallurgical Plant--NTMP) pollution was carried out. It was revealed that the viability of seeds declined similarly in gradient of the man-caused stress regardless of its nature. Dandelion coenopopulations from the EURT zone, NTMP and the background area significantly differed in the qualitative and quantitative allozyme specifications. The analysis of clonal diversity revealed phenogenetic uniqueness of all coenopopulations. Study of F1-generation metal and radio resistance showed that the seed progeny from the impact EURT zone possessed a high viability but had hidden damage that led to a low resistance to additional man-caused influences. High viability of the seeds in the F1-generation from the NTMP zone combined with increased resistance to the provocative effects of radiation and heavy metals. Significant differences in responses to the "habitual" and "n ew" factors of influence, i.e. effect of pre-adaptation in samples from EURT and NTMP zones were not found. PMID- 20968054 TI - [Phytoplankton in reservoir R-11 of Techa reservoir cascade of Industrial Association "Maiak"]. AB - Phytoplankton of reservoir R-11 was investigated at vegetative seasons of 2007 and 2008. R-11 is a locking reservoir in the cascade of Mayak PA reservoirs. The specific activity in water of R-11 ranged from 0.9 to 1.8 kBq/dm for 90Sr and from 0.98 to 3.97 kBq/dm3 for 137Cs; in bottom sediments it ranged from 20 to 400 kBq/kg for 90Sr and from 0.35 to 220 kBq/kg for 137Cs. Concentration of SO4- exceeded the maximum permissible concentration for fishing reservoirs in 5-7 times. The content of 90Sr in the phytoplankton has made 400 kBq/kg (for dry weight), and 137Cs--2.20 kBq/kg (for dry weight). The absorbed dose of irradiation for the phytoplankton calculated under the content of 137Cs and 90Sr in water and in phytoplankton (the external irradiation from activity of bottom sediments was not considered) has made 901 mGy per year. Altogether the phytoplankton of reservoir R-11 included 107 species. Such species of Cyanobacteriae as Oscillatoria agardhii Gom. was the dominant in phytoplanktonic community. Another Cyanobacteriae, Lyngbya limnetica Lemm. and Aphanizomenonflos aquae (L.) Ralfs. acted the most important part in a complex of species subdominants. According to quantitative development of the phytoplankton the reservoir R-11 can be classified as P-mezosaprobe waters. PMID- 20968055 TI - [Biological effects of phytoecdysteroids and chronic low-dose irradiation]. AB - The influence of serpistene in dose of 5 and 50 mg/kg on chronic low-dose gamma irradiation (22.6 cGy) effects on cytogenetic (abnormal sperm cell, marrow bone micronucleus) and function and morphology (thyroid and adrenal glands) parameters of mice was estimated. The serpistene modifies effects of gamma-irradiation depends on the administration regime and a dose of the substance. The most expressive radioprotective effect on endocrine organs after serpistene prophylactic administration was found. The prophylactic dose was 5 mg/kg for adrenal gland and both doses--for thyroid gland. The most expressive radioprotective effect on marrow bone cells after serpistene therapeutic administration in a dose of 5 mg/kg was found. The most expressive antimutagenic effect on somatic and germinal cells of prophylactic and therapeutic administration in a dose of 50 mg/kg was found. PMID- 20968056 TI - [Ecological and radio-ecological effects from long-term use of the lake Kyzyl Tash as a cooling reservoir by the nuclear fuel cycle facility]. AB - This review introduces long-term study findings on ecological and radiation induced regime of the water reservoir - lake Kyzyl-Tash (R-2) - used as a heat sink of nuclear-power reactors in the Southern Urals from 1948 through 2008. It was exhibited that water reservoir exploitation by the nuclear fuel cycle facility "Mayak" PA resulted in hydrological, thermal, hydrochemical and radiological ecosystem regimes changes. The central radioactive substances depot in the water reservoir was determined to be the upper 20-30 cm bed silt layers, contamination density of which in 1980-1990s amounted on average approximately 0.2 PBq/km2 (about 5 kKu/km2). Some regularities of radionuclide distribution in bed sediments and biota were ascertained. Dose estimates from ionizing exposure to fish inhabited the water reservoir were experimentally made. Dose contribution was mainly due to incorporated beta-emitters amounted up to 2-3 Gy/y in 1980s. The leading role in the reservoir life belonged to phytoplankton with its algal nuisance periodicity constituting 5-6 years for blue-green and diatomic algae, and 2-3 years for green algae. During periods of the highest development pressure phytoplankton productive capacity in the reservoir was by an order of magnitude greater compared to control water reservoirs of the region. Combined long-term impact of radiological and chemical factors did not cause irreversible changes either in fish populations or ecological system in general. It can be proved by the fact that during 1970-1980s the water reservoir R-2 was inhabited by such cleanness indicators as crawfish (Astacus leptodactylus) and shellfish (Anodonta cygnea L.). On reducing of thermal and chemical pressure in the end of 1980s some processes observed gave evidence of ecosystem restoration in the lake Kyzyl-Tash. At the present moment the situation of the water reservoir exploiting as a heat sink is stabilized with preserved self-cleaning capacity. PMID- 20968057 TI - [The cytogenetic consequences of chronic irradiation in rodent populations inhabiting the Eastern Urals Radioactive Trace zone]. AB - In bone marrow cells of rodents (Apodemus (Sylvaemus) uralensis Pall., 1811, Apodemus agrarius Pall., 1771) inhabiting the Eastern Urals Radioactive Trace (EURT) zone (Kyshtym radiation accident 1957) and adjacent areas of Urals, the chromosome instability and 90Sr accumulation in bones were investigated. Intensive mutagenic process in both species from impact plots (the soil pollution by 90Sr 2322-16690 kBq/m2) was found. Significant positive correlation of aberrant cells frequencies and 90Sr was shown. Possible causes of the lack of resistance to long-term mutagenic factor (over 100 generations since 50 years from the accident) such as migration of animals and specific configuration of the EURT zone (narrow extended territory with sharply falling gradient of radionuclide pollution), which considerably decrease the probability that certain changes will be fixed and inherited in a series of generations of rodents, are discussed. PMID- 20968058 TI - [The influence of aromatic amino acid derivatives on the complement system under ionizing radiation]. AB - Activities of the complement classical, alternative and lectin pathways were determined under conditions of X-radiation in the blood of rats treated and none treated with synthetic Schiffbase aromatic amino acid derivatives, nicotinyl-L tyrosinate or nicotinyl-L-tryptophanate, before irradiation. In case of activities of the alternative and lectin pathways no significant changes between irradiated animals and none-irradiated control animals were detected. However, the data obtained demonstrate significantly elevated activity of the classical complement cascade in the blood of irradiated animals (1 day after irradiation), as compared to those none-irradiated. This effect was less pronounced in rats treated with nicotinyl-L-tyrosinate or nicotinyl-L-tryptophanate 1 hour before irradiation. Based on the results obtained the ability of nicotinyl-L-tyrosinate and nicotinyl-L-tryptophanate to act as cyto-protectors is concluded. PMID- 20968059 TI - [The influence of consecutive application of B-190 preparation and interleukin 1beta on survival rate and bone marrow hematopoiesis of irradiated mice]. AB - The purpose of research was the experimental estimation of efficiency of consecutive application of a radioprotector B-190 and means of emergency therapy of radiating injury interleukin-1beta at acute irradiation. An estimation of treatment-and-prophylactic action of the given circuit of introduction of preparations carried out by studying 30 day-survival and average life expectancy of the lost animals, research of bone marrow hemopoiesis. It is established, that consecutive application of a radioprotector B-190 in a doze of 50 mg/kg for 15 mines up to an irradiation and interleukin-1beta in a doze of 50 mkg/kg through 15 mines after irradiating increases survival and prevents decrease in quantity of CFU-S9 at the irradiated mice in the greater degree, than their isolated introduction. PMID- 20968060 TI - [Bone mineral density in residents living on radioactive territories of Cheliabinsk Region]. AB - Operation of "Mayak" plutonium production complex resulted in radioactive contamination of the part of Chelyabinsk Region in 1950-60s. Significant gas aerosol emissions of 1311 occurred since 1948; in 1957, a radiation accident resulted in 90Sr contamination of large territories. This paper presents comparison of bone mineral density of persons lived on territories with different levels of soil 90Sr-contamination with a control group. It was found that in 1970 1975 the bone mineral density, estimated from mineral content in bone samples, in residents of contaminated areas born in 1936-1952 was significantly lower compared with the control group. For persons born in 1880-1935 such differences were not found. It was shown that the decrease in bone mineral density was not related to 90Sr exposure of osteogenic cells in the dose range from 0.1 to 1300 mGy: the coefficient of correlation between individual 90Sr-doses and bone mineral contents was not significant. The decrease in bone mineral density of persons born in 1936-1952 could be associated with exposure of thyroid and parathyroid glands (systemic regulators of calcium turnover) by 131I from gas aerosol emissions from "Mayak". Maximum gas-aerosol emissions occurred in 1948 1954 and coincided with growth and development of thyroid gland, characterizing by intensive accumulation of 131I, and with growth and maturation of the skeleton of persons born in these calendar years. PMID- 20968061 TI - [Lipids in the process of synaptic vesicle exo- and endocytosis]. AB - The phenomenon of synaptic transmission is based on the processes of synaptic vesicle exo- and endocytosis carried out with complex protein-dependent mechanisms. The SNARE-complex forming proteins (synaptobrevin, syntaxin, SNAP 25), synaptotagmin, Munc13, Munc18, NSF, alpha-SNAP are involved in exocytosis, while the synaptic vesicle endocytosis is mediated by another protein (clathrin, AP-2, epsin, endophilin, amphiphysin, dynamin, synaptojanin, Hsc70). In recent years, data on critical role of various lipids in exo- and encocytosis are collected. Most interesting results are received about significance of the cholesterol, phosphoinositides, phosphatidic and polynonsaturated fat acids in the exo-endocytosis cycle. Participation of lipid rafts in synaptic vesicle recycling is discussed. In this article, the data of the last years, including the authors' own data about role of some lipids and lipid-modifying enzimes in processes of exo- and endocytosis are presented. PMID- 20968062 TI - [Changes in the kinetics of quanta secretion-effective mechanism of synaptic transmission modulation]. AB - It is widely accepted that the leading presynaptic mechanisms underlying the synaptic plasticity involve changes of the number of neurotransmitter quanta released by one nerve pulse (the quantal content of postsynaptic response) and of the size of a single quantum. In addition, the existence of one more effective though previously ignored mechanism of modulation of synaptic plasticity was suggested related to the change in the time course (kinetics) of secretion of single neurotransmitter quanta forming the multiquantal response. This article reviews current data (including the authors' own results) on the kinetics of evoked neurotransmitter quanta secretion from motor nerve endings in peripheral synapses, mechanisms of their modulation and methods of quantitative analysis. PMID- 20968063 TI - [Polymorphism in 5-HT receptors as the background of serotonin functional diversity]. AB - The review concentrates on the role of different types and subtypes of 5-HT receptors in physiological and behavioural effects of the brain neurotransmitter serotonin. Specifically it describes: 1) the effects of 5-HT1A and 5-HT1B receptors on aggressive behavior, sexual arousal, food and water consumption; 2) the data showing reciprocal effect of 5-HT2A, 5-HT2C receptor agonists; 3) interaction of 5-HT3 and 5-HT1A-receptors in 5-HT3-induced hypothermia. The review provides converging lines of evidence that: different types and subtypes of 5-HT receptors are involved in the regulation of various kinds of behavior as additive as well as opposite factors providing neuroplasticity, compensatory and adaptive mechanism. PMID- 20968064 TI - [Regulatory role of the immune system in the organism]. AB - The paper presents modern idea of regulatory role of the human immune system in performing a number of physiological functions including intercellular interactions, reproductive process, and forming of protection against external and internal aggression. Significance of the immune system is considered and substantiated, that of genes of the human immune response in particular in provision of human survival as a biological species. PMID- 20968065 TI - [Transformation of physiological gastroprotective effects of glucocorticoids into pathological ulcerogenic consequences]. AB - The study was designed to investigate how physiological gastroprotective action of glucocorticoids could be transformed to pathological proulcerogenic effect. Time-dependent effects of single injection of dexamethasone on stress-induced gastric erosions, corticosterone and blood glucose levels, somatic parameters were investigated in fasted rats. Dexamethasone injected at the same dose attenuated or aggravated the stress-induced gastric erosions depending on the time of the injection. In case of dexamethasone injection 1-12 hrs before stress, we observed its gastroprotective action. Further increase in the time interval caused transformation of the gastroprotective action of dexamethasone to proulcerogenic effect. Accordingly to the results obtained, dexamethasone-induced long-lasting maintenance of blood glucose levels accompanied with signs of catabolic effect as well as dexamethasone-induced corticosterone deficiency may be responsible, at least partly, for the transformation of gastroprotective effect of dexamethasone to the proulcerogenic one. PMID- 20968066 TI - [Syndrome of accelerated aging induced by carcinogenic environmental factors]. AB - The available data on effect of various environmental carcinogenic factors (chemical mutagens, polycyclic aromatic hydrocarbons, nitroso compounds, aromatic amines, tobacco smoking, ionizing radiation, constant illumination, alimentary obesity) upon the organisms suggest that it induces standard pattern of changes at different levels of integration (molecular, cellular, systemic) similar to characteristics of accelerated aging. These changes are favorable to development of age-associated diseases, including cardiovascular those, malignancies, diabetes mellitus type 2, metabolic syndrome, decrease in resistance to stress, immunodepression which lead to life span reduction and premature death. PMID- 20968067 TI - [A protein with missing information about its tertiary structure folds into the compact globular structure]. AB - It has been shown by the methods of hydrodynamics (equilibrium ultracentrifugation, velocity sedimentation, intrinsic viscosity) that a fragment of the structural protein Cafl (Cafl 13.149) from the pili-like fibril Yersinia pestis is in the monomeric state and is capable of forming the compact ternary structure spontaneously, without the involvement of chaperone or other subunits. This happens despite the fact that some information about the ternary structure of this protein is provided in fibrils by the "sticky" segment Alal-Thr12 of the neighboring subunit. As previously shown, it is this segment of another molecule in the norm that is an important element of the ternary structure of the subunit itself since it interacts with the acceptor cleft and participates in the formation of the hydrophobic core. PMID- 20968068 TI - [Long-lived radicals of amino acids induced by X-ray-radiation are the source of hydrogen peroxide in aqueous medium]. AB - The formation of long-lived radicals in the solutions of casein and its hydrolysate with an equimolar mixture of amino acids was compared by measuring the X-ray-induced chemiluminescence. It was shown that free amino acids constituting the protein produce long-lived radicals. It was demonstrated that some amino acids (Leu, Ile, Val, Ser, Trp, Met, Pro, Arg, Gly, Phe) emit light of visible spectrum over a long period of time after the irradiation, which indicates the generation of long-lived radicals of these amino acids. The half life times of these radicals are several hours. Dissolving irradiated dry amino acids capable of luminescing over a long time gives rise to the formation of hydrogen peroxide in aqueous medium. PMID- 20968069 TI - [Thermal stability of lactate dehydrogenase in the complex with the anion polyelectrolyte poly(styrene sulfonate)]. AB - The temperature stability of the cytoplasmic enzyme of the glycolysis of lactate dehydrogenase from a pig muscle (isoenzyme M4) in a complex with the anion polyelectrolyte poly(styrenesulfonate) has been investigated by the methods of adiabatic differential scanning microcalorimetry, the own protein fluorescence, and circular dichroism. Calorimetric investigations of complex of lactate dehydrogenase with poly(styrenesulphonate) in 50 mM phosphate buffer at pH 7.0 have shown that the temperature of the transition and enthalpy of lactate dehydrogenase thermal denaturation sharply decreases with growing weight ratio poly(styrenesulphonate)/lactate dehydrogenase, though at 20 degrees C the enzyme activity of lactate dehydrogenase remains unchanged for several hours irrespective of the addition of poly(styrenesulphonate). The addition of phosphate ions to the solution enhances the resistance of lactate dehydrogenase to both thermal denaturation and inactivation by polyelectrolyte. The data obtained are interpreted from the viewpoint of a special role of two anion binding centers in intersubunits contacts of lactate dehydrogenase, which enhance its resistance to both thermal denaturation and destruction by polyelectrolyte. PMID- 20968070 TI - [Interaction of fibrinogen with magnetite nanoparticles]. AB - The interaction between fibrinogen and magnetite nanoparticles in solution has been studied by the methods of spin labeling, ferromagnetic resonance, dynamic and Rayleigh light scattering. It was shown that protein molecules adsorb on the surface of nanoparticles to form multilayer protein covers. The number of molecules adsorbed on one nanoparticle amounts to approximately 65 and the thickness of the adsorption layer amounts to approximately 27 nm. Separate nanoparticles with fibrinogen covers (clusters) form aggregates due to interactions of the end D-domains of fibrinogen. Under the influence of direct magnetic field, nanoparticles with adsorbed proteins form linear aggregates parallel to force lines. It was shown that the rate of protein coagulation during the formation of fibrin gel under the action of thrombin on fibrinogen decreases approximately 2 times in the presence of magnetite nanoparticles, and the magnitude of the average fiber mass-length ratio grows. PMID- 20968071 TI - [Expression of titin in the myocardium of spontaneously hypertensive rats during in the course of hypertrophy]. AB - Changes in the expression of N2B- and N2BA-isoforms of titin in the left ventricle of the myocardium of spontaneously hypertensive rats during the development of hypertrophy have been analyzed by the methods of real-time scale polymerase chain reaction and SDS gel electrophoresis. It was shown that, in early development of hypertrophy (15-week-old rats), an increase in the expression of mRNA of the titin gene and a decrease in the content of the protein itself occur. At a later stage of development (26-week-old rats), a decrease in the expression of titin at the level of both mRNA and the protein per se was observed. The results obtained can be used in the development of methods for diagnosing the development of myocardium hypertrophy. PMID- 20968072 TI - [Weak coherent radiation of OH and ortho- H2O space masers as a carrier in biocommunication: the ortho/para-conversion of H2O spin isomers?]. AB - A conception of biocommunication based on the principle of radiophysics stating that the carrier modulation takes place at the resonance frequency in the transmission-receiver system has been substantiated and proved. The coherent radiation of space OH-masers (1.6-1.7 GHz) and ortho-H2O-maser (22.3 GHz) is proposed as a source of the carrier frequency. The narrow lines of rotational transition of H2O and OH molecules in liquid water were proposed to be considered as an analog of selective resonances of transmitter and receiver in radiocommunication. The possibility of the ortho-para conversion of H2O spin isomers, induced by weak electromagnetic fields, is discussed. PMID- 20968073 TI - [Possible fundamental unity of magnetobiological "resonances"]. AB - Organisms exposed to a combination of weak, parallel directed static and alternate magnetic fields show a distinct response when the frequency of the alternate component is formally equal to the cyclotron frequencies for Ca2+ or other biologically important ions. It is impossible to explain the observable phenomenon through a magnetoinduced drift of the ions, as the Lorentz's force is too small to change ionic movements. In similar conditions, a resonance-like response arises when the alternate field is tuned to the Larmor frequency for nuclear-spin magnetic moments. The mechanism of these phenomena is also still unclear. In the report, the arguments are presented to treat both types of effects in a single context for which the existence of ion magnetic dipoles is postulated. PMID- 20968074 TI - [Effects and molecular mechanisms of the biological action of weak and extremely weak magnetic fields]. AB - A number of effects of weak combined (static and alternating) magnetic fields with an alternating component of tens and hundreds nT at a collinear static field of 42 microT, which is equivalent to the geomagnetic field, have been found: the activation of fission and regeneration of planarians Dugesia tigrina, the inhibition of the growth of the Ehrlich ascites carcinoma in mice, the stimulation of the production of the tumor necrosis factor by macrophages, a decrease in the protection of chromatin against the action of DNase 1, and the enhancement of protein hydrolysis in systems in vivo and in vitro. The frequency and amplitude ranges for the alternating component of weak combined magnetic fields have been determined at which it affects various biological systems. Thus, the optimal amplitude at a frequency of 4.4 Hz is 100 nT (effective value); at a frequency of 16.5 Hz, the range of effective amplitudes is broader, 150-300 nT; and at a frequency of 1 (0.5) Hz, it is 300 nT. The sum of close frequencies (e.g., 16 and 17 Hz) produces a similar biological effect as the product of the modulating (0.5 Hz) and carrying frequencies (16.5 Hz), which is explained by the ratio A = A0sin omega1t + A0sin omega2t = A0sin(omega1 + omega2)t/2cos(omega1 - omega2)t/2. The efficiency of magnetic signals with pulsations (the sum of close frequencies) is more pronounced than that of sinusoidal frequencies. These data may indicate the presence of several receptors of weak magnetic fields in biological systems and, as a consequence, a higher efficiency of the effect at the simultaneous adjustment to these frequencies by the field. Even with consideration of these facts, the mechanism of the biological action of weak combined magnetic fields remains still poorly understood. PMID- 20968075 TI - [Differences in the Ca2+ signaling in proliferating and differentiating myoblasts in mice]. AB - Specific features of Ca2+ -signaling in proliferating and differentiated C2C12 myoblasts have been studied. It was shown that the system of Ca2+ -signaling is reduced in proliferating myoblasts: the intracellular ATP-regulated stock is insignificant, the buffer protein is absent or present in minimum quantities in endoplasmic reticulum, and the entry of Ca2+ is not registered when its endocellular stocks are exhausted. The formation of the Ca -signaling system occurs during the initial stages of differentiation (within eight to ten hours after transfer of cell to differentiation medium). During this period, the buffer protein is accumulated, and the entry of Ca begins. During the initial stages of myoblast differentiation, the voltage-dependent entry of Ca2+ also appears. It was also shown that the stock of in mitochondria makes an insignificant contribution to increase in Ca2+ concentration in the cytoplasm. PMID- 20968076 TI - [Responses of thymocytes and splenocytes to low-intensity extremely high frequency electromagnetic radiation in normal mice and in mice with systemic inflammation]. AB - Changes in T cell subsets and expression of cytokine genes in thymocytes and splenocytes after exposure of BAL/c mice to low-intensity extremely high frequency electromagnetic radiation (42.2 GHz, 0.1 mW/cm2, exposure duration 20 min) under normal conditions and in systemic inflammation were studied using flow cytometry and the methods of reverse transcription and real-time polymerase chain reaction. It was found that the number of CD4+ and CD8+ T cells statistically significantly increased in the thymus and considerably decreased in the spleen of exposed animals. Apparently, the exposure of animals leads to an intensification of the host defense, by activating the T-cellular immunity. As for effector functions, the increased expression of IL-1beta and IFNgamma genes in thymocytes and essentially enhanced expression of IL-1beta, IL-10, and TNFalpha genes in splenocytes were observed in mice exposed against the background of a progressive inflammatory process. The experimental data obtained specify that the directed (anti-inflammatory) response of an organism to a specific combination of effective exposure parameters of electromagnetic radiation can be realized by the activation of particular immunocompetent cells and changes in the cytokine profile. PMID- 20968077 TI - [Changes in the electrophoretic mobility of erythrocytes by the action of low intensity pulse magnetic field]. AB - It has been shown that the exposure of "intact" rats and human blood to low intensity pulse magnetic field leads to similar changes in the electrophoretic mobility of erythrocytes, which may be connected with the modification of the spectrum of their membrane proteins. PMID- 20968078 TI - [Effects of weak magnetic fields on the production of reactive oxygen species in peritoneal neutrophils in mice]. AB - The influence of weak magnetic fields of different types on the rate of the formation of reactive oxygen species in mouse peritoneal neutrophils has been studied. It was found that the exposure of neutrophils activated by phorbol 12 myristate 13-acetate to the magnetic field tuned to the parametric resonance for Ca2+ ions leads to a decrease in the rate of the reactive oxygen species (ROS) generation by 23%. Conversely, the generation of ROS in neutrophils exposed to the same field but stimulated by the bacterial peptide FMLP (N-formyl-L-methionyl L-leucyl-L-phenylalanine) increased by about 21%. Pulsed magnetic fields also changed the rate of ROS generation in phorbol-stimulated neutrophils by about 20%, but the sign of the effects observed in this case was opposite to those induced by the magnetic field tuned to the parametric resonance for Ca2+ ions. PMID- 20968079 TI - [Firing-rate model of a population of adaptive neurons]. AB - A firing rate (FR) model for a population of adaptive integrate-and-fire (IF) neurons has been proposed. Unlike known FR models, it describes more precisely the unsteady firing regimes and takes into account the effect of slow potassium currents of spike-time adaptation. Approximations of the adaptive channel conductances are rewritten from voltage-dependent to spike-dependent and then to rate-dependent ones. The proposed FR model is compared to the very detailed population model, namely, the conductance-based refractory density model. The comparison of this model with the full RD model shows the coincidence of the first peak of activity after the start of stimulation as well as the stationary state. As an example of the simulation of coupled adaptive neuronal populations, a ring model has been constructed, which reproduces a visual illusion named tilt after-effect. The FR model is recommended for the mathematical analysis of neuronal population activity as well as for computationally expensive large-scale simulations. PMID- 20968080 TI - [Trigger regime of the functioning of a synaptic channel]. AB - It has been shown using the linear model describing the dynamics of biochemical reactions occurring in a synapse that, as periodic step-like impulses pass through a synaptic channel, it operates in the triggering regime. The transmission of an impulse through the channel is associated with the change of the stationary point of the corresponding dynamic system compared with the unexcited state of the synapse. As a result, the system periodically evolves between two stable stationary states. PMID- 20968081 TI - [Formation of the photosensing system function in early development]. AB - The function of simple prototypic eyes in two planarian species, the two ocular Girardia tigrina and the multiocular Polycelis tenuis, has been studied. When exposed to light, planarians display the light avoidance reaction known as negative phototaxis. This reaction has been investigated in intact animals and in head and tail fragments after their section in the course of eye regeneration. Specific features of the phototaxis reaction have been described in all groups of animals. The differences in light response recovery were shown between two planarian species and two regenerating fragments. No correlation between phototaxic reactions and the restoration of the eye structure, the number of eyes, the maturation of ganglion, the growth of regenerative blastema, and motor system has been found. The phototaxic response occurred two days after the recovery of the morphology of eyes and their connection with the brain. The participation of conserved and novel genes in early development of the eye function is discussed. PMID- 20968082 TI - [Nitrites can be reduced in retinal vessels during hypoxia and protect the retina against ischemia and apoptosis]. AB - The possibility and the mechanism of the reduction of nitrites in retinal vessels under the acute hypoxia in vivo have been investigated. An experimental model of the rat retina ischemia was elaborated using the laser coagulation of retinal vessels. It was demonstrated that the vessel thrombosis does not occur if the nitrite concentration in the vessels is increased. It was proposed that, under acute hypoxia, nitrites are reduced to NO, which results in a drastic vasodilatation. Considering that the effect takes less than a minute, this reduction cannot be due to hypoxic acidosis but is more likely associated with NO reduction by heme proteins. It was found that the increased concentration of nitrites protects the retina from the development of ischemia progress and that the preliminary administration of nitrites prevents apoptosis in the retina and a decrease in its photoelectric activity. PMID- 20968084 TI - [Effect of the impulse magnetic field on the growth bone plates in experimental animals]. AB - The influence of impulse magnetic field (1.5 T) on growth bone plates of the rabbit has been studied. It has been found that this field produces the inhibitory action on the functional activity of growth bone plates. PMID- 20968083 TI - [Effect of a model of the H-component of a typical magnetic storm on early ontogenesis in Daphnia magna Straus]. AB - The effect of a model of the H-component of a typical magnetic storm on the early ontogenesis of Daphnia magna Straus at 21 and 23 degrees C has been studied. It was shown based on the rates of the early ontogenesis that the effects of the model magnetic storm from the sudden onset of the storm to its end differ from the effects of the model magnetic storm from the recovery phase to the end of the storm. The effects of the model magnetic storm depended on temperature. The action of the model magnetic storm from the sudden onset of the storm to its end led to changes in the body length in the first progeny broods. PMID- 20968085 TI - [Effect of the extremely weak alternating magnetic fields on the regeneration of planarians and the gravitropic response of plants]. AB - The influence of extremely weak alternating magnetic fields (EW AMF) directed colinearly to the static Earth magnetic field on the rate of regeneration of planarians and the rate of gravitropic response in the stem segments of flax has been studied. The value of bioeffects of EW AMF is determined by the parameter gamma B(AC)/f, where y is the gyromagnetic ratio of the magnetic moments induced by the orbital movements of electrons in atoms, and B(AC) and f correspond to magnetic induction and frequency of the alternating magnetic component. It was shown that the magnitude of bioeffects depends on the amplitude (at fixed 1000 Hz - frequency) and frequency (at fixed 192 nT - amplitude) of the alternating component. Maxima of bioeffects are observed at gamma B(AC)/f = 0.9; 2.75, and minor maxima gamma B(AC)/f = 4.5; 6.1. The bioeffects are absent at gamma B(AC)/f = 1.8, 3.8, 5.3, 6.7. The positions of the maxima and minima of bioeffects correspond to the theoretical prediction (at gamma = 14000 Hz/microT). Primary targets for the EW AMF of this type are the magnetic moments induced by the orbital movements of electrons in atoms. PMID- 20968086 TI - [Seasonal differences in the regeneration of planarians subjected to long-term electromagnetic shielding]. AB - It has been found that the regeneration of planarians is most intensive in summer and least intensive in winter. In spring and autumn, the index of regeneration and the velocity of movement are higher than in winter but lower than in summer. Long-term electromagnetic shielding modifies the intensity of regenerative processes, and this effect is season-dependent. The stimulation is most clearly pronounced in winter and least pronounced in sommer and decreases with increasing duration of shielding. In spring, only a tendency to the stimulation of regeration is observed, which increases with the length of the observation period. PMID- 20968087 TI - [Effect of weak combined magnetic fields on the metamorphosis of the meal-worm beetle Tenebrio molitor]. AB - The effects of weak combined magnetic fields adjusted to the parametric resonance for Ca2+ and K+ and extremely weak alternating magnetic field on the metamorphosis of the meal-worm beetle Tenebrio molitor have been studied. It was shown that the exposure of pupas of insects to all above-indicated types of fields stimulates the metamorphosis. However, after the exposure to weak combined magnetic fields adjusted to the parametric resonance for Ca2+ and K+, the number of insects with anomalies increases, which is not observed by the action of the weak alternating magnetic field. PMID- 20968088 TI - [Effect of the low-frequency impulse magnetic field on the autonomic nervous system in animals]. AB - The effect of weak (up to 3.5 mT) low-frequency (up to 100 Hz) impulse magnetic field on the state of the vegetative nervous system of animals has been studied by analyzing the variability of the heart rate. The effect of the magnetic field was estimated by a specially designed complex for recording cardiac signals of animals. Several specially selected regimes of impulse magnetic fields were studied. It was shown that the impulse magnetic field possesses a high biological activity at all regimes used, and the indices of the vegetative nervous system after the exposure to the impulse magnetic field approach the values typical for normotonic animals. This makes it possible to use magnetic fields at these regimes in magnetotherapy. PMID- 20968089 TI - [Heat communication signals between maturing and adult bees that are used in thermoregulation]. AB - New types of signals triggering the hereditable programed mechanism of the heating of the sealed brood in honey bees have been discovered. The reactions of maturing bees to the heating have been investigated by the thermal imaging and calorimetric methods. The behavior of bees upon heating and cooling of brood cells has been modeled. The ability of adult bees to distinguish between alive and died pupae located in sealed cells was found. PMID- 20968090 TI - [Relation between microcirculation parameters and Pc3 geomagnetic pulsations]. AB - An individual analysis of long-term monitoring of microcirculation parameters of nine healthy volunteers showed that an increase in the geomagnetic activity led to an increase in tissue perfusion, variability of blood flow and growth of the amplitude of neurogenic and myogenic oscillations in four volunteers. It was found that the degree of microcirculation sensitivity to the level of geomagnetic activity values with time and is proportional to its average level in the period of measurement. A comparison of frequency ranges of oscillations of blood flow and variations of the geomagnetic activity shows that neurogenic and myogenic oscillations showing the highest sensitivity to the geomagnetic activity have the same frequency as geomagnetic Pc3 pulsations. The pulsations of this frequency range are excited mainly during geomagnetic disturbances, which may explain the correlation between the microcirculation parameters and the Kp index. The relation of the amplitude-frequency characteristics of Pc3-pulsations can explain the results obtained using the alternating magnetic fields. PMID- 20968091 TI - [Quantum mechanical aspects of effects of weak magnetic fields upon biological objects]. AB - Possible mechanisms of action of weak combined magnetic fields on biological systems have been discussed in terms of quantum mechanics. The approaches proposed make it possible to solve the problem of the failure to compare the energy of active factors with the energy of thermal motion (kT problem). A mechanism of action of combined magnetic fields on biosystems has been proposed. PMID- 20968092 TI - [Lednev's model: theory and experiment]. AB - The results of theoretical and experimental investigations of V.V. Lednev on interactions of weak and extremely weak magnetic fields with biosystems have been reviewed. The period since 1989, when the first version of the interference model has been suggested, until now has been considered. Some mathematical expressions, are presented, which have been published earlier in the papers that are now bibliographic rarity. The results of experimental investigations are also summarized that have been performed in this period under the supervision of V.V. Lednev in the laboratory of biophysics of intracellular regulation in the Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences. PMID- 20968093 TI - [Nuclear protein matrix from giant nuclei of Chironomus plumosus determinates polythene chromosome organization]. AB - Giant nuclei from salivary glands of Chironomus plumosus were treated in situ with detergent, 2 M NaCl and nucleases in order to reveal residual nuclear matrix proteins (NMP). It was shown, that preceding stabilization of non-histone proteins with 2 mM CuCl2 allowed to visualize the structure of polythene chromosomes at every stage of the extraction of histones and DNA. Stabilized NPM of polythene chromosomes maintains their morphology and banding patterns, which is observed by light and electron microscopy, whereas internal fibril net or residual nucleoli are not found. In stabilized NPM of polythene chromosomes, topoisomerase IIalpha and SMC1 retain their localization that is typical of untreated chromosomes. NPM of polythene chromosomes also includes sites of DNA replication, visualized with BrDU incubation, and some RNA-components. So, we can conclude that structure of NPM from giant nuclei is equal to NPM from normal interphase nuclei, and that morphological features of polythene chromosomes depend on the presence of NMP. PMID- 20968094 TI - [Nuclear heterogeneity and proliferative capacity of human adipose derived MSC like cells]. AB - Adipose derived stem cells (ADSCs) are MSC-like cells which could be easily used for regenerative medicine. Here, the morphology and proliferative capacity of human ADSCs is discribed. ADSCs were analyzed after one month of cultivation at a density of 10 cells/cm2. 21 colonies were counted. Few atypical cells (huge nuclei and cytoplasm) were found in 9 out of 17 colonies analyzed. ANOVA demonstrated that colonies also differed (P = 0.0025) in nuclei dimensions and scatter in the dimensions in each colony. Nuclei dimensions and cell density logarithms correlated in reverse proportion (-0.7; P = 0.002). Thus, ADSCs were heterogeneous and represented two types of cells: small highly proliferative and large low proliferative cells. Cell heterogeneity observed in some colonies might be due to cells registered at different cell cycle phases. Stable and typical morphology, colony-formation capability and high proliferative capacity of cells indicate visceral adipose tissue as a rich source of ADSCs. PMID- 20968095 TI - [Human subcutaneous adipose tissue subjected to cold shock as a source of viable cellular population with characteristics of multipotent mesenchymal stromal cells]. AB - Cellular population with characteristics of multipotent mesenchymal stromal cells (MMSCs) was isolated from subcutaneous adipose tissue frozen without any cryoprotectant at -70 degrees C. Under critical for the adipose tissue condition, the cells retained their viability in vitro and ability of adhesion to plastic. Cellular population was homogeneous and represented by small cells (d - 7 microm) with fibroblast-like morphology. Cells were positively stained with Abs for the Abs: CD29, CD44, CD49a, b, d, CD73, CD90, CD105, CD166, HLA ABC. Cells were negative for CD34, CD45--markers of hematopoietic cells, CD31--marker of endothelial cells, Stro-1, as well as for HLA DR, DP, DQ (flow cytometer analysis). Being induced to differentiate in vitro, the cells were able to differentiate into cells similar to cells of bone, adipose and cartilage tissue. Karyological assay of the cells isolated from human adipose tissue subjected to cold shock revealed diploid set of chromosomes, 46, XX, without aneuploidy and structural reconstructions of chromosomes. Thus, it has been established that, under extreme condition for the organism, the population of cells with a phenotype similar to miltipotent mesenchymal stromal cells is preserved in subcutaneous adipose tissue. PMID- 20968096 TI - [Changes in the proportion of A- and B-types of granules containing atrial and brain natriuretic peptides in atrial myocytes in vasorenal hypertension in rats]. AB - The system of cardiac natriuretic peptides (NP) is a very important factor opposing the effects of the rennin-angiotensin-aldosterone system (RAAS), sympathoadrenal system and vasopressin to reduce blood pressure. In the present study, we analyzed the release of atrial and brain natriuretic peptides in the myocytes of the right atrium in rats by the quantitative morphometric method using double immunocytochemical labeling of atrial granules comprising NP in vasorenal hypertension induced by the renal artery ligation. The decrease in the total amount of secretory granules in atrium myocytes by 18% was detected on the 30th day after the operation. The number of the A-type granules was reduced by 53%, and the number of B-type granules was increased by 64% in comparison with the intact animals. Our data indicate activation of NP secretion in vasorenal hypertension. The results suggest that high arterial pressure might be explained by reduced expression of NP receptors in this pathology. PMID- 20968097 TI - [Ratio of 3' --> 5'-exonuclease and DNA-polymerase activities in normal and cancer cells of rodents and humans]. AB - Mutations in the genes of corrective 3' --> 5'-exonucleases as well as in DNA polymerases lead to decrease in DNA biosynthesis accuracy all over genome. This is accompanied by the increase in mutagenesis and carcinogenesis probabilities. In this work, the activities of 3' --> 5'-exonucleases and DNA polymerases were studied in the extracts from normal and cancer cells of rodents and humans, and we are the first to measure their integral ratios. As example, in cultivated dermal fibroblasts of an adult human, the value of the ratio of activities of 3' -> 5'-exonucleases to DNA polymerase activity (3'-exo/pol) surpassed several folds the such a value for HeLa cells. Similar picture was observed during the comparison of normal fibroblasts of rat embryos and transformed fibroblasts of Chinese hamster A238. Experiments with cell-free extracts of some organs from healthy rats of various ages have shown that normal proliferating cells demonstrate higher 3' --> 5'-exonuclease activity and higher values of 3'-exo/pol that quiescent cells. Comparison of these data suggests a violation of the function of corrective 3' --> 5'-exonucleases in abnormally growing cancer cells. PMID- 20968098 TI - [Science in general practice]. PMID- 20968099 TI - [Rather entrepreneur than dentist]. PMID- 20968100 TI - [The criminal according to Cesare Lombroso]. PMID- 20968101 TI - [Diagnostics and treatment of esophageal cancers]. AB - The incidence of esophageal cancer has increased markedly during the past 3 decades, especially due to an increase of the incidence of adenocarcinoma. The prognosis for patients with esophageal cancer is poor, with a 5-year survival rate of 10-25%. The important risk factors for esophageal squamous cell carcinoma are smoking and alcohol intake. Esophageal adenocarcinomas are related to gastro esophageal reflux disease. The diagnostic procedures are not only focused on obtaining diagnoses, but also on determining how advanced the tumor is. If a patient is fit enough to undergo surgery and no evidence is found that the tumor has spread to adjacent organs or that there are distant metastases, a surgical resection is the primary treatment. In case surgical resection is not an option, palliative treatment is generally needed to reduce the complaints of dysphagia. The improvement or maintenance of the quality of life and symptom-control are important goals of both curative and palliative treatment of esophageal cancer. PMID- 20968102 TI - [A foreign body in the tongue]. AB - A 3-year-old boy was referred to the emergency department of a medical centre because of a local swelling of the tongue. Radiographic imaging concluded that it concerned a complete tooth, which had been overlooked during an earlier visit to the same department. The foreign body was removed easily under general anaesthesia. A foreign body in the lip is a feature frequently seen by family physicians and in emergency departments of medical centres. However, a foreign body in the tongue is, by contrast, less often reported. Physical examination is the key factor in diagnostics. When in doubt, a radiograph should be made. PMID- 20968103 TI - [Management for displacement of a tooth into the floor of the mouth]. AB - Displacement of a (part of a) radix or in some cases a part of a tooth into the floor of the mouth can occur during the extraction of a tooth in the mandibula. Possible causes of this are a lingual perforation of the radices or an inappropriate surgical technique. Leaving a fragment in situ in the floor of the mouth can lead to pain, swelling and trismus as a result of infection and/or spontaneous displacement of the fragment. We advise that the tooth or radix be removed as soon as possible. When experience is lacking in the removal of a tooth or radix from the floor of the mouth it is sensible to refer the patient to an oral surgeon. We also advise prescribing antibiotics in order to prevent infection. PMID- 20968104 TI - [Dental students on instruction in local anaesthesia]. AB - In order to find out how dental students feel about their education in the application of local anaesthesia, a questionnaire was distributed via e-mail among all dental students in the Netherlands. A total of 397 completed questionnaires were analyzed statistically. At all 3 dental schools in the second year instruction in theoretical aspects of local anaesthesia began. Practical teaching began in the second or third study year. A preclinical training model was used by 15% of the students in Amsterdam, 20% of the students in Nijmegen and 35% of the students in Groningen. When they administered their first injection in a human, a fellow dental student in 91-98% of all cases, 24-74% of the students felt that they were insufficiently prepared. 35-52% of the students said that they would also like to receive instruction in intraligamentary anaesthesia in the dental curriculum. Other changes in the curriculum were also frequently suggested, especially the introduction of preclinical training models (29%, 55% and 56% for Groningen, Nijmegen and Amsterdam respectively). PMID- 20968105 TI - [Theses 25 years after date 23. Developments in the prevention and treatment of xerostomia]. AB - Twenty-five years ago, the treatment of xerostomia was predominantly symptomatic. At that time, the treatment possibilities were mainly sialogogues, mouthrinses and saliva substitutes. Since then, there have been few changes in the symptomatic treatment of xerostomia. Methods to prevent the development of xerostomia or to reduce its severity were then in their infancy and methods aiming to regenerate a damaged salivary gland did not exist. During the last 2 decades, however, great changes have taken place. New radiation techniques reducing the cumulative dose on salivary glands have been introduced. At the moment techniques are being developed to regenerate the secretory potential of a salivary gland damaged by radiotherapy. In addition, biologicals have recently been introduced which make it possible to intervene in the process of disease associated with Sjogren's syndrome, by means of which here, too, a degree of regeneration of function can be achieved. PMID- 20968106 TI - Physiology of water motion detection in the medicinal leech. AB - 1. Neuronal activity resulting from stimulation by water waves occurs in ventral nerve cord-body wall preparations of the medicinal leech,Hirudo medicinalis. In segmental nerves, this activity consists of afferent compound action potentials with graded amplitudes resulting from simultaneous action potentials in many small sensory axons. Afferent input impinging on one segmental ganglion activates neuronal activity along much of the ventral nerve cord. 2. Previously identified tactile mechanoreceptors are insensitive to low-amplitude wave stimulation. Touch cell impulse activity can be evoked by moderate or strong wave stimulation, but these impulses appear to arise near the cell body, not from the peripheral receptor endings. 3. The transduction sites for wave stimulation are localized at or very near the segmental sensilla. Because of their location and modality the receptors were named 'sensillar movement receptors' (SMR). 4. S cells (Rohde's fibre) receive suprathreshold excitatory input during SMR activation without concomitant activity in the tactile mechanoreceptors. 5. The annulus erector motor neurones contralateral to the afferent SMR inflow are inhibited by SMR activation. This inhibition is also observed in ganglia adjacent to the ganglion receiving the afferent input and provides a neuronal basis for reflexive smoothing of the leech body wall. 6. Two neurones in the anterior median packet of segmental ganglia receive powerful synaptic input during SMR activation. One, cell 202,receives 10 mV excitatory potentials while the other, cell 201, receives 10 mV inhibitory potentials. PMID- 20968107 TI - A sensory system initiating swimming activity in the medicinal leech. AB - 1. Water-wave stimulation, which was previously shown to elicit swimming in intact leeches, can initiate swimming in a semi-intact leech preparation via activation of the sensillar movement receptors (SMRs), provided that 50 micron serotonin is added to the physiological saline. 2. The neuronal responses resulting from near-field stimulation of the leech body wall with a vibrating probe were recorded in peripheral nerves and in nerve-cord connectives. The response in the dorsal posterior nerve to a single vibratory pulse consists of a graded compound action potential.The units contributing to this action potential have a much lower threshold for near-field stimulation than do touch cells. They appear to be the same sensory units, the SMRs, that mediate leech sensitivity to water waves. 3. The frequency domain of the SMR sensitivity extends as low as 1 Hz. Thus, leeches could receive self-stimulation from the water vibrations created by their own swimming movements. 4. Leech physiological saline containing 20-40 m-Mg2 does not eliminate the SMR response to near-field stimulation recorded in the DP nerve;however, elevated Mg2 concentrations do eliminate the neuronal responses in the nerve cord connectives. Thus, while no chemical synapse occurs between the peripherally situated SMRs and nerve cord ganglia, a synapse may be interposed between the SMRs and the intersegmental neurones activated by near-field stimulation.5. The swim-facilitating action of serotonin occurs at unidentified sites within the ventral nerve cord, since serotonin does not alter the sensitivity of the SMRs. PMID- 20968108 TI - Hereditary arrhythmia corner: learning from challenging patients. Family with suspect LQTS. AB - A brother and sister, presented to our Arrhythmia Clinic for evaluation of possible long QT syndrome (LQTS). They are 18 and 15 years of age, respectively. Their mother has been diagnosed with LQTS and the family history is remarkable for a number of sudden deaths. The electrocardiogram (ECG) of the sister is presented in Figure 1. The siblings had been followed by pediatric cardiology since infancy and now they are referred for further evaluation. They are both asymptomatic and very active teenagers, and are not on any medications. Echocardiograms were normal. Holter monitoring also did not show any rhythm abnormalities in either sibling.The mother had been evaluated as a teenager when she had a presyncopal episode while running track in high school. Her QT interval on one 12-lead tracing showed borderline prolonged QT. She had originally been started on beta-blockers, but she had taken herself off of these over the years. The family history is significant for sudden deaths in several distant relatives. In addition, the mother's aunt had an abnormal ECG in the setting of multiple syncopal episodes. In the interim, she had been treated with beta-blockers. PMID- 20968109 TI - Canadian Health Measures Survey results - oral health statistics, 2007-2009. PMID- 20968110 TI - Matching the numerator with an appropriate denominator to demonstrate low amputation incidence associated with a London hospital multidisciplinary diabetic foot clinic. AB - AIMS: To establish a method to assess amputation incidence that addresses the problems matching a numerator with an appropriate denominator in London and to demonstrate low amputation incidence associated with the activity of our multidisciplinary diabetic foot clinic. METHODS: Hospital-coded inpatient data was examined to derive the numerator: the number of non-traumatic amputations performed on subjects with diabetes each financial year where the Primary Care Trust commissioner code was our main local Primary Care Trust. Denominators were derived from the main local Primary Care Trust's Quality and Outcomes Framework data sets. Not all Primary Care Trust subjects with diabetes receive inpatient care at our hospital, so that the denominators were corrected for the hospital's percentage market share for the provision of inpatient diabetes care for the Primary Care Trust each financial year, derived from the Dr Foster database. RESULTS: Between April 2004 and April 2009, 44 Primary Care Trust subjects with diabetes underwent 34 minor and 10 major amputations at the hospital. Although the Primary Care Trust populations with and without diabetes increased, the hospital's Primary Care Trust percentage market share decreased, so that overall denominators decreased. The mean annual incidence of minor, major and total amputations over the five financial years was 14.7, 4.2 and 18.9 per 10 000 subjects with diabetes,respectively, and 3.9, 1.1 and 5.0 per 100 000 of the general population, respectively. CONCLUSIONS: We report for the first time amputation incidence in a London population. Acknowledging the limitations of accurately defining incidence in London, we demonstrate low amputation incidence associated with our multidisciplinary diabetic foot clinic. PMID- 20968111 TI - High prevalence of diabetes mellitus in patients with liver cirrhosis. AB - AIMS: The reported prevalence of Type 2 diabetes mellitus in patients with liver cirrhosis is five times higher than in the general population. However, these data were never adjusted for classical risk factors for Type 2 diabetes. We therefore investigated the association between cirrhosis and Type 2 diabetes and adjusted for known risk factors for Type 2 diabetes. METHODS: We reviewed medical files for presence of Type 2 diabetes and potential confounders in 94 patients with cirrhosis (cases) and compared these with a control group of 107 patients with non-ulcer dyspepsia. Multiple logistic regression analysis was used to adjust for potential confounders. RESULTS: The aetiology of our cirrhosis population was alcohol (59%), viral hepatitis (10%), biliary cirrhosis (3%) or cryptogenic (28%). Prevalence of Type 2 diabetes was significantly higher in patients with cirrhosis than in control subjects: 35/94 (37%) vs. 7/107 (7%) (OR 8.5, 95% CI 3.5-20.2, P < 0.001). After adjustment for age, sex, family history of Type 2 diabetes, alcohol use and BMI, cirrhosis remained significantly associated with Type 2 diabetes (OR 13.6, 95% CI 4.3-42.9, P < 0.001). Most cases of Type 2 diabetes were already diagnosed before diagnosis of cirrhosis (21/35, 60%) or were incidentally found together with cirrhosis (5/35, 14%). CONCLUSIONS: Liver cirrhosis had a strong, independent association with Type 2 diabetes. Classical risk factors such as family history and BMI could not explain the high Type 2 diabetes prevalence in cirrhosis. Therefore, a liver-derived factor might aggravate glucose intolerance and cause Type 2 diabetes in cirrhosis. In addition, Type 2 diabetes might also cause cirrhosis through liver steatosis and fibrosis. PMID- 20968112 TI - Regression to normoglycaemia by fenofibrate in pre-diabetic subjects complicated with hypertriglyceridaemia: a prospective randomized controlled trial. AB - AIMS: Lipotoxicity has recently been shown to be an important risk factor underlying the pathogenesis of pre-diabetes. However, clinical evidence supporting the treatment of pre-diabetes by improving lipotoxicity is lacking. Here, we conducted an open-label, randomized, controlled trial to investigate whether fenofibrate, the widely used hypolipidaemic agent, might benefit pre diabetes, with metformin and diet control, the recommended intervention methods, as positive controls. METHODS: Newly diagnosed pre-diabetes patients (n = 120) with hypertriglyceridaemia (plasma triglyceride levels between 1.8 and 4.5 mmol/l) were randomly assigned by computer-generated randomization sequence to either control group (no intervention), fenofibrate group (200 mg once a day), metformin group (500 mg three times a day) or diet-controlled group (diet recommendation). Plasma biochemistry examination was performed every 2 months. The primary endpoint was the outcome of the natural course of pre-diabetes, evaluated by oral glucose tolerance test after 6-month follow-up. RESULTS: Twenty subjects in the fenofibrate group, 24 subjects in the metformin group and 25 subjects in both the diet-controlled group and the control group finished the trial. Fenofibrate, metformin and diet control had protective effects on hypertriglyceridaemic pre-diabetes, evidenced by 53.3, 70 and 30% participants regressed to normoglycaemia, respectively. The effects of fenofibrate and metformin were comparable (P > 0.05), while diet control was less effective (P < 0.05). Liver damage occurred in six subjects in the fenofibrate group and gastrointestinal symptoms occurred in four subjects in the metformin group. No serious adverse events occurred. CONCLUSION: Controlling lipotoxicity by fenofibrate could effectively ameliorate the natural course of hypertriglyceridaemic pre-diabetes. PMID- 20968113 TI - High-cocoa polyphenol-rich chocolate improves HDL cholesterol in Type 2 diabetes patients. AB - AIM: To examine the effects of chocolate on lipid profiles, weight and glycaemic control in individuals with Type 2 diabetes. METHODS: Twelve individuals with Type 2 diabetes on stable medication were enrolled in a randomized, placebo controlled double-blind crossover study. Subjects were randomized to 45 g chocolate with or without a high polyphenol content for 8 weeks and then crossed over after a 4-week washout period. Changes in weight, glycaemic control, lipid profile and high-sensitivity C-reactive protein were measured at the beginning and at the end of each intervention. RESULTS: HDL cholesterol increased significantly with high polyphenol chocolate (1.16 +/- 0.08 vs. 1.26 +/- 0.08 mmol/l, P = 0.05) with a decrease in the total cholesterol: HDL ratio (4.4 +/- 0.4 vs. 4.1 +/- 0.4 mmol/l, P = 0.04). No changes were seen with the low polyphenol chocolate in any parameters. Over the course of 16 weeks of daily chocolate consumption neither weight nor glycaemic control altered from baseline. CONCLUSION: High polyphenol chocolate is effective in improving the atherosclerotic cholesterol profile in patients with diabetes by increasing HDL cholesterol and improving the cholesterol:HDL ratio without affecting weight, inflammatory markers, insulin resistance or glycaemic control. PMID- 20968115 TI - Chronic kidney disease is but one of the many global threats to health. PMID- 20968114 TI - Patient safety systems in the primary health care of diabetes-a story of missed opportunities? AB - AIMS: Key elements of a patient safety system include mechanisms for identifying errors or safety events, methods for investigating the events and processes for acting on the findings of the investigations. A patient safety system for management of diabetes in primary care might help to reduce adverse outcomes. The aims of this study were to review the current state of research into patient safety systems for people with diabetes in primary care. METHODS: MEDLINE, EMBASE and nine other biomedical and health management databases were searched for articles published up to April 2009. Selection and review of abstracts were carried out independently by two authors. RESULTS: Abstracts of 1659 articles were identified, of which only three fulfilled the selection criteria, and these did not appear in mainstream primary care journals. These papers covered the applications of root cause analysis, videoconferencing and automated telephone support to patient safety systems for managing diabetes in primary care. CONCLUSIONS: There is very little evidence on how patient safety systems for the management of primary care diabetes can be implemented, or on how the effectiveness of such systems can be maximized. If patient safety systems do have potential to improve the processes and outcomes of care, the lack of relevant research may be regarded as a missed opportunity-investigation into the reasons for the situation is needed, with the aim of motivating and enabling further research on a range of problems identified here. PMID- 20968116 TI - Cardiac tumor. PMID- 20968118 TI - Commentary on fundamental approaches in the treatment of suspected mild-to moderate traumatic brain injury. PMID- 20968119 TI - To stent or not to stent: The question remains unanswered: Comment on "Secondary stroke prevention in the era of carotid stenting". PMID- 20968120 TI - Are surgeons ready to embrace a paradigm shift in surgical comparative effectiveness research?: Comment on "Introduction to propensity scores". PMID- 20968121 TI - Surgeon, do you know where your DALYs are?: (Can you fix a hernia with a mosquito net?): Comment on "Cost-effectiveness of groin hernia surgery in the Western Region of Ghana". PMID- 20968122 TI - Gastric remnant cancer: Is elimination of the bug the answer?: Comment on "Screening of Helicobacter pylori infection after gastrectomy for cancer or peptic ulcer". PMID- 20968123 TI - The hazard of more reporting in quality measurement: Comment on "Wrong-site and wrong-patient procedures in the universal protocol era". PMID- 20968124 TI - Center of excellence designation: Pros and cons: Comment on "Reduced access to care resulting from centers of excellence initiatives in bariatric surgery". PMID- 20968125 TI - "Say it ain't so, Joe": Comment on "Hospital process compliance and surgical outcomes in medicare beneficiaries". PMID- 20968126 TI - Paradigm shift in the treatment of blunt aortic injury: A good thing: Comment on "Thoracic aortic endografting for trauma". PMID- 20968127 TI - [Abstracts of the Czech Gynecologic and Obstetric Society Congress held on June 3 2010 in Karlovy Vary]. PMID- 20968128 TI - Barriers in cervical cancer screening programs in new European Union member states. PMID- 20968129 TI - Trends in cervical cancer incidence and mortality in Bulgaria, Estonia, Latvia, Lithuania and Romania. AB - OBJECTIVE: The burden of cervical cancer varies considerably in the European Union. In this paper, we describe trends in incidence of and mortality from this cancer in the five most affected member states. METHODS: Data on number of deaths from uterine cancers and the size of the female population of Estonia, Latvia, Lithuania, Bulgaria and Romania were extracted from the WHO mortality database. Mortality rates were corrected for inaccuracies in the death certification of not otherwise specified uterine cancer. Incidence data were obtained from the national cancer registries. Joinpoint regression was used to study the annual variation of corrected and standardized incidence and mortality rates. Changes by birth cohort were assessed for specific age groups and subsequently synthesized by computing standardized cohort incidence/mortality ratios. RESULTS: Joinpoint regression revealed rising trends of incidence (in Lithuania, Bulgaria and Romania) and of mortality (in Latvia, Lithuania, Bulgaria and Romania). In Estonia, rates were rather stable. Women born between 1940 and 1960 were at continuously increasing risk of both incidence of and mortality from cervical cancer. CONCLUSIONS: Rising trends of cervical cancer in the most affected EU member states reveal a worrying pattern that warrants urgent introduction of effective preventive actions as described in the European guidelines. PMID- 20968130 TI - Impact of implementing a nationwide cervical cancer screening program on female population coverage by Pap-tests in Estonia. AB - BACKGROUND: The objective of the EUROCHIP project in Estonia was to describe the organized cervical cancer screening program started in 2006 (after pilot studies in 2003-2005), to compare its performance with opportunistic screening, and to define priorities for improvement of the program. METHODS: Population data was retrieved from Statistics Estonia, data about performed Pap-smear tests within the screening program from the Estonian Cancer Society and from clinics and labs participating in the program, data about Pap-smear tests outside the screening program from the Estonian Health Insurance Fund, and data about cancer incidence and mortality from the Estonian Cancer Registry database. RESULTS: During the first year after implementing the nationwide cervical cancer screening program in Estonia, the number of tests outside the organized program remained high. Within the organized program, the number of Pap-tests in different age groups increased with age except for the oldest age group while population coverage with Pap-tests outside the organized screening program decreased with age. The number of cervical cancer cases at early stages increased after implementation of organized screening. The time-frame does not permit to draw any definitive conclusions. CONCLUSIONS: Implementation of organized cervical cancer screening did not decrease the volume of opportunistic screening. The factors influencing attendance in the organized cervical cancer screening program in different age groups should be studied further. Moreover, a central cancer screening registry without restrictive data protection legislation would improve data collection and enable to evaluate performance of the program on a regular basis. PMID- 20968131 TI - Past, present and future of the cervical cancer screening in Latvia. AB - OBJECTIVE: The present descriptive study summarizes the historical activity on cervical cancer screening in Latvia, assesses the current screening situation, and defines the existing and expected obstacles and problems for the implementation of a proper organized population-based cervical cancer screening program in Latvia. MATERIAL AND METHODS: Available data on cervical cancer burden were collected from Latvian cancer registry. Availability of trained medical staff and laboratory systems were obtained through the Latvian Association of Cytologists and the Health Compulsory Insurance State Agency of Latvia (HCISA). RESULTS: Cervical cancer incidence in Latvia is increasing since 1989 when the compulsory preventive gynecologic examinations were stopped. Cervical opportunistic screening program in Latvia should be performed by GPs. But only 30 out of 1470 GPs provide gynecological care for their patients while, out of 484 certified gynecology practitioners, 35 had direct contractual relationship with the HCISA while 398 had only an indirect contractual relationship with the Agency. Moreover, in Latvia, there are about 29 laboratory specialists employed with cytological testing with an average age of 57 years: 13 of them have already passed the retirement limit. CONCLUSIONS: Traditionally in Latvia, most women request gynecological services for preventive and health promotion reasons or in the case of having a gynecological disease. So the overloaded general practitioners and the lack of involvement of gynecologists are one of the main obstacles to solve for implementing an organized screening program in Latvia. Moreover insufficient availability of quality-assured services and resources for cytology testing and other services of the program, and for monitoring and evaluating the whole program, must be considered in the implementation of a comprehensive screening plan.t PMID- 20968132 TI - Cervical cancer screening in Bulgaria--past and present experience. AB - BACKGROUND: In Bulgaria the previously (1970-1985) existing population based cervical cancer screening was replaced in the early 1990s with an opportunistic model due to political and socioeconomic reasons. As a result, in the last 20 years, cervical cancer incidence and mortality rates steady increased. The objective of the EUROCHIP project in Bulgaria was to evaluate the readiness of the health system as well as health providers' attitudes to implementation in the country of a population based screening program for cervical cancer. METHODS: Using a structured questionnaire, a convenience sample of medical specialists representing different actors involved in cervical cancer prevention, treatment, financing and policy were interviewed. RESULTS: The majority of interviewed practitioners worried that organization and implementation of an effective population-based cervical cancer screening program is not possible in the current unstable health system. A nostalgic attitude to the cervical cancer screening, performed in the past and pessimistic view on the capability of the current health system to cope are strong. As main barriers to implementation of an effective program were pointed financial and organizational ones. Motivation for gynecologists to perform smear test should include better information, organization and payment. DISCUSSION: Medical specialists in Bulgaria are aware of the alarming rates of cervical cancer incidence and mortality in the country. However, due to the insufficient communication and interaction between policy makers and front-line health care staff, they do not have enough information on the ongoing programs. Absence of health policy regarding screening is considered as main barrier for implementation of an effective screening program. PMID- 20968133 TI - Cervical cancer assessment in Romania under EUROCHIP-2. AB - BACKGROUND: Inside the European project EUROCHIP-2, the Romania team has ruled out an assessment study regarding cervical cancer screening programs (CCS) in Romania, in Nov 2006-March 2007. The general purpose was to be aliened to European Council recommendations that states that an organized cervical screening program should be offered in all member states, in order to reduce the specific incidence and mortality. The aim of the study was to assess cervical cancer burden and current cervical cancer screening status in Romania and in various sub regions (DR), and also to identify problems and barriers and to propose solutions for implementing an organized cervical cancer screening program at national level. METHODS: The study was based on a statistical survey and a comprehensive literature review of the most important European, national and regional papers or studies completed in this field. RESULTS: Over 2000-2006, a total number of 22,830 new cases and 12,763 deaths from cervical cancer was registered in Romania. In 2005, the crude rate of incidence varied largely in the 8 DR between 17.8-31.3 and mortality varied between 12.3-21.5. The proportion of women tested by DRs on total female population varied between 3.2%-0.6%; the highest screening activity was observed in region VI, where run the only organized CCS in Romania. In 2005, there were one GP per 578 female population aged 25-65; regarding the specialists in 2007 per country we had: 3,012 women aged 25-65 per one gynecologist, 21,195 women per one oncologist and 13,258 women per one histopathologist. DISCUSSION AND CONCLUSION: There were no major changes in policy screening over 2000-2006 correlated with no major difference in specific mortality in Romania. Significant differences in incidence and mortality between DRs were observed in 2005, which impose deeper analyzes of local conditions and resources and local strategies to be adopted. The burden of cervical cancer is particularly high in Romania and is related to the absence of an organized CCS program or the ineffectiveness of the opportunistic screening programs. It is needed that European Council recommendations be implemented and quality assurance strategies to be checked and maintained at all screening levels in Romania. PMID- 20968134 TI - Feasibility and outcome of concurrent chemoradiotherapy for recurrent cervical carcinoma after initial surgery. AB - AIMS AND BACKGROUND: The prognosis for recurrent cervical carcinoma following initial surgery is dismal even when aggressive radiotherapy or salvage surgery is used. We retrospectively reviewed hospital records to evaluate the efficacy and feasibility of concurrent chemoradiotherapy as a salvage treatment. METHODS: From 1999 to 2007, 47 patients received salvage chemoradiotherapy. Involved-field irradiation was delivered at a median dose of 64.8 Gy (range, 36-100.2), including brachytherapy boost in 10 patients. Pelvic re-irradiation was performed in 4 of the 12 women who had a previous history of pelvic radiotherapy. All but one patient received cisplatin-based concomitant chemotherapy during radiotherapy. RESULTS: The median overall follow-up period was 27 months and for surviving patients was 57 months. The interval between initial surgery and recurrence was 22 months (range, 4-203), and the median recurrent mass size was 4 cm (range, 0.5-11). In 34 patients, recurrent tumors were confined to the pelvis (21 central and 13 peripheral). Grade 3-4 acute hematologic toxicity was the most frequent toxicity and was observed in 29 (62%) women. Five-year actuarial cumulative incidence of severe gastrointestinal and genitourinary toxicity was 13% and 7%, respectively. Thirty-three patients (70%) showed a complete response and 9 (19%) a partial response following salvage chemoradiation. Five-year overall and disease-free survival rates were 44% and 41%, respectively. CONCLUSIONS: Salvage chemoradiotherapy appears to be a feasible treatment option for women with recurrent cervical carcinoma following surgery. The treatment had a high salvage rate and acceptable late complication rate, despite being associated with substantial acute toxicity. PMID- 20968135 TI - Postoperative gemcitabine alone and concurrent with radiation therapy in locally advanced pancreatic carcinoma. AB - AIMS AND BACKGROUND: To evaluate the treatment results of gemcitabine alone and concurrent with radiotherapy after R0/R1 resection of locally advanced pancreatic cancer. METHODS AND STUDY DESIGN: From 1999 to 2005, 55 patients with stage II resected pancreatic cancer treated with gemcitabine-based radiochemotherapy were retrospectively evaluated. Initially, one cycle of induction gemcitabine was administered and followed by weekly gemcitabine concurrent with radiotherapy. After the completion of radiochemotherapy, patients received 3 additional courses of gemcitabine. RESULTS: Thirteen patients were stage IIA and 42 were stage IIB. Forty-six patients (83.6%) had R0 and 9 patients (16.4%) had R1 resection. All of the patients received induction chemotherapy and radiotherapy, all but 3 received concurrent radiochemotherapy, and 46 (84%) patients received maintenance chemotherapy. During induction, concurrent and maintenance phases of the protocol, 11%, 13.5% and 19.5% of the patients had at least one > or = grade 3 toxicity, respectively. Within a median 47 months (range, 34-105) of follow-up, 4 (7.3%) patients had isolated local recurrence, 5 (9%) patients had local recurrence and distant metastases, and 27 (49%) had only distant metastases. Median disease-free survival and overall survival were 13 (range, 4-105) and 19 months (range, 6-105), respectively. In multivariate analysis, nodal stage, AJCC stage and number of lymph nodes dissected were the significant factors affecting disease-free survival whereas Karnofsky performance status was the only significant factor for overall survival. CONCLUSIONS: The prognosis for pancreatic cancer remains poor despite adjuvant radiochemotherapy. More aggressive treatments should be considered in patients with unfavorable prognostic factors. PMID- 20968136 TI - Importance of the circumferential extent of tumors and clinical lymph node status as prognostic factors after preoperative chemoradiotherapy and surgery in patients with rectal cancer. AB - AIMS AND BACKGROUND: To evaluate the clinical factors that influence pathological and clinical outcomes after preoperative concurrent chemoradiotherapy in patients with rectal cancer. METHODS: Between 1999 and 2004, 121 patients with cT3-4 or node-positive rectal cancer received preoperative chemoradiotherapy and surgery. Preoperative radiation therapy with 45 Gy was delivered. Fluorouracil-based chemotherapy was administered to most of the patients. RESULTS: Pathological complete remission was 14.3% after preoperative chemoradiotherapy. More than 60% tumor circumferential extent was an independent adverse factor for complete remission (P = 0.011, HR 4.643, 95% CI 1.415-15.231). Local recurrence developed in 9.9% of the cases. Serum CEA level > 5 ng/ml (P = 0.057, HR 3.022, 95% CI 0.967-9.441) and > 60% circumferential extent of tumor (P = 0.064, HR 4.232, 95% CI 0.918-19.531) were marginal adverse factors for local recurrence. Five-year disease-free survival and overall survival were 72.2% and 86.6%, respectively. Disease-free survival was poor for patients with the lymph nodes > or = 1 cm in diameter (P = 0.028), cN2 stage disease (P = 0.047) and > 60% circumferential extent of tumor (P = 0.058). Multivariate analysis for disease-free survival showed that the lymph node size > or = 1 cm was an adverse factor (P = 0.019, HR 2.380, 95% CI 1.115-4.906). Patients with > 60% circumferential extent of tumor and cN2 stage had a more unfavorable survival than the other patients (disease free survival, P = 0.018; overall survival, P = 0.015). Patients with > 60% circumferential extent of tumor and/or lymph node > or = 1 cm also had an unfavorable survival (disease-free survival, P = 0.016; overall survival, P = 0.049). CONCLUSIONS: In rectal cancer, circumferential extent of tumor and clinical lymph node status were important factors for preoperative chemoradiotherapy and surgery. A further prospective study is needed to confirm and expand these findings. PMID- 20968137 TI - Outcomes of radiation therapy for T1 glottic carcinoma from an Italian regional series with doses ranging from 60 to 66 Gy. AB - AIMS AND BACKGROUND: Radiotherapy has remarkable success rates for the cure of patients affected by glottic carcinoma; local control rates are similar to surgery with lower morbidity and better functional results. Our aim was to determine local-regional control rates, overall survival, second cancer incidence, acute-late toxicity and prognostic factors in our series of T1 glottic cancer patients with radiation doses of 60 to 66 Gy. Functional results were not sufficient for statistical analysis. METHODS AND STUDY DESIGN: A retrospective study was carried out of all T1N0 glottic carcinomas treated with radiation therapy between 1996 and 2006. To be eligible, patients had to have newly diagnosed cancer and had to be treated with a curative intent by radiation therapy alone. Ninety-eight patients satisfied the eligibility requirements: 85 patients had T1a disease; 13 patients were staged as T1b. Treatment was performed for all cases with a 6 megavoltage linear accelerator. The total dose prescribed varied from 60 to 66 Gy: 2 Gy/fraction, 1 fraction/day, 5 fractions/week. During treatment, a weekly clinical evaluation was performed; endoscopic examination was performed once every two weeks. After the treatment, a clinical, endoscopic and radiological follow-up was performed every three months for the first two years, every 6 months till the fifth year, and then once a year. RESULTS: With a median follow-up of 41.5 months (range, 10-132; mean, 56.8), we registered 12 cases of local failures; 8 of them were successfully treated with salvage surgery (median time to relapse, 3-48 months). The local relapse rate was 12.2%, and disease specific survival, taking into account salvage surgery, was 6%. Thirty-four deaths were registered: 2 for local progression, 2 for distant metastasis, 4 for a new primary cancer, and 26 for non-neoplastic causes. Five- and 10-year overall survival were respectively 85.8% and 69.4%. Four cases of lung cancer were detected in the upper aerodigestive tract in our series. In terms of acute-late toxicity, no grade 3-4 dermatitis, dysphagia or hoarseness occurred. Mild dermatitis and arythenoid edema were the most common causes of toxicity. Only one patient did not complete the treatment (60 Gy instead of the planned 66 Gy). CONCLUSIONS: Our series confirmed the primary role of radiation therapy for the cure of T1N0 glottic cancer. Outcomes were good in terms of local-regional control as well as overall toxicity. Radiation therapy can be offered to T1 glottic cancer patients as a valid alternative to surgery, with high rates of functional preservation. PMID- 20968138 TI - Radiotherapy in the treatment of primary osteosarcoma--a single center experience. AB - PURPOSE: To analyze our experiences concerning radiation treatment in patients with osteosarcoma. MATERIALS AND METHODS: Since 1981, 40 patients with osteosarcoma have undergone radiotherapy in Heidelberg; 3 of them were immediately lost to follow-up. Twenty patients with metastases were treated palliatively and 17 patients were treated with a curative intent. RESULTS: Interestingly, 14 of the 17 patients treated with a curative intent were referred to our clinic during the last 8 years, whereas the number of patients referred for palliation decreased. The mean dose applied for palliation was 47 Gy (range, 26 Gy to > 70 GyE), for cure was 59 Gy (range, 45 Gy to > 70 GyE). Local control until death could be achieved in 15 of the 20 palliatively treated patients, with a mean survival of 7 months after radiation. Five patients experienced local failure with symptom recurrence, and 3 of them had received doses > 60 Gy. At last follow-up, 3 of the 17 curatively treated patients had experienced local recurrence. Median follow-up was 32 months (range, 3-144). Estimated 5-year overall survival and local control rates were 38% and 68%, respectively. Local disease-free survival was shorter in patients treated for recurrent, inoperable or incompletely resected tumors and doses below 60 Gy. CONCLUSIONS: With adequate doses, long-term local control is possible even in inoperable or incompletely resected tumors. Improvements of systemic therapy and modern radiation techniques have begun to bring the possibly curative role of radiation treatment back to the fore. However, in disseminated tumors, even doses beyond 60 Gy do not guarantee local control, suggesting an extremely low radiosensitivity of certain kinds of osteosarcoma. PMID- 20968139 TI - Influence of surgical trauma on neopterin concentrations in gastric carcinoma patients. AB - AIMS AND BACKGROUND: Impairment of immune surveillance in the immediate postoperative period may accelerate the growth of tumor cells that remain despite radical resection in advanced cases. The present study was undertaken to evaluate the impact of major surgical trauma on host cellular immunity of gastric carcinoma cases. METHODS AND STUDY DESIGN: Sixty-eight consecutive patients with gastric carcinoma were divided into three subgroups according to the classification of the American Joint Committee on Cancer Staging, and they underwent surgery with a curative intent. Thirty-eight cancer-free patients served as controls, and they underwent surgical management for benign diseases. Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM) risk adjustment system was used to estimate the operative and physiological scores of patients. Plasma cortisol, serum interleukin-6 and high sensitive C-reactive protein levels were determined in order to assess the severity of trauma-related inflammatory response. The frequency of increased neopterin concentrations of cancer patients was estimated by comparison with the average values of controls. RESULTS: Response of interleukin-6 to surgery was closely related with the postoperative cortisol of cancer patients, but not correlated with neopterin and high-sensitive C-reactive protein levels. Although the extent of tumor invasion might have gradually decreased the macrophage response to surgical trauma, the overall increase in postoperative neopterin levels of cancer cases was highly significant. However, maximal frequency of increased neopterin concentration was obtained in advanced group. CONCLUSIONS: Macrophages might recognize the traumatic challenges in every stage of gastric cancer. Increasing individual neopterin concentration was not solely specific for tumor growth, but it was partially predictive of immune competence even in advanced cases. PMID- 20968140 TI - Quality of life and fatigue in Hodgkin's lymphoma patients. AB - AIMS AND BACKGROUND: Quality of life and survival of patients with malignant diseases are improving thanks to the development in diagnostics and therapy. METHODS: We determined the quality of life and frequency and severity of fatigue with an EORTC QLQ-C30 questionnaire in 168 Hodgkin's lymphoma patients (85 women, 83 men). We scored all functional and symptom scales in cured patients (who were in complete remission for at least 10 years; mean period of survival after the treatment(s) was 16.61 years) and in those who suffered from late complications. RESULTS: The global health status score (QL2) was significantly lower in patients who had late complications (mean QL2, 45.53) than in patients with no complications (mean QL2, 67.57, P < 0.001) and in cured patients (mean QL2, 52.5) than in those who were not disease free 10 years after the treatment or who were treated actively (mean QL2, 67.48, P < 0.001). We found that fatigue level (FA) was significantly higher in patients who had been treated more than 20 years before (FA score, 53.37) than in those who were undergoing treatment (FA score, 29.35, P = 0.03). A significantly higher FA score (FA, 48.72) was observed in patients who suffered from late complications of the treatment than in those who had no complications (FA, 31.88; P = 0.001). More comorbidity can cause higher fatigue scores than observed in these groups of Hodgkin's lymphoma patients. CONCLUSIONS: Fatigue is more frequent than we think, and it has a strong effect on quality of life, so its early recognition and treatment is important and needs multidisciplinary cooperation. PMID- 20968141 TI - Magnetic resonance imaging in local staging of endometrial carcinoma: diagnostic performance, pitfalls, and literature review. AB - AIMS AND BACKGROUND: To assess the diagnostic accuracy of magnetic resonance imaging in local staging of endometrial carcinoma, and to review the results and pitfalls described in the literature. METHODS: Thirty women with a histological diagnosis of endometrial carcinoma underwent magnetic resonance imaging. Unenhanced T2-weighted and dynamic contrast-enhanced Ti-weighted sequences were obtained. Hysterectomy and salpingo-oophorectomy was performed in all patients. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for the detection of deep myometrial and cervical infiltration. RESULTS: For deep myometrial infiltration T2-weighted sequences reached a sensitivity of 85%, specificity of 76%, PPV of 73%, NVP of 87%, and accuracy of 80%, while contrast-enhanced scans reached a sensitivity of 90%, specificity of 80%, PPV of 82%, NPV of 89%, and accuracy of 85%. For cervical infiltration T2-weighted sequences reached a sensitivity of 75%, specificity of 88%, PPV of 50%, NPV of 96%, and accuracy of 87%, while contrast enhanced scans reached a sensitivity of 100%, specificity of 94%, PPV of 75%, NPV of 100%, and accuracy of 95%. CONCLUSIONS: Unenhanced and dynamic gadolinium enhanced magnetic resonance allows accurate assessment of myometrial and cervical infiltration. Information provided by magnetic resonance imaging can define prognosis and management. PMID- 20968142 TI - Modern computer technologies facilitate communication with a young cancer patient. AB - AIM: The aim of this paper is to show how new technologies may help the communication process in clinical practice in a department providing supportive care to patients undergoing cancer treatment. METHOD: Communication via Internet chat between the psychologist and a young man who sees chatting on the Internet as a natural and familiar mode of expression was shown to be useful. RESULTS: The Internet link enabled us to open a communication channel with the patient and to have a conversation that would otherwise have been impossible. CONCLUSIONS: Although verbal communication is the most important way to communicate among people, Internet communications are certainly an opportunity worth exploring, because they may open up new channels for cancer patients whose ability to speak is restricted. We might imagine using this approach in pediatric oncology, with adolescents and preadolescents, and with young adults like the patient discussed here. The case discussed highlights the enormous difference between the mere transfer of information and genuine communication, the latter involving an encounter with the patient. PMID- 20968143 TI - [11C]choline-PET-guided helical tomotherapy and estramustine in a patient with pelvic-recurrent prostate cancer: local control and toxicity profile after 24 months. AB - [11C]choline positron emission tomograhy can be useful to detect metastatic disease and to localize isolated lymph node relapse after primary treatment in case of prostate-specific antigen failure. In case of lymph node failure in prostate cancer patients, surgery or radiotherapy can be proposed with a curative intent. Some reports have suggested that radiotherapy could have a role in local control of oligometastatic lymph node disease. This is the first reported case of [11C]choline positron emission tomography-guided helical tomotherapy concomitant with estramustine for the treatment of pelvic-recurrent prostate cancer. At 24 months after the end of helical tomotherapy, prostate-specific antigen was undetectable and no late toxicities were recorded. A disease-free survival of 24 months, in the absence of any type of systemic therapy, is uncommon in metastatic prostate cancer. The therapeutic approach of the case report is discussed and a literature review on the issue is presented. PMID- 20968144 TI - Intensity-modulated radiation therapy with simultaneous integrated boost in unresected left-sided pleural mesothelioma: a case report. AB - A 77-year-old male patient with unresected malignant pleural mesothelioma, clinical stage T3N0M0 according to the New International Staging System for Diffuse Malignant Pleural Mesothelioma, received intensity-modulated radiotherapy (IMRT) with a simultaneous integrated boost (SIB) after 6 cycles of chemotherapy with cisplatin and pemetrexed. SIB-IMRT delivered 40.5 Gy (1.5 Gy/fraction) to the left pleura and 50 Gy (1.85 Gy/fraction) to the sites of macroscopic disease. Radiotherapy was well tolerated. Two months after the end of radiotherapy the patient showed grade 2 lung toxicity (febrile episodes accompanied by dry cough) that was successfully treated with steroid therapy. Local control lasted for 2 years after SIB-IMRT. Then the tumor recurred marginally to the radiation field and the patient underwent chemotherapy with pemetrexed. Three years from the diagnosis, the patient is alive and in good general condition. He only takes prednisone 5 mg/daily for exertional dyspnea. To the best of our knowledge this is the first reported use of SIB-IMRT in unresected malignant pleural mesothelioma. Considering the dosimetric advantages of SIB-IMRT and the clinical results observed in our patient, additional evaluation of this technique seems justified. PMID- 20968145 TI - Management of locally advanced cervical cancer in pregnancy: a case report. AB - BACKGROUND: Carcinoma of the cervix is the most common malignancy associated with pregnancy. In the first and second trimesters patients should receive the same treatment as is used in nonpregnant women and termination is advised. In selected cases neoadjuvant chemotherapy (NACT) could be proposed but only a few cases have been reported. CASE: A 27-year-old woman, gravida 1 para 0, at 15 weeks' gestation, was diagnosed with FIGO stage IB2 squamous cervical cancer. After refusing to terminate pregnancy, she was treated with neoadjuvant chemotherapy (cisplatin) starting at 18 weeks. A cesarean section with radical surgery was performed at 32 weeks and a healthy baby delivered. Four weeks later the patient started chemoradiation therapy. She relapsed 1 year after surgery and died when her child was 2 years old. CONCLUSION: NACT followed by radical surgery was an unsuccessful treatment in our patient; platinum-based chemotherapy was harmless to the child up to the last follow-up. PMID- 20968146 TI - Molecular characterization and response to cetuximab in a patient with refractory squamous cell anal carcinoma. AB - There are no standard chemotherapeutic options for patients with squamous cell anal carcinoma, relapsing and progressing on palliative cisplatin-based regimens. Similarly to other malignant conditions, monoclonal antibodies directed against the epidermal growth factor receptor may represent an attractive therapeutic strategy. Here we describe a patient who, based on molecular profile, benefited from the combination of irinotecan and cetuximab. PMID- 20968147 TI - Complete pathological remission in a patient with hormone-receptor positive and c erbB-2 expression-negative breast cancer treated with FAC chemotherapy during pregnancy. AB - We describe the case of a pregnant woman diagnosed with breast cancer at 26 weeks' gestation. The tumor was positive for estrogen and progesterone receptors and negative for overexpression of c-erbB-2 protein. Neoadjuvant FAC (fluorouracil, adriamycin, cytoxan) chemotherapy was started at 29 weeks' gestation. At 37 weeks, delivery was induced and the patient gave born to a healthy female baby weighing 2350 g, after which she was given a further cycle of chemotherapy and weekly paclitaxel. Clinical and radiological remission was achieved. Resection of the breast tissue showed complete pathological response and negative lymph nodes. This case illustrates how the integrated work of different specialists can obtain excellent oncological and obstetrical results in the care of pregnant women with breast cancer. PMID- 20968148 TI - Polyostotic sclerosing histiocytosis (Erdheim-Chester disease) treated with combined vertebroplasty and radiation therapy. AB - Erdheim-Chester disease is an uncommon form of non-Langherans-cell histiocytosis, with a heterogeneous range of systemic manifestations and a pattern of typical clinico-pathological and radiological features. Symmetric sclerotic radiological alterations of the long bones are peculiar, such as the infiltration of several organs by lipid-laden histiocytes. Radiation therapy has been anecdotally employed in a palliative setting in order to relieve symptoms mainly due to cerebral, retro-orbital and skeletal localizations. Exclusive osseous involvement is rarely described in the medical literature. Moreover, the role, timing and schedule of radiotherapy in this subset of patients remain controversial. We herein report on a case of osseous-only Erdheim-Chester disease treated with a combined modality approach including transoral vertebroplasty and external beam radiation therapy, which gave an analgesic effect that lasted 1 year, with no treatment-related side effects. PMID- 20968149 TI - Primary cardiac chondrosarcoma with rapid MFH-like recurrence: case report and review of tumor type. AB - We present a case report of a patient with a rare primary cardiac tumor, chondrosarcoma. After initial excision, a locally advanced recurrence appeared within six weeks at a different site in the heart with the histological features of a high-grade sarcoma. We discuss the background, management and prognosis of these rare tumors. PMID- 20968150 TI - Long-term survival of metastatic melanoma to the ileum with evidence of primary cutaneous disease after 15 years of follow-up: a case report. AB - The small bowel is the most common site of gastrointestinal metastasis from cutaneous melanoma. Malignant melanoma has a poor prognosis, especially if distant metastases appear. Although rare primary melanoma of the small bowel has been described, more frequently these lesions originate from unknown cutaneous melanoma. Here we report the case of a 58-year-old man with a diagnosis of melanoma of the ileum without evidence of primary cutaneous disease. After 15 years, during the clinical and radiological follow-up, a cutaneous melanoma in the left parietal side of the scalp, probably corresponding to the primary lesion with abdominal node metastasis, was diagnosed. After 6 months of chemotherapy with fotemustine, the patient showed a complete response. At present, he is still alive 18 years after the diagnosis of intestinal metastasis. PMID- 20968151 TI - Manual for coding and reporting haematological malignancies. PMID- 20968152 TI - Immunochemical analysis of human papillomavirus L1 capsid protein in liquid-based cytology samples from cervical lesions. AB - OBJECTIVE: To investigate using detection of human papillomavirus (HPV) L1 capsid protein to predict the course of mild or moderate cervical intraepithelial neoplasia (CIN). STUDY DESIGN: Immunocytochemical analysis using antibody against HPV L1 capsid protein was carried out on 274 Pap tests from women positive for high-risk HPV detected by hybrid capture, with cytologic diagnoses of atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), atypical squamous cell cannot exclude high-grade squamous intraepithelial lesion (HSIL) (ASC-H), HSIL and squamous cell carcinoma (SCC). Histologic diagnosis was available for patients after initial cytologic diagnosis. RESULTS: L1 capsid protein was positive in 69.79% of cervicitis, 83.53 % of CIN 1, 41.81% of CIN2, 3.13% of CIN3 and 0% of SCC. Cytologic diagnosis revealed a higher expression rate in LSIL than in ASCUS and HSIL + SCC. In 71 ASCUS/LSIL without treatment, no L1-positive cases progressed in cytology; 18.75% of L1-negative cases progressed to ASC-H/HSIL. CONCLUSION: The decreased expression of HPV L1 may correlate with progressed cytopathology. The expressions of HPV L1 in liquid-based cell specimens implied the histopathology diag- nosis of cervix. Expression of HPV L1 may have significance in treating ASCUS and LSIL. PMID- 20968153 TI - Anaplastic thyroid carcinoma: morphologic findings and PAX-8 expression in cytology specimens. AB - OBJECTIVE: To evaluate the morphologic findings most encountered in anaplastic thyroid carcinomas (ATCs) and evaluate for the expression of PAX-8. STUDY DESIGN: The cytology specimens from 21 cases of ATC were evaluated for the following several cytologic criteria: cell morphology, pleomorphism, presence or absence of multinucleated cells, colloid, neutrophilic infiltrate and well-differentiated component. Immunohistochemical studies for PAX-8 were performed on cell blocks in selected cases. RESULTS: The most common morphology present was epithelioid, followed by spindle, multinucleated giant cell and rhabdoid, with 75% demonstrating more than 1 cell morphology. Marked pleomorphism (81%), neutrophilic infiltrate (90%) and necrosis (63%) were frequent. No nuclear grooves, colloid or well-differentiated component was identified in any case. Immunocytochemical stains for PAX-8 were negative in 5 cases in which a cell block was available. CONCLUSION: ATC is a tumor with diverse morphologic characteristics, and more than 1 cell morphology is usually present. A neutrophilic infiltrate is a common finding and represents a clue to the correct diagnosis. PMID- 20968154 TI - Discordance between cytologic results in multiple thyroid nodules within the same patient. AB - OBJECTIVE: To examine the frequency of discordant cytologic results between multiple thyroid nodules biopsied in the same patient. STUDY DESIGN: In a retrospective chart review of 441 consecutive patients, 326 (73.9%) had 2 or more nodules with colloid and/or thyroid cells recovered. Cytology was classified as (A) colloid only, (B) benign colloid nodule with or without degeneration, (C) Hashimoto's, or (D) follicular or Hurthle cell neoplasm, hyperplasia or suspicious for malignancy. Discordance was defined as having at least 2 different categories in the same patient. Twenty-four predetermined factors were analyzed, including demographics, laboratory values and ultrasound characteristics. RESULTS: The results, by category, were A, 164 (18.4%); B, 575 (64.6%); C, 131 (14.7%); and D, 20 (2.2%). Overall, 126 of 326 (38.7%) patients had at least 1 discordant grouping between their nodules. Of 326 patients, 165 had 2, 94 had 3, 48 had 4, 14 had 5, and 5 had 6 nodules biopsied, of which 48 (29.1%), 39 (41.5%), 29 (60.4%), 8 (57.1%) and 2 (40.0%), respectively, showed diagnostic discordances (p = 0.0007). CONCLUSION: The high rate (38.7%) of discordance between biopsies of multiple nodules in the same patient support a recommendation to biopsy all nodules that otherwise meet criteria for biopsy, as opposed to only the largest one. PMID- 20968155 TI - Detection of Candida by calcofluor white. AB - OBJECTIVE: To assess the efficacy of calcofluor white (CFW) is compared to Gram stain and periodic acid-Schiff in detection of Candida in oral precancer and cancer. STUDY DESIGN: The study group consisted of patients with precancer (n = 45), cancer (n = 45) and control group (n = 45). Presence of Candida was confirmed by culture inoculation along with a germ tube and carbohydrate fermentation test. The cytopathologic smears were analyzed by Papanicolaou-CFW and Gram staining, whereas, tissue sections were stained by periodic acid-Schiff and CFW staining. RESULTS: Candida albicans was the predominant species identified. A highly significant association of Candida was seen more often in cancer than in precancer. Both in cytology and histopathology Candida detection by CFW was higher. In precancer it was 48.88% in smears and 40% in tissue sections, whereas, in cancer 60% in smears and 55.55% in histopathology. CONCLUSION: Among the various diagnostic tools used in the present study, the use of CFW is seen to be a simple, effective, rapid and reliable method, both in cytopathology and histopathology. PMID- 20968156 TI - Imprint cytology of axillary lymph nodes in breast carcinoma following neoadjuvant chemotherapy. AB - OBJECTIVE: To evaluate the efficacy of imprint cytology (IC) in detecting residual axillary metastasis following neoadjuvant chemotherapy (NACT) in order to check its feasibility on sentinel nodes in the posttherapy setting in patients with breast carcinoma STUDY DESIGN: Thirty women on NACT for locally advanced breast cancer were subjected to total mastectomy with axillary node dissection. Routinely stained imprints from 172 resected nodes were studied to detect residual metastasis and therapy-induced changes, adopting a semiquantitative grading system for assessing the cell yield. Sensitivity and specificity tests were performed. The effect of cellularity in detecting malignancy was statistically determined by the McNemar test. RESULTS: Of the 172 nodes, 58 (33.7%) and 64 (37.2%) were positive by IC and histopathologic examination, respectively. Sparse, moderate and high cell yield was observed in 27 (15.2%), 33 (19.4%) and 112 (66.4%) nodes, respectively. No statistically significant difference was found with respect to the cellularity of imprints. Sensitivity, specificity and diagnostic accuracy were 89.1%, 99.1% and 95.4%, respectively. The false positive and negative rates were 0.6% and 4.1%, respectively. The positive and negative predictive values were 98.3% and 93.9%, respectively. CONCLUSION: IC is a sensitive, specific and accurate method of detecting axillary metastasis in patients with down-staged tumors following chemotherapy. The fact that therapy did not affect the cell yield on IC makes the technique very applicable for assessing the sentinel nodes following NACT. PMID- 20968157 TI - Diff-Quik cytologic recognition of Chlamydophila psittaci in orolabial lesions of Stevens-Johnson Syndrome. AB - BACKGROUND: Chlamydophila psittaci causes psittacosis, an ornithosis acquired usually from infected birds. The disease is often focal and pneumonic but on rare instances can be protean and fatal. Diagnosis is by Chlamydophila serology, which may take as long as 21 days or more. The recovery of the organisms from mice, eggs or tissue culture inoculated with the patient's blood or sputum is tedious and dangerous for laboratory personnel. On occasion, C psittaci inclusion bodies have also been detected in infected cells by fluorescent antibody, Giemsa or Gimenez staining. This report describes heretofore not previously reported recognition of the causative organisms in Diff-Quik-stained clinical cytologic materials. CASE: A 17-year-old man presented with fever and sore throat, associated with Steven-Johnson syndrome, of 6 days' duration. In the touch and scrape smears of the orolabial mucosal lesions, C psittaci inclusion bodies were recognizable in Diff-Quik-stained but not with Papanicolaou-stained smears and Gram stain. There were few to numerous organisms per macrophage, which were enlarged or bloated and usually collared by polymorphonuclear leukocytes. The diagnosis was supported by a therapeutic trial with doxycycline and confirmed by a positive third serological tests for C psittaci 3 weeks after discharge. CONCLUSION: In a suspected or probable case of ornithosis, a rapid diagnosis of C psittaci inclusion bodies is possible in clinical cytology materials using Diff Quik. PMID- 20968158 TI - Sarcomatoid salivary duct carcinoma of the submandibular gland: a case report. AB - BACKGROUND: Sarcomatoid salivary duct carcinoma (sarcomatoid SDC) is a rare subtype of SDC. We encountered 1 case of sarcomatoid SDC that developed from a submandibular gland pleomorphic adenoma, and we herein report our findings. CASE: A 42-year-old female had tumentia and pain in the right submental area, and therefore she underwent a close examination, wherein a right submandibular gland neoplasm was detected. Surgery for removing the right submandibular gland was performed in addition to neck dissection. Cytology showed typical findings of conventional SDC. Moreover, isolated and scattered large spindle cells and multinucleated cells were also detected along with atypical epidermal cell clumps showing keratinization. From a histologic perspective, it appeared to be sarcomatoid SDC that developed from a pleomorphic adenoma and also involved a squamous cell carcinoma component. CONCLUSION: This is the first report on the cytologic findings ofa case of sarcomatoid SDC with a squamous cell carcinoma component. When sarcomatoid cells appear in the cytology along with findings of typical SDC, sarcomatoid SDC should thus be considered. Furthermore, squamous cell carcinoma component may be involved as in the present case, so it is necessary to be aware of the possibility thereof. PMID- 20968159 TI - Endoscopic ultrasound-guided fine needle aspiration cytology diagnosis of solid pseudopapillary tumor of the pancreas: a report of 3 cases. AB - BACKGROUND: Solid pseudopapillary tumor of the pancreas (SPTP) is an exceedingly rare pancreatic tumor. We present the clinical, endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) cytologic features and immunohistochemical findings performed on cell blocks of 3 SPTPs. CASES: Three females (17-32 years old) were admitted to our hospital due to unexplained episodic abdominal pain. EUS confirmed the presence of a mass in the body and tail of the pancreas (2 cases) and in the head (1 case), with distinct borders and occassional dilation of the peripheral part of the pancreatic duct. EUS-FNA cytology specimens consisted of single cells and aggregates of uniform polyhedral cells, forming branching papillary clusters with delicate fibrovascular cores and nuclear overlapping (2 cases) and glandlike structures (1 case). Variable hyaline, myxoid stromal elements and naked capillaries were also seen. The cells had bland nuclear features, small nucleoli, nuclear grooves in some of them and focally cytoplasmic projections. Mitoses and necrosis were not observed. The immunohistochemistry on cell blocks revealed: vimentin+ (3 cases), CA19.9+ (2 cases), cytokeratin 7+ (focal, intensive, 1 case), synaptophysin+ (1 case), MUC1+ (focal, intensive, 1 case), EMA+ (diffuse weak, 1 case), a1-antitrypsin and a1 antichymotrypsin+ (focal intensive, 2 cases), progesterone+ (1 case), chromogranin-A- (3 cases) and NSE- (3 cases). CONCLUSION: Cytologic and immunohistochemical findings were strongly suggestive of SPTP. Surgical resection confirmed the diagnosis in all cases. EUS-FNA cytology features and immunohistochemistry provide the diagnosis of SPTP with accuracy. PMID- 20968160 TI - Fine needle aspiration of follicular dendritic cell sarcoma in an HIV-positive man: a case report. AB - BACKGROUND: Follicular dendritic cell (FDC) sarcoma is an uncommon neoplasm occurring not only in lymph nodes but also in extranodal sites. Because of an increasing number of case reports, awareness of this tumor has grown. The nature of the disease and its relation to other diseases, treatment, prognosis and immunochemistry findings are being actively studied. So far, only a limited number of cytology cases describing the fine needle aspiration (FNA) biopsy findings of FDC sarcoma have been reported. CASE: A 47-year-old man had a history of hypertension and human immunodeficiency virus (HIV) infection treated with antiretroviral therapy. He developed a slowly growing, nontender right neck mass over the course of 3 years. FNA revealed sheets and thick syncytial clusters of bland cells with pale cytoplasm and indistinct cell borders, round to oval nuclei with fine or vesicular chromatin, and small nucleoli. The mass was subsequently excised. A diagnosis of FDC sarcoma was made based on the histologic appearance and the marker studies. Conclusion The diagnosis ofFDC sarcoma in FNA can be suspected if a pathologist is aware of its characteristic features. Research studies have demonstrated the presence of HIV-related FDC hyperplasia. It is likely that HIV infection may have played a role in tumor formation in this patient. (Acta PMID- 20968161 TI - Fibromatosislike metaplastic carcinoma of the breast as a diagnostic pitfall for fine needle aspiration cytology: a case report. AB - BACKGROUND Metaplastic carcinomas of the breast are uncommon, and most display marked cellular atypia. Recently, a low grade fibromatosis-like metaplastic carcinoma was found and displayed little nuclear atypia. CASE A 74-year-old woman presented with a 2.5-cm, palpable breast nodule. Mammogram was reported as suspicious for malignancy. Cytologic examination revealed smears of low cellularity with most cells lying in clusters and having a round or oval shape. Rare cells had a "spindle" shape. Nuclear features were low grade. Rare individual cells had retained cytoplasm. Lumpectomy revealed a fibromatosis-like metaplastic carcinoma. CONCLUSION: Cytologically, fibromatosis-like metaplastic carcinomas are low grade lesions producing smears of relatively low cellularity. Separation from ductal carcinomas is necessary because fibromatosis-like metaplastic carcinomas rarely metastasize to lymph nodes. PMID- 20968162 TI - The advantage of combined fine needle aspiration cytology and imaging scores over fine needle aspiration cytology score alone in a breast screening program. PMID- 20968163 TI - Pediatric pilomatrixoma of the preauricular region. PMID- 20968164 TI - Intraoperative cytodiagnosis of ciliary body medulloepithelioma masquerading as anterior ciliary staphyloma. PMID- 20968165 TI - Metastatic renal cell carcinoma presenting as shoulder monoarthritis: diagnosis based on synovial fluid cytology and immunocytochemistry. PMID- 20968166 TI - Cervical lymph node metastasis of extramedullary plasmacytoma of the tonsil presenting with granulomatous lymphadenitis in fine needle aspiration cytology. PMID- 20968167 TI - A new use for fine needle aspiration cytology in the management of patients with breast cancer. PMID- 20968168 TI - Fine needle aspiration cytology of intracranial peripheral-type primitive neuroectodermal tumor. PMID- 20968169 TI - Visceral leishmaniasis in a case of acute lymphoblastic leukemia at both remission and relapse, diagnosed by bone marrow aspiration. PMID- 20968170 TI - Primary actinomycosis of the anterior abdominal wall: rare diagnosis of a case by fine needle aspiration cytology. PMID- 20968171 TI - Hepatocellular carcinoma presenting with spinal cord compression and diagnosed on fine needle aspiration. PMID- 20968172 TI - Emerging oral cancer subtype draws concern. PMID- 20968174 TI - Editorial commenrtary: A note about the news. PMID- 20968173 TI - Clinical case: Chest pain in a diabetic. PMID- 20968175 TI - Risk factors for adenomyosis in patients with symptomatic uterine leiomyomas. AB - OBJECTIVE: The aim of the study was to evaluate the potential risk factors for adenomyosis in patients with symptomatic uterine leiomyomas. MATERIAL AND METHODS: The medical charts and histopathology reports of 1499 women who underwent hysterectomy between 2003-2007 were retrospectively reviewed. The study group was composed of 135 patients with coexisting uterine leiomyoma and adenomyosis. The control group comprised 176 patients with uterine leiomyoma without adenomyosis. RESULTS: Among 233 patients with adenomyosis 135 (57.9%) had associated uterine fibroids. Women who delivered twice or more were at increased risk for adenomyosis in relation to nulliparuos women: RR (95% CI) 2.44 (1.04 5.72), p = 0.040. No relationship was found between adenomyosis and cesarean section rate, abortions, menorrhagia or dysmenorrhea. CONCLUSION: Results of our study indicate that multiparity is a risk factor for adenomyosis in women with symptomatic leiomyomas. PMID- 20968176 TI - Late preter cant neonatal problem? AB - BACKGROUND: The survival rate and quality of life of extremely low birthweight infants remain to be one of the main challenges of modern neonatology. Therefore, pre-term children born after 32 weeks of gestation with more normal birthweight, have become a relatively minor medical problem in comparison. OBJECTIVES: The aim of the following work was to compare the frequency of complications occurring in neonatal period in groups of late preterms and full-term neonates. METHODS: A group of 725 late pre-term babies, born between 34-36 6/7 GA, constituted the study group and has been analyzed retrospectively 5040 neonates born at term comprised the control group. The results were analyzed statistically using chi square test. RESULTS: Respiratory disturbances were diagnosed in 178 neonates in the study group (24.55%), while in the control group in 138 cases (2.74%), p = 0.0000. Intrauterine infections were present in 92 neonates in the study group (12.69%) and in 327 infants in the control group (6.49%), p = 0.0000. Hiperbilirubinemia developed in 520 neonates in the study group (71.72%), and in 1895 babies in the control group (37.60%), p = 0.0000. CONCLUSIONS: (1) Respiratory disturbances, hiperbilirubinemia and intrauterine infections are more frequently observed in late preterms. (2) Increased morbidity in late preterm neonates prolongs the time of hospitalization. PMID- 20968177 TI - Some blood biochemical parameter values in a herd of American bison (Bison bison L.) from an experimental animal farm in Poland. AB - The blood samples of 17 bison (7 cows, a heifer, a young bull and 8 calves) formed the basis for conducting analyses of blood plasma. The measurements were carried out by using ionoselective electrodes aided by a Hitachi 917 biochemical analyser. An interpretation of the results was possible due to comparison with the results of similar analyses completed in the United States. Many differences in blood chemistry values in bison bred at Kurozweki were found in comparison to bison from the US. PMID- 20968178 TI - The bi-phased course of electrophysiological response of isolated snail intestine on mechanical stimulation. AB - The transepithelial potential difference and changes of diameter of isolated snail intestine as index of its motility were studied in immersed bath in control conditions and after gentle stimulation by 60 seconds of washing of the intestinal lumen. Immediate depolarization and 20% augmentation of the lumen were observed during the stimulation. After stimulation, additional transient depolarization of the transepithelial potential difference and gradual diminution of intestine lumen back to control values over a period of 20 minutes occurred. The immediate reaction was greatly influenced by the presence of sodium or chloride ion transport inhibitors, however, the late phase of the response was not. It is hypothesized that changes of transepithelial electrogenic ion transport and of intestinal motility during the stimulation mirror the inflow of intestinal content and after completion of stimulation may be related to its storage. PMID- 20968179 TI - Extremely low frequency magnetic field and the hatching rate of Fasciola hepatica eggs, the fecundity and survival of liver fluke-infected snail, Lymnaea truncatula. AB - Eggs of Fasciola hepatica were exposed for 10 days to extremely low frequency magnetic field (ELFMF) at the frequency of 50 Hz and density of 2 mT (rms). The results show an accelerated hatching of F. hepatica eggs in relation to control (non-exposed) group. The host snails, Lymnaea truncatula, were divided into three groups; those of groups I and II were infected with the miracidia of F. hepatica hatched from control egg culture, whereas those of group III were infected with miracidia hatched from eggs affected by ELFMF. Thereafter, snails of groups II and III were exposed to ELFMF for 53 days, whereas those of group I were not exposed. At day 14 post infection, a significant decrease was observed in the number of cocoons laid by snails of group III, compared with control. Also, significant mortality in group III snails was observed 42 days post infection. The increased mortality and a lower number of cocoons laid by group III snails have probably resulted from enhanced stimulation of metacercarial parthenogenetic reproduction in consequence of infecting the molluscs with miracidia reared under ELFMF. PMID- 20968180 TI - Expression of Bcl-2 and Bax proteins in thyroid glands of rats in experimental thyroiditis. AB - In the recent years, iodine was associated to the development of apoptosis in thyroid diseases. The aim of the present study is to determine the expression of pro-apoptotic and anti-apoptotic proteins, Bax and Bcl-2, in a Wistar rat experimental model of thyroiditis induced by administration of different doses of potassium iodide. Immunohistochemical staining was done with chromogen diaminobenzidine on avidin-biotin peroxidase using the Animal Research Kit (ARK), stained with antibodies to Bcl-2 and Bax proteins. The intensity and distribution of positive staining were evaluated by light microscopy on a scale of 0 to 4. Bax protein was expressed in the area of regenerating follicular cells in high percent in potassium iodide treated rats, but was not expressed in thyrocytes from control rats. Bcl-2 expression was constantly observed in thyrocytes of the control group and in the mantle-zone of lymphoid follicular infiltrates. Our results show that Bax expression is significantly higher in the Wistar rat experimental model of thyroiditis than in the control group. These data suggest that the increased expression of Bax may contribute to the role of apoptosis in the pathogenesis of experimental thyroiditis. PMID- 20968181 TI - Oral in vivo bactofection in dextran sulfate sodium treated female Wistar rats. AB - Salmonella typhimurium SL7207 carrying Cu-Zn superoxide dismutase and an N terminal deletion mutant of monocyte chemoattractant protein-1 genes was applied to dextran sodium sulfate treated female Wistar rats. Stool quality, food and water intake were monitored. Markers of oxidative stress, interleukin 1, interleukin 6 and tumor necrosis factor alpha were quantified. No differences were found in body weights, markers of oxidative stress in plasma and inflammatory markers in colon homogenates. Plasma concentrations of I11, I16 were lower in the treatment groups than in the dextran sodium sulfate group. However, dextran sodium sulfate induced inflammation could not be confirmed by plasma levels of I11, I16 and TNFalpha. Although some parameters showed a tendency to improve, the inflammation caused by administration of 4% dextran sodium sulfate during 7 days was low and contradictory to other studies. Results showed the potential synergic effect of combined bacteria-mediated antioxidative and anti inflammatory gene therapy. PMID- 20968182 TI - Ramipril affects hydrogen sulfide generation in mouse liver and kidney. AB - Hydrogen sulfide (H2S) is a modulator of various physiological and pathological processes in the cardiovascular and nervous system and plays an important role in the regulation of gastrointestinal tract, liver and kidney function. The effect of the pleiotropic action of the tissue specific angiotensin-converting enzyme inhibitor (ACEI), ramipril, exceeds renin-angiotensin aldosterone system (RAAS) blockade and involves different biological mechanisms. The aim of the study is to assess the influence of ramipril on H2S production in mouse liver and kidneys. Thirty mice (CBA) of both sexes were given intraperitoneal injections of ramipril solutions--0.125 mg (5 mg/kg--group D1) and 0.25 mg (10 mg/kg--group D2) for 5 consecutive days at the same time of the day (10:30 am). The control group received physiological saline in portions of the same volume--0.2 ml. The measurements of the tissue concentration of H2S were performed using the modified spectrophotometric method of Siegel. There was a significant rise in the tissue concentration of H2S [microg/g] in livers of group D1 (2.70 +/- 0.02 vs 2.81 +/- 0.06; P = 0.03) and group D2 (2.70 +/- 0.02 vs 2.98 +/- 0.03; P < 0.001) and a significant decrease of H2S kidney tissue concentration in group D1 (3.35 +/- 0.06 vs 3.15 +/- 0.07; P = 0.02) and in group D2 (3.35 +/- 0.06 vs 2.89 +/- 0.03; P < 0.001). Our results show that ACEI ramipril affects hydrogen sulfide generation in mouse liver and kidneys. PMID- 20968183 TI - Species of the Paramecium aurelia complex in Italy. AB - New stands of Paramecium pentaurelia were recorded in Valmarana, Veneto region in Italy and one stand of P. primaurelia was found at the same locality. PMID- 20968184 TI - New, world-wide data on the distribution of species of the Paramecium aurelia complex (Ciliophora, Protozoa). AB - This is the first report on the presence of P. biaurelia in Tasmania, an island that has probably never been investigated before for the occurrence of the P. aurelia species. P. tetraurelia was recorded in Brazil, another very poorly investigated country in terms of this species complex. New stands of P. biaurelia and P. tetraurelia were also recorded in Japan. We present data concerning the occurrence and distribution of the P. aurelia species on different continents as a background for the newly described stands of P. aurelia spp. PMID- 20968185 TI - Molecular approach to the systematics of European Tortricini (Lepidoptera: Tortricidae). AB - Tortricini is a cosmopolitan tribe of the subfamily Tortricinae of the lepidopteran family Tortricidae. The most recent systematic of Tortricini are based on the external morphology of imagines and the structure of their genital organs. The present paper is the first comparative molecular study of the representatives of this tribe. We examined DNA variation in a 606 bp fragment of COI mtDNA obtained from 23 species of Tortricini and two representatives of other tribes (Archips podanus of Archipini and Aethes hartmanniana of Cochylini). The position of Spatalistis, Tortrix, Aleimma and Acleris, and some groupings of species within Acleris were confirmed by molecular data, including the synonymization of Croesia and Phylacophora with Acleris. The positions of a few groupings of the Acleris species remain unresolved. PMID- 20968186 TI - Evaluation of genetic biodiversity in farm-bred and wild raccoon dogs in Poland. AB - The aim of the study was to analyze the intra- and inter-group diversity in farm raised and wild raccoon dogs with the use of molecular markers. Genetic differences between the particular raccoon dog groups were observed, accompanied by a relatively high intra-group genetic variation. It was noted that the wild raccoon dogs were characterized by the highest genetic diversity, compared to the three study groups of farm-bred raccoon dogs. Wild raccoon dogs and farm-bred raccoon dogs constitute separate phylogenetic groups. The results obtained suggest that farm breeding may lead to differentiation into a different phylogenetic lineage than that of the wild raccoon dogs. In each case, the genetic distance between the animals bred on the individual farms was lower than the distances between the farm-raised and wild animals. Since the Polish farm breeding is based entirely on phenotype ranking, the genotype of "native" animals is still closely related to that of wild animals. PMID- 20968187 TI - Egg quality of Japanese quail depends on layer age and storage time. AB - The aim of the study was to analyse egg quality changes of Japanese quail during the reproductive season and after several days of storage. A significantly higher egg weight was recorded in week 9 than in week 25 and week 31 of age ofbirds. The egg specific gravity value of eggs also decreased with the age of quails. The smallest yolk weight and its percentage proportion in egg mass were observed in week 25. Eggs laid in weeks 9 and 25 were characterised by similar and lower (P < or = 0.05) white weight in comparison to those examined on the last date. The highest white proportion in egg weight was recorded during the 25th week. The value of this trait was similar or smaller on the remaining dates. Similar and lower values of the white index and Haugh units, in comparison with the first date, were determined in eggs laid on weeks 25 and 31, whereas similar and greater eggshell thickness than in the 9th week of age was recorded on the last two dates of examination. Lower (P < or = 0.05) egg weight was observed after 5 and 8 than after 0 (measured on the day of laying) days of storage. Likewise, smaller egg specific gravity was recorded after three consecutive periods of storage in comparison with the eggs examined on the day of laying. Eggs examined after 3, 5 and 8 days of storage, in comparison with those stored for 0 days, were characterised by lower yolk index. Significantly smaller weight and white index than after 0 days were determined in eggs stored, respectively, for 5 and 8 as well as for 3, 5 and 8 days. Similarly, smaller numbers of Haugh units were determined after 3 consecutive storage periods in comparison with the eggs examined on the day of laying. Eggs stored for 0 and 3 days were characterised by a greater eggshell weight than those examined after 5 and 8 days. The weight of Japanese quail eggs decreased significantly from day 5 onwards, whereas the egg specific gravity-- from the 3rd day of storage. Yolk and white quality began to deteriorate already after 3 days of egg storage. It appears, therefore, that egg storage of Japanese quails before hatching lasting more than 3 days in the analysed conditions deteriorated the eggshell quality and internal egg traits. PMID- 20968188 TI - Differentiation of regenerative cells in the midgut epithelium of Epilachna cf nylanderi (Mulsant 1850) (Insecta, Coleoptera, Coccinellidae). AB - Differentiation of regenerative cells in the midgut epithelium of Epilachna cf nylanderi (Mulsant 1850) (Insecta, Coleoptera, Coccinellidae), a consumer of the Ni-hyperaccumulator Berkheya coddii (Asteracae) from South Africa, has been monitored and described. Adult specimens in various developmental phases were studied with the use of light microscopy and transmission electron microscopy. All degenerated epithelial cells are replaced by newly differentiated cells. They originate from regenerative cells which act as stem cells in the midgut epithelium. Just after pupal-adult transformation, the midgut epithelium of E. nylanderi is composed of columnar epithelial cells and isolated regenerative cells distributed among them. The regenerative cells proliferate intensively and form regenerative cell groups. In each regenerative cell group the majority of cells differentiate into new epithelial cells, while some of them still act as stem cells and persist as a reservoir of cells capable for proliferation and differentiation. Because this species is an obligate monophage of plants which accumulate nickel, proliferation and differentiation of midgut stem cells follow degeneration intensively and in a typical manner. PMID- 20968189 TI - Fine structure of the midgut epithelium of Nicoletia phytophila Gervais, 1844 (Zygentoma: Nicoletiidae: Nicoletiinae) with special emphasis on its degeneration. AB - The midgut epithelium of Nicoletia phytophila is composed of columnar digestive cells and regenerative cells that form regenerative nests. The cytoplasm of midgut epithelial cells shows typical regionalization in organelle distribution. Two types of regenerative cells have been distinguished: cells which are able to divide intensively and cells which differentiate. Spot desmosomes have been observed between neighboring regenerative cells. The occurrence of intercellular junctions is discussed. The midgut epithelium degenerates both in an apoptotic and necrotic way. Necrosis proceeds during each molting period (cyclic manner), while apoptosis occurs between each molting, when the midgut epithelium is responsible for e.g. digestion. These processes of epithelium degeneration are described at the ultrastructural level. Our studies not only add new information about fine structure of the midgut epithelium of N. phytophila, but contribute to resolving the relationships within the Zygentoma. There are no doubts about the very close sister position of Nicoletiidae and Ateluridae. The midgut epithelium characters confirm their close relationship. However we do not recommend classifying the atelurid genera only within Nicoletiidae: Nicoletiinae. PMID- 20968190 TI - Karyotypic variation in two species of jerboas Jaculus jaculus and Jaculus orientalis (Rodentia, Dipodidae) from Tunisia. AB - The karyotypes of the lesser Egyptian jerboa Jaculus jaculus and the greater Egyptian jerboa Jaculus orientalis from Tunisia are described and compared with available data particularly from Egypt. The species examined have a similar karyotype consisting of 2n = 48 chromosomes and a fundamental number of autosomes (NFa) varying from 88 to 90 in J. jaculus and from 84 to 88 in J. orientalis. The X chromosome is submetacentric in both species, while the Y is submetacentric in J. orientalis and acrocentric in J. jaculus. Most of the autosomes are meta/submetacentric but the small pairs 22 - 23 in J. jaculus and 20-23 in J. orientalis are frequently acrocentric, yielding considerable differences in the NFa within and among species. Morphological variation in these small pairs of autosomes and/or in the Y chromosome in J. orientalis may distinguish populations of the two species from Egypt and Tunisia. The differences observed either between Egypt and Tunisia or between the Tunisian Jaculus species are probably associated with chromosomal rearrangements such as pericentric inversions or heterochromatin variation. They appear of lesser magnitude than other changes (especially molecular) that have occurred during the evolution of this genus. PMID- 20968191 TI - Cytogenetic analysis of meiotic cells obtained from stallion testes. AB - A normal course of meiosis and the associated course of spermatogenesis in males are very significant from the viewpoint of animal breeding, in particular animal reproduction. This takes on special significance when studying late-maturing animals such as horses. The aim of the study was to analyse meiotic cells, with particular consideration of synaptonemal complexes obtained from the testes of young stallions and cryptorchids, based on observations of the X-Y bivalent. The analysis was performed in successive stages of meiotic division using the FISH technique. The greatest diversity and most advanced meiotic stages were observed in the normal testis of a unilateral cryptorchid. No abnormalities were observed that could have caused cryptorchidism in the analysed horses. PMID- 20968192 TI - Use of the chromosomal co-location of the minor 5S and the major 28S rDNA as a cytogenetic marker within the genus Leuciscus (Pisces, Cyprinidae). AB - The chromosomes of three species from the genus Leuciscus (the ide L. idus, the European chub L. cephalus and the common dace L. leuciscus) were examined with the FISH technique for 5S and 28S rDNA probes. The analysis showed that among the three examined species, 5S rDNA signals were located on two large and four small subtelocentric chromosomes in L. leuciscus, on one large and five small subtelocentric chromosomes in L. idus, while in L. cephalus the probe signals were found on two metacentric chromosomes and one large and one small subtelocentric chromosome pairs. In all analysed species, the 28S rDNA probe signals were placed on only one chromosome pair, subtelocentric in the common dace and the European chub, and submetacentric in the ide. The three species differed in the number of sites in which both probe signals were present. In conclusion, the co-location of the 5S and 28S rDNA proved to be a useful cytogenetic marker among the studied fishes. Moreover, this marker could be adapted to other cyprinids. PMID- 20968193 TI - Correlation of centromeric heterochromatin C-band polymorphism with breeding failure in mice. AB - The aim of the present study was to test the hypothesis about the relation between segregation of chromosomes 14 and 18 and the deterioration of mouse fertility and vitality. The analysis was possible because C-banding on chromosome 14 and chromosome 18 of the CBA/Kw and KE strains show size polymorphism. A small sized C-band on chromosome 14 is characteristic for the CBA/Kw mice, while the KE mice show small C-bands on chromosomes 18. Thus, if fertility parameters are affected in a centromere-dependent manner, we should observe non-random inheritance of both chromosome pairs in recombinant inbred (RI) strains. The results showed statistically significant preferential segregation of chromosomes 14 and 18 with small C-bands. Most of the RI strains inherited chromosome 14 from the CBA/Kw strain and chromosome 18 from the KE strain, and did not manifest a deterioration of fertility and vitality. On the contrary, RI strains that inherited chromosomes 14 and 18 from one of the parental strains, particularly the KE strain, stopped breeding or had difficulties in producing the next generation. PMID- 20968194 TI - Identification of the rate of chimerism of different tissues with microsatellite markers in chicken chimeras. AB - The goal of our study was to evaluate whether private alleles can be defined in microsatellite markers for the breeds under investigation; to evaluate if these private alleles distinguish chicken chimera when using different tissues; to trace them back to the donor: Green-Legged Partridgelike and recipient: White Leghorn chicken breeds, and further on, to estimate the level of chimerism in each tissue. Private and common alleles were defined for donor and recipient chicken breeds in 3 loci. The rate of chimerism was defined based on private alleles present in liver, heart, breast muscle, femoral muscle and gonads. The highest rate of chimerism was observed in liver. A lower rate of chimersim was observed in gonads, and femoral muscle, and finally the lowest rate of chimerism was observed in breast muscle and heart. PMID- 20968195 TI - Placebo effects in neurological diseases. AB - There is an imperious need of redefining placebo effect in contemporary times. The effects of sham medical intervention, combined with a careful observation of the natural evolution of a disease, could reveal the true efficiency and impact of active drugs. This interest is not driven only by a scientific curiosity, but also by the pragmatic fact that the standard process of approving new medicines through supportive clinical trials requires a comparison against placebo. A complete understanding of the placebo effect should include both its psychological mechanisms and the underlying neurobiology. In contrast to other type of conditions, neurological disorders could provide specific clues in understanding the placebo effect, since the pathogenic mechanisms of different diseases might interfere with neuronal circuitry involved in the perception of disease symptoms. However, there are ethical considerations dictating the limits of using placebo. This paper reviews recent articles about placebo effect, with an emphasis on its importance in several neurological conditions (Parkinson's disease, neuropathic pain, headache, multiple sclerosis, epilepsy), and intends to offer new insights on this major topic. PMID- 20968196 TI - Overview about the keloid scars and the elaboration of a non-invasive, unconventional treatment. AB - Although the healing means 2 types of biological mechanisms that seem to be "pathologic", the swell and the granulations are a normal process in the biology of the human being, representing two systemic functions: the adaptation and the morphogenesis. There is a pathological healing in which the fundamental healing phenomenon is deviated from the normal. There are three variable parameters responsible for the pathological evolution of a scar: the cellular population, the fundamental matrix and the fibers. The healing evolution can be deviated to an intense maturation with an "old", atrophic scar, or to an incomplete maturation and the result is a hypertrophic or a keloid scar. For the hypertrophic scars, the excision and the skin graft lead to good results and the relapses are rare; the keloid relapse is always at the border between the graft and the wound edge, or between the two skin grafts. These are the considerations for which the treatments are mixed, combined (surgical, drugs, physiotherapy) both in our country and abroad, but the results are still frustrating. That is why new, modern methods of treatment are used today: criotherapy, laser, ultrasounds. However, even those treatments are not very successful: tissue expander, external press therapy, corticosteroids injections, other pharmacological agents (retinoic acid, colchicines, antineoplasics). We propose a regenerative, alternative, non-invasive treatment starting from the results we obtained in a research work 4 years ago, when we irradiated the fibroblasts in an electromagnetic high frequency millimeter waves field, and we obtained the fibroblasts apoptosis and the reorganization of the collagen fibers by changing the piezoelectric emission. PMID- 20968197 TI - Mass spectrometry and renal calculi. AB - The present review represents a concise and complete survey of the literature covering 2004-2009, concerning the mass spectrometric techniques involved in the structural investigation of renal calculi. After a short presentation of the fundamental mass spectrometric techniques (MALDI-TOF, QTOF, MS-MS) as well as hyphenated methods (GC-MS, LC-MS, CE-MS), an extensive study of the urinary proteome analysis as well as the detection and quantification by mass spectrometry of toxins, drugs and metabolites from renal calculi is presented. PMID- 20968198 TI - Efficacy and safety of Cerebrolysin in patients with hemorrhagic stroke. AB - The purpose of the study was to investigate the efficacy and safety of Cerebrolysin in patients with hemorrhagic stroke. The primary objective of this trial was to assess the clinical efficacy and safety of a 10-days course of therapy with a daily administration of Cerebrolysin (50 mL i.v. per day). The trial had to demonstrate that Cerebrolysin treatment is safe in hemorrhagic stroke. METHODS: The study was performed as a prospective, randomized, double blind, placebo-controlled, parallel group study with 2 treatment groups. Efficacy measures were the Unified Neurological Stroke Scale, Barthel Index, and Syndrome Short Test. The duration of the trial was of 21 days for each patient. Out of 100 randomized patients, a total of 96 (96%) completed the study. RESULTS: Overall, no statistically significant group effects were observed based on single average comparisons at the individual visits. It could be shown that the treatment of hemorrhagic stroke with Cerebrolysin is safe and well tolerated. CONCLUSION: In the changes of UNSS, BI and SST from baseline to day 21, the group differences are not statistically significant; however, the use of Cerebrolysin in hemorrhagic stroke is safe and well tolerated and studies with a larger sample size may provide statistical evidence of Cerebrolysin's efficacy in patients with hemorrhagic stroke. PMID- 20968199 TI - Evolution of chronic hypertensive nephropathies treated with ACE inhibitors on patients in pre-dialysis stage. AB - Arterial hypertension (HT), being the main factor of negative evolution for chronic nephropathies, has imposed a careful adjustment of pharmacological treatment. The widespread use of angiotensin conversion enzyme inhibitors (ACE inhibitors) has brought into attention the side effects of this class of antihypertensive drugs. The study focuses on the clinical and paraclinical evaluation of these elements, by means of detecting variations in serum creatinine, natriuresis and diuresis levels factors. In addition, cardiac cavity measurements have been made and the results have lead to the conclusion that the decision to administer ACE inhibitors has to be well founded, and patients should be closely monitored in order to prevent complications of the primary disease. PMID- 20968200 TI - Pressure sores--a constant problem for plegic patients and a permanent challenge for plastic surgery. AB - Pressure sores can be defined as lesions caused by unrelieved pressure resulting in damage of the underlying tissue. They represent a common problem in the pathology of plegic patients and, plastic surgery has a significant role in their treatment. Pressure sores occur over bony prominences and so, they are most commonly seen at the sacrum and trochanters in paralyzed patients and at ischium for the patients who sit in a wheelchair for a long time. For these patients, surgical treatment is very important because on one hand, it stops the loss of nutrients and proteins at the site of the pressure sore, and on the other hand, it permits the initiation of neuromuscular recuperation treatment much faster. PMID- 20968201 TI - Angiogenesis in the degeneration of the lumbar intervertebral disc. AB - The goal of the study is to show the histological and biochemical changes that indicate the angiogenesis of the intervertebral disc in lumbar intervertebral disc hernia and the existence of epidemiological correlations between these changes and the risk factors of lumbar intervertebral disc hernia, as well as the patient's quality of life (QOL). We have studied 50 patients aged between 18 and 73 years old, who have undergone lumbar intervertebral disc hernia surgery, making fibroblast growth factor and vascular endothelial growth factor level measurements, as elements in the process of appreciating the disc angiogenesis. Also, pre-surgery and post-surgery QOL has been measured, as well as the intensity of the pain syndrome. We have identified factors capable of stimulating vascular endothelial growth (VEGF, FGF-2) for the examined disc material, but histological examination did not show angiogenesis. The process of angiogenesis at the degenerated intervertebral disc level affects the patient's quality of life both pre and postoperatively, and may be a predictive factor for the post operative results. Patients can prevent the appearance of angiogenesis type degenerative processes of the intervertebral disc by avoiding angiogenesis correlated factors (weight control, physical effort, and smoking). PMID- 20968202 TI - Chronic myeloid leukemia therapy in the era of tyrosine kinase inhibitors--the first molecular targeted treatment. AB - Chronic Myeloid Leukemia is the first malignant disorder with a specific genetic abnormality in the background. Known as a disease with an inexorable progression to acute leukemia for many years, its natural history has been dramatically improved by the use of tyrosine kinase inhibitors (TKI). They represent the first molecular targeted therapy addressed to a neoplastic disorder. From these new classes of drugs, Imatinib was the first drug ever used, and it remains the standard therapy for patients in chronic phase with CML, having a global survival of 86%, for 7 years. The 2nd generation of TKI (Dasatinib, Nilotinib) is indicated for the patients who are refractory or intolerant to Imatinib. The other TKI have good promises to be efficient on the mutations of BCR-ABL transcript, especially to non-responsive T315I mutation. PMID- 20968203 TI - From interstitial cystitis to chronic pelvic pain. AB - There are still many things to be found out about interstitial cystitis/painful bladder syndrome (IC/PBS) because the pathological processes underlying the condition are not yet elucidated, biological markers of the condition are not yet available, and the type and severity of symptoms can vary, so, clearly defining the condition is not yet possible. For example, it is not clearly understood whether IC/PBS represents a systemic disease, if it is localized in the bladder, or if it was initially localized in the bladder and it later evolved into a systemic disease. This condition is best managed by using a multidisciplinary approach. Management requires a good integration and knowledge of all pelvic organ systems and other systems including musculoskeletal, neurologic, and psychiatric systems. PMID- 20968204 TI - The kidney in cirrhosis with portal hypertension. AB - Ascites, dilutional hyponatremia and hepatorenal syndrome are three clinical manifestations of the same physiopathological disorder: cirrhotic portal hypertension, hyperproduction of nitric oxide, arterial vasodilation with reduction of efficient arterial volume, which have as consequences renal vasoconstriction, sympathetic stimulation, the stimulation of renin-angiotensin aldosteron system and of vasopressin secretion. In dilutional hyponatremia, the selective receptor V2 (vasopressin 1) antagonists may be efficient according to Spanish and American specialists and also according to personal experience. PMID- 20968205 TI - Rare tumors of the heart--angiosarcoma, pericardial lipoma, leiomyosarcoma. Three case reports. AB - Primary tumors of the heart, pericardium and inferior vena cava are extremely rare. Three cases of surgically/biopsy proven angiosarcoma of the right atrium, pericardial lipoma and leiomyosarcoma of inferior vena cava--demonstrated by ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI)--are presented here. PMID- 20968206 TI - Depression as an initial feature of systemic lupus erythematosus? A case report. AB - Many patients with chronic illnesses suffer from clinical depression (with percentages reported by clinical studies ranging from 15 to 60); even depression is more common in people with chronic medical illnesses, (e.g. Systemic Lupus Erythematosus) than in the general population. However, not every patient with a chronic illness suffers from depression. It is well known that some people think the persons who suffer from a chronic illness have a reason to be depressed, so, there is no need to go to a psychiatrist for treatment. The fact is that not only the medical condition can be the cause for depression and, not always, the treatment for a medical illness can supply the treatment for depression. The condition of clinical depression, associated with a chronic illness, needs to be early diagnosed and early treated because it can worsen the medical state. Systemic Lupus Erythematosus (SLE) is a chronic, autoimmune disease, which affects many organs and systems. The link between lupus and depression is controversial but it is known that negative life events, lupus activity and the treatment for disease may be capable of contributing to clinical depression. We present the case of a young woman who was diagnosed with Systemic Lupus Erythematosus and who initially presented in the psychiatric department for depressive symptoms. The case raised problems in terms of diagnosis, treatment, etiology and prognosis. PMID- 20968207 TI - Laparoscopically treated pancreatic insulinoma. Case report. AB - Usually, insulinomas are small sized, insulin secreting, benign tumors of the pancreas, and require surgical treatment. We report the case of a female patient, of 61 years old, with pancreatic insulinoma localized in the junction between the head and the istm of the pancreas, of 1,4 cm in size, which induced hypoglycemia due to endogenous insulin hypersecretion. The tumor was removed by laparoscopic enucleation in March 2009. In the postoperative period, the blood glucose level came back to normal. PMID- 20968208 TI - Cutting the Gordian knot: the blockage of the jejunal tube, a rare complication of Duodopa infusion treatment. AB - We present the case of a 21-year-old man with advanced refractory Parkinson's disease treated with Duodopa continuous infusion. With this therapy, the patient had a spectacular recovery but after six months, he experienced an aggravation of his symptoms. A failure of his pumping system was suspected but we discovered that the jejunal tube was blocked due to a knot around a bezoar. This is the first complication of this kind described with the Duodopa infusion technique. PMID- 20968209 TI - Ureteroscopy--an essential modern approach in upper urinary tract diagnosis and treatment. AB - In recent years, urology has seen a real explosion in the development of new technologies. Modern treatment techniques replaced classic therapeutic methods, among which open surgery had an important role. Endourologic therapies led to effective and safe interventions, increased patient comfort and reduced costs. The "Saint John" Emergency Clinical Hospital Department of Urology always intended to align to the new standards of urological treatment including, primarily, minimally invasive techniques, some of them being performed as national premieres. Ureteroscopy is one of them, thus introducing the rigid and semi rigid endoscopes as part of the therapeutic arsenal of our clinic in 1994 and flexible ureteroscopy in 2002. If the targeted pathology was initially limited to stone disease, ureteroscopy currently covers a wide range of affections, being used both for therapeutic but also for diagnostic purposes. Thus, the ureteroscopic approach can diagnose and treat a wide range of upper urinary tract pathologies (lithiasis, tumors, malformations, iatrogenic injuries, etc.). The new technology acquisitions made by our clinic, increased performance, resulting in a complete and fast resolution in many cases, previously implying additional effort from the surgeons. If at first the ureteroscopies' share of daily practice was modest, in recent years it has achieved an extraordinary growth, thus becoming available to both experienced surgeons and young urologists. We believe that our extensive experience in endourological approach is significant and will have a say in the technological developments, which will help both the patients and the practicing urologists. PMID- 20968210 TI - Stress levels, alexithymia, type A and type C personality patterns in undergraduate students. AB - INTRODUCTION: Since there have been a number of empirical observations that may lead to the conclusion of an increasing rate of risk behaviors in Romanian students, such as aggression, over-competitive conduct and lack of collaboration, immorality, peer pressure and even an increasing rate of suicide, and suicide attempts, we have undergone a study to indentify if there is a high rate of risk type personality patterns that may lead to these deportments. MATERIAL AND METHODS: We have selected a total number of 500 students from the three largest universities in Bucharest, Romania--"Carol Davila" University of Medicine and Pharmacy (UMF), Bucharest Polytechnics University (UPB), and the Bucharest Academy of Economical Studies (ASE). All subjects received a questionnaire containing four diagnostic tools and several demographics questions. We have chosen the Twenty Item Toronto Alexithymia Scale (TAS20), the Jenkins Activity Survey (JAS-13) and the Anger-In Questionnaire for type C personality pattern. We have also added the Columbia stress analysis questionnaire for the evaluation of stress levels and coping capacity at the moment the subjects were interviewed. RESULTS: Columbia stress survey results confirm that there is a high stress level among students of all universities, but a more detailed stratification by university, gender and analyzed factor shows a very high F factor and T factor positive responses. Alexithymia, Type A and Type C personality patterns show a much higher prevalence than the general population, especially in medical students. We have found higher frequencies in men for all of the three studied parameters CONCLUSIONS: Approaching alexithymia and type A behavior both by cognitive methods and by assessing and addressing consequential risk factors should become an issue among universities. PMID- 20968211 TI - Planning for the years to come. PMID- 20968212 TI - Maternal mortality in 2010: where are we? PMID- 20968214 TI - Interprofessional education for the health professions. PMID- 20968215 TI - Extenuating circumstances: The University of South Dakota Physician Assistant Studies program. AB - During the course of graduating 15 classes of physician assistant students at The University of South Dakota much has evolved, yet our ultimate goal remains the same: To meet the needs of South Dakota and the region. The inaugural class graduated in 1995, making this year our 15th graduating class. The purpose of this article is to provide a brief historical background and to describe the evolution of the Physician Assistant Studies program. PMID- 20968213 TI - Regional Infant and Child Mortality Review Committee: 2009 final report. AB - The 2009 annual report of the Regional Infant and Child Mortality Review Committee (RICMRC) is presented. Since 1997, RICMRC has sought to achieve its mission to "review infant and child deaths so that information can be transformed into action to protect young lives." For the year 2009, the Committee reviewed 23 deaths from Minnehaha, Turner, Lincoln, Moody, Lake, McCook, Union, Hanson, Miner and Brookings counties that met the following criteria: Children under age 18 dying subsequent to hospital discharge following delivery. Children who either died in these counties from causes sustained in them, or residents who died elsewhere from causes sustained in the 10-county region. The acronym SUID, (Sudden Unexpected Infant Death), is being increasingly used by investigators of infant deaths. SUID is an intentionally broad category used for any infant death where the cause of death is unapparent or multifactorial. Sudden Infant Death Syndrome (SIDS) is a subset of SUID. No deaths categorized as SIDS occurred in 2009. The committee has observed a stable decline in the number of deaths due to SIDS for the last several years with the exception of two SIDS deaths that occurred in 2008. The national SIDS rate of 0.55 per 1000 live births would suggest that our region should have one SIDS death per year. It would appear, on the average, that our region's SIDS incidence is close to that number. Many investigators believe that a "diagnostic drift" is occurring in the SIDS diagnosis. These investigators believe that some deaths certified as SIDS in earlier years may now be classified as "undetermined," or in the new terminology, SUID. Although the committee strives to be consistent year to year in its death investigation protocols, we have noticed that the number of deaths classified as "undetermined" has been increasing over the last few years (Figure 1). The majority of our "undetermined" manners of infant deaths appear to be related to concerns about possible asphyxial risks (e.g., overlaying, re-breathing and true suffocation). Our data may be mirroring a national trend among death investigators to increasingly recognize asphyxial risks in infant death scenes. PMID- 20968216 TI - The importance of prevention. PMID- 20968217 TI - DAKOTACARE update: Make that change: vote yes on 12! PMID- 20968218 TI - "Once upon a time..."--narrative in nursing. PMID- 20968219 TI - The relationship of physical function to social integration after stroke. AB - Stroke is a leading cause of death and a serious long-term disability in this country. Much of the research on stroke rehabilitation has focused on physical/functional recovery as the predominant measure of outcome. There is a gap in knowledge of social issues and integration into societal, family, and community roles after stroke. A descriptive, correlational survey design was used to examine the relationships of functional status, depression, and overall stroke recovery to social integration in a convenience sample of ischemic stroke survivors. The survey response rate was 21.4%. Results showed that functional status, overall stroke recovery, and depression are highly significant predictors of social integration, explaining 62% of the variance (adjusted R2). Comorbid depression was negatively (-.74) and significantly (.01, two-tailed) correlated to social integration, such that higher levels of depression are associated with lower levels of social integration. Finally, employment status after stroke dropped from 48% to 4.2%, and poststroke employment status was correlated to social integration (significance = .03). Care for patients with chronic conditions like stroke should address all domains of the individual-physical, psychosocial, and environmental. Factors including depression and perceptions of overall stroke recovery are significant and should be addressed in the rehabilitation process to better promote social integration. Social integration is an important and understudied aspect of stroke recovery that warrants further research. PMID- 20968220 TI - Changes in the acute functional and cognitive disability states of severe hemorrhagic stroke patients. AB - The purpose of this study was to characterize temporal patterns of functional and cognitive disability changes during the acute period in hemorrhagic stroke patients. The study subjects were 62 hemorrhagic stroke patients admitted to a surgical intensive care unit at a university hospital located in Incheon, South Korea. As outcome variables, functional disability, cognitive ability, and employment status were evaluated directly at 1, 3, and 6 months after admission. The results showed that significant improvements in functional and cognitive ability were observed between 1 and 6 months after admission. In terms of functional disability, subjects considered their overall functional ability (dependence on others) to be less recovered than the specific functional abilities (feeding, grooming, or toileting): 75% of the subjects stated that they were completely independent on others, whereas 92.9%, 83.9%, and 83.9% of subjects indicated that they were completely independent for feeding, grooming, and toileting at the 6-month assessments, respectively. In terms of cognitive ability, attention, communication, and memory recovery rates were found to be relatively good. However, the proportion of subjects that achieved complete problem solving and safety and social behavior recovery were lower than those that achieved attention, communication, and memory recovery. Our findings can provide the empirical evidences when neuroscience nurses use educational and supportive strategies for rehabilitation of hemorrhagic stroke patients. PMID- 20968221 TI - The future of cognitive remediation training in older adults. AB - With the growing population of older adults, nurses will need to address age related cognitive declines. Evidence demonstrates that cognitive remediation training is effective in improving neuropsychological abilities in older adults, which can translate into improved functioning in instrumental activities of daily living. The future of cognitive remediation training will incorporate health promoting factors (e.g., sleep hygiene, physical exercise), which supports neuroplasticity and cognitive reserve. By approaching cognitive health holistically, the patient will be primed to receive the maximum benefit from cognitive remediation training. A model emphasizing this approach is provided as adidactic for nurses and other health professionals providing care to their older patients. PMID- 20968222 TI - Quality of life in patients with multiple sclerosis in Turkey: relationship to depression and fatigue. AB - The purposes of this study were to assess the self-reported quality of life (QOL) in a group of Turkish patients with multiple sclerosis (MS) and to analyze whether the QOL was associated with fatigue and depression. The study used a descriptive design. A number of evaluation scales were administered to a study sample comprising 47 outpatients. The Short Form 36 for QOL, the Beck Depression Inventory for Depression, and the Visual Analogue Scale for Fatigue were used. The mean score for general QOL was 34.8 and indicated low QOL in MS patients. The results of our study have also shown that fatigue and depression strongly influence QOL in Turkish MS patients. Our findings may have important implications for the overall care of MS patients. The QOL of MS patients was affected negatively. Both fatigue and depression are common and treatable manifestations of MS, and these symptoms should be screened carefully in all MS patients. Care of MS patients requires the collaboration of all team members. Nurses have a key role as part of this team through the continuity of the care they provide and interaction with patients. Awareness of depression and fatigue can contribute to the nurses' ability to provide psychological support and enhance the QOL in MS patients. PMID- 20968223 TI - Recognizing the needs of family members of neuroscience patients in an intensive care setting. AB - This quantitative study was designed to identify the needs of family members of neuroscience patients. An adaptation of the Critical Care Family Needs Inventory was used to identify the top 10 needs of neuroscience families. Results were compared on the basis of whether the admission was planned or emergent. Needs were further examined on the basis of a family's perception of patient prognosis and communication with physicians and nurses. Most needs were recognized as being either important or very important with the need for information about the patient's care receiving the highest rating. Significant differences were noted between family members who expected their loved one to return to normal or with a slight decrease in activity versus those who expected their loved one to have a moderate to complete inability to perform normal activities. Communication with nurses was rated excellent or good significantly more often than communication with physicians. PMID- 20968224 TI - Effect of body position on cerebral oxygenation and physiologic parameters in patients with acute neurological conditions. AB - How body position influences brain tissue oxygen (PbtO2) and intracranial pressure (ICP) in critically ill neurosurgical patients remains poorly defined. In a prospective observational repeated measures study, we examined the effects of 12 different body positions on neurodynamic and hemodynamic outcomes. Thirty three consecutive patients (mean +/- SD, age = 48.3 +/- 16.6 years; 22 men), admitted after traumatic brain injury, subarachnoid hemorrhage, or craniotomy for tumor, were evaluated in a neurocritical care unit at a level 1 academic trauma center. Patients were eligible if the admission score in the Glasgow Coma Scale was < or =8 and they had a Licox CMP Monitoring System (Integra Neurosciences, Plainsboro, NJ). Patients were exposed to all 12 positions in random order. Changes from baseline to the 15-minute postposition assessment mean change scores showed a downward trend for PbtO2 for all positions with statistically significant decreases observed for supine head of bed (HOB) elevated 30 degrees and 45 degrees (p < .01) and right and left lateral positioning HOB 30 degrees (p < .05). ICP decreased with supine HOB 45 degrees (p < .01) and knee elevation, HOB 30 degrees and 45 degrees (p < .05), and increased (p < .05) with right and left lateral HOB 15 degrees. Hemodynamic parameters were similar in the various positions. Positioning practices can positively or negatively affect PbtO2 and ICP and fluctuate with considerable variability among patients. Nurses must consider potential effects of turning, evaluate changes with positioning on the basis of monitoring feedback from multimodality devices, and make independent clinical judgments about optimal positions to maintain or improve cerebral oxygenation. PMID- 20968225 TI - Guillain-Barre syndrome: management and treatment options for patients with moderate to severe progression. AB - Guillain-Barre syndrome (GBS) is a syndrome that affects the immune system and attacks the peripheral nervous system. Discussion includes defining GBS as well as its etiology and differential diagnosis. Patients with GBS are not uncommon, and therefore it is important to be educated and to have a more precise understanding. GBS patients need to be treated holistically through emotional and physical support and known effective treatments. Through this article, readers will be able to achieve a thorough understanding of GBS and management options/strategies. Clinical features and manifestation of presenting symptoms will assist in determining initial laboratory studies, imaging, and any other testing that should be performed. Proper and quick diagnosis of GBS will be critical to further optimize treatment options and to decrease the likelihood of further immediate progression. Treatment modalities will be discussed as well as management during the acute hospital course and after discharge from the acute care facility. Discussion will focus on moderate to severe cases and associating treatment plans evaluated from evidence-based practice. PMID- 20968226 TI - Cavernous malformations. AB - Cavernous malformations (CMs) are a subset of neurovascular malformations, which include arteriovenous malformations (AVMs), venous malformations, and capillary telangiectasias. CMs are referred to by many names, which may contribute to their being mistaken for malignant entities such as angiomas or hemangiomas. They are not, however, neoplastic; they are true vascular malformations with their own natural history and treatment. This article describes CMs and their clinical manifestations, methods of diagnosis, and types of treatment. CMs exist in both sporadic and familial forms. Nurses caring for patients with CMs should be aware of the specific characteristics of CMs that differentiate them from other neurovascular lesions. PMID- 20968227 TI - Biographical chronology and selected bibliography of Norman William Kingsley, pioneer in orthodontics. AB - Norman W. Kingsley (1829- 1913) of New York City was one of the great contributors to the early development of orthodontics and cleft palate therapy. His biographical chronology is presented, based largely on a little-known autobiography published in 1907 when he was 77 years old. Also presented is a Kingsley bibliography with key publications by and about this remarkable pioneer in orthodontics. PMID- 20968228 TI - Stereoradiography and related early radiographic localization techniques. AB - Enhancing interpretation, 3-D dental radiographic imaging and has become widely accepted and utilized in general dental practice. Stereoradiography is one of the earliest 3-D techniques and remains useful today for localized objects radiographically. This paper reviews the development of early radiographic localization techniques and follows stereoradiography to its current uses. PMID- 20968229 TI - Excellence in education--seasoned with a smattering of endodontics. PMID- 20968230 TI - Mosquitoes, flies and dental cavities: Dr. Howard Riley Raper's public campaign to prevent toothache. AB - Dr. Howard Riley Raper (1886-1978) was an early oral health pioneer and dental roentgenology faculty member of the Indiana Dental College (IDC) who single handedly introduced key concepts in radiology to dentistry. Due to his efforts, IDC became in 1910-11 the first dental school to have a regular course in dental radiology. Virtually all American dental schools soon added this subject to their regular curriculum. Raper's text, Elementary and Dental Radiography (1913) became the first comprehensive student textbook of dental X-ray diagnosis. In his 1933 Blue Book entitled, The New Aim in the Care of the Teeth, Raper elaborated upon his mission to prevent caries, by comparing the insidious damages of tooth decay with the threat of insect-borne disease. PMID- 20968231 TI - Looking back to the future:. PMID- 20968232 TI - COM-FSM joins the health "extended family". PMID- 20968233 TI - Disease in Micronesia: a historical survey. PMID- 20968234 TI - An analysis of FSM national health care expenditures from 1997-2005. AB - National health care expenditures in the Federated States of Micronesia (FSM) have increased from 1997-2005. However, population mortality trend is increasing particularly deaths due to lifestyle related diseases or non-communicable diseases (NCDs). Result of the national health account review shows that FSM spent so much on caring for those already sick or who will be sick but less in creating the environments or opportunities for healthy individuals to stay healthy. PMID- 20968235 TI - "Go local" island food network: using email networking to promote island foods for their health, biodiversity, and other "CHEEF" benefits. AB - Dietary- and lifestyle-related diseases are problems of epidemic proportion in the Federated States of Micronesia (FSM). Public health resources to help prevent nutrition-related problems are limited. There is also concern about biodiversity, neglect of traditional staple foods, and threatened loss of traditional knowledge. A "Go Local" campaign was initiated to increase production and consumption of locally grown foods, for their Culture, Health, Environment, Economics, and Food security ("CHEEF") benefits. To provide updates and discuss local island food topics, the Island Food Community of Pohnpei launched an interagency email network in 2003. Interested members' email addresses were recorded in distribution lists, weekly/bi-weekly emails were sent and from these messages, a database was organized to record email topic details. An analysis of all emails up to July 2009 showed that membership had expanded to over 600 listed people from all FSM states, other Pacific Island countries and beyond. Information was shared on topics ranging from scientific findings of carotenoid content in local island food cultivars, to discussions on how daily habits related to island food use can be improved. Over 200 men and women, aged 22 to 80 years, contributed items, some indicating that they had shared emails to a further network at their workplace or community. In conclusion, this email network is a simple, cost-effective method to share information, create awareness, and mobilize island food promotion efforts with potential for providing health, biodiversity and other benefits of island foods to populations in the FSM and other countries. PMID- 20968236 TI - Resistant starch in Micronesian banana cultivars offers health benefits. AB - Resistant Starch (RS) is a type of starch that is resistant to starch hydrolyzing enzymes in the stomach and thus behaves more like dietary fibre. RS has been shown to have beneficial effects in disease prevention including modulation of glycaemic index diabetes, cholesterol lowering capability and weight management, which are critically important for many people in the Federated States of Micronesia. Green bananas are known to contain substantial concentrations of RS and are a common part of the Micronesian diet. Therefore the aim of this study was to determine the RS content in banana cultivars from Pohnpei, Micronesia: Daiwang, Inahsio, Karat, Utin Kerenis and Utin Ruk, for which no such information was available. Utin Kerenis, Inahsio and Utin Ruk were found to contain the highest amounts of RS. The fate of RS after incorporation into a food product (i.e., pancakes) was also studied and a significant reduction in the RS content was found for each cultivar after cooking. Microscopy of the banana samples indicated that the overall morphology of the cultivars was similar. In conclusion, green banana, including these varieties, should be promoted in Micronesia and other places for their rich RS content and related health benefits including diabetes control. Further research is needed to more clearly determine the effects of cooking and food processing on RS. PMID- 20968237 TI - Evaluation of a "traditional food for health" intervention in Pohnpei, Federated States of Micronesia. AB - Federated States of Micronesia (FSM) faces increasing rates of non-communicable diseases related to the neglect of the traditional food system and the shift to consumption of imported food and adoption of sedentary lifestyles. To reverse this trend, a two-year, food-based intervention in one Pohnpeian community in FSM promoted local food production and consumption using a variety of approaches including education, training, agriculture and social marketing following a "Go Local" message. Foods promoted were banana, giant swamp taro, breadfruit and pandanus varieties, green leafy vegetables and fruits for their provitamin A and total carotenoids, vitamins, minerals and fiber content. An evaluation was conducted in a random sample of households (n=47) to examine the extent of dietary changes following the intervention. Results indicated increased (110%) provitamin A carotenoid intake; increased frequency of consumption of local banana (53%), giant swamp taro (475%), and local vegetables (130%); and increased dietary diversity from local food. Exposure to intervention activities was high and there were positive changes in attitudes towards local food. The intervention approaches appear to have been successful in this short period. It is likely that similar approaches in additional communities in Pohnpei and other parts of the Pacific would also be successful in promoting local food. Evidence gathering should continue to document the long-term health outcomes of increased reliance on local food. PMID- 20968238 TI - A large foodborne outbreak on a small Pacific island. AB - On March 25, 2009, the Ebeye Leroj Kitlang Memorial Health Center on the island of Ebeye in the Republic of the Marshall Islands was overwhelmed with over 100 patients presenting for vomiting and diarrhea. Epidemiologic investigation revealed that there were 174 cases among 187 attendees at a local funeral earlier in the day. Most cases had eaten served sandwiches containing egg products that had undergone severe time-temperature abuse. While no causal agents were identified, the epidemiology and clinical presentation is compatible with foodborne toxins, most likely enterotoxins of either Staphylococcus aureus or Bacillus cereus. Mitigation measures undertaken by public health centered on education of food preparers and the general public regarding safe food preparation practices. This large outbreak serves to remind us that, while there are simple and highly effective measures to prevent such foodborne disease outbreaks, we in the public health sector have a duty to improve the community's knowledge and understanding of these measures. PMID- 20968239 TI - Meeting Chamorro women's health care needs: examining the cultural impact of mamahlao on gynaecological screening. AB - Peoples of Micronesia customarily seek western medical care only when needed and not typically as a preventive care. There is a subtle reluctance to resorting to available modern biomedical practices. This article discusses cultural aspects of Chamorro women's preventive health-seeking behavior. It specifically examines the effect that the Chamorro cultural value of mamahlao, or a sense of shame, has on women getting Papanicolaou (Pap) tests and other ways mamahlao dissuades modern day Chamorro women from seeking preventive gynecological care. A purposive sample of fifteen Chamorro women living on Guam participated in this exploratory study. A semi-structured interview was administered and included questions on what mamahlao means to them, appropriate versus inappropriate reasons why women should get annual Pap tests, and the relationship between mamahlao and modesty in women. The interviews revealed women's concerns with shame, religion, and morality in their health-seeking behavior. The study suggests that for a Chamorro woman, seeking gynecological care can have negative symbolic connotations thereby for creating a sense of shame or mamahlao, in the woman. PMID- 20968241 TI - A pilot study for the primary prevention of rheumatic fever in Kosrae, Federated States of Micronesia. AB - Rheumatic fever (RF) and its sequel, Rheumatic Heart Disease (RHD) is a disease of significant medical and public health concern in the Federated States of Micronesia. In this preliminary study the feasibility of a rheumatic heart disease primary prevention strategy was examined. Throat swabs were taken from 667 school-aged children and tested for group A streptococci (GAS) by a rapid antigen detection test (RADT): a subset was also tested by conventional culture, so as to compare the RADT with the reference (conventional culture) test. GAS was detected in 124% of the children tested by either rapid antigen test or conventional culture; for RADT alone the detection rate was 11.5% and for culture alone the detection rate was 9.4%. Detection rate of GAS was analyzed in symptomatic and asymptomatic subgroups. The subgroups were compared using Fisher's exact method. The identification of children with GAS allows for their further examination and treatment so that the prevalence of GAS in this vulnerable population, currently with an annual incidence of rheumatic fever of 50-134/100,000, may be reduced. The routine testing of school-aged children appears to be possible with current resources in Kosrae and can be a cost effective public health measure. PMID- 20968240 TI - Hepatitis A in Pohnpei State, Federated States of Micronesia, 2008-2009. AB - An epidemic of infectious hepatitis caused by the hepatitis A virus was detected in Pohnpei State, Federated States of Micronesia (FSM), beginning in November 2008. Epidemiologic investigation revealed that the index case occurred in late June 2008 in a traveler from nearby Chuuk State, which itself had experienced an epidemic of hepatitis A in the first half of 2008. Most cases have been confirmed by IgM serology, the rest by a clinically compatible syndrome with either jaundice or elevated liver enzymes. The most commonly affected group has been school-aged children; it is likely that the paucity of patients in the 40-50 year age group represents immunity conferred during the previous epidemic of hepatitis A in the early 1970's, as hepatitis A is not thought to be endemic in Pohnpei. As of September 17, 2009 there have been 300 reported cases with 17 hospitalizations (6%) and one death (0.3%). The epidemic peaked in April 2009, with a sharp decline in cases in June attributable with the end of the school year, as schools were found to be the major focus of infection. Efforts to control the outbreak have centered on public awareness and improved hygiene initiatives, particularly in schools. The greatest challenge to ongoing diminution of the outbreak is the recent resumption of the school year; control efforts, especially improved hygiene, will need to be sustained with renewed vigor if we are to extinguish the outbreak. PMID- 20968242 TI - Role of GIS technology during leprosy elimination efforts in Pohnpei. AB - This article summarizes Pohnpei State Department of Health Services' utilization of GIS technology and GPS mapping of leprosy cases during the leprosy elimination efforts. Maps generated from ArcMap provided 'hotspots' or areas of high case density, thus providing for more focused screening. Introducing GIS technology in the elimination efforts has led to a diminution of the target number of screened clients per year, thus minimizing resource utilization. GPS technology as a health planning tool in small Pacific island countries can synergize local screening efforts and improve overall public health planning and implementation, in a way that is cost-effective and resource friendly. PMID- 20968243 TI - Mortality analysis of registered deaths in the FSM from 1990-2003. AB - This paper discusses the result of a mortality analysis carried out in the Federated States of Micronesia in 2005. The result shows that the population crude mortality rate decreased slightly between the years 1990-1992. Disease specific mortality was highest among the chronic, or non-communicable diseases (i.e., diabetes, stroke, cancer, heart disease combined) compared to communicable diseases and injury combined. In addition, the study suggests that mortality due to NCD is occurring among people as young as 40 years old. In order to curb this trend, the authors recommend drastic change to the current health care delivery system. PMID- 20968244 TI - Multi-drug resistant tuberculosis in Chuuk State Federated States of Micronesia, 2008-2009. AB - Multi-drug resistant tuberculosis (MDR TB) is a growing public health concern, particularly for the Pacific, where rates of tuberculosis infection are extremely high. In May 2008, a cluster of patients with MDR TB were identified in Chuuk State, Federated States of Micronesia. A multi-agency investigation led to the eventual discovery of 21 cases, and over 100 latent TB infections. Incomplete implementation of Directly Observed Therapy (DOT) and contact investigation were major contributors to the outbreak. The problem of MDR TB in Chuuk was controlled only after a concerted effort on the part of multiple agencies coupled with the highest level of political commitment. PMID- 20968245 TI - Pohnpei, FSM case study in a global health project documents its local food resources and successfully promotes local food for health. AB - This paper presents a summary of Pohnpei, Federated States Micronesia's involvement in a global health study focused on documenting traditional food systems in different parts of the world and providing evidence that local resources are critical for food security, nutrition and health. The Pohnpei study was based in Mand Community, Madolenihmw. The study found that there was a great diversity of foods locally available (381 food items documented), but these were underused. Overweight, obesity, diabetes, and vitamin A deficiency were identified as serious problems. Interventions included community meetings, school activities, and agriculture workshops, cooking classes, charcoal oven development, weight loss and planting competitions, poster campaigns and other relevant mass media. Significant dietary improvements were achieved following the intervention efforts, as well as positive changes in attitude towards local food including: decrease in average daily rice consumption from 846 g/person in 2005 to 544 g/person in 2007 (p = 0.0002); increase in provitamin A carotenoid intake from 227 microg/person in 2005 to 475 microg/person in 2007 (p = 0.02); increased frequency of consumption of local banana (53%), giant swamp taro (476%), local vegetables (130%); and increased dietary diversity (4.8 local food groups consumed in 2005 to 5.5 in 2007). Another positive outcome in Pohnpei was the popularization of the slogan "Let's Go Local." PMID- 20968246 TI - Connecting the disconnected: what FSM is doing? AB - This paper describes the effort the FSM Department of Health and Social Affairs has carried out to connect its geographically disconnected and isolated hospitals and health facilities on the same health information network. It discusses the rationale and the process for such undertaking, lists the achievements the project has made, and lays the vision for its future direction. PMID- 20968247 TI - Microphthalmia and anophthalmia in Chuuk State, Federated States of Micronesia. AB - Microphthalmia ('small eye') and anophthalmia ('no eye') are rare congenital defects of eye development. Previous studies utilizing a variety of methodologies have estimated their combined incidence at anywhere from 4 to 30 cases per 100,000 live births. In Chuuk, Federated States of Micronesia, there have been 42 cases detected since 1988, yielding an estimated incidence of 140 cases per 100,000. A number of putative genetic and environmental causes have previously been associated with microphthalmia and anophthalmia, including vitamin A deficiency. To date, it is unclear which of these factors may play a role in the alarmingly high rates observed in Chuuk. The Chuuk Division of Public Health has proposed a study to explore these potential causes, which will hopefully shed light on the prevention of these rare but debilitating conditions. PMID- 20968248 TI - Hospital medical libraries populate the Micronesian region. PMID- 20968249 TI - "Pre-health": talent search and substance abuse awareness among FSM high school leavers--a summary report. PMID- 20968250 TI - Tuberculosis trends in the Pacific: 2000-2006. AB - The objective in this manuscript is to describe the epidemiology of tuberculosis in 19 Pacific Island countries and territories by analysing routine surveillance data from 2000 to 2006. In addition, progress against World Health Organization targets is described. The setting is National Tuberculosis Programmes in 19 Pacific Island countries and territories served by the Secretariat of the Pacific Community. The study is a descriptive study of routinely collected surveillance data from 19 Pacific Island countries and territories. In 2006 there were 1585 cases of TB notified in the Pacific region. The case notification rate in the Pacific was 54/100,000 population. Almost half (49%) of all TB notifications were in the subregion of Micronesia, with 42% in Melanesia and 9% in Polynesia. Micronesia had the highest rate of TB in the region with a case notification rate of 145/100,000 population. The TB case notification rate in the Pacific increased by 10% between 2000 and 2006, from 49/100,000 to 54/100,000 population. The highest increase in rates has been in Micronesia, where the TB case notification rate rose by 39% between 2000 and 2006. In the Pacific in 2006, 71% of all TB notifications were pulmonary, and just over one third (36%) of all TB notifications were sputum smear positive. One quarter (25%) of sputum smear positive cases were in people aged 15-24 years and slightly more than half of all sputum smear positive cases were in males (52%). In Micronesia this pattern was different; 61% of all sputum smear positive cases were in males. In 2005, the treatment success rate of new sputum smear positive cases in the Pacific was 85%, equivalent to the WHO target. The treatment success rate of sputum smear positive cases rose from 78% in 2000 to 85% in 2005, an increase of 7%. In 2005, 4% of all people with TB died, and of those with sputum smear positive TB, 8% died. In 2005 in Polynesia, 13% of all people with sputum smear positive TB died. Since the year 2000, the rates of TB have increased in the Pacific region, with a relatively large increase in the subregion of Micronesia. Treatment success rates in the same time period have improved and are now at the WHO target of 85%. The conclusion is that to continue to make progress toward TB control in the region, intensified efforts may be needed in the sub-region of Micronesia while support is also maintained at current or increased levels in Melanesia and Polynesia. PMID- 20968251 TI - Human resources for public health challenges in the western Pacific--local community colleges respond. PMID- 20968252 TI - A perspective on health care development in Micronesia. PMID- 20968253 TI - Perspectives on testicular mass in a 4-year-old boy. PMID- 20968254 TI - A primer for quality assurance and improvement in Pacific island health services. AB - Quality assurance and improvement (QA/QI) systems are underdeveloped in Pacific island jurisdictions and building QA/QI capacity is one of the best opportunities for quickly improving performance of health services in the region. There is a variety of styles available for QA/QI in health care organizations and the best approach will vary with the size, scope of practice, and needs of the organization. This report briefly describes the major styles of QA/QI and provides suggestions for QA/QI program approach based on several common Pacific island scenarios. PMID- 20968255 TI - Veteran suicide. PMID- 20968256 TI - Millennial medicine hurdles. PMID- 20968257 TI - Evaluating evidence of risk for suicide among veterans. PMID- 20968258 TI - Physically demanding jobs and occupational injury and disability in the U.S. Army. AB - Effective job assignments should take into account physical capabilities to perform required tasks. Failure to do so is likely to result in increased injuries and musculoskeletal disability. OBJECTIVE: To evaluate the association between job demands and health outcomes among U.S. Army soldiers. METHODS: Multivariate Cox proportional hazards analysis is used to describe associations between job demands, hospitalizations, and disability among 261,096 enlisted Army soldiers in heavily, moderately, and lightly physically demanding occupations (2000-2005) who were followed for up to 5 years. RESULTS: Controlling for gender, race, and age, soldiers in heavily demanding jobs were at increased risk for any cause injury, on-duty injuries, any-cause hospitalizations, and any-cause disability, but not for musculoskeletal disability. CONCLUSION: Army job assignments should more accurately match physical capabilities to job demands and/or jobs should be redesigned to reduce injuries. Though musculoskeletal disorders are often the result of acute injury, the demographic and occupational risk patterns differ from acute injury. PMID- 20968259 TI - Challenges and considerations for managing suicide risk in combat zones. AB - As suicide rates in the military rise, increased attention has been placed on the effective management of high-risk service members. Military mental health professionals deployed to combat zones face a number of challenges and barriers for effective risk management that are unique to the deployed setting. To date, there exists no body of literature identifying areas in which suicide risk management differs between garrison and combat settings to guide mental health professionals in improving clinical decision making with respect to managing suicidal service members in combat zones. On the basis of experience gained during deployments to combat zones, the authors outline several key features of the deployed context that can impact suicide risk and its effective management in combat zones and integrate empirical findings relevant to each issue. Considerations for clinical care and risk management are discussed. PMID- 20968260 TI - Trauma disclosure to health care professionals by veterans: clinical implications. AB - Trauma disclosure is the initial step toward healing trauma-related distress. This study used qualitative methods to better understand factors facilitating and inhibiting change in the disclosure process. Fifty-six veterans were interviewed about their disclosure experiences between August 2004 and 2005. Emerging themes and barriers to disclosure from 23 of these interviews are reported in this article. Barriers to trauma disclosure included lack of trust in the provider, fears about the potential negative consequences of disclosure, and trauma avoidance. Providers perceived as caring and communicating at the same level as the participants facilitated disclosure, whereas providers perceived as uncaring or disinterested inhibited disclosure. Veterans reported both positive and negative reactions to initial disclosure, but nearly all agreed that disclosure was worthwhile over the long-term. Improving patient-provider communications and creating settings that facilitate trauma disclosure may improve healing after trauma. PMID- 20968261 TI - Preliminary normative data for the Evaluation of Risks Scale-Bubble Sheet Version (EVAR-B) for large-scale surveys of returning combat veterans. AB - OBJECTIVE: The Evaluation of Risks (EVAR) scale has been used to assess risk taking propensity in military samples. This report provides preliminary reliability, validity, and normative data on a modified version of the instrument designed to facilitate data entry with optical scanners, the Evaluation of Risks Bubble Sheet version (EVAR-B). METHODS: 2,015 U.S. Army soldiers completed the EVAR-B and a survey assessing risk-related behaviors 3 months after returning home from combat deployment in Iraq. RESULTS: EVAR-B demonstrated acceptable internal consistency and reliability and correlated significantly with independent measures of self-reported risk-taking behavior, including alcohol use and aggressive behavior, in the weeks preceding the survey. Tentative cut-offs significantly differentiated heavy drinkers, dangerous drivers, and soldiers reporting recent aggressive outbursts. Normative data are provided for comparison with future studies. CONCLUSIONS: The EVAR-B is a reliable and valid measure of risk-taking propensity, which provides enhanced flexibility for administration and scoring in large surveys and field environments. PMID- 20968263 TI - Arthroscopic removal of improvised explosive device (IED) debris from the wrist: a case report. AB - We present a case in which arthroscopy was used to remove foreign body debris secondary to an improvised explosive device (IED) from the wrist. The patient had noted pain for 6 months after sustaining multiple injuries after an IED detonation near the armored car in which he was traveling. He had pain on examination at the ulnar fovea with palpation and palpable clunking with forced ulnar deviation. Radiographs showed multiple small metallic objects scattered throughout the soft tissues, with one larger intra-articular object in the wrist. Metallic objects in joints can cause lead toxicity, chondral injury, and inflammatory reaction or abscess. Minimally invasive surgical treatment was proposed with the goals of further joint evaluation and excision of the metallic debris. Arthroscopic removal of the foreign body and repair of the triangular fibrocartilage complex resolved the patient's symptoms, and he had improved function at final follow-up at 22 months. PMID- 20968262 TI - Psychiatric comorbidity and mortality among veterans hospitalized for congestive heart failure. AB - A Behavioral Model of Health Services Utilization approach was used to examine the impact of comorbid mental illness on mortality of veterans admitted to Veterans Affairs medical centers in fiscal year 2001 with a primary diagnosis of congestive heart failure (n = 15,497). Thirty percent had a psychiatric diagnosis, 4.7% died during the index hospitalization, and 11.5% died during the year following discharge. Among those with mental illness, 23.6% had multiple psychiatric disorders. Multivariable logistic regression models found dementia to be positively associated with inpatient mortality. Depression alone (excluding other psychiatric disorders) was positively associated with one-year mortality. Primary care visits were associated with a reduced likelihood of both inpatient and one-year mortality. Excepting dementia, VA patients with a mental illness had comparable or higher levels of primary care visits than those having no mental illness. Patients with multiple psychiatric disorders had more outpatient care than those with one psychiatric disorder. PMID- 20968264 TI - How communication with families can both help and hinder service members' mental health and occupational effectiveness on deployment. AB - Communication with home can be beneficial to deployed service members' mental health, morale, and occupational effectiveness. Conversely a lack of communication with home increases the risk of developing mental health problems. Therefore it is important to ensure that communications media is both affordable and accessible while on deployment. However, contact with families can sometimes have negative effects, particularly when problems arise at either end. It can also be difficult for military personnel and their families if the level of contact is lower than they expected. Conversely, too much contact with home may have a negative impact on occupational effectiveness. More research is required to determine the optimal level of communication with home. Additional research is required to determine which types of communications media are most beneficial and whether the benefits of communication with home differ depending on the context of the deployment and the family status of the service member. PMID- 20968265 TI - Gender differences in traumatic event exposure and mental health among veteran primary care patients. AB - OBJECTIVE: This study evaluated gender differences in lifetime traumatic events, PTSD, and depression among VA primary care patients. METHOD: Participants were 865 adults attending primary care at one of four VA health centers (n = 681 males, 184 females). RESULTS: Mental health findings included: male PTSD 12.3% vs. female PTSD 9.2% (p > 0.05); male depression 15.9% vs. female depression 29.3% (p < 0.001). Men reported more war zone exposure (p < 0.001). Women reported more physical and sexual victimization (p < 0.001). Male logistic regression equations determined PTSD was associated with disability (OR = 3.42; 1.74-6.72, 95% CI) and war zone exposure (OR = 7.14; 3.82-13.30, 95% CI); depression was associated with war zone exposure (OR = 2.27; 1.40-3.68, 95% CI) and interpersonal violence (OR = 1.75; 1.10-2.79, 95% CI). Female PTSD was associated with sexual victimization (OR = 4.50; 1.20-16.80, 95% CI); depression was not predicted. CONCLUSIONS: We discuss findings in terms of the crucial need to improve identification and management of PTSD within VA primary care settings. PMID- 20968266 TI - Insomnia is the most commonly reported symptom and predicts other symptoms of post-traumatic stress disorder in U.S. service members returning from military deployments. AB - This study retrospectively reviewed records from current members of the U.S. military who had completed the PTSD Checklist (PCL) at 0 and 3-months after returning from deployments. Insomnia was the most commonly reported symptom of PTSD on the PCL and had the highest average severity scores. At initial screen, 41% of those who had been to Iraq or Afghanistan reported sleep problems. Those who had initially reported any insomnia had significantly higher overall scores for PTSD severity at follow-up than did service members without such a complaint. These results show that insomnia is a particularly frequent, severe, and persistent complaint in service members returning from deployment. Such complaints merit particular attention in relation to the possibility of PTSD. PMID- 20968267 TI - Effects of Iraq/Afghanistan deployments on PTSD diagnoses for still active personnel in all four services. AB - We estimate the effect of deployment location and length on risk of developing post-traumatic stress disorder (PTSD). We draw a random sample of active duty enlisted personnel serving between 2001 and 2006 from a TRICARE beneficiary database and link deployment characteristics from the contingency tracking system. Using logistic regressions, we found that deployment to Iraq/Afghanistan increases the odds of developing PTSD substantially, relative to those in other duties, with the largest effect observed for the Navy (OR = 9.06, p < 0.01) and the smallest effect for the Air Force (OR = 1.25, p < 0.01). A deployment longer than 180 days increases the odds of PTSD by 1.11 to 2.84 times compared to a short tour. For Army and Navy, a deployment to Iraq/Afghanistan further exacerbates the adverse effect of tour length. PMID- 20968268 TI - Should military dining facilities offer and promote consumption of probiotic containing foods? AB - Probiotics are defined as "live organisms which, when administered in adequate amounts confer a benefit on the host." The purpose of this review was to determine whether there is evidence-based justification to recommend purchase and promotion of probiotic-containing food in military dining facilities (DFACs). Peer-reviewed literature was searched to identify well-conducted systematic reviews and original research related to the efficacy of probiotics in preventing and/or treating acute infectious diarrhea, irritable bowel syndrome, respiratory tract infections, allergic rhinitis, dental health issues, and female urogenital conditions. Probiotics may be useful for preventing and/or treating military relevant health conditions. However, the available scientific evidence is not sufficient to warrant widespread procurement and promotion of probiotic containing food items in military DFACs. Health care practitioners considering recommending probiotics should understand that health effects and clinical outcomes discussed herein are specific to the probiotic strain, dose, and method of delivery studied in the articles cited. PMID- 20968269 TI - The last days of Sala al-Din (Saladin) "noble enemy" of the third Crusade. AB - Saladin, "noble enemy" of Richard the Lionheart and victor at the battle of Hattin, died suddenly in 1193 A.D. at the age of 56. The clinical information preserved in the historical record is insufficient to render a definitive diagnosis for Saladin's final illness, and yet, it contains enough details to narrow the list of possibilities to just a few and also to critique his treatment in light of the medical concepts of his day. PMID- 20968270 TI - Operational impact of tongue piercing on French military pilots during overseas deployments: a case report. AB - Piercing in general and particularly tongue piercing is gaining popularity in the Western world. The French army and so the French air force are concerned by this phenomenon. A case report of a pilot suffering from dental pain with operational consequences due to a dental fracture during Operation Trident (Kosovo) is presented. The dental examination highlighted the fact that the dental fracture was directly due to the presence of a tongue piercing. Tongue piercing and wearing tongue jewelry have numerous adverse effects, especially frequent dental complications. If these complications do not result in death, they can generate sufficient pain to disturb the vigilance and concentration of pilots and can have a major impact on flight security. For these reasons, tongue piercing is in total contradiction to a professional army and particularly to military pilots and aircrews. PMID- 20968271 TI - Effects of six weeks of quercetin supplementation on physical performance in ROTC cadets. AB - OBJECTIVE: To investigate the effects of 6 weeks of quercetin supplementation on physical performance during military physical training. METHODS: Using a randomized, double-blind, repeated-measures, placebo-controlled design, 58 healthy, moderately trained men and women were randomly assigned to quercetin (Q) or placebo (P) groups. Peak oxygen uptake (VO(2peak)) during maximal effort uphill treadmill running and four physical performance measures (Army Physical Fitness Test, [APFT], Baumgartner Modified Pull-Up Test [BMPU], Wingate Anaerobic Test [WanT], and a 36.6-m sprint) were evaluated before and after 42-54 days of supplementation with 1 g/d of quercetin with vitamins and other substances in a soft chew or placebo chew. RESULTS: Pretreatment-to-posttreatment changes in VO(2peak) and physical performance were not significantly different (p > 0.05) in Q and P. CONCLUSIONS: Six weeks of dietary quercetin supplementation in moderately trained individuals conducting military physical training did not improve VO(2peak) or performance on the APFT, BMPU, WAnT, and 36.6-m sprint. PMID- 20968272 TI - Equipment modification is associated with fewer stress fractures in female Israel border police recruits. AB - PURPOSE: The study was planned to assess whether combat equipment weight reduction would lead to a reduction in the incidence of stress fractures in female border police infantry recruits taking a 4-month course of basic combat training. METHOD: 213 female border police recruits, 18-19 years of age, undergoing 16 weeks of basic combat training with lighter rifle and lighter closely fitted combat vest, (total 9.4 kg) were followed prospectively for stress fracture (SFx) incidence, compared to a historical control group of 1,210 recruits who trained with traditional equipment (12.5 kg). RESULTS: Equipment modification was associated with a significant reduction in SFx from 18.3% in the control group to 8.0% in the intervention group (p < 0.0001). CONCLUSIONS: This study implies that equipment weight reduction may achieve a significant effect in SFx reduction, Approximating fighting gear to body center of gravity may enhance this effect. PMID- 20968273 TI - Mental health care provision in the U.K. armed forces. AB - Like the United States, the United Kingdom (U.K.) population expresses ongoing interest in the mental health of their nation's armed forces and veterans. Current U.K. military mental health research efforts center on the work of military and civilian academics based at King's College London. These academics work closely with NATO partners, in particular the United States, in planning for future research. Conscious of the cultural dimensions to mental health among military personnel, considerable efforts have been made to strengthen informal support mechanisms including the training of lay Trauma Risk Management (TRiM) practitioners and other welfare services. Formal healthcare support provision comes from primary care providers and Departments of Community Mental Health, which provide local case management and appropriate escalation to in-patient services where required. Although veteran's healthcare is provided by the National Health Service, considerable efforts have been made to ensure their services best meet the needs of veterans and their families. PMID- 20968274 TI - Military line leadership and tobacco control: perspectives of military policy leaders and tobacco control managers. AB - Despite progress in policy changes, tobacco use rates are still high in the military. Little is known about the views of those who create and implement tobacco control policies within the Department of Defense. These individuals determine what policy initiatives will be developed, prioritized, and implemented. We conducted key informant interviews with 16 service-level policy leaders (PLs) and 36 installation-level tobacco control managers (TCMs). PLs and TCMs believed that line leadership view tobacco control as a low priority that has minimal impact on successful mission completion. They also identified cultural factors that perpetuate tobacco use, such as low cost and easy accessibility to tobacco, smoke breaks, and uneven or unknown enforcement of current tobacco policies. PMID- 20968275 TI - Radiology corner. Bizarre parosteal osteochondromatous proliferation (BPOP), or Nora's lesion. PMID- 20968276 TI - Patterned laser trabeculoplasty. AB - BACKGROUND AND OBJECTIVE: A novel computer-guided laser treatment for open-angle glaucoma, called patterned laser trabeculoplasty, and its preliminary clinical evaluation is described. PATIENTS AND METHODS: Forty-seven eyes of 25 patients with open-angle glaucoma received 532-nm laser treatment with 100-MUm spots. Power was titrated for trabecular meshwork blanching at 10 ms and sub-visible treatment was applied with 5-ms pulses. The arc patterns of 66 spots rotated automatically after each laser application so that the new pattern was applied at an untreated position. RESULTS: Approximately 1,100 laser spots were placed per eye in 16 steps, covering 360 degrees of trabecular meshwork. The intraocular pressure decreased from the pretreatment level of 21.9 +/- 4.1 to 16.0 +/- 2.3 mm Hg at 1 month (n = 41) and remained stable around 15.5 +/- 2.7 mm Hg during 6 months of follow-up (n = 30). CONCLUSION: Patterned laser trabeculoplasty provides rapid, precise, and minimally traumatic (sub-visible) computer-guided treatment with exact abutment of the patterns, exhibiting a 24% reduction in intraocular pressure during 6 months of follow-up (P < .01). PMID- 20968277 TI - Distance dependence of the reaction rate for the reduction of metal cations by solvated electrons: a picosecond pulse radiolysis study. AB - The decay of the solvated electron generated by picosecond electron pulse radiolysis is studied by broad-band transient absorption measurements in ethylene glycol solutions containing decimolar concentrations of Cu(2+), Ni(2+), and Pb(2+) metal cations. Analysis of the nonexponential kinetics of the decays reveals molecular parameters of the electron transfer reaction. It is found that the reaction occurs at long distance for Cu(2+) solutions and is only limited to contact distance in the case of Ni(2+) solutions. The distribution of reaction distance strongly depends on the free enthalpy change of the reactions. PMID- 20968278 TI - Preparation of a cycloheptane ring from a 1,2-diketone with high stereoselectivity. AB - Treatment of 1,6-dialkylhexa-1,5-diene-3,4-diones with bis(iodozincio)methane gave zinc alkoxides of cis-5,6-dialkylcyclohepta-3,7-diene-1,3-diol in good yields at room temperature. The reaction proceeded with high stereospecificity. Bis(iodozincio)methane converted the diketone into the cis-divinylcyclopropane 1,2-diol stereoselectively; this diol transformed into the corresponding cycloheptane derivative stereospecifically via Cope rearrangement. PMID- 20968280 TI - Infrared spectroscopy of extreme coordination: the carbonyls of U(+) and UO(2)(+). AB - Uranium and uranium dioxide carbonyl cations produced by laser vaporization are studied with mass-selected ion infrared spectroscopy in the C-O stretching region. Dissociation patterns, spectra, and quantum chemical calculations establish that the fully coordinated ions are U(CO)(8)(+) and UO(2)(CO)(5)(+), with D(4d) square antiprism and D(5h) pentagonal bipyramid structures. Back bonding in U(CO)(8)(+) causes a red-shifted CO stretch, but back-donation is inefficient for UO(2)(CO)(5)(+), producing a blue-shifted CO stretch characteristic of nonclassical carbonyls. PMID- 20968281 TI - Orientation of tie-lines in the phase diagram of DOPC/DPPC/cholesterol model biomembranes. AB - We report the direction of tie-lines of coexisting phases in a ternary diagram of DOPC/DPPC/cholesterol lipid bilayers, which has been a system of interest in the discussion of biological rafts. For coexisting Ld and Lo phases, we find that the orientation angle alpha of the tie-lines increases as the cholesterol concentration increases and it also increases as temperature increases from T = 15 degrees C to T = 30 degrees C. Results at lower cholesterol concentrations support the existence of a different two-phase coexistence region of Ld and So phases and the existence of a three-phase region separating the two two-phase regions. Our method uses the X-ray lamellar D-spacings observed in oriented bilayers as a function of varying hydration. Although this method does not obtain the ends of the tie-lines, it gives precise values (+/-1 degrees ) of their angles alpha in the ternary phase diagram. PMID- 20968283 TI - Selective determination of melamine in aqueous medium by molecularly imprinted solid phase extraction. AB - A molecularly imprinted polymer able to recognize melamine in partially aqueous medium was synthesized using methacrylic acid as functional monomer and ethylene glycol dimethacrylate as cross-linking agent. The bound specificity and selectivity of the obtained material were verified by performing binding experiments with melamine and its structural analogue, 2,4,6-trimethoxy-1,3,5 triazine, respectively, using different aqueous binding media. Finally, the ability of MIP to selectively extract melamine from two real samples, a food supplement and a freeze-dried meat sample, was demonstrated. PMID- 20968282 TI - A structural mass spectrometry strategy for the relative quantitation of ligands on mixed monolayer-protected gold nanoparticles. AB - It is becoming increasingly common to use gold nanoparticles (AuNPs) protected by a heterogeneous mixture of thiolate ligands, but many ligand mixtures on AuNPs cannot be properly characterized due to the inherent limitations of commonly used spectroscopic techniques. Using ion mobility-mass spectrometry (IM-MS), we have developed a strategy that allows measurement of the relative quantity of ligands on AuNP surfaces. This strategy is used for the characterization of three samples of mixed-ligand AuNPs: tiopronin:glutathione (av diameter 2.5 nm), octanethiol:decanethiol (av diameter 3.6 nm), and tiopronin:11 mercaptoundecyl(poly ethylene glycol) (av diameter 2.5 nm). For validation purposes, the results obtained for tiopronin:glutathione AuNPs were compared to parallel measurements using nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) without ion mobility separation. Relative quantitation measurements for NMR and IM-MS were in excellent agreement, with an average difference of less than 1% relative abundance. IM-MS and MS without ion mobility separation were not comparable, due to a lack of ion signals for MS. The other two mixed-ligand AuNPs provide examples of measurements that cannot be performed using NMR spectroscopy. PMID- 20968284 TI - Reduction of dinitrogen with an yttrium metallocene hydride precursor, [(C5Me5)2YH]2. AB - Treatment of [(C(5)Me(5))(2)YH](2), 1, with KC(8) under N(2) in methylcyclohexane generates the unsolvated reduced dinitrogen complex, [(C(5)Me(5))(2)Y](2)(MU eta(2):eta(2)-N(2)), 2, and extends the range of yttrium and lanthanide LnZ(2)Z'/M (Z = monoanion; M = alkali metal) dinitrogen reduction reactions to (Z')(-) = (H)(-). The hydride complex, 1, is unique in this reactivity compared to other alkane-soluble yttrium metallocenes, [(C(5)Me(5))(2)YX](x) {X = [N(SiMe(3))(2)](-), (Me)(-), (C(3)H(5))(-), and (C(5)Me(5))(-)} which did not generate 2 when treated with KC(8). [(C(5)Me(5))(2)LnH](x)/KC(8)/N(2) reactions with Ln = La and Lu did not give isolable dinitrogen complexes. Complex 2 and the unsolvated lutetium analogue, [(C(5)Me(5))(2)Lu](2)(MU-eta(2):eta(2)-N(2)), 3, were obtained using benzene as a solvent and [(C(5)Me(5))(2)Ln][(MU-Ph)(2)BPh(2)] as precursors with excess KC(8). Complex 2 functions as a reducing agent with PhSSPh to form [(C(5)Me(5))(2)Y(MU-SPh)](2), 4, in high yield. PMID- 20968285 TI - Single and binary self-assembled monolayers of phenyl- and pentafluorophenyl based silane species, and their phase separation with octadecyltrichlorosilane. AB - In this paper, we first present the study of the formation of phenyltrichlorosilane film and self-assembled monolayers of phenylalkyltrichlorosilane (PATCl), pentafluoro-phenylalkyltrichlorosilane (PFATCl), and a mixture of the two, on silicon covered by its native oxide. These monolayers are shown to grow in two steps with characteristic time constants. The first step is characterized by a similar time constant of growth for all the studied trichlorosilane molecules and attributed to chemisorption. The second step corresponds to the arrangement between molecules, accelerated by the presence of the short alkyl chain (3-4 carbon atoms), and by mixing phenyl and pentafluoro-phenyl terminal moieties, which is accounted for by hydrogen bonding CH...FC and/or attractive quadrupolar interactions within a face-to-face phenyl/pentafluoro-phenyl alternating stack arrangement. Such results should allow improvement of intermolecular stacking within conjugated molecular domains, which is particularly important for molecular electronic devices. In the second part, we studied how PATCl, PFATCl, and their mixture phase separate with octadecyltrichlorosilane (OTS) molecules in various ratios. The way to improve phase separation was studied modifying aromatic ring to ring as well as aromatic aliphatic interactions. OTS island size and coverage are shown to be smaller with the aromatic phase that involves stronger ring to ring interactions, i.e., attractive interactions between the phenyl species by mixing phenyl and pentafluoro-phenyl rings. The best phase separation is obtained with PFATCl as the aromatic molecule. If nanoislands of aromatic molecules could not be observed in these experiments, we show that they are attainable by mixing OTS and aromatic small organotriethoxysilanes whose grafting kinetics is slower. These results pave the way to the control improvement of the composition and nanostructuration of SAMs, essential for their further use within molecular devices. PMID- 20968286 TI - Iron(III)-catalyzed consecutive aza-Cope-Mannich cyclization: synthesis of trans 3,5-dialkyl pyrrolidines and 3,5-dialkyl-2,5-dihydro-1H-pyrroles. AB - An efficient alkene aza-Cope-Mannich cyclization between 2-hydroxy homoallyl tosylamine and aldehydes in the presence of iron(III) salts to obtain 3-alkyl-1 tosyl pyrrolidines in good yields is described. The process is based on the consecutive generation of a gamma-unsaturated iminium ion, 2-azonia-[3,3] sigmatropic rearrangement, and further intramolecular Mannich reaction. Iron(III) salts are also shown to be excellent catalysts for the new aza-Cope-Mannich cyclization using 2-hydroxy homopropargyl tosylamine. PMID- 20968287 TI - C-H vs C-C bond activation of acetonitrile and benzonitrile via oxidative addition: rhodium vs nickel and Cp* vs Tp' (Tp' = hydrotris(3,5-dimethylpyrazol-1 yl)borate, Cp* = eta(5)-pentamethylcyclopentadienyl). AB - The photochemical reaction of (C(5)Me(5))Rh(PMe(3))H(2) (1) in neat acetonitrile leads to formation of the C-H activation product, (C(5)Me(5))Rh(PMe(3))(CH(2)CN)H (2). Thermolysis of this product in acetonitrile or benzene leads to thermal rearrangement to the C-C activation product, (C(5)Me(5))Rh(PMe(3))(CH(3))(CN) (4). Similar results were observed for the reaction of 1 with benzonitrile. The photolysis of 1 in neat benzonitrile results in C-H activation at the ortho, meta, and para positions. Thermolysis of the mixture in neat benzonitrile results in clean conversion to the C-C activation product, (C(5)Me(5))Rh(PMe(3))(C(6)H(5))(CN) (5). DFT calculations on the acetonitrile system show the barrier to C-H activation to be 4.3 kcal mol(-1) lower than the barrier to C-C activation. A high-energy intermediate was also located and found to connect the transition states leading to C-H and C-C activation. This intermediate has an agostic hydrogen interaction with the rhodium center. Reactions of acetonitrile and benzonitrile with the fragment [Tp'Rh(CNneopentyl)] show only C-H and no C-C activation. These reactions with rhodium are compared and contrasted to related reactions with [Ni(dippe)H](2), which show only C-CN bond cleavage. PMID- 20968288 TI - Genetic and environmental influence on maize kernel proteome. AB - Comparative targeted compositional analysis is currently an important element in the safety assessment of genetically modified plants. Profiling methods have been suggested as nontargeted tools to improve the detection of possible unintended effects. In this study, the capability of 2-dimensional electrophoresis to detect significant differences among seven conventional maize (Zea mays) cultivars grown in six different locations in Germany during two consecutive seasons was evaluated. Besides maize genotype, both geographic location and season had a significant effect on protein profiles. Differences as high as 55- and 53-fold in the quantity of specific proteins were recorded, the median observed difference being around 6- and 5-fold between the genotypes and growing locations, respectively. Understanding the variation in the quantity of individual proteins should help to put the variation of endogenous proteins and the novel proteins in the genetically modified plants in perspective. This together with the targeted analyses the profiling methods, including proteomics, could also help to get a deeper insight into the unintended alterations that might have occurred during the genetic modification process. PMID- 20968289 TI - Natural chlorate in the environment: application of a new IC-ESI/MS/MS method with a Cl18O3-internal standard. AB - A new ion chromatography electrospray tandem mass spectrometry (IC-ESI/MS/MS) method has been developed for quantification and confirmation of chlorate (ClO3-) in environmental samples. The method involves the electrochemical generation of isotopically labeled chlorate internal standard (Cl18O3-) using 18O water (H218O) he standard was added to all samples prior to analysis thereby minimizing the matrix effects that are associated with common ions without the need for expensive sample pretreatments. The method detection limit (MDL) for ClO3- was 2 ng L-1 for a 1 mL volume sample injection. The proposed method was successfully applied to analyze ClO3- in difficult environmental samples including soil and plant leachates. The IC-ESI/MS/MS method described here was also compared to established EPA method 317.0 for ClO3- analysis. Samples collected from a variety of environments previously shown to contain natural perchlorate (ClO4-) occurrence were analyzed using the proposed method and ClO3- was found to co occur with ClO4- at concentrations ranging from < 2 ng L-1 in precipitation from Texas and Puerto Rico to >500 mg kg-1 in caliche salt deposits from the Atacama Desert in Chile. Relatively low concentrations of ClO3- in some natural groundwater samples (0.1 ug L-1) analyzed in this work may indicate lower stability when compared to ClO4- in the subsurface. The high concentrations ClO3- in caliches and soils (3-6 orders of magnitude greater) as compared to precipitation samples indicate that ClO3-, like ClO4-, may be atmospherically produced and deposited, then concentrated in dry soils, and is possibly a minor component in the biogeochemical cycle of chlorine. PMID- 20968290 TI - Controlled release of biologically active silver from nanosilver surfaces. AB - Major pathways in the antibacterial activity and eukaryotic toxicity of nanosilver involve the silver cation and its soluble complexes, which are well established thiol toxicants. Through these pathways, nanosilver behaves in analogy to a drug delivery system, in which the particle contains a concentrated inventory of an active species, the ion, which is transported to and released near biological target sites. Although the importance of silver ion in the biological response to nanosilver is widely recognized, the drug delivery paradigm has not been well developed for this system, and there is significant potential to improve nanosilver technologies through controlled release formulations. This article applies elements of the drug delivery paradigm to nanosilver dissolution and presents a systematic study of chemical concepts for controlled release. After presenting thermodynamic calculations of silver species partitioning in biological media, the rates of oxidative silver dissolution are measured for nanoparticles and macroscopic foils and used to derive unified area based release kinetics. A variety of competing chemical approaches are demonstrated for controlling the ion release rate over 4 orders of magnitude. Release can be systematically slowed by thiol and citrate ligand binding, formation of sulfidic coatings, or the scavenging of peroxy-intermediates. Release can be accelerated by preoxidation or particle size reduction, while polymer coatings with complexation sites alter the release profile by storing and releasing inventories of surface-bound silver. Finally, the ability to tune biological activity is demonstrated through a bacterial inhibition zone assay carried out on selected formulations of controlled release nanosilver. PMID- 20968291 TI - Improved catalytic capability of mesoporous TiO2 microspheres and photodecomposition of toluene. AB - A series of mesoporous titanium dioxide microspheres were calcined at various temperatures to improve their photocatalytic activity. The prepared catalysts were characterized by XRD, SEM, TEM, TG-DTA, UV-vis, and N(2) adsorption desorption measurements, and their photocatalytic performances were investigated by photooxidation of gaseous toluene. As the results revealed, calcination temperatures obviously influenced the surface morphology and photocatalytic activity of the mesoporous TiO(2) microspheres. The noncalcined samples had a mesoporous structure of the anatase phase. The sample calcined at 400 degrees C showed a superior photocatalytic performance, which had a reaction rate constant 2-fold higher than that of P(25). The enhanced photoreactivity is possibly due to the synergetic effects of the mesoporous structure and light-transmittance ability of the catalysts. Two new reaction intermediates were discovered as well, and a tentative degradation pathway was proposed. PMID- 20968292 TI - Method for the synthesis of mono-ADP-ribose conjugated peptides. AB - ADP-ribosylation is an important post-translational modification involved in processes including cellular replication, DNA repair, and cell death. Despite these roles, the functions of ADP-ribosylation, in particular mono-ADP ribosylation, remain poorly understood. The development of a technique to generate large amounts of site-specific, ADP-ribosylated peptides would provide a useful tool for deconvoluting the biochemical roles of ADP-ribosylation. Here we demonstrate that synthetic histone H2B tail peptides, incorporating aminooxy or N methyl aminooxy functionalized amino acids, can be site-specifically conjugated to ADP-ribose. These peptides are recognized as substrates by the ADP ribosylation biochemical machinery (PARP1), can interact with the ADP-ribose binding proteins macroH2A1.1 and PARP9, and demonstrate superior enzymatic and chemical stability when compared to ester-linked ADP-ribose. In addition, the incorporation of benzophenone photo-cross-linkers into these peptides is demonstrated to provide a means to probe for and enrich ADP-ribose binding proteins. PMID- 20968293 TI - Ferromagnetic micropallets for magnetic capture of single adherent cells. AB - We present a magnetic micropallet array and demonstrate its capacity to recover specific, individual adherent cells from large populations and deliver them for downstream single cell analysis. A ferromagnetic photopolymer was formulated, characterized, and used to fabricate magnetic micropallets, which are microscale pedestals that provide demarcated cell growth surfaces with preservation of biophysical properties including photopatternability, biocompatibility, and optical clarity. Each micropallet holds a single adherent cell in culture, and hundreds of thousands of micropallets comprise a single micropallet array. Any micropallet in the array can be recovered on demand, carrying the adhered cell with it. We used this platform to recover selectively single cells, which were subsequently analyzed using single-cell RT-qPCR. PMID- 20968294 TI - The interaction of ruminant PrP(Sc) with soils is influenced by prion source and soil type. AB - The persistence of prions within the environment is implicated in the horizontal transmission of ovine scrapie and cervid chronic wasting disease. Description of the interaction of prion strains derived from their natural hosts with a range of soil types is imperative in understanding how prions persist in the environment and, therefore, the characteristics of prion transmission. Here, we demonstrate that all detectable ovine scrapie and bovine BSE PrP(Sc) bind to a range of soil types within 24 h. This highly efficient binding of prions to soils is characterized by truncation of desorbed PrP(Sc) in a soil-dependent manner, with clay-rich soils resulting in N-terminal truncation of the PrP(Sc) and sand-rich soils yielding full length PrP(Sc) species. PrP(Sc) did not migrate through soil columns during incubation for up to 18 months, and for all combinations of soil and prion types, a decrease in recoverable PrP(Sc) was seen over time. Persistence of PrP(Sc) within soil and their interaction with soil particles of distinct sizes was dictated by both the soil type and the source of the prion, with ovine scrapie being apparently more persistent in some soils than cattle BSE. These data indicate that natural ruminant prion strains are stable in the soil environment for at least 18 months and that PrP(Sc)-soil interaction is dictated by both the soil properties and the strain/host species of PrP(Sc). PMID- 20968295 TI - Life cycle energy and greenhouse gas emissions for an ethanol production process based on blue-green algae. AB - Ethanol can be produced via an intracellular photosynthetic process in cyanobacteria (blue-green algae), excreted through the cell walls, collected from closed photobioreactors as a dilute ethanol-in-water solution, and purified to fuel grade ethanol. This sequence forms the basis for a biofuel production process that is currently being examined for its commercial potential. In this paper, we calculate the life cycle energy and greenhouse gas emissions for three different system scenarios for this proposed ethanol production process, using process simulations and thermodynamic calculations. The energy required for ethanol separation increases rapidly for low initial concentrations of ethanol, and, unlike other biofuel systems, there is little waste biomass available to provide process heat and electricity to offset those energy requirements. The ethanol purification process is a major consumer of energy and a significant contributor to the carbon footprint. With a lead scenario based on a natural-gas fueled combined heat and power system to provide process electricity and extra heat and conservative assumptions around the ethanol separation process, the net life cycle energy consumption, excluding photosynthesis, ranges from 0.55 MJ/MJ(EtOH) down to 0.20 MJ/ MJ(EtOH), and the net life cycle greenhouse gas emissions range from 29.8 g CO2e/MJ(EtOH) down to 12.3 g CO2e/MJ(EtOH) for initial ethanol concentrations from 0.5 wt % to 5 wt %. In comparison to gasoline, these predicted values represent 67% and 87% reductions in the carbon footprint for this ethanol fuel on a energy equivalent basis. Energy consumption and greenhouse gas emissions can be further reduced via employment of higher efficiency heat exchangers in ethanol purification and/ or with use of solar thermal for some of the process heat. PMID- 20968296 TI - Terpenoids from the aerial parts of Parasenecio deltophylla. AB - Five new modified eremophilane-type sesquiterpenes (1-5), including three norsesquiterpenes (1-3), and one new monoterpene (6) were isolated from the aerial parts of Parasenecio deltophylla. Their structures were established on the basis of HRMS and NMR methods. The cytotoxicity of compounds 1-4 and 6 against selected cancer cell lines, including human promyelocytic leukemia (HL-60) and human hepatoma (Hep-G2), was evaluated. Antioxidant activities of these compounds were assessed by ABTS and DPPH methods. PMID- 20968297 TI - Enteric virus infection risk from intrusion of sewage into a drinking water distribution network. AB - Contaminants from the soil surrounding drinking water distribution systems are thought to not enter the drinking water when sufficient internal pressure is maintained. Pressure transients may cause short intervals of negative pressure, and the soil near drinking water pipes often contains fecal material due to the proximity of sewage lines, so that a pressure event may cause intrusion of pathogens. This paper presents a risk model for predicting intrusion and dilution of viruses and their transport to consumers. Random entry and dilution of virus was simulated by embedding the hydraulic model into a Monte Carlo simulation. Special attention was given to adjusting for the coincidence of virus presence and use of tap water, as independently occurring short-term events within the longer interval that the virus is predicted to travel in any branch of the distribution system. The probability that a consumer drinks water contaminated with virus is small, but when this happens the virus concentration tends to be high and the risk of infection may be considerable. The spatial distribution of infection risk is highly heterogeneous. The presence of a chlorine residual reduces the infection risk. PMID- 20968298 TI - Domain organization in Candida glabrata THI6, a bifunctional enzyme required for thiamin biosynthesis in eukaryotes. AB - THI6 is a bifunctional enzyme found in the thiamin biosynthetic pathway in eukaryotes. The N-terminal domain of THI6 catalyzes the ligation of the thiamin thiazole and pyrimidine moieties to form thiamin phosphate, and the C-terminal domain catalyzes the phosphorylation of 4-methyl-5-hydroxyethylthiazole in a salvage pathway. In prokaryotes, thiamin phosphate synthase and 4-methyl-5 hydroxyethylthiazole kinase are separate gene products. Here we report the first crystal structure of a eukaryotic THI6 along with several complexes that characterize the active sites responsible for the two chemical reactions. THI6 from Candida glabrata is a homohexamer in which the six protomers form a cage like structure. Each protomer is composed of two domains, which are structurally homologous to their monofunctional bacterial counterparts. Two loop regions not found in the bacterial enzymes provide interactions between the two domains. The structures of different protein-ligand complexes define the thiazole and ATP binding sites of the 4-methyl-5-hydroxyethylthiazole kinase domain and the thiazole phosphate and 4-amino-5-hydroxymethyl-2-methylpyrimidine pyrophosphate binding sites of the thiamin phosphate synthase domain. Our structural studies reveal that the active sites of the two domains are 40 A apart and are not connected by an obvious channel. Biochemical studies show 4-methyl-5 hydroxyethylthiazole phosphate is a substrate for THI6; however, adenosine diphospho-5beta-ethyl-4-methylthiazole-2-carboxylic acid, the product of THI4, is not a substrate for THI6. This suggests that an unidentified enzyme is necessary to produce the substrate for THI6 from the THI4 product. PMID- 20968299 TI - Proteomics and transcriptomics investigation on longissimus muscles in Large White and Casertana pig breeds. AB - Consumer complaints against the blandness of modern lean meat and the frequent reference to the more strongly flavored meat that was available years ago have prompted reconsideration of high fat-depositing typical pig breeds. Casertana and Large White pig breeds are characterized by a different tendency toward fat accumulation as they exhibit opposite genetic and physiological traits with respect to the energy metabolism. These physiological differences were investigated in longissimus lumborum muscles through proteomics (2-DE, MS/MS) and microarray approaches. Data were analyzed for pathway and network analyses, as well as GO term enrichment of biological functions. As a result, Casertana showed a greater amount of proteins involved in glycolitic metabolism and mainly rely on fast-mobilizable energy sources. Large White overexpressed cell cycle and skeletal muscle growth related genes. Metabolic behavior and other implications are discussed. PMID- 20968300 TI - Enhanced direct ambient analysis by differential mobility-filtered desorption electrospray ionization-mass spectrometry. AB - Desorption electrospray ionization (DESI) is rapidly becoming established as one of the most powerful ionization techniques allowing direct surface analysis by mass spectrometry (MS) in the ambient environment. DESI provides a significant number of unique analytical capabilities for a broad range of applications, both quantitative and qualitative in nature including biological tissue imaging, pharmaceutical quality control, in vivo analysis, proteomics, metabolomics, forensics, and explosives detection. Despite its growing adoption as a powerful high throughput analysis tool, DESI-MS analysis at trace levels often suffers from background chemical interferences generated during the electrospray ionization processes. In order to improve sensitivity and selectivity, a differential mobility (DM) ion separation cell was successfully interfaced to a custom-built DESI ion source. This new hybrid platform can be operated in two modes: the "DM-off" mode for standard DESI analysis and "DM-on mode" where DESI generated ions are detected after discrimination by the differential mobility cell. The performance of the DESI-DM-MS platform was tested with several samples typically amenable to DESI analysis, including counterfeit pharmaceuticals and binary mixtures of isobaric chemicals of importance in the pharmaceutical and food industries. In the DM-on mode, DESI-MS signal-to-noise ratios were improved by 70-190% when compared to the DM-off mode. Also, the addition of the DM cell enabled selective in-source ion activation of specific DESI-generated precursor ions, providing tandem MS-like spectra in a single stage mass spectrometer. PMID- 20968301 TI - Multiplexed detection of metabolites of narcotic drugs from a single latent fingermark. AB - An immunoassay based technique is used for the detection of psychoactive substances in the sweat deposited within fingermarks of a narcotic drug user. Magnetic particles functionalized with antimorphine and antibenzoylecgonine antibodies were used for the detection of a metabolite of heroin (morphine) and a metabolite of cocaine (benzoylecgonine), respectively. The drug metabolites were detected individually as well as simultaneously from a single fingermark. The images of the fingermarks obtained using brightfield and fluorescence microscopy were of high evidential quality with resolution to enable identification of an individual in addition to providing information on drug usage. PMID- 20968302 TI - Verification of intramolecular hybrid/parallel g-quadruplex structure under physiological conditions using novel cyanine dye H-aggregates: both in solution and on Au film. AB - The H-aggregates of a novel cyanine dye, 3,3'-di(3-sulfopropyl)-4,5,4',5'-dibenzo 9-methyl-thiacarbocyanine triethylammonium salt (MTC), have been fabricated to verify hybrid/parallel intramolecular G-quadruplexes from linear duplex and single-strand DNAs under physiological conditions. The recognition is found to be successful both in solution and on Au film. These results have shown MTC H aggregates, as a supramolecular system, may be used as a potential excellent probe for DNA structure, both in vitro and in vivo. PMID- 20968303 TI - Catalytic activity of phosphine-copper complexes for hydroboration of styrene with pinacolborane: experiment and theory. AB - We have carried out density functional theory calculations as well as experiments to rationalize the catalytic activity of various phosphine-copper complexes for the hydroboration of styrene with pinacolborane. The experimentally obtained catalytic efficiency was explained on the basis of activation barriers for consecutive reaction mechanism steps as well as by molecular orbitals and charges in the transition state. Bidentate ligands were found to be more efficient than monodentate ligands for catalytic activity. Bidentate ligands make the reactant complexes less stable than monodentate ligands due to steric hindrance. This information could be usefully utilized for new catalysts design. The calculated kinetic data were consistent with the experimental conversion efficiency in a process that was hypothesizd to undergo the addition of Cu-H to styrene as the rate-limiting step. From the electronic distribution of the HOMO and the charge of the copper atom in the transition state, it was found that styrenes substituted with electron withdrawing groups would give higher conversions, and the catalytic efficiency could be increased with properly designed electron donating ligands for the copper catalyst complex. PMID- 20968304 TI - Use of dithionite to extend the reactive lifetime of nanoscale zero-valent iron treatment systems. AB - Nanoscale zero-valent iron (NZVI) represents a promising approach for source zone control, but concerns over its reactive lifetime might limit application. Here, we demonstrate that dithionite (S2O42-), a reducing agent for in situ redox manipulation, can restore the reducing capacity of passivated NZVI. Slurries of NZVI were aged in the presence (3 days) and absence (60 days) of dissolved oxygen over a range of pH values (6-8). Upon loss of reactivity toward model pollutants{1,1,1,2-tetrachloroethane, hexavalent chromium [Cr(VI)], nitrobenzene}, aged suspensions were reacted with dithionite, and the composition and reactivity of the dithionite-treated materials were determined. NZVI aging products generally depended on pH and the presence of oxygen, whereas the amount of dithionite influenced the nature and reducing capacity of products generated from reaction with aged NZVI suspensions. Notably, air oxidation at pH >= 8 quickly exhausted NZVI reactivity despite preservation of significant Fe(0) in the particle core. Under these conditions, formation of a passive surface layer hindered the complete transformation of NZVI particles into iron(III) oxides, which occurred at lower pH. Reduction of this passive layer by low dithionite concentrations( 1 g/g of NZVI) restored suspension reactivity to levels equal to, and occasionally greater than, that of unaged NZVI. Multiple dithionite additions further improved pollutant removal, allowing at least a 15-fold increase in Cr(VI) removal [~300 mg of Cr(VI)/g of NZVI] relative to that of as-received NZVI [~20 mg of Cr(VI)/g of NZVI]. PMID- 20968305 TI - Controllable N-doping of graphene. AB - Opening and tuning an energy gap in graphene are central to many electronic applications of graphene. Here we report N-doped graphene obtained by NH3 annealing after N(+)-ion irradiation of graphene samples. First, the evolution of the graphene microstructure was investigated following N(+)-ion irradiation at different fluences using Raman spectroscopy, showing that defects were introduced in plane after irradiation and then restored after annealing in N2 or in NH3. Auger electron spectroscopy (AES) of the graphene annealed in NH3 after irradiation showed N signal, however, no N signal was observed after annealing in N2. Last, the field-effect transistor (FET) was fabricated using N-doped graphene and monitored by the source-drain conductance and back-gate voltage (Gsd-Vg) curves in the measurement. The transport property changed compared to that of the FET made by intrinsic graphene, that is, the Dirac point position moved from positive Vg to negative Vg, indicating the transition of graphene from p-type to n-type after annealing in NH3. Our approach, which provides a physical mechanism for the introduction of defect and subsequent hetero dopant atoms into the graphene material in a controllable fashion, will be promising for producing graphene-based devices for multiple applications. PMID- 20968306 TI - A pH-dependent conformational ensemble mediates proton transport through the influenza A/M2 protein. AB - The influenza A/M2 protein exhibits inwardly rectifying, pH-activated proton transport that saturates at low pH. A comparison of high-resolution structures of the transmembrane domain at high and low pH suggests that pH-dependent conformational changes may facilitate proton conduction by alternately changing the accessibility of the N-terminal and C-terminal regions of the channel as a proton transits through the transmembrane domain. Here, we show that M2 functionally reconstituted in liposomes populates at least three different conformational states over a physiologically relevant pH range, with transition midpoints that are consistent with previously reported His37 pK(a) values. We then develop and test two similar, quantitative mechanistic models of proton transport, where protonation shifts the equilibrium between structural states having different proton affinities and solvent accessibilities. The models account well for a collection of experimental data sets over a wide range of pH values and voltages and require only a small number of adjustable parameters to accurately describe the data. While the kinetic models do not require any specific conformation for the protein, they nevertheless are consistent with a large body of structural information based on high-resolution nuclear magnetic resonance and crystallographic structures, optical spectroscopy, and molecular dynamics calculations. PMID- 20968307 TI - Collision energy optimization of b- and y-ions for multiple reaction monitoring mass spectrometry. AB - Multiple reaction monitoring (MRM) is a highly sensitive and increasingly popular method of targeted mass spectrometry (MS) that can be used to selectively detect and quantify peptides and their corresponding proteins of interest within biological samples. The sensitivity of MRM-MS is highly dependent upon the tuning of transition-specific parameters, especially the collision energy (CE) applied during peptide fragmentation. Currently, empirical equations for CE work best for y-type ions and are much less effective for other types of transitions, such as b type ions and small y-type transitions across particular amide bonds, which could also be useful for MRM-MS if optimized for maximum signal transmission. In this work, we have performed a CE optimization of all transitions for 80 doubly charged peptides, the results of which were used to define separate CE equations for b-ions and y-ions, as well as for small y-type ions derived from the fragmentation of amide bonds bounded on the amino-terminal side by aspartic or glutamic acid residues (D/E-X transitions). This analysis yielded four major observations: (1) b-ions tend to require lower collision energies than y-ions for optimal fragmentation, while D/E-X transitions tend to require more; (2) CE equations predict the optimal CEs more closely when product ion m/z dependence is included, in addition to the current standard of precursor ion m/z dependence; (3) separate CE equations for y-ions, b-ions, and D/E-X transitions are more effective than the previous one-size-fits-all equations, but best results are achieved by optimizing transitions individually; and (4) while b-ions gain substantial signal from CE optimization-often increases of several-fold-they still tend to rank lower than y-ions from the same peptide. These results confirm the notion that y-ions are usually the first-choice transitions for MRM experiments but also demonstrate, for the first time, that b-ions can be viable targets as well, if the proper collision energies are used. PMID- 20968309 TI - Microbubbles loaded with nanoparticles: a route to multiple imaging modalities. AB - We report a single-step approach to producing small and stable bubbles functionalized with nanoparticles. The strategy includes the following events occurring in sequence: (i) a microfluidic generation of bubbles from a mixture of CO(2) and a minute amount of gases with low solubility in water, in an aqueous solution of a protein, a polysaccharide, and anionic nanoparticles; (ii) rapid dissolution of CO(2) leading to the shrinkage of bubbles and an increase in acidity of the medium in the vicinity of the bubbles; and (iii) co-deposition of the biopolymers and nanoparticles at the bubble-liquid interface. The proposed approach yielded microbubbles with a narrow size distribution, long-term stability, and multiple functions originating from the attachment of metal oxide, metal, or semiconductor nanoparticles onto the bubble surface. We show the potential applications of these bubbles in ultrasound and magnetic resonance imaging. PMID- 20968308 TI - Comparison of strong cation exchange and SDS-PAGE fractionation for analysis of multiprotein complexes. AB - Affinity purification of protein complexes followed by identification using liquid chromatography/mass spectrometry (LC-MS/MS) is a robust method to study the fundamental process of protein interaction. Although affinity isolation reduces the complexity of the sample, fractionation prior to LC-MS/MS analysis is still necessary to maximize protein coverage. In this study, we compared the protein coverage obtained via LC-MS/MS analysis of protein complexes prefractionated using two commonly employed methods, SDS-PAGE and strong cation exchange chromatography (SCX). The two complexes analyzed focused on the nuclear proteins Bmi-1 and GATA3 that were expressed within the cells at low and high levels, respectively. Prefractionation of the complexes at the peptide level using SCX consistently resulted in the identification of approximately 3-fold more proteins compared to separation at the protein level using SDS-PAGE. The increase in the number of identified proteins was especially pronounced for the Bmi-1 complex, where the target protein was expressed at a low level. The data show that prefractionation of affinity isolated protein complexes using SCX prior to LC-MS/MS analysis significantly increases the number of identified proteins and individual protein coverage, particularly for target proteins expressed at low levels. PMID- 20968310 TI - Fibrillation of beta-lactoglobulin at low pH in the presence of a complexing anionic polysaccharide. AB - The influence of electrostatic complexation with kappa-carrageenan was tested on the fibrillation process of beta-lactoglobulin at pH 2.0. Morphology and structural development were monitored through cross correlation dynamic light scattering, transmission electron microscopy, and atomic force microscopy. Scattering indicated that noncomplexed beta-lactoglobulin monomers aggregated to form fibrils after 15-90 min of heating at 90 degrees C. However, electrostatic protein-carrageenan complexes found in the unheated system were unchanged by the thermal process. Images and scattering results showed that carrageenan complexes slowed fibrillation kinetics, possibly through reduction in available monomer concentration. Complexes adhered to fibrils at ends and junctions in TEM images, indicating interactive affinity with the fibers, presumably as heterogeneous nucleation sites. PMID- 20968311 TI - Energetics and structural elucidation of mechanisms for gas phase H/D exchange of protonated peptides. AB - Hydrogen/deuterium exchange reactions involving protonated triglycine and deuterated ammonia (ND(3)) have been examined in the gas phase using a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. Ab initio and density functional theory (DFT) calculations have been carried out to model the exchanges and to obtain energetics and vibrational frequencies for molecules involved in the proposed exchange mechanisms. Structural optimization and frequency calculations have been performed at the B3LYP level of theory with the 6-311+G(d,p) basis set. Transition states have been calculated at the same level of theory and basis set as above using the QST2 and QST3 methods. Single-point energy calculations have been performed at the MP2/6-311+G(d,p) level. Six labile sites of protonated triglycine were found to undergo H/D exchange. Of these six labile hydrogens, two are amide, three are ammonium, and one is carboxyl. Detailed mechanisms for each of these transfers are proposed. Qualitative onium ion and tautomer mechanisms for the exchanges of ammonium and amide hydrogens, respectively, using semiempirical calculations were suggested in previous studies by Beauchamp et al. As shown by the current ab initio and DFT calculations completed during this study, the mechanisms proposed in that study are notionally correct; however, the tautomer mechanisms are shown here to be the result of the fact that a second stable isomer of protonated triglycine exists in which the amide1 carbonyl oxygen is protonated. The exchange of the carboxyl hydrogen is found to proceed via a transition state resembling an ammonium ion interacting with a carboxylate moiety via two hydrogen bonds. The current work thus provides significant mechanistic and structural detail for a considerably more in-depth understanding of the processes involved in gas phase H/D exchange of peptides. PMID- 20968314 TI - Binding energy landscape analysis helps to discriminate true hits from high scoring decoys in virtual screening. AB - Although virtual screening through molecular docking has been widely applied in lead discovery, it is still challenging to distinguish true hits from high scoring decoys because of the difficulty in accurately predicting protein-ligand binding affinities. Following the successful application of energy landscape analysis to both protein folding and biomolecular binding studies, we attempted to use protein-ligand binding energy landscape analysis to recognize true binders from high-scoring decoys. Two parameters describing the binding energy landscape were used for this purpose. The energy gap, defined as the difference between the binding energy of the native binding mode and the average binding energy of other binding modes in the "denatured binding phase", was used to describe the thermodynamic stability of binding, and the number of local binding wells in the landscapes was used to account for the kinetic accessibility. These parameters, together with the docking score, were combined using logistic regression to investigate their capability to discriminate true ligands from high-scoring decoys. Inhibitors and the noninhibitors of two enzyme systems, neuraminidase and cyclooxygenase-2, were used to test their discrimination capability. Using a five fold cross-validation, the areas under the receiver operator characteristic curves (AUCs) from the best linear combinations of parameters reached 0.878 for neuraminidase and 0.776 for cyclooxygenase-2. To make a more independent test, inhibitors and high-scoring decoys in a directory of useful decoys (DUD), the largest and most comprehensive public data set for benchmarking virtual screen programs by far, were used as independent test sets to test the discrimination capability of these parameters. The AUCs of the best linear combinations of parameters for the independent test sets were 0.750 for neuraminidase and 0.855 for cyclooxygenase-2. Furthermore, combining these two parameters with the docking scoring function improved the enrichment ratio to 200-300% compared to that using the scoring function alone. This study suggests that incorporating information from binding energy landscape analysis can significantly increase the success rate of virtual screening. PMID- 20968315 TI - Ligand electronic parameters as a measure of the polarization of the C=O bond in [M(CO)(x)L(y)]n complexes and of the relative stabilization of [M(CO)(x)L(y)](n/n+1) species. AB - The electronic description of octahedral (fac-[M(CO)(3)L(3)](n), with M = Re, Ru, and Mn, and [Cr(CO)(5)L](n)), square-planar (cis-[Pt(CO)(2)L(2)](n)), and tetrahedral ([Ni(CO)(3)L](n)) carbonyl complexes (where L = monodentate ligand) was obtained via density functional theory and natural population analyses in order to understand what effects are probed in these species by vibrational spectroscopy and electrochemistry as a function of the ligand electronic parameter of the associated L. The analysis indicates that while ligand electronic parameters may be considered as a measure of the net donor power of the ligand, the net transfer of the electron density (or charge) does not occur from the ligand to the metal ion. In [M(CO)(x)L(y)](n) carbonyl species, the charge transfer occurs from the ligand L to the oxygen atom of the bound carbon monoxides. This charge transfer translates into changes of the polarization (or permanent dipole) and the covalency of the C=O bonds, and it is this effect that is probed in IR spectroscopy. As the analysis shifts from IR radiations to electrochemical potentials, the parameters best describe the relative thermodynamic stability of the oxidized and reduced [M(CO)(x)L(y)](n/n+1) species. No relationship is found between the metal natural charge of the [M(CO)(x)L(y)](n) fragments analyzed and the parameters. Brief considerations are given on the possible design of CO-releasing molecules. PMID- 20968316 TI - Structural requirements of the ASBT by 3D-QSAR analysis using aminopyridine conjugates of chenodeoxycholic acid. AB - The human apical sodium-dependent bile acid transporter (ASBT) is a validated drug target and can be employed to increase oral bioavailability of various drug conjugates. The aim of the present study was to investigate the chemical space around the 24-position of bile acids that influences both inhibition and uptake by the transporter. A series of 27 aminopyridine and aminophenol conjugates of glutamyl-chenodeoxycholate were synthesized and their ASBT inhibition and transport kinetics (parametrized as K(i), K(t), and J(max)) measured using stably transfected ASBT-MDCK cells. All conjugates were potent ASBT inhibitors. Monoanionic conjugates exhibited higher inhibition potency than neutral conjugates. However, neutral conjugates and chloro-substituted monoanionic conjugates were not substrates, or at least not apparent substrates. Kinetic analysis of substrates indicated that similar values for K(i) and K(t) implicate substrate binding to ASBT as the rate-limiting step. Using 3D-QSAR, four inhibition models and one transport efficiency model were developed. Steric fields dominated in CoMFA models, whereas hydrophobic fields dominated CoMSIA models. The inhibition models showed that a hydrophobic or bulky substitute on the 2 or 6 position of a 3-aminopyridine ring enhanced activity, while a hydrophobic group on the 5 position was detrimental. Overall, steric and hydrophobic features around the 24 position of the sterol nucleus strongly influenced bile acid conjugate interaction with ASBT. The relative location of the pyridine nitrogen and substituent groups also modulated binding. PMID- 20968318 TI - Radiated signal characteristics of marine vessels in the cepstral domain for shallow underwater channel. AB - This work examines the distribution of cepstral energy of the radiated signal of a marine vessel and the underwater channel modeled as a block-adaptive linear system. Detailed simulation analysis of the signal at the receiver of a passive sonar has led to the observation that, in the cepstral domain the radiated signal of a marine vessel largely occupies the lower cepstral indices while the underwater channel occupies the higher indices, such that for several range and depth conditions, the two can be separated out. This finding can facilitate the design of filters in the cepstral domain for reducing distortions due to the underwater channel. The work presents analytical justification and simulation studies in this regard. PMID- 20968319 TI - Unwanted sounds generated with test tone presentation can spoil extended high frequency audiometry. AB - Unwanted sounds from a commercially available audiometer were evaluated in terms of their effects on extended high-frequency (EHF) audiometry. Although the manufacturer reported that the audiometer conformed to relevant International Electrotechnical Commission (IEC) standards, the audiograms obtained using the audiometer were erroneous because the subjects had responded falsely to noise generated with the test tone presentation before detecting the test tone. Analyses of acoustic and electric output signals revealed that the audiometer generated most of the unwanted sounds, not the earphones that were used. Based on the measurement results, clinical implications of the measurement results are discussed for conducting more reliable EHF audiometry. PMID- 20968320 TI - End level bias on direct loudness ratings of increasing sounds. AB - Three experiments on loudness of sounds with linearly increasing levels were performed: global loudness was measured using direct ratings, loudness change was measured using direct and indirect estimations. Results revealed differences between direct and indirect estimations of loudness change, indicating that the underlying perceptual phenomena are not the same. The effect of ramp size is small for the former and important for the latter. A similar trend was revealed between global loudness and direct estimations of loudness change according to the end level, suggesting they may have been confounded. Measures provided by direct estimations of loudness change are more participant-dependent. PMID- 20968321 TI - Phonemic restoration in sensorineural hearing loss does not depend on baseline speech perception scores. AB - The brain can restore missing speech segments using linguistic knowledge and context. The phonemic restoration effect is commonly quantified by the increase in intelligibility of interrupted speech when the silent gaps are filled with noise bursts. In normal hearing, the restoration effect is negatively correlated with the baseline scores with interrupted speech; listeners with poorer baseline show more benefit from restoration. Reanalyzing data from Baskent et al. [(2010). Hear. Res. 260, 54-62], correlations with mild and moderate hearing impairment were observed to differ than with normal hearing. This analysis further shows that hearing impairment may affect top-down restoration of speech. PMID- 20968322 TI - Passive cavitation mapping for localization and tracking of bubble dynamics. AB - Current acoustic techniques for studying cavitation dynamics are only readily applicable to single-bubble activity, while optical methods can only be used in transparent media. However, multi-bubble cavitation often occurs in opaque media such as biological tissue. Here, the signals received passively by each of the 64 channels of a diagnostic ultrasound array are used to localize and separate emissions from several bubble clusters cavitating in agar gel, thereby providing a method of observing cavitation dynamics. The method has a high spatiotemporal resolution and is applicable to cavitation in opaque media. PMID- 20968323 TI - Long range transmission loss of broadband seismic pulses in the Arctic under ice free conditions. AB - In 2008 the Louis S. St-Laurent (LSSL) surveyed deep Arctic waters using a three airgun seismic source. Signals from the seismic survey were detected between 400 km and 1300 km range on a directional autonomous acoustic recorder deployed in water 53 m deep off the Alaskan North Slope. Observations of received signal levels between 10-450 Hz versus LSSL range roughly fit a cylindrical transmission loss model plus 0.01 dB/km attenuation in deep ice-free waters, and fit previous empirical models in ice-covered waters. The transition between ice-free and ice covered propagation conditions shifted 200 km closer to the recorder during the survey. PMID- 20968324 TI - Fishbone-like instability in a looped-tube thermoacoustic engine. AB - Quasi-periodic bursts of acoustic oscillations were observed during the start-up process in a looped-tube thermoacoustic engine. The acoustic oscillations have a constant frequency of 111 Hz, while the bursts have "quasi-periods" in the order of 14-25 s. The quasi-periodic bursts show a new mode of amplitude growth in this thermoacoustic engine. The envelope of the acoustic oscillations has a fishbone like shape. The nature of the observed fishbone-like instabilities suggests a strong interaction between the acoustic and temperature field. PMID- 20968325 TI - Manipulation of microparticles using phase-controllable ultrasonic standing waves. AB - A method of manipulating microparticles in a liquid using ultrasound is proposed and demonstrated. An ultrasonic standing wave with nodal planes whose positions are controllable by varying the relative phase of two applied sinusoidal signals is generated using a pair of acoustically matched piezoelectric transducers. The resulting acoustic radiation force is used to trap micron scale particles at a series of arbitrary positions (determined by the relative phase) and then move them in a controlled manner. This method is demonstrated experimentally and 5 MUm polystyrene particles are trapped and moved in one dimension through 140 MUm. PMID- 20968326 TI - Short-term adaptation to accented English by younger and older adults. AB - This study examined the effects of age and hearing loss on short-term adaptation to accented speech. Data from younger and older listeners in a prior investigation [Gordon-Salant et al. (2010). J. Acoust. Soc. Am. 128, 444-455] were re-analyzed to examine changes in recognition over four administrations of equivalent lists of English stimuli recorded by native speakers of Spanish and English. Results showed improvement in recognition scores over four list administrations for the accented stimuli but not for the native English stimuli. Group effects emerged but were not involved in any interactions, suggesting that short-term adaptation to accented speech is preserved with aging and with hearing loss. PMID- 20968327 TI - Constraining the minute amount of audible energy radiated from binary collisions of light plastic spheres in conditions of incomplete angular coverage of the measured pressure. AB - Usually, the energy released as air-coupled sound following a collision is dismissed as negligible. The goal of this Letter is to quantify the value of this small but measurable quantity, since it can be useful to impact studies. Measurements of sound radiation from binary collisions of polypropylene balls were performed in order to constrain the fraction of incident energy radiated as sound in air. In the experiments, one ball is released from rest, directly above a stationary target ball. The transient acoustic waveforms are detected by a microphone rotated about the impact point at a radius of 10 cm. The sound pressure was measured as a function of the polar angle theta (the azimuthal symmetry of the problem was verified by rotating the microphone in the horizontal plane). The angular pattern has two main lobes that are asymmetric with respect to the impact plane. This asymmetry is ascribable to interference and/or scattering effects. Gaps in the acoustic measurements at the "poles" (i.e., around 0 degrees and 180 degrees ) pose a challenge similar to that of extrapolating the cosmic microwave background in the galactic "cut." The data was continued in the gaps by polynomial interpolation rather than least-squares fitting, a choice dictated by the accuracy of the reconstructed pattern. The acoustic energy radiated during the impact, estimated by multiplying the collision time by the sound intensity integrated over a spherical surface centered at the impact point, is calculated as four orders of magnitude smaller than the incident energy (0.23 MUJ versus 1.6 mJ). PMID- 20968328 TI - Detection of modulation of a 4-kHz carrier. AB - To better understand the processing of complex high-frequency sounds, modulation detection thresholds were measured for sinusoidal frequency modulation (SFM), quasi-frequency modulation (QFM), sinusoidal amplitude modulation (SAM), and random-phase FM (RPFM). At the lowest modulation frequency (5 Hz) modulation thresholds expressed as AM depth were similar for RPFM, SAM and QFM suggesting the predominance of envelope cues. At the higher modulation frequencies (20 and 40 Hz) thresholds expressed as total frequency excursions were similar for SFM and QFM suggesting a common mechanism, one perhaps based on single-channel FM-to AM conversion or on a multi-channel place mechanism. The fact that the nominal envelopes of SFM and QFM are different (SFM has a flat envelope), seems to preclude processing based on the envelope of the external stimulus. Also, given the 4-kHz carrier and the similarity to previously published results obtained with a 1-kHz carrier, processing based on temporally-coded fine structure for all four types of modulation appears unlikely. PMID- 20968330 TI - On the limitation of a diffusion equation model for acoustic predictions of rooms with homogeneous dimensions. AB - In recent years a model for predicting sound fields in enclosures has been proposed, based on the mathematical theory of diffusion. This model is held to be valid for predicting the late reverberation component of the impulse response, on the basis that sufficient reflection events must occur [Valeau et al., J. Acoust. Soc. Am. 119, 1504-1513 (2006)]. The present work determines numerically the extent of reflections necessary for the solution of the diffusion equation model to be accurate in quasi-cubic rooms. Some preliminary numerical experiments have been carried out to determine after how many mean-free times of the impulse response, which is obtained by a geometrical-acoustic approach, gives a similar result to the solution obtained from a diffusion equation model. PMID- 20968329 TI - Radiofrequency electrode vibration-induced shear wave imaging for tissue modulus estimation: a simulation study. AB - Quasi-static electrode displacement elastography, used for in-vivo imaging of radiofrequency ablation-induced lesions in abdominal organs such as the liver and kidney, is extended in this paper to dynamic vibrational perturbations of the ablation electrode. Propagation of the resulting shear waves into adjoining regions of tissue can be tracked and the shear wave velocity used to quantify the shear (and thereby Young's) modulus of tissue. The algorithm used utilizes the time-to-peak displacement data (obtained from finite element analyses) to calculate the speed of shear wave propagation in the material. The simulation results presented illustrate the feasibility of estimating the Young's modulus of tissue and is promising for characterizing the stiffness of radiofrequency ablated thermal lesions and surrounding normal tissue. PMID- 20968331 TI - Efficient evaluation of edge diffraction integrals using the numerical method of steepest descent. AB - For the problem of edge diffraction from an edge of finite length a frequency domain solution, obtained from an analytical time-domain solution, has been presented by Svensson et al. [Acta. Acust. Acust. 95, 568-572]. This formulation takes the form of a Fourier-type integral whose evaluation is expensive in the high frequency range. This paper demonstrates that by using tailored highly oscillatory quadrature methods based on asymptotic properties of the integral, accurate approximations in the high frequency case can be obtained with little computational effort. PMID- 20968332 TI - Cancellation of spurious arrivals in Green's function retrieval of multiple scattered waves. AB - The Green's function for wave propagation can be extracted by cross-correlating field fluctuations excited on a closed surface that surrounds the employed receivers. This study treats an acoustic multiple scattering medium with discrete scatterers and shows that for a given source the cross-correlation of waves propagating along most combinations of scattering paths gives unphysical arrivals. Because theory predicts that the true Green's function is retrieved, such unphysical arrivals must cancel after integration over all sources. This cancellation occurs because the scattering amplitude of each scatterer satisfies the generalized optical theorem. The cross-correlation of scattered waves with themselves does not lead to the correct retrieval of scattered waves, because the cross-terms between the direct and scattered waves is essential. PMID- 20968333 TI - Acoustic metafluids made from three acoustic fluids. AB - Significant reduction in target strength and radiation signature can be achieved by surrounding an object with multiple concentric layers comprised of three acoustic fluids. The idea is to make a finely layered shell with the thickness of each layer defined by a unique transformation rule. The shell has the effect of steering incident acoustic energy around the structure, and conversely, reducing the radiation strength. The overall effectiveness and the precise form of the layering depends upon the densities and compressibilities of the three fluids. Nearly optimal results are obtained if one fluid has density equal to the background fluid, while the other two densities are much greater and much less than the background values. Optimal choices for the compressibilities are also found. Simulations in 2D and 3D illustrate effectiveness of the three fluid shell. The limited range of acoustic metafluids that are possible using only two fluid constituents is also discussed. PMID- 20968334 TI - Computation of the acoustic radiation force using the finite-difference time domain method. AB - The computational details related to calculating the acoustic radiation force on an object using a 2-D grid finite-difference time-domain method (FDTD) are presented. The method is based on propagating the stress and velocity fields through the grid and determining the energy flow with and without the object. The axial and radial acoustic radiation forces predicted by FDTD method are in excellent agreement with the results obtained by analytical evaluation of the scattering method. In particular, the results indicate that it is possible to trap the steel cylinder in the radial direction by optimizing the width of Gaussian source and the operation frequency. As the sizes of the relating objects are smaller than or comparable to wavelength, the algorithm presented here can be easily extended to 3-D and include torque computation algorithms, thus providing a highly flexible and universally usable computation engine. PMID- 20968335 TI - Stability of the parametrically excited damped inverted pendulum: theory and experiment. AB - The parametrically driven, damped, inverted pendulum can be dynamically stabilized in particular regions of the parameter space. The impact of damping on dynamic stabilization can be stabilizing or destabilizing depending on the location in parameter space (i.e., drive frequency and amplitude). Floquet analysis and numerical simulations were used to determine the stable regions. An experiment was conducted that verifies the model. Physical explanations and simple bounding approximations are provided to summarize findings. The utility of the highly damped pendulum results are illustrated by drawing the analogy to dynamic stabilization of the Rayleigh-Taylor instability: it permits ready demonstration that dynamic stabilization is impossible in that system absent surface tension. PMID- 20968336 TI - The extended Fourier pseudospectral time-domain method for atmospheric sound propagation. AB - An extended Fourier pseudospectral time-domain (PSTD) method is presented to model atmospheric sound propagation by solving the linearized Euler equations. In this method, evaluation of spatial derivatives is based on an eigenfunction expansion. Evaluation on a spatial grid requires only two spatial points per wavelength. Time iteration is done using a low-storage optimized six-stage Runge Kutta method. This method is applied to two-dimensional non-moving media models, one with screens and one for an urban canyon, with generally high accuracy in both amplitude and phase. For a moving atmosphere, accurate results have been obtained in models with both a uniform and a logarithmic wind velocity profile over a rigid ground surface and in the presence of a screen. The method has also been validated for three-dimensional sound propagation over a screen. For that application, the developed method is in the order of 100 times faster than the second-order-accurate FDTD solution to the linearized Euler equations. The method is found to be well suited for atmospheric sound propagation simulations where effects of complex meteorology and straight rigid boundary surfaces are to be investigated. PMID- 20968337 TI - Measured wavenumber: frequency spectrum associated with acoustic and aerodynamic wall pressure fluctuations. AB - Direct measurements of the wavenumber-frequency spectrum of wall pressure fluctuations beneath a turbulent plane channel flow have been performed in an anechoic wind tunnel. A rotative array has been designed that allows the measurement of a complete map, 63*63 measuring points, of cross-power spectral densities over a large area. An original post-processing has been developed to separate the acoustic and the aerodynamic exciting loadings by transforming space frequency data into wavenumber-frequency spectra. The acoustic part has also been estimated from a simple Corcos-like model including the contribution of a diffuse sound field. The measured acoustic contribution to the surface pressure fluctuations is 5% of the measured aerodynamic surface pressure fluctuations for a velocity and boundary layer thickness relevant for automotive interior noise applications. This shows that for aerodynamically induced car interior noise, both contributions to the surface pressure fluctuations on car windows have to be taken into account. PMID- 20968338 TI - An iterative algorithm for computing aeroacoustic integrals with application to the analysis of free shear flow noise. AB - An iterative algorithm is developed for the computation of aeroacoustic integrals in the time domain. It is specially designed for the generation of acoustic images, thus giving access to the wavefront pattern radiated by an unsteady flow when large size source fields are considered. It is based on an iterative selection of source-observer pairs involved in the radiation process at a given time-step. It is written as an advanced-time approach, allowing easy connection with flow simulation tools. Its efficiency is related to the fraction of an observer grid step that a sound-wave covers during one time step. Test computations were performed, showing the CPU-time to be 30 to 50 times smaller than with a classical non-iterative procedure. The algorithm is applied to compute the sound radiated by a spatially evolving mixing-layer flow: it is used to compute and visualize contributions to the acoustic field from the different terms obtained by a decomposition of the Lighthill source term. PMID- 20968339 TI - Investigation of higher spanwise Helmholtz resonance modes in slender covered cavities. AB - Cavity aeroacoustic noise is relevant for aerospace and automotive industries and widely investigated since the 1950s. Most investigations so far consider cavities where opening length and width are of similar scale. The present investigation focuses on a less investigated setup, namely cavities that resemble the door gaps of automobiles. These cavities are both slender (width much greater than length or depth) and partially covered. Furthermore they are under influence of a low Mach number flow with a relatively thick boundary layer. Under certain conditions, these gaps can produce tonal noise. The present investigation attempts to reveal the aeroacoustic mechanism of this tonal noise for higher resonance modes. Experiments have been conducted on a simplified geometry, where unsteady internal pressures have been measured at different spanwise locations. With increasing velocity, several resonance modes occur. In order to obtain higher mode shapes, the cavity acoustic response is simulated and compared with experiment. Using the frequency-filtered simulation pressure field, the higher modes shapes are retrieved. The mode shapes can be interpreted as the slender cavity self-organizing into separate Helmholtz resonators that interact with each other. Based on this, an analytical model is derived that shows good agreement with the simulations and experimental results. PMID- 20968340 TI - Analysis of the radiated information in spinning sound fields. AB - The information content of a spinning sound field is analyzed using a combination of exact and asymptotic results, in order to set limits on how accurately source identification can be carried out. Using a transformation of the circular source to an exactly equivalent set of line source modes, given by Chebyshev polynomials, it is found that the line source modes of order greater than the source wavenumber generate exponentially small fields. Asymptotic analysis shows that the remaining, lower order, modes radiate efficiently only into a region around the source plane, with this region shrinking as the mode order is increased. The results explain the ill-conditioning of source identification methods; the successful use of low order models in active noise control; and the low radiation efficiency of subsonic jets. PMID- 20968341 TI - Sound speed profile characterization by the image source method. AB - This paper presents the first results of an imaging technique that measures the geoacoustic structure of a seafloor in shallow water areas. The devices used were a broadband (100 Hz-6 kHz) acoustic source towed by a ship and a vertical array. Among all the acoustic paths existing in the water column, two are used: the direct one and the seabed-reflected one, the latter being composed of the reflections from the seafloor's surface as well as that from each buried layer. Due to the good time resolution of the signal and to the short range configuration, the reflected signal can be modeled as a sum of contributions coming from image sources relative to the seabed layers. The seabed geometry and the sound speed profile can then be recovered with the detection and localization of these image sources. The map of the image sources is obtained by a function that combines back-propagation of signals and knowledge of the emitted pulse. The thickness and sound-speed of each layer is finally obtained by a position analysis of the image sources. The results obtained by this data-driven algorithm on both at-sea and synthetic data are satisfactory. PMID- 20968342 TI - Multistatic detection and tracking using linear maximal sequences. AB - A simulation using linear maximal sequence (m-sequence) transmissions demonstrated the potential for detecting and tracking near-surface targets. In this simulation a low power, omnidirectional source and four omnidirectional hydrophones were arbitrarily located in water approximately 4 m deep. The simulated -15 dB target traveled at 1.5 kn. Using "channel digit response" processing and "block zeroing," the direct arrival, multipaths, clutter and reverberation were rejected. (The block zeroing process is very different from other methods typically labeled as "cancellation.") With the improved signal-to interference ratio, a simple probability based algorithm demonstrated tracking at source-target distances of 250 m, the maximum range investigated. PMID- 20968343 TI - Power dissipation and temperature distribution in piezoelectric ceramic slabs. AB - A method is presented to determine power dissipation in one-dimensional piezoelectric slabs with internal losses and the resulting temperature distribution. The length of the slab is much greater than the lateral dimensions. Losses are represented using complex piezoelectric coefficients. It is shown that the spatially non-uniform power dissipation density in the slab can be determined by considering either hysteresis loops or the Poynting vector. The total power dissipated in the slab is obtained by integrating the power dissipation density over the slab and is shown to be equal to the power input to the slab for special cases of mechanically and electrically excited slabs. The one-dimensional heat equation that includes the effect of conduction and convection, and the boundary conditions, are then used to determine the temperature distribution. When the analytical expression for the power dissipation density is simple, direct integration is used. It is shown that a modified Fourier series approach yields the same results. For other cases, the temperature distribution is determined using only the latter approach. Numerical results are presented to illustrate the effects of internal losses, heat conduction and convection coefficients, and boundary conditions on the temperature distribution. PMID- 20968344 TI - Receiving sensitivity and transmitting voltage response of a fluid loaded spherical piezoelectric transducer with an elastic coating. AB - A method is presented to determine the response of a spherical acoustic transducer that consists of a fluid-filled piezoelectric sphere with an elastic coating embedded in infinite fluid to electrical and plane-wave acoustic excitations. The exact spherically symmetric, linear, differential, governing equations are used for the interior and exterior fluids, and elastic and piezoelectric materials. Under acoustic excitation and open circuit boundary condition, the equation governing the piezoelectric sphere is homogeneous and the solution is expressed in terms of Bessel functions. Under electrical excitation, the equation governing the piezoelectric sphere is inhomogeneous and the complementary solution is expressed in terms of Bessel functions and the particular integral is expressed in terms of a power series. Numerical results are presented to illustrate the effect of dimensions of the piezoelectric sphere, fluid loading, elastic coating and internal material losses on the open-circuit receiving sensitivity and transmitting voltage response of the transducer. PMID- 20968345 TI - Minimally radiating sources for personal audio. AB - In order to reduce annoyance from the audio output of personal devices, it is necessary to maintain the sound level at the user position while minimizing the levels elsewhere. If the dark zone, within which the sound is to be minimized, extends over the whole far field of the source, the problem reduces to that of minimizing the radiated sound power while maintaining the pressure level at the user position. It is shown analytically that the optimum two-source array then has a hypercardioid directivity and gives about 7 dB reduction in radiated sound power, compared with a monopole producing the same on-axis pressure. The performance of other linear arrays is studied using monopole simulations for the motivating example of a mobile phone. The trade-off is investigated between the performance in reducing radiated noise, and the electrical power required to drive the array for different numbers of elements. It is shown for both simulations and experiments conducted on a small array of loudspeakers under anechoic conditions, that both two and three element arrays provide a reasonable compromise between these competing requirements. The implementation of the two source array in a coupled enclosure is also shown to reduce the electrical power requirements. PMID- 20968346 TI - Decentralized control of sound radiation using iterative loop recovery. AB - A decentralized model-based control strategy is designed to reduce low-frequency sound radiation from periodically stiffened panels. While decentralized control systems tend to be scalable, performance can be limited due to modeling error introduced by the unmodeled interaction between neighboring control units. Since bounds on modeling error are not known in advance, it is difficult to ensure the decentralized control system will be robust without making the controller overly conservative. Therefore an iterative approach is suggested, which utilizes frequency-shaped loop recovery. The approach accounts for modeling error introduced by neighboring control loops, requires no communication between subsystems, and is relatively simple. The control strategy is evaluated numerically using a model of a stiffened aluminum panel that is representative of the sidewall of an aircraft. Simulations demonstrate that the iterative approach can achieve significant reductions in radiated sound power from the stiffened panel without destabilizing neighboring control units. PMID- 20968347 TI - A neural network based model for urban noise prediction. AB - Noise is a global problem. In 1972 the World Health Organization (WHO) classified noise as a pollutant. Since then, most industrialized countries have enacted laws and local regulations to prevent and reduce acoustic environmental pollution. A further aim is to alert people to the dangers of this type of pollution. In this context, urban planners need to have tools that allow them to evaluate the degree of acoustic pollution. Scientists in many countries have modeled urban noise, using a wide range of approaches, but their results have not been as good as expected. This paper describes a model developed for the prediction of environmental urban noise using Soft Computing techniques, namely Artificial Neural Networks (ANN). The model is based on the analysis of variables regarded as influential by experts in the field and was applied to data collected on different types of streets. The results were compared to those obtained with other models. The study found that the ANN system was able to predict urban noise with greater accuracy, and thus, was an improvement over those models. The principal component analysis (PCA) was also used to try to simplify the model. Although there was a slight decline in the accuracy of the results, the values obtained were also quite acceptable. PMID- 20968348 TI - Statistical classification of road pavements using near field vehicle rolling noise measurements. AB - Low noise surfaces have been increasingly considered as a viable and cost effective alternative to acoustical barriers. However, road planners and administrators frequently lack information on the correlation between the type of road surface and the resulting noise emission profile. To address this problem, a method to identify and classify different types of road pavements was developed, whereby near field road noise is analyzed using statistical learning methods. The vehicle rolling sound signal near the tires and close to the road surface was acquired by two microphones in a special arrangement which implements the Close Proximity method. A set of features, characterizing the properties of the road pavement, was extracted from the corresponding sound profiles. A feature selection method was used to automatically select those that are most relevant in predicting the type of pavement, while reducing the computational cost. A set of different types of road pavement segments were tested and the performance of the classifier was evaluated. Results of pavement classification performed during a road journey are presented on a map, together with geographical data. This procedure leads to a considerable improvement in the quality of road pavement noise data, thereby increasing the accuracy of road traffic noise prediction models. PMID- 20968349 TI - Attenuation of direct sound and the contributions of early reflections within symphony orchestras. AB - On concert hall stages the sound traveling between players consists of the direct sound, a floor reflection and early reflections off players and objects on stage such as instruments and music stands. In smaller music ensembles, the acoustic communication between players is normally good. In larger ensembles, there is a similar situation for short distances between players. However for ensembles like a symphony orchestra, the number of players on stage results in large distances between some players with many other players sitting in between, which block the direct sound and floor reflection paths. This study investigates the sound levels on stage with and without a large orchestra present, in the absence of any stage enclosure. Sound levels within the octave bands 63-2000 Hz on an empty stage were studied analytically, while sound levels over the same frequency range with players present were investigated in a 1:25 scale model, both without and with risers on stage. The main results are presented in terms of the attenuation introduced by the orchestra, with linear models developed to describe behavior for the octave bands 500-2000 Hz. PMID- 20968350 TI - Microstructure based model for sound absorption predictions of perforated closed cell metallic foams. AB - Closed-cell metallic foams are known for their rigidity, lightness, thermal conductivity as well as their low production cost compared to open-cell metallic foams. However, they are also poor sound absorbers. Similarly to a rigid solid, a method to enhance their sound absorption is to perforate them. This method has shown good preliminary results but has not yet been analyzed from a microstructure point of view. The objective of this work is to better understand how perforations interact with closed-cell foam microstructure and how it modifies the sound absorption of the foam. A simple two-dimensional microstructural model of the perforated closed-cell metallic foam is presented and numerically solved. A rough three-dimensional conversion of the two dimensional results is proposed. The results obtained with the calculation method show that the perforated closed-cell foam behaves similarly to a perforated solid; however, its sound absorption is modulated by the foam microstructure, and most particularly by the diameters of both perforation and pore. A comparison with measurements demonstrates that the proposed calculation method yields realistic trends. Some design guides are also proposed. PMID- 20968351 TI - Solid-perforated panel layout optimization by topology optimization based on unified transfer matrix. AB - This paper presents a numerical method for the optimization of the sequencing of solid panels, perforated panels and air gaps and their respective thickness for maximizing sound transmission loss and/or absorption. For the optimization, a method based on the topology optimization formulation is proposed. It is difficult to employ only the commonly-used material interpolation technique because the involved layers exhibit fundamentally different acoustic behavior. Thus, an optimization method formulation using a so-called unified transfer matrix is newly proposed. The key idea is to form elements of the transfer matrix such that interpolated elements by the layer design variables can be those of air, perforated and solid panel layers. The problem related to the interpolation is addressed and bench mark-type problems such as sound transmission or absorption maximization problems are solved to check the efficiency of the developed method. PMID- 20968352 TI - Analytical prediction of break-out noise from a reactive rectangular plenum with four flexible walls. AB - This paper describes an analytical calculation of break-out noise from a rectangular plenum with four flexible walls by incorporating three-dimensional effects along with the acoustical and structural wave coupling phenomena. The breakout noise from rectangular plenums is important and the coupling between acoustic waves within the plenum and structural waves in the flexible plenum walls plays a critical role in prediction of the transverse transmission loss. The first step in breakout noise prediction is to calculate the inside plenum pressure field and the normal flexible plenum wall vibration by using an impedance-mobility approach, which results in a compact matrix formulation. In the impedance-mobility compact matrix (IMCM) approach, it is presumed that the coupled response can be described in terms of finite sets of the uncoupled acoustic subsystem and the structural subsystem. The flexible walls of the plenum are modeled as an unfolded plate to calculate natural frequencies and mode shapes of the uncoupled structural subsystem. The second step is to calculate the radiated sound power from the flexible walls using Kirchhoff-Helmholtz (KH) integral formulation. Analytical results are validated with finite element and boundary element (FEM-BEM) numerical models. PMID- 20968353 TI - On the angular error of intensity vector based direction of arrival estimation in reverberant sound fields. AB - An acoustic vector sensor provides measurements of both the pressure and particle velocity of a sound field in which it is placed. These measurements are vectorial in nature and can be used for the purpose of source localization. A straightforward approach towards determining the direction of arrival (DOA) utilizes the acoustic intensity vector, which is the product of pressure and particle velocity. The accuracy of an intensity vector based DOA estimator in the presence of noise has been analyzed previously. In this paper, the effects of reverberation upon the accuracy of such a DOA estimator are examined. It is shown that particular realizations of reverberation differ from an ideal isotropically diffuse field, and induce an estimation bias which is dependent upon the room impulse responses (RIRs). The limited knowledge available pertaining the RIRs is expressed statistically by employing the diffuse qualities of reverberation to extend Polack's statistical RIR model. Expressions for evaluating the typical bias magnitude as well as its probability distribution are derived. PMID- 20968354 TI - Locating an acoustic point source scattered by a skull phantom via time reversal matched filtering. AB - This paper examines the utilization of the time reversal matched filtering method to resolve the location of an acoustic point source beneath a skull phantom (variable thickness layer), without the removal of this layer. This acoustical process is examined experimentally in a water tank immersion system containing an acoustic source, a custom-made skull phantom, and a receiving transducer in a pitch-catch arrangement. The phantom is designed to approximately model the acoustic properties of an average human skull bone (minus the diploe layer), while the variable thickness of the phantom introduces a variable time delay to the acoustic wave, relative to its entry point on the phantom. This variable delay is measured and corrected for, and a matched filtering time reversed process is used to determine the location of the point source. The results of the experiment are examined for various positions of the acoustic source behind the phantom and compared to the reference cases with no phantom present. The average distance between these two cases is found to be 4.36 mm, and within the expected deviation in results due to not accounting for the effects of refraction. PMID- 20968355 TI - Planar nearfield acoustical holography in moving fluid medium at subsonic and uniform velocity. AB - Nearfield acoustical holography (NAH) data measured by using a microphone array attached to a high-speed aircraft or ground vehicle include significant airflow effects. For the purpose of processing the measured NAH data, an improved nearfield acoustical holography procedure is introduced that includes the effects of a fluid medium moving at a subsonic and uniform velocity. The convective wave equation along with the convective Euler's equation is used to develop the proposed NAH procedure. A mapping function between static and moving fluid medium cases is derived from the convective wave equation. Then, a conventional wave number filter designed for static fluid media is modified to be applicable to the moving fluid cases by applying the mapping function to the static wave number filter. In order to validate the proposed NAH procedure, a monopole simulation at the airflow speed of Mach=-0.6 is conducted. The reconstructed acoustic fields obtained by applying the proposed NAH procedure to the simulation data agree well with directly-calculated acoustic fields. Through an experiment with two loudspeakers performed in a wind tunnel operating at Mach=-0.12, it is shown that the proposed NAH procedure can be also used to reconstruct the sound fields radiated from the two loudspeakers. PMID- 20968356 TI - Swept-tone transient-evoked otoacoustic emissions. AB - Transient-evoked otoacoustic emissions (TEOAE) are responses generated within the inner ear in response to acoustic stimuli and are indicative of normal cochlear function. They are commonly acquired by averaging post-stimulus acoustic responses recorded near the eardrum in response to brief stimuli such as clicks or tone pips. In this study a new long duration stimulus consisting of a frequency swept tone is introduced for the acquisition of TEOAEs. Like stimulus frequency generated OAEs, swept-tone responses contain embedded OAEs. With swept tone analysis, OAEs can be recovered by convolving it with a time reversed swept tone signal resulting in time-compression. In addition, higher order nonlinear OAE responses were removed from the linear TEOAE. The results show comparable phase and time-frequency properties between the click and swept-tone evoked OAEs. Swept-tone acquisition of TEOAEs has beneficial noise properties, improving the signal to noise ratio by 6 dB compared to click evoked responses thus offering testing time savings. Additionally, swept-tone analysis removed synchronized spontaneous OAE activity from the recordings of subjects exhibiting such responses in conventional click TEOAEs. Since swept-tone stimulus consists of a single frequency component at any instantaneous moment, its analysis also provides for direct comparison with stimulus-frequency OAEs and click evoked OAEs. PMID- 20968357 TI - Quantitative estimation of minor conductive hearing loss with distortion product otoacoustic emissions in the guinea pig. AB - Subclinical conductive hearing losses (CHLs) can affect otoacoustic emissions and therefore limit their potential in the assessment of the cochlear function. Theoretical considerations to estimate a minor CHL from DPOAE measurements [Kummer et al. (2006). HNO 54, 457-467] are evaluated experimentally. They are based on the fact, that the level difference of the stimulus tones L(1) and L(2) for optimal excitation of the inner ear is given by L(1)=aL(2)+b. A CHL is presumed to attenuate both L(1) and L(2) to the same extent such that excitation of the inner ear is no longer optimal. From the change of L(1) that is necessary to restore optimal excitation of the inner ear and thus to produce maximal DPOAE levels, the CHL can be estimated. In 10 guinea pig ears an experimental CHL was produced, quantified by determination of compound action potential (CAP) thresholds at 8 kHz (CHL(CAP)) and estimated from DPOAE measurements at 8 kHz (CHL(DPOAE)). CHLs up to 12 dB could be assessed. CHL(DPOAE) correlated well with CHL(CAP) (R=0.741, p=0.0142). Mean difference between CHL(DPOAE) and CHL(CAP) was 4.2+/-2.6 dB. Estimation of minor CHL from DPOAE measurements might help to increase the diagnostic value of DPOAEs. PMID- 20968358 TI - Impact of three hours of discotheque music on pure-tone thresholds and distortion product otoacoustic emissions. AB - The aim of this study was to investigate whether distortion product otoacoustic emissions (DPOAEs) are a suitable means for detecting changes in outer hair cell (OHC) functionality due to exposure to three hours of discotheque music and whether efferent reflex strength of the medial olivocochlear bundle is able to predict the ear's susceptibility to high-level noise. High-resolution DPOAEs (Deltaf(2)=47 Hz) were recorded between 3.5 and 4.5 kHz at close-to-threshold primary tone levels. For comparison, high-resolution pure-tone audiometry was conducted in the same frequency range. Efferent reflex strength was measured by means of DPOAEs at a specific frequency with and without contralateral acoustic stimulation. A significant deterioration of more than 10 dB was found for pure tone thresholds and DPOAE levels indicating that three hours of high-level noise exert a considerable influence on hearing capability and OHC functionality. A significant correlation between shifts in pure-tone threshold and shifts in DPOAE level occurred when removing data with differing calibration across measurements. There was no clear correlation between efferent reflex strength and shifts in pure-tone threshold or shifts in DPOAE level suggesting that the applied measures of efferent reflex strength may not be suitable for quantifying individual vulnerability to noise. PMID- 20968359 TI - Modeling cochlear dynamics: interrelation between cochlea mechanics and psychoacoustics. AB - A model of the cochlea was used to bridge the gap between model approaches commonly used to investigate phenomena related to otoacoustic emissions and more filter-based model approaches often used in psychoacoustics. In the present study, a nonlinear and active one-dimensional transmission line model was developed that accounts for several aspects of physiological data with a single fixed parameter set. The model shows plausible excitation patterns and an input output function similar to the linear-compressive-linear function as hypothesized in psychoacoustics. The model shows realistic results in a two-tone suppression paradigm and a plausible growth function of the 2f(1)-f(2) component of distortion product otoacoustic emissions. Finestructure was found in simulated stimulus-frequency otoacoustic emissions (SFOAE) with realistic levels and rapid phase rotation. A plausible "threshold in quiet" including finestructure and spontaneous otoacoustic emissions (SOAE) could be simulated. It is further shown that psychoacoustical data of modulation detection near threshold can be explained by the mechanical dynamics of the modeled healthy cochlea. It is discussed that such a model can be used to investigate the representation of acoustic signals in healthy and impaired cochleae at this early stage of the auditory pathway for both, physiological as well as psychoacoustical paradigms. PMID- 20968360 TI - Advantage of bimodal fitting in prosody perception for children using a cochlear implant and a hearing aid. AB - Cochlear implants are largely unable to encode voice pitch information, which hampers the perception of some prosodic cues, such as intonation. This study investigated whether children with a cochlear implant in one ear were better able to detect differences in intonation when a hearing aid was added in the other ear ("bimodal fitting"). Fourteen children with normal hearing and 19 children with bimodal fitting participated in two experiments. The first experiment assessed the just noticeable difference in F0, by presenting listeners with a naturally produced bisyllabic utterance with an artificially manipulated pitch accent. The second experiment assessed the ability to distinguish between questions and affirmations in Dutch words, again by using artificial manipulation of F0. For the implanted group, performance significantly improved in each experiment when the hearing aid was added. However, even with a hearing aid, the implanted group required exaggerated F0 excursions to perceive a pitch accent and to identify a question. These exaggerated excursions are close to the maximum excursions typically used by Dutch speakers. Nevertheless, the results of this study showed that compared to the implant only condition, bimodal fitting improved the perception of intonation. PMID- 20968361 TI - Spectral and synchrony differences in auditory brainstem responses evoked by chirps of varying durations. AB - The chirp-evoked ABR has been termed a more synchronous response, referring to the fact that rising-frequency chirp stimuli theoretically compensate for temporal dispersions down the basilar membrane. This compensation is made possible by delaying the higher frequency content of the stimulus until the lower frequency traveling waves are closer to the cochlea apex. However, it is not yet clear how sensitive this temporal compensation is to variation in the delay interval. This study analyzed chirp- and click-evoked ABRs at low intensity, using a variety of tools in the time, frequency, and phase domains, to measure synchrony in the response. Additionally, this study also examined the relationship between chirp sweep rate and response synchrony by varying the delay between high- and low-frequency portions of chirp stimuli. The results suggest that the chirp-evoked ABRs in this study exhibited more synchrony than the click evoked ABRs and that slight gender-based differences exist in the synchrony of chirp-evoked ABRs. The study concludes that a tailoring of chirp parameters to gender may be beneficial in pathologies that severely affect neural synchrony, but that such a customization may not be necessary in routine clinical applications. PMID- 20968362 TI - Trading of intensity and interaural coherence in dichotic pitch stimuli. AB - When a signal is added to noise in the NoSpi binaural configuration, a reduction in interaural coherence, rho, occurs at the signal frequency and increases in tone intensity decrease rho. Corresponding manipulations of rho result in the perception of a phantom signal which increases in loudness as rho decreases [Culling et al. (2001). J. Acoust. Soc. Am. 110, 1020-1029]. In the present study, a narrow sub-band of noise (462-539 Hz) embedded within a broadband (0-3 kHz) diotic noise was manipulated in both intensity and rho in a 3-interval, odd one-out task. In the reference intervals, rho was zero and the spectrum was flat. In the target interval, both rho and the intensity of the target band were incremented giving opposing effects on loudness. Correct identification of the target interval followed a V-shape as a function of the size of intensity increment. The minimum of this function was often at chance performance, indicating that monaurally and binaurally evoked loudness were fully traded. These results show that reduction in rho at a given frequency produces increased loudness at that frequency equivalent to up to 6 dB and consistent with an equalization-cancellation mechanism whose binaural output is strongly weighted compared to monaural excitation. PMID- 20968363 TI - Overshoot using very short signal delays. AB - The detectability of a 10-ms tone masked by a 400-ms wideband noise was measured as a function of the delay in the onset of the tone compared to the onset of the noise burst. Unlike most studies like this on auditory overshoot, special attention was given to signal delays between 0 and 45 ms. Nine well-practiced subjects were tested using an adaptive psychophysical procedure in which the level of the masking noise was adjusted to estimate 79% correct detections. Tones of both 3.0 and 4.0 kHz, at different levels, were used as signals. For the subjects showing overshoot, detectability remained approximately constant for at least 20-30 ms of signal delay, and then detectability began to improve gradually toward its maximum at about 150-200 ms. That is, there was a "hesitation" prior to detectability beginning to improve, and the duration of this hesitation was similar to that seen in physiological measurements of the medial olivocochlear (MOC) system. This result provides further support for the hypothesis that the MOC efferent system makes a major contribution to overshoot in simultaneous masking. PMID- 20968364 TI - Perceived continuity and pitch shifts for complex tones with unresolved harmonics. AB - Brief complex tone bursts with fundamental frequencies (F0s) of 100, 125, 166.7, and 250 Hz were bandpass filtered between the 22nd and 30th harmonics, to produce waveforms with five regularly occurring envelope peaks ("pitch pulses") that evoked pitches associated with their repetition period. Two such tone bursts were presented sequentially and separated by a silent interval of two periods (2/F0). When the relative phases of the two bursts were varied, such that the interpulse interval (IPI) between the last pulse of the first burst and the first pulse of the second burst was varied, the pitch of the whole sequence was little affected. This is consistent with previous results suggesting that the pitch integration window may be "reset" by a discontinuity. However, when the interval between the two bursts was filled with a noise with the same spectral envelope as the complex, variations in IPI had substantial effects on the pitch of the sequence. It is suggested that the presence of the noise causes the two tones bursts to appear continuous, hence, resetting does not occur, and the pitch mechanism is sensitive to the phase discontinuity across the silent interval. PMID- 20968365 TI - Does fundamental-frequency discrimination measure virtual pitch discrimination? AB - Studies of pitch perception often involve measuring difference limens for complex tones (DLCs) that differ in fundamental frequency (F0). These measures are thought to reflect F0 discrimination and to provide an indirect measure of subjective pitch strength. However, in many situations discrimination may be based on cues other than the pitch or the F0, such as differences in the frequencies of individual components or timbre (brightness). Here, DLCs were measured for harmonic and inharmonic tones under various conditions, including a randomized or fixed lowest harmonic number, with and without feedback. The inharmonic tones were produced by shifting the frequencies of all harmonics upwards by 6.25%, 12.5%, or 25% of F0. It was hypothesized that, if DLCs reflect residue-pitch discrimination, these frequency-shifted tones, which produced a weaker and more ambiguous pitch than would yield larger DLCs than the harmonic tones. However, if DLCs reflect comparisons of component pitches, or timbre, they should not be systematically influenced by frequency shifting. The results showed larger DLCs and more scattered pitch matches for inharmonic than for harmonic complexes, confirming that the inharmonic tones produced a less consistent pitch than the harmonic tones, and consistent with the idea that DLCs reflect F0 pitch discrimination. PMID- 20968366 TI - Musical intervals and relative pitch: frequency resolution, not interval resolution, is special. AB - Pitch intervals are central to most musical systems, which utilize pitch at the expense of other acoustic dimensions. It seemed plausible that pitch might uniquely permit precise perception of the interval separating two sounds, as this could help explain its importance in music. To explore this notion, a simple discrimination task was used to measure the precision of interval perception for the auditory dimensions of pitch, brightness, and loudness. Interval thresholds were then expressed in units of just-noticeable differences for each dimension, to enable comparison across dimensions. Contrary to expectation, when expressed in these common units, interval acuity was actually worse for pitch than for loudness or brightness. This likely indicates that the perceptual dimension of pitch is unusual not for interval perception per se, but rather for the basic frequency resolution it supports. The ubiquity of pitch in music may be due in part to this fine-grained basic resolution. PMID- 20968367 TI - Subjective scaling of spatial room acoustic parameters influenced by visual environmental cues. AB - Although there have been numerous studies investigating subjective spatial impression in rooms, only a few of those studies have addressed the influence of visual cues on the judgment of auditory measures. In the psychophysical study presented here, video footage of five solo music/speech performers was shown for four different listening positions within a general-purpose space. The videos were presented in addition to the acoustic signals, which were auralized using binaural room impulse responses (BRIR) that were recorded in the same general purpose space. The participants were asked to adjust the direct-to-reverberant energy ratio (D/R ratio) of the BRIR according to their expectation considering the visual cues. They were also directed to rate the apparent source width (ASW) and listener envelopment (LEV) for each condition. Visual cues generated by changing the sound-source position in the multi-purpose space, as well as the makeup of the sound stimuli affected the judgment of spatial impression. Participants also scaled the direct-to-reverberant energy ratio with greater direct sound energy than was measured in the acoustical environment. PMID- 20968368 TI - Stimulus factors influencing spatial release from speech-on-speech masking. AB - This study examined spatial release from masking (SRM) when a target talker was masked by competing talkers or by other types of sounds. The focus was on the role of interaural time differences (ITDs) and time-varying interaural level differences (ILDs) under conditions varying in the strength of informational masking (IM). In the first experiment, a target talker was masked by two other talkers that were either colocated with the target or were symmetrically spatially separated from the target with the stimuli presented through loudspeakers. The sounds were filtered into different frequency regions to restrict the available interaural cues. The largest SRM occurred for the broadband condition followed by a low-pass condition. However, even the highest frequency bandpass-filtered condition (3-6 kHz) yielded a significant SRM. In the second experiment the stimuli were presented via earphones. The listeners identified the speech of a target talker masked by one or two other talkers or noises when the maskers were colocated with the target or were perceptually separated by ITDs. The results revealed a complex pattern of masking in which the factors affecting performance in colocated and spatially separated conditions are to a large degree independent. PMID- 20968370 TI - Longitudinal changes in hearing sensitivity among men: the Veterans Affairs Normative Aging Study. AB - Over 35 years (1962-1996), participants of the Veterans Affairs Normative Aging Study (NAS), a study of healthy aging in men, completed up to eight audiometric assessments. This report describes the age-related hearing trajectories of screened men (n=953) aged 23 to 81 years at enrollment, estimates the typical rate of change per decade in hearing sensitivity, and compares longitudinal and cross-sectional estimates of change in hearing sensitivity. The men were followed 14 years on average. The hearing trajectories, based on a mixed-effects model analytical approach to the data, provide converging evidence that hearing loss in aging is pervasive and progressive even among men initially selected for good physical health. Typically the men accrued early losses (>25 dB HL) in hearing sensitivity at the higher frequencies beginning in the early 40s, but maintained hearing thresholds better than 25 dB HL for lower frequencies into old age. The average rate of change per year across frequencies and age was 0.69 dB. Predicted cross-sectional estimates of change in hearing sensitivity reliably approximated longitudinal trajectories, with slight misestimations in the 8th decade. PMID- 20968369 TI - Difference in precedence effect between children and adults signifies development of sound localization abilities in complex listening tasks. AB - The precedence effect refers to the fact that humans are able to localize sound in reverberant environments, because the auditory system assigns greater weight to the direct sound (lead) than the later-arriving sound (lag). In this study, absolute sound localization was studied for single source stimuli and for dual source lead-lag stimuli in 4-5 year old children and adults. Lead-lag delays ranged from 5-100 ms. Testing was conducted in free field, with pink noise bursts emitted from loudspeakers positioned on a horizontal arc in the frontal field. Listeners indicated how many sounds were heard and the perceived location of the first- and second-heard sounds. Results suggest that at short delays (up to 10 ms), the lead dominates sound localization strongly at both ages, and localization errors are similar to those with single-source stimuli. At longer delays errors can be large, stemming from over-integration of the lead and lag, interchanging of perceived locations of the first-heard and second-heard sounds due to temporal order confusion, and dominance of the lead over the lag. The errors are greater for children than adults. Results are discussed in the context of maturation of auditory and non-auditory factors. PMID- 20968371 TI - A piezoelectric bone-conduction bending hearing actuator. AB - A prototype of a novel bone-conduction hearing actuator based on a piezoelectric bending actuator is presented. The device lies flat against the skull which would allow it to form the basis of a subcutaneous bone-anchored hearing aid. The actuator excites bending in bone through a local bending moment rather than the application of a point force as with conventional bone-anchored hearing aids. Through measurements of the cochlear velocity created by the actuator in embalmed human heads, the device is shown to exhibit high efficiency, making it a possible alternative to present-day electromagnetic bone-vibration actuators. PMID- 20968372 TI - Stop-like modification of the dental fricative /d/: an acoustic analysis. AB - This study concentrates on one of the commonly occurring phonetic variations in English: the stop-like modification of the dental fricative /d/. The variant exhibits a drastic change from the canonical /d/; the manner of articulation is changed from one that is fricative to one that is stop-like. Furthermore, the place of articulation of stop-like /d/ has been a point of uncertainty, leading to confusion between stop-like /d/ and /d/. In this study, acoustic and spectral moment measures were taken from 100 stop-like /d/ and 102 /d/ tokens produced by 59 male and 23 female speakers in the TIMIT corpus. Data analysis indicated that stop-like /d/ is significantly different from /d/ in burst amplitude, burst spectrum shape, burst peak frequency, second formant at following-vowel onset, and spectral moments. Moreover, the acoustic differences from /d/ are consistent with those expected for a dental stop-like /d/. Automatic classification experiments involving these acoustic measures suggested that they are salient in distinguishing stop-like /d/ from /d/. PMID- 20968373 TI - Locus equations are an acoustic expression of articulator synergy. AB - The study investigated the articulatory basis of locus equations, regression lines relating F2 at the start of a Consonant-Vowel (CV) transition to F2 at the middle of the vowel, with C fixed and V varying. Several studies have shown that consonants of different places of articulation have locus equation slopes that descend from labial to velar to alveolar, and intercept magnitudes that increase in the opposite order. Using formulas from the theory of bivariate regression that express regression slopes and intercepts in terms of standard deviations and averages of the variables, it is shown that the slope directly encodes a well established measure of coarticulation resistance. It is also shown that intercepts are directly related to the degree to which the tongue body assists the formation of the constriction for the consonant. Moreover, it is shown that the linearity of locus equations and the linear relation between locus equation slopes and intercepts originates in linearity in articulation between the horizontal position of the tongue dorsum in the consonant and to that in the vowel. It is concluded that slopes and intercepts of acoustic locus equations are measures of articulator synergy. PMID- 20968375 TI - Perception and production boundaries between single and geminate stops in Japanese. AB - The theory of relational acoustic invariance [Pickett, E. R., et al. (1999). Phonetica 56, 135-157] was tested with the Japanese stop quantity distinction in disyllables spoken at various rates. The questions were whether the perceptual boundary between the two phonemic categories of single and geminate stops is invariant across rates, and whether there is a close correspondence between the perception and production boundaries. The durational ratio of stop closure to word (where the "word" was defined as disyllables) was previously found to be an invariant parameter that classified the two categories in production, but the present study found that this ratio varied with different speaking rates in perception. However, regression and discriminant analyses of perception and production data showed that treating stop closure as a function of word duration with an intercept term represented the perception and production boundaries very well. This result indicated that the durational ratio of adjusted stop closure (i.e., closure with an added constant) to the word was invariant and distinguished the two phonemic categories clearly. Taken together, the results support the relational acoustic invariance theory, and help refine the theory with regard to exactly what form 'invariance' can take. PMID- 20968374 TI - Adaptive auditory feedback control of the production of formant trajectories in the Mandarin triphthong /iau/ and its pattern of generalization. AB - In order to test whether auditory feedback is involved in the planning of complex articulatory gestures in time-varying phonemes, the current study examined native Mandarin speakers' responses to auditory perturbations of their auditory feedback of the trajectory of the first formant frequency during their production of the triphthong /iau/. On average, subjects adaptively adjusted their productions to partially compensate for the perturbations in auditory feedback. This result indicates that auditory feedback control of speech movements is not restricted to quasi-static gestures in monophthongs as found in previous studies, but also extends to time-varying gestures. To probe the internal structure of the mechanisms of auditory-motor transformations, the pattern of generalization of the adaptation learned on the triphthong /iau/ to other vowels with different temporal and spatial characteristics (produced only under masking noise) was tested. A broad but weak pattern of generalization was observed; the strength of the generalization diminished with increasing dissimilarity from /iau/. The details and implications of the pattern of generalization are examined and discussed in light of previous sensorimotor adaptation studies of both speech and limb motor control and a neurocomputational model of speech motor control. PMID- 20968376 TI - Spectral and temporal changes to speech produced in the presence of energetic and informational maskers. AB - Talkers change the way they speak in noisy conditions. For energetic maskers, speech production changes are relatively well-understood, but less is known about how informational maskers such as competing speech affect speech production. The current study examines the effect of energetic and informational maskers on speech production by talkers speaking alone or in pairs. Talkers produced speech in quiet and in backgrounds of speech-shaped noise, speech-modulated noise, and competing speech. Relative to quiet, speech output level and fundamental frequency increased and spectral tilt flattened in proportion to the energetic masking capacity of the background. In response to modulated backgrounds, talkers were able to reduce substantially the degree of temporal overlap with the noise, with greater reduction for the competing speech background. Reduction in foreground-background overlap can be expected to lead to a release from both energetic and informational masking for listeners. Passive changes in speech rate, mean pause length or pause distribution cannot explain the overlap reduction, which appears instead to result from a purposeful process of listening while speaking. Talkers appear to monitor the background and exploit upcoming pauses, a strategy which is particularly effective for backgrounds containing intelligible speech. PMID- 20968377 TI - Auditory spectral integration in the perception of diphthongal vowels. AB - This study considers an operation of an auditory spectral integration process which may be involved in perceiving dynamic time-varying changes in speech found in diphthongs and glide-type transitions. Does the auditory system need explicit vowel formants to track the dynamic changes over time? Listeners classified diphthongs on the basis of a moving center of gravity (COG) brought about by changing intensity ratio of static spectral components instead of changing an F2. Listeners were unable to detect COG movement only when the F2 change was small (160 Hz) or when the separation between the static components was large (4.95 bark). PMID- 20968378 TI - Relative contribution of off- and on-frequency spectral components of background noise to the masking of unprocessed and vocoded speech. AB - The present study examined the relative influence of the off- and on-frequency spectral components of modulated and unmodulated maskers on consonant recognition. Stimuli were divided into 30 contiguous equivalent rectangular bandwidths. The temporal fine structure (TFS) in each "target" band was either left intact or replaced with tones using vocoder processing. Recognition scores for 10, 15 and 20 target bands randomly located in frequency were obtained in quiet and in the presence of all 30 masker bands, only the off-frequency masker bands, or only the on-frequency masker bands. The amount of masking produced by the on-frequency bands was generally comparable to that produced by the broadband masker. However, the difference between these two conditions was often significant, indicating an influence of the off-frequency masker bands, likely through modulation interference or spectral restoration. Although vocoder processing systematically lead to poorer consonant recognition scores, the deficit observed in noise could often be attributed to that observed in quiet. These data indicate that (i) speech recognition is affected by the off-frequency components of the background and (ii) the nature of the target TFS does not systematically affect speech recognition in noise, especially when energetic masking and/or the number of target bands is limited. PMID- 20968379 TI - Perceptual sensitivity to first harmonic amplitude in the voice source. AB - Little is known about the perceptual importance of changes in the shape of the source spectrum, although many measures have been proposed and correlations with different vocal qualities (breathiness, roughness, nasality, strain...) have frequently been reported. This study investigated just-noticeable differences in the relative amplitudes of the first two harmonics (H1-H2) for speakers of Mandarin and English. Listeners heard pairs of vowels that differed only in the amplitude of the first harmonic and judged whether or not the voice tokens were identical in voice quality. Across voices and listeners, just-noticeable differences averaged 3.18 dB. This value is small relative to the range of values across voices, indicating that H1-H2 is a perceptually valid acoustic measure of vocal quality. For both groups of listeners, differences in the amplitude of the first harmonic were easier to detect when the source spectral slope was steeply falling so that F0 dominated the spectrum. Mandarin speakers were significantly more sensitive (by about 1 dB) to differences in first harmonic amplitudes than were English speakers. Two explanations for these results are possible: Mandarin speakers may have learned to hear changes in harmonic amplitudes due to changes in voice quality that are correlated with the tones of Mandarin; or Mandarin speakers' experience with tonal contrasts may increase their sensitivity to small differences in the amplitude of F0 (which is also the first harmonic). PMID- 20968380 TI - Characteristics of listener sensitivity to talker-specific phonetic detail. AB - Previous research shows that listeners are sensitive to talker differences in phonetic properties of speech, including voice-onset-time (VOT) in word-initial voiceless stop consonants, and that learning how a talker produces one voiceless stop transfers to another word with the same voiceless stop [Allen, J. S., and Miller, J. L. (2004). J. Acoust. Soc. Am. 115, 3171-3183]. The present experiments examined whether transfer extends to words that begin with different voiceless stops. During training, listeners heard two talkers produce a given voiceless-initial word (e.g., pain). VOTs were manipulated such that one talker produced the voiceless stop with relatively short VOTs and the other with relatively long VOTs. At test, listeners heard a short- and long-VOT variant of the same word (e.g., pain) or a word beginning with a different voiceless stop (e.g., cane or coal), and were asked to select which of the two VOT variants was most representative of a given talker. In all conditions, which variant was selected at test was in line with listeners' exposure during training, and the effect was equally strong for the novel word and the training word. These findings suggest that accommodating talker-specific phonetic detail does not require exposure to each individual phonetic segment. PMID- 20968381 TI - Factors influencing recognition of interrupted speech. AB - This study examined the effect of interruption parameters (e.g., interruption rate, on-duration and proportion), linguistic factors, and other general factors, on the recognition of interrupted consonant-vowel-consonant (CVC) words in quiet. Sixty-two young adults with normal-hearing were randomly assigned to one of three test groups, "male65," "female65" and "male85," that differed in talker (male/female) and presentation level (65/85 dB SPL), with about 20 subjects per group. A total of 13 stimulus conditions, representing different interruption patterns within the words (i.e., various combinations of three interruption parameters), in combination with two values (easy and hard) of lexical difficulty were examined (i.e., 13*2=26 test conditions) within each group. Results showed that, overall, the proportion of speech and lexical difficulty had major effects on the integration and recognition of interrupted CVC words, while the other variables had small effects. Interactions between interruption parameters and linguistic factors were observed: to reach the same degree of word-recognition performance, less acoustic information was required for lexically easy words than hard words. Implications of the findings of the current study for models of the temporal integration of speech are discussed. PMID- 20968382 TI - Cochlea-scaled spectral entropy predicts rate-invariant intelligibility of temporally distorted sentences. AB - Some evidence, mostly drawn from experiments using only a single moderate rate of speech, suggests that low-frequency amplitude modulations may be particularly important for intelligibility. Here, two experiments investigated intelligibility of temporally distorted sentences across a wide range of simulated speaking rates, and two metrics were used to predict results. Sentence intelligibility was assessed when successive segments of fixed duration were temporally reversed (exp. 1), and when sentences were processed through four third-octave-band filters, the outputs of which were desynchronized (exp. 2). For both experiments, intelligibility decreased with increasing distortion. However, in exp. 2, intelligibility recovered modestly with longer desynchronization. Across conditions, performances measured as a function of proportion of utterance distorted converged to a common function. Estimates of intelligibility derived from modulation transfer functions predict a substantial proportion of the variance in listeners' responses in exp. 1, but fail to predict performance in exp. 2. By contrast, a metric of potential information, quantified as relative dissimilarity (change) between successive cochlear-scaled spectra, is introduced. This metric reliably predicts listeners' intelligibility across the full range of speaking rates in both experiments. Results support an information-theoretic approach to speech perception and the significance of spectral change rather than physical units of time. PMID- 20968383 TI - Relative contribution to speech intelligibility of different envelope modulation rates within the speech dynamic range. AB - The contribution of envelope cues at different rates to intelligibility in a competing-speech task was measured as a function of the short-term envelope level. The target and background mixture was processed using tone vocoders. Envelope signals for each vocoder channel were simultaneously extracted with two low-pass filters, the cutoff frequency of one filter (L) being two octaves below that of the other (H). The envelope from the H filter was used at the peaks and that from the L filter at valleys, or vice versa. This was achieved by cross fading between the two envelope signals based on a "switching threshold" that was parametrically varied relative to the long-term RMS level of the channel signal. When the cutoff frequencies of the H and L filters were 50 and 12.5 Hz, changes in speech intelligibility occurred mainly when the switching threshold was between -18 and +10 dB. The range was slightly narrower when the cutoff frequencies of the H and L filters were 200 and 50 Hz. Intensity-importance functions for higher-rate envelope modulations suggested that levels ranging from 20 dB below to about 10 dB above the channel RMS level were important, with maximum importance for levels around -5 dB. PMID- 20968384 TI - Learning to use an artificial visual cue in speech identification. AB - Visual information from a speaker's face profoundly influences auditory perception of speech. However, relatively little is known about the extent to which visual influences may depend on experience, and extent to which new sources of visual speech information can be incorporated in speech perception. In the current study, participants were trained on completely novel visual cues for phonetic categories. Participants learned to accurately identify phonetic categories based on novel visual cues. These newly-learned visual cues influenced identification responses to auditory speech stimuli, but not to the same extent as visual cues from a speaker's face. The novel methods and results of the current study raise theoretical questions about the nature of information integration in speech perception, and open up possibilities for further research on learning in multimodal perception, which may have applications in improving speech comprehension among the hearing-impaired. PMID- 20968385 TI - The effects of the addition of low-level, low-noise noise on the intelligibility of sentences processed to remove temporal envelope information. AB - The intelligibility of sentences processed to remove temporal envelope information, as far as possible, was assessed. Sentences were filtered into N analysis channels, and each channel signal was divided by its Hilbert envelope to remove envelope information but leave temporal fine structure (TFS) intact. Channel signals were combined to give TFS speech. The effect of adding low-level low-noise noise (LNN) to each channel signal before processing was assessed. The addition of LNN reduced the amplification of low-level signal portions that contained large excursions in instantaneous frequency, and improved the intelligibility of simple TFS speech sentences, but not more complex sentences. It also reduced the time needed to reach a stable level of performance. The recovery of envelope cues by peripheral auditory filtering was investigated by measuring the intelligibility of 'recovered-envelope speech', formed by filtering TFS speech with an array of simulated auditory filters, and using the envelopes at the output of these filters to modulate sinusoids with frequencies equal to the filter center frequencies (i.e., tone vocoding). The intelligibility of TFS speech and recovered-envelope speech fell as N increased, although TFS speech was still highly intelligible for values of N for which the intelligibility of recovered-envelope speech was low. PMID- 20968386 TI - A generalized smoothness criterion for acoustic-to-articulatory inversion. AB - The many-to-one mapping from representations in the speech articulatory space to acoustic space renders the associated acoustic-to-articulatory inverse mapping non-unique. Among various techniques, imposing smoothness constraints on the articulator trajectories is one of the common approaches to handle the non uniqueness in the acoustic-to-articulatory inversion problem. This is because, articulators typically move smoothly during speech production. A standard smoothness constraint is to minimize the energy of the difference of the articulatory position sequence so that the articulator trajectory is smooth and low-pass in nature. Such a fixed definition of smoothness is not always realistic or adequate for all articulators because different articulators have different degrees of smoothness. In this paper, an optimization formulation is proposed for the inversion problem, which includes a generalized smoothness criterion. Under such generalized smoothness settings, the smoothness parameter can be chosen depending on the specific articulator in a data-driven fashion. In addition, this formulation allows estimation of articulatory positions recursively over time without any loss in performance. Experiments with the MOCHA TIMIT database show that the estimated articulator trajectories obtained using such a generalized smoothness criterion have lower RMS error and higher correlation with the actual measured trajectories compared to those obtained using a fixed smoothness constraint. PMID- 20968387 TI - On the dynamics of the clavichord: from tangent motion to sound. AB - An experimental study of variations in the sound of clavichord notes at different dynamic levels is described. Radiated acoustic signal, tangent velocity and two tangent-string contact signals are synchronously measured for all 51 notes of an unfretted instrument. More than ten repeated measures are recorded in order to obtain as much variation in dynamic level as possible. The tangent motion, expressed in terms of velocity, is studied in the time and frequency domains. A model of the tangent-string contact point velocity is proposed. Then, three aspects of the sounded tones are analyzed: SPL and its relationship to tangent velocity, spectral slope, and pitch variations. These results indicate a linear relationship between sound pressure level and tangent peak log velocity. Spectral slope seems almost constant independent of tangent velocity and dynamic level. Both tangent velocity and finger pressure are shown to influence the fundamental frequency. In conclusion, controlling both finger velocity and finger pressure may prove challenging for the player, and this may explain why the sound quality of the clavichord depends so much on the players ability. PMID- 20968388 TI - Imprecise singing is widespread. AB - There has been a recent surge of research on the topic of poor-pitch singing. However, this research has not addressed an important distinction in measurement: that between accuracy and precision. With respect to singing, accuracy refers to the average difference between sung and target pitches. Precision, by contrast, refers to the consistency of repeated attempts to produce a pitch. A group of 45 non-musician participants was asked to vocally imitate unfamiliar 5-note melodies, as well as to sing a series of familiar melodies from memory (e.g., Happy Birthday). The results showed that singers were more accurate than they were precise, and that a majority of participants could justifiably be categorized as imprecise singers. Accuracy and precision measures were correlated with one another, and conditional-probability analyses suggested that accuracy predicted precision more so than the converse. Finally, performance differences across groups of singers were greater for the imitation of unfamiliar tone sequences than for the recall of familiar melodies. PMID- 20968389 TI - Cancellous bone analysis with modified least squares Prony's method and chirp filter: phantom experiments and simulation. AB - The presence of two longitudinal waves in porous media is predicted by Biot's theory and has been confirmed experimentally in cancellous bone. When cancellous bone samples are interrogated in through-transmission, these two waves can overlap in time. Previously, the Modified Least-Squares Prony's (MLSP) method was validated for estimation of amplitudes, attenuation coefficients, and phase velocities of fast and slow waves, but tended to overestimate phase velocities by up to about 5%. In the present paper, a pre-processing chirp filter to mitigate the phase velocity bias is derived. The MLSP/chirp filter (MLSPCF) method was tested for decomposition of a 500 kHz-center-frequency signal containing two overlapping components: one passing through a low-density-polyethylene plate (fast wave) and another passing through a cancellous-bone-mimicking phantom material (slow wave). The chirp filter reduced phase velocity bias from 100 m/s (5.1%) to 69 m/s (3.5%) (fast wave) and from 29 m/s (1.9%) to 10 m/s (0.7%) (slow wave). Similar improvements were found for 1) measurements in polycarbonate (fast wave) and a cancellous-bone-mimicking phantom (slow wave), and 2) a simulation based on parameters mimicking bovine cancellous bone. The MLSPCF method did not offer consistent improvement in estimates of attenuation coefficient or amplitude. PMID- 20968390 TI - Variation in the resting frequency of Rhinolophus pusillus in Mainland China: effect of climate and implications for conservation. AB - This study describes variation patterns in the constant frequency of echolocation calls emitted at rest and when not flying ("resting frequency" RF) of the least horseshoe bat, Rhinolophus pusillus, on a broad geographical scale and in response to local climatic variables. Significant differences in RF were observed among populations throughout the species range in Mainland China, and this variation was positively and significantly related to climate conditions, especially environmental humidity, but the variability was only weakly associated with geographical distance. Sex dimorphism in the RF of R. pusillus may imply that female and male might keep their frequencies within a narrow range for sex recognition. Moreover, bats adjusted resting frequency to humidity, which may imply partitioning diet by prey size or the influence of rainfall noise. The results indicate that bats adjust echolocation call frequency to adapt to environmental conditions. Therefore, environmental selection shape the diversity of echolocation call structure of R. pusillus in geographically separated populations, and conservation efforts should focus on changes in local climate and effects of environmental noise. PMID- 20968391 TI - Discriminating features of echolocation clicks of melon-headed whales (Peponocephala electra), bottlenose dolphins (Tursiops truncatus), and Gray's spinner dolphins (Stenella longirostris longirostris). AB - Spectral parameters were used to discriminate between echolocation clicks produced by three dolphin species at Palmyra Atoll: melon-headed whales (Peponocephala electra), bottlenose dolphins (Tursiops truncatus) and Gray's spinner dolphins (Stenella longirostris longirostris). Single species acoustic behavior during daytime observations was recorded with a towed hydrophone array sampling at 192 and 480 kHz. Additionally, an autonomous, bottom moored High frequency Acoustic Recording Package (HARP) collected acoustic data with a sampling rate of 200 kHz. Melon-headed whale echolocation clicks had the lowest peak and center frequencies, spinner dolphins had the highest frequencies and bottlenose dolphins were nested in between these two species. Frequency differences were significant. Temporal parameters were not well suited for classification. Feature differences were enhanced by reducing variability within a set of single clicks by calculating mean spectra for groups of clicks. Median peak frequencies of averaged clicks (group size 50) of melon-headed whales ranged between 24.4 and 29.7 kHz, of bottlenose dolphins between 26.7 and 36.7 kHz, and of spinner dolphins between 33.8 and 36.0 kHz. Discriminant function analysis showed the ability to correctly discriminate between 93% of melon-headed whales, 75% of spinner dolphins and 54% of bottlenose dolphins. PMID- 20968392 TI - Basis of acoustic discrimination of Chinook salmon from other salmons by echolocating Orcinus orca. AB - The "resident" ecotype of killer whales (Orcinus orca) in the waters of British Columbia and Washington State have a strong preference for Chinook salmon even in months when Chinook comprise less than about 10% of the salmon population. The foraging behavior of killer whales suggests that they depend on echolocation to detect and recognize their prey. In order to determine possible cues in echoes from salmon species, a series of backscatter measurements were made at the Applied Physics Laboratory (Univ. of Wash.) Facility on Lake Union, on three different salmon species using simulated killer whale echolocation signals. The fish were attached to a monofilament net panel and rotated while echoes were collected, digitized and stored on a laptop computer. Three transducer depths were used; same depth, 22 degrees and 45 degrees above the horizontal plane of the fish. Echoes were collected from five Chinook, three coho and one sockeye salmon. Radiograph images of all specimens were obtained to examine the swimbladder shape and orientation. The results show that echo structure from similar length but different species of salmon were different and probably recognizable by foraging killer whales. PMID- 20968393 TI - Change in echolocation signals with hearing loss in a false killer whale (Pseudorca crassidens). AB - The echolocation signals of a false killer whale (Pseudorca crassidens) were collected during a wall thickness discrimination task and compared to clicks recorded during an identical experiment in 1992. During the sixteen year time period, the subject demonstrated a loss of high frequency hearing of about 70 kHz. Clicks between the two experiments were compared to investigate the effect of hearing loss on echolocation signals. There was a significant reduction in the peak frequency, center frequency and source level of clicks between the two time periods. Additionally, the subject currently produces more signals with low frequency peaks and fewer signals with high frequency peaks than she did in 1992. These results indicate the subject changed its echolocation signals to match its range of best hearing. PMID- 20968394 TI - Wind turbines and bat mortality: Doppler shift profiles and ultrasonic bat-like pulse reflection from moving turbine blades. AB - Bat mortality resulting from actual or near-collision with operational wind turbine rotors is a phenomenon that is widespread but not well understood. Because bats rely on information contained in high-frequency echoes to determine the nature and movement of a target, it is important to consider how ultrasonic pulses similar to those used by bats for echolocation may be interacting with operational turbine rotor blades. By assessing the characteristics of reflected ultrasonic echoes, moving turbine blades operating under low wind speed conditions (<6 m s(-1)) were found to produce distinct Doppler shift profiles at different angles to the rotor. Frequency shifts of up to +/-700-800 Hz were produced, which may not be perceptible by some bat species. Monte Carlo simulation of bat-like sampling by echolocation revealed that over 50 rotor echoes could be required by species such as Pipistrellus pipistrellus for accurate interpretation of blade movement, which may not be achieved in the bat's approach time-window. In summary, it was found that echoes returned from moving blades had features which could render them attractive to bats or which might make it difficult for the bat to accurately detect and locate blades in sufficient time to avoid a collision. PMID- 20969359 TI - Communication: Conditions for one-photon coherent phase control in isolated and open quantum systems. AB - Coherent control of observables using the phase properties of weak light that induces one-photon transitions is considered. Measurable properties are shown to be categorizable as either class A, where control is not possible, or class B, where control is possible. Using formal arguments, we show that phase control in open systems can be environmentally assisted. PMID- 20969360 TI - Communication: Constrained search formulation of the ground state energy as a functional of an idempotent one-matrix. AB - Despite the fact that idempotent one-particle reduced density matrices are pervasive in quantum chemistry, the understanding of a general energy functional of such idempotent density matrices for the ground state energy has been lacking. By a constrained search, we show the structure of the general functional, illuminating the contributions from various terms. For the examples of the "best idempotent density matrix" and Kohn-Sham idempotent density matrices, we contrast the functional forms and suggest how the best idempotent density matrix approach may be a good starting point for further development. PMID- 20969361 TI - Communication: Systematic shifts of the lowest unoccupied molecular orbital peak in x-ray absorption for a series of 3d metal porphyrins. AB - Porphyrins are widely used as dye molecules in solar cells. Knowing the energies of their frontier orbitals is crucial for optimizing the energy level structure of solar cells. We use near edge x-ray absorption fine structure (NEXAFS) spectroscopy to obtain the energy of the lowest unoccupied molecular orbital (LUMO) with respect to the N(1s) core level of the molecule. A systematic energy shift of the N(1s) to LUMO transition is found along a series of 3d metal octaethylporphyrins and explained by density functional theory. It is mainly due to a shift of the N(1s) level rather than a shift of the LUMO or a change in the electron-hole interaction of the core exciton. PMID- 20969362 TI - Communication: Bond length alternation of conjugated oligomers: Another step on the fifth rung of Perdew's ladder of functional. AB - In this work, we present the application of the hybrid short-range density functional theory/long-range MP2 energy gradients to the bond length alternation in polymethineimine and polyacetylene conjugated oligomers. Compared to other density functional calculations, our results are quite superior, even to fourth rung functionals, usually better than MP2 and very close to the available CCSD(T) values. PMID- 20969363 TI - Communication: Unusual dynamics of hybrid nanoparticles and their binary mixtures. AB - We present the results on the evolution of microscopic dynamics of hybrid nanoparticles and their binary mixtures as a function of temperature and wave vector. We find unexpectedly a nonmonotonic dependence of the structural relaxation time of the nanoparticles as a function of the morphology. In binary mixtures of two of the largest nanoparticles studied, we observe re-entrant vitrification as a function of the volume fraction of the smaller nanoparticle, which is unusual for such high diameter ratio. Possible explanation for the observed behavior is provided. PMID- 20969364 TI - Generalized simulated tempering for exploring strong phase transitions. AB - An extension of the simulation tempering algorithm is proposed. It is shown to be particularly suited to the exploration of first-order phase transition systems characterized by the backbending or S-loop in the statistical temperature or a microcanonical caloric curve. A guided Markov process in an auxiliary parameter space systematically combines a set of parametrized Tsallis-weight ensemble simulations, which are targeted to transform unstable or metastable energy states of canonical ensembles into stable ones and smoothly join ordered and disordered phases across phase transition regions via a succession of unimodal energy distributions. The inverse mapping between the sampling weight and the effective temperature enables an optimal selection of relevant Tsallis-weight parameters. A semianalytic expression for the biasing weight in parameter space is adaptively updated "on the fly" during the simulation to achieve rapid convergence. Accelerated tunneling transitions with a comprehensive sampling for phase coexistent states are explicitly demonstrated in systems subject to strong hysteresis including Potts and Ising spin models and a 147 atom Lennard-Jones cluster. PMID- 20969365 TI - A critical test of bivelocity hydrodynamics for mixtures. AB - The present paper provides direct noncircumstantial evidence in support of the existence of a diffuse flux of volume j(v) in mixtures. As such, it supersedes an earlier paper [H. Brenner, J. Chem. Phys. 132, 054106 (2010)], which offered only indirect circumstantial evidence in this regard. Given the relationship of the diffuse volume flux to the fluid's volume velocity, this finding adds additional credibility to the theory of bivelocity hydrodynamics for both gaseous and liquid continua, wherein the term bivelocity refers to the independence of the fluid's respective mass and volume velocities. Explicitly, the present work provides a new and unexpected linkage between a pair of diffuse fluxes entering into bivelocity mixture theory, fluxes that were previously regarded as constitutively independent, except possibly for their coupling arising as a consequence of Onsager reciprocity. In particular, for the case of a binary mixture undergoing an isobaric, isothermal, external force-free, molecular diffusion process we establish by purely macroscopic arguments-while subsequently confirming by purely molecular arguments-the validity of the ansatz j(v)=(v(1)-v(2))j(1) relating the diffuse volume flux j(v) to the diffuse mass fluxes j(1)(=-j(2)) of the two species and, jointly, their partial specific volumes v(1),v(2). Confirmation of that relation is based upon the use of linear irreversible thermodynamic principles to embed this ansatz in a broader context, and to subsequently establish the accord thereof with Shchavaliev's solution of the multicomponent Boltzmann equation for dilute gases [M. Sh. Shchavaliev, Fluid Dyn. 9, 96 (1974)]. Moreover, because the terms v(1), v(2), and j(1) appearing on the right hand side of the ansatz are all conventional continuum fluid-mechanical terms (with j(1) given, for example, by Fick's law for thermodynamically ideal solutions), parity requires that j(v) appearing on the left-hand side of that relation also be a continuum term. Previously, diffuse volume fluxes, whether in mixtures or single-component fluids, were widely believed to be noncontinuum in nature, and hence of interest only to those primarily concerned with transport phenomena in rarefied gases. This demonstration of the continuum nature of bivelocity hydrodynamics suggests that the latter subject should be of general interest to all fluid mechanicians, even those with no special interest in mixtures. PMID- 20969366 TI - Efficient on the fly calculation of time correlation functions in computer simulations. AB - Time correlation functions yield profound information about the dynamics of a physical system and hence are frequently calculated in computer simulations. For systems whose dynamics span a wide range of time, currently used methods require significant computer time and memory. In this paper, we discuss the multiple-tau correlator method for the efficient calculation of accurate time correlation functions on the fly during computer simulations. The multiple-tau correlator is efficacious in terms of computational requirements and can be tuned to the desired level of accuracy. Further, we derive estimates for the error arising from the use of the multiple-tau correlator and extend it for use in the calculation of mean-square particle displacements and dynamic structure factors. The method described here, in hardware implementation, is routinely used in light scattering experiments but has not yet found widespread use in computer simulations. PMID- 20969367 TI - Theoretical consideration of osmotic pressure in aqueous protein/salt systems based on extended hard core Lennard-Jones potential. AB - A simple and analytical pair potential function was developed to represent the osmotic pressures in aqueous protein/salt systems under various conditions. Based on a hard core Lennard-Jones (HCLJ) potential model, the new potential function considers various interactions by extending the attractive Lennard-Jones potential. A temperature-dependent coefficient term was introduced to take into account the specific properties of given materials. Comparison of the new potential function with the HCLJ model in hydrocarbon and water systems showed that consideration of the temperature dependence in the potential function was effective, especially for strong polar systems such as water. To predict the osmotic pressures of aqueous lysozyme/(NH(4))(2)SO(4) solutions of various ionic strength and pH, the energy parameters of lysozyme were correlated with the experimental cloud point temperature. The proposed model agreed fairly well with the experimental osmotic pressure data with only previously obtained parameters. PMID- 20969368 TI - Precise multipole method for calculating many-body hydrodynamic interactions in a microchannel. AB - We introduce a novel and precise method for computing many-body hydrodynamic interactions in a cylindrical microchannel. The method is generic in the sense that we can easily change the radius and the character of particles (hard spheres, droplets, permeable spheres, etc.). These features are not available in any of the existing methods. Comparison with the available results validates our method. In particular we obtain excellent agreement with the analytically known expression for the single particle friction coefficient. Additionally we observe negative hydrodynamic coupling for finite particles which are consistent with the recently reported effect for point particles. As an example we compute the velocities of polymeric chains of particles in parabolic flow and compare them to unbounded space. The method will be helpful in the understanding of physical and physicochemical processes in a wide range of bio-, geophysical, and microfluidic systems. PMID- 20969369 TI - On the equivalence of ring-coupled cluster and adiabatic connection fluctuation dissipation theorem random phase approximation correlation energy expressions. AB - The correlation energy in the direct random phase approximation (dRPA) can be written, among other possibilities, either in terms of the interaction strength averaged correlation density matrix, or in terms of the coupled cluster doubles amplitudes obtained in the direct ring approximation (drCCD). Although the corresponding dRPA correlation density matrix on the one hand, and the drCCD amplitude matrix on the other hand, differ significantly, they yield identical energies. Similarly, the analogous RPA and rCCD correlation energies calculated from antisymmetrized two-electron integrals are identical to each other despite very different underlying working equations. In the present communication, a direct correspondence between amplitudes and densities is established and investigated with perturbation theory arguments. Our analysis also sheds some light on the properties of recently proposed RPA/rCCD variants which use antisymmetrized integrals in part of the equations and nonantisymmetrized integrals in others. PMID- 20969370 TI - Surface tensions and surface potentials of acid solutions. AB - A theory is presented which allows us to quantitatively calculate the excess surface tension of acid solutions. The H(+), in the form of hydronium ion, is found to be strongly adsorbed to the solution-air interface. To account for the electrostatic potential difference measured experimentally, it is necessary to assume that the hydronium ion is oriented with its hydrogens pointing into the bulk water. The theory is quantitatively accurate for surface tensions and is qualitative for electrostatic potential difference across the air-water interface. PMID- 20969371 TI - Different approaches for evaluating exponentially weighted nonequilibrium relations. AB - The Kawasaki identity (KI) and the Jarzynski equality (JE) are important nonequilibrium relations. Both of these relations take the form of an ensemble average of an exponential function and can exhibit convergence problems when the average of the exponent differs greatly from the log of the average of the exponential function. In this work, we re-express these relations so that only selected regions need to be evaluated in an attempt to avoid these convergence issues. In the context of measuring free energies, we compare our method to the JE and the literature standard approach, the maximum likelihood estimator (MLE), and show that in a system with asymmetric work distributions it can perform as well as the MLE. For the KI, we derive an analog to the MLE to compare with our relation and show that these two new relations improve on the KI and are complimentary to each other. PMID- 20969372 TI - Variational transcorrelated method. AB - We propose a new approach to the use of Jastrow ansatz in the calculation of electron correlations, based on a modification of the transcorrelated method of Boys and Handy [Proc. R. Soc. London, Ser. A 309, 209 (1969)]. In this new method, the original transcorrelated orbital equation is replaced with a general variational equation for the reference wave function, whereas the equation for the correlation factor remains the same. The method can be applied to a single determinant Jastrow ansatz as well as to a multideterminant one. For the single determinant ansatz, we obtain a Hartree-Fock type self-consistent equation for the optimization of orbitals, and for the multideterminant ansatz we have tested a CI type equation. We apply the new method in calculations of the C(2) molecule and compare the results with those of variational quantum Monte Carlo calculations. PMID- 20969373 TI - Power series expansion of the random phase approximation correlation energy: The role of the third- and higher-order contributions. AB - We derive a power expansion of the correlation energy of weakly bound systems within the random phase approximation (RPA), in terms of the Coulomb interaction operator, and we show that the asymptotic limit of the second- and third-order terms yields the van der Waals (vdW) dispersion energy terms derived by Zaremba Kohn and Axilrod-Teller within perturbation theory. We then show that the use of the second-order expansion of the RPA correlation energy results in rather inaccurate binding energy curves for weakly bonded systems, and discuss the implications of our findings for the development of approximate vdW density functionals. We also assess the accuracy of different exchange energy functionals used in the derivation of vdW density functionals. PMID- 20969374 TI - Intramolecular energy transfer dynamics in 24-mode pyrazine by partitioning technique: A time-dependent approach. AB - We investigate the intramolecular energy transfer dynamics of the S(2) excited electronic state of pyrazine due to radiationless transitions to energetically lower-lying singlet electronic states using a new time-dependent method. The femtosecond decay of S(2) to the S(1) excited state and the picosecond decay of S(2) to the ground electronic state S(0) are studied within an efficient methodology for computing the intramolecular dynamics in multidimensional configurational spaces. Our method is based on partitioning the full configuration space into the (small) subspace of interest Q and the rest, the subspace P. The exact equations of motion for the states in Q, under the influence of P, are derived in the time domain in form of a system of integrodifferential equations. Their numerical solution is readily obtained when the Q space consists of just a few states. Otherwise, the integrodifferential equations for the states in Q are transformed into a (larger) system of ordinary differential equations, which can be solved by a single diagonalization of a general complex matrix. The former approach is applied to study the pyrazine picosecond S(2)->S(0) dynamics and the latter is applied to the study of the ultrafast pyrazine S(2)->S(1) decay dynamics. PMID- 20969375 TI - Hindered rotor models with variable kinetic functions for accurate thermodynamic and kinetic predictions. AB - We present an extension of some popular hindered rotor (HR) models, namely, the one-dimensional HR (1DHR) and the degenerated two-dimensional HR (d2DHR) models, allowing for a simple and accurate treatment of internal rotations. This extension, based on the use of a variable kinetic function in the Hamiltonian instead of a constant reduced moment of inertia, is extremely suitable in the case of rocking/wagging motions involved in dissociation or atom transfer reactions. The variable kinetic function is first introduced in the framework of a classical 1DHR model. Then, an effective temperature and potential dependent constant is proposed in the cases of quantum 1DHR and classical d2DHR models. These methods are finally applied to the atom transfer reaction SiCl(3)+BCl(3) >SiCl(4)+BCl(2). We show, for this particular case, that a proper accounting of internal rotations greatly improves the accuracy of thermodynamic and kinetic predictions. Moreover, our results confirm (i) that using a suitably defined kinetic function appears to be very adapted to such problems; (ii) that the separability assumption of independent rotations seems justified; and (iii) that a quantum mechanical treatment is not a substantial improvement with respect to a classical one. PMID- 20969376 TI - Symmetry-breaking in cumulative measures of shapes of polymer models. AB - Using numerical simulations we investigate shapes of random equilateral open and closed chains, one of the simplest models of freely fluctuating polymers in a solution. We are interested in the 3D density distribution of the modeled polymers where the polymers have been aligned with respect to their three principal axes of inertia. This type of approach was pioneered by Theodorou and Suter in 1985. While individual configurations of the modeled polymers are almost always nonsymmetric, the approach of Theodorou and Suter results in cumulative shapes that are highly symmetric. By taking advantage of asymmetries within the individual configurations, we modify the procedure of aligning independent configurations in a way that shows their asymmetry. This approach reveals, for example, that the 3D density distribution for linear polymers has a bean shape predicted theoretically by Kuhn. The symmetry-breaking approach reveals complementary information to the traditional, symmetrical, 3D density distributions originally introduced by Theodorou and Suter. PMID- 20969377 TI - On processed splitting methods and high-order actions in path-integral Monte Carlo simulations. AB - Processed splitting methods are particularly well adapted to carry out path integral Monte Carlo (PIMC) simulations: since one is mainly interested in estimating traces of operators, only the kernel of the method is necessary to approximate the thermal density matrix. Unfortunately, they suffer the same drawback as standard, nonprocessed integrators: kernels of effective order greater than two necessarily involve some negative coefficients. This problem can be circumvented, however, by incorporating modified potentials into the composition, thus rendering schemes of higher effective order. In this work we analyze a family of fourth-order schemes recently proposed in the PIMC setting, paying special attention to their linear stability properties, and justify their observed behavior in practice. We also propose a new fourth-order scheme requiring the same computational cost but with an enlarged stability interval. PMID- 20969378 TI - A self-consistent Ornstein-Zernike approximation for a fluid with a screened power series interaction. AB - We present a thermodynamically self-consistent Ornstein-Zernike approximation (SCOZA) for a fluid of spherical particles with a pair potential given by a hard core repulsion and screened power series (SPS) tails. We take advantage of the known analytic properties of the solution of the Ornstein-Zernike equation for the case in which the direct correlation function outside the repulsive core is given by the SPS tails [M. Yasutomi, J. Phys.: Condens. Matter 13, L255 (2001)]: c(r)=?(n=1) (N)exp(-z(n)r)?(tau=-1) (L(n) )K((n,tau))z(n) (tau+1)r(tau) r>1. The analytic properties are rewritten so as to be optimally suited to the numerical computations. The SCOZA is known to provide very good overall thermodynamics, remarkably accurate critical point, and coexistence curve. In this paper, we present some numerical results for parameters in c(r) which are chosen to fit the Lennard-Jones potential. We show that both the energy and the compressibility paths lead to the same thermodynamics with high accuracy due to the thermodynamic consistency condition that has been enforced. The present method will be applicable to fluids with a large variety of smooth, realistic isotropic potentials where the pair potentials can be fitted by the SPS tails. The fitting procedure is superior to that by multi-Yukawa tails which is the only method presented so far. PMID- 20969379 TI - A new algorithm for extended nonequilibrium molecular dynamics simulations of mixed flow. AB - In this work, we develop a new algorithm for nonequilibrium molecular dynamics of fluids under planar mixed flow, a linear combination of planar elongational flow and planar Couette flow. To date, the only way of simulating mixed flow using nonequilibrium molecular dynamics techniques was to impose onto the simulation box irreversible transformations. This would bring the simulation to an end as soon as the minimum lattice space requirements were violated. In practical terms, this meant repeating the short simulations to improve statistics and extending the box dimensions to increase the total simulation time. Our method, similar to what has already been done for pure elongational flow, allows a cuboid box to deform in time following the streamlines of the mixed flow and, after a period of time determined by the elongational field, to be mapped back and recover its initial shape. No discontinuity in physical properties is present during the mapping and the simulation can, in this way, be extended indefinitely. We also show that the most general form of mixed flow, in which the angle between the expanding (or contracting) direction and the velocity gradient axis varies, can be cast in a so-called canonical form, in which the angle assumes values that are multiples of pi (when a mixed flow exists), by an appropriate choice of the field parameters. PMID- 20969380 TI - Absorption spectra of e-beam-excited Ne, Ar, and Kr, pure and in binary mixtures. AB - A technique using the broadband emission of a laser plume as probe radiation is applied to record UV-visible (190-510 nm) absorption spectra of Ne, Ar, and Kr, pure and in binary mixtures under moderate e-beam excitation up to 1 MW/cm(3). In all the rare gases and mixtures, the absorption spectra show continuum related to Rg(2) (+) homonuclear ions [peaking at lambda~285, 295, and 320 nm in Ne, Ar, and Kr(Ar/Kr), respectively] and a number of atomic lines related mainly to Rg(*)(ms) levels, where m is the lowest principal quantum number of the valence electron. In argon, a continuum related to Ar(2) (*) (lambda~325 nm) is also recorded. There are also trains of narrow bands corresponding to Rg(2) (*)(nppi (3)Pi(g))< Rg(2) (*)(mssigma (3)Sigma(u) (+)) transitions. All the spectral features mentioned above were reported in literature but have never been observed simultaneously. Although charge transfer to a homonuclear ion of the heavier additive is commonly believed to dominate in binary rare-gas mixtures, it is found in this study that in Ne/Kr mixture, the charge is finally transferred from the buffer gas Ne(2) (+) ion not to Kr(2) (+) but to heteronuclear NeKr(+) ion. PMID- 20969381 TI - Giant electric field effect on the second hyperpolarizability of symmetric singlet diradical molecules. AB - This contribution reveals the effects of a static electric field on the static second hyperpolarizability gamma of symmetric singlet diradical molecules using the valence configuration interaction scheme. It is found that under the effect of a field, the component of gamma along the axis joining the two radical sites can be gigantically (approximately two to three orders) enhanced for symmetric diradicals having intermediate diradical characters with respect to those of closed-shell and pure diradical molecules in the absence of a field. Moreover, this electric field enhancement of gamma increases as a function of the diradical character. These results and their analysis propose therefore a new strategy to design materials with exceptional nonlinear optical responses. PMID- 20969382 TI - Millimeter-wave spectroscopy of H(2)C=CD: Tunneling splitting and ortho-para mixing interaction. AB - The H(2)C=CD isotopic species of vinyl radical produced in a supersonic jet expansion by ultraviolet laser photolysis was studied by millimeter-wave spectroscopy. Due to the tunneling motion of the alpha deuteron, the ground state is split into two components, 0(+) and 0(-). Tunneling-rotation transitions connecting the lower (0(+)) and upper (0(-)) components of the tunneling doublet were observed in the frequency region of 184-334 GHz, including three R- and two Q-branch transitions. Three and two pure rotational transitions in the K(a)=0 and 1 stacks, respectively, were also observed for each of the 0(+) and 0(-) states in the frequency region of 52-159 GHz. Least-squares analysis of the observed frequencies for the tunneling-rotation and pure rotational transitions with well resolved hyperfine structures yielded a set of precise molecular constants, among which the tunneling splitting in the ground state was determined to be DeltaE(0)=1187.234(17) MHz, which is 1/14 that for H(2)C=CH. The potential barrier height derived from the observed tunneling splitting by an analysis of the tunneling dynamics using a one-dimensional model is 1545 cm(-1), consistent with the value 1568 cm(-1) obtained for the normal vinyl. The observed spectrum was found to be perturbed by a hyperfine interaction connecting ortho and para levels. The constant for the interaction, which we call the ortho-para mixing Fermi contact interaction, has been determined to be deltaa(F) ((beta))=68.06(53) MHz. This is believed to be the first definite detection of such an interaction. By this interaction the ortho and para states of H(2)C=CD are mixed up to about 0.1%. The constant is more than 1000 times larger than spin-rotation interaction constants that cause ortho-para mixing in closed shell molecules and suggests extremely rapid conversion between the ortho and para nuclear spin isomers of H(2)C=CD. PMID- 20969383 TI - A guided-ion beam study of the reactions of Xe(+) and Xe(2+) with NH(3) at hyperthermal collision energies. AB - We have measured the absolute cross sections for reactions of Xe(+) and Xe(2+) with NH(3) at collision energies in the range from near-thermal to ~34 and ~69 eV, respectively. For Xe(+), the cross section for charge transfer, the only exothermic channel, decreases from ~200A(2) below 0.1 eV to ~12A(2) at the highest energies studied. The production of NH(3) (+) is the only channel observed below 5 eV, above which a small amount of NH(2) (+) is also formed. In Xe(2+) reactions, the main products observed are NH(3) (+) and NH(2) (+). The charge transfer cross section decreases monotonically from ~80 to ~6A(2) over the studied energy range. The NH(2) (+) cross section is similar to the charge transfer cross section at the lowest energies, and exhibits a second component above 0.4 eV, with a maximum of 65A(2) at 0.7 eV, above which the cross section decreases to ~30A(2) at the highest energies studied. At energies above 10 eV, a small amount of NH(+) is also observed in Xe(2+) collisions. Product recoil velocity distributions were determined at selected collision energies, using guided-ion beam time-of-flight methods. PMID- 20969384 TI - Attachment cross sections of protonated water clusters. AB - The attachment of water molecules onto size selected protonated water clusters has been experimentally investigated. Absolute attachment cross sections are measured as a function of cluster size, collision energy, and initial cluster temperature. Although thermal evaporation is ruled out in our experiment, attachment cross sections become significantly smaller than hard sphere cross sections as the collision energy increases. This feature is attributed to a transition from adiabatic to nonadiabatic regime. It is shown to be due to a dynamical effect: as the collision duration becomes shorter than the typical time required for collision energy redistribution into clusters internal energy, the attachment probability is reduced. We relate this typical time to the period of the main surface vibrational mode excited by the collisions. This hypothesis is further supported by results obtained with deuterated water clusters. PMID- 20969385 TI - Electron attachment to propargyl chloride, 305-540 K. AB - Electron attachment to propargyl chloride (HC=C-CH(2)Cl) was studied in a flowing afterglow Langmuir-probe apparatus from 305 to 540 K. The sole ion product in this temperature range is Cl(-). Electron attachment is very inefficient, requiring correction for a competing process of electron recombination with molecular cations produced in reaction between Ar(+) and propargyl chloride and subsequent ion-molecule reactions. The electron attachment rate coefficient was measured to be 1.6*10(-10)cm(3) s(-1) at 305 K and increased to 1.1*10(-9)cm(3) s(-1) at 540 K. PMID- 20969386 TI - On the intermolecular Coulombic decay of singly and doubly ionized states of water dimer. AB - A semiquantitative study of the intermolecular Coulombic decay (ICD) of singly and doubly ionized water dimer has been carried out with the help of ab initio computed ionization spectra and potential energy curves (PECs). These PECs are particular cuts through the (H(2)O)(2), (H(2)O)(2) (+), and (H(2)O)(2) (++) hypersurfaces along the distance between the two oxygen atoms. A comparison with the recently published experimental data for the ICD in singly ionized water dimers [T. Jahnke, H. Sann, T. Havermeier et al., Nat. Phys. 6, 139 (2010)] and in large water clusters [M. Mucke, M. Braune, S. Barth et al., Nat. Phys. 6, 143 (2010)] shows that such a simplified description in which the internal degrees of freedom of the water molecules are frozen gives surprisingly useful results. Other possible decay channels of the singly ionized water dimer are also investigated and the influence of the H-atom participating in the hydrogen bond on the spectra of the proton-donor and proton-acceptor molecules in the dimer is discussed. Importantly, the decay processes of one-site dicationic states of water dimer are discussed and an estimate of the ICD-electron spectra is made. More than 33% of the dications produced by Auger decay are found to undergo ICD. The qualitative results show that the ICD following Auger decay in water is also expected to be an additional source of low-energy electrons proven to be extremely important for causing damages to living tissues. PMID- 20969387 TI - Dissociation energetics of the phenol(+)?Ar(2) cluster ion: The role of pi->H isomerization. AB - The dissociation energetics in the phenol(+)?Ar(2)(2pi) cluster ion have been investigated using photoionization efficiency and mass analyzed threshold ionization spectroscopy. The appearance energies for the loss of one and two Ar atoms are determined as ~210 and ~1115 cm(-1), respectively. The difference between the appearance energy for the first Ar ligand in phenol(+)?Ar(2)(2pi) and the dissociation energy of the phenol(+)?Ar(pi) dimer (535cm(-1)) is explained by the isomerization of one pi-bound Ar ligand to the OH binding site (H-bond) upon ionization. The energy difference between phenol(+)?Ar(2)(2pi) and phenol(+)?Ar(2)(H/pi) could also be estimated to be around 325cm(-1), which corresponds roughly to the difference of the binding energy of a pi-bound and H bound Ar ligands. The binding energy of the H-bound Ar atom in phenol(+)?Ar(2)(H/pi) is derived to be ~905cm(-1). PMID- 20969388 TI - Optical response of small closed-shell sodium clusters. AB - Absorption spectra of closed-shell Na(2), Na(3) (+), Na(4), Na(5) (+), Na(6), Na(7) (+), and Na(8) clusters are calculated using a complex Bethe-Salpeter equation derived using a conserving linear response method. In the framework of a quasiparticle approach, we determine electron-hole correlations in the presence of an external field. The calculated results are in excellent agreement with experimental spectra, and some possible cluster geometries that occur in experiments are analyzed. The position and the broadening of the resonances in the spectra arise from a consistent treatment of the scattering and dephasing contributions in the linear response calculation. Comparison between the experimental and the theoretical results yields information about the cluster geometry, which is not accessible experimentally. PMID- 20969389 TI - Origin of the size-dependence of the polarizability per atom in heterogeneous clusters: The case of AlP clusters. AB - An analysis of the atomic polarizabilities alpha in stoichiometric aluminum phosphide clusters, computed at the MP2 and density functional theory (DFT) levels, the latter using the B3LYP functional, and partitioned using the classic and iterative versions of the Hirshfeld method, is presented. Two sets of clusters are examined: the ground-state Al(n)P(n) clusters (n=2-9) and the prolate clusters (Al(2)P(2))(N) and (Al(3)P(3))(N) (N<=6). In the ground-state clusters, the mean polarizability per atom, i.e., alpha/2n, decreases with the cluster size but shows peaks at n=5 and at n=7. We demonstrate that these peaks can be explained by a large polarizability of the Al atoms and by a low polarizability of the P atoms in Al(5)P(5) and Al(7)P(7) due to the presence of homopolar bonds in these clusters. We show indeed that the polarizability of an atom within an Al(n)P(n) cluster depends on the cluster size and the heteropolarity of the bonds it forms within the cluster, i.e., on the charges of the atoms. The polarizabilities of the fragments Al(2)P(2) and Al(3)P(3) in the prolate clusters were found to depend mainly on their location within the cluster. Finally, we show that the iterative Hirshfeld method is more suitable than the classic Hirshfeld method for describing the atomic polarizabilities and the atomic charges in clusters with heteropolar bonds, although both versions of the Hirshfeld method lead to similar conclusions. PMID- 20969390 TI - Excited-state lifetime of adenine near the first electronic band origin. AB - The excited-state lifetime of supersonically cooled adenine was measured in the gas phase by femtosecond pump-probe transient ionization as a function of excitation energy between 36 100 and 37 500cm(-1). The excited-state lifetime of adenine is ~2ps around the 0-0 band of the (1)L(b) pipi(*) state (36 105cm(-1)). The lifetime drops to ~1ps when adenine is excited to the (1)L(a) pipi(*) state with the pump energy at 36 800cm(-1) and above. The excited-state lifetimes of (1)L(a) and (1)L(b) pipi(*) states are differentiated in accordance with previous frequency-resolved and computational studies. PMID- 20969391 TI - Photoelectron imaging of tetrahydrofuran cluster anions (THF)(n) (-) (1<=n<=100). AB - Anionic tetrahydrofuran clusters (THF)(n) (-) (1<=n<=100) are studied with photoelectron imaging as gas-phase precursors for electrons solvated in THF. Photoelectron spectra of clusters up to n=5 show two peaks, one of which is attributed to a solvated open chain radical anion and the other to the closed THF ring. At n=6, the spectra change shape abruptly, which become more characteristic of (THF)(n) (-) clusters containing solvated electrons. From n=6-100, the vertical detachment energies (VDEs) of these solvated electron clusters increase from 1.96 to 2.71 eV, scaling linearly with n(-1/3). For fully deuterated (THF d8)(n) (-) clusters, the apparent transition to a solvated electron cluster is delayed to n=11. Extrapolation of the VDEs to infinite cluster size yields a value of 3.10 eV for the bulk photoelectric threshold. The relatively large VDEs at onset and small stabilization with increasing cluster size compared to other solvated electron clusters may reflect the tendency of the bulk solvent to form preexisting voids that can readily solvate a free electron. PMID- 20969392 TI - High resolution IR spectroscopy of HDO and HDO(N(2))(n) in helium nanodroplets. AB - We report on the IR-spectra of HDO and aggregates of HDO and N(2) embedded in superfluid helium nanodroplets in the region of the bound O-D stretch vibration. The R(0) transition 0(00)->1(01) of HDO was observed at 2738.157 50(7)cm(-1). The linewidth of this transition was determined to be 0.060(4)cm(-1). In HDO(N(2))(n) aggregates, the bound O-D stretch vibration was observed at 2732.36(1) and 2730.62(1)cm(-1) for n=1 and n=2, respectively. The line broadening amounts to 1.86(7) and 2.73(7)cm(-1), which correspond to lifetimes of 2.84(1) and 1.94(5) ps. PMID- 20969393 TI - Photoelectron spectroscopy and density functional theory study of TiAlO(y) (-) (y=1-3) and TiAl(2)O(y) (-) (y=2-3) clusters. AB - Small titanium-aluminum oxide clusters, TiAlO(y) (-) (y=1-3) and TiAl(2)O(y) (-) (y=2-3), were studied by using anion photoelectron spectroscopy. The adiabatic detachment energies of TiAlO(y) (-) (y=1-3) were estimated to be 1.11+/-0.05, 1.70+/-0.08, and 2.47+/-0.08eV based on their photoelectron spectra; those of TiAl(2)O(2) (-) and TiAl(2)O(3) (-) were estimated to be 1.17+/-0.08 and 2.2+/ 0.1eV, respectively. The structures of these clusters were determined by comparison of density functional calculations with the experimental results. The structure of TiAlO(-) is nearly linear with the O atom in the middle. That of TiAlO(2) (-) is a kite-shaped structure. TiAlO(3) (-) has a kite-shaped TiAlO(2) unit with the third O atom attaching to the Ti atom. TiAl(2)O(2) (-) has two nearly degenerate Al-O-Ti-O-Al chain structures that can be considered as cis and trans forms. TiAl(2)O(3) (-) has two low-lying isomers, kite structure and book structure. The structures of these clusters indicate that the Ti atom tends to bind to more O atoms. PMID- 20969394 TI - Dissociation of core-valence doubly excited states in NO followed by atomic Auger decay. AB - The decay processes of core-valence doubly excited states near the N K edge of NO have been studied using electron spectroscopy. Electron yields measured as a function of photon energy and kinetic energy enable the clear identification of atomic Auger lines associated with the dissociation of doubly excited states. The atomic Auger lines exhibit Doppler profiles, allowing the entire reaction scheme of such dissociation processes to be determined. PMID- 20969395 TI - Fragmentation patterns of core-ionized thymine and 5-bromouracil. AB - Photofragmentation of thymine and 5-bromouracil into cation and neutral fragments following the core ionization by soft x-rays using photoelectron-photoion photoion coincidence technique has been studied. The fragment ion mass spectra were recorded in coincidence with the C 1s photoelectron spectra. In the case of thymine, deuterated samples were used to identify fragments. Deuteration or bromination allowed us to study not only the main fragmentation channels of these pyrimidine bases, but also to investigate if replacement of an exocyclic functional group affects molecular fragmentation. We found that the dominant fragmentation channels involve only one starting geometry, and the base ring and other bond cleavages, leading to the detected fragments, are essentially identical between thymine and 5-bromouracil. In addition, the relative intensities of the strongest fragmentation channels were determined and compared with calculated appearance energies using ab initio unrestricted Hartree-Fock theory. PMID- 20969396 TI - Absolute measurement of the S(0) and S(1) lines in the electric quadrupole fundamental band of D(2) around 3MUm. AB - The electric quadrupole fundamental (v=1<-0) band of molecular deuterium around 3 MUm is accessed by cavity ring-down spectroscopy using a difference-frequency generation source linked to the Cs-clock primary standard via an optical frequency comb synthesizer. An absolute determination of the line position and strength is reported for the first two transitions (J=2<-0 and J=3<-1) of the S branch. An accuracy of 6*10(-8) is achieved for the line-center frequencies, which improves by a factor 20 previous experimental results [A. R. W. McKellar and T. Oka, Can. J. Phys. 56, 1315 (1978)]. The line strength values, measured with 1% accuracy, are used to retrieve the quadrupole moment matrix elements which are found in good agreement with previous theoretical calculations [A. Birnbaum and J. D. Poll, J. Atmos. Sci. 26, 943 (1969); J. L. Hunt, J. D. Poll, and L. Wolniewicz, Can. J. Phys. 62, 1719 (1984)]. PMID- 20969397 TI - Two-step melting of Na(41)(+). AB - The heat capacity of the mass selected Na(41) (+) cluster has been measured using a differential nanocalorimetry method. A two-peak structure appears in the heat capacity curve of Na(41) (+), whereas Schmidt and co-workers [M. Schmidt, J. Donges, Th. Hippler, and H. Haberland, Phys. Rev. Lett. 90, 103401 (2003)] observed, within their experimental accuracy, a smooth caloric curve. They concluded from the absence of any structure that there is a second order melting transition in Na(41) (+) with no particular feature such as premelting. The observed difference with the latter results is attributed to the better accuracy of our method owing to its differential character. The two structures in the heat capacity are ascribed to melting and premelting of Na(41) (+). The peak at lower temperature is likely due to an anti-Mackay to Mackay solid-solid transition. PMID- 20969398 TI - Reaction mechanism of CO oxidation on Cu(2)O(111): A density functional study. AB - The possible reaction mechanisms for CO oxidation on the perfect Cu(2)O(111) surface have been investigated by performing periodic density functional theoretical calculations. We find that Cu(2)O(111) is able to facilitate the CO oxidation with different mechanisms. Four possible mechanisms are explored (denoted as M(ER1), M(ER2), M(LH1), and M(LH2), respectively): M(ER1) is CO((gas))+O(2(ads))->CO(2(gas)); M(ER2) is CO((gas))+O(2(ads))->CO(3(ads)) >O((ads))+CO(2(gas)); M(LH1) refers to CO((ads))+O(2(ads))->O((ads))+CO(2(ads)); and M(LH2) refers to CO((ads))+O(2(ads))->OOCO((ads))->O((ads))+CO(2(ads)). Our transition state calculations clearly reveal that M(ER1) and M(LH2) are both viable; but M(ER1) mechanism preferentially operates, in which only a moderate energy barrier (60.22 kJ/mol) needs to be overcome. When CO oxidation takes place along M(ER2) path, it is facile for CO(3) formation, but is difficult for its decomposition, thereby CO(3) species can stably exist on Cu(2)O(111). Of course, the reaction of CO with lattice O of Cu(2)O(111) is also considered. However, the calculated barrier is 600.00 kJ/mol, which is too large to make the path feasible. So, we believe that on Cu(2)O(111), CO reacts with adsorbed O, rather than lattice O, to form CO(2). This is different from the usual Mars-van Krevene mechanism. The present results enrich our understanding of the catalytic oxidation of CO by copper-based and metal-oxide catalysts. PMID- 20969399 TI - Performance of some nucleation theories with a nonsharp droplet-vapor interface. AB - Nucleation theories involving the concept of nonsharp boundary between the droplet and vapor are compared to recent molecular dynamics (MD) simulation data of Lennard-Jones vapors at temperatures above the triple point. The theories are diffuse interface theory (DIT), extended modified liquid drop-dynamical nucleation theory (EMLD-DNT), square gradient theory (SGT), and density functional theory (DFT). Particular attention is paid to thermodynamic consistency in the comparison: the applied theories either use or, with a proper parameter adjustment, result in the same values of equilibrium vapor pressure, bulk liquid density, and surface tension as the MD simulations. Realistic pressure-density correlations are also used. The best agreement between the simulated nucleation rates and calculations is obtained from DFT, SGT, and EMLD DNT, all of which, in the studied temperature range, show deviations of less than one order of magnitude in the nucleation rate. DIT underestimates the nucleation rate by up to two orders of magnitude. DFT and SGT give the best estimate of the molecular content of the critical nuclei. Overall, at the vapor conditions of this study, all the investigated theories perform better than classical nucleation theory in predicting nucleation rates. PMID- 20969400 TI - (2)H-decoupling-accelerated (1)H spin diffusion in dynamic nuclear polarization with photoexcited triplet electrons. AB - In dynamic nuclear polarization (DNP) experiments applied to organic solids for creating nonequilibrium, high (1)H spin polarization, an efficient buildup of (1)H polarization is attained by partially deuterating the material of interest with an appropriate (1)H concentration. In such a dilute (1)H spin system, it is shown that the (1)H spin diffusion rate and thereby the buildup efficiency of (1)H polarization can further be enhanced by continually applying radiofrequency irradiation for deuterium decoupling during the DNP process. As experimentally confirmed in this work, the electron spin polarization of the photoexcited triplet state is mainly transferred only to those (1)H spins, which are in the vicinity of the electron spins, and (1)H spin diffusion transports the localized (1)H polarization over the whole sample volume. The (1)H spin diffusion coefficients are estimated from DNP repetition interval dependence of the initial buildup rate of (1)H polarization, and the result indicates that the spin diffusion coefficient is enhanced by a factor of 2 compared to that without (2)H decoupling. PMID- 20969401 TI - Time-resolved, optically detected NMR of fluids at high magnetic field. AB - We report on the use of optical Faraday rotation to monitor the nuclear-spin signal in a set of model (19)F- and (1)H-rich fluids. Our approach integrates optical detection with high-field, pulsed NMR so as to record the time-resolved evolution of nuclear-spins after rf excitation. Comparison of chemical-shift resolved resonances allows us to set order-of-magnitude constrains on the relative amplitudes of hyperfine coupling constants for different bonding geometries. When evaluated against coil induction, the present detection modality suffers from poorer sensitivity, but improvement could be attained via multipass schemes. Because illumination is off-resonant i.e., the medium is optically transparent, this methodology could find extensions in a broad class of fluids and soft condensed matter systems. PMID- 20969402 TI - A one-electron model for the aqueous electron that includes many-body electron water polarization: Bulk equilibrium structure, vertical electron binding energy, and optical absorption spectrum. AB - Previously, we reported an electron-water pseudopotential designed to be used in conjunction with a polarizable water model, in order to describe the hydrated electron [L. D. Jacobson et al., J. Chem. Phys. 130, 124115 (2009)]. Subsequently, we found this model to be inadequate for the aqueous electron in bulk water, and here we report a reparametrization of the model. Unlike the previous model, the current version is not fit directly to any observables; rather, we use an ab initio exchange-correlation potential, along with a repulsive potential that is fit to reproduce the density maximum of the excess electron's wave function within the static-exchange approximation. The new parametrization performs at least as well as the previous model, as compared to ab initio benchmarks for (H(2)O)(n) (-) clusters, and also predicts reasonable values for the diffusion coefficient, radius of gyration, and absorption maximum of the bulk species. The new model predicts a vertical electron binding energy of 3.7 eV in bulk water, which is 1.4 eV smaller than the value obtained using nonpolarizable models; the difference represents the solvent's electronic reorganization energy following electron detachment. We find that the electron's first solvation shell is quite loose, which may be responsible for the electron's large, positive entropy of hydration. Many-body polarization alters the electronic absorption line shape in a qualitative way, giving rise to a high energy tail that is observed experimentally but is absent in previous simulations. In our model, this feature arises from spatially diffuse excited states that are bound only by electronic reorganization (i.e., solvent polarization) following electronic excitation. PMID- 20969403 TI - The nonmonotonic concentration dependence of the mean activity coefficient of electrolytes is a result of a balance between solvation and ion-ion correlations. AB - We propose a simple model to explain the nonmonotonic concentration dependence of the mean activity coefficient of simple electrolytes without using any adjustable parameters. The primitive model of electrolytes is used to describe the interaction between ions computed by the adaptive grand canonical Monte Carlo method. For the dielectric constant of the electrolyte, we use experimental concentration dependent values. This is included through a solvation term in our treatment to describe the interaction between ions and water that changes as the dielectric constant changes with concentration. This term is computed by a Born treatment fitted to experimental hydration energies. Our results for LiCl, NaCl, KCl, CsCl, NaBr, NaI, MgCl(2), CaCl(2), SrCl(2), and BaCl(2) demonstrate that the principal reason of the nonmonotonic behavior of the activity coefficient is a balance between the solvation and ion-ion correlation terms. This conclusion differs from previous studies that assumed that it is the balance of hard sphere repulsion and electrostatic attraction that produces the nonmonotonic behavior. Our results indicate that the earlier assumption that solvation can be taken into account by a larger, "solvated" ionic radius should be reconsidered. To explain second order effects (such as dependence on ionic size), we conclude that explicit water models are needed. PMID- 20969404 TI - Spectroscopy of the copper dimer in normal fluid, superfluid, and solid (4)He. AB - Copper atoms and molecules are laser ablated into bulk liquid and solid helium, and the emission spectra of the laser excited D->X, B->X, and a->X transitions of Cu(2) are observed to exhibit clearly resolved vibrational bands. Surprisingly, for the D->X and the B->X transitions, no differences were observed for superfluid He at 1.5 K, for the normal liquid at 2.65 K, or for the 1.5 K solid at higher pressures of about 30 bars. An interpretation based on the bubble model indicates that the interaction with the He matrix is much weaker than in the case of the alkali atoms. Compared to other solid rare gas matrices, the line shifts and line widths in condensed helium are much smaller by nearly an order of magnitude. PMID- 20969405 TI - Impact of network topology on cationic diffusion and hardness of borate glass surfaces. AB - The connection between bulk glass properties and network topology is now well established. However, there has been little attention paid to the impact of network topology on the surface properties of glass. In this work, we report the impact of the network topology on both the transport properties (such as cationic inward diffusion) and the mechanical properties (such as hardness) of borate glasses with modified surfaces. We choose soda lime borate systems as the object of this study because of their interesting topological features, e.g., boron anomaly. An inward diffusion mechanism is employed to modify the glass surface compositions and hence the surface topology. We show that accurate quantitative predictions of the hardness of the modified surfaces can be made using topological constraint theory with temperature-dependent constraints. Experimental results reveal that Ca(2+) diffusion is most intense in glasses with lowest BO(4) fraction, whereas Na(+) diffusion is only significant when nonbridging oxygens start to form. These phenomena are interpreted in terms of the atomic packing and the local electrostatic environments of the cations. PMID- 20969406 TI - Pressure-dependent electronic structures in multiferroic DyMnO(3): A combined lifetime-broadening-suppressed x-ray absorption spectroscopy and ab initio electronic structure study. AB - Variations in the electronic structure and structural distortion in multiferroic DyMnO(3) were probed by synchrotron x-ray diffraction, lifetime-broadening suppressed x-ray absorption spectroscopy (XAS), and ab initio electronic structure calculations. The refined x-ray diffraction data enabled an observation of a diminished local Jahn-Teller distortion of Mn sites within MnO(6) octahedra in DyMnO(3) on applying the hydrostatic pressure. The intensity of the white line in Mn K-edge x-ray absorption spectra of DyMnO(3) progressively increased with the increasing pressure. With the increasing hydrostatic pressure, the absorption threshold of an Mn K-edge spectra of DyMnO(3) shifted toward a greater energy, whereas the pre-edge line slightly shifted to a smaller energy. We provide the spectral evidence for the pressure-induced bandwidth broadening for manganites. The intensity enhancement of the white line in Mn K-edge spectra is attributed to a diminished Jahn-Teller distortion of MnO(6) octahedra in compressed DyMnO(3). A comparison of the pressure-dependent XAS spectra with the ab initio electronic structure calculations and full calculations of multiple scattering using the code FDMNES shows the satisfactory agreement between experimental and calculated Mn K-edge spectra. PMID- 20969407 TI - Simulating polarizable molecular ionic liquids with Drude oscillators. AB - The Drude oscillator model is applied to the molecular ionic liquid 1-ethyl-3 methyl-imidazolium triflate. The range of manageable Drude charges is tested. The strength of the polarizability is systematically varied from 0% to 100%. The influence on the structure, single particle dynamics, and collective dielectric properties is investigated. The generalized dielectric constant can be decomposed into a dielectric permittivity, a dielectric conductivity, and an optical dielectric constant E(infinity). The major part of the static generalized dielectric constant comes from the collective rotation of the ions, i.e., the dielectric permittivity. The translational contribution from the dielectric conductivity is about 58% of the dielectric permittivity. For the evaluation of the optical dielectric contribution, the computational dielectric theory was adapted to the case of heterogeneous polarizabilities. In case of 100% polarizability, it reaches a value of approximately 2. PMID- 20969408 TI - Low energy (0-4 eV) electron impact to N(2)O clusters: Dissociative electron attachment, ion-molecule reactions, and vibrational Feshbach resonances. AB - Electron attachment to clusters of N(2)O in the energy range of 0-4 eV yields the ionic complexes [(N(2)O)(n)O](-), [(N(2)O)(n)NO](-), and (N(2)O)(n) (-) . The shape of the ion yields of the three homologous series differs substantially reflecting the different formation mechanisms. While the generation of [(N(2)O)(n)O](-) can be assigned to dissociative electron attachment (DEA) of an individual N(2)O molecule in the target cluster, the formation of [(N(2)O)(n)NO]( ) is interpreted via a sequence of ion molecule reactions involving the formation of O(-) via DEA in the first step. The nondecomposed complexes (N(2)O)(n) (-) are preferentially formed at very low energies (below 0.5 eV) as a result of intramolecular stabilization of a diffuse molecular anion at low energy. The ion yields of [(N(2)O)(n)O](-) and (N(2)O)(n) (-) versus electron energy show sharp peaks at the threshold region, which can be assigned to vibrational Feshbach resonances mediated by the diffuse anion state as already observed in an ultrahigh resolution electron attachment study of N(2)O clusters [E. Leber, S. Barsotti, J. Bommels, J. M. Weber, I. I. Fabrikant, M.-W. Ruf, and H. Hotop, Chem. Phys. Lett. 325, 345 (2000)]. PMID- 20969409 TI - High temperatures and high pressures Brillouin scattering studies of liquid H(2)O+CO(2) mixtures. AB - The Brillouin scattering spectroscopy studies have been conducted in a diamond anvil cell for a liquid mixtures composed of 95 mol % H(2)O and 5 mol % CO(2) under high temperatures and pressures. The sound velocity, refractive index, density, and adiabatic bulk modulus of the H(2)O+CO(2) mixtures were determined under pressures up to the freezing point at 293, 453, and 575 K. It is found from the experiment that sound velocities of the liquid mixture are substantially lower than those of pure water at 575 K, but not at lower temperatures. We presented an empirical relation of the density in terms of pressure and temperature. Our results show that liquid H(2)O+CO(2) mixtures are more compressible than water obtained from an existing equation of state of at 453 and 575 K. PMID- 20969410 TI - Heterogeneous dynamics in columnar liquid crystals of parallel hard rods. AB - In the wake of previous studies on the rattling-and-jumping diffusion in smectic liquid crystal phases of colloidal rods, we analyze here for the first time the heterogeneous dynamics in columnar phases. More specifically, we perform computer simulations to investigate the relaxation dynamics of a binary mixture of perfectly aligned hard spherocylinders. We detect that the columnar arrangement of the system produces free-energy barriers that the particles should overcome to jump from one column to another, thus determining a hopping-type diffusion. This phenomenon accounts for the non-Gaussian intercolumn diffusion and shows a two step structural relaxation that is remarkably analogous to that of out-of equilibrium glass-forming systems and gels. Surprisingly enough, slight deviations from the behavior of simple liquids due to transient cages is also observed in the direction perpendicular to this plane, where the system is usually referred to as liquidlike. PMID- 20969411 TI - Orientational dynamics of water trapped between two nanoscopic hydrophobic solutes: A molecular dynamics simulation study. AB - We investigate thoroughly the effect of confinement and solute topology on the orientational dynamics of water molecule in the interplate region between two nanoscopic hydrophobic paraffinlike plates. Results are obtained from molecular dynamics simulations of aqueous solutions of paraffinlike plates in the isothermal-isobaric ensemble. An analysis of survival time auto correlation function shows that the residence time of the water molecule in the confined region between two model nanoscopic hydrophobic plates depends on solute surface topology (intermolecular distance within the paraffinlike plate). As expected, the extent of confinement also changes the residence time of water molecules considerably. Orientational dynamics was analyzed along three different directions, viz., dipole moment, HH, and perpendicular to molecular plane vectors. It has been demonstrated that the rotational dynamics of the confined water does not follow the Debye rotational diffusion model, and surface topology of the solute plate and the extent of confinement have considerable effect on the rotational dynamics of the confined water molecules. PMID- 20969412 TI - Liquid to quasicrystal transition in bilayer water. AB - The phase behavior of confined water is a topic of intense and current interest due to its relevance in biology, geology, and materials science. Nevertheless, little is known about the phases that water forms even when confined in the simplest geometries, such as water confined between parallel surfaces. Here we use molecular dynamics simulations to compute the phase diagram of two layers of water confined between parallel non hydrogen bonding walls. This study shows that the water bilayer forms a dodecagonal quasicrystal, as well as two previously unreported bilayer crystals, one tiled exclusively by pentagonal rings. Quasicrystals, structures with long-range order but without periodicity, have never before been reported for water. The dodecagonal quasicrystal is obtained from the bilayer liquid through a reversible first-order phase transition and has diffusivity intermediate between that of the bilayer liquid and ice phases. The water quasicrystal and the ice polymorphs based on pentagons are stabilized by compression of the bilayer and are not templated by the confining surfaces, which are smooth. This demonstrates that these novel phases are intrinsically favored in bilayer water and suggests that these structures could be relevant not only for confined water but also for the wetting and properties of water at interfaces. PMID- 20969413 TI - CoPc adsorption on Cu(111): Origin of the C4 to C2 symmetry reduction. AB - The adsorption of phthalocyanines (Pc) to various surfaces has recently been reported to lead to a lowering of symmetry from C4 to C2 in scanning tunneling microscope (STM) images. Possible origins of the reduced symmetry involve the electronic structure or geometric deformation of the molecules. Here, the origin of the reduction is clarified from a comprehensive theoretical study of CoPc adsorbed on the Cu(111) surface along with the experimental STM data. Total energy calculations using different schemes for the exchange-correlation energy and STM simulations are compared against experimental data. We find that the symmetry reduction is only reproduced when van der Waals corrections are included into the formalism. It is caused by a deformation along the two perpendicular molecular axes, one of them coming closer to the surface by around 0.2 A. An electronic structure analysis reveals (i) the relevance of the CoPc interaction with the Cu(111) surface state and (ii) that intramolecular features in dI/dV maps clearly discriminate a Co-derived state from the rest of the Pc states. PMID- 20969414 TI - Curvature dependence of surface free energy of liquid drops and bubbles: A simulation study. AB - We study the excess free energy due to phase coexistence of fluids by Monte Carlo simulations using successive umbrella sampling in finite L*L*L boxes with periodic boundary conditions. Both the vapor-liquid phase coexistence of a simple Lennard-Jones fluid and the coexistence between A-rich and B-rich phases of a symmetric binary (AB) Lennard-Jones mixture are studied, varying the density rho in the simple fluid or the relative concentration x(A) of A in the binary mixture, respectively. The character of phase coexistence changes from a spherical droplet (or bubble) of the minority phase (near the coexistence curve) to a cylindrical droplet (or bubble) and finally (in the center of the miscibility gap) to a slablike configuration of two parallel flat interfaces. Extending the analysis of Schrader et al., [Phys. Rev. E 79, 061104 (2009)], we extract the surface free energy gamma(R) of both spherical and cylindrical droplets and bubbles in the vapor-liquid case and present evidence that for R >infinity the leading order (Tolman) correction for droplets has sign opposite to the case of bubbles, consistent with the Tolman length being independent on the sign of curvature. For the symmetric binary mixture, the expected nonexistence of the Tolman length is confirmed. In all cases and for a range of radii R relevant for nucleation theory, gamma(R) deviates strongly from gamma(infinity) which can be accounted for by a term of order gamma(infinity)/gamma(R)-1?R(-2). Our results for the simple Lennard-Jones fluid are also compared to results from density functional theory, and we find qualitative agreement in the behavior of gamma(R) as well as in the sign and magnitude of the Tolman length. PMID- 20969415 TI - Interpretation of high-resolution images of the best-bound wetting layers on Pt(111). AB - Two interpretations have been proposed of dark triangles observed in scanning tunneling microscopy (STM) images of the best bound, ?37*?37-R25.3 degrees , and ?39*?39-R16.1 degrees periodic water monolayers on Pt(111). In one, a "Y"-shaped tetramer of water molecules is removed, leaving a vacancy island behind; the other assumes the Y is replaced by a hexagon of H(2)O molecules, amounting to a di-interstitial. Consistent only with the di-interstitial model are thermal desorption and CO coadsorption data, STM line scans, and total energies obtained from density functional theory calculations. PMID- 20969416 TI - Atomic imaging of the monolayer nucleation and unpinning of a compound semiconductor surface during atomic layer deposition. AB - The reaction of trimethyl aluminum on the group III rich reconstructions of InAs(0 0 1) and In(0.53)Ga(0.47)As(0 0 1) is observed with scanning tunneling microscopy/spectroscopy. At high coverage, a self-terminated ordered overlayer is observed that provides the monolayer nucleation density required for subnanometer thick transistor gate oxide scaling and removes the surface Fermi level pinning that is present on the clean InGaAs surface. Density functional theory simulations confirm that an adsorbate-induced reconstruction is the basis of the monolayer nucleation density and passivation. PMID- 20969417 TI - A molecular dynamics study on heat conduction characteristics in DPPC lipid bilayer. AB - In this paper, nonequilibrium molecular dynamics simulations were performed on a single component 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine lipid bilayer in order to investigate the thermal conductivity and its anisotropy. To evaluate the thermal conductivity, we applied a constant heat flux to the lipid bilayer along and across the membrane with ambient water. The contribution of molecular interaction to the heat conduction was also evaluated. Along the bilayer plane, there is little transfer of thermal energy by the interaction between lipid molecules as compared with the interaction between water molecules. Across the bilayer plane, the local thermal conductivity depends on the constituents (i.e., water, head group, and tail group of lipid molecule) that occupy the domain. Although the intramolecular transfer of thermal energy in the tail groups of lipid molecules works efficiently to promote high local thermal conductivity in this region, the highest thermal resistance appears at the center of lipid bilayer where acyl chains of lipid molecules face each other due to a loss of covalent-bond and low number density. The overall thermal conductivities of the lipid bilayer in the directions parallel and perpendicular to the lipid membrane have been compared, and it was found that the thermal conductivity normal to the membrane is higher than that along the membrane, but it is still smaller than that of bulk water. PMID- 20969418 TI - First-principles study of hydrogen adsorption in metal-doped COF-10. AB - Covalent organic frameworks (COFs), due to their low-density, high-porosity, and high-stability, have promising applications in gas storage. In this study we have explored the potential of COFs doped with Li and Ca metal atoms for storing hydrogen under ambient thermodynamic conditions. Using density functional theory we have performed detailed calculations of the sites Li and Ca atoms occupy in COF-10 and their interaction with hydrogen molecules. The binding energy of Li atom on COF-10 substrate is found to be about 1.0 eV and each Li atom can adsorb up to three H(2) molecules. However, at high concentration, Li atoms cluster and, consequently, their hydrogen storage capacity is reduced due to steric hindrance between H(2) molecules. On the other hand, due to charge transfer from Li to the substrate, O sites provide additional enhancement for hydrogen adsorption. With increasing concentration of doped metal atoms, the COF-10 substrate provides an additional platform for storing hydrogen. Similar conclusions are reached for Ca doped COF-10. PMID- 20969419 TI - Structure and dynamics of liquid methanol confined within functionalized silica nanopores. AB - Molecular dynamics simulations have been carried out to investigate the structure and dynamics of liquid methanol confined in 3.3 nm diameter cylindrical silica pores. Three cavities differing in the characteristics of the functional groups at their walls have been examined: (i) smooth hydrophobic pores in which dispersive forces prevail, (ii) hydrophilic cavities with surfaces covered by polar silanol groups, and (iii) a much more rugged pore in which 60% of the previous interfacial hydroxyl groups were replaced by the bulkier trimethylsilyl ones. Confinement promotes a considerable structure at the vicinity of the pore walls which is enhanced in the case of hydroxylated surfaces. Moreover, in the presence of the trimethylsilyl groups, the propagation of this interface-induced spatial ordering extends down to the central region of the pore. Concerning the dynamical modes, we observed an overall slowdown in both the translational and rotational motions. An analysis of these mobilities from a local perspective shows that the largest retardations operate at the vicinity of the interfaces. The gross features of the rotational dynamics were analyzed in terms of contributions arising from bulk and surface states. Compared to the bulk dynamical behavior, the characteristic timescales associated with the rotational motions show the most dramatic increments. A dynamical analysis of hydrogen bond formation and breaking processes is also included. PMID- 20969420 TI - Kinetics of surface enrichment: A molecular dynamics study. AB - We use molecular dynamics to study the kinetics of surface enrichment (SE) in a stable homogeneous mixture (AB), placed in contact with a surface which preferentially attracts A. The SE profiles show a characteristic double exponential behavior with two length scales: xi(-), which rapidly saturates to its equilibrium value, and xi(+), which diverges as a power-law with time (xi(+)~t(theta)). We find that hydrodynamic effects result in a crossover of the growth exponent from theta?0.5 to theta?1.0. There is also a corresponding crossover in the growth dynamics of the SE layer thickness. PMID- 20969421 TI - Depletion interaction between spheres in an ideal equilibrium polymer fluid: Exact asymptotic results. AB - We use a continuum chain model and develop an analytical theory for the interaction between two spheres immersed in a fluid of ideal equilibrium polymers. The theory can be applied to both adsorbing and nonadsorbing spheres. Here we focus on two nonadsorbing spheres and determine the classical depletion interaction between them. Compact, and exact, results are derived for the asymptotic behavior of the depletion interaction, which has a Yukawa form. We show also that in the limit of large spheres (and large surface to surface separation) the Derjaguin approximation is valid. We compare our asymptotic expression with numerical solutions of an ideal equilibrium polymer fluid consisting of discrete chains. Our asymptotic approximation accurately predicts long-range interactions between small spheres. For large spheres it predicts the interaction very well over most of the separation range. We also consider a single sphere immersed in the polymer fluid and show how our results can be generalized to treat polydisperse polymer fluids, where the polydispersity is described by a Schulz-Flory distribution. PMID- 20969422 TI - Translocation of alpha-helix chains through a nanopore. AB - The translocation of alpha-helix chains through a nanopore is studied through Langevin dynamics simulations. The alpha-helix chains exhibit several different characteristics about their average translocation times and the alpha-helix structures when they transport through the nanopores under the driving forces. First, the relationship between average translocation times tau and the chain length N satisfies the scaling law, tau~N(alpha), and the scaling exponent alpha depends on the driving force f for the small forces while it is close to the Flory exponent (nu) in the other force regions. For the chains with given chain lengths, it is observed that the dependence of the average translocation times can be expressed as tau~f(-1/2) for the small forces while can be described as tau~f in the large force regions. Second, for the large driving force, the average number of alpha-helix structures N(h) decreases first and then increases in the translocation process. The average waiting time of each bead, especially of the first bead, is also dependent on the driving forces. Furthermore, an elasticity spring model is presented to reasonably explain the change of the alpha-helix number during the translocation and its elasticity can be locally damaged by the large driving forces. Our results demonstrate the unique behaviors of alpha-helix chains transporting through the pores, which can enrich our insights into and knowledge on biopolymers transporting through membranes. PMID- 20969423 TI - Curvature effects upon interactions of polymer-grafted nanoparticles in chemically identical polymer matrices. AB - We study the interactions between polymer-grafted nanoparticles immersed in a chemically identical polymer melt using a numerical implementation of polymer mean-field theory. We focus on the interpenetration width between the grafted and free chains and its relationship to the polymer-mediated interparticle interactions. To this end, we quantify the interpenetration width as a function of particle curvature, grafting density, and the relative molecular weights of the grafted and free chains. We show the onset of wetting and dewetting as a function of these quantities and explain our results through simple scaling arguments to include the effects of curvature. Subsequently, we show that the interparticle potentials correlate quantitatively with the trends displayed by the interpenetration widths. PMID- 20969424 TI - Cospectral polymers: Differentiation via semiflexibility. AB - We consider polymer structures which are known in the mathematical literature as "cospectral." Their graphs have (in spite of the different architectures) exactly the same Laplacian spectra. Now, these spectra determine in Gaussian (Rouse-type) approaches many static as well as dynamical polymer characteristics. Hence, in such approaches for cospectral graphs many mesoscopic quantities are predicted to be indistinguishable. Here we show that the introduction of semiflexibility into the generalized Gaussian structure scheme leads to different spectra and hence to distinct macroscopic patterns. Moreover, particular semiflexible situations allow us to distinguish well between cospectral structures. We confirm our theoretical results through Monte Carlo simulations. PMID- 20969425 TI - Internal and free energy in a pair of like-charged colloids: Monte Carlo simulations. AB - The effective interaction between two colloidal particles in a bath of monovalent co- and counterions is studied by means of lattice Monte Carlo simulations with the primitive model. The internal electrostatic energy as a function of the colloid distance is studied fixing the position of the colloids. The free energy of the whole system is obtained introducing a bias parabolic potential, that allows us to sample efficiently small separations between the colloidal particles. For small charges, both the internal and free energy increase when the colloids approach each other, resulting in an effective repulsion driven by the electrostatic repulsion. When the colloidal charge is large enough, on the other hand, the colloid-ion coupling is strong enough to form double layers. The internal energy in this case decreases upon approaching the colloids because more ions enter the double layer. This attractive contribution to the interaction between the colloids is stronger for larger charges and larger ionic concentrations. However, the total free energy increases due to the loss of ionic entropy, and resulting finally in a repulsive interaction potential driven by the entropic contributions. The loss of ionic entropy can be almost quantitatively reproduced with the ideal contribution, the same level of approximation as the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. The overall behavior is captured by the DLVO theory qualitatively, and a comparison is made with the functional form predicted by the theory, showing moderate agreement. PMID- 20969426 TI - Unwinding dynamics of double-stranded polymers. AB - We consider the unwinding of two lattice polymer strands of length N that are initially wound around each other in a double-helical conformation and evolve through Rouse dynamics. The problem relates to quickly bringing a double-stranded polymer well above its melting temperature, i.e., the binding interactions between the strands are neglected, and the strands separate from each other as it is entropically favorable for them to do so. The strands unwind by rotating around each other until they separate. We find that the process proceeds from the ends inward; intermediate conformations can be characterized by a tightly wound inner part, from which loose strands are sticking out, with length l~t(0.39). The total time needed for the two strands to unwind scales as a power of N as tau(u)~N(2.57+/-0.03). We present a theoretical argument, which suggests that during this unwinding process, these loose strands are far out of equilibrium. PMID- 20969428 TI - Influence of organic ions on DNA damage induced by 1 eV to 60 keV electrons. AB - We report the results of a study on the influence of organic salts on the induction of single strand breaks (SSBs) and double strand breaks (DSBs) in DNA by electrons of 1 eV to 60 keV. Plasmid DNA films are prepared with two different concentrations of organic salts, by varying the amount of the TE buffer (Tris-HCl and EDTA) in the films with ratio of 1:1 and 6:1 Tris ions to DNA nucleotide. The films are bombarded with electrons of 1, 10, 100, and 60 000 eV under vacuum. The damage to the 3197 base-pair plasmid is analyzed ex vacuo by agarose gel electrophoresis. The highest yields are reached at 100 eV and the lowest ones at 60 keV. The ratios of SSB to DSB are surprisingly low at 10 eV (~4.3) at both salt concentrations, and comparable to the ratios measured with 100 eV electrons. At all characteristic electron energies, the yields of SSB and DSB are found to be higher for the DNA having the lowest salt concentration. However, the organic salts are more efficient at protecting DNA against the damage induced by 1 and 10 eV electrons. DNA damage and protection by organic ions are discussed in terms of mechanisms operative at each electron energy. It is suggested that these ions create additional electric fields within the groove of DNA, which modify the resonance parameter of 1 and 10 eV electrons, namely, by reducing the electron capture cross-section of basic DNA units and the lifetime of corresponding transient anions. An interstrand electron transfer mechanism is proposed to explain the low ratios for the yields of SSB to those of DSB produced by 10 eV electrons. PMID- 20969427 TI - Sequence composition and environment effects on residue fluctuations in protein structures. AB - Structure fluctuations in proteins affect a broad range of cell phenomena, including stability of proteins and their fragments, allosteric transitions, and energy transfer. This study presents a statistical-thermodynamic analysis of relationship between the sequence composition and the distribution of residue fluctuations in protein-protein complexes. A one-node-per-residue elastic network model accounting for the nonhomogeneous protein mass distribution and the interatomic interactions through the renormalized inter-residue potential is developed. Two factors, a protein mass distribution and a residue environment, were found to determine the scale of residue fluctuations. Surface residues undergo larger fluctuations than core residues in agreement with experimental observations. Ranking residues over the normalized scale of fluctuations yields a distinct classification of amino acids into three groups: (i) highly fluctuating Gly, Ala, Ser, Pro, and Asp, (ii) moderately fluctuating-Thr, Asn, Gln, Lys, Glu, Arg, Val, and Cys, and (iii) weakly fluctuating-Ile, Leu, Met, Phe, Tyr, Trp, and His. The structural instability in proteins possibly relates to the high content of the highly fluctuating residues and a deficiency of the weakly fluctuating residues in irregular secondary structure elements (loops), chameleon sequences, and disordered proteins. Strong correlation between residue fluctuations and the sequence composition of protein loops supports this hypothesis. Comparing fluctuations of binding site residues (interface residues) with other surface residues shows that, on average, the interface is more rigid than the rest of the protein surface and Gly, Ala, Ser, Cys, Leu, and Trp have a propensity to form more stable docking patches on the interface. The findings have broad implications for understanding mechanisms of protein association and stability of protein structures. PMID- 20969429 TI - Free energy surfaces for the interaction of D-glucose with planar aromatic groups in aqueous solution. AB - Multidimensional potentials of mean force for the interactions in aqueous solution of both anomers of D-glucopyranose with two planar aromatic molecules, indole and para-methyl-phenol, have been calculated using molecular dynamics simulations with umbrella sampling and were subsequently used to estimate binding free energies. Indole and para-methyl-phenol serve as models for the side chains of the amino acids tryptophan and tyrosine, respectively. In all cases, a weak affinity between the glucose molecules and the flat aromatic surfaces was found. The global minimum for these interactions was found to be for the case when the pseudoplanar face of beta-D-glucopyranose is stacked against the planar surfaces of the aromatic residues. The calculated binding free energies are in good agreement with both experiment and previous simulations. The multidimensional free energy maps suggest a mechanism that could lend kinetic stability to the complexes formed by sugars bound to sugar-binding proteins. PMID- 20969430 TI - Absolute cross sections for electronic excitations of cytosine by low energy electron impact. AB - The absolute cross sections (CSs) for electronic excitations of cytosine by electron impact between 5 and 18 eV were measured by electron-energy-loss (EEL) spectroscopy of the molecule deposited at low coverage on an inert Ar substrate. The lowest EEL features found at 3.55 and 4.02 eV are ascribed to transitions from the ground state to the two lowest triplet 1 (3)A(')(pi->pi(*)) and 2 (3)A(')(pi->pi(*)) valence states of the molecule. Their energy dependent CSs exhibit essentially a common maximum at about 6 eV with a value of 1.84*10(-17) cm(2) for the former and 4.94*10(-17) cm(2) for the latter. In contrast, the CS for the next EEL feature at 4.65 eV, which is ascribed to the optically allowed transition to the 2 (1)A(')(pi->pi(*)) valence state, shows only a steep rise to about 1.04*10(-16) cm(2) followed by a monotonous decrease with the incident electron energy. The higher EEL features at 5.39, 6.18, 6.83, and 7.55 eV are assigned to the excitations of the 3 (3,1)A(')(pi->pi(*)), 4 (1)A(')(pi->pi(*)), 5 (1)A(')(pi->pi(*)), and 6 (1)A(')(pi->pi(*)) valence states, respectively. The CSs for the 3 (3,1)A(') and 4 (1)A(') states exhibit a common enhancement at about 10 eV superimposed on a more or less a steep rise, reaching, respectively, a maximum of 1.27 and 1.79*10(-16) cm(2), followed by a monotonous decrease. This latter enhancement and the maximum seen at about 6 eV in the lowest triplet states correspond to the core-excited electron resonances that have been found by dissociative electron attachment experiments with cytosine in the gas phase. The weak EEL feature found at 5.01 eV with a maximum CS of 3.8*10(-18) cm(2) near its excitation threshold is attributed to transitions from the ground state to the 1 (3,1)A(")(n->pi(*)) states. The monotonous rise of the EEL signal above 8 eV is attributed to the ionization of the molecule. It is partitioned into four excitation energy regions at about 8.55, 9.21, 9.83, and 11.53 eV, which correspond closely to the ionization energies of the four highest occupied molecular orbitals of cytosine. The sum of the ionization CS for these four excitation regions reaches a maximum of 8.1*10(-16) cm(2) at the incident energy of 13 eV. PMID- 20969431 TI - Treadmilling of actin filaments via Brownian dynamics simulations. AB - Actin polymerization is coupled to the hydrolysis of adenosine triphosphate (ATP) into adenosine diphosphate (ADP) and inorganic phosphate (P(i)). Therefore, each protomer within an actin filament can attain three different nucleotide states corresponding to bound ATP, ADP/P(i), and ADP. These protomer states form spatial patterns on the growing (or shrinking) filaments. Using Brownian dynamics simulations, the growth behavior of long filaments is studied, together with the associated protomer patterns, as a function of ATP-actin monomer concentration, C(T), within the surrounding solution. For concentrations close to the critical concentration C(T)=C(T,cr), the filaments undergo treadmilling, i.e., they grow at the barbed and shrink at the pointed end, which leads to directed translational motion of the whole filament. The corresponding nonequilibrium states are characterized by several global fluxes and by spatial density and flux profiles along the filaments. We focus on a certain set of transition rates as deduced from in vitro experiments and find that the associated treadmilling (or turnover) rate is about 0.08 monomers per second. PMID- 20969432 TI - Usability assessment of ASIBOT: a portable robot to aid patients with spinal cord injury. AB - The usability concept refers to aspects related to the use of products that are closely linked to the user's degree of satisfaction. Our goal is to present a functional evaluation methodology for assessing the usability of sophisticated technical aids, such as a portable robot for helping disabled patients with severe spinal cord injuries. The specific manipulator used for this task is ASIBOT, a personal assistance robot totally developed by RoboticsLab at the University Carlos III of Madrid. Our purpose is also to improve some aspects of the manipulator according to the user's perception. For our case study, a population of six patients with spinal cord injury is considered. These patients have been suffering spinal cord injuries for a period of time longer than 1 year before the tests are carried out. The methodology followed for the information gathering is based on the Quebec User Evaluation of Satisfaction with assistive Technology (QUEST). Different daily functions, such as drinking, brushing one's teeth and washing one's face, are considered to assess the user's perception when using ASIBOT as a technical aid. The human factor in this procedure is the main base to establish the specific needs and tools to make the end product more suitable and usable. PMID- 20969433 TI - Translation and validation of Chinese version of International Knee Documentation Committee Subjective Knee Form. AB - PURPOSE: To translate, cross-culturally adapt and validate the International Knee Documentation Committee Subjective Knee Form (IKDC-SKF-C) to Chinese. METHOD: Forward and backward translations were conducted by two bilingual professional translators. Content validity was verified by a panel of a senior orthopaedic surgeon and six physiotherapists. The IKDC-SKF-C was tested on 84 patients. Psychometric testing included internal consistency (Cronbach's alpha) and test retest reliability. Convergent validity used Spearman's correlation coefficient (rho) tests by comparing its score with the Chinese version of SF-36. RESULTS: The Internal consistency was excellent with Cronbach's alpha = 0.97. Test-retest reliability was supported with an ICC = 0.87. The IKDC-SKF-C was moderately related to concurrent measures of physical function and bodily pain (r = 0.64, p < 0.05). CONCLUSION: The translated Chinese IKDC-SKF is a reliable and valid tool with equal measurement properties and conceptual equivalent to the original version. PMID- 20969434 TI - A long way to Tipperary? Young people with complex health conditions living in residential aged care: a metaphorical map for understanding the call for change. AB - PURPOSE: There is ongoing public and private concern regarding the appropriateness of young people with complex health needs residing in nursing homes and the search for alternative living environments. Despite the demand for change, there is only tacit understanding of the key motivations behind this call for change and even less in the way of coherent arguments underlying the need for alternative solutions. The study aimed to explore the assumed truths that have formed around this topic in recent years and to reposition ambitious but ambiguous arguments regarding the need to relocate younger people from aged care facilities. METHOD: By applying the method of systematic metaphor analysis, the authors conducted a review of social discourse (i.e. media corpus of 904 published articles dated 2001-2009). RESULTS: A conceptual media map was developed to document the process of social change around this topic. Additionally, the narrative described five metaphors that outlined the experience of aged care residential homes for young people with complex health conditions, namely 'captivity', 'commodity', 'battlelines', 'fragmentation' and 'a contemporary life'. These metaphors reflected the fears and hopes held by young people and their families. CONCLUSIONS: Results indicate that young people at risk of nursing home placement are confronted with a range of distinct and complex personal dilemmas which ought to be resolved through initiatives purported to offer 'more appropriate' residential options. We conclude that principles of good quality care are in danger of becoming misplaced within over simplified interpretations of the needs of young people with complex conditions. Alignment of disability and rehabilitation policy with residential care practice will allow for more informed decisions about long-term care needs of young people, leading to quality outcomes. PMID- 20969436 TI - Treatment of burning mouth syndrome with a low-level energy diode laser. AB - OBJECTIVE: To test the therapeutic efficacy of low-level energy diode laser on burning mouth syndrome. BACKGROUND: Burning mouth syndrome is characterized by burning and painful sensations in the mouth, especially the tongue, in the absence of significant mucosal abnormalities. Although burning mouth syndrome is relatively common, little is known regarding its etiology and pathophysiology. As a result, no treatment is effective in all patients. Low-level energy diode laser therapy has been used in a variety of chronic and acute pain conditions, including neck, back and myofascial pain, degenerative osteoarthritis, and headache. METHODS: A total of 17 patients who had been diagnosed with burning mouth syndrome were treated with an 800-nm wavelength diode laser. A straight handpiece was used with an end of 1-cm diameter with the fiber end standing 4 cm away from the end of handpiece. When the laser was applied, the handpiece directly contacted or was immediately above the symptomatic lingual surface. The output used was 3 W, 50 msec intermittent pulsing, and a frequency of 10 Hz, which was equivalent to an average power of 1.5 W/cm(2) (3 W * 0.05 msec * 10 Hz = 1.5 W/cm(2)). Depending on the involved area, laser was applied to a 1-cm(2) area for 70 sec until all involved area was covered. Overall pain and discomfort were analyzed with a 10-cm visual analogue scale. RESULTS: All patients received diode laser therapy between one and seven times. The average pain score before the treatment was 6.7 (ranging from 2.9 to 9.8). The results showed an average reduction in pain of 47.6% (ranging from 9.3% to 91.8%). The burning sensation remained unchanged for up to 12 months. CONCLUSION: Low-level energy diode laser may be an effective treatment for burning mouth syndrome. PMID- 20969435 TI - Clinical experience with insulin glargine in type 1 diabetes. AB - The Diabetes Control and Complications Trial (DCCT) demonstrated the importance of optimal glycemic control achieved through intensive insulin therapy in reducing the microvascular complications associated with type 1 diabetes. However, the DCCT, which was conducted prior to the availability of insulin analogs, also reported a significant increase in severe hypoglycemia with intensive versus conventional therapy. Insulin analogs were developed to aid patients in achieving better diabetes control by providing insulins with optimized pharmacokinetic and pharmacodynamic characteristics. Insulin glargine was the first long-acting insulin analog with a 24-h duration of action, offering once-daily injection, and has now been in clinical use for over 10 years. The authors performed a systematic search of EMBASE, MEDLINE, and Web of Science (Science Citation Index) to determine the efficacy of insulin glargine in type 1 diabetes in basal-bolus insulin regimens. Randomized controlled trials have demonstrated that glycemic control with insulin glargine is at least comparable to that with neutral protamine Hagedorn (NPH) insulin in adults and in children and adolescents, and with continuous subcutaneous insulin infusion in adults. However, these same trials show a significantly lower risk for hypoglycemia with insulin glargine compared with NPH insulin in adults. PMID- 20969437 TI - Minimally invasive automated de-epithelization by precise ArF excimer laser ablation. AB - OBJECTIVE: Development of a robotic ArF excimer laser device with a three dimensional (3D) pattern scanning sensor for the controlled de-epithelization of live mouse and xenografted epidermis. SIGNIFICANCE: The animal model could be adapted to humans for automated, minimally invasive de-epithelization of cutaneous areas and therefore is of interest for cutaneous gene therapy research. MATERIALS AND METHODS: Ablation thresholds of mouse, porcine, and human skin were measured by acoustic detection methods. These ablation thresholds were used as initial parameters for dosimetry measurements. De-epithelization of live mouse and xenografted epidermis was performed by laser ablation (ArF excimer laser, lambda = 193 nm, t(p) = 20 nsec). The rectangular shape of the laser spot and a robotic arm displacement incorporating a three-dimensional patter scanning sensor allowed a polygonal tile floor irradiation of a 2-cm-diameter area. Ablated epidermis was subjected to histology. RESULTS: SCID and nude mouse skin did not entirely reflect the de-epithelization of human skin because abundant pockets of dermal keratinocytes persist in the outer root sheath of hair and cysts providing competitive foci of re-epithelization. Automated de-epithelization of human and porcine skin xenografts resulted in precise removal of keratinocytes with subcellular precision, providing a smooth live surface where epidermal transplants might engraft with little endogenous competition from residual outer root sheath from rare hairs. CONCLUSIONS: The displacement of the ArF excimer laser devices allows reproducible, smooth, and damage-free ablation of epidermal areas in the animal model. PMID- 20969438 TI - Influence of the light source and bleaching gel on the efficacy of the tooth whitening process. AB - OBJECTIVE: To examine the whitening efficacy of three whitening agents in combination with six different photoactivation systems. BACKGROUND: Bleaching techniques have achieved significant advances using photoactivation with coherent or incoherent radiation sources. METHODS: Quick White, Ena White Power, and Opalescence Endo bleaching agents, all containing 35% hydrogen peroxide, were stimulated with halogen lamp, light-emitting diode (LED), low-power diode laser, and neodymium: yttrium-aluminum-garnet (Nd:YAG), second harmonic of Nd:YAG, and Er:YAG lasers. One hundred twenty-six extracted human incisors were treated, and color change, pulpal temperature, and enamel morphological alterations were evaluated. RESULTS: Only the groups that were photoactivated using a diode laser, halogen lamp, and LED showed statistically significant differences (p < 0.005) in color change when compared with the control group (without photoactivation). All whitening protocols were safe with regard to the increase in pulpal temperature. Scanning electron microscopy showed no evidence of effects on the integrity of enamel. CONCLUSIONS: The source of irradiation is more relevant than the bleaching agent for efficient tooth whitening. In addition, photoactivation with LED was found to be the best choice: it yielded significant change in color with only a minor increase in pulpal temperature. PMID- 20969439 TI - Herpes virus reactivation by low-intensity diode and CO2 lasers. AB - BACKGROUND: The herpes virus enters into latency after symptomatic or asymptomatic herpetic infection. During latency, the virus has no impact on infected cells. However, internal or external stimuli, including certain lasers, can induce virus reactivation. OBJECTIVE: The aim was to study the reactivation power of the low-intensity diode and CO(2) lasers on the latent herpes virus. MATERIALS AND METHODS: The bovine herpesvirus 1 (BHV-1) was inoculated in either the nasal cavity or the lacrimal film of an animal model. Once the virus entered into latency, the trigeminal ganglia of animals were exposed to either a low intensity diode or CO(2) laser. The reactivation of the virus was then explored by PCR, RT-PCR, and dot-blot hybridization on nasal or lacrimal swabs. The accuracy, sensitivity, and specificity of the aforementioned techniques were compared. RESULTS: The low-intensity diode laser reactivated the herpes virus less than the CO(2) laser. The nasally inoculated virus was more liable for reactivation by both lasers. PCR was considered as the standard method for the detection of the reactivated virus. CONCLUSIONS: Low-intensity diode and CO(2) lasers can induce herpes virus reactivation, with the diode laser less likely to reactivate the virus than the CO(2) laser. PMID- 20969440 TI - Temperature increase beneath etched dentin discs during composite polymerization. AB - OBJECTIVE: The purpose of this in vitro study was to measure the temperature increase during the polymerization of a composite resin beneath acid-etched or laser-etched dentin discs. BACKGROUND DATA: The irradiation of dentin with an Er:YAG laser may have a positive effect on the thermal conductivity of dentin. This technique has not been studied extensively. MATERIALS AND METHODS: Forty dentin discs (5 mm in diameter and 0.5 or 1 mm in height) were prepared from extracted permanent third molars. These dentin discs were etched with 20% orthophosphoric acid or an Er:YAG laser, and were then placed on an apparatus developed to measure temperature increases. The composite resin was polymerized with a high-intensity quartz tungsten halogen (HQTH) or light-emitting diode unit (LED). The temperature increase was measured under the dentin disc with a J-type thermocouple wire that was connected to a data logger. Five measurements were made for each dentin disc, curing unit, and etching system combination. Differences between the initial and the highest temperature readings were taken, and the five calculated temperature changes were averaged to determine the value of the temperature increase. Statistical analysis was performed with a three-way ANOVA and Tukey HSD tests at a 0.05 level of significance. Further SEM examinations were performed. RESULTS: The temperature increase values varied significantly, depending on etching systems (p < 0.05), dentin thicknesses (p < 0.05), and curing units (p < 0.05). Temperature increases measured beneath laser etched discs were significantly higher than those for acid-etched dentin discs (p < 0.05). The HQTH unit induced significantly higher temperature increases than the LED unit (p < 0.05). The LED unit induced the lowest temperature change (5.2 degrees C) in the 1-mm, acid-etched dentin group. The HQTH unit induced the highest temperature change (10.4 degrees C) for the 0.5-mm, laser-etched dentin group. CONCLUSION: The risk of heat-induced pulpal damage should be taken into consideration during the polymerization of composite resin after laser etching when the dentin thickness is less than 0.5 mm. PMID- 20969441 TI - Pseudoepitheliomatous hyperplasia treated by photodynamic therapy with variable irradiation dose and concentration of photosensitizer. AB - OBJECTIVE: The aim of this study was to test the effectiveness of photodynamic therapy (PDT) in treating pseudoepitheliomatous hyperplasia (PEH) after skin wounding. BACKGROUND DATA: PEH is a difficult-to-treat extreme-degree acanthosis characterized by proliferation of the epithelium. Topical PDT offers an effective and non-invasive treatment for intraepithelial neoplasia and inflammatory dermatosis. These disorders and PEH show the same histological features: epidermal hyperplasia. To our knowledge, there have been no clinical trials published about therapeutic responses of PDT for PEH. MATERIALS AND METHODS: After application of 10-30% methyl aminolaevulinate (MAL) emulsion, each lesion was irradiated with 633-nm red light at a total dose of 113-339 J/cm(2). Therapeutic response was assessed by clinical examination at 3 months. RESULTS: Only 4 of 16 lesions clinically showed a minimal response. No response was observed in 12 of the 16 lesions, either with different cumulative doses or different concentrations of MAL. CONCLUSION: PEH after skin wounding responds poorly to the topical MAL-PDT. Besides removal of underlying diseases, surgical excision is still the recommended first option. PMID- 20969442 TI - Response of dental pulp cells to Er:YAG irradiation. AB - OBJECTIVE: This study aimed to investigate the response of human dental pulp cells lying on a thin dentin disc to Er:YAG irradiation. BACKGROUND DATA: Er:YAG laser irradiation has been effectively used for tooth cavity preparation with minimal damage to the dental pulp tissue. However, study of its direct effect on pulp cells has been limited. MATERIALS AND METHODS: Primary human dental pulp cells were cultured and allowed to grow on one side of 500-MUm-thick dentin discs. An Er:YAG laser at output energies of a 120, 300, or 500 mJ/pulse with a repetition rate of 10 Hz was used to ablate the non-cell surface of the dentin disc for 10 s with cooling irrigation. RESULTS: Twenty-four hours after laser irradiation, light and scanning electron micrographs revealed pulp cells with a normal fibroblastic morphology for the 120 and 300 mJ laser-treated groups. In the 500 mJ laser-treated group, many pyknotic cells with knob-like projections on the cell surface were mostly observed: the number of cells with normal morphology decreased compared to that of the other groups. However, the production of type I procollagen assessed by the enzyme immunoassay increased in the 500 mJ laser treated group significantly (p < 0.001). CONCLUSION: The low-energy Er:YAG laser (120 and 300 mJ at 10 Hz) with coolant irrigation did not cause damage to dental pulp cells at critical thickness (500 MUm) of dentin, whereas the laser of 500 mJ at 10 Hz induced greater production of type I procollagen with partial damage to the cells. PMID- 20969443 TI - The prevention of induced oral mucositis with low-level laser therapy in bone marrow transplantation patients: a randomized clinical trial. AB - BACKGROUND DATA AND OBJECTIVE: Patients who have received high doses of chemotherapy, either alone or in combination with total body irradiation often cite oral mucositis (OM) as the most debilitating side effect. The aim of this study was to investigate the clinical effects of low-level laser therapy (LLLT) on the prevention of conditioning-induced OM in hematopoietic stem cell transplantation (HSCT). METHODS: We randomized 42 patients who underwent autologous or allogeneic HSCT. A low-level InGaAlP diode laser was used, emitting light at 660 nm, 40 mW, and 4 J/cm(2). An evaluation of OM was carried out using the World Health Organization scale. RESULTS AND CONCLUSION: In the LLLT group, 57.1% of patients had an OM grade 0, 9.6% had grade 1, and 33.3% had grade 2, whereas in the control group, only 4.8% of patients were free of OM (grade 0). Our results indicate that the preventive use of LLLT in patients who have undergone HSCT is a powerful instrument in reducing OM incidence. PMID- 20969444 TI - Bond strength of resin cement to yttrium-stabilized tetragonal zirconia ceramic treated with air abrasion, silica coating, and laser irradiation. AB - OBJECTIVE: The purpose of this study was to evaluate the shear bond strength of a resin cement to yttrium-stabilized tetragonal zirconia (Y-TZP) surfaces treated with air abrasion, silica coating, or CO(2), Er:YAG, or Nd:YAG laser irradiation, or irradiated by each laser after air abrasion. BACKGROUND DATA: Optimized methods are needed to improve the adhesive bonding between resin cement and Y-TZP ceramic. METHODS: Twelve specimens were irradiated with each laser at different parameters and examined by scanning electron microscopy to determine which parameters to use in this study. One hundred forty-one Y-TZP discs were assigned to nine groups: C, no treatment; AA, air abrasion; CJ, silica coating; ER, Er:YAG laser; ND, Nd:YAG laser; CO, CO(2) laser; AA+ER, air abrasion + Er:YAG laser; AA+ND, air abrasion + Nd:YAG laser; AA+CO, air abrasion + CO(2) laser. The composite cylinders were fabricated. After the surface treatments, the specimens were silanized and composite cylinders were cemented with the resin cement. The shear bond strength test was performed after specimens were stored in water for 24 h and after thermocycling for 500 cycles. RESULTS: The highest bond strength was obtained in the AA group and was similar to that of the CJ group. In C, ER, CO, ND, AA+ND, and AA+CO groups, the shear bond strengths were similar to each other according to the Duncan test results. The lowest bond value was obtained in the AA+ER group. CONCLUSION: Although air abrasion and silica coating were the most effective surface treatment methods, CO(2) and Er:YAG laser irradiation alone or Nd:YAG laser irradiation after air abrasion may be used as an alternative treatment method to increase the bond strength between resin cement and Y-TZP material. PMID- 20969445 TI - Low-level laser therapy reduces delayed hypersensitivity reaction to ovalbumin in Balb/C mice. AB - The aim of this study was to evaluate the effect of low-level laser therapy (LLLT) in an experimental model of delayed hypersensitivity reaction (DTH). LLLT has been used clinically to treat numerous diseases and has been tested in different experimental models, but some of its effects have yet to be explained. We assessed the effects of LLLT on DTH to ovalbumin (OVA), a protein that has commonly been used as an antigen to sensitize laboratory animals. This experimental model is broadly used to assess the effects of substances that can potentially modulate the immune system and inflammatory reactions. Balb/C mice were randomly divided into four groups: (I) immunized, untreated, and challenged (n = 6); (II) not immunized, untreated, and challenged (n = 6); (III) immunized, treated with azathioprine (AZA), and challenged (n = 6); and (IV) immunized, treated with LLLT, and challenged (n = 6). Forty-eight hours after the challenge, the animals were submitted to a paw edema test and euthanized for histopathology analysis of their plantar pads. The results obtained in DTH units were as follows: Group I, 19.6 +/- 8.9; Group II, 5.8 +/- 2.6; Group III, 5.6 +/- 2.5; and Group IV, 5.2 +/- 2.6. DTH was less intense for the groups treated with AZA and laser compared with Group I (p < 0.05). We observed no statistical difference between the AZA- and LLLT-treated groups. The slides obtained from the footpad specimens showed that AZA and laser acted similarly on the normal pattern of DTH triggering. Our results suggest that treatment with LLLT has an immunomodulatory effect on DTH to OVA. PMID- 20969446 TI - Studies on function of P-glycoprotein in photodynamic therapy of endometriosis. AB - OBJECTIVE: The aim of the present study was to examine whether the effects of endometriosis-targeted photodynamic therapy (PDT), dependent on 5-aminolevulinic acid (ALA), rely on the presence of P-glycoprotein (P-gp), which is regarded as constituting one of the causes of multidrug resistance phenomenon. BACKGROUND: The significance of the undertaken studies reflects the complete absence of reports related to the modulation of P-gp activity and efficacy of PDT in patients with endometriosis. MATERIALS AND METHODS: Tissue samples of normal endometria were obtained from eight women after hysterectomy who were diagnosed with cervical intra-epithelial neoplasia. Fragments of ovarian endometriosis were obtained from 15 women. Epithelial cells were isolated from the material and in in vitro conditions were preincubated with P-gp blocker-verapamil-before ALA-PDT. The cytotoxicity was evaluated using the XTT test, allowing us to estimate cell growth inhibition. Statistical analysis of the results involved the nonparametric Wilcoxon paired rank test and the Mann-Whitney U-test using the Statistica v5 software (p < 0.05). In parallel, P-gp presence in the analyzed material was evaluated using immunohistochemistry. RESULTS: In normal endometrial epithelium, verapamil was shown to intensify phototoxic effects at 2 and 4 mmol/L ALA (p < 0.05). In endometriotic epithelium, such intensification was noted in all examined concentrations of ALA (p < 0.001). Moreover, the ectopic epithelial cells were more sensitive than eutopic epithelial cells to PDT upon ALA alone, as well as after preincubation with verapamil. Immunohistohemical analysis allowed us to demonstrate the absence of glycoprotein P in normal endometrium. In endometriosis, P-gp was localised in both the epithelium and the stroma of the examined material. CONCLUSION: Phototoxic effects could be amplified in epithelial cells of endometriotic foci by appropriate action of verapamil and 5 aminolevulinic acid. PMID- 20969447 TI - Effects of age and body mass on development of diving capabilities of gray seal pups: costs and benefits of the postweaning fast. AB - Development of adequate diving capabilities is crucial for survival of seal pups and may depend on age and body size. We tracked the diving behavior of 20 gray seal pups during their first 3 mo at sea using satellite relay data loggers. We employed quantile analysis to track upper limits of dive duration and percentage time spent diving, and lower limits of surface intervals. When pups first left the breeding colony, extreme (ninety-fifth percentile) dive duration and percentage time spent diving were positively correlated with age, but not mass, at departure. Extreme dive durations and percentage time spent diving peaked at [Formula: see text] d of age at values comparable with those of adults, but were not sustained. Greater peaks in extreme percentage time spent diving occurred in pups that had higher initial values, were older at their peak, and were heavier at departure. Pups that were smaller and less capable divers when they left the colony improved extreme dive durations and percentage time spent diving more rapidly, once they were at sea. Minimum survival time correlated positively with departure mass. Pups that were heavier at weaning thus benefitted from being both larger and older at departure, but smaller pups faced a trade-off. While age at departure had a positive effect on early dive performance, departure mass impacted on peak percentage time spent diving and longer-term survival. We speculate that once small pups have attained a minimum degree of physiological development to support diving, they would benefit by leaving the colony when younger but larger to maximize limited fuel reserves, rather than undergoing further maturation on land away from potential food resources, because poor divers may be able to "catch up" once at sea. PMID- 20969448 TI - Contrasted thermal regimes do not influence digestion and growth rates in a snake from a temperate climate. AB - Temperature influences almost all life-history traits. For a period of 3 mo, we placed four groups of snakes under four contrasted thermal treatments: (1) a natural regime (NR), based on daily variations (24-h cycle); (2) an accelerated regime (AR), where the thermoperiod fluctuated rapidly (12-h cycle); (3) a slow regime (SR; 48-h cycle); and (4) a cool stable regime (ZR; no fluctuation). The mean temperature, set at 23 degrees C, was identical for the four groups. For the first three groups (NR, AR, SR), ambient temperature fluctuated between 18 degrees C and 28 degrees C. Relative humidity and photoperiod were constant. We recorded feeding success, digestion efficiency, growth rate, activity, and ecdysis events. Differences between groups were expected because of varied exposure to the optimal temperatures, most notably in the ZR group, where the preferred body temperature for digestion (approximately 30 degrees C) would not be reached. Surprisingly, there was no significant effect of the experimental treatment on feeding rate, digestion, body mass increase, and growth rate. Our results do not conform to the paradigm stipulating that maximal body temperature selected by ectotherms necessarily corresponds to the most efficient for resource assimilation and that temperature fluctuations are essential. We propose that increasing the digestive tract's performance through body-temperature elevation trades off against elevated (parasite) energy expenditure from the rest of the body. The main advantage of high body temperatures would be to reduce the amount of time necessary to assimilate prey rather than to improve the net mass gain during digestion. PMID- 20969449 TI - Systematic review and cost analysis comparing use of chlorhexidine with use of iodine for preoperative skin antisepsis to prevent surgical site infection. AB - OBJECTIVE: To compare use of chlorhexidine with use of iodine for preoperative skin antisepsis with respect to effectiveness in preventing surgical site infections (SSIs) and cost. METHODS: We searched the Agency for Healthcare Research and Quality website, the Cochrane Library, Medline, and EMBASE up to January 2010 for eligible studies. Included studies were systematic reviews, meta analyses, or randomized controlled trials (RCTs) comparing preoperative skin antisepsis with chlorhexidine and with iodine and assessing for the outcomes of SSI or positive skin culture result after application. One reviewer extracted data and assessed individual study quality, quality of evidence for each outcome, and publication bias. Meta-analyses were performed using a fixed-effects model. Using results from the meta-analysis and cost data from the Hospital of the University of Pennsylvania, we developed a decision analytic cost-benefit model to compare the economic value, from the hospital perspective, of antisepsis with iodine versus antisepsis with 2 preparations of chlorhexidine (ie, 4% chlorhexidine bottle and single-use applicators of a 2% chlorhexidine gluconate [CHG] and 70% isopropyl alcohol [IPA] solution), and also performed sensitivity analyses. RESULTS: Nine RCTs with a total of 3,614 patients were included in the meta-analysis. Meta-analysis revealed that chlorhexidine antisepsis was associated with significantly fewer SSIs (adjusted risk ratio, 0.64 [95% confidence interval, [0.51-0.80]) and positive skin culture results (adjusted risk ratio, 0.44 [95% confidence interval, 0.35-0.56]) than was iodine antisepsis. In the cost-benefit model baseline scenario, switching from iodine to chlorhexidine resulted in a net cost savings of $16-$26 per surgical case and $349,904-$568,594 per year for the Hospital of the University of Pennsylvania. Sensitivity analyses showed that net cost savings persisted under most circumstances. CONCLUSIONS: Preoperative skin antisepsis with chlorhexidine is more effective than preoperative skin antisepsis with iodine for preventing SSI and results in cost savings. PMID- 20969451 TI - Triptorelin embonate: a 6-month formulation for prostate cancer. AB - IMPORTANCE OF THE FIELD: Luteinizing hormone releasing hormone (LH RH) agonists are the major agent for androgen deprivation therapy in advanced and metastatic prostate cancer. They also have a role in endometriosis, uterine fibroids and central precocious puberty. AREAS COVERED IN THE REVIEW: Triptorelin embonate 22.5 mg is a new, sustained-release, 6-month formulation of an LH RH agonist. It possesses longer duration of action than the current standard 3-month preparation and appears to have similar efficacy and side effects. WHAT THE READER WILL GAIN: The use of LH RH agonists for androgen deprivation in prostate cancer has increased considerably in the last 20 years. Recent work has shown that some of this usage has constituted overtreatment and it is within these newer paradigms of therapy that the new 6-month preparation is situated. TAKE HOME MESSAGE: The new 6-month LH RH preparation - triptorelin embonate - will be of help in several key areas of therapy for prostate cancer, notably as an adjunct to radiation therapy and chemotherapy. It possesses a similar effect, but with fewer side effects, than those that are now commonly available. PMID- 20969450 TI - Microdialysis for assessing intratumoral drug disposition in brain cancers: a tool for rational drug development. AB - IMPORTANCE OF THE FIELD: many promising targeted agents and combination therapies are being investigated for brain cancer. However, the results from recent clinical trials have been disappointing. A better understanding of the disposition of drug in the brain early in drug development would facilitate appropriate channeling of new drugs into brain cancer clinical trials. AREAS COVERED IN THIS REVIEW: barriers to successful drug activity against brain cancer and issues affecting intratumoral drug concentrations are reviewed. The use of the microdialysis technique for extracellular fluid (ECF) sampling and its application to drug distribution studies in brain are reviewed using published literature from 1995 to the present. The benefits and limitations of microdialysis for performing neuorpharmacokinetic (nPK) and neuropharmacodynamic (nPD) studies are discussed. WHAT THE READER WILL GAIN: the reader will gain an appreciation of the challenges involved in identifying agents likely to have efficacy in brain cancer, an understanding of the general principles of microdialysis, and the power and limitations of using this technique in early drug development for brain cancer therapies. TAKE HOME MESSAGE: a major factor preventing efficacy of anti-brain cancer drugs is limited access to tumor. Intracerebral microdialysis allows sampling of drug in the brain ECF. The resulting nPK/nPD data can aid in the rational selection of drugs for investigation in brain tumor clinical trials. PMID- 20969452 TI - Effect of microinjection of a single IVF-derived blastomere on the development of cloned embryos at the eight-cell stage in bovine. AB - This study was conducted to determine the effect of microinjection of a single blastomere from in vitro fertilization (IVF)-derived eight-cell embryo into eight cell cloned embryos harboring the gene encoding recombinant human lactoferrin (rhLF), GFP, and NEO markers in bovine. The reconstructed chimeric embryos were assessed for their development to blastocyst, or to term after transfer, and tissues of offspring were evaluated by polymerase chain reaction (PCR) for the presence of nuclear transfer (NT)-derived transgenic cells, and the cloned embryos without microinjection were used as controls. The chimeric embryos showed slightly higher blastocyst rate than that for controls. The single IVF-derived blastomere appeared to preferential contribute to inner cell mass (ICM) in the chimeric blastocysts. After transfer, the rates of development of chimeric embryos to day 60, to term, and to weaning were significantly higher than those of controls. Sixty-three chimeric blastocysts were transferred and 11 calves were born: 7 calves of them were dead, and the remaining 4 calves are apparently normal and healthy. Most of the tissues collected from dead fetus were transgenic, whereas NT-derived transgenic cells were not detected in some tissues of the living calves. Our results indicated that a single blastomere from IVF derived eight-cell embryo improves the in vivo developmental potential of transgenic cloned eight-cell embryos in bovine; however, the single IVF-derived blastomere appears to be better able to populate the ICM and many tissues of offspring than NT-derived blastomeres. PMID- 20969453 TI - Internet self-efficacy, the need for cognition, and sensation seeking as predictors of problematic use of the internet. AB - We conducted a study of the relationships between Internet self-efficacy, sensation seeking, the need for cognition, and problematic use of the Internet. The study was based on a randomly selected sample of 979 adult Internet users. Hierarchical multiple regression analysis of these subjects' responses on a questionnaire consisting of relevant items indicated that Internet self-efficacy and sensation seeking positively predicted problematic Internet use. Contrastingly, the need for cognition was significantly negatively associated with problematic Internet use. PMID- 20969454 TI - Handle with care: the impact of using Java applets in Web-based studies on dropout and sample composition. AB - In Web-based studies, Web browsers are used to display online questionnaires. If an online questionnaire relies on non-standard technologies (e.g., Java applets), it is often necessary to install a particular browser plug-in. This can lead to technically induced dropout because some participants lack the technological know how or the willingness to install the plug-in. In two thematically identical online studies conducted across two time points in two different participant pools (N = 1,527 and 805), we analyzed whether using a Java applet produces dropout and distortion of demographics in the final sample. Dropout was significantly higher on the Java applet questionnaire page than on the preceding and subsequent questionnaire pages. Age-specific effects were found only in one sample (i.e., dropouts were older), whereas sex-specific effects were found in both samples (i.e., women dropped out more frequently than men on the Java applet page). These results additionally support the recommendation that using additional technologies (e.g., Java applets) can be dangerous in producing a sample that is biased toward both younger and male respondents. PMID- 20969455 TI - Avatars and emotional engagement in asynchronous online communication. AB - The notion that an avatar can elicit a sense of emotional involvement or connection on the part of a user in asynchronous online communication was explored through a pair of content analyses of a popular online question-and answer bulletin board. In the first study, questions accompanied by an avatar not only received more answers than questions without an avatar, but the answers were more likely to be characterized by expressions of empathy. In the second study, a preference for answering questions accompanied by an avatar was found to be associated with interpersonal, altruistic motives for answering questions. Results are discussed in terms of presence and alternative explanations, as well as practical implications. PMID- 20969456 TI - Gasless laparoscopy-assisted versus open resection for gastrointestinal stromal tumors of the upper stomach: preliminary results. AB - INTRODUCTION: Gastrointestinal stromal tumors (GISTs) are rare neoplasms with malignant potential. Surgery is the definitive management for resectable nonmetastatic lesions. Although minimally invasive resection has been established for GISTs, it is still considered unfeasible when tumors are near the esophagogastric junction. This study aimed to compare the relative efficacy of gasless laparoscopy-assisted (GLA) and open approaches for resection of GISTs. PATIENTS AND METHODS: Between January 2006 and December 2008, 28 consecutive patients undergoing surgery for upper GIST were reviewed retrospectively. Among these patients, 15 underwent GLA procedures and 13 underwent open surgeries. RESULTS: Patient demographics, comorbidities, and tumor characteristics (mean tumor size and prognosis) were similar for both groups. All patients underwent wedge resection. The mean operating time (129.6 versus 110.8 minutes), mean estimated blood loss (35.5 versus 40.3 mL), mean day of first flatus (2.7 versus 3.2 days), mean tumor size (2.5 versus 2.6 cm), and tumor prognosis or complication rate (13.3% versus 7.7%) between the GLA and open surgery groups were not significantly different. The length of maximal wound (P < 0.001), visual analog scale on postoperative days 1 (P = 0.001), 2 (P = 0.001), and 3 (P = 0.001), the mean time for resuming oral intake (P = 0.028), and the length of hospital stay (P = 0.005) in the GLA group were significantly lesser than the corresponding values in the open surgery group. None of the patients had dysphagia or died. CONCLUSIONS: GLA method is a safe and feasible procedure for resecting GISTs of the upper stomach. In addition, it offers better cosmetic results, less pain, and faster recovery. PMID- 20969457 TI - Carotid intima media thickness, inflammatory markers, and endothelial activation markers in HIV Patients with lipoatrophy increased at 48 weeks regardless of use of rosiglitazone or placebo. AB - Rosiglitazone may be useful for the treatment of antiretroviral therapy associated lipoatrophy, but an association with cardiovascular disease (CVD) has been questioned in diabetics. We evaluated rosiglitazone's effect on surrogate markers of CVD in HIV-infected individuals with lipoatrophy. HIV(+) patients with lipoatrophy on thymidine-sparing regimens were randomized to rosiglitazone vs. placebo for 48 weeks. We serially assessed carotid IMT, fasting metabolic profiles, tumor necrosis factor (TNF)-alpha, soluble receptors (sTNFRI and II), interleukin (IL)-6, high-sensitivity C-reactive protein (hsCRP), myeloperoxidase (MPO), and endothelial activation markers [von Willebrand factor (vWF), soluble intercellular cell adhesion molecules-1 (sICAM-1), and vascular cell adhesion molecules-1 (sVCAM-1)]. Seventy-one subjects enrolled: 17% were female and 51%were white. Baseline characteristics were similar between groups except for higher total cholesterol in the placebo group (p = 0.04). At 48 weeks, common carotid artery (CCA) IMT changed significantly (p <= 0.05) within but not between the groups (p = 0.36): the median (IQR) increase was 0.10 (0.05, 0.25) mm and 0.15 (0, 0.25) mm in the rosiglitazone and placebo groups, respectively. hsCRP, sTNFRI and II, sVCAM-1, and vWF changed significantly (p <= 0.02) within but not between groups. Total cholesterol increased significantly in the rosiglitazone group (p = 0.008). In our study of virologically controlled subjects with lipoatrophy, rosiglitazone did not independently increase carotid IMT, endothelial activation, and inflammatory cytokines. PMID- 20969458 TI - May phylogenetic analysis support epidemiological investigation in identifying the source of HIV infection? PMID- 20969459 TI - Mapping of the self-interaction domains in the simian immunodeficiency virus Gag polyprotein. AB - To gain a better understanding of the assembly process in simian immunodeficiency virus (SIV), we first established the conditions under which recombinant SIV Gag lacking the C-terminal p6 domain (SIV GagDeltap6) assembled in vitro into spherical particles. Based on the full multimerization capacity of SIV GagDeltap6, and to identify the Gag sequences involved in homotypic interactions, we next developed a pull-down assay in which a panel of histidine-tagged SIV Gag truncation mutants was tested for its ability to associate in vitro with GST SIVGagDeltap6. Removal of the nucleocapsid (NC) domain from Gag impaired its ability to interact with GST-SIVGagDeltap6. However, this Gag mutant consisting of the matrix (MA) and capsid (CA) domains still retained 50% of the wild-type binding activity. Truncation of SIV Gag from its N-terminus yielded markedly different results. The Gag region consisting of the CA and NC was significantly more efficient than wild-type Gag at interacting in vitro with GST-SIVGagDeltap6. Notably, a small Gag subdomain containing the C-terminal third of the CA and the entire NC not only bound to GST-SIVGagDeltap6 in vitro at wild-type levels, but also associated in vivo with full-length Gag and was recruited into extracellular particles. Interestingly, when the mature Gag products were analyzed, the MA and NC interacted with GST-SIVGagDeltap6 with efficiencies representing 20% and 40%, respectively, of the wild-type value, whereas the CA failed to bind to GST SIVGagDeltap6, despite being capable of self-associating into multimeric complexes. PMID- 20969460 TI - Genotypic analysis of human immunodeficiency virus type 1 env V3 loop sequences: bioinformatics prediction of coreceptor usage among 28 infected mother-infant pairs in a drug-naive population. AB - We sought to predict virus coreceptor utilization using a simple bioinformatics method based on genotypic analysis of human immunodeficiency virus types 1 (HIV 1) env V3 loop sequences of 28 infected but drug-naive women during pregnancy and their infected infants and to better understand coreceptor usage in vertical transmission dynamics. The HIV-1 env V3 loop was sequenced from plasma samples and analyzed for viral coreceptor usage and subtype in a cohort of HIV-1-infected pregnant women. Predicted maternal frequencies of the X4, R5X4, and R5 genotypes were 7%, 11%, and 82%, respectively. Antenatal plasma viral load was higher, with a mean log(10) (SD) of 4.8 (1.6) and 3.6 (1.2) for women with the X4 and R5 genotypes, respectively, p = 0.078. Amino acid substitution from the conserved V3 loop crown motif GPGQ to GPGR and lymphadenopathy were associated with the X4 genotype, p = 0.031 and 0.043, respectively. The maternal viral coreceptor genotype was generally preserved in vertical transmission and was predictive of the newborn's viral genotype. Infants born to mothers with X4 genotypes were more likely to have lower birth weights relative to those born to mothers with the R5 genotype, with a mean weight (SD) of 2870 (+/-332) and 3069 (+/-300) g, respectively. These data show that at least in HIV-1 subtype C, R5 coreceptor usage is the most predominant genotype, which is generally preserved following vertical transmission and is associated with the V3 GPGQ crown motif. Therefore, antiretroviral-naive pregnant women and their infants can benefit from ARV combination therapies that include R5 entry inhibitors following prediction of their coreceptor genotype using simple bioinformatics methods. PMID- 20969461 TI - Single-setting laparoscopic approach to synchronous urologic tumors. AB - PURPOSE: To evaluate the feasibility and safety of two or three concomitant laparoscopic procedures in the same patient in one anesthesia session. PATIENTS AND METHODS: Data were reviewed for 32 patients for whom two or three concomitant laparoscopic surgeries at our institution were considered. Preoperative details, port position, surgical time, blood loss, complications, hospital stay, and postoperative recovery were analyzed. RESULTS: Thirty-two patients underwent two concomitant laparoscopic procedures and one patient three procedures. Surgical time was increased by 6 minutes because of the repositioning time of the patients. There were no complications during all procedures, and hospital stay was not increased, being limited only by the first procedure. CONCLUSION: Planned laparoscopic surgery for two or three urologic malignancies is feasible in one anesthesia session, thereby reducing cost and overall hospital stay for the patient without any increased risk of perioperative morbidity. The decision to continue with the second or the third procedures depends on the successful conclusion of the former procedures in a reasonable time and without any complications. PMID- 20969462 TI - Experimental model of upper-pole nephrectomy using human tridimensional endocasts: analysis of vascular injuries. AB - PURPOSE: The aim of the study is to establish an experimental model for upper pole nephrectomy using tridimensional endocasts of human kidneys. MATERIALS AND METHODS: We studied 104 kidneys from 52 adults. The ureters, veins, and arteries were dissected and injected with yellow, blue, and red polyester resin, respectively. While this resin was still in the gel state, we performed upper pole guillotine sections at various distances from the hilar zone, thereby dividing our sample in four groups: A. Hilar zone: 22 kidneys (10 with vein and ureter injection); B. 0.5 cm from the hilar zone, 32 kidneys (9 with vein and ureter); C. 1.0 cm from the hilar zone, 24 kidneys (11 with vein and ureter); and D. 1.5 cm from the hilar zone, 26 kidneys (6 with vein and ureter). We also determined the mean distance from the retropelvic artery to the section plane. RESULTS: Sections performed at the hilar region and at 0.5 cm from hilar region had an alarming rate of injuries to the retropelvic artery and vein, upper segmental artery, and upper venous trunk. In both groups, the distance between the section plane and retropelvic artery was a mean less than 1.0 cm. Sections performed at 1.0 cm and at 1.5 cm from the hilar region had a significantly lower injury rate, with mean distance between section plane and retropelvic artery more than 1.0 cm. CONCLUSIONS: Upper-pole nephrectomies performed at less than 1.0 cm from the hilar zone had a significantly high incidence of injuries in larger arteries. Nephrectomies at this level should therefore be avoided or performed with maximum care. PMID- 20969463 TI - Factors associated with sexually transmitted infection testing among men who utilize an internet-based men who have sex with men community. AB - Public health messaging encourages men who have sex with men (MSM) to be tested for sexually transmitted infections (STI) and HIV at least yearly, and more frequently depending on sexual behaviors. However, despite engaging in a range of sexual behaviors, many MSM do not participate in regular STI testing. The objective of this study was to understand factors associated with STI testing among a nonclinic-based population of men accessing an Internet-based social and sexual networking site. We asked 25,736 men to complete a comprehensive behavioral and health assessment after being recruited from an Internet site popular among men seeking social or sexual interactions with other men. Analyses were performed using multivariate logistic regression with effects significant at p < 0.05. Two separate predictive models were assessed: STI diagnosis within the past 2 years and STI testing within the past year. Regarding previous STI diagnosis, men who used a condom some of the time or never during both insertive (odds ratio [OR] = 1.72) and receptive (OR = 1.41) anal sex were significantly more likely to have had an STI in the past 2 years. For STI testing, men who never used condoms during receptive anal sex were more likely to have had an STI test within the past year (OR = 1.31), but men who had a STI history were less likely to have been tested (O = 0.24). Public health efforts directed toward MSM should continue to emphasize screening for STI other than HIV, particularly among those men prioritized during condom promotion campaigns. In addition to the benefits of learning one's STI status, the STI screening and treatment environment itself may provide an important venue for encouraging a range of sexual health promoting behaviors. PMID- 20969464 TI - Noncirrhotic portal hypertension in HIV-infected patients: a case control evaluation and review of the literature. AB - Idiopathic noncirrhotic portal hypertension (NCPH) is an infrequent but possibly underestimated cryptogenetic liver disease recently described in small series of HIV-infected patients. The exposure to antiretroviral drugs, a direct role of HIV itself, microbial translocation from the gut, or a thrombophilic propensity have been suggested as possible pathogenic mechanisms. In this case control study, we describe 11 HIV-infected patients with idiopathic NCPH and compare the activity of protein C and S, and soluble CD14 levels (a surrogate marker of the translocation of intestinal bacterial products) with 10 age- and gender-matched HIV-infected controls with no liver disease. The clinical presentation of the 11 patients with NCPH was characterised by acute variceal bleeding (2/11), ascites (2/11), portal thrombosis (2/11), and ultrasonographic and endoscopic signs of portal hypertension (11/11), with slightly high alanine transaminase (ALT) and gammaglutamyl transpeptidase (gamma-GT) levels. The FibroScan median liver stiffness was 8.1 kPa, which is inconsistent with significant fibrosis, and nodular regenerative hyperplasia was diagnosed in the 5 patients who underwent liver biopsy. The NCPH patients showed no impairment of hepatic synthesis, but had lower serum albumin levels and a higher international normalized ratio (INR) than the controls (p = 0.01), and lower protein C and S activity, although within the normal range (p = 0.02 and 0.3, respectively). No significant difference in soluble CD14 was seen between the two groups. In conclusion, the etiology of NCHP is not still established, but in order to prevent the dramatic complications of portal hypertension, all HIV-infected patients with unexplained liver enzyme abnormalities or thrombocytopenia should be considered for further investigations by means of thrombophilic screening, Doppler ultrasound evaluation, and in the presence of portal hypertension, endoscopy and liver biopsy. PMID- 20969465 TI - Mortality after diagnosis of psychiatric disorders and co-occurring substance use disorders among HIV-infected patients. AB - We examined the associations between psychiatric diagnoses, substance use disorders, health services, and mortality among 9751 HIV-infected patients (>=14 years old) in a large, private medical care program, in a retrospective cohort design over a 12-year period. All study data were extracted from computerized clinical and administrative databases. Results showed that 25.4% (n = 2472) of the 9751 study subjects had received a psychiatric diagnosis (81.1% had major depression, 17.1% had panic disorder, 14.2% had bipolar disorder, and 8.1% had anorexia/bulimia); and 25.5% (n = 2489) had been diagnosed with substance use disorder; 1180 (12.1%) patients had received both psychiatric and substance diagnoses. In comparison to patients with neither a psychiatric diagnosis nor a SU diagnosis, the highest risk of death was found among patients with dual psychiatric and substance use diagnoses who had no psychiatric treatment visits and no substance treatment (relative hazards [RH] = 4.17, 95% confidence interval [CI] = 2.35 to 7.40). Among dually diagnosed patients, receiving psychiatric and/or substance use disorder treatment somewhat reduced the risk of death compared to patients with neither diagnosis. The lowest risks of death were observed among patients with a single diagnosis who had received corresponding treatment. Our study findings suggest that screening for psychiatric and substance problems at the initiation and during the course of HIV/AIDS treatment and providing psychiatric and substance use disorder treatment may extend life for these vulnerable patients. PMID- 20969466 TI - Hepatocellular carcinoma in a teenager with perinatally acquired HIV Infection without hepatitis B or C coinfection: a case report. AB - A 19-year-old male with perinatally acquired HIV infection and AIDS (clinical stage 3) presented with a 9.1 * 5.0 cm hepatic mass. The resected mass was determined to be a hepatocellular carcinoma (HCC) without metastasis. The patient did not have active hepatitis B or C coinfection, as revealed by polymerase chain reaction (PCR), nor other risk factors for development of cirrhosis or HCC, and comprises only the second explicitly stated case of an HIV-positive individual developing HCC in the absence of concomitant hepatitis virus infection or other risk factors. This case illustrates the fact that as survival of perinatally infected individuals increases in the highly active antiretroviral therapy (HAART) era, new associations between HIV infection and other disease processes may be uncovered. PMID- 20969467 TI - Methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization predicts intensive care unit-acquired MRSA infections: true or false? PMID- 20969468 TI - Nasal swabs collected routinely to screen for colonization by methicillin resistant Staphylococcus aureus in intensive care units are a sensitive screening test for the organism in clinical cultures. AB - BACKGROUND: Many hospitals screen patients for methicillin-resistant Staphylococcus aureus (MRSA) on admission to the intensive care unit (ICU). We hypothesized that this screening information could be used to assist with empiric antibiotic decisions. METHODS: The medical records of patients admitted to a university-affiliated community hospital as well as a tertiary-care university hospital were reviewed. Patients admitted to the ICU were screened for MRSA colonization with a nasal swab that was analyzed with either chromogenic medium (hospital 1) or polymerase chain reaction (PCR) (hospital 2). The results of the nasal swab were compared with clinical culture results. RESULTS: There were 141 patients, and 167 cultures were obtained. The majority of the cultures (70%) were performed on sputum specimens in an effort to diagnose pneumonia. The remaining cultures were performed on blood (10.1%), incisions (21.5%), and urine (3.4%). The overall sensitivity of nasal swab results was 69.5%. However, the sensitivity was significantly higher for nasal swab screening performed within six days of clinical cultures compared with screening performed seven days or more before cultures were obtained. (79% vs. 46%; p < 0.0001). Sensitivity also differed significantly depending on the surveillance method, being significantly higher among patients screened with PCR within six days of developing an infection than in patients screened with chromogenic medium (88% vs. 65.5%; p = 0.006). CONCLUSION: Screening with PCR analysis of nasal swab specimens is a highly sensitive test for MRSA in clinical cultures. Clinicians may be able to use the swab results to tailor more appropriate empiric antimicrobial regimens. The results with chromogenic medium screening are markedly poorer, which suggests that clinicians should view them with caution. PMID- 20969469 TI - Neutrophil elastase inhibitor restores gut ischemia reperfusion-induced impairment of gut immunity with reduced plasma interleukin-6 concentrations in mice. AB - BACKGROUND AND PURPOSE: Gut-associated lymphoid tissue (GALT) is regarded as central mucosa-associated lymphoid tissue that influences systemic mucosal immunity. Our previous study revealed that gut ischemia and reperfusion (I/R) reduces GALT lymphocyte numbers. Because gut hypoperfusion frequently occurs in trauma, shock, and surgery patients, establishment of a therapeutic method to preserve GALT mass after gut I/R may be important for the prevention of infections. We examined the effects of sivelestat sodium hydrate, a selective inhibitor of neutrophil elastase, on GALT mass and plasma cytokine concentrations in a murine gut I/R model. METHODS: Seventy male ICR mice were randomized to the control (n = 34) or the sivelestat (n = 36) group. After intravenous cannulation of the animals, the superior mesenteric artery was occluded for 60 min. After reperfusion, physiologic saline or sivelestat 5 mg/kg hourly was infused for 24 h. Sixteen mice in the control and 22 in the sivelestat group were alive at 24 h. Twenty-six mice (n = 13 in each group) were chosen randomly for harvest of the small intestine. Lymphocytes from Peyer patches (PP), the intraepithelial space (IE), and the lamina propria (LP) were counted; and their phenotypes (alphabetaT cell receptor (TCR), gammadeltaTCR, CD4, CD8, B cell) were determined by flow cytometry. Cytokine concentrations (interleukin [IL]-6, IL-1beta, IL-10) in the plasma and bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay. RESULTS: Sivelestat treatment did not improve survival but increased PP and IE lymphocyte numbers significantly and reduced the LP CD8(+) cell percentage and plasma IL-6 concentration compared with controls. There were no significant differences between the two groups in other cell phenotypes or cytokine concentrations. CONCLUSION: Sivelestat treatment after gut I/R may be useful for maintaining gut immunity and preventing systemic inflammatory responses. PMID- 20969470 TI - Fascia-to-fascia closure with abdominal topical negative pressure for severe abdominal infections: preliminary results in a department of general surgery and intensive care unit. AB - BACKGROUND: Vacuum-assisted fascial closure (VAFC-KCI((r))) of an open abdomen is one of the latest methods. METHODS: A prospective observational study was performed with medical records of nine patients who had been treated by abdominal VAFC-KCI((r)) from March 2006 to October 2007 in the Department of Surgical Sciences, University of Insubria. The mean Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were 22.62 and 10.62, respectively. All patients had abdominal compartment syndrome and a sepsis source that was difficult to control. RESULTS: All patients survived. The mean duration of open abdomen was 22.7 days (range, 3-50 days). Primary fascial closure was possible in six patients (66%), with a closure rate of 100% when early control of the infectious source was possible (Group A) but only 40% in patients with difficult and delayed control of infection (Group B). The mean durations of open abdomen in the two groups were statistically different: 8.5 days for Group A vs. 34.2 days for Group B (p < 0.005; Student t-test). CONCLUSIONS: In our brief experience, VAFC-KCI((r)) seems to be associated with a high fascial closure rate. The complexity of the management of abdominal source control has a role in the success of primary fascial closure. The VAFC-KCI((r)) system seems to contribute positively in fascia-to-fascia abdominal closure in cases of severe abdominal infection, in particular when early surgical source control is obtained. PMID- 20969471 TI - Catheter-related vs. catheter-associated blood stream infections in the intensive care unit: incidence, microbiology, and implications. AB - BACKGROUND: Catheter-associated blood stream infections (CA-BSI) and catheter related blood stream infections (CR-BSIs) differ in the degree of proof required to show that the catheter is the cause of the infection. The U.S. Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN; formerly the National Nosocomial Infections Surveillance [NNIS] group) collects data regarding CA-BSI nationally. We hypothesized that there would be a significant difference in the rates reported according to the definition. METHODS: Prospective surveillance of CA-BSI (defined as bacteremia with no extravascular source identified) is performed in all intensive care units (ICUs) at our institution and reported as the rate per 1,000 catheter-days. In January 2006, we initiated cultures of all catheter tips to evaluate for CR-BSI (defined as a catheter tip culture with >15 colony-forming units of the same microorganism(s) found in the blood culture) in the surgical, trauma-burn, and medical ICUs. RESULTS: The CA-BSI rate across all ICUs for the 24-mo study period was 1.4/1,000 catheter-days. The CR-BSI rate was 0.4/1,000 catheter days, for a rate difference of 1.0 infections/1,000 catheter-days (p < 0.001 vs. CA-BSI). The pathogens identified in CA-BSI included many organisms that are not associated with catheter-related BSIs. CONCLUSIONS: The CR-BSI rate is significantly lower than the CA-BSI rate. The organisms identified in CA-BSI surveillance often are not common in catheter-related infections. Reporting CR-BSI thus is a more accurate measure of complications of central venous catheter use, and this rate may be more sensitive to catheter-specific interventions designed to reduce rates of BSI in the ICU. PMID- 20969472 TI - Perioperative use of antibiotics in intra-abdominal surgical infections. AB - BACKGROUND: We created a questionnaire with the aim of evaluating surgeon compliance with the guidelines for antibiotic use in the perioperative period in intra-abdominal surgical infections. We discuss the problems emerging from non adherence to these guidelines. METHODS: In the questionnaire, we tried to correlate the type of intra-abdominal infection with: (1) Time of antibiotic administration commencement; (2) type of antibiotic(s) administered; (c) duration of antibiotic administration; and (4) modification of antibiotic type/duration of administration in the presence of factors increasing the risk of treatment failure. In order to collect and process the data more easily, the patients were divided into four groups-Group A: Community patients with intra-abdominal surgical infections and simple contamination of the peritoneal cavity according to the Surgical Infection Society (SIS) guidelines; Group B: Community patients with an intra-abdominal surgical infection evolving to secondary peritonitis per SIS guidelines; Group C: Community patients with an intra-abdominal surgical infection with a high risk of surgical site infection; and Group D: Patients with recent hospitalization or nosocomial or postoperative intra-abdominal infection. RESULTS: The questionnaire was sent to the directors of 43 surgical clinics in northern Greece, and 27 answered (63%). In 81.5% of the clinics (median 22; range 15-24), depending on the type of infection, empirical antibiotic treatment commenced preoperatively. In Group A, on average, 29.6% of the clinics (median 8; range 5-16) administer antibiotics for as long as 24 h, and 11.1% (median 3; range 1-10) use antibiotics not recommended in the SIS guidelines (e.g., third- and fourth-generation cephalosporins, ciprofloxacin, imipenem-cilastatin, meropenem, or piperacillin/tazobactam). In Group B, 22.2% of clinics (median 6; range 2-15) administer antibiotics for three to five days, and 14.8% (median 4; range 1-11) use antibiotics outside SIS guidelines. In Group C, 40.7% of clinics (median 11; range 1-14) administer antibiotics for more than five days, and 14.8% (median 4; range 1-14) use antibiotics that are outside the SIS guidelines. In Group D, 11.1% of clinics (median 3; range 2-5) do not cover Enterococcus with the antibiotics administered. CONCLUSIONS: There seems to be confusion in determining the situations with simple contamination of the peritoneal cavity, whose treatment requires short-duration antibiotic administration, and in the type of antibiotics administered to various patient groups, elements that lead to prolonged or erroneous administration of antibiotic drugs. Continuous discussion and surgeon training is imperative and may be the best choice to ensure familiarity with antibiotics and their proper use and thus to minimize serious adverse events and treatment failure. PMID- 20969473 TI - Bacillus species infective arthritis after knee arthroscopy. AB - BACKGROUND: Bacillus species infection of the joints is a very rare occurrence, with sporadic reports in the medical literature. CASE REPORT: A 67-year-old woman with osteoarthritis developed infection in the knee joint after arthroscopy. Percutaneous needle aspiration of articular fluid performed post-operatively showed a positive culture for Bacillus species. The diagnosis of septic arthritis was, however, not confirmed as the results were considered contamination. Failure of treatment with beta-lactam antibiotics on two occasions and successful cure of infective arthritis by long-term administration of a fluoroquinolone confirmed iatrogenic clinical joint infection with Bacillus species. CONCLUSION: Any clinically suspected joint infection must be treated as septic arthritis until proved otherwise. PMID- 20969474 TI - Staphylococcus xylosus isolated from an otogenic brain abscess in an adolescent. PMID- 20969475 TI - Redox balance in the pathogenesis of nonalcoholic fatty liver disease: mechanisms and therapeutic opportunities. AB - Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease in the world. It encompasses a histological spectrum, ranging from simple, nonprogressive steatosis to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis and hepatocellular carcinoma. While liver-related complications are confined to NASH, emerging evidence suggests both simple steatosis and NASH predispose to type 2 diabetes and cardiovascular disease. The pathogenesis of NAFLD is currently unknown, but accumulating data suggest that oxidative stress and altered redox balance play a crucial role in the pathogenesis of steatosis, steatohepatitis, and fibrosis. We will examine intracellular mechanisms, including mitochondrial dysfunction and impaired oxidative free fatty acid metabolism, leading to reactive oxygen species generation; additionally, the potential pathogenetic role of extracellular sources of reactive oxygen species in NAFLD, including increased myeloperoxidase activity and oxidized low density lipoprotein accumulation, will be reviewed. We will discuss how these mechanisms converge to determine the whole pathophysiological spectrum of NAFLD, including hepatocyte triglyceride accumulation, hepatocyte apoptosis, hepatic inflammation, hepatic stellate cell activation, and fibrogenesis. Finally, available animal and human data on treatment opportunities with older and newer antioxidant will be presented. PMID- 20969476 TI - DJ-1 cleavage by matrix metalloproteinase 3 mediates oxidative stress-induced dopaminergic cell death. AB - Oxidative stress is commonly implicated in aging and neurodegenerative conditions such as Parkinson's disease (PD). Mutations in DJ-1 are associated with autosomal recessive early-onset PD. We investigated whether DJ-1 can be degraded in oxidative-stressed dopaminergic neuronal cells, leading to loss of its protective role against oxidative stress. We have shown previously and herein that the active form of matrix metalloproteinase-3 (MMP3) was accumulated in dopamine producing CATH.a cells in the presence of MPP(+). We show that catalytically active MMP3 cleaved DJ-1, and impaired its antioxidant function. In CATH.a cells, both monomeric and dimeric forms of DJ-1 were diminished in the presence of MPP(+), and this was reversed by MMP3 knockdown or inhibition. While DJ-1 expression was decreased in the substantia nigra of mice administered with MPTP, its degradation was largely attenuated in MMP3 knockout mice. The AKT-signaling pathway, thought to mediate the effect of DJ-1 on cell survival, was also altered. MPP(+) caused decrease in both phospho-Thr308 and phospho-Ser473 forms of AKT, and this was restored by NNGH. Our data suggest that DJ-1 is fragmented by the intracellular MMP3 in response to cell stress, abolishing the protective role of DJ-1 against oxidative damage, and this contributes to the pathogenesis of PD. PMID- 20969477 TI - The regulation of erythropoiesis by selenium in mice. AB - Redox modulation by antioxidants, such as selenium (Se), has emerged as an important regulator of erythropoiesis. Using Se-deficient (0.04 ppm), Se-adequate (0.1 ppm), and Se-supplemented (0.4 ppm) C57/BL6 mice, we show that Se deficiency caused anemia, when compared to the Se-supplemented and Se-adequate groups. Increased denaturation of hemoglobin, methemoglobin, protein carbonyls, lipid peroxidation, Heinz bodies, and osmotic fragility of erythrocytes were observed in Se-deficient mice. Increased oxidative stress upregulated forkhead transcription factor (FoxO3a) and hypoxia-inducible factor-(HIF)1alpha in the spleen and kidney of Se-deficient murine as well as in the proerythroblast G1E cells cultured in Se-deficient media. A significant increase in the expression of erythropoietin, a downstream target of HIF1alpha, and expansion of stress erythroid progenitors (burst forming units-erythroid) were seen in the Se deficient mice. Despite the increase in erythroid progenitors, lowered reticulocytes suggest a defective erythroid differentiation pathway. While Se deficiency led to increased nuclear levels of active FoxO3a, Se-adequate conditions reversed this effect and increased nuclear export by its binding partner, 14-3-3betazeta, that is under the redox control of selenoproteins. In summary, these results provide insight into the importance of adequate Se nutrition in regulating red cell homeostasis by mitigating oxidative stress dependent modulation of FoxO3a and HIF1alpha to effect differentiation of erythroid progenitors. PMID- 20969479 TI - Redox pioneer: professor Barry Halliwell. AB - Professor Barry Halliwell is recognized as a Redox Pioneer because he has published eight articles on redox biology that have been each cited more than 1000 times, and 158 articles that have been each cited more than 100 times. His contributions go back as far as 1976, when he was involved in elucidation of the Foyer-Halliwell-Asada cycle, an efficient mechanism for preventing oxidative damage to chloroplasts. His subsequent work established the important role of iron and zinc in free radical reactions and their relevance to human pathologies. Professor Halliwell is also a leader in developing novel methodology for detecting free radical intermediates in vivo, and his contributions to our knowledge of reactive nitrogen species are highly significant. His sustained excellence won him the top-cited scientist award in the United Kingdom in biomedical sciences in 1999, and in 2003 he was recognized as a highly cited scientist by Institute of Scientific Information (ISI) for work on plant antioxidants, and the same year ranked 28 out of 5494 biochemists/biologists for scientific impact. Two pieces of his scholarly work have been listed as Citation Classics by ISI, and in 2007 his laboratory was ranked number 1 worldwide based on highest citation score in research on free radicals. PMID- 20969480 TI - Apoptosis signaling kinases: from stress response to health outcomes. AB - Apoptosis is a highly regulated process essential for the development and homeostasis of multicellular organisms. Whereas caspases, a large family of intracellular cysteine proteases, play central roles in the execution of apoptosis, other proapoptotic and antiapoptotic regulators such as the members of the Bcl-2 family are also critically involved in the regulation of apoptosis. A large body of evidence has revealed that a number of protein kinases are among such regulators and regulate cellular sensitivity to various proapoptotic signals at multiple steps in apoptosis. However, recent progress in the analysis of these apoptosis signaling kinases demonstrates that they generally act as crucial regulators of diverse cellular responses to a wide variety of stressors, beyond their roles in apoptosis regulation. In this review, we have cataloged apoptosis signaling kinases involved in cellular stress responses on the basis of their ability to induce apoptosis and discuss their roles in stress responses with particular emphasis on health outcomes upon their dysregulation. PMID- 20969478 TI - High-mobility group box 1, oxidative stress, and disease. AB - Oxidative stress and associated reactive oxygen species can modify lipids, proteins, carbohydrates, and nucleic acids, and induce the mitochondrial permeability transition, providing a signal leading to the induction of autophagy, apoptosis, and necrosis. High-mobility group box 1 (HMGB1) protein, a chromatin-binding nuclear protein and damage-associated molecular pattern molecule, is integral to oxidative stress and downstream apoptosis or survival. Accumulation of HMGB1 at sites of oxidative DNA damage can lead to repair of the DNA. As a redox-sensitive protein, HMGB1 contains three cysteines (Cys23, 45, and 106). In the setting of oxidative stress, it can form a Cys23-Cys45 disulfide bond; a role for oxidative homo- or heterodimerization through the Cys106 has been suggested for some of its biologic activities. HMGB1 causes activation of nicotinamide adenine dinucleotide phosphate oxidase and increased reactive oxygen species production in neutrophils. Reduced and oxidized HMGB1 have different roles in extracellular signaling and regulation of immune responses, mediated by signaling through the receptor for advanced glycation end products and/or Toll like receptors. Antioxidants such as ethyl pyruvate, quercetin, green tea, N acetylcysteine, and curcumin are protective in the setting of experimental infection/sepsis and injury including ischemia-reperfusion, partly through attenuating HMGB1 release and systemic accumulation. PMID- 20969481 TI - Membrane topology and mutational analysis of Mycobacterium tuberculosis VKOR, a protein involved in disulfide bond formation and a homologue of human vitamin K epoxide reductase. AB - We have presented evidence that a homologue of vertebrate membrane protein vitamin K epoxide reductase (VKOR) is an important component of the protein disulfide bond-forming pathway in many bacteria. Bacterial VKOR appears to take the place of the nonhomologous DsbB found in Escherichia coli. We also determined the structure of a VKOR from a Cyanobacterium and showed that two or four conserved cysteines are required, according to different reductants for activity in an in vitro assay. Here we present evidence for the topologic arrangement in the cytoplasmic membrane of the VKOR from Mycobacterium tuberculosis (Mtb). The results show that Mtb VKOR is a membrane protein that spans the membrane 5 times with its N-terminus in the cytoplasm, C-terminus in the periplasm, and all four cysteines facing the periplasm. The essentiality of the four conserved cysteine residues has also been demonstrated in promoting disulfide bond formation in vivo and a mixed disulfide between a cysteine of DsbA of E. coli, and one of the cysteines (Cys(57)) of the VKOR homologue has been identified to be a likely intermediate in the disulfide bond-forming pathway. These studies may inform future resolution of issues surrounding the functioning of human VKOR. PMID- 20969482 TI - Identification of three immunologic correlates for HIV type 1 pathogenesis in youth. AB - To evaluate the stability and heterogeneity of cytokine and chemokine profiles in 80 youth with and without HIV-1 infection, we tested plasma samples at repeated visits without antiretroviral therapy. Among nine analytes that were quantified using multiplexing assays, interleukin 10 (IL-10), IL-18, and soluble CD30 persistently showed a positive correlation with HIV-1 viral load (Spearman rho = 0.40-0.59, p < 0.01 for all). A negative correlation with CD4(+) T cell counts (rho = -0.40 to -0.60, p < 0.01 for all) was also persistent for the three analytes. Analyses restricted to 48 AIDS-free youth (96 visits) yielded similar findings, as did multivariable models in which race, sex, age, body mass index, and time interval between visits were treated as covariates. These relationships reflected two novel features observed for all three analytes. First, their presence in plasma was relatively stable between visits (rho = 0.50-0.90, p < 0.03), regardless of HIV-1 infection status. Second, pairwise correlation was strong and persistent in HIV-1-seropositive youth (rho = 0.40-0.59, p < 0.01), but not in HIV-1, seronegatives (p > 0.13). Additional analytes, especially eotaxin/CCL11 and SDF-1beta/CXCL12, had no correlation with HIV-1-related outcomes despite their stability between visits. Overall, circulating IL-10, IL 18, and soluble CD30 could partially track unfavorable responses to HIV-1 infection in youth. These markers of persistent immune activation are individually and collectively indicative of HIV-1 pathogenesis. PMID- 20969484 TI - Structure-based insights into the catalytic power and conformational dexterity of peroxiredoxins. AB - Peroxiredoxins (Prxs), some of nature's dominant peroxidases, use a conserved Cys residue to reduce peroxides. They are highly expressed in organisms from all kingdoms, and in eukaryotes they participate in hydrogen peroxide signaling. Seventy-two Prx structures have been determined that cover much of the diversity of the family. We review here the current knowledge and show that Prxs can be effectively classified by a structural/evolutionary organization into six subfamilies followed by specification of a 1-Cys or 2-Cys mechanism, and for 2 Cys Prxs, the structural location of the resolving Cys. We visualize the varied catalytic structural transitions and highlight how they differ depending on the location of the resolving Cys. We also review new insights into the question of how Prxs are such effective catalysts: the enzyme activates not only the conserved Cys thiolate but also the peroxide substrate. Moreover, the hydrogen bonding network created by the four residues conserved in all Prx active sites stabilizes the transition state of the peroxidatic S(N)2 displacement reaction. Strict conservation of the peroxidatic active site along with the variation in structural transitions provides a fascinating picture of how the diverse Prxs function to break down peroxide substrates rapidly. PMID- 20969485 TI - What is the significance of soluble and endogenous secretory receptor for advanced glycation end products in liver steatosis in obese prepubertal children? AB - The endogenous secretory receptor for advanced glycation end products (esRAGE) and soluble RAGE (sRAGE) have been shown in human plasma and have emerged as reliable biomarkers of several pathological conditions, including insulin resistance and liver injury. We examined esRAGE and sRAGE levels in obese prepubertal children with and without liver steatosis. esRAGE and sRAGE levels were significantly lower in obese prepubertal children affected by liver steatosis and were independently related to liver steatosis. These findings suggest that AGE-RAGE pathway plays an independent role in the development of liver injury already present in this age group. PMID- 20969483 TI - Implications of HIV PrEP trials results. AB - Abstract Six randomized clinical trials have been implemented to examine the efficacy of tenofovir disoproxil fumarate (TDF) and/or TDF/emtricitabine (TDF/FTC) as preexposure prophylaxis for HIV-1 infection (PrEP). Although largely complementary, the six trials have many similar features. As the earliest results become available, an urgent question may arise regarding whether changes should be made in the conduct of the other trials. To consider this in advance, a Consultation on the Implications of HIV Pre-Exposure Prophylaxis (PrEP) Trials Results sponsored by the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and the Bill and Melinda Gates Foundation (BMGF) was held on January 29, 2010, at the Natcher Conference Center, NIH, Bethesda, MD. Participants included basic scientists, clinical researchers (including investigators performing the current PrEP trials), and representatives from the U.S. Food and Drug Administration (FDA) and the agencies sponsoring the trials: the U.S. Centers for Disease Control and Prevention (CDC), the U.S. Agency for International Development (USAID), the BMGF, and the U.S. NIH. We report here a summary of the presentations and highlights of salient discussion topics from this workshop. PMID- 20969486 TI - Current and future directions of pharmacokinetic and pharmacokinetic pharmacodynamic modelling and simulation: population approach group in Europe 19th annual meeting. AB - The Population Approach Group in Europe meeting is the annual meeting of a group of scientists interested in quantitative pharmacology approaches. This meeting provides insights on new modelling approaches and applications thereof in different therapeutic areas and in different phases of drug development, in which modelling and simulation is set 'at work'. These meeting highlights mainly focus on the contributions pertinent to this journal, such as physiology-based pharmacokinetic modelling, modelling of pharmacokinetic-pharmacodynamic relationships (including binary/categorical end points) in non-clinical studies and also include presentations of junior scientists in the annual Lewis Sheiner Student Session. PMID- 20969487 TI - Content validation of a Danish version of "The McGill Ingestive Skills Assessment" for dysphagia management. AB - This study addresses the first steps in the cross-cultural adaptation of a Danish version of the McGill Ingestive Skills Assessment (MISA), which quantifies eating and drinking abilities by scoring a meal observation. The original Canadian MISA was translated and adapted into Danish (MISA-DK). For content validation of the MISA-DK, a judgemental quantification process was applied using 13 experts. Thereafter, the MISA-DK was pilot tested by 16 occupational therapists. Finally, the MISA-DK was linked to the International Classification of Functioning, Disability and Health (ICF). Content validity of 43 items was found for 93% in terms of adequacy, 67% in terms of clarity of item description, 86% in terms of clarity of score descriptions, and 93% in terms of relevance. Thirteen of 14 sections of the instruction manual and score sheet were content valid. In light of these results, a revised MISA-DK was produced for the pilot test, which then found content validity for all sections and 98% of the items. The ICF linking resulted in 41 ICF-categories, which may reflect the complexity of eating and drinking as well as a multidimensional structure of the MISA-DK. In conclusion, the MISA-DK is prepared for psychometric testing using classical as well as modern test theory. PMID- 20969488 TI - Optimal number of biopsies to correctly identify colorectal cancer during colonoscopy. PMID- 20969489 TI - Soy food and isoflavone intake and colorectal cancer risk: the Fukuoka Colorectal Cancer Study. AB - OBJECTIVE: It has been suggested that soy food and isoflavone intake may be protective against the risk of colorectal cancer. However, epidemiologic evidence remains sparse and inconsistent. We addressed this issue in the Fukuoka Colorectal Cancer Study. MATERIAL AND METHODS: The study subjects were the 816 incident cases of histologically confirmed colorectal cancer and 815 community controls. Intakes of soy foods and isoflavones were assessed by in-person interview using a computer-assisted dietary method. Logistic regression analysis was applied to estimate odds ratio (OR) and 95% confidence interval (CI) of colorectal cancer with adjustment for dietary intakes of calcium and n-3 polyunsaturated fatty acids as well as for body mass index, physical activity, alcohol use, and other lifestyle factors. RESULTS: Energy-adjusted intakes of soy foods (dry weight) and isoflavones were inversely associated with colorectal cancer risk in men and postmenopausal women, but not in premenopausal women. The multivariate-adjusted OR for the highest versus lowest quintile was 0.65 (95% CI 0.41-1.03, p for trend = 0.03) for soy foods and 0.68 (95% CI 0.42-1.10, p for trend = 0.051) for isoflavones in men. The corresponding values for postmenopausal women were 0.60 (95% CI 0.29-1.25, p for trend = 0.053) and 0.68 (95% CI 0.33-1.40, p for trend = 0.049). The site-specific analysis showed inverse associations of soy foods (p for trend = 0.007) and isoflavones (p for trend = 0.02) with rectal cancer in men. CONCLUSION: The findings add to epidemiologic evidence for protective effects of soy foods and isoflavones in colorectal carcinogenesis. PMID- 20969490 TI - Down-regulation of Bcl-2 is mediated by NF-kappaB activation in Helicobacter pylori-induced apoptosis of gastric epithelial cells. AB - OBJECTIVE: Bcl-2 family is involved in the regulation of apoptosis. NF-kappaB activation is associated with either the expression of Bcl-2 or down-regulation of Bcl-2 depending on cell types and stimuli. Previously, we showed NF-kappaB activation, decrease in the level of Bcl-2, and apoptosis in Helicobacter pylori (H. pylori)-infected gastric epithelial cells. The present study aims to investigate the relation of Bcl-2 expression and NF-kappaB activation in H. pylori-induced apoptotic cell death of AGS (gastric adenocarcinoma) cells. MATERIAL AND METHODS: AGS cells were transfected with mutant IkappaBalpha to suppress NF-kappaB activation or Bcl-2 gene to induce overexpression of Bcl-2. mRNA expression of Bcl-2, p53 and Bax, DNA fragmentation, cell viability, and the numbers of apoptotic cells were determined. RESULTS: H. pylori induced decrease in Bcl-2, but increase in p53 and Bax at the levels of mRNA and protein in AGS cells. H. pylori-induced increment of apoptotic cells and decrease in Bcl-2 level were inhibited in the cells transfected with mutant IkappaBalpha gene as compared with the cells transfected with control vector. H. pylori-induced apoptosis determined by apoptotic cells, DNA fragmentation, and cell viability was inhibited in the cells transfected with Bcl-2 gene. CONCLUSION: Down-regulation of Bcl-2 is mediated by NF-kappaB activation, which may be the underlying mechanism of apoptosis in H. pylori-infected gastric epithelial cells. PMID- 20969491 TI - Outcome of supraselective transarterial chemoembolization in patients with hepatocellular carcinoma. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) is the most common tumor in cirrhotic patients with a median survival of only 8-10 months if untreated. Supraselective transarterial chemoembolization (STACE) is supposed to be a well-established method for treating HCC patients. In the present study, we evaluated the effect of STACE on post-transplant survival in patients with HCC. MATERIAL AND METHODS: The charts of 53 HCC patients were retrospectively analyzed. Twenty-seven patients had STACE as a bridging therapy while 26 patients were scheduled for liver transplantation (LTX) without prior STACE therapy. A total of 53% of the patients who underwent LTX preoperatively fulfilled the Milan criteria, while 70.6% fulfilled the expanded University of California, San Francisco (UCSF) transplant criteria. Primary endpoint was the post-transplant survival. Statistical analysis included Kaplan-Meier-method, log rank, and chi square tests. RESULTS: Between the LTX groups (STACE vs. non-STACE), there was no significant difference in terms of age, Child classification, Okuda stage, co morbidities, underlying disease, and post-transplant survival (p > 0.05). Independent of prior STACE, however, disease-free survival after LTX was highly significantly prolonged if LTX was performed within 3 months after initial diagnosis of HCC (p < 0.01) or if patients met the expanded transplant UCSF criteria (p = 0.02). Post-transplant survival did not depend on tumor size. CONCLUSIONS: We conclude that STACE performed prior to LTX does not secure any post-transplant survival benefit, while early LTX, i.e. within 3 months after HCC diagnosis, does improve survival regardless of whether STACE was performed or not. Additionally, fulfillment of the expanded transplant UCSF criteria leads to a prolonged post-transplant survival. PMID- 20969492 TI - Soy isoflavone delays the progression of thioacetamide-induced liver fibrosis in rats. AB - OBJECTIVE: Our aim was to investigate the effect of soy isoflavone (SI) on liver fibrosis in a thioacetamide (TAA)-induced rat model. MATERIALS AND METHODS: Twenty-eight rats were assigned to four groups: sham group, fibrosis group, low dose treatment group (LDg) and high-dose treatment group (HDg). SI (90 or 270 mg/kg) was administered daily during the model development by TAA. Standard liver tests, platelet derived growth factor-BB (PDGF-BB) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured. The expression of collagen, alpha smooth muscle actin (alpha-SMA) and transforming growth factor-beta1 (TGF-beta1) in liver tissue was determined. Electron microscopy was used to perform ultrastructural analysis of the livers. RESULTS: Hepatic fibrosis was induced by 8 weeks of TAA administration. However, following the administration of SI, collagen staining significantly declined as compared with the fibrosis group (p < 0.01). Less collagen fibers around the hepatic stellate cells (HSCs) were observed in HDg as compared to the fibrosis group and LDg. There was no significant difference in standard liver tests between the fibrosis group and the two treatment groups. The levels of PDGF-BB and TIMP-1 in the two SI-treated groups were significantly lower than in the fibrosis group (p < 0.01). The expression of alpha-SMA and TGF-beta1 in HDg was less than that in the fibrosis group and LDg (p < 0.01). CONCLUSION: Administration of a high dose of SI resulted in an obvious inhibitory effect on liver fibrosis induced by TAA in rats. One hypothesis is that the effect may be related to the inhibition of HSC activation and proliferation. PMID- 20969493 TI - Adenovirus-mediated peroxisome proliferator activated receptor gamma overexpression prevents nutritional fibrotic steatohepatitis in mice. AB - OBJECTIVE: The pathogenesis of non-alcoholic steatohepatitis is still unclear. We have demonstrated previously that peroxisome proliferator activated receptor gamma (PPARgamma) ligand protects against inflammation and fibrogenesis in experimental non-alcoholic steatohepatitis. We aim to elucidate the effect and the mechanism of PPARgamma itself on nutritional fibrotic steatohepatitis in mice. METHODS: C57BL/6J mice were fed with methionine-choline deficient (MCD) diet for 8 weeks to induce fibrotic steatohepatitis. Mice fed the MCD diet were treated with adenovirus carrying PPARgamma (Ad-PPARgamma), Ad-PPARgamma plus PPARgamma agonist rosiglitazone, or PPARgamma antagonist 2-chloro-5 nitrobenzaniliden (GW9662), respectively. The effects of up-regulation of PPARgamma in the presence or absence of its agonist/or antagonist were assessed by comparing the severity of hepatic injury, activation of hepatic stellate cells and the expression of adiponectin, heme oxygenase-1, and fibrogenic related genes. RESULTS: Mice fed with MCD diet for 8 weeks showed severe hepatic injury including hepatic steatosis, inflammatory infiltration, and fibrosis. Administration of Ad-PPARgamma significantly lowered serum alanine aminotransferase level and ameliorated hepatic steatosis, necroinflammation, and fibrosis. These effects were associated with enhanced expression of PPARgamma, up regulated expression of adiponectin and heme oxygenase-1, and down-regulated expression of tumor necrosis factor alpha, interleukin-6, alpha-smooth muscle actin, transforming growth factor beta 1, matrix metallopeptidase-2, and -9. Administration of GW9662 promoted the severity of liver histology. CONCLUSIONS: The present study provided evidences for the protective role of overexpressing PPARgamma in ameliorating hepatic fibrosing steatohepatitis in mice. Modulation of PPARgamma expression might serve as a therapeutic approach for fibrotic steatohepatitis. PMID- 20969494 TI - Increased fecal leukocytes may reflect resolution of IBD. PMID- 20969495 TI - Safety, energy efficiency, and cost efficacy of the C-Leg for transfemoral amputees: A review of the literature. AB - The purpose of this paper was to review the literature through a structured literature review and provide a grade of recommendation for patient safety, gait energy efficiency, and cost effectiveness of the C-Leg microprocessor-controlled prosthetic knee for transfemoral amputees. Medline (Ovid) and CINAHL (EBSCO) data bases were searched to identify potentially pertinent studies within the 1995 2009 time range. Studies were screened and sorted. Pertinent studies were rated for methodologic quality and for risk of bias. Following assessment of methodologic quality and bias risk, the level of evidence and a grade of recommendation was determined for each of three categories: Safety, energy efficiency, and cost effectiveness. A total of 18 articles were determined to be pertinent: seven for safety, eight for energy efficiency, and three for cost effectiveness. Methodologic quality was low with a moderate risk of bias in the safety and energy effectiveness categories. Studies in cost effectiveness received high scores for methodologic quality. Though methodologic quality varied across the selected topics, there was sufficient evidence to suggest increased efficacy of the C-Leg in the areas of safety, energy efficiency and cost when compared with other prosthetic knees for transfemoral amputees. PMID- 20969496 TI - Partial urethral obstruction: ATF3 and p-c-Jun are involved in the growth of the detrusor muscle and its motor innervation. AB - OBJECTIVE: Infravesical obstruction leads to growth of urinary bladder smooth muscle cells. The ganglion cells innervating the bladder muscle also increase in size. Stretch of detrusor muscle cells rapidly activates c-Jun NH2-terminal kinase (JNK), which phosphorylates the transcription factor c-Jun, and stimulates the synthesis of the cotranscription factor ATF3. The aim of the study was to determine whether ATF3 and p-c-Jun were involved in growth of bladder smooth muscle and ganglion cells. MATERIAL AND METHODS: The urethra was partially obstructed in female rats. After 3 days or 10 weeks bladders were weighed, fixated and cut for immunohistochemistry to demonstrate ATF3 and p-c-Jun. Ganglia were processed separately. Unoperated and sham-operated rats were used as controls. RESULTS: There was no ATF3 or p-c-Jun in control detrusor muscle. After 3 days of obstruction bladder weight had nearly doubled. Almost all nuclei in the detrusor showed immunofluorescence for ATF3 and p-c-Jun. After 10 weeks bladder weight had increased 10-fold. Almost all detrusor nuclei still showed p-c-Jun, but few had ATF3 activity. In control ganglia there was no ATF3 and only faint nuclear p-c-Jun activity. After 3 days of obstruction the ganglion cells had increased in size and many nuclei showed intense immunofluorescence for ATF3 and p-c-Jun. After 10 weeks the ganglion cell size had increased further. There was no ATF3 activity and no more p-c-Jun than in control ganglia. CONCLUSION: ATF3 and p-c-Jun seem to be involved in the growth of the detrusor muscle and its motor innervation following infravesical outlet obstruction. PMID- 20969497 TI - Speech-language pathologists' views on mentoring by people who use speech generating devices. AB - Learning to use a speech generating device (SGD), also known as a voice output communication aid (VOCA), is a challenging experience for new device learners. These learners typically rely on training from speech-language pathologists (SLPs) and may not meet other users who are competent SGD communicators. The aim of this study was to explore SLPs' perceptions of the important components of a program where adults who use an SGD mentor new learners. A total of 17 SLPs experienced in augmentative and alternative communication (AAC) participated in one of three focus groups. The focus group discussions were analysed for content themes and these were verified with participants. Thematic analysis revealed that experienced SLPs perceived that a mentoring program to improve SGD use might help people new to using SGDs. Participants were positive about SLPs collaborating with SGD mentors to support new learners. They suggested ways in which SLPs could provide assistance and guidelines for establishing a mentoring program. Potential benefits identified for new learners included opportunities to view successful use of an SGD in everyday settings and to receive support and guidance. Benefits for mentors included the satisfaction of helping new learners. PMID- 20969498 TI - Targeting RSK2 in human malignancies. AB - IMPORTANCE OF THE FIELD: p90 ribosomal S6 kinase 2 (RSK2) belongs to a Ser/Thr kinase family containing four members, RSK1 - 4, which play an essential role in a number of cellular functions including cell cycle, survival and proliferation. Recent advances reveal a crucial role of RSK2 in oncogenesis and tumor progression, making RSK2 an attractive therapeutic target for cancer treatment. AREA COVERED IN THIS REVIEW: Recent findings identifying the role of RSK2 in human cancers, including hematopoietic malignancies and solid tumors. Therapeutic implications of targeting RSK2 are also discussed with regard to clinical circumstance. WHAT THE READER WILL GAIN: A better understanding of molecular mechanisms underlying RSK2 activation and its contribution to human cancers and also insight into the development of novel targeted cancer therapy. TAKE HOME MESSAGE: The significance of RSK2 in cancer cell survival, proliferation, invasion and tumor metastasis varies amongst human malignancies and depends on the signaling properties of the oncogenes and cellular microenvironment of the transformed cells. Thus, further exploitation of RSK2 signaling and its dynamic interaction with other crucial oncogenic and pro-metastatic pathways in different human malignancies is needed for more effective therapeutic interventions. PMID- 20969499 TI - Fentanyl in postmortem forensic toxicology. AB - CONTEXT: Fentanyl is a powerful opioid used for the induction of anesthesia as well as for the management of severe pain. In recent years, transdermal fentanyl "patches" have become popular for outpatient management of chronic pain. The high potency and outpatient availability of fentanyl has also made it a highly sought after drug of abuse. Deaths in which fentanyl is detected challenge medical examiners who must decide whether a given case represents therapeutic administration or overdose. OBJECTIVES: The current review seeks to present data about fentanyl that are relevant to the interpretation of postmortem blood and tissue fentanyl concentrations as well as to highlight areas which can be helpful or misleading in the evaluation of deaths potentially related to fentanyl exposure. METHODS: Standard searching of the PubMed database for studies, case series, and case reports involving fentanyl kinetics, chemistry, and postmortem behavior was performed. Search terms typically included "postmortem" and "fentanyl," as well as "kinetics" and "analysis," where appropriate. Additional references were located as citations from reviewed papers or as conference abstracts. RESULTS AND CONCLUSIONS: The postmortem behavior of fentanyl is influenced heavily by pH changes and the antemortem kinetic behavior of the drug, especially, by its distribution. Postmortem blood fentanyl concentrations do not correlate directly with antemortem blood concentrations. Without adequate evaluation of kinetic data, investigative information and consideration of postmortem changes, misinterpretation of postmortem fentanyl results is likely. PMID- 20969500 TI - New marker for paracetamol poisoning-revolution or evolution? AB - There is a pressing need for new biomarkers that can improve the care of patients with paracetamol poisoning, a common clinical problem. In this issue of Clinical Toxicology a new marker is proposed that has a number of attractive properties. This commentary discusses the use of biomarkers in the context of the management of paracetamol-induced liver injury. New biomarkers should allow better triage and management of & "at risk" patients. PMID- 20969501 TI - When do the aminotransferases rise after acute acetaminophen overdose? AB - CONTEXT: Rising aminotransferases (ATs) [either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) are one of the first signs of hepatotoxicity following acetaminophen (APAP)] overdose (OD). However, the timing and speed of such rises are not well characterized, hampering early risk prediction. OBJECTIVE: To describe the kinetics of AT release in acute APAP OD patients who develop hepatotoxicity despite treatment. METHODS: A descriptive study of acute APAP OD patients with peak AT > 1,000 IU/L taken from the derivation subset of the Canadian Acetaminophen Overdose Study (CAOS), a large, multicenter retrospective cohort of patients hospitalized for APAP poisoning. RESULTS: Of 2,488 hospital admissions for acute APAP OD, 94 met inclusion criteria. Treatment with acetylcysteine, mostly intravenously, was begun in all cases within 24 h of ingestion. The initial AT concentration was already elevated in most patients at presentation [median 211 (IQR 77-511) IU/L obtained at 15.3 (12.1-19.2) h postingestion], and exceeded 100 IU/L in almost all patients within 24 h of ingestion. Serum AT concentrations rose rapidly [doubling time 9.5 h (95% CI: 8.7 10.4 h)], especially in patients who developed AT > 1,000 IU/L within 48 h of ingestion. Coagulopathy was worse in these patients and in those with an AT > 250 IU/L during the first 12 h of treatment with acetylcysteine. DISCUSSION AND CONCLUSIONS: An abnormal and rapidly doubling AT at presentation is more typical in severely poisoned patients, as judged by the effects on clotting. These data suggest that risk prediction instruments may be improved by incorporating both the serum AT concentration at initiation of antidotal therapy and its rate of change. Further studies using such an approach are warranted. PMID- 20969502 TI - Addition of phenylephrine to high-dose insulin in dihydropyridine overdose does not improve outcome. AB - INTRODUCTION: Vasopressors are commonly used for calcium channel blocker (CCB) induced cardiogenic shock after calcium and high-dose insulin (HDI). Vasopressor therapy is frequently used in combination with HDI to increase blood pressure and improve outcome. However, no studies have compared the efficacy of HDI to the combination of a vasopressor and HDI in dihydropyridine overdose. We conducted a study to compare the efficacy of HDI to phenylephrine (PE) plus HDI in a porcine model of dihydropyridine toxicity. METHODS: Cardiogenic shock was induced by administering a nifedipine (NP) infusion of 0.0125 mcg/kg/min until a point of toxicity, defined as a 25% decrease in the baseline product of mean arterial pressure (MAP) * cardiac output (CO). Each arm was resuscitated with 20 mL/kg of saline (NS). The nifedipine infusion continued throughout a 4-h resuscitation protocol. The HDI group was titrated up to 10 units/kg/h of insulin and the HDI/PE group was titrated up to a dose of HDI 10 units/kg/h plus PE 3.6 mcg/kg/min. RESULTS: No baseline differences were found among groups including time to toxicity. Survival was not different between the HDI and HDI/PE arms. When comparing the HDI to the HDI/PE arm no differences were found for cardiac index (CI) (p = 0.06), systemic vascular resistance (p = 0.34), heart rate (HR) (p = 0.95), mean arterial pressure (p = 0.99), pulmonary vascular resistance (PVR) (p = 0.07), or base excess (p = 0.36). CONCLUSION: In this model of nifedipine-induced cardiogenic shock, the addition of PE to HDI therapy did not improve mortality, cardiac output, blood pressure, systemic vascular resistance (SVR), or base excess. PMID- 20969503 TI - Diphenhydramine dose-response: a novel approach to determine triage thresholds. AB - CONTEXT: It is unclear how much diphenhydramine (DPH) is toxic in humans. Previous dose-response studies have had conflicting results. Objective. We sought to evaluate DPH dose-response using a unique method that utilizes acetaminophen (APAP) serum concentrations to estimate DPH doses in patients ingesting APAP/DPH in a fixed-combination product. METHODS: We retrospectively analyzed APAP/DPH only exposures in patients 2-80 years of age using case data from 15 U.S. poison centers. DPH dose was extrapolated from measured serum APAP concentrations. A clinically significant response (CSR) was predefined in terms of eight specific manifestations (e.g., coma) that would warrant emergency department intervention. Nominal logistic regression was used to model the probability of each recorded manifestation across DPH dose ranges examining fits for mg, mg/kg, log10 mg, and log10 mg/kg DPH doses. The threshold value where patients reliably became symptomatic was determined by further examining receiver operating characteristic curves. RESULTS: There were 509 cases that met inclusion criteria. Forty-five patients (9%) developed CSRs. A higher percentage of patients developed CSR at >= 7.5 mg/kg DPH and >=1 g total DPH cutoff points (p < 0.05, Fisher's exact test). The best model for predicting the probability of CSR was a logistic fit of log(10) mg/kg dose (p < 0.05). By this model, for every 1 log(10) unit increase of mg/kg DPH dose, the odds of developing a CSR increased 47-fold (95% CI 17, 154). Receiver operating characteristic analyses showed a dose-related progression of symptoms. The cut-point with greatest sensitivity (98%) versus 1 specificity (57%) corresponded to an extrapolated mg/kg DPH dose of 8.2 mg/kg (95% CI 5.6, 10.5). CONCLUSION: Our findings support the current American Association of Poison Control Centers' guideline recommendation to refer patients to the hospital for evaluation if they have ingested greater than or equal to 7.5 mg/kg of DPH. PMID- 20969504 TI - Psychosis associated with usage of herbal slimming products adulterated with sibutramine: a case series. AB - CONTEXT: Sibutramine, or its structurally related analogs, is often found as an adulterant in proprietary herbal slimming products in Hong Kong. A few solitary case reports of sibutramine-associated psychosis have been published since 2000. As the only tertiary referral center for clinical toxicology analysis in Hong Kong, we noticed that psychosis was an unusually common feature in patients taking "herbal slimming products" adulterated with sibutramine or its structurally related analogs over the past 5 years. OBJECTIVE: To examine the association between psychosis and the use of sibutramine-adulterated herbal products, in an attempt to elucidate this possible adverse drug reaction. METHODS: This retrospective study reviewed all cases hospitalized with psychotic symptoms confirmed to have used herbal slimming products adulterated with sibutramine, or its analogs, between January 2004 and October 2009. The cases' clinical features, outcome, drug history, and analytical findings of the offending slimming products were studied. Results. Among the 16 confirmed cases, 15 (94%) were female; the median age was 19 years (range: 15-47). Auditory hallucination was documented in 10 (63%), visual hallucination in 6 (38%), persecutory ideas in 6 (38%), delusions in 4 (25%), and suicidal ideation in 2 (13%). For 20 "herbal" slimming products analyzed, 16 were found to have been adulterated with sibutramine, 2 with N-desmethyl-sibutramine, and 1 with N bisdesmethyl-sibutramine. Other concomitant adulterants were also found and included phenolphthalein in 9, fenfluramine, mazindol, animal thyroid tissue in 2, hydrochlorothiazide and spironolactone in 1. Eight patients disclosed the source of the products: four through the Internet, one obtained over-the-counter locally, with three acquired outside Hong Kong. CONCLUSION: Slimming products claimed "herbal" in origin could often be adulterated with sibutramine and other Western medications. We observed an association between the use of these products and psychotic features. Further studies are warranted to study whether these adverse events are an uncommon adverse drug reaction of sibutramine. PMID- 20969505 TI - Multiple organ failure after an overdose of less than 0.4 mg/kg of colchicine: role of coingestants and drugs during intensive care management. AB - INTRODUCTION: Although the ingestion of a dose of colchicine lower than 0.5 mg/kg is usually complicated by a mortality rate less than 5%, severe complications may be associated with drug-drug interactions in case of overdose combining other drugs. CASE REPORT: A 33-year-old previously healthy woman was admitted after a drug overdose combining colchicine, atorvastatin, ibuprofen, diclofenac, and furosemide. The amount of colchicine ingested was exactly 20 mg, corresponding to 0.33 mg/kg. Despite this relatively low dose, she presented the clinical course that is usually seen with much larger colchicine ingestions. She developed acute renal and liver failure, acute lung injury, pancytopenia with sepsis, rhabdomyolysis, hypertriglyceridemia, and ultimately died on Day 14 from hyperammonemic encephalopathy, refractory hypoxemia, and cardiac arrhythmias. DISCUSSION: Serious drug-drug interactions may have complicated colchicine poisoning. In particular, atorvastatin, an inhibitor of P-glycoprotein and cytochrome P450 3A4, was likely responsible for an increased severity of rhabdomyolysis. In addition, propofol used for sedation during mechanical ventilation may have induced symptoms consistent with "propofol infusion syndrome," with further muscular injury and hypertriglyceridemia. The mechanism of death was unusual and similar to Reye's syndrome. PMID- 20969506 TI - Two cases of acute poisoning with acetamiprid in humans. AB - INTRODUCTION: Acetamiprid is a potent and a relatively new neonicotinoid insecticide. Animal studies have indicated that it has a low toxicity to mammals. Despite wide usage, human exposure resulting in toxicity is quite limited, and this is the first report in the English literature about acute acetamiprid poisoning in humans. CASE DETAILS: We herein describe two cases of acute poisoning with an insecticide formulation containing acetamiprid for suicidal purposes. Both cases experienced severe nausea and vomiting, muscle weakness, hypothermia, convulsions, and clinical manifestations including tachycardia, hypotension, electrocardiogram changes, hypoxia, and thirst in the case with the higher serum concentration of acetamiprid. The symptoms were partially similar to acute organophosphate intoxication. Supportive treatments for a variety of symptoms were sufficient for recovery, and both individuals were discharged without any complications 2 days after ingestion. PMID- 20969507 TI - Sparkle lamp ingestion: a rare cause of death. AB - A 51-year-old man was brought to the emergency department after he had drunk 200 mL of fluid from a decorative sparkle lamp. His calcium level was 4.99 mmol/L with a blood gas pH of 7.21. His calcium levels were corrected and his acidosis improved, but his stay in the intensive care department was complicated on day 10 by upper gastrointestinal hemorrhage because of caustic erosions in his stomach. Ten days after admission, he had an emergency right hemicolectomy during which residual luminescent particles were found to have eroded through his cecal mucosa. He eventually died 15 days after admission because of disseminated intravascular coagulopathy and refractory septic shock. This case demonstrates the potential for fatal toxicity associated with ingestion of a common household item. PMID- 20969508 TI - Adrenal lesion frequency: A prospective, cross-sectional CT study in a defined region, including systematic re-evaluation. AB - BACKGROUND: incidentally detected adrenal lesions have become a growing clinical problem. PURPOSE: to prospectively estimate and validate the prevalence of incidentally detected adrenal lesions (adrenal incidentaloma) in patients with or without malignant disease undergoing CT. MATERIAL AND METHODS: during 18 months all adult patients with incidentally discovered adrenal lesions detected at CT were prospectively reported from the radiology departments of all hospitals in Western Sweden (1.66 million inhabitants). Frequencies of adrenal lesions initially reported at CT and at a systematic re-evaluation were compared. The interobserver variation in blindly assessing adrenal lesions was also analyzed. RESULTS: adrenal lesions were reported and verified in 339 patients (193 females; mean age 69 years, range 30-94 years). Mean lesion size was 25.8 mm (range 8-94 mm). The mean frequency of originally reported adrenal lesions was 0.9% (range 0 2.4% between hospitals). The systematic re-evaluation of 3801 randomly selected cases showed a mean frequency of 4.5% (range 1.8-7.1% between hospitals). The re evaluation revealed 177 cases with adrenal lesions, 30% of these were submitted by the local radiologist in accordance with the study design, 23% were described in the local radiology report but not submitted to the study center, while 47% were neither locally reported nor submitted. CONCLUSION: adrenal lesions are under-reported in clinical practice. Prevalence figures for adrenal incidentalomas should therefore be interpreted with caution, especially in multi center settings. PMID- 20969509 TI - French Guiana Amerindian demographic history as revealed by autosomal and Y chromosome STRs. AB - BACKGROUND: Previous investigations of French Guiana Amerindians performed by this group included blood group and protein genetic markers, mitochondrial DNA and Y-chromosome investigations. Molecular autosomal data and more extensive Y chromosome determinations were lacking. SUBJECTS AND METHODS: The genetic variability of 15 autosome (ASTRs) and 17 Y-chromosome (YSTRs) microsatellite loci was studied in four French Guiana (Emerillon, Palikur, Wayampi, Kali'na) and one Brazilian (Apalai) Amerindian populations. A sixth group, the Peruvian Matsiguenga of the Maipurean linguistic family, was included in the data analysis since they could provide information about the past migration of people from that linguistic stock into northeastern Amazonia. RESULTS: Marked ASTR and YSTR variability was found, with 96% of the YSTR haplotypes being found in one population only. There was excellent agreement between the present and previous autosomal or uniparental results. Multidimensional scaling based on F(ST) genetic distances and population structure analysis revealed heterogeneity in gene distribution, with a clear difference between the Matsiguenga and Emerillon and the other groups. In the latter, Wilcoxon sign-rank test between observed and expected heterozygosity and the mode of allele frequency distribution revealed clues of a significant past genetic bottleneck. The Wayampi stand genetically closer to the Apalai, Palikur and Kali'na when examined for the autosome but not the Y-chromosome panel of markers, suggesting preferential female gene flow. CONCLUSION: The new data provided additional important information about the biological history of people from a remote South American region, indicating how gene diversity analyses can be used to increase understanding of human microevolutionary processes. PMID- 20969510 TI - Nucleic acid reference materials (NARMs): definitions and issues. AB - Molecular diagnostics is one of the most rapidly growing areas of laboratory medicine. This rapid growth of clinical molecular tests has outpaced the availability and development of reference methods and reference materials. Such methods and materials are important for the development, validation, and interpretation of diagnostic methods and tests. Yet, there is a lack of harmonization between the numerous international organizations currently either certifying or defining reference materials. The objective of this position paper is to review and clarify the definition, attributes and applications for the use of reference materials in the context of molecular diagnostics. PMID- 20969511 TI - Development and validation of a combined method for the biomonitoring of omega-3/ 6 fatty acids and conjugated linoleic acids in different matrices from human and nutritional sources. AB - BACKGROUND: During the last decade, the contribution of omega-3 and -6 long chain polyunsaturated fatty acids (LC-PUFA) and conjugated linoleic acids (CLA) to the prevention and development of many inflammatory and cardiovascular diseases has been of growing interest. In order to investigate the etiology of these diseases, rapid, combined and comparable methods are invaluable for monitoring both the intake and the incorporation of these fatty acids (FA). METHODS: The fatty acid methyl esters (FAME) were analyzed using a gas chromatography/flame ionization detector (GC-FID) system and quantified with an internal standard (C18:0 iso). RESULTS: An effective and rapid protocol for sample preparation and the analysis of FAME was developed and validated. The comparison of different extraction methods showed that the Hara and Radin method gave the best results for serum and erythrocyte membranes. Excellent mean within-day and day-to-day precisions for serum, erythrocytes and cow's milk LC-PUFAs demonstrated the high reproducibility of the method. Recovery rates for FAMEs in serum and milk were close to 100%. In addition, high mean method linearity (R(2)) (>0.99) was shown for serum, erythrocytes and cow's milk. The sensitivity for FA achieved by GC analysis was acceptable. CONCLUSION: With the newly adapted protocols, combined and rapid analyses of up to 46 FAMEs, including CLAs and omega-3/-6 LC-PUFAs, can be conducted with high reliability and reproducibility using serum, erythrocyte membranes or cow's milk. This provides a novel tool that can be easily implemented in epidemiological studies or clinical diagnostics. PMID- 20969512 TI - A survey of augmentative and alternative communication service provision in Hong Kong. AB - A survey was conducted to understand the service provisions for augmentative and alternative communication (AAC) in Hong Kong. The response rates of special pre school training centers and special schools were 59% and 71%, respectively. The response rate of adult settings was 18%. Results indicated that a higher proportion of students identified as having complex communication needs had access to AAC service provision in schools for children with intellectual and physical disabilities than those in special pre-school training centres and other types of special schools. Generalization of AAC service beyond the classroom setting remains problematic. Seventy-two percent of the respondents were dissatisfied with the training in AAC that they received during their basic professional preparation. More advocacy work is needed to increase awareness and knowledge of AAC use in Hong Kong. PMID- 20969513 TI - Differences among sighted individuals and individuals with visual impairments in word intelligibility presented via synthetic and natural speech. AB - This study investigated word intelligibility among sighted individuals and individuals with visual impairments for both natural and synthetic speech. Both groups of participants performed significantly better when identifying words presented via natural speech. The results also demonstrated that individuals with visual impairments were more successful than their sighted peers in understanding words presented via synthetic speech, with experience being the most critical factor in identifying words for the participants with visual impairments. Finally, the findings show the correlation between intelligibility and key factors such as age and the overall use of text-to-speech systems. PMID- 20969514 TI - Influence of the interaction of light- and self-polymerization on subsurface hardening of a dual-cured core build-up resin composite. AB - OBJECTIVE: To investigate the influence of time delay and duration of photo activation on subsurface microhardness of a dual-cured resin composite. MATERIAL AND METHODS: A commercially available dual-cured core build-up resin composite (Rebilda DC) was filled in cavities (diameter: 4.0 mm; height: 6.0 mm) of polystyrene molds and light-cured for 20 or 60 s either immediately after the filling procedure (time delay 0 s) or after a time delay of 30, 90, 180 or 300 s. Non-irradiated self-cured specimens served as a control group (n = 15). Specimens were stored in complete darkness and at 100% relative humidity at 37 degrees C for 2 weeks and cross-sectioned. Knoop Hardness Numbers (KHNs) were measured six times per depth and averaged at distances of 0.25, 0.50, 1.00, 2.00, 3.50 and 5.50 mm from the light-exposed surface. Data were statistically analyzed using one- and two-way ANOVA followed by Scheffe's post-hoc test at a level of significance of 0.05. RESULTS: Mean hardness values in all experimental groups ranged between 54.3 +/- 2.1 and 58.1 +/- 2.3 KHN. Light-curing did not significantly increase composite KHN at any depth measured. Delaying light exposure had no influence on KHN, irrespective of depth. A longer light-exposure time (60 versus 20 s) resulted in significantly higher KHN only at depths of 3.50 and 5.50 mm. CONCLUSION: Photo-activation of the tested dual-cured resin composite provided no clinically relevant benefit compared to self-curing regarding the degree of hardening. PMID- 20969515 TI - Nasal tactile sensitivity in elderly. AB - CONCLUSION: Although older people varied widely in tactile sensitivity, our results show that tactile thresholds increased with age. OBJECTIVES: The aim of this study was to evaluate the effects of aging on nasal tactile sensitivity. METHODS: A total of 160 healthy patients aged between 50 and 90 years were included. According to their age, patients were divided into groups (A, B, C, D, E, F, G, and H). From the age of 50, each group included subjects with an age range of 5 years (i.e. group A, 50-55 years; group B, 56-60 years, etc.). Each patient's outcome was assessed through the nasal monofilament test: a set of 20 Semmes-Weinstein monofilaments was used to detect nasal sensitivity for both nasal cavities. The sensitivity threshold was recorded as the minimum monofilament size from which patients could detect at least two of three stimuli. RESULTS: In groups D (66-70 years), E (71-75 years), F (76-80 years), G (81-85 years), and H (86-90 years) a significantly (p < 0.05) higher stimulus (171.1 +/- 0.34 mg vs 67.7 mg, 167.01 +/- 0.31 mg 67.7 mg, 166.54 +/- 0.28 mg 67.7 mg, 201.24 +/- 0.43 mg 67.7 mg, 165,87 +/- 0.27 mg 67.7 mg) was required to trigger a touch response in the monofilament test. PMID- 20969516 TI - Phytochemical and pharmacological potential of Medicago sativa: a review. AB - CONTEXT: Many herbal remedies have so far been employed for the treatment and management of various ailments since the beginning of human civilization. Medicago is an extensive genus of the family Leguminosae, comprising about 83 different species. Medicago sativa (Linn.) has long been used as traditional herbal medicine in China, Iraq, Turkey, India and America for the treatment of a variety of ailments. OBJECTIVES: The aim of this review was to collect all available scientific literature published and combine it into this review. The present review comprises the ethnopharmacological, phytochemical and therapeutic potential of M. sativa. METHODS: The present review includes 117 references compiled from major databases as Chemical Abstracts, Science Direct, SciFinder, PubMed, Dr. Dukes Phytochemical and Ethnobotany, CIMER, and InteliHealth. RESULTS: An exhaustive survey of literature revealed that saponins, flavonoids, phytoestrogens, coumarins, alkaloids, amino acids, phytosterols, vitamins, digestive enzymes and terpenes constitute major classes of phytoconstituents of this plant. Pharmacological reports revealed that it is used as neuroprotective, hypocholesterolemic, antioxidant, antiulcer, antimicrobial, hypolipidemic, estrogenic, and in the treatment of atherosclerosis, heart disease, stroke, cancer, diabetes and menopausal symptoms in women. CONCLUSION: M. sativa seems to hold great potential for in-depth investigation for various biological activities, especially their effects on central nervous and cardiovascular system. Through this review, the authors hope to attract the attention of natural product researchers throughout the world to focus on the unexplored potential of M. sativa, and it may be useful in developing new formulations with more therapeutic value. PMID- 20969518 TI - Diurnal expression of clock genes in pineal gland and brain and plasma levels of melatonin and cortisol in Atlantic salmon parr and smolts. AB - In Atlantic salmon, the preadaptation to a marine life, i.e., parr-smolt transformation, and melatonin production in the pineal gland are regulated by the photoperiod. However, the clock genes have never been studied in the pineal gland of this species. The aim of the present study was to describe the diurnal expression of clock genes (Per1-like, Cry2, and Clock) in the pineal gland and brain of Atlantic salmon parr and smolts in freshwater, as well as plasma levels of melatonin and cortisol. By employing an out-of-season smolt production model, the parr-smolt transformation was induced by subjecting triplicate groups of parr to 6 wks (wks 0 to 6) under a 12 h:12 h light-dark (LD) regime followed by 6 wks (wks 6 to 12) of continuous light (LL). The measured clock genes in both pineal gland and brain and the plasma levels of melatonin and cortisol showed significant daily variations in parr under LD in wk 6, whereas these rhythms were abolished in smolts under LL in wk 12. In parr, the pineal Per1-like and Cry2 expression peaked in the dark phase, whereas the pineal Clock expression was elevated during the light phase. Although this study presents novel findings on the clock gene system in the teleost pineal gland, the role of this system in the regulation of smoltification needs to be studied in more detail. PMID- 20969520 TI - Proxisome proliferator-activated receptor-alpha mediates high-fat, diet-enhanced daily oscillation of plasminogen activator inhibitor-1 activity in mice. AB - Acute thrombotic events frequently occur in the early morning among hyperlipidemic patients. The activity of plasminogen activator inhibitor-1 (PAI 1), a potent inhibitor of the fibrinolytic system, oscillates daily, and this is considered one mechanism that underlies the morning onset of acute thrombotic events in hyperlipidemia. Although several studies have reported the expression of the PAI-1 gene is under the control of the circadian clock system, the molecular mechanism of the circadian transactivation of PAI-1 gene under hyperlipidemic conditions remains to be elucidated. Here, the authors investigated whether hyperlipidemia induced by a high-fat diet (HFD) enhances the daily oscillation of plasma PAI-1 activity in mice. The mRNA levels of the PAI-1 gene were increased and rhythmically fluctuated with high-oscillation amplitude in the livers of wild-type mice fed with the HFD. Circadian expression of proxisome proliferator-activated receptor-alpha (PPARalpha) mRNA was also augmented as well as that of PAI-1. Chromatin immunoprecipitation showed the HFD induced hyperlipidemia significantly increased the binding of PPARalpha to the PAI-1 promoter. Luciferase reporter analysis using primary hepatocytes revealed CLOCK/BMAL1-mediated PAI-1 promoter activity was synergistically enhanced by cotransfection with PPARalpha/retinoid X receptor-alpha (RXRalpha), and this synergistic transactivation was repressed by negative limbs of the circadian clock, PERIOD2 and CRYPTOCHROME1. As expected, HFD-induced PAI-1 mRNA expression was significantly attenuated in PPARalpha-null mice. These results suggest a molecular link between the circadian clock and lipid metabolism system in the regulation of PAI-1 gene expression, and provide an aid for understanding why hyperlipidemia increases the risk of acute thrombotic events in the morning. PMID- 20969519 TI - Effect of continuous light on daily levels of plasma melatonin and cortisol and expression of clock genes in pineal gland, brain, and liver in atlantic salmon postsmolts. AB - Continuous light is a common practice in salmon farming, where it is used to enhance growth, induce smoltification, and regulate puberty. However, knowledge about how different tissues receive information about daylength is limited. The aim of the present study was to evaluate the daily expression of clock (Per1 like, Cry2, and Clock), the nuclear transcription factor (peroxisome proliferator activated receptor, PPAR; CCAAT/enhancer binding protein, C/EBP), and the endoplasmic reticulum (ER) stress (protein disulfide isomerase associated 3, PDIA3) genes in the pineal gland, brain, and liver of Atlantic salmon postsmolts reared under 12-h light:12-h dark (LD) regimes or under continuous light (LL) for 6 wks following transfer to seawater. All measured clock mRNAs displayed daily variations in one or more organs under LD, as well as plasma levels of melatonin. Similar variations were noted in the liver c/ebpalpha, pineal c/ebpdelta, and pdia3 mRNAs. Under LL, the clock and nuclear transcription factor mRNAs did not show any daily variation in the studied organs, with the exception of pineal pdia3. Furthermore, LL had the opposite effect on the levels of melatonin and cortisol, as observed by the increase in pineal Clock, Per2, pparalpha, and c/ebpalpha and c/ebpdelta mRNAs and decrease in liver Clock, Per2, and pparalpha mRNAs compared to those under LD. The present findings show that the expression of clock genes is affected by the light across organs and that there is a relation between PPAR, C/EBP, and clock mRNAs; however, the functional role of the individual nuclear transcription factors related to this observation remains to be established in the pineal gland and liver. (Author correspondence: Tihu@nifes.no ). PMID- 20969517 TI - Circadian profiles in the embryonic chick heart: L-type voltage-gated calcium channels and signaling pathways. AB - Circadian clocks exist in the heart tissue and modulate multiple physiological events, from cardiac metabolism to contractile function and expression of circadian oscillator and metabolic-related genes. Ample evidence has demonstrated that there are endogenous circadian oscillators in adult mammalian cardiomyocytes. However, mammalian embryos cannot be entrained independently to light-dark (LD) cycles in vivo without any maternal influence, but circadian genes are well expressed and able to oscillate in embryonic stages. The authors took advantage of using chick embryos that are independent of maternal influences to investigate whether embryonic hearts could be entrained under LD cycles in ovo. The authors found circadian regulation of L-type voltage-gated calcium channels (L-VGCCs), the ion channels responsible for the production of cardiac muscle contraction in embryonic chick hearts. The mRNA levels and protein expression of VGCCalpha1C and VGCCalpha1D are under circadian control, and the average L-VGCC current density is significantly larger when cardiomyocytes are recorded during the night than day. The phosphorylation states of several kinases involved in insulin signaling and cardiac metabolism, including extracellular signal-regulated kinase (Erk), stress-activated protein kinase (p38), protein kinase B (Akt), and glycogen synthase kinase-3beta (GSK-3beta), are also under circadian control. Both Erk and p38 have been implicated in regulating cardiac contractility and in the development of various pathological states, such as cardiac hypertrophy and heart failure. Even though both Erk and phosphoinositide 3-kinase (PI3K)-Akt signaling pathways participate in complex cellular processes regarding physiological or pathological states of cardiomyocytes, the circadian oscillators in the heart regulate these pathways independently, and both pathways contribute to the circadian regulation of L-VGCCs. PMID- 20969521 TI - 24-hour temporal pattern of NTPDase and 5'-nucleotidase enzymes in rat blood serum. AB - Circadian rhythms represent an important mechanism to prepare the organism for environmental variations. ATP, ADP, AMP, and adenosine can act as extracellular messengers in a range of biological processes and are metabolized by a number of enzymes, including NTPDases and 5'-nucleotidase. In the present study the authors report that ATPase and ADPase activities present 24-h temporal variations that peak during dark (activity) span. These findings suggest that this enzymatic temporal pattern in blood serum might be important for the normal physiology and function of the organism through the maintenance of extracellular nucleotides at physiological levels. PMID- 20969522 TI - Predicting human nocturnal nonvisual responses to monochromatic and polychromatic light with a melanopsin photosensitivity function. AB - The short-wavelength (blue) light sensitivity of human circadian, neurobehavioral, neuroendocrine, and neurophysiological responses is attributed to melanopsin. Whether melanopsin is the sole factor in determining the efficacy of a polychromatic light source in driving nonvisual responses, however, remains to be established. Monochromatic (lambda(max) 437, 479, and 532 nm administered singly and in combination with 479 nm light) and polychromatic (color temperature: 4000 K and 17000 K) light stimuli were photon matched for their predicted ability to stimulate melanopsin, and their capacity to affect nocturnal melatonin levels, auditory reaction time, and subjective alertness and mood was assessed. Young, healthy male participants aged 18-35 yrs (23.6 +/- 3.6 yrs [mean +/- SD]; n=12) participated in 12 overnight sessions that included an individually timed 30-min nocturnal light stimulus on the rising limb of the melatonin profile. At regular intervals before, during, and after the light stimulus, subjective mood and alertness were verbally assessed, blood samples were taken for analysis of plasma melatonin levels, and an auditory reaction time task (psychomotor vigilance task; PVT) was performed. Proc GLM (general linear model) repeated-measures ANOVA (analysis of variance) revealed significantly lower melatonin suppression with the polychromatic light conditions (4000 and 17000 K) compared to the "melanopsin photon-matched" monochromatic light conditions (p< .05). In contrast, subjective alertness was significantly lower under the 479 nm monochromatic light condition compared to the 437 and 532 nm monochromatic and both polychromatic light conditions. The alerting responses more reflected the total photon content of the light stimulus. The demonstration that the melatonin suppression response to polychromatic light was significantly lower than predicted by the melanopsin photosensitivity function suggests this function is not the sole consideration when trying to predict the efficacy of broadband lighting. The different spectral sensitivity of subjective alertness and melatonin suppression responses may imply a differential involvement of the cone photopigments. An analysis of the photon densities in specific wavelength bands for the polychromatic lights used in this and the authors' previous study suggests the spectral composition of a polychromatic light source, and particularly the very short-wavelength content, may be critical in determining response magnitude for the neuroendocrine and neurobehavioral effects of nocturnal light. PMID- 20969523 TI - Phase relationship between skin temperature and sleep-wake rhythms in women with vascular dysregulation and controls under real-life conditions. AB - The aim of the study was to investigate whether women with primary vascular dysregulation (VD; main symptoms of thermal discomfort with cold extremities) and difficulties initiating sleep (DIS) exhibit a disturbed phase of entrainment (Psi) under everyday life conditions. The authors predicted a phase delay of the distal-proximal skin temperature gradient and salivary melatonin rhythms with respect to the sleep-wake cycle in women with VD and DIS (WVD) compared to controls (CON), similar to that found in their previous constant-routine laboratory data. A total of 41 young healthy women, 20 with WVD and 21 matched CON without VD and normal sleep onset latency (SOL), were investigated under ambulatory conditions (following their habitual bedtimes) during 7 days of continuous recording of skin temperatures, sleep-wake cycles monitored by actimetry and sleep-wake diaries, and single evening saliva collections for determining the circadian marker of dim light melatonin onset (DLMO). Compared to CON, WVD showed increased distal vasoconstriction at midday and in the evening, as indicated by lower distal (DIST; hands and feet) and foot-calf skin temperatures, and distal-proximal skin temperature gradients (p< .05). WVD manifested distal vasoconstriction before lights-off that also lasted longer after lights-off than in CON. In parallel, WVD exhibited a longer SOL (p< .05). To define internal phase-relationships, cross-correlation analyses were performed using diurnal rhythms of wrist activity and foot skin temperature. WVD showed a phase delay in foot skin temperature (CON versus WVD: 3.57 +/- 17.28 min versus 38.50 +/- 16.65 min; p< .05) but not in wrist activity. This finding was validated by additional within-subject cross-correlation analyses using the diurnal wrist activity pattern as reference. DLMO and habitual sleep times did not differ between CON and WVD. The authors conclude that WVD exhibit a phase delay of distal vasodilatation with respect to their habitual sleep-wake cycle and other circadian phase markers, such as DLMO. A full factorial design will have to show whether the finding is specific to primary vascular dysregulation, to DIS, or to their interaction. PMID- 20969524 TI - Evening preference is related to the incidence of depressive states independent of sleep-wake conditions. AB - Although evening preference has recently been identified as a risk factor for depression, it has not been substantiated whether evening preference is a direct risk factor for depressive states, or if it is associated secondarily through other factors, such as delayed sleep timing and shortened sleep duration. The objective of this study is to investigate associations in Japanese adult subjects between evening preference and incidence of depressive states, adjusting for various sleep parameters related to depressive states. The Morningness Eveningness Questionnaire (MEQ), the Pittsburgh Sleep Quality Index (PSQI), and the Center for Epidemiologic Studies Depression Scale (CES-D) were administered to 1170 individuals (493 males/677 females; mean and range 38.5 and 20-59 yrs) to assess their diurnal preferences, sleeping states, and presence of depression symptoms. Subjects were classified into five chronotypes based on MEQ scores. Evening preference was associated with delayed sleep timing, shortened sleep duration, deteriorated subjective sleep quality, and worsened daytime sleepiness. Logistic regression analysis demonstrated that the extreme evening type (odds ratio [OR] = 1.926, p = .018) was associated with increased incidence of depressive states and that the extreme morning type (OR = 0.342, p = .038) was associated with the decreased incidence of depressive states, independent of sleep parameters, such as nocturnal awakening (OR = 1.844, p < .001), subjective sleep quality (OR = 2.471, p < .001), and daytime sleepiness (OR = 1.895, p = .001). However, no significant associations were observed between the incidence of depressive states and sleep duration, sleep timing, and sleep debt (levels of insufficient sleep). Although the findings of this study do not demonstrate a causative relationship between evening preference and depression, they do suggest the presence of functional associations between mood adjustment and biological clock systems that regulate diurnal preference. They also suggest that evening preference might increase susceptibility to the induction of mood disorders. PMID- 20969525 TI - Associations between chronotype, sleep quality, suicidality, and depressive symptoms in patients with major depression and healthy controls. AB - Research interest concerning associations between sleep characteristics and suicidality in psychopathology has been growing. However, possible linkages of suicidality to sleep characteristics in terms of sleep quality and chronotypes among depressive patients have not been well documented. In the current study, the authors investigated the possible effects of sleep quality and chronotype on the severity of depressive symptoms and suicide risk in patients with depressive disorder and healthy controls. The study was conducted on 80 patients clinically diagnosed with major depression and 80 healthy subjects who were demographically matched with the patient group. All participants completed a questionnaire package containing self-report measures, including the Beck Depression Inventory (BDI), Pittsburgh Sleep Quality Index (PSQI), Morningness-Eveningness Questionnaire (MEQ), and Suicide Ideation Scale (SIS), and subjects were interviewed with the suicidality section of the Mini-International Neuropsychiatric Interview (MINI). Results are as follows: (a) logistic regression analyses revealed that poor sleep quality and depression symptom severity significantly predicted onset of major depression; (b) morningness-type circadian rhythm may play as a significant relief factor after onset of major depression; (c) sleep variables of chronotype and sleep quality did not significantly predict suicide ideation after controlling for depressive symptoms in the major depression group; and (d) suicide ideation and poor sleep quality were antecedents of depression symptom severity in patients with major depression, and in healthy controls. Findings are discussed under the theoretical assumptions concerning possible relations between chronotype, sleep quality, depression, and suicidality. PMID- 20969526 TI - Morningness propensity in young adults born prematurely: the Helsinki study of very low birth weight adults. AB - The authors explored morningness-eveningness propensity in adults born prematurely at very low birth weight (VLBW; < 1500g) and in controls born at term. At age 21 to 29 yrs, 184 participants completed the Morningness-Eveningness Questionnaire (MEQ). Compared with controls, VLBW adults scored higher in morningness propensity (group difference: 2.8 scores, 95% confidence interval: 0.1 to 5.5; p = .042). This finding was confined to those VLBW adults whose birth weight was not small for gestational age, and remained similar when adjusting for age, sex, and working conditions. The finding is potentially important, since morningness is associated with beneficial health outcomes. PMID- 20969527 TI - Chronopharmacology of roflumilast: a comparative pharmacokinetic study of morning versus evening administration in healthy adults. AB - The human circadian system is known to affect the pharmacokinetics and pharmacodynamics of several classes of respiratory disease medications. The current study involving 16 healthy adults investigated if the time-of-day of dosing of roflumilast, a novel phosphodiesterase-4 inhibitor, affects its pharmacokinetics. The rate of drug absorption (t(max): 1.50 versus 2.00 h) and peak concentration at t(max) (C(max): 3.79 versus 3.06 ug/L) was slightly greater with morning than evening administration, but without clinical significance. The extent of drug absorption (AUC) and drug elimination (t(1/2)) did not differ between the two dosing times. The pharmacokinetics of the active main metabolite, roflumilast N-oxide, also was not affected by the time of drug administration. Finally, the safety and tolerability of roflumilast did not differ between the two different times of administration. PMID- 20969529 TI - Time-of-day effects on cognition in preadolescents: a trails study. AB - Cognitive performance fluctuates during the day due to diurnal variations in alertness level. This study examined: (1) whether cognitive performance in school aged children is affected by time-of-day; (2) which functional domains are particularly vulnerable to time-of-day effects; and (3) whether the effects are more pronounced for cognitively more demanding tasks or task conditions. Children, aged 10-12 yrs, were randomly assigned to a test session starting either at 08:30 (n = 802), 10:00 (n = 713), or 13:00 h (n = 652). Speed and accuracy of information processing were evaluated by tasks that assess input related cognitive processes (e.g., stimulus encoding), central cognitive processes (e.g., working memory, sustained attention), and output-related processes (e.g., response organization) using the Amsterdam Neuropsychological Tasks program. Time-of-day effects in children were identified in specific neurocognitive domains, such as visuospatial processing and working memory, but only under cognitively more demanding task conditions. Sustained attention showed a speed-accuracy tradeoff with increased slowness and lapses in the early morning, but with better feedback responsiveness and perceptual sensitivity than in the early afternoon. Furthermore, there was a significant interaction of time on-task with time-of-day for tempo, with the afternoon group increasing in tempo with time-on-task, and the early-morning group first showing a slowing of tempo with time-on-task, followed at the end of the task by a speed increase towards the initial levels. To conclude, the authors found time-of-day effects in preadolescents, which were confined to cognitively more demanding tasks tapping input-related and central cognitive processes. PMID- 20969528 TI - Seasonal variation of neonatal transient hyperthyrotropinemia in Tehran province, 1998-2005. AB - Seasonal aggregation and the monthly rate of neonatal transient hyperthyrotropinemia (THT) were assessed. From November 1998 to April 2005, neonates of gestational age >=37 wks, birth weight 2500-4000 g, birth length 45 55 cm, and 1st min Apgar score >3, who had thyrotropin (TSH) >=20 mU/L in their cord dried-blood specimen, but without congenital hypothyroidism, were enrolled in the study. The recall rate equals the rate of THT occurrence in this study. Of 47,945 neonates, 555 had THT (recall rate: 1.2%). The aggregated seasonal recall rate (recall for further assessment to rule out congenital hypothyroidism) was significantly higher in winter (January, February, and March) than the other seasons (p < .0001). Winter had higher recall rate in each year as compared to other seasons, but the overall rate of recalls decreased in 2001 and 2002. Excluding the first 6 months (due to erratic variations), the remaining 72 months revealed a relatively sinusoidal pattern in monthly recall rates; indeed, there was an initial 11-month high recall rates (1.7%), followed by a 33-month decrease (0.7%), a 19-month increase (1.9%), and a final 9-month decrease (0.8%). The recall rate of each of these time intervals was significantly different from that of the next time interval (p < .0001). The monthly recall rates were best fitted to cubic curve estimation and then autoregressive integrated moving average (ARIMA) (0, 1, 1) models. THT occurs significantly more in winter than in other seasons, and this suggests a possible role for time-varying factor(s) contributing to its seasonal preponderance. PMID- 20969530 TI - Estimation of the benchmark duration of shiftwork associated with weight gain in male Japanese workers. AB - The authors estimated the benchmark durations (BMDs) and their 95% lower confidence limit (BMDL) for the reference duration of shiftwork for weight gain. A 14-yr prospective cohort study was conducted in male workers at a Japanese steel company (n = 7254) who had received annual health check-ups between 1991 and 2005. The endpoints in the study were either a 5%, 7.5%, or 10% increase in body mass index (BMI) during the period of observation, compared to the BMI at entry. The association between the duration of shiftwork and weight gain was investigated using multivariate pooled logistic regression analyses with stepwise selection of covariates, including age, BMI measured during the study, drinking and smoking habits, and habitual exercise. The BMDL/BMD for shiftwork in subjects aged in their 40s or >=50 yrs was estimated using benchmark responses (BMRs) of 5% or 10% and parameters for the duration of shiftwork and other covariates. For workers aged in their 40s, the BMDL/BMD for shiftwork with a BMR of 5% was 18.6/23.0 yrs (>=7.5%) and 16.9/19.4 yrs (>=10%). For workers aged >=50 yrs, the BMDL/BMD with a BMR of 5% was 22.9/28.2 yrs (>=7.5%) and 20.6/23.6 yrs (>=10%). The reference duration of shiftwork that associated with weight gain was shown to be at least 17 yrs in middle-aged workers. Special attention should be paid to prevent weight gain at an earlier stage and not when this increase in weight has become apparent. PMID- 20969531 TI - Ethics and methods for biological rhythm research on animals and human beings. AB - This article updates the ethical standards and methods for the conduct of high quality animal and human biological rhythm research, which should be especially useful for new investigators of the rhythms of life. The editors of Chronobiology International adhere to and endorse the Code of Conduct and Best Practice Guidelines of the Committee On Publication Ethics (COPE), which encourages communication of such updates at regular intervals in the journal. The journal accepts papers representing original work, no part of which was previously submitted for publication elsewhere, except as brief abstracts, as well as in depth reviews. The majority of research papers published in Chronobiology International entails animal and human investigations. The editors and readers of the journal expect authors of submitted manuscripts to have made an important contribution to the research of biological rhythms and related phenomena using ethical methods/procedures and unbiased, accurate, and honest reporting of findings. Authors of scientific papers are required to declare all potential conflicts of interest. The journal and its editors endorse compliance of investigators to the Guide for the Care and Use of Laboratory Animals of the Institute for Laboratory Animal Research of the National Research Council, relating to the conduct of ethical research on laboratory and other animals, and the principles of the Declaration of Helsinki of the World Medical Association, relating to the conduct of ethical research on human beings. The peer review of manuscripts by Chronobiology International thus includes judgment as to whether or not the protocols and methods conform to ethical standards. Authors are expected to show mastery of the basic methods and procedures of biological rhythm research and proper statistical assessment of data, including the appropriate application of time series data analyses, as briefly reviewed in this article. The journal editors strive to consistently achieve high standards for the research of original and review papers reported in Chronobiology International, and current examples of expectations are presented herein. PMID- 20969532 TI - Habitual moderate alcohol consumption desynchronizes circadian physiologic rhythms and affects reaction-time performance. AB - The authors studied longitudinally four healthy young adults to explore if habitual evening intake of a "moderate" amount of wine alters parameters, including period (tau) of circadian rhythms. Subjects, synchronized by diurnal activity from 07.30 h +/- 60 min to 23.00 h +/- 90 min and nocturnal rest, were studied during a continuous 22-day span: 11 days without alcohol (control) and 11 days with a glass (200 mL) of wine nightly at supper (alcohol). The amount of alcohol ingested with dinner ranged from 0.28 to 0.42 g/kg/24 h/participant and the estimated evening blood alcohol level ranged from 0.02 to 0.10 g/L/participant. Single reaction time (SRT; yellow light signal), three-choice reaction time (CRT) (red, green, and yellow signals) of both hands, related cumulated errors (c-errors), as well as oral temperature (OT) and grip strength (GS) were measured four to seven times/24 h. Time series were analyzed individually to quantify 24-h means (M), circadian tau (power spectra), and cosinor, and correlation, chi(2), and t tests were performed. The sleep-wake tau (actography) was 24 h in every subject for both conditions. With alcohol, all subjects showed an OT circadian tau shorter than the control one. The SRT circadian M was longer (poorer performance) with wine versus control in three subjects, while CRT was longer with wine versus control in only one subject. Correlation analyses also showed the detrimental effect of alcohol on the same variables. Number of days with <2 c-errors was predominant in control and decreased with alcohol, especially for SRT. The desynchronization of the 10 different documented rhythms was greater with alcohol with reference to control in two of the four studied subjects. This work shows that habitual "moderate" wine drinking at supper reduces the performance of subjects, increases the level of c-errors/24 h, especially for SRT, suggesting a "moderate" amount of alcohol has the potential to increase accident risk, and it can also desynchronize circadian time organization. PMID- 20969533 TI - Comment and reply on: Interactions of cortisol, testosterone, and resistance training: influence of circadian rhythms. Chronobiol Int. 2010; 27(4): 675-705. PMID- 20969537 TI - Cerebroprotective effect of Ocimum gratissimum against focal ischemia and reperfusion-induced cerebral injury. AB - CONTEXT: Oxidative stress is believed to increase delayed neuronal death in the brain following ischemia. As a consequence, many attempts to reduce the damage resulting from cerebral ischemia under more highly oxidized conditions have focused on treatments aimed at maintaining the redox equilibrium of the local environment. Many antioxidants were shown to be neuroprotective in experimental models of cerebral ischemia and reperfusion. OBJECTIVE: The present study was designed to investigate the potential protective effects of ethanol extract of Ocimum gratissimum Linn. (Lamiaceae) (EEOg) against focal ischemia and reperfusion (I/R) insult in rat brain. MATERIALS AND METHODS: The animal model of focal I/R was established by occluding the middle cerebral artery (MCA) of male Wistar rats for 2 h, followed by 24 h reperfusion. The thiobarbituric acid reactive substances concentration, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity were determined by colorimetric assays. The characterization and quantitative analysis of phenolic content was determined using HPLC. RESULTS: MCA occlusion led to significant rise in cerebral infarct volume and lipid peroxidation, and depletion in SOD and GPx in brain. The neurological deficits were also significantly elevated by MCA occlusion. All the brain oxidative stress, damage and neurological deficits were significantly attenuated by pre-treatment with EEOg (150 or 300 mg/kg, p.o.). CONCLUSION: The overall finding suggests the neuroprotective potential of O. gratissimum in cerebral ischemia, and is mediated through its antioxidant activity. Therefore, O. gratissimum should be investigated further as a possible strategy against cerebral stroke. PMID- 20969536 TI - Foamy virus: an available vector for gene transfer in neural cells and other nondividing cells. AB - Foamy viruses (FVs) are classified to a subfamily of retrovirus presented in a wide range of hosts. None of FVs has been found to associate with any diseases in their native hosts. Such a unique biological character of FVs makes it suitable for the development of vectors for gene transfer. However, it is still controversial whether foamy virus vectors (FV vectors) can be applied to the central nervous system (CNS). In this review, we summarize the studies of FV vectors, which have been used for transduction of neural cells and other nondividing cells. We further discuss the potential mechanisms underlying the infection and propose that FVs can be used to develop transfer vectors for gene therapy in neurological disorders. PMID- 20969538 TI - Knowing is believing: information and attitudes towards physical activity during pregnancy. AB - Physical activity is safe for most pregnant women and improves maternal fitness and birth outcomes. Yet, despite evidence of benefit, prevalence rates are low. Research in other populations suggests that attitudes and information are associated with physical activity. We examined the sources and types of information that women receive about physical activity during pregnancy and their association with attitudes towards prenatal physical activity. We also investigated whether particular groups of women are more likely to receive physical activity information. Questionnaires were completed by 179 ethnically and socio-economically diverse pregnant women. Women who were younger, unpartnered, less educated and had less income were less likely to report receiving information about prenatal physical activity. Receipt of information concerning benefits and risks of activity, risks of inactivity and specific techniques was associated with more favourable attitudes towards physical activity. Women who perceived low risk of birth complications also held more favourable attitudes. Some viewed all forms of physical activity as dangerous. Results suggest that providing information about benefits and risks of prenatal physical activity may motivate pregnant women to practice better health behaviours. PMID- 20969539 TI - The association between nC60 and 17alpha-ethinylestradiol (EE2) decreases EE2 bioavailability in zebrafish and alters nanoaggregate characteristics. AB - Manufactured nanoparticles (NPs) released into surface waters will associate with other substances and these interactions may affect environmental fate and bioavailability of NPs and the associated substances. We investigated the association between aqueous aggregates of C(60) (nC(60)) and synthetic estrogen, 17alpha-ethinylestradiol (EE2), and considered nC(60) physicochemistry and EE2 bioavailability (by measuring vitellogenin (vtg1A/B) gene expression) in zebrafish. Bioavailability of EE2 was reduced with increasing concentration of nC(60) (P < 0.05), and bioavailability of EE2 decreased further after aging 28 d with nC(60). Reduction in EE2 bioavailability was correlated with computed surface area of nC(60), and reduced bioavailability of EE2 upon aging was consistent with absorption of EE2 within nC(60) aggregates. Size and zeta potential of nC(60) particles were affected by EE2 (1 MUg/L) and also by aging (28 d) in aqueous phase. Results indicate that nC(60) can reduce bioavailability of some substances and influence environmental fate and transport of associated substances. PMID- 20969540 TI - Healing of tooth extraction sockets in the streptozotocin diabetic rat model: Induction of cartilage by BMP-6. AB - Cartilage does not form in the tooth extraction socket of the normal rat. The aim of the study was to determine if adding BMP-6 to the extraction socket would cause chondrogenic differentiation in the diabetic rat. A group of 8-week-old rats were injected intraperitoneally with a diabetogenic agent, streptozotocin, and a control group received citrate buffer only. Three weeks later, the maxillary molar teeth were extracted and either BMP-6 or saline applied to the extraction sockets. Rats from each group were killed on days 3, 5, 7, and 9 after tooth extraction. In the diabetic rats treated with BMP-6, there was a cellular subperiosteal reaction at day 3 in the extra-alveolar tissues, which by day 7 had formed a large mass of cartilage. Cartilage was induced in the subperiosteal region of the socket extra-alveolar bone following the application of BMP-6 in the diabetic rat. PMID- 20969541 TI - Downregulation of serum epidermal growth factor in patients with inflammatory bowel disease. Is there a link with mucosal damage? AB - BACKGROUND: Epidermal growth factor (EGF) is a multipotent peptide which contributes to epithelial development, inhibition of gastric acid secretion, acceleration of wound healing, and promotion of angiogenesis. The aim of this study is to evaluate serum EGF concentrations in inflammatory bowel disease (IBD) patients, with regard to disease and patients' characteristics. METHODS: EGF determination was performed by a commercially available enzyme-linked immunosorbent assay. Fifty-two patients with ulcerative colitis (UC), 59 with Crohn's disease (CD), and 55 healthy controls (HC) were included in the study. RESULTS: Mean ( +/- SEM) serum EGF levels were 217.2 ( +/- 30.40) pg/mL in UC patients, 324.6 ( +/- 37.29) pg/mL in CD patients, and 453.1 ( +/- 39.44) pg/mL in HC. Serum EGF levels were significantly lower in UC and CD patients compared to HC (P < 0.0001 and P = 0.0199, respectively). Lower serum EGF levels were observed in UC compared to CD patients (P = 0.0277). Extent of the disease was found to affect serum EGF levels in UC, demonstrating significant reduction in patients with left-sided colitis and pancolitis in comparison with those with proctitis (P = 0.0190 and P = 0.0024, respectively). EGF concentration was not influenced by other characteristics of patients and disease. CONCLUSIONS: Significantly, lower levels of serum EGF are observed in IBD patients compared to HC, while disease extent plays a key role in regulation of serum EGF in UC. Downregulation of serum EGF may be correlated with different patterns of bowel inflammation, epithelial development, and wound healing in IBD. PMID- 20969542 TI - In vitro analysis of an rhGDF-5 suture coating process and the effects of rhGDF-5 on rat tendon fibroblasts. AB - We describe a dipcoating method of coating 4-0 VICRYL sutures with recombinant human growth and differentiation factor-5 (rhGDF-5), and analyze the in vitro effects of rhGDF-5 on rat tendon fibroblasts (RTFs). Part I: Eight 4-0 VICRYL sutures were coated in a dipcoat solution using rhGDF-5 solutions at concentrations of 0, 40, 200, and 1000 MUg/ml (n=32). ELISA was performed to determine the amount of rhGDF-5 that was transferred on the suture. Part II: Using a dipcoat solution of 200 MUg/ml, four sutures were passed through rat tendon, and quantified ELISA was again performed. Cell proliferation, collagen synthesis, and RTF cell migration were also analyzed. The differences in the amount rhGDF-5 transferred on the suture between the different concentration groups were statistically significant. Furthermore, rhGDF-5-stimulated RTF cell migration, cell proliferation, and collagen synthesis at dipcoat concentrations of rhGDF-5 of at least 200 MUg/ml. PMID- 20969543 TI - Scleroderma renal crisis accompanied by new-onset pulmonary arterial hypertension: an acute systemic endothelial injury? Case report and literature. AB - Systemic Sclerosis (SSc) is a multisystem connective tissue disease characterized by fibrosis of the skin and internal organs and extensive vasculopathy. We report a case of a 41 year-old white woman with a 10 year-history of limited scleroderma, who developed the rare combination of Scleroderma Renal Crisis (SRC) and Systemic Sclerosis related Pulmonary Arterial Hypertension (SScPAH) in the same time. Although the patient received the proposed antihypertensive treatment, the renal function did not recover, and she initiated on renal replacement therapy. SRC and SScPAH are two aspects of SSc vasculopathy characterized by endothelial dysfunction mediated by endothelin-1 and other vasoactive hormones. Further new studies with therapies directed towards the underlying mechanisms of SRC (i.e. endothelin-receptor antagonists), which are proven helpful in SScPAH, should take place to establish new therapeutic options and improve prognosis of these patients, for which our therapeutic armamentarium is currently poor. PMID- 20969544 TI - Fibromyalgia: knowns, unknowns, and current treatment. AB - Fibromyalgia is a chronic syndrome of diffuse musculoskeletal pain with tenderness at specific locations, often associated with persistent fatigue, cognitive and mood disorders, joint stiffness, and insomnia. Understanding the pathophysiology of fibromyalgia and the establishment of effective treatments have been complex endeavors that have not yielded simple answers. Nevertheless, recent studies have shed light on the roles of central pain processing, genetic abnormalities, and external factors on development of the fibromyalgia syndrome (FMS). These findings have led to the use of new therapies that have shown beneficial effects on symptoms. This review discusses ideas that have become accepted as well as novel associations under consideration in regard to the pathogenesis of fibromyalgia and the current and emerging therapeutics for its treatment. PMID- 20969545 TI - T-cell agents in the treatment of rheumatoid arthritis. AB - T cells play a prominent role in the pathogenesis of rheumatoid arthritis. Abatacept is the first FDA approved agent for rheumatoid arthritis that blocks the activation of T cells by interrupting the interaction between the CD28 ligand on the T cell and the CD80/86 ligand on the antigen presenting cell. Inhibition of T cell activation has pleotropic effects that lowers the downstream production of multiple cytokines. In clinical trials, abatacept is effective in treating the signs and symptoms of rheumatoid arthritis as well as in inhibiting structural damage. It has a favorable safety profile and can be used in patients who may have comorbidities that preclude the use of anti-TNF agents. While no direct head to head trials exist, a study in which both abatacept and infiximab were compared to an identical control population, suggested that the efficacy of the two drugs was similar but that there were fewer adverse effects with abatacept than with infiximab. Abatacept is an important addition to the therapeutic repertoire available to treat rheumatoid arthritis. Available data support its use as a first line agent to treat patients who have had and inadequate response to methotrexate. PMID- 20969546 TI - Osteoporosis - new treatments and updates. AB - With the aging of the population, low bone mass states will be an increasing clinical issue for both men and women. More than 2 million osteoporotic fractures occur annually in the United States and it is estimated that nearly half of American Caucasian women over the age of 50 will experience at least one fragility fracture in their lifetime. Identifying subjects at increased risk for fracture and defining rational treatment strategies that balance risks with therapeutic benefits promises to be a major focus in the decade ahead. This review focuses on several areas of active interest in osteoporosis including the use of fracture assessment tools that help quantify time sensitive fracture risks by using patient specific data, advances in bone imaging and the relationship between structure and strength, new and future drug treatments for osteoporosis, and several unusual adverse clinical syndromes linked to the use of bisphosphonates. The topics chosen for this review highlight the increased understanding of bone structure and aging and how this knowledge can help clinicians in their treatment of osteoporosis. PMID- 20969547 TI - Ankylosing spondylitis - new criteria, new treatments. PMID- 20969548 TI - Trials and tribulations in systemic lupus erythematosus. AB - The pace of clinical trials activity in systemic lupus erythematosus (SLE) continues to accelerate. After decades of reliance on largely empiric approaches, a solid evidence-based foundation to guide our use of traditional agents, such as cyclophosphamide and azathioprine, is finally developing. In addition, we are learning how to integrate relatively new immunosuppressive agents, such as mycophenolate mofetil, into the treatment of SLE. These advances provide an important backdrop for recent trials designed to determine the potential value of several promising biologic therapies for SLE. PMID- 20969549 TI - Susceptibility genes for rheumatoid arthritis - a rapidly expanding harvest. AB - In addition to the HLA locus, over 30 genetic loci have been convincingly associated with risk for rheumatoid arthritis, and the majority of these associations have been identified in the last four years. Although this is a remarkable accomplishment, the majority of the genetic risk for RA still remains to be identified. Some of this "missing heritability" will likely be due to rare genetic variation, and will require extensive resequencing of the genomes of patients with RA. In addition, with few exceptions, the function and role in disease pathogenesis of the newly defined risk genes is unknown. Thus, the initial harvest of RA loci will catalyze new lines of hypothesis driven research to determine their role in disease pathogenesis. In addition, the rapidly advancing genetic technologies should lead to a more complete definition of the genetic underpinnings or RA in the next few years. PMID- 20969550 TI - Musculoskeletal ultrasound in the diagnosis of rheumatic disease. AB - The use of musculoskeletal ultrasound (MSKUS) in rheumatology practice and research has increased steadily over the last decade. An ever-growing body of literature shows parity and even superiority of MSKUS when compared to physical examination, plain radiography, and more expensive and static imaging modalities such as MRI. While many use the modality for procedure guidance, investigators continue to demonstrate its ability to impact diagnoses in a variety of rheumatic diseases. Initial efforts focused on establishing MSKUS as a helpful tool for rheumatoid arthritis (RA), especially in the detection of synovitis and joint erosions, but numerous studies are validating the use of MSKUS as a helpful diagnostic tool for the spondyloarthropathies, crystal diseases, osteoarthritis, and other rheumatic diseases. Advances in ultrasound technology are translating into more sensitive and accurate studies. Within the research community, current efforts aim at maximizing the direct clinical impact of MSKUS by developing global or patient level assessments and simplified joint scoring systems, with improvements in intra- and inter-reader reproducibility. PMID- 20969551 TI - Psoriatic arthritis - update on pathophysiology, assessment, and management. AB - Psoriatic arthritis (PsA) is classified as a spondyloarthropathy and characterized by synovitis, enthesitis, dactylitis, and spondylitis, usually manifesting in a person with skin and nail psoriasis. Our understanding about the PsA disease state, its genetics, pathophysiology, and comorbidities, as well as our ability to assess and treat the disease, has advanced as a result of significant collaborative efforts by rheumatologists and dermatologists. This work has been primarily in the development of classification criteria, outcome measures to assess the various clinical domains, and treatment trials with agents also used for diseases such as rheumatoid arthritis (RA) and psoriasis. Biologic agents, especially the anti-TNFs, have demonstrated significant efficacy and reasonable safety in all clinical domains of the disease, resulting in amelioration of clinical symptoms, inhibition of structural damage, and improvement of function and quality of life. A number of advances in assessment and treatment have occurred in the last few years, which are highlighted in this update. This article reviews assessment and treatment of PsA, with an emphasis on recent data. PMID- 20969552 TI - Gout and its comorbidities. AB - Gout is a chronic disease in which excessively high levels of serum urate (hyperuricemia) result in tissue depositions of sodium urate crystals and intermittent inflammatory attacks. Patients who have gout frequently experience a range of comorbidities, which complicates management and affects long-term prognosis. We review some of the more important of these comorbidities and consider the extent to which gout or hyperuricemia may be either a consequence or a cause of these related conditions. In addition, we briefly consider several neurological conditions in which the presence of gout or a high serum urate level may be associated with less disease, rather than more. PMID- 20969553 TI - TNF inhibitors - new and old agents for rheumatoid arthritis. AB - The development of tumor necrosis factor (TNF) inhibitor therapy has revolutionized the treatment of rheumatoid arthritis (RA). Unfortunately, no one single agent is fully effective in every patient; different patients respond to different therapies in different ways, even to those agents with the same mechanism of action. In this regard, newer TNF inhibitor agents, such as golimumab and certolizumab pegol, are a welcome addition to the treatment armamentarium of RA. This article addresses some of the recent advances in TNF inhibitor therapy for RA, including therapy involving these two newer agents and recent recommendations about well established TNF inhibitors (infiximab, etanercept, adalimumab) that may affect various aspects of RA treatment strategies. PMID- 20969554 TI - Anti-interleukin-6 therapy in rheumatoid arthritis. AB - Recent advances in research have led to significant progress in unraveling the pathophysiology of rheumatoid arthritis (RA), including the cytokine-mediated signaling process. While therapies targeting one particular cytokine, tumor necrosis factor-alpha (TNF-alpha), have revolutionized the treatment of RA, other cytokines, including interleukin 6 (IL-6,) have been implicated in the disease process. In this review, we describe the research that ultimately led to large, randomized, controlled trials demonstrating the effectiveness of tocilizumab, a monoclonal antibody directed against the IL-6 receptor, as a potent new therapeutic agent in RA treatment. These data have shown this agent to be effective both in patients failing non-biologic DMARDs and those failing anti-TNF therapy, although the drug is currently approved for use only in the latter situation. Adverse events seen with tocilizumab therapy are also reviewed. PMID- 20969555 TI - Vitamin D in lupus - new kid on the block? AB - Vitamin D is an essential steroid hormone, with well established effects on mineral metabolism, skeletal health, and recently established effects on the cardiovascular and immune systems. Vitamin D deficiency is highly prevalent and evidence is mounting that it contributes to the morbidity and mortality of multiple chronic diseases, including systemic lupus erythematosus (SLE). Patients with SLE avoid the sun because of photosensitive rashes and potential for disease fare, so adequate oral supplementation is critical. This review will describe the prevalence of vitamin D deficiency in patients with SLE, identify risk factors for deficiency, describe the consequences of deficiency, and review current vitamin D recommendations for patients with rheumatic diseases. PMID- 20969556 TI - Beyond RAPID3 - practical use of the MDHAQ to improve doctor-patient communication. AB - A multidimensional health assessment questionnaire (MDHAQ) can enhance doctor patient communication beyond the important function of providing RAPID3 scores, preparing the patient for the encounter and saving time for the doctor. Optimal use of the MDHAQ should include the following actions: 1. the MDHAQ should be distributed to each patient at each visit in the infrastructure of care; 2. the MDHAQ helps the patient prepare for the visit by completing it in the waiting area prior to seeing the physician; 3. the clinician prepares for the visit and saves time by reviewing the MDHAQ before seeing the patient; 4. the clinician scans the review of systems and records the number of positives on the symptom checklist; 5. the clinician reviews the recent medical history information to save time and improve accuracy and completeness of critical information; and 6. routine Assessment of Patient Index Data 3 (RAPID3) scores are recorded in the medical record and entered into a flowsheet, which also includes other MDHAQ scores, laboratory tests, and medications. PMID- 20969557 TI - Rheumatoid arthritis classification criteria - It's finally time to move on! AB - The diagnosis of rheumatoid arthritis (RA) is often challenging, due to a wide spectrum of presentations, progressive changes in disease course over time, and, perhaps, most importantly, lack of a clinical or laboratory gold standard to define the presence or absence of disease. Several attempts at the creation of RA classification criteria have been undertaken; however, each time, there have been significant limitations in applying these criteria to the clinical setting. Several components of the 1987 RA criteria require the presence of established joint damage; thus, they were limited in their ability to identify patients with early disease, potentially delaying initiation of early aggressive therapy until irreversible damage had occurred. With the recognition that early, aggressive therapy has the potential to decrease RA-associated morbidity and significantly alter disease course, there is clearly a need for criteria that also will facilitate early diagnosis and encourage initiation of therapy through disease modifying drugs (DMARDs). This mission recently has been taken on by a combined task force composed of membership from both the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), the outcomes of which are discussed below. PMID- 20969558 TI - When should a sleep-deprived EEG be performed following a presumed first seizure in adults? AB - OBJECTIVES: To evaluate the effect of the interval between the seizure and the EEG recording on the yield of early sleep-deprived EEG (SD-EEG) in patients admitted following a presumed first seizure. MATERIALS AND METHODS: We retrospectively reviewed the EEG recordings and medical records of patients admitted to the Neurology Department in Assaf Harofeh Medical Center because of a presumed first seizure during a 3-year period between 2006 and 2009 and who had a SD-EEG following a first routine EEG without epileptiform discharges (EDs). RESULTS: The study group included 78 patients aged 18-78 years (mean 35 +/- 17). Previous seizures were recognized through repeated history in 32 (41%) patients. EDs were recorded in the SD-EEG in 16 (21%) patients: 13/46 (28%) with a SD-EEG performed within 3 days following the seizure and 3/32 (9%) with a later SD-EEG (P = 0.042) and in 10/32 (31%) patients in whom previous seizures were recognized and 6/46 (13%) with a first seizure (P = 0.05). CONCLUSIONS: EDs in the SD-EEG following a first diagnosed seizure occur more commonly when the test is performed within 3 days following a first seizure or when previous seizures are recognized. PMID- 20969559 TI - Medication dose reductions after pallidal versus subthalamic stimulation in patients with Parkinson's disease. AB - OBJECTIVE: To compare the medication dose reduction between deep brain stimulation (DBS) of the globus pallidus interna (GPi) vs subthalamic nucleus (STN) in matched patients with Parkinson's disease (PD). MATERIALS AND METHODS: Records of 12 patients with PD who underwent GPi-DBS at our institution from 2002 to 2008 were matched by pre-operative PD medication doses and pre-operative motor Unified Parkinson's Disease Rating Scale (UPDRS) scores to 12 cases of STN-DBS. PD medication doses were converted to levodopa equivalent doses (LEDs). RESULTS: GPi and STN groups had similar mean pre-operative LEDs and motor UPDRS scores. At 6 months post-DBS, there was no significant difference in percent reduction in LEDs between the GPi (47.95%) and STN (37.47%) groups (P = 0.52). The mean post operative 'medication off/stimulation on' motor UPDRS scores did not differ significantly between GPi (15.33) and STN (16.25) groups (P = 0.74). The mean percent reduction in motor UPDRS scores was also similar between GPi (58.44%) and STN (58.98%) patients (P = 0.94). CONCLUSIONS: We conclude that in disease matched patients with PD undergoing DBS, both GPi and STN may result in similar reduction in PD medication doses. PMID- 20969562 TI - Cytosolic StAR-related lipid transfer domain 4 (STARD4) protein influences keratinocyte lipid phenotype and differentiation status. AB - BACKGROUND: Terminally differentiating keratinocytes actively synthesize and accumulate cholesterol, which is a key constituent of intercellular lipid lamellae which contribute to the epidermal permeability barrier. While the pathway for cholesterol biosynthesis is established, intracellular transport mechanisms for this lipid are poorly understood, despite their importance in regulating organelle sterol content, keratinocyte differentiation status and the activity of lipid-responsive transcription factors involved in skin health, repair and disease. Recent data implicate proteins containing a steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain in cellular cholesterol homeostasis. OBJECTIVES: To investigate gene expression of cytosolic, cholesterol-binding StAR-related lipid transfer domain 4 (STARD4) protein in primary human keratinocytes and differentiating HaCaT keratinocytes and, by overexpression of this protein, the function of STARD4 in HaCaT keratinocyte lipid phenotype and differentiation status. METHODS: Quantitative polymerase chain reaction was utilized to measure gene expression of STARD4 relative to the housekeeping gene GAPDH. Following transient (48 h) overexpression of STARD4, keratinocyte lipid mass and lipogenesis were measured, along with expression of genes involved in cholesterol homeostasis and those encoding a range of keratinocyte differentiation markers. RESULTS: Cholesterol-binding protein STARD4 is expressed in both primary and immortalized HaCaT keratinocytes, and is repressed during Ca(2+) -dependent differentiation of the latter. Transient overexpression of STARD4 reduces endogenous [(14) C]cholesterol and cholesteryl ester biosynthesis, and triggers increased expression of SREBF2, ABCG4 and LOR, while repressing expression of ABCA1. CONCLUSIONS: The cytosolic cholesterol sensing protein STARD4 modulates both keratinocyte cholesterol homeostasis and differentiation status, increasing the efficiency of cholesterol trafficking within the cell, and amplifying and 'fine-tuning' cellular responses to this sterol. Modulation of expression of STARD4, and other members of the START family of lipid trafficking proteins, may prove useful in resolving imbalances in lipid metabolism associated with loss of epidermal barrier function in psoriasis and atopic dermatitis. PMID- 20969563 TI - A randomized, double-blind, negatively controlled pilot study to determine whether the use of emollients or calcipotriol alters the sensitivity of the skin to ultraviolet radiation during phototherapy with narrowband ultraviolet B. AB - BACKGROUND: There is contradictory evidence suggesting that emollients increase, decrease or have no effect on minimal erythema dose (MED) or minimal phototoxic dose values prior to phototherapy. Few studies have looked at the in vivo use of emollients or calcipotriol prior to narrowband ultraviolet (UV) B (NB-UVB) treatment. OBJECTIVES: To investigate whether emollients or calcipotriol alter MED readings of skin on the back of healthy subjects prior to NB-UVB irradiation. METHODS: Topical agents were applied to the backs of 20 healthy volunteers for 30 min prior to MED testing. These agents were aqueous cream, 50:50 white soft paraffin and liquid paraffin, Diprobase((r)) (Schering-Plough, Welwyn Garden City, U.K.), Epaderm((r)) (Medlock, Oldham, U.K.) and calcipotriol ointment and cream. A control MED strip was used with no topical agent applied prior to testing. MED readings were recoded as integer steps between 1 and 9 (one is lowest MED dose for skin type; eight is highest; nine is no response, i.e. a higher MED). RESULTS: The median MED was between step 5 and 6 for all treatments and control. There was no significant difference at the 5% level between control and each topical agent. The study was powered to detect a median difference of approximately 0.4-0.6 steps. CONCLUSIONS: This has important implications at a practical level when advising patients not to apply creams prior to treatment with NB-UVB. Studies where agents are applied immediately prior to phototherapy have been more likely to show that emollients block transmission of UV radiation. If they are applied at least 30 min prior to treatment, they have no effect. PMID- 20969564 TI - Systemic photoprotection in solar urticaria with alpha-melanocyte-stimulating hormone analogue [Nle4-D-Phe7]-alpha-MSH. AB - BACKGROUND: Solar urticaria is a rare photosensitivity disorder demonstrating a range of action spectra, which can inflict a very large impact on life quality despite available treatments. Melanin broadly reduces skin penetration by ultraviolet-visible wavelengths, thus increased melanization may protect in solar urticaria. OBJECTIVES: To examine quantitatively for impact of the potent alpha melanocyte stimulating hormone analogue afamelanotide ([Nle(4)-D-Phe(7)]-alpha MSH, Scenesse((r)); Clinuvel Pharmaceuticals Ltd, Melbourne, Vic., Australia) on the solar urticaria response and skin melanization. METHODS: Five patients with solar urticaria received a single dose of 16 mg subcutaneous afamelanotide implant in winter time. Melanin density was assessed spectrophotometrically from day 0 to day 60. Detailed monochromated light testing to geometric dose series (increment ) of wavelengths 300-600 nm was performed at 0, 30 and 60 days, with assessment of weal and flare area and minimum urticarial dose (MUD). Data were analysed by repeated-measures anova. RESULTS: Mean melanin density increased by day 7, peaked at day 15 and remained elevated at day 60 (P=0.03, 0.01, 0.02 vs. baseline, respectively). Baseline phototesting revealed action spectra of 320-400 (n=1), 320-500 (n=2), 300-600 (n=1) and 370-500 nm (n=1), and on afamelanotide mean rises in MUD of 1-12 and 1-3 dose increments were seen at the individual wavelengths tested, at 30 and 60 days, respectively. A significant fall in weal area occurred across responding wavelengths from 300 to 600 nm at 60 days postimplant (P=0.049 vs. baseline), accompanied by greater than twofold overall increase in MUD (P=0.058 vs. baseline). CONCLUSIONS: Melanization following afamelanotide is accompanied by reduction in solar urticaria response across a broad spectrum of wavelengths. Further study is warranted to assess clinical benefit under ambient conditions in summer. PMID- 20969565 TI - Primary cutaneous CD8+ small/medium-sized pleomorphic T-cell lymphoma, ear-type: a unique cutaneous T-cell lymphoma with a favourable prognosis. PMID- 20969566 TI - Identifying and classifying juvenile stalking behavior. AB - Despite the growing research in the area of stalking, the focus has been on adults who engage in this behavior. Unfortunately, almost no studies investigate the prevalence of this behavior in adolescents. Two cases are presented demonstrating not only that stalking occurs during the period of adolescence, but also that there is a significant difference in the motivation underlying this behavior that can be classified similarly to that of adult stalkers. Further, a suggested classification based on these two cases as well as our experience with other juveniles who have exhibited stalking behaviors is proposed. The first case involves a narcissistic youth who also possesses psychopathic traits, while the second involves a lonely, severely socially awkward teen. Juvenile stalking is a societal problem that has not yet garnered the attention it deserves, and all systems that deal with juvenile delinquency (juvenile court, law enforcement, and mental health personnel) as well as the school system must be educated to the prevalence and severity of this yet-to-be-recognized problem. PMID- 20969567 TI - Post-translational modification of glutamic acid decarboxylase 67 by intermittent hypoxia: evidence for the involvement of dopamine D1 receptor signaling. AB - Intermittent hypoxia (IH) associated with sleep apnea leads to cardio-respiratory morbidities. Previous studies have shown that IH alters the synthesis of neurotransmitters including catecholamines and neuropeptides in brainstem regions associated with regulation of cardio-respiratory functions. GABA, a major inhibitory neurotransmitter in the CNS, has been implicated in cardio-respiratory control. GABA synthesis is primarily catalyzed by glutamic acid decarboxylase (GAD). In this study, we tested the hypothesis that IH like its effect on other transmitters also alters GABA synthesis. The impact of IH on GABA synthesis was investigated in pheochromocytoma 12 cells, a neuronal cell line which is known to express active form of GAD67 in the cytosolic fraction and also assessed the underlying mechanisms contributing to IH-evoked response. Exposure of cell cultures to IH decreased GAD67 activity and GABA level. IH-evoked decrease in GAD67 activity was caused by increased cAMP - protein kinase A (PKA) - dependent phosphorylation of GAD67, but not as a result of changes in either GAD67 mRNA or protein expression. PKA inhibitor restored GAD67 activity and GABA levels in IH treated cells. Pheochromocytoma 12 cells express dopamine 1 receptor (D1R), a G protein coupled receptor whose activation increased adenylyl cyclase activity. Treatment with either D1R antagonist or adenylyl cyclase inhibitor reversed IH evoked GAD67 inhibition. Silencing D1R expression with siRNA reversed cAMP elevation and GAD67 inhibition by IH. These results provide evidence for the role of D1R-cAMP-PKA signaling in IH-mediated inhibition of GAD67 via protein phosphorylation resulting in down-regulation of GABA synthesis. PMID- 20969568 TI - The deletion of the microtubule-associated STOP protein affects the serotonergic mouse brain network. AB - The deletion of microtubule-associated protein stable tubule only polypeptide (STOP) leads to neuroanatomical, biochemical and severe behavioral alterations in mice, partly alleviated by antipsychotics. Therefore, STOP knockout (KO) mice have been proposed as a model of some schizophrenia-like symptoms. Preliminary data showed decreased brain serotonin (5-HT) tissue levels in STOP KO mice. As literature data demonstrate various interactions between microtubule-associated proteins and 5-HT, we characterized some features of the serotonergic neurotransmission in STOP KO mice. In the brainstem, mutant mice displayed higher tissue 5-HT levels and in vivo synthesis rate, together with marked increases in 5-HT transporter densities and 5-HT1A autoreceptor levels and electrophysiological sensitivity, without modification of the serotonergic soma number. Conversely, in projection areas, STOP KO mice exhibited lower 5-HT levels and in vivo synthesis rate, associated with severe decreases in 5-HT transporter densities, possibly related to reduced serotonergic terminals. Mutant mice also displayed a deficit of adult hippocampal neurogenesis, probably related to both STOP deletion and 5-HT depletion. Finally, STOP KO mice exhibited a reduced anxiety- and, probably, an increased helpness-status, that could be because of the strong imbalance of the serotonin neurotransmission between somas and terminals. Altogether, these data suggested that STOP deletion elicited peculiar 5-HT disconnectivity. PMID- 20969569 TI - Pharmacological and neurochemical characterization of the involvement of hippocampal adrenoreceptor subtypes in the modulation of acute limbic seizures. AB - Noradrenaline exerts inhibitory effects on seizure susceptibility. Subtype selective agonists and antagonists were used to identify the anticonvulsant hippocampal adrenoreceptors. Intrahippocampal dialysis was used for administration of all compounds, including pilocarpine for limbic seizure induction, and as the neurotransmitter sampling tool. The noradrenaline reuptake inhibitor maprotiline mediated anticonvulsant effects, associated with dose dependent increases in extracellular hippocampal noradrenaline, dopamine and GABA levels. At high concentrations, maprotiline produced proconvulsant effects associated with high levels of noradrenaline, dopamine and glutamate. Maprotiline's anticonvulsant effect was blocked by administration of either a selective alpha(2) - and beta(2) -antagonist. alpha(2) -Antagonist administration with maprotiline was associated with a further increase in noradrenaline and dopamine from maprotiline alone; whereas beta(2) -antagonist administered with maprotiline inhibited the dopamine increases produced by maprotiline. alpha(1A) Antagonism blocked the GABA-ergic but not the anticonvulsive effect of maprotiline. These results were confirmed as combined but not separate alpha(2) - and beta(2) -adrenoreceptor stimulation, using selective agonists, inhibited limbic seizures. Interestingly, alpha(1A) -receptor stimulation and alpha(1D) antagonism alone also inhibited seizures associated with respectively significant hippocampal GABA increases and glutamate decreases. The main findings of this study are that (i) increased hippocampal noradrenergic neurotransmission inhibits limbic seizures via combined alpha(2) - and beta(2) -receptor activation and (ii) alpha(1A) - and alpha(1D) -adrenoreceptors mediate opposite effects on hippocampal excitability. PMID- 20969571 TI - Voltage-dependent and -independent block of alpha-amino-3-hydroxy-5 methylisoxazole-4-propionate receptor channels. AB - Polyamine-containing toxins and synthetic dicationic derivatives of adamantane and phenylcyclohexyl selectively antagonize Ca(2+)-permeable alpha-amino-3 hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor channels. These compounds demonstrate voltage-dependent open-channel block and are trapped by closed channels. In this study, we describe an alternative mechanism of non-competitive AMPA receptor inhibition caused by 9-aminoacridine and some of its derivatives. These compounds exhibit similar potency against Ca(2+)-permeable and Ca(2+) impermeable AMPA receptors. The inhibition is largely voltage-independent, binding and unbinding do not require presence of agonist. We conclude that 9 aminoacridine binds to a shallow site in the AMPA receptor, which is located above the activation gate. A comparison of three-dimensional structures of the antagonists suggests that the 'V-like' shape of the hydrophobic headgroup favors voltage-dependent binding to the deep site in the channel pore, whereas the compounds possessing flat aromatic headgroups preferably bind to the shallow site. The characterization of the novel mechanism of AMPA receptor channel antagonism opens a way to develop a new family of pharmacological agents, which can be of scientific and practical importance. PMID- 20969572 TI - Identification of CD44 as a cell surface marker for Muller glia precursor cells. AB - In the retina, both neurons and glia differentiate from a common progenitor population. CD44 cell surface antigen is a hyaluronic acid receptor expressed on mature Muller glial cells. We found that in the developing mouse retina, expression of CD44 was transiently observed at or around birth in a subpopulation of c-kit-positive retinal progenitor cells. During in vitro culture, purified CD44/c-kit-positive retinal progenitor cells exclusively differentiated into Muller glial cells and not into neurons, suggesting that CD44 marks a subpopulation of retinal progenitor cells that are fated to become glia. Over expression of CD44 inhibited the extension of processes by Muller glial cells and neurons. Notch signaling is known to be involved in the specification of retinal progenitors into a glial fate. Activation of Notch signaling increased the number of CD44-positive cells, and treatment with the Notch signal inhibitor, DAPT, at early, but not later, stages of retinal development abolished both CD44-positive cells and Muller glial cells. Together, CD44 was identified as an early cell surface marker of the Muller glia lineage, and Notch signalling was involved in commitment of retinal progenitor cells to CD44 positive Muller glial precursor cells. PMID- 20969570 TI - Rapid microelectrode measurements and the origin and regulation of extracellular glutamate in rat prefrontal cortex. AB - Glutamate in the prefrontal cortex (PFC) plays a significant role in several mental illnesses, including schizophrenia, addiction and anxiety. Previous studies on PFC glutamate-mediated function have used techniques that raise questions on the neuronal versus astrocytic origin of glutamate. The present studies used enzyme-based microelectrode arrays to monitor second-by-second resting glutamate levels in the PFC of awake rats. Locally applied drugs were employed in an attempt to discriminate between the neuronal or glial components of the resting glutamate signal. Local application of tetrodotoxin (sodium channel blocker), produced a significant (~ 40%) decline in resting glutamate levels. In addition significant reductions in extracellular glutamate were seen with locally applied omega-conotoxin (MVIIC; ~ 50%; calcium channel blocker), and the mGluR(2/3) agonist, LY379268 (~ 20%), and a significant increase with the mGluR(2/3) antagonist LY341495 (~ 40%), effects all consistent with a large neuronal contribution to the resting glutamate levels. Local administration of D,L-threo-beta-benzyloxyaspartate (glutamate transporter inhibitor) produced an ~ 120% increase in extracellular glutamate levels, supporting that excitatory amino acid transporters, which are largely located on glia, modulate clearance of extracellular glutamate. Interestingly, local application of (S)-4 carboxyphenylglycine (cystine/glutamate antiporter inhibitor), produced small, non-significant bi-phasic changes in extracellular glutamate versus vehicle control. Finally, pre-administration of tetrodotoxin completely blocked the glutamate response to tail pinch stress. Taken together, these results support that PFC resting glutamate levels in rats as measured by the microelectrode array technology are at least 40-50% derived from neurons. Furthermore, these data support that the impulse flow-dependent glutamate release from a physiologically evoked event is entirely neuronally derived. PMID- 20969574 TI - Constitutive phosphorylation by protein kinase C regulates D1 dopamine receptor signaling. AB - The D(1) dopamine receptor (D(1) DAR) is robustly phosphorylated by multiple protein kinases, yet the phosphorylation sites and functional consequences of these modifications are not fully understood. Here, we report that the D(1) DAR is phosphorylated by protein kinase C (PKC) in the absence of agonist stimulation. Phosphorylation of the D(1) DAR by PKC is constitutive in nature, can be induced by phorbol ester treatment or through activation of Gq-mediated signal transduction pathways, and is abolished by PKC inhibitors. We demonstrate that most, but not all, isoforms of PKC are capable of phosphorylating the receptor. To directly assess the functional role of PKC phosphorylation of the D(1) DAR, a site-directed mutagenesis approach was used to identify the PKC sites within the receptor. Five serine residues were found to mediate the PKC phosphorylation. Replacement of these residues had no effect on D(1) DAR expression or agonist-induced desensitization; however, G protein coupling and cAMP accumulation were significantly enhanced in PKC-null D(1) DAR. Thus, constitutive or heterologous PKC phosphorylation of the D(1) DAR dampens dopamine activation of the receptor, most likely occurring in a context-specific manner, mediated by the repertoire of PKC isozymes within the cell. PMID- 20969573 TI - Amphetamine modulation of long-term potentiation in the prefrontal cortex: dose dependency, monoaminergic contributions, and paradoxical rescue in hyperdopaminergic mutant. AB - Amphetamine can improve cognition in healthy subjects and patients with schizophrenia, attention-deficit hyperactivity disorder, and other neuropsychiatric diseases; higher doses, however, can impair cognitive function, especially those mediated by the prefrontal cortex. We investigated how amphetamine affects prefrontal cortex long-term potentiation (LTP), a cellular correlate of learning and memory, in normal and hyperdopaminergic mice lacking the dopamine transporter. Acute amphetamine treatment in wild-type mice produced a biphasic dose-response modulation of LTP, with a low dose enhancing LTP and a high dose impairing it. Amphetamine-induced LTP enhancement was prevented by pharmacological blockade of D(1) - (but not D(2)-) class dopamine receptors, by blockade of beta-adrenergic receptors, or by inhibition of cAMP-PKA signaling. In contrast, amphetamine-induced LTP impairment was prevented by inhibition of post synaptic protein phosphatase-1, a downstream target of PKA signaling, or by blockade of either D(1) - or D(2)-class dopamine, but not noradrenergic, receptors. Thus, amphetamine biphasically modulates LTP via cAMP-PKA signaling orchestrated mainly through dopamine receptors. Unexpectedly, amphetamine restored the loss of LTP in dopamine transporter-knockout mice primarily by activation of the noradrenergic system. Our results mirror the biphasic effectiveness of amphetamine in humans and provide new mechanistic insights into its effects on cognition under normal and hyperdopaminergic conditions. PMID- 20969575 TI - Anti-inflammatory mechanism of ginsenoside Rh1 in lipopolysaccharide-stimulated microglia: critical role of the protein kinase A pathway and hemeoxygenase-1 expression. AB - Microglia activation plays a pivotal role in neurodegenerative diseases, and thus controlling microglial activation has been suggested as a promising therapeutic strategy for neurodegenerative diseases. In the present study, we showed that ginsenoside Rh1 inhibited inducible nitric oxide synthase, cyclooxygenase-2, and pro-inflammatory cytokine expression in lipopolysaccharide (LPS)-stimulated microglia, while Rh1 increased anti-inflammatory IL-10 and hemeoxygenase-1 (HO-1) expression. Suppression of microglial activation by Rh1 was also observed in the mouse brain following treatment with LPS. Subsequent mechanistic studies revealed that Rh1 inhibited LPS-induced MAPK phosphorylation and nuclear factor-kappaB (NF kappaB)-mediated transcription without affecting NF-kappaB DNA binding. As the increase of pCREB (cAMP responsive element-binding protein) is known to result in suppression of NF-kappaB-mediated transcription, we examined whether Rh1 increased pCREB levels. As expected, Rh1 increased pCREB, which was shown to be related to the anti-inflammatory effect of Rh1 because pre-treatment with protein kinase A inhibitors attenuated the Rh1-mediated inhibition of nitric oxide production and the up-regulation of IL-10 and HO-1. Furthermore, treatment of HO 1 shRNA attenuated Rh1-mediated inhibition of nitric oxide and reactive oxygen species production. Through this study, we have demonstrated that protein kinase A and its downstream effector, HO-1, play a critical role in the anti inflammatory mechanism of Rh1 by modulating pro- and anti-inflammatory molecules in activated microglia. PMID- 20969577 TI - Increased gelling agent concentration promotes somatic embryo maturation in hybrid larch (Larix * eurolepsis): a 2-DE proteomic analysis. AB - An integrated physiological and proteomic approach was used to investigate the effects of high gellan gum concentration in the medium during maturation of somatic embryos (SE) of hybrid larch, by comparing embryos incubated in media with a high gellan gum concentration (8 g l(-1) ) and the standard concentration (4 g l(-1) ) after 1, 3, 6 and 8 weeks of maturation. Because of the reduced availability of water in the 8 g l(-1) medium, the cultured embryos had a lower osmotic water potential (Psipi) and water contents, but higher dry weights (DWs), at 8 weeks compared with embryos cultured on the standard medium. The high gellan gum concentration induced a desiccation that is characteristic in zygotic embryo maturation. Total soluble proteins were extracted from SE with trichloroacetic acid (TCA)-acetone after 1 and 8 weeks of maturation on media with 4 and 8 g l( 1) of gellan gum, and separated by two-dimensional gel electrophoresis (2-DE) at pH 4-7. More than 1100 proteins were reproducibly detected on each gel. At 1 and 8 weeks respectively, the abundances of 62 and 49 spots detected in analyses of embryos matured at the two gellan gum concentrations, significantly differed. Among 62 significantly differing spots at 1 week of maturation, the corresponding proteins of 56 were reliably identified by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS), and were found to be mainly involved in 'carbohydrate metabolism', 'genetic information processing' or 'environmental information processing' according to kegg taxonomy. Both physiological parameters and the proteins identified suggested that the embryos were stressed when they were cultured on 4 g l(-1) of gellan gum. PMID- 20969578 TI - Ecophysiology of photosynthesis in bryophytes: major roles for oxygen photoreduction and non-photochemical quenching? AB - CO(2) fixation in mosses saturates at moderate irradiances. Relative electron transport rate (RETR) inferred from chlorophyll fluorescence saturates at similar irradiance in shade species (e.g. Plagiomnium undulatum, Trichocolea tomentella), but many species of unshaded habitats (e.g. Andreaea rothii, Schistidium apocarpum, Sphagnum spp. and Frullania dilatata) show non-saturating RETR at high irradiance, with high non-photochemical quenching (NPQ). In P. undulatum and S. apocarpum, experiments in different gas mixtures showed O(2) and CO(2) as interchangeable electron sinks. Nitrogen + saturating CO(2) gave high RETR and depressed NPQ. In S. apocarpum, glycolaldehyde (inhibiting photosynthesis and photorespiration) depressed RETR in air more at low than at high irradiance; in CO(2) -free air RETR was maintained at all irradiances. Non-saturating electron flow was not suppressed in ambient CO(2) with 1% O(2) . The results indicate high capacity for oxygen photoreduction when CO(2) assimilation is limited. Non saturating light-dependent H(2) O(2) production, insensitive to glycolaldehyde, suggests that electron transport is supported by oxygen photoreduction, perhaps via the Mehler-peroxidase reaction. Consistent with this, mosses were highly tolerant to paraquat, which generates superoxide at photosystem I (PSI). Protection against excess excitation energy in mosses involves high capacity for photosynthetic electron transport to oxygen and high NPQ, activated at high irradiance, alongside high reactive oxygen species (ROS) tolerance. PMID- 20969576 TI - AMPA receptor mediated D-serine release from retinal glial cells. AB - The N-methyl-D-aspartate receptor (NMDAR) co-agonist D-serine is important in a number of different processes in the CNS, ranging from synaptic plasticity to disease states, including schizophrenia. D-serine appears to be the major co agonist acting on retinal ganglion cell NMDA receptors, but the cell type from which it originates and whether its release can be modulated by activity are unknown. In this study, we utilized a mutant mouse line with elevated d-serine to investigate this question. Direct measurements of extracellular D-serine using capillary electrophoresis demonstrate that D-serine can be released from the intact mouse retina through an alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionate receptor (AMPAR) dependent mechanism. alpha-Amino-3-hydroxyl-5-methyl 4-isoxazole-propionate-evoked D-serine release persisted in the presence of a cocktail of neural inhibitors but was abolished after administration of a glial toxin. These findings provide the first evidence that extracellular D-serine levels in the retina can be modulated, and that such modulation is contingent upon glial cell activity. PMID- 20969579 TI - Hereditary kidney diseases: highlighting the importance of classical Mendelian phenotypes. AB - A Mendelian inheritance underlies a nonnegligible proportion of hereditary kidney diseases, suggesting that the encoded proteins are essential for maintenance of the renal function. The identification of genes involved in congenital anomalies of the kidney and in familial forms of nephrotic syndrome significantly increased our understanding of the renal development and kidney filtration barrier physiology. This review will focus on the classical phenotype and clinical heterogeneity observed in the monogenic forms of these disorders. In addition, the role of susceptibility genes in kidney diseases with a complex inheritance will also be discussed. PMID- 20969580 TI - Clues to immune tolerance: the monogenic autoimmune syndromes. AB - Autoimmune disease affects a significant proportion of the population. The etiology of most autoimmune diseases is largely unknown, but it is thought to be multifactorial with both environmental and genetic influences. Rare monogenic autoimmune diseases, however, offer an invaluable window into potential disease mechanisms. In this review, we will discuss the autoimmune polyglandular syndrome (APS1), the immunedysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), and autoimmune lymphoproliferative syndrome (ALPS). Significantly, the information gained from the study of these diseases has provided new insights into more common autoimmune disease and have yielded new diagnostics and therapeutic opportunities. PMID- 20969582 TI - A map for lineage restriction of progenitors during hematopoiesis: the essence of the myeloid-based model. AB - Most hematology and immunology textbooks describe that the first branch point from the hematopoietic stem cells (HSCs) produces two progenitors, one for myelo erythroid cells and the other for lymphoid cells including T and B cells. This model is based on the concept that the blood cell family can be subdivided into two major lineages, a myelo-erythroid lineage and a lymphoid lineage. Several alternative models have been proposed during the last three decades. We proposed the myeloid-based model in 2001, in which myeloid potential is retained in an early stage of branches toward erythroid, T-, and B-cell lineages. In this review, we focus on the point that cell differentiation models have two different facets: as a map of developmental potential and a cell fate map. These two are expressed in other words as a map for lineage restriction and a map for physiological production routes. We argue that a map of potential is first and foremost essential for the study of molecular mechanisms of lineage commitment, which is the least clarified aspect of cell differentiation. The validity of the myeloid-based model of hematopoiesis will be discussed in reference to these two issues, developmental potential and cell fate. PMID- 20969581 TI - T-cell lineage determination. AB - T cells originate from hematopoietic stem cells (HSCs) in the bone marrow but complete their development in the thymus. HSCs give rise to a variety of non renewing hematopoietic progenitors, among which a rare subset migrates to the thymus via the bloodstream. The earliest T-cell progenitors identified in the thymus are not T-lineage restricted but possess the ability to give rise to cells of many different lineages. Alternative lineage potentials are gradually lost as progenitors progress toward later developmental stages. Here, we review the early developmental events that might be involved in T-cell lineage fate determination, including the properties of possible thymus-settling progenitors, their homing into the thymus, and their T-cell lineage specification and commitment. PMID- 20969584 TI - Load and lock: the molecular mechanisms of B-lymphocyte commitment. AB - The maturation of B-lymphoid cells from hematopoietic stem cells in the bone marrow is a complex process under control of interplay between extrinsic and intrinsic factors. In addition to serving as a model for normal cell differentiation, disturbances in this process results in immunodeficiencies and malignancies, such as leukemia and lymphoma, making the subject of high relevance for modern medicine. Although the process of B lymphopoiesis has been under intense investigation, recent methodological developments within the area of cell sorting, genome-wide expression, and DNA-binding analysis has allowed for a rapid development of the understanding of B-lymphocyte differentiation. This has suggested that the path to B-lymphoid cell fate may be initiated by lineage priming reflected in the expression of lymphoid associated genes already in multipotent hematopoietic progenitors. Upon differentiation, the gene expression profile is changed to involve an increasing number of B-lineage-restricted genes linked to loss of alternative developmental potentials and B-lineage commitment. This review focuses on the molecular regulation of early B-lymphoid development and aims to provide an up to date summary of the current status of the research area. PMID- 20969583 TI - Lymphoid and myeloid lineage commitment in multipotent hematopoietic progenitors. AB - Hematopoietic stem cells (HSCs) continuously replenish all classes of blood cells through a series of lineage restriction steps that results in the progressive loss of differentiation potential to other cell lineages. This review focuses on the recent advances in understanding one of the earliest differentiation steps in HSC maturation, which involves the diversification of the lymphoid and myeloid cell lineages, the two major branches of hematopoietic cells. We discuss progress in the identification and characterization of progenitor populations downstream of HSCs, which has been a key to understanding the sequential biological events that take place along the course of differentiation into a certain hematopoietic cell type. We also discuss the importance of bone marrow microenvironment in lymphoid and myeloid lineage choice. PMID- 20969585 TI - Surprising new roles for PU.1 in the adaptive immune response. AB - The ETS family transcription factor PU.1 is one of the best-studied regulators of hematopoiesis. While research over the past two decades has established that PU.1 is essential for many aspects of lymphoid and myeloid cell development, the more recent development of the tools that enable PU.1 function to be assessed in adult mice and in specific cell lineages has led to the discovery of some surprising new roles of this versatile factor in the adaptive immune response. Despite being required for fetal lymphopoiesis, PU.1 is dispensable for the differentiation of committed B cells. There is, however, an emerging and still uncharacterized function of PU.1 as a repressor for late B-cell differentiation. In contrast, PU.1 is required at every point for the differentiation of all dendritic cells, in part, although its regulation of the crucial receptor Flt3. Within the T-cell lineage, PU.1 is required for the earliest thymic development, although the mechanism remains unknown, while recent studies have shown a previously unknown function of PU.1 in peripheral T-cell differentiation. Here, we review insights derived from these mouse models of PU.1 deficiency, with particular emphasis on these functions of PU.1 in the lymphocyte and dendritic cell lineages. PMID- 20969586 TI - Mechanisms regulating dendritic cell specification and development. AB - Understanding the diversification of dendritic cell (DC) lineages is one of the last frontiers in mapping the developmental hierarchy of the hematopoietic system. DCs are a vital link between the innate and adaptive immune responses; thus, elucidating their developmental pathways is crucial for insight into the generation of natural immunity and for learning how to regulate DCs in clinical settings. DCs arise from hematopoietic stem cells through specialized progenitor subsets under the direction of FMS-like tyrosine kinase 3 ligand (Flt3L) and Flt3L receptor (Flt3) signaling. Recent studies have revealed important contributions from granulocyte-macrophage colony-stimulating factor (GM-CSF) and type I interferons (IFNs) in vivo. Furthermore, DC development is guided by lineage-restricted transcription factors such as IRF8, E2-2, and Batf3. A critical question centers on how cytokines and lineage-restricted transcription factors operate molecularly to direct DC diversification. Here, we review recent findings that provide new insight into the DC developmental process. PMID- 20969589 TI - The intrathymic crossroads of T and NK cell differentiation. AB - T lymphocytes depend on the thymic microenvironment for initiation of the T-cell developmental program. As the progenitors in the thymus have lost the capacity to self-renew, this process depends on the constant influx of hematopoietic progenitors that originate in the bone marrow. Nevertheless, thymic emigrants are heterogeneous and retain developmental plasticity for both the myeloid and lymphoid lineages. It is the role of the thymic microenvironment to steer these uncommitted progenitors toward a T-cell fate. Still, the thymus also generates a unique population of thymic NK cells, thus raising the question of how the T versus NK lymphoid cell fate is determined intrathymically. Many factors have been implicated in the developmental pathways in the thymus, and the processes are characterized by both subtle and not so subtle modifications in gene expression. In this review, we consider the crucial factors governing lineage determination of T cells versus NK cells from bi-potent thymic NK/T precursors. Recent reports have shed new light on the complex interactions of cytokines and transcription factors at different cell fate decision branch points in thymopoiesis. We discuss the implications of these findings and propose a model that may be applicable at this critical thymic NK/T juncture. PMID- 20969590 TI - Critical roles of Bcl11b in T-cell development and maintenance of T-cell identity. AB - T-cell development primarily occurs in the thymus and involves in the interactions of many important transcription factors. Until recently, no single transcription factor has been identified to be essential for T-cell lineage commitment or maintenance of T-cell identity. Recent studies have now identified the zinc finger transcription factor Bcl11b to be essential for T-cell development and for maintenance of T-cell identity. Remarkably, T cells acquire NK cell properties upon Bcl11b deletion. These reprogrammed cells have unique properties in proliferation, cytokine dependency and killing target cells, and may therefore provide a new cell source for some cell-based therapies. PMID- 20969588 TI - From the cradle to the grave: activities of GATA-3 throughout T-cell development and differentiation. AB - GATA family transcription factors play multiple vital roles in hematopoiesis in many cell lineages, and in particular, T cells require GATA-3 for execution of several developmental steps. Transcriptional activation of the Gata3 gene is observed throughout T-cell development and differentiation in a stage-specific fashion. GATA-3 has been described as a master regulator of T-helper 2 (Th2) cell differentiation in mature CD4(+) T cells. During T-cell development in the thymus, its roles in the CD4 versus CD8 lineage choice and at the beta-selection checkpoint are the best characterized. In contrast, its importance prior to beta selection has been obscured both by the developmental heterogeneity of double negative (DN) 1 thymocytes and the paucity of early T-lineage progenitors (ETPs), a subpopulation of DN1 cells that contains the most immature thymic progenitors that retain potent T-lineage developmental potential. By examining multiple lines of in vivo evidence procured through the analysis of Gata3 mutant mice, we have recently demonstrated that GATA-3 is additionally required at the earliest stage of thymopoiesis for the development of the ETP population. Here, we review the characterized functions of GATA-3 at each stage of T-cell development and discuss hypothetical molecular pathways that mediate these functions. PMID- 20969587 TI - E proteins and the regulation of early lymphocyte development. AB - Lymphopoiesis generates mature B, T, and NK lymphocytes from hematopoietic stem cells via a series of increasingly restricted developmental intermediates. The transcriptional networks that regulate these fate choices are composed of both common and lineage-specific components, which combine to create a cellular context that informs the developmental response to external signals. E proteins are an important factor during lymphopoiesis, and E2A in particular is required for normal T- and B-cell development. Although the other E proteins, HEB and E2 2, are expressed during lymphopoiesis and can compensate for some of E2A's activity, E2A proteins have non-redundant functions during early T-cell development and at multiple checkpoints throughout B lymphopoiesis. More recently, a role for E2A has been demonstrated in the generation of lymphoid primed multipotent progenitors and shown to favor their specification toward lymphoid over myeloid lineages. This review summarizes both our current understanding of the wide-ranging functions of E proteins during the development of adaptive lymphocytes and the novel functions of E2A in orchestrating a lymphoid-biased cellular context in early multipotent progenitors. PMID- 20969591 TI - Multilayered specification of the T-cell lineage fate. AB - T-cell development from stem cells has provided a highly accessible and detailed view of the regulatory processes that can go into the choice of a cell fate in a postembryonic, stem cell-based system. But it has been a view from the outside. The problems in understanding the regulatory basis for this lineage choice begin with the fact that too many transcription factors are needed to provide crucial input: without any one of them, T-cell development fails. Furthermore, almost all the factors known to provide crucial functions during the climax of T-lineage commitment itself are also vital for earlier functions that establish the pool of multilineage precursors that would normally feed into the T-cell specification process. When the regulatory genes that encode them are mutated, the confounding effects on earlier stages make it difficult to dissect T-cell specification genetically. Yet both the positive and the negative regulatory events involved in the choice of a T-cell fate are actually a mosaic of distinct functions. New evidence has emerged recently that finally provides a way to separate the major components that fit together to drive this process. Here, we review insights into T-cell specification and commitment that emerge from a combination of molecular, cellular, and systems biology approaches. The results reveal the regulatory structure underlying this lineage decision. PMID- 20969593 TI - Expanding roles for ThPOK in thymic development. AB - The role of the zinc finger transcription factor ThPOK (T-helper-inducing POZ Kruppel-like factor) in promoting commitment of alphabeta T cells to the CD4 lineage is now well established. New results indicate that ThPOK is also important for the development and/or acquisition of effector functions by other T cell subsets, including several not marked by CD4 expression, i.e. double negative invariant natural killer T (iNKT) cells, gammadelta cells, and even memory CD8(+) T cells. There is compelling evidence that ThPOK expression in most or all of these cases is dependent on T-cell receptor signaling and that differences in relative TCR signal strength/length may induce different levels of ThPOK expression. The developmental consequences of ThPOK expression vary according to cell type, which may partly reflect differences in ThPOK levels and/or in transcriptional networks between cell types. PMID- 20969592 TI - alphabeta versus gammadelta fate choice: counting the T-cell lineages at the branch point. AB - Both alphabeta and gammadelta T cells develop in the thymus from a common progenitor. Historically distinguished by their T-cell receptor (TCR), these lineages are now defined on the basis of distinct molecular programs. Intriguingly, in many transgenic and knockout systems these programs are mismatched with the TCR type, leading to the development of gammadelta lineage cells driven by alphabetaTCR and vice versa. These puzzling observations were recently explained by the demonstration that TCR signal strength, rather than TCR type per se, instructs lineage fate, with stronger TCR signal favoring gammadelta and weaker signal favoring alphabeta lineage fates. These studies also highlighted the ERK (extracellular signal regulated kinase)-Egr (early growth response)-Id3 (inhibitor of differentiation 3) axis as a potential molecular switch downstream of TCR that determines lineage choice. Indeed, removal of Id3 was sufficient to redirect TCRgammadelta transgenic cells to the alphabeta lineage, even in the presence of strong TCR signal. However, in TCR non transgenic Id3 knockout mice the overall number of gammadelta lineage cells was increased due to an outgrowth of a Vgamma1Vdelta6.3 subset, suggesting that not all gammadelta T cells depend on this molecular switch for lineage commitment. Thus, the gammadelta lineage may in fact be a collection of two or more lineages not sharing a common molecular program and thus equipollent to the alphabeta lineage. TCR signaling is not the only factor that is required for development of alphabeta and gammadelta lineage cells; other pathways, such as signaling from Notch and CXCR4 receptors, cooperate with the TCR in this process. PMID- 20969595 TI - Regulation of the Ifng locus in the context of T-lineage specification and plasticity. AB - Study of the development of distinct CD4(+) T-cell subsets from naive precursors continues to provide excellent opportunities for dissection of mechanisms that control lineage-specific gene expression or repression. Whereas it had been thought that the induction of transcription networks that control T-lineage commitment were highly stable, reinforced by epigenetic processes that confer heritability of functional phenotypes by the progeny of mature T cells, recent findings support a more dynamic view of T-lineage commitment. Here, we highlight advances in the mapping and functional characterization of cis elements in the Ifng locus that have provided new insights into the control of the chromatin structure and transcriptional activity of this signature T-helper 1 cell gene. We also examine epigenetic features of the Ifng locus that have evolved to enable its reprogramming for expression by other T-cell subsets, particularly T-helper 17 cells, and contrast features of the Ifng locus with those of the Il17a-Il17f locus, which appears less promiscuous. PMID- 20969594 TI - Transcriptional control of invariant NKT cell development. AB - Invariant natural killer T (iNKT) cells comprise a rare lymphocyte sublineage with phenotypic and functional properties similar to T and NK cells. Akin to conventional alphabeta T cells, their development occurs primarily in the thymus, where they originate from CD4(+) CD8(+) double positive (DP) progenitors. However, the selection of iNKT cells is unique in that it is mediated by homotypic interactions of DP cells and recognition of glycolipid antigen-CD1d complexes. Additionally, iNKT cells acquire an activated innate-like phenotype during development that allows them to release cytokines rapidly following antigen exposure. Given their hybrid features, it is not surprising that the developmental program of iNKT cells partially overlaps with that of T and NK cells. Several recent reports have provided new and exciting insights into the developmental mechanisms that direct natural killer T (NKT) cell lineage commitment and maturation. In this review, we provide a discussion of the NKT cell developmental program with an emphasis on the signaling mechanisms and transcription factors that influence the ontogeny of this lineage. Continued investigations into the complex interplay of these transcription factors and their relationship with other extracellular and intracellular signaling molecules will undoubtedly provide important clues into the biology of this unusual T-cell lineage. PMID- 20969596 TI - Molecular mechanisms by which T-bet regulates T-helper cell commitment. AB - Current research suggests that a number of newly identified T-helper cell subsets retain a degree of context-dependent plasticity in their signature cytokine expression patterns. To understand this process, a major challenge is to determine the molecular mechanisms by which lineage-defining transcription factors regulate gene expression profiles in T-helper cells. This mechanistic information will aid in our interpretation of whether a T-helper cell state that expresses or retains the capacity to re-express a combination of lineage-defining transcription factors will have a stable or more flexible gene expression profile. Studies examining the developmental T-box transcription factor T-bet demonstrate the powerful information that is gained from combining in vivo analysis with basic biochemical and molecular mechanism approaches. Significantly, T-bet's ability to physically recruit epigenetic modifying complexes, in particular a Jmjd3 H3K27-demethylase and a Set7/9 H3K4 methyltransferase complex, to its target genes allows T-bet to effectively reverse and establish new epigenetic states. This observation suggests that until T-bet is permanently extinguished, T-helper cells will retain some plasticity toward a T-helper 1-like program. Therefore, insight into the complexity of T helper cell commitment decisions will be aided by determining the molecular mechanisms for lineage-defining transcription factors. PMID- 20969598 TI - Gper and ESRs are expressed in rat round spermatids and mediate oestrogen dependent rapid pathways modulating expression of cyclin B1 and Bax. AB - Spermatogenesis is a precisely controlled and timed process, comprising mitotic divisions of spermatogonia, meiotic divisions of spermatocytes, maturation and differentiation of haploid spermatids giving rise to spermatozoa. It is well known that the maintenance of spermatogenesis is controlled by gonadotrophins and testosterone, the effects of which are modulated by a complex network of locally produced factors, including oestrogens. However, it remains uncertain whether oestrogens are able to activate rapid signalling pathways directly in male germ cells. Classically, oestrogens act by binding to oestrogen receptors (ESRs) 1 and 2. Recently, it has been demonstrated that rapid oestrogen action can also be mediated by the G-protein-coupled oestrogen receptor 1 (Gper). The aim of the present study was to investigate ESRs and Gper expression in primary cultures of adult rat round spermatids (RS) and define if oestradiol (E2) is able to activate, through these receptors, pathways involved in the regulation of genes controlling rat RS apoptosis and/or maturation. In this study, we demonstrated that rat RS express ESR1, ESR2 and Gper. Short-time treatment of RS with E2, the selective Gper agonist G1 and the selective ESR1 and ERbeta agonists, 4,4',4"-(4 propyl-[1H]pyrazole-1,3,5-triyl) trisphenol (PPT) and 2,3-bis(4-hydroxyphenyl) propionitrile (DPN), respectively, determined activation of Extra-cellular signal regulated kinase (ERK1/2) through the involvement of epidermal growth factor receptor transactivation. In addition, we investigated the effects of ESRs and Gper pathway activation on factors involved in RS maturation. Expression of cyclin B1 mRNA was downregulated by E2, G1 and PPT, but not by DPN. A concomitant and inverse regulation of the pro-apoptotic factor Bax mRNA expression was observed in the same conditions, with DPN being the only one determining an increase in this factor expression. Collectively, these data demonstrate that E2 activates, through ESRs and Gper, pathways involved in the regulation of genes controlling rat RS apoptosis and differentiation such as cyclin B1 and Bax. PMID- 20969599 TI - Type 2 diabetes mellitus and testosterone: a meta-analysis study. AB - Several studies suggest that type 2 diabetes mellitus (T2DM) is often associated with male hypogonadism. Despite the well-known link, the role of testosterone replacement therapy (TRT) in T2DM has not been completely clarified. The aim of the present study was to analyse systematically the relationship between androgen levels and T2DM by reviewing and meta-analysing available prospective and cross sectional studies. In addition, a specific meta-analysis on the metabolic effects of TRT in available randomized clinical trials (RCTs) was performed. An extensive Medline search was performed including the following words: 'testosterone', 'type 2 diabetes mellitus' and 'males'. Of 742 retrieved articles, 37 were included in the study. In particular 28, 5 and 3 were cross-sectional, longitudinal and interventional studies, respectively. A further unpublished RCT was retrieved from http://www.clinicaltrials.gov. T2DM patients showed significantly lower testosterone plasma levels in comparison with non-diabetic individuals. Similar results were obtained when T2DM subjects with and without erectile dysfunction were analysed separately. Meta-regression analysis demonstrated that ageing reduced, while obesity increased, these differences. However, in a multiple regression model, after adjusting for age and body mass index (BMI), T2DM was still associated with lower total testosterone (TT) levels (adjusted r = -0.568; p < 0.0001). Analysis of longitudinal studies demonstrated that baseline TT was significantly lower among patients with incident diabetes in comparison with controls (HR = -2.08[-3.57;-0.59]; p < 0.001). Combining the results of RCTs, TRT was associated with a significant reduction in fasting plasma glucose, HbA1c, fat mass and triglycerides. Conversely, no significant difference was observed for total and high-density lipoprotein cholesterol, blood pressure and BMI. The meta analysis of the available cross-sectional data suggests that T2DM can be considered independently associated with male hypogonadism. Although only few RCTs have been reported, TRT seems to improve glycometabolic control as well as fat mass in T2DM subjects. PMID- 20969600 TI - Significance of extruded nuclear chromatin (regional nuclear shape malformation) in human spermatozoa: implications for ICSI. AB - The aim of this study was to determine the extent of DNA fragmentation and the presence of denatured single-strand or normal double-strand DNA in spermatozoa with extruded nuclear chromatin (ENC) selected by high magnification. Fresh semen samples from 55 patients were prepared by discontinuous isolate concentration gradient. Spermatozoa with normal nucleus (NN) and ENC were selected at 8400* magnification and placed on different slides. DNA fragmentation was determined by TUNEL assay. Denatured and double-stranded DNA was identified by the acridine orange fluorescence method. DNA fragmentation was not significantly different (p = 0.86) between spermatozoa with ENC (19.6%) and those with NN (20%). However, the percentage of spermatozoa with detectable denatured-stranded DNA in the ENC spermatozoon group (59.1%) was significantly higher (p < 0.0001) than in the NN group (44.9%). The high level of denatured DNA in spermatozoa with ENC suggests premature decondensation and disaggregation of sperm chromatin fibres. The results show an association between ENC and DNA damage in spermatozoa, and support the routine morphological selection and injection of motile spermatozoa at high-magnification intracytoplasmic sperm injection. PMID- 20969597 TI - Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. AB - CD4(+) T cells, also known as T-helper (Th) cells, play an important role in orchestrating adaptive immune responses to various infectious agents. They are also involved in the induction of autoimmune and allergic diseases. Upon T-cell receptor (TCR)-mediated cell activation, naive CD4(+) T cells can differentiate into at least four major lineages, Th1, Th2, Th17, and iTreg cells, that participate in different types of immune responses. Networks of cytokines and transcription factors are critical for determining CD4(+) T-cell fates and effector cytokine production. Here, we review collaboration and cross-regulation between various essential cytokines in the activation/induction of key transcription factors during the process of Th cell differentiation towards these distinct lineages. We also discuss the interactions of key transcription factors at both genetic and protein levels and the function of the resulting network(s) in regulating the expression of effector cytokines. PMID- 20969601 TI - Steady-state pharmacokinetics of oral testosterone undecanoate with concomitant inhibition of 5alpha-reductase by finasteride. AB - Oral testosterone undecanoate (TU) is used to treat testosterone deficiency; however, oral TU treatment elevates dihydrotestosterone (DHT), which may be associated with an increased risk of acne, male pattern baldness and prostate hyperplasia. Co-administration of 5alpha-reductase inhibitors with other formulations of oral testosterone suppresses DHT production and increases serum testosterone. We hypothesized that finasteride would increase serum testosterone and lower DHT during treatment with oral TU. Therefore, we studied the steady state pharmacokinetics of oral TU, 200 mg equivalents of testosterone twice daily for 7 days, alone and with finasteride 0.5 and 1.0 mg po twice daily in an open label, three-way crossover study in 11 young men with experimentally induced hypogonadism. On the seventh day of each dosing period, serum testosterone, DHT and oestradiol were measured at baseline and 1, 2, 4, 8, 12, 13, 14, 16, 20 and 24 h after the morning dose. Serum testosterone and DHT were significantly increased into and above their normal ranges similarly by all three treatments. Co-administration of finasteride at 0.5 and 1.0 mg po twice daily had no significant effect on either serum testosterone or DHT. Oral TU differs from other formulations of oral testosterone in its response to concomitant inhibition of 5alpha-reductase, perhaps because of its unique lymphatic route of absorption. PMID- 20969602 TI - Ultrasonographic and clinical correlates of seminal plasma interleukin-8 levels in patients attending an andrology clinic for infertility. AB - This study was aimed at evaluating the association between seminal plasma interleukin-8 (sIL-8) and colour-Doppler ultrasound (CDU) characteristics of the male genital tract in a series of patients fulfilling the criteria of male accessory gland infections (MAGI). Of 250 subjects seeking medical care for couple infertility, 79 (mean age: 36.4 +/- 7.5 years) met the criteria of MAGI and scored higher than the rest of the sample on the National Institutes of Health-Chronic Prostatitis Symptom Index score. All patients underwent simultaneous hormone evaluation and seminal analysis (including sIL-8), along with scrotal and transrectal CDU before and after ejaculation. After adjusting for age, sIL-8 in patients with MAGI was significantly related to several abnormal semen and CDU parameters. In particular, leucocytospermia was closely associated with sIL-8. Ejaculate volume, unlike other semen or hormonal parameters, was negatively associated with sIL-8. When scrotal CDU was performed, sIL-8 was positively related to CDU inhomogeneous, hypo-echoic, hyper-echoic epididymis and to epididymal calcifications. In addition, a positive correlation among sIL-8, hyperaemic epididymis and an increased size of epididymal tail was found. When transrectal CDU was performed, an association among sIL-8 and hyper echoic seminal vesicles, dilated ejaculatory ducts and duct calcifications was also observed. Finally, sIL-8 was positively related to prostate CDU abnormalities such as calcifications, inhomogeneous/hypo-echoic texture, hyperaemia and high arterial blood flow. No association was found with testis parameters. In conclusion, sIL-8 levels in patients with MAGI are associated with several parameters and CDU abnormalities of epididymis, seminal vesicles, ejaculatory ducts and prostate, but not of the testis. Furthermore, sIL-8 positively correlates with CDU signs of ejaculatory duct inflammatory subobstruction. PMID- 20969603 TI - The effects of increasing doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs. AB - Different doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, with or without dexmedetomidine were compared in conscious dogs. Eight animals received either dexmedetomidine (10 MUg/kg [D]), MK-467 (250 MUg/kg [M250] or dexmedetomidine (10 MUg/kg) with increasing doses of MK-467 (250 MUg/kg [DM250], 500 MUg/kg [DM500] and 750 MUg/kg [DM750], respectively). Treatments were given intravenously (i.v.) in a randomized, crossover design with a 14-day washout period. Systemic hemodynamics and arterial blood gas analyses were recorded at baseline and at intervals up to 90 min after drugs administration. Dexmedetomidine alone decreased heart rate, cardiac index and tissue oxygen delivery and increased mean arterial pressure and systemic vascular resistance 5 min after administration. DM250 did not completely prevent these early effects, while DM750 induced a decrease in mean arterial pressure. With DM500, systemic hemodynamics remained stable throughout the observational period. MK-467 alone increased cardiac index and tissue oxygen delivery and had no deleterious adverse effects. No differences in arterial blood gases were observed between treatments that included dexmedetomidine. It was concluded that MK-467 attenuated or prevented dexmedetomidine's systemic hemodynamic effects in a dose-dependent manner when given simultaneously i.v. but had no effect on the pulmonary outcome in conscious dogs. A 50:1 dose ratio (MK-467:dexmedetomidine) induced the least alterations in cardiovascular function. PMID- 20969604 TI - Studies on the pharmacokinetics and pharmacodynamics of mirtazapine in healthy young cats. AB - Mirtazapine pharmacokinetics was studied in 10 healthy cats. Blood was collected before, and at intervals up to 72 h after, oral dose of 3.75 mg (high dose: HD) or 1.88 mg (low dose: LD) of mirtazapine. Liquid chromatography coupled to tandem mass spectrometry was used to measure mirtazapine, 8-hydroxymirtazapine and glucuronide metabolite concentrations. Noncompartmental pharmacokinetic modeling was performed. Median half-life was 15.9 h (HD) and 9.2 h (LD). Using Mann Whitney analysis, a statistically significant difference between the elimination half-life, clearance, area under the curve (AUC) per dose, and AUC(infinity) /dose of the groups was found. Mirtazapine does not appear to display linear pharmacokinetics in cats. There was no significant difference in glucuronidated metabolite concentration between groups. Pharmacodynamics was studied in 14 healthy cats administered placebo, LD and HD mirtazapine orally once in a crossover, blinded trial. In comparison with placebo, cats ingested significantly more food when mirtazapine was administered. No difference in food ingestion was seen between HD and LD, but significantly more behavior changes were seen with the HD. Limited serum sampling during the pharmacodynamic study revealed drug exposure comparable with the pharmacokinetic study, but no correlation between exposure and food consumed. Mirtazapine (LD) was administered daily for 6 days with no drug accumulation detected. PMID- 20969605 TI - An inventory of the bacterial macromolecular components and their spatial organization. AB - Formerly regarded as small 'bags' of nucleic acids with randomly diffusing enzymes, bacteria are organized by a sophisticated and tightly regulated molecular machinery. Here, we review qualitative and quantitative data on the intracellular organization of bacteria and provide a detailed inventory of macromolecular structures such as the divisome, the degradosome and the bacterial 'nucleolus'. We discuss how these metabolically active structures manage the spatial organization of the cell and how macromolecular crowding influences them. We present for the first time a visualization program, lifeexplorer, that can be used to study the interplay between metabolism and spatial organization of a prokaryotic cell. PMID- 20969606 TI - Seasonal abundance and activity of the tick Dermacentor silvarum in northern China. AB - Studies on the seasonal abundance and activity of larvae, nymphs and adults of Dermacentor silvarum (Ixodida: Ixodidae), both on and off the host, were carried out over a 2-year period from February 2008 to January 2010 in northern China. During the study period, feeding ticks were removed weekly from domestic sheep and free-living ticks were collected weekly by flag-dragging in four different habitat types. Rodents were captured and inspected for immature ticks from June to September 2008. The results of this study suggest that the ticks mainly reside in shrubs and complete only one generation per year with sequential seasonal distribution and little overlap between the activity of the larvae and nymphs. Adults were most prevalent from late February to late May and peaked in number in mid-April. Larvae were found from early June to early September and peaked in number in mid-July. Nymphs were mainly distributed from late June to late September and peaked in mid-August. Adult and nymphal D. silvarum were found primarily on the ears of sheep, but no larvae were found on sheep. Additionally, an overwintering male adult population was detected on sheep after October, but no free-living adults were found by dragging. PMID- 20969607 TI - Monoclonal gammopathy without hyperglobulinemia in 2 dogs with IgA secretory neoplasms. AB - Two dogs, an 8.5-year-old intact male Golden Retriever and a 10-year-old spayed female English Springer Spaniel, each with varied clinical histories, were referred to the Colorado State University Veterinary Teaching Hospital for evaluation of hypercalcemia and severe anemia, respectively. In each dog, serum total protein and globulin concentrations were within reference intervals. Cytologic examination of bone marrow aspirates from both dogs revealed moderate to marked numbers of atypical lymphoid cells with plasma cell features. Using serum immunofixation and serum immunoglobulin (Ig) quantification, a monoclonal Ig protein was identified. In conjunction with other clinicopathologic and molecular findings, IgA secretory neoplasms, B-cell lymphoma with plasmacytoid features and multiple myeloma (MM), were diagnosed. To our knowledge, these cases represent the first descriptions of IgA-secreting neoplasms in dogs that lacked hyperglobulinemia. In cases of suspected B-cell lymphoma or MM in dogs, serum proteins should be fully evaluated for the presence of a monoclonal Ig even in dogs that lack characteristic hyperproteinemia or hyperglobulinemia. This evaluation will aid in the diagnosis of secretory B-cell lymphoma or MM leading to appropriate clinical and therapeutic case management. PMID- 20969608 TI - Application of thrombelastography/thromboelastometry to veterinary medicine. AB - Thrombelastograph analyzers are point-of-care hemostatic analyzers that provide global assessment of the hemostatic process. Thrombelastography (TEG) detects and provides a continuous recording of the changes in the viscoelastic properties of whole blood from initial clot formation through fibinolysis. TEG has been validated for use in dogs, horses, and cats. Hemostasis research using TEG has focused on test validation, alterations of TEG tracings in animals with naturally occurring diseases, and the use of TEG for monitoring various therapeutic modalities. This article reviews TEG methodology and terminology, including potential sources of preanalytical and analytical errors, the correlation between TEG and other routine hemostatic assays, and current clinical applications of TEG, with emphasis on veterinary medical practice. Data suggest that TEG may be a sensitive and useful adjunctive tool for evaluating an animal with an underlying coagulopathy, including hypercoagulability and hypocoagulability. Additional prospective studies are needed to (1) correlate TEG tracing patterns with a clinical predisposition for bleeding or thrombosis in various disease states and (2) determine whether monitoring and treating hemostatic disorders based on TEG tracings improve clinical outcome. PMID- 20969609 TI - Overweight and obesity weakly predict the development of periodontal infection. AB - AIM: The aim of this study was to investigate the association between body weight and periodontal infection in a longitudinal setting. MATERIAL AND METHODS: This study was based on a subpopulation of the Health 2000 Survey that included dentate, non-diabetic subjects aged 30-59 years, who had never smoked and who had participated in the Follow-Up Study on Finnish Adults' Oral Health approximately 4 years later (n=396). The number of new teeth with deepened (4 mm deep or deeper) periodontal pockets in the follow-up examination was used as the outcome variable. Body weight was measured using body mass index, categorized into three categories: <25.0 (normal weight), 25.0-29.9 (overweight) and 30.0 or more (obesity). Incidence rate ratios were estimated using Poisson's regression models. RESULTS: Body weight was weakly, but not statistically significantly, associated with the number of new teeth with deepened periodontal pockets among subjects who were periodontally healthy in the baseline examinations, whereas only a minuscule association was found among subjects who had periodontal infection at baseline. CONCLUSIONS: The results of this follow-up study do not provide evidence that overweight and obesity can be considered significant risk factors in the pathogenesis of periodontal infection. PMID- 20969610 TI - Peri-implant reconstruction using autologous periosteum-derived cells and guided bone regeneration. AB - AIM: This investigation evaluated the bone healing in peri-implant defects treated with periosteum-derived cells (PCs) and guided bone regeneration (GBR). MATERIAL AND METHODS: PCs were harvested from six beagle dogs and characterized in vitro with regard to their osteogenic properties. The animals were subjected to teeth extraction in the mandible, and after 3 months of healing, implant sites were drilled, bone dehiscences were created and implants were placed. Dehiscences were randomly assigned to: PCs+GBR, GBR, PCs and non-treated defects. After 3 months, the implants/adjacent tissues were processed. Bone-to-implant contact (BIC) bone fill (BF) within implant threads, and bone area (BA) in a zone lateral to the implant were obtained. RESULTS: In vitro analyses confirmed the osteogenic potential of PCs. Histometrically, no statistically significant differences were observed among the PCs+GBR, GBR and PCs groups for both BF and BIC (p>0.05), whereas these groups showed statistically higher values, as compared with the non treated group (p<0.05). With respect to BA, the PCs+GBR and GBR groups presented significantly higher means, as compared with the PCs and non-treated groups (p<0.05). CONCLUSION: Although successful outcomes have been promoted by using the combined approach, PCs in conjunction with membranes did not provide additional benefit during peri-implant bone regeneration, when compared with the therapeutic approaches used alone. PMID- 20969611 TI - 'Pseudo-Mikulicz' cells. PMID- 20969612 TI - Exploring quantitative methods for evaluation of lip function. AB - The objective was to explore quantitative methods for the measurement of lip mobility and lip force and to relate these to qualitative assessments of lip function. Fifty healthy adults (mean age 45 years) and 23 adults with diagnoses affecting the facial muscles (mean age 37 years) participated in the study. Diagnoses were Mobius syndrome (n=5), Facioscapulohumeral muscular dystrophy (n=6) and Myotonic dystrophy type 1 (n=12). A system for computerised 3D analysis of lip mobility and a lip force meter were tested, and the results were related to results from qualitative assessments of lip mobility, speech (articulation), eating ability and saliva control. Facial expressions studied were open mouth smile and lip pucker. Normative data and cut-off values for adults on lip mobility and lip force were proposed, and the diagnostic value of these thresholds was tested. The proposed cut-off values could identify all inviduals with moderate or severe impairment of lip mobility but not always the milder cases. There were significant correlations between the results from quantitative measurements and qualitative assessments. The examined instruments for measuring lip function were found to be reliable with an acceptable measuring error. The combination of quantitative and qualitative ways to evaluate lip function made it possible to show the strong relation between lip contraction, lip force, eating ability and saliva control. The same combination of assessments can be used in the future to study if oral motor exercises aimed at improving lip mobility and strength could have a positive effect on lip function. PMID- 20969613 TI - Current challenges in successful rehabilitation with oral implants. AB - Very high survival/success rates have been reported for implant treatment, irrespective of the prosthetic type of reconstruction, be those full arcs, partial dentures, combined tooth implants or single crowns. However, survival/success is commonly reported in simple Cumulative Survival/Success Rate (CSR) tables only that may overestimate the true clinical outcome; furthermore, future challenges to clinical success may originate from too rapid launching of untested novelties or recommendations to apply too bold clinical procedures, potential problems that are summarised in the present paper. PMID- 20969614 TI - Temporary nursing staff - cost and quality issues. AB - AIM: This paper is a report of a comparative study of temporary and permanent staff work activity, cost and quality of care. BACKGROUND: Temporary nurse staffing can consume significant proportions of the health service wages bill, and this is unlikely to fall owing to recruitment and retention problems, high sickness absence and the tendency for staff to work 'casually'. If temporary workers are here to stay, then what impact do they have on inpatient care? For example, do ward nursing quality and costs change when temporary staff are employed? METHOD: Ward patient dependency, nursing activity, workload, staffing and data on quality were collected using non-participant observation, document analysis, staff and patient interviews in 605 United Kingdom general and specialist wards between 2004 and 2009. These wards were divided into two groups: 368 employing only permanent staff during data collection and 237 with permanent, and temporary staff in the ward team at the time when the observations were made. FINDINGS: Workloads and time out (sickness absence, etc.) in wards employing temporary staff were greater than in units with permanent staff only, thereby justifying hiring short-term staff. Wards with temporary and permanent staff were more expensive to run and working styles were different. Overall quality scores, however, were no different in the two types of ward. CONCLUSION: Ward managers need to monitor temporary staffing and the effect they have on nursing activity and quality. Similar studies in mental health, learning disability and community nursing would generate additional insights. PMID- 20969615 TI - Continence management in acute stroke: a survey of current practices in Australia. AB - AIM: The aim of the study was to determine current national urinary incontinence management practices in Australian acute stroke units and their concordance with the National Stroke Foundation guidelines. BACKGROUND: Urinary incontinence is a common consequence after stroke and a statistically significant indicator of poor outcome, including disability and admission to institutional care. The National Stroke Foundation has produced guidelines for the acute and post-acute phase of care, offering Australian nurses evidence-based recommendations regarding stroke management including the management of urinary incontinence. METHOD: In 2007 2008, dedicated acute stroke units in Australia were identified and a senior nurse from each unit was invited to participate in a 10-minute telephone survey to ascertain their current urinary continence management practices. RESULTS: Representatives from 41 acute stroke units participated in the survey (response rate 98%). Participants from less than half of the units reported that they had a formal plan for urinary incontinence management (n=19, 46%), and the majority of those who did not would find a formal plan useful (n=15, 79%). Two-thirds of respondents stated that they would manage urinary incontinence with indwelling catheterization (n=25, 61%). Only 30% (n=12) were 'satisfied' or 'very satisfied' with urinary continence management in their acute stroke unit. CONCLUSION: A large proportion of acute stroke units were yet to establish formal urinary incontinence management plans. The implementation of evidence-based urinary incontinence management plans after stroke is integral to improving patient outcomes. An increase in resources for professional development in the assessment, treatment and management of urinary incontinence is essential to improve and maintain skills in after-stroke care. PMID- 20969616 TI - Risk assessment following self-harm: comparison of mental health nurses and psychiatrists. AB - AIM: This paper is a report of a study conducted to compare risk assessments by psychiatrists and mental health nurses following an episode of self-harm. BACKGROUND: Self-harm assessments by nurses and psychiatrists are similar in terms of overall content, but risk assessment may vary by professional discipline. To our knowledge previous researchers have not compared the positive predictive value of risk assessments by nurses and psychiatrists, the factors that inform those assessments in clinical practice or the management of people assessed as being at high risk. METHODS: We conducted a prospective cohort study (2002-2006) of 3491 individuals presenting with self-harm to three hospitals in the North West of England. A standard assessment form including detailed demographic and clinical data was completed by the assessing psychiatrist or nurse. RESULTS: The positive predictive value of risk assessments for self-harm repetition was 25% (95% CI: 20-31) among nurses and 23% (95% CI: 13-37) among psychiatrists. There was strong agreement on factors associated with high risk assessment by both professions. Following assessment of high risk, psychiatrists were much more likely than nurses to admit people for inpatient treatment (RR=5.6, 95% CI: 3.2-9.7). This difference remained highly statistically significant after controlling for case-mix differences (RR=4.3, 95% CI: 2.4-7.7). CONCLUSION: Our finding that risk assessments were comparable by profession supports the provision of nurse-led assessment services. However, inpatient admission was influenced largely by assessor type rather than patient characteristics. This has important implications for equity of care and may reflect professional differences in referral practices. PMID- 20969617 TI - Mothers' sense of security in the first postnatal week: interview study. AB - AIM: This paper is a report of a study of factors which influence mothers' sense of security during the first postnatal week. BACKGROUND: Mothers' sense of security the first postnatal week is not thoroughly elucidated in the literature. METHODS: An interview study with a qualitative descriptive design was carried out, using thematic content analysis. Fourteen mothers from three hospital uptake areas in Southern Sweden were interviewed using focus group discussions and individual interviews between May 2008 and March 2009. FINDINGS: Postnatal sense of security was dependent on support from staff, support from family and the capacity and health of the woman and the baby, and these themes had categories and sub-categories, including: Being met as an individual, being given relevant information, being prepared for the time after birth and having someone to turn to--knowing who to ask, having partner and/or significant others close at hand, mother's and the baby's own resources, being assured that her own physical health was good, and having planned follow-up regarding the baby's health after discharge. CONCLUSION: Staff attitudes should be continually discussed at all units providing maternity care. These discussions should include attitudes towards the father and the significance of his presence for the wellbeing of the family. Continued postbasic staff education in, for example, counselling and communication is necessary if services are to be improved so that parents' individual needs can be met. Preparation for the early postpartum period is important and all information given must be consistent, in particular information about breastfeeding. PMID- 20969618 TI - Diabetes Empowerment Process Scale: development and psychometric testing of the Chinese version. AB - AIM: This paper is a report of the development and psychometric testing of the Chinese version of the Diabetes Empowerment Process Scale. BACKGROUND: In people living with diabetes, empowerment can improve metabolic and psychosocial outcomes. A scale for measuring empowerment processes can also help healthcare professionals to optimize their empowering actions and would improve their interactions with people living with diabetes. METHOD: Based on literature reviews and interviews with people living with diabetes, a 27-item Chinese Diabetes Empowerment Process Scale was developed. Fifteen items were produced after item analysis and content validity testing. To test construct validity, concurrent validity and internal consistency, 211 outpatients living with diabetes completed the Chinese Diabetes Empowerment Process Scale, a Self-care Behaviour Scale and a Diabetes Empowerment Scale. Test-retest reliability was also analysed with 30 patients. The study was conducted in 2008 and 2009 in Taiwan. RESULTS: Confirmatory factor analysis indicated that a second-order factorial model with four subscales and 15 items best fitted the data. The four subscales were Mutual participation, Raising awareness, Providing necessary information and Open communication. Scores on the Chinese Diabetes Empowerment Process Scale correlated statistically significantly with those on the Self-care Behaviour Scale (r=0.21-0.40; P<0.01) and Diabetes Empowerment Scale (r=0.35 0.65; P<0.01). Reliability was supported by acceptable Cronbach's alpha (range: 0.73-0.91) and test-retest reliability scores (range: 0.75-0.83). CONCLUSION: The Chinese Diabetes Empowerment Process Scale has satisfactory validity and reliability for measuring the empowerment process of health professionals. Further studies are needed to test the applicability of the scale to other populations. PMID- 20969619 TI - Learning and development: promoting nurses' performance and work attitudes. AB - AIM: This paper is a report of a study of the relations of coaching and developing clinical practice on nurses' work place attitudes and self-reported performance, as mediated by role breadth self-efficacy and flexible role orientation. BACKGROUND: Previous research into the effectiveness of nurses' learning and development activities has mainly focused on specific skill and knowledge acquisition outcomes. Few studies investigate the relationship between learning and development activities and work attitudes or performance, or explore mediating mechanisms in this process. Previous literature suggests that malleable cognitive and motivational constructs may be important mechanisms for improving work attitudes and proactive performance. METHOD: We surveyed 404 qualified nurses from a large, metropolitan public hospital in Australia in 2006 using validated measures from previous research. Descriptive statistics, correlation analysis and hierarchical regression analyses were conducted. RESULTS: The results show a clear association between learning and development activities and work attitudes and performance. Developing clinical practice improved self-rated performance and coaching improved work attitudes. In addition, role breadth self efficacy and flexible role orientation mediated these relationships and emerge as important mechanisms in the link between learning and development and work attitudes and performance. CONCLUSION: Investment in learning and development activities for nurses improves outcomes for nurses, the organization and patients. PMID- 20969620 TI - Implementation of evidence-based nursing practice: nurses' personal and professional factors? AB - AIMS: This paper is a report of a study conducted to explore the relationship between nurses' personal and professional factors and evidence-based nursing practice. BACKGROUND: Like most health-related professions, nursing is shifting from the traditional intuition-based paradigm to evidence-based nursing practice. METHODS: A cross-sectional survey was conducted in 2007 with a convenience sample of 243 nurses from northern Israel, who worked in hospitals or in the community. Associations between background variables and evidence-based nursing practice were examined. For the purpose of finding factors that predicted behaviour, a logistic regression analysis was conducted. RESULTS: The self-reported professional behaviour of nurses with a degree was more evidence-based than that of those without a degree. Moreover, evidence-based nursing practice was more likely where there was access to a rich library with nursing and medical journals, and opportunities for working with a computer and for searching the Internet in the workplace. The variables emerging as predicting evidence-based nursing practice were: education, skills in locating various research sources, support of the organization for searching and reading professional literature, knowledge sources based on colleagues and system procedures (inhibiting variable), knowledge sources based on reading professional literature, and knowledge sources based on experience or intuition. CONCLUSION: The findings point to the need for research-based information, exposure to professional journals and, in particular, organizational support for evidence-based nursing practice. PMID- 20969621 TI - The role of mitochondrial complex III in melatonin-induced ROS production in cultured mesangial cells. AB - Melatonin is a potent scavenger of reactive oxygen (ROS) and reactive nitrogen species (RNS). At pharmacological concentrations, however, melatonin is documented to cause ROS/RNS production, especially in cultured cancerous cells. Currently, the mechanism responsible for melatonin-induced ROS generation remains elusive. In this study, we provided evidence that melatonin, at micromolar concentrations, induced rapid ROS generation by a mitochondrial-dependent mechanism in primary human mesangial (HM) cells. The melatonin-induced ROS production occurred independent of changes in Ca(2+) concentrations in the cytosol and/or in mitochondria. In mitochondria isolated from HM cells and mice kidney tissues, melatonin caused ROS production; this melatonin response was completely blocked by the complex III inhibitor antimycin A. In contrast, both the mitochondrial complex I inhibitor, rotenone, and another complex III inhibitor, myxothiazol, which interacts with complex III at a distinct site, had no significant inhibitory effect on melatonin-induced ROS generation. These results demonstrate that melatonin induced rapid ROS generation via the antimycin A-sensitive site of mitochondrial complex III. PMID- 20969622 TI - Possible roles of bilirubin and breast milk in protection against retinopathy of prematurity. AB - AIM: To explore the association of serum bilirubin level and breast milk feeding with retinopathy of prematurity (ROP) in preterm infants. METHODS: We conducted a case-control study to examine the independent and combined effects of serum bilirubin and breast milk feeding on ROP risk in infants <32 weeks gestation or with birth weight <1500 g. Cases (66 infants with ROP) were matched with controls (66 infants without ROP) based on factors known to affect ROP risk. RESULTS: When analysed using the paired t-test, the peak bilirubin levels were lower in ROP cases than in controls (mean 7.2 vs. 7.9 mg/dL; p = 0.045). Using conditional logistic regression, we found a negative association between highest serum bilirubin level and risk of ROP (OR = 0.82 per 1-mg/dL change in bilirubin; p = 0.06). There was no significant association between breast milk feeding and risk of ROP. CONCLUSION: Bilirubin may help to protect preterm infants against ROP. PMID- 20969624 TI - Survey of risk factors contributed to lymphatic metastasis in patients with oral tongue cancer by immunohistochemistry. AB - OBJECTIVES: The aim of this study was to define the biomarkers of lymphatic spread which facilitate the appropriate therapy for oral tongue squamous cell carcinoma (OTSCC) patients at early stage. Here, we investigated the expression levels of seven biomarkers in oral squamous cell carcinoma (OSCC) tissues as well as their associations with the clinicopathologic features of OTSCC patients. METHODS: The OTSCC samples were obtained from 138 patients undergoing tumor resection. Immunohistochemical staining was performed by using ColIA, ColIVA, Fn1, MMP-1, MMP-2, uPA, and D2-40 antibodies. Expression level of theses biomarkers in normal and tumor tissues were compared. Risk factors of lymphatic dissemination were evaluated by logistic regression equation. RESULTS: LVD, MMP 1, MMP-2, and uPA in cancer tissues were significantly higher than those in normal tissue, and ColIA, ColIVA, and Fn1 in cancer tissue were significantly lower than those in normal tissue. Similar results were obtained from the comparison between metastatic tumor and non-metastatic tumor. All biomarker expressions were closely related with lymph node status and clinical stage. Additionally, the regression equation demonstrated that LVD is the risk factor of lymphatic metastasis in OTSCC patients (OR = 1.732; 95% CIs: 1.167-2.057; P < 0.05). CONCLUSIONS: Down-regulation of ColIA, ColIVA, and Fn1 and up-regulation of LVD, MMP-1, MMP-2, and uPA might be important features of OSCC progression, which may exert their functions and favorably predict lymphatic dissemination for OSCC patients at relatively early stage. Among these biomarkers, increased LVD is an independent risk factor of lymphatic metastasis, which could better predict whether metastasis will occur or not. PMID- 20969623 TI - Diabetes induced immunological and biochemical changes in human colostrum. AB - AIM: This article describes the changes and relationships between biochemical and immunological parameters in the colostrum and serum of diabetic women. METHODS: Colostrum and blood samples were collected from 30 diabetic and 15 normoglycaemic women. Glucose, total protein, antibody, complement proteins (C3 and C4), fat and calorie content, amylase, lipase and superoxide dismutase (SOD) were determined. RESULTS: Glucose was higher in both the colostrum and serum of diabetic mothers compared to that of their normoglycaemic counterparts. In both groups, total protein was higher in colostrum than in serum. IgA and IgG were lower in the colostrum of hyperglycaemic mothers, whereas IgM did not vary between the groups. Colostral C3 protein was significantly lower in diabetic mothers, but colostral C4 protein was similar between normoglycaemic and hyperglycaemic mothers. Fat content was lower in the colostrum of the diabetic mothers, although calorie content did not vary between the groups. Amylase was lower in colostrum than in serum in both groups. Lipase was higher in the colostrum and serum of diabetic mothers. Colostral SOD was similar between the groups. CONCLUSIONS: Our results support the hypothesis that the colostrum of diabetic mothers suffers biochemical and immunological alterations that affect the levels of its components. PMID- 20969625 TI - Human papillomavirus in the oral cavity of children. AB - OBJECTIVE: The aim of this literature review was to identify studies conducted on the oral Human papillomavirus (HPV) infection in children. METHODS: An electronic database search was performed using the terms 'oral HPV' and 'children'. The studies on the prevalence of oral HPV in children worldwide, descriptive studies, case reports, studies on the association of oral HPV and risk factors and transmission of HPV were included. CONCLUSION: The presence of HPV in oral mucosa of children should be investigated in virtue of the various forms of transmission, and the possibility of sexual abuse eliminated, and also of its possible relation with oral carcinoma pathogenesis in children. PMID- 20969626 TI - Study of histopathological, morphological and immunohistochemical features of recurrent pleomorphic adenoma: an attempt to predict recurrence of pleomorphic adenoma. AB - BACKGROUND: Recurrent pleomorphic adenoma (RPA) is an uncommon and challenging disease. The aim of this study was to review the clinical information obtained by examining RPA patients, to determine its histomorphological features and to verify the expression of the Mcm-2 markers of cell proliferation and the expression of p-53 in pleomorphic adenoma (PA), RPA, and RPA with malignant transformation (TRPA). METHODS: A total of 10 cases of PA and 29 cases of RPA were examined in detail for the presence of nodules and their histomorphological features. Cell proliferation and expression of p-53 were detected by the immunohistochemical technique using the antibodies against Mcm-2 and p-53. RESULTS: Histopathologically, RPA is very similar to PA; the only difference found was that all the cases of RPA were multinodular. When comparing primary and recurrent tumor, no significant difference was found in terms of cell proliferation and the expression of p-53; however, in the RPA with areas of malignant transformation there was an increased expression of these proteins. CONCLUSION: This study showed that recurrences were multinodular, with nodules varying in numbers and sizes. No significant difference in histological features was found between RPA and PA. Moreover, the immunohistochemical study showed a low expression of p-53 and Mcm-2 in PA and RPA and an increased expression of these proteins in the RPA with areas of malignant transformation. PMID- 20969627 TI - Patch testing for food-associated allergies in orofacial granulomatosis. AB - BACKGROUND: Food-associated allergies, especially to benzoates and cinnamon related compounds, have been associated with orofacial granulomatosis and both standard and urticarial patch testing have been used to detect such allergies. Elimination diets have also been shown to be effective in some patients. OBJECTIVES: To compare the results of standard and urticarial patch testing in a cohort of patients with orofacial granulomatosis. MATERIALS AND METHODS: Records of 120 cases seen in two hospitals were retrieved and examined for patch test details. RESULTS: Standard patch testing was much less likely to detect allergy to benzoates and cinnamon compounds (7%) than urticarial tests (55%). All urticarial tests that were positive had shown a reaction by 60 min. CONCLUSIONS: Both standard and urticarial patch tests are required to detect food allergies in orofacial granulomatosis. The difficulties of patient self-recording of urticarial tests can be eliminated by retaining patients in the testing unit for professional reading of patches at 60 min. PMID- 20969628 TI - Mapping of titanium particles in peri-implant oral mucosa by laser ablation inductively coupled plasma mass spectrometry and high-resolution optical darkfield microscopy. AB - The present study examines the quantity, size, element signatures and distribution of titanium particles in normal oral mucosal tissue and in oral mucosa exposed to a titanium implant. Tissue samples from six healthy patients were obtained by a full thickness biopsy taken from the edge of the oral mucosa when inserting a titanium dental implant. At the abutment insertion 6 months later, a punch test biopsy of oral mucosa was taken over the implant site. Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) is a sensitive and specific multi-element microanalytical technique that demonstrated the presence of Ti particles in the tissue adjacent to implant cover-screws. The epithelial part of the control samples revealed more particles than the corresponding area of the test samples, consisting partly of newly formed scar tissue. High-Resolution Optical Darkfield Microscope (HR-ODM) confirmed the presence of particles in both the control and the test samples. The combination of LA-ICP-MS and HR-ODM appears to be a powerful combination for detection of particles in oral tissues; optical microscopy provides an overview with histological references, whereas LA-ICP-MS identifies the chemical composition. PMID- 20969629 TI - Salivary shedding of HHV-8 in people infected or not by human immunodeficiency virus 1. AB - BACKGROUND: Human herpesvirus 8 (HHV-8), the main agent involved in the etiopathogenesis of Kaposi's sarcoma (KS) is primarily transmitted through sexual contact. The potential of saliva as a source of HHV-8 transmission remains unclear. The purpose of this work was to determine the frequency of HHV-8 detection in saliva of HIV-infected individuals and their family contacts. METHODS: The study group comprised 210 individuals. Group 1: 35 HIV-infected patients; group 2: 35 non-HIV individuals; group 3: two siblings for each patient from group 1; group 4: two siblings for each individual from group 2. Each participant had non-stimulated whole saliva collected and DNA was extracted. HHV 8-DNA amplification from ORF-26 was performed using a nested PCR protocol. RESULTS: HHV-8 DNA was detected in saliva from 14/35 (40%) HIV-infected individuals and 4/35 (11.4%) non-HIV-infected individuals (OR = 5.16, CI [1.49 17.88], P = 0.006). It was also possible to amplify HHV-8 DNA in 11/70 (15.7%) relatives of HIV-infected participants and 4/70 (5.71%) relatives of non-HIV infected individuals(P = 0.041). Among the 14 group 1 patients with HHV-8 DNA detected in saliva, eight (57.1%) had a household member in whom HHV-8 DNA was also amplified (OR = 8, CI [1.58-40.29] P = 0.007). CONCLUSIONS: HHV-8 DNA is frequently found in saliva. HIV-infected individuals showed a higher frequency of detection of HHV-8 than healthy controls. HHV-8 DNA was significantly amplified in saliva of household members of HIV/HHV-8 co-infected individuals. PMID- 20969630 TI - Different expression patterns of pAkt, NF-kappaB and cyclin D1 proteins during the invasion process of head and neck squamous cell carcinoma: an in vitro approach. AB - BACKGROUND: Several signaling pathways are involved in the progression of squamous cell carcinoma. Among them, activated PI3K/Akt may result in NF-kappaB nuclear translocation, thus leading to the transcription of genes enrolled in cellular invasion and proliferation, such as cyclin D1. This study sought to evaluate the expression of pAkt, NF-kappaB and cyclin D1 proteins in head and neck squamous cell carcinoma cell lines and their respective in vitro-obtained invasive clones. METHODS: Squamous cell carcinoma cell lines originating from the tongue, pharynx and the metastatic lymph node were submitted to an in vitro invasion assay to select invasive clones. All experimental groups were submitted to immunofluorescence and Western blot assays. Statistical analysis was performed through a Student's t-test with a significance level of 5%. RESULTS: The pAkt and NF-kappaB expression differed from cytoplasm and nucleus depending on the studied cell line. The invasive clone from the tongue presented a network-like structure of pAkt's cytoplasmic expression. This lineage as well as the invasive clone from pharynx also showed pAkt and NF-kappaB nuclear transportation. Significant pAkt and NF-kappaB increases were observed in the tongue and pharynx invasive clones. Cyclin D1 was detected in the nucleus of all studied cells and was significantly enhanced in the invasive clones from tongue and pharynx. CONCLUSION: This study suggests the participation of pAkt, NF-kappaB and cyclin D1 in the invasion process of head and neck squamous cell carcinoma. Moreover, cytoplasmic pAkt network-like structure was probably related to cytoskeleton changes presented during invasion. PMID- 20969631 TI - Evaluation of collagen in connective tissue walls of odontogenic cysts--a histochemical study. AB - BACKGROUND: The purpose of this study was to evaluate the nature of collagen in the connective tissue walls of odontogenic cysts, like the odontogenic keratocyst (OKC), dentigerous cyst and radicular cyst using picrosirius red stained sections. Furthermore, it was intended to assess if the capsular connective tissue can affect the nature of overlying epithelium, thus emphasizing the role of epithelial-mesenchymal interactions in biological behaviour of the cysts. MATERIALS AND METHOD: The material for the study included 51 formalin-fixed paraffin-embedded tissue blocks (15 odontogenic keratocyst, 15 dentigerous cysts, 15 radicular cysts and four normal mucosa and two dental follicular tissue as controls), retrieved from the Department of Oral Pathology and Microbiology, MCODS, Manipal. Tissue blocks were sectioned at 5-MUm thickness, stained with picrosirius red stain and observed with polarization and light microscopy. RESULTS: Few sections of OKC and dentigerous cyst exhibited greenish-yellow birefringence in sub-epithelial region, whereas others showed a yellowish-orange birefringence under polarization microscopy. Most radicular cysts had yellowish orange to orange birefringence. Shift in colour in case OKC and dentigerous cyst was attributed to the presence of inflammation in those sections. These regions also exhibited either a change in phenotype or thickness of overlying epithelium. CONCLUSION: This technique can be used to study the nature of collagen fibres in odontogenic cyst walls. Further studies with an increased sample size and using various epithelial and mesenchymal markers and ssDNA antibodies should be carried out to confirm the effect of epithelial-mesenchymal interactions on the nature of epithelium of odontogenic cysts. PMID- 20969632 TI - Tumor angiogenesis in keratocystic odontogenic tumor assessed by using CD-105 antigen. AB - BACKGROUND: The purpose of this study was to assess and compare angiogenesis with proliferative activity in Keratocystic odontogenic tumors (KCOT) and dentigerous cysts (DC) by using monoclonal mouse anti-human antibody against CD105 (endoglin). MATERIAL AND METHODS: Angiogenesis was assessed in 38 KCOT, 27 DCs and 19 Normal Oral Mucosa (NOM) by measuring the Mean Vascular Density (MVD), Total Vascular Area (TVA) and Mean Vascular Area (MVA). Cell proliferation was assessed by obtaining Ki-67 Labeling Index (Ki-67LI) in all the groups. RESULTS: Statistically significant difference was observed in MVD, TVA, MVA and Ki-67 LI between the KCOT, DC and NOM (P=0.000). The MVD, TVA, MVA and Ki-67 LI were significantly higher in KCOT than in DC and NOM (P=0.000). The Ki-67 LI was significantly higher in NOM than in DC (P=0.000). MVD (P=0.032) and TVA (P=0.038) were significantly higher in NOM than in DC. There was significant positive correlation between Ki-67 LI and MVD, Ki-67 and TVA and Ki-67 and MVA. CONCLUSION: The result suggests that CD105 (endoglin) is strongly expressed in microvessels of KCOT compared with that in Dentigerous cyst and Normal oral mucosa. Thus, it suggests that angiogenesis may be associated with locally aggressive biological behavior of KCOT. These findings further stress on the hypothesis that the stroma of KCOT could be regarded not just as a structural support of the cyst wall, but as playing a part in the neoplastic behavior of cyst. PMID- 20969633 TI - hMLH1 immunoexpression is related to the degree of epithelial dysplasia in oral leukoplakia. AB - BACKGROUND: hMLH1 is a protein of the mammalian mismatch repair system responsible for genomic stability during repeated duplication. Relation between its altered expression linked to microsatellite instability has also been observed in oral leukoplakias (OL) and squamous cell carcinomas pointing to a possible role of hMLH1 in oral carcinogenesis. To our knowledge, this is the first study evaluating the immunoexpression of hMLH1 in OLs regarding their different degrees of epithelial dysplasia. METHODS: Sixty-two specimens of OL were classified in four groups: 17 without dysplasia, 19 with mild dysplasia, 16 with moderate dysplasia, and 10 with severe dysplasia. Immunohistochemistry for hMLH1 was performed, and percentage of positive cells was assessed. In the statistical analysis, P values <0.005 were considered significant. RESULTS: hMLH1 immunoexpression showed decreasing indexes from lesions with lower degrees of dysplasia to lesions with more severe dysplasia. Statistical difference was found mainly between suprabasal layers and total indexes. CONCLUSIONS: hMLH1 immunoexpression was inversely related to the OL degree of dysplasia. The total epithelial hMLH1 index seems to be of more clinical relevance than the evaluation stratified by layers. Our findings also suggest a role of such alterations in this pathway of DNA repair as an early event in oral carcinogenesis. PMID- 20969634 TI - Osteopontin expression in salivary gland carcinomas. AB - BACKGROUND: In several cancer types, osteopontin (OPN) expression has been correlated with tumor progression and prognosis. Two earlier studies have examined OPN expression in salivary gland carcinomas with contradictory results. METHODS: One hundred and seventy-five patients with a primary salivary gland carcinoma diagnosed from January 1, 1990 to December 31, 2005 were identified in the local pathology register, Odense University Hospital. Criteria as documented by Allred et al. were used to assess OPN immunostaining that was performed on surgical specimens. RESULTS: Osteopontin was expressed in all salivary gland carcinomas. Adenoid cystic carcinomas had the highest mean sum score (7.3) and a significantly higher proportion of carcinomas with high OPN sum score than both mucoepidermoid carcinoma and acinic cell carcinoma. Correlation of OPN expression with known prognostic factors in salivary gland carcinomas was insignificant. CONCLUSIONS: Salivary gland carcinomas express OPN. The expression does not correlate with known prognostic factors. PMID- 20969635 TI - The most important contact sensitizers in Polish children and adolescents with atopy and chronic recurrent eczema as detected with the extended European Baseline Series. AB - The differential diagnostic work-up of children with chronic eczema should involve patch testing, also in cases with confirmed atopy. In our previous study, contact allergy was detected in every second child with chronic eczema. The aim of the present study was to identify the most important sensitizers in atopic children with eczema. During an allergy screening program, 103 consecutive children aged 7-8 and 93 adolescents aged 16-17 were enrolled. The inclusion criterion was chronic recurrent eczema as detected with the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and atopy, defined as positive skin prick test to one or more common airborne or food allergens. The children were patch-tested with the newly extended European Baseline Series (EBS, 28 test substances) supplemented with propolis, thimerosal, benzalkonium chloride, and 2-phenoxyethanol. In total, 67.0% children and 58.1% adolescents were found patch test positive. Among children, 35.9% reacted to nickel, 16.5% propolis, 11.7% thimerosal, 9.7% cobalt, each 6.8% fragrance mix (FM) I and chromium, and 5.8% to FM II. Among adolescents, 37.6% reacted to thimerosal, 19.4% to nickel, 6.5% to cobalt, and 5.4% to propolis. We demonstrate the advantage of using FM II - a new addition to the EBS that detects a relatively high proportion of contact hypersensitivity among children. An important sensitizer from outside EBS is propolis, which according to the frequency of sensitization occupies rank 2 in children and rank 4 in adolescents. These data show that propolis should be included into routine patch testing in children. PMID- 20969636 TI - Characteristics and prognosis of chromophobe non-metastatic renal cell carcinoma: a multicenter study. AB - OBJECTIVES: To analyze the characteristics and the prognostic significance of chromophobe renal cell carcinomas (chRCC). METHODS: Data about 2981 patients with non-metastatic renal cell carcinomas (RCC) at the time of surgery were retrospectively collected from 26 institutions between 1998 and 2008. All patients had undergone partial or radical nephrectomies. Of the 2981 patients, 2602 patients with conventional RCC (cRCC) and 148 with chRCC were studied. Clinical and pathological parameters were determined in all patients. Recurrence free survival (RFS) and cancer-specific survival (CSS) were assessed. RESULTS: Patients with chRCC differed significantly from those with cRCC on the following parameters: younger age (P=0.026), greater female ratio (P<0.001), and larger tumor diameter (P<0.001). Both groups were alike with respect to body mass index (P=0.943), Eastern Cooperative Oncology Group performance status (P=0.163), T stage (P=0.375), and Fuhrman's grade (P=0.134). The 5-year RFS rates in patients with chRCC and cRCC were 82.7% and 83.3%, respectively (P=0.762). The 5-year CSS rates in patients with chRCC and cRCC were 88.8% and 92.2%, respectively (P=0.980). Both groups showed equivalent oncological outcomes in terms of RFS and CSS for cases stratified by T stage and Fuhrman's grade. In multivariate analysis, the histological subtype was not retained as an independent prognostic variable (RFS: P=0.893; CSS: P=0.729). CONCLUSIONS: Despite being significantly different from cRCC in terms of several clinical and pathological parameters, chRCC shows equivalent oncological outcomes. PMID- 20969637 TI - Cancer death from non-muscle invasive bladder cancer: report of the Japanese Urological Association of data from the 1999-2001 registry in Japan. AB - OBJECTIVES: Our aim was to clarify the risk factors of cancer death in order to reduce mortality from T1 bladder cancer. METHODS: The Japan registration database (1999-2001) was used for the analysis. Data were collected at least 3years after the initial diagnosis. Cause-specific survival using a Kaplan-Meier survival estimation with the log-rank method was evaluated. Univariate and multivariate analysis using the Cox proportional hazard model was also carried out. The 1997 TNM classification was used for pathological staging, and the 1973 WHO classification was used for pathological grading. RESULTS: There were 76 cancer deaths among a total of 1919 clinical T1 cases. Regardless of the subsequent treatment strategies, non-papillary tumor appearance, non-peduncular tumor stalk, multiple tumors, a tumor size greater than 3cm, positive urinary cytology and pathological grade 3 were found to be statistically significant in cancer death by univariate analysis. By multivariate analysis, non-papillary tumor appearance, positive urinary cytology and a tumor size greater than 3cm were confirmed as significant risk factors. Cancer death cases were found in 47.4% of worst-grade 2 tumors, and in 67.1% of predominantly grade 1 or 2 tumors. CONCLUSION: Non papillary tumor appearance, positive urinary cytology and a tumor size greater than 3cm should be included to enable the assessment of risk criteria in cancer death from T1 bladder cancer. PMID- 20969638 TI - Editorial Comment to Cancer death from non-muscle invasive bladder cancer: Report of the Japanese Urological Association of data from the 1999-2001 registry in Japan. PMID- 20969639 TI - Editorial Comment to Postoperative prostate-specific antigen nadir improves accuracy for predicting biochemical recurrence after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) and Duke Prostate Center databases. PMID- 20969640 TI - Transurethral resection of the prostate immediately after high-intensity focused ultrasound treatment for prostate cancer. AB - OBJECTIVES: To evaluate the long-term outcomes of transurethral resection of the prostate (TURP) immediately after high-intensity focused ultrasound (HIFU) treatment for prostate cancer (CaP). METHODS: The present retrospective study included 65 CaP patients who underwent HIFU alone and 64 patients who underwent TURP immediately after HIFU. HIFU treatment was carried out using a Sonablate-500 HIFU device (Focus Surgery, Indianapolis, IN, USA). International Prostate Symptom Score (IPSS) and the occurrence of urinary complications, such as urethral stricture during follow-up, were statistically compared between groups. RESULTS: Clinical stage tended to be lower for the HIFU+TURP group (P=0.0311), but none of the preoperative parameters differed significantly between groups. Both catheterization time (P<0.0001) and post-treatment IPSS (P<0.0001) at 6, 12, and 24months after treatment differed significantly between groups. Urethral strictures were noted in 16 (24.6%) of the HIFU-only patients and seven (10.9%) of the HIFU+TURP patients. Bladder neck contracture was noted in 11 (68.8%) of the patients with urethral stricture in the HIFU-only group, but in just two (28.6%) of the patients with urethral stricture in the HIFU+TURP group. Multiple logistic regression analyses showed that TURP resection volume (P=0.0118) was a strong factor for the prevention of urethral stricture. CONCLUSIONS: Our results suggest that combining HIFU with an immediately following TURP improves post treatment urinary status without causing additional morbidity. PMID- 20969641 TI - Editorial Comment to Transurethral resection of the prostate immediately after high-intensity focused ultrasound treatment for prostate cancer. PMID- 20969642 TI - Efficacy of extended-release tolterodine for the treatment of neurogenic detrusor overactivity and/or low-compliance bladder. AB - OBJECTIVE: To evaluate the efficacy of extended-release (ER) tolterodine 4mg/day for the treatment of neurogenic detrusor overactivity (NDO) and/or low-compliance bladder by assessing urodynamic parameters. METHODS: Forty-six patients (25 male, 21 female; mean age 57.6+/-20.7years) with NDO (n=39) and/or low-compliance bladder (n=7) were included in this 12-week single-arm study. Twenty-one patients (46%) were on clean intermittent catheterization and other patients could void on their own. A video urodynamic study was performed before and at 3 months after treatment. Changes in Overactive Bladder Symptom Score (OABSS), International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), and King's Health Questionnaire (KHQ) as well as changes in number of voids, amount of each void, and number of leaks in 24h according to the 3-day voiding diary were also evaluated before treatment and at weeks 4 and 12 after treatment. RESULTS: Bladder capacity at first sensation and maximum cystometric capacity increased significantly, by an average of 36.8mL (P=0.0402) and 82.3mL (P<0.0001), respectively. Maximum cystometric capacity increased by more than 50mL in 19 patients (49%) following treatment. Detrusor overactivity disappeared in three of 32 patients (9%), bladder capacity at first involuntary contraction increased significantly (P=0.0009), and amplitude of detrusor overactivity decreased significantly (P=0.0025). In patients with low-compliance bladder, bladder compliance increased significantly (P=0.0156). Overactive bladder symptom score, International Consultation on Incontinence Questionnaire-Short Form score, number of voids (per 24h and night-time), number of urgency episodes in 24h, number and amount of leaks in 24h, and amount of mean and maximum voided volumes all decreased significantly after treatment. CONCLUSION: Tolterodine is effective and well tolerated for the treatment of NDO and/or low-compliance bladder in patients with neurogenic bladder. PMID- 20969643 TI - Editorial comment to prepubertal testicular tumors: a 20-year experience with 40 cases. PMID- 20969644 TI - Tissue engineering and stem cells: basic principles and applications in urology. AB - To overcome problems of damaged urinary tract tissues and complications of current procedures, tissue engineering (TE) techniques and stem cell (SC) research have achieved great progress. Although diversity of techniques is used, urologists should know the basics. We carried out a literature review regarding the basic principles and applications of TE and SC technologies in the genitourinary tract. We carried out MEDLINE/PubMed searches for English articles until March 2010 using a combination of the following keywords: bladder, erectile dysfunction, kidney, prostate, Peyronie's disease, stem cells, stress urinary incontinence, testis, tissue engineering, ureter, urethra and urinary tract. Retrieved abstracts were checked, and full versions of relevant articles were obtained. Scientists have achieved great advances in basic science research. This is obvious by the tremendous increase in the number of publications. We divided this review in two topics; the first discusses basic science principles of TE and SC, whereas the second part delineates current clinical applications and advances in urological literature. TE and SC applications represent an alternative resource for treating complicated urological diseases. Despite the paucity of clinical trials, the promising results of animal models and continuous work represents the hope of treating various urological disorders with this technology. PMID- 20969645 TI - Managing the aging man in Asia: a review. AB - The aging man is becoming a major burden to Asian countries because of the current poor health status of Asian men and the aging Asian population. Life expectancy at birth for men is shorter than women by an average of 4 years in Asian countries and major causes of death are cardiovascular disease, cancers, injuries and infections. However, there are considerable variations between Asian countries because of great disparity in socioeconomic status. Male-specific disorders, such as male sexual health and urological conditions, are other major health burdens because they have a great impact on men's quality of life. More importantly, many risk factors to the causes of mortality and morbidities, such as high-risk behavior and smoking, can be improved with health promotion and early intervention. The current evidence suggests that the poor health status of men is the result of their poor health care utilization, negative health-seeking behavior, the adverse social environment for men and gender-insensitive health care delivery. However, much evidence is still needed as Asian countries have great diversity in culture, societal values and men's needs. Asian time-tested wisdom on a balanced healthy lifestyle to longevity should be explored as potential men's health promotional programs. Taking into account Asian men's health-care needs, a gender-streamlined approach and man-friendly health care delivery should be on the national agenda in managing the aging man. PMID- 20969646 TI - A novel double-tryptophan peptide pheromone controls competence in Streptococcus spp. via an Rgg regulator. AB - All streptococcal genomes encode the alternative sigma factor SigX and 21 SigX dependent proteins required for genetic transformation, yet no pyogenic streptococci are known to develop competence. Resolving this paradox may depend on understanding the regulation of sigX. We report the identification of a regulatory circuit linked to the sigX genes of mutans, pyogenic, and bovis streptococci that uses a novel small, double-tryptophan-containing sigX-inducing peptide (XIP) pheromone. In all three groups, the XIP gene (comS), and sigX have identical, non-canonical promoters consisting of 9 bp inverted repeats separated from a -10 hexamer by 19 bp. comS is adjacent to a gene encoding a putative transcription factor of the Rgg family and is regulated by its product, which we designate ComR. Deletion of comR or comS in Streptococcus mutans abolished transformability, as did deletion of the oligopeptide permease subunit oppD, suggesting that XIP is imported. Providing S. mutans with synthetic fragments of ComS revealed that seven C-terminal residues, including the WW motif, cause robust induction of both sigX and the competent state. We propose that this circuit is the proximal regulator of sigX in S. mutans, and we infer that it controls competence in a parallel way in all pyogenic and bovis streptococci. PMID- 20969647 TI - Cross-linking FtsZ polymers into coherent Z rings. AB - A key event in bacterial cytokinesis is the formation of the Z ring, which serves as a mechanical scaffold that recruits other cytokinetic proteins to establish functional divisomes. This scaffolding function of Z rings is essential throughout cytokinesis, but the underlying molecular interactions are poorly understood. Here we report that a widely conserved FtsZ binding protein, ZapA, has cytological, biochemical and biophysical properties that argue for the importance of cross-linking interactions between FtsZ polymers in the coherence of Z rings. Escherichia coli zapA null mutant cells have Z rings that are structurally looser and many helical precursors of Z rings fail to coalesce into coherent rings. Biophysical behaviour of FtsZ in the presence of ZapA reveals that ZapA not only bundles, but also cross-links FtsZ polymers, which makes it the first cross-linking protein of the bacterial cytoskeleton. Cross-linking in vitro occurs at the stoichiometry of FtsZ-ZapA interaction at the Z rings in vivo, where nearly all intracellular ZapA is dynamically associated. ZapA also stabilizes longitudinal bonds between FtsZ monomers since it promotes the polymerization of FtsZ mutants with lesions at the polymerization interface and since it reverses the inhibitory effects of SulA, a known antagonist of FtsZ longitudinal interactions. PMID- 20969648 TI - Transcriptome analysis of nitrate assimilation in Aspergillus nidulans reveals connections to nitric oxide metabolism. AB - Nitrate is a dominant form of inorganic nitrogen (N) in soils and can be efficiently assimilated by bacteria, fungi and plants. We studied here the transcriptome of the short-term nitrate response using assimilating and non assimilating strains of the model ascomycete Aspergillus nidulans. Among the 72 genes positively responding to nitrate, only 18 genes carry binding sites for the pathway-specific activator NirA. Forty-five genes were repressed by nitrate metabolism. Because nirA(-) strains are N-starved at nitrate induction conditions, we also compared the nitrate transcriptome with N-deprived conditions and found a partial overlap of differentially regulated genes between these conditions. Nitric oxide (NO)-metabolizing flavohaemoglobins were found to be co regulated with nitrate assimilatory genes. Subsequent molecular characterization revealed that the strongly inducible FhbA is required for full activity of nitrate and nitrite reductase enzymes. The co-regulation of NO-detoxifying and nitrate/nitrite assimilating systems may represent a conserved mechanism, which serves to neutralize nitrosative stress imposed by an external NO source in saprophytic and pathogenic fungi. Our analysis using membrane-permeable NO donors suggests that signalling for NirA activation only indirectly depends on the nitrate transporters NrtA (CrnA) and NrtB (CrnB). PMID- 20969649 TI - Mitochondrial translation is essential in bloodstream forms of Trypanosoma brucei. AB - The parasitic protozoa Trypanosoma brucei has a complex life cycle. Oxidative phosphorylation is highly active in the procyclic form but absent from bloodstream cells. The mitochondrial genome encodes several gene products that are required for oxidative phosphorylation, but it completely lacks tRNA genes. For mitochondrial translation to occur, the import of cytosolic tRNAs is therefore essential for procyclic T. brucei. Whether the same is true for the bloodstream form has not been studied so far. Here we show that the steady-state levels of mitochondrial tRNAs are essentially the same in both life stages. Editing of the imported tRNA(Trp) also occurs in both forms as well as in mitochondria of Trypanosoma evansi, which lacks a genome and a translation system. These results show that mitochondrial tRNA import is a constitutive process that must be mediated by proteins that are expressed in both forms of the life cycle and that are not encoded in the mitochondrial genome. Moreover, bloodstream cells lacking either mitochondria-specific translation elongation factor Tu or mitochondrial tryptophanyl-tRNA synthetase are not viable indicating that mitochondrial translation is also essential in this stage. Both of these proteins show trypanosomatid-specific features and may therefore be excellent novel drug targets. PMID- 20969652 TI - Verbal and physical violence in emergency departments: a survey of nurses in Istanbul, Turkey. AB - AIMS: The aim of this study was to determine the perceived verbal and physical violence and related factors experienced by nurses in emergency settings. BACKGROUND: Studies on violence in emergency departments indicate an increasing frequency of these incidents. However, little is known about the violence experienced by the Turkish nurses working in emergency departments. DESIGN: Survey. METHODS: The study population included 255 nurses. Data were collected using a questionnaire. RESULTS: Verbal violence was reported with a frequency of 91.4%. Of the nurses, 74.9% had been exposed to physical violence in at least several episodes during the previous 12 months. Patients' relatives were the main perpetrators, followed by patients, most of whom were male. After experiencing violence, most of the nurses reported that, they had felt fear and only 3% described that they took sick leave, while 80% did not report the incidences of violence they experienced. The nurses described that, after a violent incident, they sought support mainly from their colleagues in emergency departments rather than from the administration. Over half of the nurses (65%) felt safe 'none of the time' in emergency departments, and 89.8% of them described that patients and patient relatives may potentially exhibit violent behaviours towards the staff when they are first admitted to emergency department, while 73.7% believed that the staffing pattern and physical environment of their emergency departments were not adequate to prevent violence. Most of the nurses (83.5%) stated that they should be provided with the training that will help them prevent and manage violence as part of their in-service education, whereas 82.7% of them had not received any such training. RELEVANCE TO CLINICAL PRACTICE: The findings have implications for occupational health and safety from both employer and employee perspective. PMID- 20969651 TI - Pubertal-related changes in hypothalamic-pituitary-adrenal axis reactivity and cytokine secretion in response to an immunological stressor. AB - Pubertal development is marked by profound changes in stress reactivity. For example, following a brief stressor, such as foot shock, ether inhalation or restraint, prepubertal rats display a prolonged adrenocorticotrophic hormone (ACTH) and corticosterone response that takes twice as long to return to baseline compared to adults. Pubertal-related differences in the recovery of the hormonal stress response following a more protracted systemic stressor, such as an immunological challenge, have not yet been investigated. Moreover, it is unclear whether an immunological stressor leads to a differential cytokine response in animals before and after pubertal maturation. To examine these issues, we used a single injection of lipopolysaccharide (LPS; 0.1 mg/kg) to induce a hormonal stress and innate immune response and measured plasma ACTH, corticosterone, and the pro-inflammatory cytokines interleukin (IL)-1beta and IL-6 in prepubertal and adult male rats 0, 2, 4, 6, 8, or 24 h after LPS exposure. In a follow-up experiment, we assessed neural activation, as indexed by FOS immunohistochemistry, in the paraventricular nucleus of the hypothalamus (PVN) in prepubertal and adult males 0, 4, 8, or 24 h after a 0.1 mg/kg injection of LPS. By contrast to the prolonged response observed in prepubertal animals following a variety of acute stressors, we found that corticosterone and IL-6 responses induced by LPS recover toward baseline faster in prepubertal compared to adult rats. Along with these different peripheral responses, we also found that LPS induced neural activation in the PVN of prepubertal animals showed a faster return to baseline compared to adults. Together, these data indicate that prepubertal and adult animals react in distinct ways, both peripherally and centrally, to an immunological stressor. PMID- 20969650 TI - Sustained delayed gastric emptying during repeated restraint stress in oxytocin knockout mice. AB - We have recently shown that impaired gastric motility observed in acute restraint stress was restored following repeated restraint stress in mice. Repeated restraint stress up-regulates oxytocin mRNA expression and down-regulates corticotrophin-releasing factor (CRF) mRNA expression at the hypothalamus. Oxytocin knockout mice (OXT-KO) have been widely used to study the central oxytocin signalling pathways in response to various stressors. We studied the effects of acute and repeated restraint stress on solid gastric emptying and hypothalamic CRF mRNA expression in wild-type (WT) and OXT-KO mice. Heterozygous (HZ) parents (B6; 129S-Oxt(tm1Wsy)/J mice) were bred in our animal facility. Male OXT-KO, WT and HZ littermates were used for the study. Solid gastric emptying was measured following acute restraint stress (for 90 min) or repeated restraint stress (for five consecutive days). Expression of CRF mRNA in the paraventricular nucleus (PVN) was measured by real-time reverse transcriptase-polymerase chain reaction. There were no significant differences of gastric emptying in WT (68.4 +/- 4.1%, n = 6), HZ (71.8 +/- 3.1%, n = 6) and OXT-KO (70.6 +/- 3.1%, n = 6) mice in nonstressed conditions. Acute stress significantly delayed gastric emptying in OXT-KO mice (33.10 +/- 2.5%, n = 6) WT (39.1 +/- 1.1%, n = 6) and HZ mice (35.8 +/- 1.2%, n = 6). Following repeated restraint stress loading, gastric emptying was significantly restored in WT (68.3 +/- 4.5%, n = 6) and HZ mice (63.1 +/- 2.6%, n = 6). By contrast, gastric emptying was still delayed in OXT-KO mice (34.7 +/- 1.3%, n = 6) following repeated restraint stress. The increase in CRF mRNA expression at the PVN was much pronounced in OXT-KO mice compared to WT or HZ mice following repeated restraint stress. These findings suggest that central oxytocin plays a pivotal role in mediating the adaptation mechanism following repeated restraint stress in mice. PMID- 20969655 TI - Simple method for harvesting split-thickness skin grafts. PMID- 20969654 TI - Electrobrasion--an alternative to dermabrasion. PMID- 20969656 TI - Unique injection techniques, including volumizing the forehead, advance the ways we rejuvenate the face. Introduction. PMID- 20969658 TI - Development and validation of a 6-point grading scale in patients undergoing correction of nasolabial folds with a collagen implant. AB - BACKGROUND: Various scoring techniques prone to subjective interpretation have been used to evaluate soft tissue augmentation of nasolabial folds (NLFs). OBJECTIVE: To design and validate a reliable wrinkle assessment scoring scale. MATERIALS AND METHODS: Six photographed wrinkles of varying severity were electronically copied onto the same facial image to become a 6-point grading scale (GGS). A pilot training program (13 investigators) determined reliability, and a 12-week multicenter survey study validated the GGS scoring method. RESULTS: Pilot study inter- and intrarater scoring reliability were high (weighted kappa scores of 0.85 and 0.86, respectively). Seventy-five percent of survey investigators and independent review panel (IRP) members considered a GGS score difference of 0.5 to be a minimally perceivable difference. Interrater weighted kappa scores were 0.91 for the IRP and 0.80 for investigators. Intrarater agreements after repeat testing were 0.91 and 0.89, respectively. The baseline "live" assessment GGS mean score was 3.34, and the baseline blinded photographic assessment GGS mean score was 2.00 for the IRP and 2.16 for the investigators. CONCLUSIONS: The GGS is a reproducible method of grading the severity of NLF wrinkles. Treatment effectiveness of a dermal filler can be reliably evaluated using the GGS by comparing "live" assessments with the standard GGS photographic panel. PMID- 20969657 TI - Improvement in nasolabial folds with a hyaluronic acid filler using a cohesive polydensified matrix technology: results from an 18-month open-label extension trial. AB - BACKGROUND: Repeat treatments of nonpermanent dermal fillers are used in the long term treatment of wrinkles and folds and to volumize. OBJECTIVE To determine the safety and effectiveness of a nonanimal-sourced hyaluronic acid (HA) (which uses a cohesive polydensified matrix (CPM) technology [CPMHA]) for the treatment of nasolabial folds (NLFs) during an 18-month open-label extension trial. METHODS AND MATERIALS: Ninety-five of 118 subjects continued with this optional open label extension of a split-face, double-blind trial. All subjects received CPMHA in both NLFs at 24 weeks after treatment in this study and were assessed at weeks 32, 48, 72, and 96. Touch-ups were allowed for optimal correction. Safety was assessed according to reported adverse events (AEs) and serum antibody measurement. RESULTS: At all four post-week 24 time points, the severity of the NLFs showed a decrease from baseline on the Wrinkle Severity Rating Scale. The effects persisted in the majority (~80%) of subjects without repeat treatment for at least one interval of 48 weeks. The study filler was well tolerated, with only one related AE (injection site bruising) reported. Little potential for immunogenic reactions was identified. CONCLUSION: This CPMHA is a well-tolerated and effective treatment for at least 48 weeks in the majority of subjects for the correction of moderate to severe NLFs with repeat injections given over an 18 month period. PMID- 20969653 TI - Prenatal LPS increases inflammation in the substantia nigra of Gdnf heterozygous mice. AB - Prenatal systemic inflammation has been implicated in neurological diseases, but optimal animal models have not been developed. We investigated whether a partial genetic deletion of glial cell line-derived neurotrophic factor (Gdnf(+/-)) increased vulnerability of dopamine (DA) neurons to prenatal lipopolysaccharide (LPS). LPS [0.01 mg/kg intraperitoneal (i.p.)] or saline was administered to wild type (WT) or Gdnf(+/-) pregnant mice on gestational day 9.5. Male offspring were examined at 3 weeks, 3 and 12 months of age. There was a progressive degeneration of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) with age in Gdnf(+/-) but not in WT mice, with no observed effects on locus coeruleus (LC) noradrenergic neurons or DA neurons of the ventral tegmental area. Inflammatory markers were elevated in SN of LPS treated offspring, with exacerbation in Gdnf(+/-) mice. Intracellular accumulation of alpha-synuclein (alpha-syn) immunoreactivity in DA neurons of SN was observed in all groups of Gdnf(+/-) and in WT mice with prenatal LPS, with altered distribution between pars reticulata (pr) and pars compacta (pc). The findings suggest that prenatal LPS leads to accelerated neuropathology in the SN with age, and that a partial loss of GDNF exacerbates these effects, providing a novel model for age-related neuropathology of the nigrostriatal DA system. PMID- 20969659 TI - 12-Month controlled study in the United States of the safety and efficacy of a permanent 2.5% polyacrylamide hydrogel soft-tissue filler. AB - OBJECTIVE: To evaluate the safety and efficacy of a 2.5% polyacrylamide hydrogel in the aesthetic enhancement of nasolabial folds. METHODS AND MATERIALS: The safety and efficacy of a polyacrylamide hydrogel were compared with those of nonanimal stabilized hyaluronic acid (NASHA) in 315 subjects in a double-blind, randomized, multicenter, noninferiority trial with a 12-month follow-up. The primary efficacy end point was mean change in Wrinkle Assessment Scale (WAS) scores at 6 months. The primary safety end point was rate of serious adverse events (AEs) through 12 months after treatment. RESULTS: Polyacrylamide hydrogel was as effective as NASHA, and effectiveness persisted throughout the 12-month follow-up. Treatment-related AEs occurred with equal incidence; most were mild to moderate, transient, and related to injection procedure. One serious AE (infection) was thought to be related to treatment with polyacrylamide hydrogel; it resolved within 5 days after appropriate treatment. CONCLUSION: This 2.5% polyacrylamide hydrogel offers promise as a long-lasting soft tissue filler. It is well tolerated, as effective as NASHA in correction of nasolabial folds, and persistent. Longer evaluation is required to evaluate longer-term safety and demonstrate duration of effect beyond 12 months. This PMID- 20969660 TI - Novel hyaluronic acid dermal filler: dermal gel extra physical properties and clinical outcomes. AB - BACKGROUND: Dermal gel extra (DGE) is a new, tightly cross-linked hyaluronic acid (HA)-based dermal filler containing lidocaine engineered to resist gel deformation and degradation. OBJECTIVES: To develop a firmer gel product (DGE) and compare the efficacy and safety of DGE with nonanimal stabilized HA (NASHA) for correction of nasolabial folds (NLFs). METHODS: DGE physical properties were characterized, and 140 subjects with moderate to deep NLFs were treated with DGE and NASHA in a randomized, multicenter, split-face design study. Efficacy, pain, and satisfaction were measured using appropriate standard instruments. Adverse events were monitored throughout the study. RESULTS: DGE has a higher modulus and a higher gel:fluid ratio than other HA fillers. Similar optimal correction was observed with DGE and NASHA through 36 weeks (9 months). Study subjects required less volume (p<.001) and fewer touch-ups (p=.005) and reported less injection pain (p<.001) with DGE treatment. Most adverse events were mild to moderate skin reactions. CONCLUSIONS: DGE is a firm HA gel that required significantly less volume and fewer touch-ups to provide equivalent efficacy to NASHA for NLF correction; both dermal gels were well tolerated. DGE will provide a comfortable and cost-effective dermal filler option for clinicians and patients. PMID- 20969661 TI - Use of ultrasound to provide overall information on facial fillers and surrounding tissue. AB - BACKGROUND: Information on fillers and their behavior over time in the different layers of tissue is limited. Ultrasound may be used to visualize these fillers and their surrounding tissue to broaden knowledge. OBJECTIVE: To evaluate the use of ultrasound as a diagnostic and research tool to obtain information on facial fillers and their behavior in human tissue. METHODS AND MATERIALS: Patients with a history of facial filler treatment were examined using ultrasound in an outpatient setting. RESULTS: Seventy-two patients were examined. Hydrophilic fillers were echo visible, whereas tissue-generating fillers, permanent and resorbable, could be detected according to their tissue-generating reaction within the tissue. Filler characteristics such as longevity and reaction within the tissue and complications such as migration and granulomas could be visualized. CONCLUSION: The use of ultrasound may provide information to broaden our knowledge of facial fillers and may improve the performance and safety of filler treatments. The authors have indicated no significant interest with commercial supporters. PMID- 20969662 TI - Comparison of treatment of melomental fold rhytides with cross-linked hyaluronic acid combined with onabotulinumtoxina and cross-linked hyaluronic acid alone. AB - BACKGROUND: Hyaluronic acid and onabotulinumtoxinA combination therapy has been shown to have greater clinical effectiveness than hyaluronic acid alone for glabellar furrowing, but this is not well documented for melomental fold rhytides. OBJECTIVE: To compare the efficacy of intradermal cross-linked hyaluronic acid (HA) and onabotulinumtoxinA combination therapy with the efficacy of cross-linked HA monotherapy in patients with melomental fold rhytides. METHODS AND MATERIALS: Twenty-two patients received combination therapy to a melomental fold area while also receiving cross-linked HA and a placebo saline injection to the contralateral side. Blinded physician evaluators and patient self-evaluators clinically and photographically assessed responses during standard intervals over 12 months. RESULTS: The melomental folds treated with combination therapy had significantly greater aesthetic improvement than the monotherapy-treated side at 2 weeks and 1 month upon physician photographic review. Furthermore, the median time for return to pretreatment rhytides was 6.5 weeks longer in the combination therapy side. Patient assessment also revealed improvement over baseline for the combination therapy at 1 month. CONCLUSION: Cross-linked HA and onabotulinumtoxinA combination therapy to melomental fold rhytides may provide better overall aesthetic results and longer duration of aesthetic improvement than cross-linked HA monotherapy. PMID- 20969663 TI - Comparison of the rheological properties of viscosity and elasticity in two categories of soft tissue fillers: calcium hydroxylapatite and hyaluronic acid. AB - BACKGROUND: Two types of soft tissue filler that are in common use are those formulated primarily with calcium hydroxylapatite (CaHA) and those with cross linked hyaluronic acid (cross-linked HA). OBJECTIVE: To provide physicians with a scientific rationale for determining which soft tissue fillers are most appropriate for volume replacement. MATERIALS: Six cross-linked HA soft tissue fillers (Restylane and Perlane from Medicis, Scottsdale, AZ; Restylane SubQ from Q-Med, Uppsala, Sweden; and Juvederm Ultra, Juvederm Ultra Plus, and Juvederm Voluma from Allergan, Pringy, France) and a soft tissue filler consisting of CaHA microspheres in a carrier gel containing carboxymethyl cellulose (Radiesse, BioForm Medical, Inc., San Mateo, CA). METHODS The viscosity and elasticity of each filler gel were quantified according to deformation oscillation measurements conducted using a Thermo Haake RS600 Rheometer (Newington, NH) using a plate and plate geometry with a 1.2-mm gap. All measurements were performed using a 35-mm titanium sensor at 30 degrees C. Oscillation measurements were taken at 5 pascal tau (tau) over a frequency range of 0.1 to 10 Hz (interpolated at 0.7 Hz). Researchers chose the 0.7-Hz frequency because it elicited the most reproducible results and was considered physiologically relevant for stresses that are common to the skin. RESULTS The rheological measurements in this study support the concept that soft tissue fillers that are currently used can be divided into three groups. CONCLUSION Rheological evaluation enables the clinician to objectively classify soft tissue fillers, to select specific filler products based on scientific principles, and to reliably predict how these products will perform--lifting, supporting, and sculpting--after they are appropriately injected. PMID- 20969664 TI - Blinded evaluation of the effects of hyaluronic acid filler injections on first impressions. AB - BACKGROUND: Facial appearance has profound influence on the first impression that is projected to others. OBJECTIVE: To determine the effects that complete correction of the nasolabial folds (NLFs) with hyaluronic acid (HA) filler has on the first impression one makes. METHODS: Twenty-two subjects received injections of HA filler into the NLFs. Photographs of the face in a relaxed pose were taken at baseline, optimal correction visit, and 4 weeks after optimal correction. Three hundred four blinded evaluators completed a survey rating first impression on various measures of success for each photo. In total, 5,776 first impressions were recorded, totaling 46,208 individual assessments of first impression. RESULTS: Our findings indicate a significant improvement in mean first impression in the categories of dating success, attractiveness, financial success, relationship success, athletic success, and overall first impression at the optimal correction visit. At 4 weeks after the optimal correction visit, significance was observed in all categories measured: social skills, academic performance, dating success, occupational success, attractiveness, financial success, relationship success, athletic success, and overall first impression. CONCLUSION: Full correction of the NLFs with HA filler significantly and positively influences the first impression an individual projects. PMID- 20969665 TI - A lidocaine-containing formulation of large-gel particle hyaluronic acid alleviates pain. AB - BACKGROUND: Effective pain management is an important component of aesthetic procedures. OBJECTIVE: To compare the pain relief and safety of large-gel particle hyaluronic acid (HA) plus 0.3% lidocaine (LGP-HA+L) with that of LGP-HA without lidocaine during correction of nasolabial folds (NLFs) and to assess filler safety in different skin types. METHODS AND MATERIALS: Sixty subjects were enrolled in a randomized, double-blind, split-face study of LGP-HA and LGP-HA+L for NLF correction. Subjects assessed pain on a 100-mm visual analog scale (VAS). The primary objective was to demonstrate that more than 50% of subjects experienced pain relief with LGP-HA+L, defined as a within-subject VAS difference of at least 10 mm at the end of injection. RESULTS: LGP-HA+L resulted in pain relief in 57 (95.0%, 95% confidence interval=86.1-99.0) subjects at the end of injection. The mean within-subject VAS difference was 34.4 mm. Injection-related adverse events occurred at similar frequencies with both products. Slightly higher adverse event rates were observed with Fitzpatrick skin type IV for both compounds. The safety profiles of LGP-HA and LGP-HA+L were similar to each other in all skin types. CONCLUSION: The addition of lidocaine substantially reduces the pain of LGP-HA injection without altering safety. LGP-HA and LGP-HA+L were generally well tolerated in all Fitzpatrick skin types. PMID- 20969666 TI - Volumizing with a 20-mg/mL smooth, highly cohesive, viscous hyaluronic acid filler and its role in facial rejuvenation therapy. AB - BACKGROUND: The new 20 mg/mL hyaluronic acid (HA) dermal filler is a smooth, highly cohesive, viscous formulation developed to restore volume in aesthetic facial rejuvenation. OBJECTIVE Evaluate clinical experience with 20 mg/mL HA dermal filler to date and comment on its current and potential uses within the facial rejuvenation treatment paradigm. METHODS AND MATERIALS: In this paper, the authors review the unique physical and chemical properties of 20 mg/mL HA dermal filler as well as clinical experience with the product to date. RESULTS: Overall, the 20 mg/mL smooth, cohesive, viscous HA filler was especially effective in restoring volume in the malar region and chin. Volume loss resolved significantly in patients in clinical trials(1) and treatment effects were observed to be maintained from six to 18 months.(2) Physicians reported the agent was highly effective as well as easy to inject, sculpt and mold. The treatment was generally well tolerated and no instances of product migration from the injection site have been reported. Patient satisfaction was high, with the vast majority of trial participants acknowledging they would return for additional treatment and recommend the treatment to friends.(1,2) CONCLUSION: Initial experience shows the 20 mg/mL smooth, cohesive, viscous HA filler to be a useful addition to the facial rejuvenation armamentarium when used both alone and in combination with BTX-A. PMID- 20969667 TI - The current state of treatment of adverse reactions to injectable fillers. AB - BACKGROUND: Adverse reactions to injectable filler may be challenging to treat. The spectrum of treatment options ranges from immunomodulatory drugs (e.g., glucocorticosteroids) to antibiotics to laser therapy and surgery. OBJECTIVES: To assess how adverse reactions were treated and how they processed over time. MATERIALS AND METHODS: Participants from the Injectable Filler Safety (IFS) Study were reinterviewed to obtain data on the course of adverse reactions and the therapy. RESULTS: Forty-one participants from the IFS Study were reinterviewed; 35 (85%) received treatment, 17 (41%) with a combination of drug therapy and surgery, 14 (34%) with drug therapy only, and four (10%) with a surgical intervention. Six (15%) did not receive any treatment. Fifty-one percent of all of the treated participants reported treatment-related adverse reactions. Participants with more severe adverse reactions were more likely to be treated with a combination of drugs and surgery. In all participants, adverse reactions improved. CONCLUSION: We certainly need more evidence. Reporting positive and negative treatment outcomes is important to improve our knowledge regarding these reactions. Therefore, registries focusing on adverse reactions to injectable fillers and their treatment should be encouraged. The authors have indicated no significant interest with commercial supporters. PMID- 20969668 TI - Volumizing the glabella and forehead. PMID- 20969669 TI - Forehead recontouring using calcium hydroxylapatite. PMID- 20969670 TI - Application and use of various mass spectrometry methods in clinical microbiology. AB - When confronted with a septic patient or dealing with an emerging epidemic, clinicians, infection control specialists and microbiologists have often felt an immense 'need for speed' while waiting for culture results. Various mass spectrometry (MS) applications are about to answer most of their demands. Matrix assisted laser desorption ionization (MALDI) time-of-flight (TOF) MS of whole bacterial cells has already greatly shortened the time needed for identification of a positive culture in major diagnostic laboratories in Europe. MS is described in this article, with a special emphasis on the different systems currently commercially available for routine identification. MALDI-TOF MS remains, however, limited by the previous time-consuming culture steps, and is not suited for strain typing in epidemic contexts. These limitations can be overcome by other applications of MS in microbiology. MALDI-resequencing is a rapid method for genotyping, offering comparable results to multilocus sequence typing. New systems of broad-range PCR, associated with analyses of amplicons by electrospray ionization MS, might allow nearly full automation for the direct identification of pathogens in blood, thus bypassing the culture stage. This article describes various applications of MS methods in clinical microbiology, and provides a comparative table of these technologies. PMID- 20969671 TI - Panton-Valentine leukocidin associated staphylococcal disease: a cross-sectional study at a London hospital, England. AB - Recently, there has been international concern at the rapid emergence of highly pathogenic strains of Staphylococcus aureus associated with a toxin called Panton Valentine leukocidin (PVL). In the UK, these strains are considered to be rare and mainly severe. We estimate the proportion of staphylococcal infections that are caused by strains containing the PVL genes, and describe risk factors for these infections. Three hundred and ninety consecutive S. aureus clinical isolates, submitted for routine diagnostic purposes were screened for PVL genes. Risk factors for infection were identified from the patient medical record. 9.7% (95% CI 7.0-13.1%) of clinical isolates and 20.8% of skin and soft tissue specimens contained the genes for PVL. Methicillin-resistant S. aureus with PVL was rare (0.8% of all isolates) but PVL with methicillin-sensitive S. aureus was common (9.0% of all specimens). PVL infection was more frequent in males (OR 3.0, 95% CI 1.3-7.0), and in young adults aged 20-39 years (OR 3.7, 95% CI 1.3-10.4). Over half of PVL positive S. aureus infections originated in patients based in the community. Community-onset PVL-associated disease is common in the UK and mainly causes skin and soft tissue infections that do not require admission to hospital. Consideration should be given to current infection control strategy, which advocates household contact screening and decolonization on the assumption that PVL-associated disease is rare. PMID- 20969672 TI - Genetic diversity of noroviruses from outbreaks, sporadic cases and wastewater in Luxembourg 2008-2009. AB - The genetic diversity of norovirus strains obtained from gastroenteritis outbreaks, sporadic case surveillance and wastewater plants was compared in Luxembourg from October 2008 until June 2009. Except for GI.6 and GIV.1 strains detected exclusively in wastewater, all other genotypes were also found in human samples. Of the nine NoV genotypes detected, only three (GII.4, GIIb/II.3 and GIIc/II.12) were associated with institutional outbreaks. The majority of sequences from all sources belonged to genotype GII.4, including two potentially new sub-variants. Strains collected in the context of outbreaks may significantly under-represent the overall genetic diversity of NoVs circulating in a country. PMID- 20969673 TI - Basic principles and current applications of lung ultrasonography in the intensive care unit. AB - Until recently, the sonographic visualization of pulmonary and pleural diseases was considered a poorly accessible method, due to the inability of sound to penetrate air-filled lung. Despite its limitations, lung ultrasonography is becoming an important diagnostic tool in a growing number of pathological situations such as pneumonia, atelectasis, interstitial-alveolar syndrome, pulmonary embolism, pneumothorax and pleural effusion. The low sensitivity of CXR and the difficulties of performing CT make this technique invaluable for bedside use in the intensive care unit. Lung ultrasonography is an easily repeatable and radiation-free technique, and therefore, an attractive imaging tool for use on a daily basis, especially in the management of critically ill patients. PMID- 20969675 TI - The lower the body weight for COPD patients, the more effective is pulmonary rehabilitation? PMID- 20969674 TI - Immunohistochemical staining for transcription factor MafB in alveolar macrophages is correlated with spirometric measures of airflow limitation in smokers. AB - BACKGROUND AND OBJECTIVE: Alveolar macrophages (AM) play an important role in the pathogenesis of COPD, and their numbers are significantly increased in patients with COPD. We previously demonstrated that expression of the transcription factor, MafB, was upregulated in AM of mice exposed to cigarette smoke. The aim of this study was to investigate whether the expression of MafB is associated with the degree of airflow limitation (AFL) in smokers. METHODS: Lung tissue specimens were obtained from male patients undergoing resection of small peripheral lung tumours. The patients were classified into three groups according to smoking index and FEV1 /FVC: (i) non-smokers or non-heavy ex-smokers without AFL (FEV1 /FVC >= 0.7, smoking index <= 400) (n=8); (ii) heavy current smokers without AFL (FEV1 /FVC >= 0.7, smoking index >= 800) (n=8); and (iii) heavy current smokers with AFL (FEV1 /FVC < 0.6, smoking index >= 800) (n=8). The intensity of immunostaining for MafB in AM was quantified by image analysis. RESULTS: Immunostaining for MafB was significantly enhanced in AM of smokers with AFL compared with AM of subjects without AFL. Smoking index, FEV1/FVC and FEF(25 75%) (% predicted) were significantly correlated with the intensity of MafB immunostaining. Multiple linear regression analysis revealed that FEV1 % was also an independent negative predictor of the intensity of MafB immunostaining. CONCLUSIONS: The degree of immunostaining for MafB in AM was correlated with the degree of AFL in smokers. MafB may be involved in the pathophysiology of COPD. PMID- 20969676 TI - The association of cryoglobulinaemia with sustained virological response in patients with chronic hepatitis C. AB - Previous reports suggest cryoglobulinemia might influence the hepatitis C virus (HCV) infection clinical course and treatment response but this association has not been thoroughly evaluated. We aimed to assess the relationship between cryoglobulinemia and sustained viral response (SVR) in patients treated for HCV infection. We included patients with HCV infection treated from January 2003 through December 2006. Biochemical analyses, detection cryoglobulinemia, and liver biopsies were performed prior to treatment. Genotype 1 or 4 infections received Peg-interferon (IFN) alpha-2a or -2b for 48 weeks; genotypes 2 or 3 received IFN alpha for 24 weeks. All patients also received ribavirin. Of 329 enrolled patients, 242 (73%) were male and the median age was 43 years. Cryoglobulinemia was detected in 196 (59.6%) patients; liver biopsy was performed in 301. Multivariate analysis showed an association of cryoglobulinemia with severe active necroinflammation (A3) (adjusted odds ratio [AOR] = 9.48; 95% confidence interval [CI]: 1.50-59.92) and rheumatoid factor (RF) level (AOR = 1.01; 95% CI: 1.00-1.02). Variables associated with advanced fibrosis were age, aspartate aminotransferase and alkaline phosphatase levels, alcohol use, and presence of diabetes. Variables independently associated with SVR were cryoglobulinemia (AOR = 2.33, 95% CI: 1.26-4.32), absence of cirrhosis (AOR = 4.5, 95% CI: 1.4-14.80), and RF level (AOR = 1.008, 95% CI: 1.001-1.014). Our findings suggest cryoglobulinemia is associated with severe necroinflammatory activity in HCV-infected patients. We also provide the first evidence for an association between cryoglobulinemia and higher SVR rates, highlighting its potential role as a prognostic factor for treatment response. PMID- 20969677 TI - Kill rate of mastitis pathogens by a combination of cefalexin and kanamycin. AB - AIM: To assess the bacterial killing rate produced by a combination of cefalexin and kanamycin at two different concentration ratios. METHODS AND RESULTS: Time kill kinetics of cefalexin and kanamycin, individually and in combination, were determined against one strain each of Escherichia coli, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus dysgalactiae and Streptococcus uberis. The combination was tested using two fixed ratios (cefalexin : kanamycin ratios of 1.25 : 1 and 1 : 2.3) and two concentrations of each ratio. Time-kill curves produced with either ratio were quite similar. Against most bacterial species, higher concentrations produced faster kill. In all cases, the combination of cefalexin and kanamycin showed faster and greater kill at lower antibiotic concentrations than those observed with either drug alone. CONCLUSIONS: The combination of cefalexin and kanamycin results in a fast initial killing of major mastitis pathogens at both concentration ratios. SIGNIFICANCE AND IMPACT OF THE STUDY: The combination of cefalexin and kanamycin achieved rapid bacterial kill at concentrations and ratios that can be achieved in vivo following intramammary infusion of a mastitis treatment. PMID- 20969678 TI - Purification and characterization of an exo-type beta-N-acetylglucosaminidase from Pseudomonas fluorescens JK-0412. AB - AIMS: To purify and characterize an exo-acting chitinolytic enzyme produced from a Gram-negative bacterium Pseudomonas fluorescens JK-0412. METHODS AND RESULTS: A chitinolytic bacterial strain that showed confluent growth on a minimal medium containing powder chitin as the sole carbon source was isolated and identified based on a 16S ribosomal DNA sequence analysis and named Ps. fluorescens JK-0412. From the culture filtrates of this strain, a chito-oligosaccharides-degrading enzyme was purified to apparent homogeneity with a molecular mass of 50 kDa on SDS-PAGE gels. The kinetics, optimum pH and temperature, and substrate specificity of the purified enzyme (named as NagA) were determined. CONCLUSIONS: An extracellular chitinolytic enzyme was purified from the Ps. fluorescens JK 0412 and shown to be an exo-type beta-N-acetylglucosaminidase yielding GlcNAc as the final product from the natural chito-oligosaccharides, (GlcNAc)(n) , n = 2-5. SIGNIFICANCE AND IMPACT OF THE STUDY: As NagA is secreted extracellularly in the presence of colloidal chitin, Ps. fluorescens JK-0412 can be recognized as a potent producer for industry-level and cost-effective production of chitinolytic enzyme. This enzyme appears to have potential applications as an efficient tool for the degradation of chitinous materials and industry-level production of GlcNAc. To the best of our knowledge, this is the first report on an exo-type chitinolytic enzyme of Pseudomonas species. PMID- 20969680 TI - Getting the most out of hemoglobin A1C testing. PMID- 20969679 TI - Reducing PEX13 expression ameliorates physiological defects of late-acting peroxin mutants. AB - Proteins are targeted to the peroxisome matrix via processes that are mechanistically distinct from those used by other organelles. Protein entry into peroxisomes requires peroxin (PEX) proteins, including early-acting receptor (e.g. PEX5) and docking peroxins (e.g. PEX13 and PEX14) and late-acting PEX5 recycling peroxins (e.g. PEX4 and PEX6). We examined genetic interactions among Arabidopsis peroxin mutants and found that the weak pex13-1 allele had deleterious effects when combined with pex5-1 and pex14-2, which are defective in early-acting peroxins, as shown by reduced matrix protein import and enhanced physiological defects. In contrast, combining pex13-1 with pex4-1 or pex6-1, which are defective in late-acting peroxins, unexpectedly ameliorated mutant growth defects. Matrix protein import remained impaired in pex4-1 pex13-1 and pex6-1 pex13-1, suggesting that the partial suppression of pex4-1 and pex6-1 physiological defects by a weak pex13 allele may result from restoring the balance between import and export of PEX5 or other proteins that are retrotranslocated from the peroxisome with the assistance of PEX4 and PEX6. Our results suggest that symptoms caused by pex mutants defective in late-acting peroxins may result not only from defects in matrix protein import but also from inefficient removal of PEX5 from the peroxisomal membrane following cargo delivery. PMID- 20969681 TI - Management guidelines for patients with thyroid nodules. PMID- 20969682 TI - Survival from breast cancers managed by surgeons participating in the National Breast Cancer Audit of the Royal Australasian College of Surgeons. AB - BACKGROUND: he National Breast Cancer Audit (NBCA) of the Royal Australasian College of Surgeons has collected data on early breast cancer since 1998. In this project, deaths were traced by linkage of NBCA patient identifiers (first three digits of surname and date of birth) with the National Death Index that covers all deaths in Australia. METHODS: Death data were traced to 31 December 2007. Invasive cancers diagnosed in 1998-2005 were included in survival analyses to allow enough follow-up for assessment. Survivals were compared with survivals for similar stages recorded by the New South Wales (NSW) Cancer Registry and USA Surveillance Epidemiology and End Results (SEER) programme. Survivals were analysed by conventional clinical risk factors to see if expected differences presented. RESULTS: The 5-year survival from breast cancer of 93% for NBCA cases was the same as the SEER figure for local and regional cases combined in 1996 2004. The NBCA figure for localized cases was 97%, which was the same as for NSW. Node-positive NBCA cancers had a 5-year survival of 89%, which was slightly higher than the corresponding 86% for NSW, which may reflect exclusion from the NBCA of some cases with a poorer prognosis, including those with positive fixed nodes. As expected, lower survivals presented for older cases and those with conventional clinical risk factors. CONCLUSIONS: These survivals are credible both overall and by clinical risk factor. Opportunities present to use these data for survival monitoring and to investigate survival by socio-demographic characteristic, treatment protocol, case volume and provider characteristics. PMID- 20969683 TI - Are there anatomical barriers to laparoscopic donor nephrectomy? AB - BACKGROUND: The aim of this study was to analyse the effect of the right donor kidney and multiple arteries, on donor and recipient outcomes in the era of laparoscopic live donor nephrectomy (LLDN). METHODS: e retrospectively analysed the 200 donors and recipients who underwent a planned laparoscopic nephrectomy at two hospitals between September 1998 and December 2006. The impact of donor right kidney and multiple donor renal arteries on operative time, hospital stay, graft function, and donor and recipient complications were analysed. RESULTS: Of the total cohort (n=200), 140 (70%) were classified as Simple LLDN (left live donor kidney with single renal artery). The Complex LLDN group (n=60) contained all right-sided kidney (n=28) and left-sided kidneys with multiple renal arteries (n=32). Baseline characteristics, extraction time, conversion to open, length of admission, overall graft function and complication rates were similar between the simple and complex groups. The second warm ischaemic time in the Simple LLDN group was slightly shorter than the Complex LLDN group (32 versus 36 min P=0.016). The 1-month post-operative recipient serum creatinine level was lower in the Simple LLDN group when compared with the Complex LLDN group (117 versus 125 umol/L P=0.025). There was no difference in post op dialysis, acute rejection within 3 months or graft survival between the Simple and Complex LLDN groups. CONCLUSION: Laparoscopic procurements of right kidneys and kidneys with multiple arteries were safe and yielded kidneys with excellent function comparable with those of laparoscopic left donor nephrectomy with single artery. PMID- 20969684 TI - Open incisional biopsy is a safe and accurate technique for soft tissue tumours. AB - BACKGROUND: Accurate diagnosis of musculoskeletal tumours is important for successful treatment. Studies have reported a high risk of complications following open biopsy and have advocated core biopsy as a safer alternative; however, accuracy may be reduced with the smaller sample. The aims of this study were to determine the accuracy of open incisional biopsy, the complications (overall and those that affected subsequent management) including local recurrence and the need for further surgery. METHODS: This study was a retrospective audit of 135 consecutive open incisional biopsies of soft tissue tumours. The complications, including changes to surgical management as a direct result of complications of the biopsy, were recorded for all 135 cases. The accuracy of the open biopsy was determined by comparing the histology of the biopsy with the final histology of the 88 cases that proceeded to definitive surgical resection. RESULTS: There were two complications attributable to the biopsy (complication rate 1.5%). No complication affected the definitive management. There were three cases where the biopsy incorrectly reported a benign condition when it was malignant (benign versus malignant accuracy 96%). There were no cases of benign initially being reported as malignant. The tissue diagnosis was correct in 72 of the excised specimens (accuracy 82%). The false positive rate for malignant versus benign was 0%, sensitivity 93%, specificity 100% and positive predictor value 100%. DISCUSSION: Open incisional biopsy remains a safe and accurate method of obtaining a tissue diagnosis when the principles of biopsy are adhered to. PMID- 20969685 TI - Comparison of functional outcomes of reverse shoulder arthroplasty versus hemiarthroplasty in the primary treatment of acute proximal humerus fracture. AB - BACKGROUND: Treatment of complex proximal humeral fractures remains controversial. In cases where adequate open reduction and internal fixation cannot be achieved, hemiarthroplasty has been the traditional treatment; however, clinical results have been mixed. Reverse shoulder arthroplasty (RSA) has been suggested as an alternative, and this study aimed to compare the functional results of RSA versus hemiarthroplasty in patients with acute proximal humeral fracture. METHODS: Ten patients with acute proximal humerus fractures unsuitable for internal fixation (mean age 77) who underwent RSA for acute proximal humerus fracture unsuitable for internal fixation against the outcomes of 10 patients (mean age 75) who had previously undergone hemiarthroplasty for the same indication. Functional scores and radiographic outcomes were assessed at 22-44 months follow up. RESULTS: At follow up the mean American Shoulder and Elbow Scorev score was 65 (range 40-88) in the RSA group and 67 (26-100) in the hemiarthroplasty group. Mean Oxford Shoulder scores were 29 (15-56) and 22 (12 34), respectively. Mean forward elevation was 115 degrees (range 45-140 degrees) and active external rotation was 49 degrees (5-105 degrees) in the RSA group, versus 108 degrees (50-180 degrees) and 48 degrees (10-90 degrees) in the hemiarthroplasty group. No statistically significant differences in outcome scores or range of motion were seen. CONCLUSION: In these early results, the anticipated functional gains of RSA over hemiarthroplasty were not realized, suggesting the use of RSA for treatment of proximal humeral fractures should remain guarded. Larger prospective trials are necessary to identify the optimal management of patients in this situation. PMID- 20969687 TI - Predicting trauma patient mortality: ICD [or ICD-10-AM] versus AIS based approaches. AB - BACKGROUND: The International Classification of Diseases Injury Severity Score (ICISS) has been proposed as an International Classification of Diseases (ICD)-10 based alternative to mortality prediction tools that use Abbreviated Injury Scale (AIS) data, including the Trauma and Injury Severity Score (TRISS). To date, studies have not examined the performance of ICISS using Australian trauma registry data. This study aimed to compare the performance of ICISS with other mortality prediction tools in an Australian trauma registry. METHODS: This was a retrospective review of prospectively collected data from the Victorian State Trauma Registry. A training dataset was created for model development and a validation dataset for evaluation. The multiplicative ICISS model was compared with a worst injury ICISS approach, Victorian TRISS (V-TRISS, using local coefficients), maximum AIS severity and a multivariable model including ICD-10-AM codes as predictors. Models were investigated for discrimination (C-statistic) and calibration (Hosmer-Lemeshow statistic). RESULTS: The multivariable approach had the highest level of discrimination (C-statistic 0.90) and calibration (H-L 7.65, P= 0.468). Worst injury ICISS, V-TRISS and maximum AIS had similar performance. The multiplicative ICISS produced the lowest level of discrimination (C-statistic 0.80) and poorest calibration (H-L 50.23, P < 0.001). CONCLUSIONS: The performance of ICISS may be affected by the data used to develop estimates, the ICD version employed, the methods for deriving estimates and the inclusion of covariates. In this analysis, a multivariable approach using ICD-10-AM codes was the best-performing method. A multivariable ICISS approach may therefore be a useful alternative to AIS-based methods and may have comparable predictive performance to locally derived TRISS models. PMID- 20969686 TI - Wound infusion with local anaesthesia after laparotomy: a randomized controlled trial. AB - BACKGROUND: The use of a continuous local anaesthesia infusion after laparotomy may reduce opioid requirements and facilitate earlier return of bowel function, independent mobilization and hospital discharge. METHODS: We performed a double blinded, randomized controlled trial on 55 patients who underwent laparotomy. Patients were randomly allocated to receive a continuous infusion of either 0.2% ropivacaine or normal saline into their midline abdominal wound at the fascial level. The end points of the study were: total opioid requirements at 24 and 48 h; time to first flatus, bowel movement and independent ambulation; length of hospital stay; complications; and daily mean patient-reported pain scores at rest and movement. RESULTS: The two treatment groups were well controlled for factors that influence analgesia requirements, including age, weight, length of wound incision and type of operation. Patients allocated to ropivacaine infusion used, on average, 32 mg less morphine at 48 h (95% confidence interval 7, 57; P= 0.01). This was highly statistically significant after adjusting for age, gender and type of operation (P= 0.0006). Ropivacaine infusion was associated with a significantly decreased time to independent mobilization (P= 0.02), time to first flatus (P= 0.02) and reduced post-operative ileus (2/28 versus 9/27, chi(2) = 5.89, P= 0.02). There was no significant effect of ropivacaine infusion on time to first bowel movement (P= 0.94) nor length of hospital stay (P= 0.77). CONCLUSIONS: Local anaesthesia infusion at the fascial plane provides effective analgesia. This improves patient recovery through earlier return to bowel function and mobilization. PMID- 20969688 TI - Laparoscopic restorative proctectomy - hybrid approach or totally laparoscopic? AB - BACKGROUND: Laparoscopic rectal resection is now a technique that is emerging from experience with laparoscopic colonic resection. We review and present our experience with restorative proctectomy for cancer and compare those performed with a hybrid technique with those performed totally laparoscopically. METHODS: A total of 177 patients have undergone laparoscopic restorative proctectomy. All of the patients were planned to have the abdominal portion of their surgery performed laparoscopically and to convert to open for the rectal dissection as required. They were then stratified into those that had their surgery performed completely laparoscopically (laparoscopic group - LG), and to those who had their rectal dissection and or transection performed with an open incision (hybrid group - HG). RESULTS: Short-term outcomes were compared between the LG (n=103) and the HG (n=74). The overall complication rate was higher in the HG (12% versus 35% P<0.001), mainly with a significantly higher pelvic abscess rate and higher rate of post-operative ileus. There were no intraoperative or post-operative deaths. Length of stay was equivalent in both groups (five days). To date, distal recurrence has occurred in 7.7% of the patients, eight in the LG and four in the HG (NS). Two patients, one in each group, have had local recurrence only. CONCLUSIONS: Laparoscopic open or laparoscopic hybrid approaches are techniques that can be used in suitable patients. Both have acceptable morbidity and mortality. PMID- 20969689 TI - Surgical anatomy of the external branch of the superior laryngeal nerve. AB - BACKGROUND: The variations in the anatomy of the external branch of the superior laryngeal nerve (EBSLN) are generally classified according to the relationship of the nerve to the superior thyroid artery, or the superior pole of the thyroid. Both artery and superior pole are themselves variable landmarks, and therefore are not consistent between subjects. We sought to examine EBSLN anatomy in relation to alternate, more consistent surgical landmarks. METHODS: Fifteen hemi larynges from 20 embalmed human cadavers were dissected anatomically. Each nerve was categorized using established classification systems, and terminal branching patterns were also noted. Nerve location was recorded in relation to three different constant anatomical structures: the laryngeal prominence, midline junction of the cricothyroid muscles and ipsilateral cricothyroid joint. RESULTS: All cadavers were of European descent. The EBSLN had two branches to the cricothyroid muscle in 34% of cases. The EBSLN anatomical types found were mainly Cernea type 1 (80%), with 7% type 2a and 13% type Ni. An EBSLN was more likely to lie in an 'at risk' location if the subject was less than 160 cm tall. The EBSLN entered the crico-thyroid muscle at a median distance of 14 mm lateral from the laryngeal prominence and 8 mm inferiorly. The median distance from the medial most point of the cricothyroid muscle junction was 14 mm laterally and 14 mm superiorly, and from the cricothyroid joint the entry lay a median distance of 10 mm superiorly and 11 mm medially. CONCLUSIONS: The variability of EBSLN anatomy is again evident, as is the need for careful and knowledgeable surgical technique. New surgical landmarks for the relations of the insertion of the EBSLN reveal a deployment range for each, but one of more of these landmarks may prove useful in thyroid surgery. PMID- 20969690 TI - Laryngoscopic techniques to assess vocal cord mobility following thyroid surgery. AB - BACKGROUND: Assessment of vocal cord mobility using Macintosh laryngoscope is frequently performed after extubation following thyroid surgery to rule out laryngeal nerve palsy. This study compared patient comfort and assessment accuracy of post-operative vocal fold mobility with Macintosh laryngoscope and fibreoptic endoscope. METHODS: One hundred four physically fit patients undergoing thyroid surgery were included for the study. Tele-laryngoscopy was done to rule out pre-existing vocal cord palsy. Direct laryngoscopy (DL) was performed to each patient after extubation, followed by nasal fibreoptic endoscopy (NFE) to assess the vocal cord mobility. Tele-laryngoscopic assessment was repeated after 1 week to compare the DL and NFE findings. Patient reactivity score (PRS) and haemodynamic parameters were recorded with each technique. RESULTS: Macintosh laryngoscope could pick up 4 (50% sensitivity and 88% specificity) and fibreoptic endoscope 7 (87.9% sensitivity and 98.9% specificity) out of the 8 vocal cord palsies identified by tele-laryngoscopy. Patients had significant discomfort during DL (PRS median 3) when compared with NFE and tele laryngoscopy (PRS median 2), P<0.05. Grade 1 view of larynx in 92.1% patients during intubation worsened to grade 2 (76.3%) and grade 3 (15.8%) during extubation with DL, and a significant rise in mean arterial pressure and heart rate was observed from the baseline value till 5 min and when compared with NFE (P<0.05). CONCLUSION: NFE provides accurate assessment of vocal fold mobility with reasonable patient comfort in the immediate post-operative period. Macintosh laryngoscope fails to give optimum visualization and predisposes the patient to significant discomfort and stress. PMID- 20969691 TI - Evaluating the safety of the Harmonic Scalpel around the recurrent laryngeal nerve. AB - BACKGROUND: The Harmonic Scalpel (HS) is widely used in thyroidectomy. Determining the safety margin of using the HS near the recurrent laryngeal nerve (RLN) is helpful in preventing the injury to this nerve during thyroidectomy. METHODS: The parameters of evoked electromyography (EEMG) of vocal muscles before and after using the HS at a power level of 3 were recorded in a rabbit model. Masson staining was used to determine lateral injury caused by incisions using the HS. RESULTS: After the activated tip of the HS made contact with the RLN for >=1 s or was placed 1 mm from the nerve for 3 or 5 s or 2 mm from the nerve for 5 s, significant changes were observed in the minimal stimulus current intensity threshold, the optimal stimulus current intensity threshold, the onset latency and the wave amplitude of EEMG. After the activated HS tip touched the RLN or was placed 1 mm to the nerve for >=1 s or 2 mm to the nerve for 5 s, significant changes were found in peak latency. The thickness of injured lateral tissue was <1, 1-2 and >2 mm when using HS for 1, 3 and 5 s, respectively. CONCLUSION: When used near the RLN at a power level of 3, the activated HS tip should be >=2 mm from the nerve and the duration of incision should be <=3 s. PMID- 20969692 TI - The role of fine-needle aspiration cytology in the surgical management of thyroid cancer. AB - BACKGROUND: Diagnosis of thyroid malignancy relies on clinical assessment, imaging and fine-needle aspiration cytology 'FNAC' of thyroid nodules. The purpose of this study was to evaluate how effective synoptically reported FNAC is in clinical practice in diagnosing thyroid cancer. We also examined the effectiveness of using preoperative FNAC results to plan the type of operation for treating thyroid cancer. METHOD: A retrospective case series of all patients undergoing thyroid surgery from 1993 to 2008 was analysed. All data were collected prospectively and recorded in a dedicated endocrine surgery database. Data analysed included age, sex, preoperative FNAC result, type of surgery, final histology and complications. Cytology was reported based on a five-tiered classification system. RESULTS: There were 1373 patients in total and 125 patients with a final diagnosis of thyroid cancer. Female to male ratio was 3:1. Cytology reported as 'malignant' was confirmed as thyroid cancer in 100% of the cases. Of the patients, 47% with 'suspicious' cytology report and 14% with 'follicular/indeterminate' cytology report had a final diagnosis of cancer. Thyroid cancer subtypes were 90 patients with papillary thyroid cancer 'PTC', 24 with follicular 'FTC', eight with medullary 'MTC' and two with anaplastic cancer. Cytology was suggestive of cancer in 89% of the patients with PTC >10 mm, 75% with FTC and 88% with MTC. Transient hypocalcaemia was the commonest complication occurring in 7.2%. There were no cases of permanent hypoparathyroidism. Recurrent laryngeal nerve neuropraxia occurred in 2.4% with a permanent palsy occurring in 0.8%. There were three cancer-related deaths. CONCLUSIONS: Preoperative synoptically reported FNAC is effective when used in diagnosing and planning surgery for thyroid cancer. PMID- 20969693 TI - Medullary thyroid carcinoma presenting with an initial CEA elevation. AB - BACKGROUND: Carcinoembryonic antigen (CEA) is a tumour marker commonly associated with gastrointestinal malignancy. Patients presenting with an elevated CEA will therefore often undergo extensive investigations in order to elucidate an underlying gastrointestinal malignancy that may not be clinically apparent. However the GI tract is not the only source of CEA elevation. METHODS: We present a series of patients presenting with raised CEA levels that were initially investigated for a gastrointestinal cause, but after work up were detected to have medullary thyroid cancer. RESULTS: Four patients with raised CEA were evaluated for a gastrointestinal cause for the elevation. We discuss the non gastrointestinal causes for an elevated CEA. CONCLUSION: The paper highlights that in patients presenting with an elevated CEA, in whom a gastrointestinal cause has been ruled out, a tumour of neuroendocrine origin needs to be considered as a cause for the elevated CEA. PMID- 20969694 TI - Predictive value of the Delphian and level VI nodes in papillary thyroid cancer. AB - BACKGROUND: Recent published data has shown that metastatic involvement of the prelaryngeal or Delphian lymph node (DLN), the highest of the central (level VI) cervical lymph nodes, is highly predictive of advanced nodal disease in papillary thyroid cancer (PTC). The aims of this study were to determine the diagnostic accuracy of all the level VI cervical nodes in PTC and to determine which node group, if any, is the most accurate in predicting lateral node (N1b) disease. METHODS: This was a retrospective cohort study. Data were obtained from the University of Sydney Endocrine Surgical Unit Database and through a review of the histopathology records. The study cohort was composed of 177 consecutive patients with a final diagnosis of PTC who underwent total thyroidectomy and lymph node dissection, spanning the period from May 2001 to December 2006. RESULTS: Of the 177 patients with PTC, 86 had the DLN removed, 51 had a pretracheal node removed and 76 had the paratracheal group removed. DLN, paratracheal and pretracheal node disease was present in 21%, 39% and 46%, respectively. Lateral node (N1b) disease was present in 35%. Paratracheal node involvement was mildly predictive of further disease with patients 1.7 times more likely to have lateral node involvement (sensitivity=55%, specificity=68%). Pretracheal node involvement was moderately predictive of further disease with patients three times more likely to have lateral node involvement (sensitivity=72%, specificity=74%). DLN involvement was highly predictive of further node involvement with patients nine times more likely to have lateral node disease (sensitivity=53%, specificity=94%) and 40 times more likely to have any nodal disease (sensitivity=41%, specificity=100%). CONCLUSION: This is the first study to examine the diagnostic accuracy of all level VI lymph nodes in PTC. While, metastatic involvement of all central nodal groups is indicative of further disease, the DLN is the most accurate predictor. PMID- 20969699 TI - Response: A case of massive gastrointestinal haemorrhage (ANZ J. Surg. 2010: 80; 190-1). PMID- 20969701 TI - Bowel obstruction by a gastrointestinal stromal tumour in a Meckel's diverticulum. PMID- 20969702 TI - Interdigital pilonidal sinus in a female hairdresser. PMID- 20969703 TI - Surgical approach for end-stage achalasia - transhiatal/transthoracic oesophagectomy? PMID- 20969704 TI - Guillain-Barre syndrome following total gastrectomy/esophagectomy: A very rare and dramatic post-operative complication with a favourable outcome. PMID- 20969705 TI - Malignant melanoma of the pancreas. PMID- 20969706 TI - Transverse testicular ectopia with persisting mullerian remnant masquerading as right inguinal hernia and left undescended testis. PMID- 20969707 TI - Epidermoid cyst or ranula: a case highlighting a potential diagnostic dilemma. PMID- 20969708 TI - Systemic Mastocytosis and surgery a potential disaster. PMID- 20969709 TI - An unusual presentation of lymphoma. PMID- 20969710 TI - A case of squamous cell carcinoma in an ileoanal pouch. PMID- 20969711 TI - Systematic review of abdominal surgery for chronic idiopathic constipation. AB - AIM: Constipation is a common problem which increases in prevalence with age. Chronic constipation is complex and difficult to treat. Some patients will not respond to pharmacological therapy and therefore surgery may be considered. A systematic review of the literature was performed to determine the outcome of surgery. METHOD: Published papers were identified by a search of The Cochrane Library, MEDLINE, CINAHL and EMBASE. They were reviewed and the data were extracted. RESULTS: Forty-eight papers were identified, including 1443 patients. Eleven different procedures were described. There was inconsistency in reporting. In 65% of patients the mean frequency of defaecation increased from 1.1 to 19.7 evacuations per week. Where laxative usage was reported (971 patients), it was found that 88% of patients did not need them postoperatively. Early complications included ileus (0-16%), infection (0-13%) and anastomotic leakage (0-22%). Patient satisfaction and quality of life scores were high. Only 30% of studies included data on preoperative psychological assessment. CONCLUSION: Surgery improves constipation and is associated with a higher degree of patient satisfaction, but the quality of studies was very variable. Future controlled trials should examine the ideal therapeutic approach for different patient groups. PMID- 20969712 TI - Early complications after stapled transanal rectal resection performed using the Contour(r) TranstarTM device. AB - AIM: This study evaluated the early results (with particular reference to complications) of stapled transanal rectal resection (STARR) carried out using the CCS-30 Contour(r) TranstarTM device. The procedure was performed in a single centre on patients with obstucted defecation caused by rectocele or rectal intussusception. METHOD: From July 2007 to February 2009, 133 patients were treated. Preoperatively, all underwent clinical examination, transanal ultrasonography, anorectal manometry and cinedefaecography. Obstructed defaecation syndrome was assessed using the Cleveland Clinic Constipation Score (CCC-S). Early postoperative complications and those occurring within 6 months were recorded. RESULTS: The median follow-up period was 19 (range 12-30) months. The mean +/- standard deviation preoperative CCC-S of 19.4 +/- 7.1 decreased to 10.1 +/- 9.0 postoperatively. The early complication rate was 15.7% and included rectovaginal fistula (n = 1), rectal perforation (n = 1), posterior dehiscence (n = 4), further surgery for retained staples (n = 2), postoperative bleeding (n = 2) and postoperative impaired continence (n = 11). CONCLUSIONS: STARR using the Contour Transtar device seems to be effective for treating obstructed defaecation. However, serious complications may occur. PMID- 20969713 TI - Surgery for colonic cancer in HNPCC: total vs segmental colectomy. AB - AIM: The high reported risk of metachronous colon cancer (MCC) in hereditary nonpolyposis colorectal cancer (HNPCC) has led some authors to recommend total colectomy (TC) as the preferred operation for primary colon cancer, but this remains controversial. No previous study has compared survival after TC with segmental colectomy (SC) in HNPCC. The aim of this study was to determine the risk of developing MCC in patients with genetically proven HNPCC after SC or TC for cancer, and to compare their long-term survival. METHOD: This is a prospective cohort study of all patients referred to our unit between 1995 and 2009 with a proven germline mismatch repair gene defect, who had undergone a resection for adenocarcinoma of the colon with curative intent. All patients were offered annual endoscopic surveillance. RESULTS: Of 60 patients in the study, 39 had TC as their initial surgery and 21 had SC. After 6 years follow up, MCC occurred in eight (21%) SC patients and in none of the TC patients (P = 0.048). The risk of developing MCC after SC was 20% at 5 years. Colorectal cancer specific survival was better in TC patients (P = 0.048) but overall survival of the two groups was similar (P = 0.29). CONCLUSION: Patients with HNPCC have a significant risk of MCC after SC. This is eliminated by performing TC as the primary operation for colonic cancer. PMID- 20969714 TI - Surgeon and hospital-related risk factors in colorectal cancer surgery. AB - AIM: The aim of this study was to identify surgeon and hospital-related factors in a well-defined population-based cohort; the results of this study could possibly be used to improve outcome in colorectal cancer. METHOD: Data from the colonic (1997-2006) and rectal (1995-2006) cancer registers of the Uppsala/Orebro Regional Oncology Centre were used to assess 1697 patients with rectal and 2692 with colonic cancer. Putative risk factors and their impact on long-term survival were evaluated using the Cox proportional hazard model. RESULTS: The degree of specialization of the operating surgeon had no significant effect on long-term survival. When comparing the surgeons with the highest degree of specialization, noncolorectal surgeons demonstrated a slightly lower long-term survival for rectal cancer stage I and II (HR, 2.03; 95% CI, 1.05-3.92). Surgeons with a high case-load were not associated with better survival in any analysis model. Regional hospitals had a lower survival rate for rectal cancer stage III surgery (HR, 1.47; 95% CI, 1.08-2.00). CONCLUSION: Degree of specialization, surgeon case load and hospital category could not be identified as important factors when determining outcome in colorectal cancer surgery in this study. PMID- 20969715 TI - Surgical resection in Crohn's disease: is immunosuppressive medication associated with higher postoperative infection rates? AB - AIM: The aim of this study was to analyse postoperative infection in patients undergoing surgery for Crohn's disease (CD) according to the use of preoperative immunosuppressants, including infliximab. METHOD: With IRB approval, the records of all patients with CD who underwent abdominal surgery between 2001 and 2008 were reviewed for comorbidity, preoperative medication, type of surgery, stoma construction and postoperative complications. Patients were divided into three categories according to the preoperative medication within 90 days of surgery as follows: infliximab (IFX), other drugs including steroids and/or immunosuppressive agents (OD) and no drugs (ND). RESULTS: Two hundred and twenty five patients were identified. Preoperative comorbidity, surgical indication and type of surgery were not significantly different among the three groups. Ileocolic resection was the most common procedure [50.8%, IFX group; 61.2%, OD group; 41.3%, ND group (P = 0.09)]. Other procedures included total colectomy (16%), protectomy (15%) and others (18%). Laparoscopic surgery was performed in 47.7%, 45.9% and 29.3% of patients in the IFX, OD and ND groups, respectively (P = 0.04). There were no differences in postoperative rates of infection [pneumonia (P = 0.14), wound infection (P = 0.35), abscess (P = 0.34) or anastomotic leakage (P = 0.44)]. Reoperation was needed in 3.0%, 8.2% and 2.6% of patients in the IFX, OD and ND groups, respectively. Multiple logistic regression found no relationship between infliximab use and infection. CONCLUSION: There was no difference in the rate of postoperative complications among the groups of patients undergoing surgery for CD pretreated with IFX or other immunosuppressive drugs. PMID- 20969716 TI - Criteria for three-dimensional anorectal ultrasound assessment of response to chemoradiotherapy in rectal cancer patients. AB - AIM: The aim of this study was to identify criteria for three-dimensional anorectal ultrasonography (3D-AUS) to assess the response of rectal cancer to chemoradiotherapy; the 3D-AUS results were compared with the histopathological findings of the resected specimen. METHOD: Thirty-five patients underwent 3D-AUS and were grouped according to the presence (GI; n = 19) or absence (GII; n = 16) of anal canal invasion. All patients received chemoradiotherapy, then underwent a second 3D-AUS. The response (complete, partial or insignificant and lymph node metastasis) was evaluated. Tumour length (cm) and volume (cm(3) ), length and volume regression percentage (%), distal length regression, and distance between the distal tumour edge and the proximal border of the internal anal sphincter were measured before and after chemoradiotherapy. All patients underwent surgery, and the 3D-AUS image was compared with the histopathological findings. RESULTS: Before chemoradiotherapy, the average tumour length was similar in G1 and GII, but the volume differed significantly (P = 0.0408). The response was insignificant in seven (37%) patients, partial in 10 (53%) patients and complete in two (10%) patients in GI. The corresponding figures for GII were one (6%) patient, 12 (75%) patients and three (19%) patients (P = 0.0318). The agreement between pathological and post-chemoratherapy 3D-AUS findings was almost identical for the identification of residual tumour or complete response (kappa = 1.0) and substantial for lymph node metastases (kappa = 0.74). The mean distance to the internal anal sphincter was greater in GII. A sphincter-saving resection was performed in 2/19 patients in GI and in 14/16 patients in GII (P < 0.0001). The histopathological examination revealed a free distal margin. CONCLUSION: 3D-AUS was shown to evaluate accurately the response to chemoradiotherapy, helping in the selection of patients for a sphincter-saving resection. The distance between the tumour and the internal anal sphincter was the most important parameter in this respect. PMID- 20969717 TI - Lymph node retrieval from colorectal resection specimens for adenocarcinoma: is it worth the extra effort to find at least 12 nodes? AB - AIM: Retrieval of a minimum of 12 lymph nodes has been recommended for adequately staging a node-negative colorectal cancer (CRC). This study was designed to determine whether the extra effort expended to recover more nodes for histological examination improves the accuracy of staging. METHOD: Pathology reports, histology worklists, and haematoxylin and eosin (H&E) slides of 334 CRC resections were reviewed. The total number of nodes and the number of positive nodes harvested from the first and additional searches were recorded for each patient. RESULTS: The number of nodes retrieved from the 334 resections at the first search ranged from 0 to 57 (mean: 14.2), with 195 patients (58.4%) having >= 12 nodes. Nodal metastasis was found in 122 (33.6%) patients. Additional searches were performed on 115 patients, including 91 with < 12 nodes. The mean number of nodes recovered in these patients increased significantly, from 9.1 to 14.2 (P < 0.0001). Thirty-one additional positive nodes were found in 19 patients following the further searches, and 12 (63.2%) of the 19 patients were upstaged using the American Joint Committee on Cancer (AJCC) 6th edition (2002) staging criteria. The total number of nodes retrieved and the probability of obtaining >= 12 nodes correlated negatively with the age of the patient and the rectosigmoid location of the tumours, but positively with the specimen length, the pericolic/perirectal fat width, female gender and tumour size. CONCLUSION: Although a number of patient and specimen variables influence the number of lymph nodes retrieved, our observations support the importance of a thorough search for nodes in CRC specimens in order to achieve accurate tumour staging. PMID- 20969718 TI - Primary closure or rhomboid excision and Limberg flap for the management of primary sacrococcygeal pilonidal disease? A meta-analysis of randomized controlled trials. AB - AIM: Sacrococcygeal pilonidal disease is a common condition afflicting the young male working and student population, resulting in considerable pain, embarrassment and loss of work days. Controversy surrounds the most appropriate surgical approach to achieve low recurrence rates whilst minimizing morbidity and permitting an early return to work. This study aims to review the published literature comparing excision followed by either primary suture or rhomboid flap repair. METHODS: PubMed, EMBASE, MEDLINE and The Cochrane Library were systematically reviewed, by two independent investigators, for relevant randomized controlled trials. Keywords and MeSH terms included 'pilonidal disease', 'primary suture/repair', 'rhomboid flap' and 'limberg/modified Limberg flap'. 'Related study' function and manuscript bibliographies were searched for further relevant studies. Study quality was assessed using the Jadad score. Meta analysis was performed on pooled data, utilizing a random effects model when heterogeneity was high and a fixed effects model when heterogeneity was low. The primary end-point assessed was disease recurrence. Secondary end-points included wound dehiscence, pain scores, hospital stay and return to work. RESULTS: Six studies were eventually included for pooled analysis following exclusion of randomized controlled trials with poor methodology. Two studies compared 'off midline' (Karydakis) primary suture with the Limberg flap repair. Six hundred and forty-one patients were included (331 flap repairs). Rhomboid flap excision demonstrated a trend towards less disease recurrence (P = 0.07), lower wound infection (P = 0.001) and dehiscence (P = 0.01). However, no significant difference was found for pain scores, hospital stay or return to work. CONCLUSION: The current published literature supports the use of the rhomboid flap excision and the Limberg flap-repair procedures over primary midline suture techniques for the elective management of primary pilonidal disease. Further high quality studies are necessary to compare flap with off-midline repairs. PMID- 20969719 TI - Can the quality of colonic surgery be improved by standardization of surgical technique with complete mesocolic excision? AB - AIM: we analysed the influence of standardization of colon cancer surgery with complete mesocolic excision (CME) on the quality of surgery measured by the pathological end-points of number of harvested lymph nodes, high tie of supplying vessels, plane of mesocolic resection and rate of R0 resection. METHOD: One hundred and ninety-eight patients with colonic carcinoma who underwent radical surgery between September 2007 and February 2009 were divided into two groups, including those undergoing surgery before (93) or after (105) 1 June 2008, when complete mesocolic excision (CME) was introduced as standard in our hospital. RESULTS: The overall mean high tie increased from 7.1 (CI, 6.5-7.6) to 9.6 (8.9 10.3) cm (P<0.0001) and the mean number of harvested lymph nodes from 24.5 (22.8 26.2) to 26.7 (24.6-28.8) (P=0.0095). There were no significant increases in these end-points in open right hemicolectomy, and in laparoscopic sigmoid resection the number of lymph nodes did not increase significantly. The plane of mesocolic resection, the rate of R0 resection and the risk of complications did not change significantly. The median (range) length of hospital stay increased from 4 (2-62) to 5 (2-71) days (P=0.04). CONCLUSION: Standardization of colonic cancer surgery with CME seems to improve the quality of surgery without increasing the risk of complications. PMID- 20969720 TI - An introduction to biological nuclear magnetic resonance spectroscopy. AB - Nuclear magnetic resonance (NMR) spectroscopy is one of the most powerful analytical techniques available to biology. This review is an introduction to the potential of this method and is aimed at readers who have little or no experience in acquiring or analyzing NMR spectra. We focus on spectroscopic applications of the magnetic resonance effect, rather than imaging ones, and explain how various aspects of the NMR phenomenon make it a versatile tool with which to address a number of biological problems. Using detailed examples, we discuss the use of (1) H NMR spectroscopy in mixture analysis and metabolomics, the use of (13) C NMR spectroscopy in tracking isotopomers and determining the flux through metabolic pathways ('fluxomics') and the use of (31) P NMR spectroscopy in monitoring ATP generation and intracellular pH homeotasis in vivo. Further examples demonstrate how NMR spectroscopy can be used to probe the physical environment of a cell by measuring diffusion and the tumbling rates of individual metabolites and how it can determine macromolecular structures by measuring the bonds and distances which separate individual atoms. We finish by outlining some of the key challenges which remain in NMR spectroscopy and we highlight how recent advances such as increased magnet field strengths, cryogenic cooling, microprobes and hyperpolarisation-are opening new avenues for today's biological NMR spectroscopists. PMID- 20969721 TI - Reduced bone mineral density is not associated with significantly reduced bone quality in men and women practicing long-term calorie restriction with adequate nutrition. AB - Calorie restriction (CR) reduces bone quantity but not bone quality in rodents. Nothing is known regarding the long-term effects of CR with adequate intake of vitamin and minerals on bone quantity and quality in middle-aged lean individuals. In this study, we evaluated body composition, bone mineral density (BMD), and serum markers of bone turnover and inflammation in 32 volunteers who had been eating a CR diet (approximately 35% less calories than controls) for an average of 6.8 +/- 5.2 years (mean age 52.7 +/- 10.3 years) and 32 age- and sex matched sedentary controls eating Western diets (WD). In a subgroup of 10 CR and 10 WD volunteers, we also measured trabecular bone (TB) microarchitecture of the distal radius using high-resolution magnetic resonance imaging. We found that the CR volunteers had significantly lower body mass index than the WD volunteers (18.9 +/- 1.2 vs. 26.5 +/- 2.2 kg m(-2) ; P = 0.0001). BMD of the lumbar spine (0.870 +/- 0.11 vs. 1.138 +/- 0.12 g cm(-2) , P = 0.0001) and hip (0.806 +/- 0.12 vs. 1.047 +/- 0.12 g cm(-2) , P = 0.0001) was also lower in the CR than in the WD group. Serum C-terminal telopeptide and bone-specific alkaline phosphatase concentration were similar between groups, while serum C-reactive protein (0.19 +/- 0.26 vs. 1.46 +/- 1.56 mg L(-1) , P = 0.0001) was lower in the CR group. Trabecular bone microarchitecture parameters such as the erosion index (0.916 +/- 0.087 vs. 0.877 +/- 0.088; P = 0.739) and surface-to-curve ratio (10.3 +/- 1.4 vs. 12.1 +/- 2.1, P = 0.440) were not significantly different between groups. These findings suggest that markedly reduced BMD is not associated with significantly reduced bone quality in middle-aged men and women practicing long term calorie restriction with adequate nutrition. PMID- 20969722 TI - Somatic cell nuclear reprogramming of mouse oocytes endures beyond reproductive decline. AB - The mammalian oocyte has the unique feature of supporting fertilization and normal development, while capable of reprogramming nuclei of somatic cells toward pluripotency, and occasionally even totipotency. While oocyte quality is known to decay with somatic aging, it is not a given that different biological functions decay concurrently. In this study, we tested whether oocyte's reprogramming ability decreases with aging. We show that oocytes isolated from mice aged beyond the usual reproductive age (climacteric) yield ooplasts that retain reprogramming capacity after somatic nuclear transfer (SCNT), giving rise to higher blastocysts rates compared to young donors ooplasts. Despite the differences in transcriptome between climacteric and young ooplasts, gene expression profiles of SCNT blastocysts were very similar. Importantly, embryonic stem cell lines with capacity to differentiate into tissues from all germ layers were derived from SCNT blastocysts obtained from climacteric ooplasts. Although apoptosis-related genes were down-regulated in climacteric ooplasts, and reprogramming by transcription factors (direct-induced pluripotency) benefits from the inhibition of p53-mediated apoptosis, reprogramming capacity of young ooplasts was not improved by blocking p53. However, more outgrowths were derived from SCNT blastocysts developed in the presence of a p53 inhibitor, indicating a beneficial effect on trophectoderm function. Results strongly suggest that oocyte-induced reprogramming outcome is determined by the availability and balance of intrinsic pro- and anti-reprogramming factors tightly regulated and even improved throughout aging, leading to the proposal that oocytes can still be a resource for somatic reprogramming when they cease to be considered safe for sexual reproduction. PMID- 20969723 TI - Proteolysis of calcineurin is increased in human hippocampus during mild cognitive impairment and is stimulated by oligomeric Abeta in primary cell culture. AB - Recent reports demonstrate that the activation and interaction of the protease calpain (CP) and the protein phosphatase calcineurin (CN) are elevated in the late stages of Alzheimer's disease (AD). However, the extent to which CPs and CN interact during earlier stages of disease progression remains unknown. Here, we investigated CP and CN protein levels in cytosolic, nuclear, and membrane fractions prepared from human postmortem hippocampal tissue from aged non demented subjects, and subjects diagnosed with mild cognitive impairment (MCI). The results revealed a parallel increase in CP I and the 48 kDa CN-Aalpha (DeltaCN-Aalpha48) proteolytic fragment in cytosolic fractions during MCI. In primary rat hippocampal cultures, CP-dependent proteolysis and activation of CN was stimulated by application of oligomeric Abeta((1-42)) peptides. Deleterious effects of Abeta on neuronal morphology were reduced by blockade of either CP or CN. NMDA-type glutamate receptors, which help regulate cognition and neuronal viability, and are modulated by CPs and CN, were also investigated in human hippocampus. Relative to controls, MCI subjects showed significantly greater proteolytic levels of the NR2B subunit. Within subjects, the extent of NR2B proteolysis was strongly correlated with the generation of DeltaCN-Aalpha48 in the cytosol. A similar proteolytic pattern for NR2B was also observed in primary rat hippocampal cultures treated with oligomeric Abeta and prevented by inhibition of CP or CN. Together, the results demonstrate that the activation and interaction of CPs and CN are increased early in cognitive decline associated with AD and may help drive other pathologic processes during disease progression. PMID- 20969725 TI - The effects of clonidine on arterial baroreflex sensitivity and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with left ventricular dysfunction. AB - BACKGROUND: Clonidine is a potent sympatholytic drug with central neural effects. The aim of this study was to evaluate the effects of clonidine on arterial baroreflex sensitivity (BRS) and cardiopulmonary (CP) baroreflex control of muscle sympathetic nerve activity (MSNA) in patients with left ventricular (LV) dysfunction. METHOD: Twenty patients were randomly assigned to either clonidine or placebo groups (10 in each group). BRS (by phenylephrine method) and CP baroreflex (by lower body negative pressure) effects on sympathetic nerve activity (circulating norepinephrine and MSNA recordings) were measured before and after a 4-week treatment period. RESULTS: Clonidine lowered blood pressure and heart rate. Clonidine was accompanied not only by a decrease in plasma noradrenaline (from 444+/-196 to 260+/-144 pg ml(-1) ) but also by a reduction in directly measured MSNA (from 47+/-16 to 36+/-16 bursts min(-1) ). BRS increased significantly from 3.01+/-1.19 to 6.86+/-2.84 ms mmHg(-1) after clonidine. When expressed as per cent change in MSNA during CP baroreceptor stimulation, CP baroreflex control of MSNA was significantly increased from 9.26+/-8.93% to 28.83+/-11.96% after clonidine. However, there were no significant changes in the measured variables in the control group. CONCLUSION: Clonidine enhanced BRS and CP baroreflex control of MSNA while reducing baseline sympathetic activity in patients with LV dysfunction. PMID- 20969726 TI - Prognostic value of FEV1/FEV6 in elderly people. AB - BACKGROUND: The ratio of forced expiratory volume in 1 s and forced expiratory volume in 6 s (FEV1/FEV6) has been proposed as an alternative for FEV1/forced vital capacity (FVC) to diagnose obstructive diseases with less effort during spirometry; however, its prognostic value is unknown. We evaluated whether FEV1/FEV6 is a significant predictor of mortality in elderly subjects and compared its prognostic value with that of FEV1/FVC and FEV1. METHODS: One thousand nine hundred and seventy-one subjects, aged >65 years, participated in the population-based SA.R.A. study. During the baseline exam, a multidimensional assessment included spirometry. Vital status was determined during 6 years of follow-up. Association of all-cause, cardio-pulmonary (CP) and non-CP mortality with a low FEV1/FEV6, FEV1/FVC and FEV1 was evaluated. RESULTS: Among subjects with both survival data and acceptable spirometry including FEV6, all-cause unadjusted mortality rates were 7.00 and 2.46 per 100 person-years in subjects with FEV1/FEV6 less than and greater than or equal to lower limit of normal (LLN), respectively (mortality rate ratio: 2.84, 95%CI: 2.12-3.84). After adjustment for age, gender, FVC, smoke exposure and main comorbidities, the risk of all-cause mortality remained significantly increased in subjects with FEV1/FEV6 12 years). The effects of aging on stem cell properties and indicators of stem cell fitness such as proliferation, differentiation, circadian rhythms, stress response proteins, miRNA expression, and global histone modifications in rBMSCs were analyzed. rBMSCs demonstrated decreased capacities for proliferation and differentiation as a function of age. The production of heat shock protein 70 (HSP70) and heat shock factor 1 (HSF1) were also reduced with increasing age. The level of a core circadian protein, Rev-erb alpha, was significantly increased in rBMSCs from old animals. Furthermore, analysis of miRNA expression profiles revealed an up-regulation of mir-766 and mir-558 and a down-regulation of mir-let 7f, mir-125b, mir-222, mir-199-3p, mir-23a, and mir-221 in old rBMSCs compare to young rBMSCs. However, there were no significant age-related changes in the global histone modification profiles of the four histone core proteins: H2A, H2B, H3, and H4 on rBMSCs. These changes represent novel insights into the aging process and could have implications regarding the potential for autologous stem cells therapy in older patients. PMID- 20969727 TI - Intracranial self-stimulation induces expression of learning and memory-related genes in rat amygdala. AB - Intracranial self-stimulation (ICSS) in the lateral hypothalamus improves memory when administered immediately after a training session. In our laboratory, ICSS has been shown as a very reliable way to increase two-way active avoidance (TWAA) conditioning, an amygdala-dependent task. The aim of this work was to study, in the rat amygdala, anatomical and molecular aspects of ICSS, using the same parameters facilitating TWAA. First, we examined the activation of ipsilateral and contralateral lateral (LA) and basolateral (BLA) amygdala, the main amygdalar regions involved in the TWAA, by the immunohistochemical determination of c-Fos protein expression. Second, we tested the effects of the ICSS treatment on the expression of 14 genes related to learning and memory processes using real-time polymerase chain reaction. Results showed a bilateral increase in c-Fos protein expression in LA and BLA nuclei after ICSS treatment. We also found that Fos, brain-derived nerve growth factor (BDNF), Arc, inducible cAMP early repressor (ICER), COX-2, Dnajb1, FKpb5 and Ret genes were upregulated in the amygdala 90 min and 4.5 h post ICSS. From this set of genes, BDNF, Arc and ICER are functionally associated with the cAMP-responsive element-mediated gene transcription molecular pathway that plays a pivotal role in memory, whereas Dnajb1 and Ret are associated with protein folding required for plasticity or neuroprotection. Our results suggest that ICSS induces expression of genes related with synaptic plasticity and protein folding functions in the rat amygdaloid area, which may be involved in the molecular mechanisms by which ICSS may improve or restore memory functions related to this brain structure. PMID- 20969728 TI - Treatment of tinea capitis - a critical appraisal. AB - Griseofulvin has been introduced in 1958, ever since it remained the gold standard for the treatment of tinea capitis in the United States. Despite the availability of new antifungals like terbinafine, itraconazole and fluconazole with few exceptions not licensed for their use in children - duration of tinea capitis treatment could not be shortened. The reasons therefore are the anatomic structure of the hair follicle, the dormant sebum-production before onset of puberty, and the way of action of the new antifungals. Although data concerning the pharmacokinetics of allylamines and triazoles in childhood-populations are lacking, some experience confirms a correlation of the way of action of modern antifungals and the causative pathogen. In children the treatment of Microsporum infections of the scalp is crucial. That may be explained by the unique pharmacokinetic features of the substance of terbinafine: Terbinafine neither can be excreted by sweat nor by sebum before onset of puberty. Terbinafine is incorporated in the keratin of mature terminal hair in the anagen phase. In children it will not be built in the hair shaft and therefore it will not reach the surface of the scalp where the sheets of arthro-conidia in microsporosis are located. This peculiar fact was not yet considered in clinical studies. PMID- 20969729 TI - Isolation and functional characterization of pericytes derived from hamster skeletal muscle. AB - AIM: At the interface of tissue and capillaries, pericytes (PC) may generate electrical signals to be conducted along the skeletal muscle vascular network, but they are functionally not well characterized. We aimed to isolate and cultivate muscle PC allowing to analyse functional properties considered important for signal generation and conduction. METHODS: Pericytes were enzymatically isolated from hamster thigh muscles and further selected during a 16-30 days' cultivation period. PC markers were studied by fluorescence activated cell scanning (FACS) and immunocytochemistry. Electrical properties of the cultured PC were investigated by patch clamp technique as well as the membrane potential sensitive dye DiBAC(4) (3). RESULTS: The cultured cells showed typical PC morphology and were positive for NG2, alpha smooth muscle actin, PDGFR-beta and the gap junction protein Cx43. Expressions of at least one single or combinations of several markers were found in 80-90% of subpopulations. A subset of the patched cells expressed channel activities consistent with a Kv1.5 channel. In vivo presence of the channels was confirmed in sections of hamster thigh muscles. Interleukin-8, a myokine known to be released from exercising muscle, increased the expression but not the activity of this channel. Pharmacologic stimulation of the channel activity by flufenamic acid induced hyperpolarization of PC alone but not of endothelial cells [human umbilical vein endothelial cells (HUVEC)] alone. However, hyperpolarization was observed in HUVEC adjacent to PC when kept in co-culture. CONCLUSION: We established a culture method for PC from skeletal muscle. A first functional characterization revealed properties which potentially enable these cells to generate hyperpolarizing signals and to communicate them to endothelial cells. PMID- 20969730 TI - Expression of acid-sensing ion channels in intestinal epithelial cells and their role in the regulation of duodenal mucosal bicarbonate secretion. AB - AIMS: As little is currently known about acid-sensing ion channels (ASICs) in intestinal epithelial cells, the aims of the present study were to investigate the expression and function of ASICs in intestinal epithelial cells, particularly their physiological role in the acid-stimulated duodenal mucosal bicarbonate secretion (DMBS). METHODS: RT-PCR and digital Ca2(+) imaging were used to determine the expression and function of ASICs in HT29 cells and SCBN cells, intestinal epithelial crypt cell lines. The acid-stimulated DMBS was measured in C57 black mice in vivo to study the role of ASICs in this physiological process. RESULTS: ASIC1a mRNA expression was detected in the duodenal mucosa stripped from mice and epithelial cell lines, in which cytoplasmic free Ca2(+) ([Ca2(+) ](cyt)) in response to extracellular acidosis was also increased. In Ca2(+) -containing solutions, acidosis (pH 6.0-5.0) raised [Ca2(+) ](cyt) in both HT29 cells and SCBN cells in a similar pH-dependent manner. Acidosis-induced increase in [Ca2(+) ](cyt) was markedly inhibited by amiloride (an ASICs blocker), SK&F96365 (a blocker for non-selective cation channels), or in Ca2(+) -free solutions; but was abolished by amiloride in Ca2(+) -free solutions. However, acidosis-induced increase in [Ca2(+) ](cyt) was slightly affected by U73122 (a PLC inhibitor), or nifedipine (a voltage-gated Ca2(+) channel blocker). After acidosis raised [Ca2(+) ](cyt) , stimulation of purinergic receptors with ATP further increased [Ca2(+) ](cyt) , but acidosis-induced increase in [Ca2(+) ](cyt) was not altered by suramin. Moreover, acid-stimulated murine DMBS was significantly attenuated by amiloride. CONCLUSION: Therefore, ASICs are functionally expressed in intestinal epithelial cells, and may play a role in acid-stimulated DMBS through a Ca2(+) signalling pathway. PMID- 20969731 TI - Impaired aldosterone responsiveness in corticosteroid binding globulin deficient mice. AB - AIM: Corticosteroid binding globulin (CBG) is the high affinity plasma carrier protein for cortisol. It keeps the steroids inactive, prevents them from degradation and defines the amount of free hormone acting on target tissues. Previous findings have shown insufficient responsiveness of corticosterone in peripheral tissues in CBG-(/)- mice despite elevated free plasma corticosterone. In the large intestine, glucocorticoids synergistically enhance the pro absorptive effects of aldosterone. We therefore hypothesized that CBG-(/)- mice have reduced responsiveness to aldosterone. METHODS: We used CBG-(/)- and CBG(+/+) mice to investigate distal colonic electrogenic Na(+) absorption. An Ussing chamber was used to quantify amiloride-sensitive Na(+) transport in distal colonic mucosa (DeltaI(sc) (amil)) as a measure of the physiological effect of aldosterone. RESULTS: No differences were observed in DeltaI(sc) (amil) or aldosterone levels in animals on control diet. When Na(+) restricted, CBG(+/+) mice responded with a marked up-regulation of DeltaI(sc) (amil) (25-fold). In CBG (/)- mice this up-regulation was greatly attenuated as seen in a markedly reduced amiloride-sensitive short circuit current (reduced by ~50%), a reduced ability to lower faecal Na(+) excretion and a significantly attenuated up-regulation of the ENaC channel gamma-subunit. Diet-induced increases of total plasma aldosterone were similar in both genotypes, but CBG-(/)- mice had an increased free plasma aldosterone fraction. SUMMARY: This study defines the functional hyporesponsiveness and aldosterone resistance in distal colon of CBG-(/)- mice. This resistance occurs despite sufficient free corticosterone plasma level. Thus, steroid actions require an intrinsic but unknown function of CBG, which allows the sufficient supply of the hormone/s to the target tissue. PMID- 20969734 TI - Job satisfaction, stress and burnout associated with haemodialysis nursing: a review of literature. AB - Job dissatisfaction, stress and burnout are linked to high rates of nurses leaving the profession, poor morale and poor patient outcomes. Haemodialysis (HD) nursing is uniquely characterised by the intense-prolonged interaction with patients who require complex technological care. A review of nine papers found that factors affecting job satisfaction were aspects of nursing care, organisational factors and length of time that a nurse has been working in nephrology nursing. Factors affecting job stress and burnout were due to interpersonal relationships with physicians, patient care activities, violence and abuse from patients, organisational factors and a lack of access to ongoing education. PMID- 20969732 TI - Functional activity of Pat-1 (Slc26a6) Cl(-)/HCO3(-) exchange in the lower villus epithelium of murine duodenum. AB - AIMS: The apical membrane anion exchanger putative anion transporter-1 (Pat-1) is expressed at significant levels in the lower villus epithelium of murine duodenum. However, previous studies of Cl(-)/HCO3(-) exchange in the lower villus have failed to demonstrate Pat-1 function. Those studies routinely included luminal glucose which induces Na(+) -coupled glucose transport and acidifies the villus epithelium. Since Pat-1 has been proposed to be an electrogenic 1Cl( )/2HCO3(-) exchanger, membrane depolarization or cell acidification during glucose transport may obscure Pat-1 activity. Therefore, we investigated the effects of luminal glucose on Cl(-)(IN)/HCO3(-) (OUT) exchange activity in the lower villus epithelium. METHODS: Cl(-)(IN) /HCO (-) (OUT) exchange of villus epithelium in duodenal mucosa from Pat-1 knockout (KO), Slc26a3 [down-regulated in adenoma (Dra)] KO, cystic fibrosis transmembrane conductance regulator (Cftr) KO and wild-type (WT) littermate mice was measured using the pH-sensitive dye 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein. Short-circuit current (I(sc) ) was measured in Ussing chambers. RESULTS: During glucose absorption, Cl( )(IN)/HCO3(-) (OUT) exchange in the lower villus epithelium was abolished in the Dra KO and unaffected in the Pat-1 KO relative to WT. However, during electroneutral mannose absorption or electrogenic alpha-D-methyl glucoside absorption, Cl(-)(IN) /HCO3(-) (OUT) exchange was reduced in both Pat-1 KO and Dra KO villi. Exposure to high [K(+)] abolished Cl(-)(IN) /HCO3(-) (OUT) exchange in the Dra KO but not the Dra/Cftr double KO epithelium, suggesting that Pat-1 activity is little affected by membrane depolarization except in the presence of Cftr. CONCLUSIONS: The metabolic and electrogenic activity of glucose transport obscures Cl(-)(IN) /HCO3(-) (OUT) exchange activity of Pat-1 in the lower villus. The inhibitory effects of membrane depolarization on Pat-1 Cl(-)(IN) /HCO3(-) (OUT) exchange may require concurrent membrane association with Cftr. PMID- 20969735 TI - The use of pregabalin in the treatment of uraemic pruritus in haemodialysis patients. AB - We evaluated the effect of pregabalin in the treatment of uraemic pruritus not due to secondary hyperparathyroidism. Sixteen haemodialysis patients suffering from uraemic pruritus resistant to conventional treatment started on pregabalin 25 mg/day orally. The parameters recorded were age, time on haemodialysis, haematocrit, Ca, PO4 , Ca * PO4 product, PTH, spKt/V, eosinophil counts and IgE. The effectiveness of pregabalin on uraemic pruritus was evaluated by using visual analogue scale before and after one month of treatment. Visual analogue scale consisted of a 10-cm horizontal line scored from 0 (no itch) to 10 (worst imaginable itch). Four patients discontinued treatment due to side effects and therefore were excluded from the study. The mean age of the remaining 12 patients was 61.2 +/- 12.8 years, and the time on haemodialysis was 38 +/- 39.1 months. The haematological and biochemical profile of the patients remained without significant change at the end of the observation period. There was a statistically significant difference between visual analogue scale values before and after the one month treatment period (7.44 +/- 2.01 and 1.7 +/- 1.31, respectively), p < 0.0003. Uraemic pruritus is a common and distressing symptom in patients undergoing haemodialysis. Pregabalin appears to be an effective alternative treatment. PMID- 20969736 TI - Fungal peritonitis among the peritoneal dialysis patients of four Turkish centres. AB - This study evaluates the clinical findings and treatment of continuous ambulatory peritoneal dialysis (CAPD) patients with fungal peritonitis in Istanbul from 2000 to 2010. The clinical records of 15 patients with fungal peritonitis among the total 795 patients were reviewed for the clinical and laboratory data. The mean duration of dialysis from the initiation of treatment until the development of fungal peritonitis was 41.14 months. Fungal peritonitis was the primary episode of infection in eight patients. In five other patients previous intensive antibiotherapy was documented. The isolated mircoboes were Candida albicans in six, non-C. albicans in eight and Aspergillus fumigatus in one patient. Tenckoff catheters were removed in all cases and antifungal treatment was given for a minimum of three weeks. Two patients died in the hospital due to the fungal infection whereas others were transferred to haemodialysis. This study highlights the importance of removing the catheter and initiating antifungal therapy as soon as possible in cases of fungal peritonitis because it is responsible for high morbidity and mortality. PMID- 20969737 TI - CE: continuing education article. Prevention of infection in patients with chronic kidney disease part 1: application of infection control principles to the renal care environment. AB - This first paper, in a three-part CE series on the prevention of infection in patients with chronic kidney disease, focuses on infection susceptibility in this patient population and the application of infection control principles to the renal care environment. The second and third papers in this series will focus on specific aspects of infection control including the prevention and management of blood-borne virus and other healthcare-associated infections. PMID- 20969738 TI - Rapid development of renal failure secondary to AA-type amyloidosis in a patient with polymyalgia rheumatica. AB - Polymyalgia rheumatica (PMR) is a common chronic inflammatory disorder affecting patients over the age of 50. Renal involvement in PMR is extremely rare and very few cases of AA amyloidosis secondary to PMR have been described in literature. We present a case of a patient with history PMR who developed nephrotic range proteinuria and rapidly deteriorating renal function secondary to AA amyloidosis within 18 months of the onset of symptoms of PMR. This case reinforces the association of PMR with secondary AA amyloidosis and highlights the importance of monitoring renal function in patients with PMR. PMID- 20969739 TI - Upper extremity complications in patients with chronic renal failure receiving haemodialysis. AB - Limited data are available about disability associated with upper extremity complications in patients who receive haemodialysis for end-stage renal disease. In this study of 123 patients receiving haemodialysis, the mean Disabilities of the Arm, Shoulder and Hand (DASH) score was 31 +/- 22 points, indicating markedly greater disability than in a normal population. Dupuytren's contracture was the most frequent deformity. Brachial, radial and ulnar pulses were present in most upper limbs, but 14 (14%) of 102 patients had poor arterial perfusion pressures. Diabetic patients had residual or complete loss of protective sensation more frequently than nondiabetic patients. Motor testing with the index finger abduction and fifth finger flexion tests showed a significantly greater frequency of weakness in diabetic than nondiabetic patients. In summary, upper extremity disability was noted in haemodialysis patients, including loss of protective sensation and motor strength, both in diabetic and nondiabetic subjects. PMID- 20969740 TI - Comparison of sexual function in females receiving haemodialysis and after renal transplantation. AB - The aim of this study is to compare the sexual function of kidney transplant recipients and end-stage renal disease (ESRD) patients receiving haemodialysis (HD) in female patients. In the sample population of this study, there were 72 women in the transplant group and 40 women in the HD group. To test the differences in the quantitative variables between these two groups, an independent sample Student's t-test was performed. Sexual relationship, sexual function, sexual frequency and sexual fear in the renal transplant patients are significantly better than HD patients. Sexual intercourse satisfaction was apparently higher in the kidney recipients than in the HD patients. Twenty-one patients in transplanted group described number was 6 (15%) (p = 0.03). This study indicated that female kidney transplant recipients experienced a significantly better sexual relationship compared with the ESRD patients receiving HD. PMID- 20969741 TI - CE: continuing education article. Integration of palliative care for patients with stage 5 chronic kidney disease. AB - Patients with advanced chronic kidney disease (Stage 5 CKD) have palliative care needs similar to patients with cancer. The decision not to commence dialysis or to withdraw from active treatment can have a profound impact upon all those closely involved in the patient's care. It is essential that every effort is made to minimise the physical and psycho-social symptoms experienced by patients who require palliative care. Effective teamwork across professional boundaries and specialities will ensure that patients and their families are provided with maximum comfort during their final days. All members of the healthcare team must strive to ensure patient and family are actively encouraged in the decision making process surrounding palliative care needs. PMID- 20969742 TI - Transmembrane domain length is responsible for the ability of a plant reticulon to shape endoplasmic reticulum tubules in vivo. AB - Reticulons are integral endoplasmic reticulum (ER) membrane proteins that have the ability to shape the ER into tubules. It has been hypothesized that their unusually long conserved hydrophobic regions cause reticulons to assume a wedge like topology that induces membrane curvature. Here we provide proof of this hypothesis. When over-expressed, an Arabidopsis thaliana reticulon (RTNLB13) localized to, and induced constrictions in, cortical ER tubules. Ectopic expression of RTNLB13 was sufficient to induce ER tubulation in an Arabidopsis mutant (pah1 pah2) whose ER membrane is mostly present in a sheet-like form. By sequential shortening of the four transmembrane domains (TMDs) of RTNLB13, we show that the length of the transmembrane regions is directly correlated with the ability of RTNLB13 to induce membrane tubulation and to form low-mobility complexes within the ER membrane. We also show that full-length TMDs are necessary for the ability of RTNLB13 to reside in the ER membrane. PMID- 20969744 TI - Prognostic impact of clinical course-specific mRNA expression profiles in the serum of perioperative patients with esophageal cancer in the ICU: a case control study. AB - BACKGROUND: We previously reported that measuring circulating serum mRNAs using quantitative one-step real-time RT-PCR was clinically useful for detecting malignancies and determining prognosis. The aim of our study was to find crucial serum mRNA biomarkers in esophageal cancer that would provide prognostic information for post-esophagectomy patients in the critical care setting. METHODS: We measured serum mRNA levels of 11 inflammatory-related genes in 27 post-esophagectomy patients admitted to the intensive care unit (ICU). We tracked these levels chronologically, perioperatively and postoperatively, until the two week mark, investigating their clinical and prognostic significance as compared with clinical parameters. Furthermore, we investigated whether gene expression can accurately predict clinical outcome and prognosis. RESULTS: Circulating mRNAs in postoperative esophagectomy patients had gene-specific expression profiles that varied with the clinical phase of their treatment. Multivariate regression analysis showed that upregulation of IL-6, VWF and TGF-beta1 mRNA in the intraoperative phase (p = 0.016, 0.0021 and 0.009) and NAMPT and MUC1 mRNA on postoperative day 3 (p < 0.01) were independent factors of mortality in the first year of follow-up. Duration of ventilator dependence (DVD) and ICU stay were independent factors of poor prognosis (p < 0.05). Therapeutic use of Sivelestat (Elaspol(r), Ono Pharmaceutical Co., Ltd.) significantly correlated with MUC1 and NAMPT mRNA expression (p = 0.048 and 0.045). IL-6 mRNA correlated with hypercytokinemia and recovery from hypercytokinemia (sensitivity 80.9%) and was a significant biomarker in predicting the onset of severe inflammatory diseases. CONCLUSION: Chronological tracking of postoperative mRNA levels of inflammatory related genes in esophageal cancer patients may facilitate early institution of pharamacologic therapy, prediction of treatment response, and prognostication during ICU management in the perioperative period. PMID- 20969743 TI - The French national prospective cohort of patients co-infected with HIV and HCV (ANRS CO13 HEPAVIH): early findings, 2006-2010. AB - BACKGROUND: In France, it is estimated that 24% of HIV-infected patients are also infected with HCV. Longitudinal studies addressing clinical and public health questions related to HIV-HCV co-infection (HIV-HCV clinical progression and its determinants including genetic dimension, patients' experience with these two diseases and their treatments) are limited. The ANRS CO 13 HEPAVIH cohort was set up to explore these critical questions.To describe the cohort aims and organization, monitoring and data collection procedures, baseline characteristics, as well as follow-up findings to date. METHODS: Inclusion criteria in the cohort were: age > 18 years, HIV-1 infection, chronic hepatitis C virus (HCV) infection or sustained response to HCV treatment. A standardized medical questionnaire collecting socio-demographic, clinical, biological, therapeutic, histological, ultrasound and endoscopic data is administered at enrollment, then every six months for cirrhotic patients or yearly for non cirrhotic patients. Also, a self-administered questionnaire documenting socio behavioral data and adherence to HIV and/or HCV treatments is administered at enrollment and yearly thereafter. RESULTS: A total of 1,175 patients were included from January 2006 to December 2008. Their median age at enrollment was 45 years and 70.2% were male. The median CD4 cell count was 442 (IQR: 304-633) cells/MUl and HIV RNA plasma viral load was undetectable in 68.8%. Most participants (71.6%) were on HAART. Among the 1,048 HIV-HCV chronically co infected patients, HCV genotype 1 was predominant (56%) and cirrhosis was present in 25%. As of January, 2010, after a median follow-up of 16.7 months (IQR: 11.3 25.3), 13 new cases of decompensated cirrhosis, nine hepatocellular carcinomas and 20 HCV-related deaths were reported, resulting in a cumulative HCV-related severe event rate of 1.9/100 person-years (95% CI: 1.3-2.5). The rate of HCV related severe events was higher in cirrhotic patients and those with a low CD4 cells count, but did not differ according to sex, age, alcohol consumption, CDC clinical stage or HCV status. CONCLUSION: The ANRS CO 13 HEPAVIH is a nation-wide cohort using a large network of HIV treatment, infectious diseases and internal medicine clinics in France, and thus is highly representative of the French population living with these two viruses and in care. PMID- 20969746 TI - The PstI/RsaI and DraI polymorphisms of CYP2E1 and head and neck cancer risk: a meta-analysis based on 21 case-control studies. AB - BACKGROUND: CYP2E1 encodes a member of the cytochrome P450 superfamily of enzymes which play a central role in activating and detoxifying many carcinogens and endogenous compounds thought to be involved in the development of cancer. The PstI/RsaI and DraI polymorphism are two of the most commonly studied polymorphisms of the gene for their association with risk of head and neck cancer, but the results are conflicting. METHODS: We performed a meta-analysis using 21 eligible case-control studies with a total of 4,951 patients and 6,071 controls to summarize the data on the association between the CYP2E1 PstI/RsaI and DraI polymorphism and head and neck cancer risk, especially by interacting with smoking or alcohol. RESULTS: Compared with the wild genotype, the OR was 1.96 (95% CI: 1.33-2.90) for PstI/RsaI and 1.56 (95% CI: 1.06-2.27) for DraI polymorphism respectively. When stratified according to ethnicity, the OR increased in the Asians for both polymorphisms (OR = 2.04, 95% CI: 1.32-3.15 for PstI/RsaI; OR = 2.04, 95% CI: 1.27-3.29 for DraI), suggesting that the risk is more pronounced in Asians. CONCLUSION: Our meta-analysis suggests that individuals with the homozygote genotypes of PstI/RsaI or DraI polymorphism might be associated with an increased risk of head and neck cancer, especially in Asians. PMID- 20969747 TI - Young adolescents' independent mobility, related factors and association with transport to school. A cross-sectional study. AB - BACKGROUND: Children's independent mobility differs between groups of adolescents, but knowledge is lacking on how mobility-limiting factors interact. This study explores the association between factors that can affect young adolescents' mobility, searching for typical patterns within a geographical area where mobility is both relatively high and promoted (in this case Stockholm County, Sweden). An additional question is how clusters of limiting factors and demographic attributes relate to active commuting to school. METHODS: A sample of 7th grade students (ca 13-14 years old) in Stockholm County, Sweden, answered a survey (n = 1008). A cluster analysis was performed on variables descriptive of the respondents and of potential limitations to their independent mobility, such as fears, coping, traffic situation in the neighbourhood and parent/child opinions on mobility (18 variables and 50 categories). Active commuting to/from school was compared using proportion (with 95% confidence intervals) by cluster. RESULTS: Five consistent and distinct clusters were identified. Among the most discriminating factors were fears experienced in the neighbourhood, strategies to cope with fear, type of housing and traffic environment. Girls were over represented in the two clusters most typical of respondents experiencing fears (either several of these or darkness in particular) and boys in two others where housing (house vs. apartment) and neighbourhood conditions played a more determinant role. The proportion of active commuting among respondents was quite similar over clusters but was nonetheless higher in the cluster (over girls) reporting more fears and other factors limiting mobility. CONCLUSIONS: Whereas fears--and coping--are more typical of adolescent girls in the formation of the clusters, household and neighbourhood characteristics are more typical of boys. Broadly speaking, there seem to be two groups of girls with fears but these differ based on types of fear, ways of coping with fear and their living conditions. The association between the limitations to mobility and active commuting is unclear, the latter being higher among those disclosing a broader range of limiting factors, including fears. PMID- 20969745 TI - New directions in childhood obesity research: how a comprehensive biorepository will allow better prediction of outcomes. AB - BACKGROUND: Childhood obesity is associated with the early development of diseases such as type 2 diabetes and cardiovascular disease. Unfortunately, to date, traditional methods of research have failed to identify effective prevention and treatment strategies, and large numbers of children and adolescents continue to be at high risk of developing weight-related disease. AIM: To establish a unique 'biorepository' of data and biological samples from overweight and obese children, in order to investigate the complex 'gene * environment' interactions that govern disease risk. METHODS: The 'Childhood Overweight BioRepository of Australia' collects baseline environmental, clinical and anthropometric data, alongside storage of blood samples for genetic, metabolic and hormonal profiles. Opportunities for longitudinal data collection have also been incorporated into the study design. National and international harmonization of data and sample collection will achieve required statistical power. RESULTS: Ethical approval in the parent site has been obtained and early data indicate a high response rate among eligible participants (71%) with a high level of compliance for comprehensive data collection (range 56% to 97% for individual study components). Multi-site ethical approval is now underway. CONCLUSIONS: In time, it is anticipated that this comprehensive approach to data collection will allow early identification of individuals most susceptible to disease, as well as facilitating refinement of prevention and treatment programs. PMID- 20969748 TI - Identification of differentially expressed genes using an annealing control primer system in stage III serous ovarian carcinoma. AB - BACKGROUND: Most patients with ovarian cancer are diagnosed with advanced stage disease (i.e., stage III-IV), which is associated with a poor prognosis. Differentially expressed genes (DEGs) in stage III serous ovarian carcinoma compared to normal tissue were screened by a new differential display method, the annealing control primer (ACP) system. The potential targets for markers that could be used for diagnosis and prognosis, for stage III serous ovarian cancer, were found by cluster and survival analysis. METHODS: The ACP-based reverse transcriptase polymerase chain reaction (RT PCR) technique was used to identify DEGs in patients with stage III serous ovarian carcinoma. The DEGs identified by the ACP system were confirmed by quantitative real-time PCR. Cluster analysis was performed on the basis of the expression profile produced by quantitative real time PCR and survival analysis was carried out by the Kaplan-Meier method and Cox proportional hazards multivariate model; the results of gene expression were compared between chemo-resistant and chemo-sensitive groups. RESULTS: A total of 114 DEGs were identified by the ACP-based RT PCR technique among patients with stage III serous ovarian carcinoma. The DEGs associated with an apoptosis inhibitory process tended to be up-regulated clones while the DEGs associated with immune response tended to be down-regulated clones. Cluster analysis of the gene expression profile obtained by quantitative real-time PCR revealed two contrasting groups of DEGs. That is, a group of genes including: SSBP1, IFI6 DDT, IFI27, C11orf92, NFKBIA, TNXB, NEAT1 and TFG were up-regulated while another group of genes consisting of: LAMB2, XRCC6, MEF2C, RBM5, FOXP1, NUDCP2, LGALS3, TMEM185A, and C1S were down-regulated in most patients. Survival analysis revealed that the up-regulated genes such as DDAH2, RNase K and TCEAL2 might be associated with a poor prognosis. Furthermore, the prognosis of patients with chemo-resistance was predicted to be very poor when genes such as RNase K, FOXP1, LAMB2 and MRVI1 were up-regulated. CONCLUSION: The DEGs in patients with stage III serous ovarian cancer were successfully and reliably identified by the ACP based RT PCR technique. The DEGs identified in this study might help predict the prognosis of patients with stage III serous ovarian cancer as well as suggest targets for the development of new treatment regimens. PMID- 20969749 TI - Swordfish bill injury involving abdomen and vertebral column: case report and review. AB - BACKGROUND: Penetrating injuries of the abdomen and spinal canal that involve organic material of animal origin are extremely rare and derive from domestic and wild animal attacks or fish attacks. CASE PRESENTATION: In this case report we present the unique, as far as the literature is concerned, unprovoked woman's injury to the abdomen by a swordfish. There are only four cases of swordfish attacks on humans in the literature - one resulted to thoracic trauma, two to head trauma and one to knee trauma, one of which was fatal - none of which were unprovoked. Three victims were professional or amateur fishermen whereas in the last reported case the victim was a bather as in our case. Our case is the only case where organic debris of animal's origin remained in the spinal canal after penetrating trauma. CONCLUSIONS: Although much has been written about the management of penetrating abdominal and spinal cord trauma, controversy remains about the optimal management. Moreover, there is little experience in the management of patients with such spinal injuries, due to the fact that such cases are extremely rare. In this report we focus on the patient's treatment with regard to abdominal and spinal trauma and present a review of the literature. PMID- 20969750 TI - Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. AB - BACKGROUND: People with diabetes can suffer from diverse complications that seriously erode quality of life. Diabetes, costing the United States more than $174 billion per year in 2007, is expected to take an increasingly large financial toll in subsequent years. Accurate projections of diabetes burden are essential to policymakers planning for future health care needs and costs. METHODS: Using data on prediabetes and diabetes prevalence in the United States, forecasted incidence, and current US Census projections of mortality and migration, the authors constructed a series of dynamic models employing systems of difference equations to project the future burden of diabetes among US adults. A three-state model partitions the US population into no diabetes, undiagnosed diabetes, and diagnosed diabetes. A four-state model divides the state of "no diabetes" into high-risk (prediabetes) and low-risk (normal glucose) states. A five-state model incorporates an intervention designed to prevent or delay diabetes in adults at high risk. RESULTS: The authors project that annual diagnosed diabetes incidence (new cases) will increase from about 8 cases per 1,000 in 2008 to about 15 in 2050. Assuming low incidence and relatively high diabetes mortality, total diabetes prevalence (diagnosed and undiagnosed cases) is projected to increase from 14% in 2010 to 21% of the US adult population by 2050. However, if recent increases in diabetes incidence continue and diabetes mortality is relatively low, prevalence will increase to 33% by 2050. A middle ground scenario projects a prevalence of 25% to 28% by 2050. Intervention can reduce, but not eliminate, increases in diabetes prevalence. CONCLUSIONS: These projected increases are largely attributable to the aging of the US population, increasing numbers of members of higher-risk minority groups in the population, and people with diabetes living longer. Effective strategies will need to be undertaken to moderate the impact of these factors on national diabetes burden. Our analysis suggests that widespread implementation of reasonably effective preventive interventions focused on high-risk subgroups of the population can considerably reduce, but not eliminate, future increases in diabetes prevalence. PMID- 20969751 TI - Does probabilistic modelling of linkage disequilibrium evolution improve the accuracy of QTL location in animal pedigree? AB - BACKGROUND: Since 2001, the use of more and more dense maps has made researchers aware that combining linkage and linkage disequilibrium enhances the feasibility of fine-mapping genes of interest. So, various method types have been derived to include concepts of population genetics in the analyses. One major drawback of many of these methods is their computational cost, which is very significant when many markers are considered. Recent advances in technology, such as SNP genotyping, have made it possible to deal with huge amount of data. Thus the challenge that remains is to find accurate and efficient methods that are not too time consuming. The study reported here specifically focuses on the half-sib family animal design. Our objective was to determine whether modelling of linkage disequilibrium evolution improved the mapping accuracy of a quantitative trait locus of agricultural interest in these populations. We compared two methods of fine-mapping. The first one was an association analysis. In this method, we did not model linkage disequilibrium evolution. Therefore, the modelling of the evolution of linkage disequilibrium was a deterministic process; it was complete at time 0 and remained complete during the following generations. In the second method, the modelling of the evolution of population allele frequencies was derived from a Wright-Fisher model. We simulated a wide range of scenarios adapted to animal populations and compared these two methods for each scenario. RESULTS: Our results indicated that the improvement produced by probabilistic modelling of linkage disequilibrium evolution was not significant. Both methods led to similar results concerning the location accuracy of quantitative trait loci which appeared to be mainly improved by using four flanking markers instead of two. CONCLUSIONS: Therefore, in animal half-sib designs, modelling linkage disequilibrium evolution using a Wright-Fisher model does not significantly improve the accuracy of the QTL location when compared to a simpler method assuming complete and constant linkage between the QTL and the marker alleles. Finally, given the high marker density available nowadays, the simpler method should be preferred as it gives accurate results in a reasonable computing time. PMID- 20969753 TI - Postnatal development of depth-dependent collagen density in ovine articular cartilage. AB - BACKGROUND: Articular cartilage (AC) is the layer of tissue that covers the articulating ends of the bones in diarthrodial joints. Adult AC is characterised by a depth-dependent composition and structure of the extracellular matrix that results in depth-dependent mechanical properties, important for the functions of adult AC. Collagen is the most abundant solid component and it affects the mechanical behaviour of AC. The current objective is to quantify the postnatal development of depth-dependent collagen density in sheep (Ovis aries) AC between birth and maturity. We use Fourier transform infra-red micro-spectroscopy to investigate collagen density in 48 sheep divided over ten sample points between birth (stillborn) and maturity (72 weeks). In each animal, we investigate six anatomical sites (caudal, distal and rostral locations at the medial and lateral side of the joint) in the distal metacarpus of a fore leg and a hind leg. RESULTS: Collagen density increases from birth to maturity up to our last sample point (72 weeks). Collagen density increases at the articular surface from 0.23 g/ml +/- 0.06 g/ml (mean +/- s.d., n = 48) at 0 weeks to 0.51 g/ml +/- 0.10 g/ml (n = 46) at 72 weeks. Maximum collagen density in the deeper cartilage increases from 0.39 g/ml +/- 0.08 g/ml (n = 48) at 0 weeks to 0.91 g/ml +/- 0.13 g/ml (n = 46) at 72 weeks. Most collagen density profiles at 0 weeks (85%) show a valley, indicating a minimum, in collagen density near the articular surface. At 72 weeks, only 17% of the collagen density profiles show a valley in collagen density near the articular surface. The fraction of profiles with this valley stabilises at 36 weeks. CONCLUSIONS: Collagen density in articular cartilage increases in postnatal life with depth-dependent variation, and does not stabilize up to 72 weeks, the last sample point in our study. We find strong evidence for a valley in collagen densities near the articular surface that is present in the youngest animals, but that has disappeared in the oldest animals. We discuss that the retardance valley (as seen with polarised light microscopy) in perinatal animals reflects a decrease in collagen density, as well as a decrease in collagen fibril anisotropy. PMID- 20969752 TI - The neuronal guidance protein netrin-1 reduces alveolar inflammation in a porcine model of acute lung injury. AB - INTRODUCTION: Acute lung injury (ALI) is an inflammatory disorder of pulmonary or extrapulmonary origin. We have previously demonstrated that netrin-1 dampens murine ALI, and in an attempt to advance this finding into future clinical practice we evaluated whether netrin-1 would reduce alveolar inflammation during porcine ALI. METHODS: This was a controlled in vivo experimental study in pigs. We induced ALI through lipoploysaccharide (LPS) infusion (50 MUg/kg) for 2 hours. Following this, we exposed animals to either vehicle, intravenous netrin-1 (netrin-1 i.v.) or inhaled netrin-1 (netrin-1 inh.). Serum samples and bronchoalveolar lavage (BAL) were obtained to determine levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, interleukin-6 and interleukin-8 at baseline and 6 hours following treatment. Myeloperoxidase activity (MPO) and protein levels were determined in the BAL, and tissue samples were obtained for histological evaluation. Finally, animals were scanned with spiral CT. RESULTS: Following LPS infusion, animals developed acute pulmonary injury. Serum levels of TNF-alpha and IL-6 were significantly reduced in the netrin-1 i.v. group. BAL demonstrated significantly reduced cytokine levels 6 hours post-netrin-1 treatment (TNF-alpha: vehicle 633 +/- 172 pg/ml, netrin-1 i.v. 84 +/- 5 pg/ml, netrin-1 inh. 168 +/- 74 pg/ml; both P < 0.05). MPO activity and protein content were significantly reduced in BAL samples from netrin-1-treated animals. Histological sections confirmed reduced inflammatory changes in the netrin-1 treated animals. Computed tomography corroborated reduced pulmonary damage in both netrin-1-treated groups. CONCLUSIONS: We conclude that treatment with the endogenous anti-inflammatory protein netrin-1 reduces pulmonary inflammation during the initial stages of ALI and should be pursued as a future therapeutic option. PMID- 20969754 TI - Exploration of the postponing mechanism that delays carcinoma onset. AB - The average age at onset of malignancies arising from epithelial tissues is between 40 and 70 years old even in familial cancers. Although it is believed that the accumulation of multiple genetic alterations is needed for cancer onset, we hypothesize--based on the diversity of ages at onset for most types of epithelial cancer--that there is a postponing mechanism inside the human body that significantly delays the process of carcinogenesis. The key molecules controlling the cancer onset, here called "postponers", are hypothesized to be functioning in the individuals carrying susceptibility genes. As a consequence, cancers occur in middle age or even old age, with several decades of cancer-free lifetime for the patient. Genome-wide association studies and genomic expression profiling are suggested to identify candidate postponers. Hypothetic gene expression patterns for identifying candidate postponers are illustrated. Animal models will be helpful to test whether the absence or presence of the postponer molecules can alter the onset age of spontaneous tumors. If this hypothesis is true, by amplification of the postponing mechanism we might be able to significantly delay the onset of tumors, so that individuals carrying cancer susceptibility traits could gain an additional significant period of cancer-free life. Moreover, destructive prophylactic surgeries, e.g., for women who have BRCA1/2 gene mutations, might be avoided. PMID- 20969755 TI - Hospitalisation for rotavirus gastroenteritis in the paediatric population in the Veneto Region, Italy. AB - BACKGROUND: This study evaluates the epidemiological impact of RVGE hospitalisation in the Veneto Region during the period spanning from 2000-2007 along with the associated costs. The analysis was conducted in an area where rotavirus vaccination is not included into immunization programmes and is an attempt to assess the potential benefits of such introduction. METHODS: To update the estimates of acute RVGE hospitalisation rates in children <=5 years in the Veneto Region, we conducted an 8 year retrospective observational population based analysis (2000-2007). RESULTS: Over the study period, a total of 4,119 admissions for RVGE were reported, with a mean hospital stay of 3.5 days. The population-based hospitalisation RVGE incidence rate was 195.8 per 100,000 children aged <=5 years (lower than other European countries). CONCLUSIONS: RVGE is an important cause of paediatric hospitalisation in the Veneto Region. The data reaffirm the substantial burden of rotavirus hospitalisations in children and the potential health benefits of the vaccination as well as the possibility of adding rotavirus vaccination to the current schedule. PMID- 20969756 TI - Iron-sparing response of Mycobacterium avium subsp. paratuberculosis is strain dependent. AB - BACKGROUND: Two genotypically and microbiologically distinct strains of Mycobacterium avium subsp. paratuberculosis (MAP) exist - S and C MAP strains that primarily infect sheep and cattle, respectively. Concentration of iron in the cultivation medium has been suggested as one contributing factor for the observed microbiologic differences. We recently demonstrated that S strains have defective iron storage systems, leading us to propose that these strains might experience iron toxicity when excess iron is provided in the medium. To test this hypothesis, we carried out transcriptional and proteomic profiling of these MAP strains under iron-replete or -deplete conditions. RESULTS: We first complemented M.smegmatisDeltaideR with IdeR of C MAP or that derived from S MAP and compared their transcription profiles using M. smegmatis mc(2)155 microarrays. In the presence of iron, sIdeR repressed expression of bfrA and MAP2073c, a ferritin domain containing protein suggesting that transcriptional control of iron storage may be defective in S strain. We next performed transcriptional and proteomic profiling of the two strain types of MAP under iron-deplete and -replete conditions. Under iron-replete conditions, C strain upregulated iron storage (BfrA), virulence associated (Esx-5 and antigen85 complex), and ribosomal proteins. In striking contrast, S strain downregulated these proteins under iron replete conditions.. iTRAQ (isobaric tag for relative and absolute quantitation) based protein quantitation resulted in the identification of four unannotated proteins. Two of these were upregulated by a C MAP strain in response to iron supplementation. The iron-sparing response to iron limitation was unique to the C strain as evidenced by repression of non-essential iron utilization enzymes (aconitase and succinate dehydrogenase) and upregulation of proteins of essential function (iron transport, [Fe-S] cluster biogenesis and cell division). CONCLUSIONS: Taken together, our study revealed that C and S strains of MAP utilize divergent metabolic pathways to accommodate in vitro iron stress. The knowledge of the metabolic pathways these divergent responses play a role in are important to 1) advance our ability to culture the two different strains of MAP efficiently, 2) aid in diagnosis and control of Johne's disease, and 3) advance our understanding of MAP virulence. PMID- 20969757 TI - Copy number variation in the porcine genome inferred from a 60 k SNP BeadChip. AB - BACKGROUND: Recent studies in pigs have detected copy number variants (CNVs) using the Comparative Genomic Hybridization technique in arrays designed to cover specific porcine chromosomes. The goal of this study was to identify CNV regions (CNVRs) in swine species based on whole genome SNP genotyping chips. RESULTS: We used predictions from three different programs (cnvPartition, PennCNV and GADA) to analyze data from the Porcine SNP60 BeadChip. A total of 49 CNVRs were identified in 55 animals from an Iberian x Landrace cross (IBMAP) according to three criteria: detected in at least two animals, contained three or more consecutive SNPs and recalled by at least two programs. Mendelian inheritance of CNVRs was confirmed in animals belonging to several generations of the IBMAP cross. Subsequently, a segregation analysis of these CNVRs was performed in 372 additional animals from the IBMAP cross and its distribution was studied in 133 unrelated pig samples from different geographical origins. Five out of seven analyzed CNVRs were validated by real time quantitative PCR, some of which coincide with well known examples of CNVs conserved across mammalian species. CONCLUSIONS: Our results illustrate the usefulness of Porcine SNP60 BeadChip to detect CNVRs and show that structural variants can not be neglected when studying the genetic variability in this species. PMID- 20969758 TI - Age- and gender-specific risk of death after first hospitalization for heart failure. AB - BACKGROUND: Hospitalization for heart failure (HF) is associated with high-in hospital and short- and long-term post discharge mortality. Age and gender are important predictors of mortality in hospitalized HF patients. However, studies assessing short- and long-term risk of death stratified by age and gender are scarce. METHODS: A nationwide cohort was identified (ICD-9 codes 402, 428) and followed through linkage of national registries. The crude 28-day, 1-year and 5 year mortality was computed by age and gender. Cox regression models were used for each period to study sex differences adjusting for potential confounders (age and comorbidities). RESULTS: 14,529 men, mean age 74 +/- 11 years and 14,524 women, mean age 78 +/- 11 years were identified. Mortality risk after admission for HF increased with age and the risk of death was higher among men than women. Hazard ratio's (men versus women and adjusted for age and co-morbidity) were 1.21 (95%CI 1.14 to 1.28), 1.26 (95% CI 1.21 to 1.31), and 1.28 (95%CI 1.24 to 1.31) for 28 days, 1 year and 5 years mortality, respectively. CONCLUSIONS: This study clearly shows age- and gender differences in short- and long-term risk of death after first hospitalization for HF with men having higher short- and long-term risk of death than women. As our study population includes both men and women from all ages, the estimates we provide maybe a good reflection of 'daily practice' risk of death and therefore be valuable for clinicians and policymakers. PMID- 20969759 TI - A multi-level study of recombinant Pichia pastoris in different oxygen conditions. AB - BACKGROUND: Yeasts are attractive expression platforms for many recombinant proteins, and there is evidence for an important interrelation between the protein secretion machinery and environmental stresses. While adaptive responses to such stresses are extensively studied in Saccharomyces cerevisiae, little is known about their impact on the physiology of Pichia pastoris. We have recently reported a beneficial effect of hypoxia on recombinant Fab secretion in P. pastoris chemostat cultivations. As a consequence, a systems biology approach was used to comprehensively identify cellular adaptations to low oxygen availability and the additional burden of protein production. Gene expression profiling was combined with proteomic analyses and the 13C isotope labelling based experimental determination of metabolic fluxes in the central carbon metabolism. RESULTS: The physiological adaptation of P. pastoris to hypoxia showed distinct traits in relation to the model yeast S. cerevisiae. There was a positive correlation between the transcriptomic, proteomic and metabolic fluxes adaptation of P. pastoris core metabolism to hypoxia, yielding clear evidence of a strong transcriptional regulation component of key pathways such as glycolysis, pentose phosphate pathway and TCA cycle. In addition, the adaptation to reduced oxygen revealed important changes in lipid metabolism, stress responses, as well as protein folding and trafficking. CONCLUSIONS: This systems level study helped to understand the physiological adaptations of cellular mechanisms to low oxygen availability in a recombinant P. pastoris strain. Remarkably, the integration of data from three different levels allowed for the identification of differences in the regulation of the core metabolism between P. pastoris and S. cerevisiae. Detailed comparative analysis of the transcriptomic data also led to new insights into the gene expression profiles of several cellular processes that are not only susceptible to low oxygen concentrations, but might also contribute to enhanced protein secretion. PMID- 20969760 TI - Construction of an integrated genetic linkage map for the A genome of Brassica napus using SSR markers derived from sequenced BACs in B. rapa. AB - BACKGROUND: The Multinational Brassica rapa Genome Sequencing Project (BrGSP) has developed valuable genomic resources, including BAC libraries, BAC-end sequences, genetic and physical maps, and seed BAC sequences for Brassica rapa. An integrated linkage map between the amphidiploid B. napus and diploid B. rapa will facilitate the rapid transfer of these valuable resources from B. rapa to B. napus (Oilseed rape, Canola). RESULTS: In this study, we identified over 23,000 simple sequence repeats (SSRs) from 536 sequenced BACs. 890 SSR markers (designated as BrGMS) were developed and used for the construction of an integrated linkage map for the A genome in B. rapa and B. napus. Two hundred and nineteen BrGMS markers were integrated to an existing B. napus linkage map (BnaNZDH). Among these mapped BrGMS markers, 168 were only distributed on the A genome linkage groups (LGs), 18 distrubuted both on the A and C genome LGs, and 33 only distributed on the C genome LGs. Most of the A genome LGs in B. napus were collinear with the homoeologous LGs in B. rapa, although minor inversions or rearrangements occurred on A2 and A9. The mapping of these BAC-specific SSR markers enabled assignment of 161 sequenced B. rapa BACs, as well as the associated BAC contigs to the A genome LGs of B. napus. CONCLUSION: The genetic mapping of SSR markers derived from sequenced BACs in B. rapa enabled direct links to be established between the B. napus linkage map and a B. rapa physical map, and thus the assignment of B. rapa BACs and the associated BAC contigs to the B. napus linkage map. This integrated genetic linkage map will facilitate exploitation of the B. rapa annotated genomic resources for gene tagging and map based cloning in B. napus, and for comparative analysis of the A genome within Brassica species. PMID- 20969761 TI - An overview of ethical frameworks in public health: can they be supportive in the evaluation of programs to prevent overweight? AB - BACKGROUND: The prevention of overweight sometimes raises complex ethical questions. Ethical public health frameworks may be helpful in evaluating programs or policy for overweight prevention. We give an overview of the purpose, form and contents of such public health frameworks and investigate to which extent they are useful for evaluating programs to prevent overweight and/or obesity. METHODS: Our search for frameworks consisted of three steps. Firstly, we asked experts in the field of ethics and public health for the frameworks they were aware of. Secondly, we performed a search in Pubmed. Thirdly, we checked literature references in the articles on frameworks we found. In total, we thus found six ethical frameworks. We assessed the area on which the available ethical frameworks focus, the users they target at, the type of policy or intervention they propose to address, and their aim. Further, we looked at their structure and content, that is, tools for guiding the analytic process, the main ethical principles or values, possible criteria for dealing with ethical conflicts, and the concrete policy issues they are applied to. RESULTS: All frameworks aim to support public health professionals or policymakers. Most of them provide a set of values or principles that serve as a standard for evaluating policy. Most frameworks articulate both the positive ethical foundations for public health and ethical constraints or concerns. Some frameworks offer analytic tools for guiding the evaluative process. Procedural guidelines and concrete criteria for solving important ethical conflicts in the particular area of the prevention of overweight or obesity are mostly lacking. CONCLUSIONS: Public health ethical frameworks may be supportive in the evaluation of overweight prevention programs or policy, but seem to lack practical guidance to address ethical conflicts in this particular area. PMID- 20969762 TI - A case-control study: occupational cooking and the risk of uveal melanoma. AB - BACKGROUND: A European-wide population based case-control study (European rare cancer study) undertaken in nine European countries examined risk factors for uveal melanoma. They found a positive association between cooks and the risk of uveal melanoma. In our study we examine whether cooks or people who worked in cook related jobs have an increased uveal melanoma risk. METHODS: We conducted a case-control study during 2002 and 2005. Overall, 1653 eligible subjects (age range: 20-74 years, living in Germany) participated. Interviews were conducted with 459 incident uveal melanoma cases, 827 population controls, 180 ophthalmologist controls and 187 sibling controls. Data on occupational exposure were obtained from a self-administered postal questionnaire and a computer assisted telephone interview. We used conditional logistic regression to estimate odds ratios adjusting for the matching factors. RESULTS: Overall, we did not observe an increased risk of uveal melanoma among people who worked as cooks or who worked in cook related jobs. When we restricted the source population of our study to the population of the Federal State of Northrhine-Westphalia, we observed an increased risk among subjects who were categorized as cooks in the cases-control analysis. CONCLUSION: Our results are in conflict with former results of the European rare cancer study. Considering the rarity of the disease laboratory in vitro studies of human uveal melanoma cell lines should be done to analyze potential exposure risk factors like radiation from microwaves, strong light from incandescent ovens, or infrared radiation. PMID- 20969763 TI - Balancing high accrual and ethical recruitment in paediatric oncology: a qualitative study of the 'look and feel' of clinical trial discussions. AB - BACKGROUND: High accrual to clinical trials enables new treatment strategies to be tested rapidly, accurately and with generalisability. Ethical standards also must be high so that participation is voluntary and informed. However, this can be difficult to achieve in trials with complex designs and in those which are closely embedded in clinical practice. Optimal recruitment requires a balance of both ethical and accrual considerations. In the context of a trial of stratified treatments for children with acute lymphoblastic leukaemia (UKALL2003) we examined how recruitment looked to an observer and how it felt to the parents, to identify how doctors' communication could promote or inhibit optimal recruitment. METHODS: We audio-recorded, transcribed and analysed routine doctor-patient consultations (n = 20) and interviews between researchers and parents (n = 30 parents) across six UK treatment centres. Analysis was informed by the constant comparative method. For consultation transcripts, analysis focussed on how doctors presented the trial. We compared this with analysis of the interview transcripts which focussed on parents' perceptions and understanding of the trial. RESULTS: Parents and doctors discussed the trial in most consultations, even those that did not involve a decision about randomisation. Doctors used language allying them both with the trial and with the parent, indicating that they were both an 'investigator' and a 'clinician'. They presented the trial both as an empirical study with a scientific imperative and also as offering personalisation of treatment for the child. Parents appeared to understand that trial involvement was voluntary, that it was different from routine care and that they could withdraw from the trial at any time. Some were confused about the significance of the MRD test and the personalisation of treatment. CONCLUSIONS: Doctors communicated in ways that generally promoted optimal recruitment, indicating that trials can be embedded into clinical practice. However, parents were unclear about some details of the trial's rationale, suggesting that recruitment to trials with complicated designs, such as those involving stratified treatments, might need enhanced explanation. PMID- 20969764 TI - A computational-based update on microRNAs and their targets in barley (Hordeum vulgare L.). AB - BACKGROUND: Many plant species have been investigated in the last years for the identification and characterization of the corresponding miRNAs, nevertheless extensive studies are not yet available on barley (at the time of this writing). To extend and to update information on miRNAs and their targets in barley and to identify candidate polymorphisms at miRNA target sites, the features of previously known plant miRNAs have been used to systematically search for barley miRNA homologues and targets in the publicly available ESTs database. Matching sequences have then been related to Unigene clusters on which most of this study was based. RESULTS: One hundred-fifty-six microRNA mature sequences belonging to 50 miRNA families have been found to significantly match at least one EST sequence in barley. As expected on the basis of phylogenetic relations, miRNAs putatively orthologous to those of Triticum are significantly over-represented inside the set of identified barley microRNA mature sequences. Many previously known and several putatively new miRNA/target pairs have been identified. When the predicted microRNA targets were grouped into functional categories, biological processes previously known to be regulated by miRNAs, such as development and response to biotic and abiotic stress, have been highlighted and most of the target molecular functions were related to transcription regulation. Candidate microRNA coding genes have been reported and genetic variation (SNPs/indels) both in functional regions of putative miRNAs (mature sequence) and at miRNA target sites has been found. CONCLUSIONS: This study has provided an update of the information on barley miRNAs and their targets representing a foundation for future studies. Many of previously known plant microRNAs have homologues in barley with expected important roles during development, nutrient deprivation, biotic and abiotic stress response and other important physiological processes. Putative polymorphisms at miRNA target sites have been identified and they can represent an interesting source for the identification of functional genetic variability. PMID- 20969765 TI - Shenqi fuzheng, an injection concocted from Chinese medicinal herbs, combined with platinum-based chemotherapy for advanced non-small cell lung cancer: a systematic review. AB - BACKGROUND: Platinum-based chemotherapy has been a standard therapy for advanced non-small cell lung cancer (NSCLC), but it has high toxicity. In China, Shenqi Fuzheng, a newly developed injection concocted from Chinese medicinal herbs has been reported that may increase efficacy and reduce toxicity when combined with platinum-based chemotherapy, but little is known about it outside of China. The aim of this study was to systematically review the existing clinical evidence on Shenqi Fuzheng Injection(SFI) combined with platinum-based chemotherapy for advanced NSCLC. METHODS: Pubmed, Cochrane Library, EMBASE, CNKI, and CBM search were organized for all documents published, in English and Chinese, until April 2010. The randomized controlled clinical trials were selected based on specific criteria, in which a SFI plus platinum-based chemotherapy treatment group was compared with a platinum-based chemotherapy control group for patients with advanced NSCLC. The quality of studies was assessed by modified Jadad's scale, and Revman 4.2 software was used for data syntheses and analyses. RESULTS: Twenty nine studies were included in this review based on our selection criteria. Of them, ten studies were of high quality and the rest were of low quality, according to the modified Jadad scale. The meta-analysis showed there was a statistically significant higher tumor response (RR, 1.19; 95% CI, 1.07 to 1.32; P = 0.001) and performance status ((RR, 1.57; 95% CI, 1.45 to 1.70; P < 0.00001); but lower severe toxicity for WBC (RR, 0.37; 95% CI, 0.29 to 0.47; P < 0.00001), PLT (RR, 0.33; 95% CI, 0.21 to 0.52; P < 0.00001), HB (RR, 0.44; 95% CI, 0.30 to 0.66; P < 0.0001) and nausea and vomiting (RR, 0.32; 95% CI, 0.22 to 0.47; P < 0.00001), when the SFI plus platinum-based chemotherapy treatment group was compared with the platinum-based chemotherapy control group. Sensitivity analysis was restricted to studies with the high quality, and the result was similar when the studies with low quality were excluded. Asymmetry was observed in a funnel plot analysis, and Egger's test also indicated an evidence of publication bias (P = 0.016). CONCLUSIONS: SFI intervention appears to be useful to increase efficacy and reduce toxicity when combined with platinum-based chemotherapy for advanced NSCLC, although this result needs to be further verified by more high-quality trials. PMID- 20969766 TI - Modulation of extracellular matrix/adhesion molecule expression by BRG1 is associated with increased melanoma invasiveness. AB - BACKGROUND: Metastatic melanoma is an aggressive malignancy that is resistant to therapy and has a poor prognosis. The progression of primary melanoma to metastatic disease is a multi-step process that requires dynamic regulation of gene expression through currently uncharacterized epigenetic mechanisms. Epigenetic regulation of gene expression often involves changes in chromatin structure that are catalyzed by chromatin remodeling enzymes. Understanding the mechanisms involved in the regulation of gene expression during metastasis is important for developing an effective strategy to treat metastatic melanoma. SWI/SNF enzymes are multisubunit complexes that contain either BRG1 or BRM as the catalytic subunit. We previously demonstrated that heterogeneous SWI/SNF complexes containing either BRG1 or BRM are epigenetic modulators that regulate important aspects of the melanoma phenotype and are required for melanoma tumorigenicity in vitro. RESULTS: To characterize BRG1 expression during melanoma progression, we assayed expression of BRG1 in patient derived normal skin and in melanoma specimen. BRG1 mRNA levels were significantly higher in stage IV melanomas compared to stage III tumors and to normal skin. To determine the role of BRG1 in regulating the expression of genes involved in melanoma metastasis, we expressed BRG1 in a melanoma cell line that lacks BRG1 expression and examined changes in extracellular matrix and adhesion molecule expression. We found that BRG1 modulated the expression of a subset of extracellular matrix remodeling enzymes and adhesion proteins. Furthermore, BRG1 altered melanoma adhesion to different extracellular matrix components. Expression of BRG1 in melanoma cells that lack BRG1 increased invasive ability while down-regulation of BRG1 inhibited invasive ability in vitro. Activation of metalloproteinase (MMP) 2 expression greatly contributed to the BRG1 induced increase in melanoma invasiveness. We found that BRG1 is recruited to the MMP2 promoter and directly activates expression of this metastasis associated gene. CONCLUSIONS: We provide evidence that BRG1 expression increases during melanoma progression. Our study has identified BRG1 target genes that play an important role in melanoma metastasis and we show that BRG1 promotes melanoma invasive ability in vitro. These results suggest that increased BRG1 levels promote the epigenetic changes in gene expression required for melanoma metastasis to proceed. PMID- 20969767 TI - Epigenetic inactivation of the NORE1 gene correlates with malignant progression of colorectal tumors. AB - BACKGROUND: NORE1 (RASSF5) is a newly described member of the RASSF family with Ras effector function. NORE1 expression is frequently inactivated by aberrant promoter hypermethylation in many human cancers, suggesting that NORE1 might be a putative tumor suppressor. However, expression and mutation status of NORE1 and its implication in colorectal tumorigenesis has not been evaluated. METHODS: Expression, mutation, and methylation status of NORE1A and NORE1B in 10 cancer cell lines and 80 primary tumors were characterized by quantitative PCR, SSCP, and bisulfite DNA sequencing analyses. Effect of NORE1A and NORE1B expression on tumor cell growth was evaluated using cell number counting, flow cytometry, and colony formation assays. RESULTS: Expression of NORE1A and NORE1B transcript was easily detectable in all normal colonic epithelial tissues, but substantially decreased in 7 (70%) and 4 (40%) of 10 cancer cell lines and 31 (38.8%) and 25 (31.3%) of 80 primary carcinoma tissues, respectively. Moreover, 46 (57.6%) and 38 (47.5%) of 80 matched tissue sets exhibited tumor-specific reduction of NORE1A and NORE1B, respectively. Abnormal reduction of NORE1 was more commonly observed in advanced stage and high grade tumors compared to early and low grade tumors. While somatic mutations of the gene were not identified, its expression was re activated in all low expressor cells after treatment with the demethylating agent 5-aza-dC. Bisulfite DNA sequencing analysis of 31 CpG sites within the promoter region demonstrated that abnormal reduction of NORE1A is tightly associated with promoter CpG sites hypermethylation. Moreover, transient expression and siRNA mediated knockdown assays revealed that both NORE1A and NORE1B decrease cellular growth and colony forming ability of tumor cells and enhance tumor cell response to apoptotic stress. CONCLUSION: Our data indicate that epigenetic inactivation of NORE1 due to aberrant promoter hypermethylation is a frequent event in colorectal tumorigenesis and might be implicated in the malignant progression of colorectal tumors. PMID- 20969768 TI - DockAnalyse: an application for the analysis of protein-protein interactions. AB - BACKGROUND: Is it possible to identify what the best solution of a docking program is? The usual answer to this question is the highest score solution, but interactions between proteins are dynamic processes, and many times the interaction regions are wide enough to permit protein-protein interactions with different orientations and/or interaction energies. In some cases, as in a multimeric protein complex, several interaction regions are possible among the monomers. These dynamic processes involve interactions with surface displacements between the proteins to finally achieve the functional configuration of the protein complex. Consequently, there is not a static and single solution for the interaction between proteins, but there are several important configurations that also have to be analyzed. RESULTS: To extract those representative solutions from the docking output datafile, we have developed an unsupervised and automatic clustering application, named DockAnalyse. This application is based on the already existing DBscan clustering method, which searches for continuities among the clusters generated by the docking output data representation. The DBscan clustering method is very robust and, moreover, solves some of the inconsistency problems of the classical clustering methods like, for example, the treatment of outliers and the dependence of the previously defined number of clusters. CONCLUSIONS: DockAnalyse makes the interpretation of the docking solutions through graphical and visual representations easier by guiding the user to find the representative solutions. We have applied our new approach to analyze several protein interactions and model the dynamic protein interaction behavior of a protein complex. DockAnalyse might also be used to describe interaction regions between proteins and, therefore, guide future flexible dockings. The application (implemented in the R package) is accessible. PMID- 20969769 TI - A systematic review of the effectiveness of interventions to improve post fracture investigation and management of patients at risk of osteoporosis. AB - BACKGROUND: There is a large quality of care gap for patients with osteoporosis. As a fragility fracture is a strong indicator of underlying osteoporosis, it offers an ideal opportunity to initiate investigation and treatment. However, studies of post-fracture populations document screening and treatment rates below 20% in most settings. This is despite the fact that bone mineral density (BMD) scans are effective at identifying patients at high risk of fracture, and effective drug treatments are widely available. Effective interventions are required to remedy this incongruity in current practice. METHODS: This study reviewed randomised controlled trials (RCT) involving fully qualified healthcare professionals caring for patients with a fragility fracture in all healthcare settings. Any intervention designed to modify the behaviour of healthcare professionals or implement a service delivery change was considered. The main outcomes were BMD scanning and osteoporosis treatment with anti-resorptive therapy. The electronic databases Medline and Embase were searched from 1994 to June 2010 to identify relevant articles in English. Post-intervention risk differences (RDs) were calculated for the main outcomes and any additional study primary outcomes; the trials were meta-analysed. RESULTS: A total of 2814 potentially relevant articles were sifted; 18 were assessed in full text. Nine RCTs evaluating ten interventions met the inclusion criteria for the review. All were from North America. Four studies focused on patients with a hip fracture, three on fractures of the wrist/distal forearm, and two included several fracture sites consistent with a fragility fracture. All studies reported positive effects of the intervention for the main study outcomes of BMD scanning and osteoporosis treatment. For BMD scanning the overall risk ratio (95% CI) was 2.8 (2.16 to 3.64); the RD was 36% (21% to 50%). For treatment with anti-resorptive therapy the overall risk ratio (95% CI) was 2.48 (1.92 to 3.2); the RD was 20% (10% to 30%). CONCLUSIONS: All interventions produced positive effects on BMD scanning and osteoporosis treatment rates post-fracture. Despite sizeable increases, investigation and treatment rates remain sub-optimal. Long-term compliance with osteoporosis medications needs to be addressed, as the majority of studies reported treatment rates at six-month follow up only. Studies would be more informative if treatment criteria were defined a priori to facilitate understanding of whether patients were being treated appropriately and integrated economic analyses would be helpful for informing policy implementation decisions. PMID- 20969770 TI - A pragmatic study exploring the prevention of delirium among hospitalized older hip fracture patients: Applying evidence to routine clinical practice using clinical decision support. AB - Delirium occurs in up to 65% of older hip fracture patients. Developing delirium in hospital has been associated with a variety of adverse outcomes. Trials have shown that multi-component preventive interventions can lower delirium rates. The objective of this study was to implement and evaluate the effectiveness of an evidence-based electronic care pathway, which incorporates multi-component delirium strategies, among older hip fracture patients. We conducted a pragmatic study using an interrupted time series design in order to evaluate the use and impact of the intervention. The target population was all consenting patients aged 65 years or older admitted with an acute hip fracture to the orthopedic units at two Calgary, Alberta hospitals. The primary outcome was delirium rates. Secondary outcomes included length of hospital stay, in-hospital falls, in hospital mortality, new discharges to long-term care, and readmissions. A Durbin Watson test was conducted to test for serial correlation and, because no correlation was found, Chi-square statistics, Wilcoxon test and logistic regression analyses were conducted as appropriate. At study completion, focus groups were conducted at each hospital to explore issues around the use of the order set. During the 40-week study period, 134 patients were enrolled. The intervention had no effect on the overall delirium rate (33% pre versus 31% post; p = 0.84). However, there was a significant interaction between study phase and hospital (p = 0.03). Although one hospital did not experience a decline in delirium rate, the delirium rate at the other hospital declined from 42% to 19% (p = 0.08). This difference by hospital was mirrored in focus group feedback. The hospital that experienced a decline in delirium rates was more supportive of the intervention. Overall, post-intervention there were no significant differences in mean length of stay (12 days post versus 14 days pre; p = 0.74), falls (6% post versus 10% pre; p = 0.43) or discharges to long-term care (6% post versus 13% pre; p = 0.20). Translation of evidence-based multi-component delirium prevention strategies into everyday clinical care, using the electronic medical record, was not found to be effective at decreasing delirium rates among hip facture patients. PMID- 20969771 TI - Heterochronic evolution reveals modular timing changes in budding yeast transcriptomes. AB - BACKGROUND: Gene expression is a dynamic trait, and the evolution of gene regulation can dramatically alter the timing of gene expression without greatly affecting mean expression levels. Moreover, modules of co-regulated genes may exhibit coordinated shifts in expression timing patterns during evolutionary divergence. Here, we examined transcriptome evolution in the dynamical context of the budding yeast cell-division cycle, to investigate the extent of divergence in expression timing and the regulatory architecture underlying timing evolution. RESULTS: Using a custom microarray platform, we obtained 378 measurements for 6,263 genes over 18 timepoints of the cell-division cycle in nine strains of S. cerevisiae and one strain of S. paradoxus. Most genes show significant divergence in expression dynamics at all scales of transcriptome organization, suggesting broad potential for timing changes. A model test comparing expression level evolution versus timing evolution revealed a better fit with timing evolution for 82% of genes. Analysis of shared patterns of timing evolution suggests the existence of seven dynamically-autonomous modules, each of which shows coherent evolutionary timing changes. Analysis of transcription factors associated with these gene modules suggests a modular pleiotropic source of divergence in expression timing. CONCLUSIONS: We propose that transcriptome evolution may generally entail changes in timing (heterochrony) rather than changes in levels (heterometry) of expression. Evolution of gene expression dynamics may involve modular changes in timing control mediated by module-specific transcription factors. We hypothesize that genome-wide gene regulation may utilize a general architecture comprised of multiple semi-autonomous event timelines, whose superposition could produce combinatorial complexity in timing control patterns. PMID- 20969772 TI - Chemokine-mediated distribution of dendritic cell subsets in renal cell carcinoma. AB - BACKGROUND: Renal cell carcinoma (RCC) represents one of the most immunoresponsive cancers. Antigen-specific vaccination with dendritic cells (DCs) in patients with metastatic RCC has been shown to induce cytotoxic T-cell responses associated with objective clinical responses. Thus, clinical trials utilizing DCs for immunotherapy of advanced RCCs appear to be promising; however, detailed analyses concerning the distribution and function of DC subsets in RCCs are lacking. METHODS: We characterized the distribution of the different immature and mature myeloid DC subsets in RCC tumour tissue and the corresponding normal kidney tissues. In further analyses, the expression of various chemokines and chemokine receptors controlling the migration of DC subsets was investigated. RESULTS: The highest numbers of immature CD1a+ DCs were found within RCC tumour tissue. In contrast, the accumulation of mature CD83+/DC-LAMP+ DCs were restricted to the invasive margin of the RCCs. The mature DCs formed clusters with proliferating T-cells. Furthermore, a close association was observed between MIP-3alpha-producing tumour cells and immature CCR6+ DC recruitment to the tumour bed. Conversely, MIP-3beta and SLC expression was only detected at the tumour border, where CCR7-expressing T-cells and mature DCs formed clusters. CONCLUSION: Increased numbers of immature DCs were observed within the tumour tissue of RCCs, whereas mature DCs were found in increased numbers at the tumour margin. Our results strongly implicate that the distribution of DC subsets is controlled by local lymphoid chemokine expression. Thus, increased expression of MIP-3alpha favours recruitment of immature DCs to the tumour bed, whereas de novo local expression of SLC and MIP-3beta induces accumulation of mature DCs at the tumour margin forming clusters with proliferating T-cells reflecting a local anti-tumour immune response. PMID- 20969773 TI - Spontaneously immortalised bovine mammary epithelial cells exhibit a distinct gene expression pattern from the breast cancer cells. AB - BACKGROUND: Spontaneous immortalisation of cultured mammary epithelial cells (MECs) is an extremely rare event, and the molecular mechanism behind spontaneous immortalisation of MECs is unclear. Here, we report the establishment of a spontaneously immortalised bovine mammary epithelial cell line (BME65Cs) and the changes in gene expression associated with BME65Cs cells. RESULTS: BME65Cs cells maintain the general characteristics of normal mammary epithelial cells in morphology, karyotype and immunohistochemistry, and are accompanied by the activation of endogenous bTERT (bovine Telomerase Reverse Transcriptase) and stabilisation of the telomere. Currently, BME65Cs cells have been passed for more than 220 generations, and these cells exhibit non-malignant transformation. The expression of multiple genes was investigated in BME65Cs cells, senescent BMECs (bovine MECs) cells, early passage BMECs cells and MCF-7 cells (a human breast cancer cell line). In comparison with early passage BMECs cells, the expression of senescence-relevant apoptosis-related gene were significantly changed in BME65Cs cells. P16INK4a was downregulated, p53 was low expressed and Bax/Bcl-2 ratio was reversed. Moreover, a slight upregulation of the oncogene c-Myc, along with an undetectable level of breast tumor-related gene Bag-1 and TRPS-1, was observed in BME65Cs cells while these genes are all highly expressed in MCF-7. In addition, DNMT1 is upregulated in BME65Cs. These results suggest that the inhibition of both senescence and mitochondrial apoptosis signalling pathways contribute to the immortality of BME65Cs cells. The expression of p53 and p16INK4a in BME65Cs was altered in the pattern of down-regulation but not "loss", suggesting that this spontaneous immortalization is possibly initiated by other mechanism rather than gene mutation of p53 or p16INK4a. CONCLUSIONS: Spontaneously immortalised BME65Cs cells maintain many characteristics of normal BMEC cells and exhibit non-malignant transformation. Although this cell line displays altered patterns of gene expression, it is clearly distinct from malignant breast cancer cell line. It showed that co-inhibition of cellular senescence and mitochondrial apoptosis pathways coordinates BME65Cs cells immortalisation. Additionally, mechanisms other than gene mutation are likely to be involved in regulation of cellular functions. This study provides an insight into the relationship between cell senescence and immortalisation. BME65Cs cells will be useful in future studies of cellular senescence and tumorigenesis. PMID- 20969774 TI - CyberKnife for hilar lung tumors: report of clinical response and toxicity. AB - OBJECTIVE: To report clinical efficacy and toxicity of fractionated CyberKnife radiosurgery for the treatment of hilar lung tumors. METHODS: Patients presenting with primary and metastatic hilar lung tumors, treated using the CyberKnife system with Synchrony fiducial tracking technology, were retrospectively reviewed. Hilar location was defined as abutting or invading a mainstem bronchus. Fiducial markers were implanted by conventional bronchoscopy within or adjacent to tumors to serve as targeting references. A prescribed dose of 30 to 40 Gy to the gross tumor volume (GTV) was delivered in 5 fractions. Clinical examination and PET/CT imaging were performed at 3 to 6-month follow-up intervals. RESULTS: Twenty patients were accrued over a 4 year period. Three had primary hilar lung tumors and 17 had hilar lung metastases. The median GTV was 73 cc (range 23-324 cc). The median dose to the GTV was 35 Gy (range, 30 - 40 Gy), delivered in 5 fractions over 5 to 8 days (median, 6 days). The resulting mean maximum point doses delivered to the esophagus and mainstem bronchus were 25 Gy (range, 11 - 39 Gy) and 42 Gy (range, 30 - 49 Gy), respectively. Of the 17 evaluable patients with 3 - 6 month follow-up, 4 patients had a partial response and 13 patients had stable disease. AAT t a median follow-up of 10 months, the 1-year Kaplan-Meier local control and overall survival estimates were 63% and 54%, respectively. Toxicities included one patient experiencing grade II radiation esophagitis and one patient experiencing grade III radiation pneumonitis. One patient with gross endobronchial tumor within the mainstem bronchus developed a bronchial fistula and died after receiving a maximum bronchus dose of 49 Gy. CONCLUSION: CyberKnife radiosurgery is an effective palliative treatment option for hilar lung tumors, but local control is poor at one year. Maximum point doses to critical structures may be used as a guide for limiting toxicities. Preliminary results suggest that dose escalation alone is unlikely to enhance the therapeutic ratio of hilar lung tumors and novel approaches, such as further defining the patient population or employing the use of radiation sensitizers, should be investigated. PMID- 20969775 TI - Hepatic microRNA expression is associated with the response to interferon treatment of chronic hepatitis C. AB - BACKGROUND: HCV infection frequently induces chronic liver diseases. The current standard treatment for chronic hepatitis (CH) C combines pegylated interferon (IFN) and ribavirin, and is less than ideal due to undesirable effects. MicroRNAs (miRNAs) are endogenous small non-coding RNAs that control gene expression by degrading or suppressing the translation of target mRNAs. In this study we administered the standard combination treatment to CHC patients. We then examined their miRNA expression profiles in order to identify the miRNAs that were associated with each patient's drug response. METHODS: 99 CHC patients with no anti-viral therapy history were enrolled. The expression level of 470 mature miRNAs found their biopsy specimen, obtained prior to the combination therapy, were quantified using microarray analysis. The miRNA expression pattern was classified based on the final virological response to the combination therapy. Monte Carlo Cross Validation (MCCV) was used to validate the outcome of the prediction based on the miRNA expression profile. RESULTS: We found that the expression level of 9 miRNAs were significantly different in the sustained virological response (SVR) and non-responder (NR) groups. MCCV revealed an accuracy, sensitivity, and specificity of 70.5%, 76.5% and 63.3% in SVR and non SVR and 70.0%, 67.5%, and 73.7% in relapse (R) and NR, respectively. CONCLUSIONS: The hepatic miRNA expression pattern that exists in CHC patients before combination therapy is associated with their therapeutic outcome. This information can be utilized as a novel biomarker to predict drug response and can also be applied to developing novel anti-viral therapy for CHC patients. PMID- 20969776 TI - Macrodystrophia lipomatosa: four case reports. AB - AIM: Macrodystrophia lipomatosa is a rare cause of gigantism of limb which can be confused with other common causes like congenital lymphedema. It presents usually with loss of function and cosmetic problems. Four cases are described with emphasis on clinical presentation, differential diagnoses, imaging and treatment options. METHODS & RESULTS: Four patients of macrodystrophia lipomatosa were thoroughly examined and subjected to investigations. CONCLUSION: Besides diligent clinical examination, imaging and histopathology are crucial in clinching the diagnosis. PMID- 20969777 TI - An online network tool for quality information to answer questions about occupational safety and health: usability and applicability. AB - BACKGROUND: Common information facilities do not always provide the quality information needed to answer questions on health or health-related issues, such as Occupational Safety and Health (OSH) matters. Barriers may be the accessibility, quantity and readability of information. Online Question & Answer (Q&A) network tools, which link questioners directly to experts can overcome some of these barriers. When designing and testing online tools, assessing the usability and applicability is essential. Therefore, the purpose of this study is to assess the usability and applicability of a new online Q&A network tool for answers on OSH questions. METHODS: We applied a cross-sectional usability test design. Eight occupational health experts and twelve potential questioners from the working population (workers) were purposively selected to include a variety of computer- and internet-experiences. During the test, participants were first observed while executing eight tasks that entailed important features of the tool. In addition, they were interviewed. Through task observations and interviews we assessed applicability, usability (effectiveness, efficiency and satisfaction) and facilitators and barriers in use. RESULTS: Most features were usable, though several could be improved. Most tasks were executed effectively. Some tasks, for example searching stored questions in categories, were not executed efficiently and participants were less satisfied with the corresponding features. Participants' recommendations led to improvements. The tool was found mostly applicable for additional information, to observe new OSH trends and to improve contact between OSH experts and workers. Hosting and support by a trustworthy professional organization, effective implementation campaigns, timely answering and anonymity were seen as important use requirements. CONCLUSIONS: This network tool is a promising new strategy for offering company workers high quality information to answer OSH questions. Q&A network tools can be an addition to existing information facilities in the field of OSH, but also to other healthcare fields struggling with how to answer questions from people in practice with high quality information. In the near future, we will focus on the use of the tool and its effects on information and knowledge dissemination. PMID- 20969778 TI - PathEx: a novel multi factors based datasets selector web tool. AB - BACKGROUND: Microarray experiments have become very popular in life science research. However, if such experiments are only considered independently, the possibilities for analysis and interpretation of many life science phenomena are reduced. The accumulation of publicly available data provides biomedical researchers with a valuable opportunity to either discover new phenomena or improve the interpretation and validation of other phenomena that partially understood or well known. This can only be achieved by intelligently exploiting this rich mine of information. DESCRIPTION: Considering that technologies like microarrays remain prohibitively expensive for researchers with limited means to order their own experimental chips, it would be beneficial to re-use previously published microarray data. For certain researchers interested in finding gene groups (requiring many replicates), there is a great need for tools to help them to select appropriate datasets for analysis. These tools may be effective, if and only if, they are able to re-use previously deposited experiments or to create new experiments not initially envisioned by the depositors. However, the generation of new experiments requires that all published microarray data be completely annotated, which is not currently the case. Thus, we propose the PathEx approach. CONCLUSION: This paper presents PathEx, a human-focused web solution built around a two-component system: one database component, enriched with relevant biological information (expression array, omics data, literature) from different sources, and another component comprising sophisticated web interfaces that allow users to perform complex dataset building queries on the contents integrated into the PathEx database. PMID- 20969779 TI - Management of patients with biliary sphincter of Oddi disorder without sphincter of Oddi manometry. AB - BACKGROUND: The paucity of controlled data for the treatment of most biliary sphincter of Oddi disorder (SOD) types and the incomplete response to therapy seen in clinical practice and several trials has generated controversy as to the best course of management of these patients. In this observational study we aimed to assess the outcome of patients with biliary SOD managed without sphincter of Oddi manometry. METHODS: Fifty-nine patients with biliary SOD (14% type I, 51% type II, 35% type III) were prospectively enrolled. All patients with a dilated common bile duct were offered endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy whereas all others were offered medical treatment alone. Patients were followed up for a median of 15 months and were assessed clinically for response to treatment. RESULTS: At follow-up 15.3% of patients reported complete symptom resolution, 59.3% improvement, 22% unchanged symptoms, and 3.4% deterioration. Fifty-one percent experienced symptom resolution/improvement on medical treatment only, 12% after sphincterotomy, and 10% after both medical treatment/sphincterotomy. Twenty percent experienced at least one recurrence of symptoms after initial response to medical and/or endoscopic treatment. Fifty ERCP procedures were performed in 24 patients with an 18% complication rate (16% post-ERCP pancreatitis). The majority of complications occurred in the first ERCP these patients had. Most complications were mild and treated conservatively. Age, gender, comorbidity, SOD type, dilated common bile duct, presence of intact gallbladder, or opiate use were not related to the effect of treatment at the end of follow-up (p > 0.05 for all). CONCLUSIONS: Patients with biliary SOD may be managed with a combination of endoscopic sphincterotomy (performed in those with dilated common bile duct) and medical therapy without manometry. The results of this approach with regards to symptomatic relief and ERCP complication rate are comparable to those previously published in the literature in cohorts of patients assessed by manometry. PMID- 20969780 TI - Information discovery on electronic health records using authority flow techniques. AB - BACKGROUND: As the use of electronic health records (EHRs) becomes more widespread, so does the need to search and provide effective information discovery within them. Querying by keyword has emerged as one of the most effective paradigms for searching. Most work in this area is based on traditional Information Retrieval (IR) techniques, where each document is compared individually against the query. We compare the effectiveness of two fundamentally different techniques for keyword search of EHRs. METHODS: We built two ranking systems. The traditional BM25 system exploits the EHRs' content without regard to association among entities within. The Clinical ObjectRank (CO) system exploits the entities' associations in EHRs using an authority-flow algorithm to discover the most relevant entities. BM25 and CO were deployed on an EHR dataset of the cardiovascular division of Miami Children's Hospital. Using sequences of keywords as queries, sensitivity and specificity were measured by two physicians for a set of 11 queries related to congenital cardiac disease. RESULTS: Our pilot evaluation showed that CO outperforms BM25 in terms of sensitivity (65% vs. 38%) by 71% on average, while maintaining the specificity (64% vs. 61%). The evaluation was done by two physicians. CONCLUSIONS: Authority-flow techniques can greatly improve the detection of relevant information in EHRs and hence deserve further study. PMID- 20969781 TI - Co-receptor usage and prediction of V3 genotyping algorithms in HIV-1 subtype B' from paid blood donors experienced anti-retroviral therapy in Chinese central province. AB - BACKGROUND: This study explored co-receptor usage and prediction of V3 genotyping algorithms in HIV-1 subtype B' from paid blood donors experienced anti-retroviral therapy in Chinese central province in order to design effectively therapeutic regimen. METHODS: HIV-1 strains were isolated in treatment HIV-1 infections and treatment-naive HIV-1 infections, then co-receptor usage of HIV-1 strains was identified based on Ghost cell lines using flow cytometry. HIV-1 V3 region was amplified and submitted into web-server (WebPSSM and geno2pheno) to predict HIV-1 co-receptor usage. The feasibility of prediction HIV-1 usage with Web-server assay was analyzed by comparing prediction of V3 genotyping algorithms with HIV phenotype assay based on Ghost cell line. RESULTS: 45 HIV-1 strains and 114 HIV-1 strains were isolated from HIV-1 infections exposed anti-retroviral therapy and treatment-naive, respectively. 41% clinical viruses from ART patients and 18% from treatment-naive patients used CXCR4 as co-receptor. The net charge in the V3 loop was significantly difference in both groups. The sensitivity and specificity for predicting co-receptor capacity is 54.6% and 90.0% on 11/25 rule, 50.0% and 90% on Web-PSSM(x4r5), 68.2% and 40.0% on Geno2pheno[co-receptor]. CONCLUSION: Dual/mixed/X4 co-receptor utilization was higher in ART patients than treatment naive patients. It is should paid attention to predicting HIV-1 co-receptor usage based on V3 genotyping algorithms in HIV-1 subtype B' from paid blood donors experienced anti-retroviral therapy in Chinese central province. PMID- 20969782 TI - Differential alterations in gene expression profiles contribute to time-dependent effects of nandrolone to prevent denervation atrophy. AB - BACKGROUND: Anabolic steroids, such as nandrolone, slow muscle atrophy, but the mechanisms responsible for this effect are largely unknown. Their effects on muscle size and gene expression depend upon time, and the cause of muscle atrophy. Administration of nandrolone for 7 days beginning either concomitantly with sciatic nerve transection (7 days) or 29 days later (35 days) attenuated denervation atrophy at 35 but not 7 days. We reasoned that this model could be used to identify genes that are regulated by nandrolone and slow denervation atrophy, as well as genes that might explain the time-dependence of nandrolone effects on such atrophy. Affymetrix microarrays were used to profile gene expression changes due to nandrolone at 7 and 35 days and to identify major gene expression changes in denervated muscle between 7 and 35 days. RESULTS: Nandrolone selectively altered expression of 124 genes at 7 days and 122 genes at 35 days, with only 20 genes being regulated at both time points. Marked differences in biological function of genes regulated by nandrolone at 7 and 35 days were observed. At 35, but not 7 days, nandrolone reduced mRNA and protein levels for FOXO1, the mTOR inhibitor REDD2, and the calcineurin inhibitor RCAN2 and increased those for ApoD. At 35 days, correlations between mRNA levels and the size of denervated muscle were negative for RCAN2, and positive for ApoD. Nandrolone also regulated genes for Wnt signaling molecules. Comparison of gene expression at 7 and 35 days after denervation revealed marked alterations in the expression of 9 transcriptional coregulators, including Ankrd1 and 2, and many transcription factors and kinases. CONCLUSIONS: Genes regulated in denervated muscle after 7 days administration of nandrolone are almost entirely different at 7 versus 35 days. Alterations in levels of FOXO1, and of genes involved in signaling through calcineurin, mTOR and Wnt may be linked to the favorable action of nandrolone on denervated muscle. Marked changes in the expression of genes regulating transcription and intracellular signaling may contribute to the time dependent effects of nandrolone on gene expression. PMID- 20969785 TI - Reliability of anthropometric measures in a longitudinal cohort of patients initiating ART in West Africa. AB - BACKGROUND: Anthropometric measurements are a non invasive, inexpensive, and suitable method for evaluating the nutritional status in population studies with relatively large sample sizes. However, anthropometric techniques are prone to errors that could arise, for example, from the inadequate training of personnel. Despite these concerns, anthropometrical measurement error is seldom assessed in cohort studies. We describe the reliability and challenges associated with measurement of longitudinal anthropometric data in a cohort of West African HIV+ adults . METHODS: In a cohort of patients initiating antiretroviral treatment in Mali, we evaluated nutritional status using anthropometric measurements(weight, height, mid-upper arm circumference, waist circumference and triceps skinfold). Observers with no prior experience in the field of anthropometry were trained to perform anthropometrical measurements. To assess the intra- and inter-observer variability of the measurements taken in the course of the study, two sub-studies were carried out: one at the beginning and one at the end of the prospective study. Twelve patients were measured twice on two consecutive days by the same observer on both study occasions. The technical error of measurement (TEM) (absolute and relative value), and the coefficient of reliability (R) were calculated and compared across reliability studies. RESULTS: According to the R and relative TEM, inter-observer reliabilities were only acceptable for height and weight. In terms of intra-observer precision, while the first and second anthropometrists demonstrated better reliability than the third, only height and weight measurements were reliable. Looking at total TEM, we observed that while measurements remained stable between studies for height and weight, circumferences and skinfolds lost precision from one occasion to the next. CONCLUSIONS: Height and weight were the most reliable measurements under the study's conditions. Circumferences and skinfolds demonstrated less reliability and lost precision over time, probably as a result of insufficient supervision over the entire length of the study. Our results underline the importance of a careful observer's selection, good initial preparation, as well as the necessity of ongoing training and supervision over the entire course of a longitudinal nutritional study. Failure to do so could have major repercussions on data reliability and jeopardize its utilization. PMID- 20969784 TI - Apoptosis is increased and cell proliferation is decreased in out-of-phase endometria from infertile and recurrent abortion patients. AB - BACKGROUND: Various endometrial abnormalities have been associated with luteal phase deficiency: a significant dyssynchrony in the maturation of the glandular epithelium and the stroma and a prevalence of out-of-phase endometrial biopsy specimens. Out-of phase endometrium is a controversial disorder related to failed implantation, infertility and early pregnancy loss. Given that the regulation of the apoptotic process in endometrium of luteal phase deficiency is still unknown, the aim of this study was to evaluate cell proliferation, apoptosis and the levels of the main effector caspase, caspase-3 in the luteal in-phase and out-of phase endometrium. METHODS: Thirty-seven endometrial samples from sterile or recurrent abortion patients were included in this study: 21 in-phase samples (controls) and 16 samples with out-of-phase endometrium. Biopsy specimens of eutopic endometrium were obtained from all subjects during days 21-25 of the menstrual cycle. The endometrium with endometrial maturity of cycle day 25 or less at the time of menstruation was considered out-of phase. Endometrial tissues were fixed in 10% buffered formaldehyde. For apoptosis quantification, sections were processed for in situ immunohistochemical localization of nuclei exhibiting DNA fragmentation, by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP digoxygenin nick-end labeling (TUNEL) technique. Expressions of Proliferating Cell Nuclear Antigen (PCNA) as a marker of cell proliferation, and of cleaved caspase-3 as a marker of apoptosis, were assessed by immunohistochemistry in the luteal in-phase and out-of-phase endometrium from infertile and recurrent abortion patients. RESULTS: Luteal out-of-phase endometrium had increased apoptosis levels compared to in-phase endometrium (p < 0.05). Caspase-3 evaluation confirmed these results: the luteal out-of-phase endometrium showed augmented cleaved caspase-3 expression (p < 0.005). As well, our data demonstrated that the luteal out-of-phase endometrium expresses decreased PCNA levels (p < 0.05), showing that cell proliferation is diminished in this tissue. CONCLUSIONS: this study represents the first report describing variations at the cell proliferation and cell death levels in the out-of-phase endometrium in comparison with in-phase endometrium from infertile and recurrent abortion patients. Further studies are needed to elucidate a potential role of these alterations in the physiopathology of luteal phase deficiency. PMID- 20969783 TI - Advanced glycation end products induce chemokine/cytokine production via activation of p38 pathway and inhibit proliferation and migration of bone marrow mesenchymal stem cells. AB - BACKGROUND: Advanced glycation products (AGEs), as endogenous inflammatory mediator, compromise the physiological function of mesenchymal stem cells (MSCs). MSCs have a potential role in cell replacement therapy in acute myocardial infarction and ischemic cardiomyopathy. However, mechanisms of AGEs on MSCs are still not unveiled. METHODS: Reactive oxygen species (ROS), genes regulation, cell proliferation and migration have been detected by AGE-BSA stimulated MSCs. RESULTS: We found that in vitro stimulation with AGE-BSA induced generation of reactive oxygen species (ROS), and inhibited dose-dependently proliferation and migration of MSCs. Microarray and molecular biological assessment displayed an increased expression and secretion of Ccl2, Ccl3, Ccl4 and Il1b in a dose- and time-dependent manner. These chemokines/cytokines of equivalent concentration to those in conditioned medium exerted an inhibitory effect on MSC proliferation and migration after stimulation for 24 h. Transient elevation of phospho-p38 in MSCs upon AGE-BSA stimulation was blocked with p38 inhibitor. CONCLUSIONS: The study indicates that AGE-BSA induces production of chemokines/cytokines in a dose- and time-dependent manner via activation of ROS-p38 mediated pathway. These chemokines/cytokines exert an inhibitory effect on MSC growth and migration, suggesting an amplified dysfunction of MSCs by AGEs. PMID- 20969786 TI - Loneliness and the rate of motor decline in old age: the Rush Memory and Aging Project, a community-based cohort study. AB - BACKGROUND: Being alone, as measured by less frequent social interactions, has been reported to be associated with a more rapid rate of motor decline in older persons. We tested the hypothesis that feeling alone is associated with the rate of motor decline in community-dwelling older persons. METHODS: At baseline, loneliness was assessed with a 5-item scale in 985 persons without dementia participating in the Rush Memory and Aging Project, a longitudinal community based cohort study. Annual detailed assessment of 9 measures of muscle strength and 9 motor performances were summarized in a composite measure of global motor function. RESULTS: Linear mixed-effects models which controlled for age, sex and education, showed that the level of loneliness at baseline was associated with the rate of motor decline (Estimate, -0.016; S.E. 0.006, p = 0.005). For each 1 point higher level of loneliness at baseline, motor decline was 40% more rapid; this effect was similar to the rate of motor decline observed in an average participant 4 years older at baseline. Furthermore, this amount of motor decline per year was associated with about a 50% increased risk of death. When terms for both feeling alone (loneliness) and being alone were considered together in a single model, both were relatively independent predictors of motor decline. The association between loneliness and motor decline persisted even after controlling for depressive symptoms, cognition, physical and cognitive activities, chronic conditions, as well as baseline disability or a history of stroke or Parkinson's disease. CONCLUSIONS: Among community-dwelling older persons, both feeling alone and being alone are associated with more rapid motor decline, underscoring the importance of psychosocial factors and motor decline in old age. PMID- 20969787 TI - Explaining the impact of a women's group led community mobilisation intervention on maternal and newborn health outcomes: the Ekjut trial process evaluation. AB - BACKGROUND: Few large and rigorous evaluations of participatory interventions systematically describe their context and implementation, or attempt to explain the mechanisms behind their impact. This study reports process evaluation data from the Ekjut cluster-randomised controlled trial of a participatory learning and action cycle with women's groups to improve maternal and newborn health outcomes in Jharkhand and Orissa, eastern India (2005-2008). The study demonstrated a 45% reduction in neonatal mortality in the last two years of the intervention, largely driven by improvements in safe practices for home deliveries. METHODS: A participatory learning and action cycle with 244 women's groups was implemented in 18 intervention clusters covering an estimated population of 114 141. We describe the context, content, and implementation of this intervention, identify potential mechanisms behind its impact, and report challenges experienced in the field. Methods included a review of intervention documents, qualitative structured discussions with group members and non-group members, meeting observations, as well as descriptive statistical analysis of data on meeting attendance, activities, and characteristics of group attendees. RESULTS: Six broad, interrelated factors influenced the intervention's impact: (1) acceptability; (2) a participatory approach to the development of knowledge, skills and 'critical consciousness'; (3) community involvement beyond the groups; (4) a focus on marginalized communities; (5) the active recruitment of newly pregnant women into groups; (6) high population coverage. We hypothesize that these factors were responsible for the increase in safe delivery and care practices that led to the reduction in neonatal mortality demonstrated in the Ekjut trial. CONCLUSIONS: Participatory interventions with community groups can influence maternal and child health outcomes if key intervention characteristics are preserved and tailored to local contexts. Scaling-up such interventions requires (1) a detailed understanding of the way in which context affects the acceptability and delivery of the intervention; (2) planned but flexible replication of key content and implementation features; (3) strong support for participatory methods from implementing agencies. PMID- 20969788 TI - Genomic selection and complex trait prediction using a fast EM algorithm applied to genome-wide markers. AB - BACKGROUND: The information provided by dense genome-wide markers using high throughput technology is of considerable potential in human disease studies and livestock breeding programs. Genome-wide association studies relate individual single nucleotide polymorphisms (SNP) from dense SNP panels to individual measurements of complex traits, with the underlying assumption being that any association is caused by linkage disequilibrium (LD) between SNP and quantitative trait loci (QTL) affecting the trait. Often SNP are in genomic regions of no trait variation. Whole genome Bayesian models are an effective way of incorporating this and other important prior information into modelling. However a full Bayesian analysis is often not feasible due to the large computational time involved. RESULTS: This article proposes an expectation-maximization (EM) algorithm called emBayesB which allows only a proportion of SNP to be in LD with QTL and incorporates prior information about the distribution of SNP effects. The posterior probability of being in LD with at least one QTL is calculated for each SNP along with estimates of the hyperparameters for the mixture prior. A simulated example of genomic selection from an international workshop is used to demonstrate the features of the EM algorithm. The accuracy of prediction is comparable to a full Bayesian analysis but the EM algorithm is considerably faster. The EM algorithm was accurate in locating QTL which explained more than 1% of the total genetic variation. A computational algorithm for very large SNP panels is described. CONCLUSIONS: emBayesB is a fast and accurate EM algorithm for implementing genomic selection and predicting complex traits by mapping QTL in genome-wide dense SNP marker data. Its accuracy is similar to Bayesian methods but it takes only a fraction of the time. PMID- 20969789 TI - Structural equation modeling in medical research: a primer. AB - BACKGROUND: Structural equation modeling (SEM) is a set of statistical techniques used to measure and analyze the relationships of observed and latent variables. Similar but more powerful than regression analyses, it examines linear causal relationships among variables, while simultaneously accounting for measurement error. The purpose of the present paper is to explicate SEM to medical and health sciences researchers and exemplify their application. FINDINGS: To facilitate its use we provide a series of steps for applying SEM to research problems. We then present three examples of how SEM has been utilized in medical and health sciences research. CONCLUSION: When many considerations are given to research planning, SEM can provide a new perspective on analyzing data and potential for advancing research in medical and health sciences. PMID- 20969790 TI - Oligodendroglioma of the ciliary body: a unique case report and the review of literature. AB - BACKGROUND: To date, there is no report in the international literature of an oligodendroglioma of the ciliary body, nor is there an analysis of the possible origins of this lesion. CASE PRESENTATION: Here we report on a 52-year-old man admitted to our hospital with a ciliary body tumor revealed by clinical examination and ultrasound, computed tomography and magnetic resonance imaging studies. Following enucleation, pathological and immunohistochemical analyses were performed. Postoperative histopathological staining results included OLIGO 2(+) and GFAP(-), leading to a pathological diagnosis of oligodendroglioma of the ciliary body in the right eye (WHO grade II). CONCLUSIONS: Since malignant gliomas derive from transformed neural stem cells, the presence of oligodendroglioma in the ciliary body supports the hypothesis that gliomas can occur wherever neural stem cells exist. Tumors of the ciliary body derived from oligodendrocytes are difficult to diagnose; pathological analyses are essential. PMID- 20969791 TI - EGFR inhibitor C225 increases the radiosensitivity of human lung squamous cancer cells. AB - BACKGROUND: The purpose of the present study is to investigate the direct biological effects of the epidermal growth factor receptor (EGFR) inhibitor C225 on the radiosensitivity of human lung squamous cancer cell-H520. H520 cells were treated with different dosage of 60Co gamma ray irradiation (1.953 Gy/min) in the presence or absence of C225. The cellular proliferation, colony forming capacity, apoptosis, the cell cycle distribution as well as caspase-3 were analyzed in vitro. RESULTS: We found that C225 treatment significantly increased radiosensitivity of H-520 cells to irradiation, and led to cell cycle arrest in G1 phase, whereas 60Co gamma ray irradiation mainly caused G2 phase arrest. H-520 cells thus displayed both the G1 and G2 phase arrest upon treatment with C225 in combination with 60Co gamma ray irradiation. Moreover, C225 treatment significantly increased the apoptosis percentage of H-520 cells (13.91% +/- 1.88%) compared with the control group (5.75% +/- 0.64%, P < 0.05). CONCLUSION: In this regard, C225 treatment may make H-520 cells more sensitive to irradiation through the enhancement of caspase-3 mediated tumor cell apoptosis and cell cycle arrest. PMID- 20969793 TI - Results of a sector-wide quality improvement initiative for substance-abuse care: an uncontrolled before-after study in Catalonia, Spain. AB - BACKGROUND: The Health Department of the Regional Government of Catalonia, Spain, issued a quality plan for substance abuse centers. The objective of this paper is to evaluate the impact of a multidimensional quality improvement initiative in the field of substance abuse care and to discuss potentials and limitations for further quality improvement. METHODS: The study uses an uncontrolled, sector-wide pre-post design. All centers providing services for persons with substance abuse issues in the Autonomous Community of Catalonia participated in this assessment. Measures of compliance were developed based on indicators reported in the literature and by broad stakeholder involvement. We compared pre-post differences in dimension-specific and overall compliance-scores using one-way ANOVA for repeated measures and the Friedman statistic. We described the spread of the data using the inter-quartile range and the Fligner-Killen statistic. Finally, we adjusted compliance scores for location and size using linear and logistic regression models. RESULTS: We performed a baseline and follow up assessment in 22 centers for substance abuse care and observed substantial and statistically significant improvements for overall compliance (pre: 60.9%; post: 79.1%) and for compliance in the dimensions 'care pathway' (pre: 66.5%; post: 83.5%) and 'organization and management' (pre: 50.5%; post: 77.2%). We observed improvements in the dimension 'environment and infrastructure' (pre: 81.8%; post: 95.5%) and in the dimension 'relations and user rights' (pre: 66.5%; post: 72.5%); however, these were not statistically significant. The regression analysis suggests that improvements in compliance are positively influenced by being located in the Barcelona region in case of the dimension 'relations and user rights'. CONCLUSION: The positive results of this quality improvement initiative are possibly associated with the successful involvement of stakeholders, the consciously constructed feedback reports on individual and sector-wide performance and the support of evidence-based guidance wherever possible. Further research should address how contextual issues shape the uptake and effectiveness of quality improvement actions and how such quality improvements can be sustained. PMID- 20969794 TI - Differentiation analyses of adult suspension mononucleated peripheral blood cells of Mus musculus. AB - BACKGROUND: The purpose of this study is to determine whether isolated suspension mouse peripheral mononucleated blood cells have the potential to differentiate into two distinct types of cells, i.e., osteoblasts and osteoclasts. RESULTS: Differentiation into osteoblast cells was concomitant with the activation of the Opn gene, increment of alkaline phosphatase (ALP) activity and the existence of bone nodules, whereas osteoclast cells activated the Catk gene, increment of tartrate resistant acid phosphatase (TRAP) activity and showed resorption activities via resorption pits. Morphology analyses showed the morphology of osteoblast and osteoclast cells after von Kossa and May-Grunwald-Giemsa staining respectively. CONCLUSIONS: In conclusion, suspension mononucleated cells have the potentiality to differentiate into mature osteoblasts and osteoclasts, and hence can be categorized as multipotent stem cells. PMID- 20969792 TI - The complete mitochondrial genome of the citrus red mite Panonychus citri (Acari: Tetranychidae): high genome rearrangement and extremely truncated tRNAs. AB - BACKGROUND: The family Tetranychidae (Chelicerata: Acari) includes ~1200 species, many of which are of agronomic importance. To date, mitochondrial genomes of only two Tetranychidae species have been sequenced, and it has been found that these two mitochondrial genomes are characterized by many unusual features in genome organization and structure such as gene order and nucleotide frequency. The scarcity of available sequence data has greatly impeded evolutionary studies in Acari (mites and ticks). Information on Tetranychidae mitochondrial genomes is quite important for phylogenetic evaluation and population genetics, as well as the molecular evolution of functional genes such as acaricide-resistance genes. In this study, we sequenced the complete mitochondrial genome of Panonychus citri (Family Tetranychidae), a worldwide citrus pest, and provide a comparison to other Acari. RESULTS: The mitochondrial genome of P. citri is a typical circular molecule of 13,077 bp, and contains the complete set of 37 genes that are usually found in metazoans. This is the smallest mitochondrial genome within all sequenced Acari and other Chelicerata, primarily due to the significant size reduction of protein coding genes (PCGs), a large rRNA gene, and the A + T-rich region. The mitochondrial gene order for P. citri is the same as those for P. ulmi and Tetranychus urticae, but distinctly different from other Acari by a series of gene translocations and/or inversions. The majority of the P. citri mitochondrial genome has a high A + T content (85.28%), which is also reflected by AT-rich codons being used more frequently, but exhibits a positive GC-skew (0.03). The Acari mitochondrial nad1 exhibits a faster amino acid substitution rate than other genes, and the variation of nucleotide substitution patterns of PCGs is significantly correlated with the G + C content. Most tRNA genes of P. citri are extremely truncated and atypical (44-65, 54.1 +/- 4.1 bp), lacking either the T- or D-arm, as found in P. ulmi, T. urticae, and other Acariform mites. CONCLUSIONS: The P. citri mitochondrial gene order is markedly different from those of other chelicerates, but is conserved within the family Tetranychidae indicating that high rearrangements have occurred after Tetranychidae diverged from other Acari. Comparative analyses suggest that the genome size, gene order, gene content, codon usage, and base composition are strongly variable among Acari mitochondrial genomes. While extremely small and unusual tRNA genes seem to be common for Acariform mites, further experimental evidence is needed. PMID- 20969795 TI - Association of waterpipe smoking and road traffic crashes. AB - BACKGROUND: The purpose of this research was to examine whether waterpipe smokers experience increased risk of motor vehicle crashes. METHODS: In a telephone survey, a random sample of Iranian drivers were asked to report their age, gender, vehicle age, whether their vehicles were equipped with anti-lock braking system (ABS), average daily drive time (DDT), whether they smoked cigarette or waterpipe, whether they had diabetes mellitus (DM), number of traffic crashes during the last calendar year and whether the crash involved a pedestrian or another vehicle. RESULTS: A total of 2070 motor vehicle owners with the mean age of 41.6 +/- 11.45 were interviewed. The annual incidence of Road Traffic Crashes (RTC) was 14.9%; 14.0% involved a collision/s with other vehicles and 0.9% with pedestrians. There was an association between the RTC and male gender, DDT, being a cigarette smoker, being a waterpipe smoker and DM in univariable analysis. The association between RTC and being a waterpipe smoker and also cigarette smoker was significant in multivariable analysis after adjustment for DDT. CONCLUSIONS: Being waterpipe and/or cigarette smoker and DDT were the independent predictors of the number of traffic crashes in Poisson regression model. If the increased risk of RTC among waterpipe or cigarette smokers is seen in other studies, it would be beneficial to promote tobacco cessation and control strategies through injury prevention initiatives. PMID- 20969796 TI - When environmental changes do not cause geographic separation of fauna: differential responses of Baikalian invertebrates. AB - BACKGROUND: While the impact of climate fluctuations on the demographic histories of species caused by changes in habitat availability is well studied, populations of species from systems without geographic isolation have received comparatively little attention. Using CO1 mitochondrial sequences, we analysed phylogeographic patterns and demographic histories of populations of five species (four gastropod and one amphipod species) co-occurring in the southwestern shore of Lake Baikal, an area where environmental oscillations have not resulted in geographical isolation of habitats. RESULTS: Species with stronger habitat preferences (gastropods B. turriformis, B. carinata and B. carinatocostata) exhibit rather stable population sizes through their evolutionary history, and their phylogeographic pattern indicates moderate habitat fragmentation. Conversely, species without strong habitat preference (gastropod M. herderiana and amphipod G. fasciatus) exhibit haplotype networks with a very abundant and widespread central haplotype and a big number of singleton haplotypes, while their reconstructed demographic histories show a population expansion starting about 25 50 thousand years ago, a period marked by climate warming and increase in diatom abundance as inferred from bottom-lake sedimentary cores. CONCLUSIONS: In agreement with previous studies, we found that species reacted differently to the same environmental changes. Our results highlight the important role of dispersal ability and degree of ecological specialization in defining a species' response to environmental changes. PMID- 20969797 TI - Differential phenotyping of Brucella species using a newly developed semi automated metabolic system. AB - BACKGROUND: A commercial biotyping system (Taxa ProfileTM, Merlin Diagnostika) testing the metabolization of various substrates by bacteria was used to determine if a set of phenotypic features will allow the identification of members of the genus Brucella and their differentiation into species and biovars. RESULTS: A total of 191 different amines, amides, amino acids, other organic acids and heterocyclic and aromatic substrates (Taxa ProfileTM A), 191 different mono-, di-, tri- and polysaccharides and sugar derivates (Taxa ProfileTM C) and 95 amino peptidase- and protease-reactions, 76 glycosidase-, phosphatase- and other esterase-reactions, and 17 classic reactions (Taxa ProfileTM E) were tested with the 23 reference strains representing the currently known species and biovars of Brucella and a collection of 60 field isolates. Based on specific and stable reactions a 96-well "Brucella identification and typing" plate (MicronautTM) was designed and re-tested in 113 Brucella isolates and a couple of closely related bacteria.Brucella species and biovars revealed characteristic metabolic profiles and each strain showed an individual pattern. Due to their typical metabolic profiles a differentiation of Brucella isolates to the species level could be achieved. The separation of B. canis from B. suis bv 3, however, failed. At the biovar level, B. abortus bv 4, 5, 7 and B. suis bv 1-5 could be discriminated with a specificity of 100%. B. melitensis isolates clustered in a very homogenous group and could not be resolved according to their assigned biovars. CONCLUSIONS: The comprehensive testing of metabolic activity allows cluster analysis within the genus Brucella. The biotyping system developed for the identification of Brucella and differentiation of its species and biovars may replace or at least complement time-consuming tube testing especially in case of atypical strains. An easy to handle identification software facilitates the applicability of the MicronautTM system for microbiology laboratories. PMID- 20969798 TI - Complete plastome sequences of Equisetum arvense and Isoetes flaccida: implications for phylogeny and plastid genome evolution of early land plant lineages. AB - BACKGROUND: Despite considerable progress in our understanding of land plant phylogeny, several nodes in the green tree of life remain poorly resolved. Furthermore, the bulk of currently available data come from only a subset of major land plant clades. Here we examine early land plant evolution using complete plastome sequences including two previously unexamined and phylogenetically critical lineages. To better understand the evolution of land plants and their plastomes, we examined aligned nucleotide sequences, indels, gene and nucleotide composition, inversions, and gene order at the boundaries of the inverted repeats. RESULTS: We present the plastome sequences of Equisetum arvense, a horsetail, and of Isoetes flaccida, a heterosporous lycophyte. Phylogenetic analysis of aligned nucleotides from 49 plastome genes from 43 taxa supported monophyly for the following clades: embryophytes (land plants), lycophytes, monilophytes (leptosporangiate ferns + Angiopteris evecta + Psilotum nudum + Equisetum arvense), and seed plants. Resolution among the four monilophyte lineages remained moderate, although nucleotide analyses suggested that P. nudum and E. arvense form a clade sister to A. evecta + leptosporangiate ferns. Results from phylogenetic analyses of nucleotides were consistent with the distribution of plastome gene rearrangements and with analysis of sequence gaps resulting from insertions and deletions (indels). We found one new indel and an inversion of a block of genes that unites the monilophytes. CONCLUSIONS: Monophyly of monilophytes has been disputed on the basis of morphological and fossil evidence. In the context of a broad sampling of land plant data we find several new pieces of evidence for monilophyte monophyly. Results from this study demonstrate resolution among the four monilophytes lineages, albeit with moderate support; we posit a clade consisting of Equisetaceae and Psilotaceae that is sister to the "true ferns," including Marattiaceae. PMID- 20969799 TI - Community impacts of anthropogenic disturbance: natural enemies exploit multiple routes in pursuit of invading herbivore hosts. AB - BACKGROUND: Biological invasions provide a window on the process of community assembly. In particular, tracking natural enemy recruitment to invading hosts can reveal the relative roles of co-evolution (including local adaptation) and ecological sorting. We use molecular data to examine colonisation of northern Europe by the parasitoid Megastigmus stigmatizans following invasions of its herbivorous oak gallwasp hosts from the Balkans. Local host adaptation predicts that invading gallwasp populations will have been tracked primarily by sympatric Balkan populations of M. stigmatizans (Host Pursuit Hypothesis). Alternatively, ecological sorting allows parasitoid recruitment from geographically distinct populations with no recent experience of the invading hosts (Host Shift Hypothesis). Finally, we test for long-term persistence of parasitoids introduced via human trade of their hosts' galls (Introduction Hypothesis). RESULTS: Polymorphism diagnostic of different southern refugial regions was present in both mitochondrial and nuclear microsatellite markers, allowing us to identify the origins of northern European invaded range M. stigmatizans populations. As with their hosts, some invaded range populations showed genetic variation diagnostic of Balkan sources, supporting the Host Pursuit Hypothesis. In contrast, other invading populations had an Iberian origin, unlike their hosts in northern Europe, supporting the Host Shift Hypothesis. Finally, both British and Italian M. stigmatizans populations show signatures compatible with the Introduction Hypothesis from eastern Mediterranean sources. CONCLUSIONS: These data reveal the continental scale of multi-trophic impacts of anthropogenic disturbance and highlight the fact that herbivores and their natural enemies may face very different constraints on range expansion. The ability of natural enemies to exploit ecologically-similar hosts with which they have had no historical association supports a major role for ecological sorting processes in the recent assembly of these communities. The multitude of origins of invading natural enemy populations in this study emphasises the diversity of mechanisms requiring consideration when predicting consequences of other biological invasions or biological control introductions. PMID- 20969800 TI - Epidemiology of nasopharyngeal carriage of respiratory bacterial pathogens in children and adults: cross-sectional surveys in a population with high rates of pneumococcal disease. AB - BACKGROUND: To determine the prevalence of carriage of respiratory bacterial pathogens, and the risk factors for and serotype distribution of pneumococcal carriage in an Australian Aboriginal population. METHODS: Surveys of nasopharyngeal carriage of Streptococcus pneumoniae, non-typeable Haemophilus influenzae, and Moraxella catarrhalis were conducted among adults (>=16 years) and children (2 to 15 years) in four rural communities in 2002 and 2004. Infant seven-valent pneumococcal conjugate vaccine (7PCV) with booster 23-valent pneumococcal polysaccharide vaccine was introduced in 2001. Standard microbiological methods were used. RESULTS: At the time of the 2002 survey, 94% of eligible children had received catch-up pneumococcal vaccination. 324 adults (538 examinations) and 218 children (350 examinations) were enrolled. Pneumococcal carriage prevalence was 26% (95% CI, 22-30) among adults and 67% (95% CI, 62-72) among children. Carriage of non-typeable H. influenzae among adults and children was 23% (95% CI, 19-27) and 57% (95% CI, 52-63) respectively and for M. catarrhalis, 17% (95% CI, 14-21) and 74% (95% CI, 69-78) respectively. Adult pneumococcal carriage was associated with increasing age (p = 0.0005 test of trend), concurrent carriage of non-typeable H. influenzae (Odds ratio [OR] 6.74; 95% CI, 4.06-11.2) or M. catarrhalis (OR 3.27; 95% CI, 1.97-5.45), male sex (OR 2.21; 95% CI, 1.31-3.73), rhinorrhoea (OR 1.66; 95% CI, 1.05-2.64), and frequent exposure to outside fires (OR 6.89; 95% CI, 1.87-25.4). Among children, pneumococcal carriage was associated with decreasing age (p < 0.0001 test of trend), and carriage of non-typeable H. influenzae (OR 9.34; 95% CI, 4.71-18.5) or M. catarrhalis (OR 2.67; 95% CI, 1.34-5.33). Excluding an outbreak of serotype 1 in children, the percentages of serotypes included in 7, 10, and 13PCV were 23%, 23%, and 29% (adults) and 22%, 24%, and 40% (2-15 years). Dominance of serotype 16F, and persistent 19F and 6B carriage three years after initiation of 7PCV is noteworthy. CONCLUSIONS: Population-based carriage of S. pneumoniae, non typeable H. influenzae, and M. catarrhalis was high in this Australian Aboriginal population. Reducing smoke exposure may reduce pneumococcal carriage. The indirect effects of 10 or 13PCV, above those of 7PCV, among adults in this population may be limited. PMID- 20969801 TI - Predicting acute uncomplicated urinary tract infection in women: a systematic review of the diagnostic accuracy of symptoms and signs. AB - BACKGROUND: Acute urinary tract infections (UTI) are one of the most common bacterial infections among women presenting to primary care. However, there is a lack of consensus regarding the optimal reference standard threshold for diagnosing UTI. The objective of this systematic review is to determine the diagnostic accuracy of symptoms and signs in women presenting with suspected UTI, across three different reference standards (10(2) or 10(3) or 10(5) CFU/ml). We also examine the diagnostic value of individual symptoms and signs combined with dipstick test results in terms of clinical decision making. METHODS: Searches were performed through PubMed (1966 to April 2010), EMBASE (1973 to April 2010), Cochrane library (1973 to April 2010), Google scholar and reference checking.Studies that assessed the diagnostic accuracy of symptoms and signs of an uncomplicated UTI using a urine culture from a clean-catch or catherised urine specimen as the reference standard, with a reference standard of at least >= 10(2) CFU/ml were included. Synthesised data from a high quality systematic review were used regarding dipstick results. Studies were combined using a bivariate random effects model. RESULTS: Sixteen studies incorporating 3,711 patients are included. The weighted prior probability of UTI varies across diagnostic threshold, 65.1% at >= 10(2) CFU/ml; 55.4% at >= 10(3) CFU/ml and 44.8% at >= 10(2) CFU/ml >= 10(5) CFU/ml. Six symptoms are identified as useful diagnostic symptoms when a threshold of >= 10(2) CFU/ml is the reference standard. Presence of dysuria (+LR 1.30 95% CI 1.20-1.41), frequency (+LR 1.10 95% CI 1.04-1.16), hematuria (+LR 1.72 95%CI 1.30-2.27), nocturia (+LR 1.30 95% CI 1.08-1.56) and urgency (+LR 1.22 95% CI 1.11-1.34) all increase the probability of UTI. The presence of vaginal discharge (+LR 0.65 95% CI 0.51-0.83) decreases the probability of UTI. Presence of hematuria has the highest diagnostic utility, raising the post-test probability of UTI to 75.8% at >= 10(2) CFU/ml and 67.4% at >= 10(3) CFU/ml. Probability of UTI increases to 93.3% and 90.1% at >= 10(2) CFU/ml and >= 10(3) CFU/ml respectively when presence of hematuria is combined with a positive dipstick result for nitrites. Subgroup analysis shows improved diagnostic accuracy using lower reference standards >= 10(2) CFU/ml and >= 10(3) CFU/ml. CONCLUSIONS: Individual symptoms and signs have a modest ability to raise the pretest-risk of UTI. Diagnostic accuracy improves considerably when combined with dipstick tests particularly tests for nitrites. PMID- 20969802 TI - Altered cardiac rhythm in infants with bronchiolitis and respiratory syncytial virus infection. AB - BACKGROUND: Although the most frequent extra-pulmonary manifestations of respiratory syncytial virus (RSV) infection involve the cardiovascular system, no data regarding heart function in infants with bronchiolitis associated with RSV infection have yet been systematically collected. The aim of this study was to verify the real frequency of heart involvement in patients with bronchiolitis associated with RSV infection, and whether infants with mild or moderate disease also risk heart malfunction. METHODS: A total of 69 otherwise healthy infants aged 1-12 months with bronchiolitis hospitalised in standard wards were enrolled. Pernasal flocked swabs were performed to collect specimens for the detection of RSV by real-time polymerase chain reaction, and a blood sample was drawn to assess troponin I concentrations. On the day of admission, all of the infants underwent 24-hour Holter ECG monitoring and a complete heart evaluation with echocardiography. Patients were re-evaluated by investigators blinded to the etiological and cardiac findings four weeks after enrollment. RESULTS: Regardless of their clinical presentation, sinoatrial blocks were identified in 26/34 RSV positive patients (76.5%) and 1/35 RSV-negative patients (2.9%) (p < 0.0001). The blocks recurred more than three times over 24 hours in 25/26 RSV-positive patients (96.2%) and none of the RSV-negative infants. Mean and maximum heart rates were significantly higher in the RSV-positive infants (p < 0.05), as was low-frequency power and the low and high-frequency power ratio (p < 0.05). The blocks were significantly more frequent in the children with an RSV load of >=100,000 copies/mL than in those with a lower viral load (p < 0.0001). Holter ECG after 28 +/- 3 days showed the complete regression of the heart abnormalities. CONCLUSIONS: RSV seems associated with sinoatrial blocks and transient rhythm alterations even when the related respiratory problems are mild or moderate. Further studies are needed to clarify the mechanisms of these rhythm problems and whether they remain asymptomatic and transient even in presence of severe respiratory involvement or chronic underlying disease. PMID- 20969803 TI - Thermodynamic modeling of transcription: sensitivity analysis differentiates biological mechanism from mathematical model-induced effects. AB - BACKGROUND: Quantitative models of gene expression generate parameter values that can shed light on biological features such as transcription factor activity, cooperativity, and local effects of repressors. An important element in such investigations is sensitivity analysis, which determines how strongly a model's output reacts to variations in parameter values. Parameters of low sensitivity may not be accurately estimated, leading to unwarranted conclusions. Low sensitivity may reflect the nature of the biological data, or it may be a result of the model structure. Here, we focus on the analysis of thermodynamic models, which have been used extensively to analyze gene transcription. Extracted parameter values have been interpreted biologically, but until now little attention has been given to parameter sensitivity in this context. RESULTS: We apply local and global sensitivity analyses to two recent transcriptional models to determine the sensitivity of individual parameters. We show that in one case, values for repressor efficiencies are very sensitive, while values for protein cooperativities are not, and provide insights on why these differential sensitivities stem from both biological effects and the structure of the applied models. In a second case, we demonstrate that parameters that were thought to prove the system's dependence on activator-activator cooperativity are relatively insensitive. We show that there are numerous parameter sets that do not satisfy the relationships proferred as the optimal solutions, indicating that structural differences between the two types of transcriptional enhancers analyzed may not be as simple as altered activator cooperativity. CONCLUSIONS: Our results emphasize the need for sensitivity analysis to examine model construction and forms of biological data used for modeling transcriptional processes, in order to determine the significance of estimated parameter values for thermodynamic models. Knowledge of parameter sensitivities can provide the necessary context to determine how modeling results should be interpreted in biological systems. PMID- 20969804 TI - Spatio-temporal expression of a novel neuron-derived neurotrophic factor (NDNF) in mouse brains during development. AB - BACKGROUND: Neuron-derived neurotrophic factor (NDNF) is evolutionarily well conserved, being present in invertebrate animals such as the nematode, Caenorhabditis elegans, as well as in the fruit fly, Drosophila melanogaster. Multiple cysteines are conserved between species and secondary structure prediction shows that NDNF is mainly composed of beta-strands. In this study, we aimed to investigate the function of NDNF. RESULTS: NDNF is a glycosylated, disulfide-bonded secretory protein that contains a fibronectin type III domain. NDNF promoted migration and growth and elicited neurite outgrowth of mouse hippocampal neurons in culture. NDNF also protected cultured hippocampal neurons against excitotoxicity and amyloid beta-peptide toxicity. Western blotting showed that NDNF was exclusively expressed in the brain and spinal cord. Immunostaining indicated that NDNF was expressed by neurons and not by astrocytes. Cajal-Retzius cells, cortex neurons, hippocampus neurons, olfactory mitral cells, cerebellar purkinje cells, cerebellar granular cells and spinal neurons were found to be NDNF-positive. NDNF expression was observed in the neurons during development. CONCLUSIONS: The results of this study indicated that NDNF is a novel neurotrophic factor derived from neurons that may be useful in the treatment of neuronal degeneration diseases and nerve injuries. PMID- 20969806 TI - Differential expression pattern of an acidic 9/13-lipoxygenase in flower opening and senescence and in leaf response to phloem feeders in the tea plant. AB - BACKGROUND: Lipoxygenase (LOXs) is a large family of plant enzymes that catalyse the hydroperoxidation of free polyunsaturated fatty acids into diverse biologically active compounds, collectively named phyto-oxylipins. Although multiple isoforms of LOXs have been identified in a wide range of annual herbaceous plants, the genes encoding these enzymes in perennial woody plants have not received as much attention. In Camellia sinensis (L.) O. Kuntze, no LOX gene of any type has been isolated, and its possible role in tea plant development, senescence, and defence reaction remains unknown. The present study describes the isolation, characterization, and expression of the first tea plant LOX isoform, namely CsLOX1, and seeks to clarify the pattern of its expression in the plant's defence response as well as in flower opening and senescence. RESULTS: Based on amino acid sequence similarity to plant LOXs, a LOX was identified in tea plant and named CsLOX1, which encodes a polypeptide comprising 861 amino acids and has a molecular mass of 97.8 kDa. Heterologous expression in yeast analysis showed that CsLOX1 protein conferred a dual positional specificity since it released both C-9 and C-13 oxidized products in equal proportion and hence was named 9/13-CsLOX1. The purified recombinant CsLOX1 protein exhibited optimum catalytic activity at pH 3.6 and 25 degrees C. Real-time quantitative PCR analysis showed that CsLOX1 transcripts were detected predominantly in flowers, up-regulated during petal senescence, and down-regulated during flower bud opening. In leaves, the gene was up-regulated following injury or when treated with methyl jasmonate (MeJA), but salicylic acid (SA) did not induce such response. The gene was also rapidly and highly induced following feeding by the tea green leafhopper Empoasca vitis, whereas feeding by the tea aphid Toxoptera aurantii resulted in a pattern of alternating induction and suppression. CONCLUSIONS: Analysis of the isolation and expression of the LOX gene in tea plant indicates that the acidic CsLOX1 together with its primary and end products plays an important role in regulating cell death related to flower senescence and the JA-related defensive reaction of the plant to phloem-feeders. PMID- 20969805 TI - Aquaporin 1, a potential therapeutic target for migraine with aura. AB - The pathophysiology of migraine remains largely unknown. However, evidence regarding the molecules participating in the pathophysiology of migraine has been accumulating. Water channel proteins, known as aquaporins (AQPs), notably AQP-1 and AQP-4, appears to be involved in the pathophysiology of several neurological diseases. This review outlines newly emerging evidence indicating that AQP-1 plays an important role in pain signal transduction and migraine and could therefore serve as a potential therapeutic target for these diseases. PMID- 20969807 TI - Herbal compound "Songyou Yin" reinforced the ability of interferon-alfa to inhibit the enhanced metastatic potential induced by palliative resection of hepatocellular carcinoma in nude mice. AB - BACKGROUND: Liver resection is a widely accepted treatment for hepatocellular carcinoma (HCC). Our previous clinical study showed that the rate of palliative resection was 34.0% (1958-2008, 2754 of 8107). However, the influence of palliative resection on tumor metastasis remains controversial. The present study was conducted to evaluate the effect of palliative resection on residual HCC and to explore interventional approaches. METHODS: Palliative resection was done in an orthotopic nude mice model of HCC (MHCC97H) with high metastatic potential. Tumor growth, invasion, metastasis, lifespan, and some molecular alterations were examined in vivo and in vitro. Mice that underwent palliative resection were treated with the Chinese herbal compound "Songyou Yin," interferon-alfa-1b (IFN alpha), or their combination to assess their effects. RESULTS: In the palliative resection group, the number of lung metastatic nodules increased markedly as compared to the sham operation group (14.3 +/- 4.7 versus 8.7 +/- 3.6, P < 0.05); tumor matrix metalloproteinase 2 (MMP2) activity was elevated by 1.4-fold, with up-regulation of vascular endothelial growth factor (VEGF) and down-regulation of tissue inhibitor of metalloproteinase 2 (TIMP2). The sera of mice undergoing palliative resection significantly enhanced cell invasiveness by 1.3-fold. After treatment, tumor volume was 1205.2 +/- 581.3 mm3, 724.9 +/- 337.6 mm3, 507.6 +/- 367.0 mm3, and 245.3 +/- 181.2 mm3 in the control, "Songyou Yin," IFN-alpha, and combination groups, respectively. The combined therapy noticeably decreased the MMP2/TIMP2 ratio and prolonged the lifespan by 42.2%. Moreover, a significant (P < 0.001) reduction of microvessel density was found: 43.6 +/- 8.5, 34.5 +/- 5.9, 23.5 +/- 5.6, and 18.2 +/- 8.0 in the control and treatment groups, respectively. CONCLUSION: Palliative resection-stimulated HCC metastasis may occur, in part, by up-regulation of VEGF and MMP2/TIMP2. "Songyou Yin" reinforced the ability of IFN alpha to inhibit the metastasis-enhancing potential induced by palliative resection, which indicated its potential postoperative use in patients with HCC. PMID- 20969808 TI - Cardiovascular risk estimated after 13 years of follow-up in a low-incidence Mediterranean region with high-prevalence of cardiovascular risk factors. AB - BACKGROUND: Murcia (south-east Spain) shows increased cardiovascular (CV) morbimortality as compared to other Spanish regions. Our objective was to assess the CV risk associated with major risk factors (RF) among adult population of Murcia. METHODS: A cohort of 2314 subjects (18-70 years) with full biochemical and questionnaire data was followed-up for 13 years. Incident cases of ischemic heart disease and stroke were identified by record linkage, individual questionnaires and revision of medical records. Relative risks were obtained by multivariate Cox regression stratified by age and sex, and ischemic risk attributable to CVRF was calculated. RESULTS: After more than 26276 person-years of follow-up, 57 incident ischemic events (77% men) and 37 stroke cases (62% men) were identified. Independent risk factors of ischemic heart disease (IHD) and all CV events combined, with RR ranging from 1.6 to 2.6, were total serum cholesterol >= 240 mg/dl (HR = 2.6, 95%CI:1.3-5.1), blood pressure levels >= 140/90 mmHg (HR = 2.6, 95%CI:1.4-4.8), ever tobacco smoking (HR = 2.2; 95%CI:1.1-4.5), and diabetes (HR = 2.0; 95%CI: 1.0-3.8). No increased CV risk was detected for known participants under treatment who showed cholesterol and blood pressure values below the clinical risk threshold. Smoking was significantly associated with stroke. For all events combined, the major risk factors were hypercholesterolemia, hypertension and ever use of tobacco. Despite its high prevalence, obesity was not associated to CV risk. Most of the IHD cases were attributable to smoking (44%), hypertension (38%) and hypercholesterolemia (26%). CONCLUSIONS: In the Region of Murcia, smoking accounted for the largest proportion of cardiovascular risk, whereas hypertension displaced hypercholesterolemia as the second leading cause of CV disease. Our study deepens in our understanding of the cardiovascular epidemiology in Spanish areas of Mediterranean Europe with relatively high cardiovascular morbimortality, that are poorly represented by the available risk equations. PMID- 20969810 TI - Predictors of changes in adolescents' consumption of fruits, vegetables and energy-dense snacks. AB - Understanding the predictors of developmental changes in adolescent eating behaviours is important for the design of nutrition interventions. The present study examined associations between individual, social and physical environmental factors and changes in adolescent eating behaviours over 2 years. Consumption of fruits, vegetables and energy-dense snacks was assessed using a Web-based survey completed by 1850 adolescents from years 7 and 9 of secondary schools in Victoria, Australia, at baseline and 2 years later. Perceived value of healthy eating, self-efficacy for healthy eating, social modelling and support, and home availability and accessibility of foods were assessed at baseline. Self-efficacy for increasing fruit consumption was positively associated with the change in fruit and vegetable consumption, while self-efficacy for decreasing junk food consumption was inversely associated with the change in energy-dense snack consumption. Home availability of energy-dense foods was inversely associated with the change in fruit consumption and positively associated with the change in energy-dense snack consumption, while home availability of fruits and vegetables was positively associated with the change in vegetable consumption. Perceived value of healthy eating and modelling of healthy eating by mothers were positively associated with the change in fruit consumption. Support of best friends for healthy eating was positively associated with the change in vegetable consumption. Self-efficacy and home availability of foods appear to be consistent predictors of change in fruit, vegetable and energy-dense snack consumption. Future study should assess the effectiveness of methods to increase self-efficacy for healthy eating and to improve home availability of healthy food options in programmes promoting healthy eating among adolescents. PMID- 20969809 TI - Effect of an education programme for patients with osteoarthritis in primary care -a randomized controlled trial. AB - BACKGROUND: Osteoarthritis (OA) is a degenerative disease, considered to be one of the major public health problems. Research suggests that patient education is feasible and valuable for achieving improvements in quality of life, in function, well-being and improved coping. Since 1994, Primary Health Care in Malmo has used a patient education programme directed towards OA. The aim of this study was to evaluate the effects of this education programme for patients with OA in primary health care in terms of self-efficacy, function and self-perceived health. METHOD: The study was a single-blind, randomized controlled trial (RCT) in which the EuroQol-5D and Arthritis self-efficacy scale were used to measure self perceived health and self-efficacy and function was measured with Grip Ability Test for the upper extremity and five different functional tests for the lower extremity. RESULTS: We found differences between the intervention group and the control group, comparing the results at baseline and after 6 months in EuroQol-5D (p < 0.001) and in standing one leg eyes closed (p = 0.02) in favour of the intervention group. No other differences between the groups were found. CONCLUSION: This study has shown that patient education for patients with osteoarthritis is feasible in a primary health care setting and can improve self perceived health as well as function in some degree, but not self-efficacy. Further research to investigate the effect of exercise performance on function, as well as self-efficacy is warranted. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov. REGISTRATION NUMBER: NCT00979914. PMID- 20969811 TI - Dietary therapy: a new strategy for management of chronic pelvic pain. AB - Chronic pelvic pain (CPP) can be identified as a chronic nociceptive, inflammatory and neuropathic pain characterised by spontaneous pain and an exaggerated response to painful and/or innocuous stimuli. This pain condition is extremely debilitating and usually difficult to treat. Currently, the main approaches to treatment include counselling supported by reassuring ultrasound scanning or psychotherapy, attempting to provide reassurance using laparoscopy to exclude serious pelvic pathology, hormonal therapy and neuroablative treatment to interrupt nerve pathways. Dietary supplementation has been suggested as a means to treat chronic medical illnesses that are poorly responsive to prescription drugs or in which therapeutic options are limited, costly or carry a high side effect profile. A comprehensive search of the PubMed database was performed using the search terms 'chronic pelvic pain', 'oxidative stress', 'antioxidants' and 'dietary therapy'. The systematic review focuses on both randomised and non randomised controlled trials from 2005 onwards, in which CPP was the end point. Given the complexity and not well-understood aetiology of CPP, its treatment is often unsatisfactory and limited to partial symptom relief. Dietary therapy with antioxidants improves function of the immune system and in fighting free radical damage. Agents with antioxidant activity are able to improve CPP without undesired effects and any important metabolic changes associated with hormonal suppression therapy. In conclusion, dietary therapy with antioxidants could be considered as a new effective strategy in the long term for CPP, and may be better accepted by patients. Further randomised trials with larger series and long-term follow-up to confirm these observations are needed. PMID- 20969812 TI - A simple algorithm to eliminate ambiguities in EBSD orientation map visualization and analyses: application to fatigue crack-tips/wakes in aluminum alloys. AB - A simple algorithm is developed and implemented to eliminate ambiguities, in both statistical analyses of orientation data (e.g., orientation averaging) and electron backscattered diffraction (EBSD) orientation map visualization, caused by symmetrically equivalent orientations and the wrap-around or umklapp effect. Using crystal symmetry operators and the lowest Euclidian-distance criterion, the orientation of each pixel within a grain is redefined. An advantage of this approach is demonstrated for direct determination of the representative orientation of a grain within an EBSD map by mean, median, or quaternion-based averaging methods that can be further used within analyses or visualization of misorientation or geometrically necessary dislocation (GND) density. If one also considers the lattice curvature tensor, five components of the dislocation density tensor-corresponding to a part of the GND content-may be inferred. The methodology developed is illustrated using EBSD orientation data obtained from the fatigue crack-tips/wakes in aerospace aluminum alloys 2024-T351 and 7050 T7451. PMID- 20969813 TI - Characterization of the expression of Ang1, Ang2, and Tie2 in the Corpus Cavernosum of the rat during aging. AB - Aging is the single most significant risk factor for erectile dysfunction (ED), leading to structural modification of cavernous tissue and altering expression of vascular growth factors. The angiopoietin/Tie2 system has been recently considered as a potential target for therapy of vascular disorders, including ED. Hence, the aim of this study was to analyze expression of angiopoietin1 (Ang1), angiopoietin2 (Ang2), and their receptor Tie2 in corpus cavernosum (CC) of rat during aging (6, 12, 18, and 24 months). The expression of Ang1, Ang2, and Tie2 was studied by immunohistochemistry and immunofluorescence, followed by semiquantification after Western blotting. Both Ang1 and Ang2 were localized mainly in perivascular smooth muscle and endothelial cells, while Tie2 was strictly detected at the vascular endothelium. A significant decrease in Ang2's expression was observed at 12 months when compared with 6-month-old rats, a tendency that reverses in older animals. No significant differences were demonstrated for Ang1 or Tie2, which is consistent with their constitutive expression in CC. The ratios Ang1/Tie2 and Ang2/Tie2 were also calculated and both decrease during aging, while no marked variation was observed for Ang1/Ang2. Our results suggest that the angiopoietin/Tie2 system participate in the vascular maintenance and remodeling of the CC during aging. PMID- 20969814 TI - Biofilm formation in bacterial pathogens of veterinary importance. AB - Bacterial biofilms are structured communities of bacterial cells enclosed in a self-produced polymer matrix that is attached to a surface. Biofilms protect and allow bacteria to survive and thrive in hostile environments. Bacteria within biofilms can withstand host immune responses, and are much less susceptible to antibiotics and disinfectants when compared with their planktonic counterparts. The ability to form biofilms is now considered a universal attribute of micro organisms. Diseases associated with biofilms require novel methods for their prevention, diagnosis and treatment; this is largely due to the properties of biofilms. Surprisingly, biofilm formation by bacterial pathogens of veterinary importance has received relatively little attention. Here, we review the current knowledge of bacterial biofilms as well as studies performed on animal pathogens. PMID- 20969815 TI - Estimation of salt intake by 24 h urinary sodium excretion in a representative sample of Spanish adults. AB - The present study reports the Na intake of a representative sample of Spanish young and middle-aged adults aged 18-60 years (n 418, 53.1 % women, selected from the capitals of fifteen provinces and the surrounding semi-urban/rural area), measured with a 24 h urinary Na excretion method. To validate the paper collection of 24 h urine, the correlation between fat-free mass determined by electrical bioimpedance (50.8 (sd 11.3) kg) and that determined via urinary creatinine excretion (51.5 (sd 18.8) kg) was calculated (r 0.633, P < 0.001). Urinary Na excretion correlated with systolic and dyastolic blood pressure data (r 0.243 and 0.153, respectively). Assuming that all urinary Na (168.0 (sd 78.6) mmol/d) comes from the diet, Na excretion would correspond with a dietary salt intake of 9.8 (sd 4.6) g/d, and it would mean that 88.2 % of the subjects had salt intakes above the recommended 5 g/d. Logistic regression analysis, adjusted for sex, age and BMI, showed male sex (OR 3.678, 95 % CI 2.336, 5.791) and increasing BMI (OR 1.069, 95 % CI 1.009, 1.132) (P < 0.001) to be associated with excreting >200 mmol/d urinary Na--a consequence of the higher salt intake in men and in participants with higher BMI. The present results help us to know the baseline salt intake in the Spanish young and middle-aged adult population, and can be used as the baseline to design policies to reduce salt consumption. PMID- 20969816 TI - Expression of extracellular matrix metalloproteinase inducer in nasal polyps. AB - BACKGROUND: Extracellular matrix metalloproteinase inducer (EMMPRIN) is a transmembrane glycoprotein that belongs to the immunoglobulin superfamily. The presence of EMMPRIN in nontumoral tissues suggests a role in other physiological and pathological situations, which may be associated with increased matrix metalloproteinase expression. The purpose of this study was to investigate the expression of EMMPRIN mRNA (OMIM *606080) and to localize the EMMPRIN protein in nasal polyps and healthy nasal mucosa. METHODS: The expression of EMMPRIN was investigated in the nasal polyps of 10 patients undergoing endonasal sinus surgery and compared with nasal mucosal samples obtained from 10 healthy controls. EMMPRIN mRNA was extracted from the tissues, and then a reverse transcription-polymerase chain reaction was performed. Western blot analysis was used to analyze differences in the levels of expression of EMMPRIN protein between patients with nasal polyps and healthy controls, and the EMMPRIN protein was localized in immunohistochemical staining and quantitative analysis of immunopositivity. RESULTS: The levels of expression of EMMPRIN mRNA and protein were significantly increased in patients with nasal polyps compared with healthy controls. EMMPRIN protein was expressed in the epithelium and infiltrating inflammatory cells of nasal polyps and the healthy nasal mucosa. The percentages of the immune-stained area and the number of EMMPRIN-immunopositive inflammatory cells per millimeter were significantly elevated in nasal polyps compared with controls. CONCLUSION: EMMPRIN is expressed in nasal mucosa and in nasal polyps, and the level of EMMPRIN expression is increased in nasal polyps. These results suggest that the increased expression of EMMPRIN may play a role in the pathogenesis of nasal polyps. PMID- 20969828 TI - Geomapping generalized eigenvalue frequency distributions for predicting prolific Aedes albopictus and Culex quinquefasciatus habitats based on spatiotemporal field-sampled count data. AB - Marked spatiotemporal variabilities in mosquito infection of arboviruses require adaptive strategies for determining optimal field-sampling timeframes, pool screening, and data analyses. In particular, the error distribution and aggregation patterns of adult arboviral mosquitoes can vary significantly by species, which can statistically bias analyses of spatiotemporal-sampled predictor variables generating misinterpretation of prolific habitat surveillance locations. Currently, there is a lack of reliable and consistent measures of risk exposure based on field-sampled georeferenced explanatory covariates which can compromise quantitative predictions generated from arboviral mosquito surveillance models for implementing larval control strategies targeting productive habitats. In this research we used spatial statistics and QuickBird visible and near-infra-red data for determining trapping sites that were related to Culex quinquefasciatus and Aedes albopictus species abundance and distribution in Birmingham, Alabama. Initially, a Land Use Land Cover (LULC) model was constructed from multiple spatiotemporal-sampled georeferenced predictors and the QuickBird data. A Poisson regression model with a non-homogenous, gamma distributed mean then decomposed the data into positive and negative spatial filter eigenvectors. An autoregressive process in the error term then was used to derive the sample distribution of the Moran's I statistic for determining latent autocorrelation components in the model. Spatial filter algorithms established means, variances, distributional functions, and pairwise correlations for the predictor variables. In doing so, the eigenfunction spatial filter quantified the residual autocorrelation error in the mean response term of the model as a linear combination of various distinct Cx. quinquefasciatus and Ae. albopictus habitat map patterns. The analyses revealed 18-27% redundant information in the data. Prolific habitats of Cx. quinquefasciatus and Ae. albopictus can be accurately spatially targeted based on georeferenced field-sampled count data using QuickBird data, LULC explanatory covariates, robust negative binomial regression estimates and space-time eigenfunctions. PMID- 20969829 TI - Biacore analysis with stabilized G-protein-coupled receptors. AB - Using stabilized forms of beta1 adrenergic and A2(A) adenosine G-protein-coupled receptors, we applied Biacore to monitor receptor activity and characterize binding constants of small-molecule antagonists spanning more than 20,000-fold in affinity. We also illustrate an improved method for tethering His-tagged receptors on NTA (carboxymethylated dextran preimmobilized with nitrilotriacetic acid) chips to yield stable, high-capacity, high-activity surfaces as well as a novel approach to regenerate receptor binding sites. Based on our success with this approach, we expect that the combination of stabilized receptors with biosensor technology will become a common method for characterizing members of this receptor family. PMID- 20969830 TI - Functional reconstitution of influenza A M2(22-62). AB - Amantadine-sensitive proton uptake by liposomes is currently the preferred method of demonstrating M2 functionality after reconstitution, to validate structural determination with techniques such as solid-state NMR. With strong driving forces (two decades each of both [K(+)] gradient-induced membrane potential and [H(+)] gradient), M2(22-62) showed a transport rate of 78 H(+)/tetramer-s (pH(o) 6.0, pH(i) 8.0, nominal V(m)=-114 mV), higher than previously measured for similar, shorter, and full-length constructs. Amantadine sensitivity of the conductance domain at pH 6.8 was also comparable to other published reports. Proton flux rate was optimal at protein densities of 0.05-1.0% (peptide wt.% in lipid). Rundown of total proton uptake after addition of valinomycin and CCCP, as detected by delayed addition of valinomycin, indicated M2-induced K(+) flux of 0.1K(+)/tetramer-s, and also demonstrated that the K(+) permeability, relative to H(+), was 2.8 * 10(-6). Transport rate, amantadine and cyclooctylamine sensitivity, acid activation, and H(+) selectivity were all consistent with full functionality of the reconstituted conductance domain. Decreased external pH increased proton uptake with an apparent pK(a) of 6. PMID- 20969831 TI - Salmon cartilage proteoglycan suppresses mouse experimental colitis through induction of Foxp3+ regulatory T cells. AB - Proteoglycans (PGs) are complex glycohydrates which are widely distributed in extracellular matrix (ECM). PGs are involved in the construction of ECM, cell proliferation and differentiation. ECM components are involved in transduction of proinflammatory responses, but it is still unknown whether PGs are involved in inflammatory response. In this study, we investigated the effect of PG extracted from salmon cartilage on the progression of experimental colitis-induced in severe combined immunodeficiency mice by cell transfer from interleukin-10 (IL 10)-/- mice. IL-10-/- cell-transferred mice showed weight loss, colon shortening and histological appearance of mild colitis. Daily oral administration of PG attenuated the clinical progression of colitis in a dose-dependent manner. Colitis-induced mice showed the elevated expression of IFN-gamma, IL-12, TNF alpha, IL-21, IL-23p19, IL-6, IL-17A and retinoic acid-related orphan receptor gammat (RORgammat) in lamina propria mononuclear cells (LPMCs) and oral administration of PG suppressed the expression of these factors. Conversely, expression of Foxp3 that induces CD4+CD25+ regulatory T cells in LPMCs was enhanced by PG administration. These findings suggested that salmon PG attenuated the progression of colitis due to suppression of inflammatory response by enhancement of regulatory T cell induction. PMID- 20969832 TI - Interruption of beta-catenin suppresses the EGFR pathway by blocking multiple oncogenic targets in human glioma cells. AB - Malignant gliomas are the most common type of intrinsic central nervous system (CNS) tumors with high mortality and morbidity. beta-catenin is overexpressed in human glioblastoma and knockdown of beta-catenin inhibits glioblastoma cell proliferation and invasive ability, and induces apoptotic cell death. Furthermore, treating the nude mice carrying established subcutaneous LN229 gliomas with siRNA targeting beta-catenin intratumorally also delayed the tumor growth. However, the mechanisms of down-regulation of beta-catenin that represses glioblastoma malignancy behavior remain to be elucidated. We utilized text-mining of MEDLINE abstracts with natural language processing to establish the beta catenin biologic association network, and identified several interactions of this network with the EGFR pathway. In both in vitro and in vivo studies, our results confirmed down-regulation of beta-catenin induced reduced expression of EGFR, STAT3 and AKT1 mRNA and protein, besides, the level of phosphorylated Akt also decreased. A similar reduction in expression of CyclinD1, MMP2 and MMP9, downstream genes of the EGFR pathway, was observed. These results suggest that the Wnt/beta-catenin pathway regulates glioma cell proliferation and invasion, in part via the EGFR pathway. PMID- 20969833 TI - Responsiveness of the human auditory cortex to degraded speech sounds: reduction of amplitude resolution vs. additive noise. AB - The cortical mechanisms underlying human speech perception in acoustically adverse conditions remain largely unknown. Besides distortions from external sources, degradation of the acoustic structure of the sound itself poses further demands on perceptual mechanisms. We conducted a magnetoencephalography (MEG) study to reveal whether the perceptual differences between these distortions are reflected in cortically generated auditory evoked fields (AEFs). To mimic the degradation of the internal structure of sound and external distortion, we degraded speech sounds by reducing the amplitude resolution of the signal waveform and by using additive noise, respectively. Since both distortion types increase the relative strength of high frequencies in the signal spectrum, we also used versions of the stimuli which were low-pass filtered to match the tilted spectral envelope of the undistorted speech sound. This enabled us to examine whether the changes in the overall spectral shape of the stimuli affect the AEFs. We found that the auditory N1m response was substantially enhanced as the amplitude resolution was reduced. In contrast, the N1m was insensitive to distorted speech with additive noise. Changing the spectral envelope had no effect on the N1m. We propose that the observed amplitude enhancements are due to an increase in noisy spectral harmonics produced by the reduction of the amplitude resolution, which activates the periodicity-sensitive neuronal populations participating in pitch extraction processes. The current findings suggest that the auditory cortex processes speech sounds in a differential manner when the internal structure of sound is degraded compared with the speech distorted by external noise. PMID- 20969834 TI - Visual stimuli evoke rapid activation (120 ms) of sensorimotor cortex for overt but not for covert movements. AB - Overt and covert movements (e.g., motor imagery) have been frequently demonstrated to engage common neuronal substrates in the motor system. However, it is an open question whether this similarity is also present during early stages of stimulus-processing. We utilized the high temporal resolution of multi channel electroencephalography (EEG) in order to test whether the prior action intention (overt vs. covert movements) differentially modulates early stimulus processing stages in the cortical sensorimotor system. The subjects performed overt or covert movements contingent upon an instructive visual stimulus (indicating left or right hand performance). We introduced a novel measure, LRPrect, calculated as Lateralized Readiness Potentials from rectified EEG signals. This measure overcomes a problem related to the EEG signal variability due to polarity differences in the spatial distribution of neuronal sources. The LRPrect showed an activation already at 120 ms after stimulus onset (latN120) focally over sensorimotor cortices contralateral to the upcoming hand movement, yet only for overt but not covert movements. Thus the prior action intention differentially routes early stimulus-processing into the sensorimotor system, which might contribute to significantly different behavioral outcomes, i.e., movement generation or inhibition. The present results have implications for studies of motor inhibition and action intention. PMID- 20969835 TI - Autism in adults. New biologicial findings and their translational implications to the cost of clinical services. AB - There is increasing evidence that children with autism spectrum disorder (ASD) have differences in brain growth trajectory. However, the neurobiological basis of ASD in adults is poorly understood. We report evidence that brain anatomy and aging in people with ASD is significantly different as compared to controls-so that in adulthood they no longer have a significantly larger overall brain volume, but they do have anatomical and functional abnormalities in frontal lobe, basal ganglia and the limbic system. Further we present preliminary evidence that females have significantly greater abnormalities in brain than males to express the same symptom severity of ASD (i.e. the female brain is "protective" against developing ASD). Also we present preliminary evidence that, in adults, clinical services for autism in the United Kingdom are experiencing very significantly increased demand; but that just over 50% of people seeking a diagnosis from one expert service do not have ASD. This consumes very significant health care resources, and so we need to identify new cost-effective methods to aid current diagnostic practice. We present initial evidence offering proof of concept that brain anatomy can be used to accurately distinguish adults with autism from healthy controls, and from some other neurodevelopmental disorders (ADHD). Hence further studies are required to determine if sMRI can become an aid to current diagnostic practice in young adults with ASD. Lastly we report evidence that differences in serotonin, glutamate and GABA may partially explain neuroanatomical and neurofunctional abnormalities in people with ASD, and that genetic influences on brain maturation vary across the lifespan (with 5-HT transporter polymorphisms having significant modulatory effects in children but not adults). PMID- 20969836 TI - Role of neural afferents as mediators of estrogen effects on the hypothalamic ventromedial nucleus. AB - The effects of estrogens on the ventrolateral division of the hypothalamic ventromedial nucleus (VMNvl) are essential for its role in the regulation of female sexual behavior. Enhanced synaptogenesis and induction of progesterone receptors (PRs) are hallmarks of the actions of estrogens on the VMNvl. To investigate the influence of neural afferents in mediating these effects, we estimated the number of spine and dendritic synapses per neuron and the total number of PR-immunoreactive neurons in ovariectomized rats treated with either estradiol benzoate or vehicle, after unilateral VMN deafferentation. The estimates were performed independently in the VMNvl of the deafferented and contralateral sides, and in the VMNvl of unoperated rats (controls). The administration of estradiol benzoate did not induce any increase in the number of synapses of the deafferented VMNvl. In the contralateral VMNvl, the synaptogenic effects of estrogen were apparent, but still reduced relative to the control VMNvl, where a 25% increase in the total number of synapses was observed after estrogenic stimulation. In the absence of estrogenic stimulation, i.e., in basal conditions, deafferentation reduced the number of dendritic and spine synapses, but particularly the latter. The reduction was also visible, but less marked, in the contralateral VMNvl. Contrary to synapses, the estrogen induction of PRs was unaffected by deafferentation, and the total number of PR-immunoreactive neurons was similar in the control, deafferented and contralateral VMNvl. The results show that estrogens enhance synaptogenesis in the VMNvl by acting through neural afferents and induce PR expression by acting directly upon VMN neurons. PMID- 20969838 TI - Olfactory bulbectomy impairs the feeding response to 2-deoxy-D-glucose in rats. AB - An early study reported that, unlike sham-operated rats, rats made anosmic by olfactory bulbectomy (OBX) failed to compensate for the dilution of their diet with nonnutritive bulk by increasing their food intake. In the present study, the effects of a glucoprivic challenge, intraperitoneal-administered 350 mg/kg 2 deoxy-D-glucose (2-DG), on food intake were measured in OBX and sham-operated female rats. Sham-operated rats significantly increased their food intake, but in two separate experiments OBX rats displayed no increase in food intake during the first 2 h following administration. Blood glucose levels were nearly identical in both groups. Body weights and daily food intakes of OBX rats did not differ from the sham-operated controls throughout the studies. Bulbectomized rats also displayed a normal drinking response after an intraperitoneal injection of 1M hypertonic saline. Hypothalamic nuclei and the neural pathways mediating taste have been implicated in the feeding response to 2-DG. The present results suggest that olfactory input and olfactory neural pathways also mediate, at least in part, the feeding response to a glucoprivic challenge induced by intraperitoneal injection of 2-DG. PMID- 20969839 TI - Visual mental imagery: what the head's eye tells the mind's eye. AB - The demonstration of an implication of attentional/eye gaze systems in visual mental imagery might help to understand why some patients with visual neglect, who suffer from severe attentional deficits, also show neglect for mental images. When normal participants generate mental images of previously explored visual scenes, their oculomotor behavior resembles that used during visual exploration. However, this could be a case of encoding specificity, whereby the probability of retrieving an event increases if some information encoded with the event (in this case its spatial location) is present at retrieval. In the present study, normal participants were invited to conjure up a mental image of the map of France and to say whether auditorily presented towns or regions were situated left or right of Paris. A perceptual version of the task was administered after the imaginal condition. Thus, in the imaginal condition participants had to retrieve information from long-term memory. Vocal response times and, unbeknownst to participants, also eye movements were recorded. Participants tended to produce similar eye movements on the imaginal and on the perceptual conditions of the task. We concluded that some mechanisms involved in spontaneous oculomotor behavior may be shared in exploration of visuospatial mental images. Deficits of these common processes participating in the oculomotor exploration might contribute to imaginal neglect. PMID- 20969837 TI - Effects of maternal separation, early handling, and gonadal sex on regional metabolic capacity of the preweanling rat brain. AB - This is the first study to assess the effects of mother-infant separation on regional metabolic capacity in the preweanling rat brain. Mother-infant separation is generally known to be stressful for rat pups. Holtzman adolescent rats show a depressive-like behavioral phenotype after maternal separation during the preweanling period. However, information is lacking on the effects of maternal separation on the brains of rat pups. We addressed this issue by mapping the brains of preweanling Holtzman rat pups using cytochrome oxidase histochemistry, which reflects long-term changes in brain metabolic capacity, following two weeks of repeated, prolonged maternal separation, and compared this to both early handled and non-handled pups. Quantitative image analysis revealed that maternal separation reduced cytochrome oxidase activity in the medial prefrontal cortex and nucleus accumbens shell. Maternal separation reduced prefrontal cytochrome oxidase to a greater degree in female pups than in males. Early handling reduced cytochrome oxidase activity in the posterior parietal cortex, ventral tegmental area, and subiculum, but increased cytochrome oxidase activity in the lateral frontal cortex. The sex-dependent effects of early handling on cytochrome oxidase activity were limited to the medial prefrontal cortex. Regardless of separation group, females had greater cytochrome oxidase activity in the habenula and ventral tegmental area compared to males. These findings suggest that early life mother-infant separation results in dysfunction of prefrontal and mesolimbic regions in the preweanling rat brain that may contribute to behavioral changes later in life. PMID- 20969840 TI - Modulation of N-cadherin junctions and their role as epicenters of differentiation-specific actin regulation in the developing lens. AB - Extensive elongation of lens fiber cells is a central feature of lens morphogenesis. Our study investigates the role of N-cadherin junctions in this process in vivo. We investigate both the molecular players involved in N-cadherin junctional maturation and the subsequent function of these junctions as epicenters for the assembly of an actin cytoskeleton that drives morphogenesis. We present the first evidence of nascent cadherin junctions in vivo, and show that they are a prominent feature along lateral interfaces of undifferentiated lens epithelial cells. Maturation of these N-cadherin junctions, required for lens cell differentiation, preceded organization of a cortical actin cytoskeleton along the cells' lateral borders, but was linked to recruitment of alpha-catenin and dephosphorylation of N-cadherin-linked beta-catenin. Biochemical analysis revealed differentiation-specific recruitment of actin regulators cortactin and Arp3 to maturing N-cadherin junctions of differentiating cells, linking N cadherin junctional maturation with actin cytoskeletal assembly during fiber cell elongation. Blocking formation of mature N-cadherin junctions led to reduced association of alpha-catenin with N-cadherin, prevented organization of actin along lateral borders of differentiating lens fiber cells and blocked their elongation. These studies provide a molecular link between N-cadherin junctions and the organization of an actin cytoskeleton that governs lens fiber cell morphogenesis in vivo. PMID- 20969841 TI - Primordial germ cell proliferation is impaired in Fused Toes mutant embryos. AB - Over the first 4 days of their life, primordial germ cells invade the endoderm, migrate into and through the developing hindgut, and traverse to the genital ridge where they cluster and ultimately inhabit the nascent gonad. Specific signal-receptor combinations between primordial germ cells and their immediate environment establish successful migration and colonization. Here we demonstrate that disruption of a cluster of six genes on murine chromosome 8, as exemplified by the Fused Toes (Ft) mutant mouse model, results in severely decreased numbers of primordial germ cells within the early gonad. Primordial germ cell migration appeared normal within Ft mutant embryos; however, germ cell counts progressively decreased during this time. Although no difference in apoptosis was detected, we report a critical decrease in primordial germ cell proliferation by E12.5. The six genes within the Ft locus include the IrxB cluster (Irx3, -5, -6), Fts, Ftm, and Fto, of which only Ftm, Fto, and Fts are expressed in primordial germ cells of the early gonad. From these studies, we have discovered that the Ft locus on mouse chromosome 8 is associated with cell cycle deficits within the primordial germ cell population that initiates just before translocation into the genital ridge. PMID- 20969842 TI - Defects and rescue of the minor salivary glands in Eda pathway mutants. AB - Despite their importance to oral health, the mechanisms of minor salivary gland (SG) development are largely unexplored. Here we present in vivo and in vitro analyses of developing minor SGs in wild type and mutant mice. Eda, Shh and Fgf signalling pathway genes are expressed in these glands from an early stage of development. Developing minor SGs are absent in Eda pathway mutant embryos, and these mice exhibit a dysplastic circumvallate papilla with disrupted Shh expression. Supplementation of Eda pathway mutant minor SG explants with recombinant EDA rescues minor SG induction. Supplementation with Fgf8 or Shh, previously reported targets of Eda signalling, leads to induction of gland like structures in a few cases, but these fail to develop into minor SGs. PMID- 20969843 TI - Retinoic acid-dependent establishment of positional information in the hindbrain was conserved during vertebrate evolution. AB - Zebrafish hoxb1b is expressed during epiboly in the posterior neural plate, with its anterior boundary at the prospective r4 region providing a positional cue for hindbrain formation. A similar function and expression is known for Hoxa1 in mice, suggesting a shared regulatory mechanism for hindbrain patterning in vertebrate embryos. To understand the evolution of the regulatory mechanisms of key genes in patterning of the central nervous system, we examined how hoxb1b transcription is regulated in zebrafish embryos and compared the regulatory mechanisms between mammals and teleosts that have undergone an additional genome duplication. By promoter analysis, we found that the expression of the reporter gene recapitulated hoxb1b expression when driven in transgenic embryos by a combination of the upstream 8.0-kb DNA and downstream 4.6-kb DNA. Furthermore, reporter expression expanded anteriorly when transgenic embryos were exposed to retinoic acid (RA) or LiCl, or injected with fgf3/8 mRNA, implicating the flanking DNA examined here in the responsiveness of hoxb1b to posteriorizing signals. We further identified at least two functional RA responsive elements in the downstream DNA that were shown to be major regulators of early hoxb1b expression during gastrulation, while the upstream DNA, which harbors repetitive sequences with apparent similarity to the autoregulatory sequence of mouse Hoxb1, contributed only to later hoxb1b expression, during somitogenesis. Possible implications in vertebrate evolution are discussed based on these findings. PMID- 20969845 TI - Ptch1-mediated dosage-dependent action of Shh signaling regulates neural progenitor development at late gestational stages. AB - Sonic hedgehog (Shh) signaling regulates cell differentiation and proliferation during brain development. However, the role of Shh in neurogenesis during late gestation (embryonic day 13.5-18.5) remains unclear. Herein, we used a genetic approach and in utero electroporation to investigate the role of mouse Shh and patched homolog 1 (Ptch1), the putative receptor for Shh. Proliferating cortical intermediate (basal) progenitor cells (IPCs) were severely reduced in Shh mutant mice, suggesting that endogenous Shh signaling could play an essential role in cortical IPC development. During cortical neurogenesis, strong upregulation of Shh signaling enhanced the transition from ventricular zone (VZ) progenitors to ventralized IPCs, while low levels of signaling enhanced the generation and proliferation of cortical IPCs in the subventricular zone. The effects of Shh upregulation in this study were consistent with a phenotype of conditional loss of function of Ptch1, and the phenotype of a hypomorphic allele of Ptch1, respectively. These data indicated that endogenous Ptch1 mediates the broad effects of Shh on the transition from VZ progenitors to IPCs and activation of proliferation of the IPCs in the cortex during late gestational stages. PMID- 20969844 TI - Neuronal transcriptional repressor REST suppresses an Atoh7-independent program for initiating retinal ganglion cell development. AB - As neuronal progenitors differentiate into neurons, they acquire a unique set of transcription factors. The transcriptional repressor REST prevents progenitors from undergoing differentiation. Notably, REST binding sites are often associated with retinal ganglion cell (RGC) genes whose expression in the retina is positively controlled by Atoh7, a factor essential for RGC formation. The key regulators that enable a retinal progenitor cell (RPC) to commit to an RGC fate have not been identified. We show here that REST suppresses RGC gene expression in RPCs. REST inactivation causes aberrant expression of RGC transcription factors in proliferating RPCs, independent of Atoh7, resulting in increased RGC formation. Strikingly, inactivating REST in Atoh7-null retinas restores transcription factor expression, which partially activates downstream RGC genes but is insufficient to prevent RGC loss. Our results demonstrate an Atoh7 independent program for initial activation of RGC genes and suggest a novel role for REST in preventing premature expression in RPCs. PMID- 20969846 TI - Prolyl hydroxylation- and glycosylation-dependent functions of Skp1 in O2 regulated development of Dictyostelium. AB - O(2) regulates multicellular development of the social amoeba Dictyostelium, suggesting it may serve as an important cue in its native soil environment. Dictyostelium expresses an HIFalpha-type prolyl 4-hydroxylase (P4H1) whose levels affect the O(2)-threshold for culmination implicating it as a direct O(2)-sensor, as in animals. But Dictyostelium lacks HIFalpha, a mediator of animal prolyl 4 hydroxylase signaling, and P4H1 can hydroxylate Pro143 of Skp1, a subunit of E3(SCF)ubiquitin-ligases. Skp1 hydroxyproline then becomes the target of five sequential glycosyltransferase reactions that modulate the O(2)-signal. Here we show that genetically induced changes in Skp1 levels also affect the O(2) threshold, in opposite direction to that of the modification enzymes suggesting that the latter reduce Skp1 activity. Consistent with this, overexpressed Skp1 is poorly hydroxylated and Skp1 is the only P4H1 substrate detectable in extracts. Effects of Pro143 mutations, and of combinations of Skp1 and enzyme level perturbations, are consistent with pathway modulation of Skp1 activity. However, some effects were not mirrored by changes in modification of the bulk Skp1 pool, implicating a Skp1 subpopulation and possibly additional unknown factors. Altered Skp1 levels also affected other developmental transitions in a modification dependent fashion. Whereas hydroxylation of animal HIFalpha results in its polyubiquitination and proteasomal degradation, Dictyostelium Skp1 levels were little affected by its modification status. These data indicate that Skp1 and possibly E3(SCF)ubiquitin-ligase activity modulate O(2)-dependent culmination and other developmental processes, and at least partially mediate the action of the hydroxylation/glycosylation pathway in O(2)-sensing. PMID- 20969847 TI - TEMPOL protects human neuroblastoma SH-SY5Y cells against beta-amyloid-induced cell toxicity. AB - Amyloid-beta peptide (Abeta) has been implicated in the pathogenesis of Alzheimer's disease (AD). It can cause cell death in Alzheimer's disease by evoking a cascade of oxidative damage to neurons. Antioxidant compounds may help to elucidate and develop a treatment for Alzheimer's disease. In the present study, we investigated the protective effect of TEMPOL (4-hydroxy-2,2,6,6 tetramethyl-1-piperidinyloxy), a cyclic nitroxide which is particularly effective at reducing oxidative injury, on Abeta(1-42)-induced SH-SY5Y cell toxicity. Exposure of cells to 20 MUM Abeta(1-42) for 48 h caused viability loss and apoptotic increase, and pre-treatment with TEMPOL for 24 h significantly reduced the viability loss and apoptotic rate. In addition, TEMPOL inhibited Abeta(1-42) induced superoxide anion generation and hydroxyl radical generation to a striking degree. Based on these results, it is concluded that TEMPOL effectively protects SH-SY5Y cells against beta-amyloid-induced damage by suppressing the generation of reactive oxygen species especially, superoxide anion. PMID- 20969848 TI - Evidence for the complementary and synergistic effects of the three-alkaloid combination regimen containing berberine, hypaconitine and skimmianine on the ulcerative colitis rats induced by trinitrobenzene-sulfonic acid. AB - Ulcerative colitis involves complicated etiology and presents diverse symptoms including intestine inflammation, bowel pain and diarrhea. Anti-inflammatory drugs are the mainstay in patient care, accompanied with antidiarrhea and analgesic agents used as symptomatic treatment. A classic traditional Chinese medicine formula, Fructus Mume pill (FMP), showed remarkable therapeutic efficacy in treating ulcerative colitis. However, since it contains many herbs and countless chemicals, the underlying mechanism is not clear. In this study, we selected three alkaloids from FMP, namely, berberine, hypaconitine and skimmianine to study the individual drug effect and compare these results with the BHS combination on: 1) The recovery of ulcerative colitis rats induced by trinitrobenzene-sulfonic acid. 2) Mice with xylene-induced acute exudative edema and acetic acid-induced writhing. 3) Gastrointestinal transit inhibition, and 4) the response of HT29 cells after treatment with lipopolysaccharide. We found that the compound hypaconitine showed a potent analgesic effect, while skimmianine acted as an antidiarrhea agent and the component berberine was the key agent exerting anti-inflammatory effect. However, since berberine killed the commensal bacteria and induced lipopolysaccharide release, it could at the same time aggravate colon inflammation. The three-alkaloid combination BHS produced complementary and synergistic effects in colon inflammation recovery, relieving acetic acid-induced bowel pain and xylene-induced acute exudative edema. BHS also decreased lipopolysaccharide production and enhanced the therapeutic efficacy. It is hoped that this study will lay the foundation to further dissect and understand the FMP formula to improve the treatment with simplified and well defined drug combinations for this dreadful disease. PMID- 20969849 TI - Differential effects of chronic naltrexone treatment on food intake patterns and body weight in rats depend on their food deprivation status. AB - The aim of the present study was to assess the effect of chronic naltrexone treatment on daily patterns of food intake in food-deprived and free-feeding rats. In experiment 1, Wistar male rats had continuous access to food and water, while in experiment 2 they were deprived of food for 12h/day. Animals in both experiments were studied as follows: a baseline period (7days), followed by a treatment period (14days) with either saline or naltrexone at 10mg/kg/day. Finally, a post-treatment period (7days) was assessed. Food and water consumption were measured every 2h after the naltrexone or saline injection for 12h and once more 12h later. Experiment 1: Food intake was higher in the naltrexone group 10h after injection. Total food intake and body weight gain were higher in the naltrexone group than in the saline group in the second week of treatment and in the post-treatment period. Experiment 2: The overeating observed in the saline group in the hours following the 12h of the food deprivation period was suppressed by naltrexone, though total daily food intake was not affected. Body weight gain was initially reduced by naltrexone, but a rebound effect was observed during the post-treatment period in the naltrexone group. Naltrexone produced a differential effect on food intake and body weight that depended on the rats' food deprivation status. These results could be explained in terms of opioid receptor up-regulation that enhances the rewarding effects of food or by naltrexone-produced changes in palatability. PMID- 20969850 TI - Tempol attenuates cocaine-induced death of PC12 cells through decreased oxidative damage. AB - The association between cocaine administration and induction of oxidative stress in different brain regions suggests that oxidative damage is an important factor participating in cocaine disruption of normal central nervous system functions. In order to deal with this topic, brain penetrating exogenous antioxidants were suggested as a tool to prevent cocaine-induced oxidative damage and behavioral changes. Lately, we have shown that Tempol, a stable nitroxide radical reduced oxidative damage and attenuated the development and expression of cocaine psychomotor sensitization. To examine whether nitroxides, represented by Tempol, can exhibit protective effects against cocaine-induced cell death and to elucidate the molecular mechanism of cocaine-induced oxidative damage, we used the well established PC12 cell line model. The results showed that (1) cocaine induced cell death in a dose-dependent manner (2) and that it was reduced significantly by the stable nitroxide radical Tempol. Furthermore, (3) Tempol significantly inhibited oxidative damage induced by cocaine as reflected by mitochondrial superoxide radical and peroxide enhancement. Finally, (4) Tempol restored the total scavenging capacity which was reduced by cocaine in PC12 cells. Cumulatively, these results suggest that nitroxides such as Tempol can attenuate oxidative damage and cell death induced by cocaine and that PC12 cells can be used as an in vitro model to further investigate the precise molecular mechanism of these compounds. PMID- 20969851 TI - Clozapine and N-methyl-D-aspartate have positive modulatory actions on their respective discriminative stimulus properties in C57BL/6 mice. AB - The impairment of N-Methyl-D-Aspartate receptors is thought to contribute to negative symptoms and cognitive deficits. In vitro studies suggest that atypical antipsychotic drugs like clozapine may help to alleviate these deficits by enhancing glutamatergic function. The present study examined the in vivo interaction of clozapine with N-Methyl D-aspartate by training one group of C57BL/6 mice to discrimination 2.5 mg/kg clozapine from vehicle and another group to discriminate 30 mg/kg N-Methyl D-aspartate from vehicle in a two-lever drug discrimination task. Cross-generalization testing revealed that N-Methyl D aspartate (3-56 mg/kg) failed to substitute for clozapine in the clozapine trained mice, while clozapine (0.625 mg/kg) produced partial substitution in the N-Methyl D-aspartate-trained mice. Interestingly, administration of a low, non generalizing dose of each training drug in combination with the full range of doses of the alternate training drug produced full and dose-dependent substitution in both clozapine- and N-Methyl D-aspartate-trained mice. The alpha(1) antagonist prazosin fully and dose-dependently substituted for both clozapine and N-Methyl D-aspartate. These results suggest that the shared discriminative stimulus properties between clozapine and N-Methyl D-aspartate may be mediated through indirect mechanisms, possibly in part through alpha(1) adrenergic antagonism. PMID- 20969852 TI - Prostaglandin E(2) receptor EP(4)-selective agonist (ONO-4819) increases bone formation by modulating mesenchymal cell differentiation. AB - Prostaglandin E(2) (PGE(2)) positively regulates bone resorption and formation mainly mediated through the EP(4) receptor, a subtype of PGE(2) receptors. ONO 4819, an EP(4) receptor-selective agonist, has been shown to increase bone volume, density, and strength; however, the mechanism of these effects has yet to be fully elucidated. To explore this matter, ONO-4819 (10MUg/kg) was injected into intact rats twice a day for 5weeks, and their bones were then analyzed by morphological techniques. The effects of ONO-4819 on the differentiation of bone cells were also examined in vitro. Bone morphometric analysis showed that osteoblast number, bone volume, mineral apposition rate, and bone formation rate were significantly increased by ONO-4819, whereas osteoclast number was not affected. Immunohistochemical examination demonstrated that ONO-4819 increased the number of Runx2- and Osterix-positive osteoblasts in rats. In vitro studies using the multipotent mesenchymal cell line C3H10T1/2 showed that ONO-4819 induced alkaline phosphatase (ALPase) activity and up-regulated the mRNA expression of ALPase and Osterix. In contrast, ONO-4819 reduced the mRNA expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and inhibited adipocyte differentiation of C3H10T1/2 cells, which findings are consistent with the observation that the age-dependent increase in adipocyte number in the bone marrow was significantly suppressed in the ONO-4819-treated animals. ONO-4819 also dose-dependently increased osteoclast-like cell formation in vitro, but the required concentrations were much higher than those to induce osteoblast differentiation. These results collectively suggest that ONO-4819 increased bone formation by stimulating osteoblast differentiation and function, possibly through modulating mesenchymal cell differentiation in the bone. PMID- 20969854 TI - Activation of alpha7 nicotinic acetylcholine receptors ameliorates indomethacin induced small intestinal ulceration in mice. AB - Cholinergic anti-inflammatory actions have been shown to result mainly from the activation of alpha7 nicotinic acetylcholine receptors. Here, we investigated the possible role of alpha7 nicotinic acetylcholine receptors in the pathogenesis of indomethacin-induced small intestinal ulceration in mice. Male C57BL/6 mice were given indomethacin (10mg/kg, s.c.), and sacrificed 24h later. Nicotine (0.3 3mg/kg) and PNU-282987 (a selective agonist of alpha7 nicotinic acetylcholine receptors; 1-10mg/kg) were administered i.p. twice, at 0.5h before and 8h after indomethacin treatment, while methyllycaconitine (a selective antagonist of alpha7 nicotinic acetylcholine receptors; 10mg/kg was administered twice, at 0.5h before each nicotine treatment. Indomethacin caused severe hemorrhagic lesions in the small intestine with marked increases in myeloperoxidase (MPO) activity and inducible nitric oxide synthase (iNOS) expression in the mucosa. Pretreatment with nicotine reduced the severity of intestinal lesions in a dose-dependent manner. The protective effect of nicotine was mimicked by PNU-282987 and significantly attenuated by methyllycaconitine. The increases in MPO activity and iNOS expression induced by indomethacin were also significantly suppressed by nicotine and PNU-282987. Immunohistochemical study showed that the expression of alpha7 nicotinic acetylcholine receptors was clearly enhanced in the submucosa of the damaged area following indomethacin treatment. These results suggest that the activation of alpha7 nicotinic acetylcholine receptors ameliorates indomethacin induced small intestinal ulceration, and that this effect may result from the inhibition of iNOS expression and neutrophil migration. PMID- 20969855 TI - 5-Hydroxytryptamine potentiates neurogenic contractions of rat isolated urinary bladder through both 5-HT(7) and 5-HT(2C) receptors. AB - Serotonin (5-HT) enhances the neurogenic contractile response induced by electrical field stimulation (EFS) in the rat isolated urinary bladder. The aim of this study was to functionally characterize the receptors involved in this effect by using a range of 5-HT receptor subtype selective agonists and antagonists. 5-HT produced a concentration-dependent potentiation of contractile responses to EFS with a pEC(50) value of 6.86+/-0.24. SB-269970 (0.01, 0.1 and 1MUM), a selective 5-HT(7) receptor antagonist, caused a concentration-dependent rightward shift of the 5-HT-induced response. The pA(2) value was 8.16 with a slope of 0.46+/-0.08. Neither ketanserine nor SB-204741, 5-HT(2A) and 5-HT(2B) receptors antagonists, respectively, affected the concentration-response curve to 5-HT. However, 5-HT response was antagonized by the selective 5-HT(2C) receptor antagonist SB-242084 (0.1 and 1MUM). In the presence of 1MUM of both antagonists SB-269970 and SB-242084, 5-HT response was almost fully inhibited. 5-CT, a 5 HT(7) receptor agonist, induced a biphasic concentration-dependent potentiation of neurogenic contractions. SB-269970 concentration-dependently antagonized the first phase of 5-CT response with a pA(2) value of 8.77 and a slope not significantly different from unity (0.91+/-0.11) that suggests a competitive antagonism. WAY-161503, a 5-HT(2C) receptor agonist (0.01-10MUM), induced a concentration-dependent potentiation of contractile response to EFS while DOI (a selective 5-HT(2A) agonist) had no effect. SB-242084 (0.1 and 1MUM) antagonized the effect of WAY-161503 in a concentration-dependent manner. The current results demonstrate that 5-HT potentiates neurogenic contractions of rat isolated detrusor muscle through both 5-HT(7) and 5-HT(2c) receptors. PMID- 20969853 TI - Melittin stimulates fatty acid release through non-phospholipase-mediated mechanisms and interacts with the dopamine transporter and other membrane spanning proteins. AB - Phospholipase A(2) releases the fatty acid arachidonic acid from membrane phospholipids. We used the purported phospholipase A(2) stimulator, melittin, to examine the effects of endogenous arachidonic acid signaling on dopamine transporter function and trafficking. In HEK-293 cells stably transfected with the dopamine transporter, melittin reduced uptake of [((3))H]dopamine. Additionally, measurements of fatty acid content demonstrated a melittin-induced release of membrane-incorporated arachidonic acid, but inhibitors of phospholipase C, phospholipase D, and phospholipase A(2) did not prevent the release. Subsequent experiments measuring [(125)I]RTI-55 binding to the dopamine transporter demonstrated a direct interaction of melittin, or a melittin activated endogenous compound, with the transporter to inhibit antagonist binding. This effect was not specific to the dopamine transporter, as [(3)H]spiperone binding to the recombinant dopamine D(2) receptor was also inhibited by melittin treatment. Finally, melittin stimulated an increase in internalization of the dopamine transporter, and this effect was blocked by pretreatment with cocaine. Thus, melittin acts through multiple mechanisms to regulate cellular activity, including release of membrane-incorporated fatty acids and interaction with the dopamine transporter. PMID- 20969856 TI - Therapeutic effects of SMND-309, a new metabolite of salvianolic acid B, on experimental liver fibrosis. AB - (2E)-2-{6-[(E)-2-carboxylvinyl]-2,3-dihydroxyphenyl}-3-(3,4-dihydroxyphenyl) propenoic acid, a novel compound designated SMND-309, is a new metabolite of salvianolic acid B. The present study was carried out to investigate the effects of SMND-309 on experimental liver fibrosis in rats induced by subcutaneous injection of carbon tetrachloride and explore its possible mechanisms on the basis of biochemical, histopathologic and immunohistochemical studies. The results showed that intragastrical treatment with SMND-309 ameliorated liver function and decreased the elevation of serum hyaluronic acid, laminin, procollagen type III levels and hydroxyproline content in liver tissue. It also decreased the elevation in the malondialdehyde level and restored the decrease in superoxide dismutase and glutathione peroxidase activities. Upon histopathologic examination, the SMND-309-treated rats reduced the liver damage and the liver fibrosis grade. Moreover, the results of immunohistochemical examination showed that SMND-309 powerfully down-regulated the expression of connective tissue growth factor (CTGF) rather than transforming growth factor-beta1 (TGF-beta1) in serum and liver. Meanwhile, SMND-309 exhibits significantly higher potency compared with salvianolic acid B (Sal B) at the same dose. The antifibrotic mechanisms of SMND-309 might be associated with its ability to suppress the expression of CTGF as well as scavenge lipid peroxidation products and increase endogenous antioxidant enzyme activity. PMID- 20969857 TI - Interaction of ethyl pyruvate in vitro with NF-kappaB subunits, RelA and p50. AB - Ethyl pyruvate, an aliphatic ester derived from pyruvate, reportedly has anti inflammatory actions through inhibition of the transcription mediated by nuclear factor-kappa B (NF-kappaB). It was suggested that ethyl pyruvate inhibited NF kappaB/DNA-binding activity through the covalent modification of RelA. However, the interaction of ethyl pyruvate with RelA in vitro has not been reported. In the present study, we confirmed that treatment of cultured alveolar epithelial cells, A549 cells, with tumor necrosis factor alpha (TNFalpha) increased the NF kappaB/DNA-binding activity. When the nuclear extract of the cells was incubated with ethyl pyruvate, the NF-kappaB/DNA-binding activity was strongly inhibited. Because we previously found that the NF-kappaB/DNA complex included RelA and p50, we bacterially expressed a deletion mutant of RelA, RelA (1-220), and a full length form of p50. Incubation of RelA (1-220) or p50 with ethyl pyruvate induced dramatic changes in mobility in two types of nondenaturing gel electrophoresis. Electrophoretic mobility shift assays revealed that incubation of RelA (1-220) or p50 with ethyl pyruvate inhibited the DNA-binding activity. Furthermore, immunostaining of A549 cells revealed that ethyl pyruvate inhibited the nuclear association of RelA after TNFalpha treatment. These results suggest that ethyl pyruvate interacts with RelA and p50 to inhibit their functions at multiple points. PMID- 20969858 TI - Neferine inhibits cultured hepatic stellate cell activation and facilitates apoptosis: A possible molecular mechanism. AB - Neferine is a major alkaloid component of "Lian Zi Xin", embryos of the seeds of Nelumbo nucifera Gaertner, Nymphaeaceae. Previous studies have shown that neferine has an inhibitory effect on pulmonary fibrosis through its anti inflammatory and anti-oxidative activities and inhibition of cytokines and NF kappaB. However, it is unknown whether neferine also has an inhibitory effect on liver fibrosis through inhibition of TGF-beta1 and collagen I and facilitation of apoptosis of hepatic stellate cells. This study examined the effects of neferine on cultured hepatic stellate (HSC-T6) cells and explored its possible action mechanisms by means of MTT assay, enzyme-linked immunosorbent assay, flow cytometric annexin V-PI assay and Hoechst 33258 staining, as well as real-time PCR and western blotting. The results showed that neferine administration (2, 4, 6, 8 and 10MUmol/l) significantly decreased the TGF-beta1 and collagen I produced in HSC-T6 cells, and increased the HSC-T6 cell apoptosis in a dose-dependent manner. Neferine treatment for 48h at concentrations of 6 and 10MUmol/l significantly increased Bax and caspase 3 mRNAs and proteins, and reduced Bcl2 and alpha-smooth muscle actin (alpha-SMA) mRNAs and proteins. Our data indicate that neferine efficiently inhibits cultured HSC-T6 cell activation and induces apoptosis by increasing Bax and caspase 3 expression via the mitochondrial pathway. PMID- 20969859 TI - Transcript profiling identifies novel key players mediating the growth inhibitory effect of NS-398 on human pancreatic cancer cells. AB - Pancreatic cancer is one of the most aggressive human malignancies with an increasing incidence worldwide. Despite an increase in the number of systemic treatments available for pancreatic cancer, the impact of therapy on the clinical course of the disease has been modest, underscoring an urgent need for new therapeutic options. Although selective cyclooxygenase-2 inhibitors have been demonstrated to have cancer-preventive effects, the mechanism of their effects is not clearly known. Moreover, there have been no unbiased studies to identify novel molecular targets of NS-398 regarding pancreatic cancer. Here we undertook a gene expression profiling study to identify novel molecular targets modulating the growth inhibitory effects of NS-398 on pancreatic cancer cell lines. Our mRNA based gene expression results showed that the growth inhibitory effect of NS-398 was accompanied with an activation of G1/S and G2/M cell cycle regulation, P53 signalling, apoptotic, aryl hydrocarbon receptor and death receptor signalling pathways. Moreover, we reported, for the first time, that the growth inhibitory effect of NS-398 is mediated by down-regulation of RRM2, CTGF, MCM2 and PCNA and up-regulation of NAG-1 in all cell lines. PMID- 20969860 TI - Plasmablastic lymphoma may occur as a high-grade transformation from plasmacytoma. AB - Plasmablastic lymphoma (PBL) is an uncommon aggressive lymphoma arising most frequently in the oral cavity of HIV-infected patients. Rare cases of PBL have been reported in extraoral sites, particularly extranodal sites, as well as in immunocompetent patients. We report an unusual case of PBL in a 69-year-old, HIV negative non-immunocompromised man presenting with generalized lymphadenopathy. To our knowledge, this is the first case of PBL presented as primarily generalized lymphadenopathy in HIV-negative patients. Histologic examinations of cervical, inguinal and axillary lymph nodes demonstrated a neoplastic proliferation of large cells with extensive necrosis. The neoplastic cells formed sheets with a relatively cohesive growth pattern interspersed by small lymphocytes and plasma cells. The large tumor cells expressed MUM1, OCT-2 and BOB.1, and were negative for CD138, CD38, AE1/AE3, melan A, PLAP, S100, vimentin, CD117, CD30, ALK-1, leukocyte common antigen (CD45), T-cell, B-cell and histolytic markers, CD56, CD10 and BCL-6. The proliferation index by Ki-67 immunohistochemistry was approaching 100%. In situ hybridization for Epstein-Barr Virus-encoded RNA (EBER) was positive in large malignant cells. A diagnosis of PBL was made. These findings indicate that PBL should be included in the differential diagnosis of an HIV-negative, immunocompetent patient with generalized lymphadenopathy. The adjacent plasma cells were positive for CD138 and CD38 and show kappa-light chain restriction, but without EBER expression, raising the possibility of a preexisting or concurrent plasmacytoma and that the PBL may be a high-grade transformation from a preexisting plasma cell neoplasm following Epstein-Barr virus infection. Electron microscopy showed numerous circumferential long slender peripheral cytoplasmic projections in the large tumor cells, suggesting that some of the previously reported large B-cell lymphoma with cytoplasmic projections may actually be PBL. PMID- 20969861 TI - MT1-MMP plays an important role in an invasive activity of malignant pleural mesothelioma cell. AB - Malignant pleural mesothelioma (MPM) has a poor prognosis and is a treatment resistant tumor, which is increasing in frequency throughout the world. The poor prognosis is due to the aggressive local invasiveness rather than distant metastasis. In this study, we established a cell line of malignant mesothelioma from a clinical specimen and assessed the relationship between the expression of MT1-MMP and the invasion ability of that line, as well as the cultured cells of several other lines, using the simple method that we created previously. We established a cell line from a clinical specimen from a patient with malignant mesothelioma. We assessed the invasive activities of MPM cells in an easy-to prepare double-layered collagen gel hemisphere (DL-CGH) system that enabled us to visualize cell movements during invasion. To assess the role of MT1-MMP in the invasive activity of MPM cells, we knocked down its expression by RNA interference (RNAi). The invasion assay with DL-CGH revealed that a high expression of MT1-MMP in MPM cells was associated with aggressive invasive activity. The RNAi of MT1-MMP indicated that the expression of MT1-MMP might have a crucial role in the invasiveness of MPM cells. The MT1-MMP expression in MPM cells is related to their capacity for locally aggressive spreading into the pleura and the surrounding tissues, and MT1-MMP should be a suitable molecular target for the suppression of the invasiveness of MPM. PMID- 20969862 TI - Invasion and EMT-associated genes are up-regulated in B viral hepatocellular carcinoma with high expression of CD133-human and cell culture study. AB - Hepatocellular carcinomas (HCCs) with expression of stem/progenitor cell markers including CD133 have been reported to have more aggressive biological behavior, and epithelial-mesenchymal transition (EMT), closely related invasion, has been suggested to generate cancer stem cells. To elucidate biological characteristics of HCCs expressing CD133, we evaluated migration assay and the mRNA expression levels of CD133, invasion-associated genes [urokinase plasminogen activator receptor (uPAR), villin 2 (VIL2), and MMP1 and MMP2], and EMT regulators (Snail, Slug, Twist, E-cadherin, and N-cadherin) by real-time PCR in HCC cell lines including HepG2, Hep3B, Huh7, PLC/RFP/6, SNU423, SNU449, and SNU475. Same genes and pathological features were also investigated in 49 samples of hepatitis B virus-related human HCCs. In all HCC cell lines studied, CD133-positive cells showed higher cell migration activity and up-regulated invasion- and EMT associated genes with increased N-cadherin and decreased E-cadherin expressions compared to CD133-negative cells. The human HCCs were divided into the CD133-high group (top 40%) and the CD133-low group (bottom 40%) according to the level of CD133 mRNA. The CD133-high group showed relatively frequent vascular invasion and significantly higher expression of invasion-associated genes [uPAR (p=0.002), MMP1 (p=0.01), and MMP2 (p=0.003)] and EMT regulators [Snail (p=0.002) and Twist (p=0.0003)] compared to the CD133-low group. In conclusion, our results suggest that there is a subtype of HCC with high expression of CD133, which might have more invasive characteristics by up-regulation of invasion-associated genes and EMT-associated genes. PMID- 20969863 TI - Reprogramming of cell junction modules during stepwise epithelial to mesenchymal transition and accumulation of malignant features in vitro in a prostate cell model. AB - Epithelial to mesenchymal transition (EMT) is pivotal in tumor metastasis. Our previous work reported an EMT model based on primary prostate epithelial cells (EP156T) which gave rise to cells with mesenchymal phenotype (EPT1) without malignant transformation. To promote prostate cell transformation, cells were maintained in saturation density cultures to select for cells overriding quiescence. Foci formed repeatedly following around 8 weeks in confluent EPT1 monolayers. Only later passage EPT1, but not EP156T cells of any passage, could form foci. Cells isolated from the foci were named EPT2 and formed robust colonies in soft agar, a malignant feature present neither in EP156T nor in EPT1 cells. EPT2 cells showed additional malignant traits in vitro, including higher ability to proliferate following confluence, higher resistance to apoptosis and lower dependence on exogenous growth factors than EP156T and EPT1 cells. Microarray profiling identified gene sets, many of which belong to cell junction modules, that changed expression from EP156T to EPT1 cells and continued to change from EPT1 to EPT2 cells. Our findings provide a novel stepwise cell culture model in which EMT emerges independently of transformation and is associated with subsequent accumulation of malignant features in prostate cells. Reprogramming of cell junction modules is involved in both steps. PMID- 20969864 TI - Survival and differentiation of neuroectodermal cells with stem cell properties at different oxygen levels. AB - Freeze-lesioned regions of the forebrain cortex provide adequate environment for growth of non-differentiated neural progenitors, but do not support their neuron formation. Reduced oxygen supply, among numerous factors, was suspected to impair neuronal cell fate commitment. In the present study, proliferation and differentiation of neural stem/progenitor cells were investigated at different oxygen levels both in vitro and in vivo. Low (1% atmospheric) oxygen supply did not affect the in vitro viability and proliferation of stem cells or the transcription of "stemness" genes but impaired the viability of committed neuronal progenitors and the expression of proneural and neuronal genes. Consequently, the rate of in vitro neuron formation was markedly reduced under hypoxic conditions. In vivo, neural stem/progenitor cells survived and proliferated in freeze-lesioned adult mouse forebrains, but did not develop into neurons. Hypoperfusion-caused hypoxia in lesioned cortices was partially corrected by hyperbaric oxygen treatment (HBOT). HBOT, while reduced the rate of cell proliferation at the lesion site, resulted in sporadic neuron formation from implanted neural stem cells. The data indicate that in hypoxic brain areas, neural stem cells survive and proliferate, but neural tissue-type differentiation can not proceed. Oxygenation renders the damaged brain areas more permissive for tissue-type differentiation and may help the integration of neural stem/progenitor cells. PMID- 20969866 TI - Menin stimulates homology-directed DNA repair. AB - Menin, the nuclear protein encoded by the Multiple Endocrine Neoplasia type 1 (MEN1) gene, acts as a tumor suppressor. It interacts with a large number of proteins involved in chromatin modification, transcription, cell cycle checkpoint and DNA repair, though its exact function is not clear. We report that in human cells menin stimulates homology-directed (HD) DNA repair induced by the rare endonuclease I-SceI and it accumulates with Chk1 at the site of the double strand break. In addition, menin and Chk1 interact in vivo. Deletion of the first 228 amino acids of menin impairs the interaction with Chk1 and the ability to stimulate HD repair, suggesting that the complex menin-Chk1 on the damaged chromatin facilitates homologous recombination. PMID- 20969865 TI - Glatiramer acetate for treatment of MS: regulatory B cells join the cast of players. AB - Glatiramer acetate (GA, copolymer-1, Copaxone) is a Food and Drug Administration approved drug for the treatment of relapsing-remitting multiple sclerosis (MS). However, its mechanism of action remains ill-defined. The available evidence indicates that GA induces antigen-presenting cells with anti-inflammatory properties and promotes the generation of immunoregulatory T cells that suppress pathogenic T cells. A new study by Kala et al. (2010) now shows that B lymphocytes, which are best known for their antibody-secreting properties, contribute to the beneficial effects of GA against experimental autoimmune encephalomyelitis (EAE), the animal model of MS. This commentary discusses these new findings in the context of the pathogenesis of MS and EAE, the emerging immunoregulatory role of B cells in autoimmunity, and the relevance of B cells as targets for immunotherapy in MS. PMID- 20969867 TI - Leu628 of the KIX domain of CBP is a key residue for the interaction with the MLL transactivation domain. AB - Physical interaction between the transactivation domain (TAD) of the mixed lineage leukemia protein (MLL) and the KIX domain of the cyclic-AMP response element binding protein (CREB) binding protein (CBP) is necessary for MLL mediated transcriptional activation. We show by alanine-scanning mutagenesis that hydrophobic surface residues of KIX, especially L628, are energetically important for binding the MLL TAD. NMR studies of the KIX-L628A mutant suggest that L628 plays a crucial role in conformational transitions at the MLL binding site, necessary for high affinity interactions with MLL. Unexpectedly, MLL also binds to the c-Myb/phosphorylated kinase-inducible domain of CREB (pKID) site of KIX, highlighting the complex nature of interactions involving intrinsically disordered transcriptional activators. PMID- 20969868 TI - LIM domain protein FHL1B interacts with PP2A catalytic beta subunit--a novel cell cycle regulatory pathway. AB - Four-and-a-half LIM domain protein 1B (FHL1B) is an alternatively-spliced isoform of FHL1. In this study, FHL1B was demonstrated to interact with the beta catalytic subunit (Cbeta) of a type 2A protein phosphatase (PP2A) by yeast two hybrid screening. Domain studies using a small-scale yeast two-hybrid interaction assay revealed the mediation of protein-protein interaction by FHL1B's C terminus. Interaction between FHL1B and PP2A was further verified by co immunoprecipitation. FHL1B was also shown to shuttle between nucleus and cytoplasm at different phases of the cell cycle. These data suggest that the FHL1B/PP2A(Cbeta) interaction may illustrate a novel cell-cycle regulatory pathway. PMID- 20969869 TI - Hem-1: putting the "WAVE" into actin polymerization during an immune response. AB - Most active processes by immune cells including adhesion, migration, and phagocytosis require the coordinated polymerization and depolymerization of filamentous actin (F-actin), which is an essential component of the actin cytoskeleton. This review focuses on a newly characterized hematopoietic cell specific actin regulatory protein called hematopoietic protein-1 [Hem-1, also known as Nck-associated protein 1-like (Nckap1l or Nap1l)]. Hem-1 is a component of the "WAVE [WASP (Wiskott-Aldrich syndrome protein)-family verprolin homologous protein]" complex, which signals downstream of activated Rac to stimulate F-actin polymerization in response to immuno-receptor signaling. Genetic studies in cell lines and in mice suggest that Hem-1 regulates F-actin polymerization in hematopoietic cells, and may be essential for most active processes dependent on reorganization of the actin cytoskeleton in immune cells. PMID- 20969870 TI - Upstream open reading frames regulate the cell cycle-dependent expression of the RNA helicase Rok1 in Saccharomyces cerevisiae. AB - The RNA helicase Rok1 plays a role in rRNA processing and in control of cell cycle progression in Saccharomyces cerevisiae. We identified two upstream open reading frames (uORFs) within the ROK1 5' untranslated region, which inhibited Rok1 translation. Mutating uATG to uAAG or generation of a premature stop codon in the uORFs resulted in increased Rok1p levels. Rok1 protein levels oscillated during the cell cycle, declining at G1/S and increasing at G2. The uAAG1 mutation caused a constitutive level of Rok1 proteins throughout the cell cycle, resulting in significant delays in mitotic bud emergence and recovery from pheromone arrest. Our study reveals that the Rok1 protein level is regulated by uORFs, which is critical in cell cycle progression. PMID- 20969871 TI - Biological activities of juvenile hormone III skipped bisepoxide in last instar nymphs and adults of a stink bug, Plautia stali. AB - Juvenile hormone III skipped bisepoxide (JHSB(3)), methyl (2R,3S,10R)-2,3;10,11 bisepoxyfarnesoate was recently determined as a novel juvenile hormone (JH) in a stink bug, Plautia stali. To further confirm the biological function of JHSB(3) in this insect, its juvenilizing, reproduction-stimulating and diapause terminating activities and the presence in the hemolymph were examined. Topical application of JHSB(3) to last instar nymphs inhibited their metamorphosis in a dose-dependent fashion. In allatectomized and diapausing adults, JHSB(3) application exerted stimulatory effects on the development of ovaries and ectadenia in females and males, respectively. JHSB(3) was detected from the hemolymph of reproductively active females by gas chromatography-mass spectrometry analysis while its titer in the hemolymph collected from diapausing adults was too low to be detected. These results demonstrated that JHSB(3) has biological function as a JH in P. stali. Topical application of JHSB(3), its stereoisomers and 10R-JH III also indicated that compounds with the 2R,3S configuration were more potent than those with the 2S,3R-configuration and 2,3 double bond. PMID- 20969872 TI - Mechanisms underlying insect chill-coma. AB - At their critical thermal minimum (CT(min)) insects enter chill-coma, a reversible state where neuromuscular transmission and movement cease. The physiological mechanisms responsible for the insect CT(min) remain poorly understood despite the regular use of chill-coma onset and recovery as a means to assess evolved or acquired variation in low temperature tolerance. In this review, we summarize the use of chill-coma as a metric of thermal tolerance to date, and synthesise current knowledge on the nature and plasticity of lower thermal limits to present probable physiological mechanisms of cold-induced failure. Chill-coma is likely to be driven by an inability to maintain ionic homeostasis through the effects of temperature on ion-motive ATPases, ion channel gating mechanisms, and/or the lipid membrane, leading to a loss of nerve and muscle excitability. PMID- 20969873 TI - Computational protein design using flexible backbone remodeling and resurfacing: case studies in structure-based antigen design. AB - Computational protein design has promise for vaccine design and other applications. We previously transplanted the HIV 4E10 epitope onto non-HIV protein scaffolds for structural stabilization and immune presentation. Here, we developed two methods to optimize the structure of an antigen, flexible backbone remodeling and resurfacing, and we applied these methods to a 4E10 scaffold. In flexible-backbone remodeling, an existing backbone segment is replaced by a de novo designed segment of prespecified length and secondary structure. With remodeling, we replaced a potentially immunodominant domain on the scaffold with a helix-loop segment that made intimate contact to the protein core. All three domain trim designs tested experimentally had improved thermal stability and similar binding affinity for the 4E10 antibody compared to the parent scaffold. A crystal structure of one design had a 0.8 A backbone RMSD to the computational model in the rebuilt region. Comparison of parent and trimmed scaffold reactivity to anti-parent sera confirmed the deletion of an immunodominant domain. In resurfacing, the surface of an antigen outside a target epitope is redesigned to obtain variants that maintain only the target epitope. Resurfaced variants of two scaffolds were designed in which 50 positions amounting to 40% of the protein sequences were mutated. Surface-patch analyses indicated that most potential antibody footprints outside the 4E10 epitope were altered. The resurfaced variants maintained thermal stability and binding affinity. These results indicate that flexible-backbone remodeling and resurfacing are useful tools for antigen optimization and protein engineering generally. PMID- 20969874 TI - 18S rRNA: a tale of the tail. PMID- 20969875 TI - The interaction of capping protein with the barbed end of the actin filament. AB - The interaction of capping protein (CP) with actin filaments is an essential element of actin assembly and actin-based motility in nearly all eukaryotes. The dendritic nucleation model for Arp2/3-based lamellipodial assembly features capping of barbed ends by CP, and the formation of filopodia is proposed to involve inhibition of capping by formins and other proteins. To understand the molecular basis for how CP binds the barbed end of the actin filament, we have used a combination of computational and experimental approaches, primarily involving molecular docking and site-directed mutagenesis. We arrive at a model that supports all of our biochemical data and agrees very well with a cryo electron microscopy structure of the capped filament. CP interacts with both actin protomers at the barbed end of the filament, and the amphipathic helix at the C-terminus of the beta-subunit binds to the hydrophobic cleft on actin, in a manner similar to that of WH2 domains. These studies provide us with new molecular insight into how CP binds to the actin filament. PMID- 20969877 TI - Card15 polymorphisms in the immunopathogenesis of Crohn's disease and mycobacterial infectious diseases. PMID- 20969878 TI - Three 3D graphical representations of DNA primary sequences based on the classifications of DNA bases and their applications. AB - In this article, we introduce three 3D graphical representations of DNA primary sequences, which we call RY-curve, MK-curve and SW-curve, based on three classifications of the DNA bases. The advantages of our representations are that (i) these 3D curves are strictly non-degenerate and there is no loss of information when transferring a DNA sequence to its mathematical representation and (ii) the coordinates of every node on these 3D curves have clear biological implication. Two applications of these 3D curves are presented: (a) a simple formula is derived to calculate the content of the four bases (A, G, C and T) from the coordinates of nodes on the curves; and (b) a 12-component characteristic vector is constructed to compare similarity among DNA sequences from different species based on the geometrical centers of the 3D curves. As examples, we examine similarity among the coding sequences of the first exon of beta-globin gene from eleven species and validate similarity of cDNA sequences of beta-globin gene from eight species. PMID- 20969879 TI - Predicting ion channels and their types by the dipeptide mode of pseudo amino acid composition. AB - Ion channels are integral membrane proteins that control movement of ions into or out of cells. They are key components in a wide range of biological processes. Different types of ion channels have different biological functions. With the appearance of vast proteomic data, it is highly desirable for both basic research and drug-target discovery to develop a computational method for the reliable prediction of ion channels and their types. In this study, we developed a support vector machine-based method to predict ion channels and their types using primary sequence information. A feature selection technique, analysis of variance (ANOVA), was introduced to remove feature redundancy and find out an optimized feature set for improving predictive performance. Jackknife cross-validated results show that the proposed method can discriminate ion channels from non-ion channels with an overall accuracy of 86.6%, classify voltage-gated ion channels and ligand-gated ion channels with an overall accuracy of 92.6% and predict four types (potassium, sodium, calcium and anion) of voltage-gated ion channels with an overall accuracy of 87.8%, respectively. These results indicate that the proposed method can correctly identify ion channels and provide important instructions for drug-target discovery. The predictor can be freely downloaded from http://cobi.uestc.edu.cn/people/hlin/tools/IonchanPred/. PMID- 20969881 TI - Optimal harvesting of fish stocks under a time-varying discount rate. AB - Optimal control theory has been extensively used to determine the optimal harvesting policy for renewable resources such as fish stocks. In such optimisations, it is common to maximise the discounted utility of harvesting over time, employing a constant time discount rate. However, evidence from human and animal behaviour suggests that we have evolved to employ discount rates which fall over time, often referred to as "hyperbolic discounting". This increases the weight on benefits in the distant future, which may appear to provide greater protection of resources for future generations, but also creates challenges of time-inconsistent plans. This paper examines harvesting plans when the discount rate declines over time. With a declining discount rate, the planner reduces stock levels in the early stages (when the discount rate is high) and intends to compensate by allowing the stock level to recover later (when the discount rate will be lower). Such a plan may be feasible and optimal, provided that the planner remains committed throughout. However, in practice there is a danger that such plans will be re-optimized and adjusted in the future. It is shown that repeatedly restarting the optimization can drive the stock level down to the point where the optimal policy is to harvest the stock to extinction. In short, a key contribution of this paper is to identify the surprising severity of the consequences flowing from incorporating a rather trivial, and widely prevalent, "non-rational" aspect of human behaviour into renewable resource management models. These ideas are related to the collapse of the Peruvian anchovy fishery in the 1970's. PMID- 20969880 TI - Cancer stem cell, niche and EGFR decide tumor development and treatment response: A bio-computational simulation study. AB - Recent research in cancer biology has suggested the hypothesis that tumors are initiated and driven by a small group of cancer stem cells (CSCs). Furthermore, cancer stem cell niches have been found to be essential in determining fates of CSCs, and several signaling pathways have been proven to play a crucial role in cellular behavior, which could be two important factors in cancer development. To better understand the progression, heterogeneity and treatment response of breast cancer, especially in the context of CSCs, we propose a mathematical model based on the cell compartment method. In this model, three compartments of cellular subpopulations are constructed: CSCs, progenitor cells (PCs), and terminal differentiated cells (TCs). Moreover, (1) the cancer stem cell niche is, considered by modeling its effect on division patterns (symmetric or asymmetric) of CSCs, and (2) the EGFR signaling pathway is integrated by modeling its role in cell proliferation, apoptosis. Our simulation results indicate that (1) a higher probability for symmetric division of CSC may result in a faster expansion of tumor population, and for a larger number of niches, the tumor grows at a slower rate, but the final tumor volume is larger; (2) higher EGFR expression correlates to tumors with larger volumes while a saturation function is observed, and (3) treatments that inhibit tyrosine kinase activity of EGFR may not only repress the tumor volume, but also decrease the CSCs percentages by shifting CSCs from symmetric divisions to asymmetric divisions. These findings suggest that therapies should be designed to effectively control or eliminate the symmetric division of CSCs and to reduce or destroy the CSC niches. PMID- 20969882 TI - Direct inhibition of excision/synthesis DNA repair activities by cadmium: analysis on dedicated biochips. AB - The well established toxicity of cadmium and cadmium compounds results from their additive effects on several key cellular processes, including DNA repair. Mammalian cells have evolved several biochemical pathways to repair DNA lesions and maintain genomic integrity. By interfering with the homeostasis of redox metals and antioxidant systems, cadmium promotes the development of an intracellular environment that results in oxidative DNA damage which can be mutagenic if unrepaired. Small base lesions are recognised by specialized glycosylases and excised from the DNA molecule. The resulting abasic sites are incised, and the correct sequences restored by DNA polymerases using the opposite strands as template. Bulky lesions are recognised by a different set of proteins and excised from DNA as part of an oligonucleotide. As in base repair, the resulting gaps are filled by DNA polymerases using the opposite strands as template. Thus, these two repair pathways consist in excision of the lesion followed by DNA synthesis. In this study, we analysed in vitro the direct effects of cadmium exposure on the functionality of base and nucleotide DNA repair pathways. To this end, we used recently described dedicated microarrays that allow the parallel monitoring in cell extracts of the repair activities directed against several model base and/or nucleotide lesions. Both base and nucleotide excision/repair pathways are inhibited by CdCl2, with different sensitivities. The inhibitory effects of cadmium affect mainly the recognition and excision stages of these processes. Furthermore, our data indicate that the repair activities directed against different damaged bases also exhibit distinct sensitivities, and the direct comparison of cadmium effects on the excision of uracile in different sequences even allows us to propose a hierarchy of cadmium sensibility within the glycosylases removing U from DNA. These results indicate that, in our experimental conditions, cadmium is a very potent DNA repair poison. PMID- 20969884 TI - Urine volume dependency of specific dehydroepiandrosterone (DHEA) and cortisol metabolites in healthy children. AB - Urine volume should be considered as a confounder when using urinary free cortisol (UFF) and cortisone (UFE) to assess glucocorticoid (GC) status. We aimed to examine whether adrenal androgen (AA) metabolites may be also affected by urine volume in healthy children. To compare the flow dependence of GC and AA metabolites, specific GC metabolites were examined. In 24-h urine samples of 120 (60 boys) healthy children (4-10 yr), steroid profiles were determined by GC-MS analysis, UFF and UFE by radioimmunoassay. To assess daily AA and GC secretion rates, 7 quantitatively most important AA (?C19) and GC (?C21) metabolites were summed. Sum of DHEA and its 16alpha-hydroxylated metabolites were denoted as DHEA&M. Association of urine volume with AA (?C19, DHEA&M, DHEA, 16alpha-hydroxy DHEA, 3beta,16alpha,17beta-androstenetriol) and GC (?C21, UFF, UFE, 6beta hydroxycortisol, 20alpha-dihydrocortisol) were examined in linear regression models. Among the examined AA metabolites, 16alpha-hydroxy-DHEA (beta=0.56, p<0.0001) and DHEA (beta=0.43, p=0.05) showed relatively strong association with urine volume. A trend was seen for ?C19 (beta=0.23, p=0.08), but not for DHEA&M (p>0.1). Regarding GC metabolites, urine volume showed a stronger association with cortisol's direct metabolites, i.e., cortisone, 6beta-hydroxycortisol and 20alpha-dihydrocortisol (beta=0.4-0.6, p<0.01) than with cortisol itself (beta=0.28, p<0.05). ?C21 was not associated with urine volume. In conclusion, like UFF and UFE, renal excretion of DHEA, 16alpha-hydroxy-DHEA, 6beta hydroxycortisol, and 20alpha-dihydrocortisol may also depend on urine volume. The intrarenal production of the latter three and cortisone might explain their relative strong water-flow-dependency. Total AA or GC secretion marker appears not to be relevantly confounded by urine volume. PMID- 20969883 TI - A case for the involvement of phonological loop in sentence comprehension. AB - The specific role of the phonological loop in sentence comprehension is still a matter of debate. We tested the behavioural consequences of activity disruption in left BA40 and BA44, key regions of the phonological loop, on language comprehension using 1Hz rTMS. Comprehension was assessed by means of two tasks: a sentence-to-picture matching task, with sentences varying in length and syntactic complexity (Experiment 1), and a sentence verification task (Experiment 2). rTMS over left BA40 significantly reduced accuracy for syntactically complex sentences and long, but syntactically simpler sentences, while rTMS over left BA44 significantly reduced accuracy only for syntactically complex sentences. rTMS applied over left BA40 also impaired performance on sentences in which word order was crucial. We suggest that the neural correlates of the phonological loop, left BA40 and BA44, are both involved in the comprehension of syntactically complex sentences, while only left BA40, corresponding to the short-term store, is recruited for the comprehension of long but syntactically simple sentences. Therefore, in contrast with the dominant view, we showed that sentence comprehension is a function of the phonological loop. PMID- 20969886 TI - Recognizing people from dynamic and static faces and bodies: dissecting identity with a fusion approach. AB - The goal of this study was to evaluate human accuracy at identifying people from static and dynamic presentations of faces and bodies. Participants matched identity in pairs of videos depicting people in motion (walking or conversing) and in "best" static images extracted from the videos. The type of information presented to observers was varied to include the face and body, the face-only, and the body-only. Identification performance was best when people viewed the face and body in motion. There was an advantage for dynamic over static stimuli, but only for conditions that included the body. Control experiments with multiple static images indicated that some of the motion advantages we obtained were due to seeing multiple images of the person, rather than to the motion, per se. To computationally assess the contribution of different types of information for identification, we fused the identity judgments from observers in different conditions using a statistical learning algorithm trained to optimize identification accuracy. This fusion achieved perfect performance. The condition weights that resulted suggest that static displays encourage reliance on the face for recognition, whereas dynamic displays seem to direct attention more equitably across the body and face. PMID- 20969885 TI - Vejovine, a new antibiotic from the scorpion venom of Vaejovis mexicanus. AB - Multidrug resistant bacterial infections are one of the most important health problems in recent years. Resistance to conventional antibiotics limits the therapeutic options causing increase rate in morbid-mortality in hospitals. Therefore, new antibacterial agents with new bacterial targets have been searched and found in many different sources, including scorpion venom and scorpion hemolymph. Here, we report a new anti-microbial peptide named Vejovine. This peptide was isolated from the venom of the Mexican scorpion Vaejovis mexicanus by two steps of reversed phase high performance liquid chromatography (RP-HPLC). It is composed of 47 amino acid residues with no cysteine residues in its sequence, with a molecular weight of 4873 Da. The chemical synthesis of Vejovine was performed by the solid phase method of Merrifield, using fluoren-9 ylmethoxycarbonyl (Fmoc)-amino acids. Both the native and synthetic peptides were shown to have essentially the same activity. Vejovine inhibits growth of clinical isolates of Gram-negative multidrug resistant (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae and Acinetobacter baumanii) causing nosocomial infections with a minimum inhibitory concentration (MIC) of 4.4 MUM up to 50 MUM. This peptide has also hemolytic activity against human erythrocytes with a HC(50) value of 100 MUM. A cDNA library of the venomous gland of this scorpion provided material for cloning the gene encoding Vejovine. This peptide is a new type of antibiotic, showing less than 50% similarity to other known scorpion peptides. Vejovine is a candidate to be used as a leading compound for future development of an effective peptide against multidrug resistant bacteria. PMID- 20969887 TI - Mechanism of latency relaxation in frog skeletal muscle. AB - The latency relaxation is a small drop of tension before skeletal muscle begins to develop active tension. This phenomenon was found nearly one century ago but its origin has not been clarified. In this review, the hypotheses for its mechanism are discussed in terms of the recent experimental results using X-ray diffraction. The latency relaxation takes place almost simultaneously as the structural change of the regulatory protein troponin, an unspecified structural change of the thick filament, and increase in stiffness. It seems difficult to associate all of these with the latency relaxation by assuming a simple mechanism. PMID- 20969888 TI - Molecular mechanism analysis of Gloydius shedaoensis venom gloshedobin interaction with inhibitors by homology modeling. AB - Snake venom thrombin-like enzymes (SVTLEs) are widely applied in the treatment of thrombotic diseases, however, the molecular mechanism of its inhibition by synthetic and natural proteinaceous inhibitors is not yet understood. Here we investigated effects of protease inhibitors including phenylmethylsulfonil fluoride (PMSF), benzamidine (BMD) and its derivates on the activity of recombinant gloshedobin, a SVTLE from the snake Gloydius shedaoensis. The molecular inhibition mechanism was postulated by separately docking inhibitors into three-dimensional model of gloshedobin using protein C activator from Agkistrodon contortrix contortrix venom (ACC-C, which bear 78% identity with gloshedobin) as template. The analysis indicated that the strongest inhibitor, PMSF, was via a covalent bond with the catalytic Ser195, while other inhibitors showing weaker inhibitory activity were via hydrogen bond with Ser195 or non catalytic residues. PMID- 20969889 TI - A photographic approach to the possible mechanism of retrogradation of sweet potato starch. AB - Although the subject of starch retrogradation has been studied for about 20 years, the mechanism of starch retrogradation seems not yet to be completely established. In this paper, the possible retrogradation mechanism of sweet potato starch was postulated from four optical micrographs at the stages of melting of the starch granules, autoclaving treatment and aging. The possible process of retrogradation consists of three stages. Firstly, starch granules was swelled and melted with loss of X-ray crystallinity and formation of both crystalline and amorphous lamellae; secondly, in crystalline lamellae, amylopectin began to form nucleation when they were autoclaved; finally, the nucleus grew up to great rod like crystals as the result of congregating of amylose on plates which were composed of and prolongated by amylopectin. PMID- 20969890 TI - Proceedings of the workshop "Neuroanatomical Tracing and Systems Neuroscience: the State of the Art", 7th FENS meeting, Amsterdam, The Netherlands, July 3, 2010. PMID- 20969891 TI - Time-frequency characterization of electrocorticographic recordings of epileptic patients using frequency-entropy similarity: a comparison to other bi-variate measures. AB - Expert evaluation of electrocorticographic (ECoG) recordings forms the linchpin of seizure onset zone localization in the evaluation of epileptic patients for surgical resection. Numerous methods have been developed to analyze these complex recordings, including uni-variate (characterizing single channels), bi-variate (comparing channel pairs) and multivariate measures. Developing reliable algorithms may be helpful in clinical tasks such as localization of epileptogenic zones and seizure anticipation, as well as enabling better understanding of neuronal function and dynamics. Recently we have developed the frequency-entropy (F-E) similarity measure, and have tested its capability in mapping the epileptogenic zones. The F-E similarity measure compares time-frequency characterizations of two recordings. In this study, we examine the method's principles and utility and compare it to previously described bi-variate correspondence measures such as correlation, coherence, mean phase coherence and spectral comparison methods. Specially designed synthetic signals were used for illuminating theoretical differences between the measures. Intracranial recordings of four epileptic patients were then used for the measures' comparative analysis by creating a mean inter-electrode matrix for each of the correspondence measures and comparing the structure of these matrices during the inter-ictal and ictal periods. We found that the F-E similarity measure is able to discover spectral and temporal features in data which are hidden for the other measures and are important for foci localization. PMID- 20969892 TI - Single-sweep voltage-sensitive dye imaging of interacting identified neurons. AB - The simultaneous recording of many individual neurons is fundamental to understanding the integral functionality of neural systems. Imaging with voltage sensitive dyes (VSDs) is a key approach to achieve this goal and a promising technique to supplement electrophysiological recordings. However, the lack of connectivity maps between imaged neurons and the requirement of averaging over repeated trials impede functional interpretations. Here we demonstrate fast, high resolution and single-sweep VSD imaging of identified and synaptically interacting neurons. We show for the first time the optical recording of individual action potentials and mutual inhibitory synaptic input of two key players in the well-characterized pyloric central pattern generator in the crab stomatogastric ganglion (STG). We also demonstrate the presence of individual synaptic potentials from other identified circuit neurons. We argue that imaging of neural networks with identifiable neurons with well-known connectivity, like in the STG, is crucial for the understanding of emergence of network functionality. PMID- 20969893 TI - Novel methods for quantifying neurophysiologic properties of the human lumbar paraspinal muscles. AB - Our understanding the neurophysiologic characteristics of the human paraspinal muscles has historically been hindered by the lack of experimental techniques to examine these muscles function in vivo. In this article we describe a paired pulse transcranial magnetic stimulation (TMS) protocol to quantify intracortical facilitation (ICF) and short-interval intracortical inhibition (SICI) of the lumbar paraspinal muscles, and an electromechanical tapping protocol to measure the amplitude of the short-latency stretch reflex. Test-retest reliability of these protocols was examined across two sessions separated by 30-min in healthy adults. We assessed relative reliability by calculating the intraclass correlation coefficient (ICC), and absolute reliability was assessed via coefficient of variation (CV). ICF and SICI in the lumbar paraspinal muscles exhibited the classical facilitatory and inhibitory responses observed in appendicular skeletal muscles (~30% facilitation and inhibition, respectively). The motor evoked potential amplitude (MEP), ICF, SICI, and stretch reflex amplitude measurements did not significantly differ between the two testing sessions (p>0.05). The MEP amplitude, ICF and stretch reflex amplitude exhibited the highest relative and absolute reliability (ICC=0.89-0.91, CV=10.6-11.1%); whereas the SICI measure exhibited somewhat lower reliability (ICC=0.75, CV=20.1%). The stretch reflex protocol performed in the first testing session did not influence the TMS outcome measures in the second testing session (p>0.05). These innovative methods may be useful in studying basic physiology, the pathology of low back pain, as well as the mechanisms of action of treatment interventions. PMID- 20969894 TI - Influenza A virus replication is inhibited in IFN-lambda2 and IFN-lambda3 transfected or stimulated cells. AB - Interferons lambda (IFN-lambda) are the most recently defined members of the class III cytokine family. To investigate whether IFN-lambda2 and IFN-lambda3 displayed antiviral activity against influenza A virus (IAV), a number of cell lines induced with IFNs - as well as two established cell lines (A549-IFN-lambda2 and A549-IFN-lambda3) - were infected with IAV. Our results indicate that IFN lambda2 has statistically significant antiviral activity in A549-IFN-lambda2 (P=0.0028) although less so than IFN-lambda3, which reduced viral titer to 10% (P<0.0001). The reverse was observed for cells treated with IFNs, with IFN lambda2-treated A549 cells inhibiting IAV infection more efficiently than IFN lambda3-treated A549 cells. The antiviral effect on IFN-stimulated cells was most apparent on Vero cells (compared with MDCK and HeLa). Both IFNs significantly inhibited IAV replication and inhibition was observed in a dose-dependent manner, with an optimal IFN concentration of 20 ng/ml. IFN-lambda2 was more potent than IFN-lambda3 on Vero cells while IFN-lambda3 appeared more efficient than IFN lambda2 on MDCK and HeLa cells. PMID- 20969895 TI - Anti-apoptosis and cell survival: a review. AB - Type I programmed cell death (PCD) or apoptosis is critical for cellular self destruction for a variety of processes such as development or the prevention of oncogenic transformation. Alternative forms, including type II (autophagy) and type III (necrotic) represent the other major types of PCD that also serve to trigger cell death. PCD must be tightly controlled since disregulated cell death is involved in the development of a large number of different pathologies. To counter the multitude of processes that are capable of triggering death, cells have devised a large number of cellular processes that serve to prevent inappropriate or premature PCD. These cell survival strategies involve a myriad of coordinated and systematic physiological and genetic changes that serve to ward off death. Here we will discuss the different strategies that are used to prevent cell death and focus on illustrating that although anti-apoptosis and cellular survival serve to counteract PCD, they are nevertheless mechanistically distinct from the processes that regulate cell death. PMID- 20969896 TI - Susceptibility of Hep3B cells in different phases of cell cycle to tBid. AB - tBid is a pro-apoptotic molecule. Apoptosis inducers usually act in a cell cycle specific fashion. The aim of this study was to elucidate whether effect of tBid on hepatocellular carcinoma (HCC) Hep3B cells was cell cycle phase specific. We synchronized Hep3B cells at G0/G1, S or G2/M phases by chemicals or flow sorting and tested the susceptibility of the cells to recombinant tBid. Cell viability was measured by MTT assay and apoptosis by TUNEL. The results revealed that tBid primarily targeted the cells at G0/G1 phase of cell cycle, and it also increased the cells at the G2/M phase. 5-Fluorouracil (5-FU), on the other hand, arrested Hep3B cells at the G0/G1 phase, but significantly reduced cells at G2/M phase. The levels of cell cycle-related proteins and caspases were altered in line with the change in the cell cycle. The combination of tBid with 5-FU caused more cells to be apoptotic than either agent alone. Therefore, the complementary effect of tBid and 5-FU on different phases of the cell cycle may explain their synergistric effect on Hep3B cells. The elucidation of the phase-specific effect of tBid points to a possible therapeutic option that combines different phase specific agents to overcome resistance of HCC. PMID- 20969897 TI - Treadmill exercise represses neuronal cell death in an aged transgenic mouse model of Alzheimer's disease. AB - The present study was undertaken to further investigate the protective effect of treadmill exercise on the hippocampal proteins associated with neuronal cell death in an aged transgenic (Tg) mice with Alzheimer's disease (AD). To address this, Tg mouse model of AD, Tg-NSE/PS2m, which expresses human mutant PS2 in the brain, was chosen. Animals were subjected to treadmill exercise for 12 weeks from 24 months of age. The exercised mice were treadmill run at speed of 12 m/min, 60 min/day, 5 days/week on a 0% gradient for 3 months. Treadmill exercised mice improved cognitive function in water maze test. Treadmill exercised mice significantly reduced the expression of Abeta-42, Cox-2, and caspase-3 in the hippocampus. In parallel, treadmill exercised Tg mice decreased the phosphorylation levels of JNK, p38MAPK and tau (Ser404, Ser202, Thr231), and increased the phosphorylation levels of ERK, PI3K, Akt and GSK-3alpha/beta. In addition, treadmill exercised Tg mice up-regulated the expressions of NGF, BDNF and phospho-CREB, and the expressions of SOD-1, SOD-2 and HSP-70. Treadmill exercised Tg mice up-regulated the expression of Bcl-2, and down-regulated the expressions of cytochrome c and Bax in the hippocampus. The number of TUNEL positive cells in the hippocampus in mice was significantly decreased after treadmill exercise. Finally, serum TC, insulin, glucose, and corticosterone levels were significantly decreased in the Tg mice after treadmill exercise. As a consequence of such change, Abeta-dependent neuronal cell death in the hippocampus of Tg mice was markedly suppressed following treadmill exercise. These results strongly suggest that treadmill exercise provides a therapeutic potential to inhibit both Abeta-42 and neuronal death pathways. Therefore, treadmill exercise may be beneficial in prevention or treatment of AD. PMID- 20969898 TI - Construction of expression vectors for protein production in Gluconobacter oxydans. AB - The characteristic ability of Gluconobacter oxydans to incompletely oxidize numerous sugars, sugar acids, polyols, and alcohols has been exploited in several biotechnological processes, for example vitamin C production. The genome sequence of G. oxydans 621H is known but molecular tools are needed for the characterization of putative proteins and for the improvement of industrial strains by heterologous and homologous gene expression. To this end, promoter regions for the genes encoding G. oxydans ribosomal proteins L35 and L13 were introduced into the broad-host-range plasmid pBBR1MCS-2 to construct two new expression vectors for gene expression in Gluconobacter spp. These vectors were named pBBR1p264 and pBBR1p452, respectively, and have many advantages over current vectors for Gluconobacter spp. The uidA gene encoding beta-D glucuronidase was inserted downstream of the promoter regions and these promoter reporter fusions were used to assess relative promoter strength. The constructs displayed distinct promoter strengths and strong (pBBR1p264), moderate (pBBR1p452) and weak (pBBR1MCS-2 carrying the intrinsic lac promoter) promoters were identified. PMID- 20969899 TI - Cross-linking and immobilisation of different proteins with recombinant Verrucomicrobium spinosum tyrosinase. AB - This paper reports on the cross-linking and immobilisation of various proteins by the recombinant tyrosinase from Verrucomicrobium spinosum (Vs-tyrosinase). In general it is found that Vs-tyrosinase can readily cross-link proteins with a low degree of complexity, such as casein, but that the enzyme cannot readily cross link well folded protein substrates such as lysozyme, myoglobin, cytochrome c or Candida antarctica lipase B (CALB). However, the inclusion of phenolic compounds (phenol or caffeic acid) to reaction mixtures of these proteins can greatly enhance the levels of cross-linking. For example it is possible to prepare cross linked aggregates of industrially applicable enzymes such as CALB by simply incubating it with Vs-tyrosinase and phenol. The resulting aggregates can be collected by centrifugation and retain high levels of activity and may find applications in biocatalysis. PMID- 20969900 TI - ARDesigner: a web-based system for allosteric RNA design. AB - RNA molecules play vital informational, structural, and functional roles in molecular biology, making them ideal targets for synthetic biology. However, several challenges remain for engineering novel allosteric RNA molecules, and the development of efficient computational design techniques is vitally needed. Here we describe the development of Allosteric RNA Designer (ARDesigner), a user friendly and freely available web-based system for allosteric RNA design that incorporates mutational robustness in the design process. The system output includes detailed design information in a graphical HTML format. We used ARDesigner to engineer a temperature-sensitive AR, and found that the resulting design satisfied the prescribed properties/input. ARDesigner provides a simple means for researchers to design allosteric RNAs with specific properties. With its versatile framework and possibilities for further enhancement, ARDesigner may serve as a useful tool for synthetic biologists and therapeutic design. ARDesigner and its executable version are freely available at http://biotech.bmi.ac.cn/ARDesigner. PMID- 20969902 TI - Involvement of inhibitory factors in the inefficient entry of HIV-1 into the human CD4 positive HUT78 cell line. AB - Little is known about whether human CD4 positive T cells, the principal natural target of HIV-1, have intrinsic factors, other than the receptor/coreceptor molecules, which modulate the entry efficiency of HIV-1. In the present study, we found that human T cell lines, HUT78 and PM1, were less permissive to VSV-G mediated HIV-1 infection compared with the Jurkat cell line. Furthermore, HUT78 cells were also less sensitive to HIV-1 Env-mediated infection, while PM1 cells became susceptible to HIV-1. Real-time PCR analyses showed that less susceptibility of the cells to HIV-1 was due to block at, or prior to, reverse transcription of viral RNA. To clarify the entry efficiency of HIV-1 into these cell lines, we analyzed the internalization of p24 Ag into the cytosolic and vesicular fractions of post-nuclear extracts at 4h post-infection. When the cells were infected with HIV-1 pseudotyped with VSV-G, the amount of p24 Ag in the cytosolic fractions in both HUT78 and PM1 cells was lower than that observed in Jurkat cells. In the case of HIV-1 Env-mediated infection, however, PM1 cells exhibited comparable amounts of p24 Ag in the cytosolic fraction compared with Jurkat cells, while the amount of p24 Ag in HUT78 cells remained low. Heterokaryon experiments between susceptible and less susceptible cell lines suggested that some inhibitory factors counteracted VSV-G-mediated viral entry in PM1 and HUT78 cells, and HIV-1 Env-mediated viral entry in HUT78 cells. PMID- 20969901 TI - Roles of host and viral microRNAs in human cytomegalovirus biology. AB - Human cytomegalovirus (HCMV) has a relatively large and complex genome, a protracted lytic replication cycle, and employs a strategy of replicational latency as part of its lifelong persistence in the infected host. An important form of gene regulation in plants and animals revolves around a type of small RNA known as microRNA (miRNA). miRNAs can serve as major regulators of key developmental pathways, as well as provide subtle forms of regulatory control. The human genome encodes over 900 miRNAs, and miRNAs are also encoded by some viruses, including HCMV, which encodes at least 14 miRNAs. Some of the HCMV miRNAs are known to target both viral and cellular genes, including important immunomodulators. In addition to expressing their own miRNAs, infections with some viruses, including HCMV, can result in changes in the expression of cellular miRNAs that benefit virus replication. In this review, we summarize the connections between miRNAs and HCMV biology. We describe the nature of miRNA genes, miRNA biogenesis and modes of action, methods for studying miRNAs, HCMV encoded miRNAs, effects of HCMV infection on cellular miRNA expression, roles of miRNAs in HCMV biology, and possible HCMV-related diagnostic and therapeutic applications of miRNAs. PMID- 20969903 TI - The C-terminal region of the hepatitis B virus X protein is essential for its stability and function. AB - More than 350 million people worldwide are chronically infected with the human hepatitis B virus (HBV). Chronic HBV infections are associated with the development of hepatocellular carcinoma. While the mechanism of HBV-associated carcinoma remains undefined, it is thought to involve a combination of a continuous inflammatory response to HBV-infected hepatocytes and activities of HBV proteins such as the HBV X protein (HBx). HBx stimulates HBV replication; however, the mechanism by which HBx stimulates HBV replication remains incompletely understood. Studies performed with the woodchuck hepatitis virus (WHV) in woodchucks demonstrated that a C-terminally truncated mutant of the WHV X protein could not stimulate WHV replication. However, whether the C-terminus of HBx is important for HBx-stimulation of HBV replication is unclear. We have constructed C-terminal truncation mutants of HBx and have demonstrated that the C terminus of HBx impacts HBx stability, HBx activation of transcription, and HBx stimulation of HBV replication. These observations highlight the impact of the HBx C-terminus on HBx activities and the importance of directly analyzing HBx expression and functions in HBV-associated tumors that contain chromosomal integrants of HBV with truncations of the HBx gene. PMID- 20969904 TI - Inhibition of programmed cell death by cytomegaloviruses. AB - The elimination of infected cells by programmed cell death (PCD) is one of the most ancestral defense mechanisms against infectious agents. This mechanism should be most effective against intracellular parasites, such as viruses, which depend on the host cell for their replication. However, even large and slowly replicating viruses like the cytomegaloviruses (CMVs) can prevail and persist in face of cellular suicide programs and other innate defense mechanisms. During evolution, these viruses have developed an impressive set of countermeasures against premature demise of the host cell. In the last decade, several genes encoding suppressors of apoptosis and necrosis have been identified in the genomes of human and murine CMV (HCMV and MCMV). Curiously, most of the gene products are not homologous to cellular antiapoptotic proteins, suggesting that the CMVs did not capture the genes from the host cell genome. This review summarizes our current understanding of how the CMVs suppress PCD and which signaling pathways they target. PMID- 20969905 TI - Use of electronic group method in assessing food safety training needs and delivery methods among international college students in the U.S. AB - The purpose of this study was to determine the types of unfamiliar foods international students in the U.S. encounter and to assess food safety information that international students would like to receive for mitigating risks associated with handling and preparing unfamiliar foods. The study identified preferred instructional delivery methods and media for receiving food safety training or information. An electronic group method was used for this study. The electronic group method was chosen to maximize group efficiency by allowing participants to share ideas simultaneously and anonymously with minimal use of time and resources.Types of different (unfamiliar) foods were grouped into major categories. Fast and ready-to-eat foods, and processed and frozen foods constituted a major change for some international students, who were accustomed to homemade and fresh foods in their countries. Participants were interested in receiving information about how to safely handle and prepare unfamiliar foods in their new environment. Preferred methods for receiving food safety information included written materials, online publications, presentations, and materials provided during student orientation. Food packages, websites, and television programs were other preferred methods of receiving food safety information. PMID- 20969906 TI - Design, synthesis and biological activity of peptidomimetic analogs of insect allatostatins. AB - Allatostatins (ASTs) comprise a family of insect neuropeptides isolated from cockroaches and found to inhibit the production of juvenile hormone (JH) by the corpora allata (CA). For this reason, the ASTs can be regarded as possible IGR candidates for pest control. Six peptidomimetic analogs according to the C terminal pentapeptide of ASTs were prepared by solid-phase organic synthetic methods in an attempt to obtain new simple substitution agents. Assays of inhibition of JH biosynthesis in vitro by corpora allata from the cockroach Diploptera punctata showed that the activity of analog I (IC(50): 0.09 MUM) was more active than that of the C-terminal pentapeptide (Tyr-Xaa-Phe-Gly-Leu-NH(2), IC(50): 0.13 MUM) it mimicked and the activity of the analog II (IC(50): 0.13 MUM) proved roughly equivalent to the C-terminal pentapeptide. The results indicate that a new simple mimicry for Tyr-Xaa-Phe-Gly has been discovered; analog I may be a novel compound candidate for potential IGRs. This study will be useful for the design of new AST analogs for insect management. PMID- 20969907 TI - Peripheral activation of corticotropin-releasing factor receptor 2 inhibits food intake and alters meal structures in mice. AB - The orexigenic effect of urocortins (Ucns), namely Ucn 1, Ucn 2 and Ucn 3 through activation of corticotropin-releasing factor (CRF) receptors, has been well characterized after injection into the brain but not in the periphery. We examined the role of CRF receptor subtype 2 (CRF(2)) in the regulation of food intake using intraperitoneal (ip) injection of Ucns and the selective CRF(2) antagonist, astressin(2)-B, and CRF(2) knockout (-/-) mice. Meal structures were monitored using an automated episodic solid food intake monitoring system. Ucn 2 (3, 10 or 30 MUg/kg, ip) induced a rapid in onset, long lasting and dose dependent decrease (38%, 66% and 86%, respectively at 4h) of cumulative food intake after an overnight fast in mice. Ucn 3 anorexic effect was 10-times less potent. Astressin(2)-B (30 or 100 MUg/kg) injected ip, but not intracerebroventricularly, blocked the inhibitory effect of ip Ucn 1 and Ucn 2 (10 MUg/kg). Fasted CRF(2-/-) mice did not respond to ip Ucn 1 (10 MUg/kg). Meal microstructure analysis of the 4-h re-feeding response to an overnight fast showed that Ucn 2 (10 MUg/kg, ip) decreased meal size and duration, but increased meal frequency. In mice fed ad libitum, Ucn 2 (30 MUg/kg) injected ip before the dark phase decreased the 4-h nocturnal meal size and duration without influencing meal frequency while the 10 MUg/kg dose had no effect. These data indicate that Ucns, through peripheral CRF(2) receptor-mediated induction of satiation, inhibit the eating response to a fast more potently than the physiological nocturnal feeding in mice. PMID- 20969908 TI - The first decapeptide adipokinetic hormone (AKH) in Heteroptera: a novel AKH from a South African saucer bug, Laccocoris spurcus (Naucoridae, Laccocorinae). AB - A novel peptide of the adipokinetic hormone (AKH)/red pigment-concentrating hormone (RPCH) family has been elucidated by mass spectrometry from the corpora cardiaca of an African saucer bug species, Laccocoris spurcus. It is the first decapeptide member found in the species-rich taxon Heteroptera, has the primary sequence pGlu-Val-Asn-Phe-Ser-Pro-Ser-Trp-Gly-Gly amide and is denoted as Lacsp AKH. The first eight amino acids are identical to the octapeptide Anaim-AKH of the European saucer bug, Ilyocoris cimicoides. The synthetic peptide Lacsp-AKH elevates lipids upon injection into the hemolymph of L. spurcus at a low dose of 3 pmol. Swimming activity in this saucer bug also causes a significant increase in the lipid concentration in the hemolymph. Thus, both results point to an apparent function of the endogenous new decapeptide Lacsp-AKH in L. spurcus, namely, to regulate lipid mobilization. Isolation of an AKH peptide from the corpora cardiaca of the water bug Aphelocheirus aestivalis (Aphelocheiridae) resulted in the assignment of the octapeptide Anaim-AKH, supporting current phylogenies on the infraorder Nepomorpha. PMID- 20969909 TI - Association of HLA-G polymorphisms with nasopharyngeal carcinoma risk and clinical outcome. AB - The expression of human leukocyte antigen-G (HLA-G) in tumor cells may facilitate the escape of the tumor from immunosurveillance; thus the aim of this study was to evaluate the influence of HLA-G polymorphisms occurrence on nasopharyngeal carcinoma (NPC) susceptibility, severity, and survival. Using the restriction fragment length polymorphism-polymerase chain reaction and the amplification refractory mutation system-polymerase chain reaction method, 186 Tunisian patients and 189 healthy controls were genotyped for nonsynonymous polymorphisms in HLA-G codon 31Thr/Ser, codon 110Leu/Ile and codon 130Leu/framshift. When allele, genotype and haplotype frequencies between patients and controls were compared for each single nucleotide polymorphisms (SNP), no statistical significant differences were observed. According to the lymph node status and the tumor stages, the Ile110 allele was shown to be significantly less frequent among patients with a positive lymph node status and more severe tumor stages (stage I II vs III-IV), respectively. Moreover, the codon 130C deletion occurrence was significantly associated with a decreased NPC free disease and overall survival. Altogether our results suggest a possible role for HLA-G locus in NPC progression and aggressiveness. PMID- 20969910 TI - Evaluation of the impact of the exposure route on the human kinetic adjustment factor. AB - The objective of this study was to assess the impact of the exposure route on the human kinetic adjustment factor (HKAF), for which a default value of 3.16 is used in non-cancer risk assessment. A multi-route PBPK model was modified from the literature and used for computing the internal dose metrics in adults, neonates, children, elderly and pregnant women following three route-specific scenarios to chloroform, bromoform, tri- or per-chloroethylene (TCE or PERC). These include 24 h inhalation exposure, body-weight adjusted oral exposure and 30 min dermal exposure to contaminated drinking water. Distributions for body weight (BW), height (BH) and hepatic cytochrome P450 2E1 (CYP2E1) content were obtained from the literature, whereas model parameters (flows, volumes) were calculated from BW and BH. Monte Carlo simulations were performed and the HKAF was calculated as the ratio of the 95th percentile value of internal dose metrics in subpopulation to the 50th percentile value in adults. On the basis of the area under the parent compound's arterial blood concentration vs time curve (AUC(pc)), highest HKAFs were obtained in neonates for every scenario considered, and were the highest for bromoform (range: 3.6-7.4). Exceedance of the default value based on AUC(PC) was also observed for an oral exposure to chloroform in neonates (4.9). In all other cases, HKAFs remained below the default value. Overall, this study has pointed out the dependency of the HKAF on the exposure route, dose metrics and subpopulation considered, as well as characteristics of the chemicals investigated. PMID- 20969911 TI - Very late-onset obsessive compulsive disorder not related to intracerebral lesions; a case report. PMID- 20969912 TI - Solid-phase extraction and determination of trace amount of some metal ions on Duolite XAD 761 modified with a new Schiff base as chelating agent in some food samples. AB - A method for preconcentration of trace heavy metal ions in environmental samples has been reported. The presented method is based on the sorption of Cr(3+), Co(2+), Cu(2+), Fe(3+), Ni(2+), and Zn(2+) ions with 2-(2,4 dichlorobenzylideneamino) benzenethiol as respective chelate on modified Duolite XAD 761. The metals content of the sorbed complexes are eluted using 6 ml of 4M nitric acid. The influences of the analytical parameters including pH, amount of ligand and solid phase and condition of eluting solution, the effects of matrix ions on the retentions of the analytes were examined. The recoveries of analytes are generally higher than 94% and the RSD is between 1.5% and 2.2%. The method has been successfully applied for the evaluation of understudy metals content in some food samples. PMID- 20969913 TI - A hierarchical Bayesian model for extreme pesticide residues. AB - The number of residue measurements in an individual field trial, carried out to provide data for a pesticide registration for a particular crop, is generally too small to estimate upper tails of the residue distribution for that crop with any certainty. We present a new method, using extreme value theory, which pools information from various field trials, with different crop and pesticide combinations, to provide a common model for the upper tails of residue distributions generally. The method can be used to improve the estimation of high quantiles of a particular residue distribution. It provides a flexible alternative to the direct fitting of a distribution to each individual dataset, and does not require strong distributional assumptions. By using a hierarchical Bayesian model, our method also accounts for parameter uncertainty. The method is applied to a range of supervised trials containing residues on individual items (e.g. on individual apples), and the results illustrate the variation in tail properties amongst all commodities and pesticides. The outputs could be used to select conservative high percentile residue levels as part of a deterministic risk assessment, taking account of the variability between crops and pesticides and also the uncertainty due to relatively small datasets. PMID- 20969914 TI - Effects of Korean ginseng root extract on cisplatin-induced emesis in a rat-pica model. AB - In the present study, we investigate the effect of Korean ginseng root extract (KG) on cisplatin-induced pica in a rat model. Rats were treated with KG before (25, 50, and 100 mg/kg) or after (12.5, 25, and 50 mg/kg) a single intraperitoneal injection of cisplatin (7 and 6 mg/kg, respectively). We examined intake of kaolin and normal food as an indicator of the emetic stimulus every 24 h for 120 h. Changes in body weight, haematology and histopathology were additionally assessed. Pre-treatment with KG (25 and 50 mg/kg) significantly attenuated cisplatin-induced kaolin intake (24, 48, and 72 h) and markedly improved intake of normal food by rats at 48, 72, 96, and 120 h. Cisplatin induced kaolin intake was markedly decreased upon post-treatment of rats with KG (12.5, 25, and 50 mg/kg) at 24 h. Notably, post-treatment with the lowest KG dose resulted in a significant anti-pica effect and improved food intake until 72 h. The magnitude of body weight reduction was significantly diminished in rats pre treated/post-treated with 25, 50, and 12.5 mg/kg KG. The anti-pica effects of KG were further confirmed with haematological and histopathological findings. Our findings collectively indicate that KG improves the resistance of rats against emesis. PMID- 20969915 TI - Effects of surface pre-reacted glass-ionomer fillers on mineral induction by phosphoprotein. AB - OBJECTIVES: The aim of this study was to evaluate the mineralizing potential of ions released from surface pre-reacted glass-ionomer (S-PRG) fillers on mineral induction by phosphoprotein in vitro. METHODS: Phosvitin was used as a model of dentin phosphoprotein in this study. Phosvitin was immobilized on agarose beads with divinyl sulfone. Five aliquots of phosvitin-immobilized agarose beads were incubated in control or experimental mineralizing solution. The experimental mineralizing solutions were made from eluates of resin filled with S-PRG fillers. The beads were incubated at 37 degrees C in a shaking water bath, and aliquots were taken at several time points during the incubation. Then the beads were analyzed for calcium by atomic absorption spectrometry. RESULTS: Phosvitin immobilized agarose beads induced mineral formation after incubation for 5.3h in the metastable solution without ions eluted from S-PRG fillers. Undiluted eluates significantly reduced mineral induction time. SEM observation and X-ray diffraction revealed larger apatite crystals on the beads incubated with eluates of S-PRG fillers than with the control. CONCLUSIONS: S-PRG fillers may play a role in mineral induction. PMID- 20969916 TI - Modeling and simulation of the initial phases of chlorophyll fluorescence from Photosystem II. AB - A simple kinetic model structure for chlorophyll fluorescence (ChlF) from Photosystem II (PSII) offers practical usefulness in quantitative analysis and extraction of information from measured ChlF. In this work, the major PSII phototransduction kinetics was represented with only five state variables. Parameters were estimated through a least-squares algorithm. The developed model structure could produce the well-known OJIP pattern and fit measured ChlF. Influences of PQ pool size, active Q(B) sites, and Q(A) reduction rate on ChlF emission were simulated and discussed in light of the existing literature. PMID- 20969917 TI - Dynamics of intra-follicular glucose during luteinization of macaque ovarian follicles. AB - Glucose is important to the maturation of the oocyte and development of the embryo, while hyperglycemia results in profound reproductive and developmental consequences. However, the normal physiology of glucose in the ovary remains poorly understood. The goal of this study was to determine intra-follicular glucose dynamics during the periovulatory interval in non-human primates undergoing controlled ovarian stimulation protocols. Follicular fluid and mural granulosa cells were isolated before or up to 24h after an ovulatory hCG bolus, and the human granulosa-lutein cell line hGL5 was used. Intra-follicular glucose increased 3h after hCG, and remained at that level until 12h when levels decline back to pre-hCG concentrations. Pyruvate and lactate concentrations in the follicle were not strongly altered by hCG. Mural granulosa cell expression of hexokinase 1 and 2, and glucose-6-phosphate dehydrogenase mRNA decreased following hCG, while glycogen phosphorylase (liver form) increased following hCG. Glucose uptake by hGL5 cells was delayed until 24h following stimulation. In summary, intra-follicular glucose increases following an ovulatory stimulus and mural granulosa cells do not appear able to utilize it, sparing the glucose for the cumulus-oocyte complex. PMID- 20969919 TI - Post-exposure treatment with ginsenoside compound K ameliorates auditory functional injury associated with noise-induced hearing loss in mice. AB - Noise-induced hearing loss (NIHL) is thought to primarily involve damage to the sensory hair cells of the cochlea via mechanical and metabolic mechanisms. Unfortunately, initial studies assessing the effectiveness of post-exposure treatment after hearing loss have yielded largely disappointing results. This study explored the effects of oral treatment with Korean red ginseng (RG) and with two bioavailable ginsenoside metabolites, ginsenoside Rh1 and ginsenoside compound K (GCK), in response to NIHL in a murine model. Pharmacological treatments began 24h after noise exposure and were continued once daily for 7 days. Central auditory function was evaluated using auditory middle latency responses, and cochlear function was determined based on transient evoked otoacoustic emissions. Additionally, cochlear hair cell morphology was investigated after noise exposure. Both Korean red ginseng and compound K reduced threshold shifts, central auditory function damage, and cochlear functional and morphological deficits. In contrast, treatment with ginsenoside Rh1 did not result in recovery of NIHL in mice. These results suggest that consumption of Korean red ginseng may facilitate recovery from noise-induced hearing loss. Furthermore, one of the active constituents in ginseng is likely ginsenoside compound K. PMID- 20969918 TI - Changes in intramuscular cytokine levels during masseter inflammation in male and female rats. AB - The present study was conducted to examine cytokine profiles in the masseter muscle before and after complete Freund's adjuvant (CFA)-induced inflammation and possible sex differences in the cytokine levels. Age matched male and female Sprague Dawley rats were injected with CFA in the mid-region of the masseter muscle. Muscle tissue surrounding the injection site was extracted 6h, 1, 3 and 7 days after the injection to measure TNF-alpha, IL-1beta, IL-6 and IL-4 levels with Luminex multi-analyte profiling (xMAP) technology. The cytokine levels were compared to those obtained from naive rats. CFA injection into the masseter muscle led to a significant time effect in the level of TNF-alpha compared to that of naive rats. The pattern of changes in TNF-alpha level after CFA injection was significantly different between the male and female rats owing to the differences in basal levels. CFA injection induced significant time-dependent increases in the levels of IL-1beta and IL-6 in the masseter muscle in both male and female rats. The level of IL-4 was slightly, but significantly, reduced in both sexes at 6h and 3 days after CFA-induced inflammation. No significant sex differences were observed in the levels of IL-1beta, IL-6 or IL-4. The results provided novel information about distinct cytokine profiles during CFA-induced muscle inflammation, and the basis for further pursuing contributions of each cytokine in pain processing and analgesic responses in both sexes. PMID- 20969920 TI - Comparison of MEG responses to the sinusoidal flicker and the envelope of amplitude-modulated flicker. AB - For a flickering light with two or more frequency components, the temporal envelope of the flickering light is perceived, although there is no frequency component at the frequency of the envelope. To address the processing of the temporal envelope, we compared cortical responses to the envelope of amplitude modulated (AM) flickering lights with responses to sinusoidal flickering lights. We measured magnetoencephalographic (MEG) responses to AM and sinusoidal flickering lights while changing the frequency of the temporal envelope of AM flickering light and the stimulus frequency of sinusoidal flickering light. The result showed that the strength of the MEG response to sinusoidal flickering light increased with stimulus frequency in the low frequency range. This probably resulted from the band-pass filtering in the visual system. However, such an increase in the low frequency range was not observed for the envelope of AM flickering light. The absence of the increase in MEG responses suggests that the envelope of AM flickering light is not subject to band-pass filtering in the visual system. It is therefore possible that the envelope is represented after the band-pass filtering stage. PMID- 20969921 TI - STAT5 regulates glioma cell invasion by pathways dependent and independent of STAT5 DNA binding. AB - STAT5 activation in primary glioma was analyzed using antibody directed against phosphorylated STAT5 (pSTAT5), in all samples robust pSTAT5 immunostaining was detected, predominantly in the nucleus. We then used immunofluorescence, transcription factor binding assays and western blotting to study EGF-modulated STAT5 activation in the human U87 glioma cell line. EGF was found to upregulate pSTAT5 levels and enhances STAT5 DNA-binding activity. To address the role of STAT5 in glioma cell invasion, resting and EGF-treated U87 cells were treated with siRNA directed against STAT5 and the extent of glioma cell migration into a Matrigel matrix was monitored. EGF treatment markedly enhanced matrix invasion, and knockdown of STAT5 expression with siRNA significantly downregulated matrix invasion by both EGF-stimulated and resting glioma cells. However, transfection with a decoy oligonucleotide abolished transcriptional activation of a STAT5 target gene but failed to inhibit matrix invasion in resting U87 cells. By contrast, the decoy nucleotide abolished EGF enhancement of matrix invasion. STAT5 therefore promotes glioma cell invasion via at least two different pathways: a pathway dependent of STAT5 DNA binding, and a second pathway independent of STAT5 DNA binding. PMID- 20969922 TI - Electrophysiological properties of neurons in the robust nucleus of the arcopallium of adult male zebra finches. AB - Nucleus robust arcopallium (RA) of the songbird is a distinct forebrain region that is essential for song production. To explore the electrophysiological properties, whole cell recordings were made from adult zebra finch RA neurons in slice preparations. Based on the electrophysiological properties, neurons in RA were classified into two distinct classes. Type I neurons were spontaneously active. They had larger input resistance, longer time constant, larger time-peak of an afterhyperpolarization (AHP), and broader action potentials than those of the other class. A slow, time-dependent inward rectification was induced by hyperpolarizing current pulses in this type of neuron, and was blocked by external CsCl (2mM). Type II neurons had a more negative resting membrane potential than that of type I neurons. They were characterized by a steeper slope of the recovery from the peak of the AHP and frequency-current relationships, a higher firing threshold, and irregular spiking in response to depolarizing current injection. PMID- 20969923 TI - L-3-n-butylphthalide regulates amyloid precursor protein processing by PKC and MAPK pathways in SK-N-SH cells over-expressing wild type human APP695. AB - Amyloid precursor protein (APP) is cleaved by alpha-secretase, within the amyloid beta (Abeta) sequence, resulting in the release of a secreted fragment (alphaAPPs) and precluding Abeta production. We investigated the effects of a promising anti-AD new drug, l-3-n-butylphthalide (L-NBP), on APP processing and Abeta generation in neuroblastoma SK-N-SH cells overexpressing wild-type human APP695. L-NBP significantly increased alphaAPPs release, and reduced Abeta generation. The steady-state full-length APP levels were unaffected by L-NBP. It suggested that L-NBP regulated APP processing towards to the non-amyloidogenic alpha-secretase pathway. Protein kinase C (PKC) and mitogen activated protein (MAP) kinase might be involved in L-NBP-induced alphaAPPs secretion. L-NBP significantly increased PKCalpha and E activations, lowered PKCgamma activation and increased the phosphorylation of p44/p42 MAPK. Furthermore, PKC and MAPK inhibitors partially reduced L-NBP-induced alphaAPPs secretion. The results suggested alternative pharmacological mechanisms of L-NBP regarding the treatment of Alzheimer's disease (AD). PMID- 20969924 TI - Characterization of Aedes albopictus akirin for the control of mosquito and sand fly infestations. AB - The control of arthropod vectors of pathogens that affect human and animal health is important for the eradication of vector-borne diseases. Recent evidences showed a reduction in the survival and/or fertility of mosquitoes, sand flies and poultry red mites fed in vitro with antibodies against the recombinant Aedes albopictus akirin. These experiments were the first step toward the development of a multi-target arthropod vaccine. In this study, we showed that the oviposition of A. albopictus and Phlebotomus perniciosus fed on mice vaccinated with recombinant A. albopictus akirin was reduced by 17% and 31%, respectively when compared to controls. However, Aedes aegypti mosquitoes were not affected after feeding on vaccinated mice. These results showed that recombinant A. albopictus akirin could be used to vaccinate hosts for the control of mosquito and sand fly infestations and suggested new experiments to develop improved vaccine formulations. PMID- 20969925 TI - Safety and immunogenicity of a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125) in healthy young adults. AB - BACKGROUND: The need for worldwide seasonal and pandemic vaccine production has increased interest in the development of innovative technologies for influenza vaccine production. We evaluated a novel influenza vaccine consisting of the globular head of the HA1 domain of the A/Solomon Islands/3/2006 (H1N1) influenza virus (VAX125) genetically fused to the TLR5 ligand, flagellin, and produced in E. coli. METHODS: 128 healthy adult subjects 18-49 years old were enrolled in a clinical trial conducted in three stages at a single center. Stage 1 was an open label, dose escalation study in which the VAX125 vaccine was administered intramuscularly (im) at doses of 0.1 MUg, 0.3 MUg, 1 MUg, 2 MUg, 3 MUg, 5 MUg and 8 MUg to groups of 8 subjects each. Stage 2 was a double-blind, placebo controlled study in which subjects were randomized to receive 1.0 MUg and 2.0 MUg VAX125 vaccine doses or placebo, with 16 subjects per group. Finally, an additional 24 subjects received a 0.5 MUg dose of VAX125 in stage 3, which was a non-randomized, open label study. In all parts subjects were followed for adverse events and sera was tested by hemagglutination-inhibition (HAI) and microneutralization (MN) against egg-grown virus on days 0, 7, 14, and 28. Serum C-reactive protein (CRP), cytokine levels, and anti-flagellin antibody were also assessed. RESULTS: Vaccine was generally well tolerated and there were no serious adverse events. Pain at the injection site was the most common local adverse event, and was mild or moderate in intensity. Systemic symptoms after vaccination include fatigue and headache, and two subjects, who received either 3 or 8 MUg, had moderately severe systemic symptoms accompanied by substantial increases in serum CRP. Serum antibody responses against SI were seen by HAI and MN in most study subjects, with the geometric mean titer of post vaccination antibody increasing in a dose-dependent fashion. Overall, four-fold or greater serum HAI responses were seen in 61 of 96 (64%) subjects who received doses of 0.5 MUg or greater, including in 46 of 72 subjects who received doses from 0.5 MUg to 2 MUg. CONCLUSIONS: The globular head of the influenza HA expressed in a prokaryotic system was able to induce a functional antibody response against native virions. Vigorous responses were seen at relatively low doses of HA antigen suggesting that the addition of flagellin provided a substantial adjuvanting effect. The high levels of immune response at low doses of antigen and the relative ease of production associated with E. coli expression suggests that this approach may represent an effective strategy for enhancing the global influenza vaccine supply. PMID- 20969926 TI - Administration of dendritic cells dual expressing DcR3 and GAD65 mediates the suppression of T cells and induces long-term acceptance of pancreatic-islet transplantation. AB - Pancreatic-islet transplantation is currently regarded as the only approach to cure type 1 diabetic patients (T1D). However, recurrent autoimmunity is a critical factor contributing to graft rejection along with alloreactivity. Recently, the glutamic acid decarboxylase 65 (GAD65) was identified as the one of the major pancreatic antigens targeted by self-reactive T cells in T1D. Therefore, the T cells specific for GAD65 may be the important therapeutical target of T1D. In this study, dendritic cells (DCs) were transfected with the recombinant adenovirus, dual expressing DcR3 and GAD65 in vitro, and NOD mice were administrated with the genetically modified DCs in vivo after islet transplantation. The results demonstrated that the genetically modified DCs significantly suppressed the T cell response to GAD65, delayed onset of diabetes, improved the success and survival of islet transplantation. The findings suggest that the adoptive transfer of genetically modified DCs dual expressing DcR3 and GAD65 represent a future therapeutic potential in T1D and pancreatic-islet transplantation. PMID- 20969927 TI - The uptake of rotavirus vaccine and its effectiveness in preventing acute gastroenteritis in the community. AB - We examined the uptake of rotavirus vaccine and its effectiveness in preventing acute gastroenteritis (AGE) in the community. Data on rotavirus vaccines purchases and AGE were extracted from the computerized database of a large health maintenance organization in Israel. The incidence of AGE requiring a physician visit during 2008-09 rotavirus season among vaccinated and non-vaccinated children were compared, and vaccine effectiveness was calculated as: (1-Relative Risk)*100. During the study period, the uptake of rotavirus vaccine (mostly monovalent) reached 55.1% (N=19,108) of the studied cohort. The risk of AGE requiring a physician visit was 23.2% and 46.4% among vaccinated and unvaccinated children, respectively, yielding an effectiveness of 50.1% (95% CI: 47.5%, 52.6%). Rotavirus monovalent vaccine was highly effective in preventing AGE in the community. PMID- 20969928 TI - The role of Stat5 transcription factors as tumor suppressors or oncogenes. AB - Stat5 is constitutively activated in many human cancers affecting the expression of cell proliferation and cell survival controlling genes. These oncogenic functions of Stat5 have been elegantly reproduced in mouse models. Aberrant Stat5 activity induces also mitochondrial dysfunction and reactive oxygen species leading to DNA damage. Although DNA damage can stimulate tumorigenesis, it can also prevent it. Stat5 can inhibit tumor progression like in the liver and it is a tumor suppressor in fibroblasts. Stat5 proteins are able to regulate cell differentiation and senescence activating the tumor suppressors SOCS1, p53 and PML. Understanding the context dependent regulation of tumorigenesis through Stat5 function will be central to understand proliferation, survival, differentiation or senescence of cancer cells. PMID- 20969929 TI - Modulatory effects of serotonin on glutamatergic synaptic transmission and long term depression in the deep cerebellar nuclei. AB - The deep cerebellar nuclei (DCN) are the terminal components of the cerebellar circuitry and constitute its primary output structure. Their activity is important for certain forms of motor learning as well as generation and control of movement. DCN neurons receive glutamatergic excitatory inputs from the pontine nuclei via mossy fibres (MFs) and concomitantly receive inputs from 5-HT containing neurons of the raphe nuclei. We aimed to explore the roles of 5-HT at MF-DCN synapses by using cerebellar slices from 11 to 15-day-old rats. Bath application of 5-HT reversibly decreased the amplitude of stimulation-evoked excitatory postsynaptic currents (eEPSCs) via the activation of 5-HT1B receptors at the presynaptic terminals of the MFs. Burst stimulation of the MFs elicited long-term depression (LTD) at the MF-DCN synapses that require activation of the group I metabotropic glutamate receptor (mGluR). In the presence of 5-HT, the extent of burst-induced LTD of MF EPSCs was significantly reduced. Application of 5-HT also decreased the amplitude of mGluR-dependent slow EPSCs evoked by similar burst stimulation. Furthermore, (S)-3,5-dihydroxyphenylglycine (DHPG), a group I mGluR agonist, induced chemical LTD of MF EPSCs, and 5-HT had no significant effect on this LTD. Taken together, the results suggest that 5-HT not only has transitory inhibitory effects on MF EPSCs but also plays a role in regulating the long-term synaptic efficacy. PMID- 20969930 TI - Maternal exposure to the CB1 cannabinoid agonist WIN 55212-2 produces robust changes in motor function and intrinsic electrophysiological properties of cerebellar Purkinje neurons in rat offspring. AB - The cerebellum, which controls coordinated and rapid movements, is a potential target for the deleterious effects of drugs of abuse including cannabis (i.e. marijuana, cannabinoids). Prenatal exposure to cannabinoids has been documented to cause abnormalities in motor and cognitive development, but the exact mechanism of this effect at the cellular level has not been fully elucidated. Previous studies indicate that cannabinoids are capable of modulating synaptic neurotransmission. In addition to altering synaptic activity, cannabinoid exposure may also change intrinsic neuronal properties. In the present study several different approaches including behavioral assays, extracellular field potential recordings and whole-cell patch clamp recordings, were used to address whether maternal exposure to the CB1 cannabinoid receptor agonist WIN 55-212-2 (WIN) affects the intrinsic electrophysiological properties of Purkinje neurons. WIN treatment of pregnant rats produced a significant decrease in the rearing frequency, total distance moved and mobility of the offspring, but significantly increased the time of the righting reflex, the grooming frequency and immobility. Neuromotor function, as assessed in the grip test and balance beam test, was also significantly impaired in prenatally WIN-treated group. Prenatal exposure to WIN increased the amplitude of population spikes (PS) recorded from the cerebellar Purkinje cell layer of offspring following synaptic blockage. WIN treatment of pregnant rats also profoundly affected the intrinsic properties of Purkinje neurons in offspring. This treatment increased the firing regularity, firing frequency, amplitude of afterhyperpolarization (AHP), the peak amplitude of action potential and the first spike latency, but decreased significantly the time to peak and duration of action potentials, the instantaneous firing frequency, the rate of rebound action potential and the voltage "sag" ratio. These results raise the possibility that maternal exposure to cannabinoids may profoundly affect the intrinsic membrane properties of cerebellar Purkinje neurons of offspring by altering the membrane excitability through modulation of intrinsic ion channels. PMID- 20969931 TI - Neuronal soma migration is determined by neurite tension. AB - Neuronal migration is an intricate process involving a wide range of cellular mechanisms, some of which are still largely unknown. Using specially prepared culturing substrates, we were able to explore this and other developmental processes in networks composed of cultured locust neurons, and to analyze the role of neurite tension in these processes. Time lapse investigation shows that the shape and position of the cell soma are both linked to the extent and direction of the combined tension in its neurites. In particular, for migrating neurons (over 1-2 days) with three main neurites, a force-balance between neurite tension forces was demonstrated (SigmaF=0). The results presented here suggest that neuronal migration is strongly affected by tension in neurites rather than being entirely determined by the interaction between soma and substrate. The validity of these results to other in-vitro and in-vivo data is discussed. PMID- 20969932 TI - Repetitive adaptation induces plasticity of spatial frequency tuning in cat primary visual cortex. AB - Sensory neurons display transient changes in their response properties following prolonged exposure to an appropriate stimulus (adaptation). In adult cat primary visual cortex, spatial frequency-selective neurons shift their preferred spatial frequency (SF) after being adapted to a non-preferred SF. In anesthetized cats prepared for electrophysiological recordings in the visual cortex, we applied a non-preferred spatial frequency for two successive periods of adaptation (a recovery and interval of ~90 min separated both phases of adaptation) in order to determine if a first adaptation retained an influence on a second adaptation. The first application of a non-preferred SF shifted the tuning curve of the cell mainly in the direction of the imposed SF. The results showed that attractive shifts occurred more frequently (68%) than repulsive (12%) changes in cortical cells. The increase of responsivity was band-limited and occurred around the imposed SF, while flanked responses remained unmodified in all conditions. After a recovery period allowing neurons to restore their original SF tuning curves, we carried out a second adaptation which produced four major results: (1) a higher proportion of repulsive shifts (31%) compared to attractive shifts (49%), (2) an increase of the magnitude of the attractive shifts, (3) an additional enhancement of the evoked firing rate for the newly acquired SF, and (4) for the acquired SF the variability coefficient decreased following the second adaptation. The supplementary response changes suggest that neurons in area 17 keep a "memory" trace of the previous stimulus properties. It also highlights the dynamic nature of basic neuronal properties in adult cortex since repeated adaptations modified both the spatial frequency tuning selectivity and the response strength to the preferred spatial frequency. These enhanced neuronal responses suggest that the range of adaptation-induced plasticity available to the visual system is broader than anticipated. PMID- 20969933 TI - A novel extended sequence learning task (ESLeT) for rodents: validation and the effects of amphetamine, scopolamine and striatal lesions. AB - Neurodegenerative diseases of the basal ganglia have been associated with impairments in 'implicit learning', failing to detect repeated sequences embedded in long series of random stimuli. The present study has introduced a novel 5-step sequence learning task (ESLeT) for rats, in which the animals learn to respond to randomly occurring stimuli in a horizontal spatial array, and to chain 5 sequential stimulus-response choices to gain food reward. The rats exhibit improved performance in both speed and accuracy of responding when the sequence is predictable following the first stimulus in the chain, suggesting a comparable capacity for 'implicit learning'. Performance was more rapid but less accurate when the rats were pre-treated with the dopamine indirect agonist amphetamine, markedly disrupted in both dependent variables when pre-treated with the cholinergic antagonist, scopolamine, and modestly disrupted following bilateral striatal lesions, with distinctive patterns of error and changes in the precise patterns of stimulus-by-stimulus responding associated with each experimental treatment. The ESLeT task provides a new test with distinctive advantages for the analysis of vigilance, serial responding and procedural motor learning in animal models of human neurodegenerative disease. PMID- 20969934 TI - Molecular simulations of Taxawallin I inside classical taxol binding site of beta tubulin. AB - A new taxoid Taxawallin I (1) along with two known taxoids (2-3) were isolated from methanolic bark extract of Taxus wallichiana Zucc. Structural characterization was confirmed by mass and NMR spectral techniques. Taxawallin I exhibited significant in-vitro anticancer activity against HepG2, A498, NCI-H226 and MDR 2780AD cancer lines. Tubulin binding assay was performed to assess its tubulin binding activity. Molecular docking analysis was performed to study the potential binding mode inside the taxol binding site of beta-tubulin. PMID- 20969935 TI - Nanocarrier for the enhanced bioavailability of a cardiovascular agent: in vitro, pharmacodynamic, pharmacokinetic and stability assessment. AB - The goals of the current study were to develop and characterize a nanoemulsion of ezetimibe, evaluate its stability, lipid lowering and pharmacokinetic profile. Solubility of the drug was estimated in various oils and surfactants. Existence of nanoemulsion region was confirmed by plotting phase diagrams. Various thermodynamic stability and dispersibility tests were performed on the formulations chosen from phase diagram. Percentage transmittance, refractive index, viscosity, droplet size and zeta potential of the optimized formulations were determined. Dialysis bag method was employed to study the release rate. The formulation selected for bioavailability estimation contained Capryol 90 (10%, v/v), Crempophor EL (11.25%, v/v), Transcutol((r)) P (33.75%, v/v), and double distilled water (45%, v/v). The release rate from the nanoemulsion was highly significant (p<0.001) in contrast to the drug suspension. The level of total cholesterol in the group receiving nanoemulsion CF1 was found to be highly significant (p<0.001) in comparison to the group receiving drug suspension. Bioavailability studies in rats revealed superior absorption of ezetimibe from nanoemulsion as compared to the marketed formulation and drug suspension. The shelf life of the nanoemulsion was estimated to be 18.53 months. The present study corroborated nanoemulsion to be a promising choice to improve the bioavailability of ezetimibe. PMID- 20969936 TI - Cellular uptake and degradation behaviour of biodegradable poly(ethylene glycol graft-methyl methacrylate) nanoparticles crosslinked with dimethacryloyl hydroxylamine. AB - Crosslinked polymers with hydrolytically cleavable linkages are highly interesting materials for the design of biodegradable drug carriers. The aim of this study was to investigate if nanoparticles made of such polymers have the potential to be used also for intracellular drug delivery. PEGylated nanoparticles were prepared by copolymerization of methacrylic acid esters and N,O-dimethacryloylhydroxylamine (DMHA). The particles were stable at pH 5.0. At pH 7.4 and 9.0 the degradation covered a time span of about 14 days, following first-order kinetics with higher crosslinked particles degrading slower. Cellular particle uptake and cytotoxicity were tested with L929 mouse fibroblasts. The particle uptake rate was found to correlate linearly with the surface charge and to increase as the zeta potential becomes less negative. Coating of the particle surface with polysorbate 80 drops the internalization rate close to zero and the charge dependence disappears. This indicates the existence of a second effect apart from surface charge. A similar pattern of correlation with zeta potential and coating was also found for the degree of membrane damage while there was no effect of polysorbate on the cell metabolism which increased as the negative charge decreased. It is discussed whether exocytotic processes may explain this behaviour. PMID- 20969937 TI - Excipients enhance intestinal absorption of ganciclovir by P-gp inhibition: assessed in vitro by everted gut sac and in situ by improved intestinal perfusion. AB - In rats we examined the effects of some common excipients on the intestinal absorption of ganciclovir (GCV), a BCS-III drug and substrate of P-gp, by assessing its in vitro transfer from mucosa to serosa and in situ transepithelial permeation. In vitro, all selected excipients (concentration range 0.1-1% [w/v]) could increase the transport amount of GCV in the everted gut sac model. Whereas enhancement by F-68 demonstrated regional differences like verapamil, PEG-400, Tween-80 and EL-35 exhibited no regional differences. In situ studies were performed by an improved perfusion model, single-pass perfusion with whole small intestine, to determine more accurately the permeability of lipophobic compounds. The permeability of GCV was significantly increased by all excipients. The effects of EL-35 and F-68 were dose-dependent but those of PEG-400 and Tween-80 were not. The results suggest that enhancements of intestinal absorption of GCV by these excipients are probably due to inhibition of P-gp-mediated drug efflux. It could be deduced from their different properties that both blocking binding sites of P-gp and altering membrane fluidity were involved in their P-gp inhibition. The former mechanism might be involved for F-68, while the latter one might account for the effects of PEG-400, Tween-80 and EL-35. PMID- 20969938 TI - Postnatal development of the middle ear in New Zealand White rabbits: ossicles and tympanic ring. AB - We studied the postnatal development of the middle ear (ME) in New Zealand White rabbits. Bullae were scanned using a desktop X-ray microtomograph and 3D models of the ME ossicles as well as the tympanic ring (TR) were prepared. In 0, 1, 2 days old rabbits the ossification process was incomplete. We can therefore present quantitative data obtained from older rabbits (ages: 4-180 days) and a qualitative description at the earlier ages. For a number of the measured parameters an exponential curve could be fitted to the data, and the time constant (at which 63% of the final value was obtained) was calculated. The length of the manubrium increased rapidly in a period of about 15 postnatal days, from 1.73 mm to 4.08 mm. The distance between the tip of the malleus and the TR increased rapidly until day 30, from nearly 0 to 1.40 mm. The increase of the surface area within the TR was small as compared to inter-specimen variance, but the ratio [tympanic membrane area]/[TR area] clearly increased (from 1.00 to 1.11), with a time constant of 8.3 days. The area of the stapes footplate (FP) increased rapidly in about 15 days (from 0.72 mm(2) to 1.49 mm(2), time constant 4.8 days). The TR was nearly developed at birth whereas the stapes footplate was quite underdeveloped. The distance between the tip of the malleus and the incudomallear rotation axis increased rapidly until day 20 and varied between 3.47 mm and 5.00 mm. The distance between the tip of the incus and the rotation axis increased until day 133, from 1.39 mm to 1.69 mm. Our study shows that in rabbits the ME is underdeveloped at birth and that the functional geometry develops over the same time course as the ability to hear. The conical shape of the tympanic membrane (TM) is formed by retraction and growth of the manubrium, mainly during the first 40 days after birth. PMID- 20969939 TI - Cochlear active mechanisms in young normal-hearing subjects affected by Williams syndrome: time-frequency analysis of otoacoustic emissions. AB - The aim of this study was to investigate the functionality of cochlear active mechanisms in normal-hearing subjects affected by Williams syndrome (WS). Transient evoked otoacoustic emissions (TEOAEs) were recorded in a group of young WS subjects and a group of typically developing control subjects, all having normal-hearing thresholds and normal middle-ear functionality. We also analysed the narrow-band frequency components of TEOAEs, extracted from the broad-band TEOAE recordings by using a time-frequency analysis algorithm based on the Wavelet transform. We observed that TEOAEs and the frequency components extracted from TEOAEs measured in WS subjects had significantly lower energy compared to the controls. Also, the narrow-band frequency components of TEOAEs measured in WS subjects had slightly increased latency compared to the controls. Overall, results would suggest a subtle (i.e., sub-clinical) dysfunction of the cochlear active mechanisms in WS subjects with otherwise normal hearing. Also, results point out the relevance of using otoacoustic emissions in the audiological evaluation and monitoring of WS subjects to early identify possible subtle auditory dysfunctions, before the onset of mild or moderate hearing loss that could exacerbate language or cognitive impairments associated with WS. PMID- 20969940 TI - Spiral ganglion cell survival after round window membrane application of brain derived neurotrophic factor using gelfoam as carrier. AB - Several studies have shown that treatment with various neurotrophins protects spiral ganglion cells (SGCs) from degeneration in hair-cell deprived cochleas. In most of these studies the neurotrophins are delivered by means of intracochlear delivery methods. Recently, other application methods that might be more suited in cochlear implant patients have been developed. We have examined if round window membrane application of gelfoam infiltrated with a neurotrophin resulted in SGC survival in deafened guinea pigs. Two weeks after deafening, gelfoam cubes infiltrated with 6 MUg of brain-derived neurotrophic factor (BDNF) were deposited onto the round window membrane of the right cochleas. Electric pulses were delivered through an electrode positioned within the round window niche to electrically evoke auditory brainstem responses (eABRs). Two or four weeks after deposition of the gelfoam all cochleas were histologically examined. We found that local BDNF treatment enhances the survival of SGCs in the basal cochlear turn after two and four weeks. The treatment had no effect on SGC size or shape. In animals treated with BDNF, eABR amplitudes were smaller than in normal-hearing control animals and similar to those in deafened controls. We conclude that BDNF delivered by means of local gelfoam application provides a protective effect, which is limited compared to intracochlear delivery methods. PMID- 20969941 TI - Antihyperglycemic activity of Selaginella tamariscina (Beauv.) Spring. AB - AIM OF THE STUDY: The present study was designed to investigate the effects of the EtOH and H(2)O extracts of Selaginella tamariscina (Beauv.) Spring on hyperglycemia in diabetic rats and HepG2 cells, and to confirm the active fractions of EtOH extract in HepG2 cells. MATERIALS AND METHODS: HepG2 cells and type II diabetic rats induced by low-dose streptozotocin (STZ) and high-fat diet (HFD) were used to evaluate the hypoglycemic effect of EtOH and H(2)O extracts of Selaginella tamariscina. HepG2 cells were used to evaluate the promotive effect of different fractions of EtOH extract obtained from a polyamide column on glucose utilization. RESULTS: The results in HepG2 cells indicated that the EtOH extract had a better hypoglycemic effect than the H(2)O extract. The results in diabetic rats indicated that both EtOH extract and H(2)O extract were able to ameliorate the fasting blood glucose (FBG) level and improve oral glucose tolerance (OGTT). Total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-c), free fatty acids (FFA), tumor necrosis factor alpha (TNF-alpha), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and malondialdehyde (MDA) levels in serum were lowered. High density lipoprotein (HDL-c), insulin and superoxide dismutase (SOD) levels in serum were elevated as well as the hepatic glycogen content in diabetic rats. Compared with H(2)O extract, the effects of EtOH extract were more marked. The 80% ethanol fraction exhibited a stronger hypoglycemic effect than the aqueous and 50% ethanol fractions, but the 95% ethanol fraction did not show any appreciable effects in HepG2 cells. CONCLUSIONS: The results suggested that the EtOH extract had a better hypoglycemic effect than the H(2)O extract; the 80% ethanol fraction from polyamide column had a strong hypoglycemic activity in HepG2 cells. PMID- 20969942 TI - Inactivation of GABA(A) receptor reduces ginsenoside Rb3 neuroprotection in mouse hippocampal slices after oxygen-glucose deprivation. AB - AIM OF THE STUDY: To investigate the effect of ginsenoside Rb(3) on synaptic transmission after oxygen-glucose deprivation in vitro. MATERIALS AND METHODS: The population spike (PS) was recorded in the stratum pyramidale of mouse hippocampal slices using extracellular recordings. RESULTS: Ginsenoside Rb(3) depressed the basal synaptic transmission, which also promoted the recovery amplitude of PS after OGD in a concentration-dependent manner. The GABA(A) receptor agonist muscimol improved the recovery, which was similar to that of ginsenoside Rb(3). Moreover, the effect of ginsenoside Rb(3) in combination with muscimol was not additive. Treatment with the GABA(A) receptor antagonist bicuculline or picrotoxin, which prevented the depression of PS caused by ginsenoside Rb(3), also reduced the neuroprotection. CONCLUSION: The results indicate that the activation of the GABA(A) receptor is correlated with the neuroprotective mechanisms of ginsenoside Rb(3). PMID- 20969943 TI - Chinese medicine Tongxinluo modulates vascular endothelial function by inducing eNOS expression via the PI-3K/Akt/HIF-dependent signaling pathway. AB - AIM OF THE STUDY: To investigate the molecular mechanisms whereby the Chinese medicinal compound Tongxinluo improves vascular endothelial function through studying the induction of endothelial nitric oxide synthase (eNOS) and its upstream signaling pathway. MATERIALS AND METHODS: Hyperhomocysteinemia was induced in Wistar rats by a methionine-rich diet followed by Tongxinluo treatment. The aorta ring was isolated for measuring vascular dilation of aorta and eNOS expression. Human umbilical vein endothelial cells (HUVECs) were transfected with AP-1, NF-kappaB, HRE or eNOS reporter plasmid followed by Tongxinluo exposure. Expression of the reporter genes was measured by luciferase assay. The level of eNOS was studied by western blot and the nitric oxide content was measured using the nitrate reductase method. HUVECs were also transiently transfected with the dominant negative mutant of HIF-1, PI-3K or Akt to explore the role of HIF and PI-3K/Akt pathway in eNOS induction by Tongxinluo. RESULTS: Tongxinluo could significantly up-regulate the expression of eNOS in the aortic tissue and improve the endothelium-dependent vasodilation of the aorta ring. Additionally, Tongxinluo at various doses could significantly enhance the expression of HRE and eNOS reporter gene as well as up-regulate the protein level of eNOS. Meanwhile, Tongxinluo caused a dose-dependent increase in the NO content in the supernatant of HUVECs. Suppression of HIF-1 activation by DN-HIF or inhibition of PI-3K/Akt pathway by DeltaP85 or DN-Akt both attenuated HRE reporter gene activation and eNOS induction by Tongxinluo. CONCLUSION: Tongxinluo, a compound Chinese traditional medicine, up-regulates the expression of eNOS via the PI-3K/Akt/HIF-dependent signaling pathway, thus improving the endothelium-dependent vasodilation. PMID- 20969944 TI - Anti-inflammatory action of methanol extract of Carthamus tinctorius involves in heme oxygenase-1 induction. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The methanol extracts of Carthamus tinctorius (MEC) have long been used in traditional medicine as anti-inflammatory agent, however, the molecular mechanism by which MEC shows anti-inflammatory action is not investigated. AIM OF THE STUDY: Induction of heme oxygenase-1 (HO-1) by many medicinal herbs has been reported excellent anti-inflammatory action. Thus, the aim of the study is to explore whether anti-inflammatory action of MEC is related with HO-1 induction in RAW 264.7 cells. MATERIALS AND METHODS: The present study was designed to investigate as to MEC induces HO-1 expression so that it reduces inflammation by suppression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in cells activated with lipopolysaccharide (LPS). RESULTS: Expression of HO-1 protein by MEC in macrophages was increased in a concentration- and time-dependent manner. Treatment with MEC significantly inhibited upregulation of both iNOS and COX-2 in LPS-activated macrophages and consequently reduced production of NO and PGE(2), respectively. The reduced expression of iNOS and COX-2 by MEC was reversed by siHO-1 RNA transfection. In addition, NF-E2-related factor (Nrf2) was translocated from cytosol to nucleus by MEC. The binding of NF-kappaB as well as NF-kappaB luciferase activity was also significantly diminished by MEC. Finally, tumor necrosis factor (TNF)-alpha mediated VCAM-1 expression in endothelial cell was significantly inhibited by MEC. CONCLUSIONS: The present results show that MEC induces HO-1 expression via Nrf2 translocation and inhibits NF-kappaB activity, which may be responsible for anti-inflammatory action. Therefore, we propose that anti-inflammatory action of MEC involves at least HO-1 induction. PMID- 20969945 TI - Neural progenitors proliferation is inhibited by EphB3 in the developing subventricular zone. AB - The subventricular zone (SVZ) of the mammalian forebrain is a major source of multipotent stem cells during development, and contributes to neurogenesis throughout the lifespan of the organism. Several studies described molecules regulating adult neurogenesis, however, few of them have examined neurogenesis in the early postnatal period. Adult neurogenesis is regulated in part by ephrinB3 and its receptors, so we examined the role of EphB3 on neural stem/progenitor cell (NSPC) proliferation in early postnatal development in the SVZ. To examine NSPC proliferation, we used BrdU incorporation in both cultured NSPCs and neonatal gene-targeted knockout mice, as well as Ki67 immunostaining in EphB3(-/ ) mice. We observed a significant increase in proliferation in cultured NSPCs derived from EphB3(-/-) mice and in the SVZ of EphB3(-/-) mice. These studies support an anti-proliferative role for EphB3 in regulating NSPC numbers in the developing SVZ. PMID- 20969946 TI - The role of Smad4 in vestibular development in mice. AB - The regulation of the bone morphogenetic protein (BMP) signal transduction pathway is important in the development of the inner ear and vestibular system. We reported previously that small mothers against decapentaplegic homolog-4 (Smad4) is required for inner ear cochlear development and normal auditory function in mammals; however, the distribution and functional mechanisms of Smad4 at various stages of vestibular development remained unclear. To investigate the relationship between the Smad4 gene and vestibular organ development, we measured changes in the expression of BMP4 and Smad4 during vestibular development in C57BL/6 mice. In addition, vestibular structures, pathologic changes, and the vestibular function of chondrocyte-specific Smad4 knockout mice were compared to those of the control group. We found that the expression of Smad4 in the inner ear was delayed compared with that of BMP4. Moreover, chondrocyte-specific Smad4 knockout homozygous mice showed stunted growth and partial vestibular deformities, but it showed less histologic changes in the vestibular end-organs and saccule dysfunction. These results suggest that Smad4 participates in late stage shaping of the configuration of the vestibule and development of vestibular functional, but a Smad4-independent pathway for the inner ear vestibular BMP4 signal transduction could not be rule out. PMID- 20969947 TI - Use of high content image analysis to detect chemical-induced changes in synaptogenesis in vitro. AB - Synaptogenesis is a critical process in nervous system development whereby neurons establish specialized contact sites which facilitate neurotransmission. Early life exposure to chemicals can result in persistent deficits in nervous system function at later life stages. These effects are often the result of abnormal development of synapses. Given the large number of chemicals in commerce with unknown potential to result in developmental neurotoxicity (DNT), the need exists for assays that can efficiently characterize and quantify chemical effects on brain development including synaptogenesis. The present study describes the application of automated high content image analysis (HCA) technology for examining synapse formation in rodent primary mixed cortical cultures. During the first 15 days in vitro (DIV) cortical neurons developed a network of polarized neurites (i.e., axons and dendrites) and expression of the pre-synaptic protein synapsin increased over time. The localization of punctate synapsin protein in close apposition to dendrites also increased, indicating an increase in synapse formation. Results demonstrated that: (1) punctate synapsin protein with a spatial orientation consistent with synaptic contact sites could be selectively measured, (2) the critical period for synaptogenesis in cortical cultures was consistent with previous reports, (3) chemicals known to inhibit synapse formation decreased automated measurements of synapse number and (4) parallel evaluation of neuron density, dendrite length and synapse number could distinguish frank cytotoxicity from specific effects on synapse formation or neuronal morphology. Collectively, these data demonstrate that automated image analysis can be used to efficiently assess synapse formation in primary cultures and that the resultant data is comparable to results obtained using lower throughput methods. PMID- 20969948 TI - Specific activation of human neutrophils by scorpion venom: a flow cytometry assessment. AB - Acute lung injury following envenomation by Tityus scorpion species is due in part to activation of the inflammatory response leading to release of cytotoxic leukocyte-derived products, including cytokines and possibly reactive oxygen species (ROS). Tityus zulianus envenomation in Venezuela produces cardiorespiratory complications and death by lung injury whereas stings by Tityus discrepans produce mainly gastrointestinal and pancreatic alterations. To ascertain the role played by granulocytes in the envenomation by T. zulianus (TzV) and T. discrepans (TdV), human peripheral blood neutrophils, eosinophils, and monocytes were exposed to scorpion venoms (0.001-5 MUg/mL) and the kinetics (5-15 min) of peroxide production determined by flow cytometry, using 2',7' dichlorodihydrofluorescein diacetate (succinimidyl ester) as a fluorescent substrate. TzV induced a significantly (p<0.01) more potent increase in peroxide production in neutrophils (for 5 and 10 min of incubation), and to a lesser extent in monocytes (5-15 min), compared to TdV. TzV induced necrosis in neutrophils at doses higher than 5 MUg/mL. No effect was observed on eosinophils, suggesting that TzV specifically targets neutrophil intracellular ROS production. The TzV-stimulated pathway is protein kinase C-dependent because it was almost completely (>90%) abolished by staurosporine. The stimulatory effect is associated with the lowest molecular mass venom peptides as gel filtration fractions TzII and TzIII significantly enhanced peroxide production. The combined used of the intracellular ROS agonist, phorbol myristate acetate (PMA), and TzV produced a modest but significant increase in peroxide production suggesting the possibility of overlapping signaling cascades amongst PMA and TzV. Up-regulation of intracellular neutrophil ROS production may be an important in vivo target for TzV which could have a role to play in the cardiorespiratory complications elicited after envenomation by this species. PMID- 20969949 TI - A tool based on Ligation Detection Reaction-Universal Array (LDR-UA) for the characterization of VTEC by identification of virulence-associated and serogroup specific genes. AB - Verocytoxigenic Escherichia coli (VTEC) are zoonotic pathogens whose natural reservoir is represented by ruminants, particularly cattle. Infections are mainly acquired by consumption of undercooked contaminated food of animal origin, contact with infected animals and contaminated environment. VTEC O157 is the most frequently isolated serogroup from cases of human disease, however, other VTEC serogroups, such as O26, O111, O145 and O103, are increasingly reported as causing Hemolytic Uremic Syndrome (HUS) worldwide. The identification of VTEC is troublesome, hindering the development of effective prevention strategies. In fact, VTEC are morphologically indistinguishable from harmless E. coli and their pathogenic potential is not strictly dependent on the serogroup, but relies on the presence of a collection of virulence genes. We developed a diagnostic tool for VTEC based on the Ligation Detection Reaction coupled to Universal Array (LDR UA) for the simultaneous identification of virulence factors and serogroup associated genes. The method includes the investigation of 40 sites located in 13 fragments from 12 genes (sodCF1/F2, adfO, terB, ehxA, eae, vtx1, vtx2, ihp1, wzx, wbdI, rfbE, dnaK) and was evaluated by performing a trial on a collection of 67 E. coli strains, both VTEC and VT-negative E. coli, as well as on 25 isolates belonging to other related species. Results of this study showed that the LDR-UA technique was specific in identifying the target microorganism. Moreover, due to its higher throughput, the LDR-UA can be a valid and cheaper alternative to real time PCR-based (rt-PCR) methods for VTEC identification. PMID- 20969950 TI - Vitamin D receptor and enzyme expression in dorsal root ganglia of adult female rats: modulation by ovarian hormones. AB - Vitamin D insufficiency impacts sensory processes including pain and proprioception, but little is known regarding vitamin D signaling in adult sensory neurons. We analyzed female rat dorsal root ganglia (DRG) for vitamin receptor (VDR) and the vitamin D metabolizing enzymes CYP27B1 and CYP24. Western blots and immunofluorescence revealed the presence of these proteins in sensory neurons. Nuclear VDR immunoreactivity was present within nearly all neurons, while cytoplasmic VDR was found preferentially in unmyelinated calcitonin gene related peptide (CGRP)-positive neurons, colocalizing with CYP27B1 and CYP24. These data suggest that 1,25(OH)(2)D3 may affect sensory neurons through nuclear or extranuclear signaling pathways. In addition, local vitamin D metabolite concentrations in unmyelinated sensory neurons may be controlled through expression of CYP27B1 and CYP24. Because vitamin D deficiency appears to exacerbate some peri-menopausal pain syndromes, we assessed the effect of ovariectomy on vitamin D-related proteins. Two weeks following ovariectomy, total VDR expression in DRG dropped significantly, owing to a slight decrease in the percentage of total neurons expressing nuclear VDR and a large drop in unmyelinated CGRP-positive neurons expressing cytoplasmic VDR. Total CYP27B1 expression dropped significantly, predominantly due to decreased expression within unmyelinated CGRP-positive neurons. CYP24 expression remained unchanged. Therefore, unmyelinated CGRP-positive neurons appear to have a distinct vitamin D phenotype with hormonally-regulated ligand and receptor levels. These findings imply that vitamin D signaling may play a specialized role in a neural cell population that is primarily nociceptive. PMID- 20969951 TI - The DNA glycosylase Ogg1 defends against oxidant-induced mtDNA damage and apoptosis in pulmonary artery endothelial cells. AB - Emerging evidence suggests that mitochondrial (mt) DNA damage may be a trigger for apoptosis in oxidant-challenged pulmonary artery endothelial cells (PAECs). Understanding the rate-limiting determinants of mtDNA repair may point to new targets for intervention in acute lung injury. The base excision repair (BER) pathway is the only pathway for oxidative damage repair in mtDNA. One of the key BER enzymes is Ogg1, which excises the base oxidation product 8-oxoguanine. Previously we demonstrated that overexpression of mitochondrially targeted Ogg1 in PAECs attenuated apoptosis induced by xanthine oxidase (XO) treatment. To test the idea that Ogg1 is a potentially rate-limiting BER determinant protecting cells from oxidant-mediated death, PAECs transfected with siRNA to Ogg1 were challenged with XO and the extent of mitochondrial and nuclear DNA damage was determined along with indices of apoptosis. Transfected cells demonstrated significantly reduced Ogg1 activity, which was accompanied by delayed repair of XO-induced mtDNA damage and linked to increased XO-mediated apoptosis. The nuclear genome was undamaged by XO in either control PAECs or cells depleted of Ogg1. These observations suggest that Ogg1 plays a critical and possibly rate limiting role in defending PAECs from oxidant-induced apoptosis by limiting the persistence of oxidative damage in the mitochondrial genome. PMID- 20969952 TI - Functional characterization of methionine sulfoxide reductase A from Trypanosoma spp. AB - Methionine is an amino acid susceptible to being oxidized to methionine sulfoxide (MetSO). The reduction of MetSO to methionine is catalyzed by methionine sulfoxide reductase (MSR), an enzyme present in almost all organisms. In trypanosomatids, the study of antioxidant systems has been mainly focused on the involvement of trypanothione, a specific redox component in these organisms. However, no information is available concerning their mechanisms for repairing oxidized proteins, which would be relevant for the survival of these pathogens in the various stages of their life cycle. We report the molecular cloning of three genes encoding a putative A-type MSR in trypanosomatids. The genes were expressed in Escherichia coli, and the corresponding recombinant proteins were purified and functionally characterized. The enzymes were specific for L-Met(S)SO reduction, using Trypanosoma cruzi tryparedoxin I as the reducing substrate. Each enzyme migrated in electrophoresis with a particular profile reflecting the differences they exhibit in superficial charge. The in vivo presence of the enzymes was evidenced by immunological detection in replicative stages of T. cruzi and Trypanosoma brucei. The results support the occurrence of a metabolic pathway in Trypanosoma spp. involved in the critical function of repairing oxidized macromolecules. PMID- 20969953 TI - Apoptosis in Parkinson's disease: is p53 the missing link between genetic and sporadic Parkinsonism? AB - Parkinson's disease (PD) is a major age-related neurodegenerative disorder characterized by a massive and specific loss of dopaminergic neurons of the substantia nigra pars compacta. The cellular alterations are clinically translated into an invalidating movement disability associated to three canonical symptoms that are bradykinesia, resting tremor and rigidity. The exact causes of this neuronal loss are unknown, but a network of evidences indicates a major contribution of orchestrated cell death processes, also known as apoptosis. Apoptotic cell death is a normal process, the alteration of which triggers several pathologies including cancer and neurodegenerative disorders. Exhaustive work has been done to delineate the cellular mechanisms responsible for the exacerbated cell death of dopaminergic neurons observed in PD. Overall, the oncogene p53 has been identified as a key effector protein. This review will focus on the clues linking p53 to the etiology of PD and the evidences that this protein may be at the center of multiple signaling cascades not only altered by mutations of various proteins responsible for familial cases of PD but also on more general sporadic cases of this devastating disease. PMID- 20969954 TI - Berberine attenuates cAMP-induced lipolysis via reducing the inhibition of phosphodiesterase in 3T3-L1 adipocytes. AB - Berberine, a hypoglycemic agent, has been shown to decrease plasma free fatty acids (FFAs) level in insulin-resistant rats. In the present study, we explored the mechanism responsible for the antilipolytic effect of berberine in 3T3-L1 adipocytes. It was shown that berberine attenuated lipolysis induced by catecholamines, cAMP-raising agents, and a hydrolyzable cAMP analog, but not by tumor necrosis factor alpha and a nonhydrolyzable cAMP analog. Unlike insulin, the inhibitory effect of berberine on lipolysis in response to isoproterenol was not abrogated by wortmannin, an inhibitor of phosphatidylinositol 3-kinase, but additive to that of PD98059, an extracellular signal-regulated kinase kinase inhibitor. Prior exposure of adipocytes to berberine decreased the intracellular cAMP production induced by isoproterenol, forskolin, and 3-isobutyl-1 methylxanthine (IBMX), along with hormone-sensitive lipase (HSL) Ser-563 and Ser 660 dephosphorylation, but had no effect on perilipin phosphorylation. Berberine stimulated HSL Ser-565 as well as adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. However, compound C, an AMPK inhibitor, did not reverse the regulatory effect of berberine on HSL Ser-563, Ser-660, and Ser-565 phosphorylation, nor the antilipolytic effect of berberine. Knockdown of AMPK using RNA interference also failed to restore berberine-suppressed lipolysis. cAMP-raising agents increased AMPK activity, which was not additive to that of berberine. Stimulation of adipocytes with berberine increased phosphodiesterase (PDE) 3B and PDE4 activity measured by hydrolysis of (3)[H]cAMP. These results suggest that berberine exerts an antilipolytic effect mainly by reducing the inhibition of PDE, leading to a decrease in cAMP and HSL phosphorylation independent of AMPK pathway. PMID- 20969955 TI - Synthesis, spasmolytic activity and structure-activity relationship study of a series of polypharmacological thiobenzanilides. AB - Recently we presented a series of benzanilide derivatives with a selective spasmolytic effect on terminal ileum preparations of the guinea pig. In this report we demonstrate a further development of these compounds. The exchange of the amide oxygen against a sulfur atom resulted in an up to 325 fold increase of the antispasmodic activity of the thiobenzanilide (IC(50) of 0.1 MUM) compared to its benzanilide derivative. Considering their mode of action the compounds interacted with several molecular targets, suggesting that we identified a chemical identity able to modulate multiple targets simultaneously. Furthermore, based on this data set, we present a structure-activity relationship study supporting the important role of the sulfur atom. PMID- 20969956 TI - Detection of trace crystallinity in an amorphous system using Raman microscopy and chemometric analysis. AB - A novel analytical method to detect and characterize active pharmaceutical ingredient (API) trace crystallinity in an amorphous system using Raman microscopy and chemometric methods, namely band-target entropy minimization (BTEM) and target transformation factor analysis (TTFA) is developed. The method starts with Raman mapping measurements performed on some random areas of the amorphous system. This is followed by chemometric data analysis. In the case of a system without any a priori information, the BTEM algorithm is used to recover a set of pure component Raman spectral estimates followed by component and/or crystal structure identification. In the case of a system with some a priori information, TTFA is used to predict the presence or existence of a suspected component and/or crystal structure in the observed system. Four different amorphous systems were used as models. It is demonstrated that combined Raman microscopy and chemometric methods (BTEM or TTFA) outperformed powder X-ray diffraction (PXRD) in detecting trace crystallinity in amorphous systems. The spatial distributions of drug and polymer can also be directly obtained in order to study the homogeneity of the APIs in the solid dispersions. The present methodology appears very general and applicable to many other types of systems. PMID- 20969958 TI - Effects of esomeprazole on healing of nonsteroidal anti-inflammatory drug (NSAID) induced gastric ulcers in the presence of a continued NSAID treatment: Characterization of molecular mechanisms. AB - Proton pump inhibitors promote ulcer repair in nonsteroidal anti-inflammatory drug (NSAID)-treated patients with ongoing NSAID-induced gastric toxicity, although the underlying mechanisms remain unclear. We examined the healing mechanisms of esomeprazole on NSAID-induced gastric ulcerations in the presence of a continued NSAID treatment. Ulcerations were induced in rats by oral indomethacin (6MUmol/kg/day) for 14 days. Indomethacin administration was continued, alone or combined with equivalent acid inhibitory doses of esomeprazole (5MUmol/kg/day), lansoprazole (15MUmol/kg/day) or famotidine (20MUmol/kg/day), for additional 7 days. Stomachs were then processed for: histomorphometric analysis of mucosal injury; mucosal levels of prostaglandin E(2) (PGE(2)) and malondialdehyde (MDA); expression of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA), caspase-3, and cyclooxygenase-2 (COX-2) (Western blot); expression of Ki-67 (immunohistochemistry). Indomethacin for 14 days elicited mucosal damage, reduced PGE(2) levels and increased MDA. After additional 7 days, indomethacin induced the following effects: further enhancement of mucosal damage and MDA content; decrease in PGE(2) levels; increase in COX-2 and activated caspase-3 expression; decrease in VEGF, PCNA and Ki-67 expression. In the presence of indomethacin, esomeprazole and lansoprazole were more effective than famotidine in promoting resolution of mucosal damage. Concomitantly, esomeprazole and lansoprazole, but not famotidine, restored PCNA and Ki-67 expression, and normalized MDA levels. Moreover, esomeprazole, lansoprazole and famotidine partly counteracted caspase-3 activation, without affecting VEGF expression. The healing activity of esomeprazole on indomethacin-induced gastric ulcerations can be ascribed to two mechanisms: (1) acid-dependent reduction of pro-apoptotic signalling; (2) acid independent restoration of proliferating/repairing pathways. PMID- 20969957 TI - Synaptic dysfunction in genetic models of Parkinson's disease: a role for autophagy? AB - The past decade in Parkinson's disease (PD) research has been punctuated by numerous advances in understanding genetic factors that contribute to the disease. Common to most of the genetic models of Parkinsonian neurodegeneration are pathologic mechanisms of mitochondrial dysfunction, secretory vesicle dysfunction and oxidative stress that likely trigger common cell death mechanisms. Whereas presynaptic function is implicated in the function/dysfunction of alpha-synuclein, the first gene shown to contribute to PD, synaptic function has not comprised a major focus in most other genetic models. However, recent advances in understanding the impact of mutations in parkin and LRRK2 have also yielded insights into synaptic dysfunction as a possible early pathogenic mechanism. Autophagy is a common neuronal response in each of these genetic models of PD, participating in the clearance of protein aggregates and injured mitochondria. However, the potential consequences of autophagy upregulation on synaptic structure and function remain unknown. In this review, we discuss the evidence that supports a role for synaptic dysfunction in the neurodegenerative cascade in PD, and highlight unresolved questions concerning a potential role for autophagy in either pathological or compensatory synaptic remodeling. This article is part of a Special Issue entitled "Autophagy and protein degradation in neurological diseases." PMID- 20969959 TI - Differential effects of statins on endogenous H2S formation in perivascular adipose tissue. AB - Hydrogen sulfide (H(2)S) is a new gasotransmitter synthesized enzymatically from l-cysteine in cytosol and is oxidized in mitochondria. In the cardiovascular system, H(2)S regulates vascular tone, inhibits atherogenesis, and protects against myocardial ischemia-reperfusion injury. We examined the effect of statins on vascular H(2)S production. Male Wistar rats received pravastatin (40mg/kg/day) or atorvastatin (20mg/kg/day) for 3 weeks and then H(2)S formation was measured in aortic media, periaortic adipose tissue (PAAT) and the liver. Only atorvastatin increased H(2)S production in PAAT whereas both statins stimulated its formation in the liver. Neither statin affected H(2)S production in aortic media. H(2)S formation in post-mitochondrial supernatant was higher than in mitochondria-containing supernatant and was not influenced by statins in any tissue. In addition, oxidation of exogenous H(2)S in isolated liver mitochondria was slower in statin-treated than in control rats. These data indicate that statins increase net H(2)S production by inhibiting its mitochondrial oxidation. Statins had no effect on the activity of H(2)S-metabolizing enzyme, sulfide:quinone oxidoreductase, measured at saturating coenzyme Q concentration. Both statins reduced CoQ(9) concentration in plasma and liver, but only atorvastatin decreased CoQ(9) in PAAT. Atorvastatin attenuated phenylephrine induced contraction of PAAT+ but not of PAAT- aortic rings. Effects of atorvastatin on net H(2)S production, mitochondrial H(2)S oxidation and aortic contractility were abolished by supplementation of exogenous CoQ(9). In conclusion, lipophilic atorvastatin, but not hydrophilic pravastatin, increases net H(2)S production in perivascular adipose tissue by inhibiting its mitochondrial oxidation. This effect is mediated by statin-induced CoQ(9) deficiency and results in the augmentation of anticontractile effect of perivascular adipose tissue. PMID- 20969960 TI - Mitogen-activated protein kinases in hepatocellular carcinoma development. AB - Hepatocellular carcinoma (HCC) is among the most frequently occurring cancers and the leading causes of cancer mortality worldwide. Identification of the signaling pathways regulating liver carcinogenesis is critical in developing novel chemoprevention and targeted therapies. Mitogen-activated protein kinases (MAPKs), comprising a family of serine and threonine kinases of ERK, JNK, and p38, are important signaling components which convert external stimuli into a wide range of cellular responses, such as proliferation, survival, differentiation and migration. Due to their essential roles in these cellular functions, deregulated MAPKs are often found to contribute to the development of many cancers, including HCC. Markedly, early studies on the ERK pathway have led to the development of the multikinase inhibitor Sorafenib, the first effective systemic drug for the targeted treatment of human HCC. Recently, the functions and molecular mechanisms of JNK and p38 in HCC development have also been addressed using mouse models. In this review, we discuss the latest findings regarding the ERK, JNK and p38 MAPK signaling pathways in HCC development and their potential roles as therapeutic targets for HCC. PMID- 20969961 TI - A theory for high speed interactions in the retina circuits. AB - When looking around without fixating the eyes on any particular objects, the image changes at a high frequency without any noticeable intervals between the images. This requires a high speed generation of retina signals and high speed transmission of the signals to the vision center. As an example of high speed neural interaction, each light stimulus generates two different bipolar cells response, transmitting different pieces of information to the vision center. This doubles the speed of information transmission to the vision center. The functional significance of Kuffler's "inhibitory surround" was revealed to maintain the brightness of the perceived images within a limited range. PMID- 20969962 TI - Structures of a key interaction protein from the Trypanosoma brucei editosome in complex with single domain antibodies. AB - Several major global diseases are caused by single-cell parasites called trypanosomatids. These organisms exhibit many unusual features including a unique and essential U-insertion/deletion RNA editing process in their single mitochondrion. Many key RNA editing steps occur in ~20S editosomes, which have a core of 12 proteins. Among these, the "interaction protein" KREPA6 performs a central role in maintaining the integrity of the editosome core and also binds to ssRNA. The use of llama single domain antibodies (VHH domains) accelerated crystal growth of KREPA6 from Trypanosoma brucei dramatically. All three structures obtained are heterotetramers with a KREPA6 dimer in the center, and one VHH domain bound to each KREPA6 subunit. Two of the resultant heterotetramers use complementarity determining region 2 (CDR2) and framework residues to form a parallel pair of beta strands with KREPA6 - a mode of interaction not seen before in VHH domain-protein antigen complexes. The third type of VHH domain binds in a totally different manner to KREPA6. Intriguingly, while KREPA6 forms tetramers in solution adding either one of the three VHH domains results in the formation of a heterotetramer in solution, in perfect agreement with the crystal structures. Biochemical solution studies indicate that the C-terminal tail of KREPA6 is involved in the dimerization of KREPA6 dimers to form tetramers. The implications of these crystallographic and solution studies for possible modes of interaction of KREPA6 with its many binding partners in the editosome are discussed. PMID- 20969963 TI - The bacterial exotoxin AIP56 induces fish macrophage and neutrophil apoptosis using mechanisms of the extrinsic and intrinsic pathways. AB - It has been previously shown that the exotoxin of the important fish pathogen Photobacterium damselae ssp. piscicida is a key pathogenicity factor and is responsible for the extensive systemic apoptosis of macrophages and neutrophils seen in acute fish photobacteriosis. The focus of the present study was to further characterize the AIP56-induced apoptosis of sea bass professional phagocytes by assessing the involvement of caspases, mitochondria and oxidative stress. The resulting data indicate that the apoptotic response in peritoneal macrophages and neutrophils treated ex vivo with AIP56 involves activation of caspase-8, -9 and -3, and mitochondria as shown by loss of mitochondrial membrane potential, release of cytochrome c and over-production of ROS. These results together with previous data from this laboratory suggest that both the extrinsic and intrinsic apoptotic pathways are involved in the AIP56-induced phagocyte apoptosis. PMID- 20969964 TI - Practical constraints on estimation of source extent with MEG beamformers. AB - We aimed to determine practical constraints on the estimation of the spatial extent of neuronal activation using MEG beamformers. Correct estimation of spatial extent is a pre-requisite for accurate models of electrical activity, allows one to estimate current density, and enables non-invasive monitoring of functional recovery following stroke. The output of an MEG beamformer is maximum when the correct source model is used, so that the spatial extent of a source can in principal be determined through evaluation of different source models with the beamformer. Here, we simulated 275-channel MEG data using sources of varying spatial extents that followed the cortical geometry. These data were subsequently used to estimate the spatial extent of generic disc elements without knowledge of the underlying surface, and we compared these results to estimates based on cortical surface geometry (with and without error in surface location). We found that disc-shaped source models are too simplistic, particularly for areas with high curvature. For areas with low curvature spatial extent was underestimated, although on average there was a linear relationship between the true and estimated extent. In contrast, cortical surface models gave accurate predictions of spatial extent. However, adding small errors (>2 mm) to the estimated location of the cortical surface abolished this relationship between true and estimated extent, implying that accurate co-registration is needed with such models. Our results show that models exploiting surface information are necessary in order to model spatial extent and in turn current density, but in order to render such models applicable in practical situations, the accuracy of the cortical surface model itself needs to improve. PMID- 20969966 TI - A dynamic 4D probabilistic atlas of the developing brain. AB - Probabilistic atlases are widely used in the neuroscience community as a tool for providing a standard space for comparison of subjects and as tissue priors used to enhance the intensity-based classification of brain MRI. Most efforts so far have focused on static brain atlases either for adult or pediatric cohorts. In contrast to the adult brain the rapid growth of the neonatal brain requires an age-specific spatial probabilistic atlas to provide suitable anatomical and structural information. In this paper we describe a 4D probabilistic atlas that allows dynamic generation of prior tissue probability maps for any chosen stage of neonatal brain development between 29 and 44 gestational weeks. The atlas is created from the segmentations of 142 neonatal subjects at different ages using a kernel-based regression method and provides prior tissue probability maps for six structures - cortex, white matter, subcortical grey matter, brainstem, cerebellum and cerebro-spinal fluid. The atlas is publicly available at www.brain development.org. PMID- 20969965 TI - Scaled subprofile modeling of resting state imaging data in Parkinson's disease: methodological issues. AB - Consistent functional brain abnormalities in Parkinson's disease (PD) are difficult to pinpoint because differences from the normal state are often subtle. In this regard, the application of multivariate methods of analysis has been successful but not devoid of misinterpretation and controversy. The Scaled Subprofile Model (SSM), a principal components analysis (PCA)-based spatial covariance method, has yielded critical information regarding the characteristic abnormalities of functional brain organization that underlie PD and other neurodegenerative disorders. However, the relevance of disease-related spatial covariance patterns (metabolic brain networks) and the most effective methods for their derivation has been a subject of debate. We address these issues here and discuss the inherent advantages of proper application as well as the effects of the misapplication of this methodology. We show that ratio pre-normalization using the mean global metabolic rate (GMR) or regional values from a "reference" brain region (e.g. cerebellum) that may be required in univariate analytical approaches is obviated in SSM. We discuss deviations of the methodology that may yield erroneous or confounding factors. PMID- 20969967 TI - What semi-quantitative scoring instrument for knee OA MRI should you use? AB - Multiple techniques have been used to assess synovial morphology and change on MRI in OA. Broadly speaking these methods are divided into quantitative and semi quantitative methods. Quantitative measurements use computer-aided image processing to assess joint quantification (cartilage morphometry, bone volume, bone marrow lesion volume, meniscal position and volume, synovial volume, etc). In contrast to quantitative measures, semi-quantitative image analysis is typically much more observer dependent and generates grades or scales rather than truly continuous output. Multiple methods for semi-quantitative multi-feature assessment of the knee using conventional MRI acquisitions exist. These instruments provide for broad assessment of the whole joint and derive from knowledge from reading as to what joint features are morphologically abnormal. They are labour- and expertise-intensive compared to more automated methodologies. As a consequence of their reader dependence, precision and reliability results have not been as favourable for these instruments as their quantitative cousins. These instruments are generally based on past perceptions of what should be considered an important feature and therefore can bias future research. This said they do provide an important tool especially when quantitative methodologies are lacking or have their own inherent limitations. PMID- 20969969 TI - Molecular typing and antimicrobial susceptibility of Clostridium perfringens from broiler chickens. AB - Clostridium perfringens (Cp) causes necrotic enteritis disease in commercial poultry. Antimicrobials are used to control and treat this disease and sometimes clinical outbreaks do not respond well to certain treatments. This study was designed to isolate Cp from clinical cases, type these isolates by multiplex PCR, and determine their antimicrobial susceptibility by micro-dilution method. A total of 67 Cp isolates were obtained from 155 broiler chicken flocks. All isolates were classified as type A and non-enterotoxin producers. Lincomycin, erythromycins, and tilmicosin showed very high minimal inhibitory concentration (MIC) 50 of >=256 MUg/ml. However, tylosin, amoxicillin, ampicillin, penicillin, florfenicol, danofloxacin, enrofloxacin, chlortetracycline, doxycycline, and oxytetracycline had variable MIC50 of 64, 0.5, 1, 1, 8, 4, 8, 4, 8, 0.5 MUg/ml, respectively. It is recommended that Cp infections in Jordan be treated with either penicillins or tetracyclines especially amoxicillin and oxytetracycline. PMID- 20969970 TI - Outcomes of patients with myeloid malignancies treated with allogeneic hematopoietic stem cell transplantation from matched unrelated donors compared with one human leukocyte antigen mismatched related donors using HLA typing at 10 loci. AB - Most candidates for hematopoietic stem cell transplantation (HSCT) lack a human leukocyte antigen (HLA)-identical sibling donor. Some patients may have a related donor with whom they are mismatched at 1 antigen/allele. It is not known whether such a match is preferable to a matched unrelated donor (MUD). We evaluated the outcomes (survival, relapse, nonrelapse mortality [NRM]) of all 28 patients with a single HLA antigen/allele mismatch identified through high-resolution HLA typing at HLA-A, -B, -C, -DRB1, and -DQB1, and all 318 patients with myeloid malignancies who received transplants from a 10/10 MUD treated during the same period of time at a single institution. Overall, outcomes for patients treated from a 1-antigen/allele mismatch related donor were significantly worse than from a MUD, primarily because of increased NRM. Overall survival (OS) rates at 3 years for 1-antigen/allele mismatched related donor and MUD transplant recipients were 19% and 45% (P = .007), and NRM rates were 40% and 26% (P = .05), respectively. Patients with class I mismatches appeared to have poorer OS than did patients with class II mismatches. A higher incidence of graft rejection was identified in the mismatched related donor group (P = .02). These results indicate that transplant outcomes are better with a MUD than with a 1 antigen/allele-mismatched related donor. PMID- 20969968 TI - Napping promotes inter-session habituation to emotional stimuli. AB - The effects of a daytime nap on inter-session habituation to aversive visual stimuli were investigated. Healthy young adult volunteers viewed repeated presentations of highly negative and emotionally neutral (but equally arousing) International Affective Picture System (IAPS) photographs during two afternoon sessions separated by 2.5h. Half of the photographs were shown at both sessions (Repeated Sets) and half differed between sessions (Novel Sets). For each stimulus presentation, evoked skin conductance response (SCR), heart-rate deceleration (HRD) and corrugator supercilii EMG response (EMG), were computed and range corrected using respective maximum session-1 responses. Following each presentation, subjects rated each photograph on dimensions of pleasantness and arousability. During the inter-session interval, Nap subjects had a 120-min polysomnographically monitored sleep opportunity, whereas Wake subjects watched a non-stimulating video. Nap and Wake subjects did not differ in their subjective ratings of photographs. However, for Repeated-Set photographs, Nap subjects demonstrated greater inter-session habituation in SCR and EMG but a trend toward lesser inter-session habituation in HRD. These group differences were absent for Novel-Set photographs. Group differences across all measures were greater for negative stimuli. Occurrence of SWS during the nap was associated with greater inter-session habituation of EMG whereas occurrence of REM was associated with lesser inter-session habituation of SCR to negative stimuli. Sleep may therefore promote emotional adjustment at the level of somatic responses. Physiological but not subjective inter-session habituation to aversive images was enhanced by a daytime nap. PMID- 20969971 TI - Central metabolic fluxes in the endosperm of developing maize seeds and their implications for metabolic engineering. AB - 14C labeling experiments performed with kernel cultures showed that developing maize endosperm is more efficient than other non-photosynthetic tissues such as sunflower and maize embryos at converting maternally supplied substrates into biomass. To characterize the metabolic fluxes in endosperm, maize kernels were labeled to isotopic steady state using 13C-labeled glucose. The resultant labeling in free metabolites and biomass was analyzed by NMR and GC-MS. After taking into account the labeling of substrates supplied by the metabolically active cob, the fluxes through central metabolism were quantified by computer aided modeling. The flux map indicates that 51-69% of the ATP produced is used for biomass synthesis and up to 47% is expended in substrate cycling. These findings point to potential engineering targets for improving yield and increasing oil contents by, respectively, reducing substrate cycling and increasing the commitment of plastidic carbon into fatty acid synthesis at the level of pyruvate kinase. PMID- 20969972 TI - The renal connecting tubule: Resolved and unresolved issues in Ca(2+) transport. AB - The renal connecting tubule (CNT) localizes to the distal part of the nephron between the distal convoluted tubule and the collecting duct, and consists of two different cell types: segment-specific and intercalated cells. The former reabsorb water (H(2)O), sodium (Na(+)) and calcium (Ca(2+)) ions to the blood compartment, while secreting potassium ions (K(+)) into the pro-urine. The latter cells contribute to the renal control of the acid-base balance. Several factors and hormones tightly regulate these transport processes. Although the CNT reabsorbs only ~15% of filtered Ca(2+) load, this segment is finally decisive for the amount of Ca(2+) that appears in the urine. Impaired Ca(2+) transport across CNT can provoke severe urinary Ca(2+) excretion, called hypercalciuria. This review mainly focuses on the activity, abundance and expression of the epithelial Ca(2+) channel named Transient Receptor Potential Vanilloid 5 (TRPV5) that is the gatekeeper of active Ca(2+) reabsorption in the CNT. PMID- 20969973 TI - Pharmacoproteomics: a chess game on a protein field. AB - The application of proteomics in the field of drug discovery development and the assessment of drug administration is known as pharmacoproteomics. As a branch of proteomics--perhaps the most promising and rapidly evolving field of the post genomic era--pharmacoproteomics has inherited all the promises that pharmacogenomics has hitherto left unfulfilled. On the road to tailor-made drugs, whole protein profiles of healthy individuals have been progressively expanded, either qualitatively or quantitatively. In this review article, we provide general information about technical advancements in the field of proteomics (the pieces of this intriguing chess game) and show how this progress has furthered our understanding of biological systems. Pitfalls on the field of biomarker individuation and drug discovery and/or testing are also discussed. PMID- 20969974 TI - Termination of sustained atrial flutter and fibrillation using low-voltage multiple-shock therapy. AB - BACKGROUND: Defibrillation therapy for atrial fibrillation (AF) and flutter (AFl) is limited by pain induced by high-energy shocks. Thus, lowering the defibrillation energy for AFl/AF is desirable. OBJECTIVE: In this study we applied low-voltage multiple-shock defibrillation therapy in a rabbit model of atrial tachyarrhythmias comparing its efficacy to single shocks and antitachycardia pacing (ATP). METHODS: Optical mapping was performed in Langendorff-perfused rabbit hearts (n = 18). Acetylcholine (7 +/- 5 to 17 +/- 16 MUM) was administered to promote sustained AFl and AF, respectively. Single and multiple monophasic shocks were applied within 1 or 2 cycle lengths (CLs) of the arrhythmia. RESULTS: We observed AFl (CL = 83 +/- 15 ms, n = 17) and AF (CL = 50 +/- 8 ms, n = 11). ATP had a success rate of 66.7% in the case of AFl, but no success with AF (n = 9). Low-voltage multiple shocks had 100% success for both arrhythmias. Multiple low-voltage shocks terminated AFl at 0.86 +/- 0.73 V/cm (within 1 CL) and 0.28 +/- 0.13 V/cm (within 2 CLs), as compared with single shocks at 2.12 +/- 1.31 V/cm (P < .001) and AF at 3.46 +/- 3 V/cm (within 1 CL), as compared with single shocks at 6.83 +/- 3.12 V/cm (P =.06). No ventricular arrhythmias were induced. Optical mapping revealed that termination of AFl was achieved by a properly timed, local shock-induced wave that collides with the arrhythmia wavefront, whereas AF required the majority of atrial tissue to be excited and reset for termination. CONCLUSION: Low-voltage multiple-shock therapy terminates AFl and AF with different mechanisms and thresholds based on spatiotemporal characteristics of the arrhythmias. PMID- 20969975 TI - Great cardiac venography by contrast injection through an external irrigation catheter. PMID- 20969976 TI - Second-degree 2:1 atrioventricular block with right bundle-branch block: what is the mechanism? PMID- 20969978 TI - Analysis of the expression of retinoic acid metabolising genes during Xenopus laevis organogenesis. AB - Retinoic acid (RA) is a known teratogen that is also required endogenously for normal development of the embryo. RA can act as a morphogen, through direct binding to receptors and RA response elements in the genome, and classical studies of limb development and regeneration in amphibians have shown that it is likely to provide positional information. Availability of RA depends on both metabolic synthesis and catabolic degradation, and specific binding proteins act to further modulate the binding of RA to response elements. Here, we describe the expression of seven genes involved in metabolism (Raldh1-3), catabolism (Cyp26a and b) and binding of RA (Crabp1 and 2) during organogenesis in the clawed frog Xenopus laevis. Taken together, this data indicates regions of the embryo that could be affected by RA mediated patterning, and identifies some differences with other vertebrates. PMID- 20969977 TI - Transgenic labeling of the zebrafish pronephric duct and tubules using a promoter from the enpep gene. AB - In recent years the zebrafish has become a popular model system to study organ development and disease. To facilitate these studies, genetic tools are required which allow to modify and manipulate gene expression in organs of interest. Here we describe a zebrafish 2kb glutamyl aminopeptidase (enpep) promoter fragment, and show that it can drive gene expression specifically in the kidney during early and late development. We established a stable transgenic line using this promoter fragment that has specific GFP expression in pronephric ducts and tubules starting at 20h post-fertilization. PMID- 20969979 TI - Blood stream infections caused by Acinetobacter ursingii in an obstetrics ward. AB - The genus Acinetobacter is an important causative pathogen of nosocomial infections in the healthcare setting. The objectives of this study were to determine the species of causative pathogens and the sources of Acinetobacter blood stream infections that occurred in 2 immunocompetent pregnant women admitted to an obstetrics ward within a 2-month period. Phenotypic identification of the two isolates from blood stream infections was inconsistent among the ID test, the MicroScan WalkAway and the Vitek2 systems. In addition to the growth profile and detailed biochemical analysis, genotypic identification and phylogenetic tree analysis based on the almost complete 16S rRNA sequence and the partial rpoB gene sequence confirmed the identification of these isolates as A. ursingii. Environmental investigation of the obstetrics ward revealed A. ursingii and different strains of Acinetobacter junii in specimens obtained from the ward shower bath, although the source and route of transmission for the A. ursingii infections were not clarified. Our findings show that A. ursingii can inhabit the hospital environment. PMID- 20969980 TI - Caloric restriction and longevity: effects of reduced body temperature. AB - Caloric restriction (CR) causes a reduction in body temperature (T(b)) which is suggested to contribute to changes that increase lifespan. Moreover, low T(b) has been shown to improve health and longevity independent of CR. In this review we examine the connections between CR, T(b) and mechanisms that influence longevity and ageing. Recent findings regarding the overlapping mechanisms of CR and T(b) that benefit longevity are discussed, including changes in body composition, hormone regulation, and gene expression, as well as reductions in low-level inflammation and reactive oxygen species-induced molecular damage. This information is summarized in a model describing how CR and low T(b), both synergistically and independently, increase lifespan. Moreover, the nascent notion that the rate of ageing may be pre-programmed in response to environmental influences at critical periods of early development is also considered. Based on current evidence, it is concluded that low T(b) plays an integral role in mediating the effects of CR on health and longevity, and that low T(b) may exert independent biological changes that increase lifespan. Our understanding of the overlap between CR- and T(b)-mediated longevity remains incomplete and should be explored in future research. PMID- 20969981 TI - Genotype-phenotype correlations in a new case of 8p23.1 deletion and review of the literature. AB - We describe a 6-year-old boy carrying a de novo 5 Mb interstitial deletion of chromosome 8p23.1 identified by means of oligonucleotide array comparative genomic hybridisation (array CGH), who showed the typical signs of 8p23.1 deletion syndrome, including congenital heart defects, microcephaly, psychomotor delay and behavioural problems. In order to estimate the role of suggested candidate genes, we compared the deletion of our patient with other previously reported and molecularly characterised deletions that have been re-evaluated on the basis of the current genetic map data. The inclusion of TNKS gene in the deletion interval without any phenotypical signs of Cornelia de Lange syndrome (CdLS) invalidates TNKS as a plausible candidate gene for the syndrome itself. PMID- 20969982 TI - Array comparative genome hybridization in patients with developmental delay: two example cases. AB - Developmental delay is often a predictor of mental retardation (MR) or autism, two relatively frequent developmental disorders severely affecting intellectual and social functioning. The causes of these conditions remain unknown in most patients. They have a strong genetic component, but the specific genetic defects can only be identified in a fraction of patients. Recent developments in genomics supported the establishment of the causal link between copy number variants in the genomes of some patients and their affection. One of the techniques suitable for this analysis is array comparative genome hybridization, which can be used both for detailed mapping of chromosome rearrangements identified by classical cytogenetics and for the identification of novel submicroscopic gains or losses of genetic material. We illustrate the power of this approach in two patients. Patient 1 had a cytogenetically visible deletion of chromosome X and the molecular analysis was used to specify the gene content of the deletion and the prognosis of the child. Patient 2 had a seemingly normal karyotype and the analysis revealed a small recurrent deletion of chromosome 1 likely to be responsible for his phenotype. However, the genetic dissection of MR and autism is complicated by high heterogeneity of the genetic aberrations among patients and by broad variability of phenotypic effects of individual genetic defects. PMID- 20969983 TI - Linkage mapping of principal components for femoral biomechanical performance in a reciprocal HCB-8 * HCB-23 intercross. AB - Studies of bone genetics have addressed an array of related phenotypes, including various measures of biomechanical performance, bone size, bone, shape, and bone mineral density. These phenotypes are not independent, resulting in redundancy of the information they provide. Principal component (PC) analysis transforms multiple phenotype data to a new set of orthogonal "synthetic" phenotypes. We performed PC analysis on 17 femoral biomechanical, anatomic, and body size phenotypes in a reciprocal intercross of HcB-8 and HcB-23, accounting for 80% of the variance in 4 PCs. Three of the 4 PCs were mapped in the cross. The linkage analysis revealed a quantitative trait locus (QTL) with LOD = 4.7 for PC2 at 16 cM on chromosome 19 that was not detected using the directly measured phenotypes. The chromosome 19 QTL falls within a ~10 megabase interval, with Osf1 as a positional candidate gene. PC QTLs were also found on chromosomes 1, 2, 4, 6, and 10 that coincided with those identified for directly measured or calculated material property phenotypes. The novel chromosome 19 QTL illustrates the power advantage that attends use of PC phenotypes for linkage mapping. Constraint of the chromosome 19 candidate interval illustrates an important advantage of experimental crosses between recombinant congenic mouse strains. PMID- 20969984 TI - Layer-by-layer identification of copper alteration products in metallic works of art using the voltammetry of microparticles. AB - An in situ technique for layer-by-layer electrochemical analysis of solid surfaces using the voltammetry of microparticles is presented. The method is based on the determination of several shape-dependent parameters for voltammetric curves recorded at a graphite pencil working electrode in contact with the sample, all immersed into aqueous electrolytes. Repetitive square wave voltammetry and sequential application of constant potential reductive steps and voltammetric scans yield discernible responses for the corrosion products distributed in stratified layers on metal-based surfaces. This methodology is applied to identify alteration products of copper and copper alloys distributed in different layers in copper coupons submitted to different corrosive treatments and a contemporary brass sculpture. PMID- 20969985 TI - BCR(r)-701: a review of 10-years of sequential extraction analyses. AB - A detailed quantitative analysis was performed on data presented in the literature that focused on the sequential extraction of cadmium (Cd), chromium (Cr), copper (Cu), nickel (Ni), lead (Pb) and zinc (Zn) from the certified reference material BCR-701 (lake sediment) using the three-step harmonized BCR((r)) procedure. The accuracy of data reported in the literature, including precision and different measures of trueness, was assessed relative to the certified values for BCR-701. Forty data sets were accepted following extreme outlier removal, and statistically summarized with measures of central tendency, dispersion, and distribution form. In general, literature data were similar in their measurement precision to the expert laboratories used to certify the trace element contents in BCR-701. The overall median precision for literature reported data was 10% (range 6-19%), compared to certifying laboratories of 9% (range 4 33%). One measure of literature data trueness was assessed via a confirmatory approach using a robust bootstrap method. Only 22% of the comparisons indicated significantly different (all were lower) concentrations reported in the literature compared to certified values. The question of whether the differences are practically significant for environmental studies is raised. Bias was computed as a measure of trueness, and literature data were more frequently negatively biased, indicating lower concentrations reported in the literature for the six trace elements for the three-step sequential procedure compared to the certified values. However, 95% confidence intervals about the average bias for the 18 comparisons indicated only four instances when a mean bias of 0 (i.e., measured=certified) was not incorporated-suggesting statistical difference. Finally, Z-scores incorporating a Horwitz-type function were used to assess the general trueness of laboratory data. Of the 468 laboratory Z-score values computed, 92% were considered to be satisfactory, 5% were questionable, and 3% were unsatisfactory. A detailed examination of the methodology sections of the various studies showed that despite claiming adherence to the harmonized BCR sequential extraction protocol, significant deviations were commonly observed; particularly in moisture correction, sample mass, centrifugation specifics, shaking specifics, and incorporation of filtration. It is likely that failure to strictly adhere to the protocol adversely impacted accuracy, by increasing the degree of imprecision and resulting in more discrepant trueness values. PMID- 20969986 TI - An 8-sulfonamidoquinoline derivative with imidazolium unit as an extraction reagent for use in ionic liquid chelate extraction systems. AB - To evaluate the superiority of using a task-specific onium salt (TSOS), a novel TSOS reagent 1-methyl-3-[2-(8-quinolinylaminosulfonyl)ethyl]imidazolium chloride (HmimesqCl) was synthesized, and its performance in extraction of different divalent metal cations was investigated. This TSOS reagent has both a cationic imidazolium unit and an anionic (proton-dissociable) complexation unit for the extraction of metal cations into an ionic liquid. In the use of HmimesqCl, relatively high extraction of metals resulted in comparison with the use of its non-imidazolium analogs, without changing the extraction selectivity. PMID- 20969987 TI - Determination of triazole fungicides in environmental water samples by high performance liquid chromatography with cloud point extraction using polyethylene glycol 600 monooleate. AB - A preconcentration technique known as cloud point extraction was developed for the determination of trace levels of triazole fungicides tricyclazole, triadimefon, tebuconazole and diniconazole in environmental waters. The triazole fungicides were extracted and preconcentrated using polyethylene glycol 600 monooleate (PEG600MO) as a low toxic and environmentally benign nonionic surfactant, and determined by high performance liquid chromatography/ultraviolet detection (HPLC-UV). The extraction conditions were optimized for the four triazole fungicides as follows: 2.0 wt% PEG600MO, 2.5 wt% Na(2)SO(4), equilibration at 45 degrees C for 10 min, and centrifugation at 2000 rpm (533 * g) for 5 min. The triazole fungicides were well separated on a reversed-phase kromasil ODS C(18) column (250 mm * 4.6 mm, 5 MUm) with gradient elution at ambient temperature and detected at 225 nm. The calibration range was 0.05-20 MUg L(-1) for tricyclazole and 0.5-20 MUg L(-1) for the other three classes of analytes with the correlation coefficients over 0.9992. Preconcentration factors were higher than 60-fold for the four selected fungicides. The limits of detection were 6.8-34.5 ng L(-1) (S/N=3) and the recoveries were 82.0-96.0% with the relative standard deviations of 2.8-7.8%. PMID- 20969989 TI - Speciation and determination of thiols in biological samples using high performance liquid chromatography-inductively coupled plasma-mass spectrometry and high performance liquid chromatography-Orbitrap MS. AB - An analytical method was developed for the determination of thiols in biological samples. Reverse phase chromatography coupled to ICP quadrupole MS or Orbitrap MS was employed for the separation and detection of thiols. For the determination of total thiols, oxidized thiols were reduced using dithiothreitol (DTT). Reduction efficiencies for species of interest were found to be close to 100%. Reduced thiols were derivatized by p-hydroxymercuribenzoate (PHMB) and then separated on a C8 column. Optimization of the extraction, separation and detection steps of the HPLC-ICP-MS and HPLC-Orbitrap MS methods was carried out. Detection limits for cysteine, homocysteine, selenocysteine, glutathione, selenomethionine and cysteinyl-glycine were found to be 18, 34, 39, 12, 128 and 103 fmol, respectively, using HPLC-Orbitrap MS and 730, 1110, 440, 1110 and 580 fmol for cysteine, homocysteine, selenocysteine, glutathione, and cysteinyl-glycine using HPLC-ICP-MS. Contrary to expectation, the LODs and RSDs are higher for the HPLC ICP-MS instrument, therefore HPLC-Orbitrap MS was used for the determination of thiols in yeast samples. Three different brands of baker's yeast and a selenized yeast were analyzed. The GSH and cysteine levels found in these samples ranged from 4.45 to 17.87 MUmol g(-1) and 0.61 to 1.32 MUmol g(-1), respectively. PMID- 20969988 TI - High-performance liquid-chromatographic tandem-mass spectrometric methods for atropinesterase-mediated enantioselective and chiral determination of R- and S hyoscyamine in plasma. AB - S-hyoscyamine (S-hyo) is a toxic tropane alkaloid from plants of the solanacea family, which is extracted for pharmaceutical purposes thereby undergoing racemization (atropine). Merely the S-hyo enantiomer acts as an antagonist of muscarinic receptors (MR). Nevertheless, racemic atropine is clinically administered in e.g. ophthalmology and for symptomatic therapy of acute poisoning with organophosphorus compounds (OPCs, e.g. pesticides, nerve agents). However, very limited data are available of comparative pharmacokinetics of S- and R enantiomers in humans or other species. Therefore, we developed an enantioselective LC-ESI-MS/MS assay making use of rabbit serum containing atropinesterase (AtrE, EC 3.1.1.10) which is suitable for stereospecific hydrolysis of S-hyo into tropine and tropic acid while R-hyo is unaffected. For sample preparation plasma was incubated with human serum (not containing AtrE, procedure A) and with rabbit serum (procedure B). Afterwards, hyoscyamines were quantified by a validated previously published non-chiral LC-ESI-MS/MS method. Following procedure A the concentration of total hyo and following procedure B remaining R-hyo were determined. S-hyo was calculated by the difference between these concentrations. This assay design allowed reproducible, precise (RSD 2-9%), accurate (93-101%) and selective determination of total and individual hyoscyamines. Potential therapeutics for OPC poisoning (carbamates, oximes) and thiono-pesticides did not interfere with the assay whereas some oxon-pesticides inhibited S-hyo hydrolysis. A control experiment was designed allowing to be aware of such interferences thus avoiding the use of false results. To validate this assay, results were compared to those from a novel isocratic chiral LC-ESI MS/MS method. Separation of S-hyo (t(R) 31.1 +/- 0.2 min) and R-hyo (t(R) 33.4 +/ 0.2 min) was achieved on alpha-glycoprotein (AGP) chiral stationary phase at 40 degrees C (selectivity factor alpha 1.07). Ammoniumformate (0.01 M, pH 8.0) with 3.75% (v/v) acetonitrile served as mobile phase (300 MUL min(-1)). Hyoscyamines were detected in the positive multiple reaction monitor mode. The enantioselective assay was applied to the analysis of atropine degradation in diluted rabbit serum in vitro as well as to human in vivo plasma samples from a pesticide-poisoned patient treated with atropine. PMID- 20969990 TI - Design and evaluation of capillary electrophoresis in dynamically coated capillaries coupled with chemiluminescence detection. AB - A dynamic coating capillary electrophoresis coupled with a simplified on-line chemiluminescence detection system was designed and evaluated. In the proposed system, poly-vinylpyrrolidone was used as dynamic coating substance in the separation buffer to reduce the unwanted protein non-specific adsorption, which was first applied in capillary electrophoresis coupling with on-line chemiluminescence detection. In order to avoid complex processing, an ordinary plastic cuvette was modified as a three-way joint. The chemiluminescence reaction conditions and capillary electrophoresis separation conditions were investigated in detail. The results showed that the coated capillary can be injected protein samples at least 30 times continuously with good repeatability. Under optimal conditions, the chemiluminescence relative intensity was linear with the concentration of hemoglobin in the range of 4-1850 MUg mL(-1) and the detection limit was 2.0 MUg mL(-1) (S/N=3). The relative standard deviation of migration times and peak heights for 40 MUg mL(-1) hemoglobin were 2.5% and 4.1% (n=11) respectively. Interference of matrix effects was overcome by the calibration according to standard addition methods. Afterwards, the method was validated successfully and was applied to detect the concentration of hemoglobin in the serum of haemolytic patients. PMID- 20969991 TI - Nicking endonuclease and target recycles signal amplification assisted quantum dots for fluorescence detection of DNA. AB - An ultrasensitive fluorescence detection method for DNA based on nicking endonuclease (NEase) and target recycles assisted with CdTe quantum dots (QDs) is reported. In the detection system, when the target DNA is present, it hybridizes with a linker strand to from a duplex, in which the NEase recognizes specific nucleotide sequences and cleaves the linker strand. After nicking, the fragments of the linker strand spontaneously dissociate from the target DNA and another linker strand hybridizes to the target to trigger another strand-scission cycle. On the other hand, when the target was absent, no duplex is formed and no fragment of linker strand is produced. Then CdTe QDs and magnetic beads (MBs), which were all modified with DNA sequences complementary to that of the linker strands are added to the solution to detect the presence of a target DNA. The signal was generated through the difference in Forster resonance energy transfer (FRET) between the MB and CdTe QDs. This method indicates that one target DNA leads to cleavage of hundreds of linker DNA, increasing detection sensitivity by nearly three orders of magnitude. This method should be applicable whenever there is a requirement to detect a specific DNA sequence and can also be used for multicomponent detection. PMID- 20969992 TI - Characterization of molecular interactions of an immobilized biotinylated monolayer and streptavidin-coated microspheres by bond-rupture scanning. AB - Bond-rupture approach has been used in the understanding of biomolecular interactions of highly specific recognition, e.g., an antibody and its antigen, by a functionalized and self-assembled monolayer (SAM). One of the most challenging issues of diagnostics is to distinguish between true binding and the ever-present non-specific binding in which a species gives false results in conventional affinity methods. In this study, bond-rupture scanning was proposed to characterize bindings by introducing energy mechanically through displacement of a resonant quartz crystal. This system was able to measure the resonant frequency difference, due to mass changes and bond breakages between supramolecular interaction of biotinylated SAM and streptavidin-coated polystyrene microsphere (SCPM). Both 2-MUm and 4-MUm of SCPMs revealed two recognized desorption patterns at 4 V and 2 V amplitudes respectively. It rapidly provided confirmation of the presence of a target analyte. From this study, it can be shown that an established approach of dynamic bond-rupture scanning can be adopted as a promising diagnostic tool for investigating various interactions of bacteria or virus on an immobilized biomolecular surface by measuring the characteristic level of mechanical energy required to break bonds. PMID- 20969993 TI - Preparation of core-shell molecularly imprinted polymer via the combination of reversible addition-fragmentation chain transfer polymerization and click reaction. AB - In this paper, we demonstrated an efficient and robust route to the preparation of well-defined molecularly imprinted polymer based on reversible addition fragmentation chain transfer (RAFT) polymerization and click chemistry. The alkyne terminated RAFT chain transfer agent was first synthesized, and then click reaction was used to graft RAFT agent onto the surface of silica particles which was modified by azide. Finally, imprinted thin film was prepared in the presence of 2,4-dichlorophenol as the template. The imprinted beads were demonstrated with a homogeneous polymer films (thickness of about 2.27 nm), and exhibited thermal stability under 255 degrees C. The as-synthesized product showed obvious molecular imprinting effects towards the template, fast template rebinding kinetics and an appreciable selectivity over structurally related compounds. PMID- 20969994 TI - Optimization of silica surface with nanosize holes for immobilization of biomolecules and analysis of their interactions. AB - An evanescent-field-coupled waveguide-mode sensor of the Kretschmann configuration with a silica waveguide having nanoscale holes is an ideal tool for detection of bimolecular reactions. In the present research, an optimized surface of the sensor with cylindrical nanoscale holes was modified with sodium (1-{[6 (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]oxy}-2,5-dioxopyrrolidine-3 sulfonate) (Sulfo-EMCS) to facilitate the attachment of biomolecules; the resulting surface could be cleaned for reuse simply by changing the pH of the buffering solution. The modification is expected to be useful for wide range of molecular detection. PMID- 20969995 TI - Development of a molecularly imprinted polymer for the analysis of avermectin. AB - Five molecularly imprinted polymers (MIPs) were synthesized for a large molecule, avermectin, using different preparation techniques, monomers, and polymerization solvents. Selectivities (alpha) of each were compared using HPLC and different mobile phases containing various levels of acetic acid. Selectivity (alpha) for avermectin was greatest (alpha estimated >=18) when the polymer was prepared non covalently (utilizing only non-covalent interactions between avermectin and monomer) in chloroform using methacrylic acid (MAA) monomer and evaluated in chloroform. When evaluated in acetonitrile, an MIP prepared in acetonitrile provided better selectivity (alpha=8.4) than the polymer prepared in chloroform. Optimizing mobile phase conditions by adding acetic acid was much more important when MIPs were evaluated in chloroform than in acetonitrile. MIPs prepared with MAA provided better selectivity than a polymer prepared with acrylamide monomer. Covalent preparation of two MIPs utilizing a covalent bond between avermectin and monomer before polymerization did not improve selectivity but did improve peak shape in chromatograms. Specificity was demonstrated by comparing the selectivity of avermectin with eprinomectin (alpha=3.0), a compound with a very similar structure. Results indicate that an MIP can be prepared for the large avermectin molecule, and has the potential to simplify sample preparation and to reduce the time needed for analysis. PMID- 20969996 TI - Analysis of 2-methylthio-derivatives of isoprenoid cytokinins by liquid chromatography-tandem mass spectrometry. AB - A sensitive and reliable high-performance liquid chromatographic method with tandem mass spectrometric detection has been developed and used for the determination of 2-methylthio-cytokinin derivatives produced by the phytopathogenic actinomycete Rhodococcus fascians. The cultivation medium containing secreted cytokinins was concentrated and subjected to a solid-phase extraction (C18 and ion-exchange). The purified samples were further separated and analyzed by HPLC-ESI-MS/MS. This allowed to achieve chromatographic resolution of six highly hydrophobic cytokinin species including 2-methylthio isopentenyladenine, 2-methylthio-isopentenyladenosine, 2-methylthio-trans-zeatin and 2-methylthio-trans-zeatin riboside and their cis-isomers when a reversed phase chromatographic column (C4) and a mobile phase consisting of acetonitrile and 20 mM ammonium formate, pH 5, were used. Quantification was performed by a standard isotope dilution method using a multiple-reaction monitoring (MRM) mode. In the MRM mode, limits of detection reached 20-30 fmol and linear ranges spanned four orders of magnitude. Recovery values were between 35% and 65% and the analytical accuracy between 95% and 149%. The proposed bioanalytical method, which takes advantage of effective chromatographic separation of six 2-methyltio derivatives (including isomers of zeatin-type cytokinins) and sensitive mass spectrometric detection, may become useful for plant biologists studying the significance of these substances in plant-microbe interactions. PMID- 20969997 TI - Minimizing errors associated with calculating the location of the helical axis for spinal motions. AB - One of the more common comparative tools used to quantify the motion of the vertebral joint is the orientation and position of the (finite) helical axis of motion as well as the amount of translation along, and rotation about, this axis. A survey of recent studies that utilize the helical axis of motion to compare motion before and after total disc replacement reveals a lack of concern for the relative errors associated with this metric. Indeed, intrinsic algorithmic and experimental errors that arise when interpreting motion tracking data can easily lead to a misinterpretation of the changes caused by replacement disc devices. While previous studies examining these errors exist, most have overlooked the errors associated with the determination of the location of the helical axis and its intersection with a chosen plane. The purpose of the study presented in this paper was to evaluate the sensitivity and reliability of the helical axis of motion as a comparative tool for kinematically evaluating spinal prostheses devices. To this end, we simulated a typical spine biomechanics testing experiment to investigate the accuracy of calculating the helical axis and its associated parameters using several popular algorithms. The resultant data motivated the development of a new algorithm that is a hybrid of two existing algorithms. The improved accuracy of this hybrid method made it possible to quantify some of the changes to the kinematics of a spinal unit that are induced by distinct placements of a total disc replacement. PMID- 20969998 TI - Science of awakening. Preface. PMID- 20969999 TI - Underlying brain mechanisms that regulate sleep-wakefulness cycles. AB - Daily cycles of wakefulness and sleep are regulated by coordinated interactions between wakefulness- and sleep-regulating neural circuitry. Wakefulness is associated with neuronal activity in cholinergic neurons in the brainstem and basal forebrain, monoaminergic neurons in the brainstem and posterior hypothalamus, and hypocretin (orexin) neurons in the lateral hypothalamus that act in a coordinated manner to stimulate cortical activation on the one hand and behavioral arousal on the other hand. Each of these neuronal groups subserves distinct aspects of wakefulness-related functions of the brain. Normal transitions from wakefulness to sleep involve sleep-related inhibition and/or disfacilitation of the multiple arousal systems. The cell groups that shut off the network of arousal systems, at sleep onset, occur with high density in the ventral lateral preoptic area (VLPO) and the median preoptic nucleus (MnPN) of the hypothalamus. Preoptic neurons are activated during sleep and exhibit sleep wake state-dependent discharge patterns that are reciprocal of that observed in several arousal systems. Neurons in the VLPO contain the inhibitory neuromodulator, galanin, and the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). The majority of MnPN sleep-active neurons synthesize GABA. VLPO and MnPN neurons are sources of projections to arousal-regulatory systems in the posterior and lateral hypothalamus and the rostral brainstem. Mechanisms of sleep induction by these nuclei are hypothesized to involve GABA-mediated inhibition of multiple arousal systems. Normal cycling between discrete behavioral states is mediated by the combined influence of a sleep need that increases with continued wakefulness and an intrinsic circadian oscillation. This chapter will review anatomical and functional properties of populations of sleep-/wake-regulating neurons, focusing on recent findings supporting functional significance of the VLPO and MnPN in the regulation of sleep--wake homeostasis. Evidence indicating that MnPN and VLPO neurons have different, but complementary sleep regulatory functions will be summarized. Potential mechanisms that function to couple activity in these two sleep-regulatory neurons will be discussed. PMID- 20970000 TI - Changes in EEG pre and post awakening. AB - This chapter is concerned with behavioral and electrophysiologic evidence of awakenings. Awakenings are understood here as a state change from sleeping to waking. We will discuss the methodological issues and the problem of properly defining an awakening. With regard to phenomena preceding an awakening, we will look at arousals and compare background to event-related activity in the electroencephalography (EEG). As arousability varies between and within species, the relevant EEG correlates of this variability are described. Concerning EEG changes following an awakening, the discussion focuses on sleep inertia effects. PMID- 20970001 TI - What keeps us awake? The role of clocks and hourglasses, light, and melatonin. AB - What is it that keeps us awake? Our assumption is that we consciously control our daily activities including sleep-wake behavior, as indicated by our need to make use of an alarm clock to wake up in the morning in order to be at work on time. However, when we travel across multiple time zones or do shift work, we realize that our intentionally planned timings to rest and to remain active can interfere with an intrinsic regulation of sleep/wake cycles. This regulation is driven by a small region in the anterior hypothalamus of the brain, termed as the "circadian clock". This clock spontaneously synchronizes with the environmental light-dark cycle, thus enabling all organisms to adapt to and anticipate environmental changes. As a result, the circadian clock actively gates sleep and wakefulness to occur in synchrony with the light-dark cycles. Indeed, our internal clock is our best morning alarm clock, since it shuts off melatonin production and boosts cortisol secretion and heart rate 2-3h prior awakening from Morpheus arms. The main reason most of us still use artificial alarm clocks is that we habitually carry on a sleep depth and/or the sleep-wake timing is not ideally matched with our social/work schedule. This in turn can lead hourglass processes, as indexed by accumulated homeostatic sleep need over time, to strongly oppose the clock. To add to the complexity of our sleep and wakefulness behavior, light levels as well as exogenous melatonin can impinge on the clock, by means of their so-called zeitgeber (synchronizer) role or by acutely promoting sleep or wakefulness. Here we attempt to bring a holistic view on how light, melatonin, and the brain circuitry underlying circadian and homeostatic processes can modulate sleep and in particular alertness, by actively promoting awakening/arousal and sleep at certain times during the 24-h day. PMID- 20970002 TI - Suprachiasmatic nucleus and autonomic nervous system influences on awakening from sleep. AB - Awakening from sleep is a clear example of an event for which (biological) clocks are of great importance. We will review some major pathways the mammalian biological clock uses to ensure an efficient and coordinated wake-up process. First we show how this clock enforces daily rhythmicity onto the hypothalamo pituitary-adrenal (HPA) axis, via projections to neuroendocrine neurons within the hypothalamus. Next we demonstrate how this brain clock controls plasma glucose concentrations, via projections to sympathetic and parasympathetic pre autonomic neurons within the hypothalamus. Orexin neurons in the lateral hypothalamus appear to be an important hub in this awakening control network. PMID- 20970003 TI - Preparation for awakening: self-awakening vs. forced awakening preparatory hangs in the pre-awakening period. AB - Self-awakening (SA) is awakening by oneself at predetermined time without external means. Attempting to SA produces various kinds of preparatory changes over the course of a sleep period, including contributing to a decline in the waking threshold immediately before awakening. As a result, one can easily awake from sleep, and sleep inertia immediately after awakening from sleep reduces. In addition, daytime arousal level is higher for those who have the habit of SA. Surveys revealed that not a few people have the habit of SA and that they tend to be morningness chronotypes. Many factors are involved in the successful SA, such as psychological stress, motivation, personality trait, ambient environment, circadian and homeostatic process, and time perception. PMID- 20970004 TI - Circadian and sleep episode duration influences on cognitive performance following the process of awakening. AB - The process of waking up from an episode of sleep can produce temporary deficits in cognitive functioning and low levels of alertness and vigilance, a process referred to as sleep inertia. Cognitive ability varies as a function of time-of day; cognitive ability associated with sleep inertia also shows circadian influences with deleterious effects most pronounced when awakened from biological night, possibly paralleling the core body temperature minimum. The length of the sleep episode may contribute to the severity of sleep inertia. Short sleep episodes (<20 min) produce little cognitive impairment, probably because of a lack of slow-wave sleep in the sleep episode. With longer sleep episodes, aspects of sleep depth such as percentage of slow-wave sleep or total length of the sleep episode may be important. Finally, myriad tasks have been used to measure sleep inertia effects, and cognitive deficits associated with waking up have been demonstrated on both simple and complex tasks for both speed and accuracy. More research is needed on how the type of task may interact with sleep inertia. Tests that measure known specific aspects of cognition and that can be mapped to brain systems and neurotransmitters (e.g., the Attentional Network Test: ANT) are recommended to further understand how information processing during the process of awakening is distinct from other aspects of awareness. PMID- 20970005 TI - The cortisol awakening response in context. AB - The cortisol awakening response (CAR) is a crucial point of reference within the healthy cortisol circadian rhythm, with cortisol secretion typically peaking between 30 and 45 min post awakening. This chapter reviews the history of investigation into the CAR and highlights evidence that its regulation is relatively distinct from cortisol secretion across the rest of the day. It is initiated by awakening, under the influence of the hypothalamic suprachiasmatic nucleus, and "fine tuned" by a direct neural input to the adrenal cortex by the sympathetic nervous system. This chapter also examples the CAR in relation to other awakening-induced processes, such as restoration of consciousness, attainment of full alertness, changes in other hormones, changes in the balance of the immune system, and mobilization of the motor system, and speculates that there is a role for the CAR in these processes. PMID- 20970006 TI - Causes and correlates of frequent night awakenings in early childhood. AB - Night awakenings are a normative part of early development. In the first year, night awakenings are associated with birth order, feeding route, sleep aid use, sleep location, infant temperament and development, infant-parent attachment, family socioeconomics, and cultural norms. In the second year, additional factors build on these foundational features, including parenting practices and object attachment. As children grow, contextual factors like preschool entry or changes in family member status may influence the continuation or exacerbation of awakenings. Future research should consider the multitude of factors that influence not only awakenings but also parental perceptions, family dynamics, and cultural norms. PMID- 20970007 TI - Pathologies of awakenings: the clinical problem of insomnia considered from multiple theory levels. AB - Limit cycle-based mid-level theories that rationalize effective clinical treatments for chronic insomnia have empirical support from whole-organism studies of sleep physiology, but their relation to network-level and cellular neurobiologies remains obscure. The neurobiology of pharmacological treatments for insomnia has been increasingly understood, but has not been fully integrated with psychological theories or electroencephalographic descriptions of sleep. Better clinical diagnostic and treatment frameworks will require both greater conceptual clarity as to what an "awakening" is descriptively and detailed investigations to relate fundamental neuroscience to clinical technologies can be both accessible and diagnostically useful to clinicians. PMID- 20970009 TI - Assessing the effectiveness of intraocular pressure-lowering therapy. PMID- 20970008 TI - The neurochemistry of awakening: findings from sleep disorder narcolepsy. AB - Recent progress in our understanding of the pathophysiology of excessive sleepiness (EDS) is particularly indebted to the 1999 discovery of narcolepsy genes (i.e., hypocretin receptor and peptide genes) in animals and the subsequent discovery of hypocretin ligand deficiency in idiopathic cases of human narcolepsy cataplexy. Hypocretin deficiency is also involved in many cases of symptomatic narcolepsy and EDS. Changes in other neurotransmitter systems (such as monoamines and acetylcholine) previously reported in these conditions are likely to be secondary to the impaired hypocretin neurotransmission; however, these may also mediate the sleep abnormalities seen in hypocretin deficient narcolepsy. The pathophysiology of hypocretin non-deficient narcolepsy is debated. Similarly, the pathophysiology of idiopathic hypersomnia, another defined primary hypersomnia, is largely unknown. This chapter discusses our current understanding of the neurochemistry of EDS, a disease of awakening. PMID- 20970010 TI - Scanning laser edema index. PMID- 20970011 TI - Inferior pseudophakic retinal detachment. PMID- 20970012 TI - VEGF and refractive error. PMID- 20970013 TI - Vitrectomy for diabetic macular edema. PMID- 20970014 TI - Eye pressure and head position. PMID- 20970016 TI - Blepharoptosis and floppy eyelid. PMID- 20970018 TI - Discontinuity and its discontents. PMID- 20970019 TI - Quiz page November 2010: a young woman with metabolic acidosis, hyperammonemia, and visual disturbance. Methylmalonic acidemia complicated with toxic amblyopia. PMID- 20970020 TI - On warfarin use in kidney disease: a therapeutic window of opportunity? PMID- 20970021 TI - Using computerized provider order entry and clinical decision support to improve prescribing in patients with decreased GFR. PMID- 20970022 TI - Off-label use of phosphate binders in non-dialysis-dependent CKD. PMID- 20970023 TI - Personalized medicine and prediction of outcome in kidney transplant. PMID- 20970024 TI - Malnutrition-inflammation complex syndrome in kidney transplant recipients. PMID- 20970026 TI - Management of isolated aspergilloma causing obstruction of the kidney transplant. PMID- 20970027 TI - Green urine following exposure to flupirtine. PMID- 20970028 TI - Validation of nipple diameter and tongue movement measurements with B-mode ultrasound during breastfeeding. AB - Infant feeding problems are extremely common during breastfeeding establishment. To objectively assess infant sucking, consistent methods to analyze ultrasound images of the infant's oral cavity are required. We developed and assessed the reliability of an extensive ultrasound measurement protocol by measuring nipple diameter and placement. Midline submental ultrasound scans of 30 term breastfed infants were analyzed by two raters. Nipple diameter, nipple hard-soft palate junction distance and tongue hard-soft palate junction distance were measured on two frames: tongue-up and tongue-down. No evidence of measurement bias was found between raters and inter-rater agreement and consistency scores were high. The changes in nipple diameter and placement were consistent with previous descriptions; however, the diameter of the nipple was not consistent in either position. This method provides objective measurements representative of tongue movement, and further investigation is required to ensure usefulness when examining sucking difficulties. PMID- 20970029 TI - Localized low-dose radiotherapy for follicular lymphoma: history, clinical results, mechanisms of action, and future outlooks. AB - The extreme radiosensitivity of indolent lymphomas was reported in the early years of radiotherapy (RT). The efficacy of low-dose total body irradiation (1.5 2 Gy) was particularly demonstrative. Higher doses were considered appropriate for localized disease. The optimal (or conventional) dose of curative RT derived from the early studies was determined to be 30-35 Gy. Nevertheless, in older series addressing the tumoricidal radiation dose in non-Hodgkin's lymphomas, investigators noted that a significant number of "nodular" lymphomas were controlled with a dose of <22 Gy for >3 years. The idea of reintroducing localized low-dose radiotherapy (LDRT) for indolent non-Hodgkin's lymphomas came from a clinical observation. The first study showing the high efficacy of LDRT (4 Gy in two fractions of 2 Gy within 3 days) in selected patients with chemoresistant, indolent, non-Hodgkin's lymphomas was published in 1994. Since this first report, at least eight series of patients treated with localized LDRT have been published, showing a 55% complete response rate in irradiated sites, with a median duration of 15-42 months. How LDRT induces lymphoma cell death remains partly unknown. However, some important advances have recently been reported. Localized LDRT induces an apoptosis of follicular lymphoma cells. This apoptotic cell death elicits an immune response mediated by macrophages and dendritic cells. Follicular lymphoma is probably an ideal model to explore these mechanisms. This review also discusses the future of LDRT for follicular lymphoma. PMID- 20970030 TI - Clinical management of salivary gland hypofunction and xerostomia in head-and neck cancer patients: successes and barriers. AB - The most significant long-term complication of radiotherapy in the head-and-neck region is hyposalivation and its related complaints, particularily xerostomia. This review addresses the pathophysiology underlying irradiation damage to salivary gland tissue, the consequences of radiation injury, and issues contributing to the clinical management of salivary gland hypofunction and xerostomia. These include ways to (1) prevent or minimize radiation injury of salivary gland tissue, (2) manage radiation-induced hyposalivation and xerostomia, and (3) restore the function of salivary gland tissue damaged by radiotherapy. PMID- 20970031 TI - Validity of the graded prognostic assessment-derived index to predict brain metastatic patients' survival after Gamma Knife radiosurgery. AB - PURPOSE: To appraise whether the graded prognostic assessment (GPA)-derived index is valid for selecting patients with brain metastases for Gamma Knife (GK) radiosurgery. METHODS AND MATERIALS: A total of 56 consecutive patients in recursive partioning analysis (RPA) Class I (n = 19, 34%) and II (n = 37, 66%) formed the basis of this retrospective study. Their mean age was of 57 years with mean Karnofsky performance score of 77. Primary cancers stemmed mainly from the lungs (59%). A total of 45 patients (80%) harbored multiple tumors. The mean clinical follow-up period was 9 months. RESULTS: Kaplan-Meier analysis demonstrated that the overall median survival time (MST) for the whole series was 11.5 months: 16.5 vs. 6.5 months for RPA class I and II (p = 0.017). Multivariate Cox analysis revealed that female patients and a pre-GK good functional state were favorable prognostic factors. The favorable MST was in patients with a GPA score of 3 to 4 (17 months) followed by a GPA score of 2 to 2.5 (11 months) and GPA score 0 to 1.5 (6.5 months), but without statistical differences (p = 0.413) in between. A modified index (MGPA) is proposed with gender as a cofactor, then there existed a distinct survival differences (p = 0.028) between patients with an MGPA score of 3.5 to 5 (15 months) and with an MGPA score of 0 to 3 (7 months). In addition, the original GPA index failed to imply the difference of MST in patients with lung origin. CONCLUSIONS: The GPA-derived index is not applicable to our set of patients for comparing their survival after GK radiosurgery. The gender of the patients is a suggested cofactor to further refine the greater prognostic accuracy of the GPA index. PMID- 20970032 TI - A gene expression signature for chemoradiosensitivity of colorectal cancer cells. AB - PURPOSE: The standard treatment of patients with locally advanced rectal cancers comprises preoperative 5-fluorouracil-based chemoradiotherapy followed by standardized surgery. However, tumor response to multimodal treatment has varied greatly, ranging from complete resistance to complete pathologic regression. The prediction of the response is, therefore, an important clinical need. METHODS AND MATERIALS: To establish in vitro models for studying the molecular basis of this heterogeneous tumor response, we exposed 12 colorectal cancer cell lines to 3 MUM of 5-fluorouracil and 2 Gy of radiation. The differences in treatment sensitivity were then correlated with the pretherapeutic gene expression profiles of these cell lines. RESULTS: We observed a heterogeneous response, with surviving fractions ranging from 0.28 to 0.81, closely recapitulating clinical reality. Using a linear model analysis, we identified 4,796 features whose expression levels correlated significantly with the sensitivity to chemoradiotherapy (Q <.05), including many genes involved in the mitogen-activated protein kinase signaling pathway or cell cycle genes. These data have suggested a potential relevance of the insulin and Wnt signaling pathways for treatment response, and we identified STAT3, RASSF1, DOK3, and ERBB2 as potential therapeutic targets. The microarray measurements were independently validated for a subset of these genes using real-time polymerase chain reactions. CONCLUSION: We are the first to report a gene expression signature for the in vitro chemoradiosensitivity of colorectal cancer cells. We anticipate that this analysis will unveil molecular biomarkers predictive of the response of rectal cancers to chemoradiotherapy and enable the identification of genes that could serve as targets to sensitize a priori resistant primary tumors. PMID- 20970033 TI - Epothilone B confers radiation dose enhancement in DAB2IP gene knock-down radioresistant prostate cancer cells. AB - PURPOSE: In metastatic prostate cancer, DOC-2/DAB2 interactive protein (DAB2IP) is often downregulated and has been reported as a possible prognostic marker to predict the risk of aggressive prostate cancer (PCa). Our preliminary results show that DAB2IP-deficient PCa cells are radioresistant. In this study, we investigated the anticancer drug Epothilone B (EpoB) for the modulation of radiosensitivity in DAB2IP-deficient human PCa cells. METHODS AND MATERIALS: We used a stable DAB2IP-knock down human PCa cell line, PC3 shDAB2IP, treated with EpoB, ionizing radiation (IR), or the combined treatment of EpoB and IR. The modulation of radiosensitivity was determined by surviving fraction, cell cycle distribution, apoptosis, and DNA double-strand break (DSB) repair. For in vivo studies, the PC3shDAB2IP xenograft model was used in athymic nude mice. RESULTS: Treatment with EpoB at IC(50) dose (33.3 nM) increased cellular radiosensitivity in the DAB2IP-deficient cell line with a dose enhancement ratio of 2.36. EpoB delayed the DSB repair kinetics after IR and augmented the induction of apoptosis in irradiated cells after G(2)/M arrest. Combined treatment of EpoB and radiation enhanced tumor growth delay with an enhancement factor of 1.2. CONCLUSIONS: We have demonstrated a significant radiation dose enhancement using EpoB in DAB2IP deficient prostate cancer cells. This radiosensitization can be attributed to delayed DSB repair, prolonged G(2) block, and increased apoptosis in cells entering the cell cycle after G(2)/M arrest. PMID- 20970034 TI - Tumor relapse or radionecrosis after radiosurgery: single-photon emission computed tomography for differential diagnosis. In regard to Blonigen et al. Irradiated volume as a predictor of brain radionecrosis after linear accelerator stereotactic radiosurgery. (Int J Radiat Oncol Biol Phys 2010;77:996-1001). PMID- 20970036 TI - Response to "Standard and nonstandard craniospinal radiotherapy using helical tomotherapy." (Int J Radiat Oncol Biol Phys 2010;77:926-931). PMID- 20970038 TI - Treatment-related pneumonitis and acute esophagitis in non-small-cell lung cancer patients treated with chemotherapy and helical tomotherapy: in regard to Song et al. PMID- 20970040 TI - Response to "The negative impact of Stark law exemptions on graduate medical education and health care costs: the example of radiation oncology." (Int J Radiat Oncol Biol Phys 2010;76;1289-1294). PMID- 20970041 TI - Indirect calorimetry measurements in the ventilated critically ill patient: facts and controversies--the heat is on. AB - The provision of nutrition to critically ill patients in the ICU often receives lower priority compared with hemodynamic and ventilation control. This frequently results in a significant calorie deficit. Overestimation of daily energy expenditure may also result in adverse outcomes. In many centers, nutritional decision making is based on predictive formulas, which have been shown to underestimate true energy requirements. Such estimations are ideally performed using indirect calorimetry. Nevertheless, the use of indirect calorimetry has been limited owing to costs and technical difficulties. Controversies about its actual clinical benefits are the focus of recent clinical studies and recommendations. The aim of this review was to describe the advantages of measuring indirect calorimetry within the concept of energy-protein goal-oriented therapy. PMID- 20970042 TI - Critically ill obese and morbidly obese patients. Preface. PMID- 20970043 TI - The obesity paradox. AB - The term "obesity paradox" refers to the observation that, although obesity is a major risk factor in the development of cardiovascular and peripheral vascular disease, when acute cardiovascular decompensation occurs, for example, in myocardial infarction or congestive heart failure, obese patients may have a survival benefit. In addition, it has been suggested that obese patients tend to fare better after certain surgical procedures, such as coronary artery bypass surgery. Moreover, it appears that obese men with chronic hypertensive heart disease live longer than men of normal weight. Mounting evidence shows that obesity alone may confer a survival benefit independent of age, medical care, or therapy. Perhaps the definition of obesity needs to be revisited, and it is also possible that all fat is not equal. PMID- 20970044 TI - Pulmonary system and obesity. AB - There are several challenges in the management of respiratory failure in the obese population. Pulmonary physiology is significantly altered leading to reduced lung volumes, decreased compliance, abnormal ventilation and perfusion relationships, and respiratory muscle inefficiency. These complications can lead to a prolonged requirement for mechanical ventilation and increased intensive care-unit length of stay. PMID- 20970045 TI - Cardiovascular considerations in critically ill obese patients. AB - With a growing obese population, preventative and therapeutic strategies need to be developed to combat the complex cardiac pathophysiology related to obesity. This is paramount in the management of critically ill obese patients. This article highlights these strategies. PMID- 20970046 TI - Acute kidney injury in the critically ill, morbidly obese patient: diagnostic and therapeutic challenges in a unique patient population. AB - The growing burden of morbid obesity (body mass index >40 kg/m2) on critical care resources translates to a significant incidence of acute kidney injury (AKI) in morbidly obese (MO), critically ill patients. This article examines the literature pertinent to AKI in critically ill MO patients. After a concise review of the available epidemiologic data regarding the incidence of acute renal injury in MO individuals, the authors review the limitations and available tools for estimation of renal function in the MO population (with emphasis on the critical illness). Also described are several specific types of renal injury previously described in this population that are applicable to the critical care setting. Lastly, the authors review some of the challenges and limitations in providing renal support to critically ill MO individuals, and identify potential areas for future research in this population. PMID- 20970047 TI - Gastrointestinal system and obesity. AB - Several significant changes occur in the gastrointestinal system with obesity that can effect management in critical illness. This population is at risk for gastroesophageal reflux disease (GERD), abdominal compartment syndrome, nonalcoholic fatty liver disease (NAFLD), and an increased incidence of cholelithiasis. It is important for critical care providers to be aware of these potential complicating factors. PMID- 20970048 TI - Immunologic changes in obesity. AB - A growing body of literature suggests multifaceted alterations to the immune function in obese patients compared with a lean cohort. Although treatment in the intensive care unit has an associated risk of infectious complications, which, if any, of these immunologic alterations are causal is unclear. Obesity clearly causes abundant alterations to the immune system. Overall, the aggregate effect seems to be chronic activation of inflammatory mediators. PMID- 20970049 TI - Endocrine system and obesity. AB - Obesity is associated with significant alterations in endocrine function. An association with type 2 diabetes mellitus and dyslipidemia has been well documented. This article highlights the complexities of treating endocrine system disorders in obese patients. PMID- 20970050 TI - Venous thromboembolic disease and hematologic considerations in obesity. AB - Venous thromboembolic disease continues to be a major source of morbidity and mortality, with obese patients who are critically ill presenting some of the most at-risk patients. As the literature evolves, it has become clear that there is a complex relationship between obesity and thrombosis and atherogenesis. It is true that many of these conditions are reversible with weight loss; however, obesity remains on the rise. Management of obese patients must incorporate and consider these intricate changes in an attempt to improve patient outcomes. PMID- 20970051 TI - Airway management in the obese patient. AB - Any patient can have a difficult airway, but obese patients have anatomic and physiologic features that can make airway management particularly challenging. Obesity does not seem to be an independent risk factor for difficult intubation but is one of the several factors that need to be considered as part of an airway evaluation. To effectively manage airways in obese patients, health care providers working in the intensive care unit setting must be proficient in airway evaluation and management in all types of patients. This article discusses the risk factors for a difficult airway and the methods of managing the airway. PMID- 20970052 TI - Vascular procedures in the critically ill obese patient. AB - The increasing societal prevalence of obesity is consequential to the increasing number of critically ill obese patients. Vascular procedures are an essential aspect of care in these patients. This article reviews the general, anatomic, and physiologic considerations pertaining to vascular procedures in critically ill obese patients. In addition, the use of ultrasonography for these procedures is discussed. PMID- 20970053 TI - Ultrasound-assisted lumbar puncture in obese patients. AB - The use of ultrasound to mark landmarks for diagnostic lumbar puncture has been described in emergency medicine as well as in the anesthesia literature. One of the most difficult scenarios arises when obese patients with a body mass index (BMI) of greater than 30 present to an acute care setting, such as the emergency department or intensive care unit and require diagnostic LP. This article discusses lumbar puncture in patients with a high BMI. PMID- 20970054 TI - Bedside and radiologic procedures in the critically ill obese patient. AB - Performance of procedures upon the obese critically ill patient in the ICU or in the radiology suite, require certain considerations. Additional staff, equipment and proper ergonomics are often necessary to perform these procedures safely for both patient and staff. PMID- 20970055 TI - Tracheostomy in critical ill morbidly obese. PMID- 20970056 TI - Nutrition in critically ill obese patients. AB - Critically ill obese patients require timely nutrition in the intensive care unit. Hypocaloric, high protein nutritional feeding might have a role in critically ill obese patients. Although critically ill obese patients need special medical and nutritional care as do nonobese patients in the ICU, there are some differences in the literature about the initiation, routes, and nature of nutritional support. This article reviews the norms of nutritional care among critically ill obese patients and the differences between these patients and those with a normal BMI. PMID- 20970057 TI - Pharmacotherapy in the critically ill obese patient. AB - Despite the growing epidemic of obesity in the United States, dosing medications in such patients remains poorly studied and understood. Most recommendations are based on small independent studies, case reports, and expert opinion. Applying manufacturer kinetics and dosing recommendations in the obese patient may result in toxicity or treatment failure, leading to increased morbidity, mortality, and hospital length of stay. PMID- 20970058 TI - Trauma in obese patients. AB - As the American population grows larger in terms of weight and body mass index each year, a greater percentage of patients admitted to the trauma service are overweight or obese. Obese patients do not have the same injury patterns or outcomes of normal-weight patients. This article reviews some of the latest data regarding the injury patterns, outcomes, and areas of further studies in the obese trauma population. PMID- 20970059 TI - Bariatric surgery patients in the ICU. AB - As the incidence of bariatric surgery continues to increase, the medical community should be aware of the most common procedures, resultant anatomy, and possible complications to be better prepared to care for these patients in all situations. PMID- 20970060 TI - Special considerations in the critically ill morbidly obese child. AB - Obesity has been recognized as an increasing problem not only in North America but globally. With a significant rise in the prevalence of obesity amongst children and adolescents over the past 20 years, the comorbidities associated with obesity are also now emerging at an earlier age. These comorbidities cause specific concern and require special consideration when the morbidly obese child becomes critically ill. PMID- 20970061 TI - Critical care of the morbidly obese in disaster. AB - The prevalence of obesity in the United States is increasing, with extreme morbid obesity of body mass index greater than 40 increasing twice as fast as obesity in general. With the increased weight comes an increased risk of comorbidities, including type 2 diabetes mellitus, cardiovascular disease, respiratory problems such as obstructive sleep apnea or restrictive lung disease, skin disorders such as intertrigo and cellulitis, and urinary incontinence. Thus, patients exposed to a variety of disasters not only are increasingly overweight but also have an associated number of coexistent medical conditions that require increased support with medical devices and medications. This article focuses on management of the morbidly obese patients during disasters. PMID- 20970062 TI - Special populations critical care considerations of the morbidly obese pregnant patient. AB - The critically ill pregnant patient poses a unique challenge to the clinician, requiring a thorough understanding of normal and abnormal maternal and fetal physiology associated with pregnancy. The morbidly obese patient presents even greater challenges to the clinician, and morbidity and mortality are proportionately increased. Because increased numbers of obese pregnant women are now admitted to intensive care units, practitioners must be aware of the physiology associated with both pregnancy and obesity. A multidisciplinary approach is imperative to prevent both maternal and fetal morbidity and mortality for these very complex patients, especially when they are admitted to the ICU with critical illness. PMID- 20970063 TI - Afterword: sensitivity in caring for the obese patient. PMID- 20970064 TI - HTLV-1 and adult T-cell leukemia: insights into viral transformation of cells 30 years after virus discovery. AB - Human T-cell leukemia virus type 1 (HTLV-1), the etiological agent of adult T cell leukemia, was the first human retrovirus to be isolated. It is now the 30(th) anniversary of the initial discovery of HTLV-1. This review discusses recent insights into the role of the HTLV-1 Tax oncoprotein in cellular proliferation and the abrogation of cellular checkpoints that lead to disease progression. PMID- 20970065 TI - Detection of nighttime melatonin level in Chinese Original Quiet Sitting. AB - BACKGROUND/PURPOSE: Some research has shown that melatonin levels increase after meditation practices, but other research has shown that they do not. In our previous functional magnetic resonance imaging study, we found positive activation of the pineal body during Chinese Original Quiet Sitting (COQS). To find other supporting evidence for pineal activation, the aim of this study was to evaluate the effect of COQS on nighttime melatonin levels. METHODS: Twenty subjects (11 women and 9 men, aged 29-64 years) who had regularly practiced daily meditation for 5-24 years participated in this study. All subjects served alternately as participants in the mediation and control groups. COQS was adopted in this study. Tests were performed during two nighttime sessions. Saliva was sampled at 0, 10, 20, 30, 45, 60 and 90 minutes after COQS and tested for level of melatonin. Time period effect analysis and mixed effect model analysis were preceded by paired t test analysis. RESULTS: In the meditation group (n = 20), the mean level of melatonin was significantly higher than the baseline level at various times post-meditation (p < 0.001). Within the control group (n = 20), the mean level of melatonin at various times was not significantly different compared with baseline (p>0.05). These results suggested that the melatonin level was statistically elevated in the meditation group and almost unchanged in the control group after nighttime meditation. The urine serotonin levels detected by measuring 5-hydroxy-indole-3-acetic acid levels were also studied, but no detectable difference between the groups was found. CONCLUSION: Our results support the hypothesis that meditation might elevate the nighttime salivary melatonin levels. It suggests that COQS can be used as a psychophysiological stimulus to increase endogenous secretion of melatonin, which in turn, might contribute to an improved sense of well-being. PMID- 20970066 TI - Solifenacin and tolterodine are equally effective in the treatment of overactive bladder symptoms. AB - BACKGROUND/PURPOSE: Various antimuscarinic agents have been developed for the treatment of overactive bladder (OAB). More data comparing these agents are still required. This study evaluated the efficacy and safety of solifenacin and tolterodine in Taiwanese patients with OAB symptoms. METHODS: This was a prospective, randomized, open-label study. A total of 75 patients (25 men and 50 women) with OAB symptoms were randomized to treatment with solifenacin (n = 39) or tolterodine (n = 36). Efficacy and safety variables were assessed and compared with the baseline and between the two groups. RESULTS: At week 12, solifenacin and tolterodine demonstrated equal efficacy in reducing the number of micturition (-2.56 +/-3.31 vs. -2.44 +/- 4.56, p = 0.58), urgency (-1.70 +/- 3.07 vs. -1.15 +/- 2.68, p =0.37) and incontinence (-2.79 +/- 2.82 vs. -4.67 +/- 9.29, p =0.28) episodes per 24 hours. There was no difference in improvement of the quality of life. The patient and physician assessments of treatment benefit were not statistically different for solifenacin and tolterodine (p = 0.23 and p = 0.52, respectively), with the majority showing benefits in both groups. The incidence of major adverse events, including dry mouth (18.0%vs. 8.3%, p = 0.31) and constipation (12.8%vs. 2.8%, p = 0.20) was not significantly different. Compared with baseline, the severity of dry mouth did not increase in either group. CONCLUSION: Both solifenacin and tolterodine are effective in treating key OAB symptoms, including urinary frequency, urgency and incontinence in the Taiwanese population. Both medications are comparably effective and safe, with the most common adverse effects being dry mouth and constipation. PMID- 20970067 TI - Complete unilateral maxillary sinus opacity in computed tomography. AB - BACKGROUND/PURPOSE: Unilateral maxillary sinus opacity can be caused by many diseases, but an exact diagnosis is difficult to make. The aim of this study was to describe the pathological conditions and clinical features of patients with unilateral maxillary sinus opacity. METHODS: From 2004 to 2008, 830 consecutive patients underwent sinus surgery or endonasal endoscopic biopsy at an academic tertiary care center. The preoperative computed tomography (CT) images for these patients were reviewed, and 11 6 patients were identified with complete unilateral maxillary sinus opacification. We then analyzed presenting symptoms, physical examinations, specific CT findings, and pathology. RESULTS: The most frequent diagnoses were as follows: chronic rhinosinusitis (52.6%), fungus ball (29.3%), antrochoanal polyp (2.6%), benign tumor (10.4%), and malignancy (5.1%). Fungus ball was the most common diagnosis (10/18, 55.6%) in the subgroup of patients with isolated maxillary sinus opacity without disease in the other sinuses. Nasal discharge and foul-smelling breath were more common in inflammatory disease than in neoplastic disease. Neoplastic disease was more likely to present as epistaxis; a polyp or mass revealed by nasal endoscopy; mass effect in the cheek, palate, or gingiva; and bony erosion on CT. Erosion of the maxillary posterolateral wall and extra-sinus extension suggested malignancy. CONCLUSION: Although unilateral maxillary sinus opacity is usually inflammatory in origin, fungal sinusitis and neoplastic disorder are also likely. A careful history-taking, a thorough head and neck examination including nasal endoscopy, and CT evaluation are all imperative for reaching a correct diagnosis. PMID- 20970068 TI - Effect of physical activity on the prevalence of metabolic syndrome and left ventricular hypertrophy in apparently healthy adults. AB - BACKGROUND/PURPOSE: Metabolic syndrome and left ventricular hypertrophy (LVH) carry high cardiovascular risks. We performed a cross-sectional study to evaluate the effect of different amounts of physical activity (PA) on the prevalence of metabolic syndrome and LVH in our study population. METHODS: This study was a cross-sectional survey of 1494 apparently healthy subjects: 776 men with a mean age of 57.6 + 12.3 years, and 718 women with a mean age of 56.4+ 11.0 years. The metabolic syndrome was defined according to modified criteria of the National Cholesterol Education Program Adult Treatment Panel III. LVH was diagnosed by electrocardiography voltage criteria. The amount of PA was determined with a questionnaire and stratified into low, moderate or high levels. RESULTS: The prevalence of metabolic syndrome and its components was as follows: metabolic syndrome, 15.5%; obesity, 29.7%; high triglyceride level, 21.7%; low high-density lipoprotein-cholesterol level, 35.9%; high blood pressure, 56.9%; and impaired fasting glucose, 13.1%. A high amount of PA (> 14 km per week walking distance) was significantly associated with lower prevalence of metabolic syndrome [odds ratio (OR) = 0.53, p = 0.001], lower prevalence of obesity (OR = 0.56, p = 0.001), triglyceridemia (OR = 0.58, p = 0.007) and LVH (OR=0.37, p = 0.006). CONCLUSION: This study suggests that high amounts of PA are inversely correlated with the prevalence of metabolic syndrome and LVH in men and women. PMID- 20970069 TI - Trends in hospitalization for diabetic ketoacidosis in diabetic patients in Taiwan: analysis of national claims data, 1997-2005. AB - BACKGROUND/PURPOSE: Diabetic ketoacidosis (DKA) is a fatal complication of diabetes, and is strongly related to the quality of diabetes care. This study aimed to establish recent secular trends of incidence density (ID) of DKA in patients with diabetes in Taiwan and to explore the effects of age and sex on the risk of a DKA emergency. METHODS: Using the National Health Insurance claims data, we identified annual diabetic cohorts (around 650,000 diabetic patients annually) from 1997 to 2005, and searched for possible admissions due to DKA emergencies. We performed log-linear regression analysis to assess the trend in ID of DKA and to assess the independent effects of age and sex on the risk of DKA. RESULTS: Although the annual ID of DKA showed a slight but significant declining trend over the study period, from 6/1000 to 5/1000 person-years, the age/sex-specific analysis indicated that female patients aged <= 34 years showed a significantly increasing trend. Multivariate analysis revealed that calendar year and sex had significant but small independent effects on risk of DKA admission. In contrast, age was strongly associated with risk of DKA emergency. Compared with patients aged > 65 years, notably high adjusted rate ratios (ARRs) of DKA were observed in patients aged <15 years (ARR = 48.84) and 15-34 years (ARR =15.21). CONCLUSION: Although the overall ID of DKA linearly decreased between 1997 and 2005, significant rising trends were still observed in female diabetic patients aged < 35 years. More aggressive diabetic care programs aimed at young female patients should be considered to reduce this emergency and possibly fatal diabetic complications. PMID- 20970070 TI - Extramedullary hematopoiesis in osteopetrosis. PMID- 20970071 TI - Association of novelty seeking scores and striatal dopamine D2/D3 receptor availability of healthy volunteers: single photon emission computed tomography with 123i-iodobenzamide. AB - It has been speculated that novelty seeking (NS) behavior is related to the dopaminergic system. Fifty-two subjects completed the Tridimensional Personality Questionnaire and underwent single photon emission computed tomography with (123)I-iodobenzamide. A marginally positive correlation was noted between NS and striatal dopamine D(2)/D(3) receptor availability (r = 0.25, p =0.07). A positive association was noted between the NS scores and left striatal D(2)/D(3) receptor availability (r= 0.29, p =0.04). The results suggest that a relationship might exist between NS score and dopaminergic activity. PMID- 20970072 TI - 2010 guidelines of the Taiwan Society of Cardiology for the management of hypertension. AB - Hypertension is one of the most important risk factors for atherosclerosis related mortality and morbidity. In this document, the Hypertension Committee of the Taiwan Society of Cardiology provides new guidelines for hypertension management. The key messages are as follows. (1) The life-time risk for hypertension is 90%. (2) Both the increase in the prevalence rate and the relative risk of hypertension for causing cardiovascular events are higher in Asians than in Caucasians. (3) The control rate has been improved significantly in Taiwan from 2.4% to 21% in men, and from 5% to 29% in women in recent years (1995-2002). (4) Systolic and diastolic blood pressure (BP) = 130/80 mmHg are thresholds of treatment for high-risk patients, such as those with diabetes, chronic kidney disease, stroke, established coronary heart disease, and coronary heart disease equivalents (carotid artery disease, peripheral arterial disease, and abdominal aortic aneurysm). (5) Ambulatory and home BP monitoring correlate more closely with end-organ damage and have a stronger relationship with cardiovascular events than office BP monitoring, but the feasibility of home monitoring makes it a more attractive alternative. (6) Patients with masked hypertension have higher cardiovascular risk than those with white-coat hypertension. (7) Lifestyle changes should be encouraged in all patients, and include the following six items: S-ABCDE (Salt restriction; Alcohol limitation; Body weight reduction; Cessation of smoking; Diet adaptation; Exercise adoption). (8) When pharmacological therapy is needed, physicians should consider "PROCEED" (Previous experience of patient; Risk factors; Organ damage; Contraindication or unfavorable conditions; Expert or doctor judgment; Expense or cost; Delivery and compliance) to decide the optimal treatment. (9) The main benefits of antihypertensive agents are derived from lowering of BP per se, and are generally independent of the drugs being used, except that certain associated cardiovascular conditions might favor certain classes of drugs. (10) There are five major classes of drugs: thiazide diuretics; beta-blockers; calcium channel blockers; angiotensin-converting enzyme inhibitors (ACEIs); and angiotensin receptor blockers (ARBs). Any one of these can be used as the initial treatment, except for beta-blockers, which are only indicated in patients with heart failure, a history of coronary heart disease, and hyperadrenergic state. (11) A standard dose of any one of the five major classes of antihypertensive drugs can produce an ~10-mmHg decrease in systolic BP (rule of 10) and a 5-mmHg decrease in diastolic BP (rule of 5), after placebo subtraction. (11) Combination therapy is frequently needed for optimal control of BP, and the amount of the decrease in BP by a two-drug combination is approximately the same as the sum of the decrease by each individual drug (~20 mmHg in systolic BP and 10 mmHg in diastolic BP) if their mechanisms of action are independent, with the exception of the combination of ACEIs and ARBs. (13) An ACEI or ARB plus a calcium channel blocker or a diuretic (A + C or A + D) are reasonable two-drug combinations, and A+C + D is a reasonable three-drug combination, unless patients have special indications for beta-blockers. (14) Single-pill (fixed-dose) combinations that contain more than one drug in a single tablet are highly recommended because they reduce pill burden and cost, and improve compliance. (15) Very elderly patients (> 80 years) should be treated without delay, but BP should be reduced gradually and more cautiously. Finally, these guidelines are not mandatory; the responsible physician's decision remains most important in hypertension management. PMID- 20970073 TI - The International Journal of Adolescent Health. PMID- 20970074 TI - Are motion picture ratings reliable and valid? PMID- 20970075 TI - Reducing antisocial behavior and promoting healthy outcomes for incarcerated adolescents. PMID- 20970076 TI - Mapping a global agenda for adolescent health. AB - Major changes in health are underway in many low- and middle-income countries that are likely to bring greater focus on adolescents. This commentary, based on a 2009 London meeting, considers the need for strategic information for future global initiatives in adolescent health. Current coverage of adolescent health in global data collections is patchy. There is both the need and scope to extend existing collections into the adolescent years as well as achieve greater harmonization of measures between surveys. The development of a core set of global adolescent health indicators would aid this process. Other important tasks include adapting and testing interventions in low- and middle-income countries, growing research capacity in those settings, better communication of research from those countries, and building structures to implement future global initiatives. A global agenda needs more than good data, but sound information about adolescent health and its social and environmental determinants, will be important in both advocacy and practice. PMID- 20970077 TI - The timing of puberty: is it changing? Does it matter? AB - Whether the secular trend of a decreasing age of puberty has continued over the past 50 years remains controversial. Data that had been classically used to address this issue are reviewed and large epidemiologic studies, which had not previously been included, are now considered to challenge the conclusions of prior debates of this topic. The effect and timing of excessive weight gain are discussed in detail and recent observations about the opposing effects of obesity on the pubertal timing of girls versus boys are considered. The second half of the review examines both the causes and the long-term health consequences of early puberty, touching on the possible effect of stress and endocrine-disrupting chemicals along with the risks of reproductive cancers, metabolic syndrome, and psychosocial consequences during adolescence and beyond. PMID- 20970078 TI - The effectiveness of the motion picture association of America's rating system in screening explicit violence and sex in top-ranked movies from 1950 to 2006. AB - CONTEXT: Youth exposure to explicit film violence and sex is linked to adverse health outcomes and is a serious public health concern. The Motion Picture Association of America's (MPAA's) rating system's effectiveness in reducing youth exposure to harmful content has been questioned. PURPOSE: To determine the MPAA's rating system's effectiveness in screening explicit violence and sex since the system's initiation (1968) and the introduction of the PG-13 category (1984). Also, to examine evidence of less restrictive ratings over time ("ratings creep"). DESIGN: Top-grossing movies from 1950 to 2006 (N = 855) were coded for explicitness of violent and sexual content. Trends in rating assignments and in the content of different rating categories since 1968 were assessed. RESULTS: The explicitness of violent and sexual content significantly increased following the rating system's initiation. The system did not differentiate violent content as well as sexual content, and ratings creep was only evident for violent films. Explicit violence in R-rated films increased, while films that would previously have been rated R were increasingly assigned to PG-13. This pattern was not evident for sex; only R-rated films exhibited higher levels of explicit sex compared to preratings period. CONCLUSIONS: While relatively effective for screening explicit sex, the rating system has allowed increasingly violent content into PG-13 films, thereby increasing youth access to more harmful content. Assignment of films in the current rating system should be more sensitive to the link between violent media exposure and youth violence. PMID- 20970079 TI - Reducing drug use, human immunodeficiency virus risk, and recidivism among young men leaving jail: evaluation of the REAL MEN re-entry program. AB - PURPOSE: This study assesses the impact of REAL MEN (Returning Educated African American and Latino Men to Enriched Neighborhoods), an intervention designed to reduce drug use, risky sexual behavior and criminal activity among 16-18-year-old males leaving New York City jails. METHODS: Participants (N = 552) were recruited in city jails and randomly assigned to receive an intensive 30-hour jail/community-based intervention or a single jail-based discharge planning session. All participants were also referred to optional services at a community based organization (CBO). One year after release from jail, 397 (72%) participants completed a follow-up interview. Logistic and ordinary least squares regression was used to evaluate the impact of the intervention on drug use, risky sexual behavior, criminal justice involvement, and school/work involvement post release. RESULTS: Assignment to REAL MEN and, independently, use of CBO services, significantly reduced the odds of substance dependence (odds ratio [OR] = .52, p <= .05; OR = .41, p <= .05, respectively) 1 year after release. Those assigned to the intervention spent 29 fewer days in jail compared with the comparison group (p <= .05). Compared to non-CBO visitors, those who visited the CBO were more likely to have attended school or found work in the year after release (OR = 2.02, p <= .01). CONCLUSIONS: Jail and community services reduced drug dependence 1 year after release and the number of days spent in jail after the index arrest. While these findings suggest that multifaceted interventions can improve outcomes for young men leaving jail, rates of drug use, risky sexual behavior, and recidivism remained high for all participants after release from jail, suggesting the need for additional policy and programmatic interventions. PMID- 20970080 TI - Friendship group influences on body dissatisfaction and dieting among adolescent girls: a prospective study. AB - PURPOSE: Although some studies among adolescent girls found that friends within friendship groups were rather similar on dieting and/or body image constructs, these studies were limited by their cross-sectional designs. The current prospective study is the first to examine friendship group influences on eating disorder risk factors, including body dissatisfaction, weight concerns, dietary restraint, and dieting in adolescent girls. METHODS: Design was a two-wave prospective study with 1-year interval. Of 863 girls (mean age = 13.8, SD = .7), 344 were members of one of the 103 reciprocal friendship groups identified using social network analysis. RESULTS: Reciprocal friends were similar with respect to body image and dieting constructs. However, initial friendship group levels of body dissatisfaction, weight concerns, dietary restraint, and dieting did not predict individual body image and dieting variables 1 year later. CONCLUSIONS: The current findings attest to the significance of reciprocal friendship group correlates of eating disorder risk factors, but suggest that during early-to-mid adolescence, levels of body image concerns and dieting within reciprocal friendship groups do not influence adolescents' own body image concerns and dieting over 1 year of time. PMID- 20970081 TI - Psychological adjustment and sexual development of adolescents with disorders of sex development. AB - PURPOSE: Disorders of sex development (DSD) are a heterogeneous group of congenital conditions characterized by an atypical development of chromosomal, gonadal, or anatomical sex. Particularly at the time of expected puberty, adolescents with DSD may become aware of being different from peers. This study explores the effect of DSD on psychosocial well-being and sexual development. METHODS: We interviewed 60 adolescents aged 13-16 years with a DSD. To measure health-related quality of life, mental health, and body image, we used standardized instruments and additional questions related to sexuality and coping with DSD. Reference and control data were available from the German Health Survey for Children and Adolescents (Kiggs) and from a secondary school survey. RESULTS: The general psychological well-being of adolescents with DSD was not impaired. However, outcomes related to adolescent developmental tasks like sexual activities demonstrated impaired participation, especially girls with DSD reported fewer sexual activities than female controls. Adolescents who needed hormonal treatment to induce puberty reported impaired well-being in nearly all outcomes in contrast to those who entered puberty spontaneously. CONCLUSIONS: Interdisciplinary health care teams should focus on the pressure of conformity and openly discuss it with the adolescent in context of treatment decisions. Furthermore, special counseling concerning sexuality and coping with the condition in daily life is needed. PMID- 20970083 TI - Socioeconomic differences in smoking among Finnish adolescents from 1977 to 2007. AB - PURPOSE: Persistence of socioeconomic differences in smoking among adolescents over time is unexplored. We investigated the changes in smoking among 12-18-year old Finns from 1977 to 2007 using multiple indicators of socioeconomic status (SES) to determine whether differences between socioeconomic groups increase over time, with reduced smoking in higher socioeconomic groups. METHODS: Nationwide biennial surveys were conducted since 1977 (response rate, 59%-88%; N = 96,747) using familial and individual social position (school performance/career) indicators. Associations between socioeconomic indicators and smoking were evaluated using logistic regression analysis. RESULTS: Socioeconomic differences in smoking measured by familial SES or individual social position persisted over time, with higher rates in lower SES groups. Individual social position was more strongly related to smoking than familial SES. Differences between groups assessed by individual social position increased over time: the difference in smoking prevalence between groups with the lowest and highest individual social position among 12-14-year-old girls and boys, respectively, was 22% and 28% in 1977-1983, and 45% and 34% in 2001-2007; and in 16-18-year-old girls, 33% in 1977 1983 and 48% in 2001-2007. Smoking differences in relation to father's education increased over time: the difference in 12-14-year-old girls and boys, respectively, between the lowest and highest SES groups was 6% and 5% in 1977 1983 and 9% and 8.5% in 2001-2007; and in 16-18-year-old girls and boys, respectively, 7% and 10% in 1977-1983 and 13% and 14.5% in 2001-2007. CONCLUSIONS: Differences between socioeconomic groups among Finnish adolescents persisted or increased over 30 years, and predict differences in smoking-related diseases between socioeconomic groups in adulthood. PMID- 20970082 TI - Family support and asthma outcomes in adolescents: barriers to adherence as a mediator. AB - PURPOSE: Asthma morbidity in children is associated with family psychosocial functioning. Although the family plays a pivotal role in maintaining optimal asthma care, the mechanism of how family support influences asthma outcomes is not well understood. The purpose of this study was to examine the role of barriers to adherence in mediating the effect of family support on asthma outcomes in adolescents. METHODS: The sample included 126 adolescents with asthma aged 13-20 years, living in the Northeast United States. The sample consisted of 49% Whites and 51% minorities, including primarily Blacks (38%) followed by Hispanic (11%). Adolescents provided self-reported data. Structural equation modeling was performed to examine the direct and indirect relationships between family support and asthma outcomes. RESULTS: Family support was positively associated with asthma control and quality of life. These significant associations were mediated by barriers to adherence. Particularly, family support was found to reduce barriers concerning adolescents' negative attitudes toward medication and healthcare providers, which in turn improved asthma control and quality of life symptoms, emotional functioning, and activity domains. Adolescents' cognitive difficulty also tended to mediate the relationship between family support and emotional functioning. CONCLUSION: This study highlights the beneficial effects of family support in improving asthma outcomes in adolescents. Family support exerts the positive effect by ameliorating barriers to treatment adherence in adolescents, particularly the barriers associated with negative attitudes and cognitive challenges. The findings underscore the importance of incorporating family assessment and intervention in caring for adolescents with asthma. PMID- 20970084 TI - Does psychological distress increase the risk for motor vehicle crashes in young people? findings from the DRIVE study. AB - PURPOSE: Earlier research demonstrates increased and decreased risk of crash related to psychological distress; however, previous literature has almost entirely used retrospective study designs and has not been able to adequately control for important confounders such as exposure to driving, alcohol and drug use, or having had a previous crash. This study aimed to assess the relationship between psychological distress and risk of motor vehicle crashes. METHODS: The DRIVE study is a prospective cohort study of 20,822 novice drivers aged 17-24 years in Australia. Information on risk factors for motor vehicle crash was collected through online questionnaire and subsequently linked to police-reported crashes. Poisson regression was used to analyze risk of various crash types by low, moderate, high, and very high levels of psychological distress, taking into account other known risk factors for crash. RESULTS: Compared to the referent group with low or no distress, a protective effect against crash was observed for young people who reported a moderate amount of psychological distress in unadjusted (RR = .87; 95% CI = .76-1.00) and multivariable analyses (RR = .85; 95% CI = .74-.97). Severe psychological distress was not significantly associated with an increase or decrease in the risk of crash. Psychological distress was not significantly associated with an increased risk of single vehicle crash. CONCLUSION: Earlier studies may have overestimated risk for motor vehicle crashes associated with psychological distress. This study found little convincing evidence to support a strong risk relationship for higher levels of distress and indeed found a modest protective association for low levels of distress. PMID- 20970085 TI - The association between community physical activity settings and youth physical activity, obesity, and body mass index. AB - BACKGROUND: This study examined the association between the level of physical activity (PA) friendliness of the built environment and adolescent PA and body mass index using a national sample of youth and data collected from the communities where they reside. METHODS: Data on height, weight, and PA were taken from annual nationally representative cross-sectional Monitoring the Future surveys of 8th and 10th graders in schools, from 2001 through 2003. Measures of safety, outdoor and commercial PA settings, and urban sprawl were constructed using data collected from the communities in which the students reside. Multilevel models were run and controlled for youth and community demographic and socioeconomic characteristics. RESULTS: Increased levels of physical disorder were associated with decreased PA and higher weight. A greater number of commercial PA facilities was associated with increased PA. More compact communities were associated with lower weight and less sports participation. CONCLUSIONS: It is important to explore these associations to help guide future development patterns and land use policies to create more active neighborhoods. PMID- 20970086 TI - Medication adherence in adolescents with behaviorally-acquired HIV: evidence for using a multimethod assessment protocol. AB - PURPOSE: The present study investigated medication adherence in an understudied population, adolescents with behaviorally acquired HIV, to improve upon prior methodological limitations using concurrent collection of HIV health status markers (viral load [VL]; percentage CD4 count [CD4%]) and multimethod adherence assessment (pill count, missed doses, off-schedule dosing). METHODS: PARTICIPANTS: A total of 60 youth with behaviorally acquired HIV receiving routine care in a multidisciplinary specialty clinic in the Mid-Southern United States. Adherence was assessed by routine pharmacy pill count and self-reported 3 day recall of doses missed and doses taken off-schedule, collected concurrently with clinically obtained VL and CD4% indicators. Adherence measures were evaluated as predictors of VL and CD4% using logistic regression analyses. RESULTS: Adherence difficulties were detected by all assessment methods, with off schedule dosing appearing the most problematic (29.4% taken off-schedule). Self report of doses missed (p = .038) and off-schedule dosing (p = .021) significantly predicted detectable VL. For each percent increase in nonadherence by off-schedule dosing, there was a 2% increased likelihood of detectable VL. No adherence measure significantly correlated with CD4%; pharmacy pill count did not relate to either health status marker. CONCLUSIONS: This study is the first to document multimethod medication adherence measurement in a defined sample of adolescents with behaviorally acquired HIV, using imposed concurrent collection of CD4% and VL. Adherence difficulties were detected regardless of assessment strategy, with off-schedule dosing representing the greatest nonadherence behavior. Both 3-day recall methods predicted VL. Further investigation of adherence in larger samples of youth with behaviorally acquired HIV is needed to better understand the relationship to CD4% suppression. PMID- 20970087 TI - Impact of the MEMA kwa Vijana adolescent sexual and reproductive health interventions on use of health services by young people in rural Mwanza, Tanzania: results of a cluster randomized trial. AB - PURPOSE: To assess the impact of an adolescent sexual health intervention on the use of health services by young people in Tanzania. METHODS: Twenty communities, including 39 health facilities, were randomly allocated to the intervention or comparison arm. Health workers from the intervention arm were trained in the provision of youth-friendly health services, as part of a package of interventions. Independent process evaluations were conducted in health facilities, and simulated patients visited clinics using sexual and reproductive health problem scenarios. The impact on health facility attendances were assessed in 1998 (baseline) and 1999-2001. Reported sexually transmitted infection (STI) symptoms and use of health services were evaluated in young people in the trial cohort. RESULTS: The mean monthly attendance for STI symptoms per health facility, per month was .5 for young males and 1.0 for young females at baseline. Attendance by young males was greater in the intervention communities in 1999 2000 after adjustment for baseline differences (p = .005), and this difference increased over time (p-trend = .022). The mean difference in attendance was however relatively modest, at 1.1 per month in 2001 after adjustment for baseline (95% CI: .5, 1.7). There was weaker evidence of an intervention effect on attendance by young women (p = .087). Few condoms were distributed, although a greater number were distributed in intervention facilities (p = .008). Generally, intervention health workers tended to be less judgmental and provided more comprehensive information. CONCLUSIONS: Training staff to provide more youth friendly health services can increase the utilization of health services for suspected STIs by young people, especially among young men. PMID- 20970088 TI - Attention, learning, and arousal of experimentally sleep-restricted adolescents in a simulated classroom. AB - PURPOSE: To experimentally test whether chronic sleep restriction, which is common among adolescents, is causally related to poor learning, inattentive behaviors, and diminished arousal in a classroom-like situation. METHODS: Sixteen healthy adolescents underwent a sleep manipulation that included, in counterbalanced order, five consecutive nights of sleep deprivation (61/2 hours in bed) versus five nights of healthy sleep duration (10 hours in bed). At the end of each condition, participants viewed educational films and took related quizzes in a simulated classroom. Eight participants also underwent video and electroencephalography monitoring to assess levels of inattentive behaviors and arousal, respectively. RESULTS: As compared with the healthy sleep condition, sleep-deprived participants had lower quiz scores (p = .05), more inattentive behaviors (p < .05), and lower arousal (p = .08). CONCLUSIONS: These pilot data complement previous correlational reports by showing that chronic sleep restriction during adolescence can cause inattention, diminished learning, and lowered arousal in a simulated classroom. PMID- 20970089 TI - Lack of assertion, peer victimization, and risk for depression in girls: testing a diathesis-stress model. AB - PURPOSE: To apply a diathesis * stress model to testing the association between peer victimization and depression in a sample of preadolescent girls. METHODS: DSM-IV symptoms of depression symptoms were measured at ages 9 and 11, assertiveness and peer victimization were assessed by youth report at age 9. RESULTS: The interaction of low levels of assertiveness and high peer victimization at age 9 was predictive of depression symptoms at age 11, controlling for earlier depression symptoms. CONCLUSIONS: The results extend the published data on peer relations and depression by identifying a group of girls who may be particularly vulnerable to the stress of negative peer interactions. PMID- 20970090 TI - Preventing substance use among early Asian-American adolescent girls: initial evaluation of a web-based, mother-daughter program. AB - PURPOSE: This study examined the efficacy and generalizability of a family oriented, web-based substance use prevention program to young Asian-American adolescent girls. METHODS: Between September and December 2007, a total of 108 Asian-American girls aged 10-14 years and their mothers were recruited through online advertisements and from community service agencies. Mother-daughter dyads were randomly assigned to an intervention arm or to a test-only control arm. After pretest measurement, intervention-arm dyads completed a 9-session web-based substance use prevention program. Guided by family interaction theory, the program aimed to improve girls' psychological states, strengthen substance use prevention skills, increase mother-daughter interactions, enhance maternal monitoring, and prevent girls' substance use. Study outcomes were assessed using generalized estimating equations. RESULTS: At posttest, relative to control-arm girls, intervention-arm girls showed less depressed mood; reported improved self efficacy and refusal skills; had higher levels of mother-daughter closeness, mother-daughter communication, and maternal monitoring; and reported more family rules against substance use. Intervention-arm girls also reported fewer instances of alcohol, marijuana, and illicit prescription drug use, and expressed lower intentions to use substances in the future. CONCLUSIONS: A family-oriented, web based substance use prevention program was efficacious in preventing substance use behavior among early Asian-American adolescent girls. PMID- 20970091 TI - Do serial dilutions really dilute? PMID- 20970092 TI - Extreme homeopathic dilutions retain starting materials: A nanoparticulate perspective. AB - Homeopathy is controversial because medicines in high potencies such as 30c and 200c involve huge dilution factors (1060 and 10400 respectively) which are many orders of magnitude greater than Avogadro's number, so that theoretically there should be no measurable remnants of the starting materials. No hypothesis which predicts the retention of properties of starting materials has been proposed nor has any physical entity been shown to exist in these high potency medicines. Using market samples of metal-derived medicines from reputable manufacturers, we have demonstrated for the first time by Transmission Electron Microscopy (TEM), electron diffraction and chemical analysis by Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES), the presence of physical entities in these extreme dilutions, in the form of nanoparticles of the starting metals and their aggregates. PMID- 20970093 TI - Homeopathic prescribing for chronic conditions in feline and canine veterinary practice. AB - INTRODUCTION: The peer-review literature contains no controlled clinical research of homeopathy in cats and very little in dogs. MAIN OBJECTIVE: To collect clinical outcomes data systematically from individualised homeopathic treatment of cats and dogs that would help to inform controlled research in feline and canine homeopathy. METHODS: Twenty-one homeopathic veterinary surgeons recorded data systematically from consecutive feline and canine patients over a 12-month period. Records included: date; patient and owner identity (anonymised); medical problem treated; whether new or follow-up (FU) appointment; chronic or acute condition; owner-assessed clinical outcome (7-point scale, range -3 to +3) compared with first appointment. RESULTS: Data from 400 cats comprised a total of 372 individual chronic problems, of which 270 had FU assessment. Data from 1504 dogs comprised a total of 1408 individual chronic problems, of which 1070 had FU assessment. In both species, 22% of FUs in chronic cases received conventional medicines concurrently. In cats, 117 different chronic medical conditions in total were treated with homeopathy. Five of those conditions included >=20 cases, in which owner-reported outcomes (in decreasing rank order of frequency) were: dermatitis (69.6% patients with +2 or +3 outcome, 0% patients with -2 or -3 outcome); renal failure (57.1%, 14.3%); overgrooming (57.1%, 7.2%); arthritis (80.0%, 0%); hyperthyroidism (66.7%, 0%). In dogs, of 301 different chronic medical conditions treated in total, those most commonly recorded (>=20 cases) were: dermatitis (66.2% with +2 or +3 outcome, 5.4% with -2 or -3 outcome); arthritis (80.2%, 0.8%); pyoderma (75.8%, 0%); colitis (85.2%, 0%); fear (31.6%, 0%); epilepsy (63.6%, 4.5%); otitis externa (72.7%, 0%); diarrhoea (68.2%, 0%); urinary incontinence (73.7%, 0%); aggression (57.1%, 0%); spondylosis (81.0%, 0%); lymphoma (40.0%, 6.7%). CONCLUSIONS: A programme of controlled research in veterinary homeopathy for these feline and canine conditions is clearly indicated. PMID- 20970094 TI - Homeopathic Symphytum officinale increases removal torque and radiographic bone density around titanium implants in rats. AB - INTRODUCTION: This study evaluated the effect of Symphytum officinale in homeopathic potency (6cH), on the removal torque and radiographic bone density around titanium implants, inserted in rats tibiae. METHODS: Implants were placed in male rat tibiae, and the animals randomized to two groups (Control and S. officinale 6cH treated), which were evaluated at 7, 14, 28 and 56 days post implantation. Radiographic bone density was measured at 6 points around the implant, using digital radiographic images, when implants were inserted and at sacrifice. Removal torque of the implants was also evaluated. RESULTS: Both removal torque and radiographic bone density evaluation showed that S. officinale 6cH treatment enhanced bone formation around the micro-implants, mainly at 14 days. At 56 days, the radiographic bone density was higher in the treated group. CONCLUSIONS: We conclude that S. officinale 6cH enhances, principally at the early stages of osseointegration, bone formation around titanium implants in rats' tibiae, based on radiographic and mechanical analysis. PMID- 20970095 TI - Statins withdrawal, vascular complications, rebound effect and similitude. AB - Hahnemann considered the secondary action of medicines to be a law of nature and reviewed the conditions under which it occurs. It is closely related to the rebound effects observed with many modern drugs. I review the evidence of the rebound effect of statins that support the similitude principle. In view of their indications in primary and secondary prevention of cardiovascular diseases, statins are widely prescribed. Besides reducing cholesterol biosynthesis, they provide vasculoprotective effects (pleiotropic effects), including improvement of endothelial function, increased nitric oxide bioavailability, antioxidant properties, inhibition of inflammatory and thrombogenic responses, stabilisation of atherosclerotic plaques, and others. Recent studies suggest that suspension of statin treatment leads to a rebound imparing of vascular function, and increasing morbidity and mortality in patients with vascular diseases. Similarly to other classes of modern palliative drugs, this rebound effect is the same as a secondary action or vital reaction described by Samuel Hahnemann, and used in homeopathy in a therapeutic sense. PMID- 20970096 TI - Infection models in basic research on homeopathy. AB - INTRODUCTION: The objective of this study was to search for effective agents for the treatment of infections in animals or infected cell lines. METHODS: The Homeopathic Basic Research experiments (HomBRex) database (http://www.carstens stiftung.de/hombrex) on model biological systems in homeopathic research was searched. Eligible experiments were reviewed and analysed. RESULTS: The database contains 48 eligible experiments published from 1832 to 2009. Causative pathogens were bacteria, fungi, viruses, proto- and metazoa. In the experiments, various parameters were observed and a large set of medicines was investigated. In eight of the 48 experiments, at least one of the investigated medicines was selected according to the similia principle. Nosodes and homeopathic complexes were investigated in 8 and 14 experiments respectively. Mice were the most often used host organisms (13 experiments). In 31 experiments at least one homeopathic medicine was found effective for treatment. CONCLUSION: The results of basic research experiments may invigorate new clinical trials that investigate complementary treatments for infectious diseases. However, all experiments reviewed here await replication and no clear-cut conclusion can be drawn regarding the transferability of in vitro results to in vivo outcomes. PMID- 20970097 TI - 200 years Organon of Medicine - A comparative review of its six editions (1810 1842). AB - In 2010 the 200th anniversary of the Organon is celebrated by the homeopathic community. Samuel Hahnemann's Organon of Rational Therapeutics, published in 1810, however, marks neither the beginning of homeopathy nor the endpoint of its development. On the one hand, its contents are based on terms and concepts developed and published by Hahnemann during the preceding two decades. On the other hand, the five revised editions of the Organon that followed in the next three decades contain major changes of theory and conceptions. Hahnemann's basic idea, running through all the stages of the foundation, elaboration, and defence of his doctrine, may be detected by a comparative review of his works from a historical and philosophical perspective. PMID- 20970098 TI - International cooperation in support of homeopathy and complementary medicine in developing countries: the Tuscan experience. AB - Health is a fundamental human right which contributes to reducing poverty, and encourages social development, human safety, and economic growth. International initiatives have fallen far short of their goals. This paper describes collaboration between the region of Tuscany and Cuba, Western Sahara, Senegal and Serbia. These have introduced various forms of Complementary and Alternative Medicine, including homeopathy and Traditional Chinese Medicine into primary healthcare particularly obstetrics, and into veterinary medicine. Complementary and traditional medicine can represent a useful and sustainable resource in various fields of health care. Inclusion in the public health system must go hand in hand with scientific evaluation. PMID- 20970101 TI - Sceptical views on homeopathy: Do we really need "sceptical" homeopaths? PMID- 20970102 TI - Orthographic neighborhood size effect in Chinese character naming: orthographic and phonological activations. AB - The present study examined the effects of orthographic neighborhood (N) size on the cognitive processes underlying Chinese character reading. Previous research has shown increasing N size facilitates word naming and recognition performance in alphabetic languages. Experiment 1 revealed that a large N size was associated with a general inhibition of processes underlying character reading, in contrast to previous findings with alphabetic languages. This inhibitory effect was influenced by regularity and consistency. Experiment 2 sought to assess the effects of higher-frequency neighbors on character naming performance. The results revealed that higher-frequency neighbors with different pronunciation to the target interfered with the phonological retrieval of targets. We propose that this type of interference may have caused the N size effect observed in Experiment 1. The results of Experiment 3 revealed that a large N size facilitated target naming in the absence of higher-frequency neighbors. The current results shed light on the processes underlying character naming, and we propose possible cognitive mechanisms of the N size effect on Chinese character naming. PMID- 20970103 TI - Unimodal and crossmodal working memory representations of visual and kinesthetic movement trajectories. AB - The present study investigated whether visual and kinesthetic stimuli are stored as multisensory or modality-specific representations in unimodal and crossmodal working memory tasks. To this end, angle-shaped movement trajectories were presented to 16 subjects in delayed matching-to-sample tasks either visually or kinesthetically during encoding and recognition. During the retention interval, a secondary visual or kinesthetic interference task was inserted either immediately or with a delay after encoding. The modality of the interference task interacted significantly with the encoding modality. After visual encoding, memory was more impaired by a visual than by a kinesthetic secondary task, while after kinesthetic encoding the pattern was reversed. The time when the secondary task had to be performed interacted with the encoding modality as well. For visual encoding, memory was more impaired, when the secondary task had to be performed at the beginning of the retention interval. In contrast, memory after kinesthetic encoding was more affected, when the secondary task was introduced later in the retention interval. The findings suggest that working memory traces are maintained in a modality-specific format characterized by distinct consolidation processes that take longer after kinesthetic than after visual encoding. PMID- 20970104 TI - Mutations in NEXN, a Z-disc gene, are associated with hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disorder, is characterized by increased ventricular wall thickness that cannot be explained by underlying conditions, cadiomyocyte hypertrophy and disarray, and increased myocardial fibrosis. In as many as 50% of HCM cases, the genetic cause remains unknown, suggesting that more genes may be involved. Nexilin, encoded by NEXN, is a cardiac Z-disc protein recently identified as a crucial protein that functions to protect cardiac Z-discs from forces generated within the sarcomere. We screened NEXN in 121 unrelated HCM patients who did not carry any mutation in eight genes commonly mutated in myofilament disease. Two missense mutations, c.391C>G (p.Q131E) and c.835C>T (p.R279C), were identified in exons 5 and 8 of NEXN, respectively, in two probands. Each of the two mutations segregated with the HCM phenotype in the family and was absent in 384 control chromosomes. In silico analysis revealed that both of the mutations affect highly conserved amino acid residues, which are predicted to be functionally deleterious. Cellular transfection studies showed that the two mutations resulted in local accumulations of nexilin and that the expressed fragment of actin-binding domain containing p.Q131E completely lost the ability to bind F-actin in C2C12 cells. Coimmunoprecipitation assay indicated that the p.Q131E mutation decreased the binding of full-length NEXN to alpha-actin and abolished the interaction between the fragment of actin-binding domain and alpha-actin. Therefore, the mutations in NEXN that we describe here may further expand the knowledge of Z-disc genes in the pathogenesis of HCM. PMID- 20970106 TI - Correlation of microperimetry with fundus autofluorescence and spectral-domain optical coherence tomography in repaired macular holes. AB - PURPOSE: To investigate the correlation of microperimetry with fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT), and visual acuity (VA) in order to better characterize visual outcomes after successful macular hole (MH) surgery. DESIGN: Cross-sectional case series. METHODS: Postoperative VA, microperimetry, FAF, and SD-OCT images from 23 eyes of 23 patients who underwent successful MH surgery were obtained. FAF images were examined using the Heidelberg retina angiograph 2, and foveal structure and macular sensitivity were evaluated with SD-OCT and microperimetry. The mean retinal sensitivities within the central 9 degrees (microperimetry, mean), the retinal sensitivity of the foveal center (microperimetry, center), and the difference between the values obtained for the foveal center or mean of study and fellow eyes (microperimetry, centerdiff and microperimetry, meandiff, respectively) were measured with microperimetry. RESULTS: Microperimetry (mean) was well correlated with microperimetry (center) in both study and fellow eyes. Poor postoperative VA was correlated with large microperimetry (meandiff). Following successful MH surgery, FAF of all eyes decreased markedly. There was a positive correlation between microperimetry (centerdiff) and degree of FAF of study eyes. However, a decrease in FAF after MH surgery was not correlated well with either degree of defect in the junction between photoreceptor inner and outer segment (IS/OS) or central retinal thickness on SD-OCT. CONCLUSIONS: The amount of remaining FAF is related to macular sensitivity as measured by microperimetry after successful MH surgery. Function of photoreceptors and retinal pigment epithelium as well as integrity can be estimated by measuring the decrease in FAF after successful MH surgery. Moreover, functional correlation with microperimetry provides both morphologic and functional information on repaired MHs. PMID- 20970105 TI - Defective mitochondrial mRNA maturation is associated with spastic ataxia. AB - In human mitochondria, polyadenylation of mRNA, undertaken by the nuclear-encoded mitochondrial poly(A) RNA polymerase, is essential for maintaining mitochondrial gene expression. Our molecular investigation of an autosomal-recessive spastic ataxia with optic atrophy, present among the Old Order Amish, identified a mutation of MTPAP associated with the disease phenotype. When subjected to poly(A) tail-length assays, mitochondrial mRNAs from affected individuals were shown to have severely truncated poly(A) tails. Although defective mitochondrial DNA maintenance underlies a well-described group of clinical disorders, our findings reveal a defect of mitochondrial mRNA maturation associated with human disease and imply that this disease mechanism should be considered in other complex neurodegenerative disorders. PMID- 20970107 TI - Prevalence of glaucoma in North China: the Beijing Eye Study. AB - PURPOSE: To assess the prevalence of glaucoma in adult Chinese. DESIGN: Population-based study. METHODS: The Beijing Eye Study in 2001 included 4439 subjects with an age of 40+ years. Glaucoma was determined using the ISGEO (International Society of Geographical and Epidemiological Ophthalmology) classification scheme. RESULTS: Glaucoma was detected in 158 subjects (3.7%, 95% confidence interval [CI] 3.1%-4.2%), in which open-angle glaucoma (OAG), primary angle-closure glaucoma (PACG), and secondary glaucoma (SG) accounted for 2.6% (95% CI 2.1%-3.0%), 1.0% (95% CI 0.7%-1.3%), and 0.07% (95% CI 0%-0.1%), respectively. The overall glaucoma prevalence for the age groups of 40 to 49 years, 50 to 59 years, 60 to 69 years, and 70+ years was 2.2%, 2.5%, 4.4%, and 9.5%, respectively. Glaucoma prevalence increased significantly with age (P = .001), myopic refractive error (P < .001), and intraocular pressure (P < .001). The age-standardized prevalence of OAG, PACG, and SG was 2.5%, 1.0%, and 0.1%, respectively. Prevalence of glaucoma-related bilateral blindness or unilateral blindness was significantly (P = .02 and P = .03) higher in PACG than in OAG. Frequency of glaucoma-associated blindness and low vision was significantly higher in the rural area than in the urban region (6/62 vs 2/96, P = .04). CONCLUSIONS: In the adult population of Greater Beijing, glaucoma prevalence was 3.6% and increased with age, myopic refractive error, and intraocular pressure. Glaucoma prevalence of 3.6% was comparable with figures from Caucasian populations. The ratio of OAG to PACG of 2.6:1 agrees with recent other studies from East Asia. Glaucoma-related blindness and low vision occurred significantly more often in PACG than in OAG. PMID- 20970108 TI - Agreement among spectral-domain optical coherence tomography instruments for assessing retinal nerve fiber layer thickness. AB - PURPOSE: To assess the agreement of parapapillary retinal nerve fiber layer (RNFL) thickness measurements among 3 spectral-domain optical coherence tomography (SD-OCT) instruments. DESIGN: Observational, cross-sectional study. METHODS: Three hundred thirty eyes (88 with glaucoma, 206 glaucoma suspects, 36 healthy) from 208 individuals enrolled in the Diagnostic Innovations in Glaucoma Study (DIGS) were imaged using RTVue, Spectralis and Cirrus in a single visit. Agreement among RNFL thickness measurements was assessed using Bland-Altman plots. The influence of age, axial length, disc size, race, spherical equivalent, and disease severity on the pairwise agreements between different instruments was assessed by regression analysis. RESULTS: Although RNFL thickness measurements between different instruments were highly correlated, Bland-Altman analyses indicated the presence of fixed and proportional biases for most of the pairwise agreements. In general, RTVue measurements tended to be thicker than Spectralis and Cirrus measurements. The agreement in average RNFL thickness measurements between RTVue and Spectralis was affected by age (P = .001) and spherical equivalent (P < .001), whereas the agreement between Spectralis and Cirrus was affected by axial length (P = .004) and spherical equivalent (P < .001). Disease severity influenced the agreement between Spectralis and both RTVue and Cirrus (P = .001). Disc area and race did not influence the agreement among the devices. CONCLUSIONS: RNFL thickness measurements obtained by different SD-OCT instruments were not entirely compatible and therefore they should not be used interchangeably. This may be attributable in part to differences in RNFL detection algorithms. Comparisons with histologic measurements could determine which technique is most accurate. PMID- 20970109 TI - Hypotony after 25-gauge vitrectomy. AB - PURPOSE: To describe the incidence of hypotony after 25-gauge vitrectomy and to identify preoperative and intraoperative factors that influence the occurrence of hypotony. DESIGN: Retrospective, nonrandomized, interventional case series. METHODS: We reviewed 122 consecutive cases of 25-gauge vitrectomy for all surgical indications. The primary outcome measure was intraocular pressure (IOP) at postoperative day 1, measured with Goldmann tonometry. Secondary outcome measures were clinical signs of hypotony and other complications. RESULTS: Hypotony, defined as an IOP of 5 mm Hg or less, was found in 13.1% of cases on postoperative day 1. Clinical signs of hypotony were encountered in 7 eyes (5.7%). The risk of hypotony was significantly lower in cases with air or gas tamponade (3.3%) than in cases without tamponade (22.4%). Hypotony was encountered more often in reoperations (29.9%) than in primary operations (9.2%; statistically significant difference). In cases in which intravitreal triamcinolone was used, the risk of hypotony was significantly higher (35.3%) than in cases without triamcinolone (10.3%). Phakic eyes had significantly less chance of hypotony (6.7%) than pseudophakic eyes (15.6%) and eyes undergoing combined phacoemulsification and vitrectomy (25.0%). At postoperative day 7, all cases of hypotony recovered spontaneously. None of our cases developed endophthalmitis. CONCLUSION: Our results show that a transient hypotony occurs commonly after 25-gauge vitrectomy. Hypotony was significantly influenced by tamponade, reoperation, intraoperative lens status, and use of intravitreal triamcinolone. Although all cases of hypotony recovered spontaneously without permanent damage, the high frequency of hypotony does impose potential risks. Increased vigilance with focus on perioperative antisepsis and low tolerance of sclerotomy leakage are important for the prevention of endophthalmitis. Strategies aimed at lowering the risk of hypotony are needed to improve the safety of this promising technique. PMID- 20970110 TI - Early outcomes of descemet stripping automated endothelial keratoplasty in pseudophakic eyes with anterior chamber intraocular lenses. AB - PURPOSE: To evaluate complications and clinical outcomes of Descemet stripping automated endothelial keratoplasty in eyes with preexisting anterior chamber intraocular lenses. DESIGN: Retrospective review. METHODS: Thirty-one patients who underwent Descemet stripping automated endothelial keratoplasty and who had a preexisting anterior chamber intraocular lens were identified from May 2006 through March 2009. Patient follow-up ranged from a minimum of 1 month up to 30 months. Preoperative and postoperative best spectacle-corrected visual acuity, manifest refraction, comorbid conditions, and complications were recorded. Endothelial cell loss, graft dislocation, graft failure rates were calculated. RESULTS: The mean age at surgery was 78 +/- 9 years (range, 53 to 91 years). All eyes had pseudophakic bullous keratopathy, except 1 patient who had a failed penetrating keratoplasty graft. Excluding those patients with severely limited visual potential because of noncorneal pathologic features, the mean best spectacle-corrected visual acuity improved significantly from 20/200 to 20/400 before surgery to 20/63 at 3 months (P < .0001), 20/60 at 6 months (P = .0006), 20/50 at 12 to 15 months (n = 10; P = .004), and 20/40 between 23 and 30 months (n = 8; median, 25 months; P = .007). The preoperative mean spherical equivalent was -0.3 +/- 1.8 diopters compared with -0.15 +/- 1.5 diopters after surgery (P = .78). The graft dislocation rate was 13%, and the graft failure rate was 16%. For those patients with endothelial cell density data available, the average endothelial cell loss was 48% at a mean of 14 months. CONCLUSIONS: Although Descemet stripping automated endothelial keratoplasty surgery in patients with an anterior chamber intraocular lens remains a controversial topic, the visual and anatomic outcomes from this limited study support this approach as a surgical option in selected cases. PMID- 20970111 TI - Efficacy of marlex mesh on posterior fixation suture: an experimental study in a rabbit model. AB - PURPOSE: To develop a novel method of posterior fixation suture augmented by the application of Marlex mesh and to evaluate the surgical results in a rabbit model. DESIGN: Animal study. METHODS: SETTING: Prospective, masked-observer, controlled experimental study. STUDY POPULATION: Sixty superior rectus muscles of 30 rabbits. INTERVENTION: Each superior rectus muscle was randomly subjected to posterior fixation suture at a distance of 6 mm from the muscle insertion. The rabbits were divided into 3 groups: conventional posterior fixation suture (Conventional group), and modified posterior fixation suture using a silicone sponge (Silicone group) or using Marlex mesh (Marlex group). Nonabsorbable sutures were used for muscle-sclera (Conventional group) or muscle-implant fixation (Silicone and Marlex group) and absorbable sutures were used for implant sclera fixation (Silicone and Marlex group). MAIN OUTCOME MEASURES: The efficacy of posterior fixation suture was determined by forced duction testing toward the operated-on muscle immediately after the operation and at 8 weeks postoperatively. Eyes were enucleated at 8 weeks after surgery to measure the stability of the bond using a push pull gauge, and finally the histologic findings were evaluated. RESULTS: Immediately after posterior fixation suture and at 8 weeks postoperatively, the restrictive motion during duction toward the operated-on muscle was greater in the Marlex group compared to the other groups (P < .001). The resistance to separation of the myoscleral union was greatest in the Marlex group (P < .001). CONCLUSIONS: Posterior fixation suture can be effectively reinforced and stabilized using Marlex mesh. PMID- 20970112 TI - Reduction of anterior chamber contamination rate after cataract surgery by intraoperative surface irrigation with 0.25% povidone-iodine. AB - PURPOSE: To prove the hypothesis that during cataract surgery, repeated irrigation of the operative field with povidone-iodine of 0.25% reduces the anterior chamber bacterial contamination rate at completion of operation. DESIGN: Prospective, interventional case series. METHODS: In 404 consecutive eyes, the operative field was irrigated with infusion fluid in 202 eyes (group A) and with 0.25% povidone-iodine in 202 eyes (group B). Bacteriologic culture was performed using the following samples: ocular surface fluid after lid speculum placement and anterior chamber fluid at the completion of surgery. Anterior chamber fluid samples were collected at the beginning and completion of surgery for iodide ion concentration measurement. Corneal endothelial cell density was measured using a specular microscope before surgery and on day 7 after surgery. RESULTS: Bacterial detection rate in ocular surface fluid was not significantly different between group A (5.5%) and group B (6.0%), but the rate in anterior chamber fluid was significantly (P = .0017) reduced in group B (0%) compared with group A (5.0%). Iodide ion concentrations at the start and end of surgery were 7.5 +/- 0.7 MUg/mL and 3.5 +/- 0.7 MUg/mL, respectively, in group B and less than 0.1 MUg/mL both at the start and end of surgery in group A. Corneal endothelial cell densities were not significantly difference between groups A and B before surgery (2614 +/- 233/mm2 vs 2534 +/- 173/mm2; P = .2254) and 7 days after surgery (2463 +/- 269/mm2 vs 2338 +/- 204/mm2; P = .4044). CONCLUSIONS: In cataract surgery, repeated irrigation of the operative field with povidone-iodine at a concentration of 0.25% achieved an extremely low bacterial contamination rate in the anterior chamber at the completion of surgery. PMID- 20970113 TI - Enhanced depth imaging optical coherence tomography of the choroid in idiopathic macular hole: A cross-sectional prospective study. AB - PURPOSE: To determine the choroidal thickness in the macular area in patients with idiopathic macular hole in one eye and an unaffected fellow eye and in healthy controls. DESIGN: Cross-sectional, prospective study. METHODS: Twenty-two patients with a full-thickness unilateral idiopathic macular hole and 22 age- and sex-matched controls were recruited. Enhanced depth imaging optical coherence tomography images were obtained by using spectral-domain optical coherence tomography. The choroidal thickness was measured in the subfoveal area and 1000 MUm and 2000 MUm away from the fovea in the nasal and temporal regions. The diameter of the macular hole and the axial length were determined. RESULTS: Choroidal thickness was significantly different across the 3 groups at all locations (P < .001, analysis of variance). The choroid was significantly thinner in eyes with idiopathic macular hole and in unaffected fellow eyes than in the control group (P < .01, Tukey-Kramer test). The mean subfoveal choroidal thickness was 183.2 MUm in the idiopathic macular hole group, 196.6 MUm in the fellow-eye group, and 245.0 MUm in the control group. A negative correlation between subfoveal choroidal thickness and axial length was found in all groups (macular hole, r = -0.53, P = .01; fellow eyes, r = -0.56, P < .01; controls, r = -0.52, P = .01); in control eyes, a negative correlation was found between choroidal thickness and age (r = -0.48, P = .02). CONCLUSIONS: Choroidal thickness was reduced in eyes with idiopathic macular hole and also in fellow unaffected eyes. This may suggest a contributing role of the choroid in the pathogenesis of idiopathic macular hole. PMID- 20970114 TI - Isolated FSH deficiency revealing a granulosa cell tumor. AB - We report a case of a 41-year-old woman with a recent secondary amenorrhea and infertility. The initial assessment ruled out premature ovarian failure, polycystic ovary syndrome and led to suspect a hypothalamo-pituitary cause. However, the unusual hormone pattern with a very low level of FSH, normal levels of LH and estradiol, associated with a positive progesterone test suggested the presence of a FSH inhibiting factor: the unexpectedly high levels of inhibin B and AMH were suggestive of a granulosa cell tumor as showed by the radiologic findings. This prompted a surgical exploration, which confirmed the putative diagnosis. This case report illustrates the inhibin B and AMH values and the modern-day pelvic imaging data encountered in menstrual irregularities caused by a granulosa cell tumor. PMID- 20970115 TI - Mechanical stress enhances production of cytokines in human periodontal ligament cells induced by Porphyromonas gingivalis. AB - OBJECTIVE: We have previously reported that human periodontal ligament (hPDL) cells produced many kinds of cytokines as a result of bacterial stimulation, including stimulation with Porphyromonas gingivalis (P. gingivalis). However, the effects of mechanical stress on cytokine production in hPDL cells stimulated by periodontopathogenic bacteria are not clearly understood. In this study, we investigated the effects of mechanical stress on the production of inflammatory cytokines in hPDL cells induced by stimulation with P. gingivalis. METHODS: The hPDL cells were exposed to various levels of mechanical stress (1, 6, 10 and 50MPa) and costimulated with mechanical stress and P. gingivalis for 24h. Cytokine mRNA expressions were determined by RT-PCR. Cytokines in the culture supernatant were assessed by ELISA, and morphologic changes in hPDL cells were observed. RESULTS: The expressions of interleukin (IL)-6, IL-8 and tumor necrosis factor-alpha mRNA were observed in hPDL cells after exposure to mechanical stress. Moreover, the production of IL-6 and IL-8 increased significantly after exposure to mechanical stress ranging from 1 to 10MPa. The amount of IL-8 in the culture supernatants of hPDL cells costimulated with P. gingivalis and mechanical stress was significantly higher than the expected additive amount. The morphology of hPDL cells did not change after exposure to 6MPa, but these cells were partly detached from the Petri dish after exposure to 50MPa. CONCLUSIONS: These results suggest that local inflammation of the periodontal ligament may be induced mainly by periodontal bacteria, and mechanical stress may promote local inflammation. PMID- 20970116 TI - Exposure of P. gingivalis to noradrenaline reduces bacterial growth and elevates ArgX protease activity. AB - OBJECTIVE: Periodontitis, an infectious disease caused by periodontopathic bacteria, including Porphyromonas gingivalis, is reported to be accelerated by stress, under which noradrenaline levels are increased in the bloodstream. The purpose of this study was to evaluate the effects of noradrenaline on P. gingivalis. DESIGN: P. gingivalis was incubated in the presence of 25MUM, 50MUM, or 100MUM adrenaline or noradrenaline at 37 degrees C for 12, 24 or 36h and growth was evaluated by OD(660). Auto-inducer-2 (AI-2) was measured by luminescence of Vibrio harveyi BB 170. Expression of P. gingivalis genes was evaluated using a microarray and RT-PCR. Rgp activity of arg-gingipainA and B (Rgp) was measured with a synthetic substrate. RESULTS: Growth of P. gingivalis FDC381 was inhibited by noradrenaline at 24 and 36h. Growth inhibition by noradrenaline increased dose-dependently. Inhibition of growth partially recovered with addition of propranolol. AI-2 production from P. gingivalis showed a marked decrease with addition of noradrenaline compared with peak production levels in the control group. Microarray analysis revealed an increase in expression in 18 genes and a decrease in expression in 2 genes. Amongst these genes, expression of the protease arg-gingipainB (RgpB) gene, a major virulence factor of P. gingivalis, was further analysed. Expression of rgpB showed a significant increase with addition of noradrenaline, which was partially reduced by addition of propranolol. Cell-associated Rgp activity also increased with addition of noradrenaline. CONCLUSIONS: These results suggest that stressors influence the expression of the virulence factors of P. gingivalis via noradrenaline. PMID- 20970117 TI - The effectiveness of dialectical behaviour therapy in routine public mental health settings: An Australian controlled trial. AB - Randomised controlled studies in research environments have demonstrated dialectical behaviour therapy (DBT) to be more efficacious than treatment as usual in reducing suicidal behaviour in patients with borderline personality disorder (BPD). Limited evidence exists for the effectiveness of DBT in the treatment of BPD within routine clinical settings. This study examines the clinical and cost effectiveness of providing DBT over treatment as usual in a routine Australian public mental health service. Forty-three adult patients with BPD were provided with outpatient DBT for six months with patient outcomes compared to those obtained from patients in a wait list group receiving treatment as usual (TAU) from the same service. After six months of treatment the DBT group showed significantly greater reductions in suicidal/non-suicidal self-injury, emergency department visits, psychiatric admissions and bed days. Self-report measures were administered to a reduced sample of patients. With this group, DBT patients demonstrated significantly improved depression, anxiety and general symptom severity scores compared to TAU at six months. Average treatment costs were significantly lower for those patients in DBT than those receiving TAU. Therapists who received intensive DBT training were shown to produce significantly greater improvements in patients' suicidal and non-suicidal self injury than therapists who received only 4 day basic training. Further clinical improvements were achieved in patients offered an additional six months of DBT. This study demonstrates that providing DBT to patients within routine public mental health settings can be both clinically effective and cost effective. PMID- 20970118 TI - Glutamate as a marker of cognitive function in schizophrenia: a proton spectroscopic imaging study at 4 Tesla. AB - BACKGROUND: Cognitive deficits in schizophrenia may be related to glutamatergic dysfunction, but in vivo measurement of glutamate metabolism has been challenging. We examined the relationship between glutamate metabolism and cognitive function in schizophrenia. METHODS: Thirty subjects with DSM-IV schizophrenia and 28 healthy volunteers were studied using 4 Tesla proton echo planar spectroscopic imaging. Glutamate plus glutamine (Glx), N-acetylaspartate compounds, and Inositol concentrations in gray and white matter and broad neuropsychological function were assessed in all subjects. RESULTS: Glutamate plus glutamine was positively correlated with overall cognitive performance in the schizophrenia group (p = .0006), accounting for about 36% of the variance. No correlation was found in control subjects. Group-averaged Glx levels were similar in schizophrenia and control subjects. N-acetylaspartate compounds were reduced in cortical gray matter in the younger schizophrenia subjects (age < 30; p = .04) compared with age-matched control subjects. Inositol was increased in cortical gray (p = .002) and white matter (p = .02) in the older schizophrenia subjects (age > 30) compared with age-matched control subjects. CONCLUSIONS: Although not reduced in schizophrenia as a group, lower Glx levels correlates with impaired cognition in the illness. This suggests heterogeneity in mechanisms that regulate glutamate function in schizophrenia. Patients with reduced glutamatergic reserves may be rendered into a more severe hypoglutamatergic state with cognitive consequences. Reduced cortical gray matter N-acetylaspartate compound concentration early in the illness with normalization in older subjects is consistent with a process of early dendritic retraction with subsequent increased neuronal packing. Later in the illness, Inositol elevation suggests glial involvement. PMID- 20970119 TI - Convergent animal and human evidence suggests a role of PPM1A gene in response to antidepressants. AB - BACKGROUND: Antidepressant drugs are used as first-line treatment in depression, but response has been shown to be highly heterogeneous, with drugs often failing to have the desired therapeutic effect. We report on an integrative analysis from the Genome-Based Therapeutic Drugs for Depression (GENDEP) study using gene expression from mice to inform prioritization in a human pharmacogenetic study. METHODS: The same two antidepressants were used in mice and humans: escitalopram (a serotonin reuptake inhibitor) and nortriptyline (a norepinephrine reuptake inhibitor). The animal study used four inbred strains of mice (129S1/SvlmJ, C57LB/6J, DBA/2J, and FVB/NJ). Hippocampus mRNA levels were measured in 144 animals using the Affymetrix MOE 430 v2 chip. RESULTS: Based on gene-expression analysis of strain-by-drug interactions, 17 genes differentially expressed with nortriptyline or escitalopram versus saline were prioritized in the human pharmacogenetic analysis. Single nucleotide polymorphisms tagging common sequence variation in human orthologs of these genes were tested for association with response to antidepressants in 706 participants of the GENDEP human pharmacogenetic study, treated with escitalopram or nortriptyline for 12 weeks, with available high-quality Illumina 610 quad array genotyping. Several polymorphisms in the protein phosphatase 1A gene (PPM1A) remained significantly associated with response to nortriptyline in humans after correction for multiple comparisons within the gene. PPM1A encodes a phosphatase involved in mitogen activated protein kinase signaling and cell stress response. CONCLUSIONS: Convergent evidence from mice and humans suggests a role of the PPM1A in response to noradrenergic but not serotonergic antidepressants. PMID- 20970120 TI - Chitobiose production by using a novel thermostable chitinase from Bacillus licheniformis strain JS isolated from a mushroom bed. AB - The thermophilic Bacillus licheniformis strain JS was isolated from a bed of mushrooms, Pleurotus sajor-caju. The organism could produce a novel, single component, thermostable chitinase that was purified by ion-exchange chromatography using DEAE-cellulose in 7.64% yield and in an 8.1-fold enhancement in purity. Its molecular weight is 22kDa. The enzyme is a chitobiosidase, since the chitin hydrolysate is N(I),N(II)-diacetylchitobiose. The optimum temperature for enzyme activity is 55 degrees C, and the optimum pH is 8.0. It was completely inhibited by Hg(2+) ions whereas Co(2+) ions served as an activator. The thermostability of this enzyme is important in the bioconversion of chitinous waste and for the production of chitooligosaccharides. PMID- 20970121 TI - What is wrong in Katz's method? Comments on: "A note on fractal dimensions of biomedical waveforms". PMID- 20970122 TI - Design and evaluation of an ontology based information extraction system for radiological reports. AB - This paper describes an information extraction system that extracts and converts the available information in free text Turkish radiology reports into a structured information model using manually created extraction rules and domain ontology. The ontology provides flexibility in the design of extraction rules, and determines the information model for the extracted semantic information. Although our information extraction system mainly concentrates on abdominal radiology reports, the system can be used in another field of medicine by adapting its ontology and extraction rule set. We achieved very high precision and recall results during the evaluation of the developed system with unseen radiology reports. PMID- 20970123 TI - Inhibition of CD44 N- and O-linked glycosylation decreases endometrial cell lines attachment to peritoneal mesothelial cells. AB - The attachment of endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs) to peritoneal mesothelial cells (PMCs) with and without inhibition of N- and O-linked glycosylation, the viability of EECs and ESCs, and the expression of CD44 surface density were evaluated. Inhibition of CD44 N- and O linked glycosylation by using tunicamycin and/or B-GalNAc statistically significantly inhibited endometrial cell attachment to peritoneal mesothelial cells, suggesting a role in establishment of early endometriotic lesions. PMID- 20970124 TI - HIV-positive patients undertaking ART have longer infertility histories than age matched control subjects. AB - OBJECTIVE: To review 5 years of assisted reproductive treatments (ART) provided to couples affected by human immunodeficiency virus (HIV). DESIGN: Age-matched cohort study. SETTING: University-based tertiary center. PATIENT(S): Couples in whom the male (n = 87), female (n = 57), or both (n = 17) partners were HIV infected. The first ART cycle was compared with three sets of age-matched control subjects (3-to-1) which included 261, 171, and 51 couples, respectively. INTERVENTION(S): ART in HIV-infected couples and age-matched controls. MAIN OUTCOME MEASURE(S): Infertility duration and ART outcome. RESULT(S): When initiating ART, all three HIV-infected groups had longer infertility histories, computed from when conception was attempted or infertility diagnosed, compared with noninfected age-matched control subjects. Outcome, however, was not different when only the male or female partner was infected, though with a trend toward higher cancellation and lower pregnancy rates. When both partners were HIV infected, cancellation were higher and pregnancy rates lower (12% versus 41.2%), than in age-matched control subjects. CONCLUSION(S): Our data showed longer infertility histories in all HIV-infected couples when undertaking their first ART. Outcome, however, was not altered when only one partner--male or female--was HIV infected. Efforts should therefore aim at assuring that HIV-infected couples access ART as promptly as their noninfected counterparts. PMID- 20970125 TI - Expression and regulation of DNA methyltransferases in human endometrium. AB - The messenger RNA of the DNA methyltransferases DNMT3a and DNMT3b are expressed temporally in the endometrium across the menstrual cycle, as is the steroid hormone regulation of DNMT1, DNMT3a, and DNMT3b. This suggests that DNA methylation in endometrium is changeable during the menstrual cycle and potentially alters gene expression. PMID- 20970126 TI - Age-related distribution of basal serum AMH level in women of reproductive age and a presumably healthy cohort. AB - In this study, day 1 to 4 serum anti-Mullerian hormone (AMH) level was analyzed in 2,741 patients attending our department for reproductive medicine or reproductive surgery, including a subgroup of 1,105 women who attended an assisted reproductive technology program because of a male factor as a presumably healthy subgroup. Day 1 to 4 serum AMH levels showed an age-dependent distribution and there is a wide range of AMH in each year of age analyzed, showing that even young women are at a risk of reduced ovarian reserve. PMID- 20970127 TI - Short-term results of magnetic resonance imaging-guided focused ultrasound surgery for patients with adenomyosis: symptomatic relief and pain reduction. AB - The objective of this study was to evaluate the degree of symptomatic relief obtained after treatment with magnetic resonance-guided focused ultrasound surgery in patients with adenomyosis. Quality of life and pain assessment questionnaires from 35 women, collected on the day of treatment and up to 6 months after treatment, indicated that the treatment was safe and there was a significant reduction in symptoms. PMID- 20970128 TI - Does tranvaginal ultrasound guidance have a role in embryo transfers? PMID- 20970129 TI - In vitro fertilization-intracytoplasmic sperm injection outcomes in single- versus double-lumen oocyte retrieval needles in normally responding patients: a randomized trial. AB - We compared the retrieval efficiency of single- (direct follicular aspiration) and double-lumen-needle (attained with follicular flushing) procedures in normal responder IVF-intracytoplasmic sperm injection cycles. This prospective randomized study did not demonstrate a beneficial effect of double-lumen needle retrieval compared with single-needle retrieval in normal-responder IVF intracytoplasmic sperm injection cycles in terms of retrieved oocytes, clinical pregnancy rates, and live birth rates. PMID- 20970130 TI - Suggestions and comments for optimizing embryo transfer. PMID- 20970131 TI - Other alternatives for difficult embryo transfer. PMID- 20970133 TI - In vitro effects of peroxisome proliferator-activated receptor-gamma ligands on gene expression in lipopolysaccharide-induced endometrial and endometriotic stromal cells. AB - This in vitro study demonstrates the comparative anti-inflammatory effects of rosiglitazone and 15d-PGJ(2) in endometriosis and provides evidence for exploitation of peroxisome proliferator-activated receptor-gamma as a therapeutic target. PMID- 20970134 TI - Increased immunoreactivity to SLIT/ROBO1 and its correlation with severity of dysmenorrhea in adenomyosis. AB - Compared with normal endometrium, SLIT expression was statistically significantly higher in ectopic endometrium from women with adenomyosis, while roundabout 1 (ROBO1) immunoreactivity and microvessel density (MVD) level were statistically significantly higher in both eutopic and ectopic endometrium than normal endometrium. Both SLIT immunoreactivity in ectopic endometrium and MVD in eutopic endometrium were positively correlated with the severity of dysmenorrhea and found to be significant predicators for dysmenorrhea severity in women with adenomyosis. PMID- 20970135 TI - Warty (condylomatous) carcinoma of the cervix with extension to the endometrial cavity. PMID- 20970136 TI - Finally: the proof of concept--from animal studies, imaging and the clinical evidence of plaque rupture. PMID- 20970137 TI - Framingham risk score is associated with femoral artery intima-media thickness in asymptomatic young adults (the Bogalusa heart study). AB - OBJECTIVE: Femoral artery intima-media thickness (IMT), like carotid IMT, is a surrogate indicator of atherosclerotic coronary and peripheral vascular diseases. The Framingham risk score (FRS) is widely being used in the early prediction of coronary artery disease (CAD). However, the association between FRS and femoral artery IMT has not been studied in asymptomatic younger black and white adult population. Our objective was to examine the association between FRS and femoral artery IMT in asymptomatic younger adults. METHODS: Subjects (n=1080; 71% white, 43% male) aged 24-43 years enrolled in the Bogalusa heart study. Femoral IMT was measured by B-mode ultrasonography. Age, gender, systolic blood pressure, diastolic blood pressure, low density lipoprotein cholesterol, high density lipoprotein cholesterol, cigarette smoking and type2 diabetes were used to calculate individual FRS. RESULTS: FRS was lower in females (p=0.001) than males. Age-adjusted femoral IMT showed gender differences (males>females, p=0.001) among whites only; and no race difference in both genders. A significant positive linear relationship between tertiles of FRS and IMT of femoral artery was noted in whites and blacks alike (p for trend<0.0001). In a multivariate analysis that included FRS, race, body mass index (BMI), log insulin, log triglycerides, exercise and alcohol intake; FRS, insulin and BMI were significantly and independently associated in that order with femoral IMT. CONCLUSIONS: The findings support the use of FRS in both white and black younger adults and underscore the importance of prevention and control of FRS variables in youth. PMID- 20970138 TI - SorLA modulates atheroprotective properties of CLA by regulating monocyte migration. AB - OBJECTIVE: We have previously shown that CLA induces regression of pre established atherosclerotic lesions in apoE(-/-) mice. CLA is a known ligand of peroxisome proliferator activated receptors (PPARs) and it is postulated that CLA mediates its atheroprotective effects through activation of PPARs. Earlier work in our group identified the monocyte/macrophage cell as the primary cellular target of CLA. In this study we identified novel genes regulated by CLA during the regression of atherosclerosis and characterised a role for one of these, SorLA. SorLA is a member of the vacuolar protein sorting 10 protein (Vps10p) domain receptor family, which has structural homology with the LDLR family. METHODS AND RESULTS: Expression of SorLA was identified with its Vps10p family member Sort1 by transcriptomic analysis of murine aorta following CLA-induced regression of atherosclerosis. Decreased expression of both receptors was confirmed by real-time PCR in the aorta of CLA-supplemented mice. SorLA protein expression was predominantly localised to monocyte/macrophage cells in the vasculature by immunohistochemistry. CLA and the PPAR-gamma agonists, troglitazone, and 15-deoxy-prostaglandin (PG) J(2), decreased protein and RNA expression of SorLA in THP-1 monocytes; while pre-treatment with a PPAR-gamma antagonist established a PPAR-gamma dependent role for CLA regulation of SorLA. CLA inhibits monocyte migration. Consistent with a role for SorLA in mediating this response, overexpression of SorLA increased migration of THP-1 monocytes to monocyte chemoattractant protein-1 with a coincident increase in UPAR expression. CONCLUSION: CLA may mediate its atheroprotective effects in part through reduced expression of SorLA and a resulting inhibition of monocyte migration in vitro. PMID- 20970139 TI - Role of hemodynamic shear stress in cardiovascular disease. AB - Atherosclerosis is the main cause of morbidity and mortality in the Western world. Inflammation and blood flow alterations are new markers emerging as possible determinants for the development of atherosclerotic lesions. In particular, blood flow exerts a shear stress on vessel walls that alters cell physiology. Shear stress arises from the friction between two virtual layers of a fluid and is induced by the difference in motion and viscosity between these layers. Regions of the arterial tree with uniform geometry are exposed to a unidirectional and constant flow, which determines a physiologic shear stress, while arches and bifurcations are exposed to an oscillatory and disturbed flow, which determines a low shear stress. Atherosclerotic lesions develop mainly in areas of low shear stress, while those exposed to a physiologic shear stress are protected. The presence of areas of the arterial tree with different wall shear stress may explain, in part, the different localization of atherosclerotic lesions in both coronary and extracoronary arteries. The measurement of this parameter may help in identifying atherosclerotic plaques at higher risk as well as in evaluating the efficacy of different pharmacological interventions. Moreover, an altered shear stress is associated with the occurrence of both aortic and intracranial aneurysms, possibly leading to their growth and rupture. Finally, the evaluation of shear stress may be useful for predicting the risk of developing restenosis after coronary and peripheral angioplasty and for devising a coronary stent with a strut design less thrombogenic and more conducive to endothelization. PMID- 20970140 TI - One-year clinical outcome after provisional T-stenting for bifurcation lesions with the endothelial progenitor cell capturing stent compared with the bare-metal stent. AB - OBJECTIVE: Currently no data exists regarding the outcomes after the novel endothelial progenitor cell capturing stent (EPCcS) placement in bifurcation lesions using a provisional T-stenting. This study evaluates the 1-year clinical outcome in patients treated with the EPCcS for a bifurcation lesion using a provisional T-stenting technique and compared these to a historical control group treated with an identical bare-metal stent (BMS). METHODS: In single-center study, 178 consecutive patients with a de novo bifurcation lesion treated with an EPCcS and 465 consecutive patients treated with an equivalent BMS were included. Multivariate and propensity-score analyses were performed to adjust for differences in clinical and angiographic characteristics between the EPCcS group and the BMS group. RESULTS: At 1-year, the cumulative rate of the primary end point (cardiac death, myocardial infarction (MI), or target lesion revascularization (TLR)) was 12.4% in the EPCcS group and 17.2% in the BMS group (hazard ratio [HR] 0.70; 95% confidence interval CI, 0.44-1.12; P=0.13). The 1 year cumulative rate of TLR was lower among patients treated with EPCcS compared with the control stent as a result of fewer coronary artery bypass grafting, 10.7% vs. 12% respectively (HR 0.88; 95% CI, 0.53-1.49; P=0.64). The cumulative rate of definite ST was 0.6% in the EPCcS as compared with 0.4% in the BMS group. CONCLUSIONS: Although, the EPC stent shows favorable outcomes in the treatment of bifurcation lesions, the reduction in the cumulative rate of cardiac death, MI, or TLR as compared with the BMS was statistically non-significant. PMID- 20970141 TI - Preparation, evaluation and application of molecularly imprinted solid-phase microextraction monolith for selective extraction of pirimicarb in tomato and pear. AB - A simple, rapid and sensitive method for the determination of pirimicarb in tomato and pear using polymer monolith microextraction (PMME) based on the molecularly imprinted polymer (MIP) monolith combined with high-performance liquid chromatography-photodiodes array detector (HPLC-PAD) was developed. By optimizing the polymerization conditions, such as the nature of porogenic solvent and functional monomer, the molar ratio of the monomer and cross-linker, an pirimicarb MIP monolith was synthesized in a micropipette tip using methacrylic acid (MAA) as the functional monomer, ethylene dimethacrylate (EGDMA) as the cross-linker and the mixture of toluene-dodecanol as the porogenic solvent. The MIP monolith showed highly specific recognition for the template pirimicarb. The monolith was applied for the selective extraction of pirimicarb in tomato and pear. Several parameters affecting MIP-PMME were investigated, including the nature and volume of extraction solvent, sample volume, flow rate and sample pH. Under the optimum PMME and HPLC conditions, the linear ranges were 2.0-1400 MUg/kg for pirimicarb in tomato and pear with the correlation coefficient of above 0.999. The detection limits (s/n=3) were both 0.6 MUg/kg. The proposed method was successfully applied for the selective extraction and determination of pirimicarb in tomato and pear. PMID- 20970142 TI - Development and characterization of "push-pull" sampling device with fast reaction quenching coupled to high-performance liquid chromatography for pharmaceutical process analytical technologies. AB - A push-pull sampling system interfaced on-line to high-performance liquid chromatography (HPLC) was developed for micro-volume real-time monitoring of reaction mixtures. The device consists of concentric tubes wherein sample was continuously withdrawn through the outer tube and reaction quenchant continuously delivered through a recessed inner tube. The device allowed sampling rates of 0.1 6.0 MUL/min from a reaction vessel and stopped the reaction by passive mixing with quenchant to preserve the conditions observed in the reaction vessel. A finite element model of the system showed that reaction mixtures could be completely mixed with quenchant within 4.3s at a flow rate of 1.0 MUL/min. The model also showed that an offset distance of 1mm between the push capillary and sample capillary tips is sufficient to avoid leakage of quenchant/diluent into the bulk sample for push flow rates up to 95% of the pull flow rate. The maximum relative push flow rate was determined to be 90% of the pull flow rate experimentally. Delay between sampling and delivery to the HPLC was from 111+/-3s to 317+/-9s for pull flow rates from 1.0 to 3.0 MUL/min in agreement with expected delays based on tubing volume. Response times were from 27+/-1s to 52+/ 6s over the same flow rate range. The sampler was tested to determine the effects of sample viscosity. The sampler was also used to demonstrate periodic sampling capabilities. As a test of the system, it was used to monitor the base-catalyzed hydrolysis of aspirin for 1.5h, demonstrating its utility for monitoring an ongoing reaction. PMID- 20970143 TI - Determination of carboxylic acids in water by gas chromatography using several detectors after flow preconcentration. AB - A novel analytical method is reported that combines continuous solid-phase extraction and gas chromatography for the determination of 22 carboxylic acids in water. The highly polar and hydrophilic analytes were preferentially sorbed on a mixture of LiChrolut EN-Supelclean ENVI-18 (1:1) sorbent column and eluted with methanol; this extraction process did not require derivatisation. The extract was analysed by gas chromatography coupled to a flame ionisation detector as well as a mass spectrometer with electron impact (EI) or positive chemical ionisation modes. The highest sensitivity was achieved when using MS-EI, with good linearity in calibration curves and low detection limits (2-40ngL(-1)) for 50mL of sample. The entire procedure from raw aqueous sample to a ready-to-inject methanol solution of the acids requires less than 15min. Another benefit of this method is the good accuracy (recoveries between 93 and 102%) and precision (relative standard deviation, 3.4-6.2%), which allows the determination of carboxylic acids in environmental water and in real chlorinated and ozonated drinking water. PMID- 20970144 TI - n-Octadecylphosphonic acid grafted mesoporous magnetic nanoparticle: Preparation, characterization, and application in magnetic solid-phase extraction. AB - A new sorbent for magnetic solid-phase extraction, n-octadecylphosphonic acid modified mesoporous magnetic nano particles (OPA/MMNPs), was easily prepared via a two-step strategy. MMNPs were synthesized by a solvent-thermal process, and then OPA was grafted onto the surface of MMNPs via the strong Lewis acid/base interaction. The resultant material was characterized by transmission electron microscopy, tensionmeter, Fourier-transform infrared spectroscopy, vibrating sample magnetometry, elemental analysis, and nitrogen adsorption analysis. The results demonstrated that the particles exhibited mesoporous structure, superparamagnetic (57emu/g) and extremely hydrophobic (water contact angle of 136 degrees ) properties. To evaluate the extraction performance of the resultant sorbent, polycyclic aromatic hydrocarbons (PAHs) were chosen as model analytes. The extraction conditions were optimized. Based on these, a rapid, convenient and efficient method for the determination of PAHs in water samples was established by combination of magnetic solid-phase extraction and gas chromatography-mass spectroscopy. The linearity range of proposed method was 0.2-100MUg/L with correlation coefficients (R(2)) of 0.9726-0.9970. The intra- and inter-day relative standard deviations (RSDs) were less than 17.6%. Batch-to-batch reproducibility was acceptable with RSD values less than 12.1%. PMID- 20970145 TI - Contact angle and adsorption behavior of carboxylic acids on alpha-Al2O3 surfaces. AB - The hydrophilic character of aluminum oxide surfaces may be altered through coating such surfaces with carboxylic acids. The initially hydrophilic nature of the solid substrate changes towards a less hydrophilic character as the bulk concentration and the chain length of the acids increases. The acids employed in this work (propionic, valeric and enanthic) show a certain affinity to the liquid gas, solid-liquid and solid-gas interfaces, being the relative adsorption on them competitive. The adsorption behavior of these carboxylic acids is experimentally investigated combining pendant drop tensiometry, contact angle measurements on alpha-Al(2)O(3) polycrystalline ceramics and adsorption on particles in aqueous suspensions, as a function of the hydrocarbon chain length of the acids and their bulk concentration, at pH equal to the acids' pKa. The hydrophilic character of the coated alumina decreases with the acids concentration upon a certain concentration beyond that, it increases. The minimum of hydrophilicity is reached right before bi-layer arrangements on the adsorption pattern of the acids on the solid substrates take place. PMID- 20970146 TI - Highly efficient olefin oxidation catalysts based on regular nano-particles of titanium-containing mesoporous molecular sieves. AB - Ti-MCM-41 and Ti-MCM-48 are successfully prepared by one step synthesis and post synthesis at room temperature. The samples have been characterized by X-ray diffraction, SEM, TEM, nitrogen adsorption/desorption isotherms and UV-Vis spectroscopy. The results demonstrate the existence of an ordered mesoporous structure. The Ti species are grafted into the pure silica sieve frameworks without any evidence of the formation of non-skeleton anatase. The post-synthesis Ti-MCM-41 regular nano-particles display a higher conversion and selectivity as compared to that for both the post-synthesis Ti-MCM-48 and Ti-MCM-41 with ordinary particles, in the epoxidation of cis-cyclooctene with aqueous H(2)O(2) as an oxidant. The enhanced catalytic activity may be attributed to the existence of a higher number of isolated tetracoordinated Ti active sites and regular nano particles, which are conducive to the affinity of the reactants with active sites. PMID- 20970147 TI - Dried blood spot polymerase chain reaction screening for congenital cytomegalovirus infection. PMID- 20970148 TI - "He's dizzy when he stands up": an introduction to initial orthostatic hypotension. PMID- 20970150 TI - [Abdominal imaging case presented at the General Case Reading Session of the XXX National Congress of the SERAM, A Coruna. May 2010]. PMID- 20970151 TI - Prevalence and genetic characterization of Giardia and Cryptosporidium in cats from Italy. AB - One hundred and eighty one cats living in central Italy were tested for the presence of Giardia and Cryptosporidium infection by IFAT test and specific PCRs. Overall eight (4.4%) samples were IFAT-positive for Giardia. All the IFAT positive samples for Giardia scored positive for the PCRs, and three more samples IFAT-negative generated PCR products leading to a total 6.1% molecular positivity rate for Giardia. All the examined samples were negative for Cryptosporidium. Sequencing of samples molecularly positive to Giardia indicated that three cats harbored the zoonotic Giardia duodenalis Assemblage A, whereas all other positive animals were infected with the feline-specific G. duodenalis Assemblage F. Phylogenetic analysis carried out on the sequences obtained supported the clustering of the isolates within Assemblages A and F. The results here presented provide data on the occurrence of Giardia genotypes in cats living in close contact with humans highlighting the potential importance of this protozoan disease for the public health. PMID- 20970152 TI - Multi-centric prospective evaluation of rk39 rapid test and direct agglutination test for the diagnosis of visceral leishmaniasis in Brazil. AB - The diagnosis of visceral leishmaniasis (VL) is still a major problem in Brazil and several other countries where the disease is endemic. The use of an easy-to use and interpret, sensitive, and specific method that requires no complex infrastructure or specialized professionals, such as direct agglutination test (DAT) and the rK39-based rapid immunochromatographic test may enhance the diagnosis of disease. This study evaluated the performance of a rapid test (DiaMed- IT-LEISH(r)) and the DAT for the diagnosis of VL in 213 parasitologically confirmed cases and 119 controls with clinical suspicion of VL and confirmation of another etiology. The sensitivities and specificities of the rapid test were 93% and 97%, respectively and those of the DAT were 90% and 96%, respectively. The positive predictive values of the rapid test and the DAT were 98% and 97%, respectively and the negative predictive values were 89% and 84%, respectively. The Kappa index showed agreement between both methods classified as substantial (0.77). This study showed that the DAT and the rapid test can be used to diagnose VL in Brazil, following a pilot study for implementation of the rapid test in the health services. PMID- 20970153 TI - Duodenal pseudomelanosis. PMID- 20970155 TI - Heterotrophic cultures of microalgae: metabolism and potential products. AB - This review analyzes the current state of a specific niche of microalgae cultivation; heterotrophic growth in the dark supported by a carbon source replacing the traditional support of light energy. This unique ability of essentially photosynthetic microorganisms is shared by several species of microalgae. Where possible, heterotrophic growth overcomes major limitations of producing useful products from microalgae: dependency on light which significantly complicates the process, increase costs, and reduced production of potentially useful products. As a general role, and in most cases, heterotrophic cultivation is far cheaper, simpler to construct facilities, and easier than autotrophic cultivation to maintain on a large scale. This capacity allows expansion of useful applications from diverse species that is now very limited as a result of elevated costs of autotrophy; consequently, exploitation of microalgae is restricted to small volume of high-value products. Heterotrophic cultivation may allow large volume applications such as wastewater treatment combined, or separated, with production of biofuels. In this review, we present a general perspective of the field, describing the specific cellular metabolisms involved and the best-known examples from the literature and analyze the prospect of potential products from heterotrophic cultures. PMID- 20970156 TI - The impacts of bisphenol A (BPA) on abalone (Haliotis diversicolor supertexta) embryonic development. AB - The effects of bisphenol A (BPA) on abalone (Haliotis diversicolor supertexta) embryonic development were investigated by exposing the fertilized eggs to four different concentrations of BPA (0.05, 0.2, 2 and 10 MUg mL(-1)). Toxicity endpoints including the embryo development parameters, the physiological features and the expression profile of several reference genes (prohormone convertase 1, PC1; cyclin B, CB; and cyclin-dependent kinase 1, CDK1) were assessed. The results showed that BPA could markedly reduce embryo hatchability, increase developmental malformation, and suppress the metamorphosis behavior of larvae. The possible toxicological mechanisms hidden behind of these effects (i.e. disturbing the embryogenesis) might result from three aspects: (1) BPA disturbance the cellular ionic homeostasis and osmoregulation of abalone embryos by changing the Na+-K+-ATPase and Ca2+-Mg2+-ATPase levels; (2) BPA induced oxidative damage of embryos by significantly altering the peroxidase (POD) activities and the malondialdehyde (MDA) production; and (3) the RT-PCR analysis further demonstrated that BPA perturbed the cellular endocrine regulation and cell cycle progression by down-regulating the PC1 gene, as well as over expressing the CB and CDK1 genes. This is the first comprehensive study on the developmental toxicity of BPA to the marine abalone at morphological, physiological and molecular levels. The results in this study also indicated that the embryo tests can contribute to the ecological risk assessment of the endocrine disruptors in marine environment. PMID- 20970154 TI - Patients on HAART often have an excess of unintegrated HIV DNA: implications for monitoring reservoirs. AB - HIV establishes a latent reservoir early in infection that is resistant to anti retroviral therapy and has a slow rate of decay. It is thought that the majority of HIV DNA in treated patients is integrated since unintegrated HIV DNA appears to be unstable. Thus, to monitor the HIV latent reservoir, total HIV DNA is commonly measured in PBMC from infected individuals. We investigated how often total approaches integrated HIV DNA in treated patients. To do this, we first assessed how accurate our integration assay is and determined the error in our measurements of total and integrated HIV DNA. We demonstrated an excess of total over integrated HIV DNA was present in a subset of patients, suggesting that measurements of total HIV DNA do not always correlate to the level of integration. Determining the cause of this excess and its frequency may have important implications for understanding HIV latent reservoir maintenance. PMID- 20970157 TI - Determination of lipid peroxidation and cytotoxicity in calcium, magnesium, titanium and hectorite (SHCa-1) suspensions. AB - This paper reports data on the relative ability of CaO, CaCl2, MgO, MgCl2, TiO2, and hectorite (SHCa-1) to induce oxidative stress (as determined by lipid peroxidation, LP) in biological matrices. The effectiveness of structural (oxide form) versus soluble Ca and Mg to induce LP is compared. An assessment on cytotoxicity as affected by soluble and structural Ca, Mg, TiO2 and SHCa-1 is also addressed. LP was screened and monitored using the Thiobarbituric Acid Reactive Substances (TBARS). The extent of TBARS production was found to vary with the type and initial concentration of the soluble or structural cation, Ca or Mg respectively. Obtained results showed higher magnitude values for the latter set of experiments. In the presence of TiO2 no significant TBARS production was detected pointing out a negligible effect of TiO2 on LP. At solid concentrations ca. 100 ppm, CaO appears to be more effective than SHCa-1 to induce LP. By contrast at ca. 25 ppm, MgO appears to be more effective than the clay mineral. The SHCa-1 LP-inducing activity has been proven to closely relate to structural Ca. The prevalence of mechanisms that may induce LP but not cytotoxicity (as determined by cell growth inhibition) was also addressed. Results on cell growth inhibition as affected by soluble and structural Ca, Mg, TiO2 and hectorite provide evidence to support that structural Ca or Mg brings about significantly higher variations than soluble Ca. PMID- 20970158 TI - Spatial distribution of soil heavy metal pollution estimated by different interpolation methods: accuracy and uncertainty analysis. AB - Mapping the spatial distribution of contaminants in soils is the basis of pollution evaluation and risk control. Interpolation methods are extensively applied in the mapping processes to estimate the heavy metal concentrations at unsampled sites. The performances of interpolation methods (inverse distance weighting, local polynomial, ordinary kriging and radial basis functions) were assessed and compared using the root mean square error for cross validation. The results indicated that all interpolation methods provided a high prediction accuracy of the mean concentration of soil heavy metals. However, the classic method based on percentages of polluted samples, gave a pollution area 23.54 41.92% larger than that estimated by interpolation methods. The difference in contaminated area estimation among the four methods reached 6.14%. According to the interpolation results, the spatial uncertainty of polluted areas was mainly located in three types of region: (a) the local maxima concentration region surrounded by low concentration (clean) sites, (b) the local minima concentration region surrounded with highly polluted samples; and (c) the boundaries of the contaminated areas. PMID- 20970159 TI - Tributyltin chloride results in dorsal curvature in embryo development of Sebastiscus marmoratus via apoptosis pathway. AB - Tributyltin (TBT) is a ubiquitous marine environmental contaminant characterized primarily by its reproductive toxicity. However, the embryotoxicity of TBT has not been extensively described, especially in fishes. The aim of this study was to investigate the developmental toxicity of waterborne TBT at environmental levels (0, 0.1, 1, and 10 ng L(-1) as Sn) on Sebastiscus marmoratus embryos. Our study showed that TBT reduced the hatchability and caused apparent morphological abnormalities including dorsal curvature, severely twisted tails and pericardial edema. In addition, localized apoptosis was found in the tail regions of embryos after TBT exposure. The study provided a possible mechanistic link between apoptosis and TBT-induced twisted tails abnormality. TBT exposure induced retinoid X receptor alpha expression in S. marmoratus embryos at the 0.1 and 1 ng L(-1) group, which would be responsible for the increasing apoptotic cells induced by TBT. The results of the present study have widespread implications for environmental ecological assessment, management and the etiology of developmental defects. PMID- 20970160 TI - Matrix metalloproteinase-2 and matrix metalloproteinase-9 codistribute with transcription factors RUNX1/AML1 and ETV5/ERM at the invasive front of endometrial and ovarian carcinoma. AB - Several matrix metalloproteinases (MMPs) are implicated in the degradation of the epithelial basement membrane (BM), invasiveness, and malignancy of endometrial and ovarian carcinomas. We have recently proposed a cooperative role for RUNX1/AML1 and ETV5/ERM in myometrial infiltration during endometrioid endometrial invasiveness. In the present work, we have characterized the occurrence, levels of expression, and codistribution of gelatinases MMP-2 and -9, and the transcription factors RUNX1/AML1 and ETV5/ERM, together with collagen type IV and laminin chains of the epithelial BM in endometrioid endometrial (EEC) and ovarian endometrioid carcinoma (OEC). MMP-2 and -9 expression levels were up regulated at the invasive front of both carcinomas, and they showed a relatively high degree of volume codistribution with RUNX1/AML1 and ETV5/ERM. EEC tissue microarrays showed similar significant expression and correlation for MMPs and the transcription factors. When the array samples were grouped according to the carcinoma stages, there was significant correlation in the expression levels for both MMP-2 and -9 with ETV5/ERM. Colocalization of MMP-2 and -9 with epithelial basement membrane component collagen type IV showed close spatial association for both MMPs and discontinuation of collagen type IV expression at the invasive front in both EEC and OEC. BM components laminin alpha1, alpha2, alpha3, alpha5, and gamma2 chains, laminin alpha5 receptor basal cell adhesion molecule (BCAM), and laminin 332 were all detected both in EEC and OEC. Highest expression levels in EEC were for laminin alpha3 and in OEC for laminin alpha5 chain. Laminin gamma2 chain and laminin 332 showed discontinuous immunoreactivity in the epithelial basement membrane suggestive of proteolytic degradation. These results indicate concurrent mechanisms in expression of MMP-2 and -9, RUNX1/AML1 and ETV5/ERM, and several of the basement membrane components, which are likely to associate with the invasive stage of EEC and OEC. PMID- 20970161 TI - The use of insulin like-growth factor II messenger RNA binding protein-3 in diagnostic pathology. AB - The histologic distinction between reactive processes and malignant neoplasms and between low-grade and high-grade tumors is not always straightforward and is sometimes extremely challenging. This is especially the case when the diagnostic material is a small biopsy specimen or a cytology specimen with scant cellularity. In addition, suboptimal processing and crush artifact may limit accurate diagnosis. A reliable diagnostic biomarker that preferentially highlights malignant processes and high-grade tumors would be very valuable in segregating these entities from reactive processes and low-grade lesions. Recent extensive studies have shown that an oncoprotein, insulin like-growth factor II messenger RNA binding protein-3, is not only a prognostic biomarker but also a diagnostic molecule. This review focuses on discussing the value of insulin like growth factor II messenger RNA binding protein-3 in diagnostic pathology, with a focus on utilization of insulin like-growth factor II messenger RNA binding protein-3 in the discrimination of benign effusions from malignant effusions, malignant mesothelioma from mesothelial hyperplasia, carcinoids from high-grade neuroendocrine carcinomas, low-grade dysplasia from high-grade dysplasia, hepatocellular carcinoma from hepatic adenoma, cholangiocarcinoma and metastatic pancreatic ductal carcinoma from benign bile duct lesions, melanoma from nevi, and follicular thyroid carcinoma from follicular adenoma of the thyroid, as well as examining insulin like-growth factor II messenger RNA binding protein-3 expression in lymphomas of germinal center origin. PMID- 20970162 TI - Severe hepatosplenic schistosomiasis: clinicopathologic study of 102 cases undergoing splenectomy. AB - We present the preoperative findings of 102 patients who underwent successful splenectomy for advanced schistosomiasis japonica. All patients were symptomatic for schistosomiasis and had splenomegaly greater than or equal to II according to the Hackett criteria. Before surgery, all patients underwent clinical examination including full blood count; fibrinogen and serum protein levels; liver function tests; and serology for hepatitis B, C, and D. Ultrasound examination of the liver and spleen and liver histology for evidence of pathology were also undertaken. Ninety patients had a treatment history for schistosomiasis. Fifty six patients were seropositive for hepatitis B virus antibody, and 6 patients were seropositive for hepatitis C virus antibody. Immunohistochemical testing of the liver samples confirmed that 45 patients were positive for hepatitis B virus surface antigen, thereby indicating active infection. A total of 66.7% of patients had fibrosis stages II to III by ultrasound; and 76.5% of patients had portal vein inner diameter greater than 12 mm, indicating portal vein hypertension. A total of 83.2% of patients showed various stages of esophageal varicosis via x-ray, and 81.4% had fibrotic stages III to IV by liver biopsy. Coinfection with hepatitis B virus accelerated the development of liver fibrosis. There was moderate concordance between the fibrosis assessed by ultrasonography and histopathology, indicating that ultrasound underestimates the true pathology. Combined assessment is needed to improve the diagnosis of clinical hepatic fibrosis. PMID- 20970164 TI - Interobserver and intraobserver reproducibility in digital and routine microscopic assessment of prostate needle biopsies. AB - Advances in whole slide digital imaging in the past decade necessitate validation of these tools in each organ system in advance of clinical adoption. We assessed reproducibility in reporting prostate needle biopsy parameters among urologic pathologists using routine and digital microscopy in a consultation/second opinion-like setting. Four urologic pathologists evaluated a single core level from 50 diagnostically challenging needle biopsy specimens by routine microscopy and whole slide digital imaging. Interobserver and intraobserver agreement were calculated for primary and secondary Gleason grades, Gleason score, tumor quantitation (percentage and size in millimeters), and perineural invasion. Interobserver agreement for routine microscopy was excellent for primary Gleason grade (kappa = 0.72) and good for all other parameters (kappa ranging from 0.36 to 0.55). Whole slide digital imaging assessment yielded similar agreement for all parameters. Intraobserver agreement for primary Gleason grade and Gleason score was very good to excellent for all pathologists (all kappa >= 0.65 and >= 0.73, respectively). Size of tumor in millimeters consistently displayed higher levels of agreement than percentage of tumor across media and pathologists. Digital assessment of routinely reported cancer parameters on prostatic needle biopsy for a given scanned core level is comparable to that of routine microscopy. These findings imply that histologic interpretation using dynamic whole slide images may accurately simulate routine microscopic evaluation in the consultation setting. Implementation of whole slide digital imaging in these scenarios may significantly reduce the workload of large referral centers in the near future and impact the manner in which pathologists seek second opinion consultation on challenging cases. PMID- 20970163 TI - Repression of E-cadherin by SNAIL, ZEB1, and TWIST in invasive ductal carcinomas of the breast: a cooperative effort? AB - It has been suggested that down-regulation of E-cadherin in invasive breast ductal carcinomas is mediated by the aberrant expression of several of its transcriptional repressors, but their inhibitory role and clinical importance are not yet well established. We investigated gene and protein expression patterns of the E-cadherin repressors SNAIL, ZEB1, and TWIST in relation to clinicopathologic parameters, in a series of 88 patients with invasive breast ductal carcinomas. Up regulation of SNAIL messenger RNA (P = .008) and down-regulation of TWIST (P = .022) were associated with triple-negative tumors, whereas ZEB1 gene expression was more frequent in hormone-positive tumors (P = .004). Loss of E-cadherin was found in 19% of the tumors, but it did not correlate with aberrant expression of any of the repressors investigated herein. Nonetheless, we found that ZEB-1 protein overexpression inversely correlated with high tumor grade (P = .018), nuclear grade (P = .002), and presence of lymph nodes (P = .001), and these data were consistent with the gene expression data for ZEB1. Clinically, down regulation of ZEB1 messenger RNA was associated with poor overall survival (P = .011) and disease-free survival (P = .053), whereas patients with TWIST negative tumors had a worse overall survival (P = .008) and disease-free survival (P = .006). Our data indicate that deregulation of TWIST is somehow important in the aggressiveness of triple-negative carcinomas and poor patient outcome, whereas down-regulation of ZEB1 seems to play a role in tumor spread, metastases, and poor survival. PMID- 20970165 TI - Down-regulation of annexin A1 and A2 protein expression in intestinal-type sinonasal adenocarcinomas. AB - Annexins are a structurally related family of calcium- and phospholipid-binding proteins that have been implicated in a broad range of molecular and cellular processes. The altered expression of individual annexins has been implicated in tumor development and progression. In this study the expression of annexin A1 and annexin A2 was studied by immunohistochemistry in intestinal-type sinonasal adenocarcinoma using a study set of 57 intestinal-type sinonasal adenocarcinomas represented on an intestinal-type sinonasal adenocarcinoma tissue microarray to assess its potential role in the pathogenesis of these tumors. Our results showed that annexin A1 expression was consistently lost in 52 (91%) intestinal-type sinonasal adenocarcinomas, as compared with the normal epithelium. The expression of annexin A2 was more heterogeneous, and only 19 (33%) cases showed annexin A2 negative expression. Annexin A2 expression was correlated with the histopathological type, being lower in the mucinous type (P = .022). The loss of annexin A2 expression correlated with a reduced survival in univariate analysis (P = .004). However, the impact of annexin A2 expression on patient survival could be an indirect consequence of its association with the histopathological type, since annexin A2 expression was not found to be an independent predictor in multivariate analyses. These results suggest that annexin A1 expression is frequently and commonly lost in intestinal-type sinonasal adenocarcinoma development. Annexin A2 expression is also reduced in intestinal-type sinonasal adenocarcinoma, and this loss of expression is associated to the more aggressive histopathological types. PMID- 20970166 TI - Expression of megakaryocytic and myeloid markers in blasts of transient abnormal myelopoiesis in a stillbirth with Down syndrome: report of histopathological findings of an autopsy case. AB - Transient abnormal myelopoiesis in neonates with Down syndrome is an unusual leukemia that spontaneously regresses within several months of life and is thought to arise in the fetal liver. It is largely unknown how the leukemic blasts proliferate and differentiate in fetal tissues. We report the histopathological findings of an autopsy case of a stillbirth with transient abnormal myelopoiesis. Blood vessels in almost all organs were filled with immature leukemic cells, most of which expressed megakaryocyte antigen CD42b. In contrast, leukemic cells infiltrating the tissues, including the pericardium, expressed myeloperoxidase. These findings indicate that leukemic progenitors in transient abnormal myelopoiesis can differentiate along both megakaryocytic and myeloid lineages, which may be influenced by microenvironmental factors. Numerous dysplastic mature/immature megakaryocytes and blasts were present in the liver, whereas the bone marrow contained predominantly myeloid cells at various stages of differentiation, suggesting that the fetal liver is the major organ for proliferation of blasts in transient abnormal myelopoiesis. PMID- 20970167 TI - Atypical ductal hyperplasia on vacuum-assisted breast biopsy: suspicion for ductal carcinoma in situ can stratify patients at high risk for upgrade. AB - We evaluated 97 cases of review-confirmed atypical ductal hyperplasia found on stereotactic vacuum-assisted breast biopsy of suspicious calcifications. The number and size of foci of atypical ductal hyperplasia and presence of a micropapillary component were noted. In addition, we recorded if a case was considered "atypical ductal hyperplasia suspicious for ductal carcinoma in situ" using specific qualitative criteria. The upgrade rate was 20.6% (20/97) for all cases and 48% (12/25) for cases suspicious for ductal carcinoma in situ. Suspicion for ductal carcinoma in situ was found to be a strong predictor of upgrade with an odds ratio of 7.4 (P = .0003). Suspicious cases with nuclear features bordering on intermediate nuclear grade had the highest upgrade rate of 75% (6/8). Cases with >= 3 foci had significantly higher upgrade rates (28%) than those with less than 3 foci (11%), but focal atypical ductal hyperplasia did upgrade (P = .04). In conclusion, qualitative features of atypical ductal hyperplasia on core biopsy such as suspicion for ductal carcinoma in situ may help stratify patients at the highest risk for upgrade. PMID- 20970168 TI - Anthropogenic tracers, endocrine disrupting chemicals, and endocrine disruption in Minnesota lakes. AB - Concentrations of endocrine disrupting chemicals and endocrine disruption in fish were determined in 11 lakes across Minnesota that represent a range of trophic conditions and land uses (urban, agricultural, residential, and forested) and in which wastewater treatment plant discharges were absent. Water, sediment, and passive polar organic integrative samplers (POCIS) were analyzed for steroidal hormones, alkylphenols, bisphenol A, and other organic and inorganic molecular tracers to evaluate potential non-point source inputs into the lakes. Resident fish from the lakes were collected, and caged male fathead minnows were deployed to evaluate endocrine disruption, as indicated by the biological endpoints of plasma vitellogenin and gonadal histology. Endocrine disrupting chemicals, including bisphenol A, 17beta-estradiol, estrone, and 4-nonylphenol were detected in 90% of the lakes at part per trillion concentrations. Endocrine disruption was observed in caged fathead minnows and resident fish in 90% of the lakes. The widespread but variable occurrence of anthropogenic chemicals in the lakes and endocrine disruption in fish indicates that potential sources are diverse, not limited to wastewater treatment plant discharges, and not entirely predictable based on trophic status and land use. PMID- 20970169 TI - Use of existing water, sediment, and tissue data to screen ecological risks to the endangered Rio Grande silvery minnow. AB - A screening-level ecological risk assessment was applied to two extensive, but previously unanalyzed datasets from the middle Rio Grande (MRG) in New Mexico. The assessment evaluated how adverse water-quality effects from aquatic toxicants may have influenced the population decline of the endangered Rio Grande silvery minnow (Hybognathus amarus; silvery minnow). Standardized US Environmental Protection Agency (USEPA) screening-level ecological risk assessment procedures were applied to chemicals assessed in samples collected from the MRG between 1985 and 2003. Since more chemicals have established risk-screening criteria, relative to water-quality criteria, this approach produces more complete assessments. Chemical concentrations at some locations and times were potentially sufficient to affect fish health or produce localized mortalities. Many constituents displaying the highest risks have substantial natural sources within the watershed; native species likely would have adapted to natural instream concentrations such that actual risks might be markedly less than projected by a risk screening based on generic aquatic-life criteria. Also, highest risks found for individual and combinations of contaminants were very inconsistent both within and across the sites. As such, this risk assessment does not support the conclusion that toxicants were a primary factor causing the silvery minnow population to decline in the MRG between 1985 and 2003. The assessment indicates that sediment-borne, relative to water-borne, contaminants appeared to present the greatest risks to the silvery minnow and thus should have increased focus during future assessments of potential contaminant effects in the MRG. Contaminants of greatest concern are identified. This study presents approaches to cost-effectively assess and reduce uncertainties associated with potential water quality effects, and to help direct future assessments of water quality onto those contaminants likely to produce potentially significant effects. The techniques presented and criteria compiled are suitable for aiding similar assessments in other aquatic habitats. PMID- 20970170 TI - Modelling air pollution for epidemiologic research--part II: predicting temporal variation through land use regression. AB - Over recent years land use regression (LUR) has become a frequently used method in air pollution exposure studies, as it can model intra-urban variation in pollutant concentrations at a fine spatial scale. However, very few studies have used the LUR methodology to also model the temporal variation in air pollution exposure. The aim of this study is to estimate annual mean NO(2) and PM(10) concentrations from 1996 to 2008 for Greater Manchester using land use regression models. The results from these models will be used in the Manchester Asthma and Allergy Study (MAAS) birth cohort to determine health effects of air pollution exposure. The Greater Manchester LUR model for 2005 was recalibrated using interpolated and adjusted NO(2) and PM(10) concentrations as dependent variables for 1996-2008. In addition, temporally resolved variables were available for traffic intensity and PM(10) emissions. To validate the resulting LUR models, they were applied to the locations of automatic monitoring stations and the estimated concentrations were compared against measured concentrations. The 2005 LUR models were successfully recalibrated, providing individual models for each year from 1996 to 2008. When applied to the monitoring stations the mean prediction error (MPE) for NO(2) concentrations for all stations and years was 0.8MUg/m3 and the root mean squared error (RMSE) was 6.7MUg/m3. For PM(10) concentrations the MPE was 0.8MUg/m3 and the RMSE was 3.4MUg/m3. These results indicate that it is possible to model temporal variation in air pollution through LUR with relatively small prediction errors. It is likely that most previous LUR studies did not include temporal variation, because they were based on short term monitoring campaigns and did not have historic pollution data. The advantage of this study is that it uses data from an air dispersion model, which provided concentrations for 2005 and 2010, and therefore allowed extrapolation over a longer time period. PMID- 20970171 TI - Ischemic postconditioning attenuates renal ischemic/reperfusion injury in mongrel dogs. AB - OBJECTIVE: To investigate the effect of Postcond on renal ischemia-reperfusion (I/R) injury in a canine model. I/R injury is the most common cause of renal dysfunction. Ischemic postconditioning (Postcond) is a phenomenon by which intermittent interruptions of blood flow in the early phase of reperfusion can protect organs from I/R injury. MATERIAL AND METHODS: Forty adult male mongrel dogs were randomly divided into five groups of eight dogs each. Animals underwent 60 minutes of renal pedicle occlusion followed by reperfusion for 72 hours. Postcond was performed by 15-second, 30-second, or 1-minute I/R for six or three cycles. Blood and urine were collected at different reperfusion time points (24, 48, and 72 hours), and blood urea nitrogen (BUN), creatinine (Cr) levels, urine N acetyl-beta-D-glucosaminidase (NAG), and Cr levels were assayed. Kidney samples were harvested after I/R, and renal superoxide dismutase (SOD), malondialdehyde (MDA), and myeloperoxidase (MPO) concentrations were measured, respectively. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) assay in the tissue samples. RESULTS: Compared with the sham group, I/R resulted in renal dysfunction, decreased SOD levels, increased MDA and MPO levels, and increased apoptosis indexes. However, Postcond attenuated the aforementioned effects, the protection of which in the Postcond of 15-second reperfusion/ischemia for six cycles was the most notable. CONCLUSIONS: Postcond exerts protective effects on renal (I/R) injury. It may be a promising strategy against I/R injury in clinical practice. Its mechanisms may involve reduction of lipid peroxidation and cellular apoptosis. PMID- 20970172 TI - Modified vaporization-resection for photoselective vaporization of the prostate using a GreenLight high-performance system 120-W Laser: the Seoul technique. AB - OBJECTIVES: The most popular technique of photoselective vaporization of the prostate (PVP) for benign prostatic hyperplasia (BPH) involves vaporization only. We developed a modified vaporization-resection technique that consists of vaporizing a prostate along outlined margins and retrieving the wedge-shaped prostate tissue. We report the operative procedure and clinical outcomes of our technique with the GreenLight high performance system (HPS). METHODS: A total of 104 patients with a prostate volume greater than 40 mL who underwent PVP were included in this retrospective study. Forty patients were treated with the vaporization-only technique (Group non-S) and 64 patients with the Seoul technique (group S). The clinical outcomes were assessed at 1, 3, 6, and 12 months postoperatively using the International Prostate Symptom Score (IPSS), quality of life (QoL) score, maximum flow rate (Q(max.)), and postvoid residual urine volume (PVR). RESULTS: The Q(max.), PVR, IPSS, and QoL scores improved significantly from 1 to 12 months after the PVP compared with the baseline in both groups (P <.05). In the S group, the volume reduction of the prostate per operative time, lasing time, and laser energy were significantly smaller than in the non-S group (P <.05). In general, the overall complication rates were low in the 2 groups. Two patients were found to have prostate cancer on pathology. CONCLUSIONS: The Seoul technique for PVP showed good short-term efficacy and safety for the treatment of BPH. With this technique, we can conserve on the operative time, lasing time, and energy, and obtain prostatic tissue for pathologic evaluation. PMID- 20970173 TI - A randomized prospective controlled study for assessment of different ureteral occlusion devices in prevention of stone migration during pneumatic lithotripsy. AB - OBJECTIVE: To compare the safety and efficacy of two different ureteral occlusion devices (stone cone and entrapment net) in preventing retrograde stone migration during ureteroscopic pneumatic lithotripsy. Proximal migration of stone fragments during ureteroscopic lithotripsy is a common problem, especially when the pneumatic lithotripter is used for stone fragmentation. PATIENTS AND METHODS: A total of 195 patients with proximal ureteric stones were prospectively randomized into one of three groups in this study, with 65 patients in each group. In group I, the Stone Cone was used as a ureteral occlusive device; in group II, the N Trap was used; and in group III (control group), the patients underwent pneumatic lithotripsy without any ureteral occlusive device. RESULTS: The ureteroscopic procedure was completed successfully in 180 patients; 63 patients in group I, 59 patients in group II, and 58 patients in group III. Patients in group I showed significantly lower incidence of stone migration compared with the other 2 groups (P <.05). Both ureteral occlusive devices significantly lowered the incidence of residual fragments (>3 mm), ureteral trauma, operative time, and the need for ureteral stenting compared with control group. The stone-free rate at 3 weeks was 95.24%, 83.05%, and 72.41% in groups I, II, and III, respectively. The patients in group I had a statistically significant stone-free rate compared with the other two groups (P <.05). Auxiliary procedures were required in 3 (4.76%), 10 (16.94%), and 16 cases (27.58%) in groups I, II, and III, respectively. CONCLUSION: The use of Stone Cone or N-Trap is valuable during ureteroscopic pneumatic lithotripsy for treatment of proximal ureteral stones. Both devices significantly diminish residual fragments, the incidence of ureteral wall trauma, and the need for the auxiliary procedure. However, the stone cone was more effective in preventing proximal stone migration and the subsequent stone-free rate. PMID- 20970174 TI - Improvement of treatment-refractory atopic dermatitis by immunoadsorption: a pilot study. PMID- 20970175 TI - Insights into egg coat assembly and egg-sperm interaction from the X-ray structure of full-length ZP3. AB - ZP3, a major component of the zona pellucida (ZP) matrix coating mammalian eggs, is essential for fertilization by acting as sperm receptor. By retaining a propeptide that contains a polymerization-blocking external hydrophobic patch (EHP), we determined the crystal structure of an avian homolog of ZP3 at 2.0 A resolution. The structure unveils the fold of a complete ZP domain module in a homodimeric arrangement required for secretion and reveals how EHP prevents premature incorporation of ZP3 into the ZP. This suggests mechanisms underlying polymerization and how local structural differences, reflected by alternative disulfide patterns, control the specificity of ZP subunit interaction. Close relative positioning of a conserved O-glycan important for sperm binding and the hypervariable, positively selected C-terminal region of ZP3 suggests a concerted role in the regulation of species-restricted gamete recognition. Alternative conformations of the area around the O-glycan indicate how sperm binding could trigger downstream events via intramolecular signaling. PMID- 20970176 TI - Can hygroscopic expansion compensate polymerization shrinkage? Part I. Deformation of restored teeth. AB - OBJECTIVE: Restorative materials exhibit contraction and expansion due to polymerization and water absorption. Each process deforms and stresses a restored tooth structure in opposite direction. This study evaluated the tooth deformations during these competing processes. METHODS: Large MOD cavities were prepared in 10 extracted molars. Five were restored with a hydrophobic resin composite (Filtek Supreme, 3M ESPE) and the others with a hydrophilic resin modified glass-ionomer (Ketac Nano, 3M ESPE). The restored molars and two unrestored controls were stored in water for 24 weeks. The molars were digitized with an optical scanner at baseline, after preparation, restoration, and at 1, 2, 4, 8, 16, and 24 weeks water immersion. The digitized buccal, lingual, and restoration surfaces were analyzed to determine their deformation patterns. The results were statistically analyzed using ANOVA followed by Student-Newman-Keuls post hoc tests (p=0.05). RESULTS: The buccal and lingual tooth surfaces moved 13 14 MUm inward after restoration. After water immersion, cuspal deformation in the resin composite group gradually decreased, reversing the shrinkage deformation within four weeks. The immersed resin-modified glass ionomer group reversed shrinkage deformation within one week, and continued to expand further to 28 MUm after 24 weeks. Cuspal deformations after water immersion were significantly different with the two restoratives. Restoration surfaces also expanded after water immersion, while the control teeth showed no significant deformation. SIGNIFICANCE: Polymerization shrinkage deformation was compensated by hygroscopic expansion within 4 weeks in teeth restored with a hydrophobic resin composite, while a hydrophilic restorative over-compensated polymerization shrinkage within 1 week causing tooth expansion. PMID- 20970177 TI - Adolescent substance use, sleep, and academic achievement: evidence of harm due to caffeine. AB - Using academic achievement as the key outcome variable, 7377 Icelandic adolescents were surveyed for cigarette smoking, alcohol use, daytime sleepiness, caffeine use, and potential confounders. Structural equation modeling (SEM) was used to examine direct and indirect effects of measured and latent variables in two models: the first with caffeine excluded and the second with caffeine included. A substantial proportion of variance in academic achievement, which might otherwise have been attributed to the harmful effects of cigarette smoking and alcohol use, was found to be attributable to caffeine. Evidence was obtained that daytime sleepiness, which was found to be independently associated with usage of licit substances (nicotine and alcohol) and caffeine, may be an important mediator of the negative impact of those substances on academic achievement. Findings suggest the importance of including measurements of caffeine consumption in future studies of adolescent substance use. PMID- 20970178 TI - The developmental association of sexual self-concept with sexual behavior among adolescent women. AB - Developing a sexual self-concept is an important developmental task of adolescence; however, little empirical evidence describes this development, nor how these changes are related to development in sexual behavior. Using longitudinal cohort data from adolescent women, we invoked latent growth curve analysis to: (1) examine reciprocal development in sexual self-concept (sexual openness, sexual esteem and sexual anxiety) over a four year time frame; (2) describe the relationship of these trajectories with changes in sexual behavior. We found significant transactional effects between these dimensions and behavior: sexual self-concept evolved during adolescence in a manner consistent with less reserve, less anxiety and greater personal comfort with sexuality and sexual behavior. Moreover, we found that sexual self-concept results from sexual behavior, as well as regulates future behavior. PMID- 20970180 TI - India's invisible malaria burden. PMID- 20970179 TI - Adult and child malaria mortality in India: a nationally representative mortality survey. AB - BACKGROUND: National malaria death rates are difficult to assess because reliably diagnosed malaria is likely to be cured, and deaths in the community from undiagnosed malaria could be misattributed in retrospective enquiries to other febrile causes of death, or vice-versa. We aimed to estimate plausible ranges of malaria mortality in India, the most populous country where the disease remains common. METHODS: Full-time non-medical field workers interviewed families or other respondents about each of 122,000 deaths during 2001-03 in 6671 randomly selected areas of India, obtaining a half-page narrative plus answers to specific questions about the severity and course of any fevers. Each field report was sent to two of 130 trained physicians, who independently coded underlying causes, with discrepancies resolved either via anonymous reconciliation or adjudication. FINDINGS: Of all coded deaths at ages 1 month to 70 years, 2681 (3.6%) of 75,342 were attributed to malaria. Of these, 2419 (90%) were in rural areas and 2311 (86%) were not in any health-care facility. Death rates attributed to malaria correlated geographically with local malaria transmission ratesderived independently from the Indian malaria control programme. The adjudicated results show 205,000 malaria deaths per year in India before age 70 years (55,000 in early childhood, 30,000 at ages 5-14 years, 120,000 at ages 15-69 years); 1.8% cumulative probability of death from malaria before age 70 years. Plausible lower and upper bounds (on the basis of only the initial coding) were 125,000-277,000. Malaria accounted for a substantial minority of about 1.3 million unattended rural fever deaths attributed to infectious diseases in people younger than 70 years. INTERPRETATION: Despite uncertainty as to which unattended febrile deaths are from malaria, even the lower bound greatly exceeds the WHO estimate of only 15,000 malaria deaths per year in India (5000 early childhood, 10 000 thereafter). This low estimate should be reconsidered, as should the low WHO estimate of adult malaria deaths worldwide. FUNDING: US National Institutes of Health, Canadian Institute of Health Research, Li Ka Shing Knowledge Institute. PMID- 20970181 TI - Staff skills not staff types for community-based rehabilitation. PMID- 20970182 TI - Relationship between sedimentation rates and benthic impact on Maerl beds derived from fish farming in the Mediterranean. AB - The aim of this work was to study the dispersion of particulate wastes derived from marine fish farming and correlate the data with the impact on the seabed. Carbon and nutrients were correlated with the physico-chemical parameters of the sediment and the benthic community structure. The sedimentation rates in the benthic system were 1.09, 0.09 and 0.13 g m-2 day-1 for particulate organic carbon (POC), particulate organic nitrogen (PON) and total phosphorus (TP), respectively. TP was a reliable parameter for establishing the spatial extent of the fish farm particulate wastes. Fish farming was seen to influence not only physico-chemical and biological parameters but also the functioning of the ecosystem from a trophic point of view, particularly affecting the grazers and the balance among the trophic groups. POC, PON and TP sedimentation dynamics reflected the physico-chemical status of the sediment along the distance gradient studied, while their impact on the benthic community extended further. Therefore, the level of fish farm impact on the benthic community might be underestimated if it is assessed by merely taking into account data obtained from waste dispersion rates. The benthic habitat beneath the fish farm, Maerl bed, was seen to be very sensitive to aquaculture impact compared with other unvegetated benthic habitats, with an estimated POC-carrying capacity to maintain current diversity of 0.087 g C m-2 day-1 (only 36% greater than the basal POC input). Environmental protection agencies should define different aquaculture waste load thresholds for different benthic communities affected by finfish farming, according to their particular degree of sensitivity, in order to maintain natural ecosystem functions. PMID- 20970183 TI - Biological actions of silver nanoparticles embedded in titanium controlled by micro-galvanic effects. AB - Titanium embedded with silver nanoparticles (Ag NPs) using a single step silver plasma immersion ion implantation (Ag-PIII) demonstrate micro-galvanic effects that give rise to both controlled antibacterial activity and excellent compatibility with osteoblasts. Scanning electron microscopy (SEM) shows that nanoparticles with average sizes of about 5 nm and 8 nm are formed homogeneously on the titanium surface after undergoing Ag-PIII for 0.5 h and 1 h, respectively. Transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS) indicate that those nanoparticles are metallic silver produced on and underneath the titanium surface via a local nucleation process from the solid solution of alpha-Ti(Ag). The Ag-PIII samples inhibit the growth of both Staphylococcus aureus and Escherichia coli while enhancing proliferation of the osteoblast-like cell line MG63. Electrochemical polarization and Zeta potential measurements demonstrate that the low surface toxicity and good cytocompatibility are related to the micro-galvanic effect between the Ag NPs and titanium matrix. Our results show that the physico-chemical properties of the Ag NPs are important in the control of the cytotoxicity and this study opens a new window for the design of nanostructured surfaces on which the biological actions of the Ag NPs can be accurately tailored. PMID- 20970184 TI - Functionalizable and nonfouling zwitterionic carboxybetaine hydrogels with a carboxybetaine dimethacrylate crosslinker. AB - We have introduced a dimethacrylate carboxybetaine-based crosslinker that has excellent compatibility with zwitterionic hydrogel systems. Poly(carboxybetaine methacrylate) (pCBMA) hydrogels prepared with the new CBMA crosslinker (CBMAX) result in considerably improved solubility, homogeneity, and mechanical properties (up to 8 MPa compressive modulus) over those prepared with the commercially available N,N'-methylenebis(acrylamide) (MBAA) crosslinker. The zwitterionic nature of the CBMAX crosslinker provides continuity of ordered hydration in the CBMA hydrogel and retains its nonfouling properties. CBMAX crosslinked CBMA hydrogels had lower cell fouling than MBAA-crosslinked CBMA hydrogels and in fact reduced cell adhesion by about 90% relative to pHEMA hydrogels. Furthermore, unlike pHEMA, CBMA hydrogels are readily functionalizable. Cell adhesion on nonfouling CBMA hydrogels was controlled by cRGD functionalization. PMID- 20970185 TI - Nanofibrous architecture of silk fibroin scaffolds prepared with a mild self assembly process. AB - Besides excellent biocompatibility and biodegradability, a useful tissue engineering scaffold should provide suitable macropores and nanofibrous structure, similar to extracellular matrix (ECM), to induce desired cellular activities and to guide tissue regeneration. In the present study, a mild process to prepare porous and nanofibrous silk-based scaffolds from aqueous solution is described. Using collagen to control the self-assembly of silk, nanofibrous silk scaffolds were firstly achieved through lyophilization. Water annealing was used to generate insolubility in the silk-based scaffolds, thereby avoiding the use of organic solvents. The nano-fibrils formed in the silk-collagen scaffolds had diameters of 20-100 nm, similar with native collagen in ECM. The silk-collagen scaffolds dissolved slowly in PBS solution, with about a 28% mass lost after 4 weeks. Following the dissolution or degradation, the nanofibrous structure inside the macropore walls emerged and interacted with cells directly. During in vitro cell culture, the nanofibrous silk-collagen scaffolds containing 7.4% collagen demonstrated significantly improved cell compatibility when compared with salt leached silk scaffolds and silk-collagen scaffolds containing 20% collagen that emerged less nano-fibrils. Therefore, this new process provides useful scaffolds for tissue engineering applications. Furthermore, the process involves all aqueous, room temperature and pressure processing without the use of toxic chemicals or solvents, offering new green chemistry approaches, as well as options to load bioactive drugs or growth factors into process. PMID- 20970186 TI - Amphiphilic and biodegradable methoxy polyethylene glycol-block-(polycaprolactone graft-poly(2-(dimethylamino)ethyl methacrylate)) as an effective gene carrier. AB - A group of amphiphilic cationic polymers, methoxy polyethylene glycol-block (polycaprolactone-graft-poly(2-(dimethylamino)ethyl methacrylate)) (PECD), were synthesized by combining ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP) methods to form nanoparticles (NPs). The structures of these amphiphilic cationic polymers were characterized by (1)H NMR measurement. The PECD NPs have hydrophobic cores covered with hydrophilic PEG and cationic PDMAEMA chains. These self-assembly nanoparticles were characterized by dynamic light scattering (DLS) technique. PECD NPs can effectively condense DNA to form compact complexes of the size 65-160 nm suitable for gene delivery. The in vitro gene transfection studies of HeLa and HepG2 cells show that PECD NPs have better transfection efficiency compared to polyethylenimine (PEI) and Lipofectamine 2000 at low dose (N/P = 5). The cytotoxicity result shows that PECD NPs/DNA complexes at the optimal N/P ratio for transfection have comparable toxicity with PEI and Lipofectamine. These results indicate that PECD NPs have a great potential to be used as efficient polymeric carriers for gene transfection. PMID- 20970187 TI - An outwardly rectifying chloride channel in BeWo choriocarcinoma cell line. AB - In this study, an outwardly rectifying chloride channel was characterized in the trophoblastic cell line BeWo, a human hormone-synthesizing cell which displays many biochemical and morphological properties similar to those reported for the human cytotrophoblast. Ion channel activity was recorded in the cell attached and inside-out configurations with standard patch-clamp technology. In most of the BeWo cells studied, the channel under symmetrical N-methyl-d-glucamine (NMDG-Cl) concentration (Na(+) free solution) in both sides of the membrane exhibited spontaneous activity, an outwardly rectifying current/voltage relationship and single-channel conductances of 15 pS and 48 pS for inwards and outwards currents, respectively. The channel has a low permeability for gluconate with a relative permeability P(gluconate)/P(Cl) of 0.23, and a higher permeability to I(-). The open probability (Po) of the channel exhibited dependence with the applied membrane potential with greater activity at positive pulses. The channel activity was inhibited by the sulphonylurea hypoglycemic agent glibenclamide (50 MUM) or by diphenylamine-2-carboxylate (DPC, 500 MUM) added to the cytoplasmic side of the patch whereas conductances remained unchanged. The blockade with glibenclamide and DPC was independent of the applied membrane potential. All these results are characteristic of the outwardly rectifying Cl channel (ORCC) found in other types of cells. Neither Po, conductances nor reversal potential (Er) values were affected by the absence of intracellular Ca(2+), suggesting that the channel is not sensitive to Ca(2+). PMID- 20970188 TI - Cardiotoxicity of imatinib: At the heart of the problem. PMID- 20970189 TI - Combined testing for CCAAT/enhancer-binding protein alpha (CEBPA) mutations and promoter methylation in acute myeloid leukemia demonstrates shared phenotypic features. AB - Loss of function mutations in CCAAT/enhancer binding protein alpha (CEBPA) have been identified in acute myeloid leukemia (AML) and bi-allelic (double) CEBPA mutations are associated with improved prognosis in cases of cytogenetically normal-AML. In a subset of AML patients lacking CEBPA mutations, core promotor methylation of CEBPA has been described and is associated with a gene expression profile similar to the mutated cases including the expression of T cell associated genes such as CD7. However, the overall incidence and pattern of CEBPA mutations and core promoter methylation has not been thoroughly explored in a larger subset of AML with expression of CD7. Here we describe a simple and clinically deployable CEBPA promoter methylation test and the results of combined testing for CEBPA mutations and promoter methylation in 102 cases of AML, including 43 CD7+ cases. Overall, there were 5 methylated cases, 6 cases with double mutations, and 3 cases with single mutations. Significantly, 10 of 43 CD7+ cases (23%) had either methylated or double-mutated CEBPA. The CD7+ subset included all 5 methylated cases and 5 of the 6 cases with double mutations. All 3 cases with single mutations were CD7-. No case exhibited both hypermethylation and mutations. We find that promoter methylation accounts for half of those CD7+ cases with CEBPA dysregulating abnormalities. Furthermore, methylated cases and those with bi-allelic CEBPA mutations have similar phenotypic features including expression of CD7 and lack of co-incident NPM1 mutations. Our study suggests that methylation testing may be as important as mutation testing for identifying AML cases with CEBPA dysregulation and may be indicated in the routine prognostic workup of AML. PMID- 20970190 TI - No detected toxic concentrations in in situ algal growth inhibition tests--a convenient approach to aquatic ecotoxicology. AB - A newly proposed three-dimensional model for the effects of heavy metals on the growth of batch cultures of algae that allows the estimation of the no detected toxic effect concentration (NDEC) is presented. Two batch assays with exposure to copper were investigated in situ. As an endpoint in the in situ studies of ecotoxicology, the carrying capacity, a parameter of the logistic growth model, possesses higher sensitivity and reliability than the routine ecotoxicological endpoints in terms of the analysis based on the theoretical arguments and experimental results. Using the carrying capacity (B(f)) as the ecotoxicological endpoint, the NDEC from the proposed model is compared to the NOEC and EC(05) on the basis of field derived data. The results indicate that the NDEC is a promising possible alternative parameter to the NOEC. PMID- 20970191 TI - Influence of salinity and organic matter on the toxicity of Cu to a brackish water and marine clone of the red macroalga Ceramium tenuicorne. AB - Cu is a major active component in anti-fouling paints, which may reach toxic levels in areas with intense boat traffic and therefore is a metal of environmental concern. The bioavailability of metals is influenced by factors such as salinity and organic matter measured as total organic carbon (TOC). The influence of these two factors was studied, with a focus on brackish water conditions, by exposing a marine and a brackish water clone of the red macroalga Ceramium tenuicorne to Cu in different combinations of artificial seawater (salinity 5-150/00) and TOC (0-4 mg/L) in the form of fulvic acid (FA). In addition, the toxicity of Cu to both clones was compared in salinity 100/00 and 150/00. The results show that by increasing TOC from 0 to 2 and 4 mg/L, Cu was in general less toxic to both algal clones at all salinities tested (p<0.05). The effect of salinity on Cu toxicity was not as apparent, both a positive and negative effect was observed. The brackish water clone showed generally to be more sensitive to Cu in salinity 100/00 and 150/00 than the marine counterpart. In conclusion, FA reduced the Cu toxicity overall. The Cu tolerance of both strains at different salinities may reflect their origin and their adaptations to marine and brackish water. PMID- 20970192 TI - Evaluation of protective effects of fish oil against oxidative damage in rats exposed to methylmercury. AB - The present study evaluates a possible protective effect of fish oil against oxidative damage promoted by methylmercury (MeHg) in sub-chronically exposed rats. Reduced glutathione peroxidase and catalase enzyme activity and reduced glutathione levels were observed in MeHg-exposed animals compared to controls. Methylmercury exposure was also associated with DNA damage. Administration of fish oil to the methylmercury-exposed animals did not ameliorate enzyme activity or glutathione levels. On the other hand, a significant DNA protective effect (about 30%) was observed with fish oil treatment. There were no differences in the total mercury concentration in rat liver, kidney, heart or brain after MeHg administration with or without fish oil co-administration. Histopathological analyses showed a significant leukocyte infiltration in rat tissues after MeHg exposure, but this effect was significantly reduced after co-administration of fish oil. Taken together, our findings demonstrate oxidative damage even after low-level MeHg exposure and the protective effect of fish oil. This protection seems not to be related to antioxidant defenses or mercury re-distribution in rat tissues. It is probably due to the anti-inflammatory effects of fish oil. PMID- 20970193 TI - Foreword: an international symposium on therapeutic jurisprudence. PMID- 20970194 TI - Disposal practices for unused medications around the world. AB - Pharmaceuticals have been detected throughout the environment where at least in some cases, they have been shown to have a detrimental effect. Many result from improper patient disposal of unused pharmaceuticals via environmentally unfriendly routes, such as the sink, toilet or rubbish bin. This review surveys the current peer-reviewed literature on attitudes and practices to medicine disposal methods as reported by patients and the various medication disposal and destruction systems around the world. A literature search was carried out using the keywords 'medicines disposal', 'unused medicines', 'medicines wastage', and 'medication disposal' in the PubMed TM, ISI Web of Knowledge TM, Google Scholar TM, Medline TM, Scopus TM and International Pharmaceuticals Abstracts TM up to the end of May 2010. Twelve peer-reviewed articles with specified sample sizes were selected. The most popular methods for medication disposal were in the garbage, toilet or sink. Liquid medications were more likely to be rinsed down the sink, as opposed to solid tablets and capsules which were more likely deposited in the rubbish bin. Much confusion exists about the 'proper' way of medication disposal as many countries do not have standard medication disposal protocols. Furthermore, some pharmacies around the world refused to accept unused medications or discouraged the practice. Patients with knowledge about the impact of pharmaceuticals in the environment were more likely to return medications for proper disposal and destruction. It is concluded that it is of paramount importance that a formalized protocol for patient disposal and destruction of pharmaceuticals be implemented around the world. PMID- 20970195 TI - Prenatal depression effects on early development: a review. AB - This review of recent research on prenatal depression suggests that it is a strong predictor of postpartum depression and is more common than postpartum depression. Prenatal depression has been associated with excessive activity and growth delays in the fetus as well as prematurity, low birthweight, disorganized sleep and less responsiveness to stimulation in the neonate. Infants of depressed mothers have difficult temperament, and later in development attentional, emotional and behavioral problems have been noted during childhood and adolescence, as well as chronic illnesses in adulthood. Several variables have confounded the effects of prenatal depression including comorbid anxiety and anger as well as stressful life events. Potential mediating variables are low prenatal maternal dopamine and serotonin levels and elevated cortisol and norepinephrine. The associated intrauterine artery resistance may limit blood flow, oxygen and nutrients to the fetus. Some studies also suggest the heritability of developmental problems for the children of prenatally depressed mothers, including ADHD and antisocial behavior. Multivariate, longitudinal research is needed to disentangle these confounding and mediating variables. PMID- 20970196 TI - Applying comparative effectiveness research methods in bipolar disorders. AB - BACKGROUND: Randomized clinical trials [RCT] are the Gold Standard of medical evidence. However, observational comparative effectiveness research [CER] based on real-world data is receiving national attention. This paper demonstrates how observational CER can fill important gaps in clinical knowledge left behind by RCT approaches. An example of CER in bipolar disorders is presented. METHODS: Paid claims data from a large commercial insurer were used to identify episodes of drug therapy. Episodes were defined each time a patient initiated or restarted therapy using an antipsychotic, antidepressant or mood stabilizing medication. Episode definitions were based on calculations of continuous days of drug therapy using a 15 day gap definition. 105,440 episodes of drug therapy were included in the analysis. RESULTS: Most episodes were initiated using a mood stabilizing drug (40%) or an antidepressant (40%). Over 59% of all episodes were for augmentation therapy, followed by switching episodes (25%) and restart episodes (16%). Patient outcomes measured by either duration of uninterrupted therapy or one-year post treatment cost varied significantly with patient treatment history, especially episode type. The comparative effectiveness of alternative therapies was sensitive to the extent to which treatment history is taken into account. CONCLUSIONS: Observational research can evaluate patient outcomes across a wide range of clinical presentations with regard to the patient's treatment history. Treatment history is a major determinant of patient compliance and future treatment costs. Failure to account for treatment history can introduce bias into comparative effectiveness results. Observational CER research can also uncover important questions that require future research. PMID- 20970197 TI - Plasma from preeclamptic women activates endothelial cells via monocyte activation in vitro. AB - In this study we tested whether plasma from preeclamptic women contains factors that can activate endothelial cells in the presence of monocytes in vitro. Plasma from preeclamptic women (n=6), healthy pregnant women (n=6) and nonpregnant women (n=6) was incubated with mono-cultures and co-cultures of human umbilical vein endothelial cells (HUVEC) and monomac-6 monocytes. Reactive oxygen species (ROS) production and ICAM-1 expression were measured using flow cytometry. Whether scavenging of ROS by superoxide dismutase and catalase inhibited HUVEC ICAM-1 expression was also investigated. We found that in HUVEC co-cultured with monomac 6 cells but not in HUVEC cultured alone, ICAM-1 was upregulated after incubation with plasma from preeclamptic women but not plasma from non-pregnant women. Also in co-cultures, monomac-6 ICAM-1 was upregulated by plasma from preeclamptic women, while in both mono- and co-cultures monomac-6 ROS production was upregulated by plasma from pregnant and preeclamptic women, compared with plasma from non-pregnant women. Scavenging of ROS by superoxide dismutase and catalase resulted in a further upregulation of HUVEC ICAM-1 after incubation with plasma from preeclamptic women, compared with incubation without superoxide dismutase and catalase. These results show that endothelial cells in vitro are activated by plasma of preeclamptic women only if they are co-cultured with monocytes. This upregulation appeared not to be due to extracellular ROS production by monocytes or HUVEC, pointing to involvement of other mechanisms. Our data suggest that plasma of preeclamptic women activates monocytes, and that these monocytes subsequently activate endothelial cells. PMID- 20970198 TI - Attention orientation in parents exposed to the 9/11 terrorist attacks and their children. AB - While trauma affects both parents and their children, minimal research examines the role of information-processing perturbations in shaping reactions to trauma experienced by parents and, in turn, the effect this trauma has on their children. This study examines familial associations among trauma, psychopathology, and attention bias. Specifically, group differences in psychopathology and attention bias were examined in both adults and their children based on trauma exposure. In addition, the association between attention bias in parents and attention bias in their children was examined. Parents exposed to the 9/11 World Trade Center attacks and their children were recruited from the New York City Metropolitan area. Levels of trauma exposure, psychiatric symptoms, and attention bias to threat, as measured with the dot-probe task, were each assessed in 90 subjects, comprising of 45 parents and one of their children. These measures were examined in parents and their children separately; each parent and child was categorized on the presence of high or low levels of trauma exposure. Although trauma exposure did not relate to psychopathology, parents who were highly exposed to trauma showed greater attention bias towards threat than parents with low trauma exposure. However, the children of high trauma-exposed parents did not show enhanced attention bias towards threat, though threat bias in the high trauma-exposed parents did negatively correlate with threat bias in their children. This association between trauma and attention bias in parents was found four-to-five years after 9/11, suggesting that trauma has enduring influences on threat processing. Larger, prospective studies might examine relationships within families among traumatic exposures, psychopathology, and information-processing functions. PMID- 20970199 TI - Glandular kallikrein in the innate immune system of Atlantic salmon (Salmo salar). AB - Glandular Kallikrein is a serine-protease with trypsin-like activity and is able to generate bioactive peptides from inactive precursors. We have evaluated the presence of this protease in the different organs of the Atlantic salmon (Salmo salar). The results clearly indicate that GK and PRL are generated in the same pituitary cells based on a co-localization by confocal microscopy. Based on probed cross-reactivity between C. striata and C. carpio glandular anti-GK antibodies, we used a homologous antibody to detect the presence of GK in several salmon tissues. We have evaluated the GK expression in healthy and defied fish. P. salmonis and V. ordalii. The GK immunoreaction in organs such as leukocytes, gills and skin is considerably increased in defied fish compared to healthy fish. This increase was present in the cells of the excretory kidney and in the intercellular tissue, where the development of hematopoietic and lymphocytic lines in fish take place. One of the most interesting organs to study was the skin, bearing in mind that this is a primary barrier to all pathogens. The skin of the defied fish exhibited an increase in immunoreactivity for glandular kallikrein similar to the protease found in mucus. An immunoreactive tissue kallikrein-like protein was identified and partially separated by perfusion chromatography. Enzymatic activity of salmon muscle prokallikrein was determined before and after trypsin activation. Kallikrein activity was characterized with respect to their ability to cleave the chromogenic leaving group, p-nitroanilide, from the peptidyl kallikrein and trypsin substrate. These findings constitute a important contribution to reveal the role of kallikrein in the innate immune system of fish. PMID- 20970200 TI - Immunological consequences of ischemic stroke: immunosuppression and autoimmunity. AB - Stroke may be accompanied by immunological consequences including local autoimmunity and peripheral immune suppression. Since the blood brain barrier is disturbed cells of the immune system gain direct access to the brain parenchyma. Here local autoimmunity contributes to lesion formation and, in experimental stroke, inhibition of this immune response has been shown to be beneficial. More recently, however, stroke has been shown to also induce severe peripheral immune suppression which predisposes for subsequent bacterial infections that impair the clinical outcome. Here we summarize current knowledge on the immunological consequences of ischemic stroke and will discuss implications of these findings for our understanding of the immunopathogenesis of Multiple Sclerosis. PMID- 20970201 TI - NYHA class I heart failure is not 'mild'. PMID- 20970202 TI - Randomised trial of ramipril in repaired tetralogy of Fallot and pulmonary regurgitation: the APPROPRIATE study (Ace inhibitors for Potential PRevention Of the deleterious effects of Pulmonary Regurgitation In Adults with repaired TEtralogy of Fallot). AB - BACKGROUND: Optimal treatment for stable repaired tetralogy of Fallot (rTOF) patients with pulmonary regurgitation (PR) and related right ventricular (RV) dilatation, including timing of valve implantation, remains uncertain. We sought to study tolerability of the angiotensin-converting-enzyme (ACE) inhibitor ramipril and its effects on cardiovascular function in these patients. METHODS: Clinically stable rTOF patients with moderate/severe PR were included. A double blinded, placebo-controlled study of 6 months of ramipril vs placebo was performed. All patients underwent cardiovascular magnetic resonance (CMR), echocardiography, neurohormonal analysis, and objective cardiopulmonary exercise testing at baseline and follow-up. PRIMARY ENDPOINT: The main aim was to detect changes in RV function (primary endpoint CMR-derived RV ejection fraction). RESULTS: Seventy-two patients were enrolled and 64 qualified for the final analysis. There was no difference in the primary endpoint RV ejection fraction. RV long-axis shortening significantly improved in the ramipril group compared to placebo (RV: 2.3 +/- 3.8 vs 0.02 +/- 2.7 mm; P=0.017) as did LV long-axis shortening (1.9 +/- 4.5 vs -0.2 +/- 3.7 mm respectively; P=0.030). No clear differences were detected between ramipril and placebo for other measures. In a subgroup of patients with restrictive RV physiology, ramipril resulted in decrease in LV end-systolic volume index and increase in LVEF (-2.4 +/- 5.0 vs 2.7 +/- 3.6 mL/m(2); P=0.005, 2.5 +/- 5.0 vs -1.3 +/- 3.5%; P=0.03). Ramipril did not cause adverse events and was well tolerated. CONCLUSIONS: Ramipril is a well tolerated therapy, improves biventricular function in patients with rTOF and may have a particular role in patients with restrictive RV physiology. Larger, longer term studies are needed to determine if ACE inhibitors can improve both ventricular remodelling and clinical outcomes. ( ISRCTN: 97515585). PMID- 20970203 TI - A familial case of malignant early repolarization. PMID- 20970204 TI - Lipomatous metaplasia in ischemic cardiomyopathy: current knowledge and clinical perspective. PMID- 20970205 TI - Effects of exercise training on neurovascular responses during handgrip exercise in heart failure patients. PMID- 20970207 TI - In-hospital prescription of QT-prolonging drugs in a cohort of more than 100,000 patients. PMID- 20970208 TI - Co-occurrence of metabolic factors and the risk of coronary heart disease: a prospective cohort study in the Netherlands. AB - BACKGROUND: Prevalence of metabolic factors such as diabetes, hypertension, obesity, HDL and total cholesterol that are associated with an increased risk of coronary heart disease (CHD) is increasing worldwide. However, less is known about combinations of these factors that are associated with the highest CHD risk. Therefore, the associations between combinations of these metabolic factors and the incidence of CHD, acute myocardial infarction (AMI), and unstable angina pectoris (UAP) were studied in the Cardiovascular Registry Maastricht (CAREMA) cohort study. METHODS: The CAREMA study consists of 21,148 participants, born in 1927-1977 and randomly sampled from Maastricht and surrounding communities in 1987-1997. At baseline, all participants completed a self-administered questionnaire. Height, weight, blood pressure, total and HDL cholesterol levels were measured during a physical examination. After follow-up of maximally 16.9 years, 780 CHD, 437 AMI, and 286 UAP cases of first occurrence were registered. Incidence rate ratios (RRs) were estimated using Cox proportional hazards models adjusted for age, sex, smoking, and alcohol consumption. RESULTS: Compared with subjects without any of the metabolic factors, the RRs of CHD were 2.37, 4.34, and 7.36 for subjects with 1, 2, or >= 3 metabolic factors, respectively. These RRs were higher for AMI but lower for UAP. Especially combinations of metabolic factors that included diabetes or both a low HDL (<= 0.9 mmol/L in men; <= 1.0 mmol/L in women) and high total cholesterol (>= 6.21 mmol/L) were associated with increased risks. CONCLUSION: The risk of total CHD, AMI, and UAP varies considerably between different combinations of metabolic factors. PMID- 20970209 TI - Prevalence and risk factors for Salmonella spp. contamination in French broiler chicken flocks at the end of the rearing period. AB - A nation-wide survey was carried out in 370 randomly chosen French commercial broiler chicken flocks from October 2005 to September 2006 to determine Salmonella spp. prevalence and to identify risk factors for contamination, at the end of the rearing period. The Salmonella status of the flocks was assessed from five faecal samples (litter swabs) analysed by classical bacteriological methods. A flock with at least one contaminated sample was classified as a Salmonella positive flock. The apparent prevalence of Salmonella was 8.6% (95% CI: 5.7, 11.5%). The most prevalent serovar was S. hadar followed by S. anatum and S. mbandaka. Logistic regression methods were used to analyse the associations between husbandry practices, farm characteristics, general hygiene and the Salmonella status of the sample. The risk for Salmonella contamination of the flock at the end of the rearing period increased when neighbours helped in the placement of day-old chicks. On the contrary, the risk decreased when mobile equipment was dismantled before cleaning and disinfection, when the farm had a specific container for dead-bird disposal and when acetic acid was added to the drinking water. PMID- 20970210 TI - beta-Lactam and glycopeptide antibiotics: first and last line of defense? AB - Most infections are caused by bacteria, many of which are ever-evolving and resistant to nearly all available antibiotics. beta-Lactams and glycopeptides are used to combat these infections by inhibiting bacterial cell-wall synthesis. This mechanism remains an interesting target in the search for new antibiotics in light of failed genomic approaches and the limited input of major pharmaceutical companies. Several strategies have enriched the pipeline of bacterial cell-wall inhibitors; examples include combining screening strategies with lesser-explored microbial diversity, or reinventing known scaffolds based on structure-function relationships. Drugs developed using novel strategies will contribute to the arsenal in fight against the continued emergence of bacterial resistance. PMID- 20970211 TI - Tree genetic engineering and applications to sustainable forestry and biomass production. AB - Forest trees provide raw materials, help to maintain biodiversity and mitigate the effects of climate change. Certain tree species can also be used as feedstocks for bioenergy production. Achieving these goals may require the introduction or modified expression of genes to enhance biomass production in a sustainable and environmentally responsible manner. Tree genetic engineering has advanced to the point at which genes for desirable traits can now be introduced and expressed efficiently; examples include biotic and abiotic stress tolerance, improved wood properties, root formation and phytoremediation. Transgene confinement, including flowering control, may be needed to avoid ecological risks and satisfy regulatory requirements. This and stable expression are key issues that need to be resolved before transgenic trees can be used commercially. PMID- 20970212 TI - Symptoms 10-17 years after breast cancer radiotherapy data from the randomised SWEBCG91-RT trial. AB - BACKGROUND: Postoperative radiotherapy decreases the risk for local recurrence and improves overall survival in women with breast cancer. We have limited information on radiotherapy-induced symptoms 10-17 years after therapy. MATERIAL AND METHODS: Between 1991 and 1997, women with lymph node-negative breast cancer were randomised in a Swedish multi-institutional trial to breast conserving surgery with or without postoperative radiotherapy. In 2007, 10-17 years after randomisation, the group included 422 recurrence-free women. We collected data with a study-specific questionnaire on eight pre-selected symptom groups. RESULTS: For six symptom groups (oedema in breast or arm, erysipelas, heart symptoms, lung symptoms, rib fractures, and decreased shoulder mobility) we found similar occurrence in both groups. Excess occurrence after radiotherapy was observed for pain in the breast or in the skin, reported to occur "occasionally" by 38.1% of survivors having undergone radiotherapy and surgery versus 24.0% of those with surgery alone (absolute difference 14.1%; p=0.004) and at least once a week by 10.3% of the radiotherapy group versus 1.7% (absolute difference 8.6%; p=0.001). Daily life and analgesic use did not differ between the groups. CONCLUSIONS: Ten to 17 years after postoperative radiotherapy 1 in 12 women had weekly pain that could be attributed to radiotherapy. The symptoms did not significantly affect daily life and thus the reduced risk for local recurrence seems to outweigh the risk for long-term symptoms for most women. PMID- 20970213 TI - The importance of haemoglobin level and effect of transfusion in HNSCC patients treated with radiotherapy--results from the randomized DAHANCA 5 study. AB - BACKGROUND AND PURPOSE: Patients with head and neck squamous cell carcinoma (HNSCC) and a low level of haemoglobin (Hb) often have a poor response to radiation which may be related to hypoxia induced radioresistance. The aim of the study was to evaluate the prognostic significance of low Hb level and its modification by transfusion in HNSCC patients treated with radiotherapy. The study was performed as a subrandomization in the DAHANCA 5 trial. MATERIAL AND METHODS: Patients were randomized to treatment with the hypoxic radiosensitizer nimorazole or placebo, and in addition, patients with "low" pre-irradiation Hb values (females<13 g/dL; males<14.5 g/dL) were subrandomized to plus or minus transfusion. Transfusion was given with packed red blood cells with the aim to achieve a Hb level in the "high" value range. RESULTS: A total of 414 patients were included, 243 patients had high Hb levels and 171 patients had low Hb levels. Of the low Hb patients, 82 were randomized to receive transfusion and 89 not to receive transfusion. The treatment arms were well balanced. In the majority of patients, transfusion resulted in increased Hb levels although this tended to decline throughout treatment. Patients with high Hb levels had a significantly better probability of locoregional control, disease-specific survival and overall survival compared to 'low Hb no transfusion' patients. In the low Hb group, transfusion did not improve the outcome in locoregional control, disease-specific survival or overall survival. In multivariate analyses, T and N classifications were significant for all outcome measures, whereas there was no significant influence of transfusion or Hb level on endpoints. CONCLUSION: The univariate prognostic significance of high Hb level was demonstrated in patients with HNSCC treated with radiotherapy; however, transfusion prior to and during treatment did not improve the outcome in patients with low Hb values. PMID- 20970214 TI - Why avoid the hippocampus? A comprehensive review. AB - In this review article, we provide a detailed and comprehensive discussion of the rationale for using modern IMRT techniques to spare the subgranular zone of the hippocampus during cranial irradiation. We review the literature on neurocognitive effects of cranial irradiation; discuss clinical and preclinical data associating damage to neural progrenitor cells located in subgranular zone of the hippocampus with radiation-induced neurocognitive decline, specifically in terms of short-term memory formation and recall; and present a review of our pilot investigations into the feasibility and risks of sparing the subgranular zone of the hippocampus during whole-brain radiotherapy for brain metastases. We also introduce our phase II cooperative group clinical trial (RTOG 0933) designed to prospectively evaluate the postulated neurocognitive benefit of hippocampal subgranular zone sparing and scheduled to open in 2010. PMID- 20970215 TI - Rotational radiotherapy for prostate cancer in clinical practice. AB - BACKGROUND AND PURPOSE: Radiotherapy is the standard treatment in locally advanced prostate cancer. The latest technological improvement is modulated rotational radiotherapy, where one single rotation of the treatment machine is used to conform the dose delivery to the target and spare organs at risk, requiring less than 2 min of beam-on time per treatment fraction. MATERIALS AND METHODS: We report herein our experience from the first 46 patients treated for prostate cancer, clinical stage T1-3 with rotational therapy ("RapidArc(r)", Varian Medical systems) (RA). This patient group is compared to a group of 50 patients treated with a 5-field Intensity Modulated Radiation Therapy (IMRT) technique over the same period. The comparison parameters include target coverage, dose to OAR, treatment time and number of monitor units. Daily-IGRT using implanted gold markers is used before and after treatment to investigate intra-fractional prostate displacement. RESULTS: RA results in improved sparing of the rectum and achieves desired dose distributions with fewer monitor units and a shorter treatment time (<1.5 min versus up to 8.9 min with IMRT). This shorter treatment time also translates in a decreased risk of patient motion during treatment: daily-IGRT demonstrates reduced prostate motion (<3mm 3D vector) from 16.7% to 4.7% in RA patients. Only slight side-effects were seen in the two groups of patients. CONCLUSIONS: RA results in improved sparing of the rectum, however, at the expense of an increase in dose to the femoral heads in prostate patients. The treatment time is significantly reduced from 4.9 min on average with 5-field IMRT to 1.1 min with RA, which allows for a reduction of infractional prostate motion. PMID- 20970216 TI - Osteopontin expression predicts overall survival after liver transplantation for hepatocellular carcinoma in patients beyond the Milan criteria. AB - BACKGROUND & AIMS: Microarray data showed that osteopontin overexpression predicts early HCC-recurrence after liver resection. Osteopontin (OPN) expression could serve as a predictor of HCC-recurrence after OLT. METHODS: Osteopontin expression was investigated immunohistochemically in a unique population of 125 HCC-patients undergoing OLT between 1982 and 2002, including 81 patients (65%) outside the Milan criteria. Multivariate analysis of factors associated with median overall survival (OS) and time to recurrence (TTR) was performed. RESULTS: Osteopontin was expressed in 40/125 (32%) of the HCCs. Overall survival post-OLT at 1, 2, 3, 5 years was 77%, 62%, 52%, and 43% (median survival 37 months). Overall survival was significantly longer without expression of OPN (p < 0.05; (median OS: 56 vs. 23 months). The same was true for median TTR (p = 0.008). Outside Milan criteria, patients without OPN-expression had better prognosis (median OS: 37.8 vs. 19.2 months, p = 0.003). Tumor recurrence in patients transplanted outside Milan criteria occurred in 43% (23 of 54) of patients without and 70% (19 of 27, p = 0.018) of patients with OPN-expression after a median TTR of 83.5 vs. 13.9 months. On multivariate analysis, vascular invasion and OPN-expression were independently associated with OS and TTR in HCC-patients after OLT. CONCLUSIONS: Immunohistochemically detectable Osteopontin in HCC is an independent predictor of tumor recurrence and survival in patients beyond Milan criteria undergoing OLT. PMID- 20970217 TI - Hepatitis E: water, water everywhere - now a global disease. PMID- 20970218 TI - Glycosaminoglycans inhibit the adherence and the spreading of osteoclasts and their precursors: role in osteoclastogenesis and bone resorption. AB - The bone microenvironment (e.g. glycosaminoglycans (GAGs), growth factors) plays a major role in bone resorption, especially in the formation of osteoclasts which differentiate from the hematopoietic lineage in the presence of RANKL. Previous studies revealed that GAGs may influence osteoclastogenesis, but data are very controversial, some studies showing an inhibitory effect of GAGs on osteoclastic differentiation whereas others demonstrated a stimulatory effect. To clarify their activities, we investigated the effect of 5 families of GAGs in three different models of human/mouse osteoclastogenesis. The present data revealed that heparin inhibited osteoclastogenesis in these three models, which was confirmed by a decrease in mRNA expression of osteoclastic markers and by an inhibition of the bone resorption capacity. We also demonstrated in RAW 264.7 cells that other families of GAGs different from heparin inhibited RANKL-induced osteoclastogenesis, and that this inhibition was dependent on the length and the level of sulfation of GAGs. In the present work, heparin did not bind to RANKL and did not modulate RANKL signaling. Heparin acted at 2 distinct steps of osteoclastogenesis from human CD14(+) cells: first, heparin strongly decreased the adherence of osteoclast precursors, and secondly inhibited osteoclasts to spread and to be active. Furthermore, the second action of heparin was reversible as the removal of heparin at the end of the culture time allowed the condensed cells to spread out and showed the formation of morphological active osteoclasts. The present work clearly evidences that GAGs inhibit osteoclastogenesis in vitro and strengthens the therapeutic interest of defined GAGs in osteolytic diseases. PMID- 20970219 TI - [Public health and the health system. SESPAS Report 2010]. AB - Analysis of the relationship between public health and the health system requires definition of a conceptual framework and the choice of a particular context. The chosen context of this discussion is the management of public organizations. With this in mind, functions will be associated with organizational macroprocesses. From this point of view, this article identifies the functions-processes that any health system should develop and their goals. The current situation of public health in the health system is analyzed through the study of public health budgets and the place they occupy in the hierarchy of the health departments of the autonomous communities. The "public health" budget program represents an average of 1.34% of health expenditure in the autonomous communities in 2010. Over 20% of public health organizations of the autonomous communities have a rank lower than general directorate. These data indicate the low weight assigned to public health in the health systems of the Spanish state. To change this situation, consensus must be reached on the desired relationship between public health and the health system. Such a consensus would then have to be accepted and work would have to be undertaken to improve results. Three alternatives are proposed: (i) public health would be an organization that would be above or outside the health system; (ii) public health would be synonymous with the public health system; and (iii) public health would form part of the health system with a range of assigned functions. Finally, we provide some recommendations to help define the most effective and efficient relationship between public health and the health system. PMID- 20970220 TI - [Influence of substitution of brand name for generic drugs on therapeutic compliance in hypertension and dyslipidemia]. AB - OBJECTIVE: To determine therapeutic compliance when brand name amlodipine and simvastatin are substituted for generic drugs, and to determine patients' and physicians' opinions of this substitution. PATIENTS AND METHODS: We performed an observational study with a control group, based on a review of the medical records in six primary care centers. Participants consisted of patients >= 40 years old initiating treatment with a brand name drug (initial period), which was later substituted by a generic drug (final period). The study subgroups consisted of patients with hypertension (amlodipine) or dyslipidemia (simvastatin). The main measures were comorbidity, compliance, treatment length, biochemistry determinations, and patients' and physicians' opinions (interviews). All patients received a brand name drug for a minimum of 1 year followed by a generic drug for a minimum of 1 year (minimum continuation/patient: 24 months). RESULTS: There were 1,252 patients (groups: 49.5% amlodipine; 50.5% simvastatin). Patients treated with amlodipine (period comparison) showed better compliance (65.8 vs. 61.3%; p=0.037) and blood pressure control (48.5 vs. 45.8%; p=0.039) with the brand name drug. The percentages with simvastatin were 62.8 vs. 58.4% (p=0.041), respectively. A total of 73.6% of the physicians interviewed prescribed generic drugs and 59.2% believed that both types of drug had the same efficacy. Most of the patients interviewed (79.8%; CI: 74.3-85.3%) accepted the substitution; 55.3% (CI: 48.5-62.1%) received the appropriate information but 61.5% were confused by the different products. Lack of compliance was reported by 18.2%. CONCLUSIONS: In patients receiving amlodipine or simvastatin, compliance decreased with time, independently of the change from a band name to a generic drug. PMID- 20970221 TI - 2-Hydroxypropyl-beta-cyclodextrin strongly improves water solubility and anti proliferative activity of pyrazolo[3,4-d]pyrimidines Src-Abl dual inhibitors. AB - The main aim of this study was to enhance the solubility of pyrazolo[3,4 d]pyrimidines 1-8 able to strongly inhibit Src and Abl tyrosine kinase phosphorylation in cell-free assays and to significantly reduce leukemic and osteosarcoma cell lines growth, but characterized by very low solubility in aqueous media. Their water solubility was improved between 100 and 1000 folds by solubilization with 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and ratio of inclusion complex were determined by phase solubility method. Finally, some complexed compounds were tested on different leukemic (K-652, KU-812 and HL-60) and osteosarcoma (SaOS-2) cell lines showing a good enhancement of biological response in comparison with the not complexed compounds. PMID- 20970222 TI - Synthesis and optimization of antitubercular activities in a series of 4 (aryloxy)phenyl cyclopropyl methanols. AB - A series of [4-(aryloxy)phenyl]cyclopropyl methanones were synthesized by reaction of different benzyl alcohols with 4-chloro-4'-fluorobutyrophenone in DMF in the presence of NaH/TBAB. The methanones were further reduced to respective methanols. The antitubercular activity of these compounds was evaluated in vitro against Mycobacterium tuberculosis H37Rv. Compounds 19, 21, 35, 36 and 37 have shown minimum inhibitory concentration (MIC) of 3.12 MUg/mL, while compounds 14, 25 and 18 have shown MIC of 1.56 MUg/mL and 0.78 MUg/mL respectively. One of the compounds, cyclopropyl-4-[4-(2-piperidin-1-yl-ethoxy)benzyloxy]phenyl}methanol (36) showed 98% killing of intracellular bacilli in mouse bone marrow derived macrophages and was active against MDR, XDR and rifampicin clinical isolates resistant strains with MIC 12.5 MUg/mL. Compound 36 was orally active in vivo in mice against M. tuberculosis H37Rv with an increase in MST by 6 days with 1 log reduction in the bacillary density in lungs as compared to control on 30th day after infection. PMID- 20970223 TI - Synthesis and biological evaluation of some thiazolylpyrazole derivatives as dual anti-inflammatory antimicrobial agents. AB - The synthesis of a novel series of 4-thiazolylpyrazolyl derivatives is described in the present report. All the newly synthesized compounds were examined for their anti-inflammatory activity using cotton pellet-induced granuloma and carrageenan-induced rat paw edema bioassays. Their inhibitory activities of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), ulcerogenic effect and acute toxicity were also determined. Furthermore, all compounds were evaluated for their in vitro antimicrobial activity against Escherichia coli, Staphylococcus aureus and Candida albicans. A docking pose for compounds 8b, 10a and 10b separately in the active site of the human COX-2 enzyme and DNA-gyrase B was also obtained. The results revealed that compounds 8b, 10a and 10b exhibited good anti-inflammatory activity with no or minimal ulcerogenic effect and good safety margin. Compounds 10a and 10b were found to be the most potent anti inflammatory agents in the present study. Meanwhile, 10a and 10b displayed higher selective inhibitory activity towards COX-2 compared to indomethacin. Moreover, compounds 10a and 10b exhibited promising antibacterial against both E. coli and S. aureus. Docking studies for 8b, 10a and 10b with COX-2 (PDB ID: 1CX2) and DNA gyrase B (PDB ID: 1EI1) showed good binding profile. PMID- 20970224 TI - [An opinion survey about medical autopsy, Saint-Etienne University Hospital: are the French laws of bioethics to be revised?]. AB - PURPOSE: The aim of the medical autopsy is to define the causes of a patient's death. Although its rate has dramatically decreased, the post-mortem examination remains one of the basic tools for the assessment of medical care. The objective of this study was to identify the factors influencing the acceptance of medical autopsies. METHODS: A prospective survey was performed using questionnaire that was administered to patients and health care professionals of the Saint-Etienne university hospital. The survey consisted in several questions relating to the autopsy practice (on one's own body) and the knowledge of the procedure. RESULTS: The population surveyed consisted of 186 individuals and 112 health care professionals, including physicians, residents and nurses. The results of the study overall showed a good acceptance of autopsy. Actually, 86% of the individauls and 94.6% of health professionals would not be opposed to their own autopsy (in order to identify the cause of the death, to help relatives bereavement, to foster medical research). The main reasons of medical autopsy opposition include religion belief, body integrity, dignity and respect. Only 42.5% of patients had previously received some information about autopsies, while 33.9% of health care professionals had received a specific formation. CONCLUSION: The rate of refusal of medical autopsy was low in this survey but information relative to this procedure remains insufficient. The current law imposes to look after a nonopposition to medical autopsy of the died individual, including asking his/her relatives that markedly limit the organ donation. Modification of the French bioethical law should be beneficial to increase both medical autopsy organ donation rates. PMID- 20970225 TI - [Azathioprine-associated severe myelosuppression: indication of routine determination of thiopurine S-methyltransferase variant?]. AB - INTRODUCTION: Myelotoxicity is a well-known adverse effect of azathioprine, leading mainly to leukopenia. Other azathioprine associated hematological adverse effects are uncommon. CASE REPORT: We report a 49-year-old woman with rheumatoid arthritis and acquired hemophilia, who presented a severe myelosuppression occurring 3 weeks after an increase of her azathioprine regimen (at a daily dose of 150 mg). The patient had a heterozygous mutation of the thiopurine S methyltransferase gene (TPMT*3A). Azathioprine therapy was discontinued and she recovered at 3 weeks. The patient had no relapse of pancytopenia after a 1 year follow-up. CONCLUSION: Routine measurement of TPMT activity or determination of TPMT variant allele may be useful tests, in order to identify the subgroup of patients who are at risk to develop azathioprine induced severe myelosuppression. PMID- 20970226 TI - [Sarcoid uveitis: Diagnostic and therapeutic update]. AB - Uveitis is a common (20-50%) and early manifestation of sarcoidosis. Typical sarcoid uveitis presents with bilateral mutton fat keratic precipitates, iris nodules, and anterior and posterior synechia. Posterior involvement includes vitreitis, vasculitis and choroidal lesions. Long-term complications are common, and cystoid macular edema is the most important and sight-threatening consequence. Diagnostic work-up of sarcoidosis usually includes chest radiography or computed tomography scan, bronchoscopy with bronchoalveolar lavage, angiotensin converting enzyme, lysozyme, gallium scintigraphy and biopsy. The gold standard for the diagnosis of sarcoidosis should be obtained with histologic examination. However, an international workshop has recently established diagnostic criteria of "intraocular sarcoidosis" (sarcoidosis uveitis) on the basis of a combination of suggestive ophthalmological findings and laboratory tests, when biopsy is not performed or is negative. More recent techniques such as PET-scan and endoscopic ultrasound-guided fine-needle biopsy of intrathoracic nodes should be assessed in future prospective studies. Corticosteroids are the mainstay of treatment. Anterior and unilateral intermediate or posterior uveitis are usually treated with topical corticosteroids. Systemic corticosteroids are indicated in uveitis not responding to topical corticosteroids or in the presence of bilateral posterior involvement, especially with macular edema and occlusive vasculitis. In 5 to 20% of the patients who are corticosteroids resistant or require an unacceptable dose to maintain remission, additional immunosuppression is used, including methotrexate, leflunomide and mycophenolate mofetil. As in systemic sarcoidosis, infliximab has been recently suggested for refractory or sight threatening disease. PMID- 20970227 TI - Efficacy of reconstruction of alveolar bone using an alloplastic hydroxyapatite tricalcium phosphate graft under biodegradable chambers. AB - Our aim was to test the efficacy of a synthetic alloplastic graft under biodegradable chambers to reconstruct a horizontal bony deficiency as an alternative to autogenous, allogeneic, or xenogenic grafts. We used 11 New Zealand white rabbits. On each rabbit's mandible one test sample (grafted chamber) was placed on the (right or left) body, while its control sample (empty (E) chamber) was placed on the other side. Twelve weeks postoperatively the animals were sacrificed and the samples extracted for gross assessment, micro computed tomographic imaging, and histological and histomorphometric analyses. There was significantly more new bone with a greater surface area in the test group than in the control group, and the alloplastic graft was osteoconductive when used as an onlay graft under a synthetic biodegradable chamber. Synthetic products can be efficient alternatives to autogenic, allogeneic, or xenogenic grafts. PMID- 20970228 TI - Pathogenesis of post-traumatic ankylosis of the temporomandibular joint: a critical review. AB - Many factors have been implicated in the development of bony ankylosis following trauma to the temporomandibular joint (TMJ) or ankylosis that recurs after surgical treatment for the condition. Although many reports have been published, to our knowledge very little has been written about the pathogenesis of the process and there are few scientific studies. Over the last 70 years various treatments have been described. Different methods have been used with perceived favourable outcomes although recurrence remains a problem in many cases, and ankylosis presents a major therapeutic challenge. We present a critical review of published papers and discuss the various hypotheses regarding the pathogenesis of the condition. PMID- 20970229 TI - Disturbance and recovery of trunk stiffness and reflexive muscle responses following prolonged trunk flexion: influences of flexion angle and duration. AB - BACKGROUND: Experimental studies suggest that flexed working postures reduce passive support of the spine, which could represent a significant risk factor for the development of occupational low back disorders. Neuromuscular compensations to reduced passive stiffness include increases in baseline activity or reflexive activation of trunk muscles. Yet, alterations and recovery of the synergy between active and passive tissues following prolonged flexion in humans are currently unknown. METHODS: Twelve healthy participants were exposed to all combinations of two trunk flexion durations (2 and 16 min) and three flexion angles (33, 66, and 100% of individual flexion-relaxation angle). Load relaxation was recorded throughout exposures, whereas trunk stiffness and reflexive behaviors of the lumbar extensor muscles were investigated during dynamic responses to sudden perturbations. FINDINGS: The magnitude of load relaxation increased with increasing flexion angle. Trunk stiffness decreased and reflex gains increased following flexion exposures; for both outcomes, acute changes were larger following exposure to increasing flexion angle. Reflex gains remained elevated one hour after exposure to maximum flexion. INTERPRETATION: Exposure to prolonged trunk flexion changed trunk stiffness and reflex behavior in patterns consistent with epidemiological evidence linking such exposure with the risk of occupational low back disorders. Observed increases in reflex gains, at least among healthy individuals, may be a compensation for decreases in passive trunk stiffness following acute exposure to flexed postures. It remains to be determined whether the neuromuscular system can similarly respond to accumulated disturbances in passive structures following exposure to repeated flexion tasks. PMID- 20970230 TI - Changes in viscoelastic properties of skeletal muscles induced by subthalamic stimulation in patients with Parkinson's disease. AB - BACKGROUND: Objective measurements would be useful to document the effect of deep brain stimulation in alleviating rigidity in patients with Parkinson's disease. The aim of the study was to examine the changes of viscoelastic properties in skeletal muscles as indicators of rigidity. METHODS: Six patients in an advanced stage of Parkinson's disease participated in the study. The study took place in the off-medication conditions after one night of drug withdrawal. The wrist rigidity was examined according to the Unified Parkinson's Disease Rating Scale in both sides. Myotonometry (Myoton) was used to determine stiffness and elasticity in extensor digitorum muscles bilaterally. The measurements were repeated and compared during the stimulation-on and stimulation-off periods. FINDINGS: A comparison of mean clinical motor scores revealed a significant improvement of parkinsonian symptoms due to brain stimulation. In particular, arm rigidity improved on average from 2.83 (1-4) in stimulation-off phase to 1.17 (0 2) in stimulation-on phase (P<0.05). The mean values of elasticity and stiffness were not significantly different in stimulation-on and stimulation-off conditions. The patients with elevated clinical rigidity scores had higher mean values of stiffness (262.5 vs 211.0; P<0.05) but the differences in elasticity were not significant. INTERPRETATION: Increased rigidity is associated with increased values of viscoelastic stiffness. This paper supports the use of myotonometry for objective quantification of rigidity and in the future, this tool could prove helpful for optimizing deep brain stimulation settings in patients with Parkinson's disease. PMID- 20970231 TI - Enhanced multi-metal extraction with EDDS of deficient and excess dosages under the influence of dissolved and soil organic matter. AB - This study investigated the influence of dissolved and soil organic matter on metal extraction from an artificially contaminated soil. With high concentration of DOM, the extraction of Cu, Zn and Pb was enhanced by forming additional metal EDDS complexes under EDDS deficiency. However, the enhancement of metal extraction under EDDS excess was probably due to the soil structure being disrupted owing to humic acid enhanced Al and Fe dissolution, which induced more metals dissolving from the soils. Fulvic acid was found to enhance metal extraction to a greater extent compared with humic acid because of its high content of the carboxylic functional group. Cu extraction from the soil with high organic matter content using EDDS was the lowest due to the high binding affinity of Cu to SOM, whereas Zn extraction became the highest because of a preference for EDDS to extract Zn due to the high stability constant of ZnEDDS. PMID- 20970232 TI - Impacts of a support intervention for low-income women who smoke. AB - The objective of this pilot study was to implement and evaluate the impact of a support intervention tailored to the assessed support needs, resources and preferences of low-income women who smoke in three Canadian cities. The support intervention, informed by theoretical foundations, provided holistic one-to-one and group support over 14 weeks. The support intervention was facilitated by trained professional and peer facilitators. The impact was evaluated through analysis of qualitative and quantitative data collected at pre-, post-, and delayed post-test contacts. This analysis revealed that the intervention exerted positive impacts on smoking reduction/cessation, social networks, coping, and health behaviors. Participants reported satisfaction with the intervention. PMID- 20970233 TI - An RCT study to evaluate a targeted, theory driven healthy eating leaflet. AB - A theory based healthy eating leaflet was evaluated against an existing publicly available standard leaflet. The intervention leaflet was designed to encourage healthy eating in 18-30 year olds and was developed by modifying an existing British Nutrition Foundation leaflet. The intervention leaflet targeted attitudes and self-efficacy. Participants (n = 104) were randomly assigned either to the intervention, Foundation or a local food leaflet control condition. Cognitions were measured pre-intervention, immediately after reading the corresponding leaflet, and once again at two weeks follow-up. Critically, intentions to eat healthily were significantly greater at follow-up in the Intervention group compared to the other two groups, with the former leaflet also being perceived as more persuasive. The Intervention group also showed evidence of healthier eating at two weeks compared to the other two groups. Collectively the results illustrate the utility of a targeted theory-based approach. PMID- 20970234 TI - [Non-invasive functional evaluation of the reserve in fatigue and the diaphragm structure using transthoracic echography in B and M modes]. AB - The diaphragm is the principal respiratory muscle. Its special characteristics have made it difficult to design instruments capable of performing a non-invasive evaluation of its structure and function in humans. The present study was designed to evaluate the potential use of echography as a non-invasive method to fulfil these objectives. METHODS: The study consisted of three phases: (1) echographic study in autopsy samples (n=10) of a segment of the thoracic abdominal wall, from the bottom to the parietal peritoneum (i.e., thoracic wall, diaphragm, pleura and peritoneum structures), (2) static echographic study of the previous structures and the diaphragm in healthy subjects (n=10) to standardised lung volumes; and (3) dynamic echographic study of the contraction-relaxation of the diaphragm in the same subjects, calculating its maximum velocity of relaxation (MVrdi, mm/sec) during a specific inspiratory resistance test. RESULTS: The echography enabled the pleural and peritoneal limits of the diaphragm to be identified, and quantitate its thickness (Tdi), both ex-vivo and in-vivo, in all cases. The dynamic study of the Tdi showed a linear increase directly associated with the lung volume measurement, as well as a cyclical increase during inspiratory movements at rest. In the resistance test, the MVrdi was maximal with low loads and gradually decrease until reaching a minimum nadir (Delta~-70% of the initial value) in claudication (fatigue). The MVrdi has a high precision in diagnosing claudication. CONCLUSIONS: Transthoracic echography of the diaphragm is a non-invasive method that gives promising results in the structural and functional evaluation (i.e. fatigue risk) of that muscle. These findings are of pathophysiological interest and could be of use in the clinical care context. PMID- 20970235 TI - [Bronchial hyperresponsiveness to methacholine in children under 4 years with recurrent bronchitis]. AB - OBJECTIVE: To evaluate bronchial hyperresponsiveness in children under 4 years of age with recurrent wheezing bronchitis, and to determine if its presence or absence can predict the subsequent progression to a transient or persistent wheezing bronchitis phenotype. POPULATION AND METHODS: A bronchial challenge test was performed with methacholine using a modified tidal volume method, without sedation in a group of patients from 8 to 47 months of age with recurrent wheezing bronchitis and a control group of healthy children. A decrease in oxygen saturation of >= 5% or an increase in respiration rate of >50% [PCwheeze (PCw)] was considered a positive response. The patients were subsequently clinically followed up to assess their progress. RESULTS: A total of 63 patients and 16 controls were studied (mean age 23.9 vs. 25.2 months). The PCw was lower than the control group (<= 4 mg/ml) in 43 (68%) children from the bronchitis group (P<0.001). No significant adverse effects were observed on performing the test. After a mean follow up of 28.5 months, completed in 49 of the patients, no differences were seen between the presence of bronchial hyperresponsiveness at the beginning of the study and the subsequent progression to transient, infrequent and frequent wheezing (P=0.63). CONCLUSIONS: A high percentage of children under 4 years of age affected by wheezing bronchitis had a bronchial hyperresponse. The subsequent progression to transient or persistent wheezing bronchitis phenotype is not associated with bronchial hyperresponsiveness. PMID- 20970236 TI - [Flu and other acute respiratory infections in the working population. the impact of influenza A (H1N1) epidemic]. AB - INTRODUCTION: This study aims to asses the impact of influenza and other acute respiratory infectious diseases (ARI) on the Catalan working population between January 2007 and December 2009, including the period of the influenza virus A (H1N1) pandemic in our region. METHODS: All certified sickness absence episodes (sick-leave) due to influenza and other ARI amongst the working population of Catalonia, Spain, were analyzed from January 2007 to December 2009. Monthly and weekly incidence was calculated, as well as an influenza sick-leave threshold, in order to identify the epidemic season in the working population. RESULTS: Registered annual sick-leave incidence for influenza-like illnesses (ILI) per 100,000 workers was 1,260.6 in 2007, 915.2 in 2008 and 2,377.2 in 2009. Epidemic curves show monthly peaks in January-February each year, plus a second peak in November 2009 corresponding to the influenza virus A (H1N1) pandemic in our region. In 2009 sick-leave incidence for ILI and other ARI was higher in workers from the Health-Social Services sector than in the other workers (p<0.001). CONCLUSION: This study contributes to the knowledge on the impact of influenza and other ARI on the general workforce, during a period of time including the outbreak of influenza virus A (H1N1). PMID- 20970237 TI - [Study of prevalence and attitudes on smoking in patients on continuous home oxygen therapy. Toma study]. AB - INTRODUCTION: The objective of this study is to analyse the prevalence, attitudes and characteristics of smoking in the population of patients subjected to Long Term Domiciliary Oxygen Therapy (LTDOT) in the Community of Madrid. PATIENT AND METHODS: A representative sample of 845 subjects (of which 461 (46%) were male) was obtained from a total of 11,174 who fulfilled the inclusion criteria. The mean age was 78.25 years (95% Confidence Interval (CI): 77.55-78.95; SD=10.36). A descriptive cross-sectional study was conducted based on questionnaires as well as cooximetry. RESULTS: Forty-eight subjects (5.7%; 95%CI: 4.3%-7.5%) were smokers and 438 (51.8%; 95%CI: 48.5%-55.2%) were ex-smokers. The percentage of active smokers was higher in the 60 years or less subject group (chi(2); P<0.001). The large majority (75%) of smokers were men, their proportion being significantly higher than that of current non-smokers (chi(2); P<0.003). The mean score in the Fagerstrom Test was 3.6. More than 65% of smokers had their first cigarette up to 30 min from getting up in the morning, and 45% of these were in a preparation phase. Seventeen percent of these subjects said that they had not received advice on quitting smoking. CONCLUSIONS: There is a high rate of smoking in patients on LTDOT, with a higher probability of males and younger subjects continuing to smoke. There is a high level of physical dependency for nicotine. PMID- 20970238 TI - Medical audit using the Ten Group Classification System and its impact on the cesarean section rate. AB - OBJECTIVE: The aim of this study is to implement the Ten Group Classification System (TGCS) and evaluate whether the introduction of the medical audit cycle reduces the cesarean section (CS) rate without increasing maternal-fetal risk. STUDY DESIGN: A prospective cohort study was performed including all women who gave birth during 21 months. The study was subdivided into three consecutive periods: (1) implementation of the TGCS identifying the major CS rate contributor groups (three months), (2) audit and report changes in the CS rates to the medical and midwifery staff according to the TGCS (6 months) and (3) discontinue interventions but continue auditing the CS rates (6 months). RESULTS: The first period CS rate of 36.8% was reduced to 26.5% after the introduction of interventions in the second period (RR 0.71 IC 0.63-0.81). After the intervention was stopped, the CS rate increased again to 31.8% (RR 1.19 IC 1.09-1.32). This is a decrease of 5.08% from the basal period (RR 0.86 IC 0.76-0.97). The asphyxia rate remained unchanged for the periods studied. CONCLUSION: Auditing through the TGCS and feedback is an effective, safe, and easy-to-implement strategy to reduce the CS rate. Its diffusion would allow reduction of the CS rates in countries as ours, and by means of the TGCS, figures can be compared within individual entities and others. PMID- 20970239 TI - Effects of pentanol isomers on the phase behavior of phospholipid bilayer membranes. AB - Differential scanning calorimetry (DSC) was used to analyze the thermotropic phase behavior of dipalmitoylphosphatidylcholine (DPPC) bilayers in the presence of pentanol isomers. The concentration of each pentanol isomer needed to induce the interdigitated phase was determined by the appearance of a biphasic effect in the main transition temperatures, the onset of a hysteresis associated with the main transition from the gel-to-liquid crystalline phase, and the disappearance of the pretransition. Lower threshold concentrations were found to correlate with isomers of greater alkyl chain length while branching of the alkyl chain was found to increase biphasic behavior. The addition of a methyl group to butanol systems drastically decreased threshold concentrations. However, as demonstrated in the DPPC/neopentanol system, branching of the alkyl chain away from the -OH group lowers the threshold concentration while maintaining a biphasic effect. PMID- 20970240 TI - Optimisation of a multivalent Strep tag for protein detection. AB - The Strep tag is a peptide sequence that is able to mimic biotin's ability to bind to streptavidin. Sequences of Strep tags from 0 to 5 have been appended to the N-terminus of a model protein, the Stefin A Quadruple Mutant (SQM) peptide aptamer scaffold, and the recombinant fusion proteins expressed. The affinities of the proteins for streptavidin have been assessed as a function of the number of tags inserted using a variety of labelled and label-free bioanalytical and surface based methods (Western blots, microarray assays and surface plasmon resonance spectroscopy). The binding affinity increases with the number of tags across all assays, reaching nanomolar levels with 5 inserts, an observation assigned to a progressive increase in the probability of a binding interaction occurring. In addition a novel interfacial FRET based assay has been developed for generic Strep tag interactions, which utilises a conventional microarray scanner and bypasses the requirement for expensive lifetime imaging equipment. By labelling both the tagged StrepX-SQM(2) and streptavidin targets, the conjugate is primed for label-free FRET based displacement assays. PMID- 20970241 TI - Evidence of lipid peroxidation and protein phosphorylation in cells upon oxidative stress photo-generated by fullerols. AB - An oxidative stress (OS) state is characterized by the generation of Reactive Oxygen Species (ROS) in a biological system above its capacity to counterbalance them [1]. Exposure to OS induces the accumulation of intracellular ROS, which in turn causes cell damage in the form of protein, lipid, and/or DNA oxidations. Such conditions are believed to be linked to numerous diseases or simply to the ageing of tissues. However, the controlled generation of ROS via photosensitizing drugs or photosensitizers (PS) is now widely used to treat various tumors and other infections [2,3]. Here we present a method to track the chemical changes in a cell after exposure to oxidative stress. OS is induced via fullerols, a custom made water soluble derivative of fullerene (C(60)), under visible light illumination. Synchrotron-based Fourier Transform InfraRed Microspectroscopy (S FTIRM) was used to assess the chemical makeup of single cells after OS exposure. Consequently, a chemical fingerprint of oxidative stress was probed in this study through an increase in the bands linked with lipid peroxidation (carbonyl ester group at 1740 cm(-1)) and protein phosphorylation (asymmetric phosphate stretching at 1240 cm(-1)). PMID- 20970242 TI - Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a dynamic nuclear and sarcomeric protein. AB - Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a candidate gene for mediating FSHD pathophysiology, however, very little is known about the endogenous FRG1 protein. This study uses immunocytochemistry (ICC) and histology to provide insight into FRG1's role in vertebrate muscle development and address its potential involvement in FSHD pathophysiology. In cell culture, primary myoblast/myotube cultures, and mouse and human muscle sections, FRG1 showed distinct nuclear and cytoplasmic localizations and nuclear shuttling assays indicated the subcellular pools of FRG1 are linked. During myoblast differentiation, FRG1's subcellular distribution changed dramatically with FRG1 eventually associating with the matured Z-discs. This Z-disc localization was confirmed using isolated mouse myofibers and found to be maintained in adult human skeletal muscle biopsies. Thus, FRG1 is not likely involved in the initial assembly and alignment of the Z-disc but may be involved in sarcomere maintenance or signaling. Further analysis of human tissue showed FRG1 is strongly expressed in arteries, veins, and capillaries, the other prominently affected tissue in FSHD. Overall, we show that in mammalian cells, FRG1 is a dynamic nuclear and cytoplasmic protein, however in muscle, FRG1 is also a developmentally regulated sarcomeric protein suggesting FRG1 may perform a muscle-specific function. Thus, FRG1 is the only FSHD candidate protein linked to the muscle contractile machinery and may address why the musculature and vasculature are specifically susceptible in FSHD. PMID- 20970243 TI - Emergy evaluation and economic analysis of three wetland fish farming systems in Nansi Lake area, China. AB - Emergy and economic methods were used to evaluate and compare three fish production models, i.e., cage fish farming system, pond intensive fish rearing system and semi-natural extensive pond fish rearing system, in Nansi Lake area in China in the year 2007. The goal of this study was to understand the benefits and driving forces of selected fish production models from ecological and economic points of view. The study considered input structure, production efficiency, environmental impacts, economic viability and sustainability. Results show that the main difference among the three production systems was the emergy cost for fish feed associated with their feeding system, i.e., feeding on natural biomass such as plankton and grass or on commercial feedstock. As indicated by EYR, ELR and ESI, it can be clearly shown that the intensive production model with commercial feed is not a sustainable pattern. However, the point is that more environmentally sound patterns do not seem able to provide a competitive net profit in the short run. The intensive pond fish farming system had a net profit of 2.57E+03 $/ha, much higher than 1.27E+03 $/ha for cage fish farming system and slightly higher than 2.37E+03 $/ha for semi-natural fish farming system. With regard to the drivers of local farmer's decisions, the accessibility of land for the required use and investment ability determine the farmer's choice of the production model and the scale of operation, while other factors seem to have little effect. Theoretically, the development of environmentally sustainable production patterns, namely water and land conservation measures, greener feed as well as low waste systems is urgently needed, to keep production activities within the carrying capacity of ecosystems. Coupled emergy and economic analyses can provide better insight into the environmental and economic benefits of fish production systems and help solve the problems encountered during policy making. PMID- 20970244 TI - Stress proteins and cytokines are urinary biomarkers for diagnosis and staging of bladder cancer. AB - BACKGROUND: Cancer often involves inflammatory processes. We hypothesized that immune mediators in urine may serve as biomarkers for bladder cancer (BCa). OBJECTIVE: To investigate whether BCa might be marked by urinary levels of heat shock proteins (HSPs; HSP60, HSP70, or HSP90) or cytokines (interferon [IFN] gamma, tumor necrosis factor [TNF]-alpha, tumor growth factor [TGF]-beta, interleukin [IL]-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, or IL-13). DESIGN, SETTING, AND PARTICIPANTS: This was a case-control study with a discovery and validation phase. We examined urine from 106 consecutive patients: healthy controls (n=18); hematuria with no evidence of BCa (n=20); non-muscle-invasive BCa (n=50); and muscle-invasive BCa (n=18). The concentrations of HSPs and cytokines were assessed by enzyme-linked immunosorbent assay. In the validation phase, independent urine samples from 40 patients were analyzed (controls [n=19] and BCa [n=21]). MEASUREMENTS: We used the area under the curve (AUC) of a receiver operating characteristic analysis to determine the ability of HSPs and cytokines to mark BCa and applied a multivariate logistic regression to create a formula able to diagnose BCa. The formula was applied to the validation set without recalculation, and positive and negative predictive values were calculated. RESULTS AND LIMITATIONS: Urinary concentrations of IL-8, IL-10, and IL-13 were significantly elevated in BCa; IL-13 was the most prominent marker (AUC: 0.93; 95% confidence interval [CI], 0.85-0.99). The multivariate regression analysis highlighted HSP60 (odds ratio [OR]: 1.206; 95% CI, 1.041-1.397, p=0.003) and IL-13 (OR: 1.020; 95% CI: 1.007-1.033, p=0.012). The validation assay was performed using HSP60 and IL-13. The overall positive predictive value was 74% (95% CI, 64-84%); and the negative predictive value was 76% (95% CI, 66-86%). Since we examined a small number of patients, the results need to be confirmed in a larger cohort. CONCLUSIONS: These results suggest that it might be possible to develop a urinary biomarker for BCa and raise the possibility that expression of anti-inflammatory cytokines and HSPs might allow BCa to evade immune surveillance. PMID- 20970245 TI - Is tumor response important for renal carcinoma? PMID- 20970246 TI - Olfactory detection of prostate cancer by dogs sniffing urine: a step forward in early diagnosis. AB - BACKGROUND: Volatiles organic compounds (VOCs) in urine have been proposed as cancer biomarkers. OBJECTIVE: To evaluate the efficacy of prostate cancer (PCa) detection by trained dogs on human urine samples. DESIGN, SETTING, AND PARTICIPANTS: A Belgian Malinois shepherd was trained by the clicker training method (operant conditioning) to scent and recognize urine of people having PCa. All urine samples were frozen for preservation and heated to the same temperature for all tests. After a learning phase and a training period of 24 mo, the dog's ability to discriminate PCa and control urine was tested in a double-blind procedure. Urine was obtained from 66 patients referred to a urologist for elevated prostate-specific antigen or abnormal digital rectal examination. All patients underwent prostate biopsy and two groups were considered: 33 patients with cancer and 33 controls presenting negative biopsies. MEASUREMENTS: During each "run," the dog was asked to signal a cancer urine among six samples containing only one cancer urine and five randomly selected controls. Sensitivity and specificity of the test were assessed. RESULTS AND LIMITATIONS: The dog completed all the runs and correctly designated the cancer samples in 30 of 33 cases. Of the three cases wrongly classified as cancer, one patient was rebiopsied and a PCa was diagnosed. The sensitivity and specificity were both 91%. CONCLUSIONS: This study shows that dogs can be trained to detect PCa by smelling urine with a significant success rate. It suggests that PCa gives an odor signature to urine. Identification of the VOCs involved could lead to a potentially useful screening tool for PCa. PMID- 20970247 TI - H(2)O(2)-sensitized TiO(2)/SiO(2) composites with high photocatalytic activity under visible irradiation. AB - TiO(2)/SiO(2) composite photocatalysts were prepared by depositing of TiO(2) onto nano-SiO(2) particles. X-ray diffraction (XRD), transmission electron micrograph (TEM), Raman spectrometer, UV-Vis diffuse reflectance spectroscopy, Fourier transform infrared spectroscopy (FT-IR) were employed to characterize the properties of the synthesized TiO(2)/SiO(2) composites. These results indicated that the products without calcination were amorphous, and calcination could enhance the crystallinity of TiO(2). Increases in the amount of TiO(2) would decrease the dispersion in the composites. H(2)O(2)-sensitized TiO(2)/SiO(2) composite photocatalysts could absorb visible light at wavelength below 550 nm. The photocatalytic activity of as-prepared catalysts was characterized by methyl orange degradation. The results showed the uncalcined composite photocatalysts with amorphous TiO(2) exhibited higher photocatalytic activity under visible light, and the activity of catalysts with TiO(2) content over 30% decreased with increasing of TiO(2) content. Increases in the calcination temperature and TiO(2) content promote the formation of bulk TiO(2) and result in a decrease in activity. PMID- 20970248 TI - Dose-response modelling with two agents: application to the bioassay of oil and shoreline cleaning agents. AB - Single and joint effects of hydrocarbons and a shoreline cleaning agent (SCA) were studied by measuring the inhibition of the larval growth of sea urchin. Different dosage methods of hydrophobic compounds were compared. The results obtained in the evaluation of CytoSol toxicity revealed that the method of variable dilution of water accommodated fraction (WAF) led to the more conservative toxicological approach. Regarding to Libyan oil, the use of DMSO as carrier allowed us the evaluation of its potential toxicity in comparison with the limitations imposed to the use of WAF method. A reparametrised form of the Weibull equation was slightly modified to be useful for dose-response analysis. This was the basis for modelling single sigmoid responses, which were used to simulate biphasic profiles with addition of effects and to describe both the concentration addition (CA) and independent action (IA) hypotheses. In all cases, its descriptive ability was graphically and statistically satisfactory. The IA model was the best option to explain the combined experimental responses obtained. PMID- 20970249 TI - Process optimization for efficient dye removal by Aspergillus lentulus FJ172995. AB - Response surface methodology involving three variables with five level second order central composite experimental design was employed to optimize conditions for maximum dye removal by Aspergillus lentulus FJ172995. The interaction between three variables; glucose, urea and initial dye concentration was studied and modeled for two responses: dye removal and biomass production. The results indicate that urea is the main factor influencing dye removal whereas glucose plays a major role in biomass production. Also, initial dye concentration has depreciative effect on dye removal thereby suggesting that for the treatment of effluent containing higher concentrations of dye, nutrient input should be increased. A high dye removal efficiency (99.97%) and high uptake capacity (97.54 mg/g) was obtained in 24h using optimum process variables. PMID- 20970250 TI - Chronic toxicity of verapamil on juvenile rainbow trout (Oncorhynchus mykiss): effects on morphological indices, hematological parameters and antioxidant responses. AB - In this study, the toxic effects of verapamil (VRP) were studied on juvenile rainbow trout, Oncorhynchus mykiss, by chronic semi-static bioassay. Fish were exposed to sublethal concentrations of VRP (0.5, 27 and 270 MUg/L) for 0, 21 and 42 d. Multiple biomarkers were measured, including morphological indices, hematological parameters and antioxidant responses of different tissues (brain, gill, liver, muscle and intestine). Based on the results, there was no significant change in all parameters measured in fish exposed to VRP at environmental related concentration, but VRP-induced stress in fish exposed to higher concentrations reflected the significant changes of physiological and biochemical responses. Through principal component analysis and integrated biomarker response assessment, effects induced by VRP-stress in each test group were distinguished. Additionally, all parameters measured in this study displayed various dependent patterns to VRP concentrations and exposure time using two-way ANOVA statistic analysis. In short, the multiple responses in fish indicated that VRP induced physiological stress and could be used as potential biomarkers for monitoring residual VRP in aquatic environment; but molecular and genetic mechanisms of these physiological responses in fish are not clear and need to be further studied. PMID- 20970251 TI - Rhizosphere characteristics of zinc hyperaccumulator Sedum alfredii involved in zinc accumulation. AB - A hyperaccumulating ecotype (HE) and a non-hyperaccumulating ecotype (NHE) of Sedum alfredii were grown in a pot experiment to investigate the chemical characteristics of the rhizosphere. The results indicated that HE accumulated more Zn in the shoot than NHE after growing in both heavily and slightly polluted soil. The water soluble Zn and mobile Zn (extractable with 1M NH(4)NO(3)) fraction in both rhizosphere and bulk soils decreased considerably after growth of HE compared to NHE. However, the decreases in mobile fraction accounted for less than 8.5% of the total Zn uptake by HE indicating that HE was effective in mobilizing Zn from the non-mobile fractions. Zinc-induced root exudates reduced the soil pH (by 0.6-0.8 units) and increased dissolved organic carbon concentrations in the rhizosphere of HE compared to the bulk soil. The dissolved organic matter (DOM) from the rhizosphere of HE showed greater (1.7-2.5 times) extracting ability of Zn from various Zn minerals than those of NHE-DOM (P<0.05). Results from this study suggests that rhizosphere acidification and the exudation of high amounts of DOM with great metal extracting ability might be two important mechanisms by which HE S. alfredii is involved in activating metal in the rhizosphere. PMID- 20970252 TI - Hazardous waste management and weight-based indicators--the case of Haifa Metropolis. AB - The quantity control of hazardous waste in Israel relies primarily on the Environmental Services Company (ESC) reports. With limited management tools, the Ministry of Environmental Protection (MoEP) has no applicable methodology to confirm or monitor the actual amounts of hazardous waste produced by various industrial sectors. The main goal of this research was to develop a method for estimating the amounts of hazardous waste produced by various sectors. In order to achieve this goal, sector-specific indicators were tested on three hazardous waste producing sectors in the Haifa Metropolis: petroleum refineries, dry cleaners, and public hospitals. The findings reveal poor practice of hazardous waste management in the dry cleaning sector and in the public hospitals sector. Large discrepancies were found in the dry cleaning sector, between the quantities of hazardous waste reported and the corresponding indicator estimates. Furthermore, a lack of documentation on hospitals' pharmaceutical and chemical waste production volume was observed. Only in the case of petroleum refineries, the reported amount was consistent with the estimate. PMID- 20970253 TI - Hydrothermal preparation of diatomaceous earth combined with calcium silicate hydrate gels. AB - A novel composite for the removal of color in waste water was prepared by subjecting slurries consisting diatomaceous earth and slaked lime to a hydrothermal reaction at 180 degrees C. Subsequently, calcium silicate hydrate gels covered the surface of diatomaceous earth due to the reaction between the amorphous silica of diatomaceous earth and slaked lime. The formation of calcium silicate hydrate gels led to an increase in the specific surface area. The composites showed higher methylene blue adsorption capacity compared with diatomaceous earth. The improved adsorption capacity of the composites depended on the amount of the calcium silicate hydrate gels and their silicate anion chain lengths. PMID- 20970254 TI - Microbial fuel cell application in landfill leachate treatment. AB - The feasibility of using microbial fuel cells (MFCs) in landfill leachate treatment and electricity production was assessed under high levels of nitrogen concentration (6033 mg NL(-1)) and conductivity (73,588 MUS cm(-1)). An air cathode MFC was used over a period of 155 days to treat urban landfill leachate. Up to 8.5 kg COD m(-3)d(-1) of biodegradable organic matter was removed at the same time as electricity (344 m Wm(-3)) was produced. Nitrogen compounds suffered transformations in the MFC. Ammonium was oxidized to nitrite using oxygen diffused from the membrane. However, at high free ammonia concentrations (around 900 mg N-NH(3)L(-1)), the activity of nitrifier microorganisms was inhibited. Ammonium reduction was also resulted from ammonium transfer through the membrane or from ammonia loss. High salinity content benefited the MFC performance increasing power production and decreasing the internal resistance. PMID- 20970255 TI - Kinetics and equilibrium adsorption studies of dimethylamine (DMA) onto ion exchange resin. AB - The fine grained resin ZGSPC106 was used to adsorb dimethylamine (DMA) from aqueous solution in the present research. Batch experiments were performed to examine the effects of initial pH of solution and agitation time on the adsorption process. The thermodynamics and kinetics of adsorption were also analyzed. The maximum adsorption was found at natural pH of DMA solution and equilibrium could be attained within 12 min. The equilibrium adsorption data were conformed satisfactorily to the Langmuir equation. The evaluation based on Langmuir isotherm gave the maximal static saturated adsorption capacity of 138.89 mg/g at 293K. Various thermodynamic parameters such as free energy (DeltaG degrees ), enthalpy (DeltaH degrees ) and entropy (DeltaS degrees ) showed that the adsorption was spontaneous, endothermic and feasible. DMA adsorption on ZGSPC106 fitted well to the pseudo-second-order kinetic model. Furthermore, the adsorption mechanism was discussed by Fourier transform infrared spectroscopy (FT IR) analysis. PMID- 20970256 TI - Application of the powder of porous titanium carbide ceramics to a reusable adsorbent for environmental pollutants. AB - The aim of this study is to investigate the utilization of the powder of porous titanium carbide (TiC) ceramics as a novel adsorbent or a material for solid phase extraction (SPE). The adsorption and elution of inorganic and organic pollutants, Pb(II), 2,4,6-trichlorophenol (TCP), perfluorooctane sulfonate (PFOS), and perfluorooctanoic acid (PFOA), to the material were evaluated. The cartridge packed with TiC ceramics powder was used for the extraction test of pollutants. The solution containing pollutants at 1.0 MUg mL(-1) was passed through the TiC cartridge, and the substances were almost quantitatively removed. Furthermore, the pollutants retained in the cartridge were eluted with 3N HCl for Pb(II) and with methanol for organic pollutants. The recoveries of pollutants were over 80%. In addition, we used the TiC cartridge for the solid-phase extraction of water samples (500 mL each of the distilled water and the river water) by adding pollutants at determined concentrations. Every pollutant was adsorbed almost quantitatively, and eluted by 3N HCl or methanol. From these results, we concluded that the powder of porous TiC ceramics is a useful reusable adsorbent for the water cleanup and solid-phase extraction. PMID- 20970257 TI - Genotypic characterization of Toxoplasma gondii in sheep from Brazilian slaughterhouses: new atypical genotypes and the clonal type II strain identified. AB - Toxoplasma gondii strains are genetically diverse in South America. To date, hundreds of T. gondii isolates from different animal hosts were genotyped in Brazil, most of them are different from those identified around the world. This study aimed to determine T. gondii infection rate in sheep from Brazilian slaughterhouses, as well as the genotype of these isolates. T. gondii antibodies were detected in 66/602 (10.96%) serum samples through modified agglutination test (MAT) and indirect fluorescent antibody test (IFAT). MAT-HS and IFAT-IgG presented high concordance (0.95) and strong correlation (r=0.79). T. gondii DNA was detected in tissue samples of 33% (22/66) serum positive sheep by PCR of the 529 bp repetitive element. In the bioassay in mice, T. gondii were detected in mice brain or muscle tissues in 30% (20/66) of serum positive sheep. Positive samples were typed through Restriction Fragment Length Polymorphism (RFLP-PCR) using 11 markers: SAG1, SAG2 (5'-3'SAG2 and alt.SAG2), SAG3, BTUB, GRA6, L358, c22-8, c29-6, PK1, Apico and CS3. Of 22 samples, 13 were positive and 9 genotypes were identified. Four of these 9 genotypes are unique. Nine samples had negative results in RFLP-PCR typing, which may be due to low DNA concentration. Six isolates were virulent killing mice between 12 and 25 days postinfection. Two non virulent isolates belonged to clonal type II genotype, which were not observed in Brazil previously. These findings confirm the high diversity and high frequency of virulent genotypes among Brazilian animals. This study also proved the presence of type II T. gondii in Brazil. PMID- 20970258 TI - Prevalence of gastrointestinal parasites in primate bushmeat and pets in Cameroon. AB - To document the prevalence of gastrointestinal parasites in Cameroonian monkeys and to assess the risk of transmission to humans, we sampled 125 primates belonging to 15 species, of which 78 had been captured for bushmeat in the wild, and 47 were pets kept in urban areas. Seven nematode species, one trematode, one cestode and three protozoa were detected. Eight different parasite species were found in Cercopithecus nictitans and six in C. neglectus, C. pogonias and Cercocebus agilis. Helminths were found in 77% of monkeys, and protozoa in 36%. Trichuris sp. and Entamoeba coli were the most frequent parasites, being found in 54% and 36% of animals, respectively. Helminths were more frequent in adults than in juveniles, while the prevalence of protozoa was not age-related. No significant gender difference was found. Bushmeat monkeys had a significantly higher prevalence of helminth infection than pets (92% versus 51%), whereas there was no significant difference in the prevalence of protozoa (32% versus 43%). Among helminth species, Strongyloides fulleborni was more prevalent in bushmeat monkeys than in pets (55% versus 15%), as were Ancylostoma spp. (62% versus 9%). As these parasites are transmitted transcutaneously by infectious larva, they have a high potential for transmission to humans, during butchering. One pet monkey kept in an urban household in Yaounde was infected by Schistosoma mansoni. The potential public health implications of these findings are discussed. PMID- 20970259 TI - Prevalence and molecular typing of Giardia spp. in captive mammals at the zoo of Zagreb, Croatia. AB - A total of 131 faecal samples from 57 mammalian species housed at the zoo of Zagreb, Croatia, were tested for the presence of Giardia spp. cysts using epifluorescence microscopy. The overall prevalence (29%) was high, yet all animals were asymptomatic at the time of sampling. Positive samples were characterized by PCR and sequence analysis of both conserved and variable loci, for the identification of Giardia species and G. duodenalis assemblages and genotypes. Assemblages A and C were identified in Artiodactyla, assemblage B in Primates, Rodentia and Hyracoidea, and assemblages A, B, C and D, as well as Giardia microti, in Carnivora. Genotyping at the ITS1-5.8S-ITS2 region, at the triose phosphate isomerase, glutamate dehydrogenase and beta-giardin genes revealed extensive polymorphisms, particularly among assemblage B isolates. A phylogenetic analysis of concatenated sequences showed that isolates from captive mammals housed at the zoo are genetically different from isolates of human and domestic animal origin. This is the first survey in a zoological garden to include a molecular characterization of the parasite, and provides novel sequence data of G. duodenalis from many previously uncharacterized hosts. PMID- 20970260 TI - Mesenchymal stem cells cultured on tantalum used in early-stage avascular necrosis of the femoral head. AB - Avascular necrosis of the femoral head (ANFH) is a common ailment characterized by necrosis of bone trabecular and bone marrow. It's mainly caused by the destruction of the blood supply in the femoral head and high rate of morbidity and disability is involved. Many methods have been tried including conservative treatment as drugs, electric stimulus, shock wave and electromagnetic field therapy and surgeries as core compression, rotary osteotomy and vascularized bone graft, but neither of them has definitive effect. Recently mesenchymal stem cells (MSCs) and tantalum robust have been widely used in ANFH. They have definite cure effects but advantages and disadvantages should not be neglected. In this paper, we hypothesize that mesenchymal stem cells cultured on tantalum can be used to prevent collapse of the articular surface in patients with ANFH. Unlike current treatment modalities, it would promote the regeneration of femoral head, provide structural support and allow for bony substitution over time. PMID- 20970261 TI - [Tolerance of the contraceptive implant by prescription context (postabortion or not): Prospective study on 127 consultants]. AB - AIM: While contraceptive methods increased in number, the number of abortions has remained stable. The aim of this study was to estimate the satisfaction of women toward a contraceptive implant (Implanon((r))) available in France in order to clarify prescription. METHOD: The survey concerned 127 women who visited Angers and Nantes family planning centres between January2009 and January2010 in two implant prescription contexts (postabortion or not). They agreed to answer a first questionnaire describing the reasons for their choice. A second questionnaire was sent six months after to assess its tolerance. RESULTS: In our study, 82% of patients were using a contraceptive method prior to implant (68% in postabortion and 88% in the other group). The first reason for choosing the implant was the fear of forgetting - it was more important in the postabortion group (88% vs. 61%). The main side effects were amenorrhea (50%), weight gain (30%) and mood disorders (19%). More than one in two women (54%) was very satisfied by the implant. It should be noted that in one quarter of cases, women seek early withdrawal of the contraceptive implant (23% in postabortion and 21% in the other group), a rate that is 39% in patients under 25years and 47% in patients who reported a mood disorder. CONCLUSION: There is a tendency to better tolerance of the implant out of a context of abortion. Furthermore, mood disorders appear to be poorly tolerated. These elements encourage greater caution in prescribing the contraceptive implant in postabortion, situation in which patients have already psychological disorders, and even more among younger patients. PMID- 20970262 TI - Predicted antigenic regions of Streptococcus uberis adhesion molecule (SUAM) are involved in adherence to and internalization into mammary epithelial cells. AB - Streptococcus uberis is a significant cause of bovine mastitis throughout the world. Previous work from our laboratory demonstrated that S. uberis adhesion molecule (SUAM) is an important factor in adherence to and internalization of S. uberis into bovine mammary epithelial cells. Antibodies directed against SUAM significantly reduced bacterial adherence to and internalization into bovine mammary epithelial cells implying that SUAM is surface exposed. Objectives of this research were to: (1) predict surface exposed peptides, and (2) select peptide sequences for production of synthetic peptides with the final aim of evaluating their role in adherence and internalization and immunogenic potential. The Kyte/Doolittle hydropathicity prediction method; Chou/Fasman beta-turn prediction method; and output from Coils, Paircoil and MultiCoil scores for prediction of secondary and tertiary structures were used. Prediction algorithms resulted in identification of five overlapping regions of the SUAM sequence with the most hydrophilic valleys and the highest peaks for beta-turns. The five 15 mer SUAM epitopes selected by bioinformatic analysis were produced to evaluate the immunogenic value and pathogenic role of these putative domains. Peptides were bound to fluorescent latex beads, incubated with MAC-T bovine mammary epithelial cells, and internalization into MAC-T cells was evaluated using confocal laser and transmission electron microscopy. All peptides evaluated induced some degree of internalization of fluorescent beads into MAC-T cells; however, 2 peptides induced significantly more internalization of fluorescent beads than the other peptides evaluated. These peptides, designated III and IV, were located in the central region of SUAM, between two coiled-coil regions. Convalescent sera were tested against these biotinylated peptides for SUAM specific immune response using an indirect ELISA format. Among the 5 peptides evaluated, peptides I, II and V elicited significant serological response suggesting that the N-terminal region (peptide I), central region (peptide II) and C-terminal region (peptide V) are immunodominant epitopes of SUAM. Results will be useful to design immunotherapeutic tools based on immunodominant epitopes. PMID- 20970263 TI - Impact of very low birth weight infants on the family at 3 months corrected age. AB - BACKGROUND: Very low birth weight infants (VLBW, <1500 g) have increased impact on families compared to term infants. However, there is limited research examining this impact in the first months post-discharge. AIM: To determine maternal, neonatal, and infant characteristics associated with greater impact on the family at 3 months corrected age in VLBW infants. It was hypothesized that social/environmental and medical risk factors would be associated with higher impact. STUDY DESIGN: Maternal, neonatal, and infant data were collected prospectively. Parents completed the Impact on Family, Family Support, and Family Resource Scales. Associations between characteristics and impact scores were analyzed by t-test and Pearson's correlation. Regression models for each impact score identified significant risk factors for impact. SUBJECTS: 152 VLBW infants born February 28, 2007 to September 5, 2008 who had a follow-up evaluation at 3 months corrected age. OUTCOME MEASURE: Impact on family. RESULTS: Siblings in the home, neonatal medical risk factors, longer hospitalization, more days on ventilator or oxygen, lower gestational age, lower social support, and poorer family resources were associated with increased impact. Multivariate analyses identified siblings in the home, poorer family resources, lower gestational age, and oxygen requirement at 3 months as the most important predictors of impact. CONCLUSIONS: Social/environmental and medical risk factors contribute to impact on family. Families with identified risk factors should receive support services to assist them in coping with the burden of caring for a VLBW infant. PMID- 20970264 TI - Amplitude integrated electroencephalographic activity in infants with congenital heart disease before surgery. AB - BACKGROUND: Infants with congenital heart disease (CHD) are at risk for brain injury. An accurate tool to monitor brain function is amplitude integrated EEG (aEEG). It records both background patterns and electrographic seizure activity (EA). AIMS: Our aim was to determine aEEG patterns in infants with CHD and to determine the differences between infants with a cyanotic or an acyanotic CHD. STUDY DESIGN AND SUBJECTS: Sixty-two full term newborns had either a cyanotic CHD (transposition of the great arteries (n=24)) or an acyanotic CHD (hypoplastic left heart syndrome (n=26), critical aortic valve stenosis (n=1) or aortic coarctation (n=11)). The background patterns, sleep-wake cycling (SWC), and EA were assessed. The first 72h after starting prostaglandin E(1)-therapy were used for analysis. RESULTS: The background patterns were mildly abnormal in 45% of the infants and severely abnormal at some point during the recording in 14% of the infants. We found no differences in background patterns between the two groups. EA was present in 12 (19%) infants. EA was more frequent in infants with acyanotic CHD (OR 9.4, 95% CI 1.1-78, p=0.039). SWC was equally frequent in infants with cyanotic and infants with acyanotic CHD. A severely abnormal aEEG and EA were associated with more profound acidosis. CONCLUSIONS: Before surgery the majority of infants with a CHD had an abnormal aEEG. aEEG helped to identify EA and it was a useful tool to evaluate brain function prior to surgery in CHD. PMID- 20970265 TI - Examples of kinship analysis where Profiler PlusTM was not discriminatory enough for the identification of victims using DNA identification. AB - The identification of the victims of the 2009 Victorian bushfires disaster, as in other mass disasters, relied on a number of scientific disciplines - including DNA analysis. As part of the DVI response, DNA analysis was performed to assist in the identification of victims through kinship (familial matching to relatives) or direct (self source of sample) matching of DNA profiles. The majority of the DNA identifications made (82%) were achieved through kinship matching of familial reference samples to post mortem (PM) samples obtained from the victims. Although each location affected by the bushfires could be treated as a mini-disaster (having a small closed-set of victims), with many such sites spread over vast areas, DNA analysis requires that the short tandem repeat (STR) system used be able to afford enough discrimination between all the DVI cases to assign a match. This publication highlights that although a 9-loci multiplex was sufficient for a DVI of this nature, there were instances that brought to light the short comings of using a 9-loci multiplex for kinship matching--particularly where multiple family members are victims. Moreso it serves to reinforce the recommendation that a minimum of 12 autosomal STR markers (plus Amelogenin) be used for DNA identification of victims which relies heavily on kinship matching. PMID- 20970266 TI - Relation between alcohol consumption and traffic violations and accidents in the region of Ribeirao Preto, Sao Paulo State. AB - In recent years, alcohol consumption has been considered an important public health problem. Ethanol, the alcohol used in beverages, is a drug that affects the central nervous system (CNS) and impairs driving skills and co-ordination, increasing risk of deaths and injuries derived from crashes and road accidents. Consumption of alcoholic beverages is implicated with premature deaths, injuries and damages caused by motor vehicle crashes, which result in high costs to government and society. Considering that alcohol consumption is the main responsible factor for deaths and disabilities in young people, the aim of this work was to evaluate the prevalence of blood alcohol in offenders and/or fatal and non-fatal victims of traffic occurrences in the region of Ribeirao Preto, Sao Paulo State, from 2005 to 2007. The results revealed that in 2134 cases investigated, blood alcohol positivity was generally found in young adults, 25-45 years old and male. The study showed the high risk of drinking and driving and the importance in establishing actions of prevention and intervention to promote the reduction in the number of traffic occurrences related to consumption of alcoholic beverages. PMID- 20970267 TI - Fatalities in relation to buprenorphine snorting and ethanol co-ingestion: mechanisms of toxicity. PMID- 20970268 TI - Low-tone air-bone gaps after endolymphatic sac surgery. AB - OBJECTIVES: We detected chronic low-tone air-bone gaps (LTABGs) in some patients with Meniere's disease after endolymphatic sac surgery. The aim of the present study was to elucidate the mechanism of LTABGs after endolymphatic sac surgery. METHODS: We investigated 50 patients with Meniere's disease, who underwent surgery more than two years prior. LTABGs were defined as the three-tone average=20dB formulated by (a+b+c)/3, where a, b, and c are ABGs at 0.25, 0.5, and 1kHz, respectively (ABG +/-). The intra-operative finding was focused on identifying operculum (OPC +/-). RESULTS: The ratio of post-operative ABG(+) was 50.0% (25/50). The ratio of intra-operative OPC(+) was 72.0% (36/50). The surgery results were as follows: the ratio of complete vertigo suppression (VS(+)) was 84.0% (42/50), air-conduction hearing gain (aHG(+)) was 40% (20/50), bone conduction hearing gain (bHG(+)) was 64% (32/50), and speech discrimination gain (SDG(+)) was 28% (14/50). The post-operative ABG(+) was commonly observed in patients with intra-operative OPC(+) (chi-square test, p=0.013). aHG(+) and SDG(+) results were related to the post-operative ABG(+) (chi-square test, p=0.021 and p=0.0018, respectively). CONCLUSIONS: These data suggest that intra operative OPC(+) may be causative for post-operative ABG(+), resulting in post operative aHG(+) and SDG(+). Thus, as enlarged vestibular aqueduct syndrome and superior semicircular canal deficiency syndrome exhibit LTABGs due to the third mobile inner ear window, endolymphatic sac surgery with adequate endolymphatic sac decompression and exposure to high doses of steroids, might induce LTABGs and the beneficial results of endolymphatic sac surgery. PMID- 20970269 TI - Epilepsy and trimethylaminuria: A new case report and literature review. AB - Trimethylaminuria is a metabolic disorder characterized by the excessive excretion of trimethylamine in bodily secretions, which confers a very unpleasant odour resembling that of dead fish. Literature reports only two cases affected by trimethylaminuria and epilepsy. We describe a third patient who, from the age of seven, was affected by temporal focal seizures with nocturnal episodes of nausea, vomiting, anxiety and autonomic activation followed by headache. EEG showed focal paroxysmal abnormalities prevailing on the right temporo-parieto-occipital regions. We began administering levetiracetam and seizures stopped. Our patient also showed learning disabilities despite a normal intelligence quotient (IQ), while another described patient had an IQ varying from borderline to mild mental retardation. We discuss the association between trimethylaminuria and epilepsy, and formulate some hypotheses on the relationship between trimethylamine convulsive effect and the anticonvulsive role of levetiracetam. PMID- 20970270 TI - Renal agenesis and external iliac artery stenosis in an infant with moyamoya disease. AB - We describe a 14-month-old girl who presented with arterial ischemic stroke due to moyamoya disease, unilateral renal agenesis and external iliac artery stenosis. The association of moyamoya disease with renal agenesis and external iliac artery stenosis has not been described before. This report expands the spectrum of moyamoya disease and suggests that moyamoya disease may have an intrauterine onset. PMID- 20970271 TI - Colonoscopy practices, and colorectal cancer and polyp screening, as assessed in the French district of Isere from May to July in 2004. AB - BACKGROUND: A pilot program of organized screening for colorectal cancers was conducted in Isere, an administrative district in France. A fecal occult blood test (Hemoccult II((r))) was proposed for all individuals aged greater than 50 years (women since 1991 and men since 2002), followed by colonoscopy for those testing positive. A prospective study was carried out from May to July in 2004 and compared with a similar study conducted in 1996. The goal was to investigate colonoscopy practices, especially the role of screening. METHODS: Gastroenterologists practising in Isere (n=39/42 practitioners) completed a questionnaire including their patients' age and gender, indications, methods and results for all colonoscopies performed in those aged greater than 20 years. Any tissue samples taken were sent away for histological evaluation. RESULTS: The study involved 2558 colonoscopies (54% female, 73% patients aged greater or equal to 50 years), an increase of 35% from 1996 to 2004. Of the patients referred, 50.0% were symptomatic (pain; bowel problems: 28.7%; rectal bleeding: 21.3%), 23.5% had colonic disease and 22.5% came from screening (3.1% had positive stool tests, 17.8% had a family history). Recommendations related to family history (update of the 1998 consensus conference: screening indicated for patients with a first-degree relative diagnosed with cancer or advanced polyps aged less than 60 years) were well applied in terms of relatedness (81%) but, in 52% of cases, the age was greater than 60 years. Colonoscopy was carried out in almost all cases (0.1% failure), with complications in 0.4% of the examinations. Of the 2558 colonoscopies performed, 10% revealed advanced polyps or cancer: 30% were following a positive test compared with 8% for symptoms and 6% with a family history. Multivariate analyses showed that polyps greater or equal to 10mm or malignant tumors are 1.5 times more common in men than in women, and six times more frequently seen in patients having colonoscopy following a positive test for blood in stools than in those with a family history of colorectal cancer. The number of pathologies found increased significantly in those aged greater than 50 years. CONCLUSION: This cross-sectional survey of colonoscopy practices in Isere shows an increase in the number of colonoscopies performed between 1996 and 2004. This increase is not explained by expansion of the screening program, which was the reason for only 3% of colonoscopies. However, the best diagnostic yield for advanced polyps or cancers was obtained in screened patients (30%). PMID- 20970272 TI - Barrett's esophagus, esophageal and esophagogastric junction adenocarcinomas: the role of diet. AB - Identification of modifiable risk factors is an attractive approach to primary prevention of esophageal adenocarcinoma (EAC) and esophagogastric junction adenocarcinoma (EGJAC). We conducted a review of the literature to investigate the association between specific dietary components and the risk of Barrett's esophagus (BE), EAC and EGJAC, supposing diet might be a risk factor for these tumors. Consumption of meat and high-fat meals has been found positively associated with EAC and EGJAC. An inverse association with increased intake of fruit, vegetables and antioxidants has been reported but this association was not consistent across all studies reviewed. Few studies have examined the association between diet and BE. Additional research is needed to confirm the aforementioned association and clarify the mechanisms by which dietary components affect the risk of developing EAC and EGJAC. Future studies could advance our knowledge by emphasizing prospective designs to reduce recall bias, by using validated dietary intake questionnaires and biological measures and by considering important confounders such as gastro-esophageal reflux disease (GERD) symptoms, tobacco and alcohol use, biometrics, physical activity, and socioeconomic factors. PMID- 20970273 TI - Absence of right lobe of liver. PMID- 20970274 TI - Descriptive retrospective analysis of the diagnostic yield and morbidity of four vessel catheter-directed cerebral angiography and multidetector computed tomographic angiography (MDCTA) performed at Inkosi Albert Luthuli Central Hospital (IALCH). AB - Imaging studies are indispensable in order to determine the source, location and pattern of intra and extra-axial brain haemorrhages. In our study of 277 patients carried out over an 18 month period, the most common reason of referral was subarachnoid haemorrhage followed by trauma. Aneurysms were the most common diagnosis (36%) with anterior and posterior communicating arteries being the most common locations. Fifty percent (50%) of patients investigated had a normal study. Our findings show that the yield from MDCTA and conventional angiography was relatively comparable, however, conventional angiography was superior in detection of aneurysms; hence, in cases were the MDCTA result was found to be normal despite a high index of suspicion for a subarachnoid haemorrhage, a follow up MDCTA study or conventional angiography is useful. Moreover, conventional angiography was superior in detection of multiple aneurysms. PMID- 20970275 TI - 3-D high-frequency endovaginal ultrasound of female urethral complex and assessment of inter-observer reliability. AB - OBJECTIVES: Assessment of the urethral complex and defining its morphological characteristics with 3-dimensional endovaginal ultrasonography with the use of high frequency rotational 360 degrees transducer. Defining inter-observer reliability of the performed measurements. MATERIALS AND METHODS: Twenty-four asymptomatic, nulliparous females (aged 18-55, mean 32 years) underwent high frequency (12MHz) endovaginal ultrasound with rotational 360 degrees and automated 3D data acquisition (type 2050, B-K Medical, Herlev, Denmark). Measurements of the urethral thickness, width and length, bladder neck-symphysis distance, intramural part of the urethra as well as rhabdosphincter thickness, width and length were taken by three investigators. Descriptive statistics for continuous data was performed. The results were given as mean values with standard deviation. The relationships among different variables were assessed with ANOVA for repeated measures factors, as well as T-test for dependent samples. Intraclass correlation (ICC) was calculated for each parameter. Intra- and interobserver reliability was assessed. Statistical significance was assigned to a P value of <0.05 (two-tailed). RESULTS: Excellent reliability was observed for urethral measurements (length, width, thickness and volume) (ICC>0.8) and good reliability for rhabdosphincter measurements (ICC>0.6) between all three investigators. CONCLUSIONS: Advanced EVUS provides detailed information on anatomy and morphology of the female urethral complex. Our results show that 360 degrees rotational transducer with automated 3D acquisition, currently routinely used for proctological scanning is suitable for the reliable assessment of the urethral complex and can be applied in a routine diagnostics of pelvic floor disturbances in females. PMID- 20970276 TI - Imaging appearance of surgical sponges at 1.5 T MRI: an in vitro study. AB - OBJECTIVE: To predict the MR appearance of retained surgical textiles in the acute setting by using an in vitro phantom and body MR imaging protocols. METHODS: Three surgical sponges were embedded in clear gelatin. One of these sponges was soaked in fresh human blood and the other two sponges were embedded dry. The following sequences were acquired at 1.5 T: T1W 3D gradient echo with chemical shift saturation (VIBE, volumetric interpolated breath-hold examination), 3D gradient dual echo T1W (in and opposed phase), 2D T2W single shot fast spin echo (HASTE, half-fourier acquisition single shot turbo spin echo), and 3D T2W fast spin echo (SPACE, sampling perfection with application optimized contrast using different flip angle evolutions). RESULTS: The radiopaque marker within the surgical sponge appears as a linear hypointense structure on T1W and T2W images. Slightly increased conspicuity of the radiopaque marker is seen on the in phase gradient dual echo images compared with the opposed phase gradient dual echo images, likely due to magnetic susceptibility effect. The surgical sponge material is invisible on the T1W images and appears hypointense on the T2W images. Owing to the T1W hyperintensity and T2W hypointensity of blood, the radiopaque marker within the blood soaked gauze is visible on the T1W images but obscured on the T2W images. CONCLUSIONS: We describe the in vitro MR appearance of retained surgical sponges in order to simulate their appearance in the acute setting prior to the mass-like foreign body reaction which may occur in the chronic phase. PMID- 20970277 TI - Consistency of FMEA used in the validation of analytical procedures. AB - In order to explore the consistency of the outcome of a Failure Mode and Effects Analysis (FMEA) in the validation of analytical procedures, an FMEA was carried out by two different teams. The two teams applied two separate FMEAs to a High Performance Liquid Chromatography-Diode Array Detection-Mass Spectrometry (HPLC DAD-MS) analytical procedure used in the quality control of medicines. Each team was free to define their own ranking scales for the probability of severity (S), occurrence (O), and detection (D) of failure modes. We calculated Risk Priority Numbers (RPNs) and we identified the failure modes above the 90th percentile of RPN values as failure modes needing urgent corrective action; failure modes falling between the 75th and 90th percentile of RPN values were identified as failure modes needing necessary corrective action, respectively. Team 1 and Team 2 identified five and six failure modes needing urgent corrective action respectively, with two being commonly identified. Of the failure modes needing necessary corrective actions, about a third were commonly identified by both teams. These results show inconsistency in the outcome of the FMEA. To improve consistency, we recommend that FMEA is always carried out under the supervision of an experienced FMEA-facilitator and that the FMEA team has at least two members with competence in the analytical method to be validated. However, the FMEAs of both teams contained valuable information that was not identified by the other team, indicating that this inconsistency is not always a drawback. PMID- 20970278 TI - Formation and identification of a degradant in chlorproguanil-dapsone-artesunate (DacartTM) tablets. AB - Chlorproguanil hydrochloride, dapsone and artesunate are three compounds with anti-malarial properties developed as a triple combination drug product (DacartTM) for the treatment of malarial infections. During long-term stability studies, a degradant was observed which increased with time and had the potential to limit the shelf-life of the product. Through a combination of HPLC and spectroscopic analyses, the structure of the degradant was identified to be an adduct of a fragment of artesunate with dapsone. The response factor was determined to allow an accurate assessment of its levels in drug product. The likely mechanism for its formation is postulated to be via the water-mediated degradation of artesunate to give succinic acid followed by reaction of the liberated succinic acid with dapsone. The formation of this degradant demonstrates a potential stability risk for future combination therapies incorporating artesunate. These risks are particularly pertinent to products of this type given the climatic conditions which prevail in countries where such therapies are likely to be employed. PMID- 20970279 TI - Isolated perfused lung extraction and HPLC-ESI-MS(n) analysis for predicting bioactive components of Saposhnikoviae Radix. AB - A novel strategy for predicting bioactive components in traditional Chinese material herb was proposed, using isolated perfused rat lung (IPL) extraction and high performance liquid chromatography?tandem mass spectrometry (HPLC-MS(n)) analysis. The hypothesis is that when the IPL is perfused with the extract of Saposhnikoviae Radix (ESR), the potential bioactive components in the ESR should selectively combine with the receptor or channel of lung, by changing the pH of perfused liquid, the combining components would be eluated and then detected by HPLC-ESI-MS(n). Five compounds were detected in the desorption eluate of IPL; among these compounds, two potential bioactive compounds, prim-O glucosylcimifugin (2) and 4'-O-beta-D-glucosyl-5-O-methylvisamminol (4) were identified by comparing with the chromatography of the standard sample, and three other compounds, i.e. cimifugin (1), 5-O-methylvisamminol (3) and sec-O glucosylhamaudol (5) were determined by analysis of the structure clearage characterization of mass spectrometry. The application of IPL extraction coupled with HPLC-ESI-MS(n) for predicting potential bioactive components of TCMs is rapid, convenient, operational, economic and reliable. PMID- 20970280 TI - Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5. AB - OBJECTIVES: we tested the hypothesis that bi-directional, gene-targeted regulation of cardiomyocyte cyclic guanosine monophosphate-selective phosphodiesterase type 5 (PDE5) influences maladaptive remodeling in hearts subjected to sustained pressure overload. BACKGROUND: PDE5 expression is up regulated in human hypertrophied and failing hearts, and its inhibition (e.g., by sildenafil) stimulates protein kinase G activity, suppressing and reversing maladaptive hypertrophy, fibrosis, and contractile dysfunction. Sildenafil is currently being clinically tested for the treatment of heart failure. However, researchers of new studies have questioned the role of myocyte PDE5 and protein kinase G (PKG) to this process, proposing alternative targets and mechanisms. METHODS: mice with doxycycline-controllable myocyte-specific PDE5 gene expression were generated (medium transgenic [TG] and high TG expression lines) and subjected to sustained pressure overload. RESULTS: Rest myocyte and heart function, histology, and molecular profiling were normal in both TG lines versus controls at 2 months of age. However, upon exposure to pressure overload (aortic banding), TG hearts developed more eccentric remodeling, maladaptive molecular signaling, depressed function, and amplified fibrosis with up-regulation of tissue growth factor signaling pathways. PKG activation was inhibited in TG myocytes versus controls. After establishing a severe cardiomyopathic state, high TG mice received doxycycline to suppress PDE5 expression/activity only in myocytes. This in turn enhanced PKG activity and reversed all previously amplified maladaptive responses, despite sustained pressure overload. Sildenafil was also effective in this regard. CONCLUSIONS: these data strongly support a primary role of myocyte PDE5 regulation to myocardial pathobiology and PDE5 targeting therapy in vivo and reveal a novel mechanism of myocyte-orchestrated extracellular matrix remodeling via PDE5/cyclic guanosine monophosphate-PKG regulatory pathways. PMID- 20970281 TI - Regression of cardiac hypertrophy by cyclic guanosine monophosphate-dependent protein kinase signaling are myocytes active sources or mere beneficiaries? PMID- 20970282 TI - A dangerous fruit juice. AB - We report the case of a female patient presenting to the emergency department with postprandial syncope and atrial fibrillation. After amiodarone administration, the electrocardiogram showed marked QT prolongation associated with ventricular arrhythmias, including an episode of torsade de pointes requiring immediate electrical cardioversion. During history taking, the patient reported that she had been drinking large amounts of grapefruit juice regularly. The inhibition of amiodarone metabolism induced by grapefruit juice was responsible for enhancing the proarrhythmic effects of the drug with development of electrical storm. PMID- 20970283 TI - Evaluation of Global Registry of Acute Cardiac Events and Thrombolysis in Myocardial Infarction scores in patients with suspected acute coronary syndrome. AB - PURPOSES: We aimed to evaluate the Global Registry of Acute Cardiac Events (GRACE) and Thrombolysis in Myocardial Infarction (TIMI) scores in patients with suspected but not proven acute coronary syndrome (ACS). BASIC PROCEDURES: We conducted a secondary analysis of data from the RATPAC trial. Standardized data were collected from 2263 patients presenting to 6 emergency departments with suspected but not proven ACS. Patients were followed up by record review and postal questionnaire at 30 and 90 days after recruitment to identify major adverse events, defined as death, emergency revascularization, life-threatening arrhythmia, hospitalization for ACS, or nonfatal acute myocardial infarction (AMI). MAIN FINDINGS: Data were available for 2243 patients (mean age, 54.5 years; 58% male). The major adverse event rate was 43 (2%) of 2243 after 30 days and 62 (3%) of 2243 after 90 days. The c statistics for 30-day events were 0.717 (95% confidence interval [CI], 0.698-0.735) for GRACE and 0.682 (95% CI, 0.662 0.701) for TIMI. The corresponding 90-day c statistics were 0.726 (95% CI, 0.707 0.745) for GRACE and 0.693 (95% CI, 0.674-0.712) for TIMI. The c statistic for patient age alone was 0.656 for 30-day events and 0.689 for 90-day events. PRINCIPAL CONCLUSIONS: The GRACE and TIMI scores are little better than age alone as predictors of major adverse events in patients with suspected but not proven ACS, and thus add little to prognostic assessment of such patients. PMID- 20970284 TI - Acute peritonitis as the first presentation of valvular cardiomyopathy. AB - Valvular cardiomyopathy can present a diagnostic challenge in the absence of overt cardiac symptoms. This report describes the case of a 46-year-old woman who presented with acute peritonitis associated with vomiting and abdominal distension. Subsequent abdominal computed tomography and ultrasound revealed bibasal pleural effusions, ascites, and normal ovaries. An echocardiogram revealed that all cardiac chambers were dilated with a global decrease in contractility and severe mitral, tricuspid, and aortic regurgitation. A diagnosis of cardiomyopathy with acute heart failure, secondary to valvular heart disease, was secured. Acute peritonitis as the presenting feature of valvular cardiomyopathy is a rare clinical entity. PMID- 20970285 TI - Primary stent revascularization for critical flow-limiting middle cerebral artery stenosis presenting with rapid neurologic decline. PMID- 20970286 TI - Pulseless electrical activity in cardiac arrest: electrocardiographic presentations and management considerations based on the electrocardiogram. AB - Pulseless electrical activity (PEA), a cardiac arrest rhythm scenario with an associated poor prognosis, is defined as cardiac electrical activity without a palpable pulse. Considering both outpatient and inpatient cardiac arrest presentations, PEA as a rhythm group has been increasing over the past 10 to 20 years with a corresponding decrease in the "shockable" rhythms, such as pulseless ventricular tachycardia and ventricular fibrillation. This review focuses on electrocardiographic findings encountered in PEA cardiac arrest presentations with an emphasis on recognition of patients with a potential opportunity for successful resuscitation. PMID- 20970287 TI - Snakebite: the experience of Russell's viper antivenom in Taiwan. PMID- 20970288 TI - Presentation of an adolescent with delayed-onset massive hemorrhage and shock from a tongue piercing. PMID- 20970289 TI - Electrical alternans as a manifestation of pulmonary embolism. PMID- 20970290 TI - Acalculous cholecystitis in a healthy 4-year-old boy. PMID- 20970292 TI - Improving clinical outcomes in cardiac arrest cases through chest compression only cardiopulmonary resuscitation. PMID- 20970293 TI - Computed tomography angiography in the diagnosis of pulmonary embolism: interobserver agreement. PMID- 20970294 TI - Perception of time by professional health care workers during simulated cardiac arrest. PMID- 20970295 TI - Difficulties and possible solutions for tracheal intubation with the Airway Scope. PMID- 20970296 TI - The degree of bandemia in septic ED patients does not predict inpatient mortality. AB - BACKGROUND: A delay in diagnosis of sepsis and appropriate treatment increases subsequent mortality. An association with the degree of bandemia, or the presence of immature neutrophils in the white blood cell count, has not been explored in septic patients presenting to the emergency department (ED). We hypothesized that the presenting band levels would be higher in septic patients who die in hospital compared with survivors. METHODS: This study reviewed charts of ED patients presenting with sepsis to a single urban, academic, tertiary care ED with an annual census of 80,000 visits. Patients were included if they had bandemia assessed and were eligible for early goal-directed therapy. Reviewers blinded to the study purpose abstracted data using predetermined definitions. The band level was compared between patients who died and those who survived to discharge using the Mann-Whitney U test. Logistic regression was used to estimate the effect of bandemia levels on the odds of death. RESULTS: Ninety-six patients meeting inclusion criteria were enrolled; 2 were excluded with incomplete data. Mean age was 59 years, 53% were white, and 51% were male. Thirty-two patients (34%) died during admission. The median band levels in patients who died was 17% (range, 0% 67%); and in patients surviving to discharge, the median band level was 9% (range, 0%-77%) (difference in medians, 8%; CI(95), -27.04 to 11.04; P = .222). CONCLUSIONS: The band level on presentation was not found to be associated with inpatient mortality in ED patients with sepsis who are eligible for early goal directed therapy. PMID- 20970297 TI - Secondary spontaneous pneumothorax: which associated conditions benefit from pigtail catheter treatment? AB - OBJECTIVE: The study aimed to assess the clinical efficacy of pigtail catheter drainage for patients with a first episode of secondary spontaneous pneumothorax (SSP) and different associated conditions. METHODS: We retrospectively reviewed the records of patients with SSP who received pigtail catheter drainage as their initial management between July 2002 and October 2009. A total of 168 patients were included in the analysis; 144 (86%) males and 24 (14%) females with a mean age of 60.3 +/- 18.3 years (range, 17-91 years). Data regarding demographic characteristics, pneumothorax size, complications, treatments, length of hospital stay, and associated conditions were analyzed. RESULTS: In total, 118 (70%) patients were successfully treated with pigtail catheter drainage, and 50 (30%) patients required further management. Chronic obstructive lung disease was the most common underlying disease (57% of cases). Secondary spontaneous pneumothorax associated with infectious diseases had a higher rate of treatment failure than SSP associated with obstructive lung conditions (19/38 [50%] successful vs 78/104 [75%] successful, P = .004) and malignancy (19/38 [50%] successful vs 13/16 [81%] successful, P = .021). Moreover, patients with SSP associated with infectious diseases had a longer length of hospital stay than those with obstructive lung conditions (23.8 vs 14.5 days, P = .003) and malignancy (23.8 vs 12.1 days, P = .017). No complications were associated with pigtail catheter drainage. CONCLUSIONS: A higher rate of treatment failure was noted in SSP patients with infectious diseases; thus, pigtail catheter drainage is appropriate as an initial management for patients with SSPs associated with obstructive lung conditions and malignancy. PMID- 20970298 TI - Comparison of Pentax-AWS with Macintosh laryngoscope for tracheal intubation in simulated difficult airways. PMID- 20970299 TI - Reduction of postoperative stiffness after arthroscopic rotator cuff repair: results of a customized physical therapy regimen based on risk factors for stiffness. AB - PURPOSE: The purpose of this study was to determine the benefits of a modified rehabilitation protocol (incorporating early closed-chain overhead stretching) in reducing the risk of postoperative stiffness after arthroscopic rotator cuff repair. METHODS: During a 17-month period, we performed primary arthroscopic rotator cuff repairs in 152 patients. After surgery, patients with risk factors identified in the previous study (calcific tendonitis, adhesive capsulitis, PASTA [partial articular surface tendon avulsion]-type rotator cuff repair, concomitant labral repair, or single-tendon cuff repair) were enrolled in a modified rehabilitation protocol that added early overhead closed-chain passive motion exercises to our standard protocol; alternatively, patients without risk factors received a standard conservative rehabilitation program. Historical controls were used and comprised patients in the senior author's practice who all received the conservative rehabilitation protocol. The prevalence of postoperative stiffness was compared between the historical cohort and current study patients by use of Fisher exact tests. RESULTS: Among the 152 patients studied, 79 were positive for at least 1 of the specified risk factors and received the modified protocol. Postoperative stiffness developed in none of the 79 patients enrolled in the modified program. This finding represented a significant improvement (Fisher exact test, P = .004) over the historical controls, in which 18 of the 231 at risk patients had significant postoperative stiffness develop. CONCLUSIONS: In at risk patients (with calcific tendonitis, adhesive capsulitis, PASTA repair, concomitant labral repair, and single-tendon repair), a postoperative rehabilitation regimen that incorporates early closed-chain passive overhead motion can reduce the incidence of postoperative stiffness after arthroscopic rotator cuff repair. PMID- 20970300 TI - Study on anti-metastasis of heparin derivatives as ligand antagonist of p selectin. AB - Heparin has a potential value as therapeutic agents that block P-selectin mediated cell adhesion and prevent tumor metastasis. However, the strong anticoagulant potency limits its applicability for the anti-metastasis activity. Carboxyl and sulfate groups of heparin are closely related to its anticoagulant activity, so seven kinds of heparin derivatives related to carboxyl and sulfate groups were prepared, and their effects on anti-metastasis as ligand antagonist of p-selectin were studied. The results showed that heparin, carboxyl reduction heparin, 2-O-desulfated heparin and N-desulfated- N-acetylated heparin could inhibit the adhesion of tumor cells to endothelial cells and platelets effectively as ligand antagonist of P-selectin. PMID- 20970302 TI - Public or private magnetic resonance imaging: what do the patients think? AB - PURPOSE: We described the demographic, clinical, and attitudinal profiles of patients awaiting magnetic resonance imaging (MRI) at a private and at a hospital based facility, and hypothesized that they would not differ significantly. METHODS: A survey of patients attending a hospital facility and a privately owned venue in an Ontario city. Descriptive, bivariate, and logistic regression analyses were performed. RESULTS: A total of 314 patients provided data, with a higher response rate at the private clinic than at the hospital-based clinic (97% vs 60%). For the majority of patients (58%), the MRI was scheduled to follow up known disease; 55.8% waited more than 4 weeks; 6.4% waited more than 6 months. One-third of patients expressed a willingness to travel to the United States and pay for the MRI, 41% expressed a willingness to pay within Ontario, and 66% were willing to travel elsewhere in Ontario. They were more likely to be at the hospital-based MRI if they were being followed up for known disease and had a diagnosis of cancer, whereas those patients at the private MRI facility reported significantly more pain; 59% of the hospital-based sample and 72% of the private clinic sample reported significantly reduced quality of life because of their health problem. DISCUSSION: These data provide interesting insights into the characteristics of patients awaiting an MRI and the attitudes of patients towards public and private MRI clinics. There were significant attitudinal differences between those patients attending the 2 facilities. Pain, coupled with a long wait, may create an incentive for patients to conclude that private clinics should be permitted if the hospital environment is unable to improve access times. PMID- 20970301 TI - Structural and functional studies of CCAAT/enhancer binding sites within the human immunodeficiency virus type 1 subtype C LTR. AB - Human immunodeficiency virus type 1 (HIV-1) subtype C, which is most predominant in sub-Saharan Africa as well as in Asia and India, is the most prevalent subtype worldwide. A large number of transcription factor families have been shown to be involved in regulating HIV-1 gene expression in T lymphocytes and cells of the monocyte-macrophage lineage. Among these, proteins of the CCAAT/enhancer binding protein (C/EBP) family are of particular importance in regulating HIV-1 gene expression within cells of the monocytic lineage during the course of hematologic development and cellular activation. Few studies have examined the role of C/EBPs in long terminal repeat (LTR)-directed viral gene expression of HIV-1 subtypes other than subtype B. Within subtype B viruses, two functional C/EBP sites located upstream of the TATA box are required for efficient viral replication in cells of the monocyte-macrophage lineage. We report the identification of three putative subtype C C/EBP sites, upstream site 1 and 2 (C-US1 and C-US2) and downstream site 1 (C-DS1). C-US1 and C-DS1 were shown to form specific DNA protein complexes with members of the C/EBP family (C/EBPalpha, beta, and delta). Functionally, within the U-937 monocytic cell line, subtype B and C LTRs were shown to be equally responsive to C/EBPbeta-2, although the basal activity of subtype C LTRs appeared to be higher. Furthermore, the synergistic interaction between C/EBPbeta-2 and Tat with the subtype C LTR was also observed in U-937 cells as previously demonstrated with the subtype B LTR. PMID- 20970303 TI - Adaptive support vector regression for UAV flight control. AB - This paper explores an application of support vector regression for adaptive control of an unmanned aerial vehicle (UAV). Unlike neural networks, support vector regression (SVR) generates global solutions, because SVR basically solves quadratic programming (QP) problems. With this advantage, the input-output feedback-linearized inverse dynamic model and the compensation term for the inversion error are identified off-line, which we call I-SVR (inversion SVR) and C-SVR (compensation SVR), respectively. In order to compensate for the inversion error and the unexpected uncertainty, an online adaptation algorithm for the C SVR is proposed. Then, the stability of the overall error dynamics is analyzed by the uniformly ultimately bounded property in the nonlinear system theory. In order to validate the effectiveness of the proposed adaptive controller, numerical simulations are performed on the UAV model. PMID- 20970304 TI - Tree-like hierarchical associative memory structures. AB - In this letter we explore an alternative structural representation for Steinbuch type binary associative memories. These networks offer very generous storage capacities (both asymptotic and finite) at the expense of sparse coding. However, the original retrieval prescription performs a complete search on a fully connected network, whereas only a small fraction of units will eventually contain desired results due to the sparse coding requirement. Instead of modelling the network as a single layer of neurons we suggest a hierarchical organization where the information content of each memory is a successive approximation of one another. With such a structure it is possible to enhance retrieval performance using a progressively deepening procedure. To backup our intuition we provide collected experimental evidence alongside comments on eventual biological plausibility. PMID- 20970305 TI - Systolic and diastolic myocardial mechanics in patients with cardiac disease and preserved ejection fraction: impact of left ventricular filling pressure. AB - BACKGROUND: There are few data on the impact of left ventricular (LV) filling pressure on systolic and diastolic myocardial mechanics in patients with cardiac disease and preserved LV ejection fraction (LVEF) (>= 50%). METHODS: Patients referred for cardiac catheterization underwent comprehensive echocardiography within 20 minutes of catheterization. Strain and strain rate in longitudinal, radial, and circumferential directions and torsion were measured in systole and diastole. LV preatrial contraction pressure (pre-A) was measured and averaged over 10 cardiac cycles. RESULTS: Sixty patients were studied (mean age, 55.3 +/- 8.9 years). The 30 patients with LV pre-A >= 15 mm Hg had significantly lower longitudinal systolic strain and radial, circumferential, and torsional systolic strain rates than the 30 patients with LV pre-A < 15 mm Hg (P < .05 for all). Similar findings were seen for diastolic variables. There were significant correlations between several systolic and diastolic variables in multiple directions and LV pre-A. On multivariate analysis, the independent predictors of systolic and diastolic speckle-tracking parameters included LVEF and LV pre-A, depending on the specific parameter analyzed. CONCLUSIONS: In patients with preserved LVEF and cardiac disease, several systolic and diastolic myocardial mechanical parameters significantly correlate with LV filling pressure. These data highlight the notion that patients with preserved LVEF and elevated LV filling pressures have significant abnormalities in systolic function as detected by speckle imaging, findings that may challenge the concept of "isolated diastolic dysfunction." The extent of systolic and diastolic abnormalities in these patients may shed light on the mechanics of heart failure with preserved LVEF. PMID- 20970306 TI - Left atrial enlargement and phasic function in patients following non-ST elevation myocardial infarction. AB - BACKGROUND: Changes in left atrial (LA) volumes after ST elevation myocardial infarction are reported but have not been well described following non-ST elevation myocardial infarction (NSTEMI). METHODS: Seventy-five patients with NSTEMIs were studied within 48 hours of presentation and in follow-up at 6 and 12 months; they were compared with age-matched normal controls (n = 100). Biplane indexed LA volumes were measured, and phasic LA volumes (conduit, passive, and active emptying) were calculated. LA remodeling was defined as an increase in LA maximum volume over 12 months. RESULTS: LA maximum volume was significantly larger at baseline in patients with NSTEMIs. At 12 months, maximum LA volume increased (27.6 +/- 7.4 vs 30.2 +/- 8.9 mL/m2 P = .002), with LA remodeling present in 64% of the patients with NSTEMIs. LA passive emptying volume increased, with concurrent reductions in conduit and active emptying volumes. Although diabetes, major coronary artery disease, and a larger myocardial score were predictive of LA remodeling, E' velocity was the only independent predictor. CONCLUSIONS: Patients with NSTEMIs had progressive LA enlargement with reductions in conduit and active emptying volumes, reflecting persistent left ventricular diastolic dysfunction consequent to coronary artery disease and associated diabetes. The measurement of LA volumes after NSTEMI may be useful to monitor chronic diastolic dysfunction resulting from ischemic burden. PMID- 20970307 TI - Modified watershed technique and post-processing for segmentation of skin lesions in dermoscopy images. AB - In previous research, a watershed-based algorithm was shown to be useful for automatic lesion segmentation in dermoscopy images, and was tested on a set of 100 benign and malignant melanoma images with the average of three sets of dermatologist-drawn borders used as the ground truth, resulting in an overall error of 15.98%. In this study, to reduce the border detection errors, a neural network classifier was utilized to improve the first-pass watershed segmentation; a novel "edge object value (EOV) threshold" method was used to remove large light blobs near the lesion boundary; and a noise removal procedure was applied to reduce the peninsula-shaped false-positive areas. As a result, an overall error of 11.09% was achieved. PMID- 20970308 TI - Post-surgical unilateral temporomandibular joint dislocation treated by open reduction followed by orthodontic treatment. AB - A case of prolonged unilateral temporomandibular joint (TMJ) dislocation, which was treated by open surgical reduction and post-surgical orthodontic therapy, is presented. A 58-year-old woman presented complaining of facial asymmetry and malocclusion. She had received surgery for a malignant tumour in the right retromolar region 7 years previously. It was considered that contraction of the pterygoid muscle by surgical injury caused anterior meniscal displacement and TMJ dislocation. Since manual manipulation failed, direct open reduction was performed after separation of the lateral pterygoid muscle from the condylar head and removal of the intra-articular scar tissues. Although the condylar head was returned to the glenoid fossa, optimal occlusion was not obtained because of compensatory tooth movement and inclination. Satisfactory occlusion and symmetric facial appearance were brought about by post-surgical orthodontic therapy. PMID- 20970309 TI - Clinical significance of CD133 and hypoxia inducible factor-1alpha gene expression in rectal cancer after preoperative chemoradiotherapy. AB - AIMS: The mechanism of distant recurrence in rectal cancer after preoperative chemoradiotherapy (CRT) has yet to be fully elucidated. Further improvements in survival rates cannot be achieved without decreasing distant recurrence after preoperative CRT. Recently, it was reported that hypoxic conditions were correlated with cancer stem cell generation. Therefore, we investigated the correlation between the expression of CD133 and hypoxia inducible factor-1alpha (HIF-1alpha), and their association with clinical outcome. MATERIALS AND METHODS: Fifty-two patients with rectal cancer underwent preoperative CRT. Residual cancer cells after CRT were obtained from formalin-fixed paraffin-embedded specimens using micro-dissection. The expression levels of CD133 (PROM1) and HIF-1alpha genes were measured using real-time reverse transcription polymerase chain reaction. The correlation between expression and irradiation was evaluated using colon cancer cell lines. Immunohistochemical staining of these proteins after CRT was also investigated. RESULTS: We observed a significant inverse correlation between the gene expression of CD133 (PROM1) and HIF-1alpha genes in residual cancer cells after CRT. Elevated CD133 gene expression was associated with distant recurrence and poor recurrence-free survival. Elevated HIF-1alpha gene expression was associated with poor overall survival. In vitro, the change in gene expression levels after irradiation showed inverse patterns. Immunohistochemical analyses showed that residual cancer cells strongly expressed CD133 and lacked HIF-1alpha expression. CONCLUSION: Our results suggest that CD133 and HIF-1alpha expression is associated with tumour re-growth and distant recurrence after CRT. These results may assist in clarifying the development of future cancer therapeutics in rectal cancer patients undergoing preoperative CRT. PMID- 20970310 TI - The cost of COPD exacerbations: a university hospital--based study in Greece. AB - BACKGROUND: Hospitalization attributed to severe exacerbations is the major cost driver of Chronic Obstructive Pulmonary Disease (COPD). Given that in Greece no previous studies have addressed the economic burden of COPD, the aim of the study was to examine the hospitalization cost of COPD patients with severe exacerbations in the region of Thrace. METHODS: Sample consisted of 142 COPD patients with severe exacerbations who were admitted to the pneumonology department of the University Teaching Hospital of Alexandroupolis (UTHA) in 2006 and 2007. Data collection was performed retrospectively and resource utilization was derived from patients' files. General Linear Model univariate analysis was applied in order to test the influence of disease severity on costs. RESULTS: Mean actual cost per severe exacerbation was ?1711; the amount of ?621 is reimbursed by social security funds. Price discrepancies are observed between the actual and the nominal cost per patient in all disease stage categories. Mean hospitalization cost per COPD patient increases slightly with the severity of the disease. However, in the very severe stage it greatly increases mainly due to Intensive Care Unit (ICU) admission. In multivariate analysis the length of stay and the stage of the disease were both related to significantly increased costs, while the existence of co-morbidities exhibited marginal significant relation to increased cost. CONCLUSIONS: The cost estimation of severe exacerbations is important as it could trigger further research and also provide the opportunity of creating national epidemiological and economic data. Such data could contribute to the estimation of the total economic and societal burden of COPD in the country. PMID- 20970311 TI - Exogenous nucleosides modulate expression and activity of transcription factors in Caco-2 cells. AB - Dietary nucleotides (NTs) have an important role in cellular and humoral immunity, intestinal growth, differentiation and recovery from tissue damage. Nucleosides (NSs) are the best-absorbed chemical form of NTs in the intestinal epithelium. The aim of this study was to evaluate the effects of NSs on the activity and expression of multiple transcription factors (TFs) in Caco-2 cells, as a possible molecular mechanism by which NSs modulate gene expression in human intestinal cells. The effects of NS-supplemented media on human Caco-2 cell proliferation, viability, protein and RNA concentration were determined, and the activity and expression profiles of multiple TFs were analyzed by using an array based technology. Exogenous NSs did not affect Caco-2 cell proliferation or viability but increased the protein content in cytoplasm and nucleus and the nuclear protein/RNA ratio. The addition of NSs to the media increased the expression and activity of the TFs CCAAT displacement protein (CUX1), v-ets avian erythroblastosis virus E26 oncogene homolog 1 (ETS1) and SMAD family member 2. In contrast, NS addition decreased the expression and activity of the general upstream stimulatory factor 1 (USF1), glucocorticoid receptor (NR3C1), NFKB and tumor protein p53. In conclusion, our results suggest that exogenous NSs affect the expression and activity of several TFs involved in cell growth, differentiation, apoptosis, immune response and inflammation. PMID- 20970312 TI - Moderate caloric restriction in lactating rats programs their offspring for a better response to HF diet feeding in a sex-dependent manner. AB - We aimed to assess the lasting effects of moderate caloric restriction in lactating rats on the expression of key genes involved in energy balance of their adult offspring (CR) and their adaptations under high-fat (HF) diet. Dams were fed with either ad libitum normal-fat (NF) diet or a 30% caloric restricted diet throughout lactation. After weaning, the offspring were fed with NF diet until the age of 15 weeks and then with an NF or a HF diet until the age of 28 weeks, when they were sacrificed. Body weight and food intake were followed. Blood parameters and the expression of selected genes in hypothalamus and white adipose tissue (WAT) were analysed. CR ate fewer calories and showed lower body weight gain under HF diet than their controls. CR males were also resistant to the increase of insulin and leptin occurring in their controls under HF diet, and HF diet exposed CR females showed lower circulating fasting triglyceride levels than controls. In the hypothalamus, CR males had higher ObRb mRNA levels than controls, and CR females displayed greater InsR mRNA levels than controls and decreased neuropeptide Y mRNA levels when exposed to HF diet. CR males maintained WAT capacity of fat uptake and storage and of fatty-acid oxidation under HF diet, whereas these capacities were impaired in controls; female CR showed higher WAT ObRb mRNA levels than controls. These results suggest that 30% caloric restriction in lactating dams ameliorates diet-induced obesity in their offspring by enhancing their sensitivity to insulin and leptin signaling, but in a gender dependent manner. PMID- 20970313 TI - The function of porcine PPARgamma and dietary fish oil effect on the expression of lipid and glucose metabolism related genes. AB - Peroxisome-proliferator-activated receptor gamma (PPARgamma) plays a critical role in regulation of adipocyte differentiation and insulin sensitivity. To become functional, PPARgamma must be activated by binding an appropriate ligand. Polyunsaturated fatty acids (PUFA) are potential ligands for PPARgamma. The current experiment was designed to determine the potential for PUFA, particularly eicosapentaenoic acid and docosahexaenoic acid, to activate the function of porcine PPARgamma in vivo. Transgenic mice, expressing porcine PPARgamma in skeletal muscle were generated and fed with a high-saturated fat (beef tallow) or high-unsaturated fat (fish oil) diet for 4 months. When transgenic mice were fed a fish oil supplemented diet, the expression of adipogenic and glucose uptake genes was increased, leading to reduced plasma glucose concentration. The PPARgamma transgene increased the expression of Glut4 in the muscle. This result suggests that there was increased glucose utilization and, therefore, a reduced blood glucose concentration in the transgenic mice. Also, the plasma adiponectin was elevated by fish oil treatment, suggesting a role of adiponectin in mediating the PUFA effect. These results suggest that PUFA may serve as a natural regulator of glucose uptake in vivo and these effects are mainly through PPARgamma function. PMID- 20970315 TI - Integration of single-cell trapping and impedance measurement utilizing microwell electrodes. AB - The ability to research individual cells has been seen as important in many kinds of biological studies. In the present study, cell impedance analysis is integrated into a single-cell trapping structure. For the purpose of precise positioning, a cell manipulation and measurement microchip, which uses an alternating current electrothermal effect (ACET) and a negative dielectrophoresis (nDEP) force to move a particle and cell on measurement electrodes, is developed. An ACET and an nDEP can be easily combined with subsequent analyses based on electric fields. A microwell presented in a previous study is separated into two parts, which are regarded as the measurement electrodes. The original structure is modified for precise positioning. Numerical simulations and analyses are conducted to compute and analyze the effects of the structural parameters. The results of simulations and analyses are used to obtain the optimum structure for the cell. The capture range of the microwell can be designed for cells of various sizes. In order to demonstrate the precision of the positioning, a particle is captured, measured, and released twice. The results show that the impedance error of the particle is about 3%. Finally, the developed structure is applied to trap and measure the impedance of a HeLa cell. PMID- 20970314 TI - Adoption and utilization of sexually transmitted infections testing in outpatient substance abuse treatment facilities serving high risk populations in the U.S. AB - BACKGROUND: Although adoption and utilization of sexually transmitted infection (STI) testing is a cost effective public health intervention, it is inconsistently offered or referred out for by outpatient substance abuse treatment (OSAT) programs where at-risk racial/ethnic and sexual minorities receive services. METHODS: We explored the organizational adoption and client utilization of STI testing using a nationally representative sample of OSAT facilities in the U.S. in 2005 (N=566). Data missing at random was imputed and the resulting database was analysed using multivariate Tobit and logistic regressions. RESULTS: The analyses suggest that private non-profit facilities, which are the largest providers of OSAT treatment are less likely than public facilities to offer STI testing or to report adequate client utilization rates. Higher utilization was instead associated with professionally accredited facilities, and with facilities whose majority of clients were Latino/a, reported a history of treatment, stayed in treatment longer, or received case management. CONCLUSION: While OSAT facilities are poised to be primary intervention points for diagnosis and treatment of STIs, only a segment of these facilities provide this preventive practice or manage to refer clients out. As such, U.S. health care policy should ensure the adoption and comprehensive utilization, particularly among high risk clients, of this cost-effective prevention strategy in OSAT admission protocols. PMID- 20970316 TI - Biomolecule-stabilized Au nanoclusters as a fluorescence probe for sensitive detection of glucose. AB - In this work, biomolecule-stabilized Au nanoclusters were demonstrated as a novel fluorescence probe for sensitive and selective detection of glucose. The fluorescence of Au nanoclusters was found to be quenched effectively by the enzymatically generated hydrogen peroxide (H(2)O(2)). By virtue of the specific response, the present assay allowed for the selective determination of glucose in the range of 1.0*10(-5) M to 0.5*10(-3) M with a detection limit of 5.0*10(-6) M. The absorption spectroscopy, X-ray photoelectron spectroscopy (XPS) and fluorescence decay studies were then performed to discuss the quenching mechanism. In addition, we demonstrated the application of the present approach in real serum samples, which suggested its great potential for diagnostic purposes. PMID- 20970317 TI - Amperometric sensors based on Ni/Al and Co/Al layered double hydroxides modified electrode and their application for hydrogen peroxide detection. AB - Two different hydrogen peroxide sensors were constructed with Ni/Al and Co/Al layered double hydroxides (LDHs) modified glassy carbon electrodes (GCE). Ni (Co)/Al-LDHs were synthesized by electrochemical method and were characterized by scanning electron microscopy (SEM) and energy dispersive spectrometry (EDS). The advantages and shortcoming of the two hydrogen peroxide sensors were described in detail. Compared to Co/Al-LDHs modified electrode, sensors fabricated by Ni/Al LDHs showed quicker heterogeneous electron transfer rate constants (k(s)), lower detection and better reproducibility. But Co/Al-LDHs modified electrode held the advantages of wider linear range and higher sensitivity. Further more, the different catalytic redox mechanisms of hydrogen peroxide on the Ni/Al/GCE and Co/Al/GCE were firstly comparatively explored. PMID- 20970318 TI - Model-based inference of biochemical parameters and dynamic properties of microbial signal transduction networks. AB - Because of the inherent uncertainty about quantitative aspects of signalling networks it is of substantial interest to use computational methods that allow inferring non-measurable quantities such as rate constants, from measurable quantities such as changes in protein abundances. We argue that true biochemical parameters like rate constants can generally not be inferred using models due to their non-identifiability. Recent advances, however, facilitate the analysis of parameter identifiability of a given model and automated discrimination of candidate models, both being important techniques to still extract quantitative biological information from experimental data. PMID- 20970319 TI - Programming embryonic stem cells to neuronal subtypes. AB - Richness of neural circuits and specificity of neuronal connectivity depend on the diversification of nerve cells into functionally and molecularly distinct subtypes. Although efficient methods for directed differentiation of embryonic stem cells (ESCs) into multiple principal neuronal classes have been established, only a few studies systematically examined the subtype diversity of in vitro derived nerve cells. Here we review evidence based on molecular and in vivo transplantation studies that ESC-derived spinal motor neurons and cortical layer V pyramidal neurons acquire subtype specific functional properties. We discuss similarities and differences in the role of cell-intrinsic transcriptional programs, extrinsic signals and cell-cell interactions during subtype diversification of the two classes of nerve cells. We conclude that the high degree of fidelity with which differentiating ESCs recapitulate normal embryonic development provides a unique opportunity to explore developmental processes underlying specification of mammalian neuronal diversity in a simplified and experimentally accessible system. PMID- 20970320 TI - Control of masculinization of the brain and behavior. AB - Sex steroid hormones exert a profound influence on the sexual differentiation and function of the neural circuits that mediate dimorphic behaviors. Both estrogen and testosterone are essential for male typical behaviors in many species. Recent studies with genetically modified mice provide important new insights into the logic whereby these two hormones coordinate the display of sexually dimorphic behaviors: estrogen sets up the masculine repertoire of sexual and territorial behaviors and testosterone controls the extent of these male displays. PMID- 20970322 TI - Sphingosine kinase-1 activity and expression in human prostate cancer resection specimens. AB - PURPOSE: Sphingosine kinase-1 (SphK1) was shown in preclinical models and non genitourinary cancers to be instrumental in cancer progression, adaptation to hypoxia and in tumour angiogenesis. No data were available in human prostate cancer. The present study was designed to assess SphK1 expression and activity in radical prostatectomy specimens and to research correlations with clinical features. MATERIALS AND METHODS: Transverse section of fresh tissue was obtained from 30 consecutive patients undergoing laparoscopic prostatectomy. SphK1 enzymatic activities of tumour and normal counterpart were determined. Relationships with PSA, Gleason sum, pathological stage, resection margin status and treatment failure were researched. SphK1 pattern of expression was then assessed on tissue microarray. RESULTS: A significant 2-fold increase in SphK1 enzymatic activity(11.1 +/- 8.4 versus 5.9 +/- 3.2 (P<0.04)) was observed in cancer. The upper quartile of SphK1 activity was associated with higher PSA (16.7 versus 6.4 ng/ml, P = 0.04), higher tumor volumes (20.7 versus 9.8, P = 0.002), higher rates of positive margins (85.7% versus 28.6%, P = 0.01) and surgical failure (71.4% versus 9.5%, P = 0.003) than the lower three quartiles. Odds ratios (OR) for treatment failure showed a strong relationship with SphK1 activity (OR: 23.7, P = 0.001), positive resection margins (OR: 15.0, P = 0.007) and Gleason sum (>=4+3, OR: 8.0, P = 0.003). Tissue microarrays showed discrete epithelial expression that varied with Gleason sum with significant relationship between SphK1 expression and higher Gleason sum. CONCLUSION: In complement to preclinical literature, the demonstrated relationships between SphK1-increased activity in cancer and relevant clinical features confirm a central role for SphK1 in prostate cancer that herald promising avenues in risk-assessment and treatment. PMID- 20970321 TI - Movement, technology and discovery in the zebrafish. AB - Zebrafish provide unique opportunities for optogenetic studies of behavior. Here, we review the most recent work using optogenetic and imaging approaches to study the neuronal circuits controlling movements in the transparent zebrafish. Specifically, we focus on what we have learned from zebrafish about neuronal migration, network formation and behavioral control, and what the future may hold. PMID- 20970323 TI - Outcome of children and adolescents with relapsed acute lymphoblastic leukaemia and non-response to salvage protocol therapy: a retrospective analysis of the ALL REZ BFM Study Group. AB - AIM OF THE STUDY: Non-response (NR) to treatment of childhood relapsed acute lymphoblastic leukaemia (ALL) is an end-point of protocol therapy. Subsequent management has not yet been standardised. This study analyses different approaches after NR to aid optimising future strategies. PATIENTS AND METHODS: Ninety-three children with NR to treatment according to ALL relapse-protocols of the Berlin/Frankfurt/Muenster (BFM) Study Group (03/1990-2006/1999) were retrospectively assigned to a curative (C: intensive polychemotherapies, stem cell transplantation (SCT); n=51), palliative (P: 1-2 antineoplastic agents; n=23) or supportive (S: no antineoplastic therapy; n=19) treatment approach. RESULTS: Median survival after diagnosis of NR were 121 (C), 89 (P) and 42 (S) days, respectively (p<0.001). In cohort C, a complete remission (2ndCR) was obtained in 16/51 patients, among these 13 only after SCT, and nine children achieved partial remission. Ten of the 51 patients died from treatment-related complications, 39/51 from disease progression. Today, two patients are still in continuous CR after SCT. Adverse prognostic factors were overrepresented in the non-curative cohorts. Time-point of relapse and treatment after NR were independent predictors of survival duration. Most patients without antineoplastic treatment died at home, the majority of the others in the hospital. CONCLUSIONS: Treatment after NR has been heterogeneous and customised. Therapies with curative intent are capable of inducing 2ndCR but associated with high treatment-related morbidity, -mortality and minimal survival. NR patients may, therefore, be ideal candidates for controlled phase I/II trials, thus offering them a chance to benefit from new drugs and promoting drug development for cohorts with better prognosis. PMID- 20970324 TI - Bacteria involved in sulfur amendment oxidation and acidification processes of alkaline 'alperujo' compost. AB - Eight strains of sulfur oxidizing bacteria were isolated from alkaline 'alperujo' compost, seven being identified as Paracoccus thiocyanatus and one as Halothiobacillus neapolitanus. This was the first time that P. thiocyanatus was isolated from mature compost. Acidification capability of isolated strains was compared with type strains H. neapolitanus CIP104769, Thiobacillus denitrificans CIP104767 and Thiomonas intermedia CIP104401. Indigenous P. thiocyanatus strains were as much as or more efficient for acidifying compost than type strains. Sulfur oxidizing population naturally occurring in compost showed maximum acidification efficiency and no extra effect was found with the help of type strains. pH reduction caused by S? was paralleled by a decrease in CaCO3 and an increase in CaSO4 and salinity levels. A remarkable increase in cultivable sulfur oxidizing bacteria population along with the acidification process was also recorded. Amended compost showed a range of chemical and biological characteristics suitable for use as container media constituent. PMID- 20970325 TI - Temperature shifts induce intraspecific variation in microalgal production and biochemical composition. AB - Three Isochrysis galbana strains, one I. galbana "substrain", and one Nannochloropsis sp. strain were grown in nutrient replete conditions at 15, 20, 25, and 30 degrees C. The interactive effect of temperature and isolate on growth rate, cell volume, production, dry weight, protein content, carbohydrate content, and total lipid content was examined. Nannochloropsis sp., growth rate had no relation with temperature; all I. galbana isolates increased linearly with temperature, with no significant differences. Cell volume and dry weight decreased linearly with temperature, with significant isolate and species differences. Biovolume-production did not vary significantly with temperature, but significant isolate and species differences occurred. Although significant temperature isolate interactions existed, no consistent trends in the change of protein, carbohydrate, and lipid with temperature occurred. We indicate a need to consider temperature induced affects in application using microalgae isolates, at various taxonomic levels, as some intraspecific differences were as great as interspecific differences. PMID- 20970326 TI - The role of loading rate, backwashing, water and air velocities in an up-flow nitrifying tertiary filter. AB - The vertical distribution of nitrification performances in an up-flow biological aerated filter operated at tertiary nitrification stage is evaluated in this paper. Experimental data were collected from a semi-industrial pilot-plant under various operating conditions. The actual and the maximum nitrification rates were measured at different levels inside the up-flow biofilter. A nitrogen loading rate higher than 1.0 kg NH4-Nm(-3)_mediad(-1) is necessary to obtain nitrification activity over all the height of the biofilter. The increase in water and air velocities from 6 to 10 m h(-1) and 10 to 20 m h(-1) has increased the nitrification rate by 80% and 20% respectively. Backwashing decreases the maximum nitrification rate in the media by only 3-14%. The nitrification rate measured at a level of 0.5 m above the bottom of the filter is four times higher than the applied daily average volumetric nitrogen loading rate up to 1.5 kg NH4 N m(-3)_mediad(-1). Finally, it is shown that 58% of the available nitrification activity is mobilized in steady-state conditions while up to 100% is used under inflow-rate increase. PMID- 20970327 TI - Evaluation of microalgae cultivation using recovered aqueous co-product from thermochemical liquefaction of algal biomass. AB - This study characterized the ACP stream from the TCL of Spirulina and evaluated its potential as a nutrient source for cultivation of microalgae. TCL of 100 g of dry Spirulina resulted in 40% BioOil and 429.80% ACP. The ACP was found to have high nitrogen (16,200 mg L(-1)), phosphorus (795 mg L(-1)), potassium (11,260 mg L(-1)) and secondary and micronutrients. Growth media were prepared using ACP as sole nutrient source in deionized water at 0.2%, 0.33%, 1%, and 10% v/v concentration and compared with a standard growth medium (BG 11) for algal cultivation. Chlorella minutissima was grown in these media for 12 days and monitored for biomass concentration, total chlorophyll and lipids. Biomass productivities with the ACP added media at 0.2% and 0.1% concentration were 0.035 and 0.027 g L(-1) d(-1), respectively, compared to 0.07 g L(-1) d(-1) in BG 11. PMID- 20970328 TI - Post-anoxic denitrification driven by PHA and glycogen within enhanced biological phosphorus removal. AB - The objective of this research was to interrogate and develop a better understanding for a process to achieve post-anoxic denitrification without exogenous carbon augmentation within enhanced biological phosphorus removal (EBPR). Sequencing batch reactors fed real wastewater and seeded with mixed microbial consortia were operated under variable anaerobic-aerobic-anoxic and organic carbon loading conditions. The process consistently achieved phosphorus and nitrogen removal, while the observed specific denitrification rates were markedly higher than expected for post-anoxic systems operated without exogenous organic carbon addition. Investigations revealed that post-anoxic denitrification was predominantly driven by glycogen, an intracellular carbon storage polymer associated with EBPR; moreover, glycogen reserves can be significantly depleted post-anoxically without compromising EBPR. Success of the proposed process is predicated on providing sufficient organic acids in the influent wastewater, such that residual nitrate carried over from the post-anoxic period is reduced and polyhydroxyalkanoate (PHA) synthesis occurs. PMID- 20970329 TI - Sulfonamide derivatives of styrylheterocycles as a potent inhibitor of COX-2 mediated prostaglandin E2 production. AB - The overproduction of prostaglandin E(2) (PGE(2)) plays an important role in a variety of pathophysiological processes including inflammation and carcinogenesis. Therefore, the modulation of PGE(2) production is a promising target in the design of chemotherapeutic agents. In the present study, the inhibitory effects of a series of styrylheterocycles having either a p-SO(2)NH(2) or p-SO(2)Me group on the production of cyclooxygenase-2-mediated PGE(2) were evaluated in lipopolysaccharide-stimulated RAW264.7 murine macrophages. Among the series of styrylheterocycle derivatives, (E)-4-(2-(thiophen-3 yl)vinyl)benzenesulfonamide exhibited a potent inhibitory activity, with an IC(50) value of 0.013 MUM. The inhibitory activity against the overproduction of PGE(2) by the active compound was found to be due in part to the suppression of COX-2 mRNA expression. PMID- 20970330 TI - Mycoepoxydiene, a fungal polyketide, induces cell cycle arrest at the G2/M phase and apoptosis in HeLa cells. AB - Mycoepoxydiene (MED) is a polyketide isolated from a marine fungus associated with mangrove forests. It contains an oxygen-bridged cyclooctadiene core and an alpha,beta-unsaturated delta-lactone moiety. MED induced the reorganization of cytoskeleton in actively growing HeLa cells by promoting formation of actin stress fiber and inhibiting polymerization of tubulin. MED could induce cell cycle arrest at G2/M in HeLa cells. MED-associated apoptosis was characterized by the formation of fragmented nuclei, PARP cleavage, cytochrome c release, activation of caspase-3, and an increased proportion of sub-G1 cells. Additionally, MED activated MAPK pathways. Interestingly, the time of JNK, p38, and Bcl-2 activation did not correlate with the release of cytochrome c. This study is the first report demonstrating the action mechanism of MED against tumor cell growth. These results provide the potential of MED as a novel low toxic antitumor agent. PMID- 20970331 TI - Pyrazole derivatives from azines of substituted phenacyl aryl/cyclohexyl sulfides and their antimycobacterial activity. AB - Azines derived from substituted phenacyl aryl/cyclohexyl sulfide on treatment with excess phosphorous oxychloride in N,N-dimethylformamide have been found to yield two isomeric pyrazoles in each case. A plausible mechanism has been suggested for the formation of the products. The antimycobacterial activity of the isomeric compounds has been tested against Mycobacterium tuberculosis (MTB). PMID- 20970332 TI - Structure-based design, synthesis and A-site rRNA co-crystal complexes of novel amphiphilic aminoglycoside antibiotics with new binding modes: a synergistic hydrophobic effect against resistant bacteria. AB - Incorporation of an hydrophobic (phenethylamino)ethyl ether at C2" of N1-(HABA) 3',4'-dideoxyparomomycin led to a novel analog with an excellent antibacterial profile against a host of resistant bacteria. PMID- 20970333 TI - The incidence of symptomatic thromboembolism in patients receiving adjuvant anthracycline-based chemotherapy for early stage breast cancer. AB - Thromboembolism is a well recognised complication of systemic chemotherapy and cancer. Its incidence is frequently not reported in clinical trials of adjuvant chemotherapy for early stage breast cancer. Our own experience suggested that thromboembolic complications were common and we undertook a retrospective review of consecutive patients receiving adjuvant chemotherapy to determine the incidence and morbidity/mortality of this complication. A total of 280 consecutive patients were identified who had received adjuvant ECMF chemotherapy between January 2001 and February 2007. Thromboembolic events occurred in 21 patients (7.5%). Events were distributed across chemotherapy cycles, but were more common during CMF chemotherapy (18 cases vs 3 cases). Patients over the age of 60 years appeared to be at particular risk of thromboembolism with an event rate of 27% (15/56 patients). Thromboembolic events were associated with dose delays and cessation of chemotherapy in some patients. With a median follow up of 28 months there is no significant difference in the incidence of breast cancer recurrence (16.7% vs 14.3%, p=0.9) or overall survival (89.5% vs 89.9%, p=0.8) between patients who experienced a thromboembolic event during adjuvant chemotherapy and those who did not. Based on the incidence of thromboembolism in our unselected patient population we believe that further prospective studies are indicated seeking to identify those patients at increased risk of this important complication who might benefit from thromboprophylaxis. PMID- 20970334 TI - Nuclear compartmentalization is abolished during fission yeast meiosis. AB - In eukaryotic cells, the nuclear envelope partitions the nucleus from the cytoplasm. The fission yeast Schizosaccharomyces pombe undergoes closed mitosis in which the nuclear envelope persists rather than being broken down, as in higher eukaryotic cells. It is therefore assumed that nucleocytoplasmic transport continues during the cell cycle. Here we show that nuclear transport is, in fact, abolished specifically during anaphase of the second meiotic nuclear division. During that time, both nucleoplasmic and cytoplasmic proteins disperse throughout the cell, reminiscent of the open mitosis of higher eukaryotes, but the architecture of the S. pombe nuclear envelope itself persists. This functional alteration of the nucleocytoplasmic barrier is likely induced by spore wall formation, because ectopic induction of sporulation signaling leads to premature dispersion of nucleoplasmic proteins. A photobleaching assay demonstrated that nuclear envelope permeability increases abruptly at the onset of anaphase of the second meiotic division. The permeability was not altered when sporulation was inhibited by blocking the trafficking of forespore-membrane vesicles from the endoplasmic reticulum to the Golgi. The evidence indicates that yeast gametogenesis produces vesicle transport-mediated forespore membranes by inducing nuclear envelope permeabilization. PMID- 20970335 TI - Localization and activation of the Drosophila protease easter require the ER resident saposin-like protein seele. AB - Drosophila embryonic dorsal-ventral polarity is generated by a series of serine protease processing events in the egg perivitelline space. Gastrulation Defective processes Snake, which then cleaves Easter, which then processes Spatzle into the activating ligand for the Toll receptor. seele was identified in a screen for mutations that, when homozygous in ovarian germline clones, lead to the formation of progeny embryos with altered embryonic patterning; maternal loss of seele function leads to the production of moderately dorsalized embryos. By combining constitutively active versions of Gastrulation Defective, Snake, Easter, and Spatzle with loss-of-function alleles of seele, we find that Seele activity is dispensable for Spatzle-mediated activation of Toll but is required for Easter, Snake, and Gastrulation Defective to exert their effects on dorsal-ventral patterning. Moreover, Seele function is required specifically for secretion of Easter from the developing embryo into the perivitelline space and for Easter processing. Seele protein resides in the endoplasmic reticulum of blastoderm embryos, suggesting a role in the trafficking of Easter to the perivitelline space, prerequisite to its processing and function. Easter transport to the perivitelline space represents a previously unappreciated control point in the signal transduction pathway that controls Drosophila embryonic dorsal-ventral polarity. PMID- 20970336 TI - Electrostatic cell-surface repulsion initiates lumen formation in developing blood vessels. AB - Blood vessels function in the uptake, transport, and delivery of gases and nutrients within the body. A key question is how the central lumen of blood vessels develops within a cord of vascular endothelial cells. Here, we demonstrate that sialic acids of apical glycoproteins localize to apposing endothelial cell surfaces and generate repelling electrostatic fields within an endothelial cell cord. Both in vitro and in vivo experiments show that the negative charge of sialic acids is required for the separation of endothelial cell surfaces and subsequent lumen formation. We also demonstrate that sulfate residues can substitute for sialic acids during lumen initiation. These results therefore reveal a key step in the creation of blood vessels, the most abundant conduits in the vertebrate body. Because negatively charged mucins and proteoglycans are often found on luminal cell surfaces, it is possible that electrostatic repulsion is a general principle also used to initiate lumen formation in other organs. PMID- 20970337 TI - Sensitive period for a multimodal response in human visual motion area MT/MST. AB - The middle temporal complex (MT/MST) is a brain region specialized for the perception of motion in the visual modality. However, this specialization is modified by visual experience: after long-standing blindness, MT/MST responds to sound. Recent evidence also suggests that the auditory response of MT/MST is selective for motion. The developmental time course of this plasticity is not known. To test for a sensitive period in MT/MST development, we used fMRI to compare MT/MST function in congenitally blind, late-blind, and sighted adults. MT/MST responded to sound in congenitally blind adults, but not in late-blind or sighted adults, and not in an individual who lost his vision between ages of 2 and 3 years. All blind adults had reduced functional connectivity between MT/MST and other visual regions. Functional connectivity was increased between MT/MST and lateral prefrontal areas in congenitally blind relative to sighted and late blind adults. These data suggest that early blindness affects the function of feedback projections from prefrontal cortex to MT/MST. We conclude that there is a sensitive period for visual specialization in MT/MST. During typical development, early visual experience either maintains or creates a vision dominated response. Once established, this response profile is not altered by long-standing blindness. PMID- 20970338 TI - Fission yeast Mto1 regulates diversity of cytoplasmic microtubule organizing centers. AB - Microtubule nucleation by the gamma-tubulin complex occurs primarily at centrosomes, but more diverse types of microtubule organizing centers (MTOCs) also exist, especially in differentiated cells. Mechanisms generating MTOC diversity are poorly understood. Fission yeast Schizosaccharomyces pombe has multiple types of cytoplasmic MTOCs, and these vary through the cell cycle. Cytoplasmic microtubule nucleation in fission yeast depends on a complex of proteins Mto1 and Mto2 (Mto1/2), which localizes to MTOCs and interacts with the gamma-tubulin complex. Localization of Mto1 to prospective MTOC sites has been proposed as a key step in gamma-tubulin complex recruitment and MTOC formation, but how Mto1 localizes to such sites has not been investigated. Here we identify a short conserved C-terminal sequence in Mto1, termed MASC, important for targeting Mto1 to multiple distinct MTOCs. Different subregions of MASC target Mto1 to different MTOCs, and multimerization of MASC is important for efficient targeting. Mto1 targeting to the cell equator during division depends on direct interaction with unconventional type II myosin Myp2. Targeting to the spindle pole body during mitosis depends on Sid4 and Cdc11, components of the septation initiation network (SIN), but not on other SIN components. PMID- 20970340 TI - Stereotypical cell division orientation controls neural rod midline formation in zebrafish. AB - The development of multicellular organisms is dependent on the tight coordination between tissue growth and morphogenesis. The stereotypical orientation of cell divisions has been proposed to be a fundamental mechanism by which proliferating and growing tissues take shape. However, the actual contribution of stereotypical division orientation (SDO) to tissue morphogenesis is unclear. In zebrafish, cell divisions with stereotypical orientation have been implicated in both body-axis elongation and neural rod formation, although there is little direct evidence for a critical function of SDO in either of these processes. Here we show that SDO is required for formation of the neural rod midline during neurulation but dispensable for elongation of the body axis during gastrulation. Our data indicate that SDO during both gastrulation and neurulation is dependent on the noncanonical Wnt receptor Frizzled 7 (Fz7) and that interfering with cell division orientation leads to severe defects in neural rod midline formation but not body-axis elongation. These findings suggest a novel function for Fz7 controlled cell division orientation in neural rod midline formation during neurulation. PMID- 20970339 TI - Meiotic errors activate checkpoints that improve gamete quality without triggering apoptosis in male germ cells. AB - BACKGROUND: Meiotic checkpoints ensure the production of gametes with the correct complement and integrity of DNA; in metazoans, these pathways sense errors and transduce signals to trigger apoptosis to eliminate damaged germ cells. The extent to which checkpoints monitor and safeguard the genome differs between sexes and may contribute to the high frequency of human female meiotic errors. In the C. elegans female germline, DNA damage, chromosome asynapsis, and/or unrepaired meiotic double-strand breaks (DSBs) activate checkpoints that induce apoptosis; conversely, male germ cells do not undergo apoptosis. RESULTS: Here we show that the recombination checkpoint is in fact activated in male germ cells despite the lack of apoptosis. The 9-1-1 complex and the phosphatidylinositol 3 kinase-related protein kinase ATR, sensors of DNA damage, are recruited to chromatin in the presence of unrepaired meiotic DSBs in both female and male germlines. Furthermore, the checkpoint kinase CHK-1 is phosphorylated and the p53 ortholog CEP-1 induces expression of BH3-only proapoptotic proteins in germlines of both sexes under activating conditions. The core cell death machinery is expressed in female and male germlines; however, CED-3 caspase is not activated in the male germline. Although apoptosis is not triggered, checkpoint activation in males has functional consequences for gamete quality, because there is reduced viability of progeny sired by males with a checkpoint-activating defect in the absence of checkpoint function. CONCLUSIONS: We propose that the recombination checkpoint functions in male germ cells to promote repair of meiotic recombination intermediates, thereby improving the fidelity of chromosome transmission in the absence of apoptosis. PMID- 20970341 TI - A coordinated global control over cellular transcription. AB - Although much is known about the regulation of gene transcription in eukaryotes, it is not clear whether cells have global controls that determine overall rates of transcription. We have investigated the effects that the DNA-to-protein ratio has on both total transcription and the transcription of individual genes in the unicellular eukaryote fission yeast. Mutants altered in cell size and those blocked in cell-cycle progression were used to vary the DNA-to-protein ratio over a 5-fold range. We found that cells of sizes within 2-fold of the wild-type value regulated global transcription to maintain similar transcription rates per protein regardless of the cellular DNA content. These changes in total transcription correlated with coordinated changes in gene occupancy by RNA polymerase II. In cell-cycle-arrested mutants exceeding a certain size, total transcription rates plateaued as DNA became limiting for transcription at low DNA to-protein ratios [1]. Unexpectedly, expression levels of individual genes remained tightly coordinated with each other over the entire range of cell sizes. We propose that there is a coordinated, global control that determines the rate of transcription of most genes and that this control plays a role in regulating growth rate of the cell. PMID- 20970342 TI - Virtual breakdown of the nuclear envelope in fission yeast meiosis. AB - Asymmetric localization of Ran regulators (RanGAP1 and RanGEF/RCC1) produces a gradient of RanGTP across the nuclear envelope. In higher eukaryotes, the nuclear envelope breaks down as the cell enters mitosis (designated "open" mitosis). This nuclear envelope breakdown (NEBD) leads to collapse of the RanGTP gradient and the diffusion of nuclear and cytoplasmic macromolecules in the cell, resulting in irreversible progression of the cell cycle. On the other hand, in many fungi, chromosome segregation takes place without NEBD (designated "closed" mitosis). Here we report that in the fission yeast Schizosaccharomyces pombe, despite the nuclear envelope and the nuclear pore complex remaining intact throughout both the meiotic and mitotic cell cycles, nuclear proteins diffuse into the cytoplasm transiently for a few minutes at the onset of anaphase of meiosis II. We also found that nuclear protein diffusion into the cytoplasm occurred coincidently with nuclear localization of Rna1, an S. pombe RanGAP1 homolog that is usually localized in the cytoplasm. These results suggest that nuclear localization of RanGAP1 and depression of RanGTP activity in the nucleus may be mechanistically tied to meiosis-specific diffusion of nuclear proteins into the cytoplasm. This nucleocytoplasmic shuffling of RanGAP1 and nuclear proteins represents virtual breakdown of the nuclear envelope. PMID- 20970343 TI - Nucleoredoxin sustains Wnt/beta-catenin signaling by retaining a pool of inactive dishevelled protein. AB - Overexpression of Dishevelled (Dvl), an essential component of the Wnt signaling pathway, is frequently associated with tumors, and thus the Dvl protein level must be tightly controlled to sustain Wnt signaling without causing tumors. Kelch like 12 (KLHL12) targets Dvl for ubiquitination and degradation, suggesting its potential importance in avoiding aberrant Dvl overexpression. However, the regulatory mechanism of the KLHL12 activity remained elusive. We show here that nucleoredoxin (NRX) determines the Dvl protein level, which is revealed by analyses on NRX(-/-) mice showing skeletal and cardiovascular defects. Consistent with the previously reported Dvl-inhibiting function of NRX, Wnt/beta-catenin signaling is hyperactivated in NRX(-/-) osteoblasts. However, the signal activity is suppressed in cardiac cells, where KLHL12 is highly expressed. Biochemical analyses reveal that Dvl is rapidly degraded by accelerated ubiquitination in NRX(-/-) mouse embryonic fibroblasts, and they fail to activate Wnt/beta-catenin signaling in response to Wnt ligands. Moreover, experiments utilizing purified proteins show that NRX expels KLHL12 from Dvl and inhibits ubiquitination. These findings reveal an unexpected function of NRX, retaining a pool of inactive Dvl for robust activation of Wnt/beta-catenin signaling upon Wnt stimulation. PMID- 20970344 TI - Preoperative factors affecting the outcome of unruptured posterior circulation aneurysm surgery. AB - We retrospectively investigated preoperative variables contributing to adverse surgical outcome for repair of unruptured posterior circulation aneurysms on data collected prospectively between October 1989 and March 2010. Putative risk factors including age, sex, smoking status, positive family history, modified Rankin Score prior to the surgery, size of the aneurysm, specific site (basilar caput and trunk, vertebral artery and posterior inferior cerebellar artery), midline location, presence of calcium, thrombus or irregularity in the aneurysm on preoperative imaging, associated arteriovenous malformation and preoperative coiling were investigated using regression analyses. In a total of 121 operations, surgical mortality and morbidity was 16.3%. For patients with aneurysms less than 9mm this rate was 3.2%. Among the investigated variables we found that size, calcification of the aneurysm and age were each predictors of surgical outcome of unruptured posterior circulation aneurysms. PMID- 20970345 TI - Commentary: paraclinoid carotid aneurysms. PMID- 20970346 TI - Probing the active-site requirements of human intestinal N-terminal maltase glucoamylase: Synthesis and enzyme inhibitory activities of a six-membered ring nitrogen analogue of kotalanol and its de-O-sulfonated derivative. AB - In order to probe the active-site requirements of the human N-terminal subunit of maltase-glucoamylase (ntMGAM), one of the clinically relevant intestinal enzymes targeted for the treatment of type-2 diabetes, the syntheses of two new inhibitors are described. The target compounds are structural hybrids of kotalanol, a naturally occurring glucosidase inhibitor with a unique five membered ring sulfonium-sulfate inner salt structure, and miglitol, a six membered ring antidiabetic drug that is currently in clinical use. The compounds comprise the six-membered ring of miglitol and the side chain of kotalanol or its de-O-sulfonated derivative. Inhibition studies of these hybrid molecules with human ntMGAM indicated that they are inhibitors of this enzyme with comparable K(i) values to that of miglitol (kotalanol analogue: 2.3+/-0.6MUM; corresponding de-O-sulfonated analogue: 1.4+/-0.5MUM; miglitol: 1.0+/-0.1MUM). However, they are less active compared to kotalanol (K(i)=0.19+/-0.03MUM). These results suggest that the (3)T(2) enzyme-bound conformation of the five-membered thiocyclitol moiety of the kotalanol class of compounds more closely resembles the (4)H(3) conformation of the proposed transition state for the formation of an enzyme-substrate covalent intermediate in the glycosidase hydrolase family 31 (GH31)-catalyzed reaction. PMID- 20970347 TI - Selective accumulation of a novel antimalarial rhodacyanine derivative, SSJ-127, in an organelle of Plasmodium berghei. AB - SSJ-127, a novel antimalarial rhodacyanine derivative, has shown potent antimalarial activity against chloroquine-resistant Plasmodium strains in vitro and subcutaneous administration of SSJ-127 results in a complete cure of a mouse malaria model. SSJ-127 was detected by fluorescence microscopy in the mouse malaria parasites Plasmodium berghei after exposure of infected red blood cells to the compound in vitro and in vivo. Selective accumulation of SSJ-127 in an organelle is observed in all blood stages of live malaria parasites. The organelle is clearly different from the mitochondrion and the nucleus in terms of morphology. The shape of the organelle changed during the asexual blood stages of the parasite. There was always a close association between the organelle and the mitochondrion. These results raised the possibility that SSJ-127 accumulates in an apicoplast of the malaria parasite and affects protozoan parasite-specific pathways. PMID- 20970348 TI - Characterization of 210Pb and 137Cs radionuclides in sediment from Lake Shinji, Shimane Prefecture, western Japan. AB - The characterization and chemical behaviors of (210)Pb and (137)Cs in the surface sediment (4-7 cm depth from the bottom) from Lake Shinji, Shimane Prefecture, western Japan, are studied by grain size and phase analyses. Their activities had increasing trend in silt fractions with decreasing grain size, while those in sand fractions did with increasing grain size. The (40)K content had the general increasing trend with increasing grain size. These trends might be derived from the mineral component and the adsorption mechanism of these nuclides. By using the sequential extraction technique, most of (214)Pb, (137)Cs and (40)K were proved to be contained in silicate fraction. A part of (210)Pbex presumably existed as carbonate and iron manganese oxides for coarser grains, and as iron manganese oxides for finer grains, in addition to silicate fraction. Although (210)Pb and (137)Cs may occupy the different sites and exist in different chemical phases, the bulk contents in the samples from a variety of locations within the same lake showed a generally good correlation. This result suggests their similar depositional process within a lake in a macroscopic view, being one of the evidences for the validity of sedimentation chronology in the field. PMID- 20970349 TI - A novel hydrogen sulfide donor causes stomatal opening and reduces nitric oxide accumulation. AB - Effects of hydrogen sulfide (H(2)S) on plant physiology have been previously studied, but such studies have relied on the use of NaSH as a method for supplying H(2)S to tissues. Now new compounds which give a less severe H(2)S shock and a more prolonged exposure to H(2)S have been developed. Here the effects of one such compound, GYY4137, has been investigated to determine its effects on stomatal closure in Arabidopsis thaliana. It was found that both NaSH and GYY4137 caused stomatal opening in the light and prevented stomatal closure in the dark. Nitric oxide (NO) has been well established as a mediator of stomatal movements and here it was found that both NaSH and GYY4137 reduced the accumulation of NO in guard cells, perhaps suggesting a mode of action for H(2)S in this system. GYY4137, and future related compounds, will be important tools to unravel the effects of plant exposure to H(2)S and to determine how H(2)S may fit into plant cell signalling pathways. PMID- 20970350 TI - Salt stress differentially affects growth-mediating beta-expansins in resistant and sensitive maize (Zea mays L.). AB - Salinity mainly reduces shoot growth by the inhibition of cell division and elongation. Expansins loosen plant cell walls. Moreover, the expression of some isoforms is clearly correlated with growth. Effects of salinity on beta-expansin transcripts protein abundance were recently reported for different crop species. This study provides a broad analysis of the impact of an 8-day 100mM NaCl stress treatment on the mRNA expression of different maize (Zea mays L.) beta-Expansin isoforms using real-time quantitative RT-PCR. The composite beta-expansin protein expression was analyzed by western blotting using an anti-peptide antibody raised against a conserved 15-amino-acid region shared by vegetatively expressed beta expansin isoforms. For the first time, changes in beta-expansin transcript and protein abundance have been analyzed together with the salinity-induced inhibition of shoot growth. A salt-resistant and a salt-sensitive cultivar were compared in order to elucidate physiological changes. Genotypic differences in the relative concentration of six beta-expansin transcripts together with differences in the abundance beta-expansin protein are shown in response NaCl stress. In salt-sensitive Lector, reduced beta-expansin protein expression was found to correlate positively with reduced shoot growth under stress. A down regulation of ZmExpB2, ZmExpB6, and ZmExpB8 transcripts possibly contribute to this decrease in protein abundance. In contrast, the maintenance of shoot growth in salt-resistant SR03 might be related to an unaffected abundance of growth mediating beta-expansin proteins in the shoot. Our data suggest that the up regulation of ZmExpB2, ZmExpB6, and ZmExpB8 may sustain the stable expression of beta-expansin protein under conditions of salt stress. PMID- 20970351 TI - Short-term effects of inhalative tiotropium/formoterol/budenoside versus tiotropium/formoterol in patients with newly diagnosed chronic obstructive pulmonary disease requiring surgery for lung cancer: a prospective randomized trial. AB - OBJECTIVE: A new diagnosis of chronic obstructive pulmonary disease (COPD) is often made during the evaluation of patients requiring a surgical intervention for lung cancer. Based on initial impaired lung function, these untreated patients are often considered not fit for lung surgery. There is limited information on the short-term effectiveness of preoperative pharmacologic treatment strategies in patients with newly diagnosed COPD before lung surgery. METHODS: A prospective randomized study was conducted comparing 1-week-treatment periods of tiotropium/formoterol/budenoside (GR1) with tiotropium/formoterol (GR2) in conjunction with smoking cessation and chest physiotherapy. No patients had been previously treated for COPD. The primary end point was body plethysmography (forced expiratory volume in 1s (FEV1), forced vital capacity (FVC), and airway resistance (RAW)) at the end of each treatment period. Secondary end points were improvement of >= 10% in FEV1 (% predicted) and improvement of the severity of COPD after the 1-week treatment, as well as the rate of pulmonary complications after surgery. RESULTS: A total of 46 patients were randomized in GR1 (n=24) and GR2 (n=22). Both groups were comparable with regard to age, height, weight, smoking history, baseline body plethysmography (FVC, FEV1, and RAW), and the severity of COPD according to the Global Initiative for Obstructive Lung Disease (GOLD) staging, respectively. However, the short term effects of the treatment with regard to FEV1 (2.0 l vs 1.7 l; p=0.031) and increase of FEV1 (0.31 l vs 0.10 l; p=0.02) were better in GR1. More patients in GR1 had an improvement of >= 10% in FEV1 (p=0.004) and improvement of the severity of COPD (p=0.012) after the 1-week treatment. Fewer pulmonary complications (11.1% vs 42.9%, p=0.04) were observed in GR1 after surgery. CONCLUSIONS: Both therapies resulted in an improvement of lung function. There is benefit from adding inhalative budenoside to tiotropium and formoterol in terms of an improvement in FEV1 and the severity of COPD. These beneficial results might lead to less pulmonary complications in the postoperative period. PMID- 20970352 TI - Adaptation strategies of the sheathed cyanobacterium Lyngbya majuscula to ultraviolet-B. AB - Lyngbya majuscula is a dominant organism in the east coast of India forming characteristic mat in dried saline soils simultaneously exposed to solar radiation of the tropics. Studies on the growth response, changes in the spectral properties of the methanolic extract and protein profile of this estuarine sheathed cyanobacterium to UV-B revealed existence of effective adaptation mechanism to withstand prolonged UV-B radiation. Carotenoids along with MAAs of the organism was increased with increase in UV irradiation. Increase in thickness of the mucilaginous sheath layer as well as cellular carbohydrate content was observed upon exposure to prolonged UV-B dose. Induction of 21 and 33 kDa low molecular weight proteins, and a 99 kDa protein together with formation of distinct multilayered sheath embedding trichomes with granulated cells were the adaptive features of the organism to cope with UV-B stress. The organism was considerably revived after incubating the irradiated cells in mineral medium under florescent light and in the dark suggesting existence of photoreactivation and dark repair in this cyanobacterium. However more experiments are needed to establish the existence of photoreactivation and dark repair mechanism in the studied cyanobacterium. PMID- 20970353 TI - Chemotherapy for the conversion of unresectable colorectal cancer liver metastases to resection. AB - Resection of colorectal liver metastases (CLM) is the ultimate aim of treatment strategies in most patients with liver-confined metastatic colorectal cancer. Long-term survival is possible in selected patients with initially resectable or unresectable CLM. As a majority of patients have unresectable liver disease at the outset, there is a clear role for chemotherapy to downstage liver disease making resection possible. Studies of systemic chemotherapy with or without biologic therapy in patients with unresectable CLM have resulted in increased response rates, liver resection rates and survival. A sound physiologic rationale exists for the use of hepatic arterial infusion (HAI) therapy. Studies have shown that HAI with floxuridine combined with systemic chemotherapy increases response rates and liver resection rates in those patients with initially unresectable CLM. Toxicity from preoperative chemotherapy, biologic therapy and HAI therapy may adversely affect hepatic resection but can be kept minimal with appropriate monitoring. All conversion strategies should be decided by a multidisciplinary team. PMID- 20970354 TI - C-arm computed tomography for hepatic interventions: a practical guide. AB - With adoption of catheter-based techniques that require technically difficult catheterization, the need for imaging platforms that exploit the advantages of multiple modalities and offer three-dimensional visualization has correspondingly increased. At the authors' institution, C-arm computed tomography (CT) is routinely used to complement conventional digital subtraction angiography for transcatheter therapy. The goal of the present report is to share experience with the use of C-arm CT in hepatic interventions, with the aim to provide practical tips for optimizing image acquisition and postprocessing. Although the authors' direct experience is limited to the equipment of a single manufacturer, many of the principles and guidelines can be readily extrapolated to other C-arm CT systems. PMID- 20970355 TI - Management of recurrent airway strictures in lung transplant recipients using AERO covered stents. AB - The potential role of AERO tracheobronchial covered stents in the management of recurrent postinfectious strictures of the bronchus intermedius was studied in three lung transplant recipients. Six devices were inserted. Five of the stents migrated immediately on placement. Buildup of thick mucus was observed in all stents remaining in the airway for longer than 1 week. Strictures recurred in all patients 1, 3, and 5 months after stent deployment. Attempts at stent retrieval were successful for three of five devices. The use of AERO stents may not offer a therapeutic advantage versus balloon dilation of bronchus intermedius strictures in lung transplant recipients. PMID- 20970356 TI - Unprotected operator eye lens doses in oncologic interventional radiology are clinically significant: estimation from patient kerma-area-product data. AB - PURPOSE: To correlate operator lens dose to patient-delivered kerma-area-product (P(KA)) to evaluate the usefulness of P(KA) as a surrogate for operator eye dose if collar monitor readings are unavailable or deemed unreliable, and to evaluate if unprotected lens dose is clinically significant. MATERIALS AND METHODS: A retrospective review of peak skin doses for consecutive interventional radiology procedures performed during 2006 that had P(KA) estimates recorded was performed. Unshielded operator lens dose equivalents (LDE) were obtained from dosimetry monitors worn outside the collar shield of operating interventional radiologists. Operator LDE were correlated with patient P(KA). RESULTS: Average LDE for 2006 was 35.7 mSv +/- 32.7 (range 5.2-89.9 mSv). Patient-delivered P(KA) correlated directly with LDE, where 1 Gy cm(2) to the patient resulted in an average of 4.2 MUSv to the unprotected eyes of the primary operator (r(2) = 0.7). CONCLUSIONS: P(KA) may be useful as a surrogate measure of operator LDE if collar monitor readings are unavailable or deemed unreliable. For this study, the dose-effect threshold for cataract formation could be surpassed for some physicians within 11 years if lens dose-mitigating strategies are not routinely employed. PMID- 20970357 TI - Temporal trends in risk factors and outcome of intracerebral hemorrhage over 18 years at a tertiary care hospital in Karachi, Pakistan. AB - BACKGROUND: The purpose of this study was to analyze the baseline characteristics and outcomes of intracerebral hemorrhage (ICH) patients at our center over the last 18 years. METHODS: Patients with ICH (first-time) were identified from medical records using International Classification of Diseases, Ninth Revision codes from 1988 to 2005. Patients were divided into 2 groups, with each group spanning 9 years based on the year of admission: the old group (admitted between 1988 and 1996) and the newer group (admitted between 1997 and 2005). RESULTS: Out of 920 patients, the number of admissions with ICH increased from <40 per year (average) during 1988 to 1996 to >60 per year (average) during 1997 to 2005. The findings indicate that the percentage of cases in males decreased from 72% to 55% in the newer group as compared to the older group, while female ICH admissions increased from 28% to 45%. Mean age of ICH onset for both men and women decreased about 5 years, but this difference was not statistically significant. Frequency of diabetes (14% v 30%), dyslipidemia (3% v 18%), and the use of antihypertensive medications (29% v 69%) was higher in newer group, while the frequency of lobar hemorrhage was found to be reduced (40% v 20%) in newer group. Lower mortality (22% in the newer group v 32% in the older group) was noted. A decreased length of hospital stay for the newer group was recorded, but this difference was not found to be statistically significant. CONCLUSION: The mean age of ICH onset for both men and women has decreased about 5 years in the newer group. Men and women were equally affected in recent years as compared to male predominance in the older group. PMID- 20970358 TI - Extended cognition and the space of social interaction. AB - The extended mind thesis (EM) asserts that some cognitive processes are (partially) composed of actions consisting of the manipulation and exploitation of environmental structures. Might some processes at the root of social cognition have a similarly extended structure? In this paper, I argue that social cognition is fundamentally an interactive form of space management--the negotiation and management of "we-space"--and that some of the expressive actions involved in the negotiation and management of we-space (gesture, touch, facial and whole-body expressions) drive basic processes of interpersonal understanding and thus do genuine social-cognitive work. Social interaction is a kind of extended social cognition, driven and at least partially constituted by environmental (non neural) scaffolding. Challenging the Theory of Mind paradigm, I draw upon research from gesture studies, developmental psychology, and work on Moebius Syndrome to support this thesis. PMID- 20970359 TI - Monoclonal gammopathy: do we know its significance? PMID- 20970360 TI - Recurrent hypersomnia: a review of 339 cases. AB - Based on 339 cases this review identifies, quantifies and compares 4 clinical forms of recurrent hypersomnia (1) Kleine-Levin syndrome (KLS) (239 cases), (2) Kleine-Levin syndrome without compulsive eating (KLS WOCE) (54 cases), (3) Menstrual related hypersomnia (MRH) (18 cases) and Recurrent hypersomnia with comorbidity (RHC) (28 cases). A second part of the review considers the main current issues on recurrent hypersomnia: the predisposing factors, including a window on family cases; the pathophysiology based on clinical patterns, neuroimaging data, neuropathological examinations and cerebrospinal fluid (CSF) hypocretin-1 measurements; the issues of recurrence and of a possible disruption of the circadian timing system; the relationships between recurrent hypersomnia and mood disorders; and a note on the atypical Kleine-Levin syndrome. The main outcomes of this study are a clear nosologic distinction of the different forms of recurrent hypersomnia, the finding that the prevalence of familial cases of KLS is in the same range as in narcolepsy, the suggestion of the possible involvement of a large set of cortical and subcortical structures in recurrent hypersomnia and some clues in favour of a relationship between recurrent hypersomnia and mood disorders. PMID- 20970361 TI - Adenosine, energy metabolism and sleep homeostasis. AB - Adenosine is directly linked to the energy metabolism of cells. In the central nervous system (CNS) an increase in neuronal activity enhances energy consumption as well as extracellular adenosine concentrations. In most brain areas high extracellular adenosine concentrations, through A1 adenosine receptors, decrease neuronal activity and thus the need for energy. Adenosine may be a final common pathway for various sleep factors. We have identified a relatively specific area, the basal forebrain (BF), which appears to be central in the regulation/execution of recovery sleep after sleep deprivation (SD), or prolonged wakefulness. Adenosine concentration increases in this area during SD, and this increase induces sleep while prevention of the increase during SD abolishes recovery sleep. The increase in adenosine is associated with local changes in energy metabolism as indicated by increases in levels of pyruvate and lactate and increased phosphorylation of AMP-activated protein kinase. The increases in adenosine and sleep are associated with intact cholinergic system since specific lesion of the BF cholinergic cells abolishes both. Whether adenosine during SD is produced by the cholinergic neurons or astrocytes associated with them remains to be explored. An interesting, but so far unexplored question regards the relationship between the local, cortical regulation of sleep homeostasis and the global regulation of the state of sleep as executed by lower brain mechanisms, including the BF. The increase in adenosine concentration during SD also in cortical areas suggests that adenosine may have a role in the local regulation of sleep homeostasis. The core of sleep need is probably related to primitive functions of life, like energy metabolism. It can be noted that this assumption in no way excludes the possibility that later in evolution additional functions may have developed, e.g., related to complex neuronal network functions like memory and learning. PMID- 20970362 TI - Analysis of ACTA2 in European Moyamoya disease patients. AB - The discovery of common genetic patterns in different system vascular diseases may provide important insights into the pathogenesis of these severe medical conditions. Recently, the coincidence of mutations in ACTA2 (vascular smooth muscle cell specific isoform of alpha-actin) in families with thoracic aortic aneurysms and dissections (TAAD) and Moyamoya disease (MMD) was reported in patients of Northern European descent and a positive family history for TAAD and MMD. In this study, we analyzed the nine exons of the ACTA2 gene in central European patients with non-familial MMD, aiming to replicate previously described genetic findings and possibly identify further mutations. DNA sequencing of the nine exons and flanking intronic regions of ACTA2 was performed in 39 MMD patients with no family history for MMD or TAAD and 68 healthy controls of central European descent with custom made primers. One new mutation (R179H, heterozygous) in exon 6 of ACTA2 was found in one patient with MMD. We were not able to detect other previously described mutations. In contrast to a previous report, we did not identify significant sequence variations in ACTA2. Further combined analysis of ACTA2 and other, possibly causative, genes in larger cohorts of MMD and other vascular diseases may identify possible common disease-causing mechanisms. PMID- 20970363 TI - The influence of informal social support on risk and prognosis in spinal pain: a systematic review. AB - Spinal pain is very common and has considerable consequences for the individual (e.g. loss of employment, disability) as well as increased health care costs. It is now widely accepted that biological, psychological and social factors impact on spinal pain outcomes. The majority of research on social factors has been employment related, with little attention to the influence of informal social support (e.g. families, friends, social groups). The aim of this review is to investigate whether informal social support is associated with the occurrence and prognosis of spinal pain. Prognosis was considered in a broad sense within the biopsychosocial model inclusive of factors such as pain, function, general and psychological health. A systematic search of eight databases was conducted to search for studies who report findings on informal social support in populations with nonspecific spinal pain (i.e. no defined cause). Seventeen articles were identified and a best evidence synthesis was carried out on the data extracted from the studies. Results show that for cross-sectional designs there was inconclusive evidence of a relationship between social support and pain but moderate evidence of a relationship between social support and patient psychological outcome related to prognosis. Evidence of social support as a factor for risk of occurrence was inconclusive with three studies reporting no significant associations with the remaining two studies reporting weak associations. Evidence of an effect of social support and prognosis revealed inconsistent findings. The variation in findings may reflect ongoing difficulties surrounding the conceptualisation and measurement of informal social support. PMID- 20970364 TI - Carcinoma of mullerian origin presenting as colorectal cancer: a clinicopathologic study of 13 Cases. AB - Carcinomas of mullerian origin involving colorectum in women with no concurrent or history of gynecologic malignancies are diagnostically challenging, and its histogenetic origin is uncertain. We reviewed 13 cases of carcinoma of mullerian origin with clinical presentation mimicking primary colorectal carcinoma. The patients' average age was 63.9 years. All except 2 patients presented with mass lesions in rectosigmoid colon or rectovaginal septum. The major presenting symptoms were rectal bleeding (4/13), rectosigmoid mass (6/13), vaginal mass (1/13), and abdominal pain or constipation (2/13). The average size of tumor was 4.2 cm (range, 2.4-15.0 cm). Among the 10 patients who underwent preoperative biopsy, 5 were diagnosed to have moderately and poorly differentiated colorectal carcinoma. All tumors were surgically resected with final diagnoses of moderately differentiated endometrioid carcinoma in 6 cases, mixed serous and endometrioid carcinoma in 4 cases, malignant mixed mullerian tumor in 2 cases, and undifferentiated carcinoma in 1 case. In 9 of 13 cases, foci of endometriosis were identified adjacent to or within the tumor. One case had endosalpingiosis. Immunohistochemical stains showed, after positive results, the following: cytokeratin 7 (CK7; 13/13), estrogen receptor (13/13), progesterone receptor (10/13), cytokeratin 20 (CK20; 0/13), and CDX-2 (0/13). In conclusion, carcinoma of mullerian origin often presents as bulky mass in rectosigmoid or rectovaginal septum clinically mimicking primary colorectal cancer. Endometriosis might be an important etiologic factor. Familiarities of this unusual clinicopathologic entity, careful morphologic evaluation, and immunohistochemical stain with a panel of markers (CK7, CK20, estrogen receptor, progesterone receptor, CDX-2) will be helpful for the correct diagnosis. PMID- 20970366 TI - A new, safer, controllable field-of-view endoscope avoiding movement inside body cavities. AB - One of the greatest difficulties in endoscopic surgery is the limited field-of view (FOV) of endoscopes. During endoscopic manipulation in body cavities to expand the FOV, there is the risk of inadvertent damage to body tissues, nerves, and internal organs. The risk increases especially in surgery that is performed inside a very small cavity, or in which body tissues are very fragile. To overcome these issues, we developed a novel endoscope that can provide various FOVs without moving or bending the endoscope itself inside the body cavity and investigated the feasibility of using the new endoscope in vivo. A beam splitter was used to visualize both forward and side views, and two polarization plates and observation windows were used to avoid overlap of the two views. An endoscope having a 7-mm diameter was fabricated through which both views were clearly visualized in vivo. It took only 0.7s to change the FOV with high repeatability, with a maximum distance error of 2.8%. The new endoscope can provide forward and panoramic views without moving the endoscope; therefore, the risk of inadvertent damage to fragile body tissues can be significantly decreased. PMID- 20970365 TI - Altered beta-catenin expression related to cancer progression on actinic cheilitis and squamous cell carcinoma of the lip. AB - beta-Catenin is a bifunctional protein related to cell adhesion and gene transcription when activated by Wnt pathway. Altered expression of beta-catenin was related to loss of differentiation, more aggressive phenotype, increase of tumor invasion, and poor prognosis in a number of different cancers. Actinic cheilitis is caused by excessive exposure to ultraviolet radiation and has a high potential to suffer malignant transformation into squamous cell carcinoma (SCC) of the lip, the most frequent oral malignancy. Studies of oral cancer have shown the correlation of beta-catenin expression and oral SCC prognosis, and loss of membrane expression may be considered as a potential marker for early tumor recurrence. Thirty-five cases of actinic cheilitis and 12 cases of SCC of the lip were select and submitted to immunohistochemical staining using beta-catenin antibody. beta-Catenin was positive on the membrane for all cases. Eighty-five percent of actinic cheilitis cases showed cytoplasmatic staining, and 22% nuclear staining. Eighty-three percent of SCC was positive for beta-catenin, and none of them had nuclear staining. Cytoplasmatic and nuclear staining of beta-catenin on studied cases point to pathway alterations. Results demonstrated that beta catenin expression is altered on epithelial dysplasia, and it is related to degree of alterations. PMID- 20970367 TI - Cool aid? Health, wellbeing and place in the work of Bono and U2. AB - Through a discussion of the sounds and statements of Bono and U2, this paper explores the ways in which music can work in particular spatial contexts, contributing towards both personal and population-wide health and wellbeing. We engage critically with the idea of celebrity diplomacy, and look beyond this notion to suggest ways in which the production, circulation and consumption of music warrants greater attention within the unfolding domain of health geography. PMID- 20970368 TI - Plant phenotypic plasticity in a changing climate. AB - Climate change is altering the availability of resources and the conditions that are crucial to plant performance. One way plants will respond to these changes is through environmentally induced shifts in phenotype (phenotypic plasticity). Understanding plastic responses is crucial for predicting and managing the effects of climate change on native species as well as crop plants. Here, we provide a toolbox with definitions of key theoretical elements and a synthesis of the current understanding of the molecular and genetic mechanisms underlying plasticity relevant to climate change. By bringing ecological, evolutionary, physiological and molecular perspectives together, we hope to provide clear directives for future research and stimulate cross-disciplinary dialogue on the relevance of phenotypic plasticity under climate change. PMID- 20970369 TI - Chromosome organization and dynamics in plants. AB - The past few years have brought renewed interest in understanding the dynamics of chromosomes in interphase cells as well as during cell division, particularly meiosis. This research has been fueled by new imaging methods, particularly three dimensional, high-resolution, and live microscopy. Major contributors are also new genetic tools that allow elucidation of mechanisms controlling chromosome behavior. Recent studies in plants have explored chromatin arrangement in interphase nuclei, chromosome interactions and movement during meiotic prophase I, and mechanisms that ensure correct segregation of chromosomes during anaphase. These studies shed light on chromosome dynamics in a small-genome plant Arabidopsis thaliana, as well as in plants with large and complex genomes of polyploid origin, such as wheat and maize. PMID- 20970370 TI - The secret to life is being different: asymmetric divisions in plant development. AB - Asymmetric cell divisions (ACDs) are used to create organismal form and cellular diversity during plant development. In several embryonic and postembryonic contexts, genes that specify cell fates and networks that provide positional information have been identified. The cellular mechanisms that translate this information into a physically ACD, however, are still obscure. In this review we examine the cell polarization events that precede asymmetric divisions in plants. Using principles derived from studies of other organisms and from postmitotic polarity generation in plants, we endeavor to provide a framework of what is known, what is on the horizon and what is critically needed to develop a rigorous mechanistic understanding of ACDs in plants. PMID- 20970371 TI - Diatom cell division in an environmental context. AB - Studies of cell division in organisms derived from secondary endosymbiosis such as diatoms have revealed that the mechanisms are far from those found in more conventional model eukaryotes. An atypical acentriolar microtuble-organizing centre, centripetal cytokinesis combined with centrifugal cell wall neosynthesis, and the role of sex in relation to cell size restoration make diatoms an exciting system to re-investigate the evolution, differentiation and regulation of cell division. Such studies are further justified considering the ecological relevance of these microalgae in contemporary oceans and the need to understand the mechanisms controlling their growth and distribution in an environmental context. Recent work derived from genome-wide analyses on representative model diatoms reveals that the cell cycle is finely tuned to inputs derived from both endogenous and environmental signals. PMID- 20970372 TI - Actin dynamics in plant cells: a team effort from multiple proteins orchestrates this very fast-paced game. AB - Gazing at a giant redwood tree in the Pacific Northwest, that has grown to enormous heights over centuries, does little to convince one that plants are built for speed and versatility. Even at the cellular level, a system of polymers the cell skeleton or cytoskeleton-integrates signals and generates subcellular structures spanning scales of a few nanometers to hundreds of micrometers that coordinate cell growth. The term cytoskeleton itself connotes a stable structure. Clearly, this is not the case. Recent studies using advanced imaging modalities reveal the plant actin cytoskeleton to be a highly dynamic, ever changing assemblage of polymers. These insights along with growing evidence about the biochemical/biophysical properties of plant cytoskeletal polymers, especially those obtained by single filament imaging and reconstituted systems of purified proteins analyzed by total internal reflection fluorescence microscopy, allow the generation of a unique model for the dynamic turnover of actin filaments, termed stochastic dynamics. Here, we review several significant advances and highlight opportunities that will position plants at the vanguard of research on actin organization and turnover. A challenge for the future will be to apply the power of reverse-genetics in several model organisms to test the molecular details of this new model. PMID- 20970373 TI - Drug susceptibility of human immunodeficiency virus type 1-derived pseudoviruses from treatment-experienced patients to protease inhibitors and reverse transcriptase inhibitors, using a modified single-round assay. AB - BACKGROUND: Genotypic drug resistance assay has been the only method available to provide information related to drug resistance in South Korea since 1999. Phenotypic assay is also a useful method to predict a patient's state related to antiretroviral drug resistance. However, commercial systems and methods for phenotyping have not been introduced into South Korea. OBJECTIVES: To establish and apply modified phenotypic drug susceptibility assay using treatment experienced patients' derived HIV-1 in South Korea. STUDY DESIGN: The genotypic drug resistance and phenotypic drug susceptibility of two different methods, Stanford HIV Drug Resistance Database (Stanford DB) and modified phenotypic drug susceptibility assay were compared especially focused on the HIV-1 protease (PR) and reverse transcriptase (RT) sequences. RESULTS: There was some discordance in comparing drug susceptibility results (a modified drug susceptibility assay) with the predicted genotypic drug resistance (Stanford DB). Phenotypic drug resistance showed the following order for pseudoviruses from treatment-experienced patients infected with HIV/AIDS: Efavirenz (EFV, 21 to 1,319-fold change), Lamivudine (3TC, 31 to >189-fold change), Indinavir sulfate (IDV, 26 to 63-fold change), Amprenavir (APV, 4 to 35-fold change) and Zidovudine (AZT, 20 to 634-fold change). For patient KRC3221, the AZT-related phenotypic drug resistance was the greatest, with 634-fold change compared with the wild type. CONCLUSIONS: Application of this modified phenotypic drug susceptibility assay is expected to help in predicting drug resistance as a guideline for clinicians to obtain a combined interpretation among genotyping, phenotyping and effective clinical treatments. PMID- 20970374 TI - Controlling the aggregation propensity and thereby digestibility of allergens by Maillardation as illustrated for cod fish parvalbumin. AB - The aggregation propensity of heat-treated codfish parvalbumin is investigated upon Maillardation of the protein under food-relevant conditions. About twelve of the fourteen lysine residues had reacted with glucose under these conditions. It is shown using circular dichroism and fluorescence that extensive coupling of glucose moieties on the protein surface does not affect the secondary and tertiary structural fold nor severely impair calcium-binding under ambient conditions. The glucosylated protein has a 3 degrees C higher denaturation temperature, while the free energy change involved with denaturation is reduced by 5-10%. It is shown by establishing insight in the change in heat capacity involved in the denaturation process that glucosylation of the protein is likely to result in a lower exposed hydrophobicity in the unfolded state. Aggregation kinetics, as monitored using light scattering techniques, shows that this lower exposed hydrophobicity of the denatured state slows down the aggregation process, while the shape and size of formed aggregates are comparable to those formed by non-glucosylated protein. This lower aggregation propensity allows a significantly faster digestion of heat-treated materials by pepsin. This work demonstrates that (pre-)processing of ingredients containing potential allergens, like cod fish parvalbumin, using food-relevant conditions may provide an effective tool to minimize risks of provoked allergic responses during food consumption. PMID- 20970375 TI - Family M42 aminopeptidase from the syntrophic bacterium Symbiobacterium thermophilum: characterization using recombinant protein. AB - The chromosomal DNA of the syntrophic thermophile Symbiobacterium thermophilum contains open reading frames of the genes encoding family M42 aminopeptidases, Pep1079, Pep1080, and Pep1081. To characterize these peptidases, the genes were cloned into Escherichia coli and overexpressed. Our experiments using the recombinant proteins confirmed that Pep1079, Pep1080, and Pep1081 are components of arginyl or lysinyl aminopeptidases that require Co2+ for enzymatic activity. Coexistence of Pep1079 and Pep1080 is necessary for expressing high peptidase activity. Pep1081 enhances the activity of Pep1079 and Pep1080. PMID- 20970376 TI - A personal scientific odyssey. PMID- 20970377 TI - Mixotrophy in ciliates. AB - Mixotrophy is the occurrence of phagotrophy and phototrophy in the same organism. In ciliates the intracellular phototroph can be unicellular green algae (zoochlorellae), dinoflagellates (zooxanthellae), cryptomonads or sequestered chloroplasts from ingested algae. An intermediate mixotrophic mechanism is that where the phagotroph ingests algal cells, maintains them intact and functional in the cytoplasm for some time, but the algae are afterwards digested. This seems to occur in some species of Mesodinium. Ciliates with phototrophic endosymbionts have evolved independently in marine and freshwater habitats. The enslaved algal cells or chloroplasts provide host cells with organic matter. Mixotrophs flourish in oxygen-rich, but also in micro-aerobic waters and in the complete absence of oxygen. In the latter case, the aerobic host retains aerobic metabolism, sustained by the oxygen produced by the phototrophic endosymbionts or the sequestered chloroplasts. Mixotrophic ciliates can attain spectacular abundances in some habitats, and entirely dominate the ciliate community. PMID- 20970378 TI - Presentation with pulsatile xiphisternal bruise-Survival with a chronic ventricular rupture. AB - Ventricular free wall rupture is an acute, severe complication of myocardial infarction (MI). Accounting for 20-30% of MI mortality, ventricular rupture is fatal if not detected early and repaired surgically. The unique case of a delayed, chronic rupture is reported in a 64 year-old male who presented with a painless, pulsatile, sub-xiphisternal bruise, five years post MI. Trans-thoracic echocardiography (TTE) revealed haematoma extending posteriorly with only contrast echocardiography revealing an active communication between the sub dermal area and the heart. Urgent surgery and a prolonged period in ICU enabled sufficient enough recovery for discharge. PMID- 20970379 TI - How important is whole brain radiotherapy for treatment of primary CNS lymphoma? PMID- 20970380 TI - High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. AB - BACKGROUND: High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival. METHODS: Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer generated block randomisation to receive first-line chemotherapy based on high dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age (<60 vs >=60 years) and institution (Berlin vs Tubingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m(2)) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1.5 g/m(2)) on days 3-5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1.5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0.9. This trial is registered with ClinicalTrials.gov, number NCT00153530. FINDINGS: 551 patients (median age 63 years, IQR 55-69) were enrolled and randomised, of whom 318 were treated per protocol. In the per protocol population, median overall survival was 32.4 months (95% CI 25.8-39.0) in patients receiving whole brain radiotherapy (n=154), and 37.1 months (27.5 46.7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1.06 (95% CI 0.80-1.40; p=0.71). Thus our primary hypothesis was not proven. Median progression-free survival was 18.3 months (95% CI 11.6-25.0) in patients receiving whole brain radiotherapy, and 11.9 months (7.3-16.5; p=0.14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%). INTERPRETATION: No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors. PMID- 20970381 TI - The neurosurgical and acute care management of tuberculous meningitis: evidence and current practice. AB - Tuberculous meningitis (TBM) is the most lethal form of tuberculosis; mortality is high and survivors are often left neurologically disabled. Several factors contribute to this poor outcome, including cerebrovascular involvement with ensuing brain ischemia, hydrocephalus and raised intracranial pressure, direct parenchymal injury, hyponatremia, and seizures. However, there is little standardisation of management with respect to these aspects of care across different centers, largely because the evidence base for much of the supportive treatment of patients with TBM is poor, leading to substantial differences in management protocols. This review emphasizes some of the uncertainties and controversies pertinent to the surgical treatment of hydrocephalus in TBM and the medical supportive management of the patient during the acute phase of the illness, with the aims of raising awareness and stimulating debate. The focus is on the management of hyponatremia, cerebral hemodynamics and intracranial pressure, medical and surgical treatment for hydrocephalus, and the intensive care management of patients in the acute severe stage of the illness. Very little data are available to address these issues with good evidence and so institutional preferences are common; this is perhaps most notable for the management of hydrocephalus, and so in this the review highlights our personal practice. The brain needs protection while the source of the illness is addressed. Without attention to these aspects of management there will always be a limit to the effectiveness of antimicrobial therapy in TBM, so there is a strong imperative for the controversies to be resolved and the limitations of our current care to be addressed. Existing protocols should be rigorously examined and novel strategies to protect the brain should be explored. To this end, a prospective, multi-disciplinary and multi-centered approach may yield answers to the questions raised in this review. PMID- 20970383 TI - Re: prenatal diagnosis: what do we know of long-term outcomes? J Pediatr Urol 2010;6:204. PMID- 20970382 TI - Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial. AB - BACKGROUND: In an open-label phase 1 trial, gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2) was well tolerated and seemed to improve motor function in patients with advanced Parkinson's disease. We aimed to assess the safety and efficacy of AAV2-neurturin in a double-blind, phase 2 randomised trial. METHODS: We did a multicentre, double-blind, sham surgery controlled trial in patients with advanced Parkinson's disease. Patients were randomly assigned (2:1) by a central, computer generated, randomisation code to receive either AAV2-neurturin (5.4 * 1011 vector genomes) injected bilaterally into the putamen or sham surgery. All patients and study personnel with the exception of the neurosurgical team were masked to treatment assignment. The primary endpoint was change from baseline to 12 months in the motor subscore of the unified Parkinson's disease rating scale in the practically-defined off state. All randomly assigned patients who had at least one assessment after baseline were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT00400634. RESULTS: Between December, 2006, and November, 2008, 58 patients from nine sites in the USA participated in the trial. There was no significant difference in the primary endpoint in patients treated with AAV2 neurturin compared with control individuals (difference -0.31 [SE 2.63], 95% CI 5.58 to 4.97; p=0.91). Serious adverse events occurred in 13 of 38 patients treated with AAV2-neurturin and four of 20 control individuals. Three patients in the AAV2-neurturin group and two in the sham surgery group developed tumours. INTERPRETATION: Intraputaminal AAV2-neurturin is not superior to sham surgery when assessed using the UPDRS motor score at 12 months. However, the possibility of a benefit with additional targeting of the substantia nigra and longer term follow-up should be investigated in further studies. FUNDING: Ceregene and Michael J Fox Foundation for Parkinson's Research. PMID- 20970384 TI - Obstructive ejaculatory duct calculi in a patient with bladder augmentation and myelomeningocele. AB - Symptomatic ejaculatory duct (ED) calculi, typically composed of uric acid, carbonate apatite and calcium phosphate, or calcium phosphate in the form of hydroxyapatite, are rare occurrences. We report a case of bilateral, large ED calculi in a patient with spina bifida myelomeningocele and an augmented neurogenic bladder. A 25-year-old Caucasian male, not compliant with his urological management, presented with abdominal pain, difficulty in self catheterization, nausea and vomiting. Two of eight large struvite calculi, which blocked the urethra, were identified at the right ED. After endoscopic calculi removal, further management included bladder irrigation and infection control modalities. This case highlights the importance of clean intermittent catheterization, bladder irrigation, and routine urologic management necessary for patients with myelodysplasia and neurogenic bladder. It is the first recorded case to demonstrate the augmented bladder as an initiator of ejaculatory duct calculi in patients with an open bladder neck and spastic external sphincter. PMID- 20970385 TI - Urethroscopic holmium:YAG laser epilation of urethral diverticular hair follicles following hypospadias repair. AB - Urethral hair and diverticula are well described long-term complications following urethroplasty or hypospadias repair. Endoscopic laser ablation is an uncommonly reported treatment option for a symptomatic hair-bearing urethra, and holmium laser hair epilation has not been previously reported in the literature. We report the first case of urethroscopic holmium laser ablation of urethral diverticular hair follicles and the outcome. PMID- 20970386 TI - Does lacosamide aggravate Lennox-Gastaut syndrome? Report on three consecutive cases. AB - Lennox-Gastaut syndrome is an intractable epileptic encephalopathy, with most patients experiencing daily seizures despite therapy with multiple antiepileptic drugs. New treatments need to be tested to define their efficacy in this syndrome. Lacosamide is a new antiepileptic drug recently approved for the treatment of partial-onset seizures. We describe three patients with Lennox Gastaut syndrome resistant to conventional antiepileptic drugs whose seizures were aggravated by lacosamide. PMID- 20970387 TI - Value of 3-dimensional sonohysterography in infertility work-up. AB - STUDY OBJECTIVE: To compare the diagnostic value of 2-dimensional (2D) and 3 dimensional (3D) sonohysterography (SHG) and outpatient hysteroscopy (OH) in detecting intrauterine lesions in infertile women. DESIGN: Comparative, observational, cross-sectional study (Canadian Task Force Classification II-2). SETTING: University hospital. PATIENTS: One hundred eighty women with a normal uterine cavity at transvaginal ultrasound and hysterosalpingography (HSG) underwent infertility workup at our outpatient clinic. INTERVENTIONS: All patients underwent 2D-SHG, 3D-SHG, and OH. MEASUREMENTS AND MAIN RESULTS: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 2D-SHG and 3D-SHG were compared with OH in detecting intrauterine lesions. For 2D-SHG, sensitivity was 0.70 (95% confidence interval [CI], 0.49-0.85), specificity was 1.0 (95% CI, 0.96-1.0), PPV was 1.0 (95% CI, 0.79-1.0), NPV was 0.95 (95% CI, 0.9-0.97), and accuracy was 95.5%. For 3D-SHG, sensitivity was 0.92 (95% CI, 0.74-0.98), specificity was 1.0 (95% CI, 0.97-1.0), PPV was 1.0 (05% CI, 0.83-1.0), NPV was 0.98 (95% CI, 0.95-0.99), and accuracy was 98.8%. For OH, sensitivity was 1.0 (95% CI, 0.85-1.0), specificity was 1.0 (95% CI, 0.97-1.0), PPV was 1.0 (95% CI, 0.84-1.0), NPV was 1.0 (0.97-1.0), and accuracy was 100%. Thus, 3D-SHG is comparable to OH in diagnosing intrauterine lesions (p = .23), and both are superior to 2D-SHG (p <0.001). CONCLUSION: The diagnostic value of 3D-SHG is comparable to OH in detecting intrauterine lesions, and both are superior to 2 D-SHG. 3D-SHG should be included in the infertility workup even in women with a normal uterine cavity at transvaginal ultrasound or hysterosalpingography. PMID- 20970388 TI - Bi-directional routing of DNA mismatch repair protein human exonuclease 1 to replication foci and DNA double strand breaks. AB - Human exonuclease 1 (hEXO1) is implicated in DNA metabolism, including replication, recombination and repair, substantiated by its interactions with PCNA, DNA helicases BLM and WRN, and several DNA mismatch repair (MMR) proteins. We investigated the sub-nuclear localization of hEXO1 during S-phase progression and in response to laser-induced DNA double strand breaks (DSBs). We show that hEXO1 and PCNA co-localize in replication foci. This apparent interaction is sustained throughout S-phase. We also demonstrate that hEXO1 is rapidly recruited to DNA DSBs. We have identified a PCNA interacting protein (PIP-box) region on hEXO1 located in its COOH-terminal ((788)QIKLNELW(795)). This motif is essential for PCNA binding and co-localization during S-phase. Recruitment of hEXO1 to DNA DSB sites is dependent on the MMR protein hMLH1. We show that two distinct hMLH1 interaction regions of hEXO1 (residues 390-490 and 787-846) are required to direct the protein to the DNA damage site. Our results reveal that protein domains in hEXO1 in conjunction with specific protein interactions control bi directional routing of hEXO1 between on-going DNA replication and repair processes in living cells. PMID- 20970389 TI - Derivatization of carbonyl compounds with 2,4-dinitrophenylhydrazine and their subsequent determination by high-performance liquid chromatography. AB - Derivatization of carbonyl compounds with 2,4-dinitrophenylhydrazine (DNPH) is one of the most widely used analytical methods. In this article, we highlight recent advances using DNPH provided by our studies over past seven years. DNPH reacts with carbonyls to form corresponding stable 2,4-DNPhydrazone derivatives (DNPhydrazones). This method may result in analytical error because DNPhydrazones have both E- and Z-stereoisomers caused by the CN double bond. Purified aldehyde 2,4-DNPhydrazone demonstrated only the E-isomer, but under UV irradiation and the addition of acid, both E- and Z-isomers were seen. In order to resolve the isometric problem, a method for transforming the CN double bond of carbonyl-2,4 DNPhydrazone into a C-N single bond, by reductive amination using 2-picoline borane, has been developed. The amination reactions of C1-C10 aldehyde DNPhydrazones are completely converted into the reduced forms and can be analyzed with high-performance liquid chromatography. As a new application using DNPH derivatization, the simultaneous measurement of carbonyls with carboxylic acids or ozone is described in this review. PMID- 20970390 TI - HPLC method with fluorescence detection for the quantitative determination of flaxseed lignans. AB - We report a rapid and simple HPLC method with fluorescence detection for the quantification of the major flaxseed lignan, secoisolarisiresinol diglucoside (SDG) and its major metabolites. The method is specific for SDG, secoisolarisiresinol (SECO), enterodiol (ED) and entrolactone (EL) in rat serum. The assay procedure involves chromatographic separation using a Waters Symmetry C(18) reversed-phase column (4.6 mm x 150 mm, 5 MUm) and mobile phase gradient conditions consisting of acetonitrile (0.1% formic acid) and water (0.1% formic acid). SDG extraction from serum requires the use of Centrifuge filters while SECO, ED and EL are extracted with diethyl ether. The organic layer is evaporated and reconstituted in 100 MUL of mobile phase and 50 MUL of reconstituted sample or filtrate is injected onto the column. Total run time is 25 min. Calibration curves are linear (r2 >= 0.997) from 0.05 to 10 MUg/mL for SDG and EL and 0.01-10 MUg/mL for SECO and ED. Precision and accuracy are within USFDA specified limits. The stability of all lignans is established in auto-injector, bench-top, freeze thaw and long-term stability at -80 degrees C for 30 days. The method's reasonable sensitivity and reliance on more widely available HPLC technology should allow for its straightforward application to pharmacokinetic evaluations of lignans in animal model systems such as the rat. PMID- 20970391 TI - Effects of co-existed proteins on measurement of pesticide residues in blood by gas chromatography-mass spectrometry. AB - Accurate measurement of pesticides in biological fluids such as blood is important for quantifying environmental exposures. Beyond sample enrichment and separation, the method presented here is focused on studies of interactions between pesticides and co-existed proteins. It was experimentally demonstrated that entrapped or adsorbed pesticide residues within the folded native structures of proteins were poorly recovered using direct solvent extraction solely. We described here an effective approach termed Enzymatic Digestion-Organic Solvent Extraction (eDOSE) that utilizes the enzymatic approach to disrupt the folded structures of proteins and release entrapped or adsorbed pesticide residues. In this approach, samples were first reduced, alkylated, tryptically digested and then diluted 10 times before the subsequent extraction using an n-hexane solution. Resultant pesticide residues were determined by capillary gas chromatography coupled with a mass spectrometer. Mean recoveries of the 5 organophosphorus pesticides pre-spiked in fish blood including diazinon, parathion-methyl, malathion, parathion-ethyl and ethion were 85%, 95%, 84%, 103%, and 43% respectively using eDOSE strategy but only 24%, 45%, 40%, 27%, and 29% respectively using direct solvent extraction approach. The eDOSE approach was effective for demonstrating the critical role of folded native structure of serum albumin in adsorption of exogenous chemicals. It provides an alterative means for denaturation of proteins when the target analytes are not stable in acidic solution or entrapped within the protein aggregates caused by organic solvents such as acetone that have been applied for protein denaturation. The eDOSE approach should be able to combine with other advanced techniques of enrichment and separation for more efficient and accurate measurement of target compounds present in the context of complex biological systems. This approach can provide wide applications to the analysis of a variety of small molecules including environmental pesticide residues and metabolites as well as other toxins present in cells, tissues and biofluids. PMID- 20970392 TI - Compositionality, language and intention: commentary on "Embodied language, best fit analysis, and formal compositionality" by J. Feldman. PMID- 20970393 TI - Compositionality, context, and cognition: comment on "Embodied language, best fit analysis, and formal compositionality" by J. Feldman. PMID- 20970394 TI - Life, hierarchy, and the thermodynamic machinery of planet Earth. AB - Throughout Earth's history, life has increased greatly in abundance, complexity, and diversity. At the same time, it has substantially altered the Earth's environment, evolving some of its variables to states further and further away from thermodynamic equilibrium. For instance, concentrations in atmospheric oxygen have increased throughout Earth's history, resulting in an increased chemical disequilibrium in the atmosphere as well as an increased redox gradient between the atmosphere and the Earth's reducing crust. These trends seem to contradict the second law of thermodynamics, which states for isolated systems that gradients and free energy are dissipated over time, resulting in a state of thermodynamic equilibrium. This seeming contradiction is resolved by considering planet Earth as a coupled, hierarchical and evolving non-equilibrium thermodynamic system that has been substantially altered by the input of free energy generated by photosynthetic life. Here, I present this hierarchical thermodynamic theory of the Earth system. I first present simple considerations to show that thermodynamic variables are driven away from a state of thermodynamic equilibrium by the transfer of power from some other process and that the resulting state of disequilibrium reflects the past net work done on the variable. This is applied to the processes of planet Earth to characterize the generation and transfer of free energy and its dissipation, from radiative gradients to temperature and chemical potential gradients that result in chemical, kinetic, and potential free energy and associated dynamics of the climate system and geochemical cycles. The maximization of power transfer among the processes within this hierarchy yields thermodynamic efficiencies much lower than the Carnot efficiency of equilibrium thermodynamics and is closely related to the proposed principle of Maximum Entropy Production (MEP). The role of life is then discussed as a photochemical process that generates substantial amounts of chemical free energy which essentially skips the limitations and inefficiencies associated with the transfer of power within the thermodynamic hierarchy of the planet. This perspective allows us to view life as being the means to transform many aspects of planet Earth to states even further away from thermodynamic equilibrium than is possible by purely abiotic means. In this perspective pockets of low-entropy life emerge from the overall trend of the Earth system to increase the entropy of the universe at the fastest possible rate. The implications of the theory are discussed regarding fundamental deficiencies in Earth system modeling, applications of the theory to reconstructions of Earth system history, and regarding the role of human activity for the future of the planet. PMID- 20970395 TI - Is biology the prime driver of surface processes? Comment on "Life, hierarchy, and the thermodynamic machinery of planet Earth" by A. Kleidon. PMID- 20970397 TI - Cardiac magnetic resonance in the study of neonatal haemodynamics. AB - Circulatory failure plays a key role in the pathogenesis of mortality and key morbidity such as cerebral injury in the preterm infant. However awareness of the pathophysiology of circulatory failure itself is not well understood. Similarly there is significant uncertainty over optimal treatment approaches, particularly for inotropic therapies. Current uncertainties are perpetuated by difficulties with accurately assessing circulatory function. Cardiac magnetic resonance (CMR) imaging has produced significant advances in understanding of adult circulatory function, and acts as a powerful biomarker for interventional studies. Although routine circulatory assessment by CMR in the neonatal population is not currently a realistic goal, it could provide insights into pathophysiology; and act as an outcome measure in clinical trials in small numbers of infants in specialist centres. This review focuses on available CMR techniques, scope for use in the neonatal population, and our initial experience with the technique. PMID- 20970396 TI - [Erythropoietin treatment for late anaemia after haemolytic disease of the newborn]. AB - INTRODUCTION: After several years of erythropoietin (EPO) use in the prophylaxis of anaemia of prematurity, it also began to be administered to treat post haemolytic disease anaemia of the newborn in order to avoid blood transfusions. OBJECTIVE: To show the results obtained with EPO treatment in post-haemolytic disease anemia of the newborn. PATIENTS AND METHODS: Observational study in 13 newborns with late anaemia due to an hemolytic disease caused by Rh isoimmunization (9 cases), AB0 isoimmunization (2 cases), glucose-6-P dehydrogenase deficiency (1 case) or idiopathic (1 case). The newborns began EPO treatment when they reached the haematocrit level for a blood transfusion. RESULTS: EPO treatment was started at 26+/-7 days of life (15-46), with a haematocrit value of 21.7+/-3% (18-27) and a reticulocyte count of 3.8+/-2.2%. Blood transfusion was not necessary in 11 newborns (haematocrit of 30.7+/-4.4% and reticulocytes of 5.9+/-1.4%), and only 2 newborns were admitted for a blood transfusion (haematocrit 18+/-4.4% and reticulocytes 0.6%). Significant increases in haemoglobin and reticulocyte figures were seen after EPO treatment. CONCLUSIONS: EPO administration proved useful to avoid blood transfusion in 84% of treated newborns. No adverse events were detected which could be attributed to this treatment,. PMID- 20970398 TI - Paediatric trigger finger: Literature review and management algorithm. AB - Trigger finger in the paediatric population is a distinct condition from trigger thumb in the child or trigger finger in the adult. This paper reviews the current practices applied in the treatment of paediatric trigger finger. Intra-operative photographs are used to illustrate the anatomic anomalies that may be present. An operative algorithm is presented suggesting a step-wise approach to check all structures that may cause the symptom of triggering whilst avoiding unnecessary dissection once the cause of the trigger has been corrected. PMID- 20970399 TI - Geostatistical inference of main Y-STR-haplotype groups in Europe. AB - We examined the multifarious genetic heterogeneity of Europe and neighboring regions from a geographical perspective. We created composite maps outlining the estimated geographical distribution of major groups of genetically similar individuals on the basis of forensic Y-chromosomal markers. We analyzed Y chromosomal haplotypes composed of 7 highly polymorphic STR loci, genotyped for 33,010 samples, collected at 249 sites in Europe, Western Asia and North Africa, deposited in the YHRD database (www.yhrd.org). The data set comprised 4176 different haplotypes, which we grouped into 20 clusters. For each cluster, the frequency per site was calculated. All geostatistical analysis was performed with the geographic information system GRASS-GIS. We interpolated frequency values across the study area separately for each cluster. Juxtaposing all 20 interpolated surfaces, we point-wisely screened for the highest cluster frequencies and stored it in parallel with the respective cluster label. We combined these two types of data in a composite map. We repeated this procedure for the second highest frequencies in Europe. Major groups were assigned to Northern, Western and Eastern Europe. North Africa built a separate region, Southeastern Europe, Turkey and Near East were divided into several regions. The spatial distribution of the groups accounting for the second highest frequencies in Europe overlapped with the territories of the largest countries. The genetic structure presented in the composite maps fits major historical geopolitical regions and is in agreement with previous studies of genetic frequencies, validating our approach. Our genetic geostatistical approach provides, on the basis of two composite maps, detailed evidence of the geographical distribution and relative frequencies of the most predominant groups of the extant male European population, examined on the basis of forensic Y-STR haplotypes. The existence of considerable genetic differences among geographic subgroups in Europe has important consequences for the statistical inference in forensic Y-STR haplotype analyses. PMID- 20970400 TI - Population genetics for Y-chromosomal STRs haplotypes of Chinese Xibe ethnic group. AB - Allele and haplotype frequencies of 11 Y-chromosomal short tandem repeats (STRs) included in the PowerPlex((r)) Y Systems (Promega) were determined in a sample of 280 unrelated healthy autochthonous male individuals of the Chinese Xibe ethnic minority group living in Liaoning (northeast of China). The gene diversity values of the Y-STRs loci ranged from 0.3618 (DYS391) to 0.9686 (DYS385a/b). A total of 237 haplotypes were identified in the Y-STR loci, among which 207 were unique, 22 was found in 2 individuals, 4 were shared in 3 individuals, 3 were shared in 4 individuals, and 1 was shared in 5 individuals. The observed haplotype diversity value and discrimination capacity were 0.9984 and 0.8464, respectively. AMOVA tests demonstrated significant genetic heterogeneity between the Xibes and 16 reference populations from China and other Asian populations, justifying the establishment of local databases in the Chinese Xibe ethnic group for forensic application. PMID- 20970401 TI - Endothelin-1 and angiotensin II modulate rate and contraction amplitude in a subpopulation of mouse embryonic stem cell-derived cardiomyocyte-containing bodies. AB - Embryonic stem cell-derived cardiomyocytes (ESC-CMs) have applications in understanding cardiac disease pathophysiology, pharmacology, and toxicology. Comprehensive characterization of their basic physiological and pharmacological properties is critical in determining the suitability of ESC-CMs as models of cardiac activity. In this study we use video microscopy and quantitative PCR to investigate the responses of mouse ESC-CMs to adrenoceptor, muscarinic, angiotensin II (Ang II), and endothelin-1 (ET-1) receptor activation. Isoprenaline (10 nM-10 MUM) increased beating rate and contraction amplitude in all beating bodies (BBs), whereas carbachol (up to 1 MUM) and the I(f) channel blocker ZD-7288 (10 MUM) decreased contraction frequency. ET-1 (0.01-100 nM) reduced contraction amplitude in all BBs and increased contraction frequency in 50% of BBs; these effects were blocked by the ET(A) receptor antagonist BQ123 (250 nM). Ang II (0.01 nM-1 MUM) increased both contraction amplitude (all BBs) and frequency (in 50% of BBs), effects blocked, respectively, by losartan (100 nM) and PD123,319 (200 nM). These results indicate the presence of functional ET(A) and both AT1 and AT2 receptors in murine ESC-CMs, but their expression and or activity appears to be evident only in a limited set of BBs. PMID- 20970402 TI - Present indications for surgical treatment of morbid obesity: how to choose the best operation? PMID- 20970403 TI - Use of fluorescence lifetime technology to provide efficient protection from false hits in screening applications. AB - This article describes novel data analysis of fluorescence lifetime-based protein kinase assays to identify and correct for compound interference in several practical cases. This ability, together with inherent advantages of fluorescence lifetime technology (FLT) as a homogeneous, antibody-free format independent of sample concentration, volume, excitation intensity, and geometry, makes fluorescence lifetime a practical alternative to the established "gold standards" of radiometric and mobility shift (Caliper) assays. The analysis is based on a photochemical model that sets constraints on the values of fluorescence lifetimes in the time responses of the assay. The addition of an exponential component with free floating lifetime to the constrained model, in which the lifetimes are constants predetermined from control measurements and the preexponential coefficients are "floating" parameters, allows the relative concentration of phosphorylated and nonphosphorylated substrates to be calculated even in the presence of compound fluorescence. The method is exemplified using both simulated data and experimental results measured from mixtures of dye-labeled phosphorylated and nonphosphorylated kinase substrates. A change of the fluorescence lifetime is achieved by the phosphorylated substrate-specific interaction with a bifunctional ligand, where one binding site interacts with the phosphate group and the other interacts with the dye. PMID- 20970404 TI - Structure and lipid interactions of an anti-inflammatory and anti-atherogenic 10 residue class G(*) apolipoprotein J peptide using solution NMR. AB - The surprising observation that a 10-residue class G(*) peptide from apolipoprotein J, [113-122]apoJ, possesses anti-inflammatory and anti-atherogenic properties prompted us to delineate its structural characteristics in the presence of normal and oxidized lipid. Towards this, we have determined high resolution structure of [113-122]apoJ in solution using nuclear magnetic resonance (NMR) spectroscopy and studied its interaction with lipids, including oxidized lipids, using a number of biophysical methods. Circular dichroism and NMR studies established that in the presence of dodecylphosphocholine (DPC) micelle, this peptide adopts amphipathic alpha-helical structure. The observed Nuclear Overhauser effects indicate that the amphipathic helical structure of the peptide is stabilized by the N-terminal acetyl and C-terminal amide blocking groups. We used isothermal titration calorimetry to measure binding enthalpy of the peptide with DPC micelle, an oxidized lipid, 1-(palmitoyl)-2-(5-keto-6-octene dioyl) phosphatidylcholine (KOdiA-PC), and the mixture of these two lipids (5mol% KOdiA-PC in DPC micelle). We find that the peptide binding with DPC micelle is associated with an enthalpy change (-16.75+/-0.16 Kcal/mol) much larger than that resulting from the binding with KodiA-PC (-3.67+/-0.13 Kcal/mol). Incorporation of a small amount of KOdiA-PC (5mol%) in DPC micelle also results in the lowering of peptide binding enthalpy (-13.43+/-0.18 Kcal/mol). These results are consistent with overall negative charge and altered conformational properties of oxidized sn-2 chain of KOdiA-PC. Our results have unambiguously established the amphipathic alpha-helical structure of [113-122]apoJ peptide in the presence of DPC micelle as well as its ability to bind oxidized lipid. These in vitro results help explain the previously observed anti-inflammatory and anti-atherosclerotic properties of this peptide. PMID- 20970405 TI - CpG island hypermethylation of multiple tumor suppressor genes associated with loss of their protein expression during rat lung carcinogenesis induced by 3 methylcholanthrene and diethylnitrosamine. AB - The epigenetic mechanisms underlying the tumorigenesis caused by polycyclic aromatic hydrocarbons and nitrosamine compounds such as 3-methylcholanthrene (MCA) and diethylnitrosamine (DEN) are currently unknown. We reported previously that dynamic changes in DNA methylation occurred during MCA/DEN-induced rat lung carcinogenesis. Here, we used the same animal model to further study the evolution of methylation alterations in tumor suppressor genes (TSGs) DAPK1, FHIT, RASSF1A, and SOCS-3. We found that none of these genes were methylated in either normal or hyperplasia tissue. However, as the severity of the cancer progressed through squamous metaplasia and dysplasia to carcinoma in situ (CIS) and infiltrating carcinoma, so methylation became more prevalent. Particularly dramatic increases in the level of methylation, the average number of methylated genes, and the incidence of concurrent methylation in three genes were observed in CIS and infiltrating carcinoma. Similar but less profound changes were seen in squamous metaplasia and dysplasia. Furthermore, methylation status was closely correlated to loss of protein expression for these genes, with protein levels markedly declining along the continuum of carcinogenesis. These results suggest that progressive CpG island hypermethylation leading to inactivation of TSGs might be a vital molecular mechanism in the pathogenesis of MCA/DEN-induced multistep rat lung carcinogenesis. PMID- 20970406 TI - Inhibitors of NQO1: identification of compounds more potent than dicoumarol without associated off-target effects. AB - The enzyme NAD(P)H quinone oxidoreductase (NQO1) can function both as a detoxifying enzyme as well as chaperone protein. The latter property has been extensively characterized by the use of dicoumarol which inhibits the chaperone properties of NQO1 in cells. However, the use of this compound is compromised by its multiple "off-target" effects. Coumarin-based compounds that are more potent than dicoumarol as inhibitors of NQO1 in cells have been identified (Nolan et al., Biochem Pharmacol 2010;80:977-81). The purpose of the work reported here is to evaluate the off-target effects of these compounds when compared to dicoumarol. A range of these substituted coumarins are identified that are significantly less toxic than dicoumarol in a panel of nine cell lines. Further a number of the compounds generate much less intracellular superoxide, and many of them also show a reduced ability to induce apoptosis when compared to dicoumarol. None of these effects correlate with the ability of the compounds to inhibit the enzymatic activity of NQO1 in cells. In conclusion, potent inhibitors of NQO1 have been identified that will be more pharmacologically useful than dicoumarol for probing the function of NQO1 in cells and tissues. PMID- 20970407 TI - BMP-Id pathway targeted by cholesterol myristate suppresses the apoptosis of PC12 cells. AB - Identifying small molecules that suppress apoptosis is promising for the therapy of brain diseases. We recently showed that autocrine bone morphogenetic protein (BMP) signaling involves the effects of cholesterol myristate present in traditional Chinese medicine on mesenchymal stem cells. The present study evaluated the effects of cholesterol myristate on the apoptosis and BMP signaling of PC12 cells. PC12 cells transfected by the inhibitor of differentiation (Id1) promoter reporter construct target gene of BMP4 signaling; cholesterol myristate increases the activity of Id1 promoter. However, structurally related steroids such as cholesterol, beta-sitosterol and cholesten-3-one, lack of the myristate, did not affect the activity of Id1 promoter, suggesting that myristate is essential for the effect of cholesterol myristate. These effects depend on BMP signaling. Apoptosis analysis indicated that cholesterol myristate inhibited the apoptosis of PC12 cells induced in serum-free condition. Cholesterol myristate significantly increases the expression of BMP4, BMPRIA, p-Smad1/5/8, Id1 and its antiapoptotic target gene Bcl-xL in PC12 cells treated in serum-free condition. Moreover, BMP antagonist reduced the anti-apoptotic effect of cholesterol myristate. Thus, this study is to provide evidence that BMP-Id pathway targeted by cholesterol myristate suppresses the apoptosis of PC12 cells. Our findings are therefore of considerable therapeutic significance and provide the potential of newly exploiting cholesterol myristate and clinically in brain disease therapies. PMID- 20970408 TI - Electrophilic eicosanoids: Signaling and targets. AB - Electrophilic eicosanoids are reactive mediators that arise by non-enzymatic transformations of arachidonic acid or of its products and display varied biological actions. Various electrophilic eicosanoids have shown anti proliferative and anti-inflammatory effects, which have elicited a great interest in their study as potential therapeutic agents. A key feature of these compounds is their ability to covalently modify proteins, thus altering their structure and function. The modification of several components of the NF-kappaB pathway contributes to the anti-inflammatory effects of electrophilic eicosanoids, whereas addition to redox-sensitive proteins plays a key role in the antioxidant response. However, electrophilic eicosanoids may also have a dark side, and accumulating evidence points towards their involvement in neurotoxicity and/or neurodegeneration. The ability of some electrophilic eicosanoids to induce protein oligomerization or aggregation through various mechanisms may contribute to these effects. Biochemical and proteomic studies have led to the identification of numerous protein targets for modification by electrophilic eicosanoids, the number of which continues to expand, revealing novel potential functions for these compounds and providing a basis for their pleiotropic effects. The ample number of targets identified, together with the non-enzymatic nature of the modification argue against the potential specificity or regulation of electrophilic eicosanoid action. However, protein modification displays selectivity depending on structural features of the proteins and of the electrophilic compounds as well as on context factors such as cell type and GSH availability. Understanding the factors which control the extent and selectivity of protein modification by electrophilic eicosanoids is therefore essential to elucidate their pathophysiological roles and therapeutic potential in specific settings. PMID- 20970409 TI - An integrated reactive metabolite evaluation approach to assess and reduce safety risk during drug discovery and development. AB - Metabolic bioactivation is widely considered an undesirable event and a likely prerequisite step in the expression of drug-induced hepatotoxicity and hypersensitivity. Reducing bioactivation risk early in drug discovery, therefore, may help reduce compound attrition and provide safer drug therapies. In vitro bioactivation data and clinical dose for a large set of marketed drugs were analysed for their concordance with clinical hepatotoxicity and the data used to develop an early reactive metabolite strategy. A contingency table analysis of cytochrome P450 metabolism-dependent inhibition (CYP MDI), glutathione trapping data, and dose for >200 marketed drugs with or without a clinical hepatotoxic signal; and microsomal covalent binding data and dose for ~60 marketed compounds obtained from literature publications was performed to assess concordance with hepatotoxicity. Clinical daily dose >=100mg or glutathione adduct formation was strongly associated with hepatotoxicity (p<0.0001, p=0.003, respectively). A trend towards clinical hepatotoxicity was observed with marked CYP MDI or metabolism-dependent covalent binding >=200pmol/mg. The percentage of hepatotoxic drugs identified by high dose (67%) increased significantly when bioactivation data were combined with dose (80-100%). As CYP MDI and glutathione adduct assays do not require the synthesis of radiolabelled compound and are relatively easy to conduct, they may be of particular value for early assessment in programs with lower risk tolerance. Such information together with an overall understanding of the metabolic properties of the compound and risk/benefit considerations may trigger further assessment. Additionally hepatic transcriptomic data (e.g., Nrf2 activated gene expression) from rat toxicity studies can provide evidence of in vivo consequences of bioactivation. As attenuation of a metabolic bioactivation risk early in drug discovery could reduce compound attrition and provide safer drug therapies, we have developed a decision-based early reactive metabolite strategy that can be tailored to the needs of individual programs. PMID- 20970410 TI - Potential implication of aniline derivatives in the Toxic Oil Syndrome (TOS). AB - The Toxic Oil Syndrome (TOS) was an epidemic disease appeared in central Spain in 1981, causing over 400 deaths and affecting more than 20,000 people, mainly women and children. The disease was linked to the consumption of rapeseed oil denatured with aniline, illegally refined at the ITH oil refinery in Seville, mixed with other oils and sold as edible olive oil. Among the aniline derivatives detected in the oil batches generated by an uncontrolled deodorisation procedure during the refining process, fatty acid anilides were first postulated as the causal agents. Nevertheless, compounds identified as 3-(N-phenylamino)propane-1,2-diol (PAP) and its mono-, di-, and triacyl derivatives (mPAP, dPAP and tPAP, respectively), were subsequently considered better biomarkers of toxic oils and the best candidates for causing the intoxication. In this account, we will discuss the results obtained in recent years by our group concerning: (a) The effect of different variables intervening in the deodorisation process that could influence the formation of PAP derivatives. To this end we decided to take the aniline derivatives linked to oleic acid as compound models since this is the fatty acid present in highest amounts in rapeseed oil. The study was focused on the influence of different parameters on the formation of the diester PAP derivative (OOPAP) the monoester derivative (OPAP) and the corresponding amide (oleanilide, OA), and the interactions between any two of these variables. Of particular interest was the interaction observed between OOPAP and OA, due to its potential relevance to the final composition of the toxic oil model. (b) Xenobiochemical aspects of PAP derivatives, specifically: the stereospecific hydrolysis of OPAP and OOPAP by human pancreatic lipase, the in vitro activation of PAP by human and rat liver microsomes as well as by recombinant 450 enzymes, and the formation and stability of GSH and N-acetylcysteine adducts of a highly reactive iminoquinone intermediate generated in the biotransformation of PAP. PMID- 20970411 TI - Benzene toxicity: The role of the susceptibility factor NQO1 in bone marrow endothelial cell signaling and function. AB - The homozygous NQO1*2 polymorphism results in a null NQO1 phenotype and is a susceptibility factor for occupational benzene poisoning. NQO1 plays an important role in detoxification of benzene-derived quinones but plays a role in numerous other non-metabolic cellular functions. NQO1 is expressed in endothelial cells of bone marrow which form the vascular stem cell niche important in stem cell homing and mobilization. We therefore employed a transformed human bone marrow endothelial cell (HBMEC) line to define the effects of compromising NQO1 on endothelial function. Either inhibition or knockdown of NQO1 led to decreased expression of the adhesion molecules E-selectin, VCAM-1 and ICAM-1 and decreased functional adhesion of CD34+ progenitor cells after TNFalpha stimulation. Suicide inhibition or knockdown of NQO1 decreased NFkappaB p105 precursor and NFkappaB p50 subunit levels as well as leading to decreased nuclear levels of NFkappaB phospho-p65. An additional function of endothelial cells is tube formation and angiogenesis which was inhibited by the benzene metabolite hydroquinone suggesting that endothelial function may be affected at multiple levels after exposure of NQO1*2 polymorphic individuals to benzene. These data demonstrate that NQO1 plays an upstream role in NFkappaB signaling and adhesion molecule expression in HBMEC and that NQO1 has important regulatory effects in its own right in addition to being a marker for Nrf-2 activation. Metabolic susceptibility factors such as NQO1 have roles in addition to detoxification of reactive intermediates and interrogation of these novel roles can inform both mechanisms of toxicity and human risk assessment. PMID- 20970412 TI - Biological reactive intermediates (BRIs) formed from botanical dietary supplements. AB - The use of botanical dietary supplements is increasingly popular, due to their natural origin and the perceived assumption that they are safer than prescription drugs. While most botanical dietary supplements can be considered safe, a few contain compounds, which can be converted to biological reactive intermediates (BRIs) causing toxicity. For example, sassafras oil contains safrole, which can be converted to a reactive carbocation forming genotoxic DNA adducts. Alternatively, some botanical dietary supplements contain stable BRIs such as simple Michael acceptors that react with chemosensor proteins such as Keap1 resulting in induction of protective detoxification enzymes. Examples include curcumin from turmeric, xanthohumol from hops, and Z-ligustilide from dang gui. Quinones (sassafras, kava, black cohosh), quinone methides (sassafras), and epoxides (pennyroyal oil) represent BRIs of intermediate reactivity, which could generate both genotoxic and/or chemopreventive effects. The biological targets of BRIs formed from botanical dietary supplements and their resulting toxic and/or chemopreventive effects are closely linked to the reactivity of BRIs as well as dose and time of exposure. PMID- 20970413 TI - Lovastatin enhances paraoxonase enzyme activity and quells low-density lipoprotein susceptibility to oxidation in type 2 diabetic nephropathy. AB - OBJECTIVES: : To investigate the effect of lovastatin therapy and withdrawal on paraoxonase 1 (PON1) and arylesterase (ARE) activities, and low-density lipoprotein cholesterol (LDL-C) susceptibility to oxidation in people with type 2 diabetic nephropathy (T2DN). DESIGN AND METHODS: : Lovastatin (20mg/day) was administered to 30 people with T2DN for 90days and then withdrawn for 30days. PON1 and ARE activities were measured by the spectrophotometric method. Susceptibility of LDL-C to oxidation was determined as the production of conjugated dienes. RESULTS: : After 90days of lovastatin intervention, PON1 and ARE activities and LDL-C lag phase were significantly increased (p=0.004, 0.002, and <0.001), while after 30days of lovastatin withdrawal, PON1 and ARE activities and LDL-C lag phase had not changed significantly. CONCLUSION: : Lovastatin therapy improves PON1 and ARE activities, and LDL-C susceptibility to oxidation. Despite withdrawal of lovastatin, PON1 and ARE activities, and LDL-C susceptibility to oxidation remain unchanged in people with T2DN. PMID- 20970414 TI - Saliva S100B in professional sportsmen: High levels at resting conditions and increased after vigorous physical activity. AB - BACKGROUND: Neurological dysfunction is a key medical concern in professional sportsmen (PSM). We investigated whether saliva S100B concentrations in PSM and healthy controls are modified before and after training. METHODS: We conducted a case-control-study in 75 patients (25 PSM vs 50 controls) in which S100B saliva concentrations were expressed as absolute values and percentage of change (%) from samples drawn before (T0) and after (T1) training. RESULTS: No differences (P>0.05) between groups were found regarding clinical, monitoring and laboratory parameters. S100B both in PSM and controls was higher at T1 when compared to T0 (P<0.01). In PSM, S100B was higher than controls (P<0.001) at T0 and T1. S100B% at T0-T1 was higher (P<0.001) in PSM and in controls and between PSM and controls (P<0.001). CONCLUSIONS: Increased saliva S100B levels in PSM before and after training suggest a paracrine/autocrine protein's role connected to stressing activity, which becomes especially evident in PSMs. PMID- 20970415 TI - High LDL levels are associated with increased lipoprotein-associated phospholipase A(2) activity on nitric oxide synthesis and reactive oxygen species formation in human endothelial cells. AB - OBJECTIVE: To evaluate in vitro the effects of serum and LDL fractions isolated from hypercholesterolemic patients on nitric oxide (NO) synthesis and reactive oxygen species (ROS) production by human umbilical vein endothelial cells (HUVECs). DESIGN AND METHODS: Serum and LDL isolated from subjects with high (n=18) and normal (n=21) LDL-cholesterol levels were analyzed on NO synthesis and ROS production in vitro models of HUVECs. LDL was furthers characterized in their chemical composition and activities of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), cholesteryl ester transfer protein (CETP) and paraoxonase. RESULTS: NO bioavailability was significantly lower and ROS production higher in HUVECs incubated with serum samples from patients with high LDL-cholesterol levels in comparison to control subjects. Moreover, hypercholesterolemic patients presented higher CETP and Lp-PLA(2) activities than control subjects. LDL fractions isolated from patients and controls were not different in their chemical composition, Lp-PLA(2) activity, and their capacity to reduce NO synthesis and increase ROS production. CONCLUSION: Alterations of serum from hypercholesterolemic patients could be due to the increment in LDL concentration, main Lp-PLA(2) carrier, and not to LDL composition or intrinsic Lp-PLA(2) activity. PMID- 20970416 TI - Comparison of blood sirolimus, tacrolimus and everolimus concentrations measured by LC-MS/MS, HPLC-UV and immunoassay methods. AB - OBJECTIVES: An LC-MS/MS method was developed for simultaneous quantitation of tacrolimus, sirolimus and everolimus in whole blood, and compared to HPLC-UV and immunoassay methods. DESIGN AND METHODS: Blood (0.1mL) was analysed following solid-phase extraction and chromatographic resolution using a C18 column (45 degrees C) and mobile phase of methanol/40mM ammonium acetate/glacial acetic acid (83/17/0.1) at 200MUL/min, with positive electrospray ionisation and multiple reaction monitoring. RESULTS: Intra- and inter-day imprecision and inaccuracy were <=12.2% over a 1.5-40MUg/L calibration range. An external quality assurance programme confirmed acceptable inaccuracy and imprecision of the LC-MS/MS method, but highlighted problems with immunoassay quantitation, particularly for everolimus, showing a >30% bias in FPIA everolimus concentrations measured in pooled patient samples versus spiked drug-free whole blood. CONCLUSIONS: LC-MS/MS provides significant accuracy and precision advantages compared to HPLC and immunoassays. Discrepancies in everolimus concentrations measured by the Seradyn FPIA immunoassay require further investigation. PMID- 20970418 TI - Hypocrellin B-encapsulated nanoparticle-mediated rev-caspase-3 gene transfection and photodynamic therapy on tumor cells. AB - Gene therapy and photodynamic therapy are two kinds of important therapeutic strategies for treating malignant tumors. In order to explore the combined effects of gene therapy and PDT on tumor cells, rev-caspase-3 gene was transfected into the tumor model CNE2 cells using hypocrellin B-encapsulated nanoparticle (nano-HB) as a carrier. The transfected CNE2 cells were then irradiated by light from a LED source and the survival rate was investigated 18 h after PDT. Apoptosis was analyzed by a flow cytometer with propidium iodine (PI) staining and the active caspase-3 expression was measured using flow cytometry with phycoerythrin (PE)-conjugated anti-active caspase-3 antibody. The result from the flow cytometer showed that the level of the activated caspase-3 significantly increased up to 63.10% in the transfected CNE2 cells. The survival rate 18 h after gene transfection alone and nano-HB-mediated PDT was 96.6+/ 2.07%, 72.6+/-4.15%, respectively. However, the survival rate of the transfected CNE2 cells 18 h after LED exposure significantly decreased to 50.6+/-5.98% under the light energy of 4 J/cm(2). Apoptotic rate 18 h after the combination of gene transfection and PDT increased up to 24.65%. Our findings demonstrated that nano HB could significantly enhance the transfection efficiency of rev-caspase-3 gene in the CNE2 cells. LED irradiation could effectively kill the treated CNE2 cells and induce apoptosis, suggesting hypocrellin B-encapsulated nanoparticle as an efficient gene carrier and a novel photosensitizer. The combination of gene therapy and PDT using nanoparticle as a mediator can be developed for treating nasopharyngeal carcinoma. PMID- 20970417 TI - Upregulation of cardiac NOS due to endotoxemia and vagal overactivity contributes to the hypotensive effect of chronic ethanol in female rats. AB - We previously reported that chronic ethanol lowers blood pressure in female rats. In this study, hemodynamic, biochemical, and immunoblot analyses were performed to investigate: (i) the roles of cardiac contractility and autonomic activity in the hypotensive action of ethanol, and (ii) whether endotoxemia-induced upregulation of cardiac and/or vascular nitric oxide synthase (NOS) isoforms underlies the hypotensive and cardiac effects of ethanol. Telemetric monitoring of blood pressure, heart rate, and myocardial contractility (dP/dt(max)) was performed in female rats receiving liquid diet with or without ethanol (5% w/v, 13weeks). Autonomic control was assessed by frequency domain analysis of interbeat intervals (IBI) and systolic blood pressure (SBP). Compared with pair fed controls, ethanol caused sustained reductions in blood pressure, heart rate, and+dP/dt(max). Ethanol feeding increased the spectral power of high-frequency band (IBI(HF), 0.75-3Hz) and decreased the low-frequency band (IBI(LF), 0.25 0.75Hz) and IBI(LF/HF) ratio, suggesting increased cardiac parasympathetic dominance. In contrast, vascular tone was not affected by ethanol because SBP spectral bands and plasma norepinephrine remained unchanged. Myocardial expressions of eNOS and its upstream regulators, phosphatidylinositol 3-kinase (PI3K) and Akt, and plasma endotoxin and nitrite/nitrate were increased by ethanol. Myocardial iNOS was also increased by ethanol whereas nNOS remained unchanged and aortic levels of all NOS isoforms were not altered by ethanol. These findings suggest that facilitation of myocardial PI3K/Akt/eNOS and iNOS pathways, due possibly to ethanol-induced endotoxemia and/or increased cardiac parasympathetic dominance, might constitute a cellular mechanism for the reduced myocardial contractility and hypotension caused by ethanol in female rats. PMID- 20970419 TI - The diagnostic value of PCA3 gene-based analysis of urine sediments after digital rectal examination for prostate cancer in a Chinese population. AB - Prostate cancer gene 3 (PCA3) encodes a prostate-specific mRNA that has shown promise as a prostate cancer (PCa) diagnostic tool and is detectable in prostate cancer cells shedding into urine after digital rectal examination (DRE). In our earlier studies, a tissue test for PCA3 appeared to have greater specificity for PCa. There, we performed a clinical evaluation of PCA3 mRNA assay in urine sediments after DRE enriched with prostate cells in a Chinese population. PCA3 mRNA was detected by real-time fluorescent quantitative reverse transcription polymerase chain reaction (FQ-RT-PCR) in the urine sediments. PSA mRNA detected also by real-time FQ-RT-PCR was used to confirm the yield of prostate cells in the urine sediments beforehand and normalize PCA3 mRNA signals. The data were summarized in a receiver operating characteristic (ROC) curve to visualize the efficacy of ratio PCA3/PSA mRNA as a marker; sensitivity and specificity were calculated also. We also correlated the ratio PCA3/PSA mRNA to the biopsy results (including the presence or absence of malignancy and the Gleason score of the malignancy cases) and to the bone metastasis to evaluate its clinical value. The PCA3 mRNA expression (PCA3/PSA mRNA) in the PCa group was significantly higher than that in the BPH group. The AUC-ROC was 0.786 (95% CI: 0.683-0.889). When the cutoff value was set as 0.107, the sensitivity and specificity were 62.9% and 90.6%, respectively. The positive predictive value and negative predictive value of the PCA3 urine test was 78.6% and 81.7%, respectively. No significant correlation was found between urine PCA3 expression and Gleason score or bone metastasis. Results indicated the clinical usefulness of the PCA3/PSA mRNA of urine sediments after DRE as a molecular marker in the early diagnosis of prostate cancer, which appears to be highly specific for PCa. As a non-invasive and sample accessible assay, the PCA3/PSA mRNA may therefore be useful as an aid in the diagnosis of PCa. PMID- 20970420 TI - Effects of fibroblast origin and phenotype on the proliferative potential of limbal epithelial progenitor cells. AB - The current study investigates potential differences in fibroblast phenotype across the anterior segment of the human eye with the aim to understanding factors that support the regenerative function of human limbal epithelial progenitor cells (LEPs) during wound healing. Separate cultures of fibroblasts were established from the cornea, limbus and sclera by growth in serum supplemented medium. The resulting cultures were examined for potential differences in morphology and growth rate, as well as expression of CD34, CD45, CD90, CD141, CD271, vimentin and alpha-smooth muscle actin (alpha-sma). Finally, cultures were examined for their ability to support the growth of LEPs. While all cultures grew at a similar rate, scleral cultures often contained larger and more irregularly shaped cells which stained positive for alpha-sma. Western blotting confirmed a gradient of alpha-sma expression with lowest levels in corneal cultures. All three cultures stained positively for CD90 and vimentin, and were negative for CD34, CD45, CD141 and CD271. Only limbal or corneal irradiated fibroblasts supported the establishment of LEP cultures. While LEP colony forming efficiency and prominent expression of ABCG2, C/EBPdelta and p63 was similar with either limbal or corneal fibroblasts, limbal fibroblasts supported significantly better growth. These results indicate that scleral fibroblasts have an increased capacity for myofibroblast formation which appears to negatively impact on their ability to support LEP growth. Superior growth of LEPs in the presence of limbal fibroblasts indicates a role for limbal fibroblasts in promoting the proliferation of limbal epithelium during wound healing. PMID- 20970421 TI - Ultrastructural relationship between the AMPA-GluR2 receptor subunit and the mu opioid receptor in the mouse central nucleus of the amygdala. AB - Activation of GluR2-expressing non-calcium-permeable AMPA-type glutamate receptors in the central nucleus of the amygdala (CeA) may play an important role in integrating emotion and memory with goal-directed behaviors involved in opioid addiction. The location of non-calcium-permeable AMPA receptors within distinct neuronal compartments (i.e., soma, dendrite, or axon) is an important functional feature of these proteins; however, their ultrastructural location and subcellular relationship with mu-opioid receptors (MUOR) in the CeA are unknown. Immunocytochemical electron microscopy was used to characterize the ultrastructural distribution of GluR2 and its association with MUOR in the mouse CeA. A single-labeling analysis of GluR2 distribution employing immunoperoxidase or immunogold markers revealed that this protein was frequently affiliated with intracellular vesicular organelles, as well as the plasma membrane of CeA neuronal profiles. Among all GluR2-labeled neuronal structures, over 85% were dendrites or somata. Unlabeled axon terminals frequently formed asymmetric excitatory-type synaptic junctions with GluR2-labeled dendritic profiles. Dual labeling immunocytochemical analysis showed that GluR2 and MUOR were co-localized in neuronal compartments. Among all dual-labeled structures, approximately 80% were dendritic. Synaptic inputs to these dual-labeled dendrites were frequently from unlabeled axon terminals forming asymmetric excitatory-type synapses. The presence of GluR2 in dendritic profiles receiving asymmetric synapses suggests that activation of the non-calcium-permeable AMPA receptor plays a role in the postsynaptic modulation of excitatory signaling involving CeA neuronal circuits that coordinate sensory, affective, and behavioral processes involved in drug addiction. Given the critical role of non-calcium-permeable AMPA receptor function in neural and behavioral adaptability, their dendritic association with MUOR in CeA dendrites provides a neuronal substrate for opioid-mediated plasticity. PMID- 20970423 TI - NEMO stabilizes c-Myc through direct interaction in the nucleus. AB - The transcription factor c-Myc is a cellular oncoprotein generally upregulated in most of human cancers. NF-kappaB essential modulator (NEMO) caused phosphorylation and stabilization of c-Myc protein in the nucleus through direct interaction. The interaction caused reduced ubiquitination of c-Myc by inhibiting ubiquitinating activity of Fbw7 without blocking the interaction between c-Myc and Fbw7. As a consequence, NEMO enhanced the expression of several selected c Myc targets. Compared to the classical role as an essential subunit for the activity of IKK complex, stabilization of c-Myc by direct interaction is a unique function of NEMO, representing a new mechanism to regulate c-Myc activity. PMID- 20970422 TI - Recent advances in the development of immunotherapies for tauopathies. AB - The use of immunotherapy for Alzheimer's disease (AD) has traditionally focused on the amyloid-beta (Abeta) peptide and has shown great potential in both animal and human studies. However, an emerging body of work has begun to concentrate on tau and to develop immunization protocols designed to decrease tau pathology in AD and other tauopathies. This commentary will discuss the use of immunotherapy for AD, focusing on tau immunotherapy in the context of recent reports on the use of tau phospho-peptides in transgenic models of tau pathology. PMID- 20970424 TI - Interaction between separated consecutive complement control modules of human C1r: implications for dimerization of the full-length protease. AB - Complement control protein modules (CCP) typically mediate protein:protein interaction during immune response in vertebrates. Using NMR chemical shift perturbation mapping, we present previously lacking experimental evidence for intermolecular interactions between the CCP1 and CCP2 modules of the human C1r serine protease (SP). The identified interface is clearly distinct from that observed in the covalently linked CCP1-CCP2 pair. Structural models of the CCP1 CCP2-SP segments of two C1r molecules built on the basis of shift perturbation data are fully consistent with an extended interaction interface and suggests the possibility of a structural rearrangement as a switch between functional states of human C1r. PMID- 20970425 TI - Functions for the cardiomyokine, MANF, in cardioprotection, hypertrophy and heart failure. AB - We define cardiomyokines as heart-derived secreted proteins that affect cardiovascular function via autocrine, paracrine and/or endocrine mechanisms. The subject of this review is the cardiomyokine, mesencephalic astrocyte-derived neurotrophic factor (MANF). The expression of MANF is increased in the ischemic heart, in part, through activation of ER stress, a condition that drastically impairs the expression and secretion of most cardiomyokines. This novel function of MANF suggests that it may have important roles in the ER stressed, ischemic heart. Consistent with this are recent findings showing that MANF protects against ischemic damage, and that it is anti-hypertrophic. Accordingly, in light of its function as a potentially secreted cardiomyokine, MANF has translational potential as a novel therapy for ischemic heart disease. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure." PMID- 20970426 TI - Fluidizing the membrane by a local anesthetic: phenylethanol affects membrane protein oligomerization. AB - The exact mechanism of action of anesthetics is still an open question. While some observations suggest specific anesthetic-protein interactions, nonspecific perturbation of the lipid bilayer has also been suggested. Perturbations of bilayer properties could subsequently affect the structure and function of membrane proteins. Addition of the local anesthetic phenylethanol (PEtOH) to model membranes and intact Escherichia coli cells not only affected membrane fluidity but also severely altered the defined helix-helix interaction within the membrane. This experimental observation suggests that certain anesthetics modulate membrane physical properties and thereby indirectly affect transmembrane (TM) helix-helix interactions, which are not only involved in membrane protein folding and assembly but also important for TM signaling. PMID- 20970427 TI - beta-Barrel topology of Alzheimer's beta-amyloid ion channels. AB - Emerging evidence supports the ion channel mechanism for Alzheimer's disease pathophysiology wherein small beta-amyloid (Abeta) oligomers insert into the cell membrane, forming toxic ion channels and destabilizing the cellular ionic homeostasis. Solid-state NMR-based data of amyloid oligomers in solution indicate that they consist of a double-layered beta-sheets where each monomer folds into beta-strand-turn-beta-strand and the monomers are stacked atop each other. In the membrane, Abeta peptides are proposed to be beta-type structures. Experimental structural data available from atomic force microscopy (AFM) imaging of Abeta oligomers in membranes reveal heterogeneous channel morphologies. Previously, we modeled the channels in a non-tilted organization, parallel with the cross membrane normal. Here, we modeled a beta-barrel-like organization. beta-Barrels are common in transmembrane toxin pores, typically consisting of a monomeric chain forming a pore, organized in a single-layered beta-sheet with antiparallel beta-strands and a right-handed twist. Our explicit solvent molecular dynamics simulations of a range of channel sizes and polymorphic turns and comparisons of these with AFM image dimensions support a beta-barrel channel organization. Different from the transmembrane beta-barrels where the monomers are folded into a circular beta-sheet with antiparallel beta-strands stabilized by the connecting loops, these Abeta barrels consist of multimeric chains forming double beta sheets with parallel beta-strands, where the strands of each monomer are connected by a turn. Although the Abeta barrels adopt the right-handed beta-sheet twist, the barrels still break into heterogeneous, loosely attached subunits, in good agreement with AFM images and previous modeling. The subunits appear mobile, allowing unregulated, hence toxic, ion flux. PMID- 20970428 TI - Molecular mechanisms modulating glutamate kinase activity. Identification of the proline feedback inhibitor binding site. AB - Proline, the feedback inhibitor of bacterial glutamate kinase (GK) and plant pyrroline-5-carboxylate synthase (P5CS) enzymes, is a key regulator of the osmotic and redox balance of cells. Using kinetic assays, site-directed mutagenesis, structure-activity analyses, and docking calculations, we have identified the binding site of this metabolite in three-dimensional structures of Escherichia coli and Campylobacter jejuni GKs. The proline-binding cavity partially overlaps with the glutamate substrate site, and the interaction of both proline and glutamate with GK is modulated by a flexible, 16-residue loop linking beta-sheet 4 and alpha-helix E in the active-center cavity. This loop is also critical for regulation of plant and human P5CSs. Furthermore, our results indicate that the functional unit of the E. coli enzyme is dimeric and contains an intermolecular hydrogen-bond network that interconnects the active-center cavities of the monomers and is important for substrate binding. PMID- 20970429 TI - Binding thermodynamics of phosphorylated inhibitors to triosephosphate isomerase and the contribution of electrostatic interactions. AB - Electrostatic interactions have a central role in some biological processes, such as recognition of charged ligands by proteins. We characterized the binding energetics of yeast triosephosphate isomerase (TIM) with phosphorylated inhibitors 2-phosphoglycollate (2PG) and phosphoglycolohydroxamate (PGH). We determined the thermodynamic parameters of the binding process (K(b), DeltaG(b), DeltaH(b), DeltaS(b) and DeltaC(p)) with different concentrations of NaCl, using fluorimetric and calorimetric titrations in the conventional mode of ITC and a novel method, multithermal titration calorimetry (MTC), which enabled us to measure DeltaC(p) in a single experiment. We ruled out specific interactions of Na(+) and Cl(-) with the native enzyme and did not detect significant linked protonation effects upon the binding of inhibitors. Increasing ionic strength (I) caused K(b), DeltaG(b) and DeltaH(b) to become less favorable, while DeltaS(b) became less unfavorable. From the variation of K(b) with I, we determined the electrostatic contribution of TIM-2PG and TIM-PGH to DeltaG(b) at I=0.06 M and 25 degrees C to be 36% and 26%, respectively. The greater affinity of PGH for TIM is due to a more favorable DeltaH(b) compared to 2PG (by 19-24 kJ mol(-1) at 25 degrees C). This difference is compatible with PGH establishing up to five more hydrogen bonds with TIM. Both binding DeltaC(p)s were negative, and less negative with increasing ionic strength. DeltaC(p)s at I=0.06 M were much more negative than predicted by surface area models. Water molecules trapped in the interface when ligands bind to protein could explain the highly negative DeltaCps. Thermodynamic binding functions for TIM-2PG changed more with ionic strength than those for TIM-PGH. This greater dependence is consistent with linked, but compensated, protonation equilibriums yielding the dianionic species of 2PG that binds to TIM, process that is not required for PGH. PMID- 20970431 TI - Crystal structures of NodS N-methyltransferase from Bradyrhizobium japonicum in ligand-free form and as SAH complex. AB - NodS is an S-adenosyl-L-methionine (SAM)-dependent N-methyltransferase that is involved in the biosynthesis of Nod factor (NF) in rhizobia, which are bacterial symbionts of legume plants. NF is a modified chitooligosaccharide (COS) signal molecule that is recognized by the legume host, where it initiates symbiotic processes leading to atmospheric nitrogen fixation. We report the crystal structure of recombinant NodS protein from Bradyrhizobium japonicum, which infects lupine and serradella legumes. Two crystal forms--ligand-free NodS and NodS in complex with S-adenosyl-L-homocysteine, which is a by-product of the methylation reaction--were obtained, and their structures were refined to resolutions of 2.43 A and 1.85 A, respectively. Although the overall fold (consisting of a seven-stranded beta-sheet flanked by layers of helices) is similar to those of other SAM-dependent methyltransferases, NodS has specific features reflecting the unique character of its oligosaccharide substrate. In particular, the N-terminal helix and its connecting loop get ordered upon SAM binding, thereby closing the methyl donor cavity and shaping a long surface canyon that is clearly the binding site for the acceptor molecule. Comparison of the two structural forms of NodS suggests that there are also other conformational changes taking place upon the binding of the donor substrate. As an enzyme that methylates a COS substrate, NodS is the first example among all SAM-dependent methyltransferases to have its three-dimensional structure elucidated. Gaining insight about how NodS binds its donor and acceptor substrates helps to better understand the mechanism of NodS activity and the basis of its functional difference in various rhizobia. PMID- 20970430 TI - Robust mechanosensing and tension generation by myosin VI. AB - Myosin VI is a molecular motor that is thought to function both as a transporter and as a cytoskeletal anchor in vivo. Here we use optical tweezers to examine force generation by single molecules of myosin VI under physiological nucleotide concentrations. We find that myosin VI is an efficient transporter at loads of up to ~2 pN but acts as a cytoskeletal anchor at higher loads. Our data and the resulting model are consistent with an indirect coupling of global structural motions to nucleotide binding and release. The model provides a mechanism by which load may regulate the dual functions of myosin VI in vivo. Our results suggest that myosin VI kinetics are tuned such that the motor maintains a consistent level of mechanical tension within the cell, a property potentially shared by other mechanosensitive proteins. PMID- 20970432 TI - Synergy, structure and conformational flexibility of hybrid cellulosomes displaying various inter-cohesins linkers. AB - Cellulosomes are large extracellular multi-enzyme complexes that exhibit elevated activity on plant cell-wall polysaccharides. In the present study, the relationships between the conformational flexibility and efficacy of cellulosomes, and the inter-modules linkers of their scaffold protein were investigated. For this purpose, the length of the intrinsically disordered Ser/Thr-rich 50-residue linker connecting a Clostridium thermocellum and a Clostridium cellulolyticum cohesin in a hybrid scaffoldin (Scaf4) was changed by sequences ranging from 4 to 128 residues. The composition was also modified and new linkers composed of series of N, S or repeats of the EPPV motif were generated. Two model cellulases (Cel48F and Cel9G) appended with appropriate dockerins were subsequently bound to the engineered scaffoldins. All the resulting minicomplexes displayed the same activity on crystalline cellulose as the complex based on the initial Scaf4, and were found to be 2-fold more active than Cel48F and Cel9G bound to separate cohesins. Small-angle X-ray scattering assays of the engineered scaffoldins confirmed, however, that the size and the conformational flexibility of some of the new inter-cohesins linkers differed significantly from that of the initial 50 residue linker displayed by the parental Scaf4. Our data suggest that the synergy induced by proximity does not require a specific inter-cohesins sequence or distance. The present study reveals that complexation onto the hybrid scaffoldins modifies the type of soluble sugars released from crystalline cellulose by the selected cellulases, compared to the free enzyme system. PMID- 20970433 TI - Neuraminidase inhibitors for treatment of human and avian strain influenza: A comparative modeling study. AB - Treatment of seasonal influenza viral infections using antivirals such as neuraminidase inhibitors (NAIs) has been proven effective if administered within 48h post-infection. However, there is growing evidence that antiviral treatment of infections with avian-derived strains even as late as 6 days post-infection (dpi) can significantly reduce infection severity and duration. Using a mathematical model of in-host influenza viral infections which can capture the kinetics of both a short-lived, typical, seasonal infection and a severe infection exhibiting sustained viral titer, we explore differences in the effects of NAI treatment on both types of influenza viral infections. Comparison of our model's behavior against experimental data from patients naturally infected with avian strains yields estimates for the times at which patients were infected that are consistent with those reported by the patients, and estimates of drug efficacies that are lower for patients who died than for those who recovered. In addition, our model suggests that the sustained, high, viral titers often seen in more severe influenza virus infections are the reason why antiviral treatment delayed by as much as 6 dpi will still lead to reduced viral titers and shortened illness. We conclude that NAIs may be an effective and beneficial treatment strategy against more severe strains of influenza virus characterized by high, sustained, viral titers. We believe that our mathematical model will be an effective tool in guiding treatment of severe influenza viral infections with antivirals. PMID- 20970434 TI - Comparison studies of the structural stability of rabbit prion protein with human and mouse prion proteins. AB - BACKGROUND: Prion diseases are fatal and infectious neurodegenerative diseases affecting humans and animals. Rabbits are one of the few mammalian species reported to be resistant to infection from prion diseases isolated from other species (I. Vorberg et al., Journal of Virology 77 (3) (2003) 2003-2009). Thus the study of rabbit prion protein structure to obtain insight into the immunity of rabbits to prion diseases is very important. FINDINGS: The paper is a straight forward molecular dynamics simulation study of wild-type rabbit prion protein (monomer cellular form) which apparently resists the formation of the scrapie form. The comparison analyses with human and mouse prion proteins done so far show that the rabbit prion protein has a stable structure. The main point is that the enhanced stability of the C-terminal ordered region especially helix 2 through the D177-R163 salt-bridge formation renders the rabbit prion protein stable. The salt bridge D201-R155 linking helixes 3 and 1 also contributes to the structural stability of rabbit prion protein. The hydrogen bond H186-R155 partially contributes to the structural stability of rabbit prion protein. CONCLUSIONS: Rabbit prion protein was found to own the structural stability, the salt bridges D177-R163, D201-R155 greatly contribute and the hydrogen bond H186 R155 partially contributes to this structural stability. The comparison of the structural stability of prion proteins from the three species rabbit, human and mouse showed that the human and mouse prion protein structures were not affected by the removing these two salt bridges. Dima et al. (Biophysical Journal 83 (2002) 1268-1280 and Proceedings of the National Academy of Sciences of the United States of America 101 (2004) 15335-15340) also confirmed this point and pointed out that "correlated mutations that reduce the frustration in the second half of helix 2 in mammalian prion proteins could inhibit the formation of PrP(Sc)". PMID- 20970435 TI - Improving the relaxing effect of terbutaline with phosphodiesterase inhibitors: studies on pregnant rat uteri in vitro. AB - AIMS: Previous results by our group showed that the in vitro uterus-relaxing potency of beta(2)-adrenergic receptor (beta(2)-AR) agonists and uterine cAMP accumulation are enhanced in case of visceral inflammation. Our aim was to study the effects of the non-selective phosphodiesterase (PDE) inhibitor theophylline and the selective PDE4 inhibitor rolipram on the uteri of intact late-pregnant female rats (on days 20 and 22 of pregnancy) and of pregnant rats treated with lipopolysaccharide (LPS) to evoke preterm labor (on day 20). MAIN METHODS: The effects of theophylline and rolipram alone and of rolipram with terbutaline were investigated in isolated organ system. Contractions were evoked with KCl. The forskolin- and terbutaline-stimulated cAMP accumulations were determined by enzyme immunoassay, with or without rolipram. KEY FINDINGS: The maximum uterus relaxing effects of theophylline and rolipram decreased significantly (p<0.05) with the progression of pregnancy in intact rats. The most pronounced effect of rolipram was detected in rats challenged with LPS on day 20. Rolipram increased the in vitro effect of terbutaline both in intact and in LPS-treated rats. In the presence of rolipram, the forskolin- and terbutaline-stimulated cAMP accumulations were higher in LPS-treated than in intact rats. SIGNIFICANCE: The previous findings led us to conclude that the combined administration of PDE4 inhibitors with beta(2)-agonists is of therapeutic value for the inhibition for uterine contractions, especially in the case of genital inflammation, which often triggers preterm birth. Combination therapy in general is associated with lesser side-effects, as a consequence of lower effective doses of each drug. PMID- 20970436 TI - Bip overexpression, but not CHOP inhibition, attenuates fatty-acid-induced endoplasmic reticulum stress and apoptosis in HepG2 liver cells. AB - AIMS: In this study we investigated whether attenuation of endoplasmic reticulum stress (ER stress) could protect HepG2 cells from free fatty acid (FFA)-induced apoptosis. MAIN METHODS: Human liver cell line HepG2 cells were exposed to Sodium Palmitate (Pa) or Sodium Oleate (Ol). Apoptosis and ER stress of HepG2 cells were analyzed with flow cytometry, real-time RT-PCR and Western Blotting. An expression plasmid encoding for the ER chaperone immunoglobulin heavy chain binding protein (Bip) was transfected into HepG2 cells to attenuate ER stress. Small interfering RNA siCHOP was used to knockdown the expression of C/EBP Homologous Protein (CHOP) in HepG2. KEY FINDINGS: Pa led to cytotoxicity and apoptosis in HepG2 cells in a dose-dependent pattern and also induced ER stress indicated by increased phosphorylation of eIF2alpha, upregulation of IRE1alpha and CHOP. Bip expression levels were slightly down regulated after Pa treatment. The unsaturated fatty acid, Ol, induced neither apoptosis nor ER stress in HepG2 cells. Overexpression of Bip attenuated Pa-induced ER stress and led to a significant reduction in Pa-mediated apoptosis, indicating a requirement of ER stress for lipotoxicity in liver cells. siRNA-mediated reduction of CHOP did not protect against Pa-induced apoptosis. SIGNIFICANCE: While ER stress makes a necessary contribution to palmitate cytotoxicity, inhibition of CHOP alone is not sufficient to prevent palmitate-induced apoptosis. Our findings could advance the detailed understanding on the mechanism of high fatty acid (FFA)-induced apoptosis. PMID- 20970437 TI - Bone marrow derived cells decrease inflammation but not oxidative stress in an experimental model of acute myocardial infarction. AB - AIMS: Bone marrow cell (BMC) therapy is thought to exert beneficial effects on the infarcted heart. We assessed cardiac function and its correlation with redox status and inflammation in cardiac tissue early post-AMI in rats treated with BMC. MAIN METHODS: Male Wistar rats (8-week-old) were randomized into four groups: Sham-operated (S); AMI; S+treatment (ST) and AMI+treatment (AMIT). Therapy with BMC was carried out immediately post-experimental left anterior coronary artery ligation induced-AMI, and assessments made 48h later. Cardiac function and morphometrics were evaluated by echocardiographyc parameters in vivo. Cardiac tissue tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were measured by Western Blot. Oxidative stress parameters including reduced (GSH) and oxidized (GSSG) glutathione ratio, hydrogen peroxide level, lipid and protein oxidation, superoxide dismutase, catalase and glutathione peroxidase activities were measured spectrophotometrically. KEY FINDINGS: Ejection fraction was lower in infarcted groups and did not improve in BMC-treated animals: AMI (51+/-5%) vs. S (74+/-7%) and AMIT (56+/-10%) vs. ST groups (73+/-3%). Both TNF alpha and IL-6 myocardial expression increased post-AMI and were reduced following BMC therapy. Nonetheless, there was a decrease in GSH/GSSG ratio in infarcted groups which was greater in BMC-treated groups: AMI (8.21+/-3.8) vs. S (14.61+/-3.4) and AMIT (2.1+/-0.7) vs. ST (4.7+/-1.5). SIGNIFICANCE: The data suggest that BMC promoted a redox status favorable to the oxidation of the pro inflammatory cytokines in the myocardium, exerting an anti-inflammatory-like effect. PMID- 20970438 TI - Investigation of the cardiomyocyte dysfunction in bradykinin type 2 receptor knockout mice. AB - AIMS: Bradykinin type 2 receptor (B(2)R) is the key component to trigger the intracellular signaling pathway in response to bradykinin under physiological conditions. The present study sought to investigate whether the B(2)R gene deletion will have an impact on myocardial function. MAIN METHODS: Isolated cell shortening, patch-clamp technique, Western blot and confocal microscopy. KEY FINDINGS: Isolated cell shortening measurements showed significant reduction in B(2)R knockout (B(2)R(-/-)) left ventricular cardiac myocytes' shortening. Whole cell recordings were used to study the electrophysiological aspects of the left ventricular B(2)R(-/-) cardiomyocytes. Results showed: 1) action potential lengthening; 2) unchanged inwardly rectifying K(+) current; 3) reduced transient outward K(+) (I(to)) and L-type Ca(2+) current densities; 5) changes in kinetic properties related to I(to) and I(Ca,L). In addition, transient sarcoplasmic reticulum (SR) Ca(2+) release was found to be smaller in B(2)R(-/-) cardiomyocytes. Importantly, evidence is provided that NO constitutive production is, at least in part, responsible for the reported electrophysiological modifications observed in cardiomyocytes from B(2)R(-/-) mice. Surprisingly, NO is not involved in the SR Ca(2+) release reduction as demonstrated in the present study. SIGNIFICANCE: Taken together, our findings indicate that B(2)R plays a fundamental role in the regulation of cardiac function and Ca(2+) homeostasis, probably through a NO dependent pathway. These results may contribute to our understanding of the kinins participation in the control of cardiac function. PMID- 20970439 TI - Increased binding of cortical and hippocampal group II metabotropic glutamate receptors in isolation-reared mice. AB - Post-weaning social isolation in rodents induces behavioral alterations, including hyperlocomotion, depression- and anxiety-like behaviors, aggression, and learning and memory deficits. These behavioral abnormalities may be related to the core symptoms in patients with neuropsychiatric disorders, such as schizophrenia and depression. In view of the recent studies that the group II metabotropic glutamate receptor (mGluR2/3) is involved in neuropsychiatric disorders, the present study examined the effect of isolation rearing on the binding of the mGluR2/3 antagonist [(3)H]LY341495 to mGluR2/3 in the mouse brain by in vitro autoradiography. The [(3)H]LY341495 binding in the prefrontal cortex, cerebral cortical layers I-III and hippocampus was significantly increased by rearing in social isolation while the binding in other brain regions was not altered. A saturation binding study of hippocampal membranes from isolation reared mice revealed that the B(max) value increased significantly without any changes in the K(d) value. Moreover, the mGluR2/3 antagonist MGS0039 (1.0mg/kg, intraperitoneally) decreased the immobility time of isolation-reared mice in the forced swim test. These results suggest that isolation rearing causes an increase in mGluR2/3 densities in the prefrontal cortex and hippocampus and that the increased receptor function may contribute to pathogenic mechanisms for depression-like behavior of the isolation-reared mice. PMID- 20970440 TI - Application of toxicogenomics in hepatic systems toxicology for risk assessment: acetaminophen as a case study. AB - Hepatic systems toxicology is the integrative analysis of toxicogenomic technologies, e.g., transcriptomics, proteomics, and metabolomics, in combination with traditional toxicology measures to improve the understanding of mechanisms of hepatotoxic action. Hepatic toxicology studies that have employed toxicogenomic technologies to date have already provided a proof of principle for the value of hepatic systems toxicology in hazard identification. In the present review, acetaminophen is used as a model compound to discuss the application of toxicogenomics in hepatic systems toxicology for its potential role in the risk assessment process, to progress from hazard identification towards hazard characterization. The toxicogenomics-based parallelogram is used to identify current achievements and limitations of acetaminophen toxicogenomic in vivo and in vitro studies for in vitro-to-in vivo and interspecies comparisons, with the ultimate aim to extrapolate animal studies to humans in vivo. This article provides a model for comparison of more species and more in vitro models enhancing the robustness of common toxicogenomic responses and their relevance to human risk assessment. To progress to quantitative dose-response analysis needed for hazard characterization, in hepatic systems toxicology studies, generation of toxicogenomic data of multiple doses/concentrations and time points is required. Newly developed bioinformatics tools for quantitative analysis of toxicogenomic data can aid in the elucidation of dose-responsive effects. The challenge herein is to assess which toxicogenomic responses are relevant for induction of the apical effect and whether perturbations are sufficient for the induction of downstream events, eventually causing toxicity. PMID- 20970441 TI - Poly(ethylene glycol)-conjugated multi-walled carbon nanotubes as an efficient drug carrier for overcoming multidrug resistance. AB - The acquisition of multidrug resistance poses a serious problem in chemotherapy, and new types of transporters have been actively sought to overcome it. In the present study, poly(ethylene glycol)-conjugated (PEGylated) multi-walled carbon nanotubes (MWCNTs) were prepared and explored as drug carrier to overcome multidrug resistance. The prepared PEGylated MWCNTs penetrated into mammalian cells without damage plasma membrane, and its accumulation did not affect cell proliferation and cell cycle distribution. More importantly, PEGylated MWCNTs accumulated in the multidrug-resistant cancer cells as efficient as in the sensitive cancer cells. Intracellular translocation of PEGylated MWCNTs was visualized in both multidrug-resistant HepG2-DR cells and sensitive HepG2 cells, as judged by both fluorescent and transmission electron microscopy. PEGylated MWCNTs targeted cancer cells efficiently and multidrug-resistant cells failed to remove the intracellular MWCNTs. However, if used in combination with drugs without conjugation, PEGylated MWCNTs prompted drug efflux in MDR cells by stimulating the ATPase activity of P-glycoprotein. This study suggests that PEGylated MWCNTs can be developed as an efficient drug carrier to conjugate drugs for overcoming multidrug resistance in cancer chemotherapy. PMID- 20970442 TI - Neural activity in the frontal pursuit area does not underlie pursuit target selection. AB - The frontal pursuit area (FPA) contains neurons that are directionally selective for pursuit eye-movements. We found that FPA neurons discriminate target from distracter too late to account for pursuit directional selection. Rather, the timing of neuronal discrimination is linked to pursuit onset, suggesting a role in motor execution. We also found buildup of activity of FPA neurons prior to pursuit onset that correlated with eye acceleration. These results show that the FPA is unlikely to be involved in selection of initial pursuit direction, but could be involved in motor preparation by increasing pursuit gain prior to pursuit onset. PMID- 20970443 TI - Removal of copper(II) using chitin/chitosan nano-hydroxyapatite composite. AB - Polymeric composites made up of nano-hydroxyapatite (n-HAp) with chitin and chitosan have been prepared and studied for the removal of Cu(II) ions from the aqueous solution. The sorption capacity (SC) of n-HAp, n-HAp/chitin (n-HApC) composite and n-HAp/chitosan (n-HApCs) composite were found to be 4.7, 5.4 and 6.2 mg/g respectively with a minimum contact time of 30 min. Batch adsorption studies were conducted to optimize various equilibrating conditions like contact time, pH and selectivity of metal ion. The sorbents were characterized by FTIR, TEM, XRD and SEM with EDAX analysis. The sorption process was explained with Freundlich and Langmuir isotherms respectively. Thermodynamic parameters such as DeltaG degrees , DeltaH degrees and DeltaS degrees were calculated to understand the nature of sorption. A suitable mechanism for copper sorption was established and the selectivity of the metal ions for the composites was identified. PMID- 20970444 TI - The tissue factor pathway inhibitor 1 of Sciaenops ocellatus possesses antimicrobial activity and is involved in the immune response against bacterial infection. AB - Tissue factor pathway inhibitor 1 (TFPI-1) is a Kunitz-type serine protease inhibitor that regulates the activation of tissue factor-induced coagulation. In teleosts, TFPI-1-like sequences have been found to exist in two species (Danio rerio and Cyprinus carpio); however, the potential function of fish TFPI-1 has not been investigated. In this study, we identified and analyzed a TFPI-1 homologue, SoTFPI-1, from red drum (Sciaenops ocellatus). The deduced amino acid sequence of SoTFPI-1 is 284 residues in length and contains three Kunitz domains, an acidic N-terminus, and a basic C-terminus. SoTFPI-1 shares 49.5% and 46.9% overall sequence identities with the TFPI-1 of D. rerio and C. carpio, respectively. Quantitative real time RT-PCR analysis showed that constitutive SoTFPI-1 expression occurred, in increasing order, in kidney, brain, liver, gill, blood, spleen, muscle, and heart. Bacterial infection and lipopolysaccharide exposure upregulated SoTFPI-1 expression in kidney in time-dependent manners. Recombinant SoTFPI-1 (rSoTFPI-1) purified from Escherichia coli exhibits not only serine protease inhibitor activity but also bactericidal activity in a manner that is independent of any host factors. A synthetic peptide, TO17, corresponding to the C-terminal basic region of SoTFPI-1 also possesses antibacterial effect that is more potent than that of the full-length rSoTFPI-1. Taken together, these results demonstrate that (i) SoTFPI-1 is a biologically active serine protease inhibitor endowed with bactericidal property; (ii) provide the first indication that teleost TFPI-1 is likely to be involved in anti-microbial infection and thus is linked to innate immune defense. PMID- 20970445 TI - Contrast-enhanced ultrasound to diagnose small liver cancer in cirrhosis: friend or foe? PMID- 20970447 TI - Reflux disease as a motility disorder: treatment alternatives to acid suppression. PMID- 20970448 TI - Timing, timing, timing of deep enteroscopy! A key factor for diagnosis of small intestinal hemorrhage, but does it impact patient outcomes? PMID- 20970449 TI - Assessments of tight junction proteins occludin, claudin 5 and scaffold proteins ZO1 and ZO2 in endothelial cells of the rat blood-brain barrier: cellular responses to neurotoxicants malathion and lead acetate. AB - The blood-brain barrier (BBB) is essential for central nervous system (CNS) normal function. It is formed by endothelial cells with special characteristics, which confer the BBB with low permeability and high transendothelial electrical resistance (TEER). We previously demonstrated that malathion and lead, two neurotoxicants widely present in the environment, decrease TEER and increase permeability in in vitro models of the BBB. In this study we assessed tight junction disruption at the protein and gene expression levels using a rat brain microvascular endothelial cell line (RBE4) exposed to lead acetate at 10(-5)M and 10(-6)M, malathion at 10(-5)M, malaoxon at 10(-6)M, and their combinations. Cells were incubated with treatments for 2h, 4h, 8h, 16h, and 24h periods. Immunoblotting assessments demonstrated that protein levels of tight junction proteins occludin and claudin 5, and scaffold proteins ZO1 and ZO2 were decreased after treatments. Gene expression determinations did not correlate with the decreases in protein, indicating that the effects on these proteins were post translational. PMID- 20970450 TI - beta-D-glucan and S-adenosylmethionine serum levels for the diagnosis of Pneumocystis pneumonia in HIV-negative patients: a prospective study. AB - OBJECTIVE: To prospectively assess the diagnostic utility of S-adenosylmethionine (AdoMet) and (1->3)-beta-D-glucan (beta-D-glucan) serum markers for Pneumocystis pneumonia (PCP) in HIV-negative patients. METHODS: HIV-negative, immunocompromised patients suspected of PCP based on clinical presentation and chest imaging were included. PCP was confirmed or rejected by results of direct microscopy and/or real-time PCR on broncho-alveolar lavage (BAL) fluid. Measurement of serum beta-D-glucan and AdoMet was performed on serum samples collected at enrollment and during follow-up. Both serum beta-D-glucan and AdoMet were assessed for diagnostic accuracy and correlation with clinical and laboratory parameters. RESULTS: In 31 patients enrolled (21 PCP-positive, 10 PCP negative), AdoMet levels did not discriminate between patients with and without PCP. Elevated serum beta-D-glucan was a reliable indicator for PCP with a sensitivity of 0.90 and specificity of 0.89 at the 60 pg/ml cut-off. In PCP positive patients beta-D-glucan serum levels decreased during treatment and inversely correlated with Pneumocystis PCR cycle threshold values in BAL fluid. CONCLUSIONS: The level of beta-D-glucan--but not AdoMet--was diagnostic for PCP within the clinical context and may serve as marker for pulmonary fungal load and treatment monitoring. PMID- 20970451 TI - Single cell transcriptomics of hypothalamic warm sensitive neurons that control core body temperature and fever response Signaling asymmetry and an extension of chemical neuroanatomy. AB - We report on an 'unbiased' molecular characterization of individual, adult neurons, active in a central, anterior hypothalamic neuronal circuit, by establishing cDNA libraries from each individual, electrophysiologically identified warm sensitive neuron (WSN). The cDNA libraries were analyzed by Affymetrix microarray. The presence and frequency of cDNAs were confirmed and enhanced with Illumina sequencing of each single cell cDNA library. cDNAs encoding the GABA biosynthetic enzyme Gad1 and of adrenomedullin, galanin, prodynorphin, somatostatin, and tachykinin were found in the WSNs. The functional cellular and in vivo studies on dozens of the more than 500 neurotransmitters, hormone receptors and ion channels, whose cDNA was identified and sequence confirmed, suggest little or no discrepancy between the transcriptional and functional data in WSNs; whenever agonists were available for a receptor whose cDNA was identified, a functional response was found. Sequencing single neuron libraries permitted identification of rarely expressed receptors like the insulin receptor, adiponectin receptor 2 and of receptor heterodimers; information that is lost when pooling cells leads to dilution of signals and mixing signals. Despite the common electrophysiological phenotype and uniform Gad1 expression, WSN transcriptomes show heterogeneity, suggesting strong epigenetic influence on the transcriptome. Our study suggests that it is well-worth interrogating the cDNA libraries of single neurons by sequencing and chipping. PMID- 20970453 TI - Sphingolipids and expression regulation of genes in cancer. AB - Sphingolipids including glycosphingolipids have myriad effects on cell functions and affect cancer in aspects of tumorigenesis, metastasis and tumor response to treatments. Bioactive ones like ceramide, sphingosine 1-phosphate and globotriaosylceramide initiate and process cellular signaling to alter cell behaviors immediately responding to oncogenic stress or treatment challenges. Recent studies pinpoint that sphingolipid-mediated gene expression has long and profound impacts on cancer cells, and these play crucial roles in tumor progression and in treatment outcome. More than 10 sphingolipids and glycosphingolipids selectively mediate expressions of approximately 50 genes including c-myc, p21, c-fos, telomerase reverse transcriptase, caspase-9, Bcl-x, cyclooxygenase-2, matrix metalloproteinases, integrins, Oct-4, glucosylceramide synthase and multidrug-resistant gene 1. By diverse functions of these genes, sphingolipids enduringly affect cellular processes of mitosis, apoptosis, migration, stemness of cancer stem cells and cellular resistance to therapies. Mechanistic studies indicate that sphingolipids regulate particular gene expression by modulating phosphorylation and acetylation of proteins that serve as transcription factors (beta-catenin, Sp1), repressor of transcription (histone H3), and regulators (SRp30a) in RNA splicing. Disclosing molecular mechanisms by which sphingolipids selectively regulate particular gene expression, instead of other relevant ones, requires understanding of the exact roles of individual lipid instead of a group, the signaling pathways that are implicated in and interaction with proteins or other lipids in details. These studies not only expand our knowledge of sphingolipids, but can also suggest novel targets for cancer treatments. PMID- 20970454 TI - Use of a near-infrared diode laser to activate mouse cutaneous nociceptors in vitro. AB - A skin-nerve preparation is useful for study of heat transduction mechanisms of A and C-high threshold primary afferents (nociceptors), but the small dimension and liquid environment of the skin organ bath do not readily accommodate conventional noxious heat delivery systems. For these reasons, a 980 nm (near infrared) diode laser was tested for activation and differentiation of cutaneous afferents. Current to the laser driver was varied. Exposure time and area, angle of approach, and stand-off distance from the bath solution surface were held constant. Seventy-eight fibers were classified by: conduction velocity, mechanical threshold, and responsiveness to laser radiation. A subset of the sampled fibers was also tested for sensitivity to convective heat. Most C (30/43) and a few A (6/25) nociceptors responded to laser irradiation. All low mechanical threshold primary afferents (10/10) were unresponsive to laser irradiation. Laser sensitive fibers responded to convective heat, whereas laser-insensitive fibers did not. Laser-induced responses were consistent with literature reports of responses to traditional heat stimulation. Laser stimulation proved to be a rapid, unobtrusive method for reproducible heat stimulation of primary afferents of the mouse skin-nerve preparation. It is effective for defining subpopulations of primary afferent fibers and holds promise as a tool for gauging modification of C-fiber activity. PMID- 20970455 TI - Screening of the HLDA9 panel on peripheral blood dendritic cell populations. AB - Dendritic cells (DC) are a heterogeneous population of bone marrow derived leucocytes that are essential in the initiation of primary T lymphocyte responses. DC are identified as Lineage negative, HLA-DR(+) blood cells that can be further subdivided by CD11c to distinguish CD11c(+) DC and the CD11c(-) plasmacytoid DC. Plasmacytoid DC are the primary IFNalpha producing cells and express CD303, CD304 and CD123. The CD11c(+) myeloid DC can be divided into populations by CD1c, CD16 and CD141 expression. Despite DC being a functionally unique population, they share many cell surface antigens with myeloid lineage cells and B lymphocytes. We used flow cytometry to screen fresh human blood DC populations with the HLDA9 panel of 63 directly labelled mAb which included mAb specific for a number of B lymphocyte antigens. Of this panel, 23 mAb did not bind Lin(-)HLA-DR(+) DC and 10 bound all four populations. Eight mAb bound to the three CD11c(+) DC populations whilst no mAb tested bound to only pDC. Some of the mAb expected to bind to DC populations failed in this analysis. Overall, this screening highlighted similarities between the CD11c(+) DC subsets and the relatively immature state of peripheral blood DC. PMID- 20970456 TI - Proteotyping to establish the lineage of type A H1N1 and type B human influenza virus. AB - The ability to establish the lineage of type A H1N1 and type B human influenza virus strains using a new proteotyping approach is demonstrated. Lineage-specific signature peptides have been determined for the hemagglutinin antigen of type A H1N1 and type B influenza viruses. The detection of these peptides alone within the high resolution mass spectra of whole antigen digests enables the lineage of the strain to be rapidly and unequivocally assigned. This proteotyping approach complements conventional PCR approaches and should aid in the monitoring of the evolution of the influenza virus in both humans and animals. PMID- 20970452 TI - Functional and pathological roles of the 12- and 15-lipoxygenases. AB - The 12/15-lipoxygenase enzymes react with fatty acids producing active lipid metabolites that are involved in a number of significant disease states. The latter include type 1 and type 2 diabetes (and associated complications), cardiovascular disease, hypertension, renal disease, and the neurological conditions Alzheimer's disease and Parkinson's disease. A number of elegant studies over the last thirty years have contributed to unraveling the role that lipoxygenases play in chronic inflammation. The development of animal models with targeted gene deletions has led to a better understanding of the role that lipoxygenases play in various conditions. Selective inhibitors of the different lipoxygenase isoforms are an active area of investigation, and will be both an important research tool and a promising therapeutic target for treating a wide spectrum of human diseases. PMID- 20970457 TI - Development of an IgM-capture ELISA for Coxsackievirus A16 infection. AB - Diagnosis of Coxsackievirus A16 (CA16) infection in China relies mainly on reverse transcription-polymerase chain reaction (RT-PCR) that require expensive equipment and special trained personnel, thus making its wide application in health care settings unlikely. In this study, a novel IgM anti-CA16 assay was developed for the detection of IgM antibodies to CA16 in serum. The responses and diagnostic value of IgM for the CA16 infection were assessed by testing 1970 serum samples. The results showed that sensitivity of IgM test was 84.6% (259/306, 95% CI: 80.1-88.5), and specificity in control subjects and patients with CA16 HFMD was 99.2% (1508/1520, 95% CI: 98.6-99.6) and 90.3% (14/144, 95% CI: 84.2-94.6), respectively. The IgM positive rate reached 56.3% in the sera collected within the first day after onset, increased continuously to 95.3% at day 5 to day 7 after onset, and then reached 100% after more than 8 days. The cross-reaction rate in patients infected with other non-CA16 enteroviruses was 9.7% (14/144). These results suggest that the IgM anti-CA16 assay offers a rapid, convenient, and reliable method to detect acute CA16 infections. PMID- 20970458 TI - Evaluation of the Virus Counter(r) for rapid baculovirus quantitation. AB - The utility of a new instrument for rapid virus quantitation, the Virus Counter, was evaluated in a blind study conducted at three sites. This instrument is a substantially improved version of the original academic research instrument described previously by Stoffel and Rowlen (2005a). The addition of hydrodynamic focusing, a self-contained fluidics system and customized software for system control and data analysis has resulted in a commercially viable and available design. Baculovirus samples were provided by Protein Sciences Corporation and blinded to InDevR and Baylor College of Medicine. Protein Sciences Corporation and Baylor College of Medicine analyzed the samples by plaque assay and InDevR analyzed the samples using the Virus Counter. Serial dilution of stock viruses into growth media and buffer allowed for comparison of measured versus intended concentrations. Direct log-scale comparison between pooled Virus Counter results and pooled plaque assay results indicated a linear relationship (slope=1.1+/-0.2, R(2)=0.86) with statistically significant Pearson correlation (r=0.93, p<0.001). PMID- 20970459 TI - Metabolic and neurologic consequences of chronic lopinavir/ritonavir administration to C57BL/6 mice. AB - It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequently elicit a metabolic syndrome that may include hyperlipidemia, lipodystrophy, and insulin resistance. Metabolic dysfunction in non-HIV-infected subjects has been repeatedly associated with cognitive impairment in epidemiological and experimental studies, but it is not yet understood if antiretroviral therapy-induced metabolic syndrome might contribute to HIV-associated neurologic decline. To determine if protease inhibitor-induced metabolic dysfunction in mice is accompanied by adverse neurologic effects, C57BL/6 mice were given combined lopinavir/ritonavir (50/12.5-200/50 mg/kg) daily for 3 weeks. Data show that lopinavir/ritonavir administration caused significant metabolic derangement, including alterations in body weight and fat mass, as well as dose-dependent patterns of hyperlipidemia, hypoadiponectinemia, hypoleptinemia, and hyperinsulinemia. Evaluation of neurologic function revealed that even the lowest dose of lopinavir/ritonavir caused significant cognitive impairment assessed in multi-unit T-maze, but did not affect motor functions assessed as rotarod performance. Collectively, our results indicate that repeated lopinavir/ritonavir administration produces cognitive as well as metabolic impairments, and suggest that the development of selective aspects of metabolic syndrome in HIV patients could contribute to HIV-associated neurocognitive disorders. PMID- 20970460 TI - The proteasome-ubiquitin pathway in the Schistosoma mansoni egg has development- and morphology-specific characteristics. AB - Schistosoma mansoni eggs, consisting of an ovum surrounded by nutritive vitelline cells packaged in a tanned protein shell, are produced by paired worms residing in the mesenteric veins of the human host. The vitelline cells are degraded as the larval miracidium matures, the fully developed egg either crossing the gut wall to escape the host or becoming lodged in the host's tissues where it dies and disintegrates, inducing a potentially pathological immune response. Thus, the egg is central to both the transmission of the parasite and the aetiology of the disease. Here we present the first study investigating protein turnover in the egg. We establish that the ubiquitin-proteasome pathway (UPP) changes with egg development and furthermore, that the morphological components of the fully developed egg (the miracidium and the subshell envelope) also exhibit different proteasome subunit expression profiles. We conclude that the UPP is responsible not only for degrading the vitelline cells but is also more highly developed in the envelope than in the miracidium. The envelope is involved in the defence of the miracidium and produces the proteins that the egg secretes, presumably to facilitate its escape from the host, so the UPP probably has a multi-faceted role in the egg's biology. PMID- 20970461 TI - Metabolomics and malaria biology. AB - Metabolomics has ushered in a novel and multi-disciplinary realm in biological research. It has provided researchers with a platform to combine powerful biochemical, statistical, computational, and bioinformatics techniques to delve into the mysteries of biology and disease. The application of metabolomics to study malaria parasites represents a major advance in our approach towards gaining a more comprehensive perspective on parasite biology and disease etiology. This review attempts to highlight some of the important aspects of the field of metabolomics, and its ongoing and potential future applications to malaria research. PMID- 20970462 TI - Maturation of P300 amplitude and short-term learning as reflected by P300 habituation between trial blocks in children. AB - Although numerous studies concerning P300 have been reported in adults, few have focused on the normal development of children, particularly in relation to habituation. The aim of this study was to investigate maturation of the P300 component and its habituation (short-term automatic learning) in a sample of healthy children and adolescents. Four models of maturation of the P300 (linear, quadratic or two different linear regressions for the pre-pubertal and pubertal age groups as well as age-inverse) were applied and compared, in order to find the most adequate model according to the Bayesian Information Criterion. A visual oddball paradigm was presented to 81 healthy children and adolescents aged 6-18 years. Three blocks, each with 200 trials were recorded to assess between-block habituation. The data was best fitted to (a) an age-inverse relation between P300 latency and age, and (b) a linear relationship between P300 amplitude and age. An age-dependent effect of habituation was detected in the P300 amplitude, where a considerable amplitude decline was found in the younger children and no significant change for adolescents. Our results support the hypothesis that younger children show stronger habituation effects because they activate a larger neuronal pool from which unnecessary neurons can be excluded during short-term learning. In contrast, in adolescents, these neurons may have already been eliminated as a consequence of pruning, thus reducing habituation effects. Future studies are required to test this hypothesis because our data do not permit alternative explanations to be discarded. PMID- 20970463 TI - GABAergic pathway in a rat model of chronic neuropathic pain: modulation after intrathecal transplantation of a human neuronal cell line. AB - Current understanding of chronic pain points a decrease in level of the inhibitory neurotransmitter GABA, in the spinal dorsal horn, leading to an imbalance between excitatory and inhibitory pathways. A subcloned derivative of the human NT2 cell line (hNT2.17) which, after neuronal differentiation, secretes different inhibitory neurotransmitters such as GABA and glycine has been recently isolated. In this study, we have investigated the effect of this new cell line on peripheral nerve injury induced by chronic constriction (CCI) and notably the effect on the cellular GABAergic pathway. Our data show that the decrease in GABA expression in the spinal dorsal horn of injured animals is concomitant with a decline of its synthetic enzyme GAD67-Ir and mRNA but not GAD65. Interestingly, in transplanted animals we observed a strong induction of GAD67 mRNA with one week after graft, which is followed by a recovery of GAD67 and GABA Ir. This effect paralleled a reduction of hindpaw hypersensitivity and thermal hyperalgesia induced by CCI. These results suggest that hNT2.17 GABA cells can modulate neuropathic pain after CCI certainly by minimizing the imbalance and restoring the cellular GABAergic pathway. PMID- 20970465 TI - The "original" hepatitis B virus of Eastern chimpanzees (Pan trogrodytes schweinfurthii). AB - Little is known about Hepatitis B Virus (HBV) infections in chimpanzees. Therefore, we investigated the prevalence of chimpanzee HBV (chHBV) infections in captive, wild born chimpanzees in the sanctuary on Ngamba Island, Uganda and one sample from a wild free ranging chimpanzee. In one third of the plasma samples (32.4%; 12/37) we detected antibodies to Hepatitis B (core) antigen. Amongst those individuals HBV DNA was detected in one captive wild born and the wild chimpanzee. In contrast to the only available earlier described HBV sequence from the subspecies Pan troglodytes schweinfurthii, there was no evidence of recombination with human HBV. Our sequences therefore are likely to present the "original" chHBV from P. t. schweinfurthii. PMID- 20970466 TI - Characterization of hepatitis virus B isolated from a multi-drug refractory patient. AB - Prolonged treatment of chronic hepatitis B (CHB) with nucleoside analogues (NAs) almost invariably engenders viral resistance, and sequential NAs monotherapy can promote multi-drug resistance. This study aimed to investigate the molecular characteristics and the mutation profile of multi-drug resistant hepatitis B virus (HBV). The complete genome of HBV isolated from a multi-drug refractory patient was amplified and cloned, and 22 clones were selected for sequencing. The homology of the full-length genome between clones ranged from 98.7% to 99.9%. A precore stop codon mutation of G1896A and basic core promoter (BCP) mutations A1762T/G1764A were detected in a majority of clones. A phylogenetic analysis showed that all clones were classified as subgenotype B2. Three mutations in the surface (S) antigen region, sC76Y, sP120T and sI195M, were detected in 100%, 100% and 77.3% of the clones, respectively. In the core (C) antigen region, a mutation at codon 135 (cP135Q) was detected in 100% of clones. Lamivudine (LAM)-resistant mutations, rtL180M and rtM204V/I were detected in 86.4% of clones. Adefovir (ADV) or entecavir (ETV)-resistant mutations were not detected. Several novel mutations, such as rtT128N, rtA222T, rtS256G, rtL271M, rtS332R, and rtN/T337D, were present in a majority of clones. Furthermore, six pairs of mutations in the overlapping reverse transcriptase (RT) gene and S gene were detected. In conclusion, the complex HBV mutation profile detected in the multi-drug refractory patient highlights the problems associated with the ongoing selection of mutations, including further compensatory mutations as well as potential cross resistance mutations. PMID- 20970464 TI - Structure-based design of NS2 mutants for attenuated influenza A virus vaccines. AB - We previously characterised the matrix 1 (M1)-binding domain of the influenza A virus NS2/nuclear export protein (NEP), reporting a critical role for the tryptophan (W78) residue that is surrounded by a cluster of glutamate residues in the C-terminal region that interacts with the M1 protein (Akarsu et al., 2003). To gain further insight into the functional role of this interaction, here we used reverse genetics to generate a series of A/WSN/33 (H1N1)-based NS2/NEP mutants for W78 or the C-terminal glutamate residues and assessed their effect on virus growth. We found that simultaneous mutations at three positions (E67S/E74S/E75S) of NS2/NEP were important for inhibition of influenza viral polymerase activity, although the W78S mutant and other glutamate mutants with single substitutions were not. In addition, double and triple substitutions in the NS2/NEP glutamine residues, which resulted in the addition of seven amino acids to the C-terminus of NS1 due to gene overlapping, resulted in virus attenuation in mice. Animal studies with this mutant suggest a potential benefit to incorporating these NS mutations into live vaccines. PMID- 20970467 TI - Rare codons in uORFs of baculovirus p13 gene modulates downstream gene expression. AB - The p13 gene is a group II nucleopolyhedroviruses (NPVs) specific gene and featured by containing upstream mini ORFs (uORF) in its 5' UTR region. However, there are almost no reports published on the functions of the uORFs of p13 gene. In this study, the Luciferase Reporter Assay System was employed to investigate how the mini ORFs of Helicoverpa armigera nucleopolyhedrovirus (HearNPV) p13 gene (Ha-p13) and its rare codons regulated the downstream gene expression. After the coding sequence of uORFs in the Ha-p13 gene was fused to the luciferase reporter gene in the expression vector pGL3 and the plasmid DNA was then transfected into the Hz-AM1 cells, the translation of the fusion protein could be initiated from the start codon of the uORFs. The uAUG and its context in uORF2 seemed to be more efficient for translation initiation than that in uORF1. Mutation of the start codons in one or both of uORFs (uORF1 or uORF2) could significantly increase the expression of the downstream reporter gene. The start codon mutation in uORF1 produced a higher reporter gene expression than that in uORF2, indicating that the uORF1 could be a stronger inhibitor than the uORF2, and the length of uORFs seemed not to be crucial for down-regulating translation. The expression of both uORFs could co-regulate the associated gene expression. Substituting the rare codons in uORF1, uORF2 or both with less rare codons dramatically increased the expression of the downstream reporter gene. Rare codon mutations in both uORFs were much more efficient in up-regulating the associate gene expression than mutations in either of the two uORFs alone. PMID- 20970468 TI - Molecular characterization of rabies virus isolated from dogs in Tunisia: evidence of two phylogenetic variants. AB - In an attempt to explain temporal and geographical rabies incidence fluctuations in Tunisia, a molecular epidemiological study of rabies virus (RV) was carried out. A panel of RV isolates from dogs, collected between 1992 and 2003, from different regions in Tunisia have been analysed by direct sequencing of PCR amplified products coding for the nucleoprotein gene. New sequences have been compared to prototype sequences of Lyssavirus species and nine lineages of species 1. All Tunisian isolates belonged to species rabies virus and segregated into two rabies lineages geographically distinct: NCS lineage characterizing Northeast, Central and Northern areas of the country and NW lineage more restricted to the North-Western regions. Phylogenetic analyses showed that Tunisian RV clustered most closely to Africa 1a lineage: NCS lineage showed nucleic affiliation with isolates from Algeria and Morocco, whereas, NW lineage shared a strong relationship with Ethiopian and Sudanese strains. PMID- 20970469 TI - mRNA as gene therapeutic: how to control protein expression. AB - For many years, it was generally accepted that mRNA is too unstable to be efficiently used for gene therapy purposes. In the last decade, however, several research groups faced this challenge and not only proved the feasibility of mRNA mediated transfection with surprising results regarding transfection efficiency and duration of protein expression, but also were able to demonstrate major advantages over the use of pDNA. These advantages will be the first issue discussed in this review, which first of all addresses the notions that mRNA does not need to cross the nuclear barrier to exert its biological activity and in addition lacks CpG motifs, which reduces its immunogenicity. Secondly, it provides insight in the (in)stability of the mRNA molecule, in how mRNA can be modified to increase its half-life and in the necessities of exogenously produced mRNA to be successfully used in transfection protocols. Furthermore, this review gives an in-depth overview of the different techniques and vehicles for intracellular mRNA delivery exploited by us and other groups, comprising electroporation, gene gun injection, lipo- and polyplexes. Finally, it covers recent literature describing specific applications for mRNA based gene delivery, showing that until now most attention has been paid to vaccination strategies. This review offers a comprehensive overview of current knowledge of the major theoretical as well as practical aspects of mRNA-mediated transfection, showing both its possibilities and its pitfalls and should therefore be useful for a diverse scientific audience. PMID- 20970470 TI - Validation of brief instruments to measure adult fruit and vegetable consumption. AB - Four brief food frequency questionnaires were developed and validated to measure an adult's usual daily intake of fruit or vegetable servings over the past month. Fifty males and 50 females, aged 25-52 years, completed two fruit instruments, two vegetable instruments, and a dietary history (the reference method). Individual agreement and group mean estimation were assessed. The 5-item fruit instrument and the 15-item vegetable instrument performed best. At an individual level, the 5-item fruit instrument had 64% sensitivity and 88% specificity for assessing goal attainment (>= 2 fruit servings/day), while the 15-item vegetable instrument had 67% sensitivity and 82% specificity for measuring goal attainment (>= 3 vegetable servings/day). At a group level, the 15-item vegetable instrument closely estimated mean intake (ratio of geometric means=0.94), while the 5-item fruit instrument overestimated mean intake by 32%. Nevertheless, when it was used to rank participants, reference method fruit servings increased across the quartiles of intake. These two instruments can be used to assess goal attainment. This vegetable instrument can also be used to estimate group mean intakes, while the fruit instrument can be used to rank participants. Used appropriately, these instruments can be used for screening, monitoring, and evaluation purposes in New Zealand public health and clinical settings. PMID- 20970471 TI - Effects of endomorphins on human umbilical vein endothelial cells under high glucose. AB - The endomorphin-1 (EM1) and endomorphin-2 (EM2) are endogenous opioid peptides, which modulate extensive bioactivities such as pain, cardiovascular responses, immunological responses and so on. The present study was undertaken to investigate the effects of EM1/EM2 on the primary cultured human umbilical vein endothelial cells (HUVECs) damaged by high glucose. PI AnnexinV-FITC detection was performed to evaluate the apoptosis rate. Levels of nitric oxide (NO) and nitric oxide synthase (NOS) activity were measured by the Griess reaction and the conversion of 3H-arginine to 3H-citrulline, respectively. Endothelin-1 (ET-1) was evaluated by the enzyme-linked immunosorbent assay (ELISA). Cell proliferation was determined by the MTT viability assay. mRNA expression of endothelial nitric oxide synthase (eNOS) and ET-1 were measured by real-time PCR. Our data showed that EM1/EM2 inhibited cell apoptosis. The high glucose induced increase in expression of NO, NOS and ET-1 were significantly attenuated by pretreatment with EM1/EM2 in a dose dependent manner. In addition, EM1/EM2 suppressed the mRNA eNOS and mRNA ET-1 expression in HUVECs under high glucose conditions. Naloxone, the nonselective opioid receptor antagonist, did not influence the mRNA eNOS expression when it was administrated on its own; but it could significantly antagonize the effects induced by EM1/EM2. Furthermore, in all assay systems, EM1 was more potent than EM2. The results suggest that EM1/EM2 have a beneficial effect in protecting against the endothelial dysfunction by high glucose in vitro, and these effects were mediated by the opioid receptors in HUVECs. PMID- 20970472 TI - Perinatal hypoxia induces a long-lasting increase in unstimulated gaba release in rat brain cortex and hippocampus. The protective effect of pyruvate. AB - Hypoxia and seizures early in life can cause multiple neurological deficits and even chronic epilepsy. Here, we report the data obtained in rats exposed to hypoxia and seizures at age 10-12 postnatal days and taken in experiments 8-9 weeks after hypoxia treatment. A level of the extracellular GABA and the initial velocity of GABA uptake were measured in the brain cortex, hippocampus and thalamus using isolated nerve terminals (synaptosomes). It has been revealed that the extracellular [(3)H]GABA level maintained by cortical and hippocampal synaptosomes in standard conditions (with glucose as an energy substrate) was significantly higher in adult rats exposed to hypoxia/seizures at P10-12 than in the control ones, and, moreover, became unstable with tendency to increase. Pyruvate as a single energy substrate was shown to be a highly effective for lowering and stabilizing the extracellular [(3)H]GABA level. This effect of pyruvate was tightly correlated with increase in GABA uptake and GATs affinity to GABA. Thalamus was insensible to the action of perinatal hypoxia/seizures, and thalamic GATs, in contrast to cortical and hippocampal ones, had a lower affinity to GABA (the apparent Km is 39.2+/-3.1 MUM GABA vs 8.9+/-1.8 MUM GABA in the hippocampus). A selective vulnerability of brain regions to hypoxia is suggested to be attributed to distinct terms of their maturation at the postnatal period. Thus, perinatal hypoxia/seizures evoke a long-lasting increase in the extracellular GABA level that could be attenuated by pyruvate treatment. This effect of pyruvate is likely due to a significant increase in GATs-mediated GABA uptake and modulation of GATs kinetic properties. PMID- 20970473 TI - Up-and-down movement of a sliding actin filament in the in vitro motility assay. AB - We observed a three-dimensional up-and-down movement of an actin filament sliding on heavy mero-myosin (HMM) molecules in an in vitro motility assay. The up-and down movement occurred along the direction perpendicular to the planar glass plane on which the filament demonstrated a sliding movement. The height length of the up-and-down movement was measured by monitoring the extent of diminishing fluorescent emission from the marker attached to the filament in the evanescent field of attenuation. The height lengths whose distribution exhibits a local maximum were found around the two values, 150 nm and 90 nm, separately. This undulating three-dimensional movement of an actin filament suggests that the interactions between myosin (HMM) molecules and the actin filament may temporally be modulated during its sliding movement. PMID- 20970474 TI - Activities of bone morphogenetic proteins in prolactin regulation by somatostatin analogs in rat pituitary GH3 cells. AB - Involvement of the pituitary BMP system in the modulation of prolactin (PRL) secretion regulated by somatostatin analogs, including octreotide (OCT) and pasireotide (SOM230), and a dopamine agonist, bromocriptine (BRC), was examined in GH3 cells. GH3 cells are rat pituitary somato-lactotrope tumor cells that express somatostatin receptors (SSTRs) and BMP system molecules including BMP-4 and -6. Treatment with BMP-4 and -6 increased PRL and cAMP secretion by GH3 cells. The BMP-4 effects were neutralized by adding a BMP-binding protein Noggin. These findings suggest the activity of endogenous BMPs in augmenting PRL secretion by GH3 cells. BRC and SOM230 reduced PRL secretion, but OCT failed to reduce the PRL level. In GH3 cells activated by forskolin, BRC suppressed forskolin-induced PRL secretion with reduction in cAMP levels. OCT did not affect forskolin-induced PRL level, while SOM230 reduced PRL secretion and PRL mRNA expression induced by forskolin. BMP-4 treatment enhanced the reducing effect of SOM230 on forskolin-induced PRL level while BMP-4 did not affect the effects of OCT or BRC. Noggin treatment had no significant effect on the BRC actions reducing PRL levels by GH3 cells. However, in the presence of Noggin, OCT elicited an inhibitory effect on forskolin-induced PRL secretion and PRL mRNA expression, whereas the SOM230 effect on PRL reduction was in turn impaired. It was further found that BMP-4 and -6 suppressed SSTR-2 but increased SSTR-5 mRNA expression of GH3 cells. These findings indicate that Noggin rescues SSTR-2 but downregulates SSTR-5 by neutralizing endogenous BMP actions, leading to an increase in OCT sensitivity and a decrease in SOM230 sensitivity of GH3 cells. In addition, BMP signaling was facilitated in GH3 cells treated with forskolin. Collectively, these findings suggest that BMPs elicit differential actions in the regulation of PRL release dependent on cellular cAMP-PKA activity. BMPs may play a key role in the modulation of SSTR sensitivity of somato-lactotrope cells in an autocrine/paracrine manner. PMID- 20970475 TI - Further evaluation of the biological activity of the unique gonadotropin releasing hormone peptide in the guinea pig brain. AB - In this study we compared the biological activity of a unique form of gonadotropin-releasing hormone (GnRH) in the brain of the guinea pig (gpGnRH) with mammalian GnRH (mGnRH). In gpGnRH, the highly conserved histidine in position 2 (His(2)) and leucine in position 7 (Leu(7)) are substituted by tyrosine and valine, respectively. The gpGnRH was less potent than mGnRH in stimulating the release of luteinizing hormone (LH) in vivo in the guinea pig and displayed only low activity in the rat. The gpGnRH was more rapidly degraded by serum proteolytic enzymes than mGnRH. It is concluded that gpGnRH displays lower biological activity than mGnRH in both rat and guinea pig, which may be due in part to its greater susceptibility to proteolytic degradation besides differences in receptor affinity and/or activation. PMID- 20970476 TI - Calcineurin inhibition with systemic FK506 treatment increases dendritic branching and dendritic spine density in healthy adult mouse brain. AB - Calcineurin has been implicated as part of a critical signaling pathway for learning and memory, and recent data suggest that calcineurin activation mediates some of the neurotoxicity of the Alzheimer related neurotoxin Abeta. Immunosuppression via calcineurin inhibition with the compound FK506 is an important treatment for organ transplant patients. Here we use Golgi impregnation techniques, along with a new survival analysis-based statistical approach for analysis of dendritic complexity, to show that in healthy adult mice one week of treatment with FK506 affects both the branching patterns and dendritic spine density of cortical neurons. These results indicate that calcineurin inhibition leads to readily detectable changes in brain morphology, further implicating calcineurin related pathways in both the function and structure of the adult brain. PMID- 20970477 TI - ERP correlates of pre-attentive processing of Cantonese lexical tones: The effects of pitch contour and pitch height. AB - The pre-attentive processing of Cantonese tones was studied with an auditory passive oddball paradigm. Event-related potentials to standard and deviant auditory stimuli were recorded as participants watched a silent movie attentively. The standards and deviants differed in either pitch level or pitch contour. Mismatch negativity (MMN) and P3a were elicited by all types of deviant tones, suggesting that lexical tone was processed pre-attentively. In addition, the size and latency of MMN were sensitive to the size of pitch level change, while the latency of P3a captured the presence of pitch contour change. These results indicate that pitch contour and pitch height are two important dimensions in sensory processing of lexical tones. PMID- 20970478 TI - B-cell subsets up-regulate alpha4 integrin and accumulate in the cerebrospinal fluid in clinically isolated syndrome suggestive of multiple sclerosis onset. AB - During the pathogenesis of multiple sclerosis (MS), activated B-cells cross the inflamed endothelium of the central nervous system (CNS) to exert their effector functions, probably associated with the action of several adhesion molecules. B cell mobilization towards the CNS already occurs after the first demyelinating events suggestive of MS, known as clinically isolated syndrome (CIS). However, little is known about the role of these adhesion molecules at this early disease stage. We, therefore, evaluated the relationship between the expression of alpha4 integrin by peripheral B-cell subsets and disease activity. We found that alpha4 integrin was up-regulated in all B-cell subsets from patients with CIS and that its expression was correlated with the number of gadolinium-enhanced lesions. A comparison of B-cell subsets distribution in the CSF of patients with CIS, of patients with other inflammatory neurological diseases (OIND) and of patients with non-inflammatory neurological diseases (NIND) showed that the percentages of CSF CD19(+) B-cells were significantly higher in the CIS and OIND group. In addition, CIS and OIND CSF were enriched in switched and MZ-like memory B-cells, although all B-cell subsets were present. These results suggest that up regulation of alpha4 integrin may enhance B-cell accumulation within the CSF at the time of CIS. PMID- 20970479 TI - Quadri-pulse stimulation (QPS) induced LTP/LTD was not affected by Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene. AB - It has been reported that the brain derived neurotrophic factor (BDNF) has some functional roles in inducing plasticity in the adult human brain and the Val66Met BDNF polymorphism affects the plasticity induction. In contrast, some long lasting effects were not fully induced in subjects with non-Val-Val polymorphism. In this communication, we retrospectively investigated whether this polymorphism affects the plastic changes induced by a newly developed stimulation method (quadripulse stimulation (QPS)) in 12 subjects. Both long-term potentiation (LTP) and long-term depression (LTD) like effects were induced by QPS for 30min in any types of BDNF Val66Met polymorphisms. This finding presents a striking contrast to the previous results, which showed reduced long-term effects elicited by some other induction methods in subjects with non-Val-Val polymorphism. Although we are not able to make a final conclusion about the effect of Val66Met BDNF polymorphism on QPS because of the small number of subjects studied, QPS may be less affected by the BDNF polymorphism than several other protocols for inducing LTP/LTD-like effects in humans. Several possibilities may explain this difference. One candidate possibility is that QPS may be long enough for inducing the late LTP/LTD like effect whereas the other stimulation methods may be long enough for early but not enough for late LTP/LTD like effect. It is conspicuous that the QPS for 30min does elicit stable bidirectional long-term effects even in subjects with non-Val-Val polymorphism of BDNF. PMID- 20970480 TI - Anxiety-like behavior in the elevated-plus maze tests and enhanced IL-1beta, IL 6, NADPH oxidase-1, and iNOS mRNAs in the hippocampus during early stage of adjuvant arthritis in rats. AB - We studied anxiety-like behavior in the elevated plus-maze (EPM) tests in male Lewis rats on days 2 and 4 of adjuvant arthritis (AA). In plasma we analyzed C reactive protein (CRP), albumin, ACTH, corticosterone, in the hippocampus the mRNA expression of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), corticotrophin releasing factor (CRH), NADPH oxidases NOX1 and NOX2, and inducible NO-synthase (iNOS). EPM tests showed a higher anxiety index in AA rats on days 2 and 4 and reduction of total entries. On days 2 and 4 we found reduced plasma albumin, enhanced CRP, ACTH and corticosterone, and in the hippocampus enhanced mRNA for NOX1 and IL-1beta in AA rats, on day 4 we found enhanced mRNAs for iNOS and IL-6, and reduced mRNA for CRH. The mRNA for NOX2 did not change on any experimental day. These results suggest enhanced anxiety, as well as locomotor impairment during the early phase of AA that correlate with enhanced mRNA expressions of parameters of oxidative stress NOX1, iNOS, and inflammatory cytokines IL-1beta and IL-6 in the hippocampus. PMID- 20970481 TI - Feed-forward changes in carotid blood flow velocity during active standing. AB - Orthostatic changes induce temporary loss of circulatory regulation. Feedback systems react to cardiovascular alterations to compensate for the instability. To clarify the existence of anticipatory cardiovascular regulation during active standing, we continuously recorded blood flow velocity (BFV) in the common carotid artery and cerebral blood volume (CBV) in healthy men. The maximum BFV value decreased significantly before standing in the reaction-time condition. The decrease significantly correlated with the change in systolic blood pressure that accompanies upright standing from a supine position. The anticipatory BFV decrease disappeared during self-paced standing, and all BFV parameters significantly declined after the self-paced standing. The CBV recording showed a significant increase in oxyhemoglobin levels before standing in the reaction-time condition. Our study suggests that some feed-forward cardiovascular regulation triggered by central command could be activated before standing, and it may play a functional role in the maintenance of cerebral perfusion during standing. PMID- 20970482 TI - Deuteration as a tool in investigating the role of protons in cell signaling. AB - BACKGROUND: The mechanisms underlying the inhibitory effects of deuterium oxide (D2O; heavy water) are likely to provide insight into the fundamental significance of hydrogen bonds in biological functions. Previously, to begin elucidating the effect of D2O on physiological functions in living cells, we studied the effects of D2O on voltage-sensitive Ca2(+) channels in AtT 20 cells and showed that actin distribution, Ca2(+) currents, and beta-endorphin release were affected. However, the molecular mechanisms underlying the inhibitory effects of D2O in whole animals and living cells remain obscure, especially in the effects of D2O on the cell signaling. METHODS: We investigated the molecular mechanisms underlying the inhibitory effects of D2O on the IP3-mediated Ca2(+) signaling pathway using Ca2(+) imaging and micro-calorimetric measurements in mGluR1-expressing CHO cells. RESULTS: DHPG-induced Ca2(+) elevations were markedly reduced in D2O. Moreover, the Ca2(+) elevations were completely suppressed in H2O after receptor activation with DHPG in D2O, recovering gradually in H2O medium. Without prior stimulation in D2O, however, DHPG-induced Ca2(+) elevations in H2O were not affected. Micro-calorimetric measurements showed reduced total DHPG-evoked heat generation in D2O, while initial heat production and absorption associated with receptor activation were found to be larger. The reduction of DHPG-induced Ca2(+) elevation and heat generation in D2O medium may be due to decreased amount of IP3 by the reduced hydrolysis of PIP2. GENERAL SIGNIFICANCE: Protein structure changes due to the replacement of hydrogen with deuterium will induce the inhibitory effects of D2O by reduction of the frequency of -OH bonds. PMID- 20970483 TI - Adsorption of low-density lipoprotein, its oxidation, and subsequent binding of specific recombinant antibodies: An in situ ellipsometric study. AB - BACKGROUND: Low-density lipoprotein (LDL) particles accumulate in the arterial wall and become oxidized during atherogenesis, leading to the formation of atherosclerotic plaques. The major protein of the LDL particle, apolipoprotein B 100 (apoB-100), becomes fragmented during oxidation and a target for the immune system. METHODS: In this study we used in situ ellipsometry to monitor the adsorption of LDL to solid silica surfaces and the effects of oxidation on the structure of the adsorbed LDL layer. We additionally investigated the binding kinetics of two recombinant human antibodies with different specificities recognizing epitopes of apoB-100 in surface-bound native and CuCl2-oxidized LDL (oxLDL). The latter process was studied by adsorbing LDL and then adding the antibody and CuCl2 while continuously monitoring adsorbed amount and the thickness of the film. The molar ratios between the antibodies and surface-bound LDL and oxLDL were calculated from these data. RESULTS: Our results indicate that oxidation of surface-bound LDL induces swelling of the layer, accompanied by a slight desorption. We further found that both antibodies were able to recognize LDL and oxLDL in its adsorbed orientation. Quantitative information was obtained on the number of available binding sites on surface-bound LDL and oxLDL for these two antibodies. GENERAL SIGNIFICANCE: Using ellipsometry for real-time monitoring of adsorption, in situ oxidation of LDL and binding of specific recombinant antibodies to surface-bound LDL, will open up possibilities to map different conformations and orientations of LDL in the adsorbed state. PMID- 20970484 TI - D-Cycloserine improves the impaired sociability of the Balb/c mouse. AB - The genetically inbred Balb/c mouse strain shows evidence of impaired sociability in a standard paradigm. For example, relative to 8-week-old male outbred Swiss Webster mice, 8 week-old male Balb/c mice spend less time sniffing and in the vicinity of an enclosed 4 week-old male ICR stimulus mouse and, when allowed to interact freely with the stimulus mouse for five minutes, make fewer discrete episodes of social approach and show suppression of locomotor activity. We explored the effect of D-cycloserine (320mg/kg, intraperitoneally), a partial glycine agonist that binds to the obligatory co-agonist glycine binding site on the NMDA receptor, on the sociability of the Balb/c and Swiss-Webster mouse strains in a standard paradigm. The results show that treatment with D cycloserine increased the locomotor activity of the Balb/c mouse strain in the presence of an enclosed social stimulus mouse and when these mice were allowed to interact freely with each other. Also, D-cycloserine increased the number of discrete episodes of social approach when Balb/c mice were allowed to interact freely with social stimulus mice. However, D-cycloserine had similar effects on measures of sociability in the Swiss-Webster mouse, raising the possibility that the positive effects on the sociability of the Balb/c mouse strain may be mediated by indirect effects on locomotion, arousal, and anxiety. PMID- 20970485 TI - New furostanol saponins from Smilax aspera L. and their in vitro cytotoxicity. AB - The occurrence of the two new cis-fused A/B rings furostanol saponins (25S)-26-O beta-D-glucopyranosyl-5beta-furostan-1beta,3beta,22alpha,26-tetraol-1-O-beta-D glucopyranoside and (25S)-26-O-beta-D-glucopyranosyl-5beta-furostan 1beta,2beta,3beta,5beta,22alpha,26-hexaol and the known compounds (25S)-26-O-beta D-glucopyranosyl-5beta-furostan-3beta,22alpha,26-triol-3-O-alpha-L rhamnopyranosyl-(1 -> 2)-O-beta-D-glucopyranosyl-(1 -> 2)-O-beta-D glucopyranoside and (25S)-26-O-beta-D-glucopyranosyl-5beta-furostan 3beta,22alpha,26-triol-3-O-beta-D-glucopyranosyl-(1 -> 2)-O-beta-D glucopyranoside, trans-resveratrol, (+) catechin and (-) epicatechin in the rhizomes of Smilax aspera is reported. All saponins have been isolated as their 22-OMe derivatives, which were further subjected to extensive spectroscopic analysis. The isolated furostanol saponins were evaluated for cytotoxic activity against human normal amniotic and human lung carcinoma cell lines using neutral red and MTT assays. In vitro experiments showed significant cytotoxicity in a dose dependent manner with IC(50) values in the range of 32.98-94.53 uM. PMID- 20970486 TI - Protective effect of a new amide compound from Pu-erh tea on human micro-vascular endothelial cell against cytotoxicity induced by hydrogen peroxide. AB - A new amide, N-(3,4-dihydroxybenzoyl)-3,4-dihydroxybenzamide (1), was isolated from the Pu-erh tea made with the leaf of Camellia assamica (Mast.) Chang by special fermentation techniques with bacteria and fungus. Its structure was established by means of spectroscopic data analyses, including mass spectrometry and both 1D and 2D NMR spectroscopy. Human micro-vascular endothelial cell (HMEC) injured with H(2)O(2) was used as the model to test protective effect of compound 1 in contrast with other known compounds isolated from Pu-erh tea. These results suggested that compound 1 is a very useful compound to prevent H(2)O(2)-induced cell death of HMEC. PMID- 20970487 TI - Noninvasive and persistent transfollicular drug delivery system using a combination of liposomes and iontophoresis. AB - Iontophoresis is a promising technique for enhancing transdermal administration of charged drugs. However, conventional iontophoresis is not sufficient for effective delivery of large, hydrophilic, or electrically neutral molecules. In this study, we utilized charged liposomes as carriers, focused on a transfollicular route for delivery of the liposomes, and optimized iontophoretic conditions and lipid composition for this method in both in vitro and in vivo conditions. As a result, we identified the optimum condition (lipid composition: DOTAP/EPC/Chol=2:2:1, current supply: 0.45mA/cm(2), duration: 1h) for effective iontophoretic delivery of aqueous solution, which cannot be transferred into the skin without charged liposomes. We also examined the pharmacological effects of iontophoresis of liposomes encapsulating insulin (INS-lipo) using a rat model of type I diabetes. Interestingly, iontophoresis of INS-lipo onto a diabetes rat skin resulted in a gradual decrease in blood glucose levels, with levels reaching 20% of initial values at 18h after administration. These lower blood glucose levels were maintained for up to 24h. Significant amount of insulin were also detected in plasma 18h after iontophoresis of INS-lipo. We succeeded in developing a non-invasive and persistent transfollicular drug delivery system that used a combination of liposomes and iontophoresis. PMID- 20970488 TI - Adverse event reports following Japanese encephalitis vaccination in the United States, 1999-2009. AB - We reviewed adverse events following receipt of inactivated mouse brain-derived Japanese encephalitis (JE) vaccine reported to the U.S. Vaccine Adverse Event Reporting System (VAERS) from 1999 to 2009. During this period, VAERS received 300 adverse event reports following JE vaccination (24 per 100,000 doses distributed); 106 (35%) were classified as hypersensitivity reactions (8.4 per 100,000 doses) and four (1%) were classified as neurologic events (0.3 per 100,000 doses). Twenty-three (8%) reports described serious adverse events (1.8 per 100,000 doses distributed). There were no reports of encephalitis, meningitis, or Guillain-Barre syndrome. As reported previously, hypersensitivity reactions were common among persons receiving inactivated mouse brain-derived JE vaccine. PMID- 20970489 TI - Suppression on metastasis by rhubarb through modulation on MMP-2 and uPA in human A549 lung adenocarcinoma: an ex vivo approach. AB - AIM OF THE STUDY: The aim of this study is to determine and identify the possible molecular mechanisms of anti-cancer effect of rhubarb under the physiologically achievable concentrations by using an ex vivo approach. MATERIALS AND METHODS: Rats were orally administered rhubarb decoction and then serum metabolites were extracted, prepared and characterized to assay for the following in vitro study. The MTT assay, zymography analysis, wound healing assay, RT-PCR, and Western blot analysis were used to reveal molecular events of rhubarb metabolites in this study. Experimental metastasis model was used to investigate the in vivo anti metastatic efficacy of rhubarb. RESULTS: Our results demonstrated that cell line mobility was strongly inhibited and the enzymatic activity of MMP-2 decreased following culture with the rhubarb serum metabolite in human lung adenocarcinoma A549 cells. Further experiments demonstrated that the downregulation of MMP-2 enzymatic activity act through both transcriptional and post-translational mechanisms. NF-kappaB/c-Jun and uPA were observed involving in the inhibition of MMP-2 transcription and post-translational modification, respectively, in A549 cells treated with rhubarb serum metabolite. Further animal experiments demonstrated a significant reduction in lung metastatic colonies in rhubarb treated mice, suggesting that rhubarb contain enriched active components that block cancer metastasis. CONCLUSIONS: Our studies, both in vitro and in vivo, clearly demonstrated the anti-tumor effect of rhubarb in an experimental setting of achievable physiological concentrations and also provide possible molecular mechanisms of anti-metastatic mechanisms by rhubarb treatment. PMID- 20970490 TI - Propolis: is there a potential for the development of new drugs? AB - INTRODUCTION: Propolis has plenty of biological and pharmacological properties and its mechanisms of action have been widely investigated in the last years, using different experimental models in vitro and in vivo. Researchers have been interested in the investigation of isolated compounds responsible for propolis action; however, there is lack of clinical research on the effects of propolis. STRATEGY AND OBJECTIVES: Since propolis-containing products have been marketed and humans have used propolis for different purposes, the goal of this review is to discuss the potential of propolis for the development of new drugs, by comparing data from the literature that suggest candidate areas for the establishment of drugs against tumors, infections, allergy, diabetes, ulcers and with immunomodulatory action. CONCLUSIONS: The efficacy of propolis in different protocols in vitro and in vivo suggests its therapeutic properties, but before establishing a strategy using this bee product, it is necessary to study: (a) the chemical nature of the propolis sample. (b) Propolis efficacy should be compared to well-established parameters, e.g. positive or negative controls in the experiments. Moreover, possible interactions between propolis and other medicines should be investigated in humans as well. (c) Clinical investigation is needed to evaluate propolis potential in patients or healthy individuals, to understand under which conditions propolis may promote health. Data point out the importance of this research field not only for the readers and researchers in the scientific community waiting for further clarification on the potential of propolis but also for the pharmaceutical industry that looks for new drugs. PMID- 20970491 TI - Survival costs of reproduction in Drosophila. AB - Reproduction shortens lifespan in practically all organisms examined so far, but the underlying mechanisms remain largely unknown to date. Here I review what evolutionary and molecular biologists have learned about such "costs of reproduction" in the fruit fly (Drosophila melanogaster) since Maynard Smith's (1958) seminal discovery that sterile mutants in D. subobscura live substantially longer than fertile wildtype flies. Together with observations from the nematode worm (Caenorhabditis elegans) and other organisms, the data from Drosophila suggest that there are at least four general principles that underlie trade-offs between reproduction and lifespan: (1) trade-offs between survival and reproduction are widespread; (2) the relationship between increased lifespan and decreased fecundity can be uncoupled under certain conditions; (3) while survival costs of reproduction might not necessarily be due to competitive resource allocation, we lack robust alternative explanations for their occurrence; and (4) physiological trade-offs between reproduction and longevity do not always translate into evolutionary genetic trade-offs. I conclude that - despite much recent progress - our current understanding of the proximate basis of survival costs of reproduction remains very limited; much future work on the genetics and physiology of such trade-offs will be required to uncover their mechanistic basis. PMID- 20970492 TI - Immune modulation of learning, memory, neural plasticity and neurogenesis. AB - Over the past two decades it became evident that the immune system plays a central role in modulating learning, memory and neural plasticity. Under normal quiescent conditions, immune mechanisms are activated by environmental/psychological stimuli and positively regulate the remodeling of neural circuits, promoting memory consolidation, hippocampal long-term potentiation (LTP) and neurogenesis. These beneficial effects of the immune system are mediated by complex interactions among brain cells with immune functions (particularly microglia and astrocytes), peripheral immune cells (particularly T cells and macrophages), neurons, and neural precursor cells. These interactions involve the responsiveness of non-neuronal cells to classical neurotransmitters (e.g., glutamate and monoamines) and hormones (e.g., glucocorticoids), as well as the secretion and responsiveness of neurons and glia to low levels of inflammatory cytokines, such as interleukin (IL)-1, IL-6, and TNFalpha, as well as other mediators, such as prostaglandins and neurotrophins. In conditions under which the immune system is strongly activated by infection or injury, as well as by severe or chronic stressful conditions, glia and other brain immune cells change their morphology and functioning and secrete high levels of pro-inflammatory cytokines and prostaglandins. The production of these inflammatory mediators disrupts the delicate balance needed for the neurophysiological actions of immune processes and produces direct detrimental effects on memory, neural plasticity and neurogenesis. These effects are mediated by inflammation-induced neuronal hyper-excitability and adrenocortical stimulation, followed by reduced production of neurotrophins and other plasticity related molecules, facilitating many forms of neuropathology associated with normal aging as well as neurodegenerative and neuropsychiatric diseases. PMID- 20970493 TI - Physical exercise increases adult neurogenesis and telomerase activity, and improves behavioral deficits in a mouse model of schizophrenia. AB - Epidemiological studies indicate that among other early life challenges, maternal infection with influenza during pregnancy increased the risk of developing schizophrenia in the child. One morphological manifestation of schizophrenia is hippocampal atrophy. In the hippocampus, playing a key role in learning and memory formation, new granule cell neurons are produced throughout life from resident precursor cells. We hypothesize that individuals exposed to a maternal anti-viral immune response would presumably enter life with a challenged neural precursor cell pool and might later be susceptible to psychiatric pathologies due to reduced adult neurogenesis. We used the injection of double-stranded RNA (polyriboinosinicpolyribocytidylic acid - PolyI:C) in pregnant C57Bl/6 and nestin GFP reporter mice to induce a maternal viral-like infection and schizophrenia like behavior in the offspring. In the progeny we found impairments in the open field test and in sensorimotor gating as measured by pre-pulse inhibition of the startle response. The behavioral deficits were accompanied by reduced baseline adult hippocampal neurogenesis. Telomerase activity in neural precursor cells was reduced from birth on and telomere shortening was found in the same cell type in adult life. When we subjected the progeny of viral-like infected dams to voluntary exercise, a known stimulus of adult hippocampal neurogenesis, we could rescue the phenotype in behavior, adult neurogenesis, and cellular senescence. In summary, maternal viral-like immune response reduced telomerase activity and resulted in telomere shortening in neural precursor cells. Further we demonstrate that beneficial behavioral and cellular effects induced by exercise can be studied in a rodent model of schizophrenia. PMID- 20970494 TI - Marked changes in endogenous antioxidant expression precede vitamin A-, C-, and E protectable, radiation-induced reductions in small intestinal nutrient transport. AB - Rapidly proliferating epithelial crypt cells of the small intestine are susceptible to radiation-induced oxidative stress, yet there is a dearth of data linking this stress to expression of antioxidant enzymes and to alterations in intestinal nutrient absorption. We previously showed that 5-14 days after acute gamma-irradiation, intestinal sugar absorption decreased without change in antioxidant enzyme expression. In the present study, we measured antioxidant mRNA and protein expression in mouse intestines taken at early times postirradiation. Observed changes in antioxidant expression are characterized by a rapid decrease within 1h postirradiation, followed by dramatic upregulation within 4h and then downregulation a few days later. The cell type and location expressing the greatest changes in levels of the oxidative stress marker 4HNE and of antioxidant enzymes are, respectively, epithelial cells responsible for nutrient absorption and the crypt region comprising mainly undifferentiated cells. Consumption of a cocktail of antioxidant vitamins A, C, and E, before irradiation, prevents reductions in transport of intestinal sugars, amino acids, bile acids, and peptides. Ingestion of antioxidants may blunt radiation-induced decreases in nutrient transport, perhaps by reducing acute oxidative stress in crypt cells, thereby allowing the small intestine to retain its absorptive function when those cells migrate to the villus days after the insult. PMID- 20970495 TI - Posttranslational modification and regulation of glutamate-cysteine ligase by the alpha,beta-unsaturated aldehyde 4-hydroxy-2-nonenal. AB - 4-Hydroxy-2-nonenal (4-HNE) is a lipid peroxidation product formed during oxidative stress that can alter protein function via adduction of nucleophilic amino acid residues. 4-HNE detoxification occurs mainly via glutathione (GSH) conjugation and transporter-mediated efflux. This results in a net loss of cellular GSH, and restoration of GSH homeostasis requires de novo GSH biosynthesis. The rate-limiting step in GSH biosynthesis is catalyzed by glutamate-cysteine ligase (GCL), a heterodimeric holoenzyme composed of a catalytic (GCLC) and a modulatory (GCLM) subunit. The relative levels of the GCL subunits are a major determinant of cellular GSH biosynthetic capacity and 4-HNE induces the expression of both GCL subunits. In this study, we demonstrate that 4 HNE can alter GCL holoenzyme formation and activity via direct posttranslational modification of the GCL subunits in vitro. 4-HNE directly modified Cys553 of GCLC and Cys35 of GCLM in vitro, which significantly increased monomeric GCLC enzymatic activity, but reduced GCL holoenzyme activity and formation of the GCL holoenzyme complex. In silico molecular modeling studies also indicate these residues are likely to be functionally relevant. Within a cellular context, this novel posttranslational regulation of GCL activity could significantly affect cellular GSH homeostasis and GSH-dependent detoxification during periods of oxidative stress. PMID- 20970496 TI - Epigenetics and autosomal dominant polycystic kidney disease. AB - The roles of epigenetic modulation of gene expression and protein functions in autosomal dominant polycystic kidney disease (ADPKD) have recently become the focus of scientific investigation. Evidence generated to date indicates that one of the epigenetic modifiers, histone deacetylases (HDACs), are important regulators of ADPKD. HDACs are involved in regulating the expression of the Pkd1 gene and are the target of fluid flow-induced calcium signal in kidney epithelial cells. Pharmacological inhibition of HDAC activity has been found to reduce the progression of cyst formation and slow the decline of kidney function in Pkd1 conditional knockout mice and Pkd2 knockout mice, respectively, implicating the potential clinical application of HDAC inhibitors on ADPKD. Since the expression of HDAC6 is upregulated in cystic epithelial cells, the potential roles of HDAC6 in regulating cilia resorption and epidermal growth factor receptor (EGFR) trafficking through deacetylating alpha-tubulin and regulating Wnt signaling through deacetylating beta-catenin are also discussed. This article is part of a Special Issue entitled: Polycystic Kidney Disease. PMID- 20970498 TI - The molecular physiology of nuclear retinoic acid receptors. From health to disease. AB - The nuclear retinoic acid (RA) receptors (RARalpha, beta and gamma) are transcriptional transregulators, which control the expression of specific gene subsets subsequently to ligand binding and to strictly controlled phosphorylation processes. Consequently RARs maintain homeostasis through the control of cell proliferation and differentiation. Today, it is admitted that, analogous to the paradigm established by the hematopoietic system, most adult tissues depict a differentiation hierarchy starting from rare stem cells. Here we highlight that the integrity of RARs is absolutely required for homeostasis in adults. Indeed, strictly controlled levels of RARs are necessary for the correct balance between self-renewal and differentiation of tissue stem cells. In addition, loss, accumulation, mutations or aberrant modifications of a specific RAR lead to uncontrolled proliferation and/or to differentiation block and thereby to cancer. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease. PMID- 20970497 TI - Role of nuclear receptor SHP in metabolism and cancer. AB - Small heterodimer partner (SHP, NR0B2) is a unique member of the nuclear receptor (NR) superfamily that contains the dimerization and ligand-binding domain found in other family members, but lacks the conserved DNA-binding domain. The ability of SHP to bind directly to multiple NRs is crucial for its physiological function as a transcriptional inhibitor of gene expression. A wide variety of interacting partners for SHP have been identified, indicating the potential for SHP to regulate an array of genes in different biological pathways. In this review, we summarize studies concerning the structure and target genes of SHP and discuss recent progress in understanding the function of SHP in bile acid, cholesterol, triglyceride, glucose, and drug metabolism. In addition, we review the regulatory role of SHP in microRNA (miRNA) regulation, liver fibrosis and cancer progression. The fact that SHP controls a complex set of genes in multiple metabolic pathways suggests the intriguing possibility of developing new therapeutics for metabolic diseases, including fatty liver, dyslipidemia and obesity, by regulating SHP with small molecules. To achieve this goal, more progress regarding SHP ligands and protein structure will be required. Besides its metabolic regulatory function, studies by us and other groups provide strong evidence that SHP plays a critical role in the development of cancer, particularly liver and breast cancer. An increased understanding of the fundamental mechanisms by which SHP regulates the development of cancers will be critical in applying knowledge of SHP in diagnostic, therapeutic or preventive strategies for specific cancers. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease. PMID- 20970499 TI - Genome-wide interplay of nuclear receptors with the epigenome. AB - The nuclear receptor superfamily consists of DNA binding transcription factors that are involved in regulating a wide variety of processes such as metabolism, development, reproduction, and immune responses. Upon binding, nuclear receptors modulate transcription through affecting the local chromatin environment via recruitment of various coregulatory proteins. The recent development of new high throughput sequencing methods allowed for the first time the comprehensive examination of nuclear receptor action in the context of the epigenome. Here, we discuss how recent genome-wide analyses have provided important new insights on the interplay of nuclear receptors and the epigenome in health and disease. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease. PMID- 20970500 TI - Fibrillin-3 expression in human development. AB - Fibrillin proteins are the major components of extracellular microfibrils found in many connective tissues. Fibrillin-1 and fibrillin-2 are well studied and mutations in these proteins cause a number of fibrillinopathies including Marfan syndrome and congenital contractural arachnodactyly, respectively. Fibrillin-3 was more recently discovered and is much less well characterized. Fibrillin-1 is expressed throughout life, whereas fibrillins-2 and -3 are thought to be primarily present during development. Here, we report detailed fibrillin-3 expression patterns in early human development. A polyclonal antiserum against a C-terminal recombinant half of human fibrillin-3 was produced in rabbit. Anti fibrillin-3 antibodies were affinity-purified and antibodies cross-reacting with the other fibrillins were removed by absorption resulting in specific anti fibrillin-3 antibodies. Immunohistochemical analyses with these purified antibodies demonstrate that fibrillin-3 is temporally expressed in numerous tissues relatively evenly from the 6th to the 12th gestational week. Fibrillin-3 was found spatially expressed in perichondrium, perineurium, perimysium, skin, developing bronchi, glomeruli, pancreas, kidney, heart and testis and at the prospective basement membranes in developing epithelia and endothelia. Double immunohistochemical analyses showed that all fibrillins are globally expressed in the same organs, with a number of differences on the tissue level in cartilage, perichondrium and developing bronchi. These results suggest that fibrillin-3, compared to the other fibrillins, fulfills both overlapping and distinct functions in human development. PMID- 20970501 TI - Biphasic expression and cytokine regulation of the complement C3 in heart allograft. AB - Locally synthesized complement may play a more important role in regulating antigen-specific immune response than circulating complement; however, complement production in transplanted heart remains obscure. In the current study, we investigated local production of the complement C3 in mouse cardiac allografts and examined the relationship between C3 production and cytokine expression. The cardiac grafts of allogeneic (C57BL/6-BALB/c mice) and syngeneic mouse models were subjected to histopathological and immunohistochemical analyses for C3 expression on days 0-6 after operation. mRNA and protein expression of C3, IL-2, IFN-gamma in transplanted heart and primary culture cardiomyocytes were analyzed. Our results demonstrated that C3 mRNA exhibited biphasic patterns in transplanted heart. The first expression phase correlated with ischemical reperfusion injury over 2 days post-transplant. The second peak of C3 deposition was found only in allografts on day 5, concurrent with the secretion of IL-2 and IFN-gamma accompanied by severe diffuse leukocyte infiltration. Furthermore, in vitro studies showed that IL-2 and IFN-gamma enhanced C3 mRNA and protein production in cardiocytes. Together, these observations suggest that both ischemical reperfusion injury and the subsequent acute rejection result in elevated cardiocyte secretion of C3, and the second phase of expression appears to be regulated by cytokines secreted by the infiltrating cells. PMID- 20970502 TI - Studies of HIV-1 latency in an ex vivo model that uses primary central memory T cells. AB - HIV-1 latency is considered the last hurdle toward viral eradication in the presence of antiretroviral therapy. Studies of viral latency in vivo are complicated by the low frequency of latently infected cells found in HIV-1 patients. To be able to study the signaling pathways and viral determinants of latency and reactivation, we have developed a novel method that generates high numbers of latently HIV-1 infected cells, which are derived from human primary CD4(+) T lymphocytes. This method allows for the study of different aspects of HIV-1 latency, such as the transcription factors needed for viral reactivation and the signaling pathways involved. In this review, we describe in detail an experimental protocol for the generation of HIV-1 latency using human primary CD4(+) T cells. We also present the salient points of other latency models in the field, along with key findings arising from each model. PMID- 20970503 TI - The crystal structure of the leptospiral hypothetical protein LIC12922 reveals homology with the periplasmic chaperone SurA. AB - Leptospirosis is a world spread zoonosis caused by members of the genus Leptospira. Although leptospires were identified as the causal agent of leptospirosis almost 100 years ago, little is known about their biology, which hinders the development of new treatment and prevention strategies. One of the several aspects of the leptospiral biology not yet elucidated is the process by which outer membrane proteins (OMPs) traverse the periplasm and are inserted into the outer membrane. The crystal structure determination of the conserved hypothetical protein LIC12922 from Leptospira interrogans revealed a two domain protein homologous to the Escherichia coli periplasmic chaperone SurA. The LIC12922 NC-domain is structurally related to the chaperone modules of E. coli SurA and trigger factor, whereas the parvulin domain is devoid of peptidyl prolyl cis-trans isomerase activity. Phylogenetic analyses suggest a relationship between LIC12922 and the chaperones PrsA, PpiD and SurA. Based on our structural and evolutionary analyses, we postulate that LIC12922 is a periplasmic chaperone involved in OMPs biogenesis in Leptospira spp. Since LIC12922 homologs were identified in all spirochetal genomes sequenced to date, this assumption may have implications for the OMPs biogenesis studies not only in leptospires but in the entire Phylum Spirochaetes. PMID- 20970504 TI - Crystal structure of Salmonella typhimurium 2-methylcitrate synthase: Insights on domain movement and substrate specificity. AB - 2-Methylcitric acid (2-MCA) cycle is one of the well studied pathways for the utilization of propionate as a source of carbon and energy in bacteria such as Salmonella typhimurium and Escherichia coli. 2-Methylcitrate synthase (2-MCS) catalyzes the conversion of oxaloacetate and propionyl-CoA to 2-methylcitrate and CoA in the second step of 2-MCA cycle. Here, we report the X-ray crystal structure of S. typhimurium 2-MCS (StPrpC) at 2.4A resolution and its functional characterization. StPrpC was found to utilize propionyl-CoA more efficiently than acetyl-CoA or butyryl-CoA. The polypeptide fold and the catalytic residues of StPrpC are conserved in citrate synthases (CSs) suggesting similarities in their functional mechanisms. In the triclinic P1 cell, StPrpC molecules were organized as decamers composed of five identical dimer units. In solution, StPrpC was in a dimeric form at low concentrations and was converted to larger oligomers at higher concentrations. CSs are usually dimeric proteins. In Gram-negative bacteria, a hexameric form, believed to be important for regulation of activity by NADH, is also observed. Structural comparisons with hexameric E. coli CS suggested that the key residues involved in NADH binding are not conserved in StPrpC. Structural comparison with the ligand free and bound states of CSs showed that StPrpC is in a nearly closed conformation despite the absence of bound ligands. It was found that the Tyr197 and Leu324 of StPrpC are structurally equivalent to the ligand binding residues His and Val, respectively, of CSs. These substitutions might determine the specificities for acyl-CoAs of these enzymes. PMID- 20970505 TI - Identification and analysis of the tissue factor pathway inhibitor 2 of Sciaenops ocellatus. AB - Tissue factor pathway inhibitor 2 (TFPI-2) is a structural homologue of TFPI, a potent inhibitor of tissue factor (TF)-mediated coagulation. Although TFPI-2 has been identified at sequence level in several fish species, no study on piscine TFPI-2 has been documented. In this report, we identified and analyzed a TFPI-2 homologue, SoTFPI2, from red drum Sciaenops ocellatus. The open reading frame of SoTFPI2 is 681 bp, which encodes a 226-residue protein that shares 59.2-82.3% overall sequence identities with known fish TFPI-2. SoTFPI2 possesses three tandem Kunitz domains and is negatively charged at the N-terminus and positively charged at the C-terminus. Expression of SoTFPI2 was detected, in increasing order, in spleen, muscle, gill, brain, liver, kidney, blood, and heart. Bacterial challenge and lipopolysaccharide treatment significantly upregulated SoTFPI2 expression in kidney in time-dependent manners. Recombinant SoTFPI2 purified from Escherichia coli inhibits the proteolytic activity of trypsin and exhibits bactericidal effect on a fish pathogen. Take together, these results indicate that SoTFPI2 is a biologically active serine protease inhibitor with antibacterial property and is likely to play a role in anti-bacterial infection. PMID- 20970507 TI - Graphical models, potential outcomes and causal inference: comment on Ramsey, Spirtes and Glymour. AB - Ramsey, Spirtes and Glymour (RSG) critique a method proposed by Neumann et al. (2010) for the discovery of functional networks from fMRI meta-analysis data. We concur with this critique, but are unconvinced that directed graphical models (DGMs) are generally useful for estimating causal effects. We express our reservations using the "potential outcomes" framework for causal inference widely used in statistics. PMID- 20970506 TI - Altered fronto-cerebellar connectivity in alcohol-naive youth with a family history of alcoholism. AB - Fronto-cerebellar connections are thought to be involved in higher-order cognitive functioning. It is suspected that damage to this network may contribute to cognitive deficits in chronic alcoholics. However, it remains to be elucidated if fronto-cerebellar circuitry is altered in high-risk individuals even prior to alcohol use onset. The current study used functional connectivity MRI (fcMRI) to examine fronto-cerebellar circuitry in 13 alcohol-naive, at-risk youth with a family history of alcoholism (FH+) and 14 age-matched controls. In addition, we examined how white matter microstructure, as evidenced by fractional anisotropy (FA), related to fcMRI. FH+youth showed significantly reduced functional connectivity between bilateral anterior prefrontal cortices and contralateral cerebellar seed regions compared to controls. We found that this reduction in connectivity significantly correlated with reduced FA in the anterior limb of the internal capsule and the superior longitudinal fasciculus. Taken together, our findings reflect associated aberrant functional and structural connectivity in substance-naive FH+adolescents, perhaps suggesting an identifiable neurophenotypic precursor to substance use. Given the role of frontal and cerebellar brain regions in subserving executive functioning, the presence of premorbid abnormalities in fronto-cerebellar circuitry may heighten the risk for developing an alcohol use disorder in FH+youth through atypical control processing. PMID- 20970508 TI - Enriched white matter connectivity networks for accurate identification of MCI patients. AB - Mild cognitive impairment (MCI), often a prodromal phase of Alzheimer's disease (AD), is frequently considered to be a good target for early diagnosis and therapeutic interventions of AD. Recent emergence of reliable network characterization techniques has made it possible to understand neurological disorders at a whole-brain connectivity level. Accordingly, we propose an effective network-based multivariate classification algorithm, using a collection of measures derived from white matter (WM) connectivity networks, to accurately identify MCI patients from normal controls. An enriched description of WM connections, utilizing six physiological parameters, i.e., fiber count, fractional anisotropy (FA), mean diffusivity (MD), and principal diffusivities(lambda(1), lambda(2), and lambda(3)), results in six connectivity networks for each subject to account for the connection topology and the biophysical properties of the connections. Upon parcellating the brain into 90 regions-of-interest (ROIs), these properties can be quantified for each pair of regions with common traversing fibers. For building an MCI classifier, clustering coefficient of each ROI in relation to the remaining ROIs is extracted as feature for classification. These features are then ranked according to their Pearson correlation with respect to the clinical labels, and are further sieved to select the most discriminant subset of features using an SVM-based feature selection algorithm. Finally, support vector machines (SVMs) are trained using the selected subset of features. Classification accuracy was evaluated via leave-one-out cross validation to ensure generalization of performance. The classification accuracy given by our enriched description of WM connections is 88.9%, which is an increase of at least 14.8% from that using simple WM connectivity description with any single physiological parameter. A cross-validation estimation of the generalization performance shows an area of 0.929 under the receiver operating characteristic (ROC) curve, indicating excellent diagnostic power. It was also found, based on the selected features, that portions of the prefrontal cortex, orbitofrontal cortex, parietal lobe and insula regions provided the most discriminant features for classification, in line with results reported in previous studies. Our MCI classification framework, especially the enriched description of WM connections, allows accurate early detection of brain abnormalities, which is of paramount importance for treatment management of potential AD patients. PMID- 20970509 TI - Voxel-based morphometry studies of personality: issue of statistical model specification--effect of nuisance covariates. AB - There are an increasing number of studies on the localization of personality using voxel-based morphometry. Due to the complex analytic challenge in volumetric studies, the specification and treatment of the nuisance covariate (such as age, gender, and global measures) is currently not consistent. Here, we present a study in which we conducted voxel-based morphometry with Five-Factor Model (FFM) of personality traits (extraversion, neuroticism, openness to experience, agreeableness, and conscientiousness) that aimed to test the influence of NC specification in the determination of the results. In this study, 62 healthy subjects underwent MRI investigation and completed a German version of the FFM personality questionnaire. Voxel-based morphometry was used to investigate the correlation between the FFM personality traits and subtle brain structure. Different NC combinations were used during the model specification. Significant clusters were found only under the condition of some of the NC combinations but not under the others. In addition, we use the structure equation modeling (automated specification search from AMOS) to narrow down the possible choices of NC combinations according to a set of goodness-of-fit indices to identify well-fitted statistic models. As a final step, theoretical implications of the results are discussed, before accepting the selected model. PMID- 20970510 TI - Neural prediction of higher-order auditory sequence statistics. AB - During auditory perception, we are required to abstract information from complex temporal sequences such as those in music and speech. Here, we investigated how higher-order statistics modulate the neural responses to sound sequences, hypothesizing that these modulations are associated with higher levels of the peri-Sylvian auditory hierarchy. We devised second-order Markov sequences of pure tones with uniform first-order transition probabilities. Participants learned to discriminate these sequences from random ones. Magnetoencephalography was used to identify evoked fields in which second-order transition probabilities were encoded. We show that improbable tones evoked heightened neural responses after 200 ms post-tone onset during exposure at the learning stage or around 150 ms during the subsequent test stage, originating near the right temporoparietal junction. These signal changes reflected higher-order statistical learning, which can contribute to the perception of natural sounds with hierarchical structures. We propose that our results reflect hierarchical predictive representations, which can contribute to the experiences of speech and music. PMID- 20970511 TI - Molecular phylogenetics of porcini mushrooms (Boletus section Boletus). AB - Porcini (Boletus section Boletus: Boletaceae: Boletineae: Boletales) are a conspicuous group of wild, edible mushrooms characterized by fleshy fruiting bodies with a poroid hymenophore that is "stuffed" with white hyphae when young. Their reported distribution is with ectomycorrhizal plants throughout the Northern Hemisphere. Little progress has been made on the systematics of this group using modern molecular phylogenetic tools because sampling has been limited primarily to European species and the genes employed were insufficient to resolve the phylogeny. We examined the evolutionary history of porcini by using a global geographic sampling of most known species, new discoveries from little explored areas, and multiple genes. We used 78 sequences from the fast-evolving nuclear internal transcribed spacers and are able to recognize 18 reciprocally monophyletic species. To address whether or not porcini form a monophyletic group, we compiled a broadly sampled dataset of 41 taxa, including other members of the Boletineae, and used separate and combined phylogenetic analysis of sequences from the nuclear large subunit ribosomal DNA, the largest subunit of RNA polymerase II, and the mitochondrial ATPase subunit six gene. Contrary to previous studies, our separate and combined phylogenetic analyses support the monophyly of porcini. We also report the discovery of two taxa that expand the known distribution of porcini to Australia and Thailand and have ancient phylogenetic connections to the rest of the group. A relaxed molecular clock analysis with these new taxa dates the origin of porcini to between 42 and 54 million years ago, coinciding with the initial diversification of angiosperms, during the Eocene epoch when the climate was warm and humid. These results reveal an unexpected diversity, distribution, and ancient origin of a group of commercially valuable mushrooms that may provide an economic incentive for conservation and support the hypothesis of a tropical origin of the ectomycorrhizal symbiosis. PMID- 20970512 TI - Enduring deficits in contextual and auditory fear conditioning after adolescent, not adult, social instability stress in male rats. AB - Adolescence is a time of developmental changes and reorganization in the brain and stress systems, thus, adolescents may be more vulnerable than adults to the effects of chronic mild stressors. Most studies, however, have not directly compared stress experienced in adolescence to the same stress experience in adulthood. In the present study, adolescent (n=46) and adult (n=48) male rats underwent 16 days of social instability stress (daily 1h isolation and change of cage partners) or were non-stress controls. Rats were then tested on the strength of acquired contextual and cued fear conditioning, as well as extinction learning, beginning either the day after the stress procedure or 3 weeks later. No difference was found among the groups during the Training Phase of conditioning. Irrespective of the time between the social stress experience and fear conditioning, rats stressed in adolescence had decreased context and cue memory, and cue generalization compared to control rats, as measured by the percentage of time spent freezing in tests. Social instability stress in adulthood had no effect on any measure of fear conditioning. The results support the hypothesis that adolescence is a time of heightened vulnerability to stressors. PMID- 20970513 TI - EGFs and ERBBs--brief history and prospects. PMID- 20970515 TI - Similar gene expression profiles in smokers and patients with moderate COPD. AB - Chronic obstructive pulmonary disease (COPD) is characterized by multiple cellular and structural changes affecting the airways, lung parenchyma and vasculature, some of which are also identified in smokers without COPD. The molecular mechanisms underlying these changes remain poorly understood. With the aim of identifying mediators potentially implicated in the pathogenic processes that occur in COPD and their potential relationship with cigarette smoking, we evaluated the mRNA expression of genes involved in inflammation, tissue remodeling and vessel maintenance. Lung tissue samples were obtained from 60 patients who underwent lung resection (nonsmokers, n=12; smokers, n=12; and moderate COPD, n=21) or lung transplant (severe-to-very severe COPD, n=15). PCR arrays containing 42 genes coding for growth factors/receptors, cytokines, metalloproteinases, adhesion molecules, and vessel maintenance mediators were used. Smoking-induced changes include the up-regulation of inflammatory genes (IL 1beta, IL-6, IL-8, CCL2, and CCL8) and the decreased expression of growth factor/receptor genes (BMPR2, CTGF, FGF1, KDR and TEK) and genes coding for vessel maintenance factors (EDNRB). All these genes exhibited a similar profile in moderate COPD patients. The up-regulation of MMP1 and MMP9 was the main change associated with COPD. Inflammatory genes as well as the endothelial selectin gene (SELE) were down-regulated in patients with more severe COPD. Clustering analysis revealed a closer relationship between moderate COPD and smokers than between both subsets of COPD patients for this selected set of genes. The study reveals striking similarities between smokers and COPD patients with moderate disease emphasizing the crucial role of cigarette smoking in the genesis of these changes, and provides additional evidence of the involvement of the matrix metalloproteinase's in the remodeling process of the lung in COPD. PMID- 20970514 TI - Dilated intercellular spaces and chronic cough as an extra-oesophageal manifestation of gastrooesophageal reflux disease. AB - Chronic cough is one of the extra-oesophageal manifestations of gastrooesophageal reflux disease (GORD). It is presumed to occur either directly by microaspiration of acidic gastric contents into the airway or indirectly by a reflex triggered by contact of acidic refluxates with the oesophageal epithelium in GORD. How contact of the oesophageal epithelium with acidic refluxates promotes sensitization for chronic cough is unknown, but like heartburn, which is a necessary accompaniment, it requires acid activation of nociceptors within the oesophageal mucosa. Dilated intercellular spaces within the oesophageal epithelium, a reflection of an increase in paracellular permeability, is a histopathologic feature of both erosive and non-erosive forms of GORD. Since it correlates with the symptom of heartburn, it is hypothesized herein that the increase in paracellular permeability to acid reflected by dilated intercellular spaces in oesophageal epithelium also serves as mediator of the signals that produce the reflex-induced sensitization for cough--a sensitization that can occur centrally within the medullary Nucleus Tractus Solitarius or peripherally within the tracheobronchial tree. PMID- 20970516 TI - Activation of the EP4 prostanoid receptor induces prostaglandin E2 and pro inflammatory cytokine production in human airway epithelial cells. AB - Prostaglandin (PG)E2 mediates its effects via activation of four distinct PGE2 receptors, termed EP1-4, all of which are present on the model human airway epithelial cell line, Calu-3. We previously reported that acute activation of the EP4 subtype of the PGE2 receptor is associated with increased anion efflux from these cells, via the CFTR chloride channel. In the present study we examine the effects of longer term activation of the EP4 receptor in Calu-3 cells in an attempt to determine whether this would prove beneficial or detrimental to the airway epithelial cell environment. Using PGE1-OH, an EP4 receptor selective agonist, we determined that EP4 receptor activation was associated with increased phosphorylation of extracellular signal-related kinases (ERKs) and induction of the transcription factor early growth response factor-1 (Egr-1). Additionally, using specific enzyme-linked immunosorbent assays and quantitative PCR, we detected increased production of PGE2, IL-6, IL-8 and the chemokine monocyte chemotactic protein-1 (MCP-1) at both the protein and gene level in response to EP4 receptor activation. Intriguingly, the enhanced production of PGE2 in response to EP4 receptor activation raises the possibility of a positive feedback situation. Generally, within the airways, PGE2 is considered to have pro inflammatory effects, whilst the enhanced production of IL-6, IL-8 and MCP-1 would be associated with the recruitment and activation of inflammatory cells to the airways. Thus, we conclude that chronic activation of the EP4 receptor is associated with increased production of mediators likely to increase the pro inflammatory milieu of airway epithelial cells. PMID- 20970517 TI - Acute administration of bronchodilators on exercise tolerance in treated COPD patients. AB - Exercise intolerance is a major feature in patients with Chronic Obstructive Pulmonary Disease (COPD). Bronchodilators increase endurance time (ET) and reduce dynamic hyperinflation (DH). We evaluated whether a single-dose of salbutamol/ipratropium + flunisolide (BD+ICS), added on top of the regular treatment, may improve ET in COPD patients. In a single-blind randomized crossover pilot trial, nebulised BD+ICS or placebo (PL) was administered 30 min before a constant load cardiopulmonary test, in 22 moderate-to-severe COPD patients (FEV1: 53.9% pred). ET was the primary outcome measured. BD+ICS did not improve ET or VO2 peak with respect to PL. BD+ICS increased pre-test FEV1 and pre test Inspiratory Capacity but did not modify DH. In a retrospective analysis, patients were divided in Improvers (N=11) and Non-Improvers (N=11) according to the difference in ET between BD+ICS and PL (> 25 s). Improvers had a worst BODE index, a higher static hyperinflation and poorer Vd/Vt ratio at peak of exercise with respect to Non-Improvers. Improvers only had a significant increase from BD+ICS on pre-test FEV1 and IC. In conclusion, although a single-dose BD+ICS did not improve ET in COPD patients under regular treatment, a subgroup of more severe patients may have some benefit from that. PMID- 20970518 TI - Purification and characterization of phenoloxidase from the hemocytes of Eurygaster integriceps (Hemiptera: Scutelleridae). AB - Insects protect themselves from microbial invaders by two main immune activities, namely the cellular and humoral reactions. Phenoloxidases are oxidative enzymes that have an important role in both cell-mediated and humoral immunity. In this study, the purification and biochemical characterization of a phenoloxidase from the hemocytes of the Sunn pest Eurygaster integriceps Puton (Hemiptera: Scutelleridae) were carried out. After the final purification step, the enzyme was purified 7.31-fold with a recovery of 3.94% and a specific activity of 4.95U/mg protein. Results of the biochemical characterization showed that the purified phenoloxidase has a maximum activity at pH 6 and at 30-35 degrees C and is stable for 24-36h. Divalent cations such as Ca(2+) and Cu(2+) significantly increased the enzymatic activity and synthetic inhibitors such as phenylthiourea significantly decreased it. The purified phenoloxidase has a molecular mass of 22kDa. The current paper represents a further step towards the characterization of humoral immunity of E. integriceps in order to develop new strategies for the biological control of the Sunn pest. PMID- 20970519 TI - PubChem as a public resource for drug discovery. AB - PubChem is a public repository of small molecules and their biological properties. Currently, it contains more than 25 million unique chemical structures and 90 million bioactivity outcomes associated with several thousand macromolecular targets. To address the potential utility of this public resource for drug discovery, we systematically summarized the protein targets in PubChem by function, 3D structure and biological pathway. Moreover, we analyzed the potency, selectivity and promiscuity of the bioactive compounds identified for these biological targets, including the chemical probes generated by the NIH Molecular Libraries Program. As a public resource, PubChem lowers the barrier for researchers to advance the development of chemical tools for modulating biological processes and drug candidates for disease treatments. PMID- 20970520 TI - Evaluation of copper-induced stress on eggplant (Solanum melongena L.) seedlings at the molecular and population levels by use of various biomarkers. AB - Heavy-metal contamination is an important environmental problem in the world. It is known that high concentrations of heavy metals cause toxic damage to cells and tissues. In this study the effects of copper (Cu(2+)) contamination were determined at the molecular and population levels in eggplant (Solanum melongena L.) seedlings exposed to various concentrations of the metal ion. Inhibition of root growth, reduction in dry weight and total soluble protein content in the roots of eggplant seedlings were observed with increasing Cu(2+) concentrations. In ecotoxicology, analysis by random amplification of polymorphic DNA (RAPD) has been applied as a suitable biomarker assay for plants. For the RAPD analyses, nine RAPD primers were found to produce unique polymorphic band patterns and were subsequently used to produce a total of 80 and 168 bands in the roots of untreated and treated eggplant seedlings, respectively. The changes in RAPD profiles after Cu(2+) contamination were considered as variations, i.e. as gain and/or loss of bands compared with control seedlings. These results suggest that changes in genomic template stability could be detected with RAPD profiles and this result could be compared with the growth, dry weight and total soluble protein content of the seedlings grown at various Cu(2+) concentrations. The measurements of parameters at the molecular and population levels are fundamental to accumulate valuable information and to understand clearly the effect of a contaminant on an organism in ecotoxicology. PMID- 20970521 TI - Triggered activity, coronary sinus, and atrial fibrillation. PMID- 20970523 TI - Inappropriate pacing in a patient with managed ventricular pacing: what is the cause? PMID- 20970524 TI - Improved heart rate recovery after marked weight loss induced by gastric bypass surgery: two-year follow up in the Utah Obesity Study. AB - BACKGROUND: Obesity is associated with significantly increased cardiovascular mortality that has been attributed, in part, to sympathetic activation. Gastric bypass surgery (GBS) appears to increase long-term survival in the severely obese, but the mechanisms responsible for this increase are still being sought. Heart rate (HR) recovery after exercise reflects the balance of cardiac autonomic input from the sympathetic and parasympathetic systems. Blunted HR recovery is a very powerful predictor of increased mortality, whereas enhanced HR recovery portends a good prognosis. OBJECTIVE: The purpose of this study was to evaluate the effect of marked weight loss achieved via GBS on HR recovery. METHODS: Severely obese patients underwent submaximal exercise testing (80% predicted maximum HR) at baseline and 2 years after GBS (n = 153) or nonsurgical treatment (n = 188). RESULTS: Patients in the GBS group lost an average of 100 +/- 37 lb compared to 3 +/- 22 lb in the nonsurgical group (P <.001, GBS vs nonsurgical). Resting HR decreased from 73 bpm to 60 bpm in the GBS group and from 74 bpm to 68 bpm in nonsurgical patients (P <.001). HR recovery improved by 13 bpm in the GBS group but did not change in the nonsurgical group (P <.001 GBS vs nonsurgical). In multivariable analysis, the independent correlates of HR recovery at the 2 year time point were resting HR, treadmill time, age, body mass index, and HOMA IR (an index of insulin resistance). CONCLUSION: Marked weight loss 2 years after GBS resulted in a significant decrease in resting HR and an enhancement in HR recovery after exercise. These changes likely are attributable to improvement in insulin sensitivity and cardiac autonomic balance. Whether and to what extent this contributes to a reduction in cardiovascular mortality with GBS remains to be determined. PMID- 20970526 TI - A python module to normalize microarray data by the quantile adjustment method. AB - Microarray technology is widely used for gene expression research targeting the development of new drug treatments. In the case of a two-color microarray, the process starts with labeling DNA samples with fluorescent markers (cyanine 635 or Cy5 and cyanine 532 or Cy3), then mixing and hybridizing them on a chemically treated glass printed with probes, or fragments of genes. The level of hybridization between a strand of labeled DNA and a probe present on the array is measured by scanning the fluorescence of spots in order to quantify the expression based on the quality and number of pixels for each spot. The intensity data generated from these scans are subject to errors due to differences in fluorescence efficiency between Cy5 and Cy3, as well as variation in human handling and quality of the sample. Consequently, data have to be normalized to correct for variations which are not related to the biological phenomena under investigation. Among many existing normalization procedures, we have implemented the quantile adjustment method using the python computer language, and produced a module which can be run via an HTML dynamic form. This module is composed of different functions for data files reading, intensity and ratio computations and visualization. The current version of the HTML form allows the user to visualize the data before and after normalization. It also gives the option to subtract background noise before normalizing the data. The output results of this module are in agreement with the results of other normalization tools. PMID- 20970525 TI - Phylogenetic evaluation of the 'Typhimurium' complex of Salmonella strains using a seven-gene multi-locus sequence analysis. AB - Salmonella enterica comprises over 2500 serovars, many of which are significant foodborne pathogens in humans. The ability to subtype these microbes is difficult due to the highly clonal nature of many Salmonella strains and a lack of congruence among traditional typing approaches. This work examines the phylogenetic utility of a multi-locus sequence typing (MLST) approach to discriminate between members of a closely related collection of salmonellae, the Salmonella reference collection A (SARA). This 72 strain collection, referred to as the 'Typhimurium' complex, consists of S. Typhimurium and its four closest serological relatives. In this analysis, nucleotide sequences from seven housekeeping genes (aroC, dnaN, hemD, hisD, purE, sucA, and thrA) were PCR amplified, sequenced, and combined into a single concatenated character matrix providing 3360bp for cladistic analysis. The resultant most parsimonious tree yielded seven clades of Salmonella strains that partitioned largely along serovar divisions within the collection except for five 'Paratyphi B' strains, two 'Saintpaul' strains, and two 'Typhimurium' strains. Convergence in the SARA tree was approximately 20% indicating that the vast majority of sequence changes were phylogenetically informative. Despite a high consistency among nucleotide substitutions, analysis of congruence identified several SARA strains with recombinant alleles in the concatenated matrix. These findings point to important differences among phylogenetic contributions made by the individual genes comprising this MLST dataset. PMID- 20970527 TI - Chimeric CYP21A1P/CYP21A2 genes identified in Czech patients with congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive disorders caused by an enzymatic deficiency which impairs the biosynthesis of cortisol and, in the majority of severe cases, also the biosynthesis of aldosterone. Approximately 95% of all CAH cases are caused by mutations in the steroid 21-hydroxylase gene (CYP21A2). The CYP21A2 gene and its inactive pseudogene (CYP21A1P) are located within the HLA class III region of the major histocompatibility complex (MHC) locus on chromosome 6p21.3. In this study, we describe chimeric CYP21A1P/CYP21A2 genes detected in our patients with 21 hydroxylase deficiency (21OHD). Chimeric CYP21A1P/CYP21A2 genes were present in 171 out of 508 mutated CYP21A2 alleles (33.8%). We detected four types of chimeric CYP21A1P/CYP21A2 genes: three of them have been described previously as CH-1, CH-3, CH-4, and one type is novel. The novel chimeric gene, termed CH-7, was detected in 21.4% of the mutant alleles. Possible causes of CYP21A1P/CYP21A2 formation are associated with 1) high recombination rate in the MHC locus, 2) high recombination rate between highly homologous genes and pseudogenes in the CYP21 gene area, and 3) the existence of chi-like sequences and repetitive minisatellite consensus sequences in CYP21A2 and CYP21A1P which play a role in promoting genetic recombination. PMID- 20970528 TI - The potential of brewer's spent grain to improve the production of alpha-amylase by Bacillus sp. KR-8104 in submerged fermentation system. AB - Brewer's spent grain (BSG) was used as a solid substrate for the production of alpha-amylase by Bacillus sp. KR-8104 in a submerged fermentation system. The production of alpha-amylase was maximized through statistical optimization of the BSG concentration and incubation time using the Doehlert experimental design. The highest tested amount of BSG (5%, w/v) in the optimization process resulted in a 5.1-fold enhancement of the response. Subsequently, we studied the role of the water-soluble and -insoluble fractions of BSG in the production of alpha-amylase. The results revealed that whole BSG had a greater effect on the production of alpha-amylase than each fraction had separately. Finally, when we examined the potential of BSG to replace the constituents of a medium formula, we observed that simultaneously adding BSG, omitting dextrin, and reducing the other ingredients concentration in the culture medium improved the production of alpha amylase and made the production process more economical. PMID- 20970529 TI - A novel organic solvent tolerant protease from a newly isolated Geomicrobium sp. EMB2 (MTCC 10310): production optimization by response surface methodology. AB - Thirty-eight haloalkaliphilic bacterial strains were isolated from Sambhar Salt Lake, India and screened for their ability to secrete haloalkaliphilic proteases. Among them, a moderately halophilic, mesophilic and alkaliphilic potent strain Geomicrobium sp. EMB2 produced an extracellular protease, which was remarkably stable in organic solvents, salt, surfactants, detergents and alkaline pH. Statistically based experimental designs were applied to study the interactions and optimization of medium constituents for efficient protease production by Geomicrobium sp. EMB2. An overall 20-fold increase in protease production was achieved in the optimized medium (721 U/ml) as compared with the unoptimized medium (37 U/ml). The high production level coupled with novel properties makes it a prospective industrial enzyme. The Geomicrobium sp. EMB2 isolate is deposited in Microbial Type Culture Collection, Chandigarh, India with accession number MTCC 10310. PMID- 20970530 TI - Improved mannan-degrading enzymes' production by Aspergillus niger through medium optimization. AB - The effect of different carbon and nitrogen sources on the production of mannan degrading enzymes, focussing on beta-mannanase, by Aspergillus niger was investigated using shake flask culture. The beta-mannanase activity obtained during growth of A. niger on guar gum (GG, 1495 nkat mL(-1)) was much higher than those observed on other carbon substrates, locust bean gum (1148 nkat mL(-1)), alpha-cellulose (10.7 nkat mL(-1)), glucose (8.8 nkat mL(-1)) and carboxymethylcellulose (4.6 nkat mL(-1)). For fermentation using GG as a carbon source, bacteriological peptone gave the highest beta-mannanase activity (1744 nkat mL(-1)) followed by peptone from meat (1168 nkat mL(-1)), yeast extract (817 nkat mL(-1)), ammonium sulphate (241 nkat mL(-1)), ammonium nitrate (113 nkat mL( 1)) and ammonium chloride (99 nkat mL(-1)) when used as a nitrogen source. The composition of bacteriological peptone and initial pH of the medium were further optimized using response surface methodology (RSM). Medium consisted of 21.3 g L( 1) GG and 57 g L(-1) peptone with initial culture pH of 5.5 was optimum for beta mannanase production (2063 nkat mL(-1)) by A. niger. The beta-mannanase production obtained in this study using A. niger was significantly higher than those reported in the literature. PMID- 20970531 TI - Different target surfaces for the analysis of peptides, peptide mixtures and peptide mass fingerprints by AP-MALDI ion trap-mass spectrometry. AB - The desorption/ionization behavior of individual peptides, an equimolare peptide mixture and a tryptic digest was investigated by AP-MALDI-IT-MS using four different target materials (gold-covered stainless steel (SS), titanium nitride covered SS, hand-polished SS, and microdiamond-covered hardmetal) under identical conditions. Gold-covered as well as polished SS targets yielded comparable mass spectra for peptides and peptide mixture in the low pMol-range. The first target exhibited superior data down to the 10fMol-range. In contrast, titanium nitride covered SS and microdiamond-covered hardmetal AP-MALDI-targets yielded poor sensitivity. These observations could be correlated with the surface roughness of the targets determined by 3D-confocal-white-light-microscopy. The roughest surfaces were found for titanium nitride-covered SS and microdiamond-covered hardmetal material showing both poor MS sensitivity. A less rough surface could be determined for the hand-polished SS target and the smoothest surface was found for the gold-covered target yielding the best sensitivity of all surfaces. These differences in the roughness having a strong impact on the ultimate sensitivity obtainable for peptide samples could be corroborated by electron microscopy. A peptide mixture covering a wide range of molecular weights and a tryptic protein digest (from 2-DE) exhibit the same behavior. This clearly indicates that the smooth gold-covered SS target is the surface of choice in AP-MALDI MS proteomics. PMID- 20970532 TI - Society for Invertebrate Pathology 2009 Founders' Lecture: Donald W. Roberts--50 years of leadership in insect pathology. PMID- 20970533 TI - Implant osseointegration in the absence of primary bone anchorage: a clinical report. AB - The authors identified no report describing implant primary stability obtained by external fixation as a means to achieve osseointegration in craniofacial settings. This article describes a situation in which an implant was placed without direct contact with the resident bone; primary stability was provided by an external device. An edentulous patient was restored with 5 endosseous titanium implants to support a mandibular fixed prosthesis. An implant placed in the right central incisor position was removed after 48 hours and replaced with a shorter and narrower implant without contact with resident bone. Thus, primary stability for the implant was provided by rigid fixation to the prosthesis rather than by bone anchorage. At recall examinations after 6 and 27 months, all implants, including the implant in the right central incisor position, showed clinical and radiographic signs of osseointegration. Resonance frequency analysis indicated acceptable stability and osseointegration for all implants. Observations of this patient suggest that implant osseointegration can be achieved by providing primary stability using a fixed complete denture. Primary bone anchorage/contact does not appear to be critical to the osseointegration process. PMID- 20970534 TI - Radiation dose distribution in the external auditory canal with different prosthetic materials: a clinical report. AB - Radiotherapy (RT) is an essential component of cancer treatment and aims to deliver higher doses at target volumes and lower doses to surrounding organs to achieve higher tumor control with fewer side effects. Significant dose heterogeneities can occur during treatment of irregular surfaces with electron beams, especially in head, neck, and breast tissue. The external ear and external auditory canal have irregular surfaces, which may cause dose heterogeneity, primarily resulting in excessive doses in the normal tissues lining and adjacent to the ear canal. The purpose of this clinical report is to describe the use of an acrylic resin and an elastomeric material to fill the air cavities of the external auditory canal and compare the dosimetric parameters. The complications that occur after electron-beam therapy of the ear canal can be significantly reduced by filling the ear cavity with acrylic resin, which is a simple, feasible, and cost-effective method. PMID- 20970535 TI - Combined effects of implant insertion depth and alveolar bone quality on periimplant bone strain induced by a wide-diameter, short implant and a narrow diameter, long implant. AB - STATEMENT OF PROBLEM: Strain levels in periimplant bone are affected by implant dimensions, bone quality, and implant insertion depth, resulting in different bone maintenance characteristics. PURPOSE: The purpose of this study was to evaluate the biomechanical response of the jaw bone to a wide-diameter, short (WDS) implant, and a narrow-diameter, long (NDL) implant for various simulated clinical scenarios. MATERIAL AND METHODS: The finite element method was used to evaluate periimplant bone strain distribution for 5 * 6-mm (WDS) and 3.5 * 10.7 mm (NDL) implants. A 3-dimensional segment of the mandible was constructed from a computerized tomography image of the premolar region. Occlusal force was simulated by applying a 100-N oblique load on the abutment. Bone strain distributions for 5 different implant insertion depths and 2 different levels of alveolar bone quality were evaluated. RESULTS: For an NDL implant, approximately 60% to 80% of the bone volume surrounding the implant was subjected to 200-1000 MUstrain (MUE), and 15% to 35% was subjected to 1000-3000 MUE, regardless of the alveolar bone quality. For a WDS implant, the bone volume subjected to 1000-3000 MUE increased, and the bone volume subjected to 200-1000 MUE decreased in lower quality alveolar bone. For both implant types, bone volume experiencing strain levels less than 200 MUE, and/or greater than 3000 MUE, was predicted to be relatively small. CONCLUSIONS: In general, the thread design promoted relatively high strain around the thread tips, and the bone inside grooves was less strained. A more even and higher strain distribution in the periimplant bone was generated by the WDS implant as compared to the NDL implant. Regardless of the implant dimensions and simulated clinical scenarios, the development of high strain in the alveolar region was inevitable. Strain levels in periimplant bone were reduced as the insertion depth of the implant was increased. PMID- 20970536 TI - Sensitivity of transillumination for detecting microcracks in feldspathic and zirconia ceramic materials. AB - STATEMENT OF PROBLEM: Despite good clinical success rates of ceramic restorations, fractures of substructures made from high-strength dental ceramics remain an issue. Transillumination of ceramic restorations has been proposed as a means of quality assurance. PURPOSE: The purpose of this study was to compare the sensitivity of transillumination and the fluorescent penetrant method (FPM) in detecting microcracks in zirconia and feldspathic ceramic materials. MATERIAL AND METHODS: Two groups (n=20) of standardized plates were fabricated from zirconia ceramic (Cercon) and feldspathic ceramic (VITABLOCS Mark II for CEREC) materials, and central holes were created to induce microcracks. The plates were microscopically analyzed at *20 magnification by means of transillumination and FPM. Based on whether the criterion crack was recognized or not recognized, contingency tables were developed. Fisher's exact test for count data was used to compare frequency distributions (alpha=.05). RESULTS: Minimum crack length as detected by FPM was 18 MUm in zirconia ceramic and 17 MUm in feldspathic ceramic. For transillumination, minimum detectable crack length was 54 MUm in zirconia ceramic and 33 MUm in feldspathic ceramic. Thirty-seven percent of cracks in feldspathic ceramic plates and 64% of cracks in zirconia ceramic plates could not be detected by means of transillumination. The conditional probabilities for a crack being detected by transillumination, although it was detected by FPM, were significantly lower than 1 for both materials (P<.001). Although transillumination was less sensitive than FPM on a relative scale, it was not possible to demonstrate a general difference between the 2 analyzing techniques by using statistical methods. CONCLUSIONS: Using FPM as a relative reference system, transillumination appears to be less sensitive in detecting microcracks in ceramic components. PMID- 20970537 TI - The effect of post, core, crown type, and ferrule presence on the biomechanical behavior of endodontically treated bovine anterior teeth. AB - STATEMENT OF PROBLEM: Unresolved controversy exists concerning the remaining coronal tooth structure of anterior endodontically treated teeth and the best treatment option for restoring them. PURPOSE: The purpose of this study was to evaluate the effect of post, core, crown type, and ferrule presence on the deformation, fracture resistance, and fracture mode of endodontically treated bovine incisors. MATERIAL AND METHODS: One hundred and eighty bovine incisors were selected and divided into 12 treatment groups (n=15). The treatment variations were: with or without ferrule, restored with cast post and core, glass fiber post with composite resin core, or glass fiber post with fiber-reinforced core, and metal- or alumina-reinforced ceramic crown (n=15). The restored incisors were loaded at a 135-degree angle, and the deformation was measured using strain gauges placed on the buccal and proximal root surfaces. Specimens were subsequently loaded to the point of fracture. Strain and fracture resistance results were analyzed by 3-way ANOVA and Tukey HSD tests (alpha=.05). RESULTS: Ferrule presence did not significantly influence the buccal strain and fracture resistance for the ceramic crown groups, irrespective of core and crown type. Ferrule presence resulted in lower strains and higher fracture resistance in the metal crown groups, irrespective of core. The cast post and core showed lower strain values than groups with glass fiber posts when restored with metal crowns. CONCLUSIONS: Core type did not affect the deformation and fracture resistance of endodontically treated incisors restored with alumina-reinforced ceramic crowns. The presence of a ferrule improved the mechanical behavior of teeth restored with metal crowns, irrespective of core type. PMID- 20970538 TI - The effect of tooth and foundation restoration heights on the load fatigue performance of cast crowns. AB - STATEMENT OF PROBLEM: In badly damaged teeth and teeth with short clinical crown heights, the placement of foundation restorations has been advocated to permit the development of retention and resistance form. However, there is little information on the effect of these foundation restorations on the clinical performance of the definitive restoration. PURPOSE: The purpose of this study was to evaluate the load fatigue performance of teeth restored with posts and cores, with varying tooth heights, and to compare them with similar groups having no posts and cores. A secondary purpose was to determine whether a critical tooth height existed at which the placement of a foundation restoration resulted in no significant difference in the load fatigue performance. MATERIAL AND METHODS: Three test groups (n=10) with prepared tooth heights of 2, 3, and 4 mm were tested. These were compared with another 3 groups with similar tooth heights that were restored with prefabricated titanium posts and core heights of 4, 3, and 2 mm, respectively. Cast complete crowns were then fabricated and cemented with zinc phosphate cement. A fatigue load of 58.8 N was applied at an angle of 135 degrees to the long axis of each crown-tooth specimen. The number of cycles to preliminary failure was determined. Significant differences in cycles to preliminary failure were assessed with 1-way ANOVA, followed by Tukey HSD tests (alpha=.05). RESULTS: The group with the greatest preparation height (4 mm) and a 2-mm post-retained foundation had the highest number of cycles to preliminary failure (437,701), while the group with the shortest preparation height and no foundation had the lowest number of cycles (53,806). The Tukey HSD multiple comparison tests showed that for all 3 tooth heights, groups with foundation restorations had a significantly higher number of cycles to preliminary failure than those without foundation restorations. CONCLUSIONS: For a given tooth height, teeth restored with foundation restorations had a significantly better load fatigue performance than those with no foundation restoration. PMID- 20970539 TI - An in vitro investigation into the physical properties of irreversible hydrocolloid alternatives. AB - STATEMENT OF PROBLEM: A number of manufacturers have introduced new products that are marketed as alternatives to irreversible hydrocolloid impression materials. However, there is a paucity of laboratory and clinical research on these products compared to traditional irreversible hydrocolloid. PURPOSE: The purpose of this study was to evaluate the detail reproduction, gypsum compatibility, and linear dimensional change of 3 recently introduced impression materials designed as alternatives to irreversible hydrocolloid. MATERIAL AND METHODS: The tested materials were Position Penta Quick, Silgimix, and AlgiNot. An irreversible hydrocolloid impression material, Jeltrate Plus Antimicrobial, served as the control. The parameters of detail reproduction, gypsum compatibility, and linear dimensional change were tested in accordance with ANSI/ADA Specifications No. 18 and 19. The gypsum compatibility was tested using a type III stone (Microstone Golden) and a type IV stone (Die-Keen Green). The data were analyzed using the Kruskal-Wallis rank test and the Mann-Whitney U test (alpha=.05). RESULTS: The test materials demonstrated significantly (P<.001) better detail reproduction than the control material. Silgimix exhibited the best compatibility with Microstone, whereas AlgiNot and Position Penta Quick exhibited the best gypsum compatibility with Die-Keen. An incompatibility was observed over time between the Jeltrate control material and the Microstone gypsum material. For linear dimensional change, the mean dimension of the control material most closely approximated the distance between the lines on the test die, but it exhibited the greatest variability in measurements. All of the test materials exhibited linear dimensional change within the ADA's accepted limit of 1.0%. CONCLUSIONS: The 3 new impression materials exhibited better detail reproduction and less variability in linear dimensional change than the irreversible hydrocolloid control. Gypsum compatibility varied with the brand of gypsum used, with an incompatibility identified between the control material (Jeltrate Plus Antimicrobial) and Microstone related to surface changes observed over time. PMID- 20970540 TI - The effect of chlorine-based disinfectant on wettability of a vinyl polysiloxane impression material. AB - STATEMENT OF PROBLEM: Extended contact of impression materials with chemical disinfectant could remove surfactant, significantly altering the contact angle and wettability characteristics of an impression material. PURPOSE: The purpose of this study was to determine the effect of contact time of chemical disinfectant solution on the dynamic contact angle of a commercial vinyl polysiloxsane impression material. MATERIAL AND METHODS: Discs (3.5 * 25 mm) of heavy-body and wash consistencies of material (n=5) were fabricated and either left untreated, or subjected to spray treatment with a commercial disinfectant for various lengths of time (1, 20, or 60 minutes, or 24 hours). Treated specimens were washed and dried, after which dynamic contact angle measurements of a water droplet were determined at various points in time after deposition: 0, 2, 5, 10, 15, and 20 seconds. The same wash product was used without added surfactant (control). For a given type of impression material, contact angles were subjected to 1-way ANOVA within each droplet deposition time for all periods of disinfectant contact (alpha=.05). The Tukey-Kramer post hoc test was applied for pairwise means comparisons. RESULTS: For each impression material type, significant increases in contact angles were found as the duration of disinfectant contact increased, at each measured droplet deposition time point. For both materials containing surfactant, extended contact with chemical disinfectant resulted in increased contact angles that were not significantly different from those of the nonsurfactant-containing control product. CONCLUSIONS: Increasing the contact time between a surfactant-containing impression material and a disinfecting solution can significantly alter the resulting contact angle of the impression material and render it similar to a material depleted of surfactant. Following manufacturer-recommended chemical disinfection times reduces surfactant loss and only minimally affects surface wettability. PMID- 20970541 TI - Lingualized occlusion revisited. AB - Lingualized occlusion represents an established method for the development of functional and esthetic complete denture articulation. Since its introduction, the lingualized technique has undergone many changes. This article provides an overview of the history and development of lingualized occlusion, and addresses common misconceptions associated with the lingualized technique. In addition, a practical method for the development of lingualized denture occlusion is presented. PMID- 20970542 TI - Use of a silicone transfer index to prepare parallel guide planes. PMID- 20970543 TI - Spain's National Health System. Preface. PMID- 20970544 TI - Results of a living donor kidney promotion program. AB - BACKGROUND: Living kidney donor transplantation, a treatment option for end-stage kidney failure, may achieve better results than cadaveric donor transplantation. Although its significant use in some countries is due to the scarcity of cadaveric donors, it is also useful because it reduces waiting time for young recipients and avoids dialysis when performed before starting renal replacement therapy. Due to the high rate of cadaveric donation in Spain, there has only been a limited increase in the number of living donor kidney transplantations. METHODS: In February 2004, we initiated a program to promote living kidney donation (LKD) through an information plan that was transmitted to the patients by dialysis nephrologists and chronic kidney failure outpatient clinics. RESULTS: From February 2004 to March 2010, we evaluated 109 donor and recipient pairs: parent to child (n=48 cases; 44%), spouses (n=32 cases; 29.3%), siblings (n=27; 24.7%), and uncle and nephew (n=2; 1.8%). The mean donor age (49+/-9 years) was significantly higher than the 39+/-13 years of the recipients (P<.01). In 45 cases (41.3%), the procedure led to of living kidney donor transplantation but in 58 (53.2%), a transplantation was not performed due to recipient problems (n=53) or donor problems (n=5). In 6 cases (5.5%), the evaluation is still pending. With the initiation of this project, it has been possible to significantly increase the rate of living kidney donor transplantation in our hospital from 0.8% (March to January 2004: 16/1964) to 4.2% (February 2004 to March 2010: 43/1022 transplants; P<.01). CONCLUSION: A policy of active information together with adequate studies of the potential donor and recipient significantly increased the number of living kidney donor transplantations. The profitability of the study procedure was 50%. The most frequent cause of noncompletion of the procedure was recipient-related problems. PMID- 20970545 TI - One-year follow-up of en bloc renal transplants from pediatric donors in adult recipients. AB - OBJECTIVES: The optimal use of kidneys from small pediatric cadaveric donors remains controversial. The aim of this study was to analyze short-term graft and patient survivals of en bloc kidney transplantations compared with single cadaveric adult donor kidney transplantations. PATIENTS AND METHODS: We compared the 1-year evolution of 14 adult recipients of en bloc pediatric kidney donors (EBKT) of median age 13.5+/-14.5 months (range=3 days to 48 months) with 182 recipients of ideal adult cadaveric donors (ADT) showing a median age of 30+/-21 years (range=14-45 years). RESULTS: Besides the different age and weight of the donors, EBKT recipients were more commonly women (P=.05) and received thymoglobulin induction treatment (P=.00). Delayed graft function was higher in EBKT (46.2% vs 22.2%, P=.05), with no differences in the incidences of acute rejection episodes. Mean serum creatinine values at 3, 6, and 12 months after transplantation were 1.1+/-0.3, 1.1+/-0.2, and 1.0+/-0.2 mg/dL in the EBKT group, compared with 1.3+/-0.5 (P=.16), 1.3+/-0.5 (P=.02), and 1.3+/-0.6 (P<.01) in the ADT group. Vascular allograft complications were more frequent among EBKT. Graft survival rate at 1 year was 92% in both groups, with no differences in patient survival (100% in EBKT vs 92% in ADT; P=.49). CONCLUSIONS: EBKT from small pediatric donors show excellent graft function and 1-year survival and should be considered for transplantation into adults. PMID- 20970546 TI - Renal transplantation in old recipients from expanded criteria donors selected by kidney biopsy. AB - BACKGROUND: In Spain, the number of ideal kidney transplant donors has fallen, with at the same time an increase in the number of older recipients on the waiting list. AIM: To analyze the results of expanded criteria cadaveric donor kidney transplants into older recipients using grafts selected by kidney biopsy. PATIENTS AND METHODS: We studied 360 kidney transplant recipients who had been followed to December 2009: 180 in the study group and 180 in a control group composed of younger patients who received grafts from non-expanded criteria donors between 1999 and 2006. A paraffin-embedded kidney biopsy was evaluated by the percentages of sclerosed glomeruli, arteriolar hyalinosis, intimal wall thickening, interstitial fibrosis, and tubular atrophy. RESULTS: Significant differences were observed in donor age (63.50+/-5.46 vs 31.90+/-13.29 years; P<.001) and recipient age (58.40+/-8.80 vs 40.71+/-13.23 years; P<.001). Donor renal function was significantly worse among the expanded criteria group (90.80 vs 108.11 mL/min/1.73 m2; P=.006), remaining so over time in the recipient (at 1 year: 42.08 vs 63.71 [P<.001]; at 3 years: 41.25 vs 62.31 [P<.001], and at 7 years: 38.17 vs 64.18 [P<.001]). Censored 7-year graft survivals were 73% versus 87% (P<.001) with similar patient survivals (90.5% vs 95%; P=.39). CONCLUSIONS: Selection of expanded criteria donors by kidney biopsy resulted in good renal function as well as graft and patient survivals at 7 years in older recipients. PMID- 20970547 TI - Treatment of acute antibody-mediated rejection: a single-center experience. AB - INTRODUCTION: Acute antibody-mediated rejection (AMR) leads to graft loss. The combination of plasmapheresis (PP), intravenous immunoglobulin (IVIG), and rituximab (RTX) has been reported to be effective therapy. PATIENTS AND METHODS: Between October 2005 and September 2009, 8 (4.7%) kidney transplant recipients developed AMR, diagnosed by severe acute rejection and extensive C4d staining in peritubular capillaries. RESULTS: All patients were treated with two to six sessions of PP with IVIG added after the last PP. In two patients, RTX was prescribed after PP and IVIG. Baseline immunosuppression was based on steroids, mycophenolate mofetil or azathioprine, and tacrolimus or cyclosporine or everolimus. The presence of subsequent significant decrease in anti-HLA class I antibodies was demonstrated in a highly sensitized patient before and after transplantation with PP treatment. An increase was observed before the diagnosis of AMR. After a mean follow-up of 10 months (range=1-23), patient and graft survivals were 100% and 50%, respectively. Three patients lost their transplants to AMR refractory to treatment and one patient, due to interstitial fibrosis and tubular atrophy at 23 months after AMR. Finally, four patients recovered renal function, showing a mean serum creatinine of 2.2+/-0.45 mg/dL. CONCLUSIONS: Early diagnosis and treatment with PP, IVIG, and RTX may resolve AMR. PP before and after transplantation in high-risk patients may result in anti-HLA class I and class II antibody removal from plasma and prevention of AMR. PMID- 20970548 TI - Does the difference in donor and recipient weight influence renal graft survival? AB - INTRODUCTION: Grafts from older donors or those in recipients with a greater body mass index (BMI) as compared with the donor may develop hyperfiltration syndrome that shortens renal graft survival. OBJECTIVES: To assess whether the differences in weight and BMI between donor and recipient correlated with renal function, proteinuria, or graft survival among recipients of grafts from expanded criteria donors. MATERIALS AND METHODS: We undertook a prospective, observational study in 180 recipients of grafts from expanded criteria donors performed between 1999 and 2006. All grafts had been biopsied previously for viability. The recipients underwent immunosuppression with basiliximab, late introduction of tacrolimus, mycophenolate mofetil and steroids. The study population was divided into three groups, depending on the tertile of the donor-to-recipient weight ratio (<1, n=64; 1-1.2, n=56; >1.2, n=60), and the donor-to-recipient BMI ratio (<0.97, n=59; 0.97-1.13, n=60; >1.13, n=60). The glomerular filtration rate was estimated from the modified diet in renal disease (MDRD) equation. RESULTS: The mean age of the donors was 63.54 years and of the recipients, 58.38 years. The proportion of male-to-female donors was 52:48 and recipients 57.8:42.2 (P=NS). No significant differences in overall graft survival were observed between the tertiles. There was a negative correlation between the donor-to-recipient weight ratio and serum creatinine value at 1 (P<.001), 3 (P=.013), and 12 months (P=.005) after transplantation, and a positive correlation with the MDRD at 1 month (P<.001). No relation was noted between weight and proteinuria at 1 (P=.25), 3 (P=.51), or 12 months (P=.90). The results were similar after analyzing the ratio of the BMI to creatinine, MDRD or proteinuria, as well as in cases of a female donor to a male recipient. CONCLUSIONS: Differences in weights between the donor and the recipient did not appear to affect graft survival or proteinuria among patients receiving grafts from expanded criteria donors, though it may be related to renal function during the early posttransplant stages. PMID- 20970549 TI - Influence of interleukin-6 promoter polymorphism -174 g/c on kidney graft outcome. AB - BACKGROUND: The cytokine interleukin-6 (IL-6) is important in both immune responses and cardiovascular diseases. The IL-6 promoter polymorphism -174 G/C is associated with increased plasma concentrations of IL-6. The relationship between IL-6 polymorphisms and graft survival, cardiovascular events, and new-onset diabetes mellitus after kidney transplantation is controversial. OBJECTIVE: To analyze whether IL-6 (-174 G/C) polymorphism influences kidney graft survival or development of chronic allograft nephropathy, cardiovascular events, or new- onset diabetes. METHODS: The IL-6 promoter polymorphism (-174 G/C) was analyzed using the polymerase chain reaction with sequence-specific primers in 335 kidney transplant recipients. Data for graft survival, chronic graft nephropathy, cardiovascular events, and new-onset diabetes were obtained retrospectively from clinical records. Categorical variables were compared between individuals with CC, GG, and GC genotypes using chi2 tests. Survival analysis was performed using the Kaplan-Meier method, comparing groups using the log-rank test. RESULTS: No significant differences were observed in 5-year graft survival between individuals with CC and GC/GG genotypes (85.3% vs 77.1%; P=.22). Nor were significant differences noted in the rates of chronic allograft nephropathy (37.5% vs 33.8%; P=.48), cardiovascular events (10.0% vs 23.0%; P=.10), or new onset diabetes (7.5% vs 11.8%; P=.28). CONCLUSION: There is no association between IL-6 (-174 G/C) polymorphism and graft survival or development of chronic allograft nephropathy, cardiovascular events, or new- onset diabetes. PMID- 20970550 TI - Influence of early graft function after renal transplantation and its impact on long-term graft and patient survival. AB - OBJECTIVE: To determine whether early graft function after transplantation impacted graft and patient survivals. MATERIALS AND METHODS: Between 1981 and 2008, we performed 1308 renal transplantations. Poor early graft function was defined as a Cockroft-Gault glomerular filtration rate<60 mL/min or less at 1 and 3 months posttransplant. Patients who lost their kidney or died within the first 12 months after transplantation were excluded from the study. Multivariate statistical analysis used Cox proportional hazards models. RESULTS: Of the 1308 patients 994 (78.8%) displayed poor early graft function at 1 month after transplantation (glomerular filtration rate<60 mL/min), while 268 (21.2%) showed normal function (glomerular filtration rate>=60 mL/min). The 2- and 6-year graft survival rates among the poor early graft function group were 96.8% and 85.8%, respectively, while those among the control group were 97.0% and 88.3%, respectively. The 2- and 6-year patient survival rates in the poor early graft function were 98.5% and 89.8% versus 98.9% and 96.3% in the control group. Similar results were observed at 3 months posttransplant. Controlling for patient age, donor age, HLA-AB and -DR mismatches, cold ischemia time, acute rejection episodes, cyclosporine therapy, and waiting time for transplantation, we did not observe early graft function to be a risk factor for graft survival or patient survival. Glomerular filtration rate at 2, 5, and 6 years after kidney transplantation was significantly lower in the poor early graft function than in the control group. CONCLUSION: This study suggested that the quality of early graft function had no significant effect on graft and patient survival rate, but did have a significant influence on long-term renal function. PMID- 20970551 TI - Late conversion to mammalian target of rapamycin inhibitor/proliferation signal inhibitors in kidney transplant patients: clinical experience in the last 5 years. AB - INTRODUCTION: Treatment with proliferation signal inhibitors (PSIs; sirolimus/everolimus) is a therapeutic option for renal transplant recipients, especially those who develop chronic graft nephropathy (CGN) or a neoplasm. We sought to analyze the efficacy and safety of conversion to PSIs. MATERIAL AND METHODS: We undertook a retrospective study of 77 patients converted between January 2005 and October 2009 to PSIs: 53 sirolimus and 24 everolimus. The causes for conversion were 63% tumors, 30% for chronic graft nephropathy (CGN), and 7% for other reasons. Mean time from transplant to conversion was 8 years. Patients were followed for a mean of 18 months (range, 1-61). RESULTS: A significant 14% improvement in renal function was observed at 1 year after conversion: baseline Modification of Diet in Renal Disease (MDRD) 45+/-20 versus 51+/-20.1 mL/min/1.73 m2 (P=.03). The benefit was greater among patients converted for CGN: baseline MDRD 31.5+/-8.8 versus 40.9+/-13.1 mL/min/1.73 m2 (P=.02), a 30% increase. The side effects experienced by 40% of patients included: 12% diarrhea, 15% edema, 20% buccal aphthae, 10% pneumonitis, and 20% skin alterations. PSIs were withdrawn in 25% of patients: 13% for side effects, 2.5% for patient death, and 3.8% for graft loss. We observed increases in serum lipids and proteinuria with a mild decrease in hemoglobin. CONCLUSION: Conversion to PSIs is a safe, useful therapeutic option for carefully selected patients, when renal function has not undergone marked deterioration and there is no proteinuria. Although side effects are common, most are mild; withdrawal of PSIs was necessary in a relatively low percentage of cases. PMID- 20970552 TI - Quantitative assessment of serum free light chains in renal transplantation. AB - Plasma cell dyscrasias can cause renal disease. Sensitive methods have recently been introduced to quantify serum free light chains (sFLCs). Renal function may influence the variability of these methods, as shown in chronic kidney disease (CKD) patients, but this problem has not been widely addressed in renal transplant patients. Herein, we examined the association between polyclonal sFLC concentrations and renal function among a population of renal transplant patients. We studied 102 kidney allograft recipients and 53 CKD patients classified according to KDOQI (Kidney Disease Outcomes Quality Initiative) stages. None of them had been diagnosed with monoclonal gammopathy. sFLCs were quantified by nephelometry. Both serum kappa and lambda free light chain concentrations rose progressively through each stage of KDOQI among both transplant and nontransplant patients (P<.0001). In the former setting, sFLC concentrations significantly correlated, using a Spearman coefficient, with serum creatinine, and serum cystatin concentrations as well as estimated glomerular filtration rate: namely, 0.723, 0.797, and -0.711 for skappaFLC and 0.705, 0.759, and -0.694 for slambdaFLC, respectively (P<.0001 in all cases). Spearman correlation coefficients in nontransplant patients were: 0.559, 0.848, and -0.766 for skappaFLC and 0.702, 0.875, and -0.855 for slambdaFLC, respectively (P<.0001 in all cases). In conclusion, sFLCs must be interpreted cautiously due to their clear association with renal function. Therefore, renal transplantation did not produce changes that were different from those dependent on renal function. PMID- 20970553 TI - Toward personalized medicine in renal transplantation. AB - BACKGROUND: The pharmacokinetics of tacrolimus (TRL) are clearly affected by genetic polymorphisms in drug-metabolizing enzymes, which lead to large interindividual differences in dose-response relations. In addition, TRL has a narrow therapeutic index requiring monitoring of blood levels. The objective of the present observational, retrospective study was to associate maintenance TRL doses with various genetic markers seeking to guide optimization of the initial dose. METHODS: Results of DNA samples from 15 kidney transplant patients were correlated retrospectively with clinical information from medical records. Samples were genotyped using PHARMAchip. Association studies were performed with chi2 and Pearson tests and by analysis of variance. The study was carried out in accordance with international ethical standards of the Helsinki Declaration and approved by our ethics committee. RESULTS: Two patient groups were identified to show a difference in TRL dose requirements: a control (0.014-0.10 mg/kg/per day) and an high-dose group (0.14-0.15 mg/kg/per day). The presence of CYP3A5*1 and the null allele in GSTM1 were significantly associated (P=.01 and P=.04) with the need for higher immunosuppressive doses (>0.10 mg/kg/per day). There were no differences in plasma levels of TRL or other clinical variables between the patient groups. CONCLUSION: Determination of the CYP3A5 genotype might be used to predict initial TRL requirements, although other genetic variants also provide important information to adjust the drug dose. PMID- 20970554 TI - Ambulatory blood pressure monitoring in renal transplant patients: should it be routinely performed? AB - INTRODUCTION: Arterial hypertension is common among kidney transplant patients. It increases cardiovascular risk and is a factor for progression of renal failure. Our objective was to perform ambulatory blood pressure monitoring (ABPM) in renal transplant patients with office hypertension. METHODS: Patients were divided into 2 groups according to their mean ABPM blood pressures with treatment: well-controlled hypertension (blood pressure [BP] <130/85 mmHg), and poorly controlled hypertension (BP>130/85 mmHg). A "nondipper pattern" was defined as a decrease of <10% or an increase, and a "raiser pattern," in which mean blood pressure was greater during the nocturnal than the diurnal period. "White coat effect" was considered when the mean of 3 BP measurements in the clinic was >140/90 mmHg among well-controlled hypertensive patients as documented by ABPM. RESULTS: ABPM was performed in 53 patients: 25 (47%) "well-controlled hypertensives" and 28 (53%) "poorly controlled hypertensives." Of the latter, 24 (85%) showed a nondipper or raiser pattern with only 4 revealing dipper patterns. We compared well-controlled with poorly controlled hypertensives. The latter cohort were older (54.4+/-9.3 vs 45.5+/-13.8 years; P=.009), received grafts from older donors (56.7+/-15.0 vs 45.8+/-17 years; P=.02); had worse renal function measured by serum creatinine (1.7+/-0.5 vs 1.4+/-0.4 mg/dL, P=.03) or the Modification of Diet in Renal Disease (MDRD)=4 formula (41.8+/-14.0 vs 55.4+/ 20.5 mL/min/1.73 m2; P=.009), and displayed more proteinuria (0.30+/-0.33 vs 0.18+/-0.10 g/d, P=.08). Nondipper or raiser patients showed a higher mean body mass index (27.1 vs 21.7 kg/m2; P=.04). Among 25 well-controlled patients, 11 presented "white coat phenomenon." CONCLUSION: We observed an important "white coat" effect, a large prevalence of uncontrolled nocturnal hypertension, and a small but important incident of "masked hypertension." Factors related to hypertension control were patient age, donor age, renal function, induction use, and proteinuria. PMID- 20970555 TI - Number of peripheral blood regulatory T cells and lymphocyte activation at 3 months after conversion to mTOR inhibitor therapy. AB - BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors are effective for induction and maintenance of regulatory T cells (Tregs). OBJECTIVE: To assess the effects of conversion from calcineurin inhibitors (CNIs) to mTOR on the number of circulating Tregs and lymphocyte activation. PATIENTS AND METHODS: In 18 renal transplant recipients receiving CNI therapy (cyclosporine in 9, and tacrolimus in 9), treatment was converted to mTOR inhibitors (everolimus in 14, and rapamycin in 4). Peripheral blood samples were obtained before and 3 months after conversion. The number of circulating Tregs was measured using flow cytometry, and defined as CD4+/CD25high/CD127low/CD27+/CD62L+/CD45RO+/Foxp3+. Lymphocyte activation was assessed indirectly according to production of intracellular adenosine triphosphate (iATP) on polyclonal activation using a phytohemaglutinin assay (Immuknow; Cylex, Inc, Columbia, Maryland). RESULTS: In 15 patients (83.3%), the absolute number of Tregs increased significantly (P=.001) after conversion (median, 16.35 cells/mm3; 95% confidence interval [CI], 13.97-21.94) vs 3 months after conversion (32.03 cells/mm3; 95% CI, 26.25-41.66). The iATP production decreased from 326 ng/mL (95% CI, 302-419) to 248 ng/mL (95% CI, 196 318; P=.02), and increased in 4 patients (22.22%). No significant correlation was demonstrated between Treg concentration and change in iATP production. No rejection episodes were reported during follow-up. CONCLUSIONS: Despite the small number of patients in whom therapy was converted from CNI inhibitors to mTOR inhibitors, the data suggest an increase in the absolute number of Tregs after conversion. In addition, the concentration of activated peripheral CD4+ T cells decreased to nearly that associated with risk of infection due to overimmunosuppression. PMID- 20970556 TI - De novo anti-HLA antibodies in renal allograft recipients: a cross-section study. AB - BACKGROUND: The occurrence of anti-HLA antibodies plays a well established role in solid organ rejection. The development of x-MAP multiple bead technology (Luminex) has enabled more accurate detection and definition of these alloantibodies. METHODS: In 267 kidney transplant patients with stable allograft function for >=3 years, we analyzed the presence of anti-HLA antibodies by Luminex technology. These patients had no alloantibodies before transplantation, and the immunosuppression treatment was: tacrolimus, cyclosporine, mycophenolate mofetil, prednisone, everolimus, and/or sirolimus. RESULTS: Fifteen of the 267 patients showed anti-HLA class I antibodies and 12 showed anti-HLA class II antibodies, Seven patients had donor-specific antibodies (DSA): 1 anti-HLA class I, 5 anti-HLA class II, and 1 with both classes. No differences were found between DSA and the use or not of any specific therapy. However, in the retrospective review, we found a higher incidence of acute rejection episodes in the immediate posttransplant period among patients who developed class II DSA than those without DSA. CONCLUSIONS: The prevalence of patients with normal renal function who develop DSA beyond 3 years after transplantation was relatively low. Steroid or withdrawal replacement of calcineurin inhibitors with inhibitors of mammalian target of rapamycin seem to not be risk factors to increase the development of DSA. The finding that patients who developed DSA showed a higher rate of previous acute rejection episodes suggested that they should be monitored more frequently for HLA antibodies. PMID- 20970557 TI - Kidney transplant recipients show an increase in the ratio of T-cell effector memory/central memory as compared to nontransplant recipients on the waiting list. AB - Studies of allotolerance in animal models do not usually consider the presence of preexisting memory T cells and activated immune status. However, humans are exposed throughout life to a multitude of external agents that enhance the immune memory. In this article, we consider the effect that a previous kidney transplant has on the number of regulatory T cells (Tregs), effector memory T cells (TEM), and central memory T cells (TCM). Sixty-three patients with end-stage renal disease were studied just before being transplanted (51 first transplants and 12 retransplants). The numbers of Tregs (CD4+ CD25highCD127lowCD27+CD62L+CD45RO+FOXP3+), TEM (CD3+CD45RO+CD62L+), and TCM (CD3+CD45RO+CD62L-) cell subsets were quantified in peripheral blood by flow cytometry. The absolute number of Tregs was slightly lower in patients with previous allografts (median, 95% confidence interval [CI]: 16.7 cells/mm3, 12 20.5) than in those who received their first transplants (median, 95% CI: 19.6 cells/mm3, 19.3-29.6; P-NS). Clearer differences were found with the number of CD3+ TCM, since the transplanted patients had lower numbers (238 cells/mm3, 153 323) than those who had not yet received transplants (378 cells/mm3, 317-439; P=.029). As a result, the TEM/TCM ratios of both CD4+ and CD8+ T cells in patients with previous allografts were higher than in those who received first transplants. In conclusion, the assessment of just the number of Tregs in renal transplant patients is not enough and must be read together with the number of TEM and TCM. The TEM:TCM ratio increases in patients with previous allografts, probably due to activation of the immune response in renal transplantation. PMID- 20970558 TI - Creatinine clearance and proteinuria as early markers of kidney graft survival. AB - INTRODUCTION: In patients who receive a kidney transplant from expanded criteria donors (ECDs), few studies are available concerning the relation between the clinical characteristics, pretransplant biopsies, and graft outcomes. AIM: To identify early clinical markers predicting worse graft survival in recipients of kidneys from ECDs. MATERIALS AND METHODS: Between 1999 and 2006, we performed a prospective, observational study in 180 recipients of kidney grafts from ECDs that had undergone a preoperative biopsy to evaluate viability. The patients received immunosuppression with basiliximab, late introduction of tacrolimus, mycophenolate mofetil, and steroids. Data were gathered on demographic and posttransplantation clinical characteristics at 1, 3, 6, and 9 months, including estimates of proteinuria and of the glomerular filtration rate using the Modification of Diet in Renal Disease (MDRD) formula. RESULTS: The mean age of the donors was 63.54 years and of the recipients, 58.38 years. A creatinine clearance below the median (40 mL/min, interquartile range 32-50 mL/min) in the first posttransplant year was significantly associated with worse death-censored graft survival (log-rank 14.22, P<.0001). A proteinuria value above the median (100 mg/24 h, interquartile range 40-275 mg/24 h) at 1 year posttransplant significantly reduced the death-censored graft survival (log-rank 14.3, P<.0001). Multivariate Cox analysis showed that a creatinine clearance<40 mL/min in the first year (hazards ratio [HR] 5.7, 95% Confidence Interval [CI] 1.62-20.37; P=.007) and proteinuria at 1 year greater tan 100 mg/24 h (HR 8.3, 95% CI 2.15 32.06; P=.002) were independent risk factors for death-censored graft loss after adjusting for donor age and acute rejection episodes. CONCLUSIONS: Limited renal function and/or low proteinuria at 1 year posttransplant were associated with worse kidney graft survival among recipients of kidneys from ECDS. PMID- 20970559 TI - Renin-angiotensin system dual blockade using angiotensin receptor plus aliskiren decreases severe proteinuria in kidney transplant recipients. AB - BACKGROUND: Renin-angiotensin system (RAS) blockade has cardioprotective and renoprotective effects in the general population; however, whether dual blockade using angiotensin-receptor blockade (ARB) plus a renin inhibitor, aliskiren, can minimize severe proteinuria in kidney transplant recipients remains undetermined. OBJECTIVE: To analyze the efficacy and safety of dual blockade of the RAS with an ARB and aliskiren in kidney transplant recipients with severe proteinuria and creatinine concentration 2.5 mg/dL or less. PATIENTS AND METHODS: This prospective study included 16 patients (mean age 56 years; 10 men [62%] who had undergone cadaveric renal transplantation between 1992 and 2004. Immunosuppression therapy included a calcineurin inhibitor in 9 patients (56%) or mammalian target of rapamycin inhibitor in 7 (44%), and mycophenolate mofetil in 15 (94%). All received high-dose ARB II (1.0-3.5 g/24 h) because of marked proteinuria, with poor response. Accordingly, 11 patients also received aliskiren, and in 5 who were receiving an angiotensin-converting enzyme inhibitor, therapy was changed to aliskiren. Mean (range) follow-up was 11 (3-18) months. RESULTS: At 3 months, proteinuria decreased by 40%, and at 6 months by 60%. In addition, mean blood pressure was decreased significantly. Renal function remained stable, as did the serum potassium concentration. A slight but significant decrease in hemoglobin concentration was observed, with no clinical repercussions. CONCLUSIONS: Dual blockade of the RAS with ARB II plus aliskiren therapy demonstrated an additive effect to decrease severe proteinuria and blood pressure in kidney transplant recipients. Neither relevant adverse effects in renal function nor anemia or hyperkalemia were observed. These findings might contribute to prolonging long-term kidney graft survival. PMID- 20970560 TI - Analysis of urinary gene expression of epithelial-mesenchymal transition markers in kidney transplant recipients. AB - INTRODUCTION: Renal graft dysfunction due to acute rejection, acute tubular necrosis, or anticalcineurin toxicity with development of interstitial fibrosis or tubular atrophy are the primary causes of graft failure. Determination of kidney function using the serum creatinine concentration demonstrates low sensitivity as a marker for the diagnosis, and kidney biopsy is an invasive procedure. The levels of urinary messenger RNA of genes that regulate epithelial mesenchymal transition (EMT) can reflect early kidney damage. Thus, repeated transcriptome studies of these genes can provide information about the evolution of the graft, and possibly enable early diagnosis and treatment. OBJECTIVE: To analyze the temporal relationships between early graft evolution and gene expression of EMT biomarkers. METHODS: Of 70 kidney transplant procedures performed between January 1, 2007 and December 31, 2008, 42 were analyzed prospectively for 3 months. Analytical and clinical data were recorded, as well as histologic findings if available. Urine mRNA extraction was performed using a commercially available kit. RNA gene expression of EMT, angiotensinogen, epidermal growth factor receptor, E-cadherin, N-cadherin, transforming growth factor-beta, and bone morphogenetic protein 7 was determined at real-time quantitative polymerase chain reaction. beta2-Microglobulin was used as a reference gene. RESULTS: At 75 days posttransplantation, analysis revealed that angiotensinogen (mean [SD], 2.91 [0.70] vs 6.04 [1.24]; P=.04) and N-cadherin (1.01 [0.43] vs 4.31 [0.92]; P=.01) discriminate good evolution from acute rejection. Epidermal growth factor receptor (2.78 [0.66] vs 6.02 [1.09]; P=.33) and bone morphogenetic protein 7 (0.85 [0.33] vs 3.07 [1.37]; P=.04) discriminate good evolution vs delayed graft function. CONCLUSION: Differential gene expression at 75 days posttransplantation reflects differences related to initial histologic damage. This observation encourages design of a long-term longitudinal analysis with multiple markers to obtain early diagnosis and forecast the prognosis of graft dysfunction. PMID- 20970561 TI - Does JC polyomavirus cause nephropathy in renal transplant patients? AB - INTRODUCTION: BK polyomavirus (BKV) reactivation characterized by active viruria occurs in 23%-57% of renal allograft recipients and BKV-associated nephropathy in as many as 8% of renal allograft recipients. Only a few cases of nephritis have been attributed to JC polyomavirus (JCV) with limited information about JCV replication and its impact on graft function and survival of kidney transplant patients. We sought to determine the prevalence of BKV and JCV replication, the risk factors associated with viral reactivation, and their implications for the development of polyomavirus nephropathy (PVN) among renal transplant patients. MATERIALS AND METHODS: The study included 186 kidney transplant recipients who were transplanted between 2005 and 2009 with a 1-year follow-up. If the urine polymerase chain reaction (PCR) was positive, we performed a PCR on blood. If this was positive or renal dysfunction was present, we performed a renal biopsy. RESULTS: Viruria was positive in 72 cases (39%) and viremia in 12 (6.5%); including, 3 patients (1.6%) who developed PVN. In the patients with viruria, BKV was detected in 47% and JCV in 46%; both were detected in 7%, although the combination of viremia and nephropathy were caused by BKV in all cases. CONCLUSION: In renal transplant patients, the incidence of BKV and JCV viruria was similar, although in our series the JCV serotype did not cause viremia or PVN. Our experience suggested that JCV did not have the ability to cause PVN. PMID- 20970562 TI - Deflux injections for vesicoureteral reflux in transplanted kidneys. AB - INTRODUCTION: Vesicoureteral reflux (VUR), a complication after kidney transplantation, may be caused by recurrent urinary tract infections evaluating in life-threatening pyelonephritis and urosepsis. Open surgical correction is the standard treatment despite its morbidity. However, minimally invasive approaches are available. MATERIALS AND METHODS: Our study group describes seven patients with functioning kidney grafts and a diagnosis of VUR associated with recurrent urinary tract infections. The procedure was performed under antibiotic prophylaxis and spinal anesthesia. An endoscopic injection of 1 mL of biomaterial (copolymer of dextranomer and hyalurunic acid) was administered into the ureteral neo-orifice following the Sting technique. The catheter was removed within 24 hours in all cases. RESULTS: Between June 2009 and January 2010, nine procedures were performed in seven patients. Two patients experienced self-limiting post surgical episodes of hematuria that did not need urologic manipulation. There were no episodes of retention, ureteral obstruction, or urinary infections. One patient required a reinjection 5 months later as a result of clinical failure. Apart from this one case, the other patients showed improvements with no infectious complications. CONCLUSIONS: Endoscopic correction with VUR seems to be a reliable and safe option as a first treatment for the transplant patient. More cases are required in order to improve the learning curve and, therefore, the success rate. Closer monitoring is needed to evaluate the efficiency of the copolymer, the evolution of the reflux, and the possible long-term complications in this sort of patients. PMID- 20970563 TI - Posttransplant inflammation associated with onset of chronic kidney disease. AB - BACKGROUND: Chronic allograft nephropathy (CAN), a major complication in renal transplant patients, is an important cause of graft loss. Inflammation as measured in the pretransplant and posttransplant phases, using various markers, has been associated with worse renal function and a greater risk of cardiovascular disease and of long-term graft loss. OBJECTIVE: The objective of our study was to evaluate whether worsening inflammation in the first 3 months postoperatively was a risk factor for developing CAN. PATIENTS AND METHODS: We performed a cross-sectional study in 207 patients. The following markers of inflammation (MIF) were determined pretransplant and at 3 months after grafting: C-reactive protein (CRP) (mg/L), interleukin (IL)-6 (pg/mL), IL-10 (pg/mL), tumor necrosis factor (TNF)-alpha (pg/mL), and its soluble receptor (ng/mL), soluble IL2R (UI/mL), pregnancy-associated plasma protein A (PAPP-A; mUI/L), and IL-4 (pg/mL). We also calculated the ratio at 3 months versus the pre value of MIF. RESULTS: CAN was diagnosed after the first year in 23 patients (11.3%) always by renal biopsy performed for clinical indications. Patients with CAN showed worse inflammation, eg, MIF ratios over one, with statistically significant differences for the ratios of TNF-alpha and PAPP-A (P=.032 and P=.051 respectively). Upon multivariate logistic regression analysis, using CAN as the dependent variable and age, sex, donor age, months on dialysis, acute tubular necrosis, acute rejection, and MIF ratios as covariates, we observed that an acute rejection episode (OR=13.03; CI=2.8-60.9; P=.001), CRP ratio (OR=1.36; CI=1.07-1.73; P=.013), and PAPP-A ratio (OR=1.80; CI=0.92-3.53; P=.005) were independent markers of CAN. CONCLUSIONS: Among other factors, inflammation may determine the onset of CAN as diagnosed by renal biopsy. PMID- 20970564 TI - Addition of spironolactone to dual blockade of renin angiotensin system dramatically reduces severe proteinuria in renal transplant patients: an uncontrolled pilot study at 6 months. AB - Experimental and clinical data strongly suggest that aldosterone may contribute to proteinuria and progressive renal disease. In fact, an aldosterone antagonist seems to be effective for controlling proteinuria in native kidneys. However, there is little information about this approach in renal transplant patients, a population in whom the presence and amount of proteinuria represent risk factors for graft loss, cardiovascular disease, and death. The aim of our study was to evaluate whether addition of an aldosterone antagonist, spironolactone, provided an additional antiproteinuric effect to the angiotensin-converting enzyme inhibitor (ACEI) and angiotensin type I receptor antagonists (ARB). We evaluated the effects on severe proteinuria (4.4+/-1.4 g/d) at 6 months after prescription of spironolactone (25 mg/d) among 11 renal transplant patients with serum creatinine values less than 3 mg/dL who were under treatment with an ACEI plus an ARB. Patients were examined in the renal transplant outpatient clinic every week for the first month and twice a month thereafter. Nine patients showed a more than 50% (mean=81.5%) reduction in proteinuria not only early, but also sustained at 6 months (4.4+/-1.4 to 2.3+/-1.1 g/d) with a mild, nonsignificant deterioration in renal function (serum creatinine 1.6+/-0.32 to 1.7+/-0.54 mg/dL). This study showed that spironolactone decreased severe proteinuria among patients treated with an ACEI plus an ARB. This therapy is not recommended for patients with glomerular filtration rates below 40 mL/min. Therefore, it is suggested that using triple blockade of RAS is feasible in selected renal transplant patients to reduce proteinuria, although caution is required to avoid severe hyperkalemia. PMID- 20970565 TI - Incidence and risk factors for the metabolic syndrome and posttransplant diabetes in renal transplant recipients taking tacrolimus. AB - OBJECTIVES: We investigated the incidence and risk factors for the metabolic syndrome (MS) and posttransplant diabetes mellitus (PTDM) among renal transplant recipients on tacrolimus-based immunosuppressive regimens during the first year posttransplant. In addition, we studied the relationship between MS and PTDM with transplant renal function at 1 year. METHODS: We included the 100 patients who received a renal transplant in our unit between January 2007 and June 2008, collecting demographic, clinical and biochemical characteristics at 1, 6, and 12 months posttransplantation. We excluded 15% of patients with pretransplantation diabetes. MS was defined according to the National Cholesterol Education Program criteria and PTDM according to World Health Organization criteria. Insulin resistance at one year posttransplant was measured using the homeostasis model assessment (HOMA) index. RESULTS: Insulin therapy was required in 46% of patients during the first hospitalization and hyperglycemia was present in 65% of the cases. The incidence of PTDM decreased throughout the first year posttransplant, namely, 44%, 24%, and 13% at 1, 6, and 12 months, respectively. The incidence of MS increased to 33%, 48% and 50% at 1, 6, and 12 months, respectively. Age, body mass index, plasma fasting glucose levels at 1 month posttransplant, and pretransplant fasting triglyceridemia predicted PTDM. Rejection and in-patient hyperglycemia predicted MS. PTDM and MS were closely correlated (P=.004). The HOMA index was higher among patients with MS than other subjects at 1 year posttransplant: 3.2 (1.2) versus 2.3 (0.9; P=.035). Neither PTDM nor MS was associated with impaired plasma creatinine levels at 1 year after kidney transplantation. CONCLUSION: There was an high incidence of PTDM and MS among kidney transplant recipients treated with tacrolimus as the main immunosuppressive agent. The HOMA index was a good test of insulin resistance in this population. Screening and treatment of risk factors may avoid the development of these entities, which are related to poor cardiovascular outcomes. PMID- 20970566 TI - Inflammation, metalloproteinases, and growth factors in the development of carotid atherosclerosis in renal transplant patients. AB - BACKGROUND: Cardiovascular disease is the leading cause of death in renal transplant (RT) patients. Both traditional and emerging risk factors, some of which are controversial, have been described in the pathogenesis of cardiovascular disease. Carotid ultrasound (CUS) is considered to be an excellent diagnostic tool for subclinical atherosclerosis. OBJECTIVE: To evaluate the relationship between biomarkers of inflammation, growth factors, metalloproteinases, and the development of subclinical atherosclerosis diagnosed by using CUS. METHODS: We studied 93 RT patients (aged 54+/-12 years; 67.9% men; 13.5% with pre-RT diabetes mellitus). The following biomarkers were determined in the patients' blood hours before RT: C-reactive protein (CRP) and serum amyloid A using nephelometry; interleukin (IL) 2, 6, 8, and 10 and soluble IL-2 receptor, tumor necrosis factor (TNF) alpha, vascular endothelial growth factor (VEGF), epidermal growth factor, and monocyte chemotactic peptide using chemoluminescence; and pregnancy-associated plasma protein (PAPP)A using ELISA. A CUS was carried out during the first month after RT. RESULTS: Carotid intima media thickness (IMT) was elevated in 51% of the patients, and 50.5% of the patients had atherosclerotic plaque. Both plaque (P=.004) and IMT (P=.001) correlated with age, and the increase of IMT was progressive, on both the left and the right side. Pre-RT CRP, IL-8, TNF-alpha, VEGF, MCP-1, and PAPP-A were significantly more elevated in patients with plaque. In the multivariate analysis adjusted for clinical variables, age (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.10; P=.04), CRP (OR, 7.5; 95% CI, 2.05-27.3; P=.002), IL-8 (OR, 4.73; 95% CI, 1.27-17.6; P=.02), and PAPP-A (OR, 4.45; 95% CI, 1.22-16.2; P=.023) were independent markers of the presence of plaque. CONCLUSIONS: Age, CRP, IL-8, and PAPP-A, and not growth factors, are markers of carotid atheromatous plaque in RT patients. PMID- 20970567 TI - Risk of cardiovascular disease associated with refractory hypertension in renal transplant recipients. AB - BACKGROUND: Hypertension is common after renal transplantation, affecting as many as 80% of recipients. It is generally accepted that hypertension is associated with poor graft survival and reduced life expectancy because of increased cardiovascular risk factors. The prevalence of refractory hypertension in renal transplant recipients is unknown, and could be associated with a poor prognosis. OBJECTIVE: To investigate the effects of refractory hypertension on cardiovascular disease (CVD) after renal transplantation in 486 patients with grafts functioning for longer than 1 year. PATIENTS AND METHODS: Patients were classified into 2 groups: (1) 57 with refractory hypertension, that is, systolic blood pressure 130 mm Hg or greater or diastolic blood pressure 80 mm Hg or greater, and receiving treatment with at least 3 drugs, one of which was a diuretic; and (2) the remaining 429 patients. Patient and graft survival, and posttransplantation CVD were analyzed. RESULTS: Refractory hypertension was associated with male sex (82.5% vs 66.5% [P<.01]), poor renal function (mean [SD] serum creatinine concentration 2.2 [1.2] mg/dL vs 1.6 [0.6] mg/dL; Modification of Diet in Renal Disease score 39.2 [20.0] mL/min/1.73 m2 vs 49.2 [18.0] mL/min/1.73 m2 [P=.000]; and steroid therapy (94.7% vs 79.0% [P=.001]). In the group with refractory hypertension, 5-year patient and graft survival rates were lower, and the incidence of posttransplantation CVD was greater (relative risk, 1.7; 95% confidence interval, 1.05-2.18; P=.03). CONCLUSION: Refractory hypertension is an independent risk factor for increased cardiovascular morbidity and mortality in renal transplant recipients. PMID- 20970568 TI - Magnesemia in renal transplant recipients: relation with immunosuppression and posttransplant diabetes. AB - Hypomagnesemia, a frequent disorder in renal transplant patients related to the use of calcineurin inhibitors (CNIs), plays a causal role in insulin resistance and type 2 diabetes. Recently, hypomagnesemia has been identified as an independent predictor of new-onset diabetes after transplant (NODAT). The objective of this study was to investigate the influence of various immunosuppressive regimens on magnesemia in relation to the development of NODAT. We performed a retrospective study in 589 nondiabetic subjects who underwent serum magnesium measurements (mg/dL) on days 7 and 15 as well as at 1, 2, 3, 6, 9, and 12 months after transplantation. NODAT was diagnosed during the first year using American Diabetes Association criteria. The overall mean magnesemia was lower among CNI compared with non-CNI patients (1.73+/-0.25 vs 1.98+/-0.23; P=.000) and in patients on tacrolimus versus cyclosporine (1.72+/-0.24 vs 1.80+/ 0.26; P=.007). It was higher in patients who received anti-CD25 antibodies with delayed CNI introduction (1.83+/-0.28 vs 1.71+/-0.23; P=.000). The use of CNIs and delayed CNI introduction were identified as independent factors related to magnesemia. No differences in magnesemia were observed among patients who developed NODAT versus the non-NODAT cohort. The incidence of NODAT was higher among patients on tacrolimus versus cyclosporine (26.8% vs 18.1%; P=.026), but no differences were found between the serum Mg tertiles at any time during the study or between mean magenesemia tertiles. In conclusion, despite the fact that CNI patients showed lower magnesemia and the group of tacrolimus, the lowest magnesemia and the highest incidence of NODAT, our study did not demonstrate a relationship between the Mg levels and the occurrence of NODAT. Patients treated with anti-CD25 antibodies and delayed CNI introduction maintained higher magnesemia during the first year after transplant. PMID- 20970569 TI - Elevated serum gamma-glutamyltransferase and hypomagnesemia are not related with new-onset diabetes after transplantation. AB - BACKGROUND: New-onset diabetes mellitus after transplantation (NODAT) contributes to the risk of cardiovascular disease (CVD) and infection, reducing graft and patient survival in kidney transplant recipients. To reduce CVD and improve outcomes of kidney transplant recipients, it is of great interest to more precisely elucidate the risk factors that contribute to the development of NODAT. A previous study reported that hypomagnesemia is an independent predictor of NODAT. Elevated gamma-glutamyltransferase (GGT) activity increases the risk of incident type 2 diabetes in the general population. The objective of this study was to determine whether magnesium (Mg) and GGT were risk factors for NODAT among our population of kidney transplant recipients. METHODS: We retrospectively analyzed 205 non-previously diabetic kidney transplant recipients. GGT was measured before transplantation as well as at months 1, 2, and 12. Mg was measured at months 1, 2, and 12. NODAT was defined at month 12 and at the end of follow-up according to the "2003 international consensus guidelines." RESULTS: Although 36 patients (17.5%) developed NODAT at month 12, 55 patients (26.8%) displayed it at the end of follow-up. We did not observe any significant difference, either in mean Mg (month 1, 1.73+/-0.24 vs 1.75+/-0.30 [P=.824]; month 2, 1.71+/-0.22 vs 1.68+/-0.26 [P=.565]; month 12, 1.77+/-0.27 vs 1.80+/ 0.24 [P=.596]) or GGT values (pretransplantation, 32 +/- 27 vs 33+/-85 [P=.866]; month 1:39+/-24 vs 48+/-70 [P=.452]; month 2, 53+/-96 vs 48+/-83 [P=.739]; month 12, 40+/-37 vs 38+/-53 [P=.830]) between NODAT and non-NODAT patients at month 12 or at the end of follow-up. CONCLUSION: Hypomagnesemia and high GGT activity were not risk factors for NODAT development in kidney transplant recipients. PMID- 20970570 TI - Vitamin D deficiency in a renal transplant population: safe repletion with moderate doses of calcidiol. AB - BACKGROUND: Deficits of vitamin D are a common finding in the general population, especially among patients with chronic kidney disease. However, there are not much data about its prevalence after renal transplantation. Our aim was to analyze the calcidiol status among a cohort of kidney transplant recipients, in a region of Spain with a high number of annual sunshine hours, as well as the effects of supplementation with oral calcidiol. PATIENTS AND METHODS: We included 110 kidney transplant recipients in a retrospective observational study. Measurements of 25-hydroxyvitamin D (25OHD), calcium, phosphate, intact parathyroid hormone (iPTH), serum creatinine and albumin, 24-hour microalbuminuria, and proteinuria were performed at the same time. Patients were classified based on their serum 25OHD levels: normal (>30 ng/mL); insufficiency (16-30 ng/mL); and deficiency (<16 ng/mL). In a second analysis, we included 63 patients with 25OHD<30 ng/mL with adjusted calcium levels below 10.2 mg/dL for treatment with oral calcidiol to approach target levels of 30 to 40 ng/mL. Mineral metabolism parameters were monitored at baseline as well as 6 and 12 months after beginning treatment. RESULTS: Insufficient or deficient 25OHD levels were present in 106/110 patients (96.3%); they were normal in just four patients (3.6%). Patients with calcidiol deficiency were older. We observed no differences in sex, posttransplant follow up, serum calcium, phosphate, iPTH, glomerular filtration rate, or 24- hour albuminuria or proteinuria. The 63 patients treated with oral calcidiol received a mean dose of 8044+/-4087 IU/wk at baseline. The 61.3% of them with deficient 25OHD levels at baseline decreased to 2.1% at 6 months and 7.5% at 12 months after treatment. No significant changes in calcium, phosphate or iPTH were observed during the treatment. CONCLUSIONS: Deficits of 25 OHD was frequent after renal transplantation but improved safely with moderate doses of oral calcidiol without negative secondary effects. PMID- 20970571 TI - Cholecalciferol supplements improve vitamin D deficiency in renal transplant recipients. AB - Most renal transplant recipients display vitamin D deficiency or insufficiency. The KDIGO guidelines suggest that this deficit should be treated as in the general population. Since there are few studies about the effects of cholecalciferol in de novo renal transplant recipients, we sought to assess these effects in long-term kidney graft recipients. Among 37 renal transplant recipients (19 males, 18 females) at a mean of 105+/-82 months posttransplantation, vitamin D insufficiency or deficiency was treated with cholecalciferol (400-800 IU/d) plus calcium supplements (600-1200 mg/d of elemental calcium). These subjects were compared with 37 untreated recipients for a period between 6 and 12 months. At baseline, there were no differences between the groups in age at transplantation, sex, length of follow-up after grafting, function measured by estimated glomerular filtration rate (44.4+/-16.8 treated vs 42.0+/-15.0 mL/min/1.73 m2 untreated; P=.527); iPTH (157+/-103 treated vs 176+/ 118 pg/mL untreated; P=.461); 25OHD (14.7+/-4.7 treated vs 15.7+/-9.7 ng/mL untreated; P=.584); or 1.25OHD (34.1+/-26.0 treated vs 34.0+/-13.0 pg/mL untreated; P=.950). When compared with baseline values, iPTH (157+/-103 vs 144+/ 89 pg/mL; P=.11) and 1.25OHD levels at 6 months (34.1+/-26.0 vs 35.9+/-26.3 pg/mL; P=.282) showed no change but 25OHD levels (14.7+/-4.7 vs 22.6+/-7.4 ng/mL; P=.000) and phosphate tubular reabsorption (64%+/-17% baseline vs 69%+/-14% at 6 months; P=.030) were increased in the treated patients. There were no differences in the parameters studied in untreated patients. Among the 27 recipients followed at 12 months, iPTH was decreased compared with baseline values (157+/-103 vs 124+/-62 pg/mL; P=.024) and 25OHD remained stable with respect to the values at 6 months (21.1+/-5.3 ng/mL). No adverse effects of cholecalciferol were observed such as those to increase urinary calcium excretion. Low doses of cholecalciferol improved vitamin D status and decreased iPTH levels at 12 months. Higher doses than those used in our study are needed to increase serum 25OHD concentrations above 30 ng/mL. PMID- 20970572 TI - Effect of paricalcitol on the urinary peptidome of kidney transplant patients. AB - BACKGROUND AND OBJECTIVE: Disorders in bone mineral metabolism are common after kidney transplantation, covering, among other pathologic conditions, secondary hyperparathyroidism. Paricalcitol, a selective vitamin D receptor activator, is indicated in the prevention and treatment of secondary hyperparathyroidism. Recent evidence suggests that paricalcitol is also associated, by mechanisms not yet clarified, with improved patient survival. To clarify these unknown mechanisms, the aim of this study was to determine whether 3 months of treatment with paricalcitol modified the urinary peptidome of kidney transplant patients. METHODS: This prospective study included 42 stable kidney transplant patients, randomized in 2 groups: a group treated with 1 MUg/d paricalcitol (n=25) and a control group that did not receive paricalcitol (n=17). Urine samples of all patients were collected at baseline and after 3 months. The proteomic approach was based on magnetic bead technology coupled to MALDI-TOF mass spectrometry. RESULTS: Paricalcitol treatment produced significant changes in urinary peptidome of kidney transplant patients. Variations in urinary peptides were independent of the degree of proteinuria and of the decrease in parathyroid hormone levels. CONCLUSIONS: With this preliminary study, we obtained a profile of urinary peptides in which changes occurred due to treatment with paricalcitol. The identification of proteins to which these peptides belong may improve our knowledge about the possible pleiotropic effects of paricalcitol. PMID- 20970573 TI - Vascular thrombosis after kidney transplantation: predisposing factors and risk index. AB - Early graft thrombosis is an uncommon complication, but the vast majority of cases are unrecoverable. The aims of this study were to assess the variables involved in the development of this complication and to create a prognostic index to define which transplants, by virtue of a combination of variables, show a higher risk of thrombosis. We retrospectively analyzed a cohort of 577 cadaveric renal transplants performed between 1992 and 2009, excluding those with hypercoagulability before transplantation. The overall incidence of thrombosis was 6%. The distribution of thrombosis was examined according to recipient variables, differences in dialysis within 24 hours before transplantation (0 no dialysis, 13.8% dialysis out of hospital, and 4.2% dialysis in hospital; P=.029) and iliac vascular pathology (10% yes vs 5% no; P<.04). The donor-related factors were age above or below 60 years (11% vs 5%; P=.01), stroke versus traumatic death cause (9.3% vs 4.7%; P=.049), and graft atheroma (16.7% yes vs 5.1% no; P=.042). Immunotherapeutic factors were tacrolimus versus cyclosporine (7.4% vs 2.3%; P=.001) and use of sequential therapy (10.7% yes vs 3.3% no; P=.001). The odds ratio (OR) of thrombosis for the use of basiliximab adjusted for donor age, recipient age, and graft atheroma was 2.6 (95% CI, 1.03 to 6.63). Upon multivariate analysis, the predictive equation consisted of: stroke donor death, OR 3.88; recipient iliac vascular pathology, OR 2.81; and graft atheroma, OR 3.63. The predictive validity by receiver operating characteristic curve provided an area of 0.769 (95% CI, 0.67 to 0.87; P<.0001). The thrombosis risk index suggested that transplantation into a recipient with iliac vascular pathology, stroke as the cause of donor death, and graft atheroma multiplied the risk by 16 compared with a standard recipient without iliac vascular pathology with a traumatic cause of donor death, and without graft atheroma. PMID- 20970574 TI - Anemia control in kidney transplant patients treated with methoxy polyethylene glycol-epoetin beta (mircera): the Anemiatrans Group. AB - BACKGROUND: Kidney transplant, the gold standard treatment for chronic kidney disease (CKD), is increasingly complicated by anemia. Once-monthly dosing of methoxy polyethylene glycol-epoetin beta provides stable, sustained hemoglobin levels in CKD patients. The present study evaluated anemia control in recipients treated with methoxy polyethylene glycol-epoetin beta to correct or as conversion treatment from other erythropoiesis-stimulating agents (ESAs). PATIENTS AND METHODS: This observational, retrospective study included kidney transplant patients treated with methoxy polyethylene glycol-epoetin beta according to investigators' clinical practice. Information about demographics, CKD, anemia, blood analyses, treatment, and adverse events were collected from patients' medical charts at baseline as well as months 1, 3, and 6. RESULTS: From October 2009 to March 2010, the 285 patients in the study included: an overall mean age of 52.8+/-13.9 years with 146 females (51.2%) and 152 patients (55.1%) in stage 3 CKD. Forty-five patients (15.8%) were in the immediate posttransplant period; 51, naive- treatment (17.9%) and 189, converted subjects (66.3%). Eighty-two of the converted patients (48.0%) had previously received darbepoietin; 81 (47.4%), epoetin beta; and 8 (4.7%), epoetin alfa. The mean doses of methoxy polyethylene glycol-epoetin beta at baseline were 75.0+/-22.4 MUg per month, 95.8+/-45.5 MUg per month, and 118.9+/-58.9 MUg per month among naive, converted, and immediate posttransplant patients, respectively. Mean hemoglobin content varied from baseline to month 6, namely 10.2+/-0.7 versus 11.8+/-0.9 g/dL in naive (P<.001) and 11.4+/-1.3 versus 12.0+/-1.2 g/dL in converted patients (P=.001). Patients in the immediate posttransplant period showed mean hemoglobin values maintained between 10.4+/-1.7 g/dL at baseline and 11.5+/-1.2 g/dL at month 3. The only study-drug-related adverse event was hypertension. No patient died during the study. CONCLUSION: These preliminary results suggested that hemoglobin stability can be achieved and maintained after correction or conversion to once-monthly methoxy polyethylene glycol-epoetin beta in kidney recipients. It was well tolerated; the safety profile was that expected and comparable with shorter acting ESAs. PMID- 20970576 TI - Epidemiology of pneumonia in kidney transplantation. AB - BACKGROUND: Pneumonia remains an important cause of morbidity among solid organ transplant recipients. METHODS: We prospectively evaluated all renal transplant patients at our center from July 2003 to December 2008 who had pneumonia that required hospitalization. We gathered data regarding underlying diseases as well as pretransplant, transplant, and posttransplant characteristics. Pneumonia defined according to the Centers for Disease Control and Prevention criteria was classified depending on its origin as community acquired or nosocomial. In all patients, microbiologic samples of respiratory secretions and blood were collected at the physician's discretion. The indication to perform a fiberoptic bronchoscopy was the presence of multiple, bilateral, or diffuse pulmonary infiltrates or the absence of a clinical or radiologic response after 3 days of antimicrobial therapy. RESULTS: Among 610 kidney transplant recipients, we diagnosed 60 episodes of pneumonia in 54 patients (8.8%), of which 23 had a nosocomial origin (38%) and 37 community acquired (62%). Bacterial infection was the most frequent etiology (44%), followed by fungal in 4 (7%) and viral in 2 (3.5%). The most commonly isolated microorganism in nosocomial pneumonia was Pseudomonas aeruginosa (26%, among which 50% was multidrug resistant). In 34% there was no microbiologic isolation. The most common pathogen among community acquired pneumonias was Strepococcus pneumoniae (11%). In 54% of cases there was no microbiologic confirmation of disease. The overall accuracy of bronchoalveolar lavage was 72%. A total of 21 patients with pneumonia (35%) were admitted to the intensive care unit; of these, 14 had a nosocomial origin (60%) and 9 (15%) died due to the infection (8 [88%] of whom had nosocomial pneumonia; P=.001). CONCLUSIONS: Our data confirmed that nosocomial pulmonary infections are associated with considerable morbidity and mortality in renal transplant recipients. The performance of invasive procedures is useful for the diagnosis of pneumonia. PMID- 20970577 TI - Klebsiella pneumoniae infection in solid organ transplant recipients: epidemiology and antibiotic resistance. AB - BACKGROUND: Klebsiella pneumoniae is a well recognized source of nosocomial infection in solid-organ transplant (SOT) recipients. It is also the most common species capable of producing extended-spectrum beta-lactamases (ESBL). Its treatment can therefore be a challenge owing to antibiotic resistance. METHODS: Prospective study of all transplant recipients from July 2003 to December 2007 at our center. Klebsiellla pneumoniae infectious events were recorded. RESULTS: A total of 1,057 patients were enrolled, 509 (48%) renal, 360 (34%) liver, 78 (7%) heart, and 110 (10%) double transplants. We diagnosed 116 episodes of K. pneumoniae infection in 92 patients during the study period, of which 62 were ESBL-producing strains (53%). Thirty-four episodes had bacteremia (29%), 15 of which were caused by ESBL-producing strains. There were no strains of K. pneumoniae producing carbapanemase (KPC). Forty-seven percent of the episodes occurred during the first month after transplantation. The incidence of infection by type of transplant was: renal 11%, liver 7%, cardiac 5%, and double transplant 6% (P=.075). The major sites of infection were urinary tract 72%, surgical wound 5%, intraabdominal 6%, catheter 5%, lung 1%, bloodstream 1%, and others 2%. ESBL producing K. pneumoniae strains were more common in renal transplant patients (P=.035) and in those who required posttransplant dialysis (P=.022). There were 4 deaths in the first 30 days after the isolation of K. pneumoniae, and 3 of these cases were infections caused by ESBL-producing strains. CONCLUSIONS: There was a high incidence of ESBL-producing K. pneumoniae infections in SOT recipients and renal transplant recipients, and those who required dialysis were more likely to develop infection by this strain. No KPC-producing organisms were found in our series. The existence of such a high level of resistance is a well recognized hospital threat, and appropriate policies and interventions should be addressed in high-risk patients. PMID- 20970575 TI - Erythropoietin resistance as surrogate marker of graft and patient survival in renal transplantation: 3-year prospective multicenter study. AB - BACKGROUND: Some transplant recipients demonstrate an inadequate response to erythropoiesis-stimulating agents, or so-called erythropoietin (Epo) resistance. The cause is multifactorial. Resistance to EPO may entail a poor prognosis for the graft and the patient, although results in the literature are inconsistent, and long-term follow-up is lacking. OBJECTIVE: To evaluate whether the presence of Epo resistance at the beginning of the study was a predictive factor for graft and patient survival. MATERIALS AND METHODS: From 482 renal transplant recipients (Kidney Disease Outcomes Quality Initiative stage 3-4T) receiving Epo-stimulating agents in the Anemia and Renal Transplantation in Spain study, 101 were selected for the present study. Erythropoietin resistance was defined as a ratio of weekly Epo dosage/hemoglobin concentration>486,94 U/g/dL with a hemoglobin/<11 g/dL. Darbepoetin dosage was calculated in Epo equivalent units, with a 1:200 conversion factor. Patients were grouped as Epo-resistant (ER+) or not Epo resistant (ER-), to assess whether Epo resistance was predictive of patient and graft survival. RESULTS: There were no differences in demographic data between the 2 groups except for a higher incidence of vascular, interstitial, and diabetes-related causes of chronic renal failure in the ER+ group. At 3 years posttransplantation, graft survival was 33% in the ER+ group vs 58% in the ER- group (P=.06), and patient survival was 52% in the ER+ group vs 88% in the ER- group (P=.008). Using a Cox regression model, at 3 years, the relative risk of graft failure was 1.96 in the ER+ group (95% CI, 0.93-3.12; P=.07), and of patient death was 3.9 (95% confidence interval, 1.30-11.63; P=.01). CONCLUSION: Erythropoietin resistance is an independent risk factor for death after renal transplantation. PMID- 20970578 TI - Candiduria in renal transplant recipients: incidence, clinical repercussion, and treatment indication. AB - INTRODUCTION: The incidence of candiduria in renal transplant recipients is unknown. In clinical practice, the indications for antifungal therapy are not well established. Furthermore, there is the problem of the choice of the antifungal drug since some of them may select resistant Candida species, or interact with immunosuppressive agents or only be used intravenously. AIM: We sought to study the incidence, clinical repercussions and effectiveness of antifungal treatment to prevent recurrence of candiduria. MATERIALS AND METHODS: We examined all episodes of Candida-positive urine cultures (>50,000 cfu/mL) in 996 recipients over 2 years. We considered the Candida species, administered treatment, presence of fever, requirement for hospital admission versus outpatient case, occurrence of simultaneous bacterial urinary tract infection (UTI), antibiotic use during the week before candiduria, and presence of an indwelling urinary catheter. RESULTS: Among 996 subjects, 34 displayed 83 episodes of candiduria, yielding an accumulated incidence of 3.4% after 2 years. The frequency was higher among women (6.3% vs 1.7%, P<.001). Of the 45 outpatient episodes (54.2%), 17 were treated and one required hospitalization (5.9%). Of the 28 nontreated outpatients, two were hospitalized (7.1%, P=.68 vs treated patients). All cases of hospital admission presented simultaneous bacterial UTI, none developed candidemia, and two patients did not receive any antifungal therapy. With respect to the first episodes of each patient (n=34), 5/11 treated (45.5%) and 4/23 untreated (17.4%) patients developed recurrences (P=.095). Selection of more resistant Candida species was not observed. Fifty cases (60%) were associated with antibiotic therapy and 34 (41%) the presence of a urinary catheter. CONCLUSIONS: It does not seem necessary to treat candiduria in this setting. Antifungal therapy was not associated with either a reduction in recurrence or the appearance of more resistant species in this study. We observed no important clinical repercussions. PMID- 20970579 TI - Prophylactic therapy with valganciclovir in high-risk (cytomegalovirus D+/R-) kidney transplant recipients: a single-center experience. AB - BACKGROUND: A prospective study was performed in kidney transplant patients at risk of developing cytomegalovirus (CMV) infection (CMV D+/R-). They were treated with valganciclovir (VGC) for 3 months as prophylactic therapy. The aim was to determine the safety and efficacy of prophylactic therapy with VGC. METHODS: Antigenemia and/or polymerase chain reaction CMV was routinely performed every 2 weeks up to month 3, monthly to month 6, and every other month until the end of the first year posttranplantation, as well as when clinically indicated. RESULTS: From July 2007 to April 2010, 366 renal transplantations were performed at our center, including 34 (9%) high-risk patients for CMV infection. The median age was 47 years; 19 were males and 15 females. Twelve (35%) patients developed CMV infections: 10 (34%) gastrointestinal disease and 3 viral syndromes. The timing of the clinical manifestations was 16% (3/12) between months 1 and 3, 75% (8/12) between months 4 and 6, and 8% (1/12) in month 9 posttransplantation. CONCLUSION: Treatment with intravenous ganciclovir followed by oral VGC was successful in all patients. No opportunistic infections or allograft rejection were observed; only 1 patient developed thrombocytopenia as an adverse event to VGC. PMID- 20970580 TI - Exploring mass spectrometry suitability to examine human liver graft metabonomic profiles. AB - BACKGROUND: Transplant surgeons rely on morphologic aspects of the organ as well as clinical and histologic data to decide whether to use a graft. Metabonomics measures the "downstream" products of proteins and genes; these metabolic profiles are particularly good reporters of tissue physiologic features. Sample preparation and data acquisition are generally considered limiting steps in metabonome analysis because they are important sources of variability. State-of the-art mass spectrometry and multivariate statistical analysis have been used to explore the suitability of a metabonomic platform as a liver tissue metabonomic profiling method. OBJECTIVE: To develop robust and reliable sample processing and mass spectrometry protocols for studying human liver metabonomic profiles. MATERIALS AND METHODS: Liquid chromatography coupled with mass spectrometry was used to analyze 20 liver tissue samples from 10 discarded and 10 transplanted grafts. Principal component analysis (PCA) and projection to latent structures discriminant analysis (PLS-DA) were used for data interpretation. RESULTS: Standard operating protocols for sample processing (tissue homogenization) and data acquisition were developed. The quantification of the quality controls present in the test mix demonstrated coefficients of variation less than 15%. The PCA score plot revealed that the sample triplicate cluster was quite close. Furthermore, PLS-DA analysis demonstrated a clear separation (transplanted vs discarded) along the first component. DISCUSSION: Multivariate data analysis (PCA and PLS-DA) indicated that protocols developed in-house for sample processing and mass spectrometry data acquisition were sufficiently sensitive (approximately 1245 features) and reproducible (sample triplicate clusters and test mix quantification) to perform liver tissue metabonomic profiling. In addition, a reduced set of metabolites was selected as potential biomarkers responsible for sample discrimination. These findings encourage ongoing research into the development of a metabonomic model to assess liver graft quality and function before transplantation. PMID- 20970581 TI - New alternatives to the treatment of acute liver failure. AB - INTRODUCTION: Acute-on-chronic liver failure (ACLF) is defined as an acute deterioration of a chronic liver disease. The most effective treatment in these patients is orthotopic liver transplantation (OLT), which is highly limited by the donor shortage. The aim of this study was to increase the usefulness of hepatocyte transplantation (HT) as a bridge or alternative to OLT. METHODS: During the last 2 years, we have performed HT in 3 patients with ACLF. The diagnosis was graft cirrhosis due to hepatitis C virus in 2 of them, who were already included on waiting lists for retransplantation, and the third, unknown alcoholic cirrhosis. RESULTS: After the first HT infusion, we observed an improvement in the clinical condition in all patients, hyperammonemia, and a partial correction of the degree of encephalopathy; 1 patient was retransplanted 6 days after the first HT. DISCUSSION: The main indications for HT are inborn errors of metabolism in children. Other indications especially in adults, are acute liver failure, ACLF in patients with end-stage-liver disease who are a waiting OLT, and acute liver failure after an hepatectomy. HT may be a new treatment to improve the clinical condition in patients awaiting OLT. PMID- 20970582 TI - Comparison of anxious and depressive symptomatology among pretransplant hepatic patients and their relatives. AB - OBJECTIVE: We sought to compare the anxiety and depressive symptoms of patients undergoing pretransplant evaluation with those of their closest relatives. MATERIALS AND METHODS: We assessed 51 patients with hepatic cirrhosis and 51 relatives who were the main care giver for each patient. All subjects were assessed during the interval when the patients were hospitalized to undergo the medical assessment to determine their inclusion on the waiting list for liver transplantation. In both groups, we used a "Psychosocial Survey" and the "Hospital Anxiety and Depression Scale." RESULTS: Significant differences were observed in anxiety (P=.001), but not in depression (P=.820). Specifically, relatives presented higher levels of anxiety compared with the hepatic patients. CONCLUSION: The relatives were worse off psychologically than the patients. PMID- 20970583 TI - Influence of relatives' anxious symptomatology on the quality of life of pretransplant hepatic patients. AB - OBJECTIVES: We sought to analyze the influence of anxiety symptoms of relatives of patients undergoing a pretransplant study on the quality of life of the hepatic patients body pain, physical role, mental health, general health, vitality, social functioning, emotional role, and physical functioning. MATERIALS AND METHODS: We assessed 2 groups: 51 patients with hepatic cirrhosis and 51 of their closest relatives who were studied while the patients were hospitalized to undergo the pretransplant study. We used a "Psychosocial Survey" (in both groups), the "Hospital Anxiety and Depression Scale" (HADS) in the relatives, and the "SF-36 Health Survey" (in the patients). RESULTS: The results showed that the patients whose relatives presented clinical levels of anxiety showed the worst quality of life, specifically for the dimensions "mental health" (P=.016) and "emotional role" (P=.041). PMID- 20970584 TI - Covered metal stents for the treatment of biliary complications after orthotopic liver transplantation. AB - BACKGROUND: Biliary complications, a major source of morbidity after orthotopic liver transplantation (OLT), are increasingly being treated by endoscopic retrograde cholangiopancreatography (ERCP). Endoscopic management has been shown to be superior to percutaneous therapy and surgery. Covered self-expandable metal stents (CSEMSs) may be an alternative to the current endoscopic standard treatment with periodic plastic stent replacement. OBJECTIVE: To assess the safety and efficacy of temporary CSEMS insertion for biliary complications after OLT. METHODS: From November 2001 to December 2009, the 242 OLT performed in 226 patients included 67 cases that developed post-OLT leaks or strictures (29.6%), excluding ischemic biliary complications. CSEMSs were used in 22 patients (33%), 18 male and 4 female, with an overall median age of 55 years (range, 29-69). In house OLT patients underwent an index ERCP at 26 days (range, 8-784) after OLT. Their records were reviewed to determine ERCP findings, technical success, and clinical outcomes. RESULTS: ERCP with sphincterotomy was performed in all 22 patients, revealing 18 with biliary strictures alone (82%), 3 with strictures and leaks (14%), and 1 with strictures and choledocholithiasis (4%). All strictures were anastomotic. All patients had 1-2 plastic stents inserted across the anastomosis (11 had prior balloon dilation); stones were successfully removed, for an initial technical success rate of 100% (22/22). CSEMSs, were placed at the second ERCP in 14 patients, at the third in 7, and at the fourth in 1. With a median follow-up of 12.5 months (range, 3-25) after CSEMS removal, 21/22 patients (95.5%) remain stricture free and one relapsed, requiring repeat CSEMS insertion. Four patients experienced pain after CSEMS insertion. At CSEMS removal, migration was noted in 5 cases, into either the distal duodenum (n=4) or the proximal biliary tree (n=1), and embedding was seen in 1 case. There were no serious complications; no patients needed hepatojejunostomy. CONCLUSIONS: ERCP is a safe first-line approach for post-OLT biliary complications. It was highly successful in a population with anastomotic leaks and strictures. The therapeutic role of ERCP to manage biliary complications after OLT in the long term is not well known. In our experience, the high rate (close to 95%) of efficacy and its relative safety allowed us to use CSEMS to manage refractory biliary post-OLT strictures. CSEMS insertion may preclude most post-OLT hepatojejunostomies. PMID- 20970585 TI - Vascular complications after orthotopic liver transplantation: hepatic artery thrombosis. AB - INTRODUCTION: Hepatic artery thrombosis (HAT) is the second main cause of liver graft failure after primary nonfunction. It is the most frequent arterial complication in orthotopic liver transplantation (OLT). The consensus for early HAT definition consists of an arterial thrombosis detected during the first month after OLT. HAT is associated with markedly increased morbidity, being the leading cause of graft loss (53%) and mortality. However, improvements in postoperative care have resulted in a marked reduction of its incidence. METHODS: We performed a review of all patients who underwent liver transplantations from January 1991 to December 2009, involving 1560 subjects who underwent 1674 OLT, excluding children. To analyze the impact of the study period on HAT, we defined 3 periods: the first between January 1991 and April 1993, the second from May 1993 to December 2003, and the last from January 2004 to December 2009. RESULTS: The total number of patients with HAT was 48 (2.8%) including 32 (1.9%) early HAT and 16 (0.9%) late HAT. The incidence of HAT diminished as the surgical team gained experience from 9.3% in the first period to 2.1% in the last. Most patients with early HAT presented acute fulminant hepatic failure (30%) and most were retransplantations (81%). DISCUSSION: In general, there are 3 modalities for HAT: revascularization, retransplantation, and observation. The choice of the treatment depended on the time of diagnosis although retransplantation was the treatment of choice for most groups. Minimizing risk factors, protocols for early detection, and good operative techniques should be the standard in all centers. PMID- 20970586 TI - Introduction of fibrinogen in the treatment of hemostatic disorders during orthotopic liver transplantation: implications in the use of allogenic blood. AB - BACKGROUND: Orthotopic liver transplantation (OLT) requires a large amount of blood-derived resources. The indications for their availability in the surgery area is based on empirical protocols. The implementation of point-of-care apparatuses gives rise to the detection of hemostatic alterations due to functional deficits of fibrinogen. METHODS: To monitor coagulation disorders and other biochemical parameters, we used thromboelastometry (ROTEM(r)) and a MovlLab(r) unit, respectively. We evaluated the stability and firmness of the clot based on fibrin (FibTem test). The measurements were performed during all of the liver transplant stages: baseline, anhepatic, and reperfusion. Fibrinogen (hemocompletan) was administered to achieve maximum clot firmness, based on patient weight and the existence of surgical bleeding. This pilot cohort of 20 transplant patients (group B) compared outcomes with the 59 patients from the previous year (group A). RESULTS: Haemocompletan was administered to 45% of the 20 patients. The ratio of red blood cell components per patient diminished from 8.4 to 3.9 (53% reduction) and, fresh frozen plasma from 5.6 to 1.9 (65% reduction). Transfusions of platelet concentrates decreased by 50% with a ratio of 1.5-0.7 per patient. Likewise, 20% of transplant patients received no transfusions of blood products compared with 3.5% in the previous period. CONCLUSION: The incorporation of fibrinogen into the treatment of hemostatic disorders in OLT leads to a reduced use of allogenic blood products. We observed reduced number of patients who received transfusions, while those who underwent transfusion did so to a lesser degree. PMID- 20970587 TI - Use of fully covered self-expandable stent in biliary complications after liver transplantation: a case series. AB - AIMS: To present our case series of fully covered self-expandable metallic stents (FCSESs) placed to treat biliary stenosis after liver transplantation and leakage after failure of plastic stenting. MATERIALS AND METHODS: We retrospectively reviewed the courses of patients who had undergone liver transplantation with a biliary complication that was treated by an FCSES installed by endoscopic retrograde cholangiopancreatography. We evaluated the following variables: gender, age, indication for transplantation, time between transplant and diagnosis of the complication, number of plastic stents placed before the FCSES, and procedure-related complications. RESULTS: From April 2008 to March 2010, 11 patients who had undergone a duct-to-duct anastomosis suffered posttransplant biliary stenosis or leakage with failure of endoscopic treatment using a plastic biliary stent: Namely, eight cases of stenosis and three of biliary leaks. Three patients underwent a papillotomy to place the FCSES, with no significant morbidity. No severe complications were observed after the endoscopic treatments; two patients developed mild pancreatitis; two, hyperamylasemia; and one, mild biliary sepsis. We removed the FCSES after a mean of 280 (range=173-310) days. Five patients lost the FCSES spontaneously. One patient underwent a choledocojejunostomy and two are waiting biliary surgery. CONCLUSION: We avoided cholangiojejunostomy in 6/9 cases (not including the two deaths). Papillotomy did not engender a greater morbidity. The spontaneous loss of the stent is a problem that need to be resolved. PMID- 20970588 TI - Cardiovascular events after simultaneous pancreas-kidney transplantation. AB - OBJECTIVE: To retrospectively evaluate the incidence of cardiovascular events after functioning simultaneous pancreas-kidney transplantation (SPKT). PATIENTS AND METHODS: Cardiovascular events after 89 SPKT procedures performed at our institution from March 1995 to March 2009 were investigated. Study criteria included normal functioning of both grafts. Patients included 36 women and 53 men, with mean (range) age of 37.7 (25-66) years. Duration of diabetes mellitus was 23.6 (10-48) years, and of dialysis therapy was 19.8 (0-70) months. The exocrine pancreatic secretions were drained to the bladder in 41 patients, and enterically in 45 patients. Mean (SD) follow-up was 58.62 (34.74) months. RESULTS: During follow-up after SPKT, 9 patients (10.1%) experienced cardiovascular events including cerebrovascular accident in 4 patients, myocardial infarction (MI) in 3, and episodes of angina pectoris without evidence of coronary artery disease in 2 patients. Nevertheless, these two patients had sustained an MI that required coronary angioplasty before SPKT. Moreover, coronary angioplasty was required in 2 patients before they were enrolled in the transplantation program because of silent coronary artery disease. Four of 9 cardiovascular events occurred in the perioperative period. No deaths occurred due to cardiovascular events. Patient survival rate was 100%, with both grafts functioning in 87 (97.8%). CONCLUSION: Cardiovascular events occur relatively frequently in patients undergoing SPKT. In the present study, most events occurred in the perioperative period, but did not result in death. PMID- 20970589 TI - Prevalence of donor-transmitted coronary artery disease and its influence on heart transplant outcomes. AB - BACKGROUND: It is uncertain whether donor-transmitted coronary artery disease (DTCAD) affects heart transplant (HT) recipients. METHODS: This retrospective analysis includes records of all patients who underwent a HT at our center over an 8-year period, who survived for at least 1 month, and who were examined by coronary angiography within 2 months post-HT. We distinguished angiographically from keep ultrasonography (IVUS) detected DTCAD. Major adverse cardiovascular events (MACE) comprised death, myocardial infarction, unstable angina, coronary revascularization, and admission because of heart failure not due to an acute rejection episode. RESULTS: Among the 171 patients of mean age 53+/-13 years and including 83% men, 65 (38%) were evaluated by IVUS. Donors were aged 40+/-14 years (range=14-73). Angiographic DTCAD affected seven patients (4.1%), and IVUS detected DTCAD, 35 (53.8% of those examined by IVUS). DTCAD donors were older than non-DTCAD donors, by an average of 13 years (P=.001) for angiographic DTCAD and 18 years (P<.0001) for IVUS-detected DTCAD. Two patients underwent percutaneous revascularization upon detection of angiographic DTCAD. The angiographic- and IVUS-detected DTCAD groups did not differ significantly from the corresponding non-DTCAD groups as regards MACE incidence during 54+/-41 and 38+/-20 months follow-up, respectively. Cox regression analysis with adjustment for relevant confounders confirmed that IVUS-detected DTCAD was not a predictor of MACE (hazard ratio 1.2, 95% confidence interval 0.2-8.1). CONCLUSIONS: Among HT patients surviving>=1 month, angiographic- and IVUS-detected DTCAD showed prevalences of <10% and >50%, respectively. Neither detection method was associated with a greater long-term incidence of MACE. PMID- 20970590 TI - Proliferation signal inhibitors in heart transplantation: a 5-year experience. AB - INTRODUCTION: Calcineurin inhibitors (CNI) are associated with multiple complications, especially renal dysfunction and tumor development. Proliferation signal inhibitors (PSI) show renal protection and an antineoplastic effects, and may retard allograft vasculopathy. The objective of the current study was to present our initial experience center with PSI therapy. MATERIALS AND METHODS: We analyzed all heart transplants (HT) performed in our center who received a PSI at any time. We assessed the clinical profiles, indications for and strategies of PSI introduction, complications, causes of discontinuation, and renal functional evolutions. RESULTS: Among 604 HT performed in our center, 82 patients (13.5%) received a PSI: sirolimus (n=2) or everolimus (n=80). Their mean age was 53+/-12 years and 90% were men. PSI introduction occurred at 75+/-53 months posttransplantation. The strategy was CNI minimization in 17% of cases, and total conversion from CNI in 83%. The PSI indication was renal dysfunction (40%), tumors (38%), allograft vasculopathy (17%), and other reasons (5%). After PSI introduction, 15.8% of patients suffered a rejection episode and 20%, a significant infection. The PSI discontinuation rate was 8.5%: due to infection (2.4%), edema (1.2%), inadequate cicatrization (1.2%), and other reasons (3.7%). Creatinine was 1.68+/-0.64 mg/dL the year before and 1.72+/-0.79 mg/dL at and 1.82+/-1.61 mg/dL 1 year after PSI conversion. CONCLUSION: PSIs showed few complications with a low withdrawal rate, and maintained renal function. The main indications for their use were renal dysfunction, tumors, or development of allograft vasculopathy. PMID- 20970591 TI - Conversion of heart transplant patients from standard to sustained-release tacrolimus requires a dosage increase. AB - INTRODUCTION: It has been suggested that for adequate maintenance of tacrolimus levels, the total daily dosage should be increased when switching from the conventional twice-daily regimen tacrolimus (CT) to once-daily sustained-release tacrolimus (SR-T). OBJECTIVE: To evaluate the safety and efficacy of a 25% increase in daily dosage when switching heart transplant (HT) patients from CT to SR-T. METHODS: We switched 75 HT patients including 72% males and an overall mean age of 55.6 years from CT to SR-T using a 25% increase in daily dosage. We screened for adverse events by measurements of lipids, creatinine, glycemia, and tacrolimus in blood samples taken at 1, 3, 7, and 12 weeks after the conversion, as well as by repeated echocardiography and routine clinical examinations. RESULTS: Just two patients (2.7%) were returned to CT because of failure of SR-T to attain therapeutic levels. In the remainder of subjects, tacrolimus levels remained stable, with trough values of 8.7+/-3.2, 8.7+/-2.9, 8.3+/-2.6, and 7.5+/ 2.0 mg/dL, respectively. Twenty-three patients (31%) required no dosage change in the first 3 months, but 44 (33%) required one or two changes. No departure from therapeutic levels was associated with rejection; there was no case of severe intercurrent infection. We did not observe significant changes in glycemia, creatinine, lipid profile, or blood pressure. CONCLUSIONS: Administration of SR-T at a dosage 25% higher than the daily dosage of CT was safe. It ensured adequate tacrolimus levels in one-third of patients. Nevertheless, strict analytical surveillance is necessary during the initial months to allow dosage adjustments and to detect the minority of patients for whom SR-T does not achieve therapeutic tacrolimus levels. PMID- 20970592 TI - Temporal trends in the use of proliferation signal inhibitors in maintenance heart transplantation: a Spanish multicenter study. AB - Proliferation signal inhibitors (PSI; sirolimus, everolimus) are being increasingly used in heart transplantation. We performed an observational, retrospective, multicenter study in 9 Spanish centers seeking to describe the clinical context in which a PSI was used among maintenance heart recipients and its evolution over time. We collected a cohort of 548 patients in whom a PSI was prescribed from October 2001 to March 2009. The group was divided into 3 time periods. The use of PSI steeply increased in the 2005-2006 period, remaining stable thereafter. There were no significant differences over time with regard to age, gender, or time from transplantation to the introduction of the PSI. Everolimus usage overtook sirolimus from 2005 on; currently, >90% of the subjects with PSI indications are prescribed everolimus. Compared with earlier periods, patients in the more recent period (October 2006-March 2009) showed less vascular graft disease and better basal renal function, irrespective of the primary indication for the PSI prescription. Also, skin cancer overtook solid cancer as the main type of neoplasm in patients for whom malignancy was the primary indication for the use of the PSI. The actuarial incidence of PSI withdrawal owing to adverse effects did not change significantly over time. PMID- 20970593 TI - Incidence and risk factors for nonmelanoma skin cancer after heart transplantation. AB - INTRODUCTION: The incidence of skin cancer in heart transplant (HT) patients is higher than in the general population, reversing the proportion of cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) with a predominance of the former. The etiologic role of new immunosuppressants is not well known. We sought to ascertain the incidence of SCC and BCC in HT patients and the risk factors for its occurrence. PATIENTS AND METHODS: We report the incidence of all types of post-HT skin cancer, SCC, and BCC among adult HT patients in Spain (4089 subjects) as well as the influence of gender, age at heart transplant, immunosuppression, and sunlight exposure. RESULTS: The incidence rates of SCC and BCC, per 1000 persons/year, were 8.5 and 5.2, respectively. Males had a higher risk of SCC but not BCC. Induction therapy increased the risk of SCC and BCC. The relative risk of mycophenolate mofetil (MMF) was 0.3 (0.2-0.6; P<.0005) and azathioprine (AZA) 1.8 (1.2-2.7; P<.0032) for SCC, whereas tacrolimus and cyclosporine showed no difference. The relative risk of BCC was not affected by any immunosuppressant. CONCLUSION: Age at transplantation>45 years, induction therapy use, and high sunshine zone were risk factors for both SCC and BCC. Different immunosuppressive agents have different risks of nonmelanoma skin cancer, as AZA increases the risk of SCC and MMF is a protective factor. The relative risk of BCC was not affected by any immunosuppressor. PMID- 20970594 TI - Long-term outcome in heart transplant patients with pretransplant malignancies. AB - INTRODUCTION: Neoplasms have classically been considered a contraindication for heart transplantation (HT) because of the possibility of recurrence during immunosuppressive therapy. There are few cases of patients who suffered a pretransplant malignancy (PTM); however the appropriate interval free of a malignancy (IFoM) before heart transplantation is unclear. Our study sought to determine the long-term outcomes after transplantation among patients who had suffered a prior neoplasm compared with our overall cohort. METHODS: This retrospective, single-center study included 595 heart transplant recipients ungrafted between 1991 and 2009. We determined PTM location, histology, and IFoM. We examined donor and recipient factors and post-HT data of rejections, infections, neoplasms, and survival associated with a poor prognosis. RESULTS: Twelve patients with different types, locations, and histological grades of PTM represented 66.7% women versus 16.1% women in the overall series (P<.01). There were no differences in recipient age or clinical characteristics (diabetes mellitus, arterial hypertension, previous renal failure, or New York Heart Association class), number of emergency cases, or graft ischemia time. Mean IFoM was 114.3 months (range=5.3-350.4). After heart transplantation, there were no significant differences between the number of infections (47.9%; n=[279] vs 33.3% n=4; P=.39), rejection episodes (44.4% [259] vs 50% [6], P=0.77) or post-HT malignancies (12.2% [70] vs 0%, P=0.37) between the overall series and the patients with PTM. None of the patients with PTM suffered a recurrence of the neoplasm. Actuarial survivals at 1, 3, and 5 years were 82%, 76%, and 70% among patients without PTM and 75%, 75%, and 56% among those with PTM (P=.70). CONCLUSION: Patients with PTM and an appropriate IFoM with regard to tumor lineage showed similar rates of survival and complications as those of the overall series. This series suggested that appropriately selected patients with a cured PTM can be candidates for HT. PMID- 20970595 TI - The prognosis of noncutaneous, nonlymphomatous malignancy after heart transplantation: data from the Spanish Post-Heart Transplant Tumour Registry. AB - INTRODUCTION: Malignancy is a major complication in the management of solid organ transplant patients. Skin cancers show a better prognosis than other neoplasms, but not all others are equal: Ideally, patient management must take into account the natural history of each type of cancer in relation to the transplanted organs. We sought to determine the prognosis of various groups of noncutaneous nonlymphomatous (NCNL) cancers after heart transplantation (HT). METHODS: We retrospectively analyzed the records of the Spanish Post-Heart-Transplant Tumour Registry, which collects data on posttransplant tumors in all patients who have undergone HT in Spain since 1984. Data were included in the study up to December 2008. We considered only the first NCNL post-HT tumors. RESULTS: Of 4359 patients, 375 developed an NCNL cancer. The most frequent were cancers of the lung (n=97; 25.9%); gastrointestinal tract (n=52; 13.9%); prostate gland (n=47; 12.5%; 14.0% of men), bladder (n=32; 8.5%), liver (n=14; 3.7%), and pharynx (n=14; 3.7%), as well as Kaposi's sarcoma (n=11; 2.9%). The corresponding Kaplan Meier survival curves differed significantly (P<.0001; log-rank test), with respective survival rates of 47%, 72%, 91%, 73%, 36%, 64%, and 73% at 1 year versus 26%, 62%, 89%, 56%, 21%, 64%, and 73% at 2 years; and 15%, 51%, 77%, 42%, 21%, 64%, and 52% at 5 years post-diagnosis, respectively. CONCLUSION: Mortality among HT patients with post-HT NCNL solid organ cancers was highest for cancers of the liver or lung (79%-85% at 5 years), and lowest for prostate cancer (23%). PMID- 20970596 TI - Efficacy and tolerance of different types of prophylaxis for prevention of early aspergillosis after heart transplantation. AB - BACKGROUND: The incidence of aspergillosis (ASP) after heart transplantation (HTx) is low (<4%-5%), but the mortality is high (>78%). AIM: To determine the incidence of ASP in the first 3 months post-HTx according to the type of prophylaxis and assess the tolerance to these regimens. METHODS: This retrospective study of 571 adult HTx patients engrafted from 1991 to December 2009 included 83% males with an overall group age of 54.9+/-11 years. Three types of prophylaxis were compared: group A was no prophylaxis (n=99; 1991-1994); group B, itraconazole for 3 months (n=352; 1995-November 2004); and group C, inhaled amphotericin for 3 months (n=120; December 2004-2009). The dependent variables were the presence and severity or tracheobronchitis and invasive/disseminated disease as well as, prognosis of Aspergillus infection and tolerance to the regimen. RESULTS: The incidences of aspergillosis were 5% in group A (n=5); 1.4% in group B (n=5); and 0% in group C. Significant differences were observed between groups A versus B (P=.030) and between groups A versus C (P=.013), but there were no differences between groups B versus C. In terms of severity, there were no significant differences among the five cases of tracheobronchitis (20% group A/80% group B), five of invasive/disseminated disease (80% group A/20% group B). There were two deaths (20%) from invasive/disseminated ASP at 0.67 months after diagnosis. The mean time from HTx to ASP was 0.98+/-0.40 months. There were no adverse effects associated with itraconazole, but they occurred in 3/120 patients (2.5%) treated with inhaled amphotericin, all of whom were on mechanical ventilation, developing respiratory failure requiring amphotericin withdrawal. CONCLUSIONS: Prophylaxis with itraconazole or inhaled amphotericin was effective for the prevention and severity of pulmonary ASP in the first 3 months post-HTx. Although the incidence of early ASP was low in our series, the 20% mortality rate justified the use of preventive measures. Tolerance to both prophylactic treatments was good. PMID- 20970597 TI - Timing, etiology, and location of first infection in first year after heart transplantation. AB - BACKGROUND: Infections are the leading cause of death in the first year after heart transplantation (HTx) after the postoperative period. OBJECTIVE: To describe the timing, etiology, and location of the first infection occurring in the first year after HTx. PATIENTS AND METHODS: The study included 604 HTx procedures performed at our center from November 1987 to September 2009. Infections were classified as those requiring hospital admission or that prolonged hospital stay. Infection was established on the basis of clinical findings and supplementary test results. Etiologic diagnosis was established at microbiological culture. Infections were categorized as bacterial, viral, fungal, protozoal, or of unknown origin, and were grouped according to microorganism family. Time to occurrence of infection is given as mean (interquartile range). Locations considered were systemic, pulmonary, genitourinary, cutaneous, oropharyngeal, mediastinal, sternal, gastrointestinal, and other. RESULTS: Mean (SD) patient age was 51 (12) years, and 83.8% of patients were men. Almost half of all patients (42.9%) experienced some type of infection in the first year after HTx. The most frequently occurring infections were bacterial (49.6%) and viral (38.7%), with fewer fungal (6.3%), protozoal (1.2%), and of unknown origin (4.3%). Staphylococci were the most commonly isolated organisms (10.5%) in bacterial infections, cytomegalovirus (21.1%) in viral infections, and Candida (2.3%) and Aspergillus (2.3%) in fungal infections. Early-onset infections (n=2; 1-7 days) were caused by Candida spp, and late-onset infections (n=110; 14-182 days) by a mixed group of bacteria. The sternum was the site of early-onset infections (n=9; 6-14 days), and the genitourinary tract was the site of late onset infections (n=110; 28-180 days). CONCLUSIONS: Nearly half of HTx recipients experience a significant infection during the first year posttransplantation. Early-onset infections occur in critical care units, are caused by nosocomial organisms, and involve the sternum or mediastinum, whereas late- onset infections have a more varied etiology and preferentially affect the skin and genitourinary tract. PMID- 20970598 TI - Bone mineral density in patients with chronic obstructive pulmonary disease who are candidates for lung transplant. AB - INTRODUCTIoN: After cystic fibrosis, lung transplantation (LT) patients with prior chronic obstructive pulmonary disease (COPD) are most susceptible to loss of bone mineral density (BMD). OBJECTIVES: To determine the prevalence of BMD loss among COPD patients being evaluated as LT candidates, seeking to identify, their risk profile. PATIENTS AND METHODS: This cross-sectional study included COPD patients who were LT candidates evaluated from January 2007 to December 2009. To identify patients at risk of fracture, BMD at the femoral neck and lumbar spine was assessed by bone densitometry. For categorization, we followed the World Health Organization criteria. To evaluate the risk profile, we recorded data on age, sex, smoking, lung function forced expiratory volume in 1 second, distance covered in the 6-minute walk test, body mass index, and degree of dyspnea. We recorded individual data as well as grouped them the multidimensional BODE (Body mass index Obstruction Dyspnea Exercise capacity) index. RESULTS: The study cohort consisted of 64 patients (51 men and 13 women). The overall prevalence of low BMD in any of the explored territories was 84.4%, affecting 88.2% of men and 69.2% of women. Osteoporosis was identified in 56.2% of patients, reaching a serious degree in 11/64 (17.2%). No significant differences were observed in any evaluated parameter when patients were separated into those with normal versus pathological BMD. When patients with osteopenia and osteoporosis were compared, we observed that the former showed a lower exercise capacity (P=.023) and a higher BODE index (P=.002). CONCLUSIONS: The prevalence of a low BMD level was increased among male patients with a worse BODE index, especially due to a reduced exercise capacity. PMID- 20970599 TI - Lung transplantation for bronchiolitis obliterans after allogenic bone marrow transplantation. AB - INTRODUCTION: Bronchiolitis obliterans (BO) occurring after allogeneic bone marrow transplant (ABMT) may be an expression of lung damage of multifactorial origins. At present, it is not a usual condition for lung transplant (LT), accounting for <1% of all indications in the international registry. We sought, to describe the clinical features and outcomes of patients undergoing LT for BO after ABMT in our group. PATIENTS AND METHODS: We undertook a cross-sectional study of patients with an indication for LT due to BO after ABMT from the beginning of our program. We recorded the type of transplant, patient age, clinical course, functional outcome, and survival. RESULTS: Among 313 LT, 13 cases (4.2%) were due to BO, including 3 after ABMT (0.96%). ABMT was indicated after bone marrow aplasia in 2 cases and acute myeloid leukemia in the other patient. The patients were 2 men (both 35 years old) and 1 woman, aged 25 years. All subjects received double elective LT at 24, 20, and 9 years post ABMT. At the time of LT, all displayed severe obstructive ventilatory defects with a forced expiratory volume in 1 second (FEV1)<30% and partial respiratory insufficiency. The initial immunosuppression was cyclosporine, mycophenolate mofetil, and steroids in all cases. Two of the subjects required changes in the immunosuppressive regimen: 1 due to chronic graft rejection with subsequent functional recovery and the other due to hematologic and neurologic toxicity. After 96, 37, and 9 months, all the patients were alive with baseline dyspnea of functional class 0 and a FEV1 of about 68%. CONCLUSION: LT is an effective therapy in terms of lung function and survival for patients with respiratory failure secondary to the development of BO after ABMT. PMID- 20970600 TI - Influence of body mass index in the postoperative evolution after lung transplantation. AB - OBJECTIVE: To study the influence of body mass index (BMI) on mortality and postoperative evolution in our 10-year experience as a lung transplant group. METHODS: The study included 256 lung transplants performed between June 1999 and June 2009. BMI was stratified into 4 groups (<20 kg/m2 underweight, 20-25 normal weight, 25-30 overweight, and >30 obese) for posttransplant mortality assessment (chi-square) in relation to age, gender, pathology, and transplant type (logistic regression). Time of mechanical ventilation and length of stay in the intensive care unit and in the hospital were also analyzed (Kruskal-Wallis test). RESULTS: BMI showed a normal distribution with a mean value of 24.8+/-5 kg/m2 (range, 13 38). Although postoperative mortality was greater in the overweight (23%) and obese (23.7%) groups, it did not reach statistical significance, nor was there a significant increase in the risk of death (odds ratios of 1.06 and 1.17, respectively). Risk of death was independent of BMI and was associated with pathology (lower in emphysema) and transplant type (lower in single lung). There were no significant differences in duration of mechanical ventilation (342 hours in obese patients vs 180 in normal weight; P=.7), length of stay in the intensive care unit (18 days in obese patients vs 14 in normal weight; P=.8), or length of hospital stay of patients that were discharged (37 days in obese patients vs 43 in normal weight; P=.8). CONCLUSIONS: In our experience, BMI is not a risk factor that significantly increases postoperative mortality, probably owing to an adequate selection of recipients and an optimal posttransplant management. However, it must be considered to be a relative contraindication, because it is established in the international guidelines, obliging a correct assessment of patients, especially if there are other comorbidities. PMID- 20970601 TI - Genetic polymorphisms and individualized tacrolimus dosing. AB - BACKGROUND: Genetic polymorphisms of metabolism enzymes or intestinal drug transporters may affect pharmacokinetic responses to immunosuppressive drugs in renal transplant recipients. We sought to identify the frequency of genetic polymorphisms and their importance for individualization of tacrolimus doses. PATIENTS AND METHODS: We performed an observational study in 35 renal transplant recipients treated with tacrolimus, mycophenolate mofetil, and corticosteroids. Tacrolimus concentrations were determined by immunoanalysis (IMx method; Abbott Diagnostics, Abbott Park, Ill), on 11 blood samples per patient during the first 6 weeks after renal transplantation. For each patient, we calculated the mean value and its standard error (SEM) of the concentration/dose ratio (ng/mL/mg) of tacrolimus. The pharmacogenetic analysis included single nucleotide polymorphisms (SNPs) in the CYP3A5 (CYP3A5*3 (A6986G), CYP3A5*6 (G14690A), MDR1 (C3435T and G2677T/A) and PXR (C-25385T) genes. RESULTS: Of the patients, 62.8% (n=22) were men and the overall mean age was 55 years (95% confidence interval, 48.7-62.7). The SNP distribution was: CYP3A5*3: G/G=82.9%, A/G=17.1%; CYP3A5*6: G/G=88.6%, G/A=11.4%; MDR1 C3435T: C/C=25.7%, C/T=62.9%, T/T=11.4%; for MDR1 G2677T/A: G/G=22.9%, G/T=65.7%, T/T=11.4% and for PXR: C/T=85.7%, T/T=14.3%. Tacrolimus concentration/dose ratios in heterozygote patients for CYP3A5*3 genotypes was >120% lower than for the homozygote CYP3A5*3 genotype (0.65+/-0.04 vs 1.45+/ 0.05; P<.0001). Wild-type MDR1 (3435 C/C) genotype patients showed up to 40% lower concentration/dose ratios compared with heterozygote and homozygote genotypes (C/C; 1+/-0.07 vs C/T; 1.4+/-0.06 vs T/T; 1.37+/-0.09; P<.0001). CONCLUSION: Intestinal absorption and metabolism of tacrolimus was significantly affected by the SNPs in the CYP3A5 and MDR1 genes, which may offer a useful tool to optimize tacrolimus dosing after renal transplantation. PMID- 20970602 TI - Extended-release tacrolimus therapy in de novo kidney transplant recipients: single-center experience. AB - BACKGROUND: Available data for extended-release tacrolimus (Tac) except in clinical trials are limited. OBJECTIVE: To describe our initial experience with once-daily Tac in combination with corticosteroids and mycophenolate mofetil therapy in patients undergoing de novo renal transplantation. PATIENTS AND METHODS: In this retrospective, observational, single-center study, data were obtained for 49 adult recipients treated with extended-release Tac and 30 patients treated with standard-release Tac (control group). Mean (SD) follow-up in the 2 groups was 3.5 (2.5) months and 4.0 (2.6) months, respectively. The primary characteristics were comparable between the groups. RESULTS: The acute rejection rate in the extended-release group was 10%, and 13% in the standard release group. Patient and graft survival rates were 98% and 96% vs 100% and 90%, respectively. Renal function in the 2 groups was comparable: serum creatinine concentration 1.3 (0.2) mg/dL vs 1.45 (0.4) mg/dL. At day 14 posttransplantation, Tac doses were 0.17 mg/kg/d vs 0.14 mg/kg/d, and blood concentrations were 9.0 ng/mL vs 14.0 ng/mL. In recipients older than 60 years, lower dosages of Tac resulted in blood concentrations similar to those in younger patients, with less variation in dosage. CONCLUSIONS: Short-term experience with extended-release Tac therapy in de novo renal recipients confirms its efficacy and safety. Adjusting blood concentrations in the immediate posttransplantation period is less difficult with extended-release Tac compared with the twice-daily formulation. PMID- 20970603 TI - Pharmacokinetics of once- versus twice-daily tacrolimus formulations in kidney transplant patients receiving expanded criteria deceased donor organs: a single center, randomized study. AB - BACKGROUND: Noncompliance to immunosuppressive treatment is 1 of the risk factors for kidney graft loss. The once-daily, prolonged-release tacrolimus formulation may improve treatment adherence. We sought to compare the pharmacokinetics of both tacrolimus formulations in older de novo recipients of a cadaveric renal transplant from an expanded-criteria donor. PATIENTS AND METHODS: This randomized study included 27 patients (14 on once daily prolonged-release formulation [QD] and 13, on the twice-daily formulation [BID]), who were treated with 0.1 mg/kg per day of tacrolimus (target blood level, 5-8 ng/mL) mycophenolate mofetil prednisone and basiliximab induction. RESULTS: At 24 hours, in combination with the blood levels were 4.70+/-2.50 versus 4.70+/-3.04 ng/mL (P=NS). There were no significant differences in the AUC0-24 of tacrolimus (QD/BID) at 3 days (300.8+/ 60.15 vs 287.7+/-125.78 ng.h/mL) or 21 days (303.05+/-99.79 vs 275.26+/-75.37 ng.h/mL), nor in blood levels (ng/mL) at 1 month (8.76+/-2.46 vs 8.8+/-1.89), 3 months (7.30+/-1.72 vs 8.80+/-1.89) and 6 months (7.19+/-1.89 vs 6.60+/-1.71). At 3 days, there was a strong correlation between AUC0-24 and Cmin both for tacrolimus QD (r=.872) and BID (r = 1.0). The incidences of acute rejection episodes were: 0% versus 16.6%; graft survivals, 100% versus 92.3% (P=NS); and patient survivals, both 100%. CONCLUSION: For older de novo recipients of kidneys from expanded criteria donors tacrolimus QD is comparable to the same dose in the BID formulation with similar at least short-term transplant outcomes. PMID- 20970604 TI - Mycophenolate acid vs mycophenolate mofetil therapy. AB - BACKGROUND: Mycophenolate mofetil (MMF) is included in the basic immunosuppression regimen in heart transplantation (HTx). Classically, the mycophenolic acid (MPA) concentration has not been considered to provide clinical information. OBJECTIVE: To perform a comparative analysis of MMF dosage and MPA concentration and their effect on post-HTx renal function. PATIENTS AND METHODS: Sixty patients underwent HTx between January 2007 and April 2009, and were followed up at 4 scheduled visits in 6 months. The standard MMF dose was 1000 mg/12 h, with adjustment according to clinical criteria. The MPA concentration was determined using an enzyme-multiplied immunoassay (EMIT 2000; Siemens Healthcare Diagnostics Inc, Deerfield, Illinois), without change in dosage. The correlation between mean MMF dosage and MPA concentrations at all visits vs renal function values was analyzed using serum creatinine concentration, creatinine clearance (CrCl; Modification of Diet in Renal Disease), and glomerular filtration rate (GFR; Cockcroft-Gault formula). RESULTS: Mean (SD) patient age was 50 (13) years, and 45 of 60 (75.4%) were men. Pre-HTx values were as follows: creatinine concentration, 1.13 (0.47) mg/dL; CrCl, 81.59 (36.84) mL/min/1.73 m2; and GFR, 77.46 (30.60) mL/min. In the first 6 months post-HTx, significant negative correlations were observed between mean MPA concentration and creatinine concentration (r=.42; P=.001), CrCl (r=-.36; P=.01), and GFR (r=-.45; P=.001). No correlation was observed with mean MMF dosage. CONCLUSION: There are important differences in the relationship of MPA concentration vs MMF dosage and post-HTx renal function. Although studies with a larger number of patients are needed, treatment guided by MPA concentration seems reliable for evaluation of renal function. PMID- 20970605 TI - Evaluation of a fully automated method for the determination of sirolimus. AB - BACKGROUND: Sirolimus (SRL) is a macrocyclic lactone, indicated for prevention of organ rejection after kidney transplantation. Therapeutic drug monitoring of this agent constitutes an important part to immunosuppressive treatment because of its narrow window of therapeutic efficacy. Routine methods include manual pretreatment of samples. The aim of this study was to evaluate the performance characteristics of an automated immunoassay that does not require manual pretreatment to quantify SRL in whole blood on the Dimension analyzer. METHODS: We examined 50 whole blood samples collected routinely from kidney transplant patients treated with SRL. The samples were analyzed simultaneously by an immunoassay on an IMx analyzer (reference method), which requires manual pretreatment step versus a totally automated immunoassay on the Dimension analyzer, which does not require this pretreatment. RESULTS: The Dimension SRL assay had a functional sensitivity of <=2.4 ng/mL. Total imprecision was 15.6% at a concentration of 2.8 ng/mL; 10% at 7.9 ng/mL; and 5.2% at 18.4 ng/mL. Least squares linear regression analysis yielded an r-value of 0.973 with the following equation: SRL-D=1.204*SRL-IMx-0.251. Bland-Altman comparison showed a mean positive difference of 1.38 ng/mL (95% confidence interval, -1.10 to 3.82), namely, 17.2% for SRL Dimension. The Dimension assay to monitor SRL concentrations was an acceptable method for routine clinical use, with total assay imprecision (%CV) ranging from 10.0% to 5.2% within and above the therapeutic concentration range, respectively. CONCLUSION: SRL IMx and Sirolimus Dimension methods show a good correlation (r=0.973), but the SRL Dimension method demonstrated a positive average difference of 17.2% compared with the IMx method. The Dimension assay to monitor whole blood SRL concentration does not require a manual pretreatment step, reducing turnaround time and making this method an attractive alternative for SRL analysis. PMID- 20970606 TI - Changes in magnesium and potassium homeostasis after conversion from a calcineurin inhibitor regimen to an mTOR inhibitor-based regimen. AB - BACKGROUND: Transplant recipients treated with calcineurin inhibitors (CNIs) frequently show hyperkalemia, metabolic acidosis, and hypomagnesemia which could be deleterious for some patients. Conversion to inhibitors of mammalian target of rapamycin (mTOR) could improve these electrolytic disturbances. OBJECTIVE: To evaluate the potassium and magnesium changes due to converting patients from CNIs to mTOR inhibitors. METHODS: Retrospective review of 138 renal transplant patients who were converted from CNIs to mTOR inhibitors over a 6-month observation period. The following parameters were determined: potassium, sodium, chloride, magnesium, urea, glucose, and creatinine in blood and urine. We also analyzed plasma bicarbonate and calculated plasma and urine anion gap and plasma osmolarity. RESULTS: One month after conversion, a decrease was observed in serum creatinine (1.75+/-0.68 vs 1.61+/-0.61 mg/dL; P=.01), plasma potassium (4.60+/ 0.52 vs 4.39+/-0.53 mEq/L; P<.001), calculated plasma osmolarity (308.7+/-8.5 vs 307.4+/-8.4 mOsm/L; P<.036), fractional excretion of sodium (1.55+/-0.69 vs 1.29+/-0.65%; P<.003), and fractional excretion of magnesium (7.15+/-4.08 vs 15.84+/-3.64%; P<.001), with an increase in serum magnesium (1.77+/-0.24 vs 1.95+/-0.29 mg/dL; P<.001). At 3 and 6 months, these differences remained unchanged. The transtubular potassium gradient did not change. CONCLUSIONS: We observed a decrease in serum magnesium due to renal magnesium wasting before switching from CNIs to mTOR inhibitors. After conversion, an increase in serum magnesium was observed together with a drop in the fractional excretion of this cation. A decrease in plasma potassium levels, plasma osmolarity, and fractional excretion of sodium consistent with minor aldosterone resistance was also detected after changing the immunosuppressive treatment. PMID- 20970607 TI - Comparative analysis of adverse events requiring suspension of mTOR inhibitors: everolimus versus sirolimus. AB - BACKGROUND: Inhibitors of mammalian target of rapamycin (mTORi) have been suggested as an alternative to calcineurin inhibitors (CNIs) to treat stable renal transplant recipients. However, their use has been significantly limited owing to a high incidence of side effects. OBJECTIVE: To compare the rate of dropout (mTORi elimination and CNI reintroduction) caused by side effects among renal transplant patients converted to everolimus (EVL) or sirolimus (SRL). METHODS: Between October 1999 and February 2010, 409 subjects were converted to an mTORi at least 3 months after transplantation, including 220 (53.8%) to EVL and 189 (46.2%) to SRL. Most patients were under CNI therapy. Patients were followed for a median of 35 months (interquartile range [IQR], 18-50 months). RESULTS: mTORi treatment was prematurely eliminated due to adverse events in 112 patients. The median time between the initiation of mTORi and discontinuation was 5.7 months (IQR, 1.9-15.7 months; range, 0.2-48 months): 5.5 (IQR, 1.6-16.3) in the EVL group and 7.4 (IQR, 2.6-15.6) in the SRL group. In the EVL group, the drug was stopped in 69 patients (31.4%), and in the SRL group in 43 patients (22.8%; P=.051). The most important causes of discontinuation were severe infections (2.3% in EVL group and 4.8% in SRL group; P=.17), pneumonitis (6.8 % in EVL group and 4.8 in SRL group; P=.38), acute rejection episode (4.1% in EVL group and 1.6% in SRL group; P=.13), proteinuria (4.1% in EVL group and 1.6% in SRL group; P=.13), renal function deterioration (2.3% in EVL group and 2.1% in SRL group; P=.91), and severe dermal eruption (2.3% in EVL group and 0.5% in SRL group; P=.14). CONCLUSIONS: Although the overall incidence discontinuations due to side effects was higher in the EVL group, there was no greater frequency of severe side effects, such as pneumonitis, proteinuria, acute rejection episodes, renal function deterioration, or dermal eruptions. PMID- 20970608 TI - Pneumonitis associated with mammalian target of rapamycin inhibitors in renal transplant recipients: a single-center experience. AB - BACKGROUND: The mammalian target of rapamycin inhibitors (mTORi) sirolimus (Si) and everolimus (Ev) induce pneumonitis, an unusual but potentially fatal adverse effect. We report 8 cases of suspected mTORi-induced pneumonitis over a 9-years experience from 2000 to 2009. METHODS: The switch from a calcineurin inhibitor (CNi) was made due to chronic transplant nephropathy, tumors, nephrotoxicity, or for rejection prophylaxis. RESULTS: One hundred six patients were switched from CNi to Si (n=29) or Ev (n=134). Twenty-five additional patients were treated de novo with mTORi. The 8 patients (3 Si, 5 Ev) who developed pneumonitis included 5 females and 3 males of median age, 59.1 years (range, 40-68). The median time from switch to pneumonitis onset was 292 days (range, 60-982). The clinical presentation included fatigue (n=6), fever (n=7), dyspnea (n=6), dry cough (n=6), and weight loss (n=5). In most cases, imaging tests (chest radiograph, computerized tomography) revealed bilateral lower lobe involvement. Bronchoalveolar lavage showed a lymphocytic alveolitis in 5 subjects with negative cultures. All patients recovered after mTORi withdrawal. All patients were treated with antibiotics and five with steroids. CONCLUSION: mTORi associated pneumonitis is not a rare disease. It is equally induced by Si or Ev. Pneumonitis was not apparently dependent on the drug dose or the blood levels. Discontinuation of mTORi seems to be the safest treatment option to avoid pulmonary fibrosis or a fatal outcome. PMID- 20970609 TI - Effects of the new immunosuppressive agents on the occurrence of malignancies after renal transplantation. AB - INTRODUCTION: The risk of malignancies in renal transplant recipients is considerably greater than in the general population. The purpose of the present study was to investigate the effects on the appearance of malignancies of 3 immunosuppressive periods: azathioprine (AZA), cyclosporine (CsA), and tacrolimus (TAC). PATIENTS AND METHODS: This study included 1029 first renal transplant recipients of mean age at transplantation of 44.6+/-14.9 years with a mean follow up of 95.6+/-84.2 months. Initial immunosuppression was AZA-based (n=198), CsA based (n=524), and TAC (n=307). A total of 280 recipients were also treated with mycophenolate mofetil or mycophenolic acid. RESULTS: There were 157 patients (15.3%) who displayed>=1 malignancy; there were 95 skin (9.2%) and 74 (7.8%) non skin malignancies with presentations at 74+/-62 and 107+/-77 months, respectively (P=.003). The skin malignancies included squamous cell carcinomas (n=41), basal cell carcinomas (n=41), Kaposi sarcomas (n=7), and melanomas (n=4). Among the solid tumors, lymphoproliferative disorders (n=15), digestive tract (n=14), kidney and urinary tract (n=11), lung (n=10), and breast (n=3) carcinomas. The cumulative incidences at 5, 10, and 15 years were 6%, 10%, and 18% for skin and 3%, 7%, and 14% for non-skin malignancies, respectively. Multivariate analysis showed that age at transplant in years (P=.000) and male gender (P=.000) were the only variables associated with skin malignancies; age at transplant in years (P=.004) and treatment with OKT3 (P=.000) were associated with non-skin malignancies. Malignancies were the cause of death in 18% of recipients who died with functioning grafts. CONCLUSION: Malignancies are an important cause of morbidity and mortality among renal transplant recipients. The new immunosuppressive agents do not increase the risk of malignancies. Special surveillance is needed for older, male recipients. PMID- 20970610 TI - Mycobacterium abscessus infection in transplant recipients. AB - BACKGROUND: Mycobacterium abscessus is a ubiquitous, rapidly growing mycobacterium that colonizes organic surfaces. It is a potential pathogen, especially in immunosuppressed patients, including transplant recipients in whom disease can range from localized cutaneous lesions to disseminated infections. The purpose of this study was to describe the 12-year impact from January 1997 to December 2009 of M. abscessus infection among solid organ and bone marrow transplantations performed in adults and children. METHODS: Information was obtained from the database of our Microbiology Department concerning samples, culture methods, and in vitro susceptibility testing. Isolates were classified as contaminants (C), colonization (CL), or disease (D) following standard criteria. We reviewed the medical records of affected subjects. RESULTS: M abscessus was isolated in 76 patients (28 C, 18 CL, and 30 D), including 11 recipients, namely 8 (73%) classified as disease displaying 1 bone marrow case and solid organ cases -4 (50%) pulmonary (2 after cystic fibrosis), 2 renal, and 1 heart transplant patients. All were adults. The localization of infection showed 2 disseminated cases, both of whom shows cutaneous primary lesions, and 6 localized in 3 cases cutaneous and in 3, respiratory. CONCLUSION: Diseases caused by M abscessus have increased in the last 5 years, possibly due to the greater number of transplants and the more focused search for the lesions. Most isolates were from lung cases, especially those with infections prior to transplantation. Respiratory and cutaneous samples were predominant, with skin lesions being an important site of primary symptom previous to dissemination of infection. Although the optimal regimen remains undefined, a favorable outcome depended mainly on a rapid diagnosis and inception of treatment following susceptibility test results. PMID- 20970611 TI - Inter-alpha-trypsin inhibitor heavy chain 4 as a marker of acute rejection in pancreas allotransplantation in pigs. AB - BACKGROUND/AIMS: An early, simple, and reliable marker for acute pancreatic allograft rejection is not available. Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is an interleukin-6-dependent acute-phase positive protein that can act as an anti-inflammatory protein. We studied the response of the ITIH4 in pigs undergoing pancreas allotransplantation (PT) and evaluated this protein as a biomarker for acute graft rejection. METHODS: PT with enteric drainage of the exocrine secretion and systemic venous drainage was performed on 12 Landrace pigs. No immunosuppression was administered. Serum concentrations of glucose, amylase, lipase, insulin, C-peptide, and ITIH4 were determined daily. RESULTS: The response of ITIH4 to PT was early, intense, and prolonged, with 2 peaks in serum concentration. The first peak, which started on day 1 and reached maximum (around 6 mg/dL) on day 3, was attributed to the systemic acute phase response to surgical stress. The second peak, which exceeded the first peak and reached maximum (>8 mg/dL) on day 6, began when the recipients were still normoglycemic, and preceded onset of the diabetic state caused by acute graft rejection by an average of 4 days. CONCLUSION: Serum ITIH4 could help to predict subclinical acute graft rejection after PT in pigs. PMID- 20970612 TI - Relevance of epidermal growth factor to improve steatotic liver preservation in IGL-1 solution. AB - AIM: Static preservation solution is critical for liver graft outcomes, especially when steatosis is present. Institut Georges Lopez (IGL)-1 solution protects fatty livers effectively against cold ischemia reperfusion injury. Its benefits are mediated by nitric oxide and prevention of oxidative stress. The supplementation of IGL-1 with epidermal growth factor (EGF) enhances steatotic graft preservation by increasing adenosine triphosphate content, thereby mitigating oxidative stress and mitochondrial damage. METHODS: After steatotic livers were preserved for 24 hours in IGL-1 solution with or without EGF supplements, they were perfused ex vivo for 2 hours at 37 degrees C. The benefits of EGF were assessed by evidences of hepatic damage and function--transaminases, bile production, and flow rate--as well as by other factors presumably associated with the poor tolerance of fatty livers toward cold ischemia-reperfusion injury (IRI)--energy metabolism, mitochondrial damage, oxidative stress, eNOS activity and proinflammatory interleukin (IL) beta content. RESULTS: Steatotic livers preserved in IGL-1 solutions supplemented with EGF (10 MUg/L) showed lower transaminase levels, greater bile production, and ameliorated flow rates when compared to IGL-1 alone. In addition, energy metabolism deterioration, mitochondrial damage, oxidative stress, and cytokine IL-1 beta release were prevented. CONCLUSION: EGF addition to IGL-1 increased fatty liver graft preservation, thereby reducing steatotic liver damage against cold IRI. PMID- 20970613 TI - Portal revascularization in the setting of cavernous transformation through a paracholedocal vein: a case report. AB - Diffuse thrombosis of the entire portal system (PVT) and cavernomatous transformation of the portal vein (CTPV) represents a demanding challenge in liver transplantation. We present the case of a patient with nodular regenerative hyperplasia and recurrent episodes of type B hepatic encephalopathy concomitant with PVT as well as CTPV, successfully treated with orthotopic liver transplantation. The portal inflow to the graft was carried out through the confluence of 2 thin paracholedochal varicose veins, obtaining good early graft function and recovery of the encephalopatic episodes. This alternative should be kept in mind as an option to assure hepatopetal splanchnic flow in those cases of diffuse thrombosis and cavernomatous transformation of portal vein. PMID- 20970614 TI - Severe rhabdomyolysis after allogeneic transplantation of facial structures: a case report. AB - We present a patient with panfacial neurofibromatosis type 1 who underwent allogeneic transplantation of facial structures, which was complicated by severe rhabdomyolysis and temporary oligoanuria. Because of his underlying disease, this 35 year-old man, weighing 68 kg and with a body mass index (BMI) of 27, had undergone 17 operations for resection modeling of hypertrophied tissues, either alone or combined with static suspension techniques. He finally underwent allogeneic transplantation of facial structures. In the early hours of the postoperative period, in the context of a systemic inflammatory response syndrome, he experienced severe rhabdomyolysis, with elevation of the muscle enzyme creatine kinase producing a minor impact on kidney function. The patient was discharged home at 12 weeks after the transplantation. PMID- 20970615 TI - The 6th Congress of The Andalusian Society of Organ and Tissue Transplantation (SATOT). PMID- 20970616 TI - Can we accept donors who have suffered a resuscitated cardiac arrest? AB - INTRODUCTION AND AIMS: The shortage of donor organs has prompted increased acceptance of hearts from donors with more comorbidities. With increasing frequency, hearts are being offered from patients who have undergone a resuscitated cardiac arrest (RCA). Our aim was to compare the rate of complications in the postoperative and follow-up periods, depending on whether the transplanted organ came from a donor who had undergone an RCA. MATERIALS AND METHODS: We included all 604 heart transplantations (HTs) performed in our center from 1987 to 2009, including 25 recipients who received an organ from a donor who had undergone RCA. We considered RCA to be an in-hospital cardiac arrest that was resuscitated from the onset, with a duration of <30 minutes, and with total recovery of cardiac and hemodynamic function. We analyzed ischemia time, incidence of acute graft failure (AGF), intubation period, recovery room stay, and long-term survival. The statistical methods were Student t and chi-square tests. RESULTS: There were no differences in baseline characteristics, except that patients in the RCA group were younger (47+/-13 vs 51+/-11 years; P=.50). There were also no differences between the RCA group and the other patients in ischemia time (151+/-50 vs 154+/-53 minutes; P=.826), incidence of AGF (33% vs 24.7%; P=.311), hours of intubation (76+/-204 vs 72+/-249; P=.926), days of recovery room stay (6+/-7 vs 8+/-6; P=.453), or survival after HT (53+/-54 vs 53+/-52 months; P=.982). CONCLUSIONS: Patients receiving a heart from a patient with an in-hospital RCA and subsequent hemodynamic stability have a similar outcomes to other HT patients. PMID- 20970617 TI - International multicenter opinion study: administrative personnel from Spanish and Mexican health centers faced with human organ donation for transplantation. AB - INTRODUCTION: Administrative personnel from healthcare centers are an important opinion group given their direct relationship to patients and the general public. OBJECTIVE: The objective of this study was to analyze the attitudes of administrative personnel in Spanish and Mexican healthcare centers toward various kinds of donation. MATERIAL AND METHODS: A random selection of 418 administrative staff from 32 primary care centers and 9 hospitals in Spain and Mexico ("Proyecto Donante, Murcia") used a validated questionnaire to explore attitudes. RESULTS: Most (76%) respondents favored deceased donation. Mexican workers had the most favorable attitude (P<.001). Factors influencing this attitude (P<.05) were as follows: type of healthcare center, clinical service, personal experience of organ donation and transplantation (ODT), attitude toward living donation, attitude toward the donation of a family member's organs, discussion of ODT, partner's attitude toward ODT, participation in pro-social activities, and variables related to attitudes toward the body. Most respondents (89%) favored related living kidney donation (LKD) and 87% favored living liver donation (LLD). Mexican respondents showed the most favorable attitudes (P<.05). Factors influencing this attitude (P<.05) were as follows: personal experience of ODT, belief that a transplant is needed, willingness to accept a living organ, family discussion about ODT, partner's attitude about the matter, and respondent's awareness of the view of his or her religion toward ODT. CONCLUSION: Attitudes toward deceased organ donation were not favorable among administrative personnel from Spanish compared with Mexican centers, although attitudes toward LKD and LLD were favorable in both countries. PMID- 20970618 TI - Attitudes toward islet cell and tissue xenotransplantation among kidney and liver patients on the transplant waiting list. AB - INTRODUCTION: Research into xenotransplantation is centered on the fields of organs, tissues, and cells. However, the use of animals in this therapy is creating social rejection among the general public as well as among patients on the transplant waiting list. OBJECTIVE: The objective of this study was to analyze the attitudes of patients on the waiting list toward a possible transplantation of cells or tissues of animal origin. MATERIALS AND METHODS: The study included patients on the kidney and liver transplant waiting lists from January 2003 until December 2005 (N=373). Attitudes toward xenotransplantation were assessed using a psychosocial questionnaire about the donation of animal organs. The questionnaire was administered through a direct personal interview. RESULTS: With regard to the xenotransplantation of tissues and cells, 83% of kidney patients (n=177) were in favor and 17% (n=37) were not in favor of both options. Patients who were more in favor for tissues and also for cells were young respondents (P=.016; age P=.006) and those with a formal education (P=.002; education P=.001). Among liver patients, 85% (n=134) were in favor and 15% (n=24) were not in favor. Those who were more in favor for tissues included elderly patients (P=.028) and those with descendents (P=.001); for cells, those who were more in favor were those who were married (P=.011), were older (P=.009), and had children (P<.000). No significant differences were observed between the groups. CONCLUSION: Patients on the solid organ transplant waiting lists showed favorable attitudes toward tissue and cell xenotransplantation. PMID- 20970619 TI - Attitude toward living liver donation in transplant hospitals in Spain, Mexico and Cuba. AB - BACKGROUND: Transplantation hospitals have played a key role in developing deceased organ donation and transplantation (ODT). To reduce the number of deaths on the transplant waiting list, it is essential to encourage living liver donation (LLD). Involvement of personnel in these hospitals is crucial. PURPOSE: We analyzed the attitudes toward LLD among hospital personnel in Spain, Mexico, and Cuba. MATERIALS AND METHODS: Data were obtained from 5 transplant hospitals in Spain, Mexico, and Cuba. The sample was stratified according to job category and type of service (n=2273). A validated questionnaire about living donation was used as the instrument. RESULTS: Most respondents (82%) were in favor of related LLD. If the LLD was not related, acceptance fell to 21%. A total of 85% of physicians, 79% of nursing personnel, 74% of nursing assistants, and 83% of auxiliary staff were in favor (p<.001). A favorable attitude toward LLD was associated (P<.05) with age (37+/-10 y vs 39+/-10 y), a favorable attitude toward deceased donation, a belief that a possible transplant is needed, acceptance of LLD if necessary, a favorable attitude toward living kidney donation, family discussion about ODT, a partner's favorable attitude toward ODT, an intention to participate in prosocial activities, being a Catholic, and a belief that one's religion is in favor of ODT. CONCLUSIONS: Personnel from Spanish, Mexican, and Cuban transplantation hospitals have favorable attitudes toward LLD. This suggests that there may be an increase in LLD in the future, provided that there is the necessary sociopolitical and economic support. PMID- 20970620 TI - Evaluation of attitudes toward living organ donation: a multicenter study of compulsory secondary school education teachers. AB - BACKGROUND: There is a considerable transplant organ deficit. To offset the organ shortage, living donation is being encouraged. Young persons form a sector of the population in whom early awareness is important to encourage favorable attitudes toward donation. Teachers play important roles in education and in generating attitudes. PURPOSE: We analyzed the attitudes of secondary school teachers toward living organ donation and sought to determine the psychosocial variables that affect these attitudes. MATERIALS AND METHODS: We randomly selected Teachers from 10 secondary schools in southeastern Spain. Their attitudes toward living donation were evaluated using a validated questionnaire, which was self administered anonymously. The statistical tests were Student t test and the chi2 test. RESULTS: Regarding living kidney donation, 92% of teachers were in favor of related donation, decreasing to 16% when it was not from a related individual. In contrast, regarding related donations, 7% were not in favor, and 1% undecided. Teachers who had discussed the matter with their family and friends had more favorable attitudes (P<.05). In the case of living liver donations, 91% were in favor of related donation (falling to 20% if not related), 7% were not in favor, and 2% had doubts. Attitudes were more favorable among women, teachers with children, and those who had discussed the matter with their family and friends (P<.05). CONCLUSIONS: Teachers had favorable attitudes toward living related kidney or liver donation. Their students would receive positive information when they request relevant information. PMID- 20970621 TI - Evaluation of the law of presumed consent after brain death by Spanish journalism students. AB - INTRODUCTION: Information provided by journalists is crucial to create a climate of social opinion. This is important in organ donation and transplantation (ODT), wherein the participation of the general public is essential to obtain organs. OBJECTIVE: The objective of this study was to determine the knowledge of students taking a degree in journalism about the concept of brain death and the law of presumed consent. MATERIALS AND METHODS: The study involved 129 journalism degree students in the 2005-2006 academic year from a university in the south-east of Spain. Attitudes on the psychosocial aspects of ODT were evaluated using a validated questionnaire. The self-administered survey was completed anonymously in classes and compulsory practical sessions. RESULTS: The questionnaire completion rate was 98% (n=126). Of the students surveyed, 43% (n=54) understood the concept of brain death, 44% (n=56) stated that they had doubts, whereas 13% (n=16) believed that a person with brain death can recover and lead a normal life. Their knowledge was more accurate in the final than in the first year (54% vs 47%; P=.016). Most students 66% (n=83) believed that it would be interesting to receive an informative talk about ODT. Concerning legislation, 75% of students were against the law of presumed consent, whereas 25% were in favor. CONCLUSION: More than 50% of journalism students do not understand the concept of brain death. Furthermore, up to 75% do not accept the law of presumed consent that donation must be made. PMID- 20970622 TI - From where do our children receive information about organ donation and transplantation? AB - INTRODUCTION: The information provided about organ donation and transplantation (ODT) affects whether it is viewed favorably or unfavorably. OBJECTIVES: The objective of this study was to determine the means by which each source of information about ODT influenced attitudes of children. MATERIAL AND METHODS: Ten secondary schools from the south-east of Spain were stratified geographically. We performed a random selection of pupils from the first 4 years of compulsory secondary range, education (age 11-15 years). A validated self-administered questionnaire about attitudes toward ODT was completed anonymously. RESULTS: The adolescents had received information about ODT through several sources. The most frequent sources were television (86%), films (59%), and magazines (56%). Positive information from information sources was associated with more favorable attitudes toward ODT (P<.05); those who received negative information had more unfavorable attitudes (P<.05). CONCLUSIONS: Most information about ODT that reaches our children is through audiovisual means. Attitudes were more favorable among adolescents who have received positive information through the mass media, with more negative attitudes among those who received negative information. PMID- 20970623 TI - Welsh citizens in south-eastern Spain: a study of attitude toward organ donation. AB - INTRODUCTION: The increase in the British population, including Welsh citizens, in the south-east of Spain is generating a new social and healthcare reality that is affecting the world of transplantation. OBJECTIVES: The objectives of this study were as follows: (1) to determine the attitude of the local population originating from Wales toward the donation of their own organs, and (2) to analyze the factors that determine this attitude. MATERIALS AND METHODS: A random sample (n=126) was selected from the population in Murcia originating from Wales (November 2005-March 2006). Attitudes were evaluated using a validated questionnaire. A control group comprised the autochthonous population (n=2000). The sample was stratified according to age, gender, and geographical location. RESULTS: In this study 76% (n=96) had favorable attitudes toward donation, 6% (n=8) were against, and the remainder 18% (n=22) were not sure. Attitudes were more favorable than among the Spanish control group (76% vs 63%; P=.045). The following variables were associated with this attitude: (1) knowledge of the concept of brain death (P<.001); (2) having spoken within the family about the subject (P=.005); (3) attitude toward the donation of a family member's organs (P<.001); (4) knowing the attitude of one's religion toward donation (P=.033); and (5) attitude of one's partner toward donation (P<.001). CONCLUSION: Welsh citizens who are residents in south-eastern Spain have attitudes toward organ donation that are more favorable than those of the native Spanish population. They seem to be determined by knowing the concept of brain death and positive attitudes of one's family. PMID- 20970624 TI - Transthoracic echocardiographic findings in patients with chronic kidney disease awaiting kidney transplantation. AB - BACKGROUND: The high prevalence of classic cardiovascular risk factors in patients undergoing dialysis therapy or transplantation is associated with a 3.5- to 50-fold higher risk than in the general population. The primary cause of death in transplant recipients is cardiovascular disease. OBJECTIVE: To report echocardiographic findings using a screening protocol to detect heart disease in candidates for kidney transplantation. METHODS: Between November 2005 and December 2009, we examined 356 patients using 2-dimensional color Doppler echocardiography. RESULTS: A high prevalence of left ventricular hypertrophy, left ventricular diastolic dysfunction, valvulopathy, and valve calcification was observed. There was a positive correlation between valve calcification and female sex, age (P<.001), duration of renal replacement therapy (P=.01), peripheral arterial disease (P=.02), cerebrovascular disease (P=.005), and high concentration of lipoprotein(a) (P=.02). CONCLUSION: An echocardiographic study should be part of the initial evaluation in candidates for renal transplantation. PMID- 20970625 TI - Prevalence of cardiovascular disease in kidney transplant candidates: outpatient cardiac evaluation. AB - BACKGROUND: Cardiovascular disease is the most common cause of death after kidney transplantation. Pretransplant cardiovascular screening is an integral part of the assessment of patients with end-stage renal disease in most transplantation centers. Through this descriptive study we sought to highlight the major cardiovascular diseases that cause the high mortality rate before and after renal transplantation. METHODS: Between November 2005 and December 2009 we screened 356 patients for cardiovascular disease before inclusion in the renal transplant waiting list. All candidates underwent an analytical study, chest radiography, electrocardiogram, and echocardiography, as well as coronary angiography in high risk patients. RESULTS: Clinical evaluations were performed in 356 patients (63% men) of mean age 54.3+/-11 years. They had been on renal replacement treatment for a median 13.2 months. Risk factors included hypertension (95.8%), dyslipidemia (56.5%), smoking (53.4%), and diabetes (27.2%). Cardiovascular disease included peripheral artery disease (15%), coronary artery disease (CAD; 12.1%), and stroke (9.8%). Significant CAD was found in 89 individuals (38.4%), 73 (82%) of whom were asymptomatic. Peripheral artery disease (P=.02), high levels of total cholesterol (P=.03), triglycerides (P=.03), and C-reactive protein (P=.03) were associated with the presence of severe CAD. The main diagnoses were hypertensive heart disease (70.8%), ischemic heart disease (33.1%), aortic valve disease (24.4%), and mitral valve disease (30.1%). CONCLUSIONS: Patients with chronic kidney disease show a high prevalence of cardiovascular risk factors and ischemic heart disease, principally occult coronary artery stenosis, which could explain their high cardiovascular mortality after renal transplantation. PMID- 20970626 TI - Results of living kidney donation in Andalusia: 2006-2009. AB - Renal transplantation is the best therapeutic choice in patients with end-stage renal disease (ESRD), with donation from living donors the alternative that offers the best medium- and long-term results. Because of the limited number of cadaver donors and the progressive increase in donor age, transplantation from living donors has become the renal replacement treatment of choice. Several studies have demonstrated that donation does not increase the donor's risk of developing ESRD in the long term. Some studies have asserted that a donor's life expectancy increases as a result of the comprehensive study and screening process they must undergo. The objective of the present study was to evaluate the vital status and onset of chronic renal disease in 101 living kidney donors in Andalusia, Spain, during 2006-2009, based on data obtained from the Sistema de Informacion de la Coordinacion Autonomica de Trasplantes de Andalucia (Regional Transplants Coordination of Andalusia). Donor survival was 99%, and the only death, from lung cancer, was not associated with the surgical procedure. Only 5 transplants failed during this period, and no donors developed ESRD. Neither the probability of survival nor the risk of developing ESRD in donors was influenced by kidney donation. PMID- 20970627 TI - Renal Transplant Register of Andalusia, 2010 Report: survival in relation to the factors used in recipient selection. AB - Kidney transplantation is the best therapeutic alternative for patients suffering from end-stage renal disease (ESRD). In recent years a significant advance has been made in Andalusia in graft and recipient survival as seen in our 2009 publication. In the current work we analyzed 2989 kidney transplantations performed between January 1, 2000 and December 31, 2009 based on data obtained from the Renal Transplant Registry of Andalusia. We studied the influence on graft and patient survival of factors, such as donor and recipient age, HLA matching, HLA immunization, and duration of previous renal replacement therapy. Patient survival was influenced by age at the time of transplantation and by donor age; the younger the donor, the more it was improved. Graft survival was determined by the donor age group, with no differences at each level according to the recipient age group. No significant differences were observed in patient survival or graft or death-censored graft survival according to HLA matching. Patient and graft survivals were significantly affected by the duration of the previous renal replacement therapy. Despite this being a preliminary study, we have shown the importance of nonmodifiable factors in transplant survival, such as donor and recipient age, with HLA matching having a limited effect. These latter findings should be confirmed in the future by multivariate analyses. PMID- 20970628 TI - Influence of pharmacogenetic polymorphisms in routine immunosuppression therapy after renal transplantation. AB - Pharmacogenetics is the study of the cause of various individual responses to the same pharmacologic therapy. Genetic alterations in a single nucleotide in the genes responsible for transport and metabolism of an immunosuppression drug may modify patient response. Although pharmacogenetics is of interest, its clinical relevance remains to be demonstrated. The objective of the present study was to evaluate the effect of single-nucleotide polymorphisms (SNPs) in renal transplant recipients and their donors relative to blood concentrations of tacrolimus in the first 2 weeks posttransplantation. Seventy-one blood samples each from renal transplant recipients and their donors were analyzed using a genetic analysis system (MassARRAY; Sequenom, Inc, San Diego, California) in an attempt to characterize the more relevant SNPs of the ABCB1 and CYP3A5 genes for correlation with recipient trough concentrations of drug. Two-way analysis of variance and Bonferroni post hoc tests were used. In agreement with theoretical predictions, the wild-type genotype in ABCB1 SNPs (CC) tended to stabilize drug concentrations within the therapeutic range, whereas the T variant induced a mean increase in blood concentrations of more than 60%. These findings are in agreement with statistical tests that compared mean concentrations in various recipient-donor populations and found significant differences between them (P<.001) in CC vs TT, and P<.01 in CT vs TT). Donor genotype did not seem to be relevant. However, further studies are required to achieve more robust conclusions. PMID- 20970629 TI - Recovery of native renal function after kidney transplantation. AB - IgA nephropathy is the most frequently occurring glomerulonephritis in the developed world. It is treated in the terminal phase via dialysis and transplantation. Posttransplantation recurrence is common, but evolves slowly. Herein, recovery of native kidney function 10 years after transplantation in a patient with IgA glomerulonephritis is described, and the potential effect of immunosuppression therapy, in particular with mycophenolate mofetil, is discussed. PMID- 20970630 TI - Cases of swine flu in kidney transplant recipients in our hospital. AB - In late March 2009, an outbreak of influenza A virus infection was detected in Mexico with subsequent cases observed in many other countries. The pandemic was caused by an H1N1 virus that represents a quadruple reassortment of 2 swine strains, 1 human strain, and 1 avian strain of influenza. Until February 1, 2010, a total of 47 cases of influenza A (Inf A) were recorded by the Spanish Society of Nephrology in kidney transplant recipients. Herein we have reported our 3 cases (6.4%) in this registry. A 17-year-old girl with hepatorenal polycystosis received a liver and kidney transplant at 37 months previously. She displayed high fever and mild respiratory symptoms that resolved without treatment. A 38 year-old woman with chronic renal failure (CRF) of undetermined etiology received a kidney transplant 9 months previously. She was admitted with a 5-day history of febrile syndrome and respiratory symptoms, with extensive bilateral pneumonia and acute severe respiratory failure that required admission to the intensive care unit. Her evolution was satisfactory. A 38-year-old woman with CRF of undetermined etiology received a kidney transplant 2.5 months previously. She was admitted in November 2009 with a 2-week history of fever, myalgia, general malaise, cough, and expectoration. Her course was satisfactory. In these cases we determined H1N1 Inf A pandemic variant by detection of Inf A Matrix Protein 2 gene M2 and the specific H1 gene for influenza pandemic H1N1 2009 with reverse transcriptase polymerase chain reaction Inf A/H1N1 (Roche). The 3 cases of Inf A in kidney transplant recipients recorded in the province of Almeria occurred in young women shortly after kidney transplantation, and with no other risk factors apart from those associated with the transplantation itself. From the consideration of respiratory and renal situations, their courses were satisfactory. PMID- 20970631 TI - Urologic complications after kidney transplantation: involvement of the double-J stent and the urologic suture. AB - Urologic complications in renal transplantation are an important cause of morbidity and hospitalization. This retrospective study of 343 transplants, performed between 1999 and 2009, analyzed the incidence of urinary fistula (4.4%) and ureteral stenosis (3.5%), based upon the type of extravesical anastomosis Woodruff (W) versus Taguchi (T)-and with versus without the use of a double-J stent. The frequencies of ureteral stenosis with a W anastomosis (without a double J), W+double J, or T+double J were 3.7%, 1.5%, and 9%, respectively (P=.031). There were differences between W+double J versus T+double J (P=.015), with a hazard ratio (HR)=6.3. In relation to a double-J stent, the incidences of fistulae among patients with a double-J stent were: W (12%) versus W+double J (0.8%) versus T+double J (0%; P<.0001; HR=15.8) versus patients without a double J stent. Logistic regression showed the predictors of ureteral stenosis to be a urologic anastomosis (odds ratio 0.06, 95% confidence interval [CI]: 0.01-0.49) and delayed renal function (odds ratio 10.1, 95% CI: 1.4-72.4). Concerning fistulae, the best covariates were double-J stent (odds ratio 0.027, 95% CI: 0.003-0.227) and donor age (odds ratio 1.052, 95% CI: 1.01-1.096). A double-J stent protected against the development of a urologic fistula. Donor age was a risk factor. The W suture with a double-J stent was the best way to prevent ureteral stenosis, with delayed graft function being an important risk factor. PMID- 20970632 TI - Coping styles of patients on the liver transplant waiting list. AB - INTRODUCTION: Chronic end-stage liver disease is a difficult situation for the patient. OBJECTIVE: The objective of this study was to analyze the disease coping styles of patients on the liver transplant waiting list. MATERIALS AND METHODS: The study included 50 patients on the liver transplant waiting list. The instrument used was the Mental Adjustment to Cancer Scale (Ferrero, 94). Coping scales were as follows: fighting spirit, hopelessness, anxious preoccupation, fatalism, and negation. RESULTS: Only 6% of subjects adapted well, whereas 94% adapted badly: 89% poor fighting spirit, 32% hopelessness, 50% anxious preoccupation, 28% fatalism, and 30% negation. Of those who had a poor fighting spirit, 88% also used another type of maladaptive style. The associated statements were (P<.05) as follows: "I value my life more"; "I don't think about the disease"; "I think about people who are worse off." Regarding hopelessness, 100% of those who confessed hopelessness also showed maladaptive signs. The associated statements were (P<.05) as follows: "I cannot cheer myself up"; "I cannot help myself"; "I've given up." Regarding anxious preoccupation, nearly all of these patients (96%) provided dysfunctional answers. The most associated were (P<.05) as follows: "I don't have any plans"; "I feel a lot of anxiety"; "I'm very angry." Regarding fatalism, all of the patients also had maladaptive behavior. The main types were (P<.05) as follows: "Nothing will change things"; "I cannot control the situation"; "I don't need information." Regarding negation, Only 14% used this style, and in 86% negation was associated with other inadequate coping styles. CONCLUSIONS: Patients on the liver transplant waiting list were maladaptive to their disease. It is important to establish adequate psychological care for these patients, given the important repercussions in the posttransplantation phase. PMID- 20970633 TI - Obsessive-compulsive psychological symptoms of patients on the liver transplant waiting list. AB - INTRODUCTION: Patients on the liver transplant waiting list have increased emotional and clinical symptoms. The presence of psychopathologic symptoms associated with obsession-compulsion as a reflection of alterations due to anxiety disorders is common in these patients. OBJECTIVE: To evaluate obsessive compulsive psychopathological symptoms in patients on the liver transplant waiting list. MATERIALS AND METHODS: The study included 50 patients on the liver transplant waiting list. The instrument was the SA-45 questionnaire (Derogatis, 75), whose Spanish version was adapted by Gonzalez Rivera and De las Cuevas (1988). This dimension was evaluated using five statements. RESULTS: Among of the patients on the liver transplant waiting list, 46% had no relevant obsessive compulsive symptoms. Of these, 28% had no symptoms and 18% had some symptoms, but the overall evaluation in these patients was no greater than the cutoff point. The remaining 54% had relevant obsessive-compulsive clinical symptoms, most commonly (1) "Having difficulty making decisions" (P<3.45.10(-9)); (2) "Having difficulty concentrating" (P<1.70.10(-8)); (3) "One's mind goes blank" (P<3.04.10(-4)); (4) "Having to repeatedly check everything being done" (P<1.37.10(-1)); and (5) "Having to do things slowly to make sure they are done properly" (P<5.02.10(-1)). CONCLUSIONS: Many patients on the liver transplant waiting list have obsessive-compulsive psychopathologic symptoms. Their detection and application of adequate psychological treatment are important to minimize the effects of emotional changes onward from the pretransplant phase. PMID- 20970634 TI - Outcomes of liver transplantation in candidates with portal vein thrombosis. AB - OBJECTIVE: The objective of the present study was to analyze the incidence of portal vein thrombosis (PVT), comparing morbidity and mortality rates among those affected with and those free of this complication. In the PVT group, we also analyzed mortality related to partial (PPVT) and total (TPVT) thrombosis. METHODS: We undertook a retrospective study of orthotopic liver transplantations from deceased donors in 617 recipients from January 1991 until October 2008. Recipients were classified according to whether they had PVT. In all cases, we considered age, sex, Model for End-stage Liver Disease score, Child-Pugh score, indication for transplantation, type of thrombosis, surgical technique blood product transfusion, and survival rate. RESULTS: There were 48 patients with PVT (7.78%) among 670 transplantations in 617 recipients in our institution. Concerning the type of thrombosis, 28 (58.3%) were partial and 20 (41.7%) total with complete occlusion of the portal vein lumen. CONCLUSION: PVT in liver transplant candidates is a rare event (7.8%) that entails greater difficulty in the procedure, expressed as a longer operative time, greater consumption of blood products, and complex surgical techniques. The prognosis for these patients depends on the type of thrombosis: patients with TPVT showed a higher mortality, whereas those with PPVT had survival rates comparable to those of candidates with a permeable portal vein. PMID- 20970635 TI - Variability of the extrahepatic arterial anatomy in 500 hepatic grafts. AB - PURPOSE: To review the extrahepatic arterial anatomy in 500 consecutive liver grafts. MATERIALS AND METHODS: From April 1990 to January 2005 we performed 500 liver transplantations. We received 108 deceased donor liver grafts (21.4%) from other centers. Donor arterial anatomy was recorded as described in the surgical notes of both the donor harvest and the recipient procedures. We used the modified Michels classification scheme proposed by Busuttil. We assessed incidences of mortality, retransplantation, postreperfusion syndrome, intraoperative arrest, hemorrhagic complications, and primary malfunction, comparing with chi-squared tests. RESULTS: There were 376 type I (75.2%), 51 type II (10.2%), 32 type III (6.4%), 18 type IV (3.6%), 3 type V (0.6%), 2 type VI (0.4%) and 18 others (3.6%). No significant associations were found between arterial vascular anomalies of the graft and the studied variables. CONCLUSION: In our experience, extrahepatic arterial anomalies of the donor graft did not influence the short-term outcomes of liver transplantation. PMID- 20970636 TI - Thirteen cases of liver-kidney transplantation. AB - Combined kidney-liver transplantation is currently the best therapeutic option for patients with end-stage kidney and liver disease. We present our experience of kidney-liver transplantation in a series of 13 patients. The most frequent indications were familial amyloidotic polyneuropathy (FAP) and polycystosis of the liver and kidney. The 1- and 5-year survival rates of the liver grafts were 75% and 67%, respectively, with no kidney losses during follow-up. PMID- 20970637 TI - Intraoperative pH values after N-acetylcysteine administration during liver transplantation. AB - We investigated whether intraoperative administration of N-acetylcysteine (NAC) to liver transplant recipients affected pH values. This prospective, randomized, double-blind clinical trial included liver transplant recipients who were randomly assigned to NAC-treated (n=25) or placebo (n=25) groups. The NAC-treated group received 100 mg/kg dissolved in 5% dextrose over 15 minutes during the anhepatic phase, followed by a continuous infusion of 50 mg/kg in 5% dextrose during the next 24 hours. The placebo group received equal amounts of 5% dextrose solution during the same times. Peripheral blood samples were drawn in Ca2+-80 IU containing syringes after induction of anesthesia (I-1), at 15 minutes into the anhepatic phase (I-2) prior to the administration of NAC or placebo, at 5 minutes before reperfusion (I-3), at 5 minutes after reperfusion (I-4), at 20 minutes after reperfusion (I-5), at 60 minutes after reperfusion (I-6), and at 1 hour after completion of the procedure (I-7). pH levels, which were determined using a radiometer ABL77 (Copenhagen, Denmark), were significantly lower among the NAC than the placebo group at I-4 (P=.027) and I-5 (P=.031). An early decrease in pH values was detected in the NAC-treated group at 5 minutes before reperfusion (I 3; P=.051). We concluded that intraoperative NAC administration during the anhepatic phase of liver transplantation significantly decreased recipient pH values at 5 and 20 minutes after reperfusion, a decrease that was detected at 5 minutes before reperfusion (I-3). The decrease seemed to be associated with NAC metabolism. PMID- 20970638 TI - Efficacy and safety of entecavir and/or tenofovir for prophylaxis and treatment of hepatitis B recurrence post-liver transplant. AB - AIMS: To establish the efficacy and safety of entecavir (ETV) and/or tenofovir (TDF) in the treatment and prevention of hepatitis B virus (HBV) recurrence after liver transplantation. PATIENTS AND METHODS: Eight patients (four men) received treatment with ETV and/or TDF after liver transplantation as prophylaxis for HBV recurrence or as posttransplant treatment of HBV. Four liver transplants were in patients with HBV-associated cirrhosis who had received prior nucleos(t)ide analogue treatment until HBV DNA became undetectable. After transplantation, two of these four were treated with ETV + TDF and the other two with just TDF. All received intramuscular hepatitis B immunoglobulins. The reasons for the other four liver transplants were primary biliary cirrhosis in two cases, alcoholic cirrhosis, and hepatitis C virus. Two of the patients were donor anti-HBcAb positive/recipient anti-HBcAb-negative. They received no anti-HBV prophylaxis so they had a recurrence of HBV. These four patients required treatment with ETV+TDF for the HBV DNA to become negative. RESULTS: The mean age was 60 (39-67) years. The mean follow-up was 9.5 (3-20) months. The mean follow-up of the patients who received prophylaxis was 8.2 (3-19) months. These had no HBV recurrence. The mean follow-up of the patients who received treatment for HBV recurrence was 12 (3-19) months. ETV combined with TDF was necessary for the HBV DNA to become undetectable because this was not possible using different nucleos(t)ide analogues. There were no significant adverse effects from these drugs and no alteration of renal function during the follow-up period. CONCLUSIONS: Therapy with ETV and/or TDF seems to be efficient and safe when used in the prophylaxis and treatment of HBV recurrence after liver transplantation. They are well tolerated and seem to have no interactions with immunosuppressive medication. PMID- 20970639 TI - Posttransplantation portal thrombosis secondary to splenorenal shunt persistence. AB - PURPOSE: The aim of this study was to analyze our experience with portal vein thrombosis after liver transplantation with a persistent splenorenal shunt. MATERIALS AND METHODS: The study population included 780 liver transplantations from 1990 to 2009. We analyzed the existence of portal vein thrombosis in the immediate posttransplant period, selecting cases with a persistent splenorenal shunt requiring surgery. RESULTS: The incidence of posttransplant portal vein thrombosis was 1.41% (n=11), of which 3 (27%) had a splenorenal shunt as a possible cause (0.38% of the total). Two cases required liver retransplantation due to portal vein thrombosis, and the third a thrombectomy. In all cases the shunt was also closed. During the early postoperative follow-up of these 3 patients, 2 needed repeat surgeries because of a new portal vein thrombosis (thrombectomy) in one and a bilioperitoneum in the other. After a median follow up of 11 months, the patients showed a good evolution with no primary graft dysfunction. DISCUSSION: The portal steal phenomenon secondary to persistence of a splenorenal shunt promotes the occurrence of portal vein thrombosis. Although it is a rare cause of graft dysfunction, it must be treated early, because it can lead to a small-for-size syndrome. PMID- 20970640 TI - Survival after cardiac transplantation: influence of the previous cardiopathy in the recipient. AB - INTRODUCTION: Data from cardiac transplantation registries have demonstrated a gradual improvement in patient survival over the last decades. Nevertheless, 5 years mortality rates may reflect the multitude of physiologic processes. Registries offer valuable information regarding predictors of mortality that may help us to improve therapeutic strategies. OBJECTIVES: To determine the influence on long term recipient survival of the type of prior cardiopathy that led to cardiac transplantation. METHODS: Analysis of a 316 patient cohort who underwent heart transplantation since 1991 at a single center. RESULTS: We analyzed the main clinical variables among a cohort with a mean follow-up of 7.2 years (standard deviation [SD], 4.8). There were 84.2% men and the overall mean age of 50.06 years (SD 12.29) at the time of transplantation. We identified 11 cardiopathies as the leading causes for transplantation: severe ischemic cardiopathy (55.3%), dilated cardiomyopathy (29.1%), terminal valvular cardiopathy (5.4%), alcoholic cardiopathy (2.5%), congenital cardiopathy (1.6%), acute myocarditis (1.6%), hypertrophic cardiomyopathy (1.6%), endomyocardial fibrosis (1.3%), anthracyclin-related dilated cardiopathy (0.9%), peripartum cardiomyopathy (0.3%), and vascular allograft disease (0.3%). The mean global survival of the cohort was 4.1 years, which showed a significant increase in the recent 8 compared with the first 11 years (P=.03). Multivariate analysis only demonstrated worse survival rate among those with chronic ischemic compared with the other cardiopathies (HR 2.17; 1.21-6.2; P=.003). Nevertheless, the signification disappeared after adjusting the analysis for the presence of >=2 classical cardiovascular risk factors. CONCLUSION: Patients with chronic ischemic cardiopathy showed the leading cause for a lower survival after cardiac transplantation compared with other cardiopathies, which seemed to be related to the cardiovascular risk factors that produced the cardiopathy. PMID- 20970641 TI - Cardiac allograft vasculopathy: coronary computed tomography and virtual histology assessment. AB - INTRODUCTION: Cardiac allograft vasculopathy remains the leading cause of late morbidity and mortality in heart transplantation. The main diagnostic methods, coronary angiography or intracoronary ultrasound (when angiography is normal), are invasive. Other study methods, such as coronary computed tomography (CT) and virtual histological analysis, have not been widely assessed in this condition. OBJECTIVE: The objective of this study was to assess the correlation between data obtained from analysis of virtual histology compared with those obtained from the performance of coronary CT in cardiac transplant recipients. MATERIALS AND METHODS: During the same admission we performed coronary angiography and intravascular ultrasound with virtual histological analysis (automatic pull-back in anterior descending artery and one additional vessel if the former was normal) as well as coronary CT. RESULTS: The study included 10 patients. Virtual histology was done in segments with intimal thickening>0.5 mm, defining 2 groups of plaque, those with an inflammatory component (necrotic core>30% and calcium) versus those without it defined as the combination of both being <30%. A calcium component of the inflammatory plaque allowed coronary CT detection. CONCLUSIONS: The detection of inflammatory plaque in graft vessel disease can be based on an initial noninvasive method, such as coronary CT, although confirmation requires further study. PMID- 20970642 TI - Impact of overweight on survival and primary graft failure after heart transplantation. AB - BACKGROUND: Overweight influence on prognosis after heart transplantation remains controversial. The objective of this study was to determine the relationship between overweight and survival in this setting. METHODS: We evaluated 271 cardiac transplant recipients engrafted from 1991 to 2009 whose age was 50.3+/ 12.1 (mean; SD) years. Their body mass index (BMI) was 25.7+/-3.9 kg/m2. Regarding gender, 85.2% were males. Patients were classified by pretransplantation BMI into group A (>25 kg/m2) and group B (<25 kg/m2). We analyzed the differences in mortality and related factors. RESULTS: One hundred fifty Group A patients (55.4%) showed a slightly lower median survival (7.35 vs 8.62 years; P=.152). Group A patients were at higher risk of death within 1 year of follow-up (HR, 1.71; confidence interval [CI], 0.996-2.939; P=.051). Overweight was associated with increased mortality at 1 year after adjustment for age, recipient gender, hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, and donor-recipient heart size mismatch. The incidence of primary graft failure was also significantly increased in group A (HR, 2.74; CI, 1.17-6.40; P=.017) after adjustment for the same variables. There were no significant differences between the groups concerning surgical ischemic time, number of acute rejection episodes, and infections during the first year. CONCLUSION: In our sample, overweight was associated with increased mortality and an increased incidence of primary graft failure within 1 year after cardiac transplantation. PMID- 20970643 TI - Clinical interest of pharmacogenetic polymorphisms in the immunosuppressive treatment after heart transplantation. AB - In the transplantation field, genetic changes in a single nucleotide in the genes responsible for the transport and metabolism of an immunosuppressive drug may modify the response of the patient. The aim of this study was to evaluate the effect of single nucleotide polymorphisms (SNPs) in heart transplant recipients and their donors in association with tacrolimus and cyclosporine blood levels during the first 2 weeks after transplantation. A total of 18 blood samples from heart transplant recipients and their donors (n=36) were analyzed using Sequenom to characterize the more relevant SNPs of the ABCB1 and CYP3A5 genes for correlation with C0 (trough concentration) drug blood levels. Differences between groups were evaluated with two-way analysis of variance (ANOVA) and Bonferroni post-test. In agreement with theoretical predictions, the wild type genotype in ABCB1 SNPs (CC) tended to stabilize drug levels within the therapeutic range, whereas the T variant induced a 79% mean increase in blood levels among heterozygous (CT) and 100% among homozygous (TT) recipients. These results agreed with the mean levels in various recipient/donor populations, finding significant differences between them (P<.001 in CC vs CT and P<.01 in CT vs TT), as well as a certain influence of the donor genotype. PMID- 20970644 TI - Clinical predictors of immunotolerance in heart transplantation. AB - BACKGROUND AND AIM: The drugs routinely administered to prevent rejection often cause lethal side effects. Tolerant patients, therefore, should be identified to minimize these problems. The aim of this analysis was to identify clinical variables that may be associated with tolerance. METHODS: We recruited 522 heart transplants (HT), excluding combined procedures, retransplantations, pediatric recipients, and subjects who died in the first year to obtain a cohort of 375 patients. Two groups were distinguished by the presence of echocardiographic, clinical, or pathological evidence of rejection in the first year (15 echocardiograms and 10 protocol biopsies per patient); 99 tolerant patients were compared with 276 nontolerant patients. We analyzed clinical variables related to morbidity and mortality. RESULTS: The univariate analysis showed few differences between the groups. The multivariate analysis showed that only major histocompatibility complex (MHC)-A and MHC-DR matched recipients were significantly associated with tolerance. Thus, the likelihood of tolerance was increased by 1.7- and 2.8-fold if 1 or 2 MHC-I matches were present and by 3.4- and 3.7-fold if 1 or 2 MHC-DR matches were present, respectively survival curves showed significant differences (P=.034). Most deaths in both groups were related to immunosuppressive drugs; among tolerant subjects, deaths were due to infection and neoplasms and among nontolerant patients, deaths were due to chronic rejection, neoplasms, and infection. CONCLUSIONS: The only clinical parameter that can determined whether a HT recipient was tolerant was MHC-A and MHC-DR matching. If there is matching, a reduced immunosuppressive load should be prescribed to prevent drug toxicity. PMID- 20970645 TI - Normalization of the heart rate response to exercise 6 months after cardiac transplantation. AB - INTRODUCTION: Heart transplant recipients show an abnormal heart rate (HR) response to exercise due to complete cardiac denervation after surgery. They present elevated resting HR, minimal increase in HR during exercise, with maximal HR reached during the recovery period. The objective of this study was to study the frequency of normalization of the abnormal HR in the first 6 months after transplantation. MATERIALS AND METHODS: We prospectively studied 27 heart transplant recipients who underwent treadmill exercise tests at 2 and 6 months after heart transplantation (HT). HR responses to exercise were classified as normal or abnormal, depending on achieving all of the following criteria: (1) increased HR for each minute of exercise, (2) highest HR at the peak exercise intensity, and (3) decreased HR for each minute of the recovery period. The HR response at 2 months was compared with the results at 6 months post-HT. RESULTS: At 2 months post-HT, 96.3% of the patients showed abnormal HR responses to exercise. Four months later, 11 patients (40.7%) had normalized HR responses (P<.001), which also involved a significant decrease in the time to achieve the highest HR after exercise (124.4+/-63.8 seconds in the first test and 55.6+/-44.6 seconds in the second). A significant improvement in exercise capacity and chronotropic competence was also shown in tests performed at 6 months after surgery. CONCLUSIONS: We observed important improvements in HR responses to exercise at 6 months after HT, which may represent early functional cardiac reinnervation. PMID- 20970646 TI - Adiponectin and graft vascular disease after cardiac transplantation. AB - Graft vascular disease (GVD) is a form of accelerated atherosclerosis that involves the transplanted heart, affecting more than 40% of patients after follow up of 5 years. According to some authors, adiponectin concentration is a prognostic factor for progression of coronary atherosclerosis. Following this line of research, the objective of the present study was to analyze the relationship between adiponectin concentration and development of GVD in 52 cardiac transplant recipients. Patients were divided into 2 groups according to findings at intravascular ultrasound: group 1 with 21 patients without GVD, and group 2 with 31 patients with GVD. Patients with GVD were further divided into 2 additional groups according to results of coronary angiography: group 3 with 35 patients without GVD, and group 4 with 17 patients with any degree of GVD. No significant differences (P=.50) were observed insofar as adiponectin concentration between groups 1 and 2, and groups 3 and 4. Significant differences in adiponectin concentration were observed when the sex of the patient was considered (P=.002), with higher concentrations detected in women. Serious cardiac events were more common in patients with GVD (P=.001). Mean time between transplantation and diagnosis of GVD was 67 months in group 1, 107 months in group 2, 71 months in group 3, and 101 months in group 4. Significant differences were observed between groups 1 and 2 (P=.030). PMID- 20970647 TI - Safety and effectiveness of ivabradine after cardiac transplantation. AB - BACKGROUND: Heart denervation is the primary cause of sinus tachycardia in transplant recipients. Drugs are usually needed to treat associated symptoms. OBJECTIVE: To evaluate the safety and effectiveness of the novel I(f) channel antagonist ivabradine to control heart rate after transplantation. METHODS: Of 316 heart transplant recipients at a single center since 1991, ivabradine was administered in 15 patients, in addition to beta-blockers in 4 patients and contraindication to use of beta-blocker therapy in the others. A prospective follow-up study was conducted to identify possible adverse effects, tolerance, and drug effects on heart rate and control of symptoms. RESULTS: Of the 15 patients, 13 were men; overall mean (SD) patient age was 46 (4.6) years. In all patients, treatment was begun after verification of basal heart rate greater than 100 bpm and after other causes of sinus tachycardia had been ruled out. During follow-up of 1.13 (0.3) years, no substantial adverse effects were observed. It was possible to reach the maximum drug dosage in all patients, achieving a reduction in basal heart rate of 33 (6.2) bpm. All patients reported substantial clinical improvement, and demonstrated an increase in functional class. CONCLUSION: Ivabradine is safe, well tolerated, and effective in heart transplant recipients. PMID- 20970648 TI - Kidney failure after heart transplantation. AB - BACKGROUND AND PURPOSE: Heart transplantation is a procedure with a high mortality rate. Altered kidney function (AKF) after a heart transplant is common. The purpose of this study was to determine the incidence of and associated factors for renal dysfunction among patients who underwent heart transplantation in our hospital between January 2006 and November 2008. PATIENTS AND METHODS: This retrospective observational study was performed on all patients receiving a heart transplant between January 1, 2006 and November 15, 2008. The following variables were recorded: patient comorbidities, indication, presurgical urea and creatinine levels, donor variables, surgical procedure, and postoperative features. RESULTS: A total of 54 heart transplantations were performed with 68.5% of patients being male. The average age at transplant was 49.52 years (+/-13.45 y) and the mean weight 72.5 kg (+/-14.8 kg). Overall mortality was 28.30%. Of the 54 patients, 70.4% showed AKF during the first week after transplantation; 30.61% were in stage III according to the Acute Kidney Injury classification. There were no statistically significant differences between the group of patients with versus without renal failure, except for the extracorporeal surgery time, which was significantly longer among those patients who had AKF, and glycemia, which was also higher in the immediate postoperative period. Analysis of patient mortality showed no significant differences for the patients with AKF (80% vs 68.4%; P=31). CONCLUSIONS: The rate of acute kidney failure was high (70.4%), as was the use of chronic renal replacement therapy (28.85%), but it decreased considerably when followed over time. PMID- 20970649 TI - Mortality from renal dysfunction in heart transplant patients: creatinine versus glomerular filtration rate. AB - INTRODUCTION: One of the most common, significant problems after heart transplantation (HT) is the development of renal dysfunction. In recent years, the glomerular filtration rate (GFR) has replaced the serum creatinine as the standard parameter for its determination. Our objective was to analyze which renal function parameter (creatinine or GFR) at 1 year after HT better classified patients who will die during follow-up. PATIENTS AND METHODS: The study included 316 consecutive HT patients surviving at least 1 year after transplantation. Creatinine and GFR were determined by the Modification of Diet in Renal Disease Study (MDRD4) equation. Mortality during the follow-up was analyzed to compare both parameters using receiver operating characteristic curves. RESULTS: Over a mean follow-up of 6+/-3 years, 97 patients died (30.7%). At 1 year after HT, the patients who succumbed displayed a significantly higher mean creatinine value (1.63+/-0.65 vs 1.41+/-0.64 mg/dL; P=.004) and a more decreased GFR (53.8 vs 60.8 mL/min/1.73 m2; P=.006). Both groups had the same area under the curve, 0.61 (95% confidence interval: 0.54-0.68; P=.002). CONCLUSION: Among our population, GFR calculated by the abbreviated MDRD4 equation did not provide any additional prognostic value to serum creatinine at 1 year after HT to predict long-term mortality. PMID- 20970650 TI - Preliminary results of a prospective randomized study of cyclosporine versus tacrolimus in the development of cardiac allograft vasculopathy at 1 year after heart transplantation. AB - INTRODUCTION AND AIMS: Cardiac allograft vasculopathy (CAV) is the leading cause of death after the first year post-heart transplantation (HT). Numerous factors have been implicated in the development of CAV. The aim of this prospective randomized study was to assess the impact of cyclosporine (CsA) and tacrolimus (Tac) on the development of CAV. MATERIALS AND METHODS: From November 2006 to October 2008, 49 HT patients in our center were randomized to receive CsA or Tac. The additional treatment for all patients consisted of daclizumab induction and maintenance treatment with mycophenolate mofetil (1 g/12 hours) and steroids (withdrawal was not attempted). Thirteen patients died before coronary arteriography plus intravascular ultrasound of the left anterior descending artery was performed at 1 year after HT. Hence, the final number of patients included was 36 (18 per group). We considered significant CAV to be the presence of intimal proliferation>1 mm and/or>0.5 mm in 180 degrees . The statistical methods were Student t and chi-square tests. RESULTS: There were no differences in baseline characteristics between the two groups. Nor were there significant differences in maximum intimal proliferation between the groups (CsA 0.65+/-0.29 vs Tac 0.82+/-0.51 mm; P=.292) or in the development of significant CAV when both criteria were combined (CsA 31.6% vs Tac 38.9%; P=.642). CONCLUSIONS: One year after HT, no differences were detected in the development of significant CAV according to the type of calcineurin inhibitor used when combined with daclizumab induction and maintenance treatment with mycophenolate mofetil and steroids. PMID- 20970651 TI - Post-heart transplant tumors: chronology and impact on survival. AB - INTRODUCTION AND AIMS: Tumors are the second leading cause of death beyond the first year heart transplantation (HT). The aim of our study was to establish a chronology for the occurrence and the impact on overall survival of de novo neoplasms after HT. MATERIALS AND METHODS: We included 597 patients undergoing HT from January 1987 to December 2008. De novo tumors were classified into groups: Kaposi's sarcoma, melanoma, epidermoid skin carcinoma, other skin tumors, lung neoplasms, bladder tumors, prostate adenocarcinoma, digestive tumors, lymphomas, and other tumors. We based the study on the median value and interquartile range of the tumors to estimate their occurrence. Survival rates were calculated using Kaplan-Meier curves and the log-rank tests. We included only patients with survivals beyond 1 year after HT. RESULTS: A total of 109 tumors developed during the follow-up. There were no differences in the survival of patients who lived more than 1 year regarding the development or not of a tumor (155+/-8 vs 179+/-6 months; P=.177). CONCLUSIONS: The incidence of tumor occurrence after HT was high (18.25%). There were several periods in which the occurrence of certain tumors was more frequent, while other periods appeared to be tumor-free. As most tumors were skin cancers, their impact on overall survival was low. PMID- 20970652 TI - Considerations regarding major bleeding after cardiac transplantation. AB - Postoperative bleeding is one of the most frequent complications after cardiac surgery, leading to longer stays in the intensive care unit (ICU) and the hospital as well as increased morbidity and mortality. We designed an observational prospective study to evaluate early complications after cardiac transplantation, focusing on major bleeding and transfusion requirements. We also evaluated whether massive transfusion was related to increased morbidity and mortality. In patients who received >=6 blood units, we observed significant differences regarding the need for continuous renal replacement techniques (50% vs 12.5%; P=.01) and ICU mortality (33.3% vs 4%; P=.01). This difference in mortality was also observed when comparing plasma transfusion requirements (35.3% vs 9.4%; P=.04). The overall mortality rate was 24.50%, showing significant differences in patients with massive transfusion (83.3% vs 37.8%; P=.008). In conclusion, perioperative bleeding and massive transfusion were associated with increased morbidity and mortality in this group of patients, which may prompt a review of surgical procedures and the introduction of new techniques, such as thromboelastography. PMID- 20970653 TI - Lymphomas in heart transplant recipients: do antivirals protect against the neoplastic effect of anti-CD3 monoclonal antibody? AB - INTRODUCTION AND AIM: After cardiac allograft vasculopathy, tumors are the second leading cause of death among heart transplantation (HT) patients after the first year. Lymphomas are tumors of lymphocytic origin whose development has been associated with the use of anti-CD3 monoclonal antibody (OKT3). Some studies suggest that the use of acyclovir could counteract this effect. Our aim was to investigate the impact of gancyclovir on OKT3 and lymphoma development after HT. MATERIALS AND METHODS: We included all 239 HTs performed in our center from 1989 to 2002. We divided patients into those who received gancyclovir treatment (prophylaxis, pre-emptive therapy, or for cytomegalovirus infection) versus those who did not receive this agent at any time during follow-up (88 vs 151 patients). The statistical methods were Student's t and chi-square tests. RESULTS: There were no differences in the baseline characteristics of the patients--gender, recipient age, etiology leading to HT, diabetes, and dyslipidemia--except for a higher rate of hypertension among the group who did not receive gancyclovir (73.7 vs 60.2%; P=.03). None of the 7 patients who developed lymphomas during the follow-up received gancyclovir (0 vs 4.6%; P=.040). CONCLUSIONS: Antivirals may have a relevant role to neutralize potential neoplastic effects (especially lymphomas) associated with the use of OKT3 induction therapy. PMID- 20970654 TI - Bone mineral density in lung transplant candidates. AB - INTRODUCTION: The loss of bone mineral density (BMD) affects more than half of the patients on the waiting list for lung transplantation (LT), increasing their disease burden. OBJECTIVE: To describe the prevalence of BMD loss among patients evaluated as candidates for LT. PATIENTS AND METHODS: We included all hospitalized patients evaluated as LT candidates over the last 3 years, excluding pediatric subjects under 17 years of age. We estimated BMD in the femoral neck and lumbar spine. Categorization used the World Health Organization criteria. RESULTS: Among 156 patients, 64 (41%) had chronic obstructive pulmonary disease (COPD) with only 2 (3.1%) having densitometry before referral; 55 (35.3%), interstitial lung disease (ILD) with 9 (16.4%) BMD values; and 21 (13.5%) cystic fibrosis (CF) with only 3 (14.3%) with BMD screening. The 116 patients (74.4%) who had BMD below normal values included 84.4% of COPD, 67.3% of the ILD, and 81% of the CF patients. The detection of these patients allowed us to initiate preventive treatment depending on the degree of risk of bone fracture. Half of the patients evaluated were eventually included on the LT waiting list, with 70% of them finally receiving a transplant. CONCLUSIONS: Bone mineral loss was highly prevalent among this population but its investigation before referral for LT was scarce. Its identification allows primary or secondary prophylaxis to be started, seeking to reduce the risk of bone fracture after transplantation. PMID- 20970655 TI - Results of lung transplantation in idiopathic pulmonary fibrosis patients. AB - Lung transplantation (OLT) remains the only available therapy for patients with end-stage idiopathic pulmonary fibrosis (IPF). The objective of this study was to review our experience of OLT for end-stage IPF (IPFLT) patients, seeking to identify variables associated with survival for comparison with outcomes of other indications for LT (OILT). From October 1993 to December 2009, we performed 310 consecutive OLT in 301 patients for treatment of various end-stage pulmonary conditions. The indications for OLT were: IPF (n=89, 30.5%) chronic obstructive pulmonary disease (n=82), cystic fibrosis (n=80), bronchiectasis (n=12), alfa-1 antitrypsin deficit (n=6), primary pulmonary hypertension (n=4), bronchiolitis obliterans (n=4), other conditions (n=15). We observed significant differences in the actuarial survival between the IPFLT and the OILT groups particularly at the expense of worse perioperative 30-day and early 1-year mortality in the IPFLT group. Upon univariate and multivariate analyses, the need for cardiopulmonary bypass, previous recipient ventilator dependence, and donor age>50 years were all associated with poorer survival rates among IPF patients. In our experience, survival did not differ between patients who underwent a single versus a bilateral sequential lung transplant (BSLT); however, BSLT cases were associated with short-term damage but long-term survival. The functional results in the IPFLT group were excellent. We observed significant improvements in the values of arterial oxygen pressure (PaO2), arterial carbon dioxide pressure (PaCO2), forced vital capacity (FVC%) and forced expiratory volume in 1 second (FEV1%) at 6, 12, and 36 months compared to their pretransplant baseline results. PMID- 20970656 TI - Experience of the Reina Sofia hospital in lobar lung transplantation. AB - The number of patients awaiting lung transplantation has steadily increased over the past decade, but the number of donors has remained relatively stable. Owing to the increasing scarcity of donor lungs, especially for pediatric and small adult recipients, advanced operative strategies for the use of larger grafts for smaller recipients have been developed. Size matching between donors and recipients represents one of the organ distribution criteria widely accepted by lung transplantation teams. However, in some cases it is not possible to allocate a donor to the corresponding size-compatible recipient. To avoid possible complications derived from the implantation of oversized lungs into smaller recipients, various methods of downsizing are applied for cadaveric donor lungs, such as lobar transplantation. We review our experience in 6 patients undergoing volume reduction of the lung graft by lobar resection at the time of transplantation. Graft volume reduction by anatomic resection (lobar transplantation) is a reliable and safe procedure to overcome size disparities between the donor and the recipient of a lung transplant, and thus to maximize the number of donors. PMID- 20970657 TI - Chronic kidney disease after lung transplantation: incidence, risk factors, and treatment. AB - OBJECTIVE: The purpose of this study was to determinate the incidence of risk factors and therapeutic strategies for chronic kidney disease (CKD) among our lung transplant recipients. We also analyzed the association with 1-, 2-, and 5 years mortality after lung transplantation. PATIENTS AND METHODS: This descriptive, retrospective study of 161 patients undergoing lung transplantations between June 1999 and December 2008 assessed the incidence and severity of CKD, following the updated guidelines of the National Kidney Foundation. Using univariate and multivariate analysis, we considered the impact of multiple factors on kidney function. The relationship between CDK and mortality was assessed using Kaplan-Meier method. RESULTS: Among 161 patients, 68.6% developed CKD. The decrease in glomerular filtration rate (GFR) was sharper in the first year. Upon, multivariate analysis, the factors most strongly associated with this decrease included advanced age (odds ratio [OR]=2.0; P<.001) and cytomegalovirus (CMV) infection (OR=2.2; P=.045). Factors significantly associated in the univariate analysis were pretransplantation GFR, pulmonary disease, initial therapy containing tacrolimus, and conversion to mycophenolate mofetil. Recipients who developed CKD at 1 year after transplantation showed a strong association with mortality (P=.001). CONCLUSIONS: We observed a biphasic decrease in GFR, characterized by a rapid decrease in the first year. The development of CKD during this period was associated with an increased risk of death. To introduce renoprotective strategies, we must identify early predictors of decreasing renal function. PMID- 20970658 TI - Complications during clinical evolution in lung transplantation: pulmonary embolism. AB - BACKGROUND: Medical complications after lung transplantation (LT) are frequent despite the advances in management. The objectives of this study were to evaluate the incidence and clinical features of pulmonary embolism (PE) among LT recipients in our center. PATIENTS AND METHODS: We performed a retrospective descriptive study of 280 patients who underwent LT between June 1999 and December 2009. RESULTS: Five patients with PE (1.78%) had undergone single LT due to idiopathic pulmonary fibrosis (IPF). PE developed in the transplanted lung and was bilateral in 2 cases. The only associated risk factor was obesity in 3 patients. The clinical presentation was nonspecific; the most frequent symptom being dyspnea. Computed tomography (CT) angiography and ventilation-perfusion scan were used for diagnosis. Patients underwent treatment with low-molecular weight heparin followed by oral anticoagulation. CONCLUSIONS: Our study showed a low incidence of PE (1.78%), although we focused exclusively on this condition, excluding other entities such as deep vein thrombosis. All PE events occurred in the subpopulation of IPF transplant recipients. Possibly some factors predisposed these patients to PE, although they remain unclear. Because PE can cause significant morbidity in LT recipients, it is important to include PE in the differential diagnosis among LT patients presenting with dyspnea, hypoxia, or clinical deterioration. PMID- 20970659 TI - Role of second hematopoietic stem cell transplantation in relapsed or refractory hematologic malignancies. AB - Prognosis of patients relapsing after stem cell transplantation (SCT) is poor if no further treatment is given. A second SCT is a limited option in these high risk patients. We retrospectively analyzed the outcomes of second SCT in acute myeloid leukemia, myelodysplastic syndrome, and acute lymphoblastic leukemia after a first SCT. Twenty-five of 30 patients received second allogeneic SCT. Variables related to survival were disease status before second allogeneic SCT and time interval between transplants more than 1 year (P<.01 and P<.02 in multivariate analysis). Treatment-related mortality was 33% with no impact of the conditioning regimen on overall survival. Second allogeneic SCT in selected patients may be an option in this group with a poor outcome. PMID- 20970660 TI - Clinical utility of real-time polymerase chain reaction to quantify cytomegalovirus replication in allogeneic stem cell transplant recipients with different prevention strategies. AB - Cytomegalovirus (CMV) end-organ disease is a serious, frequent complication after allogenic stem cell transplantation (Allo-SCT). There are two prevention strategies: universal prophylaxis and preemptive therapy. Preemptive therapy is administered based on the results of sensitive techniques that detect the viral infection. We analyzed 41 peripheral blood Allo-SCT recipients: 34 received prophylaxis and seven preemptive treatment. Viral infections determined using real-time polymerase chain reaction (RT-PCR) assays occurred at an overall incidence of 65.8%. The viral loads quantified by RT-PCR were compared among the prophylaxis versus the preemptive group. Overall, the median viral load was significantly higher in the preemptive compared with the prophylaxis group (P=.002). Furthermore, within the first 100 days posttransplantation, viral load values were higher among patients undergoing preemptive therapy (P=.009). PMID- 20970661 TI - Differences in cytomegalovirus replication quantified using quantitative polymerase chain reaction and antigenemia after allogeneic stem cell transplantation. AB - Fifty percent of allogeneic stem cell recipients develop cytomegalovirus (CMV) infection in the first 100 days posttransplantation. Various methods have been used to determine CMV infections, including antigenemia assay and real-time polymerase chain reaction (RT-PCR). Although antigenemia assay has been used more frequently, this technique is less sensitive than RT-PCR. In contrast, RT-PCR has a low positive predictive value for CMV end-organ disease. Cytomegalovirus infections were analyzed in 41 peripheral blood samples from allogeneic stem cell recipients using both antigenemia assay and RT-PCR; results were discordant in 36.6% of patients. Although the antigenemia assay detected CMV replication in 29.2% of cases, RT-PCR was positive in 65.8%. In 83.3% of patients, results detected using the antigenemia assay were delayed by a median (range) of 5 (2-20) weeks compared with positive RT-PCR results. Within the first 100 days posttransplantation, higher levels of viral replication measured using RT-PCR were observed in patients with vs without antigenemia. In addition, in patients with antigenemia, viral load was significantly higher before day 100 than after (P=.01 and P=.008, respectively) compared with those without antigenemia. PMID- 20970662 TI - Design of a real-time quantitative polymerase chain reaction to assess human complement regulatory protein gene expression in polytransgenic xenograft pigs. AB - OBJECTIVE: To design a real-time quantitative polymerase chain reaction (q-PCR) to assess gene expression for hCD55, hCD59, and hCD46 in polytransgenic (PT) pigs used as xenograft donors for orthotopic liver xenotransplantation using a pig-to baboon model. MATERIALS AND METHODS: Three pairs of primers were designed using PrimerBlast and mRNA of hCD55, hCD59, and hCD46 sequences. Blood samples from five PT pigs (two males and three females) were used to isolated peripheral blood mononuclear cells (PBMCs) by means of Ficoll gradients. After DNAase digestion of isolated mRNA, we synthesized cDNA. Using SYBR-Green chemistry of q-PCR, we constructed a standard curve. Two wild-type (WT) pigs were used as negative controls, and PBMCs from two healthy human volunteers as positive controls. The amplicon length was assessed by means of agarose gel electrophoresis and PCR products, sequenced. RESULTS: We observed amplification for hCD55, hCD59, and hCD46 in all samples from the five PT pigs except for hCD55 and hCD46 in one male PT pig. Neither the human samples nor the negative controls showed amplification. The expected amplicon length was confirmed; sequencing showed high homology with human mRNA for the three proteins and no match with any known pig sequence. CONCLUSIONS: The q-PCR allowed detection of animals with the highest gene expression for hCD55, hCD59, and hCD46 for xenograft donors in transplantation experiments. PMID- 20970663 TI - Validation of xCELLigence real-time cell analyzer to assess compatibility in xenotransplantation with pig-to-baboon model. AB - OBJECTIVE: To validate the use of a microelectronic real-time cell analyzer system (RTCA) we developed a complement-mediated antibody cytotoxicity assay to investigate the compatibility of a graft and a recipient in pig-to-baboon xenotransplantation. MATERIALS AND METHODS: Fibroblasts isolated from the skin of five hCD55, hCD59, and hCD46 transgenic pigs (TP) were cultured in 96 microelectronic well plates for 17 hours. Then, we added to each microwell 20 MUL of normal sera from nine healthy adult olive baboons (Papio anubis)-three males and six females. The evolution of the cell culture was assessed every 3 minutes during the pretreatment period, at 11 hours postaddition, and every 30 minutes from 12 to 96 hours. Simultaneously, we performed a 3-(4,5-dimethylthiazole-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay. Fibroblasts from wild-type (WT) pigs were used as positive controls and microwells without serum addition from each TP as negative controls. The RTCA results were expressed as a normalized cellular index (NCI). RESULTS: Differences were observed between the five TP fibroblasts and the WT fibroblasts, with greater cytotoxicity on WT cells. Among TP, a higher cytolytic level was observed in males than females. The MTT results correlated with NCI at different times, with the minimum NCI and with the time to for NCI recovery before serum addition. The correlation was lower than that previously reported in environmental toxicity assays. CONCLUSIONS: RTCA allows a long-term assessment of the immunocytotoxic effect of baboon sera on pig cells, providing a suitable tool to perform compatibility tests for xenotransplantation. PMID- 20970664 TI - Effects of deep hypothermic preservation on posttransplant viability of tracheal grafts. AB - OBJECTIVE: Using an animal model, we performed a study to assess the effects of rapid freezing in the absence of cryoprotectants on the viability of tracheal grafts after allotransplantation. MATERIALS AND METHODS: Ten tracheal heterotopic transplantations were performed with fresh grafts just after harvesting donors, and 20, with cryopreserved specimens at 2 or 6 weeks after hypothermic storage. Cryopreservation consisted of rapid cooling in the absence of cryoadditives with storage for 2 weeks at -80 degrees C. After rewarming, grafts were transplanted into the abdominal cavity of immunosuppressed rats by being embedded into the greater omentum. Fourteen days later, the implants were removed to examine chondrocyte viability, submucosal swelling, and epithelial patterns in comparison with fresh controls. RESULTS: All allografts retained their macroscopic structure after transplantation. Respiratory epithelium was substituted by planar epithelium only in the frozen transplanted specimens. Fresh transplanted grafts exhibited 100% chondral viability in contrast with 5% viability observed among cryopreserved tracheas after transplantation. CONCLUSIONS: The method of rapid freezing was effective to preserve airway grafts. However, the quality of cryopreserved cartilage was disappointing, similar to that obtained using conventional slow-freezing protocols. PMID- 20970665 TI - New technologies developed in the 1960s, especially in the fields of immunogenetics and cell biology, inaugurated the era of organ transplantation. Preface. PMID- 20970666 TI - European marrow donor information system: concept and praxis. AB - Hematopoietic stem cell transplantation is an increasingly used treatment option for patients with severe disorders of hematopoiesis. In roughly two thirds of the cases, an unrelated donor must be sought in international databases. These searches would nowadays be unimaginable without the support of information technologies. Reliable communication and data transfer of donor and patient records between all partners in this huge network is one of the most important success factors in stem cell transplantation. The European Marrow Donor Information System (EMDIS) is an open computer network for data exchange among different unrelated hematopoietic stem cell donor registries that covers 85% of all potential unrelated stem cell donors and cord blood units worldwide. The network has spread also to North America, Australia, Asia, and Africa. The Czech Stem Cell Registry in Prague became a member of the EMDIS community at the end of 2003, when it manually processed about 300 preliminary search requests per year and exported 32 stem cell products to other countries. In 2008, it has automatically processed>14,000 preliminary requests with a doubled 63 number of exported stem cell products. PMID- 20970667 TI - Collaboration between hematopoietic stem cell donor registry and cord blood banks. AB - Despite the huge number of volunteer donors registered worldwide, only a mean of 50% of patients not having a family donor are transplanted with an unrelated donor. Since 1990, a network has been implemented among some European registries. With the help of the European Community, a more sophisticated network has been developed, the European Marrow Donor Information System (EMDIS). A new project underwent development by registries and the Bone Marrow Donor Worldwide: the EMDIS Cord Blood Registry. It will in the future permit to obtain after a search request, one report containing all of the best donors worldwide and best umbilic cord blood for each patient, taking into account possible double cord blood transplantations and other factors, such as number of nucleated cells, number of CD34+ cells, and methods of reduction. Only a strong collaboration between all hematopoietic stem cell registries and cord blood banks would allow a Registry to propose the best donor/cord blood unit for each patient in each country. Progress in the field of hematopoietic stem cell transplantation may be obtained by the parallel development of cord blood banks worldwide and bone marrow donor registries among countries that include minorities. PMID- 20970668 TI - Human leukocyte antigen proficiency testing for Central and Eastern Europe: a summary of over 10 years of activity. AB - The first trial of human leukocyte antigen (HLA) Proficiency Testing for Central and Eastern Europe (formerly Proficiency Testing of HLA class I Typing for Central and Eastern Europe) was organized in 1999 with 5 Polish institutions that were involved in HLA typing. Since then, 46 HLA laboratories in 13 countries have participated in our external proficiency testing schemes. The workshop conducted by our institution meets the expectations of the European Federation for Immunogenetics to provide data on the reliability of histocompatibility testing. Our standardization workshop currently covers serological typing of HLA class I A and B loci and DNA typing at the low- and high-resolution level of HLA class I (A, B, C) and class II (DRB1, DQB1) loci. It has >30 HLA laboratories participating each year. Thirty-two laboratories in 9 countries participated in the last session, the 15th workshop in 2009. Twenty-three laboratories submitted results of HLA class I typing by serology; 28 participated in HLA class I DNA typing and 28 participated in HLA class II DNA typing, including 5 and 7 laboratories that sent results of high-resolution typing for class I and class II specificities, respectively. Continuous improvement is seen with respect to both serology and DNA typing, although some doubtful results are still reported. PMID- 20970669 TI - Association of HLA haplotypes with paroxysmal nocturnal hemoglobinuria. AB - The pathologies of paroxysmal nocturnal hemoglobinuria (PNH) are primarily caused by somatic mutation in the PIG-A gene in hematopoietic stem cells resulting in glycosyl phosphatidylinositol deficiency and accumulation of phosphatidylinositol (PI) in plasma membranes. The mechanism of pathologic clone domination over normal hematopoietic clones in PNH patients is not yet understood. Forty-four PNH patients, including 9 with aplastic anemia traits (AA/PNH), 31 without full aplasia in bone marrow (de novo PNH, or dn/PNH), and 4 with unclassified PNH, and 200 ethnically matched controls were tested for the HLA A, B, C, DRB1, and DQB1 alleles and haplotype associations. The top block association analysis showed the primary association of PNH with 3 haplotype fragments: the class I fragment A*2501-Cw*1203-B*1801 (risk ratio [RR], 6.64; P=.00012), and 2 class II fragments: DRB1*1501-DQB1*0602 (RR, 7.09; P=.0000015) and DRB1*0401-DQB1*0301 (RR, 6.76, P=.0093). The stratified analysis revealed that the A*2501-Cw*1203 B*1801 haplotype associated preferentially with AA/PNH, and its component HLA molecule showed immunodominant antiapoptotic peptides derived from PI-activated phospholipase D; whereas the DRB1*1501-DQB1*0602 haplotype was associated strongly with dn/PNH and presented immunodominant class II-derived autopeptides. We concluded that certain HLA haplotypes were associated with PNH much more strongly than their allelic components. At least 3 HLA haplotype blocks (A*2501 Cw*1203-B*1801, DRB1*1501-DQB1*0602, and DRB1*0401-DQB1*0301) were primarily associated with PNH. Our results supported the hypothesis of the roles in AA/PNH of antiapoptotic and in dn/PNH of autoimmune mechanisms. PMID- 20970670 TI - Reactivations of cytomegalovirus, human herpes virus 6, and Epstein-Barr virus differ with respect to risk factors and clinical outcome after hematopoietic stem cell transplantation. AB - One hundred two recipients of hematopoietic stem cell transplants (HSCTs) 45, from siblings and 57 from matched unrelated donors, were followed for cytomegalovirus (CMV), human herpes virus (HHV) 6, and Epstein-Barr Virus (EBV) reactivation by quantitative polymerase chain reaction in the context of immunologic reconstitution and posttransplantation complications. CMV, EBV, and HHV6 DNA copies (>100 copies/10(5) cells) were detected in 34%, 27%, and 26% of patients, respectively. The presence of 100 copies of EBV or CMV was associated with posttransplant complications: 29/66 versus 6/36 (P<.01) or 24/66 versus 4/36 (P=.01). CMV reactivation was more frequent among patients with acute graft versus-host disease grade>=I: 17/35 versus 18/67 (P<.05). Older patient age of adults>16 year (2/16 versus 33/86; P<.05) and, to a lesser extent, CMV IgG positivity before HSCT (34/84 versus 1/10; P=.08) or an HLA-mismatched graft (9/16 versus 26/86; P=.08) constituted risk factors for CMV reactivation, which resulted in a higher rate of bacterial pneumonia (7/11 versus 28/91; P=.04). EBV reactivation risk was associated with donor EBV IgG seropositivity (28/84 versus 0/10; P=.03) and donor female gender (18/47 versus 10/55; P=.03). In contrast to EBV and CMV, EBV reactivation itself was associated with encephalitis (5/8 versus 23/94; P=.013), which was also seen as a trend among HHV6 reactivations (8/8 versus 46/94; P=.08). Multivariate analysis demonstrated that these factors play independent roles in the reactivation of the investigated herpes viruses. PMID- 20970671 TI - Interleukin-17-producing cells increase among CD4+ lymphocytes before overt manifestation of acute graft-versus-host disease. AB - Interleukin-17A is a hallmark of a subset of CD4+ lymphocytes called T(H)17. Allogeneic hematopoietic stem cell transplantation (HSCT) induces an immune response that facilitates graft acceptance, but if clinically apparent as acute graft-versus-host disease (aGvHD), it may adversely affect transplantation outcomes. TH17 cells are involved in the inflammatory processes associated with several diseases, including inflammatory bowel disease (IBD) as a prototype. In this study we investigated the presence of IL-17-producing cells among peripheral blood mononuclear cells (PBMC) of patients after HSCT. The 48 patients of median age 45 years (range, 1.0-64 years), experienced hematologic malignancies (n=45) or nonmalignant disorders (n=3), treated with matched unrelated (n=24) or sibling (n=24) transplants. We examined IL-17-producing cells in alloreactive reactions after HSCT. PBMC were stimulated with BD Leukocyte Activation Cocktail (Ionomycin, Brefeldin A, and phorbol myristic acetate (PMA)) in the presence of BD GolgiStop. After stimulation the cells were labeled with anti-CD4 and intracellular anti-IL-17A monoclonal antibodies. IL-17+ cell proportions were analyzed in the CD4+ lymphocyte gate. We observed that patients at the time of hematologic reconstitution had higher proportions of IL-17-producing cells than healthy control subjects (0.73+/-0.13 vs 0.19+/-0.06%; P=.019). Fourteen patients displayed the first symptoms of aGvHD at the time of hematologic reconstitution, when they showed lower proportions of IL-17+ cells among CD4+ lymphocytes than their counterparts lacking aGvHD at a similar time after transplantation (0.29+/ 0.09 vs 0.73+/-0.13%; P=.024). Eight patients developed aGvHD after hematologic reconstitution (median, 34 days). All of these patients displayed lower proportions of IL-17-producing CD4+ cells on the day of aGvHD compared with their initial measurements preceding this complication (0.34+/-0.14 vs 1.07+/-0.37%; P=.01). PMID- 20970672 TI - CXCL12 gene polymorphism and hematologic recovery after transplantation of peripheral blood progenitor cells. AB - Previous studies have documented that the (3'-UTR,801A>G) polymorphism of the gene encoding stromal cell-derived factor-1 (SDF-1/CXCL12) is associated with the release of CD34+ cells from the bone marrow to the peripheral circulation in autologous transplant recipients and healthy donors of allogeneic transplants. The aim of this study was to investigate whether the CXCL12 gene polymorphism is associated with the accommodation of hematopoietic stem cells in the marrow, reflected by the recovery of granulocytes and platelets after autologous transplantation of peripheral blood progenitor cells (PBPCT). CXCL12 genotyping was performed in 57 recipients of autologous PBPCs using a PCR-RFLP technique and MspI restriction enzyme. The pace of granulocyte recovery significantly correlated with the pace of platelet recovery (P<.001, Spearman's R test). Hematologic recovery was observed to be affected by the CXCL12 gene polymorphism. Patients carrying the CXCL12-3'A allele were characterized by faster recovery of both granulocytes (median, 15 vs 17 days after PBPCT; P=.027) and platelets (17 vs 21 days after PBPCT; P=.023; Mann-Whitney U test). Multiple regression analyses, considering patient age/gender, number of transplanted CD34 cells, and CXCL12-3'A allele, confirmed the independent association of the CXCL12-3'A allele with granulocyte and platelet recovery after transplantation (P=.020 in both cases). PMID- 20970673 TI - Gene-modified cellular vaccines: technologic aspects and clinical problems. AB - Activity in the cancer vaccine sector has quadrupled in the last decade. A number of therapeutic cancer vaccines are reaching the market. The huge number of clinical trials in progress is expected to undergo evaluation shortly. Whole cell tumor vaccines or gene-modified whole cells are being intensively tested in clinical trials. However, the specificity of the product makes the drug development process, including clinical trials, a considerable challenge. Their complex nature, standardization of manufacturing, and characterization often pose problems. Accordingly, to develop a well characterized controlled vaccine, more than a few factors need to be established. The final cell vaccine formulation must be characterized for product identity, purity, impurities, sterility, potency, cell viability, and total cell number. Therapeutic cancer vaccines show different clinical characteristics than cytotoxic anticancer agents. Unfortunately, the rules of clinical trial design for active immunotherapy have been adapted from the designs for examination of cancer chemotherapy. Accordingly, many research groups and clinical consortia have postulated modifications and unifications of existing clinical trial designs. A clinical development model has suggested that cancer vaccines be investigated in 2 categories of clinical trials: proof-of- principle and efficacy. Moreover, it is becoming clear that no drug demonstrates anticancer activity in all patients. Thus, intensive studies have been performed to seek specific biomarkers which could help stratify patients who are likely to respond to a particular treatment. This presents a big challenge beyond the analysis of the immune system status necessary to assess the effects of active immunotherapy. PMID- 20970674 TI - Definition of a target for immunotherapy and results of the first Peptide vaccination study in chronic lymphocytic leukemia. AB - Results of bone marrow transplantation, as well as remission phenomena after viral infections, suggest that chronic lymphocytic leukemia (CLL) might be targeted effectively by T-cell-based immunotherapy. Antigen-targeted immunotherapies represent novel treatments for CLL patients. Earlier, we screened the mRNA expression of several tumor associated antigens (TAAs), observing the presence of RHAMM/CD168, fibromodulin, syntaxin, and NY-Ren60 in 55%-90% of CLL patients. RHAMM/CD168, fibromodulin, PRAME, and MPP11 were expressed in CLL patients but not in healthy volunteers. Quantitative reverse transcriptase polymerase chain reaction revealed higher RHAMM expression in high-risk CLL patients as well as in advanced stages of the disease. CLL cases with higher RHAMM expressions showed significantly shorter median treatment-free survivals. Among patients with mutated IgVH genes, an analysis of RHAMM expression enabled us to distinguish a subgroup of patients with a favorable prognosis. In lymph nodes, RHAMM staining correlated with a higher Ki-67 index and CD40L expression. Functionally, stimulation with CD40L enhanced RHAMM expression in CLL. Because of the exquisite tissue expression of RHAMM and its high expression frequency in CLL patients, we further characterized RHAMM-specific CD8+ T cells in these patients. CD8+ T cells primed with the RHAMM-derived epitope R3, which is restricted by human leukocyte antigen (HLA)A2, lysed RHAMM+ CLL cells. Therefore, we initiated a Phase I clinical trial of R3 peptide vaccination. Four patients exhibited reduced white blood cell counts during the vaccination process. In 5/6 patients, R3-specific CD8+ T cells were detected with the corresponding peptide/HLA-A2 tetrameric complex; these populations were verified functionally in 4/5 patients using ELISpot assays. In conclusion, RHAMM expression seems to be of prognostic value, and may reflect the proliferative capacity of CLL cells; it may therefore represent an interesting target for immunotherapy. Peptide vaccination in CLL patients was safe eliciting specific CD8+ T-cell responses against the tumor antigen RHAMM. PMID- 20970675 TI - The impact of H-Y mismatches on results of HLA-matched unrelated allogeneic hematopoietic stem cell transplantation. AB - We searched for immunogenic mismatches of H-Y minor histocompatibility antigens among unrelated HLA-matched donor-recipient pairs and for their association with transplant outcomes. We included 92 patients who were treated with 10/10 HLA allele-matched, unrelated allogeneic hematopoietic stem cell transplantation (alloHSCT). H-Y genotyping was performed in the Regional Blood Center with use of the Dynal Minor Histocompatibility Antigen Typing Kit. H-Y mismatches in the graft-versus-host direction of female donor to male recipient decreased the relapse rate (6% vs 23%; P=.046) and tended to improve disease-free survival (79% vs 44%; P=.067), but it also increased the incidence of chronic graft-versus-host disease (66% vs 38%; P=.02). Thus it influenced the results of alloHSCT from HLA matched unrelated donors. The results of this study may help to explain the impact of gender differences between donor and recipient in alloHSCT. PMID- 20970676 TI - Phenotype of dendritic cells generated from peripheral blood monocytes of patients with ovarian cancer. AB - OBJECTIVES: The aim of our study was to generate dendritic cells (DCs) from peripheral blood monocytes (PBMC) of patients suffering from ovarian cancer. MATERIALS AND METHODS: Immature DCs were generated from PBMC cultured in RPMI 1640 medium with 2% human serum albumin (HSA), supplemented with recombinant human (rh) granulocyte macrophage colony stimulating factor (GM-CSF) and rh interleukin (IL)-4. After 5 days of culture, DC maturation was induced by the addition of an ovarian cancer cell line (CAOV3) lysate and after 6 days of rh tumor necrosis factor (TNF)-alpha for a further 2 days. The phenotype of the generated cells was assessed by flow cytometry for the expressions of human leukocyte antigen (HLA)-DR, costimulatory molecules (e.g., CD86, CD80), CD83, CD1a, and CD14. PBMC cultured in 2% HSA without rhIL-4, rhGM-CSF, rh-TNF-alpha, or tumor cell lysate formed the control group. RESULTS: The 2.41% (interquartile range, 1.51%-3.52%) of CD45+/CD14+ cells in cultures with rhIL-4, rhGM-CSF, rhTNF alpha and tumor cell lysate was significantly lower than in the control group (31.10%; interquartile range, 11.11%-64.06%). Cultures with rhIL-4, rhGM-CSF, rhTNF-alpha, and tumor cell lysate showed a higher percentage (19.96%; interquartile range, 9.30%-24.42%) of fully mature CD83+/CD1a-/HLA-DR+ DCs compared with control culture (6.02%; interquartile range, 3.01%-7.37%). There was no significant difference in the expression of the immature DC marker (CD1a) between the cultures. The expression of co-stimulatory markers (CD80, CD86, HLA DR) was greater (24.29%; interquartile range, 18.68%-33.95%) on DCs from cultures with rhIL-4, rhGM-CSF, TNF-alpha, and tumor cell lysate versus controls (4.93%; interquartile range, 2.67%-9.09%). CONCLUSION: Our data demonstrated that immature and mature DCs can be generated from adherent human PBMC from ovarian cancer patients cultured with rhIL-4, rhGM-CSF, rhTNF-alpha, and tumor cell lysates. PMID- 20970677 TI - Dendritic-cell tumor vaccines. AB - Most cancers remain incurable. Introduction of novel therapeutic methods, including new cytostatic regimens and targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have increased remission rates as well as improved patient survival, but the ability to cure many cancer patients remains elusive. It is thus necessary to further develop alternative strategies to improve patient prognosis. The majority of patients who respond to induction therapy inevitably relapse, mainly because of the proliferation of residual malignant cells that have escaped control by induction chemotherapy. Therefore the eradication of minimal residual disease may be crucial to prevent a relapse and achieve a long-term remission. It seems that an advantageous treatment option may be cellular immunotherapy with dendritic-cell vaccines which might induce long-term specific anticancer responses with immune memory cells, which could contribute to effective and lasting elimination of malignant cells. PMID- 20970678 TI - Wilms' tumor 1 as a novel target for immunotherapy of leukemia. AB - Wilms' tumor 1 (WT1) is a leukemia associated antigen (LAA) differentially expressed by leukemic blasts. Thus, WT1 may constitute a target for therapies such as those mediated by adoptive-specific T lymphocytes. Serological and cellular immune responses have been elicited by WT1 in patients with leukemia. Specific CD8+ T cells able to recognize this antigen can be selected by streptamers and then infused into leukemia patients. Potentially, these T cells could lyse leukemic blasts expressing WT1. The only good manufacturing practice certified technology is streptamers, which are available for antigen-specific T cell sorting. Immunocompromised patients may have their antigen-specific immune responses restored through the transfer of adoptive T cells specific for this LAA. PMID- 20970679 TI - Sign of the Zodiac as a predictor of survival for recipients of an allogeneic stem cell transplant for chronic myeloid leukaemia (CML): an artificial association. AB - BACKGROUND: Astrological or Zodiac (star) sign has been shown to be a statistically significant factor in the outcome of a variety of diseases, conditions, and phenomena. METHODS: To investigate its relevance in the context of a stem cell transplant (SCT), we examined its influence in chronic myeloid leukaemia, a disease with well-established prognostic factors. Data were collected on 626 patients who received a first myeloablative allogeneic SCT between 1981 and 2006. Star sign was determined for each patient. RESULTS: Univariate analyses comparing all 12 individual star signs showed considerable variation of 5-year probabilities of survival, 63% for Arians, to 45% for Aquarians, but without significance (P=.65). However, it was possible to pool together star signs likely to provide dichotomous results. Thus, grouping together Aries, Taurus, Gemini, Leo, Scorpio, and Capricorn (group A; n=317) versus others (group B; n=309) resulted in a highly significant difference (58% vs 48%; P=.007). When adjusted for known prognostic factors in a multivariate analysis, group B was associated with an increased risk of mortality when compared with group A (relative risk [RR], 1.37; P=.005). CONCLUSION: In this study, we show that, providing adequate care is taken, a significant relationship between patient star sign and survival post SCT for CML can be observed. This is, however, a completely erroneous result, and is based on the pooling together of observations to artificially create a statistically significant result. Statistical analyses should thus be carried out on a priori hypotheses and not to find a meaningful or significant result. PMID- 20970680 TI - Activity of the National Polish Bone Marrow Donor Registry--analysis of the matching process successfully completed with hematopoietic stem cell transplantation. AB - The activity of the National Polish Bone Marrow Donor Registry includes: (1) recruitment and typing of volunteer donors for the registry; (2) primary and confirmatory typing of patients and their families for sibling and family alternative donor transplantations; and (3) donor-recipient matching. There has been an improvement regarding the number of procedures (184 vs 201) and the successfully completed matches (102 vs 145) in 2006-2007 vs 2008-2009, respectively. The success rate of conclusive matching depended on the number of donors in a given registry and the incidence of rare HLA B-C or DR-DQ associations and specificities. In 2008-2009, Polish, German and all European registries, finally matched 129 (out of all 145) donors including 3, 18, 4 donors for patients with and 30, 68, 6 donors for patients without difficult HLA specificities and associations, respectively. Among the HLA-difficult patient group those lacking a donor in Europe and Israel were successfully matched in the USA (10/11 patients); the only one other subject was matched with a donor from Australia. PMID- 20970681 TI - Hand transplantation--Polish program. AB - BACKGROUND: Hand transplantations (HTs) are performed in specialized centers proceeding within a board-accepted transplantation program. In Poland such requirements are met by the Subdepartment or Replantation of Limbs of St. Jadwiga Hospital in Trzebnica. The goal of this study was to present the experience of the Center after 3 years of activity. MATERIAL AND METHODS: On creating the "waiting list of would-be hand recipients," we adhered to the inclusion criteria commonly used by other centers. Among 52 potential candidates seen over a 4-year period, the selection process and inclusion criteria yielded 13 patients who were preliminary candidates for an HT. They proceeded to a formal hospital admission to obtain a detailed evaluation including invasive diagnostic tests. The group consisted of 12 men of age 21-42 years with single dominant hand amputations and 1 woman of 23 years with amputations of both hands. Within this group we performed 3 HTs in 3 men of 32, 42, and 30 years old: 2006 and in 2007 at mid forearm level and in 2008 at the distal forearm level. The times elapsed from amputation to HT were 14, 6, and 7 years, respectively. RESULTS: The first patient achieved total motion of fingers equal to 63% of that of his unaffected hand. Evaluation using the SF-36 protocol gave a result of 50; by DASH, 95; by CFSS (according to Lanzetta and Petruzzo), 84 (excellent). He had only 1 mild rejection episode. Our second HT failed. The third patient has a good hand function, namely, 80% of the finger motion of the unaffected hand and sensitivity reaching his finger tips. No rejection episodes were observed. CONCLUSION: On the basis of these results, we plan to proceed with the hand transplantation program. PMID- 20970682 TI - Preclinical and clinical studies on application of human myoblasts in regeneration of the postinfarction heart. AB - Principal definitions of stem cell subdivisions as well as of the physiology of the renewal of their descendants have been elucidated in recent years. Regeneration mechanisms have been outlined using as an example the intestinal villus niche. Sources of stem cells for preclinical studies and the main conclusions from clinical trials have been developed in the vast majority in the 21st century. Meta-analyses and summaries have been focused so far on bone marrow stem cells and muscle-derived stem cells, which have been most often tried to date. Polish clinical trials on postinfarcted hearts have been consistent with the world literature regarding the major conclusions for myocardial regeneration. The controversies include possible side effects of stem cell applications. The necessity for genetic modification of the stem cells, which are mainly myoblasts, has been justified by the results of recently performed trials, initial examples including transfections of proangiogenic factors into human primary myoblast suspensions. PMID- 20970683 TI - Role of glucocorticoid-induced leucine zipper (GILZ) expression by dendritic cells in tolerance induction. AB - Dendritic cells (DCs) play a crucial role in T cell allorecognition in the context of organ transplantation and allogeneic hematopoietic stem cell transplantation (allo-HSCT). This DC function is believed to be directly involved in allo-HSCT morbidity and mortality. DC functions range from immunoaggressive responses to the promotion of tolerance, reflecting functional plasticity. This unique characteristic offers a rationale to propose generation of tolerogenic DCs as a therapeutic tool for graft-versus-host disease (GVHD). The accumulated preclinical findings support the concept that glucocorticoid-induced leucine zipper (GLIZ) expression redirects mature DC function toward a tolerogenic mode, driving differentiation of antigen-specific regulatory T cells. Taking into account the unique role of DCs within the allo-HSCT context, novel preventive and curative therapeutics for GVHD might be based on the selective induction of GILZ expression in vivo. PMID- 20970684 TI - "Medical writing" and ghostwriting as ethical challenges in medical communication. AB - In the past years, it has become increasingly apparent that ghostwriting may erode the public trust in medical science and scientific publishing. It is estimated that approximately 10% of articles published in reputed journals are ghostwritten, and this rate may be even higher in some medical specialties. Although this practice is rather universally condemned, the propriety of participation of professional writers in producing papers remains an open question. Although some believe this practice should also be banned, others argue that such stringent policy would increase nonpublication and rather encourage disclosure; but should medical writers be included as authors on the final version of manuscripts? These and other questions should be solved to maintain the high scientific and ethical standards of medical communication and public trust in medicine. PMID- 20970685 TI - Australian Society of Otolaryngology-Head and Neck Surgery meeting abstracts and housekeeping. PMID- 20970686 TI - Pneumococcal meningitis post-cochlear implantation: potential routes of infection and pathophysiology. AB - OBJECTIVE: This review describes the current concept of pneumococcal meningitis in cochlear implant recipients based on recent laboratory studies. It examines possible routes of Streptococcus pneumoniae infection to the meninges in cochlear implant recipients. It also provides insights into fundamental questions concerning the pathophysiology of pneumococcal meningitis in implant recipients. DATA SOURCES: Medline/PubMed database; English articles after 1960. Search terms: cochlear implants, meningitis, pneumococcus, streptococcus pneumonia. REVIEW METHODS: Narrative review. All articles relating to post-implant meningitis without any restriction in study designs were assessed and information extracted. RESULTS: The incidence of pneumococcal meningitis in cochlear implant recipients is greater than that of an age-matched cohort in the general population. Based on the current clinical literature, it is difficult to determine whether cochlear implantation per se increases the risk of meningitis in subjects with no existing risk factors for acquiring the disease. As this question cannot be answered in humans, the study of implant-related infection must involve the use of laboratory animals in order for the research findings to be applicable to a clinical situation. The laboratory research demonstrated the routes of infection and the effects of the cochlear implant in lowering the threshold for pneumococcal meningitis. CONCLUSION: The laboratory data complement the existing clinical data on the risk of pneumococcal meningitis post-cochlear implantation. PMID- 20970687 TI - Tackling the indigenous ear problem in Australia. PMID- 20970688 TI - Intratympanic gentamicin injections for the treatment of Meniere's disease. AB - OBJECTIVE: To assess the success rate and complications of treatment with injections of intratympanic gentamicin to the middle ear of patients with Meniere's disease. STUDY DESIGN: Case series with chart review. SETTING: A tertiary otologic private ENT clinic. SUBJECTS AND METHODS: Patients with Meniere's disease, who had not responded to medical treatment. Included in the sample were patients with Meniere's disease who had been treated with injections of gentamicin into the middle ear. After each gentamicin application, patients were monitored for their symptoms and hearing. If symptoms persisted, they received another intratympanic injection of gentamicin. This method is referred to as the variable titration method. A retrospective chart review was performed, and questionnaires were used to assess hearing, functional status, tinnitus, ear fullness sensation, and the control of vertigo attacks in response to treatment. RESULTS: Nineteen patients were sampled. Eighteen patients (94%) had complete or substantial control of vertigo. Five patients (26%) had worse hearing results on their post-treatment audiogram, averaging 13 dB hearing loss (range, 5-25 dB). In response to the questionnaires, all patients reported a significant improvement in the quality of life after treatment. CONCLUSION: The treatment was found to be highly effective. The variable titration method of injection prevents unnecessary injections for patients whose symptoms have already subsided. PMID- 20970689 TI - Chronic rhinosinusitis: an education and treatment model. AB - Research into chronic rhinosinusitis (CRS) has rapidly expanded over the last decade, resulting in a plethora of proposed etiologic and disease-modifying factors. Potentially, advancement of knowledge in this field has developed more than any other disease in otolaryngologic science. However, the teaching and education of this complex and still evolving process has lagged behind. Trainees, students, and residents may find the heterogeneous group of pathophysiologic mechanisms difficult to learn and apply to treatment decision making. Identification of the propagating factor and subsequent microbial, inflammatory, or mucociliary disease-modifying effects for a specific patient allows individual tailoring of treatment to address these factors. This facilitates a logical strategic process, rather than using one broad, ill-defined approach for each and every CRS patient. A model of CRS is presented as a teaching aid for residents and those learning about the etiology and directed treatment of this complex problem. PMID- 20970690 TI - Differentiating levels of surgical experience on a virtual reality temporal bone simulator. AB - OBJECTIVE: Virtual reality simulation is increasingly being incorporated into surgical training and may have a role in temporal bone surgical education. Here we test whether metrics generated by a virtual reality surgical simulation can differentiate between three levels of experience, namely novices, otolaryngology residents, and experienced qualified surgeons. STUDY DESIGN: Cohort study. SETTING: Royal Victorian Eye and Ear Hospital. SUBJECTS AND METHODS: Twenty-seven participants were recruited. There were 12 experts, six residents, and nine novices. After orientation, participants were asked to perform a modified radical mastoidectomy on the simulator. Comparisons of time taken, injury to structures, and forces exerted were made between the groups to determine which specific metrics would discriminate experience levels. RESULTS: Experts completed the simulated task in significantly shorter time than the other two groups (experts 22 minutes, residents 36 minutes, and novices 46 minutes; P = 0.001). Novices exerted significantly higher average forces when dissecting close to vital structures compared with experts (0.24 Newton [N] vs 0.13 N, P = 0.002). Novices were also more likely to injure structures such as dura compared to experts (23 injuries vs 3 injuries, P = 0.001). Compared with residents, the experts modulated their force between initial cortex dissection and dissection close to vital structures. Using the combination of these metrics, we were able to correctly classify the participants' level of experience 90 percent of the time. CONCLUSION: This preliminary study shows that measurements of performance obtained from within a virtual reality simulator can differentiate between levels of users' experience. These results suggest that simulator training may have a role in temporal bone training beyond foundational training. PMID- 20970691 TI - Pilomatrical carcinosarcoma. PMID- 20970692 TI - An unusual case of Epstein-Barr virus complicated by multiple cranial nerve neuropathy. PMID- 20970693 TI - Primary diffuse large B-cell lymphoma of the lacrimal sac. PMID- 20970694 TI - Pneumococcal meningitis post-cochlear implantation: preventative measures. AB - OBJECTIVE: Both clinical data and laboratory studies demonstrated the risk of pneumococcal meningitis post-cochlear implantation. This review examines strategies to prevent post-implant meningitis. DATA SOURCES: Medline/PubMed database; English articles after 1980. Search terms: cochlear implants, pneumococcus meningitis, streptococcus pneumonia, immunization, prevention. REVIEW METHODS: Narrative review. All articles relating to post-implant meningitis without any restriction in study designs were assessed and information extracted. RESULTS: The presence of inner ear trauma as a result of surgical technique or cochlear implant electrode array design was associated with a higher risk of post-implant meningitis. Laboratory data demonstrated the effectiveness of pneumococcal vaccination in preventing meningitis induced via the hematogenous route of infection. Fibrous sealing around the electrode array at the cochleostomy site, and the use of antibiotic-coated electrode array reduced the risk of meningitis induced via an otogenic route. CONCLUSION: The recent scientific data support the U.S. Food and Drug Administration recommendation of pneumococcal vaccination for the prevention of meningitis in implant recipients. Nontraumatic cochlear implant design, surgical technique, and an adequate fibrous seal around the cochleostomy site further reduce the risk of meningitis. PMID- 20970695 TI - In this issue/abstract thinking: the new normal. PMID- 20970696 TI - From children at risk to adults in need. PMID- 20970697 TI - Genomic copy number variation in disorders of cognitive development. AB - OBJECTIVE: To highlight recent discoveries in the area of genomic copy number variation in neuropsychiatric disorders including intellectual disability, autism, and schizophrenia. To emphasize new principles emerging from this area, involving the genetic architecture of disease, pathophysiology, and diagnosis. METHOD: Review of studies published in PubMed including classic studies of genomic disorders and microarray and copy number studies in normal controls, intellectual disability, autism, and schizophrenia. RESULTS: The advent of novel microarray technology has led to a revolution in the discovery of classic and novel copy number variants (CNVs) in various disorders affecting cognitive development. Across autism and schizophrenia, global CNV burden and de novo CNV burden are associated with disease. Also, specific recurrent CNVs may be associated with several DSM conditions. Each condition is also associated with heterogeneous and individually rare CNVs. CONCLUSIONS: CNVs play an important role in the genetic architecture of the childhood neuropsychiatric disorders discussed. This discovery appears to suggest an important role for the strict regulation of gene dosage in the neurodevelopmental roots of these conditions. Microarrays have emerged as high-yield tests in the diagnosis and molecular subtyping of the childhood-onset disorders involving cognitive development. In summary, CNV studies in disorders of cognitive development have revealed interesting and important new insights and have opened an avenue of investigation that holds great promise for neuropsychiatric disease. PMID- 20970699 TI - Children's problems predict adults' DSM-IV disorders across 24 years. AB - OBJECTIVE: The goal of this study was to determine continuities of a broad range of psychopathology from childhood into middle adulthood in a general population sample across a 24-year follow-up. METHOD: In 1983, parent ratings of children's problems were collected with the Child Behavior Checklist (CBCL) in a general population sample of 2,076 children and young adolescents aged 4 to 16 years. In 2007, 24 years later, 1,339 of these individuals were reassessed with the CIDI, a standardized DSM-IV interview. We used univariate logistic regression analyses to determine the associations between children's problems and adults' psychiatric disorders. RESULTS: Parent reported total problems scores in the deviant range (>85th percentile) predicted disruptive disorders in adulthood (odds ratio [OR] = 1.7, 95% confidence interval [95% CI] = 1.1-2.8). Adjusted for sex, age, and socioeconomic status in all analyses, deviant levels of parent-reported childhood anxiety predicted anxiety disorders in middle adulthood (OR = 1.6, 95% CI = 1.0 2.5). Conduct problems (i.e., cruelty to animals, lies) predicted both mood disorders (OR = 2.3, 95% CI = 1.1-4.8) and disruptive disorders (OR 2.1, 95% CI = 1.3-3.4), whereas oppositional defiant problems predicted only mood disorders (OR = 2.3, 95% CI = 1.0-5.2). Attention-deficit/hyperactivity problems did not predict any of the DSM-IV disorders in adulthood (OR = 0.8, 95% CI = 0.5-1.2). CONCLUSIONS: Children with psychopathology are at greater risk for meeting criteria for DSM-IV diagnoses in adulthood than children without psychopathology, even after 24 years. Moreover, different types of continuities of children's psychopathology exist across the lifespan. We found that anxious children, oppositional defiant children, and children with conduct problems are at greater risk for adult psychopathology. Effective identification and treatment of children with these problems may reduce long-term continuity of psychopathology. PMID- 20970698 TI - Adult outcomes of childhood dysregulation: a 14-year follow-up study. AB - OBJECTIVE: Using a general population sample, the adult outcomes of children who presented with severe problems with self-regulation defined as being concurrently rated highly on attention problems, aggressive behavior, and anxious-depression on the Child Behavior Checklist-Dysregulation Profile (CBCL-DP) were examined. METHOD: Two thousand seventy-six children from 13 birth cohorts 4 to 16 years of age were drawn from Dutch birth registries in 1983. CBCLs were completed by parents at baseline when children from the different cohorts were 4 to 16 years of age and sampled every 2 years for the next 14 years. At year 14 the CBCL and DSM interview data were collected. Logistic regression was used to compare and contrast outcomes for children with and without dysregulation, as measured by the latent-class-defined CBCL-DP. Sex and age were covaried and concurrent DSM diagnoses were included in regression models. RESULTS: Presence of childhood CBCL DP at wave 1 was associated with increased rates of adult anxiety disorders, mood disorders, disruptive behavior disorders, and drug abuse 14 years later. After controlling for co-occurring disorders in adulthood, associations with anxiety and disruptive behavior disorders with the CBCL-DP remained, whereas the others were not significant. CONCLUSIONS: A child reported to be in the CBCL-DP class is at increased risk for problems with regulating affect, behavior, and cognition in adulthood. PMID- 20970700 TI - Risk factors for conduct disorder and oppositional/defiant disorder: evidence from a New Zealand birth cohort. AB - OBJECTIVE: To examine the social, family background, and individual antecedents of conduct disorder (CD) and oppositional defiant disorder (ODD), the extent to which CD and ODD symptoms were predicted by common environmental risk factors, and the extent to which the antecedents of CD and ODD accounted for the comorbidity between the two disorders. METHOD: Data were gathered from 926 members of a New Zealand longitudinal birth cohort. The outcome measures were DSM IV symptom count measures of CD and ODD at age 14 to 16 years. Predictors measured during the period from 0 to 14 years included the following: maternal smoking during pregnancy; exposure to socioeconomic adversity; parental maladaptive behavior; childhood exposure to abuse and interparental violence; gender; cognitive ability; and affiliation with deviant peers in early adolescence. Associations between the predictors and outcome measures were modeled using structural equation modeling. RESULTS: The analyses showed that each of the predictors was significantly (p < .05) associated with CD and ODD, with the exception of gender and ODD. After model fitting, the profile of risk factors that predicted CD and ODD were largely similar. The analyses revealed that approximately 40% of the comorbidity between disorders could be accounted for by common factors. CONCLUSIONS: The data showed that CD and ODD had largely similar social and environmental antecedents. One implication of this finding is that treatment and prevention approaches that are developed for use with a particular behavior disorder may in fact reduce the incidence of both disorders. PMID- 20970701 TI - Symptoms of conduct disorder, oppositional defiant disorder, attention deficit/hyperactivity disorder, and callous-unemotional traits as unique predictors of psychosocial maladjustment in boys: advancing an evidence base for DSM-V. AB - OBJECTIVE: The incremental utility of symptoms of conduct disorder (CD), oppositional defiant disorder (ODD), attention-deficit/hyperactivity disorder (ADHD), and callous-unemotional (CU) traits for predicting psychosocial outcomes across multiple domains was examined in a community sample of 1,517 boys. METHOD: Several outcomes were assessed semiannually across a 2-year follow-up, including antisocial behavior, internalizing problems, peer conflict, and academic difficulties. Official criminal charges were also examined across adolescence. RESULTS: CD symptoms emerged as the most robust predictor of future antisocial outcomes. However, ODD symptoms predicted later criminal charges and conduct problems, and CU traits were robustly associated with serious and persistent criminal behavior in boys. Attention-deficit/hyperactivity disorder symptoms predicted increases in oppositional defiant behavior and conduct problems over time and were uniquely related to future academic difficulties. Both ADHD and ODD symptoms predicted social and internalizing problems in boys, whereas CU traits were associated with decreased internalizing problems over time. CONCLUSIONS: The current findings have implications for revisions being considered as part of the DSM-V. Specifically, incorporating CU traits into the diagnostic criteria for Disruptive Behavior Disorders (DBD) may help to further delineate boys at risk for severe and persistent delinquency. Although currently prohibited, allowing a diagnosis of ODD when CD is present may provide unique prognostic information about boys who are at risk for future criminal behavior, social problems, and internalizing problems. PMID- 20970702 TI - Psychiatric symptoms in bereaved versus nonbereaved youth and young adults: a longitudinal epidemiological study. AB - OBJECTIVE: To examine potential differences in psychiatric symptoms between parent-bereaved youth (N = 172), youth who experienced the death of another relative (N = 815), and nonbereaved youth (N = 235), aged 11 to 21 years, above and beyond antecedent environmental and individual risk factors. METHOD: Sociodemographics, family composition, and family functioning were assessed one interview wave before the death. Child psychiatric symptoms were assessed during the wave in which the death was reported and one wave before and after the death. A year was selected randomly for the nonbereaved group. RESULTS: The early loss of a parent was associated with poverty, previous substance abuse problems, and greater functional impairment before the loss. Both bereaved groups of children were more likely than nonbereaved children to show symptoms of separation anxiety and depression during the wave of the death, controlling for sociodemographic factors and prior psychiatric symptoms. One wave following the loss, bereaved children were more likely than nonbereaved children to exhibit symptoms of conduct disorder and substance abuse and to show greater functional impairment. CONCLUSIONS: The impact of parental death on children must be considered in the context of pre-existing risk factors. Even after controlling for antecedent risk factors, both parent-bereaved children as well as those who lost other relatives were at increased risk for psychological and behavioral health problems. PMID- 20970704 TI - Health care expenditures for children with autism spectrum disorders in Medicaid. AB - OBJECTIVE: To study trends in health care expenditures associated with autism spectrum disorders (ASDs) in state Medicaid programs. METHOD: Using Medicaid data from 42 states from 2000 to 2003, patients aged 17 years and under who were continuously enrolled in fee-for-service Medicaid were studied. Patients with claims related to autistic disorder (autism) were identified, as were patients with claims for any ASD other than autism. Total expenditures per treated patient consisted of Medicaid reimbursements from inpatient, outpatient, and long-term care and prescription drugs. Inflation-adjusted expenditures were compared over time and with expenditures associated with other mental health disorders. RESULTS: A total of 2,184,677 children were diagnosed with some type of mental disorder during the study period. Of these children, 69,542 had an ASD, with 49,921 having autism and the rest having another ASD. Mean total health care expenditures per child with ASD were $22,079 in 2000 (in 2003 US dollars), and rose by 3.1% to $22,772 in 2003. The treated prevalence of autism per 10,000 covered lives rose by 32.2% from 40.6 to 53.6, the highest rate of increase among all mental disorders. Total health care expenditures for ASDs per 10,000 covered lives grew by 32.8% from $1,270,435 in 2000 (in 2003 dollars) to $1,686,938 in 2003. CONCLUSIONS: Medicaid-reimbursed health care expenditures for ASD were quite substantial. Although the per patient expenditures grew slightly over time, the large increase in treated prevalence caused a considerable rise in total ASD associated health care expenditures. PMID- 20970703 TI - Neuropsychological functioning in children with Tourette syndrome with and without attention-deficit/hyperactivity disorder. AB - OBJECTIVE: Neuropsychological functioning in children with Tourette syndrome (TS) has been characterized by subtle deficits in response inhibition, visual-motor integration, and fine-motor coordination. The association of these deficits with the tics of the TS versus co-occurring attention-deficit/hyperactivity disorder (ADHD) has not been well understood because of small sample sizes and lack of adequate control conditions. We examined neuropsychological functioning in relatively large and well-characterized samples of children categorized as TS, TS plus-ADHD, ADHD, and unaffected controls. METHOD: A total of 56 children with TS only, 45 with TS-plus-ADHD, 64 with ADHD, and 71 healthy community control subjects were assessed on a battery of neuropsychological measures including the Connors' Continuous Performance Test (CPT), the Stroop Color-Word Interference Test (Stroop), the Beery Visual-Motor Integration Test (VMI), and the Purdue Pegboard Test. RESULTS: There were no differences between children with TS-only and unaffected controls on the measures of response inhibition and visual-motor integration. Boys with TS-only but not girls with TS-only were impaired in the dominant hand Purdue performance. Children with ADHD were impaired on all study measures. Children with TS-plus-ADHD revealed no deficits on the Stroop, VMI, and Purdue tests but were impaired on the sustained attention portion of the CPT. CONCLUSIONS: These results indicate that co-occurring ADHD may be responsible for the neuropsychological deficits, or at least those assessed in the present study, in children with TS. Explanations in terms of neurobiological mechanisms of co occurring TS and ADHD, as well as possible compensatory mechanisms in children with TS, are discussed. PMID- 20970707 TI - Preface. Psychological issues for the oral and maxillofacial surgeon. PMID- 20970706 TI - Low grade marginal zone B-cell lymphoma presenting as local amyloidosis in a submandibular salivary gland. AB - An unusual case of a low grade marginal zone B-cell lymphoma is reported and the literature reviewed. This case demonstrates that a diagnosis of lymphoma must be considered when there is amyloidosis in an otherwise asymptomatic submandibular salivary gland mass. PMID- 20970708 TI - The need for preoperative psychological risk assessment. AB - Adverse psychological outcomes are more prevalent among patients undergoing elective, appearance-altering surgery than are physical complications. Patients may experience depression, posttraumatic stress disorder, or an exacerbation of preexisting symptoms related to body dysmorphic disorder. Some have directed anger against themselves or against the operating surgeon with suicide, litigation, harassment, and homicide, all well documented. Although there are well-established protocols to conduct medical and anesthetic risk stratification, such protocols do not exist for psychological risk assessment (PRA). The literature related to this is reviewed, the need for PRA is discussed, and an approach to PRA for dentists and surgeons is proposed. PMID- 20970709 TI - Psychological risks associated with appearance-altering procedures: issues "facing" cosmetic surgery. AB - There is a dynamic and fluid relationship between cosmetic surgery and psychology that requires careful and constant attention from the surgeon. Surgeons all desire a "short and sweet" checklist evaluation that tells them if it is safe for the patient to undergo an elective surgical procedure. Obviously, this is wishful thinking. It is asking too much for surgeons to be able to quantify the overall psychological risk. Rather, they should objectively screen, review, and evaluate as many of the variables as possible. These include but are not limited to the surgical issue, the personality of the patient, the patient's family and/or relationships, and the overall context of the situation. Surgeons should also reflect on both their technical expertise and limitations and the patient's personal resiliency. PMID- 20970710 TI - Body dysmorphic disorder in patients who seek appearance-enhancing medical treatments. AB - Most patients who seek appearance-enhancing medical treatments report some degree of body image dissatisfaction, which is believed to motivate the pursuit of these treatments. However, patients with extreme body image dissatisfaction may be suffering from a psychiatric disorder known as body dysmorphic disorder (BDD). This article reviews BDD, including its clinical features and prevalence in medical settings. Although patients with BDD frequently seek cosmetic treatments to address their appearance-related distress, such treatments are rarely beneficial. The article concludes with recommendations for patient and provider safety. PMID- 20970711 TI - Personality disorders in patients seeking appearance-altering procedures. AB - The practice of psychological risk assessment (PRA) is an indispensable component of the screening process for patients seeking elective appearance-altering procedures (AAPs). Despite the need for more literature in PRA, some risk factors for psychological adverse outcomes have been established. Among these risk factors are personality disorders. This article provides some background regarding psychological risk factors associated with personality disorders for patients seeking AAPs and a brief introduction to personality disorders for the surgeons to be better prepared to identify these conditions while conducting a PRA. PMID- 20970712 TI - Management of the uncooperative child. AB - The management of a child who requires a medical procedure is a challenging issue for the oral and maxillofacial surgeon (OMS) and practitioners in the dental specialties. The office of the OMS is traditionally one in which short outpatient procedures are performed within brief appointment times often using only local anesthesia. For typical children, this brief procedure may be difficult, and for children with behavioral challenges, it may be impossible without the use of behavioral management techniques or pharmacologic modalities. Practitioners must be aware of current trends in pediatric mental health and should develop treatment protocols to avoid complications. PMID- 20970713 TI - Discussing adverse outcomes with patients and families. AB - Complications and undesired outcomes happen to some patients of virtually all physicians, at all stages in their careers. Bad outcomes can be a consequence of disease processes, the premorbid condition of the patient, or the errors that occur in the process of health care. These errors include, but are by no means confined to, surgeon error. Regardless of the reason for the bad outcome, the surgeon is obligated to discuss the event with the patient and the family. This article reviews the benefits, barriers, and legal implications of the discussion and describes the disclosure process. PMID- 20970715 TI - Occupational stress in oral and maxillofacial surgeons: tendencies, traits, and triggers. AB - Health professionals are subject to higher levels of stress than the average worker. Little has been written on these subjects, specifically in oral and maxillofacial surgeons. Anecdotally, dentists have been singled out as the health care professionals more likely to be subjected to severe stress, burnout, failed marriages, depression, substance abuse, and commit suicide. However, with oral and maxillofacial surgery being a particularly high-stress specialty of dentistry, a study of the dental literature regarding stress may be relevant. This article explores the myths and realities of stress and burnout in oral and maxillofacial surgeons and the coping skills, both adaptive and maladaptive used by practitioners to deal with their stress. This article also offers some practical suggestions for improving both the mental and physical health of oral and maxillofacial surgeons. PMID- 20970714 TI - Understanding and managing patients with chronic pain. AB - The specialty of oral and maxillofacial surgery has had at its core the foundations of anesthesia and pain and anxiety control. This article attempts to refamiliarize the reader with clinical pearls helpful in the management of patients with chronic pain conditions. The authors also hope to highlight the interplay of chronic pain and psychology as it relates to the oral and maxillofacial surgery patient. To that end, the article outlines and reviews the neurophysiology of pain, the definitions of pain, conditions encountered by the oral and maxillofacial surgeon that produce chronic pain, the psychological impact and comorbidities associated with patients experiencing chronic pain conditions, and concepts of multimodal treatment for patients experiencing chronic pain conditions. PMID- 20970716 TI - Psychological issues in sleep apnea. AB - The overlap of sleep disorders with various psychiatric problems is so great that one would suspect that both types of problems may have common biologic roots. An estimated 65% to 90% of adults with major depression experience some kind of sleep problem. Sleep problems also increase the risk for developing depression. Since the early days of research on disturbed sleep, clinical studies have suggested the existence of a relationship between depression and obstructive sleep apnea. PMID- 20970717 TI - Eating disorders and the oral and maxillofacial surgeon. AB - Perhaps the most challenging of all patients seeking treatment with the oral and maxillofacial surgeon (OMS) are those with eating disorders (EDs). Complex psychiatric illnesses, with their associated and significant medical sequelae, make a thorough knowledge of these disorders critical in the approach, evaluation, treatment planning, and surgical outcome in this expanding population of patients. Whether surgery for patients with EDs is elective in nature or unplanned, challenges are faced in all aspects of their care, from diagnosis to preoperative preparation, surgery, and treatment. This article identifies and outlines issues of importance for the OMS when encountering patients with known or suspected EDs and provides guidance in the management of their outpatient or inpatient treatment. PMID- 20970718 TI - End-of-Life Issues for the Oral and Maxillofacial Surgeon. AB - The oral and maxillofacial surgeon (OMS) plays a critical role when it comes to listening and answering patients' questions regarding prognosis, course of treatment, and overall expectations of what lies ahead. The OMS should remain an advocate for the patient, always keeping in mind that it is the patient's wishes that must be respected. The surgeon should champion patients' autonomy and cooperate with their families and other clinicians to ensure that patients have a "good death," defined as one that is pain free, peaceful, and dignified, at a place of their choosing with the relatives present and without futile heroic interventions. Indeed, the relationship and open communication between patient and surgeon may be one of the best treatments that the patient can have. PMID- 20970719 TI - Substance abuse issues in oral and maxillofacial practice. AB - Substance abuse has far-reaching consequences for individuals, their families, and the community. Medications with abuse potential play an important role in the management of pain and are widely prescribed by the oral and maxillofacial surgeon. Reducing the likelihood of abuse and providing appropriate pain management for the known abuser are critical aspects of perioperative patient management. Health care providers are not immune to substance abuse and may, in fact, be at an elevated risk. Identification of impaired providers is essential to help them find the appropriate treatment and counseling and to prevent harm to their patients, family, friends, or associates. PMID- 20970720 TI - Volcanoes and travel medicine. PMID- 20970721 TI - Swimming with death: Naegleria fowleri infections in recreational waters. AB - Naegleria fowleri is a free-living amoeba commonly found in warm freshwater environments such as hot springs, lakes, natural mineral water, and resort spas frequented by tourists. N. fowleri is the etiologic agent of primary amoebic meningoencephalitis (PAM), an acute fatal disease of the central nervous system that results in death in approximately seven days. Previously thought to be a rare condition, the number of reported PAM cases is increasing each year. PAM is difficult to diagnose because the clinical signs of the disease are similar to bacterial meningitis. Thus, the key to diagnosis is physician awareness and clinical suspicion. With the intent of creating awareness among travel medicine practitioners and the tourism industry, this review focuses on the presenting features of N. fowleri and PAM and offers insight into the prevention and treatment of the disease. PMID- 20970722 TI - Post-traumatic camel-related benign paroxysmal positional vertigo. AB - INTRODUCTION: Benign paroxysmal positional vertigo (BPPV) is a common form of dizziness. The causes of BPPV are not yet known but a relationship between the onset of vertigo and head trauma has been found. Among the causes of head injury related to BPPV, dropping off a camel has not been reported in literature yet. CASE REPORT: We describe two cases of persons that fell off a camel during a safari in Middle East countries. After the fall they reported vertigo symptoms that were not interpreted as BPPV. When they returned to Italy, due to symptoms persistence, they were referred to our ENT practice: we found evidence of BPPV. In a case it was a bilateral BPPV (bBPPV). DISCUSSION: Falling off a camel may be a relevant cause of BPPV. We suggest a correct evaluation of the labyrinth for BPPV with the appropriate diagnostic maneuvers and, if necessary, a treatment with repositioning maneuvers. PMID- 20970723 TI - Linking yellow fever vaccinator approval and renewal with training in travel medicine in New Zealand. AB - Yellow fever is a mosquito-borne disease, which can cause serious illness. The World Health Organization (WHO) requires travellers to have vaccination against Yellow fever for all international travel going into and from Yellow fever endemic areas in order to prevent the spread of this potentially deadly disease. Only clinics and hospitals authorised by health departments of national governments can administer the disease. Yellow fever vaccination centres are often subject to inspection in many countries, although the requirements for Yellow fever vaccinators (YFV) vary from country to country. In New Zealand, approval of YFV now requires specific postgraduate training in travel medicine or its equivalent, as well as continuing professional development to maintain this status. It is expected that this will assist in improving standards of travel medicine practice in New Zealand. PMID- 20970724 TI - Tick-borne encephalitis virus and the immune response of the mammalian host. AB - Tick-borne encephalitis (TBE) is caused by Tick-borne encephalitis virus (TBEV), one of the most prevalent arboviruses in Europe and in many parts of Asia. Transmission of TBEV to humans usually occurs by bite of an infected tick or rarely by ingestion of unpasteurized milk products of infected livestock. TBEV infection induces an innate and adaptive immune response, nevertheless it is able to replicate in several cell types of the immune system at the same time which probably contributes to the spread of the virus in the human host. Furthermore, TBEV can enter the central nervous system (CNS) by yet not well understood mechanisms via the blood brain barrier (BBB) or the olfactory neurons which leads to serious neurological disorders like meningitis, encephalitis or even meningoencephalitis. In this article we review the known facts and possible hypotheses of interaction of TBEV with components of the mammalian immune system and their implications for TBEV-mediated pathogenesis. PMID- 20970725 TI - Tick-borne encephalitis: pathogenesis and clinical implications. AB - Tick-borne encephalitis (TBE) is an important and severe neurological illness occurring in large areas of Europe and northern Asia. Only a small proportion of those infected develop clinical symptoms. The symptomatic cases are, however, characterized with fevers and debilitating encephalitis that might progress into chronic disease or fatal infections. This review summarizes data on clinical presentation, pathogenesis and pathology of TBE in humans, and of experimental TBE in animal models with the purpose to explain why is TBE such a severe disease clinically. PMID- 20970726 TI - Tick-borne encephalitis (TBE) trends in epidemiology and current and future management. AB - Tick-borne encephalitis (TBE) is considered an international health issue, as the number of risk areas and reported cases across Europe, Russia, and parts of Asia continues to increase. The incidence of TBE has fluctuated considerably from year to year in many countries, but in the past decade the number of TBE cases has significantly increased in the Baltic states, the Czech Republic, and Germany, in addition to occurring in countries previously considered to be free from TBE, such as Denmark (specifically the main island of Zealand), France, and Italy. A number of factors have been suggested to explain the increase in incidence, including climate change, and increased travel and outdoor pursuits, placing people in increased contact with infected ticks. There is no causal treatment available once infected, but TBE can be effectively prevented by vaccination, for which several vaccines are widely available. Three vaccination schedules are available for immunization against TBE, and the recommendations for TBE vaccination vary considerably across the countries in which TBE foci are found. However, plans are in place to raise awareness of TBE and to standardize the vaccination programme across Europe, with the aim of reducing the number of future cases of TBE. PMID- 20970727 TI - What tick-borne encephalitis may look like: clinical signs and symptoms. AB - Tick-borne encephalitis is a zoonosis, endemic in a vast area of Europe and Asia. Clinical spectrum of the disease ranges from mild meningitis to severe meningoencephalitis with or without paralysis. Rare clinical manifestations are an abortive form of the disease and a chronic progressive form. A post encephalitic syndrome, causing long-lasting morbidity that often affects the quality of life and sometimes also forces the individual to a change in lifestyle, develops in 35-58% of patients after acute tick-borne encephalitis. Clinical course and outcome vary by subtype of tick-borne encephalitis virus causing infection. Severity of the disease increases with the age of patients. The risk of incomplete recovery is higher for patients who have more severe clinical illness during acute stage of tick-borne encephalitis. PMID- 20970728 TI - Tick borne encephalitis TBE--vaccination in non-endemic countries. AB - The increase of TBE cases in Europe has become a problem of international public health and travel medicine, because it is not only of concern for endemic areas, but also for visitors from non-endemic countries. Although highly effective modern vaccines are on the market in 28 European countries, there are still 7, mainly Eastern European, countries with no or an uncertain number of cases and without licensed modern vaccines. The prevailing danger for travellers, however, lies in underestimation and not awareness of the disease by public authorities, travel agencies and by the travellers themselves, a lack of mandatory notifications and sometimes a lack of financial resources. Outside Europe TBE has mostly not been recognized as a travel associated disease. Recommendation for travellers to endemic countries and suggestions to extra-European travellers and health authorities as well as vaccination advices are summarized in this paper. PMID- 20970729 TI - Time to put out the lights on sleeping sickness? AB - Sleeping sickness (or Human African Trypanosomiasis, HAT) is a potentially fatal parasitic disease that affects a large proportion of sub-Saharan Africa. It was epidemic in the early 20th century before being nearly eradicated through a variety of control programmes. Despite this, there was a resurgence in the 1980s and 90s following relaxation of these programmes. Recent advances are reversing this trend once more. However, more research is required to improve diagnosis and treatment, and to better understand the epidemiology of HAT if complete eradication is to be achieved in the future. PMID- 20970730 TI - Imported cases of malaria admitted to a hospital in Western Venezuela, 1998-2009. PMID- 20970731 TI - Adsorbed monovalent diphtheria vaccine. PMID- 20970732 TI - Tungiasis among traveller. PMID- 20970734 TI - Bilateral cervical spondylolysis of C7. AB - BACKGROUND CONTEXT: Cervical spondylolysis, which is defined as a cleft between the superior and inferior articular facets of the articular pillar, is a rare condition. The sixth cervical vertebra (C6) is the level most commonly affected. Cases involving C2, C3, C4, or C5 have also been reported. However, to date, no case of C7 spondylolysis has been reported. PURPOSE: To present a rare case of bilateral spondylolysis of the seventh cervical vertebra (C7) in a 58-year-old man. STUDY DESIGN: A case report. METHODS: A 58-year-old man visited our hospital with chronic posterior neck pain radiating to the left upper extremity. Magnetic resonance imaging (MRI) study revealed left foraminal disc herniations at C5-C6 and C6-C7. Cervical spondylolysis involving C7 was discovered incidentally during computed tomography (CT)-guided transforaminal steroid injection. Plain radiographs, CT images, and MRIs were reviewed thoroughly once again. RESULTS: The patient's symptoms were relieved after he received CT-guided transforaminal steroid injections. Plain radiographs revealed a radiolucent defect in the articular pillar and cleft at the spinous process of C7. Computed tomography confirmed bilateral spondylolysis and spina bifida occulta of the C7 vertebra. Magnetic resonance imaging revealed absence of edema, which was suggestive of a chronic lesion. CONCLUSION: Involvement of C7 is not exceptional in a case of cervical spondylolysis. PMID- 20970735 TI - Huge thoracolumbar extradural arachnoid cyst excised by recapping T-saw laminoplasty. AB - BACKGROUND CONTEXT: Spinal extradural arachnoid cysts are rare expanding lesions in the spinal canal. Total removal of the cyst and repair of the dural defect is the primary treatment for symptomatic spinal extradural arachnoid cysts. PURPOSE: To report the usefulness of recapping T-saw laminoplasty in treating huge extradural arachnoid cyst. STUDY DESIGN: Case report. METHODS: We report the case of a 43-year-old man who presented with a 2-year history of progressive muscle weakness and numbness of the lower extremities. Magnetic resonance imaging (MRI) showed a huge extradural arachnoid cyst at the T12-L3 level extending into bilateral neural foramina and severe posterior compression of the spinal cord and cauda equina. RESULTS: The patient underwent total resection of the cyst and closure of the communication. En bloc recapping T-saw laminoplasty of T12-L2 including the T12-L1 and L1-L2 facet joints was performed to obtain extensive exposure and preserve posterior stability. Postoperatively, the patient achieved complete recovery of neurologic functions. Follow-up MRI demonstrated no recurrence of the cyst. Bone union after laminoplasty was obtained within 6 months. CONCLUSION: Total resection of the cyst and closure of the communication is curative for this rare lesion. Recapping T-saw laminoplasty provides extensive exposure for removal of a large cyst while allowing complete preservation of the posterior spinal elements. PMID- 20970736 TI - The relationship between disc degeneration, low back pain, and human pain genetics. AB - COMMENTARY ON: Dai F, Belfer I, Schwartz C, et al. Association of catechol-O methyltransferase genetic variants with outcome in patients undergoing surgical treatment for lumbar degenerative disc disease. Spine J 2010:10:949-957 (in this issue). PMID- 20970737 TI - Predictors and prevalence of patients undergoing additional kyphoplasty procedures after an initial kyphoplasty procedure. AB - BACKGROUND CONTEXT: Vertebral cement augmentation, including kyphoplasty, has been shown to be a successful treatment for pain relief for vertebral compression fracture (VCF). Patients can sustain additional symptomatic VCFs that may require additional surgical intervention. PURPOSE: To examine the prevalence and predictors of patients who sustain additional symptomatic VCFs that were treated with kyphoplasty. STUDY DESIGN: A retrospective review of patients who previously underwent kyphoplasty for VCFs and had additional VCFs that were treated with kyphoplasty. PATIENT SAMPLE: A total of 256 patients underwent kyphoplasty for VCFs from 2000 to 2007 at a single medical center. OUTCOME MEASURES: The outcome measure of interest was the need for an additional kyphoplasty procedure for a symptomatic VCF. METHODS: Risk factors such as age, sex, smoking status, and steroid use were assessed, as well as bisphosphonate use. Sagittal spinal alignment via Cobb angles for thoracic, thoracolumbar, and lumbar regions was assessed. RESULTS: About 22.2% of the patients had an additional symptomatic VCF that was treated with a kyphoplasty procedure. Steroid use was the only significant risk factor for predicting patients with additional symptomatic VCFs who underwent additional kyphoplasty. The average time to the second VCF was 33 days. Adjacent-level VCFs were most common in the thoracic and thoracolumbar spine. Bisphosphonate use was not shown to be protective of preventing additional VCFs during this follow-up period. CONCLUSION: This is the first single-center review of a large cohort of patients who underwent additional-level kyphoplasty for symptomatic VCFs after an index kyphoplasty procedure. Our results suggest that patients with a VCF who use chronic oral steroids should be carefully monitored for the presence of additional symptomatic VCFs that may need surgical intervention. Patients with prior thoracic VCFs who have additional back pain should be reevaluated for a possible adjacent-level fracture. PMID- 20970738 TI - Biomechanical evaluation of an expandable meshed bag augmented with pedicle or facet screws for percutaneous lumbar interbody fusion. AB - OBJECTIVE: To evaluate the biomechanics of lumbar motion segments instrumented with stand-alone OptiMesh system augmented with posterior fixation using facet or pedicle screws and the efficacy of discectomy and disc distraction. BACKGROUND CONTEXT: OptiMesh bone graft containment system has been used for vertebral compression fractures and percutaneous lumbar interbody fusion. The filled mesh bag serves as the interbody device providing structural support to the motion segment being fused. No biomechanical data of this new device are available in the literature. METHODS: Twenty-four fresh human cadaveric lumbar motion segments were divided into two groups. In the control group, multidirectional flexibility testing was conducted after an intact condition and standard transforaminal lumbar interbody fusion (TLIF) procedure. In the OptiMesh group, testing was performed following intact, stand-alone OptiMesh procedure, OptiMesh with facet screws (placed using the transfacet approach), and OptiMesh with pedicle screws and rods. Range of motion (ROM) was calculated for each surgical treatment. The lordosis and disc height change of intact and instrumented specimens were measured in the lateral radiographs to evaluate the disc space distraction. In the OptiMesh group, cyclic loading in flexion extension (FE) was applied to measure cage subsidence or collapse (10,000 cycles at 6 Nm). After biomechanical testing, all the specimens were dissected to inspect the discectomy and end plate preparation. The area of discectomy was measured. RESULTS: The mean ROM of the intact specimens was 2.7 degrees , 7.4 degrees , and 7.2 degrees in axial torsion (AT), lateral bending (LB), and FE, respectively. There was no difference between the control group and OptiMesh group. The mean ROM of the stand-alone OptiMesh system decreased to 2.4 degrees , 5.1 degrees , and 4.3 degrees in AT, LB, and FE. The ROM decreased to 0.9 degrees in AT, 2.2 degrees in LB, and 0.9 degrees in FE with OptiMesh system and facet screws. On average, OptiMesh system with pedicle screws and rods reduced the ROM to 1.3 degrees in AT, 1.6 degrees in LB, and 1.1 degrees in FE. Compared with the intact condition and stand-alone OptiMesh system, both posterior fixation options had significant statistical difference (p<.001). In AT, ROM of facet screws was lower than that of pedicle screws (p < .05). There was no statistical difference between the facet and pedicle screws in LB and FE (p > .05). The mean volume of bone graft packed into each bag was 8.3 +/- 1.5 cc. The average increase of lordosis was 0.6 degrees +/ 1.0 degrees after meshed bag was deployed. The average distraction achieved by the OptiMesh system was 1.0 +/- 0.6 mm. The average prepared area of discectomy was 42% of the total disc. The disc height change after cyclic loading was 0.2 mm. No subsidence or collapse was noticed. CONCLUSIONS: The OptiMesh system offers large volume of bone graft in the disc space with small access portals. The OptiMesh system had similar construct stability to that of standard TLIF procedure when posterior fixation was applied. However, the amount of distraction was limited without additional distraction tools. With the anterior support provided by the expandable meshed bag, facet screws had comparable construct stability to that of pedicle screws. Slightly higher stability was observed in facet screws in AT. PMID- 20970739 TI - The use of the T1 sagittal angle in predicting overall sagittal balance of the spine. AB - BACKGROUND CONTEXT: A balanced sagittal alignment of the spine has been shown to strongly correlate with less pain, less disability, and greater health status scores. To restore proper sagittal balance, one must assess the position of the occiput relative to the sacrum. The assessment of spinal balance preoperatively can be challenging, whereas predicting postoperative balance is even more difficult. PURPOSE: This study was designed to evaluate and quantify multiple factors that influence sagittal balance. STUDY DESIGN: Retrospective analysis of existing spinal radiographs. METHODS: A retrospective review of 52 adult spine patient records was performed. All patients had full-column digital radiographs that showed all the important skeletal landmarks necessary for accurate measurement. The average age of the patient was 53 years. Both genders were equally represented. The radiographs were measured using standard techniques to obtain the following parameters: scoliosis in the coronal plane; lordosis or kyphosis of the cervical, thoracic, and lumbar spine; the T1 sagittal angle (angle between a horizontal line and the superior end plate of T1); the angle of the dens in the sagittal plane; the angle of the dens in relation to the occiput; the sacral slope; the pelvic incidence; the femoral-sacral angle; and finally, the sagittal vertical axis (SVA) measured from both the dens of C2 and from C7. RESULTS: It was found that the SVA when measured from the dens was on average 16 mm farther forward than the SVA measured from C7 (p<.0001). The dens plumb line (SVA(dens)) was then used in the study. An analysis was done to examine the relationship between SVA(dens) and each of the other measurements. The T1 sagittal angle was found to have a moderate positive correlation (r=0.65) with SVA(dens), p<.0001, indicating that the amount of sagittal T1 tilt can be used as a good predictor of overall sagittal balance. When examining the other variables, it was found that cervical lordosis had a weak correlation (r=0.37) with SVA(dens) that was unexpected, given that cervical lordosis determines head position. Thoracic kyphosis also had a weak correlation (r=0.26) with SVA(C1), which was equally surprising. Lumbar lordosis had a slightly higher correlation (r=0.38), p=.006, than the cervical or thoracic spine. A multiple regression was run on the data to examine the relationship that all these independent variables have on SVA(dens). SPSS (SPSS, Inc., Chicago, IL, USA) was used to create a regression equation using the independent variables of T1 sagittal angle, cervical lordosis, thoracic kyphosis, lumbar lordosis, sacral slope, pelvic incidence, and femoral-sacral angle and the dependent variable of SVA(dens). The model had a strong correlation (r=0.80, r(2)=0.64) and was statistically significant (p<.0001). The T1 sagittal angle was the variable that had the strongest correlation with the SVA(dens) Spearman r=0.65, p<.0001, followed by pelvic incidence, p=.002, and lumbar lordosis, p=.006. We also observed that when the T1 tilt was higher than 25 degrees , all patients had at least 10 cm of positive sagittal imbalance. In addition, patients with negative sagittal balance had mostly low T1 tilt values, usually lower than 13 degrees . The other variables were not shown to have a statically significant influence on SVA. CONCLUSIONS: This analysis shows that many factors influence the overall sagittal balance of the patient, but it may be the position of the pelvis and lower spine that have a stronger influence than the position of the upper back and neck. Unfortunately, to our knowledge, there are no studies to date that have established a normal sagittal T1 tilt angle. However, our analysis has shown that when the T1 tilt was higher than 25 degrees , all patients had at least 10 cm of positive sagittal imbalance. It also showed that patients with negative sagittal balance had mostly low T1 tilt values, usually below 13 degrees of angulation. The T1 sagittal angle is a measurement that may be very useful in evaluating sagittal balance, as it was the measure that most strongly correlated with SVA(dens). It has its great utility where long films cannot be obtained. Patients whose T1 tilt falls outside the range 13 degrees to 25 degrees should be sent for full-column radiographs for a complete evaluation of their sagittal balance. On the other hand, a T1 tilt within the above range does not guarantee a normal sagittal balance, and further investigation should be performed at the surgeon's discretion. PMID- 20970740 TI - The effect of needle size inducing degeneration in the rat caudal disc: evaluation using radiograph, magnetic resonance imaging, histology, and immunohistochemistry. AB - BACKGROUND CONTEXT: The rat caudal disc has been increasingly used in studying of disc degeneration because of its simplicity, low cost, and efficiency. However, the reproducibility and standardization are essential to facilitate the investigations of biologic therapeutics at different stages of degeneration. PURPOSE: To identify the effect of different needle gauges to the degenerative response in rat caudal discs and to examine its pathogenesis by looking at the cellular and matrix changes. STUDY DESIGN: In vivo study of injury-induced rat caudal disc degeneration using needle puncture. PATIENT SAMPLE: Thirty-six Lewis rats aged 12-14 weeks. OUTCOME MEASURES: The induced degenerative discs were analyzed by plain radiograph, magnetic resonance imaging (MRI) and histological examination. Proteoglycan content was assessed by alcian blue stain. Immunohistochemistry using aggrecan, collagen II, and Sox-9 was also evaluated to investigate cell differentiation and matrix changes. METHODS: All rats were divided into three groups according to different needle gauges (18G, 20G, and 22G). Caudal discs were punctured percutaneously under image guidance. Radiographs and MRI were obtained at 2 weeks interval until 8 weeks. At each time point, three rats from each group were sacrificed for histological analysis and immunohistochemistry. RESULTS: Larger needle gauges, especially 18G, produced more deterioration of the disc when compared with smaller sizes, particularly with time. Significant differences were identified in almost all parameters compared between 18G and 22G at the 8-week time point. For the effect of time in the same needle size, the differences occurred between 2- or 4-week and 8-week time point in the 18G and 20G groups. The proteoglycan and aggrecan stain gradually decreased over time. Chondrogenic differentiation was identified within the degenerative disc by detecting Sox-9 positive cells and collagen II accumulation increased as degeneration progressed. CONCLUSIONS: The puncture induced degenerative changes in rat caudal discs can imitate the human degenerative cascade as observed in plain radiograph, MRI, histology, and immunohistochemistry. We suggest that needle size affects the occurrence of progression of degeneration; thus, the large needle size was required to accelerate the deterioration. The size of needle and time point after injury should be considered when investigating the effect of therapeutic materials to retard degeneration or regenerate the intervertebral disc. PMID- 20970741 TI - In vitro biomechanics of an expandable vertebral body replacement with self adjusting end plates. AB - BACKGROUND CONTEXT: Unstable burst fractures of the thoracolumbar spine may be treated surgically. Vertebral body replacements (VBRs) give anterior column support and, when used with supplemental fixation, impart rigidity to the injured segments. Although some VBRs are expandable, device congruity to the vertebral end plates is imprecise and may lead to stress risers and device subsidence. PURPOSE: The objective of this study was to compare the rigidity of a VBR that self-adjusts to the adjacent vertebral end plates versus structural bone allograft and with an unsupported anterior column in a traumatic burst fracture reconstruction model. STUDY DESIGN: Biomechanical flexibility testing with rod strain measurement. PATIENT SAMPLE: Twelve T11-L3 human spine segments. OUTCOME MEASURES: Range of motion, neutral zone, and posterior fixation rod stress (moments). METHODS: Flexibility testing was performed to +/- 6 Nm in flexion extension, lateral bending, and axial rotation on 12 intact human T11-L3 specimens. Burst fractures were created in L1, and flexibility testing was repeated in three additional states: subtotal corpectomy with posterior instrumentation (PI) only from T12 to L2, reconstruction with a femoral strut allograft and PI, and reconstruction with a VBR (with self-adjusting end plates) and PI. The PI consisted of pedicle screws and strain gage instrumented rods that were calibrated to measure rod stress via flexion-extension bending moments. RESULTS: There was no statistical difference in range of motion or neutral zone between the strut graft and VBR constructs, which both had less motion than the PI-only construct in flexion/extension and torsion and were both less than the intact values in flexion/extension and lateral bending (p < .05). Posterior rod moments were significantly greater for the PI-only construct in flexion/extension relative to the strut graft and VBR states (p = .03). CONCLUSIONS: This study, which simulated the immediate postoperative state, suggests that a VBR with self adjusting end plate components has rigidity similar to the standard strut graft when combined with PI. Posterior rod stress was not significantly increased with this type of VBR compared with the strut graft reconstruction. The benefits of burst fracture stabilization using a self-adjusting VBR ultimately will not be known until long-term clinical studies are performed. PMID- 20970742 TI - Transcriptomics and proteomics in the study of H1N1 2009. AB - Influenza A virus (H1N1) 2009, a new swine-origin influenza A virus, has been spread worldwidely and caused great public fear. High-throughput transcriptomics and proteomics methods are now being used to identify H1N1 and H1N1-host interaction. This article reviews recent transcriptomics and proteomics research in H1N1 diagnosis, treatment, and H1N1 virus-host interaction, to offer some help for further understanding the infection mechanism and controlling H1N1 transmission. PMID- 20970743 TI - Proteomic analysis of bovine nucleolus. AB - Nucleolus is the most prominent subnuclear structure, which performs a wide variety of functions in the eukaryotic cellular processes. In order to understand the structural and functional role of the nucleoli in bovine cells, we analyzed the proteomic composition of the bovine nucleoli. The nucleoli were isolated from Madin Darby bovine kidney cells and subjected to proteomic analysis by LC-MS/MS after fractionation by SDS-PAGE and strong cation exchange chromatography. Analysis of the data using the Mascot database search and the GPM database search identified 311 proteins in the bovine nucleoli, which contained 22 proteins previously not identified in the proteomic analysis of human nucleoli. Analysis of the identified proteins using the GoMiner software suggested that the bovine nucleoli contained proteins involved in ribosomal biogenesis, cell cycle control, transcriptional, translational and post-translational regulation, transport, and structural organization. PMID- 20970744 TI - A novel interpretation of structural dot plots of genomes derived from the analysis of two strains of Neisseria meningitidis. AB - Neisseria meningitidis is the agent of invasive meningococcal disease, including cerebral meningitis and septicemia. Because the diseases caused by different clonal groups (sequence types) have their own epidemiological characteristics, it is important to understand the differences among the genomes of the N. meningitidis clonal groups. To this end, a novel interpretation of a structural dot plot of genomes was devised and applied; exact nucleotide matches between the genomes of N. meningitidis serogroup A strain Z2491 and serogroup B strain MC58 were identified, leading to the specification of various structural regions. Known and putative virulence genes for each N. meningitidis strain were then classified into these regions. We found that virulence genes of MC58 tend more to the translocated regions (chromosomal segments in new sequence contexts) than do those of Z2491, notably tending towards the interface between one of the translocated regions and the collinear region. Within the col-linear region, virulence genes tend to occur within 16 kb of gaps in the exact matches. Verification of these tendencies using genes clustered in the cps locus was sufficiently supportive to suggest that these tendencies can be used to focus the search for and understanding of virulence genes and mechanisms of pathogenicity in these two organisms. PMID- 20970745 TI - Regulation of U6 promoter activity by transcriptional interference in viral vector-based RNAi. AB - The direct negative impact of the transcriptional activity of one component on the second one in cis is referred to as transcriptional interference (TI). U6 is a type III RNA polymerase III promoter commonly used for driving small hairpin RNA (shRNA) expression in vector-based RNAi. In the design and construction of viral vectors, multiple transcription units may be arranged in close proximity in a space-limited vector. Determining if U6 promoter activity can be affected by TI is critical for the expression of target shRNA in gene therapy or loss-of function studies. In this research, we designed and implemented a modified retroviral system where shRNA and exogenous gene expressions were driven by two independent transcriptional units. We arranged U6 promoter driving shRNA expression and UbiC promoter in two promoter arrangements. In primary macrophages, we found U6 promoter activity was inhibited by UbiC promoter when in the divergent arrangement but not in tandem. In contrast, PKG promoter had no such negative impact. Instead of enhancing U6 promoter activity, CMV enhancer had significant negative impact on U6 promoter activity in the presence of UbiC promoter. Our results indicate that U6 promoter activity can be affected by TI in a proximal promoter-specific and arrangement-dependent manner. PMID- 20970746 TI - Follow the leader: preference for specific amino acids directly following the initial methionine in proteins of different organisms. AB - It is well established that the vast majority of proteins of all taxonomical groups and species are initiated by an AUG codon, translated into the amino acid methionine (Met). Many attempts were made to evaluate the importance of the sequences surrounding the initiation codon, mostly focusing on the RNA sequence. However, the role and importance of the amino acids following the initiating Met residue were rarely investigated, mostly in bacteria and fungi. Herein, we computationally examined the protein sequences of all major taxonomical groups represented in the Swiss-Prot database, and evaluated the preference of each group to specific amino acids at the positions directly following the initial Met. The results indicate that there is a species-specific preference for the second amino acid of the majority of protein sequences. Interestingly, the preference for a certain amino acid at the second position changes throughout evolution from lysine in prokaryotes, through serine in lower eukaryotes, to alanine in higher plants and animals. PMID- 20970747 TI - Structural and functional analysis of NS1 and NS2 proteins of H1N1 subtype. AB - Influenza A virus (H1N1), a genetic reassortment of endemic strains of human, avian and swine flu, has crossed species barrier to human and apparently acquired the capability of human to human transmission. Some strains of H5N1 subtype are highly virulent because NS1 protein inhibits antiviral interferon alpha/beta production. Another protein NS2 mediates export of viral ribonucleoprotein from nucleus to the cytoplasm through export signal. In this paper, we have studied structure-function relationships of these proteins of H1N1 subtype and have determined the cause of their pathogenicity. Our results showed that non conservative mutations slightly stabilized or destabilized structural domains of NS1 or NS1-dsRNA complex, hence slightly increased or decreased the function of NS1 protein and consequently enhanced or reduced the pathogenicity of the H1N1 virus. NS2 protein of different strains carried non-conservative mutations in different domains, resulting in slight loss of function. These mutations slightly decreased the pathogenicity of the virus. Thus, the results confirm the structure function relationships of these viral proteins. PMID- 20970748 TI - Mining gene expression profiles: an integrated implementation of kernel principal component analysis and singular value decomposition. AB - The detection of genes that show similar profiles under different experimental conditions is often an initial step in inferring the biological significance of such genes. Visualization tools are used to identify genes with similar profiles in microarray studies. Given the large number of genes recorded in microarray experiments, gene expression data are generally displayed on a low dimensional plot, based on linear methods. However, microarray data show nonlinearity, due to high-order terms of interaction between genes, so alternative approaches, such as kernel methods, may be more appropriate. We introduce a technique that combines kernel principal component analysis (KPCA) and Biplot to visualize gene expression profiles. Our approach relies on the singular value decomposition of the input matrix and incorporates an additional step that involves KPCA. The main properties of our method are the extraction of nonlinear features and the preservation of the input variables (genes) in the output display. We apply this algorithm to colon tumor, leukemia and lymphoma datasets. Our approach reveals the underlying structure of the gene expression profiles and provides a more intuitive understanding of the gene and sample association. PMID- 20970749 TI - Preoperative use of incentive spirometry does not affect postoperative lung function in bariatric surgery. AB - Morbidly obese patients undergoing general anesthesia for laparoscopic bariatric surgery are considered at increased risk of a postoperative decrease in lung function. The purpose of this study was to determine whether a systematic use of incentive spirometry (IS) prior to surgery could help patients to preserve their respiratory function better in the postoperative period. Forty-one morbidly obese (body mass index [BMI] > 40 kg/m2) candidates for laparoscopic bariatric surgery were consented in the study. All patients were taught how to use an incentive spirometer but then were randomized blindly into 2 groups. The control group was instructed to use the incentive spirometer for 3 breaths, once per day. The treatment group was requested to use the incentive spirometer for 10 breaths, 5 times per day. Twenty experimental (mean BMI of 48.9 +/- 5.67 kg/m2) and 21 control patients (mean BMI of 48.3 +/- 6.96 kg/m2) were studied. The initial mean inspiratory capacity (IC) was 2155 +/- 650.08 (SD) cc and 2171 +/- 762.98 cc in the experimental and control groups, respectively. On the day of surgery, the mean IC was 2275 +/- 777.56 cc versus 2254.76 +/- 808.84 cc, respectively. On postoperative day 1, both groups experienced a significant drop of their IC, with volumes of 1458 +/- 613.87 cc (t test P < 0.001) and 1557.89 +/- 814.67 cc (t test P < 0.010), respectively. Our results suggest that preoperative use of the IS does not lead to significant improvements of inspiratory capacity and that it is a not a useful resource to prevent postoperative decrease in lung function. PMID- 20970750 TI - Dobutamine-norepinephrine, but not vasopressin, restores the ventriculoarterial matching in experimental cardiogenic shock. AB - We assessed the hemodynamic effects of guideline therapy in experimental cardiogenic shock and compared this treatment with a combination containing an alternative vasopressor (arginine vasopressin, AVP). Our hypothesis was that combined dobutamine-norepinephrine still is the superior inopressor therapy assessed by ventriculoarterial matching in both systole and diastole. Cardiogenic shock (CS) was induced by coronary microembolization in 16 pigs. Dobutamine (Dobu, 2ug/kg/min) alone and combined with either norepinephrine (NE, 100 ng/kg/min) or the pure vasopressor AVP (0.001 u/kg/min) were infused. In CS, Dobu increased cardiac output (CO) and central venous oxygen saturation (SVO2) from 74 +/- 3 mL/kg and 37 +/- 2% to 103 +/- 8 mL/kg and 49 +/- 3%. Adding NE resulted in a further improvement of CO (125 +/- 9 mL/kg) and SVO2 (59 +/- 4%) because of an increased heart rate and contractility with minimal change in systemic vascular resistance. Also, energy transfer from the ventricle to the arterial system was restored partly by Dobu and was normalized by supplementing NE. In contrast, supplemental AVP further worsened the shock state by decreasing CO (70 +/- 6 mL/kg) and SVO2 (45 +/- 5%) compared with Dobu alone. Combined Dobu-NE has an efficient hemodynamic profile in CS. A pure afterload increasing substance used in acute ischemic CS aggravates the shock state by causing a ventriculoarterial mismatch despite its use in combination with an inotropic compound. PMID- 20970751 TI - Enteral diets enriched with medium-chain triglycerides and N-3 fatty acids prevent chemically induced experimental colitis in rats. AB - The specific purpose of this study was to evaluate the significant effects of medium-chain triglycerides (MCTs) and N-3 fatty acids on chemically induced experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid (TNBS) in rats. Male Wistar rats were fed liquid diets enriched with N-6 fatty acid (control diets), N-3 fatty acid (MCT- diets), and N-3 fatty acid and MCT (MCT+ diets) for 2 weeks and then were given an intracolonic injection of TNBS. Serum and tissue samples were collected 5 days after ethanol or TNBS enema. The severity of colitis was evaluated pathologically, and tissue myeloperoxidase activity was measured in colonic tissues. Furthermore, protein levels for inflammatory cytokines and a chemokine were assessed by an enzyme-linked immunosorbent assay in colonic tissues. Induction of proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta in the colon by TNBS enema was markedly attenuated by the MCT+ diet among the 3 diets studied. Furthermore, the induction of chemokines macrophage inflammatory protein-2 and monocyte chemotactic protein-1 also was blunted significantly in animals fed the MCT+ diets. As a result, MPO activities in the colonic tissue also were blunted significantly in animals fed the MCT+ diets compared with those fed the control diets or the MCT- diets. Furthermore, the MCT+ diet improved chemically induced colitis significantly among the 3 diets studied. Diets enriched with both MCTs and N-3 fatty acids may be effective for the therapy of inflammatory bowel disease as antiinflammatory immunomodulating nutrients. PMID- 20970752 TI - Limaprost reduces motor disturbances by increasing the production of insulin-like growth factor I in rats subjected to spinal cord injury. AB - Calcitonin gene-related peptide (CGRP) released from sensory neurons increases the production of a neuroprotective substance insulin-like growth factor I (IGF I), and sensory neuron stimulation contributes to a reduction of spinal cord injury (SCI) by inhibiting inflammatory responses in rats. Because receptors for prostaglandin E2 (EP receptors) are present on sensory neurons, it is possible that prostaglandin E1 analog limaprost reduces SCI by increasing IGF-I production through sensory neuron stimulation. We examined this possibility in rats subjected to compression-trauma-induced SCI. Limaprost increased the CGRP release from dorsal root ganglion (DRG) neurons isolated from rats, and this increase was reversed by pretreatment with the EP4 receptor antagonist ONO-AE3-208. Spinal cord tissue levels of CGRP and IGF-I were increased after the induction of SCI, peaking at 2 h postinduction. The intravenous administration of limaprost enhanced increases of spinal cord tissue levels of CGRP, IGF-I, and IGF-I mRNA at 2 h after the induction of SCI. Increases of spinal cord tissue levels of tumor necrosis factor, caspase-3, myeloperoxidase, and the number of apoptotic nerve cells were inhibited by the administration of limaprost. Motor disturbances of hind legs in animals subjected to the compression-trauma-induced SCI were reduced by the administration of limaprost. These effects of limaprost were reversed completely by pretreatment with a specific transient receptor potential vanilloid 1 inhibitor SB366791 and by sensory denervation. These observations strongly suggest that limaprost may increase the IGF-I production by stimulating sensory neurons in the spinal cord, thereby ameliorating compression-trauma-induced SCI through attenuation of inflammatory responses. PMID- 20970753 TI - Paradoxically high adiponectin and the healthy obese phenotype in obese black and white 16-year-old girls. AB - Although adiponectin is correlated inversely with obesity, some obese adults without metabolic complications of obesity have paradoxically high adiponectin. Therefore, we assessed adiponectin risk factor relations in 133 obese 16-year-old school girls from a cohort of 448, focusing on paradoxically high adiponectin risk in obesity and the healthy obese phenotype. Median adiponectin (11.9 mg/L) in nonobese girls (body mass index [BMI] < 24.6 kg/m2) was selected as a cutpoint to identify high adiponectin in obese girls. Of 90 black and 43 white obese girls (BMI >= 24.6), 25 black (28%) and 13 white (30%) girls had paradoxically high adiponectin (>11.9). The 38 obese girls with adiponectin >11.9 versus the 95 obese girls with adiponectin <=11.9 had higher median high-density lipoprotein (HDL) cholesterol (54 vs 46 mg/dL, P = 0.0007) and apolipoprotein A1 (ApoA1) (181 vs 164 mg/dL, P = 0.011) and had lower insulin (14 vs 20 uU/mL, P = 0.0006). In the 133 obese girls, through stepwise regression, the adiponectin category (>11.9, <= 11.9 mg/L) was a significant independent positive determinant of HDL cholesterol (partial r2 = 8.4%, P = 0.001), ApoA1 (partial r2 = 4.1%, P = 0.025), and it was associated inversely with fasting serum insulin (partial r2 = 5.4%, P = 0.0074). By stepwise logistic regression in the 133 obese girls, the adiponectin category (high vs low) was a significant inverse explanatory variable for metabolic syndrome (odds ratio 0.20, 95% confidence intervals 0.04-0.95, P = 0.043). We conclude that paradoxically high adiponectin is associated with the healthy obese phenotype in obese adolescent black and white girls. PMID- 20970755 TI - What effects? Measuring functional outcomes in comparative effectiveness research. PMID- 20970754 TI - Protocol proposal for Friedreich ataxia molecular diagnosis using fluorescent and triplet repeat primed polymerase chain reaction. AB - Friedreich ataxia (FRDA) is the most common hereditary ataxia that is caused mainly by an unstable GAA trinucleotide expansion in the first intron of the frataxin gene. Molecular tests for FRDA diagnosis and carrier detection include polymerase chain reaction (PCR) for the GAA expansion, triplet repeat primed PCR (TP-PCR), and/or Southern blotting. TP-PCR is a method developed to detect trinucleotide expansions successfully applied to FRDA diagnosis. In our laboratory, we have included a PCR for the GAA expansion using fluorescent primers polymerase chain reaction (F-PCR) to identify normal heterozygous and affected individuals unambiguously. The purpose of our study was to reanalyze 310 samples previously diagnosed in our laboratory and compare the results with those obtained by F-PCR and TP-PCR. Eight percent of the discrepancies between the carrier and the normal individuals were identified correctly by this protocol. No discrepancy was detected in the affected individuals. These techniques are effective, and compared with Southern blotting, they are less labor-intensive and suitable for automation. We suggest a new routine protocol for FRDA diagnosis that includes F-PCR and TP-PCR. PMID- 20970756 TI - Lessons of leadership: the uncommon life of Dr Henry B. Betts. PMID- 20970757 TI - Reliability and agreement of hip range of motion and provocative physical examination tests in asymptomatic volunteers. AB - OBJECTIVE: To: (1) report passive hip range of motion (ROM) in asymptomatic young adults, (2) report the intratester and intertester reliability of hip ROM measurements among testers of multiple disciplines, and (3) report the results of provocative hip tests and tester agreement. DESIGN: Descriptive epidemiology study. SETTING: Tertiary university. PARTICIPANTS: Twenty-eight young adult volunteers without musculoskeletal symptoms, history of disorder, or surgery involving the lumbar spine or lower extremities were enrolled and completed the study. METHODS: Asymptomatic young adult volunteers completed questionnaires and were examined by 2 blinded examiners during a single session. The testers were physical therapists and physicians. Hip ROM and provocative tests were completed by both examiners on each hip. MAIN OUTCOME MEASUREMENTS: Inter-rater and intrarater reliability for ROM and agreement for provocative tests were determined. RESULTS: Twenty-eight asymptomatic adults, mean age 31 years (range, 18-51 years), with a mean modified Harris Hip Score of 99.5 +/- 1.5 and UCLA activity score of 8.8 +/- 1.2 completed the study. Intrarater agreement was excellent for all hip ROM measurements, with intraclass correlation coefficients (ICCs) ranging from 0.76 to 0.97, with similar agreement if the examiner was a physical therapist or a physician. Excellent inter-rater reliability was found for hip flexion ICC 0.87 (95% confidence interval [95% CI] 0.78-0.92), supine internal rotation ICC 0.75 (95% CI 0.60-0.84), and prone internal rotation ICC 0.79 (95% CI 0.66-0.87). The least reliable measurements were supine hip abduction (ICC 0.34) and supine external rotation (ICC 0.18). Agreement between examiners ranged from 96% to 100% for provocative hip tests, which included the hip impingement, resisted straight leg raise, Flexion Abduction External Rotation/Patrick, and log roll tests. CONCLUSIONS: Specific hip ROM measures show excellent inter-rater reliability, and provocative hip tests show good agreement among multiple examiners and medical disciplines. Further studies are needed to assess the use of these measurements and tests as a part of a hip screening examination to assess for young adults at risk for intra-articular hip disorders before the onset of degenerative changes. PMID- 20970758 TI - Association of shoulder pain with the use of mobility devices in persons with chronic spinal cord injury. AB - OBJECTIVE: To assess the prevalence of shoulder pain and its association with the use of assistive devices for mobility in persons with chronic spinal cord injury (SCI). DESIGN: Cross-sectional analysis conducted within a cohort study. SETTING: SCI service in a hospital and the community. PARTICIPANTS: Between August 2005 and January 2008, 93 participants with chronic SCI completed a standardized health questionnaire and pain questionnaire. MAIN OUTCOME MEASURES: Shoulder pain in last 6 months elicited by use of the McGill Pain Questionnaire pain diagram. RESULTS: Of the 93 participants, 65 (69.9%) reported pain at any site in the 6 months before testing. Shoulder pain, reported by 39.8% of participants, was the third most common site of pain after the legs and back. When stratified by the use of assistive mobility devices, shoulder pain was reported by 46.7% of motorized wheelchair users, 35.4% of manual wheelchair users, 47.6% of participants using aids such as crutch(es) or canes, and 33.3% of participants walking without assistance (P = .7 for comparison of 4 groups). CONCLUSIONS: Shoulder pain is highly prevalent in SCI. The authors of previous studies have largely attributed shoulder pain in SCI to manual wheelchair use. However, our results provide evidence for similarly elevated prevalence of shoulder pain among motorized wheelchair users and those patients using crutches or canes. This finding suggests that in addition to overuse injury from cyclic wheelchair propulsion, the assessment of other mechanical and nonmechanical factors that lead to shoulder pain in SCI is an unmet research need that may have treatment implications. PMID- 20970759 TI - Race, ethnicity, and employment outcomes 1, 5, and 10 years after spinal cord injury: a longitudinal analysis. AB - OBJECTIVES: (1) To compare the odds of competitive employment versus not competitive employment among a group of white, African American, and Hispanic persons with spinal cord injury (SCI) at 1, 5, and 10 years after injury; (2) to examine the changes in the odds of competitive employment versus not competitive employment over time within each racial/ethnic group, and (3) to compare the changes in the odds of competitive employment versus not competitive employment over time between the racial/ethnic groups. DESIGN: Retrospective study. SETTING: Model SCI systems. PARTICIPANTS: A total of 11,090 persons with SCI (7735 whites, 2381 African Americans, and 974 Hispanics), between ages 18 and 55 years, enrolled in the National Spinal Cord Injury Statistical Center database. MAIN OUTCOME MEASURE: Employment status dichotomized as competitively employed versus not competitively employed. RESULTS: The odds of being competitively employed at 1, 5, and 10 years after injury were 1.58, 2.55, and 3.02, times greater for whites than African Americans and 1.71, 1.86, and 1.71, respectively, times greater for whites than Hispanics. At 10 years after injury, the odds of being competitively employed were 1.77 times greater for Hispanics than for African Americans. Persons of all races/ethnicities and with SCI showed significantly greater increases in the odds of being competitively employed versus not competitively employed over time (1-5 years, 1-10 years, 5-10 years after injury); however, whites and Hispanics had greater increases in the odds of competitive employment over time compared with African Americans. CONCLUSIONS: Regardless of race, short- and long-term employment outcomes were not favorable for persons with SCI; however, African Americans and Hispanics fared worse in employment outcomes compared with whites. Rehabilitation professionals should work to improve employment outcomes for all individuals with SCI, with special emphasis on addressing specific needs of African Americans and Hispanics. PMID- 20970760 TI - A randomized controlled trial of exercise to improve mood after traumatic brain injury. AB - OBJECTIVE: To test the hypothesis that a structured aerobic exercise regimen would decrease the severity of depressive symptoms in people with traumatic brain injury (TBI) who reported at least mild depression severity at baseline. DESIGN: Prospective, randomized, controlled trial. SETTING: Community gymnasium. PARTICIPANTS: Subjects with a history of a prior TBI (6 months to 5 years post injury), recruited from the community. Inclusion criteria included scoring >= 5 on the Patient Health Questionnaire-9. Subjects were excluded if they were non English speakers, had a medical condition precluding exercise, had suicidal ideation, regularly exercised, or could not use standard aerobic exercise equipment. INTERVENTION: Weekly supervised exercise sessions over a 10-week period consisted of education, warm-up, 30 minutes of aerobic exercise, and cool down. The exercise intensity was adjusted to reach a heart rate goal of 60% of the participant's estimated maximal heart rate. MAIN OUTCOME MEASUREMENT: Beck Depression Inventory (BDI) comparing exercise to control groups. Post hoc analyses compared groups exercising >= 90 minutes or <90 minutes per week. RESULTS: Between-group comparisons at 10 weeks revealed no difference between groups on the BDI (P = .250). For the groups divided by minutes exercised per week, the high-activity group had significantly better depression scores than those in the low-activity group (P = .033). CONCLUSIONS: Although there was no statistically significant difference between the treated and the control group on mood after intervention, those persons with TBI who recounted higher levels of exercise per week also reported less depression and improved sleep, community participation, and overall quality of life. PMID- 20970761 TI - Effect of an intense wheelchair propulsion task on quantitative ultrasound of shoulder tendons. AB - OBJECTIVE: To investigate acute ultrasound changes of biceps and supraspinatus tendon appearance after an intense wheelchair propulsion task, and how these changes relate to demographic and biomechanical risk factors. DESIGN: A survey. SETTING: Research laboratory and research space at the National Veterans Wheelchair Games. PARTICIPANTS: A convenience sample of 60 manual wheelchair users were recruited through research registries and rehabilitation clinics as well as from participants at the 2007 and 2008 National Veterans Wheelchair Games. The subjects were between 18 and 65 years of age at least 1 year after injury and did not have progressive disabilities. MAIN OUTCOME MEASURES: Quantitative ultrasound (QUS) measures of biceps and supraspinatus tendon appearance, stroke frequency, resultant force, tendinopathy score, and duration of wheelchair use. RESULTS: Biceps tendon appearance after an intense propulsion task was significantly related to chronic biceps tendinopathy, duration of wheelchair use, stroke frequency, and resultant force. The subjects with a higher stroke frequency or resultant force tended to have a brighter, more organized tendon appearance compared with the prepropulsion imaging session (baseline). The subjects with tendinopathy or a longer duration of wheelchair use were more likely to have a darker, diffuse tendon appearance immediately after the propulsion task. Supraspinatus tendon appearance after propulsion was only significantly predicted by baseline QUS measures. CONCLUSIONS: QUS has proven to be sensitive to risk factors for tendon pathology. Future studies can apply grayscale-based QUS to study the development and prevention of repetitive strain injuries, particularly on an individual basis. PMID- 20970762 TI - Incidence and risk factors of falling in the postoperative lower limb amputee while on the surgical ward. AB - OBJECTIVE: To determine the incidence and risk factors of falling among amputees during the postoperative time on the surgical ward. DESIGN: Retrospective cohort. SETTING: Three tertiary acute care hospitals. PATIENTS: Subjects aged 18 years or older undergoing either a primary or revision amputation at the transtibial, knee disarticulation, or transfemoral levels. Subjects were excluded if they underwent bilateral amputations. A total of 466 charts were identified, and 370 subjects were included in the analysis. MAIN OUTCOME MEASUREMENTS: All outcome measurements were devised before data collection. The primary outcome variable was the presence of at least one fall. Details regarding falls, including the date, time, and location of the first fall, were recorded. In addition, the total number of falls and any associated injuries were documented. Secondary outcome variables included type and number of medical comorbidities, cognitive deficits, and regular use of specific medications. RESULTS: Sixty-one of 370 subjects fell at least once, giving an incidence of 16.5% (95% confidence interval [95% CI] 12.7%-20.3%). No difference was noted between the fall and no fall groups for gender, mean age, number of regular medications, and number of medical comorbidities. The fall group demonstrated a significantly longer length of stay (difference of means 32.5 days, 95% CI 17.4-47.5, P < .001). Injuries were sustained in 60.7% of those who fell. Multiple logistic regression analysis identified the major risk factors for falling as dysvascular etiology (odds ratio [OR] 2.418, 95% CI 1.043-5.606), transtibial level (OR 2.127, 95% CI 1.050 4.309), and right-sided amputation (OR 1.933, 95% CI 1.073-3.483). CONCLUSIONS: Falls and associated injuries occur commonly in the postoperative lower limb amputee on the surgical ward. Risk factors for falling include dysvascular etiology, transtibial level, and right-sided amputation. Further studies are required to characterize the mechanisms of falling in this patient population and to develop appropriate fall-prevention strategies. PMID- 20970763 TI - Evaluation, management, rehabilitation, and prevention of anterior cruciate ligament injury: current concepts. AB - The anterior cruciate ligament (ACL) is essential for both static and dynamic stability of the knee. It is commonly injured during sports activities by noncontact mechanisms that include landing with the knee in valgus and extension, sudden deceleration, change of direction, and rotation. Several modifiable and nonmodifiable risk factors predispose athletes to this injury, especially women. Early diagnosis, treatment directed to protect secondary knee structures, and rehabilitation play an important role in the management of ACL injury. Despite a lack of scientifically validated and published guidelines to help clinicians decide between conservative or surgical treatment, criteria such as pain, recurrent instability, injury to secondary structures, and desired level of activity should be considered. Accelerated rehabilitation protocols for patients who have and have not undergone an operation are available and recommended with goals of reducing complications such as recurrent injury, loss of motion, residual weakness, and associated osteoarthritis. However, injury prevention protocols could be the next big step in management of ACL injury with emphasis on reducing modifiable risk factors in susceptible individuals who participate in sports. PMID- 20970764 TI - Evaluating the relationship of calcium and vitamin D in the prevention of stress fracture injuries in the young athlete: a review of the literature. AB - Calcium and vitamin D are recognized as 2 components of nutrition needed to achieve and maintain bone health. Calcium and vitamin D have been clearly shown to improve bone density and prevent fractures at all ages. However, the literature is conflicting as to the role of these nutrients in young athletes ages 18 to 35 years, both for bone development and for the prevention of bone overuse injuries. Differences in findings may relate to study design. Although retrospective and cross-sectional studies have had mixed results, the authors of prospective studies have consistently demonstrated a relationship of increased calcium intake with an improvement in bone density and a decrease in fracture risk. A randomized trial in female military recruits demonstrated that calcium/vitamin D supplementation reduced the incidence of stress fractures. A prospective study in young female runners demonstrated reduced incidence of stress fractures and increased bone mineral density with increased dietary calcium intake. Findings from both studies suggest female athletes and military recruits who consumed greater than 1500 mg of calcium daily exhibited the largest reduction in stress fracture injuries. To date, no prospective studies have been conducted in male athletes or in adolescent athletes. In most studies, males and nonwhite participants were poorly represented. Evidence regarding the relationship of vitamin D intake with the prevention of fractures in athletes is also limited. More prospective studies are needed to evaluate the role of calcium and vitamin D intake in prevention of stress fracture injuries in both male and female adolescent athletes, particularly those participating in sports with greater incidences of stress fracture injury. PMID- 20970765 TI - Who will provide care for people with complex physical disabilities? PMID- 20970766 TI - Lumbar provocation diskography: helpful or harmful? PMID- 20970767 TI - Ultrasound-guided platelet-rich plasma injection for chronic patellar tendinopathy: a case report. PMID- 20970768 TI - A rare case of tardive dyskinesia and akathisia induced by citalopram. PMID- 20970769 TI - Axial length and outcomes of macular hole surgery assessed by spectral-domain optical coherence tomography. AB - PURPOSE: To use spectral-domain optical coherence tomography (SD OCT) to evaluate macular hole surgery outcomes and features predicting anatomic failure. DESIGN: Retrospective, interventional case series. METHODS: Fifty-two eyes of 50 consecutive patients with macular holes were examined. All eyes underwent 3-port pars plana vitrectomy with internal limiting membrane peeling. Eyes were examined after surgery by dense serial SD OCT scanning over the macula. RESULTS: Eyes with initial anatomic failure were significantly more likely to have greater axial length and refractive error and more posterior staphyloma compared with eyes with initial anatomic success (P = .031 to .0060, < .0001). Overall initial and final anatomic success rates were 92.3% (48 of 52 eyes). In highly myopic eyes with axial lengths of 26.0 mm or more, initial and final success rates were 73.3% (11 of 15 eyes) compared with 100.0% (37 of 37 eyes) of eyes with axial lengths of less than 26.0 mm (P = .0050). In highly myopic eyes, initial and final success rates were 0% (0 of 3 eyes) of eyes with axial lengths of 30.0 mm or more compared with 91.7% (11 of 12 eyes) of eyes with axial lengths of 26.0 mm or more and of less than 30.0 mm (P < .0001). Retinoschisis-like thickening of the outer retina was seen in 3 (75.0%) of 4 eyes with initial failure compared with 3 (6.3%) of 48 eyes with initial success (P = .0030). CONCLUSIONS: Axial length of 30.0 mm or more may increase the risk of anatomic failure of macular hole surgery. PMID- 20970770 TI - Interferometry in the evaluation of precorneal tear film thickness in dry eye. AB - PURPOSE: To compare tear film thickness between normal subjects and aqueous tear deficiency dry eye patients by tear interferometry. DESIGN: Prospective case control study. METHODS: Central precorneal tear film thickness was measured noninvasively using an interference thin-film thickness measurement device (Quore MSPA1100; Mamiya-OP). Tear film thickness of 14 eyes from 14 normal subjects and of 28 eyes from 28 aqueous tear deficiency dry eye patients were compared along with noninvasively measured tear meniscus height, DR-1 (Kowa) dry eye severity grading, fluorescein and rose bengal staining scores, tear film break-up time, and Schirmer test results. Among dry eye patients, 13 eyes underwent punctal occlusion, and tear film thickness was compared before and after the surgery. RESULTS: Tear film was significantly thinner in dry eye patients (2.0 +/- 1.5 MUm) than normal subjects (6.0 +/- 2.4 MUm; P < .0001). Tear film thickness showed good correlation with other dry eye examinations. After punctal occlusion, tear film thickness increased significantly from 1.7 +/- 1.5 MUm to 4.9 +/- 2.8 MUm (P = .001) with the improvement of tear meniscus height, fluorescein and rose bengal staining scores, tear film break-up time, and Schirmer test values. CONCLUSIONS: Interferometric tear film thickness measurement revealed impaired precorneal tear film formation in aqueous tear deficiency dry eyes and was useful for showing the reconstruction of tear film after punctal occlusion surgery. Interferometry of precorneal tear film may be helpful for the evaluation of aqueous tear deficiency in conjunction with other dry eye examinations. PMID- 20970771 TI - Reduction in astigmatism using propranolol as first-line therapy for periocular capillary hemangioma. AB - PURPOSE: To examine the shift in astigmatic error following the use of oral propranolol as first-line treatment for periocular capillary hemangioma. DESIGN: Retrospective observational study. METHODS: study population: Three healthy infants (1 male) clinically diagnosed with periocular capillary hemangioma. Cycloplegic refraction measurements were obtained at presentation. After a comprehensive clinical evaluation, oral propranolol therapy was starting with a loading dose and titrated up to 2 mg/kg/day under monitoring of heart rate, blood pressure, and blood glucose alterations. Clinical follow-up and repeating cycloplegic refraction measurements were undertaken at the 1-week and 1- and 3 month follow-up visits. INTERVENTION: Oral propranolol therapy for infants diagnosed with periocular capillary hemangioma. MAIN OUTCOME MEASURES: Astigmatic refractive errors before and after propranolol treatment. RESULTS: The infants' mean age at the initiation of propranolol therapy was 6.3 months (range: 3.0-8.0 months). A rapid therapeutic effect was noticed in all cases, including a major change in lesion size and color. No complications were recorded during or following treatment. The mean astigmatic error decreased from 2.83 diopters before propranolol treatment to 1.33 diopters after 1 month of treatment. The drug was well tolerated by all 3 patients and no side effects were noted. CONCLUSIONS: Infants can benefit from a rapid, meaningful reduction in periocular capillary hemangioma-induced astigmatism following oral propranolol treatment. Propranolol seems to be an effective and safe drug, which can be used as a steroid-sparing first-line treatment modality in this patient population. PMID- 20970772 TI - Clinicopathologic correlation of choroidal and retinal neovascular lesions in age related macular degeneration. AB - PURPOSE: To describe histopathologic findings in donor eyes of 3 individuals with neovascular age-related macular degeneration and to correlate with results of clinical and fluorescein angiographic studies performed before death. DESIGN: Retrospective, observational case series. METHODS: Three eyes of 3 individuals with neovascular age-related macular degeneration were obtained after death and were prepared for histopathologic examination at a tertiary care referral center. Serial sections through the macula and optic nerve were evaluated with light microscopy. Findings were correlated with results of clinical evaluation, including findings of fluorescein angiography performed from 1 week to 5 months before death. RESULTS: In Case 1, histopathologic examination revealed a thin choroidal neovascular membrane beneath a relatively intact retinal pigment epithelium (type 1 neovascularization). This correlated with an occult choroidal neovascular membrane on fluorescein angiography characterized by a stippled appearance with minimal late leakage, representing possibly the earliest clinically detectable neovascular membrane for which histopathologic correlation is available. In Case 2, histopathologic examination demonstrated subfoveal choroidal neovascularization with distinctly separate subretinal pigment epithelial (type 1) and subretinal (type 2) components, correlating to fluorescein angiographic appearance of a mixed neovascular membrane with corresponding occult and classic features. The histopathologic findings in Case 3 revealed a plexus of blood vessels in the outer retina surrounded by an abundant eosinophiolic extracellular matrix and associated with a pigment epithelial detachment. There was no communication with the choroid. This correlated with clinical findings of retinal angiomatous proliferation. CONCLUSIONS: These 3 in situ clinicopathologic correlative studies add new knowledge of the broad clinical spectrum of neovascular age-related macular degeneration. PMID- 20970773 TI - Associations of birth weight with ocular biometry, refraction, and glaucomatous endophenotypes: the Australian Twins Eye Study. AB - PURPOSE: To examine the relationship of birth weight with ocular measures in a Caucasian twin population. DESIGN: Cross-sectional study of 1498 twins (308 monozygotic and 441 dizygotic pairs) aged between 5 to 80 years participating in the Australian Twins Eye Study. METHODS: All participants underwent ophthalmic examination including bilateral cycloplegic autorefraction, keratometry, interpupillary distance (IPD), central corneal thickness, intraocular pressure (IOP), and retinal photography. Birth weight and gestation were obtained from a self-administered questionnaire. A subset of the twins also participated in the Tasmanian Infant Health Study (288) and the Childhood Blood Pressure Study (184), which collected data on birth parameters allowing for verification of data. Linear mixed models were used for the main analysis. RESULTS: Both the within pair (beta(w) 0.27, 95% confidence interval [CI] 0.15, 0.38 mm per kg increase in birth weight, P < .001) and between-pair associations (beta(B) 0.22, 95% CI 0.08, 0.35, P = .002) of birth weight with axial length were significant and of similar magnitude (difference in effect, P = .56), after adjusting for relevant confounders. In contrast, birth weight was negatively associated with corneal curvature (beta(w) -0.82, 95% CI -1.09, -0.55 diopters per kg increase; beta(B) 0.69, 95% CI -0.98, -0.41, both P < .001). These associations remained significant within dizygotic and monozygotic pairs. Refraction, anterior chamber depth, IPD, IOP, and optic disc parameters are unrelated to birth weight. CONCLUSIONS: Consistent with previous studies in singleton children, lower birth weight is associated with shorter axial length and more curved corneas in this twin study. This also adds new insights into the emmetropization process. PMID- 20970774 TI - Long-term results of photodynamic therapy for choroidal neovascularization in Japanese patients with pathologic myopia. AB - OBJECTIVE: To determine the results of photodynamic therapy (PDT) in highly myopic eyes with choroidal neovascularization (CNV). DESIGN: Open-label, consecutive, interventional case series. METHODS: Forty-eight eyes of 46 consecutive Japanese patients with a myopic CNV were studied. The eyes were treated with PDT and were followed up from 1 to 4 years. The best-corrected visual acuities (BCVAs) at the baseline and after the PDT were compared. Multivariate regression analyses were used to determine the factors that were significantly associated with the BCVA at 3 or 4 years. RESULTS: The mean follow up period was 3.2 years. Sixty-nine percent of the patients obtained angiographic closure by a single PDT treatment, and the average number of PDT treatments was 1.4. Chorioretinal atrophy developed in 61% of the eyes at 3 years and in 70% of the eyes at 4 years. The BCVA did not change significantly after the PDT. Multivariate regression analyses showed that the BCVA at 3 years was significantly correlated with the baseline BCVA and area of chorioretinal atrophy. Analyses of the 20 patients at 4 years or more showed that in 5 of 7 (71.4%) patients with juxtafoveal CNV, chorioretinal atrophy did not develop and that all had BCVA of 0.5 or better. However, in 12 of the 13 patients with a subfoveal CNV, chorioretinal atrophy developed at 4 years, and 10 of these patients had BCVA of 0.1 or worse. CONCLUSIONS: In highly myopic patients, 69% obtained angiographic closure by a single PDT treatment, and recurrence was rare. These findings indicate that PDT is still a good option for treating CNVs in highly myopic patients. PMID- 20970775 TI - Decreased accommodative response in the nondominant eye of patients with intermittent exotropia. AB - PURPOSE: To evaluate objectively the accommodative response in patients who have intermittent exotropia with a dominant eye. DESIGN: Observational cohort study. METHODS: setting: Institutional. patients: One hundred thirty-three patients younger than 15 years, including 33 patients with intermittent exotropia and equal dominance, 54 patients with intermittent exotropia with a dominant eye, and 46 patients with orthotropia or exophoria of less than 10 prism diopters. observation: A Shin-Nippon NVision-K 5001 autorefractor was used to measure the accommodative response under binocular and monocular viewing conditions at 33 cm. Patients wore spectacles to achieve distant refractive errors within 0.50 diopter in both eyes. main outcome measures: Accommodative responses of each eye in binocular and monocular viewing conditions were compared between fellow eyes and groups. RESULTS: During binocular viewing, 65% of nondominant eyes showed an accommodative lag of more than 0.5 diopter, whereas 40% of dominant eyes showed an accommodative lead. In contrast, 77% of the eyes in the equal dominance group and 59% of the normal group showed an accommodative lag of less than 0.5 diopter. During binocular viewing, patients with dominant eye intermittent exotropia showed significantly more asymmetry in the accommodative response between both eyes than patients with equal dominance intermittent exotropia and normal controls (P = .001). During monocular viewing, there was no significant difference in asymmetry between the 3 groups (P = .059). CONCLUSIONS: Patients with intermittent exotropia with a dominant eye tend to have asymmetric accommodative responses between both eyes during binocular viewing, where the nondominant eye showed a decreased accommodative response. PMID- 20970776 TI - Declining incidence of neonatal endophthalmitis in the United States. AB - PURPOSE: To determine the incidence of neonatal endogenous endophthalmitis in the United States between 1998 and 2006 and to identify associated risk factors. DESIGN: Retrospective cohort study. METHODS: We used the Nationwide Inpatient Sample database, a 20% representative sample of all hospital discharges in the United States, to help refine our understanding of this condition. International Classification of Diseases, ninth edition, codes for endophthalmitis, sepsis, and suspected endophthalmitis risk factors in hospitalized infants and neonates were searched in the database and were tracked over time. The main outcome measure was incidence of neonatal endophthalmitis over the study period. RESULTS: Of 3.64 million live births in 1998, 317 newborns were identified with endophthalmitis (8.71 cases per 100 000 live births). Of 4.14 million live births in 2006, only 183 newborns were identified with endophthalmitis (4.42 cases per 100 000 live births) by comparison. The incidence of endophthalmitis decreased at a rate of 6% per year (P = .01130) between 1998 and 2006. Neonates with endophthalmitis were more likely to have systemic bacteremia (odds ratio, 21.114; P < .0001), Candidemia (odds ratio, 2.356; P < .0001), a birth weight of less than 1500 g (odds ratio, 1.215; P < .0001), and retinopathy of prematurity (odds ratio, 2.052; P < .0001). CONCLUSIONS: We objectively validated the commonly held belief that Candidemia, bacteremia, retinopathy of prematurity, and low birth weight are significant risk factors for endophthalmitis development in infants, which seems to have had a decreasing incidence in recent years. PMID- 20970777 TI - Parathyroid incidentaloma. Literature review about three case reports. AB - BACKGROUND: Parathyroid incidentaloma is not a well-known entity. The aim of this study was to show its incidence and to discuss its management. METHODS: This was a prospective study analyzing cases of enlarged parathyroid glands discovered during thyroid surgery. The records of patients with parathyroid incidentaloma were reviewed. We also reviewed all cases of primary hyperparathyroidism (HPTPs) operated during the same period for comparison. RESULTS: Three cases of enlarged parathyroid were found. No clinical or biochemical features led us to suspect hyperparathyroidism before surgery, but a macroscopically enlarged parathyroid gland was discovered during the dissection and was removed in all three patients. CONCLUSIONS: Enlarged parathyroid glands discovered at the time of surgery may represent an early pathological stage responsible for overt primary hyperparathyroidism. In absence of major risk for recurrent nerve palsy, we recommend removal of any enlarged parathyroid discovered during neck surgery in order to avoid the risks of future surgical procedures, preserving in the same time at least one normal parathyroid gland. PMID- 20970779 TI - No replication of genotype effect of 5-HTTLPR on cortisol response to social stress in larger adolescent sample. PMID- 20970778 TI - Response inhibition and response monitoring in a saccadic countermanding task in schizophrenia. AB - BACKGROUND: Cognitive control deficits are pervasive in individuals with schizophrenia (SZ) and are reliable predictors of functional outcome, but the specificity of these deficits and their underlying neural mechanisms have not been fully elucidated. The objective of the present study was to determine the nature of response inhibition and response monitoring deficits in SZ and their relationship to symptoms and social and occupational functioning with a behavioral paradigm that provides a translational approach to investigating cognitive control. METHODS: Seventeen patients with SZ and 16 demographically matched healthy control subjects participated in a saccadic countermanding task. Performance on this task is approximated as a race between movement generation and inhibition processes; this race model provides an estimate of the time needed to cancel a planned movement. Response monitoring can be assessed by reaction time adjustments on the basis of trial history. RESULTS: Saccadic reaction time was normal, but patients required more time to inhibit a planned saccade. The latency of the inhibitory process was associated with the severity of negative symptoms and poorer occupational functioning. Both groups slowed down significantly after correctly cancelled and erroneously noncancelled stop signal trials, but patients slowed down more than control subjects after correctly inhibited saccades. CONCLUSIONS: These results suggest that SZ is associated with a difficulty in inhibiting planned movements and an inflated response adjustment effect after inhibiting a saccade. Furthermore, behavioral results are consistent with potential abnormalities in frontal and supplementary eye fields in patients with SZ. PMID- 20970782 TI - Individual differences in children's mathematical competence are related to the intentional but not automatic processing of Arabic numerals. AB - In recent years, there has been an increasing focus on the role played by basic numerical magnitude processing in the typical and atypical development of mathematical skills. In this context, tasks measuring both the intentional and automatic processing of numerical magnitude have been employed to characterize how children's representation and processing of numerical magnitude changes over developmental time. To date, however, there has been little effort to differentiate between different measures of 'number sense'. The aim of the present study was to examine the relationship between automatic and intentional measures of magnitude processing as well as their relationships to individual differences in children's mathematical achievement. A group of 119 children in 1st and 2nd grade were tested on the physical size congruity paradigm (automatic processing) as well as the number comparison paradigm to measure the ratio effect (intentional processing). The results reveal that measures of intentional and automatic processing are uncorrelated with one another, suggesting that these tasks tap into different levels of numerical magnitude processing in children. Furthermore, while children's performance on the number comparison paradigm was found to correlate with their mathematical achievement scores, no such correlations could be obtained for any of the measures typically derived from the physical size congruity task. These findings therefore suggest that different tasks measuring 'number sense' tap into different levels of numerical magnitude representation that may be unrelated to one another and have differential predictive power for individual differences in mathematical achievement. PMID- 20970781 TI - Adipose derived stem cells (ASCs) isolated from breast cancer tissue express IL 4, IL-10 and TGF-beta1 and upregulate expression of regulatory molecules on T cells: do they protect breast cancer cells from the immune response? AB - Immunomodulatory function of bone marrow derived mesenchymal stem cells in cancer has recently been investigated. But the resident mesenchymal stem cells as whole in cancer and in the breast cancer tissue have not been studied well. In the present work we isolated adipose derived stem cells (ASCs) from breast cancer and normal breast tissues to investigate the expressions of IL-4, IL-10 and transforming growth factor (TGF)-beta1 in ASCs and to see if ASCs isolated from patients can modulate the regulatory molecules on peripheral blood lymphocytes. Our results showed that IL-10 and TGF-beta1 have significantly higher mRNA expressions in ASCs isolated from breast cancer patients than those from normal individuals (P value <0.05). The culture supernatant of ASCs isolated from breast cancer patients with pathological stage III induced upregulation of the mRNA expression levels of IL-4, TGF-beta1, IL-10, CCR4 and CD25 in PBLs. In addition, the percentage of CD4+CD25(high)Foxp3(+) T regulatory cells was increased in vitro. When the same culture supernatant was added to ASCs isolated from normal subjects augmentation of the mRNA expressions of IL-4, IL-10, IL-8, MMP2, VEGF and SDF-1 in normal ASCs was also observed. These data collectively conclude that resident ASCs in breast cancer tissue may have crucial roles in breast tumor growth and progression by inducing regulatory molecules and promoting anti inflammatory reaction within the tumor microenvironment. Further investigation is required to see if the immune suppression induced by ASCs is an independent property from tumor cells or ASCs gain their immunosuppressive potential from malignant cells. PMID- 20970783 TI - Determination of free and total bisphenol A in urine of infants. AB - Infants may be particularly sensitive regarding hormonally active compounds such as Bisphenol A (BPA), which is widely distributed and exhibits weak oestrogenic activity. Since only free (unconjugated) BPA exhibits endocrine activity, both free and total (after hydrolysis of conjugates) BPA were determined in urine samples of infants to support valid risk assessments. Free BPA was observed above the LOQ in only 3 of 91 (3%) samples from 47 infants. As total BPA was observed in only 38 (42%) urine samples, with concentrations between =2 previous laparotomies and 90% in patients with <=1 [P = .001]). FE demonstrated fewer polyps than DBE, whereas VCE had detection rates similar to those of DBE. Of 387 DBE-resected and 22 surgically resected polyps, histologic analysis of 110 retrieved polyps showed adenoma or adenocarcinoma in 30.0% of polyps >20 mm and in only 1.3% of polyps <=20 mm (P < .0001). Multiple linear regression analysis showed that the number of small-bowel polyps >10 mm (X1; P = .0366) and colorectal polyps >5 mm (X2; P = .002) were independent predictors of the growth rate of small-bowel polyps (Y), and a forward stepwise selection model was constructed: Y = 0.136 * X1 + 0.289 * X2 - 0.589 (R(2) = 0.665). LIMITATIONS: Small sample size. CONCLUSIONS: DBE and VCE were useful for the management of small-bowel polyps in PJS. VCE may replace barium examinations for surveillance after polyp resection at intervals depending on the polyp growth rate. PMID- 20970792 TI - Subcutaneous emphysema of the penis and scrotum mimicking gas gangrene: a rare complication of ERCP. PMID- 20970793 TI - Endoscopic predictors of successful endoluminal eradication in sporadic duodenal adenomas and its acute complications. AB - BACKGROUND: Sporadic duodenal adenomas (SDA) are mucosal neoplasms with malignant potential. Endoscopic eradication used both resection and ablation techniques. Optimal predictors, tools, and techniques for endoscopic eradication of SDA have not been determined. OBJECTIVE: To determine endoscopic predictors of successful endoscopic eradication therapy and the acute complication profile of this therapy. DESIGN: This is a retrospective cohort analysis of 36 consecutive patients referred for management of SDA at a tertiary-care center by a single practitioner. SETTING: Single-site study. PATIENTS: This study involved adult patients referred for endoscopic management of SDA. INTERVENTIONS: Endoluminal snare resection was individualized and performed with or without submucosal injection in en bloc or piecemeal fashion. MAIN OUTCOME MEASUREMENTS: Variables including demographics, endoscopic features of the tumors, and eradication techniques applied were measured against outcomes of complete resection and acute bleeding. RESULTS: Among 36 patients, 11 were male and 25 female, with a mean age of 65.3 +/- 11.1 years. Of 33 patients who underwent attempted endoscopic resection, complete resection was achieved in 23 cases (69.7%). Statistically significant negative predictors of complete resection were age >70.5 years (P = .0302), application of argon plasma coagulation (P = .046), and increasing luminal circumference involved by tumors (P < .0001), whereas use of submucosal injection (P = .0121), snare cautery (P < .001), and en bloc resection (P < .001) were positively associated with complete eradication. There were no significant predictors of acute bleeding. LIMITATIONS: This is a retrospective analysis of a single operator's experience. CONCLUSIONS: The extent of luminal circumference involved by the tumor is the strongest predictor of successful eradication. This predictor can guide management of SDA. PMID- 20970794 TI - Prokinetics in acute upper GI bleeding: a meta-analysis. AB - BACKGROUND: Recent data suggest that administration of prokinetics before gastroscopy may be useful in patients with acute upper GI bleeding (UGIB). Published studies are limited in the number of subjects evaluated, and the conclusions are disparate. OBJECTIVE: To assess the evidence of administering prokinetic agents before EGD in acute UGIB. DESIGN AND SETTING: Comprehensive literature searches from 1990 to January 2010 were performed. We selected for meta-analysis randomized trials assessing prokinetic agents in acute UGIB. The primary outcome was the need for a repeat EGD. Secondary outcomes included endoscopic visualization, blood transfusions, duration of hospitalization, and surgery. Results were reported as odds ratios (ORs) or weighted mean differences (WMDs). RESULTS: From 487 citations identified, we selected 3 fully published articles and 2 abstracts assessing a total of 316 patients. Erythromycin (3 studies) and metoclopramide (2 studies) were compared with either placebo (2 studies) or no treatment (3 studies). A prokinetic agent significantly reduced the need for repeat EGD (OR 0.55; 95% CI, 0.32-0.94). The number of units of blood was not significantly altered (WMD, -0.40; 95% CI, -0.86 to 0.06) nor was hospital stay (WMD, -1.04; 95% CI, -2.83 to 0.76) or the need for surgery (OR 1.11; 95% CI, 0.27-4.67). Endoscopic visualization was not analyzed because the disparate definitions across studies did not allow for meaningful clinical inferences. LIMITATIONS: The results are limited by the small number of subjects. CONCLUSIONS: Intravenous erythromycin or metoclopramide immediately before EGD in acute UGIB patients decreases the need for a repeat EGD, but does not improve other clinically relevant measurable outcomes. PMID- 20970795 TI - Polypectomy rate as a quality measure for colonoscopy. AB - BACKGROUND: The adenoma detection rate (ADR) has been proposed as a robust quality indicator for colonoscopy, but it is cumbersome to calculate and not available at the time of colonoscopy. OBJECTIVE: To determine whether endoscopists' polypectomy rates (PRs) correlate with their ADRs and to calculate benchmark PRs that correlate with benchmark ADRs. DESIGN: Retrospective study. SETTING: University and Veterans Affairs endoscopy units in Portland, Oregon. SUBJECTS: Fifteen endoscopists and their patients. MAIN OUTCOME MEASUREMENTS: Proportion of patients with any adenoma and any polyp removed; correlation between ADRs and PRs. RESULTS: Fifteen endoscopists performed 2706 average-risk screening colonoscopies during the study. There was variation in the ADR for men (15.4%-44.7%) and women (6.1%-25.8%) and in the PRs for men (17.9%-66.0%) and women (11.3%-43.1%). Endoscopists' PRs correlated well with their ADRs (r(s) = 0.86, P < .001). To attain the established benchmark ADRs for men (25%) and women (15%), endoscopists needed PRs of 40% and 30%, respectively. Endoscopists attaining the benchmark PRs had a higher ADR among men (32.1% vs 18.4%, P < .001) and a higher ADR among women (21.0% vs 9.8%, P = .01) than those who did not. LIMITATIONS: Study endoscopists' approach to polypectomy may differ from that of endoscopists in other settings. CONCLUSIONS: The PR is a useful quality measure with a high degree of correlation with the ADR. PMID- 20970796 TI - Fabrication of human oral mucosal epithelial cell sheets for treatment of esophageal ulceration by endoscopic submucosal dissection. AB - BACKGROUND: Esophageal stenosis is one of the major complications of aggressive endoscopic resection. Tissue-engineered epithelial cell grafts have demonstrated effectiveness in promoting re-epithelialization and suppressing inflammation causing esophageal scarring and stenosis after endoscopic submucosal dissection (ESD) in an animal model. OBJECTIVE: To confirm the reproducibility and efficacy of a human oral mucosal epithelial cell (hOMEC) sheet cultured on temperature responsive surface in conformity with Good Manufacturing Practice guidelines. DESIGN: A preclinical study. SETTING: Good Manufacturing Practice grade cell processing center, animal laboratory. SUBJECTS: Canine esophageal ulcer models, which were made by ESD. INTERVENTIONS: Oral mucosal specimens were obtained from 7 healthy volunteers. MAIN OUTCOME MEASUREMENT: Fabricated and transplanted hOMEC sheets were subjected to histological analysis. RESULTS: The reproducibility of the fabrication of hOMEC sheets was confirmed. In this method, animal-derived materials such as 3T3 feeder layer and fetal bovine serum were successfully excluded from the culture condition. Furthermore, the environment of the culture room and safety cabinet in the cell-processing center was maintained for obtaining sterility assurances during the fabrication. Transplanted hOMEC sheets after ESD were observed to graft onto canine esophageal ulcer surfaces. LIMITATIONS: Small number of subjects, animal model. CONCLUSIONS: Cultured hOMEC sheets were fabricated without animal-derived materials and demonstrated efficacy as a medical device that promotes re-epithelialization of an esophageal ulcer after ESD. PMID- 20970797 TI - Tall men with medium body fat mass percentage display more developmental stability. AB - A symmetrical body may signal the ability of an individual to cope with developmental perturbations and may thus be considered a 'health certificate'. It is known that symmetrical men are considered more attractive by women and that their reproductive success is higher. This study examined the associations between measures of body structure and fluctuating asymmetry in young Turkish men. Weight, height, and bioelectrical impedance were measured in a sample of 250 men residing in Ankara (mean age=18.4, SD=0.6), and body mass index was calculated. Fluctuating asymmetry was measured using hand length, hand width, elbow width, wrist width, knee width, ankle width, foot length, foot width, ear length, and ear width. According to the obtained findings, there is a negative linear relationship between composite fluctuating asymmetry (CFA) and height, and a positive quadratic relationship between CFA and fat mass. These results might indicate that the tall Turkish men with medium body fat mass percentage display more developmental stability. PMID- 20970798 TI - Locking plate systems and their inherent hitches. PMID- 20970799 TI - Controversies in the management of splenic trauma. AB - BACKGROUND: The technologic innovations of the last three decades, coupled with a deeper understanding of the immunologic role of the spleen, have significantly shifted the management of splenic injuries towards non-operative approaches. However, there continuous to be a wide range of practice patterns related to the non-operative management of splenic injuries, from which the authors infer a gap between the best available evidence and its translation into practice. We sought to explore ongoing areas of controversy in the non-operative management of splenic trauma with the aim of further elucidating why these controversies continue to exist. METHODS: We explored areas of ongoing controversy in the management of splenic injury though a series of iterative surveys. We invited 70 experts in trauma care from ten countries around the world to participate. Areas of controversy explored included: indications and frequency for in-hospital and follow-up imaging, definitions of failure of non-operative management, indications for angioembolisation and non-operative management in special populations (i.e. elderly, concomitant traumatic brain injury, penetrating trauma). RESULTS: A 49% response rate was obtained. Even though a wide range of practice patterns were identified, no controversies were identified in areas that do not involve the adoption of new technologies. In areas where practice pattern variation was observed, the strong influence of the local environment was constantly identified as an impediment to changes in practice. CONCLUSIONS: We have identified that barriers present within local practice environments are the major driving forces behind controversies in the non-operative management of splenic injuries. PMID- 20970800 TI - Psychometric properties of the Chinese version of the European Heart Failure Self care Behaviour Scale. AB - BACKGROUND: Effective self-care is the cornerstone of the successful management of heart failure (HF). The European Heart Failure Self-care Behaviour Scale is a brief, reliable and valid scale to measure this important construct among patients with HF. Although the EHFScBS has been translated to different languages, no Chinese version is available. Indeed, previous findings investigating the psychometric properties of EHFScBS indicated ambiguity of the conceptual structure of this scale. AIM: The aim of this study was to translate the European Heart Failure Self-care Behaviour Scale (EHFScBS) into Chinese and to test its psychometric properties in the Chinese patients with HF. METHODS: The EHFScBS (English Version) was translated to Chinese using Brislin's forward and backward translation method. Panel review was used to examine its semantic equivalence and content validity. The EHFScBS (Chinese Version) was then tested with a convenience sample of 143 Chinese HF patients who attended a specialist clinic from January to September 2007. RESULTS: The content validity index (CVI) of the EHFScBS (Chinese version) was satisfactory (Item CVI=0.96; Scale CVI=0.89), with Cronbach's alpha 0.82. Convergent validity was supported by a moderate relationship, statistical significant with a measure for social support (r=-0.36, p<0.001). However, the findings did not support the hypothesised three factor structure of the EHFScBS (Chinese Version). Instead, all items except one fit well a two-factor structure to measure help-seeking and regimen-complying behaviours. CONCLUSION: The adequate psychometric properties and clear conceptual structure of EHFScBS (Chinese Version) warrant its use in Chinese patients with HF. PMID- 20970801 TI - Anatomical and functional changes in the upper airways of sleep apnea patients due to mandibular repositioning: a large scale study. AB - The obstructive sleep apnea-hypopnea syndrome (OSAHS) is a sleep related breathing disorder. A popular treatment is the use of a mandibular repositioning appliance (MRA) which advances the mandibula during the sleep and decreases the collapsibility of the upper airway. The success rate of such a device is, however, limited and very variable within a population of patients. Previous studies using computational fluid dynamics have shown that there is a decrease in upper airway resistance in patients who improve clinically due to an MRA. In this article, correlations between patient-specific anatomical and functional parameters are studied to examine how MRA induced biomechanical changes will have an impact on the upper airway resistance. Low-dose computed tomography (CT) scans are made from 143 patients suffering from OSAHS. A baseline scan and a scan after mandibular repositioning (MR) are performed in order to study variations in parameters. It is found that MR using a simulation bite is able to induce resistance changes by changing the pharyngeal lumen. The change in minimal cross sectional area is the best parameter to predict the change in upper airway resistance. Looking at baseline values, the ideal patients for MR induced resistance decrease seem to be women with short airways, high initial resistance and no baseline occlusion. PMID- 20970802 TI - Simultaneous determination of antidepressants by non-aqueous capillary electrophoresis-time of flight mass spectrometry. AB - Simultaneous determination of 20 antidepressants in plasma samples was carried out by non-aqueous capillary electrophoresis with time of flight mass spectrometry via electrospray ionization, where a mixture of 60 mM ammonium acetate and 1M acetic acid in acetonitrile, and water, as well as methanol (100:1:0.5, v/v/v) was selected as the background electrolyte. By using time of flight mass spectrometry, accurate mass information was obtained and the background noise was dramatically decreased, thus causing a great improvement in qualitative ability. As for the plasma sample, solid phase extraction with Oasis HLB was used. The limits of detection and quantification were in the range of 0.5 1 and 1-5 ng/ml, respectively. The sensitivity of the present method was found better, i.e. approximately 10-60 folds compared to that using photo diode array detectors because the analyte peak could be clearly distinguished from the background derived from the plasma. The present method was found very useful and practical as regards to routine analysis of plasma samples. PMID- 20970803 TI - A fast, comprehensive screening method for doping agents in urine by gas chromatography-triple quadrupole mass spectrometry. AB - The use of performance enhancing drugs in sports is prohibited. For the detection of misuse of such substances gas chromatography or liquid chromatography coupled to mass spectrometry are the most frequently used detection techniques. In this work the development and validation of a fast gas chromatography tandem mass spectrometric method for the detection of a wide range of doping agents is described. The method can determine 13 endogenous steroids (the steroid profile), 19-norandrosterone, salbutamol and 11-nor-Delta9-tetrahydrocannabinol.9carboxylic acid in the applicable ranges and to detect qualitatively over 140 substances in accordance with the minimum required performance levels of the World Anti-Doping Agency in 1ml of urine. The classes of substances included in the method are anabolic steroids, beta2-agonists, stimulants, narcotics, hormone antagonists and modulators and beta-blockers. Moreover, using a short capillary column and hydrogen as a carrier gas the run time of the method is less than 8min. PMID- 20970804 TI - Performance of a sheathless porous tip sprayer for capillary electrophoresis electrospray ionization-mass spectrometry of intact proteins. AB - The performance of a prototype porous tip sprayer for sheathless capillary electrophoresis-mass spectrometry (CE-MS) of intact proteins was studied. Capillaries with a porous tip were inserted in a stainless steel needle filled with static conductive liquid and installed in a conventional electrospray ionization (ESI) source. Using a BGE of 100 mM acetic acid (pH 3.1) and a positively charged capillary coating, a highly reproducible and efficient separation of four model proteins (insulin, carbonic anhydrase II, ribonuclease A and lysozyme) was obtained. The protein mass spectra were of good quality allowing reliable mass determination of the proteins and some of their impurities. Sheath-liquid CE-MS using the same porous tip capillary and an isopropanol-water-acetic acid sheath liquid showed slightly lower to similar analyte responses. However, as noise levels increased with sheath-liquid CE-MS, detection limits were improved by a factor 6.5-20 with sheathless CE-MS. The analyte response in sheathless CE-MS could be enhanced using a nanoESI source and adding 5% isopropanol to the BGE, leading to improved detection limits by 50-fold to 140-fold as compared to sheath liquid interfacing using the same capillary - equivalent to sub-nM detection limits for three out of four proteins. Clearly, the sheathless porous tip sprayer provides high sensitivity CE-MS of intact proteins. PMID- 20970805 TI - Large injection volumes in capillary liquid chromatography: Study of the effect of focusing on chromatographic performance. AB - This paper describes a multivariate approach to study the effect on chromatographic conditions and to optimize such conditions in capillary liquid chromatography when high injection volumes are required. Several separations have been evaluated by using isocratic and gradient solvent elution, as well as isocratic elution combined with temperature programming. In this study, easily ionisable organic compounds with low logP have been used as representative analytes. Injection volume and nature of the injection solution have been evaluated in order to increase the sensitivity (peak area) and column performance (N values). The equations obtained by multiple linear regressions and response surfaces allow achieving the optimum on-column focusing conditions for chlorophenoxy acids, carbamates and heterocyclic amines. PMID- 20970806 TI - Rapid determination of furfural in biomass hydrolysate by full evaporation headspace gas chromatography. AB - This paper reports a full evaporation (FE) headspace gas chromatographic (HS-GC) method for rapid determination of furfural in the biomass hydrolysate. The data show that a near-complete mass transfer of furfural in the sample from biomass hydrolysate to the vapor phase (headspace) was achieved within 3 min at 105 degrees C when a very small (<40 MUL) sample was added to a 20 mL headspace sample vial. The acid-catalyzed furfural decomposition under these conditions was negligible. The furfural in the vapor phase was then determined by HS-GC using a flame ionization detector. The results showed that the method has an excellent measurement precision (RSD<0.5%) and accuracy (recovery=100.2+/-1.7%) for furfural quantification in carbohydrate hydrolysate samples. The method requires no sample pretreatment, so it is simple, rapid and accurate, and suitable for applications in lignocellulosic biomass conversion to fuel ethanol or other high value-added products. PMID- 20970807 TI - A one-step process to a Janus emulsion. AB - Aqueous high internal phase volume ratio (O/W 90/10) Janus emulsions of a vegetable oil and a silicone fluid were prepared in a single step emulsification by the common vibrator equipment. The basis for the unique structure is discussed in relation to pair-wise interactions between the components with especial emphasis on the surfactant concentration in the aqueous phase. PMID- 20970808 TI - Hydrophobic/superhydrophobic oxidized metal surfaces showing negligible contact angle hysteresis. AB - Dynamic wettability of oxidized metal (aluminum and titanium) surfaces could be tuned by chemical vapor deposition (CVD) of 1,3,5,7-tetramethylcyclotetrasiloxane (D(4)(H)). This facile CVD method produces not only monomeric layers but also particulate films by changing the CVD temperature, resulting in a marked difference in the final wetting properties. In the samples prepared at 80 degrees C for ~3 days, D(4)(H) layers with thicknesses of ~0.5 nm were formed on the surfaces without discernible change in surface morphology, as evidenced by X-ray photoelectron spectroscopy and atomic force microscopy. After this D(4)(H) monomeric layer formation, the hydrophilic oxidized aluminum and titanium surfaces became hydrophobic (advancing/receding water contact angles (theta(A)/theta(R))=102-104 degrees /99-102 degrees ) showing essentially negligible contact angle hysteresis. Performing CVD of D(4)(H) at 180 degrees C for ~1 day produced opaque film with particulate morphologies with diameters in the range of 500 nm to 4 MUm observed on the surfaces. This geometric morphology enhanced the surface hydrophobicity (theta(A)/theta(R)=163 degrees /160-161 degrees ). Droplets on these negligible-hysteresis surfaces moved very easily without "pinning". PMID- 20970809 TI - Rapid room temperature synthesis of electrocatalytically active Au nanostructures. AB - We describe a facile route for the one-pot room temperature synthesis of anisotropic Au nanostructures in aqueous solution in the absence of seeds or surfactants and their electrocatalytic activity. The Au nanostructures were synthesized using piperazine derivatives 1-(2-hydroxyethyl)piperazine and 1,4 Bis(2-hydroxyethyl)piperazine as reducing agents. The Au nanostructures were characterized by spectral, transmission electron microscopic (TEM), X-ray diffraction and electrochemical measurements. The absorption spectrum of colloidal nanoparticles displays two bands ~580 and ~930 nm, corresponding to the dipole and quadrupole plasmon resonance, respectively. TEM measurements show that the Au nanostructures have penta-twined polyhedral shape with an average size of 52 nm. X-ray and selected area electron diffraction patterns reveal the existence of face centered cubic nanocrystalline Au. The concentration of Au(III) controls the stability of the nanoparticles. The nanoparticles were immobilized on 3-D silicate network pre-assembled on a conducting support to examine their electrocatalytic activity. The nanoparticle-based electrochemical interface was characterized by spectral, voltammetric and impedance measurements. The nanoparticle shows high catalytic activity in the oxidation of NADH and reduction of oxygen. Unique inverted 'V' shape voltammogram was obtained for the oxidation of NADH at less positive potential. The nanoparticle-based interface favors two step four-electron reduction of oxygen to water in neutral pH. Significant decrease in the overpotential for the oxidation of NADH and reduction of oxygen with respect to the polycrystalline Au electrode was observed. The electrocatalytic performance of the polyhedral nanoparticle is compared with the conventional citrate stabilized spherical nanoparticles. PMID- 20970810 TI - Effect of emulsion drop-size distribution upon coalescence in simple shear flow: a population balance study. AB - A population balance is used to examine the effect of the shape of the initial drop-size distribution of an emulsion upon its short and long-time evolution in simple shear flow. Initial distributions that are monodisperse, multidisperse, lognormal, bimodal, multimodal, and step functions are considered. At short times, it is shown that the rate of coalescence decreases by up to 25% for step distributions and up to 75% for lognormal distributions as the width of the distribution increases. Bimodal, multidisperse and multimodal distributions show intermediate decreases in the rate of coalescence, between these two values, with increases in the distribution width. Furthermore, it is found that the initial rate of coalescence is strongly dependent upon the presence of large drops. As the number fraction of large droplets within the distribution increases, the rate of coalescence also increases. At long times, all distributions move toward an asymptotic distribution shape in which the frequency of drops decreases algebraically with drop diameter at small drop diameters, and decreases exponentially with drop diameter at large drop diameters. Though portions of each distribution showed the expected asymptotic scaling behavior at long times, each asymptotic distribution nevertheless retains 'fingerprints' of the respective initial distribution. Overall, the rate of coalescence for a system is bounded by the initial rate, which is a function of the initial distribution shape, and the asymptotic rate, which is dependent upon the long-time scaling behavior. Finally, it is shown that the resolution with which the drop-size distribution of an emulsion is experimentally measured can have a significant effect upon predicted rates of coalescence. PMID- 20970811 TI - A longitudinal study of behavioral, emotional and social difficulties in individuals with a history of specific language impairment (SLI). AB - Children with specific language impairment (SLI) have often been reported to have associated behavioral, emotional and social difficulties. Most previous studies involve observations at a single time point, or cross sectional designs, and longitudinal evidence of the developmental trajectories of particular difficulties is limited. The Strengths and Difficulties Questionnaire was used to measure behavioral (hyperactivity and conduct), emotional and social (peer) problems in a sample of individuals with a history of SLI at four time points from childhood (age 7) to adolescence (age 16). A decrease in behavioral and emotional problems was observed from childhood to adolescence, although emotional problems were still evident in adolescence. In contrast, there was an increase in social problems. Reading skills and expressive language were related only to behavioral problems. Pragmatic abilities were related to behavioral, emotional and social difficulties. As a group, those with a history of SLI have poorer long term social and, to a lesser extent, emotional outcomes. In contrast, behavioral difficulties appear to decrease to normative levels by adolescence. Different aspects of early language abilities and reading skills exert different types and degrees of influence on behavioral, emotional and social difficulties. LEARNING OUTCOMES: Readers will be able to: (1) understand the types of behavioral, emotional and social difficulties present in individuals with a history of SLI; (2) be familiar with the developmental trajectory of these difficulties from childhood to adolescence; and (3) understand the relationships between behavioral, emotional and social difficulties and early language and literacy ability. PMID- 20970812 TI - Morphological and immunohistochemical observations on leiomyoma of the ventral ligament of the oviduct of the hen. AB - Leiomyomas of the ventral ligament (LVLs) of the oviduct from 2-year-old spent layers were examined. These tumours can be present either as single large masses or as multiple smaller nodules. The most common site of origin of the tumours was the centre of the free margin of the ventral ligament, but some small tumours were observed at the insertion of this ligament into the magnum of the oviduct. Most samples were highly vascular and some blood vessels within the tumours had vacuolation of the smooth muscle cells. These findings suggest that the proliferative processes leading to LVLs may include transformation of the blood vessels of the ventral ligament. Immunohistochemically, the tumour cells expressed vimentin, alpha-smooth muscle actin, desmin and heavy-caldesmon. These avian leiomyomas have been proposed as a model for similar tumours in other species. PMID- 20970813 TI - Intraorbital and intracranial extension of sinusitis: comparative morbidity. AB - OBJECTIVES: We hypothesized that intracranial extension of sinusitis carries greater morbidity than extension confined to the orbit and that presenting features can raise suspicion for intracranial extension. STUDY DESIGN: A retrospective review (1997 to 2006) identified 118 children with sinusitis complicated by intracranial extension or intraorbital extension. Presenting features and infecting organisms were compared using chi(2) or Fisher exact tests. Outcomes included duration of hospitalization, length of therapy and sequelae. RESULTS: Thirty-three children had intracranial extension and 85 had intraorbital extension. Children with intracranial extension were older (11.4 versus 7.6 years; P <= .001), had more preadmission encounters (1.9 versus 1.3; P = .012), longer headache duration (9.5 versus 2.8 days; P = .009), and presented more often with vomiting (73% versus 28%; P < .001) than those with intraorbital extension. Children with intracranial extension also were hospitalized (26 versus 10 days; P < .001) and treated (36 versus 24 days; P = .001) longer. Four children (3%) had persistent sequelae. CONCLUSIONS: Children with intracranial extension are hospitalized and treated longer than those with intraorbital extension of sinusitis but persistent sequelae are uncommon. Prolonged headache and protracted vomiting at presentation should alert caregivers to consider intracranial extension. PMID- 20970814 TI - A survey of trace element distribution in tissues of stone crabs (Menippe mercenaria) from South Carolina coastal waters. AB - The stone crab (Menippe mercenaria) is an important component of the estuarine food web as both predator and prey. Stone crabs live in sediment, primarily consume oysters, and as a result, have the potential to accumulate significant quantities of pollutants including metals. In South Carolina, the stone crab is becoming a targeted fishery as an ecologically sustainable seafood choice. To date, no studies have reported metals in stone crab tissues. This study examined the distribution of major and minor trace elements in chelae and body muscle, gill, and hepatopancreas. Crabs were collected from three tidal areas within Charleston County, South Carolina, with differing upland use. Results were compared by collection location and by tissue type. Concentrations of some metals associated with anthropogenic activities were up to three times higher in crabs from sites adjacent to more urbanized areas. Concentrations in edible tissues were below historical FDA levels of concern. PMID- 20970815 TI - Systemin and jasmonic acid regulate constitutive and herbivore-induced systemic volatile emissions in tomato, Solanum lycopersicum. AB - Transgenic tomato (Solanum lycopersicum) plants that overexpress the Prosystemin gene (35S::PS) and plants with a mutation in the JA biosynthetic pathway (def1) are known to exhibit a constitutive or reduced wound response, respectively. Here it is demonstrated that several independent 35S::PS lines emit high levels of specific volatiles in addition to increased accumulation of proteinase inhibitors (PIs). Furthermore, the temporal dynamics of systemically induced volatile compounds including green-leaf volatiles, terpenes, and shikimic acid-derivatives from 35S::PS and def1 plants in response to herbivore wounding and treatment with jasmonic acid (JA) are described. Application of JA induced defense protein accumulation and volatile emissions in wild type plants, but did not further increase systemic volatile emissions from 35S::PS plants. Wounding by Manduca sexta larvae induced synthesis of defense proteins and emission of volatiles in wild type plants, but not in def1 plants. Application of jasmonic acid restored the local and systemic accumulation of defense proteins in def1, as well as enhanced herbivore-induced volatile emissions. These results provide strong support for the role of prosystemin- and JA-signaling in the regulation of volatile emissions in tomato plants. PMID- 20970816 TI - Interaction of Nectarin 4 with a fungal protein triggers a microbial surveillance and defense mechanism in nectar. AB - Understanding the biochemical mechanisms by which plants respond to microbial infection is a fundamental goal of plant science. Extracellular dermal glycoproteins (EDGPs) are widely expressed in plant tissues and have been implicated in plant defense responses. Although EDGPs are known to interact with fungal proteins, the downstream effects of these interactions are poorly understood. To gain insight into these phenomena, we used tobacco floral nectar as a model system to identify a mechanism by which the EDGP known as Nectarin IV (NEC4) functions as pathogen surveillance molecule. Our data demonstrates that the interaction of NEC4 with a fungal endoglucanase (XEG) promotes the catalytic activity of Nectarin V (NEC5), which catalyzes the conversion of glucose and molecular oxygen to gluconic acid and H(2)O(2). Significantly enhanced NEC5 activity was observed when XEG was added to nectar or nectarin solutions that contain NEC4. This response was also observed when the purified NEC4:XEG complex was added to NEC4-depleted nectarin solutions, which did not respond to XEG alone. These results indicate that formation of the NEC4:XEG complex is a key step leading to induction of NEC5 activity in floral nectar, resulting in an increase in concentrations of reactive oxygen species (ROS), which are known to inhibit microbial growth directly and activate signal transduction pathways that induce innate immunity responses in the plant. PMID- 20970817 TI - A study on expression of FSH and its effects on the secretion of insulin and glucagon in rat pancreas. AB - Studies indicate that many tissues could express follicle-stimulating hormone (FSH) besides pituitary. New functions of FSH are also been recognized beyond reproduction regulation. However, no report has been made about the expression and function of FSH in rat pancreas yet. Dual-labeled immunofluorescence stain, in situ hybridization and dual-labeled immunohistochemistry stain in adjacent sections were used to study the expression of FSH and its receptor, and co localization of FSH with gonadotropin-releasing hormone (GnRH) receptor in rat pancreas. Tissue incubation and enzyme-linked immunosorbant assay (ELISA) were used to study the effects of FSH on the secretion of insulin and glucagon in rat pancreas in vitro. The results showed that rat pancreas could express FSH and its receptor, some of islet cells co-expressed FSH and its receptor, some of islet cells co-expressed FSH and GnRH receptor. FSH has the same bidirectional regulation effects on insulin and glucagon in vitro. These data suggested that rat pancreas is a target organ of FSH, and GnRH might regulate FSH through GnRH receptor in rat pancreas. FSH might regulate the endocrine function of rat pancreas through FSH receptor. PMID- 20970818 TI - PAR-4 and hTERT expression are negatively correlated after RNA interference targeting hTERT in laryngocarcinoma cells. AB - We investigated the relationship between telomerase activity and the expression of human telomerase reverse transcriptase (hTERT) and prostate apoptosis response 4 (Par-4) proteins in laryngocarcinoma cells. Following treatment with short hairpin RNA (shRNA) against hTERT, hTERT protein expression was inhibited, while Par-4 expression was increased. These changes were statistically significant (p<0.05), with Par-4 and hTERT expression being negatively correlated (p<0.05, r= 0.908). However, we found no correlation between telomerase activity and hTERT expression. Our findings suggest that hTERT exerts its anti-apoptotic effects through a telomerase-independent pathway, which is likely to intersect with the Par-4 apoptosis pathway. PMID- 20970820 TI - Autographa californica multiple nucleopolyhedrovirus ODV-E56 is a per os infectivity factor, but is not essential for binding and fusion of occlusion derived virus to the host midgut. AB - The Autographa californica multiple nucleopolyhedrovirus (AcMNPV) occlusion derived virus (ODV) envelope protein ODV-E56 is essential for oral infection of larvae of Heliothis virescens. Bioassays with recombinant clones of AcMNPV lacking a functional odv-e56 gene showed that ODV-E56 was required for infectivity of both polyhedra and to a lesser extent, purified ODV. However, binding and fusion assays showed that ODV lacking ODV-E56 bound and fused to midgut cells at levels similar to ODV of wild-type virus. Fluorescence microscopy of midguts from larvae inoculated with ODV-E56-positive and -negative viruses that express GFP indicated that ODV-E56 was required for infection of the midgut epithelium. Purified ODV-E56 bound to several proteins in midgut-derived brush border membrane vesicles, but failed to rescue infectivity of ODV-E56-negative viruses in trans. These results indicate that ODV-E56 is a per os infectivity factor (pif-5) required for primary midgut infection at a point before or after virion binding and fusion. PMID- 20970819 TI - Subcellular localization of the human papillomavirus 16 E7 oncoprotein in CaSki cells and its detection in cervical adenocarcinoma and adenocarcinoma in situ. AB - E7 is the major oncoprotein of high-risk human papillomaviruses (HPV) which causes cervical cancer. To date E7 oncoproteins have not been investigated in cervical adenocarcinoma. In this study we generated a rabbit monoclonal anti-HPV 16 E7 antibody, RabMab42-3, which recognizes a conformational epitope in the E7 carboxy-terminal zinc-finger resulting in a strong increase in the sensitivity for the detection of cell-associated HPV-16 E7 protein relative to conventional polyclonal anti-HPV-16 E7 antibodies. Using RabMab42-3, we show that the subcellular localization of endogenous HPV-16 E7 oncoprotein varies during the cell cycle in cervical cancer cells. Moreover, we demonstrate for the first time that the HPV-16 E7 oncoprotein is abundantly expressed in cervical adenocarcinoma in situ and adenocarcinoma, suggesting an important role of HPV-16 E7 for the development of these tumors. Our findings suggest that the HPV-16 E7 oncoprotein could be a useful marker for the detection of cervical adenocarcinoma and their precursors. PMID- 20970821 TI - Partition of pollution between dissolved and particulate phases: what about emerging substances in urban stormwater catchments? AB - This paper presents results about the occurrence, the concentrations of urban priority substances on both the dissolved and the particulate phases in stormwater. Samples were collected at the outlet of a dense urban catchment in Paris suburb (2.30 km(2)). 13 chemical groups were investigated including 88 individual substances. Results showed that stormwater discharges contained 45 substances among them some metals, organotins, PAHs, PCBs, alkylphenols, pesticides, phthalates, cholorophenols and one volatile organic compound, i.e. methylene chloride. With respect to the European Water Framework Directive, these substances included 47% of the priority hazardous substances (n = 8), 38% of the priority substances (n = 10). The remaining substances (n = 27) belong to a list of others specific urban substances not included in the Water Framework Directive but monitored during this work. Finally, stormwater quality was evaluated by comparing the substance concentrations to environmental quality standards (EQS) and the particulate content to Canadian sediment quality guidelines. This showed that stormwater was highly contaminated and should be treated before being discharged to receiving waters in order to avoid any adverse impact on the river quality. PMID- 20970822 TI - Biostabilization and erodibility of cohesive sediment deposits in wildfire affected streams. AB - The erosion characteristics and bed stability of wildfire-affected stream sediment were measured in an annular flume. Biofilms were grown in the flume on cohesive streambed sediments collected from a wildfire affected stream and a reference undisturbed stream in southern Alberta, Canada. Examined factors that influence sediment erosion, settling and bed stability included applied shear stress, geochemical and physical properties of the sediment, floc structural characteristics and consolidation period (2, 7, 14 days). Erosion characteristics and sediment properties were strongly influenced by wildfire, consolidation period and bed biostabilization. The fire-modified sediment was more resistant to erosion than the reference unburned sediment. Settling velocities were lower in the burned sediment due to higher organic content and porosity. The critical shear stresses for erosion were 1.6 and 1.8 times higher for the burn-associated sediment after 7 and 14 days of consolidation. The differences are related to the greater degree and spatial extent (depth) of biofilm attachment in the burned sediment. Erosion depths were 4-8 times higher in burned sediment as a result of wildfire-associated biostabilization. PMID- 20970823 TI - Host genetic factors in hepatitis B infection, liver cancer and vaccination response: a review with a focus on Africa. AB - The disease burden due to hepatitis B virus (HBV) infection remains significant; 350 million people are infected world-wide, and around half a million deaths each year are due to HBV-related liver disease and hepatocellular carcinoma (HCC). Infant immunisation against infection was introduced in the early 1980s, the vaccine is routinely administered across regions where the disease is endemic and has been shown to be safe and effective. However, the large number of older individuals with persistent infection means that disease will not be reduced significantly for several decades. Furthermore, failure to respond to the vaccination has been observed in about 5% of vaccinees and to date we have limited information on the durability of vaccine protection against infection. Hepatitis B infection and disease pathogenesis are known to be influenced by a number of factors including host genetics factors. This review aims to give an overview of the role of genetic variation in persistent HBV infection and the development of liver disease including HCC. Vaccine-induced immunity is, at least in part, heritable and we also discuss findings on the genetic control of responses to HBV vaccination. The epidemiology of HBV infection differs by world region, as does the genetic makeup of individuals originating from different regions. This review focuses on the situation in Africa, where hepatitis B is highly endemic. PMID- 20970824 TI - Emergent stenting after uncomplicated ureteroscopy: evaluation of 23 patients. AB - OBJECTIVES: To evaluate the causes of emergent stent placement during the postoperative early period after uncomplicated ureteroscopy in 23 patients. METHODS: Of 276 uncomplicated ureteroscopy procedures performed for the management of ureteral calculi, double-J stent placement was necessary on an emergent basis in 23 patients because of intolerable colic pain and extreme patient discomfort. All stents were inserted within 24 hours after the procedure. RESULTS: Of the 23 patients requiring emergent stent placement, 14 were men and 9 were women. The stones had been located in the lower ureter in 11, mid-ureter in 6, and upper ureter in 6 patients. All patients had undergone an uncomplicated procedure with no complication evident either during or immediately after ureteroscopic stone management. The intraoperative findings for the 23 patients revealed extensive edema formation, unrecognized small stones embedded in the edematous ureteral wall, unpassed small fragments gathered at the orifice, obstructing blood clots, and kinking of the ureter. A retrospective evaluation of the operative CD recordings and radiographic findings clearly showed that a longer operative time, repeated access, management of a large stone, impacted calculi with ureteral wall edema, a mildly narrowed ureteral segment, ignored caliceal small calculi, and a recent history of urinary tract infection contributed to the need for postoperative intervention. CONCLUSIONS: Ureteral catheterization, at least in the form of overnight stent placement, might prevent the formation of transient ureteral obstruction, with resultant postoperative patient discomfort and colic pain evident in selected cases. PMID- 20970825 TI - Prospective randomized trial of spinal saddle block versus periprostatic lignocaine for anesthesia during transrectal prostate biopsy. AB - OBJECTIVE: To compare the efficacy and tolerability of spinal saddle block vs periprostatic lignocaine injection for anesthesia during transrectal prostate biopsy. METHODS: A total of 75 patients were randomized to undergo prostate biopsy in 3 groups (n = 25). Group 1 had no anesthesia, group 2 had periprostatic lignocaine injection, and group 3 had spinal saddle block. All patients had sextant biopsy. The groups were assessed for pain, level of cooperativeness, willingness to have a repeat biopsy, complication rate, and the duration of the procedure. RESULTS: The mean age in the groups were, respectively, 65.0 (+/-5.7) (group 1), 65.5 (+/-9.3) (group 2), and 68.6 (+/-6.3) (group 3) years. There was no statistical difference between the groups with respect to age, prostate volume, number of biopsies taken, and the prostate-specific antigen. The mean visual analog score in the groups was, respectively, 5.7 (+/-2.3), 4.6 (+/-2.3) and 0.7 (+/-1.6) for groups 1-3. The difference between groups 1 and 2 was not statistically significant (P = .181), whereas the difference between groups 2 and 3 and groups 1 and 3 was highly statistically significant (P = .000). There were also highly statistically significant differences in levels of cooperativeness and duration of the procedure between group 3 and groups 1 and 2. The differences between the groups with respect to complication rates and willingness to have a repeat biopsy were not statistically significant. CONCLUSIONS: Spinal saddle block was a more effective method of anesthesia than periprostatic lignocaine. It did not sacrifice the current outpatient/day case setting for prostate biopsy. It could be offered routinely to patients undergoing prostate biopsy. PMID- 20970826 TI - Single-incision laparoscopic nephrectomy and heminephroureterectomy in young children using conventional instruments: first report of initial experience. AB - OBJECTIVES: To report the surgical technique and the early outcomes of nephrectomy and heminephroureterectomy by single-incision laparoscopic surgery (SILS) in children using conventional laparoscopic instruments only. METHODS: Three consecutive children (aged 3, 4 and 7 years) who underwent nephrectomy for multicystic dysplastic kidney (n = 2) and upper moiety heminephroureterectomy for duplex kidney (n = 1) by SILS were retrospectively reviewed. A standardized infraumbilical incision was used for the insertion of 3 reusable ports of 3 and 5 mm. The SILS procedure was performed by the technique of crossing 2 straight instruments. RESULTS: All 3 procedures were successfully performed by SILS without any intraoperative complications or need for conversion. The 2 nephrectomies were each completed in 120 minutes, whereas the heminephroureterectomy took 400 minutes. Only 1 dose of narcotic analgesic was required by 1 patient, and 2-6 doses of oral acetaminophen were taken for postoperative pain control. All 3 children recovered smoothly from surgery without complications. CONCLUSIONS: Nephrectomy and heminephroureterectomy by SILS using conventional instruments are technically feasible in young children. Further studies are required to investigate whether the SILS approach can become a sound alternative to standard laparoscopy. PMID- 20970827 TI - Risk factors for re-operation following tubularized incised plate urethroplasty: a comprehensive analysis. AB - OBJECTIVES: To review our 10-year experience with tubularized incised-plate (TIP) urethroplasty and determine the risk factors for reoperation. METHODS: The hospital records of 391 patients underwent the TIP procedure from April 1997 to September 2007 were reviewed retrospectively. Data were collected with respect to patient demographics, characteristics of the hypospadias malformation, intraoperative factors and postoperative outcome. Complications requiring reoperation were identified. Univariate and multivariate analyses were used to identify risk factors for reoperation. RESULTS: Median age at surgery was 2 years (range, 0.5-16). Median follow-up was 11 months (range, 3-96). Neourethral complications requiring re-operation developed in 48 patients. A total of 52 reoperations were required because of fistulae (25/6%), neourethral disruption (13/3%), meatal stenosis (13/3%), and stricture (1/0.3%). The re-operation rate was significantly higher in the presence of interrupted sutures, chordee requiring dorsal plication, penoscrotal or proximal shaft defects, a lack of neourethral vascular tissue coverage, and in children over 4 years of age. Multivariate analysis identified the last 3 of these variables as independent risk factors for reoperation. CONCLUSIONS: In addition to position of the urethral meatus and the absence of vascular covering flaps, we found that an age over 4 years at the time of surgery is an additional independent risk factor for neourethral complications requiring reoperation. PMID- 20970828 TI - Late recurrence of renal cell carcinoma: retrospective and collaborative study of the Japanese Society of Renal Cancer. AB - OBJECTIVES: To evaluate in collaboration the clinical features of late recurrence of renal cell carcinoma (RCC). Late recurrence is one of the specific biologic behaviors of RCC; however, the clinical and pathologic features of the late recurrence of RCC are not fully understood. METHODS: A total of 470 patients who had undergone curative treatment of RCC and had not developed recurrence within 10 years of follow-up were documented from 13 institutions of the board members of the Japanese Society of Renal Cancer. Multivariate analysis with Cox proportional hazards model was used to determine the pathologic and clinical factors affecting the late recurrence and survival of patients with RCC >=10 years after surgery. Survival analysis was performed using the Kaplan-Meier method. RESULTS: During the 10-28-year (median 13.2) observation period, 30 patients (6.4%) developed a late recurrence. The disease-free survival rate at 15 and 20 years was 89.5% and 78.4%, respectively. Multivariate analysis showed that lymph node metastasis was the only factor to predict for late recurrence (P = .0334). Age at nephrectomy was the only prognostic factor for overall survival on multivariate analysis (P < .0001). Of the 470 patients, 30 had developed late recurrence in 44 sites, including the lung (36.4%), kidney (25%), and bone (13.6%), followed by the brain, pancreas, adrenal gland, lymph nodes, and liver. Late recurrences in the lung or kidney were observed at any time >=10 years after nephrectomy. CONCLUSIONS: Late recurrence of RCC after initial treatment is not a rare event, and lifelong follow-up is necessary. PMID- 20970829 TI - Exposure of human seminal vesicle tissue to phosphodiesterase (PDE) inhibitors antagonizes the contraction induced by norepinephrine and increases production of cyclic nucleotides. AB - OBJECTIVES: To investigate further the role of phosphodiesterase (PDE) isoenzymes in the control of human seminal vesicle (SV) smooth muscle contractility, we examined the functional responses of isolated SV tissue to various PDE inhibitors. It has been suggested that the application of inhibitors of the PDE type 5 may facilitate SV smooth muscle relaxation and, subsequently, retard ejaculatory response. METHODS: Using the organ bath technique, strip preparations of human SV were exposed for 5 minutes to 1 MUM of the PDE inhibitors milrinone (PDE3 inhibitor), rolipram, Ro 20-1724 (PDE4 inhibitors), and sildenafil (PDE5 inhibitor). Norepinephrine (NE, alpha agonist) was then added (0,1 MUM, 1 MUM, and 10 MUM) and isometric responses were recorded. A contraction-response curve to NE in the absence of PDE inhibitors was also generated. Drug effects on the production of cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP) were measured by means of radioimmunometric assays. RESULTS: The contraction induced by NE was effectively antagonized by 1 MUM of rolipram (83.3% inhibition), Ro 20-1724 (72.3% inhibition), sildenafil (41.6% inhibition), and milrinone (37.5% inhibition). The inhibition of force generation was paralleled by a 1.6-fold to 2.8-fold increase in tissue cyclic AMP (induced by milrinone, rolipram, Ro 20-1724), and a 12-fold rise in cyclic GMP (induced by sildenafil). CONCLUSION: The findings demonstrate that PDE inhibitors can counteract the contraction of human SV mediated by alpha-adrenergic receptors and enhance levels of cyclic nucleotides. This might be of importance with regard to the identification of new options for the pharmacological treatment of premature ejaculation. PMID- 20970830 TI - Laparoscopic partial nephrectomy: a matched-pair comparison of the transperitoneal versus the retroperitoneal approach. AB - OBJECTIVES: To compare surgical and functional results of both surgical approaches to endoscopic partial nephrectomy. It is currently performed either by the transperitoneal (t) or the retroperitoneal (r) approach. METHODS: This was a retrospective, matched-pair comparison of 105 patients who underwent either transperitoneal laparoscopic (Graz) or retroperitoneoscopic (Klagenfurt) partial nephrectomy for clinical T1a renal masses. RESULTS: A total of 35 patients after transperitoneal laparoscopic and 70 patients after retroperitoneoscopic partial nephrectomy were included to this analysis after matching for age (T: 59.3 vs R: 60.1 a), preoperative glomerular filtration rate (GFR) (T: 93.2 vs R: 96.1 mL/min) and tumor size (T: 2.4 vs R: 2.5 cm). Nephrometry scores were comparable between groups and were low, medium, and high in 54.3%, 45.7%, and 0% (t) and 55.7%, 42.9%, and 1.4% (r) of patients (P = .9). Operative time (T: 139.3 minutes vs. R: 83.9 minutes; P < .001) and hospitalization (T: 7 days, R: 5 days; P < .001) were shorter in the retroperitoneoscopic group. Ischemia time (T: 24.3 minutes, R: 22.6 minutes) and postsurgical GFR (T: 86.6 vs R: 90.0 mL/min), postsurgical GFR-decrease (T: 7.1%, R: 6.2%, P = .9) and decline of hemoglobin (T: 17.1%, R: 16.6%) were comparable. Complications were 4 nephrectomies (T: n = 1, R: n = 3), 2 revisions for hemorrhage (R: n = 2), 4 pneumothorax (R: n = 4), and 2 urinary fistulas (T: n = 2). The positive surgical margin rate was comparable between groups (T: n = 3, R: n = 5). CONCLUSIONS: Transperitoneal laparoscopic and retroperitoneoscopic partial nephrectomy provide comparable surgical and functional results. One advantage of the retroperitoneoscopic access seems to be a shorter total surgical time. PMID- 20970831 TI - Medical comorbidities associated with pediatric kidney stone disease. AB - OBJECTIVES: To characterize the relationship between pediatric kidney stone disease and the presence of hypertension (HTN), diabetes mellitus (DM), and obesity. In adults, kidney stone disease has been associated with medical comorbidities such as HTN, DM, and obesity. Similar analyses have never been performed for the pediatric population. METHODS: The 2003 and 2006 Kids' Inpatient Databases were queried to identify subjects treated for kidney stone disease ("International Classification of Diseases" codes 9592.0 and 592.1). The comorbidities of HTN, DM, and obesity were identified using the provided comorbidity software. The risk of kidney stone disease associated with age, sex, and comorbidity status was evaluated using multivariate logistic regression. RESULTS: A total of 6,115,443 subjects were evaluated. Of these, 14,245 (0.2%) had a diagnosis of upper tract calculus (4092 boys and 10,045 girls, sex unavailable for 108). Age was the strongest independent predictor of stone risk (P < .0001). HTN was associated with a significantly increased risk of stone diagnosis in children <=10 years old and DM for children <=5 years old. Stone risk was not affected by obesity in any age group. CONCLUSIONS: The results of our study have shown that kidney stone disease is significantly associated with age among all children and both HTN and DM for young children. Although exploratory, these findings are novel and suggest that kidney stone disease among young children might be associated with nonrenal, systemic disease states. PMID- 20970832 TI - Penile advancement and lengthening for the management of post-circumcision traumatic short penis in adolescents. AB - OBJECTIVES: To report on the safety of combing suprapubic fat liposuction, penile suspensory ligament severing, and Z-plasty of penoscrotal webbing for penile lengthening in cases of post-circumcision traumatic short penis in adolescents. METHODS: This prospective study was conducted in 9 male patients with a mean age of 15.6 +/- 1.4 years. All patients had a short penis because of traumatic amputation of the glans in 7 patients and both glanular and partial distal corporal loss in 2 patients during circumcision. All were initially treated in childhood by penile skin advancement for phallic coverage. Penile length and circumference were measured pre- and post-operatively, both in the flaccid state at maximal stretch and in the erect state. Operative technique included Z-plasty of penoscrotal web, release of suspensory ligament, and suprapubic fat liposuction. RESULTS: Average functional penile length measured 3 months post operatively had significantly increased by 18-30 mm (mean: 23 +/- 4 mm) in the provoked, erect state. All patients had normally developed penile corpora cavernosa and wide circumference (mean: 11.7 +/- 0.2 cm). No post-operative complications occurred in any of the patients. No patients had sexual partners or were sexually active. CONCLUSIONS: The described technique of penile advancement and lengthening can be safely applied to patients with post-circumcision traumatic short penis. PMID- 20970833 TI - Safety and efficacy of once-daily trospium chloride extended-release in male patients with overactive bladder. AB - OBJECTIVES: This study used pooled data from 2 large, phase III, double-blind, randomized, placebo-controlled studies for a subgroup analysis of the safety and efficacy of trospium chloride extended-release (XR) in men with overactive bladder (OAB). METHODS: A subgroup analysis was performed on data from the 176 male patients (trospium XR, 94; placebo, 82) who participated in 1 of the 2 studies. Patients received either trospium XR 60 mg or placebo once daily for 12 weeks. RESULTS: The mean age was 66.2 years for trospium XR and 63.1 years for placebo. A history of benign prostatic hyperplasia was recorded for 29 trospium XR recipients (30.9%) and 23 placebo recipients (28.0%). A total of 19 patients (20.2%) receiving trospium XR and 15 (18.3%) receiving placebo experienced >=1 treatment-emergent adverse event considered at least possibly related to the study medication. Two trospium XR patients (2.1%) developed urinary retention; both were aged >=75 years, and 1 had a history of prostate enlargement. Treatment with trospium XR compared with placebo resulted in significantly greater decreases from baseline in the mean number of daily toilet voids (-2.5 vs -1.5; P < .05) and urgency urinary incontinence episodes (-2.3 vs -1.4; P < .05) in men at week 12 (the coprimary efficacy variables). CONCLUSIONS: Trospium XR is safe and effective in men with OAB. The risk of urinary retention is low and may be further decreased by careful patient selection. PMID- 20970834 TI - Expression of monocyte chemotactic protein 3 following simulated birth trauma in a murine model of obesity. AB - OBJECTIVE: To determine the effect of obesity on simulated birth trauma in leptin deficient obese mice as measured by relative monocyte chemotactic protein 3 (MCP 3) expression. MATERIALS AND METHODS: A total of 25 wild-type and 25 obese C57BL/6 virgin female mice underwent 1 hour of vaginal distension (VD), sham VD, or anesthesia without VD. Pelvic organ tissues were then harvested either immediately or 24-hours post VD and subsequent real-time polymerase chain reaction analysis was performed. RESULTS: Urethral MCP-3 levels in wild-type mice were elevated from baseline at 0 hours with a return to baseline at 24 hours in both VD and sham VD groups. In obese mice, there was a 6-fold elevation in MCP-3 levels at 0 hours after sham VD vs control (P <.05), which then returned to baseline levels at 24 hours. After undergoing VD, MCP-3 levels increased to 6 fold baseline values (P = .002) at 0 hours, with continued elevation in MCP-3 levels to 15 times control levels (P = .0003) at 24 hours. CONCLUSIONS: MCP-3 is significantly over-expressed in the urethral tissues of both wild-type and obese mice immediately after any urethral manipulation. At 24 hours, the MCP-3 expression patterns become divergent between VD and sham VD in obese mice. With a greater degree of trauma, MCP-3 continued to rise at 24 hours, suggesting that the underlying obesity resulted in alterations in response to tissue injury, paralleling the degree of injury. Such associations warrant further investigation into the role of MCP-3 as a chemokine for stem cell migration, with implications for subsequent tissue repair mechanisms after birth trauma. PMID- 20970836 TI - Hypertension influences recurrent stone formation in nonobese stone formers. AB - OBJECTIVES: To assess the influence of hypertension on urinary metabolites as well as recurrent stone formation. Recent studies have suggested that urolithiasis and hypertension are positively associated. However, the relationship between hypertension and lithogenic metabolites is inconsistent and requires further elucidation. METHODS: Based on the presence of hypertension, stone formers (SF) were classified into 2 groups, hypertensive SF (n = 121, 53.1%) and normotensive SF (n = 107, 46.9%), and differences in urinary metabolites between the groups were compared. Eighty-six patients (37.7%) who were followed for more than 36 months (median, 60.5 months; range, 7-170 months) were included in recurrence analyses. To exclude the influence of obesity on recurrent stone formation, recurrence analyses were performed with body mass index (BMI)-based stratification. RESULTS: Hypertensive SF had higher BMI than normotensive SF, and hypocitraturia and hyperoxaluria were more frequently observed in hypertensive SF (P <.05). In the nonobese group, hypertensive SF had a decreased time to stone recurrence (log-rank test, P = .025), whereas time to recurrence was not affected by hypertensive status in the obese group (log-rank test, P = .788). Multivariate Cox regression analysis of nonobese SF revealed that hypertension was significantly associated with stone recurrence (HR, 3.717%; 95% CI, 1.224-13.890; P = .024). CONCLUSIONS: Hypertension is associated with hypocitraturia and hyperoxaluria. Furthermore, hypertension is an independent predictive determinant for recurrent stone formation, especially in nonobese SF. PMID- 20970835 TI - Effects of estrogen, raloxifene, and levormeloxifene on the expression of Rho kinase signaling molecules in urethral smooth muscle cells. AB - OBJECTIVES: To investigate the effects of estrogen, raloxifene, and levormeloxifene on the expression of Rho-kinase signaling molecules in urethral smooth muscle cells (USMCs). METHODS: USMCs were isolated from female rats. Expression of calponin and estrogen receptors alpha (ERalpha) was detected by immunofluorescence staining. Cells were treated with estrogen, raloxifene, or levormeloxifene at 0, 1, 10, and 100 nmol/L for 48 h and then processed for Western blotting with antibodies against RhoA, Rho kinase I and II (Rock-I and Rock-II), myosin light chain (MLC), phosphorylated MLC, and beta-actin. Protein expression was quantitated by densitometry, followed by statistical analysis with beta-actin as control. RESULTS: USMCs expressed calponin and ERalpha. Treatment of USMCs with estrogen, raloxifene or levormeloxifene resulted in decreased expression of RhoA, Rock-I, Rock-II, and p-MLC in a dosage-dependent manner. CONCLUSIONS: Estrogen, raloxifene, and levormeloxifene may affect urinary continence by inhibiting the expression of Rho-kinase signaling molecules. PMID- 20970837 TI - Laparoendoscopic single-site nephrectomy in pediatric patients: initial clinical series of infants to adolescents. AB - OBJECTIVES: To present our initial clinical series of laparoendoscopic single site (LESS) nephrectomy using an umbilical incision in children ranging from infants to adolescents. Laparoscopic surgery in pediatric urology is increasingly being performed for many intra-abdominal ablative procedures, such as nephrectomy for poorly functioning kidneys. We have previously reported our initial experience with LESS surgery in the adult population. METHODS: A total of 11 pediatric patients (age range 0.1-16.2 years, mean 5.7) underwent LESS nephrectomy using an umbilical incision. The perioperative clinical parameters were reviewed retrospectively. RESULTS: The 11 LESS pediatric nephrectomies were technically successful without conversion to conventional laparoscopy or open surgery. An accessory port was used in 5 of the cases early in the clinical series. Of the 11 patients, 2 were infants, aged 39 days and 3.5 months. The mean operative time was 139 minutes (range 85-205), and the mean hospital stay was 1.5 days (range 1.0-2.1). Complications included delayed hydrocele formation in 2 male patients. CONCLUSIONS: The results of our study have shown that LESS nephrectomy using a single umbilical incision in pediatric patients is technically feasible with good outcomes. Additional studies are needed to evaluate the expected benefits of this novel technique. Also, miniaturization of currently available equipment is needed to adapt to the small working spaces available in the pediatric patient. PMID- 20970838 TI - Single-institution outcomes of open reconstruction techniques for management of pediatric and adolescent post-traumatic urethral strictures. AB - OBJECTIVES: To assess the long-term results and efficiency of open reconstruction techniques for pediatric and adolescent post-traumatic urethral strictures. METHODS: A total of 75 patients who had undergone open reconstructive urethroplasty for post-traumatic bulbous or posterior urethral obliterative strictures resulting from pelvic fracture urethral injuries were retrospectively analyzed. The mean patient age was 12.3 years (range 6-17). Of the 75 patients, 38 had a bulbar stricture and 37 had posterior urethral obliteration. Perineal end-to-end anastomotic repair, urethral pull-through, and ureteral tube graft urethroplasty were performed in 54, 20, and 1 patient, respectively. All patients were followed up by medical history and a urinary flow rate evaluation at 6 and 12 months postoperatively. RESULTS: The patients were followed up for 12-94 months (mean 43.2). The urethral strictures were successfully treated with end-to end anastomotic urethroplasty in 37 (68.5%) of 54 patients, urethral pull-through urethroplasty in 14 (70%) of 20 patients, and ureteral tube graft in 1 patient. The total primary success rate was 69.3% (52 of 75 patients). Recurrent stricture developed in 23 patients. Of these 23 patients, 7 and 11 were successfully treated with secondary end-to-end anastomosis and direct vision internal urethrotomy, respectively. The overall success rate was 93.3% (70 of 75 patients). Five patients with treatment failure were still in follow-up, with direct vision urethrotomy performed, as needed. No penile curvature, penile shortening, or urethral diverticula developed. CONCLUSIONS: The results of our study have shown that open urethral reconstruction techniques are effective for primary and secondary surgical interventions in pediatric and adolescent patients with post-traumatic urethral strictures in experienced centers. These techniques provide excellent long-term results with minimal morbidity. PMID- 20970840 TI - Development and validation of preoperative nomogram for disease recurrence within 5 years after laparoscopic radical prostatectomy for prostate cancer. AB - OBJECTIVES: To develop a nomogram that allows the prediction of disease recurrence using preoperative clinical factors for patients with clinically localized prostate cancer who are candidates for laparoscopic radical prostatectomy. Few published studies have combined the clinical prognostic factors into risk profiles that can be used to predict the likelihood of recurrence or metastatic progression after laparoscopic radical prostatectomy for prostate cancer. METHODS: Using Cox proportional hazards regression analysis, we modeled the clinical data and disease follow-up data for 2272 men with clinically localized prostate cancer who had undergone laparoscopic radical prostatectomy. The clinical data included the pretreatment serum prostate-specific antigen level, biopsy Gleason grade, clinical stage, number of positive cores, and number of negative cores. Treatment failure was recorded when clinical evidence of disease recurrence was present, the serum prostate-specific antigen level had increased (2 measurements of >=0.1 ng/mL and increasing), or the initiation of adjuvant therapy. Validation was also performed on an external data set of 1151 men. RESULTS: Treatment failure was noted in 229 of the 2272 men. The group without failure had a median follow-up of 16.7 months (range 0-120.6). The concordance index, when the nomogram was applied to the validation data set, was 0.77. The calibration in this data set was adequate. The predictions from this nomogram were more accurate than those using an open prostatectomy nomogram. CONCLUSIONS: We have externally validated a nomogram that predicts the 5-year probability of treatment failure among men with clinically localized prostate cancer treated with laparoscopic radical prostatectomy. PMID- 20970839 TI - Misconceptions and miscommunication among aging women with overactive bladder symptoms. AB - OBJECTIVES: To better understand aging women's experience with overactive bladder (OAB) symptoms and the care they receive, with the ultimate goal of improving the quality of care provided to aging women with overactive bladder. METHODS: Women seen in outpatient female urology clinics were identified by ICD-9 codes for OAB and recruited. Patients with painful bladder syndrome, mixed stress and urge incontinence, prolapse, or recent pelvic surgery were excluded. Patient focus groups were conducted by trained nonclinician moderators incorporating topics related to patients' perceptions of OAB physiology, symptoms, diagnostic evaluation, treatments, and outcomes. Qualitative data analysis was performed using grounded theory methodology. RESULTS: Five focus groups totaling 33 women with OAB were conducted. Average patient age was 67 years (range, 39-91). Older women with OAB lacked knowledge about the physiology of their disease and had poor understanding regarding the rationale for many diagnostic tests, including urodynamics and cystoscopy. The results of diagnostic studies often were not understood by older patients. Many women were dissatisfied with the care they had received. This lack of knowledge and understanding was more apparent among the elderly women in the group. CONCLUSIONS: Findings demonstrated a poor understanding of the physiology of overactive bladder and the rationale for various diagnostic modalities and treatments. This was associated with dissatisfaction with care. There is a need for better communication with older women experiencing OAB symptoms about the physiology of the condition. PMID- 20970841 TI - Unusual cause of failure of end-to-end anastomotic urethroplasty for traumatic obliterative bulbar urethral stricture. AB - End-to-end anastomotic urethroplasty (EEA) for traumatic bulbar urethral stricture has excellent long-term success rate. We encountered a patient with obliterative bulbar stricture and persistent phlegmon in perineum resulting from straddle injury. Phlegmon-excision and EEA was performed, which ended up in recurrence. Thorough excision of recurrent nodules & scar with stage-I urethroplasty was performed using 'scrotal shutter flap'. Histopathology of phlegmon of first surgery and nodules & urethral margins of second revealed amyloidosis. Stage-II urethroplasty was performed 3-months later after which he is well at 24 months follow-up. This is the first case of perineal-urethral amyloid associated with trauma. Etiology is elusive. PMID- 20970842 TI - Tubeless procedure is most important factor in reducing length of hospitalization after percutaneous nephrolithotomy: results of univariable and multivariable models. AB - OBJECTIVES: To evaluate the effects of kidney stones and patient-related parameters on the length of hospitalization (LOH), which is one important factor affecting the cost effectiveness of percutaneous nephrolithotomy (PCNL). Recently, increases in healthcare costs have highlighted the importance of evaluating the cost effectiveness of a treatment as much as its efficacy. MATERIAL AND METHOD: During an 8-year period, the records of 1669 patients with renal calculi who underwent PCNL were reviewed retrospectively. Eleven patients with urosepsis were excluded from the present study. A total of 1658 patients were categorized into 2 groups (group 1 = <=2 days; group 2 = >2 days) according to the median LOH (median = 2 days). Multivariate binary logistic regression analysis was used to detect the effects of independent variables, including the patient age, gender, body mass index, history of extracorporeal shock wave lithotripsy or open surgery, stone size and opacity, presence of hydronephrosis, and localization and number of accesses, on the LOH after PNL. RESULTS: Overall success was achieved in 86.2% of cases after one session of PCNL. The mean length of hospitalization was 2.89 +/- 1.66 days (range, 1-21). According to the outcome of the multivariate analysis, diabetes (P = .0001, OR = 1.67), impaired kidney function (P = .03, OR = 1.64), stone size (P = .031, OR = 1.31), number of accesses (P = .001, OR = 1.59), intercostal access (P = .001, OR = 1.79), and tubeless procedure (P = .0001, OR = 0.23) were variables influencing LOH. CONCLUSIONS: The presence of diabetes, a large stone burden, intercostals access, multiple accesses, and impaired kidney function prolong the LOH after PCNL. The use of the tubeless procedure was able to diminish the LOH. PMID- 20970843 TI - Think globally: cross-linguistic variation in electrophysiological activity during sentence comprehension. AB - This paper demonstrates systematic cross-linguistic differences in the electrophysiological correlates of conflicts between form and meaning ("semantic reversal anomalies"). These engender P600 effects in English and Dutch (e.g. Kolk et al., 2003; Kuperberg et al., 2003), but a biphasic N400 - late positivity pattern in German (Schlesewsky and Bornkessel-Schlesewsky, 2009), and monophasic N400 effects in Turkish (Experiment 1) and Mandarin Chinese (Experiment 2). Experiment 3 revealed that, in Icelandic, semantic reversal anomalies show the English pattern with verbs requiring a position-based identification of argument roles, but the German pattern with verbs requiring a case-based identification of argument roles. The overall pattern of results reveals two separate dimensions of cross-linguistic variation: (i) the presence vs. absence of an N400, which we attribute to cross-linguistic differences with regard to the sequence-dependence of the form-to-meaning mapping and (ii) the presence vs. absence of a late positivity, which we interpret as an instance of a categorisation-related late P300, and which is observable when the language under consideration allows for a binary well-formedness categorisation of reversal anomalies. We conclude that, rather than reflecting linguistic domains such as syntax and semantics, the late positivity vs. N400 distinction is better understood in terms of the strategies that serve to optimise the form-to-meaning mapping in a given language. PMID- 20970845 TI - Aspirin to prevent colorectal cancer: time to act? PMID- 20970844 TI - Efficacy and safety of corticosteroid injections and other injections for management of tendinopathy: a systematic review of randomised controlled trials. AB - BACKGROUND: Few evidence-based treatment guidelines for tendinopathy exist. We undertook a systematic review of randomised trials to establish clinical efficacy and risk of adverse events for treatment by injection. METHODS: We searched eight databases without language, publication, or date restrictions. We included randomised trials assessing efficacy of one or more peritendinous injections with placebo or non-surgical interventions for tendinopathy, scoring more than 50% on the modified physiotherapy evidence database scale. We undertook meta-analyses with a random-effects model, and estimated relative risk and standardised mean differences (SMDs). The primary outcome of clinical efficacy was protocol-defined pain score in the short term (4 weeks, range 0-12), intermediate term (26 weeks, 13-26), or long term (52 weeks, >=52). Adverse events were also reported. FINDINGS: 3824 trials were identified and 41 met inclusion criteria, providing data for 2672 participants. We showed consistent findings between many high quality randomised controlled trials that corticosteroid injections reduced pain in the short term compared with other interventions, but this effect was reversed at intermediate and long terms. For example, in pooled analysis of treatment for lateral epicondylalgia, corticosteroid injection had a large effect (defined as SMD>0.8) on reduction of pain compared with no intervention in the short term (SMD 1.44, 95% CI 1.17-1.71, p<0.0001), but no intervention was favoured at intermediate term (-0.40, -0.67 to -0.14, p<0.003) and long term (-0.31, -0.61 to -0.01, p=0.05). Short-term efficacy of corticosteroid injections for rotator-cuff tendinopathy is not clear. Of 991 participants who received corticosteroid injections in studies that reported adverse events, only one (0.1%) had a serious adverse event (tendon rupture). By comparison with placebo, reductions in pain were reported after injections of sodium hyaluronate (short [3.91, 3.54-4.28, p<0.0001], intermediate [2.89, 2.58-3.20, p<0.0001], and long [3.91, 3.55-4.28, p<0.0001] terms), botulinum toxin (short term [1.23, 0.67-1.78, p<0.0001]), and prolotherapy (intermediate term [2.62, 1.36-3.88, p<0.0001]) for treatment of lateral epicondylalgia. Lauromacrogol (polidocanol), aprotinin, and platelet-rich plasma were not more efficacious than was placebo for Achilles tendinopathy, while prolotherapy was not more effective than was eccentric exercise. INTERPRETATION: Despite the effectiveness of corticosteroid injections in the short term, non-corticosteroid injections might be of benefit for long-term treatment of lateral epicondylalgia. However, response to injection should not be generalised because of variation in effect between sites of tendinopathy. FUNDING: None. PMID- 20970846 TI - Corticosteroids: short-term gain for long-term pain? PMID- 20970847 TI - Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. AB - BACKGROUND: High-dose aspirin (>=500 mg daily) reduces long-term incidence of colorectal cancer, but adverse effects might limit its potential for long-term prevention. The long-term effectiveness of lower doses (75-300 mg daily) is unknown. We assessed the effects of aspirin on incidence and mortality due to colorectal cancer in relation to dose, duration of treatment, and site of tumour. METHODS: We followed up four randomised trials of aspirin versus control in primary (Thrombosis Prevention Trial, British Doctors Aspirin Trial) and secondary (Swedish Aspirin Low Dose Trial, UK-TIA Aspirin Trial) prevention of vascular events and one trial of different doses of aspirin (Dutch TIA Aspirin Trial) and established the effect of aspirin on risk of colorectal cancer over 20 years during and after the trials by analysis of pooled individual patient data. RESULTS: In the four trials of aspirin versus control (mean duration of scheduled treatment 6.0 years), 391 (2.8%) of 14 033 patients had colorectal cancer during a median follow-up of 18.3 years. Allocation to aspirin reduced the 20-year risk of colon cancer (incidence hazard ratio [HR] 0.76, 0.60-0.96, p=0.02; mortality HR 0.65, 0.48-0.88, p=0.005), but not rectal cancer (0.90, 0.63-1.30, p=0.58; 0.80, 0.50-1.28, p=0.35). Where subsite data were available, aspirin reduced risk of cancer of the proximal colon (0.45, 0.28-0.74, p=0.001; 0.34, 0.18-0.66, p=0.001), but not the distal colon (1.10, 0.73-1.64, p=0.66; 1.21, 0.66-2.24, p=0.54; for incidence difference p=0.04, for mortality difference p=0.01). However, benefit increased with scheduled duration of treatment, such that allocation to aspirin of 5 years or longer reduced risk of proximal colon cancer by about 70% (0.35, 0.20-0.63; 0.24, 0.11-0.52; both p<0.0001) and also reduced risk of rectal cancer (0.58, 0.36-0.92, p=0.02; 0.47, 0.26-0.87, p=0.01). There was no increase in benefit at doses of aspirin greater than 75 mg daily, with an absolute reduction of 1.76% (0.61-2.91; p=0.001) in 20-year risk of any fatal colorectal cancer after 5-years scheduled treatment with 75-300 mg daily. However, risk of fatal colorectal cancer was higher on 30 mg versus 283 mg daily on long-term follow-up of the Dutch TIA trial (odds ratio 2.02, 0.70-6.05, p=0.15). INTERPRETATION: Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. Benefit was greatest for cancers of the proximal colon, which are not otherwise prevented effectively by screening with sigmoidoscopy or colonoscopy. FUNDING: None. PMID- 20970848 TI - Antimicrobial peptides on calcium phosphate-coated titanium for the prevention of implant-associated infections. AB - Prevention of implant-associated infections has been one of the main challenges in orthopaedic surgery. This challenge is further complicated by the concern over the development of antibiotic resistance as a result of using traditional antibiotics for infection prophylaxis. The objective of this study was to develop a technique that enables the loading and local delivery of a unique group of cationic antimicrobial peptides (AMP) through implant surfaces. A thin layer of micro-porous calcium phosphate (CaP) coating was processed by electrolytic deposition onto the surface of titanium as the drug carrier. The broad spectrum AMP Tet213 (KRWWKWWRRC) was selected and loaded onto the CaP coating. SEM, XRD and FTIR analyses confirmed the CaP coating to be micro-porous octacalcium phosphate. By using a luminescence spectrometer technique, it was demonstrated that a 7 MUm thick porous CaP coating could load up to 9 MUg of AMP/cm2 using a simple soaking technique. The drug-loaded CaP coating (CaP-Tet213) was not cytotoxic for MG-63 osteoblast-like cells. The CaP-Tet213 implants had antimicrobial activity against both Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) bacteria with 106-fold reductions of both bacterial strains within 30 min as assessed by measuring colony-forming units (CFU). Repeated CFU assays on the same CaP-Tet213 specimen demonstrated retention of antimicrobial activity by the CaP-Tet213 surfaces through four test cycles. The susceptibility of bacteria to the CaP-Tet213 surfaces was also evaluated by assessing the inhibition of luminescence of P. aeruginosa containing a luxCDABE cassette at 4 h and 24 h with ~92% and ~77% inhibition of luminescence, respectively. It was demonstrated that CaP-Tet213 was a more efficient antimicrobial coating than CaP-MX226, CaP-hLF1-11 or CaP-tobramycin following incubation of CaP implants with equimolar concentrations of Tet213, the commercially developed antimicrobial peptide MX-226, hLF1-11 or tobramycin. A device coated with CaP-Tet213 could be a potential solution for the prevention of the peri-implant infection in orthopaedics. PMID- 20970849 TI - Functional TNFalpha gene silencing mediated by polyethyleneimine/TNFalpha siRNA nanocomplexes in inflamed colon. AB - During inflammatory bowel disease, TNFalpha is the major pro-inflammatory cytokine mainly secreted from macrophages and dendritic cells. Here, we have demonstrated that TNFalpha siRNA/polyethyleneimine loaded into polylactide at an optimal concentration of 20 g/L nanoparticles covered with polyvinyl alcohol are efficiently taken up by inflamed macrophages and inhibit TNFalpha secretion by the macrophages. Those nanoparticles have a diameter of ~380 nm and zeta potential of -8 mV at pH 7.2, and are non-cytotoxic. Complexation, interactions and protection from RNAse between TNFalpha siRNA and polyethyleneimine were higher than those using chitosan. Importantly, complexation between TNFalpha siRNA and polyethyleneimine facilitated higher rates of siRNA loading into nanoparticles, compared to Chi or free siRNA mixed with Lipofectamine. Oral administration of encapsulated TNFalpha siRNA-loaded nanoparticles specifically reduced the TNFalpha expression/secretion in colonic tissue in LPS-treated mice. In conclusion, we have shown: (1) that proposed TNFalpha siRNA-loaded NPs are prepared via a non-denaturing synthetic process; (2) a high encapsulation rate of TNFalpha siRNA complexed to polyethyleneimine into NPs; (3) effective enzymatic protection of TNFalpha siRNA by polyethyleneimine; (4) non-cytotoxicity and biodegradability of nanoparticles loaded with polyethyleneimine/TNFalpha siRNA; and (5) in vitro and in vivo significant anti-inflammatory effects at low TNFalpha siRNA dose that is specific and restricted to the colonic cells. Our results collectively indicate that polyethyleneimine/TNFalpha siRNA nanocomplexes represent an efficient therapeutic option for diseases such as IBD. PMID- 20970850 TI - Bioreducible polymer-transfected skeletal myoblasts for VEGF delivery to acutely ischemic myocardium. AB - Implantation of skeletal myoblasts to the heart has been investigated as a means to regenerate and protect the myocardium from damage after myocardial infarction. While several animal studies utilizing skeletal myoblasts have reported positive findings, results from clinical studies have been mixed. In this study we utilize a newly developed bioreducible polymer system to transfect skeletal myoblasts with a plasmid encoding vascular endothelial growth factor (VEGF) prior to implantation into acutely ischemic myocardium. VEGF has been demonstrated to promote revascularization of the myocardium following myocardial infarction. We report that implanting VEGF expressing skeletal myoblasts into acutely ischemic myocardium produces superior results compared to implantation of untransfected skeletal myoblasts. Skeletal myoblasts expressing secreted VEGF were able to restore cardiac function to non-diseased levels as measured by ejection fraction, to limit remodeling of the heart chamber as measured by end systolic and diastolic volumes, and to prevent myocardial wall thinning. Additionally, arteriole and capillary formation, retention of viable cardiomyocytes, and prevention of apoptosis was significantly improved by VEGF expressing skeletal myoblasts compared to untransfected myoblasts. This work demonstrates the feasibility of using bioreducible cationic polymers to create engineered skeletal myoblasts to treat acutely ischemic myocardium. PMID- 20970851 TI - Lactoferrin-conjugated superparamagnetic iron oxide nanoparticles as a specific MRI contrast agent for detection of brain glioma in vivo. AB - A specific contrast agent for magnetic resonance imaging (MRI) is crucial to brain tumor patients for the surgical operation or the postoperative radiology. This study explored lactoferrin-conjugated superparamagnetic iron oxide nanoparticles (Lf-SPIONs) as an MRI contrast agent for the detection of brain gliomas in vivo. The hydrodynamic diameter of about 75 nm, saturation magnetization of 51 emu/g Fe and T(2) relaxivity of 75.6 mM(-1)S(-1) of the Lf SPIONs suggested its applicability for MRI. Using a rat model of C6 glioma, Lf SPIONs provided a better picture or more sensitivity to depict brain glioma on MR images than that of SPIONs. Significantly enhanced T(2)-weighted images of brain glioma were documented in vivo with Lf-SPIONs until 48 h after injection. Moreover, Lf-SPIONs were clearly observed around vascular region of the tumor slices after 48 h. High level expression of Lf receptors was confirmed in brain tumor tissues by RT-PCR and Western Blot compared to normal brain tissues. These findings suggested that Lf-SPIONs could be potentially employed as a sensitive and specific MRI contrast agent in the diagnosis of brain glioma. PMID- 20970852 TI - Intervillous circulation in intra-uterine growth restriction. Correlation to fetal well being. AB - Magnetic resonance imaging requested for a potentially serious indication, provided a unique opportunity to explore the intervillous circulation of placentas from pregnancies complicated by Intra Uterine Growth Restriction (IUGR) and to compare them to normal cases. This allowed an innovative characterization of in vivo utero-placental blood flow, correlating a compromised intervillous circulation in IUGR to the deterioration of fetal condition. MR imaging was requested to rule out suspected posterior placental adhesive disorders in 26 patients. Twelve patients had fetuses appropriate for gestational age, while in 14 patients fetuses were affected by severe IUGR. Multiphasic dynamic contrast enhanced sagittal sequences were acquired and a quantitative analysis of signal intensity and enhancement kinetics was performed for both the entire placenta and for selected regions. Images disclosed a homogeneous perfusion overall the placenta in normal cases, while IUGR placentas displayed a slow intervillous blood flow, along with many patchy unperfused areas. Intermittent stops worsen the perfusion dynamics of the intervillous mostly in IUGR cases with an elevated ductus venosus pulsatility index. In conclusion, we proved that in IUGR placenta maternal placental blood flow is extremely compromised and that superimposed dynamic phenomena concur to worsen the intervillous circulation leading to an end stage fetal decompensation. PMID- 20970853 TI - Very late recurrences of leukemia: why does leukemia awake after many years of dormancy? AB - We report a heterogeneous group of very late recurrences of leukemia occurring more than 10 years after initial treatment including 2 cases of childhood acute lymphoblastic leukemia (ALL) which recurred after more than 20 years of remission, 2 cases of donor cell leukemia which developed more than 10 years after allograft for acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS) and 2 cases of chronic myeloid leukemia (CML) relapsing 13 and 17 years after allograft. Case descriptions are followed by a discussion regarding possible mechanisms leading to leukemia recurrence and a review of the literature. PMID- 20970854 TI - Effect of humic acid during concurrent chronic waterborne exposure of rainbow trout (Oncorhynchus mykiss) to copper, cadmium and zinc. AB - The effects of commercial dissolved organic carbon (DOC) in moderating accumulation, biochemical responses and toxicity of a waterborne mixture of copper (Cu), cadmium (Cd) and zinc (Zn) were investigated during a chronic exposure. Juvenile rainbow trout (Oncorhynchus mykiss) were exposed to a ternary metals mixture containing (nominal concentrations in MUg/l): Cu 30, Cd 15, and Zn 150 in hard water (260 mg/l as CaCO(3)) with and without addition of 5 mg/l DOC as Aldrich humic acid (HA) for 28 days. Mortality, growth, metals accumulation, ionoregulatory impairment, and oxidative stress response were measured. While growth was unaffected, 19% mortality occurred during the first week of the exposure in fish exposed to the metals mixture without added HA. The early mortality was associated with transitory whole-body sodium (Na) loss and inhibition of branchial Na(+), K(+)-ATPase activity. Although these ionoregulatory responses mechanistically suggested that Cu was the more potent toxicant than either Cd or Zn, they were not correlated uniquely with elevated tissue Cu concentrations. The effects of HA on accumulation were metal-specific and depended on the organ examined and exposure duration. Specifically, Zn accumulation occurred only in the gill early in the exposure and HA reversed it, while protection against accumulation was absent or complete for Cu and absent or partial for Cd, dependent on tissue and exposure duration. The computed ambient free metal ion activities could explain the Cd but not the Cu and Zn accumulation indicating the involvement of physiological regulatory mechanisms in defining accumulation of essential metals. Surprisingly, the metals mixture (with and without added HA) reduced the concentrations of malondialdehyde (MDA) in gill suggesting induction of reductive rather than oxidative stress. Overall these data indicate that the free metal ion activity alone is not universally a good predictor of metals mixture accumulation and chronic effects nor does consideration of the mechanisms of toxicity unambiguously identify the more potently toxic metal in a mixture. PMID- 20970855 TI - Ultrastructural effects of Celangulin V on midgut cells of the oriental armyworm, Mythimna separata walker (Lepidoptera: Noctuidae). AB - The ultrastructural effects of ingested Celangulin V (CA-V), an insecticidal component extracted from the root bark of Chinese bittersweet (Celastrus angulatus Maxim), on the midgut epithelial cells of the oriental armyworm larva (Mythimna separata Walker) were studied. Transmission electron microscopy showed that CA-V could induce a severe, time-dependent cytotoxicity of the midgut epithelial cells, which had large cytoplasmic spaces, disrupted microvilli and swollen mitochondria. The cisternae of the rough endoplasmic reticulum were excessively dilated, vesiculated and then fragmented. The nuclei were pycnotic and contained one or two divided nucleoli and agglomerated chromatin. Numerous lysosome-like vacuoles and secretion granules were observed. Finally, the CA-V resulted in cell death by necrosis with plasma membrane lysis and the cytoplasm content leakage into the migdut lumen. PMID- 20970856 TI - Ten steps to making evaluation matter. AB - This paper proposes ten steps to make evaluations matter. The ten steps are a combination of the usual recommended practice such as developing program theory and implementing rigorous evaluation designs with a stronger focus on more unconventional steps including developing learning frameworks, exploring pathways of evaluation influence, and assessing spread and sustainability. Consideration of these steps can lead to a focused dialogue between program planners and evaluators and can result in more rigorously planned programs. The ten steps can also help in developing and implementing evaluation designs that have greater potential for policy and programmatic influence. The paper argues that there is a need to go beyond a formulaic approach to program evaluation design that often does not address the complexity of the programs. The complexity of the program will need to inform the design of the evaluation. The ten steps that are described in this paper are heavily informed by a Realist approach to evaluation. The Realist approach attempts to understand what is it about a program that makes it work. PMID- 20970858 TI - Prevalence of MRSA in elective day case pediatric ENT surgical patients. AB - OBJECTIVES: Meticillin-resistant Staphylococcus aureus (MRSA) is a common pathogen implicated in hospital acquired infection. Routine preoperative screening for MRSA is current health policy in England and Wales, although children undergoing elective, routine ENT surgery are excluded from this policy. We prospectively assessed a cohort of children admitted for elective ENT surgery to assess this policy. METHODS: We examined 348 pre-operative children having routine ENT operations to assess MRSA carriage. RESULTS: We found bacteriological evidence of MRSA in only one child of the 348 tested. CONCLUSIONS: This study confirms the current policy and has implications for other countries. PMID- 20970857 TI - Restricted V gene usage and VH/VL pairing of mouse humoral response against the N terminal immunodominant epitope of the amyloid beta peptide. AB - Over the last decade, the potential of antibodies as therapeutic strategies to treat Alzheimer's disease (AD) has been growing, based on successful experimental and clinical trials in transgenic mice. Despite, undesirable side effects in humans using an active immunization approach, immunotherapy still remains one of the most promising treatments for AD. In this study, we analyzed the V genes of twelve independently isolated monoclonal antibodies raised against the N-terminal immunodominant epitope of the amyloid beta peptide (Abeta or A beta). Surprisingly, we found a high and unusual level of restriction in the VH/VL pairing of these antibodies. Moreover, these antibodies mostly differ in their heavy chain complementary determining region 3 (HCDR3) and the residues in the antibodies which contact Abeta are already present in the germline V-genes. Based on these observations and or co-crystal structures of antibodies with Abeta, the aim of the current study was to better understand the role of antibody V-domains, HCDR3 regions, key contact residue (H58) and germline encoded residues in Abeta recognition. For that purpose, we designed and produced a range of recombinant Fab constructs. All the Fabs were tested and compared by surface plasmon resonance on Abeta(1-16), Abeta(1-42) high molecular weight and Abeta(1-42) low molecular weight soluble oligomers. Although all the Fabs recognized the Abeta(1 16) peptide and the Abeta(1-42) high molecular weight soluble oligomers, they did not bind the Abeta(1-42) low molecular weight soluble oligomers. Furthermore, we demonstrated that: (1) an aromatic residue at position H58 in the antibody is essential in the recognition of Abeta and (2) Fabs based on germline V-genes bind to Abeta monomers with a low affinity. These findings may have important implications in designing more effective therapeutic antibodies against Abeta. PMID- 20970859 TI - Mutagenic impact on fish of runoff events in agricultural areas in south-west France. AB - When heavy rainfall follows herbicide application, the intense surface runoff causes stream water contamination. Aquatic organisms are then briefly exposed to a complex mixture of contaminants. The aim of the present study is to investigate the genotoxic impact of such events on fish. A model fish, the Crucian carp (Carassius carassius) was exposed in controlled conditions, for 4 days, to water sampled daily in the Save River (France). The watershed of this stream is representative of agricultural areas in south-west France. Three hydrological conditions were compared: basal flow, winter flood, and spring flood. Chemical analysis of the water samples confirmed the higher contamination of the spring flood water, mainly explained by a peak of metolachlor. Genotoxicity was evaluated by micronucleus (MN) test and comet assay in peripheral erythrocytes. A significant increase in DNA breakdowns compared to controls was detected by the comet assay for all conditions. Exposure to spring flood water resulted in the highest damage induction. Moreover, induced chromosomal damage was only detected in this condition. In addition, fish were exposed, for 4 days, to an experimental mixture of 5 herbicides representative of the spring flood water contamination. Fish exhibited moderate DNA damage induction and no significant chromosomal damage. The mutagenicity induced by field-collected water is then suspected to be the result of numerous interactions between contaminants themselves and environmental factors, stressing the use of realistic exposure conditions. The results revealed a mutagenic impact of water contamination during the spring flood, emphasizing the need to consider these transient events in water quality monitoring programs. PMID- 20970860 TI - Differential protein expression in two bivalve species; Mytilus galloprovincialis and Corbicula fluminea; exposed to Cylindrospermopsis raciborskii cells. AB - The cyanobacteria Cylindrospermopsis raciborskii is considered a threat to aquatic organisms due to the production of the toxin cylindrospermopsin (CYN). Despite the numerous reports evidencing the toxic effects of C. raciborskii cells and CYN in different species, not much is known regarding the toxicity mechanisms associated with this toxin and the cyanobacteria. In this work, a proteomics approach based in the two-dimensional gel electrophoresis and mass spectrometry was used to study the effects of the exposure of two bivalve species, Mytilus galloprovincialis and Corbicula fluminea, to CYN producing (CYN+) and non producing (CYN-) C. raciborskii cells. Additionally the activities of glutathione S-transferase (GST) and glutathione peroxidase (GPx) were determined. Alterations in actin and tubulin isoforms were detected in gills of both bivalve species and digestive gland of M. galloprovincialis when exposed to CYN- and CYN+ cells. Moreover, GST and GPx activities changed in gills and digestive tract of bivalves exposed to both C. raciborskii freeze dried cells, in comparison to control animals exposed to the green alga Chlorella vulgaris. These results suggest the induction of physiological stress and tissue injury in bivalves by C. raciborskii. This condition is supported by the changes observed in GPx and GST activities which indicate alterations in the oxidative stress defense mechanisms. The results also evidence the capacity of CYN non-producing C. raciborskii to induce biochemical responses and therefore its toxicity potential to bivalves. The heat shock protein 60 (HSP60), extrapallial (EP) fluid protein and triosephosphate isomerase homologous proteins from gills of M. galloprovincialis were down-regulated specifically with the presence of CYN+ C. raciborskii cells. The presence of CYN may lead to additional toxic effects in M. galloprovincialis. This work demonstrates that proteomics is a powerful approach to characterize the biochemical effects of C. raciborskii and to investigate the physiological condition of the exposed organisms. PMID- 20970861 TI - Liver antioxidant and plasma immune responses in juvenile golden grey mullet (Liza aurata) exposed to dispersed crude oil. AB - Dispersants are often used after oil spills. To evaluate the environmental cost of this operation in nearshore habitats, the experimental approach conducted in this study exposed juvenile golden grey mullets (Liza aurata) for 48 h to chemically dispersed oil (simulating, in vivo, dispersant application), to dispersant alone in seawater (as an internal control of chemically dispersed oil), to mechanically dispersed oil (simulating, in vivo, natural dispersion), to the water-soluble fraction of oil (simulating, in vivo, an oil slick confinement response technique) and to seawater alone (control condition). Biomarkers such as fluorescence of biliary polycyclic aromatic hydrocarbon (PAH) metabolites, total glutathione liver content, EROD (7-ethoxy-resorufin-O-deethylase) activity, liver antioxidant enzyme activities, liver lipid peroxidation and an innate immune parameter (haemolytic activity of the alternative complement pathway) were measured to assess the toxicity of dispersant application. Significant responses of PAH metabolites and total glutathione content of liver to chemically dispersed oil were found, when compared to water-soluble fraction of oil. As was suggested in other studies, these results highlight that priority must be given to oil slick confinement instead of dispersant application. However, since the same patterns of biomarker responses were observed for both chemically and mechanically dispersed oil, the results also suggest that dispersant application is no more toxic than the natural dispersion occurring in nearshore areas (due to, e.g. waves). The results of this study must, nevertheless, be interpreted cautiously since other components of nearshore habitats must be considered to establish a framework for dispersant use in nearshore areas. PMID- 20970862 TI - Cardiac syndrome X: the pathophysiology should be expanded? PMID- 20970863 TI - Predictors of the first between-herd animal movement for cattle born in 2002 in Ireland. AB - Movement of animals between farms represents a potential risk of bovine tuberculosis (BTB) and other disease transmission. The objectives of this study were to identify and quantify risk factors associated with the first between-herd movement of animals (denoted as risk move). A random sample of 1 percent of Irish calf births registered for 2002 (20,182 animals) was selected. Descriptive and survival analysis on movement over the period 2002-2005 was performed. A total of 12,119 (60%) of animals experienced a risk move over the 4-year study period. Among those that moved, 57% did so within the first 12 months of age. For animals in dairy herds, an early peak in risk move events was observed within the first 12 weeks of age; whereas in animals from suckler herds, a later risk move peak was observed between 21 and 36 weeks of age. The survival models identified a number of risk factors: two that appeared most important in predicting a risk move were gender and enterprise type. Males had a hazard ratio of 2.6 times that of females. The hazards for enterprise type, varied over time, thus a time varying covariate (ent_type*ln(time)) was included in the Cox model. At 7 days of age, females in suckler herds were at 0.14 times the hazard of females in dairy herds for risk move, and over time, the hazards converged, equalised by day 140, and then diverged, so that by 4 years of age, females in suckler herds were at 4.64 times the hazard of females in dairy herds. Herds with a history of selling animals in previous years maintained that record during the study period with increased hazard of risk move. Enterprise type interacted with gender so that relative to females, males from dairy herds were at greater hazard of risk move than males from suckler herds. Hazard of risk move was also a function of ln (herd area), so that each doubling of farm area was accompanied by a 30.6% decrease in the hazards. The main conclusion was that risk of movement related disease transmission also depends on the purpose of the movement whether for breeding or for beef finishing. While males were at greater hazard of movement than females, they would have a shorter lifespan, thus limiting the opportunity for further transmission post-movement. PMID- 20970864 TI - High prevalence of porcine circovirus viremia in newborn piglets in five clinically normal swine breeding herds in North America. AB - Porcine circovirus type 2 (PCV2) can be vertically transmitted resulting in fetal infection with or without clinical signs and lesions. The primary objective of this study was to assess the prevalence of intrauterine PCV2 infection in clinically normal newborn piglets in conventional pork production facilities. Five commercial breeding herds located in the U.S. and Mexico were included in the study. A total of 125 sows and 3-5 neonatal piglets per sow were arbitrarily selected. Blood and colostrum samples were collected from sows. Blood was collected from piglets prior to suckling. All samples were analyzed for the presence of anti-PCV2 IgG antibodies and presence and amount of PCV2 DNA. In addition, PCV2 DNA positive samples were further subtyped into PCV2a and PCV2b. All (125/125) sow colostrum samples and 96.8% (121/125) of the sow serum samples and 21.4% (107/499) of the piglet pre-suckle serum samples were positive for anti PCV2 IgG antibody. The overall PCV2 DNA prevalence was 47.2% (59/125) in sow serum, 40.8% (51/125) in sow colostrum, and 39.9% (199/499) in pre-suckle piglet serum. In the PCV2 DNA positive samples, PCV2b was detected at a higher frequency (69.5% for sow serum, 84.3% for sow colostrum, and 74.4% for piglet serum) compared to PCV2a (18.6% for sow serum, 9.8% for sow colostrum, and 15.6% for piglet serum). Concurrent PCV2a and PCV2b infection was detected in 11.9% of the sow serum, in 5.9% of the colostrum samples, and in 10.0% of the piglet serum samples. In conclusion, an unexpectedly high prevalence of PCV2 viremia was detected in healthy sows (serum and colostrum) and their pre-suckle piglets in the five breeding herds investigated and PCV2b was more prevalent than PCV2a. This information adds to the knowledge of PCV2 infection in breeding herds. PMID- 20970865 TI - (18)F-FDG PET bio-metabolic monitoring of neoadjuvant therapy effects in rectal cancer: focus on nodal disease characteristics. AB - OBJECTIVE: To evaluate efficacy of (18)F-FDG PET(CT) in the staging and re staging of patients with locally advanced rectal cancer, its potential role in predicting pathological response to neoadjuvant therapy. PATIENTS AND METHODS: Patients with confirmed diagnosis of rectal cancer (T2-4 or N+) were prospectively studied with (18)F-FDG PET before and after neoadjuvant therapy. Surgery was programmed 4-6 weeks after treatment followed by an expert histological analysis of the surgical specimen. Response to neoadjuvant treatment was assessed using two specific variables: difference in SUV (difSUV) pre/post neoadjuvant treatment and response index (RI). RESULTS: A total of 64 patients were enrolled for pathological and bio-metabolic response assessment. Compared to cN0, cN+ patients had a higher SUV(1) mean value (6.5 vs. 7.6, p=0.04) and ypN+ patients had higher SUV(2) mean values (2.4 vs 3.5, p=0.06). difSUV values of >=4 was the most efficient diagnostic parameter (sensitivity=45.8%, specificity=86.2%, positive predictive value (PPV)=73.3%, negative predictive value(NPV)=65.7%). With an RI of 66.6%, the sensitivity was 38.5%, specificity=81.5%, PPV=66.6%, and NPV=57.8%. Patients who experienced disease progression had an RI<=66% and a difSUV<=4. CONCLUSION: (18)F-FDG PET has proven to be an accurate diagnostic technique for assessing rectal cancer response to neoadjuvant therapy. The results in terms of sensitivity, specificity, PPV and NPV were similar, if not superior, to those reported with other diagnostic imaging techniques. PMID- 20970866 TI - Relationship between advanced glycation end products and increased lipid peroxidation in semen of diabetic men. AB - AIMS: Majority of diabetic male patients have disturbances in their reproductive systems. However, the mechanisms underlying these disturbances are largely unknown. Since advanced glycation end products (AGE) have a key role in oxidative stress and cell damage in diabetic complications, we hypothesize that AGEs may be involved sperm lipid peroxidation. METHODS: total AGEs in seminal plasma of 32 diabetic and 35 non-diabetic men was determined by spectrofluorimetric method and carboxy methyl lysine (CML) level was assayed using ELISA. Contents of lipid peroxidation in sperm and seminal plasma were determined by thiobarbituric acid reaction. Total antioxidant capacity (TAC) was measured by a colorimetric assay. RESULTS: total AGEs were found significantly higher in seminal plasma of diabetic men than non-diabetic group (p<0.001) whereas no significant differences in seminal plasma CML values between two groups was observed. Moreover, sperm and seminal plasma lipid peroxidation were significantly higher in diabetic subjects than non-diabetic men and a significantly lower TAC was detected in diabetic group compare to non-diabetics. CONCLUSIONS: these results showed an increment in AGEs in seminal plasma of diabetic subjects and may suggest a key role for glycation process and increased oxidative stress in reproductive system dysfunction. PMID- 20970867 TI - Insulin resistance in the middle-aged women with "Tigerish Back and Bearish Waist". AB - The objective of this study was to elucidate the role of fat distribution in predicting insulin resistance in peri- or post-menopausal women. The results demonstrated that insulin resistance increases with waist circumference and subscapular skinfold thickness but decreases with higher thigh circumflex in the peri- and post-menopausal women. PMID- 20970868 TI - Discordance between fasting glucose-based and hemoglobin A1c-based diagnosis of diabetes mellitus in Koreans. AB - We analyzed data of 35,624 non-diabetic Koreans using fasting plasma glucose (FPG) criteria and HbA1c criteria in screening for diabetes. Among the 1,491 subjects newly diagnosed with diabetes, 473 (31.6%) met the FPG criteria only (>=7.0mmol/l), 350 (23.5%) met HbA1c criteria only (>=6.5%), and 668 (44.9%) met both criteria. The DM-by-HbA1c group had significantly older age, higher proportion of women, and lower hemoglobin concentration. The DM-by-FPG group had higher systolic and diastolic blood pressure, fasting serum insulin, and HOMA-IR. Further studies are needed to determine which of these criteria is superior in predicting the risks of long-term vascular complications of diabetes. PMID- 20970869 TI - Serum gamma-glutamyl transferase, ferritin and the risk of type 2 diabetes in women from a Chinese minority. AB - AIMS: This study was to investigate the relationship of gamma-glutamyl transferase to ferritin, and their interaction on the risk of type 2 diabetes. SUBJECTS AND METHODS: A total of 436 men and 588 women were recruited. According to levels of GGT and ferritin, they were divided into three groups in each gender of each geological location (Urban or Rural), that is, Group 1 (both GGT and ferritin= median values), and group 3 (both GGT and ferritin >= median values). Odds ratios for T2D in group 2 3 compared with group 1 were analyzed by multiple logistic regressions. RESULTS: (1) The prevalence of glucose abnormalities increased across the three groups of female subjects. Correspondingly, MDA levels were also higher in group 3 than other groups. (2) GGT and ferritin were correlated with each other after controlling for BMI. (3) T2D risk was higher in group 3 than that in group 1 in female subjects, which was independent of age, BMI, and T2D family history. CONCLUSIONS: GGT and ferritin were correlated with each other, and had synergetic effect on the risk of T2D in women. The mechanism might be involved in enhanced oxidative stress. PMID- 20970870 TI - Comparison of fasting capillary glucose variability between insulin glargine and NPH. AB - The aim of this study was to compare coefficient of variation of fasting capillary blood glucose (FBG) between insulin glargine and NPH in T2DM with poorly controlled by oral antidiabetic drugs. The results demonstrated that insulin glargine was more potent in improving glycemic control than NPH with stable FBG. PMID- 20970871 TI - Nocturnal hyperglycaemia in type 2 diabetes with sleep apnoea syndrome. AB - We assessed glycaemic status in 26 overweight or obese people with type 2 diabetes suspected of having sleep apnoea syndrome (SAS). In people with SAS (n=13), nocturnal glycaemia was 38% higher, independent of body mass index (particularly during rapid eye movement sleep) compared with non-SAS subjects (p<0.008). PMID- 20970872 TI - Gender differences in trends in diabetes prevalence from 1993 to 2008 in Taiwan. AB - We examined time trends in the prevalence of diabetes using nationally representative samples, with a focus on gender differences. Data were from the Nutrition and Health Survey in Taiwan (NAHSIT), 1993-1996 (n = 2700), and NAHSIT 2004-2008 (n = 2258). Participants aged 19 years or older with adequate fasting glucose data were included. When needed, rates were standardized to the year 2000 WHO 5-year interval population for comparisons. The prevalence increased significantly in men, whose standardized rate increased from 4.6% to 9.3%. In women, the age standardized prevalence decreased slightly from 7.9% to 6.4%. High triglycerides (>= 150 mg/dL) was associated with diabetes with odds ratios (OR) of 2.14, and 2.69 (all with p<0.05) in the two surveys. High waist circumference (men >= 90 cm; women >= 80 cm) was also associated with diabetes with ORs of 2.52, and 1.93 (all with p < 0.05). We recommend the development of innovative health promotion programs targeting not only the general population, but also high risk groups such as men, to further reduce diabetes. PMID- 20970873 TI - Increased osteoprotegerin levels in women with previous gestational diabetes developing metabolic syndrome. AB - Osteoprotegerin (OPG), a novel soluble member of tumour necrosis factor receptor superfamily, has been shown to link cardiovascular disorders. The aim of this study is to investigate the potential relationship between serum OPG levels, cardiovascular risk factors and metabolic syndrome in a relatively large group of women with previous GDM. In this cross-sectional case-control study, 128 women with previous GDM and 67 age-matched controls were enrolled. Subjects were evaluated for the diagnosis of metabolic syndrome according to the criteria of the American Heart Association (AHA). Fasting glucose, insulin, serum lipids, CRP and OPG were assayed. HOMA score was calculated. Carotid intima media thickness (IMT) was measured. There was no significant increase in OPG levels in women with previous GDM when compared to controls. On the other hand, women with previous GDM developing metabolic syndrome had higher OPG levels than those without metabolic syndrome and healthy controls. Serum OPG levels were associated with obesity, insulin resistance, serum CRP and carotid IMT. Serum OPG is related to cardiovascular risk factors and metabolic syndrome, and might be involved in the development of cardiovascular disorders in women with previous GDM. PMID- 20970874 TI - User fees abolition policy in Niger: comparing the under five years exemption implementation in two districts. AB - OBJECTIVE: Analysis of the implementation process for a national user fees abolition policy aimed at children under age five organized in Niger since October 2006. METHODS: This was a study of contrasted cases. Two districts were selected, Keita and Abalak; Keita is supported by an international NGO. In 2009, we carried out socio-anthropological surveys in all the health facilities of both districts and qualitative interviews with 211 individuals. RESULTS: Keita district launched the policy before Abalak did, and its implementation was more effective. The populations and the health workers of both districts were relatively well aware of the user fees abolition. Both districts experienced significant delays in the reimbursement of treatments provided free of charge in the health centres (9 months in Keita, 24 months in Abalak). The presence of the NGO compensated for the State's shortcomings, particularly with respect to maintaining the drug supply, which became difficult because of payment delays. In Abalak, district officials reinstated user fees. CONCLUSIONS: The technical relevance of user fees abolition is undermined by the State's lack of preparation for its funding and organizational management. PMID- 20970875 TI - The gradient in health inequalities among families and children: a review of evaluation frameworks. AB - Public health policies and interventions that seek to tackle the social gradient in health need to be more adequately evaluated. The GRADIENT Project sets out to recommend public health policy options which effectively tackle health inequalities and address the gradient in health determinants among families and children in Europe. This work is underpinned by the development of a dedicated evaluation framework-a scheme that elaborates steps in a process of assessment which can act as a useful guide for decision makers. This paper presents the results from a narrative review, based on realist review principles, of 34 evaluation frameworks. It uses a set of analytical criteria, drawn from the EUHPID health development model, the Ottawa Charter for Health Promotion, and the wider literature on health inequalities, to analyse these frameworks. The findings reveal that no one suitable evaluation framework exists to evaluate whether policies and/or interventions targeting children and families reduce the health gradient. It is suggested that this work will be useful in assessing the complex nature of public health interventions and their evaluation. It will be used to develop an evaluation framework to guide decision makers to begin to understand the key drivers at each stage of the policy development and implementation cycle. PMID- 20970876 TI - Promising efficacy of sorafenib in a relapsed thymic carcinoma with C-KIT exon 11 deletion mutation. AB - Advanced thymic carcinoma (TC) is a very aggressive disease. To date there are no established treatment options for the refractory and recurrent disease and only a few prospective trials have been conducted in patients with TC. Here we present a case of a relapsed TC patient, who, by using combination chemotherapy, showed a positive response to sorafenib with C-KIT exon 11 mutation. PMID- 20970877 TI - TS expression predicts postoperative recurrence in adenocarcinoma of the lung. AB - BACKGROUND: Not all patients with lung cancer require postoperative adjuvant chemotherapy after a complete resection. However, no useful markers for either selecting appropriate candidates or for predicting clinical recurrence exist. METHODS: Tumor specimens were collected from 183 consecutive patients who underwent a complete resection for lung adenocarcinoma from 2003 to 2007 in our department. We analyzed the thymidylate synthase (TS) and dihydrofolate reductase (DHFR) expressions in the primary lung adenocarcinoma by immunohistochemisty. RESULTS: The strong expression of TS and DHFR was identified in 39 (21.3%) and 120 (65.6%) patients, respectively. The strong TS expression was identified in 11 (39.3%) of 28 patients and 28 (18.1%) of 155 patients in patients with and without recurrence, respectively (p=0.012). The strong DHFR expression was also identified in 23 (82.1%) and 97 (62.6%) of the patients with and without recurrence, respectively (p=0.045). Logistic regression models indicated the strong TS expression to be an independent factor for tumor recurrence. The strong TS and DHFR expression was associated with a poorer disease-free survival (DFS) according to the survival analysis. A multivariate analysis demonstrated the strong TS expression to be independently associated with an increased risk for poor DFS. CONCLUSIONS: The strong TS expression may be a useful marker for predicting postoperative recurrence in patients with lung adenocarcinoma following surgery. PMID- 20970878 TI - HDAC6 is required for invadopodia activity and invasion by breast tumor cells. AB - Invasion across tissue boundaries by metastatic tumor cells depends on the proteolytic degradation of the extracellular matrix, initiated by the formation of invadopodia, actin-driven membrane protrusions with matrix-degradative activity. Yet, mechanisms underlying invadopodia formation remain largely unknown. In this report, we examined the role of the histone deacetylase HDAC6 in invadopodia formation and invasion by breast cancer cells. Using small interfering RNA silencing of protein expression in highly invasive MDA-MB-231 breast adenocarcinoma cells, we show that HDAC6 is required for two-dimensional matrix proteolysis. In addition, we demonstrate that HDAC6 acts as a tubulin and cortactin deacetylase. We also report that the inhibition of HDAC6 by siRNA or treatment with HDAC inhibitor TSA results in a decreased invasion capacity of a three-dimensional type I collagen matrix by MDA-MB-231 cells. These data identify HDAC6 as a critical component of the invasive apparatus of tumor cells, in both two- and three-dimensional matrices. PMID- 20970879 TI - Psoriasis and pregnancy outcomes: a nationwide population-based study. AB - BACKGROUND: Previous research regarding pregnancy outcomes in women with psoriasis either used selective hospital-based data, or analyzed obstetric, but not infant-specific, outcomes. OBJECTIVE: We sought to investigate whether maternal psoriasis was associated with increased risk of adverse pregnancy outcomes, compared with unaffected mothers, in an unselected nationwide population-based data set. METHODS: In total, 1463 mothers with psoriasis and 11,704 randomly selected mothers without psoriasis were included. Of the 1463 mothers with psoriasis, 645 (44.1%) who had received photochemotherapy or systemic therapy within 2 years before their index deliveries were put in the severe psoriasis group. Conditional logistic regression analyses were conducted to calculate the risk of low birth weight (LBW), preterm birth, cesarean section, small for gestational age, and preeclampsia or eclampsia for these two groups, after adjusting for characteristics of the mother, father, and infant. RESULTS: The odds of LBW for women with severe psoriasis were 1.40 times those of mothers without psoriasis (95% confidence interval = 1.04-1.89) after adjusting for characteristics of the mother, father, and infant. However, mothers with mild psoriasis had no significantly higher odds of LBW, preterm birth, cesarean section, infants small for gestational age, and preeclampsia or eclampsia compared with those without psoriasis. LIMITATIONS: Patients with psoriasis were identified by diagnostic code in database, resulting in the possibility of misclassification bias. In addition, lack of information regarding maternal risk behaviors and previous adverse pregnancy outcomes may leave residual confounding. CONCLUSION: We found that pregnant women with severe psoriasis had an increased risk of LBW infants, whereas mild psoriasis was not associated with excess risk of adverse birth outcomes. PMID- 20970880 TI - Prevalence of healthcare-associated infection in Scottish intensive care units. AB - A national point prevalence survey of healthcare-associated infection (HCAI) in all acute hospitals, including intensive care units (ICUs), was carried out in Scotland from October 2005 to October 2006. The survey measured the prevalence of HCAIs to determine the burden on ICU resources. HCAI prevalence in ICUs was compared with HCAI prevalence in patients outside ICU. The prevalence of HCAI in ICU patients was 27.1%, significantly higher than HCAI prevalence in patients outside ICU, which was 9.3%. The prevalence of specific infections, namely pneumonia and lower respiratory tract, bloodstream and surgical site infections, was also significantly higher in ICU patients compared with non-ICU patients. These results highlight the burden on ICU resources from all HCAIs, regardless of site of infection. High HCAI prevalence in Scottish ICUs has major implications for patient safety and ICU resources and emphasises the need for continuing strong collaboration between intensivists and infection control teams. PMID- 20970881 TI - Compliance with hand hygiene in patients with meticillin-resistant Staphylococcus aureus and extended-spectrum beta-lactamase-producing enterobacteria. AB - Hand hygiene is considered to be the single most effective measure to prevent healthcare-associated infection. Although there have been several reports on hand hygiene compliance, data on patients with multidrug-resistant (MDR) organisms in special isolation conditions are lacking. Therefore, we conducted a prospective observational study of indications for, and compliance with, hand hygiene in patients colonised or infected with meticillin-resistant Staphylococcus aureus (MRSA) or extended-spectrum beta-lactamase (ESBL)-producing enterobacteria in surgical intensive and intermediate care units. Hand disinfectant used during care of patients with MRSA was measured. Observed daily hand hygiene indications were higher in MRSA isolation conditions than in ESBL isolation conditions. Observed compliance rates were 47% and 43% for the MRSA group and 54% and 51% for the ESBL group in the surgical intensive care unit and the intermediate care unit, respectively. Compliance rates before patient contact or aseptic tasks were significantly lower (17-47%) than after contact with patient, body fluid or patient's surroundings (31-78%). Glove usage instead of disinfection was employed in up to 100% before patient contact. However, compliance rates calculated from disinfectant usage were two-fold lower (intensive care: 24% vs 47%; intermediate care: 21% vs 43%). This study is the first to provide data on hand hygiene in patients with MDR bacteria and includes a comparison of observed and calculated compliance. Compliance is low in patients under special isolation conditions, even for the indications of greatest impact in preventing healthcare-associated infections. These data may help to focus measures to reduce transmission of MDR bacteria and improve patient safety. PMID- 20970883 TI - Microbiological survey following the conversion from a bay-room to single-room intensive care unit design. PMID- 20970884 TI - A call for clarity when discussing hydrogen peroxide vapour and aerosol systems. PMID- 20970885 TI - Intra-aortic balloon pump infection: a neglected nosocomial infection? PMID- 20970886 TI - Successful hand hygiene improvement strategy in a referral children's hospital in Armenia. PMID- 20970887 TI - Ultrasound echocardiographic gel contamination by Burkholderia cepacia in an Italian hospital. PMID- 20970888 TI - Ketamine with and without midazolam for emergency department sedation in adults: a randomized controlled trial. AB - STUDY OBJECTIVE: We assess whether midazolam reduces recovery agitation after ketamine administration in adult emergency department (ED) patients and also compared the incidence of adverse events (recovery agitation, respiratory, and nausea/vomiting) by the intravenous (IV) versus intramuscular (IM) route. METHODS: This prospective, double-blind, placebo-controlled, 2*2 factorial trial randomized consecutive ED patients aged 18 to 50 years to 4 groups: receiving either 0.03 mg/kg IV midazolam or placebo, and with ketamine administered either 1.5 mg/kg IV or 4 mg/kg IM. Adverse events and sedation characteristics were recorded. RESULTS: Of the 182 subjects, recovery agitation was less common in the midazolam cohorts (8% versus 25%; difference 17%; 95% confidence interval [CI] 6% to 28%; number needed to treat 6). When IV versus IM routes were compared, the incidences of adverse events were similar (recovery agitation 13% versus 17%, difference 4%, 95% CI -8% to 16%; respiratory events 0% versus 0%, difference 0%, 95% CI -2% to 2%; nausea/vomiting 28% versus 34%, difference 6%, 95% CI -8% to 20%). CONCLUSION: Coadministered midazolam significantly reduces the incidence of recovery agitation after ketamine procedural sedation and analgesia in ED adults (number needed to treat 6). Adverse events occur at similar frequency by the IV or IM routes. PMID- 20970889 TI - Early onset amyloid lesions lead to severe neuritic abnormalities and local, but not global neuron loss in APPPS1 transgenic mice. AB - APPPS1 transgenic mice develop amyloid-beta 42 (Abeta42)-driven early-onset cerebral beta-amyloidosis. Stereological analysis of neocortical neuron number in groups of 2-, 10-, and 17-month-old APPPS1 mice did not reveal any changes compared with wild-type control animals despite massive amyloid-beta (Abeta) load and disrupted cytoarchitecture. However, in subregions with high neuron density such as the granule cell layer of the dentate gyrus, modest but significant neuron loss was found, reminiscent of findings in previously published mouse models with late onset cerebral beta-amyloidosis and predominant amyloid-beta 40 (Abeta40) expression. PMID- 20970892 TI - [Working toward sustainable public health through the interrelation between ambiental and social factors: SESPAS report 2010]. AB - Some of the main challenges that the health of century XXI is confronting are 1) the detection and reduction of social injustices; 2) the prevention of the disease by promoting healthy lifestyles and optimizing public resources and technology; 3) the interdisciplinary approaches between different communities of knowledge and practices; and 4) the integration and coordination of sectorial policies in order to increase their effectiveness. This article analyses, firstly from a theoretical perspective, how sustainability models could contribute to address health taking this holistic approach; emphasizing the relation between social and environmental factors. Then, we explore some experiences that are being implemented in several European countries as for example, interdepartmental bodies of government, interdisciplinary research groups, and alliances between health and forest services and the civil society. We hope these innovations will inspire also to scientists, professionals, politicians and citizens in Spain, where the existing experiences fail to integrate all the areas of intervention for promoting healthy people and healthy environments. PMID- 20970890 TI - Feed efficiency, food choice, and food reward behaviors in young and old Fischer rats. AB - Increased susceptibility to energy imbalance and anorexia in old age are risk factors for malnutrition during aging, but the underlying mechanisms are not well understood. Here, we explored changes in taste-guided hedonic value ("liking") and motivation to obtain ("wanting") palatable foods as potential mediators of age-associated anorexia and weight loss in old Fischer-344 rats. "Liking" as measured by the number of positive hedonic orofacial responses to sucrose and corn oil was not different in old compared with young rats. Taste-guided, low effort "wanting" as measured by the number of licks per 10 seconds was also not different, although old rats exhibited a slight oromotor impairment as revealed by significantly increased interlick intervals. Medium effort "wanting" as measured by performance in the incentive runway was significantly decreased in old versus young rats. Although decreased net running speed was partially accountable, significantly increased duration of distractions suggested additional deficits in motivation and/or reinforcement learning. Together with early satiation on corn oil but not sucrose in aged rats, these changes are likely to have resulted in the significantly greater sucrose preference of old rats in 12-hour tests, and may ultimately lead to reduced energy intake and weight loss. PMID- 20970891 TI - Age-related cerebral atrophy in nonhuman primates predicts cognitive impairments. AB - In humans, but not in nonhuman primates, a clear relationship has been established between age-associated cognitive decline and atrophy of specific brain regions. We evaluated age-related cerebral atrophy and cognitive alterations in mouse lemur primates. Cerebral atrophy was evaluated by in vivo magnetic resonance imaging in 34 animals aged from 1.9 to 11.8 years. The caudate and splenium were atrophied in most older animals, whereas shrinkage of the hippocampus, entorhinal cortex, and septal region was identified in a subgroup of the older animals. The temporal and cingulate cortex also exhibited a severe atrophy, whereas frontal and parietal areas were spared. Measures of cognitive ability in 16 animals studied by magnetic resonance imaging (MRI) showed that both executive functions and spatial memory declined with aging. Impairment of executive functions in older animals was associated with atrophy of the septal region while spatial memory performance was related to atrophy of the hippocampus and entorhinal cortex. Mouse lemurs are the first nonhuman primates in which a clear relationship is established between age-associated cognitive alteration and cerebral atrophy. PMID- 20970893 TI - Semi-synthesis and anti-tumor activity of 5,8-O-dimethyl acylshikonin derivatives. AB - A set of twenty-two 5,8-O-dimethyl acylshikonin derivatives were designed and synthesized starting from shikonin. The cell-based investigation demonstrated that these dimethylated derivatives were less active than or equally effective to shikonin. However, the selective cytotoxicities toward MCF-7 were found among these derivatives, together with no toxicity in the normal cell. Furthermore, compounds 3f, 3p, 3r were subjected to KM mice suffering from S-180 carcinoma subcutaneously, which possessed more potent than Fluorouracil, a typical anticancer drug used clinically. So we may conclude that the modification to the mother nucleus of shikonin via the methylation is an available approach to acquiring anti-tumor agents with higher selectivity and lower toxicity. PMID- 20970894 TI - Synthesis and antibacterial activity of C-12 pyrazolinyl spiro ketolides. AB - A series of C-12 pyrazolinyl spiro ketolide derivatives were designed and synthesized. The C-12 modifications involved replacing the natural C-12 methyl group in clarithromycin core with different pyrazolinyl spiros via chemical synthesis. Potential anti-bacterial activities against both erythromycin susceptible and erythromycin-resistant bacteria were reported. PMID- 20970895 TI - 2-Azetidinone--a new profile of various pharmacological activities. AB - 2-azetidinone, a beta-lactam four member heterocyclic compound involved in research aimed to evaluate new products that possess interesting biological activities. These compounds reported for their antimicrobial and antifungal activities. Successful introduction of aztreonam as a potent inhibitor of cephalosporinase and ezetimibe as a cholesterol absorption inhibitor proved potential of 2-azetidinone moiety. Subsequently 2-azetidinones were highlighted as a potent mechanism based inhibitor of several enzymes like human tryptase, chymase, thrombin, leukocyte elastase, human cytomegalovirus protease and serine protease enzyme. These derivatives also known to possess antitubercular, anti inflammatory, antitumor, anti-HIV, antiparkinsonian, antidiabetic and vasopressin V1a antagonist activity. The present review article focuses on the pharmacological profile of 2-azetidinones with their potential activities. PMID- 20970896 TI - Impact of dietary counselling and probiotic intervention on maternal anthropometric measurements during and after pregnancy: a randomized placebo controlled trial. AB - BACKGROUND & AIMS: To establish whether probiotic supplemented dietary counselling influences maternal anthropometric measurements during and after pregnancy. METHODS: At the first trimester of pregnancy 256 women were randomly assigned to receive nutrition counselling to modify dietary intake according to current recommendations or as controls; dietary intervention groups were further randomized to receive probiotics Lactobacillus rhamnosus GG (ATCC 53103) and Bifidobacterium lactis (diet/probiotics) or placebo (diet/placebo) capsules in a double-blind manner, whilst the controls received placebo (control/placebo). The intervention lasted until the end of exclusive breastfeeding for up to six months. RESULTS: The risk of central adiposity defined as waist circumference 80 cm or more was lowered in women in the diet/probiotics group compared with the control/placebo group (OR 0.30, 95%CI 0.11-0.85, p = 0.023 adjusted for baseline BMI), whilst the diet/placebo group did not differ from the controls (OR 1.00, 95% CI 0.38-2.68, p = 0.994) at 6 months postpartum. The number needed to treat (NNT) with diet/probiotics to prevent one woman from developing a waist circumference of 80 cm or more was 4. Healthy eating pattern at 12 months postpartum (p = 0.001) and BMI prior to pregnancy (p < 0.001) were strong determinants of BMI at 12 months postpartum when adjusted for dietary intervention and exercise. CONCLUSION: The impact of probiotics-supplemented dietary counselling on central adiposity, may offer a novel means for the prevention and management of obesity. This trial was registered at clinicaltrials.gov as NCT 00167700, section 3. PMID- 20970898 TI - Referrals to the neurology clinic from oral and maxillofacial surgery clinics. AB - As part of an ongoing prospective study of referrals from surgical clinics to general neurology outpatient clinics, I audited direct referrals from oral and maxillofacial surgery clinics to neurology outpatient clinics to identify the number, sources, and any common indications for referral that might suggest specific training needs, or indicate areas for the development of care pathways. PMID- 20970897 TI - Aspects on the analysis of 210Po. AB - There has been little development regarding analysis of polonium (Po) in environmental samples since the 1960 ies. This is due to the straightforward spontaneous deposition of this element on silver (Ag), nickel (Ni) or copper (Cu) without any radiochemical separation. For many years, no radiochemical yield determinant was used and it was generally supposed that the yield was 100% after two depositions. Counting was often done using ZnS scintillation counter coupled to a photomultiplier tube. However, the use of the yield determinants (208)Po and (209)Po and the development of alpha spectrometry showed that the yield was lower. Furthermore, the tendency of Po to volatilize at low temperatures constrains the sample preparation techniques; dry-ashing cannot be used. But during the wet-ashing procedure, there are still some losses. The aim of this study was to evaluate the Po losses during wet-ashing by the use of a double tracer technique. We have found that the losses were about 30% when open glass beakers were used and about 17% when the samples were digested in microwave oven. When long-necked bottles (Kjeldahl flasks) were used, a loss of about 20% was registered. It has also been observed that (210)Pb to some extent is plating out together with its daughter nuclide Po during the electrochemical deposition. This will result in a systematic error since an unknown amount of supported (210)Po will be produced from the (210)Pb decay depending on the fraction of (210)Pb being deposited on the disc and the waiting time between deposition and measurement of the sample. A further consequence of this is that in the assessment of the (210)Pb content in the sample, very often the remaining liquid is stored after deposition for build-up of (210)Po. Since some (210)Pb is lost on the disc, the result for (210)Pb will be too low. Both these systematic errors give rise to a too high (210)Po/(210)Pb ratio. The fraction of (210)Pb which is plating out has been assessed in this study for different matrices and is about 50-90%. During the measurement by solid state Si-detectors, some Po is evaporated in the vacuum conditions contaminating the detectors. Experiments have here been done by heating the discs after deposition which indicate that less Po is evaporated from Ag than from Ni. The losses from Ag are less than that from the other metals probably due to a deeper penetration into the surface of Po. We conclude that in most aspects, Ag is better to use than the other plating metals. PMID- 20970899 TI - An audit of audit. PMID- 20970900 TI - Root porosity and radial oxygen loss related to arsenic tolerance and uptake in wetland plants. AB - The rates of radial oxygen loss (ROL), root porosity, concentrations of arsenic (As), iron (Fe) and manganese (Mn) in shoot and root tissues and on root surfaces, As tolerances, and their relationships in different wetland plants were investigated based on a hydroponic experiment (control, 0.8, 1.6 mg As L(-1)) and a soil pot trail (control, 60 mg As kg(-1)). The results revealed that wetland plants showed great differences in root porosity (9-64%), rates of ROL (55-1750 mmo1 O2 kg(-1) root d.w.d(-1)), As uptake (e.g., 8.8-151 mg kg(-1) in shoots in 0.8 mg As L(-1) treatment), translocation factor (2.1-47% in 0.8 mg As L(-1)) and tolerance (29-106% in 0.8 mg As L(-1)). Wetland plants with higher rates of ROL and root porosity tended to form more Fe/Mn plaque, possess higher As tolerance, higher concentrations of As on root surfaces and a lower As translocation factor so decreasing As toxicity. PMID- 20970901 TI - Increasing supply of dentists induces their geographic diffusion in contrast with physicians in Japan. AB - The geographical distribution of health professionals reflects behavioral characteristics of such professionals and of the health system in which they work. The spill-over hypothesis asserts that their oversupply leads to a more even geographic distribution. The current surplus of dentists in Japan is a suitable opportunity to observe such situations. This study demonstrates the transition of the geographic distribution of dentists from 1980 to 2000 in comparison with that of physicians. Using data from the Population Census and the Physician, Dentist, and Pharmacist Census, we calculated the ratio of dentists working in clinics and hospitals per population in 1980, 1990, and 2000 and the Gini coefficients according to the municipality boundaries at the end of 2000. We also plotted the municipalities on a graph, which illustrated the ratios of the dentists by population. We did the same analysis with physician data. The number of dentists increased by 71% during the 20 years studied. The ratios of dentists/100,000 population were 44.1, 58.3, and 69.7 in 1980, 1990, and 2000, respectively. The Gini coefficients for dentists by municipality were 0.270, 0.213, and 0.197, excluding the municipalities with a dental university or its hospital. In contrast, the Gini coefficients for physicians barely changed while the number of physicians increased by 60% during the same periods. The graphs for dentists appeared to indicate the ceiling of those ratios (approximately 100 dentists/100,000 population), but such a ceiling was not seen for physicians. The supply of dentists might have reached a level that generated the geographic diffusion and redistribution of dentists in Japan, in contrast with the situation involving physicians. This supports some results from other countries suggesting that saturation of local markets for health professionals may result in geographical redistribution, producing a more equal pattern of provision across the national space. PMID- 20970902 TI - Do the wealthy have a health advantage? Cardiovascular disease risk factors and wealth. AB - The use of wealth as a measure of socioeconomic status (SES) remains uncommon in epidemiological studies. When used, wealth is often measured crudely and at a single point in time. Our study explores the relationship between wealth and three cardiovascular disease (CVD) risk factors (smoking, obesity and hypertension) in a US population. We improve upon existing literature by using a detailed and validated measure of wealth in a longitudinal setting. We used four waves of data from the Panel Study of Income Dynamics (PSID) collected between 1999 and 2005. Inverse probability weights were employed to control for time varying confounding and to estimate both relative (risk ratio) and absolute (risk difference) measures of effect. Wealth was defined as inflation-adjusted net worth and specified as a six category variable: one category for those with less than or equal to zero wealth and quintiles of positive wealth. After adjusting for income and other time-varying confounders, as well as baseline covariates, the risk of becoming obese was inversely related to wealth. There was a 40%-89% higher risk of becoming obese among the less wealthy relative to the wealthiest quintile and 11 to 25 excess cases (per 1000 persons) among the less wealthy groups over six years of follow up. Smoking initiation had similar but more moderate effects; risk ratios and differences both revealed a smaller magnitude of effect compared to obesity. Of the three CVD risk factors examined here, hypertension incidence had the weakest association with wealth, showing a smaller increased risk and fewer excess cases among the less wealthy groups. In conclusion, this study found a strong inverse association between wealth and obesity incidence, a moderate inverse association between wealth and smoking initiation and a weak inverse association between wealth and hypertension incidence after controlling for income and other time-varying confounders. PMID- 20970904 TI - Applications of vacuum-assisted closure device in maxillofacial reconstruction. PMID- 20970905 TI - Second molar periodontal inflammatory disease after third molar removal in young adults. AB - PURPOSE: To assess the prevalence of periodontal inflammatory disease on the distal side of second molars after third molar removal and the association between presurgical and surgical variables and postsurgical periodontal outcomes. PATIENTS AND METHODS: Data before and after surgery from 2 studies approved by an institutional review board were used. In 1 study, 26 subjects had 4 asymptomatic third molars and in the other 49 subjects had at least 1 mandibular third molar with symptoms of pericoronitis. Full-mouth periodontal probing data, 6 sites per tooth, were obtained as a measurement of periodontal status before and after surgery. A probing depth (PD) >=4 mm on either of the 2 possible probing sites on the distal side of any second molar (D2M) served as an indicator of periodontal inflammatory disease; periodontal health was defined as all D2M PD <4 mm. Cochran Mantel-Haenszel row mean score tests compared the subjects' postsurgical periodontal status (all D2M PD <4 mm and at least 1 D2M PD >=4 mm) with respect to age and time intervals, and the Fisher exact test was used to compare ethnicity, gender, and clinical data at surgery. The McNemar test was used to assess the discordance between subjects' pre- and postsurgical periodontal status. The level of significance was set at .05. RESULTS: Of the 75 subjects, 52% were women and 65% were white. The median age at surgery was 23.6 years (interquartile range, 20.9 to 26.6 years). At enrollment, 53 of 75 subjects (71%) had at least 1 D2M PD >=4 mm. Subjects were significantly more likely to have an improved D2M periodontal status after surgery than a deteriorated status (P < .01). Fewer subjects, 17 of 75 (24%), had at least 1 D2M PD >=4 mm after surgery. D2M PD >=4 mm was more likely after surgery if presurgical D2M was PD >=4 mm (P < .01). Gender, ethnicity, age, presurgical symptoms, and data estimating the extensiveness of surgery were not significantly associated with postsurgical D2M periodontal outcomes. CONCLUSIONS: After third molar removal, periodontal inflammatory disease on the distal of D2Ms was detected significantly less often. None of the variables examined except for presurgical presence of D2M PD >=4 mm were significantly associated with postsurgical D2M periodontal inflammatory disease. PMID- 20970906 TI - Anterior iliac crest, posterior iliac crest, and proximal tibia donor sites: a comparison of cancellous bone volumes in fresh cadavers. AB - PURPOSE: The anterior iliac crest, posterior iliac crest, and proximal tibia are common cancellous donor sites used for autogenous bone grafting. Donor site selection is partly dependent on the expected volume of available bone, but reports of cancellous bone volumes at each of these sites are variable. The goal of this study was to compare the volumes of cancellous bone harvested from donor sites within the same cadaver. MATERIALS AND METHODS: Within each of 10 fresh frozen cadavers, cancellous bone was harvested from 3 donor sites-anterior iliac crest, posterior iliac crest, and proximal tibia-using established surgical techniques. Bone volumes were measured by fluid displacement. Mean compressed cancellous bone volumes from the 3 donor sites were compared among cadavers. Within each cadaver, the 3 donor sites were given a volume rank score from 1 (least volume) to 3 (most volume). RESULTS: Among cadavers, mean compressed cancellous bone volumes from the proximal tibia (11.3 mL) and posterior iliac crest (10.1 mL) were significantly greater than the anterior iliac crest (7.0 mL). Within cadavers, the mean volume rank score of the proximal tibia (mean rank, 2.7) was statistically greater than that for the posterior iliac crest (mean rank, 2.0), which was statistically greater than that for the anterior iliac crest (mean rank, 1.2). Strong correlations in bone volume existed between the proximal tibia and iliac crests (r = 0.67) and between the anterior iliac crest and posterior iliac crest (r = 0.93). CONCLUSION: The proximal tibia and posterior iliac crest yielded a significantly greater mean volume of compressed cancellous bone than the anterior iliac crest. Within individual cadaver skeletons, the proximal tibia was most likely to yield the largest cancellous volume, whereas the anterior iliac crest was most likely to yield the smallest cancellous volume. Although the proximal tibia contains relatively large volumes of cancellous bone, further investigation is required to determine how much cancellous bone can safely be harvested. PMID- 20970907 TI - Keratocystic odontogenic tumor (odontogenic keratocyst): preliminary retrospective review of epidemiologic, clinical, and radiologic features of 261 lesions from University of Turin. AB - PURPOSE: To analyze and discuss the demographic, clinical, and surgical aspects of 261 surgically treated keratocystic odontogenic tumors. PATIENTS AND METHODS: A retrospective review was performed of all cases of treated keratocystic odontogenic tumors. Statistical analysis was used to search for associations among age, presenting symptoms, location, dimension, and locularity. RESULTS: Keratocystic odontogenic tumors most commonly occurred in patients in the third and fourth decades of life. The ratio of males to females was 2:1. The mandibular angle region was the most frequently involved site. Significant associations were found between multilocular lesions and lesions larger than 31 mm (P < .00000005), a mandibular site and larger lesions (P < .05), patients younger than 41 years old and multilocular lesions (P < .05), and younger patients and larger lesions (P < .00005). CONCLUSION: It is likely that most multilocular, larger (and probably aggressive) lesions are found in patients younger than 41 years of age. PMID- 20970908 TI - In vitro study of adhesive polymethylmethacrylate bone cement bonding to cortical bone in maxillofacial surgery. AB - PURPOSE: In the treatment of midface fractures, the fragments are immobilized using screws and plates for osteosynthesis until reunion has occurred. This method involves drilling holes for the insertion of the screws, which can be associated with additional fracturing of the corresponding bone owing to the complex architecture and thin layers of facial bone. To alleviate this problem, new adhesive techniques for fixing the plates for osteosynthesis have been investigated, mitigating the detrimental effects of screw hole drilling. In the present experimental study, the strength of this adhesive bond and its resistance to hydrolysis were investigated. MATERIALS AND METHODS: To determine the adhesive bonding strength, a tension test was implemented. Osteosynthesis plates with screw holes 1.3 mm in diameter were fixed to cortical bone samples of bovine femur using ultraviolet (UV) light-curing polymethylmethacrylate bone cement. To facilitate bonding, the surface of the bone was conditioned with an amphiphilic bonding agent before cementing. UV light curing was implemented using either a conventional UV unit, such as is used in dentistry, or with a specialized UV unit with a limited emission spectrum but high luminosity. Reference control samples were prepared without application of the bone bonding agent. After this procedure, the samples were stored for 1 to 7 days at 37 degrees C submerged in 0.9% saline solution before being subjected to the tension test. RESULTS: Without the bone bonding agent, the bonding strength was 0.2 MPa. The primary average bonding strength at day 0 was 8.5 MPa when cured with the conventional UV unit and 14 MPa for the samples cured with the specialized UV unit. An almost constant average bond strength of 8 and 16 MPa was noted for all samples stored up to 7 days after curing with the conventional and specialized UV unit, respectively. CONCLUSION: With the development of a new bone bonding agent, a method is now available to promote the bonding between the hydrophilic bone surface and the hydrophobic polymethylmethacrylate bone cement by creating an interlayer that is beneficial for adhesion. In the present in vitro study, the strength of this bond and its resistance to hydrolysis were investigated. This new method could have clinical bearing in cases in which conventional fixation with screws and plates is limited, such as can occur in comminuted fractures. The observed average bonding strengths of 8 to 16 MPa support the implementation of this technique in nonload-bearing regions such as the midface, facilitating immobilization until the bone reunion is complete. PMID- 20970909 TI - Diagonal ear lobe crease and atherosclerosis: a review of the medical literature and oral and maxillofacial implications. AB - BACKGROUND: A significant number of individuals die from atherosclerotic disease of the coronary and carotid arteries without having classic risk factors and prodromal symptoms. A diagonal ear lobe crease (DELC) has been characterized in the medical literature as a marker that can identify high-risk patients having occult atherosclerosis. The oral and maxillofacial surgery literature, however, offers very little information on the subject. MATERIALS AND METHODS: The authors conducted a MEDLINE search using the key terms "earlobe crease," "ear lobe crease," "atherosclerosis," "cardiovascular disease," and "cerebrovascular disease." They selected articles published in peer-review journals and gave preference to articles reporting randomized controlled trials. RESULTS: A majority of clinical, angiographic, and postmortem reports support the premise that DELC is a valuable extravascular physical sign able to distinguish some patients at risk of succumbing to atherosclerosis of the coronary arteries. Of particular interest to oral and maxillofacial surgeons is the reported association between individuals with DELC and the development of morbid cardiovascular events associated with the administration of general anesthesia. More recently, reports using B-mode ultrasound have also linked DELC to atherosclerosis of the carotid artery, and another report has related DELC to the presence of calcified carotid artery atheromas on panoramic radiographs. A minority of studies have, however, failed to support the association between DELC and atherosclerosis. CONCLUSIONS: DELC is readily visible during presurgical/preanesthetic physical examination and, in conjunction with the patient's medical history, vital signs, and panoramic radiograph, may assist in risk assessment and the identification of individuals needing further evaluation. PMID- 20970910 TI - Metastasizing (malignant) ameloblastoma: review of a unique histopathologic entity and report of Mayo Clinic experience. AB - PURPOSE: To provide a comprehensive review of metastasizing (malignant) ameloblastoma, establish a new baseline of valid cases using histologic criteria and minimum documentation, and report 3 cases from the Mayo Clinic files. PATIENTS AND METHODS: Ninety-eight original reports of "metastasizing," "malignant," or "atypical" ameloblastoma were reviewed. The following data were gathered for reports that demonstrated well-differentiated ameloblastoma at the metastatic site: gender, ethnicity, age at time of primary tumor diagnosis, histologic pattern of primary tumor, anatomic sites of primary and metastatic tumors, interval from diagnosis of primary to diagnosis of metastasis, number of recurrences preceding metastasis, treatment responses to radiation and/or chemotherapy, presence of hypercalcemia, and length of survival after metastasis. RESULTS: Twenty-seven valid reports of metastasizing (malignant) ameloblastoma were identified; 81% originated in the mandible, recurring on average 4 times before metastasis. Lungs were the initial site of metastasis in 78% of reports, of which 71% were bilateral. The average time from diagnosis of primary to metastasis was 18 years. Over half of the patients were alive and had survived an average of 10 years since diagnosis of metastasis. Those patients who had succumbed to their disease had an average survival time of 3 years after diagnosis of metastasis. CONCLUSIONS: Metastasis of well-differentiated ameloblastoma occurs more rarely than previously believed. Metastasis to the lungs bilaterally, by the hematogenous route, usually follows multiple failed attempts at primary tumor control. The absence of malignant cytologic transformation correlates with relatively indolent metastatic site growth. Treatment of metastasizing (malignant) ameloblastoma should include close observation, thoracotomy with wedge resections, or experimental chemotherapeutic combinations. PMID- 20970912 TI - Echocardiography during CPR: more studies needed. PMID- 20970913 TI - Autoresuscitation in a child: The young Lazarus. PMID- 20970915 TI - Do patients manage to achieve pregnancy after a major complication of deeply infiltrating endometriosis resection? AB - OBJECTIVE: To evaluate the fertility status in women suffering from major postoperative complications following deep endometriosis surgery. STUDY DESIGN: A retrospective study in teaching and research hospitals (tertiary centers) including 23 women submitted to the surgical treatment for deep endometriosis and presenting a major postoperative complication. Postoperatively, women desiring pregnancy who conceived were compared to those who did not conceive using Mann Whitney test and Fisher's exact test. Main outcome measure included the pregnancy rate among these women. RESULTS: The overall intrauterine pregnancy rate was 47.8% and the live birth rate was 30.4%. There were 10 spontaneous conceptions and 3 IVF conceptions among 11 patients. Women who did not conceive were older than those who conceived (33.9 vs. 29.3 years; p = 0.02). The pregnancy rate after intestinal complications was lower than after urinary complications (33.3% vs. 83.3%; p = 0.04). CONCLUSION: Fertility remains preserved among women experiencing a major complication after removal of deep endometriosis with a live birth rate of 30.4%. Women experiencing bowel complications have a reduced probability of conception compared with those who experience a urologic complication. PMID- 20970916 TI - Epigenetic modifiers influence lineage commitment of human bone marrow stromal cells: Differential effects of 5-aza-deoxycytidine and trichostatin A. AB - Clinical imperatives for new bone to replace or restore the function of traumatized or bone lost as a consequence of age or disease has led to the need for therapies or procedures to generate bone for skeletal applications. However, current in vitro methods for the differentiation of human bone marrow stromal cells (HBMSCs) do not, to date, produce homogeneous cell populations of the osteogenic or chondrogenic lineages. As epigenetic modifiers are known to influence differentiation, we investigated the effects of the DNA demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) or the histone deacetylase inhibitor trichostatin A (TSA) on osteogenic and chondrogenic differentiation. Monolayer cultures of HBMSCs were treated for 3 days with the 5-aza-dC or TSA, followed by culture in the absence of modifiers. Cells were subsequently grown in pellet culture to determine matrix production. 5-aza-dC stimulated osteogenic differentiation as evidenced by enhanced alkaline phosphatase activity, increased Runx-2 expression in monolayer, and increased osteoid formation in 3D cell pellets. In pellets cultured in chondrogenic media, TSA enhanced cartilage matrix formation and chondrogenic structure. These findings indicate the potential of epigenetic modifiers, as agents, possibly in combination with other factors, to enhance the ability of HBMSCs to form functional bone or cartilage with significant therapeutic implications therein. PMID- 20970917 TI - Enhancement of cometabolic biodegradation of 4-chlorophenol induced with phenol and glucose as carbon sources by Comamonas testosteroni. AB - The biological degradation of phenol and 4-chlorophenol (4-CP) by Comamonas testosteroni CECT 326T has been studied. Phenol and 4-CP were treated alone as a sole carbon and energy source, but only phenol was completely degraded by C. testosteroni. Since the presence of cosubstrates can enhance the toxic compounds removal by pure cultures, phenol and glucose were added as growth substrates for cometabolic transformation of 4-CP. High efficiencies were obtained in all the experiments carried out in presence of both cosubstrates. In spite of the fact that the addition of glucose reduced the lag phase of 4-CP removal, lower phenol concentrations were required to obtain the same degradation efficiencies. The cometabolic transformation of 4-CP was closely related with the extent of phenol removal. The values of the 4-CP/biomass concentration ratio (S/X) obtained for discriminating between complete (S/X <= 0.11) and partial 4-CP (S/X >= 0.31) transformation showed a narrower range than that reported in the literature. The extent of the cometabolic 4-CP transformation in the presence of phenol could be further enhanced by using glucose as an additional carbon and energy source. However, no significant influence of glucose concentration on 4-CP removal was observed over the concentration range studied. PMID- 20970918 TI - Carbonation of brine impacted fractionated coal fly ash: implications for CO2 sequestration. AB - Coal combustion by-products such as fly ash (FA), brine and CO(2) from coal fired power plants have the potential to impact negatively on the environment. FA and brine can contaminate the soil, surface and ground water through leaching of toxic elements present in their matrices while CO(2) has been identified as a green house gas that contributes significantly towards the global warming effect. Reaction of CO(2) with FA/brine slurry can potentially provide a viable route for CO(2) sequestration via formation of mineral carbonates. Fractionated FA has varying amounts of CaO which not only increases the brine pH but can also be converted into an environmentally benign calcite. Carbonation efficiency of fractionated and brine impacted FA was investigated in this study. Controlled carbonation reactions were carried out in a reactor set-up to evaluate the effect of fractionation on the carbonation efficiency of FA. Chemical and mineralogical characteristics of fresh and carbonated ash were evaluated using XRF, SEM, and XRD. Brine effluents were characterized using ICP-MS and IC. A factorial experimental approach was employed in testing the variables. The 20-150 MUm size fraction was observed to have the highest CO(2) sequestration potential of 71.84 kg of CO(2) per ton of FA while the >150 MUm particles had the lowest potential of 36.47 kg of CO(2) per ton of FA. Carbonation using brine resulted in higher degree of calcite formation compared to the ultra-pure water carbonated residues. PMID- 20970919 TI - Forest law compliance and enforcement: the case of on-farm timber extraction in Ghana. AB - The paper investigates law compliance in case of on-farm timber extraction in Ghana. It empirically investigates compliance with rules that (i) require timber operators to obtain prior and informed consent from the farmers, (ii) require timber operators to pay appropriate and timely compensation for crop damage caused by timber extraction and (iii) ban chainsaw lumbering. The study documents a low level of compliance in all three domains. Subsequently, the paper discusses the underlying causes for the observed low compliance. The low compliance level is attributed to a legislation, and enforcement, that provides huge financial incentives for non-compliance for both farmers and timber operators, and in the latter case both with and without legal permits. At the same time the regulation is perceived to violate their moral values. The paper underlines the interests of the political elite as decisive in shaping the current regulation and the way it is implemented on the ground. It asserts that eliciting compliance requires consideration of both the instrumental and normative perspectives; else it becomes illusive. The study thus challenges the typical response of governments in developing countries, who, supported by donor agencies, attempt to elicit compliance through enhanced law enforcement efforts. The results presented on the Ghana case suggest that such an approach is unlikely to elicit compliance. PMID- 20970920 TI - Neurological involvement in patients with falciparum malaria; frequency and prognostic value. AB - OBJECTIVE: The objective of this study was to evaluate the prognostic significance of neurological manifestations in falciparum malaria. METHODS: We analyzed adult patients with malaria admitted from 2001 to 2003, diagnosed by asexual forms of Plasmodium falciparum in peripheral blood films and identified cases of malaria with neurological involvement. A patient was classified as having neurological involvement if they reported or had one or more of the following symptoms; headache, altered mental status, seizures, neck rigidity, brisk reflexes, cranial neuropathy and hyper or hypotonia. RESULTS: A total of 454 patients were included in the study. Out of these, 123 (27%) were diagnosed as complicated (severe) malaria and 331 (73%) as uncomplicated malaria at admission. Overall 70 (15.4%) patients had evidence of neurological involvement at initial evaluation. Twenty-seven patients out of 123 (22%) with complicated malaria and 43 patients out of 331 (13%) with uncomplicated malaria had neurological involvement. Over all, 16 (4%) patients died, 13 (11%) had complicated malaria (n=123) and 3 (1%) had uncomplicated malaria (n=381). Mortality in patients having neurological involvement (n=70) was 9 (13%) as compared to 7 (2%) in patients with malaria having no neurological involvement (n=384). This difference was statistically significant (p=0.012). Seizure was identified as predictor of mortality on Univariate analysis [OR 5.091 (1.835 14.121)]. CONCLUSION: Fifteen percent of patients with falciparum malaria admitted to our hospital had neurological symptoms and neurological involvement was associated with increased mortality. PMID- 20970921 TI - Accumulation and tolerance characteristics of chromium in a cordgrass Cr hyperaccumulator, Spartina argentinensis. AB - The cordgrass Spartina argentinensis, which occurs in inland marshes of the Chaco Pampean regions of Argentina, has been found to be a new chromium hyperaccumulator. A glasshouse experiment was designed to investigate the effect of Cr(6+) from 0 to 20 mmol l(-1) on growth and photosynthetic apparatus of S. argentinensis by measuring chlorophyll fluorescence parameters, gas exchange and photosynthetic pigment concentrations. Boron, calcium, chromium, copper, iron, manganese, magnesium, potassium and phosphorous concentrations were also determined. S. argentinensis showed phytotoxicity at tiller concentration of 4 mg g(-1) Cr, and symptoms of stress at tiller concentration of 1.5 mg g(-1) Cr, as well as reductions in leaf gas exchange, in chlorophyll a fluorescence parameters, in photosynthetic pigment contents and in the uptake of essential nutrients. Reductions in net photosynthetic rate could be accounted for by non stomatal limitations. Moreover, the bioaccumulator factors exceeded greatly the critical value (1.0) for all Cr treatments, and the transport factors indicated that this species has a higher ability to transfer Cr from roots to tillers at higher Cr concentrations. These results confirmed that S. argentinensis is a chromium hyperaccumulator and that it may be useful for restoring Cr-contaminated sites. PMID- 20970922 TI - Optimization of polyhydroxybutyrate (PHB) production by excess activated sludge and microbial community analysis. AB - In this study, a high value-added and biodegradable thermoplastic, polyhydroxybutyrate (PHB), was produced by excess activated sludge. The effects of the nutritional condition, aeration mode, sodium acetate concentration and initial pH value on PHB accumulation in the activated sludge were investigated. The maximum PHB content and PHB yield of 67.0% (dry cell weight) and 0.740gCODgCOD(-1) (COD: chemical oxygen demand), respectively, were attained by the sludge in the presence of 6.0gL(-1) sodium acetate, with an initial pH value of 7.0 and intermittent aeration. The analysis of the polymerase chain reaction (PCR)-denaturing gradient-gel-electrophoresis (DGGE) sequencing indicated that the microbial community of the sludge was significantly different during the process of PHB accumulation. Three PHB-accumulating microorganisms, which were affiliated with the Thauera, Dechloromonas and Competibacter lineages, were found in the excess activated sludge under different operating conditions for PHB accumulation. PMID- 20970923 TI - Performance and model of a full-scale up-flow anaerobic sludge blanket (UASB) to treat the pharmaceutical wastewater containing 6-APA and amoxicillin. AB - A full-scale test was conducted with an up-flow anaerobic sludge blanket (UASB) pre-treating pharmaceutical wastewater containing 6-aminopenicillanic acid (6 APA) and amoxicillin. The aim of the study is to investigate the performance of UASB in the condition of a high chemical oxygen demand (COD) loading rate from 12.57 to 21.02 kgm(-3)d(-1) and a wide pH from 5.57 to 8.26, in order to provide a reference for treating the similar chemical synthetic pharmaceutical wastewater containing 6-APA and amoxicillin. The results demonstrated that the UASB average percentage reduction in COD, 6-APA and amoxicillin were 52.2%, 26.3% and 21.6%, respectively. In addition, three models, built on the back propagation neural network (BPNN) theory and linear regression techniques were developed for the simulation of the UASB system performance in the biodegradation of pharmaceutical wastewater containing 6-APA and amoxicillin. The average error of COD, 6-APA and amoxicillin were -0.63%, 2.19% and 5.40%, respectively. The results indicated that these models built on the BPNN theory were well-fitted to the detected data, and were able to simulate and predict the removal of COD, 6-APA and amoxicillin by UASB. PMID- 20970924 TI - Application of grass char for Cd(II) treatment in column leaching test. AB - Various adsorbents as well as toxicants have been investigated regarding the adsorption behaviors and mechanisms. However, most of these reports were based on batch test. The discrepancy in adsorption behaviors between batch test and column test has been recognized recently. This study was to investigate the sorption behavior of Cd(II) in a novel adsorbent made from Reed char. Batch adsorption test and column leaching test were both conducted. Various influence factors including confining pressure, pH, velocity, concentration and ionic strength were studied. The velocity was found to have negligible effect on the breakthrough of Cd(II). The adsorption affinity was observed for the first time to decrease from a high value (R(d) = 130.00) to a negligible one (R(d) = 1.20) with increasing confining pressure from 0 to 100.00 kPa. The breakthrough of acid Cd(II) solution was earlier for solutions with less pH and higher ionic strength. The Cd(II) laden adsorbent was reclaimed by flushing chelants through the column. The recycled adsorbent appeared to be applicable in the following adsorption treatment. Suggestions were provided regarding the potential engineering applications. PMID- 20970925 TI - Co-administration of delta- and MU-opioid receptor agonists promotes peripheral opioid receptor function. AB - Enhancement of peripheral opioid analgesia following tissue injury or inflammation in animal models is well-documented, but clinical results of peripheral opioid therapy remain inconsistent. Previous studies in the central nervous system have shown that co-administration of MU- and delta-opioid receptor agonists can enhance analgesic outcomes; however, less is known about the functional consequences of opioid receptor interactions in the periphery. The present study examines the effects of intraplantar injection of the MU- and delta opioid receptor agonists, morphine and deltorphin, alone and in combination on behavioral tests of nociception in naive rats and on potassium-evoked release of CGRP from sciatic nerves of naive rats. Neither drug alone affected nociceptive behaviors or CGRP release. Two separate measures of mechanical nociceptive sensitivity remained unchanged after co-administration of the two drugs. In contrast, when deltorphin was co-injected with morphine, dose-dependent and peripherally restricted increases in paw withdrawal latencies to radiant heat were observed. Similarly, concentration-dependent inhibition of CGRP release was observed when deltorphin and morphine were administered in sequence prior to potassium stimulation. However, no inhibition was observed when morphine was administered prior to deltorphin. All combined opioid effects were blocked by co application of antagonists. Deltorphin exposure also enhanced the in vivo and in vitro effects of another MU-opioid receptor agonist, DAMGO. Together, these results suggest that under normal conditions, delta-opioid receptor agonists enhance the effect of MU-opioid receptor agonists in the periphery, and local co administration of delta- and MU-opioid receptor agonists may improve results of peripheral opioid therapy for the treatment of pain. PMID- 20970926 TI - The psychological impact of heavy drinking among the elderly on their co residents: the 10/66 group population based survey in the Dominican Republic. AB - BACKGROUND: There is very limited literature on alcohol use among the elderly and little is known about the impact it has on family and caregivers, especially in low and middle income countries. AIM: To estimate the independent effect of heavy alcohol use among the elderly on the psychological health of their co-residents. METHODS: This is a secondary analysis using data from the comprehensive cross sectional survey of the 10/66 dementia research group population-based research programme in the Dominican Republic. The characteristics of the elderly participants as well as the co-residents were described. The independent association of heavy drinking among the participants with psychological morbidity in their co-residents was estimated. Different models were generated to rule out potential mediating effects of disability and behavioural symptoms. RESULTS: Prevalence of heavy alcohol use in the elderly in Dominican Republic was 10.6%. There was a statistically significant independent effect of heavy alcohol use by the elderly on their co-residents mental health (PR=1.47; 95% CI 1.07-2.01) which was not accounted by disability (Sobel-Goodman test, p=0.15). Severity of psychological and behavioural symptoms partially (29.1% of the total effect) explained this association (Sobel-Goodman mediation test, p=0.006). CONCLUSIONS: Health services for the elderly in low and middle income countries will have to be configured around detection of alcohol problems among the elderly as well as offering appropriate support to their co-residents. PMID- 20970928 TI - Geotrichum candidum as etiological agent of horse dermatomycosis. AB - Fungi of the genus Geotrichum are commonly found in the environment and, in some circumstances, they may cause diseases in humans and animals. Although these fungi have been isolated from skin lesions of some animal species, their pathogenic role in horses remains uncertain. With the aim to investigate the role of Geotrichum candidum as etiological agent of dermatomycoses, a retrospective study of 64 horses presenting skin lesions and suspected to have fungal infections was carried out. For each animal, anamnestic data were recorded and fungal culture were performed using hair. Out of 64 cases, 18 (28.1%) were positive for G. candidum and only two (3.1%) for dermatophytes (i.e., one for Microsporum equinum and the other for Microsporum canis). Alopecia, desquamation, and pruritus localized mainly on head and neck were frequently observed in G. candidum infected animals. Most of G. candidum infections were recorded during spring (44.4%). Out of the 18 animals presenting G. candidum infections, eight were treated using a disinfectant with antifungal properties. After one month of treatment, the clinical lesions were healed and fungal cultures resulted negative. The high prevalence of G. candidum in skin lesions of horses and the clinical recover following antifungal treatment indicated that these yeast-like fungi might play a role as etiological agents of horse cutaneous mycoses. PMID- 20970927 TI - Psychosocial treatments for cocaine dependence: the role of depressive symptoms. AB - BACKGROUND: The association between cocaine use and depression has been frequently observed. However, less is known about the significance of depression in the treatment of cocaine use disorders. This study examined possible interrelations between drug use and depression severity among cocaine-dependent patients in psychosocial treatments for cocaine dependence. METHODS: Monthly assessed drug use and depression severity scores of N = 487 patients during 6 month psychosocial treatments for cocaine dependence were analyzed using hybrid latent growth models. RESULTS: Results indicated a moderate but statistically significant (z = 3.13, p < .01) influence of depression severity on increased drug use in the upcoming month, whereas drug use did not affect future depression severity. CONCLUSIONS: Findings suggest that depression symptoms are an important predictor of drug use outcomes during psychosocial treatments for cocaine dependence and, hence, underline the importance of adequately addressing depression symptoms to improve treatment outcomes. PMID- 20970929 TI - Host-dependent differential expression of factor H binding proteins, their affinity to factor H and complement evasion by Lyme and relapsing fever borreliae. AB - Binding of complement factor H is crucial for the resistance of Borrelia to complement-mediated lysis. This study was aimed to assess the correlation between the expression of fH binding proteins (FHBPs) during the early phase of infection (48 h after the entry of Borrelia into the blood circulation) and complement resistance of the Borrelia genus. As expected, B. afzelii, B. burgdorferi sensu stricto and B. garinii (Serotype 4, PBi) showed resistance to complement mediated lysis when incubated with human and dog complement, which coincided with the significantly higher expression (P<0.05) of the FHBPs. Similarly, B. coriaceae showed resistance to cattle complement. In non-reservoir hosts borreliae failed to induce expression of FHBPs within 48 h of complement challenge, and did not survive. It is important to note that not only the expression of FHBP but also their binding to fH is required for borrelial resistance to the complement. fH binding may depend on the coiled-coil (CC) motifs observed in the FHBPs, especially at the C terminus. A loss of the C-terminal CC motif in BgCRASP-1 of SKT-1 strain was found in in-silico CC prediction, and may be coupled with SKT 1's inability to bind factor H and evade complement-mediated attack. In contrast, the C-terminal CC motif was observed (P - 1.0) in BgCRASP-1 of PBi that may contributed to its factor H binding and human complement resistance. PMID- 20970930 TI - Isolation and characterization of a reovirus causing spleen necrosis in Pekin ducklings. AB - High rates of mortality for Pekin ducklings have been recorded in several duck farms in China since 2006. Dead ducklings were characterized by spleen necrosis, suggesting microbial infection as a cause of disease. Laboratory investigations led to the isolation of a virus strain from the spleen tissues of dead ducklings, designated DRV-HC. Subsequent experimental infections with DRV-HC resulted in marked spleen necrosis in the ducklings similar to those observed in the natural outbreaks. Electron microscopy of the cultured DRV-HC revealed viral particles that were non-enveloped and icosahedral with a mean diameter of approximately 72 nm. Agar gel precipitating tests showed that the isolate shared a common group specific antigen with chicken reovirus S1133. DNA sequencing revealed that this isolate was closely related to Muscovy duck reoviruses. Experimental infection with DRV-HC resulted in death of young chicks with necrotic foci in the liver and spleen. To the best of our knowledge, this is the first report of the isolation of a duck reovirus with high virulence in Pekin ducklings and SPF chickens. PMID- 20970931 TI - Transcriptional profiling of Toll-like receptors in chicken embryos and in the ovary during sexual maturation and in response to Salmonella enteritidis infection. AB - One of the key members of the innate immune system in many vertebrate species is the family of Toll-like receptors (TLRs). These molecules, which initiate the innate immune response and mount an anti-microbial response in both vertebrates and invertebrates, have recently been identified in the chicken genome. The recent findings of chicken TLRs (cTLRs) expression in ovarian follicles during follicular growth and in response to lipopolysaccharide (LPS) infection are very important for reproductive physiology due to the transovarian transmission of Salmonella enteritidis (SE) in laying hens. The aim of this study was to investigate the expression of the ten cTLRs identified to date, in the chicken ovary in vivo and embryos during early embryonic development, to investigate whether sexual maturation affects their ovarian mRNA abundance and to investigate the transcriptional changes of TLRs in the chicken ovary in response to SE infection. RNA was extracted from embryos from day 3 to day 10 of embryonic development as well as from the ovaries of healthy prepubertal, sexually mature and aged birds, and from sexually mature and aged SE infected birds. RT-PCR analysis revealed that all TLRs apart from TLRs 1-1 and 2-2 were expressed in the ovary of sexually mature chickens, while all TLRs apart from TLR1-1 were expressed in the chicken embryos during embryonic development. Quantitative real time PCR analysis revealed that the ovarian mRNA abundance of TLRs differ with respect to sexual maturation. SE infection resulted in a significant induction of TLR4, and 15 in the ovary of sexual mature birds, and in a significant induction of TLR15 in the ovary of aged birds, while a significant down-regulation was observed for TLR3 in the ovary of aged birds. These findings suggest that a TLR mediated immune response mechanism exists in the chicken ovary. PMID- 20970932 TI - Herbal product use by older adults. AB - In the past two decades, there has been an exponential increase in the use of medicinal herbal products around the world. In various countries, these products are classified and promoted as foods, not pharmaceuticals, which facilitate their availability on the international market without requiring a medical prescription. Since older adults (OAs) are an important and growing sector of the population in many countries, it is important to know the prevalence of their herbal product use, since many OA take herbs along with diverse quantities of prescription and over the counter medications. For this reason, it is important to be aware of the possibilities of health complications due to the concomitant use of diverse medications and herbs. OA are an especially vulnerable population, since many of the human body's physiological activities, such as renal and hepatic detoxification and clearance usually decrease with age. Additionally, information on certain herbal products is either misleading, or simply unavailable. These products may indeed be a therapeutic option, but some can be used properly only under the guidance of a health professional. Those OA taking combinations of various medications and herbal supplements are also more at risk to experience some sort of herb-drug interactions. This publication reviews selected articles related to the use of herbal products by OAs and mentions the various patterns of use and health implications of the concomitant use of herbal products and prescription medications. This topic is currently not fully understood and further research is warranted. PMID- 20970933 TI - Comments on "Gamma-hydroxybutyrate in urine and serum: additional data supporting current cut-off recommendations". PMID- 20970934 TI - Prognostic significance of tumor volume in nasopharyngeal carcinoma. AB - OBJECTIVE: To investigate the prognostic significance of primary and residual tumor volume in nasopharyngeal carcinoma. METHODS: 56 patients were included in the study. Diameters of tumors were measured from CT and MR film hardcopies. Diameter-based measurements were computed as an ellipsoid (V=4/3.pi.d1.d2.d3) to calculate diameter-based volume. It was investigated whether primary tumor volume provided prognostic information about local regional recurrence free survival (LRRFS), disease free survival (DFS), distant metastasis free survival (DMFS) and overall survival (OS) by monovariant and multivariant analysis. Kaplan-Meier survival analysis method and log-rank test were used to estimate survival analysis (95% confidence interval). Cox regression test was used for two variant and multivariant survival analysis. Statistical Package for Social Sciences (SSSP) 10.0 for Windows programme was used for data analysis. RESULTS: In the multivariate analysis, in the patients with tumor volume more than 60ml, local regional recurrence more frequently developed. The relationship between tumor volume and local regional recurrence was found significant (p=0.053). In the monovariate analysis, primary tumor volume was found to be a significant predictive value on DFS and DMFS. In the patients with tumor volume below 20ml, DFS was 60%, whereas in the patients with tumor volume above 60ml, DFS was 0% (p=0.007). The prevalence were 68% and 0% in the patients group that had tumor volume below 30ml and above 60ml respectively. DMSF ratios in the patients with primary tumor volume below 20ml and above 60ml were 86.67% and 33.3% respectively. The residual tumor volume (RTV) at first control after treatment was found to be a significant prognostic factor on LRRFS (p=0.03). CONCLUSION: The foundation of new T staging systems that consists of PTV that was found as an independent prognostic factor alone in multivariate statistical analysis may precede better prediction of prognosis and more appropriate treatment of patients having different prognostic factors. RTV in the first control after treatment was a significant prognostic factor on LRRFS. PMID- 20970935 TI - Lesions in the central tegmental tract in autopsy cases of developmental brain disorders. AB - We retrospectively analyzed central tegmental tract (CTT) lesions in 120 consecutive autopsy cases of developmental brain disorders to investigate the significance of symmetrical CTT lesions. Magnetic resonance imaging (MRI) findings of CTT lesions have been sporadically reported in various cases of child neurological diseases. In this study, symmetrical CTT lesions were observed in 25 (20.8%) among 120 cases of developmental brain disorders. These 25 cases were classified into three groups (groups I-III) in decreasing order of the severity of the lesion. Compared to five cases of group I in which CTT lesions were accompanied by diffuse tegmental damage, 20 cases of groups II or III developed relatively selective CTT lesions in which the medial longitudinal fasciculus and/or medial or lateral lemniscus were preserved. The causes of brain disorders in all three groups seemed to be different, and lysosomal disorders and congenital brain anomalies were frequently seen in cases in groups II and III, respectively. The dentato-rubro-olivary system is known to be involved in palatal myoclonus, and five out of 13 cases in group II showed myoclonic epilepsy. Compared with 95 cases without the CTT lesion, the changes in the pontine reticular formation were more closely associated with the CTT lesion than those in the inferior olivary nucleus. In conclusion, in cases of developmental brain disorders, the neuropathology of the symmetrical CTT lesion should be investigated. PMID- 20970936 TI - Somatic mosaicism for Y120X mutation in the MECP2 gene causes atypical Rett syndrome in a male. AB - Rett Syndrome (RS; MIM_312750) is a severe and progressive neurodevelopmental disorder affecting principally females. Mutations in X-Linked MECP2 gene (methyl CpG-binding protein 2; MIM_300005) have been reported as being the major cause of RS. Mutations in this gene have been described as cause of wide spectrum of neurological disorders and mental retardation in males. In some cases, mutations in MECP2 in males produce clinical picture similar to RS. Here we report the identification of the novel truncating mutation Y120X in a 4-year-old child with atypical RS phenotype. Chromosome analysis showed a normal karyotype, and blood DNA and tissue DNA analysis reveal a mosaic for the mutation. Patient's mother DNA analysis showed that this is a de novo mutation, that has never been described before in any female or male case of RS. PMID- 20970937 TI - Heterotopic pancreas: an unusual cause of epigastric pain. PMID- 20970938 TI - Postoperative FDG-PET/CT staging in GIST: is there a benefit following R0 resection? AB - AIM: Resection of the primary tumor with intraoperative staging is the standard procedure in patients with gastrointestinal stromal tumors (GIST). FDG-PET/CT has shown high accuracy when assessing treatment response in GIST patients. This study was designed to assess the accuracy of postoperative FDG-PET/CT to stage for occult tumor seeding in patients with R0 resection and without intraoperative detection of metastases. PATIENTS AND METHODS: 48 consecutive patients (mean age: 59 y) with histologically proven GIST underwent whole-body FDG-PET/CT after R0 resection without intraoperative detection of metastases. Fused data sets were assessed for metastases by a nuclear medicine physician and a radiologist. Histology of potential lesions and a clinical/radiological follow-up with a mean of 614+/-415 d served as standards of reference. RESULTS: FDG-PET/CT detected occult peritoneal metastases in 2 patients (4%). In 6 patients (13%) who later developed metastases postoperative FDG-PET/CT was falsely negative. False positive findings were detected in 5 cases (10%) caused by increased FDG-uptake due to tissue regeneration postoperatively. In 3 patients (6%) other, formerly unknown malignancies were detected. The sensitivity and specificity of FDG-PET/CT for the detection of intraoperatively occult GIST metastases were 25% and 88%, respectively. CONCLUSION: FDG-PET/CT performed immediately after R0-resection of GIST without intraoperative detection of metastases does not seem to be a sufficient tool to detect clinically occult metastases. PMID- 20970939 TI - Inverse-direction scanning improves the image quality of whole carotid CT angiography with 64-MDCT. AB - PURPOSE: The purpose of this prospective study was to clarify whether reducing the incidence of perivenous artifacts through craniocaudal scanning improves the quality of 64-multidetecter computed tomography (MDCT) angiography images of the whole carotid artery. METHODS: Forty patients underwent MDCT angiography in the caudocranial (n=20) or craniocaudal (n=20) direction in 2007. All patients were injected with 75 ml of contrast media followed by a 35-ml saline chaser bolus at 4.0 ml/s in the right antecubital vein. Maximum intensity projection (MIP) images were scored according to image quality on a scale of 1-5. Bilateral arterial and venous attenuation was measured on 10 separated slices. We compared the mean image quality score of the two groups (i.e. those scanned caudocranially and those scanned craniocaudally). We analyzed the correlation between vascular attenuation and mean image quality. RESULTS: Compared with the caudocranial group, the craniocaudal group had higher image quality scores (median, 3.70 vs. 3.40; 95% CI, 3.50-3.96 vs. 3.06-3.60; p<0.05), higher arterial attenuation (median, 550 HU vs. 489 HU; range, 270-686 vs. 302-574; p<0.05), and lower maximum venous attenuation (median, 436 vs. 1452 HU; range, 250-617 vs. 377-2044; p<0.01). Multiple regression analysis revealed that the most significant correlation factor with image quality was minimum arterial attenuation (R2=0.42, p<0.001) measured near the brachiocephalic artery. In the caudocranial group only, there was a negative correlation between right brachiocephalic venous attenuation and minimum arterial attenuation. CONCLUSIONS: Compared with conventional caudocranial scanning, craniocaudal scanning improves the image quality of 64-MDCT angiography images of the whole carotid artery. PMID- 20970940 TI - Triphasic contrast injection improves evaluation of dual energy lung perfusion in pulmonary CT angiography. AB - PURPOSE: Lung perfusion analysis at dual energy CT (DECT) is sensitive to beam hardening artifacts from dense contrast material (CM). We compared two scan and four CM injection protocols in terms of severity of artifacts and attenuation levels in the thoracic vessels. METHODS AND MATERIALS: Data of 120 patients who had undergone dual source dual energy CT pulmonary angiography for suspected acute pulmonary embolism were evaluated. Group 1 (n=30) was scanned in craniocaudal direction using 64*0.6 mm collimation; groups 2-4 (n=30 each) were scanned in caudocranial direction using 14*1.2 mm collimation. In groups 1-3 biphasic injection protocols with different amounts of CM and NaCl were investigated. In group 4 a split-bolus protocol with an initial CM bolus of 50 ml followed by 30 ml of a 70%:30% NaCl/CM mixture and a 50 ml NaCl chaser bolus was used. CT density values in the subclavian vein (SV), superior vena cava (SVC), pulmonary artery tree (PA), and the descending aorta (DA) were measured. Artifacts arising from the SV and SVC on DE pulmonary iodine distribution map were rated on a scale from 1 to 5 (1=fully diagnostic; 5=non-diagnostic) by two blinded readers. RESULTS: In protocol 4 mean attenuation in the SV (645+/-158 HU) and SVC (389+/-114 HU) were significantly lower compared to groups 1-3 (p<0.002). Artifacts in group 4 (1.1+/-0.4 and 1.5+/-0.7 for the SV and SVC, respectively) were rated significantly less severe compared to group 1 (3.2+/-1.0 and 3.0+/ 1.1), 2 (2.6+/-1.1 and 2.3+/-1.0) and 3 (1.9+/-0.9 and 1.9+/-0.7) (p<0.01 for all), whereas no significant difference was found between groups 1 and 2 for the subclavian vein (p=0.07). Attenuation in the PA was also significantly lower in group 4 (282+/-116 HU) compared to group 1 (397+/-137 HU), group 2 (376+/-115 HU) and group 3 (311+/-104 HU), but still on a diagnostic level. CONCLUSION: Split bolus injection provides sufficient attenuation for pulmonary DECT angiography while beam hardening artifacts arising from high density contrast material in the thoracic vessels can be reduced significantly. PMID- 20970941 TI - Species distribution of staphylococci from small wild mammals. AB - A total of 197 isolates of Staphylococcus from small wild animals (insectivores and rodents) were identified by partial sequencing of the rpoB and dnaJ genes. Among the identified isolates the predominant species was S. succinus (28%), followed by S. xylosus (20.8%) and S. stepanovicii (18.3%). The other 14 Staphylococcus species were occasionally isolated. PCR-RFLP of the rpoB gene digested by Hpy8I was a fast and simple method to distinguish the two subspecies of S. succinus. More than 90% of the 55 S. succinus strains isolated belonged to S. succinus subsp. casei and only 9% to S. succinus subsp. succinus. Moreover, the present study describes the first ever isolation of S. fleurettii from healthy animals. PMID- 20970942 TI - Investigation of catechol 2,3-dioxygenase and 16S rRNA gene diversity in hypoxic, petroleum hydrocarbon contaminated groundwater. AB - Detection of catechol 2,3-dioxygenase genes in aromatic hydrocarbon contaminated environments gives the opportunity to measure the diversity of bacteria involved in the degradation of the contaminants under aerobic conditions. In this study, we investigated the diversity and distribution of Comamonadaceae family (Betaproteobacteria) related catechol 2,3-dioxygenase genes, which belong to the I.2.C subfamily of extradiol dioxygenase genes. These catabolic genes encode enzymes supposed to function under hypoxic conditions as well, and may play a notable role in BTEX degradation in oxygen limited environments. Therefore, their diversity was analyzed in oxygen limited, petroleum hydrocarbon contaminated groundwater by terminal restriction fragment length polymorphism and cloning. Subfamily I.2.C related catechol 2,3-dioxygenase genes were detected in every investigated groundwater sample and a dynamic change was observed in the case of the structure of C23O gene possessing bacterial communities. To link the metabolic capability to the microbial structure, 16S rRNA gene-based clone libraries were generated and it was concluded that Betaproteobacteria were abundant in the bacterial communities of the contaminated samples. These results support the opinion that Betaproteobacteria may play a significant role in BTEX degradation under hypoxic conditions. PMID- 20970944 TI - Perfluorocarboxylic acids in cell growth media and technologically treated waters: determination with GC and GC-MS. AB - The present paper reports on an analytical method for the routine analysis of perfluorinated carboxylic acids (PFCAs). A rapid method for the derivatization, extraction and determination of PFCAs was developed. Technological samples were extracted with ethyl acetate and the anilides obtained were determined by gas chromatography-mass spectrometry (GC-MS) and gas chromatography with flame ionization detector (GC-FID). Residue levels in cell growth incubation media were determined by GC-FID. Confirmation analysis of PFCAs was carried out by GC-MS in selected ion monitoring (SIM) and total ion current (TIC) modes. The compounds were identified on the basis of retention time and comparison of primary and secondary ions. The results showed that this method provided a simple, rapid and sensitive way of analyzing PFCAs in different matrices. PMID- 20970943 TI - Preparation of penta-O-galloyl-beta-D-glucose from tannic acid and plasma pharmacokinetic analyses by liquid-liquid extraction and reverse-phase HPLC. AB - The gallotannin penta-O-galloyl-beta-D-glucose (PGG) has many biological activities including in vivo anti-cancer efficacy. We present in this paper a scaled-up protocol for its preparation in high purity from tannic acid by acidic methanolysis with typical yield of 15%. We also describe a method for the analysis of PGG in mouse plasma by HPLC and its application in preliminary pharmacokinetic studies. A liquid-liquid extraction (LLE) protocol was optimized for the extraction of PGG from mouse plasma. The extraction efficiency for PGG at 1 MUg/mL in mouse plasma was 70.0+/-1.3% (n=5). The limit of detection (LOD) for PGG was approximately 0.2 MUg/mL. Preliminary pharmacokinetic parameters of PGG following a single i.p. injection with 5% ethanol/saline vehicle in mice were established. The peak plasma PGG concentrations (C(max)) were approximately 3-4 MUM at a dose of 0.5 mg per mouse (~20 mg/kg) at 2 h post-injection (T(max)). PMID- 20970946 TI - Feasibility and preliminary outcomes of a school-based intervention for inner city, ethnic minority adolescents with undiagnosed asthma. AB - OBJECTIVE: To describe and test the feasibility of asthma self-management for adolescents with undiagnosed asthma (ASMA-Undx), an 8-week school-based intervention for urban adolescents comprised of three group and five individual coaching sessions, and academic detailing for their primary care providers (PCPs). METHODS: Thirty high school students (mean age 15.9; 92% female; 72% Latino/a) who reported symptoms of persistent asthma, but no diagnosis were randomized to ASMA-Undx or a no-treatment control group. Interviews were conducted pre- and post-intervention. RESULTS: All intervention students participated in the three group sessions; 64% received all five individual coaching sessions. Academic detailing telephone calls made by a pediatric pulmonologist reached 83% of the students' PCPs. Relative to controls, a significantly greater proportion of ASMA-Undx students were diagnosed (79% versus 6%, respectively), and prescribed asthma medication (57% versus 6%, respectively). Barriers to diagnosis and treatment included students' and parents' lack of knowledge about asthma. CONCLUSION: ASMA-Undx is a feasible and promising intervention to assist urban adolescents with undiagnosed asthma obtain a diagnosis and treatment. PRACTICE IMPLICATIONS: ASMA-Undx has the potential to reach many adolescents because it is school-based. It can serve as a model for interventions targeting other pediatric illnesses. PMID- 20970947 TI - Radiographic healing with hemispherical allogeneic femoral head bone grafting for opening-wedge high tibial osteotomy. AB - PURPOSE: The aim of this study was to investigate the remodeling process after hemispherical femoral head allograft grafting in opening-wedge high tibial osteotomy with a plate and screw. METHODS: The study group included 105 knees in 92 women and 7 knees in 7 men from January 2007 through December 2007. The radiographic bone remodeling process was determined by use of a modification of the radiologic rating system described previously by van Hemert et al. in 4 groups: group A, 7-mm plate correction; group B, 9-mm plate correction; group C, 11-mm plate correction; and group D, 13-mm plate correction. RESULTS: The postoperative femorotibial angle and tibial slope were not significantly changed at latest follow-up in comparison to immediate postoperative status. The mean follow-up period was 25.4 months (range, 18 to 30 months). In all groups radiologic bone healing higher than phase 3 was successfully achieved between 3 and 6 months. The healing process slowed with increasing correction angle. CONCLUSIONS: A hemispherical femoral head allograft is a good alternative osseous graft material when patients are selected appropriately with the following criteria: body mass index lower than 40, no symptomatic osteoarthritis of the patellofemoral joint and lateral compartment, no systemic inflammatory arthritis, no history of fracture or previous open surgery to the lower limb, and no flexion contracture. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 20970948 TI - The ability of 3 different approaches to restore the anatomic anteromedial bundle femoral insertion site during anatomic anterior cruciate ligament reconstruction. AB - PURPOSE: The purpose of this study was to determine whether drilling the femoral tunnel when performing anterior cruciate ligament (ACL) reconstruction through the accessory medial portal, as opposed to drilling the tunnel transtibially, will lead to more frequent location of the anteromedial femoral tunnel within the anatomic anteromedial bundle insertion site. METHODS: Primary anatomic double bundle reconstruction was performed on 113 patients. Intraoperatively, we placed a guide pin through the anteromedial and posterolateral tibial tunnels and accessory medial portal, attempting to reach the center of the native femoral anteromedial bundle insertion. For each approach, the position of the guide pin was classified as (1) within the center of, (2) off-center within, or (3) outside of the femoral anteromedial insertion. RESULTS: There were significant differences in the ability of each approach to reach the center of the femoral anteromedial bundle insertion. Through the tibial anteromedial tunnel, the femoral anteromedial insertion center was reached in 4.4% of cases, whereas it was off-center within and outside of the femoral anteromedial insertion in 23.0% and 72.6%, respectively. Through the tibial posterolateral tunnel, the femoral anteromedial insertion center was reached in 60.2% of cases, whereas it was off center within and outside of the femoral anteromedial insertion in 23.9% and 15.9% of cases, respectively. When approached from the accessory medial portal, the center of the femoral anteromedial insertion was reached in 100% of the cases. Ultimately, the femoral anteromedial tunnel was drilled through the tibial anteromedial tunnel in 0.9%, through the posterolateral tunnel in 62.8%, and through the accessory medial portal in 36.3% of cases. CONCLUSIONS: Drilling the femoral tunnel for the anteromedial graft through the accessory medial portal, as opposed to drilling the tunnel transtibially, leads to more frequent location of the anteromedial femoral tunnel within the anterior cruciate ligament anteromedial bundle anatomic footprint. PMID- 20970949 TI - Correlation of magnetic resonance imaging to arthroscopic findings of stability in juvenile osteochondritis dissecans. AB - PURPOSE: To determine the ability of magnetic resonance imaging (MRI) to characterize the stability of osteochondritis dissecans (OCD) fragments in juveniles. METHODS: Twenty-eight consecutive patients underwent surgery for OCD between 2004 and 2008. Of these, 23 patients had adequate preoperative imaging. There were 14 boys and 9 girls with a mean age of 12.9 years. Of the 23 lesions, 21 were located in the knee and 2 were located in the talus. On the basis of MRI, a single radiologist (1) indicated the presence or absence of 4 established magnetic resonance signs of instability, (2) classified each lesion according to a staging system for OCD stability, and (3) described the lesion as stable or unstable. These findings were compared with the arthroscopic findings. Arthroscopy was considered the gold standard for diagnosing fragment stability. RESULTS: Of the OCD lesions, 13 were found to be stable and 10 were found to be unstable. The final MRI impression was unstable in 21 patients and stable in 2 patients. This yielded a sensitivity of 100% and a specificity of 15% for diagnosing fragment instability. When 2 or more criteria were present, the specificity of MRI to classify lesion instability improved to 92%. The sensitivity, however, dropped to 50%. Concordance between arthroscopic stage and MRI stage was 30% (7 of 23). CONCLUSIONS: MRI predicted 21 of 23 lesions to be unstable, whereas arthroscopy found only 10 of these 23 lesions to be unstable. The most common pattern of false-positive findings involved lesions with an area of high signal intensity at the bone-fragment interface. MRI should not be used in isolation to determine lesion instability in young patients with juvenile OCD. PMID- 20970950 TI - Pharmacokinetic analysis of in vivo disposition of heparin-superoxide dismutase. AB - To improve the half-life and tissue targeting of SOD to suppress reactive oxygen species (ROS)-mediated injury, chemically modified derivative of superoxide dismutase (SOD) with heparin, anionized SOD (Hep-SOD), was designed. In this study, the pharmacokinetics of Hep-SOD had been studied. This study aimed to investigate the pharmacokinetics, tissue distribution and cell targeting. 125I radiolabeled Hep-SOD conjugate was administered to healthy mice by intravenous (i.v.) bolus injection. Compared with native SOD, the half-life of Hep-SOD conjugate, including t(1/2alpha) and of t(1/2beta), was lengthen and area under the plasma concentration versus time curve (AUC) of Hep-SOD was increased. The study showed that both native SOD and Hep-SOD was rapidly and widely distributed in the livers, kidneys, spleens, hearts and lungs. Furthermore, compared with Hep SOD, radioactivity of native SOD decreased more sharply over time in most tissues. Compared with native SOD, higher amount of Hep-SOD radioactivity was found in the livers. Since livers are not the known target of 125I, the most possible reason is that Hep-SOD binds to its specific targets in the livers. PMID- 20970951 TI - The angiotensin receptor blocker, telmisartan, reduces and stabilizes atherosclerosis in ApoE and AT1aR double deficient mice. AB - The renin-angiotensin system (RAS) plays critical roles in the pathogenesis of atherosclerosis. Clinical studies demonstrate that pharmacological blockade of RAS with Angiotensin II type 1 receptor (AT1R) blockers (ARBs) is effective in the treatment of patients with cardiovascular diseases. Recent studies reported that telmisartan, an ARB, has a partial agonistic effect on peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The role of PPAR-gamma mediated signaling has been implicated in regulation of not only metabolic disorders but also atherosclerosis. Here, we investigated the effects of telmisartan, which is not related to AT1R blockade, using AT1aR and apolipoprotein E (ApoE) double-deficient (ApoE-/-AT1R-/-) mice in vivo. Both genetic ablation of AT1R in ApoE-deficient (ApoE-/-) mice and administration of telmisartan (10 mg/kg/day) to ApoE-/- mice for 20 weeks reduced the development of atherosclerosis (P<0.05, respectively). Telmisartan decreased lipid deposition (P<0.01) and increased collagen contents (P<0.05) in plaques in ApoE-/- mice. Administration of telmisartan to ApoE-/-AT1aR-/- mice also inhibited the progression of atherosclerosis in aorta (P<0.05) even in mice, which have no AT1aR genetically. Moreover, in these mice, telmisartan decreased macrophage accumulation and lipid deposition, and increased collagen contents in plaques in aortic root (P<0.05, respectively), indicating stabilization of plaques. Telmisartan-treated ApoE-/-AT1aR-/- mice showed lower body weight and higher plasma high-density lipoprotein levels compared with vehicle-treated mice (P<0.05, respectively). Telmisartan lowered systolic and diastolic blood pressure in ApoE-/-AT1aR-/- mice (P<0.01). These results suggest that telmisartan has protective effects on the development of atherosclerosis and metabolic disorders beyond AT1R blockade in ApoE-deficient mice. PMID- 20970952 TI - Pharmacologic concentrations of melatonin have diverse influence on differential expressions of angiogenic chemokine genes in different hepatocellular carcinoma cell lines. AB - This study was to investigate whether melatonin (MLT) at pharmacologic concentrations (1 and 100 MUM) had potential to influence the expressions of angiogenic (CCL2, CXCL6, IL8) and angiostatic (CXCL10) chemokine genes in two hepatocellular carcinoma (HCC) cell lines with different characteristics (cell line A, HCC24/KMUH, without susceptible to amphotericin B (AmB)-induced oxidative stress; cell line B, HCC38/KMUH, susceptible to AmB-induced oxidative stress). Differential expression of gene was investigated by quantitative reverse transcriptase-polymerase chain reaction. Two genes related to oxidative stress (SOD2, VNN3) were also studied. One and 100 MUM MLT up-regulated CCL2, IL8 and CXCL10 genes in cell line A but down-regulated CCL2, CXCL6, IL8 and SOD2 genes in cell line B. CXCL10 gene was up-regulated by 1 and 100 MUM MLT in both cell lines. SOD2 gene was down-regulated by 1 and 100 MUM MLT only in cell line B. The magnitudes of gene expression fold changes of CCL2 and IL8 genes in cell line A and CCL2, CXCL6, IL8 and SOD2 genes in cell line B were similar between 1 and 100 MUM MLT. The magnitudes of gene expression fold change of up-regulated CXCL10 gene in both cell lines were smaller in 100 MUM MLT than in 1 MUM MLT. In conclusion, the responses of angiogenic chemokine genes to MLT were mainly determined by the characteristics of cancer cells. The concentration of MLT may be the main determinant for the response of angiostatic CXCL10 gene to MLT. Clinical application of MLT in patients with HCC should consider these effects. PMID- 20970953 TI - Immunotherapy for pythiosis: Effect on NTPDase activity in lymphocytes of an experimental model. AB - NTPDase (EC 3.6.1.5) occurs in lymphocytes and plays an important role in immune function, in that hydrolyzes extracellular nucleoside tri- and/or diphosphates to form AMP. Pythium insidiosum causes the disease pythiosis, a pyogranulomatous disease of horses, dogs, cattle, cats and humans. Most antifungal drugs are ineffective against this pathogen, and immunotherapy, a treatment approach that relies on the injection of P. insidiosum antigen, has been successfully used in humans and horses to manage this disease. In this study, we investigated NTPDase activity in lymphocytes from rabbits inoculated with zoospores of P. insidiosum. After immunotherapy, we investigated the relationship between enzymatic activity and the pattern of the immune response. One milliliter of zoospores was inoculated subcutaneously into the coastal region of each rabbit. An average of 17,500 viable mobile zoospores/mL of induction medium was administered. Inoculated rabbits were checked weekly, and the subcutaneous nodular area (cm2) was measured 28 days after inoculation. Rabbits that developed lesions received four doses of immunotherapy at intervals of 14 days. Blood samples were collected by heart puncture twice a month for the determination of NTPDase activity. The results demonstrated that NTPDase activity in lymphocytes was increased in relation to ATP hydrolysis (by about 100%) in pythiosis and returned to normal values after immunotherapy. The data demonstrating NTPDase activity before and after immunotherapy reinforce the previously elaborated hypothesis that the change from a Th2 to a Th1 immune response is responsible for the curative properties of immunotherapy. PMID- 20970955 TI - [Why indoor tanning must be taxed? A proposal from La Securite Solaire, WHO collaborating centre]. PMID- 20970954 TI - Butyrate, an HDAC inhibitor, stimulates interplay between different posttranslational modifications of histone H3 and differently alters G1-specific cell cycle proteins in vascular smooth muscle cells. AB - HDACs and HATs regulate histone acetylation, an epigenetic modification that controls chromatin structure and through it, gene expression. Butyrate, a dietary HDAC inhibitor, inhibits VSMC proliferation, a crucial factor in atherogenesis, and the principle mechanism in arterial and in-stent restenosis. Here, the link between antiproliferation action of butyrate and the portraits of global covalent modifications of histone H3 that it induces are characterized to understand the mechanics of butyrate-arrested VSMC proliferation. Analysis of histone H3 modifications specific to butyrate arrested VSMC proliferation display induction of histone H3-Lysine9 acetylation, inhibition of histone H3-Serine10 phosphorylation, reduction of histone H3-Lysine9 dimethylation and stimulation of histone H3-Lysine4 di-methylation, which is linked to transcriptional activation, cell cycle/mitosis, transcriptional suppression and activation, respectively. Conversely, untreated VSMCs exhibit inhibition of H3-Lysine9 acetylation, induction of H3-Serine10 phosphorylation, stimulation of H3-Lysine9 di methylation and reduction in H3-Lysine4 di-methylation. Butyrate's cooperative effects on H3-Lysine9 acetylation and H3-Serine10 phosphorylation, and contrasting effects on di-methylation of H3-Lysine9 and H3-Lysine4 suggests that the interplay between these site-specific modifications cause distinct chromatin alterations that allow cyclin D1 and D3 induction, G1-specific cdk4, cdk6 and cdk2 downregulation, and upregulation of cdk inhibitors, p15INK4b and p21Cip1. Regardless of butyrate's effect on D-type cyclins, downregulation of G1-specific cdks and upregulation of cdk inhibitors by butyrate prevents cell cycle progression by failing to inactivate Rb. Overall, through chromatin remodeling, butyrate appears to differentially alter G1-specific cell cycle proteins to ensure proliferation arrest of VSMCs, a crucial cellular component of blood vessel wall. PMID- 20970956 TI - [Stewart-Treves syndrome (angiosarcoma on lyphoedema): A rare complication of lymphoedema]. AB - Stewart-Treves syndrome (SST) or former lymphangiosarcoma is a rare complication of chronic lymphoedema mainly related to the breast cancer (90% of cases). It occurs in 0.03% of patients surviving 10 or more years after radical mastectomy. The prognosis is very poor with a five-year survival close to 10% despite the various treatment modalities. The treatment of choice is a large resection, but some authors recommend radical resection in the form of shoulder disarticulation or forequarter amputation. Surgical treatment can be preceded or followed by radiation therapy. Locally advanced tumors or metastatic forms can be treated with mono or polychemotherapy, systemic or local. PMID- 20970957 TI - Early onset ageing and service preparation in people with intellectual disabilities: institutional managers' perspective. AB - Although longevity among older adults with intellectual disabilities is increasing, there is limited information on their premature aging related health characteristics and how it may change with increasing age. The present paper provides information of the institutional manager's perception on early onset aging and service preparation for this population. We used purposive sampling to recruit 54 institutional managers who care for people with intellectual disabilities in Taiwan. The present study employed a cross-sectional design using a self-administrative structured questionnaire that was completed by the respondents in November 2009. The results showed that more than 90% of the respondents agreed with earlier onset aging characteristics of people with ID. However, nearly all of the respondents expressed that the government policies were inadequate and the institution is not capable of caring for aging people with ID, and more than half of them did not satisfy to their provisional care for this group of people. With regard to the service priority of government aging policy for people with ID, the respondent expressed that medical care, financial support, daily living care were the main areas in the future policy development for them. The factors of institutional type, expressed adequacy of government's service, respondent's job position, age, and working years in disability service were variables that can significantly predict the positive perceptions toward future governmental aging services for people with ID (adjusted R(2) = 0.563). We suggest that the future study strategy should underpin the aging characteristics of people with intellectual disabilities and its differences with general population to provide the useful information for the institutional caregivers. PMID- 20970958 TI - How do object size and rigidity affect reaching and grasping in infants with Down syndrome? AB - Reaching and grasping skills have been described to emerge from a dynamic interaction between intrinsic and extrinsic factors. The purpose of the present study was to investigate the interaction between such an intrinsic factor, Down syndrome, and extrinsic factors, such as different object properties. Seven infants with Down syndrome and seven infants with typical development were assessed at the ages of 4, 5 and 6 months. The findings showed that object size influenced the kinematics of reaching for the infants with Down syndrome and the grasping frequency for the typical infants. The object rigidity was shown to have a major influence on grasping frequency. PMID- 20970959 TI - Effects of microbubbles and ultrasound on the microcirculation: observation on the hamster cheek pouch. AB - BACKGROUND: In view of the debate on the safety of using ultrasound associated with microbubbles, we investigated the microvascular effects in situations of potential clinical interest. METHODS: Ultrasound, microbubbles, and their association were evaluated on the cheek pouch microcirculation in 96 male hamsters (n = 6 in each group): control; ischemia-reperfusion, 30 minutes total ischemia followed by reperfusion; hyperinsulinemia and hyperglycemia (substitution of the drinking water by 10% fructose solution for 3 months); and endotoxic shock (induced by Escherichia coli lipopolysaccharide). The heart rate, mean arterial pressure, number of rolling and adhered leukocytes, and arteriolar and venular diameters were analyzed. RESULTS: Heart rate and mean arterial pressure were lower in the endotoxic shock group than in the control group. Ultrasound alone or associated with microbubbles decreased the number of rolling and adhered leukocytes in the ischemia-reperfusion and hyperinsulinemia and hyperglycemia groups and increased venular diameter in the ischemia-reperfusion group. CONCLUSION: The use of ultrasound decreases inflammation. Although it has not been established that pseudo-anaphylaxis can be assessed by intravital microscopy, microbubble administration does not increase venular leukocyte adhesion. PMID- 20970960 TI - Intravenous immunoglobulin induces proliferation and immunoglobulin synthesis from B cells of patients with common variable immunodeficiency: a mechanism underlying the beneficial effect of IVIg in primary immunodeficiencies. AB - Common variable immunodeficiency (CVID) is associated with low serum immunoglobulin concentrations and an increased susceptibility to infections and autoimmune diseases. The treatment of choice for CVID patients is replacement intravenous immunoglobulin (IVIg) therapy. IVIg has been beneficial in preventing or alleviating the severity of infections and autoimmune and inflammatory process in majority of CVID patients. Although the mechanisms of action of IVIg given as 'therapeutic high dose' in patients with autoimmune diseases are well studied, the underlying mechanisms of beneficial effects of IVIg in primary immunodeficiencies are not completely understood. Therefore we investigated the effect of 'replacement dose' of IVIg by probing its action on B cells from CVID patients. We demonstrate that IVIg at low doses induces proliferation and immunoglobulin synthesis from B cells of CVID patients. Interestingly, B cell stimulation by IVIg is not associated with induction of B cell effector cytokine IFN-gamma and of transcription factor T-bet. Together, our results indicate that in some CVID patients, IVIg rectifies the defective signaling of B cells normally provided by T cells and delivers T-independent signaling for B cells to proliferate. IVIg 'replacement therapy' in primary immunodeficiencies is therefore not a merepassive transfer of antibodies to prevent exclusively the recurrent infections; rather it has an active role in regulating autoimmune and inflammatory responses through modulating B cell functions and thus imposing dynamic equilibrium of the immune system. PMID- 20970961 TI - Bone scintigraphy as a diagnostic method in unilateral hyperactivity of the mandibular condyles: a review and meta-analysis of the literature. AB - Bone scan analyses and clinical assessment are used to diagnose unilateral condylar hyperactivity (UCH). This review compares the diagnostic accuracy of planar and SPECT bone scans. Studies diagnosing patients with possible UCH using bone scans, published between 1968 and 2008, were included in this review. Of 15 articles that met the inclusion criteria, 7 presented results in sufficient detail to calculate index test characteristics. Three control studies show that the difference in uptake values of the left and right condylar regions in the normal population does not exceed 10%. The pooled sensitivity of the planar bone scan (n=130) was 0.71 (95% confidence interval: 0.57-0.82), which was significantly lower (p=0.04) than that of the bone SPECT technique (n=88), which was 0.90 (0.79-0.97). The pooled specificity of the SPECT scan was 0.95 (0.82 0.99), which did not significantly differ (p=0.58) from that of the planar scan (0.92 (0.83-0.97)). Future studies should include a diagnostic analysis of the data, including two-by-two contingency tables, so the accuracy of the diagnostic test may be evaluated. Bone scans are best performed using SPECT, conducting a quantitative analysis by calculating the percentile differences between the left and right condylar regions. PMID- 20970962 TI - The origin of traumatic neuroma development. PMID- 20970963 TI - Povidone-iodine: an anti-oedematous agent? AB - Polyvinylpyrrolidone-iodine (PVP-I) is a well-known antiseptic, widely used in various preparations and concentrations in all surgical fields. It is also used as an irrigant for open wounds and in some centres for irrigating sockets after tooth extraction. One of the authors (GA) incidentally discovered an anti oedematous effect of PVP-I after using it in low concentration as an irrigant/coolant during the surgical removal of lower third molars. A prospective randomized clinical trial was subsequently performed on 50 patients (25 control, 25 treatment group) undergoing removal of impacted lower third molars. In the treatment group a 0.5% PVP-I solution at a concentration of 0.5mg/ml (we call it as "Arakeri's iodine solution") resulted in a significant reduction in postoperative swelling compared with the control group (P<0.01). This effect of PVP-I was suspected due to its inhibitory effect on leukotriene B4 and leukocyte extravasation (chemotaxis). Further evaluation of the effects of PVP-I as an irrigant in oral and maxillofacial surgery is needed. PMID- 20970964 TI - Progress report on new antiepileptic drugs: a summary of the Tenth Eilat Conference (EILAT X). AB - The Tenth Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT X, took place in Eilat, Israel from the 25th to 29th of April 2010. About 200 basic scientists, clinical pharmacologists and neurologists from 25 countries attended the conference, whose main themes included learning from the past: Lessons learnt after 18 years of Eilat Conferences and Detecting assessing and preventing adverse effects of AEDs. Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1994. Like the previous EILAT (EILAT IX) manuscript, the current (EILAT X) manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, carisbamate, 2-deoxy-glucose, ganaxolone, huperizine A, ICA-105665, NAX-5055, retigabine, perampanel, T-2007, valnoctamide and YK3089. Since the previous Eilat Conference (EILAT IX-2008) two new AEDs; eslicarbazepine acetate and lacosamide have been marketed and three new AEDs in development not included in the EILAT IX manuscript were added: ICA-105665, perampanel and valnoctamide. The CNS efficacy of these compounds in anticonvulsant animal models as well as other disease model systems are presented in Tables 1 and 2 and their proposed mechanism of action at summarized in Table 3. PMID- 20970965 TI - PPARgamma mediates innate immunity by regulating the 1alpha,25-dihydroxyvitamin D3 induced hBD-3 and cathelicidin in human keratinocytes. AB - BACKGROUND: Production of antimicrobial peptides (AMPs) is the primary mechanism by which skin innate immunity protects against infection. Hormonally active vitamin D3 (1alpha,25-dihydroxyvitamin D3; 1,25D3) is a vital regulator of skin innate immunity, and has been shown to increase the expression and function of AMPs. OBJECTIVE: PPARgamma is a ligand-activated nuclear receptor and plays a role in keratinocyte differentiation and cutaneous homeostasis. In this study, we investigate whether 1,25D3-activated PPARgamma signaling regulates AMP expression in keratinocytes. METHODS: Subconfluent keratinocytes were treated with 1,25D3 for the indicated times. The mRNA and protein levels of AMPs were detected by RT PCR and Western blot, and the DNA binding activation of PPARgamma, VDRE and AP-1 was investigated by EMSA. To examine the role of PPARgamma, the recombinant adenovirus carrying a dominant-negative form of PPARgamma (dn-PPARgamma) was constructed and transfected into keratinocytes. RESULTS: We show here that 1,25D3 significantly enhances hBD-3 and cathelicidin expression in keratinocytes. Expression of dn-PPARgamma did not affect binding to the vitamin D-responsive element (VDRE), which is crucial for cathelicidin induction by VD3; however, it did decrease 1,25D3 induction of both hBD-3 and cathelicidin. Inhibition of the p38, ERK, and JNK signaling pathways blocked hBD-3 expression, whereas only p38 inhibition suppressed cathelicidin induction. dn-PPARgamma had no effect on ERK and JNK activity, but inhibited p38 phosphorylation and suppressed 1,25D3-induced AP-1 activation via effects on Fra1 and c-Fos proteins. CONCLUSIONS: In conclusion, PPARgamma regulates the 1,25D3-induced hBD-3 and cathelicidin expression in keratinocytes through the regulation of AP-1 and p38 activity. PMID- 20970966 TI - Physical capacity, respiratory quotient and energy expenditure during exercise in male patients with schizophrenia compared with healthy controls. AB - BACKGROUND: Despite massive research on weight gain and metabolic complications in schizophrenia there are few studies on energy expenditure and no current data on physical capacity. AIM: To determine oxygen uptake capacity, respiratory quotient (RQ) and energy expenditure during a submaximal exercise test in patients with schizophrenia and healthy controls. METHOD: Ten male patients and 10 controls were included. RQ and energy expenditure were investigated with indirect calorimetry during a cycle ergometer test. The submaximal work level was defined by heart rate and perceived exhaustion. Physical capacity was determined from predicted maximal oxygen uptake capacity (VO(2-max)). RESULTS: The patients exhibited significantly higher RQ on submaximal workloads and lower physical capacity. A significant lower calculated VO(2-max) remained after correction for body weight and fat free mass (FFM). Energy expenditure did not differ on fixed workloads. CONCLUSION: RQ was rapidly increasing in the patients during exercise indicating a faster transition to carbohydrate oxidation and anaerobic metabolism that also implies a performance closer to maximal oxygen uptake even at submaximal loads. This may restrict the capacity for everyday activity and exercise and thus contribute to the risk for weight gain. Physical capacity was consequently significantly lower in the patients. PMID- 20970967 TI - Purification of biomimetic apatite-based hybrid colloids intended for biomedical applications: A dialysis study. AB - The field of nanobiotechnology has lately attracted much attention both from therapeutic and diagnosis viewpoints. Of particular relevance is the development of colloidal formulations of biocompatible nanoparticles capable of interacting with selected cells or tissues. In this context, the purification of such nanoparticle suspensions appears as a critical step as residues of unreacted species may jeopardize biological and medical outcomes, and sample purity is thus increasingly taken into account by regulatory committees. In the present work, we have investigated from a physico-chemical point of view the purification by dialysis of recently developed hybrid colloids based on biomimetic nanocrystalline apatites intended for interacting with cells. Both Eu-doped (2mol.% relative to Ca) and Eu-free suspensions were studied. The follow-up of the dialysis process was carried out by way of FTIR, TEM, XRD, pH and conductivity measurements. Mathematical modelling of conductivity data was reported. The effects of a change in temperature (25 and 45 degrees C), dialysis medium, and starting colloid composition were evaluated and discussed. We show that the dialysis method is a well-adapted and cheap technique to purify such mineral-organic hybrid suspensions in view of biomedical applications, and we point out some of the characterization techniques that may prove helpful for following the evolution of the purification process with time. PMID- 20970968 TI - Surface grafting of a thermoplastic polyurethane with methacrylic acid by previous plasma surface activation and by ultraviolet irradiation to reduce cell adhesion. AB - The material performance, in a biological environment, is mainly mediated by its surface properties and by the combination of chemical, physical, biological, and mechanical properties required, for a specific application. In this study, the surface of a thermoplastic polyurethane (TPU) material (Elastollan((r))1180A50) was activated either by plasma or by ultra-violet (UV) irradiation. After surface activation, methacrylic acid (MAA) was linked to the surface of TPU in order to improve its reactivity and to reduce cell adhesion. Grafted surfaces were evaluated by X-ray photoelectron spectroscopy (XPS), by atomic force microscopy (AFM) and by contact angle measurements. Blood compatibility studies and cell adhesion tests with human bone marrow cells (HBMC) were also performed. If was found that UV grafting method led to better results than the plasma activation method, since cell adhesion was reduced when methacrylic acid was grafted to the TPU surface by UV. PMID- 20970969 TI - [Primary paraesophageal hiatal hernia]. PMID- 20970970 TI - The pituitary of non-pregnant and pregnant viscachas (Lagostomus maximus maximus): a comparative study by immunohistochemistry and morphometric analysis. AB - The neuroendocrine hypothalamic-pituitary axis undergoes morphological and biochemical changes throughout gestation. In viscacha, pregnancy lasts approximately 154 days, and three stages can be described: early, mid- and late pregnancy. The aim of this work was to study the pituitary LH-gonadotrophs, FSH gonadotrophs, somatotrophs, corticotrophs and thyrotrophs of non-pregnant and pregnant adult viscachas by immunohistochemistry and morphometric analysis. Immunopositive percentage area (%IA), cell percentage in the pars distalis (%PDC), number of cells per reference area (n degrees cell/RA), and major cellular (MCD) and nuclear (ND) diameters were analyzed. The different cell populations showed a well-defined morphology, immunolabeling patterns and regionalization in the pars distalis (PD). In the early pregnancy of animals the morphometric analysis demonstrated that %IA, %PDC and n degrees cell/RA increased in the FSH-gonadotrophs and decreased in the somatotrophs in relation to non pregnant animals. In mid-pregnancy, there was an increase in %IA, %PDC, and n degrees cell/RA of LH-gonadotrophs, FSH-gonadotrophs, somatotrophs, and thyrotrophs. The MCD of LH-gonadotrophs and FSH-gonadotrophs increased. In late pregnancy, the %IA, %PDC and n degrees cell/RA of LH-gonadotrophs, FSH gonadotrophs, somatotrophs and corticotrophs decreased whereas the values of the thyrotrophs remained constant. The MCD of LH-gonadotrophs, FSH-gonadotrophs and corticotrophs decreased. No significant changes were observed in the ND of the studied cell types. In conclusion, this work provides evidence for histological and morphometric changes in the different cell types of the pituitary PD in viscachas during pregnancy, probably according to the requirements of this physiological stage. PMID- 20970971 TI - Autistic disorder and phospholipids: A review. AB - Dysregulated phospholipid metabolism has been proposed as an underlying biological component of neurodevelopmental disorders such as autistic disorder (AD) and attention-deficit/hyperactivity disorder (ADHD). This review provides an overview of fatty acid and phospholipid metabolism and evidence for phospholipid dysregulation with reference to the membrane hypothesis of schizophrenia. While there is evidence that phospholipid metabolism is at least impaired in individuals with AD, it has not been established whether phospholipid metabolism is implicated in causal, mechanistic or epiphenomenological models. More research is needed to ascertain whether breastfeeding, and specifically, the administration of colostrum or an adequate substitute can play a preventative role by supplying the neonate with essential fatty acids (EFAs) at a critical juncture in their development. Regarding treatment, further clinical trials of EFA supplementation are essential to determine the efficacy of EFAs in reducing AD symptomatology and whether supplementation can serve as a cost-effective and readily available intervention. PMID- 20970972 TI - Regulation of major histocompatibility complex class II genes. AB - The major histocompatibility complex class II (MHC-II) genes are regulated at the level of transcription. Recent studies have shown that chromatin modification is critical for efficient transcription of these genes, and a number of chromatin modifying complexes recruited to MHC-II genes have been described. The MHC-II genes are segregated from each other by a series of chromatin elements, termed MHC-II insulators. Interactions between MHC-insulators and the promoters of MHC II genes are mediated by the insulator factor CCCTC-binding factor and are critical for efficient expression. This regulatory mechanism provides a novel view of how the entire MHC-II locus is assembled architecturally and can be coordinately controlled. PMID- 20970973 TI - The dendritic cell-tumor cross-talk in cancer. AB - The question as to whether the tumor grows because of or despite the host immune system is being progressively addressed with refined technology, gene targeting in mice and human translational research. The productive interplay between major actors of the antitumor immunity is actively compromised by the tumor microenvironment subverting the links between innate and cognate immunity and/or generating devastating new players. The complexity of the host-tumor equilibrium could be dissected at the reduced level of the dialogue between professional antigen presenting cells (APC), more precisely dendritic cells, and tumor cells that may profoundly dictate the outcome of the neoplasma. This review will summarize the novel mechanisms by which tumor cells regulate DC recruitment, differentiation, activation and cross-presenting functions in tumor beds and how innate players might counterbalance these interactions. Finally, we will highlight interesting strategies that harness the DC potential to fight against cancer. PMID- 20970974 TI - Diverse roles of non-diverse molecules: MHC class Ib molecules in host defense and control of autoimmunity. AB - While the prime function of classical MHC class I molecules (MHC-I) is to present peptide antigens to pathogen-specific cytotoxic T cells, non-classical MHC-I antigens perform a diverse array of functions in both innate and adaptive immunity. In this review we summarize recent evidence that non classical MHC-I molecules are not only recognized by pathogen-specific T cells but that they also serve as immunoregulatory molecules by stimulating a number of distinct non conventional T cell subsets. PMID- 20970975 TI - Targeting BAFF in autoimmunity. AB - BAFF and APRIL are TNF-like cytokines that support survival and differentiation of B cells. The early appreciation that overexpression of BAFF leads to B cell expansion and a lupus-like syndrome in mice, and the demonstration that BAFF inhibition delays lupus onset in spontaneous mouse models of SLE and other autoimmune diseases has rapidly led to the development of strategies for inhibiting both BAFF and APRIL. The commercialization of this new class of drugs has proceeded in parallel with the continuing elucidation of the biology of the cytokines and their receptors. Recent studies have uncovered a role for BAFF in enhancing both innate and adaptive immune responses and in amplifying aberrant pathways that arise during inflammation. Two phase III studies of an anti-BAFF antibody have yielded positive, although modest, results in SLE and alternate inhibitors are being tested in a variety of autoimmune diseases in which BAFF may play a pathogenic role. PMID- 20970976 TI - MK-0633, a potent 5-lipoxygenase inhibitor, in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is associated with neutrophil mediated inflammation, a potential target for treatment in COPD. We evaluated MK 0633, a 5-lipoxygenase inhibitor in patients with COPD. This was a 12 week, randomized, double-blind, multicenter study comparing MK-0633 100 mg and placebo in patients 40-75 years of age (N = 266) with COPD, post-beta-agonist forced expiratory volume in 1 s (FEV(1)) 25%-75% predicted, and an FEV(1)/forced vital capacity ratio (FVC) <= 70%. Long-acting inhaled bronchodilators were permitted for approximately 50% of patients. The primary efficacy endpoint was the change from baseline in pre-dose (trough) FEV(1) measured over the last 2 weeks of the 12 week treatment period. The change in FEV(1) over the last 2 weeks of the 12 weeks treatment period compared to baseline was 0.015 L for MK-0633 and 0.0002 for placebo (p = 0.556). For COPD Global Evaluation, 75.4% of patients receiving MK-0633 reported feeling better vs. 59.8% of patients receiving placebo (p = 0.032). There were no other significant differences between treatments. MK-0633 was well-tolerated and comparable to placebo. The 5-LO inhibitor MK-0633 was not significantly more effective than placebo in improving FEV(1) from baseline in patients with COPD, although more patients reported feeling improved with MK 0633. Clinicaltrials.gov identifier: NCT00418613. PMID- 20970978 TI - Measuring fluid flow properties of waste and assessing alternative conceptual models of pore structure. AB - Laboratory procedures were developed to obtain constitutive relations for fluid flow in refuse. Five different types of experiments were conducted for the same waste sample: a drainage experiment, multi step outflow experiment, total porosity measurement, saturated hydraulic conductivity test, and gas permeability tests. To investigate fundamental processes affecting water movement and moisture retention, samples consisted entirely of newspaper. Samples were prepared in two particle sizes and two compaction pressures and packed in compression cells to replicate stress conditions in landfills. Data were modeled using HYDRUS-1D, which allowed alternative conceptual models of the pore space to be assessed. A dual-permeability model performed significantly better than a single-porosity model for water movement, suggesting that a dual domain description is required to describe water flow in landfills with significant amounts of paper and paperboard. However, a single-porosity model was adequate for describing gas transport. Results indicated that properties of the fracture domain, the large openings between refuse particles, are significantly affected by the size of waste materials and compaction, and may be best studied with field-scale measurements. On the other hand properties of the matrix domain, the smaller pore openings within and between refuse particles, are likely amenable to laboratory study because representative samples sizes should be much smaller. PMID- 20970977 TI - The critical role of GRP78 in physiologic and pathologic stress. AB - GRP78 is a major endoplasmic reticulum chaperone as well as a master regulator of the unfolded protein response. In addition to playing an essential role in early embryonic development, recent studies have emerged specifically implicating GRP78 and chaperone integrity in the aging process and age-related diseases. Another exciting discovery is the regulation of GRP78 by insulin/IGF-1 signaling pathways impacting cell proliferation and survival. Mouse models of cancer, in combination with cell culture studies, validate the critical role of GRP78 in tumorigenesis and tumor angiogenesis. Further, these studies demonstrate the ability of GRP78 to suppress oncogenic PI3K/AKT signaling. The discovery of cell surface GRP78, in cancer cells and cells undergoing ER stress, presents a novel therapeutic strategy. PMID- 20970979 TI - Synthesis of a new Ni-phenanthroline complex and its application as an electrochemical probe for detection of nucleic acid. AB - A new DNA sensor using a nickel(II) phenanthroline complex ([Ni(phen)(2)PHPIP].2ClO(4)) as the electrochemical probe was developed. The sensor is very sensitive and selective for calf thymus DNA (ctDNA) detection in aqueous medium. The Ni-phenanthroline probe was synthesized by a two-step preparation using p-hydroxy-phenylimidazo-1,10-phenanthroline (PHPIP) as the ligand and characterized with IR, UV and MS. Some interesting electrochemical properties of the Ni-complex and the interactions of the complex with ctDNA were reported. The calculated dynamics parameters of the electrode process indicate that there are obvious interactions between the probe and the ctDNA in aqueous solution. Under constant potential conditions, the redox current peak of the probe (Ni-complex) decreases obviously as the probe interacts/binds with ctDNAs. This unexpected electrochemical behavior may suggest that a new adduct through the binding of Ni-phenanthroline complex with ctDNA is formed electrochemically. By estimation, the binding ratio of the probe and ctDNA was found to be 1:1 with a binding constant beta=4.29*10(5) mol L(-1) in aqueous solution at room temperature. PMID- 20970980 TI - Aptamer-based colorimetric biosensing of Ochratoxin A using unmodified gold nanoparticles indicator. AB - This work presents an aptasensor for Ochratoxin A (OTA) using unmodified gold nanoparticles (AuNPs) indicator. The assay method is based on the conformation change of OTA's aptamer in phosphate buffered saline (PBS) containing Mg(2+) and OTA, and the phenomenon of salt-induced AuNPs aggregation. A single measurement took only five minutes. Circular dichroism spectroscopic experiments revealed for the first time that upon the addition of OTA, the conformation of OTA's aptamer in PBS buffer changed from random coil structure to compact rigid antiparallel G quadruplex structure. This compact rigid G-quadruplex structure could not protect AuNPs against salt-induced aggregation, and thus the color change from red to blue could be observed by the naked eye. The linear range of the colorimetric aptasensor covered a large variation of OTA concentration from 20 to 625 nM and the detection limit of 20 nM (3sigma) was obtained. PMID- 20970981 TI - Real-time colorimetric detection of target DNA using isothermal target and signaling probe amplification and gold nanoparticle cross-linking assay. AB - We describe a facile gold nanoparticle (AuNP)-mediated colorimetric method for real-time detection of target DNA in conjugation with our unique isothermal target and signaling probe amplification (iTPA) method, comprising novel ICA (isothermal chain amplification) and CPT (cycling probe technology). Under isothermal conditions, the iTPA simultaneously amplifies the target and signaling probe through two displacement events induced by a combination of four specially designed primers, the strand displacement activity of DNA polymerase, and the RNA degrading activity of RNase H. The resulting target amplicons are hybridized with gold nanoparticle cross-linking assay (GCA) probes having a DNA-RNA-DNA chimeric form followed by RNA cleavage by RNase H in the CPT step. The intact GCA probes were designed to cross-link two sets of DNA-AuNPs conjugates in the absence of target DNA, inducing aggregation (blue color) of AuNPs. On the contrary, the presence of target DNA leads to cleavage of the GCA probes in proportion to the amount of amplified target DNA and the solution remains red in color without aggregation of AuNPs. Relying on this strategy, 10(2) copies of target Chlamydia trachomatis plasmid were successfully detected in a colorimetric manner. Importantly, all the procedures employed up to the final detection of the target DNA were performed under isothermal conditions without requiring any detection instruments. Therefore, this strategy would greatly benefit convenient, real-time monitoring technology of target DNA under restricted environments. PMID- 20970982 TI - Immobilization of metallothionein to carbon paste electrode surface via anti-MT antibodies and its use for biosensing of silver. AB - In this paper, heavy metal biosensor based on immobilization of metallothionein (MT) to the surface of carbon paste electrode (CPE) via anti-MT-antibodies is reported. First, the evaluation of MT electroactivity was done. The attention was focused on the capturing of MT to the CPE surface. Antibodies incorporated and mixed into carbon paste were stable; even after two weeks the observed changes in signal height were lower than 5%. Further, the interaction of MT with polyclonal chicken antibodies incorporated in carbon paste electrode was determined by square-wave voltammetry. In the voltammogram, two signals--labelled as cys(MT) and W(a)--were observed. The cys(MT) corresponded to -SH moieties of MT and W(a) corresponded to tryptophan residues of chicken antibodies. Time of interaction (300 s) and MT concentration (125 MUg/ml) were optimized to suggest a silver(I) ions biosensor. Biosensor (CPE modified with anti-MT antibody) prepared under the optimized conditions was then used for silver(I) ions detection. The detection limit (3 S/N) for silver(I) ions was estimated as 0.5 nM. The proposed biosensor was tested by detection spiking of silver(I) ions in various water samples (from very pure distilled water to rainwater). Recoveries varied from 74 to 104%. PMID- 20970983 TI - An auto-biotinylated bifunctional protein nanowire for ultra-sensitive molecular biosensing. AB - In order to obtain an ultra-sensitive molecular biosensor, we designed an auto biotinylated bifunctional protein nanowire (bFPNw) based on the self-assembly of a yeast amyloid protein, Sup35, to which protein G and a biotin acceptor peptide (BAP) were genetically fused. These auto-biotinylated bFPNws can transfer hundreds of commercially available diagnostic enzymes to an antigen-antibody complex via the biotin-avidin system, greatly enhancing the sensitivity of immune biosensing. Compared to our previously reported seeding-induced bFPNws (Men et al., 2009), these auto-biotinylated bFPNws gave greater signal amplification, reduced non-specific binding and improved stability. The auto-biotinylated self assembled bFPNw molecular biosensors were applied to detect Yersinia pestis (Y. pestis) F1 antigen and showed a 2000- to 4000-fold increase in sensitivity compared to traditional immunoassays, demonstrating the potential use of these self-assembling protein nanowires in biosensing. PMID- 20970985 TI - Reconstruction of bilateral spontaneous chronic idiopathic Achilles tendon rupture using LARS ligament: Case report. AB - Spontaneous bilateral idiopathic rupture of Achilles tendon is rare and usually results from sudden dorsiflexion of a plantar-flexed foot; the tendon is most often degenerated or diseased, and spontaneous bilateral rupture is not rare in patients suffering from chronic diseases. Management problems relate to reconstruction options and issues with early ambulation and weight bearing. We report a case of idiopathic bilateral Tendo-Achilles (TA) rupture with no obvious disease process, which was initially neglected, and subsequently reconstructed with LARS polyester ligament. The patient could be mobilized early despite bilateral involvement, but developed bilateral wound dehiscence which needed debridement and local flap coverage; aggressive rehabilitation finally leads to an excellent functional outcome. Despite the fact that artificial ligaments allow biointegration and can withstand stresses of early weight bearing, they often lead to wound related problems. Judicious use is advocated and good cases for their use maybe bilateral TA repair in neglected tears with gaps. PMID- 20970984 TI - The effect of temperature on the impedimetric response of bioreceptor hosting hydrogels. AB - Biocompatible hydrogels that serve as the hosting membrane for various bioreceptors contribute to the response of impedimetric biosensors. The temperature response of poly(2-hydroxymethacrylate) [p(HEMA)]-based hydrogel networks prepared with poly(ethylene glycol) methacrylate (PEGMA) for enhanced biocompatibility and with N-[tris(hydroxymethyl)methyl] acrylamide (HMMA) was studied. Hydrogels were cross-linked with tetraethyleneglycol diacrylate (TEGDA) and synthesized by UV initiation (2M% DMPA photoinitiator). The p(HEMA-co-PEGMA co-HMMA) based hydrogels were fabricated as discrete gel pads (D=2.5 mm, H=2 mm and V=9.82 MUL) on top of 250 MUm diameter cysteamine modified and acryloyl (polyethylene glycol)(110) N-hydroxy succinamide ester (acryloyl-PEG-NHS) derivatized gold microelectrodes set within 8-well (8W1E) cell culture biochips. Gel pads were fabricated with cross-link densities corresponding to 1, 3, 5, 7, 9 and 12 M% TEGDA and were studied by frequency dependent 3-electrode electrochemical impedance spectroscopy (1 mHz to 100 kHz; 50 mV p-t-p) and by temporal 2-electrode impedimetry (64 kHz; 50 mV p-t-p) over the temperature range 30-45 degrees C at 90% RH or in aqueous 0.1 M Tris/KCl at pH 7.2 buffer. The p(HEMA-co-PEGMA-co-HMMA) hydrogels showed an increase in the real component of impedance with increasing cross-link density and demonstrated activation energies for impedimetric transport that ranged from 15 kJ/mol (3 M%) to 20 kJ/mol (12 M%) confirming the dominance of proton migration in the impedance of the hydrogels. PMID- 20970986 TI - The effect of the iBEAM Evo carbon fiber tabletop on skin sparing. AB - Replicating the attenuation properties of the treatment tabletop are of primary importance for accurate treatment planning; however, the effect of the tabletop on the skin-sparing properties of x-rays can be overlooked. Under some conditions, the reaction of skin to the radiation can be so serious as to be the dose-limiting organ for radiotherapy treatment. Hence, an understanding of the magnitude of the reduction in skin sparing is important. Because of the development of image-guided radiotherapy, modern tabletops have been developed without the use of metal supports that otherwise provided the necessary level of rigidity. Rigidity is instead provided by compressed foam within a carbon-fiber shell, which, although it provides artefact-free imaging and high levels of rigidity, has an adverse affect on the dose in the build-up region. Representative of this type is the iBEAM evo tabletop, whose effect on the skin dose was determined at 6-MV, 10-MV, and 18-MV x-rays. Skin dose was found to increase by 60-70% owing to the tabletop, with the effect increasing with field size and decreasing with energy. By considering an endpoint of erythema, a radiobiological advantage of selecting 10 MV over 6 MV for applicable treatments was demonstrated. PMID- 20970987 TI - Proton range uncertainty due to bone cement injected into the vertebra in radiation therapy planning. AB - We wanted to evaluate the influence of bone cement on the proton range and to derive a conversion factor predicting the range shift by correcting distorted computed tomography (CT) data as a reference to determine whether the correction is needed. Two CT datasets were obtained with and without a bone cement disk placed in a water phantom. Treatment planning was performed on a set of uncorrected CT images with the bone cement disk, and the verification plan was applied to the same set of CT images with an effective CT number for the bone cement disk. The effective CT number was determined by measuring the actual proton range with the bone cement disk. The effects of CT number, thicknesses, and position of bone cement on the proton range were evaluated in the treatment planning system (TPS) to draw a conversion factor predicting the range shift by correcting the CT number of bone cement. The effective CT number of bone cement was 260 Hounsfield units (HU). The calculated proton range for native CT data was significantly shorter than the measured proton range. However, the calculated range for the corrected CT data with the effective CT number coincided exactly with the measured range. The conversion factor was 209.6 [HU . cm/mm] for bone cement and predicted the range shift by approximately correcting the CT number. We found that the heterogeneity of bone cement could cause incorrect proton ranges in treatment plans using CT images. With an effective CT number of bone cement derived from the proton range and relative stopping power, a more actual proton range could be calculated in the TPS. The conversion factor could predict the necessity for CT data correction with sufficient accuracy. PMID- 20970988 TI - A dosimetric analysis of IMRT and multistatic fields techniques for left breast radiotherapy. AB - The purpose of this study was to analyze the dosimetric difference between intensity-modulated radiation therapy (IMRT) using 3 or 5 beams and multistatic field technique (MSF) in radiotherapy of the left breast. We made comparative analysis of two kinds of radiotherapy that can achieve improved dose homogeneity. First is a MSF that uses both major and small irradiation fields at the same time. The other is IMRT using 3 or 5 beams with an inverse planning system using multiple static multileaf collimators. We made treatment plans for 16 early left breast cancer patients who were randomly selected and had undergone breast conserving surgery and radiotherapy, and analyzed them in the dosimetric aspect. For the mean values of V(95) and dose homogeneity index, no statistically significant difference was observed among the three therapies. Extreme hot spots receiving >110% of prescribed dose were not found in any of the three methods. Using Tukey's test, IMRT showed a significantly larger increase in exposure dose to the ipsilateral lung and the heart than MSF in the low-dose area, but in the high-dose area, MSF showed a slight increase. To improve dose homogeneity, the application of MSF, which can be easily planned and applied more widely, is considered optimal as an alternative to IMRT for radiotherapy of early left breast cancer. PMID- 20970989 TI - Tissue heterogeneity in IMRT dose calculation for lung cancer. AB - The aim of this study was to evaluate the differences in accuracy of dose calculation between 3 commonly used algorithms, the Pencil Beam algorithm (PB), the Anisotropic Analytical Algorithm (AAA), and the Collapsed Cone Convolution Superposition (CCCS) for intensity-modulated radiation therapy (IMRT). The 2D dose distributions obtained with the 3 algorithms were compared on each CT slice pixel by pixel, using the MATLAB code (The MathWorks, Natick, MA) and the agreement was assessed with the gamma function. The effect of the differences on dose-volume histograms (DVHs), tumor control, and normal tissue complication probability (TCP and NTCP) were also evaluated, and its significance was quantified by using a nonparametric test. In general PB generates regions of over dosage both in the lung and in the tumor area. These differences are not always in DVH of the lung, although the Wilcoxon test indicated significant differences in 2 of 4 patients. Disagreement in the lung region was also found when the Gamma analysis was performed. The effect on TCP is less important than for NTCP because of the slope of the curve at the level of the dose of interest. The effect of dose calculation inaccuracy is patient-dependent and strongly related to beam geometry and to the localization of the tumor. When multiple intensity-modulated beams are used, the effect of the presence of the heterogeneity on dose distribution may not always be easily predictable. PMID- 20970990 TI - Regulation of cell adhesions and motility during initiation of neural crest migration. AB - Accurate neural crest cell (NCC) migration requires tight control of cell adhesions, cytoskeletal dynamics and cell motility. Cadherins and RhoGTPases are critical molecular players that regulate adhesions and motility during initial delamination of NCCs from the neuroepithelium. Recent studies have revealed multiple functions for these molecules and suggest that a precise balance of their activity is crucial. RhoGTPase appears to regulate both cell adhesions and protrusive forces during NCC delamination. Increasing evidence shows that cadherins are multi-functional proteins with novel, adhesion-independent signaling functions that control NCC motility during both delamination and migration. These functions are often regulated by specific proteolytic cleavage of cadherins. After NCC delamination, planar cell polarity signaling acts via RhoGTPases to control NCC protrusions and migration direction. PMID- 20970991 TI - Structural insights into histone lysine demethylation. AB - Posttranslational modifications of histone tails are crucial epigenetic marks that regulate diverse cellular processes. Histone lysine methylation activates or represses transcription, depending on the site and degree of these modifications. Two classes of histone lysine demethylases remove histone methylation. Lysine demethylase 1 (KDM1, also known as LSD1) is a flavin adenine dinucleotide (FAD) containing enzyme that removes mono-/di-methylation. The Jumonji C-terminal domain (JmjC) family of histone demethylases uses Fe(2+) and alpha-ketoglutarate as cofactors to remove all methylation states. Structural studies have provided insights into the overall architecture, the catalytic mechanism, and the substrate specificity of histone demethylases. Here, we review these exciting advances in the structure biology of histone demethylases and discuss the general principles applicable to other histone-modifying enzymes. PMID- 20970992 TI - Dynamin architecture--from monomer to polymer. AB - Dynamins form a family of eukaryotic and prokaryotic proteins involved in membrane fission, fusion and restructuring. They have complex mechanisms of self assembly, which are coupled to the tubulation and destabilization of lipid bilayers. Recent structural data has revolutionized our understanding and is now yielding detailed insights into dynamin structure, from monomer through to polymer. Traditional division of the dynamin subunit into GTPase domain, middle domain and GTPase effector domain based on sequence alignments and biochemistry is not supported by recent structural data. A unified model of dynamin architecture is presented here, based on observation that the basic dynamin fold is conserved across evolutionary kingdoms. PMID- 20970993 TI - Structural glycobiology: biosynthesis, recognition events, and new methods. PMID- 20970994 TI - Highly efficient Bronsted acidic ionic liquid-based catalysts for biodiesel synthesis from vegetable oils. AB - Biodiesel has been produced by transesterification of canola oil with methanol in the presence of highly Bronsted acidic ionic liquids based on 1-benzyl-1H benzimidazole, and the effect of reaction temperature, type and amount of catalyst, molar ratio and reaction time investigated. The results show that the 4B ionic liquid has the highest catalytic activity and best recyclability under the optimised reaction conditions. Thus, this ionic liquid is able to catalyze the transesterification of canola oil to its methyl esters in 5 h with yields of more than 95%. Density functional calculations (B3LYP), using the 6-311G basis set, have been performed to have a better understanding on the reactivity of these catalysts. The catalytic activity of 4B for the transesterification of other vegetable oils and alcohols has also been studied. PMID- 20970995 TI - Microwave induced pyrolysis of oil palm biomass. AB - The purpose of this paper was to carry out microwave induced pyrolysis of oil palm biomass (shell and fibers) with the help of char as microwave absorber (MA). Rapid heating and yield of microwave pyrolysis products such as bio-oil, char, and gas was found to depend on the ratio of biomass to microwave absorber. Temperature profiles revealed the heating characteristics of the biomass materials which can rapidly heat-up to high temperature within seconds in presence of MA. Some characterization of pyrolysis products was also presented. The advantage of this technique includes substantial reduction in consumption of energy, time and cost in order to produce bio-oil from biomass materials. Large biomass particle size can be used directly in microwave heating, thus saving grinding as well as moisture removal cost. A synergistic effect was found in using MA with oil palm biomass. PMID- 20970996 TI - High-level expression of extracellular secretion of a beta-xylosidase gene from Paecilomyces thermophila in Escherichia coli. AB - A novel beta-xylosidase gene (designated as PtXyl43) from thermophilic fungus Paecilomycesthermophila was cloned and extracellularly expressed in Escherichia coli. PtXyl43 belonging to glycoside hydrolase (GH) family 43 has an open reading frame of 1017 bp, encoding 338 amino acids without a predicted signal peptide. No introns were found by comparison of the PtXyl43 genomic DNA and cDNA sequences. The recombinant beta-xylosidase (PtXyl43) was secreted into the culture medium in E. coli with a yield of 98.0 U mL(-1) in shake-flask cultures. PtXyl43 was purified 1.2-fold to homogeneity with a recovery yield of 61.5% from the cell free culture supernatant. It appeared as a single protein band on SDS-PAGE with a molecular mass of approx 52.3 kDa. The enzyme exhibited an optimal activity at 55 degrees C and pH 7.0, respectively. This is the first report on the cloning and expression of a GH family 43 beta-xylosidase gene from thermophilic fungi. PMID- 20970997 TI - The removal of nitrogen and organics in vertical flow wetland reactors: predictive models. AB - Three kinetic models, for predicting the removal of nitrogen and organics in vertical flow wetlands, have been developed and evaluated. These models were established by combining first-order, Monod and multiple Monod kinetics with continuous stirred-tank reactor (CSTR) flow pattern. Critical evaluations of these models using three statistical parameters, coefficient of determination, relative root mean square error and model efficiency, indicated that when the Monod/multiple Monod kinetics was combined with CSTR flow pattern it allowed close match between theoretical prediction and experiment data of nitrogen and organics removal. The kinetic coefficients (derived from Monod/multiple Monod kinetics) was found to increase with pollutant loading, indicating that the coefficients may vary based on different factors, such as influent pollutant concentration, hydraulic loading, and water depth. Overall, this study demonstrated the validity of combining Monod and multiple Monod kinetics with CSTR flow pattern for the modelling and design of vertical flow wetland systems. PMID- 20970998 TI - Life cycle assessment of energy self-sufficiency systems based on agricultural residues for organic arable farms. AB - The agricultural industry today consumes large amounts of fossil fuels. This study used consequential life cycle assessment (LCA) to analyse two potential energy self-sufficient systems for organic arable farms, based on agricultural residues. The analysis focused on energy balance, resource use and greenhouse gas (GHG) emissions. A scenario based on straw was found to require straw harvest from 25% of the farm area; 45% of the total energy produced from the straw was required for energy carrier production and GHG emissions were reduced by 9% compared with a fossil fuel-based reference scenario. In a scenario based on anaerobic digestion of ley, the corresponding figures were 13%, 24% and 35%. The final result was sensitive to assumptions regarding, e.g., soil carbon content and handling of by-products. PMID- 20970999 TI - Flocculating performances of exopolysaccharides produced by a halophilic bacterial strain cultivated on agro-industrial waste. AB - This study reports the first systematic investigation of the flocculation dynamics of exopolysaccharides (EPSs) produced by a halophilic bacterial strain grown on pretreated molasses as fermentation substrate. The potential use of these EPSs as an easily biodegradable, natural alternative for synthetic polyelectrolytes which are widely used and contain toxic and carcinogenic monomers was investigated. Flocculating activities of the EPS samples in synthetic water, synthetic sea water and natural sea water media which were used as model raw waters were monitored via the Photometric Dispersion Analyser (PDA 2000) instrument and removals were determined by measuring residual turbidities. One of the six EPS specimens, which formed the largest flocs thus performed highest turbidity removal, exhibited flocculation performance and particle removal efficiency comparable with commercial cationic, nonionic and anionic synthetic polyelectrolytes. PMID- 20971000 TI - The synthesis and SAR of novel diarylsulfone 11beta-HSD1 inhibitors. AB - In this communication, human 11beta-hydroxysteroid dehydrogenase type 1 (11beta HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11beta-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model. PMID- 20971001 TI - Indazole derivatives as novel bradykinin B1 receptor antagonists. AB - A new class of indazole-derived bradykinin B(1) antagonists and their structure activity relationships (SAR) is reported. A number of compounds were found to have low-nanomolar affinity for the human B(1) receptor and possess acceptable P gp and pharmacokinetics properties. PMID- 20971002 TI - Cholesterol-derived novel anti-apoptotic agents on the structural basis of ginsenoside Rk1. AB - Design and synthesis of cholesterol-derived anti-apoptotic agents were described. The synthesized cholesterol analogs designed on the structural basis of ginsenoside Rk1 inhibited the undesirable apoptosis of human endothelial cells, which are induced by a vascular injury. In particular, analogue 1 possessing 4,6 di-O-acetyl-2,3-dideoxyhex-2-enopyran linked to hydroxyl group of cholesterol exhibited the most effective anti-apoptotic activities at both 5 and 10 MUg/ml. PMID- 20971003 TI - N-substituted pyrrolidines and tetrahydrofurans as novel AMPAR positive modulators. AB - A series of novel AMPA receptor positive modulators displaying CNS penetration have been discovered with sub-micromolar activity and good selectivity over the cardiac channel receptor, hERG. We describe here the synthesis of these compounds which are biaryl pyrrolidine and tetrahydrofuran sulfonamides and disclose their activities against the human GluA2 flip isoform homotetrameric receptor. PMID- 20971004 TI - Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 4. In vivo active potent and selective non-competitive metabotropic glutamate receptor 2/3 antagonists. AB - This study completes a series of papers devoted to the characterization of the non-competitive mGluR2/3 antagonist properties of 1,3-dihydro benzo[b][1,4]diazepin-2-one derivatives with particular emphasis on derivatizations compatible with brain penetration and in vivo activity. Especially the compounds bearing a para-pyridine consistently showed in vivo activity in rat behavioral models after oral administration, for example, blockade of the mGluR2/3 agonist LY354740-induced hypoactivity and improvement of a working memory deficit induced either by LY354740 or scopolamine in the delayed match to position task (DMTP). Moreover, combination studies with a cholinesterase inhibitor show apparent synergistic effects on working memory impairment induced by scopolamine. PMID- 20971005 TI - Receptor agonists of macrophage migration inhibitory factor. AB - The cytokine MIF is involved in inflammation and cell proliferation via pathways initiated by its binding to the transmembrane receptor CD74. MIF also promotes AMPK activation with potential benefits for response to myocardial infarction and ischemia-reperfusion. Structure-based molecular design has led to the discovery of not only antagonists, but also the first agonists of MIF-CD74 binding. The compounds contain a triazole core that is readily assembled via Cu-catalyzed click chemistry. The agonist and antagonist behaviors were confirmed via study of MIF-dependent ERK1/2 phosphorylation in human fibroblasts. PMID- 20971006 TI - Artemisinin-quinoline hybrid-dimers: synthesis and in vitro antiplasmodial activity. AB - Novel artemisinin-quinoline hybrid-dimers were synthesized from dihydroartemisinin and different aminoquinolines at elevated temperatures (90-110 degrees C). All compounds were obtained as the beta-isomers and were tested against both chloroquine sensitive and resistant strains of Plasmodium falciparum. Hybrid-dimer 8 showed the highest antiplasmodial activity, inheriting the optimum chain length of three carbon atoms. PMID- 20971007 TI - N,N-Bis-(8-hydroxyquinoline-5-yl methyl)-benzyl substituted amines (HQNBA): peroxisome proliferator-activated receptor (PPAR-gamma) agonists with neuroprotective properties. AB - We report on the neuroprotective effects of N,N-bis-(8-hydroxyquinoline-5-yl methyl)-benzyl substituted amines (HQNBA) in a model of oxidative stress-induced nerve cell death using mouse hippocampal-derived HT22 cells. The four derivatives (JLK1472, JLK1486, JLK1522 and JLK1535) protected the HT22 cells from death at concentrations ranging from 0.1 to 1 MUM. Their action is partially dependent on their ability to act as PPARgamma agonists. These analogues also maintain GSH levels suggesting that they have indirect anti-oxidant effects. PMID- 20971008 TI - Eggshell chitin and chitin-interacting proteins prevent polyspermy in C. elegans. AB - Development requires fertilization by a single sperm. In Caenorhabditis elegans, fertilization occurs in a sperm-filled spermatheca, implying the barrier to polyspermy is generated in this compartment. Eggshell chitin synthesis is initiated at fertilization, and chitin is deposited before the zygote exits the spermatheca. Whereas polyspermy is very rare in wild-type, here we report an incidence of 14%-51% in zygotes made chitin deficient by loss of chitin synthase 1 (CHS-1), the CHS-1 substrate UDP-N-acetylglucosamine, the CHS-1-interacting protein EGG-3, or the sperm-provided protein SPE-11. The spe-11(hc90) mutant deposits chitin at the male end but fails to complete a continuous layer. The polyspermy barrier is also compromised by loss of the chitin-binding protein CBD 1 or the GLD-1-regulated LDL receptor-like EGG-1, together with its homolog, EGG 2. Loss of CBD-1 or EGG-1/2 disrupts oocyte cortical distribution of CHS-1, as well as MBK-2 and EGG-3. In CBD-1 or EGG-1/2 deficiency, chitin is synthesized but the eggshell is fractured, suggesting aberrantly clustered CHS-1/MBK-2/EGG-3 may fail to support construction of a continuous eggshell. Together, our results show that eggshell chitin is required to prevent polyspermy in C. elegans, in addition to its previously reported requirement in polar body extrusion and polarization of the zygote. PMID- 20971009 TI - Discussing the morphology of actin filaments in lamellipodia. PMID- 20971010 TI - Critical illness polyneuromyopathy (CIPNM); rehabilitation during critical illness. Therapeutic options in nursing to promote recovery: a review of the literature. AB - Following critical illness requiring prolonged mechanical ventilation and sedation, intensive care patients often present with neuromuscular weakness. This results from critical illness polyneuropathy (CIP) and critical illness myopathy (CIM). A lack of diagnostic criteria for each syndrome complicates prevention and treatment. Consequently the term critical illness polyneuromyopathy (CIPNM) has emerged and is characterised by severe weakness, reduced or absent limb reflexes and marked muscle wasting. Although clinical trials report a high incidence of CIPNM, in clinical practice it often remains undetected. The pathophysiological mechanisms that lead to neuromuscular weakness are not entirely clear, however several risk factors have been identified and will be discussed. To date, there are no specific treatments or interventions available to reduce the onset or impact of CIPNM. This paper will review the strategies employed that are supportive and aimed at controlling the associated risk factors. PMID- 20971011 TI - Arm posture score and arm movement during walking: a comprehensive assessment in spastic hemiplegic cerebral palsy. AB - Patients with hemiplegic cerebral palsy often have noticeably deviant arm posture and decreased arm movement. Here we develop a comprehensive assessment method for the upper extremity during walking. Arm posture score (APS), deviation of shoulder flexion/extension, shoulder abduction/adduction, elbow flexion/extension and wrist flexion/extension were calculated from three-dimensional gait analysis. The APS is the root mean square deviation from normal, similar to Baker's Gait Profile Score (GPS) [1]. The total range of motion (ROM) was defined as the difference between the maximum and minimum position in the gait cycle for each variable. The arm symmetry, arm posture index (API) was calculated by dividing the APS on the hemiplegic side by that on the non-involved side, and the range of motion index (ROMI) by dividing the ROM on the hemiplegic side by that on the non involved side. Using the APS, two groups were defined. Group 1 had minor deviations, with an APS under 9.0 and a mean of 6.0 (95% CI 5.0-7.0). Group 2 had more pronounced deviations, with an APS over 9.0 and a mean of 13.1 (CI 10.8 15.5) (p=0.000). Total ROM was 60.6 in group 1 and 46.2 in group 2 (p=0.031). API was 0.89 in group 1 and 1.70 in group 2 (p<0.001). ROMI was 1.15 in group 1 and 0.69 in group 2 (p=0.003). APS describes the amount of deviation, ROM provides additional information on movement pattern and the indices the symmetry. These comprehensive objective and dynamic measurements of upper extremity abnormality can be useful in following natural progression, evaluating treatment and making prognoses in several categories of patients. PMID- 20971012 TI - Modified Goal Attainment Scale outcomes for ambulatory children: with and without orthopedic surgery. AB - AIM: The purpose of this study was to determine if mobility goals were met when set and rated by the family using a modified Goal Attainment Scale following lower extremity orthopedic surgery or on follow-up without surgery. METHODS: Parents were asked to establish the top three goals for their child's mobility during a visit to the Motion Analysis Laboratory. Three groups of subjects were established: (1) 25 children with CP who had surgery, (2) 13 children with CP who did not have surgery and (3) 13 children without CP who had surgery. Goals were rated at the follow-up visit to the Motion Analysis Laboratory a mean of 12.4 months after initial visit using a non-criterion reference scale. The PODCI, Gait Deviation Index and Gillette FAQ were additional standardized tools used to measure outcomes. Data were reviewed retrospectively. RESULTS: Both groups that had surgery on average met their goals. The group that did not have surgery did not, on average, meet their goals (overall, no change). Significant improvements were noted in both surgery groups on the PODCI and Gait Deviation Index while no changes were found for the group without surgery. CONCLUSION: Generally, goals are met following orthopedic surgery when set and rated by the family using a modified Goal Attainment Scale in the Motion Analysis Laboratory. However, goals are not universally met which presents an opportunity to improve the goal setting and evaluation process. Goals identified in this study are specific and unique to the family and agree with other standardized outcome tools. PMID- 20971013 TI - Basic gait and symmetry measures for primary school-aged children and young adults. II: walking at slow, free and fast speed. AB - This study recorded basic gait data from 656 healthy primary school-aged children (5-13 years) and 81 young adults (18-27 years) whilst walking over-ground across a level walkway at varying speed. It investigated the effect of gait speed and re examined the issue of gait maturation. Participants completed 6-8 walks at self selected slow, free and fast speed along a GAITRite walkway whilst wearing athletic shoes. Outcome measures (non-normalized and normalized) were gait speed, cadence, step and stride length, step and stride time, support base, single and double support (%), stance duration (%), foot angle and associated symmetry measures. Compared to free speed, participants walked 24% slower for the slow speed and 30% faster for the fast speed (p<0.0001). Both normalized and non normalized measures of cadence, step and stride length increased with speed (p<0.001) whereas step and stride time reduced (p<0.001). As a percentage of the gait cycle, single support and stance duration increased with speed (p<0.001) whereas double support reduced (p<0.001). Foot angle was significantly less (less toe-out) for the fast speed than the free and slow speeds (p<0.001) whereas support base was unaffected by speed. Symmetry measures were unaffected by age or speed. Step and stride symmetry differentials (combining conditions) fell around 0.8 cm, whereas symmetry differentials for step and stance time, single and double support fell around 0.7%. This information can be used by clinicians and researchers to assess the gait of children. PMID- 20971014 TI - Intramolecular reductive cyclization strategy to the synthesis of (-)-6-methyl-3 hydroxy-piperidine-2-carboxylic acid, (+)-6-methyl-(2-hydroxymethyl)-piperidine-3 ol and their glycosidase inhibitory activity. AB - The first stereoselective synthesis of (2S,3R,6S)-6-methyl-3-hydroxy-piperidine-2 carboxylic acid (-)-6 and (2R,3R,6S)-6-methyl-(2-hydroxymethyl)-piperidine-3-ol (+)-7 was achieved starting from readily available d-glucose in 14 steps with 17% overall yield for both the compounds. The key feature of the present strategy includes the Wittig-olefination for the preparation of required conjugated keto azide 9 and construction of 2,3,6-trisubstituted piperidine skeleton 11 by applying intramolecular reductive cyclization of conjugated keto-azide intermediate. The glycosidase inhibitory activity of compounds 6 and 7 towards several glycosidases has been evaluated. PMID- 20971015 TI - High yield production of the medical radioisotope 167Tm by the 167Er(d,2n) reaction. AB - As part of our systematic comparison of (p,n) and (d,2n) reactions, the excitation functions of the (167)Er(d,2n)(167)Tm production reaction and reactions leading to Tm radio-impurities were investigated up to 20 MeV. A stacked foil irradiation technique and gamma-ray spectroscopy is used. The measured excitation functions are compared with results of ALICE-D, EMPIRE-D and TALYS reaction model codes and with data from our earlier investigations on natural Er. Thick target yields and contamination levels are discussed. A comparison with other charged particle production routes for (167)Tm shows that deuteron induced reactions are not competitive. PMID- 20971016 TI - Usefulness of systematic in situ gamma-ray surveys in the radiometric characterization of natural systems with poorly contrasting geological features (examples from NE of Portugal). AB - This paper focuses on the starting point of various studies that are being carried out in two possible locations being considered to host a hypothetical site for a repository for low and intermediate level radioactive waste (LILW) produced in Portugal in compliance with international requirements on the long term safety of this kind of repository. Previous studies concerning the geology of the much larger geographical areas where these locations are included were fundamental in the choice of these locations and for the design of the survey strategy. One of the fundamental assessment studies during the site-selection is the overall radiological characterization of the locations and its relation to the geology. This paper pretends to show the adequability of using a fast and reasonably inexpensive survey technique such as in situ gamma-ray portable detectors, to access the radiometric response of the systems in study by providing the radiometric mapping of the areas. The existence of adequate radiometric maps represents a critical pre-requisite to constrain both the number and spatial distribution of samples to be collected for further analysis, sustaining as well the subsequent extrapolation of results needed to fully characterise the surveyed system. Both areas were surveyed using portable gamma ray spectrometers with NaI(Tl) detectors. In situ gamma-ray measurements have clearly shown not only the poorly contrasting geological features, but also their differences representing: (i) a deformed/metamorphosed ophiolite complex and (ii) a monotonous meta-sedimentary sequence. The radiometric maps obtained have show heterogeneities that reflect mostly changes in rock-forming mineral assemblages, even in the presence of small variations of gamma radiation. These maps support objective criteria about the number/distribution of samples to be collected for subsequent comprehensive studies and reinforce the valuable contribution of in situ gamma spectrometry to assess, in radiological terms, the prevalent geological features. PMID- 20971017 TI - Transapical aortic valve replacement under real-time magnetic resonance imaging guidance: experimental results with balloon-expandable and self-expanding stents. AB - OBJECTIVE: Aortic valves have been implanted on self-expanding (SE) and balloon expandable (BE) stents minimally invasively. We have demonstrated the advantages of transapical aortic valve implantation (tAVI) under real-time magnetic resonance imaging (rtMRI) guidance. Whether there are different advantages to SE or BE stents is unknown. We report rtMRI-guided tAVI in a porcine model using both SE and BE stents, and compare the differences between the stents. METHODS: A total of 22 Yucatan pigs (45-57 kg) underwent tAVI. Commercially available stentless bioprostheses (21-25 mm) were mounted on either BE platinum-iridium stents or SE-nitinol stents. rtMRI guidance was employed as the intraoperative imaging. Markers on both types of stents were used to enhance visualization in rtMRI. Pigs were allowed to survive and had follow-up MRI scans and echocardiography at 1, 3, and 6 months postoperatively. RESULTS: rtMRI provided excellent visualization of the aortic valve implantation mounted on both stent types. The implantation times were shorter with the SE stents (60 +/- 14s) than with the BE stents (74 +/- 18s), (p=0.027). The total procedure time was 31 and 37 min, respectively (p=0.12). It was considerably easier to manipulate the SE stent during deployment, without hemodynamic compromise. This was not always the case with the BE stent, and its placement occasionally resulted in coronary obstruction and death. Long-term results demonstrated stability of the implants with preservation of myocardial perfusion and function over time for both stents. CONCLUSIONS: SE stents were easier to position and deploy, thus leading to fewer complications during tAVI. Future optimization of SE stent design should improve clinical results. PMID- 20971018 TI - First-in-man implantation of a trans-catheter aortic valve in a mitral annuloplasty ring: novel treatment modality for failed mitral valve repair. AB - The trans-catheter valve-in-valve concept has become a feasible therapeutic option for patients with failing degenerated bioprosthesis, who are deemed inoperable. However, little is known about the feasibility of this technique in failed valve annuloplasty. We report the first-in-man implantation of a trans catheter aortic valve within a mitral annuloplasty ring. Through a trans-apical trans-catheter approach, a 26-mm Sapien-Edwards valve was successfully implanted in a 72-year-old man with ischemic heart failure and failed mitral-valve annuloplasty. The present case report provides a critical appraisal of the procedural technique. PMID- 20971019 TI - Lessons from a mathematical hypothesis - modification of the endoventricular circular patch plasty. AB - OBJECTIVE: Surgical ventricular restoration has been the bailout therapy for end stage heart failure due to ischemic cardiomyopathy in patients not suitable for cardiac transplantation. The recently concluded STICH trial has stated that surgical restoration of the left ventricle does not benefit this subgroup of patients clinically as compared with revascularization alone. The reasons for failure of this trial are multifactorial. The technique of surgical ventricular restoration employed in the STICH trial was circular endoventricular patch plasty. The various drawbacks related to this technique can be offset by a modification based on a mathematical hypothesis, which should result in a more physiological ventricular geometry, with consequent late reverse remodeling and improved left-ventricular performance. METHODS: A total of 54 consecutive patients out of 102 patients with post-infarction left-ventricular aneurysms were studied before and 2 years after surgical ventricular restoration by linear endoventricular patch plasty using two-dimensional (2D) echocardiography and contrast ventriculography. RESULTS: Linear endoventricular patch plasty resulted in a decrease in end-diastolic volume (EDV) of 40.2 ml (95% confidence interval (CI): 33.6, 46.7) and stroke volume (SV) of 10.0 ml (95% CI: 6.6, 13.5) and increase in ejection fraction (EF) of 6.7% (95% CI: 5.5, 7.9). There was a further 14% decrease in EDV and SV (30%) at 2 years with increase in EF (20%). There was a persistent significant improvement in sphericity index. The changes in EDV and SV were linearly related (r=0.72, p<0.001) and persisted at 2 years following surgery. The change in EDV was linearly related to the EF (r=0.35, p=0.02). The left-ventricular shape analysis showed improvements in the anterior and anterolateral segments (effect size=1.1, p<0.001) with nonsignificant changes in the inferior segments, conforming to an ellipsoid geometry. CONCLUSIONS: Linear endoventricular patch plasty restored a physiological elliptical ventricular geometry with persistent late reverse remodeling. The decreases in EDVs following surgery were significantly linearly proportional to the decreases in SVs at rest, which conforms to the normal left-ventricular geometry. PMID- 20971020 TI - Development of a new trans-oral endoscopic approach for mediastinal surgery based on 'natural orifice surgery': preclinical studies on surgical technique, feasibility, and safety. AB - OBJECTIVE: In recent years, several surgical disciplines adopted endoscopic techniques. Presently, natural orifice approaches are under exploration to reduce surgical access trauma. We have developed a trans-oral endoscopic approach for endoscopic mediastinal surgery and have tested this new technique in preclinical studies for feasibility and safety. METHODS: We conducted an experimental anatomical study in fresh-frozen cadavers. By a midline, sublingual incision, we placed an optical scissor through a 6.0-mm trocar in the pretracheal region and created a working space; two additional trocars were placed by bi-vestibular incisions in the oral cavity. We visualized and followed the trachea down to the main bronchi. Paratracheal and subcarinal lymph nodes were resected bilaterally; the specimen could be removed through the midline channel. In an additional animal study in pigs, we tested the feasibility and safety for this surgical approach. Anatomical dissection allowed an estimate of collateral damage. RESULTS: In all cases, we could reach the target region endoscopically, and no conversion was necessary. Landmarks (the brachiocervical trunk, the azygos vein, and the pulmonary artery) were visualized easily and kept intact. A working space in the mediastinum could be established by the insufflation of air at 6-8mmHg. It was possible to harvest the specimen through the midline channel. Anatomical dissection of the cervical access route as well as of the mediastinal region showed no collateral damage. In the animal study, we encountered seroma of the surgical field due to the conditions of the animal model. The other outcomes with respect to pain and food intake were normal until the third postoperative day. No local infections occurred. Intraoperative gas exchange was normal and was not influenced by CO(2) insufflation with respect to blood gas analysis. CONCLUSION: These preclinical studies showed that the mediastinum could be reached by a trans oral endoscopic approach, based on natural orifice surgery. Complete compartment resection of the paratracheal and subcarinal lymph node stations was possible in a well-defined and clearly visible working space. This approach may enhance the extent of mediastinal resections in oncologic surgery. PMID- 20971021 TI - A method for comprehensive analysis of urinary acylglycines by using ultra performance liquid chromatography quadrupole linear ion trap mass spectrometry. AB - Acylglycines are an important class of metabolites that have been used in the diagnosis of several inborn errors of metabolism (IEM). However, current analytical methods detect only a few acylglycines. There is a need to profile these metabolites in a comprehensive manner for studying their functions and improving their diagnostic values for different IEM and potentially other diseases. We describe a sensitive method that combines the chromatographic resolving power of ultra-performance liquid chromatography (UPLC) to separate closely related metabolites including isomers with tandem mass spectrometry (MS/MS). Acylglycines were extracted from urine using an anion exchange solid phase extraction (SPE) cartridge. After UPLC separation, the acylglycines were detected on a hybrid triple quadrupole linear ion trap mass spectrometer. A set of standards were used for the development of an optimal MS acquisition method. Several acquisition modes using information derived from collision-induced dissociation breakdown curves were used to detect acylglycines. Using this method, 18 acylglycines were detected in the urine of healthy individuals and confirmed using standards, while 47 additional acylglycines were detected and tentatively identified, based on their retention and fragmentation pattern. Among the 65 acylglycines detected, only 18 of them have been previously reported in biofluids of healthy individuals. These results will be deposited in a public human metabolome database. This example illustrates that by developing a method tailored to the analysis of a class of metabolites sharing similar structural moieties, we can potentially identify many more new metabolites, thereby expanding the overall metabolome coverage. PMID- 20971022 TI - Clinical course after successful double lung transplantation in a patient with severe scoliosis. PMID- 20971023 TI - Middle ear effusions in dogs: an incidental finding? PMID- 20971024 TI - Central odontogenic fibroma. AB - Odontogenic fibroma (OF) is a benign odontogenic tumor characterized by various amounts of odontogenic epithelium in a mature fibrous stroma. Two variants can be distinguished: an intraosseous or central OF (COF) and an extraosseous or peripheral. The intraosseous variant is an extremely rare tumor that presents clinical, radiographic, and histopathologic variable findings. A thorough review of the English literature revealed 78 cases of COF so far. Thus, we report an additional case of COF occurring in the maxilla of a 36-year-old woman. In addition, we performed a brief description and discussion of the cases reported in the maxilla and mandible. PMID- 20971025 TI - [Diabetic mastopathy: a recurrent benign breast disease]. AB - Diabetic mastopathy is an uncommon benign entity occurring in young women with type 1 diabetes. Its clinical and radiological signs are not specific and often mimic a breast carcinoma. However, the benign nature of this lesion is easily recognized on histological examination, visualizing dense keloid-like fibrosis, lymphocytic lobulitis and ductitis with lymphocytic perivascular inflammation, with or without epithelioid-like fibroblasts. Surgery can generally be avoided. The evolution of this entity is characterized by the risk of local growth, bilateralisation or recurrence after surgical treatment. We present a case in which the core biopsy allowed the diagnosis of a diabetic mastopathy and we discuss its clinical, diagnostic, pathological and therapeutic particularities. PMID- 20971026 TI - [Kiwi vacuum extractor versus forceps and spatula: maternal and fetal morbidity evaluation in 169 fetal extractions]. AB - AIM: To evaluate maternal and fetal complications resulting from the use of the Kiwi vacuum extractor and to compare them with those resulting from the use of forceps or spatula. PATIENTS AND METHODS: Patients who had instrumental extraction between November 2006 and April 2007 were included in a unicentric retrospective study. Complications resulting from the use of Kiwi vacuum extractor and those of other instruments were compared. RESULTS: One hundred and sixty-nine patients where included, 79 had extraction with Kiwi vacuum extractor. The two populations (women having extraction with Kiwi and woman having extraction with spatula or forceps) were similar in terms of maternal characteristics, progress of labour and delivery. The rate of episiotomies was significantly lower with KIWI (73.1% versus 94.4%; P=0.0001), as well as was postpartum haemorrhage rate (8.9 % versus 18.9%; P=0.04). No perineal tear of second or third degree occurred with Kiwi. Kiwi vacuum extractor was associated with a higher rate of shoulder dystocia (12.8% versus 6.7%, NS), but related fetal complication rates were similar in the two groups. The extraction failure rate was significantly higher with Kiwi (11.4% versus 4.4%; P=0.04), but cesarean section rate was similar for the two groups (1.3 % versus 4.4%). DISCUSSION AND CONCLUSION: This study is the first comparing complications occurring after extraction with KIWI vacuum extractor to those occurring with other instruments. Although the results are limited by the retrospective nature of the study and the small size of the workforce, our study suggests that Kiwi vacuum extractor is associated with a lower rate of maternal complications and a rate of fetal complication similar to other kind of instruments. This instrument should be promoted and taught to younger patricians. Our study also revealed higher failure and shoulder dystocia rates. Larger studies are needed to better evaluate risks factor concerning these two complications in order to optimise the use of Kiwi vacuum extractor. PMID- 20971027 TI - Sudden death of a young male with previously undiagnosed autosomal dominant polycystic kidney disease (ADPKD). AB - Autosomal dominant polycystic kidney disease (ADPKD) is one of the best known genetic diseases. However, in only very rare cases does it present as an abnormal death followed by clarification of its genetic background. We experienced a case in which ADPKD first became evident from the results of forensic autopsy, on the basis of which all potentially affected family members were offered genetic and other medical examinations. In this way, forensic medicine was able not only to determine the cause of death but to contribute to preventive medicine as well. PMID- 20971028 TI - Ultrasonic-assisted synthesis of chrysin derivatives linked with 1,2,3-triazoles by 1,3-dipolar cycloaddition reaction. AB - The 1,3-dipolar cycloaddition reaction between 7-(3-azidopropoxy)-5 hydroxyflavone and phenylacetylene was carried out to investigate the synthesis of 7-(3-(4-phenyl-1,2,3-triazol-1-yl)propoxy)- 5-hydroxyflavone in presence of ultrasound (sono-synthesis) and absence of ultrasound (conventional method) under relatively optimized solvent and catalyst conditions. The reaction rate was notably accelerated with the help of ultrasound irradiation. An experiment was especially carried out for investigating the acceleration mechanism of ultrasound on the cycloaddition. A novel series of chrysin derivatives linked with 1,2,3 triazoles were obtained by the copper(I)-catalyzed 1,3-dipolar Huisgen cycloaddition reaction using t-BuOH/H(2)O (1:1 v/v) as reaction solvents and CuSO(4).5H(2)O/sodium ascorbate as the catalyst at room temperature in the presence of ultrasound irradiation. Their structures are elucidated by NMR, ESI MS, IR and Elemental analysis. PMID- 20971029 TI - Unusually increased arm swing in an apraxic upper limb in corticobasal syndrome. PMID- 20971031 TI - Origins of spatial, temporal and numerical cognition: Insights from comparative psychology. AB - Contemporary comparative cognition has a large repertoire of animal models and methods, with concurrent theoretical advances that are providing initial answers to crucial questions about human cognition. What cognitive traits are uniquely human? What are the species-typical inherited predispositions of the human mind? What is the human mind capable of without certain types of specific experiences with the surrounding environment? Here, we review recent findings from the domains of space, time and number cognition. These findings are produced using different comparative methodologies relying on different animal species, namely birds and non-human great apes. The study of these species not only reveals the range of cognitive abilities across vertebrates, but also increases our understanding of human cognition in crucial ways. PMID- 20971032 TI - Mechanical modeling and structural analysis of the primary plant cell wall. AB - Plant cell growth is a fundamental process during plant development whose spatial and temporal dynamics are controlled by the cell wall. Modeling mechanical aspects of cell growth therefore requires the integration of structural cell wall details with quantitative biophysical parameters. Recent advances in microscopic techniques and mechanical modeling have made significant contributions to the field of cell wall biomechanics. Live observation of cellulose microfibrils at high z-resolution now enables determining the dynamic orientation of these polymers in the different wall layers of growing cells. Mechanical modeling approaches have been developed to operate at the scale of individual molecules and will thus be able to exploit the availability of the high-resolution structural data. The combination of these techniques has the potential to make a significant and quantitative contribution to our understanding of plant growth and development. PMID- 20971030 TI - Glucocerebrosidase mutations in diffuse Lewy body disease. AB - Clinicogenetic and pathological studies have shown that mutations of the glucocerebrosidase gene (GBA) are a risk factor for Parkinson's disease and Lewy body disorders. In the present study, we have identified GBA mutations in 6.8% (4/59) of cases with a pathological diagnosis of diffuse Lewy body disease. Taken with previous studies, it appears that GBA mutations are associated with a more diffuse pattern of Lewy body distribution involving the cerebral cortex than the brainstem/limbic distribution observed in typical Parkinson's disease. PMID- 20971033 TI - From receptors to responses. PMID- 20971034 TI - Microbiota-immune system interaction: an uneasy alliance. AB - An estimated 100 trillion microbes colonize human beings, with the majority of organisms residing in the intestines. This microbiota impacts host nutrition, protection, and gut development. Alterations in microbiota composition are associated with susceptibility to various infectious and inflammatory gut diseases. The mucosal surface is not a static barrier that simply prevents microbial invasion but a critical interface for microbiota-immune system interactions. Recent work suggests that dynamic interactions between microbes and the host immune system at the mucosal surface inform immune responses both locally and systemically. This review focuses on intestinal microbiota-immune interactions leading to intestinal homeostasis, and show that these interactions at the GI mucosal surface are critical for driving both protective and pathological immune responses systemically. PMID- 20971035 TI - Synthesis and photophysical processes of an anthracene derivative containing hole transfer groups. AB - A novel luminescent compound 9,10-di-(N-carbazovinylene)anthracene (DCVA) was synthesized by Heck reaction of 9,10-dibromoanthracene and N-vinylcarbazole. The structure was characterized by MS, 1H NMR and Elemental analysis. The photoluminescent properties of DCVA have been carefully investigated by UV-vis absorption and fluorescence emission spectra. The results showed that the luminescent quantum yield of DCVA was 0.73 in THF and it emitted blue-light with the band gap of 3.60 eV estimated from the onset absorption. In addition, the light-emission of DCVA can be quenched by electron acceptor (dimethyl terephthalate), however, the fluorescent intensities of DCVA were slowly increased with the addition of electron donor (N,N-dimethylaniline). Furthermore, the molecular interactions of DCVA with fullerene (C60) and carbon nanotubes (CNTs) were also investigated, which indicated the organic luminescent compound can be used as new fluorescent probe. PMID- 20971036 TI - Investigations of preferential solvation on 1,4-dimethoxy-3-methyl anthracene 9,10-dione. AB - Preferential solvation of 1,4-dimethoxy-3-methyl anthracene-9,10-dione (DMMAD) has been investigated using optical absorption technique. The preferential solvation parameters show that the DMMAD is preferentially solvated by acetone in acetone (AC)+propan-2-ol (PROH), AC+CH2Cl2 and AC+CCl4 mixtures. DMMAD prefers PROH in PROH+CCl4 mixture. In the case of benzene+CCl4 mixture DMMAD is preferentially solvated by benzene in benzene rich region and by CCl4 in CCl4 rich region. The results have been discussed in terms of hydrogen bonding, dipole dipole and induced dipole-dipole interactions between DMMAD and solvent molecules. PMID- 20971037 TI - A study of conflict between molecular phylogeny and taxonomy in the Desmidiaceae (Streptophyta, Viridiplantae): analyses of 291 rbcL sequences. AB - Molecular phylogenetic analyses of 93 new and 198 non-redundant GenBank rbcL sequences of the family Desmidiaceae (Zygnematophyceae, Streptophyta) established 22 mostly highly supported clades, in addition to four non-supported lineages and eight single-taxon branches within the family. Nine novel clades and single-taxon branches were identified, suggesting that current taxon sampling has not reached saturation in the family. The highly polyphyletic nature of most desmid genera corroborated in this study using a large taxon set, calls for re-evaluation of the genus concept in the family Desmidiaceae that traditionally relied on features of cell morphology. Molecular phylogenetic data have shown that these morphological characters are highly homoplastic or plesiomorphic and thus cannot be used to delineate genera. The dramatic discrepancy between the currently practised systematic treatment of the family and the composition of the clades based on sequence comparisons requires emendation of almost all existing genera and description of a larger number of novel genera. The clades identified during this study provide a framework for the future emendation/description of genera in the Desmidiaceae. PMID- 20971038 TI - Sirtuin-1 regulation of mammalian metabolism. AB - Sirtuin-1 (SirT1) is a nutrient-sensing deacetylase whose levels and activity increase with caloric restriction to preserve euglycemia and promote efficient energy utilization. Focusing on data obtained in vivo, we review how SirT1 orchestrates the adaptive response to fasting by stimulating hepatic gluconeogenesis and fatty acid oxidation, increasing circulating adiponectin levels and limiting immune activation. Finally, we consider its viability as a therapeutic target for the treatment of type 2 diabetes. PMID- 20971039 TI - T cell coinhibition in prostate cancer: new immune evasion pathways and emerging therapeutics. AB - T cell-mediated adaptive immune response is controlled by both positive costimulation and negative coinhibition, generated mainly by the interaction between the B7 family and their receptor CD28 family. Coinhibition is exploited by prostate cancer as an immune evasion pathway. Overexpression of coinhibitory B7x and B7-H3 in prostate cancer correlates with poor disease outcome, whereas tumor-infiltrating immune cells have enhanced expression of PD-L1 and its receptor PD-1. New insights into the complex mechanisms governing B7 expression in the tumor microenvironment have been reported and therapies aimed at overcoming T cell coinhibition with antagonistic monoclonal antibodies are emerging as effective tumor immunotherapies. Therapies that block B7x and B7-H3, either as monotherapies or in synergism with traditional therapies, should be pursued. PMID- 20971040 TI - How artemisinin-containing combination therapies slow the spread of antimalarial drug resistance. AB - Antimalarial drug therapies containing artemisinins, 'ACTs', have become the mainstay for treating uncomplicated malaria in endemic countries. This is a major public health achievement requiring substantial political, financial and scientific input. The most compelling scientific argument for ACT deployment employed a very simple basic rationale that emphasised their role in slowing the origin of drug resistance while largely neglecting the additional role(s) of ACTs in slowing or preventing the spread of resistance once it has arisen. Recent reports suggest that early stages of resistance to artemisinins and/or its partner drugs could be occurring, thus it is timely to briefly review exactly how ACTs slow the origin and spread of resistance and to interpret the threat of resistance within this context. PMID- 20971041 TI - The effects of needle puncture injury on microscale shear strain in the intervertebral disc annulus fibrosus. AB - BACKGROUND CONTEXT: Needle puncture of the intervertebral disc (IVD) is required for delivery of therapeutic agents to the nucleus pulposus and for some diagnostic procedures. Needle puncture has also been implicated as an initiator of disc degeneration. It is hypothesized that needle puncture may initiate IVD degeneration by altering microscale mechanical behavior in the annulus fibrosus (AF). PURPOSE: Quantify the changes in AF microscale strain behavior resulting from puncture with a hypodermic needle. STUDY DESIGN: Cadaveric IVD tissue explant study. METHODS: Annulus fibrosus explants from bovine caudal IVDs that had been punctured radially with hypodermic needles were loaded in dynamic sinusoidal shear while being imaged with a confocal microscope. Digital image analysis was used to quantify local tissue strain and damage propagation with repeated shearing. RESULTS: Needle puncture changed the distribution of microscale shear strains in the AF under load from homogenous (equal to far field) to a distinct pattern of high (4* far field) and low (0.25* far field) strain areas. Repeated loading did not cause further growth of the disruption beyond the second cycle. CONCLUSIONS: Needle puncture results in a drastic alteration of microscale strain behavior in the AF under load. This alteration may directly initiate disc degeneration by being detrimental to tissue-cell mechanotransduction. PMID- 20971042 TI - Regulation of DNA strand exchange in homologous recombination. AB - Homologous recombination, the exchange of DNA strands between homologous DNA molecules, is involved in repair of many structural diverse DNA lesions. This versatility stems from multiple ways in which homologous DNA strands can be rearranged. At the core of homologous recombination are recombinase proteins such as RecA and RAD51 that mediate homology recognition and DNA strand exchange through formation of a dynamic nucleoprotein filament. Four stages in the life cycle of nucleoprotein filaments are filament nucleation, filament growth, homologous DNA pairing and strand exchange, and filament dissociation. Progression through this cycle requires a sequence of recombinase-DNA and recombinase protein-protein interactions coupled to ATP binding and hydrolysis. The function of recombinases is controlled by accessory proteins that allow coordination of strand exchange with other steps of homologous recombination and that tailor to the needs of specific aberrant DNA structures undergoing recombination. Accessory proteins are also able to reverse filament formation thereby guarding against inappropriate DNA rearrangements. The dynamic instability of the recombinase-DNA interactions allows both positive and negative action of accessory proteins thereby ensuring that genome maintenance by homologous recombination is not only flexible and versatile, but also accurate. PMID- 20971043 TI - RAD18 lives a double life: Its implication in DNA double-strand break repair. AB - Maintenance of genome stability depends on efficient and accurate repair of DNA lesions. Failure to properly repair damaged DNA can cause cell death, mutations and chromosomal instability, which eventually lead to tumorigenesis. The E3 ligase RAD18 is well-known for its function in DNA damage bypass and post replication repair (PRR) in yeast and vertebrates via its ability to facilitate PCNA mono-ubiquitination at stalled replication forks. However, emerging evidence has also indicated that RAD18 plays an important role in homologous recombination (HR) in mammalian cells, which is an error-free DNA repair pathway that mediates the repair of double-strand breaks (DSBs). Here, we review how RAD18 carries out these distinct functions in response to different types of DNA lesions. PMID- 20971044 TI - Liquid chromatography/tandem mass spectrometry assay for the simultaneous determination of cefoperazone and sulbactam in plasma and its application to a pharmacokinetic study. AB - A rapid and highly sensitive liquid chromatography-tandem mass spectrometric (LC MS/MS) method for simultaneous determination of cefoperazone sodium and sulbactam sodium in human plasma was developed. The analytes and internal standard (IS), cefuroxime sodium, were extracted from human plasma via liquid-liquid extraction with ethyl acetate and separated on a Waters Xterra C18 column within 3.5 min. Quantitation was performed on a triple quadrupole mass spectrometer employing electrospray ionization technique, operating in selected reaction monitoring (SRM) and negative ion mode. The precursor to product ion transitions monitored for cefoperazone, sulbactam and IS were m/z 644.1->528.0, 232.1->140.0, and 423.0 >362.0, respectively. The assay was validated in the linear range of 0.1-20 MUg/mL for cefoperazone and 0.02-4 MUg/mL for sulbactam. The intra- and inter-day precisions (CV%) were within 8.39% for each analyte. The recoveries were greater than 87.3% for cefoperazone and 87.2% for sulbactam. Each analyte was found to be stable during all sample storage, preparation and analytical procedures. The method was successfully applied in a pharmacokinetic study of Sulperazon injection in six hospital-acquired pneumonia (HAP) patients. PMID- 20971045 TI - [Partial trisomy and mosaicism associated with Fallot Tetralogy]. PMID- 20971046 TI - [The birth of nephrology in Brussels: P.-P. Lambert]. AB - The career and scientific contributions of Professor P.-P. Lambert (1910-1999) are outlined. They remain an outstanding example of clinical investigation, resting on a demanding bedside approach fertilized by laboratory research. P.-P. Lambert was a founding member of the Societe de nephrologie which he presided from 1960 to 1962. PMID- 20971047 TI - Body reshaping surgery after massive weight loss. PMID- 20971048 TI - Gastric banding using adjustable silastic ring in 2010. Technique, indications, results, and management. PMID- 20971049 TI - Sleeve gastrectomy: technique and results. PMID- 20971050 TI - Carbon nanotube-modified sodium dodecyl sulfate-polyacrylamide gel electrophoresis for molecular weight determination of proteins. AB - The effect of incorporating carbon nanotubes (CNTs) in the gel matrix on the electrophoretic mobility of proteins based on their molecular weight differences was investigated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). More specifically, a reduction in standard deviation in the molecular weight calibration plots by 55% in the case of multiwalled carbon nanotubes (MWCNTs) and by 34% in the case of single-walled carbon nanotubes (SWCNTs) compared with that of pristine polyacrylamide gels was achieved after incorporating an insignificant amount of functionalized CNTs into the gel matrix. A mechanism based on a more uniform pore size distribution in CNT modified polyacrylamide gel matrix is proposed. Furthermore, the impact of SWCNTs and MWCNTs on the mobility of proteins in different molecular weight regimes at a given acrylamide concentration offers a tunable gel matrix in terms of the selection of molecular weight ranges of proteins. The robustness and excellent reproducibility of the CNT-PAGE protocol are expected to have a significant impact on the molecular weight determination of newly isolated proteins. PMID- 20971051 TI - Label-free mass spectrometry-based relative quantification of proteins separated by one-dimensional gel electrophoresis. AB - Here we present a matrix-assisted laser desorption/ionization tandem time-of flight (MALDI-TOF/TOF)-based label-free relative protein quantification strategy that involves sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE) separation of proteins followed by in-gel trypsin digestion. The main problem encountered in gel-based protein quantification is the difficulty in achieving complete and consistent proteolytic digestion. To solve this problem, we developed a high-pressure-assisted in-gel trypsin digestion method that is based on pressure cycling technology (PCT). The PCT approach performed at least as well as the conventional overnight in-gel trypsin digestion approach in parameters such as number of peaks detected, number of peptides identified, and sequence coverage, and the digestion time was reduced to 45 min. The gel/mass spectrometry (MS)-based label-free protein quantification method presented in this work proved the applicability of the signal response factor concept for relative protein quantification previously demonstrated by other groups using the liquid chromatography (LC)/MS platform. By normalizing the average signal intensities of the three most intense peptides of each protein with the average intensities of spiked synthetic catalase tryptic peptides, which we used as an internal standard, we observed spot-to-spot and lane-to-lane coefficients of variation of less than 10 and 20%, respectively. We also demonstrated that the method can be used for determining the relative quantities of proteins comigrating during electrophoretic separation. PMID- 20971052 TI - Heme ladder, a direct molecular weight marker for immunoblot analysis. AB - Detection methods for immunoblot analysis are often based on peroxidase conjugates. However, molecular weight markers directly detectable for general use in such systems are not available. Here, we describe the preparation of a direct molecular weight marker consisting of heme-tagged proteins, whose enzymatic activities make them detectable simultaneously with the antigen in peroxidase based immunoblot systems. The peroxidase activity results from the covalent attachment of heme to selected engineered periplasmic proteins, catalyzed by the cytochrome c maturation system of Escherichia coli. The newly designed heme tagged proteins were combined with a previously constructed heme-tagged maltose binding protein and cytochrome c. The resulting heme ladder was shown to be suitable as a protein standard for direct molecular weight estimation in immunoblot analysis due to the peroxidase activity of its constituents. The heme ladder consists of proteins between 12 and 85 kDa and can be produced at low cost. The marker was stable when kept at 4, -20, and -80 degrees C for >6 months. PMID- 20971053 TI - Application of gelatin zymography for evaluating low levels of contaminating neutrophils in red blood cell samples. AB - Supposedly "homogeneous" red blood cell (RBC) samples are commonly obtained by "washing" whole blood free of plasma, platelets, and white cells with physiological solutions, a procedure that does not result, however, in sufficient removal of polymorphonuclear neutrophils (PMNs), leading to possible artifactual results. Pure RBC samples can be obtained only by leukodepletion procedures. Proposed here is a version of gelatin zymography adapted to detect matrix metalloproteinase 9 (MMP-9), selectively expressed by PMNs, in heterogeneous mixtures of RBCs and PMNs that can reveal contamination at levels as low as 1 PMN/106 RBCs. PMID- 20971054 TI - A fluorescence polarization assay using an engineered human respiratory syncytial virus F protein as a direct screening platform. AB - Human respiratory syncytial virus (hRSV) typically affects newborns and young children. Even though it can cause severe and, in some cases, lifelong respiratory infections, there are currently no Food and Drug Administration (FDA) approved therapeutics that control this virus. The hRSV F protein facilitates viral fusion, a critical extracellular event that can be targeted for therapeutic intervention by disrupting the assembly of a postfusion 6-helix bundle (6HB) within the hRSV F protein. Here we report the development of a fluorescence polarization (FP) assay using an engineered hRSV F protein 5-helix bundle (5HB). We generated the 5HB and validated its ability to form a 6HB in an FP assay. To test the potential of 5HB as a screening tool, we then investigated a series of truncated peptides derived from the "missing" sixth helix. Using this FP-based 5HB system, we have successfully demonstrated that short peptides can prevent 6HB formation and serve as potential hRSV fusion inhibitors. We anticipate that this new 5HB system will provide an effective tool to identify and study potential antivirals to control hRSV infection. PMID- 20971055 TI - A duplex approach for immunochemical staining and typing of proteins in Western blots. AB - The qualitative and semiquantitative Western blotting technique enables the detection of separate proteins and the determination of subtypes and fragments by specific immunological reactions. Protein typing on immunoblots is restricted to antibody-specific determination, with the result of a specific banding pattern. For protein characterization, several antibodies that recognize different epitopes within the protein sequence are used. However, repeated or parallel gel runs are needed. Here we describe a sequential determination of prion proteins in healthy and pathological states that both consist of di-, mono-, and nonglycosylated isoforms using a single blot with two antibodies from two species that recognize one antigen with two epitopes. The band signals are visualized by using different chemiluminescent substrate reactions. This application can be used in the fields of diagnostics and public health to detect full-length and fragmented proteins and can also be used for characterization of overlaying proteins. PMID- 20971056 TI - An improved malachite green assay of phosphate: mechanism and application. AB - The classical malachite green (MLG) assay of phosphate, which added MLG after molybdate to the acidified reaction solutions of phosphate, tolerated interference from papaverine, sildenafil, and some similar hydrophobic amines. Resonance Rayleigh scattering signals, the alleviation of interference by poly(vinyl alcohol), and the precipitation of some yellow complexes supported that the irreversible aggregation of the complexes of a hydrophobic amine of interference and phosphomolybdate reduced the amounts of phosphomolybdate accessible to MLG and caused the interference. By adding MLG before molybdate to the acidified reaction solutions of phosphate, the complexes of phosphomolybdate and MLG were preferentially formed before the complexes of phosphomolybdate and such a hydrophobic amine effectively aggregated; thereby, an improved MLG assay of phosphate with the resistance to common hydrophobic amines was developed. Using the improved MLG assay of phosphate and a phosphatase to release phosphate from AMP, a spectrometric method successfully estimated the half-inhibition concentrations of papaverine on the recombinant human cyclic nucleotide phosphodiesterase (PDE) isozyme 4 and the mixture of PDE isozymes from rabbit brain. Therefore, the improved MLG assay of phosphate was a favorable and universal technique for developing spectrometric methods for characterizing and screening inhibitors of enzymes that release phosphate during their actions. PMID- 20971057 TI - Application of inkjet printing technique for biological material delivery and antimicrobial assays. AB - A modified commercial inkjet printer was developed to deliver biological samples. The active Escherichia coli cells were directly printed at precisely targeted positions on agar-coated substrates via this technique to generate complex bacterial colony patterns. Viable cell arrays with a high density of 400 dots/cm(2) were obtained without the addition of any surfactants or other chemicals. Moreover, an applicable example of multiple-layer inkjet printing technique was adapted to deposit bacteria and antibiotics for antimicrobial potential assays. After fluorescent E. coli cells were printed, gradient concentrations of water-soluble antibiotics were ejected onto them to determine its minimum inhibitory concentration (MIC) to test the antimicrobial activities. This approach simplifies the experimental manipulation by replacing laborious manual loading processes with automatically controlled printing procedures, which makes it a versatile tool for high-throughput applications. PMID- 20971059 TI - Mitochondrial superoxide anion radicals mediate induction of apoptosis in cardiac myoblasts exposed to chronic hypoxia. AB - Both reactive oxygen species (ROS) and ATP depletion may be significant in hypoxia-induced damage and death, either collectively or independently, with high energy requiring, metabolically active cells being the most susceptible to damage. We investigated the kinetics and effects of ROS production in cardiac myoblasts, H9C2 cells, under 2%, 10% and 21% O2 in the presence or absence of apocynin, rotenone and carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone. H9C2 cells showed significant loss of viability within 30 min of culture at 2% oxygen which was not due to apoptosis, but was associated with an increase in protein oxidation. However, after 4 h, apoptosis induction was observed at 2% oxygen and also to a lesser extent at 10% oxygen; this was dependent on the levels of mitochondrial superoxide anion radicals determined using dihydroethidine. Hypoxia-induced ROS production and cell death could be rescued by the mitochondrial complex I inhibitor, rotenone, despite further depletion of ATP. In conclusion, a change to superoxide anion radical steady state level was not detectable after 30 min but was evident after 4 h of mild or severe hypoxia. Superoxide anion radicals from the mitochondrion and not ATP depletion is the major cause of apoptotic cell death in cardiac myoblasts under chronic, severe hypoxia. PMID- 20971058 TI - Rearrangement reactions catalyzed by cytochrome P450s. AB - Cytochrome P450s promote a variety of rearrangement reactions both as a consequence of the nature of the radical and other intermediates generated during catalysis, and of the neighboring structures in the substrate that can interact either with the initial radical intermediates or with further downstream products of the reactions. This article will review several kinds of previously published cytochrome P450-catalyzed rearrangement reactions, including changes in stereochemistry, radical clock reactions, allylic rearrangements, "NIH" and related shifts, ring contractions and expansions, and cyclizations that result from neighboring group interactions. Although most of these reactions can be carried out by many members of the cytochrome P450 superfamily, some have only been observed with select P450s, including some reactions that are catalyzed by specific endoperoxidases and cytochrome P450s found in plants. PMID- 20971060 TI - Trichosanthin affects HSV-1 replication in Hep-2 cells. AB - Trichosanthin (TCS) is a type I ribosome-inactivating protein that inhibits the replication of both human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 1 (HSV-1). The mechanism of inhibition is not clear. This investigation explored the effects of TCS on the stages of HSV-1 infection in Hep 2 cells, from attachment to release. We demonstrated that TCS reduced HSV-1 antigen and DNA content and interfered with viral replication as early as 3-15 h after infection. TCS had no effect on HSV-1 attachment, penetration or immediate early gene expression. However, the expression of early and late genes and virion release were diminished. In summary, this study demonstrates that TCS primarily affects HSV-1 replication in Hep-2 cells during the early to late infection period. PMID- 20971061 TI - Immunomodulation of monocyte-derived dendritic cells through ligation of tumor produced mucins to Siglec-9. AB - Dendritic cells (DCs) play an essential role in the induction and maintenance of an effective immune response and express multiple siglecs. In the present study, we investigated whether or not the ligation of tumor-produced mucins with Siglec 9 expressed on immature DCs is related to escape from immunosurveillance in the tumor-bearing state. Expression of Siglec-9 was up-regulated on the development of monocytes into immature DCs and was decreased in mature DCs. Binding of various mucins and artificial glycopolymers carrying poly (NeuAc alpha2,6 LacNAc) or poly (NeuAc alpha2,3 LacNAc) to Siglec-9 was demonstrated by means of a plate assay. These mucins also bound to the surface of immature DCs. When immature DCs were treated with LPS in the presence of these mucins or artificial glycopolymers, the production of IL-12 was significantly reduced, but that of IL 10 was not. Furthermore, IL-12 production was decreased to a similar level on treatment with anti-Siglec-9 mAb. Mucins prepared from serum of cancer patients actually could bind to Siglec-9. These results suggest that Siglec-9 expressed on DCs is involved in immunoregulation through ligation with mucins in an epithelial cancer patient. PMID- 20971062 TI - Association of the subunits of the calcium-independent receptor of alpha latrotoxin. AB - CIRL-1 also called latrophilin 1 or CL belongs to the family of adhesion G protein-coupled receptors (GPCRs). As all members of adhesion GPSR family CIRL-1 consists of two heterologous subunits, extracellular hydrophilic p120 and heptahelical membrane protein p85. Both CIRL-1 subunits are encoded by one gene but as a result of intracellular proteolysis of precursor, mature receptor has two-subunit structure. It was also shown that a minor portion of the CIRL-1 receptor complexes dissociates, producing the soluble receptor ectodomain, and this dissociation is due to the second cleavage at the site between the site of primary proteolysis and the first transmembrane domain. Recently model of independent localization p120 and p85 on the cell surface was proposed. In this article we evaluated the amount of p120-p85 complex still presented on the cellular membrane and confirmed that on cell surface major amount of mature CIRL 1 presented as a p120-p85 subunit complex. PMID- 20971063 TI - Connective tissue growth factor is a substrate of ADAM28. AB - ADAM28, a member of the ADAM (a disintegrin and metalloproteinase) gene family, is over-expressed by carcinoma cells and the expression correlates with carcinoma cell proliferation and progression in human lung and breast carcinomas. However, information about substrates of ADAM28 is limited. We screened interacting molecules of ADAM28 in human lung cDNA library by yeast two-hybrid system and identified connective tissue growth factor (CTGF). Binding of CTGF to proADAM28 was demonstrated by yeast two-hybrid assay and protein binding assay. ADAM28 cleaved CTGF in dose- and time-dependent manners at the Ala(181)-Tyr(182) and Asp(191)-Pro(192) bonds in the hinge region of the molecule. ADAM28 selectively digested CTGF in the complex of CTGF and vascular endothelial growth factor(165) (VEGF(165)), releasing biologically active VEGF(165) from the complex. RT-PCR and immunohistochemical analyses demonstrated that ADAM28, CTGF and VEGF are commonly co-expressed in the breast carcinoma tissues. These data provide the first evidence that CTGF is a novel substrate of ADAM28 and suggest that ADAM28 may promote VEGF(165)-induced angiogenesis in the breast carcinomas by the CTGF digestion in the CTGF/VEGF(165) complex. PMID- 20971064 TI - Myosin light chain mono- and di-phosphorylation differentially regulate adhesion and polarity in migrating cells. AB - Myosin II is a critical regulator of cell migration that generates polarity, controls protrusion, and promotes adhesion maturation and retraction of the rear. Myosin II has an ATPase motor domain that is regulated by phosphorylation of the regulatory light chain (RLC) on Thr18 and Ser19. Here, we address the activation and specific function of the two phosphorylation states of the RLC, mono- (S19) and/or di-phosphorylation (T18+S19), in cell polarity and adhesion. Specific phospho-antibodies reveal that adhesion to fibronectin via the alpha5beta1 integrin promotes localized mono- and di-phosphorylation of the RLC that follow different kinetics. Using phospho-mimetic mutants, we show that mono phosphorylation promotes adhesion maturation in protrusions resulting in focal adhesions throughout the cell. In contrast, di-phosphorylation produces large, stable actomyosin bundles and large, non-dynamic adhesions that define the rear. Finally, RLC phosphorylation regulates the assembly and stability of MIIB, but not MIIA. Our data reveal a novel mechanism by which the degree of phosphorylation of the RLC differentially controls cell adhesion and polarity. PMID- 20971065 TI - Transgenically expressed rice germin-like protein1 in tobacco causes hyper accumulation of H2O2 and reinforcement of the cell wall components. AB - Our recent report documented that the rice germin-like protein1 (OsGLP1), being a cell wall-associated protein involves in disease resistance in rice and possesses superoxide dismutase (SOD) activity as recognized by heterologous expression in tobacco. In the present study, the transgenic tobacco plants were analyzed further to decipher the detailed physiological and biochemical functions of the OsGLP1 and its associated SOD activity. The transgenic tobacco lines expressing SOD-active OsGLP1 showed tolerance against biotic and abiotic stresses mitigated by hyper-accumulating H(2)O(2) upon infection by fungal pathogen (Fusarium solani) and treatment to chemical oxidizing agent (ammonium persulfate), respectively. Histological staining revealed enhanced cross-linking of the cell wall components in the stem tissues of the transgenic plants. Fourier transform infrared spectroscopy (FTIR) analysis of the biopolymer from the stem tissues of the transgenic and untransformed plants revealed differential banding pattern of the spectra corresponding to various functional groups. Our findings demonstrate that the OsGLP1 with its inherent SOD activity is responsible for hyper accumulation of H(2)O(2) and reinforcement of the cell wall components. PMID- 20971066 TI - 4'-Acetoamido-4-hydroxychalcone, a chalcone derivative, inhibits glioma growth and invasion through regulation of the tropomyosin 1 gene. AB - Chalcones are precursors of flavonoids and have been shown to have anti-cancer activity. Here, we identify the synthetic chalcone derivative 4'-acetoamido-4 hydroxychalcone (AHC) as a potential therapeutic agent for the treatment of glioma. Treatment with AHC reduced glioma cell invasion, migration, and colony formation in a concentration-dependent manner. In addition, AHC inhibited vascular endothelial growth factor-induced migration, invasion, and tube formation in HUVECs. To determine the mechanism underlying the inhibitory effect of AHC on glioma cell invasion and migration, we investigated the effect of AHC on the gene expression change and found that AHC affects actin dynamics in U87MG glioma cells. In actin cytoskeleton regulating system, AHC increased tropomyosin expression and stress fiber formation, probably through activation of PKA. Suppression of tropomyosin expression by siRNA or treatment with the PKA inhibitor H89 reduced the inhibitory effects of AHC on glioma cell invasion and migration. In vivo experiments also showed that AHC inhibited tumor growth in a xenograft mouse tumor model. Together, these data suggest that the synthetic chalcone derivative AHC has potent anti-cancer activity through inhibition of glioma proliferation, invasion, and angiogenesis and is therefore a potential chemotherapeutic candidate for the treatment of glioma. PMID- 20971067 TI - The mammalian INO80 complex is recruited to DNA damage sites in an ARP8 dependent manner. AB - Dynamic changes in chromatin structure are essential for efficient DNA processing such as transcription, replication, and DNA repair. Histone modifications and ATP dependent chromatin remodeling are important for the alteration of chromatin structure. The INO80 chromatin remodeling complex plays an important role in HR mediated repair of DNA double-strand breaks (DSBs). In yeast, the INO80 complex is recruited to the sites of DSBs via direct interaction with phosphorylated histone H2A and facilitates the processing of DSB ends. However, the function of the mammalian INO80 complex in DNA repair is mostly unknown. Here, we show that the mammalian INO80 complex is recruited to the laser-induced DNA damage sites in a phosphorylated H2AX (gammaH2AX)-independent manner. We also found that an actin related protein, ARP8, is an important subunit that is required for the recruitment of the mammalian INO80 complex to the DNA damage sites, although the recruitment of the yeast INO80 complex requires its Nhp10 or Arp4 subunits. These results suggest that the mammalian INO80 complex is also recruited to DNA damage sites similarly to the yeast INO80 complex, but the mechanism of this recruitment may be different from that of the yeast INO80 complex. These findings provide new insights into the mechanisms of DNA repair in mammalian cells. PMID- 20971068 TI - Fish oil prevents breast cancer cell metastasis to bone. AB - The data derived from epidemiological and animal models confirm a beneficial effect of fish oil (rich in omega-3 polyunsaturated fatty acids) in the amelioration of tumor growth and progression, including breast cancer. The breast cancer patients often develop bone metastasis evidenced by osteolytic lesions, leading to severe pain and bone fracture. Using a mouse model of MDA-MB-231 human breast cancer cell metastasis to bone, here we show that fish oil diet enriched in DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) prevents the formation of osteolytic lesions in bone, indicating suppression of cancer cell metastasis to bone. These results are supported by our data showing both DHA and EPA significantly attenuate the migration/invasion of MDA-MB-231 breast cancer cells in culture. The mechanism that limits breast cancer cells to selective metastasis to bone remains hitherto unexplored. Aberrant increased expression of CD44 is associated with generation of cancer stem cells, which contribute to metastasis of breast cancer cells. We demonstrate that DHA and EPA significantly inhibit the expression of CD44 protein and mRNA by a transcriptional mechanism. Furthermore, we show markedly reduced levels of CD44 mRNA and protein in the tumors of mice, which were fed fish oil diet than those in control diet. Our data provide the first evidence for a salutary effect of fish oil on breast cancer metastasis to bone. Our results identify a novel function of the fish oil active components, DHA and EPA, which target the cell-intrinsic pro-metastatic molecule CD44 to inhibit migration/invasion. PMID- 20971069 TI - Conformational preferences of non-polar amino acid residues: an additional factor in amyloid formation. AB - Amyloid consists of beta-sheet polymers and is associated with disease and with functional assemblies. Amyloid-forming proteins differ widely in native structures and sequences. We describe here how conformational preferences of non polar amino acid residues can affect amyloid formation. The most non-polar residues promote either beta-strands (Val, Ile, Phe, and Cys, VIFC) or alpha helices (Leu, Ala, and Met, LAM), while the most polar residues promote only alpha-helices. For 12 proteins associated with disease, the localizations of the amyloid core regions are known. Eleven of these contain segments that are biased for VIFC, but essentially lack segments that are biased for LAM. For the amyloid beta-peptide associated with Alzheimer's disease and an amyloidogenic fragment of the prion protein, observed effects of mutations support that VIFC bias favors formation of beta-sheet aggregates and amyloid, while LAM bias prevents it. VIFC and LAM profiles combine information on secondary structure propensities and polarity, and add a simple criterion to the prediction of amyloidogenic regions. PMID- 20971070 TI - Inhibition of the calcium-activated chloride current in cardiac ventricular myocytes by N-(p-amylcinnamoyl)anthranilic acid (ACA). AB - N-(p-amylcinnamoyl)anthranilic acid (ACA), a phospholipase A(2) (PLA(2)) inhibitor, is structurally-related to non-steroidal anti-inflammatory drugs (NSAIDs) of the fenamate group and may also modulate various ion channels. We used the whole-cell, patch-clamp technique at room temperature to investigate the effects of ACA on the Ca(2+)-activated chloride current (I(Cl(Ca))) and other chloride currents in isolated pig cardiac ventricular myocytes. ACA reversibly inhibited I(Cl(Ca)) in a concentration-dependent manner (IC(50)=4.2 MUM, n(Hill)=1.1), without affecting the L-type Ca(2+) current. Unlike ACA, the non selective PLA(2) inhibitor bromophenacyl bromide (BPB; 50 MUM) had no effect on I(Cl(Ca)). In addition, the analgesic NSAID structurally-related to ACA, diclofenac (50 MUM) also had no effect on I(Cl(Ca)), whereas the current in the same cells could be suppressed by chloride channel blockers flufenamic acid (FFA; 100 MUM) or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS;100 MUM). Besides I(Cl(Ca)), ACA (50 MUM) also suppressed the cAMP-activated chloride current, but to a lesser extent. It is proposed that the inhibitory effects of ACA on I(Cl(Ca)) are PLA(2)-independent and that the drug may serve as a useful tool in understanding the nature and function of cardiac anion channels. PMID- 20971071 TI - Lnx-2b restricts gsc expression to the dorsal mesoderm by limiting Nodal and Bozozok activity. AB - Coordinated Nodal-related signals and Bozozok (Boz) activity are critical for the initial specification of dorsal mesoderm and anterior neuroectoderm during zebrafish embryogenesis. Overexpression of Boz expands gsc expression into the ventro-lateral marginal blastomeres where Nodal signaling is active, but is insufficient to induce ectopic gsc expression in the animal region. We found that overexpression of Boz together with depletion of Lnx-2b (previously named Lnx like, Lnx-l), but not each manipulation alone, causes robust gsc expression in all blastomeres. Furthermore, nodal-related signals are required for gsc expression in embryos with elevated Boz activity. Through targeted injection into single cells at the 128-cell stage we illustrate the role of maternally deposited Lnx-2b to restrict the expansion of gsc expression into the presumptive ectodermal region. This report provides a novel mechanism for limiting dorsal organizer specification to a defined region of the early zebrafish embryo. PMID- 20971073 TI - Deficiency of methionine sulfoxide reductase A causes cellular dysfunction and mitochondrial damage in cardiac myocytes under physical and oxidative stresses. AB - Methionine sulfoxide reductase A (MsrA) is an enzyme that reverses oxidation of methionine in proteins. Using a MsrA gene knockout (MsrA(-/-)) mouse model, we have investigated the role of MsrA in the heart. Our data indicate that cellular contractility and cardiac function are not significantly changed in MsrA(-/-) mice if the hearts are not stressed. However, the cellular contractility, when stressed using a higher stimulation frequency (2Hz), is significantly reduced in MsrA(-/-) cardiac myocytes. MsrA(-/-) cardiac myocytes also show a significant decrease in contractility after oxidative stress using H(2)O(2). Corresponding changes in Ca(2+) transients are observed in MsrA(-/-) cardiomyocytes treated with 2Hz stimulation or with H(2)O(2). Electron microscope analyses reveal a dramatic morphological change of mitochondria in MsrA(-/-) mouse hearts. Further biochemical measurements indicate that protein oxidation levels in MsrA(-/-) mouse hearts are significantly higher than those in wild type controls. Our study demonstrates that the lack of MsrA in cardiac myocytes reduces myocardial cell's capability against stress stimulations resulting in a cellular dysfunction in the heart. PMID- 20971072 TI - An improved method for enhanced production and biological activity of human secretory leukocyte protease inhibitor (SLPI) in Pichia pastoris. AB - The human secretory leukocyte protease inhibitor (SLPI) is an 11.7 kD cysteine rich protein that has been shown to possess anti-protease, anti-inflammatory, and antimicrobial properties. By using a Pichia pastoris strain that overproduces protein disulfide isomerase (PDI), we obtained greater than fivefold higher levels of SLPI than in strains expressing normal levels of PDI and containing multiple copies of the SLPI gene. Elevated levels of PDI also enhanced the specific activity of the secreted SLPI by helping it achieve a proper tertiary structure. Mass spectrometry analysis indicated a greater number of disulfide bonds in the SLPI produced by the PDI overexpression strain compared to the SLPI produced in strains with normal PDI levels. Although others have utilized a similar strategy to increase yield, we believe that this is the first example of PDI overexpression being demonstrated to enhance the folding and thus increase the biological activity of a protein produced in the yeast P. pastoris. PMID- 20971074 TI - Selective recognition of oncogene promoter G-quadruplexes by Mg2+. AB - Mg(2+) is one of the most important cations in cells, affecting the structures and functions of the proteins and nucleic acids. It should be noted that Mg(2+) is indispensable in DNA transcription, where G-quadruplex is believed to be actively involved. Therefore, it is important to investigate the influence of Mg(2+) on G-quadruplex. Here we studied the effect of Mg(2+) on G-quadruplex DNA with CD, FRET, EMSA, and PCR-stop assay. We found that various G-quadruplexes could be differentiated through simultaneous addition of both K(+) and Mg(2+), which could be used for selective identification of G-quadruplexes in promoter oncogene but not in telomere. Mg(2+) at physiological relevant concentration not only greatly enhanced the thermostability of oncogene G-quadruplexes but also efficiently protected them from unfolding by their complementary strands, which revealed the great impact of Mg(2+) on the equilibrium between promoter G quadruplex and duplex DNA. The PCR-stop assay further confirmed that Mg(2+) could affect gene transcription by stabilizing promoter G-quadruplex. The above studies were carried out for various G-quadruplexes of varying sequences in promoter oncogenes and telomeric region. Our results suggest that Mg(2+) may be a key regulator for G-quadruplexes of oncogene promoter, which can subsequently affect the expression of related genes. PMID- 20971075 TI - Protein kinase C betaII and delta/theta play critical roles in bone morphogenic protein-4-stimulated osteoblastic differentiation of MC3T3-E1 cells. AB - Bone morphogenic protein-4 (BMP-4), one of TGF-beta superfamily, is involved in bone and cartilage development, specifically tooth and bone fracture repair. In the present study, the role of protein kinase C (PKC) was investigated in BMP-4 induced differentiation of osteoblast-like MC3T3-E1 cells. PKC inhibitor UCN-01 significantly attenuated the synthesis of osteocalcin, a marker of mature osteoblast phenotype, in a dose-dependent manner as well as blocked osteroblastic differentiation and mineralization in BMP-4-treated MC3T3-E1 cells. Also, UCN-01 suppressed vascular endothelial growth factor (VEGF) production in BMP-4-treated MC3T3-E1 cells. In addition, UCN-01 remarkably suppressed BMP-4-activated PKC betaII and PKC delta/theta of PKC family proteins by Western blotting. Consistently, 2-dimensional electrophoresis (2-DE) immunoblotting revealed that UCN-01 inhibited the BMP-4-induced activation of PKC subfamilies in MC3T3-E1 cells. Taken together, our findings suggest that PKC betaII and PKC delta/theta mediate BMP-4-induced osteoblastic differentiation. PMID- 20971076 TI - Role of lymphocyte-specific protein tyrosine kinase (LCK) in the expansion of glioma-initiating cells by fractionated radiation. AB - Brain cancers frequently recur or progress as focal masses after treatment with ionizing radiation. Radiation used to target gliomas may expand the cancer stem cell population and enhance the aggressiveness of tumors; however, the mechanisms underlying the expansion of cancer stem cell population after radiation have remained unclear. In this study, we show that LCK (lymphocyte-specific protein tyrosine kinase) is involved in the fractionated radiation-induced expansion of the glioma-initiating cell population and acquisition of resistance to anticancer treatments. Fractionated radiation caused a selective increase in the activity of LCK, a Src family non-receptor tyrosine kinase. The activities of other Src family kinases Src, Fyn, and Lyn were not significantly increased. Moreover, knockdown of LCK expression with a specific small interfering RNA (siRNA) effectively blocked fractionated radiation-induced expansion of the CD133(+) cell population. siRNA targeting of LCK also suppressed fractionated radiation-induced expression of the glioma stem cell marker proteins CD133, Nestin, and Musashi. Expression of the known self-renewal-related proteins Notch2 and Sox2 in glioma cells treated with fractionated radiation was also downregulated by LCK inhibition. Moreover, siRNA-mediated knockdown of LCK effectively restored the sensitivity of glioma cells to cisplatin and etoposide. These results indicate that the non-receptor tyrosine kinase LCK is critically involved in fractionated radiation-induced expansion of the glioma-initiating cell population and decreased cellular sensitivity to anticancer treatments. These findings may provide pivotal insights in the context of fractionated radiation-based therapeutic interventions in brain cancer. PMID- 20971077 TI - Neurodegeneration in mnd2 mutant mice is not prevented by parkin transgene. AB - Parkinson's disease (PD) is a common neurodegenerative disorder. The motor neuron degeneration 2 mutant (mnd2) mouse is considered to be an animal model of PD, and exhibits striatal neuron loss, severe muscle wasting, weight loss and death before 40days of age. We found for the first time that parkin expression was decreased in the mnd2 mouse brain. Since parkin is a crucial protein for PD, the neurodegenerative disorder in mnd2 mice may be caused by parkin protein loss. We therefore examined whether compensation of parkin protein prevents neurodegenerative disorders in mnd2 mice by generating parkin-transgenic (parkin Tg) mnd2 mice. However, both parkin-Tg mnd2 mice and mnd2 mice were smaller than wild type mice. In muscle strength and survival rate, parkin-Tg mnd2 mice showed similar values to mnd2 mice. Our data suggest that repression of parkin protein does not play a major role in neurodegeneration of mnd2 mice and administration of parkin protein does not rescue mnd2 mice. PMID- 20971078 TI - Functional interaction between sequestosome-1/p62 and autophagy-linked FYVE containing protein WDFY3 in human osteoclasts. AB - Paget's disease of bone (PDB) is a late-onset disorder characterised by focal areas of increased bone resorption, with osteoclasts that are increased in size, multinuclearity, number and activity. PDB-causing missense and nonsense variants in the gene encoding Sequestosome-1/p62 (SQSTM1) have been identified, all of which cluster in and around the ubiquitin-associated (UBA) domain of the protein. SQSTM1 is ubiquitously expressed and there is, as yet, no clear reason why these mutations only appear to cause an osteoclast-related phenotype. Using co immunoprecipitation and tandem mass spectrometry, we identified a novel interaction in human osteoclast-like cells between SQSTM1 and Autophagy-Linked FYVE domain-containing protein (ALFY/WDFY3). Endogenous ALFY and SQSTM1 both localised within the nuclei of osteoclasts and their mononuclear precursors. When osteoclasts were starved to induce autophagy, SQSTM1 and ALFY relocated to the cytoplasm where they formed large aggregates, with cytoplasmic relocalisation appearing more rapid in mature osteoclasts than in precursors in the same culture. Overexpression of wild-type SQSTM1 in HEK293 cells also resulted in the formation of cytoplasmic aggregates containing SQSTM1 and endogenous ALFY, as did overexpression of a PDB-causing missense mutant form of SQSTM1, indicating that this mutation does not impair the formation of SQSTM1- and ALFY-containing aggregates. Expression of ALFY in bone cells has not previously been reported, and the process of autophagy has not been studied with respect to osteoclast activity. We have identified a functional interaction between SQSTM1 and ALFY in osteoclasts under conditions of cell stress. The difference in response to starvation between mature osteoclasts and their precursors may begin to explain the cell-specific functional effects of SQSTM1 mutations in PDB. PMID- 20971079 TI - Substrate specificity of three recombinant alpha-L-arabinofuranosidases from Bifidobacterium adolescentis and their divergent action on arabinoxylan and arabinoxylan oligosaccharides. AB - Bifidobacterium adolescentis possesses several arabinofuranosidases able to hydrolyze arabinoxylans (AX) and AX oligosaccharides (AXOS), the latter being bifidogenic carbohydrates with potential prebiotic properties. We characterized two new recombinant arabinofuranosidases, AbfA and AbfB, and AXH-d3, a previously studied arabinofuranosidase from B. adolescentis. AbfA belongs to glycoside hydrolase family (GH) 43 and removed arabinose from the C(O)2 and C(O)3 position of monosubstituted xylose residues. Furthermore, hydrolytic activity of AbfA was much larger towards substrates with a low amount of arabinose substitutions. AbfB from GH 51 only cleaved arabinoses on position C(O)3 of disubstituted xyloses, similar to GH 43 AXH-d3, making it to our knowledge, the first reported enzyme with this specificity in GH 51. AbfA acted synergistically with AbfB and AXH-d3. In combination with AXH-d3, it released 60% of arabinose from wheat AX. Together with recent studies on other AXOS degrading enzymes from B. adolescentis, these findings allowed us to postulate a mechanism for the uptake and hydrolysis of bifidogenic AXOS by this organism. PMID- 20971080 TI - Hepatitis C virus nonstructural protein-5A activates sterol regulatory element binding protein-1c through transcription factor Sp1. AB - Steatosis is an important clinical manifestation of hepatitis C virus (HCV) infection. The molecular mechanisms of HCV-associated steatosis are not well understood. Sterol regulatory element-binding protein-1c (SREBP-1c) is a key transcription factor which activates the transcription of lipogenic genes. Here we showed that the nuclear, mature SREBP-1c level increases in the nucleus of replicon cells expressing HCV-3a nonstructural protein-5A (NS5A). We further showed that HCV-3a NS5A up-regulates SREBP-1c transcription. Additional analysis showed that transcriptional factor Sp1 is involved in SREBP-1c activation by HCV 3a NS5A because inhibition of Sp1 activity by mithramycin A or a dominant negative Sp1 construct abrogated SREBP-1c promoter activation by HCV-3a NS5A. In addition, chromatin immunoprecipitation (ChIP) assay demonstrated enhanced binding of Sp1 on the SREBP-1c promoter in HCV-3a NS5A replicon cells. These results showed that HCV-3a NS5A activates SREBP-1c transcription through Sp1. Taken together, our results suggest that HCV-3a NS5A is a contributing factor for steatosis caused by HCV-3a infection. PMID- 20971081 TI - SK-PC-B70M alleviates neurologic symptoms in G93A-SOD1 amyotrophic lateral sclerosis mice. AB - SK-PC-B70M, an oleanolic-glycoside saponins fraction extracted from the root of Pulsatilla koreana, carries active ingredient(s) that protects the cytotoxicity induced by Abeta(1-42) in SK-N-SH cells. It was recently demonstrated that SK-PC B70M improved scopolamine-induced deficits of memory consolidation and spatial working memory in rats, and reduced Abeta levels and plaque deposition in the brains of the Tg2576 mouse model of Alzheimer disease. In the present study, we investigated whether SK-PC-B70M produces helpful effects on the pathology of the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis (ALS). Administration of SK-PC-B70M (100 or 400 mg/kg/day) from 8 weeks to 16 weeks of age attenuated neurological deficits of G93A-SOD1 mice in several motor-function related behavioral tests. SK-PC-B70M treatment significantly suppressed the accumulation of the by-products of lipid peroxidation, malonedialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE), in the spinal cord of G93A-SOD1 mice. Moreover, histologic analysis stained with cresyl violet or anti-choline acetyltransferase (ChAT) revealed that SK-PC-B70M suppressed neuronal loss in the ventral horn of the spinal cords of G93A-SOD1 mice. These results suggest that SK-PC-B70M affords a beneficial effect on neurologic deficits of G93A-SOD1 ALS mice. PMID- 20971082 TI - Projections of the suprachiasmatic nucleus and ventral subparaventricular zone in the Nile grass rat (Arvicanthis niloticus). AB - The phases of many circadian rhythms differ between diurnal and nocturnal species. However, rhythms within the hypothalamic suprachiasmatic nucleus (SCN), which contains the central circadian pacemaker, are very similar, suggesting that the mechanisms underlying phase preference lie downstream of the SCN. Rhythms in Fos expression in the ventral subparaventricular zone (vSPVZ), a major target of the SCN, differ substantially between diurnal Nile grass rats and nocturnal lab rats, raising the possibility that the vSPVZ modulates the effects of SCN signals at its targets. To understand better how and where the SCN and vSPVZ communicate circadian signals within the grass rat brain, we mapped their projections using the anterograde tracer biotinylated dextran amine (BDA). Adult female grass rats received unilateral BDA injections directed at the SCN or vSPVZ and their brains were perfusion-fixed several days later. Immunohistochemistry revealed that the distribution patterns of SCN and vSPVZ efferents were very similar. Labeled fibers originating in each region were heavily concentrated in the medial preoptic area, paraventricular thalamic nucleus, the subparaventricular zone, and the hypothalamic paraventricular and dorsomedial nuclei. BDA-labeled fibers from the SCN and vSPVZ formed appositions with orexin neurons and gonadotropin releasing hormone neurons, two cell populations whose rhythms in Fos expression track temporally reversed patterns of locomotor and reproductive behavior, respectively, in diurnal and nocturnal rodents. These data demonstrate that projections of the SCN and vSPVZ are highly conserved in diurnal and nocturnal rodents, and the vSPVZ projections may enable it to modulate the responsiveness of target cells to signals from the SCN. PMID- 20971083 TI - Selective MMP-inhibition with Ro 28-2653 in acute experimental stroke--a magnetic resonance imaging efficacy study. AB - Blood-brain-barrier (BBB) breakdown due to matrix metalloproteinase (MMP) activity following stroke is often associated with cerebral edema, larger infarct volumes and bad outcome. In the present study we examined a novel MMP-inhibitor (Ro 28-2653) with high selectivity for MMP2, MMP9 and membrane type 1-MMP in an acute stroke model comparing two different treatment regimens. We subjected rats to 90 min of focal cerebral ischemia followed by 3 days or 7 days of reperfusion, respectively, using the middle cerebral artery (MCA) filament occlusion technique. Ro 28-2653 was administered daily in a vehicle solution for 2 days or 6 days after ischemia, respectively. We assessed the behavior with a functional neuroscore and infarct volumes as well as blood-brain-barrier (BBB) breakdown with magnetic resonance imaging (MRI) after 3 and 7 days. Infarct edema volumes, BBB breakdown and behavior at 3 days were significantly attenuated in rats treated for 2 days with Ro 28-2653 as compared to vehicle and untreated controls. After 6 days of treatment however, infarct and BBB breakdown volumes as well as behavior did not differ significantly between the groups at 7 days. The new high selective MMP-inhibitor Ro 28-2653 significantly reduced brain injury only when administered in the first 2 days after focal cerebral ischemia. Prolonged treatment for 6 days did not show any beneficial effects possibly due to interference with protective restorative processes. PMID- 20971084 TI - Synergistic benefit of combined amlodipine plus atorvastatin on neuronal damage after stroke in Zucker metabolic rat. AB - Stroke is a major neurologic disorder and a leading cause of death in the world. We compared neuroprotective effects of single or combination therapy of amlodipine (AM) and atorvastatin (AT) in such a metabolic syndrome model Zucker rat after 90 min of transient middle cerebral artery occlusion (tMCAO). The animals were pretreated with vehicle, AM, AT, or the combination of AM plus AT for 28 days, and at 24h of tMCAO, infarct volume and immunohistochemical analyses were performed. The combination of AM plus AT treatment decreased the infarct volume stronger than each single treatment with AM or AT. The numbers of positive cells of oxidative stress markers such as 8-hydroxy-2'-deoxyguanosin (8-OHdG), 4 hydroxy-2-nonenal (4-HNE), and advanced end glycation products (AGE) and inflammation markers such as tumor necrosis factor alpha (TNF-alpha) and monocyte chemoattractant protein-1(MCP-1) decreased dramatically in the combination treated group compared with single AM- or AT-treated group. The present study showed that single AM or AT treatment showed neuroprotective effects both with antioxidative and anti-inflammatory mechanisms, but combination therapy of AM plus AT presented a further synergistic benefit in acute ischemic neural damages. PMID- 20971085 TI - Anti-TNF-alpha reduces amyloid plaques and tau phosphorylation and induces CD11c positive dendritic-like cell in the APP/PS1 transgenic mouse brains. AB - Inflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). Overexpression of tumor necrosis factor-alpha (TNF-alpha) occurs in the AD brain. Recent clinical studies have shown that the anti-TNF-alpha therapy improves cognition function of AD patients rapidly. However, the underlying mechanism remains elusive. The present study investigates the effects of intracerebroventricular injection of the monoclonal TNF-alpha antibody, Infliximab, on the pathological features of AD in the APP/PS1 double transgenic mice. We found that Infliximab administration reduced the levels of TNF-alpha, amyloid plaques, and tau phosphorylation as early as three days after daily injection of 150 MUg Infliximab for three days. The number of CD11c-positive dendritic-like cells and the expression of CD11c were found to be increased concurrently after Infliximab injection. These data suggested that the CD11c positive dendritic-like cells might contribute to the Infliximab-induced reduction of AD-like pathology. Furthermore, our results support the use of anti TNF-alpha for the treatment of AD. PMID- 20971086 TI - Chronic deficit in the expression of voltage-gated potassium channel Kv3.4 subunit in the hippocampus of pilocarpine-treated epileptic rats. AB - Voltage gated K(+) channels (Kv) are a highly diverse group of channels critical in determining neuronal excitability. Deficits of Kv channel subunit expression and function have been implicated in the pathogenesis of epilepsy. In this study, we investigate whether the expression of the specific subunit Kv3.4 is affected during epileptogenesis following pilocarpine-induced status epilepticus. For this purpose, we used immunohistochemistry, Western blotting assays and comparative analysis of gene expression using TaqMan-based probes and delta-delta cycle threshold (DeltaDeltaCT) method of quantitative real-time polymerase chain reaction (qPCR) technique in samples obtained from age-matched control and epileptic rats. A marked down-regulation of Kv3.4 immunoreactivity was detected in the stratum lucidum and hilus of dentate gyrus in areas corresponding to the mossy fiber system of chronically epileptic rats. Correspondingly, a 20% reduction of Kv3.4 protein levels was detected in the hippocampus of chronic epileptic rats. Real-time quantitative PCR analysis of gene expression revealed that a significant 33% reduction of transcripts for Kv3.4 (gene Kcnc4) occurred after 1 month of pilocarpine-induced status epilepticus and persisted during the chronic phase of the model. These data indicate a reduced expression of Kv3.4 channels at protein and transcript levels in the epileptic hippocampus. Down regulation of Kv3.4 in mossy fibers may contribute to enhanced presynaptic excitability leading to recurrent seizures in the pilocarpine model of temporal lobe epilepsy. PMID- 20971087 TI - Differential activation of medullary vagal nuclei caused by stimulation of different esophageal mechanoreceptors. AB - Esophageal mechanoreceptors, i.e. muscular slowly adapting tension receptors and mucosal rapidly adapting touch receptors, mediate different sets of reflexes. The aim of this study was to determine the medullary vagal nuclei involved in the reflex responses to activation of these receptors. Thirty-three cats were anesthetized with alpha-chloralose and the esophagus was stimulated by slow balloon or rapid air distension. The physiological effects of the stimuli (N=4) were identified by recording responses from the pharyngeal, laryngeal, and hyoid muscles, esophagus, and the lower esophageal sphincter (LES). The effects on the medullary vagal nuclei of the stimuli: slow distension (N=10), rapid distension (N=9), and in control animals (N=10) were identified using the immunohistochemical analysis of c-fos. The experimental groups were stimulated three times per minute for 3h. After the experiment, the brains were removed and processed for c-fos immunoreactivity or thioinin. We found that slow balloon distension activated the esophago-UES contractile reflex and esophago-LES relaxation response, and rapid air injection activated the belch and its component reflexes. Slow balloon distension activated the NTSce, NTSdl, NTSvl, DMNc, DMNr and NAr; and rapid air injection primarily activated AP, NTScd, NTSim, NTSis, NTSdm, NTSvl, NAc and NAr. We concluded that different sets of medullary vagal nuclei mediate different reflexes of the esophagus activated from different sets of mechanoreceptors. The NTScd is the primary NTS subnucleus mediating reflexes from the mucosal rapidly adapting touch receptors, and the NTSce is the primary NTS subnucleus mediating reflexes from the muscular slowly adapting tension receptors. The AP may be involved in mediation of belching. PMID- 20971089 TI - Effects of 5-hydroxytryptamine on substantia gelatinosa neurons of the trigeminal subnucleus caudalis in immature mice. AB - Serotonin (5-hydroxytryptamine, 5-HT) is involved in the descending modulation of nociceptive transmission in the spinal dorsal horn. The trigeminal subnucleus caudalis (Vc; medullary dorsal horn) processes nociceptive input from the orofacial region, and 5-HT-containing axons are numerous in the superficial layers of the Vc. This study examined the actions of 5-HT on the substantia gelatinosa (SG) neurons of the Vc, using gramicidin-perforated patch-clamp recording in brainstem slice preparations from immature mice. In order to clarify the possible mechanisms underlying 5-HT actions in the SG of the Vc, the direct membrane effects of 5-HT and effects of 5-HT receptor subtype agonists were examined. 5-HT induced a hyperpolarization in the majority (64/115, 56%) of the SG neurons tested. Thirty nine (34%) SG neurons showed no response, and 12 (10%) neurons responded with depolarization. The hyperpolarizing response to 5-HT was concentration-dependent (0.1-30 MUM; n=7), not desensitized by repeated application (n=22), and significantly attenuated by Ba(2+) (K(+) channel blocker; n=8). The 5-HT-induced hyperpolarization was maintained in the presence of TTX (Na(+) channel blocker), CNQX (non-NMDA glutamate receptor antagonist), AP5 (NMDA glutamate receptor antagonist), picrotoxin (GABA(A) receptor antagonist), and strychnine (glycine receptor antagonist), indicating direct postsynaptic action of 5-HT on SG neurons (n=7). The 5-HT-induced hyperpolarizing effects were mimicked by 8-OH-DPAT (5-HT(1A) receptor agonist) and alpha-methyl-5-HT (5-HT(2) receptor agonist) and blocked by WAY-100635 (5-HT(1A) receptor antagonist) and ketanserin (5-HT(2) receptor antagonist). Single-cell RT-PCR also revealed the presence of mRNA for 5-HT(1A) and 5-HT(2C) subtypes in the SG neurons. These results suggest that 5-HT acts directly on SG neurons and 5-HT-induced hyperpolarization is mediated, in part, by 5-HT(1A) receptors and 5-HT(2) receptors, as well as by the activation of K(+) channels, indicating an important role for 5-HT in the modulation of orofacial nociceptive processing at the level of the SG of the Vc in mice. PMID- 20971088 TI - Profile of minocycline neuroprotection in bilirubin-induced auditory system dysfunction. AB - Excessive hyperbilirubinemia in human neonates can cause permanent dysfunction of the auditory system, as assessed with brainstem auditory evoked potentials (BAEPs). Jaundiced Gunn rat pups (jjs) exhibit similar BAEP abnormalities as hyperbilirubinemic neonates. Sulfadimethoxine (sulfa) administration to jjs, which displaces bilirubin from serum albumin into tissues including brain, exacerbates acute toxicity. Minocycline administered prior to sulfa in jjs protects against BAEP abnormalities. This study evaluates the neuroprotective capabilities of minocycline HCl (50 mg/kg) administered 30 or 120 min after sulfa (200 mg/kg) in 16 days old jjs. BAEPs are recorded at 6 or 24 h post-sulfa. Abnormal BAEP waves exhibit increased latency and decreased amplitude. The sulfa/saline treated jjs exhibited a significantly increased interwave interval between waves I and II (I-II IWI) and significantly decreased amplitudes of waves II and III compared to the saline/saline jjs. The minocycline 30 min post-sulfa (sulfa/mino+30) group was not significantly different from the saline/saline control group, indicating neuroprotection. The minocycline 120 min post-sulfa (sulfa/mino+120) group had a significantly decreased amplitude of wave III at both 6 and 24h. These studies indicate that minocycline has a graded neuroprotective effect when administered after acute bilirubin neurotoxicity. PMID- 20971090 TI - BDNF-secreting capsule exerts neuroprotective effects on epilepsy model of rats. AB - Brain-derived neurotrophic factor (BDNF) is a well neurotrophic factor with neuroprotective potentials for various diseases in the central nervous system. However several previous studies demonstrated that BDNF might deteriorate symptoms for epilepsy model of animals by progression of abnormal neurogenesis. We hypothesized that continuous administration of BDNF at low dose might be more effective for epilepsy model of animals because high dose of BDNF was used in many studies. BDNF-secreting cells were genetically made and encapsulated for transplantation. Rats receiving BDNF capsule showed significant amelioration of seizure stage and reduction of the number of abnormal spikes at 7 days after kainic acid administration, compared to those of control group. The number of BrdU and BrdU/doublecortin positive cells in the hippocampus of BDNF group significantly increased, compared to that of control group. NeuN positive cells in the CA1 and CA3 of BDNF group were significantly preserved, compared to control group. In conclusion, low dose administration using encapsulated BDNF secreting cells exerted neuroprotective effects with enhanced neurogenesis on epilepsy model of rats. These results might suggest the importance of the dose and administrative way of this neurotrophic factor to the epilepsy model of animals. PMID- 20971091 TI - The function of hypothalamus-pituitary-adrenal axis in children with ADHD. AB - OBJECTIVE: To explore the relationship between hypothalamus-pituitary-adrenal (HPA) axis and Attention Deficit Hyperactivity Disorder (ADHD) in non-stress states. METHOD: 128 male children with ADHD aged between 6 and 14 years old were recruited, while 30 healthy male children were chosen as a control group. The diagnostic material was based on DSM-IV. The included ADHD children were further classified into the three sub-groups: ADHD-predominantly inattention type (ADHD I) (n=44), ADHD-predominantly hyperactive impulsive type (ADHD-HI) (n=32), and ADHD-combined type (ADHD-C) (n=52). The levels of cortisol and adrenocorticotropin hormone (ACTH) were evaluated by the automatic particle enzyme immunoassay and electrochemiluminescence respectively per morning (8:00 am). Intelligence test was assessed by the Raven's Standard Progressive Matrices. RESULTS: The children with ADHD had significantly lower intelligence quotient (IQ) (84.5+/-11.3) in contrast to the control group (98.6+/-12.4, P<0.01), although the lower level of IQ in ADHD-C group (79.2+/-10.7) was also found when compared with other two sub-groups [ADHD-I (85.6+/-10.4) and ADHD-HI (91.3+/ 12.6)]. In addition, no significant difference between the ADHD-HI group and the control group regarding the level of IQ were revealed. The level of cortisol in the ADHD group (226.47+/-129.12 nmol/L) was significantly lower than that of the control group (384.53+/-141.43 nmol/L, P<0.001). The level of cortisol of the ADHD-HI group (154.36+/-71.62 nmol/L) was significantly lower than that of other two groups [ADHD-I group (219.42+/-117.66 nmol/L) (P<0.01) and ADHD-C group (258.30+/-136.39 nmol/L) (P<0.01)]. There were no significant differences in the ACTH level either between the ADHD and the control group (P>0.05), or between sub groups in ADHD (P>0.05). CONCLUSION: In the non-stress states, the existence of dysfunction of the HPA axis (lower plasma cortisol) in children with ADHD might be due to the under-reactivity of the HPA axis ; the low plasma cortisol level might contribute less to the outcomes of cognitive behavior of ADHD children and instead more closely relate to the core domains of attention deficit, hyperactivity and impulsive behavior of ADHD patients. PMID- 20971092 TI - Quantitative analysis of taste bud cell numbers in fungiform and soft palate taste buds of mice. AB - Mammalian taste bud cells (TBCs) consist of several cell types equipped with different taste receptor molecules, and hence the ratio of cell types in a taste bud constitutes the taste responses of the taste bud. Here we show that the population of immunohistochemically identified cell types per taste bud is proportional to the number of total TBCs in the taste bud or the area of the taste bud in fungiform papillae, and that the proportions differ among cell types. This result is applicable to soft palate taste buds. However, the density of almost all cell types, the population of cell types divided by the area of the respective taste buds, is significantly higher in soft palates. These results suggest that the turnover of TBCs is regulated to keep the ratio of each cell type constant, and that taste responsiveness is different between fungiform and soft palate taste buds. PMID- 20971093 TI - Nociceptive behaviors were induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus in conscious adult rats and reduced by morphine and rizatriptan benzoate. AB - The trigeminovascular nociception induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus in anesthetized animals has been widely used as a model for investigation of the pathophysiology of vascular headache such as migraine. However, little is known whether pain behaviors can be induced using this model in conscious animals. Thus, to establish a new model of trigeminovascular nociception in conscious animals and to examine the effects of morphine and rizatriptan benzoate on nociceptive behaviors in this new model, we electrically stimulated the dura mater surrounding the superior sagittal sinus. We found that grooming and head-flick activities were altered partially in a frequency-dependent way and that frequencies ranging from 10 to 20 Hz more easily provoked these behaviors. Moreover, we also demonstrated that these behaviors were reduced by morphine and rizatriptan benzoate. Thus, this new model will provide a useful and appropriate tool to directly assess changes in the intensity of pain for further investigation of pathophysiological mechanisms of migraine in conscious animals. PMID- 20971094 TI - Induction of heat shock proteins in the adult rat cerebral cortex following pilocarpine-induced status epilepticus. AB - The expression pattern of a global set of Hsps in the adult rat cerebral cortex was examined during the first week following pilocarpine-induced status epilepticus (SE). Hsp70 and Hsp32 protein were induced at 1 day post-SE and decreased thereafter, whereas Hsp25 exhibited a prolonged induction with increased levels at 3 and 7 days post-SE. Hsp70 was induced in neurons, while Hsp25 and Hsp32 localized to GFAP-positive hypertrophied astrocytes. The induction of Hsp25, Hsp32 and Hsp70 at 1 day following SE suggests the involvement of these Hsps in early events after SE. Interestingly, while Hsp32 and Hsp70 expression was transient, Hsp25 demonstrated a sustained induction pattern, which may reflect an additional role of Hsp25 in subsequent remodeling events in the days following SE. PMID- 20971095 TI - Using CD133 positive U251 glioblastoma stem cells to establish nude mice model of transplanted tumor. AB - This study tried to use CD133 positive U251 glioblastoma stem cells to establish nude mice model of transplanted tumor. CD133 positive U251 stem cells were isolated and identified. Twenty-five male nude mice were divided into three groups: U251 cell group, U251 stem cell group and normal control group. U251 cells and stem cells were respectively inoculated into mouse brain to establish model of transplanted tumor. Mice growing condition and behavior were observed. Magnetic resonance imaging (MRI) was performed to detect tumor growth in brain. HE staining assay, immunohistochemical assay and CD34 marked microvascular density (MVD) test were performed. As a result, the successful rates of both model groups were 100%. Growing condition and behavior in U251 stem cell group was more significantly exaggerated and tumor growth and image in magnetic resonance in U251 stem cell group was more significantly malignant than that in U251 cell group. It could be found that models in U251 stem cell group showed stronger pathogolical malignance features than that in U251 cell group. Glial fibrillary acidic protein (GFAP) expression in U251 cell and stem cell group showed the transplanted tumor originated from astrocytes. CD34 in U251 stem cell group was highest and significantly higher than that in the other two groups. In conclusion, use of U251 stem cells to establish transplanted tumor model in nude mice is an excellent method and the model is more likely and malignant than the one established by cancer cells, which showed a new animal model to research glioma. PMID- 20971096 TI - Immunocytochemical distribution of WARP (von Willebrand A domain-related protein) in the inner ear. AB - The basic components of the epithelial, perineural, and perivascular basement membranes in the inner ear have been well-documented in several animal models and in the human inner ear. The von Willebrand A domain-related protein (WARP) is an extracellular matrix molecule with restricted expression in cartilage, and a subset of basement membranes in peripheral nerves, muscle, and central nervous system vasculature. It has been suggested that WARP has an important role in maintaining the blood-brain barrier. To date no studies on WARP distribution have been performed in the inner ear, which is equipped with an intricate vasculature network. In the present study, we determined the distribution of WARP by immunocytochemistry in the human inner ear using auditory and vestibular endorgans microdissected from human temporal bones obtained at autopsy. All subjects (n=5, aged 55-87years old) had documented normal auditory and vestibular function. We also determined the WARP immunolocalization in the mouse inner ear. WARP immunoreactivity localized to the vasculature throughout the stroma of the cristae ampullaris, the maculae utricle, and saccule in the human and mouse. In the human and mouse inner ear, WARP immunoreactivity delineated blood vessels located in the stria vascularis, spiral ligament, sub-basilar region, stromal tissue, and the spiral and vestibular ganglia. The distinct localization of WARP in the inner ear vasculature suggests an important role in maintaining its integrity. In addition, WARP allows delineation of microvessels in the inner ear allowing the study of vascular pathology in the development of otological diseases. PMID- 20971097 TI - Spinal astrocytic activation contributes to mechanical allodynia in a mouse model of type 2 diabetes. AB - Diabetic neuropathic pain (DNP) plays a major role in decreased life quality of type 2 diabetes patients, however, the molecular mechanisms underlying DNP remain unclear. Emerging research implicates the participation of spinal glial cells in some neuropathic pain models. However, it remains unknown whether spinal glial cells are activated under type 2 diabetic conditions and whether they contribute to diabetes-induced neuropathic pain. In the present study, using a db/db type 2 diabetes mouse model that displayed obvious mechanical allodynia, we found that spinal astrocyte but not microglia was dramatically activated. The mechanical allodynia was significantly attenuated by intrathecally administrated l-alpha aminoadipate (astrocytic specific inhibitor) whereas minocycline (microglial specific inhibitor) did not have any effect on mechanical allodynia, which indicated that spinal astrocytic activation contributed to allodynia in db/db mice. Further study aimed to identify the detailed mechanism of astrocyte-induced allodynia in db/db mice. Results showed that spinal activated astrocytes dramatically increased interleukin (IL)-1beta expression which may induce N methyl-D-aspartic acid receptor (NMDAR) phosphorylation in spinal dorsal horn neurons to enhance pain transmission. Together, these results suggest that spinal activated astrocytes may be a crucial component of mechanical allodynia in type 2 diabetes and "Astrocyte-IL-1beta-NMDAR-Neuron" pathway may be the detailed mechanism of astrocyte-induced allodynia. Thus, inhibiting astrocytic activation in the spinal dorsal horn may represent a novel therapeutic strategy for treating DNP. PMID- 20971098 TI - Cellular plasticity in the supraoptic and paraventricular nuclei after prolonged dehydration in the desert rodent Meriones shawi: Vasopressin and GFAP immunohistochemical study. AB - Supraoptic (SON) and paraventricular (PVN) nuclei are part of the hypothalamic neurohypophysial system, they constitute the main source for vasopressin and they represent also obvious examples of activity-dependent neuroglial plasticity. Certain physiological conditions such as dehydration are accompanied by a structural remodeling of the neurons, their synaptic inputs and their surrounding glia. In the present work, an adult Meriones shawi (a rodent adapted to desert life) is used as an animal model. Using GFAP and vasopressin expressions as indicators successively of astrocytes and neuronal activations, the effect of a prolonged episode of water deprivation on the SON and PVN, hypothalamus nuclei were examined. We studied the immunoreactivity of GFAP and vasopressin in various hydration states (total deprivation of drinking water for 1 and 2months compared to hydrated animals). Prolonged dehydration produces an important decrease of GFAP immunoreactivity in both SON and PVN after 1 and 2months of water restriction. This decrease is accompanied by increased vasopressin immunoreactivity following the same periods of water deprivation. These findings may explain a real communication between vasopressin neurons and their surrounding astrocytes, thus the retraction of astrocytes and their processes is accompanied by an enhancement of vasopressin neuron density and their projecting fibers in response to this osmotic stress situation. Furthermore, these data could open further investigations concerning the possible involvement of the communication between astrocytes and vasopressin neurons in both PVN and SON in the regulation of Meriones hydrous balance and resistance to dehydration. PMID- 20971099 TI - Polyphenol acertannin prevents TRAIL-induced apoptosis in human keratinocytes by suppressing apoptosis-related protein activation. AB - The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been implicated in the inflammatory and immune responses, and apoptosis in skin diseases, such as atopic dermatitis. Dysregulated apoptosis is associated with various pathologic conditions, including inflammation and cancer in skin. Polyphenols, including flavonoids and tannins, have been shown to have anti oxidant, anti-inflammatory and anti-tumor effects. However, the effect of acertannin on TRAIL-induced apoptosis in keratinocytes has not been determined. To assess the preventive effect of acertannin on apoptosis-mediated skin inflammation, we investigated the effect of acertannin on TRAIL-induced apoptosis in human keratinocytes. TRAIL induced nuclear damage, decreased Bid, Bcl-2, Bcl xL and survivin protein levels, increased Bax levels, induced cytochrome c release, activated caspases (-8, -9 and -3) and increased tumor suppressor p53 levels. Acertannin prevented the TRAIL-induced formation of reactive oxygen/nitrogen species, apoptosis-related protein activation and cell death. The results suggest that acertannin may reduce apoptotic effect of TRAIL on human keratinocytes by suppressing the activation of the caspase-8- and Bid-pathways and the mitochondria-mediated apoptotic pathway, leading to caspase-3 activation. The preventive effect of acertannin on TRAIL-induced apoptosis may be associated with the inhibitory effect on formation of reactive oxygen/nitrogen species. Acertannin may prevent the TRAIL-induced apoptosis-mediated skin inflammation. PMID- 20971100 TI - Putting bioactivation reactions to work: Targeting antioxidants to mitochondria. AB - The goal of this research was to test the hypothesis that bioactivation reactions could be exploited to deliver and activate mitochondria-targeted antioxidant prodrugs. The concept that bioactivation reactions could be used for prodrug delivery and activation has received little attention. Most bioactivation reactions result in the conversion of the parent drug to a reactive electrophilic metabolite, but bioactivating enzymes that catalyze elimination or hydrolytic reactions may offer potential for targeted drug delivery. Because mitochondria are the major cellular source of reactive oxygen species, there is much interest in targeting antioxidants to mitochondria. Previous studies showed that the mitochondrial fatty acid beta-oxidation pathway biotransforms a range of xenobiotic alkanoates, including omega-(phenyl)alkanoates and omega (phenoxy)alkanoates. 5,6-Dichloro-4-thia-5-hexenoate, the desamino analog of S (1,2-dichlorovinyl)-l-cysteine, is biotransformed by the fatty acid beta oxidation pathway. Hence, the prodrugs omega-(phenoxy)alkanoates, 3 (phenoxy)acrylates, and omega-(1-methyl-1H-imidazol-2-ylthio)alkanoates were expected to undergo biotransformation by the mitochondrial beta-oxidation pathway to release phenolic antioxidants and the antioxidant methimazole (Roser et al., Bioorg. Med. Chem. 18 (2010) 1441-1448). The rates of biotransformation of omega (phenoxy)alkanoates varied with the structure, and bulky substituents on the phenoxy moiety reduced rates of biotransformation; this was attributed to substrate limitations imposed by the medium-chain acyl-CoA dehydrogenase. Hence, 3-(2,6-dimethylphenoxy)acrylate was prepared; it was expected that, after conversion to its CoA thioester, 3-(2,6-dimethylphenoxy)acryloyl-CoA would be a substrate for enoyl-CoA hydratase. This expectation was correct: 3-(2,6 dimethylphenoxy)acrylate was an excellent substrate. omega-(1-Methyl-1H-imidazol 2-ylthio)alkanoates were also good substrates for the beta-oxidation pathway. Significantly, 3-(2,6-dimethylphenoxy)propanoate, 3-(2,6 dimethylphenoxy)acrylate, and 3-(1-methyl-1H-imidazol-2-ylthio)propanoate were cytoprotective in a hypoxia-reoxygenation model in rat cardiomyocytes. These results demonstrate the feasibility of exploiting bioactivation reactions for targeted drug delivery. PMID- 20971101 TI - A single nucleotide polymorphism in LRP2 is associated with susceptibility to Alzheimer's disease in the Chinese population. AB - BACKGROUND: LRP2 (also called megalin) plays a potential key role in the pathogenesis of Alzheimer's disease (AD). Recently, one genome-wide association study has revealed that the rs3755166 (G/A) polymorphism located in the LRP2 promoter is associated with development of AD in Caucasians, while there are no studies on the association LRP2 of with AD risk in Asians. METHODS: To evaluate the relationship between the rs3755166 polymorphism of the LRP2 gene and AD in the ethnic Chinese Han, we conducted a case-control study (n=361, age>50) to determine the prevalence of one common single-nucleotide polymorphism (SNP) of LRP2 (rs3755166) in patients with AD in Chinese population of Mainland China, and clarified whether this polymorphism is a risk factor for AD. RESULTS: The prevalence of the minor allele (A) in the rs3755166 polymorphism was significantly different in AD patients and control subjects (P<0.05). The rs3755166 polymorphism was associated with AD in the ethnic Chinese Han (OR=1.378, 95% CI: 1.017-1.867, P=0.039), and the results were not influenced by age, gender, or APOE status (P=0.441, P=0.94, P=0.432, respectively). CONCLUSION: Our data revealed the allele (A) of the rs3755166 polymorphism within LRP2 gene may contribute to AD risk in the Chinese Han Population. PMID- 20971102 TI - Anserine inhibits carnosine degradation but in human serum carnosinase (CN1) is not correlated with histidine dipeptide concentration. AB - BACKGROUND: We reported an association of a particular allele of the carnosinase (CNDP1 Mannheim) gene with reduced serum carnosinase (CN1) activity and absence of nephropathy in diabetic patients. Carnosine protects against the adverse effects of high glucose levels but serum carnosine concentration was generally low. METHODS: We measured the concentration of two further histidine dipeptides, anserine and homocarnosine, via HPLC. CN1 activity was measured fluorometically and for concentration we developed a capture ELISA. RESULTS: We found an association between the CNDP1 Mannheim allele and reduced serum CN1 activity for all three dipeptides but no correlation to serum concentrations although anserine and homocarnosine inhibited carnosinase activity. Patients with liver cirrhosis have low CN1 activity (0.24 +/- 0.17 MUmol/ml/h, n=7 males; normal range: 3.2 +/- 1.1, n=104; p<0.05) and CN1 concentrations (2.3 +/- 1.5 MUg/ml; normal range: 24.9 +/- 8.9, p<0.05) but surprisingly, histidine dipeptide concentrations in serum are not increased compared to controls. CONCLUSIONS: Serum histidine dipeptide concentrations are not correlated to CN1 activity. The protective effect of low CN1 activity might be related either to turnover of CN1 substrates or a protective function of dipeptides might be localized in other tissues. PMID- 20971103 TI - Development of a galactose biosensor with galactose oxidase-immobilized epidermis of Solanum lycopersicum: potential point-of-care testing for citrin deficiency in high-prevalence areas. PMID- 20971104 TI - Quercetin, a fluorescent bioflavanoid, inhibits Trypanosoma brucei hexokinase 1. AB - Hexokinases from the African trypanosome, Trypanosoma brucei, are attractive targets for the development of anti-parasitic drugs, in part because the parasite utilizes glycolysis exclusively for ATP production during the mammalian infection. Here, we have demonstrated that the bioflavanoid quercetin (QCN), a known trypanocide, is a mixed inhibitor of Trypanosoma brucei hexokinase 1 (TbHK1) (IC(50) = 4.1 +/- 0.8MUM). Spectroscopic analysis of QCN binding to TbHK1, taking advantage of the intrinsically fluorescent single tryptophan (Trp177) in TbHK1, revealed that QCN quenches emission of Trp177, which is located near the hinge region of the enzyme. ATP similarly quenched Trp177 emission, while glucose had no impact on fluorescence. Supporting the possibility that QCN toxicity is a consequence of inhibition of the essential hexokinase, in live parasites QCN fluorescence localizes to glycosomes, the subcellular home of TbHK1. Additionally, RNAi-mediated silencing of TbHK1 expression expedited QCN induced death, while over-expressing TbHK1 protected trypanosomes from the compound. In summary, these observations support the suggestion that QCN toxicity is in part attributable to inhibition of the essential TbHK1. PMID- 20971105 TI - Cloning and characterization of a venom allergen-like protein gene cluster from the pinewood nematode Bursaphelenchus xylophilus. AB - Pinewood nematode (PWN) is the causal agent of the pine wilt disease. Previous studies have suggested that secretions from the esophageal glands of PWN play an important role in pathogenicity. A cluster of three venom allergen-like protein genes and one pseudogene, Bx-vap-1, Bx-vap-2, Bx-vap-3 and Bx-vap-P, were identified within a 3.7-kb region. Additionally, three putative modification, transport and regulatory protein genes were also detected in the same flanking region of the Bx-vap gene cluster. Genes vap-1, -2 and -3 are functional and encode three major allelic variants of PWN venom allergen-like proteins. But Bx vap-P is an untranscribed pseudogene. Genes vap-1, -2 and -3 produce predicted products of 204, 206 and 203 amino acid residues, respectively, including the putative signal peptide sequence at the amino termini. In situ mRNA hybridization analysis showed that the transcripts of genes vap-1, -2 and -3 accumulated exclusively within the esophageal gland cells of Bursaphelenchus xylophilus. PMID- 20971106 TI - Trypanocidal activity and selectivity in vitro of aromatic amidine compounds upon bloodstream and intracellular forms of Trypanosoma cruzi. AB - Trypanosoma cruzi is the etiological agent of Chagas disease, an important neglected illness affecting about 12-14 million people in endemic areas of Latin America. The chemotherapy of Chagas disease is quite unsatisfactory mainly due to its poor efficacy especially during the later chronic phase and the considerable well-known side effects. These facts emphasize the need to search for find new drugs. Diamidines and related compounds are minor groove binders of DNA at AT rich sites and present excellent anti-trypanosomal activity. In the present study, six novel aromatic amidine compounds (arylimidamides and diamidines) were tested in vitro to determine activity against the infective and intracellular stages of T. cruzi, which are responsible for sustaining the infection in the mammalian hosts. In addition, their selectivity and toxicity towards primary cultures of cardiomyocyte were evaluated since these cells represent important targets of infection and inflammation in vivo. The aromatic amidines were active against T. cruzi in vitro, the arylimidamide DB1470 was the most effective compound presenting a submicromolar LD(50) values, good selectivity index, and good activity at 4 degrees C in the presence of blood constituents. Our results further justify trypanocidal screening assays with these classes of compounds both in vitro and in vivo in experimental models of T. cruzi infection. PMID- 20971107 TI - Sarcocystis cruzi: comparative studies confirm natural infections of buffaloes. AB - Controversy exists concerning whether cattle and water buffalo sustain infections with cysts of distinct arrays of species in the genus Sarcocystis. In particular, morphologically similar parasites have been alternately ascribed to Sarcocystis cruzi or to Sarcocystis levinei, depending on their occurrence in cattle or water buffalo. We used light and transmission electron microscopy, genetic analysis, and experimental infections of definitive canine hosts to determine whether consistent differences could be identified from parasites derived from several natural infections of each host, examining several tissue types (esophagus, skeletal muscles, and heart). Cysts derived from cattle and water buffalo shared similar structure; variation among 18S rRNA sequences did not segregate consistently according to intermediate host type; parasites derived from cattle and water buffalo induced similar outcomes in the canine definitive host. One cattle specimen harbored unusually large (macroscopic) sarcocysts which nonetheless conformed to previously reported ultrastructural and genetic features of S. cruzi. Finding no consistent basis to differentiate between them, we conclude that the parasites infecting each host and tissue type correspond to S. cruzi. In our sample, no phylogenetically distinct taxon was sampled which might correspond to a distinct taxon previously described as S. levinei. Either that taxon was missed by our sampling effort, or it may represent a junior synonym to S. cruzi, which would then cycle between dogs and a broader range of intermediate bovine hosts than was previously considered. PMID- 20971108 TI - Activation of the NLRP3 inflammasome by intracellular poly I:C. AB - Several RNA viruses can be detected by the inflammasome, which promotes IL-1beta and IL-18 secretion, but the underlying mechanisms of detection remain unclear. Cytosolic dsRNA is a replication intermediate of many RNA viruses. We show here that transfection of the dsRNA analogue poly I:C activates the NLRP3 inflammasome via a pathway requiring endosomal acidification. This detection is independent of the other poly I:C sensors: TLR3 and MDA5. These results suggest a mechanism by which cytosolic dsRNA produced during viral infection could activate the NLRP3 inflammasome. PMID- 20971109 TI - GC-rich intra-operonic spacers in prokaryotes: possible relation to gene order conservation. AB - Genome-scale compositional analyses of non-coding sequences from 410 microbes of varying GC-content, lineage, environment/life-style, reveal presence of a distinct trend in GC-usage in spacers between intra-operonic and extra-operonic gene-pairs. For most of the microbes, average GC-content of the intra-operonic spacers are consistently higher than those between extra-operonic unidirectional gene-pairs. Also, unidirectional gene-pairs exhibiting higher cross-species conservation, irrespective of their operonic context, house relatively GC-rich spacers. A few prokaryotes, most of which represent known cases of genome degradation, stand out as exceptions defying this trend. GC-enrichment of intra operonic spacers therefore appears to be an evolutionary strategy facilitating preservation of operonic gene-order. PMID- 20971110 TI - A mammalian insulysin homolog is regulated by enzyme IIA(Glc) of the glucose transport system in Vibrio vulnificus. AB - Vibrio vulnificus is an opportunistic human pathogen that causes severe infections in susceptible individuals. While the components of the Escherichia coli phosphoenolpyruvate: sugar phosphotransferase system (PTS) have been shown to regulate numerous targets, little such information is available for the V. vulnificus PTS. Here we show that enzyme IIA(Glc) of the PTS regulates the peptidase activity of a mammalian insulysin homolog in V. vulnificus. While interaction of IIA(Glc) with the insulysin homolog is independent of the phosphorylation state of IIA(Glc), only unphosphorylated IIA(Glc) activates the insulysin homolog. Taken together, our results suggest that the V. vulnificus insulysin-IIA(Glc) complex plays a role in survival in the host by sensing glucose. PMID- 20971111 TI - Glucocorticoid induces mesenchymal-to-epithelial transition and inhibits TGF beta1-induced epithelial-to-mesenchymal transition and cell migration. AB - Epithelial-to-mesenchymal transition (EMT) has been implicated in various physiological and pathological events. In this study, we found that the synthetic glucocorticoid dexamethasone (Dex) can inhibit transforming growth factor-beta1 induced EMT and cell migration. We also demonstrated that Dex inhibits EMT through a mechanism involving the suppression of ROS generation. Surprisingly, Dex alone induced mesenchymal-to-epithelial transition (MET). Dexamethasone treatment abolished Snail1 binding to the E-cadherin promoter, suggesting that suppression of Snail1 contributes to the above roles of Dex. Our findings demonstrate that Dex functions as both a suppressor of EMT and as an inducer of MET and therefore may be implicated in certain pathophysiological events. PMID- 20971112 TI - Reflections on the influenza vaccination of healthcare workers. AB - Despite all that is known about the dangers of nosocomial transmission of influenza to the vulnerable patient populations in our healthcare facilities, and the benefits of the influenza vaccination, the low rates of influenza vaccination among healthcare workers (HCWs) internationally shows no sign of significant improvement. With the current voluntary 'opt-in' programmes clearly failing to adequately address this issue, the time has undoubtedly come for a new approach to vaccination to be implemented. Two different approaches to vaccination delivery have been suggested to rectify this situation, mandatory vaccination and 'opt-out' declination forms. It is suggested, however, that these two approaches are inadequate when used by themselves. In order to protect the most vulnerable patients in our healthcare facilities as best we can from serious harm or death caused by nosocomial transmission of influenza, while at the same time respecting HCWs autonomy, and in many jurisdictions, the related legal right to refuse medical treatment, it is recommended that 'op-out' declination forms should be used in conjunction with restricted mandatory vaccination. This 'combined' approach would allow any HCW to refuse the influenza vaccination, but would make the influenza vaccination a mandatory requirement for working in areas where the most vulnerable patients are cared for. Those HCWs not willing to be vaccinated should be required to work in other areas of healthcare. PMID- 20971113 TI - Approaches to monitoring biological outcomes for HPV vaccination: challenges of early adopter countries. AB - In this review, we describe plans to monitor the impact of human papillomavirus (HPV) vaccine on biologic outcomes in selected international areas (Australia, Canada, Mexico, the Nordic countries, Scotland, and the United States) that have adopted this vaccine. This summary of monitoring plans provides a background for discussing the challenges of vaccine monitoring in settings where resources and capacity may vary. A variety of approaches that depend on existing infrastructure and resources are planned or underway for monitoring HPV vaccine impact. Monitoring HPV vaccine impact on biologic outcomes is a complex and challenging task, but also plays an important role in documenting the benefit of vaccination, monitoring the progress of vaccination programs, and providing data to inform vaccination and disease prevention policies. PMID- 20971114 TI - Benefits of vaccinating young adult women with a prophylactic quadrivalent human papillomavirus (types 6, 11, 16 and 18) vaccine. AB - Cervical cancer is a leading cause of cancer-related deaths worldwide. The causal role of human papillomavirus (HPV) infection in the pathogenesis of cervical cancer has prompted the development of vaccines against HPV. The highest risk of HPV infection is in women aged 16-25 years. Almost all young adult women can benefit from HPV vaccination. There is strong epidemiological and clinical support for vaccination programmes that target sexually active women in this age group to prevent HPV infection, and thus avert the development of HPV-related disease. Furthermore, the implementation of HPV vaccination programmes may benefit the development or awareness of cervical cancer prevention strategies and ultimately reduce the burden of cervical cancer and improve cervical cancer control. PMID- 20971115 TI - Is it time for a new yellow fever vaccine? AB - An inexpensive live attenuated vaccine (the 17D vaccine) against yellow fever has been effectively used to prevent yellow fever for more than 70 years. Interest in developing new inactivated vaccines has been spurred by recognition of rare but serious, sometimes fatal adverse events following live virus vaccination. A safer inactivated yellow fever vaccine could be useful for vaccinating people at higher risk of adverse events from the live vaccine, but could also have broader global health utility by lowering the risk-benefit threshold for assuring high levels of yellow fever vaccine coverage. If ongoing trials demonstrate favorable immunogenicity and safety compared to the current vaccine, the practical global health utility of an inactivated vaccine is likely to be determined mostly by cost. PMID- 20971116 TI - Survivin signalling in the heart. PMID- 20971117 TI - Innate immunity meets arteriogenesis: the versatility of toll-like receptors. PMID- 20971118 TI - Ca efflux via the sarcolemmal Ca ATPase occurs only in the t-tubules of rat ventricular myocytes. AB - The transverse (t-) tubule network is an important site for Ca influx and release during excitation-contraction coupling in cardiac ventricular myocytes; however, its role in Ca extrusion is less clear. The present study was designed to investigate the relative contributions of Ca extrusion pathways across the t tubule and surface membranes. Ventricular myocytes were isolated from the hearts of adult male Wistar rats and detubulated using formamide. Intracellular Ca was monitored using fluo-3 and confocal microscopy. Caffeine (20 mmol/L) was used to induce SR Ca release; carboxyeosin (20 MUmol/L) and nickel (10 mmol/L) were used to inhibit the sarcolemmal Ca ATPase and Na/Ca exchanger (NCX) respectively. Carboxyeosin decreased the rate constant of decay of the caffeine-induced Ca transient in control cells, but had no effect in detubulated cells, suggesting that Ca extrusion via the Ca ATPase occurs only across the t-tubule membrane. However nickel decreased the rate constant of the caffeine-induced Ca transient in control and detubulated cells, although its effect was greater in control cells, suggesting that Ca extrusion via NCX occurs across the surface and t tubule membranes. The PKA inhibitor H-89 (10 MUmol/L) was used to investigate the role of basal PKA activity in Ca extrusion; H-89 appeared to have no effect on Ca extrusion via the Ca ATPase, but reduced Ca extrusion via NCX at the t-tubules but not the surface membrane. Thus it appears that Ca extrusion via the sarcolemmal Ca ATPase occurs only at the t-tubules, and is not regulated by basal PKA activity, while Ca extrusion via NCX occurs across both the surface and t tubule membranes, but predominantly across the t-tubule membrane due, in part, to localised stimulation of NCX by PKA at the t-tubules. This may be important in heart disease, in which changes in t-tubule structure and protein phosphorylation occur. PMID- 20971119 TI - SR-targeted CaMKII inhibition improves SR Ca2+ handling, but accelerates cardiac remodeling in mice overexpressing CaMKIIdeltaC. AB - Cardiac myocyte overexpression of CaMKIIdelta(C) leads to cardiac hypertrophy and heart failure (HF) possibly caused by altered myocyte Ca(2+) handling. A central defect might be the marked CaMKII-induced increase in diastolic sarcoplasmic reticulum (SR) Ca(2+) leak which decreases SR Ca(2+) load and Ca(2+) transient amplitude. We hypothesized that inhibition of CaMKII near the SR membrane would decrease the leak, improve Ca(2+) handling and prevent the development of contractile dysfunction and HF. To test this hypothesis we crossbred CaMKIIdelta(C) overexpressing mice (CaMK) with mice expressing the CaMKII inhibitor AIP targeted to the SR via a modified phospholamban (PLB)-transmembrane domain (SR-AIP). There was a selective decrease in the amount of activated CaMKII in the microsomal (SR/membrane) fraction prepared from these double-transgenic mice (CaMK/SR-AIP) mice. In ventricular cardiomyocytes from CaMK/SR-AIP mice, SR Ca(2+) leak, assessed both as diastolic Ca(2+) shift into SR upon tetracaine in intact myocytes or integrated Ca(2+) spark release in permeabilized myocytes, was significantly reduced. The reduced leak was accompanied by enhanced SR Ca(2+) load and twitch amplitude in double-transgenic mice (vs. CaMK), without changes in SERCA expression or NCX function. However, despite the improved myocyte Ca(2+) handling, cardiac hypertrophy and remodeling was accelerated in CaMK/SR-AIP and cardiac function worsened. We conclude that while inhibition of SR localized CaMKII in CaMK mice improves Ca(2+) handling, it does not necessarily rescue the HF phenotype. This implies that a non-SR CaMKIIdelta(C) exerts SR-independent effects that contribute to hypertrophy and HF, and this CaMKII pathway may be exacerbated by the global enhancement of Ca transients. PMID- 20971120 TI - Skeletal muscle stem cells propagated as myospheres display electrophysiological properties modulated by culture conditions. AB - In cardiac regenerative therapy, transplantation of stem cells to form new myocardium is limited by their inability to integrate into host myocardium and conduct cardiac electrical activity. It is now hypothesized that refining cell sorting could upgrade the therapeutic result. Here we characterized a subpopulation of skeletal muscle stem cells with respect to their electrophysiological properties. The aim of our study was to determine whether electrophysiological parameters are compatible with cardiac function and can be influenced by culture conditions. Low-adherent skeletal muscle stem cells were isolated from the hind legs of 12-20 week old mice. After 6 days of culture the cells were analysed using patch-clamp techniques and RT-PCR, and replated in different media for skeletal muscle or cardiac differentiation. The cells generated action potentials (APs) longer than skeletal muscle APs, expressed functional cardiac Na(+) channels (~46% of the total channel fraction), displayed fast activating and inactivating L-type Ca(2+) currents, possibly conducted through cardiac channels and did not show significant Cl(-) conductance. Moreover, a fraction of cells expressed muscarinic acetylcholine receptors. Conditioning the cells for skeletal muscle differentiation resulted in upregulation of skeletal muscle-specific Na(+) and Ca(2+) channel expression, shortening of AP duration and loss of functional cardiac Na(+) channels. Cardiomyogenic conditions however, promoted the participation of cardiac Na(+) channels (57% of the total channel fraction). Nevertheless the cells retained properties of myoblasts such as the expression of nicotinic acetylcholine receptors. We conclude that skeletal muscle stem cells display several electrophysiological properties similar to those of cardiomyocytes. Culture conditions modulated these properties but only partially succeeded in further driving the cells towards a cardiac phenotype. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited". PMID- 20971121 TI - PKA and Epac synergistically inhibit smooth muscle cell proliferation. AB - Cyclic AMP signalling promotes VSMC quiescence in healthy vessels and during vascular healing following injury. Cyclic AMP inhibits VSMC proliferation via mechanisms that are not fully understood. We investigated the role of PKA and Epac signalling on cAMP-induced inhibition of VSMC proliferation. cAMP-mediated growth arrest was PKA-dependent. However, selective PKA activation with 6-Benzoyl cAMP did not inhibit VSMC proliferation, indicating a requirement for additional pathways. Epac activation using the selective cAMP analogue 8-CPT-2'-O-Me-cAMP, did not affect levels of hyperphosphorylated Retinoblastoma (Rb) protein, a marker of G1-S phase transition, or BrdU incorporation, despite activation of the Epac-effector Rap1. However, 6-Benzoyl-cAMP and 8-CPT-2'-O-Me-cAMP acted synergistically to inhibit Rb-hyperphosphorylation and BrdU incorporation, indicating that both pathways are required for growth inhibition. Consistent with this, constitutively active Epac increased Rap1 activity and synergised with 6 Benzoyl-cAMP to inhibit VSMC proliferation. PKA and Epac synergised to inhibit phosphorylation of ERK and JNK. Induction of stellate morphology, previously associated with cAMP-mediated growth arrest, was also dependent on activation of both PKA and Epac. Rap1 inhibition with Rap1GAP or siRNA silencing did not negate forskolin-induced inhibition of Rb-hyperphosphorylation, BrdU incorporation or stellate morphology. This data demonstrates for the first time that Epac synergises with PKA via a Rap1-independent mechanism to mediate cAMP-induced growth arrest in VSMC. This work highlights the role of Epac as a major player in cAMP-dependent growth arrest in VSMC. PMID- 20971122 TI - Effects of asynchronism on evolutionary games. AB - We analyze the influence of the update dynamics on symmetric 2-player evolutionary games, which are among the most used tools to study the emergence of cooperation in populations of interacting agents. A synchronous dynamics means that, at each time step, all the agents of the population update their strategies simultaneously. An extreme case of asynchronism is sequential dynamics, in which only one agent is updated each time. We first show that these two opposite update dynamics can lead to very different outcomes and that sequential dynamics is detrimental to the emergence of cooperation only when the probability of imitating the most successful neighbors is high. In this sense, we can say that, when the update dynamics has some influence, in general asynchronism is beneficial to the emergence of cooperation. We then explore the consequences of using intermediate levels of asynchronism, where only a fraction of the agents update their behavior each time. In general, the level of cooperation changes smoothly and monotonically as we gradually go from synchronous to sequential dynamics. However, there are some exceptions that should be taken into account. In addition, the results show that the possibility of agents taking irrational decisions has a key role in the sensitivity of these models to changes in the update dynamics. Explanations for the observed behaviors are advanced. PMID- 20971123 TI - Polymorphisms affecting micro-RNA regulation and associated with the risk of dietary-related cancers: a review from the literature and new evidence for a functional role of rs17281995 (CD86) and rs1051690 (INSR), previously associated with colorectal cancer. AB - In this review, we focus on the genetic variations (single nucleotide polymorphisms, SNPs) known to occur in microRNAs and in their binding sites and the susceptibility to cancers of the gastro-intestinal (GI) tract in humans. Since the sequence complementarity and the thermodynamics of binding play an essential role in the interaction of miRNA with its target mRNA, sequence variations in the miRNA-binding seed regions or in miRNA genes (either within pre , pri-, or mature miRNA regions) should reinforce, weaken, or disrupt the miRNA mRNA interaction and affect the expression of mRNA targets. Indirect evidences supporting these hypotheses are reported in the literature, essentially coming from case-control association studies. Several studies have been published on the association between miR-SNPs or SNPs within their binding sites and the risk of oesophageal, gastric, or colorectal cancer. Unfortunately, functional studies are lacking. Besides reviewing the available literature, we present here for the first time two SNPs (rs17281995 in CD86 and rs1051690 in INSR) previously associated with the risk of CRC in a Czech population are also associated with the risk in a Spanish population. Moreover, we show for the first time that both these alleles regulate differentially the amount of a reporter gene (luciferase) in an in vitro assay on HeLa cells. These findings suggest that both these SNPs may have a functional role in regulating the expression of CD-86 and INSR proteins acting at the level of the 3'UTR. More functional studies are needed in order to better understand the role of polymorphic regulatory sequences at the 3'UTR of genes. PMID- 20971124 TI - The sensitizing effect of acute nicotine on amphetamine-stimulated behavior and dopamine efflux requires activation of beta2 subunit-containing nicotinic acetylcholine receptors and glutamate N-methyl-D-aspartate receptors. AB - Nicotine has been demonstrated to enhance the subsequent use of illicit drugs in animals and humans. We previously demonstrated in female, Holtzman rats that one low dose of nicotine will potentiate locomotor activity and dopamine (DA) efflux in response to a subsequent low dose of d-amphetamine (AMPH) given 1-4 h later. In the present study, we show this also occurs in male rats and characterize the receptors required for the rapid sensitizing effect of nicotine on AMPH stimulated locomotor behavior and AMPH-induced DA efflux. Pretreatment of male, Holtzman rats with a low dose (0.1 mg/kg, i.p.) of nicotine 2-4 h before a challenge with AMPH (0.32 mg/kg, i.p.) enhanced locomotor behavior as compared to saline pretreatment. Dihydro-beta-erythroidine (DHbetaE), a relatively selective antagonist at beta2 subunit-containing (beta2*) nicotinic acetylcholine receptors (nAChR), but not methyllycaconitine (MLA), a relatively selective antagonist at alpha7 nAChRs, blocked the sensitizing effect of nicotine on AMPH-stimulated locomotor activity. Pretreatment with varenicline, a partial agonist selective for beta2* nAChRs, blocked the sensitizing effect of nicotine on AMPH-stimulated locomotor behavior. Nicotine pretreatment sensitized AMPH-induced DA overflow in slices from ventral (nucleus accumbens, NAc), but not dorsal striatum as compared to saline-pretreated rats. Nicotine sensitization of the DA overflow was blocked by DHbetaE. Pretreatment with the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK-801 (0.1 mg/kg, s.c.) 30 min before nicotine blocked sensitization of both locomotion and DA overflow in response to AMPH challenge. These results demonstrate that activation of the beta2* nAChRs and NMDA receptors are required for the rapid sensitizing effect of nicotine on AMPH actions. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 20971125 TI - Temporary inhibition of AMPA receptors induces a prolonged improvement of motor performance in a mouse model of juvenile Batten disease. AB - Mutations in the CLN3 gene cause juvenile Batten disease, a fatal pediatric neurodegenerative disorder. The Cln3-knockout (Cln3(Deltaex1-6)) mouse model of the disease displays many pathological characteristics of the human disorder including a deficit in motor coordination. We have previously found that attenuation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor activity in one-month-old Cln3(Deltaex1-6) mice resulted in an immediate improvement of their motor skills. Here we show that at a later stage of the disease, in 6-7-month-old Cln3(Deltaex1-6) mice, acute inhibition of AMPA receptors by a single intraperitoneal injection (1mg/kg) of the non-competitive AMPA antagonist, EGIS-8332, does not have an immediate effect. Instead, it induces a delayed but prolonged improvement of motor skills. Four days after the injection of the AMPA antagonist, Cln3(Deltaex1-6) mice reached the same motor skill level as their wild type (WT) counterparts, an improvement that persisted for an additional four days. EGIS-8332 was rapidly eliminated from the brain as measured by HPLC-MS/MS. Histological analysis performed 8 days after the drug administration revealed that EGIS-8332 did not have any impact upon glial activation or the survival of vulnerable neuron populations in 7-month-old Cln3(Deltaex1-6) mice. We propose that temporary inhibition of AMPA receptors can induce a prolonged correction of the pre-existing abnormal glutamatergic neurotransmission in vivo for juvenile Batten disease. PMID- 20971126 TI - Exogenous gangliosides increase the release of brain-derived neurotrophic factor. AB - Gangliosides are lipophilic compounds found in cell plasma membranes throughout the brain that play a role in neuronal plasticity and regeneration. Indeed, absence or abnormal accumulation of gangliosides has been shown to lead to neurological disorders. Experimental data have shown that exogenous gangliosides exhibit properties similar to the neurotrophins, a family of neurotrophic factors that are important in the survival and maintenance of neurons and prevention of neurological diseases. Brain-derived neurotrophic factor (BDNF) is the most abundant of the neurotrophins. This work was done to reveal the neurotrophic mechanism of exogenous gangliosides. In particular, we examined whether gangliosides promote the release of BDNF. Rat hippocampal neurons or human neuroblastoma cells were transduced with a recombinant adenovirus expressing BDNF flag to facilitate detection of BDNF. Release of BDNF was then determined by Western blot analysis and a two-site immunoassay of culture medium. The depolarizing agent KCl was used as a comparison. In hippocampal neurons, both GM1 ganglioside and KCl evoked within minutes the release of mature BDNF. In human cells, GM1 and other gangliosides released both mature BDNF and pro-BDNF. The effect of gangliosides was structure-dependent. In fact, GT1b preferentially released mature BDNF whereas GM1 released both mature and pro-BDNF. Ceramide and sphingosine did not modify the release of BDNF. This work provides additional experimental evidence that exogenous gangliosides can be used to enhance the neurotrophic factor environment and promote neuronal survival in neurological diseases. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 20971127 TI - S-norfluoxetine microinfused into the basolateral amygdala increases allopregnanolone levels and reduces aggression in socially isolated mice. AB - A decrease of brain allopregnanolone biosynthesis may play a role in emotion, impulsive behavior, and anxiety spectrum disorders by decreasing GABAergic neurotransmission. In male mice, four weeks of social isolation induces behavioral dysfunctions such as aggression, fear, and anxiety-like behavior associated with a decrease in allopregnanolone biosynthesis in selected corticolimbic structures comprising the basolateral amygdala (BLA), olfactory bulb, hippocampus, and medial prefrontal cortex. Importantly, no decrease in allopregnanolone biosynthesis has been found in the striatum and cerebellum. Given the importance of the amygdaloid complex in emotional behavior, we hypothesized that this brain area may play a pivotal role in decreasing social isolation-induced aggression. Thus, socially isolated mice were directly infused with S-norfluoxetine (S-NFLX) or pregnanolone (an analog of allopregnanolone) into the BLA and striatum. When S-NFLX (2.5, 3.75, and 5 nmol/0.2 MUl) or pregnanolone (1.25, 2.5, 3.75, and 5.0 nmol/0.2 MUl) is directly infused into the BLA, these agents dose-dependently reduced aggression (S-NFLX up to 93% and pregnanolone up to 96%) of a socially isolated mouse to a same-sex intruder. However, S-NFLX (3.75 and 5 nmol) infused directly into the striatum failed to alter aggression. Allopregnanolone content in the BLA after S-NFLX (3.75 nmol) infusion was increased by 3-fold and in the hippocampus, by 80%. Allopregnanolone levels did not change in the olfactory bulb or in the frontal cortex of the same mice. S-NFLX (3.75 nmol) infused into the striatum failed to increase the levels of allopregnanolone. These results suggest that S-NFLX, acting as a selective brain steroidogenic stimulant (SBSS), increases corticolimbic allopregnanolone levels and regulates aggression, which underscores the pivotal role of the BLA and hippocampus in the regulation of aggressiveness in socially isolated mice. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 20971128 TI - Intensive exercise: a remedy for childhood obesity? AB - BACKGROUND: Acute exercise can affect the energy intake regulation, which is of major interest in terms of obesity intervention and weight loss. OBJECTIVE: To test the hypothesis that intensive exercise can affect the subsequent energy intake and balance in obese adolescents. DESIGN: The study was conducted in 2009 and enrolled 12 obese pubertal adolescents ages 14.4+/-1.5 years old. Two exercise and one sedentary sessions were completed. The first exercise (EX(1)) and sedentary session (SED) were randomly conducted 1 week apart. The second exercise session (EX2) was conducted following 6 weeks of diet modification and physical activity (3*90 min/week) to produce weight loss. Energy intake was recorded, subjective appetite sensation was evaluated using Visual Analogue Scales and energy expenditure was measured using ActiHerats during EX(1), EX2 and SED. RESULTS: Total energy intake over the awakened period was significantly reduced by 31% and 18% during the EX(1) and EX(2) sessions compared with the SED session, respectively (p<0.01). Energy balance over the awakened period was negative during EX1, neutral during EX2 and positive during SED. There was no significant difference in terms of subjective appetite rates between sessions during the awakened hours. CONCLUSIONS: Intensive exercise favors a negative energy balance by dually affecting energy expenditure and energy intake without changes in appetite sensations, suggesting that adolescents are not at risk of food frustration. PMID- 20971129 TI - Reconciling sensory cues and varied consequences of avian repellents. AB - We learned previously that red-winged blackbirds (Agelaius phoeniceus) use affective processes to shift flavor preference, and cognitive associations (colors) to avoid food, subsequent to avoidance conditioning. We conducted three experiments with captive red-winged blackbirds to reconcile varied consequences of treated food with conditioned sensory cues. In Experiment 1, we compared food avoidance conditioned with lithium chloride (LiCl) or naloxone hydrochloride (NHCl) to evaluate cue-consequence specificity. All blackbirds conditioned with LiCl (gastrointestinal toxin) avoided the color (red) and flavor (NaCl) of food experienced during conditioning; birds conditioned with NHCl (opioid antagonist) avoided only the color (not the flavor) of food subsequent to conditioning. In Experiment 2, we conditioned experimentally naive blackbirds using free choice of colored (red) and flavored (NaCl) food paired with an anthraquinone- (postingestive, cathartic purgative), methiocarb- (postingestive, cholinesterase inhibitor), or methyl anthranilate-based repellent (preingestive, trigeminal irritant). Birds conditioned with the postingestive repellents avoided the color and flavor of foods experienced during conditioning; methyl anthranilate conditioned only color (not flavor) avoidance. In Experiment 3, we used a third group of blackbirds to evaluate effects of novel comparison cues (blue, citric acid) subsequent to conditioning with red and NaCl paired with anthraquinone or methiocarb. Birds conditioned with the postingestive repellents did not avoid conditioned color or flavor cues when novel comparison cues were presented during the test. Thus, blackbirds cognitively associate pre- and postingestive consequences with visual cues, and reliably integrate visual and gustatory experience with postingestive consequences to procure nutrients and avoid toxins. PMID- 20971131 TI - Three austin family compounds from Penicillium brasilianum exhibit selective blocking action on cockroach nicotinic acetylcholine receptors. AB - Austin (AT) and its derivatives (dehydroaustin (DAT) and acetoxydehydroaustin (ADAT)) produced by Penicillium brasilianum MG-11 exhibit toxicity to insects, yet their targets are unknown. Here, we used whole-cell patch-clamp electrophysiology to investigate the action of AT family compounds on cockroach acetylcholine (ACh), gamma-aminobutyric acid (GABA) and l-glutamate receptors expressed in the American cockroach (Periplaneta americana) neuron. U-tube application of AT or its derivatives did not induce any current amplitudes, suggesting that they did not act as agonist of these three receptors. In the second step of experiments, they were bath-applied for 1min before co-application with the corresponding ligand. We found that AT and its derivatives had no effect on GABA and l-glutamate-induced currents, whereas they significantly reduced ACh- and epibatidine-induced currents, showing that these compounds acted as selective antagonists of nicotinic acetylcholine receptors (nAChRs) expressed in the cockroach neuron. Of the compounds, DAT showed the highest blocking potency for nAChRs, differentially attenuating the peak and slowly desensitizing current amplitude of ACh-induced responses with pIC(50) (=-logIC(50) (M)) values of 6.11 and 5.91, respectively. DAT reduced the maximum normalized response to ACh without a significant shift in EC(50), suggesting that the blocking action is not competitive with ACh. PMID- 20971130 TI - Uncovering the visual "alphabet": advances in our understanding of object perception. AB - The ability to rapidly and accurately recognize visual stimuli represents a significant computational challenge. Yet, despite such complexity, the primate brain manages this task effortlessly. How it does so remains largely a mystery. The study of visual perception and object recognition was once limited to investigations of brain-damaged individuals or lesion experiments in animals. However, in the last 25years, new methodologies, such as functional neuroimaging and advances in electrophysiological approaches, have provided scientists with the opportunity to examine this problem from new perspectives. This review highlights how some of these recent technological advances have contributed to the study of visual processing and where we now stand with respect to our understanding of neural mechanisms underlying object recognition. PMID- 20971132 TI - Very small embryonic-like stem cells in cardiovascular repair. AB - Adult bone marrow (BM) harbors several small populations of cells which may contribute to cardiac and endothelial repair, such as endothelial progenitor cells (EPCs), mesenchymal stromal cells (MSCs) and very small embryonic-like cells (VSELs) expressing several markers of pluripotent stem cells (PSCs), such as Oct-4, Nanog and SSEA-1. Such cells were identified in mice bone marrow, peripheral blood and solid organs as well as in umbilical cord blood (UCB) and peripheral blood (PB) in humans. The adult BM-derived VSELs may undergo differentiation into cells derived for all three germ layers, including cardiomyocytes and vascular endothelial cells. VSELs can be isolated using a multiparameter live cell sorting technique with special gating strategy based on their small size, expression of stem cell markers (Sca-1 in mice, CXCR4 and CD133 in humans) and absence of hematopoietic lineage markers (CD45(-) Lin(-)). Experiments in murine models of myocardial infarction (MI) demonstrated population of VSELs expressed also early markers of cardiac and endothelial lineages (GATA-4, Nkx2.5/Csx, VE-cadherin, von Willebrand factor) which migrated to stromal-derived factor-1 (SDF-1) and other chemoattractant gradient and underwent rapid mobilization into peripheral blood in experimental MI mice models. Recently, we demonstrated the mobilization of VSELs expressing PSC, early cardiac and endothelial markers in patients with acute MI. In addition to BM, VSELs were also identified in several murine solid organs including the heart and brain, as well as in umbilical cord blood and peripheral blood in adult humans. We hypothesized that VSELs are quiescent progeny of epiblast-derived PSCs that are deposited during organogenesis in developing organs. In experimental MI intramyocardial injection of VSELs was more efficient than that of HSCs at improving left ventricular ejection fraction and attenuation of myocardial hypertrophy. VSELs can be useful in translational studies of cardiovascular repair. PMID- 20971134 TI - Applied biotechnology for production of immunoglobulin Y specific to hepatitis A virus. AB - A new protocol for producing polyclonal antibody against hepatitis A virus (HAV) is described. Twenty hens were immunized three times with a commercial HAV vaccine and HAV from a cell culture with three types of adjuvants: CpG oligodeoxynucleotides (CpG-ODN), incomplete Freund's adjuvant and an alum adjuvant. In each of the last two booster inoculations, blood from the birds was collected and tested for HAV antibodies. Egg yolk was separated from egg white and immunoglobulin Y (IgY) antibody was then purified by polyethylene glycol 6000. The mean yield of total protein in yolk was 22.62 mg/mL. Specific activity of the antibody was tested using commercial ELISA, Western blotting, and in vitro neutralization assay demonstrating that anti-HAV IgY bound specifically. After the first immunization, birds immunized with HAV from cell culture plus incomplete Freund's adjuvant with/without CpG-ODN showed highest levels of anti HAV IgY in serum (p<0.05). Viral combination with CpG-ODN resulted in early response of anti-HAV serum in hens, reflecting the amount of IgY transferred to the egg yolk (p<0.05). The results suggest that egg yolk may be a large scale source of specific antibodies against hepatitis A virus. Further applications of this method have yet to be tested. PMID- 20971135 TI - Inactivation of Pseudomonas aeruginosa PA01 biofilms by hyperthermia using superparamagnetic nanoparticles. AB - The primary goal of this study was to develop a new strategy to inactivate bacterial biofilms using the thermal stress derived from superparamagnetic iron oxide nanoparticles (SPIONs) in an alternating current (AC) magnetic field. A large number of studies have examined the inactivation of bacterial biofilms using antimicrobial agents; however, there have been no attempts to inactivate biofilms by hyperthermia using SPIONs. In this study, a SPION solution was added to Pseudomonas aeruginosa (P. aeruginosa) PA01 biofilm, and heat was generated by placing the nanoparticle-containing biofilm in an AC magnetic field. The heating temperature was dependent on the concentration of the added SPION solution. More than 4 log inactivation of the PA01 biofilm was obtained using a 60 mg mL(-1) SPION solution in 8 min, and this resulted in a dramatic disintegration of the bacterial cell membrane in the biofilm. This inactivation was largely due to the thermal effect. Local heating of a specific area is also possible using this method, and the heating temperature can be easily adjusted by controlling the concentration of the SPION solution. Therefore, hyperthermia using magnetic nanoparticles holds promise as an effective tool for inactivating the bacterial biofilm. PMID- 20971136 TI - A simple and rapid GC/MS method for the simultaneous determination of gaseous metabolites. AB - We modified and tuned a commercial model of a gas chromatography/mass spectrometry (GC/MS) instrument to develop a simple and rapid method for the simultaneous quantification of a variety of gas species. Using the developed method with the newly modified instrument, gas species such as H(2), N(2), O(2), CO, NO, CH(4), CO(2), and N(2)O, which are common components of microbial metabolism, were accurately identified based on their retention times and/or mass to-charge ratios (m/z) in less than 2.5 min. By examining the sensitivities and dynamic ranges for the detection of H(2), N(2), O(2), CH(4), CO(2), and N(2)O, it was demonstrated that the method developed in this study was sufficient for accurately monitoring the production and the consumption of these gaseous species during microbial metabolism. The utility of the new method was demonstrated by a denitrification study with Pseudomonas aureofaciens ATCC 13985(T). This method will be suitable for a variety of applications requiring the identification of gaseous metabolites in microorganisms, microbial communities, and natural ecosystems. PMID- 20971137 TI - Validation of an extracted tooth model of endodontic irrigation. AB - An extracted tooth model of endodontic irrigation, incorporating reproducible inoculation and irrigation procedures, was tested against Enterococcus faecalis using a variety of different irrigants in a Latin square methodology. ANOVA revealed no significant variations between the twelve teeth or experiments undertaken on different occasions; however, variation between irrigants was significant. PMID- 20971138 TI - In the blink of an eye: the contribution of microsaccadic activity to the induced gamma band response. AB - In 2008 an article by Yuval-Greenberg and colleagues initiated a lively debate within the field of induced gamma band research. Their article suggested that scalp-recorded induced gamma band responses (iGBRs) to visual stimuli could be obscured by minute movements of extraocular muscles, called microsaccades, which are associated with the saccadic spike potentials (SPs). Yuval-Greenberg et al. (2008) proposed that the temporal and spectral characteristics of SPs could mask and have been previously mistaken for cortical induced gamma band activity. This review summarises the main findings of the report by Yuval-Greenberg et al. (2008) and the research that has emerged since its publication. Microsaccades and the associated SP waveforms are described in detail and their contribution to the iGBR discussed. Different lines of argument are considered that suggest that the scalp-recorded iGBR exists separate from ocular contributions. The article then considers techniques that are widely used to remove electroencephalogram (EEG) artefacts and their potential adaptation for the removal of SPs. The review closes by pointing to future directions that researchers may explore in order to disentangle neural iGBRs and artefactual, SP-related iGBRs, and to several routes which researchers may consider in order to increase the informative value of their scalp-recorded iGBR data. We conclude that further investigation and testing is necessary to develop signal processing tools that successfully identify and correct SPs in EEG data without distorting the neural iGBR. PMID- 20971139 TI - A silencing suppressor protein (NSs) of a tospovirus enhances baculovirus replication in permissive and semipermissive insect cell lines. AB - The nonstructural protein (NSs) of the Tomato spotted wilt virus (TSWV) has been identified as an RNAi suppressor in plant cells. A recombinant Autographa californica multiple nucleopolyhedrovirus (AcMNPV) designated vAcNSs, containing the NSs gene under the control of the viral polyhedrin (polh) gene promoter, was constructed and the effects of NSs in permissive, semipermissive and nonpermissive insect cells to vAcNSs infection were evaluated. vAcNSs produced more budded virus when compared to wild type in semipermissive cells. Co infection of vAcNSs with wild type baculoviruses clearly enhanced polyhedra production in all host cells. Confocal microscopy analysis showed that NSs accumulated in abundance in the cytoplasm of permissive and semipermissive cells. In contrast, high amounts of NSs were detected in the nuclei of nonpermissive cells. Co-infection of vAcNSs with a recombinant AcMNPV containing the enhanced green fluorescent protein (egfp) gene, significantly increased EGFP expression in semipermissive cells and in Anticarsia gemmatalis-hemocytes. Absence of small RNA molecules of egfp transcripts in this cell line and in a permissive cell line indicates the suppression of gene silencing activity. On the other hand, vAcNSs was not able to suppress RNAi in a nonpermissive cell line. Our data showed that NSs protein of TSWV facilitates baculovirus replication in different lepidopteran cell lines, and these results indicate that NSs could play a similar role during TSWV-infection in its thrips vector. PMID- 20971140 TI - Mathematical modeling of drug delivery from torus-shaped single-layer devices. AB - A mathematical modeling of controlled release of drug from torus-shaped single layer devices is presented. Analytical solutions based on the pseudo-steady state approximation are derived. The reliability and usefulness of the model are ascertained by comparison of the simulation results with matrix-type vaginal ring experimental release data reported in the literature. A good agreement between the model prediction and the experimental data is observed. An analysis of the effect of the variation in torus design parameters on the solute release is also presented. The model is applicable only to torus-shaped single-layer systems wherein the initial load of drug is higher than its solubility in the polymer. PMID- 20971141 TI - All-trans retinoic acid stealth liposomes prevent the relapse of breast cancer arising from the cancer stem cells. AB - The relapse of cancer is mostly due to the proliferation of cancer stem cells which could not be eliminated by a standard chemotherapy. A new kind of all-trans retinoic acid stealth liposomes was developed for preventing the relapse of breast cancer and for treating the cancer in combination with a cytotoxic agent, vinorelbine stealth liposomes. In vitro studies were performed on the human breast cancer MCF-7 and MDA-MB-231 cells. In vivo evaluations were performed on the newly established relapse model with breast cancer stem cells. Results showed that the particle size of all-trans retinoic acid stealth liposomes was approximately 80nm, and the encapsulation efficiency was >90%. Breast cancer stem cells were identified with the CD44(+)/CD24(-) phenotype and characterized with properties: resistant to cytotoxic agent, stronger capability of proliferation, and stronger capability of differentiation. Inhibitory effect of all-trans retinoic acid stealth liposomes was more potent in cancer stem cells than in cancer cells. The mechanisms were defined to be two aspects: arresting breast cancer stem cells at the G(0)/G(1) phase in mitosis, and inducing the differentiation of breast cancer stem cells. The cancer relapse model was successfully established by xenografting breast cancer stem cells into NOD/SCID mice, and the formation and growth of the xenografted tumors were significantly inhibited by all-trans retinoic acid stealth liposomes. The combination therapy of all-trans retinoic acid stealth liposomes with vinorelbine stealth liposomes produced the strongest inhibitory effect to the relapse tumor model. It could be concluded that all-trans retinoic acid stealth liposomes could be used for preventing the relapse of breast cancer by differentiating cancer stem cells and arresting the cell-cycle, and for treating breast cancer as a co-therapy, thus providing a novel strategy for treating breast cancer and preventing relapse derived from breast cancer stem cells. PMID- 20971142 TI - Trilysinoyl oleylamide-based cationic liposomes for systemic co-delivery of siRNA and an anticancer drug. AB - Oligolysine-based cationic lipid derivatives were synthesized for delivery of siRNA, and formulated into cationic liposomes. Among various oligolysine-based lipid derivatives differing in lysine residue number and lipid moiety, trilysinoyl oleylamide (TLO)-based liposomes (TLOL) showed the highest delivery efficiency combined with minimal cytotoxicity. Delivery of siRNA using TLOL silenced target genes both in vitro and in vivo. In green fluorescent protein (GFP)-expressing tumor tissue, a significant reduction of fluorescence was observed after intratumoral administration of siGFP using TLOL compared with control siGL2. Intravenous administration of siMcl1 employing pegylated TLOL (pTLOL) reduced the expression of human Mcl1 protein in KB-xenografted tumor tissue. Despite the reduction in target protein Mcl1 expression following such systemic delivery, tumor growth was only slightly reduced compared to a siGL2 treated control group. To potentiate the anticancer activity of siMcl1, the anticancer drug suberoylanilide hydroxamic acid (SAHA) was additionally encapsulated in pTLOL. After intravenous administration of siMcl1 using SAHA loaded pTLOL (pSTLOL), a significant reduction in tumor growth was observed compared to that seen in animals treated with free SAHA or siGL2 complexed with pSTLOL. The results indicate that pTLOL could be further developed as a systemic delivery system for synergistic anticancer siRNA and a drug. PMID- 20971143 TI - pH-sensitive polymer hydrogels derived from morpholine to prevent the crystallization of ibuprofen. AB - Various pharmaceutical formulations of ibuprofen are available including oral tablets, suspensions, suppositories and transdermal gels and creams. Aqueous ibuprofen solubility is dependent on pH increasing solubility when increasing pH. The very low aqueous solubility of ibuprofen can lead to a segregation of the drug in to microdomains and possible crystallization which will affect the release profile even leading to possible damage of the mucous membrane of the stomach. Therefore, homopolymers and copolymers of N-ethylmorpholine methacrylamide (EMA) and N, N-dimethylacrylamide (DMA) hydrogels have been prepared to be applied as matrices for ibuprofen release as a method for minimizing these issues. The hydrogels were loaded with ibuprofen and the release over time was tested at 37 degrees C and at different pH values: 2, 5 and 7.4. Fourier-transform infrared spectroscopy with attenuated total reflection (FTIR ATR) was performed in order to identify the stretching vibrations of the carbonyl group for each component. Dissolution of the ibuprofen from the formulations at different pHs was studied using the ATR-FTIR spectroscopic imaging. The results showed that for DMA hydrogels, most of ibuprofen was released as non crystalline ibuprofen at pH 7.4 but it was not able to prevent crystallization at pH 2 and 5. In contrast, the EMA hydrogels were able to prevent crystallization of the ibuprofen at all pHs. Finally, it was demonstrated that there is a minimum concentration at which the polymer becomes ineffective. PMID- 20971133 TI - Motor neuron trophic factors: therapeutic use in ALS? AB - The modest effects of neurotrophic factor (NTF) treatment on lifespan in both animal models and clinical studies of Amyotropic Lateral Sclerosis (ALS) may result from any one or combination of the four following explanations: 1.) NTFs block cell death in some physiological contexts but not in ALS; 2.) NTFs do not rescue motoneurons (MNs) from death in any physiological context; 3.) NTFs block cell death in ALS but to no avail; and 4.) NTFs are physiologically effective but limited by pharmacokinetic constraints. The object of this review is to critically evaluate the role of both NTFs and the intracellular cell death pathway itself in regulating the survival of spinal and cranial (lower) MNs during development, after injury and in response to disease. Because the role of molecules mediating MN survival has been most clearly resolved by the in vivo analysis of genetically engineered mice, this review will focus on studies of such mice expressing reporter, null or other mutant alleles of NTFs, NTF receptors, cell death or ALS-associated genes. PMID- 20971144 TI - An intravesical device for the sustained delivery of lidocaine to the bladder. AB - Intravesical instillation is a single compartment therapy providing high drug concentration at the bladder and reduced systemic exposure. Therapies based on this method, however, often require repeated instillations with intermittent transurethral catheterizations due to the short drug residence time in the bladder. Here we describe an intravesical device to achieve extended and localized delivery of lidocaine to the bladder. The device is a non-resorbable system that can be non-surgically deployed into the bladder. An in vivo rabbit study showed that lidocaine concentration in the bladder tissue was higher than 0.1MUg/g during the 3 day period of device release while a single instillation yielded immeasurable amounts within 24h. The device can be used for the delivery of other therapeutic agents, currently delivered to the bladder by intravesical instillations. PMID- 20971145 TI - Effect of neuropeptide S receptor antagonists and partial agonists on palatable food consumption in the rat. AB - Neuropeptide S (NPS) is the endogenous ligand for the previously orphan G-protein coupled-receptor, now termed NPS receptor (NPSR). NPS has both anxiolytic and pro arousal properties and decreases food intake. In this work we use a rat model of palatable food intake to test in vivo different analogs of human NPS developed in our laboratories and characterized in previous in vitro experiments as partial agonists ([Ala(3)]NPS and [Aib(5)]NPS), or antagonists ([D-Cys((t)Bu)(5)]NPS and [(t)Bu-D-Gly(5)]NPS). Our results confirmed that intracerebroventricular (ICV) injection of NPS (1 nmol) decreases standard chow intake in food restricted rats as well as in freely feeding animals fed with standard or palatable food diets. [Aib(5)]NPS (30 and 60 nmol), like NPS, reduced palatable food intake, thus confirming in vivo its ability to activate NPSR. [Ala(3)]NPS (60 nmol) did not affect palatable food intake per se but blocked the anorectic effect of NPS, thus suggesting its ability to function as an antagonist in this model. Finally, [D Cys((t)Bu)(5)]NPS (20-60 nmol) and [(t)Bu-D-Gly(5)]NPS (10-30 nmol), described in previous in vitro studies as pure NPSR antagonists, did not affect palatable food intake when given alone, but fully blocked the anorectic effect of NPS. These results provide an important characterization of the pharmacological properties of these NPS analogs in vivo. Of particular relevance are the data showing that [D-Cys((t)Bu)(5)]NPS and [(t)Bu-D-Gly(5)]NPS behave as pure antagonists at NPSR regulating food intake, indicating that these molecules are suitable tools for further investigation of the physiopharmacology of the NPS/NPSR system. PMID- 20971146 TI - Pre- and posttransplantation allosensitization in heart allograft recipients: major impact of de novo alloantibody production on allograft survival. AB - The involvement of humoral response in allograft rejection has been suggested by both immunologic and histochemistry studies. In the present study, we explored the role of alloantibodies in a large cohort of heart allograft recipients followed for 15 years. Sequential samples of sera were obtained from 950 recipients of heart allografts before and after transplantation at the time when protocol endomyocardial biopsies were performed. The presence of anti-human leukocyte antigen (HLA) antibodies was investigated using complement mediated cytotoxicity and solid phase assay (SPA). Our data reveal an inverse correlation between the development of alloantibodies after transplantation and heart allograft survival. The 15-year graft survival was highest in patients who never developed alloantibodies (70%) or who displayed them only before transplantation (71%); graft survival in recipients who showed antibodies both before and after transplantation (56%), or only after transplantation (47%), was lower. The deleterious effect of antibodies on graft survival started 8 years after transplantation, suggesting that the production of de novo antibodies may have been triggered by some later event. We found that patients with de novo antibodies appearing more than 1 year after transplantation had the poorest survival. Furthermore, the development of de novo antibodies was preceded in 76% of these patients by cellular rejection grade 3 or higher, according to the International Society for Heart Transplantation (ISHT) grading criteria. Development of antibody-mediated rejection (AMR) had a significant negative impact on graft survival (16% in AMR(+) vs 63% in AMR(-) patients, p = 0.0008). Of the 23 patients with AMR, 21 displayed cytotoxic donor-specific antibodies (DSA) at the time of diagnosis, and in 18 of these cases SPA showed that they were directed against the donors' HLA. The data demonstrate that the detection of alloantibodies permits a better definition of AMR in heart allograft recipients. Identification of patients at risk for developing AMR is of great importance for early treatment of rejection episodes. PMID- 20971147 TI - Characterization of an antibody specific for HLA-A36 and not reactive with HLA A1. AB - Humoral sensitization to HLA often results in antibodies to public determinants shared among two or more antigens. Although monoclonal antibodies to A36 have been produced, there are no reports of polyclonal antibodies that react with A36 but not A1. We report here sera from a heart transplant recipient that reacted with A36 but not A1 in tests with both phenotype and single antigen panels on the Luminex platform. Flow cytometric crossmatch tests yielded positive results with an A36 bearing phenotype but not with a phenotype containing A1. A36 reactivity in solid phase assays was abrogated by absorption with cells bearing A36, but not with A1-positive cells. The frequency of B cells in this patient specific for A1 was comparable to that for individuals not sensitized to A1. These data indicate that reactivity was to an epitope present on A36 but absent from A1. PMID- 20971149 TI - Are the anterior internal capsules and nucleus accumbens suitable DBS targets for the treatment of depression? PMID- 20971150 TI - The use of the zebrafish model in stress research. AB - The study of the causes and mechanisms underlying psychiatric disorders requires the use of non-human models for the test of scientific hypotheses as well as for use in pre-clinical drug screening and discovery. This review argues in favor of the use of zebrafish as a novel animal model to study the impact of early (stressful) experiences on the development of differential stress phenotypes in later life. This phenomenon is evolutionary conserved among several vertebrate species and has relevance to the etiology of psychiatric disorders. Why do we need novel animal models? Although significant progress has been achieved with the use of traditional mammalian models, there are major pitfalls associated with their use that impedes progress on two major fronts: 1) uncovering of the molecular mechanisms underlying aspects of compromised (stress-exposed) brain development relevant to the etiology of psychiatric disorders, and 2) ability to develop high-throughput technology for drug discovery in the field of psychiatry. The zebrafish model helps resolve these issues. Here we present a conceptual framework for the use of zebrafish in stress research and psychiatry by addressing three specific domains of application: 1) stress research, 2) human disease mechanisms, and 3) drug discovery. We also present novel methodologies associated with the development of the zebrafish stress model and discuss how such methodologies can contribute to remove the main bottleneck in the field of drug discovery. PMID- 20971151 TI - Modeling fighting deprivation effect in mouse repeated aggression paradigm. AB - Male mice with a long positive fighting history develop behavioral psychopathology, which includes abnormal aggression, hostility, hyperactivity, stereotypic reactions and other behavioral phenotypes. We also found that the "winners" (mice that had each won 20 daily encounters in succession) develop an enhanced level of aggression after a no-fight period, compared to their respective levels of aggressive behavior before the fighting deprivation. Natural hedonic stimuli (such as access to females or sweet water), supplied to the winners during this no-fight period, appear to play a minor role in triggering this phenomenon. Therefore, it appears that fighting deprivation per se stimulates an elevated aggression in male mice, which also display aberrant behaviors formed under repeated experience of aggression accompanied by victories. This behavioral approach may be useful for modeling the effect of fighting deprivation in mouse paradigms based on repeated aggression. PMID- 20971152 TI - Extracts of Halenia elliptica exhibit antioxidant properties in vitro and in vivo. AB - The antioxidant properties of different extracts of Halenia elliptica was investigated by employing various established in vitro systems. The results showed that various extracts possessed strong antioxidant activity in vitro, and the 70% methanol extract (ME) had the strongest antioxidant activity. Based on our in vitro results, ME was used for investigating the antioxidant properties of H. ellipticain vivo. The liver and kidney of CCl(4)-intoxicated animals exhibited a significant decrease in superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels. Additionally, these organs exhibited a significant increase in the level of malondialdehyde (MDA). These changes were significantly reversed, in a dose-dependent manner, after treatment with ME and the standard treatment Vitamin E. Thus, it may be concluded that the ME possesses potent antioxidant properties, and might be valuable natural source of antioxidants that could be applicable to both the medical and food industries. PMID- 20971153 TI - Cisplatin induced toxicity in rat tissues: the protective effect of Lisosan G. AB - The protective effect of a powder of grain (Lisosan G) against cisplatin-induced toxicity in rats was studied. Male rats were fed with Lisosan G before injection of cisplatin and four days later they were killed and blood was collected along with hepatic, renal and testicular tissues. The results showed that cisplatin treatment increased plasma blood urea nitrogen, creatinine and hydrogen peroxide and decreased cytochrome P450 content in renal and hepatic tissues. It also reduced the plasmatic testosterone level and caused a depletion of testicular 17alpha-progesterone hydroxylase activity. In the group fed with Lisosan G and treated with cisplatin blood urea nitrogen and creatinine returned to the control level indicating a protective effect of Lisosan G. It was also observed that the ones fed with Lisosan G were able to attenuate the decrease in the P450-dependent activities and the activities of antioxidant enzymes as well. Lisosan G protected the testicular 17alpha-progesterone hydroxylase activity and increased the plasma testosterone level compared to animals treated only with cisplatin. Our results showed a protective effect of Lisosan G against the cisplatin induced toxicity. The protective effect of Lisosan G could be associated mainly with the attenuation of the oxidative stress and the preservation in antioxidant enzymes. PMID- 20971154 TI - Ways of enhancing pulp preservation by stepwise excavation--a systematic review. AB - OBJECTIVES: The best possible methods and materials in stepwise excavation for deep caries in permanent teeth were investigated. The review considers the questions from many aspects including clinical success, effects of reducing cariogenic bacteria, possibility of hardening softened dentin, and likelihood of generating tertiary dentin. DATA: This systematic review includes the use of data from randomized controlled trials, controlled clinical trials as well as from case series in which pulp exposure resulted following the treatment and removal of deep caries. Only studies of caries in permanent teeth were considered. Those involving treatment of primary teeth were excluded. SOURCES: An electronic search was conducted in the databases of MEDLINE and Igaku Chuo Zasshi (Japanese) from 1970 to 2008. The electronic search was supplemented by a manual search of the references lists of all the relevant studies. STUDY SELECTION: The electronic and manual searches of journals retrieved a total of 266 English and 130 Japanese papers. According to the inclusion and exclusion criteria, 10 English and 3 Japanese studies were finally identified. CONCLUSION: Our research suggests that stepwise excavation is effective for pulp preservation in extremely deep caries that do not show clinical symptoms of irreversible pulpitis. Calcium hydroxide, as well as antimicrobials and polycarboxylate cement combined with tannin fluoride preparation, is effective in reducing bacteria and promoting remineralization of the carious dentin that remained after stepwise excavation. Further clinical trials with a high level of study design should be conducted to identify the best methods of removing carious dentin using stepwise excavation. PMID- 20971155 TI - Cloning and characterization of Chlorobium tepidum ferritin. AB - The Chlorobium tepidum ferritin (CtFtn) gene was synthesized and cloned into a pET3a expression vector (Novagen). CtFtn was expressed in Escherichia coli and purified to electrophoretic homogeneity. Sequence analysis indicates that all the conserved amino acids required to form the Fe(2+) oxidizing ferroxidase center are present. Ftn is highly conserved from bacteria to humans, each subunit folds into a 4-helical bundle (helices A-D), with a long loop connecting helices B and C, plus a fifth short E-helix at the C-terminus. Calculations based on the secondary structure of CtFtn predict that each of these helices forms. However, the sequence of CtFtn shows a much longer C-terminus with a significant number of polar amino acids. Size-exclusion chromatography shows that CtFtn elutes at a size consistent with a 24-subunit protein cage. Incubation of CtFtn with Fe(2+) produced an increase in the absorbance at 310 nm consistent with the incorporation of iron inside CtFtn. Assays monitoring ferroxidase activity showed that CtFtn possesses ferroxidase activity but it is less active than human H chain ferritin. Additionally, the iron loading capacity of CtFtn is significantly reduced compared to proteins from other organisms. We propose that the unique extended C-terminus in CtFtn causes the decreased iron loading in CtFtn and possibly influences the slower rate of iron oxidation at the ferroxidase center. PMID- 20971156 TI - Hypoxia activates constitutive luciferase reporter constructs. AB - Hypoxia has been identified as a contributing factor in the pathophysiology of several diseases and oxygen regulation is important during stem cell development, particularly in early embryogenesis. One aspect that has emerged is the role of hypoxia-inducible factors, or HIFs in regulating the effect of hypoxia. Studies in our laboratory sought to examine the hypoxic regulation of HIF activity in placental trophoblast cells, through the use of dual-reporter luciferase assays. Our study demonstrates that hypoxic conditions cause a significant increase in the level of constitutive luciferase reporter activity. We also show that this induction is not a cell type or species-specific phenomenon and provides an alternative method for normalizing transfection efficiency in luciferase assays under hypoxic conditions. Our results suggest that in studies dealing with hypoxic conditions, caution should be used when interpreting measurements of transcriptional activity by traditional dual-reporter assays. PMID- 20971157 TI - Functional and structural evaluation of cysteine residues in the human arsenic (+3 oxidation state) methyltransferase (hAS3MT). AB - Arsenic (+3 oxidation state) methyltransferase (AS3MT) catalyzes the methylation of inorganic arsenic (iAs) and plays important role in the detoxication of this metalloid. There are fourteen cysteine residues in the human AS3MT (hAS3MT), among which twelve are absolutely conserved; Cys334 and Cys360 are unique; Cys368 and Cys369 are identified as a CysCys pair. The roles of several conserved cysteine residues in rat AS3MT and hAS3MT have been reported. Herein, the other conserved cysteine residues (Cys72, Cys271, Cys375) and the unique ones (Cys334, Cys360) were systematically replaced by serine using site-directed mutagenesis to study their functions. The mutants were investigated for enzymatic activity, kinetics, thermal stability and secondary structures. Present results indicate that C72S is completely inactive in methylation of iAs and has distinct changes in the secondary structures; Cys72 might form a critical intramolecular disulfide bond with Cys250; Cys271 and Cys375 do not affect the activity and structure of the hAS3MT. However, the mutations of Cys334 and Cys360 can decrease the enzymatic turnovers and change the conformation of the hAS3MT. The kinetic data show that Cys271, Cys334, Cys360 and Cys375 are not involved in the SAM binding. Additionally, all these cysteine residues except Cys375 affect the thermotropic properties of the hAS3MT. PMID- 20971159 TI - Mass counts: ERP correlates of non-adjacent dependency learning under different exposure conditions. AB - Miniature language learning can serve to model real language learning as high proficiency can be reached after very little exposure. In a previous study by Mueller et al. [18] German participants acquired non-adjacent syntactic dependencies by mere exposure to correct Italian sentences, but their ERP pattern differed from the one shown by native speakers. The present study follows up on that experiment using a similar design and material and is focused on two important issues: the influence of acoustic cues in the material and the impact of the learning procedure. With respect to the latter we compared alternating learning and test phases to a continuous learning and test phase. In addition, a splicing procedure eliminated prosodic cues in order to ensure that non-adjacent dependencies were learned instead of adjacent ones. Results for the continuous phase design showed a native-like biphasic ERP pattern, an N400 followed by a left-focused positivity. In the alternating design behavioural accuracy was lower and only an N400 was found. The results suggest an advantage of continuous learning phases for adult learners, possibly due to the absence of ungrammatical items present in the test phases in the alternating learning procedure. Furthermore, the replication of the earlier study with prosodically controlled material adds evidence to the general finding that syntactic non-adjacent dependencies can be learned from mere exposure to correct examples. PMID- 20971158 TI - Treatment with olanzapine, fluoxetine and olanzapine/fluoxetine alters citrate synthase activity in rat brain. AB - A growing body of evidence has indicated that energy metabolism impairment may be involved in pathophysiology of some neuropsychiatric disorders. In this study, we evaluated the effect of acute and chronic administration of fluoxetine, olanzapine and the combination of fluoxetine/olanzapine on citrate synthase activity in brain of rats. For acute treatment, Wistar rats received one single injection of olanzapine (3 or 6mg/kg) and/or fluoxetine (12.5 or 25mg/kg). For chronic treatment, rats received daily injections of olanzapine (3 or 6mg/kg) and/or fluoxetine (12.5 or 25mg/kg) for 28 days. In the present study we observed that acute administration of olanzapine inhibited citrate synthase activity in cerebellum and prefrontal cortex. The acute administration of olanzapine increased citrate synthase activity in prefrontal cortex, hippocampus and striatum and fluoxetine increased citrate synthase activity in striatum. Olanzapine 3mg/kg and fluoxetine 12.5mg/kg in combination increased citrate synthase activity in prefrontal cortex, hippocampus and striatum. In the chronic treatment we did not observed any effect on citrate synthase activity. Our results showed that olanzapine and fluoxetine increased citrate synthase activity after acute, but not chronic treatment. PMID- 20971160 TI - Mechanism of bone collagen degradation due to KOH treatment. AB - BACKGROUND: The mechanisms underlying the effect of alterations in type I collagen on bone mechanical properties are not well defined. In a previous study, male and female emu tibiae were endocortically treated with 1M potassium hydroxide (KOH) solution for 1-14days. This treatment resulted in negligible mass loss (0.5%), collagen loss (0.05%), no differences in geometrical parameters but significant changes in mechanical properties. The objective of this study was to determine the mechanism of collagen degradation due to KOH treatment in order to explain the previously observed mechanical property changes. METHODS: Bone mineral was assessed using x-ray diffraction (XRD), microhardness and backscattered electron imaging (BSE). Bone collagen was assessed using alpha chymotrypsin digestion, differential scanning calorimetry (DSC), gel electrophoresis (SDS-PAGE) and polarized light microscopy (PLM). RESULTS: BSE, microhardness and XRD revealed no changes in bone mineral due to KOH treatment. DSC showed an altered curve shape (lower and broader), indicating a change in collagen organization due to KOH treatment. Decreased alpha-chain band intensity in 14-day KOH treated groups detected using SDS-PAGE indicated alpha-chain fragmentation due to KOH treatment. PLM images revealed differences in collagen structure in terms of pattern distribution of preferentially oriented collagen between the periosteal and endocortical regions. CONCLUSION: These results suggest that endocortical KOH treatment causes in situ collagen degradation, which explains the previously reported altered mechanical properties. GENERAL SIGNIFICANCE: Compromising the organic component of bone contributes to an increase in bone fragility. PMID- 20971161 TI - A role for extracellular signal-regulated kinases 1 and 2 in the maintenance of persistent mechanical hyperalgesia in ovariectomized mice. AB - Mitogen-activated protein kinases (MAPKs) are important signaling factors in many cellular processes including cell proliferation and survival during development and synaptic plasticity induced by acute nociception in the adult. There is extensive evidence for the involvement of members of the MAPK family, the extracellular signal-regulated kinases 1 and 2 (ERKs 1/2), in the development of acute inflammatory somatic and visceral pain, but their role in the maintenance of chronic pain states is unknown. We have previously shown that ovariectomy of adult mice (OVX) generates a persistent and estrogen-dependent abdominal hyperalgesic state that lasts for several months and is not related to a persistent nociceptive afferent input. Here we have used OVX mice to study a possible role of ERK 1/2 in the spinal processing of this form of chronic abdominal hyperalgesia. Eight weeks after OVX the mice showed a robust abdominal hyperalgesia and a significant increase in the activation of ERK1/2 in the lumbosacral spinal cord. This enhanced activation was not seen in control and sham-operated mice or in regions of the cord other than lumbosacral in OVX mice. Also, the increased activation of ERK 1/2 observed in OVX mice matched the time course of the hyperalgesic state as no activation was observed at week 1 after OVX when the hyperalgesic state had not yet developed. Administration of slow release pellets containing 17beta-estradiol at week 5 post OVX reversed both the development of the hyperalgesia and the enhanced activation of ERK 1/2, suggesting that this activation, like the hyperalgesic state, was estrogen dependent. Intrathecal injections of the ERK 1/2 inhibitor U0126 successfully rescued the mice from the abdominal hyperalgesia for up to 24 h after the injection and also reversed the enhanced expression of ERK 1/2. Our study shows, for the first time, activation of ERK 1/2 in the spinal cord matching the time course of an estrogen-dependent chronic hyperalgesic state. PMID- 20971162 TI - Schizophrenia patients show augmented spatial frame illusion for visual and visuomotor tasks. AB - Previous research has identified several key processes of visual perception and visually guided action that are implicated in schizophrenia. Yet, it is not well understood whether similar or different brain mechanisms mediate the abnormalities in these two processes. To explore this issue, we examined visual and visuomotor processing in schizophrenia, utilizing an illusion known as the Roelofs effect. This illusion refers to the spatial mislocalization of an object within an off-centered frame, with the object appearing to be shifted towards the opposite direction of the frame offset. In this study, localization of the object was measured either by a direct visual response or by an immediate or delayed visuomotor (reaching-to-touch) response. Patients demonstrated significantly greater magnitudes of the Roelofs effect in all response modes, indicating the existence of excessive spatial contextual effects of the frame during the processing of visual and visuomotor information, and when the two types of information are integrated over a delayed visuomotor response condition. These results provide evidence for a hypothesis of improper inhibitory control as a common mechanism underpinning abnormal visual and visuomotor processes in this mental disorder. PMID- 20971163 TI - Electrophysiological properties of morphologically-identified medial vestibular nucleus neurons projecting to the abducens nucleus in the chick embryo. AB - Neurons in the medial vestibular nucleus (MVN) show a wide range of axonal projection pathways, intrinsic firing properties, and responses to head movements. To determine whether MVN neurons participating in the vestibulocular reflexes (VOR) have distinctive electrophysiological properties related to their output pathways, a new preparation was devised using transverse brain slices containing the chicken MVN and abducens nucleus. Biocytin Alexa Fluor was injected extracellularly into the abducens nucleus so that MVN neurons whose axons projected to the ipsilateral (MVN/ABi) and contralateral (MVN/ABc) abducens nuclei were labeled selectively. Whole-cell, patch-clamp recordings were performed to study the active and passive membrane properties, sodium conductances, and spontaneous synaptic events in morphologically-identified MVN/AB neurons and compare them to MVN neurons whose axons could not be traced (MVN/n). Located primarily in the rostral half of the ventrolateral part of the MVN, MVN/AB neurons mainly have stellate cell bodies with diameters of 20-25 MUm. Compared to MVN/n neurons, MVN/ABi and MVN/ABc neurons had lower input resistances. Compared to all other MVN neuron groups studied, MVN/ABc neurons showed unique firing properties, including type A-like waveform, silence at resting membrane potential, and failure to fire repetitively on depolarization. It is interesting that the frequency of spontaneous excitatory and inhibitory synaptic events was similar for all the MVN neurons studied. However, the ratio for miniature to spontaneous inhibitory events was significantly lower for MVN/ABi neurons compared to MVN/n neurons, suggesting that MVN/ABi neurons retained a larger number and/or more active inhibitory presynaptic neurons within the brain slices. Also, MVN/ABi neurons had miniature excitatory postsynaptic currents (mEPSCs) with slower decay time and half width compared to MVN/n neurons. Altogether, these findings underscore the diversity of electrophysiological properties of MVN neuron classes distinguished by axonal projection pathways. This represents the first study of MVN/AB neurons in brain slice preparations and supports the concept that the in vitro brain slice preparation provides an advantageous model to investigate the cellular and molecular events in vestibular signal processing. PMID- 20971164 TI - Excitatory effect of the A2A adenosine receptor agonist CGS-21680 on spontaneous and K+-evoked acetylcholine release at the mouse neuromuscular junction. AB - The mechanism of action of the A2A adenosine receptor agonist 2-p-(2 carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) in the facilitation of spontaneous (isotonic and hypertonic condition) and K+-evoked acetylcholine (ACh) release was investigated in the mouse diaphragm muscles. At isotonic condition, the CGS-21680-induced excitatory effect on miniature end-plate potential (MEPP) frequency was not modified in the presence of CdCl2 and in a medium free of Ca2+ (0Ca2+-EGTA), but it was abolished after buffering the rise of intracellular Ca2+ with 1,2-bis-(2-aminophenoxy)-ethane N,N,N',N'-tetraacetic acid tetra(acetoxy-methyl) (BAPTA-AM) and when the Ca2+ ATPase inhibitor thapsigargin was used to deplete intracellular Ca2+ stores. CGS 21680 did not have a direct effect on the Ca2+-independent neurotransmitter releasing machinery, since the modulatory effect on the hypertonic response was also occluded by BAPTA-AM and thapsigargin. CGS-21680 facilitation on K+-evoked ACh release was not altered by the P/Q-type voltage-dependent calcium channel (VDCC) blocker omega-Agatoxin IVA, but it was completely prevented by both, the L type VDCC blocker nitrendipine (which is known to immobilize their gating charges), or thapsigargin, suggesting that the effects of CGS-21680 on L-type VDCC and thapsigargin-sensitive internal stores are associated. We found that the VDCC pore blocker Cd2+ (2 mM Ca2+ or 0Ca2+-EGTA) failed to affect the CGS-21680 effect in high K+ whereas nitrendipine in 0Ca2+-EGTA+Cd2+ occluded its action. The blockade of Ca2+ release from endoplasmic reticulum with ryanodine antagonized the facilitating effect of CGS-21680 in control and high K+ concentration. It is concluded that, at the mouse neuromuscular junction, activation of A2A receptors facilitates spontaneous and K+-evoked ACh release by an external Ca2+-independent mechanism but that involves mobilization of Ca2+ from internal stores: during spontaneous ACh release stimulating directly the ryanodine-sensitive stores and, at high K+, probably modulating the L-type VDCCs which may cause the opening of the ryanodine receptors that would be directly coupled to the channels. In both cases, Ca2+ released from the endoplasmic reticulum would be capable of activating the exocytotic machinery, thus producing facilitation of ACh release. PMID- 20971165 TI - Relationships among 5-HTT genotype, life events and gender in the recognition of facial emotions. AB - Accumulating evidence has shown that a polymorphism in the promoter region of the serotonin-transporter (5-HTTLPR) modulates neural activation during the perceptual processing of emotional facial expressions. Furthermore, behavioral research has shown that attentional bias for negative information is increased in s allele carriers. We examined the interactions among 5-HTTLPR (including SNP rs25531), life events and gender on the detection of facial emotions. We found a main effect of genotype, as well as moderating effects of childhood emotional abuse (CEA) and recent life events (RLE). S homozygous participants recognized negative facial expressions at a lower intensity than the other genotype groups. This effect was more evident in female participants and in participants who had experienced life events. The 5-HTTLPR genotype affects facial emotional perception, a process which is linked to a neurobiological response to threat and vulnerability to emotional disorders. PMID- 20971166 TI - Macrocyclic diterpenoids from the Iranian plant Euphorbia bungei Boiss. AB - An acetone extract from the aerial parts of Euphorbia bungei afforded three new (2, 3 and 5) and one known (4) macrocyclic diterpenoids. Several cycloartane triterpenoids were also obtained, two of which (6a and 6b) were assayed for antiviral effects. The structures of all new compounds were elucidated using modern spectroscopic methods including 2D NMR and HRMS. PMID- 20971167 TI - Novel indole C-glycosides from Isatis indigotica and their potential cytotoxic activity. AB - Two novel indole C-glycosides, which were the first reported alkaloids C glycosides from Isatis indigotica, together with five known alkaloids were isolated. The novel alkaloids were elucidated to be indole-3-acetonitrile-4 methoxy-2-C-beta-D-glucopyranoside (1) and N-methoxy-indole-3-acetonitrile-2-C beta-D-glucopyranoside (2) on the basis of spectroscopic analysis. 1 exhibited significant cytotoxic activities against human myeloid leukemia HL-60 and human liver cancer HepG2 cells with the IC(50) of 1.3 +/- 0.1 and 2.1 +/- 0.3 MUM, respectively. 2 showed potential cytotoxic activities against HL-60 and human myeloid leukemia Mata cells with the IC(50) of 5.1 +/- 0.4 and 12.1 +/- 0.8 MUM, respectively. PMID- 20971168 TI - Time estimation of fear cues in human observers. AB - Previous research suggests that time judgments are a function of the affective properties of to-be-timed stimuli and that time judgments are longer for stimuli that are fear-inducing (e.g., Hare, 1963; Watts and Sharrock, 1984). The goals of the present study were twofold: to replicate the effect of a fear cue on time estimation, and to evaluate the mechanism underlying the effect. Seven stimulus durations in two different duration ranges (short: 250-1000 ms; long: 400-1600 ms) were employed in the bisection procedure. Adult human participants were exposed to two successive sessions, one each with the short and long range. Images from the International Affective Picture System (IAPS; Lang et al., 2008) that were rated on three scales including arousal and fear were presented as temporal stimuli. Three images that were rated high on fear and three rated low served as fear cues and neutral control images, respectively. Results indicated that for both ranges, judgments were longer for fear cues than for neutral images, and that the magnitude of the effect did not differ between ranges as measured by the bisection point. Application of scalar expectancy theory (SET; Gibbon, 1977; Church, 1984) to these results suggests that the fear effects were mediated by switch latency of an internal clock, rather than by clock speed. PMID- 20971169 TI - Categorical learning between 'male' and 'female' photographic human faces in jungle crows (Corvus macrorhynchos). AB - We trained jungle crows to discriminate among photographs of human face according to their sex in a simultaneous two-alternative task to study their categorical learning ability. Once the crows reached a discrimination criterion (greater than or equal to 80% correct choices in two consecutive sessions; binomial probability test, p<.05), they next received generalization and transfer tests (i.e., greyscale, contour, and 'full' occlusion) in Experiment 1 followed by a 'partial' occlusion test in Experiment 2 and random stimuli pair test in Experiment 3. Jungle crows learned the discrimination task in a few trials and successfully generalized to novel stimuli sets. However, all crows failed the greyscale test and half of them the contour test. Neither occlusion of internal features of the face, nor randomly pairing of exemplars affected discrimination performance of most, if not all crows. We suggest that jungle crows categorize human face photographs based on perceptual similarities as other non-human animals do, and colour appears to be the most salient feature controlling discriminative behaviour. However, the variability in the use of facial contours among individuals suggests an exploitation of multiple features and individual differences in visual information processing among jungle crows. PMID- 20971170 TI - Kinetic analysis of interactions of paraoxon and oximes with human, Rhesus monkey, swine, rabbit, rat and guinea pig acetylcholinesterase. AB - Previous in vitro studies showed marked species differences in the reactivating efficiency of oximes between human and animal acetylcholinesterase (AChE) inhibited by organophosphorus (OP) nerve agents. These findings provoked the present in vitro study which was designed to determine the inhibition, aging, spontaneous and oxime-induced reactivation kinetics of the pesticide paraoxon, serving as a model compound for diethyl-OP, and the oximes obidoxime, pralidoxime, HI 6 and MMB-4 with human, Rhesus monkey, swine, rabbit, rat and guinea pig erythrocyte AChE. Comparable results were obtained with human and monkey AChE. Differences between human, swine, rabbit, rat and guinea pig AChE were determined for the inhibition and reactivation kinetics. A six-fold difference of the inhibitory potency of paraoxon with human and guinea pig AChE was recorded while only moderate differences of the reactivation constants between human and animal AChE were determined. Obidoxime was by far the most effective reactivator with all tested species. Only minor species differences were found for the aging and spontaneous reactivation kinetics. The results of the present study underline the necessity to determine the inhibition, aging and reactivation kinetics in vitro as a basis for the development of meaningful therapeutic animal models, for the proper assessment of in vivo animal data and for the extrapolation of animal data to humans. PMID- 20971171 TI - Entrapment and release difference resulting from hydrogen bonding interactions in niosome. AB - In this study the influence of hydrogen bonding interaction between niosomal membrane and solutes on the drug loading and release was investigated. Salicylic acid (SA) and p-hydroxyl benzoic acid (p-BA) were selected as models. Niosomes were prepared with 1:1 molar ratios of various surfactants and cholesterol by film hydration technique, and the corresponding formulation variables were optimized to achieve the maximum entrapment efficiencies (EE%). The EE% of different formulations followed the trend Span 60>Span 40>Span 20>Span 80. Additionally, it was also found that the EE% of p-BA was much higher than that of SA. This difference may be due to the formation of hydrogen bond between p-BA and niosomal membrane, and the corresponding interaction diagram has been proposed and confirmed indirectly by UV spectroscopy method. The quantitative analysis of hydrogen binding interaction between solutes and niosome has been finished firstly, and the corresponding entrapment equilibrium constant K has been calculated as well. Moreover, in vitro the release of both drugs from niosomes was examined in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF), respectively. The results indicated that the release of p-BA in SIF was much slower than that in SGF, and the release rate of SA in SGF is apparently slower than that in SIF. The possible mechanism was given as well. PMID- 20971172 TI - Solubility and partitioning of carbamazepine in a two-phase supercritical carbon dioxide/polyvinylpyrrolidone system. AB - Supercritical carbon dioxide (scCO(2)) processing of drug/polymer mixtures is an environmentally friendly means of creating an impregnated polymeric carrier to enhance the aqueous dissolution rate of drugs that exhibit poor water solubility or are thermally labile. However, the role of drug solubilization and its interaction with the polymer during scCO(2) processing on the extent and rate of dissolution has been ambiguous. In this study, we examine the rate of dissolution of carbamazepine (CBZ), a hydrophobic drug for treating epilepsy, in scCO(2) (90 200bar, 35 degrees C and 45 degrees C) and its partitioning into polyvinylpyrrolidone (PVP, 10 and 29K MW) using in situ UV-vis spectroscopy. Our results show that partitioning occurs by surface adsorption and impregnation within the polymer matrix. These processes are linked to plasticization, which is dependent on PVP molecular weight, and temperature and pressure during treatment. The rate and extent of CBZ solubility is also controlled by treatment condition. The ability to tune polymer and drug simultaneously can be used to control the nature and extent of drug loading. PMID- 20971173 TI - Modeling of small-molecule release from crosslinked hydrogel microspheres: effect of crosslinking and enzymatic degradation of hydrogel matrix. AB - A diffusion-based model describing the drug release from a charged hydrogel (gelatin) microsphere undergoing enzymatic degradation is presented. The model elucidates the effect of glutaraldehyde, a crosslinking agent, on the release profile in terms of the initial drug distribution, diffusivity of the drug, degradation rate of gelatin and its ability to form polyionic complex with the drug. The model was validated by comparing with in vitro release of trypan blue, an acidic model drug, from basic gelatin microspheres. While drug release was not a simple function of glutaraldehyde concentration, the effective diffusivity was found to be inversely proportional to glutaraldehyde concentration in the form of a power function when the initial drug distribution was taken into consideration. For these reasons, the present model can accurately predict drug release with no adjustable parameters, given the collagenase concentration. The present model may help design certain release scenarios from biodegradable charged hydrogels for the oppositely charged drugs and biomolecules. PMID- 20971174 TI - In vitro aerosol characterization of Staccato((r)) Loxapine. AB - Medicinal aerosol products (metered dose and dry powder inhalers) require characterization testing over a wide range of use and pre-operating stress scenarios in order to ensure robust product performance and support submissions for regulatory approval. Aerosol characterization experiments on Staccato((r)) Loxapine for inhalation (Staccato Loxapine) product (emitted dose, particle size, and purity) were assessed at different operating settings (flow rates, ambient temperature and humidity, altitude, and orientation) and at nominal test conditions following exposure to various stresses on the device (mechanical shock, vibration, drop, thermal cycling, and light exposure). Emitted dose values were approximately 90% of the coated dose at every condition, meeting target specifications in each case. Aerosol purity was consistently >99.5% for every test setting, with no reportable impurities according to ICH standards (>0.1%). Particle size averaged 2MUm (MMAD) and was independent of the different test conditions with the exception of different airflow rates. Particle size decreased slightly with airflow, which may assist in maintaining constant deep lung deposition. The combination of high emitted dose efficiency and a particle size range ideally suited for lung deposition, along with the consistency of these key aerosol attributes, suggests that the Staccato system has distinct advantages over more traditional aerosol systems. PMID- 20971175 TI - Development and characterization of site specific target sensitive liposomes for the delivery of thrombolytic agents. AB - In recent times, search for potent and highly selective thrombolytic agents with minimal side effects has become a major area of research. The aim of the present study was to develop and characterize target sensitive (TS) liposomes encapsulating streptokinase, a thrombolytic agent. The developed TS liposomes were composed of dioleylphophatidyl ethanolamine (DOPE) and dipalmityl-c(RGDfK) (10:1mol/mol). Dipalmityl-c(RGDfK) was synthesized using typical carbodiimide chemistry using palmitic acid and c(RGDfK), while lysine was used as a spacer. Liposomes were of 100-120nm size. In vitro drug release study showed that nearly 40% drug of the entrapped drug was released in 12h in the PBS (pH 7.4), however on incubation with activated platelet about 90% of drug was released within 45min. The results suggested target sensitivity of the liposomes. Further, targeting potential was confirmed using fluorescent microscopy and flow cytometry. Clot lysis study revealed that TS liposomes could not only reduce the clot lysis time but also increase the extent of clot lysis as compared to non liposomal streptokinase solution. In conclusion, the present liposomal formulation will target the thrombolytic agent to the activated platelets in the thrombus and hence will improve the therapeutic efficacy of the drug. PMID- 20971176 TI - Protective effect of Coenzyme Q(10) against oxidative damage in human lens epithelial cells by novel ocular drug carriers. AB - The evaluation of N-trimethyl chitosan (TMC)-coated liposomes containing Coenzyme Q(10) as potential ophthalmic drug delivery system was carried out. Firstly, transcorneal permeation studies were conducted at 34 degrees C using a side-by side diffusion apparatus. The transport process of the fluorescent marker, rhodamine B, across the corneal epithelium was visualized with confocal laser scanning microscopy. Secondly, the human lens epithelial cells (HLECs) were cultured without or with Coenzyme Q(10) followed by addition of H(2)O(2). The cell viability and apoptosis were evaluated. The permeability coefficient for rhodamine B with TMC-coated liposomes increased more than two times in comparison with the value obtained for solution as control, from (0.42+/-0.018)*10(5)cms(-1) to (1.31+/-0.030)*10(5)cms(-1). Confocal laser scanning microscopy revealed that a TMC coating enhanced the transepithelial transport, dependent on the TMC concentration and contacting time. Coenzyme Q(10) elevated the cell viability and reduced the oxidative damage with the decreased percentage of apoptotic cells in a positive concentration-dependent manner. The ATP content of liposome-treated cells was increased about 2-fold compared with that of H(2)O(2)-treated cells. Together, our findings demonstrate that with the enhanced permeation effect of the TMC coating, Coenzyme Q(10)-loaded TMC-coated liposomes appear to be a promising ophthalmic drug delivery carrier with an efficacy in protecting HLECs against H(2)O(2)-induced oxidative damage. PMID- 20971177 TI - pH-sensitive Eudragit nanoparticles for mucosal drug delivery. AB - Drug delivery via vaginal epithelium has suffered from lack of stability due to acidic and enzymatic environments. The biocompatible pH-sensitive nanoparticles composed of Eudragit S-100 (ES) were developed to protect loaded compounds from being degraded under the rigorous vaginal conditions and achieve their therapeutically effective concentrations in the mucosal epithelium. ES nanoparticles containing a model compound (sodium fluorescein (FNa) or nile red (NR)) were prepared by the modified quasi-emulsion solvent diffusion method. Loading efficiencies were found to be 26% and 71% for a hydrophilic and a hydrophobic compound, respectively. Both hydrophilic and hydrophobic model drugs remained stable in nanoparticles at acidic pH, whereas they are quickly released from nanoparticles upon exposure at physiological pH. The confocal study revealed that ES nanoparticles were taken up by vaginal cells, followed by pH-responsive drug release, with no cytotoxic activities. The pH-sensitive nanoparticles would be a promising carrier for the vaginal-specific delivery of various therapeutic drugs including microbicides and peptides/proteins. PMID- 20971178 TI - Behavioral semantics of learning and crossmodal processing in auditory cortex: the semantic processor concept. AB - Two phenomena of auditory cortex activity have recently attracted attention, namely that the primary field can show different types of learning-related changes of sound representation and that during learning even this early auditory cortex is under strong multimodal influence. Based on neuronal recordings in animal auditory cortex during instrumental tasks, in this review we put forward the hypothesis that these two phenomena serve to derive the task-specific meaning of sounds by associative learning. To understand the implications of this tenet, it is helpful to realize how a behavioral meaning is usually derived for novel environmental sounds. For this purpose, associations with other sensory, e.g. visual, information are mandatory to develop a connection between a sound and its behaviorally relevant cause and/or the context of sound occurrence. This makes it plausible that in instrumental tasks various non-auditory sensory and procedural contingencies of sound generation become co-represented by neuronal firing in auditory cortex. Information related to reward or to avoidance of discomfort during task learning, that is essentially non-auditory, is also co-represented. The reinforcement influence points to the dopaminergic internal reward system, the local role of which for memory consolidation in auditory cortex is well established. Thus, during a trial of task performance, the neuronal responses to the sounds are embedded in a sequence of representations of such non-auditory information. The embedded auditory responses show task-related modulations of auditory responses falling into types that correspond to three basic logical classifications that may be performed with a perceptual item, i.e. from simple detection to discrimination, and categorization. This hierarchy of classifications determine the semantic "same-different" relationships among sounds. Different cognitive classifications appear to be a consequence of learning task and lead to a recruitment of different excitatory and inhibitory mechanisms and to distinct spatiotemporal metrics of map activation to represent a sound. The described non-auditory firing and modulations of auditory responses suggest that auditory cortex, by collecting all necessary information, functions as a "semantic processor" deducing the task-specific meaning of sounds by learning. PMID- 20971179 TI - Ablation of mixed lineage kinase 3 (Mlk3) does not inhibit ototoxicity induced by acoustic trauma or aminoglycoside exposure. AB - Jun N-terminal kinase (JNK) is activated in cochlear hair cells following acoustic trauma or exposure to aminoglycoside antibiotics. Blockade of JNK activation using mixed lineage kinase (MLK) inhibitors prevents hearing loss and hair cell death following these stresses. Since current pharmacologic inhibitors of MLKs block multiple members of this kinase family, we examined the contribution of the major neuronal family member (MLK3) to stress-induced ototoxicity, usingMlk3(-/-) mice. Immunohistochemical staining revealed that MLK3 is expressed in cochlear hair cells of C57/BL6 mice (but not in Mlk3(-/-) animals). After exposure to acoustic trauma there was no significant difference in DPOAE and ABR values betweenMlk3(-/-) and wild-type mice at 48 h following exposure or 2 weeks later. Susceptibility of hair cells to aminoglycoside toxicity was tested by exposing explanted utricles to gentamicin. Gentamicin induced hair cell death was equivalent in utricles from wild-type and Mlk3(-/-) mice. Blockade of JNK activation with the pharmacologic inhibitor SP600125 attenuated cell death in utricles from both wild-type and Mlk3(-/-) mice. These data show that MLK3 ablation does not protect against hair cell death following acoustic trauma or exposure to aminoglycoside antibiotics, suggesting that MLK3 is not the major upstream regulator of JNK-mediated hair cell death following these stresses. Rather, other MLK family members such as MLK1, which is also expressed in cochlea, may have a previously unappreciated role in noise- and aminoglycoside-induced ototoxicity. PMID- 20971181 TI - The effects of Labisia pumila var. alata on bone markers and bone calcium in a rat model of post-menopausal osteoporosis. AB - AIM OF THE STUDY: Postmenopausal osteoporosis is mainly treated with estrogen replacement therapy (ERT). However, ERT causes side effects, mainly breast cancer, uterine cancer and thromboembolic problems. Labisia pumila var. arata (LPva), a herb with phytoestrogenic effects has the potential to be used as an alternative agent to ERT. This study was conducted to determine the effects of LPva on bone biochemical markers and bone calcium content in ovariectomised rats. MATERIALS AND METHODS: Thirty two Wistar rats were divided into 4 groups, with 8 rats in each group. The first group was sham operated (Sham), the second group was ovariectomised (OVX), the third (LPva) and fourth group (ERT) were also ovariectomised and given LPva 17.5 mg/kg and Premarin((r)) 64.5 MUg/kg, respectively. Blood samples were taken before and after treatment to measure osteocalcin and C-terminal telopeptide of type 1 collagen levels using ELISA while the fifth lumbar bone samples were taken to measure bone calcium content using the Atomic Absorption Spectrophotometer (AAS). RESULTS: The osteocalcin levels were significantly higher in both the LPva and ERT groups compared to the OVX group. The CTX levels were significantly lower in both the LPva and ERT groups compared to the OVX group. However, only the ERT group had significantly higher bone calcium level compared to the OVX group. CONCLUSION: The supplementation of 17.5 mg/kg of LPva to ovariectomised rats for 8 weeks was able to prevent the changes in bone biochemical markers but failed to prevent the bone calcium loss induced by ovariectomy. PMID- 20971180 TI - Sound pressure transformations by the head and pinnae of the adult Chinchilla (Chinchilla lanigera). AB - There are three main cues to sound location: the interaural differences in time (ITD) and level (ILD) as well as the monaural spectral shape cues. These cues are generated by the spatial- and frequency-dependent filtering of propagating sound waves by the head and external ears. Although the chinchilla has been used for decades to study the anatomy, physiology, and psychophysics of audition, including binaural and spatial hearing, little is actually known about the sound pressure transformations by the head and pinnae and the resulting sound localization cues available to them. Here, we measured the directional transfer functions (DTFs), the directional components of the head-related transfer functions, for 9 adult chinchillas. The resulting localization cues were computed from the DTFs. In the frontal hemisphere, spectral notch cues were present for frequencies from ~6-18 kHz. In general, the frequency corresponding to the notch increased with increases in source elevation as well as in azimuth towards the ipsilateral ear. The ILDs demonstrated a strong correlation with source azimuth and frequency. The maximum ILDs were <10 dB for frequencies <5 kHz, and ranged from 10-30 dB for the frequencies >5 kHz. The maximum ITDs were dependent on frequency, yielding 236 MUs at 4 kHz and 336 MUs at 250 Hz. Removal of the pinnae eliminated the spectral notch cues, reduced the acoustic gain and the ILDs, altered the acoustic axis, and reduced the ITDs. PMID- 20971182 TI - The effects of aging on stem cell behavior in Drosophila. AB - Throughout life, adult stem cells play essential roles in maintaining tissue and organ function by providing a reservoir of cells for homeostasis and regeneration. A decline in stem cell number or activity may, therefore, lead to compromised organ and tissue function that is characteristic of aging. Drosophila has emerged as an ideal system for studying the relationship between stem cells and aging, as it has a short lifespan, tissues that are maintained by adult stem cells, and conserved pathways known to regulate aging. In this review, we highlight recent findings describing intrinsic and extrinsic age-related changes that affect the behavior of Drosophila germline and intestinal stem cells. We also discuss whether pathways affecting lifespan can act autonomously or non autonomously in stem cells during aging. PMID- 20971183 TI - Oxidative stress in the brain of reproductive male rats during aging. AB - Reproduction alters the male physiology. We performed a comprehensive study to examine oxidative stress in the brains of male rats with (experienced) or without (naive) reproductive activity during aging. Oxidative stress was assessed by measuring the activity of catalase, glutathione peroxidase, superoxide dismutase, glutathione S-transferase, aconitase, and aconitase reactivated, and by measuring lipid peroxidation, protein carbonylation, nitrite and nitrate levels, vitamin C levels, and glutathione (total, reduced, oxidized forms) levels in brain tissue, as well as testosterone and estradiol levels in serum. Reproductively active animals exhibited increased testosterone levels and aconitase activity, suggesting an increased metabolism. Increased antioxidant enzyme activities and increased levels of antioxidant compounds were observed, yet damage to biomolecules was also observed in experienced rats. During aging changes in oxidative stress were observed. We found higher activities of antioxidant enzymes, higher amounts of antioxidants, and more damage at six months of age among experienced animals than among naive animals. Similar antioxidant activities and levels, and damage were found between the groups at twenty-four months of age. These results add comprehensive data regarding changes in oxidative stress during aging, and suggest an explanation for the costs of reproduction. PMID- 20971184 TI - Yap1 activation by H2O2 or thiol-reactive chemicals elicits distinct adaptive gene responses. AB - The yeast Saccharomyces cerevisiae transcription factor Yap1 mediates an adaptive response to oxidative stress by regulating protective genes. H(2)O(2) activates Yap1 through the Gpx3-mediated formation of a Yap1 Cys303-Cys598 intramolecular disulfide bond. Thiol-reactive electrophiles can activate Yap1 directly by adduction to cysteine residues in the C-terminal domain containing Cys598, Cys620, and Cys629. H(2)O(2) and N-ethylmaleimide (NEM) showed no cross protection against each other, whereas another thiol-reactive chemical, acrolein, elicited Yap1-dependent cross-protection against NEM, but not H(2)O(2). Either Cys620 or Cys629 was sufficient for activation of Yap1 by NEM or acrolein; Cys598 was dispensable for this activation mechanism. To determine whether Yap1 activated by H(2)O(2) or thiol-reactive chemicals elicits distinct adaptive gene responses, microarray analysis was performed on the wild-type strain or its isogenic single-deletion strain Deltayap1 treated with control buffer, H(2)O(2), NEM, or acrolein. Sixty-five unique H(2)O(2) and 327 NEM and acrolein Yap1 dependent responsive genes were identified. Functional analysis using single-gene deletion yeast strains demonstrated that protection was conferred by CTA1 and CTT1 in the H(2)O(2)-responsive subset and YDR042C in the NEM- and acrolein responsive subset. These findings demonstrate that the distinct mechanisms of Yap1 activation by H(2)O(2) or thiol-reactive chemicals result in selective expression of protective genes. PMID- 20971185 TI - A copper chelate of thiosemicarbazone NSC 689534 induces oxidative/ER stress and inhibits tumor growth in vitro and in vivo. AB - In this study, a Cu(2+) chelate of the novel thiosemicarbazone NSC 689534 was evaluated for in vitro and in vivo anti-cancer activity. Results demonstrated that NSC 689534 activity (low micromolar range) was enhanced four- to fivefold by copper chelation and completely attenuated by iron. Importantly, once formed, the NSC 689534/Cu(2+) complex retained activity in the presence of additional iron or iron-containing biomolecules. NSC 689534/Cu(2+) mediated its effects primarily through the induction of ROS, with depletion of cellular glutathione and protein thiols. Pretreatment of cells with the antioxidant N-acetyl-l-cysteine impaired activity, whereas NSC 689534/Cu(2+) effectively synergized with the glutathione biosynthesis inhibitor buthionine sulfoximine. Microarray analysis of NSC 689534/Cu(2+)-treated cells highlighted activation of pathways involved in oxidative and ER stress/UPR, autophagy, and metal metabolism. Further scrutiny of the role of ER stress and autophagy indicated that NSC 689534/Cu(2+)-induced cell death was ER-stress dependent and autophagy independent. Last, NSC 689534/Cu(2+) was shown to have activity in an HL60 xenograft model. These data suggest that NSC 689534/Cu(2+) is a potent oxidative stress inducer worthy of further preclinical investigation. PMID- 20971187 TI - Regulation of antigen-specific CTL and Th1 cell activation through 5 Hydroxytryptamine 2A receptor. AB - Serotonin (5-Hydroxytryptamine, 5-HT) is one of the most extensively studied neurotransmitters in the central nervous system. Also expressed in peripheral tissues, 5-HT participates in vasoconstriction and in aggregation of platelets through 5-HT(2A) receptor (5-HT2AR). However, there have been few studies regarding the interaction between 5-HT and 5-HT2AR in the immune system. In the current study, we analyzed the role of 5-HT and its 5-HT2AR in the activation of antigen-specific Th1 and cytotoxic T lymphocytes (CTL) in mice. RT-PCR and western blotting analyses confirmed the expression of 5-HT2AR in both CD4 and CD8 T cells. Both antigen-specific and anti-CD3 stimulation of IL-2 and IFN-gamma production from these cells were inhibited by a selective 5-HT2AR inhibitor, sarpogrelate hydrochloride. Concanavalin A (ConA) activation of CD4(+) and CD8(+) T cells, which were purified from mouse spleen following depletion of endogenous 5-HT, was enhanced by a selective 5-HT2AR agonist, (R)-1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane (DOI). Such DOI-induced T cell activation was nullified by sarpogrelate. Moreover, an ELISPOT study showed that sarpogrelate also reduced antigen-specific induction of both CTL and Th1 cells in vivo following immunization of mice with cognate antigens. These data suggest that antigen-specific Th1 and CTL cells might be regulated by 5-HT signaling through 5 HT2AR on their surfaces and that 5-HT2AR inhibitor might have an immunosuppressive effect in vivo. PMID- 20971186 TI - C-Phycocyanin ameliorates experimental autoimmune encephalomyelitis and induces regulatory T cells. AB - For decades Experimental Autoimmune Encephalitis (EAE) has remained as an unsurpassed multiple sclerosis (MS) animal model. C-Phycocyanin (C-Pc) has been reported to exhibit pharmacological properties that may be expected to symptomatically improve EAE and MS. However, in this paper we reveal a basic underlying mechanism that may provide a new approach to the rationale of the overall beneficial effect of this natural antioxidant. We demonstrate that C-Pc is able to trigger mechanisms preventing or downgrading EAE expression and induces a regulatory T cell (Treg) response, in peripheral blood mononuclear cells (PBMC) from MS patients. These results agree with reports suggesting that Treg limit acute MS attacks and that C-Pc may act as a neuroprotector and thereby reverts the organic and functional damage in neurodegenerative disorders of the central nervous system (CNS). Moreover, evidence is provided on the antioxidant activity of C-Pc within the CNS, intended to improve the myelin and axonal damage of EAE induced Lewis rats. Our results indicate that specific Treg activation may represent a central and essential mechanism in supporting the therapeutic potential of C-Pc for MS and may lead to new and more effective therapies; this property would then complement and enhance other proven active principles such as interferons (IFN), giving rise to combined therapies. PMID- 20971188 TI - Lopinavir loaded solid lipid nanoparticles (SLN) for intestinal lymphatic targeting. AB - The poor orally available lopinavir was successfully encapsulated in glyceryl behenate based solid lipid nanoparticles (Lo-SLN) for its ultimate use to target intestinal lymphatic vessels in combined chemotherapy-the so-called Highly Active Anti-Retroviral Therapy (HAART). SLN with mean particle size of 230 nm (polydispersity index, PDI<0.27) and surface electrical charge of approx. -27mV, were produced by hot homogenization process followed by ultrasonication. Particles were characterized using differential scanning calorimetry (DSC), wide angle X-ray scattering (WAXS) and atomic force microscopy (AFM) to confirm their solid character and the homogeneous distribution of drug within the lipid matrix. In vitro release studies at pH 6.8 phosphate buffer (PBS) and at pH 1.2 HCl 0.1N showed a slow release in both media. From the intestinal lymphatic transport study it became evident that SLN increased the cumulative percentage dose of lopinavir secreted into the lymph, which was 4.91-fold higher when compared with a conventional drug solution in methyl cellulose 0.5% (w/v) as suspending agent (Lo-MC). The percentage bioavailability was significantly enhanced. The AUC for the Lo-SLN was 2.13-fold higher than that obtained for the Lo-MC of similar concentration. The accelerated stability studies showed that there was no significant change in the mean particle size and PDI after storage at 25+/-2 degrees C/60+/-5% RH. The shelf life of optimized formulation was assessed based on the remained drug content in the stabilized formulation and was shown to be 21.46 months. PMID- 20971189 TI - Correlation between in vitro and in vivo erosion behaviour of erodible tablets using gamma scintigraphy. AB - In vitro and in vivo erosion behaviour of erodible tablets consisting of glyceryl behenate and low-substituted hydroxypropylcellulose manufactured using three different methods: direct compression (DC), melt granulation (MG) and direct solidification (DS) was investigated. In vitro erosion behaviour was studied using gravimetric and scintigraphic methods. For scintigraphic investigations, the radiolabel was adsorbed onto activated charcoal and incorporated into tablets at a concentration that did not affect the erosion profile. A clinical study was carried out in six healthy volunteers using gamma scintigraphy. Tablet erosion was affected by the preparation method and was found to decrease in the order of preparation method, DC>MG>DS tablets. The mean in vivo onset time for all tablets (DC: 6.7+/-3.8 min, MG: 18.3+/-8.1 min, DS: 67+/-18.9 min) did not differ significantly from in vitro onset time (DC: 5.3+/-1 min, MG: 16.8+/-3.9 min, DS: 61.8+/-4.7 min). The mean in vivo completion times were found to be 36.6+/-9.7 (DC tablets), 70+/-18.3 min (MG tablets) and 192.5+/-39.9 min (DS tablets). Among the three different erodible tablets, MG tablets showed the highest correlation between in vitro and in vivo mean erosion profile and suggested a potential platform to deliver controlled release of water-insoluble compounds. PMID- 20971190 TI - Altered function of glutamatergic cortico-striatal synapses causes output pathway abnormalities in a chronic model of parkinsonism. AB - OBJECTIVE: In Parkinson's disease, chronic striatal dopamine depletion results in over-activity and under-activity of the indirect and direct striatal output pathways respectively. In this study, we investigated changes in the function of glutamatergic cortico-striatal synapses that contribute to abnormalities in striatal efferents. METHODS: Whole-cell recordings were performed in striatal slices prepared from adult bacterial artificial chromosome mice, chronically lesioned with 6-hydroxydopamine (6-OHDA). Paired pulse facilitation, spontaneous synaptic activity, the ratio of AMPAR to NMDAR-mediated components of excitatory postsynaptic currents, AMPAR and NMDAR kinetics, current-voltage relationship and intrinsic membrane properties were assessed in indirect and direct pathway medium spiny neurons (MSNs), which were identified on the basis of expression of GFP, driven by the promoters of A2A or D1 receptor expression. The trajectory of striatal efferents, with respect to selective targeting of the globus pallidus and substantia nigra was also compared in sham-operated versus 6-OHDA-lesioned mice. RESULTS: Dopamine depletion did not affect the number of pathway specific output neurons or the trajectory of striatal outputs. In sham-operated animals, cortico-striatal synapses of both striatal efferent populations exhibited paired pulse facilitation and similar ratios of AMPAR to NMDAR-mediated components of excitatory postsynaptic currents. Following striatal dopamine depletion, indirect pathway neurons exhibited decreased levels of paired pulse facilitation, enhanced sensitivity to presynaptic stimulation and an increase in the relative contribution of NMDAR to the EPSC but no change in spontaneous synaptic activity. In sham-operated mice, neurons of the direct pathway exhibited lower firing frequency compared to the indirect pathway following current injection. However, in 6-OHDA-lesioned mice, in the direct pathway, firing threshold was reduced, spike frequency adaptation developed and the frequency of spontaneous activity was also reduced. In addition, changes in the properties of NMDAR kinetics suggest that these receptors were desensitised. DISCUSSION: Increased synchronicity between pre and postsynaptic neurons, as indicated by decreased paired pulse facilitation, and increased sensitivity to extracellular stimulation, combined with an increase in the contribution of NMDARs to the EPSC at cortico-striatal synapses, may contribute to the over-activity of indirect pathway neurons in the parkinsonian striatum. In contrast, a decrease in spontaneous activity, postsynaptic desensitisation to excitatory stimuli and spike frequency adaptation of cortico-striatal synapses may underlie under activity of the direct pathway. PMID- 20971191 TI - Citron kinase regulates axon growth through a pathway that converges on cofilin downstream of RhoA. AB - Axon regeneration in the adult central nervous system (CNS) is prevented by inhibitory molecules present in myelin, which bind to a receptor complex that leads to downstream RhoGTP activation and axon growth cone collapse. Here, we compared expression of Citron kinase (Citron-K), a target molecule of RhoGTP in non-regenerating dorsal root ganglion neurons (DRGN) after dorsal column (DC) injury, and in regenerating DRGN after either sciatic nerve (SN) injury or preconditioning SN+DC lesion models. We show by microarray that Citron-K mRNA levels in DRGN of a non-regenerating DC injury model were elevated 2-fold compared to those of intact control DRGN. Conversely, Citron-K levels were reduced by 2 and 2.4-fold at 10 days post lesion in the regenerating SN and preconditioning SN+DC lesion models, respectively, compared to levels in control intact DRGN. Western blotting and immunohistochemistry confirmed these observations and localised Citron-K immunostaining to both DRGN and satellite glia. In dissociated, adult rat DRG cell cultures, 80% knockdown of Citron-K, in the presence of inhibitory concentrations of CNS myelin extract (CME), promoted significant disinhibited DRGN neurite outgrowth, only when cells were stimulated with neurotrophic factors. The levels of RhoGTP remained unchanged after Citron-K knockdown in the presence of CME while enhanced cofilin levels correlated with disinhibited DRGN neurite outgrowth. This observation suggests that Citron-K plays a role in axon growth downstream of Rho activation. We conclude that Citron K regulates actin polymerisation downstream of RhoA and may offer a potentially novel therapeutic approach for promoting CNS axon regeneration. PMID- 20971192 TI - Thrombospondin-1 inhibition of vascular smooth muscle cell responses occurs via modulation of both cAMP and cGMP. AB - Nitric oxide (NO) drives pro-survival responses in vascular cells and limits platelet adhesion, enhancing blood flow and minimizing thrombosis. The matricellular protein thrombospondin-1 (TSP1), through interaction with its receptor CD47, inhibits soluble guanylyl cyclase (sGC) activation by NO in vascular cells. In vascular smooth muscle cells (VSMCs) both intracellular cGMP and cAMP regulate adhesion, contractility, proliferation, and migration. cGMP can regulate cAMP through feedback control of hydrolysis. Inhibition of the cAMP phosphodiesterase-4 selectively interfered with the ability of exogenous TSP1 to block NO-driven VSMC adhesion but not cGMP accumulation, suggesting that cAMP also contributes to VSMC regulation by TSP1. Inhibition of phosphodiesterase-4 was sufficient to elevate cAMP levels, and inhibiting guanylyl cyclase or phosphodiesterase-3, or adding exogenous TSP1 reversed this increase in cAMP. Thus, TSP1 regulates VSMC cAMP levels in part via cGMP-dependent inhibition of phosphodiesterase-3. Additionally basal cAMP levels were consistently elevated in both VSMCs and skeletal muscle from TSP1 null mice, and treating null cells with exogenous TSP1 suppressed cAMP levels to those of wild type cells. TSP1 inhibited both forskolin and isoproterenol stimulated increases in cAMP in VSMCs. TSP1 also abrogated forskolin and isoproterenol stimulated vasodilation. Consistent with its ability to directly limit adenylyl cyclase-activated vasodilation, TSP1 also limited cAMP-induced dephosphorylation of myosin light chain-2. These findings demonstrate that TSP1 limits both cGMP and cAMP signaling pathways and functional responses in VSMCs and arteries, by both phosphodiesterase-dependent cross talk between these second messengers and by inhibition of adenylyl cyclase activation. PMID- 20971193 TI - C. elegans multi-dendritic sensory neurons: morphology and function. AB - PVD and FLP sensory neurons envelope the body of the C. elegans adult with a highly branched network of thin sensory processes. Both PVD and FLP neurons are mechanosensors. PVD is known to mediate the response to high threshold mechanical stimuli. Thus PVD and FLP neurons are similar in both morphology and function to mammalian nociceptors. To better understand the function of these neurons we generated strains lacking them. Behavioral analysis shows that PVD and FLP regulate movement under normal growth conditions, as animals lacking these neurons demonstrate higher dwelling behavior. In addition, PVD--whose thin branches project across the body-wall muscles--may have a role in proprioception, as ablation of PVD leads to defective posture. Moreover, movement-dependent calcium transients are seen in PVD, a response that requires MEC-10, a subunit of the mechanosensory DEG/ENaC channel that is also required for maintaining wild type posture. Hence, PVD senses both noxious and innocuous signals to regulate C. elegans behavior, and thus combines the functions of multiple mammalian somatosensory neurons. Finally, strong mechanical stimulation leads to inhibition of egg-laying, and this response also depends on PVD and FLP neurons. Based on all these results we suggest that noxious signals perceived by PVD and FLP promote an escape behavior consisting of increased speed, reduced pauses and reversals, and inhibition of egg-laying. PMID- 20971194 TI - Crystal structure of a hemojuvelin-binding fragment of neogenin at 1.8A. AB - Neogenin is a type I transmembrane glycoprotein with a large ectodomain containing tandem immunoglobulin-like and fibronectin type III (FNIII) domains. Closely related to the tumor suppressor gene DCC, neogenin functions in critical biological processes through binding to various ligands, including netrin, repulsive guidance molecules, and the iron regulatory protein hemojuvelin. We previously reported that neogenin binds to hemojuvelin through its membrane proximal fifth and sixth FNIII domains (FN5-6), with domain 6 (FN6) contributing the majority of critical binding interactions. Here we present the crystal structure of FN5-6, the hemojuvelin-binding fragment of human neogenin, at 1.8A. The two FNIII domains are orientated nearly linearly, a domain arrangement most similar to that of a tandem FNIII-containing fragment within the cytoplasmic tail of the beta4 integrin. By mapping surface-exposed residues that differ between neogenin FN5-6 and the comparable domains from DCC, which does not bind hemojuvelin, we identified a potential hemojuvelin-binding site on neogenin FN6. Neogenin FN5, which does not bind hemojuvelin in isolation, exhibits a highly electropositive surface, which may be involved in interactions with negatively charged polysaccharides or phospholipids in the membrane bilayer. The neogenin FN5-6 structure can be used to facilitate a molecular understanding of neogenin's interaction with hemojuvelin to regulate iron homeostasis and with hemojuvelin related repulsive guidance molecules to mediate axon guidance. PMID- 20971195 TI - A cDNA microarray approach for analyzing transcriptional changes in Penaeus monodon after infection by pathogens. AB - A cDNA microarray comprised of 9990 different ESTs obtained from the Penaeus monodon EST project (http://pmonodon.biotec.or.th) was employed to identify viral (white spot and yellow head viruses) and bacterial (Vibrio harveyi) responsive genes in the hemocytes of P. monodon at 6, 24 and 48 h post-injection (hpi). The number of differentially expressed genes found was highest in shrimps infected with white spot virus (1954 genes) followed by yellow head virus (1136 genes) and V. harveyi (420 genes). Changes in shrimp gene expression were highest at the late infection stage for both viruses, whilst that for V. harveyi induced gene expression was mainly found at the early infection stage, but the repression of genes was mainly found in the mid stage of infection. Shrimp genes specifically upregulated by each particular pathogen are identified and are summarized. PMID- 20971196 TI - Effects of polyamines on cellular innate immune response and the expression of immune-relevant genes in gilthead seabream leucocytes. AB - It is well known that the polyamines spermidine and spermine, along with the diamine putrescine, are involved in many cellular processes and they are known to play an important role in the control of the innate immune response in higher vertebrates. However, to the best of our knowledge, no studies have focused on their immunological implications in other vertebrates, such as fish. For this reason, the effects of polyamines on the cellular innate immune response and immune-related gene expression were evaluated in vitro, using seabream head kidney leucocytes (HKL). For this study, head-kidney leucocytes were incubated with the polyamines putrescine, spermine or spermidine (0.005 and 0.0025%) for 0.50, 1, 2 or 4 h. No significant effect was observed on either leucocyte viability or the innate cellular immune responses (peroxidase content and phagocytic and respiratory burst activities). The polyamines produced an increase in respiratory burst and phagocytic ability when leucocytes were incubated principally with putrescine (0.005 and 0.0025%) after 2 and 4 h of the experiment. Finally, the expression levels of immune-associated genes (IgM, MHCIalpha, MHCIIalpha, C3, IL-1beta, CD8, Hep, NCCRP-1, CSF-1 and TLR) were quantified by real-time PCR and some of them (C3, MHCI, CD8, IgM and Hep) were up regulated by the higher polyamine concentration. Further studies are needed to ascertain how polyamines control the immune system of seabream as well as which mechanisms are involved. PMID- 20971197 TI - Multigene phylogeny of the southern bull-kelp genus Durvillaea (Phaeophyceae: Fucales). AB - Durvillaea (southern bull-kelp) is an economically and ecologically important brown algal genus that dominates many exposed, rocky coasts in the cold-temperate Southern Hemisphere. Of its five currently-recognized species, four are non buoyant and restricted to the south-western Pacific, whereas one is both buoyant and widely distributed. Durvillaea has had an unsettled taxonomic history. Although its position within the brown algae (Phaeophyceae) has now been largely resolved through the use of molecular techniques, the taxonomic status of several Durvillaea species/morphotypes remains unresolved. Previous molecular phylogenetic studies of phaeophycean taxa have included few Durvillaea samples, and have consequently paid little or no attention to variation within this genus. The current study presents phylogenetic analyses of four genetic markers (mitchondrial: COI; chloroplast: rbcL; and nuclear: 18S and 28S) to resolve phylogenetic relationships within Durvillaea. Results support the monophyly of solid-bladed taxa D. willana, D. potatorum, and D. sp. A (an undescribed species from the Antipodes Islands), whereas the widespread, buoyant D. antarctica is paraphyletic, with solid-bladed D.chathamensis placed sister to a D. antarctica clade from northern NZ but within D. antarctica sensu lato. The phylogenetic and ecological diversity detected within D. antarctica indicate that it is a species complex of five deeply divergent clades. Under a phylogenetic species concept, Durvillaea can be interpreted as a complex of nine distinct evolutionary lineages, only one of which has an intercontinental distribution ('subantarctic'D. antarctica). PMID- 20971198 TI - Global phylogeography of the dolphinfish (Coryphaena hippurus): the influence of large effective population size and recent dispersal on the divergence of a marine pelagic cosmopolitan species. AB - Pelagic fish that are distributed circumtropically are characterised by a low population structure level as a result of a high capacity for dispersion and large population sizes. Nevertheless, historical and contemporary processes, including past demographic and/or range expansions, secondary contact, dispersal, gene flow, and the achievement of large effective population sizes, may play a part in the detection of divergence signals, especially in the case of tropical pelagic species, whose distribution range depends strongly on the sea surface temperature. The connectivity and historical demography of Atlantic, Indian, Pacific and Mediterranean populations of dolphinfish (Coryphaena hippurus) was studied using partial sequences of the mitochondrial DNA NADH dehydrogenase subunit 1 (ND1). AMOVA analyses revealed significant inter-oceanic divergence with three phylogroups located in the Indo-Pacific, Eastern Atlantic, and Mediterranean Sea, the last one being the most divergent. However, it was not possible to clearly observe any genetic differentiation between the Indo-Pacific and Atlantic populations, as has been reported for most tropical pelagic species of tuna and billfishes. This supports the assumption of recent dispersal among basins facilitated by the actual continuous distribution of dolphinfish populations. Moreover, the lack of a divergence signal for populations separated by the Panamanian Isthmus reveals that genetic drift does not exert a strong influence on tropical pelagic species with large effective population sizes. PMID- 20971199 TI - Diversification in subtropical mountains: phylogeography, Pleistocene demographic expansion, and evolution of polyphenic mandibles in Taiwanese stag beetle, Lucanus formosanus. AB - Pleistocene glacial oscillations have had profound impacts on the historical population dynamics of extant species. However, the genetic consequences of past climatic changes depend largely on the latitude and topography of the regions in question. This study investigates the effect of Pleistocene glacial periods and the Central Mountain Range on the phylogeography, historical demography, and phenotypic differentiation of a montane forest-dwelling stag beetle, Lucanus formosanus (Coleoptera: Lucanidae), which exhibits extensive mandible variations across mountain ranges in subtropical Taiwan. Analyses of mitochondrial (cox1) and nuclear (wg) loci reveal that L. formosanus originated nearly 1.6 million years ago (Mya) in the early Pleistocene period and consisted of geographically overlapping Alishan and Widespread clades. A drastic population expansion starting approximately 0.2 Mya in the Widespread clade likely resulted from altitudinal range shift of the temperate forests, which was closely tied to the arrival of the Riss glacial period in the late Middle Pleistocene. A ring-like pattern of historical gene flow among neighboring populations in the vicinity of the Central Mountain Range indicates that the mountains constitute a strong vicariant barrier to the east-west gene flow of L. formosanus populations. A geographic cline of decreasing mandible size from central to north and south, and onto southeast of Taiwan is inconsistent with the low overall phylogeographic structures. The degree of mandible variation does not correlate with the expected pattern of neutral evolution, indicating that the evolutionary diversification of this morphological weapon is most likely subject to sexual or natural selection. We hypothesize that the adaptive evolution of mandibles in L. formosanus is shaped largely by the habitat heterogeneity. PMID- 20971200 TI - Anaerobic bacteria and antibiotics: What kind of unexpected resistance could I find in my laboratory tomorrow? AB - The purpose of this article is to set out some important considerations on the main emerging antibiotic resistance patterns among anaerobic bacteria. The first point concerns the Bacteroides fragilis group and its resistance to the combination of beta-lactam+beta-lactamase inhibitor. When there is overproduction of cephalosporinase, it results in increased resistance to the beta-lactams while maintaining susceptibility to beta-lactams/beta-lactamase inhibitor combinations. However, if another resistance mechanism is added, such as a loss of porin, resistances to beta-lactam+beta-lactamase inhibitor combinations may occur. The second point is resistance to metronidazole occurring due to nim genes. PCR detection of nim genes alone is not sufficient for predicting resistance to metronidazole; actual MIC determinations are required. Therefore, it can be assumed that other resistance mechanisms can also be involved. Although metronidazole resistance remains rare for the B. fragilis group, it has nevertheless been detected worldwide and also been observed spreading to other species. In some cases where there is only a decreased susceptibility, clinical failures may occur. The last point concerns resistance of Clostridium species to glycopeptides and lipopeptides. Low levels of resistance have been detected with these antibiotics. Van genes have been detected not only in clostridia but also in other species. In conclusion, antibiotic resistance involves different mechanisms and affects many anaerobic species and is spreading worldwide. This demonstrates the need to continue with antibiotic resistance testing and surveys in anaerobic bacteria. PMID- 20971201 TI - Relevance and clinical implications of tumor cell mobilization in the autologous transplant setting. AB - Autologous transplantation of peripheral blood (PB) hematopoietic stem cells (HSCs) is a widely used strategy for reconstitution of blood cells following high dose chemotherapy for hematologic malignancies such as multiple myeloma (MM), non Hodgkin lymphoma (NHL), and acute myeloid leukemia (AML), among others. Stem cells for transplantation are usually obtained from PB after treatment with chemotherapy with or without cytokine, usually granulocyte-colony stimulating factor (G-CSF), or after treatment with cytokine alone. The use of autologous peripheral blood stem cells (PBSCs) for transplantation is associated with the risk of contamination of the graft with tumor cells; whether this impacts response rates, progression-free survival (PFS), and overall survival (OS) is still debatable. This review summarizes the controversy surrounding tumor cell mobilization (TCM), the complexity of detection of minimal residual diseases, the available diagnostic tools, differences in TCM with available mobilization regimens, and the potential effect of TCM on clinical outcome. Collectively, these data suggest that new treatment paradigms to manage hematologic malignancies, such as MM, NHL, and AML, are needed and should focus on increasing the chemosensitivity of the tumor and eliminating residual disease. PMID- 20971203 TI - Methane output of rabbits (Oryctolagus cuniculus) and guinea pigs (Cavia porcellus) fed a hay-only diet: implications for the scaling of methane production with body mass in non-ruminant mammalian herbivores. AB - It is assumed that small herbivores produce negligible amounts of methane, but it is unclear whether this is a physiological peculiarity or simply a scaling effect. A respiratory chamber experiment was conducted with six rabbits (Oryctolagus cuniculus, 1.57+/-0.31 kg body mass) and six guinea pigs (Cavia porcellus, 0.79+/-0.07 kg) offered grass hay ad libitum. Daily dry matter (DM) intake and DM digestibility were 50+/-6 g kg-0.75 d-1 and 55+/-6% in rabbits and 59+/-11 g kg-0.75 d-1 and 61+/-3% in guinea pigs, respectively. Methane production was similar for both species (0.20+/-0.10 L d-1 and 0.22+/-0.08L d-1 and represented 0.69+/-0.32 and 1.03+/-0.29% of gross energy intake in rabbits and guinea pigs, respectively. In relation to body mass (BM) guinea pigs produced significantly more methane. The data on methane per unit of BM obtained in this study and from the literature on the methane output of elephant, wallabies and hyraxes all lay close to a regression line derived from roughage-fed horses, showing an increase in methane output with BM. The regression, including all data, was nearly identical to that based on the horse data only (methane production in horses [L d-1]=0.18 BM [kg]0.97(95%CI 0.92-1.02)) and indicates linear scaling. Because feed intake typically scales to BM0.75, linear scaling of methane output translates into increasing energetic losses at increasing BM. Accordingly, the data collection indicates that an increasing proportion of ingested gross energy is lost because relative methane production increases with BM. Different from ruminants, such losses (1%-2% of gross energy) appear too small in non-ruminant herbivores to represent a physiologic constraint on body size. Nevertheless, this relationship may represent a physiological disadvantage with increasing herbivore body size. PMID- 20971202 TI - Ste50 adaptor protein governs sexual differentiation of Cryptococcus neoformans via the pheromone-response MAPK signaling pathway. AB - The mitogen-activated protein kinase (MAPK) pathways control diverse cellular functions in pathogenic fungi, including sexual differentiation, stress response, and maintenance of cell wall integrity. Here we characterized a Cryptococcus neoformans gene, which is homologous to the yeast Ste50 that is known to play an important role in mating pheromone response and stress response as an adaptor protein to the Ste11 MAPK kinase kinase in Saccharomyces cerevisiae. The C. neoformans Ste50 was not involved in any of the stress responses or virulence factor production (capsule and melanin) that are controlled by the HOG and Ras/cAMP signaling pathways. However, Ste50 was required for mating in both serotype A and serotype D C. neoformans strains. The ste50Delta mutant was completely defective in cell-cell fusion and mating pheromone production. Double mutation of the STE50 gene blocked increased production of pheromone and the hyper-filamentation phenotype of cells deleted of the CRG1 gene, which encodes the RGS protein that negatively regulates pheromone responsive G-protein signaling via the MAPK pathway. Regardless of the presence of the basidiomycota specific SH3 domains of Ste50 that are known to be required for full virulence of Ustilago maydis, Ste50 was dispensable for virulence of C. neoformans in a murine model of cryptococcosis. In conclusion, the Ste50 adaptor protein controls sexual differentiation of C. neoformans via the pheromone-responsive MAPK pathway but is not required for virulence. PMID- 20971204 TI - Transepithelial transport and intraepithelial metabolism of short-chain fatty acids (SCFA) in the porcine proximal colon are influenced by SCFA concentration and luminal pH. AB - Short-chain fatty acids (SCFA) are end products of bacterial fermentation in the colon and cecum of monogastric animals. As SCFA serve as relevant energy suppliers for colonocytes and various tissues, it is important to reveal fundamental mechanistic characteristics of their transepithelial transport subjected to transient variations of fermentations rates. We performed Ussing chamber studies with porcine (Sus scrofa) colon epithelium under physiological conditions and examined individual mucosal disappearance, metabolized loss, tissue concentrations and serosal release of acetate, propionate and butyrate by gas chromatography. Reduction of initial SCFA concentrations from 80 to 40 mmol/L resulted in diminished absolute flux rates, but the relative proportions of mucosal disappearance and intracellular metabolization of individual SCFA were slightly enhanced. Simulation of high fermentation rates by lowering the mucosal pH induced an increase in mucosal disappearance and serosal release of all SCFA, while their tissue contents trended to lower levels. With respect to the metabolization at lowered pH we found increased acetate concentrations and a decrease of propionate and butyrate. Our data indicate that the colon epithelium possesses a high adaptive capacity to ensure its energetic maintenance under various intraluminal fermentation rates by utilizing the unique features of individual SCFA as energy sources. PMID- 20971205 TI - Genetic engineering of fatty acid chain length in Phaeodactylum tricornutum. AB - Renewable diesel surrogates made from shorter chain length fatty acids have improved cold flow properties. Acyl-ACP thioesterases specific for shorter chain length fatty acids are therefore of considerable interest in the genetic engineering of biofuel producing organisms, both for their ability to increase the production of shorter fatty acids, and for their involvement in fatty acid secretion in bacterial systems. Here we show that the heterologous expression of two thioesterases, biased towards the production of lauric (C12:0) and myristic acid (C14:0), causes increased accumulation of shorter chain length fatty acids in the eukaryotic microalga Phaeodactylum tricornutum. Accumulation of shorter chain length fatty acids corresponds to transgene transcript levels. We achieved levels of C12:0 of up to 6.2% of total fatty acids and C14:0 of up to 15% by weight. Unlike observations in cyanobacteria, no significant secretion of fatty acids was observed. Instead, we found that 75-90% of the shorter chain length fatty acids produced was incorporated into triacylglycerols. Our results demonstrate that overexpression of thioesterases is a valid way to improve the biofuel production phenotype of eukaryotic microalgae. PMID- 20971206 TI - Biosynthesis of poly(3-hydroxydecanoate) and 3-hydroxydodecanoate dominating polyhydroxyalkanoates by beta-oxidation pathway inhibited Pseudomonas putida. AB - Pseudomonas putida KT2442 produces medium-chain-length polyhydroxyalkanoates consisting of 3-hydroxyhexanoate (3HHx), 3-hydroxyoctanoate (3HO), 3 hydroxydecanoate (3HD), 3-hydroxydodecanoate (3HDD) and 3-hydroxytetradecanoate (3HTD) from relevant fatty acids. P. puitda KT2442 was found to contain key fatty acid degradation enzymes encoded by genes PP2136, PP2137 (fadB and fadA) and PP2214, PP2215 (fadB2x and fadAx), respectively. In this study, the above enzymes and other important fatty acid degradation enzymes, including 3-hydroxyacyl-CoA dehydrogenase and acyl-CoA dehydrogenase encoded by genes PP2047 and PP2048, respectively, were studied for their effects on PHA structures. Mutant P. puitda KTQQ20 was constructed by knocking out the above six genes and also 3-hydroxyacyl CoA-acyl carrier protein transferase encoded by PhaG, leading to a significant reduction of fatty acid beta-oxidation activity. Therefore, P. puitda KTQQ20 synthesized homopolymer poly-3-hydroxydecanoate (PHD) or P(3HD-co-84mol% 3HDD), when grown on decanoic acid or dodecanoic acid. Melting temperatures of PHD and P(3HD-co-84mol% 3HDD) were 72 and 78 degrees C, respectively. Thermal and mechanical properties of PHD and P(3HD-co-84mol% 3HDD) were much better as compared with an mcl-PHA, consisting of lower content of C10 or C12 monomers. For the first time, it was shown that homopolymer PHD and 3HDD monomers dominating PHA could be synthesized by beta-oxidation inhibiting P. putida grown on relevant carbon sources. PMID- 20971207 TI - The microbicidal and cytoregulatory roles of NADPH oxidases. AB - Despite their prominent microbicidal roles, NADPH oxidases (NOXs) have been recently found to regulate a wide variety of physiological activities. Through generation of reactive oxygen species (ROS), NOXs actively participate in cellular activities, including NET formation, inflammasome activation and wound sensing. The microbicidal and cytoregulatory roles of NOXs are contrasted in this review. PMID- 20971208 TI - Aspergillus fumigatus cell wall components differentially modulate host TLR2 and TLR4 responses. AB - Aspergillus fumigatus conidia attenuates host proinflammatory responses through modulation of Toll-like receptor (TLR)2 and TLR4 signaling, but the precise mechanisms that mediate this effect are not known. In the present study, the role of the Aspergillus cell wall polysaccharide constituents responsible for the modulation of host capability to mount a proinflammatory response was studied. Aspergillus cell wall fractions and its major components showed differential capabilities in modulating host TLR-mediated interleukin (IL)-6 production. Beta glucan specifically suppressed TLR4-induced response, while alpha-glucan inhibited IL-6 induced through TLR2- and TLR4-stimulation. Galactomannan diminished TLR4-mediated response, while its inhibitory effects on TLR2-signaling were limited. Chitin, on the other hand, did not have significant immunomodulatory capability. The ability of the fungal cell wall to alter the immune signature of the pathogen may contribute to its virulence and the pathogenesis of co-infection. PMID- 20971209 TI - Effective recognition of HIV-1-infected cells by HIV-1 integrase-specific HLA B*4002-restricted T cells. AB - HLA-B*4002 is one of the common HLA-B alleles in the world. All 7 reported HLA B*4002-restricted HIV epitopes are derived from Gag, Nef, and Vpr. In the present study we sought to identify novel HLA-B*4002-restricted HIV epitopes by using overlapping 11-mer peptides of HIV-1 Nef, Gag, and Pol, and found that 6 of these 11-mer Pol peptides included HLA-B*4002-restricted epitopes. Analysis using truncated peptides of these 6 peptides defined 4 optimal Pol (integrase) epitopes. All epitopes previously reported had Glu at position 2 (P2), suggesting that Glu at P2 is the anchor residue for HLA-B*4002; whereas only 2 of the integrase epitopes that we here identified had Glu at P2. CTL clones specific for the 2 epitopes effectively recognized HIV-1-infected cells whereas those for other 2 epitopes only weakly recognized them. The antigen sensitivity of the former clones for the epitope peptide was much higher than that of the latter clones, suggesting 2 possibilities: 1) the former T cells have high-affinity TCRs and/or 2) the epitope peptides recognized by the former T cells are highly presented by HLA-B*4002 in HIV-1-infected cells. These integrase-specific T cells with high antigen sensitivity may contribute to the suppression of HIV-1 replication in HIV-1-infected HLA-B*4002+ individuals. PMID- 20971210 TI - Regulation between survival, persistence, and elimination of intracellular mycobacteria: a nested equilibrium of delicate balances. AB - This review elaborates on recent insights gained on the dynamic aspects of interactions between pathogen and the host intracellular machinery in tuberculosis infection. In addition we will also discuss the utility of adopting a systems biology approach, both for a better understanding of TB biology, and for the development of more effective ways for disease management. PMID- 20971211 TI - 8-Oxoguanine DNA-glycosylase repair activity and expression: a comparison between cryopreserved isolated lymphocytes and EBV-derived lymphoblastoid cell lines. AB - Several lines of evidence suggest an association between oxidative DNA-damage repair capacity and cancer risk. In particular, a DNA-glycosylase assay for removal of 8-oxoguanine (8-oxoG) in peripheral blood mononuclear cells (PBMC) has been successfully applied to identify populations with increased risk for lung cancer and squamous cell carcinomas of head and neck. In order to verify whether EBV-transformed lymphoblastoid cell lines (LCL) are a suitable surrogate for PBMC in specific DNA-repair phenotypic assays, a validation trial was conducted. PBMC from 20 healthy subjects were collected and an aliquot was transformed with EBV to obtain LCL. The ability of cell-free extracts from both cell types to incise a 3'-fluorescently labelled duplex oligonucleotide containing a single 8-oxoG (OGG assay) was evaluated. Since this activity is mediated predominantly by OGG1, the OGG1 gene expression was also measured. 8-oxoG DNA-glycosylase activity and OGG1 expression were significantly higher (p<0.0001) in LCL than in PBMC. However, while this assay was shown to be robust and reproducible when used on PBMC (intra assay CV=8%), a high intra-culture variability was observed with LCL (intra culture CV=16.8%). Neither differences on OGG1 gene expression nor the cell-cycle distribution seemed to account for this variability. Inter-individual variability of OGG activity in PBMC and LCL was not associated with OGG1 gene expression. We have therefore established a non-radioactive cleavage assay that can be easily applied to measure OGG activity in human PBMC. The use of LCL for DNA-repair genotype-phenotype correlation studies seems to be inappropriate, at least with cell-free based functional assays. PMID- 20971212 TI - Transfusion-related Plasmodium ovale malaria complicated by acute respiratory distress syndrome (ARDS) in a non-endemic country. AB - 46year old female presented with a one week history of high grade fever, chills, cough, and severe nausea. The patient had been admitted a month earlier with severe lower gastrointestinal bleeding from hemorrhoids necessitating transfusion of 7 units of packed red blood cells. Initial work-up was unremarkable. Because of persistent symptoms, the patient was admitted 2 days later. Malaria smear was positive. Due to the severity of her symptoms, she was managed as falciparum malaria and was started on intravenous quinine and oral doxycycline. On the second day of treatment the patient developed respiratory failure, requiring intubation and ventilatory support with new bilateral pulmonary infiltrates. Antimalarial treatment was continued for a total of 7 days followed by primaquine for 14 days once the blood smear results revealed Plasmodium ovale infection. The patient remained intubated in the intensive care unit (ICU) for 16 days, and was later extubated successfully with a clear chest x-ray after a total of one month hospitalization. To our knowledge, this is the first case of acute respiratory distress syndrome (ARDS) secondary to blood transfusion related P. ovale malaria infection in a non-endemic country. PMID- 20971213 TI - Implication of intracellular glutathione and its related enzymes on resistance of malaria parasites to the antimalarial drug arteether. AB - The control of malaria has been complicated by the increasing resistance of malarial parasites to multiple drugs. However, artemisinin-based drugs offer hope in the fight against drug-resistant parasites. The mode of action of these drugs remains unclear, but evidence suggests a role for free radicals in their mechanism of action. In this study, we examined the relationship between the intracellular levels of glutathione (GSH) and antioxidant enzymes and resistance to the artemisinin-based drug arteether in experimentally selected arteether resistant Plasmodium vinckei. GSH plays a critical role in the detoxification and protection of cells against oxidative stress. Our comparative studies showed a significant (2.9-fold) increase in the GSH level in arteether-resistant parasites as compared to arteether-sensitive parasites. Simultaneously, significantly increased activities of glutathione reductase, glutathione-S transferase and glucose-6-phosphate dehydrogenase and decreased activity of superoxide dismutase were recorded in resistant parasites; the activity of glutathione peroxidase was comparable in arteether-sensitive and -resistant parasites. Artemisinin derivatives act by generating free radicals and our results indicate that glutathione's antioxidant effects may counteract that drug effect and thereby contribute to the parasites' resistance to arteether and other artemisinin-based antimalarials. PMID- 20971214 TI - Prevalence and sequence comparison of Phyllodistomum folium from zebra mussel and from freshwater fish in the Ebro River. AB - We utilised DNA analysis to detect the presence of the digenean Phyllodistomum folium in three cyprinid species, Scardinius erythrophthalmus, Cyprinus carpio and Rutilus rutilus. DNA sequencing of the region containing the genes ITS1-5.8S ITS2 revealed 100% sequence identity between DNA from the sporocysts found in zebra mussels and DNA from adults located in the urinary system of 29 cyprinid fish. A second genetically different (variation=1.6%) sequence was observed in two samples from R. rutilus. In our opinion, the existence of a complex of species reported as P. folium is supported by recent genetic studies, including our own results. The overall prevalence of P. folium in mussels from the Ebro River was 4.67% in 2006, although during the summer months the rates frequently exceeded 10%. PMID- 20971215 TI - Intraspecies variability in Vipera ammodytes ammodytes venom related to its toxicity and immunogenic potential. AB - Vipera ammodytes is the most venomous European snake, whose venom has been used as antigen for immunization of antivenom-producing animals. Same as venom of any other snake, it is a complex mixture of proteins, peptides and other compounds which biochemical and pharmacological variability has been demonstrated at interspecies and intraspecies level. In this work we demonstrated intraspecific variability between 8 venom production batches using both the conventional and the new methodology. Moreover, in contrast to the literature on different venoms' variability, for the first time we were able to select those biochemical differences that are related to and give information on the venom's toxicity and immunogenicity. We have shown that methods quantifying ammodytoxin (the most toxic compound identified so far in the Vipera ammodytes ammodytes venom) content of the venom clearly distinguish between high and low immunogenic venoms. PMID- 20971216 TI - Desiderata for ontologies to be used in semantic annotation of biomedical documents. AB - A wealth of knowledge valuable to the translational research scientist is contained within the vast biomedical literature, but this knowledge is typically in the form of natural language. Sophisticated natural-language-processing systems are needed to translate text into unambiguous formal representations grounded in high-quality consensus ontologies, and these systems in turn rely on gold-standard corpora of annotated documents for training and testing. To this end, we are constructing the Colorado Richly Annotated Full-Text (CRAFT) Corpus, a collection of 97 full-text biomedical journal articles that are being manually annotated with the entire sets of terms from select vocabularies, predominantly from the Open Biomedical Ontologies (OBO) library. Our efforts in building this corpus has illuminated infelicities of these ontologies with respect to the semantic annotation of biomedical documents, and we propose desiderata whose implementation could substantially improve their utility in this task; these include the integration of overlapping terms across OBOs, the resolution of OBO specific ambiguities, the integration of the BFO with the OBOs and the use of mid level ontologies, the inclusion of noncanonical instances, and the expansion of relations and realizable entities. PMID- 20971218 TI - Synthesis and properties of a novel anisotropic self-inflating hydrogel tissue expander. AB - The advent of self-inflating hydrogel tissue expanders heralded a significant advance in the reconstructive techniques available for the surgical restoration of a wide variety of soft tissue defects. However, their use in specific applications such as cleft palate surgery is limited on account of their isotropic expansion. An anisotropic self-inflating hydrogel tissue expander has been developed which markedly increases the potential indications for which this restorative tool may be employed. These include complex pediatric soft tissue reconstructions of the palate, nose, ear and digits. Anisotropic expansion in a hydrogel polymer network composed of methyl methacrylate and vinylpyrrolidone has been achieved by annealing the xerogel under a compressive load for a specified time period. By controlling the anisotropic processing conditions and composition we have been able to accurately tailor the ultimate expansion ratio up to 1500%. The expansion rate of the xerogel has also been significantly reduced by encapsulating the polymer within a semi-permeable silicone membrane. The structure and properties of the novel anisotropic hydrogel were characterized by attenuated total reflectance infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis and small-angle neutron scattering. PMID- 20971217 TI - Biomechanics of single cortical neurons. AB - This study presents experimental results and computational analysis of the large strain dynamic behavior of single neurons in vitro with the objective of formulating a novel quantitative framework for the biomechanics of cortical neurons. Relying on the atomic force microscopy (AFM) technique, novel testing protocols are developed to enable the characterization of neural soma deformability over a range of indentation rates spanning three orders of magnitude, 10, 1, and 0.1 MUm s(-1). Modified spherical AFM probes were utilized to compress the cell bodies of neonatal rat cortical neurons in load, unload, reload and relaxation conditions. The cell response showed marked hysteretic features, strong non-linearities, and substantial time/rate dependencies. The rheological data were complemented with geometrical measurements of cell body morphology, i.e. cross-diameter and height estimates. A constitutive model, validated by the present experiments, is proposed to quantify the mechanical behavior of cortical neurons. The model aimed to correlate empirical findings with measurable degrees of (hyper)elastic resilience and viscosity at the cell level. The proposed formulation, predicated upon previous constitutive model developments undertaken at the cortical tissue level, was implemented in a three dimensional finite element framework. The simulated cell response was calibrated to the experimental measurements under the selected test conditions, providing a novel single cell model that could form the basis for further refinements. PMID- 20971219 TI - Effects of bioactive glass nanoparticles on the mechanical and biological behavior of composite coated scaffolds. AB - Biphasic calcium phosphates (BCP) scaffolds are widely used for bone tissue regeneration. However, brittleness, low mechanical properties and compromised bioactivities are, at present, their major disadvantages. In this study we coated the struts of a BCP scaffold with a nanocomposite layer consisting of bioactive glass nanoparticles (nBG) and polycaprolactone (PCL) (BCP/PCL-nBG) to enhance its mechanical and biological behavior. The effect of various nBG concentrations (1 90 wt.%) on the mechanical properties and in vitro behavior of the scaffolds was comprehensively examined and compared with that for a BCP scaffold coated with PCL and hydroxyapatite nanoparticles (nHA) (BCP/PCL-nHA) and a BCP scaffold coated with only a PCL layer (BCP/PCL). Introduction of 1-90 wt.% nBG resulted in scaffolds with compressive strengths in the range 0.2-1.45 MPa and moduli in the range 19.3-49.4 MPa. This trend was also observed for BCP/PCL-nHA scaffolds, however, nBG induced even better bioactivity and a faster degradation rate. The maximum compressive strength (increased ~14 times) and modulus (increased ~3 times) were achieved when 30 wt.% nBG was added, compared with BCP scaffolds. Moreover, BCP/PCL-nBG scaffolds induced the differentiation of primary human bone derived cells (HOBs), with significant up-regulation of osteogenic gene expression for Runx2, osteopontin and bone sialoprotein, compared with the other groups. PMID- 20971220 TI - Expanding the clinical spectrum of SPG11 gene mutations in recessive hereditary spastic paraplegia with thin corpus callosum. AB - Hereditary spastic paraplegia (HSP) represents a large group of neurological disorders characterized by progressive spasticity of the lower limbs. One subtype of HSP shows an autosomal recessive form of inheritance with thin corpus callosum (ARHSP-TCC), and displays genetic heterogeneity with four known loci. We identified a consanguineous Egyptian family with five affected individuals with ARHSP-TCC. We found linkage to the SPG11 locus and identified a novel homozygous p.Q498X stop codon mutation in exon 7 in the SPG11 gene encoding Spatacsin. Cognitive impairment and polyneuropathy, reported as frequent in SPG11, were not evident. This family supports the importance of SPG11 as a frequent cause for ARHSP-TCC, and expands the clinical SPG11 spectrum. PMID- 20971221 TI - 2-DE-based proteomic analysis of common bean (Phaseolus vulgaris L.) seeds. AB - Common bean (Phaseolus vulgaris L.) is the most important grain legume for direct human consumption. Proteomic studies in legumes have increased significantly in the last years but few studies have been performed to date in P. vulgaris. We report here a proteomic analysis of bean seeds by two-dimensional electrophoresis (2-DE). Three different protein extraction methods (TCA-acetone, phenol and the commercial clean-up kit) were used taking into account that the extractome can have a determinant impact on the level of quality of downstream protein separation and identification. To demonstrate the quality of the 2-DE analysis, a selection of 50 gel spots was used in protein identification by mass spectrometry (MALDI-TOF MS and MALDI-TOF/TOF). The results showed that a considerable proportion of spots (70%) were identified in spite of incomplete genome/protein databases for bean and other legume species. Most identified proteins corresponded to storage protein, carbohydrate metabolism, defense and stress response, including proteins highly abundant in the seed of P. vulgaris such as the phaseolin, the phytohemagglutinin and the lectin-related alpha-amylase inhibitor. PMID- 20971222 TI - Transcatheter aortic valve implantation after heart transplantation. AB - Conventional cardiac surgical procedures after orthotopic heart transplantation are generally uncommon. We report the case of a 67-year-old man who had severe symptomatic aortic stenosis develop 9 years after heart transplantation. After joint evaluation of the cardiovascular team, transcatheter aortic valve implantation was preferred due to patient medical conditions. The CoreValve prosthesis (Medtronic, Minneapolis, MN) was inserted percutaneously into the femoral artery. At 4 months postoperatively, the patient is asymptomatic in New York Heart Association functional class II. This case report provides evidence that transcatheter aortic valve implantation is safe and suitable for selected patients with severe aortic stenosis and a history of heart transplantation that must improve allograft function. PMID- 20971223 TI - Aortic root aneurysm after off-pump reduction aortoplasty. AB - We present a patient with aortic root aneurysm and severe aortic regurgitation who had a previous off-pump reduction ascending aortoplasty and external wrapping with concomitant coronary bypass grafting. Preliminary aortic dissection and erosion of the aortic intima were detected during the operation. This complication warrants the re-evaluation of the indications for reduction ascending aortoplasty and emphasizes the necessity for close follow-up. PMID- 20971224 TI - Neochordal repair of a double orifice mitral valve. AB - Native double-orifice mitral valve is an exceedingly rare valvular abnormality. A 77-year-old patient was referred for a severe mitral regurgitation, and a double orifice mitral valve with a central fibrous bridge was unexpectedly found. A flail anterior leaflet with 2 ruptured chordae was observed on the anterolateral mitral valve orifice, the leaflets on the posterior valve orifice were normally thin. Mitral valve repair was successfully performed with replacement of the 2 torn chordae by two 4/0 expanded polytetrafluoroethylene neochordae. We accordingly suggest that current mitral valve repair techniques remained a valuable option, even on central bridge double-orifice mitral valve regurgitation. PMID- 20971225 TI - Intrapericardial diaphragmatic hernia after arterial switch operation. AB - Intrapericardial diaphragmatic hernia after median sternotomy for cardiothoracic procedures is a rare complication. We describe an interesting case of diaphragmatic hernia in a 6-month-old girl presenting as cardiac tamponade, 4 months after an arterial switch operation. The diaphragmatic defect was iatrogenic and emphasizes the danger of inadvertent diaphragmatic injury during cardiac operations. PMID- 20971226 TI - Transient brachial plexus palsy: an unusual complication of paravertebral infusion of local anesthetic. AB - A continuous infusion of 0.25% bupivaciane into the parevertebral space was used for postoperative pain relief after a lung resection. On postoperative day 1, a brachial plexus palsy developed, which resolved on discontinuation of the infusion. We believe this rare complication has not been reported previously. Awareness of this possibility may avoid unnecessary investigations. PMID- 20971227 TI - Impressive combination of multiple sinus valsalvae and coronary aneurysms due to hypereosinophilic syndrome. PMID- 20971228 TI - Endovascular treatment of disseminated complex aortic vascular malformations in a patient with proteus syndrome. PMID- 20971229 TI - Axillary-coronary sequential vein graft for total endoscopic triple coronary artery bypass. AB - We describe using an axillary-coronary vein graft for robotically assisted, total endoscopic coronary artery bypass grafting. After constructing the proximal vein anastomosis to the left axillary artery under direct vision, the graft was brought into the thorax through a thoracostomy in the second left intercostal space. Under cardiopulmonary bypass with cardioplegic arrest, the distal anastomoses were completed using da Vinci (Intuitive, Sunnyvale, CA) robotic instrumentation through small portholes. This procedure marks a significant advancement in robotic total endoscopic revascularization by increasing the range of targets available for the total endoscopic approach, thereby enlarging the patient population suitable for robotic revascularization. PMID- 20971230 TI - J. Maxwell Chamberlain Memorial Paper for adult cardiac surgery. Less-invasive mitral valve operations: trends and outcomes from the Society of Thoracic Surgeons Adult Cardiac Surgery Database. AB - BACKGROUND: The purpose of this study was to examine utilization and outcomes of less-invasive mitral valve (LIMV) operations in North America. METHODS: Between 2004 and 2008, 28,143 patients undergoing isolated mitral valve (MV) operations were identified in The Society of Thoracic Surgeons Adult Cardiac Surgical Database (STS ACSD). The LIMV operations were defined as those performed with femoral arterial and venous cannulation. RESULTS: The LIMV operations increased from 11.9% of MV operations in 2004 to 20.1% in 2008 (p < 0.0001). In 2008, 26% of STS ACSD centers performed at least one LIMV operation, with a median of 3 per year. Patients in the LIMV group were younger and had fewer comorbidities. Median perfusion (135 versus 108 minutes) and cross-clamp times (100 versus 80 minutes, p < 0.0001) were longer in the LIMV group. Mitral valve repair rates were higher in the LIMV group (85% versus 67%, p < 0.0001). Adjusted operative mortality was similar (odds ratio 1.13, 95% confidence interval: 0.84 to 1.51, p = 0.47). Blood transfusion was less common (odds ratio 0.86, 95% confidence interval: 0.76 to 0.97, p < 0.0001) while stroke was more common (OR 1.96, 95% confidence interval: 1.46 to 2.63, p < 0.0001) in the LIMV group. CONCLUSIONS: In selected patients, LIMV operations can be performed with equivalent operative mortality, shorter hospital stay, fewer blood transfusions, and higher rates of MV repair than conventional sternotomy. However, perfusion and cross-clamp times were longer, and the risk of stroke was significantly higher. Beating- or fibrillating-heart LIMV techniques are associated with particularly high risks for perioperative stroke. PMID- 20971231 TI - Pacemaker and internal cardioverter defibrillator lead extraction: a safe and effective surgical approach. AB - BACKGROUND: Need for pacemaker or internal cardioverter defibrillator lead removal is increasing. Removal can be dangerous, difficult, or unsuccessful. METHODS: We retrospectively reviewed our results and the techniques we used in 365 patients from 1992 through 2009 for successful complete removal of leads and complications. Various techniques of extraction were analyzed for effectiveness and complications. The eras before (1992 to 1999) and after the availability of laser sheath extraction (2000 to 2009) are compared. RESULTS: Of 365 patients who underwent transvenous lead extraction, of which 235 were infected, and 130 had lead removal for noninfectious indication. Staphylococcus aureus was the infecting organism in 40%, and coagulase-negative Staphylococcus occurred in 33%. One-half of the organisms were methicillin resistant. Preimplant risk factors for infection included more than one device implant procedure in 105 (47%), preimplant Coumadin therapy (Bristol-Myers Squibb, Princeton, NJ) in 74 (31%), and hemodialysis in 9 (4%). Laser extraction became available in 2000. The era with the availability of laser extraction was associated with a better complete extraction rate (93% vs 89.55%) a lower bleeding rate (1.9% vs 3.1%), and complete extraction without the additional use of femoral workstation extraction tools. Mortality was 1.1%. No death was due to device removal. All deaths were the result of severe preoperative and continuing postextraction sepsis. CONCLUSIONS: A lead extraction protocol that included procedures done in an operating room environment allowing rapid, open intervention for bleeding, a varied choice of extraction tools, arterial line monitoring, transesophageal echocardiography, general anesthesia, and an experienced team yielded complete extraction in more than 90% of patients, with a low complication rate and no procedurally related deaths. PMID- 20971232 TI - Same admission cardiac catheterization and cardiac surgery: is there an increased incidence of acute kidney injury? AB - BACKGROUND: Acute kidney injury (AKI) is predictive of increased long-term mortality after cardiac surgery. Patients often undergo surgery after cardiac catheterization during the same admission for reasons of instability and threatening anatomy as well as nonurgent reasons such as patient convenience. We hypothesized that patients undergoing cardiac catheterization and cardiac surgery during the same admission are more likely to develop AKI after cardiac surgery than patients for whom surgery is performed on a later admission. METHODS: We prospectively enrolled 668 nonemergent adult cardiac surgical cases. Patients having heart catheterization were divided into two groups: cardiac catheterization followed by cardiac surgery during the same hospital admission (same admission) or catheterization followed by surgery during a later admission (later admission). The AKI was defined by an increase in serum creatinine from baseline by 50% or greater or 0.3 (mg/dL) or greater. Univariable and multivariable logistic regression and propensity-matched analyses were conducted. RESULTS: The incidence of AKI was significantly higher in the patients who had same admission cardiac catheterization and surgery (50.2%) compared with patients who had surgery on a later admission (33.7%, p = 0.009). The adjusted odds ratio for surgery on a later admission was 1.54 (95% confidence interval: 1.11 to 2.13) suggesting a 54% increased risk of AKI. Propensity-matched results were similar with 1.58 (95% confidence interval: 1.13 to 2.22). CONCLUSIONS: When cardiac catheterization and cardiac surgery occur during the same hospitalization, there is an increased risk for postoperative AKI. After cardiac catheterization, discharge and readmission for nonurgent surgery should be considered as such an approach might reduce the risk of AKI. PMID- 20971233 TI - Increased risk of transmission of hepatitis C in open heart surgery compared with vascular and pulmonary surgery. AB - BACKGROUND: We report a case of patient-to-surgeon transmission of hepatitis C virus (HCV), and the subsequent transmission of HCV to surgical patients. METHODS: In 2007, a cardiac surgeon tested positive for hepatitis C. A complete look-back investigation was initiated that involved screening of all patients on the surgeon's operating lists between September 2004 and April 2007. Genotyping and phylogenetic analyses were performed where HCV RNA was detected. RESULTS: Of the 499 patients invited to HCV testing, 431 responded, 13 of whom were found anti-HCV positive. One patient, who had surgery in August 2005, was found most likely to be the source of transmission to the surgeon. Of the 270 patients who had surgery after this incident, 10 became infected, giving an estimated rate of transmission of 3.7%. The HCV polymerase chain reaction positive samples were found to be the same genotype 1a strain by phylogenetic analyses. All the 10 subsequently infected patients had undergone open heart surgery, whereas none of the 103 noncardiac patients became infected, giving an estimated risk of transmission during open heart surgery of 6.0% (95% confidence interval [3.3% to 10.7%]). CONCLUSIONS: The transmission rate from an HCV positive surgeon to patients in a cardiothoracic setting was higher than previously reported and significantly higher during open heart surgery compared with vascular and pulmonary surgery. These results indicate the need for unequivocal routines for testing and handling of HCV positive health care workers and patients. PMID- 20971234 TI - Safety and efficacy of aprotinin and tranexamic acid in pulmonary endarterectomy surgery with hypothermia: review of 200 patients. AB - BACKGROUND: The effectiveness and safety of aprotinin in cardiac surgery has been questioned. The study aim was to compare both the blood-sparing effect and side effects of aprotinin and tranexamic acid in patients undergoing pulmonary endarterectomy. METHODS: Data were analyzed retrospectively for 200 consecutive patients who underwent pulmonary endarterectomy between October 2006 and September 2009. Pulmonary endarterectomy was performed with deep hypothermia (20 degrees C) in all patients. Antifibrinolytic therapy changed from aprotinin to tranexamic acid in June 2008 after the withdrawal of aprotinin in the United Kingdom. RESULTS: Mean age was 55.9 years, and 58% of subjects were male. One hundred patients were studied in each group. Postoperatively, a higher incidence of seizures in the first 48 hours was seen with tranexamic acid compared with aprotinin (11% versus 4%, p = 0.06). This difference became statistically significant when excluding patients with structural brain lesions from both groups (7 versus 0, p = 0.02). Tranexamic acid patients had significantly higher median blood loss (700 mL versus 525 mL, p = 0.01). There was no significant difference between the groups in reexploration for bleeding, renal failure requiring hemofiltration, intensive care unit stay, median total stay in hospital, or in-hospital mortality. CONCLUSIONS: In our experience of patients undergoing pulmonary endarterectomy, the tranexamic acid group had a higher median blood loss and more seizures. The trend to increased seizure frequency in the tranexamic acid group may be a direct consequence of this treatment, consistent with other recently published reports. PMID- 20971235 TI - Reoperations for aortic false aneurysms after cardiac surgery. AB - BACKGROUND: Aortic false aneurysm is a rare complication after cardiac surgery. Aortic dissection, infection, arterial wall degeneration, and poor surgical technique are recognized as risk factors for the occurrence of postsurgical false aneurysm. Despite some recent reports about percutaneous false aneurysm exclusion, a complex surgical reoperation is needed in most of the cases. METHODS: We retrospectively reviewed our experience in 43 patients who received a reoperation for postsurgical aortic false aneurysm in the last 14 years. Thirty three patients were male. The mean age was 60 +/- 12 years. Most of the patients received prior aortic surgery on the aortic root, the ascending aorta, the aortic arch, and the descending thoracic aorta (38 patients). False aneurysm was diagnosed during follow-up evaluation in the absence of any symptoms in 23 cases. Univariate and multivariate analyses on 18 perioperative variables were performed. RESULTS: In-hospital mortality was 6.9% (3 patients). The postoperative course was complicated in 17 cases (39%). At multivariate analysis, a preoperative history of coronary artery disease and postoperative sepsis were independent risk factors for hospital mortality. Survival rates at 1, 5, and 10 years were 94%, 79%, and 68%, respectively. Freedom from reoperation was 86% at 1 year and 72% at 5 and 10 years. CONCLUSIONS: Despite a high postoperative complication rate, a reoperation for postsurgical aortic false aneurysm can be performed with acceptable mortality and good mid-term and long-term outcomes. PMID- 20971236 TI - Invited commentary. PMID- 20971237 TI - Midterm results after endovascular treatment of acute, complicated type B aortic dissection. AB - BACKGROUND: The purpose of this study was to assess the efficacy and midterm results of endovascular treatment of acute, complicated type B aortic dissection. METHODS: Between January 2001 and February 2010, 32 patients (7 women, 25 men) with acute, complicated type B aortic dissection (mean age, 56 years; range, 35 to 83 years), defined as either aortic rupture, malperfusion, intractable pain, or uncontrolled hypertension, underwent endovascular stent graft placement with either the Gore Excluder/TAG device (n = 11), Medtronic Talent/Valiant device (n = 16), Bolton Relay (n = 2), or a combination of these stents (n = 3). Follow-up was 94% complete and averaged 26 +/- 23 months. RESULTS: Technical feasibility and success with deployment proximal to the entry tear was 87%, requiring partial or total coverage of the left subclavian artery (LSA) in 9 patients (28%). Hospital mortality was 12% +/- 11% (95% confidence limit) with 2 late deaths (17 and 98 months after implant). Causes of hospital death included rupture in 2, retrograde type A dissection in 1, and multiorgan failure in 1 patient. Three patients (11%) experienced new neurologic complications (2 paraparesis and 1 hemiparesis). Six patients with malperfusion required branch vessel stenting. Furthermore, 2 had an early type Ia endoleak. Actuarial survival at 1 and 5 years was 81% and 76%, respectively. Freedom from treatment failure at 1 and 5 years (including reintervention, aortic rupture, device-related complication, and aortic related death) was 78% and 61%, respectively. CONCLUSIONS: Endovascular stent-graft placement in acute, complicated type B aortic dissection proves to be a promising alternative therapeutic treatment modality in this relatively difficult patient cohort. Refinements, especially in stent design and application, may further improve the prognosis of patients in this life threatening situation. PMID- 20971238 TI - Invited commentary. PMID- 20971239 TI - Transluminal stenting in type A acute aortic dissection: does the Djumbodis system have any impact on false lumen evolution? AB - BACKGROUND: We reviewed our experience with the transluminal placement of the Djumbodis system in the aortic arch and isthmus in patients with type A acute aortic dissection to assess its impact on true and false aortic lumen evolution. METHODS: Between January 2005 and September 2009, 50 patients underwent surgery for type A acute aortic dissection. Twenty-eight patients (group A) were operated on by implanting the Djumbodis prosthesis, and 22 patients (group B) without the prosthesis. Contrast-enhanced computed tomography and magnetic resonance imaging controls were performed on survivors at or soon after discharge and at follow-up. RESULTS: Preoperative and operative data and complication rates were not significantly different between the two groups. Three in-hospital deaths occurred within 30 days, 1 in each group due to aortic rupture. At 1- and 4-year follow up, actuarial survival was 82% +/- 7% versus 90% +/- 6% and 73% +/- 9% versus 84% +/- 9%, in group A and B, respectively (p = 0.35). Three reoperations were performed, 2 in group A and 1 in group B (p = 0.66). At follow-up, there was no significant difference between groups regarding the ratio between true lumen and aortic diameters and false lumen patency rates at the aortic arch, isthmus, and descending aorta level. CONCLUSIONS: Placement of the Djumbodis prosthesis does not confer any additional surgical benefit and does not seem to contribute to reducing the incidence of postoperative false lumen patency in patients operated on for type A acute aortic dissection in comparison with conventional surgery. PMID- 20971240 TI - Transapical aortic valve implantation: therapy of choice for patients with aortic stenosis and porcelain aorta? AB - BACKGROUND: Conventional aortic valve replacement can be technically challenging in patients with porcelain aorta and is associated with a high rate of stroke and mortality. Porcelain aorta is even sometimes seen as contraindication for surgery. Minimally invasive off-pump transapical aortic valve implantation may be an optimal strategy to treat elderly patients with porcelain aorta requiring aortic valve replacement. METHODS: Twenty-nine patients with severe aortic stenosis and porcelain aorta underwent transapical aortic valve implantation. Mean age was 79 +/- 7.8 years (range, 64 to 93 years), with 65.5% female. Logistic EuroSCORE and the Society of Thoracic Surgeons score were 37.7% +/- 18.1% and 12.8% +/- 2.2%, respectively. Peripheral vascular disease (41.4%) and carotid artery stenosis (58.6%) were frequent, and 17.2% of patients had experienced a stroke previously. The majority of patients were redo cases (51.2%), and 10.3% were dependent on chronic hemodialysis. In 13.8% of all patients, intraoperatively detected porcelain aorta caused an attempt at conventional aortic valve replacement by means of sternotomy to be aborted. RESULTS: All valves were implanted successfully without embolization or aortic dissection. All procedures were primarily performed off-pump, but 4 patients required secondary cardiopulmonary bypass as a result of complications. Median procedure time was 80 minutes, and median intensive care unit stay was 1 day. Stroke occurred in 1 patient only. Thirty-day mortality was 17.2%. Mild paravalvular leak was seen in 31.0%, and mild to moderate regurgitation occurred in 1 patient. CONCLUSIONS: Transapical aortic valve implantation is a promising approach to treat elderly patients with porcelain aorta requiring aortic valve replacement. It is associated with acceptable outcome and low stroke rates. PMID- 20971241 TI - Invited commentary. PMID- 20971242 TI - Transapical aortic valve implantation in 194 patients: problems, complications, and solutions. AB - BACKGROUND: Transapical aortic valve implantation is a novel approach for high risk patients with severe aortic stenosis. During our learning curve, we were faced with several problems, technical difficulties, and complications, and our strategy and procedural technique evolved accordingly. We report our experience during the learning curve for establishing this new method. METHODS: Between April 2008 and January 2010, 194 patients (mean age, 80 +/- 9 years; range, 36 to 99 years) were treated by transapical aortic valve implantation. The mean Society of Thoracic Surgeons score was 23.5% +/- 19.4% (range, 2.7% to 89.5%; logistic EuroSCORE, 41% +/- 20%; range, 6% to 97%). We have established institutional guidelines on how to act in particular situations, with regard to patient selection, procedural steps, and complications concerning the procedure that have evolved according to our own experience. Mandatory angiographic visualization of the aortic root during valve deployment was introduced, combined with slow and gradual inflation of the balloon with possible correction of the valve position and its definitive position higher than we had been taught. RESULTS: Technical success was 99.5% with one conversion to conventional surgery (annulus rupture). One intraprocedural obstruction of the left coronary ostium was successfully treated by emergency stent implantation. The 30-day mortality was 5.7% for the whole group (11 of 194 patients), 3.8% for all patients without cardiogenic shock (7 of 182 patients), and 33% for the patients with cardiogenic shock (4 of 12 patients). There were 2 (1%) new clinical neurologic events postoperatively. CONCLUSIONS: A combination of patient-related evaluation and several small but precise technical modifications of the original transapical aortic valve implantation techniques reduced the rate of complications and increased success during the learning curve. PMID- 20971243 TI - Minimally invasive versus sternotomy approach for mitral valve surgery: a propensity analysis. AB - BACKGROUND: Over the past decade, minimally invasive (MI) mitral valve surgery has grown in popularity. The purpose of this study was to compare both short- and long-term outcomes of mitral valve repair and replacement performed through a MI versus traditional sternotomy (ST) incision using a propensity analysis approach to account for differences in baseline risk. METHODS: From January 2000 to December 2008, a total of 1,121 isolated mitral valve operations were performed at our institution (548 ST, 573 MI). Data were retrospectively collected on all patients, and a logistic regression model was created to predict selection to a MI versus ST approach. Propensity scores were then generated based on the regression model and matched pairs created using 1:1 nearest neighbor matching. There were 382 matched pairs in the analysis for a total sample size of 764, or 68.2% of the original cohort. Major outcomes of interest included cardiopulmonary bypass time, cross-clamp time, hospital length of stay, major in-hospital complications, and both short- and long-term survival. RESULTS: Cardiopulmonary bypass time was 117.1 +/- 2.0 minutes in the ST group and 139.7 +/- 2.6 minutes in the MI group (p < 0.0001), and cross-clamp time was 79.6 +/- 1.5 minutes in the ST group and 83.7 +/- 1.9 in the MI group (p = 0.106). The average hospital length of stay was 9.81 +/- 0.61 days among ST patients and 7.76 +/- 0.37 days among MI patients (p = 0.0043). There was no significant difference in the frequency of major in-hospital complications between groups. The mean duration of survival follow-up was 4.2 +/- 2.4 years. There was no significant difference in mortality at 30 days (p = 0.622) or 1 year (p = 0.599). In addition, there was no significant difference in long-term survival between groups (p = 0.569). CONCLUSIONS: Although minimally invasive mitral valve surgery required a slightly longer cardiopulmonary bypass time, there was no difference in cross-clamp time, morbidity, or mortality, and hospital length of stay was significantly shorter when compared with matched sternotomy control patients. PMID- 20971244 TI - Influence of patient age on procedural selection in mitral valve surgery. AB - BACKGROUND: Previous studies suggest that mitral valve replacement is comparable to repair in the elderly, and a national trend exists toward tissue valves. However, few direct comparison data are available, and this study evaluated the effects of patient age on risk-adjusted survival after mitral procedures. METHODS: From 1986 to 2006, 2,064 patients underwent isolated primary mitral operations (+/-CABG). Maximal follow-up was 20 years with a median of 5 years. Valve disease etiology was the following: degenerative, 864; ischemic, 450; rheumatic, 416; endocarditis, 98; and "other," 236. Overall, 58% had repair and 39% had concomitant coronary artery bypass grafting. Survival differences were evaluated with a Cox proportional hazards model that included baseline characteristics, valve disease etiology, and choice of repair versus replacement with tissue or mechanical valves. RESULTS: Baseline risk profiles generally were better for mechanical valves, and age was the most significant multivariable predictor of late mortality [hazard ratio = 1.4 per 10-year increment, Wald chi(2) = 32.7, p < 0.0001]. As compared with repair, risk-adjusted survival was inferior with either tissue valves [1.8, 27.6, <0.0001] or mechanical valves [1.3, 8.1, 0.0044], and no treatment interaction was observed with age (p = 0.18). At no patient age did tissue valves achieve equivalent survival to either repair or mechanical valves. CONCLUSIONS: Mitral repair is associated with better survival than valve replacement across the spectrum of patient age. If replacement is required, mechanical valves achieve better outcomes, even in the elderly. These data suggest that tissue valves should be reserved only for patients with absolute contraindications to anticoagulation who are not amenable to repair. PMID- 20971245 TI - Efficacy and safety of very low-dose self-management of oral anticoagulation in patients with mechanical heart valve replacement. AB - BACKGROUND: Self-management improves oral anticoagulation control. Here we provide data of a preplanned interim analysis of very low-dose early self controlled anticoagulation. METHODS: In a prospective, randomized, multicenter trial, 1,137 patients performed low-dose international normalized ratio (INR) self-management with a target INR range of 1.8. to 2.8 for aortic valve replacement recipients and 2.5 to 3.5 for mitral or double valve replacement recipients for the first six postoperative months. Thereafter, 379 patients continued to achieve the aforementioned INR target range (LOW group), whereas the INR target value was set at 2.0 (range, 1.6 to 2.1) for the remaining patients with aortic valve replacement and 2.3 (range, 2.0 to 2.5) for the remaining patients with mitral valve or double valve replacement. One half of this latter group had to check their INR values once a week (VL1 group) the other half twice a week (VL2 group). Patients were followed up for 24 months. RESULTS: Beyond study month six, the incidence of thromboembolic events that required hospital admission was 0.58%, 0.0%, and 0.58% in the LOW, VL1, and VL2 groups, respectively (p = 0.368). The incidence of bleeding events per patient-year was 1.16%, 1.07%, and 0.58% in the LOW, VL1, and VL2 groups, respectively (p = 0.665). Mortality rate did not differ among study groups. CONCLUSIONS: Data demonstrate the efficacy and safety of very low-dose INR self-management. PMID- 20971246 TI - Invited commentary. PMID- 20971247 TI - Moderate aortic stenosis in coronary artery bypass grafting patients more than 70 years of age: to replace or not to replace? AB - BACKGROUND: Moderate aortic stenosis in coronary artery bypass graft surgery (CABG) patients more than 70 years old is not unusual. The risk-benefit of performing a concomitant aortic valve replacement (AVR) is often difficult to assess. To stratify the risk-benefit ratio, we reviewed outcomes of CABG patients more than 70 years old with preoperative moderate aortic stenosis (valve area 1.0 to 1.6 cm(2) or indexed valve area 0.6 to 1.0 cm(2)/m(2)). METHODS: Among 263 CABG patients more than 70 years old with moderate aortic stenosis, 167 patients underwent only CABG and 96 had CABG+AVR. RESULTS: Cross-clamp time (p < 0.0001) and perioperative transient ischemic attack-cerebrovascular accident (p < 0.04) were significantly higher in the CABG+AVR group. In-hospital mortality was comparable among groups (CABG 6.0% versus CABG+AVR 4.2%; p = 0.8). At a mean follow-up of 4.5 +/- 3.0 years, 5-year survival (CABG 64.2% +/- 4.3% versus CABG+AVR 62.3% +/- 5.5%) and freedom from AVR (CABG 97.8% +/- 1.2% versus CABG+AVR 98.9% +/- 1.1%; p = 0.13) were comparable among both groups. Among patients treated with CABG alone, receiver operating characteristic curve analysis identified 26 mm Hg and 15 mm Hg as maximum and mean aortic valve gradients, respectively, for increased risk of reoperation for late AVR. Multivariate analyses for predictors of operative mortality were preoperative renal failure (odds ratio [OR] 7.64, p < 0.001) and intubation more than 48 hours (OR 11.10, p < 0.0002); for late death, ejection fraction less than 40% (OR 3.35, p < 0.02), New York Heart Association functional class III or IV (OR 2.37, p < 0.002), chronic obstructive pulmonary disease (OR 2.26, p < 0.02), and renal failure (OR 3.03, p < 0.003); for perioperative transient ischemic attack cerebrovascular accident, cross-clamp time (OR 1.02, p < 0.02) and Parsonnet score (OR 1.09, p < 0.05). CONCLUSIONS: For CABG patients more than 70 years old with minimal comorbidities especially in the presence of aortic gradients of 26/15 mm Hg or greater, concomitant AVR for moderate aortic stenosis should be performed during CABG and may be performed with minimal additional operative risk. Patients with significant comorbidities should be managed with CABG alone, owing to an increased perioperative risk, poor midterm survival, and minimal risk of AVR at 5 years. PMID- 20971248 TI - Left main coronary artery disease does not affect the outcome of off-pump coronary artery bypass grafting. AB - BACKGROUND: Left main coronary artery (LMCA) stenosis (>=50%) has historically been recognized as a risk factor among patients undergoing coronary artery bypass grafting. METHODS: From January 2002 to December 2008, a total of 665 patients, 268 of whom had significant LMCA disease, underwent isolated off-pump coronary artery bypass surgery at Shiga Medical University Hospital. We compared the clinical results in the 237 patients with LMCA stenosis (LMCA group) with those in the propensity score-matched 237 patients without LMCA stenosis (non-LMCA group). We performed off-pump surgery in all coronary artery bypass grafting cases with no exclusion criteria. RESULTS: All procedures were performed by off pump technique without conversion to on-pump. Two patients in the LMCA group (2 of 237; 0.8%) and four in the non-LMCA group (4 of 237; 1.7%) died within 30 days after surgery. Follow-up was completed in 96.2% of the patients. The rates of six year freedom from all cause death were 87.3% and 60.7% in the LMCA group and non LMCA group, respectively (p = 0.17), and the corresponding rates for the combined endpoint of cardiac death, myocardial infarction, angina pectoris, repeat coronary intervention, and heart failure were 80.4% and 70.4% (p = 0.98). Multivariate Cox regression analysis revealed chronic renal failure as a statistically significant predictor for late cardiac event. CONCLUSIONS: Off-pump coronary artery bypass grafting is feasible and safe in patients with critical LMCA stenosis and LMCA disease is not recognized as a risk factor after off-pump coronary artery bypass grafting in either the short or the long term. PMID- 20971249 TI - Invited commentary. PMID- 20971250 TI - Sutureless proximal anastomosis using the PAS-Port system: six-month patency and five-year follow-up in "all-comers". AB - BACKGROUND: The PAS-Port system (Cardica, Inc, Redwood City, CA) was used routinely for patients undergoing coronary surgery with at least one venous graft. Graft patency and clinical results were evaluated, respectively, at 6 months and 5 years after surgery. METHODS: A total of 100 patients (82 males, 18 females; mean age 68.9 +/- 12 years) underwent coronary bypass surgery with at least one PAS-Port anastomosis (total number of PAS-Port implants: n = 117). At 6 months after surgery all patients were followed up clinically and 86 patients with 101 PAS-Port implants underwent either a multidetector computed tomographic scan or coronary angiography. Actuarial freedom from MACCE (major adverse cardiac and cerebrovascular events) was assessed at 5 years after surgery. RESULTS: Six month PAS-Port patency was 88%. The inner diameter of the graft at the implant site (measured in 26 patients) did not reveal any pathologic narrowing (mean inner diameter 3.1 +/- 0.6 mm). At 5 years, freedom from overall MACCE was 79% +/ 5% and freedom from PAS-Port target vessel revascularization was 94% +/- 6%. CONCLUSIONS: The routine use of PAS-Port was associated with good vein graft patency at 6 months and a low incidence of MACCE at 5 years after surgery. No evidence of implant-related graft stenosis was detected. PMID- 20971251 TI - Invited commentary. PMID- 20971252 TI - Fourteen-year follow-up from CABADAS: vitamin K antagonists or dipyridamole not superior to aspirin. AB - BACKGROUND: Secondary prophylaxis using aspirin is standard of care after coronary artery bypass graft surgery. Limited data are available for long-term results. We evaluated the effect of aspirin, aspirin with dipyridamole, and vitamin K antagonists (VKA) on 14-year clinical outcome of patients included in the Prevention of Coronary Artery Bypass Graft Occlusion by Aspirin, Dipyridamole, and Acenocoumarol/Phenprocoumon Study (CABADAS). METHODS: All 726 Dutch patients for whom antithrombotic therapy with aspirin (n = 248), aspirin with dipyridamole (n = 234), or VKA (n = 244) was randomly allocated were included. The primary endpoint was occurrence of major adverse cardiac events (MACE). Outcomes were retrospectively evaluated during 14-year follow-up. RESULTS: Cumulative incidences for MACE over 14 years were 49%, 50%, and 59% for patients treated with aspirin, aspirin with dipyridamole, and VKA, respectively. Although the overall occurrence of MACE did not significantly differ among the three treatment groups (p = 0.12), patients treated with VKA were at higher risk of MACE than patients treated with aspirin with dipyridamole (hazard ratio 1.3, 95% confidence interval: 1.0 to 1.8, p = 0.041) and patients treated with aspirin alone (hazard ratio 1.1, 95% confidence interval: 0.86 to 1.5, p = 0.37). This difference was attributed to an increased risk of repeat revascularization in patients treated with VKA, without any differences in cardiac death and myocardial infarction among the three treatment groups. However, the observed high rate of repeat revascularization in patients treated with VKA could reflect an a priori increased probability for repeat revascularization due to the specific conditions surrounding VKA therapy (ie, more intense patient-doctor contacts). CONCLUSIONS: This study with 14-year clinical outcome provides further evidence for the use of aspirin as secondary prophylaxis after coronary artery bypass graft surgery. PMID- 20971253 TI - Invited commentary. PMID- 20971254 TI - Outcomes for surgical treatment of atrial fibrillation using cryoablation during concomitant cardiac procedures. AB - BACKGROUND: Surgical treatment of atrial fibrillation (AF) with heat-based therapies has been associated with a high rate of arrhythmia recurrence. We studied the short-term to medium-term outcomes with a unique biatrial linear ablation procedure for AF treatment using an argon-based cryoablation device during concomitant cardiac operations. METHODS: Between March 2005 and July 2008, 57 patients (47% men) with problematic AF underwent a linear endocardial ablation procedure (Star pattern) using the flexible argon-based cryoablation probe during concomitant cardiac operations. Procedures were performed with valve or coronary operations, including mitral valve replacement (25%), mitral valve repair (16%), coronary artery bypass grafts (21%), and congenital heart surgery (8%). Atrial fibrillation was persistent or long-standing persistent in 50.9% of patients. RESULTS: Kaplan-Meier survival curves (with the standard error) demonstrated 91% (3.9%) of patients were still free of their first recurrence at 6 months, 81% (5.6%) at 12 months, and 70% (6.8%) at 24 months. Time to first recurrence was not significantly associated with age (p = 0.47), gender (p = 0.52), or type of AF (p = 0.69). There were no complications attributed to the cryoablation procedure. There was one in-hospital death and one death after discharge. Twelve patients (21%) required permanent pacemaker implantation postoperatively. There were no early or late thromboembolic events. CONCLUSIONS: This study demonstrated the medium-term efficacy of cryoablation with a unique biatrial pattern of linear lesions for the treatment of AF during a concomitant cardiac operation. Short term to medium-term outcomes were at least equivalent to those reported for other energy modalities. PMID- 20971255 TI - Invited commentary. PMID- 20971257 TI - Invited commentary. PMID- 20971256 TI - Pyruvate-enriched cardioplegia suppresses cardiopulmonary bypass-induced myocardial inflammation. AB - BACKGROUND: Cardiopulmonary bypass-induced oxidative stress initiates inflammation that can damage the myocardium. This study tested whether cardioplegia enriched with the intermediary metabolite and antioxidant pyruvate dampens postbypass myocardial inflammation. METHODS: Pigs were maintained on cardiopulmonary bypass while their hearts were arrested for 60 minutes with 4:1 blood:crystalloid cardioplegia, in which the crystalloid contained 188 mM glucose +/- 24 mM pyruvate. Pigs were weaned from bypass after 30 minutes of whole blood reperfusion and recovered for 4 hours. Glutathione (GSH) and glutathione disulfide (GSSG) were measured in coronary sinus plasma to indirectly monitor myocardial GSH redox state (GSH/GSSG). Left ventricular myocardium was sampled 4 hours after cardiopulmonary bypass for analyses of C-reactive protein, matrix metalloproteinases 2 and 9 and tissue inhibitor of metalloproteinase-2 (TIMP-2), and to assess neutrophil infiltration by histology and myeloperoxidase assay. RESULTS: Coronary sinus GSH/GSSG fell 70% after cardiopulmonary bypass with control cardioplegia, but pyruvate cardioplegia produced a robust increase in coronary sinus GSH/GSSG that persisted for 4 hours after bypass. Myocardial C reactive protein content increased 5.6-fold after control bypass, and neutrophil infiltration and myeloperoxidase activity also increased, but pyruvate-fortified cardioplegia prevented these inflammatory effects. Control cardioplegia lowered myocardial TIMP-2 content by 59% and increased matrix metalloproteinase-9 activity by 35% versus nonbypass sham values, but pyruvate cardioplegia increased TIMP-2 content ninefold versus control cardioplegia and prevented the increase in matrix metalloproteinase-9. Matrix metalloproteinase-2 was not affected by bypass +/- pyruvate. CONCLUSIONS: Pyruvate-enriched cardioplegia dampens cardiopulmonary bypass-induced myocardial inflammation. Increased GSH/GSSG and TIMP-2 may mediate pyruvate's effects. PMID- 20971258 TI - Contrast pericardiography facilitates intrapericardial navigation under fluoroscopy. AB - BACKGROUND: We used contrast pericardiography during fluoroscopy to facilitate intrapericardial navigation in pigs. METHODS: In 8 juvenile pigs, we performed standard, noncontrast-enhanced fluoroscopy of the heart in an attempt to identify the location of the left and right atrial appendages, the atrioventricular (AV) groove, the coronary sinus, the superior and inferior vena cavae, and the right ventricular outflow tract. Then we injected ionic contrast into the pericardial space and repeated fluoroscopy. A subjective scoring sheet was used to grade the fluoroscopic image. Guided by the enhanced image, we placed a cardiac restraint device (CRD) around both ventricles. After 4 weeks, the pigs were humanely euthanized, and we examined the position of the CRD to verify that we had correctly identified the AV groove as well as the gross and histologic effects of intrapericardial contrast on the heart. RESULTS: Cardiac structures that were not visible on standard fluoroscopy could be delineated with substantially better clarity after intrapericardial injection of contrast. Postmortem examination showed that the CRD was positioned correctly at the AV groove and that contrast pericardiography was not associated with adverse topical effects. CONCLUSIONS: Contrast pericardiography is a technique that greatly enhances one's ability to visualize the location and configuration of cardiac structures. We used this technique to accurately locate the AV groove and to aid us in the successful placement of a CRD. Improved fluoroscopic visualization of intrapericardial structures may facilitate the development of limited access and percutaneous intrapericardial interventions. PMID- 20971259 TI - Extracorporeal membrane oxygenation in primary graft failure after heart transplantation. AB - BACKGROUND: The aim of this review was to analyze our results with extracorporeal membrane oxygenation (ECMO) support for primary graft failure (PGF) in heart transplant recipients. METHODS: A retrospective review of 239 consecutive patients who underwent heart transplantation between January 2000 and August 2009 was performed. Orthotopic, heterotopic, and heart lung transplants were included in this analysis. Over that time period, 54 patients developed PGF, of whom 39 patients required ECMO support. These 39 patients form the basis of this review. RESULTS: Thirty-four patients (87%) were successfully weaned from ECMO and 29 (74.3%) survived to hospital discharge. There were no significant differences in wean rates or complications between central and peripheral ECMO. Comparison of survival in the 39 ECMO patients to the non-PGF patients (n = 185) showed a significantly worse survival in the ECMO group (p = 0.007). When those patients who died in the first 30 days were excluded, there was no difference in overall survival between groups (p = 0.73). CONCLUSIONS: Extracorporeal membrane oxygenation provides excellent circulatory support for patients with PGF after heart transplantation with good wean and survival to discharge rates. PMID- 20971260 TI - Invited commentary. PMID- 20971261 TI - Mobile extracorporeal membrane oxygenation unit expands cardiac assist surgical programs. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is an effective technique to provide emergency mechanical circulatory or respiratory assistance in critically ill patients. A Mobile Remote Cardiac Assist unit was created to implant ECMO in patients from outside our institution and bring them back in our intensive care unit for follow-up when stabilized. This study was undertaken to evaluate the feasibility and the preliminary results of this procedure. METHODS: Between March 2006 and June 2008, 38 consecutive patients with acute cardiac or respiratory failure were implanted with percutaneous ECMO. The logistic concerns, indications, complications, and outcomes of these patients were analyzed. RESULTS: There were no logistic or technical problems during the round trip or ECMO implantation. Mean distance from our intensive care unit was 68 km (1 to 230). Maximal time limit between the phone call and implantation was 90 minutes. The indications were fulminant myocarditis, pharmacologic suicide attempt, acute myocardial infarction, postpartum cardiopathy, end-stage cardiomyopathy, with left ventricular ejection fraction of 0.19 +/- 0.05 (n = 32), or acute respiratory distress syndrome without cardiac failure (n = 6). Patients received a percutaneous venoarterial femoral ECMO with immediate reperfusion of the limb or venovenous ECMO for isolated lung failure. Seventeen patients (45%) were successfully weaned from ECMO after 9.4 +/- 8.7 days. Four patients (11%) were transplanted. One patient was switched to a left ventricular assist device and was then successfully transplanted. Twenty-one patients (55%) survived to hospital discharge. CONCLUSIONS: The Mobile Cardiac Assist unit allowed emergency implantation of ECMO support in remote institutions without any logistic or technical problems. PMID- 20971262 TI - Invited commentary. PMID- 20971263 TI - More than 30 years' experience with surgical correction of atrioventricular septal defects. AB - BACKGROUND: Outcome of surgical correction of atrioventricular septal defects (AVSD) still varies despite enhanced results. We reviewed our 30-year experience with AVSD repair and identified risk factors for mortality and reoperation. METHODS: Between 1975 and 2006, 312 patients underwent surgery for complete AVSD (n = 209; 67.0%), partial AVSD (n = 76; 24.4%), or intermediate AVSD (n = 27; 8.6%). Mean age was 2.4 +/- 3.9 years; 142 patients (45.5%) were younger than 6 months. Follow-up was 99.0% complete. RESULTS: There were 26 in-hospital deaths (8.3%) and 6 late deaths (2.1% of 283). Estimated overall survival for the total study population was 91.3%, 90.6%, and 88.6% at 1, 5, and 15 years, respectively. In the multivariable logistic regression analysis, surgical era 1975 to 1995 (p < 0.001) and younger age (p = 0.004) were found to be independent risk factors for early mortality, whereas preoperative AV valve insufficiency showed a tendency toward statistical significance (p = 0.052). Of the hospital survivors, 43 patients required a late reoperation. Estimated freedom from late reoperation was 96.4%, 89.3%, and 81.8% at 1, 5, and 15 years, respectively. Multivariable Cox regression analysis showed associated cardiovascular anomalies (p < 0.001), left AV valve dysplasia (p < 0.001), and absence of cleft closure (p = 0.003) to be independent risk factors for late reoperation. CONCLUSIONS: AVSD repair can be accomplished with good long-term results. Early surgical era, associated cardiovascular anomalies, left AV valve dysplasia, and absence of cleft closure negatively influence survival and risk of reoperation. PMID- 20971264 TI - Invited commentary. PMID- 20971265 TI - Valvular operations in patients with congenital heart disease: increasing rates from 1988 to 2005. AB - BACKGROUND: The congenital heart disease population is aging. We hypothesized that changes in rates of congenital, valvular, and noncongenital surgical operations in congenital heart patients varied with age and disease severity over the last two decades. METHODS: We performed time trend analysis using a Quebec congenital heart disease database constructed from administrative data. We included congenital heart patients of all ages having cardiac surgical operations. Heart lesions were classified as "severe" and "other." Cardiac surgical operations were grouped as congenital, valvular (including aortic), and noncongenital (arrhythmia surgery, coronary artery bypass grafting, and cardiac transplants). An adapted Aristotle score was developed to classify procedures based on surgical risk. Yearly surgical rates were measured as surgical operations per 1,000 person-years and analyzed over time using Poisson regression models stratified by age, lesion severity, and cardiac surgery category. RESULTS: From 1988 to 2005 we followed 71,979 patients for 1,009,430 person-years. We identified 17,444 cardiac surgical operations. There was a 31% increase in volumes and a 5% increase in surgical rates over time. In children, congenital surgical operations remained constant, accounting for 80% of all surgical operations. In adults, valvular operations were the most common type of surgical operations, increasing from 42% to 63% of all procedures over time. Rates of valvular operations increased significantly in all adult subgroups and in children with severe lesions. CONCLUSIONS: The need for valvular interventions has increased in the last two decades in congenital heart disease patients. These findings should be taken into account when allocating resources that will optimize outcomes for this growing population. PMID- 20971266 TI - Long-term outcome after annular mechanical mitral valve replacement in children aged less than five years. AB - BACKGROUND: When mitral valve repair in children is not possible, mitral valve replacement (MVR) is an alternative, which could result in better outcomes. We report the long-term outcome after replacement of systemic atrioventricular valve with bileaflet mechanical valves in annular position in patients less than 5 years of age. METHODS: Between 1983 and 2008, 29 MVRs were performed in children aged 1.82 +/- 1.34 years (range, 95 days to 4.6 years); the average weight was 8.06 +/- 2.92 kg (range, 4.7 to 15 kg). The main indication (86%) was severe regurgitation. Prosthesis size ranged between 17 mm and 25 mm. RESULTS: The follow-up was completed and totaled 373 patient-years (12.4 +/- 8.6). Four children presented with permanent atrioventricular block. Freedom from thromboembolic and hemorrhage events at 1, 5, 15 years was 100%, 96.1%, and 91.3%, respectively. All deaths occurred within 2 months after MVR and were 5 children (17%). No late mortality was observed. Freedom of redo MVR at 5, 10, and 15 years was 95%, 86%, and 70%, respectively. At MVR, weight 7 kg or less and age 1 year or less (p = 0.03) were associated with redo MVR. During redo MVR, a larger mechanical valve was implanted (+2 sizes), with no postoperative death. Currently, 23 patients are in New York Heart Association class I, and 1 patient is in class II. CONCLUSIONS: The results of mechanical annular MVR are acceptable in children. Anticoagulants are well tolerated, with little thromboembolic complication. Long-term results for patients who survive the hospital period are excellent, and reinterventions show safe results. PMID- 20971267 TI - Mitral valve growth after posterior annular stabilization with untreated autologous pericardial strip in children with mitral valve insufficiency. AB - BACKGROUND: Mitral valve (MV) reconstruction is the technique of choice for MV disease in infants and children. We evaluated whether our technique of posterior annulus stabilization with untreated autologous pericardial strip allows growth of anterior MV leaflet and its annulus. METHODS: Seventeen children (mean age, 9.43 +/- 6.03 years; range, 1 to 17) were prospectively followed up after MV repair for mitral insufficiency with severe annular dilation and anterior mitral leaflet prolapse. The MV repair techniques were Paneth posterior annuloplasty (n = 14) and Gerbode plication plasty (n = 3), both modified with pericardial strip stabilization of the posterior annulus (Hetzer's modification). Echocardiograms were taken perioperatively and serially during follow-up. RESULTS: Serial Doppler echocardiography showed good valve function at mean follow-up of 13.62 +/- 2.37 years. Left ventricular function was significantly improved, and mitral insufficiency was either absent or significantly decreased. Diameter of anterior MV leaflet and its annulus increased linearly in relation to body size. These findings were consistent in all patients except 3 who required reoperation 1 and 2 years postoperatively, respectively, for recurrent and progressive insufficiency. On reoperation, the pericardial strip was perfectly attached to the posterior annulus and covered by a fibrous tissues without calcification. CONCLUSIONS: Stabilization of the posterior annulus with pericardial strip prevents further posterior annular dilation and allows anterior MV leaflet and its annulus to grow in relation to body size over time, as well as preserving flexible properties of the MV orifice. PMID- 20971268 TI - Intermediate neurodevelopmental outcome after repair of ventricular septal defect. AB - BACKGROUND: Children with congenital heart disease are at risk for impaired neurodevelopmental outcome. Despite the high prevalence of ventricular septal defects relative to other cardiac defects, few studies have specifically examined this population. The purpose of this study was to provide data on the intermediate neurodevelopmental outcome for children after repair of a ventricular septal defect. METHODS: Neurodevelopmental outcome was assessed for 31 children using standardized tests of IQ, memory, visual-motor ability, and academic achievement. Standardized parent and teacher reports of behavioral and psychosocial functioning were also examined. Patients were grouped into younger (less than 6 years old; n = 18) and older (6 years and older; n = 13) cohorts. RESULTS: Full-scale IQ scores were within the normal range. Although most other domains of neurodevelopmental and behavioral functioning were comparable to normative data, patient functioning was lower than population norms in the areas of performance IQ for the younger cohort (90.6 +/- 16.1; p = 0.023), visual memory for the older cohort (84.5 +/- 15.3; p = 0.003), and visual-motor ability (87.9 +/- 14.2; p < 0.001) and adaptive behavior (94.3 +/- 15.3; p = 0.050) for the entire cohort. CONCLUSIONS: After repair of ventricular septal defects, children function within the normal range in most areas. Three of the four domains in which lower functioning was observed tap into visual cognitive abilities rather than verbal abilities. Lower mean scores in these areas were, however, generally within one standard deviation of the population mean, suggesting mild weaknesses rather than significant impairments. PMID- 20971269 TI - Invited commentary. PMID- 20971270 TI - Treatment of isolated ventricular septal defects in children: Amplatzer versus surgical closure. AB - BACKGROUND: Isolated hemodynamically significant ventricular septal defects (VSD) were previously treated surgically. Since the introduction of percutaneous (PC) devices, the management of isolated VSD has evolved. In our center, Amplatzer devices have been implanted for selected isolated perimembranous VSD since 2002. METHODS: The charts of all isolated PC perimembranous VSD closures and all surgical closures performed since 2002 were reviewed retrospectively. Clinical, electrocardiographic, and echocardiographic data were analyzed. The preclosure, immediate postclosure, and 1-month, 6-month, and 12-month postclosure results were assessed. RESULTS: Thirty-seven patients underwent PC closure, and 34 had surgical treatment. Mean follow-up was 42.1 +/- 26.0 months. The PC group was significantly older (p < 0.01) and larger in size (p < 0.001). Surgical patients had more severe congestive heart failure and a significantly lower VSD gradient (p < 0.004). At follow-up, there were no differences in the incidence of residual shunting between the two groups (p = 0.92). All valvular regurgitations improved over time, except for 3 aortic regurgitations (5.4%) in the PC group that got worse. Two permanent pacemakers were implanted for early complete heart block in the PC group, and one was implanted in the surgical group (p = 0.94). CONCLUSIONS: The surgical results in our population were excellent. The selection of patients with perimembranous VSD remains a challenge to avoid post-PC intervention complications such as heart block and aortic insufficiency. For isolated VSD, PC closure, which avoids the morbidity of open heart surgery, should be considered as part of the therapeutic armamentarium. PMID- 20971271 TI - Invited commentary. PMID- 20971272 TI - Mitral stenosis and aortic atresia in hypoplastic left heart syndrome: survival analysis after stage I palliation. AB - BACKGROUND: Mitral stenosis with aortic atresia (MS-AA) has been implicated as a risk factor for decreased survival after stage 1 palliation for hypoplastic left heart syndrome. Conflicting results were reported in the literature evaluating the association of anatomic subtypes and mortality. Our objective was to determine whether MS-AA is associated with increased mortality after stage 1 palliation. METHODS: Between January 2005 and May 2009 100 consecutive neonates with hypoplastic left heart syndrome underwent stage 1 palliation. Echocardiograms were reviewed for patency of the mitral and aortic valves as well as presence of ventriculocoronary connections (VCC). Patients were divided into (1) mitral and aortic atresia (MA-AA), (2) MS-AA, and (3) mitral and aortic stenosis groups. Survival analysis was performed, and impact of MS-AA and VCC on early and midterm survival was assessed. RESULTS: Of the 100 patients, 31 had MA AA, 42 had mitral stenosis and aortic stenosis, and 27 had MS-AA (15 with VCC and 12 without). Stage 1 palliation 30-day survival was 90% for the entire cohort and 88.9% for the MS-AA subtype (not significantly different). Six-month survival was 70% overall and 70.4% for MS-AA (not significantly different). When VCC was taken into account, MS-AA with VCC reached 93% survival (versus 50% for MS-AA without VCC; p < 0.01). CONCLUSIONS: Stage 1 palliation for hypoplastic left heart syndrome is associated with satisfactory hospital and midterm survival regardless of anatomic subtype. The variants MS-AA and MA-AA are associated with smaller ascending aorta. Mitral stenosis with aortic atresia or VCC did not adversely influence survival. PMID- 20971273 TI - Medium-term outcomes of Kawashima and completion Fontan palliation in single ventricle heart disease with heterotaxy and interrupted inferior vena cava. AB - BACKGROUND: We investigated medium-term outcomes in single-ventricle heart disease palliated with a Kawashima procedure (KP) compared with matched patients who had a standard Fontan procedure (FP). METHODS: Clinical characteristics, oxygen saturation as measured by pulse oximetry (SpO(2)) trends, and survival in 18 KP cases were compared with 36 matched controls who underwent a standard FP. Records of surgical procedures, catheterizations, noninvasive imaging, and clinical follow-up were reviewed. RESULTS: The median duration of follow-up after KP was 6.7 years. The mean SpO(2) (%) in the KP group over the follow-up period before completion Fontan was 85.1 +/- 6, and differed significantly from the control FP group (90.7 +/- 5.1, p < 0.001). Thirteen of the 18 KP patients underwent completion Fontan at a median age of 3.3 years (1.1 to 8.6) and median interval of 2.61 years (0.61 to 7.35) after KP. Mean SpO(2) after completion Fontan following KP was 88.7 +/- 7.6%. The SpO(2) in Fontan after KP was not as high as after control FP. Low SpO(2) with upward trend was noted throughout the postoperative follow-up. The overall survival in the KP group after Fontan estimated by the Kaplan-Meier method was 87% at 5 years and at 7 years. CONCLUSIONS: The KP and subsequent Fontan completion results in acceptable medium term survival, and remains the approach of choice for single-ventricle heart disease with interrupted inferior vena cava. The KP has to be undertaken with expectation for somewhat lower early SpO(2) relative to standard Fontan patients, but in anticipation that SpO(2) is likely to rise gradually with time. PMID- 20971274 TI - Invited commentary. PMID- 20971275 TI - Transfusion-free neonatal cardiopulmonary bypass using a TinyPump. AB - BACKGROUND: We devised a miniaturized circuit incorporating a TinyPump in the venous line to amplify the venous return. We compared this system to the conventional blood-primed circuit and investigated whether this circuit could maintain hematocrit levels without blood transfusion and reduce coagulation and inflammatory cascades. METHODS: Thirteen 1-week-old piglets (3.7 +/- 0.2 kg) were divided into group M (miniaturized circuits with TinyPump-assisted venous drainage without blood, n = 7) and group C (conventional circuits with blood priming, n = 6). Cardiopulmonary bypass (CPB) was performed at 150 to 180 mL.kg( 1).min(-1) for 2 hours, including 60 minutes of cardioplegic cardiac arrest. Modified ultrafiltration (MUF) was subsequently performed. Data were acquired before CPB and after the end of MUF. RESULTS: The priming volume including the hemofilter circuit of the main circuit required 152 mL in group M and 300 mL in group C. The mean hematocrit values in group M and group C were not significantly different during CPB (21.5% +/- 2.0% versus 23.2% +/- 1.3%) or after MUF (30.7% +/- 2.1% versus 32.9% +/- 4.0%). After MUF, group M had lower thrombin antithrombin complex levels (16.7 +/- 5.0 ng/mL versus 28.4 +/- 8.4 ng/mL, p < 0.01) and interleukin-8 levels (2,867 +/- 758 pg/mL versus 13,730 +/- 5,220 pg/mL, p < 0.01) than group C. The pulmonary vascular resistance index was lower in group M after MUF (4,105 +/- 862 dynes.cm(-5).kg(-1) versus 6,304 +/- 1,477 dynes.cm(-5).kg(-1), p < 0.01). The lung water content was also better in group M (83.7% +/- 0.5% versus 84.9% +/- 0.5%, p < 0.01). CONCLUSIONS: The minicircuit with TinyPump-assisted venous drainage successfully maintained acceptable hematocrit levels and the cardiopulmonary function in neonatal piglets. Employing this technique may attenuate blood requirements and inflammatory responses, thereby improving the clinical outcomes of neonatal open-heart surgery. PMID- 20971276 TI - Impact of oropharyngeal dysphagia on long-term outcomes of lung transplantation. AB - BACKGROUND: Lung transplantation, definitive therapy for end-stage lung disease, is limited long-term by allograft dysfunction including bronchiolitis obliterans syndrome (BOS). Few modifiable risk factors for pulmonary transplant-related mortality are recognized. However, oropharyngeal dysphagia frequently occurs after thoracic surgical procedures, including lung transplantation, and increases morbidity. We evaluated the impact of oropharyngeal dysphagia on survival and BOS after lung transplantation. METHODS: A total of 263 consecutive lung transplant patients were reviewed. Each underwent clinical swallowing evaluation early after surgery; 149 patients underwent additional fiberoptic or videofluoroscopic swallowing evaluation (SE). Results of SE were correlated with BOS, defined by accepted criteria, and mortality using Kaplan-Meier survival curves. Cox proportional hazard modeling assessed preoperative and postoperative variables associated with development of BOS and mortality. RESULTS: Mean follow-up was 920 +/- 560 days. The SE identified tracheal aspiration and (or) laryngeal penetration in 70.5%. Preoperative tobacco abuse, gastroesophageal reflux, and cardiopulmonary bypass independently predicted oropharyngeal dysphagia. Peak FEV(1) (forced expiratory volume in the first second of expiration) alone independently predicted BOS (hazard ratio 0.98; confidence interval 0.975 to 0.992, p < 0.0001); oropharyngeal dysphagia was not associated with BOS. Independent predictors of mortality by multivariable analysis were ventilator dependence (p = 0.038) and peak FEV(1) (p < 0.0001); normal SE was associated with improved survival (hazard ratio 0.13; confidence interval 0.03 to 0.54, p = 0.03). CONCLUSIONS: Oropharyngeal dysphagia, often overlooked on clinical examination, is common after lung transplantation. Normal deglutition may improve survival after lung transplantation, but oropharyngeal dysphagia does not independently affect BOS. Institution of protocols aimed at identifying previously unrecognized dysphagia may improve results of pulmonary transplantation. PMID- 20971277 TI - Invited commentary. PMID- 20971278 TI - Esophageal motor dysfunction and gastroesophageal reflux are prevalent in lung transplant candidates. AB - BACKGROUND: Gastroesophageal reflux and aspiration contribute to the development of bronchiolitis obliterans and accelerate graft deterioration after lung transplantation (LTx). We evaluated LTx candidates for esophageal motor abnormalities and gastroesophageal reflux. METHODS: Consecutive patients evaluated for LTx underwent 24-hour pH monitoring using a dual-channel pH probe and high-resolution esophageal manometry. High-resolution manometry was also performed in healthy control subjects. The prevalence of abnormal acid exposure was noted in the LTx candidates. RESULTS: Thirty LTx candidates and 10 control subjects were evaluated. Lung transplantation candidates had higher residual upper and lower esophageal sphincter pressures. The mean proportion of peristaltic swallows was 21% lower in LTx candidates. Both hypotensive and aperistaltic swallows were sixfold more prevalent in LTx candidates than in control subjects. All control subjects had normal high-resolution manometry whereas 23 LTx candidates (76.7%) had esophageal peristaltic dysfunction. Abnormal acid exposure time was seen in the proximal and distal esophagus in 25% and 36% of LTx candidates, respectively. Lung transplantation candidates with idiopathic pulmonary fibrosis had more aperistaltic contractions, more negative minimum intrathoracic pressure, and a higher frequency of abnormal distal esophagus acid exposure. The majority of patients with complications after LTx demonstrated motor, anatomic, or pH abnormalities. CONCLUSIONS: Disordered esophageal motor function and gastroesophageal reflux are common in LTx candidates. We believe high-resolution esophageal manometry is a valid tool to use and the abnormalities we identified may be representative of this unique patient population. The role of this study in predicting a worse outcome should be further studied in patients after LTx. PMID- 20971280 TI - Variability in defining T1N0 non-small cell lung cancer impacts locoregional failure and survival. AB - BACKGROUND: Locoregional recurrence can occur despite complete anatomic resection of T1N0 non-small cell lung cancer. That may be the result of incomplete resection or inaccurate staging. We assessed the impact of extent of nodal staging on the rate of locoregional failure and patient survival. METHODS: The records of 742 patients undergoing lobectomy, bilobectomy, or pneumonectomy for non-small cell lung cancer from 1996 to 2006 were reviewed. Operative reports and pathology reports were reviewed for the number of lymph nodes and the anatomic nodal stations examined. The Kaplan-Meier method was applied to analyze recurrence-free survival. RESULTS: A total of 119 patients with pathologically staged Ia lung cancer were identified. Histology type included 61% (n = 73) adenocarcinoma, 27% (n = 32) squamous cell cancer, and 12% (n = 14) other. Median age was 65 years (range, 34 to 88). Mean follow-up duration was 40 months (median 47; range, 1 to 121). Locoregional recurrence occurred in 20% (n = 18). The N2 nodal stations were examined in 94% (n = 112). At least one defined N1 nodal station was examined in 70% (n = 83). Station undefined N1 nodes were examined in 27% (n = 32), and no N1 nodes were examined in 3% (n = 4). Median number of N1 lymph nodes analyzed was 5 (range, 0 to 18). The locoregional recurrence rate was 14% (12 of 83) for patients with a defined N1 station node versus 31% (11 of 36) for patients in whom there were undefined N1 nodes (p = 0.03). Similar differences were seen in disease-free survival, 78.2% versus 62.6%, respectively (p = 0.06). CONCLUSIONS: Despite anatomic resection of stage Ia lung cancer and uniform analysis of N2 nodal stations, a high rate of locoregional recurrence occurs. Imprecise staging of N1 lymph nodes may contribute to the understaging and undertreatment of patients with early stage lung cancer. PMID- 20971279 TI - Respiratory virus-induced dysregulation of T-regulatory cells leads to chronic rejection. AB - BACKGROUND: Lower respiratory viral infections predispose to bronchiolitis obliterans syndrome (BOS). In addition, there is emerging evidence to support the role of autoimmunity in the pathogenesis of BOS. Because CD4(+)CD25(+)Foxp3(+) regulatory T-cells (Treg) control autoimmunity, we tested the hypothesis that respiratory virus-induced Treg dysfunction leads to BOS. METHODS: Treg frequency was monitored using flow cytometry. Apoptosis, cytokines, and antibodies were analyzed using annexin V assay, LUMINEX, and enzyme-linked immunosorbent assay, respectively. Murine studies were performed using the orthotopic tracheal transplant model. RESULTS: (A) Human studies: Treg troughs (decrease >50% of baseline) were found in 13 (43.3%) of 30 lung transplant recipients. Treg isolated during troughs revealed increased apoptosis (37.8%). Patients with Treg troughs had increased prevalence of antibodies to self-antigens collagen type I (23.1% vs 5.8% pretrough), collagen V (7.7% vs 0%), and k-alpha tubulin (30.7% vs 11.7%, p < 0.01) at 6 months post-trough. Increased number of Treg troughs correlated with more rapid onset of BOS. (B) Murine studies: Infection of tracheal transplant recipients with murine parainfleunza sendai virus led to increased Treg apoptosis (50.5%) in the draining lymph nodes. Vaccination against sendai virus prior to transplant abrogated apoptosis of Treg. In vitro, sendai virus-infected, but not naive, tracheal epithelial cells demonstrated upregulation of FasL (>3.5-fold) and induction of co-cultured Treg apoptosis (5.6 fold increase). CONCLUSIONS: Respiratory viral infections cause Treg apoptosis which leads to the development of de novo autoimmunity that may play a role in the pathogenesis of BOS. PMID- 20971281 TI - Sublobar resection provides an equivalent survival after lobectomy in elderly patients with early lung cancer. AB - BACKGROUND: Sublobar resection is indicated for early-stage non-small cell lung cancer in patients with a perioperative risk associated with impaired medical conditions. This study was conducted to investigate the clinical impact of this procedure in the elderly. METHODS: The patients who underwent complete resection for stage IA non-small cell lung cancer from 1990 and 2007 were enrolled (n = 764). Two age groups were defined as elderly (>=75 years) and younger (<75 years) patients. The 5-year survival, recurrence, and postoperative complications after sublobar resection were compared with those after standard lobectomy according to age group. RESULTS: There were 133 elderly patients (79 standard lobectomies and 54 sublobar resections) and 631 younger patients (539 standard lobectomies and 92 sublobar resections). While the 5-year survival after sublobar resection was significantly inferior to that after standard lobectomy in the younger group (64.0% and 90.9%, respectively, p < 0.0001), however, no substantial difference was observed in the elderly (67.6% and 74.3%, p = 0.92). Locoregional recurrence rates were higher in patients after sublobar resection than those after standard lobectomy in both the elderly (11.1% vs 1.3%) and the younger (12.0% vs 1.5%) groups. No significant difference in postoperative complications was observed between the types of surgery in the elderly. CONCLUSIONS: Sublobar resection for stage IA is considered to be an appropriate treatment in the elderly patients as this procedure provides an equivalent long-term outcome in comparison with lobectomy. A larger scale study with matching patients is necessary to confirm the noninferiority of sublobar resection in comparison with standard lobectomy in this population. PMID- 20971282 TI - Invited commentary. PMID- 20971283 TI - Management of localized pneumothoraces after pulmonary resection with intrapulmonary percussive ventilation. AB - BACKGROUND: Intrapulmonary percussive ventilation (IPV) aims at clearing retained secretions through oscillary vibrations generated by high frequency bursts of gas delivered into the airways at rates between 200 and 300 breaths per minute and at a delivery pressure of 10 to 20 cm water. In addition, IPV can improve recruitment of alveolar units and deliver aerosolized medications. The use of IPV to resolve challenging postlobectomy localized pneumothoraces is hereafter described. METHODS: Between January 2005 and March 2009, four patients with long term complicated postresectional residual air spaces persisting 6 months (mean, 187 days) after primary surgery were treated by IPV. The type of operation was upper lobectomy and lower lobectomy-wedge resection in 1 and 3 patients, respectively. Mean preoperative and immediate postsurgical forced expiratory volume in the first second of expiration were 2.31 L and 1.49 L, respectively. Mean preoperative and immediate postsurgical forced vital capacity were 3.13 L and 2.1 L, respectively. Patients were subjected to 12-minute-long IPV sessions up to a total of 8 to 12 sessions administered every other day in an outpatient setting. RESULTS: Complete resolution of the spaces within a mean of 22 days of beginning of treatment was noted. The post-IPV forced expiratory volume in the first second of expiration and forced vital capacity were 1.72 and 2.4 liters, respectively. No treatment-related morbidity was observed. CONCLUSIONS: Intrapulmonary percussive ventilation can be expected to decisively contribute to resolving long-term localized pneumothoraces after subtotal pulmonary resections in an outpatient setting. PMID- 20971284 TI - Invited commentary. PMID- 20971285 TI - Prognostic relevance of skip metastases in esophageal cancer. AB - BACKGROUND: Presence of nodal skip metastasis is an established prognostic factor for patients with non-small cell lung cancer. Little is known about this form of lymphatic spread in esophageal cancer. The aim of this study was to assess nodal skip metastasis and its clinical importance for patients with cancer of the esophagus. METHODS: Resected lymph nodes of 128 patients with esophageal cancer and pN1 status (adenocarcinoma, n = 67; squamous cell cancer, n = 61) were mapped according to the Japanese lymph-node classification for esophageal cancer. Skip metastases were defined as tumor-free N1 lymph nodes, whereas N2 through N4 lymph nodes harbor metastases. RESULTS: Skip metastases were present in 26 of 128 (20%) patients. There was a higher rate of skip metastasis in early tumors (39% versus 23% versus 14% for T1, T2, and T3 tumors; p = 0.032) and tumors in the middle and upper third of the esophagus (37% versus 15% for upper- and middle-third and lower-third tumors; p = 0.022). Patients with skip metastasis had a significantly better 5-year survival rate than patients with continuous metastasis (53% versus 15%; p < 0.0001). Multivariate analysis revealed skip metastasis as an independent prognostic factor. CONCLUSIONS: Skip metastasis is a common form of lymphatic spread in esophageal cancer, which is associated with a favorable prognosis. PMID- 20971286 TI - Invited commentary. PMID- 20971287 TI - Low mortality after treatment for esophageal perforation: a single-center experience. AB - BACKGROUND: Historically, esophageal perforation has been associated with significant mortality. Improvements in diagnosis, critical care, and surgical and endoscopic techniques may lead to lower mortality rates in the modern era. We reviewed our experience with the management of esophageal perforation to determine whether outcomes have improved. METHODS: We retrospectively reviewed all cases of esophageal perforation from 1997 through 2008 at our institution. Univariate and propensity-matching analysis were performed. RESULTS: We reviewed the charts of 147 patients, and 97 met eligibility criteria. There were 45 women, (46.4%); mean age was 60.7 +/- 15.6 years. Etiologies included iatrogenic in 50 (51.6%), spontaneous in 23 (23.7%), and idiopathic in 22 (22.7%). Treatment within 24 hours of presentation occurred in 55.2% of patients; 22.7% of patients were septic on presentation. Treatment included surgery in 72 patients (74.2%) and nonoperative management in 25 (25.8%). Forty-one patients (42.3%) underwent primary repair, 5 (6.9%) underwent esophageal resection, 4 (5.6%) underwent exclusion, and 22 (22.7%) underwent drainage or stent placement. Thirty-day mortality rate for the entire cohort was only 8.3% (8 patients). The mortality rate for the primary repair patients was 7.7%, and none of the resection patients died. There was similar in-hospital mortality rate between operative and nonoperative treatment groups (p = 0.96). Propensity-matching analysis showed equal morbidity (p = 0.74) and 30-day mortality (p = 0.35) between operative and nonoperative treatment groups. CONCLUSIONS: Our study represents a large series of patients treated for esophageal perforation. The results demonstrate that the overall mortality from esophageal perforation can be less than 10%. Primary repair should be considered as first-line treatment when appropriate even in patients who present more than 24 hours after perforation. Nonoperative management, in appropriate patients, can also lead to good success rates and low mortality. PMID- 20971288 TI - Anastomotic leakage after esophageal resection: new treatment options by endoluminal vacuum therapy. AB - BACKGROUND: Anastomotic leakage after esophagectomy is an important determinant of early and late morbidity and mortality. Control of the septic focus is essential when treating patients with anastomotic leakages. Surgical and endoscopic treatment options are limited. METHODS: Between 2005 and 2009, we treated 6 patients who experienced an intrathoracic anastomotic leakage after esophageal resection. After all established therapeutic measures had failed, we explored the feasibility of an endoscopically assisted mediastinal vacuum therapy. RESULTS: We were able to heal intrathoracic esophageal leakages in all 6 patients without any local complications and without the need for reoperation. One patient died because of a progressive pneumonia. CONCLUSIONS: Endoscopic vacuum-assisted closure of anastomotic leakages may help to overcome the limitations that are associated with intermittent endoscopic treatment and conventional drainage therapy. Our preliminary results suggest that this new concept may be suitable for those patients. PMID- 20971289 TI - Invited commentary. PMID- 20971290 TI - Performance of extracorporeally adjustable ventricular assist device inflow cannula. AB - PURPOSE: This study evaluated the feasibility and efficacy of a newly developed adjustable left ventricular assist device inflow cannula in a short-term calf model. DESCRIPTION: In this inflow cannula, the angle between the cannula body and the inflow cannula tip can be altered extracorporeally by manipulating 2 externalized cables connected to the cannula. The cannula tip is adjustable in any plane to a maximum of +/-15 degrees. EVALUATION: After initial prototyping in 4 calf cadavers, a Cleveland Heart left ventricular assist device was implanted with the adjustable inflow cannula placed in the left ventricular apex and the outlet to the descending aorta. Under hypovolemic conditions, the angle of the cannula tip could be changed to induce varying degrees of ventricular suction and then eliminate it, as evidenced by recorded pump and native left ventricular flows. Epicardial echocardiography and fluoroscopy in the closed-chest condition documented extracorporeal adjustments of the inflow cannula position. CONCLUSIONS: This extracorporeally adjustable inflow cannula was effective in preventing or controlling left ventricular suction. PMID- 20971291 TI - Invited commentary. PMID- 20971292 TI - Minimally invasive aortic valve replacement in a transplanted heart. AB - Heart transplantation is subject to a number of chronic complications that may limit graft survival and be detrimental to the patient's quality of life. Aortic valve stenosis is a rare complication found after cardiac transplantation, which we believe has never been described on a tricuspid normal aortic valve. In the present study, we report a case of successful aortic valve replacement performed 16 years after cardiac transplantation on an extensively calcified tricuspid valve. Surgery was performed by using a minimally invasive approach with a reverse T upper mini-sternotomy, and the aortic valve was replaced by a biological prosthesis. The postoperative course was uneventful and the patient was discharged 7 days after the operation. PMID- 20971293 TI - Accidental intraperitoneal tunneling of driveline of left ventricular assist device. AB - We report a case of accidental intraperitoneal tunneling of the driveline of a left ventricular assist device, which was detected at time of pump exchange. The driveline was completely wrapped with the greater omentum. This technical mistake made during the original left ventricular assist device implantation enabled the patient to remain free from any driveline or pump infection for 4 years and 1 month. PMID- 20971294 TI - Cardiac swinging calcified amorphous tumors in end-stage renal failure patients. AB - We recently encountered 2 patients with mobile cardiac calcified amorphous tumors who were successfully treated by surgery. Both patients had mitral annular calcification and were on hemodialysis. These tumors showed swinging motion on echocardiography and they grew rapidly. Intraoperatively, the tumors were found to be fragile and they easily detached from their origin. The histologic findings were thrombus with angiogenesis, fibrin, and calcium deposition. This rapid growing mobile tumor in end-stage renal failure patients is speculated to increase the risk of embolic events and should be included as a special entity of cardiac amorphous tumors. PMID- 20971295 TI - Surgical treatment of an amniotic fluid embolism with cardiopulmonary collapse. AB - Amniotic fluid embolism is a rare but devastating condition associated with a very high rate of morbidity and mortality. The treatment has traditionally been aggressive supportive care. We report a case of a term pregnant woman with complete cardiovascular collapse secondary to a paradoxical amniotic fluid embolism. The embolism was seen on transesophageal echocardiogram during an emergency Cesarean section as a free-floating interatrial clot through a patent foramen ovale. She was subsequently and successfully treated with immediate cardiopulmonary bypass, thromboembolectomy, and closure of the patent foramen ovale. PMID- 20971296 TI - Transatrial transcatheter tricuspid valve-in-valve implantation of balloon expandable bioprosthesis. AB - Transcatheter valve-in-valve implantation into failing mitral and aortic bioprosthetic valves have been reported. This strategy avoids performing high risk repeat cardiac surgery in elderly patients with multiple comorbidities. Tricuspid valve-in-valve implantation has not been described. We report a case of failing bioprosthetic tricuspid valve in a 48-year-old woman with carcinoid syndrome. We attempted a transatrial transcatheter approach and we successfully deployed a 26-mm Edwards Sapien balloon expandable bioprosthesis (Edwards Lifesciences, Irvine, CA) into a severely stenotic tricuspid bioprosthesis. This case demonstrates the technical feasibility and safety of this approach. Therefore, tricuspid valve-in-valve implantation may be a viable treatment alternative in carefully selected patients. PMID- 20971297 TI - Ventricular fibrillation with diminished internal mammary artery graft flow during sternal retraction. AB - Ventricular fibrillation is a common arrhythmia encountered after the termination of cardiopulmonary bypass. Risk is augmented in patients who are undergoing repeat cardiac procedures with most documented complications occurring during repeat sternotomy. Aortic valve surgery is more complex after coronary artery bypass grafting using internal mammary arteries, and it compounds the increased risk of repeat sternotomy. This case report describes a low-flow state artificially created by sternal retraction applying tension on a right internal mammary artery to posterior descending artery anastomosis, with resultant unrecognized myocardial ischemia yielding refractory ventricular fibrillation during aortic valve replacement. PMID- 20971298 TI - A novel application of cerebral oximetry in cardiac surgery. AB - We report a novel use of cerebral oximetry in cardiac surgery using the Fore Sight absolute cerebral oximeter (CAS Medical Systems Inc, Branford, CT). A patient with a persistent left superior vena cava underwent mitral and aortic valve replacement. We decided to tape and occlude the persistent left superior vena cava and used cerebral oximetry to compare left and right hemispheric oxygen saturation levels to ensure that cerebral perfusion was not impaired. The procedure was uneventful, and the patient was extubated 8 hours later without neurocognitive deficit. PMID- 20971299 TI - Sinus of Valsalva aneurysm repair with partial allograft, and 10-year follow-up. AB - Sinus of Valsalva aneurysms are rare congenital or acquired defects that frequently are manifested by rupture into adjacent cardiac structures. Most aneurysms involve a portion of the sinus, and can be surgically treated with primary or patch closure of the defect. We present a case report of a giant aneurysm that involved the entire noncoronary sinus of Valsalva, and describe a previously unreported technique with 10-year follow-up using a partial aortic allograft to reconstruct the abnormal aortic sinus, preserving the native valve leaflets and normal sinus geometry and averting use of prosthetic materials. PMID- 20971300 TI - Surgical management of patent ductus arteriosus with endocarditis. AB - A 9-year-old boy with patent ductus arteriosus complicated by infective endocarditis had not responded to antibiotic therapy and was referred to our institution. He had persistent fever and a chest roentgenogram demonstrated the presence of left lung pneumonic consolidation. An echocardiogram showed the presence of large vegetation in the pulmonary artery at the ductal opening. We successfully performed an open ductal ligation with the aid of cardiopulmonary bypass through a sternotomy and proceeded to resect the vegetation. We completed the procedure with reconstruction of the pulmonary artery. The postoperative course was uneventful. The patient was discharged after a week. PMID- 20971301 TI - Serial chest films are needed after a diagnosis of pneumopericardium because of risk of cardiac herniation. AB - A 76-year-old man was transferred to our institution with blunt chest trauma after falling off a roof. Chest computed tomography (CT) revealed left pneumothorax and pneumopericardium but no displacement of the heart into the hemithorax. These findings suggested traumatic pericardial rupture without cardiac herniation. After chest drainage, a follow-up CT scan demonstrated no pericardial or pleural air. At thoracotomy, we observed that the pericardium was torn and that the heart was exposed. The tear was repaired with direct sutures. This case report highlights the importance of reviewing the initial CT scan. PMID- 20971302 TI - Extended stent usage for persistent esophageal leak: should there be limits? AB - A patient with a spontaneous esophageal perforation was unsuccessfully managed elsewhere by repeated stent placement. Because of inability to remove the stents and persistent empyema, staged procedures of esophagectomy and later restoration of gastrointestinal continuity were necessary. PMID- 20971303 TI - Formation of a tracheoesophageal common channel after alkaline injury. AB - We describe tracheoesophageal common channel formation in a 40-year-old woman who swallowed alkaline detergent. Necrosis and fistula formation between the posterior tracheal wall and the anterior esophageal wall were visualized by panendoscopy 15 days after the injury. Urgent tracheostomy, tube hypopharyngostomy, gastrostomy, and feeding jejunostomy were performed. Tracheoesophageal common channel formed by anterior tracheal wall and posterior esophageal wall was visualized by bronchoscopy at 48 days after the injury. Progression was observed by a panendoscopy, bronchoscopy, and chest computed tomography. Sequelae included trismus, obliteration of laryngopharynx, proximal cervical esophagus, and thoracic esophagus below the carina, stomach stricture, and scarring of the scalp, neck, back, and thighs. PMID- 20971304 TI - Unique extralobar sequestration with atypical location and aberrant vessels. AB - We report a unique extralobar pulmonary sequestration in the upper thoracic region with 3 aberrant vessels connecting to the right subclavian artery, right superior pulmonary vein, and right pulmonary artery in a 20-year-old man. The sequestered lung was completely excised using a video-assisted thoracoscopic approach. PMID- 20971305 TI - Tension pneumopericardium after blunt thoracic trauma. PMID- 20971306 TI - Bronchoscopic removal of a large endobronchial fibrolipoma using an endoloop. PMID- 20971307 TI - Late presentation of a traumatic lung hernia. PMID- 20971308 TI - Endovascular management of recurrent adult coarctation of the aorta. AB - Traditional open surgical repair has proven to be an effective treatment for the management of primary and recurrent coarctation of the thoracic aorta. Potential complications at short-term and long-term follow-up have included recurrent coarctation, hypertension, premature coronary artery disease, cerebrovascular disease, and anastomotic pseudoaneurysm. Endovascular repair of recurrent coarctation of the thoracic aorta offers a less invasive treatment approach in potential high-risk surgical patients. PMID- 20971309 TI - T-graft technique under antegrade cerebral perfusion for aortic arch aneurysm. AB - We have devised a T-graft technique for selected extensive aortic arch replacement under antegrade cerebral perfusion. Under hypothermic circulatory arrest using antegrade cerebral perfusion, one graft was island-anastomosed to the supraaortic arteries. The other graft was anastomosed to the descending aorta. Proximal and distal grafts were then end-to-side anastomosed in a T-shape. During rewarming, the ascending aorta and proximal graft were anastomosed. The surgical field was good in the 6 patients included in this report. No perioperative deaths or serious complications were encountered. This procedure was effective for patients with extensive aortic arch aneurysm and relatively intact orifices of the supraaortic arteries. PMID- 20971310 TI - Repair of the calcified tricuspid aortic valve. AB - The novel technique to repair a calcified tricuspid aortic valve using reconstruction of the valve cusps with autologous pericardium is described. The technique is based on the fact that in degenerative calcified stenosis of the tricuspid aortic valve, the cusp-free margins remain mostly uncalcified, even in very severe calcification, making the repair feasible. PMID- 20971311 TI - Off-pump coronary artery bypass grafting with device closure of atrial septal defect. AB - Patients with coronary artery disease and atrial septal defect may have unique clinical characters. We describe an off-pump combined approach for intraoperative device closure of atrial septal defect during coronary artery bypass grafting. PMID- 20971312 TI - Sympathicotomy under local anesthesia: a simple way to treat primary hyperhidrosis. AB - General anesthesia has been the standard approach for sympathicotomy to treat primary hyperhidrosis. Sympathicotomy through thoracoscopic guidance is a straightforward procedure with a short operation time. Therefore we propose using local anesthesia for the procedure. The advantages of local anesthesia include avoiding endotracheal intubation and systemic anesthetics, and allowing immediate assessment by means of verbal communication with the patient. We effectively treated primary hyperhidrosis in 3 patients by thoracoscopic sympathicotomy under local anesthesia. PMID- 20971313 TI - Surgical ligation of cisterna chyli: an alternative treatment for chronic chylothorax in children. AB - Postoperative chylothorax represents one of the early and most serious complications after cardiothoracic operations. When conservative measures are not effective, an operation is mandatory. We describe a case of persistent chylothorax after a "one-and-a-half ventricle" repair in an infant with complex congenital heart disease, which was successfully treated with a transabdominal ligation of the cisterna chyli. At the 1-year follow-up, she is in excellent clinical condition, without recurrence of pleural effusion or the requirement for nutritional support. Ligation of cisterna chyli may represent a safe and effective ultimate treatment in children with persistent chylothorax. PMID- 20971314 TI - In search of blood tests for thoracic aortic diseases. AB - A number of new diagnostic screening tools have been developed for the assessment of acute and chronic diseases of the thoracic aorta. Although standardized blood based tests capable of detecting individuals at risk for aortic aneurysm and dissection disease are not yet available, our current knowledge is expanding at a rapid rate and the future is very promising. In this review, an update of the contemporary knowledge on blood tests for detecting thoracic aortic diseases in both preclinical and clinical settings is provided, offering the potential to predict adverse aortic events, such as enlargement, rupture, and dissection. PMID- 20971315 TI - Statistical methodology for analysis of endoscopic versus open saphenous vein harvest techniques. PMID- 20971316 TI - Endoscopic vein harvesting: does the learning curve influence outcomes? PMID- 20971318 TI - Congenital pulmonary steal in subclavian artery isolation. PMID- 20971320 TI - Pulmonary artery banding: the tighter the better. PMID- 20971322 TI - Fontan procedure for truncus arteriosus with functionally univentricular heart. PMID- 20971324 TI - Individual risk assessment is the best strategy for thromboembolic prophylaxis. PMID- 20971325 TI - Group prophylaxis is the best strategy. PMID- 20971326 TI - All deep vein thrombosis patients should be routinely screened for thrombophilia. PMID- 20971327 TI - The case against routine screening for thrombophilia. PMID- 20971328 TI - Anticoagulant treatment for superficial venous thrombosis. PMID- 20971329 TI - The case against anticoagulation for superficial venous thrombosis. PMID- 20971330 TI - Isolated calf vein thrombosis should be treated with anticoagulation. PMID- 20971331 TI - The case for managing calf vein thrombi with duplex surveillance and selective anticoagulation. PMID- 20971332 TI - Preface. Mental health across the lifespan. PMID- 20971333 TI - Global issues in mental health across the life span: challenges and nursing opportunities. AB - This article describes what is known about mental health in children, adolescents, adults, and the elderly globally in high-, middle- and low-income countries. The social determinants of health are described as well as the paradigm shift from focusing on psychopathology to looking at ways in which individuals and communities can embrace mental health promotion to decrease stigma and provide care for all individuals in resource-rich and resource-poor environments. The need to expand the content in nursing curricula to include mental health concepts at all levels of training, foster mental health research, and promote international collaboration around best practices is also discussed. PMID- 20971334 TI - Prevention approaches in child mental health disorders. AB - If the health of children is to be improved, systems of care for youth must organize and collaborate around an emphasis toward promotion of health and prevention of mental illness. This approach demands an understanding of the complex interplay of genes, environment, risk, and protective factors that influence the manifestation of behavior problems. The focus of this article is prevention efforts aimed at processes thought to be involved in the development of mental illnesses. A particular emphasis is on prevention strategies that reduce risk prior to the onset of an identifiable mental disorder. Included are interventions appropriate to nurses who deal with children in schools, pediatric primary care, and specialty mental health care. PMID- 20971335 TI - Medical and psychiatric comorbidities in children and adolescents: a guide to issues and treatment approaches. AB - Chronic medical illness among children and adolescents is a growing concern with implications for informal and formal caregivers. When coupled with a psychiatric comorbidity, implications grow exponentially. Nurses who care for child and adolescent populations play a crucial role in optimizing physical and mental health when they interface with patients and their caregivers. Evidence-based interventions can promote positive outcomes and enhance quality of life, whereas failure to use evidence-based approaches has serious consequences to the health of youth with medical and psychiatric comorbidities. PMID- 20971336 TI - Interventions for anxiety in the critically ill: a guide for nurses and families. AB - Anxiety is a common feeling for patients and families during the critical care experience. As anxiety for critically ill patients presents increased risks for morbidity and mortality, it is imperative that nurses strive to identify unrelieved anxiety early to prevent adverse events. Alleviating anxiety experienced by families as a result of the critical care experience involves providing assurance, allowing them to remain near the patient, providing accurate and current information, providing for their comfort, and projecting a supportive attitude. As constant care providers, nurses can have the greatest impact on creating an environment that is safe, healing, and humane for critically ill patients and their families. PMID- 20971337 TI - Traumatic brain injury in operation enduring freedom/operation iraqi freedom: a primer. AB - In greater numbers than in prior conflicts, service members deployed as part of Operation Enduring Freedom and Operation Iraqi Freedom have an increased risk of experiencing a traumatic brain injury (TBI). The basics of TBI are discussed, with particular attention paid to blast-related events, as this is a common mechanism of injury in this population. Particular attention is focused on the pharmacologic treatment of the sequlae of TBI and common comorbid conditions. PMID- 20971338 TI - Substance abuse interface with intimate partner violence: what treatment programs need to know. AB - This article provides suggestions for skill development for substance abuse (SA) treatment agencies and providers for implementing Treatment Improvement Protocol number 25: Substance Abuse Treatment and Domestic Violence. Methods for detecting, screening, intervening, and referring victims and perpetrators of intimate partner violence enrolled in SA treatment are presented. Evidence-based brief intervention is presented. A 2-minute screen for domestic violence as well as danger assessment for lethality of abuse and the Conflict Tactics Scales 2 are reviewed. A survey of interventions aimed at establishing trust, brief intervention from best practice, guidelines for safety planning, compliance strategies for SA treatment, and community resource development are presented. PMID- 20971339 TI - Medical illnesses in people with schizophrenia. AB - The physical health of people with schizophrenia is poor, and the challenges in finding effective treatment and optimizing health outcomes are significant. However, it is likely that people diagnosed with schizophrenia can be partners in the treatment of their physical health problems. Research suggests that many people with schizophrenia value physical health and will participate in health related behaviors when they are provided with the opportunity to do so. PMID- 20971340 TI - Resilience in family members of persons with serious mental illness. AB - This integrative review summarizes current research on resilience in adult family members who have a relative with a diagnosed mental disorder that is considered serious. Within the context of resilience theory, studies identifying risk/vulnerability and positive/protective factors in family members are summarized, and studies examining seven indicators of resilience, including acceptance, hardiness, hope, mastery, self-efficacy, sense of coherence, and resourcefulness, are described. Implications for clinical practice and recommendations for future research are presented. PMID- 20971341 TI - Policy issues in mental health among the elderly. AB - Americans are living longer than ever before in history. With age comes an increased risk for chronic mental health disorders. About 1 in 8 baby boomers is expected to be diagnosed with Alzheimer disease, which will amount to some ten million members of this age cohort. The prevalence of mental health disorders among the elderly is often unrecognized. One in four older adults lives with depression, anxiety disorders, or other significant psychiatric disorders. Mental health disorders are frequently comorbid in older adults, occurring with a number of common chronic illnesses such as in diabetes, cardiac disease, and arthritis. The public is becoming more aware of the aging of the population and the difficulties that are exacerbated by unmet services and limited access to mental health services. This article describes policy issues related to chronic mental health disorders and the older population. Mental health parity, a recent policy issue occurring at the national level, is discussed first followed by workforce issues specific to the discipline of nursing. PMID- 20971342 TI - Assessing and maintaining mental health in elderly individuals. AB - This article provides detailed information about assessing the mental health needs of older adults as well as strategies to maintain mental health. An overview of the public health needs of older adults is provided that includes examples of policies that ensure minimum physical and mental health for older adults. Multiple resources are described that will enable clinicians to access information that will increase their knowledge of assessment of mental health needs of older adults. PMID- 20971343 TI - Progress and challenges in neglected tropical diseases. PMID- 20971344 TI - Reflections on ADHD. PMID- 20971345 TI - Implementing the US health-care reform bill. PMID- 20971346 TI - September 11, a decade on: a call for papers. PMID- 20971347 TI - Genomic risk prediction. PMID- 20971348 TI - Realising the benefits of genetics for health. PMID- 20971351 TI - Charles Rotimi: engaging Africa in human genomic research. PMID- 20971352 TI - Rosiglitazone plus metformin to prevent type 2 diabetes mellitus. PMID- 20971353 TI - Rosiglitazone plus metformin to prevent type 2 diabetes mellitus. PMID- 20971354 TI - Rosiglitazone plus metformin to prevent type 2 diabetes mellitus. PMID- 20971356 TI - Maternal mortality for 181 countries, 1980-2008. PMID- 20971357 TI - Maternal mortality for 181 countries, 1980-2008. PMID- 20971358 TI - Maternal mortality for 181 countries, 1980-2008. PMID- 20971359 TI - Maternal mortality for 181 countries, 1980-2008. PMID- 20971361 TI - Web-surfers beware: know thy source. PMID- 20971360 TI - Significant errors. PMID- 20971363 TI - Antiretroviral therapy in low-resource settings. PMID- 20971364 TI - A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. AB - BACKGROUND: Comparison of patients with coronary heart disease and controls in genome-wide association studies has revealed several single nucleotide polymorphisms (SNPs) associated with coronary heart disease. We aimed to establish the external validity of these findings and to obtain more precise risk estimates using a prospective cohort design. METHODS: We tested 13 recently discovered SNPs for association with coronary heart disease in a case-control design including participants differing from those in the discovery samples (3829 participants with prevalent coronary heart disease and 48,897 controls free of the disease) and a prospective cohort design including 30,725 participants free of cardiovascular disease from Finland and Sweden. We modelled the 13 SNPs as a multilocus genetic risk score and used Cox proportional hazards models to estimate the association of genetic risk score with incident coronary heart disease. For case-control analyses we analysed associations between individual SNPs and quintiles of genetic risk score using logistic regression. FINDINGS: In prospective cohort analyses, 1264 participants had a first coronary heart disease event during a median 10.7 years' follow-up (IQR 6.7-13.6). Genetic risk score was associated with a first coronary heart disease event. When compared with the bottom quintile of genetic risk score, participants in the top quintile were at 1.66-times increased risk of coronary heart disease in a model adjusting for traditional risk factors (95% CI 1.35-2.04, p value for linear trend=7.3*10( 10)). Adjustment for family history did not change these estimates. Genetic risk score did not improve C index over traditional risk factors and family history (p=0.19), nor did it have a significant effect on net reclassification improvement (2.2%, p=0.18); however, it did have a small effect on integrated discrimination index (0.004, p=0.0006). Results of the case-control analyses were similar to those of the prospective cohort analyses. INTERPRETATION: Using a genetic risk score based on 13 SNPs associated with coronary heart disease, we can identify the 20% of individuals of European ancestry who are at roughly 70% increased risk of a first coronary heart disease event. The potential clinical use of this panel of SNPs remains to be defined. FUNDING: The Wellcome Trust; Academy of Finland Center of Excellence for Complex Disease Genetics; US National Institutes of Health; the Donovan Family Foundation. PMID- 20971365 TI - Phenylketonuria. AB - Phenylketonuria is the most prevalent disorder caused by an inborn error in aminoacid metabolism. It results from mutations in the phenylalanine hydroxylase gene. Phenotypes can vary from a very mild increase in blood phenylalanine concentrations to a severe classic phenotype with pronounced hyperphenylalaninaemia, which, if untreated, results in profound and irreversible mental disability. Neonatal screening programmes identify individuals with phenylketonuria. The initiation of a phenylalanine-restricted diet very soon after birth prevents most of the neuropsychological complications. However, the diet is difficult to maintain and compliance is often poor, especially in adolescents, young adults, and pregnant women. Tetrahydrobiopterin stimulates phenylalanine hydroxylase activity in about 20% of patients, and in those patients serves as a useful adjunct to the phenylalanine-restricted diet because it increases phenylalanine tolerance and allows some dietary freedom. Possible future treatments include enzyme substitution with phenylalanine ammonia lyase, which degrades phenylalanine, and gene therapy to restore phenylalanine hydroxylase activity. PMID- 20971366 TI - Escherichia coli O157. AB - Escherichia coli O157 is an uncommon but serious cause of gastroenteritis. This bacterium is noteworthy because a few, but significant, number of infected people develop the haemolytic uraemic syndrome, which is the most frequent cause of acute renal failure in children in the Americas and Europe. Many infections of E coli O157 could be prevented by the more effective application of evidence-based methods, which is especially important because once an infection has been established, no therapeutic interventions are available to lessen the risk of the development of the haemolytic uraemic syndrome. This Review takes into account the evolution and geographical distibution of E coli O157 (and its close pathogenic relatives); the many and varied routes of transmission from its major natural hosts, ruminant farm animals; and other aspects of its epidemiology, its virulence factors, the diagnosis and management of infection and their complications, the repercussions of infection including costs, and prevention. PMID- 20971367 TI - The patient has the diagnosis. PMID- 20971368 TI - Tips from a surgical educator. PMID- 20971369 TI - Base-of-skull/infratemporal fossa shell fragment retrieval. AB - PURPOSE: Shell fragments and bullets are frequently observed to have settled in the skull base and infratemporal fossa (ITF) with the impact resulting in a new surgically complicated trauma. This compact region is one of the most difficult and dangerous locations for lodged objects. When called upon to retrieve these objects, the surgeon faces a complicated challenge. The complexity of the task depends on many factors, such as size, deformation, and surface hooks, as well as identification of the precise anatomic location. MATERIALS AND METHODS: New surgical approaches and successful methods of treatment are presented. The practicability of correctly determining the location of the foreign body is also described. These methods are based on safe and successful practices used in the retrieval of 212 shell fragments from the ITF. RESULTS: In this study, 79% of the ITF fragments and bullets were retrieved by the transoral ITF method. The remaining 21% were removed via the facial path of missile entrance and a transantral approach. CONCLUSION: This article describes feasible, sensible, time saving practices resulting in lower surgical morbidity in one of the most challenging regions from which to extract lodged missiles. Osseous landmarks are used for proper localization of trajectories in the ITF by use of posteroanterior and true lateral skull radiographs, which assist in locating metal fragments. The intraoral approach, which is successfully used as a short pathway with minimal tissue damage, may encourage surgeons not to leave fragments unattended. PMID- 20971370 TI - A minipig model of maxillary distraction osteogenesis. AB - PURPOSE: To establish a porcine model for maxillary distraction osteogenesis and to document the sequence of bone formation in the zone of advancement. MATERIALS AND METHODS: Female Yucatan minipigs (n = 9) in the mixed dentition stage underwent modified Le Fort I osteotomy through a vestibular incision under general anesthesia. A unidirectional, semiburied Le Fort I distraction device was fixed across the osteotomy. The distraction protocol was 0-day latency, 1-mm/d rate for 12 days, and 24 days of fixation. Maxillary specimens (n = 9) were harvested and divided in half at the end of distraction (n = 6 sides), midfixation (n = 6), and the end of fixation (n = 6). Clinical stability, volume, and radiographic density across the zone of advancement were graded on semiquantitative scales. Specimens were stained with hematoxylin and eosin and examined with light microscopy. RESULTS: Animals tolerated the operation, the distraction and fixation periods. There were no infections and no devices failed. At the end of the distraction period, bone trabeculae were present at the periphery and fibrous tissues, and vessels, preosteoblasts, and osteoblasts were present in the center of the zone of advancement. Islands of chondrocyte-like cells appeared in 1 specimen each at midfixation and the end of fixation. At the end of fixation, clinical stability and radiographic density were graded 3/3 and bone formation was complete across the advancement zone in all specimens. CONCLUSION: A model for Le Fort I distraction osteogenesis was established. Intramembranous bone formation was the predominant mechanism of healing in the zone of advancement. Latency was not necessary for bone formation in this minipig model. PMID- 20971371 TI - Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism. AB - PURPOSE: Osteonecrosis of the jaw has been reported in patients receiving high doses of intravenous nitrogen-containing bisphosphonates (N-BPs) because of malignant disease. The exact pathomechanisms have been elusive and questions of paramount importance remain unanswered. Recent studies have indicated toxic effects of bisphosphonates on different cell types, apart from osteoclast inhibition. Multipotent stem cells play an important role in the processes of wound healing and bone regeneration, which seem to be especially impaired in the jaws of patients receiving high doses of N-BPs. Therefore, the aim of the present study was to investigate the effects of different bisphosphonate derivatives and dose levels combined with varying pH levels on the mesenchymal stem cells in vitro. MATERIALS AND METHODS: The effect of 2 N-BPs (zoledronate and ibandronate) and 1 non-N-BP (clodronate) on immortalized mesenchymal stem cells was tested at different concentrations, reflecting 1, 3, and 6 months and 1, 3, 5, and 10 years of exposure to standard oncology doses of the 2 N-BPs and equimolar concentrations of clodronate at different pH values (7.4, 7.0, 6.7, and 6.3). Cell viability and activity were analyzed using a WST assay. Cell motility was investigated using scratch wound assays and visualized using time-lapse microscopy. RESULTS: Both types of bisphosphonates revealed remarkable differences. Zoledronate and ibandronate showed a dose- and pH-dependent cellular toxicity. Increasing concentrations of both N-BPs and an acidic milieu led to a significant decrease in cell viability and activity (P < .01), with more pronounced effects for zoledronate. Equimolar concentrations of clodronate did not affect the cell survival or activity significantly, apart from the effect of pH reduction itself, which was also detectable in the patients in the control group who did not receive bisphosphonates. CONCLUSIONS: Our results have shown that high concentrations of N-BPs and a local acidic milieu, which is commonly present in infections of the jaw, might play a key role in the pathogenesis of osteonecrosis of the jaw in patients receiving high doses of N-BPs for malignant diseases. Also the potency of N-BPs might be different, suggesting a greater risk of osteonecrosis of the jaw with zoledronate. PMID- 20971372 TI - Maxillary sinus augmentation following removal of a maxillary sinus pseudocyst after a shortened healing period. AB - PURPOSE: Dome-shaped radiopacities on the floor of the maxillary sinus are commonly interpreted as a sinus cyst on radiographs during dental implant planning. They might present an obstacle in sinus grafting, leading to bone graft failure or implant loss later. The therapeutic approaches to the removal of such cystic lesions and the following sinus augmentation are still controversial. The purpose of this article is to present a modified technique that can be used for predictable removal of a maxillary sinus cyst and sinus augmentation after a shortened healing period in patients with maxillary sinus pseudocysts. MATERIALS AND METHODS: A total of 11 patients with a mean age of 43.7 years with a radiographic dome-shaped opacity in the posterior maxilla sinus were included in this study. A lateral sinus window (with a diameter of about 5 mm) was prepared, and removal of the cyst was performed with grasping forceps. Three months after removal of the cyst, a conventional sinus augmentation with xenogeneic material was undertaken. Dental implants were placed 6 months later. Panoramic radiography and coronal/axial computed tomography were performed to diagnose the sinus lesion preoperatively and for follow-up. RESULTS: A total of 11 pseudocysts were removed from the sinuses of 11 patients under local anesthesia. Histologic evaluation showed antral pseudocysts in all specimens. A soft tissue scar was evident after 3 months of healing at the time of sinus augmentation. No sinus membrane perforation was seen or occurred during the sinus augmentation. A total of 17 implants were placed and restored prosthetically. No clinical complications were observed. The patients were followed up for a mean of 29.2 months (range, 17-43 months) after prosthetic loading, during which no implants were lost and no recurrence of the antral pseudocyst was observed. CONCLUSION: The described modified surgical technique allows the minimally invasive removal of the antral pseudocyst and histologic verification of the diagnosis without compromising the nasoantral entrance as well as the anatomy of the sinus for future sinus augmentations. It can be performed under local anesthesia without endoscopic equipment while shortening the treatment period. PMID- 20971373 TI - Immediate loading of dental implants in the anterior and posterior mandible: a retrospective study of 120 cases. AB - PURPOSE: The objective of this retrospective study was to evaluate the overall success of immediately loaded implants in the mandible. This report focuses on immediately loaded anterior and posterior mandibular implants. MATERIALS AND METHODS: A total of 979 patients received 2,904 mandibular dental implants placed from January 2007 to December 2008. One hundred sixty-one of the implants were placed anterior to the mental foramen, and 95 were placed posterior to the mental foramen. All immediately loaded implants were torque tested to 35 N-cm. All were provisionally restored the day of insertion. RESULTS: A total of 256 immediately loaded mandibular dental implants were placed in a 2-year period. Of the 256 immediately loaded implants, 252 integrated and were restored and 4 failed. Of the 4 failed implants, 3 were in the anterior mandible and the fourth was in the posterior mandible. All 4 were replaced, integrated, and have been restored. The survival rate for immediately loaded implants in the anterior mandible was 99.4%, and the survival rate in the posterior mandible was 97%. CONCLUSION: Immediately loaded implants have predictable clinical success in the anterior and posterior mandible. PMID- 20971374 TI - Planning implants crown down--a systematic quality control for proof of concept. AB - PURPOSE: We evaluated an innovative approach for conventional surgical or transmucosal implantation applying backward planning with bone oriented crown down implant positions, followed by immediate restoration. MATERIALS AND METHODS: Our workflow combined computer-assisted preoperative planning with the well-known intraoperative handling of surgical templates. To guarantee optimal accuracy, the complete process was bone borne, not soft tissue borne. Furthermore, in this concept, the definite prosthesis was manufactured on a plaster cast and fixed with technical implants inserted into the model using the same drilling template applied for intraoperative guidance of the drill. This bone-based workflow avoids the accumulation of errors throughout all steps of the treatment. In the present study, we have provided a concise quantitative quality control using 4 in vivo implants. This goal was accomplished by image matching of the preoperative plan with the corresponding postoperative computed tomography scan, applying descriptive statistics, the 1-sample t test, and the Student t test. RESULTS: Statistical evaluation showed that the bone-borne drilling template provides sufficient accuracy for immediate restoration with the definite prosthesis at the end of the operation. Deviation in the apex plane was 0.8 +/- 0.42 mm, with 0.33 at the maximum. The angular deviation was 3.18 degrees +/- 0.78 degrees . CONCLUSIONS: Our workflow is a promising approach with respect to handling, accuracy, and intraoperative safety. PMID- 20971375 TI - Trigeminocardiac reflex: potential risk factor for syncope in exodontia? PMID- 20971378 TI - Trigeminal cardiac reflex: another all-or-none law? PMID- 20971379 TI - Is the midline buccal incision important for the outcome of surgically assisted rapid maxillary expansion? PMID- 20971380 TI - Does staged removal of lower third molars pose unnecessary re-operations to patients? PMID- 20971383 TI - Single degree and dual degree: we are all oral and maxillofacial surgeons. PMID- 20971385 TI - Diabetes glycemic control and periodontitis: underappreciated role of surgery. PMID- 20971386 TI - Clinical application of split skin graft from scar tissue for plastic reconstruction in post-extensive burn patients. AB - We evaluated the use of autologous split-thickness skin taken from scars on the backs of patients with extensive burns, without sufficient normal donor skin. Between 1998 and 2008, a total of 15 patients underwent 47 operations using split thickness skin grafts from scar tissue. Split-thickness skin was harvested from scars on the patient's back. In each operation, two thirds of donor skin was used at the recipient site and the remaining part was used to cover the donor site. All skin grafts survived. The skin function and appearance at the reconstruction site was improved in all cases, and reconstruction had therapeutic effects similar to those achieved by graft procedures using normal autologous split skin. Moreover, 6 months later, the skin graft procedure could be repeated at the donor site. Therefore, we concluded that split-thickness skin from scars on patients' backs is a valuable source of skin graft material that can be used repeatedly for plastic reconstruction in extensively burned patients. PMID- 20971387 TI - Orthopedic emergencies. Foreword. PMID- 20971388 TI - Orthopedic emergencies. Preface. PMID- 20971389 TI - Evaluation and management of acute cervical spine trauma. AB - The evaluation and management of cervical spine injuries is a core component of the practice of emergency medicine. This article focuses on evaluation and management of blunt cervical spine trauma by the emergency physician. Pertinent anatomy of the cervical spine and specific cervical spine fractures are discussed, with an emphasis on unstable injuries and associated spinal cord pathology. The association of vertebral artery injury with cervical spine fracture is addressed, followed by a review of the most recent literature on prehospital care. Initial considerations in the emergency department, including cervical spine stabilization and airway management, are reviewed. The most current recommendations for cervical spine imaging with regard to indications and modalities are covered. Finally, emergency department management and disposition of patients with spinal cord injuries are reviewed. PMID- 20971390 TI - Emergent evaluation of injuries to the shoulder, clavicle, and humerus. AB - This article provides a review of the evaluation and treatment of common injuries to the shoulder, humerus, and clavicle in the emergency department (ED) setting. In addition to a focused review of the shoulder's physical examination, topics include common emergent injuries such as glenohumeral dislocations, proximal humerus fractures, and acromioclavicular separations as well as less common, but important injuries including pectoralis and biceps tendon injuries and sternoclavicular dislocations. Accurate recognition and management of these injuries is essential in the optimal care of patients in the ED. PMID- 20971391 TI - Management and treatment of elbow and forearm injuries. AB - Orthopedic injuries to the upper extremity are frequently seen in the emergency department (ED). The emergency medicine practitioner must be proficient in recognizing these injuries and their associated complications, and be able to provide appropriate orthopedic management. This article highlights the most frequent forearm and elbow injuries seen in the ED. PMID- 20971392 TI - The emergent evaluation and treatment of hand and wrist injuries. AB - The anatomy of the hand is complex, which allows for the dexterity, strength, and adaptability of the most functional aspect of the musculoskeletal system. The evaluation and management of injuries to this area can be time consuming and pose a significant medicolegal risk to the emergency physician. Improperly diagnosed and managed injuries can lead to chronic pain, inability to perform activities of daily living, and even seemingly minor injuries can lead to missed work causing a significant cost to the individual and society. The purpose of this article is to review injuries to the hand and wrist and discuss diagnostic studies and treatment plans that the emergency physician can use to treat patients effectively and minimize their exposure to risk. PMID- 20971393 TI - The emergency department evaluation, management, and treatment of back pain. AB - Back pain is one of the most common symptom-related complaints for visits to primary care physicians and is the most common musculoskeletal complaint that results in visits to the emergency department (ED). With recent national health care initiatives moving toward universal coverage, an increasing number of patients with common complaints such as back pain will visit the ED. The first goal of ED assessment of patients with back pain is to evaluate for potentially dangerous causes that, if not promptly recognized, could result in significant morbidity and mortality. This article focuses on the essential elements of an efficient and effective evaluation, management and treatment of patients with back pain in the ED, with special emphasis on epidural abscess, epidural compression syndrome, malignancy, spinal stenosis, and back pain in children. PMID- 20971394 TI - Management and treatment of pelvic and hip injuries. AB - The management of pelvic fractures and hip injuries requires a multidisciplinary approach and begins in the prehospital setting. With the current advances in various investigative modalities along with the use of algorithms, the morbidity and mortality from these injuries has improved. This review discusses an outline of the current recommendations along with treatment strategies and options in the emergency department, which may vary from institution to institution based on the availability of expertise and resources and because no two trauma patients are alike with regard to the pathophysiology and injury patterns. PMID- 20971395 TI - Knee and leg injuries. AB - The knee plays a significant role in ambulation and the activities of daily living. During the course of these activities and its role in weight bearing, the knee is susceptible to a variety of different forces and the emergency physician should be familiar with the diagnosis and treatment of the injuries that result. In addition to following basic trauma protocols, thorough neurovascular and musculoskeletal examinations should be performed and supplemented with appropriate imaging. Emergency physicians should also consider recent developments in knee anatomy and function when evaluating the patient with an acutely injured knee. PMID- 20971396 TI - Leg, ankle, and foot injuries. AB - The emergency provider (EP) must be aware of the anatomy of the leg, ankle, and foot. The varied presentation of common injuries must be recognized as well as the unique presentations of uncommon injuries. The astute EP must rely on a focused history and a precise examination to avoid the pitfalls and missed injuries from an over-reliance on radiographic studies. In some cases, emergent orthopedic consultation is required. Potential complications associated with these injuries must be anticipated and avoided if possible. PMID- 20971397 TI - Pediatric orthopedic emergencies. AB - Many well seasoned emergency physicians often find it challenging to assess and treat pediatric patients regardless of the complaint. Because of anatomic and physiologic differences, pediatric patients experience orthopedic injuries that are both unique and specific to this subset of the population. Emergency physicians must be aware of these nuances to properly diagnose and treat these injuries. An understanding of fractures unique to growing bone, such as buckle/torus and greenstick types, will provoke clinicians to have a keener eye when reviewing pediatric radiographs. The Salter-Harris classification provides a proven, generally accepted stratification of injury to describe and properly disposition pediatric fractures. Emergency physicians must also recognize a distal radial fracture, because it is the most common pediatric fracture, and the many complications of the supracondylar fracture. Nursemaid's elbow and ankle injuries are further common presenting complaints that are discussed. Recognition of child abuse and the work-up of the child presenting with a limp are additional areas that the Emergency physician should feel comfortable evaluating. PMID- 20971399 TI - Essential concepts of wound management. AB - The practice of wound care has greatly improved and evolved over the years. The emergency provider (EP) can choose from a wide variety of sutures, adhesives, strips, and surgical staples, and uses proven wound closure techniques to address this common Emergency Department (ED) patient complaint. All EPs should be comfortable and proficient in the management and care of wounds in the ED. Because wound care is responsible for a large number of malpractice claims, EPs need to be aware of practices that can limit bad outcomes and thus decrease their liability risk. EPs should follow a standard examination and ensure that there is no damage to underlying structures (ie, nerves, tendons, and vasculature), and that foreign bodies are meticulously looked for and removed if found. Discharge instructions that alert the patient on warning signs of infection, and having all patients return within 48hours for a wound check are 2 ways to optimize patients' outcomes. PMID- 20971400 TI - Risk management and avoiding legal pitfalls in the emergency treatment of high risk orthopedic injuries. AB - Avoiding legal pitfalls of orthopedic injuries in the emergency department (ED) requires an understanding of certain high-risk injuries, their presentation, evaluation, and disposition. Various pitfalls pertaining to both upper and lower extremity injuries are discussed in detail, with recommendations regarding the history, physical examination, and radiographic techniques that minimize the risk inherent in these injuries. When approaching these injuries in the ED, a high level of suspicion coupled with appropriate evaluation and management will allow the practitioner to avoid mismanagement of these potential pitfall cases. PMID- 20971398 TI - Emergency orthogeriatrics: concepts and therapeutic alternatives. AB - Multidisciplinary orthogeriatric care can enhance prompt ED diagnosis, optimal pre- and postoperative care, and functional recovery in older adults with bony injuries. Emergency care providers should be cognizant of prevalent geriatric syndromes including delirium and standing level falls to minimize fracture related morbidity. Recognizing the implications of aging physiology, acute care physicians should be aware of effective alternatives to analgesia, procedural sedation, and definitive imaging to promote early surgical management and postoperative recovery. PMID- 20971401 TI - Seminars in Oncology Nursing. Introduction. PMID- 20971402 TI - Pediatric palliative care in childhood cancer nursing: from diagnosis to cure or end of life. AB - OBJECTIVES: To describe selected components of pediatric palliative care from diagnosis to cure or end of life that combine to help nurses and other clinicians achieve goals of care for children with cancer and their families. DATA SOURCES: Published articles. CONCLUSION: Pediatric palliative care is characterized by diversity of care delivery models; effect of cancer on the family as the central focus of care; and consideration of culture, spirituality, communication, and ethical standards. End-of-life issues that can be anticipated by nurses and other clinicians include symptoms of cancer or its treatment, the importance of hopefulness, the relevance of trying to be a good parent in decision making, the meaning of legacy making of ill children, and family bereavement. IMPLICATIONS FOR NURSING PRACTICE: Direct nursing care strategies to achieve pediatric palliative care goals are vital to reduce child and family suffering from cancer. PMID- 20971403 TI - Palliative care for adults across the cancer trajectory: from diagnosis to end of life. AB - OBJECTIVES: To provide an overview of palliative care across the cancer trajectory from diagnosis through treatment, the chronic phase, and end of life. DATA SOURCES: Journal articles, research reports, state of the science papers, and clinical practice experience and guidelines. CONCLUSION: Symptoms occur throughout the cancer trajectory but are more common during active treatment and at the end of life. Symptom assessment facilitates optimal management of symptoms, promotion of comfort, and improvement in quality of life. IMPLICATIONS FOR NURSING PRACTICE: Clinicians have a responsibility to anticipate and assess symptoms throughout the illness trajectory. Identification of symptoms should prompt a plan of care that is based on evidence-based guidelines and best practices. PMID- 20971404 TI - Meeting survivors' unmet needs: an integrated framework for survivor and palliative care. AB - OBJECTIVES: To propose an integrated framework for survivorship care and palliative care, explore application of this framework in cancer patients, and identify research opportunities to expand the evidence base for practice. DATA SOURCES: Peer-reviewed literature, online documents from the National Quality Forum and National Consensus Project for Quality Palliative Care, and reports from the Centers for Disease Control and the Institute of Medicine. CONCLUSION: The interface between palliative care domains and survivorship care results in prioritizing needs and coordination of care along the cancer trajectory. IMPLICATIONS FOR NURSING PRACTICE: Principles of the proposed model may be incorporated into survivorship care plans and assist with multidisciplinary care of these complex patients. PMID- 20971405 TI - Understanding the experience of caregivers: a focus on transitions. AB - OBJECTIVES: To review the current knowledge on the challenges and benefits of informal family caregiving; and propose two conceptual frameworks for studying transitions common to patients with cancer and their family caregivers through the trajectory of the disease process leading to better, more focused, individualized interventions; DATA SOURCES: A review of current and classic literature on patients with cancer and their caregivers. CONCLUSION: Caregivers often take on burdens that they are not prepared for. As they become overwhelmed with the work, they often neglect themselves, leading to physical and emotional illnesses. Not all caregivers perceive the same amount of burden. Careful assessment of each caregiver/cared-for dyad to individualize their support is critical to supporting them along the journey of a cancer diagnosis. IMPLICATIONS FOR NURSING PRACTICE: Operationalizing conceptual frameworks can accelerate nurses' understanding of patient and caregiver transitions, leading to more focused interventions and allocation of resources to assist them in these transitions. PMID- 20971406 TI - The preparation of oncology nurses in palliative care. AB - OBJECTIVES: To address the opportunities for oncology nurses to prepare for and provide palliative care support to cancer patients and families. DATA SOURCES: A review of the literature as well as synthesis of the experiences of the End-of Life Nursing Education Consortium over the past 10 years (2000-2010) were considered in summarizing implications for palliative care education in oncology. CONCLUSION: Cancer patients and their families across the cancer trajectory experience serious physical and psychosocial symptoms and spiritual concerns. Oncology nurses have contributed to the evolving field of palliative care, and the continued education of oncology nurses in this specialty is essential to quality care for patients and families IMPLICATIONS FOR NURSING PRACTICE: The need for palliative care in oncology will intensify in the future, and effective strategies for education are necessary to prepare the nursing workforce for the effective and compassionate care that patients and families deserve. PMID- 20971408 TI - Autism on the web: "oh, the places you'll go!". PMID- 20971407 TI - Developing successful models of cancer palliative care services. AB - OBJECTIVES: This article describes successful institutionally based programs for providing high-quality palliative care to persons with cancer and their family members. Challenges and opportunities for program development are also described. DATA SOURCES: Published literature from 2000 to present describing concurrent oncology palliative care clinical trials, standards, and guidelines were reviewed. CONCLUSION: Clinical trials have shown feasibility and positive outcomes and formed the basis for consensus guidelines that support concurrent oncology palliative care models. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses should advocate for all patients with advanced cancer and their families to have access to concurrent oncology palliative care from the time of diagnosis with a life-limiting cancer. PMID- 20971409 TI - A look back at research synthesis. PMID- 20971410 TI - Child sexual abuse: consequences and implications. AB - Sexual abuse is a problem of epidemic proportions in the United States. Given the sheer numbers of sexually abused children, it is vital for pediatric nurse practitioners to understand both short-term and long-term consequences of sexual abuse. Understanding consequences of sexual abuse can assist the pediatric nurse practitioner in anticipating the physical and mental health needs of patients and also may assist in the identification of sexual abuse victims. Sexual abuse typically does not occur in isolation. Implications for practice will be discussed. PMID- 20971412 TI - Recognizing and diagnosing abdominal migraines. AB - Abdominal migraine affects 1% to 4% of children and is a variant of migraine headaches. Onset is seen most often between the ages of 7 to 12 years, with girls affected more often than boys. Presenting symptoms include acute incapacitating non-colicky periumbilical abdominal pain that lasts for 1 or more hours. Pallor, anorexia, nausea, vomiting, photophobia, or headache may be associated with the episodes, and a family history of migraine headaches often is noted. The diagnostic process begins with a thorough history and physical examination and often follows a series of exclusions or elimination of other organic causes. Limited research exists regarding treatment options, but they may include pharmacologic intervention and prevention based on lifestyle modifications. PMID- 20971411 TI - Survey of insulin site rotation in youth with type 1 diabetes mellitus. AB - OBJECTIVE: Injection site rotation is an important component of insulin administration and is helpful in preventing lipodystrophy in type 1 diabetes (T1DM). We examined the number of injection/infusion sites (sites) used by youth with T1DM and their perceived barriers to using new sites for insulin. METHODS: Two hundred and one youth with T1DM completed a 24-item survey about site rotation practices and barriers to site rotation during a routine diabetes appointment. RESULTS: Fifteen percent of youth reported using at least four distinct sites in their rotation plan, while 22% reported using only one site. A negative correlation was found between number of sites used and the number of perceived barriers endorsed by youth on multiple daily injections. Fear of pain was the most common barrier endorsed by youth. CONCLUSION: Many youth with T1DM may not adhere to an adequate site rotation plan. Regular assessment of insulin sites and counseling regarding adequate site rotation is needed when managing diabetes in youth. Relaxation and distraction may help to reduce youths' fear of pain when rotating to new insulin sites. PMID- 20971413 TI - Mothers with positive or negative depression screens evaluate a maternal resource guide. AB - INTRODUCTION: Social isolation is common in mothers with high depressive symptoms. This study tested the hypothesis that a maternal resource guide that provided mothers with links to community human service agencies would be deemed more helpful by mothers with positive depression screens (PDS) compared with mothers with negative depression screens (NDS). METHOD: This investigation was a cross-sectional survey study of a convenience sample from a primary care practice based research network, the Southwestern Ohio Ambulatory Research Network (SOAR Net). English-speaking mothers who took their child(ren) to SOAR-Net practices were eligible to participate in the study. Data were collected between May 2006 and March 2009. A total of 1048 mothers completed the survey, and 234 mothers refused to participate. RESULTS: Mothers were more likely to report that "This guide is helpful to me" if they were single (odds ratio [OR] = 4.05; 95% confidence interval [CI]: 2.77-5.94), their child had public health insurance (OR = 3.59; 95% CI: 2.39-5.40), or they had PDS (OR = 3.57; 95% CI: 2.13-5.98). After adjusting for a number of demographic variables, PDS continued to be significantly associated with "This guide is helpful to me" (adjusted OR = 2.68; 95% CI: 1.58-4.56). DISCUSSION: Mothers with PDS were more likely to report that the maternal resource guide would be personally helpful compared with mothers with NDS. PMID- 20971414 TI - Constipation in the pediatric patient: an overview and pharmacologic considerations. PMID- 20971415 TI - Uveitis presenting with decreased vision and leukocoria. PMID- 20971416 TI - Rickets: a preventable growth delay. PMID- 20971417 TI - Family-centered health care/medical home: APN roles in shaping new care models. PMID- 20971418 TI - Our small world; there's so much that we share. PMID- 20971419 TI - The reliability of one vs. three trials of pain-free grip strength in subjects with rheumatoid arthritis. AB - STUDY DESIGN: Measurement Reliability. The purpose of the study was to evaluate the test-retest reliability of one vs. the mean of three trials of pain-free grip strength in participants with rheumatoid arthritis (RA). The study used was a repeated-measures, crossover design. Pain-free grip strength was measured with the Biometric E-Link Evaluation System V900S (Unit 25, Nine Mile Point Ind. Est., Gwent UK NP11 7HZ), pain levels recorded before and after grip tests with visual analog scale. High levels of test-retest reliability (intraclass correlation coefficient>=0.91) were found for both one trial and the mean of three trials of pain-free grip strength testing. Median values of grip strength for both methods produced comparable results. Clinically small but statistically significant increases in pain (p<=0.01) were found. One trial of pain-free grip strength is reliable and may save valuable clinical time while reducing the assessment burden placed on patients with RA. LEVEL OF EVIDENCE: N/A. PMID- 20971420 TI - Reflections on mobilizing the stiff hand. PMID- 20971421 TI - Evidence-based quality of care. PMID- 20971422 TI - Application of Rasch analysis in health care is increasing and is applied for variable reasons in mobility instruments. AB - OBJECTIVE: To identify the frequency of Rasch analysis use in health instrument development or refinement and the characteristics of Rasch application in mobility scales. STUDY DESIGN AND SETTING: The entire databases of Medline, CINAHL, PEDro, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews were searched until January 2009. Articles that reported the development or refinement of health instruments using Rasch analysis were included. Of the 234 articles that met inclusion, 10 were categorized as "mobility" instruments. Data were extracted relating to each instrument and the use of Rasch analysis in the development or refinement of the instruments. RESULTS: The number of articles reporting the use of Rasch analysis of health instruments is increasing, from 1 article in 1987 to 48 articles in 2007. Of the 10 mobility instruments examined, the primary reason Rasch was used varied. Reasons included assessing instrument unidimensionality, differential item functioning, rating categories, item hierarchy, and redundant items. CONCLUSION: The application of Rasch analysis in health instrument development has markedly increased in recent years. However, few mobility instruments have been developed or refined using Rasch analysis. The reasons that the Rasch model was used varied across mobility instruments. PMID- 20971423 TI - How to review a manuscript. PMID- 20971424 TI - Atavisms. PMID- 20971425 TI - Infant cognition. PMID- 20971426 TI - Multicellular development in a choanoflagellate. PMID- 20971427 TI - Stable inheritance of an acquired behavior in Caenorhabditis elegans. PMID- 20971428 TI - Chromosome segregation: taking the passenger seat. AB - The chromosomal passenger complex (CPC) is a major regulator of mitotic and meiotic chromosome segregation. Three recent papers now elucidate the mechanisms that determine the localization of the CPC to the inner centromere. PMID- 20971429 TI - Decision neuroscience: choices of description and of experience. AB - A new study suggests that individuals differentially recruit neural regions associated with decision making, depending on whether the information about the options are learned through experience or merely described. PMID- 20971430 TI - Developmental biology: a DOR connecting growth and clocks. AB - DOR, a nuclear receptor co-activator conserved from flies to humans, provides a molecular connection between ecdysone and insulin signaling, two important pathways controlling developmental timing and growth, respectively. PMID- 20971431 TI - Gene regulation: the cohesin ring connects developmental highways. AB - How does cohesin regulate gene expression and development independently of its roles in sister chromatid cohesion and chromosome segregation? Recent studies show that cohesin, through multiple mechanisms, directly controls transcription of genes that regulate morphogenesis, differentiation, cell proliferation and pluripotency. PMID- 20971432 TI - Calcium signalling: fishing out molecules of mitochondrial calcium transport. AB - Cellular energy metabolism, survival and death are controlled by mitochondrial calcium signals originating in the cytoplasm. Now, RNAi studies link three proteins - MICU1, NCLX and LETM1 - to the previously unknown molecular mechanism of mitochondrial calcium transport. PMID- 20971433 TI - Chemosensory ecology: deceiving Drosophila. AB - The Solomon's lily arum mimics the odours of yeast to attract drosophilid flies as unrewarded pollinators. PMID- 20971434 TI - Sensory ecology: night lights alter reproductive behavior of blue tits. AB - Research on songbirds indicates that streetlights influence timing of dawn chorus, egg-laying and male success in siring extra-pair young, providing new evidence that artificial lighting is an ecologically disruptive force. PMID- 20971435 TI - Actin crosslinkers: repairing the sense of touch. AB - Cells use actin bundles infused with myosin to exert contractile forces on the extracellular environment. This active tension is essential for cellular mechanosensation. Now, the role of actin crosslinkers in stabilizing and repairing the actin bundles is coming into clearer view. PMID- 20971436 TI - Optogenetic approaches in neuroscience. AB - The recently introduced term 'optogenetics' describes a variety of techniques for expressing genes in nerve cells that render them responsive to light. This approach makes use of light-sensitive channel proteins that can be used to manipulate neuronal function. Using genetic strategies, these channel proteins can be expressed in neurons defined by a common genetic identity, which can then be selectively activated or silenced through illumination. In this minireview, we shall describe the basic principles of such manipulative optogenetic approaches in neuroscience and summarize how these tools are being exploited to investigate neuronal circuits and behavior. PMID- 20971437 TI - Looking the other way: preventing vector-borne disease among travelers to the United States. AB - Millions of travelers visit the United States every year during warm months when risk of vector-borne disease is highest. The epidemiology and geographic distribution of the principal vector-borne diseases in the United States are reviewed and recommendations for visitors to reduce their risk of disease are described. Travel advice should focus on preventing Lyme disease, anaplasmosis and babesiosis in the northeast and north central States, West Nile virus disease in western plains States, and Rocky Mountain spotted fever and tularemia in the southeast; other diseases and itineraries requiring particular attention are described. All travelers to the United States should be advised to practice personal protection against arthropod bites, including appropriate use of insect repellents, especially when visiting rural and suburban areas during the warm months. PMID- 20971438 TI - Quality of malaria information provided on Internet travel operator websites. AB - BACKGROUND: Over the past 20 years, there has been a steady growth in the number of reported cases of malaria in the UK. With increasing Internet flight sales over recent years, online travel operator websites may be the only place many travellers could conceivably receive pre-travel malaria prevention advice. METHODS: 29 Travel operator websites which allow for online flight purchases to malarious areas from the UK, identified using a Google((r)) web search and the website of the International Air Transport Association, were assessed for the existence, accuracy and accessibility of malaria prevention advice available through internal and external website links. RESULTS: Eight (28%) websites provided malaria prevention information on their own pages. Five (17%) websites contained country specific malaria information relevant to the requested destination, including variation of malaria risk within that country and accurate destination specific chemoprophylaxis advice. No malaria information was available, either on internal or external links, on 8 (28%) websites. On average, it took 2.4 additional mouse clicks to access malaria information during the online flight booking process. Six of the 29 websites (21%) allowed for access to information with only 1 click. CONCLUSIONS: Malaria prevention information on online travel operator websites is most often absent or inadequate. Even on websites where such information is of good quality, it can be difficult to access. The travel industry should introduce and enforce guidelines for the malaria information provided by online travel operators. PMID- 20971439 TI - Provision of healthcare in a remote base of operations in southern Chad. AB - The Irish Defence Forces maintained a presence in south eastern Chad under the authority of the United Nations Security Council from January 2008 until May 2010, operating in a peace support role as the lead contingent in a multinational battalion. In September 2009 the task of establishing a forward operating base in a remote location within the area of operations was ordered by mission headquarters. Irish and Finnish troops duly deployed and began the task of establishing a safe and secure base from which to operate. This involved securing the location, installing accommodation, electricity, lighting and facilities for ablutions, removing natural hazards, establishing secure communications and ensuring rapid access and egress in the event of hostile contact or emergency. The incidence of disease at this location was low, with the notable exception of a limited outbreak of gastroenteritis. The high standard of engineering work carried out around the camp, especially the latrines, washing facilities and other hygiene measures, significantly contributed to minimising the transmission of infectious disease. The past experiences of the Defence Forces in Congo, Lebanon, East Timor, Eritrea and Liberia have led to a high standard of forward planning and logistical awareness within the organisation which served personnel well in this latest mission. PMID- 20971440 TI - Prevalence of Toscana virus antibodies in residents of two Ionian islands, Greece. AB - The prevalence of Toscana virus (TOSV) IgG antibodies was determined among 128 residents of two Greek islands in the Ionian Sea, Corfu and Cephalonia. In total, 47.7% of tested persons had TOSV IgG antibodies; 51.7% among residents of Corfu and 39% among residents of Cephalonia. The prevalence was higher among persons older than 60 years, who were living in the coastal areas, while no relation with occupation was observed. The high seroprevalence, combined with the high antibody titers observed, suggest that TOSV, or an antigenically-related virus, circulates or has been circulating extensively in the region. PMID- 20971441 TI - Rapid detection of human Leishmania infantum infection: a comparative field study using the fast agglutination screening test and the direct agglutination test. AB - This study aimed to evaluate the performance of a fast agglutination screening test (FAST) for serodiagnosis of human Leishmania infantum infection in Iran. FAST is based on the direct agglutination test (DAT) but combines with a higher parasite concentration and is performed with only one serum dilution. The validity of FAST for the detection of L. infantum infection in the field was compared with the direct agglutination test on 110 confirmed or patients suspected of infection with leishmaniasis, 177 healthy individuals and 41 patients with other infectious diseases who were from northwestern and southern parts of Iran. In this study, we found a 1:1600 cut-off point empirically by seeking the best correlation (90.8) between sera confirmed with visceral leishmaniasis and healthy control sera. A sensitivity of 95.4% (95% CI, 91.4 99.4) and specificity of 88.5% (95% CI, 84.2-92.8) were found with 1:1600 as a cut-off titer when DAT-confirmed cases were compared with the control groups. A good degree of agreement was found between FAST and DAT (90.8%) by Kappa analysis. FAST requires 2 h for reading the results versus the 12-18 h needed for DAT. As FAST is simple, rapid, sensitive and non-invasive and does not require a higher volume of antigens or much expertise, it can be used for screening and serodiagnosis of human L. infantum infection. PMID- 20971442 TI - First aid kits for recreational dive boats, what should they contain? AB - BACKGROUND: Well-equipped first-aid kits are necessary but not always provided on recreational dive boats. We aimed to review the types of illness and injury likely to be encountered on such boats and inform a content list for such kits. METHOD: We conducted a 3-round Delphi study by email using a volunteer panel of 18 experts drawn from diving, dive medicine and nursing. In round 1, panellists shared examples of illnesses and injuries they had come across personally. These scenarios were circulated along with findings from a literature review, including existing recommendations. In rounds 2 and 3, the list of kit for dive boats in different settings was iteratively refined through online discussion and feedback. MAIN FINDINGS: Passengers and crew on recreational dive boats may encounter a range of medical problems from minor injuries to serious accidents and non-dive-related illnesses. Recommended kit varied depending on context and setting (e.g. distance from land, qualifications and experience of crew). Consensus was quickly reached on key first-aid items but experts' views on emergency medicines differed. CONCLUSIONS: The study highlights the diversity of medical problems encountered on recreational dive boats. We offer preliminary guidance on the content of suitable first-aid kits and suggest areas for further research. PMID- 20971443 TI - Mefloquine adverse effects with atypical facial lesions in an overweight patient. AB - BACKGROUND: The recommended dosage of mefloquine to treat Plasmodium falciparum infection is 25 mg/kg, with no recommendation for dosage exceeding 1500 mg. We describe an original case of adverse reaction to mefloquine in an overweight patient. METHOD: Case report. RESULTS: A 32-year-old woman weighing 139 kg presented with uncomplicated P. falciparum infection after returning from Cameroon. She received 3250 mg of mefloquine (i.e. 23 mg/kg) administered in four doses. On day 2, she developed neuropsychiatric disorders and facial lesions. Nasal mucocutaneous vesicles and bullae, depressive mood, mild thrombocytopenia and hepatic cytolysis were evidenced. Parasitemia was negative. Recovery was complete on day 17. High mefloquine serum levels were measured (8.030 mg/L on day 3, 6.880 mg/L on day 8, and 3.370 mg/L on day 17). CONCLUSIONS: The causal relationship between mefloquine and the occurrence of these adverse effects is probable. However, as no viral or bacteriological investigations were performed, the drug responsibility remains uncertain. Mefloquine-induced bullous and facial lesions reversible upon drug withdrawal have already been described. The associated neuropsychiatric symptoms were strongly suggestive of mefloquine adverse effects, as such events are more frequently observed in cases of overdosage. Our case emphasizes the difficulties of dosage adaptation in overweight patients. PMID- 20971444 TI - Cryptococcal retropharyngeal abscess. AB - Cryptococcus neoformans is an opportunistic fungal pathogen that causes a variety of diseases in immunosuppressed patients. We describe a patient with sarcoidosis and odynophagia admitted with a large retropharyngeal abscess. Aspiration showed budding yeast and culture identified C. neoformans, confirmed by D2 large subunit rRNA gene sequencing. PMID- 20971446 TI - [ST-elevation myocardial infarction in octogerians]. AB - Coronary artery disease is the leading cause of death in developed countries and its incidence and severity is greater among older patients. So, because of the ageing of the population, clinicians will be increasingly confronted in daily practice with managing acute coronary syndrome in extreme old age and high-risk patients. Despite this demographic reality, several large randomized controlled trials evaluating the benefit-risk ratio of invasive versus conservative approach have systematically excluded elderly patients. The extrapolation of evidence based medicine, initially focused on younger patients, is often contentious in this population and because of the lack of clear and specific recommendations in the elderly, the optimal management of STEMI in octogenarians remains a topic of debate. Elderly patients present unique issues related to the ageing process and multiple comorbid diseases making difficult the extrapolation of evidence obtained on younger demographics. Data from registries seem to support, nevertheless, the benefit of primary revascularization by PCI of the culprit lesion in "selected" octogenarians with a high technical success rate, few complications, acceptable short and long-term mortality rate and quality of life. Obviously, the "ideal octogenarian" doesn't exist and all the old patients are not suitable for an invasive approach. Managing elderly patients requires not only cardiological skills but also geriatric acknowledges and the individualized geriatric assessment is the corner store of the decision process. The aim is to screen for the presence of comorbidities (cognitive disorders, functional decline, anemia, renal insufficiency...), social isolation and existence of an underlying frailty. To conclude, the optimal strategy for the management of STEMI in octogenarians is not univocal: the best approach is the one that offers the greater benefits regard considerations of general health. PMID- 20971447 TI - Effects of Lactobacillus rhamnosus GG on saliva-derived microcosms. AB - OBJECTIVE: The probiotic strain Lactobacillus rhamnosus GG (LGG) is shown to hamper the presence of mutans streptococci in saliva and may have positive effects on oral health. We investigated the effects of LGG on the cariogenic potential and microbial composition of saliva-derived microcosms. DESIGN: Single and dual species biofilms of LGG and Streptococcus mutans, and saliva-derived microcosms with or without LGG were grown in an Active Attachment Biofilm model. The microcosms were grown on bovine dentin/enamel discs in the presence or absence of sucrose (suc+/suc-). The presence of LGG was determined by multiplex ligation-dependent probe amplification (MLPA) and real-time PCR. Mutans streptococci (MS) and total viable counts, pH of the spent medium, capacity of lactate formation and integrated mineral loss in dentin was assessed. MLPA was used for identification and relative quantification of 20 oral microorganisms in the microcosms. Principal Component Analysis was applied to MLPA data. RESULTS: LGG inhibited the growth of S. mutans in dual species biofilms and did not affect the pH. LGG established in saliva-derived microcosms and reduced MS counts significantly, but did not affect pH or dentin demineralization. Simultaneous growth of the microcosms with LGG under heavy cariogenic conditions (suc+) introduced a compositional shift in the microbial community. The CFU, real-time PCR and MLPA data correlated significantly. CONCLUSION: We conclude that LGG established into and inhibited the growth of MS in complex saliva-derived biofilms, but this had no significant effect on cariogenic potential of the microcosms. This suggests that other microorganisms besides MS were responsible for increased cariogenicity of sucrose-exposed biofilms. PMID- 20971448 TI - Chemical analysis of an immunoenhancing water-soluble polysaccharide of an edible mushroom, Pleurotus florida blue variant. AB - An immunoenhancing polysaccharide isolated from the aqueous extract of the fruit bodies of the mushroom, Pleurotus florida blue variant, was found to consist of d glucose and d-galactose in a molar ratio of nearly 5:1. On the basis of sugar analysis, methylation analysis, periodate oxidation, Smith degradation, and NMR studies ((1)H, (13)C, DEPT-135, DQF-COSY, TOCSY, NOESY, ROESY, HMQC, and HMBC), the structure of the repeating unit of the polysaccharide was established as: >6)-beta-D-Glcp-(1->3)-alpha-D-glcp-(1->[6)-beta-D-Glcp-(1]3-> alpha-D=Glcp. The molecule activated macrophages, splenocytes, and thymocytes. PMID- 20971449 TI - Guest releasing from solution to solid-state triggered by cyclomaltohexaose (alpha-cyclodextrin) aggregation. AB - Supramolecuar aggregations 1 and 2 were prepared by complexing cyclomaltohexaose with two azodipyridine isomers: 4,4'-azodipyridine and 2,2'-azodipyridine, and their binding abilities and assembly behaviors were investigated comprehensively by X-ray crystallography, 2D NMR spectroscopy, and isothermal titration calorimetry. In solution, 1:1 host-guest complexation is generally assumed, whereas in the solid state, a 2:1 stoichiometry is observed. Crystal structures reveal that channel-type aggregation exists in complex 1, while a layer-type manner is the dominant packing mode in complex 2. The disparity of nitrogen atom position leads to the different binding modes and further affects the aggregation types in complexes 1 and 2. PMID- 20971450 TI - The crystal structure of potassium (1S)-D-galactit-1-ylsulfonate. AB - The structure of the crystalline addition product (1) formed between d-galactose and potassium bisulfite (potassium hydrogen sulfite) has been determined by X-ray diffraction analysis and compared with those structures reported for the related addition products from d-glucose and D-mannose. As with the latter two sulfonates, the D-galactose derived compound has an open-chain structure, with the carbon chain adopting a near planar zigzag conformation extending to the sulfur atom, similar to the d-mannose derivative but in contrast to the sickle conformation adopted by the d-glucose derivative. This last compound also differs in crystallising as a monohydrate. Inter-chain linking through cation coordination leads to a three dimensional network in the crystal. PMID- 20971451 TI - Effect of carboxymethylation conditions on the water-binding capacity of chitosan based superabsorbents. AB - A superabsorbent polymer (SAP) from chitosan was provided via carboxymethylation of chitosan, followed by cross-linking with glutaraldehyde and freeze-drying. This work was focused on an investigation of the effects of monochloroacetic acid (MCAA), sodium hydroxide, and reaction time on preparation of carboxymethyl chitosan (CMCS). The CMCS products were characterized using FTIR spectroscopy, and their degrees of substitution (DS) were measured using conductimetry and FTIR analysis. The highest DS value was obtained when the carboxymethylation reaction was carried out using 1.75g MCAA and 1.75g NaOH per g of chitosan in 4h. The water solubilities of the CMCS products at various pHs were also evaluated, and the results indicated a significant impact of the reaction parameters on the solubility of CMCS. The CMCSs with the highest DS value resulted in SAPs having the highest water-binding capacity (WBC). The WBC of the best SAP measured after 10min exposure in distilled water, 0.9% NaCl solution, synthetic urine, and artificial blood was 104, 33, 30, and 57g/g, respectively. The WBC of this SAP at pH 2-9 passed a maximum at pH 6. PMID- 20971452 TI - A new method for quantifying iodine in a starch-iodine matrix. AB - A rapid and sensitive method for quantifying iodine in intact starch granules using gas chromatography is described with detection limits as low as 0.2% (w/w) iodine in starch. Sample preparation includes NaBH(4) reduction of the various iodine species associated with starch to the colorless soluble iodide ion, followed by its quantitative derivatization to EtI using Et(3)O(+)BF4- in CH(2)Cl(2). Identification and quantification of EtI is carried out by extraction and injection of the EtI so generated in CH(2)Cl(2) into a gas chromatography mass spectrometer (GC-MS). Routine quantification of EtI was then performed using GC with a flame ionization detector (GC-FID). Results for different iodine:potassium iodide ratios of the initially bound iodine and for seven different starch matrices showed that in all cases regression coefficients for the standards were high (R(2)>0.96). PMID- 20971453 TI - Immobilization of carbohydrate epitopes for surface plasmon resonance using the Staudinger ligation. AB - The detection of carbohydrate-protein interactions is often performed using techniques that require surface immobilization of the lectin or the glycan. A commonly used assay for lectin binding is surface plasmon resonance (SPR). We describe an implementation of the Staudinger ligation as a method to immobilize carbohydrate epitopes to a biosensor surface. This was accomplished by first introducing an azide functionality to a carboxymethyldextran surface, followed by reaction with a phosphane-modified carbohydrate ligand. The chemistry employed is extremely mild and was easily adapted to a commercial biosensor system. Using this approach, we investigated the binding of jacalin and wheat germ agglutinin (WGA) to galactose, lactose, and N-acetyl-lactosamine. We observed that WGA binding shows evidence of multivalent interaction with the surface. Additionally, we found that jacalin binding was influenced by the presence of a flexible and hydrophobic galactosyl aglycone. PMID- 20971454 TI - Carbohydrate structural analysis of wheat flour arabinogalactan protein. AB - The water-extractable arabinogalactan protein (AGP) was isolated from bread wheat flour (Triticum aestivum L. variety Cadenza) and the structure of the arabinogalactan (AG) carbohydrate component was studied. Oligosaccharides, released by hydrolysis of the AG with a range of AGP-specific enzymes, were characterised by Matrix Assisted Laser Desorption Ionisation (MALDI)-Time of Flight (ToF)-Mass Spectrometry (MS), MALDI-ToF/ToF high energy collision induced dissociation (CID) and Polysaccharide Analysis by Carbohydrate gel Electrophoresis (PACE). The AG is composed of a beta-(1->3)-D-galactan backbone with beta-(1->6)-D-galactan side chains. These side chains are highly variable in length, from one to at least 20 Gal residues and are highly substituted with alpha-L-Araf. Single GlcA residues are also present at the non-reducing termini of some short beta-(1->6)-galactan side chains. In addition, the beta-(1->6) galactan side chains are also substituted with beta-L-Arap. We propose a polysaccharide structure of the wheat flour AGP that is substantially revised from earlier models. PMID- 20971455 TI - Microbial production of N-acetylneuraminic acid by genetically engineered Escherichia coli. AB - Previously, we described the production of N-acetylneuraminic acid (NeuAc) from N acetylglucosamine (GlcNAc) in a system combining recombinant Escherichia coli expressing GlcNAc 2-epimerase (slr1975), E. coli expressing NeuAc synthetase (neuB), and Corynebacterium ammoniagenes. However, this system was unsuitable for large-scale production because of its complexity and low productivity. To overcome these problems, we constructed a recombinant E. coli simultaneously overexpressing slr1975 and neuB. This recombinant E. coli produced 81mM (25g/L) NeuAc in 22h without the addition of C. ammoniagenes cells. For manufacturing on an industrial scale, it is preferable to use unconcentrated culture broth as the source of enzymes, and therefore, a high-density cell culture is required. An acetate-resistant mutant strain of E. coli (HN0074) was selected as the host strain because of its ability to grow to a high cell density. The NeuAc aldolase gene of E. coli HN0074 was disrupted by homologous recombination yielding E. coli N18-14, which cannot degrade NeuAc. After a 22h reaction with 540mM (120g/L) GlcNAc in a 5L jar fermenter, the culture broth of E. coli N18-14 overexpressing slr1975 and neuB contained 172mM (53g/L) NeuAc. PMID- 20971456 TI - The extract of Japanese soybean, Kurosengoku activates the production of IL-12 and IFN-gamma by DC or NK1.1(+) cells in a TLR4- and TLR2-dependent manner. AB - During the search for immuno-improving foods, we found that a variety of the Japanese soybean, Glycine max cv. Kurosengoku (Kurosengoku), which activated Type 1 immunity in a Toll-like receptor (TLR)4- and TLR2-dependent manner. Namely, the extract of Kurosengoku first caused production of IL-12 from DC and sequentially induced IFN-gamma production by NK1.1(+) NK cells and NKT cells. The IFN-gamma production was significantly blocked by neutralizing mAb against IL-12 or TLR4- and TLR2-deficient condition, indicating that TLR4- and TLR2-dependent activation of DC to produce IL-12 was essential for the production of IFN-gamma from spleen cells by Kurosengoku. Moreover, the extract of Kurosengoku also enhanced production of IFN-gamma from human PBMC by co-stimulation with anti-CD3 mAb in a TLR2- and TLR4-dependent manner. Thus, our findings strongly suggest that Kurosengoku might a novel immuno-improving food, which would be a useful tool for preventing the tip of immune balance in developed countries. PMID- 20971457 TI - [Ambulatory treatment of persistent air leaks using a portable chest drainage system: Preliminary results]. AB - INTRODUCTION: Persistent air leaks (PAL) is the most frequent post-operative complication in Thoracic Surgery, leading to a longer hospital stay and an increase in patient morbidity. We present a prospective study conducted in the Dr. Josep Trueta University Hospital in Gerona, involving a portable chest drainage system (PCDS) connected to a pleural drainage which allowed air leaks to be treated ambulatorily. Our aim is to demonstrate that by using this system hospital stay is reduced without increasing post-operative morbidity, and improves the quality of life of the patient. MATERIAL AND METHODS: The Thoracic Surgery Department of Gerona Hospital collected the data on 33 patients with PAL in the post-surgical period and who were treated ambulatorily with a PCDS. Post operative complications were recorded, along with the mean days of ambulatory treatment with the PCDS and the hospital days saved. RESULTS: The mean hospital stay of the 33 patients was 7.03 days. The mean number of days that the 33 patients were treated ambulatorily with the PCDS was 9.33 days. It was calculated that there was a saving of 308 hospital days. The ambulatory treatment of PAL did not increase post-operative morbidity. CONCLUSIONS: The clinical results and the management of the PCDS support the treatment of this problem in patients who do not have any other causes to remain in hospital. The study shows a saving in a considerable number of hospital days stay, with no increase in patient morbidity. All the patients preferred this system to hospital admission. PMID- 20971458 TI - [Influence of pre-surgical chemotherapy on liver parenchyma and post-surgical outcome of patients subjected to hepatectomy due to colorectal carcinoma metastases]. AB - INTRODUCTION: The aim of the study was to evaluate the relationship between the pre-surgical administration of a chemotherapy regime based on irinotecan or oxaliplatin and the development of non-alcoholic fatty liver disease (NAFLD) or sinusoidal obstruction syndrome (SOS), and the influence of these histological changes on the outcome of patients after surgical intervention. PATIENTS AND METHOD: A prospective study which included 45 patients surgically intervened due to colorectal cancer liver metastases between May 2005 and July 2009. Demographic data and the variables before during and after the operation were collected. A specimen of the resection was obtained for histological analysis following the classification parameters of the NAFLD (NASH index) and SOS scale. RESULTS: Neoadjuvant chemotherapy was given before the resection in 22 cases (study group) and 23 patients made up the control group (no chemotherapy). Borderline or diagnostic steatohepatitis was observed in 4 of the 7 patients (57.2%) who were given preoperative irinotecan (P=0.001). Seven of the 15 patients (46.7%) treated with oxaliplatin developed a moderate or severe SOS (P=0.002). There were no differences in morbidity or mortality associated to the NAFLD grade, but there was a higher rate of liver complications and longer mean hospital stay in patients with moderate/severe SOS (P=0.004 and P=0.021, respectively). CONCLUSIONS: Treatment with irinotecan was significantly associated with an increase in the incidence of steatohepatitis, but did not increase the morbidity or mortality. Patients treated with oxaliplatin had a higher incidence of SOS, an increase in liver complications and a longer mean hospital stay. PMID- 20971459 TI - [Adult systemic mastocytosis: a diagnostic challenge]. PMID- 20971460 TI - Gonadal structures in a fetus with complete androgen insensitivity syndrome and persistent Mullerian derivatives: comparison with normal fetal development. AB - OBJECTIVE: To report a case of complete androgen insensitivity syndrome (CAIS) with Mullerian duct persistence. DESIGN: Case report. SETTING: Academic hospital. PATIENT(S): A case of CAIS at 20 weeks' gestational age, and three male and one female 20-week-old fetuses for comparison. INTERVENTION(S): DNA screening for androgen receptor (AR), antimullerian hormone (AMH), and AMH receptor type 2 (AMHR2) gene mutations, and morphologic examination of Wolffian and Mullerian derivatives and immunohistochemistry for AMH, AMHR2, and bone morphogenetic protein receptor type 1A (BMPR1A) in aborted fetuses. MAIN OUTCOME MEASURE(S): Histopathologic, genetic, and immunohistochemical studies. RESULT(S): A novel mutation of AR (D767V) was identified in the index fetus. The CAIS case showed Wolffian duct degeneration, Leydig cell hyperplasia, and normally developed Sertoli cells. No AMH and AMHR2 gene sequence alterations were observed in the CAIS case, and the uterus and vagina were developed to a similar extent as found in the normal female 20-week-old fetus. The CAIS testes expressed more abundant AMH and showed fewer AMHR2-positive peritubular mesenchymal cells than the normal male testes, but BMPR1A stained similarly. CONCLUSION(S): Our study indicates that testes differentiation and development as well as the expression patterns of AMH, AMHR2, and BMPR1A are independent from AR function, at least up to the second trimester. The mechanisms by which the lack of functional androgen interferes with AMH action and Mullerian duct regression remain undefined. PMID- 20971462 TI - Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos. AB - OBJECTIVE: To validate and determine the best array-comparative genomic hybridization (aCGH; array-CGH) protocols for preimplantation genetic screening (PGS). DESIGN: Embryos had one cell removed as a biopsy specimen and analyzed by one of two array-CGH protocols. Abnormal embryos were reanalyzed by fluorescence in situ hybridization (FISH). SETTING: Reference laboratory. PATIENT(S): Patients donating embryos or undergoing PGS. INTERVENTION(S): Embryo biopsy, array-CGH, FISH reanalysis. MAIN OUTCOME MEASURE(S): Diagnosis, no result rate and error rate. RESULT(S): Method one produced 11.2% of embryos with no results and a 9.1% error rate compared with 3% and 1.9% for method two, respectively. Thereafter, only method two was used clinically. The aneuploidy rate for cleavage-stage embryos was 63.2%, significantly increasing with maternal age. The chromosomes most involved in aneuploidy were 16, 22, 21, and 15. We report the first live births after array-CGH combined with single blastomere biopsy. CONCLUSION(S): Array-CGH is proved to be highly robust (2.9% no results) and specific (1.9% error rate) when applied to rapid (24-hour) analysis of single cells biopsied from cleavage-stage embryos. This comprehensive chromosome analysis technique is the first to be validated by reanalyzing the same embryos with another technique (e.g., FISH). Unlike some alternative techniques for comprehensive chromosome screening, array-CGH does not require prior testing of parental DNA and thus advance planning and careful scheduling are unnecessary. PMID- 20971461 TI - Skin wrinkles and rigidity in early postmenopausal women vary by race/ethnicity: baseline characteristics of the skin ancillary study of the KEEPS trial. AB - OBJECTIVE: To characterize skin wrinkles and rigidity in recently menopausal women. DESIGN: Baseline assessment of participants before randomization to study drug. SETTING: Multicenter trial, university medical centers. PATIENT(S): Recently menopausal participants enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). INTERVENTION(S): Skin wrinkles were assessed at 11 locations on the face and neck using the Lemperle wrinkle scale. Skin rigidity was assessed at the forehead and cheek using a durometer. MAIN OUTCOME MEASURE(S): Skin wrinkles and rigidity were compared among race/ethnic groups. Skin wrinkles and rigidity were correlated with age, time since menopause, weight, and body mass index (BMI). RESULT(S): In early menopausal women, wrinkles, but not skin rigidity, vary significantly among races, where black women have the lowest wrinkle scores. In white women, chronological age was significantly correlated with worsening skin wrinkles, but not with rigidity. Skin rigidity correlated with increasing length of time since menopause, however, only in the white subgroup. In the combined study group, increasing weight was associated with less skin wrinkling. CONCLUSION(S): Skin characteristics of recently menopausal women are not well studied. Ethnic differences in skin characteristics are widely accepted, but poorly described. In recently menopausal women not using hormone therapy (HT), significant racial differences in skin wrinkling and rigidity exist. Continued study of the KEEPS population will provide evidence of the effects of HT on the skin aging process in early menopausal women. PMID- 20971463 TI - Use of zona pellucida-bound sperm for intracytoplasmic sperm injection produces higher embryo quality and implantation than conventional intracytoplasmic sperm injection. AB - This goal of this study was to compare the outcomes of conventional intracytoplasmic sperm injection (ICSI; control group, n = 53 couples) and a modified ICSI technique using zona pellucida (ZP)-bound sperm for injection of oocytes (test group, n = 53 couples). The proportion of high-quality embryos (grades 1 and 2) and implantation rate were significantly higher in the test group than in the control group, but the difference in fetal heart pregnancy rate was not significant despite seven more pregnancies being obtained in the test group (26 pregnancies) versus the control group (19 pregnancies) following fresh embryo transfers. PMID- 20971464 TI - Sperm toxicity of "nonspermicidal" lubricant and ultrasound gels used in reproductive medicine. AB - Three commercial, nonspermicidal gels used in fertility practice were found to be toxic to sperm in a 24-hr sperm survival assay; these included Felis, Replens, and Aquasonic Gel, which is used for transvaginal ultrasound during ovulation monitoring. In contrast, Pre-Seed did not cause any sperm toxicity, suggesting its appropriate use by patients who are trying to conceive, as well as clinicians during fertility procedures. PMID- 20971465 TI - The interovarian variation in three-dimensional ultrasound markers of ovarian reserve in women undergoing baseline investigation for subfertility. AB - OBJECTIVE: To evaluate differences in the three-dimensional (3D) ultrasound markers of ovarian reserve between the ovaries within an individual undergoing investigation for subfertility. DESIGN: Prospective observational study. SETTING: University-based assisted conception unit. PATIENT(S): Two hundred seventy women undergoing baseline early follicular phase ultrasound as an investigation for subfertility. INTERVENTION(S): Three-dimensional ultrasound scan in early follicular phase between days 2 and 5 of the menstrual cycle. MAIN OUTCOME MEASURE(S): Variations in 3D ultrasound markers of ovarian reserve between the two ovaries within same individual. RESULT(S): Two hundred fifteen subjects were analyzed for ovarian volume and antral follicle count, and 205 subjects for 3D power Doppler indices. Significant differences were noted (median, range) in the number of antral follicles measuring >6.0 mm and ovarian volume. Significant correlation was noted between the two ovaries in antral follicles measuring 6.0 mm or less, ovarian volume, and 3D power Doppler indices. On stratifying the antral follicles according to size using sonography-based automated volume calculation with postprocessing, maximum variation was seen in follicles measuring more than 6.0 mm as measured using limits of agreement. CONCLUSION(S): There are significant differences in the antral follicles measuring >6.0 mm and ovarian volume, as measured using 3D ultrasound, that require consideration when comparing the two ovaries within an individual. PMID- 20971466 TI - Dental health and lifestyle in four early mediaeval juvenile populations: comparisons between urban and rural individuals, and between coastal and inland settlements. AB - Dental stress markers such as enamel hypoplasia and caries are suitable indicators of population health and lifestyle, although they must be recorded and interpreted carefully. To date, they have been predominantly studied in adult samples, whereas juvenile remains are also affected by these lesions. In this study, dental enamel hypoplasia and caries were both evaluated on 613 non-adult individuals from four early mediaeval Moravian and Frankish skeletal series, who had experienced contrasting environments and lifestyles. The aim of this study is to assess the relationship between these biological traits and living conditions, and how this is manifested in the juvenile dental remains. Significant differences between populations were found in stress markers, dental lesions and the way these were manifested. Exposure to stressful conditions varies between urban and rural populations and is related to age groups. Although the children under investigation seem to have had different diets, it is difficult to distinguish the biological contribution (different enamel susceptibility) from the lifestyle contribution (different food, environment) in the formation of caries. Moreover, such studies must be interpreted carefully due to the possibility of intra- and inter-observer errors and the subjectivity of the scoring techniques. Nevertheless, this study also demonstrates that results of an investigation of juvenile skeletal remains can be as informative as a study of adults and that juvenile skeletons can be included in large bioarchaeological population studies. PMID- 20971468 TI - A gravitational impulse model predicts collision impulse and mechanical work during a step-to-step transition. AB - The simplest walking model, which assumes an instantaneous collision with negligible gravity effect, is limited in its representation of the collision mechanics of human gaits because the actual step-to-step transition occurs over a finite duration of time with finite impulsive ground reaction forces (GRFs) that have the same order of magnitude as the gravitational force. In this study, we propose a new collision model that includes the contribution of the gravitational impulse to the momentum change of the center of mass (COM) during a step-to-step transition. To validate the model, we measured the GRFs of six subjects' over ground walking at five different gait speeds and calculated the collision impulses and mechanical work. The data showed a significant contribution of the gravitational impulse to the momentum change during collision. To compensate for the gravity, the magnitudes of collision impulse and COM work were estimated to be much greater than in previous predictions. Consistent with the model prediction, push-off propulsion fully compensated for the collision loss, implying the step-to-step transition occurred in an energetically optimal manner. The new model predicted a moderate change in the collision mechanics with gait speed, which seems to be physiologically achievable. The gravitational collision model enables us to better understand collision dynamics during a step-to-step transition. PMID- 20971467 TI - Preclinical manifestations of organ damage associated with the metabolic syndrome and its factors in outpatient children. AB - BACKGROUND: To evaluate whether the pediatric metabolic syndrome (MetS) or its factors are useful to detect subclinical abnormalities of cardiac, liver, and glomerular damage in an outpatient population. METHODS: The population study included 799 children (age 10 +/- 3 years, mean +/- SD), 24% of whom were normalweight, 25% overweight, and 51% obese. Alanine-aminotransferase (ALT) levels, estimated glomerular filtration rate (eGFR) and HOMA-IR were analyzed in all children. Microalbuminuria (MA) and left ventricular (LV) geometry and function were evaluated in 501 and 247 children, respectively. MetS was defined using Cook's criteria. RESULTS: MetS was diagnosed in 131 children (16%). Children with MetS+ and MetS- were similar for age, gender and Tanner stage distribution. Children with MetS+ showed higher ALT levels (31 +/- 19 vs 21 +/- 11 IU/L, p<0.0001), LV mass (39 +/- 10 vs 34 +/- 10 g/h(2.7), p<0.001) and relative wall thickness (0.37 +/- 0.06 vs 0.35 +/- 0.05, p<0.01) than MetS-. The two groups were similar for MA and eGFR. At multiple logistic regression analysis, children MetS+ showed a higher risk (OR, 95% Cl) adjusted for confounding factors, of high ALT levels (1.71, 1.12-2.59, p=0.012) and concentric LV hypertrophy (2.17, 1.01-4.66, p=0.047) than children MetS-. The risk of preclinical liver and cardiac damage associated with the MetS phenotype was not higher than predicted by its single components. CONCLUSIONS: Children with MetS show a 2-fold greater risk of having high ALT levels and concentric LV hypertrophy. However, the risk of subclinical manifestations of liver and cardiac damage can be predicted equally well by the single components of the syndrome. PMID- 20971469 TI - Design, optimization and evaluation of specific affinity adsorbent for oligopeptides. AB - A major challenge in the development of affinity adsorbents is the design of specific adsorbents for target molecules. In this paper, a two-step strategy was used to design a specific adsorbent for oligopeptides. Based on the structural characteristics of target peptide DFLAE (DE5), the affinity ligand CDenHis bearing hydrophobic inclusion and electrostatic interaction sites was prepared by grafting histidine onto beta-cyclodextrin (CD) using ethylenediamine; ligands with single hydrophobic inclusion or electrostatic interaction sites (CDen and HisOMe) were used as reference ligands. Results indicated that the binding affinity (K(a)) of CDenHis with DE5 was 6.23*10(4)M(-1), 23- and 61-fold higher than that of CDen and HisOMe, respectively. Computer simulations were used to further optimize the steric configuration of CDenHis. It was found that the optimized ligand CDdnHis exhibited a much improved binding affinity for DE5 (K(a)=1.02*10(5)M(-1)). Moreover, the corresponding adsorbent A-CDdnHis not only showed much better adsorption ability compared with A-CDenHis, but also excellent adsorption specificity for DE5-containing peptides. Kinetic analysis and adsorption mechanism studies suggested that the configuration matching of CDdnHis with DE5 and the cooperation of multiple interactions led to the fast and selective adsorption of DE5-containing peptides to A-CDdnHis. PMID- 20971470 TI - Determination of fungicides in wine by mixed-mode solid phase extraction and liquid chromatography coupled to tandem mass spectrometry. AB - A novel procedure for the determination of nine selected fungicides (metalaxyl-M, azoxystrobin, myclobutanil, flusilazole, penconazole, tebuconazole, propiconazole, diniconazole and difenoconazole) in wine samples is presented. Sample enrichment and purification is simultaneously performed using mixed-mode, anion exchange and reversed-phase, OASIS MAX solid-phase extraction (SPE) cartridges. Analytes were determined by liquid chromatography coupled to tandem mass spectrometry using atmospheric pressure electrospray ionization (LC-ESI MS/MS). Parameters affecting the chromatographic determination and the extraction purification processes were thoroughly investigated. Under optimized conditions, 10 mL of wine were firstly diluted 1:1 with ultrapure water and then passed through the mixed-mode SPE cartridge at a flow of ca. 5 mLmin(-1). After a washing step with 5 mL of an aqueous NH(4)OH solution (5%, w:v), analytes were recovered with just 1 mL of methanol and injected in the LC-MS/MS system without any additional purification. The selective extraction process avoided significant changes in the ionization efficiency for red and white wine extracts in comparison with pure standards in methanol. Performance of the method was good in terms of precision (RSDs<11%) and accuracy (absolute recoveries>72%, determined against pure standards in methanol) reporting method LOQs in the range of 0.01 0.79 ngmL(-1) for target compounds, which are far below the EU maxima residue levels (MRLs) for fungicides in vinification grapes and wine. Several commercial wines from different geographic areas in Spain were analyzed. In most samples, metalaxyl-M and azoxystrobin were found at concentrations up to several ngmL(-1). PMID- 20971471 TI - Connections between structure and performance of four cationic copolymers used as physically adsorbed coatings in capillary electrophoresis. AB - In this work, the properties of four cationic copolymers synthesized in our laboratory are studied as physically adsorbed coatings for capillary electrophoresis (CE). Namely, the four copolymers investigated were poly(N-ethyl morpholine methacrylamide-co-N,N-dimethylacrylamide), poly(N-ethyl pyrrolidine methacrylate-co-N,N-dimethylacrylamide), poly(N-ethyl morpholine methacrylate-co N,N-dimethylacrylamide) and poly(N-ethyl pyrrolidine methacrylamide-co-N,N dimethylacrylamide). Capillaries were easily coated using these four different macromolecules by simply flushing into the tubing an aqueous solution containing the copolymer. The stability and reproducibility of each coating were tested for the same day, different days and different capillaries. It is demonstrated that the use of these coatings in CE can drastically reduce the analysis time, improve the resolution of the separations or enhance the analysis repeatability at very acidic pH values compared to bare silica columns. As an example, the analysis of an organic acids test mixture revealed that the analysis time was reduced more than 6-times whereas the separation efficiency was significantly increased to nearly 10-times attaining values up to 595,000 plates/m using the coated capillaries. Moreover, it was shown that all the copolymers used as coatings for CE allowed the separation of basic proteins by reducing their adsorption onto the capillary wall. Links between their molecular structure, physicochemical properties and their performance as coatings in CE are discussed. PMID- 20971472 TI - Formation of polymeric nano-emulsions by a low-energy method and their use for nanoparticle preparation. AB - Formation of polymeric O/W nano-emulsions has been studied in the water/polyoxyethylene 4 sorbitan monolaurate/ethylcellulose solution system by the phase inversion composition (PIC) method. These nano-emulsions were used for the preparation of nanoparticles by solvent evaporation. Composition variables such as O/S ratio or final water content as well as emulsification path have been found to play a key role in the formation of stable, nanometer sized emulsions. Nano-emulsions with a constant water content of 90 wt.% and O/S ratios from 50/50 to 70/30 showed an average droplet size of about 200 nm as assessed by dynamic light scattering. Mean nanoparticle diameters, as determined by transmission electron microscopy image analysis, were of the order of 50 nm and showed a slight increase as well as a broader size distribution at increasing O/S ratios. The findings verify that the low-energy emulsification methods are not only valid for aliphatic and semipolar oils, but also for a highly polar solvent such as ethylacetate containing a preformed polymer. PMID- 20971473 TI - The effect of n-, s- and t-butanol on the micellization and gelation of Pluronic P123 in aqueous solution. AB - In dilute aqueous solution unimers of copolymer P123 (E(21)P(67)E(21)) associate to form micelles, and in more concentrated solution micelles pack to form high modulus gels. We are interested in the use of the system as a templating agent in the synthesis of mesoporous materials, and the possibility of determining gel structure, hence mesoporosity, by use of n-, s- or t-butanol. Dynamic light scattering from clear dilute solutions has been used to confirm micellization, visual observation of mobility (tube inversion) to detect gel formation in concentrated solutions, oscillatory rheometry to confirm gel formation and provide values of elastic moduli over a wide temperature range, and small-angle X ray scattering to determine gel structure. As expected, clear cubic gels (fcc) formed at moderate concentrations and temperatures, e.g. 30 wt.% P123, 20 degrees C, and clear hexagonal gels at higher concentrations and temperatures. The transition on heating from cubic to hexagonal gel involved an intermediate turbid phase in which cubic and hex structures coexisted. Considering cubic gels of 35 wt.% P123 in 5 wt.% butanol/water, those in n-butanol/water had the lowest critical temperatures for gel formation and the highest maximum values for the dynamic elastic modulus (G') of the gels, a result consistent with n butanol/water being the poorest solvent for P123. PMID- 20971474 TI - Developing connections for affective regulation: age-related changes in emotional brain connectivity. AB - The regulation of affective arousal is a critical aspect of children's social and cognitive development. However, few studies have examined the brain mechanisms involved in the development of this aspect of "hot" executive functioning. This process has been conceptualized as involving prefrontal control of the amygdala. Here, using functional magnetic resonance imaging (fMRI), we investigated the brain mechanisms involved in the development of affective regulation in typically developing 5- to 11-year-olds and an adult comparison sample. Children and adults displayed differing patterns of increased anterior cingulate cortex and decreased amygdala activation during episodes in which emotion regulation was required. Specifically, amygdala activation increased in adults but decreased in children during recovery from a frustrating episode. In addition, we used effective connectivity analyses to investigate differential correlations between key emotional brain areas in response to the regulatory task demands. We found reliable increases in effective connectivity between the anterior cingulate cortex and the amygdala during periods of increased demand for emotion regulation. This effective connectivity increased with age. PMID- 20971475 TI - Distribution and mass inventory of polycyclic aromatic hydrocarbons in the sediments of the south Bohai Sea, China. AB - Recent occurrence, distribution and mass inventories of 16 priority polycyclic aromatic hydrocarbons (PAHs) proposed by USEPA in the south Bohai Sea (BS) were studied based on the analytical data of 71 surface sediment samples. The concentrations of 16 PAHs varied from 37 to 537 ngg-1 (dry weight). A clear difference was observed between the coastal Bohai Bay (CBB) and its adjacent BS (ABS) in the distribution and compositions of PAHs. The petrogenic source of phenanthrene in CBB was attributable to the industrial wastewater, fugitive fuel leakages from ships and offshore oil production. Four to six ring PAHs were predominantly from the coal and wood combustions in the whole area. The estimated PAH input to the south BS (43,000 km2, 56% of BS in area) was 36.6 ton yr-1, indicating that the study area was one of the important reservoirs of PAHs in world. PMID- 20971476 TI - Marine protected areas and pelagic fishing: the case of the Chagos Archipelago. PMID- 20971478 TI - [Hypertension as a cardiovascular risk factor: is it time to revise the paradigm?]. PMID- 20971479 TI - [Bruns syndrome caused by intraventricular neurocysticercosis]. PMID- 20971480 TI - [New oral anticoagulants for the prevention of venous thromboembolism]. PMID- 20971481 TI - [Beta-blocker treatment in elderly patients with acute heart failure in the emergency departments]. PMID- 20971483 TI - Glucosinolate biochemical diversity and innovation in the Brassicales. AB - Glucosinolates were analysed from herbarium specimens and living tissues from representative of all families of the Brassicales, following the phylogenetic schemes of Rodman et al. (1998) and Hall et al. (2002, 2004), including specimens of Akania, Setchellanthus, Emblingia, Stixis, Forchhammeria and members of the Capparaceae for which glucosinolate content had not previously been reported. The results are reviewed along with additional published data on glucosinolate content of members of the Brassicales. In addition to providing an overview of the evolution of glucosinolate biochemical diversity within the core Brassicales, there were three main findings. Firstly, the glucosinolate content of some 'orphan' taxa of the Brassicales, such as Setchellanthus and Emblingia were consistent with recent phylogentic analyses based upon DNA sequence comparisons, while further analyses of Tirania and Stixis is required. Secondly, methyl glucosinolate is found within the Capparaceae and Cleomaceae, but also, unexpectedly, within Forchhammeria, with implications for the biochemical and evolutionary origin of methyl glucosinolate and the phylogenetic relationships of Forchhammeria. Thirdly, whereas Old World Capparaceae contain methyl glucosinolate, New World Capparaceae, including New World Capparis, either contain methyl glucosinolates or glucosinolates of complex and unresolved structures, indicative of continued innovation in glucosinolate biosynthesis. These taxa may be productive sources of glucosinolate biosynthetic genes and alleles that are not found in the model plant Arabidopsis thaliana. PMID- 20971484 TI - Cycloartane glycosides from leaves of Oxyanthus pallidus. AB - From the MeOH extract of leaves of Oxyanthus pallidus, three cycloartane glycosides, named pallidiosides A-C, were isolated together with two known compounds, oleanolic acid and 3-O-beta-D-glucopyranosyl-beta-sitosterol. The structures of pallidiosides A-C were assigned on the basis of spectral studies and comparison with published literature data. The known compounds were identified by means of Co TLC and confirmed by their physical constants. PMID- 20971485 TI - Prevalence of canine methicillin resistant Staphylococcus pseudintermedius in a veterinary diagnostic laboratory in Italy. AB - The overall prevalence of methicillin-resistant Staphylococcus pseudintermedius (MRSP) was 2% (10/590) among 590 canine specimens submitted to an Italian veterinary diagnostic laboratory during a two-month period, and 21% (10/48) among Staphylococcus intermedius group (SIG) isolates. All methicillin-resistant strains exhibited additional resistance to fluoroquinolones, gentamicin, lincosamides, tetracyclines, and potentiated sulfonamides, belonged predominantly to spa type t02 and harboured SCCmec type II-III cassette. PMID- 20971486 TI - Ivermectin effects on motor coordination and contractions of isolated rat diaphragm. AB - Ivermectin, the antiparasitic drug from the macrocyclic lactones class raises attention due to its high efficiency against nematodes and arthropods and very specific toxic and side effects that it may produce in host. Dominant clinical symptoms of adverse effects and toxicity of ivermectin in animals are tremor, ataxia, CNS depression and coma which often results in mortality. In our study increasing intravenous doses of ivermectin, (6 or more times higher than therapeutic dose: 1.25, 2.5, 3.75, 5.0, 6.25 and 7.5 mg/kg), caused dose dependent disturbance of motor coordination in treated rats. The median effective dose (ED50) that was able to impair the rota-rod performance in rats treated 3 min before testing was 2.52 mg/kg. This effect weakens over time, while in the rats treated 60 min before the rota-rod test, ED50 of ivermectin was 4.21 mg/kg. Whereas, all tested doses of ivermectin did not cause any other clinical symptoms of toxicity. Ivermectin has no effect on the contractions of isolated diaphragm caused by the EFS, which effectively blocked mecamylamine (100 MUM) and pancuronium (1 and 2 MUM). Effect on motor coordination is the first detectable clinical symptom of ivermectin toxicity and apparently is a result of its central effects. PMID- 20971487 TI - Phenotypic and genotypic characteristics of Mycobacterium isolates from fighting fish Betta spp. in Malaysia. AB - Mycobacteriosis due to mycobacteria is one of the most common bacterial diseases in ornamental fish. We describe here the phenotypic and genotypic characteristics of Mycobacterium isolates from fighting fish Betta spp. using ATCC Mycobacterium marinum, Mycobacterium fortuitum and Mycobacterium chelonae as references. A total of four isolates (M1, M2, M3, M4) were obtained from four out of 106 fish samples using selective agar, and identified to Mycobacterium genus using acid fast staining and 16s rRNA gene-based genus specific polymerase chain reaction. DNA sequencing and NCBI-BLAST analysis further identified isolate M1 as M. marinum and isolates M2, M3, M4 as M. fortuitum. Morphological, physiological and biochemical tests were carried out for phenotypic characterizations. Universal M13 and wild-type phage M13 RAPD dendogram was generated to illustrate the genetic relationship of the isolates and reference strains. PMID- 20971488 TI - Streptococcus spp. and related bacteria: their identification and their pathogenic potential for chronic mastitis - a molecular approach. AB - Streptococcus spp. and related bacteria form a large group of organisms which are associated with bovine intramammary Infections (IMI). Some of them are the well known mastitis pathogens Streptococcus uberis and Streptococcus agalactiae. In addition, there are a considerable number of these gram-positive, catalase negative cocci (PNC) with unclear mastitic pathogenicity such as Aerococcus viridans which make the conventional diagnostics of PNC difficult. One diagnostic, API 20 Strep (API, Biomerieux) is recommended which, as a phenotypic assay, involves a series of miniaturized biochemical tests. Recently, preference is given to genotypic identification methods. In particular, sequencing of the 16S rRNA gene allows highly reproducible and accurate identification of bacteria and permits discovery of novel, clinically relevant bacteria. As a consequence, the aim of the present study was to compare identification of IMI-associated PNC by the API method as well as by sequencing of their 16S rRNA gene (16S). Furthermore, the correlation of these bacteria to bovine chronic mastitis and their phylogeny was investigated. 102 PNC isolated from single quarter milk samples were identified by API and 16S sequencing. Considering Streptococcus uberis, Streptococcus dysgalactiae subsp. dysgalactiae and Streptococcus agalactiae, both methods generated fully concordant results. In contrast, a very high disconcordance was observed for most of the other PNC, in particular Enterococcus spp., Aerococcus viridans and the viridans streptococci were shown as apathogenic. Lactococcus garvieae was found to be an opportunistic pathogen causing IMI during late lactation. In addition, PNC isolated from milk were frequently observed together with other bacteria, in particular with Staphylococcus spp. In these cases, the levels of somatic cell counts (SCC) were determined by the specific PNC present in the sample. Considering PNC phylogeny based on 16S sequencing, 3 major clusters were observed. They included all the common mastitis pathogens (cluster I), the Lactococcus spp., Enterococcus spp. and Aerococcus spp. (cluster II) and all the viridans streptococci (cluster III). PMID- 20971489 TI - Noninvasive ultrasound image guided surface wave method for measuring the wave speed and estimating the elasticity of lungs: A feasibility study. AB - Lung diseases, such as acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF), are closely associated with altered lung elastic properties. Pulmonary function testing and imaging are routinely performed for evaluating lung diseases. However, lung compliance, a measure of lung elastic properties, is rarely used in clinic, because it is invasive and provides only a global and arguably biased estimate of lung elastic properties. Current ultrasound methods also cannot be used for imaging lungs because ultrasound cannot penetrate the lung tissue. In this paper, an ultrasound image guided and surface wave based method is proposed to measure regional lung surface wave speed and estimate lung elasticity noninvasively. The method described here was not explored before to the best knowledge of the authors. Experiments in an ex vivo pig lung and an in vivo human lung pilot study are reported. The surface wave speed is measured to be 1.83+/-0.02m/s at 100Hz by ultrasound for the ex vivo pig lung at 3mmHg pressure, which is validated by an optical measurement. An in vivo human lung pilot experiment measures the surface wave speed to be 2.41+/-0.33m/s for the 100Hz sinusoidal wave at total lung capacity (TLC) and 0.99+/-0.09m/s at functional residual capacity (FRC). These values of wave speed fall well within the range of available literature. PMID- 20971490 TI - Identification of tolerated insertion sites in poliovirus non-structural proteins. AB - Insertion of nucleotide sequences encoding "tags" that can be expressed in specific viral proteins during an infection is a useful strategy for purifying viral proteins and their functional complexes from infected cells and/or for visualizing the dynamics of their subcellular location over time. To identify regions in the poliovirus polyprotein that could potentially accommodate insertion of tags, transposon-mediated insertion mutagenesis was applied to the entire nonstructural protein-coding region of the poliovirus genome, followed by selection of genomes capable of generating infectious, viable viruses. This procedure allowed us to identify at least one site in each viral nonstructural protein, except protein 2C, in which a minimum of five amino acids could be inserted. The distribution of these sites is analyzed from the perspective of their protein structural context and from the perspective of virus evolution. PMID- 20971491 TI - Molecular subtypes of Campylobacter spp., Salmonella enterica, and Escherichia coli O157:H7 isolated from faecal and surface water samples in the Oldman River watershed, Alberta, Canada. AB - Campylobacter spp., Salmonella enterica, and Escherichia coli O157:H7 isolated from 898 faecal, 43 sewage, and 342 surface water samples from the Oldman River were characterized using bacterial subtyping methods in order to investigate potential sources of contamination of the watershed. Among these pathogens, Campylobacter spp. were the most frequently isolated from faecal, sewage, and surface water samples (266/895, 11/43, and 91/342, respectively), followed by Salmonella (67/898, 8/43, and 29/342, respectively), and E. coli O157:H7 (16/898, 2/43, and 8/342, respectively). Salmonella Rubislaw was the most common serovar isolated from water. This serovar was also isolated from two wild bird species. Most other serovars isolated from water were either not isolated from animals or were isolated from multiple species. E. coli O157:H7 was predominantly isolated from cattle. The most common phage-types of this pathogen from cattle were also the most common among water isolates, and there were exact pulsed field gel electrophoresis and comparative genomic fingerprint matches between cattle, sewage, and water isolates. Campylobacters were commonly isolated from surface waters and faeces from most animal species. Restriction fragment length polymorphism of the Campylobacter flaA gene identified several location and host species-specific (cattle, goose, pig) fingerprints. Molecular subtyping of these bacterial pathogens shows considerable promise as a tool for determining the sources of faecal pollution of water. PMID- 20971492 TI - Interactive effects of cadmium and hypoxia on metabolic responses and bacterial loads of eastern oysters Crassostrea virginica Gmelin. AB - Pollution by toxic metals including cadmium (Cd) and hypoxia are important stressors in estuaries and coastal waters which may interactively affect sessile benthic organisms, such as oysters. We studied metabolic responses to prolonged hypoxic acclimation (2 weeks at 5% O2) in control and Cd-exposed (30 d at 50 MUg L(-1) Cd) oysters Crassostrea virginica, and analyzed the effects of these stressors on abundance of Vibrio spp. in oysters. Hypoxia-acclimated oysters retained normal standard metabolic rates (SMR) at 5% O2, in contrast to a decline of SMR observed during acute hypoxia. However, oysters spent more time actively ventilating in hypoxia than normoxia resulting in enhanced Cd uptake and 2.7-fold higher tissue Cd burdens in hypoxia. Cd exposure led to a significant decrease in tissue glycogen stores, increase in free glucose levels and elevated activity of glycolytic enzymes (hexokinase and aldolase) indicating a greater dependence on carbohydrate catabolism. A compensatory increase in activities of two key mitochondrial enzymes (citrate synthase and cytochrome c oxidase) was found during prolonged hypoxia in control oysters but suppressed in Cd-exposed ones. Cd exposure also resulted in a significant increase in abundance of Vibrio parahaemolyticus and Vibrio vulnificus levels during normoxia and hypoxia, respectively. Overall, Cd- and hypoxia-induced changes in metabolic profile, Cd accumulation and bacterial flora of oysters indicate that these stressors can synergistically impact energy homeostasis, performance and survival of oysters in polluted estuaries and have significant consequences for transfer of Cd and bacterial pathogens to the higher levels of the food chain. PMID- 20971493 TI - Confirmation of polychlorinated biphenyl (PCB) distribution in the blood and verification of simple quantitative method for PCBs based on specific congeners. AB - We measured the concentration of each polychlorinated biphenyl (PCB) congener in whole blood, plasma and blood cells, and investigated the distribution of PCBs in human blood using high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS). The PCB concentrations in plasma and whole blood in terms of lipid concentrations were almost equal, with a correlation coefficient of r=0.972. In the blood, the ratio of PCBs in blood cells to those in plasma was generally about 1:9 and the congener distribution patterns in blood cells and plasma were similar. We performed verification of a simple mass screening method by obtaining information on the main PCB congeners for investigations on human accumulation and exposure. The total concentration of the seven PCB congeners (UNEP-7) proposed to the United Nations Environment Programme (UNEP) by Muir and Morita was about 50% of the total concentration of all PCB congeners, and UNEP-30 was about 80%. The seven main congeners in the blood (MCB-7) showed a value that was about 60%, and MCB-30 showed a value that was about 90%. Determinations with the main congeners in the blood showed a correlation of r=0.990 or more between the main eight congeners (MCB-7 plus #74) and the total PCB concentration for all congeners. The results suggest that, although total PCB concentration can be effectively estimated from the main seven congeners, the main eight congeners would be preferable, and that the use of these congeners in the simple mass screening method would be effective for populations in areas uncontaminated by PCBs. PMID- 20971494 TI - Metribuzin impairs the unicell-colony transformation in the green alga Scenedesmus obliquus. AB - Active growth is a prerequisite for the formation of grazing-protective, mostly eight-celled colonies by the ubiquitous green alga Scenedesmus in response to chemical cues from zooplankton. Colonies can also be evoked by chemically quite similar manmade anionic surfactants, such as FFD-6. In this study, it was hypothesized that growth-inhibiting concentrations of the herbicide metribuzin impair the ability of Scenedesmus obliquus to form colonies in response to the surfactant morphogen FFD-6. The results confirmed that the formation of colonies in S. obliquus was hampered by metribuzin. EC50 values of metribuzin for colony inhibition (approximately 11 MUg L(-1)) were similar to those for growth and photosynthesis inhibition (12-25 MUg metribuzinL(-1)). In the absence of the colony-inducing surfactant FFD-6, S. obliquus populations were comprised of 92% unicells, having on average 1.2 cells per colony at all tested metribuzin concentrations (0-100 MUg L(-1)). In contrast, in the presence of FFD-6 and at low metribuzin concentrations (0 and 5 MUg L(-1)), S. obliquus had more than five cells per colony with a high portion of eight-celled colonies. However, increasing concentrations of metribuzin decreased the number of colonies in the FFD-6-exposed populations and caused them to remain mostly unicellular at the highest concentrations (50 and 100 MUg L(-1)). This study revealed that metribuzin impeded growth and by doing so, also obstructed the possibility for unicellular Scenedesmus to form colonies. Consequently, an increase in mortality of Scenedesmus from grazing is expected. PMID- 20971495 TI - Bisphenol A content in fish caught in two different sites of the Tyrrhenian Sea (Italy). AB - Bisphenol A (BPA) is an endocrine disruptor (ED) that is abundant in the environment because of its extensive use in human-manufactured products. In this study, the BPA concentration was measured in the muscle and liver of five edible fish, characterized by different habitat and habits, caught in two different sites of the Tyrrhenian Sea (Italy). Our results show that: (i) fish livers are about 2.5 times more polluted than muscle; (ii) fish caught in the Gulf of Naples are more polluted than those from the Latium coasts, ranging from 1.2-fold more for White Bream to 6.6-fold for Grey Mullet; and (iii) the percentages of fish found to be BPA-polluted in the Gulf of Naples ranged from 73% (for Bass) to 90% (for Mullet), while the Latium fish range from 60% (for Bass) to 90% (for Mullet). These data indicate that consumers of fish caught in the Gulf of Naples are at a greater risk for BPA-induced endocrine pathologies compared to those who consume fish caught along the Latium coasts. PMID- 20971496 TI - Endothelin-1 expression in scleroderma renal crisis. AB - The objective of the study was to investigate the role of endothelin-1 in the pathogenesis of scleroderma renal crisis in patients with systemic sclerosis. We used immunohistochemical analysis with anti-endothelin-1 and anti-von Willebrand factor antibodies in comparing kidney biopsies from patients with systemic sclerosis and scleroderma renal crisis (n = 14); from normal kidneys (n = 5); and from patients with typical hemolytic uremic syndrome and thrombotic microangiopathy (n = 5), antiphospholipid syndrome (n = 6), diabetic nephropathy (n = 5), minimal change disease with cyclosporine toxicity (n = 5), or nephroangiosclerosis (n = 5). Kidney biopsies from all systemic sclerosis patients presented specific lesions: glomerular lesions with thickened capillary walls (n = 6, 42.8%), mesangiolysis (n = 3, 21.4%), fibrin thrombi (n = 3, 21.4%), hypertrophy of juxtaglomerular apparatus (n = 5, 35.7%), arteriolar lesions showing mucinous intimal thickening and lumen mucoid occlusions (n = 13, 92.8%), proliferation of intimal cells (ie, "onion-skin" lesions; n = 13, 92.8%), fibrinoid necrosis (n = 3, 21.4%), and fibrin thrombosis (n = 4, 28.6%). Chronic lesions in large arteries showed modifications such as fibrous intimal thickening (n = 13, 92.8%). The pattern of endothelial staining for endothelin-1 in both glomeruli and arteriolar lesions appears to be specific for scleroderma renal crisis. Glomerular endothelin-1 staining without arteriolar staining was seen in hemolytic uremic syndrome; and isolated arteriolar staining (without glomerular staining) was seen in a number of conditions including antiphospholipid nephropathy, cyclosporine toxicity, and diabetic nephropathy. Endothelin-1 is overexpressed in glomeruli and arterioles of patients with scleroderma renal crisis, which suggests that endothelin-1 might be a therapeutic target in this condition. PMID- 20971497 TI - Thyroid-like follicular carcinoma of the kidney with metastases to the lungs and retroperitoneal lymph nodes. AB - Thyroid-like follicular carcinoma of the kidney is an extremely rare variant of renal cell carcinoma. Most previously reported cases presented as incidental small tumors confined to the kidney. Here we report a unique case in which the patient presented with flank pain and hematuria. Imaging studies demonstrated a large tumor in the right kidney and metastases to the lungs and retroperitoneal lymph nodes. Both the renal tumor and the sampled lung metastasis were composed almost entirely of follicles with dense, colloid-like material resembling thyroid follicular carcinoma. However, no lesion was found in the thyroid gland; and the patient's thyroid function test results were normal. The tumor cells were immunoreactive for PAX2 and PAX8 but lacked reactivity for thyroglobulin and thyroid transcription factor-1. To our knowledge, this is the first case of thyroid-like follicular carcinoma of the kidney to be initially associated with marked symptoms and widespread metastases, providing evidence that this rare variant of renal cell carcinoma can be clinically aggressive. PMID- 20971498 TI - PINK1 displays tissue-specific subcellular location and regulates apoptosis and cell growth in breast cancer cells. AB - The PINK1 gene is mutated in the germ line of patients with hereditary early onset Parkinson disease, and PINK1 prosurvival function at neuronal mitochondria has been related with the etiology of this disease. However, the expression and function of PINK1 protein in nonneuronal tissues has not been determined yet. Here, we have analyzed PINK1 protein expression and subcellular distribution in normal and neoplastic human tissues and investigated the function of PINK1 in breast carcinoma cells. PINK1 protein, as stained by a specific anti-PINK1 monoclonal antibody, was widely expressed in human tissues, displaying high expression in epithelial tissues and in the central nervous system and lower expression in tissues of mesenchymal origin. The subcellular distribution of PINK1 was cytoplasmic granular or cytoplasmic diffuse in most tissues. In breast, PINK1 was also associated with the plasma membrane. Human neoplastic tissues ranged from high PINK1 expression in carcinomas to low expression in sarcomas. In neoplastic tissues, PINK1 displayed a diffuse cytoplasmic localization, with an additional membranous localization in breast carcinoma and squamous carcinoma of lung. In the human breast carcinoma Michigan Cancer Foundation-7 cell line, ectopic expression of cytoplasmic or mitochondrial-targeted PINK1 inhibited apoptosis triggered by hydrogen peroxide and suppressed cell growth in soft agar, whereas PINK1 silencing increased hydrogen peroxide-induced apoptosis. Together, our findings indicate that the physiologic functions of PINK1 go beyond its regulatory role of mitochondria-mediated cell survival in neurons. PMID- 20971499 TI - Levels of brominated flame retardants and methoxylated polybrominated diphenyl ethers in eggs of white-tailed sea eagles breeding in different regions of Sweden. AB - Forty-four unhatched eggs from white-tailed sea eagle (Haliaeetus albicilla), collected in four regions in Sweden in 1992-2005, were analysed for contents of polybrominated diphenyl ethers (PBDEs), polybrominated biphenyl (PBB), hexabromocyclododecane (HBCD) and naturally occurring methoxylated polybrominated diphenyl ethers (MeO-PBDEs). Two freshwater areas-Lapland in the arctic zone (LAP) and inland lakes in central and southern Sweden (INL), and two brackish marine areas in the Baltic Sea-the south Bothnian Sea (SB) and the Baltic Proper (BP)-were chosen for comparison of the concentrations and congener distributions in white-tailed sea eagles with different diet and migratory patterns. The geometric mean (GM) concentrations (ng/g lipid weight (l.w.)) of ?(5)PBDE (BDE 47, -99, -100, -153, and -154) were 720 (LAP), 1500 (INL), 4 100 (SB) and 4 300 (BP), whereas BDE-209 was not detectable in any of the samples. The GM concentrations for HBCD content in LAP, INL, SB and BP were 60, 90, 150 and 140ng/g l.w., respectively, whereas the corresponding values for BB-153 were 20, 30, 100 and 120ng/g l.w. In general, the eggs from all four regions demonstrated similar patterns of PBDE congeners, with concentrations in descending order of BDE-47, -100, -99, -153 and -154. The ?(3)-MeO-BDEs (6-MeO-BDE47, 2'-MeO-BDE68, 5 Cl-6-MeO-BDE47) for these same regions (as above) were 80, 40, 340 and 240ng/g l.w., respectively. ?(3)-MeO-BDEs for LAP and INL (freshwaters) were significantly different, whereas those for SB and BP were not. The presence of MeO-PBDEs in all of the inland samples indicates that there is an as-yet unidentified source of these compounds in the freshwater ecosystem. Between the two more contaminated subpopulations from the Baltic Sea coast, SB showed significantly lower productivity than BP, but no correlation was found between productivity and PBDE, PBB and HBCD at the concentrations found in this study. PMID- 20971500 TI - LIFG-based attentional control and the resolution of lexical ambiguities in sentence context. AB - The role of attentional control in lexical ambiguity resolution was examined in two patients with damage to the left inferior frontal gyrus (LIFG) and one control patient with non-LIFG damage. Experiment 1 confirmed that the LIFG patients had attentional control deficits compared to normal controls while the non-LIFG patient was relatively unimpaired. Experiment 2 showed that all three patients did as well as normal controls in using biasing sentence context to resolve lexical ambiguities involving balanced ambiguous words, but only the LIFG patients took an abnormally long time on lexical ambiguities that resolved toward a subordinate meaning of biased ambiguous words. Taken together, the results suggest that attentional control plays an important role in the resolution of certain lexical ambiguities - those that induce strong interference from context inappropriate meanings (i.e., dominant meanings of biased ambiguous words). PMID- 20971501 TI - Dispositional, ecological and biological influences on adolescent tranquilizer, Ritalin, and narcotics misuse. AB - The primary purpose of this study was to examine the extent to which two of the three sources of risk-taking--dispositional and ecological--in adolescence and demographic variables were related to Ritalin, tranquilizer and narcotics misuse. The secondary aim of this study was to distinguish subgroups of Ritalin, tranquilizer, and narcotics misusers using dispositional, ecological and demographic variables. An archival dataset containing 1672 participants (11-18 years old) was used. Ritalin, tranquilizer, and narcotics misuse were dichotomized and hierarchical logistic regressions were computed for dispositional and ecological sources of risk-taking and demographics. To distinguish subgroups of misusers, hierarchical multinomial regressions were computed. Dispositional, ecological, and demographic variables were related to Ritalin, tranquilizer, and narcotics misuse and distinguished among non-users, experimenters/occasional misusers, and frequent misusers. Prescription drug prevention programs should incorporate demographic, dispositional, and ecological variables and should parallel the guidelines currently used for developing effective substance abuse prevention programs. PMID- 20971502 TI - "Gratuities" for donated organs: ethically indefensible. PMID- 20971503 TI - Plasmid pORF-hTRAIL and doxorubicin co-delivery targeting to tumor using peptide conjugated polyamidoamine dendrimer. AB - A combination cancer therapy was investigated via co-delivery of therapeutic gene encoding human tumor necrosis factor-related apoptosis-inducing ligand (pORF hTRAIL) and doxorubicin (DOX) using a tumor-targeting carrier, peptide HAIYPRH (T7)-conjugated polyethylene glycol-modified polyamidoamine dendrimer (PAMAM-PEG T7). T7, a transferrin receptor-specific peptide, was chosen as the ligand to target the co-delivery system to the tumor cells expressing transferrin receptors. The result of fluorescence scanning showed that about 375 DOX molecules were bound to one pORF-hTRAIL molecule. The co-delivery system was constructed based on the electrostatic interactions between pORF-hTRAIL-DOX complex and cationic PAMAM-PEG-T7. T7-modified co-delivery system showed higher efficiency in cellular uptake and gene expression than unmodified co-delivery system in human liver cancer Bel-7402 cells, and accumulated in tumor more efficiently in vivo. In comparison with single DOX or pORF-hTRAIL delivery system, co-delivery system induced apoptosis of tumor cells in vitro and inhibited tumor growth in vivo more efficiently. In mice bearing Bel-7402 xenografts, lower doses of co-delivery system (4 MUg DOX/mouse, about 0.16 mg/kg) effectively inhibited tumor growth comparable to high doses (5 mg/kg) of free doxorubicin (77% versus 69%). These results suggested that T7-mediated co delivery system of DOX and pORF-hTRAIL was a simply prepared, combined delivery platform which can significantly improve the anti-tumor effect. This co-delivery system might widen the therapeutic window and allow for the selective destruction of cancer cells. PMID- 20971504 TI - Enhancing the transdermal delivery of rigid nanoparticles using the simultaneous application of ultrasound and sodium lauryl sulfate. AB - The potential of rigid nanoparticles to serve as transdermal drug carriers can be greatly enhanced by improving their skin penetration. Therefore, the simultaneous application of ultrasound and sodium lauryl sulfate (referred to as US/SLS) was evaluated as a skin pre-treatment method for enhancing the passive transdermal delivery of nanoparticles. We utilized inductively coupled plasma mass spectrometry and an improved application of confocal microscopy to compare the delivery of 10- and 20-nm cationic, neutral, and anionic quantum dots (QDs) into US/SLS-treated and untreated pig split-thickness skin. Our findings include: (a) ~0.01% of the QDs penetrate the dermis of untreated skin (which we quantify for the first time), (b) the QDs fully permeate US/SLS-treated skin, (c) the two cationic QDs studied exhibit different extents of skin penetration and dermal clearance, and (d) the QD skin penetration is heterogeneous. We discuss routes of nanoparticle skin penetration and the application of the methods described herein to address conflicting literature reports on nanoparticle skin penetration. We conclude that US/SLS treatment significantly enhances QD transdermal penetration by 500-1300%. Our findings suggest that an optimum surface charge exists for nanoparticle skin penetration, and motivate the application of nanoparticle carriers to US/SLS-treated skin for enhanced transdermal drug delivery. PMID- 20971505 TI - A robust high-throughput sandwich cell-based drug screening platform. AB - Hepatotoxicity evaluation of pharmaceutical lead compounds in early stages of drug development has drawn increasing attention. Sandwiched hepatocytes exhibiting stable functions in culture represent a standard model for hepatotoxicity testing of drugs. We have developed a robust and high-throughput hepatotoxicity testing platform based on the sandwiched hepatocytes for drug screening. The platform involves a galactosylated microfabricated membrane sandwich to support cellular function through uniform and efficient mass transfer while protecting cells from excessive shear. Perfusion bioreactor further enhances mass transfer and cellular functions over long period; and hepatocytes are readily transferred to 96-well plate for high-throughput robotic liquid handling. The bioreactor design and perfusion flow rate are optimized by computational fluid dynamics simulation and experimentally. The cultured hepatocytes preserved 3D cell morphology, urea production and cytochrome p450 activity of the mature hepatocytes for 14 days. When the perfusion-cultured sandwich is transferred to 96-well plate for drug testing, the hepatocytes exhibited improved drug sensitivity and low variability in hepatotoxicity responses amongst cells transferred from different dates of perfusion culture. The platform enables robust high-throughput screening of drug candidates. PMID- 20971507 TI - Differential expression of PACAP receptors in postnatal rat brain. AB - Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) is a multi-functional neuropeptide that acts through activation of three common G-protein coupled receptors (VPAC1, VPAC2 and PAC1). In this study, we have investigated the gene expression profile of PAC1 isoforms (Hop1, Hip, Hip-Hop) and VPAC1, VPAC2 receptors in distinct brain regions during different stages of rat postnatal development. Using quantitative real time PCR approach we found that PAC1 isoforms were highly expressed in the cortex of newborns with marked decrease in expression during later stages of development. In contrast, mRNA levels of VPAC1, VPAC2 receptors were markedly lower in newborns in comparison to later developmental stages. Expression of PAC1 isoforms predominated in the hippocampus, while expression of VPAC1 was more prominent in the cortex and VPAC2 in the striatum and hippocampus. In addition we found that during early stages of postnatal development the expression of PAC1 receptor in the hippocampus was significantly higher in females than in males. No sex dependent differences in expression were observed for the VPAC1 and VPAC2 receptors. In summary, differential expression of PAC1, VPAC1 and VPAC2 receptors during postnatal development as well as gender dependent differences of PAC1 receptor expression in the hippocampus, will contribute to our understanding of the role of PACAP/VIP signaling system in normal brain development and function. PMID- 20971506 TI - Regeneration of the cavernous nerve by Sonic hedgehog using aligned peptide amphiphile nanofibers. AB - SHH plays a significant role in peripheral nerve regeneration and has clinical potential to be used as a regenerative therapy for the CN in prostatectomy patients and in other patients with neuropathy of peripheral nerves. Efforts to regenerate the cavernous nerve (CN), which provides innervation to the penis, have been minimally successful, with little translation into improved clinical outcomes. We propose that, Sonic hedgehog (SHH), is critical to maintain CN integrity, and that SHH delivered to the CN by novel peptide amphiphile (PA) nanofibers, will promote CN regeneration, restore physiological function, and prevent penile morphology changes that result in erectile dysfunction (ED). We performed localization studies, inhibition of SHH signaling in the CN, and treatment of crushed CNs with SHH protein via linear PA gels, which are an innovative extended release method of delivery. Morphological, functional and molecular analysis revealed that SHH protein is essential to maintain CN architecture, and that SHH treatment promoted CN regeneration, suppressed penile apoptosis and caused a 58% improvement in erectile function in less than half the time reported in the literature. These studies show that SHH has substantial clinical application to regenerate the CN in prostatectomy and diabetic patients, that this methodology has broad application to regenerate any peripheral nerve that SHH is necessary for maintenance of its structure, and that this nanotechnology method of protein delivery may have wide spread application as an in vivo delivery tool in many organs. PMID- 20971508 TI - Cyclopamine induces eosinophilic differentiation and upregulates CD44 expression in myeloid leukemia cells. AB - Cyclopamine, a plant-derived steroidal alkaloid, inhibits the hedgehog (Hh) signaling pathway by antagonizing Smoothened. This drug can induce the differentiation of myeloid leukemia cell lines and acute myeloid leukemia (AML) cells in primary culture. The treated cells were stained with Luxol-fast-blue, which is specific for eosinophilic granules. Ligation of CD44 with some specific monoclonal antibodies can reverse the differentiation of AML cells. Combined treatment with cyclopamine and a monoclonal antibody to ligate CD44 more than additively induced the differentiation of HL-60 cells. These results may provide useful information for the development of a CD44-targeted therapy in AML. PMID- 20971510 TI - The Myelodysplastic Syndromes (MDS) Foundation: a retrospective analysis of a nonprofit foundation. PMID- 20971509 TI - Erythroid response and decrease of WT1 expression after proteasome inhibition by bortezomib in myelodysplastic syndromes. AB - NF-kB is reported to be constitutively activated in a percentage of high-risk myelodysplastic syndrome carrying cytogenetic aberrations. Only few data are reported on the use of proteasome inhibitors in this subset of patients. We performed a study on efficacy and safety of bortezomib as a single agent in patients with myelodysplastic syndromes (MDS). Bortezomib was administered at 1.3mg/m(2) with a 1, 4, 8, 11-day schedule every 28 days, in 19 patients with IPSS low/intermediate 1 or intermediate2/high risk. Six out of 19 patients received all planned eight cycles. Hematologic toxicity was recorded in all patients, especially grade 3/4 neutropenia and grade 3/4 thrombocytopenia; non hematologic side effects were recorded in 7 patients, but events were all of grade 1/2 toxicity. According to IWG 2006 criteria, 4 out of 19 patients (21%) achieved erythroid response and 9 patients (47%) showed stable disease. In patients with erythroid response bone marrow WT1 levels decreased from a median of 109 copies at baseline to a median of 14 copies at the end of treatment, whereas in patients with stable disease, median WT1 copies increased either in bone marrow and peripheral blood. In conclusion, bortezomib used alone in MDS shows modest hematologic efficacy but appears to affect the WT1 gene expression, which is typically increased in these diseases. PMID- 20971511 TI - Acute toxicity of carbamazepine to juvenile rainbow trout (Oncorhynchus mykiss): effects on antioxidant responses, hematological parameters and hepatic EROD. AB - Awareness of residual pharmaceutically active compounds (PhACs) in the aquatic environment is growing as investigations into these pollutants are increasing and analytical detection techniques are improving. However, the toxicological effects of PhACs have not been adequately researched. In this study, the toxic effects of carbamazepine (CBZ), an anticonvulsant drug commonly present in surface and groundwater, was studied in juvenile rainbow trout, Oncorhynchus mykiss, by acute semi-static bioassay. Blood parameters, liver xenobiotic-metabolizing response and tissue antioxidant status were evaluated. Compared to the control group, fish exposed to CBZ (96 h LC50) showed significantly higher Er, Hb, MCHC, monocytes, neutrophil granulocytes and plasma enzymes activity, and significantly lower MCV and lymphocytes. CF and HSI were not significantly different among groups such as hepatic EROD. SOD, CAT, GPx and GR activity was significantly higher in liver of experimental groups, but decreased significantly in brain and gill. In general, antioxidant enzyme activity in intestine and muscle was less evident than in liver. Oxidative stress indices (levels of LPO and CP) were significantly higher in gill and brain, despite a trend to increased values were manifested in the remaining tissues. In short, CBZ-induced stress responses in different tissues were reflected in the oxidant stress indices and hematological parameters. However, before those parameters are used as special biomarkers for monitoring residual pharmaceuticals in aquatic environment, more detailed experiments in laboratory need to be performed in the future. PMID- 20971512 TI - A single high dose of escitalopram disrupts sensory gating and habituation, but not sensorimotor gating in healthy volunteers. AB - Early mechanisms to limit the input of sensory information to higher brain areas are important for a healthy individual. In previous studies, we found that a low dose of 10mg escitalopram (SSRI) disrupts habituation, without affecting sensory and sensorimotor gating in healthy volunteers. In the current study a higher dose of 15 mg was used. The hypothesis was that this higher dose of escitalopram would not only disrupt habituation, but also sensory and sensorimotor gating. Twenty healthy male volunteers received either placebo or 15 mg escitalopram, after which they were tested in a P50 suppression, and a habituation and prepulse inhibition (PPI) of the startle reflex paradigm. Escitalopram significantly decreased P50 suppression and habituation, but had no effect on PPI. The results indicate that habituation and sensory gating are disrupted by increased serotonergic activity, while sensorimotor gating seems relatively insensitive to such a rise. Since the patients who are frequently treated with SSRIs (patients with schizophrenia and affective disorders) might already suffer from disrupted sensory gating and habituation, the current results call for caution in the determination of a proper dose. PMID- 20971513 TI - Guggulsterone suppresses LPS induced inflammation of human middle ear epithelial cells (HMEEC). AB - OBJECTIVE: Guggulsterone is a bioactive constituent of resinous sap originating from the guggul tree, Commiphora mukul, which has been used over several thousands of years to treat various diseases, including atherosclerosis, rheumatism, and obesity. However, the effect of guggulsterone inflammatory reactions induced by lipopolysaccharide (LSP) is not known. The aim of this study was to evaluate the anti-inflammatory effect of guggulsterone on cultured human middle ear epithelial cells (HMEEC). METHODS: The effect of guggulsterone on LPS induced tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) expression was evaluated in HMEEC by real-time reverse transcription polymerase chain reaction (RT-PCR). LPS-induced COX-2 production and degradation of the inhibitor kB-alpha (IkB-alpha) were determined by Western blot analysis. RESULTS: Guggulsterone significantly inhibited LPS-induced upregulation of TNF-alpha and COX-2 in a dose-dependent manner. COX-2 protein production by LPS was significantly suppressed by the guggulsterone pretreatment. Furthermore, LPS induced IkB-alpha degradation was suppressed by the guggulsterone pretreatment. CONCLUSIONS: These results show that the guggulsterone has inhibitory effect on TNF-alpha expression and COX-2 production and it may be mediated through its inhibition of nuclear factor-kB activation. Our findings provide an insight into the molecular mechanisms underlying the anti-inflammatory activities of guggulsterone in relationship to otitis media. PMID- 20971514 TI - Acute mastoiditis in children: a retrospective study of 188 patients. AB - OBJECTIVE: The aim of this study is to define the clinical and bacteriological characteristics of acute mastoiditis (AM) in children in order to optimize diagnostic work-up and treatment. METHODS: In this retrospective study, 188 children between 3 months and 15 years of age (15+/-24 months; median+/-SD) were referred to our pediatric ENT emergency center for AM during a 7-year period (December 2001-January 2008). RESULTS: Fifty seven percent were male and 43% were female. Clinical follow-up duration was 3.9+/-0.7 months (mean+/-SEM). The incidence of AM remained stable during the whole study period. Microbiological samples (n=236) were negative in 33% of cases. The most frequently isolated germs were Streptococcus pneumoniae (51%), Streptococcus pyogenes (11.5%), Anaerobes (6.5%), and coagulase-negative Staphylococcus (6.5%). Paracentesis, puncture of retro auricular abscess under local anesthesia, and peroperative samples all contributed to isolate the involved germ(s). All the patients were hospitalized and received intravenous antibiotics, and 36.2% (n=68) underwent surgery. Several surgical procedures were necessary in 4 cases (2.1%). AM recurrences requiring a second hospitalization were observed in 8 patients (4.3%). The only observed complication was lateral sinus thrombosis (n=6; 3.2%). Surgical failures, requiring more than one surgical procedure, were more frequent in case of: (i) presence of Anaerobes (p<=0.001) or Gram-negative bacteria (p<=0.05) in microbiological samples; (ii) surgical drainage without mastoidectomy (p<=0.001). Recurrences were more frequent in AM due to Streptococcus pneumoniae. CONCLUSIONS: Based on our findings and on literature data, a protocol was established in order to standardize the management of pediatric AM in our center. The mains points are: no systematic surgery; if surgery is indicated, it must encompass a mastoidectomy; broad-spectrum intravenous antibiotic treatment covering the most commonly involved germs (3rd generation cephalosporin) and secondarily adapted to the results of microbiological samples. If the infection is not controlled after 48 h of intravenous antibiotherapy, a mastoidectomy had to be performed. PMID- 20971515 TI - Effectiveness and safety of glycoprotein IIb/IIIa inhibitors in patients with myocardial infarction undergoing primary percutaneous coronary intervention: a meta-analysis of observational studies. AB - INTRODUCTION: Meta-analyses of randomized controlled trials (RCT) showed that glycoprotein IIb/IIIa inhibitors (GPI) are associated with reduced adverse events following primary percutaneous coronary revascularization (PCI). However, the external validity of RCTs is generally limited due to their restricted inclusion of patients. The objective of this study is to evaluate the effectiveness and safety of GPI, as adjuvant therapy for primary PCI in real-life patients with myocardial infarction with ST segment elevation (STEMI) from the general population. METHODS: We identified all published peer-reviewed observational studies enrolling STEMI patients who underwent primary PCI. We performed random effect meta-analyses to determine the association of GPI with major adverse events. RESULTS: A total of 11 studies, enrolling 12,253 patients, were retained for this meta-analysis. GPI was associated with approximately 53% reduction in short-term mortality (odds ratio (OR): 0.47, 95% confidence intervals (CI): 0.32 0.68). There was a 62% reduction in long-term mortality associated with GPI (OR: 0.38, 95% CI: 0.30-0.50). GPI was associated with a 62% reduction in 30-day re infarction (OR: 0.38, 95% CI: 0.24-0.60) and 42% reduction in 30-day repeat PCI (OR: 0.58, 95% CI: 0.36-0.94). A non-significant increase in major bleeding with GPI was observed with an OR of 1.55 (95% CI: 0.92-2.62). CONCLUSIONS: GPI is associated with significant reductions in short-term mortality, re-infarction and repeat PCI, long-term mortality and an inconclusive increase in major bleeding. These results provide evidence for the safety and effectiveness of GPI as adjuvant therapy for primary PCI in real-life STEMI patients. PMID- 20971516 TI - Cardiac involvement in juvenile overlap-myositis detected by cardiac magnetic resonance imaging. PMID- 20971517 TI - Impact of statin use on heart failure mortality. AB - BACKGROUND: There is conflicting data regarding the mortality benefit of statins in patients with heart failure. The objectives of our study were to determine whether statin therapy is associated with decreased all-cause mortality and to assess the effect of incremental duration of therapy. METHODS: We studied 10,510 consecutive patients from the Veterans Affairs health system with a diagnosis of heart failure from January 2002 through December 2006. Mean follow-up was 2.66 years. Statin use and duration of therapy were identified. Veterans were classified into four groups based on duration of statin use during the study period (none, 1-25%, 26-75% and >75% use of statins). Logistic regression was performed to identify the association between incident statin use and all-cause mortality following a diagnosis of heart failure. The Kaplan-Meier method was employed to assess for differences in survival time between the four statin use classifications. RESULTS: Statin use was significantly associated with decreased all-cause mortality following a diagnosis of heart failure after controlling for age, gender, concurrent medications and comorbid diagnoses [chi(3)(2) (N = 10,510) = 1077.82, p < 0.001]. The benefit was seen within a relatively short duration (within 1 year) after starting statins, and in patients with <25% use of statins, there was no mortality benefit. CONCLUSION: Veterans who were not exposed to statin therapy at any time during the study period were 1.56 times more likely to suffer all-cause mortality. PMID- 20971519 TI - The use of palliative radiotherapy for bone metastasis. AB - BACKGROUND: The value of palliative radiotherapy (PRT) for bone metastases is well established, but little is known about its use in the general population. PURPOSE: To describe the use of PRT for bone metastases in Ontario. MATERIALS AND METHODS: This was a retrospective cohort study. Treatment records from all Ontario RT departments were linked to a population-based cancer registry to describe the use of PRT. RESULTS: 12.2% of the 434,241 patients, who died of cancer in Ontario between 1984 and 2004, received at least one course of PRT for bone metastases in the last 2 years of life. The rate of use of PRT varied across the province (inter-county range, 8.2-18.6%). Older patients and residents of poorer areas were less likely to receive PRT (p<0.0001). Patients diagnosed with cancer in a hospital with a radiotherapy facility and those who lived closer to a radiotherapy centre were more likely to receive PRT (p<0.0001). Over the study period, the use of PRT decreased in breast cancer and myeloma, but increased in prostate cancer (p<0.0001). CONCLUSIONS: Access to PRT appears to be inequitable. More effort is required to make this useful treatment available to all those who would benefit from it. PMID- 20971518 TI - Identifying and validating biomarkers for Alzheimer's disease. AB - The identification and validation of biomarkers for diagnosing Alzheimer's disease (AD) and other forms of dementia are increasingly important. To date, ELISA measurement of beta-amyloid(1-42), total tau and phospho-tau-181 in cerebrospinal fluid (CSF) is the most advanced and accepted method to diagnose probable AD with high specificity and sensitivity. However, it is a great challenge to search for novel biomarkers in CSF and blood by using modern potent methods, such as microarrays and mass spectrometry, and to optimize the handling of samples (e.g. collection, transport, processing, and storage), as well as the interpretation using bioinformatics. It seems likely that only a combined analysis of several biomarkers will define a patient-specific signature to diagnose AD in the future. PMID- 20971520 TI - A randomized trial on addition of concurrent-adjuvant chemotherapy and/or accelerated fractionation for locally-advanced nasopharyngeal carcinoma. AB - BACKGROUND AND PURPOSE: To evaluate the therapeutic benefits by adding chemotherapy (+C) and/or accelerated-fractionation (AF) for patients with T3-4N0 1M0 nasopharyngeal carcinoma. MATERIALS AND METHODS: From 1999 to 2004, 189 eligible patients were randomized to one of four treatment groups (CF/CF+C/AF/AF+C). The number of fractions/week was 5 for the CF groups and 6 for the AF groups. Patients in the +C groups were given concurrent cisplatin plus adjuvant cisplatin and fluorouracil. RESULTS: The AF+C group achieved significantly higher failure-free rate (88% at 5-year) than the CF group (63%; p=0.013), the AF group (56%; p=0.001) and the CF+C group (65%; p=0.027). As compared with CF alone, the increase in late toxicity was statistically insignificant (36% vs. 20%; p=0.25). Deaths due to cancer progression decreased (7% vs. 33%; p=0.011) but deaths due to incidental causes increased (9% vs. 2%; p=0.62). Improvement in overall survival reached borderline significance (85% vs. 66%; p=0.058). CONCLUSIONS: Concurrent-adjuvant chemotherapy combined with AF significantly reduced failure and cancer-specific deaths. Although the increase in major late toxicity and incidental deaths were statistically insignificant, a subtle increase in non-cancer deaths narrowed the overall survival gain. PMID- 20971521 TI - Tumor volume discrepancies between FDG-PET and MRI for cervical cancer. AB - PURPOSE: To compare the MRI-defined gross tumor volume (MR-GTV) to the metabolic tumor volume (Metabolic GTV) defined by FDG-PET in patients with cervical cancer. MATERIALS AND METHODS: Forty seven patients with cervical cancer underwent FDG PET/CT and MRI simulations. FDG-PET images were acquired with a spatial resolution of 5mm. MR imaging was performed on a 1.5 Tesla scanner. MR-GTV was contoured on the T2 axial images while Metabolic GTV was auto-contoured using a 40% SUV threshold. Tumor volumes were compared. RESULTS: Eighteen patients (38.3%) had tumors >=62 cc on MRI. Seventeen patients (36.2%) had tumors >=14 and <62 cc, while 12 patients (25.5%) had tumors <14 cc. 83% of patients in the >=62 cc, 23.5% in the 14-62 cc, and 16.7% in the <14 cc cohort had Grade 3 images as defined by Dimopoulos et al. In the >=62 cc cohort, MR-GTV and Metabolic GTV had a lesion coverage factor of 0.68 (mean MR-GTV(vol) 124.1, mean Metabolic GTV(vol) 119.9 cc). This fell to 0.51 (32.4, 33.1 cc) for the 14-62 cc, and 0.28 (8.4, 8.7 cc) for the <14 cc cohort. These differences were statistically significant on ANOVA testing (p<0.001). CONCLUSIONS: MRI provided better visualization of larger tumors than smaller tumors in reference to FDG-PET/CT. FDG-PET/CT visualized tumor volumes different from T2-weighted MRI, especially in tumors <14 cc in regard to location. PMID- 20971522 TI - A comparison of optic nerve dosimetry in craniospinal radiotherapy planned and treated with conventional and intensity modulated techniques. AB - BACKGROUND AND PURPOSE: Some CNS tumours present leptomeningeal dissemination. Craniospinal radiotherapy is complex and recurrences may occur at sites of target volume underdosage. IMRT, being highly conformal to the target, could theoretically underdose the optic nerves if they are not specifically targeted leading to optic nerve recurrences. We analyzed optic nerve dosimetry when they are not specifically targeted. MATERIALS AND METHODS: We designed 3D-conformal and tomotherapy plans for our last five patients treated to the craniospinal axis, not including the optic nerves in the target volume. We analyzed the dose delivered to the optic nerves, to the anterior and posterior half of the optic nerves, and to a theoretical optic nerve-PTV. RESULTS: The dose delivered to the optic nerves was similar for both plans in all patients (V95% close to 100%) except one in whom tomotherapy considerably underdosed the anterior optic nerves. The dose to the optic nerve-PTV was lower with tomotherapy in all patients. CONCLUSION: Despite not intentionally targeting the optic nerves, the dose to the optic nerves with IMRT was similar to 3D-conformal plans in most cases but left no margin for setup error. In individual cases the anterior half of the optic nerves could be significantly underdosed. PMID- 20971523 TI - Treatment of large stage I-II lung tumors using stereotactic body radiotherapy (SBRT): planning considerations and early toxicity. AB - PURPOSE: To study the dosimetric predictors of early clinical toxicity following SBRT in patients with lung tumors and planning target volumes (PTV) exceeding 80 cm(3). METHODS: Eighteen consecutive patients who were treated using volumetric modulated arc therapy (RapidArcTM) were assessed. All were either unfit or refused to undergo surgery or chemoradiotherapy. PTV planning objectives were as used in the ROSEL study protocol. Clinical toxicity was scored using Common Toxicity Criteria AE4.0. Lung volumes receiving 5, 10, 15, and 20 Gy (V(5), V(10), V(15) and V(20)) and mean lung dose were assessed and correlated to symptomatic radiation pneumonitis (RP). RESULTS: Median age, age-adjusted Charlson-comorbidity score and PTV size were 74, 7.5 and 137 cm(3), respectively. At a median follow-up of 12.8 months, 8 deaths were recorded: 5 arising from comorbidity, 2 were potentially treatment-related and 1 had local recurrence. RP was reported in 5 patients (grade 2 in 3 and grade 3 in 2). All RP occurred in plans without a high priority optimization objective on contralateral lung. Acute RP was best predicted by contralateral lung V(5) (p<0.0001). CONCLUSION: After SBRT using RapidArc in lung tumors >80 cm(3), the contralateral lung V(5) best predicts RP. Limiting contralateral lung V(5) to <26% may reduce acute toxicity. PMID- 20971524 TI - Compartmental modelling of the pharmacokinetics of a breast cancer resistance protein. AB - A mathematical model for the pharmacokinetics of Hoechst 33342 following administration into a culture medium containing a population of transfected cells (HEK293 hBCRP) with a potent breast cancer resistance protein inhibitor, Fumitremorgin C (FTC), present is described. FTC is reported to almost completely annul resistance mediated by BCRP in vitro. This non-linear compartmental model has seven macroscopic sub-units, with 14 rate parameters. It describes the relationship between the concentration of Hoechst 33342 and FTC, initially spiked in the medium, and the observed change in fluorescence due to Hoechst 33342 binding to DNA. Structural identifiability analysis has been performed using two methods, one based on the similarity transformation/exhaustive modelling approach and the other based on the differential algebra approach. The analyses demonstrated that all models derived are uniquely identifiable for the experiments/observations available. A kinetic modelling software package, namely FACSIMILE (MPCA Software, UK), was used for parameter fitting and to obtain numerical solutions for the system equations. Model fits gave very good agreement with in vitro data provided by AstraZeneca across a variety of experimental scenarios. PMID- 20971525 TI - Migration of epithelial cells on laminins: RhoA antagonizes directionally persistent migration. AB - Spatial and temporal expression of laminin isoforms is assumed to provide specific local information to neighboring cells. Here, we report the remarkably selective presence of LM-111 at the very tip of hair follicles where LM-332 is absent, suggesting that epithelial cells lining the dermal-epidermal junction at this location may receive different signals from the two laminins. This hypothesis was tested in vitro by characterizing with functional and molecular assays the comportment of keratinocytes exposed to LM-111 and LM-332. The two laminins induced morphologically distinct focal adhesions, and LM-332, but not LM 111, elicited persistent migration of keratinocytes. The different impact on cellular behavior was associated with distinct activation patterns of Rho GTPases and other signaling intermediates. In particular, while LM-111 triggered a robust activation of Cdc42, LM-332 provoked a strong and sustained activation of FAK. Interestingly, activation of Rac1 was necessary but not sufficient to promote migration because there was no directed migration on LM-111 despite Rac1 activation. In contrast, RhoA antagonized directional migration, since silencing of RhoA by RNA interference boosted unidirectional migration on LM-332. Molecular analysis of the role of RhoA strongly suggested that the mechanisms involve disassembly of cell-cell contacts, loss of the cortical actin network, mobilization of alpha6beta4 integrin out of stable adhesions, and displacement of the integrin from its association with the insoluble pool of intermediate filaments. PMID- 20971526 TI - Specificities of beta1 integrin signaling in the control of cell adhesion and adhesive strength. AB - Cells exert actomyosin contractility and cytoskeleton-dependent force in response to matrix stiffness cues. Cells dynamically adapt to force by modifying their behavior and remodeling their microenvironment. This adaptation is favored by integrin activation switch and their ability to modulate their clustering and the assembly of an intracellular hub in response to force. Indeed integrins are mechanoreceptors and mediate mechanotransduction by transferring forces to specific adhesion proteins into focal adhesions which are sensitive to tension and activate intracellular signals. alpha(5)beta(1) integrin is considered of major importance for the formation of an elaborate meshwork of fibronectin fibrils and for the extracellular matrix deposition and remodeling. Here we summarize recent progress in the study of mechanisms regulating the activation cycle of beta(1) integrin and the specificity of alpha(5)beta(1) integrin in mechanotransduction. PMID- 20971527 TI - Medical students at risk of nosocomial tuberculosis. PMID- 20971528 TI - A combination of subcuticular sutures and a drain for skin closure reduces wound complications in obese women undergoing surgery using vertical incisions. AB - Obesity is a risk factor for surgical site or wound complications in women undergoing surgery involving vertical incisions. Several investigators have reported the efficacy of subcutaneous drains in minimising the complication rate but there is no consensus on using these for surgery in obese patients. In 2006, the Scottish Surveillance of Healthcare Associated Infection Programme showed that using subcuticular sutures rather than staples to close incisions significantly reduced the risk of surgical site infection. Before January 2008 (group 1; N = 40), wound complications occurred in some obese patients in our hospital after obstetric and gynaecological surgery when only staples were used for skin closure. In January 2008 (group 2; N = 31), we changed the method of skin closure for obese patients [body mass index (BMI) > 28 kg/m(2)] and we now use a subcutaneous drain with four channels along the running tube and subcuticular sutures with interrupted, buried 4-0 polydioxanone sutures. The aim of this study was to assess the effects of these interventions for skin closure in obese women. The general characteristics (age, weight and BMI) were similar between the two groups. There were no wound complications in group 2. In group 1, wound disruptions and a seroma occurred in five (12.5%) and one (2.5%) patients, respectively. The wound complication rate in group 2 was significantly lower than that in group 1 (P = 0.0319). Thus, new materials and techniques for skin closure can reduce the wound complication rate in obese women. PMID- 20971529 TI - Preventing catheter-related bloodstream infections: an executive summary of the APIC elimination guide. AB - This article is an executive summary of the APIC Elimination Guide for catheter related bloodstream infections. Infection preventionists are encouraged to obtain the original, full-length APIC Elimination Guide for more thorough coverage of catheter-related bloodstream infections prevention. PMID- 20971530 TI - Evaluation of the duration of vanA vancomycin-resistant Enterococcus faecium carriage and clearance during a large-scale outbreak in a region of eastern France. AB - A monthly follow-up evaluation of vancomycin-resistant Enterococcus-colonized patients conducted during an outbreak in France revealed that carriage can persist for an extended period. Recurrence was observed despite as many as 3 negative cultures. As a result, we propose another definition for VRE clearance. PMID- 20971531 TI - 4-[1-(Substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids: synthesis, antimicrobial activity, QSAR studies, and antiviral evaluation. AB - A series of 4-[1-(substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzene sulphonic acids (1-20) was synthesized and evaluated, in vitro, for their antimicrobial activity and the results indicated that compounds 4-[1-(4 Nitrobenzoyl)-1H-benzoimidazol-2-yl]-benzenesulfonic acid (9) and 4-(1-octadec-9 enoyl-1H-benzoimidazol-2-yl)-benzenesulfonic acid (18) were found to be the most active ones. QSAR investigations indicated that the multi-target QSAR model was effective in describing the antimicrobial activity over the one-target QSAR models. Further the mt-QSAR model indicated the importance of the topological parameter, Balaban index (J) followed by the electronic parameter, LUMO and topological parameter, valence second order molecular connectivity index (2chiv) in describing the antimicrobial activity of synthesized compounds (1-20). PMID- 20971532 TI - Synthesis of novel alpha-santonin derivatives as potential cytotoxic agents. AB - Ten novel alpha-santonin derivatives have been synthesized as cytotoxic agents. The in vitro antitumor activity of these compounds has been evaluated against cancer cells lines. Structure-activity relationships indicate that alpha methylene-gamma-lactone and endoperoxide functionalities play important roles in conferring cytotoxicity. The compounds 2-4, possessing the alpha-methylene-gamma lactone group showed IC50 values between 5.70 and 16.40 MUM. Mixture of isomers 5 and 6, with the alpha-methylene-gamma-lactone and endoperoxide functionalities, displayed the greatest activity, with IC50 values between 1.45 and 4.35 MUM. The biological assays conducted with normal cells revealed that the compounds 2, 5 and 6 are selective against cancer cells lines tested. Bioactive lactones described herein and in our previous report did not cause disruption of the cell membrane in mouse erythrocytes. PMID- 20971533 TI - [Abdominal tuberculosis: a retrospective series of 90 cases]. AB - PURPOSE: The aim of this study was to analyze the clinical, bacteriological, radiological and therapeutic features of abdominal tuberculosis in a series of 90 patients. METHODS: This was a retrospective and descriptive multicentre study of 90 cases of abdominal tuberculosis conducted from June 1997 to June 2008. Diagnosis of tuberculosis was based on bacteriologic evidence in 12 cases, histological evidence in 55 cases and on clinical and radiologic features with favorable outcomes under specific treatment in the 23 remaining cases. RESULTS: Thirty-one patients were male and 59 were female. The mean age of the patients was 41.5 years. Family history of tuberculosis was reported in three cases. Associated risk factors were: diabetes mellitus (five cases), ethylism (one case), post-hepatitis C cirrhosis (one case), systemic lupus erythematosus treated by corticosteroids (one case). Sites of involvement were: peritoneum (78 cases), liver (14 cases), gut (nine cases) and spleen (eight cases). Forty-eight patients (53,3%) had only an abdominal involvement, nine others patients (10%) had an abdominal involvement associated with intra-abdominal lymph nodes, 16 patients (17,8%) had a respiratory involvement (pulmonary, pleural and mediastinal lymph nodes), eight patients (8,8%) presented with an extra-abdominal and extra-respiratory involvement and 10 patients (11,1%) had respiratory and extra-respiratory disease associated with abdominal involvement. Among the 54 patients who underwent laparoscopy or laparotomy, diagnosis was evoked on macroscopic examination in 51. CONCLUSION: Laparoscopy and laparotomy are still helpful for the diagnosis of abdominal tuberculosis, especially in the presence of peritoneal involvement. PMID- 20971534 TI - The success of enteral nutrition and ICU-acquired infections: a multicenter observational study. AB - BACKGROUND AND AIMS: The objective of this study was to evaluate the relationship between increasing success with enteral nutrition (EN) and acquired infection in the Intensive Care Unit (ICU). METHODS: We conducted a prospective, multicenter, observational study in 3 Medical/Surgical ICUs. We included patients mechanically ventilated in ICU more than 72 h and who received enteral nutrition only. Charts were reviewed to determine success with EN delivery and clinical outcomes. Suspected infections were adjudicated by 2 or more clinicians to determine the presence or absence of infection (rated as either probable or possible infection). RESULTS: Of the 207 patients included in this analysis, the average age was 62.0 years; APACHE II score was 23.3; BMI: 28.5; and 73% were medical. Overall, patients received 48.9% (range 0-120%) of their energy and 45.1% (range 0-120%) of their protein requirements from EN. Overall, 25.1% developed an infection after 72 h from admission, 21.7% developed an infection after 96 h from admission, and the 28-day mortality was 29.0%. In a regression model, greater amounts of energy and protein were consistently associated with a reduction in infection. However, estimates only achieved levels near statistical significance for risk of at least 1 probable infection after >96 h (Odds Ratio [0R]: 0.32, 95% Confidence Interval [CI]: 0.10-1.02, p=0.054 and OR: 0.40, 95% CI: 0.18-0.89, p=0.024 per 1000 kcal/day energy and 30 grams/day protein, respectively). In all cases, the OR was lower when considering infections that developed after 96 h compared to infections that developed after 72 h and when considering 'Probable' infections compared to all infections which included 'Possible' infections. CONCLUSIONS: Successful EN may be associated with a reduction in infectious complications, particularly after 96 h of ICU admission. PMID- 20971535 TI - A randomized crossover study of the effects of glutamine and lipid on the gastric emptying time of a preoperative carbohydrate drink. AB - BACKGROUND & AIMS: Supplementing preoperative carbohydrate drinks with glutamine may lead to benefits in addition to reducing insulin resistance, but amino acids may delay gastric emptying (GE). The effects of supplementing a preoperative carbohydrate drink (CCD) with glutamine or lipid on GE were studied. METHODS: Ten healthy male volunteers ingested 410 ml of one of three isocaloric-isovolumetric carbohydrate-based drinks labelled with (99m)Tc-DTPA: CCD (preOp((r)), Nutricia, UK, 50 g carbohydrate), CCD/G (preOp((r)), 36 g carbohydrate + 15 g glutamine) or CCD/L (preOp((r)), 36 g carbohydrate + 7 g lipid) in this randomized, blinded, three-way crossover study. After baseline measurements, GE was measured scintigraphically and blood sampled for insulin, glucose and glucagon-like peptide 1 (GLP-1) at 20 min intervals for 240 min. RESULTS: Mean (95% CI) T(90) GE times for CCD, CCD/G and CCD/L were 101 (87-115), 95 (84-107) and 87 (72-102) min, respectively. At 40 min postprandially, mean (SEM) concentrations of glucose (mmol/l) and insulin (mIU/l) were 7.5 (0.5) and 35 (5) for CCD; 6.2 (0.2) and 28 (4) for CCD/G; and 7 (0.3) and 31 (5) for CCD/L, respectively. There were no differences in postprandial GLP-1 concentrations. CONCLUSIONS: Glutamine and lipid supplementation did not prolong the GE of CCD but did 'blunt' postprandial glucose and insulin responses, independent of GLP-1 concentrations. Registered under ClinicalTrials.gov Identifier no. NCT00943020. PMID- 20971536 TI - Detection of eating disorders in patients: validity and reliability of the French version of the SCOFF questionnaire. AB - BACKGROUND & AIMS: Although eating disorders prevalence is increasing, they are often under diagnosed in cases of unspecific signs of malnutrition. Screening scales may allow earlier diagnosis and nutritional intervention. This study aimed to evaluate the validity of the French version (SCOFF-F) of the SCOFF questionnaire for the detection of eating disorders among a female patient population referred to a clinical nutrition unit. METHODS: After answering the 5 dichotomous questions of the paper version of SCOFF-F, patients were evaluated by one eating disorders specialist blinded to questionnaire results, using the MINI and Diagnosis and Statistical Manual for Mental diseases (DSM-IV) criteria as a gold standard. RESULTS: Patients with anorexia nervosa (n = 67) and with bulimia nervosa (n = 45) were assessed. Age-matched healthy female students (n = 114) served as control group. At a cut-off of two positive responses, the sensibility, specificity and the area under the curve of SCOFF-F were 94.6%, 94.7% and 97.9% respectively. Cohen's kappa coefficient between SCOFF-F and MINI results was 89%. CONCLUSIONS: The results of this study confirm the reliability of SCOFF-F as a screening and diagnostic-facilitating test for eating disorders in a French speaking female patient population. SCOFF-F should help professionals in clinical nutrition to achieve earlier diagnosis and care of eating disorder patients. PMID- 20971537 TI - British Association of Oral and Maxillofacial Surgeons first national audit in support of revalidation. AB - This is the first national audit of Fellows of the British Association of Oral and Maxillofacial Surgeon with the specific purpose of supporting consultant revalidation. The audit was performed online. There were 127 responses from 275 email invitations. The audit reflects the range of activity by consultants with over 90% being involved in dento-alveolar, trauma and oral medicine. 78% of consultants performing head and neck oncology had a database and 75% of cleft lip and palate surgeons. Contributions to audits in the last 3 years were least common in oral medicine (7%), skull base (7%), aesthetic surgery (8%), and paediatric maxillofacial surgery (12%). There were many different audits reflected in consultants responses and there is merit in focusing on specific audits suitable for national comparison and benchmarking. PMID- 20971538 TI - Metal and metalloid contamination in roadside soil and wild rats around a Pb-Zn mine in Kabwe, Zambia. AB - Metal (Cr, Co, Cu, Zn, Cd, Pb, Ni) and metalloid (As) accumulation was studied in roadside soil and wild rat (Rattus sp.) samples from near a Pb-Zn mine (Kabwe, Zambia) and the capital city of Zambia (Lusaka). The concentrations of the seven metals and As in the soil samples and Pb in the rat tissue samples were quantified using atomic absorption spectroscopy. The concentrations of Pb, Zn, Cu, Cd, and As in Kabwe soil were much higher than benchmark values. Geographic Information System analysis indicated the source of metal pollution was mining and smelting activity. Interestingly, the area south of the mine was more highly contaminated even though the prevailing wind flow was westward. Wild rats from Kabwe had much higher tissue concentrations of Pb than those from Lusaka. Their body weight and renal Pb levels were negatively correlated, which suggests that mining activity might affect terrestrial animals in Kabwe. PMID- 20971539 TI - Examining spatial variations in the prevalence of mental health problems among 5 year-old children in Canada. AB - The purpose of this study is to examine spatial variations in the prevalence rates of the three most common behaviour problems among 5-year-old children in Canada, to establish the data's suitability for potential spatial analyses of factors contributing to the prevalence of such problems. Data on kindergarten children's outcomes are routinely collected for populations of children in Canada using the Early Development Instrument (EDI), a population-level, teacher completed questionnaire. These data have been previously used to estimate prevalence rates of aggression, anxiety, and hyperactivity. The current study geographically analyzed these estimates to examine their consistency in relation to gender differences at larger provincial geographies and smaller Census Subdivision (CSD) geographies. Multilevel analyses were completed to examine the variation in prevalence at both levels of geography. Data for over 150,000 5-year olds in three Canadian provinces and 410 Census Subdivisions were available for analyses. Prevalence rates of behaviour problems estimated with the EDI showed consistent gender relationships at both levels of aggregation. Controlling for individuals' age and sex, there was significant variation at the CSD level in risk of behavioural problems, and for anxiety and aggression, this was not explained by the distribution of CSDs in different provinces. This suggests local variation in these aspects of children's behaviour, within provinces. These findings open up the opportunity to further explore the utility and variability of EDI-based spatial variation in children's mental health. PMID- 20971540 TI - Birth choices in Timor-Leste: a framework for understanding the use of maternal health services in low resource settings. AB - The high rate of maternal mortality in Timor-Leste is a persistent problem which has been exacerbated by the long history of military occupation and ongoing political crises since independence in 1999. It is similar to other developing countries where there have been slow declines in maternal mortality despite 20 years of Safe Motherhood interventions. The national Ministry of Health, United Nations (UN) agencies and non-government organisations (NGOs) have attempted to reduce maternal mortality by enacting policies and interventions to increase the number of births in health centres and hospitals. Despite considerable effort in promoting facility-based delivery, most Timorese women birth at home and the lack of midwives means few women have access to a skilled birth attendant. This paper investigates factors influencing access to and use of maternal health services in rural areas of Timor-Leste. It draws on 21 interviews and 11 group discussions with Timorese women and their families collected over two periods of fieldwork, one month in September 2006 and five months from July to December 2007. Theoretical concepts from anthropology and health social science are used to explore individual, social, political and health system issues which affect the way in which maternal health services are utilised. In drawing together a range of theories this paper aims to extend explanations around access to maternal health services in developing countries. An empirically informed framework is proposed which illustrates the complex factors that influence women's birth choices. This framework can be used by policy-makers, practitioners, donors and researchers to think critically about policy decisions and where investments can have the most impact for improving maternal health in Timor-Leste and elsewhere. PMID- 20971541 TI - Concordance between clinical and histopathologic diagnoses of oral mucosal lesions. AB - PURPOSE: To study the epidemiology of oral soft tissue lesions in New Zealand from 2002 to 2006 and to determine the concordance between the clinical diagnosis and the definitive histopathologic diagnosis achieved by general dental practitioners and by specialists. MATERIALS AND METHODS: The details from biopsy referrals and the corresponding histopathologic reports of oral soft tissue lesions were recorded into a statistical software package, and the concordance between the clinical diagnosis and histopathologic diagnosis was determined for all the lesions. RESULTS: Most biopsies were benign lesions, and both clinician groups achieved a high diagnostic concordance for these lesions. However, when considering all lesion types, the overall concordance for both groups was a moderate 50.6%, with little difference between specialists and general dental practitioners, although specialists were more accurate in diagnosing a malignant or premalignant lesion. CONCLUSIONS: The clinical and histopathologic concordance achieved by oral health practitioners in New Zealand appears to be moderate. PMID- 20971542 TI - Fluorescence-guided bone resection in bisphosphonate-related osteonecrosis of the jaws: first clinical results of a prospective pilot study. AB - PURPOSE: Surgical debridement is the therapy of choice in advanced stages of bisphosphonate-related osteonecrosis of the jaws (BRONJ). However, the therapy is currently only loosely standardized because no suitable imaging modalities exist. This study aims to redress this by exploring the suitability and reproducibility of applying a fluorescence-guided bone resection to patients with BRONJ. PATIENTS AND METHODS: This prospective pilot study comprised 15 patients with 20 BRONJ lesions (only stages II and III) with a history of intravenous bisphosphonate treatment for metastatic bone diseases. Before surgical treatment, each patient received a 10-day administration of doxycycline. Fluorescence-guided resection of necrotic bone was performed by means of a certified fluorescence lamp. Success of the procedure was proclaimed if mucosal closure was observed and symptoms were absent 4 weeks postoperatively. RESULTS: The 4-week postoperative follow-up identified a mucosal closure in 17 of 20 BRONJ lesions (85%). These patients were free of any symptoms. Failure as defined by mucosal dehiscence and exposed bone was observed in 3 of 20 BRONJ lesions (15%). CONCLUSION: The success rate of this surgical regimen of BRONJ was respectable, and thus fluorescence-guided bone resection can be considered an effective treatment for stage II and stage III BRONJ. Furthermore, the reproducibility of the technique offers an opportunity to standardize the surgical therapy. Further studies are called for that compare the fluorescence-guided bone resection with conventional surgical approaches, as well as surgical versus conservative treatment in the early stages (stages 0 and I) of BRONJ. PMID- 20971543 TI - Effect of platelet-rich plasma on a rabbit model of nicotine-compromised bone healing. AB - PURPOSE: This study aimed to evaluate the effects of platelet-rich plasma (PRP) on nicotine-compromised bone healing. MATERIALS AND METHODS: Fifteen adult New Zealand white rabbits were implanted with 1.5-g time-release nicotine pellets. Bilateral mandibular distraction osteogenesis was then performed. Autologous PRP was injected into 1 side of the distraction regenerate, whereas physiologic saline solution was injected into the contralateral side as a control. Five rabbits were killed on day 5 of active distraction, on day 11 of active distraction, and in week 2 of consolidation, respectively. RESULTS: In the PRP the platelet enrichment was 14.63 +/- 3.081-fold of that in whole blood. Plain radiography and micro-computed tomography assessment showed no significant difference between the PRP injection and control sides. Histologic examination showed more disorganized distraction tissue on the PRP injection side. CONCLUSIONS: PRP injection at an early stage of active distraction does not significantly enhance bone healing in the nicotine-compromised rabbit model of mandibular lengthening. PMID- 20971544 TI - Morbidity after iliac crest bone graft harvesting over an anterior versus posterior approach. AB - PURPOSE: For larger augmentations before implant insertions, as well as spinal arthrodesis surgery, the iliac crest is the standard source of bone grafting. This study assesses iliac morbidity after bone graft harvesting from the anterior and posterior ilium. MATERIALS AND METHODS: A total of 97 patients who underwent corticocancellous iliac crest bone harvesting for augmentations of the jaws from 2004 to 2007 at the Department of Oral and Maxillofacial Surgery, University Hospital Kiel, Kiel, Germany, were included. Their morbidity was assessed with specially designed questionnaires. RESULTS: Pain levels were rated nearly equally on a visual analog scale (1, no pain; 10, strongest pain) by the anterior and posterior groups. At 1 week after bone harvesting, pain was rated 4.9 for the anterior approach and 4.8 for posterior (P = .89). The corresponding values after 6 months were 1.4 and 1.6, respectively (P = .64). Subjective evaluation of the scars showed scores of 2.7 and 3.0, respectively (P = .76). Of the patients, 81% and 88%, respectively, would opt to undergo the operation again. CONCLUSIONS: Patients reported a noticeable reduction in quality of life after elective bone graft harvesting. Nevertheless, nearly all patients would undergo the same procedure again. Both approaches were rated similarly, so for smaller amounts of bone graft needed, the anterior and posterior approaches can be recommended, whereas the posterior approach is suitable for larger amounts. PMID- 20971545 TI - Office accreditation experiences with 3 accrediting agencies and suggestions for changes in private oral and maxillofacial surgery facility evaluations. AB - Historically, oral and maxillofacial surgeons have had considerable autonomy in operating their offices. Oral and maxillofacial surgeons have had a singular history of safety, training, and success in outpatient anesthesia in their offices. However, preventable patient morbidity and mortality in private office based surgical facilities of a variety of professions have brought increased scrutiny to the office environment. The present report describes the experiences of 3 oral and maxillofacial surgeons with 3 accrediting agencies in obtaining office accreditation and offers recommendations to be considered for the future of our specialty in terms of private office certification. PMID- 20971546 TI - Adaptive management on the central Platte River--science, engineering, and decision analysis to assist in the recovery of four species. AB - Active adaptive management is the centerpiece of a major species recovery program now underway on the central Platte River in Nebraska. The Platte River Recovery Implementation Program initiated on January 1, 2007 and is a joint effort between the states of Colorado, Wyoming, and Nebraska; the U.S. Department of the Interior; waters users; and conservation groups. This program is intended to address issues related to endangered species and loss of habitat along the Platte River in central Nebraska by managing land and water resources and using adaptive management as its science framework. The adaptive management plan provides a systematic process to test hypotheses and apply the information learned to improve management on the ground, and is centered on conceptual models and priority hypotheses that reflect different interpretations of how river processes work and the best approach to meeting key objectives. This framework reveals a shared attempt to use the best available science to implement experiments, learn, and revise management actions accordingly on the Platte River. This paper focuses on the status of adaptive management implementation on the Platte, experimental and habitat design issues, and the use of decision analysis tools to help set objectives and guide decisions. PMID- 20971547 TI - Chlorophenol degradation in soil columns inoculated with Anthracophyllum discolor immobilized on wheat grains. AB - The white-rot fungus Anthracophyllum discolor immobilized on wheat grains was evaluated for chlorophenol (2,4-dichlorophenol, 2,4,6-trichlorophenol and pentachlorophenol) degradation in allophanic soil columns activated by acidification. Columns without inoculation were used as the control to evaluate the adsorption capacity of the soil columns. The chlorophenols were removed efficiently in soil columns by both adsorption and degradation processes. In inoculated soil columns, 2,4-dichlorophenol was highly degraded and this degradation is associated with a high production of manganese peroxidase. 2,4,6 trichlorophenol was degraded to a lesser extent compared with 2,4-dichlorophenol. Pentachlorophenol was first removed by adsorption and then through degradation by the fungus. Manganese peroxidase activity was lowest when the column was fed with pentachlorophenol and highest when the column was fed with 2,4-dichlorophenol. Laccase was also produced by the fungus but to a lesser degree. PMID- 20971548 TI - Improving our legacy: incorporation of adaptive management into state wildlife action plans. AB - The loss of biodiversity is a mounting concern, but despite numerous attempts there are few large scale conservation efforts that have proven successful in reversing current declines. Given the challenge of biodiversity conservation, there is a need to develop strategic conservation plans that address species declines even with the inherent uncertainty in managing multiple species in complex environments. In 2002, the State Wildlife Grant program was initiated to fulfill this need, and while not explicitly outlined by Congress follows the fundamental premise of adaptive management, 'Learning by doing'. When action is necessary, but basic biological information and an understanding of appropriate management strategies are lacking, adaptive management enables managers to be proactive in spite of uncertainty. However, regardless of the strengths of adaptive management, the development of an effective adaptive management framework is challenging. In a review of 53 State Wildlife Action Plans, I found a keen awareness by planners that adaptive management was an effective method for addressing biodiversity conservation, but the development and incorporation of explicit adaptive management approaches within each plan remained elusive. Only ~25% of the plans included a framework for how adaptive management would be implemented at the project level within their state. There was, however, considerable support across plans for further development and implementation of adaptive management. By furthering the incorporation of adaptive management principles in conservation plans and explicitly outlining the decision making process, states will be poised to meet the pending challenges to biodiversity conservation. PMID- 20971549 TI - Monitoring the effect of restoration measures in Indonesian peatlands by radar satellite imagery. AB - In the context of the ongoing climate change discussions the importance of peatlands as carbon stores is increasingly recognised in the public. Drainage, deforestation and peat fires are the main reasons for the release of huge amounts of carbon from peatlands. Successful restoration of degraded tropical peatlands is of high interest due to their huge carbon store and sequestration potential. The blocking of drainage canals by dam building has become one of the most important measures to restore the hydrology and the ecological function of the peat domes. This study investigates the capability of using multitemporal radar remote sensing imagery for monitoring the hydrological effects of these measures. The study area is the former Mega Rice Project area in Central Kalimantan, Indonesia, where peat drainage and forest degradation is especially intense. Restoration measures started in July 2004 by building 30 large dams until June 2008. We applied change detection analysis with more than 80 ENVISAT ASAR and ALOS PALSAR images, acquired between 2004 and 2009. Radar signal increases of up to 1.36 dB show that high frequency multitemporal radar satellite imagery can be used to detect an increase in peat soil moisture after dam construction, especially in deforested areas with a high density of dams. Furthermore, a strong correlation between cross-polarised radar backscatter coefficients and groundwater levels above -50 cm was found. Monitoring peatland rewetting and quantifying groundwater level variations is important information for vegetation re-establishment, fire hazard warning and making carbon emission mitigation tradable under the voluntary carbon market or REDD (Reducing Emissions from Deforestation and Degradation) mechanism. PMID- 20971550 TI - "Zero ischemia" partial nephrectomy: novel laparoscopic and robotic technique. AB - BACKGROUND: Ischemic injury impacts renal function outcomes following partial nephrectomy. Efforts to minimize, better yet, eliminate renal ischemia are imperative. OBJECTIVE: Describe a novel technique of "zero ischemia" laparoscopic (LPN) and robotic-assisted (RAPN) partial nephrectomy. DESIGN, SETTING, AND PARTICIPANTS: Data were prospectively collected into an institutional review board-approved database. Fifteen consecutive patients underwent zero ischemia procedures: LPN (n=12), RAPN (n=3). Included were all candidates for LPN or RAPN, irrespective of tumor complexity, including tumors that were central (n=9; 60%), hilar (n=1), in solitary kidney (n=1), in patients with chronic kidney disease grade 3 or greater (n=3). Anesthesia-related monitoring included pulmonary artery catheter (ie, Swan-Ganz), transesophageal echocardiography, cerebral oximetry, electroencephalographic bispectral index, mixed venous oxygen measurements, and vigorous hydration/diuresis. Pharmacologically induced hypotension was carefully timed to correspond with excision of the deepest aspect of the tumor. Renal parenchymal reconstruction was completed under normotension, ensuring complete hemostasis. MEASUREMENTS: Intraoperative and early postoperative data were collected prospectively. RESULTS AND LIMITATIONS: All cases were successfully completed without hilar clamping. Ischemia time was zero in all cases. Median tumor size was 2.5 cm (range: 1-4); operative time was 3 h (range: 1.3-6); blood loss was 150 ml (range: 20-400); and hospital stay was 3 d (range: 2-19). Nadir mean arterial pressure ranged from 52-65 mm Hg (median: 60), typically for 1-5 min. No patient had intraoperative transfusion or complication, acute or delayed renal hemorrhage, or hypotension-related sequelae. Postoperative complications (n=5) included urine retention (n=1), septicemia from presumed prostatitis (n=1), atrial fibrillation (n=1), urine leak (n=2). Pathology confirmed renal cell carcinoma in 13 patients (87%), all with negative margins. Median pre- and postoperative serum creatinine (0.9 mg/dl and 0.95 mg/dl, respectively) and estimated glomerular filtration rate (eGFR) (75.3 and 72.9, respectively) were comparable. Median absolute and percent change in discharge serum creatinine and eGFR were 0 and 0%, respectively. CONCLUSIONS: A novel zero ischemia technique for RAPN and LPN for substantial renal tumors is presented. The initial experience is encouraging. PMID- 20971552 TI - Hepatitis B viral X protein interacts with tumor suppressor adenomatous polyposis coli to activate Wnt/beta-catenin signaling. AB - HBV X protein is a transactivator of several cellular signaling pathways including Wnt which contributes to HBV associated neoplasia. The Wnt/beta-catenin pathway is associated with HCC-initiating cells. Here we perform a functional screen for host factors involved in the transactivational properties of HBx. We identify adenomatous polyposis coli (APC) as a binding partner of HBx and further determine that HBx competitively binds APC to displace beta-catenin from its degradation complex. This results in beta-catenin upregulation in the nucleus and the activation of Wnt signaling. We show that Wnt inhibitors curcumin and quercetin target downstream beta-catenin activity and effectively repress HBx mediated regulation of c-MYC and E-cadherin. Our results provide a pathological mechanism of HBx induced malignant transformation. PMID- 20971553 TI - Synthesis and characterization of nano-pore thallium (III) ion-imprinted polymer as a new sorbent for separation and preconcentration of thallium. AB - Thallium (III) ion-imprinted polymer (IIP) particles were synthesized by preparing the ternary complex of thallium (III) ions with 5,7-dichloroquinoline-8 ol (DCQ) and 4-vinylpyridine (VP). Thermal copolymerization with methyl methacrylate (functional monomer, MMA) and ethyleneglycoldimethacrylate (cross linking monomer, EGDMA) was then performed in the presence of acetonitrile (porogen) and 2,2- azobisisobutyronitrile(initiator, AIBN). The imprinted ion was removed from polymer by stirring of the above particles with 5M HNO(3) to obtain the leached IIP particles. Moreover, control polymer (CP) particles were similarly prepared without the thallium (III) ions. The unleached and leached IIP particles were characterized by surface area analysis (BET), X-ray diffraction (XRD), Fourier transform infra-red spectroscopy (FT-IR), thermo gravimetric analysis (TGA) and scanning electron microscopy (SEM). The preconcentration of thallium (III) from aqueous solution was studied during rebinding with the leached IIP particles as a function of pH, the weight of the polymer material, the uptake and desorption times, the aqueous phase and the desorption volumes. Electrothermal atomic absorption spectrometry (ETAAS) was employed for determination of thallium in aqueous solution. The limit of detection for the method was 0.02 ng mL(-1), while the relative standard deviation for five replicates was 2.6%. PMID- 20971551 TI - Viruses and human cancer: from detection to causality. AB - The study of cancer is incomplete without taking into consideration of tumorigenic viruses. Initially, searches for human cancer viruses were fruitless despite an expansion of our knowledge in the same period concerning acute transforming retroviruses in animals. However, over the last 40 years, we have witnessed rapid progress in the tumor virology field. Currently, acknowledged human cancer viruses include Epstein-Barr virus, hepatitis B virus, hepatitis C virus, high-risk human papilloma viruses, human T-cell lymphotropic virus type 1 and Kaposi's sarcoma-associated herpesvirus. Extensive epidemiological and mechanistic studies have led to the development of novel preventive and therapeutic approaches for managing some of these infections and associated cancers. In addition, recent advances in molecular technologies have enabled the discovery of a new potential human tumor virus, Merkel cell polyomavirus, but its association with cancer remains to be validated. It is anticipated that in the next few decades many additional human cancer viruses will be discovered and the mechanisms underlying viral oncogenesis delineated. Thus, it can be expected that better tools for preventing and treating virus-associated cancer will be available in the near future. PMID- 20971554 TI - Ionic liquid ultrasound assisted dispersive liquid-liquid microextraction method for preconcentration of trace amounts of rhodium prior to flame atomic absorption spectrometry determination. AB - In this article, we consider ionic liquid based ultrasound-assisted dispersive liquid-liquid microextraction of trace amounts of rhodium from aqueous samples and show that this is a fast and reliable sample pre-treatment for the determination of rhodium ions by flame atomic absorption spectrometry. The Rh(III) was transferred into its complex with 2-(5-bromo-2-pyridylazo)-5 diethylamino phenol as a chelating agent, and an ultrasonic bath with the ionic liquid, 1-octyl-3-methylimidazolium bis (trifluoromethylsulfonyl) imide at room temperature was used to extract the analyte. The centrifuged rhodium complex was then enriched in the form of ionic liquid droplets and prior to its analysis by flame atomic absorption spectrometry, 300 MUL ethanol was added to the ionic liquid-rich phase. Finally, the influence of various parameters on the recovery of Rh(III) was optimized. Under optimum conditions, the calibration graph was linear in the range of 4.0-500.0 ng mL(-1), the detection limit was 0.37 ng mL( 1) (3S(b)/m, n = 7) and the relative standard deviation was +/-1.63% (n = 7, C = 200 ng mL(-1)). The results show that ionic liquid based ultrasound assisted dispersive liquid-liquid microextraction, combined with flame atomic absorption spectrometry, is a rapid, simple, sensitive and efficient analytical method for the separation and determination of trace amounts of Rh(III) ions with minimum organic solvent consumption. PMID- 20971555 TI - Isolation of phosphate solubilizing bacteria and their potential for lead immobilization in soil. AB - Lead (Pb), a highly toxic heavy metal forms stable compounds with phosphate (P). The potential of phosphate solubilizing bacteria (PSB) to immobilize Pb by enhancing solubilization of insoluble P compounds was tested in this research. Eighteen different PSB strains isolated from P amended and Pb contaminated soils were screened for their efficiency in P solubilization. The PSB isolated from P amended soils solubilized 217-479 mg/L of P while the PSB from Pb contaminated soil solubilized 31-293 mg/L of P. Stepwise multiple regression analysis and P solubility kinetics indicated that the major mechanism of P solubilization by PSB is the pH reduction through the release of organic acids. From the isolated bacteria, two PSB were chosen for Pb immobilization and these bacteria were identified as Pantoea sp. and Enterobacter sp., respectively. The PSB significantly increased P solubilization by 25.0% and 49.9% in the case of Pantoea sp., and 63.3% and 88.6% in the case of Enterobacter sp. for 200 and 800 mg/kg of rock phosphate (RP) addition, respectively, thereby enhancing the immobilization of Pb by 8.25-13.7% in the case of Pantoea sp. and 14.7-26.4% in the case of Enterobacter sp. The ability of PSB to solubilize P, promote plant growth, and immobilize Pb can be used for phytostabilization of Pb contaminated soils. PMID- 20971556 TI - Kinetics and equilibrium studies on biosorption of cadmium, lead, and nickel ions from aqueous solutions by intact and chemically modified brown algae. AB - The present study deals with the evaluation of biosorptive removal of Cd (II), Ni (II) and Pb (II) ions by both intact and pre-treated brown marine algae: Cystoseira indica, Sargassum glaucescens, Nizimuddinia zanardini and Padina australis treated with formaldehyde (FA), glutaraldehyde (GA), polyethylene imine (PEI), calcium chloride (CaCl(2)) and hydrochloric acid (HCl). Batch shaking adsorption experiments were performed in order to examine the effects of pH, contact time, biomass concentration, biomass treatment and initial metal concentration on the removal process. The optimum sorption conditions for each heavy metal are presented. One-way ANOVA and one sample t-tests were performed on experimental data to evaluate the statistical significance of biosorption capacities after five cycles of sorption and desorption. The equilibrium experimental data were tested using the most common isotherms. The results are best fitted by the Freundlich model among two-parameter models and the Toth, Khan and Radke-Prausnitz models among three-parameter isotherm models for Cd (II), Ni (II) and Pb (II), respectively. The kinetic data were fitted by models including pseudo-first-order and pseudo-second-order. From the results obtained, the pseudo second-order kinetic model best describes the biosorption of cadmium, nickel and lead ions. PMID- 20971557 TI - Sorption and desorption of pentachlorophenol to black carbon of three different origins. AB - Rice straw charcoal, soot and fly ash (collectively termed "black carbon" or BC), which were found to widely exist in the environment and exhibit strong sorption of many organic compounds, were prepared for this study, and recorded as RC, SC, and FC, respectively. The characterization, sorption isotherm, and the effect of pH (from 3.0 to 9.0) on sorption capacity of each BC were investigated. It is demonstrated that RC possessed the largest surface area (234.9 m(2)/g), the highest porosity (0.4392 mL/g), and the largest amount of functional groups (2.995 mmol/g) of all. All the Freundlich, Langmuir and Dual-mode model can fit the sorption data of each BC well. The pH value could apparently affect the sorption capacity of pentachlorophenol (PCP) to BCs, which reached maximum value at pH 4.0. Furthermore, in order to validate the effect of pH on desorption capacity, we designed sorption-desorption cycle experiments at pH 9.0 and then pH 7.0, and found that the effect of pH on irreversible sorption and hysteresis effects were significant. As pH value decreasing from 9.0 to 7.0, the irreversible sorption capacities for RC, FC, and SC increased, and the desorption hysteresis index (H) values of PCP increased approximately 3 times for each BC. PMID- 20971558 TI - A risk-based decision tool for the management of organic waste in agriculture and farming activities (FARMERS). AB - Currently, specific management guidelines must be implemented for guaranteeing the safe reuse of organic waste in agriculture. With that aim, this work was focused on the development of a decision support tool for a safe and sustainable management of cattle manure as fertiliser in pastureland, to control and limit metal accumulation in soil and to reduce metal biotransfer from soil to other compartments. The system was developed on the basis of an environmental risk assessment multi-compartmental model. In contrast to other management tools, a long-term dynamic modelling approach was selected considering the persistence of metals in the environment. A detailed description of the underlying flow equations which accounts for distribution, human exposure and risk characterisation of metals in the assessed scenario was presented, as well as model parameterization. The tool was implemented in Visual C++ and is structured on a data base, where all required data is stored, the risk assessment model and a GIS module for the visualization of the scenario characteristics and the results obtained (risk indexes). The decision support system allows choosing among three estimation options, depending on the needs of the user, which provide information to both farmers and policy makers. The first option is useful for evaluating the adequacy of the current management practices of the different farms, and the remaining ones provides information on the measures that can be taken to carry out a fertilising plan without exceeding risk to human health. Among other results, maximum values of application rates of manure, maximum permissible metal content of manure and maximum application times in a particular scenario can be estimated by this system. To illustrate tool application, a real case study with data corresponding to different farms of a milk production cooperative was presented. PMID- 20971559 TI - Effects from log-yard stormwater runoff on the microalgae Scenedesmus subspicatus: intra-storm magnitude and variability. AB - This paper describes the effects posed by stormwater runoff from an industrial log-yard on the microalgae Scenedesmus subspicatus. The effects of stormwater runoff sampled during two rain events were determined by exposing S. subspicatus cells to different concentrations (% v:v) of each sample. The effects were measured as the percentage change in growth rates in relation to a control culture after exposure times of 24, 48, 72 and 96 h. The runoff from the first rain event had no negative effects to S. subspicatus, posing in most cases growth stimulation, whereas the runoff from the second rain event inhibited algae growth. Differences in runoff physico-chemical characteristics combined with the hydrological factors of each rain event explained these opposite effects. The hypothesis of toxic first flush phenomenon was confirmed in the second rain event on the basis of normalized inhibitory effects and runoff volume. It was found that 42, 51 and 50% of the inhibitory effects during exposures of 24, 48 and 72 h were associated with the initial 4% of the total discharged volume. The fact that negative effects were observed in the two runoff events analyzed, raises concern about the potential environmental threats posed by runoff originated from wood based industrial areas during the entire hydrological year. PMID- 20971560 TI - Dural afferents express acid-sensing ion channels: a role for decreased meningeal pH in migraine headache. AB - Migraine headache is one of the most common neurological disorders. The pathological conditions that directly initiate afferent pain signaling are poorly understood. In trigeminal neurons retrogradely labeled from the cranial meninges, we have recorded pH-evoked currents using whole-cell patch-clamp electrophysiology. Approximately 80% of dural-afferent neurons responded to a pH 6.0 application with a rapidly activating and rapidly desensitizing ASIC-like current that often exceeded 20nA in amplitude. Inward currents were observed in response to a wide range of pH values and 30% of the neurons exhibited inward currents at pH 7.1. These currents led to action potentials in 53%, 30% and 7% of the dural afferents at pH 6.8, 6.9 and 7.0, respectively. Small decreases in extracellular pH were also able to generate sustained window currents and sustained membrane depolarizations. Amiloride, a non-specific blocker of ASIC channels, inhibited the peak currents evoked upon application of decreased pH while no inhibition was observed upon application of TRPV1 antagonists. The desensitization time constant of pH 6.0-evoked currents in the majority of dural afferents was less than 500ms which is consistent with that reported for ASIC3 homomeric or heteromeric channels. Finally, application of pH 5.0 synthetic interstitial fluid to the dura produced significant decreases in facial and hind paw withdrawal threshold, an effect blocked by amiloride but not TRPV1 antagonists, suggesting that ASIC activation produces migraine-related behavior in vivo. These data provide a cellular mechanism by which decreased pH in the meninges following ischemic or inflammatory events directly excites afferent pain sensing neurons potentially contributing to migraine headache. PMID- 20971561 TI - Trajectories of pain in adolescents: a prospective cohort study. AB - Identification of different patterns of change in pain over time - trajectories - has the potential to provide new information on the course of pain. Describing trajectories among adolescents would improve understanding of how pain conditions can develop. This prospective cohort study identified distinct trajectories of pain among adolescents (11-14 years) in the general population (n=1336). Latent class growth analysis was carried out on the self-reported frequency of back pain, headache, stomach pain and facial pain, which was collected every 3 months for 3 years. Forty four percent of adolescents had a 'painful' trajectory for at least one pain site, and 12% reported persistent pain at one or more pain site. Headache was the most common; 25% of subjects were in a 'painful' trajectory and 5% reported persistent pain. Back pain and stomach pain were also common, with 22% and 21% of subjects in painful trajectories, respectively. Facial pain was the least common, with only 10% in a painful trajectory, and 1% reporting persistent pain. Trajectory characteristics were similar at baseline across pain sites, with the more painful trajectories having significantly higher levels of depression and somatization, lower life satisfaction and more females. Trajectories did not differ significantly at baseline in physical activity levels or BMI. Agreement of trajectory membership among pain sites was moderate. In summary, reporting a painful trajectory was common among adolescents, but persistent pain was reported by a small minority, and was usually experienced at a single pain site. PMID- 20971562 TI - Pain in neonates is different. AB - Pain processing and management in neonates, especially preterm neonates, differs from older populations. In this review, a brief background on pain processing in neonatal life, pain exposure in Neonatal Intensive Care Units (NICU), the consequences of untreated pain, and the difficulties in treating procedural pain pharmacologically will be presented. A more detailed review of non pharmacological interventions for procedural pain in neonates will include sensory stimulation approaches, oral sweet solutions, and maternal interventions. Some possible mechanisms for the effectiveness of non-pharmacological interventions are offered. Finally, avenues of research into similar interventions as adjuvant therapies or drug-sparing effects in older populations are suggested. PMID- 20971563 TI - The potential for zoonotic transmission of Giardia duodenalis and Cryptosporidium spp. from beef and dairy cattle in Ontario, Canada. AB - The objective of this study was to compare the occurrence and the genotypes and species of Giardia duodenalis and Cryptosporidium spp. in beef and dairy cattle from farms in the Regional Municipality of Waterloo, Ontario, in an effort to determine the potential for zoonotic transmission from these animals. Pooled manure samples were collected from 45 dairy cattle farms and 30 beef cattle farms. The presence of Giardia cysts and Cryptosporidium oocysts was determined by immunofluorescence microscopy, while nested-PCR and DNA sequencing were used to determine genotypes and species. The overall farm prevalence was very high for both Giardia and Cryptosporidium, and was similar for dairy cattle farms (96 and 64%, respectively) and beef cattle farms (97 and 63%, respectively). However, on dairy cattle farms, G. duodenalis and Cryptosporidium spp. were detected in 44% and 6% of total pooled pen manure samples, respectively, with the occurrence of both parasites being generally higher in calves than in older animals. Most Giardia isolates were identified as either the host-adapted genotype G. duodenalis Assemblage E or the zoonotic Assemblage B. Cryptosporidium parvum and Cryptosporidium andersoni were the most frequently identified species in dairy cattle, while the non-zoonotic species Cryptosporidium ryanae and Cryptosporidium bovis were also found. On beef cattle farms, 72% and 27% of the total pooled pen manure samples were positive for Giardia and Cryptosporidium, respectively, with no obvious correlation with age. All Giardia isolates in beef cattle were identified as G. duodenalis Assemblage E, while all Cryptosporidium isolates were identified by sequence analysis as C. andersoni, although microscopic analyses, and subsequent restriction fragment length polymorphism analyses, indicated that other Cryptosporidium species were also present. The results of this study indicate that although Giardia and Cryptosporidium were identified in a higher overall percentage of the pooled beef cattle manure samples than in dairy cattle, firmly established zoonotic genotypes and species were much more common in dairy cattle than in beef cattle in this region. Dairy cattle, and especially dairy calves, may, therefore, pose a greater risk of infection to humans than beef cattle. However, these results may also provide evidence of potential zooanthroponotic transmission (human to animal). PMID- 20971564 TI - On-line 'automatic pilot' training for hand and arm motor rehabilitation after stroke. AB - As stroke being one of the most leading causes of death worldwide, even stroke survivors have to suffer from dysfunctions of limb controls and inabilities of speech or vision. Cognitive neuroscientists have found various forms of automatic behaviours in healthy people, which generally cover motor components of upper limbs and are essential for coordination and mobility relevant activities. Meanwhile, the robot-assisted therapy and functional electrical stimulation have become prominent rehabilitation techniques for patients' rehabilitation after stroke. With the integration of robot-aided therapeutic systems and the functional electrical stimulation, the on-line 'automatic pilot' training of the visual inspired stimulation for upper limbs can offer a feasible treatment for patients after stroke to recover motor performance. PMID- 20971565 TI - A novel hypurgia for cancer chemotherapy: Programmable release of antineoplastics and cytothesis agents from core-shell micro-/nano-particles. AB - As one of the main cancer therapeutic methods, chemotherapy plays a vital role in clinical practice. However, when killing the cancerous cells, the chemotherapy drugs also damage the normal cells. Side effects are still urgent problems to be solved. Cytothesis agents, like hepatocyte growth factor, can stimulate cell mitotic division and promote regeneration of blood vessel endothelium and cell migration. In this hypothesis, an adjuvant strategy for chemotherapy is proposed: the anticancer drugs and the cytothesis agents release sequentially, thus the cytothesis agents can work following the anticancer drugs killing tumor cells thoroughly, to promote normal cells proliferation. The programmable release can be achieved through micro-/nano-particles with core-shell structures that simultaneously encapsulate the two different agents in the core and shell regions, respectively. Owing to the advantages of concentrated effects, convenience, and especially its controllability, the hypothesis has potential applications in cancer chemotherapy. PMID- 20971566 TI - Could decreased vasopressin secretion be the cause of enuresis in children with migraine? Commentary on: Migraine and enuresis in children: an unusual correlation? (Medical Hypothesis 75 (2010) 120-122). PMID- 20971567 TI - The role of epigenetic regulation of membrane glycoconjugates in the attenuation of viral pandemics. AB - Cell membranes of higher organisms are covered with a dense layer of glycoconjugates which determine their interactions with other cells, intrinsic signals and environmental stimuli. The majority of pathogenic microorganisms bind to cell surface glycoconjugates and the specificity of this interaction restricts their range of hosts. Contrary to proteins, which are defined by their corresponding genes, there is no genetic template for individual glycan structures. Instead, glycan structures are encoded in a complex dynamic network of hundreds of genes that code for proteins involved in the synthesis of glycans. Large structural variability provided by glycans represents a significant evolutionary advantage and cells of all higher organisms are covered with different glycoconjugates. Here we propose a hypothesis that epigenetic regulation of the glycosylation machinery could modify surface presentation of membrane glycoconjugates, and thus render cells and whole organisms resistant to specific pathogens. This protective mechanism could be of significant importance for restricting transmission of pathogenic microorganisms and diminishing their epidemic potential. PMID- 20971568 TI - (-)-Epigallocatechin 3-gallate (EGCG) at the ocular surface inhibits corneal neovascularization. AB - Corneal neovascularization is often accompanied by inflammatory response and loss of their immune privilege which leads to significant visual impairment and worsens the prognosis of a subsequent penetrating keratoplasty. Several types of treatment are currently used. However, there are some associated limitations and complications. The consumption of (-)-epigallocatechin 3-gallate (EGCG) has been studied extensively as a potential treatment for a variety of carcinogenic and degenerative diseases due to its ability to suppress a variety of inflammatory and angiogenic factors such as NF-kappaB, IL-1beta, COX2, VEGF, and matrix metalloproteinases. These factors are involved in the development of corneal neovascularization. The safety of long-term EGCG administration as well as the drug's high solubility in water urge further investigation of the therapeutic potential of this drug. Therefore, we propose that the administration of EGCG to the ocular surface represents a new chemopreventive alternative to suppress the corneal neovascularization induced by inflammation. PMID- 20971569 TI - Parathyroid hormone(1-34)-induced apoptosis in neuronal rat PC12 cells: implications for neurotoxicity. AB - Based on accumulated evidence, we speculate that a high concentration of parathyroid hormone (PTH) may cause neurotoxicity in patients with uremia through apoptosis-induced neuropathy. In this study, we demonstrated that in vitro stimulation with PTH(1-34) induced a significant decrease in PC12 cell numbers in both dosage- and time-dependent fashions when these cells were treated with PTH(1 34) at concentrations of 0.01, 0.1 or 1.0 MUM for 24, 48, 72, and 96 h, respectively, as assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) method. Decreased numbers of PC12 cells were caused by PTH(1-34)-induced apoptotic and cytotoxic processes, as determined by DNA fragmentation, flow cytometry, and lactate dehydrogenase (LDH)-leakage assays. Upregulation of the extracellular signal-regulated kinase (ERK) and p38 signaling pathway was the underlying mechanism responsible for 1.0 MUM PTH(1-34) induced apoptosis in PC12 cells, as elucidated by Western blotting analysis and confirmed with ERK and p38 inhibitors. Furthermore, 1.0 MUM PTH(1-34)-induced apoptosis was accompanied by a release of cytochrome c and subsequent caspase-3 activation. These data suggest that a high concentration of PTH(1-34)-induced cytotoxicity and apoptosis in PC12 cells was associated with upregulation of ERK and p38 through a mitochondria-mediated apoptotic pathway. PMID- 20971570 TI - Annexin A2 as a differential diagnostic marker of hepatocellular tumors. AB - While improved imaging techniques have made it possible to detect focal liver lesions smaller than 1cm in diameter, differentiating benign lesions from hepatocellular carcinoma (HCC) still remains a challenge. To address this problem and obtain a definite diagnosis, needle core biopsies are often performed, leading to an increased need for supportive ancillary techniques in the histopathological assessment of highly differentiated hepatocellular tumors. Here we evaluate the diagnostic value of immunohistologically detected Annexin A2 (ANXA2) expression in highly differentiated liver tumors. ANXA2 is a calcium dependent phospholipid-binding protein that has been linked to malignant transformation and HCC development. Our data show that adding sinusoidal ANXA2 expression to the already established marker panel (GPC3, GS, and HSP70) increases the accuracy for the detection of well-differentiated HCC (74% sensitivity, 100% specificity). In addition, in our series, the combinations ANXA2-GPC3 and ANXA2-GS performed better compared to the other established marker combinations. In conclusion, we suggest that adding ANXA2 to the established diagnostic marker panel increases the reliability and objectivity of HCC diagnosis in liver biopsies. PMID- 20971571 TI - Three-year outcomes of a Canadian multicenter study of accelerated partial breast irradiation using conformal radiation therapy. AB - PURPOSE: To report 3-year toxicity, cosmesis, and efficacy of a multicenter study of external beam, accelerated partial breast irradiation (APBI) for early-stage breast cancer. METHODS AND MATERIALS: Between March 2005 and August 2006, 127 women aged >=40 years with ductal carcinoma in situ or node-negative invasive breast cancer <=3 cm in diameter, treated with breast-conserving surgery achieving negative margins, were accrued to a prospective study involving five Canadian cancer centers. Women meeting predefined dose constraints were treated with APBI using 3 to 5 photon beams, delivering 35 to 38.5 Gy in 10 fractions, twice a day, over 1 week. Patients were assessed for treatment-related toxicities, cosmesis, and efficacy before APBI and at specified time points for as long as 3 years after APBI. RESULTS: 104 women had planning computed tomography scans showing visible seromas, met dosimetric constraints, and were treated with APBI to doses of 35 Gy (n=9), 36 Gy (n=33), or 38.5 Gy (n=62). Eighty-seven patients were evaluated with minimum 3-year follow-up after APBI. Radiation dermatitis, breast edema, breast induration, and fatigue decreased from baseline levels or stabilized by the 3-year follow-up. Hypopigmentation, hyperpigmentation, breast pain, and telangiectasia slightly increased from baseline levels. Most toxicities at 3 years were Grade 1. Only 1 patient had a Grade 3 toxicity with telangiectasia in a skin fold inside the 95% isodose. Cosmesis was good to excellent in 86% (89/104) of women at baseline and 82% (70/85) at 3 years. The 3-year disease-free survival was 97%, with only one local recurrence that occurred in a different quadrant away from the treated site and two distant recurrences. CONCLUSIONS: At 3 years, toxicity and cosmesis were acceptable, and local control and disease-free survival were excellent, supporting continued accrual to randomized APBI trials. PMID- 20971572 TI - Long-term outcomes of stereotactic radiosurgery for treatment of cavernous sinus meningiomas. AB - PURPOSE: Patients with cavernous sinus meningiomas (CSM) have an elevated risk of surgical morbidity and mortality. Recurrence is often observed after partial resection. Stereotactic radiosurgery (SRS), either alone or combined with surgery, represents an important advance in CSM management, but long-term results are lacking. METHODS AND MATERIALS: A total of 88 CSM patients, treated from January 1991 to December 2005, were retrospectively reviewed. The mean follow-up was 86.8 months (range, 17.1-179.4 months). Among the patients, 22 were followed for more than 10 years. There was a female predominance (84.1%). The age varied from 16 to 90 years (mean, 51.6). In all, 47 patients (53.4%) received SRS alone, and 41 patients (46.6%) had undergone surgery before SRS. A dose of 14 Gy was prescribed to isodose curves from 50% to 90%. In 25 patients (28.4%), as a result of the proximity to organs at risk, the prescribed dose did not completely cover the target. RESULTS: After SRS, 65 (73.8%) patients presented with tumor volume reduction; 14 (15.9%) remained stable, and 9 (10.2%) had tumor progression. The progression-free survival was 92.5% at 5 years, and 82.5% at 10 years. Age, sex, maximal diameter of the treated tumor, previous surgery, and complete target coverage did not show significant associations with prognosis. Among the 88 treated patients, 17 experienced morbidity that was related to SRS, and 6 of these patients spontaneously recovered. CONCLUSIONS: SRS is an effective and safe treatment for CSM, feasible either in the primary or the postsurgical setting. Incomplete coverage of the target did not worsen outcomes. More than 80% of the patients remained free of disease progression during long-term follow-up. PMID- 20971573 TI - Survival outcomes in resected extrahepatic cholangiocarcinoma: effect of adjuvant radiotherapy in a surveillance, epidemiology, and end results analysis. AB - PURPOSE: The benefit of adjuvant radiotherapy (RT) after surgical resection for extrahepatic cholangiocarcinoma has not been clearly established. We analyzed survival outcomes of patients with resected extrahepatic cholangiocarcinoma and examined the effect of adjuvant RT. METHODS AND MATERIALS: Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program between 1973 and 2003. The primary endpoint was the overall survival time. Cox regression analysis was used to perform univariate and multivariate analyses of the following clinical variables: age, year of diagnosis, histologic grade, localized (Stage T1-T2) vs. regional (Stage T3 or greater and/or node positive) stage, gender, race, and the use of adjuvant RT after surgical resection. RESULTS: The records for 2,332 patients were obtained. Patients with previous malignancy, distant disease, incomplete or conflicting records, atypical histologic features, and those treated with preoperative/intraoperative RT were excluded. Of the remaining 1,491 patients eligible for analysis, 473 (32%) had undergone adjuvant RT. After a median follow-up of 27 months (among surviving patients), the median overall survival time for the entire cohort was 20 months. Patients with localized and regional disease had a median survival time of 33 and 18 months, respectively (p<.001). The addition of adjuvant RT was not associated with an improvement in overall or cause-specific survival for patients with local or regional disease. CONCLUSION: Patients with localized disease had significantly better overall survival than those with regional disease. Adjuvant RT was not associated with an improvement in long-term overall survival in patients with resected extrahepatic bile duct cancer. Key data, including margin status and the use of combined chemotherapy, was not available through the SEER database. PMID- 20971574 TI - Metastasis infiltration: an investigation of the postoperative brain-tumor interface. AB - PURPOSE: This study aims to evaluate brain infiltration of metastatic tumor cells past the main tumor resection margin to assess the biological basis for the use of stereotactic radiosurgery treatment of the tumor resection cavity and visualized resection edge or clinical target volume. METHODS AND MATERIALS: Resection margin tissue was obtained after gross total resection of a small group of metastatic lesions from a variety of primary sources. The tissue at the border of the tumor and brain tissue was carefully oriented and processed to evaluate the presence of tumor cells within brain tissue and their distance from the resection margin. RESULTS: Microscopic assessment of the radially oriented tissue samples showed no tumor cells infiltrating the surrounding brain tissue. Among the positive findings were reactive astrocytosis observed on the brain tissue immediately adjacent to the tumor resection bed margin. CONCLUSIONS: The lack of evidence of metastatic tumor cell infiltration into surrounding brain suggests the need to target only a narrow depth of the resection cavity margin to minimize normal tissue injury and prevent treatment size-dependent stereotactic radiosurgery complications. PMID- 20971575 TI - Microscopic disease extension in three dimensions for non-small-cell lung cancer: development of a prediction model using pathology-validated positron emission tomography and computed tomography features. AB - PURPOSE: One major uncertainty in radiotherapy planning of non-small-cell lung cancer concerns the definition of the clinical target volume (CTV), meant to cover potential microscopic disease extension (MDE) around the macroscopically visible tumor. The primary aim of this study was to establish pretreatment risk factors for the presence of MDE. The secondary aim was to establish the impact of these factors on the accuracy of positron emission tomography (PET) and computed tomography (CT) to assess the total tumor-bearing region at pathologic examination (CTV(path)). METHODS AND MATERIALS: 34 patients with non-small-cell lung cancer who underwent CT and PET before lobectomy were included. Specimens were examined microscopically for MDE. The gross tumor volume (GTV) on CT and PET (GTV(CT) and GTV(PET), respectively) was compared with the GTV and the CTV at pathologic examination, tissue deformations being taken into account. Using multivariate logistic regression, image-based risk factors for the presence of MDE were identified, and a prediction model was developed based on these factors. RESULTS: MDE was found in 17 of 34 patients (50%). The MDE did not exceed 26 mm in 90% of patients. In multivariate analysis, two parameters (mean CT tumor density and GTV(CT)) were significantly associated with MDE. The area under the curve of the two-parameter prediction model was 0.86. Thirteen tumors (38%, 95% CI: 24-55%) were identified as low risk for MDE, being potential candidates for reduced-intensity therapy around the GTV. In the low-risk group, the effective diameter of the GTV(CT/PET) accurately represented the CTV(path). In the high risk group, GTV(CT/PET) underestimated the CTV(path) with, on average, 19.2 and 26.7 mm, respectively. CONCLUSIONS: CT features have potential to predict the presence of MDE. Tumors identified as low risk of MDE show lower rates of disease around the GTV than do high-risk tumors. Both CT and PET accurately visualize the CTV(path) in low-risk tumors but underestimate it in high-risk tumors. PMID- 20971576 TI - Four-dimensional lung treatment planning in layer-stacking carbon ion beam treatment: comparison of layer-stacking and conventional ungated/gated irradiation. AB - PURPOSE: We compared four-dimensional (4D) layer-stacking and conventional carbon ion beam distribution in the treatment of lung cancer between ungated and gated respiratory strategies using 4DCT data sets. METHODS AND MATERIALS: Twenty lung patients underwent 4DCT imaging under free-breathing conditions. Using planning target volumes (PTVs) at respective respiratory phases, two types of compensating bolus were designed, a full single respiratory cycle for the ungated strategy and an approximately 30% duty cycle for the exhalation-gated strategy. Beams were delivered to the PTVs for the ungated and gated strategies, PTV(ungated) and PTV(gated), respectively, which were calculated by combining the respective PTV(Tn)s by layer-stacking and conventional irradiation. Carbon ion beam dose distribution was calculated as a function of respiratory phase by applying a compensating bolus to 4DCT. Accumulated dose distributions were calculated by applying deformable registration. RESULTS: With the ungated strategy, accumulated dose distributions were satisfactorily provided to the PTV, with D95 values for layer-stacking and conventional irradiation of 94.0% and 96.2%, respectively. V20 for the lung and Dmax for the spinal cord were lower with layer-stacking than with conventional irradiation, whereas Dmax for the skin (14.1 GyE) was significantly lower (21.9 GyE). In addition, dose conformation to the GTV/PTV with layer-stacking irradiation was better with the gated than with the ungated strategy. CONCLUSIONS: Gated layer-stacking irradiation allows the delivery of a carbon ion beam to a moving target without significant degradation of dose conformity or the development of hot spots. PMID- 20971577 TI - Joint leveling for advanced Kienbock's disease. AB - PURPOSE: The use of joint leveling procedures to treat Kienbock's disease have been limited by the degree of disease advancement. This study was designed to compare clinical and radiographic outcomes of wrists with more advanced (stage IIIB) Kienbock's disease with those of wrists with less advanced (stage II/IIIA) disease following radius-shortening osteotomy. METHODS: This retrospective study enrolled 31 adult wrists (30 patients; mean age, 39 y), treated with radius shortening osteotomy at 2 institutions for either stage IIIB (n = 14) or stage II/IIIA (n = 17) disease. Evaluation was performed at a mean of 74 months (IIIB, 77 mo; II/IIIA, 72 mo). Radiographic assessment determined disease progression. Clinical outcomes were determined by validated patient-based and objective measures. RESULTS: Patient-based outcome ratings of wrists treated for stage IIIB were similar to those with stage II/IIIA (shortened Disabilities of the Arm, Shoulder, and Hand score, 15 vs 12; modified Mayo wrist score, 84 vs 87; visual analog scale pain score, 1.2 vs 1.7; visual analog scale function score, 2.6 vs 2.1). The average flexion/extension arc was 102 degrees for wrists with stage IIIB and 106 degrees for wrists with stage II/IIIA Kienbock's. Grip strength was 77% of the opposite side for stage IIIB wrists versus 85% for stage II/IIIA. Postoperative carpal height ratio and radioscaphoid angle were worse for wrists treated for stage IIIB (0.46 and 65 degrees , respectively) than stage II/IIIA (0.53 and 53 degrees , respectively) disease. Radiographic disease progression occurred in 7 wrists (6 stage II/IIIA, 1 stage IIIB). The one stage IIIB wrist that progressed underwent wrist arthrodesis. CONCLUSIONS: In this limited series, clinical outcomes of radius shortening using validated, patient-based assessment instruments and objective measures failed to demonstrate predicted clinically relevant differences between stage II/IIIA and IIIB Kienbock's disease. Given the high percentage of successful clinical outcomes in this case series of 14 stage IIIB wrists, we believe that static carpal malalignment does not preclude radius shortening osteotomy. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 20971578 TI - Heart in hand: structural cardiac abnormalities that manifest as acute dysvascularity of the hand. PMID- 20971579 TI - Snapping wrist caused by tenosynovitis of the extensor carpi radialis longus tendon subsequent to subcutaneous muscle rupture in the forearm: case report. AB - We report a rare case of snapping in the dorsal wrist that was caused by extensor carpi radialis longus tenosynovitis occurring after rupture of the muscle in the middle forearm. After resection of the tendon at the wrist, the snapping disappeared. PMID- 20971580 TI - Incidence of scapholunate ligament dissociation in patients with aspiration confirmed gout. AB - PURPOSE: To determine the incidence of scapholunate (SL) dissociation in patients with aspiration-confirmed gout of the wrist and aspiration-confirmed gout in any joint excluding the wrist. METHODS: Geisinger Medical Center uses the EPIC electronic medical record system, which maintains International Classification of Diseases, 9th Revision, Clinical Modification and Current Procedural Terminology coding information for every patient encounter in our hospital system. We queried this electronic medical record system from 1998 to 2008 using the International Classification of Diseases, 9th Revision, Clinical Modification codes for gout as well as Current Procedural Terminology codes for aspiration of a minor, intermediate, or major joint. We then evaluated medical records of patients meeting criteria for the presence of wrist x-rays. We examined x-rays for SL interval, SL angle, and capitolunate angle and determined the incidence of SL dissociation in all patients with a diagnosis of gout confirmed by joint aspiration. RESULTS: We reviewed a total of 1,105 cases; 159 patients met inclusion criteria. Of 159 patients, 20 had aspiration-confirmed gout in the wrist. We determined incidence using 2 definitions: (1) one or more positive radiographic criteria for SL dissociation, and (2) two or more positive radiographic criteria. The incidence of SL dissociation in wrists with aspiration confirmed gout was 60% by definition 1 and 25% by definition 2. The average SL interval was 2.95 mm. The remaining 139 patients had aspiration-confirmed gout in joints other than the wrist. A total of 69 patients had 1 or more positive criteria for SL dissociation, whereas 18 had 2 or more positive criteria, making the incidence of SL dissociation 49.6% and 12.9%, respectively. The average scapholunate interval was 2.28 mm. The incidence of SL dissociation in patients with aspiration-confirmed gout in any joint was 50.9% and 14.5%, based on the above definitions. CONCLUSIONS: This study establishes the incidence of SL dissociation in patients with gouty arthropathy of the wrist as 60% and 25%, respectively, based on the above definitions. In addition, our study suggests that, as a result of the systemic nature of gout, a patient with aspiration confirmed gout at a joint remote from the wrist might have subclinical effects in the wrist, leading to SL dissociation over time. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 20971581 TI - Comparison of the performance of chronically versus freshly denervated autograft in nerve repair. AB - PURPOSE: Graft choice is one of the few variables over which the surgeon has control when reconstructing nerve gaps. Because repair of chronically denervated nerves generally yields inferior recovery, we hypothesized that the use of chronically denervated nerve tissue as a graft source may compromise axonal regeneration and clinical results. METHODS: A total of 45 immature female Sprague Dawley rats underwent transection of one peroneal nerve before being divided into 3 experimental groups: group A (n = 15) had acutely denervated nerve graft, group B (n = 15) had 2-month denervated nerve graft, and group C (n = 15) had 4-month denervated nerve graft. We included 10 additional rats as a sham group. After 2 months, groups A and B underwent removal of 1 cm of the contralateral peroneal nerve. For group A, this section of nerve was immediately sutured back in place to serve as a model for acute denervation. For group B, the defect was repaired with a 1-cm graft from the distal stump of the previously transected (denervated) peroneal nerve. Group C underwent the same procedure as group B, but after an additional 2 months. After 8 weeks of regeneration time, the 3 experimental groups and the sham group underwent testing. We assessed twitch contraction forces of the reinnervated extensor digitorum longus before we harvested the muscle belly for morphologic measurements. Histological nerve tissue evaluation assessed axonal regeneration. RESULTS: We detected no statistical differences for mean muscle contraction strengths between the experimental groups; nevertheless, the reinnervated extensor digitorum longus muscle bellies from the 4-month denervated nerve graft group were statistically smaller than muscles from the other 2 experimental groups (p < .05). Axon counts decreased, whereas axon diameters increased in direct correlation with the length of time of graft denervation (p < .05). No difference in axon myelination was found between experimental groups. CONCLUSIONS: Prolonged denervation of nerve graft material compromised both axon and reinnervated muscle recovery in this rodent model. PMID- 20971582 TI - Percutaneous, intramedullary fracture reduction and extension block pinning for dorsal proximal interphalangeal fracture-dislocations. AB - PURPOSE: A percutaneous, intramedullary fracture reduction technique for treatment of unstable dorsal fracture-dislocation of the proximal interphalangeal (PIP) joint is described and the clinical and radiological results are reported. METHODS: We conducted a retrospective clinical follow-up of 16 patients with 18 dorsal fracture-dislocations of the PIP joint. After closed joint reduction, we used an extension block K-wire to maintain the joint reduction. Impacted volar articular fragments were reduced percutaneously under fluoroscopy control using a pre-bent K-wire inserted through the intramedullary canal of the middle phalanx. The patients initiated passive range of motion exercises immediately after surgery. After a mean of 3 weeks, we removed the extension block K-wire and allowed free mobilization. We examined 13 patients with 15 injured fingers at a mean 5-year follow-up (range, 1-8 y). RESULTS: Radiographic reduction of the joint dislocation was achieved and maintained. The mean articular step-off decreased from 2.1 mm (range, 1.6-3.1 mm) to 0.5 mm (range, 0.0-1.2 mm). At the final follow-up, active PIP motion averaged 83 degrees (range, 65 degrees to 97 degrees ) with a mean flexion contracture of 3 degrees (range, 0 degrees to 15 degrees ). The mean visual analog scale score for digit pain was 1/10. The mean Disabilities of the Shoulder, Arm, and Hand score of 4/100 indicated little functional impairment. CONCLUSIONS: Percutaneous, intramedullary reduction of the impacted volar articular fragments associated with unstable, dorsal fracture dislocation of the PIP joint restores joint congruence and function. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 20971583 TI - Genome-wide association scan of Dupuytren's disease. AB - PURPOSE: Dupuytren's disease (DD) has a strong genetic component that is suggested by population studies and family clustering. Genetic studies have yet to identify the gene(s) involved in DD. The purpose of this study was to identify regions of the entire genome (chromosomes 1-23) associated with the disease by performing a genome-wide association scan on DD patients and controls. METHODS: We isolated genomic DNA from saliva collected from 40 unrelated DD patients and 40 unaffected controls. We conducted the genotyping using CytoSNP-Infinium HD Ultra genotyping assay on the Illumina platform. Using both log regression and mapping by admixture linkage disequilibrium analysis methods, we analyzed the single nucleotide polymorphism genotyping data. RESULTS: Single nucleotide polymorphism analysis revealed a significant association in regions for chromosomes 1, 3 through 6, 11, 16, 17, and 23. Mapping by admixture linkage disequilibrium analysis showed ancestry-associated regions in chromosomes 2, 6, 8, 11, 16, and 20, which may harbor DD susceptibility genes. Both analysis methods revealed loci association in chromosomes 6, 11, and 16. CONCLUSIONS: Our data suggest that chromosomes 6, 11, and 16 may contain the genes for DD and that multiple genes may be involved in DD. Future genetic studies on DD should focus on these areas of the genome. PMID- 20971584 TI - [Diabetic mastopathy]. AB - Diabetic mastopathy is a recently described pathological entity. Little is known about this benign condition. It usually occurs in young patients with type 1 diabetes, or having an autoimmune disorders. Clinically, this mastopathy simulates a breast cancer. Graphic tests are not very informative. The diagnosis is histological. Through a case of diabetic mastopathy occurring in a patient with diabetes on insulin for 16 years and carries multiple degenerative complications, we recall the clinical, radiological and outcome of this disease. PMID- 20971585 TI - Mortality among individuals with cannabis, cocaine, amphetamine, MDMA, and opioid use disorders: a nationwide follow-up study of Danish substance users in treatment. AB - This is a register-based cohort study of 20,581 individuals in treatment for illicit substance use disorders in Denmark between 1996 and 2006. All in all, 1441 deaths were recorded during 111,445 person-years of follow-up. Standardized mortality ratios (SMRs) associated with different primary substance types were calculated and Cox-regression analyses were performed in order to establish hazard ratios (HR) associated with injection drug use and psychiatric comorbidity. SMRs for primary users of specific substances were: cannabis: 4.9 (95% confidence interval (CI): 4.2-5.8), cocaine: 6.4 (CI: 3.9-10.0), amphetamine: 6.0 (CI: 4.2-8.3), heroin: 9.1 (CI: 8.5-9.8), and other opioids 7.7 (CI: 6.6-8.9). For MDMA ('ecstasy') the crude mortality rate was 1.7/1000 person years (CI: 0.4-7.0) and the SMR was not significantly elevated. Injection drug use was associated with significantly increased hazard ratios in users of opioids and cocaine/amphetamine. Overall, psychiatric comorbidity was not associated with increased mortality (HR: 1.1 [CI: 0.9-1.2], p=.28), but an association was found specifically among cocaine/amphetamine users (HR: 3.6 [CI: 2.1-6.4], p<.001). PMID- 20971586 TI - Analysis of visually guided eye movements in subjects after whiplash injury. AB - OBJECTIVE: The aims of present research were to analyze the visually guided eye movements of subjects suffering from the consequences of whiplash injury and the possibility to differentiate patients from feigning subject. We analyzed the role of video-nystagmography for clinical and forensic aspects. METHODS: It was a prospective case-control study. Detailed history was taken and patients were thoroughly investigated. Smooth pursuit and saccadic eye movements were assessed in 33 patients affected by imbalance following a whiplash injury. A control group of 20 subjects was also evaluated. All tests were executed in neutral neck position and after left and right trunk rotation. RESULTS: The t-test, applied to all parameters showed that difference of the parameter between the groups was not statistically significant. CONCLUSION: The visually guided eye movement evaluation does not seem to offer a clinically relevant method to differentiate patients suffering from the effects of whiplash injury from normal subjects. PMID- 20971587 TI - Repetitive transcranial magnetic stimulation (rTMS) for treatment of chronic tinnitus. AB - OBJECTIVE: There is compelling evidence that tinnitus is associated with functional alterations in the central nervous system. Repetitive transcranial magnetic stimulation (rTMS) is a potent tool for modifying neural activity at the stimulated area and at a distance along the functional anatomical connections. Depending on the stimulation parameters, cortical networks can be functionally disturbed or modulated in their activities. Low-frequency rTMS has been shown to result in a decrease in cortical excitability. The technique can alleviate tinnitus by modulating the excitability of neurons in the auditory cortex. We aimed to investigate the effects of low-frequency rTMS in patients and determine the factors that predict a beneficial outcome with rTMS treatment. METHODS: Sixteen patients (male 10, female 6) with chronic tinnitus underwent low frequency (1Hz) rTMS (intensity: 110% motor threshold; number of stimuli: 1200) to the left auditory cortex. The treatment outcome was assessed with a visual analog scale (VAS) of loudness, annoyance and duration, loudness balance test, and tinnitus handicap inventory (THI). Therapeutic success was studied according to the patients' clinical characteristics. RESULTS: A significant reduction in the VAS (loudness and annoyance) occurred immediately after rTMS, with a gradual return to pretreatment levels after 7 days. The tinnitus patients with sudden deafness were significant resistant to rTMS treatment compared with those diagnosed with age-related hearing loss. CONCLUSION: These results support the potential of rTMS as a new therapeutic tool for the treatment of chronic tinnitus. Because this study was performed with a small sample size and showed high interindividual variability in treatment effects, further development of the technique is needed before it can be recommended for clinical applications. PMID- 20971588 TI - Severe progressive sensorineural hearing loss improved after removal of large jugular foramen schwannoma. AB - We report a very rare case of hearing improvement after removal of the intracranial part of a jugular foramen schwannoma (JFS) presenting with chronic and severe progressive sensorineural hearing loss (SNHL). The patient presented with progressive hearing impairment in his right ear, lasting 2 years. The patient's pure tone audiogram revealed severe SNHL. His speech discrimination score (SDS) was 0%. Auditory-evoked brain responses (ABRs) comprised only I waves following 30-100dB stimulation, although distortion-product otoacoustic emissions (DPOAEs) had good responses. These test results indicated that his hearing impairment was retrocochlear SNHL. Magnetic resonance imaging revealed within the right jugular foramen a large intracranial-extracranial tumor that compressed the brainstem. The intracranial part of the tumor was resected through retrosigmoidal craniotomy, and the tumor was pathologically diagnosed as a schwannoma. Several months after the operation, the patient's auditory thresholds improved to a level consistent with mild SNHL, ABR V waves emerged following 60-90dB stimulation, and SDS improved significantly to 95%. This case demonstrates that hearing improvement can be achieved after surgery for JFS presenting with severe and chronic progressive SNHL, and that good DPOAE responses and the presence of ABR I waves may be predictors of postoperative hearing recovery in JFS. PMID- 20971589 TI - Migraine triggered by epileptic discharges in a Rasmussen's encephalitis patient after surgery. AB - After 2years from disconnective surgery for Rasmussen's encephalitis, a child, 9years old, began to present severe migraine attacks, lateralized to the operated side, lasting 1-2days. Video/EEG recordings during two different migraine attacks, with an interval of 6months from each other, showed, in both recordings, subsequent ictal discharges over the affected and disconnected hemisphere. Migraine and ictal discharges in both occasion disappeared with diazepam i.v. The EEGs performed during migraine-free period, on the contrary, showed very rare and mild subclinical ictal discharges. Although a casual relationship could not be excluded, a pure neuronal pathogenetic mechanism can be suggested, mediated by post- and inter-ictal cortical depression. PMID- 20971590 TI - Therapeutic apheresis from the early civilizations to the twenty-first century. PMID- 20971591 TI - An abdominal and thyroid status with Acoustic Radiation Force Impulse Elastometry -a feasibility study: Acoustic Radiation Force Impulse Elastometry of human organs. AB - PURPOSE: Acoustic Radiation Force Impulse (ARFI) is a new method for the quantification of tissue elasticity. To date, ARFI technology has not been applied systematically to establish an abdominal and thyroid status. The aim of this prospective feasibility study was to evaluate ARFI elastometry performed on various healthy abdominal organs and the thyroid gland. MATERIAL AND METHODS: 94 patients (43 females, 51 males) with a mean age of 54 years and 20 healthy controls were enrolled in the study. A routine ultrasound examination of the abdomen was scheduled in 72, and of the thyroid in 25. ARFI elastometry was performed in liver, spleen, pancreas, prostate, kidneys and thyroid gland with the ultrasound system Acuson S2000. ARFI values are proportional to tissue elasticity. Patients with ultrasonic or anamnestic evidence of diseased organs were excluded from the analysis. ARFI measurements were compared with the aid of the t-test and correlated using Spearman's correlation coefficient. RESULTS: ARFI elastometry proved feasible and the measurements obtained in the various organs differed significantly. Among healthy organs the spleen showed the highest mean ARFI velocities, followed by the kidney, thyroid, pancreas and the prostate. The lowest ARFI values were regularly found in healthy liver. Measurements in the kidneys and the spleen showed high standard deviation. CONCLUSIONS: ARFI elastometry may describe parenchymal stiffness of various abdominal organs and the thyroid gland. Further investigations are needed to compare these baseline findings in healthy organs with those of various tumours or diseases affecting the individual organs. PMID- 20971592 TI - Combined CT- and fluoroscopy-guided nephrostomy in patients with non-obstructive uropathy due to urine leaks in cases of failed ultrasound-guided procedures. AB - AIM: To report our experience of combined CT- and fluoroscopy-guided nephrostomy in patients with non-obstructive uropathy due to urine leaks in cases of failed ultrasound-guided procedures. PATIENTS AND METHODS: Eighteen patients (23 kidneys) with non-obstructive uropathy due to urine leaks underwent combined CT- and fluoroscopy-guided nephrostomy. All procedures were indicated as second-line interventions after failed ultrasound-guided nephrostomy. Thirteen males and five females with an age of 62.3+/-8.7 (40-84) years were treated. Urine leaks developed in majority after open surgery, e.g. postoperative insufficiency of ureteroneocystostomy (5 kidneys). The main reasons for failed ultrasound-guided nephrostomy included anatomic obstacles in the puncture tract (7 kidneys), and inability to identify pelvic structures (7 kidneys). CT-guided guidewire placement into the collecting system was followed by fluoroscopy-guided nephrostomy tube positioning. Procedural success rate, major and minor complication rates, CT-views and needle passes, duration of the procedure and radiation dose were analyzed. RESULTS: Procedural success was 91%. Major and minor complication rates were 9% (one septic shock and one perirenal abscess) and 9% (one perirenal haematoma and one urinoma), respectively. 30-day mortality rate was 6%. Number of CT-views and needle passes were 9.3+/-6.1 and 3.6+/-2.6, respectively. Duration of the complete procedure was 87+/-32 min. Dose-length product and dose-area product were 1.8+/-1.4 Gy cm and 3.9+/-4.3 Gy cm2, respectively. CONCLUSIONS: Combined CT- and fluoroscopy-guided nephrostomy in patients with non-obstructive uropathy due to urine leaks in cases of failed ultrasound-guided procedures was feasible with high technical success and a tolerable complication rate. PMID- 20971593 TI - Effect of cyclodextrins on the solubility and stability of candesartan cilexetil in solution and solid state. AB - Guest-host interactions of candesartan cilexetil (CAND) with cyclodextrins (CyDs) have been investigated using phase solubility diagrams (PSD), X-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC) and molecular mechanical modelling (MM). Estimates of the complex formation constant (K(11)) show that the tendency of CAND (pK(a)=6.0) to complex with CyDs follows the order: beta-CyD>HP-beta-CyD>gamma-CyD>alpha-CyD. Complex formation of CAND with beta-CyD (DeltaG degrees =-31.5 kJ/mol) is largely driven by enthalpy change (DeltaH degrees =-32.8 kJ/mol) and slightly retarded by entropy change (DeltaS degrees =-4.6J/mol K). The HPLC results indicate that complex prepared by freeze drying method is chemically not stable due to the formation of amorphous CAND. Also it may suggest formulating CAND with beta-CyD by kneading (dispersion) or co evaporation (real inclusion complex) methods into capsule rather than compressed in tablets, where the compression enhances the instability of CAND. DSC thermograms for CAND/beta-CyD complexes proved the formation of inclusion complexes with new solid phase. MM studies indicate the partial penetration of CAND into the beta-CyD cavity. PMID- 20971594 TI - An old lady with anterior chest pain and unilateral facial flushing. AB - Harlequin syndrome is rare and typically characterized by asymmetric flushing and sweating. Although it is usually considered idiopathic, literature review shows that it may be caused by lesion over lung apex or after central venous catheterization in the internal jugular vein. We present a 74-year-old woman who had been experiencing recurrent chest pain and right shoulder pain since 2 weeks ago. The tentative diagnosis was made by the emergency physician (EP) as acute coronary syndrome. The patient was given nitroglycerin treatment. Twelve hours later, the patient developed another episode of chest pain. The electrocardiogram and cardiac enzyme study results were, however, both normal. Further evaluation showed intermittent flushing over the left side of her face, as well as right-eye ptosis. A chest computed tomography (CT) was conducted, under the suspicion of Harlequin syndrome in combination with Horner syndrome, to derive the diagnosis of a right lung apex tumor. This case showed that history taking and physical examination are very important in the emergency department. It is particularly vital to observe the microchanges in the patient's symptoms and signs. It is also imperative to reassess the patient whose symptoms fail to improve under treatment, to look for other underlying lesions. PMID- 20971595 TI - ED to catheterization laboratory: a roundtable integrating trials with practice. AB - BACKGROUND: Clinical trials are the foundation underlying clinical decision making. However, stringent inclusion and exclusion criteria may reduce the generalizability of their results, especially for patients seen in the emergency department (ED). Guideline recommendations, based on clinical trials and pertinent registries, apply to broad populations, but not all patients cared for at the bedside fit the predefined categories that make guidelines practical. Furthermore, these documents may not incorporate the latest evidence. As a result, other factors (eg, individual patient characteristics, clinician experience, cost, regulatory labels, expert opinions) often result in clinical decision-making that varies from strict adherence to guideline recommendations. OBJECTIVES: These challenges demonstrate a need to integrate clinical data and guidelines advice with actual ED practice in a manner that will be consistent with decisions made later in the continuum of care. DISCUSSION: In recognition of these issues, a roundtable was convened in New York City on June 5, 2009, to discuss the implications of recent trials involving patients with non-ST-segment elevation acute coronary syndromes. Eight physicians, representing both emergency medicine and cardiology, shared information on advances and clinical trial results in antiplatelet treatment, guidelines, and other developments in patient care. This article is based on transcripts of their presentations and the ensuing discussions that were of particular importance for emergency physicians. CONCLUSIONS: Although guidelines and clinical registries can provide broad direction for practice, there is no substitute for a prospective, multidisciplinary, institution-specific, consistent, evidence-based approach to patient management. PMID- 20971596 TI - Hemodialysis as an alternative treatment of mexiletine intoxication. AB - Mexiletine is a class IB antiarrhythmic agent. Although it is primarily used in treating ventricular arrhythmias, recent indications for use of mexiletine include chronic and neuropathic pains. At high doses, mexiletine causes drowsiness, confusion, nausea, hypotension, sinus bradycardia, paresthesia, seizures, bundle branch block, atrioventricular heart block, ventricular arrhythmias, asystole, cardiovascular collapse, and coma. A 23-year-old male patient presented to the emergency department with intentional ingestion of high dose mexiletine. Despite decontamination and supportive treatment, his vitals deteriorated during the observation period; and he developed stupor and dysarthria. Patient then underwent hemodialysis. His vital signs and overall condition improved rapidly following hemodialysis treatment. In this case report, we aimed to emphasize hemodialysis as a useful alternative therapy for severe mexiletine intoxications. PMID- 20971597 TI - Prehospital treatment of patients with acute myocardial infarction with bivalirudin. AB - OBJECTIVES: Patients with acute myocardial infarction are at high risk of dying within the first hours after onset of coronary ischemia. Therefore, pharmacological intervention should be started in the prehospital setting. This study investigates the effect of the prehospital administration of bivalirudin on short-term morbidity and mortality compared to heparin plus abciximab in patients with ST-segment-elevation myocardial infarction (STEMI). METHODS: One hundred ninety-eight patients with STEMI treated with bivalirudin in the prehospital setting were prospectively collected. Coronary angiography was performed to identify the infarct-related artery. In case of a percutaneous coronary intervention, bivalirudin was given according to the guidelines. The historic control group consisted of 171 consecutive patients from the same myocardial infarction network treated with unfractioned heparin and abciximab administration before the admission to the emergency department of the percutaneous coronary intervention center. The primary outcome parameter was the incidence of major adverse cardiac events (recurrent myocardial infarction, stroke, death, target vessel revascularization for ischemia) within 30 days after the primary event. RESULTS: The overall rate of major adverse cardiac events was significantly lower in the bivalirudin group compared to the abciximab group (7.6% vs 14.6%; P = .04). The number of major bleedings was significantly higher in the abciximab group compared to the bivalirudin group (11.8% vs 3.8%; P = .03). CONCLUSIONS: The use of bivalirudin in the prehospital setting leads to a reduced rate of major cardiovascular events compared to a standard treatment with abciximab plus heparin. Bivalirudin is a reasonable choice of treatment in the prehospital setting for patients with STEMI. PMID- 20971598 TI - Large-event medicine--event characteristics impacting medical need. AB - Large events have been defined in many ways, from the vague description of a focused gathering of people to the more specific description of an event with at least 1,000 spectators and participants who are gathered at a specific location for a defined period of time. Regardless of the definition applied, the actual medical requirements vary considerably from one event to the next. The ability to predict these medical needs allows for the provision of adequate medical support. Many factors contribute to medical need at a large event, including event type, weather (particularly heat index), the presence of alcohol and / or illicit drugs, the number of participants, event duration, crowd demographics, and venue characteristics. This review will focus on the various features of large events such that the medical planner can better understand the challenge and provide adequate resource for patient care. PMID- 20971599 TI - Heterotopic pregnancy resulting from in vitro fertilization. PMID- 20971600 TI - Physical fitness cannot be used to predict the likelihood of acute coronary syndromes in ED patients with chest pain. AB - OBJECTIVE: The objective of the study was to explore the association between physical fitness and the likelihood of acute coronary syndrome (ACS) in patients presenting to the emergency department (ED) with chest pain (CP). We hypothesized that the likelihood of ACS would be lower in physically fit patients and higher in patients with exercise-induced CP. METHODS: The study involved a prospective, descriptive cohort in an academic suburban ED. Subjects were ED patients with CP admitted for suspected ACS. Demographic and clinical data were collected by trained research assistants using standardized forms. Patients were surveyed on level of fitness and whether they had ever experienced anginal type symptoms during exercise. Acute coronary syndrome was considered present if the patient had electrocardiographic evidence of infarction or ischemia; elevated troponin I levels; greater than 70% stenosis of culprit coronary artery; or a positive nuclear, echocardiographic, or treadmill stress test result. Patients readmitted within 30 days for reinfarction, cardiogenic shock, or arrhythmias were also considered to have ACS. The association between physical fitness and ACS was determined using chi(2) tests and odds ratios (ORs). RESULTS: One hundred patients were enrolled. Mean age was 55.8 (+/-15.3) years; 36% were female; 85% were white. Thirteen (13%) patients had positive troponins, 22 of 36 catheterized patients had greater than 70% coronary artery stenosis, and 6 (6%) had abnormal stress test results. There were no deaths or reinfarctions within 30 days. The rate of ACS was similar in patients who were physically fit and those who were not (24% vs 37%; OR, 0.5 [95% confidence interval, 0.2-1.3]) and in patients who had experienced exercise-induced CP and those who had not (32% vs 29%; OR, 1.2 [95% confidence interval, 0.4-3.2]). Neither the frequency nor the intensity of exercise was associated with ACS. CONCLUSIONS: Physically fit patients with CP were as likely to have ACS as those not physically fit. A history of exercise induced CP was not associated with an increased likelihood of ACS. PMID- 20971601 TI - Emergent bilateral thoracoscopy for massive hemopneumothorax with contralateral pneumothorax. PMID- 20971602 TI - Recurrent anion gap metabolic acidosis in a woman with vertebral disc disease. PMID- 20971604 TI - WITHDRAWN: Analysis of serum levels of homocysteine and oxidative stress markers in patients with Alzheimer disease. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 20971603 TI - Caregiver rating of provider participatory decision-making style and caregiver and child satisfaction with pediatric asthma visits. AB - OBJECTIVE: The purpose of this study was to examine the relationship between caregiver ratings of provider use of a participatory decision-making style and caregiver and child satisfaction with their pediatric asthma visits. METHODS: Children ages 8 through 16 with persistent asthma and their caregivers were recruited at five pediatric practices. Children were interviewed and caregivers completed questionnaires after their child's medical visits. Generalized estimating equations were used to analyze the data. RESULTS: Three hundred and twenty children were recruited. Caregivers were significantly more satisfied with providers who they perceived as using more of a participatory decision-making style (beta=17.80, p<0.001). Children (beta=-0.10, p<0.05) and caregivers (beta= 0.21, p<0.01) were significantly more satisfied with younger providers. Children were significantly more satisfied with providers who knew them better as a person (beta=2.87, p<0.001). CONCLUSIONS: Caregivers were more satisfied with providers who they perceived as involving them more during treatment decisions made during pediatric asthma visits. PRACTICE IMPLICATIONS: Providers should attempt to use a more participatory decision-making style with families during pediatric asthma visits. PMID- 20971605 TI - Reduced expression of HOXA10 in the midluteal endometrium from infertile women with minimal endometriosis. AB - Recent human and animal studies have suggested that reduced HOXA10 expression in the implantation window of eutopic endometrium may contribute to infertility in women with endometriosis. Therefore, we examined the HOXA10 transcript, protein and HOXA10 promoter methylation levels in midluteal eutopic endometrium from 17 infertile women with minimal endometriosis and 15 healthy fertile women from a Polish cohort. Real-time quantitative PCR (RQ-PCR) and western blotting analysis revealed significantly lower levels of HOXA10 transcript (P=0.019) and protein (P=0.048) levels in eutopic endometrium from infertile women with endometriosis as compared to healthy fertile women. Moreover, sodium bisulfite sequencing of three HOXA10 CpG islands showed significantly higher methylation levels of genomic DNA from midluteal eutopic endometrium from infertile women with endometriosis as compared to healthy fertile women (P=0.006). We confirmed that DNA hypermethylation can be one of the potential molecular mechanisms silencing HOXA10 expression in the midluteal endometrium associated with infertility in women with endometriosis. PMID- 20971606 TI - [A worrying negligence. Diagnosis: Diogene syndrome]. PMID- 20971607 TI - [Prevention of whooping-cough cross transmission in maternity hospital]. AB - INTRODUCTION: Reports of pertussis have been increasing since 2008 in North of France. A large part of reported cases involved healthcare workers (HCWs) in nurseries and maternity hospitals. The objective of this study was to determine HCWs' knowledge regarding pertussis and its cross-transmission in the maternity hospitals in North of France. METHODS: This study was conducted in the 38 maternity hospitals set in North of France. Head midwives and nurses, infection control teams and occupational health practitioners were asked through a self administered questionnaire survey to assess there knowledge regarding pertussis: vaccination, diagnosis, cross-transmission control. RESULTS: 36 on the 38 maternity hospitals' staffs returned the survey. Most of the respondents viewed pertussis as a serious and highly transmissible illness but 30% of them considered it a paediatric illness. Only a minority of the participants knew the last recommendations for pertussis vaccination in HCWs (37%) and in adults (16%). Only a few maternity hospitals staffs have set a formal organization to prevent and control pertussis cross-transmission. CONCLUSION: Awareness about pertussis vaccination and its cross-transmission control needs to be increased among maternity hospital staffs. A close liaison between HCWs, occupational health, infection control teams and biologists is necessary to prepare operational procedures to control pertussis cross transmission. PMID- 20971608 TI - [Methamphetamine dependence: Consequences and complications]. AB - Methamphetamine is the second illicit drug used after cannabis in North America, Asia, Oceania. It also becomes a prominent part of the European drug scene, especially in East European countries such as Czech Republic and Slovakia. Methamphetamine addiction is a serious worldwide public health problem with many consequences and complications. Significant morbidity, including cardiovascular, infectious, pulmonary, dental diseases and other systems complications are associated with methamphetamine acute or chronic use. Cognitive disorders, psychotic and mood disorders have been reported. There is also substantial evidence that methamphetamine has an adverse impact on social relationships. Treatment of methamphetamine complications is primarily supportive and need a multidisciplinary approach. It can serve as a target to initiate a treatment for the addiction problem. The use of behavioral therapies and pharmacological agents are the best therapeutic approach. PMID- 20971609 TI - Posttraumatic Cognitions Inventory (PTCI): psychometric properties and gender differences in an Israeli sample. AB - The Posttraumatic Cognitions Inventory (PTCI; Foa, Ehlers, Clark, Tolin, & Orsillo, 1999) was found to have three factors: negative view of self, negative view of world, and self-blame. We validated the PTCI among 326 Israeli adults exposed to various types of traumas. Results provided support for the original three-factors. Negative cognitions about self scale had the highest correlations with severity of PTSD and depression symptoms, whereas self-blame had only weak correlations with these measures. Among men, negative cognitions about self were associated most strongly with PTSD severity whereas among women, negative cognitions about self were associated primarily with depression. Gender may play an important role in posttraumatic cognitions and their relationship to PTSD and depression. PMID- 20971610 TI - Item and error analysis on Raven's Coloured Progressive Matrices in Williams Syndrome. AB - Raven's Coloured Progressive Matrices (RCPM) is a standardised test that is commonly used to obtain a non-verbal reasoning score for children. As the RCPM involves the matching of a target to a pattern it is also considered to be a visuo-spatial perception task. RCPM is therefore frequently used in studies in Williams Syndrome (WS), in order to match WS participants to a control group or as a single measure to predict performance on a test-condition in developmental trajectory analyses. However, little is known about the performance of participants with WS on the RCPM. The current study compared the type of errors and the difficulty of each item for 53 participants with WS to 53 typically developing children who were individually matched on the total raw score for RCPM. Results showed that the participants with WS made the same proportion of error types and that the proportion of error types changed similarly to those of typically developing controls over development. Furthermore, the differential item difficulty between the two groups was highly similar. It is therefore argued that, although participants with WS are delayed on RCPM, their performance is not atypical which suggests that RCPM performance is supported by typical mechanisms. The RCPM is therefore a useful tool to match WS to control groups or to construct developmental trajectories. PMID- 20971611 TI - Assisting people with multiple disabilities by improving their computer pointing efficiency with an Automatic Target Acquisition Program. AB - This study evaluated whether two people with multiple disabilities would be able to improve their pointing performance through an Automatic Target Acquisition Program (ATAP) and a newly developed mouse driver (i.e. a new mouse driver replaces standard mouse driver, and is able to monitor mouse movement and intercept click action). Initially, both participants had their baseline sessions. Then intervention started with the first participant. When his performance was consolidated, new baseline and intervention occurred with the second participant. Finally, both participants were exposed to maintenance phase, in which their pointing performance improved significantly. Data indicated that both participants improved their pointing efficiency with the use of ATAP and remained highly successful through maintenance phase. Implications of the findings are discussed. PMID- 20971612 TI - Spectral- and cepstral-based measures during continuous speech: capacity to distinguish dysphonia and consistency within a speaker. AB - Spectral- and cepstral-based acoustic measures are preferable to time-based measures for accurately representing dysphonic voices during continuous speech. Although these measures show promising relationships to perceptual voice quality ratings, less is known regarding their ability to differentiate normal from dysphonic voice during continuous speech and the consistency of these measures across multiple utterances by the same speaker. The purpose of this study was to determine whether spectral moments of the long-term average spectrum (LTAS) (spectral mean, standard deviation, skewness, and kurtosis) and cepstral peak prominence measures were significantly different for speakers with and without voice disorders when assessed during continuous speech. The consistency of these measures within a speaker across utterances was also addressed. Continuous speech samples from 27 subjects without voice disorders and 27 subjects with mixed voice disorders were acoustically analyzed. In addition, voice samples were perceptually rated for overall severity. Acoustic analyses were performed on three continuous speech stimuli from a reading passage: two full sentences and one constituent phrase. Significant between-group differences were found for both cepstral measures and three LTAS measures (P<0.001): spectral mean, skewness, and kurtosis. These five measures also showed moderate to strong correlations to overall voice severity. Furthermore, high degrees of within-speaker consistency (correlation coefficients >=0.89) across utterances with varying length and phonemic content were evidenced for both subject groups. PMID- 20971613 TI - The role of the cricothyroid joint anatomy in cricothyroid approximation surgery. AB - OBJECTIVES/HYPOTHESIS: Cricothyroid approximation (CTA) surgery aims at raising the voice pitch in male-to-female transsexuals. However, 30% of the patients are not satisfied with the result. The purpose of our study was to examine the cricothyroid joint (CTJ) biomechanics and to analyze if (and how) the CTJ anatomy influences the movement of the cricoid and, consequently, the elongation of the vocal fold and the voice pitch after CTA. METHODS: Twenty-four cadaver larynges were examined with high-resolution computerized tomography and MIMICS three dimensional imaging software (Materialise Interactive Medical Image Control System, Leuven, Belgium). After superimposing the two scans taken in "neutral" and in "CTA" positions, vector geometrical analysis was used to determine the effective rotation axis of the CTJ and to calculate the elongation of the vocal folds after CTA. RESULTS: Our results showed that the cricoid rotates around an axis, the position of which depends on the anatomical structure of the CTJ. Based on the location of this effective rotation axis, we could distinguish three groups. In group I (N=13), the rotation axis was located in the lower third; in group II (N=5), it was located in the middle third; and in group III (N=6), it was located in the upper third of the cricoid. The elongations of the vocal fold were 12%, 8%, and 3%, in groups I, II, and III, respectively. CONCLUSIONS: The anatomical structure of the CTJ influences directly (1) the position of the effective rotation axis and (2) the elongation of the vocal folds. PMID- 20971614 TI - The effect of oxandrolone on voice frequency in growth hormone-treated girls with Turner syndrome. AB - OBJECTIVES/HYPOTHESIS: Oxandrolone (Ox) increases height gain but may also cause voice deepening in growth hormone (GH)-treated girls with Turner syndrome (TS). We assessed the effect of Ox on objective and subjective speaking voice frequency in GH-treated girls with TS. STUDY DESIGN: A multicenter, randomized, placebo (Pl)-controlled, double-blind study was conducted. METHODS: One hundred thirty three patients were included and treated with GH (1.33 mg/m2/d) from baseline, combined with Pl or Ox in a low (0.03 mg/kg/d) or conventional (0.06 mg/kg/d) dose from the age of 8 years and estrogens from the age of 12 years. Yearly from starting Ox/Pl until 6 months after discontinuing GH+Ox/Pl, voices were recorded and questionnaires were completed. RESULTS: At start, mean (+/-standard deviation [SD]) voice frequency SD score (SDS) was high for age (1.0+/-1.2, P<0.001) but normal for height. Compared with GH+Pl, voices tended to lower on GH+Ox 0.03 (P=0.09) and significantly lowered on GH+Ox 0.06 (P=0.007). At the last measurement, voice frequency SDS was still relatively high in GH+Pl group (0.6+/ 0.7, P=0.002) but similar to healthy girls in both GH+Ox groups. Voice frequency became lower than -2 SDS in one patient (3%) on GH+Ox 0.03 and three patients (11%) on GH+Ox 0.06. The percentage of patients reporting subjective voice deepening was similar between the dosage groups. CONCLUSIONS: Untreated girls with TS have relatively high-pitched voices. The addition of Ox to GH decreases voice frequency in a dose-dependent way. Although most voice frequencies remain within the normal range, they may occasionally become lower than -2 SDS, especially on GH+Ox 0.06 mg/kg/d. PMID- 20971615 TI - Severe right ventricular outflow tract obstruction caused by non-hodgkin lymphoma: complete regression after one course of bendamustine/rituximab therapy. AB - We present the case of a 67-year-old woman presenting with symptoms of predominantly right heart failure caused by cardiac tumor infiltration. Echocardiography showed almost complete obstruction, particularly of the right ventricular outflow tract. After complete diagnostic workup, treatment with only one course of bendamustine and rituximab resulted in complete resolution of the obstruction. Right ventricular outflow tract restriction due to infiltrative large B-cell lymphoma is a rare finding. Compression of the heart and great vessels, such as by mediastinal tumors, is not as rare. Prompt and accurate diagnosis by echocardiography and immediate initiation of treatment can be lifesaving. PMID- 20971616 TI - Current perspectives on vitamin D, immune system, and chronic diseases. AB - Accumulating data support that vitamin D possesses several biological and molecular actions apart from its role in calcium homeostasis. Immune cells express vitamin D receptor and are capable of metabolizing vitamin D. Within this context, experimental studies show that vitamin D modulates immune and inflammatory responses. Epidemiologic evidence linking poor vitamin D status to autoimmune diseases, type 2 diabetes, and cardiovascular disease suggests that insufficient vitamin D may be involved in the etiology of such disorders. Given the impact of immune and inflammatory abnormalities in the development of chronic diseases, including autoimmune disorders, it is possible that vitamin D might reduce chronic disease risk by modulating the immune system. PMID- 20971617 TI - Increased hypoglycemia associated with renal failure during continuous intravenous insulin infusion and specialized nutritional support. AB - OBJECTIVE: To evaluate glycemic control for critically ill, hyperglycemic trauma patients with renal failure who received concurrent intensive insulin therapy and continuous enteral nutrition (EN) or parenteral nutrition (PN). METHODS: Adult trauma patients with renal failure who were given EN or PN concurrently with continuous graduated intravenous regular human insulin (RHI) infusion for at least 3 d were evaluated. Our conventional RHI algorithm was modified for those with renal failure by allowing greater changes in blood glucose (BG) concentrations before the infusion rate was escalated. BG concentration was determined every 1 to 2 h while receiving the insulin infusion. BG control was evaluated on the day before RHI infusion and for a maximum of 7 d while receiving RHI. Target BG during the RHI infusion was 70 to 149 mg/dL (3.9 to 8.3 mmol/L). Glycemic control and incidence of hypoglycemia for those with renal failure were compared with a historical cohort of critically ill, hyperglycemic trauma patients without renal failure given our conventional RHI algorithm. RESULTS: Twenty-one patients with renal failure who received the modified RHI algorithm were evaluated and compared with 40 patients without renal failure given our conventional RHI algorithm. Average BG concentration was significantly greater for those with renal failure (133+/-14 mg/dL or 7.3+/-0.7 mmol/L) compared with those without renal failure (122+/-15 mg/dL or 6.8+/-0.8 mmol/L), respectively (P<0.01). Patients with renal failure showed worsened glycemic variability, with 16.1+/-3.3 h/d within the target BG range, 6.9+/-3.2 h/d above the target BG range, and 1.4+/-1.1 h/d below the target BG range compared with 19.6+/-4.7 h/d (P<0.001), 3.4+/-3.0 h/d (P<0.001), and 0.7+/-0.8 h/d (P<0.01) for those without renal failure, respectively. Moderate hypoglycemia (<60 mg/dL or<3.3 mmol/L) occurred in 76% of patients with renal failure compared with 35% without renal failure (P<0.005). Severe hypoglycemia (BG<40 mg/dL or<2.2 mmol/L) occurred in 29% of patients with renal failure compared with none of those without renal failure (P<0.001). CONCLUSION: Despite receiving a modified RHI infusion, critically ill trauma patients with renal failure are at greater risk for developing hypoglycemia and have more glycemic variability than patients without renal failure. PMID- 20971618 TI - Are lifetime prevalence of impetigo, molluscum and herpes infection really increased in children having atopic dermatitis? AB - BACKGROUND: Cutaneous infections such as impetigo contagiosum (IC), molluscum contagiosum (MC) and herpes virus infection (HI) appear to be associated with atopic dermatitis (AD), but there are no reports of concrete epidemiological evidence. OBJECTIVE: We evaluated the association of childhood AD with these infections by conducting a population-based cross-sectional study. METHODS: Enrolled in this study were 1117 children aged 0-6 years old attending nursery schools in Ishigaki City, Okinawa Prefecture, Japan. Physical examination was performed by dermatologists, and a questionnaire was completed on each child's history of allergic diseases including AD, asthma, allergic rhinitis and egg allergy, and that of skin infections including IC, MC and HI, as well as familial history of AD. RESULTS: In 913 children (AD; 132), a history of IC, MC or HI was observed in 45.1%, 19.7%, and 2.5%, respectively. Multiple logistic regression analysis revealed that the odds of having a history of IC were 1.8 times higher in AD children than in non-AD children. Meanwhile, a history of MC was significantly correlated to the male gender, but not to a personal history of AD. As for HI, we found no correlated factors in this study. CONCLUSIONS: The lifetime prevalence of IC was indeed higher in young children with a history of AD. PMID- 20971619 TI - Repetitive questioning behavior in Alzheimer's disease: relationship to regional cerebral blood flow. AB - Repetitive questioning is among the most common and burdensome of the behavioral and psychological symptoms of Alzheimer's disease (AD). Regardless of the clinical significance of the repetitive questioning, the neural substrates involved remain unclear. Fifty-eight consecutive patients with AD participated in this study. The score of repetitive questioning behavior was evaluated by multiplying the severity by the frequency of the behavior. They underwent brain SPECT with (99m)Tc-ethylcysteinate dimer. Scores of repetitive questioning behavior had a significant positive correlation with regional cerebral blood flow (rCBF) in the bilateral pericallosal regions. After removing the effect of memory test scores, we found a significant positive correlation of scores of repetitive questioning behavior to rCBF in the left pericallosal region. The pericallosal region includes the upper precuneus, cingulate, and posterior cingulate cortices on 3DSRT. Repetitive questioning behavior among AD patients might be a manifestation of mental state associated with a relative increase or preservation of rCBF in the left pericallosal region. PMID- 20971620 TI - Cotterillia bromelicola nov. gen., nov. spec., a gonostomatid ciliate (Ciliophora, Hypotricha) from tank bromeliads (Bromeliaceae) with de novo originating dorsal kineties. AB - Cotterillia bromelicola nov. gen., nov. spec. was discovered in the tanks of the Mexican bromeliad Tillandsia heterophylla. Its morphology, ontogenesis, and 18S rDNA were studied with standard methods. Cotterillia has many cirral rows on both sides of the body. Uniquely, and thus used to diagnose the new genus Cotterillia, it has dorsal kineties originating de novo, producing neokinetal waves where the parental dorsal kineties reorganize to "combined rows", consisting of dorsal bristles anteriorly and of cirri posteriorly. Thus, up to four generations of bristles and cirri occur on the dorsal body surface. Cotterillia bromelicola has a gonostomatid body and adoral zone of membranelles, while the dense ciliature and the neokinetal waves resemble kahliellid hypotrichs. However, the de novo origin of anlage 1 and the molecular analyses show convincingly that Cotterillia belongs to the GonostomatidaeSmall and Lynn, 1985, for which an improved diagnosis is provided. Thus, neokinetal waves originated several times independently. The molecular differences between Trachelostyla, Gonostomum, and Cotterillia are small (<= 5%) compared to their distinct morphologies and ontogeneses, suggesting that the 18S rDNA underestimates generic diversity. Our study emphasizes the need of combined morphological, ontogenetic, and molecular investigations to unravel the complex phylogeny and evolution of hypotrich ciliates. PMID- 20971621 TI - eXiT*CBR: A framework for case-based medical diagnosis development and experimentation. AB - OBJECTIVE: Medical applications have special features (interpretation of results in medical metrics, experiment reproducibility and dealing with complex data) that require the development of particular tools. The eXiT*CBR framework is proposed to support the development of and experimentation with new case-based reasoning (CBR) systems for medical diagnosis. METHOD: Our framework offers a modular, heterogeneous environment that combines different CBR techniques for different application requirements. The graphical user interface allows easy navigation through a set of experiments that are pre-visualized as plots (receiver operator characteristics (ROC) and accuracy curves). This user-friendly navigation allows easy analysis and replication of experiments. Used as a plug-in on the same interface, eXiT*CBR can work with any data mining technique such as determining feature relevance. RESULTS: The results show that eXiT*CBR is a user friendly tool that facilitates medical users to utilize CBR methods to determine diagnoses in the field of breast cancer, dealing with different patterns implicit in the data. CONCLUSIONS: Although several tools have been developed to facilitate the rapid construction of prototypes, none of them has taken into account the particularities of medical applications as an appropriate interface to medical users. eXiT*CBR aims to fill this gap. It uses CBR methods and common medical visualization tools, such as ROC plots, that facilitate the interpretation of the results. The navigation capabilities of this tool allow the tuning of different CBR parameters using experimental results. In addition, the tool allows experiment reproducibility. PMID- 20971623 TI - Virtual microscopy-The future of teaching histology in the medical curriculum? AB - Conventional continuing education in microscopic anatomy, histopathology, hematology and microbiology has hitherto been carried out using numerous sets of sectioned tissue specimens in a microscopy laboratory. In comparison, after digitalization of the sections it would be possible to access teaching specimens via virtual microscopy and the internet at any time and place. This would make it possible to put innumerable new learning scenarios into practice. The present article elucidates the advantages of virtual microscopy in histology instruction and presents a concept of how virtual microscopy could be introduced into the teaching of microscopic anatomy in several steps. Initially, the presently existing microscopic teaching specimens would be digitalized and made available on-line without restriction. In a second step, instruction would be shifted to an emphasis on virtual microscopy, utilizing all of the advantages offered by the technique. In a third step, the microscopic contents could be networked with other anatomical, radiological and clinical content on-line, thus opening new learning perspectives for students of human and dental medicine as well as those of medically related courses of study. The advantages and disadvantages of such a concept as well as some possibly arising consequences are discussed in the following. PMID- 20971622 TI - Phytic acid protects porcine intestinal epithelial cells from deoxynivalenol (DON) cytotoxicity. AB - The purpose of this study was to evaluate the effects of phytic acid (IP(6)) as a possible inhibitor of cellular damage induced by toxic substances such as mycotoxins on a porcine intestinal epithelial cell line (IPEC-1). We first observed that a dose of 5 mM phytic acid decreases cell viability and transepithelial electrical resistance (TEER) of cell monolayer. We next investigate the effect of non-cytotoxic dose of phytic acid on the deoxinivalenol (DON) induced decreased TEER. We showed that treatment with 0.5 mM or 1.0 mM phytic acid restores the decrease in TEER caused by 25 MUM DON. In conclusion this study demonstrates that phytic acid decreased the negative effects of deoxynivalenol on the membrane integrity of the IPEC-1 intestinal epithelial cell line. PMID- 20971624 TI - Annals of anatomy. PMID- 20971625 TI - C-28/I2 and T/C-28a2 chondrocytes as well as human primary articular chondrocytes express sex hormone and insulin receptors--Useful cells in study of cartilage metabolism. AB - Sex hormones and insulin have been implicated in articular cartilage metabolism. To supplement previous findings on the regulation of matrix synthesis with 17beta estradiol and insulin and to find a possible model to study cartilage metabolism in vitro, we evaluated the expression of estrogen receptors alpha and beta (ERalpha, ERbeta), androgen receptor (AR) and insulin receptor (IR), in immortalized C-28/I2 and T/C-28a2 chondrocytes and in human primary articular cartilage cells. Chondrocytes were treated with increasing concentrations of 17beta-estradiol, dihydrotestosterone or insulin and analyzed by means of RT-PCR and Western blotting. Both cell lines as well as human articular chondrocytes expressed ER alpha and beta, AR and IR at mRNA and protein levels. In immortalized C-28/I2 chondrocytes, we showed that increasing concentrations of 17beta-estradiol diminished the 95kDa band of IR. Since 17beta-estradiol suppresses insulin-induced proline incorporation and type II collagen synthesis, as we have previously demonstrated, our findings give the first clue that 17beta estradiol may have negative effects on cartilage anabolism triggered by insulin during hormonal imbalance. Compared to chondrocytes cultured without hormones, immunostaining for ERalpha/beta, AR and IR was decreased in both cell lines after incubation of cells with the receptor-specific hormones. It can be assumed that C 28/I2 and T/C-28a2 chondrocytes interact with the respective hormones. Our findings provide a reproducible model for investigating sex hormone and insulin receptors, which are present in low concentrations in articular chondrocytes, in the tissue-specific context of cartilage metabolism. PMID- 20971626 TI - Use of gas push-pull tests for the measurement of methane oxidation in different landfill cover soils. AB - In order to optimise methane oxidation in landfill cover soils, it is important to be able to accurately quantify the amount of methane oxidised. This research considers the gas push-pull test (GPPT) as a possible method to quantify oxidation rates in situ. During a GPPT, a gas mixture consisting of one or more reactive gases (e.g., CH(4), O(2)) and one or more conservative tracers (e.g., argon), is injected into the soil. Following this, the mixture of injected gas and soil air is extracted from the same location and periodically sampled. The kinetic parameters for the biological oxidation taking place in the soil can be derived from the differences in the breakthrough curves. The original method of Urmann et al. (2005) was optimised for application in landfill cover soils and modified to reduce the analytical effort required. Optimised parameters included the flow rate during the injection phase and the duration of the experiment. 50 GPPTs have been conducted at different landfills in Germany during different seasons. Generally, methane oxidation rates ranged between 0 and 150 g m(soil air)(-3)h(-1). At one location, rates up to 440 g m(soil air)(-3)h(-1) were measured under particularly favourable conditions. The method is simple in operation and does not require expensive equipment besides standard laboratory gas chromatographs. PMID- 20971627 TI - A miniature chip for protein detection based on magnetic relaxation switches. AB - A miniature multi-sample chip for protein detection with a bench-top magnetic resonance imager was created on the basis of magnetic relaxation switches. The chip was assessed with two protein systems. Both qualitative and quantitative results for the target proteins were obtained by image analysis and relaxation time measurement, respectively. The detection of prostate specific antigen, the serum marker of human prostate cancer, showed a linear concentration range of 17.3-43.2 ng mL(-1) and a detection limit of 13.7 ng mL(-1). As proof of concept, the analysis of 18 samples with a volume of 6.37 MUL each was completed in 26 min by this chip. This technique may become an easy and efficient approach for rapid and high-throughput protein assay and protein-protein interaction screening. PMID- 20971628 TI - Bryostatins: biological context and biotechnological prospects. AB - Bryostatins are a family of protein kinase C modulators that have potential applications in biomedicine. Found in miniscule quantities in a small marine invertebrate, lack of supply has hampered their development. In recent years, bryostatins have been shown to have potent bioactivity in the central nervous system, an uncultivated marine bacterial symbiont has been shown to be the likely natural source of the bryostatins, the bryostatin biosynthetic genes have been identified and characterized, and bryostatin analogues with promising biological activity have been developed and tested. Challenges in the development of bryostatins for biomedical and biotechnological application include the cultivation of the bacterial symbiont and heterologous expression of bryostatin biosynthesis genes. Continued exploration of the biology as well as the symbiotic origin of the bryostatins presents promising opportunities for discovery of additional bryostatins, and new functions for bryostatins. PMID- 20971629 TI - The Lithistida: important sources of compounds useful in biomedical research. AB - Lithistid sponges have been an important source of structurally complex natural products with potent biological activities. Examples of compounds marketed as biological markers along with recent advances in defining the modes of action and biomedical potential of lithistid-derived compounds are presented. PMID- 20971630 TI - Chemical biotechnology--a marriage of convenience and necessity. PMID- 20971631 TI - Oscillatory signaling processes: the how, the why and the where. AB - Oscillatory processes in biological signal transduction have come under progressively increasing scrutiny in terms of their functional significance and mechanisms of emergence and regulation. Since oscillatory processes can be a by product of rapid adaptation and can also easily emerge if the feedback underlying adaptive processes is inadvertently artificially enhanced, one needs to exercise caution in both claiming the existence of in vivo oscillations and seeking to assign to them a specific functional significance. Nevertheless, oscillations can be a powerful means of encoding and transferring information both in time and in space, thus possessing important potential advantages for evolutionary selection and stabilization. Thus periodicity in the cell responses to diverse persistent external stimuli might become a more recognized and even expected feature of signaling processes. PMID- 20971632 TI - Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer. AB - PURPOSE: To determine whether irinotecan plus oxaliplatin (mIROX) is superior to irinotecan plus infusional 5-fluorouracil, leucovorin (FUFIRI) as first-line therapy of patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: A phase III, randomised, open-label multicentre study compared standard treatment with FUFIRI (irinotecan 80 mg/m(2), 5-fluorouracil 2000 mg/m(2), folinic acid 500 mg/m(2) weekly times 6) to mIROX using an identical schedule of irinotecan plus oxaliplatin 85 mg/m(2) applied on days 1, 15 and 29 of a 7-week cycle. The primary end-point was progression-free survival (PFS). RESULTS: A total of 479 eligible patients were randomly assigned. Progression-free survival was 7.2 months in the mIROX arm and 8.2 months in the FUFIRI arm [hazard ratio=1.14; 95% confidence interval (CI) 0.94-1.37; P=0.178]. Comparable results were also obtained for overall survival time with 19 months in the mIROX-arm and 22 months in the FUFIRI-arm (hazard ratio=1.08, P=0.276). Both regimens induced an identical objective response rate (ORR) of 41%, but disease control rate (ORR plus stable disease) was significantly greater in the FUFIRI group (81% versus 68%, P=0.001). Most frequent grades 1-4 side-effects of mIROX and FUFIRI treatment were nausea (80% versus 73%) and delayed diarrhoea (79% versus 68%). Grades 3-4 toxicities were generally below 10%, except for diarrhoea which was more frequent in the mIROX-arm compared to the FUFIRI-arm (19% versus 30%, P=0.006) CONCLUSION: mIROX failed to show superior activity compared to high-dose 5-FU/folinic acid plus irinotecan. Due to better tolerability the combination of high-dose 5-FU/folinic acid and irinotecan remains a standard of care in first line treatment of metastatic colorectal cancer. PMID- 20971633 TI - Would the effect of HPV vaccination on non-cervical HPV-positive cancers make the difference for its cost-effectiveness? AB - Besides cervical cancer, the human papillomavirus (HPV) is found in other cancers and may be preventable with HPV vaccination. However, these other cancers are often not accounted for in cost-effectiveness analyses of HPV vaccination. This study estimates the potential maximum effect on the cost-effectiveness ratio (CER) of HPV vaccination in preventing non-cervical HPV-positive cancers. For the Dutch situation, a mathematical equation was used to estimate the maximum impact if all cancer cases of the penis, vulva/vagina, anus, oral cavity and oro-pharynx with HPV16/18 are prevented, in terms of number of life years gained, savings and improvement in the CER of the vaccination. For other countries and for future developments, we show how the impact on the CER varies depending on the incidence of cervical/non-cervical HPV 16/18-positive cancers, vaccine costs and clinical costs. If in the Netherlands all HPV 16/18-positive cancers are prevented by vaccination in women only, compared to if only HPV 16/18-positive cervical cancer is prevented, the life years gained increase with 14%, the savings increase with 18%, and the CER decreases with 13%. If vaccination prevents HPV-positive cancers in both men and women, these figures increase to 25%, 26% and 21%, respectively. In conclusion, if HPV vaccination fully prevents all non-cervical HPV-positive cancers, this would substantially increase its cost-effectiveness. The impact of the vaccination varies depending on the incidence of cervical/non-cervical HPV16/18-positive cancers, the vaccine costs and clinical costs. Observed combinations of these parameters in different countries show a decrease in the CER between 10% and 31%. PMID- 20971634 TI - WITHDRAWN: Monocytes associate to incident cancer and mortality in man. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 20971635 TI - Biochemical characterization of two novel beta-glucosidase genes by metagenome expression cloning. AB - Two novel beta-glucosidase genes designated as bgl1D and bgl1E, which encode 172- and 151-aa peptides, respectively, were cloned by function-based screening of a metagenomic library from uncultured soil microorganisms. Sequence analyses indicated that Bgl1D and Bgl1E exhibited lower similarities with some putative beta-glucosidases. Functional characterization through high-performance liquid chromatography demonstrated that purified recombinant Bgl1D and Bgl1E proteins hydrolyzed D-glucosyl-beta-(1-4)-D-glucose to glucose. Using p-nitrophenyl-beta-D glucoside as substrate, K(m) was 0.54 and 2.11 mM, and k(cat)/K(m) was 1489 and 787 mM(-1) min(-1) for Bgl1D and Bgl1E, respectively. The optimum pH and temperature for Bgl1D was pH 10.0 and 30 degrees C, while the optimum values for Bgl1E were pH 10.0 and 25 degrees C. Bgl1D exhibited habitat-specific characteristics, including higher activity in lower temperature and at high concentrations of AlCl(3) and LiCl. Bgl1D also displayed remarkable activity across a broad pH range (5.5-10.5), making it a potential candidate for industrial applications. PMID- 20971636 TI - Factors affecting cellulose and hemicellulose hydrolysis of alkali treated brewers spent grain by Fusarium oxysporum enzyme extract. AB - The enzymatic degradation of polysaccharides to monosaccharides is an essential step in bioconversion processes of lignocellulosic materials. Alkali treated brewers spent grain was used as a model substrate for the study of cellulose and hemicellulose hydrolysis by Fusarium oxysporum enzyme extract. The results obtained showed that cellulose and hemicellulose conversions are not affected by the same factors, implementing different strategies for a successful bioconversion. Satisfactory cellulose conversion could be achieved by increasing the enzyme dosage in order to overcome the end-product inhibition, while the complexity of hemicellulose structure imposes the presence of specific enzyme activities in the enzyme mixture used. All the factors investigated were combined in a mathematical model describing and predicting alkali treated brewers spent grain conversion by F. oxysporum enzyme extract. PMID- 20971637 TI - Assessing solid digestate from anaerobic digestion as feedstock for ethanol production. AB - Ethanol production using solid digestate (AD fiber) from a completely stirred tank reactor (CSTR) anaerobic digester was assessed comparing to an energy crop of switchgrass, and an agricultural residue of corn stover. A complete random design was fulfilled to optimize the reaction conditions of dilute alkali pretreatment. The most effective dilute alkali pretreatment conditions for raw CSTR AD fiber were 2% sodium hydroxide, 130 degrees C, and 3 h. Under these pretreatment conditions, the cellulose concentration of the AD fiber was increased from 34% to 48%. Enzymatic hydrolysis of 10% (dry basis) pretreated AD fiber produced 49.8 g/L glucose, while utilizing 62.6% of the raw cellulose in the AD fiber. The ethanol fermentation on the hydrolysate had an 80.3% ethanol yield. The cellulose utilization efficiencies determined that the CSTR AD fiber was a suitable biorefining feedstock compared to switchgrass and corn stover. PMID- 20971638 TI - A control strategy of partial nitritation in a fixed bed biofilm reactor. AB - To achieve an appropriate mixture of ammonium and nitrite for anaerobic ammonium oxidation (ANAMMOX), 50% partial nitritation was optimized in a fixed bed biofilm reactor treating synthetic wastewater. Results suggested that 50% partial nitritation could be achieved by stepwise increases of influent NH4+-N at pH of 7.8+/-0.2, temperature of 30+/-1 degrees C and dissolved oxygen (DO) of 0.5-0.8 mg l(-1). Hydraulic retention time (HRT) and influent alkalinity did significantly affect partial nitritation. At HRT 12 h, 50% partial nitritation could be kept stable, regardless of influent NH4+-N variation, by controlling the influent HCO3-/NH4+ molar ratio at 1:1. The fluorescent in situ hybridization (FISH) results indicated the abundance of evolution of ammonia-oxidizing bacteria (AOB) and the nitrite-oxidizing bacteria (NOB) coincided well with the performance of partial nitritation. Furthermore, the AOB were highly affiliated with Nitrosomonas spp. and Nitrosospira spp. dominated (64.1%) in the biofilm with a compact structure during the stable 50% partial nitritation period. PMID- 20971639 TI - Cellulosic ethanol production by Zymomonas mobilis harboring an endoglucanase gene from Enterobacter cloacae. AB - Enterobactercloacae was isolated from the gut of the wood feeding termite, Heterotermes indicola, and a 2.25-kb fragment conferring cellulase activity was cloned in Escherichia coli. The cloned fragment contained a 1083-bp ORF which could encode a protein belonging to glycosyl hydrolase family 8. The cellulase gene was introduced into Zymomonas mobilis strain Microbial Type Culture Collection centre (MTCC) on a plasmid and 0.134 filter paper activity unit (FPU)/ml units of cellulase activity was observed with the recombinant bacterium. Using carboxymethyl cellulose and 4% NaOH pretreated bagasse as substrates, the recombinant strain produced 5.5% and 4% (V/V) ethanol respectively, which was threefold higher than the amount obtained with the original E.cloacae isolate. The recombinant Z. mobilis strain could be improved further by simultaneous expression of cellulase cocktails before utilizing it for industrial level ethanol production. PMID- 20971640 TI - Naphthalimide based novel organoselenocyanates: finding less toxic forms of selenium that would retain protective efficacy. AB - A series of naphthalimide based organoselenocyanates were synthesized and screened for their toxicity as well as their ability to modulate several detoxifying/antioxidative enzyme levels at a primary screening dose of 3 mg/kg b.w. in normal Swiss albino mice for 30 days. Compound 4d showed highest activity in elevating the detoxifying/antioxidant enzymes levels. PMID- 20971641 TI - Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors. AB - Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg. PMID- 20971642 TI - N-{3-[(1,1-dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl}benzamide analogs as potent Kv1.3 inhibitors. Part 1. AB - We report the synthesis and in vitro activity of a series of novel N-{3-[(1,1 dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl}benzamide analogs. These analogs showed potent inhibitory activity against Kv1.3. Several compounds, including compound 8b, showed similar potency to the known Kv1.3 inhibitor PAP-1 when tested under the IonWorks patch clamp assay conditions. PMID- 20971643 TI - A regressed phase analysis for coupled joint systems. AB - This study aims to address shortcomings of the relative phase analysis, a widely used method for assessment of coupling among joints of the lower limb. Goniometric data from 15 individuals with spastic diplegic cerebral palsy were recorded from the hip and knee joints during ambulation on a flat surface, and from a single healthy individual with no known motor impairment, over at least 10 gait cycles. The minimum relative phase (MRP) revealed substantial disparity in the timing and severity of the instance of maximum coupling, depending on which reference frame was selected: MRP(knee-hip) differed from MRP(hip-knee) by 16.1+/ 14% of gait cycle and 50.6+/-77% difference in scale. Additionally, several relative phase portraits contained discontinuities which may contribute to error in phase feature extraction. These vagaries can be attributed to the predication of relative phase analysis on a transformation into the velocity-position phase plane, and the extraction of phase angle by the discontinuous arc-tangent operator. Here, an alternative phase analysis is proposed, wherein kinematic data is transformed into a profile of joint coupling across the entire gait cycle. By comparing joint velocities directly via a standard linear regression in the velocity-velocity phase plane, this regressed phase analysis provides several key advantages over relative phase analysis including continuity, commutativity between reference frames, and generalizability to many-joint systems. PMID- 20971644 TI - Locomotion in restricted space: kinematic and electromyographic analysis of stoopwalking and crawling. AB - Stoopwalking and crawling are compulsory gait techniques in some occupational settings, as in low-seam coal mines (where vertical space may be less than 122 cm). Nine participants, six males and three females (mean=35 years+17 SD), participated in a study examining kinematic and electromyographic (EMG) responses to natural cadence stoopwalking, four-point crawling (all fours), and two-point crawling (knees only). EMG data were collected from knee extensors and flexors, and a motion analysis system was used to obtain kinematic data. The average gait velocity for stoopwalking was 1.01 (+/-0.32)m/s with an average cadence of 112.8 steps/min and stride length of 1.04 m. Four-point crawling velocity averaged 0.50 (+/-0.20)m/s, with average cadence of 86.3 steps/min and stride length of 0.69m. Two-point crawling exhibited the slowest velocity (0.32m/s) and shortest stride length (0.40 m); however, cadence was greater than four-point crawling (96.8 steps/min). EMG findings included prolonged contraction of both knee extensors and flexors (compared to normative data on normal walking), increased relative activity SD of the flexors (versus extensors) in two-point crawling, and decreased thigh muscle activity in four-point crawling. Interlimb coordination in four-point crawling trials indicated trot-like, no limb pairing, and near pace like limb contact patterns. Presence or absence of kneepads had no impact on kinematic or EMG measures (p>0.05); however, subjects complained of discomfort without kneepads (especially in two-point crawling). Results of this study have implications for work performed in underground coal mines, as well as emergency or evacuation considerations. PMID- 20971645 TI - Scripta manent? Assessing microbial risk to paper heritage. AB - Paper, like all other cultural heritage materials, degrades over time, but conservation slows down the rate of its deterioration. There is a long history of cooperation between microbiologists and conservators of libraries and archival materials, but current approaches addressing paper deterioration need urgent reassessment to take full advantage of modern microbiological methodologies. The present article discusses what we believe are the current priority research areas in assessing microbial risk to paper heritage, and reports studies on a 13th century Italian manuscript and on Leonardo da Vinci's Atlantic Codex which illustrate the problems and challenges encountered when dealing with microbial investigations of paper artworks. The potential of using a more advanced microbiological approach is highlighted. PMID- 20971646 TI - Protein kinases: evolution of dynamic regulatory proteins. AB - Eukayotic protein kinases evolved as a family of highly dynamic molecules with strictly organized internal architecture. A single hydrophobic F-helix serves as a central scaffold for assembly of the entire molecule. Two non-consecutive hydrophobic structures termed "spines" anchor all the elements important for catalysis to the F-helix. They make firm, but flexible, connections within the molecule, providing a high level of internal dynamics of the protein kinase. During the course of evolution, protein kinases developed a universal regulatory mechanism associated with a large activation segment that can be dynamically folded and unfolded in the course of cell functioning. Protein kinases thus represent a unique, highly dynamic, and precisely regulated set of switches that control most biological events in eukaryotic cells. PMID- 20971647 TI - Towards a stable noeuromycin analog with a D-manno configuration: synthesis and glycosidase inhibition of D-manno-like tri- and tetrahydroxylated azepanes. AB - Noeuromycin is a highly potent albeit unstable glycosidase inhibitor due to its hemiaminal function. While stable D-gluco-like analogs have been reported, no data are available for D-manno-like structures. A series of tri- and tetrahydroxylated seven-membered iminosugars displaying either a D-manno-or a L gulo-like configuration, were synthesized from methyl alpha-D-mannopyranoside using a reductive amination-mediated ring expansion as the key step. Screening towards a range of commercial glycosidases demonstrated their potency as competitive glycosidase inhibitors while cellular assay showed selective albeit weak glycoprotein processing mannosidase inactivation. PMID- 20971648 TI - In vitro lectin-mediated selection and characterization of rHuEPO-alpha-binding ssDNA aptamers. AB - A lectin-mediated affinity chromatographic SELEX technique was developed to generate functional ssDNA aptamers for recombinant human erythropoietin-alpha (rHuEPO-alpha), an important pharmaceutical glycoprotein for the first time. Secondary structure analysis of the aptamer clones from sequential 6th, 7th, and 8th rounds showed that a certain fragment 'CGAGAT' in the 3' primer region could be used to trace increasing evolution stringency from its hybridization at different locations, in which a specific hybridization with its complement in the 5' primer region (aptamer 807) was evolved as the prevalent one with the simplest and most common motif. Characteristics of the aptamers with lower Gibbs' free energies and K(d) values (nM) were investigated. For aptamer 813, the minimer 813 42nt formed by the random and primer regions was indispensable for the specific binding with rHuEPO-alpha. While for aptamer 807, only the random region, that is, 807-39nt, was the functional motif. Further experiments of methylation, site directed mutation and length variation showed that the loop of aptamer 807-39nt was the key region for binding with rHuEPO-alpha, and the stem should be considered as a stabilizing part. Lower cross-reactivity of aptamer 807-39nt was observed with human normal urothelium tissues than the anti-EPO monoclonal antibody AE7A5. Aptamer 807-39nt also exhibited a specific recognition for human bladder carcinoma cells and human urothelium tumors, which might provide a novel way to probe such tumors with overexpressed EPOs. PMID- 20971649 TI - Parallel synthesis and nucleic acid binding properties of C(6')-alpha functionalized bicyclo-DNA. AB - Two novel bicyclo-T nucleosides carrying a hydroxyl or a carboxymethyl substituent in C(6')-alpha-position were prepared and incorporated into oligodeoxynucleotides. During oligonucleotide deprotection the carboxymethyl substituent was converted into different amide substituents in a parallel way. T(m)-measurements showed no dramatic differences in both, thermal affinity and mismatch discrimination, compared to unmodified oligonucleotides. The post synthetic modification of the carboxymethyl substituent allows in principle for a parallel preparation of a library of oligonucleotides carrying diverse substituents at C(6'). In addition, functional groups can be placed into unique positions in a DNA double helix. PMID- 20971650 TI - Discovery and synthesis of novel luteolin derivatives as DAT agonists. AB - Luteolin, 5,7-dihydroxy-2-(3,4-dihydroxyphenyl)-4H-chromen-4-one, has been proposed and proved to be a novel dopamine transporter (DAT) activator. In order to develop this potential of luteolin, a series of novel luteolin derivatives were designed, synthesized, and evaluated for their DAT agonistic activities, utilizing constructed Chinese hamster ovary (CHO) cell lines stably expressing rat DAT. Biological screening results demonstrated that luteolin derivatives 1d, 1e, and 4c carry great DAT agonistic potency (EC(50)=0.046, 0.869, and 1.375MUM, respectively) compared with luteolin 8 (EC(50)=1.45+/-0.29MUM). Luteolin derivative 1d, notably, exhibited a 32-fold-higher DAT agonistic potency than luteolin. These luteolin derivatives represent a novel DAT agonist class, from which lead compounds useful for exploration of additional novel DAT agonists could be drawn. PMID- 20971651 TI - Clinical registries: a quantum of knowledge. PMID- 20971652 TI - Totally endoscopic removal of dislocated atrial septal defect - closure devices. PMID- 20971653 TI - Sex hormone metabolism in lung development and maturation. AB - Sex hormones are increasingly recognized as regulators of lung development. Respiratory distress syndrome (RDS) is the leading cause of morbidity in preterm neonates and occurs with a higher incidence in males. The mechanisms underlying the effects of androgens on lung development and the occurrence of RDS are only partially deciphered, and positive roles of estrogens on surfactant production and alveologenesis are relevant to our understanding of pulmonary diseases. This manuscript reviews current knowledge on androgen and estrogen metabolism and on relevant hormone targets in the fetal lung. Further investigations are needed to elucidate mechanisms orchestrating sex hormone effects on lung development. These studies aim to decrease mortality and morbidity associated with RDS and other pathologies related to lung immaturity at birth. PMID- 20971654 TI - Fast, high resolution mass spectrometry imaging using a Medipix pixelated detector. AB - In mass spectrometry imaging, spatial resolution is pushed to its limits with the use of ion microscope mass spectrometric imaging systems. An ion microscope magnifies and then projects the original spatial distribution of ions from a sample surface onto a position-sensitive detector, while retaining time-of-flight mass separation capabilities. Here, a new type of position-sensitive detector based on a chevron microchannel plate stack in combination with a 512 * 512 complementary metal-oxide-semiconductor based pixel detector is coupled to an ion microscope. Spatial resolving power better than 6 MUm is demonstrated by secondary ion mass spectrometry and 8-10 MUm spatial resolving power is achieved with laser desorption ionization. A detailed evaluation of key performance criteria such as spatial resolution, acquisition speed, and data handling is presented. PMID- 20971655 TI - Silent infarction or white matter hyperintensity and impaired attention task scores in a nondemented population: the Osaki-Tajiri Project. AB - Whether silent infarction can be completely asymptomatic remains unclear. Although the central cholinergic system affects cognition, little attention has been given to infarction. We hypothesized that specific damage to the cholinergic pathways due to infarction or white matter hyperintensity (WMH) would deteriorate cognition, especially attention. A total of 502 representative elderly participants enrolled in the Osaki-Tajiri Project in 1998 were studied. Participants with focal neurologic signs or previous history of stroke or transient ischemic attack were excluded from the analysis. MRIs were available for all participants, and the Cholinergic Pathways Hyperintensities scale (CHIPS) was used to assess vascular damage in the cholinergic pathways. The Mini-Mental State Examination (MMSE), word fluency test, Digit Symbol test, and digit span test were used to assess global cognitive function and several aspects of attention. Participants were divided into 3 groups according to the comorbidity of cerebrovascular disease (CVD) and cholinergic involvement: non-CVD, CVD with cholinergic involvement [CVD-Ch(+)], and CVD without cholinergic involvement [CVD Ch(-)]. Cognitive scores were compared among the 3 groups. In the non-CVD group, the correlations between cognitive function and the CHIPS score were examined. The CVD-Ch(+) group exhibited significantly lower scores for the Digit Symbol test compared with the other two groups, regardless of the MMSE score. In the non CVD group, the CHIPS score of white matter changes was irreversibly correlated (ie, biologically meaningful) with the Digit Symbol score in participants age >80 years. Our findings suggest that silent infarction or WMH may deteriorate attention regardless of global cognitive function by interrupting the central cholinergic pathway. PMID- 20971656 TI - Stroke risk factors and outcomes among various Asian ethnic groups in Singapore. AB - Data on interethnic differences in the Asian stroke population are limited. We evaluated the relationships among various cardiovascular risk factors, stroke subtypes, and outcomes in a multiethnic Singaporean population comprising consecutive ischemic stroke patients presenting to our tertiary center over a 1 year period. Strokes were classified based on criteria used in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Functional independence at hospital discharge was defined as a modified Rankin Scale (mRS) score of 0-2. The ethnic distribution of the study population (n = 481; mean age, 64.1 +/- 11.9 years) was 74% Chinese, 17% Malay, and 9% Indian. The prevalence of risk factors was similar in the 3 ethnic groups except for diabetes (Chinese, 39.8%; Malay, 67.5%; Indian, 52.3%; P < .001). Hypertension and hypercholesterolemia were the most common cardiovascular risk factors. Lacunar stroke was the most frequent stroke subtype (47.9%). Large-artery atherosclerotic infarctions were more prevalent in Indians (25.0%), whereas lacunar infarctions occured more frequently in Chinese (51.8%; P < .01). No differences in in-hospital mortality and functional independence at discharge were seen among the 3 ethnic groups. Despite the differences in risk factors and in stroke subtypes classified by location or underlying etiology, short-term outcome measures were similar in the 3 different Asian ethnicities in Singapore. PMID- 20971657 TI - Quantitative assessment of initial retention of bone marrow mononuclear cells injected into the coronary arteries. AB - BACKGROUND: Intracoronary injection of bone marrow mononuclear cells (BMMNC) is a common clinical protocol of cell transplantation for heart disease, but poor engraftment of donor cells in the heart, which will limit its therapeutic efficacy, is a major issue. Initial "retention" (endothelial adherence and/or extravasation) of BMMNC immediately after intracoronary injection is a key step toward successful engraftment; however, this event has not been fully characterized. The aim of this study is to quantitatively clarify the frequency of "retention" of BMMNC after intracoronary injection, determine the impact of prior induction of ischemia-reperfusion injury on "retention" efficiency, and elucidate the underlying mechanisms focusing on adhesion molecule-mediated cell cell interactions. METHODS: One million BMMNC collected from green fluorescent protein (GFP)-transgenic mice were injected into the coronary arteries of syngeneic wild-type mouse hearts under Langendorff perfusion. Retention efficiency was quantitatively estimated from the GFP-positive cell number flushed out into the coronary effluent. RESULTS: Whereas only 13.3 +/- 1.2% of injected BMMNC were retained into normal hearts, prior induction of 30-minute ischemia and 30-minute reperfusion increased the retention efficiency to 36.5 +/- 1.6% (p < 0.05, n = 8). Immunoconfocal observation further confirmed this enhanced retention after ischemia-reperfusion. Noticeably, the enhanced retention efficiency after ischemia-reperfusion treatment was diminished by administration of anti-P-selectin antibody (8.3 +/- 0.8%, p < 0.05), but was not affected by inhibiting intercellular adhesion molecule-1 (39.6 +/- 3.3%) or vascular cell adhesion molecule-1 (43.9 +/- 2.9%). CONCLUSIONS: Retention efficiency of intracoronary-injected BMMNC was poor in a model of isolated, crystalloid perfused murine hearts. An antecedent period of global ischemia-reperfusion increased the retention via P-selectin-dependent BMMNC-endothelial interaction. PMID- 20971658 TI - NonREM sleep mentation in chronically-treated persons with schizophrenia. AB - This study examined the laboratory dream content reported by 14 patients with schizophrenia and 15 controls, with a focus on reports obtained from NonREM sleep. Both the controls' and patients' frequency of dream recall following awakenings from NonREM and REM sleep were similar to values reported for healthy participants. Patients' NonREM sleep narratives were shorter than those from controls. When compared to their reports from REM sleep, both groups' NonREM sleep reports included significantly fewer words and reportable items. The controls were more likely to report a subjective feeling of bizarreness for their REM sleep reports as compared to their NonREM sleep reports. This difference was not observed in patients with schizophrenia. Taken together, these findings suggest few differences between the NonREM sleep mentation of patients with schizophrenia and of controls and that sleep stage cognitive style is comparable in both groups, with NonREM sleep reports being more thought-like, less elaborate and bizarre than REM sleep reports. PMID- 20971659 TI - Desmoplastic ameloblastoma: analysis of 17 Nigerian cases. AB - OBJECTIVE: This study aimed to add to existing knowledge on 90 cases of desmoplastic ameloblastoma (DA) previously reported in the scientific literature and analyze data that could help speculate on its biologic profile. STUDY DESIGN: From 330 cases of ameloblastoma (pooled from 573 histologically diagnosed odontogenic tumours) 17 cases of DA were retrieved and analyzed for estimated mean growth rate (EMGR) and histologic variants. EMGR for DA was compared with EMGR for conventional ameloblastoma (CA), as recorded over the same period of 38 years. RESULTS: Desmoplastic ameloblastoma had predilection for mandible (81.2%), posterior mandible being the most commonly affected, contrary to scientific literature reports of anterior maxillary predilection. Simple DA (88.0%) and DA with osteoplasia (12.0%) were the histologic variants observed. EMGR for DA (0.36 +/- 0.44 cm/mo) was significantly less than EMGR (0.71 +/- 1.16 cm/mo) for CA (P = .000480). CONCLUSION: This study speculates that DA tends to be less biologically aggressive than CA and has predilection for posterior mandible in Nigerians. PMID- 20971660 TI - Maxillary sinusitis of odontogenic origin: cone-beam volumetric computerized tomography-aided diagnosis. AB - OBJECTIVE: Study of radiographic features of maxillary sinusitis of odontogenic origin as visualized on 3-dimensional advanced imaging is essential for prompt diagnosis and appropriate management. This study attempted to describe and delineate radiographic characteristics of this condition. STUDY DESIGN: Three cases of failed endodontic therapy presenting with confounding clinical signs and symptoms were subjected to 3-dimensional imaging with cone-beam volumetric computerized tomography (CBVCT) to evaluate changes in the maxillary sinuses. RESULTS: CBVCT showed varying involvement of the ipsilateral maxillary sinus in all 3 cases. The presentation varied from presence of intrasinus fluid to reactionary osseous response within the sinus. CONCLUSIONS: CBVCT as a diagnostic aid to evaluate the involvement of the maxillary sinuses in cases of endodontic treatment failure seems to assist with formulation of a definitive diagnosis. Appropriate interventions may be instituted, including an otolaryngology consultation. PMID- 20971662 TI - JAK2V617F mutation and myeloproliferative malignancy in a patient with Type 1 Gaucher disease. PMID- 20971661 TI - Overexpression of matrix metalloproteinase (MMP)-1 and -9 in central giant cell lesions of the jaws: implications for clinical behavior. AB - OBJECTIVE: The aim of this study was to investigate the relationship between the immunohistochemical expression of MMP-1 and MMP-9 with the clinical behavior of central giant cell lesions (CGCLs) of the jaws. STUDY DESIGN: Paraffin-embedded tissue from 30 aggressive and 12 nonaggressive CGCLs was assessed for the expression of MMP-1 and MMP-9 using immunohistochemistry. RESULTS: Although cellular immunolocalization patterns of MMP-1 and MMP-9 were similar, mean values of expression estimation/SID scores of each protease were significantly higher in aggressive CGCLs in comparison with nonaggressive lesions. Moreover, linear regression analysis showed that there was a reasonably good correlation not only between the expression estimation but also among SID scores of the 2 proteolytic enzymes. CONCLUSION: The findings of this study suggest a role for MMP-1 and MMP 9 in the resorptive activity of different cellular groups in CGCLs and indicate that differences in immunoreactivity of these 2 proteolytic enzymes may underlie the distinct clinical behavior. PMID- 20971663 TI - Kinematic analysis of equine masticatory movements: comparison before and after routine dental treatment. AB - The objective of this study was to compare masticatory movements before and after dental treatment using kinematic analysis. The masticatory movements of 15 adult Warmblood horses with mild dental pathology chewing standardised hay were recorded on three consecutive days before and three times after (days 7, 21, 28) dental correction. The results of the leading mandibular tracking marker, located at the caudal edge of the inter-mandibular suture, were compared statistically. Reproducibility of measurements prior to dental treatment was excellent (P<0.05). Rostrocaudal mandibular motion was significantly reduced after dental correction (9+/-2mm vs. 8+/-2mm; P=0.046). Oscillations during the power stroke were significantly reduced after dental correction (R(2)=98.3%+/-0.3 vs. 98.8%+/-0.3; P=0.050). Although significant changes were observed in individual horses, the overall results of lateral and dorsoventral mandibular motion did not reveal significant differences. In conclusion, kinematic analysis of masticatory movements provided reproducible results and may be useful to evaluate changed movement patterns following dental correction. PMID- 20971664 TI - Clinical course of young patients with Dravet syndrome after vagal nerve stimulation. AB - Medical treatment of Dravet syndrome is disappointing. Ketogenic Diet and neurostimulation procedures as Vagus Nerve Stimulation (VNS) and Deep Brain Stimulation are in ongoing evaluation. In the present study, the long-term effectiveness of VNS on seizures, cognition and behavior was retrospectively evaluated in eight young patients with DS and medically refractory epilepsy (mean age at VNS implant: 10.28 years, range: 5-25). The average duration of treatment was 54 months (range: 12-120). Compared to baseline (mean: 55; standard deviation: 83, range: 4-200), the mean number of monthly seizures after VNS implantation was 39 +/- 67 at 3 months, 42 +/- 67 at 6 months and 38 +/- 69 at twelve months (not significant comparisons). In particular, VNS produced a mean seizure rate reduction of 12% at three months, 6% at six months, and 31% at twelve months. All patients but three experienced some reduction in seizure burden (range: 33-61%) at twelve months. Seizure outcome after one year of stimulation was rated as Mc Hugh class II (50-79% reduction in seizure frequency) in four patients, class III (<50% reduction) in one patient and class V (no improvement) in three patients. In this small case series of patients with DS, VNS therapy had a clinically significant effect in reducing seizures at twelve months in four of the eight patients. Even in patients in whom seizure reduction was not dramatic, a slight improvement in alertness and communicative skills was seen. The long-term clinical course of two selected cases is discussed. PMID- 20971665 TI - Parental catastrophizing about their child's chronic pain: are mothers and fathers different? AB - Preliminary evidence suggests that parental catastrophizing about their child's pain may be important in understanding both parental responses to their child's pain and the child's pain experience. However, little is known about potential differences between mothers and fathers. There were three aims of the present study addressing this lack of knowledge: (i) to investigate the three-factor structure of the German version of the Parental Pain Catastrophizing Scale (PCS P) (Goubert et al., 2006) in mothers and fathers of children with chronic pain, (ii) to explore differences between mothers and fathers in parental catastrophizing, (iii) to investigate the contribution of parental catastrophizing on the child's chronic pain problem and pain-related parent behavior. In a sample of 128 mothers and fathers of paediatric chronic pain patients, the invariance of the PCS-P was evaluated. Results replicated the previously established three-factor structure (i.e. rumination, magnification and helplessness) in both groups. Mothers reported higher levels of catastrophizing as compared to fathers. Specifically, mothers and fathers differed on levels of rumination; the two groups did not differ in magnification and helplessness. Maternal but not paternal catastrophizing contributed significantly in explaining the child's pain intensity whereas neither mothers' nor fathers' catastrophizing were significantly related to the child's disability. Both maternal and paternal catastrophizing contributed significantly to heightened parental solicitous responses. Fathers' but not mothers' catastrophizing also contributed to heightened distracting responses. The present findings attest to the importance of maternal and paternal catastrophizing for the child's pain characteristics and pain-related parent behavior, which are both relevant for treatment conceptualization. PMID- 20971666 TI - RECORD processing - a robust pathway to component-resolved HR-PGSE NMR diffusometry. AB - It is demonstrated that very robust spectral component separation can be achieved through global least-squares CORE data analysis of automatically or manually selected spectral regions in complex NMR spectra in a high-resolution situation. This procedure (acronym RECORD) only takes a few seconds and quite significantly improves the effective signal/noise of the experiment as compared to individual frequency channel fitting, like in the generic HR-DOSY approach or when using basic peak height or integral fitting. Results from RECORD processing can be further used as starting value estimates for subsequent CORE analysis of spectral data with higher degree of spectral overlap. PMID- 20971667 TI - Digital detection and processing of multiple quadrature harmonics for EPR spectroscopy. AB - A quadrature digital receiver and associated signal estimation procedure are reported for L-band electron paramagnetic resonance (EPR) spectroscopy. The approach provides simultaneous acquisition and joint processing of multiple harmonics in both in-phase and out-of-phase channels. The digital receiver, based on a high-speed dual-channel analog-to-digital converter, allows direct digital down-conversion with heterodyne processing using digital capture of the microwave reference signal. Thus, the receiver avoids noise and nonlinearity associated with analog mixers. Also, the architecture allows for low-Q anti-alias filtering and does not require the sampling frequency to be time-locked to the microwave reference. A noise model applicable for arbitrary contributions of oscillator phase noise is presented, and a corresponding maximum-likelihood estimator of unknown parameters is also reported. The signal processing is applicable for Lorentzian lineshape under nonsaturating conditions. The estimation is carried out using a convergent iterative algorithm capable of jointly processing the in phase and out-of-phase data in the presence of phase noise and unknown microwave phase. Cramer-Rao bound analysis and simulation results demonstrate a significant reduction in linewidth estimation error using quadrature detection, for both low and high values of phase noise. EPR spectroscopic data are also reported for illustration. PMID- 20971668 TI - Genetics of digital osteoarthritis. AB - Genetic factors contribute to the development of digital osteoarthritis, whose heritability has been estimated at 48 to 65%. Among the manifestations of digital osteoarthritis, only Heberden's nodes are transmitted by Mendelian inheritance, as a dominant trait in women and a recessive trait in men. The other forms of digital osteoarthritis are multifactorial, with a major gene and a residual multifactorial component that probably interacts with environmental factors. Hindrances to molecular studies include the absence to date of a universally accepted definition of the phenotype and the late onset of the manifestations. Genetic association studies of selected class I and II HLA genes produced conflicting results. The T303M polymorphism of the MATN3 gene, which was initially described as associated with hand osteoarthritis, may be more closely linked to trapeziometacarpal osteoarthritis than to digital osteoarthritis. Genome-wide scans have identified numerous loci linked to digital osteoarthritis. Replication has been achieved for some of these loci, most notably those located at 2p, 2q, 3p, 4q, and 7p. A recently published genome-wide association study showed that an A2BP1 gene polymorphism was significantly associated with hand osteoarthritis. Many candidate-gene studies found associations with AGC1, ASPN, ENPP1, HFE, KL, VDR, IL-1 cluster, and IL-6, although the results were not consistently reproducible. In one study, women with hand osteoarthritis had significant telomere shortening. Telomere shortening has also been reported in other age-related conditions. PMID- 20971669 TI - Short-term effect of IL-6 inhibition in spondylarthritis. PMID- 20971670 TI - Evaluation of the posture and muscular strength of the trunk and inferior members of patients with chronic lumbar pain. AB - OBJECTIVE: We examine the postural profile and muscular forces of the trunk and inferior members of patients with chronic low back pain. METHODS: In this study, we include 60 subjects forming two groups: a first group (G1) of 30 patients with chronic low back pain and a second group (G2) of 30 healthy subjects. Every subject profited from an isokinetic evaluation of the muscular forces of the trunk (at 60 and 90 degrees .s(-1)) and knees (at 60 and 120 degrees .s(-1)) and of a postural evaluation. The isokinetic evaluation was carried out using Cybex((r)) Norm II dynamometer with its Trunk Extension/Flexion (TEF) module set in concentric mode. The parameter under study was the torque peak. The postural evaluation was accomplished using the platform SATEL for the balance analysis associated with four conditions: static on stable plan open eyes (OE) then closed eyes (CE) and static on unstable plan OE then CE. The parameters under study were the averages of the total lengths, total surfaces, and the X and Y means. RESULTS: The averages of the torque peaks of the trunk flexor and extensor muscles at the speeds of 60 and 90 degrees .s(-1) were inferior in group G1 as compared to G2. The differences were statistically insignificant only for the extensor muscles (p<0.005). The averages of the torque peaks of the knee flexors and extensors at 60 and 120 degrees .s(-1) were the lowest in group G1. The differences were significant (p<0.05). The averages of postural parameters were more important in group G1, indicating a postural deficit in this group. CONCLUSION: We showed deficits of the posture and muscles of the trunk and knees of patients with chronic lumbar pain. The muscular deficit of the trunk predominates on extensors. PMID- 20971671 TI - [Pseudoaneurysm of the superficial palmar arch, following endoscopic carpal tunnel release. A case report]. AB - Pseudo-aneurysm of the superficial palmar arch following carpal tunnel release is exceptional and thus poorly reported. We present one observation, recorded on more than 1300 hands treated by endoscopic release using the "Chow" technique by a single surgeon. Ultra-sonography could be used in an attempt to locate the superficial palmar arch and thus prevent vascular damage at surgery. PMID- 20971672 TI - Prosthetic aortic heart valves: modeling and design. AB - Although heart valve replacement is among the most common cardiovascular surgical procedures, their outcome is often difficult to predict. One of the reasons is the design and choice of the materials used for the fabrication of the prostheses. This review paper describes the use of modeling techniques in prosthetic heart valve (HV) design and aims at the justification and development of a polymer based trileaflet mechanical heart valve (MHV). The closing/opening phase behavior of the bileaflet MHV was investigated. The potential problem of valve failure due to crack propagation in the brittle pyrolytic carbon leaflet was also discussed. These studies suggest that although bileaflet MHV performs satisfactorily, there are justifications for improvement. Since the native aortic HV is trileaflet and made of anisotropic and hyperelastic tissue, one possible approach to a better MHV design is based on our ability to closely mimic the natural geometry and biomaterial properties. PMID- 20971674 TI - Health geography's voluntary turn: a view from western France. AB - This paper examines the potential for prevailing Anglo-American perspectives on voluntarism to inform understanding of health and social care internationally. Focusing on the economie sociale et solidaire and its involvement in the secteur medico-social in France, it evaluates the transferability of a theorization about the evolving role of voluntary organizations and volunteers for the purpose of interpreting research on service provision in ageing communities. A case study of local associations is analyzed to uncover their emergence within evolving spaces of care, how they facilitate adjustment and create opportunities for resistance to the dual challenges of ageing and restructuring as well as the complexity underlying their multifaceted responses. The findings contribute to understanding the link between voluntarism, health and place, and address calls to expand the international scope of health geography within the 'voluntary turn' in health policy and research. PMID- 20971673 TI - Genetic variation of the mitochondrial complex I subunit NDUFV2 and Parkinson's disease. AB - NADH dehydrogenase ubiquinone flavoprotein 2 (NDUFV2), encoding a subunit of mitochondrial complex I, is a candidate gene for several neuronal diseases; schizophrenia, bipolar disorder and Parkinson disease (PD). We screened the entire coding region of NDUFV2 in 33 familial PD patients of North African Arab Berber ethnicity in which all known genetic forms of PD had been excluded. We detected one novel substitution p.K209R (c.626A>G) in one PD proband. Segregation analysis within the family is inconclusive due to small sample size, but consistent with an autosomal dominant mode of inheritance. Subsequent screening of this mutation in ethnically matched sporadic PD patients (n = 238) and controls (n = 371) identified p.K209R in one additional patient. The clinical features of the mutation carriers revealed a mild form of parkinsonism with a prognosis similar to idiopathic PD. Our findings suggest further studies addressing the role of NDUFV2 variation in PD may be warranted. PMID- 20971675 TI - Saccades compress space, time and number. AB - It has been suggested that space, time and number are represented on a common subjective scale. Saccadic eye movements provide a fascinating test. Saccades compress the perceived magnitude of spatial separations and temporal intervals to approximately half of their true value. The question arises as to whether saccades also compress number. They do, and compression follows a very similar time course for all three attributes: it is maximal at saccadic onset and decreases to veridicality within a window of approximately 50ms. These results reinforce the suggestion of a common perceptual metric, which is probably mediated by the intraparietal cortex; they further suggest that before each saccade the common metric for all three is reset, possibly to pave the way for a fresh analysis of the post-saccadic situation. PMID- 20971676 TI - Foundational numerical capacities and the origins of dyscalculia. AB - One important cause of very low attainment in arithmetic (dyscalculia) seems to be a core deficit in an inherited foundational capacity for numbers. According to one set of hypotheses, arithmetic ability is built on an inherited system responsible for representing approximate numerosity. One account holds that this is supported by a system for representing exactly a small number (less than or equal to four4) of individual objects. In these approaches, the core deficit in dyscalculia lies in either of these systems. An alternative proposal holds that the deficit lies in an inherited system for sets of objects and operations on them (numerosity coding) on which arithmetic is built. I argue that a deficit in numerosity coding, not in the approximate number system or the small number system, is responsible for dyscalculia. Nevertheless, critical tests should involve both longitudinal studies and intervention, and these have yet to be carried out. PMID- 20971677 TI - Ocular surface disease: a case of vernal keratoconjunctivitis. AB - Vernal keratoconjunctivitis (VKC) is a recurrent, chronic allergic inflammation of the ocular surface associated with remodeling of the cornea and conjunctiva, with a potential to adversely affect the patient's vision and quality of life. It affects mainly children and young adults. The purpose of this interventional case report is to present a typical case of limbal VKC, which was unresponsive to antiallergic treatment alone. A 5-year-old boy, who was previously unsuccessful with conventional anti-allergic therapy alone, presented with clinicopathological features pathognomonic of limbal VKC. The patient was successfully managed with a combination of palliative, anti-allergic and anti-inflammatory therapy. Prophylaxis with an anti-allergic pharmaceutical agent was initiated for long term use to prevent the release of allergic mediators. This case highlights the importance of prescribing the most appropriate pharmaceutical medication for VKC since conjunctival fibroproliferative lesions are often resistant to anti-allergy therapy. Allergic inflammatory mediators are responsible for the fibroproliferative changes of the conjunctiva and corneal lesions in VKC. Thus, it is crucial to prescribe the most appropriate pharmaceutical medication that will prevent the release of allergic inflammatory mediators, control the allergic inflammatory cascade and prevent ocular surface damage. The fine points of this case are presented with a review of applicable literature. PMID- 20971678 TI - Cytotoxic effect of tobacco extracts on human oral squamous cell carcinoma cell line. AB - Cancer is a public health problem worldwide. Incidences of oral carcinomas are increasing in the last decades, and the developed countries are the most affected. Current therapeutic options for this type of cancer are aggressive and/or invasive, including surgery, radiotherapy and chemotherapy. In addition, they have not yet translated into an improvement of life quality or expectancy to patients. In this scenario, new therapeutics are urgently needed and actively sought after. The goal of this study was to investigate the cytotoxic effects of tobacco crude extract (TCE) and two fractions thereof in the human lineage of oral squamous cell carcinoma, OSCC-3. Exposure of human oral cancer cells to TCE induced cell death and decreased cell viability in a dose-dependent manner. Of the fractions tested, one was able to induce significant cell death (over 50%) after 48 h treatment. DNA fragmentation and caspase-3 activation indicated that the type of cell death induced by TCE and its fraction was apoptosis. Our results indicate that tobacco contains compounds that could be useful in inducing apoptosis in cancer cells. More specifically, because of the neutral chemical nature of the fraction capable of inducing apoptosis, we postulate that the putative compound responsible for the cell death is non-polar. Further investigation is needed to uncover its chemical nature and structure. PMID- 20971679 TI - Type VI secretion regulation: crosstalk and intracellular communication. AB - Pathogens use type VI secretion systems (T6SSs) to transport proteins into the environment or host cells in response to external stimuli. T6SSs are tightly regulated together with other virulence determinants such as type III secretion systems, quorum sensing (QS), and flagella synthesis. Five pathogens (Salmonella enterica, Edwardsiella tarda, Aeromonas hydrophila, Vibrio cholerae, and Pseudomonas aeruginosa) are examined for crosstalk proteins (global regulators) that connect T6SSs to other virulence determinants. Common transcriptional regulators (TRs) include two component systems (i.e. PhoPQ), sigma(54) and sigma(54)-dependent TRs (i.e. VasH), and QS regulators. Greater understanding of this integral communication network will define what is essential for bacterial pathogenesis. PMID- 20971680 TI - Human pathogens and tetracycline-resistant bacteria in bioaerosols of swine confinement buildings and in nasal flora of hog producers. AB - Swine confinement buildings in eastern Canada are enclosed and equipped with modern production systems to manage waste. Bioaerosols of these swine confinement buildings could be contaminated by human pathogens and antimicrobial resistant bacteria which could colonize exposed workers. We therefore wanted to analyze bioaerosols of swine confinement buildings and nasal flora of Canadian hog producers to evaluate possible colonization with human pathogens and tetracycline resistant bacteria. Culturable and non-culturable human pathogens and tet genes were investigated in the bioaerosols of 18 barns. The nasal passages of 35 hog producers were sampled and total DNA was extracted from the calcium-alginate swabs to detect, by PCR, Campylobacter, C. perfringens, Enterococcus, E. coli, Y. enterocolitica, tetA/tetC, tetG and ribosomal protection protein genes. Airborne culturable C. perfringens, Enterococcus, E. coli, and Y. enterocolitica were present in the bioaerosols of 16, 17, 11 and 6 of the 18 facilities. Aerosolized total (culturable/non culturable) Campylobacter, C. perfringens, Enterococcus, E. coli and Y. enterocolitica were detected in 10, 6, 15, 18 and 2 barns, respectively. Tet genes were found in isolates of culturable human pathogens. TetA/tetC, tetG and ribosomal protection protein genes were detected in the bioaerosols of all 18 studied buildings. Campylobacter, C. perfringens, Enterococcus, E. coli, and Y. enterocolitica were found respectively in 4, 9, 17, 14 and one nasal flora of workers. One and 10 workers were positive for tetA/tetC and tetG genes, respectively. In swine confinement buildings, hog producers are exposed to aerosolized human pathogens and tetracycline-resistant bacteria that can contaminate the nasal flora. PMID- 20971681 TI - Level of agreement between field-based data collectors in a large scale injury prevention randomised controlled trial. AB - In sports injury prevention field trials, data collectors are often club volunteers with considerable knowledge of the game but with limited detailed medical backgrounds or knowledge of formal scientific processes. The aim of this paper is to determine the agreement among trained primary data collectors (PDCs) with a sport science background and no prior involvement in data collection in a large randomised controlled trial. During the 'Preventing Australian Football Injury through eXercise' (PAFIX) project, player participation and injury data were collected by trained PDCs at training and games over the 2007 and 2008 playing seasons in 40 community level Australian football teams. PDC-collected data relating to player exposure and whether or not a player sustained an injury and subsequently left the field of play was compared to the same information from independent observers (IOs) who attended one randomly selected game for each of the 40 teams. There was 98% agreement between the PDC and the IO on game details (i.e., date, time, grade and score), 79% (ICC 0.9, 95% CI 0.85-0.95) agreement on the number of players per game and 76% (ICC 0.8, 95% CI 0.69-0.91) agreement on the number of injuries sustained in the games. There was 100% agreement on whether the player left the field for all injuries. This study found that exercise and sport science students are reliable data collectors in sports injury fieldwork studies. PMID- 20971682 TI - Breast and ovarian cancer: Y do we forget about dad? PMID- 20971683 TI - Fluorescence anisotropy and resonance energy transfer: powerful tools for measuring real time protein dynamics in a physiological environment. AB - Fluorescence spectroscopy/microscopy is a versatile method for examining protein dynamics in vitro and in vivo that can be combined with other techniques to simultaneously examine complementary pharmacological parameters. The following review will highlight the advantages and challenges of using fluorescence spectroscopic methods for examining protein dynamics with a special emphasis on fluorescence resonance energy transfer and fluorescence anisotropy. Both of these methods are amenable to measurements on an ensemble of molecules as well as at the single molecule level, in live cells and in high throughput screening assays, providing a powerful set of tools to aid in the design and testing of new drugs under a variety of experimental conditions. PMID- 20971684 TI - Molecular dynamics simulations of protein dynamics and their relevance to drug discovery. AB - Molecular dynamics simulations have become increasingly useful in studying biological systems of biomedical interest, and not just in the study of model or toy systems. In this article, the methods and principles of all-atom molecular dynamics will be elucidated with several examples provided of their utility to investigators interested on drug discovery. PMID- 20971685 TI - The effect of CD34 count and clonogenic potential of hematopoietic stem cells on engraftment. AB - In this study we have determined that the number of the CD34 (+) cells in the grafts that were infused to 48 patients who underwent autologous and allogeneic hematopoietic cell transplantation and evaluated the number of colony forming units in vitro. Our aim was to determine whether there is a relation between these cell counts and post transplantation engraftment kinetics. A negative correlation was detected (p<0.05) between the CD34 (+) cell count and all colony forming units. A correlation between the CD34 (+) cell count and the kinetics of engraftment could not be demonstrated. In the autologous group, only a weak negative correlation between the CFU-GEMM and neutrophil engraftment was detected. In the allogeneic group, colony forming units did not determine the engraftment. PMID- 20971686 TI - Familial testicular torsion in three consecutive generations of first-degree relatives. AB - We report the first and largest family with testicular torsion in three consecutive generations affecting four first-degree relatives. The incidence of familial testicular torsion is under reported in the literature. We recommend eliciting family history in evaluation of acute scrotum, as a useful adjunct for clinical decision making. In families with a strong predisposition to testicular torsion, management should include family counseling about the significant risk of occurrence of this condition. PMID- 20971688 TI - N-methylpurines are heterogeneously repaired in human mitochondria but not evidently repaired in yeast mitochondria. AB - Base excision repair (BER) of dimethyl sulfate induced N-methylpurines (NMPs) was measured at nucleotide resolution in the mitochondrial DNA (mtDNA) of cultured human and yeast (Saccharomyces cerevisiae) cells. NMPs were repaired with heterogeneous rates in the human mtDNA. The nearest-neighbor nucleotides significantly affected the repair rates: NMPs between pyrimidines were repaired much faster than those between purines, and those between a purine and a pyrimidine were repaired at intermediate rates. Repair intermediates of NMPs can also be detected at certain sites of the human mtDNA, indicating an ineffectiveness of processing the intermediates at these sites by the human mitochondrial BER machinery. In contrast to the human mtDNA, the yeast mtDNA did not show detectable repair of NMPs at any sites. Furthermore, a high level of spontaneous strand breaks exists exclusively at purine sites in the yeast mtDNA. Spontaneous NMPs or oxidative lesions were unlikely to be the major causes for the spontaneous strand breaks. Rather, spontaneous depurination combined with inefficient processing of DNA nicks or single-nucleotide gaps by the yeast mitochondrial BER machinery may result in the spontaneous strand breaks. Our results unveil a striking difference in BER between human and the yeast mitochondria. PMID- 20971687 TI - Structured coculture of stem cells and disc cells prevent disc degeneration in a rat model. AB - BACKGROUND CONTEXT: Harnessing the potential of stem cells is an important strategy for regenerative medicine. This study explores the use of bilaminar coculture pellets (BCPs) of mesenchymal stem cells (MSCs) and nucleus pulposus cells (NPCs) as a cell-based therapy for intervertebral disc regeneration. Prior in vitro experiments have shown that BCP can help differentiate MSCs and substantially improve new matrix deposition. PURPOSE: To evaluate the clinical relevance of BCPs by testing the system in vivo. STUDY DESIGN/SETTING: We have designed a novel spherical BCP where MSCs are enclosed in a shell of NPCs. The pellets were tested in vivo in a rat tail model of disc degeneration. METHODS: Rat caudal intervertebral discs were denucleated and treated with BCP in a fibrin sealant (FS) carrier (controls were MSCs suspended in FS; NPCs suspended in FS; MSCs and NPCs suspended in FS; FS only; and surgery only). At 14 and 35 days after implantation, the animals were euthanized and discs were evaluated for proteoglycan content, enzyme-linked immunosorbent assay for inflammatory cytokines, cell retention using polymerase chain reaction, disc height, histology, and disc grade based on a blinded scoring system. RESULTS: The proteoglycan and cytokine levels were not significantly different among groups. The BCP group had higher cell retention than controls. Disc height and disc grade increased over time only in the BCP group. Bilaminar coculture pellets were the only treatment to show proteoglycan staining in the nucleus space at 35 days. CONCLUSIONS: This study shows that BCPs may prevent postnucleotomy disc degeneration in vivo. Larger animals and longer time points will be necessary to further judge potential clinical impact. As opposed to strategies that require growth factor supplements, predifferentiation, or genetic manipulations, BCPs are a self-sustaining and targeted method for tissue regeneration in situ. PMID- 20971689 TI - Simple and rapid analytical method for detection of amino acids in blood using blood spot on filter paper, fast-GC/MS and isotope dilution technique. AB - A simple and rapid method for quantitative analysis of amino acids, including valine (Val), leucine (Leu), isoleucine (Ile), methionine (Met) and phenylalanine (Phe), in whole blood has been developed using GC/MS. In this method, whole blood was collected using a filter paper technique, and a 1/8 in. blood spot punch was used for sample preparation. Amino acids were extracted from the sample, and the extracts were purified using cation-exchange resins. The isotope dilution method using 2H8-Val, 2H3-Leu, 2H3-Met and 2H5-Phe as internal standards was applied. Following propyl chloroformate derivatization, the derivatives were analyzed using fast-GC/MS. The extraction recoveries using these techniques ranged from 69.8% to 87.9%, and analysis time for each sample was approximately 26 min. Calibration curves at concentrations from 0.0 to 1666.7 MUmol/l for Val, Leu, Ile and Phe and from 0.0 to 333.3 MUmol/l for Met showed good linearity with regression coefficients=1. The method detection limits for Val, Leu, Ile, Met and Phe were 24.2, 16.7, 8.7, 1.5 and 12.9 MUmol/l, respectively. This method was applied to blood spot samples obtained from patients with phenylketonuria (PKU), maple syrup urine disease (MSUD), hypermethionine and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), and the analysis results showed that the concentrations of amino acids that characterize these diseases were increased. These results indicate that this method provides a simple and rapid procedure for precise determination of amino acids in whole blood. PMID- 20971690 TI - Improving cytological diagnosis of pancreatic cysts: Is it clinically necessary or just the latest fashion? PMID- 20971691 TI - Macrolane: a safe alternative for breast augmentation? PMID- 20971692 TI - Haplotype diversity of 17 Y-chromosomal STRs in Saraswat Brahmin Community of North India. AB - In this study, 17 Y-specific STR loci (DYS19, DYS389I, DS389II, DYS390, DYS391, DYS392, DYS393, DYS385a/b, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635 and Y_GATA_H4) were analyzed in 181 unrelated male individuals from three North Indian states. A total of 157 different 17-loci haplotypes were identified, 145 of which were unique. The most frequent haplotype was detected in nine instances, occurring with a frequency of 4.97%. These results, including the haplotype data at 17 Y-STR loci in the present study, provide useful information for forensic practice in the Saraswat Brahmin population in North India. PMID- 20971693 TI - Effect of buccal part designs of polyamide resin partial removable dental prosthesis on retentive force. AB - PURPOSE: To identify buccal design criteria for retainer on polyamide resin removable partial dentures. METHODS: A left upper distal extension model was used for this study. Undercut was given on the buccal side of first and second premolars. Four different retainer designs were created. Undercuts of 0.5 and 0.75 mm were used. All 4 retainer designs started from distal surface of second premolar. The retainer extended to Design 1: covering to the mesial surface of second premolar; Design 2: covering to the distal surface of first premolar; Design 3: covering to the mesial surface of first premolar; and Design 4: covering to the distal surface of canine. For the 0.75 mm undercut experiment, only Design 1 and Design 3 were used. Each experimental denture was pulled and the force maximum required to remove the denture measured. RESULTS: On 0.5 mm undercut, no significant difference was found between Designs 1 and 2 or between Designs 3 and 4. Significant differences were found between all other combinations, however. On 0.75 mm undercut, a significant difference was found between the two. CONCLUSION: The retentive force of a design for the buccal part of retainers in polyamide resin using large undercut was more effective than that of a design covering to the anterior abutment tooth. PMID- 20971694 TI - Modified mandibular advancement appliance for an edentulous obstructive sleep apnea patient: a clinical report. AB - Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder with periodic reduction or cessation of airflow during sleep. It is associated with loud snoring, disrupted sleep and observed apneas with prevalence up to 54% in elderly people. Treatment of OSA varies from simple measures such as dental appliances and nasal continuous positive airway pressure (CPAP) to surgical procedures like uvulopalatopharyngoplasty and tracheostomy. Dental appliances are a viable nonsurgical treatment alternative in patients with OSA, of which mandibular advancement appliances are most common. Edentulism which contributes to the worsening of OSA reduces the number of available therapeutic strategies and is considered a contraindication to oral appliance therapy. This clinical report describes the treatment of a 61-year old edentulous OSA patient for whom a modified mandibular advancement appliance was designed. The patient reported an improvement in AHI index and he was satisfied with the modified appliance. This clinical report describes the newer technique of fabricating oral appliance for edentulous OSA patient. PMID- 20971695 TI - The effect of two marginal designs (chamfer and shoulder) on the fracture resistance of all ceramic restorations, Inceram: an in vitro study. AB - BACKGROUND AND AIM: One of the major problems of all ceramic restorations is their probable fracture against the occlusal force. The aim of the present in vitro study is to compare the effect of two marginal designs (shoulder and chamfer) on the fracture resistance of all ceramic restorations, INCERAM. MATERIALS AND METHODS: On an extracted first maxillary premolar 50 in. chamfer margin (0.7 mm) was prepared. Ten impressions were taken using a polyvinylsiloxane. The impressions were poured with epoxy resin to fabricate dies. The same tooth was retrieved and 50 in. chamfer was converted into 90 in. shoulder (1 mm). Ten impressions were taken and ten more epoxy resin dies were fabricated. Impressions of each epoxy resin die were taken using polyvinylsiloxane impression material and poured with die stone. Alumina cores with 0.5 mm thickness fabricated on the stone dies in a dental laboratory. The alumina cores were then cemented on the epoxy resin dies and underwent a fracture test with a universal testing machine and samples were investigated from the point of view of the origin of the failure. RESULT: The mean value of fracture resistance for the chamfer samples were 610.18 +/- 58.79 N and 502.72 +/- 105.83 N for the shoulder samples. The Student's t-test revealed a statistically significant difference between groups. CONCLUSION: The result of this study indicates a relationship between the marginal design of the alumina cores and their fracture resistance. A chamfer margin could improve the biomechanical performance of posterior single crown alumina restorations. This may be because of the strong unity in the chamfer margin. PMID- 20971696 TI - Lingual myoclonus associated with brain tumour: an epileptic origin? AB - We describe a 59-year-old man, suffering from a left-sided weakness, who was diagnosed with a right frontal oligodendroglioma. One month after a craniotomy, he complained of perioral numbness and slurred speech, which lasted about an hour. Neurological examination discovered dysarthric speech and repetitive, rhythmic myoclonic jerks of the tongue and the lower lip. We suggest this lingual myoclonus was an epileptic phenomenon associated with brain tumour. PMID- 20971698 TI - Is the demand-control model still a usefull tool to assess work-related psychosocial risk for ischemic heart disease? Results from 14 year follow up in the Copenhagen City Heart study. AB - OBJECTIVES: To test the usefulness of the Demand-Control Model as predictor for ischemic heart disease (IHD). MATERIALS AND METHODS: One thousand one hundred forty six actively employed men and women from the general population of Copenhagen participated at baseline in 1993-1994. They filled in questionnaires on the Demand-Control Model, job title, work place, civil status, family income, leisure time activity, smoking, medication, social support, social relations, conflicts, job responsibility, satisfaction, and insecurity and went through a medical examination, including measurements of coronary risk factors. All deaths and hospital admissions due to IHD, including first myocardial infarction (MI) in the cohort were traced in the Danish registries of deaths and hospital admissions to June 2007. RESULTS: 104 cases of first time hospitalisation or death due to IHD including 49 cases of MI occurred during 14 years follow up. Odds ratio (OR) compared to the relaxed group was 1.1 (0.1-3.1) among women and 1.6 (0.4-4.9) among men after confounder adjustment. Neither demands nor control were significantly associated with IHD. Among men 50 years of age or more, the risk for IHD was, however, elevated in the job strain group and the active group (OR = 3.5 and 3.2 respectively). Job insecurity was, however, strongly associated with IHD in men (OR = 2.7 (1.1-5.6)) after all adjustments. The risk was increased for MI too (OR = 2.7 (1.2-6.1)). Among women, the only significant association with IHD was for job dissatisfaction (OR = 3.0 (1.2-7.6)). CONCLUSION: In this population and in a period and society characterized by relative wealth and increasing employment rates, the Demand-control Model did not predict IHD. However, the feeling of job insecurity predicted both IHD and MI among men and job dissatisfaction predicted IHD among women. PMID- 20971697 TI - The role of magnesium deficiency in cardiovascular and intestinal inflammation. AB - Hypomagnesemia continues to cause difficult clinical problems, such as significant cardiac arrhythmias where intravenous magnesium therapy can be lifesaving. Nutritional deficiency of magnesium may present with some subtle symptoms such as leg cramps and occasional palpitation. We have investigated dietary-induced magnesium deficiency in rodent models to assess the pathobiology associated with prolonged hypomagnesemia. We found that neuronal sources of the neuropeptide, substance P (SP), contributed to very early prooxidant/proinflammatory changes during Mg deficiency. This neurogenic inflammation is systemic in nature, affecting blood cells, cardiovascular, intestinal, and other tissues, leading to impaired cardiac contractility similar to that seen in patients with heart failure. We have used drugs that block the release of SP from neurons and SP-receptor blockers to prevent some of these pathobiological changes; whereas, blocking SP catabolism enhances inflammation. Our findings emphasize the essential role of this cation in preventing cardiomyopathic changes and intestinal inflammation in a well-studied animal model, and also implicate the need for more appreciation of the potential clinical relevance of optimal magnesium nutrition and therapy. PMID- 20971699 TI - Work-related risk factors of myocardial infarction. AB - OBJECTIVES: The aim of the study was to find out which occupational factors account for the risk of the myocardial infarction. MATERIAL AND METHODS: A questionnaire survey was performed during the period of one calendar year in all patients (1053 subjects, 692 men and 361 women) hospitalized at the Medical University of Lodz because of the first myocardial infarction. The questionnaire was prepared especially for the purpose of this study and consisted of two parts. The first part comprised: demographic data, health status at admittance, traditional risk factors for the ischaemic heart disease and was filled-in by physicians. Part II was done by occupational hygiene specialists and referred to education, job title and characteristics, employment data, self assessment of work-related and general stress, fatigue, socio-economic status, physical activity, alcohol intake, tobacco smoking, dietary habits. RESULTS: Mean age in the study group was 59.9 +/- 10.4 years (26-85 years), 58.7 +/- 10.0 (26-84 years) for men and 62.3 +/- 10.7 (32-85 years) for women, employment duration was 32.9+/-8.8 (4-65 years), for men 34.0 +/- 8.6 (5-65 years), for women 30.7 +/- 8.8 (4-60 years. Most of myocardial infarction cases both in the group of men and women were noted in the age interval 56-60 years, 22.3% vs. 17.4%, respectively. The majority of examined men were farmers, low and middle management and self employed workers. Among women prevailed clerks, seamstresses and farmers. The most frequent occupational risk factors were: work-related stress, experienced by 54.2% of the examined subjects, occupational noise (45,5%), dust (41,7%) and various chemical factors (33%). A majority of the study group (76.5% women and 54.4% men) linked the cardiac infarction with stress, while 39.1% men vs. 16.5% women correlated it with physical effort. CONCLUSION: Our studies indicate that, among a wide spectrum of occupational factors, stress, noise and fine particulate dust are major contributors to the increased risk of myocardial infarction. PMID- 20971700 TI - Imaging: visualizing the possibilities. PMID- 20971701 TI - Imaging with total internal reflection fluorescence microscopy for the cell biologist. AB - Total internal reflection fluorescence (TIRF) microscopy can be used in a wide range of cell biological applications, and is particularly well suited to analysis of the localization and dynamics of molecules and events near the plasma membrane. The TIRF excitation field decreases exponentially with distance from the cover slip on which cells are grown. This means that fluorophores close to the cover slip (e.g. within ~100 nm) are selectively illuminated, highlighting events that occur within this region. The advantages of using TIRF include the ability to obtain high-contrast images of fluorophores near the plasma membrane, very low background from the bulk of the cell, reduced cellular photodamage and rapid exposure times. In this Commentary, we discuss the applications of TIRF to the study of cell biology, the physical basis of TIRF, experimental setup and troubleshooting. PMID- 20971702 TI - Advances in imaging cell-matrix adhesions. AB - Adhesion is fundamental to the survival and function of many different cell types, and regulates basic events such as mitosis, cell survival and migration, in both embryonic and adult organisms. Cell-matrix adhesion also regulates the dynamic interplay between cells and surrounding tissues during processes such as immune cell recruitment, wound healing and cancer cell metastasis. The study of cell adhesion has gained momentum in recent years, in large part because of the emergence of imaging techniques that have facilitated detailed analysis of the molecular composition and dynamics of the structures involved. In this Commentary, we discuss the recent application of different imaging techniques to study cell-matrix adhesions, emphasising common strategies used for the analysis of adhesion dynamics both in cells in culture and in whole organisms. PMID- 20971703 TI - Specific tyrosine phosphorylation sites on cortactin regulate Nck1-dependent actin polymerization in invadopodia. AB - Invadopodia are matrix-degrading membrane protrusions in invasive carcinoma cells enriched in proteins that regulate actin polymerization. The on-off regulatory switch that initiates actin polymerization in invadopodia requires phosphorylation of tyrosine residues 421, 466, and 482 on cortactin. However, it is unknown which of these cortactin tyrosine phosphorylation sites control actin polymerization. We investigated the contribution of individual tyrosine phosphorylation sites (421, 466, and 482) on cortactin to the regulation of actin polymerization in invadopodia. We provide evidence that the phosphorylation of tyrosines 421 and 466, but not 482, is required for the generation of free actin barbed ends in invadopodia. In addition, these same phosphotyrosines are important for Nck1 recruitment to invadopodia via its SH2 domain, for the direct binding of Nck1 to cortactin in vitro, and for the FRET interaction between Nck1 and cortactin in invadopodia. Furthermore, matrix proteolysis-dependent tumor cell invasion is dramatically inhibited in cells expressing a mutation in phosphotyrosine 421 or 466. Together, these results identify phosphorylation of tyrosines 421 and 466 on cortactin as the crucial residues that regulate Nck1 dependent actin polymerization in invadopodia and tumor cell invasion, and suggest that specifically blocking either tyrosine 421 or 466 phosphorylation might be effective at inhibiting tumor cell invasion in vivo. PMID- 20971704 TI - BLOS1, a putative BLOC-1 subunit, interacts with SNX1 and modulates root growth in Arabidopsis. AB - Internalization and sorting of macromolecules are inherent properties of all eukaryotic cells that are achieved by vesicle trafficking. However, this process is relatively less understood in plants. An eight-subunit protein complex, BLOC 1, which is involved in endosomal transport from the endosomes to the lysosomes, has been identified in both human and mice. In this study, two homologous subunits of this complex, BLOS1 (or AtGCN5L1) and BLOS2, have been characterized in Arabidopsis. Both BLOS1 and BLOS2 interacted with SNX1 on the sorting endosomes. Inducible RNAi lines with reduced levels of BLOS1 had longer primary roots and more lateral roots. Consistently, PIN1 and PIN2 were increased in BLOS1 RNAi lines, implicating an impaired transport from the endosomes to the vacuoles. These results suggest that a putative BLOC-1 complex in Arabidopsis might mediate the vacuolar degradative transport through direct interaction with SNX1 to regulate the homeostasis of PIN1 and PIN2, which is important for plant growth and development. PMID- 20971706 TI - The invariant chain transports TNF family member CD70 to MHC class II compartments in dendritic cells. AB - CD70 is a TNF-related transmembrane molecule expressed by mature dendritic cells (DCs), which present antigens to T cells via major histocompatibility complex (MHC) molecules. In DCs, CD70 localizes with MHC class II molecules in late endosomal vesicles, known as MHC class II compartments (MIICs). MIICs are transported to the immune synapse when a DC contacts an antigen-specific CD4(+) T cell. Consequently, MHC class II and CD70 are simultaneously exposed to the T cell. Thereby, T-cell activation via the antigen receptor and CD70-mediated co stimulation are synchronized, apparently to optimize the proliferative response. We report here that the invariant chain (Ii), a chaperone known to transport MHC class II to MIICs, performs a similar function for CD70. CD70 was found to travel by default to the plasma membrane, whereas Ii coexpression directed it to late endosomes and/or lysosomes. In cells containing the MHC class II presentation pathway, CD70 localized to MIICs. This localization relied on Ii, since transport of CD70 from the Golgi to MIICs was impeded in Ii-deficient DCs. Biophysical and biochemical studies revealed that CD70 and Ii participate in an MHC-class-II independent complex. Thus, Ii supports transport of both MHC class II and CD70 to MIICs and thereby coordinates their delivery to CD4(+) T cells. PMID- 20971705 TI - Syndecan-1 couples the insulin-like growth factor-1 receptor to inside-out integrin activation. AB - Syndecan-1 (Sdc1) engages and activates the alphavbeta3 (and/or alphavbeta5) integrin when clustered in human carcinoma and endothelial cells. Although the engagement is extracellular, the activation mechanism is cytoplasmic. This talin dependent, inside-out signaling pathway is activated downstream of the insulin like growth factor-1 receptor (IGF1R), whose kinase activity is triggered by Sdc1 clustering. In vitro binding assays using purified receptors suggest that association of the Sdc1 ectodomain with the integrin provides a 'docking face' for IGF1R. IGF1R docking and activation of the associated integrin is blocked by synstatin (SSTN(92-119)), a peptide derived from the integrin engagement site in Sdc1. IGF1R colocalizes with alphavbeta3 integrin and Sdc1 in focal contacts, but fails to associate with or activate the integrin in cells either lacking Sdc1 or expressing Sdc1(Delta67-121), a mutant that is unable to form the Sdc1-integrin IGF1R ternary complex. Integrin activation is also blocked by IGF1R inhibitors or by silencing IGF1R or talin expression with small-interfering RNAs (siRNAs). In both cases, expression of the constitutively active talin F23 head domain rescues integrin activation. We recently reported that SSTN(92-119) blocks angiogenesis and impairs tumor growth in mice, therefore this Sdc1-mediated integrin regulatory mechanism might be a crucial regulator of disease processes known to rely on these integrins, including tumor cell metastasis and tumor-induced angiogenesis. PMID- 20971707 TI - The development and psychometric assessment of the adolescent sexual coercion risk scale. AB - The objective of this study was to develop a psychometric measure of risk for sexual victimization from adolescent peers. Items were generated on the basis of the literature and on consultations with a multidisciplinary group of key informants. The items were administered to a sample of 327 female Grade-9 students and examined using exploratory factor analysis. The Adolescent Sexual Coercion Risk Scale items formed two lower-order factors composed of items regarding signaling sexual boundaries and displaying risk behaviors, respectively. Subsequent confirmatory factor analysis supported the two factors, and preliminary psychometric analyses demonstrated that the factors have satisfactory internal consistency. In addition, low scores on the ability to signal sexual boundaries and high scores on risk behaviors were associated with self-reported peer sexual victimization, supporting the validity of the factors as measures of risk. Future validation and potential usage of the measure are discussed. PMID- 20971708 TI - Republished paper: the POPI trial: what does it mean for chlamydia control now? PMID- 20971709 TI - Onchocerciasis in Anambra State, Southeast Nigeria: clinical and psychological aspects and sustainability of community directed treatment with ivermectin (CDTI). AB - BACKGROUND: A cross-sectional study was performed to determine the psychological impact of onchocerciasis, and assess sustainability of the decade-old community directed treatment with ivermectin (CDTI) in Ayamelum Local Council, Anambra State, Southeast Nigeria. METHODS: Skin manifestations assessed using the rapid assessment method (RAM) in 894 subjects from 13 communities selected by multi stage sampling were classified based on the anatomical sites affected. Focus group discussions and in-depth interviews were used to obtain information on the psychological impacts and sustainability of the CDTI programme. Qualitative data were summarised while quantitative data generated were analysed using charts and tables. RESULTS: Anatomical distribution showed a preponderance of onchodermatitis on the limbs (the most exposed parts of the body) and buttocks (an area considered 'private'), thus revealing some reasons for the psychological impacts of the skin disease and the psychosocial inclination of the victims. Itching (40%) and onchocercal skin manifestations (OSDs) (34.3%) were identified as the most troublesome signs and symptoms, while the most worrisome consequence of onchocerciasis was social seclusion (or stigmatisation) (34.3%). Focus group responses revealed the persistence of psychological impacts on the victims, affecting almost all facets of their lives. The CDTI programme has performed creditably well when assessed using the sustainability indicators, yet there are still challenges in the areas of coverage, monitoring, resources, and participation. A 'quick-win' was identified whereby the CDTI chain could be utilised to deliver other health interventions. CONCLUSION: It is recommended that onchocerciasis control programmes should include aspects that would address its psychosocial impacts and threats to the sustainability of the CDTI programme. PMID- 20971710 TI - Republished paper: assessment of doctors' consultation skills in the paediatric setting: the Paediatric Consultation Assessment Tool. AB - OBJECTIVE: To determine the utility of a novel Paediatric Consultation Assessment Tool (PCAT). DESIGN: Developed to measure clinicians' communication behaviour with children and their parents/guardian, PCAT was designed according to consensus guidelines and refined at a number of stages. Volunteer clinicians provided videotaped real consultations. Assessors were trained to score communication skills using PCAT, a novel rating scale. SETTING: Eight UK paediatric units. PARTICIPANTS: 19 paediatricians collected video-recorded material; a second cohort of 17 clinicians rated the videos. MAIN OUTCOME MEASURES: Itemised and aggregated scores were analysed (means and 95% confidence intervals) to determine measurement characteristics and relationship to patient, consultation, clinician and assessor attributes; generalisability coefficient of aggregate score; factor analysis of items; comparison of scores between groups of patients, consultations, clinicians and assessors. RESULTS: 188 complete consultations were analysed (median per doctor = 10). 3 videos marked by any trained assessor are needed to reliably (r > 0.8) assess a doctor's triadic consultation skills using PCAT, 4 to assess communication with just children or parents. Performance maps to two factors - "clinical skills" and "communication behaviour"; clinicians score more highly on the former (mean (SD) 95% CI 0.52 (0.075)). There were significant differences in scores for the same skills applied to parent and child, especially between the ages of 2 and 10 years, and for information-sharing rather than relationship building skills (2-tailed significance < 0.001). Conclusions The PCAT appears to be reliable, valid and feasible for the assessment of triadic consultation skills by direct observation. PMID- 20971711 TI - Masses of the pineal region: clinical presentation and radiographic features. AB - The pineal gland is important in structure, function and in the pathology that can affect it. The significance of the pathology of the gland and its adjacent structures is twofold: anatomical location, and biological behaviour of many of the lesions. The gland is in a critical anatomic location, and as the dorsal portions of the midbrain are compressed, patients may present with obstructive hydrocephalus, and/or with focal neurology. Masses and tumours of the pineal region range widely in behaviour, from the completely benign (eg, pineal cyst) to highly malignant (eg, pineoblastoma). Masses in the pineal region may be benign cysts (most common mass), tumours of various sources as well as rare vascular malformations that result in mass effect. Tumours of the pineal region represent a variety of histologies. Germ cell tumours are the most common: germinomas (50%), teratoma (15%), and choricocarcinoma (5%). Primary tumours of the pineal region make up 15% of all pineal tumours and represent a spectrum of aggressiveness. Other less common tumours also occur in the pineal region including metastatic spread and direct invasion from tumours arising in adjacent structures. Accurate diagnosis is essential to plan appropriate management, and early referral for medical imaging is a necessary first step. Although there is significant overlap in the imaging characteristics of some pineal masses, a distinction between aggressive and benign lesions is usually possible, and invaluable preoperative information is obtained in patients who require histological diagnosis. PMID- 20971712 TI - The cure of ageing: vitamin D--magic or myth? AB - Vitamin D was initially thought only to function in calcium homeostasis. However, it has multiple roles in human health, including neuromuscular and immune modulation. Recently, its deficiency is increasingly implicated in many diseases. This discovery has led both popular culture and research to find ways that vitamin D can either treat or prevent many diseases. Since vitamin D not only affects the expression of many genes, but also has intra-individual pharmacokinetic variation, a simplistic cause and effect between vitamin D deficiency and illnesses should not be expected. Older adults pose a challenge not only because diseases become more prevalent with ageing, but they also are often complicated with other comorbidities. This article reviews the link of vitamin D deficiency and the associated medical conditions in middle aged and older adults. It also examines the variability in testing vitamin D values and evaluates dosing recommendations based on current evidence. PMID- 20971713 TI - Obesity in pregnancy: a major healthcare issue. AB - The prevalence of maternal obesity is rising, up to 20% in some antenatal clinics, in line with the prevalence of obesity in the general population. Maternal obesity poses significant risks for all aspects of pregnancy. There are risks to the mother with increased maternal mortality, pre-eclampsia, diabetes and thromboembolic disorders. There is increased perinatal mortality, macrosomia and congenital malformation. The obstetric management, with increased operative delivery rate, and increased difficulty of anaesthesia, carry risk for the obese mother. Long term complications associated with maternal obesity include increased likelihood of maternal weight retention and exacerbation of obesity. This review aims to discuss these risks with a view to suggesting management to ensure the best outcome for both the mother and the offspring. PMID- 20971714 TI - Isolated right atrium tuberculoma causing complete heart block. PMID- 20971716 TI - Coincidence of calcium pyrophosphate and monosodium urate crystals in the synovial fluid of patients with gout determined by the cytocentrifugation technique. PMID- 20971717 TI - Nailfold capillaroscopy for day-to-day clinical use: construction of a simple scoring modality as a clinical prognostic index for digital trophic lesions. AB - OBJECTIVE: Construction of a simple nailfold videocapillaroscopic (NVC) scoring modality as a prognostic index for digital trophic lesions for day-to-day clinical use. METHODS: An association with a single simple (semi)-quantitatively scored NVC parameter, mean score of capillary loss, was explored in 71 consecutive patients with systemic sclerosis (SSc), and reliable reduction in the number of investigated fields (F32-F16-F8-F4). The cut-off value of the prognostic index (mean score of capillary loss calculated over a reduced number of fields) for present/future digital trophic lesions was selected by receiver operating curve (ROC) analysis. RESULTS: Reduction in the number of fields for mean score of capillary loss was reliable from F32 to F8 (intraclass correlation coefficient of F16/F32: 0.97; F8/F32: 0.90). Based on ROC analysis, a prognostic index (mean score of capillary loss as calculated over F8) with a cut-off value of 1.67 is proposed. This value has a sensitivity of 72.22/70.00, specificity of 70.59/69.77, positive likelihood ratio of 2.46/2.32 and a negative likelihood ratio of 0.39/0.43 for present/future digital trophic lesions. CONCLUSIONS: A simple prognostic index for digital trophic lesions for daily use in SSc clinics is proposed, limited to the mean score of capillary loss as calculated over eight fields (8 fingers, 1 field per finger). PMID- 20971718 TI - Anti-beta2-glycoprotein I IgG antibodies from 1-year-old healthy children born to mothers with systemic autoimmune diseases preferentially target domain 4/5: might it be the reason for their 'innocent' profile? AB - BACKGROUND: Anti-beta2-glycoprotein-I (anti-beta2GPI) were demonstrated to be pathogenic in the antiphospholipid syndrome (APS). However, they can be detected in patients with no features of APS, especially those affected by systemic autoimmune diseases (SAD), and so in healthy children. It has been suggested that anti-beta2GPI against domain 1 (D1) associate with thrombosis, while those recognising domain 4/5 (D4/5) are present in non-thrombotic conditions. OBJECTIVE: To evaluate the fine specificity of anti-beta2GPI in adults and infants. METHODS: Three groups were examined-group A: 57 1-year-old healthy children born to mothers with SAD; group B: 33 children with atopic dermatitis; group C: 64 patients with APS. SUBJECTS: were selected based on positive anti beta2GPI IgG results. Serum samples were tested for anti-beta2GPI IgG D1 and D4/5 using research ELISAs containing recombinant beta2GPI domain antigens. RESULTS: Children (A and B) displayed preferential IgG reactivity for D4/5, whereas patients with APS were mainly positive for D1. No thrombotic events were recorded in groups A and B. CONCLUSIONS: The specificity for D4/5 suggests that anti beta2GPI IgG production in children born to mothers with SAD is a process neither linked to systemic autoimmunity nor related to the maternal autoantibody status. This unusual fine specificity might, at least partially, account for the 'innocent' profile of such antibodies. PMID- 20971719 TI - Sensorineural hearing loss at 9-13 years of age in children with a history of neonatal extracorporeal membrane oxygenation. AB - OBJECTIVE: To investigate the incidence of late-onset sensorineural hearing loss (SNHL) and study the association between neonatal extracorporeal membrane oxygenation (ECMO) and SNHL in survivors of neonatal ECMO between 9 and 13 years of age. STUDY DESIGN: Retrospective analysis of medical records of 212 neonatal ECMO survivors treated between 1987 and 1991 to identify children with complete hearing evaluation at 9-13 years of age. Patients were categorised into normal hearing (NH) and SNHL groups. Cox proportional-hazard regression analysis was used to take into account the variable age at follow-up and to assess the independent effect of each risk factor for SNHL. RESULTS: Forty-eight of the 212 patients had complete hearing evaluations at 9-13 years of age and eight of 48 patients were diagnosed as having SNHL. In two patients, SNHL was first detected between 9 and 13 years. A significant difference between the SNHL and NH groups was found in median 5 min Apgar scores, mean ECMO support duration, proportion of infants with pre-ECMO Paco(2) of <30 mm Hg, and pre-ECMO use of furosemide. No differences were found in the mean cumulative dose or duration of diuretic, muscle relaxant or aminoglycoside treatments. The occurrence of clinical seizures before ECMO and the duration of ECMO therapy were independently associated with SNHL. CONCLUSION: Clinical seizure activity prior to ECMO and the duration of ECMO therapy are independently associated with SNHL. These data confirm that there is an increased incidence of SNHL in neonatal ECMO survivors at 9-13 years of age and suggest that SNHL may also present later in childhood in this patient population. Upon recovery from acute respiratory failure and after discharge from the hospital, longitudinal neurodevelopmental follow-up of infants treated with ECMO during the neonatal period is essential. PMID- 20971720 TI - Polymorphisms of interleukin 18 in the genetics of preterm birth and bronchopulmonary dysplasia. AB - Interleukin 18 (IL-18) is an important cytokine and involved in the pathogenesis and genetics of many diseases. The authors studied two different populations of preterm infants to test whether polymorphisms within IL-18 are in association with prematurity itself or with typical pulmonary disease or measurements seen in preterm infants, such as bronchopulmonary dysplasia, pneumothoraces and application of surfactant, inhalation or mechanical ventilation. Whereas the first population of 228 preterm infants showed strong association of IL-18 with preterm birth (p<0.001), this was not confirmed in the second population of 346 preterm infants. In addition, no association with any lung condition of prematurity was observed. The authors conclude that IL-18 does not play an important role in the genetics of preterm birth nor in the development of bronchopulmonary dysplasia and other lung complications in preterm infants. Caution must be taken in the interpretation of the results of genetic association studies performed in one population. PMID- 20971721 TI - Functional cardiac MRI in preterm and term newborns. AB - OBJECTIVE: To use cardiac MRI techniques to assess ventricular function and systemic perfusion in preterm and term newborns, to compare techniques to echocardiographic methods, and to obtain initial reference data. DESIGN: Observational magnetic resonance and echocardiographic imaging study. SETTING: Neonatal Unit, Queen Charlotte's and Chelsea Hospital, London, UK. Patients 108 newborn infants with median birth weight 1627 (580-4140) g, gestation 32 (25-42) weeks. RESULTS: Mean (SD) flow volumes assessed by phase contrast (PC) imaging in 28 stable infants were left ventricular output (LVO) 222 (46), right ventricular output (RVO) 219 (47), superior vena cava (SVC) 95 (27) and descending aorta (DAo) 126 (32) ml/kg/min, with flow being higher at lower gestational age. Limits of agreement for repeated PC assessment of flow were LVO +/-50.2, RVO +/-55.5, SVC +/-20.9 and DAo +/-26.2 ml/kg/min. Mean (SD) LVO in 75 stable infants from three-dimensional models were 245 (47) ml/kg/min, with limits of agreement +/ 58.3 ml/kg/min. Limits of agreement for repeated echocardiographic assessment of LVO were +/-108.9 ml/kg/min. CONCLUSIONS: Detailed magnetic resonance assessments of cardiac function and systemic perfusion are feasible in newborn infants, and provide more complete data with greater reproducibility than existing echocardiographic methods. Functional cardiac MRI could prove to be a useful research technique to study small numbers of newborn infants in specialist centres; providing insights into the pathophysiology of circulatory failure; acting as an outcome measure in clinical trials of inotropic intervention and so guiding clinical practice in the wider neonatal community. PMID- 20971722 TI - Preliminary evaluation of a new technique of minimally invasive surfactant therapy. AB - OBJECTIVE: To investigate a method of minimally invasive surfactant therapy (MIST) to be used in spontaneously breathing preterm infants on continuous positive airway pressure (CPAP), evaluating the feasibility of the technique and the therapeutic benefit after MIST. DESIGN: Non-randomised feasibility study. SETTING: Tertiary neonatal intensive care unit. PATIENTS AND INTERVENTIONS: Study subjects were preterm infants with respiratory distress supported with CPAP, with early enrolment of 25-28-week infants (n=11) at any CPAP pressure and fractional inspired O(2) concentration (FiO(2)), and enrolment of 29-34-week infants (n=14) at CPAP pressure >=7 cm H(2)O and FiO(2) >=0.35. Without premedication, a 16 gauge vascular catheter was inserted through the vocal cords under direct vision. Porcine surfactant (~100 mg/kg) was then instilled, followed by reinstitution of CPAP. MEASUREMENTS AND RESULTS: Respiratory indices were documented for 4 h following MIST, and neonatal outcomes ascertained. In all cases, surfactant was successfully administered and CPAP re-established. Coughing (32%) and bradycardia (44%) were transiently noted, and 44% received positive pressure inflations. There was a clear surfactant effect, with lower FiO(2) after MIST (pre-MIST: 0.39+/-0.092 (mean+/-SD); 4 h: 0.26+/-0.093; p<0.01), and a modest reduction in CPAP pressure. Adverse outcomes were few: intubation within 72 h (n=3), pneumothorax (n=1), chronic lung disease (n=3) and death (n=1), all in the 25-28 week group. Outcome was otherwise favourable in both gestation groups, with a trend towards reduction in intubation in the first 72 h in the 25-28-week infants compared with historical controls. CONCLUSIONS: Surfactant can be effectively delivered via a vascular catheter, and this method of MIST deserves further investigation. PMID- 20971723 TI - Globotriaosylceramide leads to K(Ca)3.1 channel dysfunction: a new insight into endothelial dysfunction in Fabry disease. AB - AIMS: Excessive endothelial globotriaosylceramide (Gb3) accumulation is associated with endothelial dysfunction and impaired endothelium-dependent relaxation in Fabry disease. In endothelial cells, K(Ca)3.1 channels contribute to endothelium-dependent relaxation. However, the effect of Gb3 on K(Ca)3.1 channels and the underlying mechanisms of Gb3-induced dysfunction are unknown. Herein, we hypothesized that Gb3 accumulation induces K(Ca)3.1 channel dysfunction and aimed to clarify the underlying mechanisms. METHODS AND RESULTS: The animal model of Fabry disease, alpha-galactosidase A (Gla) knockout mice, displayed age-dependent K(Ca)3.1 channel dysfunction. K(Ca)3.1 current and the channel expression were significantly reduced in mouse aortic endothelial cells (MAECs) of aged Gla knockout mice, whereas they were not changed in MAECs of wild type and young Gla knockout mice. In addition, K(Ca)3.1 current and the channel expression were concentration-dependently reduced in Gb3-treated MAECs. In both Gb3-treated and aged Gla knockout MAECs, extracellular signal-regulated kinase (ERK) and activator protein-1 (AP-1) were down-regulated and repressor element-1 silencing transcription factor (REST) was up-regulated. Gb3 inhibited class III phosphoinositide 3-kinase and decreased intracellular levels of phosphatidylinositol 3-phosphate [PI(3)P]. In addition, endothelium-dependent relaxation was significantly attenuated in Gb3-treated mouse aortic rings. CONCLUSION: Gb3 accumulation reduces K(Ca)3.1 channel expression by down regulating ERK and AP-1 and up-regulating REST and the channel activity by decreasing intracellular levels of PI(3)P. Gb3 thereby evokes K(Ca)3.1 channel dysfunction, and the channel dysfunction in vascular endothelial cells may contribute to vasculopathy in Fabry disease. PMID- 20971724 TI - Correlation between catalytic activity and monomer-dimer equilibrium of bacterial alanine racemases. AB - From the reaction mechanism and crystal structure analysis, a bacterial alanine racemase is believed to work as a homodimer with a substrate, l-alanine or d alanine. We analysed oligomerization states of seven alanine racemases, biosynthetic and catabolic, from Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa, P. putida and P. fluorescens, with three different methods, gel filtration chromatography, native PAGE and analytical ultracentrifugation. All alanine racemases were proved to be in a dynamic equilibrium between monomeric and dimeric form with every methods used in this study. In both biosynthetic and catabolic alanine racemases, association constants for dimerization were high for the enzymes with high V(max) values. The enzymes with low V(max) values gave the low association constants. We proposed that alanine racemases are classified into two types; the enzymes with low and high-equilibrium association constants for dimerization. PMID- 20971725 TI - An early diagnosis of inferior vena cava thrombosis. PMID- 20971726 TI - Prediction of severe bacterial infection in children with an emergency department diagnosis of infection. AB - OBJECTIVE: To determine the relationship between near-patient-test (NPT) lactate, white blood cell count (WBC) and C-reactive protein (CRP) and severe bacterial infection (SBI) in children presenting to the emergency department (ED) with infection. METHODS: An observational cohort study was undertaken in a paediatric emergency department of a large urban teaching hospital. Data were collected from January 2007 until December 2007. Inclusion criteria were age <16 years, blood test including NPT lactate obtained in the ED and infection-related ED diagnosis. Patients were pre-assigned to risk groups according to their NPT lactate, WBC and CRP. RESULTS: 506 children were included in the study, of which 42 (8.3%) had SBI. NPT lactate, WBC and CRP were significantly higher in the SBI cohort. High risk NPT lactate (>=4 mmol/l) had a sensitivity of 38.1% (95% CI 23.6% to 54.4%) and a specificity of 89.7% (95% CI 86.5% to 92.3%); high-risk WBC (<5 or >=15*10(9)/l) had a sensitivity of 51.2% (95% CI 35.1% to 67.1%) and a specificity of 73.8% (95% CI 69.4% to 77.8%); and high-risk CRP (>=50 mg/l) had a sensitivity of 36.8% (95% CI 21.8% to 54.1%) and a specificity of 83.6% (95% CI 79.4% to 87.2%) for SBI. All three high-risk markers combined yielded a sensitivity of 5.3% (95% CI 1.5% to 17.3%) and a specificity of 99.2% (95% CI 97.6% to 99.7%) for SBI. CONCLUSION: The data from our study suggest that NPT lactate provides early diagnostic information about the risk of SBI in children presenting to the ED with a suspected infection. Combining NPT lactate with WBC and CRP resulted in a promising rule-in-tool for SBI in children in the ED which, with prospective validation, has the potential to aid early identification of SBI in children. PMID- 20971727 TI - Permanent pacemaker wire infective endocarditis. PMID- 20971728 TI - Theoretical evidence for the functional benefit of root cortical aerenchyma in soils with low phosphorus availability. AB - BACKGROUND AND AIMS: The formation of root cortical aerenchyma (RCA) reduces root respiration and nutrient content by converting living tissue to air volume. It was hypothesized that RCA increases soil resource acquisition by reducing the metabolic and phosphorus cost of soil exploration. METHODS: To test the quantitative logic of the hypothesis, SimRoot, a functional-structural plant model with emphasis on root architecture and nutrient acquisition, was employed. Sensitivity analyses for the effects of RCA on the initial 40 d of growth of maize (Zea mays) and common bean (Phaseolus vulgaris) were conducted in soils with varying degrees of phosphorus availability. With reference to future climates, the benefit of having RCA in high CO(2) environments was simulated. KEY RESULTS: The model shows that RCA may increase the growth of plants faced with suboptimal phosphorus availability up to 70 % for maize and 14 % for bean after 40 d of growth. Maximum increases were obtained at low phosphorus availability (3 um). Remobilization of phosphorus from dying cells had a larger effect on plant growth than reduced root respiration. The benefit of both these functions was additive and increased over time. Larger benefits may be expected for mature plants. Sensitivity analysis for light-use efficiency showed that the benefit of having RCA is relatively stable, suggesting that elevated CO(2) in future climates will not significantly effect the benefits of having RCA. CONCLUSIONS: The results support the hypothesis that RCA is an adaptive trait for phosphorus acquisition by remobilizing phosphorus from the root cortex and reducing the metabolic costs of soil exploration. The benefit of having RCA in low-phosphorus soils is larger for maize than for bean, as maize is more sensitive to low phosphorus availability while it has a more 'expensive' root system. Genetic variation in RCA may be useful for breeding phosphorus-efficient crop cultivars, which is important for improving global food security. PMID- 20971729 TI - CD4+ T cells sensitized by vascular smooth muscle induce vasculitis, and interferon gamma is critical for the initiation of vascular pathology. AB - Primary vasculitis is the result of idiopathic inflammation in blood vessel walls. T cells are believed to play a critical role, but the nature of the pathological T-cell response remains obscure. In this study, we provide evidence that CD4(+) T lymphocytes, activated in the presence of syngeneic vascular smooth muscle cells, were sufficient to induce vasculitic lesions after adoptive transfer to recipient mice. Additionally, the disease is triggered in the absence of antibodies in experiments in which both the donors of stimulated lymphocytes and the transfer recipients were mice that were deficient in B cells. Tracking and proliferation of the transferred cells and their cytokine profiles were assessed by fluorescence tagging and flow cytometry. Proliferating CD4(+) T cells were evident 3 days after transfer, corresponding to the occurrence of vasculitic lesions in mouse lungs. The transferred T lymphocytes exhibited Th1 and Th17 cytokine profiles and minimal Th2. However, 1 week after vasculitis induction, effector functions could be successfully recalled in Th1 cells, but not in Th17 cells. Additionally, in the absence of constitutive interferon-gamma expression, T cells sensitized by vascular smooth muscle cells failed to induce vasculitis. In conclusion, our results show that Th1 cells play a key role in eliciting vasculitis in this murine model and that induction of the disease is possible in the absence of pathogenic antibodies. PMID- 20971730 TI - Interleukin-1beta mediates the extra-intestinal thrombosis associated with experimental colitis. AB - Inflammatory bowel diseases (IBDs) are associated with an increased risk for thromboembolism, which is often manifested as deep vein thrombosis or pulmonary embolism, at extra-intestinal sites. Although some of the cytokines that contribute to IBD pathogenesis are also known to alter the coagulation pathway, it remains unclear whether these mediators also contribute to the extra intestinal thrombosis often associated with IBD. The objective of this study is to evaluate the role of interleukin (IL)-1beta in enhanced extra-intestinal thrombosis observed in mice with dextran sodium sulfate (DSS)-induced colitis. IL 1beta concentrations were measured in plasma, colon, and skeletal muscle of wild type (WT) control and colitic mice. Microvascular thrombosis was induced in cremaster muscle microvessels by using a light/dye injury model. The effects of exogenous IL-1beta on thrombus formation were determined in control WT mice. DSS induced thrombogenesis was evaluated in WT mice treated with an IL-1beta antibody and in IL-1 receptor-deficient (IL-1r(-/-)) mice. DSS-induced colonic inflammation in WT mice was associated with enhanced thrombus formation in arterioles. IL-1beta concentrations were elevated in inflamed colon and skeletal muscle. Exogenous IL-1beta enhanced thrombosis in control mice in a dose dependent manner. DSS colitic mice treated with the IL-1beta antibody as well as IL-1r(-/-) mice exhibited significantly blunted thrombogenic responses. These findings implicate IL-1beta as a mediator of enhanced microvascular thromboses that occur in extra-intestinal tissues during colonic inflammation. PMID- 20971731 TI - Down-regulation of the oncogene cyclin D1 increases migratory capacity in breast cancer and is linked to unfavorable prognostic features. AB - The oncogene cyclin D1 is highly expressed in many breast cancers and, despite its proliferation-activating properties, it has been linked to a less malignant phenotype. To clarify this observation, we focused on two key components of malignant behavior, migration and proliferation, and observed that quiescent G(0)/G(1) cells display an increased migratory capacity compared to cycling cells. We also found that the down-regulation of cyclin D1 in actively cycling cells significantly increased migration while also decreasing proliferation. When analyzing a large set of premenopausal breast cancers, we observed an inverse proliferation-independent link between cyclin D1 and tumor size and recurrence, suggesting that this protein might abrogate infiltrative malignant behavior in vivo. Finally, gene expression analysis after cyclin D1 down-regulation by siRNA confirmed changes in processes associated with migration and enrichment of our gene set in a metastatic poor prognosis signature. This novel function of cyclin D1 illustrates the interplay between tumor proliferation and migration and may explain the attenuation of malignant behavior in breast cancers with high cyclin D1 levels. PMID- 20971732 TI - Matrix metalloproteinase-9 and cell division in neuroblastoma cells and bone marrow macrophages. AB - Matrix metalloproteinases (MMPs) degrade the extracellular matrix and carry out key functions in cell development, cancer, injury, and regeneration. In addition to its well recognized extracellular action, functional intracellular MMP activity under certain conditions is supported by increasing evidence. In this study, we observed higher gelatinase activity by in situ zymography and increased MMP-9 immunoreactivity in human neuroblastoma cells and in bone marrow macrophages undergoing mitosis compared with resting cells. We studied the pattern of immunoreactivity at the different stages of cell division by confocal microscopy. Immunostaining with different monoclonal antibodies against MMP-9 revealed a precise, dynamic, and well orchestrated localization of MMP-9 at the different stages of cell division. The cellular distribution of MMP-9 staining was studied in relation to that of microtubules. The spatial pattern of MMP-9 immunoreactivity suggested some participation in both the reorganization of the nuclear content and the process of chromatid segmentation. We then used several MMP-9 inhibitors to find out whether MMP-9 might be involved in the cell cycle. These drugs impaired the entry of cells into mitosis, as revealed by flow cytometry, and reduced cell culture growth. In addition, the silencing of MMP-9 expression with small interfering RNA also reduced cell growth. Taken together, these results suggest that intracellular MMP-9 is involved in the process of cell division in neuroblastoma cells and in primary cultures of macrophages. PMID- 20971733 TI - Protease-activated receptor-2 induces myofibroblast differentiation and tissue factor up-regulation during bleomycin-induced lung injury: potential role in pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis constitutes the most devastating form of fibrotic lung disorders and remains refractory to current therapies. The coagulation cascade is frequently activated during pulmonary fibrosis, but this observation has so far resisted a mechanistic explanation. Recent data suggest that protease activated receptor (PAR)-2, a receptor activated by (among others) coagulation factor (F)Xa, plays a key role in fibrotic disease; consequently, we assessed the role of PAR-2 in the development of pulmonary fibrosis in this study. We show that PAR-2 is up-regulated in the lungs of patients with idiopathic pulmonary fibrosis and that bronchoalveolar lavage fluid from these patients displays increased procoagulant activity that triggers fibroblast survival. Using a bleomycin model of pulmonary fibrosis, we show that bleomycin induces PAR-2 expression, as well as both myofibroblast differentiation and collagen synthesis. In PAR-2-/- mice, both the extent and severity of fibrotic lesions are reduced, whereas myofibroblast differentiation is diminished and collagen expression is decreased. Moreover, fibrin deposition in the lungs of fibrotic PAR-2-/- mice is reduced compared with wild-type mice due to differential tissue factor expression in response to bleomycin. Taken together, these results suggest an important role for PAR-2 in the development of pulmonary fibrosis, and the inhibition of the PAR 2-coagulation axis may provide a novel therapeutic approach to treat this devastating disease. PMID- 20971734 TI - Mutant (CCTG)n expansion causes abnormal expression of zinc finger protein 9 (ZNF9) in myotonic dystrophy type 2. AB - The mutation that underlies myotonic dystrophy type 2 (DM2) is a (CCTG)n expansion in intron 1 of zinc finger protein 9 (ZNF9). It has been suggested that ZNF9 is of no consequence for disease pathogenesis. We determined the expression levels of ZNF9 during muscle cell differentiation and in DM2 muscle by microarray profiling, real-time RT-PCR, splice variant analysis, immunofluorescence, and Western blotting. Our results show that in differentiating myoblasts, ZNF9 protein was localized primarily to the nucleus, whereas in mature muscle fibers, it was cytoplasmic and organized in sarcomeric striations at the Z-disk. In patients with DM2, ZNF9 was abnormally expressed. First, there was an overall reduction in both the mRNA and protein levels. Second, the subcellular localization of the ZNF9 protein was somewhat less cytoplasmic and more membrane bound. Third, our splice variant analysis revealed retention of intron 3 in an aberrant isoform, and fourth quantitative allele-specific expression analysis showed the persistence of intron 1 sequences from the abnormal allele, further suggesting that the mutant allele is incompletely spliced. Thus, the decrease in total expression appears to be due to impaired splicing of the mutant transcript. Our data indicate that ZNF9 expression in DM2 patients is altered at multiple levels. Although toxic RNA effects likely explain overlapping phenotypic manifestations between DM1 and DM2, abnormal ZNF9 levels in DM2 may account for the differences in DM1. PMID- 20971735 TI - Activation of the Hh pathway in periosteum-derived mesenchymal stem cells induces bone formation in vivo: implication for postnatal bone repair. AB - While the essential role of periosteum in cortical bone repair and regeneration is well established, the molecular pathways that control the early osteogenic and chondrogenic differentiation of periosteal stem/progenitor cells during repair processes are unclear. Using a murine segmental bone graft transplantation model, we isolated a population of early periosteum-callus-derived mesenchymal stem cells (PCDSCs) from the healing autograft periosteum. These cells express typical mesenchymal stem cell markers and are capable of differentiating into osteoblasts, adipocytes, and chondrocytes. Characterization of these cells demonstrated that activation of the hedgehog (Hh) pathway effectively promoted osteogenic and chondrogenic differentiation of PCDSCs in vitro and induced bone formation in vivo. To determine the role of the Hh pathway in adult bone repair, we deleted Smoothened (Smo), the receptor that transduces all Hh signals at the onset of bone autograft repair via a tamoxifen-inducible RosaCreER mouse model. We found that deletion of Smo markedly reduced osteogenic differentiation of isolated PCDSCs and further resulted in a near 50% reduction in periosteal bone callus formation at the cortical bone junction as determined by MicroCT and histomorphometric analyses. These data strongly suggest that the Hh pathway plays an important role in adult bone repair via enhancing differentiation of periosteal progenitors and that activation of the Hh pathway at the onset of healing could be beneficial for repair and regeneration. PMID- 20971736 TI - Development of a bioengineered skin-humanized mouse model for psoriasis: dissecting epidermal-lymphocyte interacting pathways. AB - Over the past few years, whole skin xenotransplantation models that mimic different aspects of psoriasis have become available. However, these models are strongly constrained by the lack of skin donor availability and homogeneity. We present in this study a bioengineering-based skin-humanized mouse model for psoriasis, either in an autologous version using samples derived from psoriatic patients or, more importantly, in an allogeneic context, starting from skin biopsies and blood samples from unrelated healthy donors. After engraftment, the regenerated human skin presents the typical architecture of normal human skin but, in both cases, immunological reconstitution through intradermal injection in the regenerated skin using in vitro-differentiated T1 subpopulations as well as recombinant IL-17 and IL-22 Th17 cytokines, together with removal of the stratum corneum barrier by a mild abrasive treatment, leads to the rapid conversion of the skin into a bona fide psoriatic phenotype. Major hallmarks of psoriasis were confirmed by the evaluation of specific epidermal differentiation and proliferation markers as well as the mesenchymal milieu, including angiogenesis and infiltrate. Our bioengineered skin-based system represents a robust platform to reliably assess the molecular and cellular mechanisms underlying the complex interdependence between epidermal cells and the immune system. The system may also prove suitable to assess preclinical studies that test the efficacy of novel therapeutic treatments and to predict individual patient response to therapy. PMID- 20971737 TI - Matriptase is involved in ErbB-2-induced prostate cancer cell invasion. AB - Deregulation of both ErbB-2 signaling and matriptase activity has been associated with human prostate cancer (PCa) progression. In this communication, we investigated the roles of both ErbB-2 signaling in matriptase zymogen activation and matriptase in ErbB-2-induced PCa malignancy. In a human PCa cell progression model, we observed that advanced PCa C-81 LNCaP cells exhibited an aggressive phenotype with increased cell migration and invasion capacity; these cells concurrently showed both enhanced ErbB-2 phosphorylation and increased matriptase zymogen activation compared with parental C-33 LNCaP cells. Moreover, ErbB2 activation, both ligand-dependent (eg, epidermal growth factor treatment) and ligand-independent (eg, overexpression), was able to induce matriptase zymogen activation in this cell line. Inhibition of ErbB-2 activity by either the specific inhibitor, AG825, in epidermal growth factor-treated C-33 LNCaP cells or ErbB-2 knockdown in C-81 LNCaP cells, reduced matriptase activation. These observations were confirmed by similar studies using both DU145 and PC3 cells. Together, these data suggest that ErbB-2 signaling plays an important role in matriptase zymogen activation. ErbB-2-enhanced matriptase activation was suppressed by a phosphatidylinositol 3-kinase inhibitor (ie, LY294002) but not by a MEK inhibitor (ie, PD98059). Suppression of matriptase expression by small hairpin RNA knockdown in ErbB-2-overexpressing LNCaP cells dramatically suppressed cancer cell invasion. In summary, our data indicate that ErbB-2 signaling via the phosphatidylinositol 3-kinase pathway results in up-regulated matriptase zymogen activity, which contributes to PCa cell invasion. PMID- 20971738 TI - Grp78 heterozygosity regulates chaperone balance in exocrine pancreas with differential response to cerulein-induced acute pancreatitis. AB - The endoplasmic reticulum (ER) is abundant in the acinar cells of the exocrine pancreas. To test the role of ER homeostasis in acute pancreatitis, we manipulated GRP78 levels, a major ER chaperone, in mice. Grp78(+/+) and (+/-) littermates were fed either a regular diet (RD) or a high-fat diet. Acinar cells were examined for ER structure by electron microscopy, and ER chaperone levels were assessed by immunoblotting. Pancreatitis was induced by cerulein injection, and multiple pathological parameters were analyzed. Grp78(+/-) mice showed decreased GRP78 expression in acinar cells. Exocrine pancreata of RD-fed Grp78(+/ ) mice in an outbred C57BL/6 * 129/sv genetic background exhibited ER lumen dilation, a reduction in chaperones calnexin (CNX) and calreticulin (CRT), and exacerbated pancreatitis associated with high CHOP induction. With the high-fat diet regimen, Grp78 heterozygosity triggered GRP94 up-regulation and restoration of GRP78, CNX, and CRT to wild-type levels, corresponding with mitigated pancreatitis on cerulein insult. Interestingly, after backcrossing into the C57BL/6 background, RD-fed Grp78(+/-) mice exhibited an increase in GRP94 and levels of CNX and CRT equivalent to wild type, associated with decreased experimental pancreatitis severity. Administration of a chemical chaperone, 4 phenolbutyrate, was protective against cerulein-induced death. Thus, in exocrine pancreata, Grp78 heterozygosity regulates ER chaperone balance, in dietary- and genetic background-dependent manners, and improved ER protein folding capacity might be protective against pancreatitis. PMID- 20971739 TI - Identification and regulation of reticulon 4B (Nogo-B) in renal tubular epithelial cells. AB - Nogo-B is a member of the reticulon family of proteins that has been implicated in diverse forms of vascular injury. Although Nogo-B is expressed in renal tissues, its localization and function in the kidney have not been examined. Here, we report that Nogo-B is expressed specifically in the epithelial cells of the distal nephron segments in the murine kidney. After unilateral ureteral obstruction (UUO) and ischemia/reperfusion, Nogo-B gene and protein levels increased dramatically in the kidney. This increase was driven in part by injury induced de novo expression in proximal tubules. Examination of Nogo-B immunostaining in human biopsy specimens from patients with acute tubular necrosis showed similar increases in Nogo-B in cortical tubules. Mice genetically deficient in Nogo-A/B were indistinguishable from wild-type (WT) mice based on histological appearance and serum analyses. After UUO, there was a significant delay in recruitment of macrophages to the kidney in the Nogo-A/B-deficient mice. However, measurements of fibrosis, inflammatory gene expression, and histological damage were not significantly different from WT mice. Thus, Nogo-B is highly expressed in murine kidneys in response to experimental injuries and may serve as a marker of diverse forms of renal injury in tissues from mice and humans. Furthermore, Nogo-B may regulate macrophage recruitment after UUO, although it does not greatly affect the degree of tissue injury or fibrosis in this model. PMID- 20971740 TI - Silencing the expression of Ras family GTPase homologues decreases inflammation and joint destruction in experimental arthritis. AB - Changes in the expression and activation status of Ras proteins are thought to contribute to the pathological phenotype of stromal fibroblast-like synoviocytes (FLS) in rheumatoid arthritis, a prototypical immune-mediated inflammatory disease. Broad inhibition of Ras and related proteins has shown protective effects in animal models of arthritis, but each of the Ras family homologues (ie, H-, K-, and N-Ras) makes distinct contributions to cellular activation. We examined the expression of each Ras protein in synovial tissue and FLS obtained from patients with rheumatoid arthritis and other forms of inflammatory arthritis. Each Ras protein was expressed in synovial tissue and cultured FLS. Each homolog was also activated following FLS stimulation with tumor necrosis factor-alpha or interleukin (IL)-1beta. Constitutively active mutants of each Ras protein enhanced IL-1beta-induced FLS matrix metalloproteinase-3 production, while only active H-Ras enhanced IL-8 production. Gene silencing demonstrated that each Ras protein contributed to IL-1beta-dependent IL-6 production, while H Ras and N-Ras supported IL-1beta-dependent matrix metalloproteinase-3 and IL-8 production, respectively. The overlap in contributions of Ras homologues to FLS activation suggests that broad targeting of Ras GTPases in vivo suppresses global inflammation and joint destruction in arthritis. Consistent with this, simultaneous silencing of H-Ras, K-Ras, and N-Ras expression significantly reduces inflammation and joint destruction in murine collagen-induced arthritis, while specific targeting of N-Ras alone is less effective in providing clinical benefits. PMID- 20971741 TI - Combination therapy with epigallocatechin-3-gallate and doxorubicin in human prostate tumor modeling studies: inhibition of metastatic tumor growth in severe combined immunodeficiency mice. AB - The polyphenol epigallocatechin-3-gallate (EGCG) in combination with doxorubicin (Dox) exhibits a synergistic activity in blocking the growth and colony-forming ability of human prostate cell lines in vitro. EGCG has been found to disrupt the mitochondrial membrane potential, induce vesiculation of mitochondria, and induce elevated poly (ADP-ribose) polymerase (PARP) cleavage and apoptosis. EGCG in combination with low levels of Dox had a synergistic effect in blocking tumor cell growth. In vivo tumor modeling studies with a highly metastatic tumor line, PC-3ML cells, revealed that EGCG (228 mg/kg or 200 MUmol/L) appeared to sensitize tumors to Dox. EGCG combined with low levels of Dox (0.14 mg/kg or 2 MUmol/L) blocked tumor growth by PC-3ML cells injected intraperitoneally (ie, in CB17 severe combined immunodeficiencies) and significantly increased mouse survival rates. Similarly, relatively low levels of EGCG (57 mg/kg or 50 MUmol/L) plus Dox (0.07 mg/kg or 1 MUmol/L) eradicated established tumors (ie, in nonobese diabetic severe combined immunodeficiencies) that were derived from CD44(hi) tumor initiating cells isolated from PCa-20a cells. Flow cytometry results showed that EGCG appeared to enhance retention of Dox by tumor cells to synergistically inhibit tumor growth and eradicate tumors. These data suggest that localized delivery of high dosages of EGCG combined with low levels of Dox may have significant clinical application in the treatment of metastatic prostate and/or eradication of primary tumors derived from tumor-initiating cells. PMID- 20971742 TI - Lack of complement inhibitors in the outer intracranial artery aneurysm wall associates with complement terminal pathway activation. AB - Inflammation and activation of the complement system predispose to intracranial artery aneurysm (IA) rupture. Because disturbances in complement regulation may lead to increased susceptibility to complement activation and inflammation, we looked for evidence for dysregulation of the complement system in 26 unruptured and 26 ruptured IAs resected intraoperatively. Immunohistochemical and immunofluorescence results of parallel IA sections showed that deposition of the complement activation end-product C5b-9 was lacking from the luminal part of the IA wall that contained complement inhibitors factor H, C4b binding protein, and protectin as well as glycosaminoglycans. In contrast, the outer, less cellular part of the IA wall lacked protectin and had enabled full complement activation and C5b-9 formation. Decay accelerating factor and membrane cofactor protein had less evident roles in complement regulation. The Factor H Y402H variant, studied in 97 IA patients, was seen as often in aneurysm patients with or without aneurysm rupture as in the control population. The regulatory capacity of the complement system thus appears disturbed in the outer part of the IA wall, allowing full proinflammatory complement activation to occur before aneurysm rupture. Insufficient complement control might be due to matrix remodeling and cell loss by mechanical hemodynamics and/or inflammatory stress. Apparently, disturbed complement regulation leads to an increased susceptibility to complement activation, inflammation, and tissue damage in the IA wall. PMID- 20971743 TI - Small interfering RNAs induce target-independent inhibition of tumor growth and vasculature remodeling in a mouse model of hepatocellular carcinoma. AB - RNA interference mediated by small interfering RNAs (siRNAs) has emerged as a potential therapeutic approach to treat various diseases, including cancer. Recent studies with several animal models of posttraumatic revascularization demonstrated that synthetic siRNAs may produce therapeutic effects in a target independent manner through the stimulation of the toll-like receptor-3 (TLR3)/interferon pathway and suppression of angiogenesis. To analyze the impact of siRNAs on tumor angiogenesis, we injected transgenic mice developing hepatocellular carcinoma (HCC) with either control siRNAs or siRNA targeting neuropilin-1. We found that treatment with these siRNAs led to a comparable reduction in tumor liver volume and to inhibition of tumor vasculature remodeling. We further determined that TLR3, which recognizes double-stranded siRNA, was up-regulated in mouse HCC. Treatment of HCC mice with polyinosinic polycytidylic acid [poly(I:C)], a TLR3 agonist, led to both a reduction of tumor liver enlargement and a decrease in hepatic arterial blood flow, indicating that TLR3 is functional and may mediate both anti-angiogenic and anti-tumor responses. We also demonstrated that siRNAs increased interferon-gamma levels in the liver. In vitro, interferon-gamma inhibited proliferation of endothelial cells. In addition, we found that siRNAs inhibited endothelial cell proliferation and morphogenesis in an interferon-gamma-independent manner. Our results suggest that synthetic siRNAs inhibit target-independently HCC growth and angiogenesis through the activation of the innate interferon response and by directly inhibiting endothelial cell function. PMID- 20971744 TI - Primary angioplasty vs. fibrinolysis in very old patients with acute myocardial infarction: TRIANA (TRatamiento del Infarto Agudo de miocardio eN Ancianos) randomized trial and pooled analysis with previous studies. AB - AIMS: To compare primary percutaneous coronary intervention (pPCI) and fibrinolysis in very old patients with ST-segment elevation myocardial infarction (STEMI), in whom head-to-head comparisons between both strategies are scarce. METHODS AND RESULTS: Patients >=75 years old with STEMI <6 h were randomized to pPCI or fibrinolysis. The primary endpoint was a composite of all-cause mortality, re-infarction, or disabling stroke at 30 days. The trial was prematurely stopped due to slow recruitment after enrolling 266 patients (134 allocated to pPCI and 132 to fibrinolysis). Both groups were well balanced in baseline characteristics. Mean age was 81 years. The primary endpoint was reached in 25 patients in the pPCI group (18.9%) and 34 (25.4%) in the fibrinolysis arm [odds ratio (OR), 0.69; 95% confidence interval (CI) 0.38-1.23; P = 0.21]. Similarly, non-significant reductions were found in death (13.6 vs. 17.2%, P = 0.43), re-infarction (5.3 vs. 8.2%, P = 0.35), or disabling stroke (0.8 vs. 3.0%, P = 0.18). Recurrent ischaemia was less common in pPCI-treated patients (0.8 vs. 9.7%, P< 0.001). No differences were found in major bleeds. A pooled analysis with the two previous reperfusion trials performed in older patients showed an advantage of pPCI over fibrinolysis in reducing death, re-infarction, or stroke at 30 days (OR, 0.64; 95% CI 0.45-0.91). CONCLUSION: Primary PCI seems to be the best reperfusion therapy for STEMI even for the oldest patients. Early contemporary fibrinolytic therapy may be a safe alternative to pPCI in the elderly when this is not available. PMID- 20971745 TI - Impact of scar burden by single-photon emission computed tomography myocardial perfusion imaging on patient outcomes following cardiac resynchronization therapy. AB - AIMS: Ischaemic heart disease negatively impacts response to cardiac resynchronization therapy (CRT), yet the impact of infarct scar burden on clinical outcomes and its interaction with mechanical dyssynchrony have not been well described. METHODS AND RESULTS: We studied 620 NYHA classes III-IV heart failure patients with ejection fraction (EF) <= 35% and QRS duration >=120 ms referred for CRT. Included were 190 ischaemic cardiomyopathy (ICM) CRT recipients with scar burden quantified by rest-redistribution Tl(201) myocardial perfusion imaging using a 17-segment (0 = normal to 4 = absence of uptake) summed rest score (SRS). Non-ICM (NICM) CRT recipients (n = 380) and 50 patients referred for CRT with unsuccessful LV lead implant comprised the comparison groups. Echocardiographic dyssynchrony analysis was performed in a subgroup of 150 patients. Follow-up left ventricular EF (LVEF) and volumes were examined at 7 +/- 3 months in 143 patients. The outcome of death, cardiac transplant, or mechanical circulatory support was assessed in all. Over 2.1 +/- 1.6 years, ICM patients had significantly worse survival and less LVEF improvement than NICM patients (P < 0.01). Ischaemic cardiomyopathy patients with low scar burden (SRS < 27) had favourable survival and LVEF improvement, similar to NICM patients. A high scar burden (SRS >= 27) was associated with reduced survival and lack of LV functional improvement (P <= 0.01), similar to those with unsuccessful LV lead implant, whereas baseline dyssynchrony was not predictive of outcome in these patients. CONCLUSION: Extensive scar burden in ICM patients unfavourably affected clinical and LV functional outcomes after CRT, regardless of baseline dyssynchrony measures. Patients with ICM and lower scar burden had significantly better outcomes, similar to NICM patients. PMID- 20971746 TI - Stiffness of large arteries and cardiovascular risk in patients with post traumatic stress disorder. AB - AIMS: Post-traumatic stress disorder (PTSD) develops after exposure to particularly traumatic events. Its severity depends on the nature and intensity of the stressor and susceptibility of the exposed person. The present study was carried out to find out whether PTSD and its severity, resulting from deportation to Siberia in the patients' childhood (from 1940 to 1946), have any association on the somatic health status and cardiovascular risk of these persons in advanced age. METHODS AND RESULTS: Eighty patients with PTSD and 70 subjects without PTSD followed up in primary care setting were enrolled in the study. Post-traumatic stress disorder was diagnosed according to the DSM-IV criteria; severity of the symptoms included in the criteria was also assessed. All patients were subject to a standardized interview including demographic data and current and past diseases, supplemented with physical examination, biochemical tests, and aortic pulse wave velocity (PWV). The group of patients with PTSD resulting from deportation to Siberia in their childhood had higher prevalence of coronary artery disease (71.3 vs. 44.3%, P < 0.001), diabetes (26.3 vs. 11.4%, P < 0.05), and hearing impairment (23.8 vs. 2.9%, P < 0.001) than controls. They also had higher incidence of blood pressure >140/90 (86.0 vs. 65.7%, P = 0.003), fasting blood glucose >5.6 mmol/L (65.0 vs. 45.7%, P = 0.018), HDL level <1.0 mmol/L (31.3 vs. 8.6%, P = 0.0006), and triglyceride level >2.3 mmol/L (62.5 vs. 321.4%, P = 0.001). Patients with PTSD had higher PWV (13.7 vs. 12.9 m/s, P= 0.042). The magnitude of PWV increased with the severity of PTSD (P = 0.001). Stepwise logistic regression has shown that PTSD was a strong factor promoting the appearance of coronary heart disease in the former deportees group (OR 3.80; 95% CI: 1.62-8.94; P = 0.002). CONCLUSION: Several-year long deportation in childhood and PTSD elevated overall cardiovascular risk in the group of former deportees compared with the group of persons without history of such a traumatic experience. PMID- 20971747 TI - Rosuvastatin for primary prevention in patients with European systematic coronary risk evaluation risk >= 5% or Framingham risk >20%: post hoc analyses of the JUPITER trial requested by European health authorities. AB - AIMS: On the basis of the JUPITER trial, European health authorities recently approved the use of rosuvastatin to reduce first major cardiovascular events among 'high' global risk primary prevention patients defined either by Framingham risk score >20% or European systematic coronary risk evaluation (SCORE) >=5%. However, as these are post hoc analyses, data describing these subgroups have not previously been available to the clinical community. METHODS AND RESULTS: We randomized 17 802 apparently healthy men aged >=50 and women >=60 with low density lipoprotein cholesterol (LDL-C) <3.4 mmol/L, who were at an increased vascular risk due to elevated levels of C-reactive protein measured with a high sensitivity (hs) assay to rosuvastatin 20 mg daily or placebo. Patients with high global cardiovascular risk at baseline were identified by 10-year Framingham risk score >20% or SCORE risk >=5%. During 1.8-year median follow-up (maximum 5 years) of patients with Framingham risk >20%, the rate of myocardial infarction/stroke/cardiovascular death was 9.4 and 18.2 per 1000 person-years in rosuvastatin and placebo-allocated patients, respectively [hazard ratio (HR): 0.50, 95% confidence interval (CI): 0.27-0.93, P = 0.028]. Among patients with SCORE risk >=5%, the corresponding rates were 6.9 and 12.0 using a model extrapolating risk for age >=65 years (HR: 0.57, 95% CI: 0.43-0.78, P = 0.0003) and rates were 5.9 and 12.7 when risk for age was capped at 65 years (HR: 0.47, 95% CI: 0.32-0.68, P < 0.0001). CONCLUSION: In primary prevention patients with elevated hs C-reactive protein who have high global cardiovascular risk (10-year Framingham risk score >20% or SCORE risk >=5%), but LDL-C levels not requiring pharmacologic treatment, rosuvastatin 20 mg significantly reduced major cardiovascular events. PMID- 20971748 TI - Atrial septal defect: waiting for symptoms remains an unsolved medical anachronism. PMID- 20971749 TI - Blind outcome assessment: the development and use of procedures to maintain and describe blinding in a pragmatic physiotherapy rehabilitation trial. AB - OBJECTIVES: (1) To develop trial protocols which promote the achievement of blind outcome assessment. (2) To report outcome assessor beliefs regarding group allocation at follow-up assessments. (3) To document and describe instances of unblinding occurring during the trial to assist and inform rehabilitation researchers and clinicians. DESIGN: Prospective longitudinal observational study. SETTING: An NHS Hospital Trust specializing in orthopaedic surgery. SUBJECTS: One hundred and seven patients participating in a prospective pragmatic randomized controlled trial investigating physiotherapy rehabilitation following total knee arthroplasty, plus three outcome assessors. INTERVENTIONS: A protocol was developed using available research and designed to minimize instances of unblinding during a physiotherapy rehabilitation trial. Administrative, office, patient and research staff procedures were included. MAIN MEASURES: Trial questionnaires measured blind outcome assessment responses at 3 and 12 months post surgery. The outcome assessor kept a field diary recording the events surrounding instances of unblinding. Data underwent descriptive and content analysis. RESULTS: Blind outcome assessment was believed successful for n = 74 (81.32%) assessments at 3-month follow-up, and n = 83 (91.21%) at 12 months. Forty instances (n = 28 participants) of unblinding were described in the field diary. While the main cause of unblinding was participants telling the outcome assessor, in 12.5% of events the assessor drew the wrong conclusion regarding group allocation. Not all unblinding events were remembered at subsequent assessments, even in this relatively small trial. CONCLUSIONS: Blind outcome assessment was considered achievable in this trial. Specific trial protocols enabled blinding beliefs to be reported and instances of unblinding to be described. PMID- 20971750 TI - Virtual reality assessment for visuospatial neglect: importance of a dynamic task. PMID- 20971751 TI - Safety of transcranial Doppler 'bubble study' for identification of right to left shunts: an international multicentre study. AB - BACKGROUND AND PURPOSE: A recent retrospective study using an online list service established by the American Academy of Neurology has suggested that ischaemic cerebrovascular events may occur in patients who undergo 'bubble studies' (BS) with either transcranial Doppler (TCD) or transoesophageal echocardiography (TOE). The safety of TCD-BS for right to left shunt (RLS) identification was evaluated prospectively in an international multicentre study. METHODS: Consecutive patients with cerebral ischaemia (ischaemic stroke or transient ischaemic attack (TIA)) were screened for potential ischaemic cerebrovascular events following injection of microbubbles during TCD-BS for identification of RLS at three tertiary care stroke centres. TCD-BS was performed according to the standardised International Consensus Protocol. TOE-BS was performed in selected cases for confirmation of TCD-BS. RESULTS: 508 patients hospitalised with acute cerebral ischaemia (mean age 46+/-12 years, 59% men; 63% ischaemic stroke, 37% TIA) were investigated with TCD-BS within 1 week of ictus. RLS was identified in 151 cases (30%). TOE-BS was performed in 101 out of 151 patients with RLS identified on TCD-BS (67%). It was positive in 99 patients (98%). The rate of ischaemic cerebrovascular complications during or after TCD-BS was 0% (95% CI by the adjusted Wald METHOD: 0-0.6%). Structural cardiac abnormalities were identified in 38 patients, including atrial septal aneurysm (n=23), tetralogy of Fallot (n=1), intracardiac thrombus (n=2), ventricular septal defect (n=3) and atrial myxoma (n=1). CONCLUSION: TCD-BS is a safe screening test for identification of RLS, independent of the presence of cardiac structural abnormalities. PMID- 20971752 TI - Value of 1H-magnetic resonance spectroscopy chemical shift imaging for detection of anaplastic foci in diffusely infiltrating gliomas with non-significant contrast-enhancement. AB - OBJECTIVE: In diffusely infiltrating gliomas (DIG), positron emission tomography (PET) imaging is a powerful method for detection of anaplastic foci. Recently, (1)H-magnetic resonance spectroscopy chemical shift imaging (CSI) using choline/creatine (Cho/Cr) or choline/N-acetylaspartate (Cho/NAA) ratios has emerged as a new non-invasive, widely available alternative. The authors therefore correlated CSI with (11)C-methionine (MET)-PET data in a series of DIG with non-significant contrast-enhancement (CE). METHODS: Thirty-two patients with DIG were examined with single-slice CSI on a T MRI and MET-PET. Maximum pathological intratumoural ratios of CSI (=CSI(max)) and maximum tumour-to-normal brain PET ratios (=PET(max); T/N ratio) were determined. Coregistration of MRI with CSI and PET was performed, and the topographic overlap of CSI(max) and PET(max) was analysed. Histological criteria of anaplasia as well as cell proliferation rate were assessed in tumour samples inside and outside CSI(max). RESULTS: CSI showed a pathological ratio in all patients, whereas PET demonstrated a pathological T/N ratio in 21/32 patients. Topographical correlation of CSI(max) and PET(max) revealed a >= 50% overlap in 18/21 and <50% overlap in 3/21 patients, respectively. Cho/Cr(max) and Cho/NAA(max) showed a >= 50% overlap in 24/32 and a <50% overlap in 8/32 patients. Cell proliferation rate was significantly higher inside than outside the CSI(max) (13.6% vs 6.9%, p<0.001). CONCLUSION: The results indicate that CSI is a promising method for detection of anaplastic foci within DIG with non-significant CE. Intraoperative use of CSI by multimodal neuronavigation may increase the reliability of detection of malignant areas in glioma surgery and therefore optimise allocation of patients to adjuvant treatments. PMID- 20971753 TI - Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. AB - Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30-50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2-21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43 negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will all be required for disease-specific therapeutic trials in the future. PMID- 20971754 TI - MRI shows increased sciatic nerve cross sectional area in inherited and inflammatory neuropathies. AB - Measurements of the cross sectional area of the sciatic nerve are described in a group of 10 patients with genetically confirmed Charcot-Marie-Tooth disease type 1A (CMT1A), nine patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and 10 healthy controls using MRI. One mid-thigh of each individual was imaged using a short tau inversion recovery sequence and the nerve appearance evaluated radiologically with respect to the signal intensity and visibility of the internal neural structure. The cross sectional area of the sciatic nerve of each individual was measured by defining irregular enclosing regions of interest on the MRI images. The sciatic nerve area was enlarged in both CMT1A (p<0.001) and CIDP (p=0.008) compared with controls and in CMT1A compared with CIDP (p<0.001). Median (interquartile range) areas were 67.6 (16.2) mm(2) for the CIDP group, 135.9 (46.5) mm(2) for the CMT1A group and 43.3 (19.9) mm(2) for the control group. The critical upper value for discriminating pathologically enlarged nerves from normal controls with p<0.05 was 64.4 mm(2). Quantification of sciatic nerve hypertrophy on MRI may be of assistance in cases where the diagnosis is still in doubt, providing an objective pathological marker complimenting other clinical investigations. PMID- 20971755 TI - Frequency of cognitive impairment dramatically increases during the first 5 years of multiple sclerosis. AB - Previous studies have demonstrated that cognitive impairment is already present in patients suffering from a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). However, little is known about the course of cognitive impairment after the occurrence of a CIS. In order to characterise the early evolution of cognitive impairment, the authors assessed during a 5-year follow-up period a group of 24 CIS patients with high risk of developing MS. Longitudinal neuropsychological assessment was performed at two time points (baseline and year 5) in patients and controls (baseline and year 1). At year 5, 54% of patients showed cognitive impairment against 29% at baseline. Multiple regression models showed that patients with a higher T(2) lesion load at baseline had a higher cognitive impairment at year 5. This longitudinal study performed in CIS patients showed that the frequency of cognitive impairment increases dramatically during the first 5 years following a CIS and that the cognitive status at year 5 was predictable by conventional MRI parameters recorded at baseline. PMID- 20971756 TI - Incidental MRI lesions suggestive of multiple sclerosis in asymptomatic patients in Karachi, Pakistan. AB - The objective of this study was to identify asymptomatic patients with brain MRI lesions suggestive of multiple sclerosis (MS) in a low-prevalence area of Pakistan. Brain MRIs for 864 patients were reviewed at the Aga Khan University (Karachi, Pakistan) during an 8-month period of 2006 and 2007 to identify patients with lesions suggestive of MS. The lesions were characterised based on modified Barkhof criteria. Six (two females) (0.7%) of 864 patients fulfilled brain MRI criteria suggestive of MS. The mean number of MRI lesions (total lesions on T2) were 9 (range 5-14). Although Pakistan is considered a low prevalence area for MS, 0.7% of brain MRI scans in patients without clinical MS symptoms showed lesions fulfilling brain MRI criteria of MS. PMID- 20971757 TI - Pedunculopontine nucleus deep brain stimulation produces sustained improvement in primary progressive freezing of gait. AB - OBJECTIVE: To assess the efficacy of bilateral pedunculopontine nucleus (PPN) deep brain stimulation (DBS) as a treatment for primary progressive freezing of gait (PPFG). METHODS: A patient with PPFG underwent bilateral PPN-DBS and was followed clinically for over 14 months. RESULTS: The PPFG patient exhibited a robust improvement in gait and posture following PPN-DBS. When PPN stimulation was deactivated, postural stability and gait skills declined to pre-DBS levels, and fluoro-2-deoxy-d-glucose positron emission tomography revealed hypoactive cerebellar and brainstem regions, which significantly normalised when PPN stimulation was reactivated. CONCLUSIONS: This case demonstrates that the advantages of PPN-DBS may not be limited to addressing freezing of gait (FOG) in idiopathic Parkinson's disease. The PPN may also be an effective DBS target to address other forms of central gait failure. PMID- 20971758 TI - Age at onset predicts good seizure outcome in sporadic non-lesional and mesial temporal sclerosis based temporal lobe epilepsy. AB - PURPOSE: To study prognosis and prognostic predictors of sporadic non-lesional temporal lobe epilepsy (TLE). METHOD: 474 patients with TLE were consecutively seen from April 1987 to April 2004. 190 had a sporadic non-lesional TLE and a follow-up longer than 2 years. 284 patients were excluded because of family history for TLE, incomplete history, poor compliance with treatment, psychogenic seizures, no brain MRI study, presence of intracranial lesions except for scattered T2 hyperintense spots on hemispheric white matter or mesial temporal sclerosis (MTS). The following prognostic predictors were considered: age at onset of epilepsy, gender, family history of non-TLE or febrile seizures, perinatal factors, history of febrile seizures, ictal phenomena, MTS and interictal EEG. The end point was time to 24 month seizure freedom after treatment onset. The chi(2) test, Student's t test, Kaplan-Meier survival curves with log rank test (univariate analysis) and Cox proportional hazards regression models (multivariate analysis) were used to assess seizure prognosis and prognostic predictors. RESULTS: At univariate analysis, patients achieving 24 month seizure freedom had a significantly older age at onset of epilepsy (33.5 +/ 19.9 vs 17.2 +/- 14.4 years), and lower occurrence of febrile seizures (11.0% vs 24.4%) and MTS (19.0% vs 35.6%). The chance of remission was directly correlated to age at onset of seizures and inversely correlated to a history of febrile seizures and to the presence of MTS. At multivariate analysis, age at onset of epilepsy was the only significant prognostic predictor. CONCLUSION: Older age at onset predicts better prognosis in sporadic non-lesional TLE. PMID- 20971759 TI - New criteria during right ventricular pacing to determine the mechanism of supraventricular tachycardia. AB - BACKGROUND: Right ventricular pacing (RVP) during supraventricular tachycardia produces progressive QRS fusion before the QRS morphology becomes stable. This transition zone (TZ) may provide useful information for differentiating orthodromic reciprocating tachycardia (ORT) from atrioventricular nodal reentrant tachycardia and atrial tachycardia independent of entrainment success. METHODS AND RESULTS: We studied the effect of properly timed RVP on atrial timing during the TZ in 92 patients with supraventricular tachycardia who had RVP within 40 ms of the tachycardia cycle length. The TZ during RVP includes progressively fused QRS complexes and the first paced complex with a stable QRS morphology based on analysis of the 12-lead ECG. We also measured the stimulus-atrial interval from the end of the TZ and with each QRS complex thereafter until pacing was terminated or ventriculo-atrial block occurred. A fixed stimulus-atrial interval was defined as variation <10 ms during RVP. Atrial preexcitation, postexcitation, or supraventricular tachycardia termination with abrupt ventriculo-atrial block was observed within the TZ in 32 of 34 patients with ORT. A fixed stimulus-atrial interval was established within the TZ in 33 of 34 patients with ORT. At least 1 of these 2 responses was observed in all patients with ORT. None of the patients with atrioventricular nodal reentrant tachycardia or atrial tachycardia had atrial timing perturbed or a fixed stimulus-atrial interval established within the TZ. CONCLUSIONS: During RVP within 40 ms of the tachycardia cycle length, ORT is the likely mechanism when atrial timing is perturbed or a fixed stimulus atrial interval is established within the TZ. PMID- 20971761 TI - Colocalization of voltage-gated Na+ channels with the Na+/Ca2+ exchanger in rabbit cardiomyocytes during development. AB - Reverse-mode activity of the Na(+)/Ca(2+) exchanger (NCX) has been previously shown to play a prominent role in excitation-contraction coupling in the neonatal rabbit heart, where we have proposed that a restricted subsarcolemmal domain allows a Na(+) current to cause an elevation in the Na(+) concentration sufficiently large to bring Ca(2+) into the myocyte through reverse-mode NCX. In the present study, we tested the hypothesis that there is an overlapping expression and distribution of voltage-gated Na(+) (Na(v)) channel isoforms and the NCX in the neonatal heart. For this purpose, Western blot analysis, immunocytochemistry, confocal microscopy, and image analyses were used. Here, we report the robust expression of skeletal Na(v)1.4 and cardiac Na(v)1.5 in neonatal myocytes. Both isoforms colocalized with the NCX, and Na(v)1.5-NCX colocalization was not statistically different from Na(v)1.4-NCX colocalization in the neonatal group. Western blot analysis also showed that Na(v)1.4 expression decreased by sixfold in the adult (P < 0.01) and Na(v)1.1 expression decreased by ninefold (P < 0.01), whereas Na(v)1.5 expression did not change. Although Na(v)1.4 underwent large changes in expression levels, the Na(v)1.4-NCX colocalization relationship did not change with age. In contrast, Na(v)1.5-NCX colocalization decreased ~50% with development. Distance analysis indicated that the decrease in Na(v)1.5-NCX colocalization occurs due to a statistically significant increase in separation distances between Na(v)1.5 and NCX objects. Taken together, the robust expression of both Na(v)1.4 and Na(v)1.5 isoforms and their colocalization with the NCX in the neonatal heart provides structural support for Na(+) current-induced Ca(2+) entry through reverse-mode NCX. In contrast, this mechanism is likely less efficient in the adult heart because the expression of Na(v)1.4 and NCX is lower and the separation distance between Na(v)1.5 and NCX is larger. PMID- 20971760 TI - Vascular complications of cystathionine beta-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research. AB - Homocysteine (Hcy), a cardiovascular and neurovascular disease risk factor, is converted to hydrogen sulfide (H(2)S) through the transsulfuration pathway. H(2)S has attracted considerable attention in recent years for many positive effects on vascular health and homeostasis. Cystathionine beta-synthase (CBS) is the first, and rate-limiting, enzyme in the transsulfuration pathway. Mutations in the CBS gene decrease enzymatic activity, which increases the plasma Hcy concentration, a condition called hyperhomocysteinemia (HHcy). Animal models of CBS deficiency have provided invaluable insights into the pathological effects of transsulfuration impairment and of both mild and severe HHcy. However, studies have also highlighted the complexity of HHcy and the need to explore the specific details of Hcy metabolism in addition to Hcy levels per se. There has been a relative paucity of work addressing the dysfunctional H(2)S production in CBS deficiency that may contribute to, or even create, HHcy-associated pathologies. Experiments using CBS knockout mice, both homozygous (-/-) and heterozygous (+/ ), have provided 15 years of new knowledge and are the focus of this review. These murine models present the opportunity to study a specific mechanism for HHcy that matches one of the etiologies in many human patients. Therefore, the goal of this review was to integrate and highlight the critical information gained thus far from models of CBS deficiency and draw attention to critical gaps in knowledge, with particular emphasis on the modulation of H(2)S metabolism. We include findings from human and animal studies to identify important opportunities for future investigation that should be aimed at generating new basic and clinical understanding of the role of CBS and transsulfuration in cardiovascular and neurovascular disease. PMID- 20971762 TI - p120 regulates endothelial permeability independently of its NH2 terminus and Rho binding. AB - The association of p120-catenin (p120) with the juxtamembrane domain (JMD) of vascular endothelial (VE)-cadherin is required to maintain VE-cadherin levels and transendothelial resistance (TEER) of endothelial cell monolayers. To distinguish whether decreased TEER was due to a loss of p120 and not to the decrease in VE cadherin, we established a system in which p120 was depleted by short hairpin RNA delivered by lentivirus and VE-cadherin was restored via expression of VE cadherin fused to green fluorescent protein (GFP). Loss of p120 resulted in decreased TEER, which was associated with decreased expression of VE-cadherin, beta-catenin, plakoglobin, and alpha-catenin. Decreased TEER was rescued by restoration of p120 but not by the expression of VE-cadherin-GFP, despite localization of VE-cadherin-GFP at cell-cell borders. Expression of VE-cadherin GFP restored levels of beta-catenin and alpha-catenin but not plakoglobin, indicating that p120 may be important for recruitment of plakoglobin to the VE cadherin complex. To evaluate the role of p120 interaction with Rho GTPase in regulating endothelial permeability, we expressed a recombinant form of p120, lacking the NH(2) terminus and containing alanine substitutions, that eliminates binding of Rho to p120. Expression of this isoform restored expression of the adherens junction complex and rescued permeability as measured by TEER. These results demonstrate that p120 is required for maintaining VE-cadherin expression and TEER independently of its NH(2) terminus and its role in regulating Rho. PMID- 20971763 TI - The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension. AB - Hypertension alters cerebrovascular regulation and increases the brain's susceptibility to stroke and dementia. We investigated the temporal relationships between the arterial pressure (AP) elevation induced by "slow pressor" angiotensin II (ANG II) infusion, which recapitulates key features of human hypertension, and the resulting cerebrovascular dysfunction. Minipumps delivering saline or ANG II for 14 days were implanted subcutaneously in C57BL/6 mice (n = 5/group). Cerebral blood flow was assessed by laser-Doppler flowmetry in anesthetized mice equipped with a cranial window. With ANG II (600 ng . kg(-1) . min(-1)), AP started to rise after 9 days (P < 0.05 vs. saline), remained elevated at 11-17 days, and returned to baseline at 21 days (P > 0.05). ANG II attenuated the cerebral blood flow increase induced by neural activity (whisker stimulation) or endothelium-dependent vasodilators, an effect observed before the AP elevation (7 days), as well as after the hypertension subsided (21 days). Nonpressor doses of ANG II (200 ng . kg(-1) . min(-1)) induced cerebrovascular dysfunction and oxidative stress without elevating AP (P > 0.05 vs. saline), whereas phenylephrine elevated AP without inducing cerebrovascular effects. ANG II (600 ng . kg(-1) . min(-1)) augmented neocortical reactive oxygen species (ROS) with a time course similar to that of the cerebrovascular dysfunction. Neocortical application of the ROS scavenger manganic(I-II)meso-tetrakis(4 benzoic acid)porphyrin or the NADPH oxidase peptide inhibitor gp91ds-tat attenuated ROS and cerebrovascular dysfunction. We conclude that the alterations in neurovascular regulation induced by slow pressor ANG II develop before hypertension and persist beyond AP normalization but are not permanent. The findings unveil a striking susceptibility of cerebrovascular function to the deleterious effects of ANG II and raise the possibility that cerebrovascular dysregulation precedes the elevation in AP also in patients with ANG II-dependent hypertension. PMID- 20971764 TI - Endosomal KATP channels as a reservoir after myocardial ischemia: a role for SUR2 subunits. AB - ATP-sensitive K(+) (K(ATP)) channels, composed of inward rectifier K(+) (Kir)6.x and sulfonylurea receptor (SUR)x subunits, are expressed on cellular plasma membranes. We demonstrate an essential role for SUR2 subunits in trafficking K(ATP) channels to an intracellular vesicular compartment. Transfection of Kir6.x/SUR2 subunits into a variety of cell lines (including h9c2 cardiac cells and human coronary artery smooth muscle cells) resulted in trafficking to endosomal/lysosomal compartments, as assessed by immunofluorescence microscopy. By contrast, SUR1/Kir6.x channels efficiently localized to the plasmalemma. The channel turnover rate was similar with SUR1 or SUR2, suggesting that the expression of Kir6/SUR2 proteins in lysosomes is not associated with increased degradation. Surface labeling of hemagglutinin-tagged channels demonstrated that SUR2-containing channels dynamically cycle between endosomal and plasmalemmal compartments. In addition, Kir6.2 and SUR2 subunits were found in both endosomal and sarcolemmal membrane fractions isolated from rat hearts. The balance of these K(ATP) channel subunits shifted to the sarcolemmal membrane fraction after the induction of ischemia. The K(ATP) channel current density was also increased in rat ventricular myocytes isolated from hearts rendered ischemic before cell isolation without corresponding changes in subunit mRNA expression. We conclude that an intracellular pool of SUR2-containing K(ATP) channels exists that is derived by endocytosis from the plasma membrane. In cardiac myocytes, this pool can potentially play a cardioprotective role by serving as a reservoir for modulating surface K(ATP) channel density under stress conditions, such as myocardial ischemia. PMID- 20971766 TI - Phosphorescence quenching microrespirometry of skeletal muscle in situ. AB - We have developed an optical method for the evaluation of the oxygen consumption (Vo(2)) in microscopic volumes of spinotrapezius muscle. Using phosphorescence quenching microscopy (PQM) for the measurement of interstitial Po(2), together with rapid pneumatic compression of the organ, we recorded the oxygen disappearance curve (ODC) in the muscle of the anesthetized rats. A 0.6-mm diameter area in the tissue, preloaded with the phosphorescent oxygen probe, was excited once a second by a 532-nm Q-switched laser with pulse duration of 15 ns. Each of the evoked phosphorescence decays was analyzed to obtain a sequence of Po(2) values that constituted the ODC. Following flow arrest and tissue compression, the interstitial Po(2) decreased rapidly and the initial slope of the ODC was used to calculate the Vo(2). Special analysis of instrumental factors affecting the ODC was performed, and the resulting model was used for evaluation of Vo(2). The calculation was based on the observation of only a small amount of residual blood in the tissue after compression. The contribution of oxygen photoconsumption by PQM and oxygen inflow from external sources was evaluated in specially designed tests. The average oxygen consumption of the rat spinotrapezius muscle was Vo(2) = 123.4 +/- 13.4 (SE) nl O(2)/cm(3) . s (N = 38, within 6 muscles) at a baseline interstitial Po(2) of 50.8 +/- 2.9 mmHg. This technique has opened the opportunity for monitoring respiration rates in microscopic volumes of functioning skeletal muscle. PMID- 20971767 TI - A high-fructose diet worsens eccentric left ventricular hypertrophy in experimental volume overload. AB - The development of left ventricular (LV) hypertrophy (LVH) can be affected by diet manipulation. Concentric LVH resulting from pressure overload can be worsened by feeding rats with a high-fructose diet. Eccentric LVH is a different type of hypertrophy and is associated with volume overload (VO) diseases. The impact of an abnormal diet on the development of eccentric LVH and on ventricular function in chronic VO is unknown. This study therefore examined the effects of a fructose-rich diet on LV eccentric hypertrophy, ventricular function, and myocardial metabolic enzymes in rats with chronic VO caused by severe aortic valve regurgitation (AR). Wistar rats were divided in four groups: sham-operated on control diet (SC; n = 13) or fructose-rich diet (SF; n = 13) and severe aortic regurgitation fed with the same diets [aortic regurgitation on control diet (ARC), n = 16, and aortic regurgitation on fructose-rich diet (ARF), n = 13]. Fructose-rich diet was started 1 wk before surgery, and the animals were euthanized 9 wk later. SF and ARF had high circulating triglycerides. ARC and ARF developed significant LV eccentric hypertrophy after 8 wk as expected. However, ARF developed more LVH than ARC. LV ejection fraction was slightly lower in the ARF compared with ARC. The increased LVH and decreased ejection fraction could not be explained by differences in hemodynamic load. SF, ARC, and ARF had lower phosphorylation levels of the AMP kinase compared with SC. A fructose-rich diet worsened LV eccentric hypertrophy and decreased LV function in a model of chronic VO caused by AR in rats. Normal animals fed the same diet did not develop these abnormalities. Hypertriglyceridemia may play a central role in this phenomenon as well as AMP kinase activity. PMID- 20971768 TI - Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent. AB - Activation of AMP-activated protein kinase (AMPK) induces vasorelaxation in arteries from healthy animals, but the mechanisms coordinating this effect are unclear and the integrity of this response has not been investigated in dysfunctional arteries of hypertensive animals. Here we investigate the mechanisms of relaxation to the AMPK activator 5-aminoimidazole-4-carboxamide 1 beta-D-ribofuranoside (AICAR) in isolated thoracic aorta rings from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Although AICAR generated dose-dependent (10(-6)-10(-2) M) relaxation in precontracted WKY and SHR aortic rings with (E(+)) or without (E(-)) endothelium, relaxation was enhanced in E(+) rings. Relaxation in SHR E(+) rings was also enhanced at low [AICAR] (10(-6) M) compared with that of WKY (57 +/- 8% vs. 3 +/- 2% relaxation in SHR vs. WKY E(+)), but was similar and near 100% in both groups at high [AICAR]. Pharmacological dissection showed that the mechanisms responsible for the endothelium-dependent component of relaxation across the dose range of AICAR are exclusively nitric oxide (NO) mediated in WKY rings, but partly NO dependent and partly cyclooxygenase (COX) dependent in SHR vessels. Further investigation revealed that ACh-stimulated COX-endothelium-derived contracting factors (EDCF) mediated contractions were suppressed by AICAR, and this effect was reversed in the presence of the AMPK inhibitor Compound C in quiescent E(+) SHR aortic rings. Western blots demonstrated that P(Thr(172))-AMPK and P(Ser(79))-acetyl-CoA carboxylase (indexes of AMPK activation) were elevated in SHR versus WKY E(+) rings at low AICAR (~2-fold). Together these findings suggest that AMPK-mediated inhibition of EDCF-dependent contraction and elevated AMPK activation may contribute to the enhanced sensitivity of SHR E(+) rings to AICAR. These results demonstrate AMPK-mediated vasorelaxation is present and enhanced in arteries of SHR and suggest that activation of AMPK may be a potential strategy to improve vasomotor dysfunction by suppressing enhanced endoperoxide-mediated contraction and enhancing NO-mediated relaxation. PMID- 20971770 TI - Signaling through the Na/K-ATPase: implications for cardiac fibrosis. PMID- 20971769 TI - Knockout of insulin receptors in cardiomyocytes attenuates coronary arterial dysfunction induced by pressure overload. AB - Ablating insulin receptors in cardiomyocytes causes subendocardial fibrosis and left ventricular (LV) dysfunction after 4 wk of transverse aortic constriction (TAC). To determine whether these maladaptive responses are precipitated by coronary vascular dysfunction, we studied mice with cardiomyocyte-restricted knock out of insulin receptors (CIRKO) and wild-type (WT) TAC mice before the onset of overt LV dysfunction. Two weeks of TAC produced comparable increases (P < 0.05 vs. respective sham) in heart weight/body weight (mg/g) in WT-TAC (8.03 +/ 1.14, P < 0.05 vs. respective sham) and CIRKO-TAC (7.76 +/- 1.25, P < 0.05 vs. respective sham) vs. WT-sham (5.64 +/- 0.11) and CIRKO-sham (4.64 +/- 0.10) mice. In addition, 2 wk of TAC were associated with similar LV geometry and function (echocardiography) and interstitial fibrosis (picrosirius red staining) in CIRKO and WT mice. Responses to acetylcholine (ACh), N(G)-monomethyl-L-arginine (l NMMA), and sodium nitroprusside (SNP) were measured in coronary arteries that were precontracted to achieve ~70% of maximal tension development using the thromboxane A(2) receptor mimetic U-46619 (~3 * 10(-6) M). ACh-evoked vasorelaxation was absent in WT-TAC but was present in CIRKO-TAC albeit reduced relative to sham-operated animals. l-NMMA-evoked tension development was similar in vessels from CIRKO-TAC mice but was lower (P < 0.05) in WT-TAC animals vs. the respective sham-operated groups, and SNP-evoked vasorelaxation was similar among all mice. Thus estimates of stimulated and basal endothelial nitric oxide release were better preserved in CIRKO vs. WT mice in response to 2 wk of TAC. These findings indicate that maladaptive LV remodeling previously observed in CIRKO-TAC mice is not precipitated by coronary artery dysfunction, because CIRKO mice exhibit compensatory mechanisms (e.g., increased eNOS transcript and protein) to maintain coronary endothelial function in the setting of pressure overload. PMID- 20971771 TI - Stress-induced opening of the permeability transition pore in the dystrophin deficient heart is attenuated by acute treatment with sildenafil. AB - Susceptibility of cardiomyocytes to stress-induced damage has been implicated in the development of cardiomyopathy in Duchenne muscular dystrophy, a disease caused by the lack of the cytoskeletal protein dystrophin in which heart failure is frequent. However, the factors underlying the disease progression are unclear and treatments are limited. Here, we tested the hypothesis of a greater susceptibility to the opening of the mitochondrial permeability transition pore (PTP) in hearts from young dystrophic (mdx) mice (before the development of overt cardiomyopathy) when subjected to a stress protocol and determined whether the prevention of a PTP opening is involved in the cardioprotective effect of sildenafil, which we have previously reported in mdx mice. Using the 2-deoxy [(3)H]glucose method to quantify the PTP opening in ex vivo perfused hearts, we demonstrate that when compared with those of controls, the hearts from young mdx mice subjected to ischemia-reperfusion (I/R) display an excessive PTP opening as well as enhanced activation of cell death signaling, mitochondrial oxidative stress, cardiomyocyte damage, and poorer recovery of contractile function. Functional analyses in permeabilized cardiac fibers from nonischemic hearts revealed that in vitro mitochondria from mdx hearts display normal respiratory function and reactive oxygen species handling, but enhanced Ca(2+) uptake velocity and premature opening of the PTP, which may predispose to I/R-induced injury. The administration of a single dose of sildenafil to mdx mice before I/R prevented excessive PTP opening and its downstream consequences and reduced tissue Ca(2+) levels. Furthermore, mitochondrial Ca(2+) uptake velocity was reduced following sildenafil treatment. In conclusion, beyond our documentation that an increased susceptibility to the opening of the mitochondrial PTP in the mdx heart occurs well before clinical signs of overt cardiomyopathy, our results demonstrate that sildenafil, which is already administered in other pediatric populations and is reported safe and well tolerated, provides efficient protection against this deleterious event, likely by reducing cellular Ca(2+) loading and mitochondrial Ca(2+) uptake. PMID- 20971772 TI - Percutaneous image-guided adrenal cryoablation: procedural considerations and technical success. AB - PURPOSE: To assess safety, technical success, complications, and hemodynamic changes associated with the adrenal cryoablation procedure. MATERIALS AND METHODS: This retrospective review was approved by the institutional review board, with waiver of informed consent, and was compliant with the Health Insurance Portability and Accountability Act. Adult patients with adrenal metastasis who were treated with adrenal cryoablation between May 2005 and October 2009 were eligible for this review. Twelve patients (undergoing 13 procedures) with single adrenal tumors were included in the analysis. For statistical analysis, hemodynamic data were averaged for the patient undergoing the procedure twice. Technical success, safety, and local control were analyzed according to standard criteria. Hemodynamic changes during the procedure were analyzed and compared with data from an unmatched cohort of patients who underwent kidney (not in the upper pole) cryoablation (Wilcoxon rank sum test). A further subanalysis of hemodynamic changes was performed on the basis of whether preprocedural alpha- or beta-adrenergic blockade was used. RESULTS: With adrenal cryoablation, local control was achieved following treatment in 11 (92%; 95% confidence interval: 65.1%, 99.6%) of 12 tumors. One patient with known adrenal insufficiency underwent conservative ablation and developed ipsilateral adrenal recurrence, which was retreated. Five patients developed hypertensive crisis during the final, active thaw phase of the cryoablation procedure, and one patient developed hypertensive crisis in the immediate postablation period. Patients undergoing adrenal cryoablation experienced a significant increase in systolic blood pressure (P = .005), pulse pressure (P = .02), and mean arterial pressure (P = .01) when compared with the cohort of kidney cryoablation patients. Adrenal cryoablation patients who were not premedicated with an alpha-blocker (n = 5) had a higher level of systolic blood pressure increase during the cryoablation procedure when compared with their counterparts who were premedicated (n = 7) (P = .034). CONCLUSION: Adrenal cryoablation is technically feasible with a high rate of local control. Patients premedicated with the alpha blocker phenoxybenzamine appear to have a reduced risk of hypertensive crisis. PMID- 20971773 TI - Benign papilloma without atypia diagnosed at US-guided 14-gauge core-needle biopsy: clinical and US features predictive of upgrade to malignancy. AB - PURPOSE: To evaluate the diagnostic accuracy of ultrasonographically (US)-guided 14-gauge core-needle biopsy (CNB) for benign papilloma without atypia and to determine whether clinical and radiologic features could be used to predict an upgrade to malignancy. MATERIALS AND METHODS: This was an institutional review board-approved retrospective study, with a waiver of informed consent. The histologic results of US-guided CNB procedures performed from January 2006 through January 2009 were reviewed. A total of 160 benign papillomas without atypia that were diagnosed at CNB and excised surgically in 143 women (age range, 19-77 years) were assessed. Medical records and sonograms in the women were reviewed. Two radiologists working in consensus correlated imaging findings with the biopsy result to determine concordance. For the upgrade to malignancy after excision, malignant lesions were compared with nonmalignant lesions for the collected clinical and radiologic variables, which included patient age, lesion size, and lesion distance from the nipple, by using the chi(2) or Fisher exact test for categoric variables and the Mann-Whitney U test for continuous variables. RESULTS: Eight (5.0%) of 160 papillomas were upgraded to malignancy. Lesions that were 1 cm or larger (seven [11%] of 63) showed a higher upgrade rate than lesions that were smaller than 1 cm (one [1%] of 97) (P = .006). The upgrade rate was higher in patients aged 50 years or older (six [16%] of 37) than in patients younger than 50 years (two [2%] of 123) (P = .002). Lesions that were 3 cm or farther from the nipple (four [13%] of 31) showed a higher upgrade rate than lesions that were less than 3 cm from the nipple (four [3.1%] of 129) (P = .046). Upgrade rates for Breast Imaging Reporting and Data System (BI-RADS) category 3, 4a, 4b, 4c, and 5 lesions were 0%, 2.5%, 6%, 27%, and 25%, respectively (P = .010). CONCLUSION: At US-guided 14-gauge CNB, benign papilloma without atypia could be diagnosed accurately. Discordance between imaging and pathology results, as well as patient age of 50 years or older, lesion size of 1 cm or greater, lesion distance from the nipple of 3 cm or greater, and BI-RADS category may be helpful in predicting the possibility of upgrade to malignancy. PMID- 20971774 TI - Ankylosing spondylitis: patterns of radiographic involvement--a re-examination of accepted principles in a cohort of 769 patients. AB - PURPOSE: To re-examine the patterns of radiographic involvement in ankylosing spondylitis (AS). MATERIALS AND METHODS: This prospective study had institutional review board approval, and 769 patients with AS (556 men, 213 women; mean age, 47.1 years; age range, 18-87 years) provided written informed consent. Radiographs of the cervical spine, lumbar spine, pelvis, and hips were scored by using the Bath Ankylosing Spondylitis Radiology Index (BASRI) by an experienced radiologist. Differences in sacroiliitis grade between right and left sacroiliac joints, frequency of cervical- and lumbar-predominant involvement by sex, frequency of progression to complete spinal fusion, and association between hip arthritis and spinal involvement were computed for the cohort overall and for subgroups defined according to duration of AS in 10-year increments. RESULTS: Symmetric sacroiliitis was seen in 86.1% of patients. Lumbar predominance was more common during the first 20 years of the disease, after which the cervical spine and lumbar spine were equally involved. Men and women were equally likely to have cervical-predominant involvement. Complete spinal fusion was observed in 27.9% of patients with AS for more than 30 years and in 42.6% of patients with AS for more than 40 years. Patients with BASRI hip scores of 2 or greater had significantly higher BASRI spine scores. CONCLUSION: There were no sex differences in cervical-predominant involvement in AS. Hip arthritis was strongly associated with worse spinal involvement. PMID- 20971775 TI - Right and left ventricular myocardial perfusion reserves correlate with right ventricular function and pulmonary hemodynamics in patients with pulmonary arterial hypertension. AB - PURPOSE: To evaluate the relationships of right ventricular (RV) and left ventricular (LV) myocardial perfusion reserves with ventricular function and pulmonary hemodynamics in patients with pulmonary arterial hypertension (PAH) by using adenosine stress perfusion cardiac magnetic resonance (MR) imaging. MATERIALS AND METHODS: This HIPAA-compliant study was institutional review board approved. Twenty-five patients known or suspected to have PAH underwent right heart catheterization and adenosine stress MR imaging on the same day. Sixteen matched healthy control subjects underwent cardiac MR imaging only. RV and LV perfusion values at rest and at adenosine-induced stress were calculated by using the Fermi function model. The MR imaging-derived RV and LV functional data were calculated by using dedicated software. Statistical testing included Kruskal Wallis tests for continuous data, Spearman rank correlation tests, and multiple linear regression analyses. RESULTS: Seventeen of the 25 patients had PAH: 11 with scleroderma-associated PAH, and six with idiopathic PAH. The remaining eight patients had scleroderma without PAH. The myocardial perfusion reserve indexes (MPRIs) in the PAH group (median RV MPRI, 1.7 [25th-75th percentile range, 1.3 2.0]; median LV MPRI, 1.8 [25th-75th percentile range, 1.6-2.1]) were significantly lower than those in the scleroderma non-PAH (median RV MPRI, 2.5 [25th-75th percentile range, 1.8-3.9] [P = .03]; median LV MPRI, 4.1 [25th-75th percentile range, 2.6-4.8] [P = .0003]) and control (median RV MPRI, 2.9 [25th 75th percentile range, 2.6-3.6] [P < .01]; median LV MPRI, 3.6 [25th-75th percentile range, 2.7-4.1] [P < .01]) groups. There were significant correlations between biventricular MPRI and both mean pulmonary arterial pressure (mPAP) (RV MPRI: rho = -0.59, Bonferroni P = .036; LV MPRI: rho = -0.79, Bonferroni P < .002) and RV stroke work index (RV MPRI: rho = -0.63, Bonferroni P = .01; LV MPRI: rho = -0.75, Bonferroni P < .002). In linear regression analysis, mPAP and RV ejection fraction were independent predictors of RV MPRI. mPAP was an independent predictor of LV MPRI. CONCLUSION: Biventricular vasoreactivity is significantly reduced with PAH and inversely correlated with RV workload and ejection fraction, suggesting that reduced myocardial perfusion reserve may contribute to RV dysfunction in patients with PAH. PMID- 20971776 TI - Correlation of carotid artery atherosclerotic lesion echogenicity and severity at standard US with intraplaque neovascularization detected at contrast-enhanced US. AB - PURPOSE: To correlate echogenicity and severity of atherosclerotic carotid artery lesions at standard ultrasonography (US) with the degree of intraplaque neovascularization at contrast material-enhanced (CE) US. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the local ethics committee, and all patients provided informed consent. A total of 175 patients (113 [65%] men, 62 [35%] women; mean age, 67 years +/- 10 [standard deviation]) underwent standard and CE US of the carotid artery. Lesion echogenicity (class I to IV), degree of stenosis, and maximal lesion thickness were evaluated for each documented atherosclerotic lesion. The degree of intraplaque neovascularization at CE US was categorized as absent (grade 1), moderate (grade 2), or extensive (grade 3). Correlation of neovascularization with echogenicity, degree of stenosis, and maximal lesion thickness was made by using Spearman rho and chi(2) test for trend. RESULTS: In a total of 293 atherosclerotic lesions, echogenicity was inversely correlated with grade of intraplaque neovascularization (rho = -0.199, P < .001). More echolucent lesions had a higher degree of neovascularization compared with more echogenic ones (P < .001). The degree of stenosis was significantly correlated with grade of intraplaque neovascularization (rho = 0.157, P = .003). Lesions with higher degree of stenosis had higher grade of neovascularization (P = .008), and maximal lesion thickness increased with the grade of neovascularization (P < .001) and was significantly correlated with grade of neovascularization (rho = 0.233, P < .001). CONCLUSION: Neovascularization visualized with CE US correlates with lesion severity and with morphologic features of plaque instability, contributing to the concept that more vulnerable plaques are more likely to have a greater degree of neovascularization. Therefore, CE US may be a valuable tool for further risk stratification of echolucent atherosclerotic lesions and carotid artery stenosis of different degrees. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10101008/-/DC1. PMID- 20971777 TI - Volume CT dose index and dose-length product displayed during CT: what good are they? AB - The average medical radiation effective dose to the U.S. population in 2006 was estimated at approximately 3.0 mSv, an increase of 600% in a single generation. Computed tomography (CT) alone accounts for approximately half of this medical radiation dose. Ongoing advances suggest that CT will continue to be the most important contributor, by far, to medical doses in the United States. The use of ionizing radiation in medical imaging, including CT, provides valuable diagnostic information that undoubtedly benefits many patients. Exposure to radiation, however, is currently believed to carry a small, but nonzero, risk. Accordingly, the medical imaging community must ensure that the benefits of a radiologic examination in any given patient exceed the corresponding risks. It is also the responsibility of the radiologist to ensure that no more radiation is used than needed for obtaining diagnostic information in any radiologic examination, especially CT. PMID- 20971778 TI - Fluorocapsules for improved function, immunoprotection, and visualization of cellular therapeutics with MR, US, and CT imaging. AB - PURPOSE: To develop novel immunoprotective alginate microcapsule formulations containing perfluorocarbons (PFCs) that may increase cell function, provide immunoprotection for xenografted cells, and simultaneously enable multimodality imaging. MATERIALS AND METHODS: All animal experiments were approved by an Institutional Animal Care and Use Committee. Cadaveric human islet cells were encapsulated with alginate, poly-l-lysine, and perfluorooctyl bromide (PFOB) or perfluoropolyether (PFPE). In vitro viability and the glucose-stimulation index for insulin were determined over the course of 2 weeks and analyzed by using a cross-sectional time series regression model. The sensitivity of multimodality (computed tomography [CT], ultrasonography [US], and fluorine 19 [(19)F] magnetic resonance [MR] imaging) detection was determined for fluorocapsules embedded in gel phantoms. C57BL/6 mice intraperitoneally receiving 6000 PFOB-labeled (n = 6) or 6000 PFPE-labeled (n = 6) islet-containing fluorocapsules and control mice intraperitoneally receiving 6000 PFOB-labeled (n = 6) or 6000 PFPE-labeled (n = 6) fluorocapsules without islets were monitored for human C-peptide (insulin) secretion during a period of 55 days. Mice underwent (19)F MR imaging at 9.4 T and micro-CT. Swine (n = 2) receiving 9000 PFOB capsules through renal artery catheterization were imaged with a clinical multidetector CT scanner. Signal intensity was evaluated by using a paired t test. RESULTS: Compared with nonfluorinated alginate microcapsules, PFOB fluorocapsules increased insulin secretion of encapsulated human islets, with values up to 18.5% (3.78 vs 3.19) at 8-mmol/L glucose concentration after 7 days in culture (P < .001). After placement of the immunoprotected encapsulated cells into mice, a sustained insulin release was achieved with human C-peptide levels of 19.1 pmol/L +/- 0.9 (standard deviation) and 33.0 pmol/L +/- 1.0 for PFPE and PFOB capsules, respectively. Fluorocapsules were readily visualized with (19)F MR imaging, US imaging, and CT with research- and clinical-grade imagers for all modalities. CONCLUSION: Fluorocapsules enhance glucose responsiveness and insulin secretion in vitro, enable long-term insulin secretion by xenografted islet cells in vivo, and represent a novel contrast agent platform for multimodality imaging. PMID- 20971780 TI - Review paper: absorbable polymeric surgical sutures: chemistry, production, properties, biodegradability, and performance. AB - Among biomaterials used as implants in human body, sutures constitute the largest groups of materials having a huge market exceeding $1.3 billion annually. Sutures are the most widely used materials in wound closure and have been in use for many centuries. With the development of the synthetic absorbable polymer, poly(glycolic acid) (PGA) in the early 1970s, a new chapter has opened on absorbable polymeric sutures that got unprecedented commercial successes. Although several comparative evaluations of suture materials have been published, there were no serious attempts of late on a comprehensive review of production, properties, biodegradability, and performance of suture materials. This review proposes to bring to focus scattered data on chemistry, properties, biodegradability, and performance of absorbable polymeric sutures. PMID- 20971779 TI - Computer-aided classification of breast masses: performance and interobserver variability of expert radiologists versus residents. AB - PURPOSE: To evaluate the interobserver variability in descriptions of breast masses by dedicated breast imagers and radiology residents and determine how any differences in lesion description affect the performance of a computer-aided diagnosis (CAD) computer classification system. MATERIALS AND METHODS: Institutional review board approval was obtained for this HIPAA-compliant study, and the requirement to obtain informed consent was waived. Images of 50 breast lesions were individually interpreted by seven dedicated breast imagers and 10 radiology residents, yielding 850 lesion interpretations. Lesions were described with use of 11 descriptors from the Breast Imaging Reporting and Data System, and interobserver variability was calculated with the Cohen kappa statistic. Those 11 features were selected, along with patient age, and merged together by a linear discriminant analysis (LDA) classification model trained by using 1005 previously existing cases. Variability in the recommendations of the computer model for different observers was also calculated with the Cohen kappa statistic. RESULTS: A significant difference was observed for six lesion features, and radiology residents had greater interobserver variability in their selection of five of the six features than did dedicated breast imagers. The LDA model accurately classified lesions for both sets of observers (area under the receiver operating characteristic curve = 0.94 for residents and 0.96 for dedicated imagers). Sensitivity was maintained at 100% for residents and improved from 98% to 100% for dedicated breast imagers. For residents, the computer model could potentially improve the specificity from 20% to 40% (P < .01) and the kappa value from 0.09 to 0.53 (P < .001). For dedicated breast imagers, the computer model could increase the specificity from 34% to 43% (P = .16) and the kappa value from 0.21 to 0.61 (P < .001). CONCLUSION: Among findings showing a significant difference, there was greater interobserver variability in lesion descriptions among residents; however, an LDA model using data from either dedicated breast imagers or residents yielded a consistently high performance in the differentiation of benign from malignant breast lesions, demonstrating potential for improving specificity and decreasing interobserver variability in biopsy recommendations. PMID- 20971781 TI - Admissions related to alcohol. Political nystagmus. PMID- 20971783 TI - Spain takes tough stance on smoking with new legislation. PMID- 20971784 TI - Health technology assessments: what do differing conclusions tell us? PMID- 20971785 TI - Ethics experts agree that {pound}250 cap for egg donation should be lifted. PMID- 20971786 TI - Change in optic nerve head topography in healthy volunteers: an 11-year follow up. AB - AIM: To study longitudinal changes in optic nerve head (ONH) topography in healthy volunteers. METHODS: One eye each of 36 healthy volunteers was prospectively followed for 11 (7-13) years with the Heidelberg Retina Tomograph I (HRT I). All eyes had normal visual fields, non-glaucomatous ONHs, no defects on red-free nerve fibre layer photographs and intraocular pressure (IOP) <22 mm Hg. During the follow-up, no eye developed glaucoma; visual fields remained normal, and no longitudinal changes appeared in nerve fibre layers assessed from red-free photographs or ONHs assessed from stereophotographs. The median baseline and follow-up IOPs were comparable (15 mm Hg, range 10-20 mm Hg; and 16 mm Hg; range 10 to 22 mm Hg, respectively; p=0.38). Images were re-evaluated with HRT III and ONHs graded as normal, borderline or glaucomatous with the Moorfield Regression Analysis (MRA). RESULTS Significant changes in HRT parameters indicating increased ONH cupping were detected in cup area (p=0.013), cup-to disc area ratio (p=0.015), rim area (p=0.015), mean cup depth (p=0.006) and cup shape measure (p<0.001). With the MRA classification, nine eyes (9/31, 29%) had changed for the worse in the global or any of the sector classifications. CONCLUSION: Age dependent changes occur in ONH topography detectable with the HRT. PMID- 20971787 TI - The repeatability of the MPS 9000 macular pigment screener. PMID- 20971788 TI - Evidence that neurites in human epiretinal membranes express melanopsin, calretinin, rod opsin and neurofilament protein. AB - AIMS: We have previously identified neurofilament-protein-containing neurites in human epiretinal membranes (ERMs). The aim of this study was to further characterise these neurites by examining the expression of additional specific proteins in human ERMs and to correlate this expression with various retinal disease conditions. METHODS: Epiretinal membranes originating from 43 patients with proliferative vitreoretinopathy (PVR), proliferative diabetic retinopathy (PDR) or with no known pathology (idiopathic epiretinal membrane; iERM) were removed during vitrectomy at varying durations after diagnosis and immediately placed in fixative. The membranes were labelled immunohistochemically with different combinations of antibodies to the proteins melanopsin, calretinin and neurofilament (to identify subclasses of ganglion cells), rod opsin (to identify rod photoreceptors), synaptophysin and synaptic vesicle glycoprotein 2A (SV2) (identifies synaptic vesicles) and vimentin (identifies glial cells). RESULTS: Anti-melanopsin-, anti-calretinin-, anti-neurofilament- and anti-rod-opsin labelled neurites were routinely observed in the epiretinal membranes. Their presence did not appear to correlate with a specific disease condition or duration of the membrane. Generally neurites were observed in regions of glial cells. CONCLUSIONS: Based on the expression of selected markers for neurites, we show neurite processes in human ERMs of various aetiologies originating from rod photoreceptors and different populations of retinal ganglion cells, although there was no obvious correlation with specific disease condition. In addition, synaptophysin and SV2 labelling was observed associated with all types of neurites, indicating the presence of at least one component necessary for synaptic transmission. Our data suggest that the adult human retina retains a significant capacity for neuronal remodelling under various disease conditions. PMID- 20971789 TI - Distress, depression and coping in HLA-B27-associated anterior uveitis with focus on gender differences. AB - BACKGROUND/AIMS: To evaluate depression, coping with disease and stress, and the subjective impression of distress and/or life events as triggers for recurrences in HLA-B27-associated anterior uveitis (B27-AU), with attention to gender specific characteristics. METHODS: 171 patients with a history of B27-AU responded to a postal survey performed between January 2006 and April 2008 using standardised psychological questionnaires: Beck Depression Inventory, Freiburg Questionnaire on Coping with Illness, and Stress Coping Inventory. RESULTS: Patients with B27-AU differed from healthy controls showing more depressive symptoms (Beck Depression Inventory, 31.6%), applying characteristic disease coping as well as negative stress coping strategies. Female B27-AU patients tended to react with depression and male patients to use negative stress coping strategies. 57.9% of patients believed that psychological distress was a trigger for relapses, and 34.5% stated specific life events. Together, this group of patients achieved higher depression scores and used more negative disease and stress coping styles than patients without perception of distress. CONCLUSION: Patients with B27-AU patients exhibited significant psychopathology concerning depression and disease coping. Distress and life events were subjectively suspected to be a trigger. By imparting knowledge to the patients on probable development of depressive moods and the role of stress/life events as trigger for relapses, as well as offering behaviour therapy to optimise coping, may help patients to cope better with B27-AU. PMID- 20971790 TI - The conclusions of Clemson et al concerning valproic acid are premature. PMID- 20971791 TI - Intravitreal bevacizumab (Avastin) versus ranibizumab (Lucentis) for the treatment of age-related macular degeneration: a safety review. AB - AIM: To conduct a systematic review in order to compare adverse effects (AE) and the reporting of harm in randomised controlled trials (RCTs) and non-RCTs evaluating intravitreal ranibizumab and bevacizumab in age-related macular degeneration. METHODS: Medline, Embase and the Cochrane Library were searched with no limitations of language and year of publication. Studies which compared bevacizumab or ranibizumab as monotherapy with any other control group were included. Case series were included if they met predefined quality standards. RESULTS: The 2 year results of phase III trials evaluating ranibizumab show that the rates of serious ocular AE were low (<=2.1%) but indicate major safety concerns (RR 3.13, 95% CI 1.10 to 8.92). A possible signal with regard to thromboembolic events (RR 1.35, 95% CI 0.66 to 2.77) and a significant increase in non-ocular haemorrhage (RR 1.62, 95% CI 1.03 to 2.55) were also noted. In contrast to ranibizumab trials, the RCTs evaluating bevacizumab are of limited value. The main shortcomings are small sample sizes and an apparent lack of rigorous monitoring for AE. A critical assessment of the large number of published case series evaluating bevacizumab also shows that no reliable conclusions on safety can be drawn using this study design. Therefore, any perception that intravitreal bevacizumab injections are not associated with major ocular or systemic AE are not supported by reliable data. CONCLUSION: The bevacizumab studies show too many methodological limitations to rule out any major safety concerns. Higher evidence from ranibizumab trials suggests signals for an increased ocular and systemic vascular and haemorrhagic risk which warrants further investigation. PMID- 20971792 TI - Gamma knife radiosurgery for primary orbital varices: a preliminary report. AB - AIM: The aim of this retrospective study is to evaluate the authors' experience using gamma knife radiosurgery in the management of primary orbital varices. METHODS: Fourteen patients, six males and eight females, with ages ranging from 7 to 56 years of age, were treated with gamma knife radiosurgery from April 2001 to June 2005 for primary orbital varices. The median prescription peripheral dose was 16 Gy, ranging from 15 to 20 Gy, and the median maximum dose was 32 Gy, ranging from 30 to 40 Gy. The median volume of the lesion at radiosurgery was 4.5 ml (range 1.9 ml to 9.0 ml). The mean dose to optic nerve was below 10 Gy. A mean of 10 isocentres (range 8 to 13) were used for treating these lesions. RESULTS: At a median follow-up period of 36 months (range 18 to 66 months), recurrent exophthalmos and diplopia resolved in 10 patients. Two of the remaining four patients showed evidence of decrease in distensibility, while the other two remain unchanged. The median time of their presenting symptoms resolving was 7 months (range 3 to 18 months). One patient lost her sight 18 months after gamma knife radiosurgery. No patient had intraorbital haemorrhage after treatment. CONCLUSION: Gamma knife radiosurgery provides effective long-term relief of symptoms in selected patients with primary orbital varices. PMID- 20971793 TI - Dynamic interaction of formin proteins and cytoskeleton in mouse oocytes during meiotic maturation. AB - Formin-2 (Fmn2) nucleates actin filaments required for spindle migration during the metaphase of meiosis I in mouse oocytes. While recent studies showed that Fmn2 is involved in the formation of a dynamic actin meshwork on meiotic spindle and the migration of chromosomes, the precise location and the mechanism of action of Fmn2 in the mouse oocyte is not known. In this work, we show that Fmn2 is colocalized with spindle during metaphase I (MI) and this pattern is lost in nocodazole-treated oocytes. Fmn2 directly interacts with polymerized microtubules (MTs) in vitro via a well-conserved domain called formin homology 2 (FH2). Microinjection of mRNA encoding formin homology 1 (FH1)FH2 domains of Fmn2 into Fmn2-/- oocytes partially rescued the defect of polar body extrusion, while mRNAs encoding FH2 domain alone could not rescue the defect. mDia1 and mDia2, Diaphanous (Dia) subfamily of formin proteins, exhibit unique patterns of expression in mouse oocytes. While mDia1 is localized on meiotic spindle, mDia2 localization is confined in spindle poles similar to gamma-tubulin. Collectively, our results suggest that the ability of Fmn2 to directly interact with MTs and to polymerize actins via the conserved FH1FH2 domains is crucial for chromosomal migration in MI oocytes. We also show that mDia1 and mDia2 are dynamic components of meiotic spindle and pole complex during meiotic maturation of oocytes. PMID- 20971794 TI - Re: "Chronic disease in men with newly diagnosed cancer: a nested case-control study". PMID- 20971799 TI - Regulation of leptin synthesis in white adipose tissue of the female fruit bat, Cynopterus sphinx: role of melatonin with or without insulin. AB - Factors regulating leptin synthesis during adipogenesis in wild species are not well known. Studies in the female Cynopterus sphinx bat have shown that it undergoes seasonal changes in its fat deposition and serum leptin and melatonin levels. The aim of the present study was to investigate the hormonal regulation of leptin synthesis by the white adipose tissue during the period of fat deposition in female C. sphinx. This study showed a significant correlation between the seasonal changes in serum melatonin level with the circulating leptin level (r = 0.78; P < 0.05) and with the changes in body fat mass (r = 0.88; P < 0.05) in C. sphinx. A significant correlation between circulating insulin and leptin levels (r = 0.65; P < 0.05) was also found in this species. This in vivo finding suggests that melatonin together with insulin may enhance leptin synthesis by increasing adipose tissue accumulation. The in vitro study showed that melatonin interacts synergistically with insulin in stimulating leptin synthesis by adipose tissue in C. sphinx. The study showed MT(2) receptors in adipose tissue and a stimulatory effect of melatonin on leptin synthesis, which was blocked by treatment with an MT(2) receptor antagonist, suggesting that the effect of melatonin on leptin synthesis by adipose tissue is mediated through the MT(2) receptor in C. sphinx. The in vitro study showed that the synthesis of leptin is directly proportional to the amount of glucose uptake by the adipose tissue. It further showed that melatonin together with insulin synergistically enhanced the leptin synthesis by adipose tissue through phosphorylation of mitogen-activated protein kinase in C. sphinx. PMID- 20971800 TI - Exercise and vascular adaptation in asymptomatic humans. AB - Beneficial effects of exercise training on the vasculature have been consistently reported in subjects with cardiovascular risk factors or disease, whereas studies in apparently healthy subjects have been less uniform. In this review, we examine evidence pertaining to the impact of exercise training on conduit and resistance vessel function and structure in asymptomatic subjects. Studies of arterial function in vivo have mainly focused on the endothelial nitric oxide dilator system, which has generally been shown to improve following training. Some evidence suggests that the magnitude of benefit depends upon the intensity or volume of training and the relative impact of exercise on upregulation of dilator pathways versus effects of inflammation and/or oxidation. Favourable effects of training on autonomic balance, baroreflex function and brainstem modulation of sympathetic control have been reported, but there is also evidence that basal vasoconstrictor tone increases as a result of training such that improvements in intrinsic vasodilator function and arterial remodelling are counterbalanced at rest. Studies of compliance suggest increases in both the arterial and the venous sides of the circulation, particularly in older subjects. In terms of mechanisms, shear stress appears to be a key signal to improvement in vascular function, whilst increases in pulse pressure and associated haemodynamics during bouts of exercise may transduce vascular adaptation, even in vascular beds which are distant from the active muscle. Different exercise modalities are associated with idiosyncratic patterns of blood flow and shear stress, and this may have some impact on the magnitude of exercise training effects on arterial function and remodelling. Other studies support the theory that that there may be different time course effects of training on specific vasodilator and constrictor pathways. A new era of understanding of the direct impacts of exercise and training on the vasculature is evolving, and future studies will benefit greatly from technological advances which allow direct characterization of arterial function and structure. PMID- 20971801 TI - Is the -174 C/G polymorphism of the IL6 gene associated with elite power performance? A replication study with two different Caucasian cohorts. AB - A functional -174 C/G polymorphism in the interleukin-6 gene (IL6) is a candidate to explain individual variations in exercise-related phenotypes. To replicate recent findings showing an association between the G allele and GG genotype of elite power sports performance in European (Spanish) Caucasian males, we compared allelic and genotypic frequencies of the IL6 -174 C/G polymorphism among elite endurance athletes (n = 74) and power athletes (n = 81) and non-athletic control subjects (n = 205) of both sexes from Israel. All subjects were Israeli Caucasians (with an equivalent ratio of non-Ashkenazi and Ashkenazi descent in each group; 2:1). We found no differences in the genotype or allele frequencies among groups (all P > 0.3). We further compared the genotype and allele frequencies between national- (n = 109) and international-level Israeli athletes (n = 46) in the endurance and power group, and found no significant genotype or allele differences after adjusting for multiple comparisons. We repeated all the analyses after pooling the Israeli and Spanish control subjects, endurance and power elite athletes, and found no genotypic and allelic differences among groups. The results did not change when the analyses were repeated including only the best Israeli athletes (i.e. the international-level group) together with the group of elite Spanish athletes (P > 0.2). In conclusion, the results of the present study did not show an association between the G allele of the IL6 -174 G/C polymorphism and power sports performance in the Israeli (Caucasian) population. Our findings support the need to replicate association results between genetic polymorphisms and athletic status in populations of different ethnic backgrounds with the largest possible population samples. PMID- 20971802 TI - Maturation-related changes in the pattern of renal sympathetic nerve activity from fetal life to adulthood. AB - Sympathetic nerve activity (SNA) has two main properties, the presence of co ordinated bursts of activity, indicative of many nerve fibres firing at a similar time, and entrainment of the bursts to the cardiac cycle, due to inhibitory input from baroreceptors to a network of cell groups within the CNS. Although this patterning is used as a 'gold standard' for the identification of successful nerve recordings, the maturation of these basic features of SNA from fetal life to adulthood has not been investigated. Using a telemetry-based nerve amplifier, renal SNA (RSNA) was recorded in preterm (99 +/- 1 days gestation; term 147 days) and near-term fetal sheep (119 +/- 0 days gestation), without anaesthesia or paralysis, and contrasted with RSNA recorded in adult sheep. All three age groups showed a classic bursting pattern of RSNA and co-ordination of bursts with the cardiac cycle. However, the delay between diastole and the next peak in RSNA was longest in preterm fetuses (319 +/- 1 ms), compared with near-term fetuses (250 +/- 13 ms), and shortest in the adult sheep (174 +/- 38 ms). This was independent of the maturational decrease in heart rate. The near-term fetuses showed a marked but sleep-state-dependent increase in resting RSNA compared with preterm fetuses. Although entrainment with the pressure pulse suggests that the intricate circuitry within the CNS is developed in the preterm fetus, the decrease in the length of the delay suggests continuing maturation of this key feature of RSNA in the last third of gestation and after birth. PMID- 20971803 TI - The air-liquid interface and use of primary cell cultures are important to recapitulate the transcriptional profile of in vivo airway epithelia. AB - Organotypic cultures of primary human airway epithelial cells have been used to investigate the morphology, ion and fluid transport, innate immunity, transcytosis, infection, inflammation, signaling, cilia, and repair functions of this complex tissue. However, we do not know how closely these cultures resemble the airway surface epithelium in vivo. In this study, we examined the genome-wide expression profile of tracheal and bronchial human airway epithelia in vivo and compared it with the expression profile of primary cultures of human airway epithelia grown at the air-liquid interface. For comparison, we also investigated the expression profile of Calu-3 cells grown at the air-liquid interface and primary cultures of human airway epithelia submerged in nutrient media. We found that the transcriptional profile of differentiated primary cultures grown at the air-liquid interface most closely resembles that of in vivo airway epithelia, suggesting that the use of primary cultures and the presence of an air-liquid interface are important to recapitulate airway epithelia biology. We describe a high level of similarity between cells of tracheal and bronchial origin within and between different human donors, which suggests a very robust expression profile that is specific to airway cells. PMID- 20971804 TI - Cold exposure reveals two populations of microtubules in pulmonary endothelia. AB - Microtubules are composed of alpha-tubulin and beta-tubulin dimers. Microtubules yield tubulin dimers when exposed to cold, which reassemble spontaneously to form microtubule fibers at 37 degrees C. However, mammalian neurons, glial cells, and fibroblasts have cold-stable microtubules. While studying the microtubule toxicity mechanisms of the exotoxin Y from Pseudomonas aeruginosa in pulmonary microvascular endothelial cells, we observed that some endothelial microtubules were very difficult to disassemble in the cold. As a consequence, we designed studies to test the hypothesis that microvascular endothelium has a population of cold-stable microtubules. Pulmonary microvascular endothelial cells and HeLa cells (control) were grown under regular cell culture conditions, followed by exposure to an ice-cold water bath and a microtubule extraction protocol. Polymerized microtubules were detected by immunofluorescence confocal microscopy and Western blot analyses. After cold exposure, immunofluorescence revealed that the majority of HeLa cell microtubules disassembled, whereas a smaller population of endothelial cell microtubules disassembled. Immunoblot analyses showed that microvascular endothelial cells express the microtubule cold-stabilizing protein N-STOP (neuronal stable tubule-only polypeptides), and that N-STOP binds to endothelial microtubules after cold exposure, but not if microtubules are disassembled with nocodazole before cold exposure. Hence, pulmonary endothelia have a population of cold-stable microtubules. PMID- 20971805 TI - Could an increase in airway smooth muscle shortening velocity cause airway hyperresponsiveness? AB - Airway hyperresponsiveness (AHR) is a characteristic feature of asthma. It has been proposed that an increase in the shortening velocity of airway smooth muscle (ASM) could contribute to AHR. To address this possibility, we tested whether an increase in the isotonic shortening velocity of ASM is associated with an increase in the rate and total amount of shortening when ASM is subjected to an oscillating load, as occurs during breathing. Experiments were performed in vitro using 27 rat tracheal ASM strips supramaximally stimulated with methacholine. Isotonic velocity at 20% isometric force (Fiso) was measured, and then the load on the muscle was varied sinusoidally (0.33 +/- 0.25 Fiso, 1.2 Hz) for 20 min, while muscle length was measured. A large amplitude oscillation was applied every 4 min to simulate a deep breath. We found that: 1) ASM strips with a higher isotonic velocity shortened more quickly during the force oscillations, both initially (P < 0.001) and after the simulated deep breaths (P = 0.002); 2) ASM strips with a higher isotonic velocity exhibited a greater total shortening during the force oscillation protocol (P < 0.005); and 3) the effect of an increase in isotonic velocity was at least comparable in magnitude to the effect of a proportional increase in ASM force-generating capacity. A cross-bridge model showed that an increase in the total amount of shortening with increased isotonic velocity could be explained by a change in either the cycling rate of phosphorylated cross bridges or the rate of myosin light chain phosphorylation. We conclude that, if asthma involves an increase in ASM velocity, this could be an important factor in the associated AHR. PMID- 20971806 TI - Autonomic activation links CNS oxygen toxicity to acute cardiogenic pulmonary injury. AB - Breathing hyperbaric oxygen (HBO2), particularly at pressures above 3 atmospheres absolute, can cause acute pulmonary injury that is more severe if signs of central nervous system toxicity occur. This is consistent with the activation of an autonomic link between the brain and the lung, leading to acute pulmonary oxygen toxicity. This pulmonary damage is characterized by leakage of fluid, protein, and red blood cells into the alveoli, compatible with hydrostatic injury due to pulmonary hypertension, left atrial hypertension, or both. Until now, however, central hemodynamic parameters and autonomic activity have not been studied concurrently in HBO2, so any hypothetical connections between the two have remained untested. Therefore, we performed experiments using rats in which cerebral blood flow, electroencephalographic activity, cardiopulmonary hemodynamics, and autonomic traffic were measured in HBO2 at 5 and 6 atmospheres absolute. In some animals, autonomic pathways were disrupted pharmacologically or surgically. Our findings indicate that pulmonary damage in HBO2 is caused by an abrupt and significant increase in pulmonary vascular pressure, sufficient to produce barotrauma in capillaries. Specifically, extreme HBO2 exposures produce massive sympathetic outflow from the central nervous system that depresses left ventricular function, resulting in acute left atrial and pulmonary hypertension. We attribute these effects on the heart and on the pulmonary vasculature to HBO2 mediated central sympathetic excitation and catecholamine release that disturbs the normal equilibrium between excitatory and inhibitory activity in the autonomic nervous system. PMID- 20971807 TI - Design, preparation, and characterization of high-activity mutants of human butyrylcholinesterase specific for detoxification of cocaine. AB - Cocaine is a widely abused drug without a U.S. Food and Drug Administration approved medication. There is a recognized, promising anticocaine medication to accelerate cocaine metabolism, producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway [i.e., cocaine hydrolysis catalyzed by butyrylcholinesterase (BChE) in plasma]. An ideal, therapeutically valuable mutant of human BChE should have not only a significantly improved catalytic activity against (-)-cocaine but also certain selectivity for (-)-cocaine over neurotransmitter acetylcholine (ACh), such that one would not expect systemic administration of the BChE mutant to interrupt cholinergic transmission. The present study accounting for the mutation-caused changes of the catalytic activities of BChE against both (-)-cocaine and ACh by means of molecular modeling and site-directed mutagenesis has led to identification of three BChE mutants that have not only a considerably improved catalytic efficiency against (-)-cocaine but also the desirable selectivity for ( )-cocaine over ACh. Two representative BChE mutants have been confirmed to be potent in actual protection of mice from acute toxicity (convulsion and lethality) of a lethal dose of cocaine (180 mg/kg). Pretreatment with the BChE mutant (i.e., 1 min before cocaine administration) dose-dependently protected mice against cocaine-induced convulsions and lethality. In particular, all mice pretreated with the mutant (e.g., 0.02 mg or more of A199S/F227A/S287G/A328W/E441D BChE) survived. The in vivo data reveal the primary factor (i.e., the relative catalytic efficiency), determining the efficacy in practical protection of mice from the acute cocaine toxicity and future direction for further improving the efficacy of the enzyme in the cocaine overdose treatment. PMID- 20971808 TI - CEBPD reverses RB/E2F1-mediated gene repression and participates in HMDB-induced apoptosis of cancer cells. AB - PURPOSE: Recent evidence indicates that a tumor suppressor gene CEBPD (CCAAT/enhancer-binding protein delta) is downregulated in many cancers including cervical cancer, which provides a therapeutic potential associated with its reactivation. However, little is known for CEBPD activators and the effect of reactivation of CEBPD transcription upon anticancer drug treatment. In this study, we identified a novel CEBPD activator, 1-(2-hydroxy-5-methylphenyl)-3 phenyl-1,3-propanedione (HMDB). The purpose of this study is to characterize the mechanism of HMDB-induced CEBPD activation and its potential effect in cancer therapy. EXPERIMENTAL DESIGN: Methylation-specific PCR assay, reporter assay, and chromatin immunoprecipitation (ChIP) assay were performed to dissect the signaling pathway of HMDB-induced CEBPD transcription. Furthermore, a consequence of HMDB-induced CEBPD expression was linked with E2F1 and retinoblastoma (RB), which discloses the scenario of CEBPD, E2F1, and RB bindings and transcriptional regulation on the promoters of proapoptotic genes, PPARG2 and GADD153. Finally, the anticancer effect of HMDB was examined in xenograft mice. RESULTS: We demonstrate that CEBPD plays an essential role in HMDB-mediated apoptosis of cancer cells. HMDB up-regulates CEBPD transcription through the p38/CREB pathway, thus leading to transcriptional activation of PPARG2 and GADD153. Furthermore, increased level of CEBPD attenuates E2F1-induced cancer cell proliferation and partially rescues RB/E2F1-mediated repression of PPARG2 and GADD153 transcription. Moreover, HMDB treatment attenuates the growth of A431 xenografts in severe combined immunodeficient mice mice. CONCLUSIONS: These results clearly demonstrate that HMDB kills cancer cells through activation of CEBPD pathways and suggest that HMDB can serve as a superior chemotherapeutic agent with limited potential for adverse side effects. PMID- 20971809 TI - Deciphering the role of glucosamine-6-phosphate in the riboswitch action of glmS ribozyme. AB - The GlmS ribozyme is believed to exploit a general acid-base catalytic mechanism in the presence of glucosamine-6-phosphate (GlcN6P) to accelerate self-cleavage by approximately six orders of magnitude. The general acid and general base are not known, and the role of the GlcN6P cofactor is even less well understood. The amine group of GlcN6P has the ability to either accept or donate a proton and could therefore potentially act as an acid or a base. In order to decipher the role of GlcN6P in the self-cleavage of glmS, we have determined the preferred protonation state of the amine group in the wild-type and an inactive G40A mutant using molecular dynamics simulations and free energy calculations. Here we show that, upon binding of GlcN6P to wild-type glmS, the pK(a) of the amine moiety is altered by the active site environment, decreasing by about 2.2 from a solution pK(a) of about 8.2. On the other hand, we show that the pK(a) of the amine group slightly increases to about 8.4 upon binding to the G40A inactive mutant of glmS. These results suggest that GlcN6P acts as a general acid in the self-cleavage of glmS. Upon binding to glmS, GlcN6P can easily release a proton to the 5'-oxygen of G1 during self-cleavage of the backbone phosphodiester bond. However, in the G40A inactive mutant of glmS, the results suggest that the ability of GlcN6P to easily release its proton is diminished, in addition to the possible lack of G40 as an effective base. PMID- 20971810 TI - Control of translation efficiency in yeast by codon-anticodon interactions. AB - The choice of synonymous codons used to encode a polypeptide contributes to substantial differences in translation efficiency between genes. However, both the magnitude and the mechanisms of codon-mediated effects are unknown, as neither the effects of individual codons nor the parameters that modulate codon mediated regulation are understood, particularly in eukaryotes. To explore this problem in Saccharomyces cerevisiae, we performed the first systematic analysis of codon effects on expression. We find that the arginine codon CGA is strongly inhibitory, resulting in progressively and sharply reduced expression with increased CGA codon dosage. CGA-mediated inhibition of expression is primarily due to wobble decoding of CGA, since it is nearly completely suppressed by coexpression of an exact match anticodon-mutated tRNA(Arg(UCG)), and is associated with generation of a smaller RNA fragment, likely due to endonucleolytic cleavage at a stalled ribosome. Moreover, CGA codon pairs are more effective inhibitors of expression than individual CGA codons. These results directly implicate decoding by the ribosome and interactions at neighboring sites within the ribosome as mediators of codon-specific translation efficiency. PMID- 20971811 TI - Persistence of seed-based activity following segmentation of a microRNA guide strand. AB - microRNAs are ~ 22 nucleotide regulatory RNAs that are processed into duplexes from hairpin structures and incorporated into Argonaute proteins. Here, we show that a nick in the middle of the guide strand of an miRNA sequence allows for seed-based targeting characteristic of miRNA activity. Insertion of an inverted abasic, a dye, or a small gap between the two segments still permits target knockdown. While activity from the seed region of the segmented miRNA is apparent, activity from the 3' half of the guide strand is impaired, suggesting that an intact guide backbone is required for contribution from the 3' half. miRNA activity was also observed following nicking of a miRNA precursor. These results illustrate a structural flexibility in miRNA duplexes and may have applications in the design of miRNA mimetics. PMID- 20971812 TI - Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process. AB - Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. In this study, we investigated in vivo the effects of RAD001 (Everolimus), a new orally available mTOR inhibitor, on the growth of human and mouse osteosarcoma cells either alone or in combination with zoledronate (ZOL), an anti-osteoporotic drug used to treat bone metastases. RAD001 inhibited osteosarcoma cell proliferation in a dose- and time dependent manner with no modification of cell-cycle distribution. Combination with ZOL augmented this inhibition of cell proliferation, decreasing PI3K/mTOR signaling compared with single treatments. Notably, in contrast to RAD001, ZOL downregulated isoprenylated membrane-bound Ras concomitantly with an increase of nonisoprenylated cytosolic Ras in sensitive and resistant osteosarcoma cell lines to both drugs. Moreover, ZOL and RAD001 synergized to decrease Ras isoprenylation and GTP-bound Ras levels. Further, the drug combination reduced tumor development in two murine models of osteoblastic or osteolytic osteosarcoma. We found that ZOL could reverse RAD001 resistance in osteosarcoma, limiting osteosarcoma cell growth in combination with RAD001. Our findings rationalize further study of the applications of mTOR and mevalonate pathway inhibitors that can limit protein prenylation pathways. PMID- 20971813 TI - Rec8-containing cohesin maintains bivalents without turnover during the growing phase of mouse oocytes. AB - During female meiosis, bivalent chromosomes are thought to be held together from birth until ovulation by sister chromatid cohesion mediated by cohesin complexes whose ring structure depends on kleisin subunits, either Rec8 or Scc1. Because cohesion is established at DNA replication in the embryo, its maintenance for such a long time may require cohesin turnover. To address whether Rec8- or Scc1 containing cohesin holds bivalents together and whether it turns over, we created mice whose kleisin subunits can be cleaved by TEV protease. We show by microinjection experiments and confocal live-cell imaging that Rec8 cleavage triggers chiasmata resolution during meiosis I and sister centromere disjunction during meiosis II, while Scc1 cleavage triggers sister chromatid disjunction in the first embryonic mitosis, demonstrating a dramatic transition from Rec8- to Scc1-containing cohesin at fertilization. Crucially, activation of an ectopic Rec8 transgene during the growing phase of Rec8(TEV)(/TEV) oocytes does not prevent TEV-mediated bivalent destruction, implying little or no cohesin turnover for >=2 wk during oocyte growth. We suggest that the inability of oocytes to regenerate cohesion may contribute to age-related meiosis I errors. PMID- 20971814 TI - beta-catenin is constitutively active and increases STAT3 expression/activation in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. AB - BACKGROUND: The role of beta-catenin in cancer has been most studied in tumors of epithelial cell origin. The functional status and biological significance of this protein in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma is unknown. DESIGN AND METHODS: ALK-positive anaplastic large cell lymphoma cell lines and patients' tumor samples were examined for status of beta catenin expression and signaling. The subcellular localization of beta-catenin was assessed using immunohistochemistry, sub-cellular fractionation and confocal microscopy, while its transcriptional activity was studied using the TOPFlash/FOPFlash luciferase reporter assay. To examine the biological significance of beta-catenin, short interfering RNA was used to knock-down its expression; the resulting biological effects were studied using trypan-blue exclusion and MTS assay, and the impact on its various downstream targets was assessed using quantitative real-time polymerase chain reaction and western blots. RESULTS: beta-catenin was transcriptionally active in three of three ALK positive anaplastic large cell lymphoma cell lines, and this finding correlates with the nuclear localization of beta-catenin in these cells and the neoplastic cells identified in most of the patients' tumor samples. beta-catenin is biologically significant in ALK-positive anaplastic large cell lymphoma, since down-regulation of beta-catenin resulted in a significant reduction in their cell growth. Down-regulation of beta-catenin led to a marked reduction in both the total protein level and the activated/phosphorylated form of STAT3, another signaling protein previously shown to be important in the pathogenesis of ALK positive anaplastic large cell lymphoma. In contrast to some of the oncogenic tyrosine kinases, modulation of nucleophosmin-anaplastic lymphoma kinase expression did not result in any detectable change in the protein level, nuclear localization or tyrosine phosphorylation of beta-catenin; however, inhibition of nucleophosmin-anaplastic lymphoma kinase expression significantly down-regulated the transcriptional activity of beta-catenin. CONCLUSIONS: beta-catenin signaling is constitutively active in ALK-positive anaplastic large cell lymphoma and represents a previously unknown mechanism by which the high levels of STAT3 expression and activation in these tumors are sustained. Our results suggest that the interaction between oncogenic tyrosine kinases and various cell signaling proteins may be more complex than previously believed. PMID- 20971815 TI - OCT-1 function varies with cell lineage but is not influenced by BCR-ABL. AB - BACKGROUND: Despite the excellent responses to imatinib therapy observed in patients with chronic phase chronic myeloid leukemia, approximately 25% of patients display primary resistance or suboptimal response. The OCT-1 activity in mononuclear cells reflects the efficiency of active influx of imatinib. OCT-1 activity in mononuclear cells is highly variable between patients and significantly correlates with a patient's molecular response to imatinib treatment and overall survival. The present study examined whether cell lineage and BCR-ABL expression influenced OCT-1 activity. DESIGN AND METHODS: The OCT-1 activity and OCT-1 mRNA expression was assessed in pure populations of neutrophils, monocytes and lymphocytes recovered from chronic myeloid leukemia patients at diagnosis, in cytogenetic remission and normal individuals. The role of BCR-ABL on OCT-1 activity and differentiation was examined in a cell line model of ectopic BCR-ABL expression. RESULTS: The OCT-1 activity and OCT-1 mRNA expression was highest in the neutrophil population and lowest in lymphocytes (P<0.05). This was observed for patients at diagnosis, in cytogenetic remission and normal individuals. Interestingly, neutrophil OCT-1 activity was not significantly different between patients at diagnosis, in remission and normal donors. This was also observed for monocytes and lymphocytes. Furthermore, OCT-1 activity in mononuclear cells was significantly correlated with the OCT-1 activity in neutrophils (P=0.001). In a cell line model in which BCR-ABL was ectopically expressed, we found no evidence that BCR-ABL directly affected OCT-1 expression and function. However, BCR-ABL stimulated granulocyte differentiation which, in turn, led to significantly increased OCT-1 activity (P=0.024). CONCLUSIONS: These studies suggest that the predictive OCT-1 activity in patient mononuclear cells is strongly related to cell lineage, particularly the presence of neutrophils in the peripheral blood. Furthermore, BCR-ABL expression is unlikely to directly influence OCT-1 activity but may have an indirect role by enhancing granulocyte differentiation. PMID- 20971816 TI - CD117 expression in gammopathies is associated with an altered maturation of the myeloid and lymphoid hematopoietic cell compartments and favorable disease features. AB - Aberrant CD117 expression is associated with a favorable outcome in multiple myeloma. We analyzed 106 patients with symptomatic multiple myeloma (n=50), smoldering multiple myeloma (n=38) and monoclonal gammopathy of undetermined significance (n=18) to elucidate biological features of CD117(+) versus CD117(-) monoclonal gammopathies. CD117(+) (mono)clonal plasma cells were detected in 30% symptomatic multiple myeloma, 45% smoldering multiple myeloma and 72% monoclonal gammopathy of undetermined significance patients. CD117 expression was associated with higher percentages of normal bone marrow plasma cells, CD117(+) myeloid precursors and CD38(+) B lymphocytes in all monoclonal gammopathies. Conversely, the number of bone marrow CD34(+) myeloid cells and peripheral blood neutrophils was reduced among CD117(+) multiple myeloma but not monoclonal gammopathy of undetermined significance patients. CD117 expression by (mono)clonal plasma cells is associated with uniquely altered patterns of production of hematopoietic bone marrow cells with decreased peripheral blood neutrophil counts and persistence of normal residual bone marrow plasma cells. PMID- 20971817 TI - Twenty-five years of epidemiological recording on myeloid malignancies: data from the specialized registry of hematologic malignancies of Cote d'Or (Burgundy, France). AB - BACKGROUND: Epidemiological data on myeloid malignancies are very rare in the literature due to a lack of registration by cancer registries until 2000. The Registry of Hematologic Malignancies of the Cote d'Or Department in France has, however, steadfastly registered data on cases occurring in the Department since 1980, resulting, to date, in a database of over 5,000 cases classified according to the ICD-O-3 classification, following the most recent World Health Organization classification criteria. DESIGN AND METHODS: Twenty-five years of data on myeloid malignancies, including acute myeloid leukemia, myeloproliferative neoplasms, myelodysplastic syndromes and myelodysplastic/myeloproliferative syndromes were analyzed. World population standardized incidence rates were calculated as were as observed and relative survival. RESULTS: Incidence rates per 100,000 inhabitants/year were 2.5 for acute myeloid leukemia, 1.3 for myelodysplastic syndromes, 3.2 for myeloproliferative neoplasms and 0.6 for myelodysplastic/myeloproliferative syndromes. It was found that the incidence rate of myelodysplastic syndromes increased significantly over the period. The median overall survival is 8.9 months for patients with acute myeloid leukemia, 33.8 months for patients with myelodysplastic syndromes, 91.7 months for those with myeloproliferative neoplasms and 26.6 months for patients with myelodysplastic/myeloproliferative syndromes. Observed and relative 20-year survival rates are, respectively, 12% and 13% in acute myeloid leukemia, 2% and 6% in myelodysplastic syndromes and 20% and 34% in myeloproliferative neoplasms. CONCLUSIONS: These population-based data on myeloid malignancies are the first data collected over such a long period and provide interesting information for clinicians and public health authorities, particularly given the paucity of other long-term, population-based data from cancer registries. PMID- 20971818 TI - Efficacy and outcome of autologous transplantation in rare myelomas. AB - BACKGROUND: As rare myelomas, i.e. the IgD, IgE, IgM and non-secretory forms, constitute only a small proportion of any study, relatively little is known about their prognosis in the era of peripheral stem cell transplantation. DESIGN AND METHODS: We used the European Group for Blood and Marrow Transplantation Myeloma Database to compare the outcome following autologous transplantation of over 20,000 patients with common myelomas (IgG, IgA and light chain myeloma) with the outcome of patients with rare myelomas: 379 IgD, 13 IgE, 72 IgM and 976 non secretory cases. RESULTS: The study confirms the multiple adverse prognostic factors seen in IgD myeloma. Somewhat surprisingly, patients with IgD and non secretory myeloma both had higher complete remission rates before and after transplantation than patients with common myelomas. However, while the overall survival of patients with non-secretory myeloma was similar to that of the patients with common myelomas, the survival of patients with IgD myeloma was significantly worse (although better than survival rates reported for non transplanted patients); this was due to higher transplant-related mortality and relapse/progression rates. The post-transplantation survival of patients with IgE or IgM myeloma appears to be very poor. CONCLUSIONS: This study provides data on the biological features of rare myelomas. The overall survival of patients with IgD, IgE or IgM myeloma is poor following autologous transplantation but substantially better than that reported for patients who were not transplanted. PMID- 20971819 TI - Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children. AB - Background Primary mediastinal large B-cell lymphoma is a rare lymphoma accounting for no more than 3% of all B-cell lymphomas in children and adolescents. However, patients in this young age group with this lymphoma have the shortest event-free survival of patients with any B-cell lymphoma under current standard chemotherapy protocols. Lymphomas with features intermediate between primary mediastinal large B-cell lymphoma and classical Hodgkin's lymphoma (mediastinal gray zone lymphomas) have been acknowledged in the latest World Health Organization classification. Recent studies suggest that mediastinal gray zone lymphomas have an aggressive clinical course whereas patients, at least adult ones, with primary mediastinal large B-cell lymphoma might respond very well to chemotherapy in combination with anti-CD20 antibody. DESIGN AND METHODS: We aimed to evaluate whether biological differences or so far unrecognized admixed mediastinal gray zone lymphomas might explain the relatively poor outcome of pediatric patients with apparent primary mediastinal large B-cell lymphoma. We, therefore, performed a retrospective histopathological, immunohistochemical and interphase cytogenetic analysis of 52 pediatric lymphomas. RESULTS: The childhood primary mediastinal large B-cell lymphomas (n=44) showed a similar pattern of histology, immunophenotype and gains at 9p (59%) and 2p (41%) as adult cases, as determined from published data. We identified only four so far unrecognized cases of mediastinal gray zone lymphoma among 52 lymphomas registered in previous trials. Conclusions Mediastinal gray zone lymphoma is very rare in children and adolescents. It does, therefore, seem unlikely that these lymphomas account for the unsatisfactory clinical results with current therapy protocols in pediatric patients. These data have major implications for the design of future treatment protocols for mediastinal lymphomas in children and adolescents. PMID- 20971820 TI - Evaluation of gene expression signatures predictive of cytogenetic and molecular subtypes of pediatric acute myeloid leukemia. AB - BACKGROUND: Pediatric acute myeloid leukemia is a heterogeneous disease characterized by non-random genetic aberrations related to outcome. The genetic subtype is currently detected by different diagnostic procedures which differ in success rate and/or specificity. DESIGN AND METHODS: We examined the potential of gene expression profiles to classify pediatric acute myeloid leukemia. Gene expression microarray data of 237 children with acute myeloid leukemia were collected and a double-loop cross validation approach was used to generate a subtype-predictive gene expression profile in the discovery cohort (n=157) which was then tested for its true predictive value in the independent validation cohort (n=80). The classifier consisted of 75 probe sets, representing the top 15 discriminating probe sets for MLL-rearranged, t(8;21)(q22;q22), inv(16)(p13q22), t(15;17)(q21;q22) and t(7;12)(q36;p13)-positive acute myeloid leukemia. RESULTS: These cytogenetic subtypes represent approximately 40% of cases of pediatric acute myeloid leukemia and were predicted with 92% and 99% accuracy in the discovery and independent validation cohort, respectively. However, for NPM1, CEBPA, MLL(-PTD), FLT3(-ITD), KIT, PTPN11 and N/K-RAS gene expression signatures had limited predictive value. This may be caused by a limited frequency of these mutations and by underlying cytogenetics. This latter is exemplified by the fact that different gene expression signatures were discovered for FLT3-ITD in patients with normal cytogenetics and in those with t(15;17)(q21;q22)-positive acute myeloid leukemia, which pointed to HOXB-upregulation being specific for FLT3-ITD(+) cytogenetically normal acute myeloid leukemia. CONCLUSIONS: In conclusion, gene expression profiling correctly predicted the most prevalent cytogenetic subtypes of pediatric acute myeloid leukemia with high accuracy. In clinical practice, this gene expression signature may replace multiple diagnostic tests for approximately 40% of pediatric acute myeloid leukemia cases whereas only for the remaining cases (predicted as 'acute myeloid leukemia-other') are additional tests indicated. Moreover, the discriminative genes reveal new insights into the biology of acute myeloid leukemia subtypes that warrants follow up as potential targets for new therapies. PMID- 20971821 TI - Differentiating chronic lymphocytic leukemia from monoclonal B-lymphocytosis according to clinical outcome: on behalf of the GIMEMA chronic lymphoproliferative diseases working group. AB - BACKGROUND: Optimal lymphocyte parameters and thresholds for the diagnosis of chronic lymphocytic leukemia have been proposed by The National Cancer Institute sponsored Working Group and recently updated by the International Workshop on chronic lymphocytic leukemia. However, it is not clear how these criteria apply to patient management in daily clinical practice and whether the lymphocyte thresholds recommended truly predict clinical outcome in early chronic lymphocytic leukemia. DESIGN AND METHODS: For the purpose of this study, an observational database of the GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) which included 1,158 patients with newly diagnosed Binet stage A chronic lymphocytic leukemia who were observed at different primary hematology centers during the period 1991-2000, was used. RESULTS: Among 818 consecutive chronic lymphocytic leukemia patients with Rai stage 0 (i.e. no palpable lymphadenopathy or hepatosplenomegaly) who had flow cytometry evaluations at the time of diagnosis and were included in a GIMEMA database, both absolute lymphocyte count and B-cell count were of a similar value in predicting time to first treatment as continuous variables (P<0.0001). Receiver operating characteristic analysis identified an absolute lymphocyte count of 11.5*10(9)/L and an absolute B-cell count of 10.0*10(9)/L as the best thresholds capable of identifying patients who will require treatment from those with stable disease. However, in a Cox's multivariate analysis only the B-cell count retained its discriminating power (P<0.0001) and the estimated rate of progression to chronic lymphocytic leukemia requiring treatment among subjects with a B-cell count less than 10.0*10(9)/L was approximately 2.3% per year (95% CI 2.1-2.5%) while it was 2-fold higher for patients with a B-cell count of 10.0*10(9)/L or over (i.e. 5.2% per year; 95% CI 4.9-5.5%). Finally, in this community-based patient cohort, the B-cell threshold defined by investigators at the Mayo Clinic (i.e. 11.0*10(9)/L) allowed patients to be divided into two subsets with a higher and lower likelihood of treatment (P<0.0001). CONCLUSIONS: Our results, based on a retrospective patients' cohort, provide a clear justification to retain the B cell count as the reference gold standard of chronic lymphocytic leukemia diagnosis and imply that a count of 10*10(9)/L B cells is the best lymphocyte threshold to predict time to first treatment. The use of clinical outcome to distinguish chronic lymphocytic leukemia from other premalignant conditions, such as monoclonal B-cell lymphocytosis, is a pragmatic approach meeting the patients' need to minimize the psychological discomfort of receiving a diagnosis of leukemia when the risk of adverse clinical consequences is low. PMID- 20971823 TI - Allogeneic stem cell transplantation for myelodysplastic syndromes with bone marrow fibrosis. AB - BACKGROUND: Bone marrow fibrosis in patients with myelodysplastic syndrome is associated with a poor outcome, but whether the outcome after allogeneic stem cell transplantation is related to the degree of bone marrow fibrosis is unknown. DESIGN AND METHODS: Patients with myelodysplastic syndrome and known bone marrow histology (n=721) who underwent hematopoietic stem cell transplantation were classified according to the degree of bone marrow fibrosis into those without fibrosis (n=483), those with mild or moderate fibrosis (n=199) and those with severe fibrosis (n=39) and analyzed regarding engraftment, treatment-related mortality, relapse and survival. RESULTS: The degree of fibrosis was not associated with disease status or abnormal cytogenetics. The cumulative incidence of engraftment achieved at day +30 in non-fibrotic patients was 93% and was significantly lower in those with mild or moderate fibrosis (89%) and severe fibrosis (75%) (P=0.009). Neutrophil engraftment occurred later in patients with mild or moderate fibrosis and severe fibrosis than in patients without fibrosis (median 17 versus 20 versus 16 days, respectively; P=0.002). The cumulative incidence of relapse at 3 years was significantly higher in patients with severe fibrosis than in those with a lesser degree of fibrosis or no fibrosis (47% versus 28% versus 27%, respectively; P=0.04), resulting in comparable 3-year disease-free survival rates in patients without fibrosis and in those with mild or moderate fibrosis (42% versus 38%, respectively) but a lower disease-free survival rate in those with severe fibrosis (18%; P=0.002). Severe fibrosis remained an independent factor for reduced survival (hazard ratio, 1.9; P=0.006). CONCLUSIONS: Among patients with myelodysplastic syndromes, only severe fibrosis affects survival after hematopoietic stem cell transplantation while patients with mild or moderate fibrosis have an outcome comparable to that of patients without bone marrow fibrosis. PMID- 20971825 TI - Notch signaling pathway as a therapeutic target in breast cancer. AB - The highly conserved Notch signaling pathway is involved in regulating a number of key cellular processes. This pathway has been implicated in both the development and progression of breast cancer and has emerged as a possible therapeutic target. Several clinical trials are currently underway to determine if targeting the Notch pathway with drugs such as the gamma-secretase inhibitors may be an effective therapeutic strategy that improves outcomes in this disease. PMID- 20971822 TI - A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia: the GRAALL-SA1 study. AB - BACKGROUND: The prognosis of acute lymphoblastic leukemia in the elderly is poor. The GRAALL-SA1 phase II, randomized trial compared the efficacy and toxicity of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in patients 55 years or older with Philadelphia chromosome-negative acute lymphoblastic leukemia. DESIGN AND METHODS: Sixty patients received either continuous-infusion doxorubicin (12 mg/m(2)/day) and continuous-infusion vincristine (0.4 mg/day) on days 1-4 or pegylated liposomal doxorubicin (40 mg/m(2)) and standard vincristine (2 mg) on day 1, accompanied by dexamethasone, followed at day 28 by a second cycle, reinforced by cyclophosphamide. End-points were safety, outcome and prognostic factors. RESULTS: Myelosuppression was reduced in the pegylated liposomal doxorubicin arm with shorter severe neutropenia (P=0.05), shorter severe thrombocytopenia (P=0.03), and fewer red blood cell transfusions (P=0.04). Grade 3/4 infections and Gram-negative bacteremia were reduced in the pegylated liposomal doxorubicin arm (P=0.04 and P=0.02, respectively). There was a trend towards fewer cardiac events among the patients who received pegylated liposomal doxorubicin (1/29 versus 6/31). The complete remission rate was 82% and, with a median follow-up of 4 years, median event-free survival and overall survival were 9 and 10 months, respectively. Despite the better tolerance of pegylated liposomal doxorubicin, no differences in survival were observed between the two arms, due to trends towards more induction refractoriness (17 versus 3%, P=0.10) and a higher cumulative incidence of relapse (52% versus 32% at 2 years, P=0.20) in the pegylated liposomal doxorubicin arm. CONCLUSIONS: With the drug schedules used in this study, pegylated liposomal doxorubicin did not improve the outcome of elderly patients with acute lymphoblastic leukemia despite reduced toxicities. PMID- 20971824 TI - Repeated vaccination is required to optimize seroprotection against H1N1 in the immunocompromised host. AB - BACKGROUND: In 2009 the declaration by the World Health Organization of a global pandemic of influenza-H1N1 virus led to a vaccination campaign to ensure protection for immunocompromised patients. The goal of this study was to determine the efficacy of the 2009 H1N1 vaccine in patients with hematologic malignancies. DESIGN AND METHODS: We evaluated humoral and cellular immune responses to 2009 H1N1 vaccine in 97 adults with hematologic malignancies and compared these responses with those in 25 adult controls. Patients received two injections of vaccine 21 days apart and the controls received one dose. Antibody titers were measured using a hemagglutination-inhibition assay on days 0, 21 and 49 after injection of the first dose. Cellular immune responses to H1N1 were determined on days 0 and 49. RESULTS: By day 21 post-vaccination, protective antibody titers of 1:32 or more were seen in 100% of controls compared to 39% of patients with B-cell malignancies (P<0.001), 46% of allogeneic stem cell transplant recipients (P<0.001) and 85% of patients with chronic myeloid leukemia (P=0.086). After a second dose, seroprotection rates increased to 68%, (P=0.008), 73%, (P=0.031), and 95% (P=0.5) in patients with B-cell malignancies, after allogeneic stem cell transplantation and with chronic myeloid leukemia, respectively. On the other hand, T-cell responses to H1N1 vaccine were not significantly different between patients and controls. CONCLUSIONS: These data demonstrate the efficacy of H1N1 vaccine in most patients with hematologic malignancies and support the recommendation for the administration of two doses of vaccine in immunocompromised patients. These results may contribute towards the development of evidence-based guidelines for influenza vaccination in such patients in the future. PMID- 20971826 TI - Modulation of 4E-BP1 function as a critical determinant of enzastaurin-induced apoptosis. AB - Enzastaurin (LY317615.HCl) is currently in a phase III registration trial for diffuse large B-Cell lymphoma and numerous phase II clinical trials. Enzastaurin suppresses angiogenesis and induces apoptosis in multiple human tumor cell lines by inhibiting protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/AKT pathway signaling. PI3K/AKT pathway signaling liberates eukaryotic translation initiation factor 4E (eIF4E) through the hierarchical phosphorylation of eIF4E binding proteins (4E-BP). When hypophosphorylated, 4E-BPs associate with eIF4E, preventing eIF4E from binding eIF4G, blocking the formation of the eIF4F translation initiation complex. Herein, we show that enzastaurin treatment impacts signaling throughout the AKT/mTOR pathway leading to hypophosphorylation of 4E-BP1 in cancer cells of diverse lineages (glioblastoma, colon carcinoma, and B-cell lymphoma). Accordingly, enzastaurin treatment increases the amount of eIF4E bound to 4E-BP1 and decreases association of eIF4E with eIF4G, thereby reducing eIF4F translation initiation complex levels. We therefore chose to evaluate whether this effect on 4E-BP1 was involved in enzastaurin-induced apoptosis. Remarkably, enzastaurin-induced apoptosis was blocked in cancer cells depleted of 4E-BP1 by siRNAs, or in 4EBP1/2 knockout murine embryonic fibroblasts cells. Furthermore, eIF4E expression was increased and 4E-BP1 expression was decreased in cancer cells selected for reduced sensitivity to enzastaurin-induced apoptosis. These data highlight the importance of modulating 4E-BP1 function, and eIF4F complex levels, in the direct antitumor effect of enzastaurin and suggest that 4E-BP1 function may serve as a promising determinant of enzastaurin activity. PMID- 20971828 TI - ICU-acquired weakness: obstacles and interventions for rehabilitation. PMID- 20971827 TI - The Sin3p PAH domains provide separate functions repressing meiotic gene transcription in Saccharomyces cerevisiae. AB - Meiotic genes in budding yeast are repressed during vegetative growth but are transiently induced during specific stages of meiosis. Sin3p represses the early meiotic gene (EMG) by bridging the DNA binding protein Ume6p to the histone deacetylase Rpd3p. Sin3p contains four paired amphipathic helix (PAH) domains, one of which (PAH3) is required for repressing several genes expressed during mitotic cell division. This report examines the roles of the PAH domains in mediating EMG repression during mitotic cell division and following meiotic induction. PAH2 and PAH3 are required for mitotic EMG repression, while electrophoretic mobility shift assays indicate that only PAH2 is required for stable Ume6p-promoter interaction. Unlike mitotic repression, reestablishing EMG repression following transient meiotic induction requires PAH3 and PAH4. In addition, the role of Sin3p in reestablishing repression is expanded to include additional loci that it does not control during vegetative growth. These findings indicate that mitotic and postinduction EMG repressions are mediated by two separate systems that utilize different Sin3p domains. PMID- 20971829 TI - Inhibition of neutrophil migration by hemopexin leads to increased mortality due to sepsis in mice. AB - RATIONALE: The reduction of neutrophil migration to the bacterial focus is associated with poor outcome in sepsis. OBJECTIVES: The objective of this study was to identify soluble substances in the blood of septic mice that inhibit neutrophil migration. METHODS: A pool of serum obtained from mice 2 hours after the induction of severe sepsis by cecal ligation and puncture inhibited the neutrophil migration. The proteins with inhibitory activity on neutrophil migration were isolated by Blue-Sepharose chromatography, high-performance liquid chromatography, and electrophoresis, and identified by mass spectrometry. MEASUREMENTS AND MAIN RESULTS: Hemopexin was identified as the serum component responsible for the inhibition of neutrophil migration. In sepsis, the pretreatment of wild-type mice with hemopexin inhibited neutrophil migration to the focus of infection and decreased the survival rate from 87.5 to 50.0%. Hemopexin-null mice subjected to severe sepsis presented normal neutrophil migration, low bacteremia, and an improvement of 40% in survival rate. Moreover, hemopexin inhibited the neutrophil chemotaxis response evoked by C5a or macrophage inflammatory protein-2 and induced a reduction of CXCR2 and L-selectin as well as the up-regulation of CD11b expression in neutrophil membranes. The inhibitory effect of hemopexin on neutrophil chemotaxis was prevented by serine protease inhibitors or ATP. In addition, serum levels of ATP were decreased 2 hours after severe sepsis. CONCLUSIONS: These data demonstrate for the first time the inhibitory role of hemopexin in neutrophil migration during sepsis and suggest that the therapeutic inhibition of hemopexin or its protease activity could improve neutrophil migration to the focus of infection and survival in sepsis. PMID- 20971830 TI - IL-9 governs allergen-induced mast cell numbers in the lung and chronic remodeling of the airways. AB - RATIONALE: IL-9 is a pleiotropic cytokine that has multiple effects on structural as well as numerous hematopoietic cells, which are central to the pathogenesis of asthma. OBJECTIVES: The contribution of IL-9 to asthma pathogenesis has thus far been unclear, due to conflicting reports in the literature. These earlier studies focused on the role of IL-9 in acute inflammatory models; here we have investigated the effects of IL-9 blockade during chronic allergic inflammation. METHODS: Mice were exposed to either prolonged ovalbumin or house dust mite allergen challenge to induce chronic inflammation and airway remodeling. MEASUREMENTS AND MAIN RESULTS: We found that IL-9 governs allergen-induced mast cell (MC) numbers in the lung and has pronounced effects on chronic allergic inflammation. Anti-IL-9 antibody-treated mice were protected from airway remodeling with a concomitant reduction in mature MC numbers and activation, in addition to decreased expression of the profibrotic mediators transforming growth factor-beta1, vascular endothelial growth factor, and fibroblast growth factor-2 in the lung. Airway remodeling was associated with impaired lung function in the peripheral airways and this was reversed by IL-9 neutralization. In human asthmatic lung tissue, we identified MCs as the main IL-9 receptor expressing population and found them to be sources of vascular endothelial growth factor and fibroblast growth factor-2. CONCLUSIONS: Our data suggest an important role for an IL-9-MC axis in the pathology associated with chronic asthma and demonstrate that an impact on this axis could lead to a reduction in chronic inflammation and improved lung function in patients with asthma. PMID- 20971831 TI - Propioniciclava tarda gen. nov., sp. nov., isolated from a methanogenic reactor treating waste from cattle farms. AB - Two facultatively anaerobic bacterial strains, designated WR061(T) and WR054, were isolated from rice-straw residue in a methanogenic reactor treating waste from cattle farms in Japan. The two strains were phylogenetically positioned close to one another and had almost the same phenotypic properties. Cells were Gram-reaction-positive, non-motile, non-spore-forming, irregular rods. Cobalamin (vitamin B12) was required for growth. The strains utilized various carbohydrates, including hexoses and disaccharides, and produced acetate and propionate from these carbohydrates. Pentoses and polysaccharides were not utilized. They grew at 20-37 degrees C (optimum 35 degrees C) and pH 5.3-8.0 (optimum pH 6.8-7.5). Catalase and nitrate-reducing activities were detected. Aesculin was hydrolysed. The major cellular fatty acids were anteiso-C15:0 and C15:0 DMA, the major respiratory quinone was menaquinone MK-9(H4) and the genomic DNA G+C content was 69.3-69.5 mol%. The diagnostic diamino acid in the peptidoglycan was meso-diaminopimelic acid. Phylogenetic analysis based on 16S rRNA gene sequences placed the strains in the phylum Actinobacteria. Both strains were remotely related to the species in the family Propionibacteriaceae and Propionibacterium propionicum JCM 5830(T) was the most closely related type strain with a sequence similarity of 91.6 %. Based on phylogenetic, physiological and chemotaxonomic analyses, the two novel strains together represent a novel species of a new genus, for which the name Propioniciclava tarda gen. nov., sp. nov. is proposed. The type strain is WR061(T) ( = JCM 15804(T) = DSM 22130(T)). PMID- 20971832 TI - Kroppenstedtia eburnea gen. nov., sp. nov., a thermoactinomycete isolated by environmental screening, and emended description of the family Thermoactinomycetaceae Matsuo et al. 2006 emend. Yassin et al. 2009. AB - A Gram-positive, spore-forming, aerobic, filamentous bacterium, strain JFMB ATE(T), was isolated in 2008 during environmental screening of a plastic surface in grade C in a contract manufacturing organization in southern Germany. The isolate grew at temperatures of 25-50 degrees C and at pH 5.0-8.5, forming ivory coloured colonies with sparse white aerial mycelia. Chemotaxonomic and molecular characteristics of the isolate matched those described for members of the family Thermoactinomycetaceae, except that the cell-wall peptidoglycan contained LL diaminopimelic acid, while all previously described members of this family display this diagnostic diamino acid in meso-conformation. The DNA G+C content of the novel strain was 54.6 mol%, the main polar lipids were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol, and the major menaquinone was MK-7. The major fatty acids had saturated C14-C16 branched chains. No diagnostic sugars were detected. Based on the chemotaxonomic results and 16S rRNA gene sequence analysis, the isolate is proposed to represent a novel genus and species, Kroppenstedtia eburnea gen. nov. sp. nov. The type strain is JFMB-ATE(T) ( = DSM 45196(T) = NRRL B-24804(T) = CCUG 59226(T)). PMID- 20971833 TI - Plasticicumulans acidivorans gen. nov., sp. nov., a polyhydroxyalkanoate accumulating gammaproteobacterium from a sequencing-batch bioreactor. AB - Here, we describe a novel bacterium, strain TUD-YJ37(T), which can accumulate polyhydroxybutyrate (PHB) to more than 85 % (w/w) dry cell weight. The bacterium was isolated from a mixed-culture bioreactor by using a feast-famine regime and its properties were characterized. Phylogenetic analysis based on full 16S rRNA gene sequences revealed that the isolate is a member of the Gammaproteobacteria, forming an independent, deep phylogenetic lineage. It is most closely related to members of the genera Methylocaldum, Methylococcus and Natronocella, with sequence similarities below 91 %. Strain TUD-YJ37(T) was an obligately aerobic, ovoid, Gram-negative bacterium, motile by means of a polar flagellum. It utilized C2-C10 fatty acids as carbon and energy sources. The temperature range for growth was 20-35 degrees C, with an optimum of 30 degrees C; the pH range was 6.0-8.0, without a clear optimum. The major respiratory quinone was Q-8. Polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, three unidentified phospholipids, an unidentified aminolipid and another unidentified lipid. The predominant fatty acids in the membrane polar lipids were C16:1omega7c, C16:0 and C18:1omega7c. The G+C content of the genomic DNA was 67.4 mol%. On the basis of phenotypic, chemotaxonomic and molecular data, the isolate is proposed to represent a novel genus and species, for which the name Plasticicumulans acidivorans gen. nov., sp. nov. is proposed. The type strain of Plasticicumulans acidivorans is TUD-YJ37(T) ( = DSM 23606(T) = CBS 122990(T)). PMID- 20971834 TI - Pseudonocardia kunmingensis sp. nov., an actinobacterium isolated from surface sterilized roots of Artemisia annua L. AB - A Gram-positive, aerobic, actinobacterial strain with rod-shaped spores, designated YIM 63158(T), was isolated from the surface-sterilized roots of Artemisia annua L. collected from Yunnan province, south-west China. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain YIM 63158(T) belonged to the genus Pseudonocardia. The closest neighbours were 'Pseudonocardia sichuanensis' KLBMP 1115 (99.9 % 16S rRNA gene sequence similarity), Pseudonocardia adelaidensis EUM 221(T) (99.1 %) and Pseudonocardia zijingensis DSM 44774(T) (98.8 %); sequence similarities to other members of the genus Pseudonocardia ranged from 98.6 to 94.4 %. The chemotaxonomic characteristics, such as the cell-wall diaminopimelic acid, whole-cell sugars, fatty acid components and major menaquinones, suggested that the isolate belonged to the genus Pseudonocardia. The G+C content of the genomic DNA was 73.3 mol%. On the basis of physiological, biochemical and chemotaxonomic data, including low DNA DNA relatedness between the isolate and other members of the genus Pseudonocardia, it is proposed that strain YIM 63158(T) represents a novel species in this genus, with the name Pseudonocardia kunmingensis sp. nov. The type strain is YIM 63158(T) ( = DSM 45301(T) = CCTCC AA 208078(T)). [corrected]. PMID- 20971835 TI - Proposal of Solimonas aquatica sp. nov., reclassification of Sinobacter flavus Zhou et al. 2008 as Solimonas flava comb. nov. and Singularimonas variicoloris Friedrich and Lipski 2008 as Solimonas variicoloris comb. nov. and emended descriptions of the genus Solimonas and its type species Solimonas soli. AB - A bacterial strain designated NAA16(T) was isolated from a freshwater spring in Taiwan and was characterized using a polyphasic taxonomic approach. Strain NAA16(T) was aerobic, Gram-staining-negative, rod-shaped, non-spore-forming and motile by means of a single polar flagellum. Growth occurred at 20-40 degrees C (optimum, 25 degrees C), at pH 7.0-8.0 (optimum, pH 7.5) and with up to 1 % NaCl (optimum, 0.5 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that the closest relatives of strain NAA16(T) were Singularimonas variicoloris MN28(T), Sinobacter flavus CW-KD 4(T) and Solimonas soli DCY12(T), with respective sequence similarities of 96.7, 96.6 and 96.2 %. Phylogenetic trees reconstructed from 16S rRNA gene or rpoB sequences (encoding the beta-subunit of the RNA polymerase) revealed that the novel strain NAA16(T) and these three closest relatives formed an independent phylogenetic clade within the Gammaproteobacteria. Strain NAA16(T) contained C16:0, C18:1omega7c and summed feature 3 (C16:1omega7c and/or C16:1omega6c) as predominant fatty acids and possessed phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and an uncharacterized aminophospholipid as dominant polar lipids. The major isoprenoid quinone was Q-8. The DNA G+C content of strain NAA16(T) was 66.2 mol%. The taxonomic relationship of strain NAA16(T), Singularimonas variicoloris DSM 15731(T), Sinobacter flavus DSM 18980(T) and Solimonas soli LMG 24014(T) was clarified by means of a direct experimental comparison. Based on phenotypic, chemotaxonomic and phylogenetic data, the descriptions of the genus Solimonas and its type species Solimonas soli are emended. Members of the genus are Gram negative, oxidase- and catalase-positive, aerobic or facultatively anaerobic and chemo-organotrophic. Chemotaxonomically, members of the genus Solimonas possess Q 8 as the major respiratory quinone, C16:0 and C18:1omega7c as predominant fatty acids and phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and an uncharacterized aminophospholipid as dominant polar lipids; the DNA G+C content is 64.9-68.4 mol%. Phylogenetic evidence, supported by chemotaxonomic and phenotypic data, allowed us to assign strain NAA16(T) to the genus Solimonas within the novel species Solimonas aquatica sp. nov. (type strain NAA16(T) = BCRC 17835(T) = LMG 24500(T)). The reclassification of Sinobacter flavus as Solimonas flava comb. nov. (type strain CW-KD 4(T) = DSM 18980(T) = KCTC 12881(T) = CCTCC AB 206145(T)) and Singularimonas variicoloris as Solimonas variicoloris comb. nov. (type strain MN28(T) = DSM 15731(T) = LMG 22844(T)) is also proposed. PMID- 20971837 TI - Board recertification. PMID- 20971838 TI - Breast cancer risk reduction. PMID- 20971839 TI - Clinical assessment of breast cancer risk based on family history. AB - Family history is a key component of breast cancer risk assessment. Family history provides clues as to the likelihood of a hereditary breast cancer syndrome and the need for a cancer genetics referral and can be used in the setting of a breast cancer risk assessment model to estimate a woman's risk. Appropriate breast cancer screening and risk reduction management plans rely on an accurate assessment of a patient's family history. This article reviews the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer Risk Reduction and provides insight into the application of the guidelines in clinical practice. PMID- 20971840 TI - Mammographic breast density: effect on imaging and breast cancer risk. AB - Mammographic breast density has been studied for more than 30 years. Greater breast density not only is related to decreased sensitivity of mammograms because of a masking effect but also is a major independent risk factor for breast cancer. This article defines breast density and reviews literature on quantification of mammographic density that is key to future clinical and research protocols. Important influences on breast density are addressed, including age, menopausal status, exogenous hormones, and genetics of density. Young women with dense breasts benefit from digital mammographic technique. The potential use of supplemental MRI and ultrasound screening techniques in high risk women and women with dense breasts is explored, as are potential risk reduction strategies. PMID- 20971841 TI - Nonhormonal management of hot flashes for women on risk reduction therapy. AB - Hot flashes are very common in women in menopause and can have a detrimental effect on quality of life. Women on risk reduction therapy are particularly prone because treatments, such as tamoxifen, raloxifene, or oophorectomy, have the potential to exacerbate these symptoms. Hormonal treatments, despite the fact that they represent the most effective therapies, are not used for the treatment of hot flashes in these women because of concerns that they may increase the risk for breast cancer. As a result, several nonhormonal therapies have been tested in randomized placebo-controlled trials and shown to be effective, such as paroxetine, venlafaxine, desvenlafaxine, fluoxetine, citalopram, gabapentin, and pregabalin. In addition, several nonpharmacologic therapies have been tested with various successes. An additional consideration is how some of those drugs, especially fluoxetine and paroxetine, interact with the metabolism of tamoxifen. This article discusses these issues, and provides some recommendations regarding use of nonhormonal therapies for treating hot flashes in women on risk reduction therapy, with an emphasis on pharmacogenomic considerations. PMID- 20971842 TI - Breast cancer: noninvasive and special situations. PMID- 20971843 TI - Risk reduction strategies for ductal carcinoma in situ. AB - Ductal carcinoma in situ (DCIS) is a premalignant condition that, if left untreated, may progress to invasive breast cancer. After lumpectomy, DCIS can recur, and about half of recurrences are invasive. In 4 randomized trials, radiation has been shown to decrease the local recurrence rate by about half, though it does not change survival. Based on the results of 3 randomized trials, tamoxifen probably decreases cancer recurrence by about 30%, particularly in young women. Low fat diets, weight loss, and physical activity decrease invasive breast cancer recurrence and may be recommended to certain women with DCIS. Prognostic factors include age, extent of DCIS, margin status, grade, and presence of necrosis, although how these affect adjuvant therapy is unclear. Research evaluating other drugs to reduce recurrence risk and on different ways of delivering radiation continues. PMID- 20971844 TI - Perspectives on margins in DCIS: pathology. AB - All breast carcinomas must originate within the ductal/lobular system as carcinoma in situ, but only a subset of these lesions progress to invasive carcinoma. Although pathologic evaluation of the extent of ductal carcinoma in situ (DCIS), the distance to margins, and the degree of margin involvement provides an estimation of the likelihood of residual disease, the amount of disease in the remaining breast cannot be predicted with certainty. Factors other than residual disease may be more important in determining whether patients with DCIS survive or succumb to breast cancer, including biologically new ipsilateral cancers, contralateral cancers, and the degree of resistance of the normal stroma to invasion. PMID- 20971845 TI - Induction of Sirt1 by mechanical stretch of skeletal muscle through the early response factor EGR1 triggers an antioxidative response. AB - Mechanical loading of muscles by intrinsic muscle activity or passive stretch leads to an increase in the production of reactive oxygen species. The NAD dependent protein deacetylase SIRT1 is involved in the protection against oxidative stress by enhancing FOXO-driven Sod2 transcription. In this report, we unravel a mechanism triggered by mechanical stretch of skeletal muscle cells that leads to an EGR1-dependent transcriptional activation of the Sirt1 gene. The resulting transient increase in SIRT1 expression generates an antioxidative response that contributes to reactive oxygen species scavenging. PMID- 20971846 TI - Determinants of RasC specificity during Dictyostelium aggregation. AB - RasC is required for optimum activation of adenylyl cyclase A and for aggregate stream formation during the early differentiation of Dictyostelium discoideum. RasG is unable to substitute for this requirement despite its sequence similarity to RasC. A critical question is which amino acids in RasC are required for its specific function. Each of the amino acids within the switch 1 and 2 domains in the N-terminal portion of RasG was changed to the corresponding amino acid from RasC, and the ability of the mutated RasG protein to reverse the phenotype of rasC(-) cells was determined. Only the change from aspartate at position 30 of RasG to alanine (the equivalent position 31 in RasC) resulted in a significant increase in adenylyl cyclase A activation and a partial reversal of the aggregation-deficient phenotype of rasC(-) cells. All other single amino acid changes were without effect. Expression of a chimeric protein, RasG(1-77)-RasC(79 189), also resulted in a partial reversal of the rasC(-) cell phenotype, indicating the importance of the C-terminal portion of RasC. Furthermore, expression of the chimeric protein, with alanine changed to aspartate (RasG(1 77(D30A))-RasC(79-189)), resulted in a full rescue the rasC(-) aggregation deficient phenotype. Finally, the expression of either a mutated RasC, with the aspartate 31 replaced by alanine, or the chimeric protein, RasC(1-78)-RasG(78 189), only generated a partial rescue. These results emphasize the importance of both the single amino acid at position 31 and the C-terminal sequence for the specific function of RasC during Dictyostelium aggregation. PMID- 20971847 TI - New functional sulfide oxidase-oxygen reductase supercomplex in the membrane of the hyperthermophilic bacterium Aquifex aeolicus. AB - Aquifex aeolicus, a hyperthermophilic and microaerophilic bacterium, obtains energy for growth from inorganic compounds alone. It was previously proposed that one of the respiratory pathways in this organism consists of the electron transfer from hydrogen sulfide (H(2)S) to molecular oxygen. H(2)S is oxidized by the sulfide quinone reductase, a membrane-bound flavoenzyme, which reduces the quinone pool. We have purified and characterized a novel membrane-bound multienzyme supercomplex that brings together all the molecular components involved in this bioenergetic chain. Our results indicate that this purified structure consists of one dimeric bc(1) complex (complex III), one cytochrome c oxidase (complex IV), and one or two sulfide quinone reductases as well as traces of the monoheme cytochrome c(555) and quinone molecules. In addition, this work strongly suggests that the cytochrome c oxidase in the supercomplex is a ba(3) type enzyme. The supercomplex has a molecular mass of about 350 kDa and is enzymatically functional, reducing O(2) in the presence of the electron donor, H(2)S. This is the first demonstration of the existence of such a respirasome carrying a sulfide oxidase-oxygen reductase activity. Moreover, the kinetic properties of the sulfide quinone reductase change slightly when integrated in the supercomplex, compared with the free enzyme. We previously purified a complete respirasome involved in hydrogen oxidation and sulfur reduction from Aquifex aeolicus. Thus, two different bioenergetic pathways (sulfur reduction and sulfur oxidation) are organized in this bacterium as supramolecular structures in the membrane. A model for the energetic sulfur metabolism of Aquifex aeolicus is proposed. PMID- 20971848 TI - PKC{delta} is activated in a dietary model of steatohepatitis and regulates endoplasmic reticulum stress and cell death. AB - Hepatic steatosis can progress to the clinical condition of non-alcoholic steatohepatitis (NASH), which is a precursor of more serious liver diseases. The novel PKC isoforms delta and epsilon are activated by lipid metabolites and have been implicated in lipid-induced hepatic disease. Using a methionine- and choline deficient (MCD) dietary model of NASH, we addressed the question of whether hepatic PKCdelta and PKCepsilon are activated. With progression from steatosis to steatohepatitis, there was activation and increased PKCdelta protein content coincident with hepatic endoplasmic reticulum (ER) stress parameters. To examine whether similar changes could be induced in vitro, McA-RH 7777 (McA) hepatoma cells were used. We observed that McA cells stored triglyceride and released alanine aminotransferase (ALT) when treated with MCD medium in the presence of fatty acids. Further, MCD medium with palmitic acid, but not oleic or linoleic acids, maximally activated PKCdelta and stimulated ER stress. In PKCdelta knockdown McA cells, MCD/fatty acid medium-induced ALT release and ER stress induction were completely blocked, but triglyceride storage was not. In addition, a reduction in the uptake of propidium iodide and the number of apoptotic nuclei and a significant increase in cell viability and DNA content were observed in PKCdelta knockdown McA cells incubated in MCD medium with palmitic acid. Our studies show that PKCdelta activation and protein levels are elevated in an animal model of steatohepatitis, which was recapitulated in a cell model, supporting the conclusion that PKCdelta plays a role in ALT release, the ER stress signal, and cell death. PMID- 20971849 TI - A single amino acid in human APOBEC3F alters susceptibility to HIV-1 Vif. AB - Human APOBEC3F (huA3F) potently restricts the infectivity of HIV-1 in the absence of the viral accessory protein virion infectivity factor (Vif). Vif functions to preserve viral infectivity by triggering the degradation of huA3F but not rhesus macaque A3F (rhA3F). Here, we use a combination of deletions, chimeras, and systematic mutagenesis between huA3F and rhA3F to identify Glu(324) as a critical determinant of huA3F susceptibility to HIV-1 Vif-mediated degradation. A structural model of the C-terminal deaminase domain of huA3F indicates that Glu(324) is a surface residue within the alpha4 helix adjacent to residues corresponding to other known Vif susceptibility determinants in APOBEC3G and APOBEC3H. This structural clustering suggests that Vif may bind a conserved surface present in multiple APOBEC3 proteins. PMID- 20971850 TI - The rate of folding dictates substrate secretion by the Escherichia coli hemolysin type 1 secretion system. AB - Secretion of the Escherichia coli toxin hemolysin A (HlyA) is catalyzed by the membrane protein complex HlyB-HlyD-TolC and requires a secretion sequence located within the last 60 amino acids of HlyA. The Hly translocator complex exports a variety of passenger proteins when fused N-terminal to this secretion sequence. However, not all fusions are secreted efficiently. Here, we demonstrate that the maltose binding protein (MalE) lacking its natural export signal and fused to the HlyA secretion signal is poorly secreted by the Hly system. We anticipated that folding kinetics might be limiting secretion, and we therefore introduced the "folding" mutation Y283D. Indeed this mutant fusion protein was secreted at a much higher level. This level was further enhanced by the introduction of a second MalE folding mutation (V8G or A276G). Secretion did not require the molecular chaperone SecB. Folding analysis revealed that all mutations reduced the refolding rate of the substrate, whereas the unfolding rate was unaffected. Thus, the efficiency of secretion by the Hly system is dictated by the folding rate of the substrate. Moreover, we demonstrate that fusion proteins defective in export can be engineered for secretion while still retaining function. PMID- 20971851 TI - Phosphorylation of aquaporin-2 regulates its water permeability. AB - Vasopressin-regulated water reabsorption through the water channel aquaporin-2 (AQP2) in renal collecting ducts maintains body water homeostasis. Vasopressin activates PKA, which phosphorylates AQP2, and this phosphorylation event is required to increase the water permeability and water reabsorption of the collecting duct cells. It has been established that the phosphorylation of AQP2 induces its apical membrane insertion, rendering the cell water-permeable. However, whether this phosphorylation regulates the water permeability of this channel still remains unclear. To clarify the role of AQP2 phosphorylation in water permeability, we expressed recombinant human AQP2 in Escherichia coli, purified it, and reconstituted it into proteoliposomes. AQP2 proteins not reconstituted into liposomes were removed by fractionating on density step gradients. AQP2-reconstituted liposomes were then extruded through polycarbonate filters to obtain unilamellar vesicles. PKA phosphorylation significantly increased the osmotic water permeability of AQP2-reconstituted liposomes. We then examined the roles of AQP2 phosphorylation at Ser-256 and Ser-261 in the regulation of water permeability using phosphorylation mutants reconstituted into proteoliposomes. The water permeability of the non-phosphorylation-mimicking mutant S256A-AQP2 and non-phosphorylated WT-AQP2 was similar, and that of the phosphorylation-mimicking mutant S256D-AQP2 and phosphorylated WT-AQP2 was similar. The water permeability of S261A-AQP2 and S261D-AQP2 was similar to that of non-phosphorylated WT-AQP2. This study shows that PKA phosphorylation of AQP2 at Ser-256 enhances its water permeability. PMID- 20971852 TI - Identification of low molecular weight pyroglutamate A{beta} oligomers in Alzheimer disease: a novel tool for therapy and diagnosis. AB - N-terminally truncated Abeta peptides starting with pyroglutamate (AbetapE3) represent a major fraction of all Abeta peptides in the brain of Alzheimer disease (AD) patients. AbetapE3 has a higher aggregation propensity and stability and shows increased toxicity compared with full-length Abeta. In the present work, we generated a novel monoclonal antibody (9D5) that selectively recognizes oligomeric assemblies of AbetapE3 and studied the potential involvement of oligomeric AbetapE3 in vivo using transgenic mouse models as well as human brains from sporadic and familial AD cases. 9D5 showed an unusual staining pattern with almost nondetectable plaques in sporadic AD patients and non-demented controls. Interestingly, in sporadic and familial AD cases prominent intraneuronal and blood vessel staining was observed. Using a novel sandwich ELISA significantly decreased levels of oligomers in plasma samples from patients with AD compared with healthy controls were identified. Moreover, passive immunization of 5XFAD mice with 9D5 significantly reduced overall Abeta plaque load and AbetapE3 levels, and normalized behavioral deficits. These data indicate that 9D5 is a therapeutically and diagnostically effective monoclonal antibody targeting low molecular weight AbetapE3 oligomers. PMID- 20971853 TI - The N-terminal region of twitchin binds thick and thin contractile filaments: redundant mechanisms of catch force maintenance. AB - Catch force maintenance in invertebrate smooth muscles is probably mediated by a force-bearing tether other than myosin cross-bridges between thick and thin filaments. The phosphorylation state of the mini-titin twitchin controls catch. The C-terminal phosphorylation site (D2) of twitchin with its flanking Ig domains forms a phosphorylation-sensitive complex with actin and myosin, suggesting that twitchin is the tether (Funabara, D., Osawa, R., Ueda, M., Kanoh, S., Hartshorne, D. J., and Watabe, S. (2009) J. Biol. Chem. 284, 18015-18020). Here we show that a region near the N terminus of twitchin also interacts with thick and thin filaments from Mytilus anterior byssus retractor muscles. Both a recombinant protein, including the D1 and DX phosphorylation sites with flanking 7th and 8th Ig domains, and a protein containing just the linker region bind to thin filaments with about a 1:1 mol ratio to actin and K(d) values of 1 and 15 MUM, respectively. Both proteins show a decrease in binding when phosphorylated. The unphosphorylated proteins increase force in partially activated permeabilized muscles, suggesting that they are sufficient to tether thick and thin filaments. There are two sites of thin filament interaction in this region because both a 52 residue peptide surrounding the DX site and a 47-residue peptide surrounding the D1 site show phosphorylation-dependent binding to thin filaments. The peptides relax catch force, confirming the region's central role in the mechanism of catch. The multiple sites of thin filament interaction in the N terminus of twitchin in addition to those in the C terminus provide an especially secure and redundant mechanical link between thick and thin filaments in catch. PMID- 20971854 TI - Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity. AB - Neuroinflammation and associated neuronal dysfunction mediated by activated microglia play an important role in the pathogenesis of Alzheimer disease (AD). Microglia are activated by aggregated forms of amyloid-beta protein (Abeta), usually demonstrated in vitro by stimulating microglia with micromolar concentrations of fibrillar Abeta, a major component of amyloid plaques in AD brains. Here we report that amyloid-beta oligomer (AbetaO), at 5-50 nm, induces a unique pattern of microglia activation that requires the activity of the scavenger receptor A and the Ca(2+)-activated potassium channel KCa3.1. AbetaO treatment induced an activated morphological and biochemical profile of microglia, including activation of p38 MAPK and nuclear factor kappaB. Interestingly, although increasing nitric oxide (NO) production, AbetaO did not increase several proinflammatory mediators commonly induced by lipopolyliposaccharides or fibrillar Abeta, suggesting that AbetaO stimulates both common and divergent pathways of microglia activation. AbetaO at low nanomolar concentrations, although not neurotoxic, induced indirect, microglia mediated damage to neurons in dissociated cultures and in organotypic hippocampal slices. The indirect neurotoxicity was prevented by (i) doxycycline, an inhibitor of microglia activation; (ii) TRAM-34, a selective KCa3.1 blocker; and (iii) two inhibitors of inducible NO synthase, indicating that KCa3.1 activity and excessive NO release are required for AbetaO-induced microglial neurotoxicity. Our results suggest that AbetaO, generally considered a neurotoxin, may more potently cause neuronal damage indirectly by activating microglia in AD. PMID- 20971855 TI - Structural insight into the differential effects of omega-3 and omega-6 fatty acids on the production of Abeta peptides and amyloid plaques. AB - Several studies have shown the protective effects of dietary enrichment of various lipids in several late-onset animal models of Alzheimer Disease (AD); however, none of the studies has determined which structure within a lipid determines its detrimental or beneficial effects on AD. High-sensitivity enzyme linked immunosorbent assay (ELISA) shows that saturated fatty acids (SFAs), upstream omega-3 FAs, and arachidonic acid (AA) resulted in significantly higher secretion of both Abeta 40 and 42 peptides compared with long chain downstream omega-3 and monounsaturated FAs (MUFA). Their distinct detrimental action is believed to be due to a structural template found in their fatty acyl chains that lack SFAs, upstream omega-3 FAs, and AA. Immunoblotting experiments and use of APP-C99-transfected COS-7 cells suggest that FA-driven altered production of Abeta is mediated through gamma-secretase cleavage of APP. An early-onset AD transgenic mouse model expressing the double-mutant form of human amyloid precursor protein (APP); Swedish (K670N/M671L) and Indiana (V717F), corroborated in vitro findings by showing lower levels of Abeta and amyloid plaques in the brain, when they were fed a low fat diet enriched in DHA. Our work contributes to the clarification of aspects of structure-activity relationships. PMID- 20971856 TI - Mutations in mitochondrial complex III uniquely affect complex I in Caenorhabditis elegans. AB - Mitochondrial supercomplexes containing complexes I, III, and IV of the electron transport chain are now regarded as an established entity. Supercomplex I.III.IV has been theorized to improve respiratory chain function by allowing quinone channeling between complexes I and III. Here, we show that the role of the supercomplexes extends beyond channeling. Mutant analysis in Caenorhabditis elegans reveals that complex III affects supercomplex I.III.IV formation by acting as an assembly or stabilizing factor. Also, a complex III mtDNA mutation, ctb-1, inhibits complex I function by weakening the interaction of complex IV in supercomplex I.III.IV. Other complex III mutations inhibit complex I function either by decreasing the amount of complex I (isp-1), or decreasing the amount of complex I in its most active form, the I.III.IV supercomplex (isp-1;ctb-1). ctb-1 suppresses a nuclear encoded complex III defect, isp-1, without improving complex III function. Allosteric interactions involve all three complexes within the supercomplex and are necessary for maximal enzymatic activities. PMID- 20971857 TI - Carbohydrate export from the leaf: a highly regulated process and target to enhance photosynthesis and productivity. PMID- 20971858 TI - Fine quantitative trait loci mapping of carbon and nitrogen metabolism enzyme activities and seedling biomass in the maize IBM mapping population. AB - Understanding the genetic basis of nitrogen and carbon metabolism will accelerate the development of plant varieties with high yield and improved nitrogen use efficiency. A robotized platform was used to measure the activities of 10 enzymes from carbon and nitrogen metabolism in the maize (Zea mays) intermated B73 * Mo17 mapping population, which provides almost a 4-fold increase in genetic map distance compared with conventional mapping populations. Seedling/juvenile biomass was included to identify its genetic factors and relationships with enzyme activities. All 10 enzymes showed heritable variation in activity. There were strong positive correlations between activities of different enzymes, indicating that they are coregulated. Negative correlations were detected between biomass and the activity of six enzymes. In total, 73 significant quantitative trait loci (QTL) were found that influence the activity of these 10 enzymes and eight QTL that influence biomass. While some QTL were shared by different enzymes or biomass, we critically evaluated the probability that this may be fortuitous. All enzyme activity QTL were in trans to the known genomic locations of structural genes, except for single cis-QTL for nitrate reductase, Glu dehydrogenase, and shikimate dehydrogenase; the low frequency and low additive magnitude compared with trans-QTL indicate that cis-regulation is relatively unimportant versus trans-regulation. Two-gene epistatic interactions were identified for eight enzymes and for biomass, with three epistatic QTL being shared by two other traits; however, epistasis explained on average only 2.8% of the genetic variance. Overall, this study identifies more QTL at a higher resolution than previous studies of genetic variation in metabolism. PMID- 20971859 TI - Abundance and diversity of archaeal ammonia oxidizers in a coastal groundwater system. AB - Nitrification, the microbially catalyzed oxidation of ammonia to nitrate, is a key process in the nitrogen cycle. Archaea have been implicated in the first part of the nitrification pathway (oxidation of ammonia to nitrite), but the ecology and physiology of these organisms remain largely unknown. This work describes two different populations of sediment-associated ammonia-oxidizing archaea (AOA) in a coastal groundwater system in Cape Cod, MA. Sequence analysis of the ammonia monooxygenase subunit A gene (amoA) shows that one population of putative AOA inhabits the upper meter of the sediment, where they may experience frequent ventilation, with tidally driven overtopping and infiltration of bay water supplying dissolved oxygen, ammonium, and perhaps organic carbon. A genetically distinct population occurs deeper in the sediment, in a mixing zone between a nitrate- and oxygen-rich freshwater zone and a reduced, ammonium-bearing saltwater wedge. Both of these AOA populations are coincident with increases in the abundance of group I crenarchaeota 16S rRNA gene copies. PMID- 20971860 TI - Genetic characterization of plasmid-associated benzalkonium chloride resistance determinants in a Listeria monocytogenes strain from the 1998-1999 outbreak. AB - Quaternary ammonium compounds such as benzalkonium chloride (BC) are widely used as disinfectants in both food processing and medical environments. BC-resistant strains of Listeria monocytogenes have been implicated in multistate outbreaks of listeriosis and have been frequently isolated from food processing plants. However, the genetic basis for BC resistance in L. monocytogenes remains poorly understood. In this study, we have characterized a plasmid (pLM80)-associated BC resistance cassette in L. monocytogenes H7550, a strain implicated in the 1998 1999 multistate outbreak involving contaminated hot dogs. The BC resistance cassette (bcrABC) restored resistance to BC (MIC, 40 MUg/ml) in a plasmid-cured derivative of H7550. All three genes of the cassette were essential for imparting BC resistance. The transcription of H7550 BC resistance genes was increased under sublethal (10 MUg/ml) BC exposure and was higher at reduced temperatures (4, 8, or 25 degrees C) than at 37 degrees C. The level of transcription was higher at 10 MUg/ml than at 20 or 40 MUg/ml. In silico analysis suggested that the BC resistance cassette was harbored by an IS1216 composite transposon along with other genes whose functions are yet to be determined. The findings from this study will further our understanding of the adaptations of this organism to disinfectants such as BC and may contribute to the elucidation of possible BC resistance dissemination in L. monocytogenes. PMID- 20971861 TI - Distribution of antimicrobial resistance and virulence genes in Enterococcus spp. and characterization of isolates from broiler chickens. AB - Enterococci are now frequent causative agents of nosocomial infections. In this study, we analyzed the frequency and distribution of antibiotic resistance and virulence genotypes of Enterococcus isolates from broiler chickens. Fecal and cecal samples from nine commercial poultry farms were collected to quantify total enterococci. Sixty-nine presumptive enterococci were isolated and identified by API 20 Strep, and their susceptibilities to antibiotics were determined. Genotypes were assessed through the use of a novel DNA microarray carrying 70 taxonomic, 17 virulence, and 174 antibiotic resistance gene probes. Total enterococcal counts were different from farm to farm and between sample sources (P < 0.01). Fifty-one (74%) of the isolates were identified as E. faecium, whereas nine (13%), seven (10%), and two (3%) isolates were identified as E. hirae, E. faecalis, and E. gallinarum, respectively. Multiple-antibiotic resistance was evident in E. faecium and E. faecalis isolates. The most common multiple-antibiotic resistance phenotype was Bac Ery Tyl Lin Str Gen Tet Cip. Genes conferring resistance to aminoglycoside (aac, aacA-aphD, aadB, aphA, sat4), macrolide (ermA, ermB, ermAM, msrC), tetracycline (tetL, tetM, tetO), streptogramin (satG_vatE8), bacitracin (bcrR), and lincosamide (linB) antibiotics were detected in corresponding phenotypes. A range of 9 to 12 different virulence genes was found in E. faecalis, including ace, agg, agrB(Efs) (agrB gene of E. faecalis), cad1, the cAM373 and cCF10 genes, cob, cpd1, cylAB, efaA(Efs), and gelE. All seven E. faecalis isolates were found to carry the gelE gene and to hydrolize gelatin and bile salts. Results from this study showed the presence of enterococci of public and environmental health concerns in broiler chicken farms and demonstrated the utility of a microarray to quickly and reliably analyze resistance and virulence genotypes of Enterococcus spp. PMID- 20971862 TI - Inositol catabolism, a key pathway in sinorhizobium meliloti for competitive host nodulation. AB - The nitrogen-fixing symbiont of alfalfa, Sinorhizobium meliloti, is able to use myo-inositol as the sole carbon source. Putative inositol catabolism genes (iolA and iolRCDEB) have been identified in the S. meliloti genome based on their similarities with the Bacillus subtilis iol genes. In this study, functional mutational analysis revealed that the iolA and iolCDEB genes are required for growth not only with the myo-isomer but also for growth with scyllo- and d-chiro inositol as the sole carbon source. An additional, hypothetical dehydrogenase of the IdhA/MocA/GFO family encoded by the smc01163 gene was found to be essential for growth with scyllo-inositol, whereas the idhA-encoded myo-inositol dehydrogenase was responsible for the oxidation of d-chiro-inositol. The putative regulatory iolR gene, located upstream of iolCDEB, encodes a repressor of the iol genes, negatively regulating the activity of the myo- and the scyllo-inositol dehydrogenases. Mutants with insertions in the iolA, smc01163, and individual iolRCDE genes could not compete against the wild type in a nodule occupancy assay on alfalfa plants. Thus, a functional inositol catabolic pathway and its proper regulation are important nutritional or signaling factors in the S. meliloti alfalfa symbiosis. PMID- 20971863 TI - Formation of isobutene from 3-hydroxy-3-methylbutyrate by diphosphomevalonate decarboxylase. AB - Isobutene is an important commercial chemical used for the synthesis of butyl rubber, terephthalic acid, specialty chemicals, and a gasoline performance additive known as alkylate. Currently, isobutene is produced from petroleum and hence is nonrenewable. Here, we report that the Saccharomyces cerevisiae mevalonate diphosphate decarboxylase (ScMDD) can convert 3-hydroxy-3 methylbutyrate (3-HMB) to isobutene. Whole cells of Escherichia coli producing ScMDD with an N-terminal 6*His tag (His(6)-ScMDD) formed isobutene from 3-HMB at a rate of 154 pmol h(-1) g cells(-1). In contrast, no isobutene was detected from control cells lacking ScMDD. His(6)-ScMDD was purified by nickel affinity chromatography and shown to produce isobutene from 3-HMB at a rate of 1.33 pmol min(-1) mg(-1) protein. Controls showed that both His(6)-ScMDD and 3-HMB were required for detectable isobutene formation. Isobutene was identified by gas chromatography (GC) with flame ionization detection as well as by GC-mass spectrometry (MS). ScMDD was subjected to error-prone PCR, and two improved variants were characterized, ScMDD1 (I145F) and ScMDD2 (R74H). Whole cells of E. coli producing ScMDD1 and ScMDD2 produced isobutene from 3-HMB at rates of 3,000 and 5,888 pmol h(-1) g cells(-1), which are 19- and 38-fold increases compared to rates for cells producing His(6)-ScMDD. This showed that genetic modifications can be used to increase the rate at which ScMDD converts 3-HMB to isobutene. Because 3-HMB can be produced from l-leucine, ScMDD has a potential application for the production of renewable isobutene. Moreover, isobutene is a gas, which might simplify its purification from a fermentation medium, substantially reducing production costs. PMID- 20971865 TI - New blue pigment produced by Pantoea agglomerans and its production characteristics at various temperatures. AB - A bacterium capable of producing a deep blue pigment was isolated from the environment and identified as Pantoea agglomerans. The pigment production characteristics of the bacterium under various conditions were studied. The optimal agar plate ingredients for pigment production by the bacterium were first studied: the optimal ingredients were 5 g/liter glucose, 10 g/liter tryptic soy broth, and 40 g/liter glycerol at pH 6.4. Bacterial cells grew on the agar plate during the incubation, while the pigment spread into the agar plate, meaning that it is water soluble. Pigment production was affected by the initial cell density. Namely, at higher initial cell densities ranging from 10(6.3) to 10(8.2) CFU/cm(2) on the agar plate, faster pigment production was observed, but no blue pigment was produced at a very high initial density of 10(9.1) CFU/cm(2). Thus, the cell population of 10(8.2) CFU/cm(2) was used for subsequent study. Although the bacterium was capable of growing at temperatures above and below 10 degrees C, it could produce the pigment only at temperatures of >=10 degrees C. Moreover, the pigment production was faster at higher temperatures in the range of 10 to 20 degrees C. Pigment production at various temperature patterns was well described by a new logistic model. These results suggested that the bacterium could be used in the development of a microbial temperature indicator for the low-temperature storage management of foods and clinical materials. To our knowledge, there is no other P. agglomerans strain capable of producing a blue pigment and the pigment is a new one of microbial origin. PMID- 20971864 TI - High diversity and abundance of Legionella spp. in a pristine river and impact of seasonal and anthropogenic effects. AB - The diversity and dynamics of Legionella species along a French river watershed subject to different thermal and wastewater discharges during an annual cycle were assessed by 16S rRNA gene sequencing and by a fingerprint technique, single strand conformation polymorphism. A high diversity of Legionella spp. was observed at all the sampling sites, and the dominant Legionella clusters identified were most closely related to uncultured bacteria. The monthly monitoring revealed that Legionella sp. diversity changes were linked only to season at the wastewater site whereas there was some evidence for anthropogenic effects on Legionella sp. diversity downstream of the thermal bath. Quantification of Legionella pneumophila and Legionella spp. by culture and quantitative PCR (qPCR) was performed. Whereas only L. pneumophila was quantified on culture media, the qPCR assay revealed that Legionella spp. were ubiquitous and abundant from the pristine source of the river to the downstream sampling sites. These results suggest that Legionella spp. may be present at significant concentrations in many more freshwater environments than previously thought, highlighting the need for further ecological studies and culturing efforts. PMID- 20971866 TI - PCR inhibitor levels in concentrates of biosolid samples predicted by a new method based on excitation-emission matrix spectroscopy. AB - Biosolids contain a wide variety of organic contaminants that are known for their ability to inhibit PCR. During sample processing, these contaminants are coconcentrated with microorganisms. Elevated concentrations of these compounds in concentrates render samples unsuitable for molecular applications. Glycine-based elution and recovery methods have been shown to generate samples with fewer PCR inhibitory compounds than the current U.S. EPA-recommended method for pathogen recovery from biosolids. Even with glycine-based methods, PCR inhibitors still persist in concentrations that may interfere with nucleic acid amplification. This results in considerable loss of time and resources and increases the probability of false negatives. A method to estimate the degree of inhibition prior to application of molecular methods is desirable. Here we report fluorescence excitation-emission matrix (EEM) profiling as a tool for predicting levels of molecular inhibition in sample concentrates of biosolids. PMID- 20971867 TI - Multiple unique Cryptosporidium isolates from three species of ground squirrels (Spermophilus beecheyi, S. beldingi, and S. lateralis) in California. AB - Phylogenetic analyses of the 18S small-subunit (SSU) rRNA and Cryptosporidium oocyst wall protein (COWP) genes indicate that multiple unique Cryptosporidium isolates are shed by separate species of Spermophilus ground squirrels (S. beecheyi, S. beldingi, and S. lateralis) throughout California, despite some squirrel populations' being geographically isolated. The data support our assertion that Spermophilus squirrels shed novel Cryptosporidium species. PMID- 20971868 TI - Purification and characterization of an active N-acetylglucosaminyltransferase enzyme complex from Streptococci. AB - A new family of bacterial serine-rich repeat glycoproteins can function as adhesins required for biofilm formation and pathogenesis in streptococci and staphylococci. Biogenesis of these proteins depends on a gene cluster coding for glycosyltransferases and accessory secretion proteins. Previous studies show that Fap1, a member of this family from Streptococcus parasanguinis, can be glycosylated by a protein glycosylation complex in a recombinant heterogeneous host. Here we report a tandem affinity purification (TAP) approach used to isolate and study protein complexes from native streptococci. This method demonstrated that a putative glycosyltransferase (Gtf2), which is essential for Fap1 glycosylation, readily copurified with another glycosyltransferase (Gtf1) from native S. parasanguinis. This result and the similar isolation of a homologous two-protein complex from Streptococcus pneumoniae indicate the biological relevance of the complexes to the glycosylation in streptococci. Furthermore, novel N-acetylglucosaminyltransferase activity was discovered for the complexes. Optimal activity required heterodimer formation and appears to represent a novel type of glycosylation. PMID- 20971869 TI - Genotypic diversity of Borrelia burgdorferi strains detected in Ixodes scapularis larvae collected from North American songbirds. AB - We genotyped Borrelia burgdorferi strains detected in larvae of Ixodes scapularis removed from songbirds and compared them with those found in host-seeking I. scapularis nymphs sampled throughout the eastern United States. Birds are capable of transmitting most known genotypes, albeit at different frequencies than expected based on genotypes found among host-seeking nymphs. PMID- 20971870 TI - Genetic improvement of Bacillus licheniformis strains for efficient deproteinization of shrimp shells and production of high-molecular-mass chitin and chitosan. AB - By targeted deletion of the polyglutamate operon (pga) in Bacillus licheniformis F11, a derivative form, F11.1 (Deltapga), was obtained that, along with lacking polyglutamate (PGA) formation, displayed enhanced proteolytic activities. The phenotypic properties were maintained in a strain in which the chiBA operon was additionally deleted: F11.4 (DeltachiBA Deltapga). These genetically modified strains, carrying the Deltapga deletion either alone (F11.1) or together with the DeltachiBA (F11.4) deletion, were used in fermentations (20-liter scale) aiming at the deproteinization of shrimp shells in order to obtain long-chain chitin. After chemical deacetylation, the resulting chitosan samples were analyzed by nuclear magnetic resonance spectroscopy, size exclusion chromatography, and viscometry and compared to a chitosan preparation that was produced in parallel by chemical methods by a commercial chitosan supplier (GSRmbH). Though faint lipid impurities were present in the fermented polysaccharides, the viscosity of the material produced with the double-deletion mutant F11.4 (Deltapga DeltachiBA) was higher than that of the chemically produced and commercially available samples (Cognis GmbH). Thus, enhanced proteolytic activities and a lack of chitinase activity render the double mutant F11.4 a powerful tool for the production of long-chain chitosan. PMID- 20971871 TI - Modulation of Pseudomonas aeruginosa biofilm dispersal by a cyclic-Di-GMP phosphodiesterase with a putative hypoxia-sensing domain. AB - Pseudomonas aeruginosa encodes many enzymes that are potentially associated with the synthesis or degradation of the widely conserved second messenger cyclic-di GMP (c-di-GMP). In this study, we show that mutation of rbdA, which encodes a fusion protein consisting of PAS-PAC-GGDEF-EAL multidomains, results in decreased biofilm dispersal. RbdA contains a highly conserved GGDEF domain and EAL domain, which are involved in the synthesis and degradation of c-di-GMP, respectively. However, in vivo and in vitro analyses show that the full-length RbdA protein only displays phosphodiesterase activity, causing c-di-GMP degradation. Further analysis reveals that the GGDEF domain of RbdA plays a role in activating the phosphodiesterase activity of the EAL domain in the presence of GTP. Moreover, we show that deletion of the PAS domain or substitution of the key residues implicated in sensing low-oxygen stress abrogates the functionality of RbdA. Subsequent study showed that RbdA is involved in positive regulation of bacterial motility and production of rhamnolipids, which are associated with biofilm dispersal, and in negative regulation of production of exopolysaccharides, which are required for biofilm formation. These data indicate that the c-di-GMP degrading regulatory protein RbdA promotes biofilm dispersal through its two pronged effects on biofilm development, i.e., downregulating biofilm formation and upregulating production of the factors associated with biofilm dispersal. PMID- 20971872 TI - Effect of sulfadiazine-contaminated pig manure on the abundances of genes and transcripts involved in nitrogen transformation in the root-rhizosphere complexes of maize and clover. AB - The antibiotic sulfadiazine (SDZ) can enter the environment by application of manure from antibiotic-treated animals to arable soil. Because antibiotics are explicitly designed to target microorganisms, they likely affect microbes in the soil ecosystem, compromising important soil functions and disturbing processes in nutrient cycles. In a greenhouse experiment, we investigated the impact of sulfadiazine-contaminated pig manure on functional microbial communities involved in key processes of the nitrogen cycle in the root-rhizosphere complexes (RRCs) of maize (Zea mays) and clover (Trifolium alexandrinum). At both the gene and transcript level, we performed real-time PCR using nifH, amoA (in both ammonia oxidizing bacteria and archaea), nirK, nirS, and nosZ as molecular markers for nitrogen fixation, nitrification, and denitrification. Sampling was performed 10, 20, and 30 days after the application. SDZ affected the abundance pattern of all investigated genes in the RRCs of both plant species (with stronger effects in the RRC of clover) 20 and 30 days after the addition. Surprisingly, effects on the transcript level were less pronounced, which might indicate that parts of the investigated functional groups were tolerant or resistant against SDZ or, as in the case of nifH and clover, have been protected by the nodules. PMID- 20971874 TI - Promising immunomodulatory effects of selected strains of dairy propionibacteria as evidenced in vitro and in vivo. AB - Immunomodulatory properties of 10 dairy propionibacteria, analyzed on human peripheral blood mononuclear cells (PBMCs), revealed a highly strain-dependent induction of anti-inflammatory cytokine interleukin 10 (IL-10). Two selected strains of Propionibacterium freudenreichii showed a protective effect against two models of colitis in mice, suggesting a probiotic potential predicted by immune-based selection criteria for these cheese starter bacteria. PMID- 20971873 TI - Growth and virulence properties of biofilm-forming Salmonella enterica serovar typhimurium under different acidic conditions. AB - This study was designed to characterize the viability and potential virulence of bofilm-forming Salmonella enterica serovar Typhimurium under different pH levels, ranging from 5 to 7. The plate count method and real-time reverse transcription PCR (RT-PCR) were used to evaluate the survival of S. Typhimurium grown in Trypticase soy broth (TSB) adjusted to pH 5, 6, and 7 (TSB-5, TSB-6, and TSB-7, respectively) at 37 degrees C for 10 days. In TSB-5 and TSB-6, the numbers of viable cells estimated by using the real-time RT-PCR were greater than the culturable counts enumerated by the plate count method. Reflectance micro-Fourier transform infrared (micro-FTIR) spectroscopy was used to evaluate the biochemical changes in biofilm cells. Considerable changes in chemical components were observed in the biofilm cells grown in TSB-5 and TSB-6 when compared to the cells grown in TSB-7. The enterotoxin production and invasive ability of planktonic and biofilm S. Typhimurium cells were inferred by the relative levels of expression of stn and invA. The levels of expression of stn and invA were significantly increased in biofilm S. Typhimurium cells grown in TSB-5 (1.9-fold and 3.2-fold) and TSB-6 (2.1-fold and 22.3-fold) after 10 days of incubation. These results suggest that the biofilm-forming S. Typhimurium under different pH levels might change the virulence production and stress response mechanisms. PMID- 20971875 TI - Antimicrobial resistance of Campylobacter isolates from retail meat in the United States between 2002 and 2007. AB - The emergence of antimicrobial resistance in Campylobacter spp. has been a growing public health concern globally. The objectives of this study were to determine the prevalence, antimicrobial susceptibility, and genetic relatedness of Campylobacter spp. recovered by the National Antimicrobial Resistance Monitoring System (NARMS) retail meat program. Retail meat samples (n = 24,566) from 10 U.S. states collected between 2002 and 2007, consisting of 6,138 chicken breast, 6,109 ground turkey, 6,171 ground beef, and 6,148 pork chop samples, were analyzed. A total of 2,258 Campylobacter jejuni, 925 Campylobacter coli, and 7 Campylobacter lari isolates were identified. Chicken breast samples showed the highest contamination rate (49.9%), followed by ground turkey (1.6%), whereas both pork chops and ground beef had <0.5% contamination. The most common resistance was to doxycycline/tetracycline (46.6%), followed by nalidixic acid (18.5%), ciprofloxacin (17.4%), azithromycin and erythromycin (2.8%), telithromycin (2.4%), clindamycin (2.2%), and gentamicin (<0.1%). In a subset of isolates tested, no resistance to meropenem and florfenicol was seen. C. coli isolates showed higher resistance rates to antimicrobials, with the exception of doxycycline/tetracycline, than those seen for C. jejuni. Pulsed-field gel electrophoresis (PFGE) fingerprinting resulted in 1,226 PFGE profiles among the 2,318 isolates, with many clones being widely dispersed throughout the 6-year sampling period. PMID- 20971877 TI - Influence of the composition of the cellulolytic flora on the development of hydrogenotrophic microorganisms, hydrogen utilization, and methane production in the rumens of gnotobiotically reared lambs. AB - We investigated the influence of the composition of the fibrolytic microbial community on the development and activities of hydrogen-utilizing microorganisms in the rumens of gnotobiotically reared lambs. Two groups of lambs were reared. The first group was inoculated with Fibrobacter succinogenes, a non-H(2) producing species, as the main cellulolytic organism, and the second group was inoculated with Ruminococcus albus, Ruminococcus flavefaciens, and anaerobic fungi that produce hydrogen. The development of hydrogenotrophic bacterial communities, i.e., acetogens, fumarate and sulfate reducers, was monitored in the absence of methanogens and after inoculation of methanogens. Hydrogen production and utilization and methane production were measured in rumen content samples incubated in vitro in the presence of exogenous hydrogen (supplemented with fumarate or not supplemented with fumarate) or in the presence of ground alfalfa hay as a degradable substrate. Our results show that methane production was clearly reduced when the dominant fibrolytic species was a non-H(2)-producing species, such as Fibrobacter succinogenes, without significantly impairing fiber degradation and fermentations in the rumen. The addition of fumarate to the rumen contents stimulated H(2) utilization only by the ruminal microbiota inoculated with F. succinogenes, suggesting that these communities could play an important role in fumarate reduction in vivo. PMID- 20971876 TI - Ecophysiology of Fe-cycling bacteria in acidic sediments. AB - Using a combination of cultivation-dependent and -independent methods, this study aimed to elucidate the diversity of microorganisms involved in iron cycling and to resolve their in situ functional links in sediments of an acidic lignite mine lake. Using six different media with pH values ranging from 2.5 to 4.3, 117 isolates were obtained that grouped into 38 different strains, including 27 putative new species with respect to the closest characterized strains. Among the isolated strains, 22 strains were able to oxidize Fe(II), 34 were able to reduce Fe(III) in schwertmannite, the dominant iron oxide in this lake, and 21 could do both. All isolates falling into the Gammaproteobacteria (an unknown Dyella-like genus and Acidithiobacillus-related strains) were obtained from the top acidic sediment zones (pH 2.8). Firmicutes strains (related to Bacillus and Alicyclobacillus) were only isolated from deep, moderately acidic sediment zones (pH 4 to 5). Of the Alphaproteobacteria, Acidocella-related strains were only isolated from acidic zones, whereas Acidiphilium-related strains were isolated from all sediment depths. Bacterial clone libraries generally supported and complemented these patterns. Geobacter-related clone sequences were only obtained from deep sediment zones, and Geobacter-specific quantitative PCR yielded 8 * 10(5) gene copy numbers. Isolates related to the Acidobacterium, Acidocella, and Alicyclobacillus genera and to the unknown Dyella-like genus showed a broad pH tolerance, ranging from 2.5 to 5.0, and preferred schwertmannite to goethite for Fe(III) reduction. This study highlighted the variety of acidophilic microorganisms that are responsible for iron cycling in acidic environments, extending the results of recent laboratory-based studies that showed this trait to be widespread among acidophiles. PMID- 20971878 TI - Phylogenetic, microbiological, and glycoside hydrolase diversities within the extremely thermophilic, plant biomass-degrading genus Caldicellulosiruptor. AB - Phylogenetic, microbiological, and comparative genomic analyses were used to examine the diversity among members of the genus Caldicellulosiruptor, with an eye toward the capacity of these extremely thermophilic bacteria to degrade the complex carbohydrate content of plant biomass. Seven species from this genus (C. saccharolyticus, C. bescii, C. hydrothermalis, C. owensensis, C. kronotskyensis, C. lactoaceticus, and C. kristjanssonii) were compared on the basis of 16S rRNA gene phylogeny and cross-species DNA-DNA hybridization to a whole-genome C. saccharolyticus oligonucleotide microarray, revealing that C. saccharolyticus was the most divergent within this group. Growth physiology of the seven Caldicellulosiruptor species on a range of carbohydrates showed that, while all could be cultivated on acid-pretreated switchgrass, only C. saccharolyticus, C. bescii, C. kronotskyensis, and C. lactoaceticus were capable of hydrolyzing Whatman no. 1 filter paper. Two-dimensional gel electrophoresis of the secretomes from cells grown on microcrystalline cellulose revealed that the cellulolytic species also had diverse secretome fingerprints. The C. saccharolyticus secretome contained a prominent S-layer protein that appears in the cellulolytic Caldicellulosiruptor species, suggesting a possible role in cell-substrate interactions. Growth physiology also correlated with glycoside hydrolase (GH) and carbohydrate-binding module (CBM) inventories for the seven bacteria, as deduced from draft genome sequence information. These inventories indicated that the absence of a single GH and CBM family was responsible for diminished cellulolytic capacity. Overall, the genus Caldicellulosiruptor appears to contain more genomic and physiological diversity than previously reported, and this argues for continued efforts to isolate new members from high-temperature terrestrial biotopes. PMID- 20971879 TI - Identification of the Mhc region as an asthma susceptibility locus in recombinant congenic mice. AB - Mouse models of allergic asthma are characterized by airway hyperreactivity (AHR), Th2-driven eosinophilic airway inflammation, high allergen-specific IgE (anti-OVA IgE) levels in serum, and airway remodeling. Because asthma susceptibility has a strong genetic component, we aimed to identify new asthma susceptibility genes in the mouse by analyzing the asthma phenotypes of the Leishmania major resistant (lmr) recombinant congenic (RC) strains. The lmr RC strains are derived from C57BL/6 and BALB/c intercrosses and carry congenic loci on chromosome 17 (lmr1) and 9 (lmr2) in both backgrounds. Whereas the lmr2 locus on chromosome 9 contributes to a small background-specific effect on anti-OVA IgE and AHR, the lmr1 locus on chromosome 17 mediates a strong effect on Th2-driven eosinophilic airway inflammation and background-specific effects on anti-OVA IgE and AHR. The lmr1 locus contains almost 600 polymorphic genes. To narrow down this number of candidate genes, we performed genome-wide transcriptional profiling on lung tissue from C.lmr1 RC mice and BALB/c control mice. We identified a small number of differentially expressed genes located within the congenic fragment, including a number of Mhc genes, polymorphic between BALB/c and C57Bl/6. The analysis of asthma phenotypes in the C.B10-H2b RC strain, carrying the C57Bl/6 haplotype of the Mhc locus in a BALB/c genetic background, reveals a strikingly similar asthma phenotype compared with C.lmr1, indicating that the differentially expressed genes located within the C.B10-H2b congenic fragment are the most likely candidate genes to contribute to the reduced asthma phenotypes associated with the C57Bl/6 allele of lmr1. PMID- 20971880 TI - Oxidation of Z alpha1-antitrypsin by cigarette smoke induces polymerization: a novel mechanism of early-onset emphysema. AB - The acceleration of chronic obstructive pulmonary disease (COPD) by cigarette smoke (CS) in individuals with severe genetic deficiency of alpha(1)-antitrypsin (Z-AT [Glu342Lys]) exemplifies the critical importance of gene-environmental interactions to the development of COPD. We investigated the molecular basis for the interaction between Z-AT and CS. Female mice (8-10 wk old) transgenic for normal (M-AT) or Z-AT on CBA background were exposed to four 1R3F cigarettes daily for 5 days. Age and sex matched littermates not exposed to CS were used as controls. Bronchoalveolar lavage fluid and lung homogenates were assessed for inflammatory cells, neutrophil elastase, and AT conformers. Z-AT was purified from plasma, exposed to CS extract, and assessed for the development and temporal relationship between AT conformers. Mice transgenic for Z-AT developed a significant increase in pulmonary polymers after acute CS exposure (P = 0.001). There were also increased neutrophils in CS-Z lungs versus controls (P < 0.001), which were tightly correlated with polymer concentrations (r(2) = 0.93). Oxidation of human plasma Z-AT by CS or N-chlorosuccinimide greatly accelerated polymerization (P = 0.004), which could be abrogated by antioxidants (P = 0.359 versus Z control). Our data show that CS accelerates polymerization of Z-AT by oxidative modification, which, in so doing, further reduces pulmonary defense and increases neutrophil influx into the lungs. These novel findings provide a molecular explanation for the striking observation of premature emphysema in ZZ homozygotes who smoke. Further work is required to assess whether antioxidant therapy may be beneficial in Z-AT-related COPD. PMID- 20971881 TI - miR-29 is a major regulator of genes associated with pulmonary fibrosis. AB - MicroRNAs (miRNA) are small regulatory RNAs that control gene expression by translational suppression and destabilization of target mRNAs. There is increasing evidence that miRNAs regulate genes associated with fibrosis in organs, such as the heart, kidney, liver, and the lung. In a large-scale screening for miRNAs potentially involved in bleomycin-induced fibrosis, we found expression of miR-29 family members significantly reduced in fibrotic lungs. Analysis of normal lungs showed the presence of miR-29 in subsets of interstitial cells of the alveolar wall, pleura, and at the entrance of the alveolar duct, known sites of pulmonary fibrosis. miR-29 levels inversely correlated with the expression levels of profibrotic target genes and the severity of the fibrosis. To study the impact of miR-29 down-regulation in the lung interstitium, we characterized gene expression profiles of human fetal lung fibroblast IMR-90 cells in which endogenous miR-29 was knocked down. This confirmed the derepression of reported miR-29 targets, including several collagens, but also revealed up-regulation of a large number of previously unrecognized extracellular matrix-associated and remodeling genes. Moreover, we found that miR-29 is suppressed by transforming growth factor (TGF)-beta1 in these cells, and that many fibrosis-associated genes up-regulated by TGF-beta1 are derepressed by miR 29 knockdown. Interestingly, a comparison of TGF-beta1 and miR-29 targets revealed that miR-29 controls an additional subset of fibrosis-related genes, including laminins and integrins, independent of TGF-beta1. Together, these strongly suggest a role of miR-29 in the pathogenesis of pulmonary fibrosis. miR 29 may be a potential new therapeutic target for this disease. PMID- 20971882 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced MUC5AC expression: aryl hydrocarbon receptor-independent/EGFR/ERK/p38-dependent SP1-based transcription. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent environmental toxicant. Epidemiological studies have associated TCDD exposure with the development of chronic obstructive pulmonary disease, which is manifested by mucous/goblet cell hyperplasia. The purpose of this research was to elucidate the pathway/mechanisms that lead to TCDD-induced gene expression in both primary normal human bronchial epithelial cells and an immortalized cell line, HBE1, under air-liquid interface conditions. TCDD exposure induced a time-dependent elevation of MUC5AC mRNA and protein synthesis, and cytochrome p450 1A1 (CYP1A1) expression in these cells. Treatment with an aryl hydrocarbon receptor antagonist had no effect on TCDD induced MUC5AC expression, but significantly suppressed CYP1A1 induction. However, treatments with inhibitors of signaling pathways and the expression of dominant negative mutants of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK) and p38, but not the inhibition of c Jun N-terminal kinase pathway, abrogated MUC5AC induction, but not that of CYP1A1. These effects also occurred at the MUC5AC promoter-reporter level using the chimeric construct for a transient transfection study. Western blot analysis confirmed the phosphorylation of activated EGFR, ERK, and p38 signaling molecules, but not the c-Jun N-terminal kinase, in cells after TCDD exposure. Specificity protein 1 (Sp1) phosphorylation also occurred in cells after TCDD exposure. Both MUC5AC expression and the promoter activity were inhibited by mithramycin A, an inhibitor specific to Sp1-based transcription. These results lead to the conclusion that TCDD induced MUC5AC expression through a noncanonical aryl hydrocarbon receptor-independent, EGFR/ERK/p38-mediated signaling pathway mediated/Sp1-based transcriptional mechanism. PMID- 20971883 TI - Respiratory syncytial virus infection in human bone marrow stromal cells. AB - Respiratory syncytial virus (RSV) is the most common respiratory pathogen in infants and young children. The pathophysiology of this infection in the respiratory system has been studied extensively, but little is known about its consequences in other systems. We studied whether RSV infects human bone marrow stromal cells (BMSCs) in vitro and in vivo, and investigated whether and how this infection affects BMSC structure and hematopoietic support function. Primary human BMSCs were infected in vitro with recombinant RSV expressing green fluorescent protein. In addition, RNA from naive BMSCs was amplified by PCR, and the products were sequenced to confirm homology with the RSV genome. The BMSC cytoskeleton was visualized by immunostaining for actin. Finally, we analyzed infected BMSCs for the expression of multiple cytokines and chemokines, evaluated their hematopoietic support capacity, and measured their chemotactic activity for both lymphoid and myeloid cells. We found that BMSCs support RSV replication in vitro with efficiency that varies among cell lines derived from different donors; furthermore, RNA sequences homologous to the RSV genome were found in naive primary human BMSCs. RSV infection disrupted cytoskeletal actin microfilaments, altered cytokine/chemokine expression patterns, decreased the ability of BMSCs to support B cell maturation, and modulated local chemotaxis. Our data indicate that RSV infects human BMSCs in vitro, and this infection has important structural and functional consequences that might affect hematopoietic and immune functions. Furthermore, we have amplified viral RNA from naive primary BMSCs, suggesting that in vivo these cells provide RSV with an extrapulmonary target. PMID- 20971885 TI - Viral and host strategies to take advantage of the innate immune response. PMID- 20971886 TI - Productivity, utilization, and nutritive quality of dallisgrass (Paspalum dilatatum) as influenced by stocking density and rest period under continuous or rotational stocking. AB - Dallisgrass (Paspalum dilatatum) is well adapted to the Black Belt physiographic region of the southeastern United States, and information on its productivity and nutritive quality as influenced by grazing management is needed. In a 2-yr grazing experiment, replicate 0.40-ha paddocks in established dallisgrass pasture were continuously stocked, or replicate 0.40-ha paddocks were subdivided into two 0.20-ha (RS2), three 0.13-ha (RS3), or four 0.10-ha (RS4) cells and rotationally stocked with yearling beef steers. Individual cells within the RS2, RS3, and RS4 treatments were stocked for 7 d followed by 7, 14, or 21 d of rest, respectively. In 2007, 3 Angus * Simmental crossbred steers (initial BW, 354 +/- 6 kg) were assigned randomly to each paddock on July 16; in 2008, 3 Angus * Simmental crossbred steers (initial BW, 310 +/- 6 kg) were assigned randomly to each paddock on July 14. In 2007, there was no effect (P = 0.25) of stocking treatment on ADG. Steers grazing RS4, RS2, and continuously stocked paddocks had 106 (P = 0.01), 86 (P = 0.03), and 83 (P = 0.03) kg greater total BW gain per ha, respectively, than steers grazing RS3 paddocks. In 2008, there were no differences among treatments in ADG (P = 0.43) or total BW gain per ha (P = 0.90). Correlation and regression analyses revealed positive associations between steer performance and forage concentration of CP, areal mass (kg/ha) of forage DM, and areal mass of forage CP. Results indicate that productivity and quality of dallisgrass for stocker cattle production were comparable between continuous and rotational-stocking methods. PMID- 20971884 TI - Variant ABO blood group alleles, secretor status, and risk of pancreatic cancer: results from the pancreatic cancer cohort consortium. AB - BACKGROUND: Subjects with non-O ABO blood group alleles have increased risk of pancreatic cancer. Glycosyltransferase activity is greater for the A(1) versus A(2) variant, whereas O01 and O02 variants are nonfunctioning. We hypothesized: 1) A(1) allele would confer greater risk than A(2) allele, 2) protective effect of the O allele would be equivalent for O01 and O02 variants, 3) secretor phenotype would modify the association with risk. METHODS: We determined ABO variants and secretor phenotype from single nucleotide polymorphisms in ABO and FUT2 genes in 1,533 cases and 1,582 controls from 12 prospective cohort studies. Adjusted odds ratios (OR) for pancreatic cancer were calculated using logistic regression. RESULTS: An increased risk was observed in participants with A(1) but not A(2) alleles. Compared with subjects with genotype O/O, genotypes A(2)/O, A(2)/A(1), A(1)/O, and A(1)/A(1) had ORs of 0.96 (95% CI, 0.72-1.26), 1.46 (95% CI, 0.98-2.17), 1.48 (95% CI, 1.23-1.78), and 1.71 (95% CI, 1.18-2.47). Risk was similar for O01 and O02 variant O alleles. Compared with O01/O01, the ORs for each additional allele of O02, A(1), and A(2) were 1.00 (95% CI, 0.87-1.14), 1.38 (95% CI, 1.20-1.58), and 0.96 (95% CI, 0.77-1.20); P, O01 versus O02 = 0.94, A(1) versus A(2) = 0.004. Secretor phenotype was not an effect modifier (P-interaction = 0.63). CONCLUSIONS: Among participants in a large prospective cohort consortium, ABO allele subtypes corresponding to increased glycosyltransferase activity were associated with increased pancreatic cancer risk. IMPACT: These data support the hypothesis that ABO glycosyltransferase activity influences pancreatic cancer risk rather than actions of other nearby genes on chromosome 9q34. PMID- 20971887 TI - In vitro degradation of bovine myofibrils is caused by μ-calpain, not caspase-3. AB - Tenderness is a key palatability trait influencing perception of consumers of meat quality and is influenced by a multitude of factors, including postmortem proteolysis. A fundamental understanding of this biological mechanism regulating tenderness is necessary to decrease variability and increase consumer satisfaction. However, reports regarding the enzyme systems involved in postmortem tenderization are conflicting. Therefore, the objective of this study was to determine if caspase-3 is responsible for the degradation of myofibrillar proteins during aging. Bovine semitendinosus muscles were removed from 2 carcasses. Muscle from the left side of each carcass was excised 20 min postmortem and utilized for in vitro analysis of protein degradation. Muscle strips were dissected from the semitendinosus, restrained to maintain length, and placed in a neutral buffer containing protease inhibitors. Upon rigor completion, myofibrils were isolated from each strip and sarcomere length was determined. Samples with similar sarcomere lengths were selected to minimize the effect of sarcomere length on proteolysis. Myofibrils were then incubated at 22 degrees C with MU-calpain, caspase-3, or MU-calpain + caspase-3 for 0.25, 1, 3, 24, 48, or 72 h at optimum pH for enzyme activity. The semitendinosus from the right side of each carcass was excised 1 d postmortem, cut into 2.54-cm steaks, vacuum packaged, and allowed to age for 2, 4, 7, or 10 d to evaluate normal protein degradation during beef aging. Proteolysis of troponin T, alpha-actinin, and desmin was monitored using SDS-PAGE and Western blotting techniques, whereas proteolysis of titin and nebulin was monitored using SDS-vertical agarose gel electrophoresis and Western blotting. Analysis of Western blots revealed no change in abundance of intact troponin T, desmin, titin, or nebulin over time in myofibrils incubated with caspase-3. However, abundance of these proteins subjected to digestion with MU-calpain and MU-calpain + caspase-3 revealed degradation patterns similar to in situ samples. No degradation of alpha-actinin was observed in in vitro or in situ samples. Results of this study indicate MU calpain, not caspase-3, is responsible for the degradation of key myofibrillar proteins during beef aging. PMID- 20971888 TI - Net energy of soybean oil and choice white grease in diets fed to growing and finishing pigs. AB - The objectives of this experiment were 1) to determine the NE of soybean oil (SBO) and choice white grease (CWG) fed to growing and finishing pigs, 2) to evaluate the effects of inclusion rate of SBO on the NE by growing and finishing pigs, and 3) to determine if there is a difference in the NE of SBO and CWG between growing and finishing pigs. Forty-eight growing (initial BW: 22.13 +/- 1.78 kg) and 48 finishing (initial BW: 84.17 +/- 5.80 kg) barrows were used, and they were housed and fed individually. Within each stage of growth, pigs were allotted to 8 outcome groups of 6 barrows based on BW. Within each outcome group, pigs were randomly allotted to 1 of 6 groups. Two groups at each stage of growth served as an initial slaughter group. Pigs in the remaining groups were assigned to 4 dietary treatments and slaughtered at the conclusion of the experiment. The basal diet contained corn, soybean meal, and no supplemental lipids. Three additional diets were formulated by mixing 95% of the basal diet and 5% SBO, 90% of the basal diet and 10% SBO, or 90% of the basal diet and 10% CWG. Average daily gain and G:F for finishing pigs and apparent total tract digestibility of energy for growing and finishing pigs increased (linear, P < 0.05) with lipid content, but was not affected by lipid source. The lipid gain:protein gain ratio and the energy retention also increased (linear, P <= 0.05) with lipid content in growing and finishing pigs. There were no interactive effects between lipid content and stage of growth or between lipid source and stage of growth on the NE of diets and the NE of dietary lipids. The NE of diets increased (linear, P < 0.01) with increasing SBO (2,056, 2,206, and 2,318 kcal/kg for diets containing 0, 5, or 10% SBO). The NE of the diet containing 10% CWG (2,440 kcal/kg) was greater (P < 0.05) than the NE of the diet containing 10% SBO. The NE of diets was greater (P < 0.05) for finishing pigs than for growing pigs regardless of lipid content or source. The NE of SBO included at 5% (5,073 kcal/kg) was not different from the NE of SBO included at 10% (4,679 kcal/kg), but the NE of CWG (5,900 kcal/kg) was greater (P < 0.05) than the NE of SBO. The stage of growth had no impact on the NE of SBO or CWG. In conclusion, the NE of lipids is not affected by the content of dietary lipids, but the NE of CWG is greater than the NE of SBO. PMID- 20971889 TI - Effect of supplementation of dried distillers grains with solubles on forage intake and characteristics of digestion of beef heifers grazing small-grain pasture. AB - Sixteen ruminally cannulated, English-crossbred heifers (378 +/- 28.4 kg) grazing small-grain pasture (SGP) were used in a completely randomized design to evaluate effects of supplementing different amounts of corn dried distillers grains with solubles (DDGS; 0, 0.2, 0.4, and 0.6% of BW; as-fed basis) on forage intake, digestibility, and rumen fermentation characteristics. The experiment was conducted from April 6 through April 20, 2007. Heifers grazed in a single SGP with supplements offered individually, once daily at 0700 h. Forage and total OM, CP, and NDF intake were not affected (P >= 0.21) by DDGS amount. Digestibility of NDF and ether extract (EE) increased linearly (P < 0.001) when heifers consumed more DDGS. Intake of DM (kg/d and g/kg of BW), ruminal volume (L), fluid dilution rate (%/h), fluid flow rate (L/h) turnover time (h), and particle dilution rate (SGP and DDGS) were not affected (P >= 0.32) by increasing DDGS supplementation amount. In situ DDGS CP kinetic parameters were not affected (P >= 0.25) by increasing DDGS supplementation amount. Forage masticate in situ soluble CP fraction and CP effective degradability increased quadratically (P = 0.01) with increasing DDGS supplementation amount. However, amount of DDGS did not affect forage masticate CP slowly degradable fraction (%; P = 0.39) or degradation rate (%/h; P = 0.63). Rate of in situ disappearance (%/h) for DDGS DM (P = 0.94), forage masticate DM (P = 0.89), and NDF (P = 0.89) were not affected by DDGS supplementation amount, nor was rumen undegradable intake protein (% of CP) for DDGS (P = 0.28) and forage masticate samples (P = 0.93). Ruminal concentration of VFA and ammonia and ruminal pH were not affected (P >= 0.21) by increasing DDGS amount. Results indicated that DDGS can be used in SGP supplements without negatively affecting forage intake, digestibility, or ruminal fermentation. PMID- 20971890 TI - Ruminant Nutrition Symposium: Molecular adaptation of ruminal epithelia to highly fermentable diets. AB - Feeding highly fermentable diets to ruminants is one strategy to increase energy intake. The increase in short-chain fatty acid (SCFA) production and reduced ruminal pH associated with highly fermentable diets imposes a challenge to the metabolism and the regulation of intracellular pH homeostasis of ruminal epithelia. The ruminal epithelia respond to these challenges in a coordinated manner. Whereas the enlargement of absorptive surface area is well documented, emerging evidence at the mRNA and transporter and enzyme activity levels indicate that changes in epithelial cell function may be the initial response. It is not surprising that gene expression analysis has identified pathways involved in fatty acid metabolism, ion transport, and intracellular homeostasis to be the pathways dominantly affected during adaptation and after adaptation to a highly fermentable diet. These findings are important because the intraepithelial metabolism of SCFA, particularly butyrate, helps to maintain the concentration gradient between the cytosol and lumen, thereby facilitating absorption. Butyrate metabolism also controls the intracellular availability of butyrate, which is widely regarded as a signaling molecule. Current data indicate that for butyrate metabolism, 3-hydroxy-3-methylglutaryl-CoA synthase and acetyl-CoA acetyltransferase are potential regulatory points with transient up- and downregulation during diet adaptation. In addition to nutrient transport and utilization, genes involved in the maintenance of cellular tight junction integrity and induction of inflammation have been identified as differentially expressed genes during adaptation to highly fermentable diets. This may have important implications on ruminal epithelial barrier function and the inflammatory response often associated with subacute ruminal acidosis. The objective of this review is to summarize ruminal epithelial adaptation to highly fermentable diets focusing on the changes at the enzyme and transporter activity levels, as well as the underlying molecular changes at the mRNA and protein expression levels. PMID- 20971891 TI - Effects of restricting energy during the gilt developmental period on growth and reproduction of lines differing in lean growth rate: responses in feed intake, growth, and age at puberty. AB - The overall objective was to compare reproductive performance through 4 parities of gilts developed with ad libitum access to feed or with restriction of energy to 75% of ad libitum intake. Effects on growth and pubertal development are reported. The experiment was a 2 * 2 factorial with 661 gilts. One-half of the gilts (n = 330) were allowed ad libitum access to feed from weaning to breeding at 235 d of age (AL), and 331 littermates were developed with ad libitum access to feed to 123 d of age and then restricted to 75% of ad libitum intake to 235 d of age (Res). Diets for gilts on regimen AL were formulated to meet requirements for growth. All nutrients except energy and selenium were increased in the diet fed to gilts on regimen Res so that nutrient intake per unit of BW was expected to be similar to that of gilts on regimen AL. Sires of all gilts were from an industry maternal line. Dams were either an industry Large White-Landrace cross, or Nebraska selection Line 45, producing gilts denoted as LW/LR and L45X, respectively. Traits were recorded every 2 wk. Recording of feed intake and BW began at 53 d of age, and recording of backfat (BF) and LM area (LMA) began at 123 d of age. Estrus detection began at 140 d of age to determine age at puberty (AP). The G:F ratio from 123 to 235 d of age for gilts on the AL regimen was greater (0.269 vs. 0.257, P < 0.01) than for gilts on the Res regimen; the greatest difference occurred in the first 2-wk period following feed restriction. The LW/LR gilts were heavier, had less BF, and had greater LMA than L45X gilts, but interactions with feeding regimen and period of development existed. Feed restriction reduced BW, BF, LMA, and ratio of BF to BW, but had little effect on ratio of LMA to BW. More L45X gilts than LW/LR gilts (98 vs. 93%, P < 0.01) and more gilts developed on regimen AL than regimen Res (98 vs. 91%, P < 0.01) expressed estrus. Mean age at puberty was 178.6 d for LW/LR and 173.0 d for L45X gilts (P < 0.01) and 174.1 d for regimen AL and 177.5 d for regimen Res (P < 0.05). The Res regimen delayed pubertal development. Subsequently, it will be important to determine effects on reproduction through 4 parities. PMID- 20971892 TI - Altered cytochrome P450 expression in mice during pregnancy. AB - Human pregnancy is known to influence hepatic drug metabolism in a cytochrome (P450)-specific manner. However, the underlying mechanisms remain unknown, in part due to a lack of experimental models to study altered drug metabolism during pregnancy. In this study, we examined how pregnancy influences expression of major P450 isoforms in mice. Liver tissues were isolated from female FVB/N-mice at different gestational time points: prepregnancy, 7, 14, and 21 days of pregnancy, and 7 days postpartum. mRNA expression levels of major P450 isoforms (Cyp1a2, Cyp2a5, Cyp2b10, Cyp2c37, Cyp2d22, Cyp2e1, Cyp3a11, and Cyp3a41) in the liver tissues were determined by quantitative real-time polymerase chain reaction. Whereas Cyp2a5 expression was unchanged, Cyp3a41 expression was significantly increased during pregnancy. In contrast, expression of Cyp1a2, Cyp2c37, Cyp2d22, Cyp2e1, and Cyp3a11 was decreased. Expression of Cyp2d22 and Cyp2e1 isoforms correlated with that of peroxisome proliferator-activated receptor (PPAR)alpha in the mouse livers, suggesting potential involvement of PPARalpha in down-regulation of the P450 expression during pregnancy. Effects of pregnancy on expression of other P450 mouse isoforms as well as on in vivo drug disposition remain to be characterized. These results provide a guide for future studies on P450 regulation during pregnancy. PMID- 20971893 TI - A novel glucosylation reaction on anthocyanins catalyzed by acyl-glucose dependent glucosyltransferase in the petals of carnation and delphinium. AB - Glucosylation of anthocyanin in carnations (Dianthus caryophyllus) and delphiniums (Delphinium grandiflorum) involves novel sugar donors, aromatic acyl glucoses, in a reaction catalyzed by the enzymes acyl-glucose-dependent anthocyanin 5(7)-O-glucosyltransferase (AA5GT and AA7GT). The AA5GT enzyme was purified from carnation petals, and cDNAs encoding carnation Dc AA5GT and the delphinium homolog Dg AA7GT were isolated. Recombinant Dc AA5GT and Dg AA7GT proteins showed AA5GT and AA7GT activities in vitro. Although expression of Dc AA5GT in developing carnation petals was highest at early stages, AA5GT activity and anthocyanin accumulation continued to increase during later stages. Neither Dc AA5GT expression nor AA5GT activity was observed in the petals of mutant carnations; these petals accumulated anthocyanin lacking the glucosyl moiety at the 5 position. Transient expression of Dc AA5GT in petal cells of mutant carnations is expected to result in the transfer of a glucose moiety to the 5 position of anthocyanin. The amino acid sequences of Dc AA5GT and Dg AA7GT showed high similarity to glycoside hydrolase family 1 proteins, which typically act as beta-glycosidases. A phylogenetic analysis of the amino acid sequences suggested that other plant species are likely to have similar acyl-glucose-dependent glucosyltransferases. PMID- 20971894 TI - The Medicago truncatula E3 ubiquitin ligase PUB1 interacts with the LYK3 symbiotic receptor and negatively regulates infection and nodulation. AB - LYK3 is a lysin motif receptor-like kinase of Medicago truncatula, which is essential for the establishment of the nitrogen-fixing, root nodule symbiosis with Sinorhizobium meliloti. LYK3 is a putative receptor of S. meliloti Nod factor signals, but little is known of how it is regulated and how it transduces these symbiotic signals. In a screen for LYK3-interacting proteins, we identified M. truncatula Plant U-box protein 1 (PUB1) as an interactor of the kinase domain. In planta, both proteins are localized and interact in the plasma membrane. In M. truncatula, PUB1 is expressed specifically in symbiotic conditions, is induced by Nod factors, and shows an overlapping expression pattern with LYK3 during nodulation. Biochemical studies show that PUB1 has a U-box-dependent E3 ubiquitin ligase activity and is phosphorylated by the LYK3 kinase domain. Overexpression and RNA interference studies in M. truncatula show that PUB1 is a negative regulator of the LYK3 signaling pathway leading to infection and nodulation and is important for the discrimination of rhizobia strains producing variant Nod factors. The potential role of PUB E3 ubiquitin ligases in controlling plant microbe interactions and development through interacting with receptor-like kinases is discussed. PMID- 20971896 TI - The ER-localized TWD1 immunophilin is necessary for localization of multidrug resistance-like proteins required for polar auxin transport in Arabidopsis roots. AB - Multidrug resistance ABC transporters in plants are required for polar transport of the hormone auxin (indole-3-acetic acid). They are studied in animals primarily because their overexpression confers resistance to anticancer agents. Immunophilins are studied in both plants and animals for their roles in folding and trafficking of proteins, particularly those with signal transducing functions and susceptibility to immunosuppressant drugs. Previous genetic and molecular studies in Arabidopsis thaliana established a physical and functional interaction between some ABCB transporters and the TWISTED DWARF1 (TWD1) immunophilin. In this work, confocal microscopy of fluorescently tagged TWD1 shows it to reside at the endoplasmic reticulum (ER). Mutations in TWD1 caused mislocalization of ABCB1, ABCB4, and ABCB19 to the ER instead of the plasma membrane as shown by confocal microscopy of fluorescently tagged fusion proteins and transmission electron microscopy of immunogold-labeled samples in the case of ABCB19. Localization of the unrelated PIN-FORMED2 auxin transporter or plasma membrane marker proteins was not affected by loss of TWD1. Abnormal spread of auxin signaling into the elongation zone of twd1 roots, attributable to mislocalized ABCB transporters and suppressed by an auxin transport inhibitor, appeared to cause the twisted cell files characteristic of twd1 roots. PMID- 20971895 TI - RAD5A, RECQ4A, and MUS81 have specific functions in homologous recombination and define different pathways of DNA repair in Arabidopsis thaliana. AB - Complex DNA structures, such as double Holliday junctions and stalled replication forks, arise during DNA replication and DNA repair. Factors processing these intermediates include the endonuclease MUS81, helicases of the RecQ family, and the yeast SNF2 ATPase RAD5 and its Arabidopsis thaliana homolog RAD5A. By testing sensitivity of mutant plants to DNA-damaging agents, we defined the roles of these factors in Arabidopsis. rad5A recq4A and rad5A mus81 double mutants are more sensitive to cross-linking and methylating agents, showing that RAD5A is required for damage-induced DNA repair, independent of MUS81 and RECQ4A. The lethality of the recq4A mus81 double mutant indicates that MUS81 and RECQ4A also define parallel DNA repair pathways. The recq4A/mus81 lethality is suppressed by blocking homologous recombination (HR) through disruption of RAD51C, showing that RECQ4A and MUS81 are required for processing recombination-induced aberrant intermediates during replication. Thus, plants possess at least three different pathways to process DNA repair intermediates. We also examined HR-mediated double strand break (DSB) repair using recombination substrates with inducible site specific DSBs: MUS81 and RECQ4A are required for efficient synthesis-dependent strand annealing (SDSA) but only to a small extent for single-strand annealing (SSA). Interestingly, RAD5A plays a significant role in SDSA but not in SSA. PMID- 20971897 TI - A maize thiamine auxotroph is defective in shoot meristem maintenance. AB - Plant shoots undergo organogenesis throughout their life cycle via the perpetuation of stem cell pools called shoot apical meristems (SAMs). SAM maintenance requires the coordinated equilibrium between stem cell division and differentiation and is regulated by integrated networks of gene expression, hormonal signaling, and metabolite sensing. Here, we show that the maize (Zea mays) mutant bladekiller1-R (blk1-R) is defective in leaf blade development and meristem maintenance and exhibits a progressive reduction in SAM size that results in premature shoot abortion. Molecular markers for stem cell maintenance and organ initiation reveal that both of these meristematic functions are progressively compromised in blk1-R mutants, especially in the inflorescence and floral meristems. Positional cloning of blk1-R identified a predicted missense mutation in a highly conserved amino acid encoded by thiamine biosynthesis2 (thi2). Consistent with chromosome dosage studies suggesting that blk1-R is a null mutation, biochemical analyses confirm that the wild-type THI2 enzyme copurifies with a thiazole precursor to thiamine, whereas the mutant enzyme does not. Heterologous expression studies confirm that THI2 is targeted to chloroplasts. All blk1-R mutant phenotypes are rescued by exogenous thiamine supplementation, suggesting that blk1-R is a thiamine auxotroph. These results provide insight into the role of metabolic cofactors, such as thiamine, during the proliferation of stem and initial cell populations. PMID- 20971898 TI - Nucleotide parasitism by Simkania negevensis (Chlamydiae). AB - Intracellular bacteria live in an environment rich in most essential metabolites but need special mechanisms to access these substrates. Nucleotide transport proteins (NTTs) catalyze the import of ATP and other nucleotides from the eukaryotic host into the bacterial cell and render de novo synthesis of these compounds dispensable. The draft genome sequence of Simkania negevensis strain Z, a chlamydial organism considered a newly emerging pathogen, revealed four genes encoding putative nucleotide transport proteins (SnNTT1 to SnNTT4), all of which are transcribed during growth of S. negevensis in Acanthamoeba host cells, as confirmed by reverse transcription-PCR. Using heterologous expression in Escherichia coli, we could show that SnNTT1 functions as an ATP/ADP antiporter, SnNTT2 as a guanine nucleotide/ATP/H(+) symporter driven by the membrane potential, and SnNTT3 as a nucleotide triphosphate antiporter. In addition, SnNTT3 is able to transport dCTP, which has not been shown for a prokaryotic transport protein before. No substrate could be identified for SnNTT4. Taking these data together, S. negevensis employs a set of nucleotide transport proteins to efficiently tap its host's energy and nucleotide pools. Although similar to other chlamydiae, these transporters show distinct and unique adaptations with respect to substrate specificities and mode of transport. PMID- 20971899 TI - Insights into the extracytoplasmic stress response of Xanthomonas campestris pv. campestris: role and regulation of {sigma}E-dependent activity. AB - Xanthomonas campestris pv. campestris is an epiphytic bacterium that can become a vascular pathogen responsible for black rot disease of crucifers. To adapt gene expression in response to ever-changing habitats, phytopathogenic bacteria have evolved signal transduction regulatory pathways, such as extracytoplasmic function (ECF) sigma factors. The alternative sigma factor sigma(E), encoded by rpoE, is crucial for envelope stress response and plays a role in the pathogenicity of many bacterial species. Here, we combine different approaches to investigate the role and mechanism of sigma(E)-dependent activation in X. campestris pv. campestris. We show that the rpoE gene is organized as a single transcription unit with the anti-sigma gene rseA and the protease gene mucD and that rpoE transcription is autoregulated. rseA and mucD transcription is also controlled by a highly conserved sigma(E)-dependent promoter within the sigma(E) gene sequence. The sigma(E)-mediated stress response is required for stationary phase survival, resistance to cadmium, and adaptation to membrane-perturbing stresses (elevated temperature and ethanol). Using microarray technology, we started to define the sigma(E) regulon of X. campestris pv. campestris. These genes encode proteins belonging to different classes, including periplasmic or membrane proteins, biosynthetic enzymes, classical heat shock proteins, and the heat stress sigma factor sigma(H). The consensus sequence for the predicted sigma(E)-regulated promoter elements is GGAACTN(15-17)GTCNNA. Determination of the rpoH transcription start site revealed that rpoH was directly regulated by sigma(E) under both normal and heat stress conditions. Finally, sigma(E) activity is regulated by the putative regulated intramembrane proteolysis (RIP) proteases RseP and DegS, as previously described in many other bacteria. However, our data suggest that RseP and DegS are not only dedicated to RseA cleavage and that the proteolytic cascade of RseA could involve other proteases. PMID- 20971900 TI - Regulation and function of Escherichia coli sugar efflux transporter A (SetA) during glucose-phosphate stress. AB - Accumulation of certain nonmetabolizable sugar-phosphates (including alpha-methyl glucoside-6-phosphate) in Escherichia coli is growth inhibitory and elicits the glucose-phosphate stress response. The transcription factor SgrR activates transcription of the small RNA SgrS under stress conditions. SgrS represses translation of mRNAs encoding sugar transporters. The sgrR and sgrS genes are located directly upstream of setA, and this gene organization is conserved in numerous enteric species, prompting the hypothesis that SetA contributes to the glucose-phosphate stress response. SetA is a proton motive force-driven efflux pump capable of transporting various sugars and sugar analogs in vitro. This study demonstrates that setA expression is induced in response to glucose phosphate stress, and this requires SgrR. Under stress conditions, setA is cotranscribed with sgrS from the sgrS promoter. A setA mutant exhibits a growth defect under stress conditions that can be complemented by setA in trans, suggesting that SetA contributes to the optimal cellular recovery from stress. Despite previous in vitro evidence that SetA can promote efflux of the stress causing glucose analog alpha-methyl glucoside, in vivo data in this study indicate that SetA is not the major efflux pump responsible for removal of alpha methyl glucoside under stress conditions. PMID- 20971901 TI - Mapping of the Neisseria meningitidis NadA cell-binding site: relevance of predicted {alpha}-helices in the NH2-terminal and dimeric coiled-coil regions. AB - NadA is a trimeric autotransporter protein of Neisseria meningitidis belonging to the group of oligomeric coiled-coil adhesins. It is implicated in the colonization of the human upper respiratory tract by hypervirulent serogroup B N. meningitidis strains and is part of a multiantigen anti-serogroup B vaccine. Structure prediction indicates that NadA is made by a COOH-terminal membrane anchor (also necessary for autotranslocation to the bacterial surface), an intermediate elongated coiled-coil-rich stalk, and an NH(2)-terminal region involved in cell interaction. Electron microscopy analysis and structure prediction suggest that the apical region of NadA forms a compact and globular domain. Deletion studies proved that the NH(2)-terminal sequence (residues 24 to 87) is necessary for cell adhesion. In this study, to better define the NadA cell binding site, we exploited (i) a panel of NadA mutants lacking sequences along the coiled-coil stalk and (ii) several oligoclonal rabbit antibodies, and their relative Fab fragments, directed to linear epitopes distributed along the NadA ectodomain. We identified two critical regions for the NadA-cell receptor interaction with Chang cells: the NH(2) globular head domain and the NH(2) dimeric intrachain coiled-coil alpha-helices stemming from the stalk. This raises the importance of different modules within the predicted NadA structure. The identification of linear epitopes involved in receptor binding that are able to induce interfering antibodies reinforces the importance of NadA as a vaccine antigen. PMID- 20971902 TI - The Burkholderia cenocepacia LysR-type transcriptional regulator ShvR influences expression of quorum-sensing, protease, type II secretion, and afc genes. AB - Burkholderia cenocepacia is a significant opportunistic pathogen in individuals with cystic fibrosis. ShvR, a LysR-type transcriptional regulator, has previously been shown to influence colony morphology, biofilm formation, virulence in plant and animal infection models, and some quorum-sensing-dependent phenotypes. In the present study, it was shown that ShvR negatively regulates its own expression, as is typical for LysR-type regulators. The production of quorum-sensing signal molecules was detected earlier in growth in the shvR mutant than in the wild type, and ShvR repressed expression of the quorum-sensing regulatory genes cepIR and cciIR. Microarray analysis and transcriptional fusions revealed that ShvR regulated over 1,000 genes, including the zinc metalloproteases zmpA and zmpB. The shvR mutant displayed increased gene expression of the type II secretion system and significantly increased protease and lipase activities. Both ShvR and CepR influence expression of a 24-kb genomic region adjacent to shvR that includes the afcA and afcC operons, required for the production of an antifungal agent; however, the reduction in expression was substantially greater in the shvR mutant than in the cepR mutant. Only the shvR mutation resulted in reduced antifungal activity against Rhizoctonia solani. ShvR, but not CepR, was shown to directly regulate expression of the afcA and afcC promoters. In summary, ShvR was determined to have a significant influence on the expression of quorum-sensing, protease, lipase, type II secretion, and afc genes. PMID- 20971903 TI - Assembly of the type II secretion system: identification of ExeA residues critical for peptidoglycan binding and secretin multimerization. AB - Aeromonas hydrophila secretes a number of protein toxins across the outer membrane via the type II secretion system (T2SS). Assembly of the secretion channel ExeD secretin into the outer membrane is dependent on the peptidoglycan binding domain of ExeA. In this study, the peptidoglycan binding domain PF01471 family members were divided into a prokaryotic group and a eukaryotic group. By comparison of their sequence conservation profiles and their representative crystal structures, we found the prokaryotic members to have a highly conserved pocket(s) that is not present in the eukaryotic members. Substitution mutations of nine amino acids of the pocket were constructed in ExeA. Five of the substitution derivatives showed greatly decreased lipase secretion, accompanied by defects in secretin assembly. In addition, using in vivo cross-linking and in vitro cosedimentation assays, we showed that these mutations decreased ExeA peptidoglycan interactions. These results suggest that the highly conserved pocket in ExeA is the binding site for its peptidoglycan ligand and identify residues critical for this binding. PMID- 20971904 TI - Functional analysis of molybdopterin biosynthesis in mycobacteria identifies a fused molybdopterin synthase in Mycobacterium tuberculosis. AB - Most mycobacterial species possess a full complement of genes for the biosynthesis of molybdenum cofactor (MoCo). However, a distinguishing feature of members of the Mycobacterium tuberculosis complex is their possession of multiple homologs associated with the first two steps of the MoCo biosynthetic pathway. A mutant of M. tuberculosis lacking the moaA1-moaD1 gene cluster and a derivative in which moaD2 was also deleted were significantly impaired for growth in media containing nitrate as a sole nitrogen source, indicating a reduced availability of MoCo to support the assimilatory function of the MoCo-dependent nitrate reductase, NarGHI. However, the double mutant displayed residual respiratory nitrate reductase activity, suggesting that it retains the capacity to produce MoCo. The M. tuberculosis moaD and moaE homologs were further analyzed by expressing these genes in mutant strains of M. smegmatis that lacked one or both of the sole molybdopterin (MPT) synthase-encoding genes, moaD2 and moaE2, and were unable to grow on nitrate, presumably as a result of the loss of MoCo dependent nitrate assimilatory activity. Expression of M. tuberculosis moaD2 in the M. smegmatis moaD2 mutant and of M. tuberculosis moaE1 or moaE2 in the M. smegmatis moaE2 mutant restored nitrate assimilation, confirming the functionality of these genes in MPT synthesis. Expression of M. tuberculosis moaX also restored MoCo biosynthesis in M. smegmatis mutants lacking moaD2, moaE2, or both, thus identifying MoaX as a fused MPT synthase. By implicating multiple synthase-encoding homologs in MoCo biosynthesis, these results suggest that important cellular functions may be served by their expansion in M. tuberculosis. PMID- 20971905 TI - The nodulation of alfalfa by the acid-tolerant Rhizobium sp. strain LPU83 does not require sulfated forms of lipochitooligosaccharide nodulation signals. AB - The induction of root nodules by the majority of rhizobia has a strict requirement for the secretion of symbiosis-specific lipochitooligosaccharides (nodulation factors [NFs]). The nature of the chemical substitution on the NFs depends on the particular rhizobium and contributes to the host specificity imparted by the NFs. We present here a description of the genetic organization of the nod gene cluster and the characterization of the chemical structure of the NFs associated with the broad-host-range Rhizobium sp. strain LPU83, a bacterium capable of nodulating at least alfalfa, bean, and Leucena leucocephala. The nod gene cluster was located on the plasmid pLPU83b. The organization of the cluster showed synteny with those of the alfalfa-nodulating rhizobia, Sinorhizobium meliloti and Sinorhizobium medicae. Interestingly, the strongest sequence similarity observed was between the partial nod sequences of Rhizobium mongolense USDA 1844 and the corresponding LPU83 nod genes sequences. The phylogenetic analysis of the intergenic region nodEG positions strain LPU83 and the type strain R. mongolense 1844 in the same branch, which indicates that Rhizobium sp. strain LPU83 might represent an early alfalfa-nodulating genotype. The NF chemical structures obtained for the wild-type strain consist of a trimeric, tetrameric, and pentameric chitin backbone that shares some substitutions with both alfalfa- and bean-nodulating rhizobia. Remarkably, while in strain LPU83 most of the NFs were sulfated in their reducing terminal residue, none of the NFs isolated from the nodH mutant LPU83-H were sulfated. The evidence obtained supports the notion that the sulfate decoration of NFs in LPU83 is not necessary for alfalfa nodulation. PMID- 20971906 TI - Plantazolicin, a novel microcin B17/streptolysin S-like natural product from Bacillus amyloliquefaciens FZB42. AB - Here we report on a novel thiazole/oxazole-modified microcin (TOMM) from Bacillus amyloliquefaciens FZB42, a Gram-positive soil bacterium. This organism is well known for stimulating plant growth and biosynthesizing complex small molecules that suppress the growth of bacterial and fungal plant pathogens. Like microcin B17 and streptolysin S, the TOMM from B. amyloliquefaciens FZB42 undergoes extensive posttranslational modification to become a bioactive natural product. Our data show that the modified peptide bears a molecular mass of 1,335 Da and displays antibacterial activity toward closely related Gram-positive bacteria. A cluster of 12 genes that covers ~10 kb is essential for the production, modification, export, and self-immunity of this natural product. We have named this compound plantazolicin (PZN), based on the association of several producing organisms with plants and the incorporation of azole heterocycles, which derive from Cys, Ser, and Thr residues of the precursor peptide. PMID- 20971907 TI - Mismatch repair modulation of MutY activity drives Bacillus subtilis stationary phase mutagenesis. AB - Stress-promoted mutations that occur in nondividing cells (adaptive mutations) have been implicated strongly in causing genetic variability as well as in species survival and evolutionary processes. Oxidative stress-induced DNA damage has been associated with generation of adaptive His(+) and Met(+) but not Leu(+) revertants in strain Bacillus subtilis YB955 (hisC952 metB5 leuC427). Here we report that an interplay between MutY and MutSL (mismatch repair system [MMR]) plays a pivotal role in the production of adaptive Leu(+) revertants. Essentially, the genetic disruption of MutY dramatically reduced the reversion frequency to the leu allele in this model system. Moreover, the increased rate of adaptive Leu(+) revertants produced by a MutSL knockout strain was significantly diminished following mutY disruption. Interestingly, although the expression of mutY took place during growth and stationary phase and was not under the control of RecA, PerR, or sigma(B), a null mutation in the mutSL operon increased the expression of mutY several times. Thus, in starved cells, saturation of the MMR system may induce the expression of mutY, disturbing the balance between MutY and MMR proteins and aiding in the production of types of mutations detected by reversion to leucine prototrophy. In conclusion, our results support the idea that MMR regulation of the mutagenic/antimutagenic properties of MutY promotes stationary-phase mutagenesis in B. subtilis cells. PMID- 20971908 TI - Proximity of the start codon to a leaderless mRNA's 5' terminus is a strong positive determinant of ribosome binding and expression in Escherichia coli. AB - An AUG start codon is an important determinant of ribosome binding and expression of leaderless mRNAs in Escherichia coli. Using reporter constructs encoding mRNAs where the AUG start codon is preceded by untranslated leaders of various length and sequence, we find that close proximity of the start codon to the 5' terminus and the leader sequence are strong determinants of both ribosome binding and expression. PMID- 20971909 TI - Mapping interactions between germinants and Clostridium difficile spores. AB - Germination of Clostridium difficile spores is the first required step in establishing C. difficile-associated disease (CDAD). Taurocholate (a bile salt) and glycine (an amino acid) have been shown to be important germinants of C. difficile spores. In the present study, we tested a series of glycine and taurocholate analogs for the ability to induce or inhibit C. difficile spore germination. Testing of glycine analogs revealed that both the carboxy and amino groups are important epitopes for recognition and that the glycine binding site can accommodate compounds with more widely separated termini. The C. difficile germination machinery also recognizes other hydrophobic amino acids. In general, linear alkyl side chains are better activators of spore germination than their branched analogs. However, L-phenylalanine and L-arginine are also good germinants and are probably recognized by distinct binding sites. Testing of taurocholate analogs revealed that the 12-hydroxyl group of taurocholate is necessary, but not sufficient, to activate spore germination. In contrast, the 6- and 7-hydroxyl groups are required for inhibition of C. difficile spore germination. Similarly, C. difficile spores are able to detect taurocholate analogs with shorter, but not longer, alkyl amino sulfonic acid side chains. Furthermore, the sulfonic acid group can be partially substituted with other acidic groups. Finally, a taurocholate analog with an m-aminobenzenesulfonic acid side chain is a strong inhibitor of C. difficile spore germination. In conclusion, C. difficile spores recognize both amino acids and taurocholate through multiple interactions that are required to bind the germinants and/or activate the germination machinery. PMID- 20971910 TI - In vitro studies of peptidoglycan binding and hydrolysis by the Bacillus anthracis germination-specific lytic enzyme SleB. AB - The Bacillus anthracis endospore loses resistance properties during germination when its cortex peptidoglycan is degraded by germination-specific lytic enzymes (GSLEs). Although this event normally employs several GSLEs for complete cortex removal, the SleB protein alone can facilitate enough cortex hydrolysis to produce vulnerable spores. As a means to better understand its enzymatic function, SleB was overexpressed, purified, and tested in vitro for depolymerization of cortex by measurement of optical density loss and the solubilization of substrate. Its ability to bind peptidoglycan was also investigated. SleB functions independently as a lytic transglycosylase on both intact and fragmented cortex. Most of the muropeptide products that SleB generates are large and are potential substrates for other GSLEs present in the spore. Study of a truncated protein revealed that SleB has two domains. The N terminal domain is required for stable peptidoglycan binding, while the C terminal domain is the region of peptidoglycan hydrolytic activity. The C terminal domain also exhibits dependence on cortex containing muramic-delta lactam in order to carry out hydrolysis. As the conditions and limitations for SleB activity are further elucidated, they will enable the development of treatments that stimulate premature germination of B. anthracis spores, greatly simplifying decontamination measures. PMID- 20971911 TI - Glucose-dependent activation of Bacillus anthracis toxin gene expression and virulence requires the carbon catabolite protein CcpA. AB - Sensing environmental conditions is an essential aspect of bacterial physiology and virulence. In Bacillus anthracis, the causative agent of anthrax, transcription of the two major virulence factors, toxin and capsule, is triggered by bicarbonate, a major compound in the mammalian body. Here it is shown that glucose is an additional signaling molecule recognized by B. anthracis for toxin synthesis. The presence of glucose increased the expression of the protective antigen toxin component-encoding gene (pagA) by stimulating induction of transcription of the AtxA virulence transcription factor. Induction of atxA transcription by glucose required the carbon catabolite protein CcpA via an indirect mechanism. CcpA did not bind specifically to any region of the extended atxA promoter. The virulence of a B. anthracis strain from which the ccpA gene was deleted was significantly attenuated in a mouse model of infection. The data demonstrated that glucose is an important host environment-derived signaling molecule and that CcpA is a molecular link between environmental sensing and B. anthracis pathogenesis. PMID- 20971912 TI - The Rcs signal transduction pathway is triggered by enterobacterial common antigen structure alterations in Serratia marcescens. AB - The enterobacterial common antigen (ECA) is a highly conserved exopolysaccharide in Gram-negative bacteria whose role remains largely uncharacterized. In a previous work, we have demonstrated that disrupting the integrity of the ECA biosynthetic pathway imposed severe deficiencies to the Serratia marcescens motile (swimming and swarming) capacity. In this work, we show that alterations in the ECA structure activate the Rcs phosphorelay, which results in the repression of the flagellar biogenesis regulatory cascade. In addition, a detailed analysis of wec cluster mutant strains, which provoke the disruption of the ECA biosynthesis at different levels of the pathway, suggests that the absence of the periplasmic ECA cyclic structure could constitute a potential signal detected by the RcsF-RcsCDB phosphorelay. We also identify SMA1167 as a member of the S. marcescens Rcs regulon and show that high osmolarity induces Rcs activity in this bacterium. These results provide a new perspective from which to understand the phylogenetic conservation of ECA among enterobacteria and the basis for the virulence attenuation detected in wec mutant strains in other pathogenic bacteria. PMID- 20971913 TI - Structural and functional analysis of the type III secretion system from Pseudomonas fluorescens Q8r1-96. AB - Pseudomonas fluorescens Q8r1-96 represents a group of rhizosphere strains responsible for the suppressiveness of agricultural soils to take-all disease of wheat. It produces the antibiotic 2,4-diacetylphloroglucinol and aggressively colonizes the roots of cereal crops. In this study, we analyzed the genome of Q8r1-96 and identified a type III protein secretion system (T3SS) gene cluster that has overall organization similar to that of the T3SS gene cluster of the plant pathogen Pseudomonas syringae. We also screened a collection of 30 closely related P. fluorescens strains and detected the T3SS genes in all but one of them. The Q8r1-96 genome contained ropAA and ropM type III effector genes, which are orthologs of the P. syringae effector genes hopAA1-1 and hopM1, as well as a novel type III effector gene designated ropB. These type III effector genes encoded proteins that were secreted in culture and injected into plant cells by both P. syringae and Q8r1-96 T3SSs. The Q8r1-96 T3SS was expressed in the rhizosphere, but mutants lacking a functional T3SS were not altered in their rhizosphere competence. The Q8r1-96 type III effectors RopAA, RopB, and RopM were capable of suppressing the hypersensitive response and production of reactive oxygen species, two plant immune responses. PMID- 20971914 TI - A cis-encoded antisense small RNA regulated by the HP0165-HP0166 two-component system controls expression of ureB in Helicobacter pylori. AB - Expression of urease is essential for gastric colonization by Helicobacter pylori. The increased level of urease in gastric acidity is due, in part, to acid activation of the two-component system (TCS) consisting of the membrane sensor HP0165 and its response regulator, HP0166, which regulates transcription of the seven genes of the urease gene cluster. We now find that there are two major ureAB transcripts: a 2.7-kb full-length ureAB transcript and a 1.4-kb truncated transcript lacking 3' ureB. Acidic pH (pH 4.5) results in a significant increase in transcription of ureAB, while neutral pH (pH 7.4) increases the truncated 1.4 kb transcript. Northern blot analysis with sense RNA and strand-specific oligonucleotide probes followed by 5' rapid amplification of cDNA ends detects an antisense small RNA (sRNA) encoded by the 5' ureB noncoding strand consisting of ~290 nucleotides (5'ureB-sRNA). Deletion of HP0165 elevates the level of the truncated 1.4-kb transcript along with that of the 5'ureB-sRNA at both pH 7.4 and pH 4.5. Overexpression of 5'ureB-sRNA increases the 1.4-kb transcript, decreases the 2.7-kb transcript, and decreases urease activity. Electrophoretic mobility shift assay shows that unphosphorylated HP0166 binds specifically to the 5'ureB sRNA promoter. The ability of the HP0165-HP0166 TCS to both increase and decrease ureB expression at low and high pHs, respectively, facilitates gastric habitation and colonization over the wide range of intragastric pHs experienced by the organism. PMID- 20971915 TI - C-terminal domain residues important for secretion and attachment of RgpB in Porphyromonas gingivalis. AB - Porphyromonas gingivalis, a periodontal pathogen, expresses a group of surface proteins with a common C-terminal domain (CTD) that are exported by a novel secretion system to the surface, where they are covalently attached. Using RgpB as a model CTD protein, we have produced a series of site-directed mutations in the CTD sequence at conserved residues and at residues that may be modified and, hence, surface attached. The mutant RgpB proteins were expressed in a P. gingivalis host lacking functional RgpB and RgpA Arg-specific proteases. The RgpB mutants produced were Y674F, Y674F Y718F, T675Q S679Q T682Q T684Q, T693Q, F695A, D696A, N698A, G699P, G716P, T724Q, T728Q T730Q, and K732Q and a protein with a deletion of residues 692 to 702 (Delta692-702). The mutants were characterized for cell-associated Arg-specific protease activity and for cellular distribution using anti-Rgp antibodies and Western blotting of culture fractions. All the mutants exhibited cell-associated Arg-specific activity similar to that of the positive control except for the D696A and Delta692-702 mutants. For all mutants, except D696A and Delta692-702, the RgpB proteins were found modified and attached to the cell surface, which was the same profile found in the positive-control strain. Only trace amounts of the precursor form of the Delta692-702 mutant were detected in the outer membrane, with none detected in the periplasm or culture fluid although cell transcript levels were normal. The results suggest that residues 692 to 702 of the CTD, in particular, residue D696, have an important role in the attachment of RgpB at the cell surface and that without attachment secretion does not occur. PMID- 20971917 TI - Detrimental effects of hypoxia-specific expression of uracil DNA glycosylase (Ung) in Mycobacterium smegmatis. AB - Mycobacterium tuberculosis is known to reside latently in a significant fraction of the human population. Although the bacterium possesses an aerobic mode of metabolism, it adapts to persistence under hypoxic conditions such as those encountered in granulomas. While in mammalian systems hypoxia is a recognized DNA damaging stress, aspects of DNA repair in mycobacteria under such conditions have not been studied. We subjected Mycobacterium smegmatis, a model organism, to the Wayne's protocol of hypoxia. Analysis of the mRNA of a key DNA repair enzyme, uracil DNA glycosylase (Ung), by real-time reverse transcriptase PCR (RT-PCR) revealed its downregulation during hypoxia. However, within an hour of recovery of the culture under normal oxygen levels, the Ung mRNA was restored. Analysis of Ung by immunoblotting and enzyme assays supported the RNA analysis results. To understand its physiological significance, we misexpressed Ung in M. smegmatis by using a hypoxia-responsive promoter of narK2 from M. tuberculosis. Although the misexpression of Ung during hypoxia decreased C-to-T mutations, it compromised bacterial survival upon recovery at normal oxygen levels. RT-PCR analysis of other base excision repair gene transcripts (UdgB and Fpg) suggested that these DNA repair functions also share with Ung the phenomenon of downregulation during hypoxia and recovery with return to normal oxygen conditions. We discuss the potential utility of this phenomenon in developing attenuated strains of mycobacteria. PMID- 20971916 TI - Effects of deficiency and overdose of group 2 sigma factors in triple inactivation strains of Synechocystis sp. strain PCC 6803. AB - Acclimation of cyanobacteria to environmental changes includes major changes in the gene expression patterns partly orchestrated by the replacement of a particular sigma subunit with another in the RNA polymerase holoenzyme. The cyanobacterium Synechocystis sp. strain PCC 6803 encodes nine sigma factors, all belonging to the sigma(70) family. Cyanobacteria typically encode many group 2 sigma factors that closely resemble the principal sigma factor. We inactivated three out of the four group 2 sigma factors of Synechocystis simultaneously in all possible combinations and found that all triple inactivation strains grow well under standard conditions. Unlike the other strains, the DeltasigBCD strain, which contains SigE as the only functional group 2 sigma factor, did not grow faster under mixotrophic than under autotrophic conditions. The SigB and SigD factors were important in low-temperature acclimation, especially under diurnal light rhythm. The DeltasigBCD, DeltasigBCE, and DeltasigBDE strains were sensitive to high-light-induced photoinhibition, indicating a central role of the SigB factor in high-light tolerance. Furthermore, the DeltasigBCE strain (SigD is the only functional group 2 sigma factor) appeared to be locked in the high fluorescence state (state 1) and grew slowly in blue but not in orange or white light. Our results suggest that features of the triple inactivation strains can be categorized as (i) direct consequences of the inactivation of a particular sigma factor(s) and (ii) effects resulting from the higher probability that the remaining group 2 sigma factors associate with the RNA polymerase core. PMID- 20971918 TI - The biocide chlorine dioxide stimulates biofilm formation in Bacillus subtilis by activation of the histidine kinase KinC. AB - Bacillus subtilis forms biofilms in response to signals that remain poorly defined. We report that biofilm formation is stimulated by sublethal doses of chlorine dioxide (ClO(2)), an extremely effective and fast-acting biocide. ClO(2) accelerated biofilm formation in B. subtilis as well as in other bacteria, suggesting that biofilm formation is a widely conserved response to sublethal doses of the agent. Biofilm formation depends on the synthesis of an extracellular matrix that holds the constituent cells together. We show that the transcription of the major operons responsible for the matrix production in B. subtilis, epsA-epsO and yqxM-sipW-tasA, was enhanced by ClO(2), in a manner that depended on the membrane-bound kinase KinC. Activation of KinC appeared to be due to the ability of ClO(2) to collapse the membrane potential. Importantly, strains unable to make a matrix were hypersensitive to ClO(2), indicating that biofilm formation is a defensive response that helps protect cells from the toxic effects of the biocide. PMID- 20971920 TI - Volunteering and hypertension risk in later life. AB - OBJECTIVE: This study examined the relationship between volunteer activity and hypertension, a risk factor for cardiovascular disease, renal failure, and cognitive impairment. METHOD: Employing data from the Health and Retirement Study, we estimated regression models of hypertension status that include volunteer activity and psychosocial and health behavior risk factors for middle aged and older persons. RESULTS: Multivariate analyses showed volunteers had lower hypertension risk and lower systolic and diastolic blood pressure than nonvolunteers and that a threshold effect was present, whereby a modest amount of volunteer time commitment (but not a high amount) was associated with lower risk of hypertension. We did neither find support that psychosocial and health behaviors mediated this relationship nor find support for a moderating effect of volunteering for the relationships among health behaviors and hypertension. DISCUSSION: The results of this study indicate that research is needed to determine what mediates the relationship between volunteering and hypertension. PMID- 20971921 TI - Store-operated Ca2+ signaling in dendritic cells occurs independently of STIM1. AB - SOCE via CRAC channels is a critical signaling event in immune cells. Recent studies have identified key proteins underlying this process; STIM is an ER Ca2+ sensor that interacts with Orai, an intrinsic, pore-forming protein of the CRAC channel. In heterologous expression systems, STIM1 regulates SOCE by interacting with Orai1, -2, and -3. In native tissues, however, the precise roles of STIM and Orai proteins are not well defined. Here, we have investigated the molecular components of SOCE signaling in mouse DCs. We show that DCs predominantly express STIM2 and only very low levels of STIM1 compared with T lymphocytes. Upon store depletion with Tg, STIM2 aggregates and interacts selectively with Orai2. In contrast, Tg fails to aggregate STIM1 or enhance STIM1-mediated interactions with Orai proteins. Consistent with this biochemical characterization, stimulation of DCs with the adhesion molecule ICAM-1 selectively recruits STIM2 and Orai2 to the IS. Together, these data demonstrate a novel, STIM2-dependent SOCE signaling pathway in DCs. PMID- 20971922 TI - TCR revision generates functional CD4+ T cells. AB - CD4(+)Vbeta5(+) peripheral T cells in C57BL/6 mice respond to encounter with a peripherally expressed endogenous superantigen by undergoing either deletion or TCR revision. In this latter process, cells lose surface Vbeta5 expression and undergo RAG-dependent rearrangement of endogenous TCRbeta genes, driving surface expression of novel TCRs. Although postrevision CD4(+)Vbeta5(-)TCRbeta(+) T cells accumulate with age in Vbeta5 transgenic mice and bear a diverse TCR Vbeta repertoire, it is unknown whether they respond to homeostatic and antigenic stimuli and thus may benefit the host. We demonstrate in this study that postrevision cells are functional. These cells have a high rate of steady-state homeostatic proliferation in situ, and they undergo extensive MHC class II dependent lymphopenia-induced proliferation. Importantly, postrevision cells do not proliferate in response to the tolerizing superantigen, implicating TCR revision as a mechanism of tolerance induction and demonstrating that TCR dependent activation of postrevision cells is not driven by the transgene-encoded receptor. Postrevision cells proliferate extensively to commensal bacterial Ags and can generate I-A(b)-restricted responses to Ag by producing IFN-gamma following Listeria monocytogenes challenge. These data show that rescued postrevision T cells are responsive to homeostatic signals and recognize self- and foreign peptides in the context of self-MHC and are thus useful to the host. PMID- 20971923 TI - Suppression of TNF-alpha and IL-1 signaling identifies a mechanism of homeostatic regulation of macrophages by IL-27. AB - IL-27 is a pleiotropic cytokine with both activating and inhibitory functions on innate and acquired immunity. IL-27 is expressed at sites of inflammation in cytokine-driven autoimmune/inflammatory diseases, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, and sarcoidosis. However, its role in modulating disease pathogenesis is still unknown. In this study, we found that IL 27 production is induced by TNF-alpha in human macrophages (MPhi) and investigated the effects of IL-27 on the responses of primary human MPhi to the endogenous inflammatory cytokines TNF-alpha and IL-1. In striking contrast to IL 27-mediated augmentation of TLR-induced cytokine production, we found that IL-27 suppressed MPhi responses to TNF-alpha and IL-1beta, thus identifying an anti inflammatory function of IL-27. IL-27 blocked the proximal steps of TNF-alpha signaling by downregulating cell-surface expression of the signaling receptors p55 and p75. The mechanism of inhibition of IL-1 signaling was downregulation of the ligand-binding IL-1RI concomitant with increased expression of the receptor antagonist IL-1Ra and the decoy receptor IL-1RII. These findings provide a mechanism for suppressive effects of IL-27 on innate immune cells and suggest that IL-27 regulates inflammation by limiting activation of MPhi by inflammatory cytokines while preserving initial steps in host defense by augmenting responses to microbial products. PMID- 20971924 TI - IL-13Ralpha2 has a protective role in a mouse model of cutaneous inflammation. AB - IL-13 is expressed in lesions of atopic dermatitis (AD) and has been associated with increased disease severity. IL-13 has two cognate receptors: IL-13Ralpha1 and IL-13Ralpha2. Although IL-13Ralpha2 expression is known to be induced in response to IL-13 in keratinocytes, its function in AD has never been evaluated. We characterized the loss of skin barrier function and the development of cutaneous inflammation in IL-13Ralpha2-null versus wild-type BALB/c mice following an epicutaneous allergen-sensitization/challenge model that shares similarities with human AD. Mice lacking IL-13Ralpha2 had significantly increased transepidermal water loss, cutaneous inflammation, peripheral eosinophilia, and IgG1 and IgE levels compared with wild-type mice. The rate of resolution of the cutaneous inflammation was not significantly altered in the IL-13Ralpha2-null mice. IL-13 induced expression of IL-13Ralpha2 in keratinocyte cell lines and primary human keratinocytes. Depletion of IL-13Ralpha2 in a keratinocyte cell line resulted in increased STAT6 signaling in response to IL-13. In conclusion, IL-13Ralpha2 serves a protective role in the pathogenesis of allergic inflammation and loss of skin barrier function in a mouse model of AD, suggesting that it may be an important endogenous regulator of IL-13-induced cutaneous inflammation in humans. PMID- 20971919 TI - Child health, developmental plasticity, and epigenetic programming. AB - Plasticity in developmental programming has evolved in order to provide the best chances of survival and reproductive success to the organism under changing environments. Environmental conditions that are experienced in early life can profoundly influence human biology and long-term health. Developmental origins of health and disease and life-history transitions are purported to use placental, nutritional, and endocrine cues for setting long-term biological, mental, and behavioral strategies in response to local ecological and/or social conditions. The window of developmental plasticity extends from preconception to early childhood and involves epigenetic responses to environmental changes, which exert their effects during life-history phase transitions. These epigenetic responses influence development, cell- and tissue-specific gene expression, and sexual dimorphism, and, in exceptional cases, could be transmitted transgenerationally. Translational epigenetic research in child health is a reiterative process that ranges from research in the basic sciences, preclinical research, and pediatric clinical research. Identifying the epigenetic consequences of fetal programming creates potential applications in clinical practice: the development of epigenetic biomarkers for early diagnosis of disease, the ability to identify susceptible individuals at risk for adult diseases, and the development of novel preventive and curative measures that are based on diet and/or novel epigenetic drugs. PMID- 20971926 TI - Induction of cardiac angiogenesis requires killer cell lectin-like receptor 1 and alpha4beta7 integrin expression by NK cells. AB - Recent findings indicate that NK cells are involved in cardiac repair following myocardial infarction. The aim of this study is to investigate the role NK cells in infarct angiogenesis and cardiac remodeling. In normal C57BL/6 mice, myelomonocytic inflammatory cells invaded infarcted heart within 24 h followed by a lymphoid/NK cell infiltrate by day 6, accompanied by substantial expression of IL-2, TNF-alpha, and CCL2. In contrast, NOD SCID mice had virtually no lymphoid cells infiltrating the heart and did not upregulate IL-2 levels. In vitro and in vivo, IL-2-activated NK cells promoted TNF-alpha-stimulated endothelial cell proliferation, enhanced angiogenesis and reduced fibrosis within the infarcted myocardium. Adoptive transfer of IL-2-activated NK cells to NOD SCID mice improved post-myocardial infarction angiogenesis. RNA silencing technology and neutralizing Abs demonstrated that this process involved alpha4beta7 integrin/VCAM-1 and killer cell lectin-like receptor 1/N-cadherin-specific binding. In this study, we show that IL-2-activated NK cells reduce myocardial collagen deposition along with an increase in neovascularization following acute cardiac ischemia through specific interaction with endothelial cells. These data define a potential role of activated NK cells in cardiac angiogenesis and open new perspectives for the treatment of ischemic diseases. PMID- 20971925 TI - Cyclooxygenase-2 enhances antimicrobial peptide expression and killing of Staphylococcus aureus. AB - Antimicrobial peptides such as human beta-defensins (hBDs) and cathelicidins are critical for protection against infection and can be induced by activation of TLRs, a pathway that also activates cyclooxygenase(Cox)-2 expression. We hypothesized that Cox-2 is induced by TLR activation and is necessary for optimal AMP production, and that inhibitors of Cox-2 may therefore inhibit antimicrobial action. Normal human keratinocytes (NHEKs) stimulated with a TLR2/6 ligand, macrophage-activating lipopeptide-2, or a TLR3 ligand, polyinosinic-polycytidylic acid, increased Cox-2 mRNA and protein and increased PGE(2), a product of Cox-2. Treatment with a Cox-2 selective inhibitor (SC-58125) or Cox-2 small interfering RNA attenuated hBD2 and hBD3 production in NHEKs when stimulated with macrophage activating lipopeptide-2, polyinosinic-polycytidylic acid, or UVB (15 mJ/cm(2)), but it did not attenuate vitamin D3-induced cathelicidin. SC-58125 also inhibited TLR-dependent NF-kappaB activation. Conversely, treatment with Cox-derived prostanoids PGD(2) or 15-deoxy-Delta(12,14)-PGJ(2) induced hBD3 or hBD2 and hBD3, respectively. The functional significance of these observations was seen in NHEKs that showed reduced anti-staphylococcal activity when treated with a Cox-2 inhibitor. These findings demonstrate a critical role for Cox-2 in hBD production and suggest that the use of Cox-2 inhibitors may adversely influence the risk for bacterial infection. PMID- 20971927 TI - Serum antibodies critically affect virus-specific CD4+/CD8+ T cell balance during respiratory syncytial virus infections. AB - Following infection with respiratory syncytial virus (RSV), reinfection in healthy individuals is common and presumably due to ineffective memory T cell responses. In peripheral blood of healthy adults, a higher CD4(+)/CD8(+) memory T cell ratio was observed compared with the ratio of virus-specific effector CD4(+)/CD8(+) T cells that we had found in earlier work during primary RSV infections. In mice, we show that an enhanced ratio of RSV-specific neutralizing to nonneutralizing Abs profoundly enhanced the CD4(+) T cell response during RSV infection. Moreover, FcgammaRs and complement factor C1q contributed to this Ab mediated enhancement. Therefore, the increase in CD4(+) memory T cell response likely occurs through enhanced endosomal Ag processing dependent on FcgammaRs. The resulting shift in memory T cell response was likely amplified by suppressed T cell proliferation caused by RSV infection of APCs, a route important for Ag presentation via MHC class I molecules leading to CD8(+) T cell activation. Decreasing memory CD8(+) T cell numbers could explain the inadequate immunity during repeated RSV infections. Understanding this interplay of Ab-mediated CD4(+) memory T cell response enhancement and infection mediated CD8(+) memory T cell suppression is likely critical for development of effective RSV vaccines. PMID- 20971928 TI - Hoxa9 regulates Flt3 in lymphohematopoietic progenitors. AB - Early B cell factor (EBF) is a transcription factor essential for specification and commitment to the B cell fate. In this study, we show downregulation of a developmentally regulated cluster of hoxa genes, notably hoxa9, coincides with induction of EBF at the Pro-B cell stage of B cell differentiation. Analysis of the hematopoietic progenitor compartment in Hoxa9(-/-) mice revealed significantly reduced frequencies and expression levels of Flt3, a cytokine receptor important for lymphoid priming and the generation of B cell precursors (BCPs). We show that Hoxa9 directly regulates the flt3 gene. Chromatin immunoprecipitation analysis revealed binding of Hoxa9 to the flt3 promoter in a lymphoid progenitor cell line. Knockdown of Hoxa9 significantly reduced Flt3 transcription and expression. Conversely, forced expression of Hoxa9 increased Flt3 transcription and expression in a Pro-B cell line that expressed low levels of Flt3. Hoxa9 inversely correlated with ebf1 in ex vivo-isolated bone marrow progenitors and BCPs, suggesting that EBF might function to silence a Hoxa9 transcriptional program. Restoration of EBF function in an EBF(-/-) cell line induced B lineage gene expression but did not directly suppress hoxa9 transcription, revealing alternate mechanisms of Hoxa9 regulation in BCPs. These data provide new insight into Hoxa9 function and regulation during lymphoid and B cell development. Furthermore, they suggest that failure to upregulate Flt3 provides a molecular basis for the lymphoid/early B cell deficiencies in Hoxa9(-/ ) mice. PMID- 20971929 TI - Antigen-specific Th9 cells exhibit uniqueness in their kinetics of cytokine production and short retention at the inflammatory site. AB - Recently reported lines of Th9 cells, producing IL-9 and IL-10, were generated by polarization with IL-4 and TGF-beta and activation with Abs against CD3 and CD28. In this paper, we analyzed features of Th9 lines similarly polarized but activated by the "natural mode" (i.e., exposure of CD4 cells to their target Ag, hen egg lysozyme [HEL] and APCs). Main observations are the following: 1) both IL 9 and IL-10 were expressed by the line cells, but with strikingly different kinetics, with IL-9 being produced rapidly, reaching a peak on day 3 in culture and declining sharply thereafter, whereas IL-10 production increased gradually, resembling IL-4 and IL-17 production by their corresponding lineage cells; 2) reactivation of Th9, following expansion, triggered faster and higher production of both IL-9 and IL-10; 3) incubating Th9 cells in polarizing media specific for other phenotypes stimulated moderate levels of phenotype switching to Th1 or Th17 but a massive switching to Th2; 4) Th9 cells induced moderate inflammation in HEL expressing recipient eyes but only when producing high levels of IL-9; and 5) IL 9-producing donor cells were detected in the blood of Th9 recipients but not in their inflamed eyes, suggesting that similar to findings in culture, exposure to HEL in these eyes arrested the IL-9 production in Th9 cells. Collectively, these data provide new information concerning Th9 cells and reveal their uniqueness, in particular with regard to the unusual production kinetics of IL-9 and the short retention of these cells in affected target tissues. PMID- 20971930 TI - Implementing health reform and moving past "turf wars". PMID- 20971931 TI - Mandatory overtime regulations and nurse overtime. AB - A descriptive study used data from the 2004 National Sample Survey of Registered Nurses to examine the nature and occurrence of RN mandatory, voluntary overtime, paid on-call, and total work hours and their association with mandatory overtime regulations in United States. About half of the nurses worked more than 40 hrs per week. Nurses working in states regulating mandatory overtime reported lower levels of mandatory overtime hours than states without regulations or states restricting total work hours. The percent of RNs working 61 hrs and over per week in states without regulations was lower than that in states with regulations. Nurses working in nursing homes reported higher levels of the percentage of mandatory overtime hours worked than those working in hospitals. This suggested that governments need to continuously supervise healthcare institutions, including both hospitals and nursing homes, to ensure adherence to mandatory overtime regulations. PMID- 20971932 TI - The patient lock model(c): a continuum of care. AB - Nursing as a profession has the responsibility to society to protect and promote the health of individuals and communities. The intent of this conceptual model is to center the patient in his or her environment while allowing qualified, expert health professionals to provide timely, effective, cost-efficient care within their levels of competence and expertise. Significant shortages of registered nurses and other health professionals delay timely provision of quality care and affect the effectiveness of care. Care management issues are due to the complexity of individual patient's health care needs, limited access to providers, inability to afford treatment, and delay in seeking care. These challenges to the system slow efficiency in the provision of care across all settings. In presenting this conceptual model, there will be a review of nursing and the internal and external forces that affect the profession. This is an initial development phase of the model: The Patient Lock Model. PMID- 20971933 TI - Introduction: Building Global Alliances V: The Challenges of Migration For Health Professional Women. AB - The following four articles are based on presentations delivered at Building Global Alliances V: The Challenges of Migration for Health Professional Women, held in Philadelphia on December 7-8, 2008 and hosted by CGFNS International (formerly the Commission on Graduates of Foreign Nursing Schools). PMID- 20971934 TI - Trafficked women: links to migration and other forms of transnational movement. AB - This article is based on a presentation delivered to The Fifth Annual Building Global Alliances Symposium: "The Challenges of Migration for Health Professional Women," convened by CGFNS International, Philadelphia, PA, December 8, 2008. PMID- 20971936 TI - Hedonic and nucleus accumbens neural responses to a natural reward are regulated by aversive conditioning. AB - The nucleus accumbens (NAc) plays a role in hedonic reactivity to taste stimuli. Learning can alter the hedonic valence of a given stimulus, and it remains unclear how the NAc encodes this shift. The present study examined whether the population response of NAc neurons to a taste stimulus is plastic using a conditioned taste aversion (CTA) paradigm. Electrophysiological and electromyographic (EMG) responses to intraoral infusions of a sucrose (0.3 M) solution were made in naive rats (Day 1). Immediately following the session, half of the rats (n = 6; Paired) received an injection of lithium chloride (0.15 M; i.p.) to induce malaise and establish a CTA while the other half (n = 6; Unpaired) received a saline injection. Days later (Day 5), NAc recordings during infusions of sucrose were again made. Electrophysiological and EMG responses to sucrose did not differ between groups on Day 1. For both groups, the majority of sucrose responsive neurons exhibited a decrease in firing rate (77% and 71% for Paired and Unpaired, respectively). Following conditioning, in Paired rats, EMG responses were indicative of aversion. Moreover, the majority of responsive NAc neurons now exhibited an increase in firing rate (69%). Responses in Unpaired rats were unchanged by the experience. Thus, the NAc differentially encodes the hedonic value of the same stimulus based on learned associations. PMID- 20971937 TI - The effect of D-cycloserine on immediate vs. delayed extinction of learned fear. AB - We compared the effect of D-cycloserine (DCS) on immediate (10 min after conditioning) and delayed (24 h after conditioning) extinction of learned fear in rats. DCS facilitated both immediate and delayed extinction when the drug was administered after extinction training. However, DCS did not facilitate immediate extinction when administered prior to extinction training (i.e., when the interval between drug administration and shock was reduced). In addition, administering five, but not two, shocks prior to extinction training disrupted the facilitating effects of DCS on delayed extinction. These results suggest that aversive experiences prior to DCS administration can prevent it from facilitating extinction. PMID- 20971938 TI - Ginseng inhibits cardiomyocyte hypertrophy and heart failure via NHE-1 inhibition and attenuation of calcineurin activation. AB - BACKGROUND: Ginseng is a medicinal plant used widely in Asia that has gained popularity in the West during the past decade. Increasing evidence suggests a therapeutic role for ginseng in the cardiovascular system. The pharmacological properties of ginseng are mainly attributed to ginsenosides, the principal bioactive constituents in ginseng. The present study was carried out to determine whether ginseng exerts a direct antihypertrophic effect in cultured cardiomyocytes and whether it modifies the heart failure process in vivo. Moreover, we determined the potential underlying mechanisms for these actions. METHODS AND RESULTS: Experiments were performed on cultured neonatal rat ventricular myocytes as well as adult rats subjected to coronary artery ligation (CAL). Treatment of cardiomyocytes with the alpha(1) adrenoceptor agonist phenylephrine (PE) for 24 hours produced a marked hypertrophic effect as evidenced by significantly increased cell surface area and ANP gene expression. These effects were attenuated by ginseng in a concentration-dependent manner with a complete inhibition of hypertrophy at a concentration of 10 MUg/mL. Phenylephrine-induced hypertrophy was associated with increased gene and protein expression of the Na(+)-H(+) exchanger 1 (NHE-1), increased NHE-1 activity, increased intracellular concentrations of Na(+) and Ca(2+), enhanced calcineurin activity, increased translocation of NFAT3 into nuclei, and GATA-4 activation, all of which were significantly inhibited by ginseng. Upregulation of these systems was also evident in rats subjected to 4 weeks of CAL. However, animals treated with ginseng demonstrated markedly reduced hemodynamic and hypertrophic responses, which were accompanied by attenuation of upregulation of NHE-1 and calcineurin activity. CONCLUSIONS: Taken together, our results demonstrate a robust antihypertrophic and antiremodeling effect of ginseng, which is mediated by inhibition of NHE-1-dependent calcineurin activation. PMID- 20971940 TI - Nutrition status and risk factors associated with length of hospital stay for surgical patients. AB - OBJECTIVE: To diagnose the nutrition status of hospitalized patients and identify the risk factors associated with hospital length of stay (LOS). METHODS: The subjective approach and the body mass index (BMI) were used to classify the nutrition status, and other indicators (anthropometry, biochemistry, and energy intake) were analyzed regarding their association with length of hospital stay of 350 patients. The chi-square test was used to compare proportions, and the Mann Whitney or Kruskal-Wallis test was used to compare continuous measures. Linear association was verified using Spearman's rank correlation coefficient. Cox's regression model was used to investigate factors associated with LOS. RESULTS: Disease was the factor that influenced LOS the most in the studied population. Longer LOS prevailed in males (P < .0001), patients aged >=60 years (P = .0008), patients with neoplasms (P < .0001), patients who lost weight during their hospital stay (P < .0001), and malnourished patients (P = .0034). There was a negative and significant, but weak, correlation between LOS and nutrition indicators (calf circumference, arm circumference, triceps skinfold thickness, subscapular skinfold thickness, arm fat area, lymphocyte count, and hemoglobin). Among adults, well-nourished patients were 3 times more likely to be discharged sooner (P = .0002, RR = 3.3 [1.7-6.2]) than those who had some degree of malnutrition. Well-nourished patients with digestive tract diseases (DTD) were also discharged sooner than malnourished patients with the same condition (P = .02, RR = 2.5 [1.1-5.8]). In patients with neoplasms, arm circumference was an independent risk factor to assess LOS (P = .009, RR = 1.1 [1.0-1.1]). CONCLUSIONS: LOS was associated with disease and nutrition status. Among the more common diseases, nutrition status according to the subjective approach determined the LOS for patients with DTD and nutrition status according to arm circumference determined the LOS for patients with neoplasms. PMID- 20971939 TI - Temporal effects of catalase overexpression on healing after myocardial infarction. AB - BACKGROUND: Reactive oxygen species, such as hydrogen peroxide (H(2)O(2)), contribute to progression of dysfunction after myocardial infarction (MI). However, chronic overexpression studies do not agree with acute protein delivery studies. The purpose of the present study was to assess the temporal role of cardiomyocyte-derived H(2)O(2) scavenging on cardiac function after infarction using an inducible system. METHODS AND RESULTS: We developed a tamoxifen inducible, cardiomyocyte-specific, catalase-overexpressing mouse. Catalase overexpression was induced either 5 days before or after MI. Mice exhibited a 3 fold increase in cardiac catalase activity that was associated with a significant decrease in H(2)O(2) levels at both 7 and 21 days. However, cardiac function improved only at the later time point. Proinflammatory and fibrotic genes were acutely upregulated after MI, but catalase overexpression abolished the increase despite no acute change in function. This led to reduced overall scar formation, with lower levels of Collagen 1A and increased contractile Collagen 3A expression at 21 days. CONCLUSIONS: In contrast to prior studies, there were no acute functional improvements with physiological catalase overexpression before MI. Scavenging of H(2)O(2), however, reduced proinflammatory cytokines and altered cardiac collagen isoforms, associated with an improvement in cardiac function after 21 days. Our results suggest that sustained H(2)O(2) levels rather than acute levels immediately after MI may be critical in directing remodeling and cardiac function at later time points. PMID- 20971945 TI - Cardiac hamartoma in a young squirrel monkey who died suddenly. AB - A case of cardiac hamartoma in a 2-month-old squirrel monkey is reported. The monkey showed a loss of appetite and died suddenly. Microscopically, an encapsulated nodular lesion was found at the right atrial wall. The lesion consisted of irregularly shaped, slender myocytes intermingled with a few fibroblasts and collagen fibers. Neither nuclear atypia nor inflammatory cell infiltrate was seen. The constituting cells had stratified striations in the cytoplasm and reacted immunohistochemically for desmin, indicating the nature of myocytes. Based on the above findings, a diagnosis of cardiac hamartoma was made. This is the first case of cardiac hamartoma in this species. PMID- 20971946 TI - Identification of a novel A4GALT exon reveals the genetic basis of the P1/P2 histo-blood groups. AB - The A4GALT locus encodes a glycosyltransferase that synthesizes the terminal Galalpha1-4Gal of the P(k) (Gb3/CD77) glycosphingolipid, important in transfusion medicine, obstetrics, and pathogen susceptibility. Critical nucleotide changes in A4GALT not only abolish P(k) formation but also another Galalpha1-4Gal-defined antigen, P1, which belongs to the only blood group system for which the responsible locus remains undefined. Since known A4GALT polymorphisms do not explain the P1-P(k)+ phenotype, P(2), we set out to elucidate the genetic basis of P(1)/P(2). Despite marked differences (P(1) > P(2)) in A4GALT transcript levels in blood, luciferase experiments showed no difference between P(1)/P(2) related promoter sequences. Investigation of A4GALT mRNA in cultured human bone marrow cells revealed novel transcripts containing only the noncoding exon 1 and a sequence (here termed exon 2a) from intron 1. These 5'-capped transcripts include poly-A tails and 3 polymorphic sites, one of which was P(1)/P(2)-specific among > 200 donors and opens a short reading frame in P(2) alleles. We exploited these data to devise the first genotyping assays to predict P1 status. P(1)/P(2) genotypes correlated with both transcript levels and P1/P(k) expression on red cells. Thus, P(1) zygosity partially explains the well-known interindividual variation in P1 strength. Future investigations need to focus on regulatory mechanisms underlying P1 synthesis. PMID- 20971947 TI - Talin-dependent integrin activation is required for fibrin clot retraction by platelets. AB - Talin functions both as a regulator of integrin affinity and as an important mechanical link between integrins and the cytoskeleton. Using genetic deletion of talin, we show for the first time that the capacity of talin to activate integrins is required for fibrin clot retraction by platelets. To further dissect which talin functions are required for this process, we tested clot retraction in platelets expressing a talin1(L325R) mutant that binds to integrins, but exhibits impaired integrin activation ascribable to disruption of the interaction between talin and the membrane-proximal region (MPR) in the beta-integrin cytoplasmic domain. Talin-deficient and talin1(L325R) platelets were defective in retracting fibrin clots. However, the defect in clot retraction in talin1(L325R) platelets, but not talin-deficient platelets, was rescued by extrinsically activating integrins with manganese, thereby proving that integrin activation is required and showing that talin1(L325R) can form functional links to the actin cytoskeleton. PMID- 20971948 TI - Notch2 signaling is required for proper mast cell distribution and mucosal immunity in the intestine. AB - Notch receptor-mediated signaling is involved in the developmental process and functional modulation of lymphocytes, as well as in mast cell differentiation. Here, we investigated whether Notch signaling is required for antipathogen host defense regulated by mast cells. Mast cells were rarely found in the small intestine of wild-type C57BL/6 mice but accumulated abnormally in the lamina propria of the small-intestinal mucosa of the Notch2-conditional knockout mice in naive status. When transplanted into mast cell-deficient W(sh)/W(sh) mice, Notch2 null bone marrow-derived mast cells were rarely found within the epithelial layer but abnormally localized to the lamina propria, whereas control bone marrow derived mast cells were mainly found within the epithelial layer. After the infection of Notch2 knockout and control mice with L3 larvae of Strongyloides venezuelensis, the abundant number of mast cells was rapidly mobilized to the epithelial layer in the control mice. In contrast, mast cells were massively accumulated in the lamina propria of the small intestinal mucosa in Notch2 conditional knockout mice, accompanied by impaired eradication of Strongyloides venezuelensis. These findings indicate that cell-autonomous Notch2 signaling in mast cells is required for proper localization of intestinal mast cells and further imply a critical role of Notch signaling in the host-pathogen interface in the small intestine. PMID- 20971949 TI - Histidine-rich glycoprotein: the Swiss Army knife of mammalian plasma. AB - Histidine-rich glycoprotein (HRG), also known as histidine-proline-rich glyco protein, is an abundant and well-characterized protein of vertebrate plasma. HRG has a multidomain structure that allows the molecule to interact with many ligands, including heparin, phospholipids, plasminogen, fibrinogen, immunoglobulin G, C1q, heme, and Zn2(+). The ability of HRG to interact with various ligands simultaneously has suggested that HRG can function as an adaptor molecule and regulate numerous important biologic processes, such as immune complex/necrotic cell/pathogen clearance, cell adhesion, angiogenesis, coagulation, and fibrinolysis. The present review covers the proposed multifunctional roles of HRG with a focus on recent findings that have led to its emergence as a key regulator of immunity and vascular biology. Also included is a discussion of the striking functional similarities between HRG and other important multifunctional proteins found in plasma, such as C-reactive protein, C1q, beta2 glycoprotein I, and thrombospondin-1. PMID- 20971950 TI - A novel role for IL-22R1 as a driver of inflammation. AB - The interleukin (IL)-22R1 chain of the heterodimeric IL-22 receptor is not expressed on normal leukocytes, but this receptor is expressed on T cells from anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large cell lymphoma (ALCL) patients. To investigate the consequences of aberrant expression of this receptor on lymphocytes, we generated transgenic mice that express IL-22R1 on lymphocytes. The health of these animals progressively deteriorated at 8 to 12 weeks of age, as they displayed respiratory distress, rough coat and sluggish movement, and subsequent lethality due to multiorgan inflammation. The IL-22R1 transgenic animals developed neutrophilia that correlated with increased levels of circulating IL-17 and granulocyte colony-stimulating factor. In addition, these mice had increased serum IL-22 levels, suggesting that T cells expressing IL-22R1 generate IL-22 in a positive autoregulatory loop. As a result of the mouse model findings, we analyzed circulating cytokine levels in ALK(+)ALCL patients and detected elevated levels of IL-22, IL-17, and IL-8 in untreated patient samples. Importantly, IL-22 and IL-17 were undetectable in all patients who were in complete remission after chemotherapy. This study documents a previously unknown role of IL-22R1 in inflammation and identifies the involvement of IL-22R1/IL-22 in ALK(+)ALCL. PMID- 20971951 TI - The kinetics of alphaIIbbeta3 activation determines the size and stability of thrombi in mice: implications for antiplatelet therapy. AB - Two major pathways contribute to Ras-proximate-1-mediated integrin activation in stimulated platelets. Calcium and diacyglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI, RasGRP2) mediates the rapid but reversible activation of integrin alphaIIbbeta3, while the adenosine diphosphate receptor P2Y12, the target for antiplatelet drugs like clopidogrel, facilitates delayed but sustained integrin activation. To establish CalDAG-GEFI as a target for antiplatelet therapy, we compared how each pathway contributes to thrombosis and hemostasis in mice. Ex vivo, thrombus formation at arterial or venous shear rates was markedly reduced in CalDAG-GEFI(-/-) blood, even in the presence of exogenous adenosine diphosphate and thromboxane A(2). In vivo, thrombosis was virtually abolished in arterioles and arteries of CalDAG-GEFI(-/-) mice, while small, hemostatically active thrombi formed in venules. Specific deletion of the C1-like domain of CalDAG-GEFI in circulating platelets also led to protection from thrombus formation at arterial flow conditions, while it only marginally increased blood loss in mice. In comparison, thrombi in the micro- and macrovasculature of clopidogrel-treated wild-type mice grew rapidly and frequently embolized but were hemostatically inactive. Together, these data suggest that inhibition of the catalytic or the C1 regulatory domain in CalDAG GEFI will provide strong protection from athero-thrombotic complications while maintaining a better safety profile than P2Y12 inhibitors like clopidogrel. PMID- 20971953 TI - Patient-derived C-terminal mutation of FANCI causes protein mislocalization and reveals putative EDGE motif function in DNA repair. AB - Fanconi anemia (FA) is a rare familial genome instability syndrome caused by mutations in FA genes that results in defective DNA crosslink repair. Activation of the FA pathway requires the FA core ubiquitin ligase complex-dependent monoubiquitination of 2 interacting FA proteins, FANCI and FANCD2. Although loss of either FANCI or FANCD2 is known to prevent monoubiquitination of its respective partner, it is unclear whether FANCI has any additional domains that may be important in promoting DNA repair, independent of its monoubiquitination. Here, we focus on an FA-I patient-derived FANCI mutant protein, R1299X (deletion of 30 residues from its C-terminus), to characterize important structural region(s) in FANCI that is required to activate the FA pathway. We show that, within this short 30 amino acid stretch contains 2 separable functional signatures, a nuclear localization signal and a putative EDGE motif, that is critical for the ability of FANCI to properly monoubiquitinate FANCD2 and promote DNA crosslink resistance. Our study enable us to conclude that, although proper nuclear localization of FANCI is crucial for robust FANCD2 monoubiquitination, the putative FANCI EDGE motif is important for DNA crosslink repair. PMID- 20971952 TI - Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia. AB - Homoharringtonine (HHT) is a plant alkaloid that inhibits the elongation phase of translation that is currently in clinical trials. Because the intrinsically short lived antiapoptotic protein myeloid cell leukemia-1 (Mcl-1) has been reported to support the survival of chronic lymphocytic leukemia (CLL) cells, we hypothesized that inhibition of protein synthesis by HHT would decrease Mcl-1 expression and induce apoptosis in CLL. In primary CLL cells, HHT induced significant apoptosis independent of the prognostic characteristics of the patients. This was associated with inhibition of translation and decreased Mcl-1 levels in CLL cells. Mcl-1 reduction was evident as early as 2 hours and continued to decrease in the next 6-8 hours, whereas cell death started in 2 hours and continued to increase for 24 hours. Reduction of the Mcl-1 level was due to translation inhibition and proteasome degradation rather than to transcription inhibition or caspase cleavage. HHT and the transcription inhibitor SNS-032 induced synergistic cell killing. Although stromal cells induced Mcl-1 expression and protected CLL cells from the toxicity of fludarabine, this induction was reversed by HHT, which overcame stromal cell-mediated protection. Thus, these results provide a rationale for clinical development of HHT in CLL as single agent or in combinations. PMID- 20971954 TI - Immune modulation by Fas ligand reverse signaling: lymphocyte proliferation is attenuated by the intracellular Fas ligand domain. AB - Fas ligand (FasL) not only induces apoptosis in Fas receptor-bearing target cells, it is also able to transmit signals into the FasL-expressing cell via its intracellular domain (ICD). Recently, we described a Notch-like proteolytic processing of FasL that leads to the release of the FasL ICD into the cytoplasm and subsequent translocation into the nucleus where it may influence gene transcription. To study the molecular mechanism underlying such reverse FasL signaling in detail and to analyze its physiological importance in vivo, we established a knockout/knockin mouse model, in which wild-type FasL was replaced with a deletion mutant lacking the ICD. Our results demonstrate that FasL ICD signaling impairs activation-induced proliferation in B and T cells by diminishing phosphorylation of phospholipase C gamma, protein kinase C, and extracellular signal-regulated kinase 1/2. We also demonstrate that the FasL ICD interacts with the transcription factor lymphoid-enhancer binding factor-1 and inhibits lymphoid-enhancer binding factor-1-dependent transcription. In vivo, plasma cell numbers, generation of germinal center B cells, and, consequently, production of antigen-specific immunoglobulin M antibodies in response to immunization with T cell-dependent or T cell-independent antigen are negatively affected in presence of the FasL ICD, suggesting that FasL reverse signaling participates in negative fine-tuning of certain immune responses. PMID- 20971956 TI - Analgesia with noninvasive electrical cortical stimulation: challenges to find optimal parameters of stimulation. PMID- 20971955 TI - Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy. AB - Cluster of differentiation (CD)8(+) T cells exist as naive, central memory, and effector memory subsets, and any of these populations can be genetically engineered into tumor-reactive effector cells for adoptive immunotherapy. However, the optimal subset from which to derive effector CD8(+) T cells for patient treatments is controversial and understudied. We investigated human CD8(+) T cells and found that naive cells were not only the most abundant subset but also the population most capable of in vitro expansion and T-cell receptor transgene expression. Despite increased expansion, naive-derived cells displayed minimal effector differentiation, a quality associated with greater efficacy after cell infusion. Similarly, the markers of terminal differentiation, killer cell lectin-like receptor G1 and CD57, were expressed at lower levels in cells of naive origin. Finally, naive-derived effector cells expressed higher CD27 and retained longer telomeres, characteristics that suggest greater proliferative potential and that have been linked to greater efficacy in clinical trials. Thus, these data suggest that naive cells resist terminal differentiation, or "exhaustion," maintain high replicative potential, and therefore may be the superior subset for use in adoptive immunotherapy. PMID- 20971957 TI - Do we really need another biomarker to diagnose myocardial infarction after coronary artery bypass graft surgery? PMID- 20971958 TI - Emergency transfusion for acute severe anemia: a calculated risk. PMID- 20971959 TI - Spinal hypotension during elective cesarean delivery: closer to a solution. PMID- 20971960 TI - Complete intraoperative transesophageal echocardiogram imaging of the extent of an inferior vena cava mass guides surgical management. PMID- 20971961 TI - Nefopam pharmacokinetics in patients with end-stage renal disease. AB - BACKGROUND: Treatment of intense postoperative pain in patients with end-stage renal disease (ESRD) is a recurrent problem for anesthesiologists because of the risk of accumulation of numerous molecules and their metabolites. Nefopam is a potent analgesic metabolized by the liver and weakly eliminated intact in urine that may offer advantages for use in patients with ESRD because it lacks respiratory-depressive effects. However, the effects of renal failure on nefopam disposition have never been investigated. METHODS: We studied 12 ESRD patients (creatinine clearance < 20 mL/min, mean age 57 +/- 13 years) having surgery under general anesthesia to create or repair an arteriovenous fistula. Postoperatively, after complete recovery from anesthesia, each patient received a single 20-mg dose of nefopam IV over 30 minutes. Nefopam and desmethyl-nefopam concentrations in plasma samples obtained over 48 hours were determined by liquid chromatography tandem mass spectrometry. The pharmacokinetic parameter values obtained were compared with those of 12 healthy 50- to 60-year-old volunteers who also received a single 20-mg nefopam infusion over 30 minutes using a population pharmacokinetic approach. RESULTS: Healthy volunteers and ESRD patients had comparable demographic characteristics. In comparison with those volunteers, ESRD patients had a lower volume of central compartment (115 and 53 L vs. 264 L for patients not yet hemodialyzed and on chronic hemodialysis, respectively; P < 0.001) and lower mean nefopam clearance (37.0 and 27.3 L/h vs. 52.9 L/h, P < 0.001), resulting in higher mean nefopam peak concentration (121 and 223 ng/mL vs. 61 ng/mL, P < 0.001). CONCLUSIONS: Nefopam distribution and elimination are altered in patients with ESRD, resulting in heightened exposure. To avoid too high concentration peaks, it is suggested that the daily nefopam dose be reduced by 50%. PMID- 20971962 TI - Reversible lactic acidosis and electrocardiographic changes in a neurosurgical patient during propofol anesthesia. PMID- 20971963 TI - Penile blood pressure monitoring for a pediatric patient with hypomelia. PMID- 20971964 TI - Ultrasound-guided symphysis pubis injection in pregnancy. PMID- 20971965 TI - P-selectin glycoprotein ligand-1 deficiency is protective against obesity-related insulin resistance. AB - OBJECTIVE: An inflammatory process is involved in the mechanism of obesity related insulin resistance. Recent studies indicate that monocyte chemoattractant protein-1 (MCP-1) is a major chemokine that promotes monocyte infiltration into adipose tissues; however, the adhesion pathway in adipose tissues remains unclear. We aimed to clarify the adhesion molecules that mediate monocyte infiltration into adipose tissue. RESEARCH DESIGN AND METHODS: We used a DNA microarray to compare the gene expression profiles in epididymal white adipose tissues (eWAT) between db/db mice and C57/BL6 mice each fed a high-fat diet (HFD) or a low-fat diet (LFD). We investigated the change of insulin resistance and inflammation in eWAT in P-selectin glycoprotein ligand-1 (PSGL-1) homozygous knockout (PSGL-1-(/)-) mice compared with wild-type (WT) mice fed HFD. RESULTS: DNA microarray analysis revealed that PSGL-1, a major ligand for selectins, is upregulated in eWAT from both db/db mice and WT mice fed HFD. Quantitative real time RT-PCR and immunohistochemistry showed that PSGL-1 is expressed on both endothelial cells and macrophages in eWAT of obese mice. PSGL-1-(/)- mice fed HFD showed a remarkable reduction of macrophage accumulation and expression of proinflammatory genes, including MCP-1 in eWAT. Moreover, adipocyte hypertrophy, insulin resistance, lipid metabolism, and hepatic fatty change were improved in PSGL-1-(/) -mice compared with WT mice fed HFD. CONCLUSIONS: These results indicate that PSGL-1 is a crucial adhesion molecule for the recruitment of monocytes into adipose tissues in obese mice, making it a candidate for a novel therapeutic target for the prevention of obesity-related insulin resistance. PMID- 20971966 TI - Production of functional glucagon-secreting alpha-cells from human embryonic stem cells. AB - OBJECTIVE: Differentiation of human embryonic stem (hES) cells to fully developed cell types holds great therapeutic promise. Despite significant progress, the conversion of hES cells to stable, fully differentiated endocrine cells that exhibit physiologically regulated hormone secretion has not yet been achieved. Here we describe an efficient differentiation protocol for the in vitro conversion of hES cells to functional glucagon-producing alpha- cells. RESEARCH DESIGN AND METHODS: Using a combination of small molecule screening and empirical testing, we developed a six-stage differentiation protocol for creating functional alpha-cells. An extensive in vitro and in vivo characterization of the differentiated cells was performed. RESULTS: A high rate of synaptophysin expression (>75%) and robust expression of glucagon and the alpha-cell transcription factor ARX was achieved. After a transient polyhormonal state in which cells coexpress glucagon and insulin, maturation in vitro or in vivo resulted in depletion of insulin and other beta-cell markers with concomitant enrichment of alpha-cell markers. After transplantation, these cells secreted fully processed, biologically active glucagon in response to physiologic stimuli including prolonged fasting and amino acid challenge. Moreover, glucagon release from transplanted cells was sufficient to reduce demand for pancreatic glucagon, resulting in a significant decrease in pancreatic alpha-cell mass. CONCLUSIONS: These results indicate that fully differentiated pancreatic endocrine cells can be created via stepwise differentiation of hES cells. These cells may serve as a useful screening tool for the identification of compounds that modulate glucagon secretion as well as those that promote the transdifferentiation of alpha-cells to beta-cells. PMID- 20971968 TI - Letter to the editor. "Low-energy extracorporeal shock wave therapy as a treatment for medial tibial stress syndrome". PMID- 20971967 TI - Peroxisome-generated hydrogen peroxide as important mediator of lipotoxicity in insulin-producing cells. AB - OBJECTIVE: Type 2 diabetes is a complex disease that is accompanied by elevated levels of nonesterified fatty acids (NEFAs), which contribute to beta-cell dysfunction and beta-cell loss, referred to as lipotoxicity. Experimental evidence suggests that oxidative stress is involved in lipotoxicity. In this study, we analyzed the molecular mechanisms of reactive oxygen species-mediated lipotoxicity in insulin-producing RINm5F cells and INS-1E cells as well as in primary rat islet cells. RESEARCH DESIGN AND METHODS: The toxicity of saturated NEFAs with different chain lengths upon insulin-producing cells was determined by MTT and propidium iodide (PI) viability assays. Catalase or superoxide dismutase overexpressing cells were used to analyze the nature and the cellular compartment of reactive oxygen species formation. With the new H2O2-sensitive fluorescent protein HyPer H2O2 formation induced by exposure to palmitic acid was determined. RESULTS: Only long-chain (>C14) saturated NEFAs were toxic to insulin-producing cells. Overexpression of catalase in the peroxisomes and in the cytosol, but not in the mitochondria, significantly reduced H2O2 formation and protected the cells against palmitic acid-induced toxicity. With the HyPer protein, H2O2 generation was directly detectable in the peroxisomes of RINm5F and INS-1E insulin-producing cells as well as in primary rat islet cells. CONCLUSIONS: The results demonstrate that H2O2 formation in the peroxisomes rather than in the mitochondria are responsible for NEFA-induced toxicity. Therefore, we propose a new concept of fatty acid-induced beta-cell lipotoxicity mediated via reactive oxygen species formation through peroxisomal beta- oxidation. PMID- 20971969 TI - Lateral elbow tendinopathy. PMID- 20971970 TI - Letter to the editor. ''Can osteochondral grafting be augmented with microfracture in an extended-sized lesion of articular cartilage?''. PMID- 20971971 TI - Letter to the editor. "Treatment of magnetic resonance imaging--documented isolated grade III lateral collateral ligament injuries in National Football League athletes". PMID- 20971972 TI - Ghostwriters and Guest-writers. PMID- 20971974 TI - Recurrent adaptation in RNA interference genes across the Drosophila phylogeny. AB - RNA interference (RNAi) is quickly emerging as a vital component of genome organization, gene regulation, and immunity in Drosophila and other species. Previous studies have suggested that, as a whole, genes involved in RNAi are under intense positive selection in Drosophila melanogaster. Here, we characterize the extent and patterns of adaptive evolution in 23 known Drosophila RNAi genes, both within D. melanogaster and across the Drosophila phylogeny. We find strong evidence for recurrent protein-coding adaptation at a large number of RNAi genes, particularly those involved in antiviral immunity and defense against transposable elements. We identify specific functional domains involved in direct protein-RNA interactions as particular hotspots of recurrent adaptation in multiple RNAi genes, suggesting that targeted coadaptive arms races may be a general feature of RNAi evolution. Our observations suggest a predictive model of how selective pressures generated by evolutionary arms race scenarios may affect multiple genes across protein interaction networks and other biochemical pathways. PMID- 20971976 TI - Congenital H-ficolin deficiency in premature infants with severe necrotising enterocolitis. PMID- 20971975 TI - Effect of rosiglitazone on HDL metabolism in subjects with metabolic syndrome and low HDL. AB - Treatment with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone has been reported to increase HDL-cholesterol (HDL-C) levels, although the mechanism responsible for this is unknown. We sought to determine the effect of rosiglitazone on HDL apolipoprotein A-I (apoA-I) and apoA-II metabolism in subjects with metabolic syndrome and low HDL-C. Subjects were treated with placebo followed by rosiglitazone (8 mg) once daily. At the end of each 8 week treatment, subjects (n = 15) underwent a kinetic study to measure apoA-I and apoA-II production rate (PR) and fractional catabolic rate. Rosiglitazone significantly reduced fasting insulin and high-sensitivity C reactive protein (hsCRP) and increased apoA-II levels. Mean apoA-I and HDL-C levels were unchanged following rosiglitazone treatment, although there was considerable individual variability in the HDL-C response. Rosiglitazone had no effect on apoA-I metabolism, whereas the apoA-II PR was increased by 23%. The change in HDL-C in response to rosiglitazone was significantly correlated with the change in apoA-II concentration but not to changes in apoA-I, measures of glucose homeostasis, or hsCRP. Treatment with rosiglitazone significantly increased apoA-II production in subjects with metabolic syndrome and low HDL-C but had no effect on apoA-I metabolism. The change in HDL-C in response to rosiglitazone treatment was unrelated to effects on apoA-I, instead being related to the change in the metabolism of apoA-II. PMID- 20971977 TI - Suppression of inflammation in ulcerative colitis by interferon-beta-1a is accompanied by inhibition of IL-13 production. AB - OBJECTIVE: Ulcerative colitis is associated with increased interleukin 13 (IL-13) production by natural killer T cells. Taking advantage of the inhibitory actions of interferon beta on IL-13 expression, this proof-of-concept study aimed to show that decreasing IL-13 production is associated with clinical improvement of ulcerative colitis symptoms. DESIGN: Open-label interventional drug trial. SETTING: Outpatient clinical research hospital. Patients Adult patients with active ulcerative colitis (Short Clinical Colitis Activity Index (SCCAI)>= 5). Interventions Treatment with 30 MUg IM interferon-beta-1a (Avonex) weekly for 12 weeks with 6 month follow-up. MAIN OUTCOME MEASURES: Clinical response was defined as >= 3 point drop in the SCCAI for at least two consecutive monitoring visits, and cytokine production was measured in cultured peripheral blood and lamina propria mononuclear cells (LPMC) before and after treatment. RESULTS: 11 of 16 patients were clinical responders, and 4 were in remission (SCCAI <= 2) at the end of treatment. Rectal bleeding subscores improved dramatically by week 4 (38% with frank bleeding vs 87% pretreatment). Increased IL-13 production by LPMC T cells fell significantly in clinical responders (690 +/- 99 vs 297 +/- 58 pg/ml p = 0.015) but was unchanged in non-responders (542 +/- 83 vs 510 +/- 39 pg/ml). In addition, non-responders had significantly higher production of IL-17 and IL-6 pre-treatment compared to responders. CONCLUSIONS: Interferon-beta-1a induces clinical response and remission in a large subset of patients with ulcerative colitis that is associated with significant inhibition of IL-13 production. In addition, increased IL-17 and IL-6 production is associated with no response to interferon-beta. These data provide a proof-of-concept that IL-13 is an effector cytokine in ulcerative colitis and should be a target for novel therapies. PMID- 20971978 TI - P16 reactivation induces anoikis and exhibits antitumour potency by downregulating Akt/survivin signalling in hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is one of the most malignant tumours with high rate of recurrence and metastasis. In HCC, deficiency of the P16/CDK4/Rb pathway is a frequent molecular event, and transferring the P16 gene into cancer cells can induce cell cycle arrest and apoptosis, suggesting that the P16 gene is a good target in cancer gene therapy. The previous study demonstrated that P16 re expression mediated by adenovirus within cancer cells can induce cell apoptosis and exert potent antitumour efficacy in cancer xenografts in nude mice. However, the molecular mechanism of P16-induced apoptosis in cancer cells is not clear yet. In this resulting study, we found that P16 re-expression can downregulate survivin expression in HCC cells. As a member of the inhibitors of the apoptotic gene family, survivin has been reported to be overexpressed in most common human cancers and present multiple physiological and pathological functions including cell cycle control, inhibition of cell apoptosis, regulation of cell division and induction of angiogenesis, etc. Further investigation found that P16 reactivation led to a decrease of phosphorylated Akt on Thr308 and phosphorylated survivin on Thr34, then downregulated survivin expression. The P16-mediated decrease of nuclear survivin in cancer cells limited CDK4 import into nuclei, which restrained CDK4 functions of promoting cell proliferation, then exhibited the effect of cell cycle arrest and induction of detachment-induced apoptosis (anoikis). The antitumor potency of P16 by downregulating the Akt/survivin signalling was also demonstrated in HCC xenograft models in nude mice. This new insight into P16 function would help in designing better strategies for cancer gene therapy. PMID- 20971979 TI - Effect of acute hypoxia on QTc interval in respiratory patients undergoing fitness to fly tests. PMID- 20971980 TI - Nocturnal monitoring of home non-invasive ventilation: the contribution of simple tools such as pulse oximetry, capnography, built-in ventilator software and autonomic markers of sleep fragmentation. AB - Complex respiratory events, which may have a detrimental effect on both quality of sleep and control of nocturnal hypoventilation, occur during sleep in patients treated with non-invasive ventilation (NIV). Among these events are patient ventilator asynchrony, increases in upper airway resistance (with or without increased respiratory drive) and leaks. Detection of these events is important in order to select the most appropriate ventilator settings and interface. Simple tools can provide important information when monitoring NIV. Pulse oximetry is important to ensure that adequate oxygen saturation is provided and to detect either prolonged or short and recurrent desaturations. However, the specificity of pulse oximetry tracings during NIV is low. Transcutaneous capnography helps discriminate between hypoxaemia related to ventilation/perfusion mismatch and hypoventilation, documents correction of nocturnal hypoventilation and may detect ventilator-induced hyperventilation, a possible cause for central apnoea/hypopnoea and glottic closure. Data provided by ventilator software help the clinician by estimating ventilation, tidal volume, leaks and the rate of inspiratory or expiratory triggering by the patient, although further validation of these signals by independent studies is indicated. Finally, autonomic markers of sympathetic tone using signals such as pulse wave amplitude of the pulse oximetry signal can provide reliable information of sleep fragmentation. PMID- 20971981 TI - Comment on: Morbidity and mortality associated with the restrictive spirometric pattern: a longitudinal study. PMID- 20971982 TI - Proposal for a systematic analysis of polygraphy or polysomnography for identifying and scoring abnormal events occurring during non-invasive ventilation. AB - Non-invasive ventilation (NIV) is recognised as an effective treatment for chronic hypercapnic respiratory failure. Monitoring NIV during sleep may be preferable to daytime assessment. This paper reports the findings of an international consensus group which systematically analysed nocturnal polygraphic or polysomnographic tracings recorded with either volume-cycled or pressure cycled ventilators. A systematic description of nocturnal respiratory events which occur during NIV is proposed: leaks, obstruction at different levels of the upper airway (glottis and/or pharynx), with or without decrease of respiratory drive and asynchrony. PMID- 20971983 TI - Adrenomedullin attenuates ventilator-induced lung injury in mice. AB - BACKGROUND: Mechanical ventilation (MV) is a life-saving intervention in acute respiratory failure without any alternative. However, even protective ventilation strategies applying minimal mechanical stress may evoke ventilator-induced lung injury (VILI). Adjuvant pharmacological strategies in addition to lung-protective ventilation to attenuate VILI are lacking. Adrenomedullin exhibited endothelial barrier-stabilising properties in vitro and in vivo. METHODS: In untreated mice (female C57/Bl6 mice, 11-15 weeks old) and animals treated with adrenomedullin, lung permeability, local and systemic inflammation and markers of distal organ function were assessed following 2 or 6 h of mechanical ventilation with 100% oxygen and protective or moderately injurious ventilator settings, respectively. RESULTS: Adrenomedullin dramatically reduced lung permeability in VILI in mice, leading to improved oxygenation. Adrenomedullin treatment reduced myosin light chain phosphorylation, attenuated the accumulation of leucocytes in the lung and prevented the increase in lactate and creatinine levels in mice ventilated with high tidal volumes. Moreover, adrenomedullin protected against VILI even when treatment was initiated 2 h after the beginning of mechanical ventilation in a 6 h VILI mouse model. CONCLUSION: Adjuvant treatment with adrenomedullin may be a promising new pharmacological approach to attenuate VILI. PMID- 20971984 TI - Prognostic impact of intratumoral vascular invasion in non-small cell lung cancer patients. AB - OBJECTIVE: Intratumoral vascular invasion (IVI) in patients with non-small cell lung cancer (NSCLC) has been reported to be a strong independent predictor of recurrence, but it has not been incorporated in the TNM classifications including the latest 7th edition. The purpose of this study was to evaluate its significance as a risk factor for recurrence. METHODS: Between July 1992 and December 2006, 2295 consecutive patients with pathological T1-4N0-2 NSCLC underwent complete resection with systematic lymph node dissection at the National Cancer Center Hospital East. The recurrence-free proportion was estimated using the Kaplan-Meier method and differences were determined by the log rank test. Cox proportional hazard ratios were used to identify independent risk factors for recurrence. RESULTS: The proportion of recurrence-free patients at 5 years was 85.0% for patients without IVI and 51.5% for patients with IVI (p<0.001). On multivariate analyses, IVI proved to be an independently statistically significant risk factor for recurrence (HR 1.866, p<0.001). The recurrence-free proportion of patients with IVI was significantly lower than for patients without IVI in T1a (93.1% vs 69.3%, p<0.001), T1b (89.7% vs 62.7%, p<0.001), T2a (78.4% vs 53.0%, p<0.001), T2b (70.5% vs 46.4%, p=0.021) and T3 (53.1% vs 37.4%, p=0.031) subgroups. CONCLUSIONS: In resected patients with T1 4N0-2 NSCLC, IVI was an independently significant risk factor for recurrence. IVI should be examined and its data collected to be considered for the next revision of the TNM staging system. PMID- 20971985 TI - Generalized random set framework for functional enrichment analysis using primary genomics datasets. AB - MOTIVATION: Functional enrichment analysis using primary genomics datasets is an emerging approach to complement established methods for functional enrichment based on predefined lists of functionally related genes. Currently used methods depend on creating lists of 'significant' and 'non-significant' genes based on ad hoc significance cutoffs. This can lead to loss of statistical power and can introduce biases affecting the interpretation of experimental results. RESULTS: We developed and validated a new statistical framework, generalized random set (GRS) analysis, for comparing the genomic signatures in two datasets without the need for gene categorization. In our tests, GRS produced correct measures of statistical significance, and it showed dramatic improvement in the statistical power over other methods currently used in this setting. We also developed a procedure for identifying genes driving the concordance of the genomics profiles and demonstrated a dramatic improvement in functional coherence of genes identified in such analysis. AVAILABILITY: GRS can be downloaded as part of the R package CLEAN from http://ClusterAnalysis.org/. An online implementation is available at http://GenomicsPortals.org/. PMID- 20971986 TI - GAMES identifies and annotates mutations in next-generation sequencing projects. AB - MOTIVATION: Next-generation sequencing (NGS) methods have the potential for changing the landscape of biomedical science, but at the same time pose several problems in analysis and interpretation. Currently, there are many commercial and public software packages that analyze NGS data. However, the limitations of these applications include output which is insufficiently annotated and of difficult functional comprehension to end users. RESULTS: We developed GAMES (Genomic Analysis of Mutations Extracted by Sequencing), a pipeline aiming to serve as an efficient middleman between data deluge and investigators. GAMES attains multiple levels of filtering and annotation, such as aligning the reads to a reference genome, performing quality control and mutational analysis, integrating results with genome annotations and sorting each mismatch/deletion according to a range of parameters. Variations are matched to known polymorphisms. The prediction of functional mutations is achieved by using different approaches. Overall GAMES enables an effective complexity reduction in large-scale DNA-sequencing projects. AVAILABILITY: GAMES is available free of charge to academic users and may be obtained from http://aqua.unife.it/GAMES. PMID- 20971987 TI - Interoperability between phenotype and anatomy ontologies. AB - MOTIVATION: Phenotypic information is important for the analysis of the molecular mechanisms underlying disease. A formal ontological representation of phenotypic information can help to identify, interpret and infer phenotypic traits based on experimental findings. The methods that are currently used to represent data and information about phenotypes fail to make the semantics of the phenotypic trait explicit and do not interoperate with ontologies of anatomy and other domains. Therefore, valuable resources for the analysis of phenotype studies remain unconnected and inaccessible to automated analysis and reasoning. RESULTS: We provide a framework to formalize phenotypic descriptions and make their semantics explicit. Based on this formalization, we provide the means to integrate phenotypic descriptions with ontologies of other domains, in particular anatomy and physiology. We demonstrate how our framework leads to the capability to represent disease phenotypes, perform powerful queries that were not possible before and infer additional knowledge. AVAILABILITY: http://bioonto.de/pmwiki.php/Main/PheneOntology. PMID- 20971988 TI - The GMOD Drupal bioinformatic server framework. AB - MOTIVATION: Next-generation sequencing technologies have led to the widespread use of -omic applications. As a result, there is now a pronounced bioinformatic bottleneck. The general model organism database (GMOD) tool kit (http://gmod.org) has produced a number of resources aimed at addressing this issue. It lacks, however, a robust online solution that can deploy heterogeneous data and software within a Web content management system (CMS). RESULTS: We present a bioinformatic framework for the Drupal CMS. It consists of three modules. First, GMOD-DBSF is an application programming interface module for the Drupal CMS that simplifies the programming of bioinformatic Drupal modules. Second, the Drupal Bioinformatic Software Bench (biosoftware_bench) allows for a rapid and secure deployment of bioinformatic software. An innovative graphical user interface (GUI) guides both use and administration of the software, including the secure provision of pre publication datasets. Third, we present genes4all_experiment, which exemplifies how our work supports the wider research community. CONCLUSION: Given the infrastructure presented here, the Drupal CMS may become a powerful new tool set for bioinformaticians. The GMOD-DBSF base module is an expandable community resource that decreases development time of Drupal modules for bioinformatics. The biosoftware_bench module can already enhance biologists' ability to mine their own data. The genes4all_experiment module has already been responsible for archiving of more than 150 studies of RNAi from Lepidoptera, which were previously unpublished. AVAILABILITY AND IMPLEMENTATION: Implemented in PHP and Perl. Freely available under the GNU Public License 2 or later from http://gmod dbsf.googlecode.com. PMID- 20971989 TI - Mega assemblages of oligomeric aerolysin-like toxins stabilized by toxin associating membrane proteins. AB - Most beta pore-forming toxins need to be oligomerized via receptors in order to form membrane pores. Though oligomerizing toxins frequently form SDS-resistant oligomers, it was questionable whether SDS-resistant oligomers reflected native functional toxin complexes. In order to elucidate the essence of the cytocidal assemblages, oligomers of aerolysin-like toxins, aerolysin, parasporin-2 and epsilon toxin, were examined with or without SDS. On Blue Native PAGE, each toxin, which had been solubilized from target cells with mild detergent, was a much larger complex (nearly 1 MDa) than the typical SDS-resistant oligomers (~200 kDa). Size exclusion chromatography confirmed the huge toxin complexes. While a portion of the huge complexes were sensitive to proteases, SDS-resistant oligomers resist the proteolysis. Presumably the core toxin complexes remained intact while the cellular proteins were degraded. Moreover, intermediate complexes, which included no SDS-resistant oligomers, could be detected at lower temperatures. This study provides evidence for huge functional complexes of beta pore-forming toxins and emphasizes their potential variance in composition. PMID- 20972202 TI - 14-3-3 protein detection and sporadic CJD: the status quo serves well while awaiting progress. PMID- 20972203 TI - Clinical relevance of brain volume changes in patients with cerebrotendinous xanthomatosis. AB - OBJECTIVE: To quantify total and regional brain damage in subjects with cerebrotendinous xanthomatosis (CTX) using MR based quantitative measures. BACKGROUND: CTX is a rare inherited disorder characterised by progressive neurological impairment. Appropriate therapy can slow disease progression. Measures of brain volume changes have been used in several neurological disorders due to their value in assessing disease outcome and monitoring patients' evolution. METHODS: 24 CTX patients underwent conventional MRI to measure total and regional brain volumes. In five CTX patients who started therapy at baseline, clinical and MRI examinations were repeated after 2 years. Clinical disability, overall cognitive performance and cerebellar function were evaluated using the modified Rankin Scale (RS), Mini Mental Status Examination (MMSE) and cerebellar functional system score (CB-FSS). RESULTS: Measures of normalised brain, cortical and cerebellar volumes were lower in CTX patients than in healthy controls (p<0.01). Instead, there were no differences in normalised white matter volumes between the two groups (p=0.1). At regional analysis, a significant volume decrease was found in each cortical region (p<0.01 for all regions). Normalised cortical volumes correlated closely with age (r=-0.9, p<0.0001), RS (r=-0.65, p<0.001) and MMSE (r=-0.60, p<0.01). Normalised cerebellar volumes correlated closely with CB-FSS scores (r=-0.58, p<0.01). In the five CTX patients followed over time, the annual brain volume decrease was -1.1 +/- 0.2%. CONCLUSIONS: Cortical volume, rather than white matter volume, is diffusely decreased in CTX patients and correlates closely with the patient's clinical status. These data provide evidence for the presence of clinically relevant neuronal-axonal damage in the brains of CTX patients. PMID- 20972204 TI - Disorders of visual perception. AB - Visual perceptual disorders are often presented as a disparate group of neurological deficits with little consideration given to the wide range of visual symptoms found in psychiatric and neurodevelopmental disease. Here, the authors attempt a functional anatomical classification of all disorders linked to visual perception, whatever the clinical context in which they arise, including those disorders that bridge vision, emotion, memory, language and action. Guided by clinical and neuroimaging evidence, visual perceptual disorders are classified by the functional anatomical networks likely to be involved and the class of underlying dysfunction, whether topological (a localised deficit or region of hyperfunction) or hodological (a disconnection or hyperconnection). The wider perspective forces us to consider what visual functions underlie a range of symptoms sidelined by previous classificatory schemes and helps generate novel hypotheses for further research in the area. PMID- 20972205 TI - Successful repair of injured hepatic veins and inferior vena cava following blunt traumatic injury, by using cardiopulmonary bypass and hypothermic circulatory arrest. AB - Traumatic injury to the retrohepatic veins continues to carry high mortality rates. In the last few decades various management strategies have been proposed. However, treatment of such injuries still remains highly variable and technically challenging due to the surgically inaccessible location of these vessels and the consequent difficulty controlling bleeding. We report a successful repair of complete transection of the two main extraparenchymal hepatic veins and laceration of the retrohepatic inferior vena cava using cardiopulmonary bypass (CPB) and hypothermic circulatory arrest (HCA) following blunt abdominal trauma. Immediate CPB with or without HCA can be life-saving and should be considered for patients with complex isolated retrohepatic venous injuries. PMID- 20972206 TI - Impaired continuity of flow in congenital heart disease with single ventricle physiology. AB - We report the comprehensive evaluation of cardiac morphology, valve function, and three-dimensional (3D) blood flow in a pediatric patient with congenital heart disease. 3D visualization of cardiovascular flow paths and quantitative flow analysis based on flow-sensitive 4D magnetic resonance imaging (MRI) provided detailed insight into hemodynamic changes associated with valve insufficiency and the complex single ventricle physiology. Despite only moderate atrio-ventricular regurgitation (fraction=28%) a marked redirection of atrial flow and pronounced vortex flow in the entire atrium was observed. Disturbed retrograde flow was even found upstream within the left pulmonary veins (regurgitant fraction=27%) indicating interrupted continuity of flow directed through the single atrium and ventricle. Such findings indicate the potential of flow-sensitive 4D MRI to detect and quantify complex 3D flow alterations. PMID- 20972207 TI - Video-assisted thoracoscopic lobectomy in the treatment of intralobar pulmonary sequestration. AB - Pulmonary sequestration is a congenital malformation characterised by cystic, non functioning embryonic lung tissue with vascularisation of an abnormal systemic artery. They are classified as intralobar (75%) and extralobar (25%) and are more common in the left lung and lower lobes (60-90%). We report two cases of intralobar pulmonary sequestration located in the lower lobe of the left lung which were subjected to video-assisted thoracoscopic surgery (VATS). Both patients had recurrent infections for which, after performing imaging tests, they were diagnosed with intralobar pulmonary sequestration in the left lower lobe, with an afferent arterial branch to the malformation from the aorta. A lower lobectomy was performed by video-assisted surgery, dividing the aberrant aortic artery with an endostapler. A single thoracic chest tube was placed and removed on postoperative day 2 and the patients were discharged on the same day. In both cases, the pathology examination revealed intralobar pulmonary sequestration. Pulmonary sequestrations are uncommon malformations that can be operated on using minimally invasive techniques, thereby permitting early discharge and a low rate of complications. PMID- 20972208 TI - Verification of alternative splicing variants based on domain integrity, truncation length and intrinsic protein disorder. AB - According to current estimations ~95% of multi-exonic human protein-coding genes undergo alternative splicing (AS). However, for 4000 human proteins in PDB, only 14 human proteins have structures of at least two alternative isoforms. Surveying these structural isoforms revealed that the maximum insertion accommodated by an isoform of a fully ordered protein domain was 5 amino acids, other instances of domain changes involved intrinsic structural disorder. After collecting 505 minor isoforms of human proteins with evidence for their existence we analyzed their length, protein disorder and exposed hydrophobic surface. We found that strict rules govern the selection of alternative splice variants aimed to preserve the integrity of globular domains: alternative splice sites (i) tend to avoid globular domains or (ii) affect them only marginally or (iii) tend to coincide with a location where the exposed hydrophobic surface is minimal or (iv) the protein is disordered. We also observed an inverse correlation between the domain fraction lost and the full length of the minor isoform containing the domain, possibly indicating a buffering effect for the isoform protein counteracting the domain truncation effect. These observations provide the basis for a prediction method (currently under development) to predict the viability of splice variants. PMID- 20972209 TI - VKCDB: voltage-gated K+ channel database updated and upgraded. AB - The Voltage-gated K(+) Channel DataBase (VKCDB) (http://vkcdb.biology.ualberta.ca) makes a comprehensive set of sequence data readily available for phylogenetic and comparative analysis. The current update contains 2063 entries for full-length or nearly full-length unique channel sequences from Bacteria (477), Archaea (18) and Eukaryotes (1568), an increase from 346 solely eukaryotic entries in the original release. In addition to protein sequences for channels, corresponding nucleotide sequences of the open reading frames corresponding to the amino acid sequences are now available and can be extracted in parallel with sets of protein sequences. Channels are categorized into subfamilies by phylogenetic analysis and by using hidden Markov model analyses. Although the raw database contains a number of fragmentary, duplicated, obsolete and non-channel sequences that were collected in early steps of data collection, the web interface will only return entries that have been validated as likely K(+) channels. The retrieval function of the web interface allows retrieval of entries that contain a substantial fraction of the core structural elements of VKCs, fragmentary entries, or both. The full database can be downloaded as either a MySQL dump or as an XML dump from the web site. We have now implemented automated updates at quarterly intervals. PMID- 20972210 TI - BriX: a database of protein building blocks for structural analysis, modeling and design. AB - High-resolution structures of proteins remain the most valuable source for understanding their function in the cell and provide leads for drug design. Since the availability of sufficient protein structures to tackle complex problems such as modeling backbone moves or docking remains a problem, alternative approaches using small, recurrent protein fragments have been employed. Here we present two databases that provide a vast resource for implementing such fragment-based strategies. The BriX database contains fragments from over 7000 non-homologous proteins from the Astral collection, segmented in lengths from 4 to 14 residues and clustered according to structural similarity, summing up to a content of 2 million fragments per length. To overcome the lack of loops classified in BriX, we constructed the Loop BriX database of non-regular structure elements, clustered according to end-to-end distance between the regular residues flanking the loop. Both databases are available online (http://brix.crg.es) and can be accessed through a user-friendly web-interface. For high-throughput queries a web based API is provided, as well as full database downloads. In addition, two exciting applications are provided as online services: (i) user-submitted structures can be covered on the fly with BriX classes, representing putative structural variation throughout the protein and (ii) gaps or low-confidence regions in these structures can be bridged with matching fragments. PMID- 20972211 TI - WebGeSTer DB--a transcription terminator database. AB - We present WebGeSTer DB, the largest database of intrinsic transcription terminators (http://pallab.serc.iisc.ernet.in/gester). The database comprises of a million terminators identified in 1060 bacterial genome sequences and 798 plasmids. Users can obtain both graphic and tabular results on putative terminators based on default or user-defined parameters. The results are arranged in different tiers to facilitate retrieval, as per the specific requirements. An interactive map has been incorporated to visualize the distribution of terminators across the whole genome. Analysis of the results, both at the whole genome level and with respect to terminators downstream of specific genes, offers insight into the prevalence of canonical and non-canonical terminators across different phyla. The data in the database reinforce the paradigm that intrinsic termination is a conserved and efficient regulatory mechanism in bacteria. Our database is freely accessible. PMID- 20972212 TI - YEASTRACT: providing a programmatic access to curated transcriptional regulatory associations in Saccharomyces cerevisiae through a web services interface. AB - The YEAst Search for Transcriptional Regulators And Consensus Tracking (YEASTRACT) information system (http://www.yeastract.com) was developed to support the analysis of transcription regulatory associations in Saccharomyces cerevisiae. Last updated in June 2010, this database contains over 48,200 regulatory associations between transcription factors (TFs) and target genes, including 298 specific DNA-binding sites for 110 characterized TFs. All regulatory associations stored in the database were revisited and detailed information on the experimental evidences that sustain those associations was added and classified as direct or indirect evidences. The inclusion of this new data, gathered in response to the requests of YEASTRACT users, allows the user to restrict its queries to subsets of the data based on the existence or not of experimental evidences for the direct action of the TFs in the promoter region of their target genes. Another new feature of this release is the availability of all data through a machine readable web-service interface. Users are no longer restricted to the set of available queries made available through the existing web interface, and can use the web service interface to query, retrieve and exploit the YEASTRACT data using their own implementation of additional functionalities. The YEASTRACT information system is further complemented with several computational tools that facilitate the use of the curated data when answering a number of important biological questions. Since its first release in 2006, YEASTRACT has been extensively used by hundreds of researchers from all over the world. We expect that by making the new data and services available, the system will continue to be instrumental for yeast biologists and systems biology researchers. PMID- 20972214 TI - Site-directed mutagenesis of the chi subunit of DNA polymerase III and single stranded DNA-binding protein of E. coli reveals key residues for their interaction. AB - During DNA replication in Escherichia coli, single-stranded DNA-binding protein (SSB) protects single-stranded DNA from nuclease action and hairpin formation. It is known that the highly conserved C-terminus of SSB contacts the chi subunit of DNA polymerase III. However, there only exists a theoretical model in which the 11 C-terminal amino acids of SSB have been docked onto the surface of chi. In order to refine this model of SSB/chi interaction, we exchanged amino acids in chi and SSB by site-directed mutagenesis that are predicted to be of key importance. Detailed characterization of the interaction of these mutants by analytical ultracentrifugation shows that the interaction area is correctly predicted by the model; however, the SSB C-terminus binds in a different orientation to the chi surface. We show that evolutionary conserved residues of chi form a hydrophobic pocket to accommodate the ultimate two amino acids of SSB, P176 and F177. This pocket is surrounded by conserved basic residues, important for the SSB/chi interaction. Mass spectrometric analysis of chi protein cross linked to a C-terminal peptide of SSB reveals that K132 of chi and D172 of SSB are in close contact. The proposed SSB-binding site resembles those described for RecQ and exonuclease I. PMID- 20972215 TI - The Autophagy Database: an all-inclusive information resource on autophagy that provides nourishment for research. AB - Autophagy is a process of self-digestion generally observed in eukaryotes and has been shown to play crucial roles for survival under starvation and removal of deleterious substances. Despite great advances that have been made, many problems in mechanisms of autophagy remain unsolved. As a large number of autophagy related proteins are identified in each species, a database that collects data, identifies their homologs in other species and makes them available will contribute to research advancement. As no such resources exist, we built the Autophagy database (http://tp-apg.genes.nig.ac.jp/autophagy) to provide basics, up-to-date information on relevant literature, and a list of autophagy-related proteins and their homologs in 41 eukaryotes. From the database, the user can search for proteins by keywords or sequences to obtain a wealth of data including functional and structural information and find possible functional homologs of proteins whose functions have been demonstrated in other species. As proteins that bind the phospholipid, phosphatidyl inositol 3-phosphate (PI3P) are essential for autophagy to proceed, we carried out an original analysis to identify probable PI3P-binding proteins, and made the list available from the database. The database is expected to give impetus to further research on autophagy by providing basic and specialized data on the subject. PMID- 20972213 TI - A role for human Dicer in pre-RISC loading of siRNAs. AB - RNA interference is a powerful mechanism for sequence-specific inhibition of gene expression. It is widely known that small interfering RNAs (siRNAs) targeting the same region of a target-messenger RNA can have widely different efficacies. In efforts to better understand the siRNA features that influence knockdown efficiency, we analyzed siRNA interactions with a high-molecular weight complex in whole cell extracts prepared from two different cell lines. Using biochemical tools to study the nature of the complex, our results demonstrate that the primary siRNA-binding protein in the whole cell extracts is Dicer. We find that Dicer is capable of discriminating highly functional versus poorly functional siRNAs by recognizing the presence of 2-nt 3' overhangs and the thermodynamic properties of 2-4 bp on both ends of effective siRNAs. Our results suggest a role for Dicer in pre-selection of effective siRNAs for handoff to Ago2. This initial selection is reflective of the overall silencing potential of an siRNA. PMID- 20972216 TI - SCLD: a Stem Cell Lineage Database for the annotation of cell types and developmental lineages. AB - Stem cell biology has experienced explosive growth over the past decade as researchers attempt to generate therapeutically relevant cell types in the laboratory. Recapitulation of endogenous developmental trajectories is a dominant paradigm in the design of directed differentiation protocols, and attempts to guide stem cell differentiation are often based explicitly on knowledge of in vivo development. Therefore, when designing protocols, stem cell biologists rely heavily upon information including (i) cell type-specific gene expression profiles, (ii) anatomical and developmental relationships between cells and tissues and (iii) signals important for progression from progenitors to target cell types. Here, we present the Stem Cell Lineage Database (SCLD) (http://scld.mcb.uconn.edu) that aims to unify this information into a single resource where users can easily store and access information about cell type gene expression, cell lineage maps and stem cell differentiation protocols for both human and mouse stem cells and endogenous developmental lineages. By establishing the SCLD, we provide scientists with a centralized location to organize access and share data, dispute and resolve contentious relationships between cell types and within lineages, uncover discriminating cell type marker panels and design directed differentiation protocols. PMID- 20972217 TI - Assembly of a fragmented ribonucleotide reductase by protein interaction domains derived from a mobile genetic element. AB - Ribonucleotide reductase (RNR) is a critical enzyme of nucleotide metabolism, synthesizing precursors for DNA replication and repair. In prokaryotic genomes, RNR genes are commonly targeted by mobile genetic elements, including free standing and intron-encoded homing endonucleases and inteins. Here, we describe a unique molecular solution to assemble a functional product from the RNR large subunit gene, nrdA that has been fragmented into two smaller genes by the insertion of mobE, a mobile endonuclease. We show that unique sequences that originated during the mobE insertion and that are present as C- and N-terminal tails on the split NrdA-a and NrdA-b polypeptides, are absolutely essential for enzymatic activity. Our data are consistent with the tails functioning as protein interaction domains to assemble the tetrameric (NrdA-a/NrdA-b)(2) large subunit necessary for a functional RNR holoenzyme. The tails represent a solution distinct from RNA and protein splicing or programmed DNA rearrangements to restore function from a fragmented coding region and may represent a general mechanism to neutralize fragmentation of essential genes by mobile genetic elements. PMID- 20972218 TI - OrthoDB: the hierarchical catalog of eukaryotic orthologs in 2011. AB - The concept of homology drives speculation on a gene's function in any given species when its biological roles in other species are characterized. With reference to a specific species radiation homologous relations define orthologs, i.e. descendants from a single gene of the ancestor. The large-scale delineation of gene genealogies is a challenging task, and the numerous approaches to the problem reflect the importance of the concept of orthology as a cornerstone for comparative studies. Here, we present the updated OrthoDB catalog of eukaryotic orthologs delineated at each radiation of the species phylogeny in an explicitly hierarchical manner of over 100 species of vertebrates, arthropods and fungi (including the metazoa level). New database features include functional annotations, and quantification of evolutionary divergence and relations among orthologous groups. The interface features extended phyletic profile querying and enhanced text-based searches. The ever-increasing sampling of sequenced eukaryotic genomes brings a clearer account of the majority of gene genealogies that will facilitate informed hypotheses of gene function in newly sequenced genomes. Furthermore, uniform analysis across lineages as different as vertebrates, arthropods and fungi with divergence levels varying from several to hundreds of millions of years will provide essential data for uncovering and quantifying long-term trends of gene evolution. OrthoDB is freely accessible from http://cegg.unige.ch/orthodb. PMID- 20972219 TI - Co-transcriptional RNA cleavage provides a failsafe termination mechanism for yeast RNA polymerase I. AB - Ribosomal RNA, transcribed by RNA polymerase (Pol) I, accounts for most cellular RNA. Since Pol I transcribes rDNA repeats with high processivity and polymerase density, transcription termination is a critical process. Early in vitro studies proposed polymerase pausing by Reb1 and transcript release at the T-rich element T1 determined transcription termination. However recent in vivo studies revealed a 'torpedo' mechanism for Pol I termination: co-transcriptional RNA cleavage by Rnt1 provides an entry site for the 5'-3' exonuclease Rat1 that degrades Pol I associated transcripts destabilizing the transcription complex. Significantly Rnt1 inactivation in vivo reveals a second co-transcriptional RNA cleavage event at T1 which provides Pol I with an alternative termination pathway. An intact Reb1-binding site is also required for Rnt1-independent termination. Consequently our results reconcile the original Reb1-mediated termination pathway as part of a failsafe mechanism for this essential transcription process. PMID- 20972220 TI - The European Nucleotide Archive. AB - The European Nucleotide Archive (ENA; http://www.ebi.ac.uk/ena) is Europe's primary nucleotide-sequence repository. The ENA consists of three main databases: the Sequence Read Archive (SRA), the Trace Archive and EMBL-Bank. The objective of ENA is to support and promote the use of nucleotide sequencing as an experimental research platform by providing data submission, archive, search and download services. In this article, we outline these services and describe major changes and improvements introduced during 2010. These include extended EMBL-Bank and SRA-data submission services, extended ENA Browser functionality, support for submitting data to the European Genome-phenome Archive (EGA) through SRA, and the launch of a new sequence similarity search service. PMID- 20972221 TI - CaSNP: a database for interrogating copy number alterations of cancer genome from SNP array data. AB - Cancer is known to have abundant copy number alterations (CNAs) that greatly contribute to its pathogenesis and progression. Investigation of CNA regions could potentially help identify oncogenes and tumor suppressor genes and infer cancer mechanisms. Although single-nucleotide polymorphism (SNP) arrays have strengthened our ability to identify CNAs with unprecedented resolution, a comprehensive collection of CNA information from SNP array data is still lacking. We developed a web-based CaSNP (http://cistrome.dfci.harvard.edu/CaSNP/) database for storing and interrogating quantitative CNA data, which curated ~11,500 SNP arrays on 34 different cancer types in 104 studies. With a user input of region or gene of interest, CaSNP will return the CNA information summarizing the frequencies of gain/loss and averaged copy number for each study, and provide links to download the data or visualize it in UCSC Genome Browser. CaSNP also displays the heatmap showing copy numbers estimated at each SNP marker around the query region across all studies for a more comprehensive visualization. Finally, we used CaSNP to study the CNA of protein-coding genes as well as LincRNA genes across all cancer SNP arrays, and found putative regions harboring novel oncogenes and tumor suppressors. In summary, CaSNP is a useful tool for cancer CNA association studies, with the potential to facilitate both basic science and translational research on cancer. PMID- 20972222 TI - Crystal structure of a novel JmjC-domain-containing protein, TYW5, involved in tRNA modification. AB - Wybutosine (yW) is a hypermodified nucleoside found in position 37 of tRNA(Phe), and is essential for correct phenylalanine codon translation. yW derivatives widely exist in eukaryotes and archaea, and their chemical structures have many species-specific variations. Among them, its hydroxylated derivative, hydroxywybutosine (OHyW), is found in eukaryotes including human, but the modification mechanism remains unknown. Recently, we identified a novel Jumonji C (JmjC)-domain-containing protein, TYW5 (tRNA yW-synthesizing enzyme 5), which forms the OHyW nucleoside by carbon hydroxylation, using Fe(II) ion and 2 oxoglutarate (2-OG) as cofactors. In this work, we present the crystal structures of human TYW5 (hTYW5) in the free and complex forms with 2-OG and Ni(II) ion at 2.5 and 2.8 A resolutions, respectively. The structure revealed that the catalytic domain consists of a beta-jellyroll fold, a hallmark of the JmjC domains and other Fe(II)/2-OG oxygenases. hTYW5 forms a homodimer through C terminal helix bundle formation, thereby presenting a large, positively charged patch involved in tRNA binding. A comparison with the structures of other JmjC domain-containing proteins suggested a mechanism for substrate nucleotide recognition. Functional analyses of structure-based mutants revealed the essential Arg residues participating in tRNA recognition by TYW5. These findings extend the repertoire of the tRNA modification enzyme into the Fe(II)/2-OG oxygenase superfamily. PMID- 20972223 TI - Geometrical correlations in the nucleosomal DNA conformation and the role of the covalent bonds rigidity. AB - We develop a simple elastic model to study the conformation of DNA in the nucleosome core particle. In this model, the changes in the energy of the covalent bonds that connect the base pairs of each strand of the DNA double helix, as well as the lateral displacements and the rotation of adjacent base pairs are considered. We show that because of the rigidity of the covalent bonds in the sugar-phosphate backbones, the base pair parameters are highly correlated, especially, strong twist-roll-slide correlation in the conformation of the nucleosomal DNA is vividly observed in the calculated results. This simple model succeeds to account for the detailed features of the structure of the nucleosomal DNA, particularly, its more important base pair parameters, roll and slide, in good agreement with the experimental results. PMID- 20972224 TI - GCN5 and E2F1 stimulate nucleotide excision repair by promoting H3K9 acetylation at sites of damage. AB - Chromatin structure is known to be a barrier to DNA repair and a large number of studies have now identified various factors that modify histones and remodel nucleosomes to facilitate repair. In response to ultraviolet (UV) radiation several histones are acetylated and this enhances the repair of DNA photoproducts by the nucleotide excision repair (NER) pathway. However, the molecular mechanism by which UV radiation induces histone acetylation to allow for efficient NER is not completely understood. We recently discovered that the E2F1 transcription factor accumulates at sites of UV-induced DNA damage and directly stimulates NER through a non-transcriptional mechanism. Here we demonstrate that E2F1 associates with the GCN5 acetyltransferase in response to UV radiation and recruits GCN5 to sites of damage. UV radiation induces the acetylation of histone H3 lysine 9 (H3K9) and this requires both GCN5 and E2F1. Moreover, as previously observed for E2F1, knock down of GCN5 results in impaired recruitment of NER factors to sites of damage and inefficient DNA repair. These findings demonstrate a direct role for GCN5 and E2F1 in NER involving H3K9 acetylation and increased accessibility to the NER machinery. PMID- 20972225 TI - The Bowen-Conradi syndrome protein Nep1 (Emg1) has a dual role in eukaryotic ribosome biogenesis, as an essential assembly factor and in the methylation of Psi1191 in yeast 18S rRNA. AB - The Nep1 (Emg1) SPOUT-class methyltransferase is an essential ribosome assembly factor and the human Bowen-Conradi syndrome (BCS) is caused by a specific Nep1(D86G) mutation. We recently showed in vitro that Methanocaldococcus jannaschii Nep1 is a sequence-specific pseudouridine-N1-methyltransferase. Here, we show that in yeast the in vivo target site for Nep1-catalyzed methylation is located within loop 35 of the 18S rRNA that contains the unique hypermodification of U1191 to 1-methyl-3-(3-amino-3-carboxypropyl)-pseudouri-dine (m1acp3Psi). Specific (14)C-methionine labelling of 18S rRNA in yeast mutants showed that Nep1 is not required for acp-modification but suggested a function in Psi1191 methylation. ESI MS analysis of acp-modified Psi-nucleosides in a Deltanep1 mutant showed that Nep1 catalyzes the Psi1191 methylation in vivo. Remarkably, the restored growth of a nep1-1(ts) mutant upon addition of S-adenosylmethionine was even observed after preventing U1191 methylation in a Deltasnr35 mutant. This strongly suggests a dual Nep1 function, as Psi1191-methyltransferase and ribosome assembly factor. Interestingly, the Nep1 methyltransferase activity is not affected upon introduction of the BCS mutation. Instead, the mutated protein shows enhanced dimerization propensity and increased affinity for its RNA-target in vitro. Furthermore, the BCS mutation prevents nucleolar accumulation of Nep1, which could be the reason for reduced growth in yeast and the Bowen-Conradi syndrome. PMID- 20972226 TI - The best way to a woman's heart? AB - We discuss a case of an unusual presentation of gastric volvulus, the investigations and subsequent management. PMID- 20972227 TI - Is the current South African emergency medicine curriculum fit for purpose? An emergency medicine practice analysis. AB - BACKGROUND: The aim of this study was to determine whether the current South African Emergency Medicine Curriculum is appropriate for the burden of disease seen by registrars in Cape Town Emergency Centres. METHOD: This is a cross sectional retrospective audit of patients presenting to a range of secondary level emergency centres (ECs) in Cape Town. The type of clinical presentations, investigations done and procedures performed were analysed. Basic descriptive statistics are presented. RESULTS: A total of 1283 clinical presentations from three secondary level ECs in Cape Town were collated. Of these clinical presentations, 47 were not included in the South African Emergency Medicine curriculum; in addition, two were only included in the paediatrics section. 115 procedures were tabled, of these, 11 were not included in the curriculum. 730 investigations were tabled; 527 were not included in the curriculum. CONCLUSIONS: The curriculum did not cover all the clinical conditions, procedures and investigations encountered by emergency medicine (EM) registrars in Cape Town. In addition, there were multiple categories in the curriculum that were not encountered in EM practice at all. The investigations section of the curriculum correlated particularly poorly with the skills needed for the burden of disease seen in ECs in Cape Town. The curriculum should be redrafted guided by a practice analysis of EM. PMID- 20972228 TI - Achieving prehospital analgesia. PMID- 20972229 TI - Pattern of hospital referrals of children at risk of maltreatment. AB - BACKGROUND: Increasingly emergency departments (ED) and other acute services in the hospital provide first access care, especially out of hours and for poorer families. Studies of detection of child maltreatment in the hospital have focused on children presenting with injury, although maltreatment may be suspected when parents present to the hospital with problems related to violent behaviour, drug abuse or mental health problems. METHODS: A consecutive case series is described of patients referred for suspected child maltreatment from one inner-city general hospital after training was given to clinical staff and 2 years after the creation of a new post comprising a full-time, experienced child protection advisor (CPA) on-site to support clinicians with concerns about child maltreatment. RESULTS: There were 44 referrals to the CPA over 2 months in 2005, of whom just under half were initiated by clinicians caring for a parent. 15 referrals came from the ED (five followed a parent presenting to the ED), 14 from maternity obstetric services, and 15 from the neonatal or paediatric wards. Most families (38; 86%) were referred by nurses. One-quarter of referrals were already known to children's social care. CONCLUSIONS: Clinicians need to be aware that half the vulnerable children in hospital are identified through one or other parent. It is hypothesised that the availability of an experienced child protection advisor on-site, combined with child protection training, makes it possible for clinicians caring for adults with problems related to violence, drug abuse or acute mental illness, to take action to address the potential vulnerability of their children. PMID- 20972232 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1. Elbow extension as a 'rule-out' tool for significant injury. PMID- 20972233 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2. Observation is recommended even following a normal CT brain in warfarinised head injuries. PMID- 20972234 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3. Can ultrasound diagnose scaphoid fractures? PMID- 20972235 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 4. Use of the trendelenburg position to improve haemodynamics during hypovolaemic shock. PMID- 20972236 TI - Educating on CS or 'tear gas'. AB - Chlorobenzalmalononitrile or 2-chlorobenzylidene malononitrile (CS) is a commonly used riot control agent. Although generally deemed to be safe for this application, it is known that CS can cause a number of adverse effects in those exposed to it. Understanding its properties and its side effects is important in ensuring optimal medical management of its complications and, indeed, this principle applies to every chemical. As the need for CS and other law enforcement devices increases, it is important for the emergency medicine team and other specialties to be aware of correct management protocols. PMID- 20972237 TI - Images in emergency medicine. Reversible QRS complex widening after oral administration of propafenone. PMID- 20972239 TI - Intestinal Bacteroides species associated with coeliac disease. AB - AIMS: To characterise the predominant species of bacterial populations associated with duodenal biopsies of paediatric patients with active and treated coeliac disease. METHODS: 20 biopsy specimens from patients with active coeliac disease, 12 from patients with treated coeliac disease, and eight from age-matched controls were evaluated for comparative purposes. Bacteroides, Bifidobacterium and lactic acid bacteria (LAB) populations were analysed by PCR-denaturing gradient gel electrophoresis using group-specific primers. RESULTS: Bacteroides diversity was higher in biopsy specimens from controls than in those from patients with active and treated coeliac disease. Bacteroides distasonis, Bacteroides fragilis/Bacteroides thetaiotaomicron, Bacteroides uniformis and Bacteroides ovatus were more abundant in controls than in patients with coeliac disease (p<0.05). Bacteroides vulgatus was more frequently detected in controls than in patients with treated coeliac disease (p<0.01). Bacteroides dorei was more common in patients with active coeliac disease than in those with treated coeliac disease and control children (p<0.01). Bifidobacterium diversity was higher in patients with coeliac disease than in controls. Bifidobacterium adolescentis and Bifidobacterium animalis subsp lactis were more prevalent in patients with active coeliac disease than in patients with treated coeliac disease and control children. A higher LAB diversity was found in patients with treated coeliac disease and controls than in patients with active coeliac disease. Weissella spp and Lactobacillus fermentum were more frequently detected in patients with treated coeliac disease than in controls and patients with active coeliac disease. CONCLUSIONS: Bacteroides, Bifidobacterium and LAB populations in the duodenum of Spanish children with typical coeliac disease (active and treated) and controls differ in diversity and species composition; this could contribute to features of the disease. PMID- 20972240 TI - Prevalence and associations of recent physical intimate partner violence among women attending an Australian sexual health clinic. AB - BACKGROUND: The Sydney Sexual Health Centre in Australia uses a proforma tool to screen all new female clients for recent physical intimate partner violence (IPV). This study describes the prevalence and associations of recent physical IPV among women attending a sexual health clinic. METHOD: The clinic database was used to identify all first visits by women reporting recent physical IPV between September 2003 and September 2007. Women reporting, and the next two age-matched women not reporting, recent physical IPV were compared regarding clinical, demographic and behavioural variables. RESULTS: 5519 (92%) of 6013 women attending were screened and 313 (5.7%) reported recent physical IPV. Recent physical IPV was not associated with current acute sexually transmitted infections (STIs). Women reporting IPV were more likely to report current sex work (AOR 1.75, 95% CI 1.23 to 2.48), a past STI (AOR 1.58, 95% CI 1.05 to 2.39) and a prior induced (AOR 1.64, 95% CI 1.18 to 2.27) or spontaneous (AOR 1.90, 95% CI 1.08 to 3.33) abortion. They were less likely to be in a current relationship (AOR 0.73, 95% CI 0.54 to 0.98) and consistently used condoms (AOR 0.67, 95% CI 0.48 to 0.94). CONCLUSION: Women reporting recent physical IPV at a sexual health clinic were not more likely to have a current STI. The association of IPV with sex work, prior STIs and lower condom use suggests sexual health clinics would be appropriate venues to screen women for intimate partner violence. PMID- 20972241 TI - Sexual violence and conflict in Africa: prevalence and potential impact on HIV incidence. AB - BACKGROUND AND AIMS: Sexual violence (SV) is common during conflict. Despite reports of rape-related incidents of HIV infection, ecological analyses have found no association between SV and HIV at a population level. This has led to debate in the humanitarian, security and public health arenas about whether SV is an important HIV risk factor in conflict-affected settings. This paper uses published evidence on sexual violence in Africa and modelling to explore when SV may increase individual HIV risk and community HIV incidence. METHODS: Publications on sexual violence in conflict settings were reviewed and a mathematical model describing the probability of HIV acquisition was adapted to include the potential effect of genital injury and used to estimate the relative risk of HIV acquisition in 'conflict' versus 'non-conflict' situations. An analytical equation was developed to estimate the impact of SV on HIV incidence. RESULTS: A rape survivor's individual HIV risk is determined by potentially compounding effects of genital injury, penetration by multiple perpetrators and the increased likelihood that SV perpetrators are HIV infected. Modelling analysis suggests risk ratios of between 2.4 and 27.1 for the scenarios considered. SV could increase HIV incidence by 10% if rape is widespread (>40%); genital injury increases HIV transmission (threefold or more); at least 10% of perpetrators are HIV infected and underlying HIV incidence is low (<0.5%). CONCLUSION: The analysis illustrates that SV is likely to be an important HIV risk factor in some conflict-affected settings. More generally, it indicates the limitations of using broad aggregate analysis to derive epidemiological conclusions. Conflict-related initiatives offer important opportunities to assist survivors and prevent future abuses through collaborative programming on reconstruction, HIV and sexual violence. PMID- 20972242 TI - Glypican-3 expression predicts poor clinical outcome of patients with early-stage clear cell carcinoma of the ovary. AB - BACKGROUND: Glypican-3 (GPC3), a membrane-bound heparan sulphate proteoglycan, may play a role in promoting cancer cell growth and differentiation. Recent studies reported that GPC3 is overexpressed in clear cell carcinoma (CCC) of the ovary, and not other ovarian histotypes. However, in CCC patients, the relationship between the overexpression of GPC3 and prognosis has not yet been clarified. AIM: To evaluate GPC3 expression by immunohistochemistry in CCC. METHODS AND RESULTS: In 52 CCC patients, GPC3 expression was observed in 40.4%. In cases of CCC, no correlations were identified between GPC3 expression and clinicopathological factors, such as age, FIGO stage, CA125 values, peritoneal cytology, ascitic fluid volume and mortality rate, except for the residual tumour size. GPC3 expression was associated with poor progression-free survival in stage I CCC patients. The numbers of Ki-67-stained cells in GPC3-positive areas were lower than those in GPC3-negative areas. GPC3 expression may be associated with a low proliferation rate in CCC cells. In the early stage of CCC, GPC3-expressing patients tended to be resistant to taxane-based treatment. CONCLUSIONS: Results suggest that the overexpression of GPC3 may be related to the low-level proliferation of tumours; it may be associated with resistance to taxane-based chemotherapy and a poor prognosis in CCC of the ovary. PMID- 20972243 TI - Management of in situ lobular neoplasia detected on needle core biopsy of breast. AB - AIMS: To evaluate the risk of having occult ductal carcinoma in situ or invasive carcinoma in the region of a focus of lobular (in situ) neoplasia (LN) diagnosed on needle core biopsy (NCB) of breast. METHODS: All cases of LN diagnosed on NCB of breast over 10 years (2000-2009 inclusive) were reviewed. The clinical presentation, radiological appearances and final pathological diagnosis on open diagnostic biopsy (ODB) were correlated. RESULTS: 125 cases of LN on NCB were identified from diagnostic codes. Of these, 72 (58%) had a coexistent, higher grade lesion that mandated surgery. Fifty of the remaining 53 (94%) underwent ODB. The majority of patients were asymptomatic, with 68% presenting through the breast screening programme, and in 89% of patients, the target abnormality was microcalcification. Of the 50 patients, 13 (26%) had a final diagnosis of in situ or invasive carcinoma requiring therapeutic surgery. When the cases of pleomorphic LN were excluded, 21% (10/47) were upgraded. Two of these 10 cases had discordant radiology which could have been diagnosed on repeat NCB leaving an upgrade rate of 18% (8/45). In four of the eight cases of invasive malignancy, the disease was multifocal. CONCLUSIONS: LN is frequently asymptomatic, being identified by mammographic microcalcification alone. In 21% of classical LN cases, it is associated with an undiagnosed, higher-grade lesion requiring oncological management. In our view, patients with LN discovered on NCB should undergo open diagnostic biopsy. PMID- 20972245 TI - A common pattern of brain MRI imaging in mitochondrial diseases with complex I deficiency. AB - OBJECTIVE: To identify a consistent pattern of brain MRI imaging in primary complex I deficiency. Complex I deficiency, a major cause of respiratory chain dysfunction, accounts for various clinical presentations, including Leigh syndrome. Human complex I comprises seven core subunits encoded by mitochondrial DNA (mtDNA) and 38 core subunits encoded by nuclear DNA (nDNA). Moreover, its assembly requires six known and many unknown assembly factors. To date, no correlation between genotypes and brain MRI phenotypes has been found in complex I deficiencies. DESIGN AND SUBJECTS: The brain MRIs of 30 patients carrying known mutation(s) in genes involved in complex I were retrospectively collected and compared with the brain MRIs of 11 patients carrying known mutations in genes involved in the pyruvate dehydrogenase (PDH) complex as well as 10 patients with MT-TL1 mutations. RESULTS: All complex I deficient patients showed bilateral brainstem lesions (30/30) and 77% (23/30) showed anomalies of the putamen. Supratentorial stroke-like lesions were only observed in complex I deficient patients carrying mtDNA mutations (8/19) and necrotising leucoencephalopathy in patients with nDNA mutations (4/5). Conversely, the isolated stroke-like images observed in patients with MT-TL1 mutations, or the corpus callosum malformations observed in PDH deficient patients, were never observed in complex I deficient patients. CONCLUSION: A common pattern of brain MRI imaging was identified with abnormal signal intensities in brainstem and subtentorial nuclei with lactate peak as a clue of complex I deficiency. Combining clinico-biochemical data with brain imaging may therefore help orient genetic studies in complex I deficiency. PMID- 20972246 TI - Variants in CFTR untranslated regions are associated with congenital bilateral absence of the vas deferens. AB - BACKGROUND: Congenital bilateral absence of the vas deferens (CBAVD), a frequent cause of obstructive azoospermia, is generated by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite extensive testing for point mutations and large rearrangements, a small proportion of alleles still remains unidentified in CBAVD patients. METHODS AND RESULTS: Mutation scanning analysis of microsatellite variability in the CFTR gene identified two undescribed 4 bp sequence repeats (TAAA)(6) and (TAAA)(8) in intron 9 in two CBAVD patients heterozygote for either the -33G->A promoter transition or the classical [TG12T5] CBAVD mutation. This study explores the putative impact of this promoter variant by using a combination of web based prediction tools, reporter gene assays, and DNA/proteins interaction analyses. Results of transiently transfected vas deferens cells with either the -33G wild type or the -33A variant CFTR directed luciferase reporter gene confirmed that the -33A variant, which alters the FOXI1 (Forkhead box I1) binding, significantly decreases the CFTR promoter activity. It was also investigated whether regulatory elements located within the intronic tetrarepeat might influence the CFTR expression. There was evidence that both the (TAAA)(6) and the (TAAA)(8) alleles modulate the CFTR transcription and the binding affinity for FOX transcription factors, involved in the chromatin architecture. CONCLUSIONS: As the vas deferens seems to be one of the tissues most susceptible to a reduction in the normal CFTR transcripts levels, and as two mild mutations are sufficient to induce CBAVD phenotype, these findings raise the possibility that these uncommon variants may be a novel cause of CBAVD. PMID- 20972247 TI - Uptake of breast cancer prevention and screening trials. AB - BACKGROUND: Uptake of cancer trials and in particular prevention trials has been disappointing globally. METHODS: Uptake to three randomised chemotherapy breast cancer prevention trials and two dietary prevention trials in women at increased familial risk were assessed and compared with uptake of screening trials across a range of risk categories. RESULTS: Uptake of drug prevention trials remains low at 5.3-13.6%, but is significantly higher in the high (12%) compared to very high risk group (8.4%) for IBIS1 and IBIS2 combined (p=0.004). Recruitment to two dietary prevention studies via mail shot was also disappointingly low at 6.2% and 12.5%. In contrast uptake to two mammography screening trials was >90% in all risk categories. CONCLUSIONS: More work must be done to improve recruitment to prevention trials if they are to be seen as viable alternatives to risk reducing surgery. IMPACT: Trial designs and decision aids need to be developed to improve recruitment. PMID- 20972248 TI - Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib. AB - BACKGROUND: Pseudohypoparathyroidism type Ib (PHP-Ib) is due to epigenetic changes at the imprinted GNAS locus, including loss of methylation at the A/B differentially methylated region (DMR) and sometimes at the XL and AS DMRs and gain of methylation at the NESP DMR. OBJECTIVE: To investigate if quantitative measurement of the methylation at the GNAS DMRs identifies subtypes of PHP-Ib. DESIGN AND METHODS: In 19 patients with PHP-Ib and 7 controls, methylation was characterised at the four GNAS DMRs through combined bisulfite restriction analysis and quantified through cytosine specific real-time PCR in blood lymphocyte DNA. RESULTS: A principal component analysis using the per cent of methylation at seven cytosines of the GNAS locus provided three clusters of subjects (controls n=7, autosomal dominant PHP-Ib with loss of methylation restricted to the A/B DMR n=3, and sporadic PHP-Ib with broad GNAS methylation changes n=16) that matched perfectly the combined bisulfite restriction analysis classification. Furthermore, three sub-clusters of patients with sporadic PHP-Ib, that displayed different patterns of methylation, were identified: incomplete changes at all DMRs compatible with somatic mosaicism (n=5), profound epigenetic changes at all DMRs (n=8), and unmodified methylation at XL in contrast with the other DMRs (n=3). Interestingly, parathyroid hormone concentration at the time of diagnosis correlated with the per cent of methylation at the A/B DMR. CONCLUSION: Quantitative assessment of the methylation in blood lymphocyte DNA is of clinical relevance, allows the diagnosis of PHP-Ib, and identifies subtypes of PHP-Ib. These epigenetic findings suggest mosaicism at least in some patients. PMID- 20972249 TI - Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability. AB - BACKGROUND: Cerebral palsy is a heterogeneous group of neurodevelopmental brain disorders resulting in motor and posture impairments often associated with cognitive, sensorial, and behavioural disturbances. Hypoxic-ischaemic injury, long considered the most frequent causative factor, accounts for fewer than 10% of cases, whereas a growing body of evidence suggests that diverse genetic abnormalities likely play a major role. METHODS AND RESULTS: This report describes an autosomal recessive form of spastic tetraplegic cerebral palsy with profound intellectual disability, microcephaly, epilepsy and white matter loss in a consanguineous family resulting from a homozygous deletion involving AP4E1, one of the four subunits of the adaptor protein complex-4 (AP-4), identified by chromosomal microarray analysis. CONCLUSION: These findings, along with previous reports of human and mouse mutations in other members of the complex, indicate that disruption of any one of the four subunits of AP-4 causes dysfunction of the entire complex, leading to a distinct 'AP-4 deficiency syndrome'. PMID- 20972250 TI - Genetic loci associated with lipid concentrations and cardiovascular risk factors in the Korean population. AB - BACKGROUND: Dyslipidaemia, a key risk factor for cardiovascular disease (CVD), is strongly influenced by genetic factors. OBJECTIVE: To identify genetic factors affecting blood lipid concentrations and CVD risk factors in the Korean population by a candidate gene association analysis. METHODS: 21 single nucleotide polymorphisms (SNPs) that have been reported as associated with lipid concentrations in people of European ancestry were selected and their associations with CVD risk factors in Korean populations assessed. Genotype data from 7616 subjects without diabetes or lipid-lowering drugs were obtained from the Korean Association Resource (KARE) project. RESULTS: After adjustment for age and gender, five SNPs were identified that were associated with high-density lipoprotein-cholesterol (HDL-C; rs4420638: p=2.09*10-7), 11 SNPs with low-density lipoprotein-cholesterol (LDL-C; rs12654264: p=1.29*10-8) and eight SNPs with triglycerides (TG; rs4420638: p=1.80*10-6). Through analysis of multiple associations with lipid traits, after adjustment for age, gender, body mass index, smoking, alcohol consumption and hypertension, five SNPs (rs693, rs17321515, rs174547, rs688, rs4420638) were identified that were strongly associated with at least two of the following: HDL-C, LDL-C and TG. Of these, rs693, which lies in the APOB gene, was also significantly associated with the homoeostasis model assessment for insulin resistance (p=6.68*10-6) and gamma glutamyl transpeptidase (p=2.34*10-6), and rs174547, which lies in the FADS1 gene and was significantly associated with fasting plasma glucose (p=1.48*10-6). CONCLUSION: Several SNPs associated with lipid traits and CVD risk factors were identified. These findings may form the basis for further investigations to identify the causative polymorphisms in dyslipidaemia and CVD. PMID- 20972251 TI - Molecular analysis of ring chromosome 20 syndrome reveals two distinct groups of patients. AB - BACKGROUND: The ring chromosome 20 syndrome (R20) is a rare genetic disorder associated with a refractory electroclinical epilepsy syndrome and variably expressed comorbidities of intellectual disability and dysmorphism. METHODS: To understand the structure and composition of the ring chromosome 20 (r(20)) in this patient cohort, blood specimens from 28 affected individuals were analysed by cytogenetic, fluorescence in situ hybridisation, and/or high resolution whole genome single nucleotide polymorphism array analysis. RESULTS: These studies revealed two distinct groups of patients. Group 1 (N=21) was mosaic for the r(20) and a normal cell line with no detectable deletions or duplications of chromosome 20 in either cell line. The mosaic nature of these rings suggests a postzygotic origin with formation of the ring by fusion of the telomeric regions with no apparent loss of subtelomeric or telomeric DNA. Group 2 (N=7) had non-mosaic ring chromosomes with a deletion at one or both ends of the chromosome, near the ring fusion point. The non-mosaic nature of these rings is consistent with a meiotic origin. The age of onset of seizures was significantly lower in the non-mosaic patients (group 2, median age of onset 2.1 years) than in the mosaic patients (group 1, median age of onset 6.0 years). Patients from group 2 had more extensive comorbidities. CONCLUSIONS: These studies demonstrate that r(20) is molecularly heterogeneous and formed by two distinct mechanisms, which, in turn, produce different phenotypic spectrums. PMID- 20972254 TI - Rules of engagement: factors that regulate activity-dependent synaptic plasticity during neural network development. AB - Overproduction and pruning during development is a phenomenon that can be observed in the number of organisms in a population, the number of cells in many tissue types, and even the number of synapses on individual neurons. The sculpting of synaptic connections in the brain of a developing organism is guided by its personal experience, which on a neural level translates to specific patterns of activity. Activity-dependent plasticity at glutamatergic synapses is an integral part of neuronal network formation and maturation in developing vertebrate and invertebrate brains. As development of the rodent forebrain transitions away from an over-proliferative state, synaptic plasticity undergoes modification. Late developmental changes in synaptic plasticity signal the establishment of a more stable network and relate to pronounced perceptual and cognitive abilities. In large part, activation of glutamate-sensitive N-methyl-d aspartate (NMDA) receptors regulates synaptic stabilization during development and is a necessary step in memory formation processes that occur in the forebrain. A developmental change in the subunits that compose NMDA receptors coincides with developmental modifications in synaptic plasticity and cognition, and thus much research in this area focuses on NMDA receptor composition. We propose that there are additional, equally important developmental processes that influence synaptic plasticity, including mechanisms that are upstream (factors that influence NMDA receptors) and downstream (intracellular processes regulated by NMDA receptors) from NMDA receptor activation. The goal of this review is to summarize what is known and what is not well understood about developmental changes in functional plasticity at glutamatergic synapses, and in the end, attempt to relate these changes to maturation of neural networks. PMID- 20972252 TI - Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability. AB - BACKGROUND: Autism spectrum disorder (ASD) is characterised by impairments in social communication and by a pattern of repetitive behaviours, with learning disability (LD) typically seen in up to 70% of cases. A recent study using the PPL statistical framework identified a novel region of genetic linkage on chromosome 16q21 that is limited to ASD families with LD. METHODS: In this study, two families with autism and/or LD are described which harbour rare >1.6 Mb microdeletions located within this linkage region. The deletion breakpoints are mapped at base-pair resolution and segregation analysis is performed using a combination of 1M single nucleotide polymorphism (SNP) technology, array comparative genomic hybridisation (CGH), long-range PCR, and Sanger sequencing. The frequency of similar genomic variants in control subjects is determined through analysis of published SNP array data. Expression of CDH8, the only gene disrupted by these microdeletions, is assessed using reverse transcriptase PCR and in situ hybridisation analysis of 9 week human embryos. RESULTS: The deletion of chr16: 60 025 584-61 667 839 was transmitted to three of three boys with autism and LD and none of four unaffected siblings, from their unaffected mother. In a second family, an overlapping deletion of chr16: 58 724 527-60 547 472 was transmitted to an individual with severe LD from his father with moderate LD. No copy number variations (CNVs) disrupting CDH8 were observed in 5023 controls. Expression analysis indicates that the two CDH8 isoforms are present in the developing human cortex. CONCLUSION: Rare familial 16q21 microdeletions and expression analysis implicate CDH8 in susceptibility to autism and LD. PMID- 20972255 TI - Bioluminescent organs of two deep-sea arrow worms, Eukrohnia fowleri and Caecosagitta macrocephala, with further observations on Bioluminescence in chaetognaths. AB - Bioluminescence in the deep-sea chaetognath Eukrohnia fowleri is reported for the first time, and behavioral, morphological, and chemical characteristics of bioluminescence in chaetognaths are examined. Until this study, the only known species of bioluminescent chaetognath was Caecosagitta macrocephala. The luminescent organ of that species is located on the ventral edge of each anterior lateral fin, whereas that of E. fowleri runs across the center of the tail fin on both dorsal and ventral sides. Scanning electron microscopy showed that the bioluminescent organs of both species consist of hexagonal chambers containing elongate ovoid particles-the organelles holding bioluminescent materials. No other luminous organism is known to use hexagonal packing to hold bioluminescent materials. Transmission electron microscopy of particles from C. macrocephala revealed a densely packed paracrystalline matrix punctuated by globular inclusions, which likely correspond to luciferin and luciferase, respectively. Both species use unique luciferases in conjunction with coelenterazine for light emission. Luciferase of C. macrocephala becomes inactive after 30 min, but luciferase of E. fowleri is highly stable. Although C. macrocephala has about 90 times fewer particles than E. fowleri, it has a similar bioluminescent capacity (total particle volume) due to its larger particle size. In situ observations of C. macrocephala from a remotely operated vehicle revealed that the luminous particles are released to form a cloud. The discovery of bioluminescence in a second chaetognath phylogenetically distant from the first highlights the importance of bioluminescence among deep-sea organisms. PMID- 20972256 TI - Circulation of fluids in the gastrovascular system of a stoloniferan octocoral. AB - Cilia-based transport systems characterize sponges and placozoans. Cilia are employed in cnidarian gastrovascular systems as well, but typically function in concert with muscular contractions. Previous reports suggest that anthozoans may be an exception to this pattern, utilizing only cilia in their gastrovascular systems. With an inverted microscope and digital image analysis, we used stoloniferan octocoral colonies growing on microscope cover glass to quantitatively describe the movement of fluids in this system for the first time. Flow in stolons (diameter ~300 MUm) is simultaneously bidirectional, with average velocities of 100-200 MUm/s in each direction. Velocities are maximal immediately adjacent to the stolon wall and decrease to a minimum in the center of the stolon. Flow velocity is unaffected by stolonal contractions, suggesting that muscular peristalsis is not a factor in propelling the flow. Stolon intersections (diameter ~500 MUm) occur below polyps and serve as traffic roundabouts with unidirectional, circular flow. Such cilia-driven transport may be the plesiomorphic state for the gastrovascular system of cnidarians. PMID- 20972257 TI - Effects of satiation and starvation on nematocyst discharge, prey killing, and ingestion in two species of sea anemone. AB - Studies spanning 60 years with several cnidarian species show that satiation inhibits prey capture and ingestion and that starvation increases prey capture and ingestion. Most have attributed the effects of satiation to inhibition of nematocyst discharge. We hypothesized that satiation inhibits prey capture and ingestion in sea anemones (Haliplanella luciae and Aiptasia pallida) primarily by inhibiting the intrinsic adherence (i.e., holding power) of discharging nematocysts. Using a quantitative feeding assay for H. luciae, we found that satiation completely uncoupled prey killing from prey ingestion, while nematocyst mediated prey killing was only partially inhibited. Using A. pallida to measure nematocyst discharge and nematocyst-mediated adhesive force, we showed that satiation completely inhibited the intrinsic adherence of discharging nematocysts from Type B and Type C cnidocyte/supporting cell complexes (CSCCs), while only partially inhibiting nematocyst discharge from Type Bs. These inhibitory effects of satiation were gradually restored by starvation, reaching a maximum at 72 h after feeding. Thus, the effects of satiation and starvation on prey killing and ingestion in two species of acontiate sea anemones are primarily due to changes in the intrinsic adherence of nematocysts from both Type B and Type C CSCCs. PMID- 20972258 TI - Laboratory spawning and development of the Bahama lancelet, Asymmetron lucayanum (cephalochordata): fertilization through feeding larvae. AB - Here we report on spawning and development of the Bahama lancelet, Asymmetron lucayanum. Ripe adults collected in Bimini spawned the same evening when placed in the dark for 90 minutes. The developmental morphology is described from whole mounts and histological sections. A comparison between development in Asymmetron and the better known cephalochordate genus Branchiostoma reveals similarities during the early embryonic stages but deviations by the late embryonic and early larval stages. Thus, the initial positions of the mouth, first gill slit, and anus differ between the two genera. Even more strikingly, Hatschek's right and left diverticula, which arise by enterocoely at the anterior end of the pharynx in Branchiostoma, never form during Asymmetron development. In Branchiostoma, these diverticula become the rostral coelom and preoral pit. In Asymmetron, by contrast, homologs of the rostral coelom and preoral pit form by schizocoely within an anterior cell cluster of unproven (but likely endodermal) origin. Proposing evolutionary scenarios to account for developmental differences between Asymmetron and Branchiostoma is currently hampered by uncertainty over which genus is basal in the cephalochordates. A better understanding of developmental diversity within the cephalochordates will require phylogenetic analyses based on nuclear genes and the genome sequence of an Asymmetron species. PMID- 20972259 TI - Differential fertilization success between two populations of eastern oyster, Crassostrea virginica. AB - Identification of mechanisms promoting prezygotic reproductive isolation and their prevalence are key goals in evolutionary biology because of their potential role in speciation. In marine broadcast-spawning species, molecular interactions between gamete surface proteins are more important than mating behavior for determining reproductive compatibility. Evidence for differential fertilization capacity has been reported from experiments utilizing competing sperm from two males sampled within populations and between species, but to our knowledge conspecific populations that might have diverged in allopatry have never been tested on the basis of sperm competition. In the present study, the gametic compatibility and embryo survivorship from matings between two allopatric populations of Crassostrea virginica, the eastern oyster, on either side of a genetic step cline were investigated. Fertilization success, embryo survival, and paternity data all indicated an absence of strong reproductive barriers between the two oyster populations, implicating other mechanisms for maintenance of the cline step. Sperm from northern male oysters showed a tendency to produce more larvae than expected when competing with sperm from southern male oysters. Although the northern male advantage was not strong, the trend implies that long distance dispersal across the step cline might more successfully result in north to-south gene flow than the reverse, providing a mechanistic hypothesis explaining the asymmetric cline shape. PMID- 20972260 TI - Sexual system, sex ratio, and group living in the shrimp Thor amboinensis (De Man): relevance to resource-monopolization and sex-allocation theories. AB - The sexual system of the symbiotic shrimp Thor amboinensis is described, along with observations on sex ratio and host-use pattern of different populations. We used a comprehensive approach to elucidate the previously unknown sexual system of this shrimp. Dissections, scanning electron microscopy, size-frequency distribution analysis, and laboratory observations demonstrated that T. amboinensis is a protandric hermaphrodite: shrimp first mature as males and change into females later in life. Thor amboinensis inhabited the large and structurally heterogeneous sea anemone Stichodactyla helianthus in large groups (up to 11 individuals) more frequently than expected by chance alone. Groups exhibited no particularly complex social structure and showed male-biased sex ratios more frequently than expected by chance alone. The adult sex ratio was male-biased in the four separate populations studied, one of them being thousands of kilometers apart from the others. This study supports predictions central to theories of resource monopolization and sex allocation. Dissections demonstrated that unusually large males were parasitized by an undescribed species of isopod (family Entoniscidae). Infestation rates were similarly low in both sexes (~11% 12%). The available information suggests that T. amboinensis uses pure search promiscuity as a mating system. This hypothesis needs to be formally tested with mating behavior observations and field measurements on the movement pattern of both sexes of the species. Further detailed studies on the lifestyle and sexual system of all the species within this genus and the development of a molecular phylogeny are necessary to elucidate the evolutionary history of gender expression in the genus Thor. PMID- 20972262 TI - Francisella philomiragia biofilm formation and interaction with the aquatic protist Acanthamoeba castellanii. AB - The bacterium Francisella philomiragia has been isolated from environmental samples originating from around the globe. F. philomiragia-related strains cause francisellosis of both farmed and wild fish. In addition, occasional human infections caused by F. philomiragia are found in victims of near-drowning and patients with chronic granulomatous disease. We have shown that F. philomiragia forms in vitro biofilms with increased formation at 25 degrees C over 37 degrees C conditions. We found that F. philomiragia can form a biofilm in a co culture with live Acanthamoeba castellanii, an aquatic amoeba. Interestingly, amoeba-conditioned supernatant has an inhibitory effect on production of biofilm by F. philomiragia, whereas Francisella-conditioned supernatant has no effect on growth of amoebae. We have shown that F. philomiragia can infect A. castellanii after only 5 days of co-incubation and that it infects A. castellanii more quickly than the related species F. novicida does. Our studies point to a potentially overlooked interaction between F. philomiragia and Acanthamoeba. This relationship in the marine lifecycle of F. philomiragia may support the persistence of the bacterium in waterways and its ability to infect fish. An understanding of the persistence of this organism in aquatic systems through biofilm formation and its interaction with Acanthamoeba will be important in developing prevention strategies for this pathogen. PMID- 20972261 TI - Rubyspira, new genus and two new species of bone-eating deep-sea snails with ancient habits. AB - Rubyspira, a new genus of deep-sea snails (Gastropoda: Abyssochrysoidea) with two living species, derives its nutrition from decomposing whalebones. Molecular phylogenetic and morphological evidence places the new genus in an exclusively deep-sea assemblage that includes several close relatives previously known as fossils associated with Cretaceous cold seeps, plesiosaur bones, and Eocene whalebones. The ability to exploit a variety of marine reducing environments may have contributed to the evolutionary longevity of this gastropod lineage. PMID- 20972263 TI - Interruption of inositol sphingolipid synthesis triggers Stt4p-dependent protein kinase C signaling. AB - The protein kinase C (PKC)-MAPK signaling cascade is activated and is essential for viability when cells are starved for the phospholipid precursor inositol. In this study, we report that inhibiting inositol-containing sphingolipid metabolism, either by inositol starvation or treatment with agents that block sphingolipid synthesis, triggers PKC signaling independent of sphingoid base accumulation. Under these same growth conditions, a fluorescent biosensor that detects the necessary PKC signaling intermediate, phosphatidylinositol (PI)-4 phosphate (PI4P), is enriched on the plasma membrane. The appearance of the PI4P biosensor on the plasma membrane correlates with PKC activation and requires the PI 4-kinase Stt4p. Like other mutations in the PKC-MAPK pathway, mutants defective in Stt4p and the PI4P 5-kinase Mss4p, which generates phosphatidylinositol 4,5-bisphosphate, exhibit inositol auxotrophy, yet fully derepress INO1, encoding inositol-3-phosphate synthase. These observations suggest that inositol-containing sphingolipid metabolism controls PKC signaling by regulating access of the signaling lipids PI4P and phosphatidylinositol 4,5 bisphosphate to effector proteins on the plasma membrane. PMID- 20972265 TI - Adiposity and cardiovascular risk factors in a large contemporary population of pre-pubertal children. AB - AIMS: to examine the associations of several markers of adiposity and a wide range of cardiovascular risk factors and biomarkers in pre-pubertal children. METHODS AND RESULTS: four measures of adiposity,body mass index (BMI), waist circumference, dual-energy X-ray absorptiometry (DXA)-determined fat mass, and leptin concentration, were available in up to 7589 children aged 8.8-11.7 (9.9 mean) years from the Avon Longitudinal Study of Parents and Children (ALSPAC). Thirteen per cent of boys and 18.8% of girls were overweight, and 5.3% of boys and 5% of girls were obese. Body mass index was highly correlated with waist circumference (r = 0.91), DXA fat mass (r = 0.87), and leptin concentration (r = 0.75), and all had similar associations with cardiovascular risk factors. A 1 kg/m(2) greater BMI was associated with 1.4 mmHg (95% CI 1.25-1.44) higher systolic blood pressure (BP). In 5002 children, a 1 kg/m(2) greater BMI was associated with a 0.05 mmol/L (95% CI 0.036-0.055) higher non-high-density lipoprotein (HDL) cholesterol and 0.03 mmol/L (95% CI -0.034 to -0.025) lower HDL cholesterol. There were also graded associations with apolipoproteins A1 and B, interleukin-6, and C-reactive protein. Comparing children who were obese with those who were normal weight, the odds ratio for hypertension was 10.7 (95% CI 7.2-15.9) for boys and 13.5 (95% CI 9.4-19.5) for girls. CONCLUSION: in pre pubertal UK children, overweight/obesity is common and has broadly similar associations with BP, HDL cholesterol, and non-HDL cholesterol to those observed in adults. Future research should evaluate whether effective interventions to maintain healthy weight in childhood could have important benefits for adult cardiovascular risk. PMID- 20972264 TI - Coordination of storage lipid synthesis and membrane biogenesis: evidence for cross-talk between triacylglycerol metabolism and phosphatidylinositol synthesis. AB - Despite the importance of triacylglycerols (TAG) and steryl esters (SE) in phospholipid synthesis in cells transitioning from stationary-phase into active growth, there is no direct evidence for their requirement in synthesis of phosphatidylinositol (PI) or other membrane phospholipids in logarithmically growing yeast cells. We report that the dga1Deltalro1Deltaare1Deltaare2Delta strain, which lacks the ability to synthesize both TAG and SE, is not able to sustain normal growth in the absence of inositol (Ino(-) phenotype) at 37 degrees C especially when choline is present. Unlike many other strains exhibiting an Ino(-) phenotype, the dga1Deltalro1Deltaare1Deltaare2Delta strain does not display a defect in INO1 expression. However, the mutant exhibits slow recovery of PI content compared with wild type cells upon reintroduction of inositol into logarithmically growing cultures. The tgl3Deltatgl4Deltatgl5Delta strain, which is able to synthesize TAG but unable to mobilize it, also exhibits attenuated PI formation under these conditions. However, unlike dga1Deltalro1Deltaare1Deltaare2Delta, the tgl3Deltatgl4Deltatgl5Delta strain does not display an Ino(-) phenotype, indicating that failure to mobilize TAG is not fully responsible for the growth defect of the dga1Deltalro1Deltaare1Deltaare2Delta strain in the absence of inositol. Moreover, synthesis of phospholipids, especially PI, is dramatically reduced in the dga1Deltalro1Deltaare1Deltaare2Delta strain even when it is grown continuously in the presence of inositol. The mutant also utilizes a greater proportion of newly synthesized PI than wild type for the synthesis of inositol-containing sphingolipids, especially in the absence of inositol. Thus, we conclude that storage lipid synthesis actively influences membrane phospholipid metabolism in logarithmically growing cells. PMID- 20972266 TI - A data set of human endogenous protein ubiquitination sites. AB - Lysine ubiquitination is an important and versatile protein post-translational modification. Numerous cellular functions are regulated by ubiquitination, suggesting that extensive numbers of proteins, if not all, are modified with ubiquitin at certain times. However, proteome-wide profiling of ubiquitination sites in the mammalian system is technically challenging. We report the design and characterization of an engineered protein affinity reagent for the isolation of ubiquitinated proteins and the identification of ubiquitination sites with mass spectrometry. This recombinant protein consists of four tandem repeats of ubiquitin-associated domain from UBQLN1 fused to a GST tag. We used this GST-qUBA reagent to isolate polyubiquitinated proteins and identified 294 endogenous ubiquitination sites on 223 proteins from human 293T cells without proteasome inhibitors or overexpression of ubiquitin. Mitochondrial proteins constitute 14.7% of this data set, implicating ubiquitination in a wide range of mitochondrial functions. PMID- 20972268 TI - [Prevention of errors and complications in formation of esophageal layer-by-layer apparatus anastomosis]. AB - The aim of the research is to analyze the outcome of treatment of patients with cardioesophageal cancer. Subtotal resection of esophagus with gastrectomy was performed on 3 patients. On 9 patients the resection of esophagus with gastrectomy from left thoracophrenolaparotomy was performed. Gastrectomy with resection of abdominal part of esophagus was performed on 10 patients. Transhiatal mediastinal lymphadenectomy S2D2 was carried out in all cases. The esophageal anastomosis has been formed by circular apparatus EEA and SPTU. The functional condition of anastomosis was investigated by X-ray, endoscopical and endo-sonographical methods in the postoperative period. The complications caused by technical errors of esophageal anastomosis were reviewed. The regeneration of circular anastomosis depends of adequate blood supply of anastomosis, observance of safety rules of imposing circular anastomosis. Reasonable application of circular apparatus, the refined technics of imposing anastomosis, X-ray, endoscopical and endo- sonographical research methods decrease complications and promote recovery. PMID- 20972267 TI - A self-validating quantitative mass spectrometry method for assessing the accuracy of high-content phosphoproteomic experiments. AB - Protein kinase pathways play pivotal roles in cell signaling and biology. The phosphoproteome is a reflection of protein kinase pathway activation and therefore there is considerable interest in its quantification as a means to assess the wiring of signaling networks. Although different approaches for quantitative phosphoproteomics have been described, there is no data on how accurate these are for each quantified phosphorylated site. We report a liquid chromatography-MS approach to objectively assess data quality in high-content comparison of phosphoproteomes in which samples to be compared are mixed at different proportions. The experimental data is then used to derive a linear regression function that allows calculating correlation values, linearity, and accuracy. We applied the technique to investigate phosphorylation in P31/Fuj and Kasumi-1, two leukemia cells lines showing strikingly different sensitivities to scr and PI3K inhibitors. We found that phosphopeptides quantified with accuracy were not always quantified with precision because of low ion statistics contributing to variability. Thus our approach was complementary to standard methods for calculating the precision of replicate measurements based on the coefficient of variation and provided additional information on data quality for each quantified phosphopeptide. We quantified > 2250 phosphorylation sites across cell lines with different levels of sensitivity to kinase inhibitors, of which 1847 showed an accuracy variation of < 30% (with an overall mean of 22%). Hundreds of phosphorylation sites on proteins with diverse function (including kinases, transcription, and translation factors) showed significantly distinct intensities across sensitive and resistant cells lines, indicating that kinase pathways are differentially regulated in cancer cells of distinct sensitivity to signaling inhibitors. PMID- 20972269 TI - [Characteristic of cytopathological changes in urine after extracorporeal shock wave lithotripsy]. AB - The aim of the study is to assess the damage to the urothelium caused by shock waves through cytological examination of the urinary sediment in patients who had ESWL. Study included 100 otherwise healthy first-time stone-formers aged 20 to 50, who underwent ESWL on Modulit SLK machine. Urinary samples were taken before and immediately after ESWL, in two days and on the fourth day after ESWL. Control group included 20 healthy individuals. The urine was centrifuged, smears fixed by conventional MGG method and stained by azure-eosine using Pappenheim's method. Cytogram data analysis was performed using morphometric methods, allowing for qualitative and quantitative cell characteristics be translated into digital form. Student t-criteria was used for statistical evaluation of the difference of derived figure parameters. The authors put the stress on destructives processes. In order to rule out biased assessment of the cytograms, morphometric examination of urinary sediment was performed. Averaged value of the total cell index was calculated with one of the forms of cytopathology and deduced heterogeneity of cytological indices within a particular group X(cell)/ Sigmaep (X(cell) where is the average value of the total cell index with one of the forms of cytopathology within the whole sampling, Sep is the total number epithelial cells). The sum of absolute indices of cytological changes is considered as "destruction index" (DI), which reflects accumulated pathological changes in epithelial cells: DI=X(1)/Sigmaep + X(2)/Sigmaep Immediately after ESWL a statistically valid (p<0.01) significant increase in DI is registered. In two hours after the session DI is decreased, but remains rather high, and almost normalizes by the fourth day. We also explored the specificity particular for each term of examination, expressed by cytological changes. Examination of indices of heterogeneity within a group with moderately expressed destructive changes (X(1)/Sigmaep) revealed that these digital values even in healthy men are slightly above zero (0.15 +/- 0.03). Just after ESWL values rise to 0.6 +/- 0.1, then slowly decrease to 0.4 +/ 0.1 (2 hours after) and 0.25 +/- 0.07 (four days after). As to parameters specific to deep cellular changes (X(2)/Sigmaep), it is equal to zero healthy men, rises after ESWL, then decreases in two hours and almost normalizes by fourth day. Digital values for this parameter are several orders lower than for parameters of cells with moderate changes. Study results indicate that epithelial lining of the upper urinary tract undergoes cytopatho-logical changes of different degrees, still they are of transitory and reversible nature, which is proven by urinary sediment cytogram performed on the fourth postprocedure day. PMID- 20972270 TI - [Rentgenoendoscopic surgery of the complicated forms of urolithiasis with accompanying diabetes mellitus]. AB - The successful application of endoscopic contact lithotripsy and nephrolithoextraction allows saving the patients from staghorn stones without having recourse to traumatic open surgical modalities. Percutaneous removal of staghorn stones with the use of rigid-lens nephroscopes presents as an effective and less-invasive treatment option with minimal amount of intra- and postoperative complications, which is particularly important in case of presence of accompanying diabetes mellitus. PMID- 20972271 TI - [Theoretical and practical principles of dentinogenesis: hypotheses and confirmed clinically reality]. AB - The problem of maintaining dental vitality and stimulating reparative processes is a priority in modern odontology. Restorative processes depend not only on the type and size of tissue damage, but also on the protection capacity and integrity of the structural/functional pulp-dentin boundary. Primary dentin that is initiated in the intrauterine period has unique structure and composition. Secondary dentin continues to form after the tooth is erupted, then after root formation is finished, and throughout life. Actually the primary and secondary dentins have similar tissue structures developed at different stages of dentinogenesis. Primary dentinogenesis is initiated by odontoblasts located in the periphery of dental pulp. Secondary dentin as a structure already exists once root formation is complete, but at that stage is has low levels of mineralization. Formation of tertiary dentin is always reactionary to different pathologies and is initiated by so called "transitional odontoblasts" (odontoblast-like cells) and partially fibroblasts. Odontotropic and anti inflammatory medications strongly change structural characteristics of the dentin. Pulpal ability to produce dentin-like matrix (tertiary dentin) is an important component of the pulp-dentin reparative capacity. Only specific characteristics of the dentin can account for indications and contraindications for using restorative liners and explain the impact of adhesive systems on these. In this context, the interest is high to the dentin and its response and change in reaction to different stimuli. Dental caries and other pathological processes (abrasion, erosion, attrition) seriously affect dentin vital activity causing it to change to the "emergency" mode. This process is viewed not as resulting from pulp medication but as reactionary, aimed for self-preservation. In such cases the major focus is not on drug composition but on pulpal response. The pulp may be said to "form tertiary dentin for self-protection". In conclusion, the tertiary dentin that forms as a result of pathological processes (express-dentin, reparatory dentin) could be identified as a perfect barrier for the pulp necessary for keeping it vital. And investigation of mechanisms causing primary stimulation of odontoblasts and triggering the reparative processes remains a pressing problem in modern odontology. PMID- 20972272 TI - Dominated EEG patterns and their prognostic value in coma caused by traumatic brain injury. AB - Study aimed at investigation of dominated EEG patterns in traumatic coma of different severity and to elucidate their prognostic value for outcome of disease within month. A total of 53 coma patients with severe traumatic brain injury have been investigated. Exclusion criteria comprised the patients needing the neurosurgical intervention due to hemorrhage. Brain injury was visualized by conventional CT at admission. The level of consciousness was evaluated by Glasgow Coma Scale (GCS). Patients were divided in 5 groups according to GCS. Electrophysiological investigations were performed on 5th day from development of coma by application of 16 channel computer encephalography. Outcome of coma (death, vegetative state, recovery) was evaluated within month from disease onset. According to dominated EEG background activity patterns the 1st group (GCS=4) showed the delta EEG pattern in 50 % of patients, the beta EEG pattern- in 33.4% and the alpha EEG pattern - in 16.6%. The 2nd group (GCS=5) revealed the delta EEG in 40%, the beta EEG- in 6.7% and the theta EEG - in 53.3%. The 3rd group (GCS=6) showed the delta EEG pattern in 27.8% and the theta EEG pattern- in 72.2%. In 4th group (GCS=7) the theta EEG pattern found in 77.7% and the beta EEG pattern in 22.3%. The 5th group (GCS=8) revealed the theta EEG activity in 80% and beta EEG activity - in 20%. Positive correlation was found between the GCS and the frequency of theta EEG pattern (r=+0.62; p<0.05). Positive correlation was established between the frequency of delta EEG pattern, death and persistent vegetative state (r=+0.57 and r=+0.16 respectively, p<0.05) within month. Positive correlation was established between the frequency of delta EEG pattern and the size of brain injury (r=+0.3; p=0.04). Multinomial logistic regression revealed the significance of brain lesion size, GCS and EEG pattern for functional outcome of coma. In severe traumatic coma patients the delta EEG pattern is associating with deep coma state and predicts the poor functional outcome within month. PMID- 20972273 TI - Pulmonary hypertension in female patients with cardiovascular and respiratory tract disease. AB - Pulmonary arterial hypertension (PAH) is defined as a group of disease characterized by a progressive increase of pulmonary vascular resistance (PVR) leading to right ventricular failure. Aim of our study was to determine frequency of PAH in female patients with cardiovascular and pulmonary tract disease. The research was performed in 80 postmenopausal women (mean age, 54 +/- 3 yr). They were divided in groups according to the main disease: 1. Chronic obstructive pulmonary disease COPD n=16. 2. Acute pneumonia n=23. 3. Cardiovascular disease n=25. This group was compared with the control group (nonpostmenopausal women). In postmenopausal women high level of PAH by echocardiographic trial was manifested in patients with cardiovascular disease n=17 (68%); In cases of pneumonia n=13; 56,5% (P<0.001) and in COPD n=12; 75% (P=0.001). There wasn't revealed significant level of pulmonary hypertension in nonpostmenopausal women (P=0.001). By transthoracic echocardiography tricuspidal regurgitation (TR), right atrial (RA) and right ventricular (RV) dilatation was showed in every patient with important degree of PH. By electrocardiography (ECG) signs of RV and RA hypertrophy were expressed in great majority of patients with high degree of PH. Furthermore, RV hypertrophy revealed in n=64 (80%) of patients and right deviation of axis in n=60 (75%). The results have indicated that PAH is widely extended in postmenopausal period, when the protective effects of oestrogens on the endothelium decrease. The problem is actual and needs particular attention. Early diagnostic and treatment of pulmonary hypertension give the possibility to control cardiovascular and pulmonary disease and avoid complications. PMID- 20972274 TI - Enterohemorrhagic E. coli and hemolytic uremic syndrome in Georgia. AB - It is important to consider that between Jul-October 2009 in the pathologic center of infectious diseases (Tbilisi State Medical University Department of Infectious Diseases) among hospitalized patients with hemorrhagic colitis 25 patients developed HUS syndrome. Most of patients were rural residents 20 (80%), only 5 (20%) were urban. 11 (44%) patients were children, 14 (56%) were adults. Male and female rate was equal. All the patients related the onset of the disease with the consumption of notwashed raw fruits or vegetables, nonpasteurized dairy products, food from street vendors, soft cheeses made from raw milk and untreated water in areas lacking adequate chlorination. The onset of the disease was not acute: low grade fever (37,5-37,8(0)C), severe diffuse pain in abdomen accompanied with cramps, frequent bowel movement with loose, watery stools 5-6 times a day. On the 2-3rd days of disease condition was worsened by increased of intoxication and frequent bowel movement with bloody stools about 10-15-20 times a day. On the 3-4 rd days of the onset of the diarrhea developed oliguria, anuria, edema. Among other complications important were: polyserosit - 8 (32%), encephalopathy - 2 (8%), disseminated intravascular coagulation - 3 (14%), ileus 1 (4%,) acute reactive phsycosis - 1 (4)%. In 15 (60%) cases became necessary to carry out hemodialysis. died 5 patients, lethality is - 5 (20%). Treatment options included: pathogenetic and symptomatic. Thus, increased rate of patients in the recent years indicates to circulation of shiga-toxin producing E.Coli in Georgia. PMID- 20972275 TI - [Epidemiologic peculiarities of infections caused by the hepatitis B and C viruses among lung tuberculosis patients]. AB - The article presents the results of serological investigation for presence of specific markers of hepatitis B (HBV) and hepatitis C (HCV) infections in serum samples obtained from 600 patients with acute and chronic forms of lung tuberculosis (LT) and in control group I - 600 healthy adults and in control group II - 796 patients with somatic pathology from multiprofile hospital. It has been established that among LT patients frequency of revealing HBsAg and anti-HCV is statistically steady; similar indicators are among persons from both control groups. The frequency of revealing of these markers among patients with chronic forms of LT is considerably higher than frequency of their revealing in patients with acute forms of LT. At the same time, both infections in patients with LT were often presented in form of subclinical hepatitis, identified by increase in of aminotransferases activity in blood. PMID- 20972276 TI - The efficacy of topical drugs in treatment of noninflammatory acne vulgaris. AB - Treatment of Acne Vulgaris still remains as an actual problem. The purpose of the research was to study the curing process and side effects of topical drugs - Diacneal and Skinoren in patients with non-inflammatory acne vulgaris. The results of the research has confirmed the swift and stable treating effect of both preparations, that expressed in decrease in number and size of comedonal and papulo-comedonal formations, actually without side effects. Thus, in spite of divergence of either chemical composition or mechanism of action, both, Diacneal and Skinoren, may be recommended as a very good choice for monotherapy of non inflammatory acne vulgaris. PMID- 20972277 TI - Quantative EEG during baseline and various cognitive tasks in children with attention deficit/hyperactivity disorder. AB - It is known that attention deficit/hyperactivity disorder is a widely spread condition in school aged childhood population. Making of precise diagnosis is a serious problem of modern pediatric neurology. In spite of large amount of guidelines and questionnaires the unified consensus of diagnosis is still absent. Thus it is important to search additional diagnostic criteria which can help physicians to confirm ADHD. For this purposes we have used quantative EEG (QEEG) parameters. There are numerous papers regarding QEEG changes of ADHD children during baseline (resting with closed eyes, resting with opened eyes, photic stimulation, hyperventilation).But information concerning QEEG evidences during cognitive tasks is insufficient. For this purposes we have used QEEG during Raven test, reading and calculation in children with ADHD and control group. QEEG was carried out according to standard 10-20 electrode placement rule from the following derivations: F3, F4, C3, C4, P3, P4, O1, O2. We have observed that in controls fulfilling of Raven test is more difficult than reading. Thus they are eulectic but in ADHD children reading is more difficult than Raven test. Thus they are dyslexic. By means of alpha and delta bands analysis it became apparent that alpha band is inversely proportional to mental effort and delta band is directly proportional to mental activity. PMID- 20972278 TI - [Possible mechanism of behavioral disorders in rats under long term treatment with dexamethasone in neonatal period]. AB - Despite the fact that the side effects of prolonged treatment with dexamethasone are well known, information about its effects on the central nervous system is very limited. Experimental study of long-term effects of dexamethasone administration in the neonatal period on behavioral activity of rats in the open field was conducted. Four groups of newborn males were selected from the offspring of pregnant rats. The first group was left intact, the animals of second group were injected saline solution, the third group - with the dexamethasone and the fourth group - along with dexamethasone received L arginine. Tests in an open field for all groups of animals were carried out on the 45th (first test) and 60th (second test) days after birth. The results showed that the decrease in motor activity of animals and in the number of sectors crossed in the open field with a high statistical significance was observed only in the group of animals, which for four days in the neonatal period underwent dexamethasone treatment. At the same time, another group of animals, which was also injected dexamethasone in the same doses, but additionally was injected L arginine, the behavior in the open field did not differ from the intact animals or animals which were injected (as a control) saline solution. It was concluded that it is the lack of nitric oxide in the early neonatal period, which occurs as a result of dexamethasone treatment that causes observed changes in animals' behavior. PMID- 20972279 TI - [Modulating effects of androgens on development adaptive-compensatory processes in organism of experimental animals-males]. AB - The purpose of research is the definition of androgens role and myocardial androgen receptors and sex steroids in males under metabolic and hormonal "stress" induced by the experimental diabetes. Research was carried out on 60 rats-males, mass 180,0-200,0 g. The diabetes reproduced by single injection of alloxan (200mg/kg). Androgen receptors were revealed by the radiometric and radioautography methods. The content of glucose, immunoreactive insulin, testosteron, estradiol, corticosteron and somatotropin were defined in animals blood plasma. On the early terms of alloxan diabetes estradiol concentration increase against a background of testosteron decrease which causes the "feminization" of the sexual hormonal balance. On the other side the increase of androgen receptors expression by cardiomyocytes causes the intensification of myocardium tissue physiologic ability to androgens perception positively influencing on the metabolism. Consequently, androgens provoke stimulating effect on the myocard metabolism in males at early stages of the experimental diabetes. PMID- 20972280 TI - Novel protective agent GF-6 for skin wounds. AB - The aim of present investigation was the determination of specific pharmacological (wound healing) properties and the evaluation of possible irritative, allergenic and toxic effects of GF-6 - novel protective agent for skin mechanical and burn wounds. In mouse excisional wound model GF-6 (topically 0.1 ml per wound) exhibited the ability to accelerate scab rejection and full reepithelization in test wounds with no signs of bacterial contamination. GF-6 caused no irritation responses such as erythema, oedema, dotted hemorrhage, hyperkeratosis, hyperplasia, alopecia and scaling in 14-day acute dermal irritation test. As well no signs of skin hypersensitivity (itch, erythema, oedema), and histological alteration (ulceration, dotted hemorrhage, changed capillary lumen, damaged hair follicle) were observed in skin application test at all time points during the 14-day observation period, evidencing that GF-6 is non allergenic. In subchronic dermal toxicity 90-day study of five-fold concentrated GF-6 no statistically significant changes in respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behavior patterns were detected. The results of hematological study testified to no influence of the GF 6 90-day application on blood formed elements. Thus, GF-6 should be considered non-toxic, non-irritant, non-allergenic wound healing and wound protecting agent. PMID- 20972281 TI - Management of children with severe acute malnutrition a national priority. PMID- 20972282 TI - Therapeutic nutrition for children with severe acute malnutrition summary of African experience. PMID- 20972283 TI - Consensus Statement National Consensus Workshop on Management of SAM Children through Medical Nutrition Therapy. AB - JUSTIFICATION: Severe acute malnutrition (SAM) is an important preventable and treatable cause of morbidity and mortality in children below five years of age in India. The concerned stakeholders are not in agreement about the role of product based medical nutrition therapy in the management of this condition. PROCESS: In November 2009, a National Consensus Workshop was organized by the Department of Human Nutrition, All India Institute of Medical Sciences, New Delhi in collaboration with the Department of Pediatrics and Clinical Epidemiology, Sitaram Bhartia Institute of Science and Research, New Delhi, and the Sub specialty Chapter on Nutrition, Indian Academy of Pediatrics. Presentations by eminent national and international scientists, the ensuing discussions, and opinions expressed by the participants provided the basic framework for drafting the consensus statement. The draft of the consensus statement was circulated to all the participants; it underwent two revisions after consideration of their comments. OBJECTIVES: (i) Critically appraise the current global evidence on the utility of Medical Nutrition Therapy (MNT) for the management of SAM in under five children; (ii) Formulate a consensus amongst stakeholders regarding the need to introduce product based MNT for the management of SAM in under five children in India; (iii) Identify research priorities for MNT for the management of SAM in under five children in India; and (iv)Ascertain potential challenges for introducing product based MNT in India, if consensus opinion identifies such a need. RECOMMENDATIONS: Guidelines related to the role of MNT in management of children suffering from SAM are presented. Global and regional data document the effectiveness of MNT using ready-to-use therapeutic foods (RUTF) and locally formulated products. Adequate caution should be exercised to ensure that MNT for SAM does not interfere with measures for the holistic prevention of childhood undernutrition. Indian manufacture of RUTF is feasible, and can be scaled up. Product-based nutrition therapy including RUTF can be introduced on a pilot basis when a delivery design and plan of action is developed and is in place as a part of the larger system to deal with childhood undernutrition. RUTF should be used only as therapeutic and not supplementary feeding, above six months of age, and for a limited time period (4-8 weeks) until the child recovers from SAM, which should be defined in explicit treatment protocols. An urgent research issue is comparison of RUTF with home-based and locally-formulated products. PMID- 20972284 TI - Evolution of nutritional management of acute malnutrition. AB - Wasting, kwashiorkor and stunting are not usually due to either protein or energy deficiency. Treatment based upon this concept results in high mortality rates, and failure of treated children to return physiologically to normal. They become relatively obese with insufficient lean tissue. Preventive strategies have also failed. Wasting and stunting are primarily due to deficiency of type II nutrients and kwashiorkor probably due to deficiency of several type I nutrients that confer resistance to oxidative stress. Modern dietary treatments are based upon the F75 formula whilst the child is sick without an appetite, followed by F100 for rapid gain of weight. Derivative, ready-to-use therapeutic foods (RUTF) allow treatment of large numbers of children at home, are preferred by mothers and dramatically improve coverage. Children are indentified by screening in the community and treated before complications arise, using simple protocols. Successful treatment of the sick children with severe malnutrition not only depends upon these products, but appropriate management of complications. The physiology of the malnourished child is completely different from the normal child and many drugs and treatments that are safe in children with normal physiology are fatal for the malnourished child. In particular, the diagnosis and management of diarrhea and dehydration is different in the malnourished child. Giving standard treatment frequently leads to circulatory overload and death from heart failure. The challenge now is to find successful local ways to prevent malnutrition and achieve nutritional security. Until prevention works, we have to rely on fortified foods for treatment and convalescence from illness. PMID- 20972285 TI - Locally made ready to use therapeutic food for treatment of malnutrition a randomized controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of a locally made ready-to-use therapeutic food (RUTF) in decreasing mild to moderate malnutrition. DESIGN: A randomized open label, controlled trial. SETTING: Pre-schools run by the Department of Community Health in Kaniyambadi administrative block, Vellore, India; duration of follow-up 3 months from the date of recruitment. PARTICIPANTS: Pupils aged 18 -60 months with Weight-for-Age 2 SD. INTERVENTIONS: A locally produced energy-dense supplement (RUTF), and the current standard of care [teaching caregivers how to make a fortified cereal-milk supplement called High Calorie Cereal Milk (HCCM)]. MAIN OUTCOME MEASURES: Increase in weight-for-age status; increase in levels of plasma zinc, vitamin B12, serum albumin and haemoglobin. RESULTS: The Mean (SD) weight gain at 3 months was higher in the RUTF group: RUTF (n=51): 0.54 kg; (SE = 0.05; 95% CI = 0.44 - 0.65) vs HCCM (n=45): 0.38 kg;(SE = 0.06; 95% CI = 0.25 - 0.51), P = 0.047. The weight gain per kilogram of body weight was directly proportional to the severity of malnutrition. CONCLUSIONS: Community-based treatment showed weight gain in both groups, the gain being higher with RUTF. PMID- 20972286 TI - Home-based rehabilitation of severely malnourished children in resource poor setting. AB - OBJECTIVE: To evaluate the feasibility and outcome of home-based rehabilitation of severely malnourished children. DESIGN: Prospective and observational. SETTING: Rehabilitation at home (16 weeks) following initial assessment or/and stabilization at hospital. PARTICIPANTS: Thirty-four severely malnourished (weight for length < 70% of WHO reference) children between the ages of 6 months to 5 years. INTERVENTION: Initial assessment of the patient was done in hospital. Those with complications or loss of appetite were admitted in hospital and managed as per WHO guidelines. After discharge, they were managed at home using home based diets. Those without complications and with preserved appetite were directly eligible for home-based rehabilitation. Follow up was done in hospital up to 16 weeks. Dietary intake, anthropometry and morbidities were recorded during follow-up. RESULTS: Of the enrolled 34 children, 19 children were admitted in hospital and 15 children were sent home after initial assessment in hospital. Five did not clear the initial stabilization phase (2 died, 3 left hospital). Finally 29 children qualified for home based rehabilitation out of which 26 completed 16 week follow-up. During the home based management phase, the reported mean (+/-SD) calorie intake increased from 100 (+/- 5) kcal/kg/d at entry point to 243 (+/- 13) kcal/kg/d at 16 weeks (P=0.000). Similarly, reported protein intake increased from 1.1 (+/- 0.3) g/kg/d to 4.8 (+/- 0.3) g/kg/d (P=0.000). During hospital stay (n=19), children had weight gain of 9.0 (+/-5.3) g/kg/d, while during home based follow up (n=29), weight gain was 3.2 (+/- 1.5) g/kg/d only. During home based rehabilitation, only 3 (11.5%) children had weight gain of more than 5 g/kg/d by the end of 16 weeks. Weight for height percent increased from an average (+/- SD) of 62.9% (+/- 6.0%) to 80.3% (+/- 5.7%) after the completion of 16 weeks (P=0.000). Thirteen (45%) children recovered completely from malnutrition achieving a weight for length of >80; % whereas 15 (51.7%) recovered partly achieving weight for length >70;%. There was no death during the home stabilization. CONCLUSION: Home based management using home prepared food and hospital based follow up is associated with sub-optimal and slower recovery. PMID- 20972287 TI - Production and distribution of a therapeutic nutritional product for severe acute malnutrition in India: opportunities and challenges. AB - Limited resources for hospitalized treatment of Indias nearly 8 million children with severe acute malnutrition (SAM) make community management of SAM a priority. Capability to produce sufficient quantities of Ready to Use Therapeutic Food (RUTF) is one component of preparedness for community management of SAM. Production of RUTF is a simple process that consists of grinding, mixing and packaging using widely available equipment. Nitrogen flush packaging increases shelf life to 2 years though it is the most expensive and slowest step of the production process. Being a therapeutic product, quality and safety must be ensured including aflatoxin measurement and estimation of micronutrient and macronutrient content consistently. RUTF can be made in India in several production models (i) Dairy cooperatives and private manufacturers can produce large quantities to meet regional requirements, (ii) small and niche food manufacturers can produce smaller volumes but have a major presence in most parts of India; and (iii) hand made RUTF can be made by village industries for immediate local consumption. All the ingredients and equipment for RUTF are widely available in India RUTF is already being produced in India for export. Concerns from various sections of society will need to be heard before community management of SAM using therapeutic, processed nutritional products can begin. Despite apprehensions about processed RUTFs or the sections of the public health community that press for its use, withholding alternative treatment for one of the largest killers of Indias children must not be the option. It is time public health/ medical communities and civil society come together to make effective community management of SAM an immediate reality. PMID- 20972288 TI - Efficacy and safety of therapeutic nutrition products for home based therapeutic nutrition for severe acute malnutrition a systematic review. AB - CONTEXT: Severe acute malnutrition (SAM) in children is a significant public health problem in India with associated increased morbidity and mortality. The current WHO recommendations on management of SAM are based on facility based treatment. Given the large number of children with SAM in India and the involved costs to the care-provider as well as the care-seeker, incorporation of alternative strategies like home based management of uncomplicated SAM is important. The present review assesses (a) the efficacy and safety of home based management of SAM using therapeutic nutrition products or ready to use therapeutic foods (RUTF); and (b) efficacy of these products in comparison with F 100 and home-based diet. EVIDENCE ACQUISITION: Electronic database (Pubmed and Cochrane Controlled Trials Register) were scanned using keywords severe malnutrition, therapy, diet, ready to use foods and RUTF. Bibliographics of identified articles, reviews and books were scanned. The information was extracted from the identified papers and graded according to the CEBM guidelines. RESULTS: Eighteen published papers (2 systematic reviews, 7 controlled trials, 7 observational trials and 2 consensus statements) were identified. Systematic reviews and RCTs showed RUTF to be at least as efficacious as F-100 in increasing weight (WMD=3.0 g/kg/day; 95% CI -1.70, 7.70) and more effective in comparison to home based dietary therapies. Locally made RUTFs were as effective as imported RUTFs (WMD=0.07 g/kg/d; 95% CI=-0.15, 0.29). Data from observational studies showed the energy intake with RUTF to be comparable to F-100. The pooled recovery rate, mortality and default in treatment with RUTF was 88.3%, 0.7% and 3.6%, respectively with a mean weight gain of 3.2 g/kg/day. The two consensus statements supported the use of RUTF for home based management of uncomplicated SAM. CONCLUSIONS: The use of therapeutic nutrition products like RUTF for home based management of uncomplicated SAM appears to be safe and efficacious. However, most of the evidence on this promising strategy has emerged from observational studies conducted in emergency settings in Africa. There is need to generate more robust evidence, design similar products locally and establish their efficacy and cost-effectiveness in a non-emergency setting, particularly in the Indian context. PMID- 20972289 TI - NTAGI subcommittee recommendations did not overlook crucial data. PMID- 20972291 TI - Seasonal flu vaccine. PMID- 20972293 TI - Variable doses of vaccines according to age. PMID- 20972294 TI - Human papilloma virus vaccines and current controversy. PMID- 20972295 TI - Clinical screening for Congenital heart disease at birth: a prospective study in a community hospital in Kerala. AB - OBJECTIVE: To develop a clinical strategy for detection of Congenital heart disease (CHD) in the newborn through a combination of clinical signs and pulse oximetry. DESIGN: Prospective longitudinal study. SETTING: Community level hospital in the city of Kochi, Kerala. PARTICIPANTS AND INTERVENTIONS: All consecutive newborns between June 2006 and February 2009 were prospectively screened for CHD, 48 hours after birth. The on-site pediatrician performed clinical screening. A study nurse recorded pulse oximetry in a lower extremity; value of <94% was defined as abnormal. Echocardiography was performed on site by a trained research officer. A 6-week clinical follow-up evaluation was done for all. MAIN OUTCOME MEASURE: Detection of CHD by echocardiography. RESULTS: Of 5487 babies screened, 425 (7.75%) had CHD. 17 (0.31%) had major CHD, two of whom (one ALCAPA and one large VSD) were missed during the initial evaluation. The rest were minor CHD (408 patients, 7.44%), most of which normalized by 6 weeks. On multivariate analysis, murmur, central cyanosis, abnormal precordial pulsations and abnormal pulse oximetry emerged as significant predictors of CHD. The sensitivity of clinical evaluation and pulse oximetry combined was 19% for all CHDs and 20% for major CHD; specificity was 88%. CONCLUSIONS: In the community setting of a developing country, clinical evaluation and pulse oximetry after birth had a very low sensitivity for detection of CHD. Though an abnormal screening warrants prompt echocardiography, a 6 week clinical evaluation is recommended to ensure that major CHD is not missed. PMID- 20972296 TI - Measuring obesity among school-aged youth in India: a comparison of three growth references. AB - OBJECTIVE: To compare three growth references that can be used to assess the weight status of school-aged youth living in India, with a particular focus on identifying overweight and obese youth. STUDY DESIGN: Cross-sectional study. Kappa scores were used to measure agreement between growth references. Regression models were used to test for differences in weight status by grade level, gender, and school type, using each growth reference. SETTING: Private (n=4) and Government schools (n=4) in Delhi, India. PARTICIPANTS: Students (n=1818) in eighth and tenth grade attending the schools. MAIN OUTCOME MEASURES: Weight status was derived using age- and gender-specific cut-points provided by: (a) a national growth reference specific to India; (b) an international reference recommended by the International Obesity Task Force (IOTF); and (c) a new international reference recommended by the World Health Organization (WHO). RESULTS: The IOTF reference consistently classified participants in a lower weight status category, compared with the national reference (k=0.57) and the WHO reference (k=0.69). The agreement between the WHO and the national references was higher (k=0.84). CONCLUSIONS: To date, all published studies of childhood obesity in India have used the IOTF reference, the national reference, or an old WHO reference to measure weight status among school-going youth. The new WHO reference may be a better choice. Compared to the IOTF reference, it does not appear to underestimate obesity and can still be used to compare trends, globally. PMID- 20972297 TI - Profile of hemophagocytic lymphohistiocytosis in children in a tertiary care hospital in India. AB - OBJECTIVE: To describe the epidemiology, clinical features, laboratory findings, outcome and the difficulties in diagnosis and management of children with Hemo phagocytic Lymphohistiocytosis (HLH) in a tertiary children's hospital in India. STUDY DESIGN: Retrospective analysis of case records of all the children with a diagnosis of HLH from December 2006 to December 2008. SETTING: Tertiary care children's teaching hospital in Chennai, India. RESULTS: 43 children had a diagnosis of hemo-phagocytosis, of who only 33 (19 male, mean age 46 months, range 50 days-14 years) met the inclusion criteria based on the HLH 2004 protocol of the Histiocyte Society. The predominant presenting features included prolonged fever and hepatosplenomegaly. CNS symptoms were present in 36%. Anemia (Hb <9 gm/dL), and thrombocytopenia (platelets <1,00,000/mm3) were present in 97% and 72%, respectively. Among the biochemical markers, hyperferritinemia was present in 97%, and hypofibrinogenemia and high LDH in 92%. Bone marrow examination showed hemophagocytosis in 84%. Infectious agents were identified in 42% children, with viruses accounting for 2/3 of them (5 Dengue virus, 3 EBV, 1 CMV, 1 TB and 5 bacterial agents). The mean duration between the onset of symptoms and the diagnosis was 16 days. Corticosteroids were the most commonly used immunomodulatory agents (67%), followed by IVI g (64%). Cyclosporine was used in 33% and Etoposide in 15%. Improvement of laboratory parameters was noticed within 5-7 days of starting treatment. Overall survival rate was 76%. CONCLUSION: HLH should be considered in the differential diagnosis of children with prolonged fever, hepatosplenomegaly and cytopenia. Prompt recognition and appropriate therapy may result in good outcome, particularly in Infection associated HLH. PMID- 20972298 TI - Prevalence of prediabetes in school-going children. AB - OBJECTIVE: To study the prevalence of prediabetes among school children in Mysore city. DESIGN: Cross sectional study. SETTINGS: Children aged 5-10 years from three schools in Mysore city were included. Study was done over a period of 1 year during 2006-2007. PARTICIPANTS: 726 children (59.8%; males). MAIN OUTCOME: Prevalence of prediabetes. Prediabetes was defined as fasting blood sugar level between 100-125 mg/dL. RESULTS: The prevalence of prediabetes was 3.7%;. No statistically significant association was observed with major risk factors of diabetes. CONCLUSIONS: Efforts must be made to recognize type 2 diabetes in the asymptomatic prediabetes state. PMID- 20972299 TI - Short course versus 7-day course of intravenous antibiotics for probable neonatal septicemia: a pilot, open-label, randomized controlled trial. AB - OBJECTIVE: To compare a short course of antibiotics (48 to 96 hours) and a standard course of antibiotics (7 days) for probable neonatal sepsis. DESIGN: Randomized, controlled, open-labeled trial with blocking and stratification according to birth weight. SETTING: Tertiary care, referral, teaching hospital in Northern India. PARTICIPANTS: Neonates >30 wks gestation and >1000 g at birth, with probable sepsis (clinical signs of sepsis, raised C reactive protein) were enrolled. Babies with major malformations, severe birth asphyxia, meningitis, bone or joint or deep-seated infection, those who were already on antibiotics, and those undergoing surgery were excluded. Neonates, who had clinically remitted on antibiotic therapy by the time a sterile blood culture report was received were randomized. INTERVENTION: In the intervention arm, antibiotics were stopped after the 48 hour culture was reported sterile. In the control arm, antibiotics were continued to a total of 7 days. MAIN OUTCOME MEASURE: Treatment failure defined as reappearance of signs suggestive of sepsis within 15 days of stopping antibiotics, supported by laboratory evidence and adjudicated by a blinded expert committee. RESULTS: 52 neonates were randomized to receive a short course or 7 day course (n=26 each). Baseline variables were balanced in the 2 groups. There was no significant difference in the treatment failures between the 2 groups (3 babies in the 7-day group vs none in short course group, P=0.23). CONCLUSION: No difference in the treatment failure rates could be identified between short course and 7-day groups among neonates >30 weeks and > 1000 grams with probable sepsis. PMID- 20972300 TI - Clinical profile and outcome of swine flu in Indian children. AB - OBJECTIVE: To describe the clinical characteristics and outcome of Indian children infected with 2009 H1N1 influenza virus. STUDY DESIGN: Retrospective chart review. SETTING: Outpatient department and hospitalized patients in a tertiary care hospital. METHODS: Clinical details of 85 children (positive for the 2009 H1N1 virus infection tested by real time reverse transcriptas epolymerasechain reaction assay) were analyzed from medical charts. RESULTS: Of the 85 (55 boys) children positive for 2009 H1N1 virus infection, 64.7%were between 5 years to 16 years, and 35.3%were below 5 years age. The mean age of these children was 7.5+/-3.5 yr. Contact history was positive only in 22 (26%) cases. High grade fever was the most common symptom, followed by cough and rhinorrhea. Twenty-nine (34%) patients had an underlying co-morbid condition. Of the 34 patients who underwent chest radiography during evaluation, 18 children (52.9%) had findings consistent with lower respiratory tract infection. Antiviral therapy was initiated in 76 patients. Hospitalization was required in 30 (35.3%) children. Risk factors for hospitalization included underlying co-morbid condition, respiratory distress, vomiting, wheezing, diarrhea, hypotension and infiltrates/consolidation on chest radiograph. Mean length of hospitalization was 131+/-76 hours, irrespective of underlying disease. Three children developed Acute Respiratory Distress Syndrome and died. CONCLUSIONS: Clinical features and routine laboratory investigations in children with swine origin influenza were non-specific. Children with co-morbid condition, respiratory distress, vomiting, wheezing, diarrhea, hypotension and infiltrates/consolidation on chest radiograph were at higher risk of hospitalization. PMID- 20972301 TI - Deliberate self harm in children. AB - OBJECTIVE: To study the nature of deliberate self-harm (DSH) in children and to identify the associated factors. SETTING: Child Guidance Clinic attached to the Department of Pediatrics of a teaching hospital in South India. SUBJECTS: Children with history of deliberate self harm who were referred to the CGC for psychological evaluation during a 10 year period. METHODS: Children and parents were interviewed together and separately and details regarding age, sex, family and school environment, stresses and nature of self harm were documented. Psychiatric diagnosis was made based on DSM IV diagnostic criteria. RESULTS: Among the 30 children included in the study, 21 were boys and 9 were girls. Majority of children were between the ages of 11 and 13 years, the youngest being 6 years old. 76%of children had history of acute stressful life events and 62%of them had chronic ongoing stress. 62%of children had stress in the family and 41%had stress at school. Stress in the family included death of a parent, conflicts with parents or siblings, mental illness in the family, parental alcoholism and parental disharmony. Stress at school included conflicts with classmates, punishment or negative comments by teachers and learning problems. Psychiatric disorders were present in 52%of children, the commonest being depressive disorder. The commonest mode of DSH was self poisoning, and rat poison (zinc phosphide) was the commonest substance used. CONCLUSIONS: Deliberate self harm occurs in young children and the risk factors are comparable to those in adolescents. PMID- 20972302 TI - Effect of iron and zinc deficiency on short term memory in children. AB - OBJECTIVE: To evaluate the effect of iron and zinc deficiency on short term memory of children in the age group of 6-11 years and to assess the response to supplementation therapy. DESIGN: Interventional study. SETTING: 100 children in the age group of 6-11 years (subdivided into 6-8 yr and 9-11 yr groups) from an urban corporation school. METHODS: After collection of demographic data, the study children underwent hematological assessment which included serum iron, serum zinc, and hemoglobin estimation. Based on the results, they were divided into Iron deficient, Zinc deficient, and Combined deficiency groups. Verbal and nonverbal memory assessment was done in all the children. INTERVENTION: Iron (2mg/kg bodyweight in two divided doses) and zinc (5mg once-a-day) supplementation for a period of 3 months for children in the deficient group. RESULTS: All children with iron and zinc deficiency in both the age groups had memory deficits. Combined deficiency in 9-11 years group showed severe degree of affectation in verbal (P<0.01) and non-verbal memory (P<0.01), and improved after supplementation (P = 0.05 and P< 0.01, respectively). In 6-8 years group, only non-verbal form of memory (P =0.02) was affected, which improved after supplementation. CONCLUSION: Iron and zinc deficiency is associated with memory deficits in children. There is a marked improvement in memory after supplementation. Post supplementation IQ scores do not show significant improvement in deficient groups in 6-8 year olds. PMID- 20972303 TI - Prevalence of clinical and sub-clinical vitamin A deficiency among rural preschool children of West Bengal, India. AB - A community based cross-sectional study was carried out in rural areas of West Bengal with the aim to assess the prevalence of vitamin A deficiency (VAD) among rural preschool children. Clinical examination was carried out on 9,228 children for the signs and symptoms of VAD and a sub-sample of 590 children were covered for the estimation of blood vitamin A levels using dried blood spot (DBS) method. The prevalence of Bitot's spots was 0.6% (95% CI=0.44, 0.76), which is more than the public health significance, and it increased with increase in age. The prevalence was significantly higher (P<0.001) among boys (0.8%) as compared to girls (0.4%). The proportion of children with subclinical vitamin A deficiency (blood vitamin A < 20 ug/dL) was 61% (95% CI: 52.3-65.1), and it was significantly (P<0.01) higher among the children of lower socioeconomic communities. PMID- 20972304 TI - Annual risk of tuberculosis infection among the tribal children of Jhabua, Madhya Pradesh. AB - A cross sectional tuberculin survey was undertaken to estimate the Annual Risk of Tuberculosis Infection (ARTI) amongst tribal children aged 1-9 years in Jhabua district, Madhya Pradesh, India. Of the 1056 test-read children, 774 (73.3%) had no BCG scar. The prevalence of infection was estimated as 6.3% (95% CI: 4.8-7.7) and ARTI as 1.2% (95% CI: 0.9-1.5). The findings suggest that the tuberculosis situation in the tribal population of Jhabua district is not that different from the situation among the non-tribal population in the country. However, there is a need to further intensify tuberculosis control measures in the area. PMID- 20972305 TI - Outcome of live donor liver transplantation in Indian children with bodyweight <7.5 kg. AB - This case-series analyzed the outcome of live donor liver transplantation (LT) performed in children <7.5 kg from January 2008 to June 2009 at our center. Five patients (3 males, 2 females, mean age, 8.2 +/- .4 months; mean weight 6.8 +/- 0.4 kg) underwent LT. The indications of LT included biliary atresia (3) and idiopathic neonatal hepatitis (2). Postoperative complications included acute rejection (1), portal venous thrombosis (1), bile leak (1), severe hypertension (1) and bacterial sepsis (4). There were no donor related complications. The median follow-up duration is 11 months with patient and graft survival rates of 100% each, respectively. PMID- 20972306 TI - Clinical profile of H1N1 positive HIV- infected children. AB - We report five cases of HIV infected children, who presented with flu-like symptoms and were diagnosed to have H1N1 infection (swine origin influenza). Four of these children were admitted with respiratory distress and pneumonia and were managed in swine flu isolation ICU. Two children required nonivasive ventilatory support. All children recovered completely and at discharge were referred for initiation of ART. PMID- 20972307 TI - Facile covalent immobilization of cadmium sulfide quantum dots on graphene oxide nanosheets: preparation, characterization, and optical properties. AB - A facile approach for the preparation of a novel hybrid material containing graphene and an inorganic semiconducting material, cadmium sulfide quantum dots (CdS QDs), is demonstrated for the first time. First, amino-functionalized CdS QDs were prepared by modifications of the kinetic trapping method. Then, pristine graphite was oxidized and exfoliated to obtain graphene oxide nanosheets (GONS), which were then acylated with thionyl chloride to introduce acyl chloride groups on their surface. Subsequently, immobilization of the CdS QDs on the GONS surface was achieved through an amidation reaction between the amino groups located on the CdS QDs surface and the acyl chloride groups bound to the GONS surface. Fourier transform infrared spectroscopy (FT-IR), (1)H nuclear magnetic resonance ((1)H-NMR), x-ray diffraction (XRD), x-ray photoelectron spectroscopy (XPS), and energy dispersive x-ray (EDX) spectroscopy were employed to investigate the changes in the surface functionalities, while high resolution transmission electron microscopy (HR-TEM) and field emission scanning electronic microscopy (FE-SEM) were used to study the morphologies and distribution of the CdS QDs on the GONS surface. Thermogravimetric analysis (TGA) was employed to characterize the weight loss of the samples on heating. Photoluminescence (PL) measurements were used to study the optical properties of the prepared CdS QDs and the CdS graphene hybrid material. PMID- 20972308 TI - Kinetic versus strain formation of self-organized nanoholes in manganite thin films. AB - We report on the formation of self-organized rows of pits in highly epitaxial La(2/3)Sr(1/3)MnO(3) thin films on top of substrates having different structural misfits by rf magnetron sputtering. The best-defined pits form in coherently grown films at a low misfit irrespective of its nature (tensile or compressive stress). It is also found that the pit rows align along the step edges, which indicates in-phase growth instability with the step edges, irrespective of the misfit. However, out-of-phase pit rows are also found when the terrace width increases due to a decrease of the miscut angle. Pit's volume scales inversely with the lattice mismatch suggesting that structural strain alone does not favor the formation of pits. The formation of pits is analyzed within a thermodynamic model. PMID- 20972309 TI - Calibration of higher eigenmode spring constants of atomic force microscope cantilevers. AB - Standard spring constant calibration methods are compared when applied to higher eigenmodes of cantilevers used in dynamic atomic force microscopy (dAFM). Analysis shows that Sader's original method (Sader et al 1999 Rev. Sci. Instrum. 70 3967-9), which relies on a priori knowledge of the eigenmode shape, is poorly suited for the calibration of higher eigenmodes. On the other hand, the thermal noise method (Hutter and Bechhoefer 1993 Rev. Sci. Instrum. 64 1868-73) does not require knowledge of the eigenmode and remains valid for higher eigenmodes of the dAFM probe. Experimental measurements of thermal vibrations in air for three representative cantilevers are provided to support the theoretical results. PMID- 20972310 TI - Improvement of the uniformity and dipole ferromagnetism in Co nanodots assemblies on Pb/Si(111) via step tuned dimensionality variation. AB - We fabricated quasi-one-dimensional Co nanochain assemblies and two-dimensional Co nanodot assemblies on Pb/Si(111) substrates by step decoration. The morphology and magnetic properties of these two kinds of Co nanodot assemblies were investigated by in situ scanning tunneling microscopy and magneto-optical Kerr effect measurements. It was found that the steps cannot only improve the uniformity of the Co nanodots, but also increase the critical temperature T(c). Monte Carlo simulation indicates that the ferromagnetism mainly originates from the dipolar interactions and the critical temperature T(c) can be enhanced by introducing an in-plane uniaxial magnetic anisotropy via the step tuned dimensionality variation of the nanodot assemblies. PMID- 20972311 TI - Scalable flame synthesis of SiO2 nanowires: dynamics of growth. AB - Silica nanowire arrays were grown directly onto plain glass substrates by scalable flame spray pyrolysis of organometallic solutions (hexamethyldisiloxane or tetraethyl orthosilicate). The silicon dioxide films consisted of a network of interwoven nanowires from a few to several hundred nanometres long (depending on the process conditions) and about 20 nm in diameter, as determined by scanning electron microscopy. These films were formed rapidly (within 10-20 s) at high growth rates (ca 11-30 nm s(-1)) by chemical vapour deposition (surface growth) at ambient conditions on the glass substrate as determined by thermophoretic sampling of the flame aerosol and microscopy. In contrast, on high purity quartz nearly no nanowires were grown while on steel substrates porous SiO(2) films were formed. Functionalization with perfluorooctyl triethoxysilane converted the nanowire surface from super-hydrophilic to hydrophobic. Additionally, their hermetic coating by thin carbon layers was demonstrated also revealing their potential as substrates for synthesis of other functional 1D composite structures. This approach is a significant step towards large scale synthesis of SiO(2) nanowires facilitating their utilization in several applications. PMID- 20972312 TI - Correlating defect density with carrier mobility in large-scaled graphene films: Raman spectral signatures for the estimation of defect density. AB - We report a correlation between carrier mobility and defect density in large scaled graphene films prepared by chemical vapor deposition (CVD). Raman spectroscopy is used for investigating the layer number and the crystal quality of graphene films, and the defect density is estimated by the intensity ratios of the D and G peaks. By carefully controlling the growth parameters, especially the H(2)/CH(4) ratios during growth, and employing H(2) during cooling, monolayer dominant graphene films can be obtained with different D peak intensities in Raman spectra, which show good correspondence with their carrier mobility obtained by Hall measurements. Also, a progressive shift of neutrality points to a more negative gate voltage is observed with the increase in defect density. Both the connections of carrier mobility and the shift of neutrality points to a negative direction in relation to the defect density in graphene are observed for the first time in CVD-grown graphene films. With the best growth conditions, a cm scaled graphene film with carrier mobility of ~ 1350 cm(2) V(-1) s(-1) (p-type in air) can be obtained. PMID- 20972313 TI - Magnetic bead detection using nano-transformers. AB - A novel scheme to detect magnetic beads using a nano-scale transformer with a femtoweber resolution is reported. We have performed a Faraday's induction experiment with the nano-transformer at room temperature. The transformer shows the linear output voltage responses to the sinusoidal input current. When magnetic beads are placed on the transformer, the output responses are increased by an amount corresponding to the added magnetic flux from the beads when compared with the case of no beads on the transformer. In this way, we could determine whether magnetic beads are on top of the transformer in a single particle level. PMID- 20972314 TI - Tip-induced excitation of a single vortex in nano-size superconductors using scanning tunneling microscopy. AB - A single vortex is excited into nano-size Pb superconducting island structures by a local current injection from a probe tip of a scanning tunneling microscope. For the excitation, a sufficient amount and duration of the pulsed current are required. Injecting the current at peripheral sites is more effective than the center for the vortex excitation. Time-dependent Ginzburg-Landau calculations suggest that a current-induced normal-state area, which can be nucleated by the tunneling current exceeding the critical current and expanded by the Joule heating, reduces the required magnetic field for the vortex penetration and excites a vortex into the islands. PMID- 20972315 TI - Read/write schemes analysis for novel complementary resistive switches in passive crossbar memory arrays. AB - Recently a prototype of complementary resistive switches has been proposed to solve the sneak-path problem in passive crossbar memory arrays. To further evaluate the potential of this novel cell structure for practical applications, we present a modeling analysis to capture its switching dynamics and analyze its unique read/write schemes. The model is corroborated by experimental data. We found a trade-off between the read voltage window and write voltage window. The constraint from avoiding disturbance on unselected cells is critical for proper functionality, which in turn limits the writing speed. PMID- 20972316 TI - Metal-assisted electrochemical etching of silicon. AB - In this paper the metal-assisted electrochemical etching of silicon is introduced. By electrochemical measurement and sequent simulation, it is revealed that the potential of the valence band maximum at the silicon/metal interface is more negative than that of the silicon/electrolyte interface. Accordingly, holes injected from the back contact are driven preferentially to the silicon/metal interface. Consequently, silicon below metal is electrochemically etched much faster than a naked silicon surface without metal coverage. Metals such as Ag and Cu have been utilized to catalyze the electrochemical etching. Feature sizes as small as 30 nm can be achieved by metal-assisted electrochemical etching. Meanwhile, the metal-assisted electrochemical etching method enables convenient control over the etching direction of non-(100) substrates, and facilitates the fabrication of orientation-modulated silicon nanostructures. PMID- 20972317 TI - Quantum dot/carbon nanotube/silicon double heterojunctions for multi-band room temperature infrared detection. AB - We report on the observation of room temperature multi-band photocurrent response from a novel structure formed by interior loading of PbS quantum dots into carbon nanotubes grown on silicon. In addition to a mid infrared photoresponse band at ~ 0.22 eV due to the carbon nanotubes and one band at 1.1 eV corresponding to silicon, two bands in the mid/near infrared at 0.63 and 0.82 eV, corresponding to the first and second exciton bands of the PbS quantum dots, are observed in photocurrents measured at room temperature, in uncooled operation. We have also observed a red shift of the 0.63 and 0.82 eV bands with cooling that reflects a behavior typical for PbS and supports the hypothesis that these photoresponse bands are due to absorption in the PbS quantum dots. PMID- 20972318 TI - Cathodoluminescence studies of GaAs nano-wires grown on shallow-trench-patterned Si. AB - The optical properties of GaAs nano-wires grown on shallow-trench-patterned Si(001) substrates were investigated by cathodoluminescence. The results showed that when the trench width ranges from 80 to 100 nm, the emission efficiency of GaAs can be enhanced and is stronger than that of a homogeneously grown epilayer. The suppression of non-radiative centers is attributed to the trapping of both threading dislocations and planar defects at the trench sidewalls. This approach demonstrates the feasibility of growing nano-scaled GaAs-based optoelectronic devices on Si substrates. PMID- 20972319 TI - Nanopillars by cesium chloride self-assembly and dry etching. AB - We introduce a method combining cesium chloride self-assembly and inductively coupled plasma to fabricate nanopillars with uniform coverage over an entire 4 inch prepatterned silicon wafer. This method can produce pillars with average diameters ranging from 50 nm to 1.5 um, aspect ratios up to 13 and coverage ratios above 35%. Cesium chloride self-assembly utilizes the deliquescence of salt, with advantages of excellent tunability, high aspect ratio and potential for micro/nano mixed structures, which makes this technology promising in the areas of MEMS, solar cells, batteries, light emitting diodes, etc. PMID- 20972320 TI - Thermal-induced surface plasmon band shift of gold nanoparticle monolayer: morphology and refractive index sensitivity. AB - In this paper, thermal-induced behaviors of a gold nanoparticle monolayer on glass slides are investigated. First, through horizontal lifting, gold nanoparticle monolayers are transferred from a water/hexane interface to glass slides. Then thermal treatment is carried out in air, after which an apparent color change of the obtained samples is noticed, depending on the annealing temperature, reflecting a shift of the surface plasmon band (SPB). Depending on the trend of SPB shift, the overall thermal process is divided into three stages. In the first stage, SPB shows a redshift trend with concomitant band broadening. Further increase of the annealing temperature in the second stage results in an increase of interparticle distance. Thus an apparent decrease in absorbance takes place with SPB shift to shorter wavelengths. In the third stage, the SPB redshifts again. Bulk refractive index sensitivity (RIS) measurements are taken by immersing the obtained samples in solutions of various refractive indices and a linear dependence of RIS(lambda) and RIS(ext) on refractive index is concluded. In particular, the influences of parameters such as particle sizes, location of SPB, substrate effect and morphology effect on RIS are discussed in detail. The corresponding performance of each sample as a localized surface plasmon resonance based sensor is evaluated by a figure of merit (FOM) represented as FOM(lambda) and FOM(ext). It is found that the optimum annealing temperature is 500 degrees C. In terms of nanoparticle sizes, samples with a 35 nm gold nanoparticle monolayer perform better than those with 15 nm. The current strategy is simple and facile to achieve fine control of the SPB, in which large-size precision instruments or complex chemosynthesis are unnecessary. Therefore, this method has not only significance for theory but also usefulness in practical applications. PMID- 20972321 TI - Optical properties of carbon nanofiber photonic crystals. AB - Carbon nanofibers (CNFs) are used as components of planar photonic crystals. Square and rectangular lattices and random patterns of vertically aligned CNFs were fabricated and their properties studied using ellipsometry. We show that detailed information such as symmetry directions and the band structure of these novel materials can be extracted from considerations of the polarization state in the specular beam. The refractive index of the individual nanofibers was found to be n(CNF) = 4.1. PMID- 20972322 TI - Reversible light-controlled conductance switching of azobenzene-based metal/polymer nanocomposites. AB - We present a new concept of light-controlled conductance switching based on metal/polymer nanocomposites with dissolved chromophores that do not have intrinsic current switching ability. Photoswitchable metal/PMMA nanocomposites were prepared by physical vapor deposition of Au and Pt clusters, respectively, onto spin-coated thin poly(methylmethacrylate) films doped with azo-dye molecules. High dye concentrations were achieved by functionalizing the azo groups with tails and branches, thus enhancing solubility. The composites show completely reversible optical switching of the absorption bands upon alternating irradiation with UV and blue light. We also demonstrate reversible light controlled conductance switching. This is attributed to changes in the metal cluster separation upon isomerization based on model experiments where analogous conductance changes were induced by swelling of the composite films in organic vapors and by tensile stress. PMID- 20972323 TI - Li electroactivity of iron (II) tungstate nanorods. AB - We herein report the first application of a divalent iron tungstate (FeWO(4)) nanostructured material, with a wolframite structure, to a Li-ion battery anode. The FeWO(4) nanospheres and nanorods were synthesized at 180 degrees C without any surfactants or templates via a facile hydrothermal process by simply adjusting the pH. The resulting nanopowders were characterized using x-ray diffraction (XRD), field-emission scanning electron microscopy (FESEM), high resolution transmission electron microscopy (HRTEM), and Brunauer-Emmett-Teller (BET) measurements. Furthermore, we evaluated the Li electroactivity of the FeWO(4) nanorods using cyclic voltammetry and observed that their reversible capacity was over 500 mAh g(-1) after 20 cycles, which proved much higher than that of graphite-based anodes. PMID- 20972324 TI - WT1: a weak spot in KRAS-induced transformation. AB - Activating mutations in the Ras alleles are found frequently in tumors, making the proteins they encode highly attractive candidate therapeutic targets. However, Ras proteins have proven difficult to target directly. Recent approaches have therefore focused on identifying indirect targets to inhibit Ras-induced oncogenesis. For example, RNAi-based negative selection screens to identify genes that when silenced in concert with activating Ras mutations are incompatible with cellular proliferation, a concept known as synthetic lethality. In this issue of the JCI, Vicent et al. report on the identification of Wilms tumor 1 (Wt1) as a Kras synthetic-lethal gene in a mouse model of lung adenocarcinoma. Silencing of Wt1 in cells expressing an endogenous allele of activated Kras triggers senescence in vitro and has an impact on tumor progression in vivo. These findings are of significant interest given previous studies suggesting that the ability of oncogenic Kras to induce senescence versus proliferation depends on its levels of expression. PMID- 20972325 TI - The cellular response to hypoxia: tuning the system with microRNAs. AB - Adaptation to hypoxia is an essential cellular response controlled by the oxygen sensitive master transcription factor hypoxia-inducible factor 1 (HIF-1). HIF-1 expression is also controlled by specific microRNAs and, in turn, controls the expression of other microRNAs, which fine-tune adaptation to low oxygen tension. In this issue of the JCI, Ghosh and colleagues identify a unique microRNA in hypoxic endothelial cells, miR424, that promotes HIF-1 stabilization and angiogenesis. The actions of this microRNA are considered in the context of the complex interactions that act to ensure optimal endothelial adaptation to this critical environmental condition. PMID- 20972326 TI - Living or dying by RNA processing: caspase expression in NSCLC. AB - Protein expression in humans is controlled by numerous RNA processing steps that occur between transcription of a gene and translation of protein. However, the importance of such regulatory steps to human diseases, especially cancer, is just now coming to light. Changes in the alternative splicing or stability of mRNA transcribed from genes involved in cell-cycle control, cell proliferation, and apoptosis has been linked to tumor formation and progression. Nevertheless, in the majority of these cases, the identity of the regulators that control the expression of such cancer-related genes is poorly understood. In this issue of the JCI, Goehe et al. demonstrate that heterogeneous nuclear ribonuclear protein family member L (hnRNP L), a member of the hnRNP family of RNA processing factors, is specifically phosphorylated in non-small cell lung cancer (NSCLC). The phosphorylated hnRNP L, in turn, promotes expression of the antiapoptotic form of caspase-9, thereby contributing to tumorigenesis. PMID- 20972327 TI - Are there more tricks in the bag for treating thrombocytopenia? AB - Thrombocytopenia, an abnormally low number of circulating platelets, results from inadequate platelet production, splenic platelet sequestration, or accelerated platelet clearance. Platelet transfusions are now the cornerstone for treating thrombocytopenia. With an ever-expanding demand for platelets, and with many patients having an inadequate response to platelet transfusions, new strategies are needed to treat thrombocytopenia. In this issue of the JCI, Fuentes et al. present provocative data regarding the use of direct megakaryocyte infusions as a novel approach to manage this vexing clinical problem. PMID- 20972328 TI - New therapy to revert dysfunctional antibody responses during HIV-1 infection. AB - Individuals infected with HIV-1 progress to AIDS at different rates. Rapid progressors develop AIDS within 2-5 years of initial infection, compared with approximately 10 years in typical progressors. Progression to AIDS is associated with impaired humoral and cellular immunity. In this issue of the JCI, Titanji and colleagues report that activated memory B (mBAct) cells are depleted in SIV infected macaques defined as rapid progressors. Depletion was mediated by programmed death-1 (PD-1) and resulted in reduction of antibody titers specific for SIV and bacterial antigens. Interestingly, blockade of PD-1 in infected animals protected B cells from apoptosis and increased levels of SIV-specific antibodies in blood. These findings pave the way for a new therapeutic strategy aimed at improving humoral immunity in HIV-1 infection. PMID- 20972329 TI - Pharmacologic eigenvalues: beating the rap on bone marrow failure. AB - Patients suffering from sustained acute or chronic illness often have decreased white blood cell and platelet counts as well as anemia, and bone marrow studies routinely show only decreased numbers of blood precursor cells. While much has been recently learned about the cause of isolated anemia, the pathogenesis of true bone marrow failure (i.e., low bone marrow cellularity and low counts in multiple blood lineages) has remained elusive. In this issue of the JCI, Chen et al. present evidence that overactivation of mammalian target of rapamycin signaling in HSCs is found in two mouse models of bone marrow failure, and they show that treatment with rapamycin significantly normalizes the low blood counts. PMID- 20972330 TI - Pregnancy immunogenetics: NK cell education in the womb? AB - During embryo implantation and initiation of pregnancy, uterine NK (uNK) cells engage invasive fetal trophoblasts to remodel vessels that conduct blood to the placenta. This partnership, involving uNK cell receptors that recognize HLA-C ligands on trophoblasts, varies the course of human pregnancy because the genes for both receptors and ligands are extraordinarily diverse. Several pregnancy disorders are attributed to insufficient trophoblast invasion and the limitation it imposes on human reproduction. Previously, a particular combination of fetal HLA-C and maternal inhibitory uNK cell receptor was associated with predisposition for preeclampsia. In this issue of the JCI, Hiby and colleagues extend this correlation to recurrent miscarriage and fetal growth restriction, revealing the common mechanism underlying these common pregnancy syndromes. Equally important, they show that mothers with an activating receptor of similar specificity to the inhibitory receptor are less likely to suffer disordered pregnancy. PMID- 20972331 TI - Acute depletion of activated memory B cells involves the PD-1 pathway in rapidly progressing SIV-infected macaques. AB - Rapid progression to AIDS is a significant problem, especially in developing countries, where the majority of HIV-infected individuals reside. As rapid disease progression is also frequently observed in SIV-infected macaques, they represent a valuable tool to investigate the pathogenesis of this condition in humans. Here, we have shown that pathogenic SIV infection in rhesus macaques resulted in a rapid depletion (as early as week 2) of activated memory B (CD21 CD27+; mBAct) cells that was strongly associated with rapid disease progression. This depletion was progressive and sustained in rapid progressors, but less severe and transient in typical progressors. Because of the rapid and sustained depletion of mBAct cells, rapid progressors failed to develop SIV-specific Ab responses, showed a decline in non-SIV-specific Ab titers, and succumbed faster to intestinal bacterial infections. Depletion of mBAct cells was strongly associated with preferential depletion of mBAct cells expressing programmed death 1 (PD-1), and in vitro blockade of PD-1 improved their survival. Furthermore, in vivo PD-1 blockade in SIV-infected macaques enhanced Ab responses to non-SIV as well as SIV Ags. Our results identify depletion of mBAct cells as a very early predictor of rapid disease progression in pathogenic SIV infection and suggest an important role for the PD-1 pathway in depletion of mBAct cells and impaired humoral immune responses in SIV-infected macaques. PMID- 20972332 TI - Mammalian target of rapamycin activation underlies HSC defects in autoimmune disease and inflammation in mice. AB - The mammalian target of rapamycin (mTOR) is a signaling molecule that senses environmental cues, such as nutrient status and oxygen supply, to regulate cell growth, proliferation, and other functions. Unchecked, sustained mTOR activity results in defects in HSC function. Inflammatory conditions, such as autoimmune disease, are often associated with defective hematopoiesis. Here, we investigated whether hyperactivation of mTOR in HSCs contributes to hematopoietic defects in autoimmunity and inflammation. We found that in mice deficient in Foxp3 (scurfy mice), a model of autoimmunity, the development of autoimmune disease correlated with progressive bone marrow loss and impaired regenerative capacity of HSCs in competitive bone marrow transplantation. Similarly, LPS-mediated inflammation in C57BL/6 mice led to massive bone marrow cell death and impaired HSC function. Importantly, treatment with rapamycin in both models corrected bone marrow hypocellularity and partially restored hematopoietic activity. In cultured mouse bone marrow cells, treatment with either of the inflammatory cytokines IL-6 or TNF-alpha was sufficient to activate mTOR, while preventing mTOR activation in vivo required simultaneous inhibition of CCL2, IL-6, and TNF-alpha. These data strongly suggest that mTOR activation in HSCs by inflammatory cytokines underlies defective hematopoiesis in autoimmune disease and inflammation. PMID- 20972333 TI - Wilms tumor 1 (WT1) regulates KRAS-driven oncogenesis and senescence in mouse and human models. AB - KRAS is one of the most frequently mutated human oncogenes. In some settings, oncogenic KRAS can trigger cellular senescence, whereas in others it produces hyperproliferation. Elucidating the mechanisms regulating these 2 drastically distinct outcomes would help identify novel therapeutic approaches in RAS-driven cancers. Using a combination of functional genomics and mouse genetics, we identified a role for the transcription factor Wilms tumor 1 (WT1) as a critical regulator of senescence and proliferation downstream of oncogenic KRAS signaling. Deletion or suppression of Wt1 led to senescence of mouse primary cells expressing physiological levels of oncogenic Kras but had no effect on wild-type cells, and Wt1 loss decreased tumor burden in a mouse model of Kras-driven lung cancer. In human lung cancer cell lines dependent on oncogenic KRAS, WT1 loss decreased proliferation and induced senescence. Furthermore, WT1 inactivation defined a gene expression signature that was prognostic of survival only in lung cancer patients exhibiting evidence of oncogenic KRAS activation. These findings reveal an unexpected role for WT1 as a key regulator of the genetic network of oncogenic KRAS and provide important insight into the mechanisms that regulate proliferation or senescence in response to oncogenic signals. PMID- 20972334 TI - hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing. AB - Caspase-9 is involved in the intrinsic apoptotic pathway and suggested to play a role as a tumor suppressor. Little is known about the mechanisms governing caspase-9 expression, but post-transcriptional pre-mRNA processing generates 2 splice variants from the caspase-9 gene, pro-apoptotic caspase-9a and anti apoptotic caspase-9b. Here we demonstrate that the ratio of caspase-9 splice variants is dysregulated in non-small cell lung cancer (NSCLC) tumors. Mechanistic analysis revealed that an exonic splicing silencer (ESS) regulated caspase-9 pre-mRNA processing in NSCLC cells. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) interacted with this ESS, and downregulation of hnRNP L expression induced an increase in the caspase-9a/9b ratio. Although expression of hnRNP L lowered the caspase-9a/9b ratio in NSCLC cells, expression of hnRNP L produced the opposite effect in non-transformed cells, suggesting a post-translational modification specific for NSCLC cells. Indeed, Ser52 was identified as a critical modification regulating the caspase-9a/9b ratio. Importantly, in a mouse xenograft model, downregulation of hnRNP L in NSCLC cells induced a complete loss of tumorigenic capacity that was due to the changes in caspase-9 pre-mRNA processing. This study therefore identifies a cancer-specific mechanism of hnRNP L phosphorylation and subsequent lowering of the caspase-9a/9b ratio, which is required for the tumorigenic capacity of NSCLC cells. PMID- 20972335 TI - Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF alpha isoforms and promotes angiogenesis. AB - Adaptive changes to oxygen availability are critical for cell survival and tissue homeostasis. Prolonged oxygen deprivation due to reduced blood flow to cardiac or peripheral tissues can lead to myocardial infarction and peripheral vascular disease, respectively. Mammalian cells respond to hypoxia by modulating oxygen sensing transducers that stabilize the transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha), which transactivates genes governing angiogenesis and metabolic pathways. Oxygen-dependent changes in HIF-1alpha levels are regulated by proline hydroxylation and proteasomal degradation. Here we provide evidence for what we believe is a novel mechanism regulating HIF-1alpha levels in isolated human ECs during hypoxia. Hypoxia differentially increased microRNA-424 (miR-424) levels in ECs. miR-424 targeted cullin 2 (CUL2), a scaffolding protein critical to the assembly of the ubiquitin ligase system, thereby stabilizing HIF-alpha isoforms. Hypoxia-induced miR-424 was regulated by PU.1-dependent transactivation. PU.1 levels were increased in hypoxic endothelium by RUNX-1 and C/EBPalpha. Furthermore, miR-424 promoted angiogenesis in vitro and in mice, which was blocked by a specific morpholino. The rodent homolog of human miR-424, mu-miR-322, was significantly upregulated in parallel with HIF-1alpha in experimental models of ischemia. These results suggest that miR-322/424 plays an important physiological role in post-ischemic vascular remodeling and angiogenesis. PMID- 20972336 TI - Infusion of mature megakaryocytes into mice yields functional platelets. AB - Thrombopoiesis, the process by which circulating platelets arise from megakaryocytes, remains incompletely understood. Prior studies suggest that megakaryocytes shed platelets in the pulmonary vasculature. To better understand thrombopoiesis and to develop a potential platelet transfusion strategy that is not dependent upon donors, of which there remains a shortage, we examined whether megakaryocytes infused into mice shed platelets. Infused megakaryocytes led to clinically relevant increases in platelet numbers. The released platelets were normal in size, displayed appropriate surface markers, and had a near-normal circulating half-life. The functionality of the donor-derived platelets was also demonstrated in vivo. The infused megakaryocytes mostly localized to the pulmonary vasculature, where they appeared to shed platelets. These data suggest that it may be unnecessary to generate platelets from ex vivo grown megakaryocytes to achieve clinically relevant increases in platelet numbers. PMID- 20972338 TI - Identifying patient fear-avoidance beliefs by physical therapists managing patients with low back pain. AB - STUDY DESIGN: Cross-sectional. OBJECTIVES: To evaluate the accuracy with which physical therapists identify fear-avoidance beliefs in patients with low back pain by comparing therapist ratings of perceived patient fear-avoidance to the Fear-Avoidance Beliefs Questionnaire (FABQ), Tampa Scale of Kinesiophobia 11-item (TSK-11), and Pain Catastrophizing Scale (PCS). To compare the concurrent validity of therapist ratings of perceived patient fear-avoidance and a 2-item questionnaire on fear of physical activity and harm, with clinical measures of fear-avoidance (FABQ, TSK-11, PCS), pain intensity as assessed with a numeric pain rating scale (NPRS), and disability as assessed with the Oswestry Disability Questionnaire (ODQ). BACKGROUND: The need to consider psychosocial factors for identifying patients at risk for disability and chronic low back pain has been well documented. Yet the ability of physical therapists to identify fear avoidance beliefs using direct observation has not been studied. METHODS: Eight physical therapists and 80 patients with low back pain from 3 physical therapy clinics participated in the study. Patients completed the FABQ, TSK-11, PCS, ODQ, NPRS, and a dichotomous 2-item fear-avoidance screening questionnaire. Following the initial evaluation, physical therapists rated perceived patient fear avoidance on a 0-to-10 scale and recorded 2 influences on their ratings. Spearman correlation and independent t tests determined the level of association of therapist 0-to-10 ratings and 2-item screening with fear-avoidance and clinical measures. RESULTS: Therapist ratings of perceived patient fear-avoidance had fair to moderate interrater reliability (ICC2,1 = 0.663). Therapist ratings did not strongly correlate with FABQ or TSK-11 scores. Instead, they unexpectedly had stronger associations with ODQ and PCS scores. Both 2-item screening questions were associated with FABQ-physical activity scores, while the fear of physical activity question was also associated with FABQ-work, TSK-11, PCS, and ODQ scores. CONCLUSION: Therapists' ratings of perceived patient fear-avoidance were not associated with self-reported fear-avoidance scores, showing a potential disconnect between therapist judgments and commonly used fear-avoidance measures. Instead, therapist ratings had small but statistically significant correlations with pain catastrophizing and disability, findings that may support therapists' inability to discriminate fear-avoidance from these other factors. The 2-item screening questions based on fear of physical activity and harm showed potential to identify elevated FABQ physical activity scores. LEVEL OF EVIDENCE: Differential diagnosis, level 2b. PMID- 20972337 TI - Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. AB - Many common disorders of pregnancy are attributed to insufficient invasion of the uterine lining by trophoblast, fetal cells that are the major cell type of the placenta. Interactions between fetal trophoblast and maternal uterine NK (uNK) cells--specifically interactions between HLA-C molecules expressed by the fetal trophoblast cells and killer Ig-like receptors (KIRs) on the maternal uNK cells- influence placentation in human pregnancy. Consistent with this, pregnancies are at increased risk of preeclampsia in mothers homozygous for KIR haplotype A (KIR AA). In this study, we have demonstrated that trophoblast expresses both paternally and maternally inherited HLA-C surface proteins and that maternal KIR AA frequencies are increased in affected pregnancies only when the fetus has more group 2 HLA-C genes (C2) than the mother. These data raise the possibility that there is a deleterious allogeneic effect stemming from paternal C2. We found that this effect also occurred in other pregnancy disorders (fetal growth restriction and recurrent miscarriage), indicating a role early in gestation for these receptor/ligand pairs in the pathogenesis of reproductive failure. Notably, pregnancy disorders were less frequent in mothers that possessed the telomeric end of the KIR B haplotype, which contains activating KIR2DS1. In addition, uNK cells expressed KIR2DS1, which bound specifically to C2+ trophoblast cells. These findings highlight the complexity and central importance of specific combinations of activating KIR and HLA-C in maternal-fetal immune interactions that determine reproductive success. PMID- 20972339 TI - Effects of Pilates-based exercises on pain and disability in individuals with persistent nonspecific low back pain: a systematic review with meta-analysis. AB - STUDY DESIGN: A systematic review with meta-analysis. OBJECTIVES: To compare pain and disability in individuals with persistent nonspecific low back pain who were treated with Pilates exercises compared to minimal or other interventions. METHODS: Searches of Medline, CINAHL, Embase, Cochrane library, PEDro, and ProQuest Dissertations and Thesis databases were conducted. Randomized controlled trials (RCTs) were selected and reviewed if they compared pain and disability in individuals with persistent nonspecific low back pain who were treated with Pilates exercises compared to other treatment approaches. Quality of the trials was evaluated. Data for pain and disability scores were extracted. Narrative synthesis plus meta-analyses were performed, with either a fixed-effects or random-effects model, standardized mean differences (SMDs), and tests for heterogeneity. RESULTS: Seven RCTs were identified and included in the meta analyses. Data pooling was performed using RevMan 5. When compared to minimal intervention, Pilates-based exercise provided superior pain relief (pooled SMD, 2.72; 95% CI: -5.33, -0.11; P = .04) but the pooled disability scores were not significantly different (pooled SMD, -0.74; 95% CI: -1.81, 0.33;P = .17). No significant differences were found when comparing Pilates-based exercise to other forms of exercise for pain (pooled SMD, 0.03; 95% CI: -0.52, 0.58; P = .92) or disability scores (pooled SMD, -0.41; 95% CI: -0.96, 0.14; P = .14). CONCLUSION: Pilates-based exercises are superior to minimal intervention for pain relief. Existing evidence does not establish superiority of Pilates-based exercise to other forms of exercise to reduce pain and disability for patients with persistent nonspecific low back pain. However, the relatively low quality of existing studies and the heterogeneity of pooled studies in this systematic review combine to suggest that these results should be interpreted with caution. LEVEL OF EVIDENCE: Therapy, level 1a. PMID- 20972341 TI - Altered scapular orientation during arm elevation in patients with insidious onset neck pain and whiplash-associated disorder. AB - STUDY DESIGN: Controlled laboratory study using a cross-sectional design. OBJECTIVES: To investigate whether there is a pattern of altered scapular orientation during arm elevation in patients with insidious onset neck pain (IONP) and whiplash-associated disorder (WAD) compared to asymptomatic people. BACKGROUND: Altered activity in the axioscapular muscles and impairments in scapular orientation are considered to be important features in patients with cervical disorders. Scapular orientation has until now not been investigated in these patients. METHODS: A 3-dimensional tracking device measured scapular orientation during arm elevation in patients with IONP (n = 21) and WAD (n = 23). An asymptomatic group was selected for comparison (n = 20). RESULTS: The groups demonstrated a significantly reduced clavicle retraction on the dominant side compared to the nondominant side. The WAD group demonstrated an increased elevation of the clavicle compared to the asymptomatic group and the IONP group, and reduced scapular posterior tilt on the nondominant side compared to the IONP group. CONCLUSION: Altered dynamic stability of the scapula may be present in patients with cervical disorders, which may be an important mechanism for maintenance of recurrence or exacerbation of symptoms in these patients. Patients with cervical disorders may demonstrate a difference in impairments, based on their diagnosis of IONP or WAD. PMID- 20972340 TI - Comparison of graded exercise and graded exposure clinical outcomes for patients with chronic low back pain. AB - STUDY DESIGN: Quasi-experimental clinical trial. OBJECTIVES: This study compared outcomes from graded exercise and graded exposure activity prescriptions for patients participating in a multidisciplinary rehabilitation program for chronic low back pain. Our primary purpose was to investigate whether pain and disability outcomes differed based on treatment received (graded exercise or graded exposure). Our secondary purpose was to investigate if changes in selected psychological factors were associated with pain and disability outcomes. BACKGROUND: Behavioral interventions have been advocated for decreasing pain and disability from low back pain, yet relatively few comparative studies have been reported in the literature. METHODS: Consecutive sample with chronic low back pain recruited over a 16-month period from an outpatient chronic pain clinic. Patients received physical therapy supplemented with either graded exercise (n=15) or graded exposure (n=18) principles. Graded exercise included general therapeutic activities and was progressed with a quota-based system. Graded exposure included specific activities that were feared due to back pain and was progressed with a hierarchical exposure paradigm. Psychological measures were pain-related fear (Fear-Avoidance Beliefs Questionnaire, Tampa Scale for Kinesiophobia, Fear of Pain Questionnaire), pain catastrophizing (Coping Strategies Questionnaire), and depressive symptoms (Beck Depression Inventory). Primary outcome measures were pain intensity (visual analog scale) and self report of disability (modified Oswestry Disability Questionnaire). RESULTS: Statistically significant improvements (P<.01) were observed for pain intensity and disability at discharge. The rate of improvement did not differ based on behavioral intervention received (P>.05 for these comparisons). Overall, 50% of patients met criterion for minimally important change for pain intensity, while 30% met this criterion for disability. Change in depressive symptoms was associated with change in pain intensity, while change in pain catastrophizing was associated with change in disability. CONCLUSIONS: Physical therapy supplemented with graded exercise or graded exposure resulted in equivalent clinical outcomes for pain intensity and disability. The overall treatment effects were modest in this setting. Instead of being associated with a specific behavioral intervention, reductions in pain and disability were associated with reductions in depressive symptoms and pain catastrophizing, respectively. LEVEL OF EVIDENCE: Therapy, level 2b-. PMID- 20972342 TI - Static foot posture associated with dynamic plantar pressure parameters. AB - STUDY DESIGN: Controlled laboratory study. OBJECTIVE: To explore potential associations between foot posture index (FPI-6) composite scores and dynamic plantar pressure measurements, and to describe each of the 6 subscales and the FPI-6 composite scores across our sample. BACKGROUND: The FPI-6 is a static foot posture assessment comprised of 6 observations. Extreme scores have been associated with increased injury risk. However, knowledge describing the relationship between FPI-6 scores and plantar pressure distributions during gait is limited. METHODS: Participants (n = 1000; 566 males, 434 females) were predominantly active adults (mean +/- SD age, 30.6 +/- 8.0 years; body mass index, 26.2 +/- 3.7 kg/m2), who ran 3.1 +/- 1.4 d/wk. Static and dynamic foot characteristics were compared using the FPI-6 and a capacitance-based pressure platform. Correlation and hierarchical stepwise regression analyses were performed to determine the most parsimonious set of dynamic pressure data associated with FPI-6 scores. RESULTS: The mean +/- SD FPI-6 score was 3.4 +/- 2.9 (range, -6.0 to 11.0). Only 31 participants received a score of -2 (supinated foot) on any FPI-6 subscale. Classification of a pronated foot was 2.4 times more likely than a supinated foot. A 5-variable model (R = 0.57, R2 = 0.32) was developed to describe the association between dynamic plantar pressures and FPI-6 scores. CONCLUSION: The multivariate model associated with FPI-6 scores comprised clinically plausible variables which inform the association between static and dynamic foot postures. Different cutoff values may be required when using the FPI 6 to screen for individuals with supinated feet, given the limited number of high arched participants identified by FPI-6 classifications. PMID- 20972343 TI - Association between directional preference and centralization in patients with low back pain. AB - STUDY DESIGN: Prospective, longitudinal, observational cohort. OBJECTIVES: Primary aims were to determine (1) baseline prevalence of directional preference (DP) or no directional preference (no-DP) observed for patients with low back pain whose symptoms centralized (CEN), did not centralize (non-CEN), or could not be classified (NC), and (2) to determine if classifying patients at intake by DP or no-DP combined with CEN, non-CEN, or NC predicted functional status and pain intensity at discharge from rehabilitation. BACKGROUND: Although evidence suggests that patient response classification criteria DP or CEN improve outcomes, previous studies did not delineate relations between DP and CEN findings and outcomes. METHODS: Eight therapists classified patients using standardized definitions for DP and CEN. Prevalence rates for DP and no-DP and CEN,non-CEN, and NC were calculated. Ordinary least-squares multivariate regression models assessed whether multilevel classification combining DP and CEN (DP/CEN, DP/non-CEN, DP/NC, no-DP/non-CEN, and no-DP/NC categories) predicted discharge functional status (scale range, 0 to 100, with higher values representing better function) or pain intensity (scale range, 0 to 10, with higher values representing more pain). RESULTS: Overall prevalence of DP and CEN was 60% and 41%, respectively. For those with DP, prevalence rates for DP/CEN, DP/non-CEN, and DP/NC were 65%, 27%, and 8%, respectively. The amount of variance explained (R2 values) for function and pain models was 0.50 and 0.39, respectively. Compared to patients classified as DP/CEN, patients classified as DP/non-CEN or no-DP/non-CEN reported 7.7 and 11.6 functional status units less at discharge (P<.001), respectively, and patients classified as no-DP/non-CEN reported 1.7 pain units more at discharge (P<.001). CONCLUSIONS: Findings suggest that classification by pain pattern and DP can improve a therapist's ability to provide a short-term prognosis for function and pain outcomes. LEVEL OF EVIDENCE: Prognosis, level 1b-. PMID- 20972344 TI - Measures of range of motion and strength among healthy women with differing quality of lower extremity movement during the lateral step-down test. AB - STUDY DESIGN: Cross-sectional. OBJECTIVE: To determine the association between hip and ankle range-of-motion measures, as well as measures of hip muscle strength, with measures of quality of lower extremity movement, as assessed visually during the lateral step-down test in healthy women. BACKGROUND: Altered lower extremity movement pattern consisting of excessive femoral adduction and internal rotation, leading to excessive knee valgus alignment, is associated with increased risk of knee ligament injury, as well as patellofemoral pain syndrome. Previous investigations of lower extremity kinematics, using 3-dimensional motion analysis systems, document an inconsistent association between hip muscle strength and lower extremity movement pattern. Currently, it is unknown whether differences in hip muscle strength or other physical measures exist among women with differing quality of lower extremity movement as assessed by visual observation. METHODS: Two physical therapists assessed the quality of movement during the lateral step-down among 29 healthy women (mean +/- SD age, 24.3 +/- 3.2 years). Subjects were instructed on the optimal movement pattern prior to performing the test. The quality of movement was categorized as "good" or "moderate," based on a previously established 6-point scale. Several measures of hip strength (handheld dynamometer) and hip and ankle range of motion (fluid filled inclinometer and universal goniometer) were also assessed. Differences in strength and range-of-motion measures between women with good and women with moderate quality of movement were assessed with a Mann-Whitney U test. RESULTS: Both examiners found decreased ankle dorsiflexion range of motion, as measured with the knee bent (P<.05 and P<.01 for examiner 1 and 2, respectively) and in weight bearing (P<.001 and P<.01 for examiner 1 and 2, respectively) among women with a moderate quality of movement compared to women with a good quality of movement on the lateral step-down test. CONCLUSION: Following receipt of instructions on optimal lower extremity movement pattern, women who demonstrate a moderate quality of movement, as assessed visually during the lateral step-down test, exhibit decreased ankle dorsiflexion range of motion compared to women with a good quality of movement. Clinicians should consider evaluating ankle dorsiflexion range of motion when observing an altered lower extremity movement pattern during the lateral step-down test. PMID- 20972345 TI - Radiculopathy of the eighth cervical nerve. AB - STUDY DESIGN: Resident's case problem. BACKGROUND: The C8 nerve root is the least commonly encountered of cervical radiculopathies. The purpose of this resident's case problem is to provide an unusual presentation of a C8 radiculopathy, without cervical or proximal upper quarter symptoms, diagnosed by a combination of physical examination, electromyography (EMG) and nerve conduction studies (NCSs), and imaging. DIAGNOSIS: A 49-year-old, right-hand-dominant male was referred to the EMG/NCS laboratory for a suspected left ulnar neuropathy at the elbow. A physical examination, NCS, and EMG were performed, and a C8 radiculopathy involving both the anterior and posterior primary rami was identified. Following the EMG and NCS evaluation, the patient had enhanced magnetic resonance imaging studies that confirmed a foraminal C7-T1 herniation and associated small central disc protrusion. The patient was then referred to neurosurgery for further consultation and subsequent surgical intervention. The patient underwent a C7-T1 laminectomy, mesial facetectomy, and foraminotomy, and excision of a herniated disk using an operating microscope. The neurosurgeon noted that there was a large disk herniation containing some disk material immediately anterior to the C8 motor root, that impinged directly on the motor root. One month postoperatively, the patient had decreased pain and numbness and tingling in his arm and his hand weakness had improved. DISCUSSION: The report illustrates the utility of a combination of physical examination, EMG and NCSs, and imaging in the diagnosis of a C8 radiculopathy in a patient presenting with forearm and hand symptoms but without cervical or upper quarter symptoms. LEVEL OF EVIDENCE: Diagnosis, level 4. PMID- 20972346 TI - Immediate effects of lumbar spine manipulation on the resting and contraction thickness of transversus abdominis in asymptomatic individuals. AB - STUDY DESIGN: Randomized, blinded, controlled crossover trial. OBJECTIVE: To determine if thrust joint manipulation (TJM) to the lumbar spine would result in changes to the resting and contraction thickness of transversus abdominis (TrA) in healthy individuals. BACKGROUND: Recent studies have demonstrated an immediate decrease in resting thickness and an increase in contraction thickness in TrA following lumbar TJM in patients with low back pain (LBP) who met a clinical prediction rule (CPR) for spinal manipulation. This observed phenomenon has not been investigated in healthy individuals. METHODS: Thirty-five healthy participants were randomly assigned to receive a TJM or sham manipulation treatment. All participants received instruction on how to produce an isolated concentric contraction of the TrA that involved visual ultrasound imaging biofeedback. Data were analyzed using ultrasound imaging to measure changes in thickness of the TrA at rest and during contraction, following the administration of each treatment. RESULTS: There were no interactions observed between treatment and time for TrA muscle thickness at rest (P = .351) and during the contracted state (P = .761). CONCLUSION: Our results indicate that TJM to the lumbar spine does not appear to affect the resting or contraction thickness of TrA in healthy individuals. These findings are in contrast to previous research in which patients with LBP who met a CPR demonstrated an immediate decrease in resting thickness and an increase in contraction thickness in TrA following lumbar TJM. PMID- 20972347 TI - Interpreting joint pain: quantitative sensory testing in musculoskeletal management. AB - SYNOPSIS: Pain is a common complaint among clients seeking physical therapy services, yet interpretation of associated sensory changes can be difficult for the clinician. Musculoskeletal injury typically results in nociceptive pain due to noxious stimuli of the damaged muscle or joint tissues. However, with progression from acute to chronic stages, altered nociceptive processing can give rise to an array of sensory findings. Specifically, patients with chronic joint injury may present with signs and symptoms typically associated with neuropathic injury, due to changes in nociceptive processing. Clinical presentation may include expansion of hyperalgesia into adjacent and remote areas, allodynia, dysesthesias, and perceptual deficits. Quantitative sensory testing (QST) may provide an objective method of examining sensation and, thereby, of recognizing potential changes in the nociceptive pathways. The purpose of this paper is to provide an overview of altered nociceptive processing and somatosensory changes that may occur following a musculoskeletal injury without associated neural injury. Recommendations are made on clinical uses of quantitative sensory testing in orthopaedic physical therapy practice, and supporting clinical and laboratory evidence are presented. Examples related to joint injury are discussed, specifically, osteoarthritis of the knee and low back pain. Quantitative sensory testing may be a useful clinical tool to aid clinical decision making and for determination of prognosis. PMID- 20972348 TI - Association between centralization, depression, somatization, and disability among patients with nonspecific low back pain. AB - STUDY DESIGN: Secondary analysis of a prospective observational cohort study. OBJECTIVES: To evaluate whether depression and somatization subscores of the Symptom Checklist-90-Revised (SCL-90-R), which have been shown to identify chronic disability in individuals with nonspecific low back pain, are applicable to a different population of individuals with low back pain; and to determine if this potential association is confounded by a combination of centralization and subsequent treatment based on centralization. BACKGROUND: To help direct management of patients with nonspecific low back pain, recommendations include performing tests designed to identify psychosocial risk factors predictive of poor patient outcomes. SCL-90-R depression and somatization subscores have been shown to predict chronic disability among patients with low back pain. METHODS: SCL-90-R depression and somatization subscores and data on centralization were collected during the initial physical therapy examination of 231 consecutive patients treated for low back pain in 2 clinics. Disability was assessed by the Oswestry Disability Questionnaire at intake and discharge from physical therapy, and work status was determined by patient self-report at 6 and 12 months after discharge. Pain intensity was assessed by the numeric pain rating scale at the initial visit, and at 6- and 12-month follow-ups. Data were analyzed using logistic regression. RESULTS: Odds ratios for the association between depression and somatization subscores and patient outcomes ranged from 0.76 to 2.93. For analyses in which the data suggested a trend toward an association, the association was less evident following adjustment for centralization and centralization-based treatment. CONCLUSIONS: In our sample, in which all individuals received physical therapy, and those who centralized received interventions based on the direction of centralization, SCL-90-R depression and somatization subscores were moderately associated with chronic pain and disability. This association was reduced when centralization and centralization based treatment was considered in multivariable analyses. PMID- 20972350 TI - The insulin secretion-sensitivity index-2 (ISSI-2) and the measurement of beta cell function in women with gestational diabetes. PMID- 20972351 TI - Higher baseline LDL-C levels amplify the short-term benefit of early intensive statin treatment in acute coronary syndrome. AB - AIM: Some randomized studies have shown a delay of up to a few years in the statin-related survival advantage, whereas others have demonstrated an early survival benefit for some patients. We examined the short-term effects of statins in patients with acute coronary syndrome (ACS), stratified according to baseline LDL-C. METHODS: Patients with ACS (n = 180) were randomized to receive 6 months of atorvastatin (20 mg) in the Extended-ESTABLISH trial. Six months after ACS onset, all patients were treated with statins to achieve an LDL-C value of < 100 mg/dL. Patient outcomes were analyzed with respect to LDL-C at the time of ACS onset: high baseline (>= 100 mg/dL, n = 124) or low baseline (< 100 mg/dL, n = 56) LDL-C. RESULTS: The cumulative incidence rates of major adverse cardiac and cerebrovascular events (MACCE) did not significantly differ between the early statin and control groups in the high baseline groups at 6 months (p = 0.158), whereas a significant benefit of early intensive statins appeared 1 year (p = 0.034) later. In contrast, we found no significant short-term benefits of statins after either 6 months or 1 year in the low baseline group. Multivariate analysis showed that early intensive atorvastatin therapy was associated with a lower risk of MACCE at 1 year in the high baseline group (OR, 0.25; 95% CI, 0.05 to 0.83; p = 0.035). CONCLUSIONS: The effects of 6 months of intensive lipid-lowering therapy appear after 1 year in patients with ACS and baseline LDL-C >= 100 mg/dL. PMID- 20972352 TI - Serum low-density lipoprotein to high-density lipoprotein ratio as a predictor of future acute myocardial infarction among men in a 2.7-year cohort study of a Japanese northern rural population. AB - AIM: To examine and compare the predictive value of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), TC/HDL-C and LDL-C/HDL-C ratios for future cardiovascular outcomes in the general Japanese population. METHODS: A total of 24,566 eligible participants aged 18 years or older, without cardiovascular disease, were enrolled through multiphase health screening and divided into quartile groups based on lipoprotein levels or ratios. Primary endpoints of the study were definitive acute myocardial infarction (AMI) and ischemic stroke, and cases of sudden death with unknown causes were not included. We used Cox proportional hazard models to examine the relationships between the quartiles and incidences of AMI or ischemic stroke, adjusting for traditional risk factors. RESULTS: Mean age was 63.7 years for males and 60.7 years for females. Mean follow-up period was 2.7 years, and 40 cases of AMI and 182 cases of ischemic stroke were recorded. The hazard ratio (HR) for AMI was significantly higher in the top quartile of the LDL-C/HDL-C ratio and LDL-C levels, and third quartile of TC among male participants. The HR of male participants with a LDL-C/HDL-C ratio of 2.6 or higher was significantly higher than other quartiles. No association between lipoprotein levels or their ratio quartiles and ischemic stroke was seen for either sex after adjusting for risk factors. CONCLUSIONS: Our results indicated that the LDL-C/HDL-C ratio is an independent predictor for AMI, and the importance of better management of cardiovascular risks among people with high LDLC/HDLC ratios for the prevention of future cardiovascular disease. PMID- 20972353 TI - Cultivation of Enterobacter hormaechei from human atherosclerotic tissue. AB - AIM: To determine whether culturable bacterial strains are present in human atheromatous tissue and to investigate their properties using culture, quantitative PCR, metagenomic screening, genomic and biochemical methods. METHODS: We analyzed femoral atherosclerotic plaque and five pairs of diseased and healthy arterial tissue for the presence of culturable bacteria using cell cultures and genomic analysis. RESULTS: Gram negative aerobic bacilli were cultivated from the plaque tissue. Ribosomal 16S DNA amplification and sequencing identified the isolates as Enterobacter hormaechei. The isolate was resistant to ampicillin, cefazolin, and erythromycin. A circular 10 kb plasmid was isolated from the strain. Antibiotic protection assays of the isolate demonstrated invasive ability in a human monocytic cell line. To extend the study, five matched pairs of diseased and healthy aortic tissue were analyzed via quantitative PCR. Eubacterial 16S rDNA was detected in all specimens, however, E. hormaechei DNA was detected in surprisingly high numbers in two of the diseased tissues only. CONCLUSIONS: While it is well documented that inflammation is an important risk factor for vascular pathophysiology, the association of bacteria with atherosclerosis has not been clearly established, in large part due to the inability to isolate live bacteria from atheromatous tissue. This is the first study providing direct evidence of Enterobacter spp. associated with atheromatous tissues. The data suggest that chronic infection with bacteria may be an under reported etiologic factor in vascular pathogenesis. Importantly, characterization of the clinical isolate supports a model of atherogenesis where systemic dissemination of bacteria to atherosclerotic sites may occur via internalization in phagocytic cells. PMID- 20972354 TI - Nitroglycerin-mediated vasodilatation of the brachial artery may predict long term cardiovascular events irrespective of the presence of atherosclerotic disease. AB - AIM: Nitroglycerin-mediated vasodilatation (NMD) provides insight into the NTG induced bioactivity of smooth muscle. It is plausible that in dysfunctional smooth muscle cells, the response to nitroglycerin may become blunted. The relationship between impaired brachial artery NMD and subsequent cardiovascular events is not well established. METHODS: We examined brachial artery flow mediated dilatation (FMD) and NMD using ultrasound in 93 subjects (71+/-7 years, including 26 with peripheral artery disease (PAD), 37 with aortic aneurysms, 10 with PAD complicated with aneurysms, and 20 without evident arterial disease). Brachial artery responses to hyperemia and nitroglycerin were measured every minute after cuff deflation and nitroglycerin administration. Time courses of vasodilatation were assessed and maximal FMD and NMD were measured. RESULTS: The time courses in response to NTG were sigmoidal and maximal diameter reached 7.2+/ 1.6 minutes after NTG was administered sublingually. The mean FMD was 2.3+/-2.0% and the mean NMD was 17.6+/-7.1%. Subjects were prospectively followed for an average of 47+/-13 months. Eighteen subjects had an event during follow-up; events included myocardial infarction (five), unstable angina pectoris (four), stroke (two), aortic dissection (one), ruptured aortic aneurysm (three), symptomatic abdominal aortic aneurysm (two), and lower limb ischemia requiring revascularization (one). NMD and FMD were significantly lower in subjects with events than in those without an event. In a Cox proportional-hazards model, lower FMD as well as lower NMD independently predicted future cardiovascular events. CONCLUSION: Brachial artery nitroglycerin-mediated vasodilatation may add information to conventional risk stratification. PMID- 20972355 TI - Hazard assessments of manufactured nanomaterials. AB - BACKGROUND: It has been difficult to make reliable hazard assessments of manufactured nanomaterials, because the nanomaterials form large agglomerations in both in vitro and in vivo studies. OBJECTIVE: In the New Energy and Industrial Technology Development Organization (NEDO) Project of Japan, the physicochemical properties of many manufactured nanomaterials are being measured, and in vitro and in vivo studies are being performed to determine which endpoints are correspond to the hazards and risks of nanomaterials. Focusing on titanium dioxide, fullerenes and carbon nanotubes, we introduce findings made in inhalation and intratracheal installation studies overseas, and together with the findings made in the NEDO project, and also assess the hazards presented by manufactured nanomaterials. RESULTS AND CONCLUSION: A project by NEDO has succeeded in ensuring the stability of dispersion (nanoscale <100 nm) of manufactured nanomaterials, and is developing hazard assessments of manufactured nanomaterials. In these interim reports, the acceptable exposure concentration of titanium dioxide and fullerene was proposed to be 1.2 mg/m(3) and 0.8 mg/m(3) respirable dust in working environment, respectively. PMID- 20972356 TI - Enzymatic synthesis of palm olein-based fatty thiohydroxamic acids. AB - Fatty thiohydroxamic acids (FTAs) have been successfully synthesized from palm olein and thiohydroxamic acid by a one-step lipase catalyzed reaction. The use of immobilized lipase (Lipozyme RMIM) as the catalyst for the preparation reaction provides an easy isolation of the enzyme from the products and other components in the reaction mixture. The FTAs were characterized using Fourier transform infrared (FTIR) spectroscopy, proton nuclear magnetic resonance ((1)H NMR) technique and elemental analysis. The highest conversion percentage (95 %) was obtained when the process was carried out for 30 hours using urea to palm oil ratio of 6.0: 1.0 at 40 degrees C. The method employed offers several advantages such as renewable and abundant of the raw material, simple reaction procedure, environmentally friendly process and high yield of the product. PMID- 20972357 TI - Palm fatty acid biodiesel: process optimization and study of reaction kinetics. AB - The relatively high cost of refined oils render the resulting fuels unable to compete with petroleum derived fuel. In this study, biodiesel is prepared from palm fatty acid (PFA) which is a by-product of palm oil refinery. The process conditions were optimized for production of palm fatty acid methyl esters. A maximum conversion of 94.4% was obtained using two step trans-esterification with 1:10 molar ratio of oil to methanol at 65 degrees C. Sulfuric acid and Sodium hydroxide were used as acid and base catalyst respectively. The composition of fatty acid methyl esters (FAME) obtained was similar to that of palm oil. The biodiesel produced met the established specifications of biodiesel of American Society for Testing and Materials (ASTM). The kinetics of the trans esterification reaction was also studied and the data reveals that the reaction is of first order in fatty acid and methanol (MeOH) and over all the reaction is of second order. PMID- 20972358 TI - Phase behavior and hydrated solid structure in lysophospholipid/long-chain alcohol/water system and effect of cholesterol addition. AB - Phase behavior in lysophospholipid/long-chain alcohol/water system at 80 degrees C was investigated using hexanol and oleyl alcohol as the long-chain alcohol. Similarly to hydrophilic surfactant, a micellar phase in a lysophospholipid/water system transitioned to a lamellar liquid-crystalline phase by the addition of long-chain alcohol. In the oleyl alcohol system the lamellar liquid-crystalline phase was observed in wider region compared to the hexanol system. The effect of cholesterol addition on the phase behavior was also studied. The region of liquid crystalline phase and (reverse micellar + liquid-crystalline + water) phase shifted towards higher lysophospholipid concentrations. The structure of hydrated solid as well as the transition between lamellar liquid-crystalline phase and hydrated solid was analyzed by X-ray scattering measurement and differential scanning calorimetry measurement. It was revealed that the hydrated solid was alpha-type crystals with lamellar structure. The hydrated solid (gel)-liquid crystal transition temperature gradually decreased with increasing oleyl alcohol concentration and the decrement was enhanced by the addition of cholesterol. PMID- 20972359 TI - Effects of surface activity on aquatic toxicity of binary surfactant mixtures. AB - The purpose of this study was to discuss the effects of surface activity on the aquatic toxicity of binary surfactant mixtures comprising anionic, nonionic, and cationic surfactants. Surface tension was measured to determine the cmc (critical micelle concentration), and acute aquatic toxicity tests were conducted on Daphnia magna to obtain 24h-EC(50) (24h 50% effective concentration). TU (toxic unit) was calculated to evaluate the toxicity of the mixture. Most of the surfactant mixtures showed no synergistic increase in the aquatic toxicity. The mixture of anionic/nonionic surfactants showed synergistic interfacial activity with decreasing cmc, but the toxicity did not increase. The surface tension of the mixture at 24h-EC(50) (gamma(tox)), which was used as an indicator of the toxic concentration, decreased considerably and TU was >1, indicating decreased toxicity. gamma(tox) of the anionic/anionic surfactant mixture decreased when tested with hard water (hardness of 625 ppm). gamma(tox) could not be used as a toxic indicator for the anionic/cationic surfactant mixtures because they showed aquatic toxicity before their surface tension began to decrease. PMID- 20972360 TI - Biosurfactant production from n-paraffins by an air isolate Pseudomonas aeruginosa OCD1. AB - The potential production of biosurfactant was investigated with a strain of Pseudomonas aeruginosa OCD(1), which was isolated from air in our laboratory. The degradation of different hydrocarbons was studied with this microorganism. The values of surface tension and emulsification index of culture broth were very promising when n-octadecane was used as substrate. Characterization of biosurfactant revealed that the biosurfactant was rhamnolipid in nature. The surface tension of water was reduced to 31.5 mN/m from 72 mN/m with the critical micelle concentration of 35 mg/L. A low rhamnolipid concentration (< 5 mg/L) had a strong effect on reduction of surface tension. PMID- 20972361 TI - Amidation of alcohols with nitriles under solvent-free conditions using molecular iodine as a catalyst. AB - The reactions of alcohols with nitriles under solvent-free conditions, using molecular iodine as a catalyst, were investigated. The reaction of 1 phenylethanol with propanenitrile produced the amide N-(1 phenylethyl)propanamide, by dehydration and tautomerization, in 71% yield, under the following conditions: temperature=90 degrees C, alcohol:iodine molar ratio=1:0.2, alcohol:nitrile molar ratio=1:5, and reaction time=5 h. The amidation reactivity depended on the stability of the cationic intermediate formed from the alcohol. The reaction of (-)-borneol with benzonitrile produced a racemic amide in 83% yield. PMID- 20972362 TI - Crystal structure and fluorescence behavior of N,N'-bis (1-naphthylmethyl) diazonia-18-crown-6 diisothiocyanate. AB - N,N'-bis (1-naphthylmethyl)-diaza-18-crown-6 (1) showed weak emissions, suggesting that photoinduced electron transfer (PET) from the amine group to the excited naphthalene occurs. The PET fluoroionophore (1) was found to display unique photophysical properties in the presence of a guest cation. Single crystals of the HNCS salt of 1 were grown from 1 and NH(4)SCN. The crystal structure of the HNCS salt of 1 was elucidated by X-ray crystallographic analysis. The HNCS salt of 1 consists of a 1.2H(+) and 2NCS(-) ion pair. The 1.2HNCS salt gave an emission band at 332 nm. Complexation of 1 with HNCS increased the fluorescence intensity of the host by a factor of 29. The emission enhancement of 1 with HNCS was caused by the proton which dissociates from HNCS. PMID- 20972363 TI - beta-Sitosteryl (6'-O-linoleoyl)-glucoside of soybean (Glycine max L.) crude extract inhibits Y-family DNA polymerases. AB - In the screening of selective DNA polymerase (pol) inhibitors, we isolated an acylated steryl glycoside, beta-sitosteryl (6'-O-linoleoyl)-glucoside (compound 1), from the waste extract of soybean (Glycine max L.) oil. This compound exhibited a marked ability to inhibit the activities of eukaryotic Y-family pols (pols eta, iota and kappa), which are repair-related pols. Among mammalian Y family pols, the activity of mouse pol kappa was most strongly inhibited by compound 1, with an IC(50) value of 10.2 uM. On the other hand, compound 1 had no effect on the activities of other eukaryotic pols such as A-family (pol gamma), B family (pols alpha, delta, and epsilon), or X-family (pols beta, lambda and terminal deoxynucleotidyl transferase) pols. In addition, compound 1 had no effect on prokaryotic pols or other DNA metabolic enzymes such as calf primase of pol alpha, T7 RNA polymerase, T4 polynucleotide kinase, or bovine deoxyribonuclease I. Compound 1 consists of 3 groups: beta-sitosteryl (compound 2), linoleic acid (compound 3), and D-glucose (compound 4). Compound 3 inhibited the activities of all mammalian pols tested, but compounds 2 and 4 did not have any effect on the tested pols. Kinetic studies showed that the inhibition of pol kappa activity by compound 1 was noncompetitive with both the DNA template-primer and nucleotide substrate, whereas compound 3-induced inhibition was competitive with the DNA template-primer and noncompetitive with the nucleotide substrate. The relationship between the structure of compound 1 and the selective inhibition of eukaryotic Y-family pols is discussed. PMID- 20972364 TI - Depth scaling of solid phantom for intensity modulated radiotherapy beams. AB - To reduce the uncertainty of absorbed dose for high energy photon beams, water has been chosen as a reference material by the dosimetry protocols. However, solid phantoms are used as media for absolute dose verification of intensity modulated radiotherapy (IMRT). For the absorbed dose measurement, the fluence scaling factor is used for converting an ionization chamber reading in a solid phantom to absorbed dose to water. Furthermore the depth scaling factor is indispensable in determining the fluence scaling factor. For IMRT beams, a photon energy spectrum is varied by transmitting through a multileaf collimator and attenuating in media. However, the effects of spectral variations on depth scaling have not been clarified yet. In this study, variations of photon energy spectra were determined using the EGS Monte Carlo simulation. The depth scaling factors for commercially available solid phantoms were determined from effective mass attenuation coefficients using photon energy spectra. The results clarified the effect of spectral variation on the depth scaling and produced an accurate scaling method for IMRT beams. PMID- 20972365 TI - Role of wild-type p53 in apoptotic and non-apoptotic cell death induced by X irradiation and heat treatment in p53-mutated mouse M10 cells. AB - The sensitizing effects of wild-type p53 on X-ray-induced cell death and on heat induced apoptosis in M10, a radiosensitive and Trp53 (mouse p53 gene)-mutated lymphoma cell line which dies through necrosis by X-irradiation, were investigated using three M10 derived transfectants with wild-type TP53 (human p53 gene). Cell death was determined by colony formation and/or dye exclusion test, and apoptosis was detected as the changes in nuclear morphology by Giemsa staining. Expression of wild-type p53 protein increased radiosensitivity of cell death as determined by both clonogenic and dye exclusion assays. This increase in radiosensitivity was attributable largely to apoptosis induction in addition to a small enhancement of necrosis. Interestingly neither pathway to cell death was accompanied by caspase-3 activation. On the other hand, heat-induced caspase-3 dependent apoptotic cell death without transfection was further increased by the transfection of wild-type p53. In conclusion, the introduction of wild-type p53 enhanced apoptotic cell death by X-rays or heat via different mechanisms that do or do not activate caspase-3, respectively. In addition, p53 also enhanced the X ray-induced necrosis in M10 cells. PMID- 20972366 TI - The benefit of small bowel and pelvic bone sparing in excluding common iliac lymph node region from conventional radiation fields in patients with uterine cervical cancer: a dosimetric study. AB - The purpose of this study was to compare dose reduction to the small bowel and sacral bone by two-field and four-field techniques when the common iliac lymph node region is excluded from the radiation field in external beam radiotherapy of uterine cervical cancer. Thirteen patients with cervical cancer were entered into the study. Conventional treatment plans based on bony landmarks were made with parallel-opposed two-field technique (C2F) and four-field box technique (C4F). Modified C2F (M2F) and C4F (M4F) plans of excluding the common iliac lymph node region from the conventional radiation fields were created in reference to the bifurcations of pelvic arteries in computed tomography images. For each patient, the dose volume histograms for the small bowel and sacral bone resulting from the C2F, C4F, M2F, and M4F plans were compared. The volumes were obtained at 10 levels of prescribed dose, at increments of 10%, from 5 Gy to 50 Gy. By sparing both small bowel and sacral bone, the M2F and M4F plans were significantly better than the C2F and C4F plans at any dose level (p < 0.05), respectively. In addition, the M4F plan was significantly better than the M2F plan in sparing both small bowel at 10-50% of the prescribed dose (p < 0.05) and sacral bone at 40 100% of the prescribed dose (p < 0.05). The present study suggests that modified treatment planning could be useful for selected patients for reducing small bowel complications and insufficiency fracture after radiotherapy. PMID- 20972368 TI - Yin yang: A balancing act for oxidative stress. PMID- 20972369 TI - Exogenous antioxidants--Double-edged swords in cellular redox state: Health beneficial effects at physiologic doses versus deleterious effects at high doses. AB - The balance between oxidation and antioxidation is believed to be critical in maintaining healthy biological systems. Under physiological conditions, the human antioxidative defense system including e.g., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH) and others, allows the elimination of excess reactive oxygen species (ROS) including, among others superoxide anions (O2(.-)), hydroxyl radicals (OH.), alkoxyl radicals (RO.) and peroxyradicals (ROO.). However, our endogenous antioxidant defense systems are incomplete without exogenous originating reducing compounds such as vitamin C, vitamin E, carotenoids and polyphenols, playing an essential role in many antioxidant mechanisms in living organisms. Therefore, there is continuous demand for exogenous antioxidants in order to prevent oxidative stress, representing a disequilibrium redox state in favor of oxidation. However, high doses of isolated compounds may be toxic, owing to prooxidative effects at high concentrations or their potential to react with beneficial concentrations of ROS normally present at physiological conditions that are required for optimal cellular functioning. This review aims to examine the double-edged effects of dietary originating antioxidants with a focus on the most abundant compounds, especially polyphenols, vitamin C, vitamin E and carotenoids. Different approaches to enrich our body with exogenous antioxidants such as via synthetic antioxidants, diets rich in fruits and vegetables and taking supplements will be reviewed and experimental and epidemiological evidences discussed, highlighting that antioxidants at physiological doses are generally safe, exhibiting interesting health beneficial effects. PMID- 20972371 TI - Thymoquinone attenuates diethylnitrosamine induction of hepatic carcinogenesis through antioxidant signaling. AB - Hepatocellular carcinoma accounts for about 80-90% of all liver cancer and is the fourth most common cause of cancer mortality. Although there are many strategies for the treatment of liver cancer, chemoprevention seems to be the best strategy for lowering the incidence of this disease. Therefore, this study has been initiated to investigate whether thymoquinone (TQ), Nigella sativa derived compound with strong antioxidant properties, supplementation could prevent initiation of hepatocarcinogenesis-induced by diethylnitrosamine (DENA), a potent initiator and hepatocarcinogen, in rats. Male Wistar albino rats were divided into four groups. Rats of Group 1 received a single intraperitoneal (i.p.) injection of normal saline. Animals in Group 2 were given TQ (4 mg/kg/day) in drinking water for 7 consecutive days. Rats of Group 3 were injected with a single dose of DENA (200 mg/kg, i.p.). Animals in Group 4 were received TQ and DENA. DENA significantly increased alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin, thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite (NOx) and decreased reduced glutathione (GSH), glutathione peroxidase (GSHPx), glutathione-s-transferase (GST) and catalase (CAT) activity in liver tissues. Moreover, DENA decreased gene expression of GSHPx, GST and CAT and caused severe histopathological lesions in liver tissue. Interestingly, TQ supplementation completely reversed the biochemical and histopathological changes induced by DENA to the control values. In conclusion, data from this study suggest that: (1) decreased mRNA expression of GSHPx, CAT and GST during DENA-induced initiation of hepatic carcinogenesis, (2) TQ supplementation prevents the development of DENA-induced initiation of liver cancer by decreasing oxidative stress and preserving both the activity and mRNA expression of antioxidant enzymes. PMID- 20972370 TI - Deleterious effects of reactive metabolites. AB - A number of drugs have been withdrawn from the market or severely restricted in their use because of unexpected toxicities that become apparent only after the launch of new drug entities. Circumstantial evidence suggests that, in most cases, reactive metabolites are responsible for these unexpected toxicities. In this review, a general overview of the types of reactive metabolites and the consequences of their formation are presented. The current approaches to evaluate bioactivation potential of new compounds with particular emphasis on the advantages and limitation of these procedures will be discussed. Reasonable reasons for the excellent safety record of certain drugs susceptible to bioactivation will also be explored and should provide valuable guidance in the use of reactive-metabolite assessments when nominating drug candidates for development. This will, in turn, help us to design and bring safer drugs to the market. PMID- 20972372 TI - Insulin resistance is an independent correlate of high serum levels of advanced glycation end products (AGEs) and low testosterone in non-diabetic men. AB - Advanced glycation end products (AGEs) are involved in cardiovascular disease. Low testosterone level is associated with increased risks of cardiometabolic disorders as well. However, which anthropometric and metabolic variables, including AGEs, are independently correlated with low testosterone is largely unknown. In this study, we investigated whether high serum level of AGEs is one of the independent determinants of low testosterone in non-diabetic men. One hundred thirteen non-diabetic men who did not receive any drugs for hypertension and dyslipidemia underwent a complete history and physical examination, determination of blood chemistries, including serum AGEs and testosterone. Univariate analysis showed that testosterone levels were associated with waist circumference (inversely), diastolic blood pressure (BP) (inversely), mean BP (inversely), triglycerides (inversely), HDL-cholesterol, fasting plasma glucose (inversely), fasting insulin (inversely), homeostasis model assessment of insulin resistance (HOMA-IR) (inversely), AGEs (inversely) and uric acid (inversely). By the use of multiple stepwise regression analyses, HOMA-IR (p = 0.005) and triglycerides levels (p < 0.05) remained significant and were independently related to testosterone levels (R(2) = 0.168). HOMA-IR index was one of the independent determinants of serum levels of AGEs as well. The present study demonstrated for the first time that HOMA-IR was independently associated with high serum levels of AGEs and low testosterone in non-diabetic men. Insulin resistance could link elevation of AGEs to testosterone deficiency in non diabetic men. PMID- 20972373 TI - Carnitine deficiency and oxidative stress provoke cardiotoxicity in an ifosfamide induced Fanconi Syndrome rat model. AB - In addition to hemorrhagic cystitis, Fanconi Syndrome is a serious clinical side effect during ifosfamide (IFO) therapy. Fanconi syndrome is a generalized dysfunction of the proximal tubule which is characterized by excessive urinary excretion of glucose, phosphate, bicarbonate, amino acids and other solutes excreted by this segment of the nephron including L-carnitine. Carnitine is essential cofactor for beta-oxidation of long-chain fatty acids in the myocardium. IFO therapy is associated with increased urinary carnitine excretion with subsequent secondary deficiency of the molecule. Cardiac abnormalities in IFO-treated cancer patients were reported as isolated clinical cases. This study examined whether carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, provoke IFO-induced cardiomyopathy as well as exploring if carnitine supplementation using Propionyl-L-carnitine (PLC) could offer protection against this toxicity. In the current study, an animal model of carnitine deficiency was developed in rats by D-carnitine-mildronate treatment Adult male Wistar albino rats were assigned to one of six treatment groups: the first three groups were injected intraperitoneally with normal saline, D-carnitine (DC, 250 mg/kg/day) combined with mildronate (MD, 200 mg/kg/day) and PLC (250 mg/kg/day), respectively, for 10 successive days. The 4(th), 5(th) and 6(th) groups were injected with the same doses of normal saline, DC-MD and PLC, respectively for 5 successive days before and 5 days concomitant with IFO (50 mg/kg/day). IFO significantly increased serum creatinine, blood urea nitrogen (BUN), urinary carnitine excretion and clearance, creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), intramitochondrial acetyl-CoA/CoA-SH and thiobarbituric acid reactive substances (TBARS) in cardiac tissues and significantly decreased adenosine triphosphate (ATP) and total carnitine and reduced glutathione (GSH) content in cardiac tissues. In carnitine-depleted rats, IFO induced dramatic increase in serum creatinine, BUN, CK-MB, LDH, carnitine clearance and intramitochondrial acetyl-CoA/CoA-SH, as well as progressive reduction in total carnitine and ATP in cardiac tissues. Interestingly, PLC supplementation completely reversed the biochemical changes-induced by IFO to the control values. In conclusion, data from the present study suggest that: Carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, constitute risk factors and should be viewed as mechanisms during development of IFO-induced cardiotoxicity. Carnitine supplementation, using PLC, prevents the development of IFO-induced cardiotoxicity through antioxidant signalling and improving mitochondrial function. PMID- 20972374 TI - Age associated oxidative damage in lymphocytes. AB - Lymphocytes are an important immunological cell and have been played a significant role in acquired immune system; hence, may play in pivotal role in immunosenescence. Oxidative stress has been reported to increase in elderly subjects, possibly arising from an uncontrolled production of free radicals with aging and decreased antioxidant defenses. This study was aimed to evaluate the level of lipid-protein damage and antioxidant status in lymphocytes of healthy individuals to correlate between oxidative damage with the aging process. Twenty healthy individuals of each age group (11-20; 21-30; 31-40; 41-50; and 51-60 years) were selected randomly. Blood samples were drawn by medical practitioner and lymphocytes were isolated from blood samples. Malondialdehyde (MDA), protein carbonyls (PC) level were evaluated to determine the lipid and protein damage in lymphocytes. Superoxide dismutase (SOD), catalase (CAT), glutathione and glutathione dependent enzymes were estimated to evaluate the antioxidant status in the lymphocytes. Increased MDA and PC levels strongly support the increased oxidative damage in elderly subject than young subjects. The results indicated that, balance of oxidant and antioxidant systems in lymphocytes shifts in favor of accelerated oxidative damage during aging. Thus oxidative stress in lymphocytes may particular interest in aging and may play important role in immunosenescence. PMID- 20972376 TI - Ways to remember. PMID- 20972375 TI - Alpha-synuclein stimulation of astrocytes: Potential role for neuroinflammation and neuroprotection. AB - Selective loss of neurons, abnormal protein deposition and neuroinflammation are the common pathological features of neurodegenerative diseases, and these features are closely related to one another. In Parkinson's disease, abnormal aggregation and deposition of alpha-synuclein is known as a critical event in pathogenesis of the disease, as well as in other related neurodegenerative disorders, such as dementia with Lewy bodies and multiple system atrophy. Increasing evidence suggests that alpha-synuclein aggregates can activate glial cells to induce neuroinflammation. However, how an inflammatory microenvironment is established and maintained by this protein remains unknown. Findings from our recent study suggest that neuronal alpha-synuclein can be directly transferred to astrocytes through sequential exocytosis and endocytosis and induce inflammatory responses from astrocytes. Here we discuss potential roles of astrocytes in a cascade of events leading to alpha-synuclein-induced neuroinflammation. PMID- 20972377 TI - Management of multiple sclerosis and the role of respite and palliative care. PMID- 20972378 TI - Working family carers in Portugal: between the duty and the burden of caring for old vulnerable people. AB - This paper intends to reflect on some of the predominant traits of caring for older vulnerable people in Portugal, where the most common care model is a mix of informal home-based provision and support from the public and private sectors. We shall address some issues concerning the risks and limits of informal caretaking of older dependent people based on a case study of a woman who has to fulfil multiple roles, pushing her to the limit of her ability to cope. Evidence indicates that solutions to the challenges of caring for an ageing population, especially those in a vulnerable condition, require a consideration of material, social, cultural, and psychological measures. On the basis of the nature of the links between these areas, the quality of the care provided and the consequences for the working family carers, we can define standards of caring solutions for older people and hence derive policies for preventive and optimized interventions. Our final aim is to emphasize the importance of palliative care settings to improve the quality of life and minimize the suffering of both older people and their carers. PMID- 20972379 TI - Using cannabinoids in pain and palliative care. AB - Interest in the use of cannabinoids in a clinical setting is gradually increasing, particularly in patients where more conventional treatments have failed. They have been reported as offering perceived benefits in a wide range of conditions, but the major interest at present is centred on their place in pain management and in the palliation of symptoms secondary to terminal cancer and neurological disease. The potential benefits include symptomatic relief for patients suffering from intractable neuropathic pain, anorexia, anxiety and muscle spasm. There is clear consensus that cannibinoids should not be used as a first-line monotherapy, but should be considered as valuable adjuvants to more commonly indicated therapeutic options in the management of palliative care patients. Scientific evidence documenting the benefits of the canibinoids nabilone and sativex is accumulating, but needs to be evaluated carefully in the light of the paucity of available data. Both drugs are usually used under the guidance of specialist units. Nabilone and Sativex are now controlled drugs, and are frequently used outside of their licensed indication (control of chemotherapy induced nausea and vomiting) and hence particular care needs to be taken in evaluating the rational for their use. Sativex has been recently licenced for use in the management of patients with multiple sclerosis. PMID- 20972380 TI - Anatomy and physiology of pain and the management of breakthrough pain in palliative care. PMID- 20972381 TI - Evidence-based practice guidelines: a survey of subcutaneous dexamethasone administration. AB - Searching for good evidence to develop clinical practice guidelines can be challenging, as research may not be published or available. A simple question set the authors on a journey to find evidence related to the nursing administration of subcutaneous dexamethasone in the palliative setting. This article outlines the search for evidence and discusses the survey results to gather expert opinion about the nursing administration of dexamethasone. Survey results indicated that only 39% of community services gave dexamethasone via a bolus injection and 88% gave it via a continuous infusion, mainly for site preservation. The diluents used were water for injection or normal saline. Many procedural aspects were supported by current guidelines, with several services using the New Zealand Waitemata District Health Board's (2008) clinical guidelines. Developing and implementing procedural recommendations for nurses to administer this subcutaneous medication will form the next stage of the project. PMID- 20972382 TI - Music therapy in the context of palliative care in Tanzania. AB - There has been much written to support music therapy as an adjunct in managing pain and anxiety in palliative care patients in Western societies, but little written on its use in developing countries. In light of increasing numbers of terminally ill patients in Tanzania owing to HIV/AIDS and cancer, limited access to opioids, and a growing interest in palliative care support, this study looks at the application of music in this context. The study reviews the history and principles of therapeutic music and outlines its role in palliative care. A qualitative study was conducted by questionnaire of 17 professionals involved in home-based palliative care in Tanzania. Findings include beliefs about the power of music, how music is being used to bring comfort to the dying patient, and the most important aspects of helpful music to many Tanzanian palliative care patients. Music can powerfully affect body, mind and spirit. It is vocal music, which is an accepted therapeutic music tool used to bring comfort to the palliative care patient and their family members. Finally, music is an active and participatory activity in Tanzanian culture, even for the dying. PMID- 20972383 TI - Issues of power, control and choice in children's hospice respite care services: a qualitative study. AB - The changes within children's palliative care services in the UK over the last decade highlight the importance of respite provision. This article reports on an evaluation of a children's hospice in northern England that was undertaken to elicit the views of 24 service users on their experiences of respite care in the hospice: parents, children and young people, siblings, guardians and family carers. Data were collected using in-depth interviews, transcribed and submitted to framework analysis. The findings demonstrate the tensions that parents in need of respite care feel as a result of the power unconsciously exercised by staff. Redistribution of resources and reordering of priorities are recommended to prevent the inadvertent impact upon families. PMID- 20972384 TI - Comfort care packs: a little bit of hospice in hospital? AB - The Comfort Care Pack initiative is an innovation designed to enhance the inpatient experience of end-of-life patients and their carers. The carer is given a pleasantly decorated box containing a variety of items for use by the patient or the carer themselves: snacks, toiletries and items to promote comfort. This project set out to evaluate the impact of these packs by reviewing the returns of the feedback questionnaires included with the packs. From the first 220 packs, 58 questionnaires were returned, giving quantitative and qualitative data. The response to the packs was overwhelmingly positive and they were much valued by the carers. This was the case despite the fact that relatively few of the items were actually used by the recipients. It is suggested that the value of the packs to recipients lies in the gesture of being thought about during what is a difficult time for them. The implications of this are discussed. PMID- 20972385 TI - Study skills. PMID- 20972386 TI - Comparative in vivo study of gp96 adjuvanticity in the frog Xenopus laevis. AB - We have developed in the amphibian Xenopus laevis a unique non-mammalian model to study the ability of certain heat shock proteins (hsps) such as gp96 to facilitate cross-presentation of chaperoned antigens and elicit innate and adaptive T cell responses. Xenopus skin graft rejection provides an excellent platform to study the ability of gp96 to elicit classical MHC class Ia (class Ia) restricted T cell responses. Additionally, the Xenopus model system also provides an attractive alternative to mice for exploring the ability of gp96 to generate responses against tumors that have down-regulated their class Ia molecules thereby escaping immune surveillance. Recently, we have developed an adoptive cell transfer assay in Xenopus clones using peritoneal leukocytes as antigen presenting cells (APCs), and shown that gp96 can prime CD8 T cell responses in vivo against minor histocompatibility skin antigens as well as against the Xenopus thymic tumor 15/0 that does not express class Ia molecules. We describe here the methodology involved to perform these assays including the elicitation, pulsing and adoptive transfer of peritoneal leukocytes, as well as the skin graft and tumor transplantation assays. Additionally we are also describing the harvesting and separation of peripheral blood leukocytes used for flow cytometry and proliferation assays which allow for further characterization of the effector populations involved in skin rejection and anti-tumor responses. PMID- 20972387 TI - Gene delivery to postnatal rat brain by non-ventricular plasmid injection and electroporation. AB - Creation of transgenic animals is a standard approach in studying functions of a gene of interest in vivo. However, many knockout or transgenic animals are not viable in those cases where the modified gene is expressed or deleted in the whole organism. Moreover, a variety of compensatory mechanisms often make it difficult to interpret the results. The compensatory effects can be alleviated by either timing the gene expression or limiting the amount of transfected cells. The method of postnatal non-ventricular microinjection and in vivo electroporation allows targeted delivery of genes, siRNA or dye molecules directly to a small region of interest in the newborn rodent brain. In contrast to conventional ventricular injection technique, this method allows transfection of non-migratory cell types. Animals transfected by means of the method described here can be used, for example, for two-photon in vivo imaging or in electrophysiological experiments on acute brain slices. PMID- 20972388 TI - Technique to collect fungiform (taste) papillae from human tongue. AB - The sense of taste is critical for human life. It informs the body about the quality of food that will be potentially ingested and stimulates metabolic processes that prepare the alimentary canal for digestion. Steady progress is being made towards understanding the early biochemical and molecular events underlying taste transduction (for a review, Breslin and Spector, 2008). However, progress to date has largely resulted from animal models. Yet, since marked differences in receptor specificity and receptor density vary among species, human taste transduction will only be understood by using human taste tissue. Here we describe a biopsy technique to collect human fungiform papillae, visible as rounded pink anterior structures, about 0.5 mm in diameter that contain taste buds. These biopsied papillae are used for several purposes including the isolation of viable taste bud cells, in situ hybridization, immunohistochemistry and, through techniques of molecular biology, the identification of taste specific novel proteins. PMID- 20972389 TI - A thin-skull window technique for chronic two-photon in vivo imaging of murine microglia in models of neuroinflammation. AB - Traditionally in neuroscience, in vivo two photon imaging of the murine central nervous system has either involved the use of open-skull or thinned-skull preparations. While the open-skull technique is very versatile, it is not optimal for studying microglia because it is invasive and can cause microglial activation. Even though the thinned-skull approach is minimally invasive, the repeated re-thinning of skull required for chronic imaging increases the risks of tissue injury and microglial activation and allows for a limited number of imaging sessions. Here we present a chronic thin-skull window method for monitoring murine microglia in vivo over an extended period of time using two photon microscopy. We demonstrate how to prepare a stable, accessible, thinned skull cortical window (TSCW) with an apposed glass coverslip that remains translucent over the course of three weeks of intermittent observation. This TSCW preparation is far more immunologically inert with respect to microglial activation than open craniotomy or repeated skull thinning and allows an arbitrary number of imaging sessions during a time period of weeks. We prepare TSCW in CX3CR1 GFP/+ mice to visualize microglia with enhanced green fluorescent protein to <=150 MUm beneath the pial surface. We also show that this preparation can be used in conjunction with stereotactic brain injections of the HIV-1 neurotoxic protein Tat, adjacent to the TSCW, which is capable of inducing durable microgliosis. Therefore, this method is extremely useful for examining changes in microglial morphology and motility over time in the living brain in models of HIV Associated Neurocognitive Disorder (HAND) and other neurodegenerative diseases with a neuroinflammatory component. PMID- 20972390 TI - Multicolor time-lapse imaging of transgenic zebrafish: visualizing retinal stem cells activated by targeted neuronal cell ablation. AB - High-resolution time-lapse imaging of living zebrafish larvae can be utilized to visualize how biological processes unfold (for review see (1)). Compound transgenic fish which express different fluorescent reporters in neighboring cell types provide a means of following cellular interactions (2) and/or tissue-level responses to experimental manipulations over time. In this video, we demonstrate methods that can be used for imaging multiple transgenically labeled cell types serially in individual fish over time courses that can span from minutes to several days. The techniques described are applicable to any study seeking to correlate the "behavior" of neighboring cells types over time, including: 1) serial 'catch and release' methods for imaging a large number of fish over successive days, 2) simplified approaches for separating fluorophores with overlapping excitation/emission profiles (e.g., GFP and YFP), 3) use of hypopigmented mutant lines to extend the time window available for high resolution imaging into late larval stages of development, 4) use of membrane targeted fluorescent reporters to reveal fine morphological detail of individual cells as well as cellular details in larger populations of cells, and 5) a previously described method for chemically-induced ablation of transgenically targeted cell types; i.e., nitroreductase (NTR) mediated conversion of prodrug substrates, such as metronidazole (MTZ), to cytotoxic derivatives (3,5). As an example of these approaches, we will visualize the ablation and regeneration of a subtype of retinal bipolar neuron within individual fish over several days. Simultaneously we will monitor several other retinal cell types, including neighboring non-targeted bipolar cells and potential degeneration-stimulated retinal stem cells (i.e., Mupsilonller glia). This strategy is being applied in our lab to characterize cell- and tissue-level (e.g., stem cell niche) responses to the selective loss and regeneration of targeted neuronal cell types. PMID- 20972391 TI - Adult and embryonic skeletal muscle microexplant culture and isolation of skeletal muscle stem cells. AB - Cultured embryonic and adult skeletal muscle cells have a number of different uses. The micro-dissected explants technique described in this chapter is a robust and reliable method for isolating relatively large numbers of proliferative skeletal muscle cells from juvenile, adult or embryonic muscles as a source of skeletal muscle stem cells. The authors have used micro-dissected explant cultures to analyse the growth characteristics of skeletal muscle cells in wild-type and dystrophic muscles. Each of the components of tissue growth, namely cell survival, proliferation, senescence and differentiation can be analysed separately using the methods described here. The net effect of all components of growth can be established by means of measuring explant outgrowth rates. The micro-explant method can be used to establish primary cultures from a wide range of different muscle types and ages and, as described here, has been adapted by the authors to enable the isolation of embryonic skeletal muscle precursors. Uniquely, micro-explant cultures have been used to derive clonal (single cell origin) skeletal muscle stem cell (SMSc) lines which can be expanded and used for in vivo transplantation. In vivo transplanted SMSc behave as functional, tissue-specific, satellite cells which contribute to skeletal muscle fibre regeneration but which are also retained (in the satellite cell niche) as a small pool of undifferentiated stem cells which can be re-isolated into culture using the micro-explant method. PMID- 20972392 TI - Estimating virus production rates in aquatic systems. AB - Viruses are pervasive components of marine and freshwater systems, and are known to be significant agents of microbial mortality. Developing quantitative estimates of this process is critical as we can then develop better models of microbial community structure and function as well as advance our understanding of how viruses work to alter aquatic biogeochemical cycles. The virus reduction technique allows researchers to estimate the rate at which virus particles are released from the endemic microbial community. In brief, the abundance of free (extracellular) viruses is reduced in a sample while the microbial community is maintained at near ambient concentration. The microbial community is then incubated in the absence of free viruses and the rate at which viruses re-occur in the sample (through the lysis of already infected members of the community) can be quantified by epifluorescence microscopy or, in the case of specific viruses, quantitative PCR. These rates can then be used to estimate the rate of microbial mortality due to virus-mediated cell lysis. PMID- 20972393 TI - Preparation of highly coupled rat heart mitochondria. AB - The function of mitochondria in generation of cellular ATP in the process of oxidative phosphorylation is widely recognised. During the past decades there have been significant advances in our understanding of the functions of mitochondria other than the generation of energy. These include their role in apoptosis, acting as signalling organelles, mammalian development and ageing as well as their contribution to the coordination between cell metabolism and cell proliferation. Our understanding of biological processes modulated by mitochondria is based on robust methods for isolation and handling of intact mitochondria from tissues of the laboratory animals. Mitochondria from rat heart is one of the most common preparations for past and current studies of cellular metabolism including studies on knock-out animals. Here we describe a detailed rapid method for isolation of intact mitochondria with a high degree of coupling. Such preparation of rat heart mitochondria is an excellent object for functional and structural research on cellular bioenergetics, transport of biomolecules, proteomic studies and analysis of mitochondrial DNA, proteins and lipids. PMID- 20972394 TI - Specific marking of HIV-1 positive cells using a Rev-dependent lentiviral vector expressing the green fluorescent protein. AB - Most of HIV-responsive expression vectors are based on the HIV promoter, the long terminal repeat (LTR). While responsive to an early HIV protein, Tat, the LTR is also responsive to cellular activation states and to the local chromatin activity where the integration has occurred. This can result in high HIV-independent activity, and has restricted the usefulness of LTR-based reporter to mark HIV positive cells. Here, we constructed an expression lentiviral vector that possesses, in addition to the Tat-responsive LTR, numerous HIV DNA sequences that include the Rev-response element and HIV splicing sites. The vector was incorporated into a lentiviral reporter virus, permitting highly specific detection of replicating HIV in living cell populations. The activity of the vector was measured by expression of the green fluorescence protein (GFP). The application of this vector as reported here offers a novel alternative approach to existing methods, such as in situ PCR or HIV antigen staining, to identify HIV positive cells. The vector can also express therapeutic genes for basic or clinical experimentation to target HIV-positive cells. PMID- 20972395 TI - Axoplasm isolation from rat sciatic nerve. AB - Isolation of pure axonal cytoplasm (axoplasm) from peripheral nerve is crucial for biochemical studies of many biological processes. In this article, we demonstrate and describe a protocol for axoplasm isolation from adult rat sciatic nerve based on the following steps: (1) dissection of nerve fascicles and separation of connective tissue; (2) incubation of short segments of nerve fascicles in hypotonic medium to release myelin and lyse non-axonal structures; and (3) extraction of the remaining axon-enriched material. Proteomic and biochemical characterization of this preparation has confirmed a high degree of enrichment for axonal components. PMID- 20972396 TI - Single cell transfection in chick embryos. AB - A central theme in developmental biology is the diversification of lineages and the elucidation of underlying molecular mechanisms. This entails a thorough analysis of the fates of single cells under normal and experimental conditions. To this end, transfection methods that target single progenitors are a prerequisite. We describe here a technically straightforward method for transfecting single cells in chicken tissues in-ovo, allowing reliable lineage tracing as well as genetic manipulation. Specific tissue domains are targeted within the somite or neural tube, and DNA is injected directly into the epithelium of interest, resulting in sporadic transfection of single cells. Using reporters, clonal populations may consequently be traced for up to three days, and behavior of genetically manipulated clonal populations can be compared with that of controls. This method takes advantage of the accessibility of the chick embryo along with emerging tools for genetic manipulation. We compare and discuss its advantages over the widely-used electroporation method, and possible applications and use in additional in-vivo models are also suggested. We advocate the use of this method as a significant addition and complement for existing lineage tracing and genetic interference tools. PMID- 20972397 TI - Isolation of stem cells from human pancreatic cancer xenografts. AB - Cancer stem cells (CSCs) have been identified in a growing number of malignancies and are functionally defined by their ability to undergo self-renewal and produce differentiated progeny. These properties allow CSCs to recapitulate the original tumor when injected into immunocompromised mice. CSCs within an epithelial malignancy were first described in breast cancer and found to display specific cell surface antigen expression (CD44+CD24(low/-)). Since then, CSCs have been identified in an increasing number of other human malignancies using CD44 and CD24 as well as a number of other surface antigens. Physiologic properties, including aldehyde dehydrogenase (ALDH) activity, have also been used to isolate CSCs from malignant tissues. Recently, we and others identified CSCs from pancreatic adenocarcinoma based on ALDH activity and the expression of the cell surface antigens CD44 and CD24, and CD133. These highly tumorigenic populations may or may not be overlapping and display other functions. We found that ALDH+ and CD44+CD24+ pancreatic CSCs are similarly tumorigenic, but ALDH+ cells are relatively more invasive. In this protocol we describe a method to isolate viable pancreatic CSCs from low-passage human xenografts. Xenografted tumors are harvested from mice and made into a single-cell suspension. Tissue debris and dead cells are separated from live cells and then stained using antibodies against CD44 and CD24 and using the ALDEFLUOR reagent, a fluorescent substrate of ALDH. CSCs are then isolated by fluorescence activated cell sorting. Isolated CSCs can then be used for analytical or functional assays requiring viable cells. PMID- 20972398 TI - Assessment of cerebral lateralization in children using functional transcranial Doppler ultrasound (fTCD). AB - There are many unanswered questions about cerebral lateralization. In particular, it remains unclear which aspects of language and nonverbal ability are lateralized, whether there are any disadvantages associated with atypical patterns of cerebral lateralization, and whether cerebral lateralization develops with age. In the past, researchers interested in these questions tended to use handedness as a proxy measure for cerebral lateralization, but this is unsatisfactory because handedness is only a weak and indirect indicator of laterality of cognitive functions. Other methods, such as fMRI, are expensive for large-scale studies, and not always feasible with children. Here we will describe the use of functional transcranial Doppler ultrasound (fTCD) as a cost-effective, non-invasive and reliable method for assessing cerebral lateralization. The procedure involves measuring blood flow in the middle cerebral artery via an ultrasound probe placed just in front of the ear. Our work builds on work by Rune Aaslid, who co-introduced TCD in 1982, and Stefan Knecht, Michael Deppe and their colleagues at the University of Munster, who pioneered the use of simultaneous measurements of left- and right middle cerebral artery blood flow, and devised a method of correcting for heart beat activity. This made it possible to see a clear increase in left-sided blood flow during language generation, with lateralization agreeing well with that obtained using other methods. The middle cerebral artery has a very wide vascular territory (see Figure 1) and the method does not provide useful information about localization within a hemisphere. Our experience suggests it is particularly sensitive to tasks that involve explicit or implicit speech production. The 'gold standard' task is a word generation task (e.g. think of as many words as you can that begin with the letter 'B'), but this is not suitable for young children and others with limited literacy skills. Compared with other brain imaging methods, fTCD is relatively unaffected by movement artefacts from speaking, and so we are able to get a reliable result from tasks that involve describing pictures aloud. Accordingly, we have developed a child-friendly task that involves looking at video-clips that tell a story, and then describing what was seen. PMID- 20972399 TI - Assaying locomotor activity to study circadian rhythms and sleep parameters in Drosophila. AB - Most life forms exhibit daily rhythms in cellular, physiological and behavioral phenomena that are driven by endogenous circadian (=24 hr) pacemakers or clocks. Malfunctions in the human circadian system are associated with numerous diseases or disorders. Much progress towards our understanding of the mechanisms underlying circadian rhythms has emerged from genetic screens whereby an easily measured behavioral rhythm is used as a read-out of clock function. Studies using Drosophila have made seminal contributions to our understanding of the cellular and biochemical bases underlying circadian rhythms. The standard circadian behavioral read-out measured in Drosophila is locomotor activity. In general, the monitoring system involves specially designed devices that can measure the locomotor movement of Drosophila. These devices are housed in environmentally controlled incubators located in a darkroom and are based on using the interruption of a beam of infrared light to record the locomotor activity of individual flies contained inside small tubes. When measured over many days, Drosophila exhibit daily cycles of activity and inactivity, a behavioral rhythm that is governed by the animal's endogenous circadian system. The overall procedure has been simplified with the advent of commercially available locomotor activity monitoring devices and the development of software programs for data analysis. We use the system from Trikinetics Inc., which is the procedure described here and is currently the most popular system used worldwide. More recently, the same monitoring devices have been used to study sleep behavior in Drosophila. Because the daily wake-sleep cycles of many flies can be measured simultaneously and only 1 to 2 weeks worth of continuous locomotor activity data is usually sufficient, this system is ideal for large-scale screens to identify Drosophila manifesting altered circadian or sleep properties. PMID- 20972400 TI - Visualization of larval segmental nerves in 3(rd) instar Drosophila larval preparations. AB - Drosophila melanogaster is emerging as a powerful model system for studying the development and function of the nervous system, particularly because of its convenient genetics and fully sequenced genome. Additionally, the larval nervous system is an ideal model system to study mechanisms of axonal transport as the larval segmental nerves contain bundles of axons with their cell bodies located within the brain and their nerve terminals ending along the length of the body. Here we describe the procedure for visualization of synaptic vesicle proteins within larval segmental nerves. If done correctly, all components of the nervous system, along with associated tissues such as muscles and NMJs, remain intact, undamaged, and ready to be visualized. 3(rd) instar larvae carrying various mutations are dissected, fixed, incubated with synaptic vesicle antibodies, visualized and compared to wild type larvae. This procedure can be adapted for several different synaptic or neuronal antibodies and changes in the distribution of a variety of proteins can be easily observed within larval segmental nerves. PMID- 20972401 TI - Transnuclear mice with pre-defined T cell receptor specificities against Toxoplasma gondii obtained via SCNT. AB - Lymphocytes, such as T cells, undergo genetic V(D)J recombination, to generate a receptor with a certain specificity. Mice transgenic for a rearranged antigen specific T cell receptor (TCR) have been an indispensable tool to study T cell development and function. However, such TCRs are usually isolated from the relevant T cells after long-term culture often following repeated antigen stimulation, which unavoidably selects for T cells with high affinity. Random genomic integration of the TCR alpha- and beta-chain and expression from non endogenous promoters can lead to variations in expression level and kinetics. Epigenetic reprogramming via somatic cell nuclear transfer provides a tool to generate embryonic stem cells and mice from any cell of interest. Consequently, when SCNT is applied to T cells of known specificity, these genetic V(D)J rearrangements are transferred to the SCNT-embryonic stem cells (ESCs) and the mice derived from them, while epigenetic marks are reset. We have demonstrated that T cells with pre-defined specificities against Toxoplasma gondii can be used to generate mouse models that express the specific TCR from their endogenous loci, without experimentally introduced genetic modification. The relative ease and speed with which such transnuclear models can be obtained holds promise for the construction of other disease models. PMID- 20972402 TI - Mutagenesis and functional analysis of ion channels heterologously expressed in mammalian cells. AB - We will demonstrate how to study the functional effects of introducing a point mutation in an ion channel. We study G protein-gated inwardly rectifying potassium (referred to as GIRK) channels, which are important for regulating the excitability of neurons. There are four different mammalian GIRK channel subunits (GIRK1-GIRK4)--we focus on GIRK2 because it forms a homotetramer. Stimulation of different types of G protein-coupled receptors (GPCRs), such as the muscarinic receptor (M2R), leads to activation of GIRK channels. Alcohol also directly activates GIRK channels. We will show how to mutate one amino acid by specifically changing one or more nucleotides in the cDNA for the GIRK channel. This mutated cDNA sequence will be amplified in bacteria, purified, and the presence of the point mutation will be confirmed by DNA sequencing. The cDNAs for the mutated and wild-type GIRK channels will be transfected into human embryonic kidney HEK293T cells cultured in vitro. Lastly, whole-cell patch-clamp electrophysiology will be used to study the macroscopic potassium currents through the ectopically expressed wild-type or mutated GIRK channels. In this experiment, we will examine the effect of a L257W mutation in GIRK2 channels on M2R-dependent and alcohol-dependent activation. PMID- 20972403 TI - Assessing stomatal response to live bacterial cells using whole leaf imaging. AB - Stomata are natural openings in the plant epidermis responsible for gas exchange between plant interior and environment. They are formed by a pair of guard cells, which are able to close the stomatal pore in response to a number of external factors including light intensity, carbon dioxide concentration, and relative humidity (RH). The stomatal pore is also the main route for pathogen entry into leaves, a crucial step for disease development. Recent studies have unveiled that closure of the pore is effective in minimizing bacterial disease development in Arabidopsis plants; an integral part of plant innate immunity. Previously, we have used epidermal peels to assess stomatal response to live bacteria (Melotto et al. 2006); however maintaining favorable environmental conditions for both plant epidermal peels and bacterial cells has been challenging. Leaf epidermis can be kept alive and healthy with MES buffer (10 mM KCl, 25 mM MES-KOH, pH 6.15) for electrophysiological experiments of guard cells. However, this buffer is not appropriate for obtaining bacterial suspension. On the other hand, bacterial cells can be kept alive in water which is not proper to maintain epidermal peels for long period of times. When an epidermal peel floats on water, the cells in the peel that are exposed to air dry within 4 hours limiting the timing to conduct the experiment. An ideal method for assessing the effect of a particular stimulus on guard cells should present minimal interference to stomatal physiology and to the natural environment of the plant as much as possible. We, therefore, developed a new method to assess stomatal response to live bacteria in which leaf wounding and manipulation is greatly minimized aiming to provide an easily reproducible and reliable stomatal assay. The protocol is based on staining of intact leaf with propidium iodide (PI), incubation of staining leaf with bacterial suspension, and observation of leaves under laser scanning confocal microscope. Finally, this method allows for the observation of the same live leaf sample over extended periods of time using conditions that closely mimic the natural conditions under which plants are attacked by pathogens. PMID- 20972404 TI - Intracranial orthotopic allografting of medulloblastoma cells in immunocompromised mice. AB - Medulloblastoma is the most common pediatric tumor of the nervous system. A large body of animal studies has focused on cerebellar granule neuron precursors (CGNPs) as the cell-of-origin for medulloblastoma. However, the diverse clinical presentations of medulloblastoma subtypes in human patients (nodular, desmoplastic, classical and large cell/anaplastic), and the fact that medulloblastoma is found in a subset of human patients with no ectopic expression of CGNP marker, suggest that the cellular and molecular origins of medulloblastoma are more complex and far from being completely deciphered. Therefore, it is essential to determine whether there is an alternative medulloblastoma tumor cell-of-origin based on which cell-type specific therapeutic modality can be developed. To this end, intracranial orthotopic allografting of genetically marked tumor cell types followed by subsequent analyses of secondary tumor development in recipients will allow determination of the cellular origin of tumor-initiating cells. Here we describe the experimental protocol for intracranial orthotopic allografting of medulloblastoma cells derived from primary tumor tissue, and this procedure can also be used for transplanting cells from established cell lines. PMID- 20972405 TI - Live cell response to mechanical stimulation studied by integrated optical and atomic force microscopy. AB - To understand the mechanism by which living cells sense mechanical forces, and how they respond and adapt to their environment, a new technology able to investigate cells behavior at sub-cellular level with high spatial and temporal resolution was developed. Thus, an atomic force microscope (AFM) was integrated with total internal reflection fluorescence (TIRF) microscopy and fast-spinning disk (FSD) confocal microscopy. The integrated system is broadly applicable across a wide range of molecular dynamic studies in any adherent live cells, allowing direct optical imaging of cell responses to mechanical stimulation in real-time. Significant rearrangement of the actin filaments and focal adhesions was shown due to local mechanical stimulation at the apical cell surface that induced changes into the cellular structure throughout the cell body. These innovative techniques will provide new information for understanding live cell restructuring and dynamics in response to mechanical force. A detailed protocol and a representative data set that show live cell response to mechanical stimulation are presented. PMID- 20972406 TI - Establishing primary adult fibroblast cultures from rodents. AB - The importance of using primary cells, rather than cancer cell lines, for biological studies is becoming widely recognized. Primary cells are preferred in studies of cell cycle control, apoptosis, and DNA repair, as cancer cells carry mutations in genes involved in these processes. Primary cells cannot be cultured indefinitely due to the onset of replicative senescence or aneuploidization. Hence, new cultures need to be established regularly. The procedure for isolation of rodent embryonic fibroblasts is well established, but isolating adult fibroblast cultures often presents a challenge. Adult rodent fibroblasts isolated from mouse models of human disease may be a preferred control when comparing them to fibroblasts from human patients. Furthermore, adult fibroblasts are the only available material when working with wild rodents where pregnant females cannot be easily obtained. Here we provide a protocol for isolation and culture of adult fibroblasts from rodent skin and lungs. We used this procedure successfully to isolate fibroblasts from over twenty rodent species from laboratory mice and rats to wild rodents such as beaver, porcupine, and squirrel. PMID- 20972407 TI - Co-culture models of Pseudomonas aeruginosa biofilms grown on live human airway cells. AB - Bacterial biofilms have been associated with a number of different human diseases, but biofilm development has generally been studied on non-living surfaces. In this paper, we describe protocols for forming Pseudomonas aeruginosa biofilms on human airway epithelial cells (CFBE cells) grown in culture. In the first method (termed the Static Co-culture Biofilm Model), P. aeruginosa is incubated with CFBE cells grown as confluent monolayers on standard tissue culture plates. Although the bacterium is quite toxic to epithelial cells, the addition of arginine delays the destruction of the monolayer long enough for biofilms to form on the CFBE cells. The second method (termed the Flow Cell Co culture Biofilm Model), involves adaptation of a biofilm flow cell apparatus, which is often used in biofilm research, to accommodate a glass coverslip supporting a confluent monolayer of CFBE cells. This monolayer is inoculated with P. aeruginosa and a peristaltic pump then flows fresh medium across the cells. In both systems, bacterial biofilms form within 6-8 hours after inoculation. Visualization of the biofilm is enhanced by the use of P. aeruginosa strains constitutively expressing green fluorescent protein (GFP). The Static and Flow Cell Co-culture Biofilm assays are model systems for early P. aeruginosa infection of the Cystic Fibrosis (CF) lung, and these techniques allow different aspects of P. aeruginosa biofilm formation and virulence to be studied, including biofilm cytotoxicity, measurement of biofilm CFU, and staining and visualizing the biofilm. PMID- 20972408 TI - Visualizing cell-to-cell transfer of HIV using fluorescent clones of HIV and live confocal microscopy. AB - By fusing the green fluorescent protein to their favorite proteins, biologists now have the ability to study living complex cellular processes using fluorescence video microscopy. To track the movements of the human immunodeficiency virus core protein during cell-to-cell transmission of human immunodeficiency virus, we have GFP-tagged the Gag protein in the context of an infectious molecular clone of HIV, called HIV Gag-iGFP. We study this viral clone using video confocal microscopy. In the following visualized experiment, we transfect a human T cell line with HIV Gag-iGFP, and we use fluorescently labeled uninfected CD4+ T cells to serve as target cells for the virus. Using the different fluorescent labels we can readily follow viral production and transport across intercellular structures called virological synapses. Simple gas permeable imaging chambers allow us to observe synapses with live confocal microscopy from minutes to days. These approaches can be used to track viral proteins as they move in from one cell to the next. PMID- 20972409 TI - In utero electroporation followed by primary neuronal culture for studying gene function in subset of cortical neurons. AB - In vitro study of primary neuronal cultures allows for quantitative analyses of neurite outgrowth. In order to study how genetic alterations affect neuronal process outgrowth, shRNA or cDNA constructs can be introduced into primary neurons via chemical transfection or viral transduction. However, with primary cortical cells, a heterogeneous pool of cell types (glutamatergic neurons from different layers, inhibitory neurons, glial cells) are transfected using these methods. The use of in utero electroporation to introduce DNA constructs in the embryonic rodent cortex allows for certain subsets of cells to be targeted: while electroporation of early embryonic cortex targets deep layers of the cortex, electroporation at late embryonic timepoints targets more superficial layers. Further, differential placement of electrodes across the heads of individual embryos results in the targeting of dorsal-medial versus ventral-lateral regions of the cortex. Following electroporation, transfected cells can be dissected out, dissociated, and plated in vitro for quantitative analysis of neurite outgrowth. Here, we provide a step-by-step method to quantitatively measure neuronal process outgrowth in subsets of cortical cells. The basic protocol for in utero electroporation has been described in detail in two other JoVE articles from the Kriegstein lab. We will provide an overview of our protocol for in utero electroporation, focusing on the most important details, followed by a description of our protocol that applies in utero electroporation to the study of gene function in neuronal process outgrowth. PMID- 20972410 TI - Assaying beta-amyloid toxicity using a transgenic C. elegans model. AB - Accumulation of the beta-amyloid peptide (Abeta) is generally believed to be central to the induction of Alzheimer's disease, but the relevant mechanism(s) of toxicity are still unclear. Abeta is also deposited intramuscularly in Inclusion Body Myositis, a severe human myopathy. The intensely studied nematode worm Caenorhabditis elegans can be transgenically engineered to express human Abeta. Depending on the tissue or timing of Abeta expression, transgenic worms can have readily measurable phenotypes that serve as a read-out of Abeta toxicity. For example, transgenic worms with pan-neuronal Abeta expression have defects is associative learning (Dosanjh et al. 2009), while transgenic worms with constitutive muscle-specific expression show a progressive, age-dependent paralysis phenotype (Link, 1995; Cohen et al. 2006). One particularly useful C. elegans model employs a temperature-sensitive mutation in the mRNA surveillance system to engineer temperature-inducible muscle expression of an Abeta transgene, resulting in a reproducible paralysis phenotype upon temperature upshift (Link et al. 2003). Treatments that counter Abeta toxicity in this model [e.g., expression of a protective transgene (Hassan et al. 2009) or exposure to Ginkgo biloba extracts (Wu et al. 2006)] reproducibly alter the rate of paralysis induced by temperature upshift of these transgenic worms. Here we describe our protocol for measuring the rate of paralysis in this transgenic C. elegans model, with particular attention to experimental variables that can influence this measurement. PMID- 20972411 TI - Imaging protein-protein interactions in vivo. AB - Protein-protein interactions are a hallmark of all essential cellular processes. However, many of these interactions are transient, or energetically weak, preventing their identification and analysis through traditional biochemical methods such as co-immunoprecipitation. In this regard, the genetically encodable fluorescent proteins (GFP, RFP, etc.) and their associated overlapping fluorescence spectrum have revolutionized our ability to monitor weak interactions in vivo using Forster resonance energy transfer (FRET). Here, we detail our use of a FRET-based proximity assay for monitoring receptor-receptor interactions on the endothelial cell surface. PMID- 20972412 TI - Making sense of listening: the IMAP test battery. AB - The ability to hear is only the first step towards making sense of the range of information contained in an auditory signal. Of equal importance are the abilities to extract and use the information encoded in the auditory signal. We refer to these as listening skills (or auditory processing AP). Deficits in these skills are associated with delayed language and literacy development, though the nature of the relevant deficits and their causal connection with these delays is hotly debated. When a child is referred to a health professional with normal hearing and unexplained difficulties in listening, or associated delays in language or literacy development, they should ideally be assessed with a combination of psychoacoustic (AP) tests, suitable for children and for use in a clinic, together with cognitive tests to measure attention, working memory, IQ, and language skills. Such a detailed examination needs to be relatively short and within the technical capability of any suitably qualified professional. Current tests for the presence of AP deficits tend to be poorly constructed and inadequately validated within the normal population. They have little or no reference to the presenting symptoms of the child, and typically include a linguistic component. Poor performance may thus reflect problems with language rather than with AP. To assist in the assessment of children with listening difficulties, pediatric audiologists need a single, standardized child appropriate test battery based on the use of language-free stimuli. We present the IMAP test battery which was developed at the MRC Institute of Hearing Research to supplement tests currently used to investigate cases of suspected AP deficits. IMAP assesses a range of relevant auditory and cognitive skills and takes about one hour to complete. It has been standardized in 1500 normally hearing children from across the UK, aged 6-11 years. Since its development, it has been successfully used in a number of large scale studies both in the UK and the USA. IMAP provides measures for separating out sensory from cognitive contributions to hearing. It further limits confounds due to procedural effects by presenting tests in a child-friendly game-format. Stimulus-generation, management of test protocols and control of test presentation is mediated by the IHR-STAR software platform. This provides a standardized methodology for a range of applications and ensures replicable procedures across testers. IHR-STAR provides a flexible, user-programmable environment that currently has additional applications for hearing screening, mapping cochlear implant electrodes, and academic research or teaching. PMID- 20972413 TI - The use of carboxyfluorescein diacetate succinimidyl ester (CFSE) to monitor lymphocyte proliferation. AB - Carboxyfluorescein succinimidyl ester (CFSE) is an effective and popular means to monitor lymphocyte division. CFSE covalently labels long-lived intracellular molecules with the fluorescent dye, carboxyfluorescein. Thus, when a CFSE-labeled cell divides, its progeny are endowed with half the number of carboxyfluorescein tagged molecules and thus each cell division can be assessed by measuring the corresponding decrease in cell fluorescence via Flow cytometry. The capacity of CFSE to label lymphocyte populations with a high fluorescent intensity of exceptionally low variance, coupled with its low cell toxicity, make it an ideal dye to measure cell division. Since it is a fluorescein-based dye it is also compatible with a broad range of other fluorochromes making it applicable to multi-color flow cytometry. This article describes the procedures typically used for labeling mouse lymphocytes for the purpose of monitoring up to 8 cell divisions. These labeled cells can be used both for in vitro and in vivo studies. PMID- 20972414 TI - Gramicidin-based fluorescence assay; for determining small molecules potential for modifying lipid bilayer properties. AB - Many drugs and other small molecules used to modulate biological function are amphiphiles that adsorb at the bilayer/solution interface and thereby alter lipid bilayer properties. This is important because membrane proteins are energetically coupled to their host bilayer by hydrophobic interactions. Changes in bilayer properties thus alter membrane protein function, which provides an indirect way for amphiphiles to modulate protein function and a possible mechanism for "off target" drug effects. We have previously developed an electrophysiological assay for detecting changes in lipid bilayer properties using linear gramicidin channels as probes. Gramicidin channels are mini-proteins formed by the transbilayer dimerization of two non-conducting subunits. They are sensitive to changes in their membrane environment, which makes them powerful probes for monitoring changes in lipid bilayer properties as sensed by bilayer spanning proteins. We now demonstrate a fluorescence assay for detecting changes in bilayer properties using the same channels as probes. The assay is based on measuring the time-course of fluorescence quenching from fluorophore-loaded large unilamellar vesicles due to the entry of a quencher through the gramicidin channels. We use the fluorescence indicator/quencher pair 8-aminonaphthalene 1,3,6-trisulfonate (ANTS)/Tl(+) that has been successfully used in other fluorescence quenching assays. Tl(+) permeates the lipid bilayer slowly but passes readily through conducting gramicidin channels. The method is scalable and suitable for both mechanistic studies and high-throughput screening of small molecules for bilayer-perturbing, and potential "off-target", effects. We find that results using this method are in good agreement with previous electrophysiological results. PMID- 20972415 TI - Design and construction of a cost effective headstage for simultaneous neural stimulation and recording in the water maze. AB - Headstage preamplifiers and source followers are commonly used to study neural activity in behavioral neurophysiology experiments. Available commercial products are often expensive, not easily customized, and not submersible. Here we describe a method to design and build a customized, integrated circuit headstage for simultaneous 4-channel neural recording and 2-channel simulation in awake, behaving animals. The headstage is designed using a free, commercially available CAD-type design package, and can be modified easily to accommodate different scales (e.g. to add channels). A customized printed circuit board is built using surface mount resistors, capacitors and operational amplifiers to construct the unity gain source follower circuit. The headstage is made water-proof with a combination of epoxy, parafilm and a synthetic rubber putty. We have successfully used this device to record local field potentials and stimulate different brain regions simultaneously via independent channels in rats swimming in a water maze. The total cost is < $30/unit and can be manufactured readily. PMID- 20972416 TI - In vivo visualization of synaptic vesicles within Drosophila larval segmental axons. AB - Elucidating the mechanisms of axonal transport has shown to be very important in determining how defects in long distance transport affect different neurological diseases. Defects in this essential process can have detrimental effects on neuronal functioning and development. We have developed a dissection protocol that is designed to expose the Drosophila larval segmental nerves to view axonal transport in real time. We have adapted this protocol for live imaging from the one published by Hurd and Saxton (1996) used for immunolocalization of larval segmental nerves. Careful dissection and proper buffer conditions are critical for maximizing the lifespan of the dissected larvae. When properly done, dissected larvae have shown robust vesicle transport for 2-3 hours under physiological conditions. We use the UAS-GAL4 method to express GFP-tagged APP or synaptotagmin vesicles within a single axon or many axons in larval segmental nerves by using different neuronal GAL4 drivers. Other fluorescently tagged markers, for example mitochondria (MitoTracker) or lysosomes (LysoTracker), can be also applied to the larvae before viewing. GFP-vesicle movement and particle movement can be viewed simultaneously using separate wavelengths. PMID- 20972417 TI - Assessing endothelial vasodilator function with the Endo-PAT 2000. AB - The endothelium is a delicate monolayer of cells that lines all blood vessels, and which comprises the systemic and lymphatic capillaries. By virtue of the panoply of paracrine factors that it secretes, the endothelium regulates the contractile and proliferative state of the underlying vascular smooth muscle, as well as the interaction of the vessel wall with circulating blood elements. Because of its central role in mediating vessel tone and growth, its position as gateway to circulating immune cells, and its local regulation of hemostasis and coagulation, the the properly functioning endothelium is the key to cardiovascular health. Conversely, the earliest disorder in most vascular diseases is endothelial dysfunction. In the arterial circulation, the healthy endothelium generally exerts a vasodilator influence on the vascular smooth muscle. There are a number of methods to assess endothelial vasodilator function. The Endo-PAT 2000 is a new device that is used to assess endothelial vasodilator function in a rapid and non-invasive fashion. Unlike the commonly used technique of duplex ultra-sonography to assess flow-mediated vasodilation, it is totally non-operator-dependent, and the equipment is an order of magnitude less expensive. The device records endothelium-mediated changes in the digital pulse waveform known as the PAT (peripheral Arterial Tone) signal, measured with a pair of novel modified plethysmographic probes situated on the finger index of each hand. Endothelium-mediated changes in the PAT signal are elicited by creating a downstream hyperemic response. Hyperemia is induced by occluding blood flow through the brachial artery for 5 minutes using an inflatable cuff on one hand. The response to reactive hyperemia is calculated automatically by the system. A PAT ratio is created using the post and pre occlusion values. These values are normalized to measurements from the contra-lateral arm, which serves as control for non-endothelial dependent systemic effects. Most notably, this normalization controls for fluctuations in sympathetic nerve outflow that may induce changes in peripheral arterial tone that are superimposed on the hyperemic response. In this video we demonstrate how to use the Endo-PAT 2000 to perform a clinically relevant assessment of endothelial vasodilator function. PMID- 20972418 TI - Changes in mammary gland morphology and breast cancer risk in rats. AB - Studies in rodent models of breast cancer show that exposures to dietary/hormonal factors during the in utero and pubertal periods, when the mammary gland undergoes extensive modeling and re-modeling, alter susceptibility to carcinogen induced mammary tumors. Similar findings have been described in humans: for example, high birthweight increases later risk of developing breast cancer, and dietary intake of soy during childhood decreases breast cancer risk. It is thought that these prenatal and postnatal dietary modifications induce persistent morphological changes in the mammary gland that in turn modify breast cancer risk later in life. These morphological changes likely reflect epigenetic modifications, such as changes in DNA methylation, histones and miRNA expression that then affect gene transcription. In this article we describe how changes in mammary gland morphology can predict mammary cancer risk in rats. Our protocol specifically describes how to dissect and remove the rat abdominal mammary gland and how to prepare mammary gland whole mounts. It also describes how to analyze mammary gland morphology according to three end-points (number of terminal end buds, epithelial elongation and differentiation) and to use the data to predict risk of developing mammary cancer. PMID- 20972419 TI - Structure and mechanism of the S component of a bacterial ECF transporter. AB - The energy-coupling factor (ECF) transporters, responsible for vitamin uptake in prokaryotes, are a unique family of membrane transporters. Each ECF transporter contains a membrane-embedded, substrate-binding protein (known as the S component), an energy-coupling module that comprises two ATP-binding proteins (known as the A and A' components) and a transmembrane protein (known as the T component). The structure and transport mechanism of the ECF family remain unknown. Here we report the crystal structure of RibU, the S component of the ECF type riboflavin transporter from Staphylococcus aureus at 3.6-A resolution. RibU contains six transmembrane segments, adopts a previously unreported transporter fold and contains a riboflavin molecule bound to the L1 loop and the periplasmic portion of transmembrane segments 4-6. Structural analysis reveals the essential ligand-binding residues, identifies the putative transport path and, with sequence alignment, uncovers conserved structural features and suggests potential mechanisms of action among the ECF transporters. PMID- 20972420 TI - Support for a synaptic chain model of neuronal sequence generation. AB - In songbirds, the remarkable temporal precision of song is generated by a sparse sequence of bursts in the premotor nucleus HVC. To distinguish between two possible classes of models of neural sequence generation, we carried out intracellular recordings of HVC neurons in singing zebra finches (Taeniopygia guttata). We found that the subthreshold membrane potential is characterized by a large, rapid depolarization 5-10 ms before burst onset, consistent with a synaptically connected chain of neurons in HVC. We found no evidence for the slow membrane potential modulation predicted by models in which burst timing is controlled by subthreshold dynamics. Furthermore, bursts ride on an underlying depolarization of ~10-ms duration, probably the result of a regenerative calcium spike within HVC neurons that could facilitate the propagation of activity through a chain network with high temporal precision. Our results provide insight into the fundamental mechanisms by which neural circuits can generate complex sequential behaviours. PMID- 20972421 TI - Spatially addressed combinatorial protein libraries for recombinant antibody discovery and optimization. AB - Antibody discovery typically uses hybridoma- or display-based selection approaches, which lack the advantages of directly screening spatially addressed compound libraries as in small-molecule discovery. Here we apply the latter strategy to antibody discovery, using a library of ~10,000 human germline antibody Fabs created by de novo DNA synthesis and automated protein expression and purification. In multiplexed screening assays, we obtained specific hits against seven of nine antigens. Using sequence-activity relationships and iterative mutagenesis, we optimized the binding affinities of two hits to the low nanomolar range. The matured Fabs showed full and partial antagonism activities in cell-based assays. Thus, protein drug leads can be discovered using surprisingly small libraries of proteins with known sequences, questioning the requirement for billions of members in an antibody discovery library. This methodology also provides sequence, expression and specificity information at the first step of the discovery process, and could enable novel antibody discovery in functional screens. PMID- 20972422 TI - Cultured cambial meristematic cells as a source of plant natural products. AB - A plethora of important, chemically diverse natural products are derived from plants. In principle, plant cell culture offers an attractive option for producing many of these compounds. However, it is often not commercially viable because of difficulties associated with culturing dedifferentiated plant cells (DDCs) on an industrial scale. To bypass the dedifferentiation step, we isolated and cultured innately undifferentiated cambial meristematic cells (CMCs). Using a combination of deep sequencing technologies, we identified marker genes and transcriptional programs consistent with a stem cell identity. This notion was further supported by the morphology of CMCs, their hypersensitivity to gamma irradiation and radiomimetic drugs and their ability to differentiate at high frequency. Suspension culture of CMCs derived from Taxus cuspidata, the source of the key anticancer drug, paclitaxel (Taxol), circumvented obstacles routinely associated with the commercial growth of DDCs. These cells may provide a cost effective and environmentally friendly platform for sustainable production of a variety of important plant natural products. PMID- 20972423 TI - Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. AB - Endothelial cells establish an instructive vascular niche that reconstitutes haematopoietic stem and progenitor cells (HSPCs) through release of specific paracrine growth factors, known as angiocrine factors. However, the mechanism by which endothelial cells balance the rate of proliferation and lineage-specific differentiation of HSPCs is unknown. Here, we demonstrate that Akt activation in endothelial cells, through recruitment of mTOR, but not the FoxO pathway, upregulates specific angiocrine factors that support expansion of CD34(-)Flt3(-) KLS HSPCs with long-term haematopoietic stem cell (LT-HSC) repopulation capacity. Conversely, co-activation of Akt-stimulated endothelial cells with p42/44 MAPK shifts the balance towards maintenance and differentiation of the HSPCs. Selective activation of Akt1 in the endothelial cells of adult mice increased the number of colony forming units in the spleen and CD34(-)Flt3(-) KLS HSPCs with LT HSC activity in the bone marrow, accelerating haematopoietic recovery. Therefore, the activation state of endothelial cells modulates reconstitution of HSPCs through the modulation of angiocrine factors, with Akt-mTOR-activated endothelial cells supporting the self-renewal of LT-HSCs and expansion of HSPCs, whereas MAPK co-activation favours maintenance and lineage-specific differentiation of HSPCs. PMID- 20972424 TI - Primary cilia regulate mTORC1 activity and cell size through Lkb1. AB - The mTOR pathway is the central regulator of cell size. External signals from growth factors and nutrients converge on the mTORC1 multi-protein complex to modulate downstream targets, but how the different inputs are integrated and translated into specific cellular responses is incompletely understood. Deregulation of the mTOR pathway occurs in polycystic kidney disease (PKD), where cilia (filiform sensory organelles) fail to sense urine flow because of inherited mutations in ciliary proteins. We therefore investigated if cilia have a role in mTOR regulation. Here, we show that ablation of cilia in transgenic mice results in enlarged cells when compared with control animals. In vitro analysis demonstrated that bending of the cilia by flow is required for mTOR downregulation and cell-size control. Surprisingly, regulation of cell size by cilia is independent of flow-induced calcium transients, or Akt. However, the tumour-suppressor protein Lkb1 localises in the cilium, and flow results in increased AMPK phosphorylation at the basal body. Conversely, knockdown of Lkb1 prevents normal cell-size regulation under flow conditions. Our results demonstrate that the cilium regulates mTOR signalling and cell size, and identify the cilium-basal body compartment as a spatially restricted activation site for Lkb1 signalling. PMID- 20972425 TI - GAPDH mediates nitrosylation of nuclear proteins. AB - S-nitrosylation of proteins by nitric oxide is a major mode of signalling in cells. S-nitrosylation can mediate the regulation of a range of proteins, including prominent nuclear proteins, such as HDAC2 (ref. 2) and PARP1 (ref. 3). The high reactivity of the nitric oxide group with protein thiols, but the selective nature of nitrosylation within the cell, implies the existence of targeting mechanisms. Specificity of nitric oxide signalling is often achieved by the binding of nitric oxide synthase (NOS) to target proteins, either directly or through scaffolding proteins such as PSD-95 (ref. 5) and CAPON. As the three principal isoforms of NOS--neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS)--are primarily non-nuclear, the mechanisms by which nuclear proteins are selectively nitrosylated have been elusive. Glyceraldehyde-3 phosphate dehydrogenase (GAPDH) is physiologically nitrosylated at its Cys 150 residue. Nitrosylated GAPDH (SNO-GAPDH) binds to Siah1, which possesses a nuclear localization signal, and is transported to the nucleus. Here, we show that SNO GAPDH physiologically transnitrosylates nuclear proteins, including the deacetylating enzyme sirtuin-1 (SIRT1), histone deacetylase-2 (HDAC2) and DNA activated protein kinase (DNA-PK). Our findings reveal a novel mechanism for targeted nitrosylation of nuclear proteins and suggest that protein-protein transfer of nitric oxide groups may be a general mechanism in cellular signal transduction. PMID- 20972426 TI - Nascent nitrosylases. AB - Protein S-nitrosylation is thought to be mediated primarily by nitric oxide synthases. S-nitrosylated GAPDH is now shown to function within signal transduction cascades as a nuclear nitrosylase. Along with other recent demonstrations of regulated protein-protein transnitrosylation, these findings point to a new mechanism of signal transduction with transformative implications for nitric oxide biology and redox signalling. PMID- 20972427 TI - Rickettsia Sca2 is a bacterial formin-like mediator of actin-based motility. AB - Diverse intracellular pathogens subvert the host actin-polymerization machinery to drive movement within and between cells during infection. Rickettsia in the spotted fever group (SFG) are Gram-negative, obligate intracellular bacterial pathogens that undergo actin-based motility and assemble distinctive 'comet tails' that consist of long, unbranched actin filaments. Despite this distinct organization, it was proposed that actin in Rickettsia comet tails is nucleated by the host Arp2/3 complex and the bacterial protein RickA, which assemble branched actin networks. However, a second bacterial gene, sca2, was recently implicated in actin-tail formation by R. rickettsii. Here, we demonstrate that Sca2 is a bacterial actin-assembly factor that functionally mimics eukaryotic formin proteins. Sca2 nucleates unbranched actin filaments, processively associates with growing barbed ends, requires profilin for efficient elongation, and inhibits the activity of capping protein, all properties shared with formins. Sca2 localizes to the Rickettsia surface and is sufficient to promote the assembly of actin filaments in cytoplasmic extract. These results suggest that Sca2 mimics formins to determine the unique organization of actin filaments in Rickettsia tails and drive bacterial motility, independently of host nucleators. PMID- 20972428 TI - Direct observation and mapping of spin waves emitted by spin-torque nano oscillators. AB - Dynamics induced by spin-transfer torque is a quickly developing topic in modern magnetism, which has initiated several new approaches to magnetic nanodevices. It is now well established that a spin-polarized electric current injected into a ferromagnetic layer through a nanocontact exerts a torque on the magnetization, leading to microwave-frequency precession detectable through the magnetoresistance effect. This phenomenon provides a way for the realization of tunable nanometre-size microwave oscillators, the so-called spin-torque nano oscillators (STNOs). Present theories of STNOs are mainly based on pioneering works predicting emission of spin waves due to the spin torque. Despite intense experimental studies, until now this spin-wave emission has not been observed. Here, we report the first experimental observation and two-dimensional mapping of spin waves emitted by STNOs. We demonstrate that the emission is strongly directional, and the direction of the spin-wave propagation is steerable by the magnetic field. The information about the emitted spin waves obtained in our measurements is of key importance for the understanding of the physics of STNOs, and for the implementation of coupling between individual oscillators mediated by spin waves. Analysis shows that the observed directional emission is a general property inherent to any dynamical system with strongly anisotropic dispersion. PMID- 20972429 TI - The role of collagen in bone apatite formation in the presence of hydroxyapatite nucleation inhibitors. AB - Bone is a composite material in which collagen fibrils form a scaffold for a highly organized arrangement of uniaxially oriented apatite crystals. In the periodic 67 nm cross-striated pattern of the collagen fibril, the less dense 40 nm-long gap zone has been implicated as the place where apatite crystals nucleate from an amorphous phase, and subsequently grow. This process is believed to be directed by highly acidic non-collagenous proteins; however, the role of the collagen matrix during bone apatite mineralization remains unknown. Here, combining nanometre-scale resolution cryogenic transmission electron microscopy and cryogenic electron tomography with molecular modelling, we show that collagen functions in synergy with inhibitors of hydroxyapatite nucleation to actively control mineralization. The positive net charge close to the C-terminal end of the collagen molecules promotes the infiltration of the fibrils with amorphous calcium phosphate (ACP). Furthermore, the clusters of charged amino acids, both in gap and overlap regions, form nucleation sites controlling the conversion of ACP into a parallel array of oriented apatite crystals. We developed a model describing the mechanisms through which the structure, supramolecular assembly and charge distribution of collagen can control mineralization in the presence of inhibitors of hydroxyapatite nucleation. PMID- 20972430 TI - An acoustic rectifier. AB - The detection of acoustic signals is of relevance for a range of practical applications, for example in medical diagnostics. However, whereas rectification of electric current and other energy forms such as thermal flux has been demonstrated, acoustic rectification has not yet been achieved. Here, on the basis of the earlier theoretical proposal of an 'acoustic diode', we present the first experimental demonstration of a rectified energy flux of acoustic waves. A one-dimensional acoustic rectifier is fabricated by coupling a superlattice with a layer of ultrasound contrast agent microbubble suspension. A significant rectifying effect is observed within two frequency bands at locations that agree well with theoretical predictions. Following optimization of the concentration of the microbubble suspension, rectifying ratios can be as high as ~10(4). This realization of an acoustic rectifier should have substantial practical significance, for example in the focusing of ultrasound in medical applications. PMID- 20972431 TI - Microscopic rotary mechanism of ion translocation in the F(o) complex of ATP synthases. AB - The microscopic mechanism of coupled c-ring rotation and ion translocation in F(1)F(o)-ATP synthases is unknown. Here we present conclusive evidence supporting the notion that the ability of c-rings to rotate within the F(o) complex derives from the interplay between the ion-binding sites and their nonhomogenous microenvironment. This evidence rests on three atomic structures of the c(15) rotor from crystals grown at low pH, soaked at high pH and, after N,N' dicyclohexylcarbodiimide (DCCD) modification, resolved at 1.8, 3.0 and 2.2 A, respectively. Alongside a quantitative DCCD-labeling assay and free-energy molecular dynamics calculations, these data demonstrate how the thermodynamic stability of the so-called proton-locked state is maximized by the lipid membrane. By contrast, a hydrophilic environment at the a-subunit-c-ring interface appears to unlock the binding-site conformation and promotes proton exchange with the surrounding solution. Rotation thus occurs as c-subunits stochastically alternate between these environments, directionally biased by the electrochemical transmembrane gradient. PMID- 20972432 TI - Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen specific memory of haptens and viruses. AB - Hepatic natural killer (NK) cells mediate antigen-specific contact hypersensitivity (CHS) in mice deficient in T cells and B cells. We report here that hepatic NK cells, but not splenic or naive NK cells, also developed specific memory of vaccines containing antigens from influenza, vesicular stomatitis virus (VSV) or human immunodeficiency virus type 1 (HIV-1). Adoptive transfer of virus sensitized NK cells into naive recipient mice enhanced the survival of the mice after lethal challenge with the sensitizing virus but not after lethal challenge with a different virus. NK cell memory of haptens and viruses depended on CXCR6, a chemokine receptor on hepatic NK cells that was required for the persistence of memory NK cells but not for antigen recognition. Thus, hepatic NK cells can develop adaptive immunity to structurally diverse antigens, an activity that requires NK cell-expressed CXCR6. PMID- 20972433 TI - The TLX1 oncogene drives aneuploidy in T cell transformation. AB - The TLX1 oncogene (encoding the transcription factor T cell leukemia homeobox protein-1) has a major role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T cell transformation downstream of TLX1 remain to be elucidated. Here we show that transgenic expression of human TLX1 in mice induces T-ALL with frequent deletions and mutations in Bcl11b (encoding B cell leukemia/lymphoma-11B) and identify the presence of recurrent mutations and deletions in BCL11B in 16% of human T-ALLs. Most notably, mouse TLX1 tumors were typically aneuploid and showed a marked defect in the activation of the mitotic checkpoint. Mechanistically, TLX1 directly downregulates the expression of CHEK1 (encoding CHK1 checkpoint homolog) and additional mitotic control genes and induces loss of the mitotic checkpoint in nontransformed preleukemic thymocytes. These results identify a previously unrecognized mechanism contributing to chromosomal missegregation and aneuploidy active at the earliest stages of tumor development in the pathogenesis of cancer. PMID- 20972434 TI - Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. AB - Bitter taste receptors (TAS2Rs) on the tongue probably evolved to evoke signals for avoiding ingestion of plant toxins. We found expression of TAS2Rs on human airway smooth muscle (ASM) and considered these to be avoidance receptors for inhalants that, when activated, lead to ASM contraction and bronchospasm. TAS2R agonists such as saccharin, chloroquine and denatonium evoked increased intracellular calcium ([Ca2(+)](i)) in ASM in a Gbetagamma-, phospholipase Cbeta (PLCbeta)- and inositol trisphosphate (IP3) receptor-dependent manner, which would be expected to evoke contraction. Paradoxically, bitter tastants caused relaxation of isolated ASM and dilation of airways that was threefold greater than that elicited by beta-adrenergic receptor agonists. The relaxation induced by TAS2Rs is associated with a localized [Ca2(+)](i) response at the cell membrane, which opens large-conductance Ca2(+)-activated K(+) (BK(Ca)) channels, leading to ASM membrane hyperpolarization. Inhaled bitter tastants decreased airway obstruction in a mouse model of asthma. Given the need for efficacious bronchodilators for treating obstructive lung diseases, this pathway can be exploited for therapy with the thousands of known synthetic and naturally occurring bitter tastants. PMID- 20972435 TI - Geometrical confinement of gadolinium-based contrast agents in nanoporous particles enhances T1 contrast. AB - Magnetic resonance imaging contrast agents are currently designed by modifying their structural and physiochemical properties to improve relaxivity and to enhance image contrast. Here, we show a general method for increasing relaxivity by confining contrast agents inside the nanoporous structure of silicon particles. Magnevist, gadofullerenes and gadonanotubes were loaded inside the pores of quasi-hemispherical and discoidal particles. For all combinations of nanoconstructs, a boost in longitudinal proton relaxivity r(1) was observed: Magnevist, r(1) ~ 14 mM(-1) s(-1)/Gd(3+) ion (~ 8.15 * 10(+7) mM(-1) s( 1)/construct); gadofullerenes, r(1) ~ 200 mM(-1) s(-1)/Gd(3+) ion (~ 7 * 10(+9) mM(-1) s(-1)/construct); gadonanotubes, r(1) ~ 150 mM(-1) s(-1)/Gd(3+) ion (~ 2 * 10(+9) mM(-1) s(-1)/construct). These relaxivity values are about 4 to 50 times larger than those of clinically available gadolinium-based agents (~ 4 mM(-1) s( 1)/Gd(3+) ion). The enhancement in contrast is attributed to the geometrical confinement of the agents, which influences the paramagnetic behaviour of the Gd(3+) ions. Thus, nanoscale confinement offers a new and general strategy for enhancing the contrast of gadolinium-based contrast agents. PMID- 20972436 TI - Training a molecular automaton to play a game. AB - Research at the interface between chemistry and cybernetics has led to reports of 'programmable molecules', but what does it mean to say 'we programmed a set of solution-phase molecules to do X'? A survey of recently implemented solution phase circuitry indicates that this statement could be replaced with 'we pre mixed a set of molecules to do X and functional subsets of X'. These hard-wired mixtures are then exposed to a set of molecular inputs, which can be interpreted as being keyed to human moves in a game, or as assertions of logical propositions. In nucleic acids-based systems, stemming from DNA computation, these inputs can be seen as generic oligonucleotides. Here, we report using reconfigurable nucleic acid catalyst-based units to build a multipurpose reprogrammable molecular automaton that goes beyond single-purpose 'hard-wired' molecular automata. The automaton covers all possible responses to two consecutive sets of four inputs (such as four first and four second moves for a generic set of trivial two-player two-move games). This is a model system for more general molecular field programmable gate array (FPGA)-like devices that can be programmed by example, which means that the operator need not have any knowledge of molecular computing methods. PMID- 20972437 TI - Rapid electronic detection of probe-specific microRNAs using thin nanopore sensors. AB - Small RNA molecules have an important role in gene regulation and RNA silencing therapy, but it is challenging to detect these molecules without the use of time consuming radioactive labelling assays or error-prone amplification methods. Here, we present a platform for the rapid electronic detection of probe hybridized microRNAs from cellular RNA. In this platform, a target microRNA is first hybridized to a probe. This probe:microRNA duplex is then enriched through binding to the viral protein p19. Finally, the abundance of the duplex is quantified using a nanopore. Reducing the thickness of the membrane containing the nanopore to 6 nm leads to increased signal amplitudes from biomolecules, and reducing the diameter of the nanopore to 3 nm allows the detection and discrimination of small nucleic acids based on differences in their physical dimensions. We demonstrate the potential of this approach by detecting picogram levels of a liver-specific miRNA from rat liver RNA. PMID- 20972438 TI - A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. AB - We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 * 10-12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 * 10-11) on 19q12 maps to CCNE1 and rs11892031 (P = 1 * 10-7) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 * 10-11) and a tag SNP for NAT2 acetylation status (P = 4 * 10-11), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis. PMID- 20972439 TI - Genome-wide association studies of 14 agronomic traits in rice landraces. AB - Uncovering the genetic basis of agronomic traits in crop landraces that have adapted to various agro-climatic conditions is important to world food security. Here we have identified ~ 3.6 million SNPs by sequencing 517 rice landraces and constructed a high-density haplotype map of the rice genome using a novel data imputation method. We performed genome-wide association studies (GWAS) for 14 agronomic traits in the population of Oryza sativa indica subspecies. The loci identified through GWAS explained ~ 36% of the phenotypic variance, on average. The peak signals at six loci were tied closely to previously identified genes. This study provides a fundamental resource for rice genetics research and breeding, and demonstrates that an approach integrating second-generation genome sequencing and GWAS can be used as a powerful complementary strategy to classical biparental cross-mapping for dissecting complex traits in rice. PMID- 20972440 TI - Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. AB - Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 * 10-10 and rs6687758, OR = 1.09, P = 2.27 * 10-9, 3q26.2 (rs10936599, OR = 0.93, P = 3.39 * 10-8), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 * 10-10 and rs7136702, OR = 1.06, P = 4.02 * 10-8) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 * 10-10). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered. PMID- 20972441 TI - Genome-wide patterns of genetic variation among elite maize inbred lines. AB - We have resequenced a group of six elite maize inbred lines, including the parents of the most productive commercial hybrid in China. This effort uncovered more than 1,000,000 SNPs, 30,000 indel polymorphisms and 101 low-sequence diversity chromosomal intervals in the maize genome. We also identified several hundred complete genes that show presence/absence variation among these resequenced lines. We discuss the potential roles of complementation of presence/absence variations and other deleterious mutations in contributing to heterosis. High-density SNP and indel polymorphism markers reported here are expected to be a valuable resource for future genetic studies and the molecular breeding of this important crop. PMID- 20972442 TI - Whole-genome sequencing and comprehensive variant analysis of a Japanese individual using massively parallel sequencing. AB - We report the analysis of a Japanese male using high-throughput sequencing to * 40 coverage. More than 99% of the sequence reads were mapped to the reference human genome. Using a Bayesian decision method, we identified 3,132,608 single nucleotide variations (SNVs). Comparison with six previously reported genomes revealed an excess of singleton nonsense and nonsynonymous SNVs, as well as singleton SNVs in conserved non-coding regions. We also identified 5,319 deletions smaller than 10 kb with high accuracy, in addition to copy number variations and rearrangements. De novo assembly of the unmapped sequence reads generated around 3 Mb of novel sequence, which showed high similarity to non reference human genomes and the human herpesvirus 4 genome. Our analysis suggests that considerable variation remains undiscovered in the human genome and that whole-genome sequencing is an invaluable tool for obtaining a complete understanding of human genetic variation. PMID- 20972443 TI - Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes. AB - Ligand-induced proteolysis of Notch produces an intracellular effector domain that transduces essential signals by regulating the transcription of target genes. This function relies on the formation of transcriptional activation complexes that include intracellular Notch, a Mastermind co-activator and the transcription factor CSL bound to cognate DNA. These complexes form higher-order assemblies on paired, head-to-head CSL recognition sites. Here we report the X ray structure of a dimeric human Notch1 transcription complex loaded on the paired site from the human HES1 promoter. The small interface between the Notch ankyrin domains could accommodate DNA bending and untwisting to allow a range of spacer lengths between the two sites. Cooperative dimerization occurred on the human and mouse Hes5 promoters at a sequence that diverged from the CSL-binding consensus at one of the sites. These studies reveal how promoter organizational features control cooperativity and, thus, the responsiveness of different promoters to Notch signaling. PMID- 20972444 TI - Analysis of replication profiles reveals key role of RFC-Ctf18 in yeast replication stress response. AB - Maintenance of genome integrity relies on surveillance mechanisms that detect and signal arrested replication forks. Although evidence from budding yeast indicates that the DNA replication checkpoint (DRC) is primarily activated by single stranded DNA (ssDNA), studies in higher eukaryotes have implicated primer ends in this process. To identify factors that signal primed ssDNA in Saccharomyces cerevisiae, we have screened a collection of checkpoint mutants for their ability to activate the DRC, using the repression of late origins as readout for checkpoint activity. This quantitative analysis reveals that neither RFC(Rad24) and the 9-1-1 clamp nor the alternative clamp loader RFC(Elg1) is required to signal paused forks. In contrast, we found that RFC(Ctf18) is essential for the Mrc1-dependent activation of Rad53 and for the maintenance of paused forks. These data identify RFC(Ctf18) as a key DRC mediator, potentially bridging Mrc1 and primed ssDNA to signal paused forks. PMID- 20972445 TI - Cotranscriptional exon skipping in the genotoxic stress response. AB - Pre-mRNA splicing is functionally coupled to transcription, and genotoxic stresses can enhance alternative exon inclusion by affecting elongating RNA polymerase II. We report here that various genotoxic stress inducers, including camptothecin (CPT), inhibit the interaction between Ewing's sarcoma proto oncoprotein (EWS), an RNA polymerase II-associated factor, and YB-1, a spliceosome-associated factor. This results in the cotranscriptional skipping of several exons of the MDM2 gene, which encodes the main p53 ubiquitin ligase. This reversible exon skipping participates in the regulation of MDM2 expression that may contribute to the accumulation of p53 during stress exposure and its rapid shut-off when stress is removed. Finally, a splicing-sensitive microarray identified numerous exons that are skipped in response to CPT and EWS-YB-1 depletion. These data demonstrate genotoxic stress-induced alteration of the communication between the transcriptional and splicing machineries, which results in widespread exon skipping and plays a central role in the genotoxic stress response. PMID- 20972446 TI - Molecular organization of the COG vesicle tethering complex. AB - Multisubunit tethering complexes of the CATCHR (complexes associated with tethering containing helical rods) family are proposed to mediate the initial contact between an intracellular trafficking vesicle and its membrane target. To begin elucidating the molecular architecture of one well-studied example, the conserved oligomeric Golgi (COG) complex, we reconstituted its essential subunits (Cog1, Cog2, Cog3 and Cog4) and used single-particle electron microscopy to reveal a y-shaped structure with three flexible, highly extended legs. Labeling experiments established that the N termini of all four subunits interact along the proximal segment of one leg, whereas three of the four C termini are located at the tips of the legs. Our results suggest that the central region of the Cog1 Cog2-Cog3-Cog4 complex, as well as the distal regions of at least two legs, all participate in interactions with other components of the intracellular trafficking machinery. PMID- 20972447 TI - Molecular architecture of the TRAPPII complex and implications for vesicle tethering. AB - Multisubunit tethering complexes participate in the process of vesicle tethering- the initial interaction between transport vesicles and their acceptor compartments. TRAPPII (named for transport protein particle II) is a highly conserved tethering complex that functions in the late Golgi apparatus and consists of all of the subunits of TRAPPI and three additional, specific subunits. We have purified native yeast TRAPPII and characterized its structure and subunit organization by single-particle EM. Our data show that the nine TRAPPII components form a core complex that dimerizes into a three-layered, diamond-shaped structure. The TRAPPI subunits assemble into TRAPPI complexes that form the outer layers. The three TRAPPII-specific subunits cap the ends of TRAPPI and form the middle layer, which is responsible for dimerization. TRAPPII binds the Ypt1 GTPase and probably uses the TRAPPI catalytic core to promote guanine nucleotide exchange. We discuss the implications of the structure of TRAPPII for coat interaction and TRAPPII-associated human pathologies. PMID- 20972449 TI - The 'omics revolution and our understanding of sperm cell biology. AB - The foundations of proteomics are to study gene products and their regulatory roles within cells. Paradoxically, the only evidence that sperm cells make new proteins is through mitochondrial protein synthesis. Yet despite this, spermatozoa are the perfect candidates for mass spectrometry and hence, proteomic analysis. These enterprising cells use a plethora of post-translational modifications in order to gain functionality following their production within the testis. By using a combination of two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), and more recently liquid chromatography-mass spectrometry (LC-MS)/MS, recent advances in sperm cell biology, through the use of proteomics, is making unparalleled progress. The protein inventory lists being generated have shed light on transmembrane proteins, kinases and chaperones never previously recognized. In addition, the ability to isolate either phosphopeptides or glycopeptides and quantify the differences between cells of two different populations make proteomic analysis of spermatozoa a real chance to finally answer some age old questions. PMID- 20972448 TI - NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1. AB - Classic nuclear export signals (NESs) confer CRM1-dependent nuclear export. Here we present crystal structures of the RanGTP-CRM1 complex alone and bound to the prototypic PKI or HIV-1 Rev NESs. These NESs differ markedly in the spacing of their key hydrophobic (Phi) residues, yet CRM1 recognizes them with the same rigid set of five Phi pockets. The different Phi spacings are compensated for by different conformations of the bound NESs: in the case of PKI, an alpha-helical conformation, and in the case of Rev, an extended conformation with a critical proline docking into a Phi pocket. NMR analyses of CRM1-bound and CRM1-free PKI NES suggest that CRM1 selects NES conformers that pre-exist in solution. Our data lead to a new structure-based NES consensus, and explain why NESs differ in their affinities for CRM1 and why supraphysiological NESs bind the exportin so tightly. PMID- 20972450 TI - The role of cysteine-rich secretory proteins in male fertility. AB - The cysteine-rich secretory proteins (CRISPs) are a subgroup of the CRISP, antigen 5 and Pr-1 (CAP) protein superfamily, and are found only in vertebrates. They show a strong expression bias to the mammalian male reproductive tract and the venom of poisonous reptiles. Within the male reproductive tract CRISPs have been implicated in many aspects of male germ cell biology spanning haploid germ cell development, epididymal maturation, capacitation, motility and the actual processes of fertilization. At a structural level, CRISPs are composed of two domains, a CAP domain, which has been implicated in cell-cell adhesion, and a CRISP domain, which has been shown to regulate several classes of ion channels across multiple species. Herein, we will review the current literature on the role of CRISPs in male fertility, and by inference to related non-mammalian protein, infer potential biochemical functions. PMID- 20972451 TI - The paternal epigenome and embryogenesis: poising mechanisms for development. AB - The scope of paternal contributions during early embryonic development has long been considered limited. Dramatic changes in chromatin structure throughout spermatogenesis have been thought to leave the sperm void of complex layers of epigenetic regulation over the DNA blueprint, thus leaving the balance of that regulation to the oocyte. However, recent work in the fields of epigenetics and male factor infertility has placed this long-held, and now controversial dogma, in a new light. Elegant studies investigating chromatin and epigenetic modifications in the developing sperm cell have provided new insights that may establish a more critical role for the paternal epigenome in the developing embryo. DNA methylation, histone tail modifications, targeted histone retention and protamine incorporation into the chromatin have great influence in the developing sperm cell. Perturbations in the establishment and/or maintenance of any of these epigenetic marks have been demonstrated to affect fertility status, ranging in severity from mild to catastrophic. Sperm require this myriad of chromatin structural changes not only to serve a protective role to DNA throughout spermatogenesis and future delivery to the egg, but also, it appears, to contribute to the developmental program of the future embryo. This review will focus on our current understanding of the epigenetics of sperm. We will discuss sperm-specific chromatin modifications that result in genes essential to development being poised for activation early in embryonic development, the disruption of which may result in reduced fecundity. PMID- 20972453 TI - The low frequency of clinical resistance to PDGFR inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be related to the limited repertoire of possible PDGFRA kinase domain mutations in vitro. AB - Myeloproliferation with prominent eosinophilia is associated with rearrangements of PDGFR-A or -B. The most common rearrangement is FIP1L1-PDGFRA (FP). The majority of patients with PDGFR-rearranged myeloproliferation respond to treatment with imatinib. In contrast to BCR-ABL-positive chronic myelogenous leukemia, only few cases of imatinib resistance and mutations of the FP kinase domain have been described so far. We hypothesized that the number of critical residues mediating imatinib resistance in FP in contrast to BCR-ABL might be limited. We performed an established systematic and comprehensive in vitro resistance screen to determine the pattern and frequency of possible TKI resistance mutations in FP. We identified 27 different FP kinase domain mutations including 25 novel variants, which attenuated response to imatinib, nilotinib or sorafenib. However, the majority of these exchanges did not confer complete inhibitor resistance. At clinically achievable drug concentrations, FP/T674I predominated with imatinib, whereas with nilotinib and sorafenib, FP/D842V and the compound mutation T674I+T874I became prevalent. Our results suggest that the PDGFR kinase domain contains a limited number of residues where exchanges critically interfere with binding of and inhibition by available PDGFR kinase inhibitors at achievable concentrations, which might explain the low frequency of imatinib resistance in this patient population. In addition, these findings would help to select the appropriate second-line drug in cases of imatinib-resistant disease and may be translated to other neoplasms driven by activated forms of PDGFR-A or -B. PMID- 20972452 TI - Exit from dormancy in microbial organisms. AB - Bacteria can exist in metabolically inactive states that allow them to survive conditions that are not conducive for growth. Such dormant cells may sense when conditions have improved and re-initiate growth, lest they be outcompeted by their neighbours. Growing bacteria turn over and release large quantities of their cell walls into the environment. Drawing from recent work on the germination of Bacillus subtilis spores, we propose that many microorganisms exit dormancy in response to cell wall muropeptides. PMID- 20972454 TI - Mutant p53 subverts p63 control over KLF4 expression in keratinocytes. AB - Genetic experiments established that p63 is crucial for the development and maintenance of pluri-stratified epithelia and KLF4 for the barrier function of the skin. KLF4 is one of the factors that reprogram differentiated cells to iPS. We investigated the relationship between p63 and KLF4 using RNA interference, overexpression, chromatin immunoprecipitation and transient transfections with reporter constructs. We find that p63 directly represses KLF4 in normal keratinocytes (KCs) by binding to upstream promoter sites. Unlike p63, KLF4 levels are high in the upper layers of human skin and increase upon differentiation of KCs in vitro. In HaCaT KCs, which harbor two mutant alleles of p53, inactivation of p63 and of mutant p53 leads to KLF4 repression. p63 and p53 mutants are bound to sites in the KLF4 core promoter. Importantly, expression of the H179Y and R282Q p53 mutants in primary KCs is sufficient to activate endogenous KLF4. Finally, immunohistochemical analysis of tissue arrays confirms increased coexpression of KLF4 and mutant p53 in squamous cell carcinomas. Our data indicate that suppression of KLF4 is part of the growth-promoting strategy of p63 in the lower layers of normal epidermis, and that tumor-predisposing p53 mutations hijack p63 to a different location on the promoter, turning it into an activator of this reprogramming factor. PMID- 20972455 TI - The reduced and altered activities of PAX5 are linked to the protein-protein interaction motif (coiled-coil domain) of the PAX5-PML fusion protein in t(9;15) associated acute lymphocytic leukemia. AB - The paired box domain of PAX5 was reported to fuse with the sequence of promyelocytic leukemia (PML) to produce PAX5-PML chimeric protein in two patients with B-cell acute lymphoblastic leukemia. In the present studies, we found, by gel shift assays, that PAX5-PML bound to a panel of PAX5-consensus sequence acts as a homodimer with reduction of its DNA-binding affinities in comparison with wild-type PAX5. In transient transfection assays using 293T and HeLa cells, and retrovirus transduction of murine hematopoietic stem/progenitor cells together with quantitative real-time polymerase chain reaction analysis, PAX5-PML inhibited wild-type PAX5 target gene transcriptional activity. Studies comparing PAX5-PML with PAX5-PML(DeltaCC) demonstrated that the coiled-coil (CC) protein interaction domain located within the PML moiety was required for PAX5-PML homodimer complex formation and partial transcriptional repression of genes controlled by PAX5. Fluorescent microscopic examination of transiently expressed YFP-tagged proteins in HeLa and 293T cells demonstrated that YFP-PAX5-PML and YFP PAX5-PML(DeltaCC) exhibited a diffuse granular pattern within the nucleus, similar to PAX5 but not PML. By fluorescent recovery after photobleach (FRAP), we have shown that PAX5-PML fusion protein has reduced intranuclear mobility compared with wild-type PAX5. Furthermore, the dimerization domain (CC) of PML was responsible for the reduced intranuclear mobility of PAX5-PML. These results indicate that the CC domain of PAX5-PML is important for each of the known activities of PAX5-PML fusion proteins. PMID- 20972456 TI - SUMO E3 ligase activity of TRIM proteins. AB - SUMOylation governs numerous cellular processes and is essential to most eukaryotic life. Despite increasing recognition of the importance of this process, an extremely limited number of small ubiquitin-like modifier (SUMO) protein ligases (E3s) have been identified. Here we show that at least some members of the functionally diverse tripartite motif (TRIM) superfamily are SUMO E3s. These TRIM proteins bind both the SUMO-conjugating enzyme Ubc9 and substrates and strongly enhance transfer of SUMOs from Ubc9 to these substrates. Among the substrates of TRIM SUMO E3s are the tumor suppressor p53 and its principal antagonist Mdm2. The E3 activity depends on the TRIM motif, suggesting it to be the first widespread SUMO E3 motif. Given the large number of TRIM proteins, our results may greatly expand the identified SUMO E3s. Furthermore, TRIM E3 activity may be an important contributor to SUMOylation specificity and the versatile functions of TRIM proteins. PMID- 20972457 TI - Sugar-free approaches to cancer cell killing. AB - Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials. Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels. Enforcement of glycolysis inhibits apoptosis induced by cytokine deprivation. Conversely, antiglycolytic agents enhance cell death induced by radio- and chemotherapy. Synergistic effects are likely due to regulation of the apoptotic machinery, as glucose regulates activation and levels of proapoptotic BH3-only proteins such as Bim, Bad, Puma and Noxa, as well as the antiapoptotic Bcl-2 family of proteins. Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death, which can proceed through necrosis or through mitochondrial or caspase-8-mediated apoptosis. We will discuss how oncogenic pathways involved in metabolic stress signaling, such as p53, AMPK (adenosine monophosphate-activated protein kinase) and Akt/mTOR (mammalian target of rapamycin), influence sensitivity to inhibition of glucose metabolism. Finally, we will analyze the rationale for the use of antiglycolytic inhibitors in the clinic, either as single agents or as a part of combination therapies. PMID- 20972459 TI - WW domain-mediated interaction with Wbp2 is important for the oncogenic property of TAZ. AB - The transcriptional co-activators YAP and TAZ are downstream targets inhibited by the Hippo tumor suppressor pathway. YAP and TAZ both possess WW domains, which are important protein-protein interaction modules that mediate interaction with proline-rich motifs, most commonly PPXY. The WW domains of YAP have complex regulatory roles as exemplified by recent reports showing that they can positively or negatively influence YAP activity in a cell and context-specific manner. In this study, we show that the WW domain of TAZ is important for it to transform both MCF10A and NIH3T3 cells and to activate transcription of ITGB2 but not CTGF, as introducing point mutations into the WW domain of TAZ (WWm) abolished its transforming and transcription-promoting ability. Using a proteomic approach, we discovered potential regulatory proteins that interact with TAZ WW domain and identified Wbp2. The interaction of Wbp2 with TAZ is dependent on the WW domain of TAZ and the PPXY-containing C-terminal region of Wbp2. Knockdown of endogenous Wbp2 suppresses, whereas overexpression of Wbp2 enhances, TAZ-driven transformation. Forced interaction of WWm with Wbp2 by direct C-terminal fusion of full-length Wbp2 or its TAZ-interacting C-terminal domain restored the transforming and transcription-promoting ability of TAZ. These results suggest that the WW domain-mediated interaction with Wbp2 promotes the transforming ability of TAZ. PMID- 20972458 TI - Chemical-induced cancer incidence and underlying mechanisms in Fen1 mutant mice. AB - A critical observation in sporadic cancers is that not all individuals are equally prone to developing cancer following exposure to a given environmental carcinogen. Epidemiological studies have suggested that the difference in the timing of cancer onset in response to exogenous DNA damage is likely attributable to genetic variations, such as those associated with base excision repair (BER) genes. To test this long-standing hypothesis and elucidate how a genetic variation in the BER gene flap endonuclease 1 (FEN1) results in susceptibility to environment insults and causes cancer, we established a mutant mouse model carrying a point mutation (E160D) in Fen1. We demonstrate that the E160D mutation impairs the ability of FEN1 to process DNA intermediate structures in long-patch BER using nuclear extracts or reconstituted purified BER proteins. E160D cells were more sensitive to the base-damaging agents methylnitrosourea and hydrogen peroxide, leading to DNA strand breaks, chromosomal breakage and chromosome instabilities in response these DNA insults. We further show that E160D mice are significantly more susceptible to exposure to methylnitrosourea and develop lung adenocarcinoma. Thus, our current study demonstrates that a subtle genetic variation (E160D) in BER genes (FEN1) may cause a functional deficiency in repairing base damage, such that individuals carrying the mutation or similar mutations are predisposed to chemical-induced cancer development. PMID- 20972460 TI - Epigenetic regulations in hematopoietic Hox code. AB - Hox genes encode DNA-binding proteins that are deployed in overlapping domains along various body axes during embryonic development. This sequential activation of Hox genes in temporal and spatial mode, the Hox code, is critical for the proper positioning of segmented structures along those axes, which include the vertebrate, limbs and, also digestive and reproductive tracts. It remains unknown how Hox genes are regulated to determine the identity of hematopoietic stem cells and their derivatives, which migrate and express most Hox genes. The key questions are whether the hematopoietic system has an axis, how epigenetic mechanisms restrict expression of Hox genes to specific cell types and what role Hox genes play in leukemic transformation? Taking in account these questions, we propose a combinatorial axial model of hematopoietic Hox code to predict the positional identity of the hematopoietic cells. This model will provide new insight into epigenetic therapy in leukemia. PMID- 20972461 TI - Cancer-associated IDH mutations: biomarker and therapeutic opportunities. AB - The discovery of somatic mutations in the isocitrate dehydrogenase (IDH) enzymes through a genome-wide mutational analysis in glioblastoma represents a milestone event in cancer biology. The nature of the heterozygous, point mutations mapping to arginine residues involved in the substrate binding inspired several research teams to investigate their impact on the biochemical activity of these enzymes. Soon, it became clear that the mutations identified impaired the ability of IDH1 and IDH2 to catalyze the conversion of isocitrate to alpha-ketoglutarate (alphaKG), whereas conferring a gain of a novel enzymatic activity leading to the reduction of alphaKG to the metabolite D2-hydroxyglutarate (D-2HG). Across glioma as well as several hematologic malignancies, mutations in IDH1 and IDH2 have shown prognostic value. Several hypotheses implicating the elevated levels of D 2HG and tumorigenesis, and the therapeutic potential of targeting mutant IDH enzymes will be discussed. PMID- 20972462 TI - Inhibition of p53 induces invasion of serous borderline ovarian tumor cells by accentuating PI3K/Akt-mediated suppression of E-cadherin. AB - Serous borderline ovarian tumors (SBOTs) are slow-growing, non-invasive ovarian epithelial neoplasms. SBOTs are considered to be distinct entities that give rise to invasive low-grade serous carcinomas (LGCs), which have a relatively poor prognosis and are unrelated to high-grade serous carcinomas (HGCs). The mechanisms underlying the progression of non-invasive SBOTs to invasive epithelial ovarian carcinomas are not understood. We recently established short term cultures of SBOT cells from tumor biopsies and showed that inactivation of p53, retinoblastoma (Rb) and/or PP2A by the simian virus 40 (SV40) large (LT) and small T antigens extends the life span of the cells and endows them with the ability to invade Matrigel-coated transwells. In this study, we show that concurrent inhibition of p53 and Rb by the SV40 LT produces cells (referred to as SBOT4-LT) with increased life span and cell invasion. To distinguish the roles of p53 and Rb in the progression from SBOTs to invasive ovarian carcinomas, we performed small interfering RNA-mediated knockdown of endogenous p53 in a spontaneously immortalized SBOT cell line, SBOT3.1, which increased cell invasion. This increased invasive activity was associated with the transcriptional downregulation of E-cadherin, correlated with an increase in PIK3CA levels and the increased activation of Akt. Conversely, in invasive LGC derived MPSC1 cells, enhancing the levels of p53 decreased cell invasion and diminished the phosphatidylinositol 3-kinase (PI3K)/Akt-mediated downregulation of E-cadherin. Inhibition of Rb also enhanced invasiveness, but did not affect the levels of PIK3CA and E-cadherin in SBOT3.1 cells, suggesting that it functions by a different pathway. To our knowledge, this study is the first to show that p53 has an important role in the progression from SBOTs to invasive carcinomas. In addition, our findings suggest that downregulation of E-cadherin by the PI3K/Akt pathway contributes to this progression. PMID- 20972463 TI - GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin. AB - The Kruppel-like zinc-finger protein GLI1 functions as a downstream transcription factor of Hedgehog signaling and plays a pivotal role in the cellular proliferation of many types of tumors, including pancreatic ductal adenocarcinoma (PDA). PDA develops from dysplastic lesions called pancreatic intraepithelial neoplasia (PanIN) through a multistep carcinogenesis process that changes its cellular characteristics, including a mucin expression profile. Increased expression of a gel-forming mucin, MUC5AC, was previously revealed as a major biomarker for the poor prognosis of PDA patients, but the molecular mechanisms responsible for its expression and correlation with poor prognosis are not fully understood. Here we show that MUC5AC is a direct transcriptional target of GLI1 in PDA cells. Overexpression of GLI1 enhanced MUC5AC expression, and a double knockdown of GLI1 and GLI2 suppressed endogenous MUC5AC expression in PDA cells. Luciferase reporter assays revealed that GLI1 and GLI2 can activate the MUC5AC promoter through its conserved CACCC-box-like cis-regulatory elements. We also found that GLI1-upregulated MUC5AC was expressed in the intercellular junction between cultured PDA cells and interfered with the membrane localization of E cadherin, leading to decreased E-cadherin-dependent cell-cell adhesion and promoting the migration and invasion of PDA cells. Consistently, GLI1 induced the nuclear accumulation and target gene expression of beta-catenin in a MUC5AC dependent manner. Finally, immunohistochemical analysis revealed that GLI1 expression statistically correlated with MUC5AC expression and also with altered subcellular localization of E-cadherin and beta-catenin in PanIN lesions and PDA. This evidence revealed a new aspect of GLI1 function in modulating E cadherin/beta-catenin-regulated cancer cell properties through the expression of a gel-forming mucin. PMID- 20972464 TI - Genomic characterization of asymptomatic CT-detected lung cancers. AB - Computed tomography (CT) screening of lung cancer allows the detection of early tumors. The objective of our study was to verify whether initial asymptomatic lung cancers, identified by high-resolution low-dose CT (LD-CT) on a high-risk population, show genetic abnormalities that could be indicative of the early events of lung carcinogenesis. We analyzed 78 tumor samples: 21 (pilot population) from heavy smokers with asymptomatic non-screening detected early stage lung cancers and 57 from 5203 asymptomatic heavy smoker volunteers, who underwent a LD-CT screening study. During surgical resection of the detected tumors, tissue samples were collected and short-term cultures were started for karyotype evaluation. Samples were classified according to the normal (NK) or aneuploid (AK) karyotype. The NK samples were further analyzed by the Affymetrix single-nucleotide polymorphisms (SNPs) technology. Metaphase spreads were obtained in 73.0% of the selected samples: 80.7% showed an AK. A statistically significant correlation was found between presence of vascular invasion and abnormal karyotype. A total of 10 NK samples were suitable for SNPs analysis. Subtle genomic alterations were found in eight tumors, the remaining two showing no evidence to date of chromosomal aberrations anywhere in the genome. Two common regions of amplification were identified at 5p and 8p11. Mutation analysis by direct sequencing was conducted for the K-RAS, TP53 and EGFR genes, confirming data already described for heavy smokers. We show that: (i) the majority of screening-detected tumors are aneuploid; (ii) early-stage tumors tend to harbor a less abnormal karyotype; (iii) whole genome analysis of NK tumors allows for the detection of common regions of copy number variation (such as amplifications at 5p and 8p11), highlighting genes that might be considered candidate markers of early events in lung carcinogenesis. PMID- 20972465 TI - Impact of critical care outreach on hematopoietic stem cell transplant recipients: a cohort study. AB - Serious morbidity and mortality can occur after hematopoietic SCT (HSCT). Critical care outreach (CCO) can provide timely access to intensive care for hospitalized patients in need of urgent stabilization but has not been examined in HSCT. Rapid Assessment of Critical Events (RACE) team was introduced at our centre January 1, 2005. A retrospective cohort study was performed. Patients undergoing HSCT between January 1, 2000 and December 31, 2004 (n=520) formed the 'before' cohort and patients transplanted between January 1, 2005 and December 31, 2007 (n=294) formed the 'after' cohort. Non-relapse mortality at day 100 after transplant was not different in the two cohorts (26 (8.8%) post-RACE vs 53 (10.2%) pre-RACE, P=0.62). The number of failed organs at time of transfer to intensive care unit (ICU) was reduced in the post-RACE cohort (1.9 +/- 0.8 vs 2.3 +/- 1.0, P=0.04) and the incidence of cardiovascular failure was lower (23.8 vs 43.8%, P=0.04). Other secondary outcomes were not different, including the frequency of ICU admission. RACE may contribute to earlier stabilization during critical illness in patients undergoing HSCT but does not reduce non-relapse mortality. CCO should be studied prospectively in patients undergoing HSCT to better evaluate its role. PMID- 20972466 TI - SCT without growth factor in multiple myeloma: engraftment kinetics, bacteremia and hospitalization. AB - SCT is important in the management of multiple myeloma. In the United States, the standard of care is administration of growth factors to accelerate neutrophil recovery after SCT. The need for growth factors after transplant has not been investigated recently. We analyzed a cohort of 166 patients at our institution who underwent autologous transplant for multiple myeloma without receiving growth factors after transplant and compared them with 498 patients who received standard filgrastim beginning on posttransplant day 5. A neutrophil count of 500/MUL was achieved in a median of 12.5 days in patients receiving growth factor, compared with 13.5 days in those not receiving growth factor (P<0.001). Platelet engraftment was identical (median, 14.5 days; P=0.12) in both groups, despite a lower median number of CD34+ cells infused in patients who did not receive growth factors. Incidence of nonstaphylococcal bacteremia was identical in both groups. The median hospital stay was 3.5 days shorter in the group not receiving growth factor. It is feasible and reasonable to perform autologous SCT for multiple myeloma without administering growth factors. PMID- 20972467 TI - Unrelated hematopoietic stem cell donors as research subjects. PMID- 20972468 TI - High-dose chemotherapy with autologous stem cell rescue for relapse after allo SCT in multiple myeloma. PMID- 20972469 TI - The conundrum of HLA-DRB1*14:01/*14:54 and HLA-DRB3*02:01/*02:02 mismatches in unrelated hematopoietic SCT. AB - Uncertainty still exists on the role of polymorphisms outside the HLA-DRB1 binding site or inside the HLA-DRB3 binding groove in unrelated hematopoietic SCT (HSCT). The ideal model to solve the conundrum consists of the transplants mismatched for HLA-DRB1*14:01/*14:54 and/or for HLA-DRB3*02:01/*02:02. A task force was set up in Italy to recruit transplanted pairs defined as HLA-DRB1*14:01 before 2006, the year crucial for the proper definition of the HLA-DRB1*14:54 allele in molecular biology. Out of 2723 unrelated pairs, 189 transplanted in Italy from 1995 to 2006 were HLA-DRB1*14:01 positive; 103/189 pairs with good historical DNA were retyped for HLA-DRB1*14 and HLA-DRB3 at-high resolution level; 31/103 pairs had HLA-DRB1*14 and/or HLA-DRB3 mismatched; 99/103, having complete clinical data, underwent statistical analysis for OS, TRM, disease-free survival and acute and chronic GvHD. No significant involvement of HLA DRB1*14:01/*14:54 or HLA-DRB3*02:01/*02:02 mismatches was found, either alone or combined. Our findings suggest that disparities at exon 3 of the HLA-DRB1 gene seem unlikely to influence the outcome after HSCT. The same may be envisaged for HLA-DRB3(*)02:01 and (*)02:02 alleles which, although differing in the Ag binding site, seem unable to modulate an appreciable immune response in an HSCT setting. PMID- 20972470 TI - Plerixafor with and without chemotherapy in poor mobilizers: results from the German compassionate use program. AB - The CXCR4-inhibitor plerixafor mobilizes hematopoietic stem cells amplifying the effects of granulocyte-CSF (G-CSF). Before approval plerixafor was used in a compassionate use program (CUP) for patients who failed a previous mobilization. In the German CUP 60 patients from 23 centers (median age 56.5 years (2-75)) were given 240 MUg/kg plerixafor SC 9-11 h before apheresis. A total of 78.3% (47/60) received G-CSF for 4 days before plerixafor administration; 76.6% of those (36/47) yielded at least 2.0 * 10(6) CD34(+) cells/MUL. The median cell yield was 3.35 * 10(6) CD34+ cells/kg (0-29.53). Nine patients received plerixafor alone or with G-CSF for less than 4 days mobilizing a median of 3.30 * 10(6) CD34+ cells/kg (1.6-5.6). There was no significant difference between G-CSF application for 4 days and for a shorter period of time (P=0.157). A total of 47 patients received plerixafor plus G-CSF combined with chemotherapy yielding a median of 3.28 * 10(6) CD34+ cells/kg (0-24.79). In all, 40 of 60 patients (66.7%) proceeded to transplantation, and achieved a timely and stable engraftment. Side effects were rare and manageable. In conclusion, mobilization with plerixafor in poor mobilizers is safe and results in a sufficient stem cell harvest in the majority of patients. PMID- 20972471 TI - Safety and efficacy of high-dose ranimustine, cytarabine, etoposide and CY (MCVAC) regimen followed by autologous peripheral blood stem cell transplantation for high-risk diffuse large B-cell lymphoma. AB - The efficacy of high-dose chemotherapy followed by autologous hematopoietic SCT for relapsed diffuse large B-cell lymphoma (DLBCL) has been reported, but an optimal conditioning regimen has not been determined. This study was conducted to evaluate the safety and efficacy of the MCVAC regimen (consisting of ranimustine (MCNU), cytarabine, etoposide and CY) followed by autologous peripheral blood stem cell transplantation (PBSCT) for patients with high-risk or relapsed DLBCL. A total of 40 patients with DLBCL who received the MCVAC regimen followed by autologous PBSCT were retrospectively evaluated. Median follow-up duration of the surviving patients was 51.2 months (range, 5.4-151.2 months). At 5-year OS and PFS were 73.7% (95% confidence interval (CI), 58.6-88.8) and 62.5% (95% CI, 46.8 78.2), respectively. Although relapse remained the most frequent cause of treatment failure, late-onset adverse events were observed, including two cases of severe pulmonary impairment, and two cases of therapy-related myelodysplastic syndromes (MDS)/AML. In conclusion, the MCVAC regimen would be an effective and tolerable conditioning regimen without TBI for autologous PBSCT for high-risk or relapsed DLBCL. However, late-onset pulmonary toxicity and MDS/AML should be monitored. PMID- 20972472 TI - Antigen-presenting cell function in the tolerogenic liver environment. AB - The demands that are imposed on the liver as a result of its function as a metabolic organ that extracts nutrients and clears gut-derived microbial products from the blood are met by a unique microanatomical and immunological environment. The inherent tolerogenicity of the liver and its role in the regulation of innate and adaptive immunity are mediated by parenchymal and non-parenchymal antigen presenting cells (APCs), cell-autonomous molecular pathways and locally produced factors. Here, we review the central role of liver APCs in the regulation of hepatic immune function and also consider how recent insights may be applied in strategies to target liver tolerance for disease therapy. PMID- 20972474 TI - DecisionDx-GBM Gene Expression Assay for Prognostic Testing in Glioblastoma Multiform. AB - It is estimated that approximately 22,000 Americans will be diagnosed with tumor of the brain or nervous system in 2010. Among primary brain tumors, approximately 60% are gliomas, the most common and most malignant of which is glioblastoma multiforme (GBM).The DecisionDx-GBM test is a multigene expression assay that is designed to predict which patients are likely to experience long-term (> 2 years) progression-free survival. PMID- 20972473 TI - The Immune Tolerance Network at 10 years: tolerance research at the bedside. AB - Immune tolerance-inducing therapies reprogramme immune cells to eliminate pathogenic immune responses while preserving protective immunity. The Immune Tolerance Network (ITN), sponsored by the US National Institutes of Health, was established in 1999 to evaluate new tolerance-inducing therapies and carry out mechanistic studies using a unique interactive approach in partnership with industry, academia and foundations. Ten years later, the ITN has carried out approximately 36 clinical trials and tolerance studies examining innovative tolerogenic approaches in the settings of allergy, autoimmune diseases and organ transplantation. ITN investigators have published more than 80 original research papers based on this work. This Timeline article summarizes the progress and challenges of clinical research in the ITN. PMID- 20972475 TI - BRAF p.Val600Glu (V600E) Testing for Assessment of Treatment Options in Metastatic Colorectal Cancer. AB - Colon and rectal cancer (CRC) are the third most common cancer in the United States and cause approximately 50,000 deaths per year. The anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab (Erbitux(r)) and panitumumab (Vectibix(r)) have been recently introduced to treat CRC. However, the response rate with these agents is low and they are associated with serious adverse effects. Accordingly biomarkers that can predict those patients that will respond to treatment may have clinical utility. The p.Val600Glu sequence variant (often called V600E) in the BRAF gene has been investigated as a biomarker to predict patients that will not respond to treatment with the anti-EGFR monoclonal antibodies. PMID- 20972476 TI - The 2009 pandemic H1N1 influenza vaccination in France: who accepted to receive the vaccine and why? AB - INTRODUCTION: Previous studies investigating determinants of 2009 (H1N1) pandemic influenza vaccine acceptance have focused on target groups such as healthcare workers. Few studies in the European Union have examined the self-reported reasons as well as predictive socio-demographic and health factors for pandemic influenza vaccine acceptance in the general population, even though influenza vaccine was recommended for all people. METHODS: A nationwide telephone survey was conducted in France during the peak of the outbreak that occurred in December 2009 in adults (>= 16 years), using a proportional random-digit dialing. RESULTS: Interviews were completed by 1003 individuals, of whom 275 (27.4%) either had received pandemic influenza vaccine during the last weeks or intended to get vaccinated in the next weeks. Acceptance rates of pandemic vaccine were significantly higher among men, more educated and wealthier people, as well as persons who had a prior experience of influenza vaccination. The patterns of self reported reasons for vaccine acceptance could be broadly divided into 3 groups related to (1) the mental representation of the threat - in particular the beliefs associated with the severity and personal vulnerability to the illness, (2) the perception of efficacy and safety of the vaccine, and (3) trust/distrust toward those advocating the vaccine. CONCLUSIONS: This national study indicates that social and cognitive determinants of pandemic influenza vaccine acceptance among French adults were relatively similar to those identified by previous studies of acceptance of seasonal influenza vaccine. PMID- 20972478 TI - [The Civilian Society, the National Health Service and the Scientific Societies]. PMID- 20972477 TI - Identifying sleep disturbances in Huntington's disease using a simple disease focused questionnaire. AB - Sleep disturbances have been shown to affect patients with various neurological diseases, including Huntington's disease (HD). We therefore aimed to develop a sleep questionnaire that could be used by clinicians to help identify sleep disturbances in patients with the disease.Design A detailed questionnaire was used that was modelled on recent sleep questionnaires used for Parkinson's disease patients, and developed after consultation with sleep specialists. This questionnaire contained 45 questions that focused on different sleep-related issues such as duration, quality of sleep, abnormal nocturnal behaviour and quality of life. Setting Questionnaires were either completed in the home environment or in clinic.Participants 66 patients, 38 carers and 60 non-carers were recruited.Measurements & Results Various sleep-related difficulties were identified in a significantly greater proportion of HD patients compared to control subjects, with both quality and quantity of sleep being affected. Conclusions Disturbed sleep in HD may contribute towards the deterioration of the patient's ability to do activities of daily living and have a significantly deleterious effect on the quality of life of both patients and carers. This simple questionnaire should aid the clinician by providing subjective insight into the patient's sleep patterns that could enable more effective, individual specific treatment to be instigated and ultimately improve quality of life. PMID- 20972479 TI - [A reflection on the progress and development of surgery]. PMID- 20972480 TI - [Minimally invasive thoracic surgery: a fifteen-years experience]. AB - The evolution of surgical techniques has rendering possible for thoracic surgery to be performed efficiently and safely, with less aggressive approaches. Being less traumatic, minimally invasive surgery allows a faster post-operative recovery, less complications and reduces in patient days and morbidity. The authors consider as minimally invasive approaches the video-assisted thoracic surgery, as well as the minithoractomy and the ministernotomy. The present paper reviews thoracic surgeries performed for the last 15 years in a cardiothoracic surgical unit using a minimally invasive surgical approach. PMID- 20972481 TI - [Computed tomographic angiography in the evaluation of acute pulmonary thromboembolism]. AB - Computed tomographic andiography has becoming the main diagnostic imaging method for the evaluation of patients with suspected pulmonary embolism (PE), due to its high sensitivity and specificity and potential cost-effectiveness. The advances in multidetector computed tomography (MDCT) scanners and optimization of scanning protocols via thinner collimation and faster scanning times have greatly improved the ability to detect PE. The diagnosis is made by direct visualization of a low attenuation filling defect (intraluminal thrombus) that partially or completely occludes a contrast filled artery. Differentiate between acute and chronic PE is often possible through the identification of characteristic findings, such as the diameter of the affected artery and the location and relationship of the thrombus to the vessel walls. Awareness of the major error factors in the CT diagnosis of PE can help further increase the sensitivity and specificity of this imaging method. PMID- 20972482 TI - [Intra-thoracic goiter: analysis of the Department's experience]. AB - A review of all clinical files with pre-operative diagnosis of intra-thoracic goiter operated in our Department from 2001-2009 was made. We identified 30 patients, of which 66% were females. 63% of the patients were asymptomatic, 46% had clinical or radiological findings of mediastinal structures compression and 2 patients were ventilated prior to surgery. 50% of the patients were operated on through an inferior transverse cervicotomy, the remaining were operated on through partial or complete sternotomy, with cervical approach. 6,6% of patients (n=2) had an intra-operative diagnosis of invasive thymoma, 3,3% (n=1) had a very invasive mediastinal tumor and 3,3% (n=1) had an ectopic thyroid. Average surgical length of time was of 83 minutes. In 10% of patients (n=3) post operative invasive ventilation was required, one of which for unilateral permanent lesion of the recurrent laryngeal nerve. In the long term follow-up we assessed 18 patients. The median follow up was 53 months. One patient died at the 15th post-operatory day of pneumonia, one expired at the 30th day for anaplasic thyroid carcinoma progression and one died at the 18 month from invasive thymoma progression. One patient currently reveals evidence of local recurrence 3 patients are currently taking levothyroxine and one is taking propiltiouracil. Pathological studies revealed that 66% of cases were multinodular goiter and neoplasia was present in 13% of the patients. Other results were thymic pathology in 13% of cases (n=4), parathyroid cyst in 3,3% (n=1), and ectopic thyroid in 3,3% (n=1(. PMID- 20972483 TI - [Vascular Ehlers-Danlos syndrome with extensive involvement of thoracic and abdominal aorta in three young women of the same family]. AB - Vascular Ehlers-Danlos syndrome is a rare genetic and hereditary disorder that affects and weakens the structure and sustentability of medium and large size arteries, causing severe clinical complications, often fatal, such as is the case of spontaneous ruptures, aneurysms or arterial dissections. Concomitantly, spontaneous intestinal perforations may occur, as well as uterine ruptures, following a pregnancy and during the peripartum period. The authors report the clinical cases of three young females of the same family, with the diagnosis of vascular Ehlers-Danlos syndrome, coursing with severe involvement of the aorta (ascending aortic anerysm, dissection of the thoracoabdominal aorta), who underwent successful surgical management and were evaluated from 6 to 18 years after the operations. To complete the clinical presentation of the cases, the authors review the most recent literature and discuss the main features of this entity, namely its genetic origin, the arterial morphology and structural alterations, its clinical expression, the diagnosis and the challenges faced by the therapeutical approach, wether it would be the conventional arterial reconstructive surgery or the most recently introduced endovascular intervention. PMID- 20972484 TI - [Supra-aortic trunks occlusive disease: three different treatment approaches]. AB - Unlike carotid bifurcation atherosclerotic stenosis, supra-aortic trunks (SAT) occlusive disease is rare and its revascularization uncommon, accouting for less than 10% of the operations performed on the extracranial brain-irrigating arteries. There are three different treatment approaches: transthoracic, extra anatomic cervical and endovascular. Endovascular repair is gaining popularity as first-line therapy for proximal lesions with favorable anatomy because of its low morbidity and rare mortality. Extra-anatomic bypass is a safe and durable reconstruction and should be considered in patients with single vessel disease, with cardiopulmonary high-risk or with limited life expectancy. If cardiac surgery is needed, central transthoracic reconstruction is preferable, and the two procedures should be combined. The long-term patency of bypasses with aortic origin, specially when multiple vessels are involved, is superior to other repair techniques. We present three clinical cases that illustrate each of these therapeutic strategies: central brachiocephalic revascularization and synchronous cardiac surgery in a patient with complex SAT atherosclerosis disease; subclavian carotid transposition for disabling upper limb claudication; and subclavian artery stenting for subclavian-steal syndrome. Surgical approach selection should be based on the individual patient's anatomy and operative risk. PMID- 20972485 TI - [The management of carotid reestenosis--an experience with the conventional surgery]. AB - The authors report a series of 26 consecutive patients, 20 men and 6 women, age range 47-80 years, average age of 66 years, who underwent conventional surgery for the treatment of carotid reestenosis. The surgical management consisted in the resection of a segment of the common carotid-internal carotid arteries and interposition of a prosthetic graft, followed by ligation of the external carotid, in 3 patients; in the remainder 23 cases a venous bypass graft was interposed from the common carotid to the internal carotid artery, above the lesion, with preservation of the external carotid artery flow and ligation of the internal carotid, just below the anastomosis. There was no operative mortality and the significant morbility consisted in a cervical hematoma in one patient, transient disphonia in two cases and transient disphagia in one patient. During the mean follow up time of 43 months, one patient developed a significant reestenosis of the venous graft and another patient developed an aneurysm of the venous graft, both conditions requiring surgical repair. Based on the early and late results of this experience, the authors elect the open conventional surgery as the method of choice for the treatment of carotid reestenosis. PMID- 20972486 TI - [Concomitant syphilitic aneurysms of the thoracic and abdominal aorta. Case report]. AB - The aneurismatic aortic disease is one of the most frequent conditions challenging the vascular surgeon. It can be caused by atherosclerosis, vasculitis, trauma, infection or others. The treatment, even when elective, can be associated to high rates of morbid-mortality, related to the etiology, anatomic location and type of treatment. The authors describe the case of a patient with concomitant syphilitic aneurysms of the descending thoracic aorta, pararenal and aortic bifurcation. The diagnostic presumption was supported by clinical and epidemiology data (the patient was treated for a syphilitic saccular infrarenal aortic aneurysm 5 years before). The etiology was confirmed by the pathological studies of the surgical specimen. PMID- 20972487 TI - [Congenital vascular malformations: epidemiology, classification and therapeutic basis]. AB - Congenital vascular malformations are part of the rare diseases of angiology and vascular surgery and can present in a variety of forms. They rise a lot of doubts and many diagnostic and therapeutic challenges. Treatment options are widely variable and often debated; surgeons usually have doubts about the best procedure to adopt. It is also an area of great anatomic and functional variability where the confusion regarding the nomenclature and classifications has been frequent, rendering difficult to adopt standardized measures. There have been significant advances in the recent years towards reaching a consensus. Based on his practical clinical experience and past work on these issues, the author reviews the epidemiology, the classifications and the therapeutic basis of this pathology. The author emphasizes the fact that the International Society for the Study of Vascular Anomalies (ISSVA) classification provides a useful framework for classifying vascular anomalies, as well as the therapeutic percutaneous embolization using polidocanol foam to control venous malformations. PMID- 20972488 TI - [Large aneurysm of a brachiocephalic arteriovenous fistula]. PMID- 20972489 TI - Facile, solvent and ligand free iron catalyzed direct functionalization of N protected tetrahydroisoquinolines and isochroman. AB - An efficient method for an iron catalyzed oxidative indolation and methoxyphenylation of N-protected tetrahydroisoquinolines and isochroman is described including subsequent facile deprotection. PMID- 20972490 TI - Synthesis and properties of colloidal heteronanocrystals. AB - Colloidal heteronanocrystals (HNCs) can be regarded as solution-grown inorganic organic hybrid nanomaterials, since they consist of inorganic nanoparticles that are coated with a layer of organic ligand molecules. The hybrid nature of these nanostructures provides great flexibility in engineering their physical and chemical properties. The inorganic particles are heterostructured, i.e. they comprise two (or more) different materials joined together, what gives them remarkable and unique properties that can be controlled by the composition, size and shape of each component of the HNC. The interaction between the inorganic component and the organic ligand molecules allows the size and shape of the HNCs to be controlled and gives rise to novel properties. Moreover, the organic surfactant layer opens up the possibility of surface chemistry manipulation, making it possible to tailor a number of properties. These features have turned colloidal HNCs into promising materials for a number of applications, spurring a growing interest on the investigation of their preparation and properties. This critical review provides an overview of recent developments in this rapidly expanding field, with emphasis on semiconductor HNCs (e.g., quantum dots and quantum rods). In addition to defining the state of the art and highlighting the key issues in the field, this review addresses the fundamental physical and chemical principles needed to understand the properties and preparation of colloidal HNCs (283 references). PMID- 20972491 TI - Ligand development in the Ni-catalyzed hydrocyanation of alkenes. AB - The addition of HCN to alkenes is a very useful reaction for the synthesis of functional organic substrates. Industrially the nickel-catalyzed hydrocyanation has gained considerable importance mainly because of the production of adiponitrile in the DuPont process. In this process the hydrocyanation of butadiene is carried out using aryl phosphite-modified nickel catalyst. Since the performance of organo-transition metal complexes is largely determined by the ligand environment of the metal, fundamental understanding and ligand development is of pivotal importance for any progress. This feature article gives an account of the development and application of different mono- and bidentate phosphorus based ligands in the Ni-catalyzed hydrocyanation reaction of alkenes. Special attention will be paid to the development of insight and understanding of the ligand structural and electronic properties towards the improvement of the catalyst performance in terms of stability, activity, and selectivity. PMID- 20972492 TI - Photocatalytic disproportionation of nitrite to dinitrogen and nitrate in an aqueous suspension of metal-loaded titanium(IV) oxide nanoparticles. AB - Photocatalytic reaction of a nitrite ion in aqueous suspensions of bare and metal loaded TiO(2) particles was examined without electron and hole scavengers under irradiation of UV light. In the bare TiO(2) system, disproportionation of NO(2)( ) to N(2) (or N(2)O) and NO(3)(-) with nitrogen balance (NB) and redox balance (ROB) close to unity within experimental errors was observed, although the reaction was slow. Palladium (Pd)-loaded TiO(2) particles exhibited an extraordinarily large rate of disproportionation of NO(2)(-) in their aqueous suspension, i.e. NO(2)(-) was almost completely converted to N(2) (or N(2)O) and NO(3)(-) even after only 3 h of photoirradiation, both the values of NB and ROB being close to unity. This result suggests that Pd loaded on TiO(2) particles acted as storage sites for photogenerated electrons and effectively transferred the electrons to NO(2)(-) and, therefore, that the reduction process in the photocatalytic disproportionation of NO(2)(-) was accelerated by Pd loaded on TiO(2). Effects of the amount of Pd and pH of the suspension on the reaction rate were also examined. PMID- 20972493 TI - The zone-refine driven growth of jellyfish-like core-shell nanowires. AB - Thermal evaporation of a Sn-silica mixture produces core-shell nanowires assembled into jellyfish-like structures. The growth mechanism involves zone refine driven phase separation at the solid-liquid interface. The materials emit blue and red lights; the luminescence centers are discussed and verified. PMID- 20972494 TI - Synergistic effect of crystal and electronic structures on the visible-light driven photocatalytic performances of Bi(2)O(3) polymorphs. AB - Three polymorphs of Bi(2)O(3) were selectively synthesized via solution-based methods. The phase structures of the as-prepared samples were confirmed by X-ray powder diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). UV-vis diffuse reflectance spectroscopy was employed to study the optical properties of Bi(2)O(3) polymorphs, and the band gaps were estimated to be 2.80, 2.48, and 3.01 eV for alpha-Bi(2)O(3), beta-Bi(2)O(3), and delta-Bi(2)O(3), respectively. The photocatalytic performances of the oxides were investigated by decomposing methyl orange and 4-chlorophenol under visible irradiation at room temperature. It was observed that beta-Bi(2)O(3) displayed much higher photocatalytic performance than N-doped P25. Among the three polymorphs of Bi(2)O(3), the photocatalytic activities followed the order: beta-Bi(2)O(3) > alpha-Bi(2)O(3) > delta Bi(2)O(3), which was in good accordance with the photoluminescence spectra measurement results. The synergistic effect of the crystal and electronic structures on the photocatalytic performances of Bi(2)O(3) polymorphs was investigated. The much better photocatalytic activity of beta-Bi(2)O(3) was considered to be closely related to its smaller band gap, higher crystallinity and unique tunnel structure. PMID- 20972495 TI - Photoinduced charge transfer in ZnO/Cu(2)O heterostructure films studied by surface photovoltage technique. AB - ZnO/Cu(2)O heterostructure films were prepared by a two-step electrodeposition method in aqueous solution on fluorine-doped tin oxide (FTO) substrates. Scanning electron microscopy (SEM), X-ray powder diffraction (XRD) and UV-vis transmission measurements were utilized to characterize the films. Surface photovoltage (SPV) technique was used to investigate the process of photoinduced charge transfer. The results show that there is an electric field located at the interface between ZnO and Cu(2)O film and the photoinduced electrons in Cu(2)O film inject into ZnO under the effect of interfacial electric field with visible light irradiation. While under ultraviolet light illumination, the photoinduced electrons in Cu(2)O film accumulate at the surface of Cu(2)O film instead of injecting into ZnO under the action of surface built-in electric field of Cu(2)O film. The work function measurements confirm that the direction of interfacial electric field is from ZnO to Cu(2)O. These results are help to future design of high performance heterostructure photovoltaic devices. PMID- 20972496 TI - On the performance of Cu-BTC metal organic framework for carbon tetrachloride gas removal. AB - The performance of Cu-BTC metal organic framework for carbon tetrachloride removal from air has been studied using molecular simulations. According to our results, this material shows extremely high adsorption selectivity in favour of carbon tetrachloride. We demonstrate that this selectivity can be further enhanced by selective blockage of the framework. PMID- 20972497 TI - Multilayered nanofibers from stacks of single-molecular thick nanosheets of hexakis(alkoxy)triphenylenes. AB - Symmetrically substituted hexakis(alkoxy)triphenylene (HAT) derivatives were assembled into single molecular thick 2D nanosheets, which stacked further to give multilayered nanofibers through a convenient solution process. Detailed information on molecular arrangement was unraveled by various imaging techniques and diffraction studies. PMID- 20972498 TI - Drug encapsulation within self-assembled microglobules formed by thermoresponsive supramolecules. AB - An 8-(phenyl)-2'-deoxyguanosine derivative self-assembles in aqueous media into discrete hexadecamers that further self-assemble above 32 degrees C into microglobules that encapsulate the drug doxorubicin. PMID- 20972499 TI - Reporters in the nanoworld: diffusion of single molecules in mesoporous materials. AB - Mesoporous materials have a high potential for a number of different applications in Materials Science such as in molecular sieving, as masks for the formation of nanometre-sized metallic wires, as novel drug-delivery systems or as advanced host systems for catalysis. For many of these applications a thorough understanding of the interaction of guest molecules within the host matrix is required. In this tutorial review, we cover recent single-molecule experiments that allow the investigation of host-guest dynamics with unprecedented detail. We will show how molecules diffusing in samples with (almost) perfect domain ordering still show a large heterogeneity in their mobility and interaction with the host. With the presented methodology it is now possible to dramatically improve our understanding of host-guest interactions and in return develop new nano-structured mesoporous materials with properties optimised for a certain application. PMID- 20972500 TI - Thin film of sulfonated zinc phthalocyanine/layered double hydroxide for achieving multiple quantum well structure and polarized luminescence. AB - Ordered thin films based on alternate assembly of zinc phthalocyanine complex and layered double hydroxide monolayers have been fabricated, which exhibit multiple quantum well structure and well-defined polarized luminescence. PMID- 20972501 TI - Instantaneous dissolution of cellulose in organic electrolyte solutions. AB - Herein a novel class of solvent systems for cellulose is introduced. Surprisingly, organic electrolyte solutions, which contain just a small molar fraction of ionic liquid, dissolve instantaneously large amounts of cellulose. The solvation properties of the solvent systems, required for dissolving the polymer, are discussed here. PMID- 20972502 TI - In situ study on molecular diffusion phenomena in nanoporous catalytic solids. AB - As an omnipresent phenomenon in nature, diffusion is among the rate-determining processes in many technological processes. This is in particular true for catalytic conversion in nanoporous materials. We provide a critical review of the possibilities of exploring diffusion phenomena over microscopic dimensions in such media by direct experimental observation. By monitoring the probability distribution of molecular displacements as a function of time, the pulsed field gradient technique of NMR (PFG NMR) records the rate of molecular re distribution. By varying the observation time, PFG NMR is thus able to trace even hierarchies of transport resistances as occurring, e.g., in catalyst particles in the form of binder-compacted assemblages of zeolite crystallites. Alternatively, and complementary to this information, interference microscopy (IFM) and IR microscopy (IRM) are able to follow the evolution of intracrystalline concentration profiles during uptake and release. This allows, in particular, an accurate quantification of the transport resistances on the surface of the individual crystallites and of the probability that reactant molecules from the gas phase, upon colliding with the external surface, are able to penetrate through such "surface barriers" into the crystal bulk phase. Being able to distinguish between different molecular species, IRM is able to record the evolution of intracrystalline concentration profiles even during multi-component adsorption and catalytic reactions (169 references). PMID- 20972503 TI - Lyotropic liquid crystalline phases from helical beta-peptides as alignment media. AB - Lyotropic liquid crystalline (LLC) phases from helical beta-peptides are proposed as novel water-based alignment media. In contrast to alpha-peptides, beta peptides form LLCs at very short chain lengths and at concentrations as low as 1 percent. Spectra obtained in these LLC phases are artefact-free and lead to RDCs of the desired size. First indications towards enantiodiscrimination are provided. PMID- 20972504 TI - A tetraalkylated pyrene building block for the synthesis of pyrene-fused azaacenes with enhanced solubility. AB - The synthesis and characterisation of a soluble pyrene-fused tetraazaoctacene derivative has been achieved by developing a key pyrene-based building block with four solubilising groups. PMID- 20972505 TI - Protein-water electrostatics and principles of bioenergetics. AB - Despite its diversity, life universally relies on a simple basic mechanism of energy transfer in its energy chains-hopping electron transport between centers of electron localization on hydrated proteins and redox cofactors. Since many such hops connect the point of energy input with a catalytic site where energy is stored in chemical bonds, the question of energy losses in (nearly activationless) electron hops, i.e., energetic efficiency, becomes central for the understanding of the energetics of life. We show here that standard considerations based on rules of Gibbs thermodynamics are not sufficient, and the dynamics of the protein and the protein-water interface need to be involved. The rate of electronic transitions is primarily sensitive to the electrostatic potential at the center of electron localization. Numerical simulations show that the statistics of the electrostatic potential produced by hydration water are strongly non-Gaussian, with the breadth of the electrostatic noise far exceeding the expectations of the linear response. This phenomenon, which dramatically alters the energetic balance of a charge-transfer chain, is attributed to the formation of ferroelectric domains in the protein's hydration shell. These dynamically emerging and dissipating domains make the shell enveloping the protein highly polar, as gauged by the variance of the shell dipole which correlates with the variance of the protein dipole. The Stokes-shift dynamics of redox-active proteins are dominated by a slow component with the relaxation time of 100-500 ps. This slow relaxation mode is frozen on the time-scale of fast reactions, such as bacterial charge separation, resulting in a dramatically reduced reorganization free energy of fast electronic transitions. The electron transfer activation barrier becomes a function of the corresponding rate, self consistently calculated from a non-ergodic version of the transition-state theory. The peculiar structure of the protein-water interface thus provides natural systems with two "non's"-non-Gaussian statistics and non-ergodic kinetics to tune the efficiency of the redox energy transfer. Both act to reduce the amount of free energy released as heat in electronic transitions. These mechanisms are shown to increase the energetic efficiency of protein electron transfer by up to an order of magnitude compared to the "standard picture" based on canonical free energies and the linear response approximation. In other words, the protein-water tandem allows both the formation of a ferroelectric mesophase in the hydration shell and an efficient control of the energetics by manipulating the relaxation times. PMID- 20972506 TI - Topochemical synthesis and catalysis of metal nanoparticles exposed on crystalline cellulose nanofibers. AB - Topochemical synthesis of gold nanoparticles (AuNPs) was achieved on crystalline cellulose single nanofibers (CSNFs), which were tailored from native cellulose. Exposed AuNPs@CSNFs composite exhibited an excellent catalytic efficiency: the turnover frequency of the AuNPs@CSNFs was up to 840 times that of conventional polymer-supported AuNPs, for a model aqueous reduction reaction. Our novel strategy provides a promising solution to realize efficient use of limited noble metals using natural bioresources. PMID- 20972507 TI - Tetra-end-linked oligonucleotides forming DNA G-quadruplexes: a new class of aptamers showing anti-HIV activity. AB - The biophysical and biological properties of unprecedented anti-HIV aptamers are presented. The most active aptamer (1L) shows a significant affinity to the HIV protein gp120. PMID- 20972508 TI - The effect of active-site isoleucine to alanine mutation on the DHFR catalyzed hydride-transfer. AB - Comparison of the nature of hydride transfer in wild-type and active site mutant (I14A) of dihydrofolate reductase suggests that the size of this side chain at position 14 modulates H-tunneling. PMID- 20972509 TI - Re-investigation of the thermal decomposition of Co(CO)4SiCl3 adsorbed on silica. AB - Evidence is provided that thermal decomposition of Co(CO)(4)SiCl(3) adsorbed on silica in a hydrogen atmosphere results in the formation of metallic cobalt nanoparticles covered with a Co(2)SiO(4)/CoO shell instead of cobalt silicide nanoparticles, as had been reported previously. PMID- 20972510 TI - The growing disparity between clinical trial complexity and investigator compensation. PMID- 20972511 TI - Effect of systemic hypertension on right ventricular morphology and function: an echocardiographic study. AB - BACKGROUND: Hypertension is an important cardiovascular risk factor worldwide. It is associated with left ventricular hypertrophy (LVH). Both diastolic and systolic dysfunction may occur in hypertensive heart disease. The ventricles are structurally and functionally interdependent on each other. This was an echocardiographic study intended to describe the impact of left ventricular pressure overload and hypertrophy due to hypertension on right ventricular morphology and function. METHODS: One hundred subjects with systemic hypertension and 50 age- and gender-matched normotensive control subjects were used for this study. Two-dimensional (2-D), M-mode and Doppler echocardiographic studies were done to evaluate the structure and function of both ventricles. Data analysis was done using the SPSS 16.0 (Chicago, Ill). Statistical significance was taken as p < 0.05. RESULTS: Age and gender were comparable between the two groups. Hypertensive subjects had significantly increased left ventricular end-diastolic dimensions, posterior wall thickness, interventricular septal thickness, left atrial dimensions and left ventricular mass and index. The mitral valve E/A ratio was reduced among hypertensive subjects when compared to normal controls (1.15 +/ 0.75 vs 1.44 +/- 0.31, respectively; p < 0.05). A similar pattern was found in the tricuspid E/A ratio (1.14 +/- 0.36 vs 1.29 +/- 0.30, respectively; p < 0.05). Hypertensive subjects also had reduced right ventricular internal dimensions (20.7 +/- 8.0 vs 23.1 +/- 3.1 mm, respectively; p < 0.001) but similar peak pulmonary systolic velocity. The mitral e/a ratio correlated well with the tricuspid e/a ratio. CONCLUSION: Systemic hypertension is associated with right ventricular morphological and functional abnormalities. Right ventricular diastolic dysfunction may be an early clue to hypertensive heart disease. PMID- 20972512 TI - Effect of the haeme oxygenase-1/endogenous carbon monoxide system on atherosclerotic plaque formation in rabbits. AB - BACKGROUND: To investigate the effect of the haeme oxygenase-1/carbon monoxide (HO-1/CO) system on atherosclerotic plaque formation and its possible mechanism. METHODS: For 12 weeks, rabbits were given a 1.5% cholesterol diet (Ch group, n = 8) or a 1.5% cholesterol diet plus an HO-1 inducer, haemin (Hm group, n = 8), or an HO-1 inhibitor, zinc protoporphyrin IX (Znpp-IX, Zn group, n = 8) by intraperitoneal injection. RESULTS: Compared with the normal control group (C group, n = 8), serum levels of lipids and oxidised low-density lipoproteins (ox LDL) increased significantly in all experimental groups (p < 0.01). However, no significant differences were observed among the three experimental groups (p > 0.01). Compared with the control group, aortic nitric oxide (NO) production and nitric oxide synthase (cNOS) activity decreased markedly, whereas carbon monoxide (CO) production and HO-1 activity increased markedly in the Ch group (p < 0.01). This was associated with an increase in the area of aortic plaque of 54.00 +/- 4.16%. Compared with the Ch group, CO production and HO-1 activity increased markedly, while aortic HO activity and CO production decreased significantly in the Hm group. The area of aortic plaque was significantly reduced in the Hm group (17.88 +/- 3.01%), whereas the area of aortic plaque was significantly increased in the Zn group (61.13 +/- 3.50%). Compared with the Ch group, aortic endothlin-1 expression in the Hm group reduced significantly, while in the Zn group it was significantly higher than in the Ch group (p < 0.01). CONCLUSION: The HO-1/CO system plays an inhibitory role in atherosclerotic plaque formation. This role was not mediated by regulating serum lipids and ox-LDL, but was related to the reciprocal relationship between the HO-1/CO and NOS/NO systems in atherosclerosis and the down-regulated expression of endothlin-1 (ET-1), which inhibits the proliferation of vascular smooth muscle cells. PMID- 20972513 TI - Letter to the editor. PMID- 20972514 TI - Risk factors associated with intermediate and long-term mortality following vascular surgery in South African patients. AB - There are few data on predictors of mortality following vascular surgery in South African patients. While in the developed world, peri-operative risk factors are also associated with intermediate-term survival, it is likely that the weighting and even the clinical risk factors may be different in South African patients due to the epidemiology of cardiovascular disease in developing countries. The aim of this study was therefore to determine risk factors associated with intermediate and long-term mortality in South African vascular surgical patients. DESIGN: A retrospective cohort study was conducted. Intermediate and long-term survival was determined by subsequent hospital visits or admissions. For patients who did not return to the hospital, the patient or patient's next of kin was contacted telephonically. The outcome of the patient, and the time to the outcome following the surgical procedure were recorded. Bivariate and multivariate analysis was conducted using Cox regression analysis to determine predictors of intermediate term mortality. RESULTS: Only hypertension and diabetes were associated with intermediate and long-term mortality at the bivariate level of analysis with p < 0.10. There was no co-linearity between hypertension and diabetes. Hypertension was the only predictor of intermediate and long-term survival retained in the multivariate model (hazard ratio 3.86, 95% confidence interval 0.83-15.4, p = 0.086). CONCLUSION: In contrast to developed-world observations, peri-operative clinical risk indices were not associated with intermediate and long-term survival in South African vascular surgical patients. Instead, two risk factors that were identified in the South African National Burden of Disease study were associated with mortality. It appears that a 'western lifestyle' (and the presence of associated risk factors) may be more important predictors of intermediate and long-term mortality than peri-operative risk predictors of cardiac events in South African vascular surgical patients. This study highlights an important public health issue for the South African population where the most important determinants of mortality are continued exposure to risk factors (such as hypertension and diabetes) in the community, with little modification of these risk factors through primary health surveillance and management, even after surgical admission for pathology known to be associated with these risk factors. PMID- 20972515 TI - Coping and metabolic syndrome indicators in urban black South African men: the SABPA study. AB - Urbanisation is associated with obesity, hypertension and development of the metabolic syndrome (MS). We aimed to assess the use of different coping styles and their influence on increases in MS indicators and target end-organ damage (TOD) in urban black African men. A sample of 53 men was classified as clear high active (AC, n = 30) or passive coping (PC, n = 23) responders, using the Amirkhan African validated coping style indicator. Blood pressure (BP) was recorded with an aneroid sphygmomanometer and waist circumference (WC) was determined. Carotid intima-media thickness (CIMT) and microalbuminuria were analysed to determine TOD. Fasting serum and eight-hour urine samples revealed elevated MS indicators in AC men. Strong associations existed between MS indicators and TOD in AC but not PC men. To conclude, only BP and seeking social support were positively associated with TOD in urban PC African men, while in urban AC African men, most MS indicators were positively associated with TOD, i.e. sub-clinical atherosclerosis and renal impairment. PMID- 20972516 TI - The reliability of chest radiographs in predicting left atrial enlargement. AB - INTRODUCTION: Estimates of left atrial size in patients with suspected cardiac disease play an important role in predicting prognosis and events, as well as treatment decisions. Two methods are commonly used to estimate left atrial size: chest radiography and cardiac ultrasound. This study aims to determine the test characteristics by comparing the use of radiographs to cardiac ultrasound (the gold-standard test). METHODS: Data from patients older than 18 years admitted to Steve Biko Academic Hospital during 2000-2003 who had both chest radiographs and cardiac ultrasound were included in this cross-sectional, retrospective analysis. Chest radiographs were classified into three quality classes, and the sub-carinal angle (SCA) and sub-angle distance (SAD) were measured twice in all available radiographs by two observers. Intra- and inter-observer variability (three methods) as well as the predictive value of the carinal angle and sub-angle distance measurements were determined using logistic regression (with left atrial enlargement - determined by ultrasound as comparator). RESULTS: Data for 159 patients were available (154 cardiac ultrasounds and 178 chest radiographs). Intra-observer variability for chest radiograph measurements was low with almost perfect concordance (p = 0.000). Inter-observer variability was higher for supine radiographs. Using logistic regression, a linear model was identified which was statistically significant only for erect radiographs. While goodness-of-fit analysis showed that the model fits the data, performance characteristics were poor, with high sensitivity and low specificity, and an area under the ROC curve of 0.62-0.63, depending on type of radiograph and measurement (SCA or SAD). Linearity in the logit of the dependent variable was assessed, and found to be present at the extremes of SCA measurements for the supine radiograph data and in the first three quartiles for erect radiograph data. A nonlinear model determined by fractional polynomial analysis did not perform significantly better than the original linear model. Cut-off values for the SCA of 72 degrees and 84 degrees (erect and supine radiographs, respectively) were found to give the best compromise between sensitivity and specificity. The corresponding cut-off values for SAD were 24.1 and 26.9 mm. CONCLUSION: Assessment of either SCA or SAD to determine left atrial size was equivalent and repeatable, both with the same observer and between two observers (less so for supine radiographs). While this measure was precise, it was found not to be very accurate. Therefore, chest radiographs are not reliable in predicting left atrial enlargement. PMID- 20972517 TI - The grapefruit: an old wine in a new glass? Metabolic and cardiovascular perspectives. AB - Grapefruit is a popular, tasty and nutritive fruit enjoyed globally. Biomedical evidence in the last 10 years has, however, shown that consumption of grapefruit or its juice is associated with drug interactions, which, in some cases, have been fatal. Grapefruit-induced drug interactions are unique in that the cytochrome P450 enzyme CYP3A4, which metabolises over 60% of commonly prescribed drugs as well as other drug transporter proteins such as P-glycoprotein and organic cation transporter proteins, which are all expressed in the intestines, are involved. However, the extent to which grapefruit-drug interactions impact on clinical settings has not been fully determined, probably because many cases are not reported. It has recently emerged that grapefruit, by virtue of its rich flavonoid content, is beneficial in the management of degenerative diseases such as diabetes and cardiovascular disorders. This potentially explosive subject is reviewed here. PMID- 20972519 TI - Update on smoking cessation techniques. PMID- 20972518 TI - Congenital absence of the left circumflex coronary artery and an unusually dominant course of the right coronary artery. AB - Congenital absence of the left circumflex artery (LCX) is a very rare congenital anomaly of the coronary circulation, and only a few cases have been reported in the literature. We report on a 55-year-old female with atypical chest pain. Routine coronary angiography showed a normal left anterior descending coronary artery (LAD), no LCX and a dominant right coronary artery (RCA), which continued beyond the crux, running the full course of the LCX and terminating in the left atrial branch. Neither aortography nor pulmonary angiography showed a separate ostium for the LCX. There were no atherosclerotic lesions in the coronary arteries, or ischaemia on stress myocardial perfusion imaging. Multidetector row computed tomography (MDCT) was performed to confirm the diagnosis. PMID- 20972520 TI - Reaching target LDL cholesterol has become more affordable with launch of ezetimibe/simvastatin combination in South Africa. PMID- 20972521 TI - Osteoporosis: a cardiovascular risk factor equivalent to type 2 diabetes. PMID- 20972522 TI - Focus on 2010 South African Heart Congress: dangers of switching anti hypertension medication. PMID- 20972523 TI - The J-shaped curve: fact or fiction? PMID- 20972524 TI - Anti-thrombotic trials in atrial fibrillation, the RELY study. PMID- 20972525 TI - Focus on 2010 ESC Congress: new ESC guidelines and data on dabigatran. PMID- 20972526 TI - Effective single-drug approach is welcomed for deep-vein thrombosis treatment. PMID- 20972527 TI - SHIFTING the burden of heart failure. PMID- 20972528 TI - Low-dose omega-3 fatty acids in margarines prove disappointing as secondary prevention. PMID- 20972530 TI - [Are specialists in ethics necessary in daily routine surgery?]. PMID- 20972531 TI - [In vitro allergy diagnosis in dermatology]. PMID- 20972532 TI - Why are reproductively parasitic fish males so small?--influence of tactic specific selection. AB - Despite the wide prevalence of alternative reproductive tactics, little attention has been paid to why reproductively parasitic males are so small. In this study, we tackled this issue in a shell-brooding fish Lamprologus callipterus. Sneaky 'dwarf males' of this fish remain much smaller than bourgeois conspecifics throughout their life and employ a unique parasitic tactic, i.e. entering into a gastropod shell where a female is spawning, passing through the space between the female and shell wall and staying behind her to ejaculate throughout the spawning event. Here, we tested the prediction that they remain small to get past her through the shell spaces by interpopulation comparison. We showed, across populations, a negative allometry for sexual size dimorphism, an exponential increase of female size with an increase in shell size and a negative correlation between the magnitude of sexual size dimorphism and shell size. These results suggest that the inner spaces strongly regulate dwarf male size. We conclude that the small bodies of dwarf males arise from adaptation to their unique reproductive behaviour. PMID- 20972534 TI - Mercury accumulation in the clam, Galatea paradoxa (Born 1778) at the Volta estuary, Ghana. AB - The concentration of mercury in the tissues of the clam, Galatea paradoxa at in the Volta estuary, Ghana, were analysed over an 18-month period, from March 2008 to August 2009. The concentrations were well below the International Human Consumption Advisory Limit of THg (0.5 MUg/g wet weight). The concentrations in the tissues of the different clam size classes were between 6 and 18 times lower than the WHO Safety Reference Standard. Variation in the mean mercury concentration in the different clam size classes was not significant (p > 0.05) for clams from Aveglo but were highly significant (p < 0.0001) for clams from Ada, indicating a possible effect of size on accumulation. G. paradoxa is therefore suitable for human consumption based on the WHO Safety Reference Standards. PMID- 20972533 TI - Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-alpha in mice. AB - AIMS/HYPOTHESIS: Metformin is widely used for the treatment of type 2 diabetes. Although it reduces hepatic glucose production, clinical studies show that metformin may reduce plasma dipeptidyl peptidase-4 activity and increase circulating levels of glucagon-like peptide 1 (GLP-1). We examined whether metformin exerts glucoregulatory actions via modulation of the incretin axis. METHODS: Metformin action was assessed in Glp1r(-/-), Gipr(-/-), Glp1r:Gipr(-/-), Pparalpha (also known as Ppara)(-/-) and hyperglycaemic obese wild-type mice with or without the GLP-1 receptor (GLP1R) antagonist exendin(9-39). Experimental endpoints included glucose tolerance, plasma insulin levels, gastric emptying and food intake. Incretin receptor expression was assessed in isolated islets from metformin-treated wild-type and Pparalpha(-/-) mice, and in INS-1 832/3 beta cells with or without peroxisome proliferator-activated receptor (PPAR)-alpha or AMP-activated protein kinase (AMPK) antagonists. RESULTS: In wild-type mice, metformin acutely increased plasma levels of GLP-1, but not those of gastric inhibitory polypeptide or peptide YY; it also improved oral glucose tolerance and reduced gastric emptying. Metformin significantly improved oral glucose tolerance despite loss of incretin action in Glp1r(-/-), Gipr(-/-) and Glp1r(-/-) :Gipr(-/ ) mice, and in wild-type mice fed a high-fat diet and treated with exendin(9-39). Levels of mRNA transcripts for Glp1r, Gipr and Pparalpha were significantly increased in islets from metformin-treated mice. Metformin directly increased Glp1r expression in INS-1 beta cells via a PPAR-alpha-dependent, AMPK-independent mechanism. Metformin failed to induce incretin receptor gene expression in islets from Pparalpha(-/-) mice. CONCLUSIONS/INTERPRETATION: As metformin modulates multiple components of the incretin axis, and enhances expression of the Glp1r and related insulinotropic islet receptors through a mechanism requiring PPAR alpha, metformin may be mechanistically well suited for combination with incretin based therapies. PMID- 20972535 TI - Potential occupational exposures in the Reiss-Engelhorn-Museen Mannheim/Germany. AB - The Reiss-Engelhorn-Museen in Mannheim, Germany requested support from a toxicological laboratory in evaluating occupational exposures before a cleanup and renovation period in 2006. Samples of dust and dirt and scrapings of exhibits were collected from several locations. Following toxicologically relevant compounds could be identified by gas chromatography - mass spectrometry (GC/MS) by comparison with a mass spectra library: dichlorodiphenyl trichloroethane (DDT) and its breakdown product dichlorodiphenyl dichloroethane (DDD) as well as dichlorodiphenyl dichlorethylene (DDE), methoxychlor, nicotine, and camphor. In recent times various insecticides have been used to protect museum artefacts against moths, woodborers and other insect pests. Caution has to be made because the presence of hazardous compounds can result in security problems for museum staff as well as for visitors. PMID- 20972536 TI - Correlation between anatomical findings and symptoms in women with pelvic organ prolapse using an artificial neural network analysis. AB - INTRODUCTION AND HYPOTHESIS: The aim of the present study was to assess the relationship between lower urinary tract symptoms, anatomical findings, and baseline characteristics in women with pelvic organ prolapse (POP). METHODS: A cross-sectional observational study was performed, enrolling consecutive women seeking cares for lower urinary tract symptoms (LUTS) with evidence of POP. Data regarding baseline characteristics, LUTS, and physical examination were gathered for each patient. Multivariate analysis (multiple linear regression (MLR)) and artificial neural networks (ANNs) were performed to design predicting models. RESULTS: A total of 1,344 women were included. Age, BMI, pelvic organ prolapse quantification (POP-Q) stage I, and previous surgery for urinary incontinence resulted predictors of urgency and stress incontinence. POP-Q stages III-IV were related to voiding dysfunction and POP symptoms. Age, BMI, and menopausal status resulted predictors for sexual dysfunction. Receiver operating characteristic comparison confirmed that ANNs were more accurate than MLRs in identifying predictors of LUTS. CONCLUSIONS: LUTS result from a fine interaction between baseline characteristics and anatomical findings. ANNs are valuable instrument for better understanding complex biological models. PMID- 20972537 TI - Validation of web-based administration of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire (PISQ-12). AB - INTRODUCTION AND HYPOTHESIS: We studied a web-based version of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire (PISQ-12). METHODS: A randomized crossover study in which subjects completed both a web-based and paper based version of the PISQ-12, with a 2-week separation between the completion of the two versions. Demographic data and questionnaire preferences were also assessed. Group 1 completed the web version first, and group 2 completed the paper version first. RESULTS: We recruited 52 women and 50 (96.2%) completed the study. Demographic data were similar for the two groups. There was no difference in total PISQ-12 score (P = 0.41) and a high degree of correlation between versions (r = 0.88). Women preferred the web-based PISQ-12 (77.6%) over the paper based version. CONCLUSION: The web-based version of the PISQ-12 is a reliable alternative to the standard paper-based version and was preferred by women in this study regardless of age, race, and education. PMID- 20972538 TI - Sacral neuromodulation: emerging technology with expanding indications. PMID- 20972539 TI - Sacral neuromodulation stimulation in fecal incontinence. AB - Fecal incontinence (FI) is a common problem treated by many different interventions. No treatment is optimal. Based on its success for urinary incontinence, sacral nerve stimulation (SNS) has been used successfully outside the United States for FI. In direct comparison with standard medical treatment or the artificial bowel sphincter, SNS overall appeared superior. Currently, SNS is awaiting FDA approval in the United States. PMID- 20972540 TI - Alternative approaches to sacral nerve stimulation. AB - Bladder dysfunction is a very prevalent disorder and often refractory to behavioral and pharmacologic therapies. Sacral nerve stimulation is an approved method of managing urinary urgency, frequency, urge incontinence, and urinary retention. Alternative approaches to neuromodulation are being developed. The purpose of this paper is to describe emerging approaches to neuromodulation for voiding dysfunction. A current review of alternative methods of neuromodulation is discussed. This includes stimulation of the tibial nerve via a percutaneous approach, methods of stimulating the pudendal nerve to obtain afferent stimulation through sacral roots S2-S4, chemo-neuromodulation using botulinum toxin, and anogenital stimulation. These various methods are described and the current literature reviewed. Neuromodulation is an alternative to traditional management of voiding dysfunction. A benefit of neuromodulation is that it is minimally invasive and reversible. New sites of stimulation are being developed to add to our treatment options. PMID- 20972541 TI - Sacral neuromodulation stimulation for IC/PBS, chronic pelvic pain, and sexual dysfunction. AB - This study aims to review the use of sacral neuromodulation in the patient population with painful bladder syndrome/interstitial cystitis (PBS/IC), chronic pelvic pain (CPP), and sexual dysfunction. A literature review of the current research was carried out. This article highlights the current research findings and uses of sacral neuromodulation in patients with PBS/IC, CPP, vulvar vestibulitis, and erectile dysfunction. Current research on sacral neuromodulation on the abovementioned patient population has shown potential efficacy in pilot studies, though larger, multi-centered trials with long-term follow-up are needed. PMID- 20972542 TI - Procedural techniques in sacral nerve modulation. AB - Sacral neuromodulation involves a staged process, including a screening trial and delayed formal implantation for those with substantial improvement. The advent of the tined lead has revolutionized the technology, allowing for a minimally invasive outpatient procedure to be performed under intravenous sedation. With the addition of fluoroscopy to the bilateral percutaneous nerve evaluation, there has been marked improvement in the placement of these temporary leads. Thus, the screening evaluation is now a better reflection of possible permanent improvement. Both methods of screening have advantages and disadvantages. Selection of a particular procedure should be tailored to individual patient characteristics. Subsequent implantation of the internal pulse generator (IPG) or explantation of an unsuccessful staged lead is straightforward outpatient procedure, providing minimal additional risk for the patient. Future refinement to the procedure may involve the introduction of a rechargeable battery, eliminating the need for IPG replacement at the end of the battery life. PMID- 20972543 TI - Current opinion: complications and troubleshooting of sacral neuromodulation. AB - The complications of sacral neuromodulation have been minimized as technology has improved. The main surgical complication remains to be surgical site infection. We review evidence-based suggestions and procedure-specific techniques that reduce the infection rate to less than 2%. In the past, surgical revision was reported as high as 40%. The current revision rate at Mayo Clinic Florida is 10%. The most common reason for surgical revision is either battery end-of-life or loss of effectiveness. We review the best practices of the procedure and a systematic approach to troubleshoot loss of effectiveness. PMID- 20972544 TI - Sacral nerve stimulation in the elderly. AB - Sacral neuromodulation has become a widely accepted form of therapy in the overall spectrum of treatment options for urinary urgency and frequency, urge urinary incontinence, and some forms of nonobstructive urinary retention. Voiding dysfunction is very common in geriatric patients, and urgency and urge urinary incontinence are among the most prevalent forms of urinary problems in this population. Despite the fact that many different treatment options are available for these conditions, successful treatment of voiding problems in the elderly is often quite challenging. This may be exacerbated by underlying comorbidities which preclude or limit the utility of some therapies including medications. Published literature on the use and clinical outcomes of sacral nerve stimulation in older adults was reviewed and summarized. Available clinical studies examining the use of sacral neuromodulation in geriatric patients are reviewed and placed in the context of the overall treatment of voiding dysfunction in the elderly population. Sacral neuromodulation may represent a viable, minimally invasive treatment option for some older adults. PMID- 20972545 TI - Urinary retention in women and sacral neuromodulation. AB - The remit of this article is to provide an overview of urinary retention in women, taking into account the predisposing factors, aetiology, investigations and treatments. The information presented is based on a widespread search of the English literature using multiple library sites on the internet and on personal experience. Urinary retention occurs when there is impaired bladder emptying, resulting in a high post-void urinary residual. It is often associated with restricted voiding. The aetiology is manifold and thus the symptomatic patient may present to the urologist, gynaecologist, neurologist or physician. Once the problem is identified, and predisposing factors excluded (e.g. opiates), the patient has to be investigated fully. In the Department of Uro-Neurology at the National Hospital for Neurology and Neurosurgery in the UK, we advocate the use of urethral sphincter assessments, including urethral pressure studies, ultrasound volume assessment and electromyography. This article will take a detailed look at all aspects of assessing these patients. In those in whom diagnosis is reached, sacral neuromodulation (SNM) is the treatment of choice. As a modality, SNM has its supporters but also its detractors. Thus, it is essential that all patients are fully counselled before undergoing this surgery. Urinary retention in women is still poorly understood. This article serves to demystify the issues raised in having this condition, by looking closely at the currently known science. It is clear that some patients may be diagnosed with Fowler's syndrome and may thus be more treatable by SNM than others, but this still leaves a significant proportion of patients with no diagnosis and no satisfactory therapy. A great deal of work still needs to be done on the understanding of the pathogenesis, the provision of more distinct investigations and the development of better treatment modalities. PMID- 20972546 TI - Advances in the role of sacral nerve neuromodulation in lower urinary tract symptoms. AB - Sacral neuromodulation has been developed to treat chronic lower urinary tract symptoms, resistant to classical conservative therapy. The suspected mechanisms of action include afferent stimulation of the central nervous system and modulation of activity at the level of the brain. Typical neuromodulation is indicated both in overactivity and in underactivity of the lower urinary tract. In the majority of patients, a unilateral electrode in a sacral foramen and connected to a pulse generator is sufficient to achieve significant clinical results also on long term. In recent years, other urological indications have been explored. PMID- 20972547 TI - Patient selection for sacral nerve stimulation. AB - Sacral neuromodulation is an established treatment modality for urge incontinence, urinary retention, and urgency/frequency syndromes. Potential indications as well as approved indications will be reviewed with emphasis on clinical characteristics that predict success. Therapeutic trial-either a peripheral nerve evaluation or a staged implant-remains the most accurate predictor of success. Initial patient selection is based upon clinical indicators such as history and physical examination as well as urodynamic finding. Contraindications to sacral neuromodulation and the importance of using a therapeutic trial as the best predictor of successful patient selection will also be addressed. PMID- 20972548 TI - Mechanisms of action of sacral neuromodulation. AB - The lower urinary tract dysfunction encompasses voiding, postvoiding, and storage symptoms. Conventional treatment modalities include pharmacotherapy and behavioural therapy. Sacral neuromodulation (SNM) is a safe and minimally invasive treatment modality that has recently gained wide acceptance in the management of urinary urge incontinence, urge frequency, and nonobstructive urinary retention, in particular, among those patients with conditions refractory to conventional methods. We searched multiple electronic databases through June 30, 2009 for eligible studies. We examined published clinical and experimental studies concerning the mechanisms of action of SNM. In the first part of the manuscript, we describe the anatomy and functions of the lower urinary tract including the reflexes involved in its functions and then review the pathophysiology of major types of the lower urinary tract dysfunction. In the second part, we discuss different ways for SNM to control various types of voiding dysfunction. The lower urinary tract dysfunctions affect millions of people worldwide and have a severe impact on their quality of life. SNM offers a safe and minimally invasive modality in the treatment of voiding dysfunctions, especially in patients with conditions refractory to conventional therapies. PMID- 20972549 TI - The winding path to sacral foramen neural modulation: a historic chronology. AB - In the decade of the 1970's, the NIH was captivated by the dream of harnessing electrical stimulation for widespread therapeutic goals. After the success of pacemakers in the 1960's hopes were high that a number of compromised body functions could be helped. These included hearing loss, seizure disorders, scoliosis, pain control, and in spinal cord injury patients: the restoration of lost limb function, walking and breathing, and bladder control. It was a comprehensive program involving numerous research centers and included a wide variety of talent, from chemical and electrical engineers to PhDs and MDs from a variety of disciplines. The University of California in San Francisco was invited to be part of the program, largely because of its leadership status in the field of urodynamics at the time. Research was carried out throughout the decade in the successful attempt to make neural stimulation an everyday therapy for compromised bladder function. The program was carried out in phases. Initial efforts were directed at direct stimulation of the bladder wall, then the spinal cord directly, and finally the sacral roots. The goal was to achieve synergic voiding. While that didn't happen, intermittent voiding was achieved and a whole new meaning to the term modulation therapy opened up. The following paper discusses the research path into the development of sacral nerve stimulation from the lab through clinical trials to FDA approval. Critical observations linking the human situation to the lab experimental observations are underscored. The pitfalls in transition from the university environment to commercial application are depicted, along with all the human roadblocks that arose. It was a 25-year program that influenced the careers of many "fellows" worldwide. It culminated in successful patient therapy because of the generous collaborative efforts of many academic centers in Europe and North America. It was an era where all the necessary elements were in place-the NIH leadership, the combination of research talent and lab animal availability, adequate funding, and a high level of subject interest. The research environment prior to and after this time period was not nearly as friendly, either politically nor fiscally, to this sort of research program. Had it not been for this mix of forces the therapy may never have evolved. PMID- 20972550 TI - Foreword: sacral nerve stimulation now and in the future. PMID- 20972551 TI - Comparing the discriminative stimuli produced by either the neuroactive steroid pregnanolone or the benzodiazepine midazolam in rats. AB - RATIONALE: Neuroactive steroids might be therapeutic alternatives for benzodiazepines because they have similar anxiolytic, sedative, and anticonvulsant effects, and their actions at different modulatory sites on gamma aminobutyric acid(A) (GABA(A)) receptors might confer differences in adverse effects. OBJECTIVES: This study used drug discrimination to compare discriminative stimuli produced by positive GABA(A) modulators that vary in their site of action on GABA(A) receptors. METHODS: Two groups of rats discriminated either 3.2 mg/kg of pregnanolone or 0.56 mg/kg of midazolam from vehicle while responding under a fixed ratio 10 schedule of food presentation. RESULTS: Pregnanolone, midazolam, and flunitrazepam produced >= 80% drug-lever responding in both groups; each drug was more potent in rats discriminating pregnanolone. Pentobarbital produced >= 80% drug-lever responding in all rats discriminating pregnanolone, and in 1/3 of the rats discriminating midazolam with larger doses decreasing response rates to <20% of control. Morphine and ketamine produced predominantly saline-lever responding in both groups. Flumazenil antagonized midazolam and flunitrazepam in both groups; slopes of Schild plots were not different from unity, and pA (2) values for flumazenil ranged from 5.86 to 6.09. Flumazenil did not attenuate the discriminative stimulus effects of pregnanolone. CONCLUSIONS: The midazolam and pregnanolone discriminative stimuli were qualitatively similar, although the effects of pentobarbital were not identical in the two groups. Although acute effects of midazolam and pregnanolone are similar, suggesting that neuroactive steroids might retain the therapeutic effects of benzodiazepines, differences emerge during chronic treatment, indicating that neuroactive steroids might produce fewer adverse effects than benzodiazepines. PMID- 20972552 TI - Effects of cocaine hydrolase on cocaine self-administration under a PR schedule and during extended access (escalation) in rats. AB - RATIONALE AND OBJECTIVES: Previously, Albu-CocH, a cocaine hydrolase derived from human butyrylcholinesterase, blocked cocaine-induced reinstatement of drug seeking in rats. In the present study, rats were treated with Albu-CocH while self-administering cocaine under a progressive ratio (PR) schedule during 2-h sessions and under a fixed-ratio 1 (FR 1) schedule during 6-h sessions. METHODS: In experiment 1, rats were treated with saline or Albu-CocH (2 or 4 mg/kg) before a single 2-h cocaine (0.2 mg/kg) self-administration (PR) session. In experiment 2, rats were treated with Albu-CocH or saline for the first seven of the 21-day 6 h sessions prior to cocaine (0.2 or 0.4 mg/kg) self-administration sessions (FR 1). RESULTS: In experiment 1, Albu-CocH (vs saline) reduced cocaine infusions immediately following treatment compared with sessions pretreatment and posttreatment. In experiment 2, the Albu-CocH-treated groups (vs saline) showed an initial twofold to threefold increase in 0.2 and 0.4 mg/kg cocaine infusions over the 7 days of treatment, but they decreased to the infusion levels of saline controls by day 7. Cocaine (0.4 mg/kg) intake in the saline-treated group was elevated during the last 3 days of 6-h access compared with the first 3 days, indicating an escalation effect. Responding for 0.4 mg/kg (but not 0.2 mg/kg) cocaine during 2-h sessions after the 21 days of 6-h access was elevated in the saline groups (compared with 2-h sessions before long access) but not in the Albu CocH-treated groups. CONCLUSIONS: Albu-CocH decreased cocaine infusions under the PR schedule, indicating a reduced reward value of cocaine (experiment 1). However, Albu-CocH, compared with saline, temporarily increased cocaine infusions during long access. The post-long access 2-h cocaine intake was not increased in the Albu-CocH-treated groups as it was in the saline-treated groups. Albu-CocH is an effective agent for reducing cocaine reward under conditions of low cocaine exposure and chronic treatment. PMID- 20972553 TI - Retention modelling of polychlorinated biphenyls in comprehensive two-dimensional gas chromatography. AB - In this paper, we use a quantitative structure-retention relationship (QSRR) method to predict the retention times of polychlorinated biphenyls (PCBs) in comprehensive two-dimensional gas chromatography (GC*GC). We analyse the GC*GC retention data taken from the literature by comparing predictive capability of different regression methods. The various models are generated using 70 out of 209 PCB congeners in the calibration stage, while their predictive performance is evaluated on the remaining 139 compounds. The two-dimensional chromatogram is initially estimated by separately modelling retention times of PCBs in the first and in the second column ((1) t (R) and (2) t (R), respectively). In particular, multilinear regression (MLR) combined with genetic algorithm (GA) variable selection is performed to extract two small subsets of predictors for (1) t (R) and (2) t (R) from a large set of theoretical molecular descriptors provided by the popular software Dragon, which after removal of highly correlated or almost constant variables consists of 237 structure-related quantities. Based on GA-MLR analysis, a four-dimensional and a five-dimensional relationship modelling (1) t (R) and (2) t (R), respectively, are identified. Single-response partial least square (PLS-1) regression is alternatively applied to independently model (1) t (R) and (2) t (R) without the need for preliminary GA variable selection. Further, we explore the possibility of predicting the two-dimensional chromatogram of PCBs in a single calibration procedure by using a two-response PLS (PLS-2) model or a feed-forward artificial neural network (ANN) with two output neurons. In the first case, regression is carried out on the full set of 237 descriptors, while the variables previously selected by GA-MLR are initially considered as ANN inputs and subjected to a sensitivity analysis to remove the redundant ones. Results show PLS-1 regression exhibits a noticeably better descriptive and predictive performance than the other investigated approaches. The observed values of determination coefficients for (1) t (R) and (2) t (R) in calibration (0.9999 and 0.9993, respectively) and prediction (0.9987 and 0.9793, respectively) provided by PLS-1 demonstrate that GC*GC behaviour of PCBs is properly modelled. In particular, the predicted two-dimensional GC*GC chromatogram of 139 PCBs not involved in the calibration stage closely resembles the experimental one. Based on the above lines of evidence, the proposed approach ensures accurate simulation of the whole GC*GC chromatogram of PCBs using experimental determination of only 1/3 retention data of representative congeners. PMID- 20972554 TI - Critical review or scientific opinion paper: arsenosugars--a class of benign arsenic species or justification for developing partly speciated arsenic fractionation in foodstuffs? AB - In this opinion paper the toxicokinetic behaviour of arsenosugars is reviewed and compared with that of inorganic arsenic and arsenobetaine. It is concluded that the arsenosugars are similar to inorganic arsenic in terms of metabolite formation and tissue accumulation. As a pragmatic means of generating uniform data sets which adequately represent the toxicity of arsenic in food we recommend reporting partly speciated arsenic concentrations in food commodities in three fractions: i) toxic inorganic arsenic as arsenate (after oxidation); ii) arsenobetaine as established non-toxic arsenic; and iii) potentially toxic arsenic, which includes arsenosugars and other organoarsenicals. PMID- 20972556 TI - Using one-dimensional (1D) and two-dimensional (2D) quantitative proton (1H) nuclear magnetic resonance spectroscopy (q NMR) for the identification and quantification of taste compounds in raw onion (Allium cepa L.) bulbs and in aqueous solutions where onion tissues are soaked. AB - Solutions obtained by soaking onion (Allium cepa L.) bulbs samples in water are frequently consumed, either directly or as part of dishes, both at home or in the food industry. However, little information is available regarding the extracted metabolites and the extraction mechanisms. In this article, the composition of raw onion extracts and of aqueous solutions where raw onion tissues were soaked was investigated directly by quantitative proton nuclear magnetic resonance spectroscopy (q (1)H NMR). The assignment of NMR signals was performed, with less than 3% (in area) of unidentified peaks. Analyses of one-dimensional (1)H NMR spectra with additional two-dimensional NMR studies showed 20 regions of interest where 3 saccharides, 17 amino acids, and 5 organic acids were detected and quantified. Resonance assignment with chemical shift was done for each saccharide, as well as for each amino acid and organic acid, with additional work on spin-spin coupling pattern and on observed and not observed correlations from correlation spectroscopy studies. Quantification of saccharides was performed and qualified by works on peak decomposition algorithms. Complementary studies by high-performance liquid chromatography, mass spectroscopy and tandem mass spectroscopy, and thin layer chromatography and preparative layer chromatography were carried out in order to validate the NMR results on identification. PMID- 20972557 TI - Earlier discovery of pregabalin's dependence potential might have been possible. PMID- 20972558 TI - Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level. AB - OBJECTIVE: It has been reported that leflunomide and its active metabolite, A771726, are substrates of the ABCG2 (BCRP) transporter in vitro. Recent genome wide association studies have shown that ABCG2 transporter modulates serum uric acid (UA) levels. We explored the role of ABCG2 genotypes in the pharmacokinetics of A771726 and the relationship between serum UA levels and pharmacokinetics of A771726 in healthy participants. METHODS: Twenty-four healthy individuals were recruited and genotyped for ABCG2. After administration of a single dose of 20 mg leflunomide, plasma concentrations of A771726 were measured. Serum UA levels were measured just before medication, and ABCG2 c.421C>A and c.34G> A polymorphism were genotyped. RESULTS: ABCG2 c.421C>A but not c.34G>A substantially influenced the pharmacokinetics of A771726. A771726 C(max) was 30% higher, area under the concentration-time curve (AUC) 83% larger, and oral clearance (CL/F) 41% lower in c.421C>A carriers than in noncarriers. Serum UA levels were also higher in carriers than in noncarriers and exhibited a strong and positive correlation with A771726 AUC (Spearman r = 0.6746, P = 0.0003), but a negative correlation was observed with A771726 CL/F (Spearman r = -0.6616, P = 0.0004). CONCLUSION: ABCG2 c.421C>A but not c.34G>A polymorphism appears to be a major determinant of interindividual variability in A771726 disposition. Additionally, serum UA levels exhibited a strong correlation with exposure to A771726. PMID- 20972559 TI - Pharmacological properties and physiological function of a P2X-like current in single proximal tubule cells isolated from frog kidney. AB - Although previous studies have provided evidence for the expression of P2X receptors in renal proximal tubule, only one cell line study has provided functional evidence. The current study investigated the pharmacological properties and physiological role of native P2X-like currents in single frog proximal tubule cells using the whole-cell patch-clamp technique. Extracellular ATP activated a cation conductance (P2X(f)) that was also Ca2+-permeable. The agonist sequence for activation was ATP = alphabeta-MeATP > BzATP = 2-MeSATP, and P2X(f) was inhibited by suramin, PPADS and TNP-ATP. Activation of P2X(f) attenuated the rundown of a quinidine-sensitive K+ conductance, suggesting that P2X(f) plays a role in K+ channel regulation. In addition, ATP/ADP apyrase and inhibitors of P2X(f) inhibited regulatory volume decrease (RVD). These data are consistent with the presence of a P2X receptor that plays a role in the regulation of cell volume and K+ channels in frog renal proximal tubule cells. PMID- 20972560 TI - A tandem duplication of manganese superoxide dismutase in Nosema bombycis and its evolutionary origins. AB - Microsporidia are a group of obligate intracellular eukaryotic parasites with small genomes. They infect animals from a wide variety of phyla, including humans. Two manganese superoxide dismutase (MnSOD) genes, designated NbMnSOD1 and NbMnSOD2, were found to be organized in a tandem array within the Nosema bombycis genome. The genes, both 678 bp in length, were found to be more similar to each other than they are to homologous genes of other Microsporidia, suggesting that the tandem duplication occurred subsequent to the development of this lineage. Reverse transcript PCR shows that mRNA for both genes is present in the spores. Analysis of the primary structure, hydrophobic cluster analysis, target signal analysis, and phylogenetic analysis all indicate that NbMnSOD1 is dimeric and targeted to the cytosol. NbMnSOD2 seems to have changed more rapidly and is under less evolutionary constraint than NbMnSOD1 suggesting that NbMnSOD2 may function under different conditions or in different tissues of its host rather than simply resulting in an increase in expression. A phylogenetic analysis of MnSOD sequences from eukaryotes, Archaea, and bacteria shows the microsporidial MnSODs to be grouped with the bacteria suggesting a possible horizontal gene transfer. PMID- 20972562 TI - Placing the effects of leaf litter diversity on saprotrophic microorganisms in the context of leaf type and habitat. AB - Because of conflicting results in previous studies, it is unclear whether litter diversity has a predictable impact on microbial communities or ecosystem processes. We examined whether effects of litter diversity depend on factors that could confound comparisons among previous studies, including leaf type, habitat type, identity of other leaves in the mixture, and spatial covariance at two scales within habitats. We also examined how litter diversity affects the saprotrophic microbial community using terminal restriction fragment length polymorphism to profile bacterial and fungal community composition, direct microscopy to quantify bacterial biomass, and ergosterol extraction to quantify fungal biomass. We found that leaf mixture diversity was rarely significant as a main effect (only for fungal biomass), but was often significant as an interaction with leaf type (for ash-free dry mass recovered, carbon-to-nitrogen ratio, fungal biomass, and bacterial community composition). Leaf type and habitat were significant as main effects for all response variables. The majority of variance in leaf ash-free dry mass and C/N ratio was explained after accounting for treatment effects and spatial covariation at the meter (block) and centimeter (litterbag) scales. However, a substantial amount of variability in microbial communities was left unexplained and must be driven by factors at other spatial scales or more complex spatiotemporal dynamics. We conclude that litter diversity effects are primarily dependent on leaf type, rather than habitat type or identity of surrounding leaves, which can guide the search for mechanisms underlying effects of litter diversity on ecosystem processes. PMID- 20972561 TI - Balance of neutral and deterministic components in the dynamics of activated sludge floc assembly. AB - Understanding the processes that generate patterns of community structure is a central focus of ecological research. With that aim, we manipulated the structure of bacterial activated sludge to test the influence of the species richness and composition of bacterial communities on the dynamics of activated sludge floc assembly in lab-scale bioreactors. Bacterial community structure was analyzed using denaturing gradient gel electrophoresis of RT-PCR amplified 16S rRNA. Fingerprinting of four parallel reactors, started with the same source communities added in different proportions, converged to patterns that were more similar than expected by chance, suggesting a deterministic selection in floc development. Evidence for neutral dynamics was suggested by the dependence of the rate of replacement of species (bacterial taxa-time relationships) on the number of available species in the source community. Further indication of stochastic dynamics was obtained by the application of the Sloan neutral model for prokaryotes. The fitting of the observed data to the model predictions revealed that the importance of the stochastic component increased with the size of the reservoir of species richness from which the community is drawn. Taken together, the results illustrate how both neutral and deterministic dynamics operate simultaneously in the assembly of the bacterial floc and show that the balance of the two depends on the richness of the source community. PMID- 20972563 TI - Diffusion tensor of water in model articular cartilage. AB - We used Monte Carlo simulations of Brownian dynamics of water to study anisotropic water diffusion in an idealised model of articular cartilage. The main aim was to use the simulations as a tool for translation of the fractional anisotropy of the water diffusion tensor in cartilage into quantitative characteristics of its collagen fibre network. The key finding was a linear empirical relationship between the collagen volume fraction and the fractional anisotropy of the diffusion tensor. Fractional anisotropy of the diffusion tensor is potentially a robust indicator of the microstructure of the tissue because, to a first approximation, it is invariant to inclusion of proteoglycans or chemical exchange between free and collagen-bound water in the model. We discuss potential applications of Monte Carlo diffusion-tensor simulations for quantitative biophysical interpretation of magnetic resonance diffusion-tensor images of cartilage. Extension of the model to include collagen fibre disorder is also discussed. PMID- 20972564 TI - MR imaging of the brachial plexus: comparison between 1.5-T and 3-T MR imaging: preliminary experience. AB - OBJECTIVE: To compare 1.5-T and 3-T magnetic resonance (MR) imaging of the brachial plexus. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained from 30 healthy volunteers and 30 consecutive patients with brachial plexus disturbances. MR was prospectively performed with comparable sequence parameters and coils with a 1.5-T and a 3-T system. Imaging protocols at both field strengths included T1-weighted turbo spin-echo (tSE) sequences and T2-weighed turbo spin-echo (tSE) sequences with fat saturation. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) between muscle and nerve were calculated for both field strengths. The visibility of brachial plexus nerve at various anatomic levels (roots, interscalene area, costoclavicular space, and axillary level) was analyzed with a four-point grading scale by two radiologists. MR imaging diagnoses and pathological findings were also compared qualitatively. RESULTS: SNR and CNRs were significantly higher on 3-T MR images than on 1.5-T MR images (Friedman test) for all sequences. Nerve visibility was significantly better on 3-T MR images than on 1.5-T MR images (paired sign test). Pathological findings (n = 30/30) were seen equally well with both field strengths. MR imaging diagnoses did not differ for the 1.5- and 3-T protocols. CONCLUSIONS: High-quality MR images of the brachial plexus can be obtained with 3 T MR imaging by using sequences similar to those used at 1.5-T MR imaging. In patients and healthy volunteers, the visibility of nerve trunks and cords at 3-T MR imaging appears to be superior to that at 1.5-T MR imaging. PMID- 20972565 TI - Radiological findings of renal leiomyomas: a report of five surgically confirmed cases. AB - BACKGROUND: To describe radiological features of renal leiomyomas. METHODS: We retrospectively reviewed radiological findings of surgically confirmed renal leiomyomas in five patients. Three patients only underwent CT examinations, while two patients received both CT and MR examinations. RESULTS: Six renal leiomyomas were found in the five patients, which located in the right kidney. Four tumors were at the periphery of the kidney, one tumor was in the renal parenchyma, and one tumor located in the renal pelvis. At plain CT scans, five lesions were homogeneous dense with three hyperdense and two isodense, while one lesion was heterogeneous dense. At MR imaging, one lesion was heterogeneous signal and two lesions were homogeneous signal. After i.v. contrast materials, all lesions demonstrated homogenous or heterogeneous enhancement which were lower than the renal cortex at the corticomedullary phase. A trend of continuous and homogeneous enhancement was observed in dynamic enhancement on CT and MR imaging. CONCLUSION: Renal leiomyomas have some characteristic radiological findings, such as homogeneous density or signal peripheral mass with well-defined margins, less heterogeneous or homogeneous enhancement than adjacent renal cortex at the corticomedullary phase, a trend of continuous and homogeneous on later phase of dynamic scanning. PMID- 20972566 TI - Commentary on "Seroma as a late complication after breast augmentation" by V.D. Pinchuk, O.V. Tymofii. PMID- 20972567 TI - Computer-aided design and manufacturing and rapid prototyped nanoscale hydroxyapatite/polyamide (n-HA/PA) construction for condylar defect caused by mandibular angle ostectomy. AB - The fracture or defect of the mandibular condyle is one of the serious complications during angle-reduction ostectomy. Reconstruction of such defects also is a daunting task. The case report describes a method based on computer aided design/computer-aided manufacturing (CAD/CAM) and rapid prototyping nanoscale hydroxyapatite/polyamide (n-HA/PA) for individual design, fabrication, and implantation of a mandibular condyle. A 27-year-old woman with a square shaped face who had previously undergone mandibular angle reduction reported with malocclusion, deviated mouth, collapse of the right side of the face, and masticatory problems. The reason for the problems was the unintended removal of the condyle during the ostectomy procedure. Using computed tomography (CT) data, a biomimetic n-HA/PA scaffold, and CAD/CAM for rapid prototyping by three dimensional (3D) printing, a perfect-fitting condylar implant was fabricated. A surgical guide system also was developed to reproduce the procedures accurately so a perfect fit could be obtained during surgery. The patient ultimately regained reasonable jaw contour and appearance, as well as appreciable temporomandibular joint (TMJ) function. PMID- 20972568 TI - Surgical management of binder syndrome: lessons learned. PMID- 20972569 TI - "Number needed to read"--how to facilitate clinical trials in MR-angiography. AB - PURPOSE: To evaluate the effect of the number of readers on the statistical results in peripheral MRA. MATERIALS AND METHODS: 40 patients with peripheral arterial occlusive disease were included as a sample dataset in this study, randomly separated into two matched groups with n = 20 patients (group 1- gadobutrol, group 2--gadoterate meglumine) who underwent a continuous table movement MRA of the peripheral vessels at 3 T. Image quality (IQ) of 17 vessel segments was evaluated by 5 independent readers. The effect of the number of readers on significance and statistical power was statistically analyzed. RESULTS: Image quality in group 1 (gadobutrol) ranks significantly higher compared to group 2 (gadoterade meglumine) with a diagnostic IQ in 97% vs. 78% (p < 0.0001). For the diagnostic/non-diagnostic IQ assessment significance was reached with one reader 1/5 times (20%), with two readers in 4/10 (40%), with three readers in 6/10 (60%), with four readers in 4/5 (80%), with five readers in 1/1 (100%). Power considerations showed considerable gain when increasing the number of readers. CONCLUSION: Increasing the number of readers in a diagnostic MRA-study can be used to achieve a higher power or to decrease the number of subjects included with maintained statistical validity. PMID- 20972570 TI - Views, landmarks, and routes: how do desert ants negotiate an obstacle course? AB - The Australian desert ant Melophorus bagoti often follows stereotypical routes through a cluttered landscape containing both distant panoramic views and obstacles (plants) to navigate around. We created an artificial obstacle course for the ants between a feeder and their nest. Landmarks comprised natural objects in the landscape such as logs, branches, and tussocks. Many ants travelled stereotypical routes home through the obstacle course in training, threading repeatedly the same gaps in the landmarks. Manipulations altering the relations between the landmarks and the surrounding panorama, however, affected the routes in two major ways. Both interchanging the positions of landmarks (transpositions) and displacing the entire landmark set along with the starting position of the ants (translations) (1) reduced the stereotypicality of the route, and (2) increased turns and meanders during travel. The ants might have used the entire panorama in view-based travel, or the distal panorama might prime the identification and use of landmarks en route. Despite the large data set, both options (not mutually exclusive) remain viable. PMID- 20972572 TI - Sidestream dark field imaging: the evolution of real-time visualization of cutaneous microcirculation and its potential application in dermatology. AB - Technological advances during the last years have enhanced the image quality of the microcirculation. Intravital microscopy (IM) has been considered the "gold standard" for many years, but it can be used mostly in anesthetized animals which is a disadvantage. The nailfold videocapillaroscopy, a non-invasive examination that includes a microscope with an epiillumination system, came afterward, but its major disadvantage is the restricted area available for investigation namely the nailfold capillary bed. The orthogonal polarization spectral (OPS) imaging technique, where reflected light allows the visualization of the microcirculation, was the next non-invasive exam, but it still presents some drawbacks such as suboptimal capillary visualization and image blurring due to red blood cell movements. Excessive probe pressure modifies red blood cell velocity. There is suboptimal imaging of capillaries due to motion-induced image blurring by movements of OPS device, tissue and/or flowing red blood cells. Sidestream dark field (SDF) imaging is the newest tool for microcirculatory research. Illumination is provided by concentrically placed light-emitting diodes to avoid image blurring and to enhance image contrast. It represents a simple and non-invasive imaging technique, with low cost, good portability and high sensitivity that provides fine, well-defined images. In addition, the microcirculation can be studied through laser Doppler flowmetry (LDF) or reflectance-mode confocal-laser-scanning microscopy (RCLM). However, LDF cannot show microcirculatory vessels and high cost of RCLM can be an inconvenience. New applications of SDF technique could include skin microcirculatory evaluation and allow dermatological studies on psoriasis, skin tumors and leprosy. PMID- 20972571 TI - Short-term outcomes following laparoscopic resection for colon cancer. AB - BACKGROUND: Laparoscopic resection for colon cancer has been proven to have a similar oncological efficacy compared to open resection. Despite this, it is performed by a minority of colorectal surgeons. The aim of our study was to evaluate the short-term clinical, oncological and survival outcomes in all patients undergoing laparoscopic resection for colon cancer. METHODS: From July 2005 to December 2008, 202 consecutive patients underwent laparoscopic resection for colon cancer. Surgery was analysed on an intention to treat basis. The mean follow-up was 24.3 months. RESULTS: Two hundred twenty-two patients underwent resection for colon cancer. Two hundred two underwent laparoscopic resection (91%). One hundred sixteen were male patients. Mean age was 65.9 years (range = 24-91). The median length of stay was 6.6 days (mean = 7.1 days). One hundred eighty-eight of 202 (93.1%) were completed laparoscopically. Fourteen (6.9%) were converted. The overall morbidity rate was 15.8%. There were three clinically apparent anastomotic leaks. The 30-day mortality was 1 (0.5%). The mean nodal yield was 13.4 (range = 8-37) nodes. There were no positive margins detected. Overall survival in laparoscopically treated colon cancer was 88.1%. In those patients with non-metastatic disease, the overall survival was 90.7% (165/182). CONCLUSION: Laparoscopic resection for colon cancer is achievable in 85% (188/222) of patients. This facilitates adequate oncological clearance. It is associated with a low morbidity rate and favourable short-term survival outcomes. This data reflects the potential outcomes dedicated MIS colorectal units will have to offer colon cancer patients once laparoscopic colorectal surgery becomes the de facto surgical approach. PMID- 20972573 TI - Subjective and objective outcomes of tympanoplasty surgery at National Hospital Abuja, Nigeria 2005-2009. AB - The objective of this study is to determine the subjective and objective outcomes of tympanoplasty surgery carried out in patients with otitis media and to identify factors responsible for these outcomes. The study setting is tertiary care urban referral hospital in a developing economy and the study methodology is a prospective analysis of patients with diagnosis of chronic suppurative otitis media that had tympanoplasty with or without mastoidectomy between May 2005 and September 2009 at National Hospital Abuja. Subjects were evaluated for age, sex, size and site of perforation, status of operated ear(s) (dry/discharging), status of the contralateral ear, surgical technique, subjective and objective pre operative and post-operative hearing scores, average post-operative follow-up time, and post-operative complications, and results were statistically analyzed. A total of 45 patients (51 ears) were operated. Age distribution was 8-52 years. Type 1 tympanoplasty was done in 41 patients and Type 3 in 4 patients. Seven of the patient had concomitant mastoid surgery (cortical mastoidectomy). 3/51 of the cases had discharging ears at surgery. 16/45 of the patients (19/51 ears) had cartilage graft tympanoplasty, while 29/45 (32 ears) had temporalis fascia tympanoplasty. 15/16 of the cartilage group as well as 26/29 of the fascia group reported subjective hearing improvement, whilst the actual graft take was 12/16 of the cartilage group and 23/29 of the fascia group. Objective hearing improvement was observed in all of the cartilage as well as 26/29 of the fascia group. This study confirms success of tympanoplasty among Nigerians, and recommends that subjective hearing assessment should form part of indicators for success following tympanoplasty. PMID- 20972574 TI - Ultrasound lung "comets" increase after breath-hold diving. AB - The purpose of the study was to analyze the ultrasound lung comets (ULCs) variation, which are a sign of extra-vascular lung water. Forty-two healthy individuals performed breath-hold diving in different conditions: dynamic surface apnea; deep variable-weight apnea and shallow, face immersed without effort (static maximal and non-maximal). The number of ULCs was evaluated by means of an ultrasound scan of the chest, before and after breath-hold diving sessions. The ULC score increased significantly from baseline after dynamic surface apnea (p = 0.0068), after deep breath-hold sessions (p = 0.0018), and after static maximal apnea (p = 0.031). There was no statistically significant difference between the average increase of ULC scores after dynamic surface apnea and deep breath-hold diving. We, therefore, postulate that extravascular lung water accumulation may be due to other factors than (deep) immersion alone, because it occurs during dynamic surface apnea as well. Three mechanisms may be responsible for this. First, the immersion-induced hydrostatic pressure gradient applied on the body causes a shift of peripheral venous blood towards the thorax. Second, the blood pooling effect found during the diving response Redistributes blood to the pulmonary vascular bed. Third, it is possible that the intense involuntary diaphragmatic contractions occurring during the "struggle phase" of the breath hold can also produce a blood shift from the pulmonary capillaries to the pulmonary alveoli. A combination of these factors may explain the observed increase in ULC scores in deep, shallow maximal and shallow dynamic apneas, whereas shallow non-maximal apneas seem to be not "ULC provoking". PMID- 20972575 TI - Age, muscle fatigue, and walking endurance in pre-menopausal women. AB - Aging is associated with loss of endurance; however, aging is also associated with decreased fatigue during maximal isometric contractions. The aims of this study were to examine the relationship between age and walking endurance (WE) and maximal isometric fatigue (MIF) and to determine which metabolic/fitness components explain the expected age effects on WE and MIF. Subjects were 96 pre menopausal women. Oxygen uptake (walking economy) was assessed during a 3-mph walk; aerobic capacity and WE by progressive treadmill test; knee extension strength by isometric contractions, MIF during a 90-s isometric plantar flexion (muscle metabolism measured by (31)P MRS). Age was related to increased walking economy (low VO(2), r = -0.19, P < 0.03) and muscle metabolic economy (force/ATP, 0.34, P = 0.01), and reduced MIF (-0.26, P < 0.03). However, age was associated with reduced WE (-0.28, P < 0.01). Multiple regression showed that muscle metabolic economy explained the age-related decrease in MIF (partial r for MIF and age -0.13, P = 0.35) whereas walking economy did not explain the age-related decrease in WE (partial r for WE and age -0.25, P < 0.02). Inclusion of VO(2max) and knee endurance strength accounted for the age-related decreased WE (partial r for WE and age = 0.03, P > 0.80). In premenopausal women, age is related to WE and MIF. In addition, these results support the hypothesis that age-related increases in metabolic economy may decrease MIF. However, decreased muscle strength and oxidative capacity are related to WE. PMID- 20972576 TI - The influence of physical exercise on the generation of TGF-beta1, PDGF-AA, and VEGF-A in adipose tissue. AB - Adipose tissue is an important organ that produces and secretes hormones and cytokines, including TGF-beta1, PDGF-AA, and VEGF-A. The goal of the present study was to investigate the influence of a single session of acute exercise, as well as the prolonged endurance training on the production of TGF-beta1, PDGF-AA, and VEGF-A in the subcutaneous white adipose tissue in rats. Rats were randomly divided into two groups: untrained (UT, n = 30) and trained rats (T, subjected to 6-week endurance training with increasing load, n = 29). Both groups were subjected to an acute exercise session with the same work load. The rats were killed before (UTpre, Tpre), immediately after (UT0h, T0h), or 3 h (UT3h, T3h) after exercise and adipose tissue samples collected. Growth factor mRNA was evaluated using RT-PCR; the protein levels were measured before and after training (UTpre and Tpre) using the immunoenzymatic method. TGF-beta1 and PDGF-AA mRNA levels were decreased in the UT3h rats compared to the UTpre rats (P = 0.0001 and P = 0.03, respectively), but the VEGF-A mRNA level remained unchanged in the UT0h and UT3h rats compared to UTpre rats. TGF-beta1, PDGF-AA and VEGF-A mRNA levels were decreased in the T3h rats compared to Tpre (P = 0.0002, P = 0.02, and P = 0.03, respectively). TGF-beta1, PDGF-AA and VEGF-A mRNA levels significantly increased in the Tpre rats compared to UTpre (all P = 0.0002). However, the protein levels remained constant. In conclusion, prolonged physical exercise increases growth factor mRNA in adipose tissue but not protein levels. PMID- 20972577 TI - Reply on Baker's comments to Nolte and Noakes: "change in body mass accurately and reliably predicts change in body water after endurance exercise". PMID- 20972578 TI - Interval training for patients with coronary artery disease: a systematic review. AB - Interval training (IT) may induce physiological adaptations superior to those achieved with conventional moderate-intensity continuous training (MCT) in patients with coronary artery disease (CAD). Our objectives were (1) to systematically review studies which have prescribed IT in CAD, (2) to summarize the findings of this research including the safety and physiological benefits of IT, and (3) to identify areas for further investigation. A systematic review of the literature using computerized databases was performed. The search yielded two controlled trials and five randomized controlled trials (RCTs) enrolling 213 participants. IT prescribed in isolation or in combination with resistance training was shown to induce significant and clinically important physiological adaptations in cardiac patients. IT was also shown to improve cardiorespiratory fitness (e.g. VO(2max), VO(2AT)), endothelial function, left ventricle morphology and function (e.g. ejection fraction) to a significantly greater extent when compared with conventional MCT. No adverse cardiac or other life-threatening events occurred secondary to exercise participation in these studies. However, these findings must be interpreted with caution, as methodological limitations were present in all trials reviewed. In conclusion, robustly designed RCTs with thorough and standardized reporting are required to determine the risk and benefits of IT in the broader cardiac patient population. Further research is required to determine optimal IT protocols for the use in cardiac rehabilitation programmes, potentially contributing to novel exercise prescription guidelines for this patient population. PMID- 20972580 TI - Description of gamontogonic and sporogonic stages of Hepatozoon spp. (Apicomplexa, Hepatozoidae) from Caudisoma durissa terrifica (Serpentes, Viperidae). AB - Three specimens of Caudisoma durissa terrifica infected with Hepatozoon spp. were studied. One was parasitized by one type of gamont and the other two were each infected by two morphologically different gamonts. Utilizing morphology and morphometry analysis, we concluded that three types of gamonts were very similar and may represent the same Hepatozoon species, but at least three different Hepatozoon species were infecting the C. durissa terrifica snakes in this study. Some of this species caused erythrocyte modifications. The sporogonic development of Hepatozoon sp. was observed from 12 h to the 20th day after female Culex quinquefasciatus blood meals. PMID- 20972581 TI - Laparoscopic repair of colonoscopic perforation: a new standard? AB - BACKGROUND: Scientific evidence demonstrating interest in the laparoscopic approach for surgical repair of colonoscopic perforations is still lacking. The authors retrospectively reviewed the records of 43 patients who suffered from colonic perforations after colonoscopy between 1989 and 2008 in two tertiary centers in order to compare the results of the laparoscopic and the open approaches to repair. METHODS: The patients' demographic data, perforation location, therapy, and outcome were recorded from the medical charts. Forty-two patients were managed operatively (19 laparoscopies and 23 laparotomies). In three patients who underwent explorative laparoscopy, the procedure had to be converted to laparotomy due to surgical difficulties. The patients who underwent laparotomy management had a longer period between the colonoscopy and the surgery (P=0.056) and more stercoral contaminations. RESULTS: The mean hospital stay was shorter for the laparoscopy group (P=0.02), which had fewer postoperative complications (P=0.01) and no mortality (NS). CONCLUSION: This series demonstrates that early laparoscopic management of colonoscopic perforation is safe. Laparoscopic management may lead to reduced surgical and psychological stress for the patient because of its low morbidity and mortality rates and shorter hospital stay. However, the procedure should be converted to a laparotomy if necessary. PMID- 20972582 TI - Right colectomy: is it a safe and feasible totally laparoscopic approach with transvaginal specimen extraction. PMID- 20972579 TI - Role of the ubiquitin system in regulating ion transport. AB - Ion channels and transporters play a critical role in ion and fluid homeostasis and thus in normal animal physiology and pathology. Tight regulation of these transmembrane proteins is therefore essential. In recent years, many studies have focused their attention on the role of the ubiquitin system in regulating ion channels and transporters, initialed by the discoveries of the role of this system in processing of Cystic Fibrosis Transmembrane Regulator (CFTR), and in regulating endocytosis of the epithelial Na(+) channel (ENaC) by the Nedd4 family of ubiquitin ligases (mainly Nedd4-2). In this review, we discuss the role of the ubiquitin system in ER Associated Degradation (ERAD) of ion channels, and in the regulation of endocytosis and lysosomal sorting of ion channels and transporters, focusing primarily in mammalian cells. We also briefly discuss the role of ubiquitin like molecules (such as SUMO) in such regulation, for which much less is known so far. PMID- 20972583 TI - A case-controlled comparison of single-site access versus conventional three-port laparoscopic appendectomy. AB - BACKGROUND: The aim of this study was to compare patients who underwent single site access laparoscopic appendectomy (SSALA) to those who underwent conventional three-port laparoscopic appendectomy (TPLA) in a case-controlled manner. METHODS: Consecutive patients who underwent SSALA for suspected acute appendicitis between April and September 2009 were retrospectively compared to those who underwent TPLA between January and December 2008 in a case-controlled manner. The patients were matched for age, gender, and pathological findings. The main outcome measurements included postoperative recovery, morbidities, and mortalities. RESULTS: During the study period, a total of 30 patients underwent SSALA and these were matched with 60 TPLA patients. There were no significant differences in the mean operative time, hospital stay, and 30-day morbidity rate between the two groups. None of the patients required conversion. Two patients with significant contamination and abscess collection noted during SSALA required a relaparotomy for peritoneal lavage and adhesiolysis due to prolonged ileus. CONCLUSIONS: SSALA is feasible and the perioperative outcome was comparable to that of TPLA. However, future prospective studies will need to evaluate whether SSALA can adequately tackle patients with significant peritoneal contamination. PMID- 20972584 TI - Comparison of laparoscopy-assisted and total laparoscopic Billroth-I gastrectomy for gastric cancer: a report of short-term outcomes. AB - BACKGROUND: The safety and efficacy of laparoscopic gastrectomy in the treatment of early gastric cancer have been demonstrated in many clinical studies. Most surgeons prefer laparoscopy-assisted gastrectomy with extracorporeal anastomosis rather than total laparoscopic procedures because of the technical difficulties of intracorporeal anastomosis. This study assessed the efficacy of total laparoscopic Billroth-I (B-I) gastrectomy. METHODS: We conducted a retrospective analysis of a single surgeon's experience. We reviewed patients with gastric cancer who underwent laparoscopic B-I gastrectomy (n=83) and classified them into laparoscopy-assisted distal gastrectomy (LADG; n=41) and total laparoscopic distal gastrectomy (TLDG; n=42) groups. Short-term surgical variables and outcomes were compared between the groups. RESULTS: There was no difference in gender, mean age, body mass index, or tumor characteristics between the groups. Estimated blood loss was significantly less in TLDG (21.2+/-36.8 g) than in LADG (62.5+/-81.6 g). Anastomotic leakage was not recorded in either group, and there was no difference in the incidence of other postoperative complications. Postoperative hospital stay was shorter for TLDG (10.6+/-2.6 days) than for LADG (12.0+/-3.5 days). Serum C-reactive protein level on day 7 after surgery was significantly lower in TLDG (2.58+/-2.57 mg/ml) than LADG (4.85+/-6.17 mg/ml); however, the level on day 1 or 4 was not significantly different. There was no difference in nutritional status or clinical symptoms during the 3 months after surgery. CONCLUSIONS: TLDG can be performed safely after appropriate experience with LADG. Our results imply that TLDG may lead to faster recovery, better cosmesis, and improved quality of life in the short-term compared with LADG. Because of the limitations of a retrospective analysis on the study and a patient selection bias, a prospective randomized study should be conducted to reach definitive conclusions. PMID- 20972585 TI - Real-time intraoperative detection of tissue hypoxia in gastrointestinal surgery by wireless pulse oximetry. AB - OBJECTIVE: Dehiscence or leakage after bowel anastomoses is associated with high morbidity and mortality. Perfusion and local tissue oxygenation (StO2), independent of systemic oxygen saturation, are fundamental determinants of anastomotic viability. Because current technology is limited for monitoring local StO2 at bowel anastomoses, our goal was to construct a wireless pulse oximeter (WiPOX) to monitor real-time intraoperative tissue oxygenation, permitting identification of compromised anastomotic perfusion. METHODS: We have: (a) designed a handheld device capable of real-time monitoring of serosal and mucosal StO2 through endoscopic ports with wireless data transmission to standard intraoperative monitors, (b) constructed the WiPOX using materials meeting FDA regulations for intraoperative use and reuse, (c) performed accuracy testing in humans by comparing the WiPOX to standard pulse oximeters, and (d) tested WiPOX efficacy for detecting early tissue hypoxia in stomach, intestines, and kidneys in anesthetized rats and swine. RESULTS: In humans, WiPOX demonstrated accuracy within 3% compared with commercially available pulse oximeters. Application of the WiPOX in rats and swine demonstrated normal serosal and mucosal StO2 and pulse rates in healthy small bowel and stomach. Within 30 s of compromised perfusion, the WiPOX detected bowel hypoxia over a wide range of oxygen saturation (p<0.005). A greater degree of hypoxia was detected in mucosal versus serosal measurements during early ischemia, despite normal appearance of tissue. The onboard sensor-processor unit permitted noninvasive pulse oximetry and integration with current intraoperative monitoring. The contact pressure-sensing head allowed for consistent, high-quality StO2 waveform readouts despite the presence of body fluids. CONCLUSIONS: We have constructed, validated, and successfully tested a novel wireless pulse oximeter capable of detecting intraoperative tissue hypoxia in open or endoscopic surgery. This device will aid surgeons in detecting anastomotic vascular compromise and facilitate choosing an ideal site for bowel anastomosis by targeting well-perfused tissue with optimal healing capacity. PMID- 20972588 TI - Psychometric evaluation and feasibility of the Greek Pittsburgh Sleep Quality Index (GR-PSQI) in patients with cancer receiving chemotherapy. AB - PURPOSE: Quality of sleep in patients with cancer is regarded as of utmost importance. The aim of the present study was to assess psychometric properties and feasibility of the Greek version of the Pittsburgh Sleep Quality Index (GR PSQI). METHODS: Following a "forward-backward" procedure, the scale was translated into Greek. The GR-PSQI was administered as a self-report instrument to 209 consecutive patients with cancer during active-phase chemotherapy treatment. For stability analysis purposes, a subgroup of 60 patients completed the GR-PSQI on two occasions, 14-21 days apart. All participants also completed the Insomnia Severity Index, the Epworth Sleepiness Scale-Greek version, a Sleep Quality-Visual Analogue Scale and the Hospital Anxiety and Depression Scale-Greek version. Validity and reliability analyses were performed for GR-PSQI data. RESULTS: The Chronbach's alpha for the global GR-PSQI score was 0.76. Test-retest reliability analysis for the global GR-PSQI score yielded a high intra-class correlation coefficient of 0.82 (p < 0.001). Exploratory factor analysis generated a two-factor structure for the GR-PSQI, [quality of nocturnal sleep] and [daily disturbances and management of sleep problems]. This construct was further supported by its high correlations with similar content instruments, as well as by the instrument's ability to discriminate well between contrasting groups of patients with different levels of anxiety, depression and performance status. CONCLUSIONS: The present findings support the GR-PSQI as a reliable, stable over time and valid sleep quality instrument when administered to patients with cancer during chemotherapy treatment; however, it is suggested that the use of a two-factor scoring method (instead of the traditional unidimensional) could improve its sensitivity in this patient group. PMID- 20972589 TI - Posaconazole versus fluconazole or itraconazole for prevention of invasive fungal infections in patients undergoing intensive cytotoxic therapy for acute myeloid leukemia or myelodysplasia: a cost effectiveness analysis. AB - INTRODUCTION: Invasive fungal infections (IFI) remain a clinical concern in hematological patients with prolonged neutropenia because they are a major cause of morbidity and mortality. In a recent randomized trial, prophylaxis with posaconazole was associated with fewer IFI and related deaths relative to a fluconazole or itraconazole (Flu/Itra) control group (p < 0.001). In the current study, a cost effectiveness analysis was conducted to estimate the economic value of posaconazole as an alternative to Flu/Itra when used to prevent IFI in this patient population. METHODS: A decision analysis model was developed using clinical and economic data from randomized comparative trials, the economic literature, and from expert opinion. The data were then used to estimate the incremental cost per life year saved with oral posaconazole prophylaxis relative to Flu/Itra from the Canadian provincial health care system perspective. The base case results were then tested with a sensitivity analysis which evaluated extremes in the incidence of IFI as well as variations in their cost of management. RESULTS: Prophylaxis with posaconazole provides increased efficacy and an overall cost savings of approximately $Can4,259 per patient. Despite variations in the base case parameters, the sensitivity analysis suggested stability in the primary findings. Posaconazole was associated with an overall cost savings (range = $Can1,765 to $Can4,505) in all of the scenarios evaluated. Optimal cost effectiveness was obtained because the drug was able to avoid the more resource intensive Aspergillus infections. CONCLUSIONS: Prophylaxis with posaconazole in cancer patients with prolonged neutropenia is not only cost effective but also cost saving. The economic benefits were due to the drug's ability to reduce the incidence of high cost fungal infections, particularly Aspergillus species. PMID- 20972590 TI - Treatment of through-and-through bone lesion using autologous growth factors and xenogeneic bone graft: a case report. AB - BACKGROUND: This pilot case study aimed at evaluating the possibility of achieving optimal hard and soft tissue regeneration using plasma rich in growth factors (PRGF) and anorganic bovine bone (ABB) for the surgical treatment of a large through-and-through periapical bone lesion. CASE REPORT: Maxillary incisors of a patient with through-and-through periapical lesion of endodontic origin were treated using modern endodontic surgical technique with the adjunct of PRGF. The PRGF clot was positioned over the palatal side of the lesion while the remaining bone defect was grafted with PRGF and ABB. A collagen membrane embedded with plasma very rich in growth factors covered the graft. Post-operative pain and swelling were negligible, and soft tissue healing was very fast. One-year clinical and radiographic outcome showed complete healing and functionality. DISCUSSION: The addition of PRGF to ABB could improve the regenerative process, reducing postoperative symptoms and resulting in a fast and predictable hard and soft tissue healing. PMID- 20972591 TI - Tuberculosis and anti-TNF treatment: experience of a central London hospital. AB - Reactivation of latent tuberculosis (TB) is an established risk of anti-tumour necrosis factor alpha (anti-TNF) therapy. We report five cases of active TB occurring in 703 patients treated with anti-TNF therapy over a 10-year period in a central London hospital and review our screening practices for identifying latent TB prior to anti-TNF treatment. Four patients were receiving adalimumab and one patient etanercept at the time of TB diagnosis. Four of the five patients were born in countries with a high TB prevalence. Two of the five patients were healthcare workers. All patients had normal chest radiographs prior to anti-TNF treatment. Our data emphasise that country of origin is important in the determining risk of latent TB and that a normal chest radiograph does not exclude latent TB. PMID- 20972592 TI - Sarcoid-like granulomatosis in patients treated with anti-TNFalpha factors. A case report and review of the literature. AB - This report describes a 56-year-old woman who developed granulomatous lesions consistent with sarcoidosis during adalimumab therapy for rheumatoid arthritis. Cervical and axillary lymphadenopathy developed approximately 21 months after adalimumab administration. Non-caseating epithelioid cell granulomas consistent with sarcoidosis were detected both in an axillary lymph node specimen and in the bone marrow. Diseases showing similar histologic changes, especially tuberculosis, were excluded, and a diagnosis of sarcoidosis was made. Adalimumab was discontinued, and recovery was observed. The current case is, to our knowledge, the first to describe adalimumab-induced non-caseating granulomas in lymph nodes and bone marrow without pulmonary involvement in a patient treated for rheumatoid arthritis. PMID- 20972593 TI - Low-level laser therapy on hands of patients with rheumatoid arthritis. PMID- 20972594 TI - 18F-FDG PET as a diagnostic procedure in large vessel vasculitis-a controlled, blinded re-examination of routine PET scans. AB - Large vessel vasculitis can be visualized by 18F-FDG positron emission tomography (PET). However, the diagnostic value of 18F-FDG PET is yet to be determined. We therefore performed a study to evaluate this technique for the diagnosis of giant cell arteritis (GCA) and Takayasu arteritis (TA). Patients with GCA or TA, who fulfilled the American College of Rheumatology (ACR) criteria and also had a pathologic PET scan in clinical routine, were selected. These PET scans, as well as PET scans obtained from age- and sex-matched control patients, were independently re-evaluated by two experienced nuclear medicine experts. PET scans of 20 patients (17 GCA, 3 TA) and 20 controls were evaluated. In 85% of the examinations, both observers agreed on the diagnosis or exclusion of vasculitis. Specificity was calculated with 80% and sensitivity with 65%, yielding an overall diagnostic accuracy of 72%. The mean maximum standardized uptake values (SUVmax) of the subclavian region was significantly higher in vasculitis than in control patients (2.77 +/- 1.02 vs 2.09 +/- 0.64; difference 0.69; CI(95%): 0.14-1.24, p = 0.0161). SUVmax of the iliacal regions did not differ significantly. Receiver- operating characteristics (ROC) analysis revealed the highest sensitivity of 90% (CI(95%): 68-99%) and specificity of 45% (CI(95%): 23-69%) for a SUVmax cut-off point of 1.78 (AUC 0.72, (CI(95%): 0.56-0.86). PET findings are reproducible and independent of the observer. The low sensitivity and specificity indicate that enhanced vascular uptake might be overrated if clinical details are suggestive for vasculitis. Therefore, the diagnosis of large vessel vasculitis should not be based on PET findings only. PMID- 20972595 TI - Association of an intronic SNP of SLC2A9 gene with serum uric acid levels in the Chinese male Han population by high-resolution melting method. AB - SLC2A9 is a novel identified urate transporter influencing uric acid metabolism. It has been suggested that the single-nucleotide polymorphisms in SLC2A9 may affect the serum UA levels. The present study was designed to investigate rs6855911 polymorphism in intron 7 of SLC2A9 in a total of 372 Chinese male subjects. We examined 166 gout patients, as well as 206 healthy male volunteers in this study. DNA was purified from peripheral blood, and the rs6855911 polymorphism was evaluated using high-resolution melting (HRM) analysis and direct sequencing. Demographic and clinical data obtained from the patients and controls among the genotype groups were analyzed. A/A and A/G genotypes were unambiguously distinguished with HRM technology. The occurrence of the homozygous type (G/G) was completely absent among the study population. The prevalence of the A/A and A/G genotype was 96.0% and 4.0%, respectively. Genotyping based on HRM was fully concordant with sequencing. The G allele frequency was significantly higher in the low-uric-acid group than in the high-uric-acid group. The genotype distribution and allele frequencies were not significantly different between gout and control subjects (p = 0.04). However, serum uric acid levels in the A/G genotype subjects were significantly lower than those with the A/A genotypes (p < 0.01). Rapid and accurate genotyping analysis of SLC2A9 can be done with HRM. The polymorphism rs6855911 in SLC2A9 may be a genetic marker to assess risk of hyperuricemia among Chinese male Han population. PMID- 20972596 TI - Current role of lateral cervical spine radiograph: a case report. AB - We report a case showing the classic features of a Hangman's cervical spine fracture following a motor vehicle collision. Because this injury was not diagnosed at ED presentation, this case also illustrates the select subset of trauma patients for whom the almost obsolete lateral cervical spine radiograph remains an important part of the radiographic trauma series. PMID- 20972597 TI - In vivo efficacy of doripenem (DRPM) against Pseudomonas aeruginosa in murine chronic respiratory tract infection model. AB - Doripenem is a carbapenem antibiotic with broad-spectrum coverage of gram positive and gram-negative bacteria, including Pseudomonas aeruginosa, and is considered to be as effective as meropenem. The in vivo activity of doripenem was thus compared with that of meropenem in a chronic lower respiratory P. aeruginosa infection mouse model. The number of viable bacteria in the lungs of mice after treatment with doripenem, meropenem, and saline was 2.01 +/- 0.69, 2.03 +/- 0.48, and 3.90 +/- 1.40 log10 CFU/lung, respectively. The number of viable bacteria in the lungs of mice treated with doripenem and meropenem was significantly lower than that in lungs of controls. Histopathological examination of lung specimens from the control group revealed promotion of the inflammatory response in chronic bronchial infection. However, the groups treated with doripenem and meropenem showed weaker inflammatory responses. These results suggest that doripenem treatment is effective against chronic airway infection with P. aeruginosa. PMID- 20972598 TI - First molecular characterization of feline immunodeficiency virus in Turkey. AB - In this study, strains of feline immunodeficiency virus (FIV), designated TR-D, TR-Mo and TR-Mi, isolated from three cats in Turkey, were characterized. PCR products (859 bp) from the envelope (env) gene region were amplified and sequenced, and possible geographical differences in the env gene region of Turkish FIV strains are discussed. Phylogenetic analysis of two strains showed that FIV subtype B was present in Turkey. Phylogenetic analysis showed that one new Turkish FIV strain occupies a separate branch from known clusters (subtypes A to E) from the USA, Canada, Europe and Japan. PMID- 20972599 TI - Kynurenine metabolism in health and disease. AB - Kynurenine is a small molecule derived from tryptophan when this amino acid is metabolised via the kynurenine pathway. The biological activity of kynurenine and its metabolites (kynurenines) is well recognised. Therefore, understanding the regulation of the subsequent biochemical reactions is essential for the design of therapeutic strategies which aim to interfere with the kynurenine pathway. However, kynurenine concentration in the body may not only be determined by the efficiency of kynurenine synthesis but also by the rate of kynurenine clearance. In this review, current knowledge about the mechanisms of kynurenine production and routes of its clearance is presented. In addition, the involvement of kynurenine and its metabolites in the biology of different T cell subsets (including Th17 cells and regulatory T cells) and neuronal cells is discussed. PMID- 20972600 TI - Comparison of composite disease activity indices for rheumatoid arthritis. AB - To evaluate the composite disease activity indices for rheumatoid arthritis (RA), we compared disease activities and the changes therein calculated using the Disease Activity Score based on 28 joint counts using erythrocyte sedimentation rate (DAS28-ESR), DAS28-CRP (C-reactive protein), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) in a cohort of 1,412 patients with RA. The median (1st; 3rd quartile) scores were 4.20 (3.31; 5.14) for DAS28-ESR, 3.44 (2.59; 4.36) for DAS28-CRP, 13.6 (7.49; 21.1) for SDAI, and 12.0 (6.9; 18.9) for CDAI. Absolute scores and their changes were significantly correlated (p < 0.0001) in all combinations among these four disease activity indices; however, their correlations were lower in males than in females. Correlations between disease activity indices and the clinical and acute phase reactant variables were different according to disease activity index, sex and age. A comparison of the number of patients in each disease activity category according to the disease activity indices using kappa-statistics revealed an almost perfect agreement between SDAI and CDAI (kappa = 0.871), a moderate agreement between DAS28-ESR and SDAI (kappa = 0.415) or CDAI (kappa = 0.427), but only fair agreement between DAS28-ESR and DAS28-CRP (kappa = 0.329). For the selection of a disease activity index for an evaluation of RA patients, both the convenience and the characteristics of the respective disease activity index should be considered. PMID- 20972601 TI - Amyloid beta-induced FOXRED2 mediates neuronal cell death via inhibition of proteasome activity. AB - Proteasome inhibition has been regarded as one of the mediators of Abeta neurotoxicity. In this study, we found that FOXRED2, a novel endoplasmic reticulum (ER) residential protein, is highly up-regulated by Abeta in rat cortical neurons and SH-SY5Y cells. Over-expression of FOXRED2 inhibits proteasome activity in the microsomal fractions containing ER and interferes with proteasome assembly, as evidenced by gel filtration and native gel electrophoresis analysis. In contrast, reduced expression of FOXRED2 rescues Abeta-induced inhibition of proteasome activity. FOXRED2 is an unstable protein with two degradation boxes and one KEN box, and its N-terminal oxidoreductase domain is required for proteasome inhibition. Ectopic expression of FOXRED2 induces ER stress-mediated cell death via caspase-12, which is inhibited by Salubrinal. Further, down-regulation of FOXRED2 expression attenuates Abeta induced cell death and the ER stress response. These results suggest that up regulated FOXRED2 inhibits proteasome activity by interfering with 26S proteasome assembly to contribute to Abeta neurotoxicity via an ER stress response. PMID- 20972602 TI - A primer on common statistical errors in clinical ophthalmology. AB - Although biomedical statistics is part of any scientific curriculum, a review of the current scientific literature indicates that statistical data analysis is an area that frequently needs improvement. To address this, we here cover some of the most common problems in statistical analysis, with an emphasis on an intuitive, tutorial approach rather than a rigorous, proof-based one. The topics covered in this manuscript are whether to enter eyes or patients into the analysis, issues related to multiple testing, pitfalls surrounding the correlation coefficient (causation, insensitivity to patterns, range confounding, unsuitability for method comparisons), and when to use standard deviation (SD) versus standard error of the mean (SEM) "antennas" on graphs. PMID- 20972603 TI - Current practices of driving restriction implementation for patients with brain tumors. AB - Brain tumors may impair functioning in several neuro-cognitive domains and interfere with sophisticated tasks, such as driving motor vehicles. No formalized national guidelines or recommendations for driving restrictions in patients with brain tumors exist in the US. We created and administered a 24 question survey to 1,157 US medical practitioners, mostly neurosurgeons, radiation oncologists, and medical oncologists, to identify their knowledge of local driving restriction laws and their practice patterns regarding driving restriction instructions to brain tumor patients. Response were collected from 251 (21.7%) and analyzed from 221 (19%) recipients. Seventy-one percent of the respondents indicated they discuss driving recommendations/restrictions with brain tumor patients, with 82% primarily basing this on seizure activity. Approximately 28% of respondents were unsure if they are required by their State's motor vehicle licensing authority to report medically impaired drivers. Respondents felt that longer periods of restriction prior to re-evaluation are warranted in patients with malignant versus benign brain tumors and high versus low grade gliomas. Only 25% of respondents use formal, standardized testing to determine driving eligibility and approximately 31% address driving restrictions in every patient with a brain tumor. This survey highlights the lack of consensus regarding the responsibilities of physicians treating brain tumor patients in designing and enforcing driving restrictions. We propose that a panel of experts generate driving restriction guidelines to be used in conjunction with objective testing of motor and sensory impairment. These would aid practitioners in developing individualized driving restrictions for every brain tumor patient. PMID- 20972604 TI - Bietti crystalline dystrophy and choroidal neovascularisation. AB - Bietti crystalline dystrophy is a rare autosomal recessive condition characterised by the presence of crystals in the retina and is followed by retinal and choroidal degeneration. We present a novel finding of juxtafoveal choroidal neovascularisation in Bietti crystalline dystrophy and demonstrate a spectral domain optical coherence tomography image of this disorder. PMID- 20972605 TI - Manual small incision cataract surgery in the United Kingdom. PMID- 20972606 TI - Tenecteplase in the treatment of acute pulmonary thrombo-embolism. AB - This is a retrospective study documenting the use of tenecteplase in 41 cases of suspected or confirmed pulmonary embolism receiving in-hospital tenecteplase as per weight-adjusted dosing in addition to standard heparin and oral anticoagulant therapy. The presenting symptoms of dyspnoea, chest pain, hemoptysis and syncope were found in 40 (97.56%), 19 (46.34%), 6 (14.63%) and 9 (21.95%) patients, respectively. There was one case of mortality who was a 26 yrs old female of postpartum pulmonary thrombo-embolism with severe hypotension, cyanosis, bilateral crepitations in lungs and pulmonary hypertension. In the 40 survived patients, there was alleviation of dyspnoea and hemoptysis in all patients. Significant reduction in tachycardia (P < 0.0001) and increase in the oxygen saturation (SaO2) (P < 0.0001) were seen at discharge as compared to at the time of presentation. Eighteen patients had hypotension which recovered in all patients till the time of discharge (P < 0.0001). There was a significant reduction in right ventricular systolic pressure in all 18 patients who underwent 2-D echocardiography both before and after the tenecteplase therapy. Resolution of pulmonary embolism on CT pulmonary angiography was documented in only two patients. No bleeding events or any other adverse events were reported during this study. The present study suggests favourable efficacy of tenecteplase in patients with suspected or confirmed acute pulmonary embolism. Although no major adverse events were noted, a large prospective study on the use of tenecteplase in pulmonary embolism is suggested. PMID- 20972608 TI - Volunteer effect and compromised randomization in the Mayo Project of screening for lung cancer. AB - It has been confirmed recently that the volunteer effect in lung cancer screening is characterized by higher lung cancer mortality risk in self-selected screening participants. The Mayo Lung Project, the most influential trial of screening for lung cancer ever completed, was conducted in nonvolunteer Mayo Clinic outpatients, with a peculiar study design that rendered the randomization vulnerable to the volunteer effect. Of all nonvolunteers randomized in the Mayo Lung Project, only those allocated in the screened group were asked consent to participate in the trial. The final Mayo Lung Project report stated that 655 randomized nonvolunteers refused screening and were excluded from the study, thus documenting violation of the rule that no selection should occur after randomization. The long-term follow-up of the Mayo Lung Project showed an enigmatic result which has never been explained: the lung cancer mortality was 13% higher in the screening intervention group than in the control group [4.4 (95% CI 3.9-4.9) vs. 3.9 (95% CI 3.5-4.4) per 1,000 person-years; P = 0.09]. Such overrepresented mortality is consistent with the volunteer effect and supports the concept that the Mayo Lung Project randomization was compromised by the post randomization self-selection of participant nonvolunteers. PMID- 20972609 TI - Glutamoyl diester of the dietary polyphenol curcumin offers improved protection against peroxynitrite-mediated nitrosative stress and damage of brain mitochondria in vitro: implications for Parkinson's disease. AB - Oxidative/nitrosative stress plays a crucial role in Parkinson's disease (PD) by triggering mitochondrial dysfunction. Nitrosative stress is mediated by reactive species such as peroxynitrite (PN) which could damage biomolecules thereby impinging on the cellular machinery. We observed that PN (0-1000 MUM) inhibited brain mitochondrial complex I (CI) activity in a dose-dependent manner with concomitant tyrosine nitration of proteins. We also observed that exposure to PN at low concentrations (62.5-125 MUM) significantly decreased the mitochondrial membrane potential and affected the mitochondrial integrity at higher doses (500 750 MUM) as indicated by the mitochondrial swelling experiment. Therefore, it could be surmised that compounds that prevent such mitochondrial damage might have therapeutic value in neurological conditions such as PD. We previously showed that curcumin could detoxify PN and protect against CI inhibition and protein nitration. However, the therapeutic potential of curcumin is constrained by limited bioavailability. To address this issue and obtain improved antioxidants, three bioconjugates of curcumin (Di-demethylenated piperoyl, di valinoyl and di-glutamoyl esters) were generated and tested against PN-mediated nitrosative stress and mitochondrial damage. We found that among the bioconjugates, the glutamoyl diester of curcumin showed improved protection against PN-dependent CI inhibition and protein nitration compared to other conjugates. Di-glutamoyl curcumin protected dopaminergic neurons against 1-methyl 4-phenylpyridinium (MPP(+))-mediated neuronal death. These effects were improved compared to curcumin alone suggesting that di-glutamoyl curcumin could be a better neuroprotective agent in neurodegenerative diseases such as PD. PMID- 20972610 TI - Evaluation of colloidal silica suspension as efficient additive for improving physicochemical and in vitro biological properties of calcium sulfate-based nanocomposite bone cement. AB - In the present study new calcium sulfate-based nanocomposite bone cement with improved physicochemical and biological properties was developed. The powder component of the cement consists of 60 wt% alpha-calcium sulfate hemihydrate and 40 wt% biomimetically synthesized apatite, while the liquid component consists of an aqueous colloidal silica suspension (20 wt%). In this study, the above mentioned powder phase was mixed with distilled water to prepare a calcium sulfate/nanoapatite composite without any additive. Structural properties, setting time, compressive strength, in vitro bioactivity and cellular properties of the cements were investigated by appropriate techniques. From X-ray diffractometer analysis, except gypsum and apatite, no further phases were found in both silica-containing and silica-free cements. The results showed that both setting time and compressive strength of the calcium sulfate/nanoapatite cement improved by using colloidal silica suspension as cement liquid. Meanwhile, the condensed phase produced from the polymerization process of colloidal silica filled the micropores of the microstructure and covered rodlike gypsum crystals and thus controlled cement disintegration in simulated body fluid. Additionally, formation of apatite layer was favored on the surfaces of the new cement while no apatite precipitation was observed for the cement prepared by distilled water. In this study, it was also revealed that the number of viable osteosarcoma cells cultured with extracts of both cements were comparable, while silica-containing cement increased alkaline phosphatase activity of the cells. These results suggest that the developed cement may be a suitable bone filling material after well passing of the corresponding in vivo tests. PMID- 20972607 TI - Identification and characterization of high temperature stress responsive genes in bread wheat (Triticum aestivum L.) and their regulation at various stages of development. AB - To elucidate the effect of high temperature, wheat plants (Triticum aestivum cv. CPAN 1676) were given heat shock at 37 and 42 degrees C for 2 h, and responsive genes were identified through PCR-Select Subtraction technology. Four subtractive cDNA libraries, including three forward and one reverse subtraction, were constructed from three different developmental stages. A total of 5,500 ESTs were generated and 3,516 high quality ESTs submitted to Genbank. More than one-third of the ESTs generated fall in unknown/no hit category upon homology search through BLAST analysis. Differential expression was confirmed by cDNA macroarray and by northern/RT-PCR analysis. Expression analysis of wheat plants subjected to high temperature stress, after 1 and 4 days of recovery, showed fast recovery in seedling tissue. However, even after 4 days, recovery was negligible in the developing seed tissue after 2 h of heat stress. Ten selected genes were analyzed in further detail including one unknown protein and a new heat shock factor, by quantitative real-time PCR in an array of 35 different wheat tissues representing major developmental stages as well as different abiotic stresses. Tissue specificity was examined along with cross talk with other abiotic stresses and putative signalling molecules. PMID- 20972611 TI - Strategies for the assessment of protein aggregates in pharmaceutical biotech product development. AB - Within the European Immunogenicity Platform (EIP) ( http://www.e-i-p.eu ), the Protein Characterization Subcommittee (EIP-PCS) has been established to discuss and exchange experience of protein characterization in relation to unwanted immunogenicity. In this commentary, we, as representatives of EIP-PCS, review the current state of methods for analysis of protein aggregates. Moreover, we elaborate on why these methods should be used during product development and make recommendations to the biotech community with regard to strategies for their application during the development of protein therapeutics. PMID- 20972612 TI - Posttetanic potentiation in mdx muscle. AB - X-linked muscular dystrophy of the mouse (mdx) has been reported to progressively remodel skeletal muscle to preferentially reduce fast fiber composition. Despite this, mdx muscle displays normal levels of posttetanic potentiation (PTP). Since PTP may primarily depend on phosphorylation of the myosin regulatory light chain (RLC) in fast muscle fibers, maintenance of PTP with mdx disease progression is paradoxical and may represent an adaptation of the diseased muscle. This study assesses the role of RLC phosphorylation during PTP of mdx muscle. Extensor digitorum longus muscles were isolated from mdx and from C57BL/10 (control) mice at ~50 (young) and ~300 (adult) days and stimulated in vitro (25 degrees C) to induce PTP. During potentiation, muscles were harvested for subsequent determination of RLC phosphorylation levels. Immunofluorescence was used to assess muscle fiber type composition and no age effects were found. The magnitude of PTP was higher (P < 0.05) in mdx than control muscles at both young (mdx: 21.9 +/- 1.6%; control: 17.7 +/- 1.2%) and adult (mdx: 30.4 +/- 1.8%; control: 23.2 +/ 2.2%) ages. However, RLC phosphate content was similar between all groups both at rest and following stimulation. Our results are consistent with a model where the sensitivity of mdx muscle to RLC phosphorylation-induced force potentiation is increased by disease- and age-dependent alterations in excitation-contraction coupling noted for mdx and aging muscle. PMID- 20972613 TI - The important health impact of where a child lives: neighborhood characteristics and the burden of lead poisoning. AB - Toxins and other health threats can cause health problems, whether they are present in the child's own home, other neighborhood homes where the child spends time, or common areas such as playgrounds. We assess the impact of where a child lives on the burden of lead poisoning. Statewide lead screening data was obtained from the Rhode Island Department of Health. Block group level indicators of old housing and poverty were obtained from the US Census. Of the 204,746 study children, 35,416 (17.3%) had a blood lead level>=10 MUg/dL. The proportion of study children who were lead poisoned in each block group ranged from 0.0 to 48.6%. The proportion of study children with an elevated blood lead level increased from 8% among children living in block groups in the lowest quintile of poverty to 31% for those in the highest quintile for poverty. Old housing also had an important impact on the risk of lead poisoning. The proportion of children with an elevated blood lead level increased from 7% among children living in block groups in the lowest quintile for pre-1950 housing to 27% for those in the highest quintile for pre-1950 housing. The adjusted odds ratio was 1.64 for the highest quintile of poverty and 1.77 for the highest quintile of pre-1950 housing. The findings of this large, statewide study demonstrate the powerful impact of where children live on the risk of lead poisoning. The findings have important implications for understanding the problem of lead poisoning and for planning primary prevention programs. PMID- 20972614 TI - A metric space approach to the information channel capacity of spike trains. AB - A novel method is presented for calculating the information channel capacity of spike trains. This method works by fitting a chi-distribution to the distribution of distances between responses to the same stimulus: the chi-distribution is the length distribution for a vector of Gaussian variables. The dimension of this vector defines an effective dimension for the noise and by rephrasing the problem in terms of distance based quantities, this allows the channel capacity to be calculated. As an example, the capacity is calculated for a data set recorded from auditory neurons in zebra finch. PMID- 20972616 TI - The relationship between parents' and children's automatic thoughts in a college student sample. AB - Research demonstrates the importance of early social interactions in the development of schemas and automatic thoughts. It does not appear, however, that the existing research examines intergenerational correlations in automatic thoughts. As a result, this study explores the relationship between the automatic thoughts of parents and those of their college-age children in a sample of 252 college students and their mothers and fathers. Results of this study suggest that there are significant relationships between parents' and college students' positive automatic thoughts. Different trends by gender also are noted in the relationships among variables for male and female college students with their mothers and fathers. Further, mothers' positive ATs predicted the positive ATs of their college students, with mothers' ratings of their own communication with their college students mediating partially this relationship. Finally, college students' anxiety and self-esteem is predicted significantly by their mothers' anxiety and self-esteem (respectively) as well as their own positive and negative ATs. These findings suggest the possibility that ATs play a role in the intergenerational transmission of certain domains of psychological functioning. PMID- 20972615 TI - The hypothesis of apraxia of speech in children with autism spectrum disorder. AB - In a sample of 46 children aged 4-7 years with Autism Spectrum Disorder (ASD) and intelligible speech, there was no statistical support for the hypothesis of concomitant Childhood Apraxia of Speech (CAS). Perceptual and acoustic measures of participants' speech, prosody, and voice were compared with data from 40 typically-developing children, 13 preschool children with Speech Delay, and 15 participants aged 5-49 years with CAS in neurogenetic disorders. Speech Delay and Speech Errors, respectively, were modestly and substantially more prevalent in participants with ASD than reported population estimates. Double dissociations in speech, prosody, and voice impairments in ASD were interpreted as consistent with a speech attunement framework, rather than with the motor speech impairments that define CAS. PMID- 20972617 TI - Biologic role of activated leukocyte cell adhesion molecule overexpression in breast cancer cell lines and clinical tumor tissue. AB - The activated leukocyte cell adhesion molecule (ALCAM) is overexpressed in many mammary tumors, but controversial results about its role and prognostic impact in breast cancer have been reported. Therefore, we evaluated the biologic effects of ALCAM expression in two breast cancer cell lines and a larger cohort of mammary carcinomas. By stable transfections, MCF7 cells with ALCAM overexpression and MDA MB231 cells with reduced ALCAM levels were generated and analyzed in functional assays and cDNA microarrays. In addition, an immunohistochemical study on 347 patients with breast cancer with long-term follow-up and analysis of disseminated tumor cells (DTCs) was performed. In both cell lines, high ALCAM expression was associated with reduced cell motility. In addition, ALCAM silencing in MDA-MB231 cells resulted in lower invasive potential, whereas high ALCAM expression was associated with increased apoptosis in both cell lines. Among genes which were differentially expressed in clones with altered ALCAM expression, there was an overlap of 15 genes between both cell lines, among them cathepsin D, keratin 7, gelsolin, and ets2 whose deregulation was validated by western blot analysis. In MDA-MB231 cells, we observed a correlation with VEGF expression which was validated by enzyme-linked immuno sorbent assay (ELISA). Our IHC results on primary breast carcinomas showed that ALCAM expression was associated with an estrogen receptor-positive phenotype. In addition, strong ALCAM immunostaining correlated with nodal involvement and the presence of tumor cells in bone marrow. By Kaplan-Meier analysis, strong ALCAM expression in ductal carcinomas correlated with shorter recurrence-free intervals (P=0.048) and overall survival (OAS, P=0.003). Our results indicate that the biologic role of ALCAM in breast cancer is complex, but overexpression might be relevant for outcome in ductal carcinomas. PMID- 20972619 TI - A multi-gene transcriptional profiling approach to the discovery of cell signature markers. AB - A profile of transcript abundances from multiple genes constitutes a molecular signature if the expression pattern is unique to one cell type. Here we measure mRNA copy numbers per cell by normalizing per million copies of 18S rRNA and identify 6 genes (TIE1, KDR, CDH5, TIE2, EFNA1 and MYO5C) out of 79 genes tested as excellent molecular signature markers for endothelial cells (ECs) in vitro. The selected genes are uniformly expressed in ECs of 4 different origins but weakly or not expressed in 4 non-EC cell lines. A multi-gene transcriptional profile of these 6 genes clearly distinguishes ECs from non-ECs in vitro. We conclude that (i) a profile of mRNA copy numbers per cell from a well-chosen multi-gene panel can act as a sensitive and accurate cell type signature marker, and (ii) the method described here can be applied to in vivo cell fingerprinting and molecular diagnosis. PMID- 20972618 TI - Current and future role of ultrafiltration in CRS. AB - Ultrafiltration has been used in patients with decompensated HF and volume overload refractory to diuretics. Criteria for the initiation of renal replacement therapy (RRT) in the ICU are oliguria, anuria, urea, creatinine, Na and K blood concentrations, pulmonary edema unresponsive to diuretics, uncompensated metabolic acidosis, temperature >40 degrees C, uremic complication, and overdose with a dialyzable toxin. Moreover, the treatment of acute renal failure requires a different style and philosophy from renal replacement therapy for chronic renal failure. The degree and the location of renal lesion, the entity, the gravity of the concomitant acute or chronic cardiac damage, the weight of a trauma, surgical stress, or septic complication they determine a variability of clinical picture that can modify the prescription and the timing of RRT and the monitoring technology. In the presence of cardiac alterations due to a condition of chronic heart failure, all the acute events contribute to the progression of the cardiac insufficiency and the patient will always have as a result an ulterior reduction in the cardiac function. It derives the opportunity to put more precociously in action everything of it how much serves for a real cardioprotection. A valid hemodynamic monitoring is essential to reach the lowest possible value of pressure of left ventricular filling, without reduction in the cardiac output, increase in the cardiac frequency or the ulterior activation of the neurohormones. An early ultrafiltration allows a more easy control of the circulating mass but also an effective neurohormonal purification and of all the inflammation mediators. PMID- 20972620 TI - Evaluating osteochondral defect repair potential of autologous rabbit bone marrow cells on type II collagen scaffold. AB - The feasibility of using genipin cross-linked type II collagen scaffold with rabbit bone marrow mesenchymal stem cells (RBMSCs) to repair cartilage defect was herein studied. Induction of RBMSCs into chondrocytic phenotype on type II collagen scaffold in vitro was conducted using TGF-beta 3 containing medium. After 3-weeks of induction, chondrocytic behavior, including marker genes expression and specific extracellular matrix (ECM) secretion, was observed. In the in vivo evaluation experiment, the scaffolds containing RBMSCs without prior induction were autologous implanted into the articular cartilage defects made by subchondral drilling. The repairing ability was evaluated. After 2 months, chondrocyte-like cells with lacuna structure and corresponding ECM were found in the repaired sites without apparent inflammation. After 24 weeks, we could easily find cartilage structure the same with normal cartilage in the repair site. In conclusion, it was shown that the scaffolds in combination of in vivo conditions can induce RBMSCs into chondrocytes in repaired area and would be a possible method for articular cartilage repair in clinic and cartilage tissue engineering. PMID- 20972621 TI - Proteomic analysis of MON810 and comparable non-GM maize varieties grown in agricultural fields. AB - Worldwide maize is the second major agricultural commodity and around one-fourth is currently biotech, with significant application of the insect resistant event MON810 particularly in the European Union. Grains are the major commercialized part of the plant, and can be harvested after maturity (for food and feed purposes) or at late milky-starchy stage (for forage uses, with the whole plant). We assessed possible proteomic unintended effects of the MON810 transgene using two-dimensional gel electrophoresis coupled to mass spectrometry. To keep in a realistic scenario we used plants grown in agricultural fields in a region where ~50% of maize was MON810, and analyzed grains at milky-starchy stage. In maize, differential transcripts and metabolites between GM and comparable non-GM varieties tend to be variety specific. Thus, we analyzed two variety pairs, DKC6575/Tietar and PR33P67/PR33P66 which are considered representative of Food and Agriculture Organization 700 and 600 varieties commercially grown in the region. MON810 and non-GM milky-starchy grains had virtually identical proteomic patterns, with a very small number of spots showing fold-variations in the 1-1.8 range. They were all variety specific and had divergent identities and functions. Although 2DE allows the analysis of a limited dataset our results support substantial equivalence between MON810 and comparable non-GM varieties. PMID- 20972622 TI - Ageing-induced decline in physical endurance in mice is associated with decrease in cardiac SUR2A and increase in cardiac susceptibility to metabolic stress: therapeutic prospects for up-regulation of SUR2A. AB - Ageing is characterized by decline in physical endurance which has been suggested to be partly due to diminished functional and adaptive reserve capacity of the heart. Ageing is associated with decrease in numbers of sarcolemmal ATP-sensitive K(+) (K(ATP)) channels, but whether this has anything to do with ageing-induced decline in physical endurance is yet to be determined. We have previously shown that the numbers of sarcolemmal K(ATP) channels are controlled by the level of expression of SUR2A, a K(ATP) channel regulatory subunit. Here, we have found that ageing decreases the level of SUR2A mRNA in the heart without affecting expression of pore-forming K(ATP) channel subunits, Kir6.1 and Kir6.2. This effect of ageing was associated with decrease in levels of fully-assembled sarcolemmal K(ATP) channels. At the same time, ageing was associated with decreased physical endurance. In order to determine whether increased expression of SUR2A would counteract ageing-induced decrease in physical endurance, we have taken advantage of mice which SUR2A levels are regulated by more efficient CMV promoter. These mice had increased resistance of cardiomyocytes to metabolic stress/hypoxia and increased physical endurance when compared to the wild type. In transgenic mice, ageing did not affect the level of SUR2A mRNA in the heart and the level of fully-assembled sarcolemmal K(ATP) channels. The effect of increased SUR2A to resistance of cardiomyocytes to hypoxia and physical endurance was retained in old mice. The magnitude of these effects was such that they were significantly increased even when compared to those in wild type young mice. We conclude that (1) the level of SUR2A expression in the heart is important factor in regulating physical endurance, (2) ageing-induced decrease in cardiac SUR2A is, at least in part, responsible for ageing-induced decline in physical fitness and (3) up-regulation of SUR2A could be a viable strategy to counteract ageing induced decline in physical endurance. PMID- 20972623 TI - Biogerontology in Ukraine: update. AB - Recent biogerontological findings in Ukraine are critically reviewed. It is stressed that cooperation of efforts within and between departments, institutions and countries is an efficient mode of coping with the complex problems of aging. A wide spectrum of aging research was traditionally performed in state-funded institutions throughout the country, focusing primarily on the neuro-humoral regulation, immune system, adaptation, oxidative stress, comparative analysis and life span extension. Mitochondria and associated oxidative stress seem to be a crossroad of "wet" and in silico research traffics aimed underpinning mechanisms of aging and life span extension. For instance, the highest coefficients of determination of the mammalian maximum life span were associated with mitochondrial DNA base composition and insertions into the nuclear DNA (NUMTs). The main conclusions of the multidirectional investigative endeavors could concisely be described as: modifications of the mitochondrial membrane resulted in alterations in ROS generation, metabolism, and life span; coordinated action of the key antioxidant genes and enzymes is an important issue in successful aging; lateral hypothalamic area could be a morpho-functional center of anti aging in CNS; lymphoid tissue microenvironment is crucial in determination of functionality of the transplanted cells; gene and polypeptide therapy proved to be a perspective approach in treatment of accelerated aging; artificial atmosphere with optimal gaseous composition could be an efficient mean for life span extension and viability enhancement. PMID- 20972624 TI - Azathioprine-induced severe cholestatic hepatitis in patient carrying TPMT*3C polymorphism. AB - CASE DESCRIPTION: A 40-year-old man with pemphigus foliaceus developed a jaundice and pruritus three weeks after starting azathioprine 100 mg daily. Laboratory investigations revealed a severe cholestatic hepatitis. Azathioprine-induced hepatitis was suspected. The dosage of thiopurine methyltransferase activity showed a low activity of the enzyme and the genotype of this enzyme found a TPMT*3C heterozygous mutant allele. Azathioprine was withdrawn. The icterus regressed progressively and the hepatic tests normalised slowly. The patient had no further episodes of hepatitis over a follow-up period of 6 months. CONCLUSION: Although, hematotoxicity seems to be associated with homozygous TPMT variants, a possible association between azathioprine hepatotoxicity and a TPMT*3C genotype should be investigated further. PMID- 20972625 TI - Modeling respiratory movement signals during central and obstructive sleep apnea events using electrocardiogram. AB - Obstructive sleep apnea (OSA) causes a pause in airflow with continuing breathing effort. In contrast, central sleep apnea (CSA) event is not accompanied with breathing effort. CSA is recognized when respiratory effort falls below 15% of pre-event peak-to-peak amplitude of the respiratory effort. The aim of this study is to investigate whether a combination of respiratory sinus arrhythmia (RSA), ECG-derived respiration (EDR) from R-wave amplitudes and wavelet-based features of ECG signals during OSA and CSA can act as surrogate of changes in thoracic movement signal measured by respiratory inductance plethysmography (RIP). Therefore, RIP and ECG signals during 250 pre-scored OSA and 150 pre-scored CSA events, and 10 s preceding the events were collected from 17 patients. RSA, EDR, and wavelet decomposition of ECG signals at level 9 (0.15-0.32 Hz) were used as input to the support vector regression (SVR) model to recognize the RIP signals and classify OSA from CSA. Using cross-validation test, an optimal SVR (radial basis function kernel; C = 2(8) and epsilon = 2(-2) where C is the coefficient for trade-off between empirical and structural risk and epsilon is the width of epsilon-insensitive region) showed that it correctly recognized 243/250 OSA and 139/150 CSA events (95.5% detection accuracy). Independent test was performed on 80 OSA and 80 CSA events from 12 patients. The independent test accuracies of OSA and CSA detections were found to be 92.5 and 95.0%, respectively. Results suggest superior performance of SVR using ECG as the surrogate in recognizing the reduction of respiratory movement during OSA and CSA. Results also indicate that ECG-based SVR model could act as a potential surrogate signal of respiratory movement during sleep-disordered breathing. PMID- 20972626 TI - Computational hemodynamics in cerebral aneurysms: the effects of modeled versus measured boundary conditions. AB - Modeling of flow in intracranial aneurysms (IAs) requires flow information at the model boundaries. In absence of patient-specific measurements, typical or modeled boundary conditions (BCs) are often used. This study investigates the effects of modeled versus patient-specific BCs on modeled hemodynamics within IAs. Computational fluid dynamics (CFD) models of five IAs were reconstructed from three-dimensional rotational angiography (3DRA). BCs were applied using in turn patient-specific phase-contrast-MR (pc-MR) measurements, a 1D-circulation model, and a physiologically coherent method based on local WSS at inlets. The Navier Stokes equations were solved using the Ansys(r)-CFXTM software. Wall shear stress (WSS), oscillatory shear index (OSI), and other hemodynamic indices were computed. Differences in the values obtained with the three methods were analyzed using boxplot diagrams. Qualitative similarities were observed in the flow fields obtained with the three approaches. The quantitative comparison showed smaller discrepancies between pc-MR and 1D-model data, than those observed between pc-MR and WSS-scaled data. Discrepancies were reduced when indices were normalized to mean hemodynamic aneurysmal data. The strong similarities observed for the three BCs models suggest that vessel and aneurysm geometry have the strongest influence on aneurysmal hemodynamics. In absence of patient-specific BCs, a distributed circulation model may represent the best option when CFD is used for large cohort studies. PMID- 20972627 TI - Functional properties of gluten-free pasta produced from amaranth, quinoa and buckwheat. AB - The use of amaranth, quinoa and buckwheat for the production of gluten-free pasta was investigated in the present study. The aim of the work was to produce pasta of good textural quality, in particular, low cooking loss, optimal cooking weight and texture firmness. The results demonstrated that pasta produced from amaranth had decreased texture firmness and cooking time, while pasta from quinoa mainly showed increased cooking loss. In buckwheat pasta the least negative effects were observed. By combination of all three raw materials to one flour blend in the ratio of 60% buckwheat, 20% amaranth and 20% quinoa, dough matrix was improved. After decreasing dough moisture to 30%, addition of an increased amount of egg white powder of 6% and addition of 1.2% emulsifier (distilled monoglycerides) texture firmness as well as cooking quality of gluten-free pasta produced from such a flour blend reached acceptable values comparable to wheat pasta. PMID- 20972628 TI - Development of computerized adaptive testing (CAT) for the EORTC QLQ-C30 physical functioning dimension. AB - PURPOSE: Computerized adaptive test (CAT) methods, based on item response theory (IRT), enable a patient-reported outcome instrument to be adapted to the individual patient while maintaining direct comparability of scores. The EORTC Quality of Life Group is developing a CAT version of the widely used EORTC QLQ C30. We present the development and psychometric validation of the item pool for the first of the scales, physical functioning (PF). METHODS: Initial developments (including literature search and patient and expert evaluations) resulted in 56 candidate items. Responses to these items were collected from 1,176 patients with cancer from Denmark, France, Germany, Italy, Taiwan, and the United Kingdom. The items were evaluated with regard to psychometric properties. RESULTS: Evaluations showed that 31 of the items could be included in a unidimensional IRT model with acceptable fit and good content coverage, although the pool may lack items at the upper extreme (good PF). There were several findings of significant differential item functioning (DIF). However, the DIF findings appeared to have little impact on the PF estimation. CONCLUSIONS: We have established an item pool for CAT measurement of PF and believe that this CAT instrument will clearly improve the EORTC measurement of PF. PMID- 20972629 TI - Using Rasch analysis to form plausible health states amenable to valuation: the development of CORE-6D from a measure of common mental health problems (CORE-OM). AB - PURPOSE: To describe a new approach for deriving a preference-based index from a condition specific measure that uses Rasch analysis to develop health states. METHODS: The CORE-OM is a 34-item instrument monitoring clinical outcomes of people with common mental health problems. The CORE-OM is characterised by high correlation across its domains. Rasch analysis was used to reduce the number of items and response levels in order to produce a unidimensional measure and to generate a credible set of health states corresponding to different levels of symptom severity using the Rasch item threshold map. RESULTS: The proposed methodology resulted in the development of CORE-6D, a 2-dimensional health state descriptive system consisting of a unidimensional 5-item emotional component (derived from Rasch analysis) and a physical symptom item. Inspection of the Rasch item threshold map of the emotional component helped identify a set of 11 plausible health states, which, combined with 3 physical symptom item levels, form 33 plausible health states that can be used for the valuation of the instrument, resulting in the development of a preference-based index. CONCLUSIONS: This is a useful new approach to develop preference-based measures from existing instruments with high correlations across domains. The CORE-6D preference-based index will enable calculation of Quality-Adjusted Life Years in people with common mental health problems. PMID- 20972630 TI - Measuring the health status burden in hemodialysis patients using the SF-36(r) health survey. AB - PURPOSE: The SF-36, a generic measure of 8 domains of health-related quality of life (HRQOL), has been widely used to examine HRQOL of end-stage renal disease (ESRD) patients undergoing hemodialysis (HD). The current study synthesizes existing literature to examine which SF-36 domains capture the largest burden in this patient population. METHODS: A literature search of published studies that presented descriptive statistics for baseline SF-36 scale scores from HD patients was conducted. Disease burden was estimated by comparing HD patients' SF-36 scores to those from either a control group or a general population normative sample taken from the same country. For each study, Cohen d effect sizes for between-sample differences were calculated for each scale. RESULTS: Twenty-six articles that matched set criteria were identified. Estimation of differences between HD patients and comparison groups showed that the SF-36 physical functioning scale yielded the largest weighted mean effect size across studies (d = 1.46), followed by the general health (d = 1.29) and role physical (d = 1.21) scales. CONCLUSIONS: Among the eight domains of the SF-36, physical functioning, general health, and role physical scales best captured disease burden for HD patients. The disease burden negatively impacts physical HRQOL more strongly than mental HRQOL. PMID- 20972631 TI - Identification of a large rearrangement in CYLD as a cause of familial cylindromatosis. AB - Pathogenic mutations in CYLD can be identified in patients affected with Brooke Spiegler syndrome, (Familial) Cylindromatosis or multiple familial trichoepithelioma. To date, only technologies which are able to identify small point mutations in CYLD, such as sequence and WAVE analysis, were used. Here we describe the identification of a larger rearrangement identified by Quantitative PCR analysis of CYLD, indicating that a combination of these technologies is necessary when searching for pathogenic mutations in CYLD. PMID- 20972632 TI - Breast cancer surgery trend changes since the introduction of BRCA1/2 mutation screening: a retrospective cohort analysis of 158 mutation carriers treated at a single institution. AB - BACKGROUND: Bilateral mastectomy in women diagnosed with unilateral breast cancer is on the rise in the USA. One contributing factor is increased awareness of contralateral breast cancer risk. Positive testing for deleterious mutation in BRCA1/2 is a concrete measure of this contributing factor. We hypothesize that breast cancer surgery trend change is temporally associated with the introduction of BRCA1/2 genetic testing around 1996. METHODS: Our study cohort included 158 BRCA1 or BRCA2 mutation carriers diagnosed with unilateral breast cancer between 1963 and 2009. Mutation carriers with ovarian cancer or bilateral breast cancer were excluded. Breast surgery and breast reconstruction surgery trends were analyzed according to year of breast cancer diagnosis or when bilateral mastectomy was performed, respectively. RESULTS: Surgery trends changed significantly over time. We observed a significant drop in the rate of unilateral mastectomy (P < 0.001) after the period 1996-2000, and the rate of bilateral mastectomy appears to be on the rise, up to 30.3% between 2006 and 2009. Breast reconstruction trends also changed significantly over time, with a significant rise in the rate of free flap reconstruction to 58.8% between 2006 and 2009. CONCLUSIONS: Our results demonstrated a significant decrease in unilateral mastectomy with a rise in bilateral mastectomy after the period 1996-2000, a period which encompassed the year when genetic testing of the two BRCA1/2 genes became commercially available, hence supporting our hypothesis. PMID- 20972633 TI - Assessment of cosmesis after breast reconstruction surgery: a systematic review. AB - BACKGROUND: Breast reconstruction (BR) is undertaken to improve cosmetic outcomes, but how this is optimally assessed is uncertain. This review summarises current methods for assessing cosmesis after reconstructive surgery and makes recommendations for future practice. METHODS: A comprehensive systematic review identified all studies with 20 or more participants that evaluated the cosmetic outcome of BR. Four evaluation criteria (reporting of study inclusion criteria, type and timing of BR and timing of assessment) were used to assess study quality. Articles reporting at least three of the four criteria were considered robust and further summarised to report methods of cosmetic assessment, assessor details and the scoring systems used. RESULTS: 122 primary papers assessed cosmesis in 11,308 women with median follow-up of 28.8 months (range 18.0-42.9 months). Cosmesis was assessed by either healthcare professionals or patients in 33 (27.1%) and 37 studies (30.3%), respectively, and by both professionals and patients in 52 (42.6%). Professional assessments included 43 (40.2%) clinical, 49 (45.8%) photographic and 13 (12.1%) geometric assessments conducted by between 1 and 26 observers. Surgeons were most frequently involved in assessments (n = 71, 67.6%), but in 38 (36.1%) papers the assessor's profession was not reported. Twenty-seven (25.7%) papers used previously published assessment scale. Patients' views were assessed in 89 studies, using questionnaires (n = 63) or interviews (n = 12); 14 (15.7%) did not report how patients' views were obtained. CONCLUSIONS: Current methods for assessing the cosmetic outcome of BR vary widely. A valid patient-centred assessment method is required to fully understand the outcomes of BR and to inform decision-making. PMID- 20972635 TI - Thoracoscopic esophagectomy in prone position. AB - INTRODUCTION: Esophagectomy can be performed by different minimal invasive techniques. We report a technique of Ivor Lewis esophagogastrectomy with manual anastomosis performed by thoracoscopy in prone position. Readers are encouraged to view the streaming video that accompanies this article. CASE REPORT: A 51-year old man was consulted for adenocarcinoma of the distal esophagus without lymph nodes invasion. Anesthesia was realized using a double-lumen endotracheal tube. The procedure started with the patient supine, and five abdominal trocars were placed. Celiac lymphadenectomy, wide Kocher maneuver, and pyloroplasty were performed. A wide gastric tube was advanced through the hiatus into the right chest. Subsequently the patient was placed in prone position and three trocars (two 5-mm, one 10-mm) were placed in the 5th, 7th, and 9th right intercostal space. The intrathoracic esophagus was dissected, and mediastinal lymphadenectomy with en bloc resection of the left inferior mediastinal pleura was performed. After sectioning the azygos vein, the esophagus was transected by scissors 1 cm cranially. A completely thoracoscopic manual double-layer anastomosis was performed using running sutures with PDS 2/0 (externally) and Maxon 4/0 (internally). Finally the patient was replaced supine; the gastric tube was fixed to the hiatus, and the specimen was retrieved by suprapubic incision. RESULTS: Thoracoscopy lasted 157' (anastomosis 40'), laparoscopy 160', and second laparoscopy 20'. Blood loss was 170 cc. The patient was discharged on postoperative day 6. CONCLUSIONS: Thoracoscopy in prone position allows the surgeon to perform a thoracoscopic esogastric anastomosis completely manually using only three trocars and without selective lung desufflation. PMID- 20972636 TI - Atypical ductal hyperplasia in directional vacuum-assisted biopsy of breast microcalcifications: considerations for surgical excision. AB - BACKGROUND: Our goal was to analyze clinicopathologic features of patients with atypical ductal hyperplasia (ADH) diagnosed on directional vacuum-assisted biopsy (DVAB) targeting microcalcifications to identify factors predicting the presence of carcinoma. MATERIALS AND METHODS: We retrospectively evaluated the clinical, mammographic, and histologic features of 140 patients with DVAB-diagnosed ADH who underwent either segmental excision (86.4%) or mammographic follow-up (>=2 years; 13.6%). Cases with mass lesions or ipsilateral cancer were excluded. RESULTS: In 16 cases, carcinoma was found on excision. All cases without excision showed no new abnormalities on mammographic follow-up. Only the amount of calcifications removed (<=95%) significantly correlated with the rate of upgrade of ADH to carcinoma (P = .037). Significant histologic predictors of upgrade to carcinoma included number of terminal duct-lobular units (TDLU; >2) involved (P = .0306), presence of significant cytologic atypia suspicious for intermediate or high grade carcinoma (P < .0001), and necrosis (P = .0006). Among ADH cases without significant atypia and/or necrosis, the extent of ADH (<=2 vs. >2 TDLU involved) was not a significant predictor of carcinoma (P = 1.0000). CONCLUSIONS: ADH associated with calcifications in the absence of a mass lesion can be categorized into different risk groups using a multidisciplinary approach with correlation of histologic and mammographic findings. ADH lesions with significant cytologic atypia and/or necrosis are most likely to be associated with carcinoma and should be excised. ADH without these features, regardless of extent of involvement, and with >95% removal of the targeted calcifications, is associated with a minimal risk (<3%) of carcinoma and may undergo mammographic follow-up only. PMID- 20972637 TI - Molecular imaging of vasa vasorum neovascularization via DEspR-targeted contrast enhanced ultrasound micro-imaging in transgenic atherosclerosis rat model. AB - PURPOSE: Given that carotid vasa vasorum neovascularization is associated with increased risk for stroke and cardiac events, the present in vivo study was designed to investigate molecular imaging of carotid artery vasa vasorum neovascularization via target-specific contrast-enhanced ultrasound (CEU) micro imaging. PROCEDURES: Molecular imaging was performed in male transgenic rats with carotid artery disease and non-transgenic controls using dual endothelin1/VEGFsp receptor (DEspR)-targeted microbubbles (MB(D)) and the Vevo770 micro-imaging system and CEU imaging software. RESULTS: DEspR-targeted CEU-positive imaging exhibited significantly higher contrast intensity signal (CIS)-levels and pre /post-destruction CIS-differences in seven of 13 transgenic rats, in contrast to significantly lower CIS-levels and differences in control isotype-targeted microbubble (MB(C))-CEU imaging (n = 8) and in MB(D) CEU-imaging of five non transgenic control rats (P < 0.0001). Ex vivo immunofluorescence analysis demonstrated binding of MB(D) to DEspR-positive endothelial cells; and association of DEspR-targeted increased contrast intensity signals with DEspR expression in vasa vasorum neovessel and intimal lesions. In vitro analysis demonstrated dose-dependent binding of MB(D) to DEspR-positive human endothelial cells with increasing %cells bound and number of MB(D) per cell, in contrast to MB(C) or non-labeled microbubbles (P < 0.0001). CONCLUSION: In vivo DEspR targeted molecular imaging detected increased DEspR-expression in carotid artery lesions and in expanded vasa vasorum neovessels in transgenic rats with carotid artery disease. Future studies are needed to determine predictive value for stroke or heart disease in this transgenic atherosclerosis rat model and translational applications. PMID- 20972638 TI - 3rd European Biobed Workshop. Universita Cattolica del Sacro Cuore, Piacenza, Italy, 30 August-September 2010. PMID- 20972639 TI - Validation efforts and flexibilities of an eight-year-old human juvenile lumbar spine using a three-dimensional finite element model. AB - The objective of this study was to develop a finite element model of the lumbar spinal column of an eight-year-old human spine and compare flexibilities under pure moments, adult, and pediatric loading with different material models. The geometry was extracted from computed tomography scans. The model included the cortical and cancellous bones, growth plates, ligaments, and discs. Adult, adolescent, and pediatric material models were used. Flexion (8 Nm), extension (6 Nm), lateral bending (6 Nm), and axial rotation (4 Nm) moments representing adult loads were applied to the three material models. Pediatric loading (0.5 Nm) was applied under these loadings to the eight-year-old spine using adult and pediatric material models. Flexibilities depended on spinal level, loading mode, and material model. Outputs incorporating the pediatric material model responded with increased flexibilities compared to the adult and adolescent material models, with one exception. This was true for the adult and pediatric loading conditions. While the sagittal and coronal bending responses were not considerably different between the adult and pediatric loadings, axial rotation responses were greater under the adult loading. This model may be used to determine intrinsic responses, such as stresses and strains, for improved characterizations of the juvenile spine behavior. PMID- 20972640 TI - The relation between arm/shoulder problems and quality of life in breast cancer survivors: a cross-sectional and longitudinal study. AB - BACKGROUND: This cross-sectional and longitudinal study of breast cancer survivors (BCSs) examines the associations between arm/shoulder problems (ASPs), which consist of pain, restricted mobility and lymphedema, and different aspects of quality of life (QoL). METHODS: BCSs who had breast surgery, axillary lymph node dissection and radiotherapy (n = 255) were examined in 2004 (mean 4.1 years post-surgery) and a sub-sample (n = 187) was re-examined in 2007. ASPs was rated clinically in 2004 and by self-report (EORTC BR23) in 2004 and 2007. QoL was self reported with The Short Form-36 (SF-36) and The Impact of Cancer scale (IOC). RESULTS: In 2004 BCSs with ASPs showed significantly poorer mean scores in most SF-36 domains compared to those without. No group differences were observed for positive IOC domains, while BCSs with ASPs showed significantly poorer mean scores in the negative ones. BCSs with clinically defined movement restriction showed significantly poorer SF-36 and negative IOC mean scores than those with clinically defined lymphedema. The longitudinal sub-study of self-rated pain, restricted mobility and lymphedema showed significant changes over time only for negative IOC domains in the pain group. Self-rated restricted mobility and lymphedema were significantly associated with most SF-36 domains both in 2004 and 2007, while few were associated with pain. Self-rated pain and restricted mobility showed significant associations with negative IOC domains. IMPLICATIONS FOR CANCER SURVIVORS: Not only lymphedema, but pain and restricted mobility in the arm/shoulder are significantly associated with poor QoL in BCSs at long-term. These problems should be diagnosed and treated in order to improve QoL. PMID- 20972641 TI - Ability to walk 1/4 mile predicts subsequent disability, mortality, and health care costs. AB - BACKGROUND: Mobility, such as walking 1/4 mile, is a valuable but underutilized health indicator among older adults. For mobility to be successfully integrated into clinical practice and health policy, an easily assessed marker that predicts subsequent health outcomes is required. OBJECTIVE: To determine the association between mobility, defined as self-reported ability to walk 1/4 mile, and mortality, functional decline, and health care utilization and costs during the subsequent year. DESIGN: Analysis of longitudinal data from the 2003-2004 Medicare Current Beneficiary Survey, a nationally representative sample of Medicare beneficiaries. PARTICIPANTS: Participants comprised 5895 community dwelling adults aged 65 years or older enrolled in Medicare. MAIN MEASURES: Mobility (self-reported ability to walk 1/4 mile), mortality, incident difficulty with activities of daily living (ADLs), total annual health care costs, and hospitalization rates. KEY RESULTS: Among older adults, 28% reported difficulty and 17% inability to walk 1/4 mile at baseline. Compared to those without difficulty and adjusting for demographics, socioeconomic status, chronic conditions, and health behaviors, mortality was greater in those with difficulty [AOR (95% CI): 1.57 (1.10-2.24)] and inability [AOR (CI): 2.73 (1.79-4.15)]. New functional disability also occurred more frequently as self-reported ability to walk 1/4 mile declined (subsequent incident disability among those with no difficulty, difficulty, or inability to walk 1/4 mile at baseline was 11%, 29%, and 47% for instrumental ADLs, and 4%, 14%, and 23% for basic ADLs). Total annual health care costs were $2773 higher (95% CI $1443-4102) in persons with difficulty and $3919 higher (CI $1948-5890) in those who were unable. For each 100 persons, older adults reporting difficulty walking 1/4 mile at baseline experienced an additional 14 hospitalizations (95% CI 8-20), and those who were unable experienced an additional 22 hospitalizations (CI 14-30) during the follow up period, compared to persons without walking difficulty. CONCLUSIONS: Mobility disability, a simple self-report measure, is a powerful predictor of future health, function, and utilization independent of usual health and demographic indicators. Mobility disability may be used to target high-risk patients for care management and preventive interventions. PMID- 20972642 TI - An audit of the impact of a stroke unit in an acute teaching hospital. AB - BACKGROUND: Previous audits of stroke care in 2002 and 2005 in our institution recommended organised and specialised care of stroke patients. A stroke unit was therefore established in June 2008. AIM: This audit assessed the impact of the establishment of an acute stroke unit on the care of stroke patients. METHOD: A review of consecutive patients admitted and diagnosed with acute stroke between June 2008 and December 2008 was carried out. Comparison was made with 55 consecutive patients surveyed in 2005. RESULTS: Marked improvements in the management of acute stroke patients were noted, particularly time to computerised tomography of brain, aspirin administration and multidisciplinary involvement. Significantly, the average length of hospital stay was reduced by a mean of 10 days from 29.3 +/- 28 in 2005 to 19.6 +/- 20 following the establishment of a stroke unit (p = 0.018). CONCLUSIONS: The stroke unit has greatly improved the care of acute stroke patients. Further areas for improvement are highlighted. PMID- 20972643 TI - Effects of ibutilide on inhibiting heart rate and rapidly terminating atrial flutter in canine. AB - Ibutilide is a newer class-III antiarrhythmic agent approved for clinical use. We sought to investigate its electrophysiological effects in canines and also the underlying mechanism of conversion of atrial flutter (AFL). For this purpose, 15 male mongrel dogs were anesthetized, intubated with tracheal tube, and heart was exposed and connected to electrodes. Electrophysiologic variables were measured with and without ibutilide (10-min infusion-dose: 0.10 mg/kg; 30-min later, maintaining dose: 0.01 mg/min) which included heart rate, conduction of intra- and inter-atrium, conduction ratio of isthmus, and ERP. Ibutilide had a significant inhibitory effect on sinus atrial node, peak response time was 20-30 min, and heart rate returned to the baseline after 2 h. One canine had 5 s sinus pause, and the other had 2:1 atrioventricular conduction post-administration. Atrial, ventricular, and pulmonary vein ERP was significantly prolonged (P < 0.05). No significant differences were observed regarding conduction of intra atrium, inter-atrium, and isthmus. It was, therefore, concluded that ibutilide had suppressive effect on sinus atrial and atrioventricular nodes. Ibutilide rapidly terminated AFL due to the reentrant wave front's inability to proceed as the refractory period was protracted and hence caused the whole excitable gap of the reentrant circuit to be affected by refractoriness. PMID- 20972644 TI - Synthesis and characterization of an exopolysaccharide by antarctic yeast strain Cryptococcus laurentii AL100. AB - An exopolysaccharide-producing Antarctic yeast strain was selected and identified as Cryptococcus laurentii AL100. The physiological properties of the strain and its ability to utilize and biotransform different carbon sources (pentoses, hexoses, and oligosaccharides) into exopolysaccharide and biomass were investigated. Sucrose was chosen as a suitable and accessible carbon source. The biosynthetic capacity of the strain was studied in its dynamics at different sucrose concentrations (20, 30, 40, and 50 g/L) and temperatures (22 and 24 degrees C). The maximum biopolymer quantity of 6.4 g/L was obtained at 40 g/L of sucrose, 22 degrees C temperature and 96-h fermentation duration. The newly synthesized microbial carbohydrate was a heteropolysaccharide having the following monosaccharide composition: arabinose, 61.1%; mannose, 15.0%; glucose, 12.0%; galactose, 5.9%; and rhamnose, 2.8%. It was characterized by polydispersity of the polymer molecule, 60% of it having molecular mass of 4200 Da. The exopolysaccharide demonstrated good emulsifying and stabilizing properties with regard to oil/water emulsions and a pronounced synergistic effect with other hydrocolloids such as xanthan gum, guar gum, and alginate. PMID- 20972645 TI - Hospital mortality of patients with severe traumatic brain injury is associated with serum PTX3 levels. AB - BACKGROUND: Traumatic brain injury (TBI) is a worldwide cause of morbidity and mortality. Pentraxin 3 (PTX3) is a humoral component of the innate immune system which has been studied as a marker of inflammatory, infections or cardiovascular pathologies. To investigate the association between serum levels of PTX3 and the hospital mortality of patients with severe TBI. METHODS: The independent association between serum PTX3 levels after severe TBI (Glasgow Coma Scale, GCS <= 8) and hospital mortality was analyzed in a prospective study of 83 consecutive patients by a multiple logistic regression analysis. The leukocyte count in the same sample was analyzed as another marker of inflammatory response. RESULTS: The mean age of patients was 35 years and 85% were male. Serum PTX3 levels were determined 18.0 (SD +/- 17.0) h after TBI. Patients who died showed a mean serum PTX3 level of 9.95 MUg/ml (SD +/- 6.42) in comparison to 5.46 MUg/ml (SD +/- 4.87) of the survivor group (P = 0.007). Elevated serum PTX3 levels remain significantly associated with mortality (P = 0.04) in the subset of patients with isolated TBI (n = 34). There were no differences in the leukocytes count measured in the same blood sample used for PTX3 determination in survivors and non-survivors (P = 0.56). The final multiple logistic regression model including age, pupillary examination, GCS, associated trauma, and PTX3 levels shows that serum levels of PTX3 which were higher than 10 MUg/ml were independently associated with the patients mortality (adjusted OR 3.06, CI 95% 1.03-9.15, P = 0.04). CONCLUSIONS: Serum PTX3 levels after severe TBI are independently associated with higher hospital mortality and may be a useful marker of TBI and its prognosis. PMID- 20972646 TI - Metabolic and clinical effects of the supplementation of a functional mixture of amino acids in cerebral hemorrhage. AB - BACKGROUND: Oral supplementation of a specific mixture of essential and non essential amino acids has been shown to modulate hypercatabolism in patients with chronic heart failure, leading to improved clinical outcome. The aim of this study was to test whether such effects could be replicated in an acute clinical model of hypercatabolism. METHODS: After approval by the Ethics Committee, patients with acute brain hemorrhage admitted to the Neurosurgical ICU were randomly assigned to receive enterally for 14 days 20% of their estimated nitrogen requirements as a standard protein supplement (control group; n = 9) or as a functional amino acid mixture (Aminotrofic(r), Errekappa Euroterapici; study group; n = 10). Metabolic and clinical outcome measures were monitored. RESULTS: In the study group, insulin sensitivity and total lymphocyte count appeared to improve when compared with control patients. Less positive blood cultures were found in the study group against control patients (4 vs. 7, respectively; P = 0.05). Also, mortality in the study group was reduced than in control patients (60 vs. 77%; P = n.s.). CONCLUSIONS: Supplementation with specific amino acids in critically ill patients may modulate metabolic response and improve clinical outcome. PMID- 20972647 TI - Intensive versus conventional insulin therapy in critically ill neurologic patients: still searching for the sweet spot. PMID- 20972648 TI - New vector tools with a hygromycin resistance marker for use with opportunistic pathogens. AB - The ability of many bacterial strains to tolerate antibiotics can limit the number of molecular tools available for research of these organisms. To help address this problem, we have modified a diverse set of vectors to include a broadly expressed hygromycin resistance (HmR) marker. Hygromycin B is an aminoglycoside antibiotic not used to treat infections in humans and has antimicrobial activity against a wide range of microorganisms. Vectors with four replication origins are represented, with potential applications including general cloning, allelic replacement, and transcriptional analysis. We show that vectors with the broad host range pBBR1-replicon conferred HmR to Achromobacter xylosoxidans, Acinetobacter baumannii, Pseudomonas aeruginosa, and Serratia marcescens, and a pC194-based vector was able to confer HmR to Francisella tularensis. We also used a subset of these plasmids to manipulate the genome of S. marcescens. Each vector has an origin of transfer for conjugation, and is also able to replicate in Saccharomyces cerevisiae to take advantage of the powerful yeast recombineering system. PMID- 20972651 TI - A randomized, double-blind, placebo-controlled trial of anticholinergic medication for nonresponders to desmopressin for monosymptomatic nocturnal enuresis. PMID- 20972650 TI - Endogenous ouabain: a link between sodium intake and hypertension. AB - The sodium pump, an ancestral enzyme with conserved ability to bind ouabain, plays a key role in salt conservation and is regulated by aldosterone and endogenous ouabain (EO). Plasma EO is elevated in about 45% of patients with essential hypertension and correlates with blood pressure. The relationship of EO with Na(+) balance is complex. Na(+) depletion raises circulating EO, whereas acute saline loads have no effect on EO in essential hypertension, and ambient levels of EO are unrelated to the saline sensitivity of blood pressure. Short term periods of high dietary salt elevate EO and the relationship with salt balance in normal individuals is V-shaped, whereas the long-term relationship is likely to be L-shaped. Normal individuals suppress the high EO transient triggered by high-salt diets and avoid hypertension. In contrast, patients with elevated EO on normal Na(+) intakes have hypertension related to poor modulation of EO biosynthesis, clearance, or both. PMID- 20972649 TI - Wharton's jelly mesenchymal stem cells as candidates for beta cells regeneration: extending the differentiative and immunomodulatory benefits of adult mesenchymal stem cells for the treatment of type 1 diabetes. AB - Mesenchymal stem cells (MSC) are uniquely capable of crossing germinative layers borders (i.e. are able to differentiate towards ectoderm-, mesoderm- and endoderm derived cytotypes) and are viewed as promising cells for regenerative medicine approaches in several diseases. Type I diabetes therapy should potentially benefit from such differentiated cells: the search for alternatives to organ/islet transplantation strategies via stem cells differentiation is an ongoing task, significant goals having been achieved in most experimental settings (e.g. insulin production and euglycaemia restoration), though caution is still needed to ensure safe and durable effects in vivo. MSC are obtainable in high numbers via ex vivo culture and can be differentiated towards insulin producing cells (IPC). Moreover, recent reports evidenced that MSC possess immunomodulatory activities (acting on both innate and acquired immunity effectors) which should result in a reduction of the immunogenicity of transplanted cells, thus limiting rejection. Moreover it has been proposed that MSC administration should be used to attenuate the autoimmune processes which lead to the destruction of beta cells. This review illustrates the recent advances made in differentiating human MSC to IPC. In particular, we compare the effectiveness of the differentiation protocols applied, the markers and functional assays used to characterize differentiated progeny, and the in vivo controls. We further speculate on how MSC derived from Wharton's jelly of human umbilical cord may represent a more promising regenerative medicine tool, as recently demonstrated for endoderm-derived organs (as liver) in human subjects, also considering their peculiar immunomodulatory features compared to other MSC populations. PMID- 20972652 TI - Phase I study of the oral mammalian target of rapamycin inhibitor everolimus (RAD001) in Japanese patients with relapsed or refractory non-Hodgkin lymphoma. AB - Phase I study was conducted to evaluate the safety, pharmacokinetics (PK) and efficacy of the oral mammalian target of rapamycin inhibitor, everolimus (RAD001), in patients with relapsed or refractory non-Hodgkin lymphoma (NHL). Patients received everolimus 5 or 10 mg orally once daily. Dose escalation was based on the safety assessment and the probability of dose-limiting toxicities (DLTs) using a Bayesian logistic model. DLTs were evaluated in six patients at each dose level during the initial 28 days of study treatment. A total of 13 patients were enrolled; 5 mg (seven) and 10 mg (six). No DLTs were observed at either dose level. Frequently observed potentially drug-related adverse events included leukopenia (8/13), thrombocytopenia (8/13), elevated hepatic transaminase (9/13), stomatitis (7/13), anemia (6/13), and nasopharyngitis (6/13). All adverse events were reversible. Non-infectious pneumonitis (grade 1) in one patient resolved following discontinuation of everolimus. Two patients with diffuse large B cell lymphoma and two patients with follicular lymphomas achieved objective responses with an overall response rate of 31% (4/13). The pharmacokinetic profiles were not different from those in non-Japanese patients. Everolimus was well tolerated at doses up to 10 mg/day and showed potential efficacy in relapsed or refractory NHL, warranting further investigation. PMID- 20972653 TI - Surgical variables influence metal ion levels after hip resurfacing. AB - BACKGROUND: Metal-on-metal bearings in surface arthroplasty are associated with prolonged periods of elevated ion circulation. However, there exists some controversy regarding the effect of different surgical variables on the concentration of metal ions in whole blood of patients after hip resurfacing. QUESTIONS/PURPOSES: We sought to confirm which clinical and radiographic parameters are associated with elevated levels of cobalt, chromium, and molybdenum after unilateral metal-on-metal surface arthroplasty. METHODS: We retrospectively reviewed 91 patients with a minimum followup of 24 months (mean, 37 months; range, 24-55 months). The clinical variables consisted of age, gender, preoperative severity of osteoarthritis, component size, and functional outcome measures using the Harris hip score and UCLA activity score. The radiographic parameters included acetabular inclination and version as well as femoral component alignment from both the anteroposterior and lateral radiographs. RESULTS: A smaller femoral head diameter was associated with larger levels of cobalt and chromium. We observed a negative correlation between ion levels and the Harris hip score or UCLA score. A larger acetabular inclination showed a direct relationship with the concentration of metal ions. Severity of preoperative osteoarthritis, acetabular version, femoral stem-shaft and valgus angle, and anterior orientation of the femoral component had no effect on the circulating metal ion levels. CONCLUSIONS: The data suggest a smaller implant diameter, larger cup inclination, and lower postoperative functional scores are associated with increased cobalt and chromium levels after metal-on-metal hip resurfacing. PMID- 20972654 TI - The accuracy of digital radiography in orthopaedic applications. AB - BACKGROUND: Recent advances in technology and the use of image archiving and communication systems (PACS) has led some institutions to abandon conventional plain film radiography and rely solely on digital computed radiography. The level of accuracy of digital radiography in measuring distances for orthopaedic applications is unclear. QUESTIONS/PURPOSES: Is it possible to accurately measure small distances using digital radiographs and PACS software? MATERIALS AND METHODS: A model for measuring articular step-off was created using a commercially produced radiographic phantom with predetermined markings at known distances. Radiographs were taken using both indirect and direct computed radiography systems, then uploaded to a PACS system. Eighteen observers measured the distance between standardized, preselected points on the radiographic phantom. The measured values were compared with the known values for each measurement. RESULTS: The mean measured values differed by 0 and 0.1 mm (SD, 0.5 mm) for indirect and direct radiographs, respectively, when measuring short distances and 1.4 mm and 2.6 mm (SD, 1.0 mm) for indirect and direct radiographs, respectively, when measuring longer distances. The intraclass correlation coefficient (ICC) for interobserver reliability was 0.82 for indirect and 0.75 for direct digital radiography. The ICC for intraobserver reliability was 0.94 for indirect and 0.90 for direct digital radiography. CONCLUSION: Although the mean measured values were very accurate (within 0.1 mm for a known distance of 3.2 mm), the SD of measurements (0.5 mm) could affect the interpretation of data, especially in clinical situations such as evaluating the quality of fracture reduction. PMID- 20972656 TI - Switching epoetin alfa and epoetin zeta in patients with renal anemia on dialysis: Posthoc analysis. AB - INTRODUCTION: epoetin zeta is a recently introduced recombinant erythropoietin, designed to be biologically similar to epoetin alfa. This posthoc analysis evaluated the impact of switching patients with chronic kidney disease (CKD) on hemodialysis from epoetin alfa to epoetin zeta, or vice versa, on hemoglobin concentration, epoetin dose, and patient safety. METHODS: data were analyzed from three published trials: two 24-week randomized, double-blind (maintenance and induction) studies and a 56-week, open-label, follow-on study involving adult patients with CKD stage 5, maintained on hemodialysis, and receiving epoetin alfa or epoetin zeta. Patients had either completed and switched treatments within the maintenance study, or had completed the induction or maintenance study on epoetin alfa and then switched to, and completed at least 12 weeks of follow-up treatment on, epoetin zeta. Mean hemoglobin levels and epoetin dose were evaluated pre- (0 4 weeks before) and post- (8-12 weeks after) switch, and were considered equivalent for the two treatments if the upper and lower limits of the 95% confidence intervals (CIs) for the intraindividual differences in mean values fell within accepted limits. RESULTS: overall, 481 patients were included in the analysis. Mean hemoglobin concentration was maintained at target levels (10.5 12.5 g/dL) throughout the drug switch. The mean differences in hemoglobin concentration and associated 95% CIs following the switch remained within prespecified equivalence limits (+/- 1.0 g/dL). The 95% CIs of the mean difference in weekly epoetin dose postswitch also remained within prespecified equivalence margins (+/- 45 IU/kg; upper limit 17.83 IU/kg, lower limit -10.91 IU/kg). Both treatments were similarly well tolerated. CONCLUSION: our data suggest that epoetin alfa and epoetin zeta therapy can be interchanged without any clinically significant alteration in efficacy, safety, or epoetin dose, in patients with CKD on dialysis receiving stable epoetin maintenance therapy. PMID- 20972657 TI - En-gendering choice: preferences for exercising in gender-segregated and gender integrated groups and consideration of overweight status. AB - BACKGROUND: Understanding the contextual preferences that people have for engaging in a health-enhancing physical activity has been identified as particularly important, as these preferences have been implicated in the maintenance of active lifestyle behaviors. PURPOSE: The primary purpose of this study was to examine adults' preferences for exercising in both gender-segregated and gender-integrated physical activity groups. The secondary purpose was to examine whether overweight status moderates adults' preferences for gender segregated groups relative to gender-integrated groups. METHOD: Survey data were obtained from a representative sample of 772 adults (N (males) = 407; N (females) = 365) in a large city in the United Kingdom. RESULTS: Males and females reported a stronger preference for exercising with members of their own gender relative to exercising in gender-integrated groups. In addition, overweight participants were found to report an accentuated relative preference for gender-segregated groups when compared to normal weight respondents. CONCLUSION: These findings suggest that both within-group gender composition and overweight status should be considered as salient contextual factors when attempting to implement successful group-based exercise programs. PMID- 20972658 TI - Impaired striatal dopamine output of homozygous Wfs1 mutant mice in response to [K+] challenge. AB - Loss of function of the Wfs1 gene causes Wolfram syndrome, a rare multisystem degenerative disorder. Mutant mice with targeted Wfs1 gene disruption (Wfs1 KO) display morphological and behavioral impairments that are not well understood. The present study aimed to investigate the striatal dopamine output of wild-type, heterozygous, and homozygous Wfs1 null-mutant mice using in vivo microdialysis technique. The baseline dopamine output in striatum was similar in all three animal groups. The application of 100 mM [K+]-rich modified Ringer solution caused in homozygous Wfs1 mutant mice an increase of dopamine output by 400%, while in wild-type and heterozygous animals, the increase of the dopamine output yielded up to 1,200%. In sum, the homozygous Wfs1 mutant mice (AUC0-3 = 0.212 nM/MUl h) show significantly decreased striatal dopamine output in response to high-concentration [K+] challenge as compared with wild-type or heterozygous Wfs1 mutant conspecifics (AUC0-3 = 0.427 and 0.505 nM/MUl h, respectively). This could explain at least some of the behavioral alterations in Wfs1 mutant mice. PMID- 20972659 TI - Part I. Development of a model system for studying nitric oxide in tumors: high nitric oxide-adapted head and neck squamous cell carcinoma cell lines. AB - The free radical nitric oxide (NO) is over-expressed in many tumors, including head and neck squamous cell carcinomas (HNSCC); however, the role NO plays in tumor pathophysiology is still not well understood. We, herein, report the development of an in vitro model system which can be used to probe the role of NO in the carcinogenesis of HNSCC. Five HNSCC cell lines were adapted to a high NO (HNO) environment by gradually introducing increasing concentrations of DETA NONOate, a nitrogen-based NO donor, to cell media. The adaptation process was carried out until a sufficiently high enough donor concentration was reached which enabled the HNO cells to survive and grow, but which was lethal to the original, unadapted ("parent") cells. The adapted HNO cells exhibited analogous morphology to the parent cells, but grew better than their corresponding parent cells in normal media, on soft agar, and in the presence of hydrogen peroxide, an oxygen-based free radical donor. These results indicate that the HNO cell lines are unique and possess biologically different properties than the parent cell lines from which they originated. The HNO/parent cell lines developed herein may be used as a model system to better understand the role NO plays in HNSCC carcinogenesis. PMID- 20972664 TI - Reconstruction of the irradiated extended abdominoperineal excision (APE) defect for locally advanced colorectal cancer. AB - PURPOSE: There is substantial evidence for neoadjuvant chemoradiotherapy and extended abdominoperineal excision (APE) for improving local recurrence rates and overall survival for rectal carcinoma. While oncologic outcomes are improved, the large irradiated defect in the pelvic floor can potentiate poor operative outcomes. We describe a reconstructive option, the inferior gluteal artery myocutaneous (IGAM) transposition flap, which can enable wide tumour resections by providing substantial non-irradiated tissue bulk. METHODS: Ten consecutive patients underwent either standard APE with direct primary closure or extended APE with IGAM transposition flap reconstruction between 2007 and 2009 for mStage I-IIIC disease. Patients underwent staging computed tomography and pelvic magnetic resonance imaging, and neoadjuvant chemoradiotherapy after multi disciplinary team discussion. Eight patients underwent extended APE and IGAM transposition flap reconstruction due to locally advanced stage of their carcinoma. Oncologic, reconstructive and post-operative outcomes were assessed. RESULTS: All cases demonstrated good closure of the APE defect, with no intra operative perforations and no immediate operative complications. Histological margins were clear (R0) in all specimens, with mean closest distance to margin 10.8 mm (range 4-20 mm). Mean follow-up was 11.3 months, with no locoregional recurrences. There was no donor site morbidity and no perineal hernia; patients reported high degrees of satisfaction with aesthetic outcome. CONCLUSION: As the extended APE becomes increasingly utilized for rectal carcinoma, a reliable reconstructive option is increasingly important. The IGAM island transposition flap imports well-vascularized, non-irradiated tissue to reconstruct the defect, provides tissue bulk and potentiates good oncologic and reconstructive outcomes. PMID- 20972665 TI - [Therapeutic neuromodulation in primary headaches]. AB - Neuromodulatory techniques have developed rapidly in the therapeutic management of refractory headaches. Invasive procedures comprise peripheral nerve stimulation (particularly occipital nerve stimulation), vagus nerve stimulation, cervical spinal cord stimulation and hypothalamic deep brain stimulation. Transcutaneous electrical nerve stimulation, repetitive transcranial magnetic stimulation and transcranial direct current stimulation are noninvasive variants. Based on current neuroimaging, neurophysiological and clinical studies occipital nerve stimulation and hypothalamic deep brain stimulation are recommended for patients with chronic cluster headache. Less convincing evidence can be found for their use in other refractory headaches such as chronic migraine. No clear recommendation can be given for the other neuromodulatory techniques. The emerging concept of intermittent stimulation of the sphenopalatine ganglion is nonetheless promising. Robust randomized and sham-controlled multicenter studies are needed before these therapeutic approaches are widely implemented. Due to the experimental nature all patients should be treated in clinical studies. It is essential to confirm the correct headache diagnosis and the refractory nature before an invasive approach is considered. Patients should generally be referred to specialized interdisciplinary outpatient departments which closely collaborate with neurosurgeons who are experienced in the implantation of neuromodulatory devices. It is crucial to ensure a competent postoperative follow-up with optimization of stimulation parameters and adjustment of medication. PMID- 20972666 TI - [Ludwig II of Bavaria - the "fairy tale king": his last years from a psychiatric point of view]. AB - Ludwig II of Bavaria (Germany) entered the political stage at the age of 18, following the premature death of his father Maximilian II in 1864. At that time, Ludwig was a very handsome, slender young man; he was enthusiastic and had a pronounced taste for fine arts and music, and was admired by the people as a "fairy tale king". However, already during the first years of his reign, he displayed traits that fulfilled the ICD-10 criteria for schizotypal disorder together with a combined cluster B personality disorder. They became even more pronounced over time. Towards the end of his life, Ludwig developed "imperial madness", a typical pattern of behavioural excesses including craving for power, splendour, construction, unrestrained spending, excessive eating and sexual exploitation, revenge with a tendency for cruelty, and an inclination for theatrical and sometimes irrational acts. This complex syndrome is usually manifested in excessively egocentric rulers who have almost unlimited power or, in the case of Ludwig II, an overwhelming desire to possess it. His imperial madness was possibly contributed to by an orbitofrontal brain syndrome. One conjecture is that this condition reflected a neurodegenerative process; another is that a primary deficit, initiated by brain damage following a severe bout of meningitis during Ludwig's babyhood, played a role. In this case, functional compensation by other brain areas may have eventually been counteracted by chronic substance abuse in his thirties. The monarch's life ended tragically when he was 40 by which time he had become adipose and had lost most of his teeth; meanwhile, he was placed under tutelage, dismissed and detained. Before his death by drowning in Lake Starnberg (suicide? attempted escape??), Ludwig apparently killed his psychiatrist, Bernhard von Gudden, who carelessly served as his sole attendant. Yet Ludwig's image as the beautiful fairy tale king is still alive in the hearts of successive generations of Bavarians and in the fascination demonstrated by the masses of tourists from throughout the world who visit (against his formerly declared wishes) his "dream castles". PMID- 20972667 TI - [The relationship between psychiatry and neurology]. AB - Neurology and psychiatry deal with diseases of the (central) nervous system. Historically neurological disorders are related to a proven organic basis, whereas psychiatric disorders are mainly defined by the phenomenology and course of the symptoms. Neuroscientific research methods such as molecular genetics, neurochemistry, neurophysiology, neuropathology, functional (SPECT, PET, fMRI) or structural (MRI) imaging have dramatically increased our knowledge of psychiatric and neurological disorders in the last 20 years. Accordingly diagnostic and therapeutic procedures and the long-term prognosis of numerous diseases in both disciplines have substantially improved (i.e. pharmacotherapy, psychotherapy, functional neurosurgery). For major brain disorders - such as dementia of the Alzheimer type - close collaboration between both disciplines is developing in diagnosis, therapy and care. Due to common neurobiological research topics, educational programs, medical training and the challenges of assuring appropriate care to patients with brain disorders, further cooperation between neurology and psychiatry is expected and necessary. PMID- 20972669 TI - Abstracts of the Osteoporosis Conference 2010. November 28-December 1, 2010. Liverpool, United Kingdom. PMID- 20972668 TI - Epidemiology and seasonal variation of distal radius fractures in Oulu, Finland. AB - The purpose of this study was to assess changes in epidemiology and reasons for wintertime excess of distal radius fractures in Oulu, Finland. Our results showed that age-specific incidence of distal radius fractures in elderly women in Finland has increased compared with a previous study. Slippery pavement surfaces assessed by a new meteorological model partly explained wintertime excess of fractures, but factors beyond weather are contributing to seasonality. INTRODUCTION: In this report, we describe the epidemiology and seasonal variation of distal radius fractures in Oulu, Finland, with a focus on the effect of weather and slippery pavement conditions. METHODS: Records of patients aged >=16 years living in Oulu with a distal radius fracture during the year 2008 were reviewed. Demographic data and details of the injury were assessed from medical records, and fractures were classified according to AO classification. Population data for Oulu during the year 2008 were used to calculate crude incidence as well as sex- and age-specific incidence rates. The number of wintertime fractures was compared with those related to pavement surface slipperiness using a unique weather and pavement condition model of the Finnish Meteorological Institute. RESULTS: The crude incidence was 258/100,000 person-years. Sex- and age-specific incidence rates rose to 1,107/100,000 person-years for females and 466/100,000 person-years for males aged >=80 years. Poisson regression analysis showed that the number of fractures was 2.5 (95% confidence interval (CI), 1.6 to 4.0; P < 0.001) times greater on slippery winter days compared with non-winter days whereas on normal winter days fractures were 1.4 (95% CI, 1.1 to 1.9; P = 0.01) times greater. Both low- and high-energy injuries resulted in similar fracture patterns by AO classification. CONCLUSIONS: Our results suggest that the epidemiology of distal radius fractures in elderly women in Finland has changed compared with a previous study. Weather analysis showed that the slipperiness of the pavement could partly explain the wintertime excess of distal radius fractures. PMID- 20972670 TI - How the vestibular system modulates tactile perception in normal subjects: a behavioural and physiological study. AB - Caloric vestibular stimulation (CVS) is a physiological technique demonstrated to transiently improve hemianaesthesia in right brain-damaged patients (Bottini et al. in Exp Brain Res 99(1):164-169, 1994, Nature 376:778-781, 1995, Neurology 65(8):1278-1283, 2005). Recent studies suggest that these effects are based on the anatomical overlapping between vestibular and tactile projections (Bottini et al. in Nature 376:778-781, 1995) in the human brain. However, much less is known about behavioural effects of this manipulation on normal subjects. We aimed to explore tactile perception during left ear CVS in normal subjects. We administered seventeen right-handed normal subjects with different types of tactile stimuli (above and below threshold) during left ear CVS. To further ensure standardized procedure, tactile stimulation was delivered through a tool developed ad hoc for the experiment. The experiment was divided in 3 conditions: (1) Baseline, (2) PostCVS and (3) Delayed CVS. We found a main effect of stimulus type (F ((2,32)) = 907.712; P = 0.000) and condition (F ((2,32)) = 55.505; P = 0.000). Moreover, post hoc comparisons revealed that below threshold stimuli are most affected by CVS (t ((16)) = -11.213; P = 0.000). Left ear CVS modulates tactile perception also in normal subjects. Moreover, this modulation seems to be selective for below threshold stimuli and not caused by attentive processes. A multisensory phenomenon is possibly the best explanation for this interaction between touch and vestibular systems, corroborated also by the anatomical evidence and by the previous knowledge about interaction with the environment. PMID- 20972671 TI - Left pulmonary artery ligation. PMID- 20972672 TI - Little League shoulder: a growth plate injury. PMID- 20972673 TI - Appearance of the delta phalanx (longitudinally bracketed epiphysis) with MR imaging. AB - The delta phalanx is an unusual condition occurring in the hand or the foot that can be distinguished from a secondary ossification center on radiographic evaluation based on the well-defined phalangeal epiphyses typically evident by 24 30 months of age. MR imaging of the delta phalanx offers the advantage of visualizing sites of unossified bone before the age these findings are typically visible with radiography. We describe the case of a 15-month-old boy who presented with soft-tissue fusion of the third and fourth digits of the right hand. Radiograph and MR evaluation revealed soft-tissue intra-axial syndactyly of the third and fourth digits and a delta phalanx involving the proximal phalanx of the involved fourth digit. PMID- 20972675 TI - Proteomic analysis in non-denaturing condition of the secretome reveals the presence of multienzyme complexes in Penicillium purpurogenum. AB - Proteins secreted by filamentous fungi play key roles in different aspects of their biology. The fungus Penicillium purpurogenum, used as a model organism, is able to degrade hemicelluloses and pectins by secreting a variety of enzymes to the culture medium. This work shows that these enzymes interact with each other to form high molecular weight, catalytically active complexes. By using a proteomics approach, we were able to identify several protein complexes in the secretome of this fungus. The expression and assembly of these complexes depend on the carbon source used and display molecular masses ranging from 300 to 700 kDa. These complexes are composed of a variety of enzymes, including arabinofuranosidases, acetyl xylan esterases, feruloyl esterases, beta glucosidases and xylanases. The protein-protein interactions in these multienzyme complexes were confirmed by coimmunoprecipitation assays. One of the complexes was purified from sugar beet pulp cultures and the subunits identified by tandem mass spectrometry. A better understanding of the biological significance of these kinds of interactions will help in the comprehension of the degradation mechanisms used by fungi and may be of special interest to the biotechnology industry. PMID- 20972674 TI - Functional and molecular imaging with MRI: potential applications in paediatric radiology. AB - MRI is a very versatile tool for noninvasive imaging and it is particularly attractive as an imaging technique in paediatric patients given the absence of ionizing radiation. Recent advances in the field of MRI have enabled tissue function to be probed noninvasively, and increasingly MRI is being used to assess cellular and molecular processes. For example, dynamic contrast-enhanced MRI has been used to assess tissue vascularity, diffusion-weighted imaging can quantify molecular movements of water in tissue compartments and MR spectroscopy provides a quantitative assessment of metabolite levels. A number of targeted contrast agents have been developed that bind specifically to receptors on the vascular endothelium or cell surface and there are several MR methods for labelling cells and tracking cellular movements. Hyperpolarization techniques have the capability of massively increasing the sensitivity of MRI and these have been used to image tissue pH, successful response to drug treatment as well as imaging the microstructure of the lungs. Although there are many challenges to be overcome before these techniques can be translated into routine paediatric imaging, they could potentially be used to aid diagnosis, predict disease outcome, target biopsies and determine treatment response noninvasively. PMID- 20972676 TI - Comparison of biological removal via nitrite with real-time control using aerobic granular sludge and flocculent activated sludge. AB - The process of nitrification-denitrification via nitrite for nitrogen removal under real-time control mode was tested in two laboratory-scale sequencing batch reactors (SBRs) with flocculent activated sludge (R1) and aerobic granular sludge (R2) to compare operational performance and real-time control strategies. The results showed that the average ammonia nitrogen, total inorganic nitrogen (TIN), and chemical oxygen demand (COD) removal during aeration phase were 97.6%, 57.0%, and 90.1% in R2 compared with 98.6%, 48.7%, and 88.1% in R1. The TIN removed in both SBRs was partially due to the presence of simultaneous nitrification denitrification via nitrite, especially in R2. The specific nitrification and denitrification rates in R2 were 0.0416 mg NH4+ -N/gSS-min and 0.1889 mg NO X)- N/gSS-min, which were 1.48 times and 1.35 times that of R1. The higher rates for COD removal, nitrification, and denitrification were achieved in R2 than R1 with similar influent quality. Dissolved oxygen (DO), pH, and oxidization reduction potential, corresponding to nutrient variations, were used as diagnostic parameters to control the organic carbon degradation and nitrification denitrification via nitrite processes in both SBRs. The online control strategy of granular SBR was similar to that of the SBR with flocculent activated sludge. However, a unique U-type pattern on the DO curve in granular SBR was different from SBR with flocculent activated sludge in aerobic phase. PMID- 20972678 TI - Risk factors and outcomes for anastomotic leakage in colorectal surgery: a single institution analysis of 1576 patients. AB - BACKGROUND: Anastomotic leakage is associated with high mortality, high reoperation rate, and increased hospital length of stay. Although many studies have examined the risk factors for anastomotic leak, large prospective series that report on long-term survival rates are lacking. METHODS: Data of 1576 patients who underwent primary resection and anastomosis for colorectal adenocarcinoma at a single institution from 1984 to 2004 were prospectively collected. Anastomotic leaks (LEK) were classified as radiological (RAD), local (LOC), or generalised (GEN). Logistic regression analysis of 21 variables was undertaken. Overall survival, cancer-related survival, and disease-free survival were analysed using the Kaplan-Meier method. RESULTS: Mean age of the patients was 67 years (SD = 12.5) and 834 (52.9%) were male. An LEK was more likely when relatively major gynaecological (tubo-oophorectomy, P = 0.004; hysterectomy, P = 0.006) or urological (total cystectomy, P = 0.014) procedures were performed during the same operative session. Other significant factors were anterior resection (P < 0.001), anastomosis using an intraluminal stapling device (P = 0.005), abdominal drain via laparoscopic port (P = 0.024), postoperative blood transfusion (P < 0.001), primary cancer site at the rectum (P = 0.016), and TNM stage of T2 or higher (P = 0.026). Having an LEK showed significant impact on overall (P = 0.021), cancer-related (P = 0.006), and disease-free (P = 0.001) survival. CONCLUSION: In this prospective study, advanced tumour stage, distal site, and need for postoperative blood transfusion were associated with increased rates of anastomotic leakage. In addition to their high risk of immediate postoperative morbidity and mortality, both localized and generalized leaks had similarly negative impacts on overall, cancer-related, and disease-free survival. PMID- 20972679 TI - A quantitative assessment of changing trends in internet usage for cancer information. AB - BACKGROUND: The internet is an important source of healthcare information. To date, assessment of its use as a source of oncologic information has been restricted to retrospective surveys. METHODS: The cancer-related searches of approximately 361,916,185 people in the United States and the United Kingdom were examined. Data were collected from two separate 100-day periods in 2008 and 2010. RESULTS: In 2008, there were 97,531 searches. The majority of searches related to basic cancer information (18,700, 19%), followed by treatment (8404, 9%) and diagnosis (6460, 7%). This compares with 179,025 searches in 2010 representing an increase of 183%. In 2008 breast cancer accounted for 21,102 (21%) individual searches, increasing to 85,825 searches in 2010. In 2010 a total of 0.2% (321) of searches focused on litigation, with those searching for breast cancer information most likely to research this topic (P=0.000). CONCLUSION: Use of the internet as a source of oncological information is increasing rapidly. These searches represent the most sensitive information relating to cancer, including prognosis and litigation. It is imperative now that efforts are made to ensure the reliability and comprehensiveness of this information. PMID- 20972680 TI - Positron-emission tomography findings indicating the involvement of the whole body skin in subcutaneous panniculitis-like T cell lymphoma. PMID- 20972681 TI - Cellular and paracellular transplants for spinal cord injury: a review of the literature. AB - BACKGROUND: Experimental approaches to limit the spinal cord injury and to promote neurite outgrowth and improved function from a spinal cord injury have exploded in recent decades. Due to the cavitation resulting after a spinal cord injury, newer important treatment strategies have consisted of implanting scaffolds with or without cellular transplants. There are various scaffolds, as well as various different cellular transplants including stem cells at different levels of differentiation, Schwann cells and peripheral nerve implants, that have been reviewed. Also, attention has been given to different re-implantation techniques in avulsion injuries. METHODS: Using standard search engines, this literature is reviewed. CONCLUSION: Cellular and paracellular transplantation for application to spinal cord injury offers promising results for those patients with spinal cord pathology. PMID- 20972682 TI - Very long-term follow-up of cognitive function in adults treated in infancy for hydrocephalus. AB - PURPOSE: The aim was to investigate the very long-term cognitive outcome in adults who had been shunt treated for hydrocephalus during their first year of life. METHODS: In a population-based series of 72 children born in 1967-1978 and shunt treated for infantile hydrocephalus, 43 were found to have a normal cognitive function when assessed at 6-17 years of age. Twenty-five of them agreed to participate in a follow-up study of cognition at a mean age of 35 years (range, 30-41 years). The Wechsler Adult Intelligence Scale (WAIS-III) was used. RESULTS: The median full-scale IQ was 101 (range, 83-120), median verbal IQ was 104 (81-115) and performance IQ was 99 (80-127). The corresponding IQs in childhood in the 16 subjects who had been tested previously with the WISC were 101 (84-124), 108 (86-135), and 101 (73-124). Specific cognitive deficits were found for working memory and processing speed. Shunt complications did not affect IQ. CONCLUSION: This very long-term follow-up study of normally gifted children with hydrocephalus revealed that, as adults, they still had preserved cognitive functions despite recurrent shunt dysfunction. The results are encouraging and represent a tribute to neurosurgical intervention. Continued follow-up studies are needed since the etiological panorama and treatment procedures of children with hydrocephalus are changing over time. PMID- 20972683 TI - Treatment and outcomes for pediatric head injuries in Mississippi. AB - OBJECT: This report summarizes the treatments and outcomes of a large series of patients with pediatric head injuries (PHIs), who were admitted to a tertiary pediatric trauma center at the University of Mississippi Medical Center from January 1, 2003 through December 31, 2006. METHODS: Data were retrieved from the Department of Neurosurgery's Brain Trauma Registry (BTR) on patients who are <=16 years old. Data include Glasgow Coma Scale (GCS) and injury severity scores (ISS) on admission and Glasgow Outcome Scale (GOS) scores at 6 months follow-up. RESULTS: The BTR registered 554 patients with accidental and nonaccidental PHIs. Follow-up was complete in 98.2%. Aggressive first-tier management with ventricular drainage was used to lower intracranial pressure. Vasopressors were used only to correct hypotension. Second-tier therapies were used infrequently. Craniectomies (14 patients) were associated with good outcomes (GOS 4-5) in nine patients; hypothermia (six patients) and barbiturate (four patients) therapies were ineffective. All 439 patients with ISS <25 showed good outcomes. Fifteen of 16 patients with GCS >8 and ISS >=25 had good outcomes. In 134 patients with severe PHIs (GCS <=8), all 45 with ISS <25 and 46 with ISS >=25 showed good outcomes. Forty-three patients with GCS <=8 and ISS >=25 had poor outcomes. Of these patients, 38 died; 22 died within 3 days of admission. CONCLUSIONS: This study indicated that poor outcomes occurred only in PHIs with severe generalized trauma. While 28.4% of patients with GSC <=8 died, more than half of these sustained nonsurvivable injuries. Aggressive medical management with ventricular drainage was the mainstay of therapy. PMID- 20972684 TI - A 5-year prospective assessment of advanced Parkinson disease patients treated with subcutaneous apomorphine infusion or deep brain stimulation. AB - Prospective comparative long-term data on the effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and continuous subcutaneous infusion of apomorphine (CSAI) in patients with advanced Parkinson disease (PD) are lacking. We report 5-year follow-up of 25 PD patients treated with either STN-DBS (n = 13) or CSAI (n = 12) who fulfilled CAPSIT-PD criteria. Cohorts were matched for disease duration and severity of motor complications. Baseline clinical and neuropsychological status did not differ among cohorts. Patients were assessed with the UPDRS, MMSE, HAMD-17 and Neuropsychiatric Inventory (NPI).Twelve subjects reached the 5-year follow-up with STN-DBS (one was lost at follow-up) versus two in the CSAI cohort. Drop-outs with CSAI were due to subcutaneous nodules (n = 2), insufficient control of motor fluctuations and dyskinesia (n = 4), death for unrelated reasons (n = 3) and one was lost at follow-up. Average apomorphine dose at last visit was 83.4 +/- 19.2 mg/day and average treatment duration was 30 months. At 1-year as well as at last follow-up (intention-to treat analysis), both therapies decreased daily off-time but only STN-DBS reduced dyskinesia duration and severity. Decrement of medications was greater with STN DBS. There was a significant worsening of NPI after STN-DBS, primarily because four subjects developed apathy. PMID- 20972685 TI - An unusual mimicker of a sepsis outbreak: ergot intoxication. AB - Methylergonovine (MEV) is a semi-synthetic ergot alkaloid used in the prevention and control of postpartum hemorrhage. This report describes 12 newborns born on the same day in a local country hospital in Turkey and developed sepsis-like symptoms and encephalopathy within the first 6 h of life due to accidental administration of MEV instead of vitamin K in the delivery room. The major features of MEV poisoning were lethargy (41.7%), seizure (75.0%), feeding intolerance (66.6%), hypoventilation (58.3%), irritability (25%), and peripheral circulatory abnormalities (58.3%). As a conclusion, clinical findings of ergot toxicity in newborns cannot be distinguished from infectious disease or neonatal encephalopathy. PMID- 20972686 TI - Neonatal severe hyperparathyroidism: further clinical and molecular delineation. AB - We report a newborn female from a consanguineous Sri Lankan family with clinical and biochemical features of neonatal severe hyperparathyroidism (NSHPT). Mutation screening of the calcium-sensing receptor (CASR) gene in genomic DNA revealed a homozygous truncating mutation (c.679C>T, predicting p.R227X), confirming the clinical diagnosis. Other mutations at the R227 position are reported to cause varying degrees of hypercalcemia and hyperparathyroidism, but this nonsense variant is novel and expected to induce unremitting hyperparathyroidism from birth onward. In our patient with NSHPT, early bisphosphonate therapy was crucial in counteracting the marked hypercalcemia and allowed for safe surgical intervention ("total" parathyroidectomy, "thymectomy and hemithyroidectomy") at 3 months of age. CONCLUSION: This report highlights the continuing challenges in diagnosis and management of this life-threatening condition. PMID- 20972687 TI - Footprint analysis of flatfoot in preschool-aged children. AB - Our aim in this study was to analyze the footprint measurements of flatfoot in a population of preschool-aged children. Three footprint measurements, the Clarke's angle (CA), Chippaux-Smirak index (CSI), and Staheli arch index (AI), were used for comparison with clinical diagnosis. A total of 2,638 static footprints of children aged from 3 to 6 years were recorded. The clinical diagnosis as a gold standard compared with the results of the CA, CSI, and AI and displayed in a receiver operating characteristic (ROC) curve. In order to illustrate the diagnostic accuracy in clinical settings, their likelihood ratios were calculated given their cutoff points, and their pretest/posttest probabilities were plotted as the Fagan nomogram. The optimal cutoff points for CA, CSI, and AI were 14.04 degrees , 62.70%, and 107.42%, respectively, and all of them showed high sensitivity. The areas under curves were 0.91, 0.95, and 0.92, respectively. The positive predictive values were 0.84, 0.91, and 0.85, and the negative predictive values were 0.82, 0.85, and 0.85, respectively. The positive likelihood ratio values for CA, CSI, and AI were 4.09, 7.52, and 4.61, and the negative likelihood ratio values were 0.18, 0.14, and 0.13, respectively. In conclusion, this study demonstrated that footprint analysis methods are suitable for diagnosing flatfoot in preschool-aged children, and that the most appropriate cutoffs are as follows: CA <= 14.04 degrees , CSI > 62.70%, and AI > 107.42%. The CSI had a predictive probability of more than 90% and is recommended in screening for flatfoot in preschool-aged children. PMID- 20972688 TI - Polish 2010 growth references for school-aged children and adolescents. AB - Growth references are useful in monitoring a child's growth, which is an essential part of child care. The aim of this paper was to provide updated growth references for Polish school-aged children and adolescents and show the prevalence of overweight and obesity among them. Growth references for height, weight, and body mass index (BMI) were constructed with the lambda, mu, sigma (LMS) method using data from a recent, large, population-representative sample of school-aged children and adolescents in Poland (n = 17,573). The prevalence of overweight and obesity according to the International Obesity Taskforce definition was determined with the use of LMSGrowth software. Updated growth references for Polish school-aged children and adolescents were compared with Polish growth references from the 1980s, the Warsaw 1996-1999 reference, German, and 2000 CDC references. A positive secular trend in height was observed in children and adolescents from 7 to 15 years of age. A significant shift of the upper tail of the BMI distribution occurred, especially in Polish boys at younger ages. The prevalence of overweight or obesity was 18.7% and 14.1% in school-aged boys and girls, respectively. The presented height, weight, and BMI references are based on a current, nationally representative sample of Polish children and adolescents without known disorders affecting growth. Changes in the body size of children and adolescents over the last three decades suggest an influence of the changing economical situation on anthropometric indices. PMID- 20972689 TI - [Repeated percutaneous chemical sympathectomy as a therapeutic option for treating PAD II]. AB - The value of percutaneous chemical lumbar sympathectomy (LSE) for the treatment of peripheral arterial disease (PAD) is still being discussed controversially. In particular, a benefit for Fontaine stage II PAD could not yet be shown. This case report is about a patient suffering from Fontaine stage II PAD. By applying five LSE in regular intervals good symptom control could be achieved and maintained for more than 5 years. The case is an occasion to call for larger controlled studies designed to find out the efficacy of LSE for the treatment of stage II PAD. Mechanisms and available data are discussed. PMID- 20972690 TI - Identification of a potent activator of Akt phosphorylation from a novel series of phenolic, picolinic, pyridino, and hydroxamic zinc(II) complexes. AB - The discovery of small-molecule modulators of signaling pathways is currently a particularly active area of research. We aimed at developing unprecedented metal based activators of Akt signaling which can potentially find applications as tools for regulating glucose metabolism downstream of Akt or serve as lead structures for developing antidiabetic drugs. In this context, a highly diverse library of 11 new zinc(II) complexes with phenolic, picolinic, pyridino, and hydroxamic ligands, all containing features beneficial for medicinal purposes, was prepared and screened in an assay that detected levels of phospho-Akt in lysates from NIH3T3 cells after treatment with the compounds. The complexes featuring hydroxamic ligands were found to be the most prominent activators of Akt among the molecules prepared, with the most efficient compound acting at submicromolar concentrations. Further characterization revealed that this compound induces phosphorylation of the Akt downstream effector glycogen synthase kinase 3beta, but does not act as an inhibitor of tyrosine phosphatases or PTEN. PMID- 20972691 TI - Pathogenicity and virulence of the present hantaviruses in Bosnia and Herzegovina: the impact on renal function. AB - Dobrava (DOBV) and Puumala (PUUV) viruses are endemic throughout the Balkans and cause haemorrhagic fever with renal syndrome (HFRS). The aim of this study was to assess the impact of two different hantaviruses on renal function in HFRS patients during the acute stage of illness. We also aimed to assess the DOBV and PUUV distribution between symptomatic HFRS patients and asymptomatic hantavirus antibody-positive subjects. The study included 264 symptomatic HFRS patients and 63 asymptomatic hantavirus antibody-positive healthy subjects. In our study, 131 (49.6%) HFRS patients were regarded as PUUV- and 69 (26.1%) as DOBV-infected patients, while in 64 (24.2%) of HFRS patients that showed all clinical and biochemical signs of HFRS, the causal hantavirus could not be determined with commercially available tests. DOBV-infected patients were associated with more requirements for haemodialysis treatment, lower diuresis and higher serum creatinine and urea values compared to PUUV-infected patients. PUUV was significantly predominant in asymptomatic hantavirus antibody-positive subjects (69.8%) compared to HFRS patients. DOBV was present in 17.5% of asymptomatic subjects and, interestingly, the preferential hantavirus serotype could not be determined in 12.7% of the asymptomatic antibody-positive subjects. PMID- 20972692 TI - Outcome of hospitalized MDR-TB patients: Israel 2000-2005. AB - MDR-TB has emerged in Israel following an immigrations wave from the Former Soviet Union (FSU) and Ethiopia. The purpose of this study was to outline characteristics and outcome of hospitalized MDR-TB patients. We retrospectively summarized charts of MDR-TB patients hospitalized in the national referral tuberculosis centers from January 2000 to December 2005, and followed them for 2 years. One hundred thirty-two patients were identified with a median age of 40 years and male predominance (77%). The majority of the patients were immigrants from FSU (83%) and Ethiopia (7.6%). They were characterized by alcohol (25.8%) and IV drug abuse (23.5%), presented with advanced disease manifested by hypoalbuminemia (50.8%) and smear positivity (70.5%). Cure was achieved in 50.3% and 30.4% died. Factors independently associated with death were patients' age (OR = 1.036 for each year, 95%CI 1.0-1.1, p = 0.014), hypoalbuminemia (OR = 2.95, 95%CI 1.1-7.6, p = 0.025), smear positivity at diagnosis (OR = 3.7, 95%CI 1.2 11.4, p = 0.023), alcohol abuse (OR = 4.8, 95%CI 1.7-13.7, p = 0.004) and XDR-TB resistance pattern (OR 8.3, 95%CI 1.5-44.6, p = 0.014). This study brings out the poor prognosis of a highly vulnerable immigration population. Efforts should be focused on earlier diagnosis and treatment in a well controlled hospital environment and to professional support groups to attend to this population's special needs. PMID- 20972693 TI - Utility of antimicrobial susceptibility-based algorithms for the presumptive identification of genotypically-defined community-associated methicillin resistant Staphylococcus aureus at a London teaching hospital. AB - PURPOSE: Community-associated methicillin-resistant Staphylococcus aureus (CA MRSA) strains are classically characterised by susceptibility to most non-beta lactam antimicrobial agents. We sought to determine whether antimicrobial susceptibility (AMS)-based algorithms could be used to presumptively identify CA MRSA in a hospital MRSA collection. METHODS: Over a three-month period, all MRSA were tested for AMS, staphylococcal cassette chromosome mec (SCCmec) type, presence of the Panton-Valentine leukocidin (PVL) genes and spa type. CA-MRSA isolates were defined genotypically using a combination of spa and SCCmec type. AMS based algorithms were developed and tested for their sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: Ciprofloxacin susceptibility (p < 0.001) and fusidic acid resistance (p = 0.044) were independent predictors of CA-MRSA in a multivariate model. Although 98.5% of HA-MRSA were ciprofloxacin resistant, so too were 36.6% of CA-MRSA. Algorithms based on ciprofloxacin-susceptibility and fusidic acid resistance performed best, with specificity and NPV >90% and sensitivity and PPV >70%. CONCLUSIONS: Our data indicate that while ciprofloxacin-susceptible isolates are likely to be CA-MRSA, the use of ciprofloxacin-susceptibility as a marker of CA MRSA would miss approximately one third of CA-MRSA isolates. Therefore, AMS patterns have limited utility for the identification of genetically-defined CA MRSA in our setting. PMID- 20972694 TI - Tumoral calcinosis associated with hypercalcemia in a patient with chronic renal failure. AB - A 56-year-old male with chronic renal failure was admitted to the hospital because of progressive hip pain, appetite loss, general fatigue, and hypercalcemia. Slight pain had developed in the left hip 3 months before the initiation of hemodialysis, which subsequently developed into hyperalgesia. The patient was suspected to have sarcoidosis based on the elevated serum angiotensin converting enzyme and lysozyme levels, and the ocular finding characterized by punched out chorioretinal scarring, although this could not be confirmed by histological evaluations. There was an abnormal uptake of gallium in the dependent portion of the tumoral calcinosis, which could have suggested either the presence of granulomatous sarcoid tissue within the calcified mass or active calcification associated with an inflammatory reaction. Elevated serum concentrations of 1,25-dihydroxyvitamin D3, which should be implicated in the development of hypercalcemia, promptly decreased after the administration of steroids. Steroid administration subsequently led to a decrease in the serum calcium and relief of the hip pain. This was a rare case of sarcoidosis associated with symptomatic tumoral calcinosis and hypercalcemia. The diagnostic significance of a gallium scan in this case will also be discussed. PMID- 20972695 TI - Methylprednisolone pulse therapy combined with mizoribine following tonsillectomy for immunoglobulin A nephropathy: clinical remission rate, steroid sparing effect, and maintenance of renal function. AB - BACKGROUND: The long-term prognosis of immunoglobulin A nephropathy (IgAN) is reportedly poor. In Japan, tonsillectomy-steroid pulse therapy has frequently been used for treatment of early IgAN, with favorable outcomes. However, steroid usage is sometimes limited due to adverse reactions. To reduce the total dose of steroids, we have been using mizoribine (MZR) in combination with tonsillectomy steroid pulse therapy since 2004. Here we report a retrospective evaluation of our protocol outcome. METHODS: Forty-two patients aged <70 years with histopathologically confirmed IgAN and an estimated glomerular filtration rate (eGFR) of 30 ml/min/1.73 m(2) or higher were enrolled. After giving informed consent, all the patients underwent bilateral tonsillectomy. One week later, intravenous methylprednisolone pulse therapy (500 mg/day) was administered for 3 days, followed by oral prednisolone (30 mg/day and tapered to 0 over 7 months) and MZR (150 mg/day for 11 months). The complete remission (CR) rate and renoprotective effect were assessed. RESULTS: The CR rate at 6, 12, and 24 months was 33.3, 69.1, and 76.2%, respectively. Despite a relatively low total steroid dose, renal function was satisfactorily maintained for 24 months or longer with no relapse. The eGFR in patients with stage 3 chronic kidney disease was significantly improved at 6 months after start of treatment. Three patients (7.1%) had mild and transient adverse events. CONCLUSION: This protocol appears to be highly effective and safe for IgAN patients with renal dysfunction. PMID- 20972696 TI - Angiogenesis in chronic rhinosinusitis with nasal polyps and in antrochoanal polyps. AB - OBJECTIVES AND STUDY DESIGN: Angiogenesis may be related to the pathogenesis and prognosis of chronic rhinosinusitis with nasal polyposis. This cross-sectional study, in a tertiary university hospital, evaluates angiogenesis parameters in nasal polyps, antrochoanal polyps and middle turbinates. SUBJECTS: Nasal polyps obtained from 24 consecutive patients, were compared to 10 normal middle turbinates and to 11 antrochoanal polyps. METHODS: Analyzing for the expression of the angiogenic marker CD34 by immunohistochemistry. Blood vessels count, vascular surface density and microvessel density were measured by manual and computerized methods. RESULTS: Angiogenesis was significantly higher in nasal polyps compared to control turbinates and to antrochoanal polyps (p = 0.0001 and p = 0.007, respectively). Antrochoanal polyps showed significantly more angiogenesis than normal middle turbinates (p = 0.001). Angiogenesis was not elevated in sub-groups of nasal polyposis patients considered to have worse prognosis. CONCLUSIONS: Angiogenesis probably plays a role in the pathogenesis of both nasal polyposis and antrochoanal polyps. However, the significantly higher angiogenesis found in nasal polyps compared to antrochoanal polyps may support a different mechanism of growth. The lack of difference between angiogenesis and nasal polyposis patients sub-groups, may imply that angiogenesis is not associated with the prognosis of chronic rhinosinusitis with nasal polyposis. PMID- 20972697 TI - The influence of statin treatment on the inflammatory biomarkers YKL-40 and HsCRP in patients with stable coronary artery disease. AB - OBJECTIVE: The inflammatory biomarker YKL-40 is elevated and associated with mortality in patients with stable coronary artery disease (CAD). The aim was to investigate the influence of statin treatment and lipid status on serum YKL-40 and Hs-CRP in patients with stable CAD. DESIGN: Serum YKL-40, HsCRP, total cholesterol, HDL-c, LDL-c and triglycerides levels were measured in 404 statin treated and in 404 matched non-statin treated patients with stable CAD. RESULTS: YKL-40 was significantly higher in non-statin treated 110 ug/l (median) compared with 65 ug/l in statin treated (p < 0.001). HsCRP was 3.3 mg/l in non-statin treated compared with 2.1 mg/l in statin treated (p < 0.001). YKL-40 was not related to cholesterol levels for either statin or non-statin treated patients in the univariate analysis. In statin treated patients, HsCRP was related to a high level of total-cholesterol (p = 0.01) and a low level of HDL-c (p < 0.001). CONCLUSIONS: HsCRP, but not YKL-40, is associated with the cholesterol levels in statin treated patients. This indicates that YKL-40 could be a superior prognostic biomarker in patients with stable CAD, since it is independent of changes in cholesterol levels in both statin and non-statin treated patients. PMID- 20972698 TI - Detrimental effect of increasing sugar concentrations on ethanol production from maize or decorticated sorghum mashes fermented with Saccharomyces cerevisiae or Zymomonas mobilis: biofuels and environmental biotechnology. AB - The efficiency of ethanol fermentation, as affected by grain source (maize and decorticated red sorghum), total sugar concentration (13 or 20 degrees Plato) and type of microorganism (Saccharomyces cerevisiae or Zymomonas mobilis) was studied. Maize mashes yielded 0.32 l ethanol kg(-1) ground grain whereas mashes prepared with decorticated red sorghum produced 0.28 l ethanol kg(-1). Both microorganisms yielded similar amounts of ethanol. However, high-gravity mashes (20 degrees Plato) yielded lower amounts of ethanol compared to counterparts adjusted to 13 degrees Plato (0.28 vs. 0.22 l ethanol kg(-1) ground grains). In decorticated sorghum mashes adjusted to 20 degrees P, Z. mobilis produced 40 ml kg(-1) more ethanol compared to S. cerevisiae. In addition, Z. mobilis had a lower dependency on nitrogenous compounds. PMID- 20972699 TI - Increase in antioxidant and antihypertensive activity by Oenococcus oeni in a yeast autolysis wine model. AB - Accelerated autolysis of Saccharomyces cerevisiae mc2 in synthetic wine medium enabled the release of 3.7 mg peptide nitrogen/l, concomitantly with an increase in antioxidant properties (243 micromol FeSO(4)/l in the case of ferric reducing antioxidant power and 0.5% in 2,2-diphenyl-1-picrylhydrazyl radical scavenging) and antihypertensive activity (22% in angiotensin I-converting enzyme inhibitory activity). Sequential inoculation of a proteolytic Oenococcus oeni strain in the synthetic medium after yeast autolysis produced an increase in peptide nitrogen concentration of 1.5 mg/l after 48 h of growth. After this incubation time an improvement in antihypertensive and antioxidant activities was detected. Oenococcus oeni X(2)L could give additional value to wine because of the bioactive peptides with multifunctional beneficial activity released as consequence of its proteolytic activity. PMID- 20972700 TI - Acidic pH conditions induce dissociation of the haem from the protein and destabilise the catalase isolated from Aspergillus terreus. AB - The stability (half-life, t(1/2)) of the large catalase (CAT) isolated from Aspergillus terreus was decreased under acidic conditions (maximum t(1/2) approximately 8.5 months at pH <= 6) versus alkaline conditions (t(1/2) approximately 15 months at pH 8-12). Acidic conditions induce the dissociation of haem from CAT, as revealed from a reduction in the Soret peak intensity at 405 nm and an increase in the peak current at Fe(3+)/Fe(2+) redox potentials. This increase in current is attributed to the facile electron transfer from the free haem generated on the electrode surface as a result of its disintegration from the insulating protein matrix. The haem isolated from CAT at acidic condition was reconstituted with apo-CAT at alkaline denaturing conditions to regenerate the CAT activity. PMID- 20972701 TI - Effects of temperature and initial pH on biohydrogen production from food processing wastewater using anaerobic mixed cultures. AB - This study attempted to determine the optimal temperature and initial cultivation pH by conducting a series of batch tests in stirred-tank bioreactor using fructose-producing wastewater as an organic substrate. The bioreactor temperature was controlled at 35-55 degrees C with an initial pH of 4-8. Hydrogen production efficiency was assessed using specific hydrogen production potential (SHPP) and the maximum specific hydrogen production rate (SHPR(m)). Experimental results indicated that temperature and initial pH markedly affected SHPP and SHPR(m), volatile fatty acids distribution as well as the ratio of butyrate/acetate (BHu/HAc). Two-fold higher SHPP and SHPR(m) were obtained at thermophilic condition (55 degrees C) than those at mesophilic condition (35 degrees C). The optimal initial pH was 6 for hydrogen production with peak values of SHPP of 166.8 ml-H(2)/g-COD and SHPR(m) of 26.7 ml-H(2)/g-VSS-h for fructose-processing wastewater. Molasses-processing wastewater had a higher SHPP (187.0 ml-H(2)/g COD) and SHPR(m) (42.7 ml-H(2)/gVSS-h) than fructose-processing wastewater at pH 6. The DGGE profiles indicated that molasses-processing wastewater is a better substrate than fructose-processing wastewater for growth of hydrogen-producing bacteria due to the high staining intensity of bands. PMID- 20972702 TI - Biological differences between two allopatric populations of Amblyomma cajennense (Acari: Ixodidae) in Argentina. AB - The fertility of hybrids from two distinct populations of Amblyomma cajennense from different ecological regions of Northern Argentina was analyzed. Two colonies of A. cajennense from El Rey National Park (RNP), Salta Province (24o41'S, 64o36'W), and Copo National Park (CNP), Santiago del Estero Province (25o55'S, 61o43'W) were established infesting rabbits with adults collected from vegetation. Reproductive parameters of the first generation in laboratory of each colony and their crosses were evaluated considering engorged weight of females, engorged period of females, pre-oviposition period of females, minimum egg incubation period, reproductive efficiency index [REI = number of eggs laid/weight of the females in mg], and fertility efficiency index [FEI = number of hatched larvae/weight of the females in mg]. Infestations were made as follows: Group 1) RNP males and females; Group 2) CNP males and females; Group 3) males from CNP and females from RNP; Group 4) males from RNP and females from CNP. The engorgement weight of the females from CNP that mated with males from RNP was significantly lighter than those of the engorged females obtained in the other 3 crosses, and the engorged period of the females from CNP that mated with males from RNP was significantly longer that the engorged period of the females belonging to the remaining groups. The females from group 3 and 4 had a FEI extremely low in comparison with the FEI obtained from the engorged females originated from the groups 1 and 2. Biological implication of these findings is discussed. PMID- 20972703 TI - Evaluation of a workplace disability prevention intervention in Canada: examining differing perceptions of stakeholders. AB - INTRODUCTION Workplace disability prevention is important, but stakeholders can differ in their appreciation of such interventions. We present a responsive evaluation of a workplace disability prevention intervention in a Canadian healthcare organization. Three groups of stakeholders were included: designers of the intervention, deliverers, and workers. The aim was to examine the appreciation of this intervention by analyzing the discrepancies with respect to what these various stakeholders see as the causes of work disability, what the intervention should aim at to address this problem, and to what extent the intervention works in practice. METHODS A qualitative research method was used, including data-triangulation: (a) documentary materials; (b) semi-structured interviews with the deliverers and workers (n = 14); (c) participatory observations of group meetings (n = 6); (d) member-checking meetings (n = 3); (e) focus-group meetings (n = 2). A grounded theory approach, including some ethnographic methodology, was used for the data-analysis. RESULTS Stakeholders' perceptions of causes for work disability differ, as do preferred strategies for prevention. Designers proposed work-directed measures to change the workplace and work organizations, and individual-directed measures to change workers' behaviour. Deliverers targeted individual-directed measures, however, workers were mostly seeking work-directed measures. To assess how the intervention was working, designers sought a wide range of outcome measures. Deliverers focused on measurable outcomes targeted at reducing work time-loss. Workers perceived that this intervention offered short-term benefits yet fell short in ensuring sustainable return-to-work. CONCLUSION This study provides understanding of where discrepancies between stakeholders' perceptions about interventions come from. Our findings have implications for workplace disability prevention intervention development, implementation and evaluation criteria. PMID- 20972704 TI - Development and characterization of RAPD and microsatellite markers for genetic variation analysis in the critically endangered yellow catfish Horabagrus nigricollaris (Teleostei: Horabagridae). AB - Random-amplified polymorphic DNA (RAPD) and microsatellite markers were developed and used for the analysis of genetic variability in the critically endangered yellow catfish Horabagrus nigricollaris, sampled from the Chalakkudy River, Kerala, India. Eight RAPD and five microsatellite markers were detected to genotype the species. In RAPD, the 73 fragments were 20.55% polymorphic, whereas 4 polymorphic loci (80%) were obtained in microsatellites. In microsatellites, the number of alleles across the 5 loci was 1-5, and the range of heterozygosity was 0.25-0.5. The mean observed number of alleles was 2.4, and the effective number was 1.775 per locus. The average heterozygosity across all investigated samples was 0.29, indicating a significant deficiency of heterozygotes in this species. RAPD and microsatellite methods report a low degree of gene diversity and lack of genetic heterogeneity in the population of H. nigricollaris, emphasizing the need for fishery management, conservation, and rehabilitation of this species. PMID- 20972705 TI - Antiparkinsonian effects of aqueous methanolic extract of Hyoscyamus niger seeds result from its monoamine oxidase inhibitory and hydroxyl radical scavenging potency. AB - Hyoscyamus species is one of the four plants used in Ayurveda for the treatment of Parkinson's disease (PD). Since Hyoscyamus niger was found to contain negligible levels of L-DOPA, we evaluated neuroprotective potential, if any, of characterized petroleum ether and aqueous methanol extracts of its seeds in 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in mice. Air dried authenticated H. niger seeds were sequentially extracted using petroleum ether and aqueous methanol and were characterized employing HPLC-electrochemistry and LCMS. Parkinsonian mice were treated daily twice with the extracts (125-500 mg/kg, p.o.) for two days and motor functions and striatal dopamine levels were assayed. Administration of the aqueous methanol extract (containing 0.03% w/w of L-DOPA), but not petroleum ether extract, significantly attenuated motor disabilities (akinesia, catalepsy and reduced swim score) and striatal dopamine loss in MPTP treated mice. Since the extract caused significant inhibition of monoamine oxidase activity and attenuated 1-methyl-4-phenyl pyridinium (MPP+) induced hydroxyl radical (.OH) generation in isolated mitochondria, it is possible that the methanolic extract of Hyoscyamus niger seeds protects against parkinsonism in mice by means of its ability to inhibit increased .OH generated in the mitochondria. PMID- 20972706 TI - Virulence of Brucella abortus isolated from cattle and water buffalo. AB - Brucellosis has been documented in domestic water buffalo (Bubalus bubalis) but published literature is limited despite the importance of this species in tropical agricultural systems. The objective of this study was to compare the virulence of Brucella abortus isolates recovered from cattle and water buffalo. Nineteen strains of B. abortus from cattle and domestic water buffalo in Trinidad were intraperitoneally inoculated into BALB/c mice. Spleens were cultured for B. abortus and histopathological severity scores were calculated based on lymphoid depletion, lymphoid necrosis, splenitis, and macrophage accumulation. A general linear model approach was used to estimate the effect of isolate source (cattle versus water buffalo) on virulence. Isolates of water buffalo origin were significantly less virulent in the mouse model based on recovered B. abortus from splenic tissues, spleen/weight ratio, and lymphoid necrosis but not overall histopathological severity scores. Further investigation of isolates recovered from water buffalo might provide the key to the development of procedures for brucellosis control in tropical environments. PMID- 20972707 TI - Comparison of (semi-)automatic and manually adjusted measurements of left ventricular function in dual source computed tomography using three different software tools. AB - To assess the accuracy of (semi-)automatic measurements of left ventricular (LV) functional parameters in cardiac dual-source computed tomography (DSCT) compared to manually adjusted measurements in three different workstations. Forty patients, who underwent cardiac DSCT, were included (31 men, mean age 58 +/- 14 years). Multiphase reconstructions were made with ten series at every 10% of the RR-interval. LV function analysis was performed on three different, commercially available workstations. On all three workstations, end-systolic volume (ESV), end diastolic volume (EDV), LV ejection fraction (LVEF) and myocardial mass (MM) were calculated as automatically as possible. With the same DSCT datasets, LV functional parameters were also calculated with as many manual adjustments as needed for accurate assessment for all three software tools. For both semi automatic as well as manual methods, time needed for evaluation was recorded. Paired t-tests were employed to calculate differences in LV functional parameters. Repeated measurements were performed to determine intra-observer and inter-observer variability. (Semi-)automatic measurements revealed a good correlation with manually adjusted measurements for Vitrea (LVEF r = 0.93, EDV r = 0.94, ESV r = 0.98 and MM r = 0.94) and Aquarius (LVEF r = 0.96, EDV r = 0.94, ESV r = 0.98 and MM r = 0.96). Also, good correlation was obtained for Circulation, except for LVEF (LVEF r = 0.45, EDV r = 0.93, ESV r = 0.92 and MM r = 0.86). However, statistically significant differences were found between (semi )automatically and manually adjusted measurements for LVEF (P < 0.05) and ESV (P < 0.001) in Vitrea, all LV functional parameters in Circulation (P < 0.001) and EDV, ESV and MM (<0.001) in Aquarius Workstation. (Semi-)automatic measurement of LV functional parameters is feasible, but significant differences were found for at least two different functional parameters in all three workstations. Therefore, expert manual correction is recommended at all times. PMID- 20972708 TI - Coding and traceability for products of human origin. PMID- 20972709 TI - Resistance to HER2-targeted therapy: mechanisms of trastuzumab resistance and possible strategies to overcome unresponsiveness to treatment. AB - Trastuzumab has shown significant efficacy in HER2-overexpressing breast cancers and is approved for patients whose tumors carry this abnormality, both in the metastatic and in the adjuvant settings. However, several issues about its optimal use remain unresolved. Many breast cancer patients with HER2 overexpression do not respond to initial therapy with trastuzumab (Herceptin((r))), and a vast majority of these develop resistance to this monoclonal antibody within one year. This review discusses the molecular mechanisms leading to the development of trastuzumab resistance, including circulating HER2 extracellular domain, loss of PTEN, activation of alternative pathways (e.g. IGFR), and receptor-antibody interaction block. Additionally, the possibility of exploring these aberrations as therapeutic targets that potentially overcome resistance to trastuzumab is highlighted. PMID- 20972710 TI - [Current aspects of breast carcinoma: 2]. PMID- 20972711 TI - [Possibilities in oncoplastic and reconstructive surgery for patients with breast cancer]. AB - Although systemic treatment strategies are improving continuously, breast surgery still plays a central role in the management of breast cancer. Because breast conserving therapy is feasible in more than two thirds of breast cancer patients, breast surgeons should be aware of the different oncoplastic techniques. The development of skin sparing techniques combined with immediate reconstruction provides good cosmetic results in many cases in which mastectomy is required. Therefore the reconstructive element should be offered and integrated in the therapy plan as soon as mastectomy is indicated. PMID- 20972712 TI - [Effects of proteolytic enzyme therapy with Wobe Mugos against chemotherapy induced toxicity in breast cancer patients - results of a pilot study]. AB - BACKGROUND: Wobe Mugos((r)) is an enzyme preparation containing the proteases trypsin and papain from the pancreatic calf and commonly used in complementary medicine. From non-randomized studies, its multiple favorable effects including the reduction of adverse events from radiotherapy and chemotherapy in oncology patients have been reported. METHODS: Patients with invasive breast cancer receiving adjuvant or palliative chemotherapy between 2005 and 2006 and who were scheduled for at least two further cycles of this specific chemotherapy were included in this pilot study. A specific toxicity of at least grade 2 using the NCI common toxicity criteria which occurred during the preceeding cycle and was relevant to the patient was recorded. This specific toxicity, e.g. grade 2 emesis, was again evaluated after two analogously administered further chemotherapy cycles in which Wobe Mugos((r)) had been coadministered. The hypothesis was that specific toxicites of individual patients will be reduced by this enzyme therapy. The majority of the 57 consecutive patients received palliative chemotherapy. Peroral enzyme therapy was coadministered with two uncracked coated tablets three times daily on all days of a chemotherapy cycle except on the day of chemotherapy administration. RESULTS: Tolerability was good. Positive and neutral effects on toxicity parameters were observed in 11 and 42 patients, respectively, and a negative influence in 4 women. CONCLUSION: We observed only a marginal influence of Wobe Mugos((r)) in patients with breast cancer who had experienced at least a grade 2 toxicity in the preceding cycle and who received two further identical cycles of this chemotherapy in conjunction with the enzyme preparation. Randomized studies on homogenous patient populations are necessary. PMID- 20972713 TI - Fertility preservation and infertility treatment in breast cancer patients. AB - About 12% of breast cancer cases occur before the age of 35 years. Thus, young patients may consider preservation of ovarian function during cytotoxic therapy and/or childbearing after treatment. Besides the exposure to cytotoxic agents over several months, a significant number of patients will need sequential antihormonal therapy for years. Thus, even young patients at diagnosis may have to postpone pregnancy for years. At that time, the probability of pregnancy may per se be considerably reduced. Young patients per se carry a worse prognosis compared to their postmenopausal counterparts. Ovaries may harbor viable tumor cells. Premenopausal patients have a higher prevalence of BRCA gene mutation than older patients. Thus, even if the ovaries are preserved, the risk of developing cancer in the ovary may be high. Normal menstrual cyclicity after chemotherapy/antihormonal therapy does not preclude premature ovarian failure. After antineoplastic therapy, it is recommended to wait at least for two months before the evaluation of the ovarian function. The most reliable parameter to assess the ovarian reserve is the anti-muellerian factor (AMH; Muellerian Inhibiting Factor, MIF). Four randomized studies have investigated the protective effect of the GnRH analogue goserelin on ovarian function. Due to the inconsistent results observed, the concurrent administration of GnRH analogues with cytostatic chemotherapy now has to be considered experimental and cannot be recommended. Emergency in vitro fertilization may be performed between breast cancer diagnosis and the start of chemotherapy in selected cases. Extracorporal in vitro fertilization may be performed and the resultant embryo cryopreserved to preserve fertility. PMID- 20972714 TI - Pattern formation, long-term transients, and the Turing-Hopf bifurcation in a space- and time-discrete predator-prey system. AB - Understanding of population dynamics in a fragmented habitat is an issue of considerable importance. A natural modelling framework for these systems is spatially discrete. In this paper, we consider a predator-prey system that is discrete both in space and time, and is described by a Coupled Map Lattice (CML). The prey growth is assumed to be affected by a weak Allee effect and the predator dynamics includes intra-specific competition. We first reveal the bifurcation structure of the corresponding non-spatial system. We then obtain the conditions of diffusive instability on the lattice. In order to reveal the properties of the emerging patterns, we perform extensive numerical simulations. We pay a special attention to the system properties in a vicinity of the Turing-Hopf bifurcation, which is widely regarded as a mechanism of pattern formation and spatiotemporal chaos in space-continuous systems. Counter-intuitively, we obtain that the spatial patterns arising in the CML are more typically stationary, even when the local dynamics is oscillatory. We also obtain that, for some parameter values, the system's dynamics is dominated by long-term transients, so that the asymptotical stationary pattern arises as a sudden transition between two different patterns. Finally, we argue that our findings may have important ecological implications. PMID- 20972715 TI - Spatiotemporal variation of mistletoes: a dynamic modeling approach. AB - Mistletoes are common aerial stem-parasites and their seeds are dispersed by fruit-eating birds. In the mutually beneficial relationships between mistletoes and bird species that disperse mistletoes' seeds, the preference of birds for infected trees influences the spread of mistletoes and the spatiotemporal pattern formation of mistletoes. We formulate a deterministic model to describe the dynamics of mistletoes in an isolated patch containing an arbitrary number of trees. We establish concrete criterions, expressed in terms of the model parameters, for mistletoes establishing in this area. We conduct numerical simulations based on a field study to reinforce and expand our results. PMID- 20972716 TI - Alternating host cell tropism shapes the persistence, evolution and coexistence of epstein-barr virus infections in human. AB - Epstein-Barr virus (EBV) infects and can persist in a majority of people worldwide. Within an infected host, EBV targets two major cell types, B cells and epithelial cells, and viruses emerging from one cell type preferentially infect the other. We use mathematical models to understand why EBV infects epithelial cells when B cells serve as a stable refuge for the virus and how switching between infecting each cell type affects virus persistence and shedding. We propose a mathematical model to describe the regulation of EBV infection within a host. This model is used to study the effects of parameter values on optimal viral strategies for transmission, persistence, and intrahost competition. Most often, the optimal strategy to maximize transmission is for viruses to infect epithelial cells, but the optimal strategy for maximizing intrahost competition is for viruses to mainly infect B cells. Applying the results of the within-host model, we derive a model of EBV dynamics in a homogeneous population of hosts that includes superinfection. We use this model to study the conditions necessary for invasion and coexistence of various viral strategies at the population level. When the importance of intrahost competition is weak, we show that coexistence of different strategies is possible. PMID- 20972717 TI - Fluoride-induced oxidative stress in three-dimensional culture of OS732 cells and rats. AB - Exposure to excessive fluoride poses a threat to human health, including increased susceptibility to developing the skeletal fluorosis. Despite its recognized importance as an endemic disease, little is known about how fluoride directly impacts on osteoblasts. We previously reported that fluoride-stimulating monolayer-cultured osteoblast proliferation or inhibiting cell viability depended on fluoride-exposure concentration and period, both accompanied with active oxidative stress. The purpose of this study was to provide extra insight into skeletal fluorosis by comparing their regulation of oxidative stress in rats and OS732 cells (a human osteoblast-like cell line) cultured in the three-dimensional approach. Our in vivo and in vitro studies proved that exposure to fluoride promoted varying extents of oxidative stress. Three-dimensional cultured OS732 cells revealed the action of fluoride on cell viability from excitatory to inhibitory trend according to fluoride-exposure concentration and time. The study provided insight into the mechanism of skeletal fluorosis. Also, this study distinguished itself by identifying oxidative stress as a potential modulator of osteogenesis in skeletal fluorosis. PMID- 20972719 TI - Nitric oxide inhibits ghrelin-induced cell proliferation and ERK1/2 activation in GH3 cells. AB - Ghrelin stimulates growth hormone release and cell proliferation, which strongly supports a significant role for this peptide in the control of growth hormone releasing adenomas function and growth. Nitric oxide can influence the stimulatory effects of ghrelin on growth hormone secretion in growth hormone releasing adenomas. However, the effect of nitric oxide (NO) on ghrelin-induced cell proliferation and the mechanism of this effect in the adenoma were not clarified. In this study, we observed that ghrelin, at a concentration of 10-9 to 10-6 M, significantly increased BrdU incorporation into rat GH3 cells. A NO donor, S-nitroso-N-acetylpenicillamine (SNAP), blunted basal, and ghrelin-induced cell proliferation. A blocker of NO synthase, Nw-nitro-L-arginine methyl ester hydrochloride (NAME), had no influence on these actions. The activation of extracellular signal-regulated kinase (ERK) 1/2 was examined by western blotting. The results showed that SNAP reduced ghrelin-stimulated ERK1/2 activation but NAME had no influence on this activation. Together, this study indicates that NO inhibited ghrelin-induced cell proliferation by blocking ERK1/2 activation in GH3 cells. PMID- 20972720 TI - Metabolic acidosis as a complication of intravenous dextrose administration in a patient with insulinoma. AB - There are few cases published in literature in which the use of intravenous dextrose as treatment for an insulinoma resulted in a metabolic acidosis. This is due perhaps to the usual method of administration, which is usually at low concentrations, for limited periods or low volumes. We present the case of a woman with suspected insulinoma by laboratory findings in which an endogenous hyperinsulinism was observed. During hospitalization, the patient required a progressive increase of the glucose infusion to prevent severe hypoglycemia. Two days before surgery, the patient presented symptoms of malaise and muscle weakness and a metabolic acidosis with hypokalemia became apparent in the blood analysis. This metabolic imbalance was attributed to a long period of treatment with high volume of intravenous dextrose infusion. If large doses of dextrose are required in a patient with an insulinoma, then the possibility of a metabolic imbalance must be considered during the follow-up. When the suspicion of an insulinoma is high, and all the attempts of pre-operative localization fail, patients should be derived early to specialized centers with modern imaging techniques, so that surgery is not delayed, and this rare and threatening complication could be avoided. PMID- 20972721 TI - Expression and somatic mutations of SDHAF2 (SDH5), a novel endocrine tumor suppressor gene in parathyroid tumors of primary hyperparathyroidism. AB - To investigate the SDHAF2 gene and its effect on primary hyperparathyroidism. Parathyroid tumors causing primary hyperparathyroidism (pHPT) are one of the more common endocrine neoplasias. Loss of heterozygosity at chromosome 11q13 is the most common chromosomal aberration in parathyroid tumors occurring in about 40% of sporadic tumors. Only 15-19% display somatic mutations in the MEN1 gene, which suggest that this chromosomal region may harbor additional genes of importance in parathyroid tumor development. The SDHAF2 (formerly SDH5) gene is a recently identified neuroendocrine tumor suppressor gene at this locus, and inherited mutations of the SDHAF2 gene has been linked to familial paraganglioma. We demonstrate that the SDHAF2 gene is expressed in parathyroid tissue using RT-PCR. Because detection of inactivating mutations is the major criterion for validating a candidate tumor suppressor, we used automated sequencing of the coding region and intron/exon boundaries in 80 sporadic parathyroid adenomas from patients with pHPT. A known polymorphisms (A to G substitution; rs879647) was identified in 9/80 parathyroid tumors but no tumor-specific somatic mutational aberrations, such as nonsense, frameshift, or other inactivating mutations were identified. The SDHAF2 gene is expressed in parathyroid tissue. However, somatic mutations of the SDHAF2 tumor suppressor gene are unlikely to frequently contribute to parathyroid tumor development in sporadic pHPT. PMID- 20972718 TI - Extrapituitary growth hormone. AB - Pituitary somatotrophs secrete growth hormone (GH) into the bloodstream, to act as a hormone at receptor sites in most, if not all, tissues. These endocrine actions of circulating GH are abolished after pituitary ablation or hypophysectomy, indicating its pituitary source. GH gene expression is, however, not confined to the pituitary gland, as it occurs in neural, immune, reproductive, alimentary, and respiratory tissues and in the integumentary, muscular, skeletal, and cardiovascular systems, in which GH may act locally rather than as an endocrine. These actions are likely to be involved in the proliferation and differentiation of cells and tissues prior to the ontogeny of the pituitary gland. They are also likely to complement the endocrine actions of GH and are likely to maintain them after pituitary senescence and the somatopause. Autocrine or paracrine actions of GH are, however, sometimes mediated through different signaling mechanisms to those mediating its endocrine actions and these may promote oncogenesis. Extrapituitary GH may thus be of physiological and pathophysiological significance. PMID- 20972722 TI - Association of the TGrI29 microsatellite in thyroglobulin gene with autoimmune thyroiditis in a Argentinian population: a case-control study. AB - Autoimmune thyroid disease (AITD) is a multifactorial disorder that involves a putative association with thyroid autoantigen-specific and immune regulatory genes, as well as environmental factors. The thyroglobulin gene is the main identified thyroid autoantigen-specific gene associated to autoimmune thyroiditis. The aim of this work was to test for evidence of allelic association between autoimmune thyroiditis (AT) and thyroglobulin polymorphism markers in Argentinian patients. We studied six polymorphisms distributed throughout all the thyroglobulin gene: four microsatellites (Tgms1, Tgms2, TGrI29, and TGrI30), one insertion/deletion polymorphism (IndelTG-IVS18), and one exonic single nucleotide polymorphism (c.7589G>A) in 100 AT patients and 100 healthy control subjects. No differences in allele and genotype frequencies distribution were observed between autoimmune thyroiditis cases and controls for Tgms1, Tgms2, TGrI30, IndelTG IVS18, and c.7589G>A. However, when we analyzed autoimmune thyroiditis patients with the TGrI29 microsatellite we found a significant association between the 197 bp allele and autoimmune thyroiditis (33.50% vs. 19.00% in control group) (P = 0.001). In addition, a significant major prevalence of the 197/201-bp genotype has been also seen in autoimmune thyroiditis subjects (59% vs. 24% in control group, P < 0.0001). In conclusion, our work showed the association between the thyroglobulin gene and autoimmune thyroiditis in Argentinian population and supports the described evidence of thyroglobulin as a thyroid-specific gene linked to AITD. PMID- 20972723 TI - Undiagnosed thyroid dysfunction, thyroid antibodies, and iodine excretion in a Mediterranean population. AB - The prevalence of thyroid dysfunction varies in different populations. The aim of this cross-sectional study was to analyze the prevalence of undiagnosed thyroid dysfunction and thyroid antibodies and their relationship with urine iodine excretion in a representative sample of 1,124 (55.5% women; mean age: 44.8 +/- 15.2 years) non-hospitalized Mediterranean adults, in Catalonia (Spain). Free thyroxine, thyroid-stimulating hormone, thyroperoxidase and thyroglobulin antibodies, and urine iodine were measured. Undiagnosed thyroid dysfunction was 5.3% (hypothyroidism 3.8%; 56.66% of these subjects were women). The total (diagnosed + undiagnosed) thyroid dysfunction was 8.9% (71.15% women). Thyroperoxidase antibodies were positive in 2.4% of men and 9.4% of women and thyroglobulin antibodies, in 1.3% of men and 3.8% of women. No differences were observed in urine iodine between groups with thyroid dysfunction and euthyroidism, or between subjects with positive or negative antibodies. In subjects over 60, undiagnosed thyroid dysfunction was 9.8% (hypothyroidism 6.9%, hyperthyroidism 3.3%; 36.36% women) and total thyroid dysfunction 13.61% (53.12% women). Women and men over 60 had similar thyroid dysfunction prevalence. Thus, aggressive case-finding should be recommended in both, over 60. PMID- 20972724 TI - Effects of sex steroid hormones, thyroid hormone levels, and insulin regulation on thyrotoxic periodic paralysis in Chinese men. AB - Our study is to determine the expression of thyroid hormone, sex hormone, insulin, and C-peptide in Chinese male patients with thyrotoxic periodic paralysis (TPP). This study covered 102 patients with hyperthyroidism from Xijing Hospital. According to whether occurrence of TPP or not, patients were divided into two groups (those that were hyperthyroid with and without TPP) that were, matched with age, blood pressure, urea, and creatinine. We found the body mass index (BMI) in patients with TPP was higher than that in pure hyperthyroidism patients. The levels of the total thyroxine (T4), free triiodothyronine (FT3), and free thyroxine (FT4) were significantly lower in patients with TPP compared with pure hyperthyroidism patients, while serum testosterone levels were higher compared with pure hyperthyroidism patients. Moreover, after glucose administration, the concentration of insulin at 60, 120, and 180 min were significantly higher in patients with TPP than those in pure hyperthyroidism patients. The insulin area under the curve (AUC) was significantly increased in patients with TPP compared with pure hyperthyroidism patients. The levels of thyroid hormone, sex hormone, and insulin were different in Chinese male patients with TPP compared to those with only hyperthyroidism. PMID- 20972725 TI - Primary aldosteronism due to adrenocortical adenoma with concurrent ileum carcinoid tumor: case report. AB - Primary aldosteronism (PA) with synchronous carcinoid syndrome is extremely rare occurrence. In this article, we describe a case of PA due to adrenocortical adenoma ("aldosteronoma") and concurrent malignant carcinoid tumor of ileum. The patient was treated with synchronous right adrenalectomy and resection of the ileum. This case is an example of concomitant presence of two types of tumors, effectively managed surgically. We report a case of a nonclassical form of multiple endocrine neoplasia type 1 (MEN 1) syndrome. PMID- 20972726 TI - Exogenous Cushing's syndrome due to topical corticosteroid application: case report and review literature. AB - Prolonged use of topical corticosteroids causes systemic adverse effects including Cushing's syndrome and hypothalamic-pituitary-adrenal (HPA) axis suppression, which is less common than that of the oral or parenteral route. At least 43 cases with iatrogenic Cushing syndrome from very potent topical steroid usage (Clobetasol) in children and adult have been published over the last 35 years particularly in developing countries. In children group (n = 22), most are infants with diaper dermatitis and two cases who had started topical application at a very early age and died from severe disseminated CMV infection. For the adult group (n = 21), the most common purpose of steroid use was for treatment of Psoriasis. The recovery period of HPA axis suppression was 3.49 +/- 2.92 and 3.84 +/- 2.51 months in children and adult, respectively. We report on an 8-month-old female infant who developed Cushing's syndrome and adrenal insufficiency after diaper dermatitis treatment through the misuse of Clobetasol without doctor's prescription. Physiologic dose of hydrocortisone was prescribed to prevent an adrenal crisis for 3 months and discontinued when HPA axis recovery was confirmed by normal morning cortisol and ACTH levels. PMID- 20972727 TI - Haptoglobin phenotype in women with preeclampsia. AB - In pre-eclampsia, poor placentation causes both oxidative and endoplasmic reticulum stress of the placenta. The anti-oxidative protein Haptoglobin has three phenotypes: 1-1, 1-2, and 2-2. Haptoglobin 1-1 is a more potent antioxidant. Our objective was to determine whether haptoglobin 1-1 was less common in women with preeclampsia which is a disease with an oxidatives-stress component, compared to the healthy population. Haptoglobin phenotype was compared in 240 healthy and 120 preeclamptic gravida in a case-control study. Statistical analysis was performed using Chi square test. The prevalence of haptoglobin 1-1 was 13% among healthy women and 6% among preeclamptic women (P=0.049). Secondary analysis was also performed. The prevalence of haptoglobin 1-1 is higher in healthy compared to preeclamptic subjects, a finding compatible with a protective role. Haptoglobin 1-1 might have a protective role in preeclampsia. Further work is needed with more Hp 1-1 subjects before we can conclude on the possible use of Haptoglobin phenotype to assess the risk of preeclampsia. PMID- 20972728 TI - Clinical, biochemical, and molecular findings in Argentinean patients with goitrous congenital hypothyroidism. AB - We describe the clinical, biochemical, and molecular findings of a cohort of Argentinean patients with congenital hypothyroidism (CH) and goiter studied to characterize iodide organification and thyroglobulin (TG) defects. 20 CH patients (16 unrelated) were grouped according to serum TG levels and a perchlorate discharge test (PDT) in: group 1 (G1): nine patients with high TG and PDT > 10% who were studied for tiroperoxidase (TPO), dual oxidase 2 (DUOX2), and dual oxidase A2 (DUOXA2) defects and group 2 (G2): 11 patients with low TG and PDT < 10% studied for TG defects. Goiter characteristics, outcome, and TT4 and TT3 levels without treatment were compared between groups. 6/9 G1 patients harbored mutations in TPO gene and 3/9 in DUOX2 gene. In G2, mutations of TG gene were found in 3/11 homozygous, 5/11 compound heterozygous, and 3/11 heterozygous patients. Goiter was only evidenced by thyroid scan in the neonatal period in both groups; was moderately enlarged in patients diagnosed during infancy. In the late detected patients, goiter was big and nodular in G1 while diffuse and moderate in G2. Early detected patients grew and developed normally while those diagnosed late were severely mentally retarded in G1 and only mildly retarded in G2. Thyroid hormone levels of G1 were significantly lower than those of G2 P < 0.01. Molecular approach to characterize defects in organification and TG defects was optimized by TG measurements and PDT. Clinical and biochemical differences based on molecular findings will allow further investigations on genotype phenotype relationships. PMID- 20972729 TI - The effects of the receptor for advanced glycation end products (RAGE) on bone metabolism under physiological and diabetic conditions. AB - It has been reported that AGEs and the receptor for AGEs (RAGEs) have been linked to the pathogenesis of diabetic microangiopathy. However, the relationship between RAGE and alteration in bone metabolism is unclear. Therefore, in order to determine the role of RAGE in bone metabolism, we investigated the effects of RAGE deletion on bone metabolism under physiological and diabetic conditions using RAGE knockout mice (RAGE-KO). Eight-week-old male RAGE-KO and wild-type littermates (WT) were intraperitoneally injected with either streptozotocin or vehicle. Mice were classified into four groups: (1) nondiabetic WT; (2) nondiabetic RAGE-KO; (3) diabetic WT; and (4) diabetic RAGE-KO. After 12 weeks of streptozotocin or vehicle treatment, the physical properties of femora and the static and dynamic parameters of bone histomorphometry of tibiae were assessed. The deletion of RAGE affected neither body weights nor hemoglobin A1c levels. RAGE deletion resulted in increased bone mineral density due to decreased osteoclast function under physiological conditions that is no accumulation of AGEs. In contrast, lacking RAGE did not affect the alteration in bone metabolism under diabetic conditions, suggesting that AGEs-RAGE interaction may not be involved in the pathogenesis of diabetic osteopenia, although RAGE plays a crucial role in bone metabolism. PMID- 20972730 TI - Analysis of differential gene expression by fiber-optic BeadArray and pathway in prolactinomas. AB - Prolactinomas are the most common secretory pituitary tumors; however, their pathogenesis is unclear. In order to explore the pathogenesis of prolactinomas, we used fiber-optic BeadArray to examine gene expression profiles in five prolactinomas compared with three normal pituitaries. Three down-regulated genes and one up-regulated gene were chosen for validation by quantitative real-time reverse-transcription polymerase chain reaction. We then performed pathway analysis on the identified differentially expressed genes using the Kyoto Encyclopedia of Genes and Genomes. Array analysis showed significant increases in the expression of 27 genes and 3 expressed sequence tags (ESTs), and decreases in 182 genes and 9 ESTs, including HIG1 domain family, member 1B, S100 calcium binding protein A9, angiopoietin 2, interleukin 8, hydroxyprostaglandin dehydrogenase 15-(NAD), suppression of tumorigenicity18, and WNT inhibitory factor 1. Pathway analysis showed that the P53 and GnRH signaling pathways may play an important role in tumorigenesis of prolactinomas. Our data suggest fiber optic BeadArray combined with pathway analysis of differential gene expression profile appears to be a valid approach for investigating the pathogenesis of tumors. PMID- 20972731 TI - The glucose-induced synthesis of insulin in liver. AB - Pancreatic beta cells, stimulated by glucose, are known to synthesize and secrete insulin. As liver diseases are reported to cause diabetes mellitus, studies were conducted to determine the possibility of glucose-induced insulin synthesis in the liver cells. The glucose-induced insulin synthesis was determined by in vitro translation of mRNA from the hepatocytes. The cDNA from mRNA was prepared and sequence analysis was performed. Incubation of hepatocytes from the liver of adult mice (n=10) with glucose (0.02 M) resulted in the insulin synthesis [0.03 (mean)+/-0.006 (S.D.) MUunits/mg/h] compared to the pancreatic beta cells [0.04+/ 0.004 MUunits/mg/h]. Immunohistochemical study also demonstrated the glucose induced synthesis of insulin in liver cells. Incubation of the mice hepatocytes with glucose resulted in the synthesis of insulin mRNA. The purified mRNA which was used to prepare cDNA resulted in the formation of proinsulin I and proinsulin II genes corresponding to 182 and 188 base pairs, respectively. Sequence analysis of the cDNA indicated that proinsulin I as well as proinsulin II gene could be involved in the synthesis of insulin by hepatocytes. These results suggested that insulin synthesis in both hepatic and pancreatic cells could be involved in the control of diabetes mellitus. PMID- 20972732 TI - Islet NADPH oxidase activity is modulated unevenly by different secretagogues. AB - NADPH oxidase expression and activity have been measured in pancreatic islets under normal conditions, but its potential modulatory role upon insulin secretion remains unclear. We have currently studied NADPH oxidase activity in islets isolated from normal rats as well as the effect of its inhibition upon insulin secretion stimulated by different secretagogues. Glucose, arginine, fatty acids and KCl increased islet NADPH oxidase activity in a stimulus-dependent manner. DPI inhibited such increase in different proportions and affected unevenly insulin secretion, namely, it decreased the effect of high glucose, increased that of oleic acid and KCl, without changing the one induced by palmitic acid. Our data provide evidence that the contribution of NADPH activity to reactive oxygen species production in normal rat islets as well as its effect upon insulin secretion is uneven and highly stimulus-dependent. PMID- 20972733 TI - Common melanocortin-3 receptor variants are not associated with obesity, although rs3746619 does influence weight in obese individuals. AB - The melanocortin-3 receptor is a vital link in the leptin-melanocortin signaling pathway in the brain and has a role in the regulation of energy homeostasis. It was hypothesized that common polymorphisms in MC3R could increase susceptibility for the development of obesity, but different studies have led to contradictory results. In this study, we investigated the association of SNPs in MC3R with the development of obesity in an extensive Caucasian population. Using the HapMap, we selected two tagSNPs (rs6127698 and rs3746619) that cover all of the common genetic variation in MC3R and genotyped them in 1008 obese cases and 313 normal weight controls. Statistical analysis of the data showed that none of the analyzed SNPs were associated with obesity. However, linear regression analysis did show that SNP rs3746619 has an influence on weight (P=0.015) in the obese population only. Furthermore, a trend for association with BMI in the obese population was observed for this SNP (P=0.039). Taken together, these data are consistent with the involvement of rs3746619 in weight regulation among obese individuals. However, further research including replication of our results is necessary to elucidate the role of MC3R in complex obesity. PMID- 20972734 TI - Intra-left ventricular systolic asynchrony in patients with overt hyperthyroidism. AB - Hyperthyroidism causes a variety of adverse effects on the cardiovascular system. Left ventricular (LV) asynchrony is defined as loss of the simultaneous peak contraction of corresponding cardiac segments. The aim of this study was to assess systolic asynchrony in patients with overt hyperthyroidism. Asynchrony was evaluated in 27 patients with overt hyperthyroidism and 21 controls. All the patients and controls were subjected to a tissue synchronization imaging (TSI). The time to regional peak systolic tissue velocity (Ts) in LV by the six-basal six-mid-segmental model was measured on ejection phase TSI images and four TSI parameters of systolic asynchrony were computed. All TSI parameters of LV asynchrony increased in hyperthyroid patients compared to controls: the standard deviation (SD) of the 12 LV segments Ts (35.7+/-14.4 vs 20.1+/-10.1, P<0.0001); the maximal difference in Ts between any 2 of the 12 LV segments (111.9+/-40.7 vs 65.9+/-30.7, P<0.0001); the SD of the 6 basal LV segments (31.2+/-18.2 vs 16.8+/ 9.7, P=0.01); and the maximal difference in Ts between any 2 of the 6 basal LV segments (76.6+/-42.0 vs 44.4+/-25.7, P=0.005). Patients with overt hyperthyroidism present evidence of LV asynchrony by TSI. PMID- 20972735 TI - Association of XIAP and P2X7 receptor expression with lymph node metastasis in papillary thyroid carcinoma. AB - The expression of X-linked inhibitor of apoptosis (XIAP) and the P2X7 receptor were demonstrated in a variety of tumors. The purpose of the present study was to investigate the associations of XIAP and P2X7 receptor expression with the clinicopathological features of patients with papillary thyroid carcinoma (PTC). In this cross-sectional study, a total of 62 cases were examined, including 43 patients with PTCs and 19 with benign nodular goiters. XIAP and P2X7 receptor expression were examined by immunohistochemical methods on formalin-fixed, paraffin-embedded thyroid tissues. The staining intensity and extent were evaluated and scored using a semi-quantitative method. The immunohistochemical staining score integrating the intensity and extent of XIAP and P2X7 receptors in PTCs was higher than in nodular goiters. XIAP (OR: 5.6, 95% CI: 1.5-21.1, P=0.009) and P2X7 receptor (OR: 6.1, 95% CI: 1.5-24.4, P=0.007) expression were associated with lymph node metastasis in PTCs. In logistic regression analysis, P2X7 receptor expression, tumor size, and capsular infiltration were predictors for lymph node metastasis (P=0.001). Our results suggested that XIAP and P2X7 receptor expression may predict the aggressiveness of PTC. PMID- 20972737 TI - Positive correlations of liver enzymes with metabolic syndrome including insulin resistance in newly diagnosed type 2 diabetes mellitus. AB - It has long been proposed that elevation of liver enzymes including alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyltransferase (GGT) may be associated with insulin resistance (IR). In the present study, we aimed to investigate the association of the above mentioned liver enzymes with IR by using hyperinsulinemic euglycemic clamp, as well as their relationship with individual component of metabolic syndrome (MetS) in 95 newly diagnosed type 2 diabetes (T2DM) Chinese patients. All the diagnosed patients did not use drugs for treatment of diabetes or dyslipidemia previously and were divided into IR and non-IR groups. The results showed that IR group had significantly higher ALT, AST, and GGT (P<0.01, P<0.01, and P<0.05, respectively) compared with non-IR group. According to the individual MetS component, ALT and AST were significantly increased in patients with high blood pressure compared with those without (both P<0.001); ALT and GGT were increased in patients with high triglyceride (P<0.05 and P<0.01); AST was increased in patients with central obesity (P<0.05). In correlation analysis, a significant association was found between the three liver enzymes and clamp insulin sensitivity index (all P<0.001). In the linear regression analysis, ALT was the determinant of clamp ISI, independent of age, sex, BMI, and fasting and OGTT 2 h plasma glucose (P<0.0001). In conclusion, liver enzymes, especially ALT, were significantly associated with IR according to direct clamp assessment, which were independent of the traditional risk factors in diabetic patients; and individual liver enzymes may have different relationship with individual component of MetS. PMID- 20972736 TI - Effects of metformin plus gliclazide compared with metformin alone on circulating endothelial progenitor cell in type 2 diabetic patients. AB - Circulating endothelial progenitor cells (EPCs) play an important role in the development and progression of diabetic vascular complications. The aim of this study was to investigate the effects of gliclazide plus metformin (GLIMET) compared with metformin alone (MET) on number and function of circulating EPCs in T2DM patients. Patients with newly diagnosed T2DM were randomly divided into two groups, receiving the following treatments for 16 weeks: MET group (assuming metformin 500-2500 mg/day, n=24) and GLIMET group [assuming gliclazide (modified release, 30-60 mg/day)+metformin (250-1000 mg/day), n=23]. Circulating EPCs were quantified by flow cytometry, and the ability to uptake LDL and stain for lectin were used as another method of characterizing EPCs ex vivo. The functions of circulating EPCs were evaluated by colony-forming units (CFU) and migration. The status of oxidative stress was analyzed by serum-free malonaldehyde (MDA) and superoxide dismutase (SOD). There were no significant differences in clinical characteristics and number and function of circulating EPCs between two groups at baseline. Glycemic responses were similar after treatments. Compared with MET group, GLIMET group was associated with an increase in circulating EPCs number, DiLDL-lectin-positive EPCs, and migration. The mean improvements in MDA and SOD of GLIMET group were more strongly upregulated than those of MET group. This study demonstrated that both metformin mono-treatment and metformin plus gliclazide combination treatment provided with improvements in number and function of circulating EPCs. Compared with metformin mono-treatment, early use of combination therapy with gliclazide plus metformin made more effective improvements in circulating EPCs. PMID- 20972738 TI - WS1 gene mutation analysis of Wolfram syndrome in a Chinese patient and a systematic review of literatures. AB - Wolfram syndrome is a rare hereditary disease characterized by diabetes mellitus and optic atrophy. The outcome of this disease is always poor. WFS1 gene mutation is the main cause of this disease. A patient with diabetes mellitus, diabetes insipidus, renal tract disorder, psychiatric abnormality, and cataract was diagnosed with Wolfram syndrome. Mutations in open reading frame (ORF) of WFS1 gene was analyzed by sequencing. Mutations in WFS1 gene was also summarized by a systematic review in Pubmed and Chinese biological and medical database. Sequencing of WFS1 gene in this patient showed a new mutation, 1962G>A, and two other non-sense mutations, 2433A>G and 2565G>A. Systematic review included 219 patients in total and identified 172 WFS1 gene mutations, most of which were located in Exon 8. These mutations in WFS1 gene might be useful in prenatal diagnosis of Wolfram syndrome. PMID- 20972740 TI - Utilizing nasal-tragus length to estimate optimal endotracheal tube depth for neonates in Taiwan. AB - OBJECTIVE: To assess the application of the nasal-tragus length (NTL) to predict the proper endotracheal tube (ETT) depth; also, as relatively thinner size of Asian than Caucasian, the fitness of using the NTL to estimate the optimal ETT depth for neonates in Taiwan was examined. METHODS: The newborn infants who do need intubation orally were included. Those with midface dysmorphism, craniofacial anomalies, head trauma and/or facial injury in whom it was unable to measure NTL, were excluded. The data were collected after a satisfactory ETT tip position was confirmed on chest roentgenogram. Equations were established via the polynomial and the linear regression of the NTL and the actual ETT; simplified formulae as NTL+0.5 and NTL+1 were assumed accordingly. Paired t test was used to assess the coefficients. RESULTS: The 63 neonates, weighing 410 through 4,196 g and with gestation 21 through 41 weeks, were enrolled. No statistical difference was found between the actual ETT depth and the estimated ETT depth via the NTL+1 cm in neonates weighing <= 2,500 g (n=41, p=0.06), and also between the actual ETT depth and the estimated ETT depth via the NTL+0.5 cm in group weighing >2,500 g (n=22, p=0.171). CONCLUSIONS: Using the NTL to predict the optimal ETT depth with the formula, NTL plus 1 cm, was clinically practical for newborn infants in Taiwan weighing <= 2,500 g, and a modified formula, NTL plus 0.5 cm, was more suitable for neonates weighing >2,500 g. PMID- 20972741 TI - High TIMM17A expression is associated with adverse pathological and clinical outcomes in human breast cancer. AB - BACKGROUND: Mitochondrial dysfunction can be associated with genomic instability and has been implicated in the pathogenesis of several human malignancies, including breast cancer (BC). The mitochondrial protein, translocase of inner mitochondrial membrane 17 homolog A (TIMM17A) contributes to a pre-protein import complex, essential for mitochondrial function. In this study, TIMM17A mRNA expression was evaluated in benign and malignant breast tissues and correlated with pathological and clinical outcomes. METHODS: Breast cancer tissues (n = 127) and normal tissues (n = 33) underwent RNA extraction and reverse transcription, transcript levels were determined by using real-time quantitative PCR and normalized against CK19. Transcript levels were compared and then analysed against tumour size, tumour grade, oestrogen receptor (ER) status, nodal involvement, TNM stage, Nottingham prognostic index (NPI) and clinical outcome over a 10-year follow-up period. RESULTS: Compared to normal tissue (mean transcript level = 12.7), TIMM17A mRNA expression was higher in BC (62, p = 0.006), TNM-1 (37.9, p = 0.05), TNM-2 (114, p = 0.034), NPI-2 (81, p = 0.041), patients with progressive disease (169, p = 0.017) and those who died from BC (179, p = 0.026). Expression increased with tumour grade; grade 1 versus 2 (12.1 vs.70, p = 0.007), grade 1 versus 3 (12.1 vs.73, p = 0.065, [not significant] NS) and grade 1 versus 2 and 3 (12.1 vs. 72, p = 0.0048). Higher transcript levels were associated with ER-alpha positivity (94 vs. 31.6, p = 0.073, NS) and ER-beta negativity (82 vs. 16, p = 0.015). Nodal positivity was significantly associated with higher transcript levels (101 vs. 28.1, p = 0.046). Compared to disease-free patients (mean transcript level = 24.6), TIMM17A expression was significantly higher in those with progressive disease and patients who died of BC (179, p = 0.037). Higher transcript levels were significantly associated with poorer overall survival after a median follow-up of 10 years (p = 0.010). TIMM17A expression emerged as a strong independent predictor of overall survival in multivariate analysis (p = 0.033). CONCLUSION: TIMM17A mRNA expression is significantly associated with unfavourable pathological parameters including tumour grade, nodal positivity, TNM stage and NPI; in addition to adverse clinical outcomes such as progressive disease, disease-free and overall survival. TIMM17A offers utility as a prognostic marker and a novel mitochondrial target for potential therapeutic strategies. PMID- 20972742 TI - Mammography and ultrasound features of triple-negative breast cancer. AB - BACKGROUND: Triple-negative breast cancer is characterized as a cancer with a high malignancy potential and a poor prognosis. Therefore, early detection of this subtype of breast cancer is vital. In this paper, we describe the mammography and ultrasound findings of triple-negative breast cancer in a large population and investigate the specific features of this subtype. METHODS: From January 2007 to April 2010, mammography and ultrasound findings of 88 patients with triple-negative breast cancer were retrospectively reviewed. In this cohort, 52 patients underwent neoadjuvant chemotherapy. We compared the pathological chemotherapy effects and radiological findings among these patients. Mammograms were reviewed according to the Japanese mammography guideline. Ultrasound findings were classified as masses, low echoic area, distortions, and calcifications. Noted features included shapes, patterns of internal echoes, posterior echoes, vascularity, and elasticity scores. RESULTS: On mammography, triple-negative breast cancers frequently presented with a mass (62.4%). Masses with microlobulated margins were the most frequent (39.6%), indistinct (32.0%) and circumscribed (20.8%) were commonly observed, but spiculated margins were rare (4.7%). On ultrasound, cancers were more likely to present as a mass (92.5%), and less likely to show attenuating posterior echoes (8.8%). Of the 40 cases obtained via elasticity imaging, 35 (87.5%) lesions were scored as 4 or 5. There were no significant differences in the mammography or ultrasound findings between the chemotherapy effects. CONCLUSION: Mammography and ultrasound imaging together revealed that the morphological features of triple-negative breast cancer include a lobulated mass, with less attenuating posterior echoes, some vascularity, and low elasticity. PMID- 20972744 TI - Developing combination drugs in preclinical studies. AB - Although combination drugs have been available for many years, it is only recently that preclinical guidelines have been released by the Food and Drugs Administration (FDA) and EMEA and as yet they are not part of the ICH process. In addition, the World Health Organisation and FDA have issued guidelines for combination drugs developed specifically to treat HIV infections. Depending on the type of combination (marketed drug/marketed drug; marketed drug/NME and NME/NME), the scope and complexity of studies can vary greatly. In all cases, however, a key issue is the potential for pharmacokinetic and/or toxicologic interaction between the components. For a marketed drug/marketed drug combination, a detailed review of the preclinical data available may suffice; particularly when the components have a history of co-administration at about the same dose and ratio as that of the proposed combination. For a marketed drug/NME combination, in addition to a review of the data for the marketed drug, a full ICH programme of studies will be required for the NME, and a study of up to 90 days duration (in one species) for the combination. With an NME/NME combination, each component will require a full ICH battery of studies and a combination study in one species. In all cases, additional studies may be needed to address data gaps. Given the many novel and complex issues that arise when developing combination drugs, we recommend that, whenever possible, the preclinical study strategy is discussed with the regulatory authorities. PMID- 20972743 TI - Experimental diabetes attenuates calcium mobilization and proliferative response in splenic lymphocytes from mice. AB - The present study was conducted to investigate the effects of the diabetic condition on cytosolic free Ca(2+) concentration, [Ca(2+)](i), and the proliferation of splenic lymphocytes from mice. Diabetes was induced in mice by intraperitoneal injection of alloxan. [Ca(2+)](i) and the proliferation ex vivo of splenic lymphocytes isolated from mice were examined using fura-2 and 3-(4,5 dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide, respectively. Diabetes caused a significant increase in resting [Ca(2+)](i) and significantly reduced the ability of concanavalin A (Con A; a T-lymphocyte-selective mitogen) to increase [Ca(2+)](i), but not that of lipopolysaccharide (LPS; a B-lymphocyte selective mitogen). In addition, diabetes significantly reduced Con A-stimulated but not LPS-stimulated lymphocyte proliferation. Verapamil (an L-type Ca(2+) channel blocker) inhibited Con A-induced increases in [Ca(2+)](i) and proliferation in lymphocytes from control and diabetic mice to a similar extent, respectively. These results suggest that diabetes attenuates Con A-stimulated T lymphocyte proliferation by decreasing [Ca(2+)](i) via reduction of Ca(2+) entry through L-type Ca(2+) channels. PMID- 20972745 TI - Preclinical evaluation of juvenile toxicity. AB - A pediatric assessment is now a required component of every New Drug Application in North America or Marketing Authorization Application in Europe, unless a waiver has been granted previously. Nonclinical juvenile toxicity studies are usually required as part of this assessment. The protocols for juvenile toxicity studies are devised in consultation with the FDA or EMEA. It is important to approach the regulatory authority well in advance in order not to delay the marketing authorization of the drug and to confirm the need or not to perform a preclinical evaluation in juvenile animals. The choice of species and the design of juvenile studies are based on a series of complex considerations, including: the therapeutic use of the drug, the age at which children will be treated, the duration of treatment, and potential age- or species-specific differences in pharmacokinetics or toxicity. PMID- 20972746 TI - Necropsy and sampling procedures in rodents. AB - Necropsy is a major step of most studies using laboratory animals. During necropsy, tissue and organ changes noticeable grossly can be recorded, and important tissue samples can be stored for subsequent evaluation. It is therefore important that the personnel in charge of this key experimentation step be adequately trained and aware of the study endpoints. PMID- 20972747 TI - Histopathology procedures: from tissue sampling to histopathological evaluation. AB - Histological procedures aim to provide good quality sections that can be used for a light microscopic evaluation of human or animal tissue changes in either spontaneous or induced diseases. Routinely, tissues are fixed with neutral formalin 10%, embedded in paraffin, and then manually sectioned with a microtome to obtain 4-5 MUm-thick paraffin sections. Dewaxed sections are then stained with hematoxylin and eosin (H&E) or can be used for other purposes (special stains, immunohistochemistry, in situ hybridization, etc.). During this process, many steps and procedures are critical to ensure standard and interpretable sections. Key recomendations are given here to achieve this objective. PMID- 20972748 TI - Principles and methods of immunohistochemistry. AB - Immunohistochemical techniques detect antigens in tissue sections by means of immunological and chemical reactions. This technique is highly sensitive and specific and can detect a wide variety of antigens in multiple animal species. This chapter reviews common immunohistochemical methods used in the characterization of normal and pathologic tissue and the reagents used. Pretreatments such as blocking steps for endogenous activities and antigen retrieval are included. Standard procedures on formalin-fixed, paraffin-embedded tissues as well as method standardization for new antibodies and troubleshooting are emphasized. PMID- 20972749 TI - Tissue microarrays and digital image analysis. AB - Tissue microarrays (TMAs) have recently emerged as very valuable tools for high throughput pathological assessment, especially in the cancer research arena. This important technology, however, has yet to fully penetrate into the area of toxicology. Here, we describe the creation of TMAs representative of samples produced from conventional toxicology studies within a large-scale, multi institutional pan-European project, PredTox. PredTox, short for Predictive Toxicology, formed part of an EU FP6 Integrated Project, Innovative Medicines for Europe (InnoMed), and aimed to study pre-clinically 16 compounds of known liver and/or kidney toxicity. In more detail, TMAs were constructed from materials corresponding to the full face sections of liver and kidney from rats treated with different drug candidates by members of the consortium. We also describe the process of digital slide scanning of kidney and liver sections, in the context of creating an online resource of histopathological data. PMID- 20972750 TI - Micronucleus assay and labeling of centromeres with FISH technique. AB - The cytokinesis-block micronucleus (CBMN) assay has since many years been applied for in vitro genotoxicity testing and biomonitoring of human populations. The standard in vitro/ex vivo micronucleus test is usually performed on human lymphocytes and has become a comprehensive method to assess genetic damage, cytostasis, and cytotoxicity. The predictive association between the frequency of micronuclei (MN) in cytokinesis-blocked lymphocytes and cancer risk has recently been demonstrated. MN frequencies can be influenced by inherited (or acquired) genetic polymorphisms (or mutations) in genes responsible for the metabolic activation, detoxification of clastogens, and for the fidelity of DNA replication. An important advantage of the CBMN assay is its ability to detect both clastogenic and aneugenic events by centromere and kinetochore identification and contributes to the high sensitivity of the method. The objective of the present chapter is to review the mechanisms of induction of micronuclei, the method of the micronucleus assay and its combination with centromeric labeling in the FISH technique. Furthermore, an overview is given of recent results obtained by our laboratory by the application of the micronucleus assay. PMID- 20972751 TI - The use of bacterial repair endonucleases in the comet assay. AB - The comet assay is a sensitive electrophoretic method for measuring DNA breaks at the level of single cells, used widely in genotoxicity experiments, biomonitoring, and in fundamental research. Its sensitivity and range of application are increased by the incorporation of an extra step, after lysis of agarose-embedded cells, in which the DNA is digested with lesion-specific endonucleases (DNA repair enzymes of bacterial or phage origin). Enzymes with specificity for oxidised purines, oxidised pyrimidines, alkylated bases, UV induced cyclobutane pyrimidine dimers, and misincorporated uracil have been employed. The additional enzyme-sensitive sites, over and above the strand breaks detected in the standard comet assay, give a quantitative estimate of the number of specific lesions present in the cells. PMID- 20972752 TI - Manual whole-cell patch-clamping of the HERG cardiac K+ channel. AB - Delayed ventricular repolarization, as measured by a prolongation of the QT interval on the electrocardiogram, is a major safety issue in the drug development process. It is now recognized that most cases of drug-induced QT prolongation arise from direct pharmacological inhibition of the human ether-a-go go-related gene (HERG) cardiac K+ channel. It is standard practice to test a drug's ability to interact with the HERG channel prior to entry into clinical trials. This testing is used, as part of a larger battery of tests, to help predict the cardiac safety profile of a drug. Manual whole-cell patch-clamping provides the most sensitive and accurate way to examine the biophysical and pharmacological properties of the HERG cardiac K+ channel. PMID- 20972753 TI - Generation and analysis of transcriptomics data. AB - Transcript profiling ("Transcriptomics") is a widely used technique that obtains information on the abundance of multiple mRNA transcripts within a biological sample simultaneously. Therefore, when a number of such samples are analysed, as in a scientific experiment, large and complex data sets are gene-rated. Here, we describe the use of one method commonly used to generate transcriptomics data, namely the use of Affymetrix GeneChip microarrays. Data generated in transcriptomics experiments can be analysed using a multitude of approaches, but a common goal is to identify those transcripts whose abundance is altered by the experimental conditions, or which differ between sets of samples. Here, we describe a simple approach, the calculation of the volcano score, which identifies transcripts with altered abundance, taking into account both the magnitude of the alteration and its statistical significance. PMID- 20972754 TI - Protocols of two-dimensional difference gel electrophoresis to investigate mechanisms of toxicity. AB - In recent years, several global omics technologies have been increasingly used to better understand the molecular mechanisms of drug toxicity. Two-dimensional difference gel electrophoresis (2D-DIGE) is a large-scale proteomics high resolution gel-based quantitative method widely used to detect protein expression alterations after drug treatment. The 2D-DIGE technology is based on the labeling of proteins with different fluorescent dyes, allowing the separation of different samples on the same gel with the use of an internal standard, thus reducing the complexity of spot pattern comparison and providing a reliable method applied to toxicology studies for the detection of modulated proteins in targeted organs. PMID- 20972755 TI - Protocols and applications of cellular metabolomics in safety studies using precision-cut tissue slices and carbon 13 NMR. AB - Numerous xenobiotics are toxic to human and animal cells by interacting with their metabolism, but the precise metabolic step affected and the biochemical mechanism behind such a toxicity often remain unknown. In an attempt to reduce the ignorance in this field, we have developed a new approach called cellular metabolomics. This approach, developed in vitro, provides a panoramic view not only of the pathways involved in the metabolism of physiologic substrates of any normal or pathologic human or animal cell but also of the beneficial and adverse effects of xenobiotics on these metabolic pathways. Unlike many cell lines, precision-cut tissue slices, for which there is a renewed interest, remain metabolically differentiated for at least 24-48 h and allow to study the effect of xenobiotics during short-term and long-term incubations. Cellular metabolomics (or cellular metabonomics), which combines enzymatic and carbon 13 NMR measurements with mathematical modeling of metabolic pathways, is illustrated in this brief chapter for studying the effect of insulin on glucose metabolism in rat liver precision-cut slices, and of valproate on glutamine metabolism in human renal cortical precision-cut slices. The use of very small amounts of test compounds allows to predict their toxic effect and eventually their beneficial effects very early in the research and development processes. Cellular metabolomics is complementary to other omics approaches, but, unlike them, provides functional and dynamic pieces of information by measuring enzymatic fluxes. PMID- 20972756 TI - Statistical analysis of quantitative RT-PCR results. AB - Real-time reverse transcription polymerase chain reaction (RT-PCR) represents a benchmark technology in the detection and quantification of mRNA. Yet, accurate results cannot be realized without proper statistical analysis of RT-PCR data. Here, we examine some of the issues concerning RT-PCR experiments that would benefit from rigorous statistical treatment, including normalization, quantification, efficiency estimation, and sample size calculations. Examples are used to illustrate the methods. PMID- 20972757 TI - Evaluation of mitochondrial respiration in cultured rat hepatocytes. AB - Mitochondrial dysfunction is a major mechanism whereby drugs can induce liver injury and other serious side effects, such as lactic acidosis and rhabdomyolysis, in some patients. Several in vitro and in vivo investigations can be performed in order to determine if drugs can disturb mitochondrial fatty acid oxidation (FAO) and the oxidative phosphorylation (OXPHOS) process, deplete hepatic mitochondrial DNA (mtDNA), or trigger the opening of the mitochondrial permeability transition pore (MPT). Among these investigations, mitochondrial respiration is a relatively easy test to measure the potential toxicity of a drug. The use of cells instead of isolated mitochondria allows one to test the toxic effect of a parent compound and its metabolites. The use of rat hepatocytes can detect drugs involved in drug-induced liver injuries (DILI). The method consists in measuring oxygen consumption by using a Clark electrode in a chamber containing a suspension of hepatocytes pre-incubated with drug. PMID- 20972758 TI - FETAX assay for evaluation of developmental toxicity. AB - The Frog Embryo Teratogenesis Assay Xenopus (FETAX) test is a development toxicity screening test. Due to the small amount of compound needed and the capability to study organogenesis in a short period of time (96 h), FETAX test constitutes an efficient development toxicity alert test when performed early in drug safety development. The test is conducted on fertilized Xenopus laevis mid blastula stage eggs over the organogenesis period. Compound teratogenic potential is determined after analysis of the mortality and malformation observations on larva. In parallel, FETAX test provides also information concerning embryotoxic effect based on larva length. PMID- 20972759 TI - Evaluation of embryotoxicity using the zebrafish model. AB - The embryonic zebrafish model offers the power of whole-animal investigations (e.g., intact organism, functional homeostatic feedback mechanisms, and intercellular signaling) with the convenience of cell culture (e.g., cost- and time-efficient, minimal infrastructure, small quantities of nanomaterial solutions required). The model system overcomes many of the current limitations in rapid to high-throughput screening of drugs/compounds and casts a broad net to evaluate integrated system effects rapidly. Additionally, it is an ideal platform to follow up with targeted studies aimed at the mechanisms of toxic action. Exposures are carried out in 96-well plates so minimal solution volumes are required for the assessments. Numerous morphological, developmental, and behavioral endpoints can be evaluated noninvasively due to the transparent nature of the embryos. PMID- 20972760 TI - Protocols of in vitro protein covalent binding studies in liver. AB - Xenobiotics, including therapeutic agents, can produce a variety of beneficial, as well as adverse, effects in mammals. One potential source of drug-mediated toxicity stems from metabolic activation of the parent compound, typically catalyzed by one or more members of the cytochrome P450 family of enzymes. The resulting electrophile, if not quenched by low molecular weight endogenous nucleophiles, can form covalent adducts to cellular proteins, potentially resulting in enzyme inactivation, cell death, or formation of an immunogenic species. The toxicological consequences of exposure to such reactive intermediates range from mild inflammation to organ failure, anaphylaxis, and death. At Merck Research Laboratories, the potential of drug candidates to bind covalently to proteins is evaluated at the lead optimization stage of drug discovery by incubating a radiolabeled analog of the compound in question with liver microsomal preparations (under oxidative conditions) or whole cells (full cellular metabolic capability), typically derived from rat and human liver. A semi-automated method based on the Brandel Harvester technique then is used to measure the formation of covalent adducts of the test compound to liver proteins. This assay is viewed as an important component of drug discovery programs, since the findings are employed to guide specific efforts to abrogate bioactivation issues through informed structural modification of lead compounds. PMID- 20972761 TI - Utilization of MALDI-TOF to determine chemical-protein adduct formation in vitro. AB - Biological reactive intermediates can be created via metabolism of xenobiotics during the process of chemical elimination. They can also be formed as by products of cellular metabolism, which produces reactive oxygen and nitrogen species. These reactive intermediates tend to be electrophilic in nature, which enables them to interact with tissue macromolecules, disrupting cellular signaling processes and often producing acute and chronic toxicities. Quinones are a well-known class of electrophilic species. Many natural products contain quinones as active constituents, and the quinone moiety exists in a number of chemotherapeutic agents. Quinones are also frequently formed as electrophilic metabolites from a variety of xeno- and endobiotics. Hydroquinone (HQ) is present in the environment from various sources, and it is also a known metabolite of benzene. HQ is converted in the body to 1,4-benzoquinone, which subsequently gives rise to hematotoxic and nephrotoxic quinone-thioether metabolites. The toxicity of these metabolites is dependent upon their ability to arylate proteins and to produce oxidative stress. Protein tertiary structure and protein amino acid sequence combine to determine which proteins are targets of these electrophilic quinone-thioether metabolites. We have used cytochrome c and model peptides to view adduction profiles of quinone-thioether metabolites, and have determined by MALDI-TOF analysis that these electrophiles target specific residues within these model systems. PMID- 20972762 TI - Utilization of LC-MS/MS analyses to identify site-specific chemical protein adducts in vitro. AB - Biologically reactive intermediates are formed following metabolism of xenobiotics, and during normal oxidative metabolism. These reactive species are electrophilic in nature and are capable of forming stable adducts with target proteins. These covalent protein modifications can initiate processes that lead to acute tissue injury or chronic disease. Recent advancements in mass spectrometry techniques and data analysis has permitted a more detailed investigation of site-specific protein modifications by reactive electrophiles. Knowledge from such analyses will assist in providing a better understanding of how specific classes of electrophiles produce toxicity and disease progression via site-selective protein-specific covalent modification. Hydroquinone (HQ) is a known environmental toxicant, and its quinone-thioether metabolites, formed via the intermediate generation of 1,4-benzoquinone (1,4-BQ), elicit their toxic response via the covalent modification of target proteins and the generation of reactive oxygen species. We have utilized a model protein, cytochrome c, to guide us in identifying 1,4-BQ- and 1,4-BQ-thioether derived site-specific protein modifications. LC-MS/MS analyses reveals that these modifications occur selectively on lysine and glutamic acid residues of the target protein, and that these modifications occur within identifiable "electrophile binding motifs" within the protein. These motifs are found within lysine-rich regions of the protein and appear to be target sites of 1,4-BQ-thioether adduction. These residues also appear to dictate the nature of post-adduction chemistry and the final structure of the adduct. This model system will provide critical insight for in vivo adduct hunting following exposure to 1,4-BQ-thioethers, but the general approaches can also be extended to the identification of protein adducts derived from other classes of reactive electrophiles. PMID- 20972763 TI - One-dimensional western blotting coupled to LC-MS/MS analysis to identify chemical-adducted proteins in rat urine. AB - The environmental toxicant hydroquinone (HQ) and its glutathione conjugates (GSHQs) cause renal cell necrosis via a combination of redox cycling and the covalent adduction of proteins within the S3 segment of the renal proximal tubules in the outer stripe of the outer medulla (OSOM). Following administration of 2-(glutathion-S-yl)HQ (MGHQ) (400 MUmol/kg, i.v., 2 h) to Long Evans (wild type Eker) rats, Western analysis utilizing an antibody specific for quinol thioether metabolites of HQ revealed the presence of large amounts of chemical protein adducts in both the OSOM and urine. By aligning the Western blot film with a parallel gel stained for protein, we can isolate the adducted proteins for LC-MS/MS analysis. Subsequent database searching can identify the specific site(s) of chemical adduction within these proteins. Finally, a combination of software programs can validate the identity of the adducted peptides. The site specific identification of covalently adducted and oxidized proteins is a prerequisite for understanding the biological significance of chemical-induced posttranslational modifications (PTMs) and their toxicological significance. PMID- 20972764 TI - Identification of chemical-adducted proteins in urine by multi-dimensional protein identification technology (LC/LC-MS/MS). AB - Recent technological advancements in mass spectrometry facilitate the detection of chemical-induced posttranslational modifications (PTMs) that may alter cell signaling pathways or alter the structure and function of the modified proteins. To identify such protein adducts (Kleiner et al., Chem Res Toxicol 11:1283-1290, 1998), multi-dimensional protein identification technology (MuDPIT) has been utilized. MuDPIT was first described by Link et al. as a new technique useful for protein identification from a complex mixture of proteins (Link et al., Nat Biotechnol 17:676-682, 1999). MuDPIT utilizes two different HPLC columns to further enhance peptide separation, increasing the number of peptide hits and protein coverage. The technology is extremely useful for proteomes, such as the urine proteome, samples from immunoprecipitations, and 1D gel bands resolved from a tissue homogenate or lysate. In particular, MuDPIT has enhanced the field of adduct hunting for adducted peptides, since it is more capable of identifying lesser abundant peptides, such as those that are adducted, than the more standard LC-MS/MS. The site-specific identification of covalently adducted proteins is a prerequisite for understanding the biological significance of chemical-induced PTMs and the subsequent toxicological response they elicit. PMID- 20972765 TI - Optimization of SELDI for biomarker detection in plasma. AB - The surface-enhanced laser desorption ionization (SELDI) technology is a promising approach not only for the research of biomarkers in the blood of patients in clinical applications but also in preclinical studies to assess the drug-induced toxicities. The optimization of the SELDI platform is a crucial step before running plasma samples from preclinical toxicity studies. First, mass spectrometer parameters such as the laser energy and ion focus mass values should be assessed in order to obtain the highest quality of spectra. Second, the coefficient of variation of the intensity, resolution, and signal-to-noise ratio of the peaks detected in reference samples should be evaluated and used as quality control criteria. Last, a systematic evaluation of technical bias such as the spot and chip position and the bioprocessor sequence number may be achieved using the appropriate multivariate statistical analyses. PMID- 20972766 TI - Differential proteomics incorporating iTRAQ labeling and multi-dimensional separations. AB - Considerable effort is currently being expended to integrate newly developed "omics"-based approaches (proteomics, transcriptomics, and metabonomics) into preclinical safety evaluation workflows in the hope that more sensitive prediction of toxicology can be achieved as reported by Waters and Fostel (Nat. Rev. Genet. 5(12):936-948, 2004) and Craig et al. (J. Proteome Res. 5(7):1586 1601, 2006). Proteomic approaches are well placed to contribute to this effort as (a) proteins are the metabolically active products of genes and, as such, may provide more sensitive and direct predictive information on drug-induced liabilities and (b) they have the potential to determine tissue leakage markers in peripheral fluids. Here, we describe a workflow for proteomic semi quantitative expression profiling of liver from rats treated with a known hepatotoxicant using a multiplexed isobaric labeling strategy and multi dimensional liquid chromatography. PMID- 20972767 TI - NMR and MS methods for metabonomics. AB - Metabonomics, also often referred to as "metabolomics" or "metabolic profiling," is the systematic profiling of metabolites in bio-fluids or tissues of organisms and their temporal changes. In the last decade, metabonomics has become increasingly popular in drug development, molecular medicine, and other biotechnology fields, since it profiles directly the phenotype and changes thereof in contrast to other "-omics" technologies. The increasing popularity of metabonomics has been possible only due to the enormous development in the technology and bioinformatics fields. In particular, the analytical technologies supporting metabonomics, i.e., NMR, LC-MS, UPLC-MS, and GC-MS have evolved into sensitive and highly reproducible platforms allowing the determination of hundreds of metabolites in parallel. This chapter describes the best practices of metabonomics as seen today. All important steps of metabolic profiling in drug development and molecular medicine are described in great detail, starting from sample preparation, to determining the measurement details of all analytical platforms, and finally, to discussing the corresponding specific steps of data analysis. PMID- 20972768 TI - Absolute quantification of toxicological biomarkers by multiple reaction monitoring. AB - With the advent of "-omics" technologies, there has been an explosion of data generation in the field of toxicology, as well as in many others. As new candidate biomarkers of toxicity are being regularly discovered, the next challenge is to validate these observations in a targeted manner. Traditionally, these validation experiments have been conducted using antibody-based technologies such as Western blotting, ELISA, and immunohistochemistry. However, this often produces a significant bottleneck as the time, cost, and development of successful antibodies are often far outpaced by the generation of targets of interest. In response to this, recently there have been several developments in the use of triple quadrupole (QQQ) mass spectrometry (MS) as a platform to provide quantification of proteins by multiple reaction monitoring (MRM). This technology does not require antibodies; it is typically less expensive and quicker to develop, and has the opportunity for more accessible multiplexing. The speed of these experiments combined with their flexibility and ability to multiplex assays makes the technique a valuable strategy to validate biomarker discovery. PMID- 20972769 TI - Down-regulation of endothelial TLR4 signalling after apo A-I gene transfer contributes to improved survival in an experimental model of lipopolysaccharide induced inflammation. AB - The protective effects of high-density lipoprotein (HDL) under lipopolysaccharide (LPS) conditions have been well documented. Here, we investigated whether an effect of HDL on Toll-like receptor 4 (TLR4) expression and signalling may contribute to its endothelial-protective effects and to improved survival in a mouse model of LPS-induced inflammation and lethality. HDL cholesterol increased 1.7-fold (p<0.005) and lung endothelial TLR4 expression decreased 8.4-fold (p<0.005) 2 weeks after apolipoprotein (apo) A-I gene transfer. Following LPS administration in apo A-I gene transfer mice, lung TLR4 and lung MyD88 mRNA expression, reflecting TLR4 signalling, were 3.0-fold (p<0.05) and 2.1-fold (p<0.05) lower, respectively, than in LPS control mice. Concomitantly, LPS induced lung neutrophil infiltration, lung oedema and mortality were significantly attenuated following apo A-I transfer. In vitro, supplementation of HDL or apo A-I to human microvascular endothelial cells-1 24 h before LPS administration reduced TLR4 expression, as assessed by fluorescent-activated cell sorting, and decreased the LPS-induced MyD88 mRNA expression and NF-kappaB activity, independently of LPS binding. In conclusion, HDL reduces TLR4 expression and signalling in endothelial cells, which may contribute significantly to the protective effects of HDL in LPS-induced inflammation and lethality. PMID- 20972770 TI - Macroglomeruli for fruit odors change blend preference in Drosophila. AB - The olfactory circuitry of Drosophila melanogaster is becoming increasingly clear. However, how olfactory processing translates into appropriate behavioral responses is still poorly understood. Using a sibling species approach, we tested how a perturbation in the olfactory circuitry affects odor preference. In a previous study, we found that the sibling species of D. melanogaster, the specialist D. sechellia, overrepresents a sensillum, ab3, the A neuron of which is sensitive to hexanoate esters, characteristic of the species' sole host, the Morinda citrifolia fruit. Concordantly, the corresponding glomerulus, DM2, is enlarged. In this study, we found that the ab3B neuron, the expansion of which was previously assumed to be pleiotropic and of no ecological significance, is in fact tuned to another morinda fruit volatile, 2-heptanone (HP). Axons of this neuron type arborize in a second enlarged glomerulus. In behavioral experiments we tested how this has affected the fly's odor preference. We demonstrate that D. sechellia has a reversed preference for the key ligands of these macroglomeruli, especially at high concentrations. Whereas D. melanogaster was repelled by high concentrations of these odors, D. sechellia was highly attracted. This was the case for odors presented singly, but more notably for blends thereof. Our study indicates that relatively simple changes, such as a shift in sensillar abundance, and concordant shifts in glomerular size, can distort the resulting olfactory code, and can lead to saltatory shifts in odor preference. D. sechellia has exploited this to align its olfactory preference with its ecological niche. PMID- 20972771 TI - Trends on schizophrenia admissions during the deinstitutionalisation process in Spain (1980-2004). AB - BACKGROUND: The deinstitutionalisation reform in Spain started after 1980 with the aim of reducing the need for hospitalisation, length of stay and the number of psychiatric hospital beds, as well as fostering psychiatric patient's involvement in the community. The aim of this study was to review how this reform process has affected the management of schizophrenic patients from 1980 to 2004. METHODS: Longitudinal (1980-2004) study describing variables related to hospital morbidity in schizophrenia patients. RESULTS: Hospital admission rate has gradually increased from 1980 to 2004 from 3.71 admissions per 10,000 inhabitants to 5.89, respectively. Considering the type of admission, emergency or elective, whilst the latter has slightly decreased from 2.24 in 1980 to 1.72 in 2004, the first has almost tripled from 1.47 to 4.17. The point-prevalence of schizophrenic patients receiving inpatient treatment each year has decreased 78% in this period. Length of stay, in days per admission episode, has also decreased from 148 days in 1980 to 35 days in 2004. CONCLUSION: One of the main impacts of the psychiatric health care reform in Spain has been the considerable reduction in hospital capacity devoted to schizophrenic patients, based on the significant decrease in point-prevalence. Thus, it seems relevant to design new studies to quantify the resource reallocation to other areas of care, such as pharmacological treatment and community services. PMID- 20972772 TI - Comparative study of Factor Xa fluorogenic substrates and their influence on the quantification of LMWHs. AB - Low molecular weight heparins (LMWHs) are recognised as the preferred anticoagulants in the prevention and treatment of venous thromboembolism. Anti Factor Xa (anti-FXa) levels are used to monitor the anticoagulant effect of LMWHs and such assays are routinely employed in hospital diagnostic laboratories. In this study, a fluorogenic anti-FXa assay was developed using a commercially available fluorogenic substrate with an attached 6-amino-1-naphthalene sulfonamide (ANSN) fluorophore and was used for the determination of two LMWHs, enoxaparin and tinzaparin and the heparinoid, danaparoid. The assay was based on the complexation of heparinised plasma with 100 nM exogenous FXa and 25 MUM of the fluorogenic substrate Mes-D-LGR-ANSN (C(2)H(5))(2) (SN-7). The assay was tested with pooled plasma samples spiked with anticoagulant concentrations in the range 0-1.6 U mL(-1). The statistically sensitive assay range was 0-0.4 U mL(-1) for enoxaparin and tinzaparin and 0-0.2 U mL(-1) for danaparoid, with assay variation typically below 10.5%. This assay was then compared with a previously published fluorogenic anti-FXa assay developed with the peptide substrate, methylsulfonyl-D: -cyclohexylalanyl-glycyl-arginine-7-amino-4-methylcoumarin acetate (Pefafluor FXa). Both assays were compared in terms of fluorescence intensity, lag times and sensitivity to anticoagulants. PMID- 20972773 TI - Synthesis and analytical characterisation of copper-based nanocoatings for bioactive stone artworks treatment. AB - Biological agents play an important role in the deterioration of cultural heritage causing aesthetic, biogeophysical and biogeochemical damages. Conservation is based on the use of preventive and remedial methods. The former aims at inhibiting biological attack, and the latter aims at eradicating the biological agents responsible for biodeterioration. Here, we propose the preparation and the analytical characterisation of copper-based nanocoating, capable of acting both as a remedy and to prevent microbial proliferation. Core shell CuNPs are mixed with a silicon-based product, commonly used as a water repellent/consolidant, to obtain a combined bioactive system to be applied on stone substrates. The resulting coatings exert a marked biological activity over a long period of time due to the continuous and controlled release of copper ions acting as biocides. To the best of our knowledge, this is the first time that a multifunctional material is proposed, combining the antimicrobial properties of nanostructured coatings with those of the formulations applied to the restoration of stone artworks. A complete characterisation based on a multi-technique analytical approach is presented. PMID- 20972774 TI - Dissociable cognitive mechanisms underlying human path integration. AB - Path integration is a fundamental mechanism of spatial navigation. In non-human species, it is assumed to be an online process in which a homing vector is updated continuously during an outward journey. In contrast, human path integration has been conceptualized as a configural process in which travelers store working memory representations of path segments, with the computation of a homing vector only occurring when required. To resolve this apparent discrepancy, we tested whether humans can employ different path integration strategies in the same task. Using a triangle completion paradigm, participants were instructed either to continuously update the start position during locomotion (continuous strategy) or to remember the shape of the outbound path and to calculate home vectors on basis of this representation (configural strategy). While overall homing accuracy was superior in the configural condition, participants were quicker to respond during continuous updating, strongly suggesting that homing vectors were computed online. Corroborating these findings, we observed reliable differences in head orientation during the outbound path: when participants applied the continuous updating strategy, the head deviated significantly from straight ahead in direction of the start place, which can be interpreted as a continuous motor expression of the homing vector. Head orientation-a novel online measure for path integration-can thus inform about the underlying updating mechanism already during locomotion. In addition to demonstrating that humans can employ different cognitive strategies during path integration, our two-systems view helps to resolve recent controversies regarding the role of the medial temporal lobe in human path integration. PMID- 20972775 TI - Comparison of length judgments and the Muller-Lyer illusion in monkeys and humans. AB - Visuo-spatial magnitude judgements are abstract in that they are detached from the specific sensory parameters on which they are based. Nevertheless, the visual system is actively reconstructing and interpreting the outside world, which sometimes causes reproducible geometric illusions. Here, we investigated the visual length perception of rhesus macaques, an Old World monkey species, in a delayed match-to-sample task and compared the non-human primates' performance to the length judgment of human participants under identical conditions. The quantitative analysis of the length discrimination shows that humans and macaques both show a distance and size effect in judging length and have almost identical length judgment characteristics as determined by the widths of the discrimination functions and the Weber fractions. Moreover, both monkeys and humans were subject to the geometric Muller-Lyer illusion caused by inward or outward pointing 'arrows' at the ends of a line, resulting in over- or underestimation of length, respectively. The strength of the illusion effects (i.e., the magnitude of length misjudgement for stimuli with inward and outward pointing arrows at the end of the lines) was in the range between 1.17 and 1.57 degrees of visual angle for both monkeys and the human participants, and thus very similar between the two primate species. Our results suggest that the visuo-spatial mechanisms underlying simple horizontal line-length perceptions in the human and macaque monkey are qualitatively and quantitatively similar, offering the possibility to investigate the neural correlates of geometric illusions in the monkey and to translate the findings to the human visual system. PMID- 20972777 TI - Alpha waves: a neural signature of visual suppression. AB - Alpha waves are traditionally considered a passive consequence of the lack of stimulation of sensory areas. However, recent results have challenged this view by showing a modulation of alpha activity in cortical areas representing unattended information during active tasks. These data have led us to think that alpha waves would support a 'gating function' on sensorial stimulation that actively inhibits unattended information in attentional tasks. Visual suppression occurring during a saccade and blink entails an inhibition of incoming visual information, and it seems to occur at an early processing stage. In this study, we hypothesized that the neural mechanism through which the visual system exerts this inhibition is the active imposition of alpha oscillations in the occipital cortex, which in turn predicts an increment of alpha amplitude during a visual suppression phenomena. We measured visual suppression occurring during short closures of the eyelids, a situation well suited for EEG recordings and stimulated the retinae with an intra-oral light administered through the palate. In the behavioral experiment, detection thresholds were measured with eyes steady open and steady closed, showing a reduction of sensitivity in the latter case. In the EEG recordings performed under identical conditions we found stronger alpha activity with closed eyes. Since the stimulation does not depend on whether the eyes were open or closed, we reasoned that this should be a central effect, probably due to a functional role of alpha oscillation in agreement with the 'gating function' theory. PMID- 20972776 TI - What is the optimal anesthetic protocol for measurements of cerebral autoregulation in spontaneously breathing mice? AB - Autoregulation, an important feature of the cerebral circulation, is affected in many diseases. Since genetically modified mice are a fundamental tool in biomedical research, including neuro(bio)logy also in this specie measurements of cerebral autoregulation (CA) are mandatory. However, this requires anesthesia that unfortunately significantly impacts cerebral perfusion and consequently might distort CA measurements directly or by altering arterial pCO(2). The latter can be avoided by artificial ventilation but requires several control measurements of blood gases, each consuming at least 100 MUl of blood or 5% of a mouse's blood volume. To avoid such diagnostic hemorrhage, we systematically analyzed the effect of different common anesthetic protocols used for rodents in spontaneously breathing mice on CA measured with Laser speckle perfusion imaging. Halothane, Isoflurane and Pentobarbital abrogated CA and Ketamin/Xylazine as well as Chloralose had a moderate reproducibility. In contrast, the rather rarely used anesthetic Ethomidate applied in low doses combined with local anesthetics had the best reproducibility. Although with this anesthesia the lower CA limit was lower than with Ketamin/Xylazine and Chloralose as reported in the handful of papers so far dealing with CA in mice, we suggest Ethomidate as the anesthetic of choice for CA measurements in spontaneously breathing mice. PMID- 20972778 TI - Exploring structural learning in handwriting. AB - Structural learning suggests that the human nervous system learns general rules that can be applied when controlling actions involving similar structures (e.g. using a variety of bicycles when learning to ride). These general rules can then facilitate skill acquisition in novel but related situations (e.g. a new bicycle). We tested this concept by investigating whether learned asymmetries in handwriting (greater ease in moving the hand rightwards and downwards within Western-educated populations) are present in the non-preferred hand as predicted by structural learning. We found these asymmetries in both hands of a right handed population when tracing abstract shapes. We then ruled out biomechanical explanations by finding the same results with a left-handed population. These findings provide support for structural learning and explain: (1) the rapidity with which individuals can learn to write with their non-preferred hand; (2) the presence of a higher abstract (effector independent) level within voluntary motor control organisation. PMID- 20972781 TI - Imaging characteristics of lipofibromatosis presenting as a shoulder mass in a 16 month-old girl. AB - Lipofibromatosis is a rare, benign fibrofatty tumor of childhood. Since the tumor was first characterized in 2000, only a few additional cases have been reported. The classic presentation of lipofibromatosis is a slow-growing mass arising in a distal extremity, with boys more commonly affected than girls. We report a 16 month-old girl who presented with a lipofibromatosis in her left scapular region that increased 30% in size during a 6-week period. Although previous case reports of lipofibromatosis have emphasized immunohistological findings, this paper focuses on imaging findings and discusses the utility of imaging in the differential diagnosis of pediatric soft-tissue tumors. PMID- 20972779 TI - Functional reorganization of upper-body movement after spinal cord injury. AB - Survivors of spinal cord injury need to reorganize their residual body movements for interacting with assistive devices and performing activities that used to be easy and natural. To investigate movement reorganization, we asked subjects with high-level spinal cord injury (SCI) and unimpaired subjects to control a cursor on a screen by performing upper-body motions. While this task would be normally accomplished by operating a computer mouse, here shoulder motions were mapped into the cursor position. Both the control and the SCI subjects were rapidly able to reorganize their movements and to successfully control the cursor. The majority of the subjects in both groups were successful in reducing the movements that were not effective at producing cursor motions. This is inconsistent with the hypothesis that the control system is merely concerned with the accurate acquisition of the targets and is unconcerned with motions that are not relevant to this goal. In contrast, our findings suggest that subjects can learn to reorganize coordination so as to increase the correspondence between the subspace of their upper-body motions with the plane in which the controlled cursor moves. This is effectively equivalent to constructing an inverse internal model of the map from body motions to cursor motions, established by the experiment. These results are relevant to the development of interfaces for assistive devices that optimize the use of residual voluntary control and enhance the learning process in disabled users, searching for an easily learnable map between their body motor space and control space of the device. PMID- 20972782 TI - Production of indole-3-acetic acid and related indole derivatives from L tryptophan by Rubrivivax benzoatilyticus JA2. AB - Rubrivivax benzoatilyticus JA2 produces indoles with simultaneous utilization of L-tryptophan. Fifteen chromatographically distinct indole derivatives were detected from the L-tryptophan-supplemented cultures of R. benzoatilyticus JA2. Nine of these were identified as, indole 3-acetamide, Methoxyindole-3-aldehyde, indole 3-aldehyde, methoxyindole-3-acetic acid, indole 3-acetic acid, indole-3 carboxylic acid, indole-3-acetonitrile, indole, and trisindoline. Tryptophan stable isotope feeding confirmed the indoles produced are from the supplemented L tryptophan. Indole 3-acetic acid is one of the major products of L-tryptophan catabolism by R. benzoatilyticus JA2 and its production was influenced by growth conditions. Identification of indole 3-acetamide and tryptophan monooxygenase activity suggests indole 3-acetamide routed IAA biosynthesis in R. benzoatilyticus JA2. The study also indicated the possible multiple pathways of IAA biosynthesis in R. benzoatilyticus JA2. PMID- 20972783 TI - Trichoderma harzianum SQR-T037 rapidly degrades allelochemicals in rhizospheres of continuously cropped cucumbers. AB - To alleviate the stress of continuous cropping for cucumber continuous cropping (CCC) system, a beneficial fungus Trichoderma harzianum SQR-T037 (SQR-T037) was isolated and applied to soil to degrade allelochemicals exuded from cucumber plants in a Rhizobox experiment. The following phenolic acids (PAs), classified as allelochemicals, were isolated and identified from cucumber rhizospheres: 4 hydroxybenzoic acid, vanillic acid, ferulic acid, benzoic acid, 3-phenylpropionic acid, and cinnamic acid. Mixed PAs added in potato dextrose broth, each with 0.2 gram per liter, were completely degraded by SQR-T037 after 170 h of incubation. In Rhizobox experiments, inoculation of SQR-T037 in the CCC soil also degraded the PAs exuded from cucumber plant roots. This degradation was 88.8% for 4 hydroxybenzoic acid, 90% for vanillic acid, 95% for benzoic acid, and 100% for ferulic acid, 3-phenylpropionic acid, and cinnamic acid at 45 days after plantation. Simultaneously, a significant (p >= 0.05) decrease in the disease index of Fusarium wilt and an increase in dry weights of cucumber plants were obtained in pot experiments by application of SQR-T037. This was mostly attributed to degradation of PAs exuded from cucumber roots in CCC soil by SQR T037 and alleviation of the allelopathic stress. Application of beneficial microorganisms, such as SQR-T037 that biodegrades allelochemicals, is a highly efficient way to resolve the problems associated with continuous cropping system. PMID- 20972784 TI - Production of tranilast [N-(3',4'-dimethoxycinnamoyl)-anthranilic acid] and its analogs in yeast Saccharomyces cerevisiae. AB - Biological synthesis of therapeutic drugs beneficial for human health using microbes offers an alternative production strategy to the methods that are commonly employed such as direct extraction from source organisms or chemical synthesis. In this study, we evaluated the potential for yeast (Saccharomyces cerevisiae) to be used as a catalyst for the synthesis of tranilast and various tranilast analogs (cinnamoyl anthranilates). Several studies have demonstrated that these phenolic amides have antioxidant properties and potential therapeutic benefits including antiinflammatory, antiproliferative, and antigenotoxic effects. The few cinnamoyl anthranilates naturally produced in plants such as oats and carnations result from the coupling of various hydroxycinnamoyl-CoAs to anthranilic acid. In order to achieve the microbial production of tranilast and several of its analogs, we engineered a yeast strain to co-express a 4 coumarate/CoA ligase (4CL, EC 6.2.1.12) from Arabidopsis thaliana and a hydroxycinnamoyl/benzoyl-CoA/anthranilate N-hydroxycinnamoyl/benzoyltransferase (HCBT, EC 2.3.1.144) from Dianthus caryophyllus. This modified yeast strain allowed us to produce tranilast and 26 different cinnamoyl anthranilate molecules within a few hours after exogenous supply of various combinations of cinnamic acids and anthranilate derivatives. Our data demonstrate the feasibility of rapidly producing a wide range of defined cinnamoyl anthranilates in yeast and underline a potential for the biological designed synthesis of naturally and non naturally occurring molecules. PMID- 20972786 TI - High-flexion TKA in patients with a minimum of 120 degrees of pre-operative knee flexion: outcomes at six years of follow-up. AB - We prospectively evaluated outcomes of high-flexion total knee arthroplasty in 165 patients who had advanced arthritis with a minimum 120-degree pre-operative knee flexion, with a mean follow-up of 77 months. Patients were divided into two groups according to their ability to perform full-range (heel-to-buttock) pre operative knee flexion (group A) and the inability to do so (group B). The overall clinical rating was "excellent" in 96% of patients and "good" in 4% of patients. Mean maximum knee flexion decreased from 137.9 degrees to 134.8 degrees , with no statistical difference between pre- and post-operative knee flexion. However, patients in group A had significantly decreased knee flexion (146.2 degrees vs. 135.0 degrees , p < 0.001), whereas patients in group B exhibited no change in knee flexion (133.7 degrees vs. 134.7 degrees , p = 0.14). We found that 14.7%, 36.5% and 43.0% of the studied patients could engage in kneeling, Thai polite style sitting and cross-legged sitting, respectively, with no significant differences between groups A and B. The survival rates for any reoperation and prosthesis-related problem (such as early loosening) at six years were 98.3% and 100%, respectively. At six-year follow-up in patients with well preserved pre-operative knee flexion, the high-flexion knee prosthesis provided a favourable outcome without improving knee flexion. PMID- 20972785 TI - Primed tumor-reactive multifunctional CD62L+ human CD8+ T cells for immunotherapy. AB - T cell-mediated immunotherapy against malignancies has been shown to be effective for certain types of cancer. However, ex vivo expansion of tumor-reactive T cells has been hindered by the low precursor frequency of such cells, often requiring multiple rounds of stimulation, resulting in full differentiation, loss of homing receptors and potential exhaustion of the expanded T cells. Here, we show that when using highly purified naive CD8+ T cells, a single stimulation with peptide pulsed, IFNgamma/LPS-matured dendritic cells in combination with the sequential use of IL-21, IL-7 and IL-15 is sufficient for extensive expansion of antigen specific T cells. Short-term expanded T cells were tumor-reactive, multifunctional and retained a central-memory-like phenotype (CD62L+, CCR7+, CD28+). The procedure is highly reproducible and robust as demonstrated for different healthy donors and for cancer patients. Such short-term tumor-antigen primed, multifunctional T cells may therefore serve as a platform to target different malignancies accessible to immunotherapy. PMID- 20972787 TI - Core decompression and osteonecrosis intervention rod in osteonecrosis of the femoral head: clinical outcome and finite element analysis. AB - The osteonecrosis of the femoral head implies significant disability partly due to pain. After conventional core decompression using a 10-mm drill, patients normally are requested to be non-weight bearing for several weeks due to the risk of fracture. After core decompression using multiple small drillings, patients were allowed 50% weight bearing. The alternative of simultaneous implantation of a tantalum implant has the supposed advantage of unrestricted load bearing postoperatively. However, these recommendations are mainly based on clinical experience. The aim of this study was to perform a finite element analysis and confirm the results by clinical data after core decompression and after treatment using a tantalum implant. Postoperatively, the risk of fracture is lower after core decompression using multiple small drillings and after the implantation of a tantalum rod according to finite element analysis compared to core decompression of one 10-mm drill hole. According to the results of this study, a risk of fracture exists only during extreme loading. The long-term results reveal a superior performance for core decompression presumably due to the lack of complete bone ingrowth of the tantalum implant. In conclusion, core decompression using small drill holes seems to be superior compared to the tantalum implant and to conventional core decompression. PMID- 20972788 TI - Co-culturing of Lactobacillus paracasei subsp. paracasei with a Lactobacillus delbrueckii subsp. delbrueckii mutant to make high cell density for increased lactate productivity from cassava bagasse hydrolysate. AB - To increase the productivity of lactic acid, a co-culture of lactobacilli was made by mixing 1:1 ratio of Lactobacillus paracasei subsp. paracasei and a fast growing L. delbrueckii subsp. delbrueckii mutant. The culture was embedded on to polyurethane foam (PUF) cubes as a biofilm and used for fermentation. In order to prevent the cell leakage, the PUF cubes were further entrapped in calcium cross linked alginate. The maximum lactic acid production using a high cell density free culture was >38 g l(-1) from ~40 g l(-1) of reducing sugar within 12 h of fermentation. Using PUF biofilms, the same yield of lactic acid attained after 24 h. When the cubes were further coated with alginate it took 36 h for the maximum yield. Even though, the productivity is slightly lesser with the alginate coating, cell leakage was decreased and cubes were reused without much decrease in production in repeated batches. Using a conventional control inoculum (3%, w/v), it took 120 h to yield same amount of lactic acid. PMID- 20972789 TI - Congener selectivity during polychlorinated biphenyls degradation by Enterobacter sp. LY402. AB - The relationship between the selectivity of a particular polychlorinated biphenyls (PCBs) congener and its biodegradability under the same concentration, especially by Enterobacter sp. LY402, is less well studied. To measure congener selectivity of Enterobacter sp. LY402, several influencing factors were studied. The results showed LY402 effectively degraded coplanar 3,4,3',4'-chlorobiphenyl (CB) at a concentration of 0.05 MUM, but not 0.5 MUM. The degradation rates of 2,4,5,2',3'-CB and 2,4,5,2',4',5'-CB were increased significantly when the sample constituents were changed from 12 to 5 congeners or to one congener. This indicated that bioremediation of individual congener was affected by other congeners present in the mixture. Moreover, for PCBs containing one chlorine on each phenyl ring, the reactivity preference of LY402 was 2,2'-CB >= 3,3'-CB ? 4,4'-CB. For two ortho chlorines congeners of PCBs, 2,2'-CB was degraded faster than 2,6-CB. Although 2,6-CB and 4,4'-CB were poorly degraded, the addition of one (i.e., 2,4,4'-CB and 2,6,3'-CB) or two more chlorines (i.e., 2,4,2',4'-CB) on the phenyl ring significantly increased their biodegradability. In addition, comparing the two congeners of ortho-meta-chlorinated biphenyl, 2,3,2',3'-CB with neighbor meta chlorines was degraded slower than 2,5,2',5'-CB with interval meta chlorines. All these indicated that the transformation rates of PCBs were not consistent with the number of chlorines, and PCBs containing the same numbers of chlorines but at different positions also resulted in different conversions. In principle, the extents of effect caused by the position of chlorine substituents on the degradation of PCBs by LY402 were ortho- > meta- > para-CB. In conclusion, the congener selectivity of LY402 was determined by many factors, including the composition of the congeners, their concentrations in the mixture and location and number of chlorine substituents on the phenyl rings. PMID- 20972790 TI - Characterization of outer membrane proteins of Escherichia coli in response to phenol stress. AB - Gram-negative bacteria are generally more tolerant to disinfectants than Gram positive bacteria due to outer membrane (OM) barrier, but the tolerant mechanism is not well characterized. We have utilized comparative proteomic methodologies to characterize the OM proteins of E. coli K-12 K99+ in response to phenol stress and found that nine proteins were altered significantly. They were OM proteins OmpA, FadL, LamB, and OmpT, cytoplasmic-associated proteins AceA and EF-Tu, inner membrane protein AtpB, putative capsid protein Q8FewO, and unknown location protein Dps. They were reported here for the first time to be phenol-tolerant proteins. The alteration and functional characterization of the four OM proteins were further investigated using western blotting, genetically modified strains with gene deletion and gene complementation approaches. Our results characterized the functional OM proteins of E. coli in resistance to phenol, and provide novel insights into the mechanisms of bacterial disinfectant-tolerance and new drug targets for control of phenol-resistant bacteria. PMID- 20972791 TI - Short regions of sequence identity between the genomes of bacteria and human. AB - The interaction between bacteria and human is still incomplete. With the recent availability of many microbial genomes and human genome, as well as the series of basic local alignment search tool (BLAST) programs, a new perspective to gain insight into the interaction between the bacteria and human is possible. This study is to determine the possibility of existence of sequence identity between the genomes of bacteria and human, and try to explain this phenomenon in term of bacteriophages and other genetic mobile elements. BLAST searches of the genomes of bacteria, bacteriophages, and plasmids against human genome were performed using the resources of the National Center for Biotechnology Information (NCBI). All studied bacteria contain variable numbers of short regions of sequence identity to the genome of human, which ranged from 27 to 84 nt. They were found at multiple sites within the human genome. The short regions of sequence identity existed between the genomes of bacteria and human, and a hypothesis that viruses, especially bacteriophages, might play a significant role in shaping the genomes of bacterial and human, and contribute to the short regions of sequence identity is developed. PMID- 20972792 TI - Fine-tuning of chemotactic response in E. coli determined by high-throughput capillary assay. AB - In E. coli, chemotactic behavior exhibits perfect adaptation that is robust to changes in the intracellular concentration of the chemotactic proteins, such as CheR and CheB. However, the robustness of the perfect adaptation does not explicitly imply a robust chemotactic response. Previous studies on the robustness of the chemotactic response relied on swarming assays, which can be confounded by processes besides chemotaxis, such as cellular growth and depletion of nutrients. Here, using a high-throughput capillary assay that eliminates the effects of growth, we experimentally studied how the chemotactic response depends on the relative concentration of the chemotactic proteins. We simultaneously measured both the chemotactic response of E. coli cells to L: -aspartate and the concentrations of YFP-CheR and CheB-CFP fusion proteins. We found that the chemotactic response is fine-tuned to a specific ratio of [CheR]/[CheB] with a maximum response comparable to the chemotactic response of wild-type behavior. In contrast to adaptation in chemotaxis, that is robust and exact, capillary assays revealed that the chemotactic response in swimming bacteria is fined-tuned to wild-type level of the [CheR]/[CheB] ratio. PMID- 20972793 TI - Arabidopsis DAL1 and DAL2, two RING finger proteins homologous to Drosophila DIAP1, are involved in regulation of programmed cell death. AB - Programmed cell death (PCD) is a precise, genetically controlled cellular process with important roles in plant growth, development, and response to biotic and abiotic stress. However, the genetic mechanisms that control PCD in plants are unclear. Two Arabidopsis genes, DAL1 and DAL2 (for Drosophila DIAP1 like 1 and 2), encoding RING finger proteins with homology to DIAP1 were identified, and a series of experiments were performed to elucidate their roles in the regulation of PCD and disease resistance. Expression of DAL1 and DAL2 genes was induced in Arabidopsis plants after inoculation with virulent and avirulent strains of Pseudomonas syrinage pv. tomato (Pst) DC3000 or after infiltration with fumonisin B1 (FB1). Plants with mutations in the DAL1 and DAL2 genes displayed more severe disease after inoculation with an avirulent strain of Pst DC3000, but they showed similar disease severity as the wild-type plant after inoculation with a virulent strain of Pst DC3000. Significant accumulations of reactive oxygen species (ROS) and increased cell death were observed in the dal1 and dal2 mutant plants after inoculation with the avirulent strain of Pst DC3000. The dal mutant plants underwent extensive PCD upon infiltration of FB1 and displayed higher levels of ROS accumulation, callose deposition, and autofluorescence than the wild-type plants. Our data suggest that DAL1 and DAL2 may act as negative regulators of PCD in Arabidopsis. PMID- 20972794 TI - Recombinase technology: applications and possibilities. AB - The use of recombinases for genomic engineering is no longer a new technology. In fact, this technology has entered its third decade since the initial discovery that recombinases function in heterologous systems (Sauer in Mol Cell Biol 7(6):2087-2096, 1987). The random insertion of a transgene into a plant genome by traditional methods generates unpredictable expression patterns. This feature of transgenesis makes screening for functional lines with predictable expression labor intensive and time consuming. Furthermore, an antibiotic resistance gene is often left in the final product and the potential escape of such resistance markers into the environment and their potential consumption raises consumer concern. The use of site-specific recombination technology in plant genome manipulation has been demonstrated to effectively resolve complex transgene insertions to single copy, remove unwanted DNA, and precisely insert DNA into known genomic target sites. Recombinases have also been demonstrated capable of site-specific recombination within non-nuclear targets, such as the plastid genome of tobacco. Here, we review multiple uses of site-specific recombination and their application toward plant genomic engineering. We also provide alternative strategies for the combined use of multiple site-specific recombinase systems for genome engineering to precisely insert transgenes into a pre determined locus, and removal of unwanted selectable marker genes. PMID- 20972795 TI - Regeneration of transgenic plants by Agrobacterium-mediated transformation of somatic embryos of juvenile and mature Quercus robur. AB - A protocol was developed for genetic transformation of somatic embryos derived from juvenile and mature Quercus robur trees. Optimal transformation conditions were evaluated on the basis of the results of transient GUS expression assays with five oak embryogenic lines and a strain of Agrobacterium tumefaciens (EHA105) harbouring a p35SGUSINT plasmid containing a nptII and a uidA (GUS) genes. For stable transformation, embryo clumps at globular/torpedo stages (4-10 mg) were inoculated with EHA105:p35SGUSINT bacterial cultures, cocultivated for 4 days and selected in proliferation medium with 75 mg/l of kanamycin. Putatively transformed masses appeared after 20-30 weeks of serial transfers to selective medium. Histochemical and molecular analysis (PCR and Southern blot) confirmed the presence of nptII and uidA genes in the plant genomes. Transformation efficiencies ranged from up to 2% in an embryogenic line derived from a 300-year old tree, to 6% in a juvenile genotype. Twelve independent transgenic lines were obtained from these oak genotypes, and transgenic plantlets were recovered and acclimatized into the soil. This is the first demonstration of the production of transformed somatic embryos and regenerated plants from juvenile and mature trees of Q. robur and suggests the possibility of introducing other genetic constructions to develop trees that are tolerant/resistant to pathogens and/or biotic stresses. PMID- 20972796 TI - Morphological and physiological regeneration in the auditory system of adult Mecopoda elongata (Orthoptera: Tettigoniidae). AB - Orthopterans are suitable model organisms for investigations of regeneration mechanisms in the auditory system. Regeneration has been described in the auditory systems of locusts (Caelifera) and of crickets (Ensifera). In this study, we comparatively investigate the neural regeneration in the auditory system in the bush cricket Mecopoda elongata. A crushing of the tympanal nerve in the foreleg of M. elongata results in a loss of auditory information transfer. Physiological recordings of the tympanal nerve suggest outgrowing fibers 5 days after crushing. An anatomical regeneration of the fibers within the central nervous system starts 10 days after crushing. The neuronal projection reaches the target area at day 20. Threshold values to low frequency airborne sound remain high after crushing, indicating a lower regeneration capability of this group of fibers. However, within the central target area the low frequency areas are also innervated. Recordings of auditory interneurons show that the regenerating fibers form new functional connections starting at day 20 after crushing. PMID- 20972797 TI - Zebrafish: an exciting model for investigating the spatio-temporal pattern of enteric nervous system development. AB - AIM: Recently, the zebrafish (Danio rerio) has been shown to be an excellent model for human paediatric research. Advantages over other models include its small size, externally visually accessible development and ease of experimental manipulation. The enteric nervous system (ENS) consists of neurons and enteric glia. Glial cells permit cell bodies and processes of neurons to be arranged and maintained in a proper spatial arrangement, and are essential in the maintenance of basic physiological functions of neurons. Glial fibrillary acidic protein (GFAP) is expressed in astrocytes, but also expressed outside of the central nervous system. The aim of this study was to investigate the spatio-temporal pattern of GFAP expression in developing zebrafish ENS from 24 h post fertilization (hpf), using transgenic fish that express green fluorescent protein (GFP). METHODS: Zebrafish embryos were collected from transgenic GFP Tg(GFAP:GFP)(mi2001) adult zebrafish from 24 to 120 hpf, fixed and processed for whole mount immunohistochemistry. Antibodies to Phox2b were used to identify enteric neurons. Specimens were mounted on slides and imaging was performed using a fluorescent laser confocal microscope. RESULTS: GFAP:GFP labelling outside the spinal cord was identified in embryos from 48 hpf. The patterning was intracellular and consisted of elongated profiles that appeared to migrate away from the spinal cord into the periphery. At 72 and 96 hpf, GFAP:GFP was expressed dorsally and ventrally to the intestinal tract. At 120 hpf, GFAP:GFP was expressed throughout the intestinal wall, and clusters of enteric neurons were identified using Phox2b immunofluorescence along the pathway of GFAP:GFP positive processes, indicative of a migratory pathway of ENS precursors from the spinal cord into the intestine. CONCLUSION: The pattern of migration of GFAP:GFP expressing cells outside the spinal cord suggests an organized, early developing migratory pathway to the ENS. This shows for the first time that Tg(GFAP:GFP)(mi2001) zebrafish model is an ideal one to study spatio-temporal patterning of early ENS development. PMID- 20972798 TI - Small bowel incarceration in recurrent perineal hernia after abdominoperineal resection. PMID- 20972799 TI - Weather sensitivity in migraineurs. AB - The scientific evidence for weather being a trigger factor for migraine attacks is inconclusive. We investigated the association between weather components and the onset and severity of attacks. Headache diaries of 20 migraineurs were analyzed retrospectively and correlated in 4-h intervals to atmospheric air pressure, temperature, and relative air humidity in Berlin (Germany) for a period of 12 consecutive months. Absolute values and relative changes within the preceding 24 h were analyzed. Migraine attacks started most frequently at 4 a.m. and reached the highest intensity between 4 and 8 a.m. A highly significant association between meteorological variables and the occurrence of migraine attacks was found in six patients. The onset of an attack as well as high headache intensity was associated with lower temperature and higher humidity. Our data indicate that a subgroup of migraineurs is highly sensitive to changes of certain weather components. PMID- 20972801 TI - Mechanical bowel preparation and antimicrobial prophylaxis in elective colorectal surgery in Switzerland--a survey. AB - BACKGROUND: The aim of this study was to assess the use of mechanical bowel preparation (MBP) and antimicrobial prophylaxis in elective colorectal surgery in Switzerland. METHODS: Ninety-eight heads of surgical departments in Switzerland and 42 visceral surgeons in private practice were asked to answer an 18-item questionnaire in October 2008 about arguments in favor of or against MBP. The participants also indicated whether they use MBP and antimicrobial prophylaxis in colorectal surgery, and if so, what agents were used. Of the participants, 117/140 (83%) responded. Additional data were collected pertaining to the respondents' experience and work situation. RESULTS: MBP was used significantly more often for rectal surgery than for left colonic resections (83% vs. 53%; p < 0.001) and more often for left than for right colonic resections (53% vs. 43%; p = 0.001), regardless of the open or laparoscopic approach. Younger surgeons and surgeons with a higher case load in colorectal surgery used MBP significantly less frequently in open right colonic resections. For MBP, cathartics were used in 90% of patients, and enemas were used in 10% of patients. Of the respondents, 37% considered MBP to be useful, even very useful. Based on the literature, because of introduction of fast-track protocols or for considerations of patient comfort, 86% of the respondents had changed the bowel preparation regime during the last 10 years in terms of a reduction of the quantity of cathartics or restricted the indications for MBP. Antimicrobial prophylaxis was used by 100% of the respondents, 88% used a single prophylactic dose only, while 70% administered the antibiotics 30-59 min before the incision. Most of the surgeons used second generation cephalosporins in combination with metronidazole, and 24% changed the antibiotic agent or reduced the duration of administration of antibiotics during the last 10 years. CONCLUSIONS: MBP is often used in open and laparoscopic rectal surgery, but not in right colonic resections. Scientific evidence regarding MBP has yielded a rethinking about rigorous bowel preparation regimes. As of now, surgeons in Switzerland are not yet unanimously ready to abandon MBP in elective colorectal surgery. In Switzerland, surgeons are influenced by the benefit of antimicrobial prophylaxis in colorectal surgery. PMID- 20972800 TI - Lung function in adults following in utero and childhood exposure to arsenic in drinking water: preliminary findings. AB - PURPOSE: Evidence suggests that arsenic in drinking water causes non-malignant lung disease, but nearly all data concern exposed adults. The desert city of Antofagasta (population 257,976) in northern Chile had high concentrations of arsenic in drinking water (>800 MUg/l) from 1958 until 1970, when a new treatment plant was installed. This scenario, with its large population, distinct period of high exposure, and accurate data on past exposure, is virtually unprecedented in environmental epidemiology. We conducted a pilot study on early-life arsenic exposure and long-term lung function. We present these preliminary findings because of the magnitude of the effects observed. METHODS: We recruited a convenience sample consisting primarily of nursing school employees in Antofagasta and Arica, a city with low drinking water arsenic. Lung function and respiratory symptoms in 32 adults exposed to >800 MUg/l arsenic before age 10 were compared to 65 adults without high early-life exposure. RESULTS: Early-life arsenic exposure was associated with 11.5% lower forced expiratory volume in 1 s (FEV(1)) (P = 0.04), 12.2% lower forced vital capacity (FVC) (P = 0.04), and increased breathlessness (prevalence odds ratio = 5.94, 95% confidence interval 1.36-26.0). Exposure-response relationships between early-life arsenic concentration and adult FEV(1) and FVC were also identified (P trend = 0.03). CONCLUSIONS: Early-life exposure to arsenic in drinking water may have irreversible respiratory effects of a magnitude similar to smoking throughout adulthood. Given the small study size and non-random recruitment methods, further research is needed to confirm these findings. PMID- 20972802 TI - Pharmacokinetics of cysteamine in a cystinosis patient treated with hemodialysis. PMID- 20972803 TI - Measurement of saliva tacrolimus levels in pediatric renal transplant recipients. AB - The aim of this study was to investigate whether a strong and clinically applicable correlation exists between saliva and whole-blood tacrolimus levels measured by high-performance liquid chromatography-tandem mass spectrometry. A high degree of correlation would potentially allow pain-free saliva sample collection to replace blood sampling for the measurement of tacrolimus levels. Enrolled in the study were 37 children (24 boys) aged 8-18 years [median (IQR) 16.2 (12.9-17.5) years] attending the renal transplant clinic at the Royal Manchester Children's Hospital and 77 paired blood saliva samples were collected. The mean (SD) saliva tacrolimus level was 0.14 (0.16), range 0-0.7 MUg/l. In ten cases, tacrolimus was not detected in the saliva despite being present in blood. The ratio of blood-to-saliva tacrolimus levels varied from 2.6 to 550. The Pearson product-moment correlation suggested a weak linear relationship between tacrolimus levels in blood and saliva with a coefficient 0.36. Individual patients did not demonstrate consistent tacrolimus blood/saliva ratios with a mean correlation of 0.08. Additional experiments excluded saliva contamination with blood and sample collection and storage conditions as causes of poor correlation. The measurement of saliva tacrolimus levels in place of or as an adjunct to blood sampling therefore cannot be recommended. PMID- 20972804 TI - Complementary and alternative medicine use in pediatric cancer reported during palliative phase of disease. AB - PURPOSE: The objectives of this study were to assess the frequency, types, and potential determinants of complementary and alternative medicine (CAM) use, and consideration of CAM use, collected from parents with children during the palliative phase of disease. METHODS: Eligible parent respondents were identified by their primary care team. Demographic information and questionnaires were completed by the parent in the presence of a research nurse (DT). We conducted univariate logistic regression to identify predictors of parents who considered CAM use and children who actually used CAM. Descriptions of types of CAM were categorized according to the National Center for Complementary and Alternative Medicine. RESULTS: A total of 77 parents participated. Only 22 children (29%) had received some type of CAM, with 42 parents (55%) having considered its use for their child. Whole medical systems (n = 17) and biologically based therapies (n = 15) were the most frequently considered CAM, with whole medical systems (n = 6) being the most frequently used CAM. Family and disease variables were not indicative of CAM use. However, parents with higher education and those with a family member with cancer were more likely to consider CAM use, while parents were less likely to consider CAM as children were farther from time of relapse. CONCLUSIONS: The study provides initial insight into CAM use, and consideration of use, in children with cancer receiving palliative care. Further research is required to determine if the gap between CAM use and consideration is important, why this gap exists, and whether CAM has beneficial effects in this population. PMID- 20972805 TI - Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity--state of the art. AB - Antiemetic drug development can follow the same logical path as antineoplastic drug development from appropriate preclinical models through Phase I, Phase II, and Phase III testing. However, due to the marked success of antiemetic therapy over the last 25 years, placebo antiemetic treatment against highly or moderately emetogenic chemotherapy is not acceptable. Promising antiemetic agents therefore rapidly reach Phase III testing, where they are substituted into or added to effective and accepted regimens. One challenge of antiemetic drug development is determining whether substitution is indeed acceptable or whether prior regimens must be maintained intact as a basis for further antiemetic drug development. An additional challenge is the classification of emetogenic level of new antineoplastic agents. Accurate reporting of emetogenicity of such antineoplastic agents in the absence of preventive antiemetic treatment may not be available. However, at the 2009 Multinational Association of Supportive Care in Cancer (MASCC)/European Society of Medical Oncology (ESMO) Consensus Conference, an expert panel used best available data to establish rankings of emetogenicity. Oral chemotherapeutic agents are ranked separately from intravenous agents, recognizing intrinsic differences in emetogenicity as well as differing schedules of administration. Since oral chemotherapeutic agents are often administered in extended regimens, the distinction between acute and delayed emesis is less clear, and cumulative emesis must be considered. As control of vomiting has improved, attention has shifted to control of nausea, a related but distinct and equally important problem. Additional efforts will be necessary to understand mechanisms of nausea and to identify optimal remedies. PMID- 20972806 TI - Aversive memory in sepsis survivor rats. AB - Sepsis is an infectious insult resulting in disturbances in the normal regulation of many organic systems, including the central nervous system. This study aims to evaluate aversive memory as well as its variances-posttraumatic memory and memory of extinction-in survivor rats submitted to sepsis by cecal ligation and perforation (CLP) at 10, 30, and 60 days after CLP, utilizing the inhibitory avoidance (IA) task paradigm. Male Wistar rats underwent either CLP or sham surgery under anesthesia. Sepsis group received antibiotics and fluid support, whereas sham group received only fluid replacement. The rats were divided in four different tasks: (1) aversive memory after 10, 30, and 60 days after CLP; (2) memory of extinction 60 days after CLP; (3) aversive memory-two trainings paradigm 10 days after CLP; and (4) posttraumatic memory 10 days after CLP. The aversive memory was impaired at 10, 30, but not 60 days after CLP, However, no damage was found in aversive memory after two training sessions. Additionally, there was no damage to the memory of extinction 60 days after CLP. Posttraumatic memory impairment was also observed. In this regard, we believe that our results provide relevant insights into the mechanisms involved in the cognitive deficits associated with sepsis. PMID- 20972807 TI - CD3 in Lewy pathology: does the abnormal recall of neurodevelopmental processes underlie Parkinson's disease. AB - CD3zeta is a subunit of the CD3 molecule that, until recently, appeared restricted to T cells and natural killer cells. However, experimental studies have demonstrated a role of CD3zeta in dendritic outgrowth in the visual system as well as in synaptic plasticity. Given the increasing evidence for uncharacteristic recapitulation of neurodevelopmental processes in neurodegenerative diseases, in this study, we evaluated brains from subjects with Parkinson's disease and Lewy body dementia for evidence of aberrant CD3 expression. Our data shows marked CD3zeta in association with the alpha-synuclein containing pathological lesions, i.e., Lewy bodies and Lewy neurites, in the brains of subjects with Parkinson's disease and Lewy body dementia. This finding raises the novel concept of CD3 dysregulation in these disorders as a pathogenic factor and also furthers the increasing evidence that the recall of aberrant neurodevelopmental processes underlies the pathogenesis of neurodegenerative diseases. PMID- 20972808 TI - Controlling a vancomycin-resistant enterococci outbreak in a Brazilian teaching hospital. AB - The purpose of this article was to describe a 2.5-year interventional program designed to control the dissemination after a large hospital outbreak of vancomycin-resistant enterococci (VRE) in a tertiary-care university hospital. A VRE working group was designated to work specifically on controlling VRE intrahospital dissemination after the detection of the first VRE infection at in our hospital in June 2007. The intervention consisted in the interruption of new admissions during a period of 15 days and closure of the index case unit, microbiological surveillance of rectal swabs for VRE, cohorting patients and staff, immediate application of contact precautions, and continuous education. From July 2007 to December 2009, 8,692 rectal swabs were cultured for VRE and 321 (3.7%) were positive. An expressive reduction of the detection of new positive rectal swabs cultures was seen during the year 2009 (1.5%) when compared to 2008 (4.2%) and 2007 (7.2%) (p < 0.005). The annual ratio of VRE per 1,000 admissions reduced from 20.3 in 2007 to 10.07 and 3.82 in 2008 and 2009, respectively (p < 0.001). The continuous microbiologic surveillance for VRE and strict and prompt contact precautions for VRE patients were the fundamental aids in the control of VRE. PMID- 20972809 TI - Acceleration of the direct identification of Staphylococcus aureus versus coagulase-negative staphylococci from blood culture material: a comparison of six bacterial DNA extraction methods. AB - To accelerate differentiation between Staphylococcus aureus and coagulase negative staphylococci (CNS), this study aimed to compare six different DNA extraction methods from two commonly used blood culture materials, i.e. BACTEC and BacT/ALERT. Furthermore, we analysed the effect of reduced blood culture incubation for the detection of staphylococci directly from blood culture material. A real-time polymerase chain reaction (PCR) duplex assay was used to compare the six different DNA isolation protocols on two different blood culture systems. Negative blood culture material was spiked with methicillin-resistant S. aureus (MRSA). Bacterial DNA was isolated with automated extractor easyMAG (three protocols), automated extractor MagNA Pure LC (LC Microbiology Kit M(Grade)), a manual kit MolYsis Plus and a combination of MolYsis Plus and the easyMAG. The most optimal isolation method was used to evaluate reduced bacterial incubation times. Bacterial DNA isolation with the MolYsis Plus kit in combination with the specific B protocol on the easyMAG resulted in the most sensitive detection of S. aureus, with a detection limit of 10 CFU/ml, in BacT/ALERT material, whereas using BACTEC resulted in a detection limit of 100 CFU/ml. An initial S. aureus or CNS load of 1 CFU/ml blood can be detected after 5 h of incubation in BacT/ALERT 3D by combining the sensitive isolation method and the tuf LightCycler assay. PMID- 20972810 TI - DNA bacterial load in children and adolescents with pneumococcal pneumonia and empyema. AB - The purpose of this investigation was to evaluate a rapid quantitative real-time polymerase chain reaction (PCR) for the direct detection and quantification of pneumococcal DNA bacterial load (DBL) in patients with pneumonia and empyema. DBL and molecular serotype detection was determined by DNA quantification of the pneumolysin (ply) gene and an additional capsular gene by real-time PCR. Plasma or pleural fluid samples from children and adolescents with confirmed pneumococcal pneumonia were analyzed. DBL was correlated with clinical parameters and outcomes. One hundred and sixty-nine patients with pneumococcal pneumonia (145 empyema) had bacterial cultures and real-time PCR assays performed. Among them, 41 (24.3%) had positive results for both, 4 (2.4%) had positive culture alone, and 124 (73.3%) had positive real-time PCR alone. The pleural fluid DBL was lower in patients with prior antibiotics (p = 0.01) and higher in patients with positive culture (p < 0.001). The pleural fluid DBL was positively correlated with serum C-reactive protein (p = 0.009), pleural fluid neutrophils (p < 0.001), and pleural fluid glucose (p < 0.001). The plasma and pleural fluid DBL were higher in patients with >=8 days of hospital stay (p = 0.002), and the pleural fluid DBL was positively correlated with the number of hours of pleural drainage (p < 0.001). Quantification of pneumococcal DBL by real-time PCR may be helpful for the diagnosis and clinical management of pediatric patients with pneumonia and empyema. PMID- 20972811 TI - How a coating is hydrated ahead of the advancing contact line of a volatile solvent droplet. AB - The wettability of coatings is very sensitive to the amount of solvent they may contain. When a droplet of volatile solvent, such as water, is deposited on a substrate, its vapor may quickly condensate just ahead of the contact line. We give an estimation of the extent of solvent uptake by a coating of variable thickness e , in front of an advancing contact line of given velocity U . Depending on the values of e and U , we observe three regimes: at low velocity and for a thin coating, the coating adsorbs a fraction of solvent that can quickly equilibrate across its entire thickness, so that it mainly appears solvophilic, while this is not the case for a thick coating. For high velocities, regardless the coating thickness, the coating ahead of the contact line does not have enough time to adsorb a significant amount of solvent, so that it mainly appears solvophobic. All these phenomena appear to be controlled by a molecular cut-off length. PMID- 20972812 TI - The cross-talk between the urokinase receptor and fMLP receptors regulates the activity of the CXCR4 chemokine receptor. AB - The receptor (CXCR4) for the stromal-derived factor-1 (SDF1) and the urokinase receptor (uPAR) are up-regulated in various tumors. We show that CXCR4 transfected cells migrate toward SDF1 on collagen (CG) and do not on vitronectin (VN). Co-expression of cell-surface uPAR, which is a VN receptor, impairs SDF1 induced migration on CG and allows migration on VN. Blocking fMLP receptors (fMLP R), alpha-v integrins or the uPAR region capable to interact with fMLP-Rs, impairs migration of uPAR/CXCR4-transfected cells on VN and restores their migration on CG. uPAR co-expression also reduces the adherence of CXCR4 expressing cells to various components of the extracellular matrix (ECM) and influences the partitioning of beta1 and alpha-v integrins to membrane lipid rafts, affecting ECM-dependent signaling. uPAR interference in CXCR4 activity has been confirmed in cells from prostate carcinoma. Our results demonstrate that uPAR expression regulates the adhesive and migratory ability of CXCR4-expressing cells through a mechanism involving fMLP receptors and alpha-v integrins. PMID- 20972813 TI - Genetics of photoreceptor degeneration and regeneration in zebrafish. AB - Zebrafish are unique in that they provide a useful model system for studying two critically important problems in retinal neurobiology, the mechanisms responsible for triggering photoreceptor cell death and the innate stem cell-mediated regenerative response elicited by this death. In this review we highlight recent seminal findings in these two fields. We first focus on zebrafish as a model for studying photoreceptor degeneration. We summarize the genes currently known to cause photoreceptor degeneration, and we describe the phenotype of a few zebrafish mutants in detail, highlighting the usefulness of this model for studying this process. In the second section, we discuss the several different experimental paradigms that are available to study regeneration in the teleost retina. A model outlining the sequence of gene expression starting from the dedifferentiation of Muller glia to the formation of rod and cone precursors is presented. PMID- 20972815 TI - The crystalline phase of cellulose changes under developmental control in a marine chordate. AB - The native form of cellulose is a fibrillar composite of two crystalline phases, the triclinic I(alpha) and monoclinic I(beta) allomorphs. Allomorph ratios are species-specific, and this gives rise to natural structural variations in cellulose crystals. However, the mechanisms contributing to crystal formation remain unknown. We show that the two crystalline phases of cellulose are tailored to distinct structures during different developmental stages of the tunicate chordate Oikopleura dioica. Larval cellulose consisting of I(alpha) allomorph constitutes the body cuticle fin, whereas adult cellulose consisting of I(beta) allomorph frames a mucous filter-feeding device, the "house." Both structures are secreted from the epidermis in accordance with the mutually exclusive expression patterns of two distinct putative cellulose synthase genes. We discuss a possible linkage between structural variations of the crystalline phases of cellulose and the underlying evolutionary genetics of cellulose biosynthesis. PMID- 20972814 TI - Mesenchymal stem cells or cardiac progenitors for cardiac repair? A comparative study. AB - In the past, clinical trials transplanting bone marrow-derived mononuclear cells reported a limited improvement in cardiac function. Therefore, the search for stem cells leading to more successful stem cell therapies continues. Good candidates are the so-called cardiac stem cells (CSCs). To date, there is no clear evidence to show if these cells are intrinsic stem cells from the heart or mobilized cells from bone marrow. In this study we performed a comparative study between human mesenchymal stem cells (hMSCs), purified c-kit(+) CSCs, and cardiosphere-derived cells (CDCs). Our results showed that hMSCs can be discriminated from CSCs by their differentiation capacity towards adipocytes and osteocytes and the expression of CD140b. On the other hand, cardiac progenitors display a greater cardiomyogenic differentiation capacity. Despite a different isolation protocol, no distinction could be made between c-kit(+) CSCs and CDCs, indicating that they probably derive from the same precursor or even are the same cells. PMID- 20972816 TI - Blood lymphocyte blastogenesis in patients with thyroid dysfunction: ex vivo response to mitogen activation and cyclosporin A. AB - OBJECTIVE: To evaluate lymphocyte activation following mitogen and cyclosporin A (CsA) administration in peripheral blood of hyperthyroxinaemic and hypothyroid patients. MATERIALS AND METHODS: Lymphocyte activation was evaluated by determining blastogenesis in 48 h cultured blood lymphocytes obtained from eight hyperthyroxinaemic and eight hypothyroid patients, following phytohaemagglutinin (PHA)-induced stimulation in the absence or presence of CsA. Twelve healthy volunteers served as controls. RESULTS AND CONCLUSIONS: Lymphocytes from hypothyroid patients exhibited reduced response to PHA and lower sensitivity to CsA compared with control, which could be attributed to their reduced activation capability coexisting with hypothyroidism. In hyperthyroxinaemic samples, the actions of high CsA concentrations were mostly targeted toward activated lymphoblasts. Considering the cellular targets that thyroid hormones and CsA may share, the therapeutic implications of their cross-talk need careful consideration. PMID- 20972817 TI - Up-regulation of HIV-1 transduction in nondividing cells by double-strand DNA break-inducing agents. AB - Efficient HIV-1 transduction depends on a number of cellular co-factors. Cellular double-strand DNA break (DSB) repair proteins have been proposed, by ourselves and others, to be required for efficient HIV-1 transduction. Expression and/or activity of these DNA repair proteins can be induced by the introduction of DSBs into the host cell genome. HIV-1 transduction was up-regulated by treatment with DSB-inducing agents in both drug-arrested cells and differentiated neuronal cells. The presented data support the hypothesis that DSB repair proteins are involved in the early steps of the retroviral life-cycle. PMID- 20972818 TI - Reduction of galactose inhibition via the mutation of beta-galactosidase from Caldicellulosiruptor saccharolyticus for lactose hydrolysis. AB - For the removal of galactose inhibition, the predicted galactose binding residues, which were determined by sequence alignment, were replaced separately with Ala. The activities of the Ala-substituted mutant enzymes were assessed with the addition of galactose. As a consequence, amino acid at position 349 was correlated with the reduction in galactose inhibition. The F349S mutant exhibited the highest activity in the presence of galactose relative to the activity measured in the absence of galactose among the tested mutant enzymes at position 349. The K (i) of the F349S mutant (160 mM), which was 13-fold that of the wild type enzyme, was the highest among the reported values of beta-galactosidase. The wild-type enzyme hydrolyzed 62% of 100 g lactose/l with the addition of 30 g galactose/l, whereas the F349S mutant hydrolyzed more than 99%. PMID- 20972819 TI - Quantitative evaluation of the effects of cold exposure of rats on the expression levels of ten FABP isoforms in brown adipose tissue. AB - We quantitatively examined the transcript levels of ten fatty acid-binding protein (FABP) isoforms in the brown adipose tissue (BAT) of rats kept at room temperature and of rats exposed to the cold by Northern blotting using the synthesized RNA of each isoform as an external standard. FABP3-5 were expressed in BAT of both rats maintained at room temperature and those exposed to the cold. FABP4 was the most abundantly expressed isoform, but its transcript level was not significantly affected by cold exposure. FABP3 was slightly expressed in the BAT of rats maintained at room temperature and its transcript level was elevated ten fold by cold exposure. FABP5 was also elevated four fold by cold exposure but the amount of its mRNA in BAT was negligible. PMID- 20972820 TI - Biofilm productivity and concomitant cell autolysis in a membrane bioreactor. AB - Phanerochaete chrysoporium morphology and manganese peroxidase (MnP) productivity was characterised in a scalable, modularised 1145 cm(3) membrane gradostat reactor in response to switching between an enhanced production medium and a nutrient limited feed (50% C and N reduction). Irrespective of the feed composition used nutrients permeating from the lumen of the ultrafiltration membrane matrix established nutrient gradients across the immobilised biofilm with distinct primary, stationary and decline growth phases observed. Severe nutrient C and N limitation did not change the cyclic nature of enzyme production (MnP(max) = 189.5 U l(-1)) but did reduce the overall bioreactor efficiency from 32 to 22 U l(-1) day(-1). Stress induced secondary metabolism resulted in concomitant cell autolysis causing biomass loss and increased operational flux after 20 days in the 33 day bioreactor operation cycle. PMID- 20972821 TI - Transformation of sweet orange [Citrus sinensis (L.) Osbeck] with pthA-nls for acquiring resistance to citrus canker disease. AB - The COOH terminal of pthA encoding three nuclear localizing signals (NLS) was amplified by polymerase chain reaction (PCR) from the plasmid of Xanthomonas axonopodis pv. citri, the pathogen of citrus canker disease. Then the sense and antisense strands of the nls were cloned into pBI121 vector. pthA-nls driven by the CaMV35 s promoter was transferred into sweet orange via Agrobacterium mediated transformation. Successful integration was confirmed by PCR and Southern blotting, and 12 sense-nls (nls (+)) and 9 antisense-nls (nls (-)) transgenic clones were obtained. The expression of nls fragment was analyzed by RT-PCR, Real time q-PCR and Western blotting, in which the specific NLS protein was detected only in nls (+) transgenic clones. In an in vitro assay, when pin-puncture inoculation was performed with 2.5 * 10(7) cfu/ml of bacterial solution, the nls (+) transgenic clones showed no typical lesion development, while typical symptoms were observed in the wild types and the nls (-) transgenic clones. In vivo assay results indicated that the nls (+) transgenic clones showed less disease incidence, in comparison with the wild types and the nls (-) transgenic clones, when pin-puncture inoculation was performed with 10(4)-10(5) cfu/ml. The minimum disease incidence was 23.3% for 'Sucarri' sweet orange and 33.3% for 'Bingtang' sweet orange. When 10(4)-10(7) cfu/ml of pathogen was spray inoculated, the nls (+) transgenic clones did not show any symptom, and even the concentration raised to 10(9) cfu/ml, the disease incidence was 20-80%, while the wild types and the nls (-) transgenic clones had 100% disease development with whatever concentration of inoculum. Two transgenic clones were confirmed to be resistant to citrus canker disease in the repeated inoculation. The results suggested that the transformation of nls sense strands may offer an effective way to acquire resistance to citrus canker disease. PMID- 20972822 TI - Work-related musculoskeletal disorders in athletic trainer. AB - INTRODUCTION Athletic trainers often work for elongated and irregular hours or days, and need to react in emergency situations. These professionals are at risk for work-related musculoskeletal disorders (WMSDs). This study investigated the WMSDs experienced by athletic trainers (ATs), plus related personal and occupational factors. METHODS A customized questionnaire with subject's demographic and WMSDs information was constructed and administered in all accessible ATs in Taiwan. In addition to descriptive analysis of demographics and WMSDs, the relationship between personal/occupational-related factors and WMSD symptoms were also evaluated. Results A total of 146 effective questionnaires were returned. The results indicated that a 48.5% prevalence rate of athletic trainers in Taiwan, and these disorders are mainly located in low back (42%), finger (38%) and shoulder (26%) regions. Logistic regression revealed that average work hour (odds ratio (OR) = 1.834, 95% confidence interval (CI): 1.066 3.156) and continue education participation (OR = 0.346, 95% CI: 0.140-0.854) were the most significant predictors for WMSDs occurrence. Performing taping was the most significant predictor for the low back (OR = 28.274, 95% CI: 2.568 311.423) and finger (OR = 19.535, 95% CI:2.273-167.912) symptoms; while performing providing first aid (OR = 12.128, 95% CI:3.881-37.899) was the most significant predictor for the shoulder's. Conclusion This study revealed that athletic trainers in Taiwan area suffered from high rate of WMSDs, and the relationship between WMSDs and specific job features were reported. Preventive and therapeutic modifications of the work environment to decrease the occurrence of WMSDs are in need for athletic trainers and other similar professions. Further research examining safe patient handling ergonomics, proper equipment in the context of athletic training and professional development strategies must be pursued. PMID- 20972823 TI - Comments from the trenches: Proposed Changes to the DSM-V classification of pathological gambling. AB - The proposed DSM-V changes related to the pathological gambling diagnosis hold far-reaching implications, yet these modifications have been met with little public attention. This letter addresses the three changes proposed including the diagnosis' reclassification alongside other addictive behaviors, the lowering of the pathological gambling threshold to the endorsement of 4 symptoms, and the removal of the "illegal acts" criterion. Support for the initial change is well documented, but there is evidence to suggest that the latter two changes should be reconsidered. PMID- 20972824 TI - Carina as a useful and reliable radiological landmark for detection of accidental arterial placement of central venous catheters. AB - Central venous catheters are commonly used in the management of critically ill patients. Their insertion can be challenging in hemodynamically unstable patients and in those with altered thoracic anatomy. Although ultrasound guided insertion can reduce this problem, this facility may not be available in all locations and in all institutions. Accidental arterial puncture is one of the very serious complications that can occur during central venous catheter insertion. This is usually detected clinically by bright color and projectile/pulsatile flow of the returning blood. However, such means are known to be misleading especially in hypoxic and hemodynamically unstable patients. Other recognized measures used to identify arterial puncture would be blood gas analysis of the returning blood, use of pressure transducer to identify waveform pattern and the pressures. In this article, we propose that trachea and carina can be used as a reliable radiological landmark to identify accidental arterial placement of central venous catheters. We further conclude that this information could be useful especially when dealing with post-resuscitation victims and hemodynamically unstable critically ill patients. PMID- 20972825 TI - Safety of avoiding routine use of axillary dissection in early stage breast cancer: a systematic review. AB - Physicians are moving away from routine axillary lymph node dissection (ALND) in clinically node-negative breast cancer. We conducted a systemic review on the safety of this policy. Pubmed and Cochrane library were searched for. Sixty-eight studies were included: studies of clinically node-negative patients in the pre sentinel node (SN) era; observational studies of SN-negative patients, without ALND; comparative studies of SN-negative patients, with a non-ALND and an ALND group; SN-positive studies, of patients without ALND. Primary endpoint was the pooled axillary recurrence rate (ARR) of each category; secondary endpoint was overall survival (OS) rate. In pre-SN studies, with larger tumors and less systemic therapy, ARR without ALND after 5-10 years follow-up was 12-18%, with 5% reduced OS. In the observational SN-negative studies, with median follow-up of 36 months, the pooled ARR was 0.6% (95% CI 0.6-0.8). In the comparative SN-negative studies, pooled ARR was 0.4% (95% CI 0.2-0.6) without ALND versus 0.3% (95% CI 0.1-0.6) with ALND at 31 and 47 months, respectively, and no survival disadvantage. In SN-positive studies, ARR was up to 1.7% (95% CI 1.0-2.7) at 30 months. For patients with an H&E positive SN the ARR without ALND was 5% after 23 months, which may imply rates as high as 13 and 18% after 5 and 8 years. In conclusion, this systematic review confirms the safety of omitting ALND in SN negative patients. There is a potential role for avoiding ALND in selected SN positive patients, but eligibility criteria and the role of systemic therapy need further to be elucidated. PMID- 20972826 TI - The molecular fingerprint of cardiac dyssynchrony and cardiac resynchronization therapy. AB - To date, cardiac resynchronization therapy remains the only treatment that enhances systolic function while improving long-term outcome and survival. Here, we review the molecular alterations associated with dyssynchronous heart failure and their reversibility induced by cardiac resynchronization therapy. We focus upon the molecular portrait of dyssynchronous heart failure and how cardiac resynchronization therapy influences electrophysiologic, metabolic and adrenergic pathways. PMID- 20972827 TI - Resveratrol inhibits proliferation and promotes apoptosis of neuroblastoma cells: role of sirtuin 1. AB - Resveratrol prolongs lifespan and prevent cancer formation; however, the mechanisms are not understood. Here we evaluated the cell-cycle inhibition and apoptosis of resveratrol in B65 neuroblastoma cells, and we also studied the effects of resveratrol on the mammalian silent information regulator 2 (SIRT1). Results show that resveratrol reduces cell viability and causes apoptosis at 24 h of treatment. Resveratrol partially blocked cell proliferation, and significantly increased the fraction of cells arrested in the S phase. The role of SIRT1 in cell-cycle effects mediated by resveratrol was studied through changes in the expression of SIRT1 using western blot. Exposure to resveratrol decreased SIRT1 content, concomitant with an increase in the acetylated form of sirtuin substrates p53 and NFkappa-beta. Treatment of B65 neuroblastoma cells with resveratrol also reduced the content of the phosphorylated form of AKT. Exposure to the SIRT1 inhibitors nicotinamide and sirtinol altered neither cell viability nor the fraction of apoptotic cells. Furthermore, when cells were exposed simultaneously to resveratrol and nicotinamide or sirtinol, no changes were observed in the fraction of apoptotic cells. Our results show that a decrease in SIRT1 content, caused by exposure to resveratrol, does not appear to be involved in cell-cycle arrest or activation of apoptosis. PMID- 20972828 TI - Tuberoinfundibular peptide of 39 residues- immunoreactive fibers in the zona incerta and the supraoptic decussations terminate in the neuroendocrine hypothalamus. AB - Tuberoinfundibular peptide of 39 residues (TIP39) is expressed by neurons in the subparafascicular area, the posterior intralaminar complex of the thalamus and the pontine medial paralemniscal nucleus. TIP39-positive fibers from these areas do not form individual bundles or fascicles, they join other pathways to reach their innervated brain areas. Fibers arise from TIP39 perikarya located in the subparafascicular area and the posterior intralaminar complex of the thalamus could be followed to the hypothalamus. After uni- and bilateral posterolateral surgical deafferentations of the hypothalamus, accumulation of TIP39 immunoreactivity was observed in the fibers caudal to the knife cut, while it disappeared completely rostral to the transection. In serial sections of the forebrain, we could follow TIP39-ir fibers coursing within the zona incerta and the supraoptic decussations. TIP39-positive fibers that join the incerto hypothalamic pathway reach the medio-dorsal part of the hypothalamus and form moderate to high density networks in the dorsomedial and paraventricular nuclei. The other set of TIP39-positive axons from the subthalamic area join the fibers of the supraoptic decussations and run in an antero-medial direction through the most ventral portion of the hypothalamus up to the retrochiasmatic area, where they crossover. A certain portion of these TIP39-positive fibers terminates in the territories of the arcuate and the medial preoptic nuclei, as well as in the retrochiasmatic area. PMID- 20972830 TI - Peer support within Clubhouse: a grounded theory study. AB - Peer support facilitates recovery. However, little is known about the role of peer support within the Clubhouse model. This article reports on Clubhouse members' experiences of peer support and the outcomes they identify from engaging in this phenomenon. Grounded theory guided the study design involving 17 semi structured interviews conducted with 10 Clubhouse members. Constant comparison and open coding were undertaken to identify underlying concepts within transcripts. A conceptual model of peer support was derived from Clubhouse members' experience. Four levels of peer support emerged: Social inclusion and belonging; shared achievement through doing; interdependency; and at the deepest level, intimacy. Peer support within Clubhouse is a multi-layered construct in terms of depth and nature of relationships. Clubhouse appears to contribute a unique tier within the layered construct of peer support. This tier is based on the sharing of achievement through working together on shared tasks within the work-ordered day Clubhouse structure. PMID- 20972831 TI - Synchronized turbo apoptosis induced by cold-shock. AB - In our research on the role of apoptosis in the pathogenesis of the autoimmune disease systemic lupus erythematosus (SLE), we aim to evaluate the effects of early and late apoptotic cells and blebs on antigen presenting cells. This requires the in vitro generation of sufficiently large and homogeneous populations of early and late apoptotic cells. Here, we present a quick method encountered by serendipity that results in highly reproducible synchronized homogeneous apoptotic cell populations. In brief, granulocytic 32Dcl3 cells are incubated on ice for 2 h and subsequently rewarmed at 37 degrees C. After 30-90 min at 37 degrees C more than 80-90% of the cells become early apoptotic (Annexin V positive/propidium iodide negative). After 24 h of rewarming at 37 degrees C 98% of the cells were late apoptotic (secondary necrotic; Annexin V positive/propidium iodide positive). Cells already formed apoptotic blebs at their cell surface after approximately 20 min at 37 degrees C. Inter-nucleosomal chromatin cleavage and caspase activation were other characteristics of this cold shock-induced process of apoptosis. Consequently, apoptosis could be inhibited by a caspase inhibitor. Finally, SLE-derived anti-chromatin autoantibodies showed a high affinity for apoptotic blebs generated by cold-shock. Overall, cold-shock induced apoptosis is achieved without the addition of toxic compounds or antibodies, and quickly leads to synchronized homogeneous apoptotic cell populations, which can be applied for various research questions addressing apoptosis. PMID- 20972832 TI - Characterization of carotid artery plaques with USPIO-enhanced MRI: assessment of inflammation and vascularity as in vivo imaging biomarkers for plaque vulnerability. AB - To evaluate ultra small superparamagnetic iron oxide particles (USPIO) enhanced magnetic resonance (MR) imaging for characterization of atherosclerotic carotid plaques by assessing vascularity and plaque inflammation, besides contrast enhanced MR angiography (CE-MRA) of the carotid artery stenosis. Twelve patients with severe carotid artery stenosis, scheduled for endarterectomy, underwent MRI of the carotid artery bifurcation using SHU 555 C at a dose of 40 MUmol Fe/kg BW. The MR imaging protocol comprised pre- and post-contrast T2*-w, a first-pass CE MRA and dynamic T1-w sequences. For quantitative data analysis, the signal intensities (SI) were measured and SNR-data (SNR = SI(blood/plaque/bone marrow)/standard deviation(noise)) as well as DeltaSI-data (SNR(post)-SNR(pre)) were calculated. In addition, two radiologists rated the diagnostic performance of first-pass MRA according to a four level decision scale. Staining of anti dextran (SHU 555 C) and anti-CD68 (macrophages) was performed for immunohistological confirmation. Plaque sections with a T2*-w signal decline (intracellular USPIO accumulation in macrophages) showed significantly changes (mean -14%, 95% CI, -5 to -20%; P < 0.01) and corresponding plaque regions had significantly higher (15.15 +/- 1.76 vs. 5.22 +/- 1.50; P < 0.01) T1-w enhancement data (global estimation of vascularity). The first-pass MRA of the supra-aortal vessels provided images of diagnostic quality. Representative immunohistology sections revealed colocalization of dextran- and CD68 immunoreactive cells. USPIO-enhanced MRI is feasible for in vivo assessment of vascularity and macrophage content in atherosclerotic carotid plaques, determining an association of these potential imaging biomarkers of plaque vulnerability. Diagnostic MRA of the supra-aortal vessels can be imaged additionally with a single administration of SHU 555 C. PMID- 20972833 TI - The assessment of Shin's method for the prediction of creatinine kinase-MB elevation after percutaneous coronary intervention: an intravascular ultrasound study. AB - Cardiac enzyme release is common after percutaneous coronary intervention (PCI). At present there is no established relationship between the quantity of necrotic core and dense calcium, as assessed by Shin's method using intravascular ultrasound virtual histology (VH-IVUS), and post-PCI creatinine kinase-MB (CK-MB) elevation. A total of 112 consecutive patients with unstable angina and a normal pre-PCI CK-MB level were imaged using VH-IVUS. Patients were divided into 2 groups according to the presence (CK-MB group, n = 22) or absence (non CK-MB group, n = 90) of a post-PCI CK-MB elevation >1.0 the upper limit of normal (3.6 ng/ml). Using Shin's method contours were drawn around the IVUS catheter (instead of the lumen), and the vessel. Mean area and volume of necrotic core and dense calcium were significantly greater in CK-MB group than in non CK-MB group (1.7 +/ 0.9 mm(2) vs. 0.9 +/- 0.6 mm(2), P < 0.001; 17.2 +/- 8.8 mm(3) vs. 8.8 +/- 5.8 mm(3), P < 0.001, and 0.9 +/- 0.6 mm(2) vs. 0.4 +/- 0.4 mm(2), P = 0.001; 9.1 +/- 5.8 mm(3) vs. 3.9 +/- 3.7 mm(3), P < 0.001, respectively). Percent necrotic core and dense calcium areas calculated by external elastic membrane (EEM) area were significantly greater in CK-MB group than in non CK-MB group (11.9 +/- 5.1 vs. 6.6 +/- 4.0%, P < 0.001 and 6.5 +/- 4.0 vs. 3.0 +/- 2.9%, P < 0.001, respectively). In the multivariate analysis, dense calcium volume and percent necrotic core to EEM at the most diseased segment were the only independent predictors of post-PCI CK-MB elevation (odds ratio: 1.22; 95% confidence interval: 1.09-1.37, P < 0.001 and odds ratio: 1.26; 95% confidence interval: 1.12-1.43, P < 0.001). Lesions with a greater amount of dense calcium volume and percent necrotic core to EEM, which can be easily identified and quantified on VH IVUS analyzed using Shin's method, are responsible for post-PCI CK-MB elevation. With a rapid analyzing time, Shin's method may increase the identification of high risk lesions likely to induce a post-procedural myocardial injury in the catheterization laboratory facilitating on-line clinical decision making. PMID- 20972834 TI - In vitro measurements of flow using multislice computed tomography (MSCT). AB - To examine in vitro whether an assessment of flow in normal and obstructed vessels is essentially possible using modern multislice CT-scanners. An experimental model allowed known stenoses to be perfused at defined flow rates. Aorta and coronary arteries were simulated by silicone tubes. A pulsatile pump was used to perfuse water through the system with intermittent injection of a bolus of radio-opaque contrast agent. CT-measurements were carried out with slice orientation perpendicular to the tubes. 50-90% concentric stenoses were examined 5 times at 4 different stenosis slice distances. A mathematical algorithm calculated the temporal density changes within a ROI in the tube cross-sections. Quantitative assessment of the data simultaneously acquired with the 16-slice system for the "coronary" and "aortal" time-density curves showed that the model allowed for exclusion of a >= 80% stenosis grade with a 99% probability when the slopes of the density increase quotient was > 0.79; a stenosis grade of >= 90% could be excluded when the slopes of the density increase quotient was > 0.52. A Quotient > 0.94 for "peak density" was associated with a 99% probability of a stenosis grade >= 70%. The 64-slice system allowed stenosis grades of >= 80% to be discriminated from lower grades. The general feasibility of the in vitro approach was verified in an in vivo model. The spatial, contrast and temporal resolution of CT scanners with at least 16 detector rows enables qualitative and semiquantitative assessment of stenotic changes in flow. PMID- 20972835 TI - Assessment of acute myocardial infarction: current status and recommendations from the North American society for Cardiovascular Imaging and the European Society of Cardiac Radiology. AB - There are a number of imaging tests that are used in the setting of acute myocardial infarction and acute coronary syndrome. Each has their strengths and limitations. Experts from the European Society of Cardiac Radiology and the North American Society for Cardiovascular Imaging together with other prominent imagers reviewed the literature. It is clear that there is a definite role for imaging in these patients. While comparative accuracy, convenience and cost have largely guided test decisions in the past, the introduction of newer tests is being held to a higher standard which compares patient outcomes. Multicenter randomized comparative effectiveness trials with outcome measures are required. PMID- 20972837 TI - Fusarium sacchari: a cause of exogenous fungal endophthalmitis: first case report and review of literature. AB - A case of exogenous fungal endophthalmitis due to Fusarium sacchari is being reported. It has never been reported in this clinical entity before; hence, to the best of our knowledge, this is first report of F. sacchari as a cause of exogenous fungal endophthalmitis and also the first time when this fungus has been isolated from an Indian patient. PMID- 20972836 TI - Combination efficacy of voriconazole and amphotericin B in the experimental disease in immunodeficient mice caused by fluconazole-resistant Cryptococcus neoformans. AB - The therapeutic efficacy of amphotericin B and voriconazole alone and in combination with one another were evaluated in immunodeficient mice (BALB/c-SCID) infected with a fluconazole-resistant strain of Cryptococcus neoformans var. grubii. The animals were infected intravenously with 3 * 10(5) cells and intraperitoneally treated with amphotericin B (1.5 mg/kg/day) in combination with voriconazole (40 mg/kg/days). Treatment began 1 day after inoculation and continued for 7 and 15 days post-inoculation. The treatments were evaluated by survival curves and yeast quantification (CFUs) in brain and lung tissues. Treatments for 15 days significantly promoted the survival of the animals compared to the control groups. Our results indicated that amphotericin B was effective in assuring longest-term survival of infected animals, but these animals still harbored the highest CFU of C. neoformans in lungs and brain at the end of the experiment. Voriconazole was not as effective alone, but in combination with amphotericin B, it prolonged survival for the second-longest time period and provided the lowest colonization of target organs by the fungus. None of the treatments were effective in complete eradication of the fungus in mice lungs and brain at the end of the experiment. PMID- 20972838 TI - Quality of life in Parkinson's disease patients: validation of the Short-Form Eight-item Parkinson's Disease Questionnaire (PDQ-8) in Taiwan. AB - PURPOSE: This study sought to evaluate the Chinese version of the eight-item Parkinson's Disease Questionnaire (PDQ-8), through standard psychometric techniques. METHODS: A cross-sectional study was conducted on 100 Parkinson's disease patients attending a Movement Disorders Unit. Neurologists' assessments were based on Hoehn and Yahr, Schwab and England and Unified Parkinson's Disease Rating Scales. Patients' self-evaluations included the Taiwanese Depression Questionnaire, the 39-item Parkinson's Disease Questionnaire (PDQ-39) and PDQ-8, pain, and Pittsburgh Sleep Quality Index. Analyses for internal consistency, inter-rater reliability, and construct validity were performed. RESULTS: There was no evidence of floor or ceiling effects. The alpha coefficient was 0.81. Correlation of social support and bodily discomfort with the PDQ-8 was modest (0.46 and 0.36, respectively). PDQ-8 convergent validity with the PDQ-39 was very high (r = 0.96), and known-groups validity proved satisfactory. CONCLUSIONS: The results of this study suggest the PDQ-8 is a valid and reliable disease-specific health-related quality-of-life instrument for Parkinson's disease in Taiwan when used independently of the PDQ-39. PMID- 20972839 TI - Temozolomide for corticotroph pituitary adenomas refractory to standard therapy. AB - To highlight the potential of temozolomide (TMZ) to induce rapid tumor regression in patients with aggressive corticotroph adenomas (CA) that are refractory to surgery and radiation therapy and to review use of TMZ in other pituitary tumors. We present a case of a 56-year-old male with a 3 cm CA treated with transphenoidal surgery (TSS) and conventional radiotherapy in the same year. His hypercortisolemia recurred 11 years later with rapid tumor growth (to 4.2 * 2.5 cm) and he underwent a second TSS with good resection. The tumor recurred 6 months later with ophthalmoplegia. Over 16 months he underwent an additional three surgeries (two TSS, one craniotomy) and repeated conventional radiotherapy. Ki67 staining index on surgical specimens was 5-6%. Temozolomide is an oral alkylating agent approved for glioblastoma multiforme treatment that has only recently shown promise in treating some pituitary tumors. In this patient TMZ was started at 150 mg/m2/day, titrated to 200 mg/m2/day, taken 5 days per month. The only significant side effect was moderate nausea. After 10 weeks, the tumor showed a remarkable 60% regression with objective improvement in ophthalmoplegia. Treatment of aggressive CAs represents a therapeutic challenge and in some cases surgical debulking and radiotherapy are of limited success. Few reports of CAs responsive to TMZ have been reported in the literature. To our knowledge, this case represents the most rapid robust CA shrinkage response reported to date. Further randomized clinical trials of TMZ in the treatment of aggressive pituitary adenomas are warranted. PMID- 20972841 TI - A case of gastritis cystica profunda. PMID- 20972840 TI - Serum opacity factor enhances HDL-mediated cholesterol efflux, esterification and anti inflammatory effects. AB - Serum opacity factor (SOF) is a streptococcal protein that disrupts the structure of human high density lipoproteins (HDL) releasing lipid-free apo A-I while forming a large cholesteryl ester-rich particle and a small neo HDL. Given its low cholesterol and high phospholipid contents, we tested the hypotheses that neo HDL is a better substrate for cholesterol esterification via lecithin:cholesterol acyltransferase (LCAT), better than HDL as an acceptor of THP-1 macrophage cholesterol efflux, and improves reduction of oxidized LDL-induced production of inflammatory markers. We observed that both cholesterol efflux and esterification were improved by recombinant (r)SOF treatment of whole plasma and that the underlying cause of the improved cholesterol esterification in plasma and macrophage cholesterol efflux to rSOF-treated plasma was due to the rSOF-mediated conversion of HDL to neo HDL. Moreover, the reduction of secretion of TNF-alpha and IL-6 by THP-1 cells by neo HDL was twice that of HDL. Studies in BHK cells overexpressing cholesterol transporters showed that efflux to neo HDL occurred primarily via ABCA1 not ABCG1. Thus, rSOF improves two steps in reverse cholesterol transport with a concomitant reduction in the release of macrophage markers of inflammation. We conclude that rSOF catalyzes a novel reaction that might be developed as a new therapy that prevents or reverses atherosclerosis via improved reverse cholesterol transport. PMID- 20972842 TI - Appropriate fluid for intravenous maintenance therapy in hospitalized children- current status. PMID- 20972843 TI - Severe hemolytic disease of newborn due to non Rh D antibody. PMID- 20972844 TI - Sphenoid sinus basaloid squamous cell carcinoma presenting as a sellar mass: report a case with review of the literature. AB - Basaloid squamous cell carcinoma (BSCC) is a distinctive variant of squamous cell carcinoma (SCC) with more aggressive behavior. It occurs preferentially in the upper aerodigestive tract. Sinonasal tract BSCC is uncommon, and only limited studies have been reported in literature. In these studies, most BSCCs arose from the nasal mucosa with or without extension to the paranasal sinuses. Rare reported cases of BSCC involved only the paranasal sinus. In this report, we present a case of a female patient with a sphenoid sinus mass. Clinically, the patient had progressively decreasing vision and headache. Magnetic resonance imaging (MRI) and computerized tomographic (CT) scan showed an infiltrating tumor mass involving the sphenoid sinus and the sella with compression of the optic nerve. Pathologic examination revealed an invasive basaloid epithelial neoplasm that was arranged in lobules, nests and cords. The tumor also showed palisading of peripheral cells, focal abrupt squamous differentiation and in situ carcinoma in the surface mucosa. In the immunohistochemical studies, this tumor revealed a strongly positive nuclear staining for p63. The morphologic and ancillary studies indicated a BSCC. To the best of our knowledge, this is the first report of sinonasal tract BSCC that mainly involved the sphenoid bone and sella. In this region, BSCC should be distinguished from benign and malignant neoplasms that more often affect sella and base of skull, such as pituitary adenoma with extensive necrosis, small cell neuroendocrine carcinoma (SCNC), olfactory neuroblastoma, malignant germ cell tumor, paranasal adenoid cystic carcinoma (ACC), and a variety of metastatic malignancies. PMID- 20972845 TI - Efficacy and safety of flavocoxid compared with naproxen in subjects with osteoarthritis of the knee- a subset analysis. AB - OBJECTIVE: twice-daily flavocoxid, a cyclooxygenase and 5-lipoxygenase inhibitor with potent antioxidant activity of botanical origin, was evaluated for 12 weeks in a randomized, double-blind, active-comparator study against naproxen in 220 subjects with moderate-severe osteoarthritis (OA) of the knee. As previously reported, both groups noted a significant reduction in the signs and symptoms of OA with no detectable differences in efficacy between the groups when the entire intent-to-treat population was considered. This post-hoc analysis compares the efficacy of flavocoxid to naproxen in different subsets of patients, specifically those related to age, gender, and disease severity as reported at baseline for individual response parameters. METHODS: in the original randomized, double-blind study, 220 subjects were assigned to receive either flavocoxid (500 mg twice daily) or naproxen (500 mg twice daily) for 12 weeks. In this subgroup analysis, primary outcome measures including the Western Ontario and McMaster Universities OA index and subscales, timed walk, and secondary efficacy variables, including investigator global assessment for disease and global response to treatment, subject visual analog scale for discomfort, overall disease activity, global response to treatment, index joint tenderness and mobility, were evaluated for differing trends between the study groups. RESULTS: subset analyses revealed some statistically significant differences and some notable trends in favor of the flavocoxid group. These trends became stronger the longer the subjects continued on therapy. These observations were specifically noted in older subjects (>60 years), males and in subjects with milder disease, particularly those with lower subject global assessment of disease activity and investigator global assessment for disease and faster walking times at baseline. CONCLUSIONS: initial analysis of the entire intent-to-treat population revealed that flavocoxid was as effective as naproxen in managing the signs and symptoms of OA of the knee. Detailed analyses of subject subsets demonstrated distinct trends in favor of flavocoxid for specific groups of subjects. PMID- 20972846 TI - Urologists' attitudes regarding information sharing with prostate cancer patients -is there a common ground for collaboration with family physicians? AB - Clinicians often fail to adequately meet prostate cancer patients' information needs, and patients may receive different kinds of information from their doctors. This study aims to describe urologists' attitudes regarding information sharing with prostate cancer patients and to compare these findings with the previously published attitudes of Israeli family physicians. A questionnaire (11 items) was mailed to 87 board-certified practicing urologists. Fifty-four physicians (66%) completed the questionnaires. Sixty-one percent of respondents stated that patients should be told the complete truth about their disease. Ninety-six percent of respondents felt competent at breaking bad news and stated they would discuss emotions with patients. The majority of physicians would provide general information when referring for a medical procedure, discussing treatment options or a patient's prognosis. Fifty-seven percent of respondents preferred that patients be autonomous in their decision making. Only 26% of respondents believed that family physicians should communicate medical information to patients at the preliminary diagnostic stages. There was no significant difference in the attitudes expressed by urologists and family physicians towards the amount of information they would share with prostate cancer patients and in their preferences regarding treatment decision making. Urologists in Israel recognize the importance of sharing information with prostate cancer patients. Although urologists share similar attitudes with family physicians, they do not recognize the role that family physicians play in caring for prostate cancer patients. Further studies are needed to design and implement effective ways to improve the communication and collaboration between urologists and family physicians for the benefit of prostate cancer patients. PMID- 20972847 TI - [Tutankhamun and sickle-cell anaemia]. AB - After casting doubt on malaria as the cause of death for Tutankhamun, the author points out that the hypothesis of homozygotic sickle-cell anaemia, or a double HbS/beta0thal heterozygosis, is hardly more credible. To have any chance of being valid, any such hypothesis would have to involve a combination of at least three rare factors: survival until the age of 19 of a subject with homozygotic sickle cell anaemia, with a probability at birth as to a life expectancy of more than five years probably standing at less than 5%, and with, for all bone sequelae and anomalies, osteonecrosis whose location is characteristic, not of sickle-cell anaemia, but rather of a case of Freiberg-Kohler syndrome, which is also rare, but which is on the other hand fully compatible with the condition of the mummy's skeleton. PMID- 20972849 TI - Pringle maneuver deteriorates gut barrier dysfunction induced by extended-liver radiofrequency ablation. AB - BACKGROUND: Large volume radiofrequency ablation (RFA) of the liver disrupts intestinal mucosa barrier with subsequent bacterial translocation. AIMS: To investigate the effect of the Pringle maneuver applied concurrently with extended liver RFA on gut barrier integrity and bacterial translocation. MATERIALS AND METHODS: Rats were subjected to 30% liver RFA following laparotomy (group RFA), RFA plus 30 min Pringle (group RFA + P), Pringle (group P) or sham operation (group S). Intestinal tissue specimens were excised for histopathological examination and assessment of mucosal morphometry, apoptotic activity, mitotic activity and oxidative state. Tissue specimens were collected from the mesenteric lymph nodes, non-ablated liver parenchyma, kidneys and lungs for bacterial culture. Blood samples were collected from the portal and systemic circulation for endotoxin level measurement. RESULTS: In group RFA + P, intestinal histopathologic lesions, mucosal atrophy and crypt cell apoptosis were more prominent compared to group RFA. Mitotic activity was suppressed. Oxidative stress was equally induced in all experimental groups. The incidence of positive bacterial cultures, bacterial counts and endotoxin levels were higher in group RFA + P compared to the other groups. CONCLUSION: The application of the Pringle maneuver concurrently with extended liver RFA aggravates gut barrier dysfunction with more aggressive translocation of endotoxins and intestinal bacteria. PMID- 20972850 TI - Formal patient education improves patient knowledge of hepatitis C in vulnerable populations. AB - BACKGROUND: Hepatitis C (HCV) knowledge is limited in injection drug users (IDU). Vulnerable populations including IDUs are disproportionally affected by HCV. Effective HCV education can potentially reduce disparity in HCV prevalence and its outcome in this population. AIM: This study aimed to assess the impact of formal HCV education and factors associated with improved HCV knowledge in the vulnerable population. METHODS: Over 18 months, 201 HCV-infected patients underwent a 2-h standardized education and completed demographic and pre- and post-education questionnaires. RESULTS: Patient characteristics were: 69% male, mean age 49+/-10, 49% White (26% AA, 10% Latino), 75% unemployed, 83% high school education and above, 64% were IDU, and 7% were HIV co-infected. On multivariate analysis, baseline knowledge scores were higher in patients with at least a high school education (coef 7.1, p=0.045). Baseline knowledge scores were lower in African Americans (coef -12.3, p=0.004) and older patients (coef -0.7, p=0.03). Following HCV education, the overall test scores improved significantly by 14% (p=0.0001) specifically in the areas of HCV transmission (p=0.003), general knowledge (p=0.02), and health care maintenance (p=0.004). There was a high compliance with liver specialty clinic attendance following education. CONCLUSIONS: Formal HCV education is effective in improving HCV knowledge. Although White race, younger age, and higher education were predictors of having more HCV knowledge prior to education, all patients independent of racial background had a significant improvement in their knowledge after education. Therefore, promoting effective HCV education among vulnerable populations may be an important factor in reducing the disparities in HCV disease. PMID- 20972851 TI - Obese patients have stronger peristalsis and increased acid exposure in the esophagus. AB - BACKGROUND: Obesity is a risk factor for GERD and a potential modulator of esophageal motility. AIM: To assess whether obese patients differ from non-obese patients in terms of esophageal motility and reflux. METHODS: Patients (n = 332) were categorized in GERD and controls after clinical assessment, esophageal manometry, and pH monitoring. Non-obese (BMI 16-29.9) and obese (BMI 30-68) were compared in regard of distal esophageal amplitude (DEA), LES pressure (LESP), manometric diagnosis, and esophageal acid exposure (EAE). RESULTS: Obese showed higher DEA in both controls (122 +/- 53 vs. 97 +/- 36 mmHg, p = 0.041) and GERD patients (109 +/- 38 vs. 94 +/- 46 mmHg, p < 0.001), higher LESP in GERD patients (20.5 +/- 10.6 vs. 18.2 +/- 10.6 mmHg, p = 0.049), higher frequency of nutcracker esophagus in controls (30 vs. 0%, p = 0.001), lower frequency of ineffective motility in GERD patients (6 vs. 20%, p = 0.001), and higher EAE in both controls [total EAE: 1.6% (0.7-5.1) vs. 0.9% (0.2-2.4), p = 0.027] and GERD patients [upright EAE: 6.5% (3.8-11.1) vs. 5.2% (1.5-10.6), p = 0.048]. Multiple linear regression showed that BMI was associated either with EAE (p < 0.001), DEA (p = 0.006), or LESP (in men, p = 0.007). CONCLUSIONS: Obese patients differed from non-obese in terms of esophageal motility and reflux, regardless of the presence of GERD. Obese patients showed stronger peristalsis and increased acid exposure in the esophagus. PMID- 20972852 TI - Esophageal stenting for leaks and strictures: a benign intervention for a benign indication? PMID- 20972853 TI - Variations in healthcare access and utilization among Mexican immigrants: the role of documentation status. AB - The objective of this study is to identify differences in healthcare access and utilization among Mexican immigrants by documentation status. Cross-sectional survey data are analyzed to identify differences in healthcare access and utilization across Mexican immigrant categories. Multivariable logistic regression and the Blinder-Oaxaca decomposition are used to parse out differences into observed and unobserved components. Mexican immigrants ages 18 and above who are immigrants of California households and responded to the 2007 California Health Interview Survey (2,600 documented and 1,038 undocumented immigrants). Undocumented immigrants from Mexico are 27% less likely to have a doctor visit in the previous year and 35% less likely to have a usual source of care compared to documented Mexican immigrants after controlling for confounding variables. Approximately 88% of these disparities can be attributed to predisposing, enabling and need determinants in our model. The remaining disparities are attributed to unobserved heterogeneity. This study shows that undocumented immigrants from Mexico are much less likely to have a physician visit in the previous year and a usual source of care compared to documented immigrants from Mexico. The recently approved Patient Protection and Affordable Care Act will not reduce these disparities unless undocumented immigrants are granted some form of legal status. PMID- 20972854 TI - Hepatocellular carcinoma in the caudate lobe of the liver: variations of its feeding branches on arteriography. AB - There are usually multiple caudate arteries arising from the right, left, and middle hepatic arteries, and they are frequently connected to each other. Therefore, hepatocellular carcinoma (HCC) in the caudate lobe is frequently fed by multiple branches arising from different origins. HCC located in the Spiegel lobe is usually fed by the caudate arteries derived from the right and/or left hepatic artery. HCC in the paracaval portion is mainly fed by the caudate artery derived from the right hepatic artery; with low frequency, it is fed by the caudate artery derived from the left hepatic artery. HCC in the caudate process is usually fed by the caudate artery derived from the right hepatic artery. Because of the complexity and overlap of vascular territories, the tumor-feeding branch of a recurrent HCC lesion in the caudate lobe frequently changes on follow up arteriograms. In addition, several extrahepatic collateral vessels supply the recurrent tumor. To perform effective transcatheter arterial chemoembolization (TACE) for HCC in the caudate lobe, radiologists should have sufficient knowledge of vascular anatomy supplying HCC in the caudate lobe. PMID- 20972855 TI - Comparison of magnetic resonance imaging and multidetector computed tomography for evaluating intraductal tumor extension of breast cancer. AB - Magnetic resonance imaging (MRI) and computed tomography (CT) can be used for pretreatment evaluation of intraductal tumor extension of breast cancer. Images of intraductal tumor extension obtained by MRI and multidetector CT (MDCT) are shown to illustrate the similarities and differences in the imaging features of these two techniques. MRI is an excellent tool and MDCT is a fair one for evaluating intraductal tumor extension of breast cancer. PMID- 20972856 TI - Accurate measurement of pulsatile flow velocity in a small tube phantom: comparison of phase-contrast cine magnetic resonance imaging and intraluminal Doppler guidewire. AB - PURPOSE: We compared the accuracy of magnetic resonance imaging (MRI) measurements of pulsatile flow velocity in a small tube phantom using different spatial factors versus those obtained by intraluminal Doppler guidewire examination (as reference). MATERIALS AND METHODS: We generated pulsatile flow velocities averaging about 20-290 cm/sec in a tube of 4 mm diameter; we performed phase-contrast cine MRI on pixels measuring 1.00(2)-2.50(2) mm(2). We quantified spatial peak flow velocities of a single pixel and a cluster of five pixels and spatial mean velocities within regions of interest enclosing the entire lumen in the phantom's cross-section. Finally, we compared the measurements of temporally mean and maximum flow velocity with the Doppler measurements. RESULTS: Linear correlation was excellent between both measurements of spatial peak flow velocities in one pixel. The highest spatial resolution using spatial peak flow velocities of a single pixel allowed the most accurate MRI measurements of both temporally mean and maximum pulsatile flow velocity (r = 0.97 and 0.99, respectively: MRI measurement = 0.95x + 8.9 and 0.88x + 24.0 cm/s, respectively). Otherwise, MRI measurements were significantly underestimated at lower spatial resolutions. CONCLUSION: High spatial resolution allowed accurate MRI measurement of temporally mean and maximum pulsatile flow velocity at spatial peak velocities of one pixel. PMID- 20972857 TI - Apparent diffusion coefficient measurement in a moving phantom simulating linear respiratory motion. AB - PURPOSE: The aim of this study was to examine the effect of simulated linear respiratory motion on apparent diffusion coefficient (ADC) measurements. MATERIALS AND METHODS: Six rectangular test tubes (14 * 92 mm) filled with either water, tomato ketchup, or mayonnaise were positioned in a box containing agarose gel. This box was connected to a double-acting pneumatic cylinder, capable of inducing periodic linear motion in the long-axis direction of the magnetic bore (23-mm stroke). Diffusion-weighted magnetic resonance imaging was performed for both the static and moving phantoms, and ADC measurements were made in the six test tubes in both situations. RESULTS: In the three test tubes whose long axes were parallel to the direction of motion, ADCs agreed well between the moving and static phantom situations. However, in two test tubes that were filled with fluids that had a considerably lower diffusion coefficient than the surrounding agarose gel, and whose long axes were perpendicular to the direction of motion, the ADCs agreed poorly between the moving and static phantom situations. CONCLUSION: ADC measurements of large homogeneous structures are not affected by linear respiratory motion. However, ADC measurements of inhomogeneous or small structures are affected by linear respiratory motion due to partial volume effects. PMID- 20972858 TI - Application of (18)F-fluorodeoxyglucose positron emission tomography to detection of proximal lesions of obstructive colorectal cancer. AB - PURPOSE: In cases of obstructive colorectal cancer (CRC), preoperative diagnosis of the proximal lesion is often difficult when the primary lesion impedes the passage of the endoscope. The aim of this study was to evaluate the usefulness of fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in such cases. MATERIALS AND METHODS: A total of 52 obstructive CRC patients who underwent preoperative FDG-PET and subsequent surgical resection were retrospectively reviewed. The correlation between characteristics of the proximal lesion and FDG-PET findings was analyzed statistically. RESULTS: There was a significant correlation between the proximal lesion size and the maximum standardized uptake value (P = 0.00016). Abnormal FDG accumulation in the proximal colon indicated the existence of proximal cancer or adenoma with a sensitivity of 50% and a specificity of 100%. There was a significant difference in the distribution of tumor size between the cases with proximal abnormal accumulation and those with no proximal accumulation (P = 0.00014). A proximal tumor of >=8 mm can be demonstrated by an accumulation of FDG with a sensitivity of 94.1%. CONCLUSION: FDG-PET can estimate the existence of a proximal lesion and its size. Results may contribute to decisions regarding the type of surgery in cases of obstructive CRC. PMID- 20972859 TI - Segmental acquisition method for stationary objects in (18)F-fluorodeoxyglucose positron emission tomography tests. AB - PURPOSE: We investigated whether images of stationary objects obtained by segmental acquisition with positron emission tomography using 2-deoxy-2-[(18)F] fluoro-D: -glucose (FDG-PET) are of a quality equivalent to those obtained by conventional continuous acquisition. MATERIALS AND METHODS: Phantoms filled with FDG and mid-abdominal regions of 18 patients who underwent FDG-PET tests were imaged by both continuous and segmental acquisition methods. The total acquisition time was set to 3 min; in the segmental acquisition mode, imaging for 15 s was repeated 12 times. Segmental images (SIs) obtained by superimposition of the reconstructed images were compared quantitatively and visually with continuous images (CIs). RESULTS: In all the phantom and clinical studies, SIs were never worse than CIs. The variances of the background counts of SIs were 9.8% and 13.0% less those of CIs in phantom and clinical studies, respectively. Visual assessments showed that SIs provided better detection of hot areas and superior image quality when compared to CIs. CONCLUSION: For stationary objects, the quality of images obtained by the segmental method is equivalent to that of images obtained conventionally by continuous acquisition. Moreover, under some conditions SIs provide better results than CIs. PMID- 20972860 TI - Malignant solitary fibrous tumor of the pleura: computed tomography-pathological correlation and comparison with computed tomography of benign solitary fibrous tumor of the pleura. AB - PURPOSE: The aim of this study was to determine the computed tomography (CT) pathological correlation of malignant solitary fibrous tumors of the pleura (MSFP) and to compare these findings with CT findings of benign solitary fibrous tumors of the pleura (BSFTP). MATERIALS AND METHODS: We retrospectively identified the clinical, CT, and pathological findings in seven cases of MSFP. There was a CT-pathological correlation for the MSFPs. Additionally, 12 cases of BSFTP from case files were compared with the clinical and CT features of the MSFPs. RESULTS: On CT, the MSFP appeared as a heterogeneously enhancing mass >10 cm (100%). Pleural metastasis (57.1%) and lung metastasis (14.3%) were associated. In the CT-pathological correlation, the enhancing area was mixed cellular and collagenous tissue with hypercellularity, mitosis, and pleomorphism. Hemorrhage, necrosis, cystic, or myxoid degeneration produced areas of intratumoral low attenuation. MSFPs showed a higher incidence of intratumoral low attenuation areas (P = 0.034) and pleural metastasis (P = 0.009); and on CT, MSFPs tended to be larger than BSFTPs (P = 0.076). CONCLUSION: MSFPs showed a >10 cm pleural mass with low-attenuation regions on CT, which corresponded to hemorrhage, necrosis, cystic, or myxoid degeneration. MSFPs had a higher incidence of intratumoral low-attenuation areas and pleural metastasis, and on CT they tended to be larger than BSFTPs. PMID- 20972861 TI - Magnetic resonance imaging findings of fibroepithelial polyp of the vulva: radiological-pathological correlation. AB - We describe the magnetic resonance (MR) imaging findings in a 20-year-old woman with a fibroepithelial polyp of the vulva. Within the lesion, abundant fibrous tissue was visualized as stratiform hypointense areas on T2-weighted magnetic resonance imaging (MRI) scans. At the center of the attachment site, clustered fatty tissue was revealed as linear hyperintense areas on T1-weighted MRI. A mild degree of edematous stroma including less fibrosis and cellularity was demonstrated as hyperintense areas on T2-weighted MRI and hypointense areas on T1 weighted MRI. Although the MRI findings of fibroepithelial polyps of the vulva are often similar to those of aggressive angiomyxoma, angiomyofibroblastoma, and cellular angiofibroma, a fibroepithelial polyp should be considered when radiological images demonstrate the following features: stratiform hypointense areas surrounded by patchy hyperintense areas on T2-weighted MRI and hyperintense areas on T1-weighted MRI. PMID- 20972862 TI - Fibroadenoma of the axillary accessory breast: diagnostic value of dynamic magnetic resonance imaging. AB - Accessory breast is synonymous with polymastia or supernumerary breast tissue. An accessory breast without a nipple or areola is rare. We report a case of fibroadenoma of an accessory breast with no nipple or areola in a 41-year-old woman who presented with a right axillary mass associated with five small nodules in the normally situated breast. Magnetic resonance imaging (MRI) showed the accessory breast surrounding the tumor. We ignored the presence of the component surrounding the mass and made a preoperative diagnosis of an axillary mass of possible metastases from multiple breast cancers or breast cancer of unknown origin associated with multiple breast fibroadenomas. From a retrospective view, based on the histological results, MRI and dynamic MRI demonstrated a tiny component of breast-like tissue surrounding the axillary mass and an enhancement pattern typical of fibroadenoma for the axillary mass. For the later diagnosis of the axillary mass, the interpretation of whether the component of breast tissue surrounding the axillary mass was present is crucial. If the component exists, a tumor that originated from the accessory breast should be foremost in the differential diagnosis. Dynamic MRI appears to contribute to the diagnosis of fibroadenoma of an accessory breast before biopsy or surgical resection. PMID- 20972863 TI - Epithelial-myoepithelial carcinoma of the parotid gland: correlation of dynamic magnetic resonance imaging, (18)F-fluorodeoxyglucose-positron emission tomography, and pathological findings. AB - We encountered two cases of epithelial-myoepithelial carcinoma (EMC), a rare low grade malignant tumor of the parotid gland. These two EMCs showed similar imaging findings: gradual contrast enhancement on dynamic magnetic resonance imaging (MRI), intense (18)F-fluorodeoxyglucose (FDG) uptake in the solid tumor portion, and little enhancement and little FDG uptake in the hemorrhagic necrotic tumor portion. When a parotid gland tumor shows gradual MRI contrast enhancement and focally intense FDG uptake, EMC should be included in the differential diagnosis. PMID- 20972864 TI - Magnetic resonance elastography of the liver: preliminary results and estimation of inter-rater reliability. AB - PURPOSE: The aim of this study was to estimate inter-rater reliability and validate magnetic resonance elastography (MRE) as a tool to measure liver elasticity. MATERIALS AND METHODS: The study protocol was approved by the institutional review board at our institution. In all, 10 normal volunteers and 110 patients, who provided written informed consent, were enrolled. The pathological fibrosis score was applied as a standard reference of liver fibrosis in 21 patients. MRE was performed with a 1.5-T magnetic resonance imaging scanner with a cylindrical passive longitudinal shear wave driver placed over the right chest wall to deliver vibrations. A gradient-echo MRE sequence was used to acquire axial wave images, which were automatically converted to elastograms representing elasticity (in kilopascals, or kPa). The region of interest was placed in the right lobe of the liver on elastograms by two raters independently. To evaluate interrater reliability, the intraclass correlation coefficient was calculated. The elasticity measurements correlated with the pathological fibrosis score (F1-F4) in 21 patients. RESULTS: The intraclass correlation coefficient was almost perfect (0.993) between the elasticities measured by the two raters. The mean elasticity value for patients with F4 was 5.7 kPa; F3, 4.4 kPa; F2, 3.1 kPa; F1, 2.2 kPa; and F0, 2.1 kPa. CONCLUSION: MRE is a reliable tool to measure liver elasticity. PMID- 20972865 TI - Cadmium, copper, iron, and zinc concentrations in kidneys of grey wolves, Canis lupus, from Alaska, Idaho, Montana (USA) and the Northwest Territories (Canada). AB - Cadmium, copper, iron, and zinc levels were measured in the kidneys of 115 grey wolves (Canis lupus) from Idaho, Montana and Alaska (United States), and from the Northwest Territories (Canada). No significant differences in the levels of iron or copper were observed between locations, but wolf kidneys from more northern locations had significantly higher cadmium levels (Alaska > Northwest Territories > Montana ~ Idaho), and wolves from Alaska showed significantly higher zinc than other locations. Additionally, female wolves in Alaska had higher iron levels than males, and adult wolves in Montana had higher copper levels than subadults. PMID- 20972866 TI - Hemoptysis in a teenager with congenital heart disease. PMID- 20972867 TI - Long-term outcome of sirolimus-eluting stent implantation for left main coronary artery stenosis in infancy. AB - Drug-eluting stents (DES) have markedly reduced the incidence of coronary in stent restenosis. However, DES may be still vulnerable to coronary thrombus, and the long-term outcome remains unknown, especially in infancy. Here, we present a 9-month-old infant, who developed severe stenosis of the left main coronary artery after surgery for Brand-White-Garland syndrome, and was successfully treated with DES. He was healthy and his cardiac function had improved to the normal level at 6 years old. An angiographic examination and computed tomography showed the complete persistence of DES and no evidence of intimal thickening. PMID- 20972868 TI - Brain maturity and brain injury in newborns with cyanotic congenital heart disease. AB - Patients with congenital heart disease (CHD) are at high risk for adverse neurodevelopmental outcomes. The aim of this work was to assess brain maturity and brain injury in newborns with cyanotic CHD using proton magnetic resonance spectroscopy (MRS). The study included 38 newborns with cyanotic CHD (study group) and 20 healthy full-term newborns (control group) matched together regarding gestational age and sex. Three-dimensional MRS showed that the mean ratio of N-acetylaspartate to choline (Ch) was significantly lower in newborns with cyanotic CHD (0.55 +/- 0.08) compared with controls (0.67 +/- 0.11) (p < 0.001). However, the mean ratio of lactate to Ch metabolite was significantly higher in the studied cases (0.14 +/- 0.04) compared with controls (0.09 +/- 0.04) (p < 0.001). The mean value for average diffusivity was 1.41 +/- 0.06 in newborns with cyanotic CHD compared with 1.27 +/- 0.07 in control newborns (p < 0.001), and the mean value for white-matter fractional anisotropy was 0.19 +/- 0.03 in cyanotic newborns and 0.25 +/- 0.08 in controls (p < 0.001). Newborns with cyanotic CHD are at increased risk of cerebral white matter injury as well as poor brain maturity. MRS provides a surrogate marker for early detection of such brain abnormalities. PMID- 20972869 TI - Isolated intra-articular pseudorheumatoid nodule of the knee. AB - The authors describe a case of an isolated intra-articular pseudorheumatoid nodule of the knee in an 18-year-old male patient without a diagnosis of rheumatoid arthritis. The patient initially presented with a 3 year history of anterior knee pain and was found to have a 2.8 * 2.1 cm lobulated soft-tissue mass. Histologic findings showed fibrinoid necrosis and chronic inflammatory changes that were consistent with those of a pseudorheumatoid or rheumatoid nodule, and surgical excision of the nodule was curative. A review of the literature revealed no prior cases of an intra-articular pseudorheumatoid nodule or rheumatoid nodule in a patient without clinical or serologic evidence of rheumatoid arthritis. PMID- 20972870 TI - Gorham-Stout disease: the experience of the Rizzoli Institute and review of the literature. AB - Gorham-Stout disease (also known as "disappearing bone disease") was first described by Jackson in 1838, but was properly defined by Gorham and Stout in a series of 24 patients in 1954-1955. It is a rare disease of unknown etiology (about 200 cases reported in the literature) characterized by spontaneous progressive resorption of bone without malignant proliferation of vascular structures. The diagnosis is one of exclusion and it is based on combined histological, radiological, and clinical features. Benign vascular proliferation with fatty bone marrow and thinning of bony trabeculae is a typical histological feature. Standard radiographs of disappearing bone disease show progressive bony resorption with adjacent soft tissue involvement. Most cases of Gorham-Stout disease resolve spontaneously, but prognosis remains unpredictable. This study reports 13 cases of Gorham-Stout disease treated in our institution from 1968 to 2008. The aim of the work was to review our series and the literature on this rare disease, as well as to evaluate whether or not an optimal treatment can be identified and recommended. PMID- 20972871 TI - Review of common and unusual causes of lateral ankle pain. AB - Lateral ankle pain is a common clinical presentation having several important causes, including lateral ligament injury, peroneal tendon injury, sinus tarsi syndrome, and nerve entrapments. However, other causes should be kept in mind in patients with unusual patterns of pain or intractable symptoms. We present a review of common and some unusual causes of lateral ankle pain including a review of post-operative imaging findings following surgery for lateral ankle ligament and peroneal tendon injuries. PMID- 20972872 TI - Clinical impact of K-ras mutation in colorectal cancer patients treated with adjuvant FOLFOX. AB - BACKGROUND: K-ras proto-oncogene is commonly mutated in colorectal cancer (CRC) and has been associated with predictive markers for anti-EGFR (epidermal growth factor receptor) therapy. However, the prognostic role of K-ras status is still unclear. The aim of this study was to evaluate the association between k-ras status and addition of oxaliplatin to fluorouracil plus leucovorin (FOLFOX) chemotherapy in CRC patients with curative surgical resection. METHODS: Sixty-six patients with stage II or III CRC were treated with FOLFOX or fluorouracil plus leucovorin (FL) followed by curative surgery between January 2004 and October 2007. K-ras status was assessed by direct sequencing. RESULTS: Fifteen patients (22.7%) had K-ras mutations of codon 12 (11/15) or codon 13 (4/15). There were no significant differences in clinicopathological parameters, such as age, sex, stage, or adjuvant regimen between the wild-type K-ras and mutant K-ras. With a median follow-up of 41.6 months (range 25.1-72.3 months), median disease-free survival (DFS) and overall survival (OS) were not reached. With regard to K-ras status, DFS and OS were not statistically different (P = 0.269 and P = 0.917, respectively). Even in the group treated with FOLFOX only, neither DFS (P = 0.651) nor OS (P = 0.265) was significantly different according to K-ras status. With the exception of tumor location in DFS and OS, no differences in other variables were observed. Proximal colon cancer patients had a longer DFS than distal CRC patients (P = 0.079); this trend was maintained only in the wild-type K-ras group (P = 0.051). CONCLUSIONS: These results showed that K-ras status was not associated with clinical outcome in patients treated with adjuvant FOLFOX. PMID- 20972873 TI - Phase I and pharmacokinetic study of lonafarnib, SCH 66336, using a 2-week on, 2 week off schedule in patients with advanced solid tumors. AB - PURPOSE: This phase I study was performed to determine the safety profile, maximum tolerated dose (MTD) and biological activity of lonafarnib (SCH 66336). Single-dose and multi-dose pharmacokinetics were conducted. METHODS: Twenty-one patients with advanced solid tumors were enrolled. Each patient received single dose administration on day 1, cycle 1 then switched to a twice daily (BID) dosing regimen on days 2-14 of a 28-day cycle; subsequent cycles continued BID dosing on days 1-14. Dose-limiting toxicity (DLT) was assessed during the cycle one; toxicity evaluation was closely monitored throughout the treatment. Radiographic scans were completed to assess tumor response. Blood and urine pharmacokinetics were evaluated on days 1 and 14 in cycle 1. SCH 66336- induced farnesylation inhibition was assessed via conversion of prelamin A to lamin in buccal mucosa. RESULTS: DLT and most common adverse events were diarrhea, fatigue, nausea and anorexia. No grade 3 or 4 hematological toxicities were observed. Nineteen of 21 patients were evaluable for response; short-term stable disease was observed in 5 patients. SCH 66336 systemic exposure increased with dose; however, drug accumulation was higher than projected. Renal excretion of parent drug was negligible. Farnesyl transferase inhibition was detected at the 200 and 300 mg BID doses. CONCLUSION: The MTD and recommended phase II dose is 200 mg BID on days 1-14 of a 28-day dosing regimen. The plasma concentration profile suggests the pharmacokinetics of SCH 66336 is dose and time dependent. Farnesyl transferase target inhibition was observed at doses of lonafarnib recommended for further study. PMID- 20972874 TI - The PI-3 kinase-Akt-MDM2-survivin signaling axis in high-risk neuroblastoma: a target for PI-3 kinase inhibitor intervention. AB - PURPOSE: Studies of SF1126, an RGDS targeted, water-soluble prodrug of LY294002, are currently nearing completion in two adult Phase I trials. Herein, we performed a preclinical evaluation of SF1126 as a PI-3K inhibitor for Phase I trials in the treatment of recurrent neuroblastoma (NB). METHODS: The effects of SF1126 on pAkt-MDM2 cell signaling, proliferation, apoptosis, and migration were determined using a panel of NB cell lines, and anti-tumor activity was determined using a xenograft model of NB. RESULTS: SF1126 blocks MDM2 activation, IGF-1 induced activation of Akt, and the upregulation of survivin induced by IGF-1. It also increases sensitivity to doxorubicin in vitro and was found to exhibit marked synergistic activity in combination with doxorubicin. Treatment disrupts the integrin alphavbeta3/alphavbeta5-mediated organization of the actin cytoskeleton as well as the alpha4beta1/alpha5beta1-mediated processes essential to metastasis. In vivo, SF1126 markedly inhibits tumor growth in NB xenografted mice (P < 0.05). CONCLUSIONS: A pan PI-3 kinase inhibitor has potent antitumor activity and induces apoptosis in multiple neuroblastoma cell lines. The observed effects of SF1126 on the p-Akt-MDM2-survivin axis suggest a patient selection paradigm in which NB tumors with increased pAkt-MDM2-survivin signaling may predict response to SF1126 alone or in combination with standard chemotherapy regimens that contain anthracyclines. PMID- 20972875 TI - Preliminary study of the types of traumatic peripheral nerve injuries by ultrasound. AB - OBJECTIVES: To investigate the types of traumatic peripheral nerve injuries by ultrasound (US). To demonstrate the efficacy of US in case of peripheral nerve injuries and, in particular, its importance of demonstrating and monitoring the appearances of the nerve itself. METHODS: Two hundred and two patients, of which 117 subsequently underwent operative treatment, were prospectively examined by US in such a way that the transducer was moved to the nerve damaged region from the normal nerve located near a known anatomical landmark. The ultrasound features of the traumatic peripheral nerve injuries were classified according to abnormal fascicle, perineurium, epineurium, and peripheral tissues of peripheral nerve. RESULTS: The ultrasound features of the traumatic peripheral nerve injuries were classified into 7 types. In the 117 cases that underwent operative treatment, the accuracy of classification by using US was 93.2%. CONCLUSIONS: Ultrasound seems to be a valuable investigation for evaluating the type of traumatic peripheral nerve injury. PMID- 20972876 TI - Impact of minimising door-to-balloon times in ST-elevation myocardial infarction to less than 30 min on outcome: an analysis over an 8-year period in a tertiary care centre. AB - BACKGROUND: Guidelines recommend door-to-balloon times (DBTs) below 60 min for patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). The purpose of this study was to determine if an optimised STEMI-protocol reduces DBT and increases the number of patients to receive PCI within 60 min of hospital presentation. We hypothesised that DBT of <30 min can be accomplished for the majority of patients. METHODS AND RESULTS: Between 2001 and 2008 data from 1,146 consecutive patients with acute STEMI admitted for primary PCI within 12 h after symptom-onset were analysed. Times to angioplasty from symptom-onset (pain-to-balloon time, PBT) and from hospital arrival (DBT) to PCI and clinical outcomes were analysed. In the end of 2003 numerous strategies were implemented to reduce revascularisation times. These strategies resulted in a stable reduction of median DBT to 29 min [interquartile range (IQR) 22-39]. Overall, 94% of patients had median DBT < 60 min and 56% <30 min. Consequently, PBT was significantly reduced from median 218 min (IQR 168-286) to 167 min (IQR 119-245) for non-transferred patients. Major cardiac adverse events (composite of congestive heart failure, reinfarction and cardiac death) were significantly associated with DBT > 30 min and age, systolic blood pressure, anterior infarction, PBT > 4 h, cardiogenic shock as well as multivessel disease. CONCLUSIONS: A dedicated STEMI-protocol including several hospital strategies is feasible during daily clinical practice to decrease revascularisation times, results in a greater proportion of patients achieving guideline recommendations, and is associated with an improved clinical outcome. PMID- 20972877 TI - Effect of PAR2 in regulating TNF-alpha and NAD(P)H oxidase in coronary arterioles in type 2 diabetic mice. AB - Protease-activated receptor-2 (PAR2) is expressed in endothelial cells and mediates endothelium-dependent vasodilation. We hypothesized that PAR2 regulates tumor necrosis factor-alpha (TNF-alpha)-induced coronary arteriolar dysfunction in type 2 diabetic (db/db) mice. To test this, coronary arterioles from WT control, db/db, db/db mice treated with PAR2 antagonist FSLLRY-NH2 (db/db+FSLLRY NH2) and db/db mice null for TNF (db(TNF-)/db(TNF-)) were isolated and pressurized (60 cmH2O) without flow. Although vasodilation to the endothelium independent vasodilator sodium nitroprusside (SNP) was not different among WT, db/db, db/db+FSLLRY-NH2 and db(TNF-)/db(TNF-), endothelium-dependent acetylcholine (ACh)- and flow-mediated vasodilation were impaired in db/db mice but were enhanced in db(TNF-)/db(TNF-) mice and db/db mice treated with PAR2 antagonist. NOS inhibitor N (G)-nitro-L-arginine-methyl ester (L-NAME) significantly reduced ACh-induced dilation in WT, db(TNF-)/db(TNF-) and db/db+FSLLRY-NH2, but did not alter the vasodilation in db/db mice. In contrast, cyclooxygenase (COX) inhibitor indomethacin (Indo) did not alter ACh-induced vasodilation in these four groups of mice. PAR2-activating peptide (PAR2-AP, 2 Furoyl-LIGRLO-am)-induced dilation was higher in db/db mice than that in WT, db(TNF-)/db(TNF-) and db/db mice treated with PAR2 antagonist. These effects were abolished by denudation, or in the presence of L-NAME or Indo. Protein expressions of TNF-alpha, PAR2, gp91(phox) and p47(phox) in the heart and isolated coronary arterioles were higher in db/db mice compared to WT mice. Administration of PAR2 antagonist to db/db mice reduced protein expression of TNF alpha, gp91(phox) and PAR2. Protein expression of gp91(phox) and p47(phox) was lower in db(TNF-)/db(TNF-) compared to db/db mice. These results indicate that PAR2 plays a pivotal role in endothelial dysfunction in type 2 diabetes by up regulating the expression/production of TNF-alpha and activating NAD(P)H oxidase subunit p47(phox). PMID- 20972878 TI - Effect of low-intensity resistance training on arterial function. AB - Although high-intensity resistance training increases central arterial stiffness, moderate-intensity resistance training does not. However, the effects of low intensity resistance training on arterial stiffness are unknown. The aim of this study was to investigate the effect of low-intensity resistance training with short inter-set rest period (LSR) on arterial stiffness. Twenty-six young healthy subjects were randomly assigned to training (10 males, 3 females) and control groups (9 males, 4 females). The subjects performed LSR twice a week at 50% of one repetition maximum for 10 weeks. Training consisted of five sets of ten repetitions with an inter-set rest period of 30 s. Changes in brachial-ankle pulse wave velocity (baPWV) and brachial flow-mediated dilation (FMD) were assessed before and after the intervention period. After the intervention period, one repetition maximum strength increased (by 9-38%, P < 0.05 to <0.001; increases varied among the exercise types), baPWV decreased (from 1,093 +/- 148 to 1,020 +/- 128 cm/s, P < 0.05), and brachial FMD increased (from 9.7 +/- 1.3 to 11.8 +/- 1.9%, P < 0.05). These values did not change in the control group. These results suggest that LSR reduced arterial stiffness and improved vascular endothelial function. PMID- 20972879 TI - The incidence of stress symptoms and heart rate variability during sleep and orthostatic test. AB - This study examined the relation of self-reported stress to cardiac autonomic modulation in real-life conditions. The participants for the study were healthy male (N = 59) and female (N = 40) employees (age 40 +/- 10 years). A single-item question and a 14-item questionnaire on perceived stress were administered to the participants before the experimental night. RR-intervals (RRI) were recorded during night sleep and an orthostatic test after awakening at home. The RRI data were analyzed for heart rate (HR) and heart rate variability (HRV) in time and frequency domains. Nocturnal urinary stress hormone (cortisol, adrenal and noradrenal) secretion was also analyzed. Based on the self-reported stress, the participants were divided into either low or high stress group. The results showed that higher incidence of stress symptoms was significantly associated with lower HRV in the orthostatic test regardless of age and gender. Differences between the stress groups in HRV indices were approximately 20-50 and 30-75% in supine and standing positions, respectively. No difference was found in nocturnal HR, HRV, or stress hormone secretion between the stress groups. Higher incidence of stress symptoms was significantly associated with greater decrease of HRV from night sleep to the orthostatic test, as a response to awakening. In conclusion, the present findings support the view that autonomic modulation measured in the orthostatic test, but not during night sleep, is related to self-reported stress. PMID- 20972880 TI - Validation of the SenseWear Armband at high intensity exercise. AB - The SenseWear Armband (SWA) has been shown to be a valid and practical tool to assess energy expenditure during habitual physical activity. However, previous studies have focused on low-to-moderate intensity activities. The purpose of this study was to assess the validity of the SWA during high intensity exercise. Twenty (ten males, ten females) endurance trained subjects, 24.3 (+/-2.8) years of age, performed three 10-min treadmill runs at 65, 75, and 85% of their VO(2max) each and also ran outside for 30 min at their preferred speed. Energy expenditure was measured with the SWA (software version 6.1) and a portable indirect calorimetry system (Jaeger Oxycon Mobile((r))). The SWA showed a ceiling effect around an intensity of ten METs. Since all subjects exceeded that intensity range during the exercise trials, the SWA significantly underestimated energy expenditure at high intensities. The intra-individual correlations between MET values calculated by the SWA and values derived from the Oxycon, however, were significant for all but two subjects (r = 0.390-0.933, mean = 0.66 +/- 0.25). While providing accurate results for energy expenditure during low-to moderate intensity physical activities, the SWA does not provide accurate estimates of energy expenditure at high intensity levels. The threshold for accurate measurements seems to be around an intensity of ten METs. PMID- 20972881 TI - Unique paleopathology in a pre-Columbian mummy remnant from Southern Peru--severe cervical rotation trauma with subluxation of the axis as cause of death. AB - We describe the multidisciplinary findings in a pre-Columbian mummy head from Southern Peru (Cahuachi, Nazca civilisation, radiocarbon dating between 120 and 750 AD) of a mature male individual (40-60 years) with the first two vertebrae attached in pathological position. Accordingly, the atlanto-axial transition (C1/C2) was significantly rotated and dislocated at 38 degrees angle associated with a bulging brownish mass that considerably reduced the spinal canal by circa 60%. Using surface microscopy, endoscopy, high-resolution multi-slice computer tomography, paleohistology and immunohistochemistry, we identified an extensive epidural hematoma of the upper cervical spinal canal-extending into the skull cavity-obviously due to a rupture of the left vertebral artery at its transition between atlas and skull base. There were no signs of fractures of the skull or vertebrae. Histological and immunohistochemical examinations clearly identified dura, brain residues and densely packed corpuscular elements that proved to represent fresh epidural hematoma. Subsequent biochemical analysis provided no evidence for pre-mortal cocaine consumption. Stable isotope analysis, however, revealed significant and repeated changes in the nutrition during his last 9 months, suggesting high mobility. Finally, the significant narrowing of the rotational atlanto-axial dislocation and the epidural hematoma probably caused compression of the spinal cord and the medulla oblongata with subsequent respiratory arrest. In conclusion, we suggest that the man died within a short period of time (probably few minutes) in an upright position with the head rotated rapidly to the right side. In paleopathologic literature, trauma to the upper cervical spine has as yet only very rarely been described, and dislocation of the vertebral bodies has not been presented. PMID- 20972882 TI - Diffuse panbronchiolitis in a 67-year-old Chinese man. PMID- 20972884 TI - Oxidation of pharmaceutically active compounds by a ligninolytic fungal peroxidase. AB - Pharmaceuticals are an important group of emerging pollutants with increasing interest due to their rising consumption and the evidence for ecotoxicological effects associated to trace amounts in aquatic environments. In this paper, we assessed the potential degradation of a series of pharmaceuticals: antibiotics (sulfamethoxazole), antidepressives (citalopram hydrobromide and fluoxetine hydrochloride), antiepileptics (carbamazepine), anti-inflammatory drugs (diclofenac and naproxen) and estrogen hormones (estrone, 17beta-estradiol, 17alpha-ethinylestradiol) by means of a versatile peroxidase (VP) from the ligninolytic fungus Bjerkandera adusta. The effects of the reaction conditions: VP activity, organic acid concentration and H(2)O(2) addition rate, on the kinetics of the VP based oxidation system were evaluated. Diclofenac and estrogens were completely degraded after only 5-25 min even with a very low VP activity (10 U l(-1)). High degradation percentages (80%) were achieved for sulfamethoxazole and naproxen. Low or undetectable removal yields were observed for citalopram (up to 18%), fluoxetine (lower than 10%) and carbamazepine (not degraded). PMID- 20972883 TI - Resting developments: a review of fMRI post-processing methodologies for spontaneous brain activity. AB - Analytic tools for addressing spontaneous brain activity, as acquired with fMRI during the "resting-state," have grown dramatically over the past decade. Along with each new technique, novel hypotheses about the functional organization of the brain are also available to researchers. We review six prominent categories of resting-state fMRI data analysis: seed-based functional connectivity, independent component analysis, clustering, pattern classification, graph theory, and two "local" methods. In surveying these methods, we address their underlying assumptions, methodologies, and novel applications. PMID- 20972885 TI - Dementia in Swedish twins: predicting incident cases. AB - Thirty same-sex twin pairs were identified in which both members were assessed at baseline and one twin subsequently developed dementia, at least 3 years subsequent to the baseline measurement, while the partner remained cognitively intact for at least three additional years. Eighteen of the 30 cases were diagnosed with Alzheimer's disease. Baseline assessments, conducted when twins' average age was 70.6 (SD = 6.8), included a mailed questionnaire and in-person testing. Which twin would develop dementia was predicted by less favorable lipid values (higher apoB, ratio of apoB to apoA1, and total cholesterol), poorer grip strength, and-to a lesser extent-higher emotionality on the EAS Temperament Scale. Given the long preclinical period that characterizes Alzheimer's disease, these findings may suggest late life risk factors for dementia, or may reflect changes that are part of preclinical disease. PMID- 20972886 TI - Production of double repeated B subunit of Shiga toxin 2e at high levels in transgenic lettuce plants as vaccine material for porcine edema disease. AB - Pig edema disease is a bacterial disease caused by enterohemorrhagic Escherichia coli. E. coli produces Shiga toxin 2e (Stx2e), which is composed of one A subunit (Stx2eA) and five B subunits (Stx2eB). We previously reported production of Stx2eB in lettuce plants as a potential edible vaccine (Matsui et al. in Biosci Biotechnol Biochem 73:1628-1634, 2009). However, the accumulation level was very low, and it was necessary to improve expression of Stx2eB for potential use of this plant-based vaccine. Therefore, in this study, we optimized the Stx2eB expression cassette and found that a double repeated Stx2eB (2* Stx2eB) accumulates to higher levels than a single Stx2eB in cultured tobacco cells. Furthermore, a linker peptide between the two Stx2eB moieties played an important role in maximizing the effects of the double repeat. Finally, we generated transgenic lettuce plants expressing 2* Stx2eB with a suitable linker peptide that accumulate as much as 80 mg per 100 g fresh weight, a level that will allow us to use these transgenic lettuce plants practically to generate vaccine material. PMID- 20972887 TI - Measurement of negativity bias in personal narratives using corpus-based emotion dictionaries. AB - This study presents a novel methodology for the measurement of negativity bias using positive and negative dictionaries of emotion words applied to autobiographical narratives. At odds with the cognitive theory of mood dysregulation, previous text-analytical studies have failed to find significant correlation between emotion dictionaries and negative affectivity or dysphoria. In the present study, an a priori list dictionary of emotion words was refined based on the actual use of these words in personal narratives collected from close to 500 college students. Half of the corpus was used to construct, via concordance analysis, the grammatical structures associated with the words in their emotional sense. The second half of the corpus served as a validation corpus. The resulting dictionary ignores words that are not used in their intended emotional sense, including negated emotions, homophones, frozen idioms etc. Correlations of the resulting corpus-based negative and positive emotion dictionaries with self-report measures of negative affectivity were in the expected direction, and were statistically significant, with medium effect size. The potential use of these dictionaries as implicit measures of negativity bias and in the analysis of psychotherapy transcripts is discussed. PMID- 20972888 TI - In vivo impedance evaluation of Au/PI microelectrode with surface modulated by alkanethiolate self-assembled monolayers. AB - The goal of this study was to verify that a fully implanted microelectrode with modulated surface may have a reduced rising rate of total impedance and a longer life time. In the previous work, alkanethiolate self-assembled monolayers (SAMs) surface as protein-resistant spacer or cell-repulsive dense-packed spacer has been verified from in vitro experiments. In this study, microelectrodes with the same surface modulation were implanted into the subcutaneous layers of Wistar rats. Nine rats were implanted with the microelectrodes and the total impedance data were measured every 24 h for 2 weeks after implantation. An equivalent electrical circuit model of the electrode-tissue interface was established and parameters were estimated by using an optimization algorithm. Four out of nine rats had manifested acute inflammation reaction and the rests revealed only slight tissue response. Histological examination for the inflammatory group showed fibroblasts, macrophages, and polymorphonuclear leukocytes in adjacent to the electrode contact surface. In the inflammatory group, no significantly difference in total impedance was found in both types of electrodes. However, the trend of total impedance of SAMs-treated electrodes could maintain a steady state value after 1 week. For the non-inflammatory group, both types of electrodes could reduce the impedance value within implanted days. The tissue resistance might be related to the thickness of cells adhered upon the electrode contacts. PMID- 20972889 TI - Indoor and outdoor sources of size-resolved mass concentration of particulate matter in a school gym-implications for exposure of exercising children. AB - INTRODUCTION: It has been noticed many times that schools are buildings with high levels of particulate matter concentrations. Several authors documented that concentrations of particulate matter in indoor school microenvironments exceed limits recommended by WHO namely when school buildings are situated near major roads with high traffic densities. In addition, exercise under conditions of high particulate concentrations may increase the adverse health effects, as the total particle deposition increases in proportion to minute ventilation, and the deposition fraction nearly doubles from rest to intense exercise. SITE AND METHODS: Mass concentrations of size-segregated aerosol were measured simultaneously in an elementary school gym and an adjacent outdoor site in the central part of Prague by two pairs of collocated aerosol monitors-a fast responding photometer DusTrak and a five stage cascade impactor. To encompass seasonal and annual differences, 89 days of measurements were performed during ten campaigns between 2005 and 2009. RESULTS AND DISCUSSION: The average (all campaigns) outdoor concentration of PM(2.5) (28.3 MUg m(-3)) measured by the cascade impactors was higher than the indoor value (22.3 MUg m(-3)) and the corresponding average from the nearest fixed site monitor (23.6 MUg m(-3)). Indoor and outdoor PM(2.5) concentrations exceeded the WHO recommended 24-h limit in 42% and 49% of the days measured, respectively. The correlation coefficient (r) between corresponding outdoor and indoor aerosol sizes increased with decreasing aerodynamic diameter of the collected particles (r = 0.32-0.87), suggesting a higher infiltration rate of fine and quasi-ultrafine particles. Principal component analysis revealed five factors explaining more than 82% of the data variability. The first two factors reflected a close association between outdoor and indoor fine and quasi-ultrafine particles confirming the hypothesis of high infiltration rate of particles from outdoors. The third factor indicated that human activity is the main source of indoor emission of coarse particles. The fourth factor involved only outdoor variables showing the resuspension of coarse ambient aerosol on dry and warm days without its seeming effect on the indoor coarse PM levels. Having in mind that high concentrations of both fine and coarse aerosol were frequently observed in the studied space, our results suggest that indoor exercise in polluted urbanized areas may increase the overall exposure and thus represent a potential health risk to young individuals during physical education at schools. PMID- 20972890 TI - Triggering of the antibacterial activity of Bacillus subtilis B38 strain against methicillin-resistant Staphylococcus aureus. AB - When cultured in minimal growth medium, the B38 strain of Bacillus subtilis did not exhibit any antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) clinical isolate. Coculturing B38 strain with viable MRSA cells weakly increased antibacterial activity production (20 AU/ml). Addition of dead MRSA cells in a B38 culture, increased by 8-fold the B. subtilis strain antibacterial activity reaching 160 AU/ml against MRSA strain. This antibacterial activity recovered from cell-free supernatants was stimulated by an autoinducing compound which is sensitive to the action of proteinase K suggesting a proteinaceous nature. This compound was heat-stable till 80 degrees C and showed a molecular mass around 20 kDa as determined by SDS-PAGE. These results suggest that the production of antibacterial compounds by B38 strain is dependent on the amount of the autoinducing compound. PMID- 20972891 TI - Hydrolytic enzyme of cellulose for complex formulation applied research. AB - To improve the enzymatic hydrolytic efficiency and reduce the supplementation of enzymes, the mixture designed experimental approach was used to optimize the composition of enzyme mixture and promote the hydrolysis of ball-milled corn stover. From the experimental results, a synergistic effect was found when combinations of the three enzymes, two kinds of cellulases and a kind of xylanase, were used. The optimal hydrolysis of pretreated corn stover accorded with enzymes activity ration of FPU/CMCase/beta-glucosidase/xylanase = 4.4:1:75:829, and the hydrolysis efficiency of corn stover increased significantly compared with using individual enzyme. The results indicated that the mixture design experiment could be an effective tool for optimized enzyme mixture for lignocellulose hydrolysis. PMID- 20972892 TI - Investigation of yeast invertase immobilization onto cupric ion-chelated, porous, and biocompatible poly(hydroxyethyl methacrylate-n-vinyl imidazole) microspheres. AB - Cupric ion-chelated poly(hydroxyethyl methacrylate-n-vinyl imidazole) (poly(HEMA VIM)) microspheres prepared by suspension polymerization were investigated as a specific adsorbent for immobilization of yeast invertase in a batch system. They were characterized by scanning electron microscopy, surface area, and pore size measurements. They have spherical shape and porous structure. The specific surface area of the p(HEMA-VIM) spheres was found to be 81.2 m2/g with a size range of 70-120 MUm in diameter, and the swelling ratio was 86.9%. Then, Cu(II) ion chelated on the microspheres (546 MUmol Cu(II)/g), and they were used in the invertase adsorption. Maximum invertase adsorption was 51.2 mg/g at pH 4.5. Cu(II) chelation increases the tendency from Freundlich-type to Langmuir-type adsorption model. The optimum activity for both free and adsorbed invertase was observed at pH 4.5. The optimum temperature for the poly(HEMA-VIM)/Cu(II) invertase system was found to be at 55 degrees C, 10 degrees C higher than that of the free enzyme at 45 degrees C. V(max) values were determined as 342 and 304 U/mg enzyme, for free and adsorbed invertase, respectively. K(m) values were found to be same for free and adsorbed invertase (20 mM). Thermal and pH stability and reusability of invertase increased with immobilization. PMID- 20972893 TI - Does lactoferrin behave as an immunohistochemical oncofetal marker in bone and cartilage human neoplasms? AB - By immunohistochemistry, lactoferrin (LF) has been extensively investigated in human neoplastic tissues; moreover, LF is able to promote bone growth in a murine model. Until now, no systematic studies on human osteocartilagineous fetal samples have been performed in comparison to corresponding neoplastic specimens to verify if LF may represent an oncofetal marker in this field of pathology. By a monoclonal antibody (clone 1A1; Biodesign International; w.d. 1:75) the distribution pattern of LF in bones of 25 human fetal tissues (8-34 gestation weeks), 10 adults (47-82 years) and 30 cartilage as well as 27 bone tumours (9-76 years) was analyzed. LF was encountered in 23/57 cases of osteocartilagineous tumors and namely in 10/10 giant cell tumours, 5/7 osteoid osteomas, 3/3 chondroblastomas, 3/3 chondromyxoid fibromas, 1/1 myeloma, 1/1 adamantinoma. No LF immunoexpression was detected in osteosarcomas, chondrosarcomas, ossifying fibromas, osteochondroma and enchondromas. In embryo-fetal tissues, LF immunoreactivity was localized in mesenchymal cells as well as in chondroblasts at the 8th gestational week and in immature osteocytes and osteoblasts up to the 18th gestation week, with a considerable decrease by the 24th week. No LF expression was found in any bone district since the 30th and up to the 34th week of gestation as well as in corresponding adult samples. Our findings indicate a role for LF as a bone growth regulator in the early phases of the human endochondral ossification, although the hypothesis of LF as oncofetal marker appears questionable in bone tumours. PMID- 20972894 TI - MR Imaging of activated hepatic stellate cells in liver injured by CCl4 of rats with integrin-targeted ultrasmall superparamagnetic iron oxide. AB - OBJECTIVE: To demonstrate the feasibility of the ultrasmall superparamagnetic iron oxide (USPIO) modified by cyclo (Arg-Gly-Asp-Try-Cys) peptide (c(RGDyC) USPIO) for targeting hepatic stellate cells (HSCs). MATERIALS AND METHODS: A c(RGDyC)-USPIO probe was prepared by conjugating c(RGDyC) with USPIO through a thiol-maleinide interaction. The specificity of c(RGDyC)-USPIO for HSCs was investigated in vitro. In vivo, normal and fibrosis rats were treated with either c(RGDyC)-USPIO or USPIO, and magnetic resonance imaging (MRI) of the rats performed after administration of the probes for 4 h. The T2 relaxation times changes before and after probe injection were analyzed and the locations of probes in normal or injured mice were identified histologically. RESULTS: The hydrodynamic size of c(RGDyC)-USPIO was 13 +/- 3 nm. HSCs took up more specific probes than plain ones. The reduction of T2 relaxation times in fibrosis rat by c(RGDyC)-USPIO was much greater than that by USPIO (P < 0.05). Prussian blue staining and transmission electron microscopy of the injured rat liver treated with c(RGDyC) demonstrated that c(RGDyC)-USPIO were specifically engulfed by the activated HSCs. CONCLUSION: In vivo cellular targeted imaging of activated HSCs in liver fibrosis using c(RGDyC)-USPIO targeting alpha(v)beta(3) integrins was feasible using a clinical 1.5-Tesla MR system. PMID- 20972895 TI - Disease-relevant autoantibodies in first episode schizophrenia. PMID- 20972896 TI - The interaction between dietary protein and bone health. AB - The role of dietary protein in bone health has been controversial. On the one hand, a plentiful supply of dietary amino acids has been considered important to support bone remodeling while on the other hand there have been concerns that the dietary acid load associated with protein consumption promotes hypercalciuria and loss of bone calcium stores. This article reviews the effect of dietary protein on bone mass and bone density, and the effect on markers of bone resorption and formation and also on fracture risk, looking at both cross-sectional and longitudinal studies and examining both meat and vegetable protein including soy and milk basic protein. The results are not entirely consistent and suggest that the interaction between dietary protein and other components in a mixed diet, such as calcium intake and vegetables and fruit to neutralize acid, are important and may determine whether high-protein diets are beneficial to bone health. Overall the results suggest that dietary protein has a modest beneficial effect on bone markers and bone density. This effect has yet to be consistently linked to reduced fracture risk, probably because of the role of other etiological factors such as the risk of falls. There is not enough evidence currently to suggest that animal protein is superior or inferior to vegetable protein, or that milk or soy protein, respectively, is more favorable than other protein sources. PMID- 20972897 TI - Increasing fatty acid production in E. coli by simulating the lipid accumulation of oleaginous microorganisms. AB - Unlike many oleaginous microorganisms, E. coli only maintains a small amount of natural lipids in cells, impeding its utility to overproduce fatty acids. In this study, acetyl-CoA carboxylase (ACC) from Acinetobacter calcoaceticus was expressed in E. coli to redirect the carbon flux to the generation of malonyl CoA, which resulted in a threefold increase in intracellular lipids. Moreover, providing a high level of NADPH by overexpressing malic enzyme and adding malate to the culture medium resulted in a fourfold increase in intracellular lipids (about 197.74 mg/g). Co-expression of ACC and malic enzyme resulted in 284.56 mg/g intracellular lipids, a 5.6-fold increase compared to the wild-type strain. This study provides some attractive strategies for increasing lipid production in E. coli by simulating the lipid accumulation of oleaginous microorganisms, which could aid the development of a prokaryotic fatty acid producer. PMID- 20972898 TI - Production of a novel and cold-active killer toxin by Mrakia frigida 2E00797 isolated from sea sediment in Antarctica. AB - The psychrotolerant yeast Mrakia frigida 2E00797 isolated from sea sediment in Antarctica was found to be able to produce killer toxin against the pathogenic yeast (Metschnikowia bicuspidata WCY) in crab. When the psychrotolerant yeast was grown in the medium with pH 4.5 and 3.0% (wt/vol) NaCl and at 15 degrees C, it could produce the highest amount of killer toxin against the pathogenic yeast M. bicuspidata WCY. The crude killer toxin activity against the pathogenic yeast M. bicuspidata WCY was the highest when it grew at 15 degrees C in the assay medium with 3.0% (wt/vol) NaCl and pH 4.5. At temperatures higher than 25 degrees C, the killing activity produced by M. frigida 2E00797 was completely lost and after the crude killer toxin was pre-incubated at temperatures higher than 40 degrees C for 4 h, the killing activity was also completely lost. The killer toxin produced by M. frigida 2E00797 could kill only M. bicuspidata WCY, Candida tropicalis and Candida albicans among all the fungal species and bacterial species tested in this study. PMID- 20972899 TI - [Associations of triple-phase enhancement multi-slice CT scan with histological differentiation and lymphovascular invasion in gastric cancer]. AB - OBJECTIVE: To explore the associations of triple-phase enhancement multi-slice CT scan with histological differentiation and lymphovascular invasion in advanced gastric cancer. METHODS: Patients with gastric cancer undergoing surgical resection between January 2006 and December 2009 were included, all of whom underwent routine and two-phase contrast enhancement multi-slice CT examinations of the upper abdomen before surgery. Patients with incomplete data were excluded. Postoperative specimens were used for evaluation of histological differentiation, microscopic lymphovascular invasion, and CD34 and D2-40 expression. Associations between contrast enhancement ratio (CER) of triple-phase multi-slice CT scan and differentiation as well as lymphovascular invasion were analyzed. RESULTS: A total of 64 patients were included. There were significant associations between CER and tumor differentiation (P<0.05). Compared to those without microvascular invasion, CER of the arterial phase in gastric cancer with microvascular invasion was significantly higher (0.61+/-0.28 vs. 0.46+/-0.14, P<0.05), and that of the arterial-parenchymal phase was significantly lower(1.81+/-0.39 vs. 2.28+/-0.80, P<0.05). However, gastric cancers with lymphatic invasion were associated with significantly higher CER of the parenchymal phase than their counterparts(1.25+/ 0.57 vs. 1.00+/-0.35, P<0.05). CONCLUSION: CER of triple-phase multi-slice CT scan can reveal the differentiation of gastric cancer and is associated with microvascular and lymphatic invasion. PMID- 20972900 TI - [Use of inflammatory factors combined with multi-slice spiral computer tomography for preoperative staging and operative strategy in colon cancer]. AB - OBJECTIVE: To determine the clinical value of C-reactive protein(CRP), fibrinogen (FIB), or serum amyloid A protein (SAA) combined with 64 multi-slice computed tomography (MSCT) for preoperative staging and operative strategy in colon cancer. METHODS: Patients with colon cancer were prospectively enrolled at the West China Hospital of Sichuan University from November 2007 to July 2009,and were equally randomized into 3 groups undergoing different preoperative evaluation: MSCT combined with CRP(CRP group), MSCT combined with FIB (FIB group), and MSCT combined with SAA (SAA group). The agreement between preoperative staging and postoperative pathologic staging and that between expected surgical procedure and procedure adopted were compared. RESULTS: Baseline characteristics among three groups were similar(P>0.05). In CRP group, the accuracies of preoperative staging T, N, M and TNM were 65.7%, 72.4%, 100% and 66.7%, respectively. In FIB group, the accuracies of preoperative staging T, N, M and TNM were 71.4%, 74.3%, 99.0% and 65.7%, respectively. In SAA group, the accuracies of preoperative staging T, N, M and TNM were 60.0%, 55.2%, 96.2%and 51.4%, respectively. The accuracies of N and TNM staging in CRP group and FIB group were significantly higher than those in SAA group(P<0.05). However, there were no significant differences between FIB and CRP group(P>0.05). There were no significant differences in accuracy of predicting surgical procedures among three groups(93.3%, 92.3% and 87.6%, P>0.05). CONCLUSION: Combined assessment of MSCT and CRP or FIB may improve the accuracy of preoperative staging and procedure prediction, and is superior to MSCT combined with SAA. PMID- 20972901 TI - [Evaluation of surgical outcomes using imaging study for patients with slow transit constipation complicated with outlet obstruction]. AB - OBJECTIVE: To explore the clinical significance of multiple radiography of the pelvis in the evaluation of surgical outcomes for patients with slow transit constipation complicated with outlet obstruction. METHODS: Patients with slow transit constipation complicated with outlet obstruction were diagnosed by multiple radiography of the pelvis after screening using colon transit study. Surgery was performed according to the cause of the obstruction. Anorectal angle and the locations of perineum, pelvic peritoneum, and bladder were assessed by multiple radiography of the pelvis one month after surgery. The changes in locations of pelvic organs were assessed and the imaging appearance after the release of obstruction was observed. RESULTS: A total of 48 patients were included. Rectocele repair, partial mucosectomy with rectopexy, and hysteropexy were performed. All the patients were followed up with a mean length of 19(6-58) months. Excluding 2 patients who had no symptomatic improvement, the mean bowel movements was 1.9 times per day in the remaining 46 patients(95.8%). Preoperative anorectal angle at the squeezing phase was(128.09+/-13.82) degree and the difference between squeezing and resting phase was (11.14+/-12.58) degree, while the postoperative angle was (180.26+/-9.98) degree and the difference(20.01+/ 13.11) degree(P<0.05). Preoperative location of the perineum at the squeezing phase was(-2.05+/-0.83) cm and the difference was(2.23+/-0.78) cm, while postoperative location was (-0.50+/-1.13) cm and the difference was (2.18+/-1.04) cm(P<0.05). Preoperative location of the pelvic peritoneum at the squeezing phase was(4.91+/-1.32) cm and the difference was (1.32+/-0.89) cm, while postoperative location was (2.62+/-2.53) cm and the difference was (3.28+/-0.68) cm (P<0.05). Preoperative bladder location at the squeezing phase in patients with urological symptoms was (3.92+/-2.51) cm and the difference was(1.39+/-1.27) cm, while postoperative location was (2.15+/-1.55) cm and the difference was (1.98+/-1.54) cm(P<0.05). CONCLUSION: Multiple imaging of the pelvis provides objective evidence in the evaluation of surgical outcomes for patients with chronic slow transit constipation complicated with outlet obstruction. PMID- 20972902 TI - [Construction and application of evaluation system of laparoscopic colorectal surgery based on clinical data mining]. AB - OBJECTIVE: To construct a clinical database for laparoscopic colorectal surgery in Chinese population using computerized technique. METHODS: A clinical database system was constructed and used in multi-/single-center studies on laparoscopic colorectal surgery. RESULTS: The data of more than 1200 cases in the Nanfang Hospital during the past year were collected retrospectively. The database was used as the platform for "Southern China Laparoscopic Colorectal Surgery Study Group (SCLCSG)" and was used in the first stage of the clinical research of "Multicenter retrospective study of laparoscopic and open procedure for colorectal cancer" among 11 hospitals in Southern China. In order to test the system, the database was also used in "comparative study on oncologic results of laparoscopic versus open radical resection for rectal carcinoma". CONCLUSIONS: The evaluation system is reliable and efficient. This system has established a clinical database for laparoscopic colorectal cancer surgery and can be widely applied for the clinical research for colorectal cancer. PMID- 20972903 TI - [Analysis on misdiagnosis of 271 patients with rectal cancer]. AB - OBJECTIVE: To investigate the common reasons for the misdiagnosis of rectal cancer. METHODS: A retrospective study was performed in 568 cases of rectal cancer in the Changhai Hospital from January 2007 to December 2008. Age at diagnosis, gender distribution, symptom, delay in diagnosis, TNM stage, and grade of differentiation were recorded and analyzed. The importance of digital examination and colonoscopy were addressed. RESULTS: Two hundred and seventy one(47.7%) out of 568 patients were misdiagnosed for iatrogenic reasons. Rectal cancer patients who presented hematochezia were more likely to be misdiagnosed. There were 110 cases of stage III(40.6%) and 68 cases of stage IV(12.5%) in patients who were misdiagnosed, which was significantly higher than those who were diagnosed correctly(P<0.05). Patients under 40 years old were more likely to be misdiagnosed, and their correct diagnosis was often delayed longer and the tumors were in more advanced stage as compared to the older groups(P<0.05). CONCLUSIONS: The misdiagnosis rate of rectal cancer is high. Tumor stage of patients misdiagnosed is significantly more advanced than those who are correctly diagnosed. Digital examination and colonoscopy should be emphasized, especially for patients under the age of 40. PMID- 20972905 TI - [Intestinal obstruction caused by gallstone: report of 5 cases and review of the literature]. AB - OBJECTIVE: To explore clinical features, diagnostic methods and treatment of gallstone ileus. METHODS: Clinical data of 5 patients with gallstone ileus were analyzed retrospectively. Pertinent literature from China between 2000 and 2009 were reviewed. The disease onset, clinical manifestations, imaging characteristics, diagnosis and treatment of gallstone ileus were studied. RESULTS: Four out of 5 patients were female aged over 60, of whom 3 had a previous history of cholelithiasis, 2 had a history of cholangiojejunostomy internal drainage procedure. Four patients underwent enterotomy and gallstone extraction combined with hepatobiliary operation, while one underwent enterotomy alone. There was no postoperative recurrence. A review of the literature from China revealed 441 cases with intestinal obstruction caused by gallstone, consisting 1.15% of all the cases with bowel obstruction. 67.12% were female. 73.56% were elderly. 87.92% were from cystoenteral fistula. Site of bowel obstruction in ileum was 64.17% of the cases. 71.89% were misdiagnosed with other types of obstruction. Two hundred twenty-five patients underwent enterotomy and gallstone extraction combined with hepatobiliary operation, which carried a lower rate of postoperative recurrence and malignancy (P<0.05) than enterotomy alone. There were no statistical significant differences in the occurrence of postoperative cystoenteral fistula, wound infection, pulmonary infection, cure rate, and mortality(P>0.05). CONCLUSIONS: The incidence of gallstone ileus is low and more common in female elderly. The gallstones often drain through cystoenteral fistula and lodge in the ileum. Enterotomy without hepatobiliary operation is associated with potential risk of recurrence and development of gallbladder malignancy. Combined hepatobiliary operation is recommended in patients without significant comorbidities. PMID- 20972904 TI - [Efficacy of postoperative chemoradiation for stage III low rectal cancer]. AB - OBJECTIVE: To evaluate the efficacy of postoperative chemoradiation for stage III low rectal cancer. METHODS: A total of 132 patients with stage III low rectal cancer, including 69 males and 63 females, were identified and divided into two groups: group A received chemoradiation while group B underwent chemotherapy alone. RESULTS: Eighteen patients developed local recurrence after five years of follow-up, with 6 cases(8.3%) in group A and 12(22.2%) in group B(P<0.05). In patients with distant metastasis(n=65), 37(47.4%) were in group A and 28(51.9%) in group B, and the difference was not statistically significant(P>0.05). The 5 year survival rates for group A and group B were 47.4% and 29.6%, respectively(P<0.05). Radiation proctitis was found in 6 cases in group A. CONCLUSIONS: Postoperative chemoradiation can reduce local recurrence rate and improve 5-year survival compared to chemotherapy alone. However, it has little effect on the distant metastasis. Postoperative chemoradiation is safe and effective for low rectal cancer. PMID- 20972906 TI - [Factors associated with recurrence and prognosis in patients with gastric gastrointestinal stromal tumors]. AB - OBJECTIVE: To investigate factors associated with postoperative recurrence and prognosis in gastric gastrointestinal stromal tumors(gastric GIST). METHODS: Clinical data of 107 patients with gastric GIST who underwent surgical resection at the Zhejiang Province Hospital of the Integrated Traditional Chinese and Western Medicine between January 1987 and December 2008 were analyzed retrospectively. Factors associated with recurrence were explored. RESULTS: Surgery was radical in 83 patients(radical group) and palliative in 24 patients(palliative group). Thirty-one patients developed recurrence in the radical group. Tumor size greater than 5 cm, incompleteness of tumor envelope, and local invasion were associated with tumor recurrence(P<0.05), while gender, age, tumor location, and mitosis were not. The median survival time was 13 months in patients with recurrence and 78 month in those without recurrence, and the difference was statistically significant(P<0.05). The median survival was 54(range, 7-246) months in the radical group and 6 (range, 1-25) in the palliative group, and the difference was also statistically significant(P<0.05). CONCLUSION: Tumor size, integrity of tumor envelope, and local invasion are predictive for recurrence in GIST. PMID- 20972907 TI - [Mutation and expression of WNT8b gene and SHH gene in Hirschsprung disease]. AB - OBJECTIVE: To investigate the relationship of WNT8b and SHH genes mutation and Hirschsprung disease(HSCR) in Chinese children. METHODS: Preoperative whole blood preparations in 72 children with sporadic HSCR from northeast China were collected(study group). Seventy-two healthy children were used as controls(matched for sex and age). Genomic DNA was obtained from peripheral blood. Exon 1 of WNT8b gene and the exon 1 of SHH gene were analyzed for gene mutation. The mutation products were automatically sequenced. The levels of WNT8b and SHH mRNA were detected by quantitative real-time PCR(qRT-PCR) in blood samples. RESULTS: On sequencing, 13 out of 72 children with HSCR had WNT8b gene mutation in the coding area, including heterozygosity deletion in 8 cases (11.1%) and base replacement in 5(6.9%). Eleven children with HSCR had SHH gene mutation in the coding area including heterozygosity deletion in 7 cases(9.7%) and base replacement in 4(5.6%). No mutations in WNT8b and SHH genes were found in the control group. The WNT8b and SHH mRNA levels were different between the study group and the control group(30.01+/-1.13 vs. 17.33+/-0.62, and 28.25+/-1.27 vs. 18.94+/-0.31, P<0.05). CONCLUSIONS: WNT8b and SHH mutations and abnormal expressions are present in the peripheral blood of children with sporadic HSCR. These two genes may be related to the development of sporadic HSCR in children in the northeastern China. PMID- 20972908 TI - [Study of loss of heterozygosity at 9p21 and P16 expression in gastrointestinal stromal tumors]. AB - OBJECTIVE: To evaluate the impact of loss of heterozygosity (LOH) at chromosome 9p21 and P16(INK4A)(CDKN2A) expression on the prognosis of gastrointestinal stromal tumor (GIST). METHODS: A total of 51 cases with GISTs were characterized by immunohistochemistry and evaluated for LOH at 9p21 by microsatellite analysis in 4 markers(D9S1751, D9S1846, D9S942 and D9S1748). Associations of LOH at 9p21 and P16(INK4A) expression encoded by CDKN2A with clinicopathological parameters and prognosis in GISTs were analyzed. RESULTS: The frequency of 9p21 LOH was 37.0% (10/27) at D9S1751, 37.5%(12/32) at D9S1846, 42.1%(16/38) at D9S942 and 24.2%(8/33) at D9S1748. The overall frequency of LOH at 9p21 was 63.3%(31/49). In 21 samples of 51 GISTs(41.2%), P16 expression was not detected. Loss of P16 expression was 60%(12/20) in high risk group and 23.5%(4/17) in very low and low risk groups(P<0.05). The 5-year overall survival rate of p16-negative patients was 70.8%, while in P16-positive patients it was 92.0%(P<0.05). CONCLUSIONS: LOH at 9p21 is a frequent event in GIST. Loss of CDKN2A gene at 9p21 may contribute to the progression and malignant transformation of GIST. P16 expression in GIST is associated with prognosis. PMID- 20972909 TI - [Association of Omi/HtrA2 expression and prognosis in patients with gastric carcinoma]. AB - OBJECTIVE: To explore the expression of serine protease Omi/HtrA2 in gastric carcinoma tissue and its association with clinicopathological features and prognosis. METHODS: Omi/HtrA2 protein expression levels were detected by immunohistochemistry method in resected gastric carcinomas(n=68), adjacent noncancerous tissues(n=15), and normal tissues(n=15), and its association with clinicopathological features and prognosis were analyzed. RESULTS: Omi/HtrA2 expression was positive in 73.5%(50/68) of gastric cancer tissues, which was significantly higher than that in adjacent noncancerous tissues and normal tissues(P<0.05). There were no significant differences in Omi/HtrA2 expression with respect to sex, age, tumor size, and depth of invasion(all P>0.05). Omi/HtrA2 expression level was significantly associated with tumor differentiation, extent of lymph node metastasis, and tumor stage(all P<0.05). Overall 5-year survival rate of patients with gastric carcinoma was 63.3%. Five year survival rate was higher in Omi/HtrA2 positive cases than Omi/HtrA2 negative cases(72.0% vs. 61.1%), however the difference was not statistically significant. CONCLUSIONS: Omi/HtrA2 expression is more common in gastric carcinoma. Omi/HtrA2 expression is associated with tumor differentiation, extent of lymph node metastasis, and tumor stage. PMID- 20972910 TI - [Use of serum protein profiling for early diagnosis of gastric cancer]. AB - OBJECTIVES: To identify serum biomarkers associated with early gastric cancer. METHODS: Serum proteins or peptides were purified with weak cation exchange magnetic beads in 433 patients with gastric cancer and 120 healthy subjects. Distinct peaks were selected using Biomarker Wizard software. The area under receiver operating characteristic curve(AUC) was generated to analyze discrimination capability of peaks between gastric cancers and health people. RESULTS: Thirteen distinct peaks were identified between 42 gastric cancer and 42 health people matched by age and gender(P<0.001). There were 5 peaks (2745, 2768, 6629, 3402, and 6436 m/z) with AUC greater than 0.8. Peak of 6629 m/z was identified to be transthyretin. The sensitivity and specificity of 6629 m/z were 65.5% and 92.0%. The sensitivity of 6629 m/z was 59.4% in I(A gastric cancer. CONCLUSION: Transthyretin precursor may be of value in the early diagnosis of gastric cancer. PMID- 20972911 TI - [Omega-6 polyunsaturated fatty acid promotes colon carcinogenesis]. AB - OBJECTIVE: To investigate whether omega-6 polyunsaturated fatty acid promotes colon carcinogenesis through downregulation of P53-dependent growth inhibition. METHODS: Colon carcinogenesis was induced by injection of azoxymethane (AOM) intraperitoneally. Experimental animals were randomly divided into four groups, receiving regular diet and intraperitoneal injection of normal saline(control group), high omega-6 polyunsaturated fatty acid diet with intraperitoneal injection of normal saline(Corn oil group), regular diet with intraperitoneal injection of AOM(AOM group), or high omega-6 polyunsaturated fatty acid diet with intraperitoneal injection of AOM (Corn oil+AOM group). Aberrant crypt focis (ACFs) were observed after methylene blue staining and enumerated. Colonic mucosa PCNA and P53 expressions were assessed by RT-PCR and Western blotting, and location of P53 in the colon crypt focis was determined by immunohistochemical staining. RESULTS: Amounts of ACFs was 1.2+/-0.3 in the control group, 1.3+/-0.4 in the Corn oil group, 41.0+/-4.8 in the AOM group, and 73.3+/-9.9 in the Corn oil+AOM group, the differences were statistically significant(P<0.05). The expression of P53 in normal crypt focis was higher than that in ACFs. High omega 6 polyunsaturated fatty acid dietary significantly promoted AOM-induced colon PCNA expression, and enhanced AOM-mediated P53 inhibition in colon mucosa. CONCLUSION: High omega-6 polyunsaturated fatty acid diet can enhance AOM-induced inhibition of P53 in colon mucosa, resulting in overexpression of PCNA, formation of ACF, and carcinogenesis in the colon. PMID- 20972912 TI - Effectiveness and cost offset analysis of group CBT for hypochondriasis delivered in a psychiatric setting: an open trial. AB - Hypochondriasis is highly prevalent in medical settings, has detrimental effects for affected individuals, and is associated with high societal costs. Although cognitive behavior therapy (CBT) has been shown to be effective in the treatment of hypochondriasis, it is not widely available because of a lack of properly trained therapists. Therefore, it is essential to evaluate therapy forms that require less therapist time. The authors investigated the effect and economic impact of group CBT delivered in a psychiatric setting among 24 people with hypochondriasis. A within-group design with prolonged baseline was used, and all participants received 10 weeks of group-based treatment. The primary outcome measures were the Health Anxiety Inventory and the Illness Attitude Scales. Results indicate significant improvement on both measures at posttreatment and 6 month follow-up (Cohen's d = 1.03-1.72). Medical and nonmedical costs were substantially lowered. The authors conclude that group-based CBT delivered in a psychiatric setting is an effective and potentially highly cost-effective treatment for hypochondriasis. PMID- 20972913 TI - Proposing love on the way to school: mobility, sexuality and youth transitions in South Africa. AB - Young people's daily mobility in sub-Saharan Africa remains largely invisible and under-researched. Drawing on qualitative and quantitative data from the Child Mobility Project in South Africa, we show how young people's daily journeys (to school and other places) shape, and are shaped by, the possibility of sexual encounters. Young women are seen to be at risk of sexual violence as they travel around their neighbourhoods and fears of sexual violence and transgressive relationships lead to controls over their mobility, with potentially negative consequences for education and social opportunities. However, mobility can also present opportunities for welcomed sexual encounters and experimentation, which are seen as part of growing up. We discuss the implications for young women's ability to negotiate safe routes to adulthood. PMID- 20972915 TI - Learning from the past: young Indigenous people's accounts of blood-borne viral and sexually transmitted infections as resilience narratives. AB - The Indigenous Resilience Project is an Australian community-based participatory research project using qualitative methods to explore young Aboriginal and Torres Strait Islander people's views of blood-borne viral and sexually transmitted infections (BBV/STI) affecting their communities. In this paper we present an analysis of narratives from young people who had a previous BBV/STI diagnosis to explore how they actively negotiate the experience of BBV/STI infection to construct a classic resilience narrative. We examine two overarching themes: first, the context of infection and diagnosis, including ignorance of STI/BBV prior to infection/diagnosis and, second, turning points and transformations in the form of insights, behaviours, roles and agency. Responding to critical writing on resilience theory, we argue that providing situated accounts of adversity from the perspectives of young Indigenous people prioritises their subjective understandings and challenges normative definitions of resilience. PMID- 20972914 TI - Contraceptive medicalisation, fear of infertility and teenage pregnancy in Brazil. AB - In Brazil, as in many other countries, teenage pregnancy is widely recognised as a public health problem. Buttressed by a public health science of the economics of teenage pregnancy that emphasises the postponement of parenthood as key to poverty reduction, young people's lack of appreciation for medical knowledge of contraceptives is most often credited for failed attempts to reduce teenage pregnancy. Based on a longitudinal ethnographic study conducted in Pelotas, Brazil, with young people over the course of 10 years, our study found that young women who became teenage parents did not lack medical knowledge but were, rather, highly medicalised. Not only were they intensely concerned with the ill-effects of oral contraceptives on possible future fertility, they also engaged in intricate routines of contraceptive-use as a way of testing and safeguarding their fecundity. Our analysis attends to the way these practices are shaped by the problematisation of the economics of teenage pregnancy, as well as by the gendering of cultural norms relating to the transition to adulthood. We theorise the results by considering how contraceptive medicalisation enabled some women to engage with the authority of normative society, while developing a potent off stage critique of this authority and of what they considered to be discriminatory messages imbedded in scientific discourses on teenage pregnancy. PMID- 20972916 TI - Homophobia, stigma and HIV in Jamaican prisons. AB - Success in addressing HIV and AIDS among men who have sex with men, a key population in the global epidemic, is impeded by homophobia. Homophobia as a barrier to HIV prevention and AIDS treatment is a particularly acute problem in the prison setting. In this qualitative study, we explore HIV and AIDS, stigma and homosexuality in the largest all male prison in Jamaica by conducting iterative in-depth interviews with 25 inmates. Participant narratives unveil a purposeful manipulation of beliefs related to homosexuality that impedes an effective response to HIV and AIDS both in prison and wider society. Findings indicate that homophobia is both a social construction and a tangible tool used to leverage power and a sense of solidarity in a larger political and economic landscape. This use of homophobia may not be unique to Jamaica and is an important issue to address in other low- and middle-income post-colonialist societies. PMID- 20972917 TI - Gold Digger or Video Girl: the salience of an emerging hip-hop sexual script. AB - Concerns have been expressed in the common discourse and scholarly literature about the negative influence of Hip-Hop on its young listeners' ideas about sex and sexuality. Most of the scholarly literature has focused on the impact of this urban, Black media on young African American girls' sexual self-concept and behaviours. In response to this discourse, Stephens and Phillips (2003) proposed a Hip-Hop sexual scripting model that theorises about specific sexual scripts for young African American women. Their model includes eight different sexual scripts including the Gold Digger script. The present study proposes a ninth emerging script - the Video Girl. Participants were 18 female African American college students, between the ages of 18 and 30 years old from a large urban public university in the Southwest USA. Using q-methodology the present study found support for the existence of a Video Girl script. In addition, the data indicates that this script is distinct but closely related to Stephens and Phillips' Gold Digger script. These findings support their theory by suggesting that Hip-Hop sexual scripts are salient and hold real meaning for this sample. PMID- 20972918 TI - Treatment of dairy manure using the microwave enhanced advanced oxidation process under a continuous mode operation. AB - The microwave enhanced advanced oxidation process (MW/H(2)O(2)-AOP) was used to treat dairy manure for solubilization of nutrients and organic matters. This study investigated the effectiveness of the MW/H(2)O(2)-AOP under a continuous mode of operation, and compared the results to those of batch operations. The main factors affecting solubilization by the MW/H(2)O(2)-AOP were heating temperature and hydrogen peroxide dosage. Soluble chemical oxygen demand (SCOD) and volatile fatty acids (VFA) increased with an increase of microwave (MW) heating temperature; very high concentrations were obtained at 90 degrees C. Insignificant amounts of ammonia and reducing sugars were released in all runs. An acidic pH condition was required for phosphorus solubilisation from dairy manure. The best yield was obtained at 90 degrees C with an acid dosage of 1.0 %; about 92 % of total phosphorus and 90 % of total chemical oxygen demand were in the soluble forms. The MW/H(2)O(2)-AOP operated in a continuous operation mode showed pronounced synergistic effects between hydrogen peroxide and microwave irradiation when compared to a batch system under similar operating conditions, resulting in much better yields. PMID- 20972919 TI - Effect of alkyl hydroxybenzenes on the properties of dioxygenases. AB - The aim of the present work was to investigate the influence of alkylhydroxybenzenes (AHBs) and tyrosol, which belong to cell differentiation factors d(1) group of autoregulators on properties of biodegradation enzymes, catechol 1,2-dioxygenase (Cat 1,2-DO) and methylcatechol 1,2-dioxygenase (MCat 1,2-DO) of Rhodococcus opacus 6a. AHBs were found to have a greater effect on MCat 1,2-DO than on Cat 1,2-DO. It was expressed by more pronounced changes in the activity of MCat 1,2-DO with unsubstituted catechol at different AHB concentrations and by increasing thermostability of MCat 1,2-DO compared to Cat 1,2-DO under the protective action of AHBs. The compound C(7)-AHB shifted the maximum of dioxygenase activities towards higher temperatures and increased their operation optimum. AHBs changed the specificity constant of dioxygenases by decreasing/increasing the K(m)/V(max) value. For example, the increase in the V(max) value of 3,6-dichlorocatechol oxidation by Cat 1,2-DO in the presence of C(7)-AHB was 300-fold higher compared to the same reaction without AHB. The influence of cell differentiation factors on the properties of dimeric enzymes has been shown for the first time. It gives an idea of how the specificity of enzymes can be changed in vivo when strains contact new substrates. The work has shown the possibility of modification of the properties of dimeric enzymes towards the extension of enzyme activity with difficulty converted substrates or in more extreme conditions, which may be important for biotechnological processes. PMID- 20972920 TI - Homology modeling of anti-parathion antibody and its interaction with organophosphorous pesticides and analogues. AB - The mechanism of specific recognition in pesticide immunochemistry was investigated by computer-based strategy, and a rapid method for the identification of antibody specificity was developed. Based on the previously produced anti-parathion monoclonal antibody (mAb), the DNA sequence was analyzed by polymerase chain reaction (PCR). From the translated amino acid sequences, a three-dimensional structure of the antibody was constructed by homology modeling method, and then it was coordinated by 1 ns molecular dynamics under the explicit solvent condition. The stereochemical property and folding quality were further assessed by Procheck and Profile-3D. The self-compatibility score for the antibody model was 98.7, which was greater than the low score 46.2 and close to the top score 102.6. In addition, parathion and several structural analogues were docked to the constructed antibody structure. The docking results showed that the interaction energy (-40.54 kcal/mol) of antibody-parathion complex was the lowest among all the tested pesticides, which accounted for the high specificity of the antibody to parathion and perfectly matched with the experimental data. Moreover, three residues, Phe165, Asp107 and Thr100 were recognized as the most important residues for antibody reacting with parathion. The interaction energy negatively correlated with the antibody specificity. PMID- 20972921 TI - Pesticide dissipation curves in peach, pear and tomato crops in Uruguay. AB - Dissipation curves of azoxystrobin and of the neonicotinoids acetamiprid and thiacloprid in peach; azinphos-methyl and carbaryl in pear and azoxystrobin, chlorfenapyr and chlorpyrifos in high-tunnel tomato crops were studied in the Southern region of Uruguay. An analytical methodology based on solid phase extraction (SPE) and detection by High Performance Liquid Chromatography with Diode Array Detector (HPLC/DAD) was used for acetamiprid and thiacloprid. Coupled SPE and detection by Gas Chromatography with Mass Selective Detector (GC/MSD) was used for the detection of azinphos-methyl, azoxystrobin, carbaryl, chlorfenapyr and chlorpyrifos residues. Curves were modeled mathematically with Solver program of Microsoft Excel. The best fit for acetamiprid and thiacloprid in peach was achieved with the exponential model (r(2)=0.961 and 0.944, respectively). In the case of peach fruits there is not a Maximum Residue Limit (MRL) for acetamiprid in the Codex Alimentarius, while 0.5 mg/kg is the value rated for thiacloprid. The MRLs accepted by the European Union (EU) are 0.1 mg/kg for acetamiprid and 0.3 mg/kg for thiacloprid. According to the curves determined in these experiments, thiacloprid residues 10 to 12 days after application (daa) were below the MRLs established by both sources. In the case of acetamiprid, 25 daa would be required, according to the exponential mathematical model, to get residues levels below the MRL values established by the EU. For azinphos methyl in pear, the residues detected were mathematically fitted to an exponential model (r(2)=0.999). According to it, residue levels under the MRL established by the EU (0.05 mg/kg) are gotten in our conditions in 20 daa. In plastic tunnel tomato chlorfenapyr residues were not detected from 16 daa, having the dissipation curve an exponential trend. In the same condition, there was not a decay of the azoxystrobin concentration during a 24-day trial, being it around 0.40 +/- 0.05 mg/kg. PMID- 20972922 TI - Multiresidue analysis of organophosphate and pyrethroid pesticides in duplicate diet solid food by pressurized liquid extraction. AB - An analytical method was developed for determining organophosphate pesticides (OPP) and pyrethroid pesticides (PYR) in duplicate-diet solid food. The method consisted of pressurized liquid extraction (PLE) with dichloromethane followed by cleanup with gel permeation and solid phase extraction columns and gas chromatography/mass spectrometry (GC/MS) analysis. Quantitative recoveries (73 117 %) of the target pesticides were obtained for spiked duplicate-diet food samples. The percent standard deviation (% RSD) of replicate food samples was within +/- 20 %. Another method was developed for determining a common OPP metabolite, 3, 5, 6-trichloro-2-pyridinol (TCP) in duplicate-diet food. The method consisted of a PLE with methanol followed by liquid-liquid partitioning, derivatization, and GC/MS analysis. Recoveries of TCP ranged from 83 to 101 % for spiked duplicate-diet food samples. The % RSD of replicate food samples was within +/- 15 %. The results confirmed that these methods are reliable and robust, and that they can be used in routine analysis. In addition, a storage stability study for a common OPP, chlorpyrifos (CPF), in solid food samples was performed. The fortified (15)N-(13)C-labeled CPF was stable over 16 mo storage at -20 degrees C in the dark. The developed analytical methods were successfully applied to 278 duplicate-diet food samples from preschool children, demonstrating that these methods are robust and suitable for routine analysis in future exposure monitoring studies. PMID- 20972923 TI - Separation and identification of heterocyclic nitrogen compounds in biooil derived by fast pyrolysis of chicken manure. AB - N-heterocyclics were separated from a biooil, generated by the pyrolysis of chicken manures by column chromatography over neutral alumina and silica, and identified by Pyrolysis Field Ionization Mass Spectrometry (Py-FIMS) and Electrospray Ionization Mass Spectrometry (ESI-MS). Identities of chemical structures, whose presence was indicated by ESI-MS, were confirmed by comparing the Collision-Induced Dissociations (CID's) mass spectra of unknown and standards. The following seven base structures were identified: pyrazine, benzoquinoline, carbazole, phenylpyridine, indole, pyrazole and pyridine. Available hydrogens bonded to ring carbons and nitrogens on the seven N heterocyclics were increasingly substituted by alkyl groups, mainly methylene groups (m/z 14) to yield mono-, di-, tri- methyl N-heterocyclics. In some instances, longer alkyl chains, such as ethyl, propyl, up to heptyl groups were the substituents. PMID- 20972924 TI - Afraid of death. PMID- 20972925 TI - Why do they leave? Factors associated with job termination among personal assistant workers in home care. AB - Recruiting and retaining an adequate number of personal support workers in home care is both challenging and essential to allowing elders to age in place. A mixed-method, longitudinal study examined turnover in a sample of 261 personal support workers in Maine; 70 workers (26.8%) left their employment in the first year of the study. Logistic regression analysis indicated that younger age and lack of health insurance were significant predictors of turnover. Analysis of telephone interviews revealed three overarching themes related to termination: job not worthwhile, personal reasons, and burnout. Implications of study findings for gerontological social workers are outlined. PMID- 20972926 TI - Grandparenting in the 21st century: issues of diversity in grandparent-grandchild relationships. AB - Although previous literature has demonstrated the importance of age, ethnicity, and socioeconomic status in understanding grandparent-grandchild relationships, additional factors contribute to a more complete and nuanced understanding of multigenerational relationships. Thorough understanding of the role of diversity requires examination of the discrete impacts of grandparents' gender, sexual orientation, and physical and/or cognitive limitations on the relationship. This article focuses on these 3 important, yet overlooked, issues of diversity, with a focus on strength-based and empowerment-oriented strategies and their implications for practice, policy, and future research. PMID- 20972927 TI - Exploring the nature of same-sex relationships. AB - This study explored the relationship structure and experiences of 145 people in the United States, aged 50 and above, in long-term, same-sex relationships. A survey assessed relationship satisfaction and roles, caregiving, shared assets, and relationship protection and support. The ENRICH couple scales revealed high scores in communication, conflict resolution, and couple satisfaction. Most participants had taken steps to protect shared assets and assign legal authority to their partners. Participants expressed differing views regarding marriage. This study reveals distinctions based on gender and age that will inform practice with this population. PMID- 20972928 TI - Hoarding cases involving older adults: the transition from a private matter to the public sector. AB - Hoarding interventions with older adults require significant resources from multiple public agencies, yet recidivism occurs frequently. To improve services through better coordination, some communities have formed multiagency hoarding teams (MAHT), which include aging services. MAHTs requested this mixed methods study to understand the progression of cases through the public sector. Quantitative data collected on 52 cases involving adults ages 60+ identified steps in this process. Qualitative data collected from MAHT members were the basis for case studies illustrating the progression of cases through the public sector. Findings have implications for social workers involved in local service coordination, training, and policy. PMID- 20972929 TI - Causal attributions of dementia among Korean American immigrants. AB - To better understand conceptualizations of dementia, this study explored causal attributions of dementia among 209 Korean Americans, using a self-administered questionnaire in Korean. Findings show that Korean Americans endorsed various causal attributions. Factor analysis yielded 3 dimensions of their attributions including psychological, physical/environmental, and cognitive/social. Bivariate analyses showed that younger age and higher education were related to more physical/environmental attributions, and younger age was related to more cognitive/social attributions. The study provides an understanding of causal attributions of dementia that practitioners need to understand to provide culturally competent practice and highlights a need to customize public education messages by specific ethnic groups. PMID- 20972930 TI - Rhetoric to action: a study of stakeholder perceptions of aging well in two local communities. AB - This qualitative study of local perceptions of policy goals and action in relation to aging reports 31 stakeholder interviews within 2 Australian communities exploring (a) the meaning of aging well; and (b) preferred policy actions to achieve positive aging outcomes. Findings suggest that community perceptions of aging well are broadly consistent with the goals of national and international policy frameworks in focusing on 3 dimensions--health, social engagement, and security. Further, participants believe that achievement of positive aging outcomes requires a mix of self-help, community action, and government intervention--particularly government support and encouragement for aging well initiatives. PMID- 20972932 TI - [Multiparametric MRI of the prostate: method for early detection of prostate cancer?]. AB - Current approaches for the early detection of prostate cancer are controversially discussed because the disease is characterized by a high incidence rate with a relatively low morbidity rate, availability of only limited prognostic markers, and continued therapy-related morbidity. Conventional morphological MRI does not play a role in early detection since small tumor foci cannot be delineated. However, if there is clinical suspicion for prostate cancer, multiparametric MRI is currently the most accurate method for detecting and characterizing suspicious lesions in the prostate. The potential to identify the so-called "index lesion", i. e., the tumor area that is most aggressive and determines treatment, is particularly important. This information can increase the accuracy of prostate biopsy and serve as a biomarker for follow-up during active surveillance. The method may considerably contribute to the urgently required separation of clinically significant from clinically insignificant prostate cancers. PMID- 20972934 TI - [A wireless communication system for interventional MRI]. AB - The available MR-compatible communication systems, which are typically designed for diagnostic exams, are mostly based on tubular sound transmission. In other settings, modern commercially available communication systems with ear protection allow wireless communication in noisy environments. The application of MR compatible wireless headsets in interventional radiology precludes tube contact with sterile surfaces and hindrance of the interventionalist's range of motion. The system introduced here allows wireless communication within the scanner room without influencing MR image quality. PMID- 20972933 TI - [Actual review of diagnostics and endovascular therapy of intracranial arterial stenoses]. AB - Approximately 6 - 50% of all ischemic strokes are caused by intracranial arterial stenosis (IAS). Despite medical prevention, patients with symptomatic IAS have a high annual risk for recurrent ischemic stroke of about 12%, and up to 19% in the case of high-grade IAS (>= 70%). Digital subtraction angiography remains the gold standard for the diagnosis and grading of IAS. However, noninvasive imaging techniques including CT angiography, MR angiography, or transcranial Doppler and duplex ultrasound examinations are used in the clinical routine to provide additional information about the brain structure and hemodynamic. However, for technical reasons, the grading of stenoses is sometimes difficult and inaccurate. To date, aspirin is recommended as the treatment of choice in the prevention of recurrent ischemic stroke in patients with IAS. IAS patients who suffer a recurrent ischemic stroke or transient ischemic attack while taking aspirin can be treated with endovascular stenting or angioplasty in specialized centers. The periprocedural complication rate of these endovascular techniques is about 2 - 7% at experienced neuro-interventional centers. The rate of re-stenosis is reported between 10 and 40% depending on patient age and stenosis location. Further randomized studies comparing medical secondary prevention and endovascular therapy are currently being performed. With regard to the improvement of endovascular methods and lower complication rates, the indication for endovascular therapy in IAS could be broadened especially for stenosis in the posterior circulation. PMID- 20972935 TI - Reduction of uterus dose in clinical thoracic computed tomography. AB - PURPOSE: The aim of this study was to investigate the potential dose reduction in the uterus as a result of lead apron protection during thoracic CT scans. Moreover, the distribution of the radiation dose in the uterus was determined in order to obtain information about the ratio of internally and externally scattered radiation. MATERIALS AND METHODS: The uterus doses during thoracic CT were determined by measuring organ doses using an Alderson-RANDO(r)-Phantom and thermoluminescent dosimeters. A 0.25 mm lead equivalent protective apron was used to shield the abdominal area. Three measurement conditions were evaluated: without lead apron, covered with lead apron and wrapped with lead apron. The uterus dose with and without shielding describes the mean value and standard deviation of all examinations and all measurement points in the organ. RESULTS: The uterus dose by thoracic CT was measured to be approximately 66.5 +/- 3.1 uGy. If the abdomen is covered with a 0.25 mm Pb equivalent lead apron in the front area and on both sides, the uterus dose is reduced to 49.4 +/- 2.8 uGy (26% reduction, p < 0.001). If a lead apron is wrapped around the abdomen, providing 0.50 mm Pb shielding in the anterior section due to overlap, and 0.25 mm Pb in the posterior section and on both sides, the uterus dose is reduced even more to 43.8 +/- 2.5 uGy (34% reduction, p < 0.001). The dose distribution when the lead apron covers the abdomen shows that the shielding is effective for the scatter radiation that comes from the anterior part. Moreover, the wrapped apron protects the uterus from all directions and is even more effective for dose reduction than the covering apron. CONCLUSION: Our findings demonstrate that protective aprons are an effective dose reduction technique without additional costs and little effect on patient examination time. PMID- 20972936 TI - [Protocol optimization of three-dimensional spiral CT of craniofacial bones]. AB - PURPOSE: To identify and optimize parameters determining the diagnostic quality of three-dimensional surface models derived from craniofacial spiral CT. MATERIALS AND METHODS: Three dry bone skull specimens were scanned with 1-slice, 4-slice, and 16-slice spiral CT. A total of 60 surface models were calculated with variation of several parameters of the CT scan and calculation of the primary data set and SSD reformations. Two observers evaluated the quality of the resulting models independently using a structured questionnaire. RESULTS: Slice thickness was the only independent factor that influenced image quality. The quality of the 1-slice CT models was poor in all cases. The 4-slice CT models were rated as superior, but also showed relevant impairments. In contrast, the 16 slice CT models provided improved quality with only minor shortcomings. CONCLUSION: Actual clinical applications of three-dimensional models for surgical planning or guidance require high quality of the underlying CT data sets. The slice thickness should not exceed 1 mm. CT examination should be performed using a 4-slice system, or preferably a 16-slice system with a dedicated post processing protocol. PMID- 20972937 TI - Estimation of the minimum dose required to measure ventricular width in follow-up cranial computed tomography (CCT) in children with hydrocephalus. AB - PURPOSE: To estimate the minimum dose needed at follow-up cranial computed tomography (CCT) to reliably determine ventricular width in children with hydrocephalus. MATERIALS AND METHODS: For the study, a phantom was created using the calvarium of an infant which was filled with gelatin and the shaped inner cones of two carrots serving as lateral ventricles. The phantom was scanned ten times with two multi-slice CTs (LightSpeed Ultra, GE, and Somatom Sensation, Siemens), using a tube current of 400, 350, 300, 250, 200, 150, and 100 mA, and a tube voltage of 140, 120, 100, and 80 kV. The width of both lateral ventricles was measured at 4 sites. The values derived from scans performed at 380/400 mA and 140 kV (LightSpeed/Somatom) served as a reference. Measurements scored 1 point if they did not differ by more than 0.5 mm from the reference values. RESULTS: The radiation dose can be reduced from 61.0 mGy to 9.2 mGy (15.1%) with LightSpeed and from 55.0 mGy to 8.0 mGy (14.6%) with Somatom without impairing the reliability of ventricular width measurements. However, in the case of both scanners, certain combinations of tube voltage and current yielded less reliable measurements although the dose was higher and the pixel noise was lower. CONCLUSION: There is no single cut-off dose or setting for tube voltage and current which guarantees reliable ventricular width measurements with the least radiation exposure for both scanners. As a guideline, it is safe to use the standard protocols with a reduced tube current of 100 kV. PMID- 20972938 TI - [Time-Resolved Contrast-Enhanced MR Angiography of the Lower Limbs: Solving the Problem of Venous Overlap]. PMID- 20972939 TI - Combination therapy with nateglinide and telmisartan ameliorates insulin resistance in zucker Fatty rats by suppressing advanced glycation end product receptor axis. AB - Advanced glycation end products (AGEs) and their receptor (RAGE) have been shown to play a role in insulin resistance. We have previously shown that combination therapy with nateglinide (NAT) and telmisartan (TEL) improves postprandial metabolic derangements in Zucker fatty (ZF) rats, an animal model of insulin resistance with obesity. However, effects of combination therapy on insulin resistance remain unknown. We investigated here whether combination therapy with TEL and NAT could ameliorate insulin resistance in ZF rats by suppressing AGE RAGE axis. NAT and/or TEL inhibited insulin receptor substrate-1 (IRS-1) serine phosphorylations at 307 and 636/639 residues in the liver of ZF rats. Further, combination therapy with NAT and TEL, but not each monotherapy alone, significantly restored the decrease in hepatic IRS-1 tyrosine phosphorylation in these animals. In addition, serum levels of AGEs, RAGE expression levels in the liver and hepatic AGE-RAGE index were decreased in NAT plus TEL-treated ZF rats. The present study suggests that combination therapy with NAT and TEL could ameliorate insulin resistance in ZF rats by suppressing the AGE-RAGE axis in the liver. PMID- 20972940 TI - Comparison of effects of protein kinase A, mitogen-activated protein kinase, and cyclin-dependent kinase blockers on rabbit ovarian granulosa cell functions. AB - The aim of the present study was to define the role of protein kinase A (PKA)-, mitogen-activated protein kinase (MAPK)-, and cyclin-dependent kinase (CDK) dependent pathways in the control of ovarian cell functions. The effects of PKA, MAPK, and CDK blockers (KT 5720, PD 98059, and olomoucine, respectively), given at doses of 0.001-10.0 MUg/ml medium on functions of cultured rabbit granulosa cells were examined. Expression of PKA, MAPK/ERK1,2, secretory activity (IGF-I output), and proliferation (proliferating cell nuclear antigen, PCNA) in these cells were determined by RIA, immunocytochemistry and Western blotting. A PKA inhibitor, KT 5720 suppressed the expression of PKA and MAPK/ERK1,2, the IGF-I release, and the ratio of PCNA-positive cells in granulosa cells. A MAPK blocker, PD 98059 reduced the expression of MAPK/ERK1,2 (but not PKA), the IGF-I release, and percentage of PCNA-positive cells. A CDK blocker, olomoucine, increased the PKA expression, decreased the expression of MAPK/ERK1,2 and PCNA, but did not affect the IGF-I release. These observations confirm the involvement of PKs in control of basic ovarian functions and demonstrate the involvement of PKA in stimulation of ovarian cell proliferation and MAPK (but not CDK) and in promotion of ovarian IGF-I release. Different activity and specificity of the PKA, MAPK, and CDK blockers in their effects on PCNA and IGF-I suggests different biological role of these PKs in control of proliferative and secretory functions of rabbit ovarian cells. PMID- 20972941 TI - Islets in early life are resistant to detrimental effects of a high-fat maternal diet: a study in rats. AB - Offspring of rats fed high-fat diets during pregnancy and lactation develop glucose intolerance and islet dysfunction in adulthood. Because other models of developmental programming of glucose intolerance are associated with defective islet development, we investigated whether high-fat exposure during fetal or neonatal life impairs islet development and function, thereby contributing to islet dysfunction in later life. Female rats were fed control or high-fat diets and their pups cross-fostered after birth to represent 4 groups with each combination of control and high-fat diet for the natural and foster mother. In a time course study, pups were kept with the natural mother until weaning. Pancreases were analysed for insulin content, beta cell mass, and islet number. Isolated islets were studied for insulin secretory responses and susceptibility to palmitate-induced apoptosis assessed by caspases 3/9 activity. Pancreatic insulin content and beta cell mass were increased in pups exposed to maternal high-fat diets after birth, whereas glucose-stimulated insulin secretion from islets of high-fat offspring at 5 and 11 days of age was lower than controls. Islets from control rats of 2-14 days of age were resistant to the pro-apoptotic effects of palmitate seen in older animals. The immature beta cell is therefore insensitive to toxic effects of palmitate and may compensate for the inhibitory effects on insulin secretion by increasing beta cell mass. The data suggest that susceptibility to glucose intolerance in offspring of dams fed high-fat diets may not be a consequence of deleterious effects on beta cell mass in early life. PMID- 20972942 TI - Lipolysis index: evaluation of a new tool for metabolic assessment in epidemiological studies on obesity. AB - Lipid mobilization through adipocyte lipolysis is central for energy metabolism and is decreased in obesity. However, the factors of importance for lipolytic activity in the general population are not known. To further examine this we performed a cross-sectional study on teenagers and adults. We constructed and evaluated a simple index of lipolytic activity (ratio of fasting p-glycerol and body fat %) in population based samples in 316 teenagers (BMI 16-51 kg/m (2)) and 3,039 adults (BMI 16-70 kg/m (2)). In the adults, multiple regression analysis showed that waist and BMI but not age, plasma insulin, plasma noradrenaline or waist-to-hip ratio contributed independently and inversely to lipolytic activity (partial r=-0.37 and -0.28, respectively, p<0.0001). Together waist and BMI explained about 45% of the variability of lipolysis. Waist was a stronger factor than BMI in stepwise regression. The same analysis in teenagers showed that only BMI contributed independently and inversely to lipolytic activity (partial r= 0.90, p<0.0001) and explained about 55% of lipolysis variation. BMI had the strongest effect on lipolysis in lean teenagers. The results were the same for men and women. At all levels of lipolytic activity plasma fatty acid levels were elevated in obese subjects (p<0.0001). We conclude that during adolescence BMI is the major factor negatively influencing lipolytic activity, in particular among lean young subjects. In adulthood central fat accumulation together with increasing BMI decreases lipolysis. In spite of low lipolytic activity circulating fatty acid levels are increased in obesity, probably due to an adipose mass effect. PMID- 20972943 TI - A matter of the heart: myocardial metastases in neuroendocrine tumors. AB - The aim of the present study was to evaluate frequency, clinical spectrum, and treatment of myocardial metastases in patients with histologically proven neuroendocrine tumors by analysis of our database and literature review. The literature on cardiac metastases in patients with neuroendocrine tumors published from 1973 to the present was reviewed for age, sex, primary tumor localization, metastases, symptoms, complications, treatment, diagnostic methods, and histology. Patient records from our institution were analyzed retrospectively for cardiac metastases detected by any diagnostic means and detailed patient histories are given. 4 patients with myocardial metastases could be identified in our database (n=550) while literature review identified 41 published cases. Mean age at initial diagnosis was 57.5 years (females=13, males=28), primary tumor localizations were foregut (n=7), midgut (n=28), hindgut (n=1), or unknown (n=3). Carcinoid syndrome was reported for 28 patients. Cardiac involvement was right ventricular only (n=10), left-ventricular only (n=11), or biventricular (n=10). Diagnosis was obtained by echocardiography (n=21), CT/MRI (n=12) and other methods (n=9), or by autopsy (n=9). We describe visualization of cardiac metastases by (68)Ga-DOTATOC-PET/CT for the first time. Clinical presentation ranged from asymptomatic patients to cardiac arrest. Follow-up times ranged from <1 month up to 12 years. Clinicians treating patients with neuroendocrine tumors should be aware of the heart as a possible site of metastatic disease. Echocardiography and MRI are the methods of choice for follow-up, while PET/CT might contribute to earlier and more frequent detection. Management of cardiac metastases requires close cooperation between specialists of internal medicine, nuclear medicine, and cardiac surgery. PMID- 20972945 TI - Serum levels of the adipokine fasting-induced adipose factor/angiopoietin-like protein 4 depend on renal function. AB - Fasting-induced adipose factor/angiopoietin-like protein 4 (FIAF/Angptl4) was recently introduced as a novel adipokine influencing glucose and lipid homeostasis. In the current study, we quantified circulating FIAF/Angtl4 levels in patients on chronic hemodialysis (CD) as compared to controls with a glomerular filtration rate above 50 ml/min. FIAF/Angptl4 was determined by ELISA in control (n=60) and CD (n=60) patients and correlated to clinical and biochemical measures of renal function, glucose and lipid metabolism, as well as inflammation, in both groups. Median serum FIAF/Angptl4 levels were more than 5 fold higher in CD patients (48.3 MUg/l) as compared to control subjects (8.4 MUg/l) (p<0.001). Furthermore, serum creatinine independently predicted FIAF/Angptl4 concentrations in multiple regression analyses in control subjects (p<0.01). In CD patients, C-reactive protein was independently and positively associated with circulating FIAF/Angptl4 (p<0.01). Taken together, we show that serum FIAF/Angptl4 levels are significantly increased in end-stage renal disease and independently associated with markers of renal function in control subjects. PMID- 20972944 TI - Somatostatin analogues do not affect calcium metabolism in patients with acromegaly and primary hyperparathyroidism [corrected] due to MEN 1-like syndrome. AB - Patients with clinical features of MEN 1 without mutations in the menin gene fulfill the criteria of MEN1-like syndrome. Primary hyperparathyroidism (PHP) is the most frequent clinical finding in both syndromes and is usually treated by surgery. However, PHP has been reported to respond to somatostatin analogues (SSA) in MEN 1 patients. 7 patients with PHP in the context of MEN 1-like syndrome (and absence of mutations in the menin gene) were enrolled in the study and treated with SSA for 6 months for the non-PHP disease before parathyroidectomy. Serum ionized calcium, phosphorus, and PTH concentrations, and 24-h urinary calcium and phosphorus excretion were measured before and after SSA therapy. Mean serum ionized calcium, phosphorus, and PTH concentrations did not significantly change after a 6-month course with SSA. SSA scintigraphy did not reveal uptake in the neck region corresponding to the parathyroid adenoma identified at surgery and confirmed at histology. However, immunohistochemistry revealed SS-type 2A receptor in parathyroid tissue samples of 6 out of 7 patients. SSA therapy does not affect calcium-phosphorus metabolism in patients with MEN 1-like syndrome, suggesting that the drug has no role in controlling PHP in these subset of patients. PMID- 20972946 TI - Circulating Reg1alpha proteins and autoantibodies to Reg1alpha proteins as biomarkers of beta-cell regeneration and damage in type 1 diabetes. AB - Type 1 diabetes is an autoimmune disease where beta-cells are in a constant process of death and renewal. Reg genes play a role in beta-cells regeneration. Reg proteins may be target of an autoimmune response in type 1 diabetes with consequent production of autoantibodies and failure of regeneration. The objective of this work was to characterize the role of Reg1alpha proteins and anti-Reg1alpha antibodies as biomarkers of beta-cell regeneration and damage. Serum levels of Reg1alpha protein were investigated in 87 type 1 diabetic subjects (31 newly diagnosed and 56 long standing), 63 type 2 diabetic subjects, 39 subjects with systemic lupus erythematosus (SLE), a nonpancreatic autoimmune disorder, and 64 healthy subjects. The presence of anti-Reg1alpha antibodies and correlation with metabolic, immune, and genetic parameters were analyzed in diabetic subjects. Increased levels of Reg1alpha protein were observed in newly diagnosed (p=0.002), and long standing (p=0.001) type 1 diabetes patients and type 2 diabetic subjects (p<0.001). Anti-Reg1alpha antibodies were found in 47% of patients with type 1 diabetes. No correlation was found with metabolic, immune, and genetic parameters. Patients with SLE showed no increase in Reg1alpha protein. We report here for the first time raised serum Reg1alpha protein in type 1 and type 2 diabetes and anti-Reg1alpha antibodies in type 1 diabetes. Reg1alpha levels appear not to be influenced by genetic or metabolic control. These findings allow considering future studies on Reg1alpha protein and autoantibody as new tools in the evaluation and monitoring of beta-cells regeneration and autoimmunity. PMID- 20972948 TI - Typical and unusual sonoelastographic patterns of breast cystic lesions: impact on BI-RADS classification. AB - PURPOSE: To describe the sonoelastographic appearance of breast cysts (simple, complicated-cysts with sedimentation and complex-cysts with internal solid parts). To assess the influence of sonoelastography on the BI-RADS classification of complicated cysts. MATERIALS AND METHODS: A prospective study was conducted and all cysts diagnosed by the same radiologist between May 2007 and July 2008 in our breast unit were included. Each lesion was assessed according to BI-RADS and the Tsukuba elasticity score using a Hitachi 8500 US device. Cytology or histopathology was obtained for complicated and complex cysts. RESULTS: 49 simple, 43 complicated and 14 complex cysts were detected. The elasticity patterns were divided into 4 categories: typical BGR (blue-green-red) pattern, appearance similar to that described for solid. lesions, variants of BGR, an inverse score of 3. The BGR pattern was predominant in breast cysts. Atypical elasticity patterns were mostly associated with complicated and complex cysts. BI RADS classification of complicated cysts before and after elastography showed a statistically significant difference in terms of final category assessment (most of the complicated cysts were downgraded to BI-RADS 2 after elastography). CONCLUSION: Being aware of the wide spectrum of elastographic patterns of breast cysts and considering elastography when assessing the BI-RADS category of complicated cysts may lead radiologists to better patient management. PMID- 20972947 TI - The impact of first trimester screening and early fetal anomaly scan on invasive testing rates in women with advanced maternal age. AB - PURPOSE: To evaluate the acceptance of noninvasive screening for trisomy 13, 18, 21 and the impact on invasive testing rates in women at an age>=35 years. MATERIALS AND METHODS: In a retrospective analysis from 2003-2006 including 13 268 women>=35 years old with singleton pregnancies and 3133 invasive procedures, we evaluated the prenatal detection rate of aneuploidies in two cohorts. Group 1: advanced maternal age as sole indication, group 2: additional abnormalities and/or suspicious maternal serum parameters. In an additional analysis from 1998 2006 including 31,076 patients>=35 years, we investigated the shift in time of sonography at 11+0-13+6, 14+0-17+6 and 18+0-22+6 gestational weeks (gw). RESULTS: Among 13,268 women, 3133 invasive tests were performed with a significant decrease over time (-17%). 9% of women chose invasive testing after a normal ultrasound (group 1, n=1,267) and 14% in the case of additional markers (group 2, n=1,866). 102 cases of aneuploidy were disclosed. The proportion of detected aneuploidies was 0.86% in group 1 and 4.9% in group 2. No change in the overall detection rate (90-93%) was observed. The number of patients>=40 years increased significantly (+2.8%). There was an increase in examinations at 11+0-13+6 gw (+8%), a decrease at 14+0-17+6 gw (-10.3%) and no significant change at 18+0-22+6 gw over time. CONCLUSION: Increasing numbers of women>=35 years of age rely on the individually adjusted risk figure to make a decision about invasive testing. The application of these selective procedures can reduce the rates of invasive testing with fewer losses of normal fetuses and led to an earlier diagnosis of aneuploidies. PMID- 20972949 TI - [Computer-aided cognitive behavioral therapy for depression]. AB - OBJECTIVE: The aim of this study was to conduct a systematic literature search in order to assess effectiveness of computer- and internet-based cognitive behavioural therapy (CCBT). METHODS: Medline, Cochrane Library, Web of Science and PsycINFO were searched for relevant articles. Only RCTs were included. Effect sizes were calculated and quality of studies was assessed. RESULTS: 16 studies were retrieved and included. Effect sizes depended on therapist time involvement and control group intervention (waiting list vs. active control group) and ranged between 0.0 and 1.1. CONCLUSIONS: CCBT provides an effective and potentially cost effective interventional strategy for depressive disorders. Effects of no and minimal contact therapies are confounded with conditions of control groups and need further investigation. While patients with Major Depression seem to benefit from computer-based therapy with regular therapist contact, it remains unclear whether unattended self-help interventions over the internet are effective for this patient population. However, these interventions are effective in patients with mild to moderate depressive symptomatology. CCBT may serve as a first step of treatment within stepped care approaches and may help to offer treatment to individuals in remote areas and to decrease barriers to seek psychiatric care caused by stigma perception. PMID- 20972950 TI - [Does early use of ECT reduce the hospital stay period in major depressive episodes?]. AB - OBJECTIVE: ECT is an effective and safe therapy with fast response for depressive disorders. Nevertheless it's mostly used for therapy resistance. In antidepressive treatments fast response may be related with antidepressive efficacy. We studied, if earlier ECT could result in a shorter hospital stay period after the treatment. METHODS: The hospital stay period after ECT and CGI changes of 34 depressed patients with immediate ECT were compared to those of 19 patients, who had to wait for this treatment while being treated conservatively in another psychiatric hospital without ECT-possibility. RESULTS: Patients with early ECT could be dismitted from hospital at a mean of 57 days after the first ECT, patients who had to wait for this treatment at a mean of 100 days after the first ECT. CGI-changes were similar in both groups. CONCLUSIONS: Early use of ECT may reduce hospital stay periods in depressed patients. PMID- 20972951 TI - [Forensic addiction treatment in Germany (section 64 of the penal code): three therapeutically and predicatively relevant clusters of drinkers]. AB - OBJECTIVE: According to section 64 of the German penal code, offenders may be sentenced to compulsory addiction treatment in forensic mental hospitals. An expert witness assesses each candidate regarding the prognosis of treatment. Frequently, optimistic assessments are not confirmed, and approximately half of the patients are returned to prison. The study aims at learning more about patients' characteristics relevant for treatment outcome by considering subgroups of patients. METHODS: 150 drinkers treated according to art. 64 were interviewed and psychologically assessed in an early stage of treatment. Therapists reported on treatment outcome. A cluster analysis was conducted. RESULTS: Like in former research, 3 considerably differing subgroups of patients could be identified. CONCLUSIONS: A "multi-problem" subgroup with early onset of severe behavior problems has a very small chance to profit from treatment. In this group of offenders, the prospects of a detention according to art. 64 of the penal code should be assessed very critically. On the other hand, efforts must be taken to refine treatment methods adequate for this high risk group. PMID- 20972952 TI - [Schizophrenic diseases, psychosis and homicide: the importance of community psychiatry for the prevention of offences]. AB - OBJECTIVE: Even though homicides of psychotic patients are relatively rare, they have a great impact on the public opinion about the mentally ill. Current literature indicates that psychotic patients are at an increased risk to commit violent offences. The risk of this group to commit a homicide is even more increased. The question of our study was to find out whether past homicides of schizophrenic patients could have been avoided if treatment had been administered properly. METHODS: Review of 39 homicide cases, committed by patients who had been psychotic during the offence. RESULTS: 10.2 % of the homicides could have been prevented in the absence of mistakes of therapists or legal authorities. Another 15.4 % of the homicides could have probably been avoided in case of communication between the treating therapists and family of the patient previously to the offence. CONCLUSIONS: The whole family of the patient should be involved in the therapy. Possibilities are home visits on the basis of community care. Furthermore, threats of psychotic patients should be taken seriously. PMID- 20972953 TI - NOTES for the cardia: antireflux therapy via transluminal access. AB - BACKGROUND AND STUDY AIMS: The current standard for surgical antireflux therapy is laparoscopic Nissen fundoplication, but natural orifice transluminal endoscopic surgery (NOTES) enables even less invasive access to the peritoneal cavity. We therefore aimed to evaluate a NOTES approach to antireflux therapy. PATIENTS AND METHODS: An animal study including 24 pigs (16 nonsurvival and eight survival). After the peritoneal cavity had been accessed via the rectosigmoid, the gastroesophageal junction (GEJ) was laid open using conventional endoscopic instruments. Thereafter, a transcutaneously introduced hook was used for tunneling and lifting of the distal esophagus. Finally, an antireflux ring was placed around the cardia. Animals were observed over 10 days in the survival series. Correct application of the prosthesis, adverse events as a result of the procedure, and bacterial contamination were evaluated by autopsy. RESULTS: The esophagogastric junction was strengthened by applying the ring prosthesis in 22 of 24 animals. Four bleeding episodes were observed, three of which were handled endoscopically. Correct placement of the prosthesis was accomplished in 21 of 22 animals. In the survival series, 1 pig died after transhiatal herniation of the stomach, and 1 pig suffered from peritonitis due to intraoperative contamination. In 7 of the 8 survival animals, no bacterial growth was noted by smear culture. The intervention had to be performed as a hybrid NOTES procedure in all cases. CONCLUSION: Exposure of the GEJ and placement of an antireflux prosthesis via a hybrid NOTES procedure is feasible, despite some complications. This approach may be considered as a basis for optimization and further development of pure NOTES antireflux procedures. PMID- 20972954 TI - Prediction of common bile duct stones in the earliest stages of acute biliary pancreatitis. AB - BACKGROUND AND STUDY AIMS: Accurate prediction of common bile duct (CBD) stones in acute biliary pancreatitis is warranted to select patients for early therapeutic endoscopic retrograde cholangiopancreatography (ERCP). We evaluated commonly used biochemical and radiological predictors of CBD stones in a large prospective cohort of patients with acute biliary pancreatitis who were undergoing early ERCP. PATIENTS AND METHODS: 167 patients with acute biliary pancreatitis who were undergoing early ERCP (< 72 hours after symptom onset) in 15 Dutch hospitals in 2004 - 2007 were prospectively included. Abdominal ultrasonography and/or computed tomography (CT) was performed on admission and complete liver biochemistry determined daily. We used univariate logistic regression to assess associations between CBD stones found during ERCP (gold standard) and the following parameters: (1) clinical: age, sex, predicted severity; (2) radiological: dilated CBD, impacted stone in CBD; and (3) biochemical: bilirubin, gamma-glutamyltransferase (GGT), alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). RESULTS: Out of 167 patients, 94 (56 %) had predicted severe acute biliary pancreatitis, 51 (31%) exhibited a dilated CBD and 15 (9%) had CBD stones on ultrasonography and/or CT. ERCP was performed at a median of 0 days (interquartile range 0 - 1) after admission. CBD stones were found during ERCP in 89/167 patients (53%). In univariate analysis, the only parameters significantly associated with CBD stones were GGT (per 10 units increase: odds ratio 1.02, 95% CI 1.01 - 1.03, P = 0.001) and alkaline phosphatase (per 10 units increase: odds ratio 1.03, 95% CI 1.00 - 1.05, P = 0.028). These and all other tested parameters, however, showed poor positive predictive value (ranging from 0.53 to 0.69) and poor negative predictive value (ranging from 0.46 to 0.67). CONCLUSIONS: The results of this study suggest that commonly used biochemical and radiological predictors of the presence of CBD stones during ERCP in the earliest stages of acute biliary pancreatitis are unreliable. PMID- 20972955 TI - Endoscopic submucosal dissection in gastric neoplasia - experience from a European center. AB - BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is a promising technique for the resection of early gastric neoplasia. There are only a few data from the Western world to date. METHODS: Over a 7-year-period, 104 gastric lesions were treated with ESD in a European referral center, of which 91 were included in this study. A total of 66 lesions were early gastric cancer (EGC) and 25 were adenomas. Of the EGCs, 11 lesions (16.7 %) fulfilled the guideline criteria (EGC-GC) and 55 lesions (83.3 %) fulfilled the expanded resection criteria (EGC-EC) of the Japanese guidelines for the treatment of gastric cancer. RESULTS: ESD was technically possible in 85 lesions (93.4 %). In six lesions ESD was not possible due to non-lifting. En bloc resection rates for all lesions, ECGs-GC, ECGs-EC, and adenomas were 87.1 %, 100 %, 88.2 %, and 79.2 %, respectively. R0 en bloc resection rates were 74.1 %, 90 %, 68.6 %, and 79.2 %, respectively. Complications were: one perforation during piecemeal endoscopic mucosal resection of a lesion in which ESD was judged to be impossible (1.2 %); three clinically relevant bleedings (3.5 %); one gastric ischemia (1.2 %); and four strictures (4.7 %). No mortality was observed. There were five recurrences after piecemeal resection (50 %) compared with only one after en bloc resection (1.5 %; P < 0.05). The rate of recurrence for EGCs was 5.6 %, and this were seen exclusively after piecemeal resection. CONCLUSIONS: Our data show that ESD is a feasible technique in Europe even in patients with EGC according to the extended criteria. Resection rates are promising and complication rates are acceptable. Results are worse compared with large studies from Japan but still excellent regarding the learning curve of the method. ESD should be offered as the treatment of choice for early gastric neoplasia especially when en bloc resection cannot be performed with other resection techniques. PMID- 20972958 TI - Radioactivity. AB - This appendix provides selected properties of radioisotopes commonly used in the molecular biology laboratory. PMID- 20972956 TI - Effect of virtual endoscopy simulator training on performance of upper gastrointestinal endoscopy in patients: a randomized controlled trial. AB - BACKGROUND: Skills in gastrointestinal endoscopy mainly depend on experience and practice. Patients upon whom trainees perform their first endoscopic examinations are likely to suffer more discomfort and prolonged procedures. Training on endoscopy simulators may reduce the time required to reach competency in patient endoscopy. PATIENTS AND METHODS: Residents in internal medicine without experience of endoscopy were randomized to a group who trained on a simulator before conventional training (group S) or one that received conventional training only (group C) before starting upper gastrointestinal endoscopy in patients. After endoscopy, discomfort and pain were evaluated by patients, who were blind to the beginners' training status. Results in terms of time, technique (intubation, pyloric passage, J-maneuver), and diagnosis of pathological entities were evaluated by experts. RESULTS: From 2003 to 2007, 28 residents were enrolled. Comparing group S with group C in their first ten endoscopic examinations in patients, time taken to reach the duodenum (239 seconds (range 50 - 620) vs. 310 seconds (110 - 720; P < 0.0001) and technical accuracy ( P < 0.02) were significantly better in group S. Diagnostic accuracy did not differ between the groups. Fourteen residents (7 simulator-trained, 7 not simulator-trained) continued endoscopy training. After 60 endoscopic examinations, investigation time was still shorter in group S. Technical and diagnostic accuracy improved during on-patient training in both groups; here differences between groups were no longer observable. There were no significant differences in discomfort and pain scores between the groups after 10 and after 60 endoscopies. Discomfort and pain were higher than for endoscopy performed by experts. CONCLUSION: This randomized controlled trial shows that virtual simulator training significantly affects technical accuracy in the early and mid-term stages of endoscopic training. It helps reduce the time needed to reach technical competency, but clinically the effect is limited. Simulator training could be useful in an endoscopy training curriculum but cannot replace on-patient training. PMID- 20972959 TI - Transgenic and gene-targeted mouse lines for toxicology studies. AB - This unit contains an extensive tabular listing of transgenic and gene-targeted mice useful in toxicological studies. Each listing contains a brief description of the phenotype, relevant references, and where applicable, commercial sources. PMID- 20972960 TI - Common stock solutions and buffers. PMID- 20972961 TI - Standard laboratory equipment. AB - This appendix lists pieces of equipment that are standard in the modern toxicology laboratory, i.e., items used extensively in this manual and thus not usually included in the individual materials lists. No attempt has been made to list all items required for each procedure in the Materials list of each protocol; rather, those lists note those items that might not be readily available in the laboratory or that require special preparation. See SUPPLIERS APPENDIX for contact information for commercial vendors of laboratory equipment. PMID- 20972962 TI - Molecular biology techniques. AB - Protocols presented in Current Protocols in Toxicology sometimes include molecular biological, biochemical, and other biological techniques that may not be fully described in this manual. Although it may be reasonable to assume that readers have at least a basic understanding of these techniques, there are times when a full step-by-step description of a procedure is helpful. This appendix lists common molecular biology techniques (some of which are described in this manual) and provides references to specific units in its sister publications Current Protocols in Molecular Biology, Current Protocols in Immunology, and Current Protocols in Cell Biology, which describe the methods in more detail. PMID- 20972963 TI - Enzymatic amplification of DNA by PCR: standard procedures and optimization. AB - The polymerase chain reaction (PCR) is used to enzymatically amplify small quantities of specific DNA sequences. The reaction must optimized to specifically amplify the sequences and primers of interest; this includes titration of magnesium chloride and selection of enhancing agents, if appropriate, to minimize nonspecific primer target interactions and maximize the specificity, sensitivity, and yield. PMID- 20972964 TI - Detection and quantitation of radiolabeled proteins in gels and blots. AB - This unit provides procedures for detecting an quantifying radiolabeled proteins in SDS-polyacrylamide gels or blots. Autoradiography requires fixed, dried gels before exposure to X-ray film. The results may be enhanced by using intensifying screens and/or preflashing the film. Alternatively fluorography with organic scintillant-impregnated gels may be used to enhance signal. The autoradiogram may be quantified by densitometry. Phosphorimaging is a useful alternative to film exposure. PMID- 20972965 TI - Northern blot analysis of RNA. AB - This unit describes the processes of extracting RNA from tissues and analyzing it by northern blot hybridization to probe the expression of a particular gene at the transcriptional level. PMID- 20972966 TI - Techniques for mammalian cell tissue culture. AB - This appendix opens with detailed discussions on the latest principles of sterile technique and preparation of culture media. Step-by-step protocols describe trypsinizing and subculturing monolayer cultures, passaging suspension cultures, freezing and thawing cells, counting cells using a hemacytometer, and preparing cells for transport. PMID- 20972967 TI - One-dimensional SDS gel electrophoresis of proteins. AB - Electrophoresis is used to separate complex mixtures of proteins (e.g., from cells, subcellular fractions, column fractions, or immunoprecipitates), to investigate subunit compositions, and to verify homogeneity of protein samples. It can also serve to purify proteins for use in further applications. In polyacrylamide gel electrophoresis, proteins migrate in response to an electrical field through pores in a polyacrylamide gel matrix; pore size decreases with increasing acrylamide concentration. The combination of pore size and protein charge, size, and shape determines the migration rate of the protein. In this unit, the standard Laemmli method is described for discontinuous gel electrophoresis under denaturing conditions, that is, in the presence of sodium dodecyl sulfate (SDS). Both full-size and minigel formats are detailed. Several modifications are provided for specific applications. For separation of peptides and small proteins, the standard buffers are replaced with either a Tris-tricine buffer system or a modified Tris buffer in the absence of urea. Continuous SDS PAGE is a simplified method in which the same buffer is used for both the gel and electrode solutions and the stacking gel is omitted. Other protocols cover the preparation and use of ultrathin gels and gradient gels, and the simultaneous preparation of multiple gels. PMID- 20972968 TI - Classification of thyroid follicular lesions based on nuclear texture features- lesion size matters. PMID- 20972969 TI - Injection laryngoplasty with micronized dermis: a 10-year experience with 381 injections in 344 patients. AB - OBJECTIVE: Micronized Dermis (MD) has been used for injection laryngoplasty for correction of glottic insufficiency since 2000. There is controversy whether the material is temporary or permanent. This is a retrospective review of 381 injections in 344 patients. From this review, we hope to better define the role of MD in injection laryngoplasty. METHOD: Retrospective chart review from a single surgeon (2000-2010) RESULTS: The indications for MD were for both temporary and permanent correction of glottic insufficiency. The diagnoses were: vocal fold paralysis (n = 216), scar (n = 51), atrophy (n = 42), sulcus (n = 22), and others (n = 13). The material has the best effect when placed into the membranous vocal fold just lateral to the vocal ligament. The operative and postoperative complication was 1.05%. Twenty-nine percent of all injections resulted in unwanted absorption. Overinjection was needed and transcervical approach was preferred to prevent implant extrusion with overinjection. The median volume of injected material has increased from 0.8 cc to 1.0 cc over the decade. In 159 patients with long-term follow-up (>1 year), there was a 14% incidence of reinjection. Despite this, the overall need for open procedures in patients with long-term follow-up was 20%. CONCLUSIONS: Despite the problems of inconsistency in preparation, slow absorption and need for overinjection, micronized dermis is a safe allograft material that has long-term (>1 year) stability. The material may reduce the need for open surgery. It can be used for both temporary and permanent vocal fold augmentation. PMID- 20972970 TI - Intralesional corticosteroid injection and dilatation provides effective management of subglottic stenosis in Wegener's granulomatosis. AB - OBJECTIVES/HYPOTHESIS: To describe our experience with the use of intralesional corticosteroid injection and dilatation (ILCD) in the management of subglottic stenosis (SGS). STUDY DESIGN: Retrospective chart review. METHODS: A retrospective chart review was performed of all patients with SGS requiring ILCD, from 2003 to 2008, at the Department of Otolaryngology-Head and Neck Surgery, Mount Sinai Hospital, Toronto, Canada. RESULTS: Twelve patients with SGS underwent 36 ILCD operations with a mean of three procedures per patient. We identified eight patients with Wegener's granulomatosis (WG) and four patients without WG. The eight WG patients received an average of 3.37 procedures, whereas non-WG patients required an average of 2.25 procedures. This maintained airway patency and symptom control for an average of 11.9 and 8.1 months, respectively. Only one complication was identified, and no long-term sequelae were found. No patients required new tracheotomies and one patient with a previous tracheotomy was successfully decannulated. CONCLUSIONS: Our data supports the use of ILCD as a safe and effective treatment of SGS in both WG and non-WG patients. PMID- 20972971 TI - Viscosimetric detection in size-exclusion chromatography (SEC/GPC): The Goldwasser method and beyond. AB - Size-exclusion chromatography (SEC or GPC) is the most widely used separation method to characterize polymers. The high level of complexity of most polymeric materials necessitates the use of not only concentration-sensitive detection but also structure-sensitive detection. Viscometry is usually used in conjunction with a concentration-sensitive detector and universal calibration to determine molecular weights of polymers. Goldwasser proposed to use a viscometer as a single detector to determine number-average molecular weights, M(n) (ACS Symposium Series, 521, 143). The method is particularly of interest when concentration-sensitive detection is not available, because the sample is isorefractive or not UV-absorbing, or because composition is not constant (copolymers). It has known very little applications so far. It actually does not only allow determining M(n), but also the number hydrodynamic volume distribution. This opens a wider range of applications for the Goldwasser method. Size-exclusion chromatography only yields inaccurate molecular weight distributions for some complex branched polymers. Hydrodynamic volume distributions have then a strong potential for comparative studies owing to their far higher accuracy. Our experimental tests highlight the fact that the method is highly sensitive to noise and careful optimization of the injection concentration is needed, but number distribution can be obtained as well as M(n). PMID- 20972972 TI - Evaluation of comprehensive on-line liquid chromatography thermally assisted hydrolysis and methylation-gas chromatography-mass spectrometry for characterization of sulfonated lignins. AB - Sulfonated lignins, used as dispersants in agrochemical formulations, have been characterized by hyphenation of ion-pair RPLC and thermally assisted hydrolysis and methylation-GC-MC (THM-GC-MS). The chemical structure of a series of selected lignins was evaluated, both in terms of overall composition and in terms of composition as a function of molecular size. Some sulfonated lignins give rise to unstable formulations. In the compositional analysis, these samples were found to yield additional fragments. A newly developed comprehensive method made it possible to monitor the occurrence of these fragments as a function of molecular size. In addition to differences in the molecular size between "good" and "bad" batches, clear differences in chemical composition were established. PMID- 20972973 TI - Separation of water-soluble polymers using capillary-channeled polymer fiber stationary phases. AB - Chromatographic separations of synthetic and natural polymers are usually affected by a size exclusion chromatography (SEC) mechanism. Although SEC is a proven method of separation based on hydrodynamic size, a chromatographic method based solely on chemical interactions would present certain advantages. This laboratory has been investigating the use of capillary-channeled polymer (C-CP) fibers as stationary phases in HPLC for the separation of biomacromolecules. C-CP fibers allow highly efficient fluid transport and an amorphous surface structure, minimizing mass transfer effects commonly associated with porous, packed-bed technologies. Choice of the base fiber identity allows flexibility in the potential types of solute-surface interactions. Two water-soluble polymers, glycolic acid ethoxylate 4-nonylphenyl ether, and poly(4-vinylpyridine hydrochloride), were used as test solutes because of their similarities to polymers of interest in the consumer products industry. SEC separation of this pair was not possible due to the similarities in hydrodynamic size. Poly(ethylene terephthalate), polyester and nylon-6 C-CP fibers were evaluated as stationary phase materials. The former was found to offer superior chromatographic separations and recoveries when operating under what would be considered to be typical RP separation conditions: a flow rate of 1 mL/min and gradient of 0-100% H(2)O/ACN with 0.06% TFA over 5 min. PMID- 20972974 TI - 2-D chromatography applied to the study of block copolymers synthesized by nitroxide-mediated controlled free-radical seeded emulsion polymerization. AB - 2-D chromatography with gradient polymer elution chromatography in the first dimension was used to characterize a series of block copolymers prepared by nitroxide-mediated controlled free-radical seeded emulsion polymerization. The data provide a detailed picture of the different populations generated during the successive stages of the reaction. In particular, deviations from ideal conditions, such as an exothermic temperature spike, are obvious from the 2-D chromatogram, and its interpretation provides unique insight into the reaction mechanisms. Finally, atomic force microscopy images obtained on films cast from copolymer solutions evidence the relationship between polymer microstructure and film morphology. PMID- 20972975 TI - Potential of a metal-organic framework as a new material for solid-phase extraction of pesticides from lettuce (Lactuca sativa), with analysis by gas chromatography-mass spectrometry. AB - The metal-organic framework (infinity)[(La(0.9)Eu(0.1))(2)(DPA)(3)(H(2)O)(3)] was tested for extraction of pyrimicarb, procymidone, malathion, methyl parathion and alpha- and beta-endosulfan from lettuce, with analysis using GC/MS in SIM mode. Experiments were carried out in triplicate at two fortification levels (0.1 and 0.5 mg/kg), and resulted in recoveries in the range of 78-107%, with RSD values between 1.6 and 8.0% for (infinity)[(La(0.9)Eu(0.1))(2)(DPA)(3)(H(2)O)(3)] sorbent. Detection and quantification limits ranged from 0.02 to 0.05 mg/kg and from 0.05 to 0.10 mg/kg, respectively, for the different pesticides studied. The method developed was linear over the range tested (0.05-10.0 MUg/mL), with correlation coefficients ranging from 0.9990 to 0.9997. Comparison between (infinity)[(La(0.9)Eu(0.1))(2)(DPA)(3)(H(2)O)(3)] and conventional sorbent (silica gel) showed better performance of the (infinity)[(La(0.9)Eu(0.1))(2)(DPA)(3)(H(2)O)(3)] polymeric sorbent for all pesticides tested. PMID- 20972976 TI - Simultaneous determination of methylxanthines in different types of tea by a newly developed and validated TLC method. AB - The aim of this paper is to develop a new simple, fast and economical method for simultaneous quantitative determination of methylxanthine compounds based on TLC combined with image analysis. To obtain certain results, both extraction and chromatographic separation were optimized. The optimum extraction conditions were maceration in ethanol-water 8:2, v/v. The chromatographic separations were done on the silica gel F(254) TLC plates developed with chloroform-dichloromethane isopropanol, 4:2:1 v/v/v. Detection was performed under UV lamp at 254 nm and the evaluation of the chromatographic plate was based on digital processing of chromatographic images. The developed TLC method was validated for parameters such as specificity, linearity and range, LOD and LOQ, precision, robustness and accuracy. This method was then applied for determination of caffeine, theobromine and theophylline in different types of tea, commercially available. Moreover, the content of methylxanthines detected and determined in commercial tea samples can be used as chemical marker in quality control. PMID- 20972977 TI - Templating synthesis of preloaded Doxorubicin in hollow mesoporous silica nanospheres for biomedical applications. PMID- 20972978 TI - Highly stable transparent amorphous oxide semiconductor thin-film transistors having double-stacked active layers. PMID- 20972979 TI - Generating electricity from biofluid with a nanowire-based biofuel cell for self powered nanodevices. PMID- 20972980 TI - De novo design of silicon-bridged molecule towards a bipolar host: all-phosphor white organic light-emitting devices exhibiting high efficiency and low efficiency roll-off. PMID- 20972981 TI - Metal-organic frameworks: a rapidly growing class of versatile nanoporous materials. AB - Metal-organic frameworks (MOFs) represent a new class of hybrid organic-inorganic supramolecular materials comprised of ordered networks formed from organic electron donor linkers and metal cations. They can exhibit extremely high surface areas, as well as tunable pore size and functionality, and can act as hosts for a variety of guest molecules. Since their discovery, MOFs have enjoyed extensive exploration, with applications ranging from gas storage to drug delivery to sensing. This review covers advances in the MOF field from the past three years, focusing on applications, including gas separation, catalysis, drug delivery, optical and electronic applications, and sensing. We also summarize recent work on methods for MOF synthesis and computational modeling. PMID- 20972983 TI - Stimulation of cell adhesion at nanostructured teflon interfaces. PMID- 20972982 TI - Surface functionalization of porous coordination nanocages via click chemistry and their application in drug delivery. PMID- 20972985 TI - Systems biology of mammalian cells: a report from the Freiburg conference. PMID- 20972990 TI - Free-solution interaction assay of carbonic anhydrase to its inhibitors using back-scattering interferometry. AB - Back-scattering interferometry (BSI) is a label-free, free-solution, small-volume technique used for characterizing binding interactions, which is also relevant to a growing number of biosensing applications including drug discovery. Here, we use BSI to characterize the interaction of carbonic anhydrase enzyme II with five well-known carbonic anhydrase enzyme II inhibitors (+/- sulpiride, sulfanilamide, benzene sulfonamide, dansylamide, and acetazolamide) in the presence of DMSO. Dissociation constants calculated for each interaction were consistent with literature values previously obtained using surface plasmon resonance and fluorescence-based competition assays. Results demonstrate the potential of BSI as a drug-screening tool which is fully compatible with DMSO and does not require immobilization or labeling, therefore allowing binding interactions to be characterized in the native state. BSI has the potential for reducing labor costs, sample consumption, and assay time while providing enhanced reliability over existing techniques. PMID- 20972992 TI - Chip-based CE for rapid separation of 8-aminopyrene-1,3,6-trisulfonic acid (APTS) derivatized glycans. AB - Fluorescently labeled carbohydrates released from glycoproteins were separated using a commercially available microfluidic chip electrophoresis system. While the instrumentation was primarily designed for DNA analysis it was found that the application base can be easily expanded using the development software provided by the manufacturer. The carbohydrates were released by enzymatic digestion (PNGase F) from glycoproteins present in human plasma after boronic acid - lectin affinity enrichment. After fluorescent labeling with 8-aminopyrene-1,3,6 trisulfonic acid the carbohydrates were separated based on capillary gel electrophoresis mechanism and detected by a fluorescence detector using a blue (470 nm) LED. The separation was completed in 40 s in a microfluidic channel of 14 mm length. Glucose ladder carbohydrate oligomers differing by one glucose unit were baseline separated up to a 20-mer with the main limitation being the detection sensitivity. As expected, the observed resolution in these experiments did not approach that of standard CE with 20 times longer separation distance; however, the chip-based analysis excelled in the speed of the separation. Similar electrophoretic profiles of glycans released from plasma glycoproteins were obtained using a standard CE equipment with 35 cm separation length and microfluidic chips with a separation distance of only 14 mm. PMID- 20972986 TI - Therapeutic potential of neuropeptide Y (NPY) receptor ligands. AB - Neuropeptide Y (NPY) is widely distributed in the human body and contributes to a vast number of physiological processes. Since its discovery, NPY has been implicated in metabolic regulation and, although interest in its role in central mechanisms related to food intake and obesity has somewhat diminished, the topic remains a strong focus of research concerning NPY signalling. In addition, a number of other uses for modulators of NPY receptors have been implied in a range of diseases, although the development of NPY receptor ligands has been slow, with no clinically approved receptor therapeutics currently available. Nevertheless, several interesting small molecule compounds, notably Y2 receptor antagonists, have been published recently, fueling optimism in the field. Herein we review the role of NPY in the pathophysiology of a number of diseases and highlight instances where NPY receptor signalling systems are attractive therapeutic targets. PMID- 20972995 TI - Effect of mobile phase pH, aqueous-organic ratio, and buffer concentration on electrospray ionization tandem mass spectrometric fragmentation patterns: implications in liquid chromatography/tandem mass spectrometric bioanalysis. AB - Liquid chromatography/tandem mass spectrometry (LC/MS/MS) based on selected reaction monitoring (SRM) is the standard methodology in quantitative analysis of administered xenobiotics in biological samples. Utilizing two SRM channels during positive electrospray ionization (ESI) LC/MS/MS method development for a drug compound containing two basic functional groups, we found that the response ratio (SRM1/SRM2) obtained using an acidic mobile phase was dramatically different from that obtained using a basic mobile phase. This observation is different from the well-established phenomenon of mobile phase affecting the [M+H](+) response, which is directly related to the amount of the [M+H](+) ions produced during the ionization. Results from follow-up work reported herein revealed that the MS/MS fragmentation patterns of four drug or drug-like compounds are affected not only by the pH, but also by the aqueous-organic ratio of the mobile phase and the buffer concentration at a given apparent pH. The observed phenomenon can be explained by invoking that a mixture of [M+H](+) ions of the same m/z value for the analyte is produced that is composed of two or more species which differ only in the site of the proton attachment, which in turn affects their MS/MS fragmentation pattern. The ratio of the different protonated species changes depending on the pH, aqueous-organic ratio, or ionic strength of the mobile phase used. The awareness of the mobile phase dependency of the MS/MS fragmentation pattern of precursor ions of identical m/z value will influence LC/MS/MS-based bioanalytical method development strategies. Specifically, we are recommending that multiple SRM transitions be monitored during mobile phase screening, with the MS/MS parameters used for each SRM optimized for the composition of the mobile phase (pH, organic percentage, and ionic strength) in which the analyte elutes. PMID- 20972996 TI - Direct analysis of cellulose in poplar stem by matrix-assisted laser desorption/ionization imaging mass spectrometry. AB - Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) was applied to the analysis of the spatial distribution of cellulose on a cross section of juvenile poplar (Populus deltoids) stems. Microcrystalline cellulose (MCC) was used to optimize matrix (2,5-dihydroxybenzoic acid) application and instrument parameters for the detection of low hexose oligomers, which originated from cellulose in the solid phase. A section of poplar cellulose isolated from juvenile poplar stem which consisted primarily of glucose (~95%) and minor components such as xylose and lignin was used for the MALDI-IMS studies. The mass spectrum of poplar cellulose consisted of a series of evenly spaced signals having a difference of 162 m/z units, which was similar to that of MCC in linear and reflectron positive ion modes. MS images of cellulose compounds with sodium ion adducts were generated and illustrated the distribution of cellulose on the surface of the poplar stem. PMID- 20972998 TI - Using mass spectrometry to detect buffalo salivary odorant-binding protein and its post-translational modifications. AB - A large number of mammalian odorant-binding proteins, which are lipocalins, have been studied. These proteins participate in peri-receptor events by selecting and carrying odorant molecules. The present study aimed at identifying the buffalo salivary odorant-binding protein (sOBP), and to determine its post-translational modification using mass spectrometry. The buffalo salivary 21 kDa protein was initially separated adopting sodium dodecyl sulfate-polyacrylamide gel electrophoresis and it was identified as sOBP with high statistical reliability using liquid chromatography/tandem mass spectrometry (LC/MS/MS) and SEQUEST, for the first time. Further, the post-translationally modified peptides were screened adopting MS/MS. A total of four post-translational modifications, namely glycation at lysine-(59), hydroxylation at lysine-(134), ubiquitination at lysine (121), and dihydroxylation in lysine-(108), were recorded. Moreover, these modifications have not been identified in buffalo salivary odorant-binding protein. PMID- 20972997 TI - Analysis of epoxyeicosatrienoic acids by chiral liquid chromatography/electron capture atmospheric pressure chemical ionization mass spectrometry using [13C] analog internal standards. AB - The metabolism of arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) is thought to be mediated primarily by the cytochromes P450 (P450s) from the 2 family (2C9, 2C19, 2D6, and 2J2). In contrast, P450s of the 4 family are primarily involved in omega oxidation of AA (4A11 and 4A22). The ability to determine enantioselective formation of the regioisomeric EETs is important in order to establish their potential biological activities and to asses which P450 isoforms are involved in their formation. It has been extremely difficult to analyze individual EET enantiomers in biological fluids because they are present in only trace amounts and they are extremely difficult to separate from each other. In addition, the deuterium-labeled internal standards that are commonly used for stable isotope dilution liquid chromatography/mass spectrometry (LC/MS) analyses have different LC retention times when compared with the corresponding protium forms. Therefore, quantification by LC/MS-based methodology can be compromised by differential suppression of ionization of the closely eluting isomers. We report the preparation of [(13)C(20)]-EET analog internal standards and the use of a validated high-sensitivity chiral LC/electron capture atmospheric pressure chemical ionization (ECAPCI)-MS method for the trace analysis of endogenous EETs as their pentafluorobenzyl (PFB) ester derivatives. The assay was then used to show the exquisite enantioselectivity of P4502C19-, P4502D6-, P4501A1-, and P4501B1-mediated conversion of AA into EETs and to quantify the enantioselective formation of EETs produced by AA metabolism in a mouse epithelial hepatoma (Hepa) cell line. PMID- 20972999 TI - Fragmentation of the tryptophan cluster [Trp9-2H]2- induced by different activation methods. AB - Electrospray ionization (ESI) of tryptophan gives rise to multiply charged, non covalent tryptophan cluster anions, [Trp(n)-xH](x-), in a linear ion trap mass spectrometer, as confirmed by high-resolution experiments performed on a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. The smallest multiply charged clusters that can be formed in the linear ion trap as a function of charge state are: x = 2, n = 7; x = 3, n = 16; x = 4, n = 31. The fragmentation of the dianionic cluster [Trp(9)-2H](2-) was examined via low energy collision-induced dissociation (CID), ultraviolet photodissociation (UVPD) at 266 nm and electron-induced dissociation (EID) at electron energies ranging from >0 to 30 eV. CID proceeds mostly via charge separation and evaporation of neutral tryptophan. The smallest doubly charged cluster that can be formed via evaporation of neutral tryptophans is [Trp(7)-2H](2-), consistent with the observation of this cluster in the ESI mass spectrum. UVPD gives singly charged tryptophan clusters ranging from n = 2 to n = 9. The latter ion arises from ejection of an electron to give the radical anion cluster, [Trp(9)-2H](-.). The types of gas-phase EID reactions observed are dependent on the energy of the electrons. Loss of neutral tryptophan is an important channel at lower energies, with the smallest doubly charged ion, [Trp(7)-2H](2-), being observed at 19.8 eV. Coulomb explosion starts to occur at 19.8 eV to form the singly charged cluster ions [Trp(x)-H](-) (x = 1-8) via highly asymmetric fission. At 21.8 eV a small amount of [Trp(2)-H-NH(3)](-) is observed. Thus CID, UVPD and EID are complementary techniques for the study of the fragmentation reactions of cluster ions. PMID- 20973000 TI - Structural characterization and identification of oleanane-type triterpene saponins in Glycyrrhiza uralensis Fischer by rapid-resolution liquid chromatography coupled with time-of-flight mass spectrometry. AB - Oleanane-type triterpene saponins (OTS) are major active ingredients in Glycyrrhiza uralensis. In this work, a rapid-resolution liquid chromatography with time-of-flight mass spectrometry (RRLC/TOF-MS) method has been developed to characterize and identify OTS from G. uralensis. The major diagnostic ions and fragmentation pathways from thirteen OTS have been characterized for the first time. At a low fragmentor voltage of 120 V in positive ion mode, the precursor ion [M + H](+) or/and [M + Na](+) was obtained for accurate determination of molecular formula. When the fragmentor voltage was increased to 425 V, abundant characteristic fragment ions were observed for structural characterization. Neutral losses of sugar moieties, such as glucuronic acid (GlcA, 176 Da), glucose (Glc, 162 Da) and rhamnose (Rha, 146 Da), were commonly observed in the MS spectra for prediction of the sugar number and sequences. Other typical losses included AcOH (60 Da), CH(2)O (30 Da), 2 * H(2)O (2 * 18 Da) and HCOOH (46 Da) from [Aglycone + H-H(2)O](+) (named [B](+)), corresponding to the presence of a C(22)-acetyl group, C(24)-hydroxyl group, C(22)-hydroxyl group or C(30) carboxyl group on the aglycone moiety, respectively. In particular, characteristic ring cleavages of the aglycone moieties on A- and B-rings were observed. Based on the fragmentation patterns of reference compounds, nineteen OTS have been identified in an extract of G. uralensis, thirteen of which were unambiguously identified and the other six were tentatively assigned. PMID- 20973001 TI - Electrospray tandem quadrupole fragmentation of quinolone drugs and related ions. On the reversibility of water loss from protonated molecules. AB - Selected reaction monitoring (SRM) of quinolone drugs showed different sensitivities in aqueous solution vs. biological extract. The authors suggested formation of two singly protonated molecules with different behavior, one undergoing loss of H(2)O and the other loss of CO(2), so that SRM transitions might depend on the ratios of these forms generated by the electrospray. These surprising results prompted us to re-examine several quinolone drugs and some simpler compounds to further elucidate the mechanisms. We find that the relative contributions of loss of H(2)O vs. loss of CO(2) in tandem mass spectrometric (MS/MS) experiments depend not only on molecular structure and collision energy, but also, in certain cases, on the cone voltage. We further find that many product ions formed by loss of H(2)O can reattach a water molecule in the collision cell, whereas ions formed by loss of CO(2) do not. Since reattachment of H(2)O can occur after water loss in the cone region and prior to selection of the precursor ion, this effect leads to the dependence of MS/MS spectra on the cone voltage used in creating the precursor ion, which explains the formerly observed effect on SRM ratios. Our results support the earlier conclusion that varying amounts of two ions of the same m/z value are responsible for problems in the analysis of these drugs, but the origin is in dehydration/rehydration reactions. Thus, SRM transitions for certain complex compounds may be comparable only when monitored under equivalent ion-forming conditions, including the voltage used in the production of the protonated molecules in the electrospray ionization (ESI) source. PMID- 20973002 TI - Characterization of metal-labelled peptides by matrix-assisted laser desorption/ionization mass spectrometry and tandem mass spectrometry. AB - Metal labelling of peptides and proteins using high-affinity metal-chelating compounds has found widespread applications in the medical and bioanalytical fields. In the present study we investigated the analysis of peptides derivatized either with cysteine- or amino group-directed metal-bound DOTA (1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid) chelators in matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The metal complexes of DOTA were shown to be stable under MALDI-MS conditions. The introduction of the metal label led in a number of cases to significantly increased signal-to-noise (S/N) values and thus improved sensitivity of the labelled peptides compared to their unlabelled counterparts, especially for multiply labelled peptides. The presence of the labels did alter the tandem mass spectrometric (MS/MS) behaviour, namely the formation of sequence specific a-, b- and y-ion series, in dependence of the position of the label within the peptide sequence. For cysteine derivatized peptides several label-specific reporter ions and characteristic immonium ions could be identified. Amino-directed labelling led only to the formation of characteristic immonium ions in epsilon-amino groups of lysine, whereas N-terminal labelling in some cases led to the formation of a(1)- and b(1) ions. The results clearly show that MALDI-MS is suitable for the analysis of metal-labelled peptides, which was also confirmed in liquid chromatography (LC)/MALDI-based identification of proteins in a model protein mixture labelled with Cys-reactive DOTA. Here, in comparison to a run with alkylated cysteines, more than 50% more cysteine-containing peptides were identified. PMID- 20973003 TI - Charge-state-derivation ion detection using a super-conducting nanostructure device for mass spectrometry. AB - Mass spectrometry (MS) is a method of analyzing ions based on their mass/charge (m/z) ratios. The m/z peak identification requires speculation on the ionic unit charge states. This problem can be solved by using superconducting junction devices to measure the kinetic energies of single molecules. However, the kinetic energy measurement is followed by the dead time of 1-20 us, which is fatally slow for modern high-resolution time-of-flight (TOF) analyzers. In this paper, we demonstrate that a superconducting nano-stripline detector (SSLD) composed of a 10-nm-thick and 800-nm-wide NbN strip realizes the charge-state derivation, and furthermore satisfies the ideal MS detector specifications such as a nano-second response, a short recovery time, a wide mass range, and no noise. PMID- 20973004 TI - Analysis of exemestane and 17beta-hydroxyexemestane in human urine by gas chromatography/mass spectrometry: development and validation of a method using MO TMS derivatives. AB - Trimethylsilylation of anabolic agents and their metabolites is frequently achieved by using the derivatization mixture N-methyl-N (trimethylsilyl)trifluoroacetamide (MSTFA)/NH(4)I/2-mercaptoethanol. Nevertheless, artifacts were formed when this mixture was employed in the monitoring of exemestane and its main metabolite 17beta-hydroxyexemestane prior to GC-MS analysis. These artifacts were identified as the N methyltrifluoroacetamide (MTFA) and trimethylsiloxyethylmercapto products of the respective trimethylsilyl (TMS) derivatives. Furthermore, artifact formation was evaluated taking the structure (1,4-diene-3-keto-6-exomethylene) of the compounds into account. Although these artifacts are relevant for investigations regarding the derivatization process and may be of interest in many fields, they are detrimental to cope with the requirements of the World Anti-Doping Agency (WADA) in terms of the limits of detection (LODs) required. To overcome this issue, a method using an alternative derivatization was proposed: formation of methyloxime TMS derivatives through double derivatization using O methylhydroxylamine/pyridine and MSTFA/TMS imidazole after enzymatic hydrolysis and liquid-liquid extraction. Samples from an excretion study after administration of exemestane to healthy volunteers were analyzed by the proposed method and detection of both exemestane and its main metabolite was possible. This method showed excellent results for both analytes meeting the LODs required for antiestrogenic agents (50 ng/mL) established by WADA. The method was validated for the main metabolite, it was robust and cost-effective for qualitative and quantitative purposes, with LOD and LOQ of 10 ng/mL and 25 ng/mL, respectively. PMID- 20973005 TI - Atmospheric pressure-electron capture dissociation of peptides using a modified PhotoSpray ion source. AB - An improved in-source atmospheric pressure-electron capture dissociation (AP-ECD) method is described. Building upon the early example of Laprevote's group, photoelectrons generated within a commercial PhotoSpray atmospheric pressure photoionization source are used to induce ECD of multiply charged peptide ions originating from an upstream heated nebulizer device. To attain high sensitivity, the method makes use of a novel electropneumatic-heated nebulizer to assist in the creation and transmission of multiply charged ions from sample solutions. Here, we demonstrate that readily interpretable AP-ECD spectra of infused peptides can be acquired from 100 fmol sample consumed, on a chromatographic time scale, using a conventional quadrupole time-of-flight (Q-ToF) mass spectrometer otherwise incapable of ECD/ETD experiments. Though much work remains to be done to develop and characterize the method, the results indicate that AP-ECD has the potential to be a practical new tool for the mass spectrometric analysis of peptides and proteins. PMID- 20973006 TI - Examination of the translocation of sulfonylurea herbicides in sunflower plants by matrix-assisted laser desorption/ionisation mass spectrometry imaging. AB - Pesticides are widely used in agriculture to control weeds, pests and diseases. Successful control is dependent on the compound reaching the target site within the organism after spray or soil application. Conventional methods for determining uptake and movement of herbicides and pesticides include autoradiography, liquid scintillation and chromatographic techniques such as high performance liquid chromatography (HPLC). Autoradiography using radiolabelled compounds provides the best indication of a compound's movement within the plant system. Autoradiography is an established technique but it relies on the synthesis of radiolabelled compounds. The distribution of four sulfonylurea herbicides in sunflower plants has been studied 24 h after foliar application. The use of matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) images of protonated molecules and fragment ions (resulting from fragmentation at the urea bond within the sulfonylurea herbicides) has provided evidence for translocation above and below the application point. The translocation of nicosulfuron and azoxystrobin within the same plant system has also been demonstrated following their application to the plant stem. This study provides evidence that MALDI-MSI has great potential as an analytical technique to detect and assess the foliar, root and stem uptake of agrochemicals, and to reveal their distribution through the plant once absorbed and translocated. PMID- 20973007 TI - o-(Pentafluorobenzyloxycarbonyl)benzoyl chloride: a novel electrophoric derivatisation reagent for amino compounds designed for negative ion chemical ionisation mass spectrometry. AB - The synthesis of a novel electrophoric derivatisation reagent, o (pentafluorobenzyloxycarbonyl)benzoyl chloride, is described. The reagent was tested against selected primary and secondary amino compounds as analytical targets. The derivatives exhibit excellent mass spectral properties under negative ion chemical ionisation (NICI), i.e. reduced fragmentation and thus high ion current for the targeted m/z during analysis. Since the reagent bears a pentafluorobenzyl ester group, resulting mass NICI mass spectra were expectedly dominated by dissociative resonance electron capture typically observed with these compounds. The reagent is suitable for detecting volatile primary and secondary amines with high sensitivity. Background is reduced by a shift in detected m/z and retention time, as demonstrated for the analysis of the drug methylphenidate from human plasma. PMID- 20973008 TI - Fragmentation investigation of brassinosteroid compounds by ion trap and quadrupole time-of-flight mass spectrometry. AB - The fragmentation mechanisms of three types of brassinosteroids (BRs), 23,24-tris epicastasterone, epicastasterone, tris-epicastasterone, 24-epibrassinolide and 6 deoxo-24-epicastasterone, have been extensively investigated by tandem mass spectrometry (MS(n), n = 1, 2, 3, 4, 5) with the assistance of high mass accuracy quadrupole time-of-flight mass spectrometry (QToF MS). The electrospray ionization (ESI) mass spectrometric fragmentation pathways of these five BRs were comprehensively elucidated for the first time. Cleavages of side chains, neutral losses of water or other molecules and opening of a ring induce the main fragmentation patterns. The results from the present study can potentially afford important guidance for the structural elucidation of different BRs and provide some fundamental data for metabolomic analysis of BRs. PMID- 20973009 TI - Rapid probe and isolation of bioactive compounds from Dioscorea panthaica using human serum albumin functionalized magnetic nano-particles (HSA-MNPs)-based ligand fishing coupled with electrospray ionization mass spectrometry. AB - The chemical diversity of secondary metabolites in medicinal plant makes it a huge challenge to isolate the bioactive compounds from herbal extracts, so quick recognition of the bioactive ones is of vital importance for improving the efficiency of isolation. In this study, a ligand fishing experiment based on human serum albumin functionalized magnetic nano-particles (HSA-MNPs) was performed to probe the bioactive components in a traditional Chinese medicinal plant, Dioscorea panthaica. The minor compounds fished out by HSA-MNPs were identified by electrospray ionization mass spectrometry (ESI-MS), and then separated from the extract of the whole plant by one or two steps of column chromatography under the guidance of ESI-MS. Four biologically active compounds, progenin II, progenin III, dioscin and gracillin, were isolated much faster than in the normal lengthy phytochemical procedure. The present study demonstrates that biological macromolecule (protein, enzyme, receptor, et al.) functionalized MNPs may serve as baits to recognize bioactive small molecules in complex herbal extracts. It is expected that a macromolecule functionalized MNPs-based ligand fishing experiment coupled with ESI-MS may accelerate the process of identification and isolation of bioactive components from medicinal plants, and thus benefit the speed of drug discovery. PMID- 20973010 TI - Rapid characterization of triterpene saponins from Conyza blinii by liquid chromatography coupled with mass spectrometry. AB - Conyza blinii Le'vl is a medicinal herb used for the treatment of inflammation in Chinese folk medicine. Its major bioactive constituents are triterpene saponins, most of which contain 6-8 sugar residues. In this report, electrospray ionization tandem mass spectrometry fragmentation behaviors of bisdesmosidic triterpene saponins (conyzasaponin A, B, and C) were studied in both positive and negative ion modes with an ion-trap mass spectrometer. In full scan mass spectrometry, these saponins gave predominant [M-H](-) and [M+Na](+) ions, which determined the molecular weights. In tandem mass spectrometry (MS(n), n = 2-4), the [M-H](-) and [M+Na](+) ions yielded fragments [Y(0alpha)-H](-) and [B(alpha)+Na](+), which were diagnostic for the structures of the triterpene skeleton and sugar chains. The structural elucidation was approved by accurate mass data using IT-TOF-MS. An interpretation guideline based on MS(n) (n = 2-4) diagnostic ions was proposed in order to elucidate the chemical structures of unknown triterpene saponins in C. blinii extract. The saponins in C. blinii were separated by liquid chromatography with a methanol/acetonitrile/water solvent system, and then analyzed by ion-trap and IT-TOF mass spectrometers. Based on the interpretation guideline, a total of 35 triterpenoid saponins were tentatively identified. Among them, 15 saponins had been previously reported, and the other 20 saponins were reported from Conyza species for the first time. This study indicates that LC/MS is a powerful technology for the rapid characterization of complicated saponins in herbal extracts. PMID- 20973011 TI - Azo-group reduction during the matrix-assisted laser desorption/ionization process in the presence of 2,5-dihydroxybenzoic acid. AB - Some time ago, we published an announcement that the azo group that closes model cyclic peptides is often reduced in matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) in the presence of 2,5-dihydroxybenzoic acid (2,5 DHB) as the matrix. In this work, we demonstrate that these peptides are ionized in all DHB matrix isomers, although threshold ionization laser energies as well as the reduction ratios differ in each matrix. Using a NALDI plate, we confirmed that their reduction depends on the presence of DHB matrix and that the hydrogen atoms participating in the reaction come from the DHB matrix hydroxyl group. We show that the reduction ratio is affected by the overall covalent structure of the peptide, by the presence of a free carboxyl group in DHB matrix, by the mutual position of the hydroxyl and carboxyl groups, as well as the laser beam intensity. Based on these results, it can be concluded that the azo-group reduction in cyclic peptides is a very complex process and we are far from fully understanding its nature. We hope that our experimental results will help to shed some light on the MALDI process that still remains mysterious in some of its aspects. PMID- 20973013 TI - Poly(3,4-ethylenedioxypyrrole)-modified emitter electrode for substitution of homogeneous redox buffer agent hydroquinone in electrospray ionization mass spectrometry. PMID- 20973012 TI - Analysis of multiple mycotoxins in beer employing (ultra)-high-resolution mass spectrometry. AB - The objective of the presented study was to develop and optimize a simple, high throughput method for the control of 32 mycotoxins (Fusarium and Alternaria toxins, aflatoxins, ergot alkaloids, ochratoxins, and sterigmatocystin) in beer. Due to the broad range of their physicochemical properties, the sample preparation step was simplified as much as possible to avoid analyte losses. The addition of acetonitrile to beer samples enabled precipitation of abundant matrix components. The clean-up efficiency was controlled by ambient mass spectrometry employing a direct analysis in real time (DART) ion source. For determination of analytes, ultra-high-performance liquid chromatography hyphenated with high resolution mass spectrometry utilizing an orbitrap (U-HPLC-orbitrapMS) or time-of flight (TOFMS) technology was used. Because of significantly better detection capabilities of the orbitrap technology, the U-HPLC-orbitrapMS method was chosen as a determinative step and fully validated. To compensate matrix effects, matrix matched calibration was employed. The lowest calibration levels for most of the target mycotoxins ranged from 1 to 8 ug L(-1) beer and the recoveries of analytes were in range from 86 to 124%. PMID- 20973016 TI - Conformation and packing of porphyrin polymer chains deposited using electrospray on a gold surface. PMID- 20973017 TI - Zurich's contributions to 50 years development of Bruker. PMID- 20973018 TI - Pure protein microspheres by calcium carbonate templating. PMID- 20973020 TI - Asymmetric bromolactonization catalyzed by a C3-symmetric chiral trisimidazoline. PMID- 20973021 TI - Versatile functionalization of nanoelectrodes by oligonucleotides via pyrrole electrochemistry. AB - Surface modification at the nanometer scale is a challenge for the future of molecular electronics. In particular, the precise anchoring and electrical addressing of biological scaffolds such as complex DNA nanonetworks is of importance for generating bio-directed assemblies of nano-objects for nanocircuit purposes. Herein, we consider the individual modification of nanoelectrodes with different oligonucleotide sequences by an electrochemically driven co polymerization process of pyrrole and modified oligonucleotide sequences bearing pyrrole monomers. We demonstrate that this one-step technique presents the advantages of simplicity, localization of surface modification, mechanical, biological and chemical stability of the coatings, and high lateral resolution. PMID- 20973022 TI - Complexation of phenol and thiophenol by amine N-oxides: isothermal titration calorimetry and ab initio calculations. AB - To develop a new solvent-impregnated resin (SIR) system for removal of phenols from water, the complex formation of dimethyldodecylamine N-oxide (DMDAO), trioctylamine N-oxide (TOAO), and tris(2-ethylhexyl)amine N-oxide (TEHAO) with phenol (PhOH) and thiophenol (PhSH) is studied. To this end we use isothermal titration calorimetry (ITC) and quantum chemical modeling (on B3LYP/6-311G(d,p) optimized geometries: B3LYP/6-311+G(d,p), B3LYP/6-311++G(2d,2p), MP2/6 311+G(d,p), and spin component scaled (SCS) MP2/6-311+G(d,p); M06-2X/6 311+G(d,p)//M06-2X/6-311G(d,p), MP2 with an extrapolation to the complete basis set limit (MP2/CBS), as well as CBS-Q). The complexes are analyzed in terms of structural (e.g., bond lengths) and electronic elements (e.g., charges). Furthermore, complexation and solvent effects (in benzene, toluene, and mesitylene) are investigated by ITC measurements, yielding binding constants K, enthalpies DeltaH(0), Gibbs fre energies DeltaG(0), and entropies DeltaS(0) of complex formation, and stoichiometry N. The ITC measurements revealed strong 1:1 complex formation between both DMDAO-PhOH and TOAO-PhOH. The binding constant (K=1.7-5.7*10(4) M(-1)) drops markedly when water-saturated toluene was used (K=5.8*10(3) M(-1)), and pi-pi interaction with the solvent is shown to be relevant. Quantum mechanical modeling confirms formation of stable 1:1 complexes with linear hydrogen bonds that weaken on attachment of electron-withdrawing groups to the amine N-oxide moiety. Modeling also showed that complexes with PhSH are much weaker than those with PhOH, and in fact too weak for ITC determination. CBS-Q incorrectly predicts equal or even higher binding enthalpies for PhSH than for PhOH, which invalidates it as a benchmark for other calculations. Data from the straightforward SCS-MP2 method without counterpoise correction show very good agreement with the MP2/CBS values. PMID- 20973023 TI - Glucosamine-6-sulfamate analogues of heparan sulfate as inhibitors of endosulfatases. PMID- 20973025 TI - Temperature-dependent prediction of the liquid entropy of ionic liquids. AB - Modeling of the temperature-dependent liquid entropy of ionic liquids (ILs) with great accuracy using COSMO-RS is demonstrated. The minimum structures of eight IL ion pairs are investigated and the entropy, calculated from ion pairs, is found to differ on average only 2% from the available experimental values (119 data points). For calculations with single ions, the average error amounts to 2.6% and stronger-coordinating ions tend to give higher deviations. Additionally, the first parameterization of the standard liquid entropy for ILs is presented in the context of traditional volume-based thermodynamics (S(l)(0)=1.585 kJ mol(-1) K( 1) nm(-3).r(m)(3)+14.09 J mol(-1) K(-1)), which sheds light on the statistical treatment of ionic interactions. The findings provide the first direct access to accurate predictions of liquid entropies of ILs, which are tedious and time consuming to measure. PMID- 20973026 TI - The role of electrode curvature in controlling electron transfer between the photosynthetic reaction center protein and gold nanoelectrodes. PMID- 20973027 TI - Synthesis, two-photon absorption and optical limiting properties of multi branched styryl derivatives based on 1,3,5-triazine. AB - Five new multi-branched two-photon absorption triazine chromophores (T1-T5) with different donor strength, conjugation length, and direction of charge transfer have been designed and synthesized. The one-photon fluorescence, fluorescence quantum yields, and two-photon properties have been investigated. The two-photon absorption (2PA) cross sections measured by the open aperture Z-scan technique were determined to be 447, 854, 1023, 603, and 766 GM for T1, T2, T3, T4, and T5, respectively. This result indicates that their 2PA cross section values (sigma) increase with increasing electron-donating strength of the end group, extending the conjugation length of the system, and introducing electron-withdrawing perfluoroalkyl as side groups to the end donor. In addition, the sigma value of T5 is also larger than that of T1, which provides evidence that the sigma value is relative to the direction of charge transfer (from the ends to the center of the molecule or from the center to the ends). Moreover, significant enhancement of the two-photon absorption cross section was achieved by introducing a thiophene moiety to a conjugated C==C bond. At the same time, the optical limiting behavior for these chromophores was studied by using a focused 800 nm laser beam with pulses of 140 fs duration. It was found that these molecules also exhibit good optical limiting properties. These initial results clearly demonstrate that multi-branched triazine chromophores are a highly suitable class of two-photon absorbing materials. PMID- 20973028 TI - Facile single-step conversion of macroalgal polymeric carbohydrates into biofuels. PMID- 20973032 TI - Evaluating the psychometric properties of the Mental Health Continuum-Short Form (MHC-SF). AB - There is a growing consensus that mental health is not merely the absence of mental illness, but it also includes the presence of positive feelings (emotional well-being) and positive functioning in individual life (psychological well being) and community life (social well-being). We examined the structure, reliability, convergent validity, and discriminant validity of the Mental Health Continuum-Short Form (MHC-SF), a new self-report questionnaire for positive mental health assessment. We expected that the MHC-SF is reliable and valid, and that mental health and mental illness are 2 related but distinct continua. This article draws on data of the LISS panel of CentERdata, a representative panel for Longitudinal Internet Studies for the Social Sciences (N = 1,662). Results revealed high internal and moderate test-retest reliability. Confirmatory factor analysis (CFA) confirmed the 3-factor structure in emotional, psychological, and social well-being. These subscales correlated well with corresponding aspects of well-being and functioning, showing convergent validity. CFA supported the hypothesis of 2 separate yet related factors for mental health and mental illness, showing discriminant validity. Although related to mental illness, positive mental health is a distinct indicator of mental well-being that is reliably assessed with the MHC-SF. PMID- 20973033 TI - Generalized anxiety disorder: clinical presentation, diagnostic features, and guidelines for clinical practice. AB - Generalized anxiety disorder (GAD) is a prevalent and disabling disorder characterised by persistent worrying, anxiety symptoms, and tension. General practitioners and mental healthcare professionals frequently misdiagnose the presenting symptoms. This article addresses the clinical presentation of GAD and provides guidelines for discriminating GAD from other disorders, based on theoretical considerations and clinical experience. Debate relating to the validity of the definition of GAD is discussed, and suggestions are made for improving the criteria for GAD, which may guide future versions of classification systems such as the Diagnostic and Statistical Manual. PMID- 20973034 TI - A content analyses of guided imagery scripts: a strategy for the development of cultural adaptations. AB - This paper proposes a first step in deciding whether it is necessary to develop a cultural adaptation by comparing the cultural characteristics of an intervention with the same characteristics of a specific group. Larger cultural differences suggest a greater need to conduct a cultural adaptation. This recommendation stems from the cultural match theory (CMT) which, explains that therapeutic outcomes increase as interventions are more similar to the cultural characteristics of specific treatment groups. However, the CMT has rarely been tested, partly because strategies to effectively measure the cultural characteristics of an intervention are still lacking. This article addresses this gap by assessing two dimensions of the self-orientation relevant to cultural adaptations, namely, idiocentrism--the tendency to define oneself in isolation from others--and allocentrism--the tendency to define oneself in relationship to others--through a content analysis of guided imagery scripts. Two independent evaluators analyzed 123 guided imagery scripts (published during 1989-2008) using 6 theoretically derived categories to analyze idiocentrism versus allocentrism. Results indicated that idiocentric elements were 1.5 to 52.3 times more frequently used than were allocentric ones. The implications of these findings for the development of culturally adapted interventions are discussed. PMID- 20973043 TI - Monophasic parapharyngeal synovial sarcoma diagnosed by cytology, immunocytochemistry, and molecular pathology: case report and review of the literature. AB - Synovial sarcoma (SS) of the head and neck region are rare, accounting for less than 10% of all head and neck soft tissue sarcomas. A limited number of SS have been reported in the parapharyngeal space and these reports have all been based on histological examination of resection material. The diagnosis of monophasic SS on cytology is extremely difficult. We report the first case where a SS was correctly diagnosed on a fine needle aspirate by cytology with the assistance of immunocytochemistry and fluorescence in situ hybridization. We will emphasize the importance of ancillary techniques, such as immunocytochemistry and cytogenetic/molecular pathology, in avoiding diagnostic pitfalls and correctly diagnosing monophasic SS on cytologic material. We will propose an algorithmic approach to accurately diagnose parapharyngeal spindle cell neoplasms with the use of appropriate ancillary studies in conjunction to morphological features. PMID- 20973044 TI - Different strokes: Pap-test and Babes method are not one and the same. PMID- 20973045 TI - Surviving cancer with strength: experts convene to discuss ways of improving life for cancer survivors. PMID- 20973049 TI - Malformations in infants of diabetic mothers. Teratology 25:385-94. 1982. PMID- 20973050 TI - Prepregnancy obesity: a complex risk factor for selected birth defects. AB - Obesity is associated with increased risk of many adverse health conditions. During pregnancy, obesity presents particularly important challenges for both mother and baby. Over the last 20 years, studies have emerged indicating an association between prepregnancy weight and risks of birth defects. However, few studies have examined the mechanisms through which this association occurs. Understanding the underlying mechanisms may provide clues to public health strategies for the prevention of birth defects associated with maternal obesity. This article briefly reviews existing literature on the association between maternal obesity and birth defects, discusses potential underlying mechanisms, and suggests research needed to improve our understanding of this important association. PMID- 20973051 TI - The fetal alcohol syndrome in mice: an animal model. Teratology 15:223-30. 1977. PMID- 20973052 TI - Morphogenesis of malformations in hamsters caused by retinoic acid: relation to dose and stage at treatment. Teratology 5:103-18. 1972. PMID- 20973053 TI - Congenital minamata disease: intrauterine methylmercury poisoning. Teratology 18:285-8. 1978. PMID- 20973054 TI - Altered health outcomes in adult offspring of Sprague Dawley and Wistar rats undernourished during early or late pregnancy. AB - BACKGROUND: Birth weight in humans has been inversely associated with adult disease risk. Results of animal studies have varied depending on species, strain, and treatment. METHODS: We compared birth weight and adult health in offspring following 50% maternal undernutrition on gestation days (GD) 1-15 (UN1-15) or GD 10-21 (UN10-21) in Sprague Dawley and Wistar rats. Offspring from food-deprived dams were weighed and cross-fostered to control dams. Litters were weighed during lactation and initiating at weaning males were fed either control or a high-fat diet. Young and mature adult offspring were evaluated for obesity, blood pressure (BP), insulin response to oral glucose, and serum lipids. Nephron endowment, renal glucocorticoid receptor, and renin-aldosterone-angiotensin system components were measured. RESULTS: The UN10-21 groups had birth weights lower than controls and transient catch up growth by weaning. Neither strain demonstrated obesity or dyslipidemia following prenatal undernutrition, but long term body weight deficits occurred in the UN groups of both strains. High-fat diet fed offspring gained more weight than control offspring without an effect of prenatal nutrition. Sprague Dawley were slightly more susceptible than Wistar rats to altered insulin response and increased BP following gestational undernutrition. Nephron endowment in Sprague Dawley but not Wistar offspring was lower in the UN10-21 groups. Glucocorticoid and renin-aldosterone-angiotensin system pathways were not altered. CONCLUSIONS: The most consistent effect of maternal undernutrition was elevated BP in offspring. Long-term health effects occurred with undernutrition during either window, but the UN10-21 period resulted in lower birth weight and more severe adult health effects. PMID- 20973055 TI - The effect of drugs with ion channel-blocking activity on the early embryonic rat heart. AB - This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the I(Kr)/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or I(Kr)/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing. PMID- 20973057 TI - Effect of frontal plane tibiofemoral angle on the stress and strain at the knee cartilage during the stance phase of gait. AB - Subject-specific three-dimensional finite element models of the knee joint were created and used to study the effect of the frontal plane tibiofemoral angle on the stress and strain distribution in the knee cartilage during the stance phase of the gait cycle. Knee models of three subjects with different tibiofemoral angle and body weight were created based on magnetic resonance imaging of the knee. Loading and boundary conditions were determined from motion analysis and force platform data, in conjunction with the muscle-force reduction method. During the stance phase of walking, all subjects exhibited a valgus-varus-valgus knee moment pattern with the maximum compressive load and varus knee moment occurring at approximately 25% of the stance phase of the gait cycle. Our results demonstrated that the subject with varus alignment had the largest stresses at the medial compartment of the knee compared to the subjects with normal alignment and valgus alignment, suggesting that this subject might be most susceptible to developing medial compartment osteoarthritis (OA). In addition, the magnitude of stress and strain on the lateral cartilage of the subject with valgus alignment were found to be larger compared to subjects with normal alignment and varus alignment, suggesting that this subject might be most susceptible to developing lateral compartment knee OA. PMID- 20973058 TI - Changes in in vivo knee loading with a variable-stiffness intervention shoe correlate with changes in the knee adduction moment. AB - External knee adduction moment can be reduced using footwear interventions, but the exact changes in in vivo medial joint loading remain unknown. An instrumented knee replacement was used to assess changes in in vivo medial joint loading in a single patient walking with a variable-stiffness intervention shoe. We hypothesized that during walking with a load modifying variable-stiffness shoe intervention: (1) the first peak knee adduction moment will be reduced compared to a subject's personal shoes; (2) the first peak in vivo medial contact force will be reduced compared to personal shoes; and (3) the reduction in knee adduction moment will be correlated with the reduction in medial contact force. The instrumentation included a motion capture system, force plate, and the instrumented knee prosthesis. The intervention shoe reduced the first peak knee adduction moment (13.3%, p = 0.011) and medial compartment joint contact force (12.3%; p = 0.008) compared to the personal shoe. The change in first peak knee adduction moment was significantly correlated with the change in first peak medial contact force (R(2) = 0.67, p = 0.007). Thus, for a single subject with a total knee prosthesis the variable-stiffness shoe reduces loading on the affected compartment of the joint. The reductions in the external knee adduction moment are indicative of reductions in in vivo medial compressive force with this intervention. PMID- 20973059 TI - REST corepressor (CoREST) repression induces phenotypic gene regulation in advanced osteoarthritic chondrocytes. AB - Alternations in cartilage chondrocyte phenotype characteristic by the decreased type II collagen and aggrecan together with increased type X collagen synthesis serve as a beacon for osteoarthritis progression. However, little is known about the underlying molecular mechanisms. The current study seeks to discover molecules that involved in osteoarthritic chondrocytes phenotype regulation. Differential proteomics was generated with two-dimensional gel electrophoresis between normal articular cartilage (NAC) and advanced osteoarthritic cartilage (AOC). Those differentially expressed proteins were identified by mass spectrometry. The down-regulation of a neuronal silencer, the REST corepressor (CoREST) in AOC, was verified by Western blot. CoREST silencing was performed in primarily cultured NAC chondrocytes with specific siRNA to reveal the possible involvement of CoREST repression in chondrocyte phenotypic genes modulation. Ninteen differentially expressed proteins were screened and identified. Among these proteins, CoREST, HHL, and zinc finger protein 155 were estimated to be possible gene modulators. CoREST protein level was verified to be down-regulated by 69.5% (p < 0.001) in AOC. In response to CoREST knock-down by 64.8% (p < 0.001) in NAC chondrocytes, the gene expression level of the chondrocyte terminal differentiation marker gene, collagen X was found to be up-regulated by 40.0% (p = 0.017), whereas the chondrocyte differentiation phenotypic genes, collagen II and aggrecan were down-regulated by 71.4% (p < 0.001) and 57.6% (p < 0.001), respectively. The results indicate that the silencing of CoREST by siRNA transfection in NAC may reflect CoREST repression in AOC, which results in phenotypic genes modulation and suggests a homeostatic role of this transcription factor in articular chondrocyte. PMID- 20973060 TI - Interaction of periosteal explants with articular chondrocytes alters expression profile of matrix metalloproteinases. AB - Periosteal tissue is a source of growth factors and of osteochondral progenitor cells which makes it suitable for implantation in chondral defects as known in autologous chondrocyte implantation. The aim of this study was to determine the interaction between periosteal tissue and articular chondrocytes with respect to catabolic effectors such as matrix metalloproteinases (MMPs) and IL-6. Human articular chondrocytes were cultured for up to 28 days as micromass pellets in coculture either with physical contact to periosteal explants or allowing paracrine interactions only. Expression, secretion, and activation of MMPs and IL 6 were analyzed in chondrocytes, periosteum, and culture supernatants. Both coculture conditions influence gene expression levels of MMPs and IL-6 in a time , culture-, and tissue-dependent manner. Coculturing of periosteum with chondrocytes promotes gene expression and secretion of IL-6. In periosteum, physical contact inhibits MMP-2 and MMP-13 gene expression while paracrine coculture induces expression of IL-6, MMP-2, -7, and -13. Pro-MMP-2, -7, and -13 were detected in supernatants of all culture regimens whereas pro-MMP-9 was secreted from periosteum only. As a balanced amount of MMP activity is likely required to achieve sufficient integration of the regenerate tissue with the surrounding healthy cartilage, an exceeding expression of proteinases might result in degradation, hypertrophy or rejection of the graft. PMID- 20973061 TI - A novel MSC-seeded triphasic construct for the repair of osteochondral defects. AB - Mesenchymal stem cells (MSC) are increasingly replacing chondrocytes in tissue engineering based research for treatment of osteochondral defects. The aim of this work was to determine whether repair of critical-size chronic osteochondral defects in an ovine model using MSC-seeded triphasic constructs would show results comparable to osteochondral autografting (OATS). Triphasic implants were engineered using a beta-tricalcium phosphate osseous phase, an intermediate activated plasma phase, and a collagen I hydrogel chondral phase. Autologous MSCs were used to seed the implants, with chondrogenic predifferentiation of the cells used in the cartilage phase. Osteochondral defects of 4.0 mm diameter were created bilaterally in ovine knees (n = 10). Six weeks later, half of the lesions were treated with OATS and half with triphasic constructs. The knees were dissected at 6 or 12 months. With the chosen study design we were not able to demonstrate significant differences between the histological scores of both groups. Subcategory analysis of O'Driscoll scores showed superior cartilage bonding in the 6-month triphasic group compared to the autograft group. The 12 month autograft group showed superior cartilage matrix morphology compared to the 12-month triphasic group. Macroscopic and biomechanical analysis showed no significant differences at 12 months. Autologous MSC-seeded triphasic implants showed comparable repair quality to osteochondral autografts in terms of histology and biomechanical testing. PMID- 20973063 TI - Inhibiting nerve growth factor or its receptors downregulates calcitonin gene related peptide expression in rat lumbar dorsal root ganglia innervating injured intervertebral discs. AB - Nerve growth factor (NGF) and its dual structurally unrelated receptors, tropomyosin-related kinase A (TrkA) or p75 neurotrophin receptor (p75(NTR)), cause the pathogenesis of discogenic pain. To investigate the sensory innervation of injured rat lumbar intervertebral disc (IVD), we examined the expression of neuropeptides such as calcitonin gene-related peptide (CGRP) at dorsal root ganglia (DRG) by inhibiting NGF or its dual receptors. Sprague-Dawley rats with multiply punctured L5-L6 IVD were used. Six experimental groups were prepared: naive, sham control, and four agent-treated groups with punctured IVD (vehicle, anti-NGF antibody, anti-TrkA antibody, and anti-p75(NTR) antibody). Retrograde neurotracer Fluoro-Gold (FG) was applied together except for the naive group. Their lumbar DRG were harvested and immunolabeled for CGRP. FG-labeled DRG neurons were most prevalent at L1 and L2 DRG, and the proportion of FG-labeled CGRP-immunoreactive DRG neurons in the vehicle group was significantly elevated (p < 0.05) compared with the sham group, while those of antibody-treated groups, especially in the anti-p75(NTR) group, significantly decreased compared with the vehicle group (p < 0.05). Direct intradiscal application of antibody to NGF or its receptors suppressed CGRP expression, and p75(NTR) antagonism induced the most profound suppression. PMID- 20973062 TI - Accelerated aging of intervertebral discs in a mouse model of progeria. AB - Intervertebral disc degeneration (IDD) is a common and debilitating disorder that results in reduced flexibility of the spine, pain, and reduced mobility. Risk factors for IDD include age, genetic predisposition, injury, and other environmental factors such as smoking. Loss of proteoglycans (PGs) contributes to IDD with advancing age. Currently there is a lack of a model for rapid investigation of disc aging and evaluation of therapeutic interventions. Here we examined progression of disc aging in a murine model of a human progeroid syndrome caused by deficiency of the DNA repair endonuclease, ERCC1-XPF (Ercc1( /Delta) mice). The ERCC1-deficient mice showed loss of disc height and degenerative structural changes in their vertebral bodies similar to those reported for old rodents. Compared to their wild-type littermates, Ercc1(-/Delta) mice also exhibit other age-related IDD characteristics, including premature loss of disc PG, reduced matrix PG synthesis, and enhanced apoptosis and cell senescence. Finally, the onset of age-associated disc pathologies was further accelerated in Ercc1(-/Delta) mice following chronic treatment with the chemotherapeutic agent mechlorethamine. These results demonstrate that Ercc1( /Delta) mice represent an accurate and rapid model of disc aging and provide novel evidence that DNA damage negatively impacts PG synthesis. PMID- 20973064 TI - Expression of matrix metalloproteinase regulator, RECK, and its clinical significance in osteosarcoma. AB - Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a novel membrane-anchored matrix metalloproteinase inhibitor, have been shown to be associated with prognosis and suppress tumor progression through angiogenesis inhibition in many cancers. In this study, the expression of RECK in osteosarcoma was examined, and its clinical significance was firstly evaluated. RECK expression was immunohistochemically examined in osteosarcoma from 49 patients. By summing intensity and proportion scores, these patients were categorized as weak and strong. RECK expression in the primary tumor was strong in 27 patients (55.1%) and was weak in the rest of the patients. The 5-year survival rate of patients with RECK-strong tumor (81.5%) was significantly higher than that of patients with RECK-weak tumor (36.4%; p = 0.003). Reduced RECK expression significantly correlated with metastasis (p = 0.010) and recurrence (p = 0.004). A multivariate analysis confirmed that reduced RECK expression was an independent and significant factor to predict a poor prognosis (p = 0.017). RECK status is a useful prognostic factor in osteosarcoma, and an independent prognostic factor contributing to the determination of more adequate therapy strategies for each patient. PMID- 20973065 TI - Benefits of thin-shelled acetabular components for metal-on-metal hip resurfacing arthroplasty. AB - The theoretical advantage of using thinner acetabular components in hip resurfacing has not yet been clinically verified. Our purpose was to test the hypothesis of bone conservation and assess the effects of using a thinner acetabular component on hip biomechanics and clinical outcome. We compared the bone conservation, biomechanical results, and functional outcomes between hips in 35 patients who received bilateral metal-on-metal resurfacing arthroplasties with acetabular components of 5 mm thickness on one side and 3.5 mm thickness on the other. Acetabular abduction angle and acetabular anteversion were measured using Ein-Bild-Roentgen-Analysis software. Medial acetabular wall thickness and position of the hip center of rotation were measured using Image J software. The change in position of the hip center of rotation was minimal and did not reach significance. Thin-shelled components showed greater bone conservation on the acetabular side measured by an increase in the medial acetabular wall thickness. Bone conservation on the femoral side was achieved as well with thin shells. Range of motion, pain scores, and complication rates were comparable. No appreciable difference was found in bone-cup radiographic appearance between the two types of components. These data suggest that patients can experience good clinical outcomes for resurfacing with either thin or thick-shelled acetabular components. However, thin-shelled components preserve acetabular bone stock and allow the use of a larger femoral component. The use of thinner acetabular components is an improvement in bone conservation for a hip resurfacing design. PMID- 20973066 TI - Electromagnetic induction heating of an orthopaedic nickel--titanium shape memory device. AB - Shape memory orthopaedic implants made from nickel-titanium (NiTi) might allow the modulation of fracture healing, changing their cross-sectional shape by employing the shape memory effect. We aimed to show the feasibility and safety of contact-free electromagnetic induction heating of NiTi implants in a rat model. A water-cooled generator-oscillator combination was used. Induction characteristics were determined by measuring the temperature increase of a test sample in correlation to generator power and time. In 53 rats, NiTi implants were introduced into the right hind leg. The animals were transferred to the inductor, and the implant was electromagnetically heated to temperatures between 40 and 60 degrees C. Blood samples were drawn before and 4 h after the procedure. IL-1, IL 4, IL-10, TNF-alpha, and IFN-gamma were measured. Animals were euthanized at 3 weeks. Histological specimens from the hind leg and liver were retrieved and examined for inflammatory changes, necrosis, and corrosion pits. Cytokine measurements and histological specimens showed no significant differences among the groups. We concluded that electromagnetic induction heating of orthopedic NiTi implants is feasible and safe in a rat model. This is the first step in the development of new orthopedic implants in which stiffness or rigidity can be modified after implantation to optimize bone-healing. PMID- 20973068 TI - This volume of New Directions for Youth Development offers perspectives and strategies for engaging American youth. PMID- 20973070 TI - Do we have what it takes to put all students on the graduation path? AB - According to current estimates, more than a quarter of all students and over 40 percent of African American and Hispanic students do not graduate from high school on time. The vast majority of those young people who do not graduate with their peers drop out. The enormous costs to these individuals, their communities, and our society require us to invest in systems that accurately identify young people at risk of dropping out and provide the supports necessary to keep them on track to graduation. This chapter offers a framework for action that calls on communities to identify the scale and scope of the dropout problem and understand why students disengage from school; transform or replace low-performing schools; install early warning and multitiered response systems that provide comprehensive, targeted, and intensive supports to students in and out of school; establish supportive policies and resource allocations; and build community will and capacity so positive changes are deeply implemented and sustained. PMID- 20973071 TI - How do we ensure that everyone graduates? An integrated prevention and tiered intervention model for schools and districts. AB - Schools with large numbers of students falling off the graduation path need comprehensive reforms that create a solid foundation of high-quality instruction and positive behavioral supports for all students. They also need data-driven response systems that provide targeted and intensive interventions for students who need additional academic and social supports. This article offers a systematic plan for dropout prevention at the district and school levels that integrates research-based recommendations into a coherent, three-tiered model. The model provides a way to coordinate all types of interventions and replace the patchwork of fragmented programs that often allows students to fall through the cracks. PMID- 20973072 TI - Powerful learning with public purpose. AB - Boredom and failure combine in a toxic brew that propels too many young people off the graduation path. Research shows that engaged students are more likely to perform well academically, that students who are challenged are less likely to be bored and disengaged, and that high-quality instruction and meaningful activities are key factors in promoting a culture of engagement and achievement in and outside the classroom. With data and real-world examples, the author shows how students and their communities are benefiting from collaborative student-led projects. These projects stem from What Kids Can Do, a program that advocates for learning that engages students as knowledge creators and that promotes young people as valued resources and critical voices in policy debates about school, society, and world affairs. PMID- 20973073 TI - Using technology to engage and educate youth. AB - Given that information age technologies are as natural to the Net generation as breathing, it is time to provide learning experiences that maximize their use in schools. The authors argue that integrating technology into learning is central to creating the meaningful learning opportunities needed to engage and motivate youth today. To achieve this potential, however, technology must support a new paradigm of teaching and learning. This chapter discusses common elements and challenges to implementing pioneering high school reform models that promote one to-one student-computer ratios, collaborative learning environments, problem- and project-based instruction, and interdisciplinary teaching. PMID- 20973074 TI - Joining forces: the benefits of integrating schools and community providers. AB - Reforms aimed at expanding learning for low-income children must do more than add hours and days to the school year; they must push beyond the traditional boundaries of school-based learning and find ways to maximize and integrate the assets that cities, districts, and communities can offer. This article reviews research on how schools are using extended learning time to promote student engagement and achievement. A key finding is that successful efforts use partnerships with outside organizations to provide academic support and enrichment activities that build students' skills and connections with an expanded network of supportive adults. The challenge is to ensure that these partnerships are not mere add-ons, designed only to plug extracurricular holes and seen as peripheral to the core academic work of schools. They must be part of a larger system that integrates in-school and out-of-school learning and improves outcomes for youth. PMID- 20973075 TI - College knowledge: a critical component of college and career readiness. AB - Policy has traditionally emphasized the completion of academic requirements as the gateway to postsecondary education. There is, however, growing understanding that youth need to develop a wide range of knowledge, skills, abilities, and personal resources for career success, civic engagement, and lifelong learning. It also is necessary to address the social, informational, and financial barriers to college that many first-generation and low-income youth come up against. Allowing youth to participate in programs that provide access to college campuses and classes, through dual or concurrent enrollment, early college models, or expanded learning opportunities, is an effective way to help students gain college knowledge and see themselves as college students. This article offers an expanded definition of college and career readiness and profiles three programs drawn from a larger review of twenty-three programs designed to support college and career success for students from underrepresented groups. PMID- 20973076 TI - Expanding the pathway to postsecondary success: how recuperative back-on-track schools are making a difference. AB - Districts and states that have begun to get traction in improving their graduation rates are pursuing a reform agenda that includes both the redesign of failing high schools and the development of multiple alternative pathways that help young people get back on track to graduation and to postsecondary education. Unlike traditional alternative education, new back-on-track models assume that challenge, not remediation, will make the most difference, especially for youth who are over age for grade and far behind in accumulating the credits they need. The goal is for students to make up for lost time by accelerating their learning so that they can complete high school and move successfully to postsecondary education and careers. Although these small schools do not in themselves constitute a replacement or transformation strategy for large low-performing high schools, they are a necessary part of a comprehensive approach to turning such schools around. PMID- 20973077 TI - The new dropout challenge: bridging gaps among students, parents, and teachers. AB - Interview and survey data reveal significant disconnects among the insights and perspectives of dropouts, parents, teachers, and administrators on the causes and solutions to the dropout challenge. Many educators, for example, do not see boredom as a factor for most dropouts, while young people who drop out see it as the central cause. The author argues that if these disconnects are not more fully understood and bridged, they will continue to set back efforts to keep more students in school and on track to graduate ready for postsecondary education. Models for how communities can engage these constituencies in productive dialogue and transformative action are included in reports and in Grad Nation, a guidebook that helps communities tackle their dropout crises. PMID- 20973078 TI - The Mobile story: data-driven community efforts to raise graduation rates. AB - Through sustained community organizing and strategic partnerships, the Mobile (Alabama) County Public School System is improving achievement and creating beat the-odds schools that set and achieve high academic expectations despite the challenges of poverty and racial disparity. The authors chart how Mobile's Research Alliance for Multiple Pathways, funded through the U.S. Department of Labor's Multiple Pathways Blueprint Initiative, is identifying gaps in services throughout the community, analyzing the data about dropouts, benchmarking other communities, studying best practices, and mobilizing the community to expect and demand higher graduation rates. These activities are resulting in early identification of off-track students and coordination of school- and community based reforms. PMID- 20973079 TI - A greater society: the transformation of the federal role in education. AB - The federal role in education will soon be transformed in ways that could produce an even greater society than President Lyndon B. Johnson envisioned. The authors identify underlying principles of this new role and describe how it represents a significant departure from the past. Historically, for example, the federal government has been prescriptive about the kinds of practices that states and districts must adopt as a condition of receiving federal funds, but it has not specified outcomes. Under the new approach, the federal government would specify the goals and outcomes while allowing states, districts, and schools flexibility in how they use federal funds to innovate and adopt best practices. The authors argue for immediate action. Every day of delay, they note, yields another seven thousand dropouts and leaves schools and communities without the tools and resources that can help turn the situation around. PMID- 20973084 TI - Reply to Lawler: feeding competition, cooperation, and the causes of primate sociality. AB - This is a reply to Richard Lawler's commentary on our previous work [Lawler, 2011; this issue] in which he develops a set of operational models to test socioecological theories of the evolutionary importance of feeding competition. We strongly agree that we need to critically re-evaluate the basic assumptions of all models of primate sociality, and to verify the explanatory power of alternative models. We also feel Lawler's commentary provides an important opportunity to broaden the debate concerning the fundamental roles of cooperation, competition, and aggression in understanding primate social systems. Lawler provides a number of suggestions as to how models developed in primate socioecology might be tested. We agree with these suggestions, make further suggestions, and call for specific operational definitions so that researchers might begin to develop and test various methodologies. However, we also call for testing alternative theories. Current socioecological theory is based on the assumption that competition and positive selection is always in operation and has driven the evolution of living organisms. We believe that this "explanation of choice" often is treated as an assumed truth to which data are forced to fit, rather than being seen as a theory to be tested. Furthermore, we agree with Weiss and Buchanan [2009. The Mermaid's Tale: Four Billion Years of Cooperation in the Making of Living Things] that on ecological and developmental scales, where organisms actually live out their lives, cooperation may play a more fundamental role than competition. PMID- 20973086 TI - The exponent 3/2 at pyramidal nanoindentations. AB - The analysis of published loading curves reveals the exponent 3/2 to the depth for nanoindentations with sharp pyramidal or conical tips. This has geometric reasons, as it occurs independent on the bonding states and indentation mechanisms. Nevertheless, most mathematical deductions and finite element simulations of nanomechanical parameters in the literature continue using the experimentally not supported Hertzian exponent 2. Therefore, numerous published loading curves of various authors are plotted using the experimental exponent 3/2 to present unbiased proof for its generality with metals, oxides, semiconductors, biomaterials, polymers, and organics. Linearity is independent of equipment and valid for load controlled, or depth controlled, or continuous stiffness, or AFM force measurements. The linearity with exponent 3/2 often extends from the nano- into the microindentation ranges. The tip rounding and taper influence of the "geometrical similar" indenters are discussed. When kinks occur in such linear plots through the origin, these indicate change of the materials' mechanical properties under pressure by phase transition. These events are discussed for nanoindentations with respect to the known hydrostatic transformation pressures that are, of course, always higher than the necessary indentation mean pressure. Numerous Raman, as well as X-ray and electron diffraction results from the literature support the phase transitions that are now easily detected. Nanoporous materials first fill the pores upon indentation. Published loading curves exhibit more information than hitherto assumed. PMID- 20973087 TI - The link between sensation seeking and aggression: a meta-analytic review. AB - Substantial empirical evidence supports low resting heart rate (HR) as the best replicated psychophysiological correlate of aggression [Ortiz and Raine, 2004]; however, researchers continue to debate the explanatory mechanisms of the phenomenon. Sensation seeking has been proposed as a possible outcome of low resting HR that may lead to aggressive tendencies but findings have been inconsistent in terms of showing a relationship between sensation seeking and aggression. A meta-analysis was conducted on 43 independent effect sizes, from studies with a total of 32,217 participants, to test the hypothesis that sensation seeking would be positively related to aggression across studies. A significant overall effect size was found (d = .1935, P<.001), supporting the hypothesis. Moderator analyses revealed that the relationship differed based on participant and methodological characteristics, such as participant age and the nature of the aggression measurement; however, these conclusions are limited by the uneven number of studies in many of the moderator classes. Overall, the findings provide support for higher levels of aggression in high sensation seekers and have theoretical implications for arousal theory. Further research on the links between arousal, sensation seeking and aggression can inform clinicians about potential interventions. PMID- 20973088 TI - Risk and protective factors associated with patterns of antisocial behavior among nonmetropolitan adolescents. AB - This study used latent class analysis (LCA) to identify patterns of antisocial behavior (ASB) in a sample of 1,820 adolescents in a nonmetropolitan region of the Northeast. Self-reported ASBs including stealing, fighting, damaging property, and police contact were assessed. LCA identified four classes of ASB including a non-ASB class, a mild, a moderate, and a serious ASB class. Multinomial logistic regression indicated that parent-child relationships served as a protective factor against engaging in ASB and peer, school, and community risk and protective factors differentiated mild patterns of ASB from more intense patterns of involvment. These findings suggest utility in using the LCA to better understand predictors of adolescent ASB to inform more effective prevention and intervention efforts targeting youth who exhibit different patterns of behavior. PMID- 20973091 TI - Evolution of ZDDP-derived reaction layer morphology with rubbing time. AB - Functional additives, particularly extreme pressure and antiwear additives, in formulated oil will compete to adsorb and function in tribological contacts. A low-polarity commercial base oil, poly-alpha-olefin (PAO), blended with zinc dialkyl dithiophosphates (ZDDP) has been studied. The tribological performance was evaluated using a ball-on-disk test rig under mixed rolling-sliding conditions in the boundary lubrication regime at 90 degrees C. An adapted in situ interferometry technique was used to monitor the additive-derived reaction layer formation. The thickness of the reaction layer evolves with rubbing until reaching a limiting thickness value of approximately 70 nm. The evolution of the topography and mechanical properties of the ZDDP-derived reaction layer with rubbing time were studied using Atomic Force Microscopy. A constant roughening and hardening of the additive-derived layer with rubbing time is observed and related to the different tribological performance of the layer at different rubbing times. PMID- 20973094 TI - Clinical application and outcome of the internal mammary artery perforator (IMAP) free flap for soft tissue reconstructions of the upper head and neck region in three patients. AB - BACKGROUND: The fasciocutaneous internal mammary artery perforator (IMAP) island flap allows for superior esthetical and functional skin cover in the head and neck region in combination with limited donor site morbidity. Its modification as a free flap allows reconstruction of more cranial defects. PATIENTS AND METHODS: Three IMAP free flaps varying from 7 * 4 cm2 to 10 * 6 cm2 were transplanted in three patients with a mean age of 59 years (range, 54-69 years). Enhancement of the flap's vascular pedicle at least doubles the diameter of the internal mammary vessels to be anastomosed. RESULTS: Coverage with excellent texture and color match was uneventfully obtained and the flaps' donor sites were primarily closed in all three cases. CONCLUSIONS: Our experience proves the consistent feasibility of successful transplantation of the IMAP free flap. Because of its characteristics, we suggest contemplating the use of this flap in the upper head and neck region. PMID- 20973096 TI - Is group psychotherapy effective in older adults with depression? A systematic review. AB - OBJECTIVE: Earlier reviews and meta-analyses have consistently concluded that psychological treatment of depression is effective in older adults. We conducted a systematic review randomised controlled trials of group psychotherapy to present the best available evidence in relation to its effectiveness in older adults with depressive disorders. METHODS: Electronic databases were searched to identify randomised controlled trials. Selected studies were quality assessed and data extracted by two reviewers. RESULTS: Six trials met the inclusion criteria. The trials included in the review examined group interventions based on the cognitive behavioural therapy (CBT) model with active therapeutic interventions or waiting list controls. Group psychotherapy is an effective intervention in older adults with depression in comparison to waiting list controls, the overall effect size is very modest (MD = -3.92, 95%CI: -6.18, -1.67). The reported benefits of group intervention in comparison to other active interventions did not reach statistical significance. The benefits of group psychotherapy were maintained at follow-up. The quality of the studies varied and studies were heterogeneous. CONCLUSIONS: Although quality of many studies was not optimal, the results of this meta analysis support the results of earlier meta analyses. Group cognitive behavioural therapy is effective in older adults with depression. PMID- 20973097 TI - Novel influenza A (H1N1) viral infection in pediatric patients with sickle-cell disease. AB - BACKGROUND: The 2009 novel influenza A (H1N1) pandemic has had profound public health implications all over the world. The majority of patients infected with the novel strain have recovered uneventfully. However, certain populations have been defined who appear to be at increased risk of complications due to H1N1 infections. This review summarizes the clinical course of five patients with sickle cell, four of whom had confirmed H1N1 infection, and one whom had a presumed H1N1 infection. PROCEDURE: The clinical presentation, hospital course, and treatment of five pediatric patients with sickle-cell disease and H1N1 infection were reviewed retrospectively. RESULTS: In this case series, our patients experienced complications such as the acute chest syndrome, acute marrow suppression of red cell production, pain crisis, and hematuria. CONCLUSIONS: In this population, who are at increased risk for bacterial superinfection as well as complications from the influenza virus itself, vigilance toward diagnosis and aggressive treatment will continue to be important as long as the novel virus is in circulation. PMID- 20973101 TI - Simultaneous tumors: acute myeloid leukemia infiltrating mediastinal ganglioneuroblastoma. AB - We report the case of a child presenting with concurrent thoracic ganglioneuroblastoma and acute myeloid leukemia. The peculiarity was the close relation between the two tumors with the latter infiltrating the former one. Histological and genomic studies indicate the different clonal origins of the malignancies in the patient, and we hypothesized that GNB and AML developed independently. Our observation suggests that in patients with more than one tumor, though discovered at different times, one neoplasm is not always secondary. PMID- 20973099 TI - 2009 pandemic influenza A (H1N1) virus infection in pediatric oncology and hematopoietic stem cell transplantation patients. AB - BACKGROUND: Pediatric oncology and hematopoietic stem cell transplantation (HSCT) patients are at high risk for influenza infection and its associated complications. Little is known about infection with novel 2009 influenza A (H1N1) in this population. PROCEDURE: Prospective laboratory surveillance identified all children with positive influenza test results from 4/27/09-12/5/09. 2009 H1N1 infection was confirmed by PCR subtyping; cases in which subtyping was not performed were considered probable. Medical records of all pediatric oncology and HSCT cases were reviewed. RESULTS: Thirty children with cancer or HSCT had laboratory-confirmed influenza A. Patients with ALL (18), CNS tumors (4), CML (1), Ewing sarcoma (1), Hodgkin lymphoma (1), LCH (1), severe aplastic anemia (1), and HSCT (3), had confirmed (5) and probable (25) H1N1 by rapid (22; 73%), DFA (4; 13%), or RVP (4; 13%) assays. Most frequent presenting signs and symptoms were fever (93%; median 38.6 degrees C), cough (97%), and rhinorrhea (83%). Ten patients required hospitalization for a median of 5 days, most commonly for fever and neutropenia (8). Imaging demonstrated lower respiratory tract involvement in three patients. There were no concomitant bacteremias; one patient had rhinovirus co-infection. Three patients required ICU care; 1 developed ARDS, multi-organ failure, and died after 5 days. Chemotherapy was delayed in five patients. Oseltamivir was administered to 28 patients; 1 patient developed an oseltamivir resistant strain and was treated with zanamivir. CONCLUSIONS: 2009 influenza A H1N1 infection in children with cancer and HSCT is mild in most patients, but can lead to serious complications. PMID- 20973102 TI - Pediatric histiocytic sarcoma clonally related to precursor B-cell acute lymphoblastic leukemia with homozygous deletion of CDKN2A encoding p16INK4A. AB - Histiocytic sarcoma (HS) is a rare malignancy of tissue histiocytes with a dismal prognosis. We report a 4-year-old male who developed HS during maintenance chemotherapy for precursor B-cell acute lymphoblastic leukemia (pre-B ALL). Both tumors showed identical clonal immunoglobulin and T-cell receptor gene re arrangement patterns, as well as homozygous deletion of the CDKN2A gene encoding p16(INK4A). These data suggest a clonal relationship between the two neoplasms despite their distinct lineages. Since CDKN2A deletion predisposes to development of HS in experimental models, the cytogenetic features of the patient's pre-B ALL may have predisposed to this change in lineage. PMID- 20973107 TI - Ecological vulnerability in wildlife: application of a species-ranking method to food chains and habitats. AB - Nature development in The Netherlands is often planned on contaminated soils or sediments. This contamination may present a risk for wildlife species desired at those nature development sites and must be assessed by specific risk assessment methods. In a previous study, we developed a method to predict ecological vulnerability in wildlife species by using autecological data and expert judgment; in the current study, this method is further extended to assess ecological vulnerability of food chains and terrestrial and aquatic habitats typical for The Netherlands. The method is applied to six chemicals: Cd, Cu, Zn, dichlorodiphenyltrichloroethane, chlorpyrifos, and ivermectin. The results indicate that species in different food chains differ in vulnerability, with earthworm-based food chains the most vulnerable. Within and between food chains, vulnerability varied with habitat, particularly at low trophic levels. The concept of habitat vulnerability was applied to a case study of four different habitat types in floodplains contaminated with cadmium and zinc along the river Dommel, The Netherlands. The alder floodplain forest habitat contained the most vulnerable species. The differences among habitats were significant for Cd. We further conclude that the method has good potential for application in mapping of habitat vulnerability. PMID- 20973108 TI - Concentrations of perfluorinated compounds in human blood from twelve cities in China. AB - We detected nine perfluorinated compounds (PFCs) in 233 human whole-blood samples collected from 12 cities (from 12 provinces and districts) in China. Perfluorinated compounds could be detected in all blood samples, with perfluorooctane sulfonate (C8, PFOS) as the most prominent PFC. Mean PFOS concentrations were measured at 3.06 to 34.0 ug/L, accounting for the majority of the total perfluorinated compounds (SigmaPFCs) (54-87%) in blood samples, except those from Kunming. Perfluorooctane sulfonate and perfluorohexane sulfonate (C6, PFHxS) concentrations were positively correlated in blood samples (p < 0.01). Significant relations among perfluorooctanoate (C8, PFOA), perfluorononanoic acid (C9, PFNA), perfluorodecanoic acid (C10, PFDA), and perfluoroundecanoic acid (C11, PFUnDA) (p < 0.05) were also observed in the present study, indicating that they may come from a similar exposure pathway in China. In general, gender related differences were found for PFHxS and SigmaPFCs concentrations, which were significantly higher in males than in females (p < 0.05). In the 20- to 29-year age group, gender influence was also found for PFHxS and PFOS concentrations. The mean blood concentration of PFOS (10.6 ug/L) in the present study was comparable with results from other countries, while PFOA and PFHxS (1.39 ug/L and 0.57 ug/L, respectively) were often lower. This can probably be attributed to a different exposure pathway of the general population in China as compared to other countries. PMID- 20973109 TI - Florid cutaneous papillomatosis. AB - Florid cutaneous papillomatosis is an obligate paraneoplastic syndrome. Originally described by Schwartz and Burgess, and also known as the Schwartz Burgess syndrome, it is a widespread eruption resembling viral warts yet with no evidence of human papilloma virus infection. We review this entity and its implications. PMID- 20973110 TI - Variations in labeling protocol influence incorporation, distribution and retention of iron oxide nanoparticles into human umbilical vein endothelial cells. AB - Various studies have shown that various cell types can be labeled with iron oxide particles and visualized by magnetic resonance imaging (MRI). However, reported protocols for cell labeling show a large variation in terms of labeling dose and incubation time. It is therefore not clear how different labeling protocols may influence labeling efficiency. Systematic assessment of the effects of various labeling protocols on labeling efficiency of human umbilical vein endothelial cells (HUVEC) using two different types of iron oxide nanoparticles, i.e. super paramagnetic iron oxide particles (SPIOs) and microparticles of iron oxide (MPIOs), demonstrated that probe concentration, incubation time and particle characteristics all influence the efficiency of label incorporation, label distribution, label retention and cell behavior. For SPIO the optimal labeling protocol consisted of a dose of 12.5 ug iron/2 ml/9.5 cm(2) and an incubation time of 24 h, resulting in an average iron load of 12.0 pg iron/per cell (uptake efficiency of 9.6%). At 4 h many SPIOs are seen sticking to the outside of the cell instead of being taken up by the cell. For MPIO optimal labeling was obtained with a dose of 50 ug iron/2 ml/9.5 cm(2). Incubation time was of less importance since most of the particles were already incorporated within 4 h with a 100% labeling efficiency, resulting in an intracellular iron load of 626 pg/cell. MPIO were taken up more efficiently than SPIO and were also better tolerated. HUVEC could be exposed to and contain higher amounts of iron without causing significant cell death, even though MPIO had a much more pronounced effect on cell appearance. Using optimal labeling conditions as found for HUVEC on other cell lines, we observed that different cell types react differently to identical labeling conditions. Consequently, for each cell type separately an optimal protocol has to be established. PMID- 20973111 TI - Iron oxide particles covered with hexapeptides targeted at phosphatidylserine as MR biomarkers of tumor cell death. AB - The aim of the study was to evaluate the ability of a new MR contrast agent to detect cell death as a biomarker of the efficacy of anti-cancer treatment. The phosphatidylserine-targeted hexapeptide (E3) was coupled to pegylated ultrasmall iron oxide nanoparticles (USPIO) that can be detected by magnetic resonance imaging (MRI) and by electron paramagnetic resonance (EPR). USPIO binding to staurosporine-treated TLT (transplantable liver tumor) cells, evaluated by X-Band EPR, indicated twice as much binding of USPIO grafted with the E3 peptide, compared with USPIO grafted with a scrambled peptide or ungrafted USPIO. In vivo experiments were carried out using TLT cells implanted intramuscularly into NMRI mice, and tumor cell death was induced by irradiation. After intravenous injection of the different types of USPIO, the accumulation of contrast agent was evaluated ex vivo by X-band EPR, in vivo by L-band EPR and by T(2)-weighted MRI. In irradiated tumors there was greater accumulation of the targeted USPIO particles compared with control particles or compared with the targeted particles in untreated tissues. In conclusion, phosphatidylserine-targeting of USPIO particles can detect dying tissues. This molecular targeted system should be evaluated further as a potential biomarker of tumor response to treatment. PMID- 20973112 TI - Imaging monocytes with iron oxide nanoparticles targeted towards the monocyte integrin MAC-1 (CD11b/CD18) does not result in improved atherosclerotic plaque detection by in vivo MRI. AB - Imaging of macrophages with superparamagnetic iron oxide particles (SPIO) has been performed to improve detection of atherosclerotic plaque inflammation in human and mouse studies by molecular magnetic resonance imaging (MRI). Since affinity of the monocyte/macrophage integrin MAC-1 (CD11b/CD18) is upregulated in inflammation, we generated a contrast agent targeting CD11b (CD11b-SPIOs) for improved macrophage detection in plaques. CD11b-SPIOs and non-targeted SPIOs (control-SPIOs) were incubated in vitro with human monocytes/macrophages. As quantified by SPIO-induced MRI signal extinction, intracellular iron-content was significantly higher in monoytes/macrophages incubated with CD11b-SPIO than with control-SPIO in vitro (p < 0.05), suggesting an improved uptake of CD11b-SPIOs into monocytes. Therefore, the aortic arch (AA) and vessel branches of ApoE(-/-) knockout mice on a Western-type diet were imaged before and 48 h after contrast agent injection of either CD11b-SPIOs or control-SPIOs, using a 9.4 T animal MRI system. The SPIO-induced change in the MRI signal was quantified, as well as the macrophage-content by anti-CD68 immunhistochemistry and the iron-content by Prussian-blue staining. However, SPIO-induced signal extinction in in vivo-MRI was similar in CD11b-SPIO and control-SPIO-injected animals, with a non significant trend towards an improved uptake of CD11b-SPIOs in the subclavian artery and subsections of the AA. These data correlated well with the results obtained by histology. Although in vitro MRI-data indicated an increased uptake of targeted CD11b-SPIOs in monocytes/macrophages, in vivo mouse data do not allow improved atherosclerotic plaque detection compared WITH non-targeted SPIOs. Therefore, CD11b-targeted MRI contrast labelling of monocytes/macrophages does not seem to be a successful strategy in stable atherosclerotic plaques such as found in the ApoE(-/-)-knockout-model. However, the impressive correlation between MRI and histology data encourages further development of inflammation- and plaque-specific contrast agents for vulnerable plaque imaging. PMID- 20973113 TI - Highly constrained backprojection for improving dynamic 3He MR ventilation imaging in rats. AB - The highly constrained backprojection algorithm (HYPR) has recently been shown to allow accelerated acquisition in various fields of MRI, including angiography, perfusion and diffusion imaging as well as hyperpolarized gas imaging. Increase in temporal resolution is of particular interest in the case of small animal ventilation imaging due to the high respiration rate. In the present study, the two-dimensional HYPR technique and its iterative version (I-HYPR) were applied to (3)He ventilation imaging in rats. Two imaging protocols were used for two separate groups of animals. A single inspiration protocol consisted of (3)He imaging of the lungs during gas inflow and a following apnea. A multiple inspiration protocol involved spontaneous breathing of (3)He contained in a gas reservoir. Series of HYPR frames with four-fold increase in the temporal resolution were obtained in the case of the single inspiration experiment. For the multiple inspiration protocol, series of HYPR images corresponding to four different echo times were obtained and were used to reconstruct T(2)(*) maps at the inspiration and the expiration phases of the breathing cycle. The feasibility of using the two-dimensional HYPR technique for different (3)He ventilation protocols in small animals is demonstrated. Image quality and signal kinetics representations are compared for two variants of the HYPR algorithm. PMID- 20973114 TI - Towards MRI contrast agents responsive to Ca(II) and Mg(II) ions: metal-induced oligomerization of dota-bisphosphonate conjugates. AB - In magnetic resonance imaging (MRI), paramagnetic complexes are utilized as contrast agents. Much attention has been paid to the development of new contrast agents responsive to pH, temperature or concentration of various components of body liquids. We report a new type of MRI probe sensing the concentrations of calcium and magnesium in biological media. The ligand do3ap(BP) combines a dota like chelator with a bisphosphonate group. In the complex, the Gd(III) ion is entrapped in the macrocyclic cavity whereas the bisphosphonate group is not coordinated and therefore is available for coordination with endogenous metal ions. In the presence of metal ions, Gd-do3ap(BP) appears to show formation of coordination oligomers leading to an unprecedented increase in r(1) up to 200 500%. The extremely high relaxivity response makes this type of compound interesting for further studies as MRI ion-responsive probes for biomedical research. PMID- 20973115 TI - Organic elemental analysis: a new universal approach to authenticity/quality control of pharmaceuticals. PMID- 20973116 TI - The rylene colorant family--tailored nanoemitters for photonics research and applications. AB - This Review summarizes the latest advances in the field of rylene dyes and rylene nanoemitters for applications in photonics, and describes the influence of the dye design on the optical properties, the self-assembly, the molecular interactions, as well as the labeling specificity of the compounds. The interplay between tailored (macro)molecular design and bulk/single-molecule spectroscopy enables complex processes to be explained, for example, the kinetics of energy transfer processes or (bio)catalysis. Such investigations are essential for the ultimate design of optimized nanoemitters, and require a close cooperation between spectroscopists and preparative organic chemists. PMID- 20973117 TI - alpha-Chymotrypsin-catalyzed reaction confined in block-copolymer vesicles. AB - Herein the reactivity of the enzyme alpha-chymotrypsin in the confinement of polystyrene-block-poly(acrylic acid) (PS-b-PAA) vesicles was investigated. Enzyme and substrate molecules were encapsulated in PS-b-PAA vesicles with internal diameters ranging from 26 nm to 165 nm during the formation of the vesicles. While the loading efficiencies of enzyme and substrate molecules were practically identical for vesicles of identical size, they were found to increase with decreasing vesicle size. The kinetics of the alpha-chymotrypsin catalyzed hydrolysis of N-succinyl-Ala-Ala-Phe-7-amido-4-methylcoumarin (AMC) was evaluated following the increase of the absorption of the product 7-amino-4-methylcoumarin by UV/Vis spectroscopy. The values of the catalytic turnover number obtained for reactions inside vesicles with different sizes showed an increase of up to fourteen times compared to the bulk value with decreasing vesicle volume, while the values of the Michaelis-Menten constant decreased, respectively. This increase in reactivity of alpha-chymotrypsin is attributed to the effect of vesicle-wall interactions in the finite encapsulated space, where the reagents could diffuse, leading to enhanced collision frequencies. PMID- 20973118 TI - Fluoride sensing by catechol-based pi-electron systems. AB - We have developed new catechol-based sensors that can detect fluoride via fluorescence or optical absorption even in the presence of other halides. The level and sensitivity of detection of the sensing molecules is dependent on the chromophore length, which is controlled by the number of thiophene units (one to three) within the chromophore. The sensor with three thiophene units, (E)-2-(2,2' terthiophen-5-yl)-3-(3,4-dihydroxyphenyl)acrylonitrile, gives the best response to fluoride. By using fluorescence measurements fluoride is detectable over the concentration range 1.7 MUM to 200 MUM. Importantly, when adsorbed onto a solid support the fluorescent catechol dye can be used to detect the presence of fluoride in aqueous solution. PMID- 20973120 TI - Oxidative dehydrogenation of propane over a VO2-exchanged MCM-22 zeolite: a DFT study. AB - The adsorption and the mechanism of the oxidative dehydrogenation (ODH) of propane over VO(2)-exchanged MCM-22 are investigated by DFT calculations using the M06-L functional, which takes into account dispersion contributions to the energy. The adsorption energies of propane are in good agreement with those from computationally much more demanding MP2 calculations and with experimental results. In contrast, B3LYP binding energies are too small. The reaction begins with the movement of a methylene hydrogen atom to the oxygen atom of the VO(2) group, which leads to an isopropyl radical bound to a HO-V-O intermediate. This step is rate determining with the apparent activation energy of 30.9 kcal mol( 1), a value within the range of experimental results for ODH over other silica supports. In the propene formation step, the hydroxyl group is the more reactive group requiring an apparent activation energy of 27.7 kcal mol(-1) compared to that of the oxy group of 40.8 kcal mol(-1). To take the effect of the extended framework into account, single-point calculations on 120T structures at the same level of theory are performed. The apparent activation energy is reduced to 28.5 kcal mol(-1) by a stabilizing effect caused by the framework. Reoxidation of the catalyst is found to be important for the product release at the end of the reaction. PMID- 20973119 TI - Chemotherapeutic evaluation of a synthetic tubulysin analogue-dendrimer conjugate in c26 tumor bearing mice. PMID- 20973121 TI - Anti-inflammatory arene--chromium complexes acting as specific inhibitors of NOD2 signalling. AB - Inflammation is a hallmark of microbial infection in mammals and is the result of a pathogen-induced release of inflammatory effectors. In humans a variety of germ line encoded receptors, so-called pattern-recognition receptors, respond to conserved signatures on invading pathogens, which results in the transcriptional activation of pro-inflammatory responses. Inflammation is often detrimental to the host and leads to tissue damage and/or systemic dysfunctions. Thus, specific inhibitors of these pathways are desirable for medical interventions. Herein we report on the synthesis and use of some chromium-containing compounds (arene- Cr(CO)3 complexes) with a core structure related to anti-inflammatory diterpenes produced by the sea whip Pseudopterogorgia elisabethae. By using cell-based reporter assays we identified complexes with a potent inhibitory activity on tumour necrosis factor (TNF), Toll-like receptor (TLR), and nucleotide binding domain, leucine-rich repeat-containing receptor (NLR) pathways. Moreover, we found one complex to be a specific inhibitor of inflammatory responses mediated by the NLR protein NOD2, a pivotal innate immune receptor involved in bacterial recognition. Synthesis and characterisation of a set of derivatives of this substance revealed structural requirements for NOD2 specificity. Taken together, our studies suggest this type of arene--Cr(CO)3 complex as a potential lead for the development of antiphlogistica and pharmacologically relevant NOD2 inhibitors. PMID- 20973122 TI - Pan-PPAR agonists based on the resveratrol scaffold: biological evaluation and docking studies. PMID- 20973123 TI - [The role of prevention activities in population health promotion in Russia]. AB - The article presents the methodology to be applied to any class of disease, the socially dangerous illnesses included. The need in the organization of intersectoral coordination body to manage disease prevention activities and certification of disease prevention technologies is discussed. The necessity to implement the medical science achievements in the common public health practice is emphasized. The possibility to organize the intermediate structures contributing to surmount the gap between theory and practice is discussed. To actualize the principles of prevention and population dispanserization corresponding normative legal base, financing, political support of ruling political parties, sweeping implementation of historical experience and consideration of international experience in the field of prevention practice are needed. PMID- 20973124 TI - [The impact of health care on premature mortality of population]. AB - The comparative analysis of population mortality in Tverskaya oblast in 1996 and 2008 is presented. The results revealed the increase of population losses due to the premature mortality. Based on the discovered patterns and characteristics of population mortality indicators the evaluation of medical organizational factors impact on population mortality in Tverskaya oblast is presented. The controllable factors impacting the formation of mortality level due to factual causes of death are determined. In particular, in studying the factors impacting the premature mortality the expertise technique was applied to evaluate the tactics of implemented medical treatment, the causes entailed the premature death and the possibility to prevent the terminal outcome. The study results can be largely applied in the activities of health authorities and medical institutions related to the development of target programs of decreasing the preventable population mortality including specific causes of death in various subjects of the Russian Federation. The territorial characteristics of health care network and resource supply of health system in particular region are taken into account. PMID- 20973125 TI - [The issues of population reproductive health in Voronezhskaya oblast and means of its improvement]. AB - The article deals with the results of analysis of demographic indicators of natural migration of population in Voronezhskaya oblast in 1999-2008 revealing particular characteristics. The state of reproductive health of population in oblast is characterized by stable preservation of lower level of birth rate, higher indicators of total mortality and negative natural growth of population. The allotment of "maternal capital" at the birth of second child from 2006 and increase of one-time dowry at child birth in the Voronezh region ceased the birth rate falling and mapped out a growth trend. To ameliorate the demographic situation in the region the chief public health directorate of Voronezhskaya oblast upheld in 2007 "The strategy of development of obstetrics service in Voronezhskaya oblast in 2008-2010". The purpose of the document is to improve organization, quality and accessibility of medical care to pregnant women, parturient women, newborns and gynecological patients and birthrate growth. PMID- 20973126 TI - [The medical social and medical demographic issues of childless families]. AB - The article deals with medical social and medical demographic characteristics of childless families. The analysis of causes the families decided to postpone the child birth is presented. The birth reserve is determined and the means to increase the effectiveness of management of reproductive health support and directions of family policy on different hierarchical levels are discussed. PMID- 20973127 TI - [The methodological prerequisites of elaboration of advanced regional patterns of medical care provision to population]. AB - The article deals with the characteristics of medical demographic indicators, morbidity indicators, public health resources indices and medical care volumes in Federal okrugs. The analysis provided a basis to develop the designed and adjusted standards of main volumetric indicators for territorial programs of public guarantees of free-of-charge medical care to population of the Russian Federation according the Federal okrugs. PMID- 20973128 TI - [The issues of organization of consultative diagnostic care to population in the subject of the Russian Federation]. AB - The article deals with the basic issues of state of regional health system. The issues of resource supply of diagnostic service in the regions and technical conditions of diagnostic technologies are discussed. The attention is focused on the need to develop the organization of diagnostic care to population. The essential approaches to its organization on the regional level are proposed. PMID- 20973129 TI - [The input of Russian medical community into organization of science (second half of XIX-early XX centuries)]. AB - The article presents data on the activities of medical community in the second half of XIX-early XX century targeted to the development of organization of medical science. PMID- 20973130 TI - [Vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in the blood serum, tumor and renal parenchyma of patients with renal cell carcinoma]. AB - Serum, tumor and renal parenchyma levels of VEGF and VEGFR2 were compared in patients with renal carcinoma (RC) with reference to basic clinicomorphological characteristics of the disease. VEGF and VEGFR2 were estimated in 37 RC patients and 57 healthy controls (serum levels only). VEGF and VEGFR2 were detected in all the samples. Their concentrations in the serum were the same in the patients and controls. The tumor tissue contained more VEGF than renal parenchyma. In unfavorable clinicomorphological features the tumor contained higher content of VEGF, higher VEGF/VEGFR2, lower VEGFR2. Thus, angiogenic factors studied closely correlate with clinicomorphological characteristics of renal carcinoma: primary tumor size, stage of the disease, tumor differentiation, tumor pseudocapsule invasion. PMID- 20973131 TI - [Surgical treatment of vesicovaginal fistulas]. AB - To improve surgical outcomes in patients with complicated recurrent, radiation induced, giant and multiple vesicovaginal fistulas, we have developed a new combined method of fistuloplasty (patent 21350999). The method was used in 12 of 32 operations made in 1997-2007 in the urological clinic of the Kazan Medical University for vesicovaginal fistula in patients aged 19 to 72 years. The technique was applied in women with vesicovaginal fistula located close to the ureteral orifice. Good results of the operation were achieved due to leak-proof sutures, accurate dissection of the bladder from the vagina and intact blood supply of the tissues. Two surgical approaches were used: transvesical and vaginal. Neither complications nor relapses occurred in all 12 patients operated by the proposed technique of combined fistuloplasty which proved to be effective in recurrent, complicated, combined fistulas and is a method of choice in complicated, recurrent, radiation-induced, giant and multiple fistulas. PMID- 20973132 TI - [Surgical correction of overactive bladder resistant to standard therapy]. AB - Surgical treatment was given to 45 patients with overactive bladder: transurethral detrusorotomy was made in 21 patients (group 1), bladder hydrodilation (BH) was made in 24 patients (group 2). Detrusorotomy was performed by transurethral median cut of the bladder posterior wall by needle electrode leading to destroyment of intramural sympathic and parasympathic nervous fibres. Hydrodilation of the bladder was made under intravesical pressure equal to systolic arterial pressure with 2 min exposure. On day thirty after the operation regress of the lower urinary tract symptoms was registered in 20 (95.2%) patients of group 1 and 11 (45.8%) patients of group 2. Urge to voiding (UV) disappeared in 90.5% patients of group 1 and in 45.8% of group 2 (p < 0.05), the number of patients with miction pain reduced 6-fold and 1.9-fold, with UV--8.5 and 1.2 fold, respectively (p < 0.05). The number of diurnal mictions in group 1 decreased 3.2-fold vs 1.9-fold in group 2. The bladder size in urgency in group 1 patients increased 2.5-fold, the pressure fell also 2.5-fold. In group 2 these parameters changed only 1.2 times (p < 0.05). Cystometry recorded recurrent detrusor overactivity in 13 (54.2%) patients after hydrodilation and only in 3 (14.3%)--after cut of the bladder wall (p < 0.05). Thus, transurethral detrusorotomy in overactive bladder resistant to conventional treatment is much more effective than hydrodilation. The operation is low invasive and is well tolerated. Simple performance and good short-time results are advantages of this technique. PMID- 20973133 TI - [Efficacy of combined treatment of women with chronic cystitis associated with intracellular infections]. AB - Forty female patients with urethrocystitis received sparfloxacin in a daily dose 400 mg for 20 days in combination with canefron H (50 drops three times a day for 8 weeks). Twenty patients received one more course of canefron H 4 months after etiopathogenetic therapy. The analysis of the treatment results allows the conclusion that sparfloxacin is highly effective in urethrocystitis associated with intracellular infections. Sparfloxacin provides complete urine sterility. 97.5% females after the combined treatment had no recurrences for a year while before the treatment remission lasted for 4.1 +/- 1.7 months. A preventive administration of canefron H improves microcirculation in the bladder wall and prevents recurrence in patients with urethrocystitis associated with intracellular infections given basic sparfloxacin therapy. PMID- 20973134 TI - [Immunocorrecting therapy of chronic bacterial prostatitis]. AB - A total of 55 patients aged 20-59 years with recurrent chronic bacterial prostatitis (RCBP) entered a trial of immunomodulator panavir. The study group consisted of 40 patients. They were given standard treatment and panavir. The control group (n = 15) matched by all the studied characteristics received standard treatment only. Blood count, bacteriological characteristics of prostatic secretion, immunological status, subjective parameters were studied. RCBP patients were diagnosed to have marked disorders of interferon status. The addition of panavir to standard treatment of RCBP patients significantly improved treatment results. Therefore, panavir is recommended as an adjuvant in combined RCBP treatment. PMID- 20973135 TI - [Sexual function rehabilitation of men with pituitary tumors]. AB - A prospective trial of the methods of sexual rehabilitation of 31 men with pituitary tumors has shown that therapy with testosterone and chorionic gonadotropin effectively corrects hypogonadism and sexual disorders. In insufficient efficacy normalization of sexual function is achieved with tadalafil. Both methods of treatment had no negative effect on the size of the prostatic gland and PSA level except 2 patients with somatotropinoma on testosterone. In the course of chorionic gonadotropin treatment pituitary tumor increased in size in 3 patients. PMID- 20973136 TI - [Acute urinary retention in prostatic adenoma]. PMID- 20973137 TI - [Urological and nephrological diseases in HIV-infected patients and drug addicts]. AB - The article analyses literature on nephrological and urological pathology in HIV infected and drug-addicted patients, compares original results of the treatment of nephrological and urological diseases in such patients, analyses clinical evidence, surgical interventions, causes of complications and lethal outcomes, indicates markers of renal insufficiency, proposes treatment policy which can improve treatment results of the above grave pathology. PMID- 20973138 TI - [Informative value of radiodiagnosis methods of pyelo-ureteral strictures in kidney anomaly]. AB - A total of 98 patients aged 18-67 years (mean age 42.5 +/- 10.3 years) suspected to have a pelviureteral stricture (PUS) were examined using ultrasound investigation in B-mode (BUI), excretory urography (EU), angiography, slice and multislice computed tomography (SCT, MSCT). This combined examination allowed to make diagnosis of hydronephrosis in 83 (84.7%) patients including PUS diagnosis in 48 (57.8%) patients. Basing on CT findings PUS was operated in 41 (85.4%) patients. Sensitivity, specificity and accuracy of BUI in detection of the level of the upper urinary tract obstruction was 92.8, 75.0, 89.3%, EU--94.5, 77.8, 92.2, SCT--100, 97, 98.1%, respectively. MSCT detected the level of the obstruction in all the cases. PUS was identified by BUI in 26.5, 89.3, 65.6, EU- in 81.3, 73.7, 79.1, by SCT in 90.5, 96.8, 94.2, MSCT--96.3, 100, 97.8% cases. Thus, MSCT is most effective in radiodiagnosis of PUS and can be recommended as a method of choice in PUS. PMID- 20973139 TI - [Remote results of using synthetic loop in the treatment of urinary incontinence in females (8-year study results)]. AB - Out of 21 female patients who had undergone TVT operation for stress urinary incontinence from March 2000 to February 2001, 15 females responded to the interview in the telephone survey conducted in 2009. A Russian version of the King's Health Questionnaire was used. Seven (46.8%) patients assessed the effect of the operation as good, 4 (26.6%) patients--as satisfactory, 2 (13.3%) and 2 (13.3%) as bad and poor, respectively. Thus, a positive effect was achieved in 11 (73.4%) responders, while a negative effect was seen in 4 (26.6%) patients. Nine (60%) patients experienced no effect of urination problem on quality of life, 3 (20%) and 3(20%) patients experienced moderate and strong effect, respectively. Frequent voiding, urgencies at night, imperative voiding and urgent urinary incontinence were recorded in 3 (20%), 4 (26.7%), 2 (13.3%) and 2 (13.3%) patients, respectively. All 15 (100%) responders stated no incontinence in cough, sneezing and physical activity. Thus, our 8-year follow-up confirms that TVT operation is highly effective in stress urinary incontinence in women. PMID- 20973140 TI - [Efficacy of magnetolaser therapy of patients with an inflammatory form of chronic abacterial prostatitis]. AB - To assess efficacy of magnetolaser therapy (KAP-ELM-01 Andro-Gin unit) in the treatment of inflammatory chronic abacterial prostatitis (ICAP), 68 ICAP patients were divided into 2 groups. Group 1 patients (n = 33) received standard therapy. Group 2 patients received standard therapy plus magnetolaser (ML) therapy. The effect was assessed by the symptoms scale and indices of kallirrein-kinin system. After treatment pain relieved by 36,9%, on the average, in group 1 and by 63.1% in group 2. Lower urinary tract symptoms regressed insignificantly in both groups: by 4.8% and 7.1%, respectively. Quality of life improved by 27.6 and 65.5%, respectively. Kallikrein activity in prostatic secretion remained high in both groups. A 21.7% rise (p < 0.05) of prokallikrein level was seen after treatment only in group 2. Activity of KKS inhibitors (alpha2-MG and alphal-PI) in prostatic secretion normalized in group 2. Total activity of serin proteinases lowered in both groups (p < 0.05). High activity of alphal-PI (8.21 + 1.97 U/ml) persisted in group 1. Thus, standard treatment of ICAP does not result in biochemical normalization of prostatic secretion. ML therapy is more effective. PMID- 20973141 TI - [Epidemiology of bladder cancer in the Samara region]. AB - Correlation and regression analyses were used to study effects of exogenic and endogenic epidemiological factors. The findings of the two methods were almost identical. Of epidemiological factors in males under 50 years of age most essential were smoking and drinking regime. With age, cancer of the bladder more frequently arises due to infravesical and urinary inflammation. In males over 70 years of age smoking and infravesical obstruction are leading causes. Smoking is a leading cause of bladder cancer in women of all age groups. A drinking regime is the second cause of bladder cancer in patients under 60 years of age, while inflammation is more essential for bladder cancer onset in patients over 60. PMID- 20973142 TI - [Laparoscopic operations in patients with chronic renal failure on peritoneal dialysis]. AB - The aim of our study was analysis of efficacy of laparoscopic operations for treatment of complications arising in patients with terminal chronic renal failure (TCRF) on peritoneal dialysis (PH). A total of 86 TCRF patients participated in the trial. The study group consisted of 36 patients who have undergone laparoscopic surgery for correction of dysfunction of the peritoneal catheter, for treatment of acute and progressive chronic diseases of the abdomen. A control group included 50 patients treated with laparotomy. All the patients were on the dialysis for 1-48 months. After laparoscopic operations 7 patients were switched on hemodialysis. In the control group peritoneal dialysis was discontinued in 30% patients, lethality in this group was twice higher. Thus, laparoscopic operations allow prolongation of peritoneal dialysis in dysfunction of peritoneal catheter and in development of acute and progression of chronic surgical diseases of the abdomen. PMID- 20973143 TI - [First experience of using lantox (botulinum toxin A) in chronic pelvic pain syndrome combined with bladder emptying dysfunction]. AB - Chronic pelvic pain syndrome (CPPS), often observed in practical urology, in some cases is accompanied with obstructive voiding due to inadequate relaxation of the urethral striped sphincter. TUR of the bladder neck in such cases is low effective and patients have to do intermittent autocatherization. Lantox, a botulinic toxin A, was used in a woman suffering from CPPS for 24 years. The patient has undergone two TURs of the bladder cervix. As the effect was insignificant she had to do regular intermittent autocatheterization of the bladder for 4 years. A lantox injection (100 units) was made in the external urethral sphincter. A subjective response (a 73.3% reduction of pain intensity) and voiding improvement shown by an urodynamic investigation were achieved as well as the absence of residual urine which abolished the need in autocatheterisation. The case demonstrates high efficacy of lantox both in relief of CPPS and improvement of voiding. PMID- 20973144 TI - Second-generation BCR-ABL kinase inhibitors in CML. PMID- 20973145 TI - Second-generation BCR-ABL kinase inhibitors in CML. PMID- 20973146 TI - Second-generation BCR-ABL kinase inhibitors in CML. PMID- 20973147 TI - CISH and susceptibility to infectious diseases. PMID- 20973148 TI - CISH and susceptibility to infectious diseases. PMID- 20973149 TI - Geographic differences in Medicare spending. PMID- 20973150 TI - New recommendations on duty hours from the ACGME. PMID- 20973151 TI - The ACGME's final duty-hour standards-special PGY-1 limits and strategic napping. PMID- 20973152 TI - Asymptomatic idiopathic superior venacavo-azygous aneurysm. PMID- 20973153 TI - Newborn infant pain assessment using heart rate variability analysis. AB - OBJECTIVES: Systems controlling cardiovascular function are closely coupled with the perception of pain. Heart rate variability (HRV) is a well-established noninvasive measure of cardiac autonomic control. We hypothesized that pain may alter HRV in the newborn infant and that HRV analysis could be used as an indicator of prolonged pain in the newborn infant. METHODS: To test the hypothesis, we measured the magnitude of the heart rate high-frequency variations using an innovative High Frequency Variability Index (HFVI) in newborn infants at risk of postoperative pain. We investigated newborn infants with a gestational age (GA) more than 34 weeks, and who were admitted after a major surgical procedure. Inclusions ranged from 2 to 72 hours after the surgery. The postoperative pain was scored using EDIN scale (neonatal pain and discomfort scale) at the end of the 2 hours recording period. The infants were separated in: (1) Group "Low EDIN," when EDIN<5; and (2) Group "High EDIN," when EDIN >=5. Predictive positive and negative values of a threshold value of HFVI in assessing pain have been studied. RESULTS: Twenty-eight newborn infants were enrolled in the study (mean GA=37.8+/-1.5 wk) at a median delay between the surgery and the recording of 5 hours. Mean EDIN were 2+/-1 and 7+/-2 in respectively the groups "Low EDIN" and "High EDIN." The 2 groups were similar for GA, basal heart and respiratory rates, SpO2, mean arterial blood pressure, and morphine infusion rate. HFVI was significantly lower in the group "High EDIN" than in the group "Low EDIN" (0.7+/-0.2 vs. 1.2+/-0.3, respectively; P<0.01). An HFVI <0.9 was able to predict an EDIN score >=5, with a sensitivity of 90%, and a specificity of 75%. DISCUSSION: The results of this study indicate that postoperative pain is associated with a decreased high-frequency HRV in full-term newborn infants. Our findings suggest that HRV could be used as an indicator to assess prolonged pain in the newborn infants. PMID- 20973154 TI - Neuroma removal for neuropathic pain: efficacy and predictive value of lidocaine infusion. AB - OBJECTIVE: Injury to peripheral nerves associated with trauma, amputation, or surgery may lead to the formation of neuromas that can produce severe pain refractory to pharmacotherapy. Ectopic impulse activity arising in blindly ending axons within the neuroma, which contain abnormal accumulations of sodium channels, is thought to be a major contributor to this pain. The effect of surgical excision has remained controversial. Here we report a prospective study on the effect of neuroma removal on pain. METHODS: A series of 6 patients with chronic neuropathic pain owing to neuromas after nerve injury were studied before and 3 months after neuroma excision. Quantitative sensory testing included measurement of areas of brush-evoked allodynia, pinprick hyperalgesia, and mechanical and thermal thresholds. The hypothesis that the analgesic response to a preoperative, intravenous infusion of the sodium channel blocker lidocaine can predict outcome of surgery was also tested. RESULTS: Surgery only relieved spontaneous pain in 2 out of the 6 patients. One of those patients had a prior poor response to neuroma removal. In one patient the pain worsened. Response to surgical removal of neuromas was not predicted by the response to preoperative infusion of intravenous lidocaine. DISCUSSION: Our findings suggest that, as a therapeutic maneuver, surgical excision of neuromas should be reserved for only those patients with intractable pain, who have failed to respond to other therapies. However, prior poor response to neuroma removal does not preclude relief of pain after a new excision. PMID- 20973155 TI - Morphine versus oxycodone in pancreatic cancer pain: a randomized controlled study. AB - OBJECTIVE: According to experimental findings, oxycodone (OX) could have some advantages over morphine (MO) in clinical models of visceral pain. It was hypothesized that OX could have some advantages over MO in terms of efficacy and dose escalation in pancreatic cancer pain. METHODS: Sixty patients with pancreatic cancer with a pain intensity rating of 4/10 who required opioids were included in the study. Patients were randomized to receive 30 mg/d of sustained release oral MO or sustained release oral OX (20 mg/d). Opioid doses were increased according to the clinical needs. Daily doses of opioids, pain and symptom intensity were recorded at admission (T0) and at weekly intervals for the subsequent 4 weeks (T1, T2, T3, and T4), with an extension at 8 weeks (T8). Opioid escalation index (OEI) as percentage (OEI %) and in mg (OEI mg) was calculated. RESULTS: Nineteen and 20 patients in groups OX and MO, respectively, were followed for the entire period of study (T4). No differences between groups were found in age (P=0.400), Karnofsky (P=0.667), or escalation indexes at T4 and T8 (OEImg, P=0.945 and OEI %, P=0.295). No statistical differences in pain and symptoms intensity between the groups were observed. CONCLUSION: OX and MO provided similar analgesia and adverse effects with similar escalating doses in patients with pancreatic cancer pain, resembling observations reported in the general cancer pain population. The experimental hypothesis that OX would be superior to MO in the clinical model of pancreatic cancer pain was not confirmed. PMID- 20973156 TI - The close link between retinoid signalling and the alpha-secretase ADAM10 and its potential for treating Alzheimer's disease (commentary on Jarvis et al.). PMID- 20973157 TI - A large trophic quilt. AB - Plants and invertebrate herbivores are major constituents of terrestrial food webs. Identifying component species and tracing their interactions in highly diverse communities are a monumental task. Novotny et al. 2010 present the first broad conspectus of herbivore-plant interactions in a forest in Papua New Guinea. In more than 15 years, nearly 7000 feeding links were traced between about 200 plants and 1500 insect herbivores. Although staggering, these figures might represent only 15% of the total herbivore richness and interaction diversity in that lowland forest. Standardized comparisons also showed distinctive specialization and diversification patterns in different feeding guilds, restricting the possibility of using any single guild as surrogate for the entire assemblage. PMID- 20973158 TI - The specific origin of the simple and complex spikes in Purkinje neurons. PMID- 20973159 TI - Varicella-zoster virus. Preface. PMID- 20973160 TI - The chemokine system in experimental and clinical hematology. Preface. PMID- 20973161 TI - A bone eating abdominal aortic aneurysm. PMID- 20973162 TI - Life-threatening lower gastrointestinal bleeding in a teenager. PMID- 20973163 TI - RETRACTED: A novel membrane-based anti-diabetic action of atorvastatin. PMID- 20973164 TI - Role of PPAR-gamma in inflammation. Prospects for therapeutic intervention by food components. AB - Peroxisome proliferator activated receptor gamma (PPARgamma) is a ligand dependent transcription factor and a member of the nuclear receptor superfamily. Acting as sensors of hormones, vitamins, endogenous metabolites and xenobiotic compounds, the nuclear receptors control the expression of a very large number of genes. PPARgamma has been known for some time to regulate adipocyte differentiation, fatty acid storage and glucose metabolism, and is a target of anti-diabetic drugs. More recently, PPARgamma has been recognized as playing a fundamentally important role in the immune response through its ability to inhibit the expression of inflammatory cytokines and to direct the differentiation of immune cells towards anti-inflammatory phenotypes. A feature of PPARgamma is the structural diversity of its ligands, which encompass endogenous metabolites, dietary compounds and synthetic drugs. The high and increasing incidence of inflammatory and allergic disease, coupled with encouraging results from recent clinical trials, suggest that natural PPARgamma agonists found in foods may be beneficial to human health by acting as anti inflammatory molecules. PPARgamma is therefore not only a target of the pharmaceutical industry, but also of great potential interest to the food industry, since it is activated by several natural dietary constituents. The prospects for dietary intervention in inflammatory disease have improved somewhat over the last few years, and are reviewed here. PMID- 20973166 TI - Infant transmission. HIV-positive women who want children may feel stigmatized. PMID- 20973165 TI - Prevention. Study reveals that vaginal gel reduces HIV, herpes. PMID- 20973167 TI - Funding, other trends imperil global response to HIV/AIDS. PMID- 20973168 TI - Treatment. Employee's allegations survive test under False Claims Act. PMID- 20973169 TI - Prisons. New diet plan not deliberately indifferent to inmate's needs. PMID- 20973170 TI - [I6/7 Position of minors in nursing decisions]. PMID- 20973171 TI - [Radiation physiology of higher nervous activity: results and perspectives]. AB - Reflex forming and stabilization, the typological peculiarities of the experimental animals' higher nervous activity were discussed. The problems of the central nervous system functional reactions to irradiation in small doses, the chronic irradiation in particular, influence to higher nervous activity of heavy particles irradiation and neurochemical mechanisms of the disturbances in the central nervous system require further experimental investigations. PMID- 20973172 TI - [Evolution of endocrine glands and neuroendocrine systems: the "humoral code"]. AB - Origin of complex neuroendocrine systems in evolution seems to be based on the signalling functions of molecules produced by separate groups of cells and glands, and each of these molecules "is coding" some distinct conditions of internal milieu and environment for the cell and the whole organism. Use of such "coding" molecules for the integration of the separate glands in the neuroendocrine systems permits to guaranty supply of vital substances to the organism regardless of external and internal disrupting circumstances, and to retain ability to alter the levels of the hormones produced by these systems in accordance with changes in internal milieu and environment. PMID- 20973173 TI - [Autoregulative processes and structural principle of functional selective mobilization]. AB - Autoregulative systems are being formed through dynamical changeability of structural components. Initial structural organization determinates possible variants of regulative connections with different probabilities resulting in a more successful formation of one system and retarding in the appearance of another one. It emphasized the domination of structural principle of functional selective mobilization during the creation of physiological, pathological and ambivalent systems (having, accordingly, adaptive, disadaptive and ambivalent significance). That's why result of system activity has not a dominant role in the process of system formation (the result, if it has adaptive significance, only promotes the consolidation of previously formed regulative connections). PMID- 20973174 TI - [Fundamental-applied aspects of systemic inflammation in terms of physiologic and typical pathological process]. AB - The concept of systemic inflammatory response syndrome (SIRS) by sepsis as well as quality of SIRS criteria, classification, and PIRO system has been a subject to analytical criticism in terms of theory of physiologic and typical pathological process. It has been disclosed SIRS can be considered only as the syndrome, that solves particular clinical tasks, but not as a basic model of pathogenesis of critical states. In authors' opinion it is more correctly to discuss systemic inflammation as a typical pathologic process that appears as a complex of one or another "resuscitation" syndrome in a clinical course. PMID- 20973175 TI - [Chaperones in regulation and restoration of physiological functions]. AB - Protective effects of the HSP70 expression in heat stress, sleep deprivation, epilepsy, enhanced anxiety, psycho-emotional stress, physical loads, are described, and data on the HSP70 effects upon characteristics of sleep and somatic-visceral functions in homeothermic animals are cited. Prospects of using the HSP70 "inductors" are discussed as well as the HSP70 preparations use in therapy of large range of pathological conditions. PMID- 20973176 TI - [The diversity of mechanisms of the ion channels blockade as a way towards designing new pharmacological agents]. AB - Dysfunctions of glutamatergic synaptic neurotransmission often accompany various CNS disorders. Action of excessive glutamate, which causes excitotoxic effects by neuron depolarization and massive calcium influx can lead to cell death. Despite obvious importance of development of anti-glutamic neuroprotectors, among great number of known antagonists of ionotropic glutamate receptors only memantine is used in medicinal practice. One of the sources of numerous side effects caused by glutamate receptor antagonists is that the drugs usually inhibit receptors, which mediate both normal and pathological CNS processes. A possible approach to overcoming the problem is to develop the drugs whose action is enhanced in potentially pathological conditions such as high-frequency activation, high glutamate concentration, depolarized membrane, etc. Action of many classes of antagonists depends on pattern of receptor activation and on membrane voltage. In the present work, we discuss several peculiarities of channel blocking mechanisms from the viewpoint of neuroprotector development. In particular, we compare channel blockers which demonstrate different types of interaction with the channel gating machinery, we consider different types of voltage dependence and consider action of channel blockers, which can permeate through the channel. We conclude that meticulous analysis of the mechanism of action of the glutamate receptor channel antagonists could help to approach predicting of in vivo action using in vitro data. PMID- 20973177 TI - [N. O. Pirogov and physiology]. PMID- 20973178 TI - [Operative isolated chemohyperthermal perfusion of the lung with ablation of pulmonary metastases]. AB - The authors have got their first experience with chemohyperthermal perfusion of the lung in 4 patients. The method and technique of the operation of ablation of metastases in the lungs with preliminary chemohyperthermal perfusion are described. All the patients survived the operative interventions. PMID- 20973179 TI - [Cardiotoxicity in performing chemotherapy of breast cancer by the data of retrospective multicenter "case-control" investigation]. AB - The authors describe results of 5 year observations of the state of the cardiovascular system in 1643 women who underwent nonajuvant and adjuvant polychemotherapy of breast cancer within the framework of retrospective multicenter case-control investigation. The total frequency of registration of acute cardiotoxicity was 39.3% at standard visits, and 75.2% at unplanned visits. The frequency of late toxicity was 34.5% according to clinical-echocardiography findings, and 100% according to the data of echocardiography of patients with risk factors and markers of cardiotoxicity. The necessity of joint management of such patients by oncologists and cardiologists is stressed. PMID- 20973180 TI - [Endoscopy in diagnosis and treatment of complicated esophageal anastomoses]. AB - The authors describe an experience with treatment of 115 patients with complicated course after esophagogastroanastomoses and esophagojejunoanastomoses using endoscopic techniques. The diagnostic manipulations and algorithm of treatment of patients with early and late complications in the area of nutritional anastomoses were developed. Thanks to high tech minimally invasive interventions (bougienage, balloon dilatation, stenting, endoscopic hemostasis, dissection of scar strictures) traumatic reoperations could be avoided. PMID- 20973181 TI - [Experimental-clinical reasons for application of endoprostheses of reperen for plasty of the abdominal wall]. AB - The work presents results of a morphological investigation of tissues in the zone of implantation of synthetic material in creation of experimental model of ventral hernia. A comparative characteristic of a reaction of tissues on reperen and polypropylene is given. A number of principal advantages of reperen as compared with polypropylene were detected in plasty of hernial hilus. An analysis of the first experience of operative treatment of hernias by nonstrain methods using reperen in clinic is made. PMID- 20973182 TI - [A new approach to treatment of the intraabdominal hypertension syndrome in patients with diffuse peritonitis]. AB - Results of treatment of 49 patients with diffuse purulent peritonitis were analyzed. The patients were divided into two statistically similar groups. The control group of patients consisted of 27 patients treated using traditional methods. Patients of the main group (22) were treated by the same method, but the defect of the abdominal wall was closed using wide-meshed reticular polypropylene endoprosthesis with total size of the meshes not less than 70% of the general square surface. During every programmed sanation the prosthesis was cut longitudinally along the whole length and sutured so that the level of intraabdominal pressure was not more that 15 mm Hg. In the nearest postoperative period the main group patients had endotoxicosis 1.3 less, and the motor evacuatory function of the intestine was 2.2 times higher which resulted in 1.3 times less postoperative lethality. In the long-term postoperative period excellent results of treatment became 13.3% more often, good results were 12.7% as compared with the control group. PMID- 20973183 TI - [One-stage operations for left side colon obstruction]. AB - A method of intraoperative lavage of the colon was used for the improvement of results of treatment of patients with cancer of the left colon. The method allowed performing one-stage operations and forming primary anastomosis. Incompetence of the anastomosis was noted in one case, no reoperation was needed. Postyopetrative lethality was 3.4%. PMID- 20973184 TI - [The possibilities of surgical and combined treatment of patients with locally disseminated renal cell carcinoma]. AB - A comparative analysis of surgical and combined treatment of renal carcinoma in 84 patients has shown that preoperative embolization of the renal arteries failed to reduce blood loss and duration of operation, failed to increase recurrence free period and 3 to 5 years survival of the patients. Specific features of combined interventions are described. PMID- 20973185 TI - [Surgical treatment of fibromuscular dysplasia of renal arteries in adults]. AB - The authors have analyzed an experience with treatment of 16 patients. All the patients had renovascular hypertension (RVH) and 3 of them had renal dysfunction. Revascularization of the kidneys (RK) was fulfilled in 11 patients by shunting (9) or prosthesis (2) of the renal arteries. In 7 patients percutaneous endovascular angioplasty (PEA) was used. There were neither complications nor lethal outcomes. Arterial pressure normalized in 7 patients and in 9 RVH was better. In the long-term period (at the average within 21 months) 14 patients were followed-up. In 3 patients having perimedial and intimal fibroplasty of RA after PEA restenoses were diagnosed. They had repeated RK. Renal function became better in 1 patient, in 2 patients there was no substantial dynamics. All shunts were passable. The analysis of the data has shown that liquidation of RVH in patients with FMD of RA has inverse dependence on its duration, and decision on the method of RK depends on the type of RA, experience of the specialists, the patients desire included. PMID- 20973186 TI - [Transluminal balloon angioplasty as a method of choice in treatment of critical ischemia of lower extremities]. AB - The authors analyzed results of treatment of 127 patients. A new direction in the endovascular treatment of critical ischemia of the lower extremities is substantiated on the basis of a combination of methods of subintimal and intraluminal angioplasty. For the first time all the patients with critical ischemia of lower extremities, and having no irreversible changes of the extremity requiring amputation at the level of the low leg or femur, must be considered as good candidates for translumbar balloon angioplasty. PMID- 20973187 TI - [The diagnostics and treatment of pain syndrome after operation for hernias of the intervertebral discs of the lumbosacral area of the backbone]. AB - The results of treatment of 42 patients after eradication of hernias of intervertebral discs of the lumbosacral area of the spine with a recurrent pain syndrome were analyzed within the period from 2 months to 3 years after surgery. Almost all the patients were found to have a combination of two or more factors, responsible for the development of pain syndrome. Lumbostenosis and spondiloarthrosis were noted more often. Complex and specially directed medical actions allow getting regress of the pain syndrome and stable remission in 69% of the patients. PMID- 20973188 TI - [Using dissection of the internal anal sphincter with its hypertrophy in children]. AB - Treatment of chronic constipations in children still remains an actual problem. In the period from 1996 to 2008 we made 4739 ultrasonic investigations in 3526 patients. Thickness of the internal anal sphincter was found in 1.72% of children. Operation of sphincterotomy of the internal anal sphincter was performed on 41 patients, its efficiency being studied within 1-2, 3-5 and 7-10 years. This intervention was shown to reestablish independent emptying in more than 70% of patients. PMID- 20973189 TI - [Modern specificity of surgical infection of bones and joints in children]. AB - A comparative study of frequency, structure and specific features of the clinical course was fulfilled in 2456 children with surgical infection of bones and joints (SIBJ) in the period from 1970 to 1985 and 1986 to 2006. The work used clinical, instrumental, radiation, laboratory, microbiological, immunological and statistical methods of investigations. Specific features of SIBJ in children at the present time are: 1) pathomorphosis of hematogenic osteomyelitis; 2) the appearance of previously not noted new forms of SIBJ--fetal osteomyelitis and arthritis, chronic recurring multifocal osteomyelitis, syndrome SAPHO and increasing frequency of previously rare BCG-osteomyelitis, exogenous osteomyelitis, sacroiliitis and inervertebral disciitis; 3) widening the spectrum of SIBJ pathogens with an increasing significance of involutionary forms of bacteria, elevation of their resistence to antibiotics and antiseptics, increase of the factors promoting the development of immunodeficient states in childhood. PMID- 20973190 TI - [Embolization of cerebral aneurysms in acute period of hemorrhage complicated by the development of vasospasm]. AB - Results of endovascular treatment of cerebral aneurysms in acute period of hemorrhage complicated by the development of vasospasm in 80 patients were analyzed. The results of treatment of patients with vasospasm were worse. The appearance of vasospasm did not depend of the severity of the patient's state, so all the patients independent on their state need prophylactic measures against this complication. Based on the analysis a strategy of embolization of aneurysms in acute period of hemorrhage complicated by the development of vasospasm was worked out. PMID- 20973191 TI - [Thoracoscopic sympathsplanchnectomy in treatment of patients with unresectable cancer of the pancreas]. AB - The authors have analyzed experience with treatment of pain syndrome in 45 patients, in 31 of them thoracoscopic sympathsplanchnectomy was fulfilled. The operation was shown to give a pronounced analgetic effect and improved quality of life of patients. PMID- 20973192 TI - [Surgical strategy for external biliary fistulas]. AB - The authors have analyzed results of the diagnostics and treatment of 68 patients with external biliary fistulas developed after operative procedures on the liver, bile ducts and duodenum. The character of operative interventions was established to depend, first of all, on the causes of the development of biliary fistula. After different surgical procedures in the postoperative period there were 16.2% of complications with 4.4% of lethal outcomes. PMID- 20973193 TI - [Experience with treatment of patients with villous adenoma of the large intestine]. AB - The authors analyzed an experience with treatment of 176 patients. It was shown that increasing colonoscopy allowed clear differentiation of neoplasm in the colon, decision on the strategy of treatment. The effective method is endoscopic resection of intestine mucosa. PMID- 20973194 TI - [Laparoscopic resection of primary and metastatic malignant tumors of the adrenals]. AB - An analysis was made of experience with treatment of 24 patients who underwent laparoscopic adrenalectomy for adrenocortical carcinomas (in 7 patients) and metastases in adrenals (in 17 cases). Laparoscopic adrenalectomy was shown to be a safe and effective method of treatment of primary and metastatic tumors of the adrenals. The method can replace open operative intervention in the majority of patients with metastases to adrenals and primary cancer of the adrenals. PMID- 20973195 TI - [Experience with treatment of gonarthrosis by the method of arthroscopic sanation of the joint]. AB - The authors made an analysis of treatment of 165 patients during 12 months, arthroscopic sanation of the joint being used in 75 patients. The technique of operation is described in comparison with traditional therapy in patients after arthroscopic sanation. In 76% of the patients there was improvement of the joint functions (traditional therapy gave improvement in 45.6%). PMID- 20973196 TI - [A rare observation of Mirizzi syndrome, complicated by arrosive bleeding from cystic artery]. PMID- 20973197 TI - [Certain problems of teaching operative surgery and topographic anatomy]. AB - The article presents a discussion of different methods of teaching operative surgery and topographic anatomy in medical colleges (prediploma training) and education after diploma. PMID- 20973198 TI - [Certain aspects of the diagnostics and surgical treatment of antalgic scoliosis with hernias of the intervertebral discs of the lumbosacral area of the backbone]. PMID- 20973199 TI - [Principles of treatment of bradyarrhythmias in patients with dysfunction of the left ventricle without indications to cardioresynchronizing therapy]. PMID- 20973200 TI - [Historical aspects of classifications of postoperative ventral hernias]. PMID- 20973201 TI - [Attendance rate in the Polish Cervical Cancer Screening Program in the years 2007-2009]. AB - BACKGROUND: In Poland in 2007, according to the National Cancer Registry 3431 women were diagnosed with cervical cancer and 1907 died. To change the unfavorable epidemiologic situation, in 2005 the Ministry of Health (MH), the National Health Fund (NHF) and the Polish Gynecological Society following WHO/IARC guidelines developed a National Population-Based Cervical Cancer Screening Program. Its implementation and roll-out started in 2006. The target population are women aged 25 to 59 insured in the National Health Fund. A Pap test is done with a three-year interval, free of charge. The system is based on personal invitations sent by regular post. Invitation to screening is supported by a social educational campaign "Choose Life" run under one slogan and logo across the whole country The NHF data base enables identification of women to screen. Pap smears are collected by gynecologists and since 2008 also by midwives trained and certified by the Program National Coordinating Center Pap test results are reported in the Bethesda 2001 system. The Screening Program has its system of quality assurance and control and is supported by a specially designed computer data base called SIMP (System of Information Monitoring in Prophylaxis) with online access to all records. In addition to organized, population-based screening there is also opportunistic screening in Poland practiced either by private gynecological practices or by some units that cooperate with the National Health Fund, but do Pap tests as an element of comprehensive gynecological examination. Those smears are not registered in the SIMP. AIM: Our aim was analysis of attendance rate in the Cervical Cancer Screening Program in the years 2007-2009. We also investigated correlation between screening coverage and invitation sending schedule, as well as between coverage and screening accessibility determined by the number of gynaecological practices where Pap smears are collected. MATERIAL AND METHODS: Attendance rate in the Screening Program was evaluated for the years 2007, 2008 and 2009. The analysis included screening coverage in all voivodeships in the 12 months of the year as well as the number of gynaecological practices participating in the Program. In addition, the place of residence of screening attenders (urban/rural area) was taken into account. For the analysis the SIMP (System of Information Monitoring in Prophylaxis) data were used. Statistical analysis was performed using Statistica 9.0 software. P-values < 0.05 were considered statistically significant. RESULTS: The target population in the years 2007-2009 was 9,727,842 women. Personal invitations were sent to 99.7% of them. Pap Smears were collected from 24.14% of the target women (in 2007--21.25%; in 2008--24.39%; in 2009--26.77%). We noted that the number of 1400 gynecological practices participating in the Program was the minimal value to observe a significant increase in the number of Pap smears collected (p = 0.000). Polish women do not attend screening in the winter months. However when a batch of invitations was sent in the spring or summer months, within two following months we could observe an increase in the number of Pap smears collected (p = 0.000). There are significant differences in the screening uptake in particular regions of Poland (a stable trend). Compared to urban women, rural women participate in the screening more often (p = 0.003). CONCLUSION: All Pap test results including opportunistic screening should be registered in the SIMP In the regions where particularly low attendance rates were observed, an intensive promotional campaign should be run to encourage participation in the screening. Also, sending a repeated invitation to non-compliers should be considered. The currently unfavorable schedule of invitation sending should be changed. According to the analysis performed, invitations should be more effective if sent on a regular basis (in small but regular batches), more intensively in the summer and spring months. In the winter season it would probably be better to focus on an extensive media campaign followed by sending a large number of personal invitations. PMID- 20973202 TI - [Human papilloma virus genotyping in women with CIN 1]. AB - INTRODUCTION: Cervical cancer remains a considerable diagnostic and therapeutic problem in Poland. Despite progress in creating an active cancer prevention program in our country Poland occupies one of the last places in the EU in terms of cervical cancer- morbidity and mortality Supplement of secondary prevention of primary prophylaxis-HPV 16, 18 vaccination, offers hope for improvement of the situation. Epidemiology of individual HPV types differs, depending on the geographical location of the study population. So far in Poland, we have had no reliable data on the participation of selected oncogenic HPV types in the development of cervical pathology OBJECTIVE: Identification of the most frequent, oncogenic HPV types in women diagnosed with CIN 1, from the Central and Western Poland. MATERIAL: In the course of the conducted studies, genotyping of 13 types of human papilloma virus has been done in 126 HPV DNA-positive women diagnosed with CIN 1. METHOD: Each cell material in which the presence of HPVDNA identified 13 types of oncogenic human papillomavirus was subsequently subjected to genotyping using the molecular test--Linear Array HPV Genotyping (Roche Diagnostics). RESULTS AND CONCLUSION: In women from the Central and Western Poland diagnosed with CIN 1, HPV 16 (53.97%) was the most common, followed by HPV 33 (21.3%), HPV 18 (16.67%), HPV 31 (10.32%), HPV 45 (7.94%), HPV 52 (1.59%). Current HPV vaccines are designed to protect against two of the three most common genotypes, in women diagnosed with CIN 1 in Central and Western Poland. PMID- 20973203 TI - [Prognostic value of histopathology in cervical cancer patients]. AB - Cervical cancer is the sixth cause of cancer morbidity and the seventh cause of cancer death among women in Poland. The rising tendency of cervical adenocarcinoma morbidity and the decrease of cervical squamous cell carcinoma have been observed. Many authors emphasize the worse outcome of cervical adenocarcinoma patients, when compared with the squamous cell cancer. OBJECTIVES: The assessment of prognostic value of histopathology in cervical cancer patients. MATERIAL AND METHODS: The retrospective analysis of 142 cervical adenocarcinoma and 242 squamous cell cancer patients, treated between January 1989 and December 1999, at Gynecological Oncology Department of Maria Sklodowska-Curie Memorial Cancer Center in Warsaw, has been performed, In each case, the clinical diagnosis was histologically confirmed. All patients were treated with surgery and/or radiotherapy The above methods were used as the routine therapeutic modalities, during the analyzed period. The analysis of the overall survival (OS) and the disease-free survival (DFS), in dependence on the selected clinico-pathological factors, was performed. RESULTS: The percentage of the 5-year OS for cervical adenocarcinoma patients amounted to 45.0%, whereas for squamous cell cancer to 62.5%. The difference was statistically significant (p = 0.05). In spite of higher percentage of cervical adenocarcinoma, diagnosed at early stage, when compared with squamous cell cancer the outcome of the whole adenocarcinoma group was worse. CONCLUSIONS: Regardless of the other clinico-pathological factors, adenocarcinoma was associated with poorer survival Identification of women who are at risk and different treatment modalities for both types of tumor should be the subject of future studies. PMID- 20973204 TI - [Expression of survivin, SDF-1 and CXCR4 on tumor cells in ovarian cancer]. AB - BACKGROUND: epithelial ovarian cancer (EOC) has the highest mortality rate among patients with gynecologic malignancies. Lack of specific and early symptoms and of screening tests causes that most patients are diagnosed in advanced stage of disease. Radical surgery followed by chemotherapy does not bring satisfactory curative effects. OBJECTIVES: the urgent need exists to define the optimum biomarker for ovarian cancer to predict patients' response to curative therapy. Our current study aimed at correlation between the expression of survivin, SDF-1, CXCR-4 on tumor tissue and clinical outcome of patients with ovarian cancer. RESULTS: We showed that survivin expression correlates with histological grading of the tumor. No correlation was found in terms of SDF-1/ CXCR-4 expression and clinicopathologic data. CONCLUSIONS: further studies covering larger number of patients are needed to determine whether SDF-1 and CXCR-4 might be considered as biomarkers for ovarian cancer. PMID- 20973205 TI - [Do chromosomal abnormalities reappear in subsequent pregnancies and how often?]. AB - OBJECTIVE: Genetic factors are the most common causes of spontaneous abortions. 50% to 80% of first-trimester abortions reveal-chromosome abnormalities. Evidence for the recurrence of the same or another chromosome abnormality in the next pregnancy is scarce. THE AIM: The aim of our study was to estimate recurrence risk of abortus aneuploidy and to find out whether karyotyping of the abortus allows the prognose subsequent pregnancy outcomes. MATERIAL AND METHODS: Paraffin embedded chorions have undergone cytogenetic examination using FISH with chromosome-specific probes. 57 chorions from 26 women have been assessed, including chorions from two consecutive abortions from 18 women and chorions from three consecutive abortions from 5 women. RESULTS: 38.6% of 57 specimens had chromosome aberrations. The most prevalent anomalies were 16, 21 and 18 trisomies. 23 patients had a subsequent abortion karyotyped; 15 had a normal initial karyotype and 8 had an aberrant initial karyotype. 3 out of the 8 patients had a repeated chromosome anomaly 5 out of the 15 patients who initially miscarried an aneuploid embryo, had a subsequent miscarriage of an aneuploid embryo. Only 3 (13.04%) out of the 23 patients displayed aneuploidy in each abortus. CONCLUSION: (1) Chromosome aberrations can reappear in subsequent pregnancies in the same patient and may be the cause of recurrent miscarriages. (2) The value of embryo/fetal karyotyping is not decisive in prognosis of subsequent pregnancy outcome. (3) Abnormal fetal karyotype can occur regardless of other causes of pregnancy loss. PMID- 20973206 TI - [Maternal active or passive smoking in relation to some neonatal morphological parameters and complications]. AB - OBJECTIVE: To determine the relationship between maternal active and passive smoking and neonatal morphological parameters, as well as some neonatal complications in full-term newborns. METHODS: 150 women with uncomplicated, singleton pregnancies were assessed by means of a patient questionnaire. Neonates were divided into 3 groups according to obtained information on maternal smoking status--active smoking: n=51, passive smoking: n=49, non-smoking: n=50. Immediately after birth morphological parameters such as: birthweight, body length, head and chest circumference were assessed. RESULTS: Values of birthweight, body length, head and chest circumference in newborns born to active smoking mothers were significantly lower than in newborns of passive smoking and non-smoking mothers. No significant differences in values of RBC, WBC, PLT Hemoglobin and Hematocrit between the studied groups have been detected. Oxygen hood was applied significantly more often in case of newborns from active smoking mothers than in the control subjects. In groups of newborns from active and passive smoking mothers, hyperbilirubinemia and signs of early onset infection were diagnosed significantly more frequently than in the control subjects. CONCLUSIONS: Active maternal smoking, as opposed to passive maternal smoking, leads to decreased birthweight, body length, head and chest circumference. Full term newborns born to active smoking mothers often need to be treated with oxygen hood during the first hours after birth. Maternal smoking, both active and passive, leads to an increased risk of hyperbilirubinemia and early onset infection in neonates. PMID- 20973207 TI - [Colposcopy of the vagina--a frequently omitted part of the colposcopic examination]. AB - Colposcopy of the vagina is a part of the colposcopic examination which is often omitted. It is an extremely serious mistake that makes the colposcopic examination less valuable. The instrumentarium, technique of the examination and distinctive features of colposcopic images showing vaginal changes have been presented in detail. PMID- 20973208 TI - [Prostate specific antigen in women]. AB - PSA-prostate specific antigen is considered to be a useful marker in the diagnosis and monitoring of prostate cancer Currently PSA was also detected in serum and tissues of women. We reviewed the literature dealing with the existence and role of this marker in women. PMID- 20973209 TI - [The role of physiotherapy in selected gynecological disorders]. AB - Physical training is a method supporting pharmacological and surgical treatment by shortening the time of recovery and effectiveness of the entire treatment. Many kinds of such methods, despite their availability remain unpopular and unused. The aim of the following study was to present possibilities of aiding the processes of curing by means of new physical methods. Guidelines for the treatment of adnexitis and rehabilitation after operative treatment were presented. PMID- 20973211 TI - [Resting-state brain connectivity and its clinical application]. PMID- 20973210 TI - [Statement of Polish Gynecological Society experts about Pharmaton Matruelle for pregnant and breastfeeding women]. PMID- 20973212 TI - [The Chinese translations for "pulmonary hypertension" and associated terms should be standardized]. PMID- 20973213 TI - [Comparison of deficits in visual cortex between anisometropic and strabismic amblyopia by fMRI retinotopic mapping]. AB - OBJECTIVE: To study the neural mechanism of visual cortical deficits between anisometropic and strabismic amblyopia comparatively by BOLD-fMRI retinotopic mapping. METHODS: Ten anisometropic amblyopes, 10 strabismic amblyopes and 9 normal subjects underwent fMRI with retinotopic mapping and luminous spots stimuli (spatial frequency: 6 cpd, contrast: 0.5). 1.5T MRI system was used to obtain functional images of visual cortex. Responses in primary and secondary visual cortex were compared among the dominant (normal subject group), anisometropic and strabismic amblyopic eyes by one-way ANOVA, successively analyzed by paired-samples t test between amblyopic eyes and fellow fixing eyes (anisometropic and strabismic amblyopia group respectively). Their fMRI deficits of amblyopes were analyzed regressively in two amblyopia groups respectively. RESULTS: The result of one-way ANOVA showed significantly a lower activation (average T value) in V1, V2, V3, Vp and V7 visual areas (P < 0.05, P values 0.018, 0.007, 0.002, 0.000, 0.025 respectively) between anisometropic amblyopia and normal group. This was in accordance with the result of paired-samples t test between amblyopic eyes and fellow fixing eyes in anisometropic amblyopia group (P < 0.05, P values 0.035, 0.007, 0.020, 0.009, 0.023 respectively). Statistical difference was found in V1, V2 and Vp areas between strabismic amblyopia and normal group (P < 0.05, P values 0.010, 0.007 & 0.003 respectively). The paired samples t test in strabismic amblyopia group showed statistical difference only in V2, Vp areas (P < 0.05, P values 0.026 and 0. 009 respectively. ). So the two results were discordant. Between the two amblyopic groups, there was no statistical difference (P > 0.05) except in V7 area (P < 0.05, P value = 0.048). There was no causal relation between the primary visual cortical deficits and the secondary cortex in amblyopia (P > 0.05). CONCLUSION: Anisometropic amblyopia and strabismic amblyopia both have functional deficits in the primary and secondary visual cortex. The neural mechanism of secondary visual cortical deficits may be more complex than decreased cortex activation induced by the deficit of primary cortex. In the primary cortex, strabismic amblyopia and anisometropic amblyopia have neuronal deficits and/or abnormal interaction. In addition, strabismic amblyopia may also have suppressive influences of the fixing eyes upon the amblyopic eyes. Anisometropic amblyopia has the neural undersampling at a high spatial frequency in the secondary visual cortex as compared to amblyopic amblyopia. PMID- 20973214 TI - [FMRI study of linguistic cortex in healthy Chinese individuals]. AB - OBJECTIVE: To study the linguistic-functional cortex and identify the effect of age and sex on normal language processing by ER-fMRI and to observe whether a left or right predominance for linguistic-functional cortex exits or not. METHODS: A total of 50 healthy Chinese volunteers with right-hand dominance were divided into 4 groups according to gender and age: Group A, young male (< or =50 yr); Group B, young female ( < OR =50 yr); Group C, old male ( >50 yr); Group D, old female ( >50 yr). Each group finished 2 tasks of reading Chinese words loudly and silently. RESULTS: There were no statistical differences of activated voxel and intensity changes in linguistically functional cortex between healthy male and female individuals of different decades. The activated areas include bilateral frontal lobe, temporal lobe, parietal lobe, occipital lobe and bilateral cerebellar hemisphere. And there were no statistical difference of activated voxel and intensity changes in bilateral activated areas. Although the activated areas were not quite the same between two tasks and more activation elicited by overt-reading, but there was no statistical difference of activated voxel and intensity changes in the same activated areas. CONCLUSION: There is no age and gender difference in linguistic-function regions of healthy individual whose native language is Chinese. It is bilateral-equilibrium and no linguistic hemisphere's predominance exits. This characteristic is different from the left hemisphere dominance of western languages. Although there is no statistical difference of activated voxel and intensity change between overt-reading and covert-reading, the activated areas of covert-reading are so unreliable that the way of covert-reading to study the linguistic-function regions of human brain is improper to some extent. PMID- 20973215 TI - [Central mechanism of electric-acupuncture at Zusanli (ST36) for gastric mucous membrane protection with FMRI]. AB - OBJECTIVE: To explore the central mechanism of acupuncture in protecting gastric mucous membrane by a composite analysis of gastric mucous membrane related indices in peripheral blood and functional MRI (fMRI) signal changes after electric-acupuncturing Zusanli (ST36) acupoint. METHODS: Sixteen healthy adult volunteers were divided into true acupoint group (A) and sham acupoint group (B). Zusanli acupoint was used for Group A. Peripheral blood was drawn 5 min before and 5, 15, 25, 30 min after needle-removal for the detection of gastric mucous membrane related indices. fMRI was performed during acupuncture and the acquired fMRI data were analyzed by SPM2 (P < 0.001). RESULTS: The levels of calcitonin gene related peptide (CGRP) and prostaglandin E2 (PGE2) increased while those of endothelin (ET) and gastrin (GAS) decreased significantly after acupuncture in Group A (P < 0.01). And there was no significant change in Group B (P > 0.05). Acupuncturing Zusanli activated the bilateral middle frontal gyrus, caudate, left precentral and postcentral gyri, hypothalamus, anterior cingulate cortex, right hippocampus, insula and cerebellar hemisphere. But acupuncturing the sham acupoint only activated the paracentral lobule and cerebellar hemisphere. CONCLUSION: Acupuncturing Zusanli acupoint activates certain cortex areas and multiple systems to stimulate the release of neurotransmitters and regulate the peripheral humoral factors to achieve the protection of gastric mucous membrane. PMID- 20973216 TI - [Evaluation of blood oxygen level in hepatocellular carcinoma with noninvasive magnetic resonance multi-echo R2* technique and its clinical significance]. AB - OBJECTIVE: To probe the relationship of clinical and pathological features of hepatocellular carcinoma (HCC) with the blood oxygen level by the technique of noninvasive magnetic resonance multi-echo R2*. METHODS: Multi-echo R2* sequence was carried out pre-operatively in a total of 46 patients with pathologically proved HCC. The T2* and R2* values of HCC, liver, spleen and paraspinous muscle on T2* and R2* maps and the ratios of HCC to liver (H/L), spleen (H/S) and muscle (H/M) were calculated. Different groups were defined according to such clinical parameters as the serum AFP level, lesion dimension, Edmondson's grade, ascites, capsula, liver cirrhosis, intrahepatic daughter foci or tumor-emboli in portal vein respectively. The differences in T2* and R2* values and the ratios between different groups were analyzed. RESULTS: In contrast with T2* value, the R2* value of HCC was less than that of liver or spleen (P < 0.05). Difference in R2* ratio of H/M (0.81 +/- 0.26 vs. 1.23 +/- 0.39) was found between positive and negative groups of AFP (P = 0.047, t = 2.248). And so was the same difference (0.83 +/- 0.24 vs. 1.23 +/- 0.43) between the lesions with or without capsula (P = 0.046, t = 2.257). The R2* ratio of H/S in hepatic cirrhosis group (1.01 +/- 0.58) was higher than that in noncirrhosis one (0.53 +/- 0.17) (P = 0.035, t = 2.247) whereas the T2* ratio of H/S was reversed (1.42 +/- 0.92 vs. 2.64 +/- 1.15) (P = 0.036, t = 2.230). The differences in T2* ratio of H/M in the group with or without intrahepatic daughter foci (1.18 +/- 0.47 vs. 2.24 +/- 1.71) (P = 0.048, t = 2.115), and in T2* value in the group with or without tumor-emboli in portal vein (27.24 +/- 11.90 ms vs. 46.70 +/- 38.40 ms) (P = 0.049, t = 2.046) were shown to be significant. However, no differences in MR parameters between other groups were observed (P > 0.05). CONCLUSION: The blood oxygen level parameters, R2* and T2* values and the ratios are related to some clinical and pathological features of HCC. And the blood oxygen level is affected by multiple factors. PMID- 20973217 TI - [Imaging of magnetically labeled single-cell by 7.0 T MR]. AB - OBJECTIVE: To detect magnetically labeled single cells in vitro by using 7.0T MRI system and to optimize the parameters used for labeled cell imaging. METHODS: The endothelial cells ECV-304 were incubated with self-synthesized Fe2O3-PLL Prussian blue stain was employed for identifying intracellular irons. Agarose phantoms of dispersed labeled cells were made with an cell concentration of 2 x 10(3)/ml. 3D FLASH sequence was employed for the detection of single cells and the cell concentration calculated by counting the number of dark points in MR images; The investigators compared the effects of gradient echo sequence (2D-FLASH) and spin echo sequence (MSME) upon the imaging of magnetically labeled single cells; Also the effects of different echo times (Es) and resolutions of magnetic nanoparticle relaxation upon the imaging of cells were analyzed. RESULTS: The endothelial cells ECV-304 were labeled successfully and the labeling efficiency reached almost 100%. Prussian blue staining of Fe2O3-PLL labeled cells revealed the cytoplasmic presence of iron. Single cells were detected as isolated dark points and the cell concentration corresponded with the actual data. The 2D-FLASH sequence had a much stronger T2* effect than MSME sequence in single cell detection. The T2* effect increased with the prolongation of TE. The signal loss fell significantly as the resolution decreased. And it reached almost zero when the voxel size reached 200 microm3. CONCLUSIONS: 7.0T MR system is able to detect magnetically labeled single cells. The optimization of imaging sequences enhances the sensitivity of magnetically labeled single cells. Thus it provides a better method for in vivo detection of single cells. PMID- 20973218 TI - [Prospective study of Han's acupoint nerve stimulator for preventing relapse of detoxified heroin addicts]. AB - OBJECTIVE: To assess the efficacy of transcutaneous electrical acupoint stimulation (TEAS) in preventing the relapse of detoxified heroin users in a period of 12 months. METHODS: A total of 164 rehabilitating heroin users in Shanghai area were recruited after compulsory detoxification treatment for a period ranging from 3 months to 3 years. The TEAS was executed by the device named Han's acupoint nerve stimulator (HANS). The patients were treated with HANS for at least 3 months. All the subjects were then followed up for one year and relapse was monitored by monthly heroin/morphine urinalysis. RESULTS: Of 164 rehabilitating former heroin addicts, 53 remained drug-free at the end of 12 months observation period as judged by negative urinalysis while 35 become relapsed as documented by positive urine tests. The rest 76 dropped off due to various reasons and were all counted into the category of "relapsed". Thus, our data indicated 32.3% rehabilitating heroin users could stay sober for at least one year, which is significantly higher than the existing reports that less than 5% detoxified abusers would stay drug free for one year with no further intervention. No obvious correlation was found between the susceptibility of relapse and the duration of compulsory detoxification. CONCLUSION: Compared to the existing literatures, our results indicate that HANS could produce a marked decrease of the relapse rate of rehabilitating heroin users after compulsory detoxification. PMID- 20973219 TI - [Disability and common treatment strategies associated with knee pain in a rural Chinese population]. AB - OBJECTIVE: To estimate the burden of disability and health services use by people with knee pain, with or without radiographic evidence of osteoarthritis (OA), in rural northern China. METHODS: A population-based cross-sectional survey was conducted among 1030 residents of Wuchuan County, Inner Mongolia, aged 50 years old and over. The participants completed an interviewer-based questionnaire and obtained bilateral weight-bearing posterior-anterior semi-flexed knee radiographs. RESULTS: Of 1027 participants with knee radiographs, 513 (50%) participants reported knee pain in most days of at least a month over the past 12 months. Of those with knee pain, 109 (21%) had radiographic OA (Kellgren Lawrence grade > or =2) in symptomatic knees. Adjusting for age, gender, BMI, education and back pain, the presence of knee pain was associated with a significantly greater difficulty in walking, climbing 10 steps, stooping, performing cleaning chores and preparing meals. Among 513 subjects with knee pain, the presence of radiographic disease was significantly associated with the presence of unbearable pain (36% vs. 59%), restricted activity (39% vs. 64%), use of NSAIDs (78% vs. 88%) and consulting a doctor over the last 12 months (33% vs. 59%). CONCLUSION: Knee pain is associated with significant physical disability in rural China The prevalent use of NSAIDs for knee pain and a low use of knee surgery should be of particular concerns. These findings will be useful to guide the distribution of future health care resources and preventive strategies. PMID- 20973220 TI - [The effect of neoadjuvant chemotherapy on patient controlled intravenous analgesia postoperatively in ovarian cancer patients]. AB - OBJECTIVE: To investigate the effect of neoadjuvant chemotherapy on patient controlled intravenous analgesia (PICA) postoperatively in ovarian cancer patients. METHODS: Sixty three patients with ovarian cancer (ASA I--III grade) were selected. They were divided into 2 groups according to with or without neoadjuvant chemotherapy: neoadjuvant chemotherapy group (N) 33 cases, direct operation group (D) 30 cases. Both of them were completed with tumor cell reduction-extinction operation under total intravenous general anesthesia. Patients' chemotherapy-induced peripheral neuropathy (CIPN) was assessed by the total neuropathy score exclusively clinically-based (TNSc) preoperatively, the assessment of analgesic effect and side-effect was performed postoperatively. RESULTS: No statistically significant difference between the two groups (P > 0.05) on ages, body mass index, ASA grades and Karnofsky scores. Patients in group N were significantly lower than that of group D (P < 0.05) on the VAS scores at 2, 4, 8 h postoperatively, the pressure times and effective times of Bolus and the total consumption amount of analgesic drug in the whole process of analgesia treatment But the scores on nausea and vomiting of group N were significantly higher than that of group D (P < 0.05). There were no significant differences on Bruggemann comfort scale at 2, 4, 8, 12 h postoperatively, dizziness scores, pruritus scores and Ramsay Sedation scores between this two groups (P > 0.05). There was negative linear correlation between the total consumption amount of analgesic drug in the whole process of analgesia treatment and TNSc scores (r = -0.881, P = 0.048), and there was positive linear correlation between nausea scores and TNSc scores (r = 0.920, P = 0.027). CONCLUSION: Patients with neoadjuvant chemotherapy have peripheral neuropathy at different degree before operation. The more serious of peripheral neuropathy, the less demand of PCIA analgesic drug postoperatively and with more side effects occur, such as nausea. PMID- 20973221 TI - [Epidemiological study of women adults with mixed urinary incontinence in China]. AB - OBJECTIVE: To investigate the prevalence and the epidemiological factors of female mixed urinary incontinence (MUI) in China. METHODS: In February to July 2006, 19 024 subjects aged over 20 years old in 6 Chinese regions including Northwest, Southwest, Northern China, Eastern China, Northeast and South China were selected. Questionnaires were used to investigate the general characters and the lower urinary tract symptoms in these subjects. RESULTS: The overall prevalence of mixed urinary incontinence was 9.4% among these women and it increased with advancing age. In multiple logistic models, age, vaginal delivery, constipation, pelvic organ prolapse, chronic pelvic pain, respiratory system disease, menstrual disorder, urinary system disease, alcohol consumption, pelvic surgery, obesity as well as high educational level were independent risk factors for mixed urinary incontinence. CONCLUSION: The prevalence of MUI increases with advancing age. Vaginal delivery, constipation and pelvic organ prolapse are risk factors for mixed urinary incontinence in China while high educational level is a protective factor. PMID- 20973222 TI - [Modified minimally invasive percutaneous pedicle screws osteosynthesis for the treatment of thoracolumbar fracture without neural impairment]. AB - OBJECTIVE: To explore the feasibility and efficacy of modified minimally invasive percutaneous pedicle screws osteosynthesis for the treatment of thoracolumbar vertebral compression fracture. METHODS: Twenty cases of thoracolumbar fracture without neural impairment were enrolled. None needed laminotomy decompression. With the aid of C-arm image intensifier, the GSS II pedicle screws were inserted through four small longitudinal incisions and modified surgical instruments. Perioperative parameters and postoperative imaging indices were compared with those undergoing conventional open pedicle screws osteosynthesis in other 20 cases. RESULTS: There was no significant difference in operative time between minimal invasive group and conventional group (P > 0.05); but the length of incisions, length of hospital stay, the volume of operative hemorrhage and post operative drainage in minimal invasive group were significantly shorter than those in conventional group (P < 0.05); in each group, the comparisons of Cobb's angle, anterior vertebral height and disc height between pre and post-operation were all significantly different (P > 0.05); The incidence rate of chronic lower back pain in minimal invasive group was obviously lower than conventional group during the follow-up visit. CONCLUSION: The percutaneous internal pedicle screw fixation using modified instruments has the advantages of simple manipulation, less trauma and hemorrhage, quicker recovery, less pain, shorter hospital stay and a lower incidence rate of chronic lower back pain. PMID- 20973223 TI - [Arthroscopic treatment of acute greater tuberosity fractures of the humerus]. AB - OBJECTIVE: To study the outcome in the arthroscopic treatment of acute greater tuberosity fractures. METHODS: Twelve cases with acute great tuberosity fractures received reduction with arthroscopic treatment from August 2006 to December 2007. There were 7 males and 5 females. Eight cases were on left side and 4 on right side. The patients were operated at a mean age of 38 years old (range: 2745). The fractured fragments in displacements were greater than 5 mm. X-ray film and Constant score were used to evaluate the post-operative outcome. RESULTS: Three hollowed threaded screws with a washer were used to fix the big fractured fragments. The post-operative follow-up was a mean of 18 months (range: 14-33). The fracture fixations were excellent and bone union occurred. The patients received a mean Constant score of 92 (86-100) at the last follow-up. CONCLUSION: Arthroscopic treatment of acute greater tuberosity fractures is quite efficacious. PMID- 20973224 TI - [Analysis of risk factors for reversible posterior leukoencephalopathy syndrome in lupus]. AB - OBJECTIVE: To analyze the different risk factors for reversible posterior leukoencephalopathy syndrome (RPLS) in systemic lupus erythematosus (SLE). METHODS: The clinical and imaging characteristics of 2 cases were described in details. The literature reports for 33 cases of SLE and RPLS were reviewed systematically. The etiologies of SLE and RPLS were analyzed for all 35 cases. RESULTS: Thirty-five cases of SLE patients were complicated with RPLS, 32 cases suffered hypertension, 3 cases had no hypertension, 1 case was explicitly related with rituximab and 1 case was related with cyclosporine therapy. CONCLUSION: SLE complicated by RPLS has different causes, such as hypertension, SLE involving central nervous system and drug neurotoxicity. PMID- 20973225 TI - [Correlative factors of traumatic embolism in superficial cerebral vein]. AB - OBJECTIVE: To analyze the correlative factors of traumatic embolism in superficial cerebral vein and explore their corresponding treatments. METHODS: A total of 74 cases were divided into 3 groups according to their injury mechanisms. Group A: traumatic brain injury in superficial cerebral vein with cerebral contusion, acute intracerebral hematoma and subdural hematoma in the same place; Group B: traumatic brain injury in superficial cerebral vein with acute intracerebral hematoma, subdural hematoma and skull fracture in the same place; Group C: traumatic brain injury in superficial cerebral vein with acute subdural hematoma and skull fracture in the same place, without cerebral contusion or acute intracerebral hematoma. They were divided into different groups according to gender, age, pre-operative GCS and cerebral hernia. RESULTS: Among 74 cases, 28, 39 and 7 cases belonged to groups A, B and C respectively. There was significant difference among injured veins in three groups (P < 0.01). Cerebral infarction was found in 37 cases in groups A and B while only 2 cases in group C. Cerebral infarction had no correlation with sex, age, pre-operative GCS and cerebral hernia. CONCLUSION: Injuries in superficial cerebral vein are mainly caused by skull fracture, contre-coup injury and shearing force. Cerebral infarction often exists if there is cerebral contusion. It is necessary to protect injured primary superficial cerebral veins and ambient venous network, remove intracranial hematoma and large bone flap to reduce intracranial hypertension and dilute blood post-operatively to prevent venous embolism. PMID- 20973226 TI - [Experimental study of laparoscopical lumbar interbody fusion with polyporus composite phosphate calcium and rhBMP-2 compounds in sheep]. AB - OBJECTIVE: To study the efficacy of polyporus composite phosphate calcium and rhBMP-2 compounds with laparoscopical lumbar interbody fusion in sheep. METHODS: Fourteen uniform-weight adult sheep were randomly divided into three groups for LA-5 interbody fusion with titanium mesh. Autogenous bone and titanium mesh was applied with open anterior technique in group 1 (n=4). In group 2, 4 sheep were operated with laparoscope technique for LA-5 interbody fusion with composite phosphate calcium (CPC) and titanium mesh. In group 3, 6 sheep underwent laparoscopical L4-5 interbody fusion with titanium mesh as well as polyporus composite phosphate calcium and rhBMP-2 compounds. At Weeks 6 and 12 post operation, the sheep were sacrificed for imaging, biomechanic and morphological examinations. RESULTS: Although there was no statistical difference between open and laparoscopical interbody fusion group when comparing the remaining disc and endplate decorticated, bone fusion occurred in 3 groups after 3 months. A much larger amount of bony callus was observed earlier in laparoscopical L4-5 interbody fusion group with titanium mesh as well as polyporus composite phosphate calcium and rhBMP-2 compounds than two other groups. CONCLUSION: Polyporus composite phosphate calcium and rhBMP-2 compounds are suitable prosthetic materials for clinical trials. When these materials are utilized with a laparoscopical technique, satisfactory interbody fusion may be achieved. PMID- 20973227 TI - [Significance and expression of FKHR and AKT after subarachnoid hemorrhage in rat brain cortex]. AB - OBJECTIVE: To study the significance and expression of FKHR and AKT after subarachnoid hemorrhage (SAH) in rat brain cortex. METHODS: Twenty-four rats were randomly divided into three groups: sham, SAH and SAH plus nimodipine (n=8 each). A reliable SAH model was established by double injections of blood into cistern magna in Wistar rats. The neurological scores were measured by Loeffler and the expressions of FKHR, P-FKHR, AKT and P-FKHR detected by Western blot. RESULTS: Compared with sham group, the neurological score of SAH group obviously decreased (P < 0.05), the expression of FKHR became elevated in rat cortex (P < 0.01), the expression of AKT had no change and the expressions of P-AKT and P-FKHR obviously decreased (all P < 0.01). But the neurological score markedly increased (P < 0.01) and the expressions of P-AKT and P-FKHR became elevated (all P < 0.01) after administration of nimodipine. CONCLUSION: Both P-AKT and P-FKHR are involved in the process of brain cortex damage induced by SAH. The protective effects of nimodipine on brain injury induced by SAH may be related to the elevated expressions of P-AKT and P-FKHR in brain cortex. PMID- 20973228 TI - [Advantages and disadvantages of auto analyzer versus manual microscope and their complementation in blood cell examinations]. PMID- 20973229 TI - [Emphasizing complementation of different methods and interaction of related subjects, and further upgrading the level of cellulomorphological diagnosis]. PMID- 20973230 TI - [The practice of translational medicine at Harvard Medical School and its implication in China]. PMID- 20973231 TI - [Clinical application of review criteria for complete blood analysis]. AB - OBJECTIVE: To evaluate the review criteria for complete blood analysis. METHODS: total of 8820 blood samples taken at our hospital were detected both by the Sysmex XE-2100 automated blood cell analyzer and double-blind method microscopy. The performance of two review criteria were evaluated by statistical analysis. The parameters, such as true and false positive rates, true and false negative rates, sensitivity, specificity, positive predictive value, negative predictive value, total effective rate, test effectiveness and re-examination rate were calculated according to the criteria of XE-2100 hematology analyzer re examination standards coordination group of Society of Laboratory Medicine of Chinese Medical Association. And a study was conducted to determine the improved clinical effectiveness over the criteria. RESULTS: The values of true and false positive rates, true and false negative rates, sensitivity, specificity, positive predictive values, negative predictive value, total effective rate, test effectiveness and reexamination rate were 13.0%, 27.2%, 55.3%, 4.5%, 74.3%, 67.0%, 32.4%, 92.5%, 68.3%, 21.2%, and 40.2% respectively. The re-examination rate decreased to 33.8% and the total effective rate increased to 74.7% according to our improved review criteria. And there was no missed diagnosis of leukemic cells. It was found that 2069 samples (23.5%) needed manual microscopy for WBC differential analysis, 847 had abnormal cells and no leukemia was missed. CONCLUSIONS: The automatic blood cell analyzer and WBC differential analysis review criteria have great clinical utilities. The review criteria of blood cell analysis may be improved according to patient source and instrument performance so as to better meet the needs of clinical application. PMID- 20973232 TI - [Establishment and evaluation of review criteria for ADVIA 120/2120 and different series of hematology analyzers]. AB - OBJECTIVE: To establish the suitable review criteria for ADVIA 120/2120 and those for different series of hematology analyzers. METHODS: A total of 2400 samples, including 6 blood neoplasms, were detected with ADVIA 120/2120 hematology analyzer, in which 1200 samples were detected by Sysmex XE-2100 and Beckman Coulter LH750 hematology analyzers. In the meantime, blood smears were reviewed, and the results were analyzed statistically. The new review criteria were established by consulting and modifying the one as recommended by an international consensus group. Finally 300 samples were selected to validate the new review criteria. RESULTS: The results of 2400 samples detected by ADVIA 120/2120 hematology analyzer were analyzed statistically according to the international consensus review rules and blood smear positive criteria formulated by Chinese experts. The true positive rate was 22.1% (n = 530), false positive rate 28.1% (n = 675), true negative rate 44.3% (n = 1063), false negative rate 5.5% (n = 132), and the smear review rate 50.2% (n = 1205). The false negative rate was over the acceptable limit of 5%. The new review criteria were established by amending the blood smear positive criteria, i. e. increasing the percentage of band neutrophils, eosinophils, basophils and monocytes and adjusting the international consensus review rules. Then the results were re analyzed. The true positive rate, false positive rate, true negative rate and false negative rate were 15.5% (n = 371), 18.7% (n = 449), 61.6% (n = 1479) and 4.2% (n = 101) respectively. The smear review rate was 34.2% (n = 821) and no specimen of blood neoplasms was missed. On that basis, the current review criteria for ADVIA 120/2120, XE-2100 and LH750 hematology analyzer were proposed by adding some specific parameters. The results of 1200 samples with three instruments were analyzed according to the current criteria. And the false negative rates were 4.3%, 4.6% and 4.6%, and false positive rate 14.7%, 17.5% and 12.7% respectively. And no specimen of blood neoplasm was missed. The false negative rates of three instruments were 3.8%, 4.3% and 4.0% in validation teses. CONCLUSION: The review criteria for three different series of hematology analyzers have been formulated for large general hospitals. PMID- 20973233 TI - [Value of imprint in bone marrow morphological examination]. AB - OBJECTIVE: To explore the role of bone marrow (BM) imprint in the diagnosis of hematological diseases. METHODS: Between January 2002 and June 2008, a total of 3024 cases with BM smears, imprints and sections conducted simultaneously were recruited. There were 1667 males and 1357 females with a median age of 55 years old (range: 7 to 92). The cellularity on imprint and smear was evaluated with the standard cellularity on BM section. With the integrative diagnosis (including all examinations and clinical outcomes) as the standard, the diagnostic accuracy of hematological diseases were compared between BM imprint, smear and section groups. Another 79 cases of lymphoma and 114 cases of plasma cell myeloma (PCM) were selected for a correlation analysis of tumor cell infiltration patterns. RESULTS: BM imprint contained hematopoietic and non-hematopoietic regions and cells retained integrated structure. The cellularity evaluation by imprint was superior to smear overall. In BM imprint group, the diagnostic accuracy for hypersplenism (n = 130), metastatic carcinoma (n = 67), refractory anemia with excess blasts, myeloproliferative neoplasm (n = 174), and PCM (n = 94) were better than smear group (96.9% vs 80.7%, 91.0% vs 76.1%, 92.6% vs 81.5%, 92.5% vs 76.4%, and 97.8% vs 92.6% respectively, all P < 0.05); And the diagnostic accuracy for megaloblastic anemia (n = 69), acute myeloid leukemia (n = 104), refractory cytopenia with unilineage dysplasia (n = 15), refractory cytopenia with multilineage dysplasia (n = 22), and lymphoplasmacytic lymphoma (n = 12) were higher than biopsy section group (100% vs 84.0%, 91.3% vs 74.0%, 86.7% vs 60.0%, 90. 9% vs 72.7%, and 66.6% vs 50.0% respectively, all P < 0.05); And the diagnostic accuracy for myelodysplastic/myeloproliferative neoplasm (n = 26) was higher than smear group (76.3%, P < 0.05) and biopsy section group (78.2%, P < 0.05). Excellent correlations existed between BM imprint and section of the patients with lymphoma or with PCM (r = 0.90, r = 0.78, both P < 0.05). CONCLUSIONS: BM imprint contains the characteristics of both smear and section. BM imprint is superior to smear for an evaluation of cellularity. And it is also better than section for an analysis of cytological changes. PMID- 20973234 TI - [Metabolic syndrome may be better at predicting the prognosis of coronary artery disease than other traditional cardiovascular risk factors]. AB - OBJECTIVE: The prevalence of cardiovascular risk factors is growing. People with metabolic syndrome (MS) plus five cardiovascular risk factors are at a higher risk of developing coronary artery disease (CAD). The effect of metabolic syndrome on outcomes in patients with preexisting CAD has not been well studied. The present study was conducted to assess the prevalence, characteristics and long-term prognosis of CAD with metabolic syndrome and to determine which factor is the most influential prognostic factor of CAD. METHODS: The DESIRE (drug eluting stent impact on revascularization) registry represented a database of 2368 CAD patients between July 2003 and September 2004. The median long-term follow-up was 3.5 years (293 -1855 days). Metabolic syndrome was based on the modified version of Adult Treatment Panel (ATP) III Definition of Metabolic Syndrome in 2005 using body mass index (BMI) instead of waist circumference. We tested the utility of MS and its components to predict the incidence of major adverse cardiac and cerebral events (MACCE) in a large cohort of patients undergoing revascularization. RESULTS: The presence of MACCE was predicted only by MS (OR = 1.319, 95% CI 1.020 - 1.706, P = 0.035) but not other cardiovascular risk factors, such as advance age, male, smoking, high LDL cholesterol and CAD family history. MS was present in 45.6% (high fasting glucose 44.5%; high triglyceride 45.0%; low HDL 50.8%; high blood pressure 61.4%; high BMI 60.7%). CONCLUSION: Among the traditional cardiovascular risk factors, only metabolic syndrome has a primary predictive ability for MACCE in CAD patients. PMID- 20973235 TI - [Application of modified single port laparoscopic radical cystoprostatectomy and orthotopic ileal neobladder]. AB - OBJECTIVE: To evaluated the feasibility and therapeutic effect of laparoscopic endoscopic single-site surgery (LESS) for radical cystoprostatectomy and orthotopic ileal neobladder. METHODS: Between November 2008 and August 2009, 8 male patients with bladder cancer underwent modified single port laparoscopic cystoprostatectomy and orthotopic ileal neobladder with a home-made multichannel port made up of two stretchable rings and a surgical glove with trocars and valves attached to its fingers. A 4 - 5 cm midline incision was made in lower abdomen and the multichannel port placed into this incision. Laparoscopic instrument was extended through the multichannel port. Another port was placed at the umbilicus site for laparoscope. The investigators performed the modified single port transperitoneal technique neobladder extracorporeally and urethro pouch anastomosis under laparoscopy with a slipknot running suture technique. The perioperative and postoperative data were collected and analyzed prospectively. RESULTS: In all cases, no conversion into conventional laparoscopic or open surgery was necessary. The mean operative duration, including extended lymph node dissection, was 399 min (range: 355 - 455 min). Mean estimated blood loss was 154 ml (range: 90 -210 ml). The mean postoperative hospital stay was 15 d (range: 14 18 d). No peri-operative mortality was reported. One case had delirium 2 days postoperatively and there was no port-related complication. The pathological report confirmed surgical margins were tumor-free for all cases. The average number of removed lymph node was 20. The mean follow-up period was 6.1 months (range: 2.0 -10.0 months). All patients remained disease-free until the last follow-up. CONCLUSIONS: With a reduction of 4 ports, modified single port laparoscopic radical cystectomy with orthotopic ileal neobladder is technically feasible with a low complication rate. Our initial outcome is encouraging, but additional work and a further follow-up are warranted to critically compare the oncological outcome with open surgery. PMID- 20973236 TI - [Effects of extracellular calcium concentration on platelets aggregation, coagulation indices and thromboelastography]. AB - OBJECTIVE: To detect the effect of extracellular Ca2+ concentrations on test results of coagulation-related parameters. METHODS: Blood samples of outpatient medical volunteers were collected and then different doses of calcium chloride added. The rate of platelet aggregation (n = 42), prothrombin time (PT), thrombin time (TT) and activated partial thromboplastin time (APTT) (n = 21) and parameters of thromboelastography (n = 30) were detected according to the standard protocols by plasma turbidimetry, coagulation and recalcification respectively. RESULTS: When the plasma Ca2+ concentration was in the range of 0.1 - 33.7 mmol/L, the rate of platelet aggregation gradually increased with a increasing concentration of Ca2+. And the rates induced by adenosine diphosphate (ADP) and arachidonic acid (AA) were (51.8 +/- 9.6)% - (94.7 +/- 4.8)% and (64.4 +/- 12.2)% - (93.2 +/- 5.5)% respectively. When the Ca2+ concentration was 39.0 mmol/L, the rate decreased markedly [ADP (9.1 +/- 5.3)%, AA (11.1 +/- 4.5)%, both P < 0.01]. When the Ca2+ concentration was in the range of 0.1 - 33.7 mmol/L, the values of PT gradually increased with a increasing concentration of Ca2+. The values of TT changed in "V"-type and became minimum when the calcium concentration was 4.4 mmol/L. The values of APTT decreased with higher calcium concentrations and could not be determined when the concentration increased above 0.5 mmol/L. When the Ca2+ concentration was in the range of 0.4 - 27.3 mmol/L, the values of reaction time and coagulation time of thromboelastography changed in "V"-type and became nearly minimal at the Ca2+ concentration of about 2.1 mmol/L. The values of alpha angle and maximum amplitude changed in "V"-type and became maximal at the Ca2+ concentration of 2.1 mmol/L. CONCLUSIONS: The effect of Ca2+ concentration on the testing results of coagulation-related parameters is significant. A high calcium ( > or = 39 mmol/L) can inhibit the platelet aggregation, coagulation factor activity and blood coagulation. The Ca2+ concentration of 2.1 mmol/L seems to be the optimal concentration for thromboelastography by recalcification method. PMID- 20973237 TI - [Measurement of anatomical relationships of facial nerve canal related to middle ear and mastoid surgery on multi-slice computed tomography-multiplanar reformation images]. AB - OBJECTIVE: To investigate the anatomical relationships of facial nerve canal related to middle ear and mastoid surgery by multi-slice computed tomography (MSCT) and its multiplanar reconstruction ( MPR) technology. METHODS: High resolution CT scanning with multislice spiral CT of temporal bones without bone abnormality of 373 ears in 187 adult patients were examined. All original images were processed by MPR. The distances between facial nerve canal (FNC) and jugular foramen (JF), lateral surface of mastoid bone (M), external acoustic canal (EAC), posterior fossa dural plate (PFD), sigmoid sinus (SS), promontory (P), cochlear window (CW), pyramidal eminence (PE), posterior semicircular canal (PSC), oval window (OW), head of malleus (MH), incus lenticular process (ILP) and lateral semicircular canal (LSC) were measured on different MPR images. These measurements were also analyzed with respects to side, gender, pneumatization and jugular foramen position differences. RESULTS: On average, FNC-JF was 5.43 mm, FNC-M 15.99 mm, FNC-EAC 4.42 mm, FNC-PFD 9.01 mm, FNC-SS 9.44 mm, FNC-P 6.02 mm, FNC-CW 6.51 mm, FNC-PE 2.64 mm, FNC-PSC 3.12 mm, FNC-OW 1.19 mm, FNC-MH 2.27 mm, FNC-ILP 3.09 mm and FNC-LSC 0.90 mm. FNC-M was longer in males than that of females (P < 0.05). FNC-JF and FNC-SS were longer on left side than those of the right (P < 0.05). FNC-PFD was shorter on left side (P < 0.05). FNC-PFD, FNC-EAC, FNC-SS and FNC-M were longer in well pneumatized mastoids than those of poorly pneumatized mastoids (P < 0.05). FNC-PE was longer in poorly pneumatized mastoids than that of well pneumatized mastoids (P < 0.05). FNC-PFD, FNC-P, FNC-CW and FNC PSC were longer in bones with jugular foramen variation than those of bones without jugular foramen variation (P < 0.05). FNC-JF, FNC-SS and FNC-M were longer in bones without jugular foramen variation than those of bones with jugular foramen variation (P < 0.05). CONCLUSIONS: Anatomical relationships of facial nerve canal related to middle ear and mastoid surgery can be accurately measured on MSCT-MPR images. It is helpful to avoid injuring facial nerve in middle ear and mastoid surgery. PMID- 20973238 TI - [Therapeutic experience of childhood stage III neuroblastoma]. AB - OBJECTIVE: To evaluate the long-term outcomes of childhood stage III neuroblastoma (NB) and its associated prognostic factors. METHODS: Children with newly diagnosed NB were enrolled into the protocol of NB-99 and followed up from January 1999 to May 2007. The relevant data were collected. And the statistics was processed by SPSS 10.0. RESULTS: Thirty children with stage III NB were found among all 101 children with NB. There were 19 males and 11 females. The mean age at diagnosis was (33 +/- 30) months. Abdomen and thorax were by far the most common sites of primary tumor (16 and 10 respectively). Twenty-one NB children had favorable pathology classification. Eleven NB children were treated according to the mediate-risk protocol, 6 children received autologous stem cell transplantation (ASCT) after chemotherapy and 5 patients had no therapy of cis retinoic acid. Follow-up was conducted for 5 - 96 months. A complete response or an excellent partial remission was observed in 28 patients. Seven patients relapsed or progressed at the primary tumor site or bone marrow. The estimated cumulative probabilities of event-free survival and overall survival at 4 years for these 30 patients were 74% +/- 9% and 77% +/- 8% respectively. On univariate analysis, pathological type, high levels of LDH and ferritin, non-therapy of cis retinoic acid were associated with a worse survival (chi2 = 9.48, 6.82, 9.17, 9.06, all P < 0.05). As to the multivariate estimates of hazards ratio, high levels of LDH and ferritin, no ASCT and non-therapy of cis-retinoic acid were associated with a worse survival (OR = 3.95, 3.44, 2.64, 1.27, all P < 0.05). CONCLUSION: Stage III NB children with favorable histologic features, normal LDH, normal serum ferritin, receive ASCT, and treated with cis-retinoic acid have a lower risk of relapse. PMID- 20973239 TI - [Effects of S-adenosylmethionine on gastric cancer cell lines SGC-7901 and BGC 823]. AB - OBJECTIVE: To observe the effects of S-adenosylmethionine (SAM) on cell proliferation, cell cycles, apoptosis and invasive capacity of gastric cancer cell lines SGC-7901 and BGC-823 and detect the methylation status and expression of c-myc and urokinase-type plasminogen activator (uPA). METHODS: The effect of SAM on proliferation of SGC-7901 and BGC-823 cells were determined by MTT assay. SGC-7901 and BGC-823 cells were treated with different concentrations of SAM (0, 2, 4 mmol/L) for 72 h. Then flow cytometry was used to detect the change of cell cycles and apoptosis; Transwell assay to detect the invasion; RT-PCR and Western blot to detect the expression of c-myc and uPA; and MSP to detect the methylation of c-myc and uPA. RESULTS: SAM displayed a growth-inhibiting effect on SGC-7901 and BGC-823 cells in a dose- and time-dependent manner after exposure to SAM at different concentrations (0.5 - 32 mmol/L) for 24, 48 and 72 h, cell proliferation were significantly restrained (all P < 0.05); 72 h IC50 SGC-7901 5.40 mmol/L and BGC-823 4.01 mmol/L. After treating SGC-7901 and BGC-823 with different concentrations of SAM, the cell percentages of G0/G1 phase significantly increased (P < 0.05 and P < 0.01) while the cell proliferation indices significantly decreased (P < 0.05 and P < 0.01). Compared with control group (0.33 +/- 0.09), the cell apoptosis of 2 mmol/L (5.79 +/- 0.75) and 4 mmol/L groups (10.19 +/- 0.60) of SGC-7901 were obviously reduced (all P < 0.01). Compared with control group (0.95 +/- 0.19), the cell apoptosis of 2 mmol/L (6.23 +/- 0.75) and 4 mmol/L groups (11.82 +/- 1.14) of BGC-823 were obviously reduced (all P < 0.01). The cell invasive capacity were significantly restrained (P < 0.01). The invasion inhibition ratio of 2 mmol/L and 4 mmol/L groups of SGC-7901 were 51.07% and 80.69% respectively. The invasion inhibition ratio of 2 mmol/L and 4 mmol/L groups of BGC-823 were 48.57% and 84.10% respectively. The expressions of c-myc and uPA significantly decreased (P < 0.05 and P < 0.01). There was no expression of c-myc in 2 mmol/L group of BGC-823. The methylation of c-myc and uPA genes in two cell lines were reversed after SAM treatment. CONCLUSIONS: SAM can induce the apoptosis of SGC-7901 and BGC-823, block the cell cycles at G0/G1 phase and suppress the proliferation and invasion of these two cell lines. SAM can reverse the methylation of c-myc and uPA in these two cell lines and reduce their expression. SAM may act as a methyl donor to restrain the development and progression of tumor when hypomethylation is widely present in cancer. PMID- 20973240 TI - [Study of serotype distribution, antimicrobial resistance patterns and molecular epidemiology in 148 isolates of invasive Streptococcus pneumoniae]. AB - OBJECTIVE: To investigate the serotype distribution, antimicrobial resistance patterns and molecular epidemiology of Streptococcus pneumoniae (S. pneumoniae) isolated from invasive pneumococcal diseases in order to provide rationales for antibiotics application and immunity control of S. pneumoniae. METHODS: A total of 148 isolates of invasive S. pneumoniae were collected from blood, cerebrospinal fluid and other sterile body fluids from 15 regions between January 2005 and August 2008 nationwide. Agar dilution method was used to determine the minimal inhibitory concentrations (MICs) of penicillin and other antibiotics against these isolates. Simplified chessboard system and capsule swelling reaction were used for serotyping of S. pneumoniae. Multilocus sequence typing (MLST) was used to determine the genetic relationship of 53 strains of serogroup 19. RESULTS: Twenty serotypes/serogroups were identified in 148 strains. The prevalent serotypes (70.9%) were 19A, 19F, 3, 23F, 5, 6, 14 and 9 respectively. Serotypes 19A (22.3%, 33/148) and 19F (16.9%, 25/148) were the most frequent type observed. And serotypes 3 (7.4%, 11/148) and 23F (6.8%, 10/148) were less prevalent. Of all 36 strains isolated from infants under 2 years old, 33.3% (12/36) were covered by 7-valent pneumococcal conjugate vaccine (PCV7). The resistant rates to amoxicillin/clavulanic acid, erythromycin and other antibiotics in PCV7-related pneumococcal strains were significantly higher than those in PCV7-unrelated group (P < 0.05). Fifty-three strains of serogroup-19 were genotyped by MLST and 9 sequence types (STs) identified. ST320 (52.8%, 28/53) and ST271 (22.6%, 12/53) were the most frequent STs. CONCLUSIONS: The major serotypes of invasive S. pneumoniae are 19A, 19F, 3 and 23F. Antimicrobial resistant S. pneumoniae has become a serious issue of public health. PMID- 20973241 TI - [Effects of Tongxinluo on repeated hypoxic tolerance in mice]. AB - OBJECTIVE: To observe the effects of Tongxinluo (TXL) on repeated hypoxic tolerance in mice and explore the underlying mechanisms. METHODS: Mice were randomly divided into groups of repeated hypoxia (control) and TXL according to body weights. The mice in each group were exposed to acute repeated hypoxia for 0 run (H0), 1 run (H1), 3 runs (H3) and 5 runs (H5). The animal's tolerance time of each hypoxic exposure was recorded. Western blot was used to measure the protein levels of hypoxia inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in cortex tissue. RESULTS: The hypoxic tolerance time in control and TXL groups significantly increased run by run. Both HIF-1alpha and VEGF proteins in two groups increased gradually. Compared with control group, the tolerance time in H1 of TXL group [(18.0 +/- 2.4) minvs (15.6 +/- 2.0) min], H3 [(68.3 +/- 13.2) min vs (41.7 +/- 9.0) min) and H5 (85.9 +/- 7.0) min vs (51.4 +/ 14.4) min] increased (P < 0.05 or P < 0.01); the HIF-1alpha protein expression in H1 of TXL group (0.95 +/- 0.04 vs 0.79 +/- 0.02), H3 (1.01 +/- 0.03 vs 0.85 +/ 0.02), H5 (1.16 +/- 0.02 vs 0.92 +/- 0.03) increased (P < 0.05 or P < 0.01); the VEGF protein expression in H3 of TXL group (1.14 +/- 0.02 vs 0.89 +/- 0.03), H5 (1.34 +/- 0.05 vs 0.99 +/- 0.07) increased (P < 0.05 or P < 0.01). CONCLUSIONS: Under repeated hypoxia, an organism has a strong adaptive ability. The rises of HIF-1alpha and VEGF may be an adaptive mechanism. TXL can increase obviously the adaptive ability of mice to hypoxia. PMID- 20973242 TI - [More and more physicians]. PMID- 20973243 TI - [Wrong choice of antidiabetics can be disastrous]. PMID- 20973244 TI - [Antibiotic-resistant bacteria and feminized fishes. Physicians as environmental marauders]. PMID- 20973245 TI - [Mass screening for autism can be a reality in the 2,5-year check ups. Child health services have a key position in early diagnosis--if the studies are correct]. PMID- 20973246 TI - [The unique role of child health services--early recognition of autism. Experiences with new routines in child health care in Gothenburg]. PMID- 20973247 TI - [Hazards with mobile phones during driving. Time for a more stringent legislation and smarter technology according to a pilot study]. PMID- 20973248 TI - [Risk factor control in peripheral arterial disease can be improved. Registry study of secondary prophylactic drug therapy]. PMID- 20973249 TI - [Guidelines for anticoagulation in patients with valve prosthesis. More supposition than scientific evidence]. PMID- 20973250 TI - ["Ascites" could be an abdominal cyst]. PMID- 20973251 TI - [Ghrelin deficiency following gastrectomy a possible indication for ghrelin analogues]. PMID- 20973252 TI - [The National Board of Health and Welfare: compulsory measures are per definition always a deviation that should be analyzed]. PMID- 20973253 TI - [Buy fast food--get statins for free]. PMID- 20973254 TI - [Cancer and the significance of vitamin B deficiency]. PMID- 20973255 TI - XX Annual Meeting of the Latin American Society for Pediatric Endocrinology (SLEP) Lima, Peru, October 11-14, 2008. PMID- 20973256 TI - Second International Symposium of the Fima Lifshitz Research Center held in Praia de Forte, Salvador, Bahia, Brazil on May 27-29, 2009. PMID- 20973257 TI - Moving toward personalized medicine: treatment-focused genetic testing of women newly diagnosed with ovarian cancer. AB - OBJECTIVES: The presence of a germline BRCA mutation defines a genotype-specific group of women whose invasive ovarian cancer is associated with an increasingly well-defined prognostic and chemosensitivity biological profile. To determine the criteria that may be used to select patients for BRCA treatment-focused genetic testing, we performed a systemic literature search of studies that assessed BRCA1 and BRCA2 mutation frequency in women with ovarian cancer unselected for family history. The results are discussed with regard to the added clinical value gained by identifying a germline BRCA mutation at the time of the ovarian cancer diagnosis. METHODS: BRCA-related studies were identified in the CD-ROM databases PubMed (including MEDLINE), PsychINFO, and CINAHL and included in the review if they met the following criteria: they (a) assessed mutation frequency in women with ovarian cancer who were unselected for family history and ethnicity, (b) were published in a peer-review journal, (c) between January 1997 and October 2009, and (d) in the English language. RESULTS: Studies investigating the prevalence of BRCA1 or BRCA2 mutations in ovarian cancer patients unselected for family history or ethnicity have found a pathological BRCA mutation rate of approximately 3% to 17%. Without a significant family history, specific features that may be used to target treatment-focused BRCA testing in the ovarian cancer setting include young age at onset (G50 years), high-grade serous tumor histology, and specific ethnicity associated with known BRCA founder mutations. CONCLUSIONS: We believe that given the growing appreciation of the prognostic significance of BRCA mutations and the differential chemosensitivity shown by these tumors, as well as the potential of novel agents such as poly(ADP-ribose) polymerase inhibitors, the identification of a germline BRCA mutation concurrent with a new diagnosis of ovarian cancer will significantly impact on tailoring personalized ovarian management in the future. PMID- 20973258 TI - Gene expression profiling and cancer-related pathways in type I endometrial carcinoma. AB - INTRODUCTION: Malignant transformation of type I endometrium involves alteration in gene expression with subsequent uncontrolled proliferation of altered cells. OBJECTIVE: The main objective of the present study was to identify the cancer related genes and gene pathways in the endometrium of healthy and cancer patients. MATERIALS AND METHODS: Thirty endometrial tissues from healthy and type I EC patients were subjected to total RNA isolation. The RNA samples with good integrity number were hybridized to a new version of Affymetrix Human Genome GeneChip 1.0 ST array. We analyzed the results using the GeneSpring 9.0 GX and the Pathway Studio 6.1 software. For validation assay, quantitative real-time polymerase chain reaction was used to analyze 4 selected genes in normal and EC tissue. RESULTS: Of the 28,869 genes profiled, we identified 621 differentially expressed genes (2-fold) in the normal tissue and the tumor. Among these genes, 146 were up-regulated and 476 were down-regulated in the tumor as compared with the normal tissue (P < 0.001). Up-regulated genes included the v-erb-a erythroblastic leukemia viral oncogene homolog 3 (ErbB3), ErbB4, E74-like factor 3 (ELF3), and chemokine ligand 17 (CXCL17). The down-regulated genes included signal transducer and activator transcription 5B (STAT5b), transforming growth factor A receptor III (TGFA3), caveolin 1 (CAV1), and protein kinase C alpha (PKCA). The gene set enrichment analysis showed 10 significant gene sets with related genes (P < 0.05). The quantitative polymerase chain reaction of 4 selected genes using similar RNA confirmed the microarray results (P < 0.05). CONCLUSIONS: Identification of molecular pathways with their genes related to type I EC contribute to the understanding of pathophysiology of this cancer, probably leading to identifying potential biomarkers of the cancer. PMID- 20973259 TI - Limits of 18F-fluorodeoxyglucose positron emission tomography in recurrence diagnosis of borderline ovarian tumor. AB - Most borderline ovarian tumors (BOT) occur in young women and exhibit a low malignant behavior. Nevertheless, an accurate long-term follow-up is required because, frequently, recurrence arises after many years from primary treatment, especially in patients affected by BOT with invasive peritoneal implants, which have a worse prognosis. We report the case of a pelvic recurrence of serous BOT firstly suspected by physical examination but misdiagnosed by 18F fluorodeoxyglucose positron emission tomography and computed tomography and identified only by magnetic resonance imaging, 7 years after primary treatment. We also reviewed the literature concerning the role of 18F-fluorodeoxyglucose positron emission tomography in the management and follow-up of BOT. PMID- 20973260 TI - Association of vascular endothelial growth factor gene polymorphisms with susceptibility to epithelial ovarian cancer. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is a major angiogenic factor involved in a number of pathological processes, including neovascularization, a crucial step in the development of solid malignancies. The aim of this study was to investigate the association of polymorphisms in the VEGF gene with susceptibility to epithelial ovarian cancer (EOC). METHODS: This case control study included 303 EOC patients and 303 healthy controls. Genotyping of the VEGF gene polymorphisms at j460C/T, j1154G/A, j2578C/A, and +936C/T were performed by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: No significant difference was found in allele and genotype distributions of the -460C/T, +936C/T, and -2578C/A polymorphisms between patients and controls. However, the frequencies of -1154G/A genotype and allele were significantly different between the two groups (P = 0.037, P = 0.013). Compared with the G/A + A/A genotype, the G/G genotype could significantly increase the risk of developing EOC (odds ratio, 1.64; 95% confidence interval, 1.12Y2.39). The haplotype analysis suggested that the -460T/ -1154A/ -2578C haplotype exhibited a decrease in the risk of developing EOC compared with the -460T/ -1154G/ -2578C haplotype (odds ratio, 0.644; 95% confidence interval, 0.415-0.999). CONCLUSIONS: The study suggested a possible association between the VEGF -1154G/A polymorphism with susceptibility to EOC, but there is no support for an association of the VEGF -460C/T, +936C/T, and 2578C/A polymorphisms with the risk for EOC. PMID- 20973261 TI - Malignancies diagnosed during pregnancy and treated with chemotherapy or other modalities (review of 27 cases): multicenter experiences. AB - BACKGROUND: Cancer is the second leading cause of death in women of reproductive age. The most common tumors diagnosed during pregnancy are breast and cervix cancer, Hodgkin lymphoma and non-Hodgkin lymphoma, leukemias, and malignant melanoma. The aim of therapy in pregnancy is to give optimal treatment to the mother without harm to the fetus. In the first trimester, organogenesis continues, so chemotherapy should not be given because of increasing risk of spontaneous abortion, fetal malformation, and mortality. We evaluated mostly seen tumors during pregnancy and assessed treatment type and outcome of pregnancy after chemotherapy in our population. METHODS: We retrospectively analyzed 27 patients who have been treated during pregnancy or after the delivery because of several malignancies. RESULTS: The tumors associated with pregnancy were breast cancer, hematologic malignancies,gynecologic malignancies, sarcomas, and others. The chemotherapy regimens were given in 17 of 27 patients in the second or third trimester of pregnancy. Four of the patients were diagnosed with cervical cancer, hemangiopericytoma, chronic myeloid leukemia,and breast cancer during the first trimester, so their pregnancies were ended by therapeutic abortion. Although 1 of the 3 fetuses who were exposed to chemotherapy in utero at the second or third trimester was born prematurely and low birth weight was diagnosed in the other 2 fetuses, fetal malformation was not seen in any of them. There were 7 normal and 9 cesarean deliveries. Twenty-three healthy babies survived from 27 pregnancies, of whom 17 babies were exposed to chemotherapeutic agents. CONCLUSIONS: We reported herein 27 patients with malignancies diagnosed during pregnancy; 17 patients received chemotherapy during the gestational period without any fetal or maternal abnormalities. Because of the low incidence of malignancy during pregnancy, our report is noteworthy. PMID- 20973262 TI - Healing America. PMID- 20973263 TI - The restricted ovulator chicken: a unique animal model for investigating the etiology of ovarian cancer. AB - OBJECTIVE: The main goal of this study was to compare the incidence of ovarian cancer (OC) in 2 genetically different lines of hens--one that generally fails to lay eggs (the mutant "restricted ovulator" [RO] strain) and the other consisting of the wild-type (WT) siblings of the mutant RO hens. METHODS: Individual egg production data were obtained over a 972-day period for 31 RO hens and 33 WT hens. At 38 months of age, hens were killed, and their abdominal cavities were examined for any gross evidence of tumors. Samples of ovarian tissue were processed and assessed for histopathology and protein expression of ovalbumin. Plasma estradiol concentrations were also determined. RESULTS: Only 1 (3%) of the 31 RO hens was diagnosed with OC as compared with 9 (27%) of the 33 WT hens (P G 0.05). Wild-type hens laid more eggs than did RO hens during the 31-month collection period (average of 422 vs 28, respectively; P < 0.05). Although there was no difference in overall rate of ovulation between hens with and without OC, WT hens diagnosed with OC laid a greater percentage of their total number of eggs in the first year of production. Plasma estradiol concentrations were higher (P < 0.01) in RO versus WT hens. CONCLUSIONS: The results of this study strongly suggest that the number of ovulatory events is directly related to the incidence of OC in chickens. Clearly, other factors modify the risk of OC because there was no difference in ovulation rate between WT hens with and without OC. The mutant RO hen represents a valuable animal model for studying the etiology of OC. PMID- 20973264 TI - Syndecan-1 overexpression promotes tumor growth and angiogenesis in an endometrial cancer xenograft model. AB - OBJECTIVES: Upregulation of syndecan-1, a member of the transmembranous proteoglycans that serves as a coreceptor for a wide pool of extracellular ligands, has been well documented in enabling the promotion of growth and invasion of endometrial cancer. As a step toward understanding a potential role for syndecan-1 in this process, we questioned whether syndecan-1 upregulates tumor-promoting characteristics, particularly, angiogenesis in an in vivo human xenograft tumor model. METHODS: Human syndecan-1 was stably transfected into human endometrial adenocarcinoma 1A cells, and resulting transfectants were subcutaneously grafted into athymic mice; their outcomes were examined with respect to the enhancement of tumor growth and angiogenesis by immunohistochemistry, immunoblotting, and zymography. RESULTS: Overexpression of syndecan-1 promoted tumor growth concomitant with increased angiogenesis in tumor xenografts as evidenced by an increase in immunoreactivity for vascular endothelial growth factor and vascular endothelial cell marker CD34. Furthermore, zymographic studies revealed that syndecan-1 overexpression markedly enhanced activities of matrix metalloproteinases 2 and 9. CONCLUSIONS: This is the first in vivo xenograft analysis providing evidence that supports that syndecan-1 has a critical role in carcinogenic progression, particularly, contributing to the development of angiogenesis and invasive phenotype in association with matrix metalloproteinases 2 and 9 activations in endometrial cancer. PMID- 20973265 TI - Medical costs and outcomes for Australian women with ovarian cancer: a patient level analysis over 2.5 years. AB - OBJECTIVE: As treatment costs for gynecological cancer escalate, real-world data on use of resources and costs becomes increasingly important. This study investigated medical costs, quality of life, and survival end points for women with ovarian cancer in Australia. METHODS: Women with primary epithelial ovarian cancer referred for chemotherapy (n =85) were recruited through 7 hospitals in Australia. Overall survival, progression-free interval, and quality-adjusted life years were assessed by stage using the Cox proportional hazards models. Direct medical costs, including those for surgeries, hospitalizations, supportive care, chemotherapy, and adverse effects (while on chemotherapy), were calculated over 2.5 years and assessed by nonparametric bootstrapping. RESULTS: Quality-adjusted life years decreased with increased disease stage at diagnosis and ranged from 2.3 for women with stage I or II disease to 1.3 for those with stage IV disease. A total of AU $4.1 million (2008) were spent on direct medical costs for 85 women over approximately 2.5 years. Medical costs were significantly higher for women with stage III or IV disease compared with that for women with stage I or II disease ($50,945 vs $31,958, P < 0.01) and/or women who experienced surgical complications and/or adverse effects requiring hospitalization while on chemotherapy ($57,821 vs $34,781, P < 0.01). Costs after first-line chemotherapy were significantly higher for women with advanced disease (mean, $20,744) compared with those for women with early disease (mean, $5525; P < 0.01). CONCLUSIONS: Whereas for women with early-stage ovarian cancer, costs are concentrated in the period of primary treatment, cumulated costs are especially high for women with recurrent disease rising rapidly after first-line therapy. PMID- 20973266 TI - Malignant transformation arising from mature cystic teratoma of the ovary: a retrospective study of 20 cases. AB - OBJECTIVES: Mature cystic teratoma (MCT) of the ovary rarely undergoes malignant transformation (MT). Malignant transformation carries a significantly worse prognosis than epithelial ovarian cancer, regardless of whether postoperative chemotherapy or radiotherapy is applied. The rarity of this tumor has posed a significant challenge to developing standardized postoperative management protocols. The aim of this study was to review our experience with MT and to describe our current treatment practices. METHODS: A retrospective chart review of these patients was performed that identified 20 women treated for MT of MCT at our centers between 1988 and 2008. RESULTS: The median age was 52.5 (range, 29 77) years. Fifteen patients had squamous cell carcinoma (SCC), and 5 patients had other histological subtypes. The International Federation of Gynecology and Obstetrics stage distribution was as follows: 11 were stage I, 4 were stage II, 4 were stage III, and 1 was stage IV. All patients underwent an initial laparotomy. Eleven patients received adjuvant treatment: 8 were treated with chemotherapy, 2 with concurrent chemoradiation therapy, and 1 with radiation therapy. Platinum based chemotherapy was the first-line regimen. The overall 1-year survival rate was 70%. Significant correlations between overall survival and age, stage, and residual tumor were presented (P = 0.044, P = 0.0107, P < 0.0001, respectively). Eight patients with advanced stage died of their disease. Four patients, however, were treated with adjuvant chemotherapy or concurrent chemoradiation therapy and survived more than 1 year. One stage III patient had a disease-free interval of 2 years. Two cases of SCC treated with combination platinum/taxane chemotherapy temporarily responded. In the other 2 cases of SCC, concurrent chemoradiation therapy with nedaplatin also resulted in tumor regression. CONCLUSIONS: The prognosis of MT is highly dependent on age, stage, and optimal cytoreduction. Adjuvant treatment has not been standardized, although our experience supports the use of combination platinum/taxane chemotherapy. PMID- 20973267 TI - Randomized phase III study of canfosfamide in combination with pegylated liposomal doxorubicin compared with pegylated liposomal doxorubicin alone in platinum-resistant ovarian cancer. AB - OBJECTIVE: To evaluate the safety and efficacy of canfosfamide in combination with pegylated liposomal doxorubicin (PLD) in platinum-resistant ovarian cancer (OC). METHODS: Patients with platinum-refractory or -resistant (primary or secondary) OC were randomized to receive canfosfamide at 1000 mg/m2 and PLD at 50 mg/m2 intravenously or PLD alone at 50 mg/m2 intravenously on day 1 every 28 days until tumor progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Other end points were objective response rate and safety. The study was originally planned for 244 patients. The trial was temporarily placed on hold after 125 patients were randomized while the results of another trial were being reviewed and the sponsor decided not to resume enrollment. The interim analysis became the final analysis. RESULTS: The median PFS was 5.6 months for canfosfamide + PLD (n = 65) versus 3.7 months for PLD (n = 60) (hazards ratio, 0.92; P = 0.7243). A preplanned subgroup analysis showed that 75 patients with platinum-refractory or primary platinum-resistant OC had a median PFS of 5.6 months for canfosfamide + PLD versus 2.9 months for PLD (hazards ratio, 0.55; P = 0.0425). Hematologic adverse events were 66% on the canfosfamide + PLD arm versus 44% on the PLD arm, manageable with dose reductions. Nonhematologic adverse events were similar for both arms. The incidence of palmar-plantar erythrodysesthesia and stomatitiswas lower on canfosfamide + PLD(23%, 31%, respectively) versus (39%, 49%, respectively) on PLD. CONCLUSIONS: Overall median PFS showed a positive trend but was not statistically significant. The median PFS in the platinum-refractory and primary platinum-resistant OC patients was significantly longer for canfosfamide + PLD versus PLD. Canfosfamide may ameliorate the palmar-plantar erythrodysesthesia and stomatitis known to be associated with PLD. Further study of this active well tolerated regimen in platinum-refractory and primary platinum-resistant OC is planned. This study was registered at www.clinicaltrials.gov: NCT00350948. PMID- 20973268 TI - Transvaginal color Doppler imaging in the detection of ovarian cancer in a large study population. AB - INTRODUCTION: The aim of the study was to compare the diagnostic accuracy of grayscale sonography and that of color Doppler imaging in the diagnosis of ovarian malignancy in a prospective study by the Sardinia-Navarra group. METHODS: The study was performed as a collaborative work at the 2 European university departments of obstetrics and gynecology between 1997 and 2007. A total of 2148 pelvic masses in 1997 women on whom transvaginal sonography were performed before surgical exploration were included in the study. An adnexal mass was first studied in grayscale sonography, and any cystic mass in which the echo architecture was not suggestive of benign tumor was categorized as malignant. Second, any solid excrescences or solid portions of the tumor were evaluated with color/power Doppler sonography. A mass was graded malignant if flow was shown within the excrescences or the solid areas and benign if there was no flow or if flow was only peripheral. RESULTS: Four hundred sixty-eight masses were malignant. Color Doppler evaluation was more accurate in the diagnosis of adnexal malignancies in comparison with grayscale sonography because of a significantly higher specificity (94% vs 89%, P = 0.001), with similar sensitivity (95% vs 98%, P = 0.44). The pretest probability of ovarian cancer was 22%, and this probability rose to 82% when the diagnosis was suggested by color Doppler evaluation. The diagnostic accuracy of the tests was also dependent on menopausal status. CONCLUSIONS: The evaluation of vessel distribution by color Doppler sonography in adnexal masses increases the diagnostic accuracy of grayscale sonography in the detection of adnexal malignancies in a large study population. PMID- 20973269 TI - Pamela Miles: Reiki vibrational healing. Interview by Bonnie Horrigan. PMID- 20973270 TI - Relationship between ABCF2 expression and response to chemotherapy or prognosis in clear cell adenocarcinoma of the ovary. AB - OBJECTIVES: The purpose of this study was to evaluate the association of ABCF2 (adenosine triphosphate-binding cassette superfamily F2) protein expression with response to chemotherapy and prognosis in patients with clear cell adenocarcinoma (CCC) of the ovary. METHODS: One hundred sixty-five patients with CCC were studied, and cytoplasmic ABCF2 expression was detected by immunohistochemical staining. All patients underwent platinum-based primary chemotherapy followed by primary surgery. RESULTS: Adenosine triphosphate-binding cassette superfamily F2 expression was detected in 118 (71.5%) of 165 patients and was not related to age or clinical stage. The response rate to chemotherapy in 38 patients with measurable disease was 47.3% (18/38). The response rate tended to be higher in patients without ABCF2 expression than in those with ABCF2 expression; however, this difference was not significant (66.7% vs 34.8%, P = 0.096). There was no significant difference in overall survival between ABCF2-positive and ABCF2 negative cases (median survival time, 1175 vs 1257 days; P = 0.24). CONCLUSIONS: Adenosine triphosphate-binding cassette superfamily F2 protein was highly expressed in CCC of the ovary, but expression was not related to age, clinical stage, chemoresponse, or prognosis. PMID- 20973271 TI - Peritoneal tuberculosis: a retrospective review of 20 cases and comparison with primary peritoneal carcinoma. AB - INTRODUCTION: To evaluate the clinical features of peritoneal tuberculosis (TB) and to compare them with those of primary peritoneal carcinoma (PPC). METHODS: We conducted a retrospective review of women with peritoneal TB who were managed at Samsung Medical Center from January 1996 to October 2006. As a control sample, patients with a diagnosis of PPC during the same period were also selected for comparison. RESULTS: During the study period, we identified 20 female patients with peritoneal TB. The median age was 39 years (range, 23-69 years), and the median cancer antigen 125 (CA-125) level was 448 U/mL (range, 32-1725 U/mL). Seventeen patients with PPC whom we examined were older, with a median age of 63 years (range, 50-73 years); their median CA-125 level was higher at 1848 U/mL (range, 42-14,380 U/mL). Compared with those of PPC, the radiologic findings of peritoneal TB indicated less severe involvement of the omentum and the mesentery (P = 0.03). Among the 20 patients who underwent operations, 6 (30%) underwent exploratory laparotomy; 12 (60%), diagnostic laparoscopy; and 2 (10%), laparoscopy converted to laparotomy because of severe adhesion. Frozen tissue sections revealed chronic granulomatous tissue reaction in 15 (83.3%) of 18 women with peritoneal TB. CONCLUSIONS: Maintaining a high index of suspicion is very important for the successful treatment of peritoneal TB, especially in developing countries. Age, CA-125 level, and omental involvement as identified by computed tomography may be helpful for the differential diagnosis of peritoneal TB and PPC. PMID- 20973272 TI - The best medicine. PMID- 20973273 TI - Nup88 expression is associated with myometrial invasion in endometrial carcinoma. AB - BACKGROUND: The nuclear pore complex protein Nup88 has been shown in previous studies to be overexpressed in tumor cells and to be associated in breast cancer with all clinical and biological features defining a more aggressive phenotype. METHODS: In this pilot study, Nup88-mRNA expression was studied in a series of 29 endometrial carcinomas, of which 27 belonged to the endometrioid variety, the remaining 2 being papillary serous tumors, to verify if Nup88 plays a similar role in endometrial carcinoma as the one described in breast cancer. The tumor samples were obtained directly at the operating suite and fresh frozen at the time of hysterectomy. Nup88-mRNA expression was studied in them by means of differential reverse transcriptase-polymerase chain reaction. Nup88-mRNA expression was correlated with the clinical features of the tumors. RESULTS: A significant correlation (r = 0.41, P = 0.027) was found between growing levels of Nup88-mRNA expression and depth of myometrial invasion. There was no correlation between Nup88-mRNA expression and the other 2 available clinical parameters, that is, tumor grade (r = 0.05, P = 0.79) and surgical stage (r = -0.18, P = 0.34). CONCLUSIONS: From these results, it is concluded that Nup88 expression seems indeed to be associated with a distinct feature of tumor aggressiveness (myometrial invasion) in endometrial carcinoma and that larger studies are therefore probably worthwhile. PMID- 20973274 TI - Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for the treatment of recurrent endometrial carcinoma confined to the peritoneal cavity. AB - Our objective was to determine if cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a feasible therapeutic option for treatment of peritoneal recurrence of endometrial carcinoma. Between August 2002 and May 2007, 5 patients with recurrent endometrial carcinoma confined to the peritoneal cavity who underwent CRS with HIPEC. Cisplatin (1 mg/kg) and mitomycin C (0.7 mg/kg) were perfused at an inflow temperature of 46 to 48-C for 90 minutes under systemic hypothermia (32 degrees C). Of the 5 patients treated, histopathological type and International Federation of Gynecology and Obstetrics stage were as follows: IB endometrioid (n = 1), IIIA endometrioid (n = 1), IIIC endometrioid (n = 2), and IC endometrioid + pseudosarcomatoid component (n = 1). The mean interval from initial surgery to CRS with HIPEC was 47.5 months (10-120 months). In all patients, CRS was complete. One patient with pseudosarcomatoid component developed recurrent disease 10 months after surgery and died 2 months later. One patient experienced early recurrence with a malignant pleural effusion and died. Three patients are alive and disease free at 7, 23, and 39 months from surgery with good performance status. Regarding the toxicity of the procedure, highly selected patients with recurrent endometrial carcinoma confined to the peritoneal cavity may benefit from improved survival after CRS with HIPEC. PMID- 20973275 TI - [Witchcraft medicine and folklore in Wushierbingfang ('Prescriptions for fifty two diseases')]. AB - One important characteristic of early stage of TCM is the intermixture of witches medicine and folklore. A few witch prescriptions in Wushierbingfang ('Prescriptions for fifty-two diseases') indicated the residual traces of the mixture of witch and medicine in the medical literatures. The witch prescriptions recorded in Wushierbingfang ('Prescriptions for fifty-two diseases') could be divided into supplication, Yu-step, exorcism, Nuo ritual and peach wood charms etc. Witchcraft developed into folklore and the application of witchcraft sometimes manifested as the form of folklore, which were also reflected in the records of ('Prescriptions for fifty-two diseases'). PMID- 20973276 TI - [The impact of the study of contemporary and Confucian comments on the classic Neijing (Internal Classic) and its commentary and subcommentary]. AB - The argumentation between the contemporary and old Confucian classics schools had a profound and lasting impact on the Traditional Chinese Academy, so as to evolve into two kinds of attitude towards the scholarship which influenced TCM which was based on traditional Chinese culture. These impacts reflected in the following three aspects: first, the differences between the words of different versions of Neijing (Internal Classic); second, the formation of some theories of Neijing (Internal Classic) such as the attachment of five zang-organs and five phases; third, the annotated methods for (Neijing (Internal Classic) of the physicians of past generations. PMID- 20973277 TI - [Brief history of the development of artificial pneumothorax]. AB - Artificial pneumothorax (AP), was one kind of surgery for pulmonary tuberculosis which injects the air into the pleural cavity by needle tubes to form the artificial pneumothorax. It was applied in a clinic by the Italian physician Carlo Forlanini in 1894. In the subsequent 20 years, this therapy has not been paid attention to in medical circles until 1912 when it received recognition and gradually became the primary therapy of pulmonary tuberculosis in Europe and America. AP began to be used in pulmonary tuberculosis from 1928 to 1930 in Shanghai, China, then throughout the whole country. In the 1950s, with the appearance of streptomycin, streptomycin and rifampicin, AP gradually withdrew from the front-line of clinical practice and became a thing of the past. PMID- 20973278 TI - Transplantation of mouse embryonic stem cells induces hematopoietic and tissue chimerism in rats. AB - Embryonic stem cells (ESC) can differentiate into all cell lineages, and ESC-like cells were shown to induce hematopoietic chimerism and tolerance in allogeneic models. The aim of our study was to test the capacity of mouse ESC (mESC) to engraft in rats in a xenotransplantation setting. Forty-six rats were transplanted intravenously with 1 million mESC, without immunosuppression (group 1, n = 23) or with cyclosporine (group 2, n = 23). Three months after mESC transplantation, skin grafts were performed from allogeneic, xenogeneic identical to mESC, or xenogeneic third party donors. At day 27 post-transplant, we detected circulating mouse cells in the blood of 4/23 and 5/23 animals of group 1 and group 2, respectively. Chimerism was confirmed by PCR. We also identified long term surviving murine cells within livers of chimeric animals. Skin grafts showed no difference in survival between allogeneic and xenogeneic donors. Transplantation of xenogeneic mouse ESC induced short-term chimerism in the blood and persistent tissue chimerism in the liver of recipient rats, but did not induce tolerance to skin grafts. Improved immunosuppressive protocols should be tested to prolong chimerism and allow tolerance. PMID- 20973279 TI - Ending analysis: comparative views. PMID- 20973280 TI - Collateral damage: grief and recovery after losing a training analyst due to an ethical violation. PMID- 20973281 TI - Psychoanalysts translating psychoanalysts today. PMID- 20973282 TI - Battling the life and death forces of sadomasochism. PMID- 20973283 TI - Object relations in clinical psychoanalysis. PMID- 20973284 TI - Kohut today. PMID- 20973285 TI - Child/adolescent analysts at work in the present space. PMID- 20973286 TI - Psychoanalysis and virtual reality. PMID- 20973287 TI - Telephone analysis. PMID- 20973288 TI - Three regional approaches to the worldwide problem of the decrease in the number of patients and trainees. PMID- 20973289 TI - Psychosis and regression. PMID- 20973290 TI - Abstracts of the 6th International Symposium on Neuroprotection and Neurorepair. Rostock, Germany. October 1-4, 2010. PMID- 20973291 TI - Extended anaesthesia and nasotracheal intubation of a red kangaroo (Macropus rufus). AB - Anaesthesia requires maintenance of a patent airway. Nasotracheal intubation of a red kangaroo (Macropus rufus) was performed when the inability to open the animal's mouth prevented orotracheal intubation. Nasotracheal intubation was easy to perform, secured the airway and permitted delivery of supplemental oxygen, isoflurane and intermittent positive pressure ventilation. PMID- 20973292 TI - Cryptosporidium andersoni in Western Australian feedlot cattle. AB - Cryptosporidium andersoni has not been previously reported in feedlot beef cattle in Western Australia. Faecal samples were collected from 10 groups of cattle ranging in age from 11 to 36 months in five different feedlots in Western Australia. The incidence of C. andersoni ranged from 0% to 26%. There were no clinical signs associated with C. andersoni infection, but there was a significant reduction in rate of gain of 0.44 kg in infected animals compared with negative pen mates. Cryptosporidium andersoni is characterised by large oocysts (7.4 x 5.5 MUm) and was confirmed by 18S sequencing. PMID- 20973293 TI - Insulin resistance in elderly. PMID- 20973295 TI - Structural and morphological changes in rat ventricular myocardium induced by chronic systemic hypoxi. AB - AIM: to explore the effects of chronic systemic hypoxia on myocardial structure and morphology. In addition, the goal of present study is to develop a hypoxia induced heart failure model in rats. METHODS: Sprague-Dawley male rats, weighing 220-250 g at the time of recruitment were randomly allocated into 7 groups (n = 4 per group), the control normoxia group was exposed to room air, while the hypoxia groups were caged in a plexiglas hypoxic chamber (8% O2 and 92% N2) for 28 days. Structural and morphological changes of ventricular myocardium were determined at day 28, while blood gas parameters were measured at day 1, 3, 7, 14, 21, and 28. RESULTS: histopathologic and morphologic evaluation showed massive hypertrophy accompanied by damage of the intercalated disk (ID) structure, angiogenesis, necrosis, fibrosis, and apoptosis as a hallmark of ventricular remodeling. At the end of treatment, there were increases of LV (2.79 vs 3.71) and RV (1.72 vs 2.54) wall thicknesses, and also in hypertrophy index (from 3.19 to 5.74). Blood gas analysis revealed metabolic acidosis compensated by respiratory alkalosis. There was an observed decrease of blood gas parameters in hypoxia group compared to control group: PO2 (24.7 vs 96.4 mm Hg), PCO2 (18.2 vs 40.4 mm Hg), O2 saturation (25.5 vs 94.1 %), and HCO3 (10.1 vs 23.4 mmol/L). On the other hand an increase in hemoglobin level (221.5 vs 120.3 g/L), haematocrit level (68.6 vs 45.2 %), and red blood cell count (10.4 vs 6.9 MUL/1000) could be observed. CONCLUSION: our data clearly show that chronic systemic hypoxia causes massive ventricular hypertrophy accompanied by severe structural and morphological impairment of ventricular myocardium, which eventually results in cardiac failure. PMID- 20973294 TI - Calcium channel blocker (diltiazem) inhibits apoptosis of vascular smooth muscle cell exposed to high glucose concentration through lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) pathway. AB - AIM: to examine the role of diltiazem in the prevention of VSMC apoptosis exposed to high glucose through inhibition of LOX-1 expression. METHODS: we performed experimental study on the primary culture of VSMCs. Expression LOX-1, and Caspase 3 activity (a key regulatory protease at which many signaling pathways merge for the execution of apoptosis) were measured by Elisa. Data were expressed as mean +/- SEM. The statistical significance was assessed by one-way analysis of variance (ANOVA) followed by post hock analysis by Turckey test, p<0.05 was considered statistically significant. RESULTS: chronic exposed VSMC to high glucose concentration (25 mM), increase cytosolic Ca++ concentration (3127 +/- 413.89 v.s. 2011.81 +/- 410.93 unit/cell, p<0.01), expression of LOX-1 ((506.80 +/- 10.47 v.s. 458.40 +/- 36.49 ng/ml, p<0.05), and caspase-3 activity (129.98 +/ 5.97 v.s. 114.73 +/- 10.84%, p<0.05) respectively, compare exposed to 5mM glucose concentration. LOX-1 was related to caspase-3 activity, pre-treated with inhibitor LOX-1 activity, k-carragenan before being exposed to glucose 25 mM, prevents the increasing of caspase-3 activity (96.41 +/- 5.11 v.s. 129.98 +/- 5.98 %, p<0.01). Pre incubation with 10MUM of diltiazem before being exposed to 25 mM glucose concentration significantly inhibits the elevation of cytosolic Ca++ concentration (2149.61 +/- 339.49 v.s. 3127 +/- 413.89 unit/cell, p<0.01), LOX-1 expression (468,60 +/- 14.44 v.s. 506.80 +/- 10.47 ng/ml, p < 0.05), and caspase-3 activity (82.50 +/- 9.90 v.s. 129.98 +/- 5.97%, p<0.01). CONCLUSION: overall, these results demonstrate that high glucose induces VSMCs apoptosis through caspase-3 pathway. This effect appears to be inhibited by diltiazem through decreasing LOX-1 expression and activity. PMID- 20973296 TI - Helicobacter pylori-related chronic gastritis. PMID- 20973297 TI - Diagnosis and management of cardiogenic pulmonary edema. AB - Acute cardiogenic pulmonary edema (ACPE) is a common cardiogenic emergency with a quite high in-hospital mortality rate. ACPE is defined as pulmonary edema with increased secondary hydrostatic capillary pressure due to elevated pulmonary venous pressure. Increased hydrostatic pressure may result from various causes including excessive administration of intravascular volume, obstruction of pulmonary venous outflow or secondary left ventricular failure due to left ventricular systolic or diastolic dysfunction. ACPE must be distinguished from pulmonary edema associated with injury of alveolar capillary membrane caused by various etiologies, i.e. direct pulmonary injury such as pneumonia and indirect pulmonary injury such as sepsis. Numerous clinical manifestations may differentiate ACPE and Non-ACPE. ACPE usually presents with a history of acute cardiac catastrophe. Physical examination reveals a low-flow state, S3 gallop, jugular venous distention and fine crepitant rales with auscultation. The diagnosis of pulmonary edema is made based on symptoms and clinical signs are found through history taking, physical examination, ECG, chest X-ray, echocardiography and laboratory tests including blood gas analysis and specific biomarkers. Medical treatment of ACPE has 3 main objectives, i.e.: (1) reduced venous return (preload reduction); (2) reduced resistance of systemic vascular (afterload reduction); and (3) inotropic support in some cases. Treatment that can be administered includes: vasodilator when there is normal or high BP, diuretics when there is volume overload or fluid retention, and inotropic drugs when there is hypotension or signs of organ hypoperfusion. Intubation and mechanical ventilation may be necessary to achieve adequate oxygenation. PMID- 20973298 TI - Data brief from the Circumpolar Health Observatory. Introduction and population [2010-1] PMID- 20973299 TI - Preventing vascular access infections. PMID- 20973300 TI - Understanding patient concerns. PMID- 20973301 TI - The buttonhole technique: strategies to reduce infections. AB - The buttonhole technique has gained popularity over the last decade in the United States. The fact that it is a relatively new technique, which requires a change to current cannulation practice, has contributed to several unforeseen complications that have led to increased infection rates in AV fistulae. To keep this technique a viable option for patients, it will be necessary to understand the potential infection risks and implement strategies to reduce the incidence of infection. PMID- 20973302 TI - Infection control 101. AB - Healthcare professionals in dialysis must provide safe, quality care, including the use of basic infection control practices when caring for immunocompromised patients on dialysis. These practices are not new, and for most, are integrated into the routine provision of dialysis care. The challenge within the existing time constraints is to make sure routine practices do not lapse into shortcuts around infection control practices. This article reviews basic infection control as a reminder of its importance in the daily provision of health care. PMID- 20973303 TI - Buttonhole cannulation in adult patients on hemodialysis: an increased risk of infection? AB - In the U.S., the rope-ladder technique for cannulating arteriovenous fistulas has been the technique of choice in patients on hemodialysis. Recently, the buttonhole cannulation technique has been gaining popularity. Based upon review of the literature and developments in clinical practice, an important question is posed regarding infection rates in those utilizing this technique. This article discusses those findings, presents a change in practice, and provides recommendations for practice. PMID- 20973304 TI - Preventing infections in hemodialysis fistula and graft vascular accesses. AB - The Centers for Medicare & Medicaid Services has placed a strong focus on vascular access infections by relating dialysis access infections to patient quality of life and access longevity. Hemodialysis providers are challenged to assess, identify, monitor, and prevent access infections. Education and practice changes can decrease the risk of an access infection and preserve a patient's access for many years. Knowledge is an armored suit when winning a battle to protect a lifeline by staff and patients as a team. PMID- 20973305 TI - Hemodialysis catheter care: current recommendations for nursing practice in North America. AB - Vascular access is essential for hemodialysis (HD). Many patients require a catheter for HD, either long-term or short-term, if they do not have a functional fistula or graft. Catheter-related complications, such as bacteremias and catheter dysfunction, can be reduced with consistent use of recommended practices for catheter management. This article will detail the complications, challenges, and the need for best practices. It will describe current recommended practices of catheter care and how they are integrated into the care of patients on HD in North America. PMID- 20973306 TI - Prevention of hemodialysis central line-associated bloodstream infections in acutely ill individuals. AB - An arteriovenous access is preferred for hemodialysis, but the use of tunneled, cuffed catheters may be necessary in the inpatient setting with acute kidney injury when immediate hemodialysis is required and fistula immaturity or access complications are present. Care of the dialysis central venous catheter is paramount in the prevention of central line-associated bloodstream infections in acutely ill individuals. One institution's approach to hemodialysis central venous catheter care and a quality improvement projectfor selecting tunneled catheters will highlight their changing practice. PMID- 20973307 TI - A practical review of the kidney dialysis outcomes quality initiative (KDOQI) guidelines for hemodialysis catheters and their potential impact on patient care. AB - In North America, the creation of the arteriovenous fistula is the optimal form of access for patients on hemodialysis (HD). However, the majority of patients start HD with a hemodialysis catheter, and many continue to use a catheter 90 days after placement. Additionally, as the population of patients on HD grows older, the number of patients dependant on a catheter as their permanent mode of HD access increases. Although catheters are not the preferred choice for HD access, when they are used the proper care and treatment of these devices may decrease patient morbidity and mortality. PMID- 20973308 TI - A continuous quality improvement project to decrease hemodialysis catheter infections in pediatric patients: use of a closed luer-lock access cap. AB - Catheter infections are a significant problem in pediatric hemodialysis. To reduce infection rates, the use of closed luer-lock access connectors, which create a mechanically and microbiogically closed system while allowing unobstructed blood flow, was implemented Infection rates fell from 7.8 infections per 1000 patient days to 3.65 infections per 1000 patient days after the switch to the closed connector (t = 0.04). The adoption of a closed connector system appeared to produce a significant reduction in bloodstream infections. PMID- 20973309 TI - A new quality approach to reducing vascular access infections. AB - Infections in patients on chronic hemodialysis pose tremendous long-term health issues because these patients are inherently susceptible to infection. This is due to prolonged periods of vascular usage and that the body systems of these patients are already immunosuppressed due to end stage renal disease and dialysis. Exposure to bacterial; nosocomial, and other infections related to vascular accesses cause morbidity and mortality. Whether the patient has a central venous catheter, an arteriovenous graft, or the access of choice--the arteriovenous fistula, a quality approach to reducing infection can be used to improve patient outcomes. PMID- 20973310 TI - Antimicrobial lock solutions: an approach to reduce catheter-related bacteremia. AB - Catheters create a highway for bacteria to migrate into the bloodstream and are associated with increased mortality. Infections associated with catheter use contribute to making infection the second leading cause of death in patients with ESRD. This article reviews the growing research that indicates antimicrobial catheter-locking solutions are effective at preventing catheter-related bacteremia by inhibiting the growth of biofilm containing organisms in a catheter lumen and preventing colonization of bacteria. PMID- 20973311 TI - Niacin therapy for phosphorus control in dialysis. PMID- 20973312 TI - Certification and associated fees: where does my certification examination fee go? PMID- 20973313 TI - Development of a modified 100-gram oral glucose tolerance test for diagnosis of gestational diabetes mellitus and its diagnostic accuracy. AB - OBJECTIVE: To develop a modified 100-g oral glucose tolerance test (100-g OGTT) for the diagnosis ofgestational diabetes mellitus (GDM) in order to reduce the number of values needed for the test. MATERIALS AND METHODS: Patient charts ofpregnant women who completed the 100-g OGT test at the antenatal clinic, Siriraj Hospital between 2005 and 2006 were reviewed. Cases diagnosed with GDM using standard 100-g OGTT were selected. In non-GDM cases, the last 100-g OGTT test was selected. Diagnostic performances of each glucose value and two or three values in various combinations were determined. RESULTS: One thousand seven hundred sixty three women completed GDM diagnosis throughout their pregnancy Four hundred three women had GDM while 1360 subjects were non-GDM. Considering single glucose values, the highest level of accuracy, and the best ROC curve were obtained from the value at 2 hours after glucose ingestion (2-h glucose value) with 93.00% accuracy and the area under the ROC curve of 0.961. The combination of 2-h glucose value with fasting plasma glucose (FPG) showed 93.25% accuracy. FPG combined with 1-h and 2-h glucose values achieved 100% sensitivity with 92% accuracy. CONCLUSION: FPG in combined with 1-h and 2-h glucose values is an interesting alternative for the diagnosis of GDM. PMID- 20973314 TI - Nutritional supplements in health-conscious pre-/ post-menopausal Thai women. AB - OBJECTIVE: To survey prevalence, knowledge, attitude, and factors affecting the behavior of nutritional supplement consumption in health-conscious pre-/post menopausal Thai women. MATERIAL AND METHOD: A survey was conducted in 327 women, aged 40-67 years, who were new participants in the health promotion education program of Siriraj Menopause Clinic, Gynecologic Endocrinology Unit, Department of Obstetrics and Gynecology, Faculty of Medicine Siriraj Hospital, Mahidol University, between January and July 2008. The participants completed a self administering questionnaire inquiring their demographic data, attitude, knowledge, and behavior of supplement consumption. The participants were divided into three groups, i.e., current-, past-, and never-users, and then compared. RESULTS: The majority (54.7%) of the presented participants consumed at least one kind of supplements, 37.3% and 17.4% were current-and past-users, respectively. The current-, past-, and never-users were not different in age, medical diseases, education levels, reading frequency, and economic status. The majority of participants obtained the information ofsupplements from newspaper or magazine. The users primarily purchased the supplements from hospitals or clinics. All participants had knowledge on health promotion and supplement products, however, 7.6% and 11.5% of such knowledge, respectively, was inaccurate. All participants had both positive and negative attitudes on supplement consumption, the negative attitude was found in 33.4% of the items tested. The never-users had trivial but statistically significant (p < 0.001) more accurate knowledge and more negative attitude than other groups had. CONCLUSION: More than 50% of health-conscious pre /post-menopausal Thai women are ever-users of nutritional supplements. A lot of misunderstanding and misconception do exist even in the health-conscious women, regardless of their consumption behaviors. More education on this issue should be provided in order to reduce unnecessary expenditure and increase the efficiency of supplement consumption expenditure. PMID- 20973315 TI - Outcome of pregnancies complicated by twin-twin transfusion syndrome in King Chulalongkorn Memorial Hospital. AB - OBJECTIVE: To study perinatal outcomes of pregnancies complicated by twin-twin transfusion syndrome (TTTS), which were treated with the authors' intervention modalities. Maternal outcomes of these populations were also explored. MATERIAL AND METHOD: All pregnancies diagnosed TTTS that delivered in King Chulalongkorn Memorial Hospital between January 2000 and November 2009 were enrolled in this descriptive study Patients' data before August 2008 were retrospectively assessed. Perinatal survival, neonatal morbidities, and maternal outcomes were recorded and analyzed. Antenatal ultrasonographic findings were also analyzed to determine prognostic factors on perinatal outcomes. RESULTS: Twenty-five cases of TTTS were recruited in the present study. Overall perinatal survival was 58% (29/50) with no significant difference in perinatal in among various stages of disease (p = 0.19). Survival in stage I-II, stage III, and stage IV were 64.3%, 45.8%, and 75%, respectively. There was no maternal mortality in the present study The most common maternal morbidity was preeclampsia (6/25; 24%). Progression of disease was the only significant prognostic fact or for perinatal mortality (p < 0.001). CONCLUSION: Overall perinatal mortality rate of TTTS in the presented populations was still high (42%). Progression of disease was the only significant prognostic factor for poor perinatal outcome in the preset study Since the case number of the present study was too small, the conclusion that the prognosis of the conservatively treated TTTS was unrelated to the staging cannot be drawn. PMID- 20973316 TI - Effect of activated charcoal in reducing paracetamol absorption at a supra therapeutic dose. AB - BACKGROUND: Activated charcoal (AC) is recommended for treatment of acute poisoning, thereby decreasing gastrointestinal tract absorption. AC from different sources may have different adsorptive capacity. The AC that is available in Thailand has not been proven yet for its efficacy The authors simulated paracetamol overdose model for the present study. OBJECTIVE: To assess the efficacy of AC that is available in Thailand in decreasing absorption of paracetamol at supratherapeutic dose. MATERIAL AND METHOD: This was a two-arm, prospective, crossover study. Washout period was 1 week Twelve healthy male volunteers participated. All volunteers were randomly assigned to either sequence of control-experiment (CE) or EC. The participants ingested 60 mg/Kg of paracetamol at Time=0. At Time = 0.25 hour, they ingested 50 g of AC as slurry with 250 ml of water when they were assigned as E, but drank 250 mL of water when were assigned as C. Blood samples were serially collected for determination of paracetamol concentration and calculating pharmacokinetic parameters, area under the time-concentration curve (AUC (0, infinity)). RESULTS: Means of the AUC (0, infinity) were 313.7 +/- 29.8 and 184.8 +/- 91.6 mg-h/ L in the control and experimental arm, respectively It was statistically different (p = 0.01). CONCLUSION: The tested AC was found to be able to reduce the absorption of the supratherapeutic dose of paracetamol. PMID- 20973317 TI - Guillain-Barre syndrome: a clinical study in King Chulalongkorn Memorial Hospital. AB - BACKGROUND: Guillain-Barre Syndrome (GBS) is an acute,fatal, but treatable polyradiculopathy. Clinical data concerning this entity is scarce in Thailand The purpose of the present study was to describe clinical profiles and management of GBS as well as to determine prognostic factors in GBS. MATERIAL AND METHOD: Clinical data of GBS in King Chulalongkorn Memorial Hospital during 2002-2007 were searched by using in-patients hospital database. Asbury and Cornblath's criteria were applied for the diagnosis of GBS. Clinical data, electrophysiological data, management, and clinical prognostic factors were collected and analyzed by SPSS version 16. RESULTS: Fifty-five patients with GBS were recruited, 26 wire male and 29 were female. Mean age was 43 +/- 17 years. History of antecedent infection included: respiratory tract 29%, gastrointestinal tract 7%, ear 2%, and non-specific infection 14%. Initial presentations were limb weakness 87%, limb numbness 78%, bulbar weakness 31%, and facial weakness 18%. Electrodiagnostic study revealed demyelinating process in 54% and axonopathy in 46%. Twenty-nine patients received intravenous immunoglobulin while 13 patients underwent plasmapheresis. Clinical outcomes were satisfactory in most of the patients and only two patients died from sepsis and pneumonia. On discharge, the status of the patients were Hughes grade 1-4 in 73%, 14%, 5%, and 4% respectively. Bulbar paresis as the presenting symptom was the only clinical prognostic factor that significantly determined airway compromised and subsequently respiratory failure. CONCLUSION: Clinical features of GBS in the present series were characterized by generalized muscle weakness with mild numbness in combination with facial and bulbar paresis in nearly half of patients. Respiratory failure was encountered in 9% of cases. Clinical outcomes were satisfactory in most of the patients with or without specific treatment. The most significant predictor for adverse clinical course was the bulbar paresis as a presenting symptom and patients who presented with less disability score had a better recovery. PMID- 20973318 TI - Prognostic factors for survival in colorectal cancer patients. AB - OBJECTIVE: To determine the prognostic value for survival of pretreatment characteristics and treatments in stage 1-IV colorectal cancer (CRC) patients. MATERIAL AND METHOD: The present retrospective cohort study was conducted by reviewing 287files of stage I-IV CRC patients. Fifteen clinical variables were investigated through analysis as prognostic factors for survival. RESULTS: The median survival time for CRC patients, colon and rectal cancer patients were 37.2, 43.2, and 29.5 months respectively The 5-year survival rates of CRC patients were 38.6%. 5-year stage-specific survivals for stage I, II, III and IV CRC were 100%, 68%, 44%, and 2% respectively (p < 0.001). Sixty eight percent of CRC patients were in stages III and IV Multivariate analysis revealed age > or =60 years old, WHO performance status 3, stage III and IV disease and poorly differentiated histology as poor prognostic factors for survival, whereas treatment with complete surgical resection and adjuvant chemotherapy was a good prognostic factor for survival in CRC. CONCLUSION: As the majority of patients were in advanced stages with poor prognosis, early stage disease identification and treatment with newer agents would likely improve survival of high-risk CRC patients. PMID- 20973319 TI - Quality of life of myasthenia gravis patients. AB - OBJECTIVE: To investigate the impact of myasthenia gravis (MG) on the quality of life (QOL) of MG patients. MATERIAL AND METHOD: QOL was assessed with SF-36 questionnaire. RESULTS: Thirty-one patients participating in the present study, 74.2% female, with an average age of 44.9 years old. From the SF-36 questionnaire, emotional well being had the lowest score while other components were in average or high range. Ocular and mild generalized MG had better physical functioning than moderate generalized MG With treatment, those who had no or minimal symptoms had better QOL in both physical and mental aspects. Immunosuppressant was not associated with poor QOL. CONCLUSION: QOL of Thai MG patients is better than Westerners. However, MG still has significant impact to both physical and mental aspects. More emphasis is needed for mental aspects. The degree of disease control is very important in QOL and the use of immunosuppressant does not impair QOL. PMID- 20973320 TI - Accuracy of pediatric triage at Siriraj Hospital, Bangkok, Thailand. AB - BACKGROUND: Siriraj Hospital is a busy 2500-bed hospital located in Bangkok, Thailand It has over 1.7 million outpatients, including 120,000 emergency room visits a year, 20,000 of which are pediatric patients. The Pediatric Triage (Pedtriage) system has been in used since the year 2001, but the factors that affect the performance of triage nurse have not been evaluated. OBJECTIVE: To compare the performance non-pediatric nurses who are responsible for pediatric patients in the emergency room before and after pediatric triage training at Siriraj Hospital. MATERIAL AND METHOD: Pediatric Triage Training was set up for emergency room and outpatient department nurses between June and October 2006 The training consisted of 5 hours of didactic sessions on the concepts of pediatric triage and 4-5 hour sessions where the nurses were allowed to triage actual pediatric patients under the supervision ofa triage-training nurse. A pre-test and post-test examination was administered. The outcome of triage performance was categorized into under-triage if the patient had an urgent or emergent condition and was triaged as non-urgent, over-triage if a patient had a non-urgent condition and was triaged as urgent or emergent. Statistical description included percent, averages, and standard deviation where appropriate. A standard 4x4 contingency table was used to calculate the sensitivity and specificity. For comparison of performance, a post-hoc analysis was done where the nurses were divided into two groups, those with work experience ofless than or equal to 5 years (group 1) and more than 5 years (group 2). An independent samples t-test was used to determine the difference in performance between the two groups. RESULTS: Overall, performance on pre-test-post-test differedsignificantly before and after training. The nurses in Group 1 had higher pre-test scores (Group 1 mean = 62.35%, Group 2 mean = 52.41%, p-value = 0.001), were less likely to overtriage (Group 1 mean = 4.11%, Group 2 mean = 6.46%, p-value = 0.021) and had higher specificity oftriage than Group 2 (Group 1 mean = 95.61, Group 2 = 92.39, p-value = 0.019). However, the nurses in Group 2 had more improvement in their post-test scores (percent of improvement from pre-test: Group I mean = 8.56%, Group 2 = 34.69%, p-value = 0.005). CONCLUSION: Work experience is an important consideration in the triage knowledge and performance of non-pediatric nurses during triage training. PMID- 20973321 TI - Safety of initiating early enteral feeding with slow volume advancement in preterm infants. AB - OBJECTIVE: To determine the safety of enteral feeding within 24 hours of life with slow volume increase on the incidence of necrotizing enterocolitis (NEC) and late-onset sepsis (LOS). DESIGN: Prospective descriptive study. MATERIAL AND METHOD: Between January 1998 and December 2001, 117 preterm infants with birth weight < or =1750 g were recruited prospectively, 102 in the human-milk-fed group (HMG) and 15 in the formula-fed group (FG). Feeds were advanced by increments of 10 mL/kg/d, aimed at 150 mL/kg/d in 15 days. Charts of 146 preterm infants admitted during 1996-1997 were reviewed for pre-study incidences of NEC and LOS. RESULTS: NEC developed 3.92% in HMG and 20% in FG (p =.044). LOS developed 2.94% in HMG and 13.33% in FG (p = 0.122). The overall incidence of NEC was almost similar (5.98% vs. 6.16%) while that of LOS was lower (4.27% vs. 12.32%) when compared to the pre-study incidences. CONCLUSION: The present study provides a practice that seems to reduce LOS risk without increasing NEC risk and confirms the protective effect of human milk against NEC. PMID- 20973322 TI - Efficacy of symptomatic control of knee osteoarthritis with 0.0125% of capsaicin versus placebo. AB - BACKGROUND: Knee osteoarthritis (OA) is prevalent and associated with both pain and functional disability. Current treatments aim to alleviate mild to moderate symptoms by various methods. Topical capsaicin (0.075% and 0.05%) has been evaluated for the treatment of the painful joints. A burning sensation was the most common side effect at these strengths. Therefore, the authors aimed to evaluate the efficacy of 0.0125% capsaicin gel (Capsika gel) compared to a placebo (the vehicle gel) in patients with symptomatic OA knee. MATERIAL AND METHOD: This was a cross-over; double blinded, randomized, controlled trial of 100 patients with mild to moderate knee OA. All of the patients received either capsaicin gel or placebo gel applied to the affected knee, three times daily for 4 weeks with one week washout period after which the treatment switched to either capsaicin gel or placebo gel for the next 4 weeks. A blinded examiner used the visual analog scale (VAS) and WOMAC score to do weekly assessments. RESULTS: Subjects averaged 61 years of age (range, 44 to 82). During the enrollment phase, only female farmers presented. Mean body weight and height was 62.97 +/- 10.25 kg and 1.54 +/- 0.053 m, respectively The respective baseline VAS and WOMAC score was 6.40 +/- 1.64 and 51.65 +/- 13.3. The severity of OA, according to the KL criteria was: 83 patients with grade 2 and 16 with grade 3. The respective mean difference of VAS and total WOMAC score in the capsaicin group vs. the placebo group was statistically significant (p < 0.05). The mean difference of the WOMAC pain, stiffness and functional subscales in the capsaicin vs. the placebo group was also significant (p < 0.05). The only adverse event reported was a burning sensation. During the 4-week treatment with capsaicin, approximately 67% of patients had a burning sensation but none withdrew for this reason. CONCLUSION: 0.0125% capsaicin gel was an effective treatment in mildly to moderately painful OA knees. The burning sensation reported by patients in the capsaicin group was less disturbing than in previous studies and none of the present patients withdrew for this reason. PMID- 20973323 TI - Effect of cataract on electroretinographic response. AB - OBJECTIVE: To study the effect of cataract on electroretinographic responses. MATERIAL AND METHOD: Thirty subjects with dense cataracts underwent electroretinogram (ERG) recordings before and after cataract surgery, using RETIport32 (Roland Instruments, Germany). The degree of cataract was classified according to the Lens Opacities Classification System III (LOCS III). No significant eye diseases were noted in all subjects. Following the International Society for Clinical Electrophysiology of Vision (ISCEV), scotopic, mesopic, photopic, oscillatorypotentials and 30 Hz flicker ERG responses were recorded. The mean amplitudes of a- and b-waves, pre and post-cataract surgery were analyzed using the paired t-test. RESULTS: Following cataract surgery, most of the ERG responses were slightly increased but the difference was not statistically significant. However, the mesopic b-wave amplitude was decreased significantly after cataract surgery. CONCLUSION: Most of the ERG waves after cataract surgery were slightly higher than pre-operative waves, but the differences were not statistically significant. The ERG remains a reliable guide in evaluation of the visual prognosis before cataract surgery. PMID- 20973325 TI - Refractive errors survey in primary school children (6-12 year old) in 2 provinces: Bangkok and Nakhonpathom (one year result). AB - BACKGROUND: Refractive error is an important cause of preventable visual impairment and blindness worldwide. Population-based studies will continue to be a key part in identification ofthe magnitude and the importance of this common eye disease. OBJECTIVE: To assess the prevalence of the refractive error in primary school-aged children in Bangkok and Nakhonpathom together with the provision of the appropriately free of charge spectacles. MATERIAL AND METHOD: A Population-based cross-sectional analytic study was conducted between October 2008 and September 2009. Random selection of geographically defined clusters was used to identify the study sample. The examination included visual acuity (VA) by Snellen chart and pinhole correction, autorefraction under cycloplegic refraction, ocular motility evaluation, examination of the external eye, anterior segment, media, and fundus. Ophthalmologists screened for ocular abnormalities. RESULTS: Among 2340 children, 1100 in Bangkok and 1240 in Nakhonpathom were examined The prevalence of refractive error in Bangkok and Nakhornpathom were 12.7% and 5.7% respectively. Refractive error was the cause in 97.6% of eyes with reduced vision, amblyopia in 0.5%, other causes in 0.8%, and unexplained causes in 1.1%. CONCLUSION: The present study showed a relative high prevalence of uncorrected refractive error in the central part of Thailand especially in Bangkok. Eye health education and screening is recommended to evaluate the need for refractive correction with appropriate prescription of spectacles. PMID- 20973324 TI - Evaluating the effects of ice application on patient comfort before and after botulinum toxin type A injections. AB - OBJECTIVE: To evaluate the efficacy of ice application in reducing pain during botulinum toxin type A injections. DESIGN: Prospective, randomized, single-blind clinical study. MATERIAL AND METHOD: Sixty patients who underwent botulinum toxin A treatment on their faces were included in the present study, divided into three groups, group 1 had ice applied 5 minutes before the injection, group 2 ice was applied 5 minutes after the injection, and group 3 served as a control, receiving an injection without ice application. A numeric pain distress scale was used to assess pain intensity. Any complications arising from the injections were also recorded. RESULTS: Sixty patients were studied between July 2007 and March 2008. The ages ranged from 32 to 76 years (mean, 58.15 +/- 10.51 years) and 49 (81.7%) were female. Forty-five (75.0%) had hemifacial spasm and fifteen (25.0%) had blepharospasm. The numeric pain distress scale was completed immediately after the injections and the results were 3.55 +/- 1.85, 5.15 +/- 2.81 and 6.1 +/- 2.63 in groups 1, 2, and 3 respectively. The ratings indicated that pain was significantly reduced in group 1 compared to group 3 (p = 0.005), but there was not a significant difference between groups 1 and 2 (p = 0.109) or between groups 2 and 3 (p = 0.448). There was a significant difference in the rate of bleeding after the injections between groups 1 and 2 (p = 0.0472), but no significant difference between groups 1 and 3 (p = 0.106) and groups 2 and 3 (p=1). CONCLUSION: Using an ice application 5 minutes before or after injection showed no difference but both significantly reduce pain compared to without ice application, while 5-minute application before injection had significantly decreased the bleeding compared to both 5 minutes after injection and without ice application. The ice application is helpful in pain relief whereas the before injection has lesser bleeding than after-injection modality. PMID- 20973326 TI - Fractures of the hyoid bone and thyroid cartilage in suicidal hanging. AB - OBJECTIVE: To analyze the frequency of hyoid bone and thyroid cartilage fractures caused by suicidal hanging in Thai people and compare the different methods of visualizing the those fractures. Results could be used for forensic purposes. MATERIAL AND METHOD: A prospective study of hyoid bone and thyroid cartilage fractures in Thai people who died from suicidal hanging between November 2008 and August 2009. The authors confirmed suicides, based on history, crime scene investigation, autopsy reports, and other police information, visual and palpatory examination, and stereomicroscopy with or without 1% Toluidine. Neck dissection was performed following the protocol of Prinsloo and Gordon. Results and data analysis were performed via SPSS version 16. RESULTS: Twenty male cases of suicidal hanging were reviewed. Fractures of the hyoid bone and/or thyroid cartilage were found in five cases (25%). Two cases ofthe hyoid bone fracture, two cases of thyroid cartilage fracture, and one case was both bone fractures. Mean age of all cases, non-fracture, and fracture cases were 42.40, 35.93, and 61.80 years, respectively The knot was at the back of the neck in most cases (12 cases, 60%) and at the left, front, and right in four, two, and two cases, respectively. However there was no relation between location ofthe knot at the neck and fractures of hyoid bone and thyroid cartilage (p=1). Incomplete and complete hanging were found in 11 and nine cases. Five cases with fractures of the hyoid bone and/or thyroid cartilage were incomplete hanging. The visual and palpatory examination did not detect the fracture of hyoid bone in all 20 cases but stereomicroscopy and stereomicroscopy with Toluidine blue stain detected fracture in three cases. For detecting thyroid cartilage fractures, all three methods had the same result. CONCLUSION: Fractures of the hyoid bone and thyroid cartilage in 25% of Thais who died of suicidal hanging were related with older ages and incomplete hanging but not related with location of the knot. The stereomicroscopic method is fast and effective in detecting fractures of the hyoid bone and thyroid cartilage. PMID- 20973327 TI - Changes in cadmium exposure among persons living in cadmium-contaminated areas in northwestern Thailand: a five-year follow-up. AB - OBJECTIVE: To determine changes in cadmium exposure among persons aged 15 years and older who lived in the 12 cadmium-contaminated villages in northwestern Thailand. MATERIAL AND METHOD: Urinary cadmium was measured among villagers in 2004. An exposure reduction campaign was conducted soon afterwards, and in 2009, urinary cadmium was measured among people living in the same villages. The survey participants were asked about their smoking status and consumption of rice grown locally in cadmium-contaminated areas. Both were the two main routes of cadmium exposure in these villages. RESULTS: Seven thousand six hundred ninety seven and 6748 persons participated in the first and second surveys, respectively. The proportion of current smokers was higher in the first survey (34.9%) than the second survey (31.5%). The proportion of persons who consumed rice grown locally decreased from 88.0% in the first survey to 50.5% in the second survey. Of persons who consumed rice grown locally, the proportion of those with urinary cadmium > or =2 microg/g creatinine increased from 55.5% in the first survey to 61.3% in the second survey. Of persons consuming rice purchased from other areas, the proportion of those with urinary cadmium > or =2 microg/g creatinine decreased from 46.7% in the first survey to 35.6% in the second survey. In both surveys, the adjusted odds ratio for increasing prevalence of high urinary cadmium associated with consumption of locally grown rice was greater than that for tobacco smoking. CONCLUSION: Urinary excretion of cadmium significantly decreased after environmental cadmium exposure was reduced. PMID- 20973328 TI - Pattern of statins' utilization at Ramathobodi Hospital, 2005 to 2007. AB - BACKGROUND: The use of statins at Ramathibodi, a teaching hospital, has been rising rapidly OBJECTIVE: Determine how price, volume, and drug mix (use of five brands and one generic) affect expenditure. MATERIAL AND METHOD: Dispensing records of the six statins were retrieved from database and analyzed for factors contributing to increased drug expense. RESULTS: Overall, statins' expenditure rose 35.6% and 6.4% in 2006 and 2007 respectively, mainly from civil servant outpatients who are more likely to be prescribed with brand drugs, even among new patients. In all schemes, volume effect was positive, more people use statins, and each one used a larger quantity of drug in 2007 than in 2005. The price effect was negative. Drug mix effect indicated that there was a shift from higher to lower priced drugs in capitation scheme and from lower to higher priced original drugs in a fee-for-service scheme. CONCLUSION: There is a trend of more statins utilization but with a different pattern of drug prescribed between health schemes and possible drug over-prescribed in some patients. However indication for statin use was not studied, which needs to be considered. With high use of original drugs, effective policy initiative to promote generic drug use should be implemented in order to efficiently use the limited health care resources. PMID- 20973329 TI - Surgical management of Brunner's gland hamartoma causing upper GI hemorrhage: report of two cases and literature review. AB - Brunner's gland hamartomas are uncommon benign tumor of the duodenum. Most lesions are small and asymptomatic. Occasionally, those lesions may be large and manifest as a rare cause of upper GI hemorrhage or duodenal obstruction. The authors report here two cases of Brunner's gland hamartoma presenting with upper GI hemorrhage that were not amenable to endoscopic polypectomy thus requiring surgical resection. The literature on Brunner's gland hamartoma was reviewed. PMID- 20973331 TI - When optometrists attended think tanks. AB - This paper discusses the organization of the Bradford Woods Conference in Indiana that began optometry think tank meetings in 1954, the Allenberry Conference held annually for many years starting in 1967, and the Blue Sky Conference in Michigan that started concurrently with Allenberry. These were freewheeling meetings with enthusiastic exchange of often visionary ideas. PMID- 20973330 TI - Recalcitrant solar urticaria induced by UVA and visible light: a case report. AB - A 41-year-old man presented with a ten-year history of recurrent erythema and swelling of skin that occurred following sun exposure even as little as ten minutes. The lesion affected only on the sun exposed area. A phototesting was carried out and revealed that urticaria was induced following ultraviolet A (UVA) and visible light exposure. Solar urticaria (SU) from UVA and visible light was diagnosed. Many treatment options including combination of oral antihistamines, psoralen plus UVA (PUVA) photochemotherapy, narrowband UVB (NBUVB, 311 nm) phototherapy, and plasmapheresis were tried in the presented patient without significant response. Although various treatments are available, managing SU remains a challenging problem in many patients. PMID- 20973332 TI - The elite school; 25 years later! & optometry and its future in India. PMID- 20973333 TI - A case of giant cell glioblastoma: a mimicker of a cerebral metastasis. AB - We report a rare case of giant cell glioblastoma that was difficult to distinguish from cerebral metastasis. The MRI finding was a ring-enhancing well circumscribed solitary brain tumor that was very similar to cerebral metastasis. Even when MRI results were considered together with the findings by magnet resonance spectroscopy and perfusion-weighted MRI, it was hard to distinguish between giant cell glioblastoma and cerebral metastasis before surgery. When we find a solitary ring-enhancing intracranial mass with little tendency of invasion, we need to consider the possibility of giant cell GBM as a differential diagnosis. PMID- 20973334 TI - 'Filthy vessels': milk safety and attempts to restrict the spread of bovine tuberculosis in Queensland. AB - Bovine tuberculosis is a dangerous mycobacterium that can be conveyed to humans in the meat and milk of cattle. By the mid-1800s, when health scientists began arguing about its zoonotic potential and danger to humans, the disease was well established in Australian cattle herds. This article examines the Queensland response to bovine tuberculosis from the late 1800s to the 1940s, when the problem of tubercular cattle could no longer be ignored. It shows that despite widespread concern about milk safety and increasing knowledge of the disease's aetiology, the Queensland government directed its milk safety activities towards public health education rather than the inadequacies of the dairy industry's approach to bovine tuberculosis. As such, it was tardy in addressing bovine tuberculosis. PMID- 20973335 TI - A dissident voice in New Zealand wartime sex education. AB - Sex education in wartime New Zealand focused primarily on adults and was concerned with community stability in aberrant times. In 1943 Dr. Clara Lee's bold move to ask a group of New Zealand women candidly about their sexual experiences caused her dismissal as lecturer in sex hygiene to military women. This encounter provides an important counter discourse to the dominantly held contemporary sex education framework of marital love and premarital chastity. PMID- 20973336 TI - Away from the mainstream: medical women in one region of rural New South Wales. AB - Despite recent research on the difficulties associated with attracting women to the rural medical workforce, and the perception that the image of the rural doctor is male, women have had a history in rural medicine in southwest New South Wales that spans a century. This paper explores the contribution to medicine of women medical practitioners working within one geographical area of rural New South Wales. It traces these women, documenting the diversity of women's medical work and some of the challenges faced. Based largely on data from contemporary reports in two local newspapers, the Daily Express and The Daily Advertiser, this paper shows that some of the silence associated with the role of women in rural medicine could be attributed to them holding positions at the margins of what is depicted as 'real' medicine, in fields that include public health and education. PMID- 20973337 TI - Eradicating smallpox in Indonesia: the archipelagic challenge. AB - From 1804 to 1974, the colonial Dutch East Indies government and the postcolonial Indonesian state attempted to tackle the problem of smallpox. The vaccination efforts in the colonial era virtually eliminated smallpox by 1940. Unfortunately, as a consequence of the war smallpox was reintroduced into the archipelago in 1947. Indonesia finally succeeded in eradicating smallpox in 1974 through campaigns of mass vaccination and surveillance. In the last few years of the fight against smallpox, a detection system was set up in order to have every suspected case of smallpox isolated and investigated by the health authorities until verified in the government laboratory at Bandung. This paper looks at the impact of the archipelagic nature of Indonesia on the smallpox eradication campaigns. PMID- 20973338 TI - Reflections, memories, and sources 'The cleanest man on earth': Harcourt Whipple Ellis and the NLA Australian newspapers. AB - The National Library of Australia (NLA) Australian Newspapers project went public in July 2008, but many historians and researchers are as yet unaware of its existence, or of its great potential for their research. This article will demonstrate the revolutionary potential of this project for the history of medicine in Australia. Using the case ofa largely-forgotten Western Australian chemist, dentist, and optician, Harcourt Whipple Ellis, a search of the NLA Australian Newspapers project produces a substantial amount of information on his at times scandalous career, a general physical description, a verbatim quotation, and many other witnesses statements attributed to him. These newspaper articles flesh out' Ellis, and also provide valuable insights into early-twentieth-century life in Perth. PMID- 20973339 TI - Dr. William Theodore Hodge: pioneer surgeon-apothecary in early-twentieth-century Western Australia. AB - In 2008 I chanced upon the lonely grave of Dr. William Theodore Hodge, buried in 1934, in the Derby Pioneer and Aboriginal Cemetery. He turned out to be the founding doctor of the practice in which I have worked for the past thirty years. Dr. Hodge migrated from England in 1896. He was the first western trained doctor to work in the Perth suburb of Claremont and in the wheat-belt town of Kellerberrin. He was an innovative and inventive modern doctor who became a legend in the Kimberley where he died tragically, on the day prior to his retirement, at the age of seventy-five. His story is illustrative of the life and medical practice of a pioneering doctor in metropolitan, rural, and remote practice in Western Australia at the end of the nineteenth and the early years of the twentieth centuries. PMID- 20973340 TI - Ageing in the seventeenth and eighteenth centuries. PMID- 20973341 TI - "Sooty empiricks" and natural philosophers: the state of chemistry in the seventeenth century. PMID- 20973342 TI - Divine illumination, mechanical calculators, and the roots of modern reason. PMID- 20973343 TI - Tricks of transference: Oka Asajiro (1868-1944) on Laissez-faire capitalism. PMID- 20973344 TI - Molecular medicine; the road to the better integration of the medical sciences in the twenty-first century. AB - The history of the evolution of medical research is characterized by a long period of division between the basic biological sciences and the health sciences, reflecting the seventeenth-century trends towards the experimental and the empirical. It was not until the middle of the twentieth century that, by their ability to straddle both worlds, the work of small groups of basic scientists in the U.S.A. and Europe led to closer integration between the medical sciences. This change in direction is well exemplified by the work of the Cambridge scientists Max Perutz, Vernon Ingram and Herman Lehmann, from 1950 onwards. Their research, and its later development by others, was to lay the basis for what became known as 'molecular medicine', and at the same time set the scene for a more integrated approach to medical research that continued into the new millennium. PMID- 20973345 TI - From applied microbiology to biotechnology: science, medicine and industrial renewal. AB - In the late 1970s politicians and civil servants were acutely aware of the chronic decline of the manufacturing sector as a source of employment in Britain. At a time of fear of mass unemployment, sources of new work were urgently sought. Biotechnology had been promoted by visionaries since the early twentieth century. With oil prices soaring, its potential to produce substitutes for petroleum derivatives seemed newly attractive. At the beginning of 1976, John Bu'Lock at Manchester brought the attention of the new President of the Royal Society, Lord Todd, to the developments in enzyme and fermentation technologies. Both the Society and government began to take biotechnology seriously. In 1979 the Society organized a groundbreaking meeting, 'New horizons in industrial microbiology'. In parallel, John Ashworth, the chief scientist of the government think-tank the Central Policy Review Staff, prompted by American developments in genetic engineering, its commercial exploitation and regional development, led thinking among government officials. The Spinks enquiry into biotechnology was consequently formed in 1979 as a collaborative enterprise of the Advisory Council for Applied Research and Development, the Advisory Board for the Research Councils and the Royal Society. The recommendations for far-reaching collaboration between research councils, government and industry were not fully implemented. However, even the limited implementation led to new models of science that would be significant in the emergence of a reconstruction of science. PMID- 20973346 TI - Operative management of intra-articular distal interphalangeal joint fractures of the hand. AB - The management of intra-articular fractures of the hand represents a challenge. Large articular fragments require reduction and operative fixation. A number of surgical techniques have been described in literature, with variable results. Distal interphalangeal joint fractures have been fixed by various methods including screw, plate and suture techniques. Generally operative fixation is indicated when more than 30% of the articular surface is involved with or without subluxation of the joint. The aim of surgery is to reduce the fracture fragments anatomically whilst providing osseous stability, and to commence early active movement of the joint to prevent stiffness. In this review we aim to summarise the main management options for intra-articular distal interphalangeal fractures, placing particular emphasis on surgical treatment. PMID- 20973347 TI - Primary hip arthroplasty templating on standard radiographs. A stepwise approach. AB - In the past decade, the indications for hip replacements broadened and media induced patients' expectations in terms of function and longevity have been rising steadily. Improved technology addressed wear and fixation issues. However, more attention should be given to optimising hip biomechanics as this is essential to restore function. Pre-operative hip templating allows anticipating the correct implant position and potential difficulties prior to surgery. As such it is an essential part of the implantation process. We propose a four-step approach for hip templating on a standardised standing pelvic radiograph: 1. Identify anatomical landmarks (the medullary canal, the greater and lesser trochanter, the acetabular roof and the teardrop); 2. Assess the quality of the radiograph (femoral rotation, pelvic inclination and symmetry); 3. Identify mechanical references (the original acetabular and femoral rotation centre, the femoral and acetabular offset and the leg length and hip length discrepancy); 4. Optimise implant positioning to restore hip biomechanics. Hip templating helps recognising "difficult hips" where restoration of the original hip anatomy is no option. These hips should be approached carefully with a well defined pre operative plan to minimise the chances of complication while maximising hip function. Although it is mainly under these circumstances that hip templating is a major asset, we believe that performing systematically a standardised preoperative templating should contribute to improved hip arthroplasty function and outcome. PMID- 20973348 TI - Platelet enriched plasma for acute muscle injury. AB - Hamstring muscle strains are among the most common injuries in sport, but despite increasing research into the epidemiology, aetiology and management the rates of both injury and re-injury remain high. Typically, hamstring injury management is conservative, but recently the use of autologous platelet enriched plasma (PEP), has been proposed as a treatment tool which may optimise muscle regeneration and enhance clinical outcomes. Unfortunately however, there remains little scientific evidence for the clinical use of these techniques in muscle injuries. This report outlines the current clinical evidence for the use of PEP in muscle injuries. A case report of a patient with a grade II semi-membranosus muscle strain, injected with PEP while concurrently using platelet inhibitors will illustrate the clinical, radiological and theoretical challenges of this new technique. Further clinical research into the clinical utility of PEP in muscle injury is required and it is incumbent on Sports Physicians and researchers to address this research deficit, if PEP is to live up to its high public profile. PMID- 20973349 TI - Outcome of latissimus dorsi transfer for irreparable rotator cuff tears. AB - The aim of this retrospective study was to assess the mid- and long-term functional and radiological results following latissimus dorsi transfer for symptomatic irreparable tears of the supra- and infraspinatus tendons (postero superior cuff tears). Twenty-six shoulders with an irreparable posterosuperior rotator cuff tear were assessed preoperatively and after latissimus dorsi transfer, using the Constant score and standard radiographs to determine the degree of osteoarthritis and to measure the acromio-humeral distance. After a minimal follow-up of one year (range: 13 to 124 months) we observed a significant increase in Constant score from 39 to 60 points at the time of the last follow-up (p < 0.00001). Eighty-five percent of the patients were satisfied or very satisfied with the result and would undergo the same surgery again. An increase in the grade of gleno-humeral osteoarthritis was noted in 38.5% of the operated shoulders, and this was associated with a lower Constant score. We noted a decrease in acromio-humeral distance, indicating further proximalisation of the humeral head, but this was not significant (p = 0.049). PMID- 20973350 TI - Ultrasonographic evaluation of the shoulder in asymptomatic overhead athletes. AB - This study aimed to evaluate the efficiency of ultrasonography (US) in the examination of soft tissue anatomical structures of the shoulder in overhead athletes. The study evaluated the shoulders of overhead elite premier league athletes involved in basketball, handball, volleyball, body building, and water polo. US examination of both shoulders was performed prospectively in 45 asymptomatic overhead athletes and 43 asymptomatic volunteers matched for age. On US examination, subacromial-subdeltoid bursa effusion was observed in 16 of the dominant shoulders and in 2 of the non-dominant shoulders of 45 overhead athletes and in none of the asymptomatic volunteers. The mean thickness of the subacromial subdeltoid bursa was significantly larger in the dominant and non-dominant shoulders of the overhead athletes than in the asymptomatic volunteers (p < 0.001, p < 0.05 respectively). Ultrasonography appeared as an effective, convenient and non-invasive tool for the early diagnosis of shoulder pathologies occurring in overhead athletes, even in the asymptomatic stage. PMID- 20973351 TI - Internal fixation of proximal humerus fractures with the polarus intramedullary nail. AB - The optimal treatment method for displaced proximal humeral fractures continues to be under debate. There are a variety of fixation techniques, none of which has been proven to be more effective. We retrospectively studied 24 patients with displaced proximal humerus fractures, treated with the Polarus intramedullary nail. All patients were followed radiographically and clinically for one year. Clinical outcome was assessed with the Constant score. All fractures went on to clinical and radiographic union. Mean time to union was 9.2 weeks (range: 9-16). Only one patient with a 3-part fracture had an asymptomatic malunion and one patient had iatrogenic radial nerve palsy, which spontaneously recovered. In total, 83.3% of the patients had an excellent or good clinical outcome. The Polarus nail appeared in this study as an effective device to treat proximal humeral fractures, with good overall functional results and a low complication rate. PMID- 20973352 TI - The Outerbridge-Kashiwaghi procedure in elbow arthroscopy. AB - We evaluated the results of the arthroscopic Outerbridge-Kashiwaghi procedure in a retrospective review of 20 elbows in 19 patients with a mean followup of 2 years (range : 6 months - 4 years). Range of motion improved from 94 degrees (range: 15 degrees-140 degrees) to 123 degrees (range: 110 degrees-140 degrees). Visual analogue scales for pain improved from 5.8 (range: 2 -8) to 1.8 (range: 0 8). The Mayo Performance Index increased from 54 (range: 15-85) to 88 (range: 45 100). The results were good to excellent in 16 elbows, fair in two and poor in two. Seventeen patients were better (85%), 3patients remained unchanged (15%). In elbows with severe arthritis, pain relief was minimal. The arthroscopic Outerbridge-Kashiwaghi procedure appeared in this study as a good surgical option in mild to moderate elbow arthritis, with significant pain relief and increased elbow mobility and function. PMID- 20973353 TI - Dorsal nail plate fixation of distal radius fractures. AB - Intramedullary fixation of distal radius fractures is an emerging concept. The Dorsal Nail Plate is a new device that links a specifically designed stem to a small distal plate; bone fixation is supported by fixed-angle screws. The device is inserted dorsally using a minimally invasive technique ; its indications are unstable dorsally displaced extra-articular or simple articular distal radius fractures. To evaluate the results obtained with this implant, we retrospectively studied 47 extra-articular (36 cases) or simple articular (11 cases) dorsally displaced distal radius fractures in 46 patients treated with this technique. Patients had a mean follow-up of 11 months and were evaluated radiographically and clinically using the Mayo Wrist Score and the DASH score systems. The minimally invasive operative technique is described. Complications occurred in three cases. Two were observed intra-operatively--partial rupture of extensor pollicis longus tendon--and one postoperatively--loosening of one epiphyseal screw. Excellent reduction was obtained at operation in all but two patients; loss of initial reduction was observed in 2 fractures. All fractures were considered healed radiologically at 40 days. Average final DASH score was 6 (0 20). According to the Mayo Wrist score, 29 patients had excellent, 12 good and 5 satisfactory results. The Dorsal Nail Plate (DNP) has shown to effectively stabilize distal radius fractures with dorsal displacement, leading to an early satisfactory functional recovery. Accurate surgical technique minimizes soft tissue dissection and reduces the risk of complications. PMID- 20973354 TI - Radiological determination of the anatomic hip centre from pelvic landmarks. AB - There are various methods to locate the rotation centre of the hip joint on standard pelvic radiographs. When the geometry of both femoral heads is abnormal, a number of methods are available to locate the physiological hip centre from anatomical landmarks on pelvic radiographs. The accuracy and reliability of six methods were retrospectively investigated on 115 standard pelvic radiographs of both hips of healthy individuals. As a reference against the hip joint centre predicted by these methods, we used the true anatomical centre of the femoral head. Measurements were normalized in relation to pelvic height. The calculated hip rotation centre most closely approached the true anatomical centre of the femoral head when the acetabular teardrop was used as a landmark. PMID- 20973355 TI - Prediction of posttraumatic femoral head osteonecrosis by quantitative intraosseous aspirate and core biopsy analysis: a prospective study. AB - Twenty-two patients with unreduced hip dislocation or fracture dislocation were prospectively evaluated. Intraosseous aspiration, marrow fluid analysis and core biopsy histological analysis was performed from the supero-lateral (test group) and central part (control group) of the femoral head. After appropriate surgical treatment and postoperative management, they were followed up for 2 years by clinical, radiological and magnetic resonance imaging evaluation. Eight patients eventually developed avascular necrosis (AVN) of the femoral head. The analysis of test samples revealed that 9 patients had an aspirate volume of < 1 cc ; marrow morphology of 11 hips showed necrotic cells; 12 patients had a core biopsy histology suggestive of dead osseous fragments and necrotic osteocytes. In contrast, all the control samples had an aspirate volume of > 1cc and showed viable cells on histology. Intra-operative assessment of marrow-aspirate volume (< 1cc), marrow morphology and core biopsy histology from the superolateral part of femur head can fairly predict the development of subsequent ONFH after trauma; the correlation is statistically significant (p < 0.05). PMID- 20973356 TI - Modular proximal femoral replacement in salvage hip surgery for non-neoplastic conditions. AB - Addressing severe proximal femoral bone loss in revision hip surgery is a challenging reconstructive problem. The use of modular proximal femoral megaprostheses is one of many available options to address this. This is a retrospective review of 15 patients who had undergone limb salvage at our institution using a modular proximal femoral replacement. There were 8 males and 7 females with a mean age of 67 years (34 to 85) and a mean follow-up of 60 months (1 to 99). Indications included re-implantation for deep infection in nine patients, aseptic loosening in three, periprosthetic fracture in two and painful excision arthroplasty in one. Mean Harris hip score increased from 28 (13 to 49) pre-operatively to 69 (39 to 85) at final follow-up (paired t-test, p < 0.0001) and mean Toronto Extremity Salvage score increased from 26% (14 to 40) to 71% (35 to 82) (paired t-test, p < 0.0001). Prosthesis survival with revision as the endpoint was 87% at 5 years. There were two dislocations (14%) and there was failure to eradicate deep infection in two. Modular proximal femoral replacement provided good function and versatility with an acceptable complication rate for patients with severe proximal femoral bone loss with or without infection. PMID- 20973357 TI - Treatment of distal femoral fractures in elderly diabetic patients using minimally invasive percutaneous plating osteosynthesis (MIPPO). AB - The aim of this study was to evaluate the results of minimally invasive percutaneous plate osteosynthesis (MIPPO) of distal femoral fractures in elderly diabetic patients with osteoporotic bone. Thirteen supracondylar or intercondylar femoral fractures were treated by MIPPO with a locked plate without bone grafting. All fractures healed, with only one delayed union in a patient who had deep infection. Results were evaluated using Schatzker and Lambert's criteria; all patients had excellent, moderate or good results except one with a poor result. Minimally invasive percutaneous locked plating provided favorable results in the treatment of distal femoral fractures in this geriatric population. PMID- 20973358 TI - Iliotibial band traction syndrome in guided motion TKA. A new clinical entity after TKA. AB - This study aimed at systematic documentation of lateral knee pain in a consecutive series of 1102 cruciate-substituting, guided motion total knee arthroplasties (TKA) (Journey, Smith and Nephew, Memphis, TN, USA) performed in 1085 patients; 1070 knees were available for review. Follow-up time ranged from one to five years, with a mean of 2.5 years. Symptoms mimicking the well known iliotibial band (ITB) friction syndrome were observed in 77 knees (7.2%). Initial conservative treatment consisted of anti-inflammatory medication (77 knees) and local steroid injection (35 knees). The pain persisted in 22 knees (2%), leading to a surgical release of the iliotibial band. Other surgical interventions included revision for infection (6 knees, 0.5%), revision for tibial component loosening (6 knees, 0.5%), revision for tibiofemoral dislocation (3 knees, 0.3%), revision for patellar component loosening (5 knees, 0.4%), revision for instability (1 knee, 0.1%) and secondary patellar resurfacing (1 knee, 0.1%). The overall survivorship with partial or total implant revision as an endpoint was 98%. The development of lateral knee pain in association with the use of a guided motion design can be explained by the forced posterior translation of the lateral condyle in flexion. The asymmetric cam and post mechanism, acting as a hard driver of posterior femoral translation and internal tibial rotation during flexion, does not allow for the natural kinematic variability occurring in native knees. This repetitive and forced stretching of the ITB seems to induce a painful traction syndrome in some patients. PMID- 20973359 TI - Differences in metal ion release following cobalt-chromium and oxidized zirconium total knee arthroplasty. AB - Ions are released from all metals after implantation in the body through processes of corrosive and mechanical wear. The aim of this study was to investigate whether serum metal ion levels are raised in patients following total knee arthroplasty. Serum levels of chromium, cobalt, aluminium, molybdenum and zirconium were measured in two groups of patients at a minimum of 3 years after knee arthroplasty. Twenty three patients had a cobalt-chromium femoral component and 14 patients had an oxidized zirconium femoral component, acting as a control group as this femoral component is free from cobalt and chromium. All patients had the same titanium tibial base plates, and no patellae were resurfaced. Despite the lack of cobalt and chromium in the prostheses used in the control group, no statistically significant differences in serum cobalt and chromium ion levels were found between the groups. On the basis of these results there does not appear to be any significant rise in serum metal ion levels following total knee arthroplasty several years after implantation. PMID- 20973360 TI - Ankle fracture classification: an evaluation of three classification systems : Lauge-Hansen, A.O. and Broos-Bisschop. AB - The interobserver variability and the ability of the Lauge-Hansen, A.O. and Broos Bisschop classification systems to encompass all the ankle fracture patterns were investigated in a study of the radiographs of 293 patients with a total of 294 malleolar fractures. Three different orthopaedic surgeons independently evaluated the sets of ankle radiographs. The examiners classified the ankle fractures using the Lauge-Hansen, A.O. and Broos-Bisschop systems. The overall percentage of unclassified fracture patterns was 0.7% with the Broos-Bisschop system, 10% with the Lauge-Hansen system and 8.7% with the A.O. system. The concordance rate using Kappa coefficient ranged from 0.327 to 0.408 for the Broos-Bisschop system, from 0.174 to 0.476 for the Lauge-Hansen system and from 0.397 to 0.483 for the A.O. system. These results show that these three classification systems have in common a considerable interobserver variability deficiency which restricts their validity in selection of treatment options, prognosis and comparison between different materials. PMID- 20973361 TI - Early results of distal metatarsal osteotomy through minimally invasive approach for mild-to-moderate hallux valgus. AB - A prospective study was performed on 24 patients to evaluate the early results of our experience with minimally invasive distal metatarsal osteotomy to treat mild to-moderate hallux valgus deformities in adults. After failure of conservative treatment and persistence of footwear-related pain, a percutaneous distal first metatarsal osteotomy was performed, stabilized by a Kirschner wire, followed by immediate weight bearing. At final follow-up, clinical assessment showed that 31 of 36 patients were satisfied with their results. At a mean of 21 months, weight bearing foot radiographs showed significant change compared with the preoperative status : the average corrections of hallux valgus angle and first intermetatarsal angle achieved were 13.10 and 5.40, respectively (p < 0.001). No cases showed nonunion, malunion, overcorrection, transfer metatarsalgia or osteonecrosis. The technique appeared in this study to be an effective, safe and simple option for correction of a painful mild-to-moderate hallux valgus deformity. PMID- 20973362 TI - Scoliosis surgery: correction not correlated with instrumentation, quality of life not correlated with correction or instrumentation. AB - The authors conducted a retrospective study on 24 consecutive adolescent scoliosis patients, 11 of whom were instrumented with hooks and 13 with hooks and screws (hybrid technique). The mean preoperative Cobb angle was 62.2 degrees (range: 48 degrees-96 degrees). The mean correction of the primary curve was 56.6% at followup after +/- 1.18 years ; there was no statistically significant difference between groups. Special attention was given to the postoperative quality of life (QOL) by means of the following scores: COMI patient self assessment, SF-36, ODI, and VAS. Again, there was no statistical difference between groups but, interestingly, there was no correlation between QOL and degree of correction, after a follow-up period of +/- 2.1 years. Nevertheless, on the COMI patient self-assessment, there was a high level of satisfaction with treatment. Further studies should concentrate on how to achieve a high QOL, and abandon the best possible correction as a primary endpoint of success. PMID- 20973363 TI - Practical considerations in the making and use of high-dose antibiotic-loaded bone cement. AB - Local antibiotic delivery with antibiotic loaded acrylic bone cement has been used extensively in the management of chronic osteomyelitis and implant related infections. Though newer drug delivery vehicles are being investigated, it remains the most widely used local antibiotic delivery vehicle in orthopaedic surgery. Self-made antibiotic loaded bone cement beads, which are cheaper and antibiotic specific, have been shown to elute less effectively than commercial antibiotic loaded cement beads. We offer several tips for increasing the elution and effectiveness of antibiotic loaded bone cement in clinical practice. PMID- 20973364 TI - A simplified technique for anterior cervical discectomy and fusion using a screw plate implanted over the Caspar distractor pins. AB - The author presents a simplified technique for midline screw-plate fixation in fusion procedures after anterior cervical discectomy, in which the plate is introduced over the Caspar distractor pins. The Uniplate system used, with a single screw in each vertebral body, minimizes bone damage to the vertebral body as the screws can be fixed in the holes previously used for the Caspar distractor pins. This simplified version of the classical anterior cervical fusion technique saves surgical time, facilitates screw insertion, and obviates the need for manipulations to stabilize the plate before the screws are inserted. It provides immediate stability comparable to other plate systems. To the author's knowledge, this is the first report on cervical fusion with the Uniplate system with the plate being introduced over the Caspar distractor pins. PMID- 20973365 TI - Late rupture of flexor pollicis longus tendon 10 years after volar buttress plate fixation of a distal radius fracture: a case report. AB - We report the case of a complete rupture of flexor pollicis longus tendon in a 30 year old-man 10 years after open reduction and internal fixation of a distal radius fracture with a volar buttress plate. PMID- 20973366 TI - Isolated volar fracture-dislocation of the scaphoid with acute carpal tunnel syndrome: a case report. AB - Dislocations and fracture-dislocations of the scaphoid are rare injuries. When they occur in a volar direction, they may be complicated by median nerve compression. While volar dislocations and fracture-dislocations of the scaphoid presenting late with median nerve compression have been reported, such injuries presenting with acute median nerve compression have not been reported. We describe a case of volar fracture-dislocation of the proximal half of the scaphoid causing median nerve compression and presenting with acute carpal tunnel syndrome. Urgent open reduction and internal fixation of the scaphoid along with decompression of the median nerve achieved prompt relief of the neurological symptoms. PMID- 20973367 TI - Displaced intracapsular fracture complicating transient osteopoenia of the hip in pregnancy: timing of surgery. AB - A patient who presented with a displaced subcapital fracture of the proximal femur in her third trimester of pregnancy is reported. Following delivery of the baby with an emergency caesarean section, the fracture was immediately reduced and fixed using cannulated screws. The outcome of her fracture management for this rare condition is discussed. Only seven cases have been reported in the literature and we review the possibility that this condition may be a systemic rather than a purely localised problem as previously believed. PMID- 20973368 TI - Neglected bilateral femoral neck fracture associated with pregnancy and primary hyperparathyroidism. AB - We report a case of neglected bilateral femoral neck fracture related with transient osteoporosis in pregnancy (TOP) and primary hyperparathyroidism, in a 33-year-old female who presented with a fracture of both femoral necks without any history of trauma 20 days after delivery. Her pain was at first accepted as common musculoskeletal discomfort following labour, and the final diagnosis was made only 25 days after fracture. She was treated with primary internal fixation with cannulated lag screws and received medical treatment for hyperparathyroidism and TOP. She was followed up for 29 months following the operation. No complications, and more specifically no avascular necrosis (AVN) were noted during this time interval. The patient made a complete functional recovery. We would like to emphasize that major medical problems may be underdiagnosed during the last pregnancy trimester and postpartum period. Delay in the diagnosis and treatment of a femoral neck fracture is an important but not a decisive factor for the development of AVN. PMID- 20973369 TI - Outsourcing administrative functions: service organization demonstrations and Florida Medicaid PCCM program costs. AB - This study examines the cost implications of outsourcing Medicaid functions to the private sector. We examine the expenditures for enrollees in three Medicaid primary care case management (PCCM) demonstration projects compared to Florida's PCCM program from February 2002-February 2003. The RAND two-part model was used to analyze the medica expenditures for enrollees in each program. After adjusting for sociodemographic factors and the probability of service use, we found that all three demonstration projects reduced expenditures compared to the PCCM program. The implications from the study are that Medicaid programs may want to consider outsourcing PCCM functions after further studies examine the utilization experience for enrollees in these programs. PMID- 20973370 TI - Does outsourcing affect hospital profitability? AB - Organizations outsource non-core service functions to achieve cost reductions and strategic benefits, both of which can impact profitability performance. This article examines relations between managerial outsourcing decisions and profitability for a multi-state sample of non-profit hospitals, across 16 states and four regions of the United States. Overall regression results indicate that outsourcing does not necessarily improve hospital profitability. In addition, we identify no profitability impact from outsourcing for urban hospitals, but somewhat positive effects for teaching hospitals. Our regional analysis suggests that hospitals located in the Midwest maintain positive profitability effects with outsourcing, but those located in the South realize negative effects. These findings have implications for cost reduction efforts and the financial viability of non-profit hospitals. PMID- 20973371 TI - A prescription for turning self-pay accounts into revenue. AB - The antidote for a healthy bottom line is a streamlined payment recovery process from self-pay patients. Due to the current high unemployment rate and a resulting spike in self-pay patients, CFOs must be proactive and identify self-pay debt recovery solutions to stay in the black. It is vital to design an effective and efficient process that works for the specific needs of the hospital or practice. Utilizing metrics, reconditioning patients to pay at point-of-service, training associates to appropriately request payment, and understanding the limitations of the business office are key elements to financial health. Identifying an accounts receivable management partner could significantly reduce headaches and strain on staff and time. PMID- 20973372 TI - What does free cash flow tell us about hospital efficiency? A stochastic frontier analysis of cost inefficiency in California hospitals. AB - Hospitals are facing substantial financial and economic pressure as a result of health plan payment restructuring, unfunded mandates, and other factors. This article analyzes the relationship between free cash flow (FCF) and hospital efficiency given these financial challenges. Data from 270 California hospitals were used to estimate a stochastic frontier model of hospital cost efficiency that explicitly takes into account outpatient heterogeneity. The findings indicate that hospital FCF is significantly linked to firm efficiency/inefficiency. The results indicate that higher positive cash flows are related to lower cost inefficiency, but higher negative cash flows are related to higher cost inefficiency. Thus, cash flows not only impact the ability of hospitals to meet current liabilities, they are also related to the ability of the hospitals to use resources effectively. PMID- 20973373 TI - Medical tourism private hospitals: focus India. AB - This article examines demand factors for sophisticated medical treatments offered by private hospitals operating in India. Three types of medical tourism exist: Outbound, Inbound, and Intrabound. Increased profitability and positive growth trends by private hospital chains can be attributed to rising domestic income levels within India. Not all of the chains examined were financially solvent. Some of the hospital groups in this sample that advertised directly to potential Inbound medical tourists appear to be experiencing negative cash flows. PMID- 20973374 TI - Can long-term care insurance be fixed? AB - Long-term care insurance has not sold well in the United States. The issues are cost, complex financial problems, uncertainty about inflation, and concerns about the future of health care in general. The heart of the problem may well be that this insurance does not cover the relevant risk, and a solution is suggested in Section 6 of this article. PMID- 20973375 TI - Measuring economies of scale at the city market level. AB - Data envelopment analysis (DEA) techniques have been applied to the assessing efficiency and productivity among individual hospitals. In this article, we employ DEA to address whether economies of scale exist among hospital markets by first assessing individual hospitals operating in 2005 in the State of Florida and then by comparing hospital markets' efficiency relative to each other. The interest in hospital markets stems from issues relating to mergers among hospitals or the reallocation of services (inputs) among hospitals in a market area, particularly as occupancy rates and reimbursements are tending to fall. Facing more competition and stringent financial conditions, hospitals would benefit from decreasing costs by exploiting economies of scale. PMID- 20973376 TI - Avoiding the trap in the HITECH Act's incentive timeframe for implementing the EHR. AB - The American Recovery and Reinvestment Act of 2009, often called the Stimulus Package or the Stimulus Bill, contains a section called the Health Information Technology for Economic and Clinical Health Act (HITECH Act). The HITECH Act made several significant changes to the current HIPAA Security and Privacy Rules and provided funds and incentives to increase the use of electronic health records (EHRs) by eligible physicians and eligible hospitals, as discussed below. The HITECH Act also provides funding for the Office of the National Coordinator for Health Information Technology, which oversees technology standards, implementation strategies, and impact assessment. The goals of the Office of National Coordinator are to achieve use of an EHR for each person in the country by 2014 and to develop a nationwide health information technology infrastructure in support of the first goal. Further, the HITECH Act provides funding for establishing at least 70 regional centers to help promote the adoption of EHRs. These centers are to offer technical assistance, guidance, and information on best practices to help providers achieve meaningful use of EHRs. This article will define the EHR, discuss the HITECH Act EHR stimulus, and explain the problem with the HITECH Act EHR incentive time-frame. PMID- 20973377 TI - A psychosocial approach to dentistry for the underserved: incorporating theory into practice. AB - BACKGROUND: Dentistry for the underserved is more than an egalitarian social issue--it is a key factor in the health and social progress of our nation. The first signs or manifestations of several diseases such as varicella (i.e., chicken pox and shingles), STDs, and influenza become apparent in the oral cavity. The value of access to quality dentistry is an immeasurable factor in maintaining general medical health of people and fulfilling their psychosocial needs of pain reduction and enhanced cosmetics. In the United States, for the most part, only the middle and upper classes receive non-extraction, restorative, and prosthetic dentistry that is economically within their ability to pay. In addition, uninsured and poverty-level individuals often must face overwhelming long waiting lists, unnecessary referrals, lack of choice, and bureaucratic hurdles when seeking primary dental care. Therefore, it seems pertinent to put forth the question: What are the critical values and beliefs of psychosocial theory that can underscore the practice of dentistry for underserved populations in the United States? METHODS: The widely employed public health theory, the health belief model (HBM), is applied to evaluate psychosocial factors in dental care for the underserved. The HBM is used to predict and explain behavioral changes in dental health and associated belief patterns. RESULTS: The HBM as applied to dentistry for the underserved predicts self-perceptions of susceptibility and seriousness of dental disease, health status, cues to action, and self-efficacy. Furthermore, patients can make judgments about benefits, costs, and risks of dental treatment. CONCLUSIONS: A theoretical approach to dentistry employing the HBM, mediated by values and culture, can provide significant insights into patient thinking, beliefs, and perceptions. These insights can mediate access to and use of primary care dental services by underserved populations. PRACTICE IMPLICATIONS: Evidence-based practice (i.e., based on research using the scientific method) has been put forth as the future of modern dentistry. However, the practice of dentistry need not just be evidence based, but have its roots clearly grounded in theory. PMID- 20973378 TI - Resolution of lesions on STIR images is associated with improved lameness status in horses. AB - Magnetic resonance (MR) imaging is important in diagnosing musculoskeletal injuries in horses. However, there is still much to learn regarding the significance of lesions identified in equine MR images. Of particular importance is the clinical significance of signal change as a function of pulse sequence. We hypothesized that a resolution of tendon, ligament, and bone marrow lesions on short-tau inversion recovery (STIR) images would be associated with a return to soundness, and that a persistence of tendon and ligament lesions on only T1 weighted (T1w) gradient recalled echo (GRE) images would not be associated with persistent lameness. The medical records and MR images of 27 horses that had a hyperintense lesion in initial STIR MR images followed by a subsequent follow-up MR imaging examination were reviewed. Horses whose tendon or ligament lesions had resolved on STIR images at the time of the recheck examination were significantly more likely to be sound than horses whose lesions persisted on STIR images (P = 0.039). This association did not exist in horses with bone marrow lesions (P = 1.00). Horses whose tendon or ligament lesions persisted only on T1w GRE images were no more likely to be sound than horses whose lesion persisted on at least one other sequence type (P = 0.26). However, the low number of horses included in this analysis may have precluded identification of a significant difference in lameness status. Tendon or ligament lesions visualized on STIR images may represent active lesions that may contribute to lameness in the horse. PMID- 20973379 TI - Clinical magnetic resonance volumetry of the hippocampus in 58 epileptic dogs. AB - Hippocampal atrophy, which is a component of hippocampal sclerosis and recognized commonly in human intractable epilepsy, is controversial in canine epilepsy. We examined the hippocampal volume in 58 epileptic dogs and 35 control dogs using magnetic resonance (MR) images, and calculated the relative hippocampal volume asymmetry of the right and left hippocampus. Subjectively, there were visible MR imaging abnormalities in seven of the 58 epileptic dogs (12%). The hippocampel volume asymmetric ratio of epileptic dogs (5.84 +/- 4.47%) was significantly greater than that of control dogs (1.62 +/- 0.88%). Using a cutoff threshold asymmetric ratio of 6% that is indicated in human epilepsy, 28 epileptic dogs (48%) were characterized as having unilateral hippocampus atrophy. The hippocampal volume asymmetry ratio cannot be used to detect bilateral atrophy. In conclusion, although less frequent than that observed in human epilepsy patients, hippocampal atrophy may occur in canine epilepsy. PMID- 20973380 TI - Effect of head and neck position on pharyngeal diameter in horses. AB - Dynamic nasopharyngeal collapse with upper airway obstruction is an important cause of exercise intolerance in performance horses. Its underlying pathophysiology is not fully understood. We hypothesize that head position affects pharyngeal diameter, and thus head position may be a contributing factor to nasopharyngeal obstruction. Fifteen adult healthy horses were subjected to endoscopy and radiography at rest. The pharyngeal diameter was measured at nine different head and neck positions. The effect of sedation and breathing cycle on the pharyngeal diameter was determined, and the relationship between the head angle and the pharyngeal diameter was analyzed. There was a significant influence of head and neck position on pharyngeal diameter, with head position having the major effect (P < 0.001); neck position was less important, but still significant (P < 0.05). The smallest pharyngeal diameter was found at the dorsal, flexed position, which is a clinically important head position in dressage horses. The largest pharyngeal diameter was found at the extended midway position. At each head level, the pharyngeal diameter decreased with flexing the head and it increased with extending the head. The head angle was not associated with pharyngeal diameter, and neither sedation status nor breathing cycle significantly affected pharyngeal diameter. A decrease in pharyngeal diameter will limit the airflow through the upper respiratory tract, and it may result in turbulence with subsequent dynamic collapse. Head and neck position should therefore be considered a possible contributing factor in horses with suspected nasopharyngeal dysfunction. PMID- 20973381 TI - The effect of a technical quality assessment of hip-extended radiographs on interobserver agreement in the diagnosis of canine hip dysplasia. AB - Experienced and inexperienced observers evaluated the assessability of 50 radiographs (25 dogs) and determined the hip status (dysplasia/nondysplasia and final scoring according Federation Cynologique Internationale [FCI]-criteria) individually. A radiographic technical quality assessment was performed in a separate reading session. Interobserver agreement in determining dysplasia/nondysplasia and FCI-scoring did not significantly increase with the increasing quality of a radiograph, irrespective whether these observers are experienced or not. There was a significant agreement between the technical quality assessment and assessability (P < 0.0005). Despite the effort to objectify radiographic quality and to present high-quality radiographs to observers, interobserver agreement on dysplasia/nondysplasia and final scoring, remains low, even in the experienced group. Although increased radiographic quality narrows the range of scoring, the range remains unacceptably high. PMID- 20973382 TI - Imaging diagnosis--nasal septal and laryngeal cyst-like malformationsin a Thoroughbred weanling colt diagnosed using ultrasonography and magnetic resonance imaging. AB - A foal was examined for abnormal upper airway noise. Endoscopically, there were narrowed nasal passages and an extralumenal mass of the cranial trachea. Using ultrasonography and magnetic resonance (MR) imaging of the larynx and cranial cervical trachea, irregular margins of the laryngeal cartilages and first tracheal ring containing areas consistent with fluid were identified. In MR images, a widened nasal septum was seen that contained material consistent with fluid. Postmortem examination confirmed the diagnosis of nasal septal, laryngeal, and cranial cervical tracheal cyst-like lesions. This is a unique congenital condition, in which premortem imaging was instrumental in defining the abnormalities. PMID- 20973383 TI - Imaging diagnosis--celiac artery pseudoaneurysm associated with a migrating grass awn. AB - The ultrasound and computed tomography findings of a retroperitoneal pseudoaneurysm associated with a grass awn are described in a 10-month-old dog. Ultrasound was used to localize the lesion and surrounding reaction as well as to determine its relationship with the celiac artery, but inadequate Doppler settings hindered the diagnosis of its vascular nature. Dual phase CT enabled further characterization, particularly its close relationship with the major retroperitoneal vessels. The imaging examination was fundamental in recommending nonsurgical therapy. The dog died as a consequence of the rupture of this pseudoaneurysm. A grass awn was confirmed. PMID- 20973384 TI - Imaging diagnosis--intrapericardial right auricle aneurysm in a dog. AB - An 11-year-old, male, Pekinese was examined because of a sporadic, nonresponsive, nonproductive cough. Radiographically there was cardiomegaly and a soft tissue mass in the cranial mediastinum. Echocardiographically, chronic degenerative valvular disease was diagnosed. Furthermore, a large anechoic structure located cranial to the right atrium was detected. Computed tomography was performed to define the mediastinal mass and a right auricle aneurysm was diagnosed. The dog died suddenly 1 day after the diagnostic imaging procedures. At necropsy, a right auricular aneurysm without discontinuity of the pericardial sac was confirmed. Intrapericardial right auricular aneurysm should be included in the differential diagnoses of cranial mediastinal masses. PMID- 20973385 TI - Contrast harmonic ultrasonographic appearance of focal space-occupying renal lesions. AB - To describe the contrast-enhanced ultrasonographic appearance of various focal, space-occupying renal lesions and determine its value in their detection and characterization. Following baseline B-mode sonography of 15 dogs and one cat with renal space-occupying lesion(s), contrast-enhanced sonography was performed. The resulting images were evaluated qualitatively using conspicuity and number of lesions, and enhancement patterns were assessed during early arterial and late corticomedullary phases. Renal lesions were malignant in the cat (renal cell carcinoma) and 10 dogs (four renal cell carcinoma, two histiocytic sarcoma, one B cell lymphoma, two hemangiosarcoma metastasis, one ch emodectoma metastasis) and benign in five dogs (two abscesses, one traumatic hematoma, one idiopathic hematoma, one hemorrhagic/necrotic nodule). Substantial overlap was present regarding the baseline sonographic features of benign vs. malignant lesions. With contrast-enhanced sonography, all renal cell carcinomas were characterized by large tortuous arteries, sometimes enhancing slightly earlier than vessels in the surrounding normal kidney. During the late corticomedullary phase, renal cell carcinomas had intense homo- or heterogeneous, iso- or slightly hypoechoic enhancement, which decreased progressively. Compared with renal cell carcinoma, histiocytic sarcoma and lymphoma had smaller and less obvious arteries, and an earlier loss of enhancement during the late phase. All hemangiosarcoma metastases appeared as nonenhancing nodules during the early arterial and late corticomedullary phases of enhancement, and additional lesions were detected. Histiocytic sarcoma and benign lesions had increased conspicuity with baseline sonography. The descriptions provided herein will be valuable as more work is done to establish the role of contrast-enhanced sonography in the assessment of renal lesions. PMID- 20973386 TI - Ultrasonographic appearance of the intravascular transit of agitated saline in normal dogs following ultrasound guided percutaneous splenic injection. AB - Portosystemic shunts (PSSs) allow portal blood to bypass the liver and enter the systemic circulation. Definitive diagnosis requires surgical identification, positive contrast portography, ultrasonography, or scintigraphy. This study was designed as a preliminary step to developing an alternative/adjuvant protocol to these imaging modalities. The main goals were to establish a technique for ultrasound-guided percutaneous trans-splenic injection of agitated saline, to evaluate the feasibility of performing the test to explore the postsplenic portal vasculature highlighted by the microbubbles, and to ascertain whether agitated saline microbubbles cross the sinusoidal barrier. Agitated saline was injected into the spleen of 20 healthy sedated dogs under sonographic guidance. The transducer was then repositioned to visualize the portal vein, the caudal vena cava, and the right atrium through different acoustic windows. Satisfactory results were achieved in all dogs. The microbubbles were visualized in all dogs as small intense echo signals within the portal vein at the level of the porta hepatis immediately after injection. In 18 out of 20 dogs, the echogenic signal of the microbubbles disappeared immediately once within the hepatic parenchyma, whereas in two dogs, the echoes from the microbubbles lasted for several seconds within the intrahepatic portal vasculature. The absence of microbubbles beyond the sinusoidal barrier in all of the healthy dogs included in this study makes trans-splenic injection of agitated saline a candidate as an adjuvant technique for the diagnosis of PSS, being easy to perform and repeat, as well as safe and technically feasible. PMID- 20973387 TI - Ultrasonographic percutaneous anatomy of the caudal lumbar region and ultrasound guided lumbar puncture in the dog. AB - Subarachnoid lumbar puncture is used commonly in the dog for cerebrospinal fluid collection and/or myelography. Here in we describe the percutaneous ultrasound anatomy of the lumbar region in the dog and a technique for ultrasound-guided lumbar puncture. Ultrasound images obtained ex vivo and in vivo were compared with anatomic sections and used to identify the landmarks for ultrasound-guided lumbar puncture. The ultrasound-guided procedure was established in cadavers and then applied in vivo in eight dogs. The anatomic landmarks for the ultrasound guided puncture, which should be identified on the parasagittal oblique ultrasound image are the articular processes of the fifth and sixth lumbar vertebrae and the interarcuate space. The spinal needle is directed under ultrasound-guidance toward the triangular space located between the contiguous articular processes of the fifth and sixth lumbar vertebrae and then advanced to enter the vertebral canal. Using these precise ultrasound anatomic landmarks, an ultrasound-guided technique for lumbar puncture is applicable in the dog. PMID- 20973388 TI - Ultrasonographic findings in the lumbosacral joint of 43 horses with no clinical signs of back pain or hindlimb lameness. AB - The transrectal ultrasonographic appearance of the lumbosacral joint was assessed in 43 horses with no history or clinical evidence of back pain or hindlimb lameness. In the majority of horses (34/43, 79.1%) the lumbosacral disc had uniform or mildly heterogeneous echogenicity. However, variation in the ultrasonographic appearance of the lumbosacral joint was also identified, including hyperechogenic regions within the lumbosacral disc with or without an acoustic shadow, and mild or moderate irregularity of the opposing surfaces of the last lumbar and the first sacral vertebral bodies. Marked irregularity of the bony surfaces or marked disruption of the lumbosacral disc was not seen in any horse. The mean distance between the ventral aspects of the last lumbar and first sacral vertebrae was 14.2 mm (range: 7.1-26.5 mm, median: 14.4 mm). The degree of protrusion of the ventral aspect of the lumbosacral disc ranged from 0 to 5 mm (mean: 1.32 mm, median: 1.2 mm). The mean angle between the ventral surfaces of the last lumbar and first sacral vertebrae was 147 degrees (range: 118-165 degrees, median: 150 degrees). There was no significant effect of age, breed, gender, or the size of the horses on either subjective findings in the lumbosacral joint or objective measurements. PMID- 20973389 TI - Transrectal ultrasonography of the left adrenal gland in healthy horses. AB - Little information is available on medical imaging of the adrenal glands in horses. We investigated the feasibility of transrectal ultrasonography to characterize the normal equine adrenal gland. Transrectal ultrasonography was performed in 25 healthy horses using a 7.5 MHz linear array probe at a displayed depth of 8 cm. Transrectal ultrasonography of the right adrenal gland was not feasible. For the left adrenal gland, the left kidney, the abdominal aorta, the left renal artery, the left renal vein, and the cranial mesenteric artery were used as landmarks. The size of the left adrenal gland was variable, but it generally appeared as a long, flat structure with a hyperechoic medulla surrounded by a hypoechoic cortex. The most cranial part of the gland could not be delineated appropriately in 11 horses (44%). The mean (+/-SD) thickness of the gland and medulla was 0.66 +/- 0.15cm (n = 25) and 0.28 +/- 0.09 cm (n = 25) near the caudal pole, 0.87 +/- 0.25 cm (n = 14) and 0.40 +/- 0.18 cm (n = 12) near the cranial pole, and 0.89 +/- 0.18 cm (n = 25) and 0.36 +/- 0.13 cm (n = 25) in the middle of the gland, respectively. The mean (+/-SD) length of the entire adrenal gland and of the medulla was 6.22 +/- 0.77 cm (n = 14) and 5.45 +/- 0.71 cm (n = 6), respectively. Transrectal ultrasonography allowed adequate visualization of the left adrenal gland in horses. PMID- 20973390 TI - An in-house phantom as an alternative to commercially available Doppler flow phantoms. AB - Learning the principles and application of Doppler ultrasound is difficult and requires repeated practice. Flow phantoms provide a method of teaching Doppler techniques before their application in clinical patients; however, commercially available flow phantoms are expensive. Herein we describe an easily constructed, economic Doppler flow phantom, utilizing readily available products, for use as a training aid. PMID- 20973391 TI - Ultrasonographic features of pyonephrosis in dogs. AB - Pyonephrosis refers an infected hydronephrotic kidney which arise from pyelonephritis followed by exudate accumulation in a dilated renal pelvis or hydronephrosis followed by ascending infection. Pyonephrosis may cause serious systemic complications, making prompt and reliable diagnosis critical. Clinical and ultrasonographic findings are used for the diagnosis of pyonephrosis in humans, but these findings have not been investigated in dogs. We reviewed ultrasonographic features in pyonephrosis in 18 dogs. Ten dogs with hydronephrosis were also evaluated to compare with the pyonephrosis patients. In most dogs with pyonephrosis, hyperechoic contents completely filled the dilated renal pelvis (n = 8) or a fluid-debris level was observed (n = 8). Hyperechoic contents were dispersed in renal pelvis in only two of the 18 dogs. Hyperechoic, edematous mesentery, and peritoneal and retroperitoneal effusion, which represented peritoneal and retroperitoneal inflammation, were observed in the perinephric region in 11 dogs. Compared with pyonephrosis, and as expected, hydronephrosis was characterized by anechoic contents within the urine-filled collecting system and there were no definitive findings to suspect peritonitis. Thus, there is a distinct difference in the sonographic appearance of pyonephrosis vs. hydronephrosis in dogs. PMID- 20973392 TI - Calculation and usage of the thyroid to background ratio on the pertechnetate thyroid scan. AB - Feline hyperthyroidism is a common endocrine disorder. A single dose of 148MBq (4mCi) 131I is 95-98% effective for the treatment of hyperthyroidism in cats; however, the cause for treatment failures has not been determined. In a series of 113 hyperthyroid cats having pertechnetate thyroid scintigraphy before treatment using a standard 148MBq (4mCi) 131I dose, the thyroid to salivary gland (T:S) ratio and the thyroid to background (T:B) ratio were calculated. Results in 107 (95%) cats successfully treated were compared with results in six (5%) cats that remained hyperthyroid after treatment. T:B ratio was significantly higher for cats that had treatment failure (median 13.0, range 3.6-73.0) than for cats successfully treated (median 4.4, range 1.2-69.0) (P = 0.02), whereas there was no significant difference in their T:S ratios (P = 0.2). The T:B ratio is a new approach to evaluating the thyroid pertechnetate scan with the intent of identifying which hyperthyroid cats may fail treatment using a standard 148 MBq (4 mCi) 131 dose and which, therefore, require a higher dose. PMID- 20973394 TI - The incriminating role of reactive oxygen species in idiopathic male infertility: an evidence based evaluation. AB - The male factor is considered a major contributory factor to infertility. Apart from the conventional causes for male infertility such as varicocoele, cryptorchidism, infections, obstructive lesions, cystic fibrosis, trauma and tumours, a new and important cause has been identified as being responsible for the so-called idiopathic male infertility: oxidative stress. Oxidative Stress (OS) is a condition that occurs when the production of Reactive Oxygen Species (ROS) overwhelms the antioxidant defense produced against them. In male reproductive pathological conditions, the OS significantly impairs spermatogenesis and sperm function, which may lead to male infertility. Reactive Oxygen Species (ROS) known as free radicals are oxidizing agents generated as a result of metabolism of oxygen and have at least one unpaired electron that make them very reactive species. Spermatozoa generate Reactive Oxygen Species (ROS) in physiological amounts, which play a role in sperm functions during sperm capacitation, Acrosome Reaction (AR) and oocyte fusion, but they need to be controlled and their concentrations maintained at a level that is not deleterious to the cells. Administration of antioxidants in patients with 'male factor' infertility has begun to attract considerable interest. The main difficulty of such an approach is our incomplete understanding of the role of free radicals in normal and abnormal sperm function leading to male infertility. The purpose of the present review is to address the relationship between ROS and idiopathic male factor infertility. PMID- 20973393 TI - Proof of principle of ocular sparing in dogs with sinonasal tumors treated with intensity-modulated radiation therapy. AB - Intensity-modulated radiation therapy (IMRT) allows optimization of radiation dose delivery to complex tumor volumes with rapid dose drop-off to surrounding normal tissues. A prospective study was performed to evaluate the concept of conformal avoidance using IMRT in canine sinonasal cancer. The potential of IMRT to improve clinical outcome with respect to acute and late ocular toxicity was evaluated. Thirty-one dogs with sinonasal cancer were treated definitively with IMRT using helical tomotherapy and/or dynamic multileaf collimator (DMLC) delivery. Ocular toxicity was evaluated prospectively and compared with a comparable group of historical controls treated with conventional two-dimensional radiotherapy (2D-RT) techniques. Treatment plans were devised for each dog using helical tomotherapy and DMLC that achieved the target dose to the planning treatment volume and limited critical normal tissues to the prescribed dose volume constraints. Overall acute and late toxicities were limited and minor, detectable by an experienced observer. This was in contrast to the profound ocular morbidity observed in the historical control group treated with 2D-RT. Overall median survival for IMRT-treated and 2D-treated dogs was 420 and 411 days, respectively. Compared with conventional techniques, IMRT reduced dose delivered to eyes and resulted in bilateral ocular sparing in the dogs reported herein. These data provide proof-of-principle that conformal avoidance radiotherapy can be delivered through high conformity IMRT, resulting in decreased normal tissue toxicity as compared with historical controls treated with 2D-RT. PMID- 20973395 TI - Antidiabetic effect of essential oil from Artemisia sieberi growing in Jordan in normal and alloxan induced diabetic rats. AB - The aim of this study was to evaluate the effects of essential oil extracted from aerial parts of Artemisia sieberi in normal and alloxan induced diabetic rats. Fifty rats were divided into five groups of 10 each. Group I normal rats received 1 mL day(-1) of dimethyl sulfoxide (control); group II normal rats received a single dose (80 mg kg(-1) b.wt.) of essential oil extract of Artemisia sieberi; group III diabetic rats received 1 mL day-of dimethyl sulfoxide; group IV diabetic rats received the oil extract (80 mg kg(-1) b.wt.); group V diabetic rats received metformin (14.2 mg kg(-1) b.wt.). All treatments were orally administered once a day for six weeks. Changes in blood glucose concentration, body weight and food and water intake were measured and the data obtained were compared with that of metformin. The essential oil extract significantly (p < 0.05) lowered blood glucose level as well as food and water intake in diabetic rats accompanied by an increase in body weight gain with no apparent side effect when compared with untreated diabetic rats. These effects were found to be closely similar to that of metformin, a common antidiabetic drug. On other hand, no apparent improvement on body weight gain in diabetic rats treated with metformin. In addition, for all parameters measured, the oil extract showed no effect in normal rats. In conclusion, the essential oil of Artemisia sieberi exhibited antidiabetic activity in alloxan-induced diabetic rats. Present findings support the possible use of the essential oil of Artemisia sieberi as a remedy for diabetes mellitus in humans. PMID- 20973396 TI - Effect of bright light on shift work nurses in hospitals. AB - The aim of this study are to assess, in a hospital setting, the effects of Bright Light (BL) on the rhythms in body temperature, plasma melatonin, plasma cortisol and subjective alertness during shift work. In our experimental design, 34 healthy shift work nurses from a university hospital were exposed to bright light (4500 lux) during two break times (21:15 to 22; 00 and 3:15 to 4:00) for four consecutive weeks. In this survey, the subjects were studied under 24 h of realistic conditions during which their plasma cortisol and plasma melatonin was measured at 3 h intervals. In addition, their body temperatures were measured during and after night shift work. Subjective alertness and fatigue were evaluated with the Karolinska Sleepiness Scale (KSS) and Visual Analog Scale (VOI). It was found that bright light administration significantly suppressed nighttime melatonin levels during night shift, most strongly at 2:00 a.m. A one way ANOVA, with repeated measurement design, revealed that Bright Light (BL) tended to increase cortisol levels and body temperature and improved alertness significantly during night shift. These results demonstrate that photic stimulation in a hospital setting can have a powerful influence on the adjustment of the circadian system. PMID- 20973397 TI - Hypocalcemic seizures in breastfed infants with rickets secondary to severe maternal vitamin D deficiency. AB - This study was done to evaluate if nursing mothers of infants with rickets have vitamin D deficiency, and to evaluate the relationship between maternal vitamin D levels with hypocalcemic seizures in infants with rickets. We selected a cohort of breastfed infants with rickets. Infants were included in this study if they were breastfed and presented with any of the following clinical criteria: delayed motor milestones or delayed teething, were found to have specific rachitic bony signs, or presented with hypocalcemic seizures. We checked serum calcium (Ca), phosphorus (P), alkaline phosphatase, 25 hydroxy vitamin D [25(OH)D] and parathyroid hormone (PTH) levels in both infants and their mothers. Out of 32 children who met the clinical criteria for rickets, 23 (72%) had vitamin D level less than 20 ng mL(-1). Twenty two mothers (69%) had vitamin D deficiency (25 hydroxy vitamin D < 20 ng mL(-1)). Mothers of nine infants who presented with hypocalcemic seizures had severe vitamin D deficiency, (p = 0.005). We conclude that maternal vitamin D deficiency is common in nursing mothers of infants diagnosed with rickets. Invariably mothers of infants presenting with hypocalcemic seizures have severe vitamin D deficiency. Hypocalcemic seizures in infants secondary to maternal vitamin D deficiency might be prevented by supplementation of vitamin D. PMID- 20973398 TI - Symptomatologic versus neuroimaging predictors of in-hospital survival after intracerebral haemorrhage. AB - Symptomatological prediction of Intracerebral haemorrhage (ICH) mortality is a simple and effective method compared to pathological predictors. In this study we considered consciousness level as an easily measurable predictor and compared it to haemorrhage location, intraventricular penetration and haemorrhage size derived from Computerized Tomography (CT) to predict mortality using a parametric survival analysis model. Two hundred and thirty eight ICH patients from a neurology hospital ward were enrolled into this comparative study. Patient history was documented with respect to mortality and a questionnaire outlining background variables and medical history was completed for them. Consciousness level was clinically evaluated by a physician while haemorrhage size and location were determined via computerized tomographic scanning reports. Data were entered into the computer and analyzed according to the Weibull parametric survival analysis model using STATA 8 statistical software. Males constituted 47.1% of the 238 patients, 52.9% were females. The age range of the patients varied from 13 to 88 years, with a mean age of 62.4 +/- 13.6 (Mean +/- SD). Half of the patients survived more than 20 days. Using the Weibull regression model, the only significant independent symptomatological predictor of mortality was found to be the level of consciousness. Cumulative hazard during the 90 days was compared for different levels of consciousness. Application of Weibull to pathological predictors of ICH mortality showed that the two independent predictors were haemorrhage size and intraventricular penetration. Results of statistical modelling didn't provide evidence of priority for pathological predictors of survival compared to easily measurable levels of consciousness as a symptomatological predictor. Easily measurable symptoms of level of consciousness can be used as a survival predictor of stroke due to intra-cerebral haemorrhage when compared to pathological indicators. PMID- 20973399 TI - Assessment of coagulation state and its related factors in thalassemia intermedia patients referred to thalassemia research center at Booali Sina Hospital Sari/IR Iran in 2007. AB - A high incidence of thromboembolic events have been reported among thalassemia intermedia patients especially in splenectomized patients. This study has been conducted to evaluate the coagulation state of patients referred to thalassemia research center at Booali Sina Teaching Hospital, Sari, Iran. This descriptive cross sectional study was performed in 2007. Sixty thalassemia intermedia patients aged older than 10 years were enrolled. After recording demographic and therapeutic data of the participants, the plasma levels of Coagulant factors were measured. Obtained Data were analyzed using SPSS 13 software and t-test and chi square tests. Of 60 studied patients, 62% were female. The mean age of the patients was 26.6 +/- 9.3 years. ASA tablet were used in 53.3%. None of the patients have experienced thromboembolic events. Decrease in protein C has been observed in 60%. Antithrombin III was decreased in 42% and protein S declined in 10% of the patients. Mutation in factor V leiden was seen in 3%. Splenectomy performed in 53.3% and there was no significant relation between low level of protein C and protein S, antithrombin III and presence of factor V Leiden with splenectomy (p > 0.05). Regarding to the high incidence of low levels of protein C, protein S and antithrombin III among thalassemia intermedia patients, there is an increased risk of thromboembolic events in the patients. PMID- 20973400 TI - Antifungal activity of extracts of Rosmarinus officinalis and Thymus vulgaris against Aspergillus flavus and A. ochraceus. AB - The antifungal activity of ethanolic extracts of Rosmarinus officinalis and Thymus vulgaris were tested against strains of Aspergillus flavus and A. ochraceus, since these two species are common contaminants of cereals and grains and are able to produce and accumulate mycotoxins. The methodology used is based on measuring the inhibition halos produced by discs impregnated with the extracts and establishing their Minimum Inhibitory Concentration (MIC) as well as the Minimum Fungicide Concentration (MFC). The results obtained suggest that the assayed extracts affect the proper development of A. flavus and A. ochraceus; leading to a lower MIC (1200 ppm) and MFC (2400 ppm) for T. vulgaris extract against A. ochraceus than against A. flavus. The results show, that the extracts of Rosmarinus officinalis and Thymus vulgaris used at low concentrations could have significant potential for the biological control of fungi in foodstuffs. PMID- 20973401 TI - Etiology of pediatric chronic kidney diseases in north-west of Iran. AB - The aim of this study was to evaluate the etiology of pediatric Chronic Kidney Disease (CKD) in a tertiary care hospital in north-west of Iran. Medical records of admitted children with CKD in Children's Hospital of Tabriz from 1999 to 2009 were studied retrospectively. CKD was defined as GFR less than 60 mL min(-1) 1.73 m2 for more than 3 month. The etiology of CKD was determined by clinical, biological, radiological and histopathological examination. During 10 years 115 children including 61 boys (53%) and 54 girls (47%) were studied. The mean age of patients was 8.1 +/- 3.53 years (range: 4 months to 14 years). Urological abnormalities were the most common cause of CKD (36.5%) followed by acquired glomerular diseases (23.5%), hereditary nephropathies (21.7%), unknown etiology (9.5%) and systemic diseases (6%). The most common urologic anomaly was vesicoureteral reflux (VUR) that accounted for 24.3% of total etiologies followed by obstructive uropathies. Focal segmental glomerulosclerosis was the most frequent glomerular disease and was responsible for 13.9% of patients. Nephronophtisis, cystinosis, infantile polycystic disease and congenital nephrotic syndrome were the most frequent hereditary nephropathies in a descending order. Frequency of parental consanguinity in patients with hereditary nephropathy was significantly higher than other patients (p = 0.001). High frequency of VUR in present study compared with developed countries necessitates more efforts for improving the management and follow up of urinary tract infections. PMID- 20973402 TI - The survey of Helicobacter pylori infection in infant. AB - This present study was designed to determine the prevalence of H. pylori in infants and correlation of this infection with age. In a prospective descriptive study in Tabriz children hospital, we conducted analysis of children within age 2 year or younger who had H. pylori infection that were diagnosed with endoscopies and biopsy. Prevalence of infection was higher in the infants whose mothers had a low education level (p = 0.045). The H. pylori prevalence didn't differ between exclusively breastfeeding to six months and infants who had never breast fed (26.6% vs. 13.3%) (p = 0.2). We could not find any correlation between rate of infection and age of patients which used by regression model for analysis and t test (p = 0.5). Based on our study the prevalence of H. pylori infection in infants living in North West of Iran was low. We could not find any correlation between rate of infection and age of patients. PMID- 20973403 TI - Bactericidal efficacy of electrochemically activated solutions and of commercially available hypochlorite. AB - Electrochemical activation (ECA) has been developed as a quick and efficient method of hypochlorite production, and many claim increased efficacy when compared to conventional disinfectant solutions. Numerous potential applications, including hospital disinfection, waste-water treatment, routine drinking water disinfection and biological decontamination have been suggested. In this study, three solutions were produced by electrochemical activation of 0.5% NaCl and compared to commercially available NaOCl. The NaOCl concentration and pH of each solution was measured, and the minimum bactericidal concentration of each was determined using seven common microbial pathogens. All solutions were effective, the most significant of which was the ECA anolyte solution. This is notable due to its neutral pH and antimicrobial efficacy that is four times that of commercially available NaOCl. This process may lead to production of a highly effective yet non-caustic disinfectant that would have countless scientific, medical, military and public health applications. PMID- 20973404 TI - Potential biomarkers for differentiation of benign prostatic hyperplasia and prostate cancer. AB - This study aims to evaluate the role of free/total prostate-specific antigen (PSA) ratio, serum total sialic acid level and cathepsin D activity in the differentiation of prostate cancer and benign prostatic hyperplasia (BPH). The study looked at 100 patients with BPH, 75 patients with organ-confined or locally advanced prostate cancer, and a control group of 50 healthy volunteers. Prostate cancer patients showed significantly higher total sialic acid level and cathepsin D activity and lower free/total PSA ratio than those in the BPH group. The results suggest that combined measurement of serum total sialic acid and/or cathepsin D activity with free/total PSA ratio could serve as a useful adjunct to conventional diagnostics for the differentiation of prostate cancer and BPH. PMID- 20973405 TI - Stability of haematology parameters on the LH750: comparison of Sarstedt Monovettes and BD Vacutainers. AB - Haematological analysis of white blood cells, red blood cells and platelets is used to aid diagnosis and treatment. Although most laboratories aim to analyse haematology samples on the day of collection, this is not always possible, particularly when the laboratory is remote from the patient. The integrity of a haematological sample is known to depend on time and temperature: measurement technique has already been found to have an impact on stability. This study aims to evaluate whether or not the type of EDTA specimen tube affects the stability, and the effect on stability using two commonly used blood collection systems (Becton Dickinson Vacutainers and Sarstedt Monovettes). Blood was drawn from 20 volunteers and stored refrigerated. Haematological analysis was conducted on a Beckman Coulter LH750 haematology analyser at multiple time points up to 72 h. The results were examined using analysis of variance (ANOVA), to look for imprecision both within-run and between run. Stability assessment was performed using an in-house method based on the manufacturer's stated precision limits. An analyte was classed as unstable when the cumulative SD/CV exceeded the precision limits of that assay. The method used to assess stability was found to provide robust stability information that matched data provided by the manufacturer and other researchers. Accurate full blood count results can be obtained on samples up to 48 h, provided that the samples are stored in a refrigerator. The tube type was found to have minimal impact on the stability of haematological samples. PMID- 20973406 TI - Crystal violet staining to quantify Candida adhesion to epithelial cells. AB - In vitro studies of adhesion capability are essential to characterise the virulence of Candida species. However, the assessment of adhesion by traditional methods is time-consuming. The aim of the present study is the development of a simple methodology using crystal violet staining to quantify in vitro adhesion of different Candida species to epithelial cells. The experiments are performed using Candida albicans (ATCC 90028), C. glabrata (ATCC 2001), C. parapsilosis (ATCC 22019) and C. tropicalis (ATCC 750). A human urinary bladder epithelial cell line (TCC-SUP) is used. Yeast and epithelial cells were stained with crystal violet, epithelial cells were then destained using intermediate washing, and the dye in the yeast cells was extracted with acetic acid. The method was validated for the different Candida reference species by comparison with traditional microscope observation and enumeration. The method was then used to assess Candida adhesion to epithelial cells and also to silicone. For all Candida spp. high correlation values (r2= 0.9724-0.9997) between the number of adherent yeasts (microscope enumeration) and absorbance values were obtained for an inoculum concentration >10(6) cells/mL. The proposed technique was easy to perform and reproducible, enabling the determination of adhesion ability of Candida species to an epithelial cell line. PMID- 20973407 TI - Non-coding small (micro) RNAs of Pseudomonas aeruginosa isolated from clinical isolates from adult patients with cystic fibrosis. AB - MicroRNAs are a class of small non-coding RNAs widely reported in eukaryotic multicellular organisms. In this study, a number of small non-coding micro (mi)RNA species in clinical isolates of prokaryote Pseudomonas aeruginosa were obtained from the sputum of adult patients with cystic fibrosis (CF) utilising a DynaExpress miRNA cloning kit, and five miRNAs of 16-47 nucleotides that were smaller than those encountered or described (80-100 nucleotides) previously in bacterial systems were described. This report presents data on these unknown cellular miRNAs cloned from P. aeruginosa isolates from CF patients. Adapting a computational miRNA prediction model that takes advantage of the highly conserved known miRNA hair pin stems regions, the results revealed that the fold structure of the microRNAs had a high homology to the recently reported human bacterial infection response (BiR)-related microRNA, mi-146, associated with the Toll-like receptor (TLR) family, which is the primary evolutionarily conserved sensors of pathogen-associated molecular patterns (PAMPs), and known to trigger host inflammatory and immune responses. PMID- 20973408 TI - Structural analysis and expression of the full-length cytochrome P450 gene operon in Campylobacter lari. AB - Two sets of PCR primers are constructed to clone the cytochrome P450 structural gene, including putative promoter and terminator structures, and its adjacent genetic loci in Campylobacter lari isolates. The putative open reading frames (ORFs) of the P450 genes from 11 C. lari isolates (n=5 for urease-negative (UN) C. lari; n=6 urease-positive thermophilic campylobacters [UPTC]) examined consisted of 1365 or 1371 bases (455 or 457 amino acid residues), differing from those of the other thermophilic campylobacters (1359 [453] for C. jejuni and C. upsaliensis; 1368 [456] for C. coli). Each of the putative ORFs from the 11 isolates examined was also shown to carry start and stop codons and ribosome binding sites. Two putative promoter structures, consisting of sequences at the 35- and -10-like regions were also identified upstream of the ORFs. A single copy of the P450 gene in the genome was identified with UN C. lari JCM2530(T) and UPTC CF89-12, based on Southern blot hybridisation analysis. In addition, when reverse transcription polymerase chain reaction (RT-PCR) analyses were carried out, the transcription of the P450 structural gene in C. lari organisms in vivo was confirmed. The transcription initiation site for the gene was also determined. High nucleotide sequence similarities (95.2-98.8%) of the full-length P450 structural gene were shown with each of the 12 C. lari isolates. The UN C. lari and UPTC organisms showed similar findings with the neighbour-joining method, based on the sequence information of the P450 structural gene. PMID- 20973409 TI - Hepatitis C virus prevalence and serotypes associated with HIV in The Gambia. AB - Hepatitis C virus (HCV) serotypes are important in the epidemiology and pathogenesis of HCV-related disease, but little is known of this connection in West Africa. Coinfection with human immunodeficiency virus (HIV) is associated with significant morbidity and mortality. This study aims to determine the prevalence of HCV and its serotypes associated with HIV in The Gambia. A total of 1500 individuals referred to the Royal Victoria Teaching Hospital for HIV serology between July and December, 2002 were screened for antibodies to HIV and subsequently for HCV, and seropositive samples were typed. This study shows HIV and HCV prevalence of 6.7% and 1.6%, respectively, with a co-infection rate of 0.6%. Serotype 2 showed the highest prevalence (58.1%), followed by serotype 1 (19.4%). Prevalence of HCV serotype 3 was 6.5% and five samples were untypeable. Co-infection of HIV-1 with HCV serotype 1 showed a prevalence of 44.4%, and with HCV serotype 2 of 33.3%. The findings support the evidence to suggest the West African subregion as the origin of HCV serotype 2. It also demonstrates the need for routine HCV screening of HIV-infected persons and blood donations, and calls for further studies to elucidate the sources of the HCV virus. PMID- 20973410 TI - Assessment of inhibition/growth-promoting properties of new agents on moulds: description of a simple bio-imaging technique. PMID- 20973411 TI - Susceptibility of Escherichia coli and Staphylococcus aureus isolates from a district general hospital in the U.K. to tigecycline and other antimicrobials. PMID- 20973412 TI - The lactate gap revisited: variable interference with lactate analyses in ethylene glycol poisoning. PMID- 20973413 TI - Evaluation of the Sebia Capillarys zone electrophoresis system for monoclonal paraprotein analysis. PMID- 20973414 TI - Hyperchromatic crowded cell groups in gynaecological liquid-based cytology samples. AB - Cervical cytology screening is a complex and demanding procedure. Correct diagnosis depends on accurate interpretation of cells, including dense clusters known as hyperchromatic crowded cell groups (HCCG). These groups are frequently encountered in liquid-based cytology (LBC) samples and can be difficult to identify as a specific cell type. Although usually benign and thus often overlooked, they may occasionally represent severely abnormal cells. Thus, their correct interpretation is vital for accurate reporting. Such groups are responsible for false-positive and false-negative reporting and have been implicated in cases of missed dyskaryosis and cervical cancer. Normal and abnormal cells of both squamous and glandular origin, together with non epithelial elements, may present as HCCG and this review uses the authors' experience with SurePath to describe the morphological criteria used to evaluate them when screening. Despite the introduction of semi-automated screening systems for LBC, there is currently no complete replacement for human interpretation of cell morphology in cytology screening. PMID- 20973415 TI - New Dentistry Today Web site launched! PMID- 20973416 TI - Medical emergencies: are you prepared? AB - Billy Tyne sailed ill-equipped directly into a "perfect storm" at the cost of his boat, his crew, and his life. As a profession, we must not allow our own hubris to ignore the challenges that we are now facing: increasingly complex medical histories, more patients desiring sedation treatment, and more dentists expanding their scope of clinical services. Sadly, a nationally recognized set of guidelines has yet to be adopted. In the meantime, each member of the profession must be prepared to properly respond to any medical crisis that may occur in the dental office. The 6 links of survival provides a solid basis to meet that need. PMID- 20973417 TI - Wyatt Wilson, Acteon Group. Interview by Damon Adams. PMID- 20973418 TI - Pathogenesis of periodontitis: role of cytokines in host response. AB - There is no doubt that plaque bacteria are necessary to initiate disease and drive the chronic inflammatory response in the periodontal tissues. At the same time, there is strong evidence that destructive processes occurring as part of the host inflammatory response are responsible for the majority of the hard- and soft-tissue breakdown leading to the clinical signs of periodontitis. The characteristic clinical signs of chronic periodontitis occur mainly as a result of activation of host-derived immune and inflammatory defense mechanism. IL-1 and TNF induce expression of other mediators that amplify the inflammatory response, such as prostaglandins, and lead to production of lytic enzymes and stimulate the production of chemokines. Investigations on the soluble protein delivery of antagonists to IL-1 and TNF in animal models have shown promising results. Collectively, the clinical, radiographic, and biochemical findings of these experiments show that IL-1 and TNF-alpha antagonists block the progression of the inflammatory cell infiltrate towards the alveolar crest and the recruitment of osteoclasts, and prevent the periodontal lesions may destroy the soluble cytokine antagonists prior to their peak activity, which may necessitate more frequent administration of the active agents to the defects. Thus, gene transfer of TNF receptor antagonists and IL-1ra may offer a more efficient mode of delivery of disease controlling agents to the periodontal structures. Periodontal treatment through the ages has focused on the reduction of bacterial infection by mechanical removal of infectious agents (i.e., SRP). Attempts at elimination of infectious agents often do not represent a definitive therapy in periodontitis, necessitating the administration of more sophisticated biological treatment modalities. A thorough understanding of the host inflammatory response in periodontal pathogenesis presents the opportunity for exploiting new treatment strategies for periodontitis by means of host response modulation. The rationale behind this approach is to aid the host in its fight against infectious agents by supplementing the natural inherent defense mechanism or to modify its responses by changing the course of inflammatory systems. Therefore, pharmaceutical inhibition of host response pathways that mimic endogenous anti-inflammatory mechanisms may prove to be an effective strategy for treating periodontal diseases. This would require the development of polypharmaceutical approaches controlling all pathways associated with inflammation and tissue destruction. Current research has focused on the use of SDD as a treatment modality, and SDD is the only systemically used host modulatory drug approved by the United States Food and Drug Administration. PMID- 20973419 TI - Aesthetic success: tissue management and impressions. PMID- 20973420 TI - Aesthetic treatment of dark root syndrome. PMID- 20973421 TI - Reduce seating times with digital technology: a case report. PMID- 20973422 TI - The endodontic Glidepath: "Secret to rotary safety". AB - The endodontic Glidepath is the secret to radicular rotary safety. This article has offered a definition of Glidepath, explained why it is important in producing optimum endodontic mechanics, and described how to prepare a Glidepath for radicular shaping. Four obstacles to Glidepath preparation have been identified along with the solution for each one. Four manual motions have been distinguished that, if used properly, will produce a safe rotary result and an endodontic experience that you truly control. PMID- 20973423 TI - Joint vibration analysis in routine restorative dentistry. PMID- 20973424 TI - Reinforcing the basics of infection control. PMID- 20973425 TI - Improving implant impressions. PMID- 20973426 TI - Stabilizing partial dentures using small-diameter implants. PMID- 20973428 TI - Ergonomic positioning: a few degrees add years to your career. PMID- 20973427 TI - The E-appliance: an invaluable therapeutic tool. PMID- 20973429 TI - Lead and bisphenol A concentrations in the Canadian population. AB - BACKGROUND: Lead is a known toxicant that occurs naturally in the environment. Bisphenol A (BPA) is an industrial chemical used primarily in polycarbonate plastic and epoxy resins. It has been 30 years since lead exposure was measured at a national level, and it is the first time for a national assessment of BPA exposure. DATA AND METHODS: Data are from the 2007-2009 Canadian Health Measure Survey. Lead in whole blood (PbB) and urinary BPA were measured in 5319 and 5476 respondents aged 6 to 79, respectively. Geometric means (GMs) are presented by age group and sex for PbB (pg/dL), volume-based BPA (microg/L), and creatinine standardized BPA (microg/g creatinine). Adjusted least squares geometric means (LSGMs) for PbB and BPA are presented by selected covariates. RESULTS: PbB was detected in 100% of the population, with a GM concentration of 1.34 microg/dL. Adults aged 60 to 79 and males had significantly higher GM PbB concentrations. Lower household income, being born outside Canada, living in a dwelling at least 50 years old, current or former smoking, and drinking alcohol at least once a week were associated with higher PbB concentrations. Urinary BPA was detected in 91% of the population, with a GM concentration of 1.16 microg/L (1.40 microg/g creatinine). Children aged 6 to 11 had significantly higher GM creatinine standardized BPA concentrations than did other age groups. INTERPRETATION: Although PbB concentrations have declined dramatically since the 1970s, socio demographic characteristics, the age of dwellings, and certain lifestyle behaviours are associated with higher levels. Given the short half-life of orally ingested BPA and the high frequency of detection, the CHMS data suggest continual widespread exposure in the Canadian population. PMID- 20973430 TI - 14-year diabetes incidence: the role of socio-economic status. AB - BACKGROUND: Diabetes prevalence is associated with low socioeconomic status (SES), but less is known about the relationship between SES and diabetes incidence. DATA AND METHODS: Data from eight cycles of the National Population Health Survey (1994/1995 through 2008/2009) are used. A sample of 5,547 women and 6,786 men aged 18 or older who did not have diabetes in 1994/1995 was followed to determine if household income and educational attainment were associated with increased risk of diagnosis of or death from diabetes by 2008/2009. Three proportional hazards models were applied for income and for education--for men, for women and for both sexes combined. Independent variables were measured at baseline (1994/1995). Diabetes diagnosis was assessed by self-report of diagnosis by a health professional. Diabetes death was based on ICD-10 codes E10-E14. RESULTS: Among people aged 18 or older in 1994/1995 who were free of diabetes, 7.2% of men and 6.3% of women had developed or died from the disease by 2008/2009. Lower-income women were more likely to develop type 2 diabetes than were those in high-income households. This association was attenuated, but not eliminated, by ethno-cultural background and obesity/overweight. Associations with lower educational attainment in unadjusted models were almost completely mediated by demographic and behavioural variables. INTERPRETATION: Social gradients in diabetes incidence cannot be explained entirely by demographic and behavioural variables. PMID- 20973431 TI - Hospitalization risk in a type 2 diabetes cohort. AB - BACKGROUND: Using a health outcome research framework, the hospitalization risk for a type 2 diabetes (T2DM) cohort is evaluated. Diabetes is "ambulatory care sensitive"--a condition largely manageable with appropriate care in the community. Thus, hospitalization may represent a negative care outcome. DATA AND METHODS: Analyses were conducted by linking data from the Canadian Community Health Survey (CCHS) cycle 1.1 to the Canadian Hospital Morbidity Database for respondents identified as having T2DM. Logistic regression was used to examine the association between the likelihood of all-cause hospitalization within two years of the survey date and patients' characteristics, care path, and health system characteristics. RESULTS: When the effects of demographic, socio-economic and health status characteristics were taken into account, physical inactivity and former or current smoking were significantly associated with an increased likelihood of hospitalization for those with type 2 diabetes. Specialist visits were positively related to hospitalization (OR = 1.4), whereas the relationship with general practitioner visits was negative (OR = 0.7). Regional hospital use patterns were significantly associated with hospitalization (OR = 2.6). INTERPRETATION: Regional patterns of hospital use are important for hospitalization: T2DM residents of health regions with generally higher hospitalization rates were more likely to be hospitalized than were those living elsewhere. In terms of care path, GP consultations were associated with a lower risk of hospitalization. Specialist consultations, likely a marker of disease severity, had the reverse effect. PMID- 20973432 TI - Regional patterns of risk for sexually transmitted infections in British Columbia. AB - BACKGROUND: Although rates of sexually transmitted infection (STI) tend to be higher in urban Canada, the province of British Columbia has recently seen above average rates in the northern health regions. DATA AND METHODS: Data from the 2005 Canadian Community Health Survey were used to examine sexual behaviour risks by geography and age in British Columbia. Two outcomes were investigated: ever diagnosed with an STI, and did not use a condom during last sexual intercourse. Region was categorized as metropolitan and non-metropolitan (Northern, representing more rural and remote communities, and Southern). Multivariate logistic regression was used to determine associations between the two outcomes and region, age, and other socio-demographic variables. Normalized weights accounted for sampling design. RESULTS: In adjusted analysis, older age (25 to 49) and being female were significantly associated with previously having an STI and not using a condom during last sex. Being a non-drinker was inversely associated with the former outcome, and being an occasional drinker was inversely associated with both outcomes, compared with being a regular drinker. When stratified by region, the relationship between older age and not using a condom was particularly strong in Northern non-metropolitan regions. INTERPRETATION: The results highlight the importance of considering older individuals in the design of STI preventive interventions, particularly in non-metropolitan and rural and remote regions, where access to testing and treatment may be limited. PMID- 20973433 TI - Health-promoting factors and good health among Canadians in mid- to late life. AB - According to results from the Canadian Community Health Survey-Healthy Aging, 76% of Canadians in mid-life (45 to 64) and 56% of seniors reported good health in 2009. This is based on a definition of health composed of: positive self perceived general and mental health, functional ability, and independence in activities of daily living. Good health existed even in the presence of chronic conditions such as high blood pressure, arthritis and back problems, all of which were common among people aged 45 or older. Eight modifiable factors were associated with good health: smoking status, body mass index, physical activity, diet, sleep, oral health, stress, and social participation. Eighty-four percent of the younger age group and 91% of seniors reported positive tendencies on four or more of these factors. The more factors on which positive tendencies were reported, the greater the likelihood of having good health. PMID- 20973434 TI - An update on cancer survival. AB - Statistics Canada routinely produces cohort-based estimates for cancer survival; the most recent were based on cases diagnosed from 1992-2000. This report provides predicted survival estimates for cases diagnosed more recently. Using records from the Canadian Cancer Registry linked to the Canadian Vital Statistics Death Data Base, cancer- and age-specific estimates of relative survival have been calculated for 2004-2006. The five-year relative survival ratio (RSR) for all cancers combined was 62%, and ranged from 6% for pancreatic cancer to 98% for cancer of the thyroid. The RSR was typically higher at younger than older ages, with exceptions for some common cancers. From 1992-1994 to 2004-2006, the five year RSR for a number of cancers increased--usually slightly, but in some cases, appreciably (for example, the age-standardized RSR for non-Hodgkin lymphoma rose from 51% to 63%; for leukemia, from 44% to 54%; and for liver, 9% to 17%). PMID- 20973435 TI - Validation of self-rated mental health. AB - BACKGROUND: This article assesses the association between self-rated mental health and selected World Mental Health-Composite International Diagnostic Interview (WMH-CIDI)-measured disorders, self-reported diagnoses of mental disorders, and psychological distress in the Canadian population. DATA AND METHODS: Data are from the 2002 Canadian Community Health Survey: Mental Health and Well-being. Weighted frequencies and cross-tabulations were used to estimate the prevalence of each mental morbidity measure and self-rated mental health by selected characteristics. Mean self-rated mental health scores were calculated for each mental morbidity measure. The association between self-rated mental health and each mental morbidity measure was analysed with logistic regression models. RESULTS: In 2002, an estimated 1.7 million Canadians aged 15 or older (7%) rated their mental health as fair or poor. Respondents classified with mental morbidity consistently reported lower mean self-rated mental health (SRMH) and had significantly higher odds of reporting fair/poor mental health than did those not classified with mental morbidity. Gradients in mean SRMH scores and odds of reporting fair/poor mental health by recency of WMH-CIDI-measured mental disorders were apparent. A sizeable percentage of respondents classified as having a mental morbidity did not perceive their mental health as fair/poor. INTERPRETATION: Although self-rated mental health is not a substitute for specific mental health measures it is potentially useful for monitoring general mental health. PMID- 20973436 TI - [The 15th Congress of European Society of Hand Surgery. Bucharest, June 23-26, 2010]. PMID- 20973437 TI - The Peacock versus the louse (pediculus humanus corporis): one soldier's contribution to combating trench fever in the First World War. AB - Trench fever became a major worry for the Allied High Command during the First World War because of its debilitating effects on troop performance. The causes of the fever were not previously known, but entomological research identified the body louse (pediculus humanus corporis) as the carrier, and the Royal Army Medical Corps developed effective methods of control through disinfestation. These were markedly influenced by the researches of a young entomologist, Alexander David Peacock, which were conducted under campaign conditions. Peacock subsequently occupied a Chair of Zoology at St. Andrews University for 30 years. PMID- 20973438 TI - James Ross (1837-1892) and his forgotten neurology textbook of 1881. AB - James Ross (1837-1892) was an Aberdeen medical graduate who, after 13 years in rural general practice, mainly in Lancashire, became a pathologist and then physician to the Manchester Royal Infirmary and professor of medicine at Owens College, Manchester. In mid-career he developed a major interest in clinical neurology and became, apart from Byrom Bramwell in Edinburgh, the only contemporary British physician outside London who had widely recognised neurological expertise. Ross made several notable original contributions to neurological knowledge, particularly in relation to aphasia and peripheral neuritis. He wrote the entire contents of the two editions of the massive two volume A Treatise on the Diseases of the Nervous System (1881 and 1883), which was very favourably reviewed and commercially successful but which, like its author who died at the height of his powers, was soon forgotten once William Gowers' A Manual of Diseases of the Nervous System became available in the late 1880s. PMID- 20973439 TI - The Triple Qualification examination of the Scottish medical and surgical colleges, 1884-1993. AB - The Triple Qualification (TQ) examination of the three Scottish medical colleges was founded in 1884 in the aftermath of the Medical Act of 1858, to offer a medical qualification that would have equal status with that of the universities and other medical schools. Continued efforts to amend the Act had threatened that the universities might dominate basic medical education to the exclusion of the colleges, which opposed this perceived threat to their viability. The TQ proved surprisingly durable and catered for a changing constituency of candidates over the century of its existence, offering a route to medical qualification for individuals from Great Britain and Ireland, the dominions and such diverse groups as exiled Jews from Europe and Rhodesians following independence. This article examines the origins and structure of the examination and assesses the changing candidate profile over the century of its existence. PMID- 20973440 TI - Cerebri anatome: Thomas Willis and his circle. PMID- 20973441 TI - The catalogue of the Ripley Corpus: alchemical writings attributed to George Ripley (d. ca. 1490). AB - The period 1471 to 1700 saw the accretion of a large corpus of alchemical works associated with the famous English alchemist George Ripley, Canon of Bridlington (d. ca. 1490). Evaluation of Ripley's alchemy is hampered by uncertainty over the composition of the corpus, the dating and provenance of individual texts, and the difficulty of separating genuine from spurious attributions. The Catalogue of the Ripley Corpus (CRC) provides a first step in ordering these diverse materials: a descriptive catalogue of approximately forty-five alchemical treatises, recipes and poems attributed to Ripley, with an index of all known manuscript copies. PMID- 20973442 TI - Quality information from the grapevine. AB - A letter by Lucien Herr, a highly regarded leading French intellectual at the time of World War I, provides capsule portraits of chemists such as Gabriel Bertrand, Paul Lebeau, Charles Moureu, and Georges Urbain. It makes us better aware of who they were and of how their contemporaries saw their work, which had much to do with their personalities, whether congenial or abrasive. This article is concerned with the kind of information carried by the so-called grapevine. It can be invaluable to the historian, for the light it sheds on the character of a scientist. The document drawn upon, from World War I (1915), depicts graphically the personalities of some of the French chemists engaged in the rush to design and produce chemical weapons. It is a frank and even brutal appraisal of their strengths and weaknesses. This is the kind of evaluation that scientists routinely engage in, but devoid of the hyperbole, pro or con, which usually flavours it. PMID- 20973443 TI - The advantage and disadvantage of peripheral ignorance: the gas adsorption controversy. AB - In the early history of surface chemistry, in the 1920s, the nature of gas adsorption was a pivotal subject. A theory created by Michael Polanyi in the peripheral Hungary contradicted the received view originating from the American Irving Langmuir. When working out his theory, Polanyi had not even heard of Langmuir's rival description. However, Polanyi emigrated from Hungary to Germany, the centre of his field, and tried to defend his adsorption theory in the circle of the leading experts, including Einstein and Fritz Haber. This controversy seemed vital to his survival as a scientist and as an immigrant. The aim of this article is to recapitulate this controversy, with its sad undercurrents, the role of local science, methods of argumentation, and the work of a central scientific community. PMID- 20973444 TI - Dreams as historical artifacts. PMID- 20973445 TI - Sexual abuse of the child: a treatment model for the incestuous family. PMID- 20973446 TI - Complexity and accountability: the witches' brew of psychiatric genetics. AB - This paper examines the role of complexity in descriptions of the aetiology of common psychiatric disorders. While scientists attest to the discovery of an underlying reality of complex inheritance--the so-called 'witches' brew' of genetic and non-genetic factors--we argue that 'complexity' also performs rhetorical work. In our analysis of scientific review papers (1999-2008), we find a relatively stable genre of accountability in which descriptions of complexity appear to neutralize past failures by incorporating different and sometimes competing methodological perspectives. We identify two temporal strategies: retrospective accounting, which reconstructs a history of psychiatric genetics that deals with the recent failures, citing earlier twin studies as proof of the heritability of common psychiatric disorders; and prospective accounting, which engages in the careful reconstruction of expectations by balancing methodological limitations with moderated optimism. Together, these strategies produce a simple to-complex narrative that belies the ambivalent nature of complexity. We show that the rhetorical construction of complexity in scientific review papers is oriented to bridging disciplinary boundaries, marshalling new resources and reconstructing expectations that justify delays in gene discovery and risk prediction. PMID- 20973447 TI - Living lawns, dying waters: The suburban boom, nitrogenous fertilizers, and the nonpoint source pollution dilemma. AB - The March 1963 issue of Consumer Bulletin included a four-page article titled "How to grow a better lawn", the lead paragraph of which assured readers that "one does not have to be an expert or spend large sums of money to have a good lawn. It is necessary, however, to follow certain established practices in the construction and maintenance of any lawn." These two assertions may have struck readers, as I suspect they would strike lawngrowers today, as somewhat contradictory. Given the list of established practices that followed--"the construction of the lawn base, with proper grading, drainage, and preparation of the seedbed; selection of the type of grass and spreading of the seed; and maintenance, including fertilizing, mowing, and control of weeds"--it is difficult to imagine how the homeowner could have accomplished all of this without large sums of money or expertise. In fact, building lawns in the manner described by Consumer Bulletin required tremendous amounts of both. Recognizing these established practices in lawn construction and maintenance as a technological system allows us to better understand the persistence of this grassy landscape in America. PMID- 20973448 TI - Exploring and communicating knowledge of trees in the early royal society. AB - For nearly 150 years after its foundation, Fellows of the Royal Society collected information on trees, investigated their anatomy and physiology, promoted planting and improved planting practices, and introduced, naturalized and classified foreign species. Their discoveries and advice were widely disseminated and used. Historians have generally neglected this interest, although the Society's first publication was an influential work on trees. They have also overlooked the significance of Stephen Hales's remark in Vegetable Staticks--that he hoped his enquiries into the nature of plants would improve skills in agriculture and gardening-and his linking of sap movement to tree pruning. Fellows' experiments and field trials not only advanced knowledge of the structure, nutrition and growth of trees but also provided empirical evidence supporting instructions for cultivating them. PMID- 20973449 TI - Hooke's figurations: a figural drawing attributed to Robert Hooke. AB - The experimental philosopher Robert Hooke (1635-1703) is known to have apprenticed to the leading painter Peter Lely on his first arrival in London in the late 1640s. Yet the relevance of Hooke's artistic training to his mature draughtsmanship and identity has remained unclear. Shedding light on that larger interpretive problem, this article argues for the attribution to Hooke of a figural drawing now in Tate Britain (T10678). This attributed drawing is especially interesting because it depicts human subjects and bears Hooke's name functioning as an artistic signature, both highly unusual features for his draughtsmanship. From evidence of how this drawing was collected and physically placed alongside images by leading artists in the early eighteenth century, I suggest how it can offer new insight into the reception of Hooke and his graphic work in the early Enlightenment. PMID- 20973450 TI - William Maddock Bayliss's therapy for wound shock. AB - During World War I, military surgeons discovered that patients die from wound shock because their blood pressure falls catastrophically. William Maddock Bayliss produced experimental shock by bleeding anaesthetized cats, which lowers their blood pressure. He restored pressure by infusing salt solution containing enough gum acacia to generate the colloid osmotic pressure ordinarily contributed by the plasma proteins. Ernest Henry Starling had demonstrated that as plasma flows through the capillaries the colloid osmotic pressure of its proteins retains water. From 1917 to 1919 Bayliss and Starling served on the Special Investigation Committee on Surgical Shock and Allied Conditions of the Medical Research Committee. Both gum-saline and blood transfusions were used successfully on wound-shocked soldiers, but we do not know how many were treated, and the effectiveness of whole blood in comparison with gum-saline was not ascertained. Today the colloid osmotic pressure in transfusion solutions is usually provided by dextran or human albumin. Vast quantities are used, but Bayliss's role in the development of this clever biophysical therapy has been almost forgotten. PMID- 20973451 TI - The Danish pharmaceutical industry--preconditions and establishment. PMID- 20973452 TI - The rise and fall of celebrity promotion of prescription products in direct-to consumer advertising. PMID- 20973453 TI - A history of the women's professional pharmacy fraternities, 1913-1988. PMID- 20973454 TI - Lapis de Goa: the 'Cordial Stone'--part two. PMID- 20973455 TI - Two tiers of materia medica. PMID- 20973456 TI - Has pharmacy adequately promoted pharmaceutical discoveries to the public? AB - In summary, twentieth-century British and American cards published by the organisations of pharmacy albeit a limited window into public relations--suggest that relatively little attention was given to offering the public an understanding of the science basis of pharmacy or the nature of pharmacy research. On the other hand, clear hints of this came from industry despite being diluted, some might say tainted, with overt commercialism. Thus it is suggested that the public came to associate industry with pharmacy research, a suggestion that needs to be examined in the light of other approaches to PR. It is, of course, not surprising that PR from pharmacy's professional bodies has focused largely on community practice. However, it is reasonable to ask, What is the cost in terms of professional image when opportunities to promote an understanding of the science of pharmacy are given little attention? Indeed, it seems to me that it was soon forgotten that an emphasis placed on the science base of pharmacy was very much behind the successful efforts in establishing the Pharmaceutical Society and a professional image for pharmacy. I suggest, too, that the pattern of limited science PR contributes, unconsciously, to current concerns over the place of scientists in the new professional society. As is well known, interminable debate exists over what the public sees as 'professional'. Even so, I think few would disagree that an image of science can be more than helpful. Maybe, in the current upheaval for British pharmacy, there is a case for the publication of free cards analogous to those recently produced by the School of Pharmacy, although only so long as they indicate, by way of context, both the science and humanity demanded for pharmacy practice. PMID- 20973457 TI - Ahmad al-Damanhuri (1689-1778) and the utility of expertise in early modern Ottoman Egypt. AB - Eighteenth-century Arabic manuscripts in the "uncommon sciences"--a range of mathematical, astronomical, astrological, medical, and divinatory practices number in the thousands. In light of the economic and social upheaval over the eighteenth century this sustained production must be understood from perspectives of both intellectual and social history. Ahmad al-Damanhuri's writings and his rise from rural orphan to head of al-Azhar Mosque suggest the role and value of expertise in the uncommon sciences, particularly as these fields brought religious scholars and ruling military elites into close relations. Precisely because the uncommon sciences bridged these two social classes, this expertise was important for individuals' social and intellectual formation. Recognizing the significance of the uncommon sciences for the history of this period offers a new reading of the work of the chronicler 'Abd al-Rahman al-Jabarti, who used language and exemplars from the uncommon sciences to reflect on the proper and just relationship between expertise (embodied by the religious scholarly class) and the emerging state. PMID- 20973458 TI - Political order and the ambivalence of expertise: Count Rumford and welfare reform in late eighteenth-century Munich. AB - From 1784 to 1798, the military expert and natural philosopher Benjamin Thompson, Count Rumford, worked in Munich for Elector Karl Theodor of Bavaria on a series of reforms that demanded a careful articulation of the reformer's expertise. This case study of Rumford's welfare reforms posits that the ambivalent nature of expertise, which relies simultaneously on generally accessible and on exclusive knowledge, was already present in the conceptual framework of Rumford's mechanical experimental philosophy and that this ambivalence was visible in the performative practice of the experimenter. Gestures of revelation and concealment and of displaying and obscuring were crucial to Rumford's (temporary) success in establishing his authority in Bavaria. Challenged by local advisers, the reformer called on a newly emergent form of public. Rumford's conceptual and practical articulation of expertise thus contributed to an increasing polarization of the political order in the Bavarian capital. PMID- 20973459 TI - High-calcium milk prevents overweight and obesity among postmenopausal women. AB - BACKGROUND: The Sixth National Nutrition Survey 2003 revealed that the highest prevalence of overweight and obesity among Filipino female adults (30.8%) was found in the age group from 40 to 59 years. Obesity is associated with a number of chronic diseases, including cardiovascular disease, hypertension, and diabetes. Low calcium intake has been identified as a potential contributing factor to overweight and obesity. OBJECTIVE: To assess the effect of a high calcium,fortified, low-fat milk drink with added vitamin D versus a low-calcium placebo drink on anthropometric measurements of postmenopausal women. METHODS: Women who were at least 5 years postmenopausal were invited to participate in the study. Potential participants underwent three stages of screening: initial interview, dual-energy x-ray absorptiometry, and blood testing for biochemical screening. Anthropometric indices were measured at baseline and the end of the study. Sixty women were qualified to participate in the study. The women were randomly assigned to two groups, one of which received 400 ml of the high-calcium milk daily for 16 weeks while the other received the placebo drink. RESULTS: No significant increases were observed in the anthropometric indices of the subjects receiving the high-calcium fortified milk at the end of the study. However, there were significant increases in the weight (p = .008), body mass index (p = .007), and waist (p = .018) and hip (p = .003) circumferences of the subjects receiving the placebo drink. CONCLUSIONS: A change in dietary calcium intake may be a useful measure as part of an overall approach to prevent the occurrence of overweight and obesity among postmenopausal women. PMID- 20973460 TI - Nutritional value of locally produced foods and potential for developing age appropriate complementary foods for children under 2 years of age in Mali. AB - BACKGROUND: Promotion of dietary diversity using locally available nutritious foods is an effective approach in low-income areas to improve the quality of young children's diet and, hence, their growth and development. OBJECTIVE: To identify the nutritional values of locally acceptable, feasible, affordable, and sustainable foods and develop a number of recipes that could be used to complement effectively nutrient intakes provided through breastfeeding to children 6 to 23 months of age in Bandiagara, Mali. METHODS: Structured questionnaires were used to obtain lists of all locally available foods during village assembly meetings and identify the food basket of households and child feeding practices during interviews with mothers and fathers. The nutritional values of the foods were estimated, and the Malian food composition table was used to identify the combinations that would result in the most nutritious recipes. RESULTS: Breastfeeding was widely practiced, but the rate of exclusive breastfeeding during the first 6 months of life was extremely low (7%). The practice of early introduction of water and complementary foods was a problem. Forty recipes for improved dishes, including puddings, drinks and juices, purees, salads, and soups, were proposed. The nutritional values of the 10 most nutritious of these recipes, the types and quantities of the ingredients, and the method of preparation of each recipe are described. CONCLUSIONS: Locally produced indigenous foods in rural Mali were used to develop energy- and nutrient-dense complementary foods for children. Further research is needed to test the short- and long-term effects of consuming these dishes on the nutritional status of children 6 to 23 months of age in Mali. PMID- 20973461 TI - The nutritional status of school-aged children: why should we care? AB - BACKGROUND: The nutritional status of school-aged children impacts their health, cognition, and subsequently their educational achievement. The school is an opportune setting to provide health and nutrition services to disadvantaged children. Yet, school-aged children are not commonly included in health and nutrition surveys. An up-to-date overview of their nutritional status across the world is not available. OBJECTIVE: To provide a summary of the recent data on the nutritional status of school-aged children in developing countries and countries in transition and identify issues of public health concern. METHODS: A review of literature published from 2002 to 2009 on the nutritional status of children aged 6 to 12 years from Latin America, Africa, Asia, and the Eastern Mediterranean region was performed. Eligible studies determined the prevalence of micronutrient deficiencies or child under- and overnutrition using biochemical markers and internationally accepted growth references. RESULTS: A total of 369 studies from 76 different countries were included. The available data indicate that the nutritional status of school-aged children in the reviewed regions is considerably inadequate. Underweight and thinness were most prominent in populations from South-East Asia and Africa, whereas in Latin America the prevalence of underweight or thinness was generally below 10%. More than half of the studies on anemia reported moderate (> 20%) or severe (> 40%) prevalence of anemia. Prevalences of 20% to 30% were commonly reported for deficiencies of iron, iodine, zinc, and vitamin A. The prevalence of overweight was highest in Latin American countries (20% to 35%). In Africa, Asia, and the Eastern Mediterranean, the prevalence of overweight was generally below 15%. CONCLUSIONS: The available data indicate that malnutrition is a public health issue in school aged children in developing countries and countries in transition. However, the available data, especially data on micronutrient status, are limited. These findings emphasize the need for nutrition interventions in school-aged children and more high-quality research to assess nutritional status in this age group. PMID- 20973462 TI - The effectiveness of quality protein maize in improving the nutritional status of young children in the Ethiopian highlands. AB - BACKGROUND: Undernutrition is a persistent problem in Africa, especially in rural areas where the poor largely depend on staples and have limited access to a diverse diet. Quality protein maize (QPM) consists of maize varieties biofortified with increased lysine and tryptophan levels. Several studies in controlled settings have indicated the positive impact of QPM on the nutritional status of children. OBJECTIVE: Two 1-year, randomized, controlled studies were undertaken to measure the effect of QPM on the nutritional status of children consuming typical maize-based diets when QPM was cultivated by their households in the western Ethiopian highlands. METHODS: The first study used a cluster randomized design with 151 children aged 5 to 29 months; the second study used a completely randomized design with 211 children aged 7 to 56 months. In both studies, half of the households were provided with QPM seed and the other half with seed of an improved conventional maize variety. RESULTS: Undernutrition was pervasive, and maize was the dominant food in the children's complementary diets. In the first study a positive effect of QPM was observed for weight but not height, with children in the QPM group recovering from a drop in weight-for height. In the second study, children consuming conventional maize progressively faltered in their growth, whereas children consuming QPM did not change significantly in height-for-age and had a marginal increase in weight-for-age. CONCLUSIONS: These studies indicate that in major maize-producing and -consuming areas of Africa, home cultivation and use of QPM in children's diets could reduce or prevent growth faltering and may in some cases support catch-up growth in weight. PMID- 20973463 TI - Psychomotor development in children with iron deficiency and iron-deficiency anemia. AB - BACKGROUND: Iron deficiency and iron-deficiency anemia are the most common nutritional deficiencies in children, especially in developing countries. Iron deficiency anemia in infancy is associated with impaired neurodevelopment. Studies have shown an association between iron deficiency without anemia and adverse effects on psychomotor development. OBJECTIVE: To determine the effects of iron deficiency and iron-deficiency anemia on psychomotor development in childhood. METHODS: . We evaluated psychomotor development in healthy children with iron deficiency and iron-deficiency anemia with the use of the Denver II Developmental Screening Test (DDST-II). If the child score was more than 90th percentile compared to children in the same age group, the test was scored as "delay" it was scored as a "caution" if the child score was between the 75th and 90th percentiles. The test result was interpreted as "normal," if there was no delay and only one "caution" for any item. If the child had one or more "delays" or more than two "cautions," the result was classified as "abnormal." RESULTS: DDST-II scores were abnormal in 67.3% of subjects with iron-deficiency anemia, 21.6% of those with iron deficiency, and 15.0% of control subjects. The difference from the control group in the percentage of abnormal scores was significant for subjects with iron-deficiency anemia (p < .01) but not for those with iron deficiency (p = 0.203); p > .05. (p-value, post-hoc comparison of 2 groups.) CONCLUSIONS: Iron-deficiency anemia impaired psychomotor development during childhood. However, the evidence on the adverse effects of iron deficiency remains controversial. The Denver II Developmental Screening Test is a valuable test to detect early developmental delays, especially in infants with risk factors. PMID- 20973464 TI - Impact of vaccination against chicken Newcastle disease on food intake and food security in rural households in Tanzania. AB - BACKGROUND: Small-scale poultry production has the potential to increase animal source food consumption, improve household income, and reduce food insecurity. OBJECTIVE: To assess the impact of a chicken Newcastle disease vaccination program on consumption of chicken and eggs among women and children, income, and food insecurity in rural Tanzanian households. METHODS: Comparisons were made between households from three project villages, which participated in a Newcastle disease vaccination program for chickens, and three control villages, which did not participate. Household interviews were done with mothers from a random sample in March 2008 (237 households) and March 2009 (261 households). RESULTS: After the first year of vaccinations (three rounds), project households kept significantly more chickens and tended to be more food secure than control households. Mothers from project households ate significantly more eggs than their counterparts in control households. A similar trend was observed among children. In 2009, fewer chickens were vaccinated in the project villages than in 2008, and more chickens were independently vaccinated in the control villages. This corresponded with an increase in ownership of chickens, a reduction in food insecurity, and improved consumption of eggs in control villages, whereas chicken ownership and egg consumption decreased and food insecurity remained relatively stable in project villages. We saw no differences between project and control villages in income earned from chicken and egg sales. CONCLUSIONS: Our findings suggest that an increase in chicken Newcastle disease vaccination can lead to an increase in ownership of chickens and egg consumption and may also have an effect on reducing household food insecurity. PMID- 20973465 TI - Daily use of Sprinkles micronutrient powder for 2 months reduces anemia among children 6 to 36 months of age in the Kyrgyz Republic: a cluster-randomized trial. AB - BACKGROUND: Iron-deficiency anemia is widespread among young children in the Kyrgyz Republic, and there is an urgent need to identify an effective intervention to address this significant public health problem. OBJECTIVE: To test the effectiveness of a 2-month intervention with daily home fortification of complementary food using micronutrient powder (Sprinkles) in reducing anemia among children 6 to 36 months of age in the Kyrgyz Republic. METHODS: In this cluster-randomized, community-based effectiveness trial conducted in three regions of the Kyrgyz Republic, 24 clusters of children aged 6 to 36 months were randomly assigned to two groups. The intervention group (12 clusters, n = 1,103) received 60 sachets of micronutrient powder (12.5 mg elemental iron), which were taken as one sachet daily for 2 months. The control group (12 clusters, n = 1,090) did not receive micronutrient powder until after the study period. Blood hemoglobin concentration was assessed at the start and end of the intervention. RESULTS: From baseline to follow-up, the mean hemoglobin concentration in the intervention group increased by 7 g/L, whereas it decreased by 2 g/L in the control group (p < .001). The prevalence of anemia (hemoglobin < 110 g/L) in the intervention group decreased from 72% at baseline to 52% at follow-up, whereas it increased from 72% to 75% in the control group (p < .001). Compliance with the intervention was high, with children consuming on average 45 of the 60 sachets given. CONCLUSIONS: A course of 60 Sprinkles micronutrient powder sachets taken daily for 2 months is effective in improving hemoglobin levels and reducing the prevalence of anemia among young children in the Kyrgyz Republic. PMID- 20973466 TI - Prevalence of prehypertension and hypertension among adolescent high school girls in Tabriz, Iran. AB - BACKGROUND: There are few studies of the prevalence of elevated blood pressure that include Iranian adolescent girls. OBJECTIVE: The aim of this cross-sectional study was to determine the blood pressure status and its relationship with body mass index (BMI) in adolescent girls attending high school in Tabriz, Iran. METHODS: A sample of 985 girls was selected by stepwise random sampling from five districts of Tabriz. Blood pressure, weight, and height of the subjects were measured and BMI was calculated. Blood pressure measurements were categorized as normal, prehypertension, or hypertension using the 2004 Fourth Report blood pressure screening recommendations. Overweight and obesity were defined according to International BMI Cut Off Points for adolescents. RESULTS: The prevalence rates of of prehypertension and hypertension were 13.9% and 19.4%, respectively. Obesity and overweight were seen in 2.8% and 16.4% of subjects, respectively. The prevalence rates of hypertension and prehypertension increased with increasing BMI. CONCLUSIONS: Hypertension and prehypertension were highly prevalent in the studied adolescent girls. Obesity was associated with an increased risk of elevated blood pressure. Further studies are needed to identify other risk factors for high blood pressure in our studied population. Routine blood pressure measurements in adolescent girls of our community are suggested to prevent high blood pressure in adolescence and its complications in later life. PMID- 20973467 TI - Explanation of experimental results of mixed micelles of homologous surfactants through a MM2 bidimensional modeling. AB - A computational modeling (in gas phase) to study the disposition of the homologous surfactants in a bidimensional simple model of mixed and homogeneous micelles was performed for the case of R-trimethylammonium bromide surfactants with different linear R lengths from R = C(5) to C(17). First, the bidimensional homogeneous (one component) micelle was modeled, and as a second step, heterogeneous (two components) bidimensional micelles were modeled. The difference in the number of carbon atoms between hydrocarbon chains of the surfactants in the heterogeneous micelles, Deltan(C), ranged from 2 to 8. Results were contrasted with experimental data obtained at our own laboratory. The exothermic values of the steric energy changes showed strong attraction between components of homologous surfactants mixture, especially when one of the surfactants has a long chain. It may be argued that the inclusion of a shorter surfactant in the mixture and the twisting of the longer surfactant makes the bidimensional arrangement formation more exothermic. All predictions were in agreement with previous experimental results. PMID- 20973468 TI - Ionic liquid-mediated formation of 5-hydroxymethylfurfural-a promising biomass derived building block. PMID- 20973469 TI - Bulk heterojunction photovoltaics using broadly absorbing small molecules based on 2-styryl-5-phenylazo-pyrrole. AB - Three new soluble small molecules (B, B6, and A) with a low band gap based on 2 styryl-5-phenylazo-pyrrole were synthesized. Molecules B and B6 contained pyrrole and N-hexylpyrrole, respectively, as the central unit, which was connected to N,N dimethylphenyl-4-azo on one side of the pyrrole molecule. Molecule A contained N hexylpyrrole as the central unit, which was connected to anthracenyl-9-azo on one side of the pyrrole molecule. The other side of the pyrrole molecule was connected to cyanovinylene 4-nitrophenyl for all molecules. The long-wavelength absorption maximum of the molecules was located at 601-637 nm, and their optical band gap was 1.62-1.67 eV. The photovoltaic properties have been investigated using blends of B, B6, or A with PCBM, and it was found that the device based on A:PCBM had a higher power conversion efficiency (PCE) (2.06%) than the devices based on B:PCBM (1.33%) and B6:PCBM (1.36%). This has been attributed to the higher hole mobility, the lower band gap of A relative to that of B or B6, and the higher energy difference between the LUMO of A and PCBM. The effect of solvent annealing and thermal-solvent annealing on the photovoltaic response of the device based on the A:PCBM blend has been investigated, and it was found that the devices based on solvent-treated and subsequent thermally annealed blends have PCEs of 2.56 and 2.83%, respectively. The increase in the PCE has been attributed to the enhanced crystallinity of the blend and the improvement in the charge transport due to a reduction in the difference between the electron and hole mobility in the blend. PMID- 20973470 TI - A systematic study of thermochromic aromatic donor-acceptor materials. AB - Molar mixtures (1:1) of electron-rich dialkoxynapthalene (Dan) and electron deficient 1,4,5,8-napthalenetetracarboxylic diimide (Ndi) derivatives form highly tunable, columnar mesophases with a dark red color due to a charge transfer absorbance derived from alternating face-centered stacking. Certain Dan-Ndi mixtures undergo a dramatic color change from dark red to an almost colorless material upon crystallizing from the mesophase. Macroscopic morphology of the solid is not changed during this process. In order to investigate the origins of this interesting thermochromic behavior, Dan and Ndi side chains were systematically altered and their 1:1 mixtures were studied. We have previously speculated that the presence or absence of steric interactions due to side chain branching on the aromatic units controlled the level of color change associated with crystallization. Results from the present study further refine this conclusion including a key crystal structure that provides a structural rationale for the observed results. PMID- 20973471 TI - Theoretical studies of CH4 inside an open-cage fullerene: translation-rotation coupling and thermodynamic effects. AB - Molecules trapped inside fullerenes exhibit interesting quantum behavior, including quantization of their translational degrees of freedom. In this study, a theoretical framework for predicting quantum properties of nonlinear small molecules in nonsymmetric open-cage fullerenes (OCFs) has been described along the lines of similar theories which treat small molecules inside C(60) and clathrate cages. As an example, the coupled translational-rotational energy structure has been calculated for the case of CH(4) inside a known OCF. The calculated energy levels have been used to calculate the equilibrium fraction of incorporated CH(4) as well as the translational heat capacity for the encapsulated molecule. The heat capacity shows an anomalous maximum at 239 K for CH(4) and 215 K for CD(4) which are not present in free methane. PMID- 20973472 TI - Synthesis, characterization, and modeling of naphthyl-terminated sp carbon chains: dinaphthylpolyynes. AB - We report a combined study on the synthesis, spectroscopic characterization, and theoretical modeling of a series of alpha,omega-dinaphthylpolyynes. We synthesized this family of naphthyl-terminated sp carbon chains by reacting diiodoacetylene and 1-ethynylnaphthalene under the Cadiot-Chodkiewicz reaction conditions. By means of liquid chromatography (HPLC), we separated the products and recorded their electronic absorption spectra, which enabled us to identify the complete series of dinaphthylpolyynes Ar-C(2n)-Ar (with Ar = naphthyl group and n = number of acetilenic units) with n ranging from 2 to 6. The longest wavelength transition (LWT) in the electronic spectra of the dinaphthylpolyynes red shifts linearly with n away from the LWT of the bare termination. This result is also supported by DFT-LDA simulations. Finally, we probed the stability of the dinaphthylpolyynes in a solid-state precipitate by Fourier-transform infrared spectroscopy and by differential scanning calorimetry (DSC). PMID- 20973473 TI - From an eight-component self-sorting algorithm to a trisheterometallic scalene triangle. AB - Using motifs from 3-fold completive self-sorting in an eight-component library, we report on the design and fabrication of a fully dynamic trisheterometallic scalene triangle, a demanding supramolecular structure that complements the so far known triangular structures. PMID- 20973474 TI - Bivalent ligands of CXCR4 with rigid linkers for elucidation of the dimerization state in cells. AB - To date, challenges in the design of bivalent ligands for G protein-coupled receptors (GPCRs) have revealed difficulties stemming from lack of knowledge of the state of oligomerization of the GPCR. The synthetic bivalent ligands with rigid linkers that are presented here can predict the dimer form of CXCR4 and be applied to molecular probes in cancerous cells. This "molecular ruler" approach would be useful in elucidating the details of CXCR4 oligomer formation. PMID- 20973475 TI - Surface modification of self-assembled one-dimensional organic structures: white light emission and beyond. AB - Surface modification is an important method to functionalize micro /nanostructures, but substrates are mainly confined to robust inorganic compounds. We develop here a facile method to modify the surface of a fragile organic 1D microstructure. The bulk molecules and surface modifier were designed with orthogonal solubility to protect the molecular crystals from destruction under the reaction conditions. As a proof of concept, white-light-emitting 1D microstructures were obtained by grafting red chromophores onto the surface of self-assembled blue-emissive microwires via a heterophase S(N)2 reaction. Spatial distribution of the two species is visualized by fluorescent lifetime mapping, which reveals a core-shell structure. The ability to postfunctionalize organic 1D structures enables many applications, where the surface property plays key roles, such as an organic P-N junction and a biosensor. PMID- 20973476 TI - Assembly modulation by adjusting countercharges of heterobimetallic supramolecular polymers composed of tris(spiroborate) twin bowls. AB - Heterobimetallic supramolecular polymers were prepared by treatment of the supramolecular polymers composed of tris(spiroborate) type molecular connecting modules with a potassium cation. On the other hand, the addition of a barium cation led to dissociation of the supramolecular polymer chain. Modulation of polymer formation was realized by the use of small metal cations as a control factor. PMID- 20973477 TI - Interconversion of hydroxylated and methoxylated polybrominated diphenyl ethers in Japanese medaka. AB - Polybrominated diphenyl ethers (PBDEs), hydroxylated (OH) and methoxylated (MeO), have been widely detected in aquatic environments. However, relationships among these structurally related compounds in exposed organisms are unclear. To elucidate biotransformation relationships among BDE-47, 6-OH-BDE-47, and 6-MeO BDE-47, dietary accumulation, maternal transfer, and tissue distribution of these compounds and their transformation products were investigated in sexually mature Japanese medaka (Oryzias latipes). In addition, transformation of each compound was determined in vitro using liver microsomes of medaka. OH-PBDEs and MeO-PBDEs were not detected in fish exposed to BDE-47. However, significant concentrations of 6-OH-BDE-47 were detected in medaka or microsomes exposed to 6-MeO-BDE-47. Significant concentrations of 6-MeO-BDE-47 were also measured in fish exposed to 6-OH-BDE-47, but 6-MeO-BDE-47 was not detected in microsomes exposed to 6-OH-BDE 47. Similar patterns of transformation products were observed in medaka eggs from adult fish during exposure. This study presents direct in vivo evidence of biotransformation of 6-MeO-BDE-47 to 6-OH-BDE-47. In addition, this is the first study to demonstrate biotransformation of 6-OH-BDE-47 to 6-MeO-BDE-47. Demethylation of 6-MeO-BDE-47 was the primary transformation pathway leading to formation of 6-OH-BDE-47 in medaka, while the previously hypothesized formation of OH-PBDEs from synthetic BDE-47 did not occur. Biotransformation products formed in adult female medaka were transferred to eggs. PMID- 20973478 TI - Low-cost inorganic solar cells: from ink to printed device. PMID- 20973479 TI - ATP enhances neuronal differentiation of PC12 cells by activating PKCalpha interactions with cytoskeletal proteins. AB - PKCalpha is a key mediator of the neuronal differentiation controlled by NGF and ATP. However, its downstream signaling pathways remain to be elucidated. To identify the signaling partners of PKCalpha, we analyzed proteins coimmunoprecipitated with this enzyme in PC12 cells differentiated with NGF and ATP and compared them with those obtained with NGF alone or growing media. Mass spectrometry analysis (LC-MS/MS) identified plectin, peripherin, filamin A, fascin, and beta-actin as potential interacting proteins. The colocalization of PKCalpha and its interacting proteins increased when PC12 cells were differentiated with NGF and ATP. Peripherin and plectin organization and the cortical remodeling of beta-actin were dramatically affected when PKCalpha was down-regulated, suggesting that all three proteins might be functional targets of ATP-dependent PKCalpha signaling. Taken together, these data demonstrate that PKCalpha is essential for controlling the neuronal development induced by NGF and ATP and interacts with the cytoskeletal components at two levels: assembly of the intermediate filament peripherin and organization of cortical actin. PMID- 20973480 TI - Characterization of molecular systems and monitoring of chemical reactions in ionic liquids by nuclear magnetic resonance spectroscopy. PMID- 20973481 TI - Chemical profiling with modeling differentiates wild and farm-raised salmon. AB - Classifications of fish production methods, wild or farm-raised salmon, by elemental profiles or C and N stable isotope ratios combined with various modeling approaches were determined. Elemental analysis (As, Ba, Be, Ca, Co, Cd, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, P, Pb, Sr, Ti, and Zn) of wild and farm-raised salmon samples was performed using an inductively coupled plasma atomic emission spectroscopy. Isotopic and compositional analyses of carbon and nitrogen were performed using mass spectrometry as an alternative fingerprinting technique. Each salmon (king salmon, Oncorhynchus tshawytscha ; coho salmon, Oncorhynchus kisutch ; Atlantic salmon, Salmo salar ) was analyzed from two food production practices, wild and farm raised. Principal component analysis (PCA) and canonical discriminant analysis (CDA) were used for data exploration and visualization. Five classification modeling approaches were investigated: linear discriminate function, quadratic discriminant function, neural network, probabilistic neural network, and neural network bagging. Methods for evaluating model reliability included four strategies: resubstitution, cross-validation, and two very different test set scenarios. Generally speaking, the models performed well, with the percentage of samples classified correctly depending on the particular choice of model and evaluation method used. PMID- 20973482 TI - Chemical structures of corn stover and its residue after dilute acid prehydrolysis and enzymatic hydrolysis: insight into factors limiting enzymatic hydrolysis. AB - Advanced solid-state NMR techniques and wet chemical analyses were applied to investigate untreated corn stover (UCS) and its residues after dilute acid prehydrolysis (DAP) and enzymatic hydrolysis (RES) to provide evidence for the limitations to the effectiveness of enzyme hydrolysis. Advanced solid-state NMR spectral-editing techniques as well as 1H-13C two-dimensional heteronuclear correlation NMR (2D HETCOR) were employed. Our results indicated that dilute acid prehydrolysis selectively removed amorphous carbohydrates, increased aromatic CH/other protonated -C?C- and enriched alkyl CH and CH2 components. Cinnamic acids were increased, and proteinaceous materials and N-containing degradation or condensation compounds were absorbed or coprecipitated in RES. 2D HETCOR experiments indicated a close association between lignin and the residual carbohydrates. Ketones/aldehydes were not detected in the DAP, in contrast to a report in which an appreciable amount of ketones/aldehydes was generated from the acid pretreatment of a purified cellulose in the literature. This suggested that acid pretreatment may modify the structure of purified cellulose more than biomass and that biomass may be a better substrate than model biopolymers and compounds for assessing structural changes that occur with industrial processing. On the basis of NMR and wet chemical analyses, we found the following factors could cause the limitations to the effectiveness of enzymatic hydrolysis: (1) chemical modification of carbohydrates limited the biologically degradable carbohydrates available; (2) cinnamic acids in the residue accumulated; (3) accessibility was potentially limited due to the close association of carbohydrates with lignin; and (4) proteinaceous materials and N-containing degradation or condensation compounds were absorbed or coprecipitated. PMID- 20973483 TI - In vivo characterization of a dual adenosine A2A/A1 receptor antagonist in animal models of Parkinson's disease. AB - The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6 hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model. PMID- 20973484 TI - Reliability and storage capacity: a compromise illustrated in the two-step spin crossover system [Fe(bapbpy)(NCS)(2)]. AB - The design of bistable magnetic systems should enable the storage of information by manipulation of the spin degrees of freedom. However, such a strategy relies on the preparation of target objects, whose environment must be controlled to favor a hysteretic behavior. Here, we report the successful modeling of a highly cooperative two-step spin-crossover iron(II) compound, [Fe(bapbpy)(NCS)(2)]. The magnetic susceptibility measurements and low- and high-temperature hysteretic cycles reflect the presence of an intermediate phase, which controls the memory storage capacity of this material. It is shown that the hysteresis loop widths can be traced theoretically by evaluating the electrostatic contributions between the transiting units. Despite the apparent reduction of intermolecular interactions upon cooling, it is suggested that the enhanced fluctuations of the Madelung field are responsible for the observed hysteresis width changes. This counterintuitive scenario makes the preparation of information storage devices an even more challenging task, where theoretical inspections are very insightful. PMID- 20973485 TI - Synthetic human serum albumin Sudlow I binding site mimics. AB - Here, we report the design, synthesis, and characterization of molecularly imprinted polymer (MIP) derived mimics of the human serum albumin (HSA) Sudlow I site-the binding site for the anticoagulant warfarin. MIP design was based upon a combination of experimental ((1)H NMR) and computational (molecular dynamics) methods. Two MIPs and corresponding nonimprinted reference polymers were synthesized and characterized (scanning electron microscopy; nitrogen sorption; and Fourier transform infrared spectroscopy). MIP-ligand recognition was examined using radioligand binding studies, where the largest number of selective sites was found in a warfarin-imprinted methacrylic acid-ethylene dimethacrylate copolymer (MAA-MIP). The warfarin selectivity of this MIP was confirmed using radioligand displacement and zonal chromatographic studies. A direct comparison of MIP-warfarin binding characteristics with those of the HSA Sudlow I binding site was made, and similarities in site population (per gram polymer or protein) and affinities were observed. The warfarin selectivity of the MIP suggests its potential for use as a recognition element in a MIP-based warfarin sensor and even as a model to aid in understanding and steering blood-plasma protein regulated transport processes or even for the development of warfarin sensors. PMID- 20973486 TI - Nanocontact electrification through forced delamination of dielectric interfaces. AB - This article reports patterned transfer of charge between conformal material interfaces through a concept referred to as nanocontact electrification. Nanocontacts of different size and shape are formed between surface functionalized polydimethylsiloxane (PDMS) stamps and other dielectric materials (PMMA, SiO(2)). Forced delamination and cleavage of the interface yields a well defined charge pattern with a minimal feature size of 100 nm. The process produces charged surfaces and associated fields that exceed the breakdown strength of air, leading to strong long-range adhesive forces and force-distance curves, which are recorded over macroscopic distances. The process is applied to fabricate charge-patterned surfaces for nanoxerography demonstrating 200 nm resolution nanoparticle prints and applied to thin film electronics where the patterned charges are used to shift the threshold voltages of underlying transistors. PMID- 20973487 TI - In vivo delivery of silica nanorattle encapsulated docetaxel for liver cancer therapy with low toxicity and high efficacy. AB - Mesoporous silica nanomaterial is one of the most promising candidates as drug carrier for cancer therapy. Herein, in vitro and in vivo study of silica nanorattle (SN) with mesoporous and rattle-type structure as a drug delivery system was first reported. Hydrophobic antitumor drug docetaxel (Dtxl) was loaded into the PEGylated silica nanorattle (SN-PEG) with a diameter of 125 nm via electrostatic absorption. In human liver cancer cell Hep-G2, the half-maximum inhibiting concentration (IC(50)) of silica nanorattle encapsulated docetaxel (SN PEG-Dtxl) was only 7% of that of free Dtxl at 72 h. In vivo toxicity assessment showed that both nanocarrier of silica nanorattle (40 mg/kg, single dose) and SN PEG-Dtxl (20 mg/kg of Dtxl, three doses) had low systematic toxicity in healthy ICR mice. The SN-PEG-Dtxl (20 mg/kg, intravenously) showed greater antitumor activity with about 15% enhanced tumor inhibition rate compared with Taxotere on the marine hepatocarcinoma 22 subcutaneous model. The results prove that the SN PEG-Dtxl has low toxicity and high therapy efficacy, which provides convincing evidence for the silica nanorattle as a promising candidate for a drug delivery system. PMID- 20973489 TI - Triptycene: no homoconjugation effect for extending optical properties of pi conjugated oligomers. AB - 1,5- and 1,8-bis(bifluorenyl)anthracene were synthesized and converted to their corresponding bis(bifluorenyl)triptycenes and bis(bifluorenyl)-9,10 dihydroanthracenes. Analysis of their optical properties shows no feature of extended conjugation in the triptycene pair. The electronic spectra of the triptycene and dihydroanthracene pairs are in fact superimposable. There is definite evidence that triptycene displays zero homoconjugation effect. PMID- 20973488 TI - Synthesis and discovery of water-soluble microtubule targeting agents that bind to the colchicine site on tubulin and circumvent Pgp mediated resistance. AB - Two classes of molecules were designed and synthesized based on a 6-CH(3) cyclopenta[d]pyrimidine scaffold and a pyrrolo[2,3-d]pyrimidine scaffold. The pyrrolo[2,3-d]pyrimidines were synthesized by reacting ethyl 2-cyano-4,4 diethoxybutanoate and acetamidine, which in turn was chlorinated and reacted with the appropriate anilines to afford 1 and 2. The cyclopenta[d]pyrimidines were obtained from 3-methyladapic acid, followed by reaction with acetamidine to afford the cyclopenta[d]pyrimidine scaffold. Chlorination and reaction with appropriate anilines afforded (+/-)-3.HCl-(+/-)-7.HCl. Compounds 1 and (+/-) 3.HCl had potent antiproliferative activities in the nanomolar range. Compound (+/-)-3.HCl is significantly more potent than 1. Mechanistic studies showed that 1 and (+/-)-3.HCl cause loss of cellular microtubules, inhibit the polymerization of purified tubulin, and inhibit colchicine binding. Modeling studies show interactions of these compounds within the colchicine site. The identification of these new inhibitors that can also overcome clinically relevant mechanisms of drug resistance provides new scaffolds for colchicine site agents. PMID- 20973490 TI - Development of a selective light-emitting diode photolytic NO(2) converter for continuously measuring NO(2) in the atmosphere. AB - A photolytic converter of nitrogen dioxide (NO(2)) to nitric oxide (NO) using light-emitting diodes (LEDs) has been designed to measure NO(2) in the troposphere. The typical electrical power consumption of the photolytic converter (PLC) is only 44 W. The maximum conversion efficiency of NO(2) to NO of the photolytic converter is around 90%, which is higher than that of metal halides or high-pressure Xe arc lamps (up to ~70%). The conversion efficiency of the PLC was almost constant for at least 2.5 months. The conversion efficiency of peroxyacetyl nitrate by the LED-PLC was measured to be 2.6 +/- 0.1% (1sigma). The interference of HONO using the PLC was experimentally estimated to be less than 3%, which is within the uncertainty of the instrument. An intercomparison of NO(2) measurements between the PLC-CLD and the laser-induced fluorescence (LIF) technique was conducted, and the NO(2) concentrations measured by the PLC-CLD method were in agreement with those obtained by the LIF technique, within the uncertainties of the instruments. Continuous observations were made on Fukue Island, a remote area. These results demonstrate the performance of the PLC for continuous ambient measurements. PMID- 20973491 TI - Chemistry of carbon dioxide relevant to its utilization: a personal perspective. AB - This presentation provides a review of the author's research group's contributions to the organometallic chemistry of carbon dioxide with a focus on incorporating this information into the development of an effective means for producing chemicals from this greenhouse gas. The types of chemistry addressed include insertion reactions of CO(2) into M-H, M-C, and M-O bonds as well as seminal contributions related to the copolymerization reactions of CO(2) and cyclic ethers. Relevant to this latter subject, efforts were made to place the author's achievements into perspective with the accomplishments of other investigators, but these efforts were not meant to be exhaustive. PMID- 20973492 TI - Synthesis and in vitro antitumor effect of vinblastine derivative-oligoarginine conjugates. AB - Vinblastine is a widely used anticancer drug with undesired side effects. Its conjugation with carrier molecules could be an efficient strategy to reduce these side effects. Besides this, the conjugate could exhibit increased efficiency against resistant cells, e.g., due to the altered internalization pathway. Oligoarginines, as cell-penetrating peptides, can transport covalently attached compounds into different kinds of cells and enhance the efficiency of those compounds. We report here the coupling of vinblastine through its carboxyl group at position 16 with the N-terminal amino function of L-Trp methyl ester. After hydrolysis of the ester group, 17-desacetylvinblastineTrp was conjugated to the N terminal amino group of oligoarginine via the C-terminal carboxyl group of the Trp moiety in solution. The antitumor effect of conjugates was studied on sensitive and resistant human leukemia (HL-60) cells in vitro. Our data suggest that all conjugates investigated possess an antiproliferative effect against the studied cells. However, the effect was dependent on the number of Arg residues in the conjugates: Arg8 > Arg6 ? Arg4. The conjugate with Arg8 exhibited similar efficicacy as compared with free 17-desacetylvinblastineTrp. The in vitro studies also showed that the tubulin binding ability of vinblastine was essentially preserved even in the octaarginine conjugate. We also observed that two isomers were formed during conjugation. These isomers showed different levels of activity against tubulin polymerization in vitro and in vivo. The 17 desacetylvinblastineTrp-Arg8-1 isomer conjugate possessed high selectivity against the mitotic spindles. HRMS and NMR data suggest that 17 desacetylvinblastineTrp-Arg8-1 and 17-desacetylvinblastineTrp-Arg8-2 are epimers at the tryptophan alpha carbon atom. PMID- 20973493 TI - Switching high two-photon efficiency: from 3,8,13-substituted triindole derivatives to their 2,7,12-isomers. AB - Bridging the triindole core and triarylboryl acceptor by an ethenylene linker at the 3,8,13- or 2,7,12-position, the resultant 3-BET and 2-BET show two-photon absorption (TPA) cross sections of delta = 2100 and 2500 GM (at 810 nm by femtosecond pulses in THF), respectively. The TPA enhancement of the 2,7,12 isomers is also found when comparing 3-BYT and 2-BYT (delta = 870 and 1900 GM) and 3-NET and 2-NET (36 and 400 GM). PMID- 20973494 TI - Enhanced target-specific accumulation of radiolabeled antibodies by conjugating arginine-rich peptides as anchoring molecules. AB - We have devised and estimated a new strategy to prolong the residence time of radiolabeled antibodies in tumor in which an octaarginine peptide (R8) was used as an anchoring molecule to fix antibodies against CD20 (NuB2; IgG2a) on tumor cells. Conjugation of R8 with antibodies was performed by maleimide-thiol chemistry using thiol groups generated by reducing the disulfide bonds of the antibody. The R8-conjugated NuB2 was then reacted with succinimidyl meta [125I]iodobenzoate to prepare [125I]SIB-NuB2(I) (0.92 R8/NuB2) and [125I]SIB NuB2(III) (3.38 R8/NuB2). Both SIB-NuB2(I) and SIB-NuB2(III) exhibited size exclusion HPLC elution profiles and immunoreactivity to CD20-positive cells similar to those of NuB2. NuB2(I) also possessed isoelectric focusing (IEF) profile similar to NuB2. However, NuB2(III) registered a broad IEF band toward higher pI. When incubated with CD20-positive cells, [125I]SIB-NuB2(I) and [125I]SIB-NuB2(III) exhibited 1.4 and 4.0 times higher cell-associated radioactivity than [125I]SIB-NuB2. After the cells were washed and reincubated in a fresh medium for 3 h, [125I]SIB-NuB2(I) and [125I]SIB-NuB2(III) exhibited significantly higher cell-associated radioactivity than [125I]SIB-NuB2. In biodistribution studies in normal mice, while both [125I]SIB-NuB2(I) and [125I]SIB-NuB2 exhibited similar biodistribution profiles, [125I]SIB-NuB2(III) showed faster clearance from the blood and higher hepatic radioactivity levels than [125I]SIB-NuB2. In SCID mice bearing CD20-positive xenografts, [131I]SIB NuB2(I) exhibited significantly higher radioactivity in xenografts than those of [125I]SIB-NuB2 with no significant increase being observed in other tissues. The findings indicate that appropriate R8 modification of antibodies satisfies both specific targeting ability of antibody and strong cell-association property of R8, which was reflected in the increased radioactivity levels in tumor. These findings supported the applicability of this approach to enhance target-specific accumulation of radiolabeled antibodies. PMID- 20973495 TI - Synthesis of N-terminally linked protein and peptide dimers by native chemical ligation. AB - Dimerization can be utilized to double the molecular weight of proteins and peptides and potentially increase their avidity of binding to target receptors. These dimerization effects may be utilized to increase in vivo half-lives in a manner similar to PEGylation and may also improve biological activity. In this paper, we report a new strategy for the synthesis of N-terminally linked protein and peptide homodimers utilizing native chemical ligation to conjugate a short dithioester linker to the N-terminal cysteines of protein and peptide monomers to form dimers in a single step. This strategy is general and has been applied to the production of dimers from three recombinantly expressed polypeptides, the IgG binding domain Protein G, an HIV entry inhibitor peptide C37H6, and human interleukin-1 receptor antagonist (IL-1ra). The biological activities of the C37H6 and IL-1ra dimers produced by these methods were retained or even slightly increased when compared to their corresponding monomers. PMID- 20973496 TI - Dissociation kinetics of an enzyme-inhibitor system using single-molecule force measurements. AB - We report on an improved method to interpret single molecule dissociation measurements using atomic force microscopy. We describe an easy to use methodology to reject nonspecific binding events, as well as estimating the number of multiple binding events. The method takes nonlinearities in the force profiles into account that result from the deformation of the used polymeric linkers. This new method is applied to a relevant enzyme-inhibitor system, latent matrix metalloprotease 9 (ProMMP-9, a gelatinase), and its inhibitor, tissue inhibitor of metalloproteases 1 (TIMP 1), which are important players in cancer metastasis. Our method provides a measured kinetic off-rate of 0.010 +/- 0.003 s( 1) for the dissociation of ProMMP9 and TIMP1, which is consistent with values measured by ensemble methods. PMID- 20973497 TI - Total synthesis of quinolizidine (-)-217A. AB - We report here the construction of quinolizidine ring systems by intramolecular cyclization of suitable functionalized piperidines via a reductive amination sequence. This reaction proceeds with a total stereocontrol at C4. The preparation of the piperidine precursors is based on a chain elongation of a piperidine aldehyde either by aldolization or by Wittig reaction. We applied this second route to the total synthesis of quinolizidine (-)-217A from (S)-methyl 2 ((S)-1-((R)-1-phenylethyl)piperidin-2-yl)propanoate 5. PMID- 20973498 TI - Oblique self-assemblies and order-order transitions in polypeptide complexes with PEGylated triple-tail lipids. AB - We report on highly ordered oblique self-assemblies in ionic complexes of PEGylated triple-tail lipids and cationic polypeptides, as directed by side-chain crystallization, demonstrating also reversible oblique-to-hexagonal order-order transitions upon melting of the side chains. This is achieved in bulk by complexing cationic homopolypeptides, poly-l-lysine (PLys), poly-l-arginine (PArg), and poly-l-histidine (PHis), in stoichiometric amounts with anionic lipids incorporating two hydrophobic alkyl tails and one hydrophilic polyethylene glycol (PEG) tail in a star-shaped A(2)B geometry. Based on Fourier transform infrared spectroscopy (FTIR), the PLys and PArg complexes fold into alpha-helical conformation. Aiming to periodicities at different length scales, that is, hierarchies, the PEG tails were selected to control the separation of the polypeptide helices in one direction while the alkyl tails determine the distance between the hydrophilic polypeptide/PEG layers, resulting in an oblique arrangement of the helices. We expect that the high overall order, where the self assembled domains are in 2D registry, is an outcome of a favorable interplay of plasticization due to the hydrophobic and hydrophilic lipid tails combined with the shape persistency of the peptide helices and the crystallization of the lipid alkyl chains. Upon heating the complexes over the melting temperature of the alkyl tails, an order-order transition from oblique to hexagonal columnar morphology was observed. This transition is reversible, that is, the oblique structure with 2D correlation of the helices is fully returned upon cooling, implying that the alkyl tail crystallization guides the structure formation. Also PHis complex forms an oblique self-assembly. However, instead of alpha-helices, FTIR suggests formation of helical structures lacking intramolecular hydrogen bonds, stabilized by steric crowding of the lipid. The current study exploits competition between the soft and harder domains, which teaches on concepts toward well-defined polypeptide-based materials. PMID- 20973499 TI - Gold(I)-catalyzed addition of carboxylic acids to alkynes. AB - Au(I)-catalyzed hydroacyloxylation of alkynes with carboxylic acids is described. PPh3AuCl/AgPF6 catalyst affords the Markonikov addition products, whereas PPh3AuCl/AgOTf catalyst gives the more stable isomerized products via the Markonikov products. PMID- 20973500 TI - Gold(I) catalyzes the intermolecular hydroamination of alkynes with imines and produces alpha,alpha',N-triarylbisenamines: studies on their use as intermediates in synthesis. AB - alpha,alpha',N-triarylbisenamines have been efficiently formed and isolated for the first time. The synthesis is based on an unprecedented gold(I)-catalyzed double intermolecular hydroamination between N-arylamines and aryl alkynes. This reaction constitutes a new example of the intriguing behavior of gold as catalyst in organic synthesis. The reactivity of these bisenamines for three different reactions, leading to potentially useful intermediates, is also shown. In particular, hindered azabicycles [3.2.0], which present excellent UVA and UVB absorption properties, are obtained by addition of triarylbisenamines to propiolates following an unexpected mechanism. PMID- 20973501 TI - Identification strategy using combined mass spectrometric techniques for elucidation of phase I and phase II in vitro metabolites of lipophilic marine biotoxins. AB - Combining mass spectrometric tools, a total of 47 in vitro metabolites of okadaic acid (OA), dinophysistoxins 1 and 2 (DTX1 and DTX2), yessotoxin (YTX), azaspiracid1 (AZA1), and pectenotoxin 2 (PTX2) could be detected and confirmed after an incubation with rat liver S9-mix. In a first step, liquid chromatography (LC) combined with tandem mass spectrometry (MS/MS) was used as a screening tool for the identification of in vitro metabolites of lipophilic marine biotoxins. Metabolic phase I and phase II reactions were screened for metabolites by calculating and subsequently monitoring theoretical MS transitions. In a second step, metabolites were confirmed by determination of accurate masses using high resolution MS provided by Orbitrap technology. Subsequently, product ion spectra, precursor ion spectra, and MS3 spectra were recorded for structure elucidation of metabolites. While all investigated toxins were found to form various oxygenated metabolites during the oxidative phase I metabolism, those metabolites varied in the number of added oxygen atoms and in the number of individual isomers. No hints were obtained concerning the formation of glutathione adducts, and a conjugation with glucuronic acid was detected for AZA1 only. PMID- 20973502 TI - Solar-light photoamperometric and photocatalytic properties of quasi-transparent TiO2 nanoporous thin films. AB - Transparent photocatalytic surfaces are of ever increasing importance for many applications on self-cleaning windows and tiles in everyday applications. Here, we report the formation and photocatalytic testing of a quasi-transparent thin and nanoporous titania films deposited on glass plates. Sputtered Ti thin films were anodized in fluoride-ion-containing neutral electrolytes to form optically semitransparent nanoporous films, which transformed to be completely transparent after thermal annealing. The nanoporous films were studied at different stages, such as before and after anodization, as well as after thermal annealing using scanning electron microscopy (SEM), X-ray diffraction (XRD), and UV-vis and Raman spectroscopy. It was observed that anodization at 20 V of high-temperature deposited titanium films resulted in regular nanopore films with pore diameters of 30 nm. Structural investigations on the transparent nanopore arrays reveal the presence of anatase phase TiO(2) even after annealing at 500 degrees C, which was confirmed by XRD and Raman spectroscopy measurements. The solar-light induced photocatalytic decomposition of stearic acid and photoconductivity characteristics of these nanoporous thin films are also presented. PMID- 20973503 TI - Site-selective lanthanide doping in a nonanuclear yttrium(III) cluster revealed by crystal structures and luminescence spectra. AB - A series of lanthanide-doped nonanuclear yttrium(III) clusters with general formulas (Y(9-x)Ln(x))(acac)(16)(MU(3)-OH)(8)(MU(4)-O)(MU(4)-OH) (Ln = Pr, Eu, Tb, Dy, and Yb) were synthesized. Characterization by single-crystal X-ray diffraction allowed for analysis of relative populations of yttrium (Z = 39) and dopant trivalent lanthanide (Z = 59-70) at every crystallographic metal position. Nonuniform distribution of ions along the three different sites seems to be correlated to the site volume and the ratio of ionic radii. In support, luminescence spectra of europium(III)-doped nonanuclear clusters were measured over a wide range of dopant concentrations. Emission intensities of peaks characteristic of specific sites correlate well with the site population determined through X-ray diffraction. PMID- 20973504 TI - Retraction. Suzuki-miyaura and sonogashira coupling of 6-chloropurines and nucleosides in water. PMID- 20973505 TI - Total synthesis of Phytophthora mating hormone alpha1. AB - Total synthesis of Phytophthora mating hormone alpha1 (1) has been demonstrated. The required stereochemistries (methyl) are achieved by applying CuI-(S)-Tol BINAP-catalyzed conjugate addition of Grignard reagents to alpha,beta-unsaturated esters. PMID- 20973506 TI - Kinetic basis of sugar selection by a Y-family DNA polymerase from Sulfolobus solfataricus P2. AB - DNA polymerases use either a bulky active site residue or a backbone segment to select against ribonucleotides in order to faithfully replicate cellular genomes. Here, we demonstrated that an active site mutation (Y12A) within Sulfolobus solfataricus DNA polymerase IV (Dpo4) caused an average increase of 220-fold in matched ribonucleotide incorporation efficiency and an average decrease of 9-fold in correct deoxyribonucleotide incorporation efficiency, leading to an average reduction of 2000-fold in sugar selectivity. Thus, the bulky side chain of Tyr12 is important for both ribonucleotide discrimination and efficient deoxyribonucleotide incorporation. Other than synthesizing DNA as the wild-type Dpo4, the Y12A Dpo4 mutant incorporated more than 20 consecutive ribonucleotides into primer/template (DNA/DNA) duplexes, suggesting that this mutant protein possesses both a DNA-dependent DNA polymerase activity and a DNA-dependent RNA polymerase activity. Moreover, the binary and ternary crystal structures of Dpo4 have revealed that this DNA lesion bypass polymerase can bind up to eight base pairs of double-stranded DNA which is entirely in B-type. Thus, the DNA binding cleft of Dpo4 is flexible and can accommodate both A- and B-type oligodeoxyribonucleotide duplexes as well as damaged DNA. PMID- 20973507 TI - Lysophosphatidylcholine is generated by spontaneous deacylation of oxidized phospholipids. AB - Elevated levels of lysophosphatidylcholine (lysoPC), present in oxidatively damaged low-density lipoprotein (oxLDL), are implicated in cardiovascular complications. LysoPC is generated by free radical-catalyzed oxidation of polyunsaturated PCs to oxidatively truncated phosphophatidylcholines (oxPCs). It is known that oxPCs are especially susceptible to hydrolysis by platelet activating factor acetylhydrolase, a phospholipase (PL) A(2) that exists in plasma largely in association with LDL. Drugs that aim to prevent the generation of lysoPC by inhibiting this PLA(2)-catalyzed hydrolysis are in advanced clinical trials. We now report that spontaneous deacylation oxPCs, such as 1-palmityl-2-(4 hydroxy-7-oxo-5-heptenoyl)-sn-glycero-3-phosphocholine, occurs readily under physiological conditions of temperature and pH (t(1/2) = 30 min at 37 degrees C and pH 7.4). We also show that this reaction proceeds through an intramolecular transesterification mechanism. Because antiphospholipase drugs cannot block this nonenzymatic pathway to lysoPC, additional therapeutic measures may be needed to avoid the pathological consequences of the newly discovered biomolecular chemistry of oxPCs. PMID- 20973508 TI - (-)-Lytophilippine A: synthesis of a C1-C18 building block. AB - The convergent enantioselective synthesis of a protected C1-C18 building block for the total synthesis of (-)-lytophilippine A was achieved. A catalytic asymmetric Gosteli-Claisen rearrangement and an Evans aldol reaction served as key C/C-connecting transformations during the assembling of the C1-C7 subunit (10 steps from 4, 29%). The synthesis of the C8-C18 segment was achieved utilizing d galactose as inexpensive ex-chiral-pool starting material (15 steps, 15%). The merger of the subunits was accomplished by a remarkably efficient sequence consisting of esterification and ring-closing metathesis (five steps, 56%). PMID- 20973510 TI - Electrowetting on paper for electronic paper display. AB - The use of paper as a material for various device applications (such as microfluidics and energy storage) is very attractive given its flexibility, versatility, and low cost. Here we demonstrate that electrowetting (EW) devices can be readily fabricated on paper substrates. Several categories of paper have been investigated for this purpose, with the surface coating, roughness, thickness, and water uptake, among the most important properties. The critical parameter for EW devices is the water contact angle (CA) change with applied voltage. EW devices on paper exhibit characteristics very close to those of conventional EW devices on glass substrates. This includes a large CA change in oil ambient (90-95 degrees ), negligible hysteresis (~2 degrees ), and fast switching times of ~20 ms. These results indicate the promise of low-cost paper based EW devices for video rate flexible e-paper on paper. PMID- 20973509 TI - Intrinsically disordered PEP-19 confers unique dynamic properties to apo and calcium calmodulin. AB - PEP-19 (Purkinje cell protein 4) is an intrinsically disordered protein with an IQ calmodulin (CaM) binding motif. Expression of PEP-19 was recently shown to protect cells from apoptosis and cell death due to Ca(2+) overload. Our initial studies showed that PEP-19 causes novel and dramatic increases in the rates of association of Ca(2+) with and dissociation of Ca(2+) from the C-domain of CaM. The goal of this work was to study interactions between the C-domain of CaM (C CaM) and PEP-19 by solution nuclear magnetic resonance (NMR) to identify mechanisms by which PEP-19 regulates binding of Ca(2+) to CaM. Our results show that PEP-19 causes a greater structural change in apo C-CaM than in Ca(2+)-C-CaM, and that the first Ca(2+) binds preferentially to site IV in the presence of PEP 19 with exchange characteristics that are consistent with a decrease in Ca(2+) binding cooperativity. Relatively weak binding of PEP-19 has distinct effects on chemical and conformational exchange on the microsecond to millisecond time scale. In apo C-CaM, PEP-19 binding causes a redistribution of residues that experience conformational exchange, leading to an increase in the number of residues around Ca(2+) binding site IV that undergo conformational exchange on the microsecond to millisecond time scale. This appears to be caused by an allosteric effect because these residues are not localized to the PEP-19 binding site. In contrast, PEP-19 increases the number of residues that exhibit conformational exchange in Ca(2+)-C-CaM. These residues are primarily localized to the PEP-19 binding site but also include Asp93 in site III. These results provide working models for the role of protein dynamics in the regulation of binding of Ca(2+) to CaM by PEP-19. PMID- 20973511 TI - Long-lasting antioxidant protection: a regenerable BHA analogue. AB - Introduction of an octyltelluro group ortho to the phenolic moiety in 3-tert butyl-4-hydroxyanisole (BHA) was found to significantly improve the antioxidant characteristics of the material. In contrast to BHA and the corresponding ortho substituted octylthio- (9c) and octylseleno (9b) derivatives, the organotellurium 9a was regenerable when assayed for its capacity to inhibit azo-initiated peroxidation of linoleic acid in a chlorobenzene/water two-phase system containing N-acetylcysteine as a stoichiometric reducing agent, and peroxyl radicals were quenched more efficiently than with alpha-tocopherol. In the homogeneous phase, inhibition of styrene autoxidation occurred with a rate constant kinh as large as 1 * 10(7) M(-1) s(-1) but with a low (n = 0.4) stoichiometric factor. Evans-Polanij plots of log (kinh) versus BDE(O-H), which are usually linear for phenols with similar steric crowding reacting by H-atom transfer, revealed that compound 9a was more than 2 orders of magnitude more reactive than expected. Although further mechanistic investigations are needed, it seems that the ortho-arrangement of an alkyltelluro group and hydroxyl should be considered a privileged structure for phenolic antioxidants. PMID- 20973512 TI - New paradigm in ionization: multiply charged ion formation from a solid matrix without a laser or voltage. AB - Laserspray ionization (LSI) is a new approach to producing multiply charged ions from solids on surfaces by laser ablation of matrixes commonly used in matrix assisted laser desorption/ionization (MALDI). We show that the only necessity of the laser for producing multiply charged ions is to deliver particles or droplets of the matrix/analyte mixture to an ionization zone which is simply a heated inlet to the vacuum of the mass spectrometer. Several other methods for delivering sample are demonstrated to produce nearly equivalent results. One example shows the use of an air gun replacing the laser and producing mass spectra of proteins by shooting pellets into a metal plate which has matrix/analyte applied to the opposite side and near the ion entrance inlet to the mass spectrometer. Multiply charged ions of proteins are produced in the absence of any electric field or laser and with only the need of a heated ion entrance capillary or skimmer. The commonality of the matrix with MALDI and the mild conditions necessary for formation of ions brings into question the mechanism of formation of multiply charged ions and the importance of matrix structure in this process. PMID- 20973513 TI - beta-cyclodextrin-functionalized silver nanoparticles for the naked eye detection of aromatic isomers. AB - We report herein the development of a highly robust, quantitative, sensitive, and naked eye colorimetric detection method for different isomers of aromatic compounds using beta-CD-modified silver nanoparticle (AgNPs) probes. This assay relies on the distance-dependent optical properties of Ag nanoparticles and the different inclusion binding strength of the aromatic guests to beta-CD host. In the presence of different isomers of aromatic compounds, AgNPs could be rapidly induced to aggregate, thereby resulting in apricot-to-red color change. The variety and concentration of different isomers of aromatic compounds could be determined by monitoring with the naked eye or a UV-vis spectrometer. The present detection limit for different isomers of aromatic compounds is 5 * 10(-5) M. We believe that the surface architectures of AgNPs after the introduction of the CD based host-guest recognition would be applicable for a range of chemical and bioanalytical molecular sensing systems in aqueous media. PMID- 20973515 TI - Ligand replacement-induced fluorescence switch of quantum dots for ultrasensitive detection of organophosphorothioate pesticides. AB - The development of a simple and on-site assay for the detection of organophosphorus pesticed residues is very important for food safety and exosystem protection. This paper reports the surface coordination-originated fluorescence resonance energy transfer (FRET) of CdTe quantum dots (QDs) and a simple ligand-replacement turn-on mechanism for the highly sensitive and selective detection of organophosphorothioate pesticides. It has been demonstrated that coordination of dithizone at the surface of CdTe QDs in basic media can strongly quench the green emission of CdTe QDs by a FRET mechanism. Upon the addition of organophosphorothioate pesticides, the dithizone ligands at the CdTe QD surface are replaced by the hydrolyzate of the organophosphorothioate, and hence the fluorescence is turned on. The fluorescence turn on is immediate, and the limit of detection for chlorpyrifos is as low as ~0.1 nM. Two consecutive linear ranges allow a wide determination of chlorpyrifos concentrations from 0.1 nM to 10 MUM. Importantly, the fluorescence turn-on chemosensor can directly detect chlorpyrifos residues in apples at a limit of 5.5 ppb, which is under the maximum residue limit allowed by the U.S. Environmental Protection Agency. The very simple strategy reported here should facilitate the development of fluorescence turn-on chemosensors for chemo/biodetection. PMID- 20973516 TI - Degradation of a model naphthenic acid, cyclohexanoic acid, by vacuum UV (172 nm) and UV (254 nm)/H2O2. AB - The mechanism of hydroxyl radical initiated degradation of a typical oil sands process water (OSPW) alicyclic carboxylic acid was studied using cyclohexanoic acid (CHA) as a model compound. By use of vacuum ultraviolet irradiation (VUV, 172 nm) and ultraviolet irradiation in the presence of hydrogen peroxide UV(254 nm)/H(2)O(2), it was established that CHA undergoes degradation through a peroxyl radical. In both processes the decay of the peroxyl radical leads predominantly to the formation of 4-oxo-CHA, and minor amounts of hydroxy-CHA (detected only in UV/H(2)O(2)). In UV/H(2)O(2), additional 4-oxo-CHA may also have been formed by direct reaction of the oxyl radical with H(2)O(2). The oxyl radical can be formed during decay of the peroxyl-CHA radical or reaction of hydroxy-CHA with hydroxyl radical. Oxo- and hydroxy-CHA further degraded to various dihydroxy-CHAs. Scission of the cyclohexane ring was also observed, on the basis of the observation of acyclic byproducts including heptadioic acid and various short chain carboxylic acids. Overall, the hydroxyl radical induced degradation of CHA proceeded through several steps, involving more than one hydroxyl radical reaction, thus efficiency of the UV/H(2)O(2) reaction will depend on the rate of generation of hydroxyl radical throughout the process. In real applications to OSPW, concentrations of H(2)O(2) will need to be carefully optimized and the environmental fate and effects of the various degradation products of naphthenic acids considered. PMID- 20973517 TI - Selective detection of As(III) at the Au(111)-like polycrystalline gold electrode. AB - Selective electrochemical detection of As(III) using a highly sensitive platform based on a Au(111)-like surface is described. The Au(111)-like surface was achieved for the first time by the partial reductive desorption of n-butanethiol (n-BT) from polycrystalline gold (poly-Au), on which a self-assembled monolayer (SAM) of n-BT was formed previously, which allows the selective blockage of the Au(100) and Au(110) surface domains by n-BT while the Au(111) domain remains bare. Square wave anodic stripping voltammetry (SWASV) using the Au(111)-like poly-Au electrode confirms the successful detection of As(III) without any interference from Cu(II). The fabricated electrode is stable and highly sensitive even in the presence of Cu(II), and it shows a linear response for As(III) up to 15 MUM. The detection limit (S/N = 3) toward As(III) is 0.28 ppb, which is far below the guideline value given by World Health Organization (WHO). The electrode was applicable for the analysis of spiked arsenic in tap water containing a significant amount of various other ion elements. The results indicate that the Au(111)-like poly-Au electrode could be promising for the electrochemical detection of trace level of As(III) in real samples without any interference from Cu(II). PMID- 20973518 TI - Synthesis of 2-aminobenzoxazoles using tetramethyl orthocarbonate or 1,1 dichlorodiphenoxymethane. AB - The synthesis of 2-aminobenzoxazoles can be readily achieved by two versatile, one-pot procedures utilizing commercially available tetramethyl orthocarbonate or 1,1-dichlorodiphenoxymethane, an amine, and an optionally substituted 2 aminophenol. The reactions were conducted under mild conditions and provided 2 aminobenzoxazoles in modest to excellent yields. A variety of amines and substituted 2-aminophenols were used to investigate the scope of the reactions. PMID- 20973519 TI - Biocatalytic separation of N-7/N-9 guanine nucleosides. AB - Vorbruggen coupling of trimethylsilylated 2-N-isobutanoylguanine with peracetylated pentofuranose derivatives generally gives inseparable N-7/N-9 glycosyl mixtures. We have shown that the two isomers can be separated biocatalytically by Novozyme-435-mediated selective deacetylation of the 5'-O acetyl group of peracetylated N-9 guanine nucleosides. PMID- 20973520 TI - Catalytic enantioselective synthesis of 4-vinyl-2-trichloromethyloxazoline: an access to enantioenriched vinylglycinol surrogate. AB - Cationic Pd(II) catalysts generated from chiral biphenyl diphosphine complexes or from COP-Cl promote enantioselective cyclization of E- and Z-configured allylic bis-trichloroacetimidates to highly enantioenriched 2-trichloromethyl-4 vinyloxazoline. This represents an exclusive example for olefin amination in high yield and enantioselectivity with trichloroacetimidate as the N-nucleophile by using a cationic palladium(II) complex as a catalyst providing an easy-to deprotect enantioenriched vinylglycinol derivative. PMID- 20973521 TI - Impact of solvent quality on nanoparticle dispersion in semidilute and concentrated polymer solutions. AB - We investigated how solvent quality affects the stability of polymer-grafted nanoparticles in semidilute and concentrated polymer solutions, which extends our previous studies on these types of dispersions in good solvents [Langmuir 2008, 24, 5260-5269]. As discussed in the current article, dynamic light scattering (DLS) was used to quantify the diffusion of polydimethylsiloxane-grafted silica nanoparticles, or PDMS-g-silica, in bromocyclohexane as well as in PDMS/bromocyclohexane solutions. We established that bromocyclohexane is a theta solvent for PDMS by varying the temperature of the solutions with PDMS-g-silica nanoparticles and detecting their aggregation at a theta temperature of T(Theta) = 19.6 degrees C. Using this temperature as a benchmark for the transition between good and bad solvent conditions, further stability tests were carried out in semidilute and concentrated polymer solutions of PDMS in bromocyclohexane at T = 10-60 degrees C. Irrespective of temperature, i.e., solvent quality, we found that the nanoparticles dispersed uniformly when molecular weight of the graft polymer was greater than that of the free polymer. However, when the free polymer molecular weight was greater than that of the graft polymer, the nanoparticles aggregated. Visual studies were also used to confirm the correspondence between nanoparticle stability and graft and free polymer molecular weights in a wide range of marginally poor solvents with PDMS. Further, the correspondence between nanoparticle stability and instability with graft and free polymer molecular weight and solvent quality was also supported with self-consistent mean-field calculations. Thus, by relating experiment and theory, our results indicate that nanoparticle stability in semidilute and concentrated polymer solutions is governed by interactions between the graft and free polymers under conditions of variable solvency. PMID- 20973522 TI - Synthesis of an ortho-triazacyclophane: N,N',N''-trimethyltribenzo-1,4,7 triazacyclononatriene. AB - N,N',N''-trimethyltribenzo-1,4,7-triazacyclononatriene has been synthesized via sequential palladium-catalyzed Buchwald-Hartwig N-arylation reactions affording the 9-membered triaza o-cyclophane in 35% overall yield. An X-ray crystal structure shows the new cyclophane to have a C2-symmetric saddle conformation, as compared to the crown conformation exhibited by the related carbocyclic cyclotriveratrylene (CTV). PMID- 20973523 TI - Sustained antibacterial activity from triclosan-loaded nanostructured mesoporous silicon. AB - In this work, nanostructured particles of porous silicon are demonstrated to act as an effective carrier for the sustained delivery of antibacterial agents with an enhanced inhibitory activity. Methods are described for the incorporation of significant amounts of the established antibacterial compound triclosan (Irgasan) into mesoporous silicon of varying porosities. Such materials were characterized by a combination of scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), X-ray diffraction (XRD), thermal gravimetric analysis (TGA), and antimicrobial assays. Assessment of antibacterial activity was carried out versus the bacterium Staphylococcus aureus as a function of time with concomitant assessment of triclosan release; significant, sustained inhibition of bacterial growth is demonstrated in the triclosan-containing porous Si for time intervals greater than 100 days. Significantly, enhanced dissolution (relative to room temperature equilibrium solubility) of the triclosan was observed for the initial 15 days of drug release, inferring some amorphization or nanostructuring by the porous Si matrix. PMID- 20973524 TI - Theoretical investigation of the rubicordifolin cascade. AB - The results of a theoretical investigation on the complex cascade reaction leading to the natural product rubicordifolin are reported. These computations analyze the discrete transformations that are required during the conversion of the vinyl naphthoquinone starting material into the natural product, including two pseudopericyclic cyclizations as well as a diastereoselective, hetero-Diels Alder reaction. PMID- 20973525 TI - Synthesis and electrochemical and theoretical studies of V-shaped donor-acceptor hexaazatriphenylene derivatives for second harmonic generation. AB - In this article we describe novel synthetic strategies toward well-defined disubstituted conjugated hexaazatriphenylene (HAT) derivatives. The systems are designed as novel V-shaped chromophores displaying C2 symmetry suitable for nonlinear optical investigations. Different donor moieties and linkers have been used in order to tune the electrochemical properties as well as the absorption spectra of the novel HAT derivatives. MUbeta values as high as 1010 * 10(-48) esu have been obtained for a derivative containing the electron-rich dibutylamino moiety. Theoretical calculations have been performed showing a reasonable agreement with the experimental results and supporting the two-dimensional NLO character of these chromophores. PMID- 20973527 TI - Ozone oxidation of surface-adsorbed polycyclic aromatic hydrocarbons: role of PAH surface interaction. AB - The heterogeneous chemistry of surface-adsorbed polycyclic aromatic hydrocarbons (PAHs) plays key roles in nanoscience, environmental science, and public health. Experimental evidence shows that the substrate can influence the heterogeneous oxidation of surface-bound PAHs, however, a mechanistic understanding of the role of the surface is still lacking. We examine the effects of the PAH-substrate interaction on the oxidation of surface-adsorbed anthracene, pyrene, and benzo[a]pyrene by ozone (O(3)) using density functional theory. We find that some O(3) oxidation mechanisms for these planar PAH molecules lead to nonplanar intermediates or products, the formation of which may necessitate partial desorption or "lift-off" from a solid substrate. The energy penalty for partial desorption of each PAH from the surface is estimated for four different substrate types on the basis of literature data and accounted for in the thermodynamic analysis of the reaction pathways. We find that the attractive PAH-substrate interaction may render oxidation pathways involving nonplanar intermediates or products thermodynamically unfavorable. The influence of the PAH-substrate interaction could contribute in part to the variations in PAH oxidation kinetics and product distributions that have been observed experimentally. Our choice of test molecules enabled us to identify trends in reactivity and product formation for four types of potentially reactive site (zigzag, armchair, bridge, and internal), allowing us to infer products and mechanisms of O(3) oxidation for PAHs of larger sizes. Implications for atmospheric chemistry and the stability of graphene in the presence of O(3) are discussed. PMID- 20973526 TI - The conformational free-energy landscape of beta-D-mannopyranose: evidence for a (1)S(5) -> B(2,5) -> (O)S(2) catalytic itinerary in beta-mannosidases. AB - The mechanism of glycosidic bond cleavage by glycosidases involves substrate ring distortions in the Michaelis complex that favor catalysis. Retaining beta mannosidases bind the substrate in a (1)S(5) conformation, and recent experiments have proposed an unusual substrate conformational pathway ((1)S(5) -> B(2,5) -> (O)S(2)) for the hydrolysis reaction. By means of Car-Parrinello metadynamics simulations, we have obtained the conformational free-energy surface (FES) of a beta-d-mannopyranose molecule associated with the ideal Stoddart conformational diagram. We have found that (1)S(5) is among the most stable conformers and simultaneously is the most preactivated conformation in terms of elongation/shortening of the C1-O1/C1-O5 bonds, C1-O1 orientation, and charge development at the anomeric carbon. Analysis of the computed FES gives support to the proposed (1)S(5) -> B(2,5) -> (O)S(2) catalytic itinerary, showing that the degree of preactivation of the substrate in glycoside hydrolases (GHs) is related to the properties of an isolated sugar ring. We introduce a simple preactivation index integrating several structural, electronic, and energetic properties that can be used to predict the conformation of the substrate in the Michaelis complex of any GH. PMID- 20973528 TI - Toluene-filled polypyrrole microvessels: entrapment and dynamics of encapsulated perylene. AB - Solid-supported and free-standing polypyrrole microcapsules were synthesized by deposition of the polymer onto toluene droplets. The polymer forms an encapsulating thin layer on the droplet surface. The encapsulation of the solvent was verified by FTIR measurements. Entrapment of other guest molecules can be achieved by using a solution of the guest molecules to prepare the droplets. This was demonstrated with perylene, a hydrophobic fluorescent molecule with well established spectroscopic properties. The encapsulation of perylene was probed with fluorescence spectroscopic techniques and optical microscopy. Time-resolved measurements allowed determination of relaxation dynamics of the fluorophore trapped in the capsules. It was shown that the rotational diffusion of perylene in toluene droplets is best described as a prolate rotor. The reorientation data suggest an increased solvent viscosity within the capsule. PMID- 20973529 TI - Saturation of surfactant structure at the single-walled carbon nanotube surface. AB - Density gradient ultracentrifugation (DGU) and fluorescence spectroscopy are used to probe the limiting behaviors of the dynamic response of surfactant structure at the single-walled carbon nanotube (SWNT) surface to reorganizing forces, including changes in surfactant concentration and electrolyte screening. DGU results indicate that, as surfactant (sodium dodecyl sulfate, SDS) concentration is increased, SDS adsorbed on metallic SWNTs becomes limited in its ability to reorganize before SDS adsorbed on semiconducting species. A diameter-dependent enhancement is observed in photoluminescence intensities from semiconducting SWNTS upon initial titration with NaCl. This response to electrostatic screening diminishes as SDS concentration is increased. The results are understood as a saturation of the surfactant structural response, defined as both a loss in ability to increase SDS loading at the SWNT surface and a loss in ability to reorient surface structure in response to a reorganizing force. Saturation of response is found to be reversible and also occurs as a result of restricting SDS mobility. These results confirm several aspects of recent molecular dynamics simulations of SDS behavior on SWNTs and have important implications for tunability of density-based separation approaches using cosurfactant systems that include SDS. PMID- 20973530 TI - Why did incorporation of acrylonitrile to a linear polyethylene become possible? Comparison of phosphine-sulfonate ligand with diphosphine and imine-phenolate ligands in the Pd-catalyzed ethylene/acrylonitrile copolymerization. AB - Palladium-catalyzed coordination-insertion copolymerization of ethylene with acrylonitrile (AN) proceeded only by using phosphine-sulfonate (P-SO(3)) as a ligand among the neutral and anionic ligands we examined, those are phosphine sulfonate (P-SO(3)), diphosphine (P-P), and imine-phenolate (N-O). In order to answer a question that is unique for P-SO(3), theoretical and experimental studies were carried out for the three catalyst systems. By comparing P-SO(3) and P-P, it was elucidated that (i) the pi-acrylonitrile complex [(L-L')PdPr(pi-AN)] is less stable than the corresponding sigma-complex [(L-L')PdPr(sigma-AN)] in both the phosphine-sulfonato complex (L-L' = P-SO(3)) and the diphosphine complex (L-L' = P-P) and (ii) the energetic difference between the pi-complex and the sigma-complex is smaller in the P-SO(3) complexes than in the P-P complexes. Thus, the energies of the transition states for both AN insertion and its subsequent ethylene insertion relative to the most stable species [(L L')PdPr(sigma-AN)] are lower for P-SO(3) than for P-P. The results nicely explain the difference between these two types of ligands. That is, ethylene insertion subsequent to AN insertion was detected for P-SO(3), while aggregate formation was reported for cationic [(L-L)Pd(CHCNCH(2)CH(3))] complex. Aggregate formation with the cationic complex can be considered as a result of the retarded ethylene insertion to [(L-L)Pd(CHCNCH(2)CH(3))]. In contrast, theoretical comparison between P-SO(3) and N-O did not show a significant energetic difference in both AN insertion and its subsequent ethylene insertion, implying that ethylene/AN copolymerization might be possible. However, our experiment using [(N O)PdMe(lutidine)] complex revealed that beta-hydride elimination terminated the ethylene oligomerization and, more importantly, that the resulting Pd-H species lead to formation of free N-OH and Pd(0) particles. The beta-hydride elimination process was further studied theoretically to clarify the difference between the two anionic ligands, P-SO(3) and N-O. PMID- 20973531 TI - Isotruxene-derived cone-shaped organic dyes for dye-sensitized solar cells. AB - The synthesis, electronic properties, and performance in dye-sensitized solar cells (DSSCs) of four cone-shaped organic dyes (ITD, ITD-Th, ITD-Hx, and ITD-OM) containing the isotruxene pi-scaffold are reported. Selective substitution of the unsymmetrical isotruxene core with two diarylamino donors and one cyanocarboxylic acid acceptor was achieved by using a prefunctionalized dibromoisotruxene building block. The ortho-para-branched isotruxene core allows strong electronic couplings among the donors and the acceptor, leading to red-shifted absorption profiles with significant charge-transfer character. All four isotruxene dyes display reversible anodic waves in cyclic voltammagrams with both HOMO and LUMO potentials suitable for application in DSSCs. The DSSCs fabricated with these cone-shaped organic dyes exhibited high open-circuit voltages (0.67-0.76 V) and fill factors (0.67-0.72) with a power conversion efficiency (eta) up to 5.45%, which is 80% of the ruthenium dye N719-based standard cell fabricated and measured under the same conditions. PMID- 20973532 TI - Enhanced hopping conductivity in low band gap donor-acceptor molecular wires Up to 20 nm in length. AB - We have measured the current-voltage characteristics of conjugated oligo tetrathiafulvalene-pyromelliticdiimide-imine (OTPI) wires ranging in length from 2.5 to 20.2 nm, contacted by Au electrodes. OTPI wires were built from Au substrates using alternating donor (tetrathiafulvalene, TTF) and acceptor (pyromelliticdiimide, PMDI) building blocks linked via aryl imine groups. Metal molecule-metal junctions consisting of approximately 100 wires in parallel were prepared by contacting the wire films with an Au-coated atomic force microscope tip. The long OTPI wires exhibit a narrow band gap (<1.5 eV) and multiple redox states, which facilitate carrier injection from the Au contacts for hopping transport. We observe the theoretically predicted change in direct current (DC) transport from tunneling to hopping as a function of systematically controlled wire length, as well as strongly enhanced wire conductivity (0.02 S/cm) in the hopping regime. Hopping conduction is confirmed by length-, temperature-, and field-dependent transport measurements. These nanoscale transport measurements illuminate the role of molecular length and bond architecture on molecular conductivity and open opportunities for greater understanding of hopping transport in conjugated polymer films. PMID- 20973533 TI - Antioxidant vitamins in barley green biomass. AB - Two malting hulled varieties (Sebastian, Malz) and one nonmalting hull-less variety (AF Lucius) were used to assess vitamins C and E in the green biomass of young plants of spring barley ( Hordeum vulgare L.) in three stages of growth and development (BBCH 29, 31, 32-33). The samples from sampling I (BBCH 29) had statistically significantly higher vitamin C content and vitamin E activity compared to sampling I (BBCH 31). The highest average vitamin content was determined in the malting variety Sebastian (vitamin C, 520 mg 100 g(-1) DM; vitamin E, 73.06 mg kg(-1) DM) compared to the varieties Malz (501 mg 100 g(-1) DM; 61.84 mg kg(-1) DM) and AF Lucius (508 mg 100 g(-1) DM; 67.81 mg 100 g(-1) DM). The locality Kromeriz (Czech Republic, CR), with vitamin C and E contents of 524 mg 100 g(-1) DM and 68.74 mg kg(-1) DM, respectively, proved to be more suitable for growing green biomass compared to the locality Zabcice (CR) (content of vitamins C and E, 477 mg 100 g(-1) DM and 66.39 mg kg(-1) DM, respectively). During the research period (2005-2007), it was determined that the green mass of young plants of spring barley was a significant source of vitamins C and E in the growth stage BBCH 29; in later samplings (BBCH 32-33) the vitamin levels dropped (by as much as 48%). These vitamins are important antioxidants for human health. Therefore, "green barley" can be recommended for the preparation of natural dietary supplements and is preferred to synthetic vitamin preparations. PMID- 20973534 TI - Design and characterization of HER-2-targeted gold nanoparticles for enhanced X radiation treatment of locally advanced breast cancer. AB - Our purpose was to develop a human epidermal growth factor receptor-2 (HER-2) targeted nanotechnology-based radiosensitizer. HER-2 is overexpressed in 20-30% of all breast cancers and up to 2-fold higher in locally advanced disease (LABC). Trastuzumab was derivatized with a polyethylene glycol (OPSS-PEG-SVA) cross linker to produce trastuzumab-PEG-OPSS. These immunoconjugates were analyzed by SDS-PAGE, and their immunoreactivity was assessed by flow cytometry using HER-2 overexpressing SK-BR-3 breast cancer cells. Reacting trastuzumab with increasing ratios of PEG resulted in an increase in molecular weight from approximately 148 kDa to 243 kDa, associated with increasing PEG substitution (0.6 to 18.9 PEG chains per trastuzumab). Attachment of approximately 7 PEG chains per trastuzumab resulted in 56% retention in immunoreactivity assessed by flow cytometry. The conjugates were then linked to 30 nm AuNPs. Using a novel (123)iodine-radiotracer based assay that overcomes the current limitations of spectrophotometric quantification of biological molecules on AuNPs we estimate 14.3 +/- 2.7 antibodies were attached to each AuNP when 2 * 10(11) AuNPs were reacted with 20 MUg of trastuzumab-PEG-OPSS. Specificity of trastuzumab-PEG-AuNPs for HER-2 and internalization in SK-BR-3 cells was demonstrated by comparing the uptake of trastuzumab-PEG-AuNPs or PEG-AuNPs by darkfield microscopy. The ability of trastuzumab-PEG-AuNPs in combination with 300 kVp X-rays to enhance DNA double strand breaks (DSBs) in SK-BR-3 cells was assessed by immunofluorescence using the gamma-H2AX assay. gamma-H2AX assay results revealed 5.1-fold higher DNA-DSBs with trastuzumab-PEG-AuNPs and X-radiation as compared to treatment with X radiation alone. The trastuzumab-PEG-AuNPs are a promising targeted nanotechnology-based radiosensitizer for improving LABC therapy. The design and systematic approaches taken to surface modify and characterize trastuzumab-PEG AuNPs described in this study would have application to other molecularly targeted AuNPs for cancer treatment. PMID- 20973535 TI - Improved in vitro assays of superoxide anion and 1,1-diphenyl- 2-picrylhydrazyl (DPPH) radical-scavenging activity of isoflavones and isoflavone metabolites. AB - Free radical-scavenging activity of isoflavones and some isoflavone metabolites have been described previously, but the results are inconsistent. The objective of the present study was to find out the pivotal factors that influence an accurate detection of both superoxide anion and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity. We here showed for the first time that organic solvents, including methanol, ethanol and acetone, were of strong superoxide radical-scavenging activity at concentrations down to 0.1% (v/v), however, no such activity was observed with acetonitrile at concentrations up to 2.0% (v/v). In DPPH assay, we found that the DPPH radical-scavenging ratio increased together with the extended reaction time. Based on our findings, improved in vitro assays for the detection of radical-scavenging activity of both isoflavones (daidzein and genistein) and isoflavone metabolites, including dihydrodaidzein (DHD), dihydrogenistein (DHG), and O-desmethylangolensin (O-Dma), were established. PMID- 20973536 TI - Nonadditive protein accumulation patterns in Maize (Zea mays L.) hybrids during embryo development. AB - Heterosis describes the superior performance of heterozygous F(1)-hybrid plants compared to their homozygous parental inbred lines. In the present study, heterosis was detected for length, weight, and the time point of seminal root primordia initiation in maize (Zea mays L.) embryos of the reciprocal F(1) hybrids UH005xUH250 and UH250xUH005. A two-dimensional gel electrophoresis (2-DE) proteome survey of the most abundant proteins of the reciprocal hybrids and their parental inbred lines 25 and 35 days after pollination revealed that 141 of 597 detected proteins (24%) exhibited nonadditive accumulation in at least one hybrid. Approximately 44% of all nonadditively accumulated proteins displayed an expression pattern that was not distinguishable from the low parent value. Electrospray ionization-tandem mass spectrometry (ESI-MS/MS) analyses and subsequent functional classification of the 141 proteins revealed that development, protein metabolism, redox-regulation, glycolysis, and amino acid metabolism were the most prominent functional classes among nonadditively accumulated proteins. In 35-day-old embryos of the hybrid UH250xUH005, a significant up-regulation of enzymes related to glucose metabolism which often exceeded the best parent values was observed. A comparison of nonadditive protein accumulation between rice and maize embryo data sets revealed a significant overlap of nonadditively accumulated proteins suggesting conserved organ- or tissue-specific regulatory mechanisms in monocots related to heterosis. PMID- 20973537 TI - Fluorescent caged compounds of 2,4-dichlorophenoxyacetic acid (2,4-d): photorelease technology for controlled release of 2,4-D. AB - A novel controlled-release formulation (CRF) of the herbicide 2,4 dichlorophenoxyacetic acid (2,4-D) was developed to reduce its negative environmental impacts by improving its herbicidal efficacy. The 2,4-D was chemically caged by coupling with photoremovable protecting groups (PRPGs) of coumarin derivatives. Photophysical studies of caged compounds showed that they all exhibited strong fluorescence properties. Controlled release of 2,4-D was achieved by irradiating the caged compounds using UV-vis light (310, 350, and 410 nm). The effect of various factors such as pH, solvent, and different substituents at the seventh position of coumarin moiety on the rate of photorelease was studied. The herbicidal activity of caged compounds and 4 (hydroxymethyl)-7-substituted coumarins was studied against Vigna radiata . The new formulation provided greater control over the release of 2,4-D by UV-vis light and also demonstrated the potential of the PRPGs not only to act as a delivery device but also to possess herbicidal activity after photorelease. PMID- 20973538 TI - Engineering nonspherical hollow structures with complex interiors by template engaged redox etching. AB - Despite the significant advancement in making hollow structures, one unsolved challenge in the field is how to engineer hollow structures with specific shapes, tunable compositions, and desirable interior structures. In particular, top-down engineering the interiors inside preformed hollow structures is still a daunting task. In this work, we demonstrate a facile approach for the preparation of a variety of uniform hollow structures, including Cu(2)O@Fe(OH)(x) nanorattles and Fe(OH)(x) cages with various shapes and dimensions by template-engaged redox etching of shape-controlled Cu(2)O crystals. The composition can be readily modulated at different structural levels to generate other interesting structures such as Cu(2)O@Fe(2)O(3) and Cu@Fe(3)O(4) rattles, as well as Fe(2)O(3) and Fe(3)O(4) cages. More remarkably, this strategy enables top-down engineering the interiors of hollow structures as demonstrated by the fabrication of double walled nanorattles and nanoboxes, and even box-in-box structures. In addition, this approach is also applied to form Au and MnO(x) based hollow structures. PMID- 20973539 TI - Detection of vibrational bending mode nu8 and overtone bands of the propargyl radical, HCCCH2 X 2B1. AB - Infrared (IR) absorption spectra of matrix-isolated HCCCH(2) have been measured. Propargyl radicals were generated in a supersonic pyrolysis nozzle, using a method similar to that described in a previous study (Jochnowitz, E. B.; Zhang, X.; Nimlos, M. R.; Varner, M. E.; Stanton, J. F.; Ellison, G. B. J. Phys. Chem. A 2005, 109, 3812-3821). Besides the nine vibrational modes observed in the previous study, this investigation detected the HCCCH(2) X (2)B(1) out-of-plane bending mode (nu(8)) at 378.0 (+/-1.9) cm(-1) in a cryogenic argon matrix. This is the first experimental observation of nu(8) for the propargyl radical. In addition, seven overtone and combination bands have also been detected and assigned. Ab initio coupled-cluster anharmonic force field calculations were used to guide the analysis. Furthermore, nu(12), the HCCCH(2) in-plane bending mode, has been assigned to 333 (+/-10) cm(-1) based on the detection of its overtone (2nu(12), 667.7 +/- 1.0 cm(-1)) and a possible combination band (nu(10) + nu(12), 1339.0 +/- 0.8 cm(-1)). This is the first experimental estimation of nu(12) for the propargyl radical. PMID- 20973540 TI - Phthalocyanine-pyrene conjugates: a powerful approach toward carbon nanotube solar cells. AB - In the present work, a new family of pyrene (Py)-substituted phthalocyanines (Pcs), i.e., ZnPc-Py and H(2)Pc-Py, were designed, synthesized, and probed in light of their spectroscopic properties as well as their interactions with single wall carbon nanotubes (SWNTs). The pyrene units provide the means for non covalent functionalization of SWNTs via pi-pi interactions. Such a versatile approach ensures that the electronic properties of SWNTs are not impacted by the chemical modification of the carbon skeleton. The characterization of ZnPc Py/SWNT and H(2)Pc-Py/SWNT has been performed in suspension and in thin films by means of different spectroscopic and photoelectrochemical techniques. Transient absorption experiments reveal photoinduced electron transfer between the photoactive components. ZnPc-Py/SWNT and H(2)Pc-Py/SWNT have been integrated into photoactive electrodes, revealing stable and reproducible photocurrents with monochromatic internal photoconversion efficiency values for H(2)Pc-Py/SWNT as large as 15 and 23% without and with an applied bias of +0.1 V. PMID- 20973541 TI - Temperature tunable micellization of polystyrene-block-poly(2-vinylpyridine) at Si-ionic liquid interface. AB - Highly ordered and stable micelles formed from both symmetric and asymmetric block copolymers of polystyrene-block-poly(2-vinylpyridine) (PS-b-P2VP) at the Si ionic liquid (IL) interface have been investigated by scanning force microscopy (SFM) and transmission electron microscopy (TEM). The 1-butyl-3-methylimidazolium trifluoromethanesulfonate IL, a selective and temperature-tunable solvent for the P2VP block, was used and gave rise to block copolymer micelles having different morphologies that strongly depended on the annealing temperature. The effects of film thickness, molecular weight of block copolymers, and experimental conditions, such as preannealing, rinsing, and substrate properties, on the morphologies of block copolymer micelles were also studied. In addition, spherical micelles consisting of PS core and P2VP shell could also be obtained by core-corona inversion by annealing the as-coated micellar film in the IL at high temperatures. The possible mechanism for micelle formation is discussed. PMID- 20973542 TI - An improved global model for air-sea exchange of mercury: high concentrations over the North Atlantic. AB - We develop an improved treatment of the surface ocean in the GEOS-Chem global 3-D biogeochemical model for mercury (Hg). We replace the globally uniform subsurface ocean Hg concentrations used in the original model with basin-specific values based on measurements. Updated chemical mechanisms for Hg0/Hg(II) redox reactions in the surface ocean include both photochemical and biological processes, and we improved the parametrization of particle-associated Hg scavenging. Modeled aqueous Hg concentrations are consistent with limited surface water observations. Results more accurately reproduce high-observed MBL concentrations over the North Atlantic (NA) and the associated seasonal trends. High seasonal evasion in the NA is driven by inputs from Hg enriched subsurface waters through entrainment and Ekman pumping. Globally, subsurface waters account for 40% of Hg inputs to the ocean mixed layer, and 60% is from atmospheric deposition. Although globally the ocean is a net sink for 3.8 Mmol Hg y-1, the NA is a net source to the atmosphere, potentially due to enrichment of subsurface waters with legacy Hg from historical anthropogenic sources. PMID- 20973543 TI - Highly diastereo- and enantioselective organocatalytic michael addition of alpha ketoamides to nitroalkenes. AB - The first organocatalytic enantio- and diastereoselective conjugate addition of alpha-ketoamides to nitroalkenes has been achieved using a bifunctional amino thiourea catalyst. In this new approach, the substrate amide proton plays a critical role in the formation of the Michael anti-adducts in high yields and high stereoselectivities. To illustrate the high synthetic potential of this methodology, the diastereo- and enantioselective synthesis of a hexasubstituted cyclohexane via a Michael-Michael-Henry cascade reaction is described. PMID- 20973544 TI - Beyond photovoltaics: semiconductor nanoarchitectures for liquid-junction solar cells. PMID- 20973545 TI - Increased water resistance of CTMP fibers by oat (Avena sativa L.) husk lignin. AB - The insertion of oat husk lignin onto chemithermomechanical pulp (CTMP) fibers was studied to increase fiber hydrophobicity. The pretreated pulp samples were subsequently used for preparation of handsheets for characterization. Treatment of CTMP with laccase in the presence of oat husk lignin resulted in a significant increase in hydrophobicity of the handsheet surface, as indicated by dynamic contact angle analysis. Water absorption time of 8 s was obtained with initial contact angle of 118 degrees . Although the handsheet's brightness was reduced by 33%, tensile index was only subtly decreased. Neither laccase nor oat husk lignin alone gave much improved water absorption times. Therefore, handsheets made of laccase-treated pulp with and without oat husk lignin were further examined by XPS, which suggested that both laccase and oat husk lignin were inserted onto CTMP fibers. The oat husk lignin was distributed as heterogeneous aggregates on the handsheet surface whereas laccase was uniformly distributed. Evidence was obtained that the adsorbed laccase layer formed a noncovalent base for the insertion of oat husk lignin onto fiber surfaces. PMID- 20973546 TI - Transport behavior of surrogate biological warfare agents in a simulated landfill: effect of leachate recirculation and water infiltration. AB - An understanding of the transport behavior of biological warfare (BW) agents in landfills is required to evaluate the suitability of landfills for the disposal of building decontamination residue (BDR) following a bioterrorist attack on a building. Surrogate BW agents, Bacillus atrophaeus spores and Serratia marcescens, were spiked into simulated landfill reactors that were filled with synthetic building debris (SBD) and operated for 4 months with leachate recirculation or water infiltration. Quantitative polymerase chain reaction (Q PCR) was used to monitor surrogate transport. In the leachate recirculation reactors, <10% of spiked surrogates were eluted in leachate over 4 months. In contrast, 45% and 31% of spiked S. marcescens and B. atrophaeus spores were eluted in leachate in the water infiltration reactors. At the termination of the experiment, the number of retained cells and spores in SBD was measured over the depth of the reactor. Less than 3% of the total spiked S. marcescens cells and no B. atrophaeus spores were detected in SBD. These results suggest that significant fractions of the spiked surrogates were strongly attached to SBD. PMID- 20973547 TI - Increased accumulation of sulfur in lake sediments of the high arctic. AB - We report a synchronous increase in accumulation of reduced inorganic sulfur since c. 1980 in sediment cores from eight of nine lakes studied in the Canadian Arctic and Svalbard (Norway). Sediment incubations and detailed analyses of sediment profiles from two of the lakes indicate that increases in sulfur accumulation may be due ultimately to a changing climate. Warming-induced lengthening of the ice-free season is resulting in well-documented increases in algal production and sedimentation of the resulting detrital matter. Algal detritus is a rich source of labile carbon, which in these sediments stimulates dissimilatory sulfate reduction. The sulfide produced is stored in sediment (as acid volatile sulfide), converted to other forms of sulfur, or reoxidized to sulfate and lost to the water column. An acceleration of the sulfur cycle in Arctic lakes could have profound effects on important biogeochemical processes, such as carbon burial and mercury methylation. PMID- 20973548 TI - Furan-2,5-dimethylene-tethered bis-imidacloprid insecticide conferring high potency. AB - Bis-imidacloprid (bis-IMI) analogues with suitable alkylene spacers have plant systemic insecticidal properties. The alkylene-tethered bis-IMI binds in a unique mode to the insect nicotinic acetylcholine receptor (nAChR) wherein the chloropyridine moieties are embraced by two distinct and distant domains. The heptamethylene spacer optimally bridges these two subsites, yet the linker itself binds in a relatively nonspecific manner. This investigation examines the hypothesis that a bis-IMI analogue with a heteroaromatic tether, which undergoes specific interaction(s) with the newly recognized receptor cavity, may enhance the potency relative to those of the alkylene-tethered derivatives. Remarkably, a novel bis-IMI with a furan-2,5-dimethylene fulcrum showed highest receptor potency and insecticidal activity among the analogues with various chemotype spacers. The nAChR structural model, simulating the binding site interactions of the furan-2,5-dimethylene-tethered bis-IMI, reveals that the furan ring is nestled in a hydrophobic pocket, consisting of three aromatic amino acids, and is stabilized via hydrogen bonding. PMID- 20973549 TI - Separation of disaccharides by comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry. Application to honey analysis. AB - A new method based on comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC*GC-ToF MS) has been developed for the first time for the analysis of complex mixtures of disaccharides previously converted to their trimethylsilyl oximes (TMSO). Among the different experimental parameters considered for optimization, both the column set combination and the dimensions of the second-dimension column were found to be the most significant with regard to the complete resolution of structurally similar disaccharides. Application of the optimized method to honey analysis allowed the separation of most of the honey disaccharides previously described in the literature. Furthermore, 12 other unknown disaccharides have been separated by this method and characterized from their mass spectral data. PMID- 20973550 TI - Inhibition of melanogenesis and oxidation by protocatechuic acid from Origanum vulgare (oregano). AB - Antioxidant and antimelanogenesis activities of protocatechuic acid (1) from Origanum vulgare (oregano) were investigated. The antioxidative capacity of 1 was confirmed from its free-radical-scavenging activities, inhibition of lipid peroxidation, and suppression of reactive oxygen species in H(2)O(2)-induced BNLCL2 cells. The inhibition by 1 of tyrosinase and DOPA oxidase activity and melanin production was possibly related to the down-regulation of melanocortin-1 receptor, microphthalmia-associated transcription factor, tyrosinase, tyrosinase related proteins-2, and tyrosinase-related proteins-1 expression in alpha melanocyte-stimulating hormone-induced B16 cells. After a gel containing 1 was applied to mice, the values of L* slightly increased, and a* and erythema-melanin levels of skin were reduced by comparing the values of untreated control groups, indicating 1 can reduce melanin production. These results suggest that 1 may act as an effective quencher of oxidative attackers with antimelanogenesis properties. PMID- 20973551 TI - Highly brominated antimicrobial metabolites from a marine Pseudoalteromonas sp. AB - Extracts of a marine Pseudoalteromonas sp. (CMMED 290) isolated from the surface of a nudibranch collected in Kaneohe Bay, Oahu, displayed significant antimicrobial activity against methicillin-resistant Staphylococcus aureus. Bioassay-guided fractionation of the lipophilic extract led to the isolation and structure elucidation of two new highly brominated compounds, 2,3,5,7 tetrabromobenzofuro[3,2-b]pyrrole (1) and 4,4',6-tribromo-2,2'-biphenol (2). In addition, we have identified the known compounds pentabromopseudilin and bromophene. We describe the isolation and structure elucidation of the compounds 1 and 2 together with their antimicrobial activities against methicillin resistant Staphylococcus aureus. PMID- 20973552 TI - Design, synthesis, and preclinical evaluation of new 5,6- (or 6,7-) disubstituted 2-(fluorophenyl)quinolin-4-one derivatives as potent antitumor agents. AB - Our previous exploration of 2-phenylquinolin-4-ones (2-PQs) has led to an anticancer drug candidate 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1-P-Na). In order to develop additional new drug candidates, novel 2-PQs were designed, synthesized, and evaluated for cytotoxic activity. Most analogues, including 1b, 2a,b, 3a,b, 4a,b, and 5a,b, exhibited significant inhibitory activity (IC(50) of 0.03-8.2 MUM) against all tested tumor cell lines. As one of the most potent analogue, 2-(3-fluorophenyl)-5-hydroxy-6 methoxyquinolin-4-one (3b) selectively inhibited 14 out of 60 cancer cell lines in a National Cancer Institute (NCI) evaluation. Preliminary mechanism of action study suggested that 3b had a significant effect on the tyrosine autophosphorylation of insulin-like growth factor-1 receptor (IGF-1R). Safety pharmacology profiling of 3b showed no significant effect on normal biological functions of most enzymes tested. Furthermore, sodium 2-(3-fluorophenyl)-6 methoxy-4-oxo-1,4-dihydroquinolin-5-yl phosphate (15), the monophosphate of 3b, exceeded the activity of doxorubicin and was comparable to CHM-1-P-Na in a Hep3B xenograft nude mice model. In summary, 15 is a promising clinical candidate and is currently under preclinical study. PMID- 20973553 TI - The effect of high pressure-high temperature processing conditions on acrylamide formation and other Maillard reaction compounds. AB - The effect of high pressure-high temperature (HPHT) processing on the formation of acrylamide and other Maillard-type reaction compounds was investigated in order to elucidate the impact of HPHT conditions on the different stages of the Maillard reaction. This study was performed in equimolar asparagine-glucose model systems that were treated at various HP/HT conditions (100-115 degrees C, 400 700 MPa, 0-60 min), and, for comparison, the model system was also heat-treated at ambient pressure. On the treated samples, the concentration of acrylamide, reactants, hydroxymethylfurfural, organic acids, and melanoidins was determined and the pH prior to and after treatment was measured. Based on the measured responses, the retarding effect of high pressure on the overall Maillard reaction was demonstrated; no or little differences were observed between 400 and 700 MPa. The study was conducted in two types of buffer, i.e. phosphate and MES buffer. In case of acrylamide, aspartic acid and browning, a higher concentration was generated in the MES buffer system, but these differences with the phosphate buffer system could be ascribed to pH changes resulting from the application of combined high pressure and high temperature. Based on the results, acrylamide formation is not expected to pose a major hazard to HPHT-treated products. PMID- 20973554 TI - Excited-state vibrational coherence in methanol solution of Zn(II) tetrakis(N methylpyridyl)porphyrin: charge-dependent intermolecular mode frequencies and implications for electron-transfer dynamics in photosynthetic reaction centers. AB - The nature of the intermolecular vibrational modes between the redox-active chromophores and the protein medium in the photosynthetic reaction center is central to an understanding of the structural origin of the quantum efficiency of the light-driven charge-separation reactions that result in storage of solar energy. In recent work on this issue, we have characterized the low-frequency vibrational coherence of Zn(II) meso-tetrakis(N-methylpyridyl)porphyrin (ZnTMPyP) and compared it to that from bacteriochlorophyll a in polar solution and in the small light-harvesting subunits B820 and B777. The charge-transfer character of ZnTMPyP's pi* excited states afford us the opportunity to characterize how the intermolecular vibrational modes and potential with the surrounding medium are affected by the charge on the porphyrin macrocycle. The excited-state vibrational coherence observed with Q-band (S(1) state) excitation at 625 nm of ZnTMPyP in methanol solution contains dominant contributions from a pair of rapidly damped (effective damping time gamma < 400 fs) components that are assigned to the hindered translational and librational porphyrin-solvent intermolecular modes. The 256 cm(-1) mean frequency of the intermolecular modes is significantly higher than that observed previously in the ground state, 79 cm(-1), with Soret-band excitation at 420 nm [Dillman et al., J. Phys. Chem. B. 2009, 113, 6127-6139]. The increased mode frequency arises from the activation of the ion-dipole and ion induced-dipole terms in the intermolecular potential. In the ground state, the pi electron density of ZnTMPyP is mostly confined to the region of the porphyrin macrocycle. In the excited state, the pi-electron density is extensively delocalized from the porphyrin out to two of the peripheral N-methylpyridyl rings, each of which carries a single formal charge. The charge-dependent terms contribute to a significant stabilization of the equilibrium geometry of the porphyrin-solvent complex in the excited state. In the photosynthetic reaction center, these terms will play an important role in trapping the charged products of the forward, charge-separation reactions, and the location of the bacteriopheophytin acceptor in a nonpolar region of the structure enhances the rate of the secondary charge-separation reaction. PMID- 20973555 TI - Gas-phase structure and fragmentation pathways of singly protonated peptides with N-terminal arginine. AB - The gas-phase structures and fragmentation pathways of the singly protonated peptide arginylglycylaspartic acid (RGD) are investigated by means of collision induced-dissociation (CID) and detailed molecular mechanics and density functional theory (DFT) calculations. It is demonstrated that despite the ionizing proton being strongly sequestered at the guanidine group, protonated RGD can easily be fragmented on charge directed fragmentation pathways. This is due to facile mobilization of the C-terminal or aspartic acid COOH protons thereby generating salt-bridge (SB) stabilized structures. These SB intermediates can directly fragment to generate b(2) ions or facilely rearrange to form anhydrides from which both b(2) and b(2)+H(2)O fragments can be formed. The salt-bridge stabilized and anhydride transition structures (TSs) necessary to form b(2) and b(2)+H(2)O are much lower in energy than their traditional charge solvated counterparts. These mechanisms provide compelling evidence of the role of SB and anhydride structures in protonated peptide fragmentation which complements and supports our recent findings for tryptic systems (Bythell, B. J.; Suhai, S.; Somogyi, A.; Paizs, B. J. Am. Chem. Soc. 2009, 131, 14057-14065.). In addition to these findings we also report on the mechanisms for the formation of the b(1) ion, neutral loss (H(2)O, NH(3), guanidine) fragment ions, and the d(3) ion. PMID- 20973556 TI - Selective formation of a latticed nanostructure with the precise alignment of DNA templated gold nanowires. AB - A very efficient method is introduced to selectively align and uniformly separate lambda-DNA molecules and thus DNA-templated gold nanowires (AuNW's) using a combination of molecular combing and surface-patterning techniques. By the method presented in this work, it is possible to obtain parallel and latticed nanostructures consisting of DNA molecules and thus DNA-templated AuNW's aligned at 400 nm intervals. DNA-templated AuNW's are uniformly formed with an average height of 2.5 nm. This method is expected to hold potential for the integration of nanosized building blocks applicable to nanodevice construction. PMID- 20973557 TI - Effect of ionic liquid on prototropic and solvatochromic behavior of fluorescein. AB - The effect of a water-miscible room-temperature ionic liquid (IL), 1-butyl-3 methylimidazolium tetrafluoroborate ([bmim][BF(4)]), on the behavior of a common and popular probe fluorescein is assessed. Depending on solubilizing milieu and conditions, fluorescein may exist in one or more of its prototropic forms (cationic, neutral (zwitterionic, quinoid, and lactone), monoanionic (phenolate and carboxylate), and dianionic) in the solution. Information regarding the various prototropic forms of fluorescein in buffer-rich aqueous IL mixtures ([bmim][BF(4)] <= 50 wt %, mole fraction <0.1) at different pH is obtained via UV vis absorbance and fluorescence. The addition of [bmim][BF(4)] is found to cause lactonization of fluorescein in the solution. Hydrolytic instability of IL [bmim][BF(4)] is observed to be much lower than that of NaBF(4). Absorbance and fluorescence from fluorescein are observed to be insignificant when dissolved in neat [bmim][BF(4)], suggesting the presence of predominantly the lactone form. The IL [bmim][BF(4)] behaves similar to apolar media in this context. It is demonstrated that various prototropic forms of fluorescein may be generated within [bmim][BF(4)] by the addition of buffer of appropriate pH. Significant bathochromic shift in absorbance and fluorescence band maxima of dianionic fluorescein as concentration of [bmim][BF(4)] is increased correlates well with the decrease in the hydrogen-bond-donating acidity of the medium. The lack of good linear correlation between the Stokes shift and the orientational polarizability suggests the possible presence of specific Coulombic interaction between the IL cation and the fluorescein dianion within the mixture. It is established that IL [bmim][BF(4)] has an interesting and unique effect on the prototropic behavior of fluorescein. PMID- 20973558 TI - Adsorption and separation of organic six-membered ring analogues on neutral Cd(II)-MOF generated from asymmetric schiff-base ligand. AB - A new CdL(2)-MOF was synthesized based on an asymmetric Schiff-base ligand LH, which is obtained by condensation of 5-formyl-8-hydroxyquinoline and 3 pyridinecarboxylic acid hydrazide. A series of organic six-membered ring analogues, namely, 1,4-dioxane, cyclohexane, cyclohexene, benzene, cyclohexanone, and cyclohexanol, can be absorbed by the CdL(2) porous framework in liquid-phase to generate G(n)?CdL(2) (n = 1 and 2) host-guest complexes. In addition, the CdL(2) host framework displays different affinity for these six-membered ring substrates and can effectively separate them under mild conditions (i.e., 1, 4 dioxane > cyclohexane > cyclohexene and benzene > cyclohexanone > cyclohexanol). The empty CdL(2) displays strong green-yellow emission. Furthermore, these host guest systems show an interesting guest-driven luminescent emission, and the emission intensities of these guest-loaded complexes are effectively reduced. PMID- 20973559 TI - Novel loss-of-function putative aminotransferase alleles cause biosynthesis of capsinoids, nonpungent capsaicinoid analogues, in mildly pungent chili peppers (Capsicum chinense). AB - Capsinoids are a group of nonpungent capsaicinoid analogues produced in Capsicum fruits. They have similar bioactivities to capsaicinoids such as suppression of fat accumulation and antioxidant activity. They are more palatable ingredients in dietary supplements than capsaicinoids because of their low pungency. Previous studies on nonpungent Capsicum annuum cultivars showed that capsinoid biosynthesis is caused by loss-of-function putative aminotransferase (p-amt) alleles. This study showed that three mildly pungent cultivars of Capsicum chinense (Zavory Hot, Aji Dulce strain 2, and Belize Sweet) contain high levels of capsinoid. It was shown that these cultivars have novel p-amt alleles, which contain mutations that differ from those of C. annuum. Sequence analysis of p-amt in Belize Sweet revealed that a 5 bp insertion (TGGGC) results in a frameshift mutation. A transposable element (Tcc) was found in the p-amt of Zavory Hot and Aji Dulce strain 2. Tcc has features similar to those of the hAT transposon family. This was inserted in the fifth intron of Zavory Hot and in third intron of Aji Dulce strain 2. The p-amt alleles harboring Tcc cannot produce an active p AMT. These mildly pungent cultivars will provide a new natural source of capsinoids. PMID- 20973560 TI - Computational medicinal chemistry. PMID- 20973563 TI - Thermodynamic properties of N-isopropylacrylamide in water: solubility transition, phase separation of supersaturated solution, and glass formation. AB - The solubility of N-isopropylacrylamide (NIPA) in water was found to discretely change at 25 degrees C. The highly concentrated NIPA solution separated into two solutions, the concentrations of which were higher than the solubility below 25 degrees C and lower than the solubility above 25 degrees C. The X-ray crystallographic analysis indicated that a NIPA crystal formed in the aqueous solution was H(2)O free. When the aqueous NIPA phase-separated solutions were cooled down to -90 degrees C at a rate faster than 35 degrees C/min, the glassy structure formed. On the other hand, the crystalline solid formation of NIPA and H(2)O were observed when the solutions were cooled to -50 degrees C at a slower rate than 3 degrees C/min. The DSC measurements of the phase-separated solutions revealed that the energy levels of NIPA were +15.2, +11.5, and -0.08 kJ/mol (regarding the crystalline solid state at 25 degrees C as the ground state) for the liquid state, the H(2)O-poor solution and the H(2)O-rich solution in the phase-separated state, respectively. The experimental results are explained in terms of the molecular assemblies of NIPA and H(2)O molecules in the solutions. PMID- 20973561 TI - Assessment of chemoselective neoglycosylation methods using chlorambucil as a model. AB - To systematically assess the impact of glycosylation and the corresponding chemoselective linker upon the anticancer activity/selectivity of the drug chlorambucil, herein we report the synthesis and anticancer activities of a 63 member library of chlorambucil-based neoglycosides. A comparison of N-alkoxyamine , N-acylhydrazine-, and N-hydroxyamine-based chemoselective glycosylation of chlorambucil revealed sugar- and linker-dependent partitioning among open- and closed-ring neoglycosides and corresponding sugar-dependent variant biological activity. Cumulatively, this study represents the first neoglycorandomization of a synthetic drug and expands our understanding of the impact of sugar structure upon product distribution/equilibria in the context of N-alkoxyamino-, N hydroxyamino-, and N-acylhydrazine-based chemoselective glycosylation. This study also revealed several analogues with increased in vitro anticancer activity, most notably D-threoside 60 (NSC 748747), which displayed much broader tumor specificity and notably increased potency over the parent drug. PMID- 20973564 TI - Mechanism of xylobiose hydrolysis by GH43 beta-xylosidase. AB - Glycoside hydrolases cleave the glycosidic linkage between two carbohydrate moieties. They are among the most efficient enzymes currently known. beta Xylosidases from glycoside hydrolase family 43 hydrolyze the nonreducing ends of xylooligomers using an inverting mechanism. Although the general mechanism and catalytic amino acid residues of beta-xylosidases are known, the nature of the reaction's transition state and the conformations adopted by the glycon xylopyranosyl ring along the reaction pathway are still elusive. In this work, the xylobiose hydrolysis reaction catalyzed by XynB3, a beta-xylosidase produced by Geobacillus stearothermophilus T-6, was explicitly modeled using first principles quantum mechanics/molecular mechanics Car-Parrinello metadynamics. We present the reaction's free energy surface and its previously undetermined reaction pathway. The simulations also show that the glycon xylopyranosyl ring proceeds through a (2,5)B-type transition state with significant oxacarbenium ion character. PMID- 20973565 TI - Quantitative analysis of human cerebrospinal fluid proteins using a combination of cysteine tagging and amine-reactive isobaric labeling. AB - Highly complex and dynamic protein mixtures are hardly comprehensively resolved by direct shotgun proteomic analysis. As many proteins of biological interest are of low abundance, numerous analytical methodologies have been developed to reduce sample complexity and go deeper into proteomes. The present work describes an analytical strategy to perform cysteinyl-peptide subset enrichment and relative quantification through successive cysteine and amine-isobaric tagging. A cysteine reactive covalent capture tag (C3T) allowed derivatization of cysteines and specific isolation on a covalent capture (CC) resin. The 6-plex amine-reactive tandem mass tags (TMT) served for relative quantification of the targeted peptides. The strategy was first evaluated on a model protein mixture with increasing concentrations to assess the specificity of the enrichment and the quantitative performances of the workflow. It was then applied to human cerebrospinal fluid (CSF) from post-mortem and ante-mortem samples. These studies confirmed the specificity of the C3T and the CC technique to cysteine-containing peptides. The model protein mixture analysis showed high precision and accuracy of the quantification with coefficients of variation and mean absolute errors of less than 10% on average. The CSF experiments demonstrated the potential of the strategy to study complex biological samples and identify differential brain related proteins. In addition, the quantification data were highly correlated with a classical TMT experiment (i.e., without C3T cysteine-tagging and enrichment steps). Altogether, these results legitimate the use of this quantitative C3T strategy to enrich and relatively quantify cysteine-containing peptides in complex mixtures. PMID- 20973566 TI - A universal approach to fabricate ordered colloidal crystals arrays based on electrostatic self-assembly. AB - We present a novel and simple method to fabricate two-dimensional (2D) poly(styrene sulfate) (PSS, negatively charged) colloidal crystals on a positively charged substrate. Our strategy contains two separate steps: one is the three-dimensional (3D) assembly of PSS particles in ethanol, and the other is electrostatic adsorption in water. First, 3D assembly in ethanol phase eliminates electrostatic attractions between colloids and the substrate. As a result, high quality colloidal crystals are easily generated, for electrostatic attractions are unfavorable for the movement of colloidal particles during convective self assembly. Subsequently, top layers of colloidal spheres are washed away in the water phase, whereas well-packed PSS colloids that are in contact with the substrate are tightly linked due to electrostatic interactions, resulting in the formation of ordered arrays of 2D colloidal spheres. Cycling these processes leads to the layer-by-layer assembly of 3D colloidal crystals with controllable layers. In addition, this strategy can be extended to the fabrication of patterned 2D colloidal crystals on patterned polyelectrolyte surfaces, not only on planar substrates but also on nonplanar substrates. This straightforward method may open up new possibilities for practical use of colloidal crystals of excellent quality, various patterns, and controllable fashions. PMID- 20973567 TI - Global protein-protein interaction network in the human pathogen Mycobacterium tuberculosis H37Rv. AB - Analysis of the protein-protein interaction network of a pathogen is a powerful approach for dissecting gene function, potential signal transduction, and virulence pathways. This study looks at the construction of a global protein protein interaction (PPI) network for the human pathogen Mycobacterium tuberculosis H37Rv, based on a high-throughput bacterial two-hybrid method. Almost the entire ORFeome was cloned, and more than 8000 novel interactions were identified. The overall quality of the PPI network was validated through two independent methods, and a high success rate of more than 60% was obtained. The parameters of PPI networks were calculated. The average shortest path length was 4.31. The topological coefficient of the M. tuberculosis B2H network perfectly followed a power law distribution (correlation = 0.999; R-squared = 0.999) and represented the best fit in all currently available PPI networks. A cross-species PPI network comparison revealed 94 conserved subnetworks between M. tuberculosis and several prokaryotic organism PPI networks. The global network was linked to the protein secretion pathway. Two WhiB-like regulators were found to be highly connected proteins in the global network. This is the first systematic noncomputational PPI data for the human pathogen, and it provides a useful resource for studies of infection mechanisms, new signaling pathways, and novel antituberculosis drug development. PMID- 20973568 TI - Prediction of tyrosine sulfation with mRMR feature selection and analysis. AB - Protein tyrosine sulfation is a ubiquitous post-translational modification (PTM) of secreted and transmembrane proteins that pass through the Golgi apparatus. In this study, we developed a new method for protein tyrosine sulfation prediction based on a nearest neighbor algorithm with the maximum relevance minimum redundancy (mRMR) method followed by incremental feature selection (IFS). We incorporated features of sequence conservation, residual disorder, and amino acid factor, 229 features in total, to predict tyrosine sulfation sites. From these 229 features, 145 features were selected and deemed as the optimized features for the prediction. The prediction model achieved a prediction accuracy of 90.01% using the optimal 145-feature set. Feature analysis showed that conservation, disorder, and physicochemical/biochemical properties of amino acids all contributed to the sulfation process. Site-specific feature analysis showed that the features derived from its surrounding sites contributed profoundly to sulfation site determination in addition to features derived from the sulfation site itself. The detailed feature analysis in this paper might help understand more of the sulfation mechanism and guide the related experimental validation. PMID- 20973569 TI - Compid: a new software tool to integrate and compare MS/MS based protein identification results from Mascot and Paragon. AB - Tandem mass spectrometry-based proteomics experiments produce large amounts of raw data, and different database search engines are needed to reliably identify all the proteins from this data. Here, we present Compid, an easy-to-use software tool that can be used to integrate and compare protein identification results from two search engines, Mascot and Paragon. Additionally, Compid enables extraction of information from large Mascot result files that cannot be opened via the Web interface and calculation of general statistical information about peptide and protein identifications in a data set. To demonstrate the usefulness of this tool, we used Compid to compare Mascot and Paragon database search results for mitochondrial proteome sample of human keratinocytes. The reports generated by Compid can be exported and opened as Excel documents or as text files using configurable delimiters, allowing the analysis and further processing of Compid output with a multitude of programs. Compid is freely available and can be downloaded from http://users.utu.fi/lanatr/compid. It is released under an open source license (GPL), enabling modification of the source code. Its modular architecture allows for creation of supplementary software components e.g. to enable support for additional input formats and report categories. PMID- 20973572 TI - Preparation and characterization of nanomaterials for sustainable energy production. AB - The use of nanotechnology to develop a suite of sustainable energy production schemes is one of the most important scientific challenges of the 21st century. The challenge is to design, to synthesize, and to characterize new functional nanomaterials with controllable sizes, shapes, and/or structures. To summarize the progress of the research and development made in this important field, the Fuel Chemistry Division of the American Chemical Society (ACS) organized a symposium on "Nanotechnology for Sustainable Energy and Fuels" during the 240th ACS National Meeting in Boston, MA on August 22-26, 2010, with the ACS Catalysis Division as the cosponsor. This symposium was a global gathering of leading scientists at the intersection of energy and nanotechnology. The topics discussed at the symposium included nanotechnology, not only for traditional fossil fuel production but also for novel processes for renewable energy applications. This article aims to highlight some of the most exciting advances presented at the symposium, including the preparation and characterization of nanomaterials for clean fuel production, CO(2) capture, solar cells and solar fuels, energy conversion and storage materials, hydrogen storage materials, and fuel cells. Finally, possible future developments in this important and timely area are discussed. PMID- 20973573 TI - Correlating physico-chemical with toxicological properties of nanoparticles: the present and the future. AB - Nanotoxicology is still a new discipline. In this Perspective, both its origins and its future trends are discussed. In particular, we note several issues we consider important for publications in this field. PMID- 20973574 TI - Photochemically controlled synthesis of anisotropic Au nanostructures: platelet like Au nanorods and six-star Au nanoparticles. AB - We report the shape-controlled synthesis of anisotropic Au nanostructures through TiO(2)-assisted photochemical reduction of HAuCl(4). By using this method, we have successfully synthesized the platelet-like Au nanorods and six-star Au nanoparticles. Importantly, the platelet Au nanorod exhibits the unique asymmetric five-twinned structure. The colloidal TiO(2) sols were used as both the photocatalyst to initiate the reaction and the stabilizing agent for the produced Au nanostructures. Significantly, in this photochemical process, the tunable irradiation intensity allows us to kinetically control the crystal evolution at various growth stages, leading to the shape difference of ultimate gold nanostructures. Our synthetic method shows a great potential as an alternative or supplement to the other wet chemical approaches for the shape control of metallic nanostructures. PMID- 20973575 TI - Direct detection of hole gas in Ge-Si core-shell nanowires by enhanced Raman scattering. AB - We report the direct detection of hole accumulation in the core of Ge-Si core shell nanowire heterostructures by a Fano resonance between free holes and the F2g mode in Raman spectra. Raman enhancements of 10-10 000 with respect to bulk were observed and explained using finite difference time domain simulations of the electric fields concentrated in the nanowire. Numerical modeling of the radial carrier concentration revealed that the asymmetric line-shape is strongly influenced by inhomogeneous broadening. PMID- 20973576 TI - Preface to the molecular surface chemistry and its applications special issue. PMID- 20973577 TI - Photodissolution of ferrihydrite in the presence of oxalic acid: an in situ ATR FTIR/DFT study. AB - The photodissolution of the iron oxyhydroxide, ferrihydrite, in the presence of oxalic acid was investigated with vibrational spectroscopy, density functional theory (DFT) calculations, and batch geochemical techniques that determined the composition of the solution phase during the dissolution process. Specifically, in situ attenuated total reflection Fourier transform infrared spectroscopy (ATR- FTIR) was used to determine the structure of the adsorbed layer during the dissolution process at a solution pH of 4.5. DFT based computations were used to interpret the vibrational data associated with the surface monolayer in order to help determine the structure of the adsorbed complexes. Results showed that at pH 4.5, oxalate adsorbed on ferrihydrite adopted a mononuclear bidentate (MNBD) binding geometry. Photodissolution at pH 4.5 exhibited an induction period where the rate of Fe(II) release was limited by a low concentration of adsorbed oxalate due to the site-blocking of carbonate that was intrinsic to the surface of the ferrihydrite starting material. Oxalate displaced this initial carbonate over time, and the dissolution rate showed a corresponding increase. Irradiation of oxalate/ferrihydrite at pH 4.5 also ultimately led to the appearance of carbonate reaction product (distinct from carbonate intrinsic to the starting material) on the surface. PMID- 20973578 TI - Prospects for resolving chemical structure by atomic force microscopy: a first principles study. AB - In a recent paper, the chemical structure of a molecule was resolved by means of atomic force microscopy (AFM): using a metal tip terminated in a CO molecule, the authors could image the internal bonding arrangement of a pentacene molecule with remarkable spatial resolution (notably better than with other tip terminations), as verified by their first-principles calculations. Here we further explore with first-principles calculations the mechanisms, applicability, and capabilities of this approach for a wider range of situations, by varying the imaged molecule and the tip beyond the experimental cases. In our simulations, a high atomic resolution is found to be dominated by the electronic structure of the last two atoms on the tip apex which are set perpendicularly to the sample molecule. For example, tips terminated in CH(4) or pentacene itself (both having a C-H apex) yield similar images, while tips terminated in O(2) or CO give quite different images. While using a CO-terminated tip successfully resolves the chemical structure of pentacene and of other extended planar networks based on C(6) rings, this tip fails to resolve the structures of benzene (with its single C(6) ring) or nonplanar C(6) networks, such as C(60) or small-diameter carbon nanotubes. Defects (such as N substitution for a C-H group) were also found to significantly influence the image resolution. Our findings indicate that further application of this approach requires, for each sample, careful selection of a suitable "imaging" molecule as tip termination. PMID- 20973579 TI - Interaction of hydrogen with ZnO: surface adsorption versus bulk diffusion. AB - The interaction of hydrogen (H) and a ZnO(0001)-O surface has been investigated using a temperature programmed desorption (TPD) technique. When the surface is exposed to atomic hydrogen below 400 K, hydrogen is adsorbed on the surface. As the hydrogen exposure increases, bulk diffusion of hydrogen takes place. The existence of surface and bulk hydrogen has been confirmed using X-ray photoelectron spectroscopy (XPS). When the ZnO surface dosed with hydrogen is heated, surface hydrogen is desorbed at 432 K and bulk hydrogen is evolved at ~539 K. Diffusion of hydrogen into the ZnO bulk is an activated process, and the activation energy is estimated to be 0.19 eV. PMID- 20973580 TI - Interaction of carbon monoxide with Au(111) modified by ion bombardment: a surface spectroscopy study under elevated pressure. AB - Gold based model systems exhibiting the structural versatility of nanoparticle ensembles and being accessible for surface spectroscopic investigations are expected to provide new information about the adsorption of carbon monoxide, a key process influencing the CO oxidation activity of this noble metal in nanoparticulate form. Accordingly, in the present work the interaction of CO is studied with an ion bombardment modified Au(111) surface by means of a combination of photoelectron spectroscopy (XPS and UPS), sum frequency generation vibrational spectroscopy (SFG), and scanning tunneling microscopy (STM). While no adsorption was found on intact Au(111), data collected on the ion bombarded surface at cryogenic temperatures indicated the presence of stable CO adsorbates below 190 K. A quantitative evaluation of the C 1s XPS spectra and the surface morphology explored by STM revealed that the step edge sites created by ion bombardment are responsible for CO adsorption. The identification of the CO binding sites was confirmed by density functional theory (DFT) calculations. Annealing experiments up to room temperature showed that at temperatures above 190 K unstable adsorbates are formed on the surface under dynamic exposure conditions that disappeared immediately when gaseous CO was removed from the system. Spectroscopic data as well as STM records revealed that prolonged CO exposure at higher pressures of up to 1 mbar around room temperature facilitates massive atomic movements on the roughened surface, leading to its strong reordering toward the structure of the intact Au(111) surface, accompanied by the loss of the CO binding capacity. PMID- 20973581 TI - Performance of a biomimetic oxidation catalyst immobilized on silicon wafers: comparison with its gold congener. AB - With the aim of extending the usefulness of an existing biomimetic catalytic system, cobalt porphyrin catalytic units with thiol linkers were heterogenized via chemical grafting to silicon wafers and utilized for the catalytic oxidation of hydroquinone to p-benzoquinone. Atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS) were used to analyze the morphology and composition of the heterogeneous catalyst. The results of the catalytic oxidation of hydroquinone obtained with porphyrins grafted on silicon were compared with those obtained earlier with the same catalyst in homogeneous phase and immobilized on gold. It was found that the catalysis could run over 400 h, without showing any sign of deactivation. The measured catalytic activity is at least 10 times higher than that measured under homogeneous conditions, but also 10 times lower than that observed with the catalytic unit immobilized on gold. The reasons of this discrepancy are discussed in term of substrate influence and overlayer organization. The silicon-immobilized catalyst has potential as an advanced functional material with applications in oxidative heterogeneous catalysis of organic reactions, as it combines long-term relatively high activity with low cost. PMID- 20973582 TI - First direct visualization of spillover species emitted from pt nanoparticles. AB - We studied the methanol adsorption behavior of Pt nanoparticles that were vacuum deposited on a TiO(2)(110) surface at room temperature by using an ultrahigh vacuum (UHV) scanning tunneling microscope (STM). A large number of bright spots were observed on fivefold-coordinated Ti (Ti(5c)) rows of the TiO(2)(110) surface after exposure of the Pt/TiO(2)(110) to methanol vapor. We assigned the bright spots to methoxy species. These were mobile and were found to hop along the Ti(5c) rows. In situ time-resolved STM observations of the formation and migration of the bright spots on the Pt/TiO(2)(110) were carried out in the presence of methanol. The bright spots were produced at the periphery of the Pt nanoparticles and migrated to the substrate Ti(5c) rows. We discuss the spillover process and behavior of the methoxy species on the Pt/TiO(2)(110). PMID- 20973583 TI - Adsorption and decomposition of cyclohexanone (C6H10O) on Pt(111) and the (2 * 2) and (?3 * ?3)r30 degrees -Sn/Pt(111) surface alloys. AB - Adsorption and decomposition of cyclohexanone (C(6)H(10)O) on Pt(111) and on two ordered Pt-Sn surface alloys, (2 * 2)-Sn/Pt(111) and (?3 * ?3)R30 degrees Sn/Pt(111), formed by vapor deposition of Sn on the Pt(111) single crystal surface were studied with TPD, HREELS, AES, LEED, and DFT calculations with vibrational analyses. Saturation coverage of C(6)H(10)O was found to be 0.25 ML, independent of the Sn surface concentration. The Pt(111) surface was reactive toward cyclohexanone, with the adsorption in the monolayer being about 70% irreversible. C(6)H(10)O decomposed to yield CO, H(2)O, H(2), and CH(4). Some C-O bond breaking occurred, yielding H(2)O and leaving some carbon on the surface after TPD. HREELS data showed that cyclohexanone decomposition in the monolayer began by 200 K. Intermediates from cyclohexanone decomposition were also relatively unstable on Pt(111), since coadsorbed CO and H were formed below 250 K. Surface Sn allowed for some cyclohexanone to adsorb reversibly. C(6)H(10)O dissociated on the (2 * 2) surface to form CO and H(2)O at low coverages, and methane and H(2) in smaller amounts than on Pt(111). Adsorption of cyclohexanone on (?3 * ?3)R30 degrees -Sn/Pt(111) at 90 K was mostly reversible. DFT calculations suggest that C(6)H(10)O adsorbs on Pt(111) in two configurations: by bonding weakly through oxygen to an atop Pt site and more strongly through simultaneously oxygen and carbon of the carbonyl to a bridged Pt-Pt site. In contrast, on alloy surfaces, C(6)H(10)O bonds preferentially to Sn. The presence of Sn, furthermore, is predicted to make the formation of the strongly bound C(6)H(10)O species bonding through O and C, which is a likely decomposition precursor, thermodynamically unfavorable. Alloying with Sn, thus, is shown to moderate adsorptive and reactive activity of Pt(111). PMID- 20973584 TI - Probing enantioselectivity on chirally modified Cu(110), Cu(100), and Cu(111) surfaces. AB - Temperature programmed desorption methods have been used to probe the enantioselectivity of achiral Cu(100), Cu(110), and Cu(111) single crystal surfaces modified by chiral organic molecules including amino acids, alcohols, alkoxides, and amino-alcohols. The following combinations of chiral probes and chiral modifiers on Cu surfaces were included in this study: propylene oxide (PO) on L-alanine modified Cu(110), PO on L-alaninol modified Cu(111), PO on 2-butanol modified Cu(111), PO on 2-butoxide modified Cu(100), PO on 2-butoxide modified Cu(111), R-3-methylcyclohexanone (R-3-MCHO) on 2-butoxide modified Cu(100), and R 3-MCHO on 2-butoxide modified Cu(111). In contrast with the fact that these and other chiral probe/modifier systems have exhibited enantioselectivity on Pd(111) and Pt(111) surfaces, none of these probe/modifier/Cu systems exhibit enantioselectivity at either low or high modifier coverages. The nature of the underlying substrate plays a significant role in the mechanism of hydrogen bonding interactions and could be critical to observing enantioselectivity. While hydrogen-bonding interactions between modifier and probe molecule are believed to induce enantioselectivity on Pd surfaces (Gao, F.; Wang, Y.; Burkholder, L.; Tysoe, W. T. J. Am. Chem. Soc. 2007, 129, 15240-15249), such critical interactions may be missing on Cu surfaces where hydrogen-bonding interactions are believed to occur between adjacent modifier molecules, enabling them to form clusters or islands. PMID- 20973585 TI - Evidence of the synergetic role of charged species and atomic oxygen in the molecular etching of PTFE surfaces for hydrophobic surface synthesis. AB - The transformation of a poly(tetrafluoroethylene) (PTFE) hydrophobic surface into a superhydrophobic one using a low pressure RF plasma is explored using optical emission spectrometry (OES), X-ray photoelectron spectroscopy (XPS), water contact angle (WCA) measurements, mass measurements, and atomic force microscopy (AFM). It is shown that the increase in contact angle is due to an increase of roughness provoked by a chemical etching of the surface. We propose a molecular mechanism for etching that requires the simultaneous presence of atomic oxygen and negatively charged species (electrons) at the PTFE surface. PMID- 20973586 TI - Selective oxidation of cyclohexanol and 2-cyclohexen-1-ol on O/Au(111): the effect of molecular structure. AB - We combine reactivity studies with infrared reflection absorption spectroscopy to provide molecular-scale insights into the oxidation of two cyclic alcohols, cyclohexanol and 2-cyclohexen-1-ol, by atomic oxygen adsorbed on Au(111). The two alcohols share common features in their reaction pathways: they are both activated by Bronsted acid-base reactions with adsorbed oxygen. Cyclic ketones, cyclohexanone and 2-cyclohexen-1-one, are the major products, formed from cyclohexanol and 2-cyclohexen-1-ol, respectively. These ketones also undergo secondary ring C-H bond activation. The product distributions reflect a substantial difference in the secondary reactions for these two ketones, which correlate with their gas-phase acidity. The allylic alcohol (2-cylohexen-1-ol) has a greater degree of ring C-H activation, yielding the diketone (2-cyclohexene 1,4-dione) and phenol. Our results provide clear evidence for the importance of C?C functionalities in determining the reactivity of molecules in heterogeneous oxidative transformations promoted on Au-based materials. PMID- 20973587 TI - Understanding the effect of cobalt particle size on Fischer-Tropsch synthesis: surface species and mechanistic studies by SSITKA and kinetic isotope effect. AB - Co/gamma-Al(2)O(3) catalysts with particle sizes in the range of 4-15 nm were investigated by isothermal hydrogenation (IH), temperature programmed hydrogenation (TPH), and steady-state isotopic transient kinetic analysis (SSITKA). Kinetic isotope effect experiments were used to probe possible mechanisms on Co/gamma-Al(2)O(3) with different particle size. It was found that CO dissociated on Co/gamma-Al(2)O(3) catalysts at 210 degrees C. The total amount of CO(2) formed following the dissociation depends on the cobalt crystal size. O-Co binding energy was found to be highly dependent on the Co metal particle size, whereas similar C-Co binding energy was found on catalysts with different Co particle size. Very strongly bonded carbon and oxygen surface species increased with decreasing particle size and acted as site blocking species in the methanation reaction. SSITKA experiments showed that the intrinsic activity (1/tau(CH(x))) remained constant as the particle size increased from 4 to 15 nm. The number of surface intermediates (N(CH(x))) increased with increasing particle size. The apparent activation energies were found similar for these catalysts, about 85 kJ/mol. D(2)-H(2) switches further confirmed that the particle size did not change the kinetically relevant steps in the reaction. The reactivity of the active sites on the 4 nm particles was the same as those on the 8, 11, and 15 nm particles, and only the number of total available surface active sites was less on the 4 nm particles than on the others. PMID- 20973588 TI - First ruthenium organometallic complex of antibacterial agent ofloxacin. Crystal structure and interactions with DNA. AB - An organometallic ruthenium complex of quinolone antibacterial agent ofloxacin, [(eta(6)-p-cymene)RuCl(O,O-oflo)].2.8H(2)O (1.2.8H(2)O), was isolated, and its crystal structure was determined. In this "piano-stool" complex, quinolone is bidentately coordinated to the metal through the ring carbonyl and one of the carboxylic oxygen atoms. Interactions of the title complex with DNA were studied by spectroscopic methods [electronic, fluorescence, and circular dichroism (CD)] and atomic force microscopy (AFM). It was established that the electrostatic attraction between the ruthenium complex and DNA in a solution is important for binding because interactions were observed only in a solution with low ionic strengths. An induced-CD (ICD) signal was observed in a solution of DNA and the title complex, which proves interaction between ruthenium and macromolecules. Competitive binding between cisplatin and 1 to DNA revealed that cisplatin prevents binding of 1. Our experiments revealed that binding of the title complex to DNA occurs also if guanine N7 is protonated. AFM has shown that the title complex provokes DNA shrinkage. Preliminary biological tests have also been performed. PMID- 20973590 TI - Screening lectin-binding specificity of bacterium by lectin microarray with gold nanoparticle probes. AB - To develop a novel high-throughput tool for monitoring specific affinity of microbes with lectins, a kind of lectin microarray has been fabricated by immobilizing lectins on epoxide-derivatized glass slides and used to capture microbes. The capturing events are marked by attachment of lectin-conjugated gold nanoparticles followed by silver deposition to enhance the resonance light scattering (RLS) of the particles. The interactions of 16 lectins with four bacteria and one fungus were profiled by this approach. We demonstrated that the gold-nanoparticle-labeled array was suitable for identifying the binding affinity of lectin with bacterium, as well as determining the bacterium with high sensitivity. More importantly, we found that the growth of microbial strains in different culture media resulted in significant changes in their binding affinities with lectins, which might be important to the pathogenesis of the organisms. PMID- 20973591 TI - Controlled sulfur oxygenation of the ruthenium dithiolate (4,7-bis-(2'-methyl-2' mercaptopropyl)-1-thia-4,7-diazacyclononane)RuPPh(3) under limiting O(2) conditions yields thiolato/sulfinato, sulfenato/sulfinato, and bis-sulfinato derivatives. AB - The ruthenium(II) dithiolate complex (bmmp-TASN)RuPPh(3) (1) reacts with O(2) under limiting conditions to yield isolable sulfur oxygenated derivatives as a function of reaction time. With this approach, a family of sulfur-oxygenates has been prepared and isolated without the need for O-atom transfer agents or column chromatography. Addition of 5 equiv of O(2) to 1 yields the thiolato/sulfinato complex (bmmp-O(2)-TASN)RuPPh(3) (2) in 70% yield within 5 min. Increasing the reaction time to 12 h yields the sulfenato/sulfinato derivative (bmmp-O(3) TASN)RuPPh(3) (3) in 82% yield. Longer reaction times and/or additional O(2) exposure yield the bis-sulfinato complex (bmmp-O(4)-TASN)RuPPh(3) (4). All products remain in the Ru(II) oxidation state under the conditions employed. Stoichiometric hydrolysis of acetonitrile to acetamide by 2 and 3 is observed in mixed acetonitrile, methanol, PIPES buffer (pH = 7.0) mixtures. The Ru(III)/(II) reduction potential of -0.85 V (versus ferrocenium/ferrocene) for 1 shifts to 0.39 and -0.26 V for 2 and 3, respectively, because of the decreased donor ability of sulfur upon oxygenation. X-ray diffraction studies reveal a decrease in Ru-S bond distances upon oxygenation by 0.045(1) and 0.158(1) A for the sulfenato and sulfinato donors, respectively. Conversely, sulfur-oxygenation increases the Ru-P bond distance by 0.061(1) A from 1 to 2 and an additional 0.027(1) A from 2 to 3. Density functional theory investigations using the BP86 and B3LYP functionals with a LANL2DZ basis set for Ru and the 6-31G(d) basis set for all other atoms reveal a direct correlation between the oxygenation level and the Ru-P distance with an increase of 0.031 A per O-atom. PMID- 20973592 TI - Molecular dynamics simulations on the mechanism of transporting methylamine and ammonia by ammonium transporter AmtB. AB - AmtB is one of the ammonium transporter proteins facilitating the ammonium transport across the cellular membranes. Experimentally, the substrate used in in vitro studies is the radio labeled [(14)C]methylammonium, rather than ammonium itself. To explore the similarity and difference of the conduction mechanism of methylamine and ammonia molecules through AmtB, molecular dynamics simulations on 22 carefully designed systems were performed, which demonstrated that methylamine could be automatically transported in a very similar way to ammonia. The driving force for the conduction is mainly the hydrogen bond network comprising His168, His318, and Tyr32, working in coordination with NH-pi interaction with residue Trp212. Then, Ser263 translocated the substrates from the exit gate into the cytoplasm by hydrogen bond interaction. The aromatic ring of Trp212 acted like a springboard to facilitate the translocation of the substrates from site Am2 to Am4 via NH-pi interaction. Without the mediation of Trp212, further movement of substrate in the channel would be hampered by the strong hydrogen bonding from His168. In agreement with experimental results, the substrates could be transported by W212F mutant but not by W212A within the simulation time as long as 20 ns. In addition, we predicted that the mutants S263D and S263C remain the function of the transporter but S263A does not. The difference of transporting the two substrates is that methylamine involves more hydrophobic interactions than ammonia. In conclusion, methylamine molecule is a good mimic for investigating the translocation mechanism of ammonium transporter AmtB. PMID- 20973593 TI - The structure of past and future lives in depression. AB - This study assessed the organization of past autobiographical knowledge in individuals with either current major depressive disorder (MDD), MDD in remission, or no history of MDD (the control group). Participants generated personal lists of "life chapters," dividing both their past and potential future into subjectively meaningful episodes or themes (e.g., "married life"). They were then given a list of potentially chapter-descriptive positive or negative attributes and sorted them according to the different chapters. Results revealed that, relative to the control group, MDD participants selected more negative attributes overall, showed greater redundancy for negative attributes (i.e., using the same ones repeatedly across chapters) and reduced redundancy for positive attributes, and exhibited greater compartmentalization (i.e., the negative and positive attributes were clustered separately across different chapters). A similar pattern emerged for the remitted MDD group relative to controls, with the exception of negative redundancy, which was not elevated. For future chapters, there were no group differences. Finally, a greater number of past depressive episodes was associated with increasingly reduced positive redundancy. These data reveal a "depressogenic" structuring of past (but not future) knowledge in MDD that is also evident in a remitted MDD group, with the exception of negative redundancy, which appears to be a marker of the acute state. These findings shed light on important aspects of the organization of past knowledge that are likely to be linked to maladaptive processing biases in those with a depression history. PMID- 20973594 TI - Clarifying the role of defensive reactivity deficits in psychopathy and antisocial personality using startle reflex methodology. AB - Prior research has demonstrated deficits in defensive reactivity (indexed by potentiation of the startle blink reflex) in psychopathic individuals. However, the basis of this association remains unclear, as diagnostic criteria for psychopathy encompass two distinct phenotypic components that may reflect differing neurobiological mechanisms-an affective-interpersonal component and an antisocial deviance component. Likewise, the role of defensive response deficits in antisocial personality disorder (APD), a related but distinct syndrome, remains to be clarified. In the current study, the authors examined affective priming deficits in relation to factors of psychopathy and symptoms of APD using startle reflex methods in 108 adult male prisoners. Deficits in blink reflex potentiation during aversive picture viewing were found in relation to the affective-interpersonal (Factor 1) component of psychopathy, and to a lesser extent in relation to the antisocial deviance (Factor 2) component of psychopathy and symptoms of APD-but only as a function of their overlap with affective interpersonal features of psychopathy. These findings provide clear evidence that deficits in defensive reactivity are linked specifically to the affective interpersonal features of psychopathy and not to the antisocial deviance features represented most strongly in APD. PMID- 20973596 TI - Overcoming negative reactions of nonbeneficiaries to employment equity: the effect of participation in policy formulation. AB - In 2 experimental studies, we examined a way to overcome nonbeneficiaries' resistance to employment equity (EE) policies-participation in formulating the policy. We operationalized participation in terms of instrumental versus noninstrumental voice and proposed that nonbeneficiaries would be more likely to support an EE policy when allowed instrumental participation in the policy's development. Further, we proposed psychological ownership as the mediating mechanism underlying the effects of instrumental participation. Study 1 examined participation effects for a gender-based EE policy and Study 2 for a race-based EE policy. As predicted, we found that nonbeneficiaries (men in Study 1; Whites in Study 2) in the instrumental participation condition expressed greater behavioral intentions to promote the policy (Studies 1 and 2) and were more likely to engage in a behavior promoting the policy (Study 2). We also found support for psychological ownership as the underlying mediating mechanism in both studies. Contributions to theory and practice are discussed. PMID- 20973595 TI - Does attention-deficit/hyperactivity disorder have a dimensional latent structure? A taxometric analysis. AB - An understanding of the latent structure of attention-deficit/hyperactivity disorder (ADHD) is essential for developing causal models of this disorder. Although some researchers have presumed that ADHD is dimensional and others have assumed that it is taxonic, there has been relatively little research directly examining the latent structure of ADHD. The authors conducted a set of taxometric analyses using data from the NICHD Study of Early Child Care and Youth Development (ns between 667 and 1,078). The results revealed a dimensional latent structure across a variety of different analyses and sets of indicators for inattention, hyperactivity/impulsivity, and ADHD. Furthermore, analyses of correlations with associated features indicated that dimensional models demonstrated stronger validity coefficients with these criterion measures than dichotomous models. These findings jibe with recent research on the genetic basis of ADHD and with contemporary models of ADHD. PMID- 20973598 TI - Timing and aging: slowing of fastest regular tapping rate with preserved timing error detection and correction. AB - This study assessed motor limits of regular tapping, timing error detection, and correction in 60 participants aged from 19 to 98 years. Rate limitations on motor production were estimated from the average inter-tap interval when tapping as fast as possible for 30 s. Timing error detection required participants to judge whether a sound sequence presented at a slow, intermediate, or fast speed contained an irregularity because of phase shift. This was performed with or without synchronizing to the sounds. On the basis of the just-detectable positive phase shift (JND), participants synchronized with sequences containing phase shifts that were subliminal, just detectable or supraliminal. On average, JNDs were 9% of the inter-onset interval and by and large were not affected by synchronization tapping. Speed of error correction was estimated from the number of tones to return within 20% of the preshift synchronization error. Consistent with previous findings of motor slowing with aging, the fastest inter-tap interval increased with age. However, there was no age-related decline in JNDs or speed of error correction, both of which reflect predictive abilities for intervals within the motor repertoire of human adults. These results point towards intact timing error processing up to an advanced age. In assessing timing abilities in the brain of older adults, it is important to differentiate between motor slowing and its impact on rhythmic behavior (e.g., walking pace) from anticipatory mechanisms ('what to expect when') and how these are used to adjust the timing of actions ('what to do when'). PMID- 20973599 TI - Contextual interference effects in sequence learning for young and older adults. AB - Practice of different tasks in a random order induces better retention than practicing them in a blocked order, a phenomenon known as the contextual interference (CI) effect. Our purpose was to investigate whether the CI effect exists in sequence learning, such that practicing different sequences in a random order will result in better learning of sequences than practicing them in blocks, and whether this effect is affected by aging. Subjects practiced a serial reaction time task where a set of three 4-element sequences were arranged in blocks or in a random order on 2 successive days. Subjects were divided into 4 groups based on a 2-GROUP (young or old) by 2-ORDER (random or blocked practice) between-subject design. Three days after practice (Day 5), subjects were tested with practiced and novel sequences to evaluate sequence-specific learning. The results replicate the CI effect in sequence learning in both young and older adults. Older adults retained sequences better when trained in a random condition than in a blocked condition, although the random condition incurs greater task switching costs in older adults during practice. Our study underscores the distinction between age-related effects on learning vs. performance, and offers practical implications for enhancing skill learning in older adults. PMID- 20973601 TI - Aging and involuntary attention capture: electrophysiological evidence for preserved attentional control with advanced age. AB - The present study examined whether people become more susceptible to capture by salient objects as they age. Participants searched a target display for a letter in a specific color and indicated its identity. In Experiment 1, this target display was preceded by a non-informative cue display containing one target-color box, one ignored-color box, and two white boxes. On half of the trials, this cue display also contained a salient-but-irrelevant abrupt onset. To assess capture by the target-color cue, we used the N2pc component of the event-related potential, thought to reflect attentional allocation to the left or right visual field. The target-color box in the cue display produced a substantial N2pc effect for younger adults and, most importantly, this effect was not diminished by the presence of an abrupt onset. Therefore, the abrupt onset was unable to capture attention away from the target-color cue. Critically, older adults demonstrated the same resistance to capture by the abrupt onset. Experiment 2 extended these findings to irrelevant color singleton cues. Thus, we argue that the ability to attend to relevant stimuli and resist capture by salient-but-irrelevant stimuli is preserved with advancing age. PMID- 20973600 TI - Emotional experience improves with age: evidence based on over 10 years of experience sampling. AB - Recent evidence suggests that emotional well-being improves from early adulthood to old age. This study used experience-sampling to examine the developmental course of emotional experience in a representative sample of adults spanning early to very late adulthood. Participants (N = 184, Wave 1; N = 191, Wave 2; N = 178, Wave 3) reported their emotional states at five randomly selected times each day for a one week period. Using a measurement burst design, the one-week sampling procedure was repeated five and then ten years later. Cross-sectional and growth curve analyses indicate that aging is associated with more positive overall emotional well-being, with greater emotional stability and with more complexity (as evidenced by greater co-occurrence of positive and negative emotions). These findings remained robust after accounting for other variables that may be related to emotional experience (personality, verbal fluency, physical health, and demographic variables). Finally, emotional experience predicted mortality; controlling for age, sex, and ethnicity, individuals who experienced relatively more positive than negative emotions in everyday life were more likely to have survived over a 13 year period. Findings are discussed in the theoretical context of socioemotional selectivity theory. PMID- 20973603 TI - Older adults' configural processing of faces: role of second-order information. AB - Problems with face recognition are frequent in older adults. However, the mechanisms involved have only been partially discovered. In particular, it is unknown to what extent these problems may be related to changes in configural face processing. Here, we investigated the face inversion effect (FIE) together with the ability to detect modifications in the vertical or horizontal second order relations between facial features. We used a same/different unfamiliar face discrimination task with 33 young and 33 older adults. The results showed dissociations in the performances of older versus younger adults. There was a lack of inversion effect during the recognition of original faces by older adults. However, for modified faces, older adults showed a pattern of performance similar to that of young participants, with preserved FIE for vertically modified faces and no detectable FIE for horizontally modified faces. Most importantly, the detection of vertical modifications was preserved in older relative to young adults whereas the detection of horizontal modifications was markedly diminished. We conclude that age has dissociable effects on configural face-encoding processes, with a relative preservation of vertical compared to horizontal second order relations processing. These results help to understand some divergent results in the literature and may explain the spared familiar face identification abilities in the daily lives of older adults. PMID- 20973604 TI - Working memory training in older adults: evidence of transfer and maintenance effects. AB - Few studies have examined working memory (WM) training-related gains and their transfer and maintenance effects in older adults. This present research investigates the efficacy of a verbal WM training program in adults aged 65-75 years, considering specific training gains on a verbal WM (criterion) task as well as transfer effects on measures of visuospatial WM, short-term memory, inhibition, processing speed, and fluid intelligence. Maintenance of training benefits was evaluated at 8-month follow-up. Trained older adults showed higher performance than did controls on the criterion task and maintained this benefit after 8 months. Substantial general transfer effects were found for the trained group, but not for the control one. Transfer maintenance gains were found at follow-up, but only for fluid intelligence and processing speed tasks. The results are discussed in terms of cognitive plasticity in older adults. PMID- 20973605 TI - Effects of aging and divided attention on memory for items and their contexts. AB - It is commonly found that memory for context declines disproportionately with aging, arguably due to a general age-related deficit in associative memory processes. One possible mechanism for such deficits is an age-related reduction in available processing resources. In two experiments we compared the effects of aging to the effects of division of attention in younger adults on memory for items and context. Using a technique proposed by Craik (1989), linear functions relating memory performance for items and their contexts were derived for a Young Full Attention group, a Young Divided Attention group, and an Older Adult group. Results suggested that the Old group showed an additional deficit in associative memory that was not mimicked by divided attention. It is speculated that both divided attention and aging are associated with a loss of available processing resources that may reflect inefficient frontal lobe functioning, whereas the additional age-related decrement in associative memory may reflect inefficient processing in medial-temporal regions. PMID- 20973607 TI - Perceptions of the cognitive compensation and interpersonal enjoyment functions of collaboration among middle-aged and older married couples. AB - Perceptions of cognitive compensation and interpersonal enjoyment of collaboration were examined in three hundred middle-aged and older couples who completed measures of perceptions of collaboration, cognitive ability, marital satisfaction, an errand task and judged their spouse's affiliation. Older adults (especially men) endorsed cognitive compensation and interpersonal enjoyment and reported using collaboration more frequently than middle-aged adults. Greater need for cognitive compensation was related to lower cognitive ability only for older wives. Greater marital satisfaction was associated with greater interpersonal enjoyment. These two functions related to reports of more frequent use of collaboration and perceptions of spousal affiliation in a collaborative task. PMID- 20973606 TI - Personality and risk for Alzheimer's disease in adults 72 years of age and older: a 6-year follow-up. AB - [Correction Notice: An erratum for this article was reported in Vol 26(2) of Psychology and Aging (see record 2011-05802-001). This article contains an error in the Discussion, under the Implications, Caveats, Future Directions heading. The third paragraph includes the sentences that should have been removed. The corrected paragraph appears in the correction.] We conducted secondary analyses to determine the relationship between longstanding personality traits and risk for Alzheimer's disease (AD) among 767 participants 72 years of age or older who were followed for more than 6 years. Personality was assessed with the NEO-FFI. We hypothesized that elevated Neuroticism, lower Openness, and lower Conscientiousness would be independently associated with risk of AD. Hypotheses were supported. The finding that AD risk is associated with elevated Neuroticism and lower Conscientiousness can be added to the accumulating literature documenting the pathogenic effects of these two traits. The link between lower Openness and AD risk is consistent with recent findings on cognitive activity and AD risk. Findings have implications for prevention research and for the conceptualization of the etiology of AD. PMID- 20973608 TI - Stability and change in intelligence from age 11 to ages 70, 79, and 87: the Lothian Birth Cohorts of 1921 and 1936. AB - Investigating the predictors of age-related cognitive change is a research priority. However, it is first necessary to discover the long-term stability of measures of cognitive ability because prior cognitive ability level might contribute to the amount of cognitive change experienced within old age. These two issues were examined in the Lothian Birth Cohorts of 1921 and 1936. Cognitive ability data were available from age 11 years when the participants completed the Moray House Test No. 12 (MHT). The Lothian Birth Cohort 1936 (LBC1936) completed the MHT a second time at age 70. The Lothian Birth Cohort 1921 (LBC1921) completed the MHT at ages 79 and 87. We examined cognitive stability and change from childhood to old age in both cohorts, and within old age in the LBC1921. Raw stability coefficients for the MHT from 11-70, 11-79, and 11-87 years were .67, .66, and .51, respectively; and larger when corrected for range restriction in the samples. Therefore, minimum estimates of the variance in later-life MHT accounted for by childhood performance on the same test ranged from 26-44%. This study also examined, in the LBC1921, whether MHT score at age 11 influenced the amount of change in MHT between ages 79 and 87. It did not. Higher intelligence from early life was apparently protective of intelligence in old age due to the stability of cognitive function across the lifespan, rather than because it slowed the decline experienced in later life. PMID- 20973610 TI - Representation of serial order in pigeons (Columba livia). AB - In Experiment 1, 2 groups of pigeons were trained to respond to either a 4-item (A->B->C->D) or 5-item (A->B->C->D->E) list. After learning their respective list, half of the subjects were trained on a positive pair with reinforcement provided when pairs were responded to in the order true to that of the original sequence (4-item: B->C; 5-item: B->D). The remaining subjects were trained on a negative pair with reinforcement provided for responding to the pairs in the order opposite to that learned in the original sequence (4-item: C->B; 5-item: D >B). Subjects in the positive pair condition learned their respective pair faster than did subjects in the negative pair condition. In Experiment 2, after reaching criterion on a 4-item list, subjects received 16 BC probe trials spread across 4 sessions of training. Subjects performed significantly above chance on the probe trials. The performance of our subjects in Experiments 1 and 2 demonstrates that, similar to monkeys, pigeons form a representation of the lists that they learn. PMID- 20973609 TI - Effects of repetition on associative recognition in young and older adults: item and associative strengthening. AB - Young and older adults studied word pairs and later discriminated studied pairs from various types of foils including recombined word-pairs and foil pairs containing one or two previously unstudied words. We manipulated how many times a specific word pair was repeated (1 or 5) and how many different words were associated with a given word (1 or 5) to tease apart the effects of item familiarity from recollection of the association. Rather than making simple old/new judgments, subjects chose one of five responses: (a) Old-Old (original), (b) Old-Old (rearranged), (c) Old-New, (d) New-Old, (e) New-New. Veridical recollection was impaired in old age in all memory conditions. There was evidence for a higher rate of false recollection of rearranged pairs following exact repetition of study pairs in older but not younger adults. In contrast, older adults were not more susceptible to interference than young adults when one or both words of the pair had multiple competing associates. Older adults were just as able as young adults to use item familiarity to recognize which word of a foil was old. This pattern suggests that recollection problems in advanced age are because of a deficit in older adults' formation or retrieval of new associations in memory. A modeling simulation provided good fits to these data and offers a mechanistic explanation based on an age-related reduction of working memory. PMID- 20973611 TI - Classical conditioning of autonomic fear responses is independent of contingency awareness. AB - The role of contingency awareness in classical conditioning experiments using human subjects is currently under debate. This study took a novel approach to manipulating contingency awareness in a differential Pavlovian conditioning paradigm. Complex sine wave gratings were used as visual conditional stimuli (CS). By manipulating the fundamental spatial frequency of the displays, we were able to construct pairs of stimuli that varied in discriminability. One group of subjects was given an "easy" discrimination, and another was exposed to a "difficult" CS+ and CS-. A 3rd group was exposed to a stimulus that was paired with the unconditional stimulus (UCS) 50% of the time and served as a control. Skin conductance response (SCR) and continuous UCS expectancy data were measured concurrently throughout the experiment. Differential UCS expectancy was found only in the easy discrimination group. Differential SCRs were found in the easy discrimination group as well as in the difficult discrimination group, but not in the 50% contingency control. The difficult discrimination group did not exhibit differential UCS expectancy but did show clear differential SCR. These observations support a dual process interpretation of classical conditioning whereby conditioning on an implicit level can occur without explicit knowledge about the contingencies. The role of contingency awareness in classical conditioning experiments using human subjects is currently under debate. This study took a novel approach to manipulating contingency awareness in a differential Pavlovian conditioning paradigm. Complex sine wave gratings were used as visual conditional stimuli (CS). By manipulating the fundamental spatial frequency of the displays, we were able to construct pairs of stimuli that varied in discriminability. One group of subjects was given an "easy" discrimination, and another was exposed to a "difficult" CS+ and CS-. A 3rd group was exposed to a stimulus that was paired with the unconditional stimulus (UCS) 50% of the time and served as a control. Skin conductance response (SCR) and continuous UCS expectancy data were measured concurrently throughout the experiment. Differential UCS expectancy was found only in the easy discrimination group. Differential SCRs were found in the easy discrimination group as well as in the difficult discrimination group, but not in the 50% contingency control. The difficult discrimination group did not exhibit differential UCS expectancy but did show clear differential SCR. These observations support a dual process interpretation of classical conditioning whereby conditioning on an implicit level can occur without explicit knowledge about the contingencies. PMID- 20973612 TI - Formulations of zero-order, pH-dependent, sustained release matrix systems by ionotropic gelation of alginate-containing mixtures. AB - BACKGROUND: Matrix type, monolithic, dosage forms suitable for controlled release that exhibit pH-dependent behavior are considerably less common than similarly behaving multiparticulated, enterically coated dosage forms, although simpler and less expensive to make. AIM: Evaluate the properties of alginates and alginate containing systems to produce pH-sensitive, monolithic, controlled release dosage forms that perform acceptably and determine their limits of application in regard with stability, pH and Ca(++) sensitivity, and appropriated rate of release. METHOD: Mixtures of the ionic gum sodium alginate (Na Alg.) with other gel forming gums such as propylene glycol alginate (PGA), xanthan, or hydroxypropyl methylcellulose have been evaluated for applicability in the manufacture of controlled release dosage forms with three drugs of different solubility and ionic character. Mixture have been compressed into tablets and tested under a variety of pHs to simulate transit through the GI tract, in the presence of Ca(++), and for stability. RESULTS: These mixtures have been able to sustain drug release for up to 12 hours with acceptable performance going from acidic to alkaline pHs to simulate travel through the GI tract and in the presence of Ca(++). Release rate has been adjusted by selecting a suitable Na Alg./other gum combination at an appropriated ratio. CONCLUSIONS: Mixtures of Na Alg. with a number of other gums have been demonstrated suitable to manufacture pH-sensitive, matrix-type solid dosage forms with release-controlling properties for up to 12 hours. PMID- 20973613 TI - Crestal bone resorption around platform-switched dental implants with fine threaded neck after immediate and delayed loading. AB - Bone resorption and peri-implantitis are some of the most important problems of dental implantology. The implant macrodesign might decrease initial bone loss. The aim of this longitudinal study was to investigate crestal bone loss around screw type, tapered implants showing a fine threaded neck and platform switching design. In 32 patients of a dental practice, 147 maxillary implants with a diameter of 3.7 mm and 4.2 mm were placed and loaded according to clinical criteria. Immediate loading was exclusively performed in 3.7 mm diameter implants when adequate splinting and implant stability could be guaranteed (n=50). The remaining implants were loaded delayed. The bone level change was measured mesially and distally of the implant shoulder using follow-up X-rays and calculated per year in a linear mixed model. Bone resorption was low in all groups (3.7 immediate: -0.06 mm/year; 3.7 delayed: -0.16 mm/year; 4.2 delayed: 0.09 mm/year) after a mean follow-up period of 1.6 years (0.5-3.2 years). Based on the results of this study, it can be concluded that this implant macrodesign showed negligible bone resorption for all loading times. Immediate loading seems to be a reliable treatment option in the maxilla when clinical criteria are considered. PMID- 20973614 TI - Clinical, biomechanical and biological aspects of immediately loaded dental implants: a critical review of the literature. AB - In recent years, the use of immediately loaded implants became more acceptable as a standard protocol for completely edentulous lower jaw and/or partially edentulous upper jaw cases, predominantly in the anterior region, after it was one of the cornerstones of the early protocols to avoid any occlusal loading of the implants for at least 3 months. This technique could potentially provide immediate function and aesthetics to the patient. This review aims to present the clinical indications of the immediately loaded protocol according to the individual cases and the corresponding risk factors and contraindications. The clinical, biomechanical and biological requirements concerning bone quality, occlusal loading and implant primary stability are discussed. Primary stability in immediate loading is determined rather by surgical than biological parameters. Peri-implant osteogenesis leading to secondary stability depends on the same biological factors than in unloaded implant healing. However, specific mechanical effects on the biology of immediate loading osseointegration are yet to be investigated. PMID- 20973615 TI - The influence of biocomposites containing genetically modified flax fibers on gene expression in rat skeletal muscle. AB - In many studies, natural flax fibers have been proven to be resistant and surgically suitable. Genetically modified flax fibers, derived from transgenic flax expressing three bacterial genes for the synthesis of poly-3-hydroxybutyric acid (PHB), have better mechanical properties than unmodified flax fibers. The aim of this study was to examine the biocompatibility of composites containing flax fibers from transgenic polyhydroxybutyrate producing (M50) and control (wt NIKE) plants in a polylactide (PLA) matrix in rat Musculus latissimus dorsi. For this purpose, effects of biocomposites on the expression of growth factors and osteogenic differentiation, in particular the mRNA expression of vascular endothelial growth factor, insulin like growth factor 1, insulin like growth factor 2, collagen-1, collagen-2 and myostatin, were analyzed using quantitative RT-PCR. The biocomposites did not show any inflammation response after subcutaneous insertion. The results following subcutaneous insertion of PLA alone and PLA-M50 showed no significant changes on the gene expression of all tested genes, whereas PLA-wt-NIKE reduced the mRNA amount of myostatin, VEGFA and IGF2, respectively. It can be asserted that modified flax membranes with PHB and other organic substances have a good biocompatibility to the muscle and they do not disrupt the muscle function. Furthermore, composites from transgenic flax plants producing PHB did not differ from composites of non-transgenic flax plants. PMID- 20973616 TI - Factors associated with duloxetine treatment among patients with major depressive disorder in Veterans Health Administration: a retrospective study. AB - OBJECTIVE: To examine the predictors of duloxetine monotherapy versus other antidepressants among patients with major depressive disorder (MDD) in the Veterans Health Administration (VHA). METHODS: Patients initiating duloxetine or other antidepressants between October 1, 2005 and October 1, 2007 were extracted from the Veterans Integrated Service Network (VISN)16 data warehouse. All patients included had at least one MDD diagnosis prior to the initiation of duloxetine or other antidepressants. Patients with prior diabetes, schizophrenia, or bipolar disorder diagnosis were excluded. Logistic regression was used to identify predictors of duloxetine initiation versus other antidepressants. RESULTS: Among 448 duloxetine and 11,629 non-duloxetine patients identified, more duloxetine-treated patients had pre-index opioid use (62.72% vs. 22.03%), substance abuse (36.38% vs. 27.72%), or reported pain (60.94% vs. 46.29%) than non-duloxetine treated patients (all p-values <0.001). Prior users of long-acting (odds ratio [OR] = 8.98, 95% confidence interval [CI]: 6.95, 11.60) and short acting (OR = 3.32, 95% CI: 2.60, 4.23) opioids were more likely to initiate duloxetine than those not. Patients who experienced moderate or severe pain or substance abuse were also more likely to initiate duloxetine (OR = 1.43, 95% CI: 1.07, 1.90; 1.50, 95% CI: 1.16, 1.92; 1.41, 95% CI: 1.14, 1.75; respectively). Other significant predictors included being female, white, having non-VHA insurance, prior hospitalization, emergency room visits, dyslipidemia and hypertension (all p-values <0.05). KEY LIMITATIONS: It is a retrospective analysis among VHA patients of a single VISN. CONCLUSION: Among the VHA patients with MDD, prior opioid use was the strongest predictor of duloxetine initiation, followed by moderate-to-severe pain and substance abuse diagnosis. PMID- 20973617 TI - Nursing home-acquired pneumonia: a review of risk factors and therapeutic approaches. AB - OBJECTIVE: To review the risk factors, etiologic profile, treatment approaches, and guidelines for the management of nursing home-acquired pneumonia (NHAP). RESEARCH DESIGN AND METHODS: A search of the current literature was conducted using the MEDLINE and Embase databases. This search, limited to studies performed in humans and published in English between January 1, 1990 and October 31, 2009, included the terms 'acquired pneumonia', 'associated pneumonia', 'nursing home', 'long-term care', 'institution', and 'healthcare'. RESULTS: Older age, male gender, swallowing difficulty, and inability to take oral medications are all significant risk factors for pneumonia. Medications such as antipsychotics and anticholinergics, histamine receptor blockers and proton pump inhibitors have also been linked to higher risk of pneumonia. The etiology of NHAP overlaps with that of community-acquired pneumonia (CAP), with Streptococcus pneumoniae and Haemophilus influenzae as predominant pathogens in long-term care facilities. In patients who require hospitalization, Chlamydophila pneumoniae, Staphylococcus aureus, and influenza virus have also been identified. In contrast, the etiology of severe NHAP overlaps with that of hospital-acquired pneumonia (HAP), with S. aureus, including methicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa, and enteric Gram-negative bacilli as important causative pathogens. Therapy is dependent on disease severity and, on the treatment setting. Respiratory fluoroquinolones or beta-lactams plus a macrolide are recommended in patients with NHAP. Patients hospitalized with severe NHAP may require triple combination therapy that covers both MRSA and P. aeruginosa. However, there is little evidence of the clinical superiority of one regimen over another, making it challenging to establish guidelines for the treatment of NHAP in the nursing home setting. CONCLUSION: There is a pressing need for clinical trials of antibiotic therapy in nursing home patients that would help establish uniform guidelines to standardize therapy in the nursing home setting. PMID- 20973618 TI - Client evaluation of a specialist inpatient parent-infant psychiatric service. AB - OBJECTIVE: The aim of this paper was to collect feedback on a specialist parent infant psychiatric service in terms of client satisfaction with inpatient treatment, and the impact on health outcomes of providing written information about available support options in the community following discharge. METHODS: Women (n = 37) from consecutive admissions between January 2006 and December 2007 were contacted by telephone and administered a service quality evaluation questionnaire. RESULTS: Women were happy with the quality of inpatient care provided but suggested areas of improvement included continuity of staff during the inpatient stay and better communication between inpatient and outpatient services post-discharge. At discharge, women were not confident with their ability in coping with motherhood but confidence with parenting skills increased post-discharge. Use of recommended post-discharge community support and/or health services was poor. CONCLUSION: As adherence with discharge recommendations was less than ideal, greater involvement of primary/community health care professionals, and active participation of clients and carers, in discharge planning is required. Increased emphasis on the practical skills of motherhood as well as opportunities to develop the mother-infant relationship may assist mothers in gaining confidence to interact with their baby and pick up infant cues. PMID- 20973620 TI - The Boomerangs Parenting Program for Aboriginal parents and their young children. AB - OBJECTIVE: Using three case studies, this paper describes the development and evaluation of 'The Boomerangs Aboriginal Circle of Security Parenting Camp Program', which is a clinical intervention based on an attachment framework using the Circle of Security and Marte Meo, and drawing on traditional Aboriginal culture. METHODS: Three mothers from an Aboriginal Australian background with preschool age children attended the 20-session Boomerangs Program, including an initial camp and a second camp after 6 weeks. The camp provided the opportunity for parent empowerment and to explore the strengths and resources of the mother to facilitate better mother-child interactions and relationship, in a naturalistic setting. RESULTS: All three mothers gave positive feedback on the program in increasing the awareness, sensitivity and responsiveness of their interactions with their children, and this was reflected in the results of the questionnaires and observation of the mother-child interactions during play. CONCLUSION: This program offers the first ever evaluation of an intense parenting program using camps for Aboriginal Australians. This study is to be considered as an exploratory exercise - a first step in a process of exploring applicability and adapting parenting camps for Aboriginal families. PMID- 20973621 TI - Correction of hyperbilirubinemia in gunn rats using clinically relevant low doses of helper-dependent adenoviral vectors. AB - Crigler-Najjar syndrome type I is a severe inborn error of bilirubin metabolism caused by a complete deficiency of uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) and results in life-threatening unconjugated hyperbilirubinemia. Lifelong correction of hyperbilirubinemia by liver-directed gene therapy using a helper-dependent adenoviral (HDAd) vector has been previously reported in the Gunn rat, a model of Crigler-Najjar syndrome, but was only achieved using high doses (>= 3 * 10(12) viral particles [vp]/kg), which are likely to elicit a severe toxic response in humans. Therefore, in this study, we investigate strategies to achieve correction of hyperbilirubinemia in the Gunn rat using clinically relevant low HDAd doses. We have found that correction of hyperbilirubinemia in the Gunn rat can be achieved with a low dose of 5 * 10(11) vp/kg by using an HDAd vector bearing a more potent UGT1A1 expression cassette. Furthermore, by using hydrodynamic injection of the improved HDAd vector, correction of hyperbilirubinemia in the Gunn rat can be achieved using an even lower dose of 5 * 10(10) vp/kg. Although hydrodynamic injection as performed in rats is not acceptable in humans, clinically attractive, minimally invasive methods have been successfully developed to mimic hydrodynamic injection of HDAd vector in non-human primates. Therefore, using an improved expression cassette combined with a more efficient method of vector delivery permits correction of hyperbilirubinemia in the Gunn rat using clinically relevant low HDAd doses and may thus pave the way to clinical application of HDAd vectors for Crigler-Najjar syndrome gene therapy. PMID- 20973619 TI - Succinic semialdehyde dehydrogenase: biochemical-molecular-clinical disease mechanisms, redox regulation, and functional significance. AB - Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1, ALDH5A1; E.C. 1.2.1.24; OMIM 610045, 271980) deficiency is a rare heritable disorder that disrupts the metabolism of the inhibitory neurotransmitter 4-aminobutyric acid (GABA). Identified in conjunction with increased urinary excretion of the GABA analog gamma-hydroxybutyric acid (GHB), numerous patients have been identified worldwide and the autosomal-recessive disorder has been modeled in mice. The phenotype is one of nonprogressive neurological dysfunction in which seizures may be prominently displayed. The murine model is a reasonable phenocopy of the human disorder, yet the severity of the seizure disorder in the mouse exceeds that observed in SSADH-deficient patients. Abnormalities in GABAergic and GHBergic neurotransmission, documented in patients and mice, form a component of disease pathophysiology, although numerous other disturbances (metabolite accumulations, myelin abnormalities, oxidant stress, neurosteroid depletion, altered bioenergetics, etc.) are also likely to be involved in developing the disease phenotype. Most recently, the demonstration of a redox control system in the SSADH protein active site has provided new insights into the regulation of SSADH by the cellular oxidation/reduction potential. The current review summarizes some 30 years of research on this protein and disease, addressing pathological mechanisms in human and mouse at the protein, metabolic, molecular, and whole animal level. PMID- 20973622 TI - Obsessions and compulsions in children with Asperger's syndrome or high functioning autism: a case-control study. AB - OBJECTIVE: To compare the clinical characteristics and symptom severity of children with obsessive disorder (OCD) plus autism spectrum disorders (ASD) with those of children with OCD plus Tourette's syndrome (TS) or OCD alone. METHOD: Children with OCD and ASD (OCD/ASD) (n = 12, mean age = 14.33, range: 12-18) were compared to children with OCD and TS (OCD/TS) (n = 12, mean age = 13.92, range: 9 17) and children with OCD-alone (OCD) (n = 12, mean age = 12.92, range: 9-17) on measures of obsessive-compulsive (OC) symptom frequency, severity, interference and other clinical variables. RESULTS: Patients from the OCD/ASD group rated their OC symptoms as equally distressing, time consuming and contributing to a similar level of interference in functioning as patients in the OCD/TS and OCD groups. The types of symptoms were similar across groups but patients with OCD/TS reported greater frequency of ordering and arranging compulsions, and a trend towards more sexual obsessions. Patients with OCD/ASD reported more peer relationship problems compared with the other two groups. CONCLUSIONS: Children with ASD may experience a similar level of impairment from OC symptoms as children with TS plus OCD and children with OCD only. It is suggested that it is useful to establish both diagnoses given that obsessions and compulsions may respond to treatment, and their alleviation may improve functioning in children on the autism spectrum. PMID- 20973623 TI - The social determinants of mental health: implications for research and health promotion. AB - Social determinants of health have come to greater prominence through the recent work of the WHO Commission on the Social Determinants of Health, and the Marmot Review of Health Inequalities in England. These reports also have significant implications for promotion of mental health in developed countries. In particular they reflect a growing research interest in the view that certain adverse social conditions may detrimentally affect mental or physical health by acting as chronic stressors. However, although the case for chronic arousal of stress systems as a risk factor for mental health is empirically well-founded, questions remain about how and why psychological exposure to certain kinds of proximal social conditions might contribute to such arousal. In this paper we argue that combining evidence and ideas from a number of disciplines, including public health research and psychiatry, presents an opportunity to understand the relationship better, and so inform complementary strategies in treatment, prevention and health promotion. PMID- 20973624 TI - Detailed long-term outcome analysis after decompressive craniectomy for severe traumatic brain injury. AB - OBJECTIVE: To assess detailed long-term clinical outcome at least 1 year after decompressive craniectomy (DC) in patients with severe traumatic brain injury (TBI). METHODS: One hundred and thirty-one patients with severe TBI underwent DC between September 1997 and September 2005. Outcome was measured using the Glasgow Outcome Scale (GOS). Detailed outcome analysis was performed using Glasgow Outcome Scale Extended, Short-Form 36 (SF-36), Beck Depression Inventory, Trail Making Test B (TMT-B), Digit-Symbol Test (DST) and Barthel Index (BI). RESULTS: Sixty-three patients (48.1%) died during their initial hospital stay, 27 (20.6%) were discharged in a vegetative state, 32 (24.4%) with severe disability and nine (6.9%) with moderate disability (GOS 3 and 4, respectively). At time of follow-up 75 patients (67.7%) were either dead or in a vegetative state. Thirty patients with GOS >2 were recruited for a detailed outcome analysis: Major depression, neurologic deficits and impaired TMT-B and DST performances were common and significantly more prevalent than in normative controls. Yet, patients reported only modestly reduced SF-36 and high BI scores. CONCLUSIONS: Despite multiple health-related problems after DC, many patients proved highly functional in activities of daily living and reported qualities of life not significantly inferior to that of healthy individuals. Depression was common and requires to be addressed with patients and caregivers. Better targeted therapies could improve neuropsychological and psychiatric outcomes in this complex cohort. PMID- 20973625 TI - Recreational physical activities among children with a history of severe traumatic brain injury. AB - OBJECTIVE: To describe leisure time physical activity (LTPA) and physical capabilities such as balance, muscle strength and walking performance and to evaluate the associations between physical capabilities and LTPA among children post-traumatic brain injury (TBI) as compared to a peer group of typically developed (TD) controls. PARTICIPANTS: Convenience sample of 15 children, 1.5-7 years post-severe TBI and 15 age- and sex-matched controls. MAIN OUTCOME MEASURES: LTPA by the Godin and Shephard (G&S) questionnaire. Balance tests-the Timed Up and Go test (TUG) and functional reach test (FRT). Maximal isometric strength was assessed by using a hand-held dynamometer; walking dynamics were recorded by an electronic mat and the 6 minute walk test and energy expenditure index (EEI). Perceived exertion was rated by the OMNI scale. RESULTS: Children post-severe TBI participate significantly less in LTPA as compared to TD controls (p < 0.01). Walking performance was comparable between groups except for step length which was significantly shorter among children post-TBI. Hip extensor strength and balance performance were significantly lower among children post TBI. Balance performance was positively associated with LTPA. CONCLUSIONS: This study suggests that attention should be directed towards improving balance performance as part of the training repertoire of children and adolescents with post-severe TBI. The efficacy of such a training programme, in particular its contribution to LTPA participation, should then be further assessed. PMID- 20973626 TI - Reliability of the Community Balance and Mobility Scale (CB&M) in high functioning school-aged children and adolescents who have an acquired brain injury. AB - PRIMARY OBJECTIVE: To examine inter-rater, intra-rater and test-re-test reliability of the Community Balance and Mobility Scale (CB&M) and compare reliability in live vs videotape rating contexts for children with acquired brain injury (ABI). RESEARCH DESIGN: Repeated measures design. METHODS AND PROCEDURES: Seven physiotherapists (PTs) were trained as assessors. The primary assessor administered and scored baseline CB&M while the second assessor observed and scored independently (inter-rater reliability). Re-assessment occurred 3-10 days later by primary assessor (test-re-test reliability). Assessments were videotaped. MAIN OUTCOMES AND RESULTS: There were 32 participants with ABI (mean age = 14 years 1 month (SD = 2 years 1 month)). Baseline mean scores were 67.4% (18.2) and 66.7% (18.3) for primary and second assessor, respectively. Primary assessors' re-test mean score was 69.3%. Inter-rater reliability ICC was 0.93 (95% confidence interval (CI) = 0.87-0.97). Test-re-test ICC was 0.90 (95%CI = 0.81-0.95) and Bland-Altman plot indicated greatest test-re-test differences for mid-range CB&M scores. Minimum detectable change (MDC90) was 13.5% points. CONCLUSIONS: The CB&M showed excellent reliability in youth. Reliability was comparable for live and videotape rating approaches, meaning that the easier and less expensive live-rating can be recommended. Future work should focus on evaluation of responsiveness to change in rehabilitation centre and community intervention contexts. PMID- 20973627 TI - An examination of the factor structure of the Revised Illness Perception Questionnaire modified for adults with mild traumatic brain injury. AB - OBJECTIVE: Factors influencing outcome after mild traumatic brain injury (MTBI) remain poorly understood. In other health conditions patient illness perceptions have been associated with outcome and have provided targets for effective interventions. These have not been systematically explored in MTBI and identifying reliable and valid measures of illness perceptions in MTBI is a first step before such concepts can be explored in clinical and research settings. METHOD: This study investigated the factor structure and internal consistency reliability of the Illness Perceptions Questionnaire-Revised (IPQ-R) modified for MTBI in a sample of 147 adults recruited within 3 months of injury. RESULTS: The results demonstrated a close replication of the original factor structure although there were notable exceptions likely to be specific to MTBI and potentially other acutely injured populations. Final scales showed good internal consistency although factors relating to causal attribution were less so. CONCLUSION: The IPQ-R (MTBI) provides an acceptable measure of key components of injury perceptions after MTBI. Minor refinements appear required if this measure is to make a contribution to research and clinical practice in injury-based populations such as MTBI. PMID- 20973628 TI - Longitudinal outcomes of patients with traumatic brain injury: a preliminary study. AB - PRIMARY OBJECTIVE: To examine the long-term global clinical outcomes of TBI patients from 1 week to 10 years post-injury. RESEARCH DESIGN: A retrospective study was conducted at a level I trauma centre. METHODS AND PROCEDURES: A total of 327 TBI patients were recruited retrospectively in this longitudinal study and the score of Glasgow Outcome Scale Extended (GOSE) was then documented as an indicator of the clinical outcomes. MAIN OUTCOMES AND RESULTS: The results presented that less than one-in-three patients recovered well within 2 weeks after trauma. Around 40% of patients were evaluated as favourable outcomes within 6 months post-injury. Less than 30% of TBI patients could gain favourable outcomes at 3 years post-injury and over half of patients still could not recover well at 6 years. Five patients' outcomes were continuously followed until 10 years and the results indicated that they started to have good outcomes after 3 years post-injury. CONCLUSIONS: This study might be the first one to longitudinally evaluate the outcomes of patients from 1 week to 10 years post injury and revealed that patients still may have difficulties in social interactions and family relationships until 6 years post-injury, even though they could live and work independently. Hence, professionals should pay attention to the underlying factors causing their difficulties within the long-term recovery process. PMID- 20973629 TI - Use of the International Classification of Functioning, Disability and Health (ICF) in patients with traumatic brain injury. AB - INTRODUCTION: Many tools exist for assessing the functioning of a patient with traumatic brain injury. Possible benefits of the ICF in TBI rehabilitation are currently under discussion. GOAL: The study explored to what extend the ICF is useful to organize existing clinical information and to retrospectively evaluate the effect of interventions in patients with TBI. METHOD: A retrospective patient record study was conducted. Medical records of 100 patients admitted to the Slovenian University Rehabilitation Institute from 2007-2009 were linked to the ICF. RESULTS: The majority of the functional problems at the level of body functions corresponded to mental and movement-related functions. Within the list of activities and participation, the patients experienced more difficulties in tasks that require intellectual effort, communicational ability, mobility and self-care. The ICF detected substantial improvement after rehabilitation regarding body functions and activities related to mobility and self-care and little improvement regarding mental functions and related activities. Some important environmental factors were also identified. CONCLUSIONS: The translation of the information about functioning into the ICF format provided a well-structured functional profile of the selected group of patients in a language-independent format. ICF also clearly outlined the environmental factors important for the recovery and functioning. PMID- 20973630 TI - Neuroanatomical correlates of the clock drawing test in patients with traumatic brain injury. AB - OBJECTIVE: The clock drawing test (CDT) is a quick and easy to administer test that has traditionally shown parietal lobe dysfunction. The aim of this study was to correlate performance on the CDT with the presence of acute traumatic cerebral injuries sustained after traumatic brain injury (TBI). METHODS: A retrospective study was conducted on 170 patients with TBI of all severity admitted to an acute care setting. These patients sustained different types of injuries (epidural haematoma, subdural haematoma, subarachnoid haemorrhage, intraparenchymal haematoma and brain oedema) in different sites (frontal, temporal, parietal, occipital lobes, bilateral and right or left hemisphere). RESULTS: The CDT total score was significantly lower for subjects presenting subarachnoid haemorrhage (4.80 +/- 3.34 vs 7.04 +/- 3.14, t(168df) = 4.477, p < 0.001) and for those presenting brain oedema (4.50 +/- 3.06 vs 6.69 +/- 3.38, t(168df) = 4.214, p < 0.001), parietal injury (5.15 +/- 3.17 vs 6.42 +/- 3.52, t(168df) = 2.416, p = 0.017) or bilateral injuries (5.28 +/- 3.31 vs 6.62 +/- 3.44, t(168df) = 2.569, p = 0.011) compared to those who did not. CONCLUSION: This study provides empirical evidence of the relationship between TBIs and results on the CDT, supporting previous studies done with other populations. PMID- 20973631 TI - Temporospatial characteristics of gait in patients with lower limb muscle hypertonia after traumatic brain injury. AB - OBJECTIVE: To characterize gait characteristics of adults with traumatic brain injury (TBI) and lower limb muscle hypertonia, distinguishing gait adaptations inherent to TBI motor impairment from those of healthy subjects walking at slower speed. METHODS: Temporospatial and kinematic data of 31 patients with TBI (41 +/- 30 months post-injury) walking at self-selected speed (free speed) were compared with 31 healthy subjects walking at free and very slow speeds using an optoelectronic motion analysis system. RESULTS: All step parameters differed (p < 0.05) between more affected (MA) and less affected (LA) sides in TBI except foot angle and toe clearance. Significant differences existed between TBI and controls in most parameters regardless of speed. These differences frequently involved the LA side. In TBI, most temporospatial parameters significantly correlated with stride velocity, whereas the averaged lower limb Ashworth score on the MA side (2.1 +/- 0.4) showed few significant correlations. CONCLUSIONS: Gait deviations in subjects with TBI and lower limb muscle hypertonia cannot be solely explained by slower walking. The preponderance of changes involving the LA side particularly suggests prevalent use of compensatory walking strategies. Temporospatial gait parameters are not closely related to static measures of muscle hypertonia after TBI. PMID- 20973632 TI - Active versus passive management of post-acquired brain injury challenging behaviour: a case study analysis of multiple operant procedures in the treatment of challenging behaviour maintained by negative reinforcement. AB - PRIMARY OBJECTIVE: Operant conditioning interventions are effective in the management of post-acute ABI challenging behaviour. However, when this serves an avoidance or escape function, reinforcement approaches may be ineffective. In this paper the utility of a range of operant-derived ABI interventions is considered specifically with regard to behaviour whose prime function is avoidance or escape from rehabilitation activities. METHODS AND PROCEDURES: Efficacy of three operant interventions was determined by describing a single case study whose aggressive behaviour served an avoidance-escape function. Two interventions comprised variants of differential reinforcement: differential reinforcement of incompatible behaviour (DRI) and differential reinforcement of low rates of responding (DRL). The third intervention comprised situational time out (STO) and sustained verbal prompting. MAIN OUTCOME: Despite reports of the efficacy of DRI and DRL, neither was beneficial in this case. However, STO and sustained verbal prompting proved highly effective in reducing aggression. CONCLUSIONS: Results are discussed in relation to two levels of explanation: function and cognition. Special emphasis is laid upon the extent to which interventions actively involve the patient and the degree of intrusiveness necessary for staff to implement therapeutic procedures. The case demonstrates how a scientifically-derived formulation regarding behaviour disorder can support multiple treatment options. PMID- 20973633 TI - Mass spectrometry and pollen allergies. PMID- 20973636 TI - First Aegean International Conference on Molecular Recognition. AB - This meeting report describes some of the highlights of the First Biennial Aegean International Conference on Molecular Recognition that took place in Hersonissos, Crete, Greece, between 6 and 11 June 2010. The conference comprised four sessions devoted to: dynamic and combinatorial molecular recognition; B-cell epitope prediction, synthesis and vaccines; nanotechnology approaches to molecular recognition; and host-pathogen interactions. A total of 35 oral communications and 15 posters were presented. The second Aegean International Conference on Molecular Recognition is scheduled to take place in the spring of 2012. PMID- 20973635 TI - Modern challenges in therapeutic protein production. AB - The Modern Challenges in Therapeutic Protein Production conference hosted 44 delegates from the UK and Germany and was organized by EuroSciCon. The aim of the meeting was to look at the challenges that currently face the production of therapeutic proteins and to attempt to demystify some of the novel approaches and new technologies that are being developed and could have applications in this area. The Chair, Brendan Fish (GlaxoSmithKline, Barnard Castle, UK), gave a detailed introduction to the conference and finished with a summation at the end. PMID- 20973637 TI - At the crossroads of ubiquitin signaling and mass spectrometry. AB - Ubiquitin signaling regulates a wide variety of cellular events, although it is mostly known to mediate protein degradation by the proteasome complex. The rapid development in mass spectrometry offers state-of-the-art technologies for addressing biological challenges in ubiquitin signaling. The First Conference on Proteomics of Protein Degradation & Ubiquitin Pathways in Vancouver, Canada, covers the latest progress in key topics of the field and fosters collaborative interactions among researchers. PMID- 20973638 TI - Isobaric protein and peptide quantification: perspectives and issues. AB - An important challenge for proteomics is the ability to compare protein levels across biological samples. Since their introduction, isotopic and isobaric peptide labeling have played an important role in relative quantitative comparisons of proteomes. One important drawback of most of the isotopic-labeling techniques is an increase in sample complexity. This problem was successfully addressed with the construction of isobaric labeling strategies, such as isobaric tag for relative and absolute quantification (iTRAQ), tandem mass tagging, the cleavable isobaric affinity tag, dimethylated leucines and isobaric peptide termini labeling. Furthermore, numerous applications for multiplexing using iTRAQ and tandem mass tagging have been reported. PMID- 20973639 TI - Peptide fractionation in proteomics approaches. AB - Peptide fractionation is extremely important in proteomics approaches. Full proteome characterization is desired from complex organisms, and with growing interest in post-translational modifications an extended protein sequence coverage is required. Peptide fractionation techniques have the great challenge of feeding current mass spectrometers in a way in which these issues are met. Peptide fractionation can be divided into three simple components: the column characteristics; the mobile phase; and peptide properties (charge, polarity, hydrophobicity and size). The current challenges are in the combination of these three components to allow comprehensive proteomics studies to be improved. PMID- 20973640 TI - Development of multidimensional liquid chromatography and application in proteomic analysis. AB - As a complementary approach to 2D-PAGE, multidimensional liquid chromatography (MDLC) separation methods have been widely applied in all kinds of biological sample investigations. MDLC coupled with mass spectrometry is playing an important role in proteome research owing to its high speed, high resolution and high sensitivity. Among MDLC strategies, ion-exchange chromatography together with reversed-phase LC is still a most widely used chromatography in proteome analysis; other chromatographic methods are also frequently used in protein prefractionations. Recent MDLC technologies and applications to a variety of proteome analyses have achieved great development. The diversity of combinations of different chromatography modes to set up MDLC systems was demonstrated and discussed. Novel developments of MDLC techniques such as ultra-pressure system, array-based separation and monolithic material are also included in this article. PMID- 20973641 TI - Large-scale protein interactome mapping: strategies and opportunities. AB - Interactions between proteins are central to any cellular process, and mapping these into a protein network is informative both for the function of individual proteins and the functional organization of the cell as a whole. Many strategies have been developed that are up to this task, and the last 10 years have seen the high-throughput application of a number of those in large-scale, sometimes proteome-wide, interactome mapping efforts. Although initially the quality of the data produced in these screening campaigns has been questioned, quality standards and empirical validation schemes are now in place to ensure high-quality data generation. Through their integration with other 'omics' data, interactomics datasets have proven highly valuable towards applications in different areas of clinical importance. PMID- 20973642 TI - Bioactive molecules of Taenia solium metacestode, a causative agent of neurocysticercosis. AB - Neurocysticercosis (NC), an infection of the CNS with Taenia solium metacestode, exemplifies formidable public health concerns associated with significant morbidity and mortality. The disease is a complex phenomenon involving molecular cell biological cross-talks between the parasite and human host. To effectively combat NC, specific diagnosis and proper management are prerequisites. Bioactive molecules implicated in host-parasite interactions and parasitic homeostasis should be elucidated. This article provides an overview of currently available serological biomarkers, especially those comprising low-molecular-weight proteins, and discusses available immunoproteomics for identification of such molecules. T. solium metacestode bioactive molecules, which might be critically implicated in the progression of NC disease, are summarized. Comprehensive understanding of the biochemical properties and biological functions of bioactive molecules may contribute to the development of novel intervention strategies against NC. PMID- 20973643 TI - Salivary peptidomics. AB - In recent years, there has been an increased interest in the study of saliva. This bodily fluid contains a vast number of protein species, the salivary peptidome, of low molecular weight, comprising approximately 40-50% of the total secreted proteins, in addition to peptides generated by proteolysis of proteins of different sources. Owing to the presence of other components, in particular mucins and enzymes, some distinctive requirements and precautions related to sample collection, time of analysis, sample preservation and treatment are necessary for the successful analysis of salivary peptides. More than 2000 peptides compose the salivary peptidome, from which only 400-600 are directly derived from salivary glands, suggesting an important qualitative peptide contribution of other sources, namely of epithelial cells. Proteolysis events are the main supply for the peptidome and considerable efforts have been made to identify the resulting fragments, the cleavage sites and the involved proteases. The salivary proteins more prone to proteolysis are proline-rich proteins (PRPs; acidic PRPs and basic PRPs), statherin, histatins and P-B peptide. Gln-Gly cleavages are largely associated with PRP classes, while Tyr-Gly cleavages are related to histatin 1 and to the P-B peptide. The interest in saliva has been growing for clinical purposes, as it is an alternative sample to other traditional bodily fluids, such as blood or urine, since it involves an easy and noninvasive collection. In fact, apart from its usefulness as a source of information for the prognosis, diagnosis and treatment of oral diseases, such as Sjogren's syndrome, gum disease, tooth decay or oral cancer, saliva might also be seen as a potential tool to the diagnosis of systemic diseases. Owing to the enormous amount of previously discovered salivary peptide species, in this article, we attempt to harmonize the nomenclature, following International Union of Pure and Applied Chemistry recommendations. PMID- 20973644 TI - Proteomic analysis in the identification of allergenic molecules. AB - Conventional and innovative strategies can be exploited to identify and characterize new allergenic proteins. With the aim of obtaining suggestions for future improvements, this article describes our attempt to understand and describe some of the advantages and pitfalls of the methodologies and procedures often used in this field. The analysis includes the protein extract preparation, starting from the allergenic source, the separation of the proteins contained in a mixture and the detection, identification and characterization of IgE-binding molecules. Classic and emerging proteomic technologies, including mass spectrometry-based methodologies, Edman degradation procedure, microarray-based techniques and bioinformatics search strategies, have been explored. A comparative analysis of biochemistry-based proteomics and molecular biology strategies has also been given. PMID- 20973645 TI - Proteomic analysis of zymogen granules. AB - Zymogen granules (ZGs) are specialized storage organelles in the exocrine pancreas that allow the sorting, packaging and regulated apical secretion of digestive enzymes. ZG constituents play important roles in pancreatic injury and disease. The molecular mechanisms underlying these processes are still poorly defined. Thus, there is currently great interest in the identification and characterization of ZG components. Recent proteomic studies have greatly enhanced our knowledge regarding potential new 'players' in ZG biogenesis and regulated secretion. In this article, we present the latest advancements in and insights into the analysis of the ZG proteome by the combination of organelle isolation, protein separation, mass spectrometry and validation of protein identification. Recent developments in the analysis of ZG proteins from pancreatic juice and related proteins from saliva are also discussed. PMID- 20973646 TI - Proteomics of osteoarthritic chondrocytes and cartilage. AB - Osteoarthritis (OA) is characterized by irreversible destruction of the articular cartilage. OA affects more than 100 million individuals worldwide and has a major impact on patients' quality of life. The lack of effective therapy that prevents, inhibits or reverses the progress of OA often leaves only the option of surgical interventions. Thus, identification of the factors that contribute to OA pathogenesis is necessary for better understanding of OA pathobiology and discovery of effective therapies. Recent proteomic studies have been conducted to identify pathological mediators and biomarkers of OA, which have pinpointed novel pathways involved in cartilage degeneration. This article summarizes the recent findings, compares major techniques used in OA proteomics and discusses key proteins in OA and their potential use as therapeutic targets. PMID- 20973647 TI - Natural glycan microarrays. AB - Glycan microarrays are emerging as increasingly used screening tools with a high potential for unraveling protein-carbohydrate interactions: probing hundreds or even thousands of glycans in parallel, they provide the researcher with a vast amount of data in a short time-frame, while using relatively small amounts of analytes. Natural glycan microarrays focus on the glycans' repertoire of natural sources, including both well-defined structures as well as still-unknown ones. This article compares different natural glycan microarray strategies. Glycan probes may comprise oligosaccharides from glycoproteins as well as glycolipids and polysaccharides. Oligosaccharides may be purified from scarce biological samples that are of particular relevance for the carbohydrate-binding protein to be studied. We give an overview of strategies for glycan isolation, derivatization, fractionation, immobilization and structural characterization. Detection methods such as fluorescence analysis and surface plasmon resonance are summarized. The importance of glycan density and multivalency is discussed. Furthermore, some applications of natural glycan microarrays for studying lectin and antibody binding are presented. PMID- 20973648 TI - Deciphering proteins and their functions in the regenerating retina. AB - Neurons of the mammalian CNS, including retinal ganglion cells, lack, in contrast to the PNS, the ability to regenerate axons spontaneously after injury. Regeneration of the CNS is extremely complex and involves various molecular factors and cells. Therewith the regenerative process remains an enormous scientific and clinical challenge. This article provides an overview of proteins that play a crucial role in axon regeneration of retinal ganglion cells and their underlying signaling pathways. In this context, we elucidate the role of 2D gel electrophoresis and highlight some additional proteins, altered upon regeneration by using this highly sensitive method. PMID- 20973655 TI - In vitro activity of human chorionic gonadotropin (hCG) on myometrium contractility. AB - LH/hCG receptor has been found in extragonadal tissues in human and animals. The myometrium presents such receptors but their functional role is still not clear. Aim of our study was to test the activity of human chorionic gonadotropin (hCG) on bovine uterine contractility. Uterine strips from cows both during follicular and luteal phases were mounted in an organ bath and then exposed to increased doses of hCG. The amplitude of the myometrium contractions were significantly decreased in the follicular and luteal phase but the frequency was not affected. These findings prove a relaxing effect of hCG in the bovine uterus, as already shown in the sow and human, and its possible functional role in modulating uterine contractility. PMID- 20973656 TI - Salmonella Virchow and Salmonella Weltevreden in a random survey of the Asian house gecko, Hemidactylus frenatus, in houses in northern Australia. AB - BACKGROUND: Salmonella enterica serotype Virchow is the most common cause of invasive nontyphoid salmonellosis in North Queensland, particularly in infants, but the zoonotic source is unknown. This study aimed at determining (i) the prevalence of the introduced Asian house gecko, Hemidactylus frenatus, in houses in North Queensland and (ii) whether they were a potential source of Salmonella Virchow. METHODS: Asian house geckos were collected in a random survey of houses in Townsville, North Queensland. Gut contents underwent microbiological analysis within 2 h of removal using both direct plating and enrichment broth methods. Any organism found to be a presumptive Salmonella spp. was then sent to a reference lab for confirmation of genus/species, serotyping, and phage typing if indicated. RESULTS: One hundred Asian house geckos were collected from 57 houses. Geckos were present in 100% of houses surveyed, and prevalence of Salmonella in large intestinal contents was 7% (95% confidence interval 2, 12%). Three serotypes were found: Virchow (phage type 8), Weltevreden, and an untypable subspecies 1 serotype 11:-:1,7. CONCLUSION: Since Salmonella Virchow (phage type 8) is associated with invasive disease, the introduced Asian house gecko may play a significant role in the epidemiology of sporadic salmonellosis in places invaded by these peridomestic reptiles. These results justify more detailed epidemiological studies on the role of the Asian house gecko in sporadic salmonellosis and development of evidence-based strategies to decrease this potential zoonotic hazard. PMID- 20973657 TI - Bartonella henselae and the potential for arthropod vector-borne transmission. AB - INTRODUCTION: Bartonella henselae, the causative agent of the illness referred to as cat scratch disease, is a common infection, particularly in children, and clinicians need to be aware of its potential transmission to humans by arthropod vectors such as fleas and ticks in addition to animal bites and scratches. The absence of a vertebrate bite or scratch does not preclude infection with B. henselae. MATERIALS AND METHODS: Literature regarding arthropod transmission of B. henselae was reviewed. RESULTS: B. henselae appears to be transmitted among cats and dogs in vivo exclusively by arthropod vectors (excepting perinatal transmission), not by biting and scratching. In the absence of these vectors disease does not spread. On the other hand, disease can be spread to humans by bites and scratches, and it is highly likely that it is spread as well by arthropod vectors. DISCUSSION: Clinicians should be aware that a common illness, infection with B. henselae, can be transmitted by arthropod vectors and a history of an animal scratch or bite is not necessary for disease transmission. PMID- 20973658 TI - Medium-mediated effects increase cell killing in a human keratinocyte cell line exposed to solar-simulated radiation. AB - PURPOSE: The objective of this study was to investigate whether cell culture medium is a biologically relevant exposure medium that can be employed in non ionising photobiological investigations. METHODS: The effect of solar-simulated irradiation on cell culture medium and its ability to elicit cell death was studied. The role of reactive oxygen species (ROS), cell secreted factors, and the contribution of individual components of the medium were investigated. RESULTS: Cell death was found to be primarily mediated through the formation of ROS via riboflavin photosensitisation and degradation in the cell culture medium. Phenol red was found to significantly reduce the cell killing ability of riboflavin. Exposures in riboflavin-free medium resulted in significantly increased cell survival compared to identical exposures in riboflavin containing medium. CONCLUSIONS: This study has shown that solar radiation toxicity is augmented by cell culture medium due to the presence of riboflavin. Results suggest that exposures performed in phenol red-free medium may serve to increase phototoxic effects if riboflavin is present. Riboflavin-free media is recommended for solar radiation investigations to eliminate concerns regarding riboflavin photosensitisation and nutrient deprivation. PMID- 20973659 TI - Gross motor coordination in relation to weight status and age in 5- to 12-year old boys and girls: a cross-sectional study. AB - OBJECTIVE: The purpose of this study was to investigate differences in gross motor coordination in healthy-weight, overweight, and obese children of different ages. METHODS: Using a cross-sectional design, data were collected in 954 Flemish primary school children (500 girls, 454 boys) stratified in consecutive age groups (5-7 years, 8-9 years, 10-12 years). Weight status (healthy-weight, overweight, obese) was defined according to the International Obesity Task Force body mass index (BMI) cut-off points for children. Gross motor coordination was assessed by means of the Korperkoordinationstest fur Kinder (KTK). RESULTS: Childhood overweight and particularly obesity were found to result in poorer KTK performances (p < 0.001), with the most apparent effect of BMI on items requiring physical properties next to dynamic body coordination. Expressed as an age related Motor Quotient (MQ), overall KTK performance was featured by a BMI * AGE interaction (p < 0.01). Healthy-weight children displayed similar MQs across age groups (p = 0.999). Overweight and obese children in the 10-12-year-old group showed significantly poorer motor coordination performance compared with the corresponding 5-7-year-old group (p < 0.01). Less than 20% of the healthy-weight participants was identified as being motor impaired, while that proportion increased to 43.3% and up to 70.8% in children with overweight and obesity, respectively. CONCLUSION: Results indicate that BMI-related differences in gross motor coordination were more pronounced as children belonged to an older age group. Although this outcome needs to be confirmed in future longitudinal research, it emphasizes the need of an early focus on motor skill improvement to encourage overweight and obese children to be physically active. PMID- 20973660 TI - Strategies used by community-based organizations to evaluate their locally developed HIV prevention interventions: Lessons learned from the CDC's innovative interventions project. AB - Community-based organizations (CBOs) play an important role in health promotion efforts and the delivery of HIV prevention interventions for at-risk minority populations. CBOs may also develop their own interventions but often lack the capacity or funds to rigorously evaluate them. The Innovative Interventions project of the Centers for Disease Control and Prevention (CDC) funded three CBOs to rigorously evaluate the efficacy of interventions they had developed and were delivering to Black women, Black men who have sex with men (MSM), and adolescent males in juvenile justice settings, respectively. The evaluation results have been reported elsewhere. This article describes operational issues that the CBOs identified as being particularly salient to their evaluations and the strategies they developed to address the issues and successfully complete their evaluations. These issues included the development of organizational capacity to conduct a rigorous outcome evaluation, difficulties with recruitment and retention of evaluation participants, and the use of process monitoring data to improve intervention delivery. The strategies described in this article can be used by CBOs when evaluating their locally developed HIV prevention interventions and may be of interest to funding agencies and researchers that collaborate with CBOs to evaluate their interventions. PMID- 20973661 TI - Preventing AIDS through live movement and sound: Efficacy of a theater-based HIV prevention intervention delivered to high-risk male adolescents in juvenile justice settings. AB - Male adolescents who cycle through the juvenile justice system are at high risk for HIV infection, yet there are few HIV prevention interventions for this high risk population. This study evaluates the efficacy of Preventing AIDS through Live Movement and Sound (PALMS), an innovative, theory-based HIV risk reduction intervention that uses theatrical performances and role-play. The study used a nonrandomized concurrent comparison group design. A total of 289 predominantly African American males aged 12-18 from two juvenile justice facilities in Philadelphia, PA were enrolled. At 6-month follow-up, PALMS participants demonstrated greater increases in HIV and condom use knowledge and improved attitudes toward HIV testing and toward persons living with HIV/AIDS than did those in the comparison condition. PALMS participants were also significantly more likely to use a condom during their last sexual contact with a non-main female partner than comparison participants. This theater-based HIV prevention intervention is a potential resource for changing knowledge, attitudes, and behaviors of adolescents in juvenile justice settings. PMID- 20973662 TI - Coping, drug use, and religiosity/spirituality in relation to HIV serostatus among gay and bisexual men. AB - Cross-sectional data were collected on a sample of 259 gay and bisexual, male identified individuals as part of a larger study of the psychosocial functioning of lesbian, gay, bisexual, and transgender persons. Analyses considered differences between HIV-positive and HIV-negative men in relation to active and religious coping strategies; avoidant coping strategies (specifically, illicit drug use); and the psychosocial states of anxiety, hostility, and depression in relation to self-reported HIV-status of the participants. As compared with HIV negative men, the HIV positive participants indicated a greater likelihood of engaging in illicit substance use within the previous 3 months, as well as higher levels of both active and religious coping strategies. Illicit substance use also was found to be related to higher levels of depression, anxiety, and hostility. A multivariate model indicated a significant difference in substance-based and active coping strategies among the men surveyed, with persons with a self reported HIV-positive serostatus endorsing higher levels of both strategies. These results and their implications for prevention and future research are discussed, rooted in the understanding that a complex reality for coping is often enacted by HIV-positive men. PMID- 20973663 TI - The role of peer support on condom use among Black and Latino MSM in three urban areas. AB - This article examines the sociodemographic/behavioral variables associated with low peer support of condom use and the relation between low peer support of condom use and unprotected anal sex for Black and Latino MSM in cities heavily impacted by the HIV/AIDS epidemic. Our findings indicate that perceived low peer support of condom use is associated with increased odds of recent unprotected anal intercourse (UAI) among Black and Latino MSM, regardless of male partner type. Although many participants reported having high peer support of condom use, this analysis highlights a considerable subgroup of Black and Latino MSM, 21% and 30%, respectively, who report low peer support of condoms. Given the prevalence of low peer support of condom use and its association with UAI in these highly impacted MSM populations, we recommend future intervention work that draws upon Black and Latino MSM's peer and social network members to reduce HIV risk behaviors. PMID- 20973664 TI - Stigma against HIV-infected persons among migrant women living in Shanghai, China. AB - We examined the characteristics of 601 female migrants in Shanghai regarding stigmatizing attitudes toward people living with HIV/AIDS (PLWHA). A community based cross-sectional study was conducted July and August 2008, using an anonymous questionnaire. Most participants (88%) were married, 9.2% reported multiple sexual partners, 19.1% knew about voluntary counseling and testing clinics, and 3.7% had been tested for HIV. About half (56.4%) agreed that people who acquire HIV/AIDS through sex or drug use deserve it. About 80% admitted that they were afraid of PLWHA. Low knowledge of HIV/AIDS, being older, low levels of education, and longer duration in Shanghai were correlates for having stigmatizing attitudes, while having premarital sex and/or multiple sex partners correlated with less stigma. HIV-related stigma among female migrants in Shanghai is common. Future stigma reduction prevention and intervention programs among female migrants should target those who are older, less educated, and have lived in Shanghai relatively longer. PMID- 20973665 TI - Condom access: Associations with consistent condom use among female sex workers in two northern border cities of Mexico. AB - To determine whether condom access is associated with consistent condom use among female sex workers (FSWs) in Tijuana and Ciudad Juarez, between 2004 and 2006 we administered a questionnaire to 924 FSWs who reported unprotected sex with a client in the past 2 months. Of these women, 43% reported consistent ("often" or "always") condom use, 74% said condoms were available, and 38% reported having access to free condoms. In a logistic regression, factors positively associated with consistent condom use were condom availability (adjusted odds ratio [AOR] = 2.00; 95% confidence interval [CI]: 1.32-3.03), condom affordability (AOR = 1.72; 95% CI: 1.25-2.38) and self-efficacy (AOR = 2.16; 95% CI: 1.54-3.04). Factors inversely associated with consistent condom use included poor financial status (AOR = 0.65; 95% CI: 0.47-0.90), methamphetamine use (AOR = 0.58; 95% CI: 0.40 0.83), alcohol use (AOR = 0.68; 95% CI: 0.49-0.96), and recent injection drug use (AOR = 0.62; 95% CI: 0.39-0.97). While increased condom availability may improve condom use among FSWs in general, interventions to broaden condom use among lower income and drug-using FSWs are critically needed. PMID- 20973666 TI - Central American sex workers' introduction of the female condom to different types of sexual partners. AB - Formative research was conducted in El Salvador and Nicaragua to inform promotion of female condoms to sex workers. Two rounds of focus groups with sex workers were conducted, with female condom training and supplies provided. Structured interviews with sex workers and direct observations of health educators were conducted. One third of sex acts were protected with female condoms in the previous 7 days. Women recommended nonpaying partners as "first try" partners but most frequently reported trying female condoms with clients. With clients, women preferred female condoms over male condoms but expressed no preference with nonpaying partners. Lack of exposure to female condoms among men and women was cited as a key barrier to female condom use. Strategies for persuading all partner types to try the female condom are suggested, and we provided promotional messages, based on results, to assist sex workers in introducing female condoms to different partners. PMID- 20973667 TI - Integrating women's human rights into global health research: an action framework. AB - This article uses Scale of Change theory as a framework to guide global health researchers to synergistically target women's health outcomes in the context of improving their right to freedom, equity, and equality of opportunities. We hypothesize that health researchers can do so through six action strategies. These strategies include (1) becoming fully informed of women's human rights directives to integrate them into research, (2) mainstreaming gender in the research, (3) using the expertise of grass roots women's organizations in the setting, (4) showcasing women's equity and equality in the organizational infrastructure, (5) disseminating research findings to policymakers in the study locale to influence health priorities, and (6) publicizing the social conditions that are linked to women's diseases. We explore conceptual and logistical dilemmas in transforming a study using these principles and also provide a case study of obstetric fistula reduction in Nigeria to illustrate how these strategies can be operationalized. Our intent is to offer a feasible approach to health researchers who, conceptually, may link women's health to social and cultural conditions but are looking for practical implementation strategies to examine a women's health issue through the lens of their human rights. PMID- 20973668 TI - Multielement stoichiometry in aquatic invertebrates: when growth dilution matters. AB - Element concentrations in organisms can be variable, often causing deviations from otherwise consistent, taxon-specific multielement stoichiometries. Such variation can have considerable ecological consequences, yet physiological mechanisms remain unclear. We tested the influence of somatic growth dilution (SGD) on multiple element concentrations under different bioenergetic conditions. SGD occurs when rapid individual growth causes a disproportional gain in biomass relative to gain of a specific element. SGD can strongly affect elements in various organisms, but we lack a general framework to unify results across studies and assess its overall importance. We derived the general conditions that trigger SGD from an element accumulation model. We parameterized the model with bioenergetic and element-specific rates summarized from the literature to compare SGD effects on 15 elements (nonessential metals, essential trace elements, macronutrients) in three aquatic invertebrate taxa. For all taxa, we found that SGD (1) occurs to some degree for all 15 elements over realistic ranges of growth and ingestion rates and (2) has the greatest effect on elements with low efflux (excretion) rates, including certain nonessential metals (e.g., MeHg, Po), essential trace elements, and macronutrients (e.g., N, Fe). Thus, SGD can strongly affect concentrations of a spectrum of elements under natural conditions. These results provide a framework for predicting variation in the elemental composition of animals. PMID- 20973669 TI - Phenotypic plasticity in adult life-history strategies compensates for a poor start in life in Trinidadian guppies (Poecilia reticulata). AB - Low food availability during early growth and development can have long-term negative consequences for reproductive success. Phenotypic plasticity in adult life-history decisions may help to mitigate these potential costs, yet adult life history responses to juvenile food conditions remain largely unexplored. I used a food-manipulation experiment with female Trinidadian guppies (Poecilia reticulata) to examine age-related changes in adult life-history responses to early food conditions, whether these responses varied across different adult food conditions, and how these responses affected overall reproductive success. Guppy females reared on low food as juveniles matured at a later age, at a smaller size, and with less energy reserves than females reared on high food as juveniles. In response to this setback, they changed their investment in growth, reproduction, and fat storage throughout the adult stage such that they were able to catch up in body size, increase their reproductive output, and restore their energy reserves to levels comparable to those of females reared on high food as juveniles. The net effect was that adult female guppies did not merely mitigate but surprisingly were able to fully compensate for the potential long-term negative effects of poor juvenile food conditions on reproductive success. PMID- 20973670 TI - Travel optimization by foraging bumblebees through readjustments of traplines after discovery of new feeding locations. AB - Animals collecting resources that replenish over time often visit patches in predictable sequences called traplines. Despite the widespread nature of this strategy, we still know little about how spatial memory develops and guides individuals toward suitable routes. Here, we investigate whether flower visitation sequences by bumblebees Bombus terrestris simply reflect the order in which flowers were discovered or whether they result from more complex navigational strategies enabling bees to optimize their foraging routes. We analyzed bee flight movements in an array of four artificial flowers maximizing interfloral distances. Starting from a single patch, we sequentially added three new patches so that if bees visited them in the order in which they originally encountered flowers, they would follow a long (suboptimal) route. Bees' tendency to visit patches in their discovery order decreased with experience. Instead, they optimized their flight distances by rearranging flower visitation sequences. This resulted in the development of a primary route (trapline) and two or three less frequently used secondary routes. Bees consistently used these routes after overnight breaks while occasionally exploring novel possibilities. We discuss how maintaining some level of route flexibility could allow traplining animals to cope with dynamic routing problems, analogous to the well-known traveling salesman problem. PMID- 20973673 TI - Contraception: Adherence? Compliance? Successful use? And how do we know? PMID- 20973674 TI - Perceived intrinsic barriers to physical activity among rural mothers. AB - BACKGROUND: The purpose of this study was to identify and determine the influence of perceived intrinsic barriers to physical activity among mothers living in rural areas. METHODS: Mothers were identified through a study of child-parent dyads in the predominantly rural states of New Hampshire and Vermont. Using a telephone interview, we asked mothers (n = 1691) about their level of physical activity and assessed eight potential barriers to physical activity. Data were analyzed using chi-square tests, t tests, and analysis of variance (ANOVA) comparisons for groups within each variable. We used multiple regression analysis to assess associations between perceived barriers to physical activity and self reported levels of physical activity. RESULTS: Each barrier was inversely associated with physical activity. Multivariate models that included terms for all potential barriers and covariates identified three barriers associated with lower levels of physical activity: lack of self-discipline, lack of time, and lack of interest. CONCLUSIONS: Rural mothers are less likely to be physically active if they identify lack of self-discipline, time, or interest as barriers, suggesting that they have difficulty prioritizing exercise for themselves. Interventions aimed at increasing physical activity for mothers should specifically consider these barriers. One possible solution may be to support infrastructure that facilitates active living as the default option, to remove the issue of having to purposefully engage in physical activity as a separate aspect of a mother's life. PMID- 20973675 TI - Mediterranean diet and weight loss: meta-analysis of randomized controlled trials. AB - BACKGROUND: The epidemiological evidence supporting a causal link between Mediterranean diets and body weight is contrasting. We evaluated the effect of Mediterranean diets on body weight in randomized controlled trials (RCTs) using a meta-analysis. METHODS: We searched English and non-English publications in PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials from inception to January, 2010. Two evaluators independently selected and reviewed eligible studies. Sixteen randomized controlled trials, with 19 arms and 3,436 participants (1,848 assigned to a Mediterranean diet and 1,588 assigned to a control diet) were included. RESULTS: In a random-effects meta-analysis of all 19 arms, the Mediterranean diet group had a significant effect on weight [mean difference between Mediterranean diet and control diet, -1.75 kg; 95% confidence interval (CI), -2.86 to -0.64 kg] and body mass index (mean difference, -0.57 kg/m2, -0.93 to -0.21 kg/m2). The effect of Mediterranean diet on body weight was greater in association with energy restriction (mean difference, -3.88 kg, -6.54 to -1.21 kg), increased physical activity (-4.01 kg, -5.79 to -2.23 kg), and follow up longer than 6 months (-2.69 kg, -3.99 to -1.38 kg). No study reported significant weight gain with a Mediterranean diet. CONCLUSIONS: Mediterranean diet may be a useful tool to reduce body weight, especially when the Mediterranean diet is energy-restricted, associated with physical activity, and more than 6 months in length. Mediterranean diet does not cause weight gain, which removes the objection to its relatively high fat content. These results may be useful for helping people to lose weight. PMID- 20973676 TI - College students' use of electronic communication with parents: links to loneliness, attachment, and relationship quality. AB - Despite the ubiquitous use of new communication technologies, gaps in our knowledge remain regarding who is likely to rely on particular technologies and potential ramifications of these forms of communication on individuals' relationships and adjustment. In an online survey, 211 college students reported on their use of electronic communication with a parent who they identified as their closest family member. Results indicated that students who report more frequent phone conversations with parents also report more satisfying, intimate, and supportive parental relationships, but those students who use a social networking site to communicate with parents report higher levels of loneliness, anxious attachment, as well as conflict within the parental relationship. The findings offer new evidence on how electronic communication technology with parents is related to adjustment in college students. Our study also suggests that further research is needed using longitudinal designs to understand better young adults' use of technology to communicate in today's society. PMID- 20973677 TI - Assessment of fatigue after blood transfusion in palliative care patients: a feasibility study. AB - BACKGROUND: Blood transfusions are often used as a potential treatment for cancer related fatigue in anaemic palliative care patients. However, evidence of benefit using validated outcomes measures is lacking. AIM: The aim of this study was to test the feasibility of using two such tools; the Brief Fatigue Inventory and FACT F-fatigue subscale, to measure change in fatigue following a blood transfusion. METHOD: Anemic cancer patients receiving specialist palliative care and undergoing transfusion for fatigue, completed the tools pre- and 3 days post transfusion. RESULTS: Thirty patients with cancer-related fatigue who received a blood transfusion completed the study. Both measures were capable of detecting statistical and clinically significant change in fatigue following transfusion. Furthermore, the measures showed significant differences between patients that did, or did not, report an overall improvement in fatigue. Patients found the measures easy to complete with no preference for one over another. Future clinical trials of blood transfusion for the management of fatigue should incorporate these validated outcome measures. PMID- 20973678 TI - Nuclear transfer-specific defects are not apparent during the second week of embryogenesis in cattle. AB - Somatic cell nuclear transfer (NT)-specific effects on postblastocyst early cattle embryogenesis were investigated by comparison to in vitro-produced (IVP) embryos grown under identical conditions to embryonic days (E) 14 and 15. Recipient effects were excluded by transferring mixed batches of NT and IVP embryos into each cow. Embryo recovery rates, proportions with an epiblast and embryo, as well as epiblast dimensions did not differ between NT and IVP embryos. A developmental expression profile was determined for nine trophoblast markers, two inner cell mass (ICM)/epiblast markers, and E-cadherin at nine time points between E7 and E26, providing a molecular gene signature assay for developmental progression. Gene expression levels for these genes (Cdx2, Elf5, Mash2, Ifn-tau, Furin, Kunitz1, Pag11, Gata3, Oct4 and Ifitm3) were equal in NT and IVP embryos of equivalent length. Furthermore, the average residual deviation of all 10 genes did not differ significantly suggesting an overall "normality" in gene expression of E14/15 NT embryos. The absence of NT-specific defects during the second, highly selective, week of cattle embryogenesis is interpreted as supportive for the view that NT-associated defects are predominantly of an epigenetic nature. PMID- 20973679 TI - Housekeeping gene transcript abundance in bovine fertilized and cloned embryos. AB - The objective of this study was to compare housekeeping gene expression levels, relative to total mRNA, across different stages of bovine preimplantation development in embryos generated by IVF and somatic cell nuclear transfer (SCNT). We first analyzed the levels of total RNA recovered from different stages of preimplantation development. A similar RNA level was observed from oocytes to 16 cell stage embryos with a significant increase at morula and blastocyst stages. Then we used an absolute mRNA determination method that accounts for the RNA level in the embryo by quantifying copies of transcripts normalized to loaded cDNA amount. The number of housekeeping genes mRNA copies per nanogram of cDNA was compared among samples obtained from different stages of preimplantation IVF derived embryos. None of the genes analyzed (GAPDH, PPIA, ACTB, RPL15, GUSB, and Histone H2A.2) maintained constant levels throughout preimplantation development, indicating that they are not suitable for normalizing gene expression across developmental stages. We then compared expression of housekeeping genes between IVF and SCNT embryos at different embryonic stages. We found different levels of transcript abundance between IVF and SCNT embryos for GAPDH, RPL15, GUSB, and ACTB. On the other hand, Histone H2A.2 and PPIA were similar between IVF and SCNT embryos at each stage analyzed, although they varied across stages as previously mentioned. PMID- 20973680 TI - Modulation of serum interleukin-18 concentrations and hepatitis B virus DNA levels during interferon therapy in patients with hepatitis B e-antigen-positive chronic hepatitis B. AB - The aim of this study was (1) to determine plasma values of interleukin-18 (IL 18) in patients with different clinical manifestations of hepatitis B (HB) and (2) to analyze the correlation between presence of circulatory levels of IL-18 and levels of HB virus (HBV) DNA during interferon-alpha (IFN-alpha)-induced HBe seroconversion in patients with chronic HB (CHB). The IL-18 levels in serum did not significantly differ between healthy control subjects (99 +/- 25 pg/mL), HB immune patients (85 +/- 33), and asymptomatic carriers of HB surface antigen (144 +/- 44 pg/mL). In contrast, anti-HBe (HBV DNA <104 copies/mL, 555 +/- 248, P < 0.05), anti-HBe (HBV DNA >104 copies/mL, 280 +/- 85, P < 0.05), and HBe-antigen reactive (373 +/- 108, P < 0.0001) patients with symptomatic CHB had significantly elevated levels in circulation compared with healthy control subjects (99 +/- 25 pg/mL). An inverse correlation was found between serum HBV DNA copies and IL-18 levels during therapy (r = -0.54, P < 0.001). We consistently observed an IFN-alpha-induced suppression of viral replication, which was followed by the alanine aminotransferase (ALT) flare. There was a significant increase in IL-18 production after the ALT flare, where the peak of IL-18 preceded or coincided with the time of HBe seroconversion in patients who cleared the virus. These results suggest that IL-18 is involved in the pathogenesis of CHB and that IFN-alpha therapy can augment the production of IL 18 in patients with CHB. PMID- 20973681 TI - Interleukin-6-174 and tumor necrosis factor alpha-308 polymorphisms enhance cytokine production by human macrophages exposed to respiratory viruses. AB - Interleukin-6-174 (IL-6-174) and tumor necrosis factor alpha-308 (TNFalpha-308) are high-cytokine-producing genotypes that are known to increase the susceptibility to infectious diseases, but their influence on cytokine production induced by respiratory viruses is unknown. We exposed human monocyte-derived macrophages from IL-6-174, TNFalpha-308, and normal genotype donors to different respiratory viruses. Respiratory syncytial virus (RSV) stimulation was associated with higher IL-6 concentrations in IL-6-174 donors than in normal donors (P = 0.015); 2 of 7 (29%) polymorphic donors were poor responders compared with 6 of 7 (86%) normal donors (P = 0.002). Adenovirus, influenza virus, and RSV stimulations were associated with higher TNFalpha concentrations in TNFalpha-308 donors than in normal donors (P = 0.03, <0.01, <0.01). A similar trend was seen with rhinovirus stimulation, but this was not significant. These results show that IL-6-174 and TNFalpha-308 gene polymorphisms lead to enhanced production of the respective cytokines when exposed to specific respiratory viruses. This, in turn, may influence the susceptibility to, severity of, and recovery from respiratory virus infections, or influence the immune response to and reactogenicity of viral vaccines. PMID- 20973682 TI - Patterns of antihypertensive treatment in patients with acute severe hypertension from a nonneurologic cause: Studying the Treatment of Acute Hypertension (STAT) registry. AB - STUDY OBJECTIVE: To assess antihypertensive treatment practices and outcomes for patients with acute severe hypertension requiring hospitalization. DESIGN: Subanalysis of a multicenter, observational, cross-sectional study. DATA SOURCE: The STAT registry (data from 25 hospitals). PATIENTS: A total of 1184 consecutive adults with acute severe hypertension (systolic blood pressure [SBP] >= 180 mm Hg, diastolic blood pressure >= 110 mm Hg), without a neurologic reason for admission, receiving two or more intermittent intravenous antihypertensive doses or a continuous intravenous infusion within 24 hours of hospitalization. MEASUREMENTS AND MAIN RESULTS: Patients started intravenous antihypertensive therapy 1.3 (median [interquartile range (IQR) 0.5-3.2]) hours after the qualifying SBP (median 204 [IQR 190-221] mm Hg). Labetalol (27%), metoprolol (21%), and nitroglycerin (20%) were the most frequent initial intravenous choices. For the 43% of patients administered two or more intravenous agents sequentially, the 24% receiving three or more, and the 8% receiving four or more, median SBPs at the time of the second, third, and fourth additions were 186 (IQR 168-211), 176 (IQR 152-196), and 164 (IQR 143-193) mm Hg, respectively. Most common continuous intravenous infusions were nitroglycerin (30%), nicardipine (13%), and labetalol (7%). After the first intravenous agent, an SBP decrease of 10-25% was achieved at 1 and 6 hours in 48% and 72%, respectively. Of the 6% without at least a 10% decrease in SBP during the entire hospitalization, labetalol (28%), hydralazine (21%), and metoprolol (17%) were the most frequent initial intravenous choices. Hypotension (SBP <= 90 mm Hg) occurred in 5% and was most common with intravenous nitroglycerin (39%). Oral antihypertensives were started within 1 and 6 hours after the first intravenous therapy in 13% and 34% of patients, respectively, with many patients (61%) receiving three or more oral agents during hospitalization. CONCLUSION: Pharmacologic treatment of acute severe hypertension in patients with nonneurologic causes is heterogeneous and often not consistent with Joint National Committee recommendations. Patients received numerous intravenous agents, experienced variable decreases in SBP, often failed to receive timely oral therapy, and a clinically relevant proportion developed hypotension. PMID- 20973683 TI - Pharmacogenetic impact of UDP-glucuronosyltransferase metabolic pathway and multidrug resistance-associated protein 2 transport pathway on mycophenolic acid in thoracic transplant recipients: an exploratory study. AB - STUDY OBJECTIVE: To assess the contribution of polymorphisms in the uridine diphosphate glucuronosyltransferase gene (UGT) and the multidrug resistance associated protein 2 gene (ABCC2) to mycophenolic acid (MPA) pharmacokinetics and clinical outcomes in thoracic transplant recipients. DESIGN: Open-label, cross sectional study. SETTING: Transplant clinic in Vancouver, British Columbia, Canada. PATIENTS: Sixty-eight thoracic (36 lung, 32 heart) transplant recipients who were receiving steady-state oral mycophenolate mofetil. MEASUREMENTS AND MAIN RESULTS: Eleven blood samples were obtained from each patient over a 12-hour dosing period. Plasma concentrations of MPA (active metabolite of mycophenolate mofetil), the MPA metabolites 7-Omycophenolic acid glucuronide (MPAG) and acyl glucuronide (AcMPAG), and free MPA were measured, and dose-normalized conventional pharmacokinetic parameters were determined by noncompartmental methods. Genetic polymorphisms in UGT and ABCC2 were determined by sequencing, and their contributions to pharmacokinetic variability were investigated by using multivariate analysis. For both the lung and heart transplant groups, the UGT2B7 variant 802T (Tyr(268) or UGT2B7*2, rs7439366) and the UGT2B7 variant -138A modified AcMPAG exposure (2.5-3.7-fold and 9.3-12.3-fold higher AcMPAG area under the concentration-time curve [AUC] and AcMPAG:MPA ratio, respectively). In an exploratory analysis, occurrences of rejection, infection, anemia, and leukopenia were associated with an AcMPAG AUC greater than 50 MUg.hour/ml and an AcMPAG:MPA ratio greater than 2. CONCLUSION: UGT2B7 is a promising gene candidate that may influence MPA pharmacokinetics clinically; however, larger clinical pharmacogenetic studies in thoracic transplant subpopulations are warranted to corroborate the role of AcMPAG and UGT2B7 variants in optimizing mycophenolate mofetil therapy. PMID- 20973684 TI - Suboptimal use of inhaled corticosteroids in children with persistent asthma: inadequate prescription, poor drug adherence, or both? AB - STUDY OBJECTIVE: To assess the use of inhaled corticosteroids in children with persistent asthma, including patients' adherence to these drugs and physicians' prescribing patterns, by using a novel drug adherence measure, the Proportion of Prescribed Days Covered (PPDC). DESIGN: Retrospective analysis. DATA SOURCE: Two administrative claims databases in Quebec, Canada. PATIENTS: Two thousand three hundred fifty-five children aged 5-15 years with persistent asthma who used more than 3 doses/week on average of a short-acting beta-agonist during a 12-month period before beginning treatment with inhaled corticosteroids between 1997 and 2005. MEASUREMENTS AND MAIN RESULTS: The PPDC measure was defined as the total days' supply dispensed divided by the total days' supply prescribed. During the 12-month follow-up period, 20% of the children received only one prescription for inhaled corticosteroids with no prescribed renewals. The mean number of prescriptions (including prescribed renewals) was 5.0, corresponding to only 152 days' supply prescribed. Mean PPDC (drug adherence) was 62.4%. Only 25% of the patients had controlled asthma, based on the use of 3 or fewer doses/week of short-acting beta(2)-agonists and absence of moderate-to-severe exacerbations. CONCLUSION: A large percentage of children with persistent asthma were prescribed intermittent rather than daily inhaled corticosteroids, and patient adherence to these drugs was suboptimal even though children had free access to their drugs. Many of these patients continued to experience poor asthma control. The PPDC adherence measure developed for this study allowed a better understanding of the gap between treatment goals and asthma control. PMID- 20973685 TI - Bivalirudin versus unfractionated heparin for prevention of hemofilter occlusion during continuous renal replacement therapy. AB - STUDY OBJECTIVE: To evaluate the safety and efficacy of bivalirudin compared with heparin for preventing hemofilter occlusion during continuous venovenous hemofiltration (CVVH). DESIGN: Prospective, randomized, double-blind study. SETTING: University-affiliated hospital. PATIENTS: Ten critically ill adults (median age 58 yrs, 70% male) with acute renal failure who, without anticoagulation, experienced hemofilter survival time of 24 hours or less during CVVH. INTERVENTION: Patients were randomized to receive bivalirudin 2 mg/hour (five patients) or heparin 400 units/hour (five patients) administered prefilter into the extracorporeal circuit. MEASUREMENTS AND MAIN RESULTS: Patients had a median Acute Physiology and Chronic Health Evaluation (APACHE) II score of 24, Sequential Organ Failure Assessment (SOFA) score of 11, and reduced antithrombin activity (75.5 units/dl). Baseline characteristics were not significantly different between groups. Study drug was administered in 40 hemofilters (18 from bivalirudin-treated patients, 22 from heparin-treated patients). The primary efficacy outcome was hemofilter survival time, defined as the interval of time between commencement of CVVH with a new extracorporeal circuit (hemofilter) and hemofilter failure. Compared with no anticoagulation, the addition of bivalirudin or heparin significantly improved hemofilter survival time (mean +/- SD 10 +/- 5 hrs with no anticoagulation vs 22 +/- 18 hrs with anticoagulation, p=0.0005). Hemofilter survival time was significantly increased in patients receiving bivalirudin versus those receiving heparin (29.6 +/- 20.7 vs 16.5 +/- 13.6 hrs, p=0.045). Independent predictors of hemofilter survival were use of bivalirudin therapy and increased antithrombin III activity. No patients randomized to bivalirudin experienced any bleeding or thrombosis events; one patient who received heparin developed alveolar hemorrhage, and one developed a lower extremity deep vein thrombosis. CONCLUSION: Compared with heparin, bivalirudin was more efficacious in prolonging hemofilter survival time and was well tolerated. Additional studies of bivalirudin for prevention of hemofilter occlusion during continuous renal replacement therapy are warranted. PMID- 20973686 TI - Reduced health care expenditures after enrollment in a collaborative cardiac care service. AB - STUDY OBJECTIVE: To assess the impact of a collaborative cardiovascular risk reduction service (Collaborative Cardiac Care Service [CCCS]) on total health care expenditures after an incident acute coronary event. DESIGN: Matched, retrospective cohort study. DATA SOURCE: Kaiser Permanente Colorado (KPCO) databases. PATIENTS: Patients who had an incident coronary event between January 1999 and June 2004 and were either enrolled (CCCS group) or never enrolled in the CCCS (No CCCS group). Patients in the CCCS group (628 patients) were matched in a 1:1 ratio to patients in the No CCCS group (628 patients) by Chronic Disease Score (CDS) and total health care expenditures in the 180 days before the index coronary event (baseline). MEASUREMENTS AND MAIN RESULTS: Drug purchases and medical utilization encounters were extracted from the KPCO administrative and claims databases after the incident coronary event until death, KPCO plan termination, 3 years later, or December 31, 2005, whichever came first (follow up). Expenditure estimates from the plan's decision support system (in 2007 U.S. dollars) were applied to each utilization encounter. A $1/follow-up day cost was applied to all patients in the CCCS group. Expenditures/follow-up day were modeled with adjustment for matching variables, patient characteristics, baseline expenditures, and intracorrelations of matched patients. Patients in the No CCCS group were slightly older and were more likely to be female and have had a myocardial infarction as their incident event compared with those in the CCCS group. During follow-up, there were 12 and 98 cardiac-related deaths and 16 and 188 all-cause deaths for the CCCS and No CCCS groups, respectively; mean and median total health care expenditures/day were $39 and $20, respectively, for the CCCS group, and $108 and $45, respectively, for the No CCCS group (all p<0.001). After adjustment, total health care expenditures for patients in the CCCS group were approximately $60/day ($21,900/yr) lower than those for patients in the No CCCS group (p<0.001; adjusted R(2)=0.29 with log-transformed expenditures). CONCLUSION: The comprehensive and aggressive implementation of secondary cardiac prevention strategies and close monitoring and follow-up of patients with coronary artery disease provided by the CCCS were associated with reduced health care expenditures. PMID- 20973687 TI - Vancomycin-resistant enterococcal urinary tract infections. AB - Enterococci are a common cause of urinary tract infections (UTIs) among hospitalized patients. The rising prevalence of vancomycin-resistant enterococci (VRE) is of particular concern within many institutions because of its association with increased mortality and health care costs, as well as limited treatment options. Clinicians need to differentiate between VRE-associated urinary colonization, asymptomatic bacteriuria, and UTIs in order to determine the need for treatment, optimal therapeutic options, and length of therapy. Unnecessary use of antibiotics in patients simply colonized and not infected with VRE in the urine has become a large problem in both hospitals and long-term care facilities. A PubMed-MEDLINE search was conducted to identify all English language literature published between January 1975 and March 2010 in order to summarize diagnostic criteria and treatment options for VRE UTIs. Several antimicrobials are discussed, with the specific focus on those with the potential to treat VRE UTIs and susceptibility patterns of VRE from urinary sources: ampicillin, amoxicillin, daptomycin, doxycycline, fosfomycin, imipenem cilastatin, linezolid, nitrofurantoin, penicillin, piperacillin, quinupristin dalfopristin, tetracycline, and tigecycline. Recommendations for empiric treatment of enterococcal UTIs and definitive treatment of VRE UTIs, including an evidence-based treatment algorithm, are proposed. Ampicillin generally is considered the drug of choice for ampicillin-susceptible enterococcal UTIs, including VRE. Nitrofurantoin, fosfomycin, and doxycycline have intrinsic activity against enterococci, including VRE, and are possible oral options for VRE cystitis. Linezolid and daptomycin should be reserved for confirmed or suspected upper and/or bacteremic VRE UTIs among ampicillin-resistant strains. Use of other antimicrobials, such as quinupristin-dalfopristin and tigecycline, should be evaluated on a case-by-case basis due to concerns of toxicity, resistance, and insufficient supportive data. Additional clinical data are needed to determine the optimal management and duration of therapy for VRE UTIs. PMID- 20973688 TI - Trisodium citrate: an alternative to unfractionated heparin for hemodialysis catheter dwells. AB - The use of tunneled hemodialysis catheters, or permcaths, either for temporary dialysis access before arteriovenous fistula or arteriovenous graft maturation or for long-term dialysis access, is associated with increased risk of catheter clotting and infection. Catheter locking solutions are routinely used to maintain patency in these catheters between dialysis sessions. Unfractionated heparin has traditionally been used for this purpose; however, trisodium citrate (also known as sodium citrate or citrate) has recently been shown to be an efficacious alternative to heparin as a locking solution. Citrate exerts both its anticoagulant and antimicrobial properties by chelating calcium to disrupt the normal coagulation pathway and by interfering with the formation of biofilm and the bacterial cell wall. Citrate is at least equivalent to heparin as an anticoagulant and antimicrobial agent for catheter locking, and in some clinical studies citrate was shown to be superior. Two different concentrations of sodium citrate were previously available; however, concerns of safety led to the removal of citrate 46.7% from the United States and Canadian markets in 2000, leaving only citrate 4% available for use as a catheter locking solution. The systemic hypocalcemic effects that were reported with citrate 46.7% have not been observed with citrate 4% in clinical trials, and the risk of systemic anticoagulation and bleeding was shown to be lower than that with unfractionated heparin. In addition, most comparative cost data indicate that citrate is a more cost effective alternative than heparin; however, costs can vary by institution. Despite inconclusive evidence of clinical superiority, citrate 4% appears to provide a safe and at least equivocal alternative to heparin as a catheter locking agent. PMID- 20973689 TI - Diabetes mellitus and increased risk of cancer: focus on metformin and the insulin analogs. AB - Type 2 diabetes mellitus has been associated with an increased risk of hepatic, pancreatic, colon, endometrial, breast, and bladder cancer. Although a mechanism of action for the increased risk has been postulated, no definitive evidence has been completely elucidated in the medical literature. Results of recently released studies documented the use of specific antidiabetic drugs with increased rates of cancer. The insulin analog glargine was the focus of four observational studies published in 2009 that outlined an increase in the rates of cancer associated with its use. In contrast, the use of metformin has been shown to possibly decrease the rate of specific cancers when used in the treatment of type 2 diabetes. These data regarding cancer risk and antidiabetic drugs are contradictory and at this time are inconclusive. Until results of long-term randomized prospective studies are available to elucidate a correlation with cancer and insulin, we must continue treating diabetes in order to avert the long term complications of the disease. PMID- 20973690 TI - Treatment options for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. AB - Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare neurodegenerative disease caused by the decreased ability of cells to produce sufficient energy in the form of adenosine 5' triphosphate. Although it is one of the most common maternally inherited mitochondrial disorders, its exact incidence is unknown. Caused most frequently by an A-to-G point mutation at the 3243 position in the mitochondrial DNA, MELAS syndrome has a broad range of clinical manifestations and a highly variable course. The classic neurologic characteristics include encephalopathy, seizures, and stroke-like episodes. In addition to its neurologic manifestations, MELAS syndrome exhibits multisystem effects including cardiac conduction defects, diabetes mellitus, short stature, myopathy, and gastrointestinal disturbances. Unfortunately, no consensus guidelines outlining standard drug regimens exist for this syndrome. Many of the accepted therapies used in treating MELAS syndrome have been identified through a small number of clinical trials or isolated case reports. Currently, the drugs most often used include antioxidants and various vitamins aimed at minimizing the demands on the mitochondria and supporting and maximizing their function. Some of the most frequently prescribed agents include coenzyme Q(10), l-arginine, B vitamins, and levocarnitine. Although articles describing MELAS syndrome are available, few specifically target education for clinical pharmacists. This article will provide pharmacists with a practical resource to enhance their understanding of MELAS syndrome in order to provide safe and effective pharmaceutical care. PMID- 20973693 TI - Comparison between the Framingham and prospective cardiovascular of Munster scores for risk assessment of coronary heart disease in human immunodeficiency virus-positive patients in Pernambuco, Brazil. AB - BACKGROUND: The Framingham score is used in most studies on human immunodeficiency virus (HIV)-positive patients to estimate the risk for coronary heart disease; however, it may have some limitations for detecting risk among these individuals. OBJECTIVE: The aim of this study was to evaluate the agreement between the Framingham and Prospective Cardiovascular of Munster (PROCAM) scores among HIV-positive individuals and to investigate the factors associated with disagreement between the two scores. METHOD: A cross-sectional study was conducted in a population of HIV/acquired immunodeficiency syndrome (AIDS) patients attending the outpatient's clinics of two reference centers for HIV/AIDS in Pernambuco, Brazil. Agreement between the Framingham and PROCAM scores was evaluated using the kappa index. From this analysis, a variable called "disagreement between scores" was created, and univariate and multivariate analysis were performed to investigate the factors associated with this variable. RESULTS: The prevalence of low, moderate, and high risk were, respectively, 78.7%, 13.5%, and 7.8% by Framingham score and 88.5%, 4.3%, and 7.2% by PROCAM (kappa = 0.64, P <= 0.0001). Agreement in the subgroup with metabolic syndrome by the International Diabetes Federation (IDF) (kappa = 0.51, P <= 0.0001) and the National Cholesterol Education Program (NCEP) (kappa = 0.59, P <= 0.0001) criteria was moderate. The Framingham score identified greater proportion of women with moderate risk. Factors independently associated with disagreement were: smoking, sex, age, low-density lipoprotein cholesterol, diastolic blood pressure, and metabolic syndrome. CONCLUSION: There was a good agreement between the Framingham and PROCAM scores in HIV-positive patients, but a higher proportion of moderate-high risk was identified by the Framingham score. This disagreement should be evaluated in cohort studies to observe clinical outcomes over the course of time. PMID- 20973694 TI - Growing-up with a substance-dependent parent: development of subjective risk and protective factors. AB - A qualitative phenomenological study of high-risk adolescents, who are children of substance-dependent parents, explored the presence of subjective risk and protective factors. Nineteen adolescents were interviewed, all of whom had a father or both parents either actively dependent on psychoactive substances or recovering from substance dependence. The participants were assigned to one of two groups, based on the degree to which they maintained normative lives or had misused substances themselves. It was found that certain perceptions of the participants, concerning themselves and their parents, served as either subjective risk or protective factors, respectively. Implications for the treatment of this population are outlined. PMID- 20973695 TI - beta-Cell neogenesis: experimental considerations in adult stem cell differentiation. AB - The contribution of stem cells derived from adult tissues to the recovery of pancreatic islets from chemical injury is controversial. Analysis of nonhematopoietic differentiation of bone marrow-derived cells has yielded positive and negative results under different experimental conditions. Using the smallest subset of bone marrow cells lacking immuno-hematopoietic lineage markers, we have detected incorporation and conversion into insulin-producing cells. Donor cells identified by genomic markers silence green fluorescent protein (GFP) expression as a feature of differentiation, in parallel to expressing PDX-1 and proinsulin. Here we elaborate potential experimental difficulties that might result in false-negative results. The use of GFP as a reporter protein is suboptimal for differentiation experiments: (a) the bone marrow of GFP donors partially expresses the reporter protein, (b) differentiating bone marrow cells silence GFP expression, and (c) the endocrine pancreas is constitutively negative for GFP. In addition, design of the experiments, data analysis, and interpretation encounter numerous objective and subjective difficulties. Rigorous evaluation under optimized experimental conditions confirms the capacity of adult bone marrow-derived stem cells to adopt endocrine developmental traits, and demonstrates that GFP downregulation and silencing is a feature of differentiation. PMID- 20973696 TI - Special education teachers' perceptions of benefits, barriers, and components of community-based vocational instruction. AB - This study investigated special education teachers' perceptions of the benefits, barriers, and components of community-based vocational instruction (CBVI). Participants included special education teachers (N 68) from randomly selected high schools in Illinois who had experience delivering vocational curriculum to students with disabilities. Data collection occurred via a survey. Special education teachers perceived CBVI to result in numerous benefits for students with disabilities. Limited resources, requirements of the No Child Left Behind Act, and student issues were identified as barriers to implementation. Incongruence existed between teachers' ratings of the importance and use of the components of CBVI. Years of teaching experience, types of students with disabilities served, size of school, and experience with CBVI affected teachers' perceptions of CBVI. PMID- 20973697 TI - Children and youth with fetal alcohol spectrum disorders: summary of intervention recommendations after clinical diagnosis. AB - Children with fetal alcohol spectrum disorders (FASDs) present with a wide range of developmental disabilities; however, clinical standards of care after a diagnosis are not well established. This retrospective review summarizes the types of intervention recommendations generated by an interdisciplinary FASD diagnostic team for 120 children ages 0.2 to 16.5 years receiving an FASD diagnosis at the University of Washington FAS Diagnostic & Prevention Network Clinic. Intervention recommendations documented in a FASD diagnostic summary report and submitted to each patient's medical record were subject to masked review and content analysis. Intervention recommendations were compared across 3 FASD diagnostic groups and selected demographic variables. The results show the type and frequency of services, supports, and resources recommended to a clinical sample of children with FASD. PMID- 20973698 TI - Status and trends in the direct support workforce in self-directed supports. AB - Self-directed programs that allow individuals with intellectual and developmental disabilities to exercise greater control over their finances have become increasingly common in recent years. At the same time, challenges in the recruitment, retention, and training of direct support workers in the field have grown more acute. In this article, the authors investigate the status of the direct support workforce for people using self-directed supports in 1 Midwestern state, based on the results of a statewide survey of service users. Although additional research is needed, the results of this study suggest that people who use self-directed funding options are satisfied with their ability to direct staffing, though challenges remain. Among these challenges, the presence of higher than expected wages but lower than expected benefits provision compared with traditional services may have serious policy and staff retention ramifications that affect the long-term viability of self-directed funding options. In addition, staff training remains a challenge, with service users in this sample reporting low rates of training beyond a general skill set. Implications of these findings are discussed. PMID- 20973700 TI - Public policy and outcomes for persons with intellectual disability: extending and expanding the public policy framework of AAIDD's 11th Edition of Intellectual Disability: Definition, Classification, and Systems of Support. PMID- 20973699 TI - Medicaid-covered alcohol and drug treatment use among people with intellectual disabilities: evidence of disparities. AB - For some, community inclusion facilitates access to alcohol and drugs and, therefore, the potential for developing substance abuse disorders. However, little is known about substance abuse treatment use among people with intellectual disabilities. Using standardized performance measures, substance abuse treatment utilization was examined for Medicaid-covered people with intellectual disabilities and substance abuse (N=9,484) versus people without intellectual disabilities (N=915,070). The sociobehavioral model of healthcare use guides multivariate logistic regression analyses of substance abuse treatment utilization patterns, revealing disability-related disparities. Factors associated with utilization included being non-White, living in a nonurban area, having a serious mental illness, and living in a state with a generous Medicaid plan for substance abuse treatment. Implications relate to health policy, service delivery patterns, and the need for cross-system collaboration in the use of integrated treatment approaches. PMID- 20973701 TI - Transitional assessment model for students with severe and/or multiple disabilities: competency-based community assessment. PMID- 20973702 TI - Children, disability, and chronic care. PMID- 20973703 TI - Children and youth with intellectual or developmental disabilities living in congregate care settings (1977-2009): Healthy People 2010 Objective 6.7b outcomes. PMID- 20973705 TI - The association between a common FCGR2A polymorphism and C-reactive protein and coronary artery disease revisited. AB - INTRODUCTION: the FcgammaRIIa receptor is responsible for the clearance of large immune complexes and recently has been proved to be a C-reactive protein (CRP) receptor as well. A polymorphism in the corresponding FCG2RA gene resulting in an amino acid change (R131H) has been implicated, with conflicting results in the pathogenesis of various autoimmune or inflammatory disorders (e.g., atherosclerosis and coronary artery disease [CAD]). METHODS: we recently developed a real-time polymerase chain reaction and melting curve analysis method for the genotyping of the above polymorphism. We further looked at its validity with bioinformatics study and DNA sequencing. Then we genotyped 134 CAD patients and 45 angiographically normal controls and determined serum high-sensitivity CRP by nephelometry (Dade-Behring). Also, we used apparently healthy platelet donors (n = 206) as a larger control group. RESULTS: our method is accurate and devoid of problems with homologs and copy number variants. The need for reference materials is stressed. There were statistically significant differences (p < 0.05) between the CAD patients and each of the two other control groups, with the percentage of RR genotype rising from 6.5% and 11% in the control groups to an average of 19% in all CAD patients (17%, 24%, and 18.5% in stable angina, unstable angina, and myocardial infarction, respectively). In a logistic regression model that included known risk factors for CAD including CRP, the RR genotype remained a significant predictor for CAD (odds ratio: 6.3 [1.1-36.3]). Also after linear regression analysis, CRP levels were reduced in the RR carriers (vs. HH + HR), controlling for age, sex, and disease (marginal p = 0.07). CONCLUSIONS: with our accurate genotyping method, the RR genotype was correlated with atherothrombotic CAD events. The inverse correlation found between CRP levels and genotype supports the in vitro data of RR cells binding CRP stronger than HH. PMID- 20973706 TI - Time course and predictors of health-related quality of life improvement and medication satisfaction in children diagnosed with attention deficit/hyperactivity disorder treated with the methylphenidate transdermal system. AB - OBJECTIVE: The aim of this study was to evaluate the time course and predictors of improvement in health-related quality of life (HRQL) and medication satisfaction in children diagnosed with attention-deficit/hyperactivity disorder (ADHD) and treated with the methylphenidate transdermal system (MTS). METHODS: Temporal relationships between ADHD symptoms, medication satisfaction, and HRQL measures were examined via latent growth curve, structural path, and growth mixture models. RESULTS: Higher levels of medication satisfaction at the end of titration predicted greater increases in family HRQL (p=0.004) and, to a lesser extent, child HRQL (p=0.068) throughout the study. At 4 of 6 (p<0.05) and 5 of 6 (p<0.10) contemporaneous time points, ADHD symptoms predicted child HRQL. At 2 of 6 (p<0.05) and 3 of 6 (p<0.10) contemporaneous time points, ADHD symptoms predicted family HRQL. ADHD did not predict child or family HRQL improvements at subsequent time points. A uniform pattern of change for child HRQL was noted, with most HRQL change following the pattern of symptom change during titration. Three distinct patterns of change were noted for family HRQL. CONCLUSIONS: In most cases, medication satisfaction, ADHD symptoms, and HRQL improved simultaneously, suggesting that HRQL was not a delayed response to improvement in symptoms. Children showed a uniform pattern of improvement in HRQL that followed symptom change; three distinct patterns of change were found for improvement in family HRQL. PMID- 20973707 TI - A 6-month, open-label, extension study of the tolerability and effectiveness of the methylphenidate transdermal system in adolescents diagnosed with attention deficit/hyperactivity disorder. AB - OBJECTIVE: The aim of this study was to evaluate the tolerability and effectiveness of the methylphenidate transdermal system (MTS) over 6 months in adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: This was an industry-sponsored, 30-center, open-label study of subjects aged 13-17 years with ADHD. Subjects were dose-optimized with MTS (10-30 mg/9 hours) over 5 weeks and then dose-maintained for up to 5 months. Tolerability evaluations included treatment-emergent adverse events (TEAEs) and dermal responses. Effectiveness was assessed with the ADHD-Rating Scale-IV (ADHD-RS-IV). RESULTS: A total of 162 subjects received MTS treatment. The majority of TEAEs (>99%) were mild or moderate in intensity, and the most frequently reported TEAE was decreased appetite (15.4%). Thirteen subjects discontinued the study due to TEAEs. The majority (93.6%) of dermatologic reactions indicated mild erythema. There was significant improvement in mean ADHD-RS-IV total scores from study entry to end point (p<0.001). CONCLUSION: Slightly more than half (54.0%) of subjects completed this 6-month, open-label extension study of MTS; the primary reason for discontinuation was withdrawn consent (36.0%). Reported TEAEs and skin tolerability findings were similar to those observed with MTS use in children and adolescents. MTS treatment resulted in a decrease in ADHD symptoms as rated by clinicians. PMID- 20973708 TI - A double-blind, randomized, placebo/active controlled crossover evaluation of the efficacy and safety of Ritalin (r) LA in children with attention deficit/hyperactivity disorder in a laboratory classroom setting. AB - OBJECTIVES: The primary objective of this study was to demonstrate efficacy of Ritalin((r)) LA 20 mg by showing superiority to placebo and noninferiority to Medikinet((r)) Retard in a laboratory classroom setting. Secondary objectives included safety/tolerability and further efficacy parameters. METHODS: A total of 147 children with attention-deficit/hyperactivity disorder (ADHD) diagnosed by the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) and aged 6 14 (81% males) and known to be methylphenidate (MPH) responders were enrolled in this multicenter, double-blind, randomized, placebo/active-controlled, three period (7 days each) crossover study. The Swanson, Kotlin, Agler, M-Flynn, and Pelham (SKAMP) scale was used for efficacy ratings. The mean of SKAMP Combined ratings performed at 10:30 a.m., at 12:00 a.m., and at 1:30 p.m. was defined as the primary parameter. RESULTS: In all, 146 patients completed all treatment periods. Intensity and frequency of adverse events were comparable between the two formulations. Ritalin((r)) LA demonstrated superiority compared to placebo (p<0.0001). The observed difference in the SKAMP scores between Ritalin((r)) LA and Medikinet((r)) Retard between the hours 1.5 until 4.5 did not exceed the noninferiority margin (p=0.0003); therefore, the difference is regarded as not clinically relevant. Similar results were obtained for the secondary efficacy variables. CONCLUSION: Ritalin((r)) LA is an efficacious, well-tolerated treatment option for children aged 6-14 with ADHD. PMID- 20973709 TI - Childhood stimulant treatment and teen depression: is there a relationship? AB - Recent preclinical data have raised the possibility that prepubertal treatment of attention-deficit/hyperactivity disorder (ADHD) with stimulant medication might increase risk for later depression. The current longitudinal study investigated whether children with ADHD who were treated with stimulant medication displayed heightened levels of adolescent depression. Adolescents diagnosed with ADHD during childhood who had received a minimum of 1 year of treatment with stimulant medication were compared to adolescents with a childhood history of ADHD who were never treated with stimulants and a demographically matched comparison group on self-reports of depressive symptoms and diagnoses of depressive disorders. Both subgroups with childhood ADHD reported significantly higher dimensional ratings of depression and categorical rates of depressive disorders relative to the comparison group (all p<0.05), yet those who were and were not medicated did not differ from one another. Results indicate that, while childhood ADHD increases risk for adolescent depression, stimulant treatment for ADHD neither heightens nor protects against such risk. PMID- 20973710 TI - A pharmacological functional magnetic resonance imaging study probing the interface of cognitive and emotional brain systems in pediatric bipolar disorder. AB - OBJECTIVE: This functional magnetic resonance imaging (fMRI) study investigated the effects of pharmacotherapy on brain function underlying affect dysregulation and cognitive function in pediatric bipolar disorder (PBD). METHOD: Healthy controls (HC) (n=14; mean age =14.1 +/- 2.4 years) and unmedicated PBD patients with manic or hypomanic episodes (n=17; mean age =14.3 +/- 1.1 years) were matched on intelligence quotient (IQ) and demographic factors. The fMRI studies were performed at baseline and after 14 weeks, during which PBD patients were treated initially with second-generation antipsychotics (SGAs) followed by lamotrigine monotherapy. The pediatric affective color-matching task was used where subjects matched the color of a positive, negative, or neutral word with one of the two colored circles below in each of the trials. There were five blocks of each emotional word type, with 10 trials per block. RESULTS: Behavioral data showed that the PBD group was modestly slower and less accurate than the HC, regardless of condition or treatment status. The blood oxygen level-dependent (BOLD) signal activity was reduced with treatment in the PBD group relative to the HC group during the negative versus neutral condition in bilateral dorsolateral prefrontal cortex (DLPFC), right posterior cingulate gyrus, parahippocampal gyrus, and inferior parietal lobule, but increased in left ventromedial prefrontal cortex (VMPFC). Similarly, during the positive versus neutral condition, the PBD group, relative to HC, showed reduced activity in right DLPFC, precuneus, and inferior parietal lobule and increased activity in the right VMPFC. However, within the PBD group, there was treatment related decrease in VMPFC and DLPFC. Improvement on Young Mania Rating Scale (YMRS) score significantly correlated with the decreased activity in VMPFC within the patient group. CONCLUSIONS: Pharmacotherapy in PBD patients led to differential effort with persistently increased activity in the affective regions and decreased activity in the cognitive regions relative to HC, demonstrating altered mechanisms of affective and cognitive systems of brain function, regardless of symptom response. PMID- 20973711 TI - Six months of treatment with risperidone may be associated with nonsignificant abnormalities of liver function tests in children and adolescents: a longitudinal, observational study from Turkey. AB - OBJECTIVE: Risperidone is a promising agent for the treatment of schizophrenia, Tourette's disorder, mood disorders, and disruptive behavior disorders in young populations. However, adverse effects of risperidone may take a long time to emerge. The objective of this study was to investigate the changes in the liver function tests (LFTs) associated with more than 6 months of risperidone treatment in children and adolescents. METHOD: A total of 102 youths treated with risperidone for more than 6 months were eligible for the study. For this study, patients' baseline and follow-up weight and hepatobiliary function tests, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), and serum bilirubin levels, were measured at baseline and at 6 months. RESULTS: Asymptomatic abnormalities of LFTs, mostly ALP elevation, were found in 38.2% of the cases, and marked elevation of liver enzymes was found in 0.8% of cases treated with risperidone. The mean levels of liver enzymes and bilirubin of the patients were significantly higher than the baseline after first and sixth months of treatment. However, there was no statistically significant change in the liver enzymes and bilirubin levels between the first and sixth months. There was no significant relationship between changes in weight and liver enzymes and bilirubin levels after 6 months of risperidone treatment. CONCLUSION: These findings suggest that risperidone treatment in the long term commonly leads to liver function changes, although at therapeutic doses in children and adolescents it may rarely induce a serious hepatic toxicity. Concomitant use of antidepressants and methylphenidate and variations in age and pubertal status are limitations of present study. Further studies are needed to assess the importance and role of other variables over LFT abnormalities in youth population. PMID- 20973712 TI - Line-item analysis of the Aberrant Behavior Checklist: results from two studies of aripiprazole in the treatment of irritability associated with autistic disorder. AB - OBJECTIVES: The aim of this study was to evaluate the efficacy of aripiprazole in the treatment of discrete symptoms of irritability associated with autistic disorder, as well as other symptoms captured on the Aberrant Behavior Checklist (ABC). METHODS: This was a post hoc analysis of data from two 8-week, randomized, double-blind, multicenter trials to evaluate the efficacy of aripiprazole dosed flexibly (2-15 mg/day, n=47) or fixed (5, 10, or 15 mg/day, n = 166) versus placebo (flexibly dosed, n = 51; fixed dose, n = 52). The effects of treatment on the 58 ABC items were evaluated. RESULTS: Statistically significantly greater improvement was seen with aripiprazole versus placebo (p < 0.05) for all arms in both trials on the ABC-Irritability total subscale score and on the following individual ABC-Irritability items: Mood changes quickly, cries/screams inappropriately, and stamps feet/bangs objects. Several additional items measuring tantrum-like behaviors improved in the flexibly dosed trial and at least one arm of the fixed-dose trial (p < 0.05). Measures of self-injurious behavior, which had low baseline values, demonstrated numerical, but not statistically significant, improvement in both trials. Statistically significantly greater improvement in ABC Stereotypic Behavior and Hyperactivity total subscale scores was also consistent across all arms in both trials. In particular, there was a cluster of items related to hyperkinesis that were consistently sensitive to treatment. CONCLUSIONS: Aripiprazole is efficacious in the treatment of irritability in children and adolescents with autistic disorder, particularly with respect to symptoms associated with tantrum behavior. PMID- 20973713 TI - Symptom improvement and residual symptoms during acute antidepressant treatment in pediatric major depressive disorder. AB - OBJECTIVE: Knowing the timing of specific depressive symptom improvement will enable clinicians to prepare their patients well and improve treatment outcome, whereas recognizing which depressive symptoms may show delayed improvement will help clinicians to provide additional interventions early in treatment. In a prospective open-label fluoxetine study, we investigated the timing of depressive symptom improvement during acute treatment, and identified common remaining symptoms following 4, 8, and 12 weeks of acute treatment in depressed youths. METHOD: A total of 168 children and adolescents, aged 7-18 years, with primary diagnoses of major depressive disorder (MDD) received 12 weeks of fluoxetine treatment. Youths were evaluated using the Kiddie Schedule for Affective Disorders and Schizophrenia. The outcome measure included the Children's Depression Rating Scale-Revised. RESULTS: All depressive symptoms improved, particularly during the first 4 weeks of acute treatment. Forty-seven percent of remitters reported at least one residual symptom following 12 weeks, with most common residual symptoms being impaired school performance, insomnia, and irritability. CONCLUSIONS: Residual symptoms are common, even among remitters, at the end of 12 weeks of acute treatment. There is a need for clinicians to monitor symptom improvement and potentially provide additional interventions for the more resistant symptoms, such as insomnia and school performance. PMID- 20973714 TI - A comparison of various methods of measuring antidepressant medication adherence among children and adolescents with major depressive disorder in a 12-week open trial of fluoxetine. AB - OBJECTIVE: In this study, we examined antidepressant (fluoxetine) medication adherence in children and adolescents with major depressive disorder (MDD). Using electronic monitoring (EM) as the "reference standard," we compared various methods of measuring antidepressant medication adherence (including EM, pill counts, and medication diaries) among children and adolescents with MDD and examined the relationship between EM medication adherence and depression severity across time. We then suggested recommendations for clinical researchers and practicing clinicians regarding medication adherence assessment. METHOD: Thirty one child and adolescent outpatients with MDD who enrolled in a 12-week open trial of fluoxetine had their antidepressant medication adherence assessed at each visit, using EM, pill counts, and parent and patient medication diaries. Depression severity was assessed by the Children's Depression Rating Scales Revised at each visit. RESULTS: Twelve-week least squares mean estimates of medication adherence for the entire sample was high, regardless of the adherence assessment method, although the overall adherence among the four methods (EM, pill, parent diary, patient diary) was significantly different (87.5% vs. 90.6% vs. 93.1% vs. 93.3%, respectively, p=0.0002). Adjusted mean symptom severity was significantly lower for the EM "adherent" group than for the EM "nonadherent" group over the 12 weeks of treatment (35.6 vs. 43.8, p=0.008). CONCLUSION: Overall, EM medication adherence for the depressed youth in this study is high. Compared with EM, there is a tendency of pill counts and medication diaries to overestimate medication adherence. However, pill count adherence better approximates EM adherence, and compliance with returning medication diaries is poor. Youth who are adherent to fluoxetine treatment have lower symptom severity over the course of treatment. Recommendations are provided. PMID- 20973715 TI - Rapid quetiapine loading in youths with bipolar disorder. AB - OBJECTIVE: The aim of this study was to evaluate the tolerability and efficacy of rapid quetiapine loading in youth diagnosed with pediatric bipolar disorder (PBD). METHOD: Quetiapine was started at 100 mg/day, and increased to 400 mg/day by day 5 in 75 bipolar children (6-16 years), presenting in an acute manic or hypomanic episode. Subsequent dose adjustments were predicated on the clinical picture. Response was defined as a >= 50% reduction in baseline scores on the Young Mania Rating Scale (YMRS). Clinical Global Impression-Improvement Scale (CGI-I) scores of "2 much improved" or "1 very much improved" were used as secondary measures of response. Remission was defined as a YMRS score of <= 12. Adverse events, blood pressure, weight change, somnolence, extrapyramidal syndrome (EPS), and akathisia were monitored to determine tolerability. RESULTS: At 8 weeks, 94% of the sample had a CGI-I score <= 2, and 70% were in remission at 6 months. Sedation was reported by 50% of subjects during the first week; this rate dropped to 5.6% at 6 months. CONCLUSION: The findings indicate that rapid dose administration of quetiapine in children and adolescents with PBD is generally well tolerated and efficacious. PMID- 20973717 TI - Bipolar disorder and valproate-induced hyperammonemic encephalopathy in an adolescent with diabetes. PMID- 20973718 TI - Thrombocytopenia secondary to the use of quetiapine. PMID- 20973719 TI - Risperidone: switching from brand name to generic. PMID- 20973720 TI - An interview with Hakim Djaballah, Ph.D. Interview by Vicki Glaser. AB - Dr. Hakim Djaballah is Director of the High-Throughput Screening (HTS) Core Facility at Memorial Sloan-Kettering Cancer Center (MSKCC), in New York City. He has several years of industrial experience in preclinical drug discovery, working in both pharmaceutical and biotechnology companies. He has been involved in developing and screening antibacterials, antivirals, and antifungals, as well as identifying targets in various therapeutic areas, including diabetes, central nervous system, cardiovascular system, oncology, and inflammation. He obtained his B.S. in biochemistry with biotechnology from the University of Birmingham and completed his Ph.D. in biochemistry at the University of Leicester, both in England. He was recruited to MSKCC in 2003 to set up and direct the HTS Core Facility, a drug discovery laboratory involved in both chemical and RNAi screening. Dr. Djaballah was the recipient of the 2007 Robots and Vision User Recognition Award. Sponsored by the Robotic Industries Association and the Automated Imaging Association, the award is presented every 2 years to individuals in institutions that have successfully implemented robots in their work. PMID- 20973722 TI - High-content assay to identify inhibitors of dengue virus infection. AB - Dengue virus (DENV) infections are vectored by mosquitoes and constitute one of the most prevalent infectious diseases in many parts of the world, affecting millions of people annually. Current treatments for DENV infections are nonspecific and largely ineffective. In this study, we describe the adaptation of a high-content cell-based assay for screening against DENV-infected cells to identify inhibitors and modulators of DENV infection. Using this high-content approach, we monitored the inhibition of test compounds on DENV protein production by means of immunofluorescence staining of DENV glycoprotein envelope, simultaneously evaluating cytotoxicity in HEK293 cells. The adapted 384-well microtiter-based assay was validated using a small panel of compounds previously reported as having inhibitory activity against DENV infections of cell cultures, including compounds with antiviral activity (ribavirin), inhibitors of cellular signaling pathways (U0126), and polysaccharides that are presumed to interfere with virus attachment (carrageenan). A screen was performed against a collection of 5,632 well-characterized bioactives, including U.S. Food and Drug Administration-approved drugs. Assay control statistics show an average Z' of 0.63, indicative of a robust assay in this cell-based format. Using a threshold of >80% DENV inhibition with <20% cellular cytotoxicity, 79 compounds were initially scored as positive hits. A follow-up screen confirmed 73 compounds with IC50 potencies ranging from 60 nM to 9 MUM and yielding a hit rate of 1.3%. Over half of the confirmed hits are known to target transporters, receptors, and protein kinases, providing potential opportunity for drug repurposing to treat DENV infections. In summary, this assay offers the opportunity to screen libraries of chemical compounds, in an effort to identify and develop novel drug candidates against DENV infections. PMID- 20973723 TI - Use of vaporized hydrogen peroxide decontamination during an outbreak of multidrug-resistant Acinetobacter baumannii infection at a long-term acute care hospital. AB - OBJECTIVES: To describe vaporized hydrogen peroxide (VHP) as an adjuvant in the control of multidrug-resistant (MDR) Acinetobacter baumannii infection in a long term acute care hospital (LTACH) and to describe the risk factors for acquisition of MDR A. baumannii infection in the LTACH population. DESIGN: Outbreak investigation, case-control study, and before-after intervention trial. SETTING: A 54-bed LTACH affiliated with a tertiary care center in northeastern Ohio. METHODS: Investigation of outbreak with clinical and environmental cultures, antimicrobial susceptibility testing, polymerase chain reaction assay of repetitive chromosomal elements to type strains, and case-control study; and intervention consisting of comprehensive infection control measures and VHP environmental decontamination. RESULTS: Thirteen patients infected or colonized with MDR A. baumannii were identified from January 2008 through June 2008. By susceptibility testing, 10 (77%) of the 13 isolates were carbapenem-resistant. MDR A. baumannii was found in wound samples, blood, sputum, and urine. Wounds were identified as a risk factor for MDR A. baumannii colonization. Ventilator associated pneumonia was the most common clinical syndrome caused by the pathogen, and the associated mortality was 14% (2 of the 13 case patients died). MDR A. baumannii was found in 8 of 93 environmental samples, including patient rooms and a wound care cart; environmental and clinical cultures were genetically related. Environmental cultures were negative immediately after VHP decontamination and both 24 hours and 1 week after VHP decontamination. Nosocomial acquisition of the pathogen in the LTACH ceased after VHP intervention. When patients colonized with MDR A. baumannii reoccupied rooms, environmental contamination recurred. CONCLUSION: Environmental decontamination using VHP combined with comprehensive infection control measures interrupted nosocomial transmission of MDR A. baumannii in an LTACH. The application of this novel approach to halt the transmission of MDR A. baumannii warrants further investigation. PMID- 20973724 TI - Method for automated monitoring of hand hygiene adherence without radio-frequency identification. AB - Many efforts to automatically measure hand hygiene activity depend on radio frequency identification equipment or similar technology that can be expensive to install. We have developed a method for automatically tracking the use of hand hygiene dispensers before healthcare workers enter (or after they exit) patient rooms that is easily and quickly deployed without permanent hardware. PMID- 20973725 TI - Bloodstream infections caused by metallo-beta-lactamase/Klebsiella pneumoniae carbapenemase-producing K. pneumoniae among intensive care unit patients in Greece: risk factors for infection and impact of type of resistance on outcomes. AB - OBJECTIVE: To determine risk factors for bloodstream infections (BSIs) caused by Klebsiella pneumoniae producing metallo-beta-lactamases (MBLs) or K. pneumoniae carbapenemases (KPCs), as well as risk factors for mortality associated with carbapenem-resistant K. pneumoniae, among intensive care unit (ICU) patients. METHODS: Two case-control studies were conducted in a patient cohort with K. pneumoniae BSIs in an 8-bed ICU in a Greek hospital from January 1, 2007, through December 31, 2008. In study 1, patients with K. pneumoniae BSIs were allocated among 3 groups according to isolate susceptibility profile: (1) carbapenem susceptible insolates (control group), (2) MBL-producing isolates, or (3) KPC producing isolates. The MBL and KPC groups were compared with the control group to identify risk factors for development of K. pneumoniae BSI. In study 2, patients with K. pneumoniae BSIs who died were compared with survivors to identify risk factors for mortality. RESULTS: Fifty-nine patients had K. pneumoniae BSIs (22 with carbapenem-susceptible isolates, 18 with MBL-producing isolates, and 19 with KPC-producing isolates). All KPC-producing isolates carried the bla(KPC-2) gene, and 17 of 18 MBL-producing isolates carried bla(VIM-1). Acute Physiology and Chronic Health Evaluation II score (odds ratio, 1.13 [95% confidence interval, 1.03-1.25]; [Formula: see text]) was independently associated with KPC-producing K. pneumoniae BSIs. Nine (41%) of 22 control patients, 8 (44%) of 18 MBL group patients, and 13 (68%) of 19 KPC group patients died in the ICU. Nine (41%) of 22 control patients, 10 (56%) of 18 MBL group patients, and 15 (79%) of 19 KPC group patients died in the hospital. Isolation of KPC-producing K. pneumoniae was an independent predictor of ICU death ([Formula: see text]) and in-hospital death ([Formula: see text]) but not infection-attributable death. CONCLUSIONS: BSIs due to KPC-producing K. pneumoniae resulted in significantly increased mortality. The accurate and rapid detection of these pathogens is necessary for therapeutic considerations and for the implementation of infection control measures to contain them. PMID- 20973726 TI - How soon is now? The urgent need for randomized, controlled trials evaluating treatment of multidrug-resistant bacterial infection. PMID- 20973727 TI - Aerosolized plus intravenous colistin versus intravenous colistin alone for the treatment of ventilator-associated pneumonia: a matched case-control study. AB - OBJECTIVES: The incidence of ventilator-associated pneumonia (VAP) due to multidrug-resistant (MDR) organisms is increasing. Intravenous (IV) colistin or aerosolized (AS) plus IV colistin have been recently used to treat these life threatening infections. The purpose of this study was to compare the efficacy and safety of AS plus IV colistin versus IV colistin alone for patients with MDR VAP due to gram-negative bacteria. METHODS: A retrospective matched case-control study was performed at the Intensive Care Unit of the University Hospital of Heraklion, Greece, from January 2005 through December 2008. Forty-three patients with VAP due gram-negative MDR pathogens received AS plus IV colistin and were matched on the basis of age and Acute Physiology and Chronic Health Evaluation II score with 43 control patients who had received IV colistin alone. RESULTS: Demographic characteristics, clinical status, and gram-negative isolated pathogens were similar between the 2 treatment groups. Acinetobacter baumannii (66 cases [77%]) was the most common pathogen, followed by Klebsiella pneumoniae (12 cases [14%]) and Pseudomonas aeruginosa (8 cases [9.3%]). No colistin resistant strains were isolated from patients in either group. No significant differences between the 2 groups were observed regarding eradication of pathogens (P = .679), clinical cure (P = .10), and mortality (P = .289). Eight patients (19%) in each treatment group developed reversible renal dysfunction. No AS colistin-related adverse events were recorded. CONCLUSIONS: Addition of AS colistin to IV colistin did not provide additional therapeutic benefit to patients with MDR VAP due to gram-negative bacteria. PMID- 20973728 TI - Epidermal cells delivered for cutaneous wound healing. AB - Re-epithelialization is the first and most important step in cutaneous wound healing. The vital role of epidermal cells, or keratinocytes, in accelerating wound healing has long been established. The technique of delivering the cultured and uncultured epidermal cells to the wound bed takes a variety of forms including cultured epithelial autografts (CEAs), tissue-engineered skin equivalent, epidermal suspension and microbead-loaded composite. These techniques, together with the keratinocyte culturing method and scaling up equipment, are still the ongoing research. Application of these techniques also bears direct impact on the outcome of the wounded patients. Best understanding of the delivery technique and its relationship with the culturing method and delivery vehicle could benefit not only the wounded patient but also the development of tissue-engineered skin equivalent. PMID- 20973729 TI - Highlights from the November 2010 issue of DNA and Cell Biology. PMID- 20973730 TI - The effect of search condition and advertising type on visual attention to Internet advertising. AB - This research was conducted to examine the level of consumers' visual attention to Internet advertising. It was predicted that consumers' search type would influence visual attention to advertising. Specifically, it was predicted that more attention to advertising would be attracted in the exploratory search condition than in the goal-directed search condition. It was also predicted that there would be a difference in visual attention depending on the advertisement type (advertising type: text vs. pictorial advertising). An eye tracker was used for measurement. Results revealed that search condition and advertising type influenced advertising effectiveness. PMID- 20973731 TI - Commensal Escherichia coli isolate resistant to eight classes of antimicrobial agents in the United States. AB - To increase understanding of community-acquired resistance, stool samples from 477 nonhospitalized persons in Maryland and Michigan, from 2004 to 2008, were screened for ceftriaxone resistance. Seven (1.5%) yielded ceftriaxone-resistant Escherichia coli; one isolate was resistant to all eight antimicrobial classes routinely tested: aminoglycosides, beta-lactam/beta-lactamase inhibitor combinations, cephems, penicillins, folate pathway inhibitors, phenicols, quinolones, and tetracyclines. The extensively resistant isolate was from a 50 year-old woman who denied antimicrobial use, hospitalization, or international travel within 6 months. Meat (beef, chicken, and pork) and eggs were consumed within 1 month before stool collection. Further studies are warranted to understand potential sources, including the food supply, of resistant E. coli. PMID- 20973732 TI - Occurrence and distribution of various genetic structures of class 1 and class 2 integrons in Salmonella enterica isolates from foodborne disease patients in Korea for 16 years. AB - We have investigated the distribution of integrons among 752 multidrug-resistant Salmonella isolates from human febrile and/or diarrheal patients during 1992-2007 and analyzed their genetic characteristics. Here, we report extensive integron analysis results within human isolates during the last 16 years. The gene or gene cassette(s) in the class 1 integrons found in the isolates were dfrA7, dfrA12 orfF-aadA2, aadA2, bla(PSE1), dfrA1-aadA1, dfrA17-aadA5, bla(OXA1)-aadA1, aadB aadA1, aadA22, aadA1, and aac6'Ib-bla(OXA1)-aadA2. Class 2 integrons harboring dfrA1-sat2-aadA1 gene cassette were also found in four isolates. Twenty-nine isolates including one Salmonella Schleissheim isolate had two integrons harboring aadA2 and bla(PSE1) in their variable regions of 1.0 and 1.2 kb amplicons, respectively, which have been also found in Salmonella genomic island 1 (SGI1) of multidrug-resistant Salmonella Typhimurium DT104. The presence of SGI1 in Salmonella Schleissheim isolate was proved by SGI1-specific polymerase chain reaction. We first report a Salmonella Schleissheim having SGI1, Salmonella Typhimurium and Salmonella Heidelberg having the class 2 integron with dfrA1-sat2 aadA1 cassettes, Salmonella London with the aac6'Ib-bla(OXA1)-aadA2 gene cassette, Salmonella Chailey with the gene cassette of aadA22, and coexistence of two class 1 integrons carrying aadA22 and dfrA12-orfF-aadA2 in Salmonella Typhimurium. PMID- 20973733 TI - Extremely high-frequency therapy in oncology. AB - OBJECTIVE: This article represents a review of the literature, mainly from Russian sources, dealing with the therapeutic application of low-intensity electromagnetic radiation in the millimeter band applied to experimental and clinical oncology. METHOD: At the early stage of these studies, efficacy and safety of millimeter electromagnetic radiation (extremely high frequency [EHF]) was proved for various types of malignant tumors. The majority of the further studies demonstrated the high efficacy and safety of millimeter wave radiation in treating patients suffering from both benign and malignant tumors. RESULTS: Developments led to treatment on skin melanoma, cancer of the ear-nose-throat, bowel and breast cancer, cancer of the uterus, lung, and stomach, solid tumors, as well as lymphoma. The main indications for this therapy are (1) preparation prior to radical treatment; (2) prevention and treatment of side-effects and complications from chemotherapy and radiotherapy; (3) prevention of metastases, relapses, and dissemination of the tumor; (4) treatment of the paraneoplastic syndrome; and (5) palliative therapy of incurable patients. CONCLUSIONS: In spite of the fact that not all mechanisms underlying effects of EHF therapy are known as yet, this therapeutic modality has been shown to have great potential in clinical oncology from studies performed in Eastern Europe and Russia. PMID- 20973734 TI - Reasons, perceived efficacy, and factors associated with complementary and alternative medicine use among Malaysian patients with HIV/AIDS. AB - OBJECTIVES: The primary objective of this study was to evaluate the pattern of use, reasons for use, and perceived effect of complementary and alternative medicine (CAM), accompanied by identification and comparison of the factors that are potentially associated with CAM use. DESIGN: This cross-sectional study was carried out in 325 randomly sampled patients with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), at HIV/AIDS referral clinics in the Hospital Sungai Buloh, Malaysia. Simple random sampling was used, where randomization was done using patients' medical record numbers. SUBJECTS AND METHODS: Semistructured face-to-face interviews were conducted using 38 questions pertaining to type, pattern, perceived efficacy, adverse effects, and influential factors associated with CAM use. In addition, CD4 count and viral load readings were recorded. RESULTS: Of 325 randomly sampled patients with HIV/AIDS, 254 of them were using some forms of CAM, resulting in a utilization rate of 78.2%. Vitamins and supplements (52.6%), herbal products (33.8%), and massage (16.6%) were the top three most frequently used CAM modalities. Sociodemographic factors including education level (p = 0.021, r(s) = 0.148), monthly income (p = 0.001, r(s) = 0.260), and family history of CAM use (p = 0.001, r(s) = 0.231) were significantly associated and positively correlated with CAM use. However, the majority of these patients (68%) did not disclose CAM use to health care professionals. About half of those who rated their health as good or very good perceived it as a result of CAM use. CONCLUSIONS: This study confirmed the range of 30%-100% CAM use among individuals infected with HIV/AIDS. Although, on the one hand some types of CAM reduced viral load and enhanced the immune system, on the other hand some forms of CAM produced a detrimental effect on the virological suppression, opening this platform to more research and investigation in order to optimize the use of CAM among patients with HIV/AIDS. PMID- 20973735 TI - Effect of t'ai chi exercise on biochemical profiles and oxidative stress indicators in obese patients with type 2 diabetes. AB - OBJECTIVE: This study aimed to validate the effects of a simplified, gentle form of t'ai chi chuan in patients with type 2 diabetes and who are also obese. DESIGN: The study was designed to be a randomized controlled trial. SETTING: This study was conducted in the department of metabolism and endocrinology at Cheng Ching Hospital, in Taichung, Taiwan. SUBJECTS: The study subjects were hospital based patients with type 2 diabetes and who were also obese (ages 40-70, with a body-mass index [BMI] range of 30-35). The patients were randomly selected and grouped into t'ai chi exercise (TCE) and conventional exercise (CE) groups. INTERVENTIONS: After receiving instruction in t'ai chi, the TCE group and the CE group practiced three times per week, including one practice session lasting up to 1 hour, for 12 weeks. OUTCOME MEASURES: Hemoglobin A1C, serum lipid profile, serum malondialdehyde, and C-reactive protein were measured. Physical parameters of body weight and BMI were also measured. Diet and medications of participants were monitored carefully while biochemical and physical conditions were analyzed. RESULTS: After 12 weeks, hemoglobin A1C values of the TCE group did not decrease (8.9 +/- 2.7% : 8.3 +/- 2.2%; p = 0.064). BMI (33.5 +/- 4.8 : 31.3 +/- 4.2; p = 0.038) and serum lipids, including triglyceride (214 +/- 47 mg/dL : 171 +/- 34 mg/dL; p = 0.012) and high density lipoprotein cholesterol (38 +/- 16 mg/dL : 45 +/- 18 mg/dL; p = 0.023) had significant improvements. Serum malondialdehyde tended to decrease from baseline (2.66 +/- 0.78 MUmol/L : 2.31 +/- 0.55 MUmol/L; p = 0.035), and C-reactive protein also decreased (0.39 +/- 0.19 mg/dL : 0.22 +/- 0.15 mg/dL; p = 0.014). No improvements occurred in BMI, lipids, and oxidative stress profiles in the CE group. CONCLUSIONS: T'ai chi exercise practiced by patients who are obese and have type 2 diabetes is efficient and safe when supervised by professionals and helps improve parameters, such as BMI, lipid profile, C-reactive protein, and malondialdehyde. Periodic monitoring of blood glucose, blood pressure, heart rate, breathing, physical fitness, and symptoms of discomfort of patients who exercise helps prevent injury. Simple, gentle TCE can be applied as regular daily exercise for patients with type 2 diabetes even when such patients are obese. PMID- 20973736 TI - Laser phototherapy for Stevens-Johnson syndrome: a case report. AB - BACKGROUND AND OBJECTIVE: Stevens-Johnson syndrome (SJS) is a life-threatening dermatosis characterized by epidermal sloughing and stomatitis. We report the case of a 7-year-old boy in whom laser phototherapy (LPT) was highly effective in reversing the effects of an initial episode of SJS that had apparently developed in association with treatment with phenobarbital for a seizure disorder. The patient was first seen in the intensive care unit (ICU) of our institution with fever, cutaneous lesions on his extremities, trunk, face, and neck; mucosal involvement of his genitalia and eyes (conjunctivitis); ulcerative intraoral lesions; and swollen, crusted, and bleeding lips. He reported severe pain at the sites of his intraoral and skin lesions and was unable to eat, speak, swallow, or open his mouth. MATERIALS AND METHODS: Trying to prevent and minimize secondary infections, gastric problems, pain, and other complications, the patient was given clindamycin, ranitidine, dipyrone, diphenhydramine (Benadryl) drops, and morphine. In addition, he was instructed to use bicarbonate solution and Ketoconazole (Xylogel) in the oral cavity. Because of the lack of progress of the patient, the LPT was selected. RESULTS: At 5 days after the initial session of LPT, the patient was able to eat gelatin, and on the following day, the number and severity of his intraoral lesions and his labial crusting and swelling had diminished. By 6 days after his initial session of LPT, most of the patient's intraoral lesions had disappeared, and the few that remained were painless; the patient was able to eat solid food by himself and was removed from the ICU. Ten sessions of LPT were conducted in the hospital. The patient underwent three further and consecutive sessions at the School of Dentistry, when complete healing of his oral lesions was observed. CONCLUSION: The outcome in this case suggests that LPT may be a new adjuvant modality for SJS complications. PMID- 20973737 TI - Effect of pulse Nd:YAG laser on bond strength and microleakage of resin to human dentine. AB - OBJECTIVES: The purpose of this study was to investigate the effect of pulse Nd:YAG laser on human dentine adhesion by optimizing the laser parameter combination and comparing it with other pretreatment methods for dentine adhesion. BACKGROUND DATA: In recent decades, many scholars have been seeking an optimal method to enhance the bond strength of resin to human dentine. However, little improvement has been achieved. In this study, pulse Nd:YAG laser was studied as a pretreatment method for dentine adhesion. MATERIALS AND METHODS: Two hundred ten freshly extracted, caries-free human premolars were used in this study, which was conducted after approval from the IRB. Ninety of them were selected and randomly divided into nine groups, according to parameter combinations of pulse Nd:YAG laser. Tensile-bond strength was tested, and the laser parameter combination was optimized for later experiments. The other teeth were randomly divided into six groups: laser-irradiated, acid-etched, laser + acid, 10-3 solution, laser + 10-3 solution, and negative control (unconditioned). Each group had 20 specimens: 10 for tensile-bond strength tests and the other 10 for microleakage examination. After the bond-strength test, the fractured surfaces were examined under scanning electronic microscopy. RESULTS: The bond strengths fluctuated with different laser-parameter combinations applied and showed significant differences in different laser-parameter groups (p < 0.01). The highest mean of tensile-bond strength was found in the group irradiated with the parameter combination of 1 W/15 Hz. In the contrasting experiments, the laser irradiated group, the 10-3 solution group, and the laser + 10-3 solution groups showed higher tensile-bond strength and lower microleakage than did the other three groups (p < 0.05). CONCLUSIONS: Pulse Nd:YAG laser, 10-3 solution, and their combination showed favorable effects on bond strength and adaptation of resin to human dentine and can be used to pretreat dentine surfaces before adhesion. The optimal parameter combination of pulse Nd:YAG laser was determined to be 1 W/15 Hz in this study. PMID- 20973738 TI - Does low-level laser therapy have an antianesthetic effect? A review. AB - Because local anesthetics are vasodilators, they tend to be absorbed into the bloodstream from the operative field as a result of the vasodilation of peripheral arterioles. To counteract this vasodilation, vasoconstrictive agents are often included in local anesthetic solutions to provide a longer duration of anesthesia. Low-level laser therapy (LLLT) has the same benefits, such as microcirculation activation and more-efficient tissue metabolism, analgesic effects, and vasodilatation. If LLLT is used to prevent pain postoperatively, improvements in local circulation and increased vasodilatation may increase the absorption of a local anesthetic agent. This may reduce the duration of the anesthesia, thereby allowing postoperative pain management to begin sooner. The maximal intensity of pain occurs during the first hours after surgery, when the local anesthetic has worn off. Theoretically, postoperative pain control can be increased with the use of a local anesthetic with a more-prolonged action. If a treatment method has both analgesic and antianesthetic effects, then the method may block its own effects. We review whether LLLT applied postoperatively to operated-on areas has an antianesthetic effect, that is, whether pain in the first hours after surgery was greater for patients who received LLLT than for control patients. Not too much evidence supports the antianesthetic effects of LLLT. However, additional experimental and clinical studies must be performed to investigate the effects of LLLT on the duration of anesthesia. PMID- 20973739 TI - A prospective randomized comparison between early (<48 hours of onset of colicky pain) versus delayed shockwave lithotripsy for symptomatic upper ureteral calculi: a single center experience. AB - BACKGROUND AND PURPOSE: The role of early/emergency shockwave lithotripsy (SWL) in symptomatic upper ureteral calculi has still not been established. We have performed a randomized comparison between early (<48 hours) vs delayed (>48 hours) SWL for symptomatic upper ureteral stones less than 1 cm to evaluate the feasibility, safety, and efficacy of early SWL in these patients. PATIENTS AND METHODS: One hundred and sixty consecutive patients with a single radiopaque upper ureteral stone <1 cm, who presented with an episode of colicky pain and who were undergoing treatment between July 2008 and June 2009 in our department were included. The patients were hospitalized and randomized into two groups-group A: SWL was performed within 48 hours of onset of colicky pain (early SWL) using the electromagnetic lithotripter (Dornier Alpha Compact) along with analgesics and hydration therapy; group B: SWL was performed after 48 hours (delayed SWL) along with analgesics and hydration therapy. The statistical analysis was performed in two groups regarding the patient demographic profile, presence of hydronephrosis, time to stone clearance, success rates, number of sessions needed, auxiliary procedures, modified efficiency quotient (EQ), and complications. RESULTS: Eighty patients were enrolled in each group. The mean stone size was 7.3 mm in group A vs 7.5 mm in group B (P = 0.52). The stone fragmentation rate was 88.75% in group A vs 91.2% in group B (P = 0.35). The overall 3-month stone-free rate was 86.3% (69/80) for group A vs 76.2% (61/80) for group B (P = 0.34). The mean time taken for stone clearance was significantly less in group A than in group B (10.2 days vs 21.1 days; P = 0.01). The number of sessions needed in group A were significantly less than in group B (1.3 vs 2.7; P = 0.01). The auxiliary procedure rate was also significantly lesser in group A than group B (16.3% vs 32.5%; P = 0.001). The modified EQ (in %) was 67.2 in group A vs 59.4 in group B (P = 0.21). The steinstrasse formation and requirement for percutaneous nephrostomy (PCN) were significantly less in group A (P:0.02 and P:0.01 respectively). CONCLUSIONS: Early SWL (within 48 hours of onset of colicky pain) is feasible, safe, and highly efficacious in the management of symptomatic proximal ureteral stones <1 cm, resulting in a lesser requirement of number of SWL sessions, time taken for stone clearance, auxiliary procedure rate, and fewer complications in comparison with delayed SWL. PMID- 20973740 TI - Optimizing vesicourethral anastomosis healing after robot-assisted laparoscopic radical prostatectomy: lessons learned from three techniques in 1900 patients. AB - BACKGROUND AND PURPOSE: Creation of an optimally apposed, tension-free, well supported vesicourethral anastomosis remains the cornerstone for anastomotic healing after radical prostatectomy. We report the effect of three techniques of bladder neck reconstruction during robot-assisted radical prostatectomy on anastomotic leak, stricture formation, and continence recovery. PATIENTS AND METHODS: Between January 2005 to September 2009, 1900 consecutive patients underwent robotic-assisted laparoscopic prostatectomy (RALP) by a single surgeon. Of these, the first 214 underwent vesicourethral conventional anastomosis (CA); the next 303 men underwent anterior reconstruction (AR) only; and last 1383 men underwent total anatomic restoration (TR). Data elements included patient age, body mass index, preoperative biopsy Gleason score and prostate-specific antigen level, prostate volume, total operative time, console time, time for performing vesicourethral anastomosis, estimated blood loss, tumor stage, and margin status on final pathologic findings. Primary end points were rates of clinically significant anastomotic leaks, bladder neck contractures, and time to return of continence. Chi-square and Fisher exact tests were used for analysis of categoric variables. The Cox proportional hazard model was used for both univariate and multivariate analysis. RESULTS: Clinically significant anastomotic leakage and bladder neck strictures were significantly fewer in the reconstructed groups (2.3% vs 1.0% vs 0.3% and 3.7% vs 1.3% vs 0.5% in the CA, AR, and TR groups, P < 0.01). Continence rates at 1, 6, 12, 26, and 52 weeks after RALP were also significantly better at all time points with AR and TR compared with CA alone (P < 0.001). CONCLUSIONS: TR of the continence mechanism optimizes vesicourethral anastomosis healing and hastens early continence return after RALP. PMID- 20973741 TI - A novel technique for detecting putative horizontal gene transfer in the sequence space. AB - Horizontal transfer (HT) is the event of a DNA sequence being transferred between species not by inheritance. This phenomenon violates the tree-like evolution of the species under study turning the trees into networks. At the sequence level, HT offers basic characteristics that enable not only clear identification and distinguishing from other sequence similarity cases but also the possibility of dating the events. We developed a novel, self-contained technique to identify relatively recent horizontal transfer elements (HTEs) in the sequences. Appropriate formalism allows one to obtain confidence values for the events detected. The technique does not rely on such problematic prerequisites as reliable phylogeny and/or statistically justified pairwise sequence alignment. In conjunction with the unique properties of HT, it gives rise to a two-level sequence similarity algorithm that, to the best of our knowledge, has not been explored. From evolutionary perspective, the novelty of the work is in the combination of small scale and large scale mutational events. The technique is employed on both simulated and real biological data. The simulation results show high capability of discriminating between HT and conserved regions. On the biological data, the method detected documented HTEs along with their exact locations in the recipient genomes. Supplementary Material is available online at www.libertonline.com/cmb. PMID- 20973742 TI - Alignment-free sequence comparison (II): theoretical power of comparison statistics. AB - Rapid methods for alignment-free sequence comparison make large-scale comparisons between sequences increasingly feasible. Here we study the power of the statistic D2, which counts the number of matching k-tuples between two sequences, as well as D2*, which uses centralized counts, and D2S, which is a self-standardized version, both from a theoretical viewpoint and numerically, providing an easy to use program. The power is assessed under two alternative hidden Markov models; the first one assumes that the two sequences share a common motif, whereas the second model is a pattern transfer model; the null model is that the two sequences are composed of independent and identically distributed letters and they are independent. Under the first alternative model, the means of the tuple counts in the individual sequences change, whereas under the second alternative model, the marginal means are the same as under the null model. Using the limit distributions of the count statistics under the null and the alternative models, we find that generally, asymptotically D2S has the largest power, followed by D2*, whereas the power of D2 can even be zero in some cases. In contrast, even for sequences of length 140,000 bp, in simulations D2* generally has the largest power. Under the first alternative model of a shared motif, the power of D2*approaches 100% when sufficiently many motifs are shared, and we recommend the use of D2* for such practical applications. Under the second alternative model of pattern transfer,the power for all three count statistics does not increase with sequence length when the sequence is sufficiently long, and hence none of the three statistics under consideration canbe recommended in such a situation. We illustrate the approach on 323 transcription factor binding motifs with length at most 10 from JASPAR CORE (October 12, 2009 version),verifying that D2* is generally more powerful than D2. The program to calculate the power of D2, D2* and D2S can be downloaded from http://meta.cmb.usc.edu/d2. Supplementary Material is available at www.liebertonline.com/cmb. PMID- 20973743 TI - EDAR: an efficient error detection and removal algorithm for next generation sequencing data. AB - Genomic sequencing techniques introduce experimental errors into reads which can mislead sequence assembly efforts and complicate the diagnostic process. Here we present a method for detecting and removing sequencing errors from reads generated in genomic shotgun sequencing projects prior to sequence assembly. For each input read, the set of all length k substrings (k-mers) it contains are calculated. The read is evaluated based on the frequency with which each k-mer occurs in the complete data set (k-count). For each read, k-mers are clustered using the variable-bandwidth mean-shift algorithm. Based on the k-count of the cluster center, clusters are classified as error regions or non-error regions. For the 23 real and simulated data sets tested (454 and Solexa), our algorithm detected error regions that cover 99% of all errors. A heuristic algorithm is then applied to detect the location of errors in each putative error region. A read is corrected by removing the errors, thereby creating two or more smaller, error-free read fragments. After performing error removal, the error-rate for all data sets tested decreased (~35-fold reduction, on average). EDAR has comparable accuracy to methods that correct rather than remove errors and when the error rate is greater than 3% for simulated data sets, it performs better. The performance of the Velvet assembler is generally better with error-removed data. However, for short reads, splitting at the location of errors can be problematic. Following error detection with error correction, rather than removal, may improve the assembly results. PMID- 20973744 TI - Antioxidant supplementation improves platelet membrane fluidity in idiopathic retinal periphlebitis (Eales' disease). AB - PURPOSE: Oxidative damage to cellular membranes plays an important role in the pathobiology of tissue injury. Retinal photoreceptors and platelets are an easy target of oxidants because of high proportion of polyunsaturated fatty acids. A tertiary-care center-based prospective study was undertaken to study the effect of antioxidant supplementation over membrane fluidity in platelets in idiopathic retinal periphlebitis (Eales' disease) for the first time. METHODS: Assay of thiobarbituric acid reactive substances (TBARS) levels was done following a standard protocol and membrane fluidity in platelets was estimated using a fluorescent probe, 1,6-diphenyl-1,3,5-hexatrience, in 15 cases and 12 healthy controls. Prednisolone (1 mg/kg) in a weekly tapering dose for 6 weeks and a commercially available antioxidant preparation [lutein 3.2 mg (containing zeaxanthin 256 mcg), L-glutathione 5 mg, vitamin E 15 IU, vitamin C 150 mg, zinc 40 mg, copper 2 mg, selenium 40 mcg, and manganese 5 mg] was administered once a day for 3 months to all the cases. Pre- and postantioxidant supplementation platelet TBARS and membrane fluidity levels were assessed in all the cases. RESULTS: Significant increase was observed in TBARS levels in the cases when compared with controls (P = 0.01). Platelet fluorescence polarization was significantly higher in cases, indicating decreased membrane fluidity, when compared with controls (P = 0.005). Antioxidant supplementation led to marked decrease in TBARS levels (P = 0.01) and improved levels of platelet membrane fluidity (P = 0.001). CONCLUSION: Antioxidant supplementation leads to significant decrease in oxidative stress and a significant improvement in platelet membrane fluidity, thereby helping to prevent retinal photoreceptor dysfunction. PMID- 20973745 TI - Bile acid sequestrants and diabetes: introduction and overview to the supplement. AB - Diabetes is a global epidemic. The recommended goals for glycated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), and blood pressure are achieved only in a very small minority of patients. In this supplement to Metabolic Syndrome and Related Disorders, we review the data showing that the bile acid sequestrant colesevelam lowers both HbA1c and LDL-C in patients with diabetes. These data make colesevelam an attractive therapy to get more patients to achieve their LDL-C and HbA1c goals. PMID- 20973746 TI - Enhanced endothelialization on surface modified poly(L-lactic acid) substrates. AB - Improved biodegradable vascular grafts and stents are in demand, particularly for pediatric patients. Poly(L-lactic acid) (PLLA) is an FDA-approved biodegradable polymer of potential use for such applications. However, tissue culture studies have shown that endothelial cell (EC) attachment and growth occurs relatively slowly on PLLA surfaces. This slow growth has been attributed to the fact that PLLA represents a hydrophobic substrate, relatively devoid of active functional groups. As a result, the slow EC recovery on the luminal side of PLLA stents provides an increased risk of induced thrombosis. In the present study, surface modification of PLLA substrates has been examined as a potential route to enhance EC growth. For this purpose, PLLA surfaces were modified via pulsed plasma deposition of thin films of poly(vinylacetic acid). The -COOH surface groups, introduced by the plasma deposition, were employed to conjugate fibronectin (FN), followed by attachment of vascular endothelial growth factor to FN. Pig Aorta ECs (PAE) and kinase-insert domain-containing receptor (KDR)-transfected PAE showed increased cell adhesion and proliferation, as well as substantially improved cell retention under fluidic shear stress on surface-modified PLLA compared with untreated PLLA. Although KDR-transfected PAE exhibited better cell proliferation than PAE, normal EC functions, including EC morphology, nitric oxide production, and KDR expression, were observed when cells were grown on surface-modified PLLA. The results obtained clearly indicate that this combined surface modification technique using poly(vinylacetic acid) deposition, FN conjugation, and vascular endothelial growth factor surface delivery can enhance endothelialization on PLLA, particularly when employed in conjunction with the growth of KDR transfected ECs. PMID- 20973747 TI - Autogenous bone marrow stromal cell sheets-loaded mPCL/TCP scaffolds induced osteogenesis in a porcine model of spinal interbody fusion. AB - This study was designed to investigate whether a tissue-engineered construct composed of autogenous cell sheets and a polycaprolactone-based bioresorbable scaffold would enhance bone regeneration and spinal interbody fusion in a large animal model. Porcine-derived autogenous bone marrow stromal cells (BMSCs) cultured into multilayered cell sheets were induced into osteogenic differentiation with dexamethasone, l-ascorbic acid, and beta-glycerol phosphate. These cell sheets were assembled with bioresorbable scaffolds made from medical grade poly(epsilon-caprolactone) incorporating 20% beta-tricalcium phosphate (mPCL/TCP) as tissue-engineered BMSC constructs. L2/3, L4/5 discectomies and decortication of the vertebral end plates were performed on 16 SPF Yorkshire pigs through an anterolateral approach. The tissue-engineered BMSC constructs were transplanted into the prepared intervertebral disc spaces of half of the pigs (n = 8), whereas cell-free mPCL/TCP served as controls in the remaining pigs. New bone formation and spinal fusion were evaluated at 3 and 6 months using microcomputed tomography, histology, fluorochrome bone labeling, and biomechanical testing. New bone formation was evident as early as 3 months in the BMSC group. At 6 months, bony fusion was observed in >60% (5/8) of segments in the BMSC group. None of the control animals with cell-free scaffold showed fusion at both time points. Biomechanical evaluation further revealed a significantly increased segmental stability in the BMSC group compared with the cell-free group at 6 months postimplantation (p < 0.01). These findings suggest that mPCL/TCP scaffolds loaded with in vitro differentiated autogenous BMSC sheets could induce bone formation and interbody fusion. This in turn resulted in enhanced segmental stability of the lumbar spine. PMID- 20973748 TI - Short-term cultivation of in situ prevascularized tissue constructs accelerates inosculation of their preformed microvascular networks after implantation into the host tissue. AB - Inosculation of preformed microvessels with the host microvasculature represents a promising approach to accelerate vascularization of tissue constructs. Herein, we analyzed whether cultivation of prevascularized tissue constructs promotes inosculation by reducing the perivascular cell coverage of the preformed microvessels. Poly(ester-urethane) scaffolds were implanted into FVB/N-TgN (Tie2/green fluorescent protein [GFP]) 287 Sato mice to generate prevascularized tissue constructs with GFP-positive microvessels. These constructs were then cultivated for 3 or 10 days before implantation into dorsal skinfold chambers of FVB/N mice to analyze inosculation and vascularization by intravital fluorescence microscopy and immunohistochemistry. Noncultivated tissue constructs served as controls. Cultivation reduced the number of alpha-smooth muscle actin-positive preformed microvessels within the constructs and increased the production of vascular endothelial growth factor. After 3 days of cultivation, tissue constructs still exhibited good cell viability, whereas apoptotic cell death was massively increased in the 10-day-cultivated group. After implantation, inosculation of preformed microvessels was accelerated in the 3-day-cultivated constructs. This resulted in an improved vascularization, as indicated by an increased functional microvessel density and blood perfusion. Immunohistochemical detection of GFP-positive microvessels revealed that internal and external inosculation occurs in parallel. In conclusion, this study demonstrates that inosculation of in situ prevascularized tissue constructs can be easily accelerated by destabilization of preformed microvessels and angiogenic activation during short-term cultivation. PMID- 20973749 TI - Nanofiber matrices promote the neuronal differentiation of human embryonic stem cell-derived neural precursors in vitro. AB - The potential of human embryonic stem (ES) cells as experimental therapies for neuronal replacement has recently received considerable attention. In view of the organization of the mature nervous system into distinct neural circuits, key challenges of such therapies are the directed differentiation of human ES cell derived neural precursors (NPs) into specific neuronal types and the directional growth of axons along specified trajectories. In the present study, we cultured human NPs derived from the NIH-approved ES line BGO1 on polycaprolactone fiber matrices of different diameter (i.e., nanofibers and microfibers) and orientation (i.e., aligned and random); fibers were coated with poly-L-ornithine/laminin to mimic the extracellular matrix and support the adhesion, viability, and differentiation of NPs. On aligned fibrous meshes, human NPs adopt polarized cell morphology with processes extending along the axis of the fiber, whereas NPs on plain tissue culture surfaces or random fiber substrates form nonpolarized neurite networks. Under differentiation conditions, human NPs cultured on aligned fibrous substrates show a higher rate of neuronal differentiation than other matrices; 62% and 86% of NPs become TUJ1 (+) early neurons on aligned micro- and nanofibers, respectively, whereas only 32% and 27% of NPs acquire the same fate on random micro- and nanofibers. Metabolic cell activity/viability studies reveal that fiber alignment and diameter also have an effect on NP viability, but only in the presence of mitogens. Our findings demonstrate that fibrous substrates serve as an artificial extracellular matrix and provide a microenviroment that influences key aspects of the neuronal differentiation of ES-derived NPs. PMID- 20973750 TI - Tissue-engineered skin preserving the potential of epithelial cells to differentiate into hair after grafting. AB - The aim of this study was to evaluate whether tissue-engineered skin produced in vitro was able to sustain growth of hair follicles in vitro and after grafting. Different tissues were designed. Dissociated newborn mouse keratinocytes or newborn mouse hair buds (HBs) were added onto dermal constructs consisting of a tissue-engineered cell-derived matrix elaborated from either newborn mouse or adult human fibroblasts cultured with ascorbic acid. After 7-21 days of maturation at the air-liquid interface, no hair was noticed in vitro. Epidermal differentiation was observed in all tissue-engineered skin. However, human fibroblast-derived tissue-engineered dermis (hD) promoted a thicker epidermis than mouse fibroblast-derived tissue-engineered dermis (mD). In association with mD, HBs developed epithelial cyst-like inclusions presenting outer root sheath like attributes. In contrast, epidermoid cyst-like inclusions lined by a stratified squamous epithelium were present in tissues composed of HBs and hD. After grafting, pilo-sebaceous units formed and hair grew in skin elaborated from HBs cultured 10-26 days submerged in culture medium in association with mD. However, the number of normal hair follicles decreased with longer culture time. This hair-forming capacity after grafting was not observed in tissues composed of hD overlaid with HBs. These results demonstrate that epithelial stem cells can be kept in vitro in a permissive tissue-engineered dermal environment without losing their potential to induce hair growth after grafting. PMID- 20973751 TI - Microscale versus nanoscale scaffold architecture for mesenchymal stem cell chondrogenesis. AB - Nanofiber scaffolds, produced by the electrospinning technique, have gained widespread attention in tissue engineering due to their morphological similarities to the native extracellular matrix. For cartilage repair, studies have examined their feasibility; however these studies have been limited, excluding the influence of other scaffold design features. This study evaluated the effect of scaffold design, specifically examining a range of nano to micron sized fibers and resulting pore size and mechanical properties, on human mesenchymal stem cells (MSCs) derived from the adult bone marrow during chondrogenesis. MSC differentiation was examined on these scaffolds with an emphasis on temporal gene expression of chondrogenic markers and the pluripotent gene, Sox2, which has yet to be explored for MSCs during chondrogenesis and in combination with tissue engineering scaffolds. Chondrogenic markers of aggrecan, chondroadherin, sox9, and collagen type II were highest for cells on micron-sized fibers (5 and 9 MUm) with pore sizes of 27 and 29 MUm, respectively, in comparison to cells on nano-sized fibers (300 nm and 600 to 1400 nm) having pore sizes of 2 and 3 MUm, respectively. Undifferentiated MSCs expressed high levels of the Sox2 gene but displayed negligible levels on all scaffolds with or without the presence of inductive factors, suggesting that the physical features of the scaffold play an important role in differentiation. Micron-sized fibers with large pore structures and mechanical properties comparable to the cartilage ECM enhanced chondrogenesis, demonstrating architectural features as well as mechanical properties of electrospun fibrous scaffolds enhance differentiation. PMID- 20973752 TI - Establishing a transport protocol for the delivery of melanocytes and keratinocytes for the treatment of vitiligo. AB - We have previously developed a cell delivery and transfer technology for delivering autologous keratinocytes and melanocytes to patients with vitiligo. However, for this technology to benefit many patients geographically distant from the cell culture facility transportation issues need to be overcome. In this study we begin to investigate this by looking at what role surface chemistry and medium supplements, including fetal calf serum, CO2 gassing, and temperature, play in influencing cell viability. Cells were maintained on carriers for up to 48 h outside of a CO2 incubator at 37 degrees C and their subsequent ability to adhere and become organized into a new epithelium with appropriately located melanocytes was assessed. Consistently good viability and performance on an in vitro wound bed model was achieved by maintaining cells for 48 h adherent to a 20% acrylic acid coated carrier at lower (around 23 degrees C rather than 37 degrees C) temperatures in the medium preperfused with CO2 before transport. Under these circumstances fetal calf serum was not required. In summary, the surface chemistry of the transport substrate and an appropriately CO2 buffered medium at near room temperature can extend the effective performance life of these cultured cells to at least 48 h from when they leave standard incubator conditions. PMID- 20973753 TI - Method for decellularizing skeletal muscle without detergents or proteolytic enzymes. AB - Decellularized skeletal muscle is a promising model that can be used to study cell-matrix interactions and changes that occur in muscle extracellular matrix (ECM) in myopathies and muscle wasting diseases. The goal of this study is to develop a novel method to decellularize skeletal muscle that maintains the native biochemical composition and structure of the ECM. This method consists of sequential incubation of mouse tibialis anterior muscles in latrunculin B, high ionic strength salt solution, and DNase I and avoids use of proteases or detergents that degrade the ECM. Characterization of the decellularized muscles using hematoxylin and eosin staining along with DNA quantification suggested complete removal of DNA, whereas biochemical analyses indicated no loss of collagens and only a slight reduction in glycosaminoglycans. Western blot analysis of decellularized tissues showed removal of the vast majority of the contractile proteins actin and myosin, and morphological analysis using scanning electron microscopy suggested removal of myofibers from decellularized muscle tissues. Passive mechanical testing of decellularized muscle bundles revealed the typical nonlinear behavior, similar to that of intact muscle. Together, these results suggest that the protocol developed successfully decellularizes skeletal muscle without altering its composition and mechanical function. PMID- 20973754 TI - [BMT 2010. Proceedings of the 44th Annual meeting of the German Association for BioMedical Technology 3 country meeting - Germany, Austria & Switzerland]. PMID- 20973755 TI - Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: A mechanistic basis for utility. AB - The inclusion of certain polymers within solid dispersion or lipid-based formulations can maintain drug supersaturation after dispersion and/or digestion of the vehicle, leading to improvements in bioavailability and variability in exposure. This review presents an overview of the fundamental principles that underpin drug precipitation mechanisms, describes the mechanisms by which precipitation may be inhibited, discusses the methods that can be used to identify polymeric precipitation inhibitors (PPIs), and summarizes current literature evidence of the most effective PPIs. Preliminary data from our laboratory is also presented, which describes the precipitation inhibition behavior of 53 polymeric materials using supersaturated solutions of danazol as a model, poorly water-soluble drug. These studies identify a group of PPIs with superior precipitation inhibition qualities, the majority of which are cellulose based. These new results in combination with previous published data indicate that PPIs represent an appealing new technology with the potential to improve drug absorption for poorly water-soluble drugs. The molecular determinants of polymer utility, however, remain relatively poorly understood, although the cellulose derivates appear, in general, to provide the most benefit. More detailed studies are therefore required to define the parameters that most effectively predict and quantify the drug-polymer relationships that control precipitation inhibition. PMID- 20973756 TI - Effects of isotretinoin on spermatogenesis of rats. AB - BACKGROUND: The results of studies on the effects of retinoids on spermatogenesis are controversial. OBJECTIVES: We evaluated time- and dose-dependent effects of isotretinoin on spermatogenic activity by apoptosis, cyclin D1, E2F, p53 expressions, and Johnsen's scores. METHODS: The rats were divided into three groups. In the 1st group (n = 18), 1 mg/mL/day and in the 2nd group (n = 18) 2 mg/mL/day isotretinoin were administered for 21 days. Flower oil was given to the 3rd (n = 6) control group. On the 7th (groups 1a and 2a), 14th (groups 1b and 2b), and 21st (groups 1c and 2c) days, six rats from the 1st group and six rats from the 2nd group were sacrificed and bilateral orchiectomy was done. RESULTS: The number of cyclin D1 and E2F-positive cells decreased nonsignificantly parallel to days in the 1st group, whereas there was a statistically significant decrease in the 2nd group for the same cells. The p53-positive cells in groups 1c and 2c were increased significantly. CONCLUSIONS: Further studies on the effects of retinoids on spermatogenesis should be conducted. It may be wise to administer contraception to male patients, especially during high-dose and long-term retinoid therapy. PMID- 20973757 TI - Methodologies for investigating drug metabolism at the early drug discovery stage: prediction of hepatic drug clearance and P450 contribution. AB - The attrition rate in drug development is being reduced by continuous advances in science and technology introduced by various academic institutions and pharmaceutical companies. This has been certainly noticeable in reducing the frequency with which unfavorable absorption, distribution, metabolism, and elimination (ADME) characteristics of any candidate drug causes failure in clinical development. Nonetheless, it is important that the objectives in reducing attrition during later stages of development are matched by information generated in the earliest stage of discovery. In this review, we summarize the methodologies employed during the early stages of drug discovery and discuss new findings in the areas of (1) drug metabolism enzymes, (2) the contribution of cytochrome P450 enzymes (P450, CYP) to hepatic metabolism, (3) prediction of hepatic intrinsic clearance, (4) reaction phenotyping, and (5) the metabolic differences between highly homologous enzymes such as CYP3A4 and CYP3A5. The total contribution of P450 and UDP-glucuronosyltransferases to drug metabolism is reported to be more than 80%; therefore, glucuronidation is increasingly recognized as an important clearance pathway in addition to that of P450 enzymes. When estimating the contribution of P450, interpreting the results of inhibition studies using a single P450 inhibitor can lead to false conclusions. For instance, 1-aminobenzotriazole and SKF-525A have a varying range of IC(50) values for inhibition of drug exidation-reaction by different CYP450 enzymes. There are disparities between methodologies at early stage drug discovery and late stage development. For example, although the drug depletion approach for the prediction of hepatic intrinsic clearance may not be desirable at late stages of development, it is suitable at the early drug discovery stage since kinetic characterization and measurement of specific drug metabolites are not required. Data from protein binding assays in plasma and/or liver microsomes is an integral part to predicting hepatic clearance; therefore, the prediction methods for protein binding have been addressed in terms of automation and in silico prediction. The approach to reaction phenotyping using recombinant P450 microsome data are reviewed as this approach enables combining the drug depletion method with appropriate scaling factors to predict clearance values. CYP3A enzymes have broad substrate specificities and are responsible for the oxidative metabolism of more than 50% of clinically used drugs. Although CYP3A4 is the most abundant CYP3A isoform in adult human liver, CYP3A5 may contribute more to CYP3A-mediated drug oxidation by human liver microsomes than CYP3A4 does, especially in Japanese subjects, who typically have a relatively high frequency of genetic CYP3A5 expression. Lack of efficacy and presence of serious side effects in some sub group of patients remain the biggest sources of drug failure at late stage of drug development. Advances in appreciation of inter-individual variabilities in ADME, by creation of virtual individuals and use of appropriate information from early discovery may lead to a better anticipation of variable clinical and toxicological outcome following administration of any new drug candidate. Thus may also help with dosing strategies which minimize the potential side effects and maximize the clinical benefits. Accordingly, front-loading of efforts for characterizing the candidate drugs at early stages of discovery is recommended. PMID- 20973758 TI - The role of metabonomics at the interface between drug metabolism and safety assessment. AB - Safety assessment of candidate drugs is a key stage in drug development and one which represents a significant attritional hurdle. There is also a focused effort in drug metabolism studies to assess bioactivation potential based on the notion this could lead to the risk of macromolecule adduct formation and subsequent toxicological consequences. However, characterization of the molecular mechanisms of drug toxicity still remains an enormous challenge. Recent advancements in 'omics sciences, and in particular metabonomics, has enabled some elucidation or insights into toxicological sequelae. Metabonomics is a global metabolic profiling framework which utilizes high resolution analytics (typically NMR and mass spectrometry) together with chemometric statistical tools (such as principal component analysis and partial least squares) to derive an integrated picture of both endogenous and xenobiotic metabolism. This review details some of the current progress in the application of metabonomics in drug safety and metabolism. PMID- 20973759 TI - Targeting the resistance of pancreatic cancer cells to nutrient deprivation: anti austerity compounds. AB - The emerging "anti-austerity" anti-cancer therapeutic strategy targets the ability of certain cancer cell lines, particularly pancreatic cancer, to survive nutrient deprivation. While biochemical pathways for the tolerance to nutrient deprivation are still not well understood, a growing number of inhibitors of this process are being discovered. A number of natural products have been isolated, structurally characterized and evaluated as inhibitors of austerity, thereby providing valuable initial structure-activity relationship data. PMID- 20973760 TI - Drug eluting coronary artery stents. AB - Atherosclerosis is the primary cause of coronary heart disease, which is characterized by a narrowing (stenosis) of the arteries that supply blood to tissues of the heart. Over the past decade, the use of "Bare metallic stents" during Percutaneous Transluminal Coronary Angioplasty (PTCA) has become a common practice for treating the coronary arterial stenosis. However, the restenosis is common problem in patients receiving stents. Recently, Drug-Eluting Stents (DES) with synthetic polymer coatings which act as drug reservoirs and elute drugs over a period of several weeks or months have emerged to tackle restenosis. The polymer coatings on these stents contain various drugs like immunosuppressive drugs, anti-neoplastic drugs, anti-inflammatory drugs, migration inhibitor drugs and enhanced healing drugs that inhibit thrombus formation, inflammation or cellular proliferation which in turn prevent restenosis. Different methods like dip coating, dip spin coating, ultrasonic spray coating and ink-jet coating help to coat stent uniformly. Drug from the stent can be released by diffusion, dissolution or ion exchange mechanism. There are some disadvantages of the polymer coated stents and hence they are being superseded by completely bioabsorbable stents. Such stents are heading for clinical trials and may hit the market soon. This review gives a glimpse over DES and the future prospects of DES. PMID- 20973761 TI - The role of transforming growth factors beta1 and beta3 in pre- and post-natal pulmonary surfactant development. AB - The aim was to explore the pulmonary surfactant regulatory effect of TGF-beta1 and TGF-beta3 during pre- and post-natal porcine development. Pigs on embryonic day 99 (E94) (term = 114 days) and 1-h (D0) and 15-day (D20) neonates were killed to obtain whole lungs. DSPC (disaturated phosphatidylcholine) was separated from other phospholipids, and chemical methods were used to determine the amounts of DSPC, TPL (total phospholipids) and TP (total protein) in BALF (bronchoalveolar lavage fluid). TPL was elevated at E94. DSPC in TPL was significantly higher in the D20 group than in the E94 group. Reductions in TP correlated with developmental age. The levels of TGF-beta1 and TGF-beta3 mRNA were determined by RT (reverse transcription)-PCR and Northern blot. The expression of TGF-beta1 mRNA was low at E94, increased at D0 and then decreased at D20. The expression of TGF-beta3 was high at E94, reduced at D0, and then elevated at D20. We further examined the effect of exogenously administered TGF-1 on the expression of SPs (surfactant proteins) and cytidine triphosphorylate: CCT (phosphocholine cytidylyltransferase) activity in porcine fetal lung cells cultured for 5 days. The results indicated that TGF-beta1 inhibited the expression of all three SPs (SP-A, SP-B and SP-C) and CCT activity, but did not alter the expression level of SP-D transcripts. We conclude that TGF-1 inhibits the expression of surfactant components. The alterations of TGF-beta3 seem to partly explain the pulmonary surfactant changes observed in development, but this result needs further investigation. PMID- 20973762 TI - Determination of CO2 sensitivity of micro-organisms in shaken bioreactors. I. Novel method based on the resistance of sterile closure. AB - Influence of carbon dioxide on growth and product kinetics of industrially important micro-organisms is essential for the interpretation of a bioprocess. In this research, the CO2 effects on productivity and growth rate of micro-organisms have been studied by using a variety of kplug. The applied method is based on a different concentration of CO2 in the headspace of ventilation flasks. The presented method is simple, inexpensive and shows similar results compared to large-scale fermentation regarding the evolution of CO2 in a batch system. For the investigation of the proposed method, experiments employing Arxula adeninivorans LS3, Corynebacterium glutamicum (DM1730 and ATCC WT13032) and Hansenula polymorpha DSM70277 as model organisms in the ventilation flasks are performed. The fermentations in the RAMOS (respiratory activity monitoring system) device were carried out with a normal aeration rate (1 vvm) and under the same operating conditions as the ventilation flask f1. The modified unsteady state model was used to predict the operation conditions of a biological system in the ventilation flasks. In the present study, a novel and easy method for the quantification of CO2 sensitivity of micro-organisms in shaken bioreactors (called ventilation flask) was achieved. PMID- 20973763 TI - Determination of CO2 sensitivity of micro-organisms in shaken bioreactors. II. Novel online monitoring method. AB - In the present study, a new online monitoring method for the determination of the CO2 sensitivity of micro-organisms, based on the values of the respiration factors [OTR (oxygen transfer rate) and CTR (carbon dioxide transfer rate)], obtained by using the RAMOS (respiratory activity monitoring system) device considering a variety of aeration rates in the measuring flask, is investigated. Based on the data of the OTR, obtained by RAMOS under a variety of specific aeration rates, the proposed new method was developed as an online monitoring method for CO2 sensitivity of micro-organisms in shaken bioreactors. A maximum accumulated CO2 concentration of 12% was derived in applied methods, provided that the cultivation system is carried out under optimal conditions. Additionally, to predict these conditions, an unsteady-state gas transfer model in shaken bioreactors would be very advantageous. The data of OTR obtained using the RAMOS device were analysed and recalculated by a programme considering the calibration factor (Cf). The major advantage of the new method is the possibility to determine the metabolic activity, regardless of manual sampling. PMID- 20973764 TI - The role of T-cell reactivity towards the autoantigen alpha-NAC in atopic dermatitis. AB - BACKGROUND: A subgroup of patients with atopic dermatitis (AD) produces IgE autoantibodies to human proteins which may be present in inflamed skin and perpetuate cutaneous inflammation. OBJECTIVES: In order to investigate mechanisms of 'autoallergy' for AD we studied T-cell responses to the autoallergen Hom s 2, the human transcriptional coactivator alpha-nascent polypeptide-associated complex (alpha-NAC). METHODS: Specific proliferation of blood lymphocytes from 30 patients and 12 healthy control individuals was investigated by flow cytometry. The proliferation of skin- and blood-derived T cells was assessed in limiting dilution assays. T-cell clones (TCC) were generated from peripheral blood and from biopsies of lesional skin of patients with AD and the phenotype and cytokine patterns were determined. RESULTS: alpha-NAC-specific T-cell responses were detected in patients and control individuals. alpha-NAC induced a significantly higher proliferation of CCR4+ (compared with CCR4-) and CLA+ (compared with CLA-) T cells from the circulation. Limiting-dilution assays revealed a high proliferation of blood and skin-infiltrating lymphocytes in the presence of alpha NAC compared with control cultures. alpha-NAC-specific TCC generated from lesional skin of AD predominantly produced interferon-gamma and some TCC also produced interleukin-17. The cytokine pattern of alpha-NAC TCC may contribute to keratinocyte apoptosis and eczema formation in AD. CONCLUSIONS: alpha-NAC specific TCC can be generated from blood and lesional skin of patients with AD. These TCC produce not only Th2 but also Th1 cytokines which may explain the Th1 phenotype of inflammation in AD. PMID- 20973765 TI - Risk factors for genital lichen sclerosus in men. AB - BACKGROUND: Lichen sclerosus (LS) is an inflammatory disease of the skin and mucous membranes. Its aetiology is still unknown. OBJECTIVES: To determine risk factors for genital LS in men. METHODS: In a case-control study, 73 patients with LS, consecutively diagnosed at the City Dispensary for Skin and Venereal Diseases in Belgrade, were compared with 219 male patients visiting the same institution because of tinea cruris. Univariate and multivariate logistic regression analyses were used for analysis of data collected. RESULTS: According to multivariate logistic regression analysis, risk factors for male LS were as follows: a personal history of genital injury [odds ratio (OR) 28.1, 95% confidence interval (CI) 5.2-150.8], vitiligo (OR 23.1, 95% CI 2.2-240.2), alopecia areata (OR 8.8, 95% CI 1.1-68.5) and hypercholesterolaemia (OR 3.1, 95% CI 1.1-8.2), and a family history of alopecia areata (OR 24.3, 95% CI 2.1-280.7), diseases of the thyroid gland (OR 9.1, 95% CI 2.3-36.2) and other autoimmune diseases (OR 8.6, 95% CI 1.3 58.6). CONCLUSIONS: The results of the present study are in line with the hypothesis that trauma of the penis is a possible trigger of symptoms in genetically predisposed individuals and that personal and family histories of autoimmune disorders are risk factors for male LS. PMID- 20973766 TI - Assessing peristomal skin changes in ostomy patients: validation of the Ostomy Skin Tool. AB - BACKGROUND: Peristomal skin problems are common and are treated by a variety of health professionals. Clear and consistent communication among these professionals is therefore particularly important. The Ostomy Skin Tool (OST) is a new assessment instrument for the extent and severity of peristomal skin conditions. Formal tests of reliability and validity are necessary for its use in clinical practice, research, and education. OBJECTIVES: To estimate inter- and intra nurse assessment variability of the OST and validity by comparison to a 'gold standard' (GS) defined by an expert panel. METHODS: Thirty photographs of peristomal skin were presented twice to 20 ostomy care nurses--10 from Denmark (DK) and 10 from Spain (ES)--to determine intra- and inter nurse assessment variability. The same photographs were presented to an international group of experts (dermatologist and ostomy care nurses), to establish a GS for comparison and validation of the results. RESULTS: A high intra-nurse assessment agreement, kappa=0.84, was found with no differences in the intra-nurse assessments from the two groups of nurses (DK and ES). The inter-nurse assessment agreement was 'moderate to good', kappa=0.54, with the agreement between the experts higher, kappa=0.70. A high correlation between the scores from the nurses and the GS were seen in the lower part of the two scales [Discoloration, Erosion, Tissue overgrowth (DET) score<7)]. CONCLUSION: The study supported the validity of the OST. It is suggested that a categorical scale can be used to illustrate the severity of the DET scores. PMID- 20973767 TI - Tropism of herpes simplex virus type 1 to nonmelanoma skin cancers. AB - BACKGROUND: Current treatments for nonmelanoma skin cancer include surgery, Mohs micrographic surgery, radiation, cryosurgery, photodynamic therapy, local chemotherapy and application of immunomodulators such as imiquimod. However, all have a 5-year recurrence rate of 1-40%. Gene therapy for the treatment of skin cancers is a promising new approach, as delivery of the vectors to the skin is simple and safety issues can be properly addressed. OBJECTIVES: To develop an ex vivo organ culture system for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) tumours, and to test the feasibility of applying oncolytic viruses to these tumours. METHODS: We first optimized conditions for the maintenance of BCC and SCC tissues in organ culture, and demonstrated viability of the tissues ex vivo for 3-7 days. The tropism of two potential oncolytic viral vectors, herpes simplex virus type 1 (HSV-1) and adenovirus (AD), was next evaluated. RESULTS: Immunohistological analysis revealed that HSV-1 targeted tumour cells that expressed p63 and did not express keratin 15 or keratin 14 markers of keratinocytes. Further examination indicated that uninfected BCC and SCC tissues express two isoforms of p63 mRNA, and HSV-1 infection specifically enhanced expression of the TAp63 isoform. Furthermore, following infection, both HSV-1 and AD induced apoptosis in the BCC and SCC cells as indicated by the induction of activated caspase-3. CONCLUSIONS: The results indicated a specific pattern of viral tropism to skin cancer cells that are critical for maintenance of the tumour. This new experimental system should aid in the analysis of new therapeutic modalities, such as oncolytic viruses, for future treatment of these skin tumours. PMID- 20973768 TI - Dermatofibrosarcoma protuberans: 35 patients treated with Mohs micrographic surgery using paraffin sections. AB - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) has conventionally been treated with wide local excision. More recently Mohs micrographic surgery (MMS) has been advocated. OBJECTIVES: To assess our departmental experience with DFSP in the context of a literature review relating to DFSP treated with MMS. METHODS: This was a case review of 35 patients with DFSP treated between 1998 and 2009 with MMS using paraffin-embedded sections. RESULTS: Seventeen patients required one horizontal layer to clear their tumour, 10 patients needed two and eight patients needed three layers or more. The median preoperative clinical size was 6 cm(2) (range 0.75-54.8) and the median postoperative wound size was 46.8 cm(2) (range 4-145.2). Tumour persistence has not been observed in any of our patients after a median follow-up duration of 29.5 months (range 6-146). CONCLUSIONS: We present 35 DFSP patients, none of whom showed persistent tumour after treatment with 'slow' MMS using paraffin sections. We advocate MMS as the treatment of choice for DFSP, especially for tumours over the head and neck region where tissue conservation is particularly important. PMID- 20973769 TI - Redistribution of the nuclear protein IFI16 into the cytoplasm of ultraviolet B exposed keratinocytes as a mechanism of autoantigen processing. AB - BACKGROUND: The skin has long been recognized as a prominent target tissue in systemic lupus erythematosus (SLE) which plays a crucial role in the initiation and perpetuation of the autoimmune reaction cascade as a consequence of ultraviolet (UV)-induced keratinocyte apoptosis. Antibodies against IFI16 (interferon-inducible protein 16) have been detected in the sera of patients with SLE. OBJECTIVES: To verify whether the induction of autoimmunity against IFI16 involves redistribution of this nuclear protein in keratinocytes during UVB induced cell death. METHODS: An in vitro epidermal model was developed to investigate the fate of the IFI16 protein in keratinocytes after irradiation with UVB; both keratinocyte monolayers and human skin explants were used. IFI16 expression and localization were also analysed in diseased skin sections of patients with SLE. RESULTS: We demonstrated that IFI16, normally restricted to the nucleus, can be induced to appear in the cytoplasm under conditions of UVB induced cell injury. This nucleus to cytoplasm translocation was also observed in skin explants exposed to UVB and in the diseased skin sections from patients with SLE. In addition, IFI16 was found in the supernatants of UVB-exposed keratinocytes. CONCLUSIONS: The finding that IFI16 is present in the cytoplasm of diseased skin cells from patients with SLE and the demonstration of IFI16 in the supernatants of UVB-exposed keratinocytes, suggest that UVB irradiation or other stimuli may favour an abnormal IFI16 presentation to the afferent limb of the immune system and potentially an autoimmune response against the protein itself. PMID- 20973770 TI - A randomized comparative study of tolerance and satisfaction in the treatment of actinic keratosis of the face and scalp between 5% imiquimod cream and photodynamic therapy with methyl aminolaevulinate. AB - BACKGROUND: Photodynamic therapy (PDT) and imiquimod are two excellent treatments for actinic keratosis but are often not well tolerated by patients. OBJECTIVES: To ascertain which treatment is better tolerated and which produces greater patient satisfaction. A secondary objective was to determine the factors related to the patient's tolerance to each treatment. METHODS: Patients with at least five actinic keratosis lesions on the face and scalp were selected. The patients were randomized to receive treatment with PDT with methyl aminolaevulinate or treatment with imiquimod. Tolerance, satisfaction and predisposition to repeat the treatment were evaluated. RESULTS: Most patients exhibited good or acceptable tolerance to both PDT and imiquimod treatment. There was a higher percentage of patients treated with PDT (93%) who were very satisfied compared with imiquimod (62%) (P=0.004). Most patients treated with either one of the two options would repeat the same treatment. No significant relationship was found between age, sex, working time exposed to the sun, phototype and hair colour and the tolerance to both treatments. CONCLUSIONS: Both PDT and imiquimod are treatments that are generally well tolerated. While both treatments provide a high level of satisfaction, PDT appears to be slightly superior in this regard. PMID- 20973771 TI - Impact of etanercept treatment on ultraviolet B-induced inflammation, cell cycle regulation and DNA damage. AB - BACKGROUND: Current studies indicate that treatment with tumour necrosis factor (TNF)-alpha blockers plus ultraviolet (UV) B phototherapy results in higher relative Psoriasis Area and Severity Index reduction as compared with TNF-alpha monotherapy. OBJECTIVES: This study aimed to investigate the acute impact of etanercept on UVB-induced inflammation, cell cycle regulation and DNA damage. METHODS: Eleven subjects diagnosed with psoriasis who fulfilled the indication criteria for etanercept treatment were studied. A healthy skin site on the upper back was treated with UVB at 2 minimal erythema doses (MED). After 1, 24 and 72 h punch biopsies were taken from this site. Following the 72 h biopsy etanercept 50 mg was administered subcutaneously. After 48 h, 2 MED was given on healthy skin adjacent to previously treated skin sites. Again, after 1, 24 and 72 h punch biopsies were taken from this site. UVB- as well as UVB plus etanercept-treated skin was assessed by means of colorimetry and immunohistochemical studies for caspase 3, cyclin D(1), interleukin-12, Ki-67, p16, p53, survivin, thymine dimers and TNF-alpha. RESULTS: Erythema formation did not differ significantly between UVB- and UVB plus etanercept-treated sites. Comparisons between UVB- and UVB plus etanercept-treated sites at a given time (1, 24, 72 h) did not result in significant differences in immunoreactivity of the markers investigated, except for cyclin D(1), p53 and survivin. Immunoreactivity of cyclin D(1) and p53 was significantly decreased in UVB plus etanercept-treated sites at 24 h. Survivin expression was significantly higher in UVB plus etanercept-treated skin as compared with UVB monotherapy. CONCLUSIONS: Our data indicate that combined treatment with broadband UVB and TNF-alpha blockers might increase the risk of photocarcinogenesis by influencing apoptotic as well as antiapoptotic pathways. PMID- 20973772 TI - Dermatological manifestations of inherited cancer syndromes in children. AB - Various cutaneous signs presenting in childhood, for example cafe-au-lait macules, may have systemic cancer associations. Indeed, this may be the first manifestation of the underlying cancer predisposition. The syndromes covered in this review fall into four main categories: (i) DNA damage processing defects including Fanconi anaemia, ataxia telangiectasia, Bloom syndrome, Rothmund Thomson syndrome, constitutional mismatch repair defects and xeroderma pigmentosum; (ii) signalling pathway defects, including naevoid basal cell carcinoma and Costello syndromes; (iii) primary immunodeficiency syndromes; and (iv) syndromes that do not fit this molecular classification, such as X-linked dyskeratosis congenita. This review focuses on the dermatological findings of these conditions. Some of these conditions exhibit a milder heterozygous phenotype and this should be elicited in the family history. Where the dermatological findings are subtle, a targeted family history can provide clues towards making a diagnosis. Nondermatological features of each condition are summarized too, together with molecular testing strategies, which will direct genetic counselling and screening. This review will enable the dermatologist and other clinicians in the early recognition and molecular confirmation of underlying cancer-predisposing syndromes. This allows the possibility of surveillance and prevention strategies to be initiated in a timely manner, in affected children and other at-risk family members. PMID- 20973773 TI - Antinuclear antibodies associate with loss of response to antitumour necrosis factor-alpha therapy in psoriasis but do not necessarily predict treatment failure. PMID- 20973774 TI - Co-operative signalling through DP(1) and DP(2) prostanoid receptors is required to enhance leukotriene C(4) synthesis induced by prostaglandin D(2) in eosinophils. AB - BACKGROUND AND PURPOSE: Prostaglandin (PG) D(2) has emerged as a key mediator of allergic inflammatory pathologies and, particularly, PGD(2) induces leukotriene (LT) C(4) secretion from eosinophils. Here, we have characterized how PGD(2) signals to induce LTC(4) synthesis in eosinophils. EXPERIMENTAL APPROACH: Antagonists and agonists of DP(1) and DP(2) prostanoid receptors were used in a model of PGD(2) -induced eosinophilic inflammation in vivo and with PGD(2) stimulated human eosinophils in vitro, to identify PGD(2) receptor(s) mediating LTC(4) secretion. The signalling pathways involved were also investigated. KEY RESULTS: In vivo and in vitro assays with receptor antagonists showed that PGD(2) -triggered cysteinyl-LT (cysLT) secretion depends on the activation of both DP(1) and DP(2) receptors. DP(1) and DP(2) receptor agonists elicited cysLTs production only after simultaneous activation of both receptors. In eosinophils, LTC(4) synthesis, but not LTC(4) transport/export, was activated by PGD(2) receptor stimulation, and lipid bodies (lipid droplets) were the intracellular compartments of DP(1) /DP(2) receptor-driven LTC(4) synthesis. Although not sufficient to trigger LTC(4) synthesis by itself, DP(1) receptor activation, signalling through protein kinase A, did activate the biogenesis of eosinophil lipid bodies, a process crucial for PGD(2) -induced LTC(4) synthesis. Similarly, concurrent DP(2) receptor activation used Pertussis toxin-sensitive and calcium dependent signalling pathways to achieve effective PGD(2) -induced LTC(4) synthesis. CONCLUSIONS AND IMPLICATIONS: Based on pivotal roles of cysLTs in allergic inflammatory pathogenesis and the collaborative interaction between PGD(2) receptors described here, our data suggest that both DP(1) and DP(2) receptor antagonists might be attractive candidates for anti-allergic therapies. PMID- 20973775 TI - Roles of affinity and lipophilicity in the slow kinetics of prostanoid receptor antagonists on isolated smooth muscle preparations. AB - BACKGROUND AND PURPOSE: The highly lipophilic acyl-sulphonamides L-798106 and L 826266 showed surprisingly slow antagonism of the prostanoid EP3 receptor system in guinea-pig aorta. Roles of affinity and lipophilicity in the onset kinetics of these and other prostanoid ligands were investigated. EXPERIMENTAL APPROACH: Antagonist selectivity was assessed using a panel of human recombinant prostanoid receptor-fluorimetric imaging plate reader assays. Potencies/affinities and onset half-times of agonists and antagonists were obtained on guinea-pig-isolated aorta and vas deferens. n-Octanol-water partition coefficients were predicted. KEY RESULTS: L-798106, L-826266 and the less lipophilic congener (DG)-3ap appear to behave as selective, competitive-reversible EP3 antagonists. For ligands of low to moderate lipophilicity, potency increments for EP3 and TP (thromboxane-like) agonism on guinea-pig aorta (above pEC50 of 8.0) were associated with progressively longer onset half-times; similar trends were found for TP and histamine H1 antagonism above a pA2 limit of 8.0. In contrast, L-798106 (EP3), L 826266 (EP3, TP) and the lipophilic H1 antagonists astemizole and terfenadine exhibited very slow onset rates despite their moderate affinities; (DG)-3ap (EP3) had a faster onset. Agonism and antagonism on the vas deferens EP3 system were overall much faster, although trends were similar. CONCLUSIONS AND IMPLICATIONS: High affinity and high liphophilicity may contribute to the slow onsets of prostanoid ligands in some isolated smooth muscle preparations. Both relationships are explicable by tissue disposition under the limited diffusion model. EP3 antagonists used as research tools should have moderate lipophilicity. The influence of lipophilicity on the potential clinical use of EP3 antagonists is discussed. PMID- 20973776 TI - Discrete cue-conditioned alcohol-seeking after protracted abstinence: pattern of neural activation and involvement of orexin1 receptors. AB - BACKGROUND AND PURPOSE: The enduring propensity for alcoholics to relapse even following years of abstinence presents a major hurdle for treatment. Here we report a model of relapse following protracted abstinence and investigate the pattern of neuronal activation following cue-induced reinstatement and administration of the orexin1 receptor antagonist SB-334867 in inbred alcohol preferring rats. EXPERIMENTAL APPROACH: Rats were trained to self-administer alcohol under operant conditions and divided into two groups: immediate (reinstated immediately following extinction) and delayed (extinguished and then housed for 5 months before reinstatement). Prior to reinstatement, animals were treated with vehicle (immediate n= 11, delayed n= 11) or SB-334867 (20 mg.kg-1 i.p.; immediate n= 6, delayed n= 11). Fos expression was compared between each group and to animals that underwent extinction only. KEY RESULTS: SB-334867 significantly attenuated cue-induced reinstatement in both groups. Immediate reinstatement increased Fos expression in the nucleus accumbens (NAc), infra limbic (IL), pre-limbic (PrL), orbitofrontal (OFC) and piriform cortices, the lateral and dorsomedial hypothalamus, central amygdala and basolateral amygdala (BLA), and the bed nucleus of the stria terminalis. Following delayed reinstatement, Fos expression was further elevated in cortical structures. Concurrent with preventing reinstatement, SB-334867 decreased Fos in NAc core, PrL and OFC following immediate reinstatement. Following protracted abstinence, SB-334867 treatment decreased reinstatement-induced Fos in the PrL, OFC and piriform cortices. CONCLUSIONS AND IMPLICATIONS: Cue-induced alcohol seeking can be triggered following protracted abstinence in rats. The effects of SB-334867 on both behaviour and Fos expression suggest that the orexin system is implicated in cue-induced reinstatement, although some loci may shift following protracted abstinence. PMID- 20973777 TI - Salinomycin sensitizes cancer cells to the effects of doxorubicin and etoposide treatment by increasing DNA damage and reducing p21 protein. AB - BACKGROUND AND PURPOSE: Salinomycin (Sal) has recently been shown to inhibit various cancer stem cells. Here, we investigated whether Sal could sensitize cancer cells to the effects of doxorubicin (DOX) or etoposide (ETO). EXPERIMENTAL APPROACH: Using the Comet assay, immunocytochemistry and Western blot analysis, we assessed the ability of Sal to increase DNA breakage. We performed a cell proliferation assay to determine cell viability, cellular detachment, increased pre-G1 region, Annexin V staining and TUNEL assay to measure the ability of Sal to increase apoptosis. KEY RESULTS: Sal increased DNA breakage and phosphorylated levels of p53 and H2AX. Sal also induced the formation of DNA foci with pH2AX and 53BP1. Furthermore, Sal increased the sensitivity of cancer cells to the apoptotic effects of DOX or ETO. We found that pH2AX, pBRCA1, p53BP1 and pChk1 levels were greatly increased after co-treatment of Sal with DOX or ETO. The level of anti-apoptotic p21 protein was increased by DOX or ETO but decreased by Sal, which increased proteasome activity. CONCLUSIONS AND IMPLICATIONS: This is the first study to report that Sal increases DNA damage, and this effect plays an important role in the increased apoptosis caused by Sal. Overall, we demonstrated that the ability of Sal to sensitize cancer cells to the effects of DOX or ETO is associated with an increase in DNA damage and a decrease in anti-apoptotic protein p21 levels. These results may contribute to the development of Sal-based chemotherapy for cancer patients receiving DOX or ETO treatment. PMID- 20973778 TI - CRF2 mediates the increased noradrenergic activity in the hypothalamic paraventricular nucleus and the negative state of morphine withdrawal in rats. AB - BACKGROUND AND PURPOSE: Recent evidence suggests that corticotropin-releasing factor (CRF) receptor signalling is involved in modulating the negative symptoms of opiate withdrawal. In this study, a series of experiments were performed to further characterize the role of CRF-type 2 receptor (CRF2) signalling in opiate withdrawal-induced physical signs of dependence, hypothalamus-pituitary-adrenal (HPA) axis activation, enhanced noradrenaline (NA) turnover in the hypothalamic paraventricular nucleus (PVN) and tyrosine hydroxylase (TH) phosphorylation (activation), as well as CRF2 expression in the nucleus of the solitary tract-A2 noradrenergic cell group (NTS-A2). EXPERIMENTAL APPROACH: The contribution of CRF2 signalling in opiate withdrawal was assessed by i.c.v. infusion of the selective CRF2 antagonist, antisauvagine-30 (AS-30). Rats were implanted with two morphine (or placebo) pellets. Six days later, rats were pretreated with AS-30 or saline 10 min before naloxone and the physical signs of abstinence, the HPA axis activity, NA turnover, TH activation and CRF2 expression were measured using immunoblotting, RIA, HPLC and immunohistochemistry. KEY RESULTS: Rats pretreated with AS-30 showed decreased levels of somatic signs of naloxone-induced opiate withdrawal, but the corticosterone response was not modified. AS-30 attenuated the increased production of the NA metabolite, 3-methoxy-4-hydroxyphenylglycol, as well as the enhanced NA turnover observed in morphine-withdrawn rats. Finally, AS-30 antagonized the TH phosphorylation at Serine40 induced by morphine withdrawal. CONCLUSIONS AND IMPLICATIONS: These results suggest that physical signs of opiate withdrawal, TH activation and stimulation of noradrenergic pathways innervating the PVN are modulated by CRF2 signalling. Furthermore, they indicate a marginal role for the HPA axis in CRF2-mediation of opiate withdrawal. PMID- 20973779 TI - Interaction of diltiazem with an intracellularly accessible binding site on Ca(V)1.2. AB - BACKGROUND AND PURPOSE: Diltiazem inhibits Ca(V)1.2 channels and is widely used in clinical practice to treat cardiovascular diseases. Binding determinants for diltiazem are located on segments IIIS6, IVS6 and the selectivity filter of the pore forming alpha1 subunit of Ca(V)1.2. The aim of the present study was to clarify the location of the diltiazem binding site making use of its membrane impermeable quaternary derivative d-cis-diltiazem (qDil) and mutant alpha1 subunits. EXPERIMENTAL APPROACH: Ca(V)1.2 composed of alpha1, alpha2-delta and beta2a subunits were expressed in tsA-201 cells and barium currents through Ca(V)1.2 channels were recorded using the patch clamp method in the whole cell configuration. qDil was synthesized and applied to the intracellular side (via the patch pipette) or to the extracellular side of the membrane (by bath perfusion). KEY RESULTS: Quaternary derivative d-cis-diltiazem inhibited Ca(V)1.2 when applied to the intracellular side of the membrane in a use-dependent manner (59 +/- 4% at 300 uM) and induced only a low level of tonic (non-use-dependent) block (16 +/- 2% at 300 uM) when applied to the extracellular side of the membrane. Mutations in IIIS6 and IVS6 that have previously been shown to reduce the sensitivity of Ca(V)1.2 to tertiary diltiazem also had reduced sensitivity to intracellularly applied qDil. CONCLUSION AND IMPLICATIONS: The data show that use dependent block of in Ca(V)1.2 by diltiazem occurs by interaction with a binding site accessible via a hydrophilic route from the intracellular side of the membrane. PMID- 20973781 TI - Suppression of hippocampal epileptic seizures in the kainate rat by Poisson distributed stimulation. AB - PURPOSE: Hippocampal deep brain stimulation (DBS) is an experimental therapy for patients with pharmacoresistant temporal lobe epilepsy (TLE). Despite the successful clinical application of DBS, the optimal stimulation parameters are undetermined. We evaluate the efficacy of a new form of DBS, using continuous stimuli with Poisson distributed intervals (Poisson distributed stimulation, PDS) in the kainate (KA) rat model, a validated model for human TLE. METHODS: Status epilepticus was elicited by injection of KA (i.p.). After development of spontaneous seizures, rats were implanted with hippocampal DBS- and depth electroencephalography (EEG) electrodes. After baseline EEG monitoring, one group of rats (n = 13) was treated with PDS and a second (n = 11) received regular high frequency stimulation (HFS) at 130 Hz. Stimulation intensity was 100 MUA below the threshold for induction of epileptiform EEG activity. RESULTS: Stimulation intensity was significantly lower for PDS (156 +/- 20 MUA) than HFS (207 +/- 23 MUA; p < 0.02). Seven (54%) of 13 rats treated with PDS and 5 (45%) of 11 rats treated with HFS experienced a significant reduction in seizure frequency. In PDS improved rats, seizure frequency was reduced to 33% (p < 0.01) of baseline value and in HFS-improved rats to 50% (p < 0.01). After termination of PDS, seizure rate returned to baseline value. DISCUSSION: Continuous hippocampal PDS significantly reduces the number of spontaneous seizures. Compared to regular HFS, there is a slightly larger number of improved rats and a larger efficacy at a considerably lower stimulus intensity. The first two observations leave room for optimization, whereas a lower intensity is beneficial for battery life. PMID- 20973780 TI - Effects of beta-adrenoceptor stimulation on delayed rectifier K(+) currents in canine ventricular cardiomyocytes. AB - BACKGROUND AND PURPOSE: While the slow delayed rectifier K(+) current (I(Ks)) is known to be enhanced by the stimulation of beta-adrenoceptors in several mammalian species, phosphorylation-dependent regulation of the rapid delayed rectifier K(+) current (I(Kr)) is controversial. EXPERIMENTAL APPROACH: In the present study, therefore, the effect of isoprenaline (ISO), activators and inhibitors of the protein kinase A (PKA) pathway on I(Kr) and I(Ks) was studied in canine ventricular myocytes using the whole cell patch clamp technique. KEY RESULTS: I (Kr) was significantly increased (by 30-50%) following superfusion with ISO, forskolin or intracellular application of PKA activator cAMP analogues (cAMP, 8-Br-cAMP, 6-Bnz-cAMP). Inhibition of PKA by Rp-8-Br-cAMP had no effect on baseline I(Kr). The stimulating effect of ISO on I(Kr) was completely inhibited by selective beta1-adrenoceptor antagonists (metoprolol and CGP-20712A), by the PKA inhibitor Rp-8-Br-cAMP and by the PKA activator cAMP analogues, but not by the EPAC activator 8-pCPT-2'-O-Me-cAMP. In comparison, I(Ks) was increased threefold by the activation of PKA (by ISO or 8-Br-cAMP), and strongly reduced by the PKA inhibitor Rp-8-Br-cAMP. The ISO-induced enhancement of I(Ks) was decreased by Rp-8-Br-cAMP and completely inhibited by 8-Br-cAMP. CONCLUSIONS AND IMPLICATIONS: The results indicate that the stimulation of beta1-adrenoceptors increases I(Kr), similar to I(Ks), via the activation of PKA in canine ventricular cells. PMID- 20973782 TI - Assessing the unmet treatment need in partial-onset epilepsy: looking beyond seizure control. AB - Patients with resistant epilepsy are often coprescribed multiple medications and are more likely to experience drug-drug interactions and adverse events (AEs). A new generation of antiepileptic drugs (AEDs) has been developed with improved safety/tolerability profiles. To evaluate the unmet treatment needs in epilepsy, a comprehensive search of the English-language literature was conducted on Medline and other databases using the terms "partial epilepsy" and "focal seizure," focusing on newer AEDs. Sixty-nine articles were identified. Most patients experienced AEs, which were generally mild-moderate in severity. Drug drug interactions existed for 6 of 11 AEDs for which data were available. There is evidence for depressive symptoms being associated with zonisamide, and mood stabilizing effects were shown for lamotrigine and pregabalin. Levetiracetam and eslicarbazepine improved cognitive function. Vigabatrin may increase the risk of developing psychosis. Health-related quality of life (HRQoL) was inversely correlated with seizure frequency. Discontinuation rates were often high, although treatment retention improved with slower dose titration. Adjunctive therapy with newer AEDs has the potential to enhance HRQoL and treatment continuation in patients with partial epilepsy. There remains room for improvement in the management of epilepsy, and better treatments and longer-term trials are needed to meet the special requirements of refractory patients. PMID- 20973783 TI - Contamination in veterinary hospitals. PMID- 20973784 TI - Prevalence of hepatic lesions at post-mortem examination in dogs and association with pancreatitis. AB - OBJECTIVES: To assess the prevalence of canine chronic hepatitis (CH) and other liver diseases in first opinion practice and identify associations with concurrent chronic pancreatitis (CP). METHODS: One large section of left lateral lobe of liver was taken from 200 unselected canine post-mortem examinations from first opinion practices. Histological changes were categorised based on WSAVA criteria. Prevalence of CH and other liver diseases were calculated. Relative risks (RR) for liver histopathology in association with CP and for CH in different breeds were also calculated. RESULTS: The prevalence of CH was 12%. Some breeds had an increased RR of CH, although sample sizes were small. Dogs with CP had an increased RR of reactive hepatitis but no significant association with the other liver diseases. CLINICAL SIGNIFICANCE: CH is common in the first opinion dog population but less common than CP. CP was significantly associated with reactive hepatitis but not CH. Possible breed associations mirrored another recent UK study. Some dogs with CP may be erroneously diagnosed clinically as having CH on the basis of increased serum liver enzymes because of concurrent reactive hepatitis if the diagnosis is not confirmed histologically. PMID- 20973785 TI - Evaluation of surface contamination with staphylococci in a veterinary hospital using a quantitative microbiological method. AB - OBJECTIVES: To evaluate microbial contamination of the environment in a veterinary hospital using standards recommended for human hospitals and to provide a baseline against which further investigations can be compared. METHODS: Surfaces were sampled twice daily for five consecutive days using a contact-based counting method to measure the levels of staphylococci in colony forming units (cfu) per cm2. RESULTS: Current recommendations for human hospitals were applied in this study; all samples with <2.5 cfu/cm2 staphylococci were considered to have passed and those with >=2.5 cfu/cm2 to have failed. Of all the samples, 55.9% failed. The ICU did not have significantly higher failure rates than other areas of the hospital. The floor as a surface was associated with greater than a threefold increase in odds of elevated cfu concentrations relative to the door handle. CLINICAL SIGNIFICANCE: This study provides information on the microbiological cleanliness of a veterinary teaching hospital using techniques and standards adopted by the food industry and recommended for human hospitals. This data can be used as a baseline for other hospitals, to evaluate the effectiveness in improvements in hygiene and cleaning measures and to design effective hospital cleaning protocols and assess ongoing hygiene standards. PMID- 20973786 TI - Static and dynamic ultrasonography for the early diagnosis of canine hip dysplasia. AB - OBJECTIVE: To determine the feasibility of sonographical examination of hip joints in non-sedated puppies and to assess the value of static and dynamic ultrasonography for the early diagnosis of canine hip dysplasia (CHD). METHODS: Prospective study was carried out. Five hundred and sixty-six puppies between the ages of 16 and 49 days underwent sonographical determination of the alpha-angle, joint laxity and distraction value (DV). Sonographical parameters were correlated to conventional radiographic CHD classification in the adult dogs. RESULTS: alpha Angles between 74 degrees and 89 degrees (X+/-sd=82.8 degrees +/-2.31 degrees ) were measured. Despite the feasibility of sonographical hip assessment in puppies, no statistically significant correlation was found between sonographical determinations of the alpha-angle, joint laxity, DV and conventional radiographic hip joint classification at the age of 12 to 24 months. CLINICAL SIGNIFICANCE: Results of our study suggest that static and dynamic ultrasonography of hip joints in puppies between 16 and 49 days of age is technically feasible but cannot be recommended for detecting puppies that will develop CHD between the ages of 12 and 24 months. PMID- 20973787 TI - Propagation of a partial incomplete ossification of the humeral condyle in an American cocker spaniel. AB - A hypoattenuating lesion in the left humeral condyle of an American cocker spaniel consistent with partial incomplete ossification of the humeral condyle was observed on computed tomography. Left forelimb lameness developed over the following three weeks at which time repeat computed tomography examination confirmed propagation of the lesion. Lameness resolved following placement of a transcondylar positional screw, suggesting that lameness was secondary to condylar instability. To the authors' knowledge this is the first report of propagation of an intracondylar lesion in a dog. PMID- 20973788 TI - Hypomyelination in three Weimaraner dogs. AB - Hypomyelination syndrome of the Weimaraner dog is a disease characterised by a reduction or absence of myelin in the axons of the central nervous system (CNS) exclusively. The objective of this study was to analyse the cause of this deficiency of myelin. Tissue samples of the CNS of three Weimaraner dogs with neurological signs were fixed in 10% formalin and embedded in paraffin wax, and histochemical, immunohistochemical and ultrastructural studies were performed. Histochemical staining with haematoxylin and eosin and Kluver-Barrera techniques showed generalised pallor in the peripheral areas of the ventral and lateral funiculi of the spinal cord. Immunohistochemical analysis showed a weak expression of both proteolipid protein (PLP) and myelin basic protein (MBP) and a marked decrease of Olig2(+) cells in the demyelinated areas. The immunohistochemical findings suggested a myelination or remyelination failure because of the smaller population of oligodendrocytes. However, PLP gene mutations may also be the cause of the decrease of PLP expression as described in other species. PMID- 20973789 TI - Proliferative and necrotising otitis in a kitten: first demonstration of T-cell mediated apoptosis. AB - Otitis externa in cats is relatively uncommon. This report describes a case of a rare, visually distinctive, proliferative and necrotising otitis in a three-month old Persian kitten. The cat had proliferative, erythematous and necrotic tissue covering most of the proximal pinnae and vertical ear canals. On histopathological examination, the most striking feature was the existence of scattered apoptotic-appearing keratinocytes within severely hyperplastic epithelium. For the first time, immunohistochemistry was used to show a closed association between CD3(+) T cells and caspase-3 stained keratinocytes, consistent with a keratinocyte apoptosis by epidermal-infiltrating T cells. Treatment was initiated using topical tacrolimus twice daily and an ear cleanser once daily. A marked improvement was observed after 10 days of treatment and the lesions completely resolved over a period of three weeks. The origin of T cells directed against keratinocytes is currently unknown. PMID- 20973790 TI - Transformation of a thymic branchial cyst to a carcinoma with pulmonary metastasis in a dog. AB - A 9-year-old, female neutered Dalmatian was evaluated for acute onset of dyspnoea. Thoracocentesis on presentation yielded 1300 ml sanguineous fluid, while thoracic radiology and ultrasonography showed a mixed-echoic cavitary cranial mediastinal mass, sternal lymph node enlargement and pleural effusion. Surgical exploration of the thorax revealed a multi-lobulated red/brown cranial mediastinal mass and multiple similarly coloured ovoid nodules within several lung lobes. Histopathology revealed thymic branchial cysts with neoplastic transformation and examination of the lung was consistent with metastasis. Despite initially recovering well, acute sepsis and pyothorax resulted in cardiac arrest 8 days postoperatively. This is the first veterinary report of neoplastic transformation of a thymic branchial cyst with pulmonary metastasis. PMID- 20973794 TI - Role of BNIP3 in proliferation and hypoxia-induced autophagy: implications for personalized cancer therapies. AB - Autophagy is a regulated degradation pathway functioning in both cell survival and cell death. Its role in cancer is controversial because autophagy can be either protective or destructive to tumor cells, depending on individual genetic signatures and treatment conditions. Hypoxia is common in solid tumors, correlating with chemoresistance and poor prognosis. We have detected autophagic cell death in hypoxic cancer cells occurring independently of apoptosis through a mechanism involving the hypoxia-inducible protein, Bcl-2/E1B-nineteen kilodalton interacting protein (BNIP3). Loss of BNIP3 was protective against hypoxia-induced autophagy and cell death. Unexpectedly, BNIP3 ablation also caused differential cell cycle progression in vitro and increased cellularity in vivo. Collectively, these results support the emerging theory that autophagy could be effectively targeted as an alternative cell death pathway in hypoxic and/or apoptosis resistant tumors. Furthermore, our data suggest that BNIP3 may be a potential target molecule in this pathway. PMID- 20973793 TI - New cancer targets emerging from studies of the Von Hippel-Lindau tumor suppressor protein. AB - Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) causes the most common form of kidney cancer. pVHL is part of a complex that polyubiquitinates the alpha subunit of the heterodimeric transcription factor HIF. In the presence of oxygen, HIF1alpha is prolyl hydroxylated by EglN1 (also called PHD2); this modification recruits pVHL, which then targets HIF1alpha for proteasomal degradation. In hypoxic or pVHL-defective cells, HIF1alpha accumulates, binds to HIF1beta, and transcriptionally activates genes such as VEGF. VEGF inhibitors and mTOR inhibitors, which indirectly affect HIF, are now approved for the treatment of kidney cancer. EglN1 is a 2-oxoglutarate-dependent dioxygenase; such enzymes can be inhibited with drug-like small molecules and EglN1 inhibitors are currently being tested for the treatment of anemia. EglN2 (PHD1) and EglN3 (PHD3), which are EglN1 paralogs, appear to play HIF-independent roles in cell proliferation and apoptosis, respectively, and are garnering interest as potential cancer targets. A number of JmjC-containing proteins, including RBP2 and PLU-1, are 2-oxoglutarate-dependent dioxygenases that demethylate histones. Preclinical data suggest that inhibition of RBP2 or PLU-1 would suppress tumor growth. PMID- 20973795 TI - Discovery of genomic alterations through coregulation analysis of closely linked genes: a frequent gain in 17q25.3 in prostate cancer. AB - Despite its high incidence as the second most common tumor in males worldwide, primary prostate cancer has been associated with few recurrent chromosomal gains and deletions that are consistent across various studies. Few studies have explored how chromosomal alterations are coupled to abnormal gene expression. Here, we review the major genomic aberrations associated with prostate cancer and describe how detailed transcriptional and computational analyses allowed us to discover a recurrent chromosomal gain in a small region on chromosome 17. Fluorescent in situ hybridization confirmed the presence of a copy number gain in 17q25.3 in tumor-associated preneoplastic lesions of the prostate, 65% of primary tumors, and metastatic samples. These results suggest the involvement of this gain at all steps of prostate cancer progression. PMID- 20973796 TI - MicroRNAs in cancer: personalizing diagnosis and therapy. AB - MicroRNAs (miRNAs) are 19-24nt noncoding RNAs that have been implicated in the pathogenesis of both solid and hematological malignancies. Frequently located in fragile chromosomal regions, miRNAs are essential to key biological functions, such as cellular differentiation, apoptosis, and growth. miRNAs may serve as either tumor suppressors or oncogenes. As a result, they have the potential to serve as both biomarkers and therapeutic agents in cancer. Based on our presentation at the recent Towards Personalized Cancer Medicine conference held in Barcelona, Spain, May 19-21, 2010, we provide an overview of the current knowledge of miRNA deregulation in solid and hematological malignancies and their application as biomarkers of disease. PMID- 20973797 TI - From genomic landscapes to personalized cancer management-is there a roadmap? AB - Despite rapid progress in annotating the human genome, progress in biomarker discovery has been limited, in part, due to the restricted adoption of biomarker analysis in clinical trials. In this short review we present a roadmap to drive progress in the field of personalized cancer management and patient stratification. We suggest that improved understanding of disease biology and drug response in advance of clinical trial design would enable novel biomarkers to be identified and prospectively evaluated during early phase trials; there will also be value in banked material from completed clinical trials to identify and validate biomarkers. Such progress requires standardized tissue collection protocols, novel bioinformatics strategies integrated with functional genomics analysis, and next generation sequencing technologies. We argue that the failure to adopt these methods rapidly into clinical trial design will increase late stage drug attrition, waste trial resources, and risk patient harm within unselected cohorts. PMID- 20973798 TI - Predictive biomarkers in the management of EGFR mutant lung cancer. AB - Activating mutations in the form of deletions in exon 19 (del 19) or the missense mutation L858R in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) predict outcome to use of EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Pooled data from several phase II studies show that gefitinib and erlotinib induce responses in over 70% of NSCLC patients harboring EGFR mutations, with progression-free survival (PFS) ranging from 9 to 13 months. Two studies in Caucasian and Asian patients have confirmed that these subgroups of patients attain PFS up to 14 months. These landmark outcomes have been accompanied by new challenges, primarily the additional role of chemotherapy and the management of tumors with the secondary T790M mutation that confers resistance to EGFR TKIs. Mechanisms of resistance to reversible EGFR TKIs should be further clarified and could be related to modifications in DNA repair. PMID- 20973800 TI - Advancing personalized cancer therapy by detection and characterization of circulating carcinoma cells. AB - Early dissemination, blood circulation, or homing of single tumor cells in bone marrow and other organs is usually undetectable at primary diagnosis, even by high resolution imaging technologies. However, ultrasensitive approaches now enable the detection of "occult" tumor cells. Many researchers are currently focusing on circulating tumor cells (CTC) in peripheral blood, and several publications have described associations of CTC in patients with metastatic cancer and worse prognosis. However, evidence has emerged that the currently used detection methods lack sensitivity or specificity to track all CTC, especially those that have lost characteristic epithelial features. Therefore, new developments in this field are of utmost interest and will be reviewed here. Moreover, molecular CTC analysis will provide insights into the selection of tumor cells and resistance mechanisms in patients undergoing systemic therapies. This information might support assessing individual prognosis, stratifying patients at risk to systemic therapies, and monitoring therapeutic efficacy. PMID- 20973799 TI - Primary trastuzumab resistance: new tricks for an old drug. AB - Trastuzumab is the first Food and Drug Administration (FDA)-approved therapeutic targeting a HER-family receptor tyrosine kinase (HER2/ErbB2/neu). Although trastuzumab is effective in the treatment of HER2-positive breast cancer, a substantial proportion of patients will not respond to trastuzumab-based regimens (primary resistance), and those who do respond will often lose clinical benefits (i.e., secondary resistance). Although multiple mechanisms underlying the development of secondary trastuzumab resistance have been identified, few studies have specifically examined the basis of primary trastuzumab resistance. Here, we review these studies, which together demonstrate that trastuzumab induces phenotypic changes in tumor cells, even when they are not growth inhibited by trastuzumab, including changes in gene expression. These changes have important clinical implications, including the sensitization of malignant cells to other therapeutic drugs. In light of these observations, we propose that the conventional definition of resistance as it pertains to trastuzumab and, perhaps, to other targeted therapeutics, may require revision. The results of these studies will be useful in informing the direction of future basic and clinical research focused on overcoming primary trastuzumab resistance. PMID- 20973801 TI - Breast cancer genomics: normal tissue and cancer markers. AB - Mammography is a powerful screening tool for early detection of breast cancer, but it has limitations in terms of both specificity and sensitivity. Imaging tools such as MRI that complement mammography are too costly to serve as first line screens. Recently, progress has been made on blood markers, particularly microRNAs and proteins. There are new methods for protein marker discovery directly in blood, but they are limited in the number of patients that can be examined. An alternative is to discover markers as transcripts in tissues, followed by development of blood protein tests for those that perform best. To identify genes that are overexpressed in malignancy it is paramount to include normal control tissues from healthy individuals. Here we report the identification of potential breast cancer markers, including some that are overexpressed in aggressive disease. PMID- 20973802 TI - Novel anti-fatty acid synthase compounds with anti-cancer activity in HER2+ breast cancer. AB - Fatty acid synthase (FASN) expression and activity has emerged as a common phenotype in most human carcinomas, including breast cancer, and its expression is tightly linked to HER2 signaling pathways. The development of inhibitors of FASN activity has consequently appeared as a novel antitarget modality for treating cancer. However, the clinical use of FASN inhibitors, such as cerulenin, C75, and epigallocatechin 3-gallate (EGCG), is limited by anorexia and induced body weight loss or by its low in vivo potency and stability. Here, we summarize the design and development of G28UCM, the lead-compound of a novel family of synthetic FASN inhibitors, with both in vitro and in vivo activity in a human breast cancer model of FASN(+) and HER2(+) . PMID- 20973803 TI - Clinical and immunological determinants of severe/refractory asthma (SRA): association with Staphylococcal superantigen-specific IgE antibodies. AB - BACKGROUND: Demographic and immunological determinants of severe refractory asthma (SRA) are not well characterized. Because Staphylococcus aureus enterotoxins with superantigenic activity have been associated with upper and lower airway inflammation, we aimed to evaluate the association of sensitization to Staphylococcal enterotoxins with asthma severity and various asthma phenotypes. METHODS: The study included 109 patients with SRA diagnosed according to the American Thoracic Society Workshop 2000, and 101 patients with nonsevere asthma, followed for at least 12 months. Specific IgE to Staphylococcus enterotoxins and total IgE and eosinophil cationic protein concentrations were measured in serum with immunoassays. FINDINGS: A significant risk for severe asthma was associated with female gender [Odds Ratio (OR) = 2.04], history of wheezing in childhood (OR = 2.47), presence of hypersensitivity to aspirin (OR = 1.96) and with body mass index (OR = 3.08). The mean level of enterotoxin specific IgE was 3-fold higher in patients with severe asthma when compared to patients with nonsevere asthma (P = 0.01). Serum-specific IgE to enterotoxins was significantly associated with low respiratory function parameters (FEV1, FEV1/FVC and MEF 25/75) and increased airway reversibility in response to albuterol. The presence of specific IgE to enterotoxin carried a significant risk for patients to have serum total IgE level above 100 kU/l (OR = 7.84). INTERPRETATION: Specific immunological response to enterotoxins is associated with clinical and immunological parameters of asthma severity, suggesting a role for Staphylococcal enterotoxins in the asthma pathogenesis. PMID- 20973804 TI - Alternatively activated macrophages and impaired phagocytosis of S. aureus in chronic rhinosinusitis. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by biased Th2 inflammation and CRS without nasal polyps (CRSsNP) by a Th1 immune response. Colonization by Staphylococcus aureus is increased in CRSwNP. We aimed to determine macrophage phenotypes in nasal mucosa of CRSwNP and CRSsNP and to examine phagocytosis of S. aureus in these pathologies. METHODS: Macrophage phenotyping was performed by immunohistochemical staining on nasal mucosa sections from 28 patients; in addition flow cytometry analysis was performed. Tissue homogenate protein levels of IFN-gamma, IL-5, IL-6, IL-1beta, TGF-beta, eosinophil cationic protein (ECP) and total IgE were analyzed and correlated with macrophage subtypes. Phagocytosis of S. aureus was analyzed by flow cytometry. Survival of S. aureus in Thp1 cells in the presence of polarizing cytokines was studied in vitro. RESULTS: By immunohistochemical analysis more M2 macrophages were present in CRSwNP than in CRSsNP. This also was positively correlated with increased levels of IL-5, ECP and locally produced IgE and decreased levels of IL 6, IL-1beta and IFN-gamma. FACS analysis of dissociated nasal tissue confirmed the presence of increased numbers of M2 macrophages (CD206(+) HLADR(+) CD14(+) CD11c(+) CD20(-) ) in CRSwNP as compared to controls, while the number of M1 macrophages (CD206(-) HLADR(+) CD14(+) CD11c(int) CD16(-) CD20(-) ) was not different. Phagocytosis of S. aureus by human tissue derived macrophages was reduced in CRSwNP as compared to macrophages from the control inferior turbinates. CONCLUSIONS: Decreased phagocytosis of S. aureus and an M2 activation phenotype in CRSwNP could potentially contribute to persistence of chronic inflammation in CRSwNP. PMID- 20973805 TI - Caudal cruciate ligament damage in dogs with cranial cruciate ligament rupture. AB - OBJECTIVE: To investigate the incidence of caudal cruciate ligament (CaCL) damage in dogs with cranial cruciate ligament rupture (CCLR). STUDY DESIGN: Prospective clinical study. ANIMALS: Dogs (n=24) admitted for surgical stabilization of the stifle after CCLR and 8 healthy dogs with intact cranial cruciate ligament (CCL) and CaCL studied as controls. METHODS: Preoperative radiographs and stifle joint images (arthrotomy, 6; arthroscopy, 18) were collected from dogs with CCLR. Severity of arthritis, synovitis, CCL damage, and CaCL damage were assessed using numerical rating scales. The CaCL was probed to determine whether minor fraying or a full thickness defect in the ligament was present. Data collected from the study population were compared with the control population of dogs. RESULTS: The CaCL was damaged in 21/24 (88%) of dogs with CCLR; 6/24 (25%) had a full thickness defect in the CaCL. Severity of stifle synovitis and severity of damage to the CaCL were positively correlated (P<.05). CONCLUSIONS: The CaCL is damaged in a high percentage of dogs with CCLR. A significant and positive correlation exists between the degree of synovitis present and the extent of CaCL damage. CLINICAL RELEVANCE: In dogs with CCLR, cruciate ligament pathology typically involves both the CCL and CaCL. As the severity of synovitis and the extent of CaCL damage are related, this observation supports the hypothesis that stifle synovitis may contribute to CCL and CaCL degeneration and subsequent damage. PMID- 20973806 TI - Surface display of respiratory syncytial virus glycoproteins in Lactococcus lactis NZ9000. AB - AIMS: A system for displaying heterologous respiratory syncytial virus (RSV) glycoproteins on the surface of Lactococcus lactis NZ9000 was developed. METHODS AND RESULTS: Fusion of the USP45 signal peptide and the cA (C terminus of the peptidoglycan-binding) domains of AcmA, a major autolysin from L. lactis, to the N- and C-terminal of the target proteins, respectively, was carried out. The target protein was the major immunogenic domain of either the F (40.17-kDa) or G (11.49-kDa) glycoprotein domains of the RSV. Whole-cell ELISA readings obtained after 24 h of induction showed an increase in protein expression as the cA domain repeats increased, for the G glycoprotein of RSV. On the other hand, the F glycoprotein indicated decreasing expression levels as the number of cA domain repeats increased. The difference in the expression levels of the F and G domains may be attributed to the different sizes of the antigenic domains. CONCLUSIONS: The size and properties of the target proteins are vital in determining the amount of antigenic domains being displayed on the surface of live cells. SIGNIFICANCE AND IMPACT OF THE STUDY: The system demonstrated here can aid in the utilization of the generally regarded as safe (GRAS) bacteria L. lactis, as a vaccine delivery vehicle to surface display the antigenic proteins of RSV. PMID- 20973807 TI - Microbiological quality of raw milk produced in Estonia. AB - AIMS: The microbial quality of farm bulk-tank raw milk produced in Estonia during years 2004-2007 was investigated. METHODS AND RESULTS: Bulk-tank milk samples were analysed for lactic acid bacteria count (LABC), psychrotrophic bacteria count (PBC), aerobic spore-forming bacteria count (ASFBC), total bacterial counts using BactoScan and somatic cell count (SCC) using Fossomatic. Randomly selected psychrotrophic isolates were subjected to 16S-23S PCR-ribotyping. LABC remained below 10(4) CFU ml(-1) in most samples, while psychrotrophic micro-organisms dominated in 60% of farms. PBC ranged from 4.2 * 10(2) to 6.4 * 10(4) CFU ml(-1), and ASFBC varied from 5 to 836 CFU ml(-1). CONCLUSIONS: In general, the microbiological quality of the farm bulk-tank milk was good - more than 91% of samples contained <50,000 CFU ml(-1), and SCC in the majority of samples did not exceed the internationally recommended limits. Genus Pseudomonas spp. was the dominating spoilage flora with Pseudomonas fluorescens as the prevailing species. SIGNIFICANCE AND IMPACT OF THE STUDY: Specific bacterial groups (LABC, PBC and ASFBC), not analysed routinely by dairies, were determined in bulk-tank raw milk of numerous dairy farms during 4-year period. Based on the survey, dairy plants can better control their supply chains and select farms (milk) for the production of specific products, i.e. milk with low PBC and high LABC for cheesemaking. PMID- 20973808 TI - Diffuse lower limb lipoatrophy. AB - Lipoatrophic panniculitis is the term used to describe those panniculitides in which atrophy of the subcutaneous fat is the main residual lesion. They can be classified as primary or secondary. Primary lipoatrophic panniculitis is idiopathic, whereas secondary lipoatrophic panniculitides include those because of infection, malignancy, pancreatic disorders or connective tissue diseases. Usually, these entities are characterized by the appearance of tender, erythematous nodules or plaques that resolve leaving one or several localized areas with loss of subcutaneous fat. We report a 76-year-old female who developed diffuse and symmetric lipoatrophy of lower limbs after an extensive inflammatory process affecting both extremities from thighs to ankles. Histopathologic assessment revealed a lobular panniculitis with a lymphohistiocytic infiltrate, foamy macrophages and lipophagic granuloma formation. The most striking feature in our patient was the clinical presentation as a symmetrical diffuse inflammatory process resulting in lipoatrophy of the lower limbs. PMID- 20973809 TI - Atypical fibroxanthoma in an HIV-infected individual. AB - Atypical fibroxanthoma is a neoplasm primarily occurring in older patients, with a predilection for photo-damaged skin of the head and neck. Compared to the immunocompetent population, patients infected with HIV have a higher risk of certain malignancies including non-Hodgkin lymphoma, Kaposi's sarcoma and skin cancer. Although atypical fibroxanthoma has been reported in another immunocompromised group, namely organ transplant recipients, there are no previous reports in the published literature of this tumour arising in patients infected with HIV. We report a case of an atypical fibroxanthoma arising in a 71- year old HIV-positive male. PMID- 20973810 TI - Home care nurses' decisions about the need for and amount of service at the end of life. AB - AIMS: We explore home care nurse decision-making about the need for and amount of service by clients and families at the end of life. We identify factors nurses refer to when describing these decisions, situated within contextual features of nursing practice. BACKGROUND: Home care nurses are often responsible for decisions which have an impact on the access of clients and families to services at the end of life. Understanding how these decisions, are made, factors that are considered, and contextual influences is critical for improving access and enhancing care. METHODS: Qualitative data were collected between 2006 and 2008 from two samples of home care nurses: the first group (n = 29) recorded narrative descriptions of decisions made during visits to families. The second group (n = 27) completed in-person interviews focusing on access to care and their interactions with clients and families. Data were analysed with thematic coding and constant comparison. FINDINGS: Participants described assessing client and family needs and capacity. These assessments, at times integrated with considerations about relationships with clients and families, inform predictive judgements about future visits; these judgments are integrated with workload and home health resource considerations. In describing decisions, participants referred to concepts such as expertise, practice ideals and approaches to care. CONCLUSION: Findings highlight the role of considerations of family caregiver capacity, the influence of relationships and the importance of the context of practice, as part of a complete understanding of the complexity of access to care at the end of life. PMID- 20973811 TI - Effects of a home-based walking program on perceived symptom and mood status in postoperative breast cancer women receiving adjuvant chemotherapy. AB - AIM: This paper is a report of a study analysing the effect of a home-based walking exercise program on symptoms and mood distress among breast cancer women receiving chemotherapy postoperatively. BACKGROUND: Treatment-related symptoms, mood distress and decline in physical activity have been identified as major complaints among cancer patients. Studies on the efficacy of home-based walking exercise for symptoms and mood did not fully describe the exercise prescriptions that could be safe and beneficial for women with breast cancer, especially these receiving adjuvant chemotherapy. METHOD: This is a prospective, randomized clinical trial. In 2008-2009, participants were recruited from the oncology outpatient clinic of a medical center in Taiwan, and were assigned to either the exercise group (n=19) or the control group (n=21). Women in the exercise group participated in a moderate-intensity home-based walking program for 12 weeks during their chemotherapy treatments. Symptoms, mood status and physical activity level were measured at baseline, 6- and 12-week follow-up. Data were analysed by two-way repeated-measures analysis of variance. RESULTS: Women in the exercise group reported significantly lower symptom severity scores and mood disturbance compared with those in the control group throughout the study period. CONCLUSION: Regular moderate-intensity exercise can play an important role in improving treatment-related symptoms and mood in women with breast cancer. A home-based walking exercise program can be easily incorporated into care for women with breast cancer undergoing chemotherapy. PMID- 20973817 TI - Parental perception of overweight and underweight in children and adolescents. AB - AIMS: To compare the parental perception of overweight and underweight in their children to objective criteria, based on body mass index (BMI), waist circumference and triceps skinfold thickness, and to explore the effects of potential determinants. METHODS: Logistic regression of anthropometric measurements, socio-demographic characteristics and self-reported parental height and weight on the parental perception of their child's weight status in 3770 children aged 2-19. RESULTS: Seventy per cent of overweight/obese children and 40.8% of underweight children were perceived having normal weight by parents. In 2- to 5-year-old overweight children, 91.2% were considered to have normal weight. For a given BMI, primary school age children, adolescents and girls had a higher probability to be assigned as overweight, whereas adolescents and girls had a lower probability to be assigned as underweight. Overweight parents more readily assigned their children as underweight, but there was no effect of parental educational level or parental underweight. CONCLUSION: Parental ability to recognize overweight or underweight in their offspring was generally poor. The findings emphasize the need for objective criteria based on physical measurements in the routine follow up of children, as parental ability to recognize weight problems in their children is nonreliable. PMID- 20973818 TI - CRP as a predictive of neonatal sepsis and its role in differentiating the aetiologies. PMID- 20973819 TI - Empyema in a rural hospital in Zimbabwe in the 1980s. PMID- 20973820 TI - Implementation of the transradial approach for coronary procedures is not associated with an elevated complication rate and elevated radiation patient exposure. AB - BACKGROUND: The transradial approach for coronary procedures is associated with a low complication rate, but specific training is considered mandatory. METHODS: Procedural characteristics (contrast dye: CD; fluoroscopy time: FT, patient radiation dose: RD) and local complication rates were prospectively assessed in 784 consecutive patients who underwent transradial coronary procedures. The study was divided into an implementation (2008-IP) and an evaluation period (2009-EP). Transradial (N = 624) and transfemoral (N = 842) procedural characteristics were compared in the EP. RESULTS: The amount of CD (mL) of transradial coronary angiography was similar between IP (75 [IQR 60-100]) and EP (70 [55-100]; P = 0.630). In contrast, FT (min) of transradial coronary angiography could be reduced from IP (4.4 [3.2-6.8]) to EP (4.1 [2.7-6.5]; P = 0.036), whereas RD (MUGy * qcm) was similar (IP: 1623 [1042-3026]); EP (1576 [944-2530]; P = 0.149). Safety data showed a low complication rate: 0.2% access failure, 0.1% dissection, 0.7% vessel closure. Transfemoral procedures were followed by significantly more procedure- related transfusions (1.3% vs. 0%; P = 0.003). The comparison between transfemoral and transradial procedures demonstrated prolonged FT for transradial procedures (transfemoral 2.9 [1.7-5.5]; transradial 4.1 [2.7-6.5]; P = 0.002), whereas CD was similar (transfemoral 70 [55-100]; transradial 70 [55-100]; P = 0.248). The prolonged FT was restricted to coronary angiography but did not differ for PCI (transfemoral 9.7 [5.8-18.1]; transradial 8.9 [5.3-16.5]; P = 0.433). CONCLUSION: A transradial program can be implemented with safety; therefore, the transradial approach should be preferred in suitable patients. Since spasm occurrence was the major determinant of procedural failure, further effort is need to develop better strategies for spasm prevention. PMID- 20973821 TI - Dilation of the septal collateral artery and subsequent cardiac tamponade during retrograde percutaneous coronary intervention using a microcatheter for chronic total occlusion. AB - Microcatheters are often used for percutaneous coronary intervention via the retrograde approach through a collateral channel for chronic total occlusion lesions. Recently, we encountered an alarming case in which a septal collateral artery was dilated after the removal of a microcatheter. This dilated septal artery ruptured spontaneously and resulted in a cardiac tamponade, which was successfully treated by pericardiocentesis and coil embolization. PMID- 20973822 TI - Cyanoacrylate for septal ablation in hypertrophic cardiomyopathy. AB - OBJECTIVE: Alcohol septal ablation (ASA) has been shown to be an effective treatment in patients with hypertrophic obstructive cardiomyopathy (HOCM) who are refractory to medical treatment. We describe an alternative approach for septal ablation with glue (cyanoacrylate), which is particularly useful in patients with the collateral formation to the right coronary artery in whom ASA is contraindicated. METHODS: In our method left coronary ostium was cannulated with 6-8F guiding catheter. Septal branch was cannulated with a 4F catheter and a microcatheter then cyanoacrylate mixture was instilled into the septal artery. Immediate polymerization prevents the leak into the left anterior descending coronary artery, and also into the right coronary artery (RCA) via septal collaterals. RESULTS: Glue septal ablation (GSA) was performed in 18 patients (6 patients had collateral branches to RCA). Immediately after the procedure peak left ventricular outflow (LVOT) gradient reduced significantly both in cardiac catheterization (65.0 +/- 13.8 vs. 14.2 +/- 5.7 mmHg, P < 0.001) and Doppler echocardiographic measurements (75.8 +/- 19.9 vs. 18.0 +/- 9.1 mmHg, P < 0.001). LVOT tract gradient reduction persisted after 6 months follow-up. Septal wall thickness (20.2 +/- 3.7 mm vs. 16.5 +/- 3.2 mm, P = 0.003) reduced and NYHA functional class (3.1 +/- 0.4 vs. 2.2 +/- 0.3, P < 0.001) improved. There was no significant complication during the procedure and within 6 months follow-up period. CONCLUSIONS: GSA seems to be an efficient and safe approach to HOCM, especially in patients with the collateral formation. Further experience is needed in order to assess the long-term efficacy and safety of this technique. PMID- 20973823 TI - Recent epidemiology of Clostridium difficile infection during hematopoietic stem cell transplantation. AB - Given the limited information on Clostridium difficile infection (CDI) during hematopoietic stem cell transplantation (HSCT), we examined the recent epidemiology of CDI in HSCT recipients at our institution. During the two-yr retrospective study period (2005-2006), 361 transplants were performed: 60% allogeneic and 40% autologous. Among all hospitalized patients in a non-outbreak setting, CDI rates in HSCT recipients were ninefold higher than those in general patients and 1.4-fold higher than those in patients with cancer (24.0 vs. 2.6 vs. 16.8/10,000 patient-days respectively). Sixty-two episodes of CDI occurred in 51 (14%) HSCT recipients: 39 (18%) allogeneic vs. 12 (8%) autologous (p = 0.01). Almost half of CDI episodes occurred within 30 d post-HSCT and 22% before HSCT. Clostridium difficile toxin assay was initially positive in 28% of the first, 31% of the second and 27% of the third stool samples tested. All but one patient responded to therapy with metronidazole or vancomycin. Severe CDI occurred in one patient and recurrent CDI in two patients. CDI is common during HSCT especially in allogeneic transplants during the peri-HSCT period. Prospective studies to better define the epidemiology and identify unique risk factors for CDI and more accurate tests to confirm the diagnosis in this population are needed. PMID- 20973824 TI - Kidney from uncontrolled donors after cardiac death with one hour warm ischemic time: resuscitation by extracorporal normothermic abdominal perfusion "in situ" by leukocytes-free oxygenated blood. AB - The availability of brain death donors is restricted by many factors. Use of uncontrolled donors after cardiac death could be a promising perspective, but the limiting factor in uncontrolled donation after cardiac death is the warm ischemic time. The purpose of our work was to develop an in situ kidney preservation protocol with application of the extracorporal normothermic abdominal perfusion for organ resuscitation in uncontrolled donors after cardiac death. The main attention was paid to the elimination of leukocytes as the key damaging factor from modified donor oxygenated blood circulating in the device. In 2009, we had 10 uncontrolled donors with warm ischemic time from 45 to 92 min; a normothermic extracorporal perfusion device was applied, providing preservation and restoration of kidney after ischemic damage. In 6 out of 20 kidney recipients, graft function was recovered immediately. All kidney grafts are functioning, and to the end of the third month, the average creatinine was 118.5 +/- 19.9 mM. Treatment of ischemically damaged kidney by normothermic extracorporal perfusion with leukocyte depletion before procurement seems to be a challenging protocol for expanding donors' pool and demands further study. PMID- 20973825 TI - The long-term outcome of treated sensitized patients who undergo heart transplantation. AB - BACKGROUND: Sensitized patients prior to heart transplantation are reportedly at risk for hyperacute rejection and for poor outcome after heart transplantation. It is not known whether the reduction of circulating antibodies pre-transplant alters post-transplant outcome. METHODS AND RESULTS: Between July 1993 and July 2003, we reviewed 523 heart transplant patients of which 95 had pre-transplant panel reactive antibody (PRAs) >10%; 21/95 were treated pre-transplant for circulating antibodies. These 21 patients had PRAs > 10% (majority 50-100%) and were treated with combination therapy including plasmapheresis, intravenous gamma globulin and rituximab to reduce antibody counts. The 74 untreated patients with PRAs > 10% (untreated sensitized group) and those patients with PRAs < 10% (control group) were used for comparison. Routine post-transplant immunosuppression included triple-drug therapy. After desensitization therapy, circulating antibody levels pre-transplant decreased from a mean of 70.5 to 30.2%, which resulted in a negative prospective donor-specific crossmatch and successful heart transplantation. Compared to the untreated sensitized group and the control group, the treated sensitized group had similar five-yr survival (81.1% and 75.7% vs. 71.4%, respectively, p = 0.523) and freedom from cardiac allograft vasculopathy (74.3% and 72.7% vs. 76.2%, respectively, p = 0.850). CONCLUSION: Treatment of sensitized patients pre-transplant appears to result in acceptable long-term outcome after heart transplantation. PMID- 20973826 TI - Surgical injuries of pancreatic allografts during procurement. AB - Quality of most procured pancreata is considered acceptable or good by surgeons, but remains difficult to ascertain. Little is known on how often pancreata are refused for transplantation during back-table inspection. Purpose of this study was to determine the frequency and type of problems responsible for refusal during back-table inspection and to identify possible risk factors. All 134 pancreata accepted and procured for whole-organ transplantation and transported to the Leiden University Medical Center in the period February 2002 until May 2008 were included. These were retrospectively analyzed on donor characteristics, procurement characteristics, and (non-)critical problems. A total of 111 (82.8%) pancreata were transplanted while 23 (17.2%) were refused for transplantation during back-table inspection, regardless of procurement region (chi(2) = 0.16 p = 0.93). Fourteen pancreata (13.4%) were refused solely because of surgical injuries. In refused pancreata, on average 2.7 critical problems per pancreas were found and 0.6 non-critical problems (vs. 0.3 in transplanted pancreata, t = 1.83 p = 0.08). Chances of refusal increased in pancreata from older donors (odds ratio 1.08 [1.02-1.14]) procured in centers not performing pancreas transplantations (odds ratio 7.95 [2.43-25.97]). We conclude that pancreatic allografts are frequently refused during back-table inspection, partly because of the surgical injuries suggesting that quality of procurement may be improved. PMID- 20973828 TI - Changes in motor unit characteristics after eccentric elbow flexor exercise. AB - Morphological evidence suggests that fast-twitch fibers are prone to disruption of their membrane structures by eccentric exercise. However, it is unclear how this is reflected in the discharge rate and action potential propagation of individual motor units, especially at high contraction levels. High-density surface electromyograms were recorded from biceps brachii muscle and decomposed to individual motor unit action potentials at isometric contraction levels between 10% and 75% of maximal voluntary contraction (MVC) before intermittent maximal elbow flexor eccentric exercise, and two hours (2H), two days (2D) and four days (4D) post-exercise. Maximal voluntary force decreased by 21.3+/-5.6% 2H and by 12.6+/-11.1% 2D post-exercise. Motor unit discharge rate increased and mean muscle fiber conduction velocity decreased, at the highest isometric contraction levels only (50% and 75% of MVC) at 2H post-exercise. These results indicate that eccentric exercise can disturb the function of motor units active at high contraction levels in the early stages after exercise, which seems to be compensated by the central nervous system with an increase in neural drive during submaximal isometric contractions. PMID- 20973829 TI - Previous-day hypohydration impairs skill performance in elite female field hockey players. AB - The purpose of this study was to determine the effects of 2% hypohydration on skill performance in elite female field hockey players following intermittent exercise in the heat. Eight elite female field hockey players performed 50 min of a field hockey-specific intermittent treadmill running protocol (FHITP) in hot environmental conditions (33 degrees C, 60% relative humidity) in different hydration states: euhydrated (EUH) and hypohydrated by 2% body mass (HYPO). Hydration status was manipulated via a period (121+/-10 min) of passive hyperthermia (40 degrees C, 75% relative humidity) and controlled fluid intake 1 day preceding testing. Ad libitum fluid intake was permitted throughout both trials. Field hockey skill tests were performed pre- and post-FHITP. Skill performance time increased (P=0.029) in the HYPO trial compared with the EUH trial, which may be attributed to an increase in penalty time (P=0.024). Decision making time increased (P=0.008) in the HYPO trial and was significantly impaired compared with EUH (P=0.016) pre-FHITP. Ad libitum drinking appeared to be sufficient to maintain decision-making performance as no interaction effects were evident post-FHITP. Players who commence match-play in a state of hypohydration may be susceptible to decrements in skill and decision-making performance. PMID- 20973827 TI - Submandibular gland and caries susceptibility in the obese Zucker rat. AB - BACKGROUND: Obesity is a prevalent disorder characterized as marked insulin resistance and low grade inflammation. We tested the hypothesis that obesity upregulates inflammatory markers in the submandibular gland in association with derangements of its architecture and pre-disposition to caries in obese Zucker rats (OZR). We also examined the potential impact of chromium picolinate (Cr(Pic)3), a nutritional supplement suggested to improve glycemic control, on the aforementioned parameters. DESIGN: Male OZR were treated with diets lacking and containing 5 or 10 mg/kg chromium (as Cr(Pic)3) from 6 weeks to about 6 months of age; lean Zucker rats (LZR) served as controls. Thereafter, glycemic status, salivary tissue architecture, and the levels of several inflammatory markers were determined in association with caries susceptibility. RESULTS: OZR showed reduced insulin sensitivity, increased ratio of phospho-nuclear factor kappa B (NF-kappaB) to total NF-kappaB, and increased intercellular adhesion molecule-1 level but similar histological features compared to LZR. Importantly, compared to LZR, OZR displayed rampant caries and a tendency for reduced dentin mineral density. Treatment of OZR with Cr(Pic)3 attenuated upregulation of these proinflammatory indicators in association with reduced severity of caries without improving insulin sensitivity. CONCLUSIONS: Obesity promotes proinflammatory changes within the submandibular gland, without affecting glandular architecture, in association with rampant caries; Cr(Pic)3 treatment provided some protective effects. PMID- 20973830 TI - Proteomic analysis of rat skeletal muscle submitted to one bout of incremental exercise. AB - Exercise can alter gene transcriptional and protein translational rates leading to changes in protein abundance toward adaptation to exercise. We investigated the alterations in protein abundance in skeletal muscle after one bout of an exhaustive exercise through proteomic analysis. Gastrocnemius muscles were sampled from non-exercised control rats and from rats exercised on a treadmill with incremental increases in speed until exhaustion (approximately 30 min). Rats were sacrificed 3 and 24 h after exercise cessation. Two-dimensional gel electrophoresis was performed and spots with a significant alteration in relative volume were identified by mass spectrometry. Six spots presented statistically significant altered abundances after exercise. The spots identified as the metabolic related proteins triosephosphate isomerase 1, glyceraldehyde-3 phosphate dehydrogenase, the beta subunit of pyruvate dehydrogenase E(1) and carnitine palmitoyltransferase 2 were all more abundant after exercise. One spot identified as heat shock cognate 70 was also more abundant after exercise. One spot demonstrated a decreased abundance after exercise and was identified as alpha-actin. These results suggest that a single session of exhaustive incremental exercise in untrained muscle can alter thin filaments synthesis/degradation rate and enhance cytosolic and mitochondrial proteins synthesis. The identified proteins may be important to a general preconditioning of skeletal muscle for subsequent exercise sessions. PMID- 20973831 TI - Doping and supplementation: the attitudes of talented young athletes. AB - There is evidence of a small but significant proportion of adolescents engaging in doping practices. Young athletes face very specific pressures to achieve results as they strive for a career at an elite level. This study used an anonymized questionnaire to survey 403 (12-21 years old) talented young athletes' attitudes toward performance-enhancing substances and supplements. Two-thirds of the sample comprised males. Athletes were generally against the use of doping substances to enhance sporting performance. Within this generally unfavorable view, males tended to express a more permissive attitude toward performance enhancing methods than females. Those convinced of the necessity of supplementation for sporting success were also more likely to express permissive attitudes. When asked whether they would take a "magic" drug that, while undetectable, would significantly enhance performance, the overwhelming majority of athletes said "no," but many thought others would take the substance. Interestingly, there was a significant association between the projected use of the hypothetical drug by competitors and the individual respondent's willingness to take the hypothetically "magic" substance. The study offers an insight into young athletes' attitudes toward specific forms of performance enhancement, and the strength of their beliefs in the face of a tempting hypothetical scenario. PMID- 20973832 TI - History of leukemia-lymphoma cell lines. AB - We outline the near 50-year history of leukemia-lymphoma (LL) cell lines - a key model system in biomedicine. Due to the detailed documentation of their oncogenomic and transcriptional alterations via recent advances in molecular medicine, LL cell lines may be fitted to parent tumors with a degree of precision unattainable in other cancers. We have surveyed the corpus of published LL cell lines and found 637 examples that meet minimum standards of authentication and characterization. Alarmingly, the rate of establishment of new LL cell lines has plummeted over the last decade. Although the main hematopoietic developmental cell types are represented by cell lines, some LL categories stubbornly resist establishment in vitro. The advent of engineering techniques for immortalizing primary human cells that maintain differentiation means the time is ripe for renewed search for in vitro models from un(der)represented hematologic entities. Given their manifold applications in biomedicine, there is little doubt that LL derived cell lines will continue to play a vital part well into the next half century as well. PMID- 20973833 TI - Bone morphogenetic protein 2 may be a good predictor of success in oocyte fertilization during assisted reproductive technology. AB - The aim of this study was to determine whether the bone-morphogenetic proreins-2 (BMP-2) or -7 (BMP-7) levels in follicular fluid (FF) are associated with success in oocyte fertilization during assisted reproductive technology (ART) treatment. Twenty-four cycles in 24 patients who underwent oocyte retrieval in Sugiyama clinic were included in this retrospective study. The patients were divided into two groups according to the success or failure of fertilization. FF samples were obtained from a single follicle in each patient, and the levels of BMP-2, BMP-7, Anti-Mullerian hormone (AMH), estradiol and progesterone from FF were measured, and evaluated in relation to the ART outcomes. The BMP-2 levels correlated positively with the AMH levels in FF (r(2) = 0.4928), but there was no statistically significant difference between BMP-7 and AMH levels. The BMP-2 and BMP-7 levels had no relation with either progesterone or estradiol levels, but BMP-2 levels in the fertilized group were significantly higher than those in the unfertilized group (P < 0.05). The BMP-2 levels in FF positively correlated with the AMH levels in FF, and those in the fertilized group were significantly higher than in the unfertilized group. Therefore, the BMP-2 levels in FF could be a predictive marker for fertilization. PMID- 20973834 TI - Derivation, characterization and differentiation of a new human embryonic stem cell line from a Chinese hatched blastocyst assisted by a non-contact laser system. AB - Currently worldwide attention has focused on the derivation of human embryonic stem cells (hESCs) for future therapeutic medicine. However, the majority of existing hESCs are directly or indirectly exposed to non-human materials during their derivation and/or propagation, which greatly restrict their therapeutic potential. Besides the efforts to improve culture systems, the derivation procedure, especially blastocyst manipulation, needs to be optimized. We adopted a non-contact laser-assisted hatching system in combination with sequential culture process to obtain hatched blastocysts as materials for hESC derivation, and derived a hESC line ZJUhES-1 of a Chinese population without exposure to any non-human materials during blastocyst manipulation. ZJUhES-1 satisfies the criteria of pluripotent hESCs: typically morphological characteristics; the expression of alkaline phosphatase, human telomerase reverse transcriptase and multiple hESC-specific markers including SSEA-3, SSEA-4, TRA-1-60, TRA-1-81, OCT 4, Nanog, Rex-1, Sox-2, UTF-1, Connexins 43 and 45, TERF-1 and TERF-2, Glut-1, BCRP-1/ABCG-2, GDF3, LIN28, FGF4, Thy-1, Cripto1/TDGF1, AC133 as well as SMAD1/2/3/5; extended proliferative capacity; maintenance of a stable male karyotype after long-term cultivation; and robust multiple-lineage developmental potentials both in vivo and in vitro. Moreover, ZJUhES-1 has distinct identity revealed from DNA fingerprinting. Our xeno-free blastocyst manipulation procedure may promote the progression toward clinical-grade hESC derivation. PMID- 20973835 TI - Anticancer drug sensitivity testing using an oxygen electrode apparatus. AB - Conventional anticancer drug sensitivity testing methods, such as succinate dehydrogenase inhibition (SDI), histoculture drug-response assay (HDRA) and collagen gel droplet embedded culture drug sensitivity testing (CD-DST), all require primary culturing and are extremely complex tests that require considerable time for analysis. A major drawback of these methods is that if culturing is not performed properly, ambiguous results are produced. Therefore, we developed an oxygen electrode apparatus that uses cellular metabolism as an indicator of anticancer drug sensitivity and investigated its usefulness in 29 breast cancer patients with the following histopathological classifications: papillotubular carcinoma (n= 15); solid tubular carcinoma (n= 6); and scirrhous carcinoma (n= 8). Comparison of anticancer drug sensitivity testing results obtained using the conventional HDRA method and those obtained using the oxygen electrode apparatus showed significant reproducibility between the two methods. In addition, similar anticancer drug sensitivity testing results using the oxygen electrode apparatus were obtained for in vivo testing of nude mice transplanted with established cancer cell lines. These findings suggest that the oxygen electrode apparatus is a useful procedure in anticancer drug sensitivity testing that provides better reproducibility and that is faster, more convenient, and less expensive than other testing methods. PMID- 20973836 TI - Establishment of induced pluripotent stem cells from human neonatal tissues. AB - Following the success in establishing human induced pluripotent stem (iPS) cells, research into various applications of the cells derived from human iPS cells has begun in earnest. The use of iPS cell-derived cells in clinical therapies is one of the most exciting of the possible applications. However, the risk of tumorigenicity is the biggest potential obstacle to use iPS cell derivatives in the clinic. It should be noted that the human cells used to generate iPS cell lines may have acquired genetic mutations and these might influence the tumorigenicity of the cells. In particular, the cells of older people have a higher risk of genetic mutations than those of younger people. Here, we show that iPS cells could be derived from short-term cultures of neonatal tissues. The established human iPS cells expressed various markers of undifferentiated cells and formed teratoma in immunodeficient mice. The human iPS cells derived from neonatal tissues may represent a clinical material possessing less tumorigenicity. PMID- 20973837 TI - Eight case reports on sex-hormone profiles in sexually mature male Down syndrome. AB - Down syndrome (DS) is a congenital disorder usually caused by an extra copy of chromosome 21. Although the number of postpubertal patients with DS is increasing, only limited information is available on their gonadal and sexual development. The aim of this case report was to examine sex-hormone profiles in sexually mature male patients with DS. Eight postpubertal male patients with trisomy 21 (mean age 28 years, range 15-54 years) participated in this study. The serum level of luteinizing hormone and follicle-stimulating hormone was significantly elevated and testosterone was slightly decreased. The testicular volume was smaller in all eight cases than that observed in healthy male subjects. The elevated luteinizing hormone and follicle-stimulating hormone levels, the lower testosterone levels and a smaller testicular volume observed in all eight cases suggest a significant degree of germinal cell hypoplasia in mature male patients with DS. PMID- 20973838 TI - Stress controversies: post-traumatic stress disorder, hippocampal volume, gastroduodenal ulceration*. AB - Stress in mammals triggers a neuroendocrine response mediated by the hypothalamic pituitary-adrenal axis and the autonomic nervous system. Increased activity of these two systems induces behavioural, cardiovascular, endocrine and metabolic cascades that enable the individual to fight or flee and cope with the stress. Our understanding of stress and stress-response mechanisms is generally robust. Here, however, we review three themes that remain controversial and perhaps deserve further scrutiny and investigation before they achieve canonical status. The themes are, first, hypocortisolaemia in post-traumatic stress disorder (PTSD). A reduction rather than a stress-induced increase in adrenal glucocorticoid levels, as seen in major depressive disorder (MDD), is puzzling and furthermore is not a consistent feature of PTSD. Overall, studies on PTSD show that glucocorticoid levels may be normal or higher or lower than normal. The second theme concerns the reduction in volume of the hippocampus in MDD attributed to the neurotoxicity of hypercortisolaemia. Again, as for hypocortisolaemia in PTSD, reduced hippocampal volume in MDD has been found in some but not all studies. Third, the discovery of a causal association between Helicobacter pylori and peptic ulcers apparently brought to an end the long-held view that peptic ulceration was caused predominantly by stress. However, recent studies suggest that stress can cause peptic ulceration in the absence of H. pylori. Predictably, the aetiological pendulum of gastric and duodenal ulceration has swung from 'all stress' to 'all bacteria' followed by a sober realisation that both factors may play a role. This raises the question as to whether stress and H. pylori interact, and if so how? All three controversies are of clinical significance, pose fundamental questions about stress mechanisms and offer important areas for future research. PMID- 20973839 TI - Moving from efficacy trials to practical implementation of Internet-based BIs. Introduction to the special issue. PMID- 20973840 TI - Breaking new ground in the study and practice of alcohol brief interventions. AB - This article amplifies the decision to subtitle the INEBRIA2009 Conference 'Breaking New Ground'. The effectiveness of screening and brief intervention (SBI) for hazardous and harmful drinking is now well-established for primary health care and is promising for other medical settings. In addition, significant advances in the implementation of SBI are being made in various parts of the world. But, because of the need to establish efficacy and effectiveness, and perhaps too because of a preoccupation with meta-analysis of existing research findings, progress in other aspects of the theory and practice of SBI has been slower than ideal. There may also be a risk of complacency in the SBI field of study. For these reasons and others, the Conference Organizing Committee decided to focus the conference and invite presentations on a number of specific topics in the field of alcohol SBI and these are listed here followed by a discussion of other areas in which new ground needs to be broken.[Heather N. Breaking new ground in the study and practice of alcohol brief interventions. PMID- 20973841 TI - NICE work if you can get it: Development of national guidance incorporating screening and brief intervention to prevent hazardous and harmful drinking in England. AB - This paper describes the development of the first set of national guidance focused on the prevention of alcohol problems in England. These guidelines were produced by the National Institute for Health and Clinical Excellence (NICE) working with a multidisciplinary program development group of scientists, practitioners and lay members. In this work, screening and brief alcohol interventions represent a key element of a comprehensive public health strategy to prevent alcohol-related risk and harm across the population. The first controlled trials of brief alcohol intervention were published in the mid to late 1980's and there are now around 60 published trials in this field. After 25 years of accumulated evidence in this field, brief alcohol interventions have yet to make a significant impact on routine clinical practice. While it is imperative to have good science to make the case for brief intervention delivery, this work is in vain if practitioners are unwilling or unable to use these interventions with their patients. Evidence from the alcohol field and other clinical areas indicates that national prioritisation of brief alcohol intervention activity, by a body, such as NICE, is likely to be a key driver of implementation by practitioners. This paper summarises a suite of complementary system-level and practice recommendations, which were published by NICE in June 2010, and considers their likely impact on screening and brief alcohol in England.[Kaner E. NICE work if you can get it: Development of national guidance incorporating screening and brief intervention to prevent hazardous and harmful drinking in England. PMID- 20973842 TI - Community pharmacy service users' views and perceptions of alcohol screening and brief intervention. AB - INTRODUCTION AND AIMS: Community pharmacists have the potential to deliver alcohol screening and brief interventions (SBI) to pharmacy users. However, little is known if SBI would be utilised and views of people who might use the service. Therefore, the aim was to investigate potential barriers and enablers of pharmacy SBI. DESIGN AND METHODS: Purposive sampling was used to select four pharmacies within the London borough of Westminster, UK. Semistructured interview schedule recorded participants' views of pharmacy SBI. The Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) was incorporated to record views of high and low-risk drinkers. Categorical data were analysed and content analysis undertaken. RESULTS: Of the 237 participants (149 female) approached 102 (43%) agreed to be interviewed (63 female). Of these 98 completed AUDIT-C, with 51 (52%) identified as risky drinkers. Risky drinkers were significantly identified among the younger age group (chi(2) =11.03, P=0.004), professional occupations (chi(2) =10.41, P=0.015), with higher qualifications (chi(2)=10.46, P=0.033), were least frequent visitors to a pharmacy (chi(2) =11.58, P=0.021) and more frequently identified in multiple pharmacy establishments than independents (chi(2) =8.52, P=0.004). Most were willing to discuss drinking (97, 96%) and accept written information (99, 98%). Accessibility and anonymity were reported as positive aspects and concerns were expressed about lack of privacy and time (pharmacist and user). DISCUSSION AND CONCLUSIONS: This study reports the first results of pharmacy users' views on SBI. Regardless of drinking status, most were willing to utilise the service and positive about pharmacists' involvement.[Dhital R, Whittlesea CM, Norman IJ, Milligan P. Community pharmacy service users' views and perceptions of alcohol screening and brief intervention. PMID- 20973843 TI - Grasping the thistle: The role of alcohol brief interventions in Scottish alcohol policy. AB - ISSUE: Scotland has experienced a substantial rise in alcohol-related harm, which is now one of the biggest public health challenges it faces. APPROACH: Alcohol problems in Scotland are described along with national alcohol policy response in addressing them. The role of a program of Alcohol Brief Interventions is discussed therein. KEY FINDINGS: In Scotland, considerable proportions of the population are drinking hazardously or harmfully, common across different age and socioeconomic groups. Rising consumption has been set in wider environmental changes with alcohol becoming more available and affordable. Scotland has had one of the fastest growing chronic liver disease mortality rates in the world at a time when rates in most of Western Europe are falling. Scotland's alcohol policy has an explicit aim to reduce population consumption and includes legislative measures to tackle price and availability. A national program to deliver Alcohol Brief Interventions for hazardous drinkers is a key plank of this wider strategy. A portfolio of studies will monitor and evaluate national policy and, through contribution analysis, describe the role Alcohol Brief Interventions play in reducing alcohol misuse. IMPLICATIONS: Effective alcohol policy recognises that determinants of health not only lie at individual level, but include wider social, environmental and economic factors. Scotland's policy is addressing these determinants with both population-based and population-targeted interventions. CONCLUSION: Scotland has a serious problem with alcohol. A comprehensive, evidence-based, resourced alcohol policy is being implemented, which will need continual review to ensure it remains anchored in evidence while maintaining its ambition.[Graham LJC, MacKinnon D. GRASPING THE THISTLE: The role of alcohol brief interventions in Scottish alcohol policy. PMID- 20973844 TI - Alcohol identification and brief advice in England: A major plank in alcohol harm reduction policy. AB - Screening and brief interventions form a vital plank in England's plans to reduce alcohol-related harm. This article clarifies the use of terminology in England to describe various drinking categories and screening and brief interventions. It details efforts to implement these interventions, including recent incentive packages that have been put in place to encourage primary care to implement these interventions. It describes the Screening and Intervention Programme for Sensible Drinking research program that is underway to clarify tools and methods to introduce and support these interventions.[Lavoie D. Alcohol identification and brief advice in England: A major plank in alcohol harm reduction policy. PMID- 20973845 TI - What process research tells us about brief intervention efficacy. AB - ISSUE: This article explores mechanisms of the efficacy of brief intervention (BI). APPROACH: We conducted a BI trial at the emergency department of the Lausanne University Hospital, of whom 987 at-risk drinkers were randomised into BI and control groups. The overall results demonstrated a general decrease in alcohol use with no differences across groups. The intention to change was explored among 367 patients who completed BI. Analyses of 97 consecutive tape recorded sessions explored patient and counsellor talks during BI, and their relationship to alcohol use outcome. KEY FINDINGS: Evaluation of the articulation between counsellor behaviours and patient language revealed a robust relationship between counsellor motivational interviewing (MI) skills and patient change talk during the intervention. Further exploration suggested that communication characteristics of patients during BI predicted changes in alcohol consumption 12 months later. Moreover, despite systematic training, important differences in counsellor performance were highlighted. Counsellors who had superior MI skills achieved better outcomes overall, and maintained efficacy across all levels of patient ability to change, whereas counsellors with inferior MI skills were effective mostly with patients who had higher levels of ability to change. Finally, the descriptions of change talk trajectories within BI and their association with drinking 12 months later showed that final states differed from initial states, suggesting an impact resulting from the progression of change talk during the course of the intervention. IMPLICATION: These findings suggest that BI should focus on the general MI attitude of counsellors who are capable of eliciting beneficial change talk from patients. [Daeppen J-B, Bertholet N, Gaume J. What process research tells us about brief intervention efficacy. PMID- 20973846 TI - Internet-based interventions for problem drinkers: From efficacy trials to implementation. AB - AIMS: Internet-based interventions (IBIs) for problem drinkers have been in existence for over a decade. In that time, IBIs have increased in sophistication and there is the beginning of a solid research base suggesting their efficacy. A growing number of problem drinkers are using IBIs and attempts have been made to explore how IBIs can be integrated within primary care and other health-care settings. This symposium provided an overview of IBIs for problem drinkers and highlighted some of the important issues in their development and implementation. RATIONALE: IBIs appear to be at a 'cusp' as technology and intervention practices are merged together in an attempt to provide better health care for problem drinkers. The timing of the 2009 International Network on Brief Interventions for Alcohol Problems Conference was ideal for a presentation and discussion of the role that IBIs play now that IBIs have started to shift into the mainstream of services for problem drinkers. SUMMARY: The presentations in this symposium covered the 'bench to bedside' aspects of the development and evaluation of IBIs. They included a systematic review of the research to-date in this field, a report on the results from a just completed randomised controlled trial, a report on an effectiveness trial of implementing IBIs in multiple university settings and a consideration of the cost-effectiveness of IBIs.[Cunningham JA, Khadjesari Z, Bewick BM, Riper H. Internet-based interventions for problem drinkers: From efficacy trials to implementation. PMID- 20973847 TI - Conducting economic evaluations of screening and brief intervention for hazardous drinking: Methods and evidence to date for informing policy. AB - ISSUES: Many policy review articles have concluded that alcohol screening and brief intervention (SBI) is both cost-effective and cost-beneficial. Yet a recent cost-effectiveness review for the United Kingdom's National Institute for Health and Clinical Excellence suggests that these conclusions may be premature. APPROACH: This article offers a brief synopsis of the various types of economic analyses that may be applied to SBI, including cost analysis, cost-effectiveness analysis, cost-utility analysis, cost-benefit analysis and other types of economic evaluation. A brief overview of methodological issues is provided, and examples from the SBI evaluation literature are provided. KEY FINDINGS, IMPLICATIONS AND CONCLUSIONS: The current evidence base is insufficient to draw firm conclusions about the cost, cost-effectiveness or cost-benefit of SBI and about the impact of SBI on health-care utilisation.[Cowell AJ, Bray JW, Mills MJ, Hinde JM. Conducting economic evaluations of screening and brief intervention for hazardous drinking: Methods and evidence to date for informing policy. PMID- 20973849 TI - Telephonic screening and brief intervention for alcohol misuse among workers contacting the employee assistance program: A feasibility study. AB - INTRODUCTION AND AIMS: Substantial empirical support exists for alcohol screening, brief intervention, and referral to treatment (SBIRT) in medical, but not non-medical settings such as the workplace. Workplace settings remain underutilised for delivering evidenced-based health services. This research aims to translate medical research into behavioural health-care practice in a telephonic call centre acting as a point of entry into an Employee Assistance Program (EAP). The goal of the study is to examine the feasibility of implementing routine telephonic alcohol SBIRT in an EAP call centre and assess whether routine SBIRT results in increased identification of workers who misuse alcohol. DESIGN AND METHODS: The design was pretest-posttest, one-group, pre experimental. An alcohol SBIRT program developed based on World Health Organization recommendations was implemented in one EAP call centre serving one large employer. Workers were offered screening using the Alcohol Use Disorder Identification Test (AUDIT) during intake, brief counselling using motivational interviewing, referral to counselling, and follow-up. RESULTS: At 5 months, 93% of workers contacting the EAP completed the AUDIT-C: 40% prescreened positive and 52% went on to screen at moderate or high risk for an alcohol problem. Overall identification rate (18%) approached general US population estimates. Most agreed to follow-up and three-quarters set an appointment for face-to-face counselling. DISCUSSION AND CONCLUSIONS: Integration of routine alcohol SBIRT into EAP practice is feasible in telephonic delivery systems and increases identification and opportunity for brief motivational counselling. When SBIRT is seamlessly integrated workers are willing to answer questions about alcohol and participate in follow-up.[McPherson TL, Goplerud E, Derr D, Mickenberg J, Courtemanche S. Telephonic screening and brief intervention for alcohol misuse among workers contacting the employee assistance program: A feasibility study. PMID- 20973848 TI - Alcohol screening and brief intervention in primary care: Absence of evidence for efficacy in people with dependence or very heavy drinking. AB - ISSUES: Although screening and brief intervention (BI) in the primary-care setting reduces unhealthy alcohol use, its efficacy among patients with dependence has not been established. This systematic review sought to determine whether evidence exists for BI efficacy among patients with alcohol dependence identified by screening in primary-care settings. APPROACH: We included randomised controlled trials (RCTs) extracted from eight systematic reviews and electronic database searches published through September 2009. These RCTs compared outcomes among adults with unhealthy alcohol use identified by screening who received BI in a primary-care setting with those who received no intervention. KEY FINDINGS: Sixteen RCTs, including 6839 patients, met the inclusion criteria. Of these, 14 excluded some or all persons with very heavy alcohol use or dependence; one in which 35% of 175 patients had dependence found no difference in an alcohol severity score between groups; and one in which 58% of 24 female patients had dependence showed no efficacy. CONCLUSION AND IMPLICATIONS: Alcohol screening and BI has efficacy in primary care for patients with unhealthy alcohol use, but there is no evidence for efficacy among those with very heavy use or dependence. As alcohol screening identifies both dependent and non-dependent unhealthy use, the absence of evidence for the efficacy of BI among primary-care patients with screening-identified alcohol dependence raises questions regarding the efficiency of screening and BI, particularly in settings where dependence is common. The finding also highlights the need to develop new approaches to help such patients, particularly if screening and BI are to be disseminated widely.[Saitz R. Alcohol screening and brief intervention in primary care: Absence of evidence for efficacy in people with dependence or very heavy drinking. PMID- 20973850 TI - Alcohol screening and brief intervention in a policing context: A mixed methods feasibility study. AB - INTRODUCTION AND AIMS: There is a strong association between alcohol and offending behaviour and 25% of police time involves alcohol-related incidents. This pilot study aimed to investigate the feasibility of delivering alcohol screening and brief intervention (ASBI) to individuals arrested for offences linked to drinking behaviour. DESIGN AND METHODS: Participants were detainees arrested for public order or assault offences in one North East police station in England. Following a 2 h training session, 10 Detention Officers (DOs) conducted ASBI over 3 months during routine police work. In-depth interviews with the DOs provided further details about the acceptability of ASBI procedures. RESULTS: Of 704 target arrestees, 229 (33%) agreed to participate in the study. Most were male (81%), white British (95%) and under the age of 30 (62%). Fifty-nine per cent screened positively for an alcohol use disorder (50% were hazardous, 15% harmful and 35% dependent drinkers), although 23% detainees either refused or were unable to complete the screening tool. Of the 134 participants that screened positively, 98% were willing to receive brief intervention. DOs reported mixed views about ASBI; while half were positive about the process the remaining DOs expressed reservations about the appropriateness of the policing context for ASBI. DISCUSSION AND CONCLUSIONS: Despite limited training, DOs were able to deliver ASBI during routine police work. These findings provide a promising platform for future evaluative research on brief intervention outcomes in this setting. However, the issue of coercion needs to be explored more fully with both detainees and DOs.[Brown N, Newbury-Birch D, McGovern R, Phinn E, Kaner E. Alcohol screening and brief intervention in a policing context: A mixed methods feasibility study. PMID- 20973851 TI - Do attitudes about unhealthy alcohol and other drug (AOD) use impact primary care professionals' readiness to implement AOD-related preventive care? AB - INTRODUCTION AND AIMS: To explore the association between primary care professionals' (PCPs) attitudes towards unhealthy alcohol and other drug (AOD) use (from risky use through dependence) and readiness to implement AOD-related preventive care. DESIGN AND METHODS: Primary care professionals from five health centres in Sao Paulo were invited to complete a questionnaire about preventive care and attitudes about people with unhealthy AOD use. Logistic regression models tested the association between professional satisfaction and readiness. Multiple Correspondence Analysis assessed associations between stigmatising attitudes and readiness. RESULTS: Of 160 PCPs surveyed, 96 (60%) completed the questionnaire. Only 25% reported implementing unhealthy AOD use clinical prevention practices; and 53% did not feel ready to implement such practices. Greater satisfaction when working with people with AOD problems was significantly associated with readiness to implement AOD-related preventive care. In Multiple Correspondence Analysis two groups emerged: (i) PCPs ready to work with people with unhealthy AOD use, who attributed to such patients lower levels of dangerousness, blame for their condition and need for segregation from the community (suggesting less stigmatising attitudes); and (ii) PCPs not ready to work with people with unhealthy AOD use, who attributed to them higher levels of dangerousness, blame, perceived level of patient control over their condition and segregation (suggesting more stigmatising attitudes). DISCUSSION AND CONCLUSIONS: More stigmatising attitudes towards people with unhealthy AOD use are associated with less readiness to implement unhealthy AOD-related preventive care. Understanding these issues is likely essential to facilitating implementation of preventive care, such as screening and brief intervention, for unhealthy AOD use. [Amaral-Sabadini MB, Saitz R, Souza-Formigoni MLO. Do attitudes about unhealthy alcohol and other drug (AOD) use impact primary care professionals' readiness to implement AOD-related preventive care? PMID- 20973852 TI - Dose-response expectancies for alcohol: Validation and implications for brief interventions. AB - INTRODUCTION AND AIMS: Brief interventions for alcohol problems are informed by elements of behavioural motivation theories and behaviour change models. However, motivations across drinking occasions have yet to be explored. This paper addresses this need and presents initial validity statistics for a new construct, Dose Response Expectancies for Alcohol Metrics (DREAM) that can be used to investigate expectancies across the drinking session and thus inform novel interventions. DESIGN AND METHODS: Twenty-seven participants completed a test retest reliability assessment. Hypothesised systematic relationships between the hypothetical number of drinks consumed across a drinking session and anticipated affective responses were assessed. RESULTS: The DREAM questionnaire yielded good test-retest statistics for anticipated happiness and nausea in the hours following drinking. Consistent with hypotheses, DREAM yielded a systematic relationship between anticipated alcohol dose and affective response. DISCUSSION AND CONCLUSIONS: DREAM offers a novel means to investigate alcohol dose-response expectancies across drinking sessions and to therefore provide a theoretical platform that can be used to inform effective brief interventions for young people.[Adey GE, Moore SC, Chestnutt IG. Dose-response expectancies for alcohol: Validation and implications for brief interventions. PMID- 20973853 TI - Main reasons for hospital admissions by women with a history of methadone maintenance. AB - INTRODUCTION AND AIMS: Although clinical studies have noted that women with opioid use disorders use have high levels of mental and physical health disorders and are exposed to high levels of violence, it is not known whether this occurs at a level of severity that warrants hospital admission. DESIGN AND METHODS: Administrative data from a jurisdictional methadone program were linked with hospital inpatient records from 1998 to 2002 to determine the main reasons for hospital admission for a cohort of women with a prior or ongoing history of methadone maintenance. Rates of hospital admissions by the cohort were compared with hospitalisations by all women without an opioid-related hospital diagnosis from 1998 to 2002. RESULTS: After controlling for age, country of birth and marital status, women with a history of methadone maintenance had more frequent hospital admissions for the mental and behavioural disorders [relative risk (RR) 3.9 (95% confidence intervals (CI): 3.7, 4.0)], diseases of the skin and subcutaneous tissue [RR 2.1 (95% CI: 1.9, 2.3)]; injuries and poisonings [RR 2.0 (95% CI: 1.9, 2.1)] and infectious and parasitic diseases [RR 1.4 (95% CI: 1.2, 1.6)]. At a more detailed level of diagnostic specificity, the methadone cohort was admitted more often for hepatitis C, septicaemia and head injuries. DISCUSSION AND CONCLUSION: The elevated risk of hospital admission for a number of disorders suggests that women with a history of methadone maintenance experience these health events at a level of severity warranting hospital admission. Further contextual work is necessary to determine the effective preventive and management strategies.[Burns L, Conroy E, Mattick RP. Main reasons for hospital admissions by women with a history of methadone maintenance. PMID- 20973854 TI - Alcohol consumption in sport: The influence of sporting idols, friends and normative drinking practices. AB - INTRODUCTION AND AIMS: High-profile sportspeople are posited as role models for others. We examine whether university sportspeople and non-sportspeople's perceptions of high-profile sportspeople's (sports stars) and friends perceived drinking behaviours are related to their own drinking behaviours. Further, we examine the importance of drinking with competitors after sports events. DESIGN AND METHODS: A convenience sample of 1028 participants (58% females, n=652 sportspeople) from two Australian universities were approached at sporting and university venues. Participants completed a survey booklet containing demographic questions, the Alcohol Use Disorders Identification Test (AUDIT, alcohol measure), perceived drinking of high-profile sportspeople and friends (social norms), and for sportspeople only, items assessing the importance of drinking with competitors. Bivariate and multivariate analyses were used to assess relationships. RESULTS: Both sporting and non-sporting participants perceived high-profile sportspeople to drink less than themselves and their friends. Small significant bivariate relationships were found between high-profile sportspeople's perceived drinking and self-reported drinking for sportspeople (r=0.20, P <0.0005). However, in multivariate regression models the perceived drinking behaviours of high-profile sportspeople were not significant predictors of sportspeople's drinking, and were negatively related to non-sportspeople's drinking. The practice of drinking with competitors after sports and games accounted for an additional 6.1% of the unique variance in AUDIT-scores (P<0.0005). DISCUSSION AND CONCLUSIONS: Sports stars are touted as negative role models when it comes to drinking. Contrary to expectations high-profile sportspeople were not perceived to be heavy drinkers and their perceived drinking was not predictive of others drinking. Friends' and normative drinking practices were predictors of drinking.[O'Brien KS, Kolt GS, Webber A, Hunter JA. Alcohol consumption in sport: The influence of sporting idols, friends and normative drinking practices. PMID- 20973855 TI - Factors affecting criminal recidivism among participants in the Magistrates Early Referral Into Treatment (MERIT) program in New South Wales, Australia. AB - INTRODUCTION AND AIMS: The Magistrates Early Referral Into Treatment (MERIT) program is a diversionary program for people with substance use (primarily illicit drug) problems, based in New South Wales, Australia. The aim of this study was to assess factors relevant to recidivism among MERIT participants. DESIGN AND METHODS: A longitudinal study utilising administrative data was conducted. MERIT participants entering the program after 1 August 2004 and with a finalisation date of prior to 31 December 2005 were included in the study. Recidivism records for this cohort were obtained for the period 1 August 2004 and 31 December 2007 and linked to MERIT administrative data. Cox proportional hazards modelling was used to identify predictors of recidivism. RESULTS: A total of 1160 MERIT participants were included in the analysis. Compared to non completers, completion of the MERIT program was associated with a 30% reduction in risk of recidivism. Factors associated with increased risk of recidivism following MERIT included principal drug other than cannabis and higher number of prior convictions. Discussion and Conclusions. Although the design of this study does not permit causal conclusions, these results suggest the MERIT program may be associated with reduced criminal offending. The identification of factors associated with increased risk of recidivism may be helpful in identifying participants in need of higher intensity interventions.[Larney S, Martire KA. Factors affecting criminal recidivism among participants in the Magistrates Early Referral Into Treatment (MERIT) program in New South Wales, Australia. PMID- 20973858 TI - Changing trends in newborn sepsis in Sagamu, Nigeria: bacterial aetiology, risk factors and antibiotic susceptibility. AB - AIM: Sepsis is a major contributor to newborn deaths in the developing world. The objective is to determine the prevalence of newborn sepsis, the bacterial pathogens and antibiotic sensitivity pattern of the isolates. METHOD: A study of consecutive babies hospitalised in Sagamu, Nigeria, with risk factors for or clinical features of sepsis was retrospectively done between January 2006 and December 2007, and prospectively between January and December 2008. Positive blood culture defined neonatal sepsis, and the antibiotic sensitivity pattern of the organisms was also determined. RESULTS: There were 1050 admissions, and 174 (16.5%) babies had positive blood culture. Of the 527 babies with risk factors and clinical features of sepsis, 174 (33.3%) had confirmed sepsis: 119 (22.5%) had early-onset sepsis, while 55 (10.4%) had late-onset sepsis. The incidence of neonatal sepsis in the hospital was 51.3/1000 live births. Weight less than 1.5 kg, prolonged labour, prolonged rupture of membranes and lower socio-economic status were risk factors for sepsis. Staphylococcus aureus (31.0%), Klebsiella (23.0%), and coagulase-negative Staphylococcus (12.6%) and Escherichia coli (11.0%) were the leading aetiologies. The isolates were most sensitive to levofloxacin (95.7%), ofloxacin (95.1%), cefotaxime (86.7%) and ceftazidime (81.3%). Their sensitivity was 56.4% to cefuroxime and gentamicin, which are commonly used. CONCLUSION: The prevalence of sepsis was high in this cohort of high-risk infants. The low in vitro sensitivity of the leading microbes to commonly used drugs is challenging. Guidelines on the reduction of emergence of drug resistance must be provided and instituted in newborn units. PMID- 20973859 TI - Trial of a developmental screening tool in remote Australian Aboriginal communities: a cautionary tale. AB - AIM: To trial the Brigance developmental screening tool as an instrument for identifying Australian Aboriginal children at risk of developmental disability and requiring diagnostic developmental assessment. METHODS: We conducted a cross sectional study of Australian Aboriginal children, aged 3-7 years, resident in three remote communities in the Northern Territory. Following informed consent, children were screened by a paediatrician using the Brigance screen. RESULTS: There were 195 children identified as eligible, and 124 (64%) participated. All children screened, scored below the cut-off for detecting children likely to have developmental disabilities or academic delays. Furthermore, all children scored below the at-risk cut-offs that indicate high probability of disabilities in at risk children. CONCLUSIONS: The Brigance screen identified all children in these high-risk Aboriginal communities as well behind their age peers. Language and cultural relevance, and the method of administration limit the use of this screening tool. However, we cannot ignore the uniformly poor performance on a mainstream tool used with children expected to succeed in a mainstream educational setting. Recommendations include adapting an appropriate instrument to guide developmental surveillance and monitoring in remote Australian Aboriginal communities. This study further supports the pressing need for quality early childhood services that address the significant risk confronting Aboriginal children and prepare them in a way that ensures school and future success. PMID- 20973856 TI - Anxiety diagnoses in smokers seeking cessation treatment: relations with tobacco dependence, withdrawal, outcome and response to treatment. AB - AIMS: To understand the relations among anxiety disorders and tobacco dependence, withdrawal symptoms, response to smoking cessation pharmacotherapy and ability to quit smoking. DESIGN: Randomized placebo-controlled clinical trial. Participants received six 10-minute individual counseling sessions and either: placebo, bupropion SR, nicotine patch, nicotine lozenge, bupropion SR + nicotine lozenge or nicotine patch + nicotine lozenge. SETTING: Two urban research sites. PARTICIPANTS: Data were collected from 1504 daily smokers (>9 cigarettes per day) who were motivated to quit smoking and did not report current diagnoses of schizophrenia or psychosis or bupropion use. MEASUREMENTS: Participants completed baseline assessments, the Composite International Diagnostic Interview and ecological momentary assessments for 2 weeks. FINDINGS: A structured clinical interview identified participants who ever met criteria for a panic attack (n = 455), social anxiety (n = 199) or generalized anxiety disorder (n = 99), and those who qualified for no anxiety diagnosis (n = 891). Smokers with anxiety disorders reported higher levels of nicotine dependence and pre-quit withdrawal symptoms. Those ever meeting criteria for panic attacks or social anxiety disorder showed greater quit-day negative affect. Smokers ever meeting criteria for anxiety disorders were less likely to be abstinent at 8 weeks and 6 months post-quit and showed no benefit from single-agent or combination-agent pharmacotherapies. CONCLUSIONS: Anxiety diagnoses were common among treatment seeking smokers and were related to increased motivation to smoke, elevated withdrawal, lack of response to pharmacotherapy and impaired ability to quit smoking. These findings could guide treatment assignment algorithms and treatment development for smokers with anxiety diagnoses. PMID- 20973860 TI - Health-related quality of life in children with achalasia. AB - AIMS: To assess self-reported QoL in children with achalasia aged 5-18 and compare this with both disease and healthy control children in a prospective study. METHODS: All children diagnosed with achalasia at one hospital were asked to participate in this study by completing the self-report module of the validated PedsQLTM generic QoL assessment. All children attending a tertiary paediatric gastroenterology clinic from February 2009 to May 2009 with chronic constipation or inflammatory bowel disease were asked to participate in this study as disease controls. The PedsQLTM considers physical, emotional, social and school domains and is scored from 0-100. Healthy children were also recruited from the same site. Groups were compared using Analysis of Variance with Tukey's post-hoc test. RESULTS: One hundred and sixty one children completed the assessment (90 (56%) male, mean age 11.3 yrs +/- 3.4 years) including 17 children with achalasia, 44 with chronic constipation, 59 with inflammatory bowel disease and 41 healthy children. QoL was significantly lower in the achalasia group compared to both children with IBD (73 vs. 82, p = 0.035) and healthy children (73 vs. 84, p = 0.005), and was comparable to that of children with chronic constipation (73 vs. 74, p = 0.99). CONCLUSION: Children with achalasia report a significantly lower QoL compared to children with inflammatory bowel disease and healthy children. PMID- 20973861 TI - A simplified table improves the recognition of paediatric hypertension. AB - AIM: Unrecognised and untreated hypertension can lead to significant morbidity and mortality over time. In a 2003 chart review, we found that our providers only recognised 15% of hypertensive blood pressure (BP). Our objective was to determine whether a simplified BP table improves the recognition of elevated BP in children. METHODS: We developed a simplified BP table for children 3-18 years and posted it in provider work areas beginning August 2006. We reviewed a retrospective sample of well visits for children aged 3-18 years, with equal numbers by sex and year of age, presenting at a university-based paediatric clinic between January and August 2007. Visit notes for all children with elevated BP values >= 90th percentile were reviewed to identify whether the provider recognised that the BP was elevated. RESULTS: In 493 well visits, 85 (17.2%) children had pre-hypertensive (90th to < 95th percentile) and 100 (20.3%) had hypertensive (>= 95th percentile) BP values. Providers recognised elevations in 34 (40%) pre-hypertensive and 77 (77%) hypertensive measurements. Recognition was significantly more common for those in the hypertensive than the pre hypertensive range (chi2 = 24.9, degrees of freedom= 1, P < 0.001). Compared with our 2003 data, recognition of hypertensive BP values was significantly greater (77% vs. 15%) (t = 14.479, degrees of freedom = 98, P <0.001) after introduction of the simplified BP table. CONCLUSIONS: Use of a simplified BP table can lead to significantly improved recognition of elevated BP in children. PMID- 20973862 TI - Development of a culturally appropriate health-related quality of life measure for human immunodeficiency virus-infected children in Thailand. AB - AIM: Develop a reliable and valid self-report health-related quality of life (HRQOL) instrument for human immunodeficiency virus (HIV)-infected children in Thailand. METHODS: The Thai Quality of Life for HIV-infected Children instrument, the ThQLHC (an HRQOL measure that uses the Pediatric Quality of Life Inventory as a generic core and a 17-item HIV-targeted scale), was developed and administered cross-sectionally to 292 HIV-infected children in Thailand. The disease-targeted scale included HIV-related symptoms, ability to adhere with their treatment regimens and self-image. The internal consistency reliability (Cronbach's alpha) and construct validity of the ThQLHC scales were then evaluated. RESULTS: Internal consistency reliability coefficients ranged from 0.57 to 0.82, with four of five scales reaching the minimal acceptable level (>0.70). Significant associations were found between poor HRQOL and poor self rated disease severity, care giver's rated overall quality of life, cluster of differentiation (CD) 4 percent and plasma HIV ribonucleic acid level. CONCLUSION: Reliable and valid disease-targeted HRQOL measures for HIV-infected children are essential in the assessment of therapeutic effectiveness. The findings of this cross-sectional survey provide support for the reliability and validity of the ThQLHC as an HRQOL outcome measure for HIV-infected Thai children. PMID- 20973863 TI - Maternal psychosocial factors around delivery on development of 2-year-old children: A prospective cohort study. AB - AIM: To explore whether maternal psychosocial factors around delivery are related to development of 2-year-old children. METHODS: Pregnant women going to the hospital for delivery were recruited, and their children were observed at 24 months. A total of 186 mother-child dyads completed the measurement. Self-report data of maternal psychosocial factors around delivery were selected from the Taiwanese version of the short-form 36. The Comprehensive Developmental Inventory for Infants and Toddlers was completed by interviewers and the main care givers for the child at 2 years old. RESULTS: Using the multiple linear regression analysis and adjusting for potential confounders, maternal vitality around delivery was found to have a significantly positive relationship with the whole Comprehensive Developmental Inventory for Infants and Toddlers (P = 0.005) and self-help development (P = 0.001), but work stress had a significantly negative relationship with motor development (seldom, P = 0.050; always, P = 0.048). CONCLUSIONS: Maternal vitality around delivery was beneficial to a child's self help development, while work stress seemed to be an adverse effect on child's motor development in later life. It is important to improve the psychosocial health of pregnant women. PMID- 20973864 TI - Has anti-D prophylaxis increased the rate of positive direct antiglobulin test results and can the direct antiglobulin test predict need for phototherapy in Rh/ABO incompatibility? AB - AIM: To determine the impact of Rhesus (Rh) D prophylaxis on positive direct antiglobulin test (DAT) results and ability of a DAT grade to predict an infant's need for phototherapy. METHODS: Laboratory and infant medical records were reviewed for DAT status, DAT grade, interventions for hyperbilirubinemia including phototherapy, blood transfusion, exchange transfusion and intravenous immunoglobulin. Two epochs of DAT results were reviewed, the first in the era prior to Rh D prophylaxis, the second after introduction of standardised Rh D prophylaxis for Rh negative women. RESULTS: A total of 165 DAT-positive infants' medical records were reviewed. The number of positive DAT results increased from 1.5% to 2.3% (P < 0.0001) following introduction of anti-Rh D prophylaxis, the increase related to an increase in anti-D DATs (7.4% to 32% -P < 0.0001). An infant with a DAT grade of 5-8 was 2.6 times more likely to need phototherapy than an infant with a DAT grade of 2-4 (odds ratio (OR), 2.571; 95% confidence interval (CI), 1.225-5.393; P = 0.08) and an infant with a DAT grade of 10-12 was 4.7 times more likely to need phototherapy than an infant with a DAT grade of 2-4 (OR, 4.724; 95% CI, 1.602-13.926, P =0.013). CONCLUSIONS: Rh D prophylaxis has increased positive DAT results, which may increase the number of unnecessary bilirubin measurements. A low or high DAT grade is strongly predictive of whether an infant does or does not require phototherapy. However, an intermediate DAT requires concomitant bilirubin measurements to determine phototherapy requirements. PMID- 20973865 TI - Drowning for love: the aquatic victim-instead-of-rescuer syndrome: drowning fatalities involving those attempting to rescue a child. AB - INTRODUCTION: Non-intentional child drowning remains a leading cause of child mortality. A related and secondary syndrome is composed of those who drown in impulsive, altruistic attempts to go to the aid of a drowning child. Such 'rescuers' who attempt to save a drowning child may themselves drown, a tragic event we term the AVIR syndrome or aquatic victim-instead-of-rescuer. METHODS: This study is composed of a five-year (1 July 2002 to 30 June 2007) total population Australian survey, using the National Coroners Information System to identify cases and an analysis of every immersion rescuer-victim dyad where the primary 'victim' was a child and where the 'rescuer' drowned. RESULTS: In Australia (2002-2007), 17 rescuers drowned in 15 incidents in which the primary victim was a drowning child. In 93% of the incidents, the primary 'child-victim' survived, 82% of the victims were unfamiliar with the aquatic location (i.e. were a visitor) and 76% of the victims were a male parent, partner of first-degree relative. Alcohol was not generally involved. CONCLUSION: We define the AVIR syndrome as one that typically involves the following: a male, parent, partner or relative; an unfamiliar water hazard; a 'rescuer' who is a tourist; alcohol is not usually involved; and the primary victim usually survives. We posit that an increased awareness of such risks, the promotion of rudimentary rescue skills (e.g. being able to throw a lifeline) and increased advocacy for parents to learn the simple and basic life-saving skills of non-contact rescue will help reduce these drowning tragedies. PMID- 20973866 TI - The importance of physical education classes in pre-school children. AB - AIM: The purpose of this study was to analyse differences between total physical activity (TPA) and moderate-to-vigorous PA (MVPA) of pre-school children during daily school hours when they attended the physical education class (PED) and school days without PE class (NPED) and to assess the contribution of PE classes to TPA in school hours. METHODS: The sample was composed of 193 pre-school healthy children (96 girls) aged from three to five years old and was conducted between February and December of 2008. Children wore accelerometers for at least four consecutive days during school hours. Data were analysed with specific software, age-specific counts-per-minute cut-off points and a 5 s epoch were used. Independent and general linear model repeated measures were used to assess differences between gender and differences between different days within each gender, respectively. RESULTS: Boys engaged more MVPA than girls (P < 0.05). During PED, pre-school children engaged significantly more in TPA and MVPA than during NPED (P < 0.05). PE class contributed, on average, 27.7% for the TPA and 32.8% of daily MVPA during PED in both gender. CONCLUSION: The results of this study suggest that structured PA such as a PE class increased the daily TPA and MVPA level of pre-school children. PMID- 20973867 TI - Lifestyle and demographic correlates of poor mental health in early adolescence. AB - AIM: To determine the constellation of lifestyle and demographic factors that are associated with poor mental health in an adolescent population. METHODS: The Raine Study 14-year follow-up involved primary care givers and their adolescent children (n= 1860). The Child Behaviour Checklist (CBCL) was used to assess adolescent mental health. We examined diet, socio-demographic data, family functioning, physical activity, screen use and risk-taking behaviours with mental health outcomes using linear regression. RESULTS: Adolescents with higher intakes of meat and meat alternatives and 'extras' foods had poorer mental health status. Adverse socio-economic conditions, higher hours of screen use and ever partaking in the health risk behaviours of smoking and early sexual activity were significantly associated with increasing CBCL scores, indicative of poorer functioning. CONCLUSIONS: By identifying the lifestyle and demographic factors that accompany poorer mental health in early adolescence, we are able to better understand the context of mental health problems as they occur within an adolescent population. PMID- 20973868 TI - The effect of combined steroid and calcium channel blocker injection on human hypertrophic scars in animal model: a new strategy for the treatment of hypertrophic scars. AB - BACKGROUND: Hypertrophic scars (HScs) are inelastic scars that can cause functional loss and disfigurement. Decorin regulates collagen fibrillogenesis, and its expression is lower in HScs than in normal skin and during wound healing. OBJECTIVE: To evaluate the efficacy of combined verapamil and triamcinolone in treating HScs. METHODS: Excised human HSc fragments from surgically treated burned patients were divided into three groups: A (normal saline), B (verapamil), and C (verapamil and triamcinolone). The specimens were bilaterally implanted in the back of nude mice, treated using intralesional injections, and observed for 4 weeks. We compared the fibroblast viability and proliferation, decorin staining, and scar weights to evaluate treatment efficacy. RESULTS: Viability and proliferation of HSc fibroblasts from groups B and C were significantly lower at all time intervals after transplantation (p<.001). Treatment (Groups B and C) stimulated strong decorin staining by 4 weeks. Nonsignificant differences in changes in scar weight were observed between groups. CONCLUSIONS: We present the first evidence of verapamil-augmented decorin expression spatially correlated with collagen bundles in HScs. Combination therapy can reduce the dosage of each drug but achieve equal or better efficacy than monotherapy, reducing the side effects of a single drug. The authors have indicated no significant interest with commercial supporters. PMID- 20973870 TI - Applying a propensity score-based weighting model to interrupted time series data: improving causal inference in programme evaluation. AB - Often, when conducting programme evaluations or studying the effects of policy changes, researchers may only have access to aggregated time series data, presented as observations spanning both the pre- and post-intervention periods. The most basic analytic model using these data requires only a single group and models the intervention effect using repeated measurements of the dependent variable. This model controls for regression to the mean and is likely to detect a treatment effect if it is sufficiently large. However, many potential sources of bias still remain. Adding one or more control groups to this model could strengthen causal inference if the groups are comparable on pre-intervention covariates and level and trend of the dependent variable. If this condition is not met, the validity of the study findings could be called into question. In this paper we describe a propensity score-based weighted regression model, which overcomes these limitations by weighting the control groups to represent the average outcome that the treatment group would have exhibited in the absence of the intervention. We illustrate this technique studying cigarette sales in California before and after the passage of Proposition 99 in California in 1989. While our results were similar to those of the Synthetic Control method, the weighting approach has the advantage of being technically less complicated, rooted in regression techniques familiar to most researchers, easy to implement using any basic statistical software, may accommodate any number of treatment units, and allows for greater flexibility in the choice of treatment effect estimators. PMID- 20973869 TI - Phase-II trial of combination treatment of interferon-alpha, cimetidine, cyclooxygenase-2 inhibitor and renin-angiotensin-system inhibitor (I-CCA therapy) for advanced renal cell carcinoma. AB - We have recently reported favorable responses to a combination treatment comprising cimetidine, a cyclooxygenase-2 inhibitor and a renin-angiotensin system inhibitor in metastatic renal cell carcinoma (RCC). In view of the potential synergistic effects of these three agents and interferon-alpha (I-CCA therapy), we conducted a phase-II trial to examine the efficacy and toxicity of I CCA as first-line treatment. Fifty-one patients with advanced RCC received natural interferon-alpha (3-6 million U thrice/week) and cimetidine (800 mg), cyclooxygenase-2 inhibitor meloxicam (10 mg), and renin-angiotensin-system inhibitor candesartan (4 mg) or perindopril (4 mg) orally daily. Memorial Sloan Kettering Cancer Center prognostic categories were favorable, intermediate and poor in 10 (20%), 31 (61%) and 10 (20%) patients, respectively. The primary end point was the objective response rate (ORR) and the secondary end-points included clinical benefit, progression-free survival (PFS), overall survival (OS) and safety. Median follow-up was 19 months. Complete response (CR) was observed in four patients (8%) and partial response in seven (14%), yielding an ORR of 22%. None of the four patients who achieved CR relapsed during the 16- to 81-month follow up. The ORR were 17% in the favorable- or intermediate-risk group and 40% in the poor-risk group. The other 24 patients (45%) had stable disease for at least 6 months, resulting in a clinical benefit rate of 67%. The median PFS and OS were 12 and 30 months, respectively. Grade 3/4 toxicities were never observed. The I-CCA therapy, providing favorable responses and low toxicity profiles, is worthy of further consideration as a first-line therapy for metastatic RCC. PMID- 20973871 TI - Possible solutions for barriers in incident reporting by residents. AB - RATIONALE, AIMS AND OBJECTIVES: Incident reporting can contribute to safer health care. Since the rate of reporting by residents is low, it is useful to investigate which barriers exist and how these can be solved. METHODS: Data were collected in a large teaching hospital in the Netherlands. The hospital uses a confidential, voluntary and web-based incident reporting system. Residents working in the hospital participated in focus group discussions to explore barriers and possible solutions. A grounded theory approach was used to analyse the transcribed discussions. RESULTS: In each focus group six to eight residents participated, resulting in a total number of 22 participants. After three focus group discussions, information saturation had been reached. Residents do not report all incidents because of a negative attitude towards incident reporting, because they experience a non-stimulating culture and because of a lack of perceived ability to report. Residents suggest several solutions to solve the barriers: providing the possibility to report anonymously, providing feedback, creating an incident reporting culture, simplifying the procedure, clarifying what and how to report, and exciting residents to report. CONCLUSIONS: Residents have useful suggestions to resolve the barriers that prevent them from reporting incidents. They include solutions that influence attitude, culture and perceived ability. These suggestions should be considered when making an effort to improve incident reporting by residents. PMID- 20973872 TI - Fidelity to clinical guidelines using a care pathway in the treatment of first episode psychosis. AB - OBJECTIVE: To evaluate the implementation of clinical practice guidelines in the initial stages of treatment of first episode psychosis, through use of a care pathway within one area mental health service. METHODS: A fidelity audit was undertaken using data from local Early Psychosis Care Pathway documents, completed for the cohort of clients with early psychosis seen in the first 2 years of an integrated early psychosis programme model, at St Vincent's Mental Health Service, Melbourne, Australia. RESULTS: The utilisation of a care pathway greatly supported both the documentation of clinical process and fidelity to clinical guidelines in early psychosis treatment. Excellent adherence (over 80%) was achieved for therapeutic alliance with the client, conducting a comprehensive bio-psychosocial assessment, medical investigations, reduction of client trauma and increased orientation to the service and the mental health systems of care, and for contact with family. Good adherence (over 70%) was achieved for client re integration to the community and promotion of carer well-being; the service plans to focus on these areas in future service improvement initiatives, along with a focus on physical health assessment and enhancing primary care liaison. CONCLUSIONS: The process of formally operationalizing and implementing clinical guidelines utilizing a care pathway within an area mental health service has proved to be an effective way to ensure fidelity with standard agency practices and protocols. The integrated approach, supported by quality assurance initiatives, provides an excellent goodness-of-fit within an established area mental health service. PMID- 20973874 TI - Social science, behavioural medicine, and the tomato effect. AB - 'Behavioural medicine' is poised to contribute to the quality of health to the benefit of patients and physicians. There is a need for medical students and residents to better understand the field of behavioural medicine, and for practising physicians to incorporate it in medical education and clinical practice. This paper seeks to correct an erroneous conceptualization of behavioural medicine as being limited to psychosocial and mental health adjustments, and to provide examples of selected applications for medical conditions, including those that are not primarily regarded as requiring changes in lifestyle or psychotherapy. In fact, there are dramatic treatment and intervention protocols available that employ behavioural procedures that can provide relief for patients in all medical and dental specialties and that deserve to be considered along with conventional treatment protocols. PMID- 20973873 TI - Clinical judgement and the medical profession. AB - OBJECTIVES: Clinical judgment is a central element of the medical profession, essential for the performance of the doctor, and potentially generating information also for other clinicians and for scientists and health care managers. The recently renewed interest in clinical judgement is primarily engaged with its role in communication, diagnosis and decision making. Beyond this issue, the present article highlights the interrelations between clinical judgement, therapy assessment and medical professionalism. METHODS: Literature review and theory development. RESULTS: The article presents different methodological approaches to causality assessment in clinical studies and in clinical judgement, and offers criteria for clinical single case causality. The article outlines models of medical professionalism such as technical rationality and practice epistemology, and characterizes features of professional expertise such as tacit knowledge, reflection in action, and gestalt cognition. CONCLUSIONS: Consequences of a methodological and logistical advancement of clinical judgment are discussed, both in regard to medical progress and to the renewal of the cognitive basis of the medical profession. PMID- 20973875 TI - Impact of initial pattern of care on hospital costs in a cohort of incident lung cancer cases. AB - RATIONALE, AIMS AND OBJECTIVES: Lung cancer is a disease with high consumption of health care resources. The aim of this study was to describe hospital costs due to lung cancer care from diagnosis until death or end of the study follow-up, in a cohort of incident cases, by using administrative data. METHODS: Particular attention was given to the determinants of total costs and the impact of the initial treatment approach on the process of costs accumulation. Incident cases were identified by the local Cancer Registry (January 2000-December 2003) among the residents of Turin (Italy). Per patient hospital care has been determined from administrative databases (outpatient radiotherapy records and hospital discharge records). Costs determinants were identified via a multivariable generalized linear model (GLM), with a Gamma cost distribution and a logarithmic link function. To assess the time effect over the cost accumulation process for non-small-cell lung cancer cases, the same GLM Gamma model was repeated at different follow-up periods. Analyses were stratified by cancer histotype. RESULTS: Results evidenced the relevant role of initial patterns of care on the cost accumulation process, with increased midterm costs associated with curative patterns of care. CONCLUSION: The use of administrative data enabled hospital lung cancer care to be described, and related costs to be estimated. PMID- 20973876 TI - Taking the PACIC back to basics: the structure of the Patient Assessment of Chronic Illness Care. AB - RATIONALE, AIMS AND OBJECTIVES: The Patient Assessment of Chronic Illness Care (PACIC) is a widely used 20-item measure consisting of five subscales. Published factor analyses of PACIC scores have produced conflicting results on the measure's factorial validity, and therefore some confusion as to the utility of its subscales. We aim to reduce this confusion by reviewing the evidence on the PACIC's factorial validity, exploring the statistical issues it raises, and considering more broadly what such analyses can reveal about the validity of the PACIC. METHODS: To achieve these aims we review six published studies on the PACIC's factorial validity, present confirmatory factor analyses of our own PACIC data from 251 chronic care patients, and assess the PACIC with respect to its status as a reflective or a formative measure. RESULTS: Our statistical analyses support the view that a 5-factor model does not fit the structure of the PACIC, and highlight a variety of technical issues that confront researchers who wish to factor analyse the measure. However, we argue that, as the PACIC is more accurately seen as a formative measure, such analyses do not provide information that should be used to assess the PACIC's validity. CONCLUSIONS: We conclude that, while it is important to continue examining the reliability and validity of the PACIC in a variety of ways, traditional analyses of its factorial validity (and internal consistency) are inappropriate. Meanwhile, use of the subscales is defensible as long as they continue to meet other types of reliability and validity requirements. PMID- 20973877 TI - Psychometric properties of a scale to measure investment in the sick role: the Illness Cognitions Scale. AB - RATIONALE, AIMS AND OBJECTIVES: A person's beliefs about their illness may contribute to recovery and prognosis. Some degree of acceptance of illness and its impact is necessary to integrate the presence of a chronic disorder into one's lifestyle and adhere to necessary components of illness management; however, some individuals can become 'stuck' and have difficulty adjusting out of the sick role. Inventories exist to measure illness cognitions, attitudes and behaviours as they relate to hypochondria and psychosomatic illness, but there is no extant measure of sick role inertia. We describe the psychometric properties of a new scale, the Illness Cognitions Scale (ICS), a metric of investment in the sick role. METHODS: The ICS was administered to 97 individuals with bipolar or schizoaffective disorder, and the psychometric properties of the scale measured. Dimensionality was assessed using Principal Components Analysis with Oblimin rotation. RESULTS: The scale has a strong internal consistency, with a Cronbach's alpha of 0.858. Results of a factor analysis suggested the presence of one main factor, with three other smaller, related sub-factors, capturing aspects of maladaptive illness beliefs. CONCLUSION: The ICS is a 17-item, internally validated scale measuring difficulty adjusting out of the sick role. The scale predominantly measures a single construct. Further research on external validity of the ICS is required as well as determination of the clinical significance and patient acceptability of the scale. PMID- 20973878 TI - Informed decision-making before changing to RDT: a comparison of microscopy, rapid diagnostic test and molecular techniques for the diagnosis and identification of malaria parasites in Kassala, eastern Sudan. AB - OBJECTIVES: Rapid diagnostic tests (RDTs) are promoted for the diagnosis of malaria in many countries. The question arises whether laboratories where the current method of diagnosis is microscopy should also switch to RDT. This problem was studied in Kassala, Sudan where the issue of switching to RDT is under discussion. METHODS: Two hundred and three blood samples were collected from febrile patients suspected of having malaria. These were subsequently analysed with microscopy, RDT (SD Bioline P.f/P.v) and PCR for the detection and identification of Plasmodium parasites. RESULTS: Malaria parasites were detected in 36 blood samples when examined microscopically, 54 (26.6%) samples were found positive for malaria parasites by RDT, and 44 samples were positive by PCR. Further analysis showed that the RDT used in our study resulted in a relatively high number of false positive samples. When microscopy was compared with PCR, an agreement of 96.1% and k = 0.88 (sensitivity 85.7% and specificity 100%) was found. However, when RDT was compared with PCR, an agreement of only 81.2 and k = 0.48 (sensitivity 69% and specificity 84%) was found. CONCLUSION: PCR has proven to be one of the most specific and sensitive diagnostic methods, particularly for malaria cases with low parasitaemia. However, this technique has limitations in its routine use under resource-limited conditions, such as our study location. At present, based on these results, microscopy remains the best option for routine diagnosis of malaria in Kassala, eastern Sudan. PMID- 20973880 TI - Variety and variability of glycosidase activities in an Oenococcus oeni strain collection tested with synthetic and natural substrates. AB - AIMS: To evaluate the capacity of Oenococcus oeni strains to release aroma compounds from glycosylated precursors by measuring glycosidase activities with both synthetic and natural substrates. METHODS AND RESULTS: Five glycosidase activities were investigated in 47 O. oeni strains using synthetic substrates. This screening revealed that activity levels vary considerably, not only for each strain (depending on the substrate tested), but also between strains. Fifteen strains exhibiting different activity profiles were further analysed using natural substrates extracted from both untoasted and toasted oak. In the latter, various amounts of aromatic compounds were measured, thus confirming the specific potentials of the selected strains, but the results were different from those obtained using synthetic substrates. In addition, the use of toasted wood extracts significantly increased the release of wood aromas, which minimized differences between strains. CONCLUSIONS: The capability of O. oeni to hydrolysate glycoconjugate aroma precursors is strain-dependent and variable, depending on the substrate. SIGNIFICANCE AND IMPACT OF THE STUDY: Instead of synthetic substrates, natural aroma precursors should be used for an adequate evaluation of the glycosidase potential of O. oeni. PMID- 20973881 TI - Interpreting the SDS-PAGE protein patterns with self-organizing maps: application for the characterization of mosquito-pathogenic Bacillus strains. AB - AIMS: To present the pairwise comparison of potential mosquito-pathogenic Bacillus strains based on their SDS-PAGE protein patterns and to evaluate their characteristic toxicity patterns. METHODS AND RESULTS: In this work, 20 Bacillus strains were subjected to qualitative toxicity tests against Aedes aegypti and Culex quinquefasciatus larvae. The selected strains were then characterized by SDS-PAGE protein profiles. The highly heterogeneous multiple protein components of protein patterns were analysed using self-organizing map (SOM), a 'visualization and clustering' tool. Members of mosquitocidal Bacillus species were classified in four distinct clusters, and then toxicity patterns were examined. Cluster (1, 1) comprised of three highly toxic strains of Bacillus sphaericus: SPH88, 1593 and KSD-4; cluster (1, 2) consisted of two B. sphaericus strains: SSII-1 and Bsp-R that showed weak larvicidal activity; cluster (2, 1) constituted two B. sphaericus strains: WHO2297 and ISPC-5 that possessed moderate toxicity; and cluster (2, 2) contained four B. thuringiensis ssp. israelensis strains: ONR-60A, HD500, IPS70 and IPS82 belonging to serotype H14 but exhibited moderate to high mosquito larvicidal toxicity. CONCLUSIONS: SOM served as a colour-coded alternate for easy visualization of similarities or dissimilarities between the strains even at the infra subspecies level. Furthermore, characteristic toxicity patterns of Bacillus strains of different clusters were determined. SIGNIFICANCE AND IMPACT OF THE STUDY: Analysis of electrophoretic protein patterns using SOM provides a better insight into the inter-relationships of bacterial strains through similarity-based clustering and pairwise comparison of two strains. PMID- 20973882 TI - Sequence analysis of the S gene region in HBV DNA from patients positive for both HBsAg and HBsAb tests. AB - AIMS: To study the characteristics of mutation in the amino acids coded by the S gene region in the HBV DNA sequence and to comprehensively explore and analyze the cause of the double positive result phenomena in both HBsAg and HBsAb tests. METHODS: Specimens collected from 43 cases of chronic hepatitis B patients with positive results for both HBsAg and HBsAb tests were used as the experimental group; specimens collected from 43 cases randomly picked from all patients with chronic hepatitis B with a single positive result for HBsAg test were used as the control group. In HBV DNA, the S gene region was amplified and sequenced. Amino acid sequences were grouped, and mutations were analyzed based on the sequencing results. RESULTS: The patients were infected with HBV of the genotype B and C and those who with genotype C show more mutations than genotype B carriers. Compared with the control group, the experimental group had a marked increase in S gene amino acid mutations; a higher amino acid mutation rate was observed in the first loop (aa124-137) of the a-determinant (aa124-147) and there was a statistical difference (genotype B: 2.68% vs. 0.00%, P = 0.041; genotype C: 7.14% vs. 2.01%, P < 0.001). CONCLUSION: The first loop in a-determinant of S gene sequence possesses a large numbers of mutated amino acids, leading to changes of antigenicity and simultaneous positive results in both HBsAg and HBsAb tests finally. PMID- 20973883 TI - Combined pre-S deletion and core promoter mutations related to hepatocellular carcinoma: A nested case-control study in China. AB - AIM: To investigate the roles of biomedical factors, hepatitis B virus (HBV) DNA levels, genotypes, and specific viral mutation patterns on the progression of hepatocellular carcinoma (HCC) in Qidong, China. METHODS: A total of 2387 males (aged 20-65 years) who were seropositive for the hepatitis B surface antigen (HBsAg), but had not been diagnosed with HCC, were recruited to a community-based HCC screening study from August, 1996. Evaluation of virological parameters at recruitment was determined for 196 HCC patients during 10 years of follow-up and 323 controls. RESULTS: After adjustment for age at recruitment, history of cigarette smoking and alcohol consumption, alanine aminotransferase (ALT) elevation, alpha-fetoprotein (AFP) levels >20 ng/mL, hepatitis B e antigen positive, HBV DNA levels >=4.00 log(10) copies/mL, pre-S deletion, T1653 mutation, T1762/A1764 double mutations, and T1766 and/or A1768 mutations were associated with subsequent risk of HCC. A significant biological gradient of HCC risk by HBV DNA levels from less than 2.69 log(10) copies/mL to 6.00 log(10) copies/mL or greater was observed. HBV with a complex mutation combination pattern (pre-S deletion, T1762/A1764 double mutations, and T1766 and/or A1768 mutations) rather than a single mutation was associated with the development of HCC. The longitudinal observation demonstrated a gradual combination of pre-S deletion, T1762/A1764 double mutations, and T1766 and/or A1768 mutations during the development of HCC. CONCLUSIONS: AFP levels >20 ng/mL, high HBV DNA levels, pre-S deletion, and T1762/A1764 double mutations at recruitment were independent risk factors of HCC. Combination of pre-S deletion and core promoter mutations increased the risk of HCC. PMID- 20973884 TI - Mesalamine-induced B7-H1 expression on hepatic stellate cells attenuates autoimmune liver injury. AB - AIM: Hepatic stellate cells (HSCs) have immune regulatory functions. Mesalamine is an effective immune regulatory drug for inflammatory bowel disease. Thus, we hypothesized that mesalamine may also modulate the immune regulatory functions of HSCs. Since B7-H1 plays a crucial role in regulating T-cell apoptosis, we evaluated if mesalamine induces B7-H1 expression on HSCs, and if so, whether mesalamine attenuates autoimmune liver injury in vivo. METHODS: LX-2 cells, an immortalized human HSC cell line, and human peripheral T-cells were used in this study. B7-H1 expression on LX-2 cells following mesalamine treatment was examined by using flow cytometry. Cell viability was analyzed by MTS assay. Concanavalin-A (ConA) mice hepatitis model was used for in vivo study. RESULTS: Flow cytometry showed that mesalamine treatment increased the B7-H1-expressing LX-2 cell fraction from 45.4% to 88.2%, of which increment is equivalent to that of positive control (29.9%, interferon gamma-treated cells). Human T-cells incubated with LX-2 cells showed significantly less cell viability in the presence of mesalamine than cells without mesalamine treatment (P < 0.001). Histological examination revealed that hepatic necroinflammation was significantly attenuated by mesalamine pretreatment (P = 0.019), although serum levels of aminotransferases were not significantly reduced. During the 24-h period following ConA injection, 1 of 10 mice pretreated with mesalamine and 3 of 10 mice without pretreatment died. CONCLUSION: These results demonstrate that mesalamine enhances B7-H1 expression on HSCs, and thus, induces T-cell apoptosis and attenuates autoimmune liver injury. PMID- 20973885 TI - Organic anion transporter 1B1 (SLCO1B1) polymorphism and gallstone formation: High incidence of Exon4 CA genotype in female patients in North India. AB - AIM: Gallstone disease is an important cause of abdominal morbidity Organic anion transport protein 1B1 (OATP1B1) (encoded by SLCO1B1) is a major transporter protein for bile salt uptake in enterohepatic circulation of bile salts. Disturbance in this pathway can decrease relative concentration of bile salts in gallbladder and may lead to formation of gallstones. We investigated role of SLCO1B1 polymorphisms [(Exon4 C > A (Pro155Thr; rs11045819) and Ex6 + 40T > C (Val174Ala; rs4149056)] in conferring interindividual susceptibility to gallstone disease. METHODS: A total of 173 healthy controls and 226 gallstone patients (USG positive) were recruited. Genotyping was done by using standard polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The observed control frequencies of both polymorphisms of SLCO1B1 gene [(Exon4 C > A (Pro155Thr; rs11045819) and Ex6 + 40T > C (Val174Ala; rs4149056)] were in agreement with Hardy-Weinberg equilibrium. The frequency CA genotype and A allele of Exon4 C > A polymorphism was higher in gallstones patients (12.4% and 6.2%) as compared to controls (5.2% and 2.6%) which was statistically significant [(P = 0.029; OR = 2.31; 95% CI = 1.1-5.0); (P = 0.034; OR = 2.22; 95% CI = 1.1 4.8)], respectively). However, distribution of genotypes and alleles of Ex6 + 40T > C polymorphism was almost similar between gallstone patients and controls. Haplotype analysis showed frequency of A,T haplotype consisting of was significantly higher in gallstone patients as compared to controls and was imposing risk for the disease (P = 0.036; OR = 2.34; 95% CI = 1.0-5.1). CONCLUSION: These results suggest that SLCO1B1 Exon4 C > A polymorphism confers increased risk for gallstone disease in North Indian population. PMID- 20973886 TI - A fourth dimension in decision making in hepatology. AB - Today, the assessment of liver function in patients suffering from acute or chronic liver disease is based on liver biopsy and blood tests including synthetic function, liver enzymes and viral load, most of which provide only circumstantial evidence as to the degree of hepatic impairment. Most of these tests lack the degree of sensitivity to be useful for follow-up of these patients at the frequency that is needed for decision making in clinical hepatology. Accurate assessment of liver function is essential to determine both short- and long-term prognosis, and for making decisions about liver and non-liver surgery, TIPS, chemoembolization or radiofrequency ablation in patients with chronic liver disease. Liver function tests can serve as the basis for accurate decision-making regarding the need for liver transplantation in the setting of acute failure or in patients with chronic liver disease. The liver metabolic breath test relies on measuring exhaled (13) C tagged methacetin, which is metabolized only by the liver. Measuring this liver-specific substrate by means of molecular correlation spectroscopy is a rapid, non-invasive method for assessing liver function at the point-of-care. The (13) C methacetin breath test (MBT) is a powerful tool to aid clinical hepatologists in bedside decision-making. Our recent findings regarding the ability of point-of-care (13) C MBT to assess the hepatic functional reserve in patients with acute and chronic liver disease are reviewed along with suggested treatment algorithms for common liver disorders. PMID- 20973887 TI - Efficacy of short-term dexamethasone therapy in acute-on-chronic pre-liver failure. AB - AIM: Acute-on-chronic pre-liver failure (pre-ACLF) is defined as a severe acute episode of chronic hepatitis B characterized by serum bilirubin of 171 umol/L or more, alanine aminotransferase of five times or more the upper limit of normal and prothrombin activity of more than 40%, having a potential for progression to acute-on-chronic liver failure (ACLF). This study is to evaluate the efficacy of short-term dexamethasone in pre-ACLF. METHODS: One hundred and seventy patients were assigned to dexamethasone therapy and control group at a ratio of 1:2. For the two groups, we compared biochemical indicators, the incidence of ACLF and mortality. The influential factors on the mortality of patients with pre-ACLF were studied by Cox proportional hazards models. RESULTS: The significantly lower incidence of ACLF and higher survival rate were observed in patients on dexamethasone therapy (8.9%, 96.4%, respectively) than in control patients (70.2%, 52.6%, respectively; P < 0.001). Dexamethasone treatment was an independent factor influencing the survival rate (P < 0.001, odds ratio = 0.055, 95% confidence interval = 0.013-0.225). During 4 weeks of treatment, serum bilirubin levels of survival patients were significantly lower in the dexamethasone group than control group. CONCLUSION: Five-day dexamethasone therapy is effective in improving the liver function and survival rate of patients with pre-ACLF. PMID- 20973888 TI - New therapeutic approaches in the treatment of diabetic keratopathy: a review. AB - The cornea is densely innervated, and the integrity of these nerve fibres is critical in maintaining the refractive and protective functions of the cornea. Many ocular and systemic diseases can adversely affect corneal sensory nerves and consequently impair their function, with vision loss being the inevitable consequence of severe corneal neurotrophic ulceration. However, current standard treatments regimens are often ineffective. Over the past three decades, the role of growth factors in maintaining the normal structure and function of the cornea, and in corneal epithelial healing, has become increasingly evident. Many preclinical and clinical trials have shown that growth factors and cytokines can significantly enhance epithelialization (epithelial proliferation and migration) and consequently accelerate wound healing. More recently, local/topical administration of insulin, naltrexone (opioid antagonist) and nicergoline (ergoline derivatives) were found to improve, and significantly increase, the corneal wound healing rate. This report reviews the major attributes of these growth factors and therapeutic agents that may be used in ameliorating impaired corneal wound healing, and presents a perspective on the potential clinical use of these agents as a new generation of ophthalmic pharmaceuticals for the treatment of diabetic keratopathy. PMID- 20973889 TI - In vivo study comparing an X-shaped polymethylmethacrylate and a cylindrical collagen implant for deep sclerectomy. AB - BACKGROUND: Study in vivo characteristics of a polymethylmethacrylate (PMMA) implant compared to the standard cylindrical collagen implant for deep sclerectomy (DS). DESIGN: Six-month comparative study. SAMPLES: Twenty eyes of ten rabbits. METHODS: Eyes were randomized to have DS with PMMA implant in one eye and collagen implant in the opposite eye. The growth of the new subconjunctival drainage vessels was assessed by combined fluorescein and indocyanin green anterior segment angiography; intrascleral and subconjunctival blebs were imaged by ultrasound biomicroscopy (UBM). At six months, outflow facility (C) was measured by anterior chamber perfusion and portions of one side of the DS were compared to portions on the 180 degrees opposite side and native sclera on histology. RESULTS: The mean IOP preoperatively and at one, four, twelve, and twenty-four weeks was comparable in both groups (P > 0.1). UBM showed a statistically insignificant quicker regression of the subconjunctival bleb as well as a durable intrascleral lake in the PMMA group (P > 0.05). New drainage vessels were initially observed one month after surgery; they were more numerous in the PMMA group on angiographic and histological findings at 6 months (P < 0.05). The mean C increased significantly after surgery compared to preoperative values (P < 0.05) and no difference was observed between the implants (0.24 +/- 0.06 ul/min/mmHg [PMMA] and 0.23 +/- 0.07 ul/min/mmHg [collagen implant]) (P = 0.39). CONCLUSIONS: Deep sclerectomy performed with PMMA or collagen implants showed similar IOP lowering effects, outflow facility increase, and degree of inflammatory reaction. PMID- 20973891 TI - Comparison of two retinal nerve fibre layer thickness measurement patterns of RTvue optical coherence tomography. AB - BACKGROUND: To evaluate the agreement and repeatability between operator dependent centring and automatic centring retinal nerve fibre layer thickness measurement patterns (RNFL3.45 and NHM4) of RTvue optical coherence tomography in normal and glaucomatous eyes. DESIGN: Cross-sectional observational study. PARTICIPANTS: A total of 153 eyes from 149 normal subjects and subjects with glaucoma were analysed. METHODS: The retinal nerve fibre layer thickness was measured using RNFL3.45 and NHM4 three times on the same day to determine the repeatability and agreement between the two scan patterns. MAIN OUTCOME MEASURES: Student's paired t-testing, intra-class correlation coefficient, coefficient of variation, test-retest viability, Pearson's correlation coefficient and Bland Altman analysis of retinal nerve fibre layer thickness measurements. RESULTS: The difference between RNFL3.45 and NHM4 measurements was statistically significant by paired t-testing (P=0.003) only in severe glaucoma group. The Pearson's correlation test showed a high degree of correlation of the mean retinal nerve fibre layer thickness (r=0.949). Bland-Altman plots showed that the differences between RNFL3.45 and NHM4 were smaller at thicker retinal nerve fibre layer values, but larger at thinner retinal nerve fibre layer values. The intra-class correlation coefficient for RNFL3.45 (and lower 95% confidence interval) in normal and glaucomatous eyes was 0.990 (0.985 confidence interval) and 0.997 (0.995 confidence interval), respectively. The intra-class correlation coefficient for NHM4 in normal and glaucomatous eyes was 0.989 (0.983 confidence interval) and 0.995 (0.992 confidence interval), respectively. The test-retest variability for RNFL3.45 and NHM4 ranged from 3.98 to 9.75um in normal eyes, and from 4.10 to 13.34um in glaucomatous eyes. CONCLUSION: Measurements of retinal nerve fibre layer thickness by RNFL3.45 and NHM4 are in good agreement. PMID- 20973890 TI - Differential gene expression pattern of diabetic rat retinas after intravitreal injection of erythropoietin. AB - BACKGROUND: To profile the pattern of gene expression in diabetic rat retinas with or without intravitreal injection of erythropoietin. DESIGN: By using streptozotocin-induced diabetic rats, after intravitreal injection of erythropoietin, neurosensory retinas were collected to determine the effect of erythropoietin on gene expression. PARTICIPANTS: Three groups of Sprague-Dawley rats were studied: normal control (15), diabetic rats with saline injection (15) and diabetic rats with intravitreal erythropoietin treatment (15). METHODS: Diabetes was induced by intra-peritoneal injection of streptozotocin. Intravitreal injection of erythropoietin was performed at the following time points: 0, 30 and 120 days after diabetes onset. Four days after each injection at above-mentioned time points, the retinas were harvested for microarray assay. The real-time PCR was used to evaluate the microarray data. RESULTS: Genes encoding inflammatory factors, such as interleukin-2 and interleukin-11, which were upregulated in the diabetic retinas, were restored after erythropoietin treatment. Genes encoding pro-apoptotic effectors, like Tnfrsf5, Bid3 and Bcl2l1, were also upregulated in diabetic rats and attenuated in erythropoietin-treated group. In addition, real-time PCR were employed to confirm the changes of the genes Trex2, G1P2, DHX58, RGD1311906 and LOC689064, which have not been reported in diabetic retinopathy. CONCLUSIONS: Intravitreal erythropoietin treatment is able to normalize the gene expression responsible for pro-apoptotic and inflammatory responses noted in diabetic retinas. PMID- 20973893 TI - Repair of blowout orbital floor fracture by periosteal suturing. AB - The study objective was to evaluate the outcome of a periosteal suturing technique in eyes with orbital blowout fractures. Fifteen orbital floor fractures were classified into: type 1, linear fracture; type 2, middle fracture; and type 3, posterior fracture extending two-thirds into the orbit. The feasibility of periosteal suturing without silicone plates or one of minimal size was determined. The improvement of ocular movements and surgical complications were evaluated. A complete suture of the torn periosteum without implanting a silicone plate was achieved in 2/2 (100%) type 1 cases, 5/7 (71%) type 2 cases and 0/6 (0%) type 3 cases. A partial fixation was achieved in 3/6 (50%) type 3 cases with an implantation of a silicone plate of approximate one-third of the usual size in one case. Conventional surgery with silicone plates after failed periosteal suture was required in 2/7 (29%) type 2 cases and 3/6 (50%) type 3 cases. Eye movements were improved postoperatively in all eyes, and a complete range of eye movements was achieved in 6/7 (86%) cases with complete periosteal closure, 1/3 (33%) of cases with partial closure and 2/5 (40%) cases without closure. In conclusion, periosteal suturing can minimize the need for silicone plates especially for anterior or middle orbital floor factures. PMID- 20973894 TI - Modified draping technique for topical anaesthesia ophthalmic surgery. AB - We describe a simple modified technique for draping the eye in cataract surgery under topical anaesthesia. This method minimizes prolapse of the eyelashes into the surgical field without compromising patient comfort and confers several advantages over previously used techniques. PMID- 20973895 TI - Combined trabeculotomy-trabeculectomy augmented with 5-fluorouracil in paediatric glaucoma. AB - BACKGROUND: To describe our experience of combined trabeculotomy-trabeculectomy in paediatric glaucomas with a special emphasis on the use of 5-fluorouracil and releasable sutures. DESIGN: Retrospective review carried out at Manchester Royal Eye Hospital, UK, a tertiary referral centre. PARTICIPANTS: Twenty-nine eyes of 21 consecutive patients with congenital glaucoma undergoing combined trabeculotomy-trabeculectomy augmented with 5-fluorouracil. METHODS: 5 Fluorouracil augmented combined trabeculotomy-trabeculectomy was carried out with intense postoperative management and suture adjustment of releasable sutures within the first 3 weeks after surgery. Peribleb 5-fluorouracil injections were given repeatedly if there were signs of aggressive bleb scarring. MAIN OUTCOME MEASURES: Absolute success was defined as intraocular pressure of 21 mmHg or less, clear cornea and absence of progressive glaucomatous optic disc changes at last follow up, whereas qualified success was defined as these endpoints with anti-glaucoma medication. RESULTS: Absolute success was achieved in 19 out of 29 eyes (65.5%), and a further 4 (13.8%) had qualified success. There was no difference in the surgical outcomes of primary infantile glaucoma and secondary causes of paediatric glaucoma such as anterior segment dysgenesis. Combined trabeculotomy-trabeculectomy had a significantly greater success rate as a secondary procedure rather than as a primary procedure. CONCLUSION: 5 Fluorouracil-enhanced combined trabeculotomy-trabeculectomy with releasable sutures appears to be an effective procedure for congenital glaucoma refractory to goniotomy. It is less effective as a primary procedure when severe corneal haze prevents goniotomy in newborn congenital glaucoma. Intense postoperative monitoring including active bleb manipulation with needling and 5-fluorouracil injections may increase the success of the procedure. PMID- 20973896 TI - Poor utility of intraocular pressure correction formulae in individual glaucoma and glaucoma suspect patients. AB - BACKGROUND: To compare Pascal dynamic contour tonometry (DCT) measurements with Goldmann applanation tonometry (GAT) readings after adjustment with correction formulae in a population of Caucasian glaucoma and glaucoma suspect patients. DESIGN: Retrospective cross-sectional case series in a specialist glaucoma practice. PARTICIPANTS: Consecutive glaucoma and glaucoma suspect Caucasian patients. METHODS: Case notes review of the GAT and DCT intraocular pressure (IOP) measurements from patients who presented on a non-acute basis over a 30 month period. The GAT measurement was adjusted with six different correction formulae. Agreement between GAT IOP, adjusted GAT IOP and DCT IOP was evaluated with the Bland-Altman analysis. MAIN OUTCOME MEASURES: Agreement between GAT IOP (both unadjusted and adjusted) and DCT IOP. RESULTS: Data from 200 patients with a mean age of 58.4 (+/-12.7) years were analysed. The mean central corneal thickness was 554.8 (+/-36.9) um and the mean corneal hysteresis was 9.8 (+/-1.9) mm Hg. Sixty five (32.5%) had confirmed glaucomatous optic neuropathy. GAT IOP demonstrated poor agreement with DCT IOP. GAT IOP was on average 2.1 mm Hg less than DCT IOP. None of the six correction formulae resulted in improved agreement with DCT IOP. General linear model analysis found no statistically significant measurement differences between the glaucoma and glaucoma suspect groups. CONCLUSIONS: GAT demonstrated poor agreement with DCT, and agreement did not improve after adjustment with correction formulae. Our results suggest that correction formulae for GAT IOP are unsuitable to clinically approximate 'true' IOP in Caucasian glaucoma and glaucoma suspect patients. PMID- 20973897 TI - Diabetic retinopathy management by Australian optometrists. AB - BACKGROUND: To survey the current diabetic retinopathy screening and management practices of Australian optometrists following the release of the 1997 National Health Medical Research Council Diabetic Retinopathy Management Guidelines. DESIGN: Cross-sectional national survey, primary care setting. PARTICIPANTS: 1000 Australian optometrists across different states. METHODS: A self-administered questionnaire was sent to 1000 optometrists across all states during 2007/2008. MAIN OUTCOME MEASURES: Use of retinal camera, screening practices/attitudes and behaviour in diabetic retinopathy management. RESULTS: 568 optometrists (57%) responded to the survey. Patients' unpreparedness to drive post dilation (51%) and the fear of angle closure glaucoma (13%) were the two main barriers to optometrists not performing dilated ophthalmoscopy. Those who had strong desire to screen for diabetic retinopathy were more likely to use a retinal camera (p<0.005). Use of a retinal camera was significantly associated with an increased confidence in detecting clinical signs of diabetic retinopathy including macular oedema (P<0.001). Optometrists who read the guidelines at least once were 2.5 times (P<0.001) more likely to have confidence in detecting macular oedema than those who had never read the guidelines. Although they may be confident in diagnosis, and may use retinal cameras for screening, nearly 60% of optometrists would not refer patients with macular oedema to an ophthalmologist. CONCLUSIONS: Despite their self-reported desire for involvement in diabetic retinopathy, the management of macular oedema by Australian optometrists needs improvement. The use of retinal cameras and promotion of the 2008 NHMRC guidelines should be encouraged to improve overall optometric diabetic retinopathy management, particularly with macular oedema. PMID- 20973898 TI - Experimental investigation of needles, syringes and techniques for intravitreal injections. AB - BACKGROUND: To assess the techniques and materials used in intravitreal injections. DESIGN: Descriptive study realized at the Vision Institute of the Federal University of Sao Paulo, Brazil. SAMPLES: Different brands of needles and syringes, as well as enucleated porcine eyeballs. METHODS: The ultra-structures of commonly used needles were analysed by scanning electron microscope, and they were compared using different criteria, such as irregularities and debris from the lubrication process. The scleral incision was also assessed using needles of different brands and sizes. Accuracies in drug administration were studied by comparing the residual and delivered volume of needles and also by the analysis of reflux after intravitreal injections. MAIN OUTCOME MEASURES: Efficiency and quality of materials used in intravitreal injections. RESULTS: Ultra-structure analyses showed that all needles had different types of irregularities. Some photographs showed debris from the lubrication process, especially in BD needles. Scleral incision analysis showed a tendency of reducing the ocular damage with increasing gauge (P=0.024). The investigation of delivery accuracy showed that almost all needles underdosed the amount injected (P<0.05), and that the reflux could be minimized by tunnelled injections with thinner needles. CONCLUSION: Needles used in intravitreal injections possess many irregularities in their structures, which may cause different injection outcomes. Analyses of scleral incisions showed that the larger the needle gauge, the lesser the scleral damage and the risk of complications. Moreover, drug administration inaccuracies might be one of the causes for some unsuccessful attempts of treatment. PMID- 20973892 TI - Intermediate- and longer-term visual outcomes after cataract surgery: the Blue Mountains Eye Study. AB - BACKGROUND: Limited data are available on long-term cataract surgical outcomes. We aimed to compare intermediate-term (up to 5 years) and longer-term (5-10 years) post-surgery visual outcomes in an older Australian population. DESIGN: Population-based cohort. PARTICIPANTS: Persons aged 49+ years, living in the Blue Mountains area, west of Sydney. METHODS: Of 3654 baseline participants of Blue Mountains Eye Study, 75% of survivors were seen at each of the 5- and 10 year follow-up visits; 90 participants (130 eyes) underwent incident cataract surgery during the first 5 years and returned to both follow-up visits. MAIN OUTCOME MEASURES: Changes in visual acuity over time, and ocular conditions affecting visual acuity. RESULTS: After the first (intermediate-term) follow-up period, 33/128 eyes (26%) had presenting visual acuity <6/12. Similarly, after the second (longer-term) period, 27/119 eyes (23%) had presenting visual acuity <6/12. Uncorrected refractive error accounted for 22/33 eyes (66%) with reduced presenting visual acuity at the intermediate term and for 16/27 eyes (59%) at the longer-term follow-up visits. Of 10 eyes with reduced best-corrected visual acuity after longer term, five (50%) were attributed to posterior capsular opacification. Of 115 eyes with refractive error data, 82 (71%) and 70 (61%) were emmetropic, at the intermediate-term and longer-term visits, respectively. CONCLUSION: Over a longer term post cataract surgery, three quarters of eyes achieved presenting visual acuity >=6/12 and nearly two-thirds achieved emmetropia. Uncorrected refractive error and posterior capsular opacification were the main causes of poor vision in operated eyes, a finding emphasizing the need for ongoing eye care services post cataract surgery. PMID- 20973899 TI - Spontaneous resolution of corneal decompensation after big-bubble deep anterior lamellar keratoplasty with intraoperative Descemet's membrane perforation. PMID- 20973900 TI - Management of neovascular glaucoma with transscleral cyclophotocoagulation with diode laser alone versus combination transscleral cyclophotocoagulation with diode laser and intravitreal bevacizumab. AB - BACKGROUND: Trans-scleral cyclophotocoagulation with diode laser has been well documented in the management of neovascular glaucoma. More recently, intravitreal bevacizumab has been increasingly employed to treat neovascular diseases of the eye. This study reports our initial experience with trans-scleral cyclophotocoagulation alone versus the combination of trans-scleral cyclophotocoagulation and intravitreal bevacizumab for management of neovascular glaucoma. DESIGN: Retrospective uncontrolled comparative case series PARTICIPANTS: A total of 31 eyes of 30 consecutive patients were included - 11 eyes in the trans-scleral cyclophotocoagulation alone group and 20 in the combination trans-scleral cyclophotocoagulation and intravitreal bevacizumab group. METHODS: The records of all patients diagnosed with neovascular glaucoma undergoing trans-scleral cyclophotocoagulation with or without intravitreal bevacizumab performed by a single ophthalmic surgeon in a glaucoma specialist centre were reviewed. MAIN OUTCOME MEASURES: Data collected included intraocular pressure, anterior segment neovascularisation, best-corrected visual acuity, use of medications and complications. RESULTS: Mean reduction in intraocular pressure was 33.5 mmHg in the trans-scleral cyclophotocoagulation group and 23.7 mmHg in the combination group, a difference of 9.8 mmHg (95% CI -1.5, 21.1). Complications included hypotony in three (27%) eyes in the trans-scleral cyclophotocoagulation group and two (10%) eyes in the combination group. Three eyes required evisceration. CONCLUSIONS: Trans-scleral cyclophotocoagulation alone is effective in lowering intraocular pressure in neovascular glaucoma. In this study, the addition of intravitreal bevacizumab to trans-scleral cyclophotocoagulation did not statistically advantage treatment outcomes. PMID- 20973901 TI - Anterior chamber gas bubble following pneumatic retinopexy in a young, phakic patient. PMID- 20973902 TI - Upregulation of the production of interferon-gamma and the gene expression of the inducible nitric oxide synthase after excimer laser ablation in rat corneas. PMID- 20973904 TI - Clinical evaluation of the Softec HD aberration-free aspheric intraocular lens. PMID- 20973903 TI - Glaucoma progression associated with altered cerebral spinal fluid levels of amyloid beta and tau proteins. PMID- 20973905 TI - Intraocular pressure elevation in isolated extraocular muscle infiltration by leukaemia. PMID- 20973906 TI - Vascular risk factors in glaucoma: a review. AB - Glaucoma, one of the major causes of blindness in the world, is a progressive optic neuropathy. Elevated intraocular pressure is a well-known major risk factor for glaucoma. In addition, there is growing evidence that vascular factors may play a role in glaucoma pathogenesis. Systemic (e.g. hypertension, diabetes) and ocular vascular factors (e.g. ocular blood flow, ocular perfusion pressure) have been assessed for associations with glaucoma. However, direct and convincing evidence for primary mechanisms of glaucoma is still lacking. The aim of this review is to summarize the evidence implicating vascular factors in the pathogenesis of glaucoma, with particular emphasis on the role of ocular blood flow and ocular circulation as risk factors for primary open angle glaucoma. PMID- 20973908 TI - Comparison of the FreeHand(r) robotic camera holder with human assistants during endoscopic extraperitoneal radical prostatectomy. AB - OBJECTIVE: * To assess, in a prospective randomized study, the efficiency of the FreeHand(r) (Prosurgics Ltd, Bracknell, UK) compared to manual camera control during the performance of endoscopic extraperitoneal radical prostatectomy (EERPE). PATIENTS AND METHODS: * Three surgeons performed 50 EERPE for localized prostate cancer. In group A (n= 25), procedures were performed with manual control of the camera by the assistant, whereas group B (n= 25) patients were treated with the assistance of the FreeHand(r) robotic device. * The EERPE procedure was divided into several steps. * Total operation duration, time for each surgical step, number of camera movements, number of movement errors, number of times the lens was cleaned, blood loss and margin status were compared. RESULTS: * No statistically significant difference was observed in terms of patient age, preoperative prostate-specific antigen level, Gleason score, positive cores and prostate volume. * The average operation duration required for the performance of each step did not differ significantly between the two groups. * Significant differences in favour of the FreeHand(r) camera holder were observed in case of horizontal and zooming camera movement, camera cleaning and camera errors. * Vertical camera movements were performed significantly faster by the human assistant compared to the robotic camera holder. * The average total operation duration was similar for both groups. * Positive surgical margins were detected in one patient in each group (4% of the patients). CONCLUSIONS: * A comparison of the FreeHand(r) robotic camera holder with human camera control during EERPE showed a similar time requirement for the performance of each step of the procedure. * The robotic system provided accurate and fast movements of the camera without compromising the outcome of the procedure. PMID- 20973907 TI - Controls on pathogen species richness in plants' introduced and native ranges: roles of residence time, range size and host traits. AB - Introduced species escape many pathogens and other enemies, raising three questions. How quickly do introduced hosts accumulate pathogen species? What factors control pathogen species richness? Are these factors the same in the hosts' native and introduced ranges? We analysed fungal and viral pathogen species richness on 124 plant species in both their native European range and introduced North American range. Hosts introduced 400 years ago supported six times more pathogens than those introduced 40 years ago. In hosts' native range, pathogen richness was greater on hosts occurring in more habitat types, with a history of agricultural use and adapted to greater resource supplies. In hosts' introduced range, pathogen richness was correlated with host geographic range size, agricultural use and time since introduction, but not any measured biological traits. Introduced species have accumulated pathogens at rates that are slow relative to most ecological processes, and contingent on geographic and historic circumstance. PMID- 20973909 TI - Prospective randomized trial of three different methods of nephrostomy tract closure after percutaneous nephrolithotripsy. AB - OBJECTIVE: * To evaluate the safety and efficacy of 'tubeless' nephrostomy tract closure in reducing postoperative morbidity after percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: * In all, 31 patients undergoing PCNL were randomized into three groups, each with a different method of nephrostomy tract closure: using either a gelatin matrix haemostatic sealant (FloSeal), fascial stitch or Cope loop nephrostomy tube. * We compared operative time, estimated blood loss (EBL), postoperative stay, analgaesics use, changes in creatinine and haemoglobin levels, and stone clearance rate, as well as postoperative short-form (SF)-36 quality-of-life and pain analogue scores at five different time points after surgery. * All data were analysed using a one-way anova test. * A repeated measures anova test was used selectively to assess the progression of SF-36 and pain analogue scores. RESULTS: * The preoperative variables operative time, EBL, postoperative stay (P = 0.45), analgaesia use (P = 0.79), changes in creatinine (P = 0.28) and haemoglobin (P = 0.09) levels, and postoperative SF-36 scores were not significantly different. * In contrast, the differences in analogue pain scales at 1 week after surgery (P = 0.02) and the trends of analogue pain score progression (P = 0.03) were statistically significant. * Three patients underwent second-look procedures for residual stones and there was one case of postoperative pyelonephritis in a multiple sclerosis patient. CONCLUSIONS: * The Cope loop closure patients recovered fastest, while FloSeal closure patients experienced initial increase in pain followed by resolution at 1 month. * As a result of the small study group sizes, it is difficult to show any significant difference in postoperative pain, especially in long-term follow-up; further clinical evaluation is necessary. PMID- 20973910 TI - Simulation models of obesity: a review of the literature and implications for research and policy. AB - Simulation models (SMs) combine information from a variety of sources to provide a useful tool for examining how the effects of obesity unfold over time and impact population health. SMs can aid in the understanding of the complex interaction of the drivers of diet and activity and their relation to health outcomes. As emphasized in a recently released report of the Institute or Medicine, SMs can be especially useful for considering the potential impact of an array of policies that will be required to tackle the obesity problem. The purpose of this paper is to present an overview of existing SMs for obesity. First, a background section introduces the different types of models, explains how models are constructed, shows the utility of SMs and discusses their strengths and weaknesses. Using these typologies, we then briefly review extant obesity SMs. We categorize these models according to their focus: health and economic outcomes, trends in obesity as a function of past trends, physiologically based behavioural models, environmental contributors to obesity and policy interventions. Finally, we suggest directions for future research. PMID- 20973911 TI - The levelling off of the obesity epidemic since the year 1999--a review of evidence and perspectives. AB - The purpose was to investigate a possible levelling off in the obesity epidemic, by systematically reviewing literature and web-based sources. Eligible studies and data sources were required to have at least two measures of obesity prevalence since 1999. A literature and Internet search resulted in 52 studies from 25 different countries. The findings supported an overall levelling off of the epidemic in children and adolescents from Australia, Europe, Japan and the USA. In adults, stability was found in the USA, while increases were still observed in some European and Asian countries. Some evidence for heterogeneity in the obesity trends across socioeconomic status (SES) groups was found. The levelling off was less evident in the lower-SES groups. No obvious differences between genders were identified. We discussed potential explanations for a levelling off and the utility of investigating obesity trends to identify the driving forces behind the epidemic. It is important to emphasize that the levelling off is not tantamount to calling off the epidemic. Additionally, it is worthwhile to keep in mind that previous stable phases have been followed by further increases in the prevalence of obesity. Therefore, research into the causes, prevention and treatment of obesity should remain a priority. PMID- 20973912 TI - Role of protein kinase C in caerulein induced expression of substance P and neurokinin-1-receptors in murine pancreatic acinar cells. AB - Substance P (SP) is involved in the pathophysiology of acute pancreatitis (AP) via binding to its high-affinity receptor, neurokinin-1-receptor (NK1R). An up regulation of SP and NK1R expression was observed in experimental AP and in caerulein-stimulated pancreatic acinar cells. However, the mechanisms that lead to this up-regulation are not fully understood. In this study, we showed the role of protein kinase C (PKC) in caerulein-induced SP and NK1R production in isolated mouse pancreatic acinar cells. Caerulein (10(-7) M) stimulation rapidly activated the conventional PKC-alpha and novel PKC-delta as observed by the phosphorylation of these molecules. Pre-treatment of pancreatic acinar cells with Go6976 (1-10 nM) and rottlerin (1-10 MUM) inhibited PKC-alpha and PKC-delta phosphorylation, respectively, but not the other way round. At these concentrations used, PKC-alpha and PKC-delta inhibition reversed the caerulein induced up-regulation of SP and NK1R, indicating an important role of PKCs in the modulation of SP and NK1R expression. Further experiments looking into signalling mechanisms showed that treatment of pancreatic acinar cells with both Go6976 and rottlerin inhibited the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). Inhibition of PKC-alpha or PKC-delta also affected caerulein-induced transcription factor activation, as represented by nuclear factor-kappaB and AP-1 DNA-binding activity. The findings in this study suggested that PKC is upstream of the mitogen-activated protein kinases and transcription factors, which then lead to the up-regulation of SP/NK1R expression in caerulein-treated mouse pancreatic acinar cells. PMID- 20973914 TI - Dorothy's Tin Man: long-term survival of a heart transplant patient without immunosuppressive therapy? PMID- 20973913 TI - Long-term renal allograft survival in the United States: a critical reappraisal. AB - Renal allograft survival has increased tremendously over past decades; this has been mostly attributed to improvements in first-year survival. This report describes the evolution of renal allograft survival in the United States where a total of 252 910 patients received a single-organ kidney transplant between 1989 and 2009. Half-lives were obtained from the Kaplan-Meier and Cox models. Graft half-life for deceased-donor transplants was 6.6 years in 1989, increased to 8 years in 1995, then after the year 2000 further increased to 8.8 years by 2005. More significant improvements were made in higher risk transplants like ECD recipients where the half-lives increased from 3 years in 1989 to 6.4 years in 2005. In low-risk populations like living-donor-recipients half-life did not change with 11.4 years in 1989 and 11.9 years in 2005. First-year attrition rates show dramatic improvements across all subgroups; however, attrition rates beyond the first year show only small improvements and are somewhat more evident in black recipients. The significant progress that has occurred over the last two decades in renal transplantation is mostly driven by improvements in short-term graft survival but long-term attrition is slowly improving and could lead to bigger advances in the future. PMID- 20973915 TI - Therapeutic potential for CD39 in renal transplantation: there is hope. PMID- 20973916 TI - Native renal cysts and dialysis duration are risk factors for renal cell carcinoma in renal transplant recipients. AB - Urinary tract cancers are the third most common cancers in renal transplant recipients (RTX). This study examined the impact of dialysis duration and native renal cyst(s) (NRC) on renal cell carcinoma (RCC) occurrence among 1036 RTX followed-up from 1995 to July 2007. Abdominal ultrasonography was planned within 1-month of transplant, then every 5 years, or 2 years if renal cysts developed. Based on presence and time of development of NRC, RTX were grouped into those with no (No-NRC), new (New-NRC), preexisting (Pre-NRC) and time-indeterminate NRC (TI-NRC). Ten asymptomatic RTX were diagnosed with RCC at a median of 5.8 years posttransplant and had 5-year graft and patient survivals of 90% and 100%, respectively, following appropriate therapy. RCC occurred only in Pre-NRC and TI NRC who had significantly longer dialysis duration than No- or New-NRC (6.7 +/- 3.9 and 3.3 +/- 3.2 vs. 2.7 +/- 3.1 and 2.6 +/- 2.4 years, respectively). These results suggest that NRC and increased dialysis duration are risk factors for RCC posttransplant. Since early treatment of RCC gives excellent outcomes, regular ultrasonography performed within a month of transplantation, then every 5 years for those without cysts and every 2 years for those with cysts for early detection of RCC is recommended. PMID- 20973918 TI - Lives in translation. PMID- 20973917 TI - Synthesis, molecular docking, and biological evaluation of novel triazole derivatives as antifungal agents. AB - Twenty-eight novel triazole derivatives (compounds 1a-v, 2a-f) have been synthesized for structure-activity relationship studies as antifungal agents. The compounds were designed on the basis of the structure of fluconazole and molecular modeling of the active site of the cytochrome P450 14alpha-demethylase (CYP51). All of them are reported for the first time. Their chemical structures are characterized by (1) H NMR, (13) C NMR, LC-MS, and elemental analysis. The antifungal activities have been evaluated in vitro by measuring the minimal inhibitory concentrations (MICs). Compounds 1a-v exhibited higher activity against nearly all fungi tested except Aspergillus fumigatus (A. fum) than fluconazole (FCZ). The computational molecular docking experiments indicated that the inhibition of CYP51 involves a coordination bond with iron of the heme group, a hydrophilic H-bonding region, a hydrophobic region, and a narrow hydrophobic binding cleft. PMID- 20973920 TI - Altered immune phenotype in peripheral blood cells of patients with scleroderma associated pulmonary hypertension. AB - Pulmonary arterial hypertension is a common and fatal complication of scleroderma that may involve inflammatory and autoimmune mechanisms. Alterations in the gene expression of peripheral blood mononuclear cells have been previously described in patients with pulmonary arterial hypertension. Our goal is to identify differentially expressed genes in peripheral blood mononuclear cells in scleroderma patients with and without pulmonary hypertension as biomarkers of disease. Gene expression analysis was performed on a Microarray Cohort of scleroderma patients with (n = 10) and without (n = 10) pulmonary hypertension. Differentially expressed genes were confirmed in the Microarray Cohort and validated in a Validation Cohort of scleroderma patients with (n = 15) and without (n = 19) pulmonary hypertension by RT-qPCR. We identified inflammatory and immune-related genes including interleukin-7 receptor (IL-7R) and chemokine receptor 7 as differentially expressed in patients with scleroderma-associated pulmonary hypertension. Flow cytometry confirmed decreased expression of IL-7R on circulating CD4+ T-cells from scleroderma patients with pulmonary hypertension. Differences exist in the expression of inflammatory and immune-related genes in peripheral blood cells from patients with scleroderma-related pulmonary hypertension compared to those with normal pulmonary artery pressures. These findings may have implications as biomarkers to screen at-risk populations for early diagnosis and provide insight into mechanisms of scleroderma-related pulmonary hypertension. PMID- 20973921 TI - Late onset sporadic dilated cardiomyopathy caused by a cardiac troponin T mutation. AB - Mutations in TNNT2, encoding cardiac troponin T, commonly shows early onset, aggressive dilated cardiomyopathy (DCM). This observation may influence the decision of whether to undertake clinical genetic testing for TNNT2 in later onset DCM. Further, the trigger for late onset DCM remains enigmatic. A 70-year old woman, previously healthy with a left ventricular ejection fraction of 50% 55% at age 69, presented with DCM of unknown cause and a 4-month history progressive heart failure requiring cardiac transplantation. Clinical genetic testing revealed a novel TNNT2 R139H mutation but no relevant variants in 18 other DCM genes. Her explanted heart showed partial fatty replacement in the right ventricle. Sequencing for five arrhythmogenic right ventricular dysplasia genes was negative. Functional studies in porcine cardiac skinned fibers reconstituted with the mutant R139H troponin T protein showed decreased Ca(2+) sensitivity at pH 7, characteristic of DCM. Because fatty infiltration may acidify the myocellular environment, maximal force development examined at pH 6.5 was diminished, suggesting a possible environmental trigger. We conclude that the TNNT2 R139H mutation was likely to be disease causing. Further, later age of onset may not be relevant to exclude genetic testing for TNNT2 mutations. PMID- 20973923 TI - Clinical and translational science: from bench-bedside to global village. PMID- 20973922 TI - Rationale and design of the treatment of hyponatremia based on lixivaptan in NYHA class III/IV cardiac patient evaluation (THE BALANCE) study. AB - Hyponatremia is a common electrolyte disorder in patients with heart failure (HF) associated with cognitive dysfunction and increased mortality and rehospitalization rates. Loop diuretics worsen renal function, produce neurohormonal activation, and induce electrolyte imbalances. Lixivaptan is a selective, oral vasopressin V(2) -receptor antagonist that improves hyponatremia by promoting electrolyte-free aquaresis without significant side effects. The Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation (BALANCE) study is a randomized, double-blind, placebo controlled, phase 3 trial designed to evaluate the effects of lixivaptan on serum sodium in patients hospitalized with worsening heart failure (target N= 650), signs of congestion and serum sodium concentrations <135 mEq/L. Other endpoints include assessment of dyspnea, body weight, cognitive function, and days of hospital-free survival. Patients are randomized 1:1 to lixivaptan or matching placebo for 60 days, with a 30-day safety follow-up. Doses of lixivaptan or placebo are adjusted based on serum sodium and volume status. Lixivaptan was shown to increase serum sodium and reduce body weight, without renal dysfunction or hypokalemia. BALANCE seeks to address unmet questions regarding the use of vasopressin antagonists including their effects on cognitive function and clinical outcomes in patients with hyponatremia and worsening heart failure. PMID- 20973924 TI - Training and career development for comparative effectiveness research workforce development: CTSA Consortium Strategic Goal Committee on comparative effectiveness research workgroup on workforce development. AB - As comparative effectiveness research (CER) increasingly becomes a national priority, there are increased needs for training and workforce development in this area. Particularly important CER competencies include clinical epidemiology, biomedical informatics, economic analyses, systematic reviews, clinical practice guideline development, use of large databases and electronic health records for research, practice-based research, implementation and dissemination, health services research, and decision analysis. Institutions funded by Clinical and Translational Science Awards (CTSAs) should be one of the central stakeholders in providing training and career development in CER. Survey results regarding the current CER capacity and needs of CTSAs are presented, and recommendations are provided. Volume 5: 258-262. PMID- 20973925 TI - Advancing the science of team science. AB - The First Annual International Science of Team Science (SciTS) Conference was held in Chicago, IL April 22-24, 2010. This article presents a summary of the Conference proceedings. PMID- 20973926 TI - Erythropoiesis-stimulating agents and heart failure. AB - Anemia is a common comorbidity in heart failure (HF) patients. Its occurrence and severity are associated with worse prognosis. Although the etiology of anemia is multifactorial, inappropriate erythropoietin (EPO) production and/or bone-marrow resistance to EPO appear crucial in majority of anemic HF patients. Consequently, treatment based on this pathophysiological background may prove to be most effective and beneficial. In a number of smaller clinical studies, administration of erythropoiesis-stimulating agents (ESAs) to anemic HF patients improved a number of surrogate endpoints, including left ventricular function, exercise capacity, renal function, and different quality of life parameters. However, two larger, phase II studies, did not fully confirm these promising results. Furthermore, many concerns have been raised on the safety of ESAs after the recent publication of studies correcting anemia in patients with chronic kidney disease (CKD). On the other hand, chronic HF population varies significantly from CKD patients, with different comorbidities, renal function, and etiology of anemia. Moreover, ESAs have been shown to possess robust nonhematopoietic effects in the heart, namely inhibition of apoptosis and stimulation of neovascularization. Therefore, large-scale trials with ESAs are required to examine the effect and safety of anemia treatment in HF patients. PMID- 20973927 TI - Allopurinol attenuates oxidative stress and cardiac fibrosis in angiotensin II induced cardiac diastolic dysfunction. AB - AIMS: Oxidative stress and fibrosis is implicated in cardiac remodeling and failure. We tested whether allopurinol could decrease myocardial oxidative stress and attenuate cardiac fibrosis and left ventricular diastolic dysfunction in angiotensin II (AngII)-induced hypertensive mice. METHODOLOGY: We used 8-week-old male C57BL/6J mice, in which angiotensin II was subcutaneously infused for 4 weeks to mimic cardiac remodeling and fibrosis. They were treated with either normal saline or allopurinol in daily doses, which did not lower blood pressure. RESULTS: Allopurinol improved diastolic dysfunction in angiotensin II-induced hypertensive mice, which was associated with the amelioration of cardiac fibrosis. However, allopurinol showed no effect on the increased systolic blood pressure by angiotensin II infusion. The ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) [GSH/GSSG] was decreased and malondialdehyde levels were increased in the hearts of AngII-treated mice. Allopurinol also inhibited both the decrease in the GSH/GSSG ratio and the increase in malondialdehyde levels in the heart. Infusion of AngII-induced upregulation of transfer growth factor (TGF)-beta1, Smad3 expression and downregulation of Smad7 expression. Treatment with allopurinol reduced cardiac levels of TGF-beta1, Smad3, and increased Smad7 expression. CONCLUSIONS: These results suggest that allopurinol prevents pathological remodeling of the heart in AngII-induced hypertensive mice. The antioxidative effect of allopurinol contributes to the regression of AngII induced cardiac diastolic dysfunction. These effects of allopurinol to prevent cardiac fibrosis are mediated at least partly through modulation of the TGF beta1/Smad signaling pathway. PMID- 20973928 TI - MITF--past, present and future. PMID- 20973929 TI - Estela Medrano, 1943-2010. PMID- 20973930 TI - Lighting a path to pigmentation: mechanisms of MITF induction by UV. AB - While sunlight is important for life, ultraviolet radiation (UVR) can have harmful and mutagenic effects. This duality is particularly relevant to human skin, in which UVR both participates in evolutionarily important photochemical reactions yet may act as a potential carcinogen. UVR can upregulate production of melanin, the "tanning response" that serves a photoprotective function. This genetic program is centrally tuned by the transcription factor MITF, a master regulator of melanogenesis and melanocyte function. In this review, we discuss the myriad consequences of UV exposure for skin homeostasis, highlighting the diverse pathways activated by this ultraviolet radiation. PMID- 20973931 TI - Oncogenic RAF: a brief history of time. PMID- 20973934 TI - Boris Bastian. PMID- 20973933 TI - The aryl hydrocarbon receptor (AHR), a novel regulator of human melanogenesis. AB - Skin cancer, chloracne and hyperpigmentation have been associated with the exposure to environmental contaminants such as polychlorinated biphenyls, dioxins or polycyclic aromatic hydrocarbons. These compounds are xenobiotic high-affinity ligands for the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor with important physiological roles in, for example, the control of cell proliferation and inflammation. We show here that exposure of normal human melanocytes to the most potent dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), results in activation of the AHR signaling pathway and an AHR-dependent induction of tyrosinase activity, the key enzyme of the melanogenic pathway. In accordance with the upregulation of tyrosinase enzyme activity, total melanin content was also elevated in TCDD-exposed melanocytes. Neither the induction of tyrosinase enzyme activity or of total melanin could be attributed to enhanced cell proliferation, but was rather due to the induction of tyrosinase and tyrosinase-related protein 2 gene expression. Thus, the AHR is able to modulate melanogenesis by controlling the expression of melanogenic genes. PMID- 20973935 TI - Mouse melanoma models and cell lines. PMID- 20973932 TI - PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibits V600E-positive melanomas. AB - Targeted intervention of the B-Raf V600E gene product that is prominent in melanoma has been met with modest success. Here, we characterize the pharmacological properties of PLX4032, a next-generation inhibitor with exquisite specificity against the V600E oncogene and striking anti-melanoma activity. PLX4032 induces potent cell cycle arrest, inhibits proliferation, and initiates apoptosis exclusively in V600E-positive cells in a variety of in vitro experimental systems; follow-up xenograft studies demonstrate extreme selectivity and efficacy against melanoma tumors bearing the V600E oncoproduct. The collective data support further exploration of PLX4032 as a candidate drug for patients with metastatic melanoma; accordingly, validation of PLX4032 as a therapeutic tool for patients with melanoma is now underway in advanced human (Phase III) clinical trials. PMID- 20973937 TI - Abstracts of the 23rd Annual Meeting of the Japanese Society for Pigment Cell Research. November 27-28, 2010. Tokyo, Japan. PMID- 20973938 TI - Abstracts of Melanoma 2010 Congress, the 7th International Melanoma Research Congress and the 4th Melanoma & Skin Cancer Centres Meeting. November 4-7, 2010. Sydney, Australia. PMID- 20973940 TI - Abstracts from the meeting Parasite to Prevention: Advances in the Understanding of Malaria. Edinburgh, United Kingdom. October 20-22, 2010. PMID- 20973942 TI - Chylous effusion presenting in a 37-year-old woman with severe hypothyroidism: a case report. AB - INTRODUCTION: We report what is to the best of our knowledge the second adult case of chylothorax clearly associated with severe hypothyroidism in the English language medical literature. To the best of our knowledge, this is the first case of its kind reported without a prior history of malignancy. CASE PRESENTATION: A 37-year-old Hispanic woman with no reported significant past medical history initially presented with shortness of breath and inability to lose weight. She was found to have a large chylous effusion requiring chest-tube drainage, as well as severe hypothyroidism. After several weeks of thyroid hormone-replacement therapy, the formation of chylous pleural fluid in the patient greatly diminished, and the chest tube was removed. Upon long-term follow-up her minimal residual effusion remains stable on serial chest radiographs. CONCLUSION: Although the exact pathophysiologic relation between low thyroid hormone levels and chyle formation remains to be elucidated, hypothyroidism should be a diagnostic consideration in patients with chylous effusions, especially those refractory to conventional treatments. PMID- 20973943 TI - Hashimoto's encephalopathy presenting with neurocognitive symptoms: a case report. AB - INTRODUCTION: Hashimoto's encephalopathy is a neurological disorder of unknown cause associated with thyroid autoimmunity. The disease occurs primarily in the fifth decade of life and may present in two types - a sudden vasculitic type or a progressive subacute type associated to cognitive dysfunction, confusion and memory loss. CASE PRESENTATION: We report the case of a 62-year-old Hispanic woman, previously healthy, who developed a subacute onset of declining upper brain function. Serologic studies demonstrated high levels of antithyroid antibodies. Electroencephalographic and magnetic resonance image findings were consistent with Hashimoto's encephalopathy. CONCLUSION: Hashimoto's encephalopathy is a diagnosis of exclusion. This unusual disorder is often under recognized because of the multiple and protracted neurocognitive manifestations; therefore, it is important to be aware of the clinical manifestations to make a correct diagnosis. PMID- 20973941 TI - Simultaneous bilateral hip replacement reveals superior outcome and fewer complications than two-stage procedures: a prospective study including 1819 patients and 5801 follow-ups from a total joint replacement registry. AB - BACKGROUND: Total joint replacements represent a considerable part of day-to-day orthopaedic routine and a substantial proportion of patients undergoing unilateral total hip arthroplasty require a contralateral treatment after the first operation. This report compares complications and functional outcome of simultaneous versus early and delayed two-stage bilateral THA over a five-year follow-up period. METHODS: The study is a post hoc analysis of prospectively collected data in the framework of the European IDES hip registry. The database query resulted in 1819 patients with 5801 follow-ups treated with bilateral THA between 1965 and 2002. According to the timing of the two operations the sample was divided into three groups: I) 247 patients with simultaneous bilateral THA, II) 737 patients with two-stage bilateral THA within six months, III) 835 patients with two-stage bilateral THA between six months and five years. RESULTS: Whereas postoperative hip pain and flexion did not differ between the groups, the best walking capacity was observed in group I and the worst in group III. The rate of intraoperative complications in the first group was comparable to that of the second. The frequency of postoperative local and systemic complication in group I was the lowest of the three groups. The highest rate of complications was observed in group III. CONCLUSIONS: From the point of view of possible intra- and postoperative complications, one-stage bilateral THA is equally safe or safer than two-stage interventions. Additionally, from an outcome perspective the one stage procedure can be considered to be advantageous. PMID- 20973944 TI - Late presentation of sorafenib-associated rash: a case report. AB - INTRODUCTION: Sorafenib, an oral multitargeted tyrosine kinase inhibitor, is licensed for the treatment of hepatocellular carcinoma. Rash is one of the most common side effects of its use, generally appearing within days to a few weeks of commencing treatment. We report the first case of rash appearing nine months after starting treatment with sorafenib. CASE PRESENTATION: A 75-year-old Caucasian man initially presented with asymptomatic transient jaundice. He was diagnosed with Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma after extensive investigation. He tolerated sorafenib 400 mg twice a day before presenting nine months later with a rash, confirmed to be drug-induced. CONCLUSIONS: Sorafenib is a drug of choice in Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma. It can cause protracted rash quite late into treatment. Successful management of the rash could contribute to achieving stable disease in hepatocellular carcinoma over a significant period of time. PMID- 20973945 TI - Haemodynamics and oxygenation improvement induced by high frequency percussive ventilation in a patient with hypoxia following cardiac surgery: a case report. AB - INTRODUCTION: High frequency percussive ventilation is a ventilatory technique that delivers small bursts of high flow respiratory gas into the lungs at high rates. It is classified as a pneumatically powered, pressure-regulated, time cycled, high-frequency flow interrupter modality of ventilation. High frequency percussive ventilation improves the arterial partial pressure of oxygen with the same positive end expiratory pressure and fractional inspiratory oxygen level as conventional ventilation using a minor mean airway pressure in an open circuit. It reduces the barotraumatic events in a hypoxic patient who has low lung compliance. To the best of our knowledge, there have been no papers published about this ventilation modality in patients with severe hypoxaemia after cardiac surgery. CASE PRESENTATION: A 75-year-old Caucasian man with an ejection fraction of 27 percent, developed a lung infection with severe hypoxaemia [partial pressure of oxygen/fractional inspiratory oxygen of 90] ten days after cardiac surgery. Conventional ventilation did not improve the gas exchange. He was treated with high frequency percussive ventilation for 12 hours with a low conventional respiratory rate (five per minute). His cardiac output and systemic and pulmonary pressures were monitored.Compared to conventional ventilation, high frequency percussive ventilation gives an improvement of the partial pressure of oxygen from 90 to 190 mmHg with the same fractional inspiratory oxygen and positive end expiratory pressure level. His right ventricular stroke work index was lowered from 19 to seven g-m/m2/beat; his pulmonary vascular resistance index from 267 to 190 dynes*seconds/cm5/m2; left ventricular stroke work index from 28 to 16 gm-m/m2/beat; and his pulmonary arterial wedge pressure was lowered from 32 to 24 mmHg with a lower mean airway pressure compared to conventional ventilation. His cardiac index (2.7 L/min/m2) and ejection fraction (27 percent) did not change. CONCLUSION: Although the high frequency percussive ventilation was started ten days after the conventional ventilation, it still improved the gas exchange. The reduction of right ventricular stroke work index, left ventricular stroke work index, pulmonary vascular resistance index and pulmonary arterial wedge pressure is directly related to the lower respiratory mean airway pressure and the consequent afterload reduction. PMID- 20973946 TI - New diagnostics for tuberculosis: fulfilling patient needs first. AB - BACKGROUND: An effective tuberculosis (TB) control programme requires early diagnosis and immediate initiation of treatment. Any delays in diagnosing TB not only impair a patient's prognosis, but also increase the risks of transmitting the disease within the community. Unfortunately, the most recent TB diagnostic tools still depend on high-infrastructure laboratories, making them poorly adapted for use in resource-limited settings. Additionally, existing tests show poor performance in diagnosing TB in children, people living with HIV/AIDS, and extrapulmonary forms of the disease. As a consequence, TB patients are still to date left with either fair access to poor diagnostics or poor access to fair diagnostics. DISCUSSION: This article discusses recent efforts to identify the minimal test specifications for a new TB point-of-care diagnostic test through an approach based on medical and patient needs. As a first step, survey interviews with field practitioners were designed in order to identify the top-priority medical needs in resource-limited settings concerning new TB diagnostics. Subsequently, an expert meeting convening field practitioners, laboratory experts, diagnostic test developers and researchers was held with the objective of defining the minimal test specifications for a new TB point-of-care test that would meet the identified medical needs. Finally, gaps in, as well as potential solutions for, enabling the development of adequate, patient needs-driven, low cost new TB diagnostic tests specifically designed for vulnerable populations are discussed. SUMMARY: Any new TB point-of-care diagnostic test should be designed to meet minimal specifications satisfying the most urgent medical needs in resource-poor settings. The major gaps for developing a new TB point-of-care test include identification of new biomarkers, simplification of technological platforms, development of adequate and accessible specimen banks, and identification and definition of reference standards for diagnosis of childhood TB. Innovative research and development funding ensuring de-linkage of research and development costs from the price of the new product, such as a prize fund mechanism, could help focus these efforts towards the delivery of a much-needed point-of-care diagnostic test for TB. PMID- 20973947 TI - Formalization of taxon-based constraints to detect inconsistencies in annotation and ontology development. AB - BACKGROUND: The Gene Ontology project supports categorization of gene products according to their location of action, the molecular functions that they carry out, and the processes that they are involved in. Although the ontologies are intentionally developed to be taxon neutral, and to cover all species, there are inherent taxon specificities in some branches. For example, the process 'lactation' is specific to mammals and the location 'mitochondrion' is specific to eukaryotes. The lack of an explicit formalization of these constraints can lead to errors and inconsistencies in automated and manual annotation. RESULTS: We have formalized the taxonomic constraints implicit in some GO classes, and specified these at various levels in the ontology. We have also developed an inference system that can be used to check for violations of these constraints in annotations. Using the constraints in conjunction with the inference system, we have detected and removed errors in annotations and improved the structure of the ontology. CONCLUSIONS: Detection of inconsistencies in taxon-specificity enables gradual improvement of the ontologies, the annotations, and the formalized constraints. This is progressively improving the quality of our data. The full system is available for download, and new constraints or proposed changes to constraints can be submitted online at https://sourceforge.net/tracker/?atid=605890&group_id=36855. PMID- 20973948 TI - Neurobrucellosis with transient ischemic attack, vasculopathic changes, intracerebral granulomas and basal ganglia infarction: a case report. AB - INTRODUCTION: Central nervous system involvement is a rare but serious manifestation of brucellosis. We present an unusual case of neurobrucellosis with transient ischemic attack, intracerebral vasculopathy granulomas, seizures, and paralysis of sixth and seventh cranial nerves. CASE PRESENTATION: A 17-year-old Caucasian man presented with nausea and vomiting, headache, double vision and he gave a history of weakness in the left arm, speech disturbance and imbalance. Physical examination revealed fever, doubtful neck stiffness and left abducens nerve paralysis. An analysis of his cerebrospinal fluid showed a pleocytosis (lymphocytes, 90%), high protein and low glucose levels. He developed generalized tonic-clonic seizures, facial paralysis and left hemiparesis. Cranial magnetic resonance imaging demonstrated intracerebral vasculitis, basal ganglia infarction and granulomas, mimicking the central nervous system involvement of tuberculosis. On the 31st day of his admission, neurobrucellosis was diagnosed with immunoglobulin M and immunoglobulin G positivity by standard tube agglutination test and enzyme-linked immunosorbent assay in both serum and cerebrospinal fluid samples (the tests had been negative until that day). He was treated successfully with trimethoprim and sulfamethoxazole, doxycyline and rifampicin for six months. CONCLUSIONS: Our patient illustrates the importance of suspecting brucellosis as a cause of meningoencephalitis, even if cultures and serological tests are negative at the beginning of the disease. As a result, in patients who have a history of residence or travel to endemic areas, neurobrucellosis should be considered in the differential diagnosis of any neurologic symptoms. If initial tests fail, repetition of these tests at appropriate intervals along with complementary investigations are indicated. PMID- 20973949 TI - Subclinical responses in healthy cyclists briefly exposed to traffic-related air pollution: an intervention study. AB - BACKGROUND: Numerous epidemiological studies have demonstrated adverse health effects of a sedentary life style, on the one hand, and of acute and chronic exposure to traffic-related air pollution, on the other. Because physical exercise augments the amount of inhaled pollutants, it is not clear whether cycling to work in a polluted urban environment should be encouraged or not. To address this conundrum we investigated if a bicycle journey along a busy commuting road would induce changes in biomarkers of pulmonary and systematic inflammation in a group of healthy subjects. METHODS: 38 volunteers (mean age: 43 +/- 8.6 years, 26% women) cycled for about 20 minutes in real traffic near a major bypass road (road test; mean UFP exposure: 28,867 particles per cm3) in Antwerp and in a laboratory with filtered air (clean room; mean UFP exposure: 496 particles per cm3). The exercise intensity (heart rate) and duration of cycling were similar for each volunteer in both experiments. Exhaled nitric oxide (NO), plasma interleukin-6 (IL-6), platelet function, Clara cell protein in serum and blood cell counts were measured before and 30 minutes after exercise. RESULTS: Percentage of blood neutrophils increased significantly more (p = 0.004) after exercise in the road test (3.9%; 95% CI: 1.5 to 6.2%; p = 0.003) than after exercise in the clean room (0.2%; 95% CI: -1.8 to 2.2%, p = 0.83). The pre/post cycling changes in exhaled NO, plasma IL-6, platelet function, serum levels of Clara cell protein and number of total blood leukocytes did not differ significantly between the two scenarios. CONCLUSIONS: Traffic-related exposure to particles during exercise caused a small increase in the distribution of inflammatory blood cells in healthy subjects. The health significance of this isolated change is unclear. PMID- 20973950 TI - Reduction of missed appointments at an urban primary care clinic: a randomised controlled study. AB - BACKGROUND: Missed appointments are known to interfere with appropriate care and to misspend medical and administrative resources. The aim of this study was to test the effectiveness of a sequential intervention reminding patients of their upcoming appointment and to identify the profile of patients missing their appointments. METHODS: We conducted a randomised controlled study in an urban primary care clinic at the Geneva University Hospitals serving a majority of vulnerable patients. All patients booked in a primary care or HIV clinic at the Geneva University Hospitals were sent a reminder 48 hrs prior to their appointment according to the following sequential intervention: 1. Phone call (fixed or mobile) reminder; 2. If no phone response: a Short Message Service (SMS) reminder; 3. If no available mobile phone number: a postal reminder. The rate of missed appointment, the cost of the intervention, and the profile of patients missing their appointment were recorded. RESULTS: 2123 patients were included: 1052 in the intervention group, 1071 in the control group. Only 61.7% patients had a mobile phone recorded at the clinic. The sequential intervention significantly reduced the rate of missed appointments: 11.4% (n = 122) in the control group and 7.8% (n = 82) in the intervention group (p < 0.005), and allowed to reallocate 28% of cancelled appointments. It also proved to be cost effective in providing a total net benefit of 1846. - EUR/3 months. A satisfaction survey conducted with 241 patients showed that 93% of them were not bothered by the reminders and 78% considered them to be useful. By multivariate analysis, the following characteristics were significant predictors of missed appointments: younger age (OR per additional decade 0.82; CI 0.71-0.94), male gender (OR 1.72; CI 1.18-2.50), follow-up appointment >1 year (OR 2.2; CI: 1.15 4.2), substance abuse (2.09, CI 1.21-3.61), and being an asylum seeker (OR 2.73: CI 1.22-6.09). CONCLUSION: A practical reminder system can significantly increase patient attendance at medical outpatient clinics. An intervention focused on specific patient characteristics could further increase the effectiveness of appointment reminders. PMID- 20973951 TI - Tyrosine phosphorylation of Grb14 by Tie2. AB - BACKGROUND: Growth factor receptor bound (Grb) proteins 7, 10 and 14 are a family of structurally related multi-domain adaptor proteins involved in a variety of biological processes. Grb7, 10 and 14 are known to become serine and/or threonine phosphorylated in response to growth factor (GF) stimulation. Grb7 and 10 have also been shown to become tyrosine phosphorylated under certain conditions. Under experimental conditions Grb7 is tyrosine phosphorylated by the Tie2/Tie-2/Tek angiogenic receptor tyrosine kinase (RTK). Furthermore, Grb14 has also been shown to interact with Tie2, however tyrosine phosphorylation of this Grb family member has yet to be reported. RESULTS: Here we report for the first time tyrosine phosphorylation of Grb14. This phosphorylation requires a kinase competent Tie2 as well as intact tyrosines 1100 and 1106 (Y1100 and Y1106) on the receptor. Furthermore, a complete SH2 domain on Grb14 is required for Grb14 tyrosine phosphorylation by Tie2. Grb14 was also able to become tyrosine phosphorylated in primary endothelial cells when treated with a soluble and potent variant of the Tie2 ligand, cartilage oligomeric matrix protein (COMP) Ang1. CONCLUSION: Our results show that Grb14, like its family members Grb7 and Grb10, is able to be tyrosine phosphorylated. Furthermore, our data indicate a role for Grb14 in endothelial signaling downstream of the Tie2 receptor. PMID- 20973952 TI - Comparing etoricoxib and celecoxib for preemptive analgesia for acute postoperative pain in patients undergoing arthroscopic anterior cruciate ligament reconstruction: a randomized controlled trial. AB - BACKGROUND: The efficacy of selective cox-2 inhibitors in postoperative pain reduction were usually compared with conventional non-selective conventional NSAIDs or other types of medicine. Previous studies also used selective cox-2 inhibitors as single postoperative dose, in continued mode, or in combination with other modalities. The purpose of this study was to compare analgesic efficacy of single preoperative administration of etoricoxib versus celecoxib for post-operative pain relief after arthroscopic anterior cruciate ligament reconstruction. METHODS: One hundred and two patients diagnosed as anterior cruciate ligament injury were randomized into 3 groups using opaque envelope. Both patients and surgeon were blinded to the allocation. All of the patients were operated by one orthopaedic surgeon under regional anesthesia. Each group was given either etoricoxib 120 mg., celecoxib 400 mg., or placebo 1 hour prior to operative incision. Post-operative pain intensity, time to first dose of analgesic requirement and numbers of analgesic used for pain control and adverse events were recorded periodically to 48 hours after surgery. We analyzed the data according to intention to treat principle. RESULTS: Among 102 patients, 35 were in etoricoxib, 35 in celecoxib and 32 in placebo group. The mean age of the patients was 30 years and most of the injury came from sports injury. There were no significant differences in all demographic characteristics among groups. The etoricoxib group had significantly less pain intensity than the other two groups at recovery room and up to 8 hours period but no significance difference in all other evaluation point, while celecoxib showed no significantly difference from placebo at any time points. The time to first dose of analgesic medication, amount of analgesic used, patient's satisfaction with pain control and incidence of adverse events were also no significantly difference among three groups. CONCLUSIONS: Etoricoxib is more effective than celecoxib and placebo for using as preemptive analgesia for acute postoperative pain control in patients underwent arthroscopic anterior cruciate ligament reconstruction. TRIAL REGISTRATION NUMBER: NCT01017380. PMID- 20973953 TI - Genome-wide survey and analysis of microsatellites in nematodes, with a focus on the plant-parasitic species Meloidogyne incognita. AB - BACKGROUND: Microsatellites are the most popular source of molecular markers for studying population genetic variation in eukaryotes. However, few data are currently available about their genomic distribution and abundance across the phylum Nematoda. The recent completion of the genomes of several nematode species, including Meloidogyne incognita, a major agricultural pest worldwide, now opens the way for a comparative survey and analysis of microsatellites in these organisms. RESULTS: Using MsatFinder, the total numbers of 1-6 bp perfect microsatellites detected in the complete genomes of five nematode species (Brugia malayi, Caenorhabditis elegans, M. hapla, M. incognita, Pristionchus pacificus) ranged from 2,842 to 61,547, and covered from 0.09 to 1.20% of the nematode genomes. Under our search criteria, the most common repeat motifs for each length class varied according to the different nematode species considered, with no obvious relation to the AT-richness of their genomes. Overall, (AT)n, (AG)n and (CT)n were the three most frequent dinucleotide microsatellite motifs found in the five genomes considered. Except for two motifs in P. pacificus, all the most frequent trinucleotide motifs were AT-rich, with (AAT)n and (ATT)n being the only common to the five nematode species. A particular attention was paid to the microsatellite content of the plant-parasitic species M. incognita. In this species, a repertoire of 4,880 microsatellite loci was identified, from which 2,183 appeared suitable to design markers for population genetic studies. Interestingly, 1,094 microsatellites were identified in 801 predicted protein coding regions, 99% of them being trinucleotides. When compared against the InterPro domain database, 497 of these CDS were successfully annotated, and further assigned to Gene Ontology terms. CONCLUSIONS: Contrasted patterns of microsatellite abundance and diversity were characterized in five nematode genomes, even in the case of two closely related Meloidogyne species. 2,245 di- to hexanucleotide loci were identified in the genome of M. incognita, providing adequate material for the future development of a wide range of microsatellite markers in this major plant parasite. PMID- 20973955 TI - A plague on five of your houses--statistical re-assessment of three pneumonic plague outbreaks that occurred in Suffolk, England, between 1906 and 1918. AB - BACKGROUND: Plague is a re-emerging disease and its pneumonic form is a high priority bio-terrorist threat. Epidemiologists have previously analysed historical outbreaks of pneumonic plague to better understand the dynamics of infection, transmission and control. This study examines 3 relatively unknown outbreaks of pneumonic plague that occurred in Suffolk, England, during the first 2 decades of the twentieth century. METHODS: The Kolmogorov-Smirnov statistical test is used to compare the symptomatic period and the length of time between successive cases (i.e. the serial interval) with previously reported values. Consideration is also given to the case fatality ratio, the average number of secondary cases resulting from each primary case in the observed minor outbreaks (termed R(minor)), and the proportion of individuals living within an affected household that succumb to pneumonic plague via the index case (i.e. the household secondary attack rate (SAR)). RESULTS: 2 of the 14 cases survived giving a case fatality ratio of 86% (95% confidence interval (CI) = {57%, 98%}). For the 12 fatal cases, the average symptomatic period was 3.3 days (standard deviation (SD) = 1.2 days) and, for the 11 non index cases, the average serial interval was 5.8 days (SD = 2.0 days). R(minor) was calculated to be 0.9 (SD = 1.0) and, in 2 households, the SAR was approximately 14% (95% CI = {0%, 58%}) and 20% (95% CI = {1%, 72%}), respectively. CONCLUSIONS: The symptomatic period was approximately 1 day longer on average than in an earlier study but the serial interval was in close agreement with 2 previously reported values. 2 of the 3 outbreaks ended without explicit public health interventions; however, non-professional caregivers were particularly vulnerable - an important public health consideration for any future outbreak of pneumonic plague. PMID- 20973956 TI - The prevalence and correlates of depression and anxiety in a sample of diabetic patients in Sharjah, United Arab Emirates. AB - BACKGROUND: Type 2 diabetes is very prevalent in the Gulf region, particularly in the United Arab Emirates (UAE) which has the second highest prevalence in the world. Factors contributing to this include changes in diet, adoption of sedentary lifestyles, and the consequent increase in rates of obesity. These changes are primarily due to rapid economic development and affluence. The aim of this study was to estimate the prevalence of psychological distress and its correlates in diabetic patients in the United Arab Emirates. METHODS: Patients diagnosed with diabetes attending diabetes mini-clinics in the primary health care centres or hospitals of Sharjah were invited to participate in this cross sectional study. Patients were interviewed using structured questionnaires to gather data on socio-demographics, lifestyle factors, diabetes complications, and medication usage. The K6 was administered as a screening tool for mental health concerns. RESULTS: Three hundred and forty-seven participants completed the interview. The majority of participants were females (65.4%) and the mean age was 53.2 (sd = 14.6). Approximately 12.5% of patients obtained a score of 19 or above (cut-off score) on the K6, indicating possible mental health concerns. Twenty four percent had diabetes complications, mainly in the form of retinopathy, peripheral vascular disease and peripheral neuropathy. A significant relationship was found between scores on the K6, these complications of diabetes and the use of oral hypoglycemic and lipid lowering therapies. CONCLUSIONS: The results of this study demonstrate a strong correlation between mental health status and diabetic complications. In particular, patients who are depressed tended to have poorer self-care, more severe physical symptoms and were less likely to adhere to prescribed care regimens. These findings raise the possibility that improving the mental health as part of a comprehensive management plan for diabetes may improve the overall long term outcomes of these patients. PMID- 20973954 TI - Urokinase-type plasminogen activator and arthritis progression: contrasting roles in systemic and monoarticular arthritis models. AB - INTRODUCTION: Urokinase-type plasminogen activator (u-PA) has been implicated in tissue destruction/remodeling. The absence of u-PA results in resistance of mice to systemic immune complex-driven arthritis models; monoarticular arthritis models involving an intra-articular (i.a.) antigen injection, on the other hand, develop more severe arthritis in its absence. The aims of the current study are to investigate further these contrasting roles that u-PA can play in the pathogenesis of inflammatory arthritis and to determine whether u-PA is required for the cartilage and bone destruction associated with disease progression. METHODS: To determine how the different pathogenic mechanisms leading to arthritis development in the different models may explain the contrasting requirement for u-PA, the systemic, polyarticular, immune complex-driven K/BxN arthritis model was modified to include an i.a. injection of saline as a local trauma in u-PA-/- mice. This modified model and the antigen-induced arthritis (AIA) model were also used in u-PA-/- mice to determine the requirement for u-PA in joint destruction. Disease severity was determined by clinical and histologic scoring. Fibrin(ogen) staining and the matrix metalloproteinase (MMP)-generated neoepitope DIPEN staining were performed by immunohistochemistry. Gene expression of inflammatory and destructive mediators was measured in joint tissue by quantitative PCR. RESULTS: In our modified arthritis model, u-PA-/- mice went from being resistant to arthritis development following K/BxN serum transfer to being susceptible following the addition of an i.a. injection of saline. u-PA-/- mice also developed more sustained AIA compared with C57BL/6 mice, including reduced proteoglycan levels and increased bone erosions, fibrin(ogen) deposition and DIPEN expression. Synovial gene expression of the proinflammatory mediators (TNF and IL-1beta), aggrecanases (ADAMTS-4 and -5) and MMPs (MMP3 and MMP13) were all sustained over time following AIA induction in u-PA-/- mice compared with C57BL/6 mice. CONCLUSIONS: We propose that u-PA has a protective role in arthritis models with 'wound healing-like' processes following local trauma, possibly through u-PA/plasmin-mediated fibrinolysis, but a deleterious role in systemic models that are critically dependent on immune complex formation and complement activation. Given that cartilage proteoglycan loss and bone erosions were present and sustained in u-PA-/- mice with monoarticular arthritis, it is unlikely that u-PA/plasmin-mediated proteolysis is contributing directly to this tissue destruction/remodeling. PMID- 20973958 TI - BALL--biochemical algorithms library 1.3. AB - BACKGROUND: The Biochemical Algorithms Library (BALL) is a comprehensive rapid application development framework for structural bioinformatics. It provides an extensive C++ class library of data structures and algorithms for molecular modeling and structural bioinformatics. Using BALL as a programming toolbox does not only allow to greatly reduce application development times but also helps in ensuring stability and correctness by avoiding the error-prone reimplementation of complex algorithms and replacing them with calls into the library that has been well-tested by a large number of developers. In the ten years since its original publication, BALL has seen a substantial increase in functionality and numerous other improvements. RESULTS: Here, we discuss BALL's current functionality and highlight the key additions and improvements: support for additional file formats, molecular edit-functionality, new molecular mechanics force fields, novel energy minimization techniques, docking algorithms, and support for cheminformatics. CONCLUSIONS: BALL is available for all major operating systems, including Linux, Windows, and MacOS X. It is available free of charge under the Lesser GNU Public License (LPGL). Parts of the code are distributed under the GNU Public License (GPL). BALL is available as source code and binary packages from the project web site at http://www.ball-project.org. Recently, it has been accepted into the debian project; integration into further distributions is currently pursued. PMID- 20973957 TI - Use of homologous and heterologous gene expression profiling tools to characterize transcription dynamics during apple fruit maturation and ripening. AB - BACKGROUND: Fruit development, maturation and ripening consists of a complex series of biochemical and physiological changes that in climacteric fruits, including apple and tomato, are coordinated by the gaseous hormone ethylene. These changes lead to final fruit quality and understanding of the functional machinery underlying these processes is of both biological and practical importance. To date many reports have been made on the analysis of gene expression in apple. In this study we focused our investigation on the role of ethylene during apple maturation, specifically comparing transcriptomics of normal ripening with changes resulting from application of the hormone receptor competitor 1-methylcyclopropene. RESULTS: To gain insight into the molecular process regulating ripening in apple, and to compare to tomato (model species for ripening studies), we utilized both homologous and heterologous (tomato) microarray to profile transcriptome dynamics of genes involved in fruit development and ripening, emphasizing those which are ethylene regulated.The use of both types of microarrays facilitated transcriptome comparison between apple and tomato (for the later using data previously published and available at the TED: tomato expression database) and highlighted genes conserved during ripening of both species, which in turn represent a foundation for further comparative genomic studies. The cross-species analysis had the secondary aim of examining the efficiency of heterologous (specifically tomato) microarray hybridization for candidate gene identification as related to the ripening process. The resulting transcriptomics data revealed coordinated gene expression during fruit ripening of a subset of ripening-related and ethylene responsive genes, further facilitating the analysis of ethylene response during fruit maturation and ripening. CONCLUSION: Our combined strategy based on microarray hybridization enabled transcriptome characterization during normal climacteric apple ripening, as well as definition of ethylene-dependent transcriptome changes. Comparison with tomato fruit maturation and ethylene responsive transcriptome activity facilitated identification of putative conserved orthologous ripening-related genes, which serve as an initial set of candidates for assessing conservation of gene activity across genomes of fruit bearing plant species. PMID- 20973959 TI - Communication, perception and behaviour during a natural disaster involving a 'Do Not Drink' and a subsequent 'Boil Water' notice: a postal questionnaire study. AB - BACKGROUND: During times of public health emergencies, effective communication between the emergency response agencies and the affected public is important to ensure that people protect themselves from injury or disease. In order to investigate compliance with public health advice during natural disasters, we examined consumer behaviour during two water notices that were issued as a result of serious flooding. During the summer of 2007, 140,000 homes in Gloucestershire, United Kingdom, that are supplied water from Mythe treatment works, lost their drinking water for up to 17 days. Consumers were issued a 'Do Not Drink' notice when the water was restored, which was subsequently replaced with a 'Boil Water' notice. The rare occurrence of two water notices provided a unique opportunity to compare compliance with public health advice. Information source use and other factors that may affect consumer perception and behaviour were also explored. METHOD: A postal questionnaire was sent to 1,000 randomly selected households. Chi-square, ANOVA, MANOVA and generalised estimating equation (with and without prior factor analysis) were used for quantitative analysis. RESULTS: In terms of information sources, we found high use of and clear preference for the local radio throughout the incident, but family/friends/neighbours also proved crucial at the onset. Local newspapers and the water company were associated with clarity of advice and feeling informed, respectively. Older consumers and those in paid employment were particularly unlikely to read the official information leaflets. We also found a high degree of confusion regarding which notice was in place at which time, with correct recall varying between 23.2%-26.7%, and a great number of consumers believed two notices were in place simultaneously. In terms of behaviour, overall non-compliance levels were significantly higher for the 'Do Not Drink' notice (62.9%) compared to the 'Boil Water' notice (48.3%); consumers in paid employment were not likely to comply with advice. Non-compliance with the general advice to boil bowser water was noticeably lower (27.3%). CONCLUSION: Higher non-compliance during the 'Do Not Drink' notice was traced to the public's limited knowledge of water notices and their folk beliefs about the protection offered from boiling water. We suggest that future information dissemination plans reduce reliance on official leaflets and maximise the potential of local media and personal networks. Current public health education programmes are recommended to attend to insufficient and incorrect public knowledge about precautionary actions. PMID- 20973960 TI - MicroRNA profiling of tomato leaf curl New Delhi virus (tolcndv) infected tomato leaves indicates that deregulation of mir159/319 and mir172 might be linked with leaf curl disease. AB - BACKGROUND: Tomato leaf curl virus (ToLCV), a constituent of the genus Begomovirus, infects tomato and other plants with a hallmark disease symptom of upward leaf curling. Since microRNAs (miRs) are known to control plants developmental processes, we evaluated the roles of miRNAs in Tomato leaf curl New Delhi virus (ToLCNDV) induced leaf curling. RESULTS: Microarray analyses of miRNAs, isolated from the leaves of both healthy and ToLCNDV agroinfected tomato cv Pusa Ruby, revealed that ToLCNDV infection significantly deregulated various miRNAs representing ~13 different conserved families (e.g., miR319, miR172, etc.). The precursors of these miRNAs showed similar deregulated patterns, indicating that the transcription regulation of respective miRNA genes was perhaps the cause of deregulation. The expression levels of the miRNA-targeted genes were antagonistic with respect to the amount of corresponding miRNA. Such deregulation was tissue-specific in nature as no analogous misexpression was found in flowers. The accumulation of miR159/319 and miR172 was observed to increase with the days post inoculation (dpi) of ToLCNDV agroinfection in tomato cv Pusa Ruby. Similarly, these miRs were also induced in ToLCNDV agroinfected tomato cv JK Asha and chilli plants, both exhibiting leaf curl symptoms. Our results indicate that miR159/319 and miR172 might be associated with leaf curl symptoms. This report raises the possibility of using miRNA(s) as potential signature molecules for ToLCNDV infection. CONCLUSIONS: The expression of several host miRNAs is affected in response to viral infection. The levels of the corresponding pre-miRs and the predicted targets were also deregulated. This change in miRNA expression levels was specific to leaf tissues and observed to be associated with disease progression. Thus, certain host miRs are likely indicator of viral infection and could be potentially employed to develop viral resistance strategies. PMID- 20973962 TI - Physician's manual reporting underestimates mortality: evidence from a population based HIV/AIDS treatment program. AB - BACKGROUND: In clinical and cohort research, mortality estimates are often derived from manual reports generated by physicians or electronic reports from vital event registries. We examined the rate of underreporting of deaths by manual methods as compared with electronic reports from a vital event registry. METHODS: The retrospective analyses included deaths among participants registered in an observational cohort who initiated highly-active antiretroviral therapy (HAART) between August 1, 1996 and June 30, 2006. Deaths were routinely reported manually by physicians and through annual electronic record linkages with a population-based vital event registry. Multivariate logistic regression was carried out to assess independent predictors of death reporting by manual methods. RESULTS: Of the 3,116 individuals included in the analyses, 622 (20.0%) died during follow-up. Manual reporting by physicians only identified 377 (60.6%), while electronic linkages captured 598 (96.1%) of all deaths. Multivariate analysis indicated that deaths among individuals with lower CD4 cell count, higher HIV plasma viral load, a history of injection drug use, and under the care of an HIV-experienced physicians were more likely to be reported manually. Furthermore, non-accidental deaths were more likely to be reported manually, and manual reporting of deaths increased over time. CONCLUSIONS: Relying only on manual reports to ascertain deaths significantly underestimates the total number of deaths in the population. This can generate important biases when evaluating the impact of therapeutic interventions in the populational setting. PMID- 20973966 TI - Effects of fenofibrate on lipid profiles, cholesterol ester transfer activity, and in-stent intimal hyperplasia in patients after elective coronary stenting. AB - BACKGROUND: The association between modulation of detailed lipoprotein profiles and cholesterol ester transfer (CET) activity by peroxisome proliferator activated receptor (PPAR)-a agonists in patients with coronary artery disease remains unclear. We assessed lipid profiles, plasma CET activity, and in-stent intimal hyperplasia after fenofibrate treatment in patients who underwent elective coronary stenting. METHODS: Forty-three consecutive patients who underwent elective coronary stenting were randomized to the fenofibrate group (300 mg/day for 25 weeks, n = 22) or the control group (n = 21). At baseline and follow up, CET activity and lipoprotein profiles were measured, and quantitative coronary angiography was performed. RESULTS: In the fenofibrate group, the levels of large very low-density lipoprotein cholesterol, and small low-density lipoprotein (LDL) cholesterol decreased and those of small high-density lipoprotein (HDL) cholesterol increased. Besides, CET activity decreased independent of the effect of fenofibrate on total and LDL cholesterol. The reduction of CET activity significantly correlated with the increase in LDL particle size (r = 0.47, P = 0.03) and the decrease of triglycerides in large HDL subclasses (r = 0.48, P = 0.03). Although there were no significant differences in restenosis parameters between the two groups, low CET activity significantly correlated with the inhibition of neointimal hyperplasia (r = 0.56, P = 0.01). CONCLUSIONS: Fenofibrate inhibited CET activity and thereby improved atherogenic lipoprotein profiles, and reduced intimal hyperplasia after coronary stenting. PMID- 20973961 TI - Phospholipase D promotes Arcanobacterium haemolyticum adhesion via lipid raft remodeling and host cell death following bacterial invasion. AB - BACKGROUND: Arcanobacterium haemolyticum is an emerging bacterial pathogen, causing pharyngitis and more invasive infections. This organism expresses an unusual phospholipase D (PLD), which we propose promotes bacterial pathogenesis through its action on host cell membranes. The pld gene is found on a genomic region of reduced %G + C, suggesting recent horizontal acquisition. RESULTS: Recombinant PLD rearranged HeLa cell lipid rafts in a dose-dependent manner and this was inhibited by cholesterol sequestration. PLD also promoted host cell adhesion, as a pld mutant had a 60.3% reduction in its ability to adhere to HeLa cells as compared to the wild type. Conversely, the pld mutant appeared to invade HeLa cells approximately two-fold more efficiently as the wild type. This finding was attributable to a significant loss of host cell viability following secretion of PLD from intracellular bacteria. As determined by viability assay, only 15.6% and 82.3% of HeLa cells remained viable following invasion by the wild type or pld mutant, respectively, as compared to untreated HeLa cells. Transmission electron microscopy of HeLa cells inoculated with A. haemolyticum strains revealed that the pld mutant was contained within intracellular vacuoles, as compared to the wild type, which escaped the vacuole. Wild type-infected HeLa cells also displayed the hallmarks of necrosis. Similarly inoculated HeLa cells displayed no signs of apoptosis, as measured by induction of caspase 3/7, 8 or 9 activities. CONCLUSIONS: These data indicate that PLD enhances bacterial adhesion and promotes host cell necrosis following invasion, and therefore, may be important in the disease pathogenesis of A. haemolyticum infections. PMID- 20973968 TI - Diagnostic indices for vertiginous diseases. AB - BACKGROUND: Vertigo and dizziness are symptoms which are reported frequently in clinical practice. We aimed to develop diagnostic indices for four prevalent vertiginous diseases: benign paroxysmal positional vertigo (BPPV), Meniere's disease (MD), vestibular migraine (VM), and phobic postural vertigo (PPV). METHODS: Based on a detailed questionnaire handed out to consecutive patients presenting for the first time in our dizziness clinic we preselected a set of seven questions with desirable diagnostic properties when compared with the final diagnosis after medical workup. Using exact logistic regression analysis diagnostic scores, each comprising of four to six items that can simply be added up, were built for each of the four diagnoses. RESULTS: Of 193 patients 131 questionnaires were left after excluding those with missing consent or data. Applying the suggested cut-off points, sensitivity and specificity were 87.5 and 93.5% for BPPV, 100 and 87.4% for MD, 92.3 and 83.7% for VM, 73.7 and 84.1% for PPV, respectively. By changing the cut-off points sensitivity and specificity can be adjusted to meet diagnostic needs. CONCLUSIONS: The diagnostic indices showed promising diagnostic properties. Once further validated, they could provide an ease to use and yet flexible tool for screening vertigo in clinical practice and epidemiological research. PMID- 20973963 TI - Sugar-fermenting yeast as an organic source of carbon dioxide to attract the malaria mosquito Anopheles gambiae. AB - BACKGROUND: Carbon dioxide (CO2) plays an important role in the host-seeking process of opportunistic, zoophilic and anthropophilic mosquito species and is, therefore, commonly added to mosquito sampling tools. The African malaria vector Anopheles gambiae sensu stricto is attracted to human volatiles augmented by CO2. This study investigated whether CO2, usually supplied from gas cylinders acquired from commercial industry, could be replaced by CO2 derived from fermenting yeast (yeast-produced CO2). METHODS: Trapping experiments were conducted in the laboratory, semi-field and field, with An. gambiae s.s. as the target species. MM X traps were baited with volatiles produced by mixtures of yeast, sugar and water, prepared in 1.5, 5 or 25 L bottles. Catches were compared with traps baited with industrial CO2. The additional effect of human odours was also examined. In the laboratory and semi-field facility dual-choice experiments were conducted. The effect of traps baited with yeast-produced CO2 on the number of mosquitoes entering an African house was studied in the MalariaSphere. Carbon dioxide baited traps, placed outside human dwellings, were also tested in an African village setting. The laboratory and semi-field data were analysed by a chi2-test, the field data by GLM. In addition, CO2 concentrations produced by yeast-sugar solutions were measured over time. RESULTS: Traps baited with yeast produced CO2 caught significantly more mosquitoes than unbaited traps (up to 34 h post mixing the ingredients) and also significantly more than traps baited with industrial CO2, both in the laboratory and semi-field. Adding yeast-produced CO2 to traps baited with human odour significantly increased trap catches. In the MalariaSphere, outdoor traps baited with yeast-produced or industrial CO2 + human odour reduced house entry of mosquitoes with a human host sleeping under a bed net indoors. Anopheles gambiae s.s. was not caught during the field trials. However, traps baited with yeast-produced CO2 caught similar numbers of Anopheles arabiensis as traps baited with industrial CO2. Addition of human odour increased trap catches. CONCLUSIONS: Yeast-produced CO2 can effectively replace industrial CO2 for sampling of An. gambiae s.s.. This will significantly reduce costs and allow sustainable mass-application of odour-baited devices for mosquito sampling in remote areas. PMID- 20973965 TI - Association between vitamin D insufficiency and tuberculosis in a Vietnamese population. AB - BACKGROUND: Recent in vitro evidence suggests a link between vitamin D status and the risk of tuberculosis (TB). This study sought to examine the association between vitamin D status, parathyroid hormone (PTH) and the risk of TB in a Vietnamese population. METHODS: The study was designed as a matched case-control study, which involved 166 TB patients (113 men and 53 women), who were age-and sex matched with 219 controls (113 men and 106 women). The average age of men and women was 49 and 50, respectively. TB was diagnosed by the presence of acid-fast bacilli on smears from sputum, and the isolation of M. tuberculosis. All patients were hospitalized for treatment in a TB specialist hospital. Controls were randomly drawn from the general community within the Ho Chi Minh, Vietnam. 25 hydroxyvitamin D [25(OH)D] and PTH was measured prior to treatment by an electrochemiluminescence immunoassay (ECLIA) on a Roche Elecsys. A serum level of 25(OH)D below 30 ng/mL was deemed to be vitamin D insufficient. RESULTS: The prevalence of vitamin D insufficiency was 35.4% in men with TB and 19.5% in controls (P = 0.01). In women, there were no significant differences in serum 25(OH)D and serum PTH levels between TB patients and controls. The prevalence of vitamin D insufficiency in women with TB (45.3%) was not significantly different from those without TB (47.6%; P = 0.91). However, in both genders, serum calcium levels in TB patients were significantly lower than in non-TB individuals. Smoking (odds ratio [OR] 1.25; 95% confidence interval [CI] 1.10 - 14.7), reduced 25(OH)D (OR per standard deviation [SD]: 1.14; 95% CI 1.07 - 10.7) and increased PTH (OR per SD 1.13; 95% CI 1.05 - 10.4) were independently associated with increased risk of TB in men. CONCLUSION: These results suggest that vitamin D insufficiency was a risk factor for tuberculosis in men, but not in women. However, it remains to be established whether the association is a causal relationship. PMID- 20973967 TI - Quantification of the physiochemical constraints on the export of spider silk proteins by Salmonella type III secretion. AB - BACKGROUND: The type III secretion system (T3SS) is a molecular machine in gram negative bacteria that exports proteins through both membranes to the extracellular environment. It has been previously demonstrated that the T3SS encoded in Salmonella Pathogenicity Island 1 (SPI-1) can be harnessed to export recombinant proteins. Here, we demonstrate the secretion of a variety of unfolded spider silk proteins and use these data to quantify the constraints of this system with respect to the export of recombinant protein. RESULTS: To test how the timing and level of protein expression affects secretion, we designed a hybrid promoter that combines an IPTG-inducible system with a natural genetic circuit that controls effector expression in Salmonella (psicA). LacO operators are placed in various locations in the psicA promoter and the optimal induction occurs when a single operator is placed at the +5nt (234-fold) and a lower basal level of expression is achieved when a second operator is placed at -63nt to take advantage of DNA looping. Using this tool, we find that the secretion efficiency (protein secreted divided by total expressed) is constant as a function of total expressed. We also demonstrate that the secretion flux peaks at 8 hours. We then use whole gene DNA synthesis to construct codon optimized spider silk genes for full-length (3129 amino acids) Latrodectus hesperus dragline silk, Bombyx mori cocoon silk, and Nephila clavipes flagelliform silk and PCR is used to create eight truncations of these genes. These proteins are all unfolded polypeptides and they encompass a variety of length, charge, and amino acid compositions. We find those proteins fewer than 550 amino acids reliably secrete and the probability declines significantly after ~700 amino acids. There also is a charge optimum at -2.4, and secretion efficiency declines for very positively or negatively charged proteins. There is no significant correlation with hydrophobicity. CONCLUSIONS: We show that the natural system encoded in SPI-1 only produces high titers of secreted protein for 4-8 hours when the natural psicA promoter is used to drive expression. Secretion efficiency can be high, but declines for charged or large sequences. A quantitative characterization of these constraints will facilitate the effective use and engineering of this system. PMID- 20973969 TI - Accessibility to health care facilities in Montreal Island: an application of relative accessibility indicators from the perspective of senior and non-senior residents. AB - BACKGROUND: Geographical access to health care facilities is known to influence health services usage. As societies age, accessibility to health care becomes an increasingly acute public health concern. It is known that seniors tend to have lower mobility levels, and it is possible that this may negatively affect their ability to reach facilities and services. Therefore, it becomes important to examine the mobility situation of seniors vis-a-vis the spatial distribution of health care facilities, to identify areas where accessibility is low and interventions may be required. METHODS: Accessibility is implemented using a cumulative opportunities measure. Instead of assuming a fixed bandwidth (i.e. a distance threshold) for measuring accessibility, in this paper the bandwidth is defined using model-based estimates of average trip length. Average trip length is an all-purpose indicator of individual mobility and geographical reach. Adoption of a spatial modelling approach allows us to tailor these estimates of travel behaviour to specific locations and person profiles. Replacing a fixed bandwidth with these estimates permits us to calculate customized location- and person-based accessibility measures that allow inter-personal as well as geographical comparisons. DATA: The case study is Montreal Island. Geo-coded travel behaviour data, specifically average trip length, and relevant traveller's attributes are obtained from the Montreal Household Travel Survey. These data are complemented with information from the Census. Health care facilities, also geo coded, are extracted from a comprehensive business point database. Health care facilities are selected based on Standard Industrial Classification codes 8011-21 (Medical Doctors and Dentists). RESULTS: Model-based estimates of average trip length show that travel behaviour varies widely across space. With the exception of seniors in the downtown area, older residents of Montreal Island tend to be significantly less mobile than people of other age cohorts. The combination of average trip length estimates with the spatial distribution of health care facilities indicates that despite being more mobile, suburban residents tend to have lower levels of accessibility compared to central city residents. The effect is more marked for seniors. Furthermore, the results indicate that accessibility calculated using a fixed bandwidth would produce patterns of exposure to health care facilities that would be difficult to achieve for suburban seniors given actual mobility patterns. CONCLUSIONS: The analysis shows large disparities in accessibility between seniors and non-seniors, between urban and suburban seniors, and between vehicle owning and non-owning seniors. This research was concerned with potential accessibility levels. Follow up research could consider the results reported here to select case studies of actual access and usage of health care facilities, and related health outcomes. PMID- 20973970 TI - Early and mid term mortality after coronary artery bypass grafting in women depends on the surgical protocol: retrospective analysis of 3441 on- and off-pump coronary artery bypass grafting procedures. AB - BACKGROUND: Since 2002 MI and stroke, not cancer, are leading causes of death in women. We studied 30-days and 1 year mortality of 3441 patients undergoing coronary artery bypass grafting (CABG) operations in our institution performed either conventionally or off pump (OPCAB). Our objective was to investigate the gender-related mortality in both groups. PATIENTS AND METHODS: Between 2004 and 2008, 3441 patients (733 women, 2708 men) underwent CABG. 252 women and 854 men were operated using OPCAB, 481 women and 1854 men using extracorporeal circulation (ECC). Medical data was prospectively entered and retrospectively reviewed. 30-days and one year mortality rates were analyzed with Kaplan-Meier estimates and Cox proportional hazards models. Linear and logistic regression models were used to test gender differences. RESULTS: a) 30-day mortality using ECC: 5.2% in women vs. 2.5% in men (p = 0.001). One year ECC mortality: 8.7% in women vs. 4.8% in men (p = 0.0008). b) OPCAB: 30-days and 1 year mortality in women measured 1.7%. Mortality in men was 2.1% after 30 days and 3.7% after one year c) gender specific mortality: 30 days mortality in women was 1.7% using OPCAB and 5.2% using ECC (p = 0.002), one year mortality in women was 1.7% using OPCAB vs. 8.7% using ECC (p = 0.0004). In men, 30-days mortality in OPCAB was 2.1%, one year mortality was 3.7%; using ECC early and late mortality was 2.5% and 4.8%. CONCLUSIONS: Female gender is a strong independent predictor and risk factor of increased early and midterm postoperative mortality rates when ECC is used. OPCAB significantly reduces early and midterm postoperative mortality in women and may therefore be proposed as the preferred revascularization technique in female patients. PMID- 20973964 TI - Genomic analysis and relatedness of P2-like phages of the Burkholderia cepacia complex. AB - BACKGROUND: The Burkholderia cepacia complex (BCC) is comprised of at least seventeen Gram-negative species that cause infections in cystic fibrosis patients. Because BCC bacteria are broadly antibiotic resistant, phage therapy is currently being investigated as a possible alternative treatment for these infections. The purpose of our study was to sequence and characterize three novel BCC-specific phages: KS5 (vB_BceM-KS5 or vB_BmuZ-ATCC 17616), KS14 (vB_BceM-KS14) and KL3 (vB_BamM-KL3 or vB_BceZ-CEP511). RESULTS: KS5, KS14 and KL3 are myoviruses with the A1 morphotype. The genomes of these phages are between 32317 and 40555 base pairs in length and are predicted to encode between 44 and 52 proteins. These phages have over 50% of their proteins in common with enterobacteria phage P2 and so can be classified as members of the Peduovirinae subfamily and the "P2-like viruses" genus. The BCC phage proteins similar to those encoded by P2 are predominantly structural components involved in virion morphogenesis. As prophages, KS5 and KL3 integrate into an AMP nucleosidase gene and a threonine tRNA gene, respectively. Unlike other P2-like viruses, the KS14 prophage is maintained as a plasmid. The P2 E+E' translational frameshift site is conserved among these three phages and so they are predicted to use frameshifting for expression of two of their tail proteins. The lysBC genes of KS14 and KL3 are similar to those of P2, but in KS5 the organization of these genes suggests that they may have been acquired via horizontal transfer from a phage similar to lambda. KS5 contains two sequence elements that are unique among these three phages: an ISBmu2-like insertion sequence and a reverse transcriptase gene. KL3 encodes an EcoRII-C endonuclease/methylase pair and Vsr endonuclease that are predicted to function during the lytic cycle to cleave non-self DNA, protect the phage genome and repair methylation-induced mutations. CONCLUSIONS: KS5, KS14 and KL3 are the first BCC-specific phages to be identified as P2-like. As KS14 has previously been shown to be active against Burkholderia cenocepacia in vivo, genomic characterization of these phages is a crucial first step in the development of these and similar phages for clinical use against the BCC. PMID- 20973971 TI - Bacteremic community-acquired pneumonia due to Klebsiella pneumoniae: clinical and microbiological characteristics in Taiwan, 2001-2008. AB - BACKGROUND: Klebsiella pneumoniae is the major cause of community-acquired pyogenic infections in Taiwan. This retrospective study evaluated the clinical and microbiological characteristics of bacteremic community-acquired pneumonia due to K. pneumoniae in Taiwanese adults. METHODS: The clinical characteristics of bacteremic community-acquired pneumonia (CAP) in adults due to K. pneumoniae were compared to those of adults with bacteremic CAP due to Streptococcus pneumoniae at a tertiary medical center in Taiwan from 2001-2008. Risk factors for mortality of bacteremic CAP due to K. pneumoniae were analyzed. All clinical isolates of K. pneumoniae were examined for capsular serotypes, hypermucoviscosity phenotype, aerobactin and rmpA gene. RESULTS: K. pneumoniae was the dominant cause of bacteremic CAP and was associated with a more fulminant course and a worse prognosis than bacteremic CAP due to Streptococcus pneumoniae. Initial presentation with septic shock and respiratory failure were independent risk factors for both early and total mortality. Serotype K1 and K2 comprised around half of all isolates. There were no significant differences in the clinical characteristics of patients with bacteremic CAP due to K1/K2 and non K1/K2 isolates. Hypermucoviscosity phenotype as well as the aerobactin and rmpA genes were highly prevalent in the K. pneumoniae isolates. CONCLUSIONS: K. pneumoniae continued to be the dominant cause of bacteremic CAP in Taiwanese adults during 2001-2008. Initial presentation with septic shock and respiratory failure were independent risk factors for both early and total mortality from K. pneumoniae bacteremic CAP. Serotypes K1/K2 comprised around half of all isolates, but did not predispose patients to a poor clinical outcome. Physicians should be aware of the poor prognosis of any patient with bacteremic K. pneumoniae CAP and monitor these patients more closely. PMID- 20973972 TI - Use of antenatal care services in Kassala, eastern Sudan. AB - BACKGROUND: Antenatal care is named as one of the four pillars initiatives of the Safe Motherhood Initiative. While many of routine antenatal care procedure have little effect on maternal mortality and morbidity, some of these have been ascertained as beneficial. The aim of this study was to investigate coverage of antenatal care and identify factors associated with inadequacy of antenatal care in Kassala, eastern Sudan. METHODS: A cross-sectional community-based study was carried out in Kassala, eastern Sudan during September-October 2009. Household surveys were conducted. Structured questionnaires were used to gather data from women who had been pregnant within the last year, or pregnant more than 14 weeks. RESULTS: Out of 900 women investigated for antenatal care coverage, 811(90%) women had at least one visit. Only 11% of the investigated women had >= four antenatal visits, while 10.0% had not attended at all. Out of 811 women who attended at least one visit, 483 (59.6%), 303 (37.4%) and 25 (3.1%) women attended antenatal care in the first, second and third trimester, respectively. In logistic regression analyses, while maternal age and residence were not associated with inadequacy of antenatal care (<2 visits), high parity (OR = 2.0, CI = 1.1-3.5; P = 0.01) and husband education <= secondary level (OR = 2.4, CI = 1.3-4.2; P = 0.002) were associated with inadequacy of antenatal care. CONCLUSIONS: Antenatal care showed a low coverage in Kassala, eastern Sudan. This low coverage was associated with high parity and low husband education. PMID- 20973973 TI - New insight into the dynamic properties and the active site architecture of H-Ras p21 revealed by X-ray crystallography at very high resolution. AB - BACKGROUND: In kinetic crystallography, the usually static method of X-ray diffraction is expanded to allow time-resolved analysis of conformational rearrangements in protein structures. To achieve this, reactions have to be triggered within the protein crystals of interest, and optical spectroscopy can be used to monitor the reaction state. For this approach, a modified form of H Ras p21 was designed which allows reaction initiation and fluorescence readout of the initiated GTPase reaction within the crystalline state. Rearrangements within the crystallized protein due to the progressing reaction and associated heterogeneity in the protein conformations have to be considered in the subsequent refinement processes. RESULTS: X-ray diffraction experiments on H-Ras p21 in different states along the reaction pathway provide detailed information about the kinetics and mechanism of the GTPase reaction. In addition, a very high data quality of up to 1.0 A resolution allowed distinguishing two discrete subconformations of H-Ras p21, expanding the knowledge about the intrinsic flexibility of Ras-like proteins, which is important for their function. In a complex of H-Ras*GppNHp (guanosine-5'-(beta,gamma-imido)-triphosphate), a second Mg2+ ion was found to be coordinated to the gamma-phosphate group of GppNHp, which positions the hydrolytically active water molecule very close to the attacked gamma-phosphorous atom. CONCLUSION: For the structural analysis of very high-resolution data we have used a new 'two-chain-isotropic-refinement' strategy. This refinement provides an alternative and easy to interpret strategy to reflect the conformational variability within crystal structures of biological macromolecules. The presented fluorescent form of H-Ras p21 will be advantageous for fluorescence studies on H-Ras p21 in which the use of fluorescent nucleotides is not feasible. PMID- 20973974 TI - Assessment of fall-related self-efficacy and activity avoidance in people with Parkinson's disease. AB - BACKGROUND: Fear of falling (FOF) is common in Parkinson's disease (PD), and it is considered a vital aspect of comprehensive balance assessment in PD. FOF can be conceptualized differently. The Falls-Efficacy Scale (FES) assesses fall related self-efficacy, whereas the Survey of Activities and Fear of Falling in the Elderly (SAFFE) assesses activity avoidance due to the risk of falling. This study aimed at investigating the validity and reliability of FES and SAFFE in people with PD. METHODS: Seventy-nine people with PD (mean age; 64 years, SD 7.2) completed the Swedish version of FES(S), SAFFE and the physical functioning (PF) scale of the 36-Item Short-Form Health Survey (SF-36). FES(S) and SAFFE were administered twice, with an 8.8 (SD 2.3) days interval. Assumptions for summing item scores into total scores were examined and score reliability (Cronbach's alpha and test-retest reliability) were calculated. Construct validity was assessed by examining the pattern of Spearman correlations (rs) between the FES(S)/SAFFE and other variables, and by examining differences in FES(S)/SAFFE scores between fallers and non-fallers, genders, and between those reporting FOF and unsteadiness while turning. RESULTS: For both scales, item mean scores (and standard deviations) were roughly similar and corrected item-total correlations exceeded 0.4. Reliabilities were >= 0.87. FES(S)-scores correlated strongest (rs, -0.74, p < 0.001) with SAFFE-scores, whereas SAFFE-scores correlated strongest with PF-scores (rs, -0.76, p < 0.001). Both scales correlated weakest with age (rs <= 0.08). Experiencing falls, unsteadiness while turning, and FOF was associated with lower fall-related self-efficacy and higher activity avoidance. CONCLUSIONS: This study provides initial support for the score reliability and validity of the FES(S) and SAFFE in people with PD. PMID- 20973975 TI - A novel form of human disease with a protease-sensitive prion protein and heterozygosity methionine/valine at codon 129: Case report. AB - BACKGROUND: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder in humans included in the group of Transmissible Spongiform Encephalopathies or prion diseases. The vast majority of sCJD cases are molecularly classified according to the abnormal prion protein (PrPSc) conformations along with polymorphism of codon 129 of the PRNP gene. Recently, a novel human disease, termed "protease-sensitive prionopathy", has been described. This disease shows a distinct clinical and neuropathological phenotype and it is associated to an abnormal prion protein more sensitive to protease digestion. CASE PRESENTATION: We report the case of a 75-year-old-man who developed a clinical course and presented pathologic lesions compatible with sporadic Creutzfeldt-Jakob disease, and biochemical findings reminiscent of "protease sensitive prionopathy". Neuropathological examinations revealed spongiform change mainly affecting the cerebral cortex, putamen/globus pallidus and thalamus, accompanied by mild astrocytosis and microgliosis, with slight involvement of the cerebellum. Confluent vacuoles were absent. Diffuse synaptic PrP deposits in these regions were largely removed following proteinase treatment. PrP deposition, as revealed with 3F4 and 1E4 antibodies, was markedly sensitive to pre-treatment with proteinase K. Molecular analysis of PrPSc showed an abnormal prion protein more sensitive to proteinase K digestion, with a five-band pattern of 28, 24, 21, 19, and 16 kDa, and three aglycosylated isoforms of 19, 16 and 6 kDa. This PrPSc was estimated to be 80% susceptible to digestion while the pathogenic prion protein associated with classical forms of sporadic Creutzfeldt Jakob disease were only 2% (type VV2) and 23% (type MM1) susceptible. No mutations in the PRNP gene were found and genotype for codon 129 was heterozygous methionine/valine. CONCLUSIONS: A novel form of human disease with abnormal prion protein sensitive to protease and MV at codon 129 was described. Although clinical signs were compatible with sporadic Creutzfeldt-Jakob disease, the molecular subtype with the abnormal prion protein isoforms showing enhanced protease sensitivity was reminiscent of the "protease-sensitive prionopathy". It remains to be established whether the differences found between the latter and this case are due to the polymorphism at codon 129. Different degrees of proteinase K susceptibility were easily determined with the chemical polymer detection system which could help to detect proteinase-susceptible pathologic prion protein in diseases other than the classical ones. PMID- 20973976 TI - Estimating time since infection in early homogeneous HIV-1 samples using a poisson model. AB - BACKGROUND: The occurrence of a genetic bottleneck in HIV sexual or mother-to infant transmission has been well documented. This results in a majority of new infections being homogeneous, i.e., initiated by a single genetic strain. Early after infection, prior to the onset of the host immune response, the viral population grows exponentially. In this simple setting, an approach for estimating evolutionary and demographic parameters based on comparison of diversity measures is a feasible alternative to the existing Bayesian methods (e.g., BEAST), which are instead based on the simulation of genealogies. RESULTS: We have devised a web tool that analyzes genetic diversity in acutely infected HIV-1 patients by comparing it to a model of neutral growth. More specifically, we consider a homogeneous infection (i.e., initiated by a unique genetic strain) prior to the onset of host-induced selection, where we can assume a random accumulation of mutations. Previously, we have shown that such a model successfully describes about 80% of sexual HIV-1 transmissions provided the samples are drawn early enough in the infection. Violation of the model is an indicator of either heterogeneous infections or the initiation of selection. CONCLUSIONS: When the underlying assumptions of our model (homogeneous infection prior to selection and fast exponential growth) are met, we are under a very particular scenario for which we can use a forward approach (instead of backwards in time as provided by coalescent methods). This allows for more computationally efficient methods to derive the time since the most recent common ancestor. Furthermore, the tool performs statistical tests on the Hamming distance frequency distribution, and outputs summary statistics (mean of the best fitting Poisson distribution, goodness of fit p-value, etc). The tool runs within minutes and can readily accommodate the tens of thousands of sequences generated through new ultradeep pyrosequencing technologies. The tool is available on the LANL website. PMID- 20973977 TI - Application of volumetric modulated arc therapy (VMAT) in a dual-vendor environment. AB - BACKGROUND AND PURPOSE: The purpose of this study was to assess plan quality and treatment time achievable with the new VMAT optimization tool implemented in the treatment planning system Oncentra MasterPlan(r) as compared to IMRT for Elekta SynergyS(r) linear accelerators. MATERIALS AND METHODS: VMAT was implemented on a SynergyS(r) linear accelerator (Elekta Ltd., Crawley, UK) with Mosaiq(r) record and verify system (IMPAC Medical Systems, Sunnyvale, CA) and the treatment planning system Oncentra MasterPlan(r) (Nucletron BV, Veenendaal, the Netherlands). VMAT planning was conducted for three typical target types of prostate cancer, hypopharynx/larynx cancer and vertebral metastases, and compared to standard IMRT with respect to plan quality, number of monitor units (MU), and treatment time. RESULTS: For prostate cancer and vertebral metastases single arc VMAT led to similar plan quality as compared to IMRT. For treatment of the hypopharynx/larynx cancer, a second arc was necessary to achieve sufficient plan quality. Treatment time was reduced in all cases to 35% to 43% as compared to IMRT. Times required for optimization and dose calculation, however, increased by a factor of 5.0 to 6.8. CONCLUSION: Similar or improved plan quality can be achieved with VMAT as compared to IMRT at reduced treatment times but increased calculation times. PMID- 20973978 TI - Transplanted bone marrow stem cells relocate to infarct penumbra and co-express endogenous proliferative and immature neuronal markers in a mouse model of ischemic cerebral stroke. AB - BACKGROUND: Several studies demonstrate that neurogenesis may be induced or activated following vascular insults, which may be important for neuronal regeneration and functional recovery. Understanding the cellular mechanism underlying stroke-associated neurogenesis is of neurobiological as well as neurological/clinical relevance. The present study attempted to explore potential homing and early development of transplanted bone marrow stem cells in mouse forebrain after focal occlusion of the middle cerebral artery, an experimental model of ischemic stroke. RESULTS: Bone marrow stem cells isolated from donor mice were confirmed by analysis of surface antigen profile, and were pre-labeled with a lipophilic fluorescent dye PKH26, and subsequently transfused into recipient mice with middle cerebral artery coagulation. A large number of PKH26 labeled cells were detected surrounding the infarct site, most of which colocalized with immunolabelings for the proliferating cell nuclear antigen (PCNA) and some also colocalized with the immature neuronal marker doublecortin (DCX) during 1-2 weeks after the bone marrow cells transfusion. CONCLUSIONS: The present study shows that transplanted bone marrow cells largely relocate to the infarct penumbra in ischemic mouse cerebrum. These transplanted bone marrow cells appear to undergo a process of in situ proliferation and develop into putative cortical interneurons during the early phase of experimental vascular injury. PMID- 20973979 TI - Socioeconomic status and duration and pattern of sickness absence. A 1-year follow-up study of 2331 hospital employees. AB - BACKGROUND: Sickness absence increases with lower socioeconomic status. However, it is not well known how this relation depends on specific aspects of sickness absence or the degree to which socioeconomic differences in sickness absence may be explained by other factors.The purpose of the study was to examine differences in sickness absence among occupational groups in a large general hospital; how they depend on combinations of frequency and duration of sickness absence spells; and if they could be explained by self-reported general health, personal factors and work factors. METHODS: The design is a 1-year prospective cohort study of 2331 hospital employees. Baseline information include job title, work unit, perceived general health, work factors and personal factors recorded from hospital administrative files or by questionnaire (response rate 84%). Sickness absence during follow-up was divided into short (1-3 days), medium (4-14 days) and long (>14 days) spells, and into no absence, "normal" absence (1-3 absences of certain durations) and "abnormal" absence (any other absence than "normal"). Socioeconomic status was assessed by job titles grouped in six occupational groups by level of education (from doctors to cleaners/porters). Effects of occupational group on sickness absence were adjusted for significant effects of age, gender, general health, personal factors and work factors. We used Poisson or logistic regression analysis to estimate the effects of model covariates (rate ratios (RR) or odds ratios (OR)) and their 95% confidence intervals (CI). RESULTS: With a few exceptions sickness absence increased with decreasing socioeconomic status. However, the social gradient was quite different for different types of sickness absence. The gradient was strong for medium spells and "abnormal" absence, and weak for all spells, short spells, long spells and "normal" absence. For cleaners compared to doctors the adjusted risk estimates increased 4.2 (95% CI 2.8-6.2) and 7.4 (95% CI 3.3-16) times for medium spells and "abnormal" absence, respectively, while the similar changes varied from 0.79 to 2.8 for the other absence outcomes. General health explained some of the social gradient. Work factors and personal factors did not. CONCLUSIONS: The social gradient in sickness absence was different for absences of different duration and patterns. It was strongest for absences of medium length and "abnormal" absence. The social gradient was not explained by other factors. PMID- 20973981 TI - Patterns of physical activity in different domains and implications for intervention in a multi-ethnic Asian population: a cross-sectional study. AB - BACKGROUND: The benefits of regular physical activity for quality of life and disease prevention have been well documented. Identification of low activity groups would facilitate interventional programs. Many studies have focussed on leisure time activity, which may not capture the spectrum of physical activity relevant to disease prevention. Furthermore, few studies have been conducted in urban Asian settings. METHODS: We evaluated physical activity in different domains (leisure time, occupational, household and transportation) and its sociodemographic determinants in 4750 adult Chinese, Malay, and Asian Indian Singaporeans. Physical activity was assessed using locally validated questionnaires. RESULTS: Occupational and household activity contributed substantially more to total physical activity than leisure time or transportation activity. However, when only activity of at least moderate intensity was considered leisure time activity contributed most to total physical activity. Higher socio-economic status was associated with more leisure time activity, but less total physical activity due to reduced activity in the other domains. Chinese ethnicity was also associated with less total physical activity as a result of less activity in non-leisure time domains. CONCLUSIONS: In assessing levels of physical activity and recommending changes, it is important to consider physical activity in different domains. Focus on leisure-time physical activity alone could identify the wrong groups for intervention and miss opportunities for increasing physical activity in populations. PMID- 20973980 TI - Smoking reduces surfactant protein D and phospholipids in patients with and without chronic obstructive pulmonary disease. AB - BACKGROUND: Pulmonary surfactant D (SP-D) has important regulatory functions for innate immunity and has been implicated as a biomarker for chronic obstructive pulmonary disease (COPD). We hypothesized that COPD patients would have reduced bronchoalveolar lavage (BAL) fluid SP-D levels compared to healthy smoking and non-smoking controls. METHODS: BAL SP-D and phospholipids were quantified and corrected for dilution in 110 subjects (65 healthy never smokers, 23 smokers with normal spirometry, and 22 smokers with COPD). RESULTS: BAL SP-D was highest in never smokers (mean 51.9 MUg/mL +/- 7.1 MUg/mL standard error) compared to both smokers with normal spirometry (16.0 MUg/mL +/- 11.8 MUg/mL) and subjects with COPD (19.1 MUg/mL +/- 12.9 MUg/mL; P < 0.0001). Among smokers with COPD, BAL SP-D correlated significantly with FEV1% predicted (R = 0.43; P < 0.05); however, the strongest predictor of BAL SP-D was smoking status. BAL SP-D levels were lowest in current smokers (12.8 MUg/mL +/- 11.0 MUg/mL), intermediate in former smokers (25.2 MUg/mL +/- 14.2 MUg/mL; P < 0.008), and highest in never smokers. BAL phospholipids were also lowest in current smokers (6.5 nmol +/- 1.5 nmol), intermediate in former smokers (13.1 nmol +/- 2.1 nmol), and highest in never smokers (14.8 nmol +/- 1.1 nmol; P < 0.0001). CONCLUSIONS: These data suggest that smokers, and especially current smokers, exhibit significantly reduced BAL SP-D and phospholipids compared to nonsmokers. Our findings may help better explain the mechanism that leads to the rapid progression of disease and increased incidence of infection in smokers. PMID- 20973982 TI - Comparison of darbepoetin alfa dosed weekly (QW) vs. extended dosing schedule (EDS) in the treatment of anemia in patients receiving multicycle chemotherapy in a randomized, phase 2, open-label trial. AB - BACKGROUND: Chemotherapy-induced anemia (CIA) is responsive to treatment with erythropoiesis-stimulating agents (ESAs) such as darbepoetin alfa. Administration of ESAs on a synchronous schedule with chemotherapy administration could benefit patients by reducing clinic visits and potentially enhancing on-time chemotherapy delivery. METHODS: This phase 2, 25-week, open-label study evaluated the noninferiority of darbepoetin alfa administered weekly vs. as an extended dosing schedule (every 2 or 3 weeks) in patients with CIA. Patients were randomized 1:1 to an extended dosing schedule (EDS: darbepoetin alfa 300 MUg Q2W if chemotherapy was QW, Q2W, or Q4W or darbepoetin alfa 500 MUg Q3W if chemotherapy was Q3W) or weekly (150 MUg QW regardless of chemotherapy schedule). Stratification factors included chemotherapy cycle length, screening hemoglobin (<10 g/dL vs. >=10 g/dL), and tumor type (lung/gynecological vs. other nonmyeloid malignancies). The primary endpoint was change in hemoglobin from baseline to Week 13. RESULTS: Seven hundred fifty-two patients (374 QW patients; 378 EDS patients) received >=1 dose of darbepoetin alfa and were included in the analysis. Demographics and disease state were similar between groups. Seventy-one percent of patients in the EDS group and 76% in the QW group achieved the target hemoglobin of >=11.0 g/dL. There was a minimal difference in the primary endpoint of mean change in hemoglobin (baseline to Week 13) between the QW and the EDS groups (-0.04 g/dL; 95% confidence interval: -0.26, 0.17 g/dL). The upper limit of the 95% confidence interval was less than the prespecified limit of <0.75 g/dL, supporting noninferiority of the EDS dosing schedule. Reported adverse events were similar between groups. A slight increase in transfusions was reported in the QW group. CONCLUSION: Darbepoetin alfa, when administered synchronously with chemotherapy, on an EDS appears to be similarly efficacious to darbepoetin alfa weekly dosing with no unexpected adverse events. This study provides prospective data on how multiple dosing regimens available with darbepoetin alfa can be synchronized with chemotherapy administered across a range of dosing schedules. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00144131. PMID- 20973983 TI - Hunter disease eClinic: interactive, computer-assisted, problem-based approach to independent learning about a rare genetic disease. AB - BACKGROUND: Computer-based teaching (CBT) is a well-known educational device, but it has never been applied systematically to the teaching of a complex, rare, genetic disease, such as Hunter disease (MPS II). AIM: To develop interactive teaching software functioning as a virtual clinic for the management of MPS II. IMPLEMENTATION AND RESULTS: The Hunter disease eClinic, a self-training, user friendly educational software program, available at the Lysosomal Storage Research Group (http://www.lysosomalstorageresearch.ca), was developed using the Adobe Flash multimedia platform. It was designed to function both to provide a realistic, interactive virtual clinic and instantaneous access to supporting literature on Hunter disease. The Hunter disease eClinic consists of an eBook and an eClinic. The eClinic is the interactive virtual clinic component of the software. Within an environment resembling a real clinic, the trainee is instructed to perform a medical history, to examine the patient, and to order appropriate investigation. The program provides clinical data derived from the management of actual patients with Hunter disease. The eBook provides instantaneous, electronic access to a vast collection of reference information to provide detailed background clinical and basic science, including relevant biochemistry, physiology, and genetics. In the eClinic, the trainee is presented with quizzes designed to provide immediate feedback on both trainee effectiveness and efficiency. User feedback on the merits of the program was collected at several seminars and formal clinical rounds at several medical centres, primarily in Canada. In addition, online usage statistics were documented for a 2-year period. Feedback was consistently positive and confirmed the practical benefit of the program. The online English-language version is accessed daily by users from all over the world; a Japanese translation of the program is also available. CONCLUSIONS: The Hunter disease eClinic employs a CBT model providing the trainee with realistic clinical problems, coupled with comprehensive basic and clinical reference information by instantaneous access to an electronic textbook, the eBook. The program was rated highly by attendees at national and international presentations. It provides a potential model for use as an educational approach to other rare genetic diseases. PMID- 20973984 TI - Differential effects of pre and post-payment on neurologists' response rates to a postal survey. AB - BACKGROUND: Monetary incentives are an effective way of increasing response rates to surveys, though they are generally less effective in physicians, and are more effective when the incentive is paid up-front rather than when made conditional on completion. METHODS: In this study we examine the effectiveness of pre- and post-completion incentives on the response rates of all the neurologists in the UK to a survey about conversion disorder, using a cluster randomised controlled design. A postal survey was sent to all practicing consultant neurologists, in two rounds, including either a book token, the promise of a book token, or nothing at all. RESULTS: Three hundred and fifty-one of 591 eligible neurologists completed the survey, for a response rate of 59%. While the post-completion incentive exerted no discernible influence on response rates, a pre-completion incentive did, with an odds-ratio of 2.1 (95% confidence interval 1.5-3.0). CONCLUSIONS: We conclude that neurologists, in the UK at least, may be influenced to respond to a postal survey by a pre-payment incentive but are unaffected by a promised reward. PMID- 20973985 TI - Development of an intervention program to increase effective behaviours by patients and clinicians in psychiatric services: Intervention Mapping study. AB - BACKGROUND: Health clinicians perceive certain patients as 'difficult' across all settings, including mental health care. In this area, patients with non-psychotic disorders that become long-term care users may be perceived as obstructing their own recovery or seeking secondary gain. This negative perception of patients results in ineffective responses and low-quality care by health clinicians. Using the concept of illness behaviour, this paper describes the development, implementation, and planned evaluation of a structured intervention aimed at prevention and management of ineffective behaviours by long-term non-psychotic patients and their treating clinicians. METHODS: The principles of Intervention Mapping were applied to guide the development, implementation, and planned evaluation of the intervention. Qualitative (individual and group interviews), quantitative (survey), and mixed methods (Delphi-procedure) research was used to gain a broad perspective of the problem. Empirical findings, theoretical models, and existing evidence were combined to construct a program tailored to the needs of the target groups. RESULTS: A structured program to increase effective illness behaviour in long-term non-psychotic patients and effective professional behaviour in their treating clinicians was developed, consisting of three subsequent stages and four substantial components, that is described in detail. Implementation took place and evaluation of the intervention is being carried out. CONCLUSIONS: Intervention Mapping proved to be a suitable method to develop a structured intervention for a multi-faceted problem in mental health care. PMID- 20973986 TI - Increased spinal prodynorphin gene expression in reinflammation-associated hyperalgesia after neonatal inflammatory insult. AB - BACKGROUND: Neuroplasticity induced by neonatal inflammation is the consequence of a combination of activity-dependent changes in neurons. We investigated neuronal sensitivity to a noxious stimulus in a rat model of neonatal hind-paw peripheral inflammation and assessed changes in pain behaviour at the physiological and molecular levels after peripheral reinflammation in adulthood. RESULTS: A decrease in paw withdrawal latency (PWL) after a heat stimulus was documented in rats that received inflammatory injections in their left hind paws on postnatal day one (P1) and a reinflammation stimulus at postnatal 6-8 weeks of age, compared with normal rats. An increase in the expression of the prodynorphin (proDYN) gene was noted after reinflammation in the spinal cord ipsilateral to the afferents of the neonatally treated hind paw. The involvement of the activation of extracellular signal-regulated kinases (ERK) in peripheral inflammatory pain hypersensitivity was evidenced evident by the increase in phospho-ERK (pERK) activity after reinflammation. CONCLUSIONS: Our results indicate that peripheral inflammation in neonates can permanently alter the pain processing pathway during the subsequent sensory stimulation of the region. Elucidation of the mechanism underlying the developing pain circuitry will provide new insights into the understanding of the early pain behaviours and the subsequent adaptation to pain. PMID- 20973987 TI - Measurement invariance of the kidney disease and quality of life instrument (KDQOL-SF) across veterans and non-veterans. AB - BACKGROUND: Studies have demonstrated that perceived health-related quality of life (HRQOL) of patients receiving hemodialysis is significantly impaired. Since HRQOL outcome data are often used to compare groups to determine health care effectiveness it is imperative that measures of HRQOL are valid. However, valid HRQOL comparisons between groups can only be made if instrument invariance is demonstrated. The Kidney Disease Quality of Life-Short Form (KDQOL-SF) is a widely used HRQOL measure for patients with chronic kidney disease (CKD) however, it has not been validated in the Veteran population. Therefore, the purpose of this study was to examine the measurement invariance of the KDQOL-SF across Veterans and non-Veterans with CKD. METHODS: Data for this study were from two large prospective observational studies of patients receiving hemodialysis: 1) Veteran End-Stage Renal Disease Study (VETERAN) (N = 314) and 2) Dialysis Outcomes and Practice Patterns Study (DOPPS) (N = 3,300). Health-related quality of life was measured with the KDQOL-SF, which consists of the SF-36 and the Kidney Disease Component Summary (KDCS). Single-group confirmatory factor analysis was used to evaluate the goodness-of-fit of the hypothesized measurement model for responses to the subscales of the KDCS and SF-36 instruments when analyzed together; and given acceptable goodness-of-fit in each group, multigroup CFA was used to compare the structure of this factor model in the two samples. Pattern of factor loadings (configural invariance), the magnitude of factor loadings (metric invariance), and the magnitude of item intercepts (scalar invariance) were assessed as well as the degree to which factors have the same variances, covariances, and means across groups (structural invariance). RESULTS: CFA demonstrated that the hypothesized two-factor model (KDCS and SF-36) fit the data of both the Veteran and DOPPS samples well, supporting configural invariance. Multigroup CFA results concerning metric and scalar invariance suggested partial strict invariance for the SF-36, but only weak invariance for the KDCS. Structural invariance was not supported. CONCLUSIONS: Results suggest that Veterans may interpret the KDQOL-SF differently than non-Veterans. Further evaluation of measurement invariance of the KDQOL-SF between Veterans and non Veterans is needed using large, randomly selected samples before comparisons between these two groups using the KDQOL-SF can be done reliably. PMID- 20973988 TI - A critical synthesis of literature on the promoting action on research implementation in health services (PARIHS) framework. AB - BACKGROUND: The Promoting Action on Research Implementation in Health Services framework, or PARIHS, is a conceptual framework that posits key, interacting elements that influence successful implementation of evidence-based practices. It has been widely cited and used as the basis for empirical work; however, there has not yet been a literature review to examine how the framework has been used in implementation projects and research. The purpose of the present article was to critically review and synthesize the literature on PARIHS to understand how it has been used and operationalized, and to highlight its strengths and limitations. METHODS: We conducted a qualitative, critical synthesis of peer reviewed PARIHS literature published through March 2009. We synthesized findings through a three-step process using semi-structured data abstraction tools and group consensus. RESULTS: Twenty-four articles met our inclusion criteria: six core concept articles from original PARIHS authors, and eighteen empirical articles ranging from case reports to quantitative studies. Empirical articles generally used PARIHS as an organizing framework for analyses. No studies used PARIHS prospectively to design implementation strategies, and there was generally a lack of detail about how variables were measured or mapped, or how conclusions were derived. Several studies used findings to comment on the framework in ways that could help refine or validate it. The primary issue identified with the framework was a need for greater conceptual clarity regarding the definition of sub-elements and the nature of dynamic relationships. Strengths identified included its flexibility, intuitive appeal, explicit acknowledgement of the outcome of 'successful implementation,' and a more expansive view of what can and should constitute 'evidence.' CONCLUSIONS: While we found studies reporting empirical support for PARIHS, the single greatest need for this and other implementation models is rigorous, prospective use of the framework to guide implementation projects. There is also need to better explain derived findings and how interventions or measures are mapped to specific PARIHS elements; greater conceptual discrimination among sub-elements may be necessary first. In general, it may be time for the implementation science community to develop consensus guidelines for reporting the use and usefulness of theoretical frameworks within implementation studies. PMID- 20973989 TI - Timing of birth for women with a twin pregnancy at term: a randomised controlled trial. AB - BACKGROUND: There is a well recognized risk of complications for both women and infants of a twin pregnancy, increasing beyond 37 weeks gestation. Preterm birth prior to 37 weeks gestation is a recognized complication of a twin pregnancy, however, up to 50% of twins will be born after this time. The aims of this randomised trial are to assess whether elective birth at 37 weeks gestation compared with standard care in women with a twin pregnancy affects the risk of perinatal death, and serious infant complications. METHODS/DESIGN: DESIGN: Multicentred randomised trial. INCLUSION CRITERIA: women with a twin pregnancy at 366 weeks or more without contraindication to continuation of pregnancy. Trial Entry & Randomisation: Following written informed consent, eligible women will be randomised from 36+6 weeks gestation. The randomisation schedule uses balanced variable blocks, with stratification for centre of birth and planned mode of birth. Women will be randomised to either elective birth or standard care. Treatment Schedules: Women allocated to the elective birth group will be planned for elective birth from 37 weeks gestation. Where the plan is for vaginal birth, this will involve induction of labour. Where the plan is for caesarean birth, this will involve elective caesarean section. For women allocated to standard care, birth will be planned for 38 weeks gestation or later. Where the plan is for vaginal birth, this will involve either awaiting the spontaneous onset of labour, or induction of labour if required. Where the plan is for caesarean birth, this will involve elective caesarean section (after 38 and as close to 39 weeks as possible). Primary Study Outcome: A composite of perinatal mortality or serious neonatal morbidity. SAMPLE SIZE: 460 women with a twin pregnancy to show a reduction in the composite outcome from 16.3% to 6.7% with adjustment for the clustering of twin infants within mothers (p = 0.05, 80% power). DISCUSSION: This is a protocol for a randomised trial, the findings of which will contribute information about the optimal time of birth for women with an uncomplicated multiple pregnancy at and beyond 37 weeks gestation. PMID- 20973990 TI - Genome-wide identification of Saccharomyces cerevisiae genes required for tolerance to acetic acid. AB - BACKGROUND: Acetic acid is a byproduct of Saccharomyces cerevisiae alcoholic fermentation. Together with high concentrations of ethanol and other toxic metabolites, acetic acid may contribute to fermentation arrest and reduced ethanol productivity. This weak acid is also a present in lignocellulosic hydrolysates, a highly interesting non-feedstock substrate in industrial biotechnology. Therefore, the better understanding of the molecular mechanisms underlying S. cerevisiae tolerance to acetic acid is essential for the rational selection of optimal fermentation conditions and the engineering of more robust industrial strains to be used in processes in which yeast is explored as cell factory. RESULTS: The yeast genes conferring protection against acetic acid were identified in this study at a genome-wide scale, based on the screening of the EUROSCARF haploid mutant collection for susceptibility phenotypes to this weak acid (concentrations in the range 70-110 mM, at pH 4.5). Approximately 650 determinants of tolerance to acetic acid were identified. Clustering of these acetic acid-resistance genes based on their biological function indicated an enrichment of genes involved in transcription, internal pH homeostasis, carbohydrate metabolism, cell wall assembly, biogenesis of mitochondria, ribosome and vacuole, and in the sensing, signalling and uptake of various nutrients in particular iron, potassium, glucose and amino acids. A correlation between increased resistance to acetic acid and the level of potassium in the growth medium was found. The activation of the Snf1p signalling pathway, involved in yeast response to glucose starvation, is demonstrated to occur in response to acetic acid stress but no evidence was obtained supporting the acetic acid induced inhibition of glucose uptake. CONCLUSIONS: Approximately 490 of the 650 determinants of tolerance to acetic acid identified in this work are implicated, for the first time, in tolerance to this weak acid. These are novel candidate genes for genetic engineering to obtain more robust yeast strains against acetic acid toxicity. Among these genes there are number of transcription factors that are documented regulators of a large percentage of the genes found to exert protection against acetic acid thus being considered interesting targets for subsequent genetic engineering. The increase of potassium concentration in the growth medium was found to improve the expression of maximal tolerance to acetic acid, consistent with the idea that the adequate manipulation of nutrient concentration of industrial growth medium can be an interesting strategy to surpass the deleterious effects of this weak acid in yeast cells. PMID- 20973992 TI - Transcriptional activity of transposable elements in maize. AB - BACKGROUND: Mobile genetic elements represent a high proportion of the Eukaryote genomes. In maize, 85% of genome is composed by transposable elements of several families. First step in transposable element life cycle is the synthesis of an RNA, but few is known about the regulation of transcription for most of the maize transposable element families. Maize is the plant from which more ESTs have been sequenced (more than two million) and the third species in total only after human and mice. This allowed us to analyze the transcriptional activity of the maize transposable elements based on EST databases. RESULTS: We have investigated the transcriptional activity of 56 families of transposable elements in different maize organs based on the systematic search of more than two million expressed sequence tags. At least 1.5% maize ESTs show sequence similarity with transposable elements. According to these data, the patterns of expression of each transposable element family is variable, even within the same class of elements. In general, transcriptional activity of the gypsy-like retrotransposons is higher compared to other classes. Transcriptional activity of several transposable elements is specially high in shoot apical meristem and sperm cells. Sequence comparisons between genomic and transcribed sequences suggest that only a few copies are transcriptionally active. CONCLUSIONS: The use of powerful high throughput sequencing methodologies allowed us to elucidate the extent and character of repetitive element transcription in maize cells. The finding that some families of transposable elements have a considerable transcriptional activity in some tissues suggests that, either transposition is more frequent than previously expected, or cells can control transposition at a post transcriptional level. PMID- 20973991 TI - Annotation and comparative analysis of the glycoside hydrolase genes in Brachypodium distachyon. AB - BACKGROUND: Glycoside hydrolases cleave the bond between a carbohydrate and another carbohydrate, a protein, lipid or other moiety. Genes encoding glycoside hydrolases are found in a wide range of organisms, from archea to animals, and are relatively abundant in plant genomes. In plants, these enzymes are involved in diverse processes, including starch metabolism, defense, and cell-wall remodeling. Glycoside hydrolase genes have been previously cataloged for Oryza sativa (rice), the model dicotyledonous plant Arabidopsis thaliana, and the fast growing tree Populus trichocarpa (poplar). To improve our understanding of glycoside hydrolases in plants generally and in grasses specifically, we annotated the glycoside hydrolase genes in the grasses Brachypodium distachyon (an emerging monocotyledonous model) and Sorghum bicolor (sorghum). We then compared the glycoside hydrolases across species, at the levels of the whole genome and individual glycoside hydrolase families. RESULTS: We identified 356 glycoside hydrolase genes in Brachypodium and 404 in sorghum. The corresponding proteins fell into the same 34 families that are represented in rice, Arabidopsis, and poplar, helping to define a glycoside hydrolase family profile which may be common to flowering plants. For several glycoside hydrolase familes (GH5, GH13, GH18, GH19, GH28, and GH51), we present a detailed literature review together with an examination of the family structures. This analysis of individual families revealed both similarities and distinctions between monocots and eudicots, as well as between species. Shared evolutionary histories appear to be modified by lineage-specific expansions or deletions. Within GH families, the Brachypodium and sorghum proteins generally cluster with those from other monocots. CONCLUSIONS: This work provides the foundation for further comparative and functional analyses of plant glycoside hydrolases. Defining the Brachypodium glycoside hydrolases sets the stage for Brachypodium to be a grass model for investigations of these enzymes and their diverse roles in planta. Insights gained from Brachypodium will inform translational research studies, with applications for the improvement of cereal crops and bioenergy grasses. PMID- 20973993 TI - The individual-cell-based cryo-chip for the cryopreservation, manipulation and observation of spatially identifiable cells. II: functional activity of cryopreserved cells. AB - BACKGROUND: The cryopreservation and thawing processes are known to induce many deleterious effects in cells and might be detrimental to several cell types. There is an inherent variability in cellular responses among cell types and within individual cells of a given population with regard to their ability to endure the freezing and thawing process. The aim of this study was to evaluate the fate of cryopreserved cells within an optical cryo apparatus, the individual cell-based cryo-chip (i3C), by monitoring several basic cellular functional activities at the resolution of individual cells. RESULTS: In the present study, U937 cells underwent the freezing and thawing cycle in the i3C device. Then a panel of vital tests was performed, including the number of dead cells (PI staining), apoptotic rate (Annexin V staining), mitochondrial membrane potential (TMRM staining), cytoplasm membrane integrity and intracellular metabolism (FDA staining), as well as post-thawing cell proliferation assays. Cells that underwent the freezing - thawing cycle in i3C devices exhibited the same functional activity as control cells. Moreover, the combination of the multi parametric analysis at a single cell resolution and the optical and biological features of the device enable an accurate determination of the functional status of individual cells and subsequent retrieval and utilization of the most valuable cells. CONCLUSIONS: The means and methodologies described here enable the freezing and thawing of spatially identifiable cells, as well as the efficient detection of viable, specific, highly biologically active cells for future applications. PMID- 20973994 TI - On the origin of Acochlidia and other enigmatic euthyneuran gastropods, with implications for the systematics of Heterobranchia. AB - BACKGROUND: A robust phylogenetic hypothesis of euthyneuran gastropods, as a basis to reconstructing their evolutionary history, is still hindered by several groups of aberrant, more or less worm-like slugs with unclear phylogenetic relationships. As a traditional "order" in the Opisthobranchia, the Acochlidia have a long history of controversial placements, among others influenced by convergent adaptation to the mainly meiofaunal habitats. The present study includes six out of seven acochlidian families in a comprehensive euthyneuran taxon sampling with special focus on minute, aberrant slugs. Since there is no fossil record of tiny, shell-less gastropods, a molecular clock was used to estimate divergence times within Euthyneura. RESULTS: Our multi-locus molecular study confirms Acochlidia in a pulmonate relationship, as sister to Eupulmonata. Previous hypotheses of opisthobranch relations, or of a common origin with other meiofaunal Euthyneura, are clearly rejected. The enigmatic amphibious and insectivorous Aitengidae incerta sedis clusters within Acochlidia, as sister to meiofaunal and brackish Pseudunelidae and limnic Acochlidiidae. Euthyneura, Opisthobranchia and Pulmonata as traditionally defined are non-monophyletic. A relaxed molecular clock approach indicates a late Palaeozoic diversification of Euthyneura and a Mesozoic origin of the major euthyneuran diversity, including Acochlidia. CONCLUSIONS: The present study shows that the inclusion of small, enigmatic groups is necessary to solve deep-level phylogenetic relationships, and underlines that "pulmonate" and "opisthobranch" phylogeny, respectively, cannot be solved independently from each other. Our phylogenetic hypothesis requires reinvestigation of the traditional classification of Euthyneura: morphological synapomorphies of the traditionally defined Pulmonata and Opisthobranchia are evaluated in light of the presented phylogeny, and a redefinition of major groups is proposed. It is demonstrated that the invasion of the meiofaunal habitat has occurred several times independently in various euthyneuran taxa, leading to convergent adaptations previously misinterpreted as synapomorphies. The inclusion of Acochlidia extends the structural and biological diversity in pulmonates, presenting a remarkable flexibility concerning habitat choice. PMID- 20973995 TI - Overexpression of PtrABF gene, a bZIP transcription factor isolated from Poncirus trifoliata, enhances dehydration and drought tolerance in tobacco via scavenging ROS and modulating expression of stress-responsive genes. AB - BACKGROUND: Drought is one of the major abiotic stresses affecting plant growth, development and crop productivity. ABA responsive element binding factor (ABF) plays an important role in stress responses via regulating the expression of stress-responsive genes. RESULTS: In this study, a gene coding for ABF (PtrABF) was isolated from Poncirus trifoliata (L.) Raf. PtrABF had a complete open reading frame of 1347 bp, encoding a 448 amino acid peptide, and shared high sequence identities with ABFs from other plants. PtrABF was subcellularly targeted to the nucleus, exhibited transactivation activity in yeast cell and could bind to ABRE, supporting its role as a transcription factor. Expression levels of PtrABF were induced by treatments with dehydration, low temperature and ABA. Ectopic expression of PtrABF under the control of a CaMV 35S promoter in transgenic tobacco plants enhanced tolerance to both dehydration and drought. Under dehydration and drought conditions, the transgenic plants accumulated lower levels of reactive oxygen species compared with wild type, accompanied by higher activities and expression levels of three antioxidant enzymes. In addition, steady-state mRNA levels of nine stress-responsive genes coding for either functional or regulatory proteins were induced to higher levels in the transgenic lines with or without drought stress. CONCLUSIONS: PtrABF is a bZIP transcription factor and functions in positive modulation of drought stress tolerance. It may be an important candidate gene for molecular breeding of drought-tolerant plants. PMID- 20973997 TI - Slowing of axonal regeneration is correlated with increased axonal viscosity during aging. AB - BACKGROUND: As we age, the speed of axonal regeneration declines. At the biophysical level, why this occurs is not well understood. RESULTS: To investigate we first measured the rate of axonal elongation of sensory neurons cultured from neonatal and adult rats. We found that neonatal axons grew 40% faster than adult axons (11.5 um/hour vs. 8.2 um/hour). To determine how the mechanical properties of axons change during maturation, we used force calibrated towing needles to measure the viscosity (stiffness) and strength of substrate adhesion of neonatal and adult sensory axons. We found no significant difference in the strength of adhesions, but did find that adult axons were 3 times intrinsically stiffer than neonatal axons. CONCLUSIONS: Taken together, our results suggest decreasing axonal stiffness may be part of an effective strategy to accelerate the regeneration of axons in the adult peripheral nervous system. PMID- 20973996 TI - Genomic survey of the ectoparasitic mite Varroa destructor, a major pest of the honey bee Apis mellifera. AB - BACKGROUND: The ectoparasitic mite Varroa destructor has emerged as the primary pest of domestic honey bees (Apis mellifera). Here we present an initial survey of the V. destructor genome carried out to advance our understanding of Varroa biology and to identify new avenues for mite control. This sequence survey provides immediate resources for molecular and population-genetic analyses of Varroa-Apis interactions and defines the challenges ahead for a comprehensive Varroa genome project. RESULTS: The genome size was estimated by flow cytometry to be 565 Mbp, larger than most sequenced insects but modest relative to some other Acari. Genomic DNA pooled from ~1,000 mites was sequenced to 4.3* coverage with 454 pyrosequencing. The 2.4 Gbp of sequencing reads were assembled into 184,094 contigs with an N50 of 2,262 bp, totaling 294 Mbp of sequence after filtering. Genic sequences with homology to other eukaryotic genomes were identified on 13,031 of these contigs, totaling 31.3 Mbp. Alignment of protein sequence blocks conserved among V. destructor and four other arthropod genomes indicated a higher level of sequence divergence within this mite lineage relative to the tick Ixodes scapularis. A number of microbes potentially associated with V. destructor were identified in the sequence survey, including ~300 Kbp of sequence deriving from one or more bacterial species of the Actinomycetales. The presence of this bacterium was confirmed in individual mites by PCR assay, but varied significantly by age and sex of mites. Fragments of a novel virus related to the Baculoviridae were also identified in the survey. The rate of single nucleotide polymorphisms (SNPs) in the pooled mites was estimated to be 6.2 * 10 5 per bp, a low rate consistent with the historical demography and life history of the species. CONCLUSIONS: This survey has provided general tools for the research community and novel directions for investigating the biology and control of Varroa mites. Ongoing development of Varroa genomic resources will be a boon for comparative genomics of under-represented arthropods, and will further enhance the honey bee and its associated pathogens as a model system for studying host-pathogen interactions. PMID- 20973998 TI - An investigation of patterns in hemodynamic data indicative of impending hypotension in intensive care. AB - BACKGROUND: In the intensive care unit (ICU), clinical staff must stay vigilant to promptly detect and treat hypotensive episodes (HEs). Given the stressful context of busy ICUs, an automated hypotensive risk stratifier can help ICU clinicians focus care and resources by prospectively identifying patients at increased risk of impending HEs. The objective of this study was to investigate the possible existence of discriminatory patterns in hemodynamic data that can be indicative of future hypotensive risk. METHODS: Given the complexity and heterogeneity of ICU data, a machine learning approach was used in this study. Time series of minute-by-minute measures of mean arterial blood pressure, heart rate, pulse pressure, and relative cardiac output from 1,311 records from the MIMIC II Database were used. An HE was defined as a 30-minute period during which the mean arterial pressure was below 60 mmHg for at least 90% of the time. Features extracted from the hemodynamic data during an observation period of either 30 or 60 minutes were analyzed to predict the occurrence of HEs 1 or 2 hours into the future. Artificial neural networks (ANNs) were trained for binary classification (normotensive vs. hypotensive) and regression (estimation of future mean blood pressure). RESULTS: The ANNs were successfully trained to discriminate patterns in the multidimensional hemodynamic data that were predictive of future HEs. The best overall binary classification performance resulted in a mean area under ROC curve of 0.918, a sensitivity of 0.826, and a specificity of 0.859. Predicting further into the future resulted in poorer performance, whereas observation duration minimally affected performance. The low prevalence of HEs led to poor positive predictive values. In regression, the best mean absolute error was 9.67%. CONCLUSIONS: The promising pattern recognition performance demonstrates the existence of discriminatory patterns in hemodynamic data that can indicate impending hypotension. The poor PPVs discourage a direct HE predictor, but a hypotensive risk stratifier based on the pattern recognition algorithms of this study would be of significant clinical value in busy ICU environments. PMID- 20973999 TI - Data-driven identification of co-morbidities associated with rheumatoid arthritis in a large US health plan claims database. AB - BACKGROUND: In drug development, it is important to have an understanding of the full spectrum of co-morbidities to be expected in the group of patients with the disease of interest. It is usually a challenge to identify the less common events associated with the target disease, even if these events are severe. The purpose of this study is to identify co-morbidities associated with rheumatoid arthritis (RA) as compared with a control group, using a large health care database. METHODS: Marketscan US claims database was used for this retrospective cohort study. Selected were records of persons aged at least 16 Y with at least two claims for RA, and with active insurance status on June 30, 2007. The control group had at least two claims for eczema/dermatitis. Controls were matched by age, gender and insurance status (Medicare or not). All co-morbidities with an ICD9 diagnostic code were identified in the RA and control groups, during a one year window. Relative risks (RRs) were calculated. Diagnoses were rank-ordered by magnitude of RR. Codes covering RA and arthropathy were excluded. In order to get stable estimates, rank-ordering was performed for diagnoses occurring in at least 20 persons in the control group. RESULTS: Records were selected of 62,681 persons with RA (mean age was 59.0 Y, with 73.8% female, Medicare-covered 35%). A total of 6,897 different ICD9 diagnostic codes were recorded, with 2,220 codes in at least 20 persons of the control group [listed with Relative Risk]. Apart from joint/bone related conditions, strong associations with RA (RR > 3) were found for Adverse effect medicinal and biological substance not elsewhere classified, Unspecified adverse effect drug properly administered, Idiopathic fibrosing alveolitis, Osteomyelitis, Immune deficiency, Elevated sedimentation rate, Tuberculin test reaction abnormal or positive, Anemia and Cushing syndrome. CONCLUSIONS: Data on a large number (> 60,000) of patients with a diagnosis of RA were used to analyze and to list a large number (> 2,000) of co-morbidities. Rank ordering of RRs of diagnostic codes is a tool to identify quickly many conditions associated with RA. PMID- 20974000 TI - Defining human mesenchymal stem cell efficacy in vivo. AB - Allogeneic human mesenchymal stem cells (hMSCs) can suppress graft versus host disease (GvHD) and have profound anti-inflammatory and regenerative capacity in stroke, infarct, spinal cord injury, meniscus regeneration, tendinitis, acute renal failure, and heart disease in human and animal models of disease. There is significant clinical hMSC variability in efficacy and the ultimate response in vivo. The challenge in hMSC based therapy is defining the efficacy of hMSC in vivo. Models which may provide insight into hMSC bioactivity in vivo would provide a means to distinguish hMSCs for clinical utility. hMSC function has been described as both regenerative and trophic through the production of bioactive factors. The regenerative component involves the multi-potentiality of hMSC progenitor differentiation. The secreted factors generated by the hMSCs are milieu and injury specific providing unique niches for responses in vivo. These bioactive factors are anti-scarring, angiogenic, anti-apoptotic as well as regenerative. Further, from an immunological standpoint, hMSC's can avoid host immune response, providing xenographic applications. To study the in vivo immuno regulatory effectiveness of hMSCs, we used the ovalbumin challenge model of acute asthma. This is a quick 3 week in vivo pulmonary inflammation model with readily accessible ways of measuring effectiveness of hMSCs. Our data show that there is a direct correlation between the traditional ceramic cube score to hMSCs attenuation of cellular recruitment due to ovalbumin challenge. The results from these studies verify the in vivo immuno-modulator effectiveness of hMSCs and support the potential use of the ovalbumin model as an in vivo model of hMSC potency and efficacy. Our data also support future directions toward exploring hMSCs as an alternative therapeutic for the treatment of airway inflammation associated with asthma. PMID- 20974002 TI - Detection of poliovirus by ICC/qPCR in concentrated water samples has greater sensitivity and is less costly using BGM cells in suspension as compared to monolayers. AB - The integrated cell culture quantitative reverse transcriptase PCR (ICC/qRT-PCR) method is used in our lab to detect enteroviruses in environmental waters. Typically we utilize monolayers of 3 cell lines; buffalo green monkey kidney (BGM), human colonic carcinoma (CACO-2) and African rhesus monkey kidney (MA104) with the intent of providing one or more permissive hosts to a wide range of enteroviruses. In this study the BGM cell line was used to compare poliovirus infectivity in conventional monolayer cultures to BGM cells in suspensions. Propagated virus was subsequently amplified by qRT-PCR. Our PCR data showed lower cycle threshold (Ct) values in the suspensions which corresponded to a higher rate of infectivity than that observed in the monolayers. The difference in Ct values was determined statistically significant by One-way ANOVA (0.000). Infecting BGM cells in suspensions required less hands-on time, less chance of contamination and was more cost effective than utilizing the conventional monolayer technique. PMID- 20974001 TI - Central nitrergic system regulation of neuroendocrine secretion, fluid intake and blood pressure induced by angiotensin-II. AB - BACKGROUND: Nitric oxide (NO) synthesis has been described in several circumventricular and hypothalamic structures in the central nervous system that are implicated in mediating central angiotensin-II (ANG-II) actions during water deprivation and hypovolemia. Neuroendocrine and cardiovascular responses, drinking behavior, and urinary excretions were examined following central angiotensinergic stimulation in awake freely-moving rats pretreated with intracerebroventricular injections of Nomega-nitro-L-arginine methyl ester (L NAME, 40 MUg), an inhibitor of NO synthase, and L-arginine (20 ug), a precursor of NO. RESULTS: Injections of L-NAME or ANG-II produced an increase in plasma vasopressin (VP), oxytocin (OT) and atrial natriuretic peptide (ANP) levels, an increase in water and sodium intake, mean arterial blood pressure and sodium excretion, and a reduction of urinary volume. L-NAME pretreatment enhanced the ANG-II response, while L-arginine attenuated VP and OT release, thirst, appetite for sodium, antidiuresis, and natriuresis, as well as pressor responses induced by ANG-II. DISCUSSION AND CONCLUSION: Thus, the central nitrergic system participates in the angiotensinergic responses evoked by water deprivation and hypovolemia to refrain neurohypophysial secretion, hydromineral balance, and blood pressure homeostasis. PMID- 20974003 TI - A novel multifunctional oligonucleotide microarray for Toxoplasma gondii. AB - BACKGROUND: Microarrays are invaluable tools for genome interrogation, SNP detection, and expression analysis, among other applications. Such broad capabilities would be of value to many pathogen research communities, although the development and use of genome-scale microarrays is often a costly undertaking. Therefore, effective methods for reducing unnecessary probes while maintaining or expanding functionality would be relevant to many investigators. RESULTS: Taking advantage of available genome sequences and annotation for Toxoplasma gondii (a pathogenic parasite responsible for illness in immunocompromised individuals) and Plasmodium falciparum (a related parasite responsible for severe human malaria), we designed a single oligonucleotide microarray capable of supporting a wide range of applications at relatively low cost, including genome-wide expression profiling for Toxoplasma, and single nucleotide polymorphism (SNP)-based genotyping of both T. gondii and P. falciparum. Expression profiling of the three clonotypic lineages dominating T. gondii populations in North America and Europe provides a first comprehensive view of the parasite transcriptome, revealing that ~49% of all annotated genes are expressed in parasite tachyzoites (the acutely lytic stage responsible for pathogenesis) and 26% of genes are differentially expressed among strains. A novel design utilizing few probes provided high confidence genotyping, used here to resolve recombination points in the clonal progeny of sexual crosses. Recent sequencing of additional T. gondii isolates identifies >620 K new SNPs, including ~11 K that intersect with expression profiling probes, yielding additional markers for genotyping studies, and further validating the utility of a combined expression profiling/genotyping array design. Additional applications facilitating SNP and transcript discovery, alternative statistical methods for quantifying gene expression, etc. are also pursued at pilot scale to inform future array designs. CONCLUSIONS: In addition to providing an initial global view of the T. gondii transcriptome across major lineages and permitting detailed resolution of recombination points in a historical sexual cross, the multifunctional nature of this array also allowed opportunities to exploit probes for purposes beyond their intended use, enhancing analyses. This array is in widespread use by the T. gondii research community, and several aspects of the design strategy are likely to be useful for other pathogens. PMID- 20974004 TI - Psychiatric diagnoses and punishment for misconduct: the effects of PTSD in combat-deployed Marines. AB - BACKGROUND: Research on Vietnam veterans suggests an association between psychological problems, including posttraumatic stress disorder (PTSD), and misconduct; however, this has rarely been studied in veterans of Operation Iraqi Freedom or Operation Enduring Freedom. The objective of this study was to investigate whether psychological problems were associated with three types of misconduct outcomes (demotions, drug-related discharges, and punitive discharges.) METHODS: A population-based study was conducted on all U.S. Marines who entered the military between October 1, 2001, and September 30, 2006, and deployed outside of the United States before the end of the study period, September 30, 2007. Demographic, psychiatric, deployment, and personnel information was collected from military records. Cox proportional hazards regression analysis was conducted to investigate associations between the independent variables and the three types of misconduct in war-deployed (n = 77,998) and non-war-deployed (n = 13,944) Marines. RESULTS: Marines in both the war-deployed and non-war-deployed cohorts with a non-PTSD psychiatric diagnosis had an elevated risk for all three misconduct outcomes (hazard ratios ranged from 3.93 to 5.65). PTSD was a significant predictor of drug-related discharges in both the war-deployed and non-war-deployed cohorts. In the war-deployed cohort only, a specific diagnosis of PTSD was associated with an increased risk for both demotions (hazard ratio, 8.60; 95% confidence interval, 6.95 to 10.64) and punitive discharges (HR, 11.06; 95% CI, 8.06 to 15.16). CONCLUSIONS: These results provide evidence of an association between PTSD and behavior problems in Marines deployed to war. Moreover, because misconduct can lead to disqualification for some Veterans Administration benefits, personnel with the most serious manifestations of PTSD may face additional barriers to care. PMID- 20974005 TI - Intravital spectral imaging as a tool for accurate measurement of vascularization in mice. AB - BACKGROUND: Quantitative determination of the development of new blood vessels is crucial for our understanding of the progression of several diseases, including cancer. However, in most cases a high throughput technique that is simple, accurate, user-independent and cost-effective for small animal imaging is not available. METHODS: In this work we present a simple approach based on spectral imaging to increase the contrast between vessels and surrounding tissue, enabling accurate determination of the blood vessel area. This approach is put to test with a 4T1 breast cancer murine in vivo model and validated with histological and microvessel density analysis. RESULTS: We found that one can accurately measure the vascularization area by using excitation/emission filter pairs which enhance the surrounding tissue's autofluorescence, significantly increasing the contrast between surrounding tissue and blood vessels. Additionally, we found excellent correlation between this technique and histological and microvessel density analysis. CONCLUSIONS: Making use of spectral imaging techniques we have shown that it is possible to accurately determine blood vessel volume intra-vitally. We believe that due to the low cost, accuracy, user-independence and simplicity of this technique, it will be of great value in those cases where in vivo quantitative information is necessary. PMID- 20974006 TI - alpha-TEA-induced death receptor dependent apoptosis involves activation of acid sphingomyelinase and elevated ceramide-enriched cell surface membranes. AB - BACKGROUND: Alpha-tocopherol ether-linked acetic acid (alpha-TEA), an analog of vitamin E (RRR-alpha-tocopherol), is a potent and selective apoptosis-inducing agent for human cancer cells in vivo and in vitro. alpha-TEA induces apoptosis via activation of extrinsic death receptors Fas (CD95) and DR5, JNK/p73/Noxa pathways, and suppression of anti-apoptotic mediators Akt, ERK, c-FLIP and survivin in breast, ovarian and prostate cancer cells. RESULTS: In this study, we demonstrate that alpha-TEA induces the accumulation of cell surface membrane ceramide, leading to co-localization with Fas, DR5, and FADD, followed by activation of caspases-8 and -9 and apoptosis in human MDA-MB-231 breast cancer cells. alpha-TEA treatment leads to increased acid sphingomyelinase (ASMase) activity by 30 min, peaking at 4 hrs, which is correlated with ASMase translocation from cytosol to the cell surface membrane. Functional knockdown of ASMase with either the chemical inhibitor, desipramine, or siRNA markedly reduces alpha-TEA-induced cell surface membrane accumulation of ceramide and its co localization with Fas, DR5, and FADD, cleavage of caspases-8 and -9 and apoptosis, suggesting an early and critical role for ASMase in alpha-TEA-induced apoptosis. Consistent with cell culture data, immunohistochemical analyses of tumor tissues taken from alpha-TEA treated nude mice bearing MDA-MB-231 xenografts show increased levels of cell surface membrane ceramide in comparison to tumor tissues from control animals. CONCLUSION: Taken together, these studies demonstrate that ASMase activation and membrane ceramide accumulation are early events contributing to alpha-TEA-induced apoptosis in vitro and perhaps in vivo. PMID- 20974007 TI - Breakpoint structure of the Anopheles gambiae 2Rb chromosomal inversion. AB - BACKGROUND: Alternative arrangements of chromosome 2 inversions in Anopheles gambiae are important sources of population structure, and are associated with adaptation to environmental heterogeneity. The forces responsible for their origin and maintenance are incompletely understood. Molecular characterization of inversion breakpoints provides insight into how they arose, and provides the basis for development of molecular karyotyping methods useful in future studies. METHODS: Sequence comparison of regions near the cytological breakpoints of 2Rb allowed the molecular delineation of breakpoint boundaries. Comparisons were made between the standard 2R+b arrangement in the An. gambiae PEST reference genome and the inverted 2Rb arrangements in the An. gambiae M and S genome assemblies. Sequence differences between alternative 2Rb arrangements were exploited in the design of a PCR diagnostic assay, which was evaluated against the known chromosomal banding pattern of laboratory colonies and field-collected samples from Mali and Cameroon. RESULTS: The breakpoints of the 7.55 Mb 2Rb inversion are flanked by extensive runs of the same short (72 bp) tandemly organized sequence, which was likely responsible for chromosomal breakage and rearrangement. Application of the molecular diagnostic assay suggested that 2Rb has a single common origin in An. gambiae and its sibling species, Anopheles arabiensis, and also that the standard arrangement (2R+b) may have arisen twice through breakpoint reuse. The molecular diagnostic was reliable when applied to laboratory colonies, but its accuracy was lower in natural populations. CONCLUSIONS: The complex repetitive sequence flanking the 2Rb breakpoint region may be prone to structural and sequence-level instability. The 2Rb molecular diagnostic has immediate application in studies based on laboratory colonies, but its usefulness in natural populations awaits development of complementary molecular tools. PMID- 20974008 TI - Evaluation of the soft tissue biocompatibility of MgCa0.8 and surgical steel 316L in vivo: a comparative study in rabbits. AB - BACKGROUND: Recent studies have shown the potential suitability of magnesium alloys as biodegradable implants. The aim of the present study was to compare the soft tissue biocompatibility of MgCa0.8 and commonly used surgical steel in vivo. METHODS: A biodegradable magnesium calcium alloy (MgCa0.8) and surgical steel (S316L), as a control, were investigated. Screws of identical geometrical conformation were implanted into the tibiae of 40 rabbits for a postoperative follow up of two, four, six and eight weeks. The tibialis cranialis muscle was in direct vicinity of the screw head and thus embedded in paraffin and histologically and immunohistochemically assessed. Haematoxylin and eosin staining was performed to identify macrophages, giant cells and heterophil granulocytes as well as the extent of tissue fibrosis and necrosis. Mouse anti CD79alpha and rat anti-CD3 monoclonal primary antibodies were used for B- and T lymphocyte detection. Evaluation of all sections was performed by applying a semi quantitative score. RESULTS: Clinically, both implant materials were tolerated well. Histology revealed that a layer of fibrous tissue had formed between implant and overlying muscle in MgCa0.8 and S316L, which was demarcated by a layer of synoviocyte-like cells at its interface to the implant. In MgCa0.8 implants cavities were detected within the fibrous tissue, which were surrounded by the same kind of cell type. The thickness of the fibrous layer and the amount of tissue necrosis and cellular infiltrations gradually decreased in S316L. In contrast, a decrease could only be noted in the first weeks of implantation in MgCa0.8, whereas parameters were increasing again at the end of the observation period. B-lymphocytes were found more often in MgCa0.8 indicating humoral immunity and the presence of soluble antigens. Conversely, S316L displayed a higher quantity of T-lymphocytes. CONCLUSIONS: Moderate inflammation was detected in both implant materials and resolved to a minimum during the first weeks indicating comparable biocompatibility for MgCa0.8 and S316L. Thus, the application of MgCa0.8 as biodegradable implant material seems conceivable. Since the inflammatory parameters were re-increasing at the end of the observation period in MgCa0.8 it is important to observe the development of inflammation over a longer time period in addition to the present study. PMID- 20974009 TI - Performance of HRP-2 based rapid diagnostic test for malaria and its variation with age in an area of intense malaria transmission in southern Tanzania. AB - BACKGROUND: The use of malaria rapid diagnostic tests (RDTs) has been widely advocated to improve Plasmodium falciparum diagnosis, especially in settings where quality microscopy is not available. RDTs based on the detection of histidine-rich protein 2 (HRP-2) can remain positive for several weeks after an infection is cured, due to the persistence of HRP-2 antigens. As a result, test specificity may vary between age groups with different prevalence of P. falciparum infection. METHODS: A community-based cross-sectional survey, carried out in southern Tanzania in July and August 2004, evaluated the performance of the Paracheck Pf in comparison with microscopy (number of P. falciparum parasites/200 leucocytes). A sample of 598 individuals living in an area of intense malaria transmission had demographic data collected before an RDT was performed. HRP-2 test sensitivity, specificity, positive and negative predictive values were calculated and compared between distinct age groups, using microscopy as "gold standard". RESULTS: The overall malaria prevalence was 34.3% according to microscopy and 57.2% according to the HRP-2 test. The HRP-2 test had a sensitivity of 96.1%, a specificity of 63.1%, a positive predictive value of 57.6% and a negative predictive value of 96.9%. The test sensitivity was higher (ranging from 98% to 100%) amongst people less than 25 years of age, but decreased to 81.3% in older adults. The HRP-2 test specificity varied between age groups, ranging from 25% among children of five to nine years of age, to 73% among adults aged 25 or more. The test positive predictive value increased with malaria prevalence, while the negative predictive value was consistently high across age groups. CONCLUSIONS: These results suggest that the performance of HRP 2 tests in areas of intense malaria transmission varies by age and the prevalence of P. falciparum infection. The particularly low specificity among children will lead to the over-estimation of malaria infection prevalence in this group. PMID- 20974010 TI - Roles of zinc and metallothionein-3 in oxidative stress-induced lysosomal dysfunction, cell death, and autophagy in neurons and astrocytes. AB - Zinc dyshomeostasis has been recognized as an important mechanism for cell death in acute brain injury. An increase in the level of free or histochemically reactive zinc in astrocytes and neurons is considered one of the major causes of death of these cells in ischemia and trauma. Although zinc dyshomeostasis can lead to cell death via diverse routes, the major pathway appears to involve oxidative stress.Recently, we found that a rise of zinc in autophagic vacuoles, including autolysosomes, is a prerequisite for lysosomal membrane permeabilization and cell death in cultured brain cells exposed to oxidative stress conditions. The source of zinc in this process is likely redox-sensitive zinc-binding proteins such as metallothioneins, which release zinc under oxidative conditions. Of the metallothioneins, metallothionein-3 is especially enriched in the central nervous system, but its physiologic role in this tissue is not well established. Like other metallothioneins, metallothionein-3 may function as metal detoxicant, but is also known to inhibit neurite outgrowth and, sometimes, promote neuronal death, likely by serving as a source of toxic zinc release. In addition, metallothionein-3 regulates lysosomal functions. In the absence of metallothionein-3, there are changes in lysosome-associated membrane protein-1 and -2, and reductions in certain lysosomal enzymes that result in decreased autophagic flux. This may have dual effects on cell survival. In acute oxidative injury, zinc dyshomeostasis and lysosomal membrane permeabilization are diminished in metallothionein-3 null cells, resulting in less cell death. But over the longer term, diminished lysosomal function may lead to the accumulation of abnormal proteins and cause cytotoxicity.The roles of zinc and metallothionein 3 in autophagy and/or lysosomal function have just begun to be investigated. In light of evidence that autophagy and lysosomes may play significant roles in the pathogenesis of various neurological diseases, further insight into the contribution of zinc dynamics and metallothionein-3 function may help provide ways to effectively regulate these processes in brain cells. PMID- 20974011 TI - Mitochondrially-targeted expression of a cytoplasmic male sterility-associated orf220 gene causes male sterility in Brassica juncea. AB - BACKGROUND: The novel chimeric open reading frame (orf) resulting from the rearrangement of a mitochondrial genome is generally thought to be a causal factor in the occurrence of cytoplasmic male sterility (CMS). Both positive and negative correlations have been found between CMS-associated orfs and the occurrence of CMS when CMS-associated orfs were expressed and targeted at mitochondria. Some orfs cause male sterility or semi-sterility, while some do not. Little is currently known about how mitochondrial factor regulates the expression of the nuclear genes involved in male sterility. The purpose of this study was to investigate the biological function of a candidate CMS-associated orf220 gene, newly isolated from cytoplasmic male-sterile stem mustard, and show how mitochondrial retrograde regulated nuclear gene expression is related to male sterility. RESULTS: It was shown that the ORF220 protein can be guided to the mitochondria using the mitochondrial-targeting sequence of the beta subunit of F1 ATPase (atp2-1). Transgenic stem mustard plants expressed the chimeric gene containing the orf220 gene and a mitochondrial-targeting sequence of the beta subunit of F1-ATPase (atp2-1). Transgenic plants were male-sterile, most being unable to produce pollen while some could only produce non-vigorous pollen. The transgenic stem mustard plants also showed aberrant floral development identical to that observed in the CMS stem mustard phenotype. Results obtained from oligooarray analysis showed that some genes related to mitochondrial energy metabolism were down-regulated, indicating a weakening of mitochondrial function in transgenic stem mustard. Some genes related to pollen development were shown to be down-regulated in transgenic stem mustard and the expression of some transcription factor genes was also altered. CONCLUSION: The work presented furthers our understanding of how the mitochondrially-targeted expression of CMS associated orf220 gene causes male sterility through retrograde regulation of nuclear gene expression in Brassica juncea. PMID- 20974012 TI - Preventive effects of Flos Perariae (Gehua) water extract and its active ingredient puerarin in rodent alcoholism models. AB - BACKGROUND: Radix Puerariae is used in Chinese medicine to treat alcohol addiction and intoxication. The present study investigates the effects of Flos puerariae lobatae water extract (FPE) and its active ingredient puerarin on alcoholism using rodent models. METHODS: Alcoholic animals were given FPE or puerarin by oral intubation prior or after alcohol treatment. The loss of righting reflex (LORR) assay was used to evaluate sedative/hypnotic effects. Changes of gama-aminobutyric acid type A receptor (GABAAR) subunits induced by alcohol treatment in hippocampus were measured with western blot. In alcoholic mice, body weight gain was monitored throughout the experiments. Alcohol dehydrogenase (ADH) levels in liver were measured. RESULTS: FPE and puerarin pretreatment significantly prolonged the time of LORR induced by diazepam in acute alcoholic rat. Puerarin increased expression of gama-aminobutyric acid type A receptor alpha1 subunit and decreased expression of alpha4 subunit. In chronic alcoholic mice, puerarin pretreatment significantly increased body weight and liver ADH activity in a dose-dependent manner. Puerarin pretreatment, but not post-treatment, can reverse the changes of gama-aminobutyric acid type A receptor subunit expression and increase ADH activity in alcoholism models. CONCLUSION: The present study demonstrates that FPE and its active ingredient puerarin have preventive effects on alcoholism related disorders. PMID- 20974013 TI - Validation of a functional screening instrument for dementia in an elderly sri lankan population: comparison of modified bristol and blessed activities of daily living scales. AB - BACKGROUND: Cognitive tests have been used in population surveys as first stage screens for dementia but are biased by education. However functional ability scales are less biased by education than the cognitive scale and thus can be used in screening for dementia. OBJECTIVE: To validate Activities of Daily Living (ADL) scale appropriate for use in assessing the presence of dementia in an elderly population living in care homes in Sri Lanka. METHOD: Sinhalese version of the modified Bristol and Blessed scale was administered to subjects aged 55 years and above residing in 14 randomly selected elders' homes. Receiver Operating Characteristic (ROC) was used to determine the cut-off scores of both the scales. RESULTS: Based on the ROC analysis, optimal cut off score of the modified Bristol scale was 20 with a sensitivity of 100%, specificity of 74.2% and the area under the curve 0.933(95% CI: 0.871-0.995) while the optimal cut off score of the modified Blessed scale was 10.5 with a sensitivity of 100%, specificity of 71% and the area under the curve 0.892 (95% CI: 0.816-0.967). CONCLUSION: The findings confirm that both the scales can be used in screening for dementia in the elderly living in care homes in Sri Lanka. PMID- 20974015 TI - Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. AB - In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0.05) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0.05; somatisation, P < 0.05; depression, P < 0.05; and anger hostility, P < 0.05), the HADS (HADS global score, P < 0.05; and HADS-anxiety, P < 0.06), and by the CCL (problem solving, P < 0.05) and the UFC level (P < 0.05). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic like activity in rats and beneficial psychological effects in healthy human volunteers. PMID- 20974016 TI - Management of sword-swallower injuries. AB - OBJECTIVE: To report an unusual case of hypopharyngeal perforation in a sword swallower, with emphasis on management options. METHOD: Case report and review of the English language literature concerning sword-swallowing injuries to the hypopharynx and oesophagus. RESULTS: A 29-year-old male sword-swallower suffered hypopharyngeal perforation during a performance. The patient received conservative management, with intensive care unit admission, infectious disease consultation, intravenous antibiotics, discontinuation of oral intake and close observation. He progressed well, resumed oral intake on hospital day six, and was discharged home on hospital day eight. CONCLUSION: Sword-swallowing is an unusual vocation which may lead to potentially devastating injuries. This case report and review of the literature illustrates the management options for such hypopharyngeal and oesophageal injuries. PMID- 20974014 TI - Molecular mechanisms of pluripotency and reprogramming. AB - Pluripotent stem cells are able to form any terminally differentiated cell. They have opened new doors for experimental and therapeutic studies to understand early development and to cure degenerative diseases in a way not previously possible. Nevertheless, it remains important to resolve and define the mechanisms underlying pluripotent stem cells, as that understanding will impact strongly on future medical applications. The capture of pluripotent stem cells in a dish is bound to several landmark discoveries, from the initial culture and phenotyping of pluripotent embryonal carcinoma cells to the recent induction of pluripotency in somatic cells. On this developmental time line, key transcription factors, such as Oct4, Sox2 or Nanog, have been revealed not only to regulate but also to functionally induce pluripotency. These early master regulators of development control developmental signalling pathways that affect the cell cycle, regulate gene expression, modulate the epigenetic state and repair DNA damage. Besides transcription factors, microRNAs have recently been shown to play important roles in gene expression and are embedded into the regulatory network orchestrating cellular development. However, there are species-specific differences in pluripotent cells, such as surface marker expression and growth factor requirements. Such differences and their underlying developmental pathways require clear definition and have major impacts on the preclinical test bed of pluripotent cells. PMID- 20974017 TI - Use of trans-septal mattress suture of Little's area for anterior epistaxis. AB - BACKGROUND: In some cases of epistaxis, anterior packing and/or electrocoagulation are not sufficient and suturing is needed. However, standard suturing techniques are sometimes ineffective. This paper reports the use of a new kind of trans-septal mattress suture, based on regional vascular anatomy, in this clinical context. METHODS: Four adult patients with haemorrhage in Little's area underwent standard suturing, but bleeding persisted. These patients were successfully treated with trans-septal mattress suturing, using four punctures around the haemorrhage site. RESULTS: No relapses or complications were observed over a six-month follow-up period. CONCLUSION: In cases of persistent bleeding from Little's area, suturing should surround the bleeding area. The described suturing method is simple, efficacious and cheap. PMID- 20974018 TI - Endoscopic trans-sphenoidal removal of cholesterol granuloma of the petrous apex: case report and literature review. AB - OBJECTIVE: We report a case of cholesterol granuloma of the petrous apex which was surgically treated via an endoscopic trans-sphenoidal approach. METHODS: Case report and review of the literature concerning cholesterol granulomas of the petrous apex and their management. RESULTS: The lesion was approached endoscopically via a bilateral sphenoidotomy with removal of the vomer. A large cholesterol granuloma was evacuated and marsupialised. The patient made an uneventful recovery. CONCLUSION: Trans-sphenoidal access to the petrous apex represents an alternative route for the drainage and ventilation of cholesterol granulomas. This approach is the technique of choice when the cholesterol granuloma abuts the posterior wall of the sphenoid sinus. The trans-sphenoid approach, unlike other lateral approaches to the petrous apex, spares cochlear and vestibular function and allows post-operative endoscopic follow up. PMID- 20974019 TI - Seroepidemiological studies indicate frequent and repeated exposure to Campylobacter spp. during childhood. AB - The annual number of episodes of clinical gastroenteritis caused by Campylobacter spp. in The Netherlands is estimated to be 75 000, i.e. once per 200 person life years. This number is based on extrapolation of culture results from population based studies. The number of culture-confirmed cases of Campylobacter infection peaks in the first 3 years of life and again between the ages of 20 and 25 years. The seroepidemiology of Campylobacter describes the relationship between age and exposure to Campylobacter and reflects both symptomatic and asymptomatic infections. Using a validated ELISA system, antibodies to Campylobacter were measured in an age-stratified sample (n=456) of the PIENTER serum collection of the Dutch general population. The seroprevalence of Campylobacter IgG antibodies increased with age, reaching almost 100% at age 20 years. Antibody levels steadily increased with age until young adulthood, suggesting repeated exposure to Campylobacter. In conclusion, seroepidemiological data demonstrated repeated exposures to Campylobacter throughout life, most of which do not lead to clinical symptoms. From young adulthood, >95% of the population in The Netherlands had serological evidence for exposure to Campylobacter. PMID- 20974020 TI - Outcomes of hospitalized patients with bacteraemic and non-bacteraemic community acquired pneumonia caused by Streptococcus pneumoniae. AB - In contrast to bacteraemic pneumococcal community-acquired pneumonia (CAP), there is a paucity of data on the clinical characteristics and outcomes of non bacteraemic pneumococcal CAP. This retrospective study compared the outcome of hospitalized patients with bacteraemic and non-bacteraemic pneumococcal CAP treated at a medical centre from 2004 to 2008. Data on clinical outcomes including all-cause mortality, length of hospital stay, need for intensive-care unit admission and extrapulmonary involvement were analysed. In all, 221 patients with pneumococcal pneumonia (87 bacteraemic, 134 non-bacteraemic) were included. Patients with bacteraemic pneumococcal pneumonia (BPP) were older than those with non-BPP (46.2 +/- 30.7 years vs. 21.7 +/- 30.8 years, P<0.001) and were more likely to have underlying medical diseases (66.7% vs. 33.6%, P<0.001). The overall mortality rates at 7, 14, and 30 days were significantly higher in BPP than non-BPP patients (12.6% vs. 2.2%, 14.9% vs. 3.7%, 19.5% vs. 5.1%, all P<0.01). Multivariate logistic regression analysis showed that pneumococcal bacteraemia was correlated with extrapulmonary involvement (odds ratio 5.46, 95% confidence interval 1.97-15.16, P=0.001). In conclusion, S. pneumoniae bacteraemia increased the risk of mortality and extrapulmonary involvement in patients with pneumococcal CAP. PMID- 20974022 TI - Functionalities of free and open electronic health record systems. AB - OBJECTIVES: The aim of this study was to examine open-source electronic health record (EHR) software to determine their level of functionalities according to the International Organization for Standardization (ISO) standards. METHODS: ISO standards were used as a guideline to determine and describe the reference architecture and functionalities of a standard electronic health record system as well the environmental context for which the software has been built. Twelve open source EHR systems were selected and evaluated according to two-dimensional criteria based on ISO/TS 18308:2004 functional requirements and ISO/TR 20514:2005 context of the EHR system. RESULTS: Open EHR software programs mostly fulfill structural, procedural, evolutional, and medicolegal requirements at the minimal and full functionality levels. Communication, privacy, and security requirements are accomplished in less than 23 percent of the cases, mainly at minimal functional level. Ethical, cultural, and consumer requirements still need to be fulfilled by free and open-source EHR applications. CONCLUSIONS: Most analyzed systems had several functional limitations. Nevertheless, especially for clinicians and decision makers in developing countries, open-source EHR systems are an option. The limited functionalities are likely to become requirements for further releases of open-source EHR systems. PMID- 20974023 TI - Male enhancement products: kudos to the FDA. PMID- 20974021 TI - Adult intensive-care patients with 2009 pandemic influenza A(H1N1) infection. AB - In France, the surveillance of hospitalized cases of pandemic influenza was implemented in July 2009 and restricted to intensive-care unit (ICU) patients in November. We described the characteristics of the 1065 adult patients admitted to ICUs and analysed risk factors for severe outcome (mechanical ventilation or death). Eighty-seven percent of cases were aged 15-64 years. The case-fatality ratio was 20%. The risk for severe outcome increased with age and obesity while this association was negative for chronic respiratory disease. Late antiviral therapy was associated with a severe outcome in ICU patients with risk factors (adjusted OR 2.0, 95% CI 1.4-3.0). This study confirms the considerable contribution of young adults to A(H1N1) 2009 mortality. It shows the role of obesity as an independent risk factor for severe disease, and of early antiviral therapy as a protective factor, at least in patients with risk factors. PMID- 20974024 TI - Legends in urology. PMID- 20974025 TI - Multiple physician recommendations for prostate cancer treatment: a Pandora's box for patients? AB - OBJECTIVE: Patients turn to their physicians for information and guidance when making a prostate cancer treatment decision. The objectives of this study were to determine the likelihood of men consulting with and receiving treatment recommendations from different providers (urologists, radiation oncologists, and primary care physicians), the content of these recommendations, the perceived influence of recommendations and which recommendations, if any, were associated with prostate cancer treatment decisions. METHODS: One hundred and fifty-eight participants with localized prostate cancer completed a survey regarding their treatment decision-making process. Associations between treatment choice and urologist recommendations, consultations with radiation oncologists and primary care physicians, potential side effects and other factors were examined using regression analysis. RESULTS: Among men consulting multiple providers, more than half received at least one treatment recommendation. Most men chose a treatment recommended by at least one provider. The likelihood of choosing a treatment increased when the urologist recommended it. Consulting a radiation oncologist decreased and increased likelihood of choosing a radical prostatectomy and radiation, respectively. CONCLUSION: Most men consulted multiple providers and received multiple treatment recommendations. Recommendations appear to play a significant role in prostate cancer treatment decision-making. PMID- 20974026 TI - Histological subtypes of prostatic cancer: a comparative survival study. AB - INTRODUCTION: Variant histological subtypes of prostatic cancer occur uncommonly and are associated with poor survival, as has been ascertained through limited series and case reports. Here a population-based analysis of prostatic cancer is provided, to better analyze the survival behavior of these subtypes. MATERIALS AND METHODS: The American SEER registry was used to review prostatic cancer diagnosed from 1988 to 2003, classified according to the International Classification of Diseases for Oncology. Kaplan-Meier and proportional hazards analyses were performed on adenocarcinomas and five infrequent variant subtypes to determine their overall survival behavior, allowing corrections for follow up inequity, age, stage, histological grade, and year of diagnosis. RESULTS: A total of 455,296 cases of prostatic cancer were reviewed, of which over 99% were conventional adenocarcinomas. The remaining variants studied included ductal carcinomas (0.141%), mucinous adenocarcinomas (0.103%), small cell carcinomas (0.056%), carcinosaromas (0.07%) and embryonal carcinosarcomas (0.06%). With age, stage and grade effects were corrected for in the multivariate analysis, conventional adenocarcinomas, mucinous adenocarcinomas and ductal carcinomas exhibited similar survival behavior. Small cell carcinomas and carcinosarcomas exhibited poor survival, even with correction. The embryonal variant of carcinosarcoma affected pediatric patients and had an overall survival similar to conventional prostatic cancer. Ductal carcinomas, small cell carcinomas and both types of carcinosarcoma tended to present with metastases more frequently than conventional disease. CONCLUSIONS: Prostatic cancer subtype can have a major bearing on overall survival and likely reflects intrinsic differences in biological behavior. PMID- 20974027 TI - Cesium 131 versus iodine 125 implants for prostate cancer: evaluation of early PSA response. AB - INTRODUCTION: Given the shorter half-life of cesium-131 (Cs-131) compared to iodine-125 (I-125), we hypothesized that initial PSA outcomes may differ. We compare initial PSA outcomes in men undergoing Cs-131 prostate brachytherapy to men treated with I-125. PATIENTS AND METHODS: The first post-treatment PSA (obtained 3-6 months after the procedure) was compared in patients undergoing I 125 prostate brachytherapy to that of patients undergoing Cs-131 prostate brachytherapy at the same institution. Comparisons included the total cohort as well as low and intermediate risk patients. RESULTS: Mean pre-treatment PSA was 6.9 ng/mL in the I-125 cohort, and 6.9 ng/mL in the Cs-131 cohort. Mean initial post-treatment PSA was 0.9 ng/mL (range < 0.1-4.6) in the I-125 cohort and 1.2 ng/mL (range < 0.1-23.5) in the Cs-131 patients. For low risk patients, mean pre treatment PSA was 5.8 ng/mL in the I-125 cohort, and 5.1 ng/mL in the Cs-131 cohort. Initial mean post-treatment PSA for low risk patients was 1.2 ng/mL (range < 0.1-4.6) in the I-125 group and 1.0 ng/mL (range < 0.1-2.9) in the Cs 131 patients (p = 0.37). For intermediate risk patients, mean pre-treatment PSA was 7.3 ng/mL in the I-125 cohort, and 7.3 ng/mL in the Cs-131 cohort. Mean initial post-treatment PSA in intermediate risk patients was 1.5 ng/mL (range < 0.1-2.9) in the I-125 group and 1.2 ng/mL (range < 0.1-4.6) in the Cs-131 patients (p = 0.52). CONCLUSIONS: Given the shorter half-life of Cs-131 compared to I-125, we hypothesized that initial post-brachytherapy PSA levels were similar between men receiving treatment with Cs-131 and I-125. The aim of the present study is not to predict long term outcome after Cs-131 prostate brachytherapy, but rather to simply compare initial PSA outcomes in men undergoing prostate brachytherapy with I-125 to Cs-131. Long term data are needed to document cancer control achieved with Cs-131. PMID- 20974028 TI - Implantation of electromagnetic transponders following radical prostatectomy for delivery of IMRT. AB - INTRODUCTION: Radiation therapy (RT) after radical prostatectomy (RP) has been associated with a survival benefit in both the adjuvant and salvage setting. Nevertheless, optimal targeting of the prostate bed following surgery remains challenging. The Calypso 4D Localization System (Calypso Medical Technologies, Seattle, WA, USA) is a target positioning device that continuously monitors the location of three implantable electromagnetic transponders. We describe our technique of ultrasound-guided placement of these transponders into the prostate bed for adjuvant and salvage RT. METHODS: Seventeen patients presenting to Fox Chase Cancer Center for postoperative RT underwent transrectal ultrasound-guided placement of Calypso beacons. The three transponders were placed approximately 1 cm apart in a triangular fashion around the vesico-urethral anastomosis and in the retrovesicular tissue. RESULTS: All patients were successfully implanted without periprocedural complications. Appropriate beacon position was confirmed by CT scan performed at the time of RT simulation. Intensity-modulated radiation therapy was delivered at a dose of 68 Gy (range 64-68). Treatment was well tolerated with no Grade 3 or 4 toxicities. Grade > 2 enteritis was not observed, and there were no cases of rectal bleeding. Genitourinary toxicity was noted in 10 patients and consisted of Grade 1 and 2 frequency and dysuria. No patient developed gross hematuria or urinary retention. All patients (9/9) with at least 6 months of follow up after treatment had an undetectable PSA. CONCLUSIONS: The placement of Calypso transponders for adjuvant/salvage RT is a safe and efficacious method for treatment targeting with an acceptable acute toxicity profile. PMID- 20974029 TI - The case for conservative management in the treatment of patients with non-muscle invasive micropapillary bladder carcinoma without carcinoma in situ. AB - INTRODUCTION: Micropapillary carcinoma is a rare pathologic variant of urothelial cell carcinoma. Intravesical bacillus Calmette-Guerin (BCG) has been reported to be ineffective and to entail an increased risk of development of non-organ confined, metastatic disease. We assess the treatment response and disease progression in patients with micropapillary carcinoma of the bladder. MATERIALS AND METHODS: The study comprised 18 patients with micropapillary carcinoma of the bladder who underwent transurethral resection of a bladder tumor and multiple random biopsies between 1997 and 2003. We retrospectively analyzed treatment response and clinical and pathological cancer evolution related to cancer stage and the percentage of the micropapillary component of the cancer. RESULTS: Seven of the 18 patients (38.8%) had carcinoma in situ. At diagnosis, 8 of the 18 patients had non-muscle-invasive bladder cancer; 6 of these patients were treated with intravesical BCG therapy and were alive and free of disease at a median follow up of more than 5 years. Ten of the 18 patients had muscle-invasive bladder cancer; 8 of these patients underwent radical cystectomy, and 7 of the 8 patients (87.5%) had non-organ-confined disease in cystectomy specimens. Seventy percent of patients with muscle-invasive disease at diagnosis had a micropapillary carcinoma component of more than 50% in transurethral resection of the bladder specimens, compared with only 25% of patients with non-muscle invasive disease. Patients treated successfully with intravesical BCG therapy had a low micropapillary carcinoma component. The 5-year disease-specific survival rate was significantly lower in patients with muscle-invasive disease (30%) than in patients with non-muscle-invasive disease (87.5%) after a median follow up of 52 months (p = 0.001), and it was also significantly lower in patients with a high percentage of the micropapillary component of the carcinoma. CONCLUSIONS: This retrospective study of 18 patients with micropapillary carcinoma of the bladder suggests that tumor stage and patient outcome may be related to the percentage of the micropapillary component of the carcinoma. Radical surgery is mandatory in muscle-invasive disease, even though patients with lymph node involvement die from the disease. In non-muscle-invasive disease and in the absence of associated carcinoma in situ, intravesical BCG treatment may be offered when the micropapillary component of the carcinoma component is a small percentage. PMID- 20974030 TI - Does a perioperative belladonna and opium suppository improve postoperative pain following robotic assisted laparoscopic radical prostatectomy? Results of a single institution randomized study. AB - INTRODUCTION: Robotic assisted laparoscopic radical prostatectomy (RALP) is a common treatment for localized prostate cancer. Despite a primary advantage of improved postoperative pain, patients undergoing RALP still experience discomfort. Belladonna, containing the muscarinic receptor antagonists atropine and scopolamine, in combination with opium as a rectal suppository (B & O) may improve post-RALP pain. This study evaluates whether a single preoperative B & O results in decreased postoperative patient-reported pain and analgesic requirements. MATERIALS AND METHODS: Patients undergoing RALP at Virginia Mason Medical Center between November 2008 and July 2009 were offered the opportunity to enter a randomized, double-blind, placebo-controlled trial. Exclusion criteria included: glaucoma, bronchial asthma, convulsive disorders, chronic pain, chronic use of analgesics, or a history of alcohol or opioid dependency. Surgeons were blinded to suppository placement which was administered after induction of anesthesia. All patients underwent a standardized anesthesia regimen. Postoperative pain was assessed by a visual analog scale (VAS) and postoperative narcotic use was calculated in intravenous morphine equivalents. RESULTS: Ninety nine patients were included in the analysis. The B & O and control groups were not significantly different in terms of age, body mass index, operative time, nerve sparing status or prostatic volume. Postoperative pain was significantly improved during the first two postoperative hours in the B & O group. Similarly, 24-hour morphine consumption was significantly lower in patients who received a B & O. No adverse effects secondary to suppository placement were identified. CONCLUSION: Preoperative administration of B & O suppository results in significantly decreased postoperative pain and 24-hour morphine consumption in patients undergoing RALP. PMID- 20974032 TI - Significance of prostate weight on peri and postoperative outcomes of robot assisted laparoscopic extraperitoneal radical prostatectomy. Editorial comment. PMID- 20974031 TI - Significance of prostate weight on peri and postoperative outcomes of robot assisted laparoscopic extraperitoneal radical prostatectomy. AB - INTRODUCTION: To determine the significance of prostate weight (PW) on clinical and pathological outcomes in patients undergoing da Vinci robot assisted laparoscopic extraperitoneal radical prostatectomy (EP-RARP). METHODS: From November 2008 to January 2010, 295 men underwent EP-RARP at our institution. We retrospectively reviewed our database and stratified patients into four groups based on pathologic PW: Group 1, less than 30 g; Group 2, 30 g to less than 50 g; Group 3, 50 g to less than 80 g; and Group 4, 80 g or larger. We prospectively compared these groups with respect to patient age, body mass index, prostate specific antigen, Gleason score, pathological stage, margin status, operative time, blood loss, transfusion rate and length of stay. Statistical analysis was performed using SYSTAT 13 software. An analysis of variance (ANOVA) model was used to compare the continuous variables among the groups. Chi-square and Fisher's exact tests were used to compare categorical variables. RESULTS: Of the 295 patients, 10, 182, 91, and 12 had a PW of less than 30 g; 30 g to less than 50 g; 50 g to less than 80 g; and 80 g or larger, respectively. A significant difference was found in age, prostate weight and prostate-specific antigen values among the four groups (p < 0.05). Patients in Group 4 had larger prostates, were older (mean age 65 years), had higher pretreatment prostate-specific antigen (median 5.85 ng/mL) and lower Gleason score (mean 6.2). Based on the D'Amico risk stratification, our study showed a trend toward higher risk disease, presence of extra capsular extension, seminal vesicle invasion and positive margin status in Groups 1, 2 and 3 rather than in Group 4. No significant differences in operative time, estimated blood loss, transfusion rate, hospital stay, and postoperative complication rate were observed among the four groups. CONCLUSIONS: Da Vinci robot assisted laparoscopic extraperitoneal radical prostatectomy (EP-RARP) is feasible in patients with larger prostates, offering acceptable operative times, blood loss, hospital stay and complication rates. In our cohort of patients, we found pathologically smaller prostates are generally associated with higher Gleason score, higher risk group stratification and positive surgical margin status. Although technically challenging, increased prostate weight should not be considered a contraindication for EP-RARP if performed by experienced surgeons. PMID- 20974033 TI - Lower extremity neuropathy after robot assisted laparoscopic radical prostatectomy and radical cystectomy. AB - INTRODUCTION: To describe the incidence and outcomes of lower extremity neuropathies in a series of robot assisted laparoscopic radical prostatectomy (RALRP) and robot assisted laparoscopic radical cystectomy (RALRC) patients with 9 months follow up. Additionally, we compare this cohort to other published series of lithotomy based surgery and describe strategies for minimizing risk. MATERIALS AND METHODS: We performed a retrospective analysis of 179 consecutive patients who underwent either RALRP or RALRC at a single institution during a 17 month period. We included all patients who experienced bothersome lower extremity pain, weakness, or numbness at any time during their postoperative course. We further defined postoperative neuropathy as de-novo symptoms presenting in the first week postoperatively. Chart review and telephone survey were used to further characterize these patients. RESULTS: Six out of 179 patients complained of lower extremity neuropathic symptoms by 9 months of follow up. Probable injuries to the common peroneal, lateral femoral cutaneous, and obturator nerves were found. Three patients met our criteria for postop neuropathy making the incidence 1.68%. All patients remained ambulatory throughout their course. At 9 months follow up, only one patient, a man with metastatic bladder cancer, had activity limiting neuropathic symptoms. CONCLUSIONS: With routine use of common risk minimizing strategies, RALRP or RALRC may result in lower extremity europathy at rates similar to other lithotomy based procedures described in the literature. PMID- 20974034 TI - A novel reconstructive option for long upper ureter obliteration. AB - INTRODUCTION: Injuries of the upper (lumbar) portion of the ureter are rare; however, their reconstruction may pose considerable challenges. We describe a novel technique of surgical reconstruction in case of a long upper ureteral obliteration that may be a viable treatment option in select patients. MATERIALS AND METHODS: Reconstruction of a iatrogenic 5 cm injury to the upper ureter, consisting of 2 cm obliteration and 1.5 cm stenotic segments on its sides, unsuitable for an end-to-end reanastomosis, was performed using a novel technique of augmented pelvic flap anastomotic ureteroplasty. The injured ureteral segment was excised, the ureteral stump was spatulated on the medial aspect and the lateral tissue defect was replaced by a flap from the posterior surface of the renal pelvis. RESULTS: The procedure was successfully performed avoiding more aggressive and morbid management choices. To date, patient's renal function is stable and there is no clinical or radiographic evidence of obstruction. CONCLUSIONS: The described augmented anastomotic ureteroplasty using a pelvic flap is a useful surgical solution for select patients with long upper ureteral obliteration that cannot be managed by a direct reanastomosis. This technique may represent a valid addition to the urologic surgical armamentarium. PMID- 20974035 TI - A novel reconstructive option for long upper ureter obliteration. Editorial comment. PMID- 20974036 TI - Management of a persistent ileo-ureteric anastomotic leak with bilateral ureteric occlusion using angioplasty balloon catheters. AB - The ileal conduit continues to be the most common form of urinary diversion performed worldwide. As a result of improved surgical technique the perioperative mortality and morbidity for patients undergoing ileal conduit urinary diversion has reduced remarkably. However, one early complication that may occur is that of urinary leak at the ileo-ureteric anastomosis. Urinary anastomotic leaks may be associated with significant morbidity and mortality. Although a small initial leakage postoperatively is common, the problem arises in cases of continued urinary leakage from the ileo-ureteric anastomosis. We report the management of a persistent ileo-ureteric anastomotic leak using angioplasty balloons catheters to occlude both ureters. PMID- 20974037 TI - Radical nephrectomy via epidural-only anesthesia. AB - We present what we believe is, to the best of our knowledge, the first report of open radical nephrectomy performed under epidural-only anesthesia. Our patient had localized renal cell carcinoma requiring open nephrectomy, but he also had comorbid emphysema that precluded general anesthesia. Epidural anesthesia, which bypassed the pulmonary system, allowed us to perform the surgery. PMID- 20974038 TI - Spontaneous descent of a cryptorchid testicle after the first stage of a planned 2 stage laparoscopic Fowler-Stephens orchidopexy. AB - We present the case of a 6-month-old boy with an intra-abdominal testicle that spontaneously descended into the scrotum after the first stage of a planned 2 stage laparoscopic Fowler-Stephens orchidopexy. To our knowledge this has not been reported. PMID- 20974039 TI - Management of adenocarcinoma of the female urethra: case report and brief review. AB - INTRODUCTION: We present a case of a differentiated adenocarcinoma of the female urethra, which caused dysuria and voiding dysfunction. MATERIALS AND METHODS: A 54-year-old female presented with dysuria and the sensation of incomplete voiding. RESULTS: An ultrasound-guided biopsy showed a urethral carcinoma. A magnetic resonance imaging (MRI) scan showed a high-stage tumor. The patient had a pelvic exenteration. The patient was free of disease after 2 years of follow up. CONCLUSION: Urethral carcinoma is a rare malignancy. A biopsy is necessary to make a diagnosis. MRI is the best imaging for tumor staging. Small tumors are treated with a single modality option including sparing surgery or radiotherapy. Advanced disease should be treated with a multimodality of options including neoadjuvant radiotherapy given concomitantly with chemotherapy followed by surgery. PMID- 20974040 TI - Psoas abscess from ureteric stone perforation. AB - This case illustrates a rare complication of an impacted ureteric stone which eroded through the wall of the ureter leading to formation of a psoas abscess. Ureteric stent placement and percutaneous drainage of the abscess were insufficient to resolve the problem. Renal scan revealed poor function and the left kidney was removed. It showed evidence of acute supporative pyelonephritis with nephrolithiasis. PMID- 20974041 TI - Adrenal insufficiency as presenting feature of non-Hodgkin lymphoma. AB - Lymphomatous involvement of an adrenal gland during the course of a lymphoma is common, but a primary presentation of adrenal insufficiency in a patient with lymphoma involving both adrenal glands is rare. We describe a 36-year-old man with non-Hodgkin lymphoma (NHL) who presented with adrenal insufficiency. His evaluation consisted of several imaging modalities, including positron emission tomography-computed tomography (PET-CT) scans, which were helpful in defining the extent of disease prior to treatment and in monitoring the patient's response to treatment. Our case illustrates the importance of preoperative evaluation to exclude a lymphoma, particularly in patients with bilateral renal and/or adrenal masses. PMID- 20974042 TI - Adrenal insufficiency as presenting feature of non-Hodgkin lymphoma. Editorial comment. PMID- 20974043 TI - Office based urology trials. PMID- 20974044 TI - Open clinical uro-oncology trials in Canada. PMID- 20974045 TI - Self-organization of the compositional gradient structure in hyaluronic acid and poly(N-isopropylacrylamide) blend film. AB - A compositional gradient structure in hyaluronic acid (HA) and poly(N isopropylacrylamide) (PIPAAm) blend film was self-organized from a homogeneous aqueous solution in a plasma-treated polystyrene dish (PTPSD), and the formation mechanisms of the gradient structure were studied by casting the same solution on PTPSD and a non-treated polystyrene dish (NTPSD) under ambient and vacuum conditions. The formation of a compositional gradient structure in HA/PIPAAm blend film was confirmed by scanning electron microscopy, energy dispersive X-ray (EDX) mapping analysis and step-scan photoacoustic Fourier transformed infrared spectroscopy (PAS-FT-IR) measurements. The EDX mapping measurements for Na element revealed that the HA component gradually decreases from the dish-side to the air-side of the film cast on PTPSD, while for the film cast on NTPSD no such obvious change was observed on the cross-section. Further studies on the films prepared on PTPSD and NPTPSD under ambient and vacuum conditions demonstrated that the hydrophilic interaction and the solvent evaporation rate were the most significant factors leading to the formation of a compositional gradient structure in the HA/PIPAAm blend system. PMID- 20974046 TI - Intracellular signalling pathways and mood disorders. AB - Findings are summarized about basic intracellular signalling pathways influencing neurotransmission and involved in neurodegenerative or neuropsychiatric disorders. Psychotropic drugs used in the therapy of a series of mental disorders, mood disorders especially, show neurotrophic or neuroprotective effects after long-term treatment. Thus, beyond adenylate cyclase, guanylate cyclase and calcium system, attention has been paid to the tyrosine kinase pathway and Wnt pathway. New neurochemical hypotheses of mood disorders are disclosed; they were formulated on the basis of known effects of antidepressants or mood stabilizers on intracellular signal transduction, i.e. on the function, plasticity and survival of neurons. These hypotheses focus on the constituents of intracellular signalling pathways that could be studied as biological markers of mood disorders: transcription factor CREB, neurotrophin BDNF and its trkB receptor, anti-apoptotic factor Bcl2, pro-apoptotic enzyme GSK3, caspases, calcium, and a number of mitochondrial functions related to brain energy metabolism. PMID- 20974047 TI - Isolation and characterization of neural crest stem cells from adult human hair follicles. AB - Neural crest (NC) is a transient embryonic tissue, whose cells are motile and multipotent until they reach their destination and differentiate according to microenvironmental cues into a variety of cell types. However, a subpopulation of these cells remains multipotent. They were found, among other locations, in a bulge of adult murine whisker follicle and were designated epidermal neural crest stem cells (EPI-NCSCs). The aim of this work is to ascertain whether the EPI NCSCs could be isolated from human hair follicles as well. Due to their exceptional properties, they could represent potential candidates for stem cell therapy. The presented work focuses on the isolation and characterization of EPI NCSCs from human skin. We obtained a population of cells that expressed markers of NC, NC progeny and general stem cell markers. After prolonged cultivation, the subpopulation of cells spontaneously differentiated into some of NC derivatives, i.e. neurons, smooth muscle cells and Schwann cell progenitors. Targeted differentiation with neuregulin 1 highly increased the number of Schwann cells in the culture. Human EPI-NCSCs could also grow under non-adherent conditions and form 3-dimensional spheres. Microarray analysis was performed and gene profile of human EPI-NCSCs was compared with the list of key genes of murine EPI-NCSCs and the list of genes up-regulated in newly induced NC cells. This revealed 94% and 88% similarity, respectively. All presented results strongly support the NCSC identity and multipotency of isolated human cells. These cells could thus be used in regenerative medicine, especially because of the easy accessibility of donor tissue. PMID- 20974048 TI - Advanced rai stage in patients with chronic lymphocytic leukaemia correlates with simultaneous hypermethylation of plural tumour suppressor genes. AB - Hypermethylation of CpG islands within gene promoters is one of various mechanisms of gene silencing involved in the pathogenesis of human cancer. By using methylation-specific polymerase chain reaction we explored aberrant promoter methylation of five tumour suppressor genes in 29 patients with chronic lymphocytic leukaemia. Aberrant methylation of DLC1, SHP1, p15 and p16 occurred, respectively, in 89.7 %, 70 %, 62.1 % and 31 % of patients at diagnosis. Lamin A/C was unmethylated in all the samples. Hypermethylation of at least one gene was detected in 96.6 % of patients. Concurrent methylation of two or more genes correlated with Rai stage at diagnosis. PMID- 20974049 TI - Leukaemia inhibitory factor inhibits cardiomyogenesis of mouse embryonic stem cells via STAT3 activation. AB - The leukaemia inhibitory factor is a cytokine that exhibits pleiotropic activities in a wide range of cell types. There are evidences that leukaemia inhibitory factor-regulated signalling pathways are involved in cardiomyogesis and maintenance of cardiomyocytes. In the present work we studied the effect of leukaemia inhibitory factor on cardiomyogenesis of embryonic stem cells together with the role of serum-born factors. We showed that leukaemia inhibitory factor had an inhibitory effect during both the induction and progression phases of cardiomyogenesis of embryonic stem cells. The leukaemia inhibitory factor mediated inhibition of cardiomyogenesis was abolished by inhibitors of STAT3 activity. These results suggest that leukaemia inhibitory factor- activated STAT3 is responsible for the inhibition of cardiomyogenesis in embryonic stem cells. PMID- 20974050 TI - The autophagy-lysosomal pathway is involved in TAG degradation in the liver: the effect of high-sucrose and high-fat diet. AB - This study was designed to test the role of liver lipases in the degradation of liver triacylglycerols (TAG) and to determine the effect of dietary induced TAG accumulation in the liver on regulation of their lipolysis. Male Wistar rats were administered high-fat or high-sucrose diet for two weeks. Individual lipases (HL; TGH; LAL) were identified according to their different pH optimum. Administration of both diets resulted in liver TAG accumulation (HFD >>> HSD). The only lipase capable to hydrolyse intracellular TAG was LAL. On standard diet, LAL activity towards both endogenous and exogenous substrates was up-regulated in fasting and downregulated in fed state. The intensity of autophagy determined according to the LC3-II/LC3-I protein ratio followed a similar pattern. HFD led to an increase of this ratio, elevation of LAL activity in phagolysosomal fraction and abolishment of fasting/fed-dependent differences. LAL activity significantly correlated with ketogenesis in all groups (r = 0.86; P < 0.01). In the HFD group, we determined the enhanced release of lysosomal enzymes (glucuronidase, LAL) into the cytosol. Dgat-1 expression was up-regulated in HFD- and HSD-fed groups, which indicates increased FFA esterification. We demonstrated that LAL is a dominant enzyme involved in degradation of intracellular TAG in the liver and its translocation into the fraction of active (auto)phagolysosomes is stimulated by diet-induced TAG accumulation. Autophagy is stimulated under the same conditions as LAL and may represent the mechanism ensuring the substrate enzyme contact in autophagolysosomes. In fatty liver, destabilization of (auto)phagolysosomes may contribute to their susceptibility to further stress factors. PMID- 20974051 TI - Gene regulation by BCL3 in a cervical cancer cell line. AB - BCL3 is a putative proto-oncogene deregulated in haematopoieitic and solid tumours. It has been suggested that its oncogenic effects could be mediated, at least in part, by inducing proliferation and inhibiting cell death. To provide more insight into the mediators of these effects, we used an unbiased approach to analyse the mRNA expression changes after knocking-down BCL3 using specific shRNAs. One hundred eighty genes were up-regulated and sixtynine genes were down regulated after knocking down BCL3. Function analyses showed enrichment in genes associated with cellular growth and proliferation, cell death and gene expression. We found that STAT3, an important oncogene in human cancer, was the central node of one of the most significant networks. We validated STAT3 as a bona fide target of BCL3 by additional interference RNA and in silico analyses of previously reported lymphoma patients. PMID- 20974052 TI - Symptoms experienced by HIV-infected Individuals on antiretroviral therapy in KwaZulu-Natal, South Africa. AB - Symptom management in HIV/AIDS is a critical issue that influences the quality of life of those living with the disease. Although the goals of treating the numbers living with HIV/AIDS have not yet been achieved, availability of antiretroviral therapies (ARVs) has been expanded to many clinical settings in KwaZulu-Natal, the epicenter of HIV infection in South Africa. The South African Department of Health (2007) estimates indicate that 5.54 million South Africans are living with HIV/AIDS, whereas UNAIDS (2007) estimates suggest that 18.8% of the population in South Africa is affected. Because the symptom experience may influence adherence to ARVs and quality of life, this study focused on the prevalence of symptoms reported by patients (N = 149) diagnosed with HIV/AIDS and adherence to medications and appointments. Self-report data were obtained from this community based sample of HIV-infected patients who received care in outpatient clinics in Durban, KwaZulu-Natal, South Africa. With an average of three side effects, the most frequently reported by the study participants were fatigue/tiredness (41%), rashes (40%), headaches (32%), insomnia (31%), sadness (24%), disturbing dreams (23%), numbness (22%), pain (22%), and self-appearance (20%). On a scale of 1 to 10 (10 being worst possible), those with symptoms reported an average intensity of 4.2 (SD = 2.0), and the degree to which symptoms affected activity levels was 3.2 (SD = 2.2). Although intensity of symptoms and effects on activity levels were strongly correlated (r = .78, p < .001), there were no significant relationships between adherence and the intensity of symptoms or the relationship of symptoms with activity levels. Logistic regression analyses indicate that the presence of a greater number of symptoms was not associated with greater adherence (odds ratio = 2.27, 95% confidence interval = 0.60-8.70, ns). However, those who reported higher adherence were 1.5 times more likely to report greater physical health than low adherers (p = .04). High adherers were also 1.6 times more likely to report greater psychological health than low adherers (p = .03). This suggests that further study is needed to investigate adherence motivations for those living with HIV/AIDS in South Africa because adherence seems not to be linked to the frequency of symptoms or limitations on activity related to symptoms. PMID- 20974053 TI - Feasibility trial of guided imagery and control interventions in mock subjects. AB - This article reports a Phase I feasibility trial of a guided imagery intervention in 20 healthy volunteers. Structural equivalence of a placebo control intervention of listening to audio book segments was evaluated. Content analysis of participant journals and exit interviews suggest suitability and acceptability of both the guided imagery and control interventions. Suggestions for their use in future clinical trials are discussed. PMID- 20974054 TI - Symptom management strategies used by elderly patients after coronary artery bypass surgery. AB - The purpose of this secondary analysis was to describe symptom management strategies used by elderly patients (n = 236) 3 and 6 weeks after coronary artery bypass surgery (CABS). Three weeks after surgery, the most frequently used strategies were rest to manage shortness of breath (53%) and fatigue (53%), medications for incision pain (24%), and repositioning for swelling (35%) and sleep disturbance (18%). Overall, fewer patients experiencing sleep disturbances (39%), incision pain (39%), swelling (46%), and appetite problems (17%) reported using a strategy to manage their symptom. Nurses must assist patients in symptom identification and problem solving to accomplish effective symptom management. PMID- 20974055 TI - The professional self-image of registered home nurses in Flanders (Belgium): a cross-sectional questionnaire survey. AB - Despite their necessity and relevance, studies examining the professional self image of nurses and instruments to measure this professional self-image in the homecare setting are scarce. This study highlights both the positive self-image of home nurses and the existence of a delicate balance between the large degree of autonomy that home nurses have and the need to feel supported in their professional role and responsibility. The practice environment, including time pressure, workload, and insufficient support, needs to be addressed to keep it from having a negative impact on the professional self-image of home nurses in the long-term. PMID- 20974056 TI - Age-related effects on symptom status and health-related quality of life in persons with HIV/AIDS. AB - Health-related quality of life (HRQOL) is linked to symptom status and may be related to age in HIV-positive persons. Data were collected in a multisite HIV positive sample (N = 1,217) using an HIV-specific HRQOL and three symptom status instruments according to the Wilson and Cleary HRQOL model. Multiple stepwise linear regression analysis found that younger age predicted higher sexual function (DeltaR(2) = .12, p < .01) and older age predicted greater provider trust (DeltaR(2) = .04, p < .01). No significant differences were found in symptom status or the other seven HRQOL dimensions. Although older HIV-positive persons reported more comorbidities, they did not report more symptoms. PMID- 20974057 TI - Perspectives of staff nurses toward patient- and family-initiated call light usage and response time to call lights. AB - This survey study describes nurses' perspectives about call light usage and response time. Staff perceived call lights as being patient safety related (52%) and meaningful (81.6%), and answering calls prevented them from doing the critical aspects of their role (43.8%). Staff's perspectives toward call lights should be surveyed on a regular basis. PMID- 20974058 TI - The feasibility of Web-based surveys as a data collection tool: a process evaluation. AB - This study used a cross-sectional survey design with a concurrent process evaluation to examine the feasibility of using Web surveys in a population of acute care neonatal and pediatric nurses. The purpose of conducting a process evaluation was to understand if using strategies such as maximizing face-to-face communication with participants, sending reminder notices, and providing continuous support would encourage nurses to use a Web-based survey. In addition, we sought feedback about where nurses completed the survey, the number of sittings and length of time it took, and why participants that selected the print mode chose not to use the Web. PMID- 20974059 TI - Using message framing to achieve long-term behavioral changes in persons with diabetes. AB - This study examines how the framing of educational information affects changes in health-related knowledge, attitudes, and behavior. Patients with diabetes viewed either a gain- or a loss-framed informational video about proper foot care and its importance for the prevention of health-threatening problems. The gain-framed messages sustained long-term positive behavioral change. Regression analyses showed that changes in attitudes were predicted by changes in knowledge and that both framing and attitudes were predictors of long-term behavior. This study is important for nurses and certified diabetes educators in that it demonstrates that gain-framed messages are effective in sustaining health-promoting behavior. PMID- 20974060 TI - Self-directed sexually transmitted infection testing: providing noninvasive sexual health services. AB - A literature review that addressed the possible reasons sexually transmitted infection (STI) rates are increasing indicated that self-directed STI testing for gonorrhea and chlamydia should be trialed. As such, a self-directed STI testing kit was developed and piloted for 6 months, during which 182 bathhouse patrons accessed services from both an on-site nurse and through the self-directed kits. In total, 127 of these individuals presented for testing from the nurse, with the remaining using the self-directed testing kits. Community/Participant feedback indicated that this testing method was a welcome adjunct to traditional services, thus suggesting that self-directed testing should be further explored. PMID- 20974061 TI - The effects of an animation distraction intervention on pain response of preschool children during venipuncture. AB - OBJECTIVE: The purpose of this study was to identify the effects of an animation distraction intervention on pain response of preschoolers during venipuncture. METHOD: The research employed a nonequivalent control group pretest-posttest quasi-experimental design. The experimental group (n = 20) was provided with an animation distraction intervention using a laptop computer during their first venipuncture, and the control group (n = 20) received standard treatment. RESULTS: There were statistically significant differences in self-reported pain response, behavioral pain response, blood cortisol, and blood glucose between the experimental group and the control group. CONCLUSION: This intervention requires minimum effort and time and may be a cost-effective and convenient nursing intervention that could be used easily in clinical settings. PMID- 20974062 TI - Raising stroke awareness among rural dwellers with a Facts for Action to Stroke Treatment-based educational program. AB - Stroke is the third leading cause of death in the United States with 780,000 new and/or recurrent strokes each year. Interventions aimed at the onset of stroke symptoms have been successful in decreasing long-term neurological deficits; however, providing the prompt medical interventions in rural areas involves unique challenges. To decrease time-to-treatment in rural areas, education about symptoms of stroke and the need for immediate medical attention are critical. The objective of this study was to measure the effectiveness of the Facts for Action to Stroke Treatment (FAST)-based educational intervention program focused on the improving knowledge about stroke of 402 rural-dwelling adults. Using a paired means t test, the participants had a significant increase in knowledge from pretest to posttest (p = .000). Of those, 215 subjects participated in 2-month follow-up testing with the paired t test showing that the increased score from pretest to 2-month follow-up remained significant (p = .000). The authors concluded that the FAST-based program was an effective tool to use when teaching recognition of stroke symptoms and the need for immediate medical intervention to rural adults. PMID- 20974063 TI - Satisfaction and use of a spiritually based mantram intervention for childbirth related fears in couples. AB - This study assessed patient satisfaction with the use of a spiritually based (mantram/sacred word) intervention in expecting couples. A mixed-methods design, experimental repeated measures with interviews at 6-month follow-up was conducted. Satisfaction was moderate to high. Mantram was used for labor pains and uncertainty. Implications include scheduling flexible classes earlier in pregnancy. A larger randomized study is needed to assess intervention effectiveness. PMID- 20974065 TI - Perceptions and experiences after radical prostatectomy in Turkish men: a descriptive qualitative study. AB - Radical prostatectomy (RP) can significantly influence men's quality of life. Data from the Ministry of Health's Fight With Cancer Office Directorate in 2003 show that prostate cancer is third among the 10 most common types of cancer in men, with an incidence of 5.97% in the population. The objectives of this study were to define the experiences and perceptions of Turkish men who have undergone RP and to determine the views and suggestions of men who had undergone RP as to their discharge training content. Following the RP, urinary incontinence (UI) and erectile dysfunction (ED) negatively affect the daily life of men. It has been determined that men need support to deal with these problems they met. Being discharged without obtaining information from the health care staff regarding home catheter care and UI and ED management causes men to experience difficulties and find it difficult to cope when faced with these problems. PMID- 20974064 TI - Personality traits and chronic illness: a comparison of individuals with psychiatric, coronary heart disease, and HIV/AIDS diagnoses. AB - This secondary analysis used the five-factor model of personality to examine personality traits in four samples of patients with chronic disorders. Profiles of personality traits differed across disorders. Although participants with psychiatric disorders and participants with HIV/AIDS had similar patterns of personality traits, patients with psychiatric disorders were more extreme on all traits except agreeableness. Patients with hyperlipidemia and those who had cardiothoracic transplants had similar patterns. Nurses and researchers need to consider personality traits that drive patterns of behavior in designing more effective ways to promote better health and manage disease. PMID- 20974067 TI - Health care professionals' attitudes about obesity: an integrative review. AB - Stigma and discrimination against obese people are common and related to individual attitudes about obesity. Despite a robust field of study on attitudes related to obesity, no integrative review of health providers' beliefs exist. Fifteen studies (1990-2007) on various health care providers are examined along with practice implications. Analysis indicates that attitudes toward overweight patients, although primarily still negative, have improved over time. Findings indicate that care dispensed to obese patients is not as likely to be affected by health care providers' attitudes as in the past. Implications include the need for additional research, awareness education, and practice guidelines. PMID- 20974068 TI - A theory-based problem-solving approach to recruitment challenges in a large randomized field trial. AB - Despite best-laid plans, recruitment problems arise in large field trials. Research teams must work hard on problem solving and push comfort zones to sustain recruitment and accrual levels. A systematic theory-based problem-solving approach helped us look deeply for challenges and implement strategies continuously to sustain accrual to our target enrollment. PMID- 20974066 TI - Validation and testing of the Acceptability E-scale for web-based patient reported outcomes in cancer care. AB - The performance of the Acceptability E-scale was tested in a sample of 627 adult and older adult patients from various oncology clinics who completed an electronic symptoms survey. The revised Acceptability E-scale has strong psychometric properties and can be useful in assessing the acceptability and usability of computerized health-related programs in oncology and other health population. PMID- 20974069 TI - Triangulating the extrinsic risk factors for inpatient falls from the fall incident reports and nurse's and patient's perspectives. AB - This study triangulated the extrinsic risk factors for inpatient falls from incident reports and nurse's and patient's perspectives. Similar perspectives were shared on the patient-room-design-associated factors. Patients' concerns focused on their needs not being met in time. Fall prevention should have a priority on addressing patients' needs. PMID- 20974070 TI - Posttraumatic stress among mothers of very low birthweight infants at 6 months after discharge from the neonatal intensive care unit. AB - This correlational study examined how mother's posttraumatic stress disorder (PTSD) symptoms are related to characteristics of the mother and her infant, as well as to mother-infant interaction and infant development, in 21 mothers of very low birthweight infants. Twenty-three percent of mothers scored in the clinical range on a measure of PTSD. How ill the infant was during the NICU hospitalization was related to mothers' PTSD symptoms. Mothers with greater PTSD symptoms were less sensitive and effective at structuring interaction with their infant. PMID- 20974071 TI - An exploration of nurses' perceptions regarding the implementation of a best practice guideline on the assessment and management of foot ulcers for people with diabetes. AB - The aim of this qualitative study was to explore nurses' perceptions regarding the implementation of a best practice guideline (BPG) on the assessment and management of foot ulcers for people with diabetes. Fourteen nurses from a community care setting and three hemodialysis units participated in five focus groups and one individual interview. The findings focus on key points regarding the impact of BPG implementation in the areas of patient outcomes, nursing practice, and interdisciplinary teamwork. PMID- 20974072 TI - Precipitating factors associated with delirium among long-term care residents with dementia. AB - This cross-sectional study (N = 155) investigated precipitating factors associated with delirium among long-term-care residents with dementia and assessed their cumulative effect on the likelihood of having delirium. Use of physical restraints (odds ratio [OR] = 4.64, 95% confidence interval [CI] = 2.61 8.27) was the factor most associated, and the likelihood of being in delirium increased with the number of associated precipitating factors present (OR = 2.53, 95% CI = 1.42-4.49). Given their frailty, only a few precipitating factors need be present to increase the likelihood of these residents being in delirium, hence the need for increased nurse awareness of the risks posed by use of physical restraints with respect to the cognitive function of elderly residents with dementia. PMID- 20974073 TI - Measuring illness uncertainty in men undergoing active surveillance for prostate cancer. AB - BACKGROUND AND PURPOSE: Uncertainty is an aversive experience and plays an important role in the lives of men undergoing active surveillance (AS; earlier referred to as watchful waiting) for early-stage prostate cancer. Yet reliable and valid measures of uncertainty have not been fully tested in this population. This secondary analysis therefore tested the reliability of the Mishel Uncertainty in Illness Scale Community Form (MUIS-C; M.H. Mishel, 1997b) for use with men undergoing AS for prostate cancer. METHODS: Item-Total correlations were conducted on the 23 items of the MUIS-C with four samples of men undergoing AS. RESULTS: Cronbach's alpha for the full MUIS-C was .908; 22 of 23 items showed significant positive correlations with the total score. Removing the item without a significant correlation from the reliability analysis increased Cronbach's alpha to .913. CONCLUSIONS: The Mishel Uncertainty in Illness Scale-Community Form for Active Surveillance is a reliable and valid tool for measuring uncertainty with men undergoing AS for prostate cancer. PMID- 20974074 TI - Nursing Student Research Assistant Program: A strategy to enhance nursing research capacity building in a Magnet status pediatric hospital. AB - For busy clinicians, time to conduct research is scarce. A novel solution, the Nursing Student Research Assistant Program (NS-RAP), was designed in collaboration with area nursing schools to build research capacity at a pediatric hospital. Undergraduate and graduate nursing students participated in a variety of research experiences that, in turn, aided the conduct of clinician-initiated research at the pediatric hospital. In this article, conceptualization, implementation, outcomes, challenges, and future directions of NS-RAP are discussed. PMID- 20974075 TI - Risk factors associated with unplanned endotracheal self-extubation of hospitalized intubated patients: a 3-year retrospective case-control study. AB - This 3-year retrospective case-control study aimed to identify risk factors associated with unplanned endotracheal self-extubation (UESE) of hospitalized intubated patients and to compare unplanned and planned extubation groups' characteristics of patients and nurses, vital signs, serum laboratory values, Glasgow Coma Scale scores, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, and use of physical restraints and sedatives. The study found that most UESEs occurred during evening or night shifts or during shifts staffed by nurses with less experience and less education. Most of the self-extubated patients (80%) were physically restrained. Pulse rate and APACHE II score were both significant predictors of UESE. Efforts to prevent UESEs should include identification of patients at higher risk. PMID- 20974076 TI - Relationship between job stress level and coping strategies used by Hong Kong nurses working in an acute surgical unit. AB - OBJECTIVE: The aim of this study is to explore the relationship between job stress and coping strategies of Hong Kong nurses working in an acute surgical unit. METHOD: This is a descriptive correlational study. Data were collected from 98 Hong Kong surgical nurses using the Nursing Stress Scale and the Jalowiec Coping Scale. RESULTS: Results showed that workload (M = 15.36), lack of support (M = 13.32), and inadequate preparation (M = 12.33) are the most common stressors for Hong Kong surgical nurses. The most frequent strategies used by nurses to cope with stress can be characterized as evasive (M = 19.23), confrontive (M = 17.46), and optimistic (M = 15.81), all of which are also rated as the most effective strategies in reducing stress levels. Only the confrontive, optimistic, supportant, and emotive coping strategies reveal significant correlations (p < .05) with the stress levels of nurses, whereas the evasive, fatalistic, palliative, and self-reliant strategies showed no significant correlation with stress levels (p > .05). CONCLUSION: Recognizing the impacts of job-related stress and making use of effective coping methods play a vital role in reducing nurse's stress. A change in leadership styles from the managerial level and reallocation of manpower may help reduce job stress. The use of confrontive and optimistic coping strategies in reducing job-related stress for surgical nurses should be advocated and promoted in their daily work. PMID- 20974077 TI - Online research in older adults: lessons learned from conducting an online randomized controlled trial. AB - The Internet has revolutionized health care delivery. With the increasing number of online users and the advancement of eHealth technologies, many health care studies have been conducted online. However, online research is still a relatively new field, and many methodological issues still need to be investigated. Over the years, the authors have conducted studies on various aspects of online health intervention research, including development and usability testing of online health interventions, Web surveys, and an online randomized controlled trial employing older adult online users. The purpose of this article was to describe lessons learned from conducting an online randomized controlled trial designed to improve older adults' health behaviors focusing on methodological issues and strategies to overcome them. PMID- 20974078 TI - Rural Black women's thoughts about exercise. AB - This ethnographic study explored 20 southern rural Black women's thoughts about and practices of exercise. Qualitative analysis revealed four factors: (a) exercise and the heart, (b) barriers to exercise, (c) reasons to exercise, and (d) taking action. Findings may assist clinicians and researchers to develop prevention interventions for this population. PMID- 20974079 TI - The effects of psychoeducation and telephone counseling on the adjustment of women with early-stage breast cancer. AB - BACKGROUND: Throughout the illness trajectory, women with breast cancer experience issues that are related to physical, emotional, and social adjustment. Despite a general consensus that state-of-the-art treatment for breast cancer should include educational and counseling interventions to reduce illness or treatment-related symptoms, there are few prospective, theoretically based, phase specific randomized, controlled trials that have evaluated the effectiveness of such interventions in promoting adjustment. PURPOSE: The aim of this study is to examine the physical, emotional, and social adjustment of women with early-stage breast cancer who received psychoeducation by videotapes, telephone counseling, or psychoeducation plus telephone counseling as interventions that address the specific needs of women during the diagnostic, postsurgery, adjuvant therapy, and ongoing recovery phases of breast cancer. DESIGN: Primary data from a randomized controlled clinical trial. SETTING: Three major medical centers and one community hospital in New York City. METHODS: A total of 249 patients were randomly assigned to either the control group receiving usual care or to one of the three intervention groups. The interventions were administered at the diagnostic, postsurgery, adjuvant therapy, and ongoing recovery phases. Analyses were based on a mixed model analysis of variance. MAIN RESEARCH VARIABLES AND MEASUREMENT: Physical adjustment was measured by the side effects incidence and severity subscales of the Breast Cancer Treatment Response Inventory (BCTRI) and the overall health status score of the Self-Rated Health Subscale of the Multilevel Assessment Instrument. Emotional adjustment was measured using the psychological well-being subscale of the Profile of Adaptation to Life Clinical Scale and the side effect distress subscale of BCTRI. Social adjustment was measured by the domestic, vocational, and social environments subscales of the Psychosocial Adjustment to Illness Scale. FINDINGS: Patients in all groups showed improvement over time in overall health, psychological well-being, and social adjustment. There were no significant group differences in physical adjustment, as measured by side effect incidence, severity, or overall health. There was poorer emotional adjustment over time in the usual care (control) group as compared to the intervention groups on the measure of side effect distress. For the telephone counseling group, there was a marked decline in psychological well-being from the adjuvant therapy phase through the ongoing recovery phase. There were no significant group differences in the dimensions of social adjustment. CONCLUSION: The longitudinal design of this study has captured the dynamic process of adjustment to breast cancer, which in some aspects and at various phases has been different for the control and intervention groups. Although patients who received the study interventions improved in adjustment, the overall conclusion regarding physical, emotional, and social adjustment is that usual care, which was the standard of care for women in both the usual care (control) and intervention groups, supported their adjustment to breast cancer, with or without additional interventions. IMPLICATIONS FOR NURSING: The results are important to evidence based practice and the determination of the efficacy and cost-effectiveness of interventions in improving patient outcomes. There is a need to further examine adjustment issues that continue during the ongoing recovery phase. KEY POINTS: Psychoeducation by videotapes and telephone counseling decreased side effect distress and side effect severity and increased psychological well-being during the adjuvant therapy phase. All patients in the control and intervention groups improved in adjustment. Adjustment issues are still present in the ongoing recovery phase. PMID- 20974080 TI - Participation of elder persons, families, and health care teams in hospital discharge destination decisions. AB - This study identified that hospitalized elder persons and their family preferred active or collaborative level of participation (LOP) in discharge destination decisions, whereas health care team members (HCTMs) preferred passive LOP. Recognition of preferred LOP by HCTMs is instrumental to developing discharge plans that are tailored to the individual's need and are realistic and achievable. PMID- 20974081 TI - The Barthel Index: comparing inter-rater reliability between nurses and doctors in an older adult rehabilitation unit. AB - OBJECTIVE: To ensure accuracy in recording the Barthel Index (BI) in older people, it is essential to determine who is best placed to administer the index. The aim of this study was to compare doctors' and nurses' reliability in scoring the BI. METHODS: Sixty-five consecutive patients admitted to an older adult rehabilitation unit were assessed using the BI. Four raters recorded the BI on all patients. BI scores were compared for equivalence on the level of agreement between raters. RESULTS: Near-perfect correlation in the total scores between raters indicated that the final score is reliable. There was a statistically significant bias by doctors who gave a higher BI score than nurses with a mean difference of 1.2 (95% confidence interval). Nurses demonstrated good and very good agreement on all 10 items, whereas doctors demonstrated good agreement on only 5 items. CONCLUSION: The BI is highly reliable when recorded by nurses with low interrater variation, whereas between doctors, there is greater variation. When assessing older adult's activities of daily living, there is greater interrater reliability in the BI score when the patient is observed performing the activities of daily living compared to the self-report method. PMID- 20974082 TI - The effect of a double-regression hospital bed on interface pressure. AB - This study examines, for the first time, the differences of interface pressure in different positions on a standard hospital bed and a double-regression hospital bed. For both beds, the interface pressure was recorded in four supine positions and three lateral positions in 49 healthy volunteers (30 men and 19 women). The results demonstrate, independently of the bed type, that when a supine and lateral position is indicated, the 0 degrees and 30 degrees positions, respectively, are preferable. We also show that patients requiring prolonged upper body elevation may benefit from the use of a double-regression hospital bed that reduces the maximum pressure and the pressure surface greater than 32 mm Hg at the sacrum and heel sites. PMID- 20974083 TI - Perceptions of informed consent for care practices: hospitalized patients and nurses. AB - In a descriptive comparative survey study, nurse and patient perceptions differed regarding the practices of information giving, allowing decision making, and informed consent for nursing procedures during hospitalization. Nurses should consider giving patients more information about primary physical needs and activities related to nursing care (e.g., bowel/bladder needs, wound, and hygiene). PMID- 20974084 TI - Measurement of cognitive function in chronic heart failure: a feasibility study. AB - Assessment of cognition is critical to providing optimal care to individuals with heart failure. Traditional neuropsychological batteries are time consuming. This pilot study obtained feasibility data for a brief neuropsychological battery. Mean administration time was 40 +/- 7.5 minutes, averting subject fatigue, and the battery was sensitive to cognitive impairments. PMID- 20974085 TI - Familismo: influence on Hispanic health behaviors. AB - This study explored the impact of hepatitis C infection among a convenience sample of adult Hispanic men and women. Data were collected through a demographic form and audiotaped responses to a vignette. Krueger's transcription-based focus group method of analysis was used to analyze the qualitative data. The major theme, familismo (importance of family), emerged from the data with individual health behavior defined by family needs and expressed by "doing right" by the family. Therefore, health promotion and disease treatment framed within a "healthy family" philosophy and health intervention message may be more culturally acceptable and effective among Hispanic populations. PMID- 20974086 TI - Nursing staffing, nursing workload, the work environment and patient outcomes. AB - Nurse staffing (fewer RNs), increased workload, and unstable nursing unit environments were linked to negative patient outcomes including falls and medication errors on medical/surgical units in a mixed method study combining longitudinal data (5 years) and primary data collection. PMID- 20974087 TI - Health disparities or data disparities: sampling issues in hepatitis B Virus infection among Asian American Pacific Islander studies. AB - Hepatitis B virus (HBV) infection in Asian American Pacific Islanders (AAPIs) is an important health problem that must be recognized and addressed by the U.S. public health policy. However, AAPIs have been to a large degree invisible in public health data and debates and their interests have been disregarded. Moreover, an estimation of HBV infection rates reported from the National Nutritional and Health Survey Examinations III was 1.25 million; however, an estimate based on AAPI-targeted studies places the number at almost 2 million. This article discusses the perils of application of textbook methods of sampling coverage, selection, and nonresponse in studies related to AAPIs and the importance to note that some rapidly increasing racial/ethnic groups such as AAPIs have linguistic and cultural differences and these differences often cause such groups to be omitted from data collection. PMID- 20974088 TI - Nursing staff perceptions of physical function in hospitalized older adults. AB - Physical function is a common complication of hospitalized older adults, resulting in increased morbidity, mortality, institutionalization, and cost. Nursing staff play a central role in the hospital experience for older adults, including the promotion of physical function. Although quality geriatric care requires an organizational approach, there are no empirically based guidelines to promote the physical function of hospitalized older adults. A first step to develop an organizational intervention is to identify nursing staff perceptions of physical function, defined as basic activities of daily living (eating, dressing, toileting, transferring, bathing, and continence), in hospitalized older adults, including their beliefs about prevalence, risk factors, onset, effective interventions, and institutional barriers and facilitators to promoting physical function. Using purposive sampling, six focus groups yielding 55 participants were conducted at one of two sites, a suburban community hospital in New Jersey and an urban teaching hospital in New York, using a semistructured interview. Each site provided three focus groups composed of nursing staff cohorts as follows: two groups of registered nurses (staff nurses, managers, advanced practice nurses, and educators) and one group of patient care associates. There were important similarities identified in the themes of each group. Participants identified a system-level approach to preventing functional decline, including multimodal interventions and system-level enablers. PMID- 20974089 TI - Tai Chi for older nurses: a workplace wellness pilot study. AB - PURPOSE: The purpose of this pilot study was to assess the feasibility of a Tai Chi workplace wellness program as a cost effective way of improving physical and mental health, reducing work related stress, and improving work productivity among older nurses in a hospital setting Design A randomized control trial of two groups (control and Tai Chi group). DESIGN: A randomized control trial of two groups (control and Tai Chi group). SETTINGS: Northeastern academic medical center. SUBJECTS: A convenience sample of eleven female nurses (mean age 54.4 years). INTERVENTION: The Tai Chi group (n = 6) was asked to attend Tai Chi classes once a week offered at their worksite and to practice on their own for 10 minutes each day at least 4 days per week for 15 weeks. Controls (n = 5) received no intervention. MEASURES: SF-36 Health Survey, Nursing Stress Scale (NSS), Perceived Stress Scale (PSS), Sit-and-Reach test, Functional Reach test, the Work Limitations Questionnaire, workplace injury and unscheduled time off. ANALYSIS: The two study groups were compared descriptively and changes across time in the intervention versus control were compared. RESULTS: The Tai Chi group took no unscheduled time-off hours, whereas, the control group was absent 49 hours during the study period. There was also a 3% increase in work productivity and significant improvement in functional reach (p=0.03) compared to the control group. Other outcomes were not statistically significant. CONCLUSION: This pilot study demonstrates the feasibility of Tai Chi with older female workers as a cost effective wellness option in the workplace; thus encouraging replication with a larger sample. Methodological implications were also addressed. PMID- 20974090 TI - Recruiting Chinese American adolescents to HIV/AIDS-related research: a lesson learned from a cross-sectional study. AB - The purpose of this article was to report identified barriers and challenges experienced in the recruiting process of Chinese American adolescents to a cross sectional HIV/AIDS-related study. Snowball sampling method was used to recruit Chinese American adolescents from Chinese American communities in a U.S. Midwestern state. Barriers and challenges to recruitment were reviewed and analyzed from Chinese cultural perspectives in the hope of aiding researchers and health care providers understand and facilitate future recruitment of Chinese Americans for HIV/AIDS prevention studies. Barriers to recruitment were found related to the taboo topic of sexual issues in Chinese culture, unawareness and denial of HIV/AIDS risks, authoritarian parenting style in Chinese culture, and the required active consents. Facilitating factors of recruiting Chinese American adolescents to future HIV/AIDS prevention research or intervention programs are discussed. Information provided in this article may increase nurses' awareness of various barriers that they might encounter when they conduct research or address HIV/AIDS-related topics of Chinese American adolescents. PMID- 20974091 TI - Strategies to recruit difficult-to-reach home health care nurses for research. AB - Strategies to access a stratified random sample of New England home health care agencies and nurses are described. The combined strategies resulted in a sample of 123 home health care agencies and 2,459 home healthcare nurses from the six New England states. The results will inform researchers aiming to achieve data representativeness and clinicians critiquing the rigor of evidence. PMID- 20974092 TI - Challenges and strategies for recruitment and retention of vulnerable research participants: promoting the benefits of participation. AB - The purpose of this article was to describe recruitment and retention of vulnerable hematopoietic cell transplant patients participating in a longitudinal intervention study. Utilizing Swanson's theory of caring model, nurse researchers facilitated patients' visualization of how study participation could enable them to share their experience and further clinical insights. PMID- 20974094 TI - Qualitative data collection with children. AB - Qualitative researchers have clear methods to guide them in data collection with adult participants, but little is known about effective interview techniques with children. The findings from this methodological study on qualitative interviews with children indicate that children are able to articulate their experiences in interviews. PMID- 20974093 TI - Research strategies that result in optimal data collection from the patient medical record. AB - Data obtained from the patient medical record are often a component of clinical research led by nurse investigators. The rigor of the data collection methods correlates to the reliability of the data and, ultimately, the analytical outcome of the study. Research strategies for reliable data collection from the patient medical record include the development of a precise data collection tool, the use of a coding manual, and ongoing communication with research staff. PMID- 20974095 TI - The effectiveness of an osteoporosis prevention program among women in Taiwan. AB - The purpose of this study was to develop an osteoporosis prevention program based on the Health Belief Model. This study found that the prevention program improved osteoporosis preventive behaviors among women in Taiwan. Health professionals could use this model to plan and evaluate their osteoporosis prevention programs. PMID- 20974096 TI - Effects of patient teaching, educational materials, and coaching using telephone on dyspnea and physical functioning among persons with heart failure. AB - Heart failure (HF) is a major cause of death in Thailand and other developing countries. This study shows that a coaching using telephone program is an accessible and feasible strategy that helps patients with HF to self-manage HF symptoms, decrease dyspnea, and improve physical functioning at home. PMID- 20974097 TI - Evaluation of the Tiredness Management Guide: a pilot study. AB - The Tiredness Management Guide (TMG), developed by N. W. Troy and P. Dialgas Pelish (1995), consists of 59 interventions that may be helpful in decreasing maternal fatigue in the postpartum period. The purpose of this pilot study was to evaluate which interventions mothers perceived as most helpful and thus reduce the length of the TMG and update its relevance. A convenience sample of 30 Women, Infants, and Children Program (WIC) participants between the ages of 18 and 35 years completed a demographic tool and the TMG. The 25 most helpful interventions can be placed into the following broad categories: rest and relaxation, time management, rearranging usual activities, relief/prevention of hemorrhoids/constipation, signs of infection, and emotional support. PMID- 20974098 TI - Abstracting pain management documentation from the electronic medical record: comparison of three hospitals. AB - BACKGROUND: Pain management science results are derived from research conducted using medical record. APPROACH: This article describes methodological issues arising from abstracting pain management documentation (PMD) from the electronic medical record in three hospitals. After approval, PMD data were collected from the patient's history and physical, discharge summary, operative care notes, computerized nursing flow sheets, progress notes, and medication records. RESULTS: Each acute care facility required a different approach to abstract data. Inconsistent documentation in pain management assessments, interventions, and reassessments were identified across hospitals. DISCUSSION: Inconsistencies pose measurement threats and hinder benchmarking efforts. Work to standardize PMD across propriety computer systems is warranted. PMID- 20974099 TI - Validity of the Braden and Waterlow subscales in predicting pressure ulcer risk in hospitalized patients. AB - The aim of this study was to evaluate the validity of the Braden and Waterlow subscales in predicting pressure ulcer risk in hospitalized patients. This is a secondary analysis of a prospective cohort study. Braden sensory perception and friction/shear subscales and Waterlow mobility and appetite subscales were the most relevant predictors. PMID- 20974100 TI - The validity of self-report weight and height as a surrogate method for direct measurement. AB - Bland-Altman analysis used to determine the extent of bias, agreement, and precision between self-report and the "gold standard" of actual weight and height measurement revealed significant discrepancies between methods. Use of self report data by health care providers and researchers should be made based on the clinical situation, patient safety, and research goals. PMID- 20974101 TI - Intervention development: assessing critical parameters from the intervention recipient's perspective. AB - Before effective nursing interventions can be translated into practice, they must undergo critical examination. Although randomized controlled trials provide evidence of effectiveness, other intervention parameters require evaluation before effectiveness trials are initiated. This article describes methods for evaluating six parameters of nursing interventions (necessity, acceptability, feasibility, fidelity, safety, and effectiveness) and emphasizes the importance of assessing them from the intervention recipient's perspective. PMID- 20974102 TI - Acute care patient falls: evaluation of a revised fall prevention program following comparative analysis of psychiatric and medical patient falls. AB - Eliminating falls and fall-associated injuries are priorities in health care. This study examined the impact of revised fall prevention interventions on psychiatric and medical patient falls. After policy revisions were well established, psychiatric falls diminished and medical falls increased. A contributing factor to the medical population finding was policy intervention noncompliance. PMID- 20974103 TI - Interdisciplinary health science research collaboration: strengths, challenges, and case example. AB - The mandate for interdisciplinary health research is clear, but barriers persist and researchers are unprepared for collaborative roles. This article explores strengths/challenges/facilitative approaches for interdisciplinary research. Teen Eating and Activity Mentoring in Schools, an example of interdisciplinary research, uses comprehensive communication and information management to enhance interdisciplinary research. PMID- 20974104 TI - Promoting nursing research and innovation by staff nurses. AB - Promoting nursing research participation is challenging. Since the creation of an internal fund for research and innovation, 11 projects have received funding with a doubling of staff participation. The success of this novel funding opportunity highlights the need for this type of support and demonstrates success in promoting nursing research. PMID- 20974105 TI - Mectizan((r)) procurement and delivery for onchocerciasis mass drug administration programmes. AB - The discovery of Mectizan has engendered a safe onchocerciasis chemoprevention tool. To make the drug available promptly to people at risk of onchocerciasis, a procurement and delivery mechanism has been put in place around the Mectizan Donation Program, which oversees the Merck donation of Mectizan. The number of yearly approved treatment doses has increased rapidly since 1988 from 255,000 to more than 80 million in 2007 and 2008. Cumulatively, from 1987 to 2008 more than 697 million treatment doses have been approved corresponding to 1.5 billion Mectizan tablets shipped. Although the current demand for treatment is met, the ultimate goal is to cover all people at risk. A comprehensive drug policy from recipient countries is still needed to back up the current efficient procurement and delivery mechanism in order to attain the ultimate to goal, and is equally important for scaling up mass drug administration as part of national neglected tropical disease control/elimination strategies. PMID- 20974106 TI - Management of adenolymphangitis and lymphoedema due to lymphatic filariasis in resource-limited North-eastern Nigeria. AB - Procedures for health facility-based management of lymphoedema and adenolymphangitis (ADL) have proved very effective in some countries. Unfortunately, in resource-poor communities of Africa where health facilities are few, overburdened and inaccessible, an alternative approach is required. Community-based care (CC), patient care (PC) and health facility care (HC) approaches were compared. In the CC arm, communities were required to select one of their members for care-giving to its affected members, while in the PC, participants were allocated to groups under a leader with responsibility for care giving to group members. In HC, care was given by the nearest health facility. Caregivers from the three arms were trained and supplies were kept at the local government health office. At the sixth month of intervention, 325 lymphoedema and adenolymphangitis patients had been recruited into the study as participants. Within 12 months, compliance with hygiene practices increased from 29.4% to 62.6% and ADL episodes declined from 43.1% to 4.4% in the community designs arm and the cost on the health system was minimal. However, in the patient and health care arms, compliance and accessibility to supplies was severely affected by poor coordination, delay in resource collection leading to very minimal effect on lesions, odour, ADL frequency and duration. Participants abandoned the health facilities after the second visit. Community care approach was more culturally acceptable and effective for the management lymphoedema and ADL than other approaches. PMID- 20974107 TI - Structural characterization of CYP165D3, a cytochrome P450 involved in phenolic coupling in teicoplanin biosynthesis. AB - Teicoplanin is a glycopeptide antibiotic with activity against Gram-positive bacteria and remains one of the last lines of clinical defense against certain bacterial infections. We have cloned, expressed, and purified the cytochrome P450 OxyE (CYP165D3) from the teicoplanin biosynthetic gene cluster of Actinoplanes teichomyceticus, which is responsible for the phenolic coupling of the aromatic side chains of the first and third peptide residues in the teicoplanin peptide. The crystal structure of OxyE has been determined to 2.5A resolution, revealing the probable binding surface for the carrier protein substrate and an extension of the active site into a pocket located above the beta-1 sheet. The binding of potential substrates to OxyE shows that peptidyl carrier protein-bound linear peptides bind to OxyE, albeit with low affinity in the absence of a phenolic cross-link that should normally be installed by another Oxy protein in the teicoplanin biosynthetic pathway. This result indicates that the carrier protein alone is not sufficient for tight substrate binding to OxyE and that the Oxy proteins sense the structure of the bound peptide in addition to the presence of the carrier protein, a feature distinct from other carrier protein/P450 systems. PMID- 20974108 TI - Electro-pharmacological profile of a mitochondrial inner membrane big-potassium channel from rat brain. AB - Recent studies have indicated a calcium-activated large conductance potassium channel in rat brain mitochondrial inner membrane (mitoBK channel). Accordingly, we have characterized the functional and pharmacological profile of a BK channel from rat brain mitochondria in the present study. Brain mitochondrial inner membrane preparations were subjected to SDS-PAGE analysis and channel protein reconstitution into planar lipid bilayers. Western blotting and antibodies directed against various cellular proteins revealed that mitochondrial inner membrane fractions did not contain specific proteins of the other subcellular compartments except a very small fraction of endoplasmic reticulum. Channel incorporation into planar lipid bilayers revealed a voltage dependent 211 pS potassium channel with a voltage for half activation (V(1/2)) of 11.4+/-1.1mV and an effective gating charge z(d) of 4.7+/-0.9. Gating and conducting behaviors of this channel were unaffected by the addition of 2.5mM ATP, and 500 nM charybdotoxin (ChTx), but the channel appeared sensitive to 100 nM iberiotoxin (IbTx). Adding 10mM TEA at positive potentials and 10mM 4-AP at negative or positive voltages inhibited the channel activities. These results demonstrate that the mitoBK channel, present in brain mitochondrial inner membrane, displays different pharmacological properties than those classically described for plasma membrane, especially in regard to its sensitivity to iberiotoxin and charybdotoxin sensitivity. PMID- 20974109 TI - Oligonol, an oligomerized lychee fruit-derived polyphenol, activates the Ras/Raf 1/MEK1/2 cascade independent of the IL-6 signaling pathway in rat primary adipocytes. AB - Oligonol is a lychee fruit-derived low-molecular form of polyphenol. In this study, the effect of Oligonol on the mitogen activated-protein kinase (MAPK) signaling pathway in primary adipocytes was investigated to examine the mechanism underlying the enhanced levels of phosphorylated extracellular-signaling regulatory kinase1/2 (ERK1/2) that accompany an in vitro increase in lipolysis. Oligonol significantly elevated the levels of activated Ras and the phosphorylation of Raf-1 and MAPK/ERK kinase1/2 (MEK1/2) with no increase in pan Raf-1 and -MEK1/2 proteins. The increase in phosphorylation of Raf-1 and MEK1/2 with Oligonol was inhibited completely by pretreatment with GW5074, a selective Raf-1 inhibitor, or PD98059, a selective MEK1/2 inhibitor. IL-6 also activated the MAPK signaling pathway in adipocytes through the association with its receptor. IL-6-induced phosphorylation of Raf-1 and MEK1/2 was significantly inhibited by pretreatment with the IL-6 receptor antibody. Under such a condition, however, the levels of phosphorylated Raf-1 and MEK1/2 with Oligonol still remained significantly higher, and there was a significant decrease in secretion of IL-6 from adipocytes, compared with untreated control cells. These results suggest that Oligonol activates the Ras/Raf-1/MEK1/2 signaling pathway, independent of the IL-6 signaling pathway, leading to activation of ERK1/2 proteins in primary adipocytes. PMID- 20974110 TI - A translationally relevant thromboembolic stroke model for the study of secondary hemorrhage after thrombolysis in rats. AB - Secondary hemorrhage after thrombolysis in ischemic stroke is an important complication, which has been difficult to study in preclinical disease models. We have established and characterized a model of thromboembolic middle cerebral artery occlusion in rats. Advantages of this model include a very low rate of spontaneous recanalization and good reperfusion after intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA). In vivo T2* MR imaging and postmortem assays were used for quantification of secondary brain hemorrhage. In our protocol, 12 thrombin-induced autologous blood clots are injected into the internal carotid artery. No spontaneous reperfusion occurs in the first 24h. However, injection of rt-PA 2 or 4h thereafter leads to reperfusion of the MCA territory consistent infarcts, increased blood-brain barrier permeability, and secondary hemorrhage. Remarkably, clinically important factors known to affect the extent and likelihood of secondary hemorrhage such as hypertension and delayed onset of thrombolysis also increase hematoma size in the model. Thus, the model may serve to investigate the pathophysiology of thrombolysis-induced hemorrhage in thromboembolic ischemia as well as potential adjunctive therapies to prevent this complication. PMID- 20974111 TI - The non-coding RNA BC1 is down-regulated in the hippocampus of Wistar Audiogenic Rat (WAR) strain after audiogenic kindling. AB - The aim of this study was to identify molecular pathways involved in audiogenic seizures in the epilepsy-prone Wistar Audiogenic Rat (WAR). For this, we used a suppression-subtractive hybridization (SSH) library from the hippocampus of WARs coupled to microarray comparative gene expression analysis, followed by Northern blot validation of individual genes. We discovered that the levels of the non protein coding (npc) RNA BC1 were significantly reduced in the hippocampus of WARs submitted to repeated audiogenic seizures (audiogenic kindling) when compared to Wistar resistant rats and to both naive WARs and Wistars. By quantitative in situ hybridization, we verified lower levels of BC1 RNA in the GD hilus and significant signal ratio reduction in the stratum radiatum and stratum pyramidale of hippocampal CA3 subfield of audiogenic kindled animals. Functional results recently obtained in a BC1-/- mouse model and our current data are supportive of a potential disruption in signaling pathways, upstream of BC1, associated with the seizure susceptibility of WARs. PMID- 20974112 TI - Cortical spreading depression affects reactive oxygen species production. AB - Cortical spreading depression (CSD) is a reversible electrophysiological phenomenon that is not associated with tissue damage under normal blood supply. The induction of CSD during ischemia causes an increase in tissue damage, while pre-conditioning with CSD decreases the damage induced by a subsequent episode of ischemia. The mechanisms underlying these effects are not clear. Because the production of reactive oxygen species (ROS) is involved in tissue damage during ischemia-reperfusion, the aim of the present study was to evaluate the effects of CSD on superoxide production (O(2)(-)), on hydrogen peroxide (H(2)O(2)) production and on superoxide dismutase (SOD) activity in the cerebral cortex. CSD was induced by KCl application on the cortical surface in rats. O(2)(-) production was evaluated using dihydroethidium (DHE) that is oxidized to the fluorescent dye ethidium (HEt) by O(2)(-). The extracellular level of H(2)O(2) was evaluated by microdialysis sampling and HPLC analysis. SOD activity was evaluated with a histochemical assay. The results showed an increase in H(2)O(2) production, an increase in SOD activity and a decrease in O(2)(-) concentration 1h after CSD induction. PMID- 20974113 TI - Mortalin overexpression attenuates beta-amyloid-induced neurotoxicity in SH-SY5Y cells. AB - Amyloid-beta peptide (Abeta) is shown to be toxic to the mitochondria and implicates this organelle in the pathogenesis of Alzheimer's disease. Previous studies suggest that targeting mitochondria for protection may be a useful strategy to reduce Abeta-induced neurotoxicity. Mortalin is the mitochondrial located member of the heat shock protein 70 family, which serves as a major mitochondrial molecular chaperone and plays a key role in mitochondrial import of proteins. Several studies have demonstrated the protective potential of Hsp75 overexpression against apoptosis induced by various forms of stresses. To investigate whether mortalin overexpression could provide protective effects on Abeta toxicity, SH-SY5Y cells were used to transfect human mortalin gene and then treated with Abeta(1-42) for 24h. It is found that overexpression of mortalin efficiently attenuated Abeta(1-42)-induced cell viability damage and apoptosis. Additionally, inhibition of mortalin expression by mortalin-specific siRNA oligonucleotides sensitized SH-SY5Y cells to Abeta(1-42)-induced neurotoxicity. Furthermore, mortalin overexpression significantly inhibited the Abeta(1-42) induced depolarization of mitochondrial membrane potential, reversed the Abeta(1 42)-induced reduction in cytochrome c oxidase activity and ATP generation, and suppressed the Abeta(1-42)-induced reactive oxygen species accumulation and lipid peroxidation. Together, our results suggest that mortalin can afford protection against Abeta(1-42)-induced neurotoxicity in SH-SY5Y cells. These beneficial effects of mortalin overexpression may be attributable to its roles in maintaining mitochondrial function and reducing oxidative stress. PMID- 20974114 TI - Time will tell: deficits of temporal information processing in patients with visual field loss. AB - Visual field loss after brain lesions is commonly determined using perimetric tests of light detection (perimetry). Many patients with visual field defects complain about perceptual difficulties in areas that are perimetrically normal. To look at a potential cause for such difficulties, we topographically determined temporal characteristics of visual information processing in those patients and compared them to those of healthy subjects. In nine patients with visual field loss we measured thresholds of double-pulse resolution (DPR), i.e., the minimum perceivable duration of a temporal gap between two light pulses, at eccentricities up to 20 degrees . Furthermore, high-resolution maps of visual reaction times (RT) were obtained in a computer-based campimetric test. Performance was compared to healthy controls from a cross-sectional study of temporal perception across the life span (Toelz Temporal Topography Study). Compared to healthy subjects, DPR thresholds and RTs in patients are elevated in the entire visual field, including areas that are perimetrically intact. Performance on temporal variables depends on the degree of intactness of the respective visual field position. DPR thresholds correlate considerably with RTs, and both parameters increase with eccentricity. However, whereas DPR thresholds are increased around blind regions relative to the intact field, this is not the case for RTs. Temporal processing in patients with cerebral vision loss is impaired to a certain extent independently from perimetric light detection performance. This may partly explain reported subjective perceptual problems. The findings may have important implications for visual rehabilitation, i.e., the potential generalization of light detection training to temporal processing performance. PMID- 20974115 TI - Antagonistic effects of ultra-low-molecular-weight heparin on Abeta25-35-induced apoptosis in cultured rat cortical neurons. AB - Low-molecular-weight heparin (LMWH) and ultra-low-molecular-weight heparin (ULMWH) are heparin's derivatives, having various pharmacological effects. The present study aims to investigate the effect of ULMWH on amyloid beta peptide (Abeta25-35)-induced neurotoxicity in cultured rat cortical neurons, and LMWH was employed as a positive control agent. The neurons were incubated with Abeta25-35 (35MUM), Abeta25-35 plus ULMWH (2, 10, 50 MUg/ml) or LMWH (10 MUg/ml) for 24h. The cell viability was assessed by MTT and LDH release. FITC-Annexin V/PI double staining, Hoechst 33258 staining, TUNEL and Western blotting for bcl-2 and caspase-3 were employed to measure the neuron apoptosis. Furthermore, the intracellular Ca(2+) concentration was measured by a fluorescent dye, Fura-2/AM. The results showed that ULMWH significantly increased cell viability and the protein expression levels of bcl-2 and decreased the LDH release, the number of apoptotic cells, the concentration of intracellular Ca(2+) and the protein expression levels of caspase-3 in cortical neurons, suggesting that ULMWH can obviously reduce Abeta25-35-induced neurotoxic effects and might act as a potential agent for Alzheimer's disease. PMID- 20974117 TI - Interesting linkage between wound healing and hepatoprotective activities. PMID- 20974116 TI - 1,3-Butadiene: Biomarkers and application to risk assessment. AB - 1,3-Butadiene (BD) is a known rodent and human carcinogen that is metabolized mainly by P450 2E1 to three epoxides, 1,2-epoxy-3-butene (EB), 1,2:3,4 diepoxybutane (DEB) and 1,2-epoxy-3,4-butanediol (EB-diol). The individual epoxides vary up to 200-fold in their mutagenic potency, with DEB being the most mutagenic metabolite. It is important to understand the internal formation of the individual epoxides to assign the relative risk for each metabolite and to understand the molecular mechanisms responsible for major species differences in carcinogenicity. We have conducted extensive exposure-biomarker studies on mice, rats and humans. Using low exposures that range from current occupational levels to human exposures from tobacco smoke has provided evidence that mice are very different from humans, with mice forming ~200 times more DEB than humans at exposures of 0.1-1.5ppm BD. While no gender differences have been noted in mice and rats for globin adducts or N-7 guanine adducts, female rats and mice had 2-3 fold higher Hprt mutations and DNA-DNA cross-links, suggesting a gender difference in DNA repair. Numerous molecular epidemiology studies have evaluated globin adducts and Hprt mutations, SCEs and chromosomal abnormalities. None of the blinded studies have shown evidence of human genotoxicity at current occupational exposures and studies of globin adducts have shown similar or lower formation of adducts in females than males. If one calculates the EB dose equivalents for the three species, mice clearly differ from rats and humans, being ~44 and 174 times greater than rats and humans, respectively. These data provide a scientific basis for improved risk assessment of BD. PMID- 20974119 TI - Factor XIII subunits in human tears; their highly elevated levels following penetrating keratoplasty. AB - BACKGROUND: As blood coagulation factor XIII (FXIII) is of high importance in wound healing, we determined the concentrations of FXIII A and B subunits (FXIII A and FXIII-B) and their complex (FXIII-A(2)B(2)) in normal tears and in tears from patients undergoing penetrating keratoplasty (PKP). METHODS: FXIII complex and subunit concentrations were measured by highly sensitive chemiluminescent ELISAs in tears from 60 healthy volunteers and from 31 patients undergoing corneal transplantation. RESULTS: In non-stimulated tears from healthy volunteers, low but consistent amounts of FXIII-A and FXIII-B (medians: 2.13 MUg/L and 7.22 MUg/L, respectively) were measured, mostly in non-complexed form. Following stimulation of tear secretion FXIII levels moderately decreased, but if normalized to protein concentration they did not change. One day after PKP FXIII levels became highly elevated, then gradually decreased, but even on day 7 significantly exceeded pre-surgery values. The elevation of tear FXIII levels was significantly higher in PKP patients who later developed neovascularization of donor cornea. CONCLUSIONS: FXIII subunits are low concentration components of normal tear. The striking elevation of FXIII subunit and FXIII-A(2)B(2) concentrations after PKP suggests the involvement of FXIII in corneal wound healing. Perioperatively measured high FXIII levels in tears seem to represent a risk of neovascularization. PMID- 20974120 TI - Wnt/beta-catenin dependent cell proliferation underlies segmented lateral line morphogenesis. AB - Morphogenesis is a fascinating but complex and incompletely understood developmental process. The sensory lateral line system consists of only a few hundred cells and is experimentally accessible making it an excellent model system to interrogate the cellular and molecular mechanisms underlying segmental morphogenesis. The posterior lateral line primordium periodically deposits prosensory organs as it migrates to the tail tip. We demonstrate that periodic proneuromast deposition is governed by a fundamentally different developmental mechanism than the classical models of developmental periodicity represented by vertebrate somitogenesis and early Drosophila development. Our analysis demonstrates that proneuromast deposition is driven by periodic lengthening of the primordium and a stable Wnt/beta-catenin activation domain in the leading region of the primordium. The periodic lengthening of the primordium is controlled by Wnt/beta-catenin/Fgf-dependent proliferation. Once proneuromasts are displaced into the trailing Wnt/beta-catenin-free zone they are deposited. We have previously shown that Wnt/beta-catenin signaling induces Fgf signaling and that interactions between these two pathways regulate primordium migration and prosensory organ formation. Therefore, by coordinating migration, prosensory organ formation and proliferation, localized activation of Wnt/beta-catenin signaling in the leading zone of the primordium plays a crucial role in orchestrating lateral line morphogenesis. PMID- 20974121 TI - JAK-STAT signalling is required throughout telotrophic oogenesis and short-germ embryogenesis of the beetle Tribolium. AB - In Drosophila, the JAK-STAT signalling pathway regulates a broad array of developmental functions including segmentation and oogenesis. Here we analysed the functions of Tribolium JAK-STAT signalling factors and of Suppressor Of Cytokine Signalling (SOCS) orthologues, which are known to function as negative regulators of JAK-STAT signalling, during telotrophic oogenesis and short-germ embryogenesis. The beetle Tribolium features telotrophic ovaries, which differ fundamentally from the polytrophic ovary of Drosophila. While we found the requirement for JAK-STAT signalling in specifying the interfollicular stalk to be principally conserved, we demonstrate that these genes also have early and presumably telotrophic specific functions. Moreover, we show that the SOCS genes crucially contribute to telotrophic Tribolium oogenesis, as their inactivation by RNAi results in compound follicles. During short-germ embryogenesis, JAK-STAT signalling is required in the maintenance of segment primordia, indicating that this signalling cascade acts in the framework of the segment-polarity network. In addition, we demonstrate that JAK-STAT signalling crucially contributes to early anterior patterning. We posit that this signalling cascade is involved in achieving accurate levels of expression of individual pair-rule and gap gene domains in early embryonic patterning. PMID- 20974122 TI - Adipocyte derived paracrine mediators of mammary ductal morphogenesis controlled by retinoic acid receptors. AB - We generated a transgenic (Tg)-mouse model expressing a dominant negative-(DN) RARalpha, (RARalphaG303E) under adipocytes-specific promoter to explore the paracrine role of adipocyte retinoic acid receptors (RARs) in mammary morphogenesis. Transgenic adipocytes had reduced level of RARalpha, beta and gamma, which coincided with a severely underdeveloped pubertal and mature ductal tree with profoundly decreased epithelial cell proliferation. Transplantation experiments of mammary epithelium and of whole mammary glands implicated a fat pad dependent paracrine mechanism in the stunted phenotype of the epithelial ductal tree. Co-cultures of primary adipocytes, or in vitro differentiated adipocyte cell line, with mammary epithelium showed that when activated, adipocyte-RARs contribute to generation of secreted proliferative and pro migratory factors. Gene expression microarrays revealed a large number of genes regulated by adipocyte-RARs. Among them, pleiotrophin (PTN) was identified as the paracrine effectors of epithelial cell migration. Its expression was found to be strongly inhibited by DN-RARalpha, an inhibition relieved by pharmacological doses of all-trans retinoic acid (atRA) in culture and in vivo. Moreover, adipocyte-PTHR, another atRA responsive gene, was found to be an up-stream regulator of PTN. Overall, these results support the existence of a novel paracrine loop controlled by adipocyte-RAR that regulates the mammary ductal tree morphogenesis. PMID- 20974123 TI - Male gametogenesis without centrioles. AB - The orientation of the mitotic spindle plays a central role in specifying stem cell-renewal by enabling interaction of the daughter cells with external cues: the daughter cell closest to the hub region is instructed to self-renew, whereas the distal one starts to differentiate. Here, we have analyzed male gametogenesis in DSas-4 Drosophila mutants and we have reported that spindle alignment and asymmetric divisions are properly executed in male germline stem cells that lack centrioles. Spermatogonial divisions also correctly proceed in the absence of centrioles, giving rise to cysts of 16 primary spermatocytes. By contrast, abnormal meiotic spindles assemble in primary spermatocytes. These results point to different requirements for centrioles during male gametogenesis of Drosophila. Spindle formation during germ cell mitosis may be successfully supported by an acentrosomal pathway that is inadequate to warrant the proper execution of meiosis. PMID- 20974124 TI - PAM-1616, a selective peroxisome proliferator-activated receptor gamma modulator with preserved anti-diabetic efficacy and reduced adverse effects. AB - Peroxisome proliferator-activated receptor (PPAR) gamma is known to be a key regulator of insulin resistance. PAM-1616 is a novel, non-thiazolidinedione small molecule compound synthesized in Dong-A Research Center. In this study, we characterized the pharmacological and safety profiles of PAM-1616 as a selective PPARgamma modulator. PAM-1616 selectively binds to human PPARgamma (IC(50), 24.1+/-5.6 nM) and is a partial agonist for human PPARgamma with an EC(50) of 83.6+/-43.7 nM and a maximal response of 24.9+/-7.1% relative to the full agonist, rosiglitazone. PAM-1616 was selective for human PPARgamma than for human PPARalpha (EC(50), 2658+/-828 nM) without activating human PPARdelta, which makes it a selective modulator of PPARgamma. Treatment of high fat diet-induced obese C57BL/6J mice with PAM-1616 for 21 days improved HOMA-IR. Furthermore, PAM-1616 significantly improved hyperglycemia in db/db mice with little side effect when orally administered at a dose of 1 mg/kg/day for 28 days. Intriguingly, PAM-1616 was seen to increase the gene expression of inducible glucose transporter (GLUT4), while it partially induced that of a fatty acid carrier, aP2 in 3T3-L1 adipocytes, and it also showed partial recruitment of an adipogenic cofactor, TRAP220 as compared to rosiglitazone. PAM-1616 did not cause a significant increase in plasma volume of ICR mice when orally administered at a dose of 10 mg/kg/day for 9 days. PAM-1616 increased the expression of fluid retention inducing genes such as serum/glucocorticoid-regulated kinase (SGK)-1 to a lesser extent as compared to rosiglitazone in human renal epithelial cells. These results suggest that PAM-1616 acts as a selective modulator of PPARgamma with excellent antihyperglycemic property. The differential modulation of target gene by PAM-1616 might contribute to the improved side effect profiles. PMID- 20974126 TI - Stemness markers characterize IGR-CaP1, a new cell line derived from primary epithelial prostate cancer. AB - Deciphering molecular pathways involved in the early steps of prostate oncogenesis requires both in vitro and in vivo models derived from human primary tumors. However the few recognized models of human prostate epithelial cancer originate from metastases. To date, very few models are proposed from primary tumors and immortalizing normal human prostate cells does not recapitulate the natural history of the disease. By culturing human prostate primary tumor cells onto human epithelial extra-cellular matrix, we successfully selected a new prostate cancer cell line, IGR-CaP1, and clonally-derived subclones. IGR-CaP1 cells, that harbor a tetraploid karyotype, high telomerase activity and mutated TP53, rapidly induced subcutaneous xenografts in nude mice. Furthermore, IGR-CaP1 cell lines, all exhibiting negativity for the androgen receptor and PSA, express the specific prostate markers alpha-methylacyl-CoA racemase and a low level of the prostate-specific membrane antigen PSMA, along with the prostate basal epithelial markers CK5 and CK14. More importantly, these clones express high CD44, CD133, and CXCR4 levels associated with high expression of alpha2beta1 integrin and Oct4 which are reported to be prostate cancer stemness markers. RT PCR data also revealed high activation of the Sonic Hedgehog signalling pathway in these cells. Additionally, the IGR-CaP1 cells possess a 3D sphere-forming ability and a renewal capacity by maintaining their CSC potential after xenografting in mice. As a result, the hormone-independent IGR-CaP1 cellular clones exhibit the original features of both basal prostate tissue and cancer stemness. Tumorigenic IGR-CaP1 clones constitute invaluable human models for studying prostate cancer progression and drug assessment in vitro as well as in animals specifically for developing new therapeutic approaches targeting prostate cancer stem cells. PMID- 20974125 TI - Role of gamma-synuclein in microtubule regulation. AB - Gamma-synuclein is a neuronal protein found in peripheral and motor nerve systems. It becomes highly expressed in metastatic but not in primary tumor or normal tissues. The close association between gamma-synuclein expression and cancer spreading has been demonstrated in a broad range of malignancies. Our previous study showed that exogenous expression of gamma-synuclein in ovarian and breast cancer cells significantly enhanced cell migration and resistance to paclitaxel-induced apoptotic death. In our current research, we found that gamma synuclein can affect microtubule properties and act as a functional microtubule associated protein. In vitro assays revealed that gamma-synuclein can bind and promote tubulin polymerization, induce the microtubule bundling and alter microtubule morphology developed in the presence of microtubule associated protein 2 (MAP2). Using cancer cell lysate, gamma-synuclein protein was found to be localized in both cytosolic compartment and extracted cytoskeleton portion. Immunofluorescence staining demonstrated that gamma-synuclein can colocalize with microtubule in HeLa cells and decrease rigidity of microtubule bundles caused by paclitaxel. In human ovarian cancer epithelial A2780 cells, gamma-synuclein overexpression improved cell adhesion and microtubule structure upon paclitaxel treatment. Importantly, it led to microtubule-dependent mitochondria clustering at perinuclear area. These observations suggest that overexpression of gamma synuclein may reduce cell chemo-sensitivity of tumor cells through decreasing microtubule rigidity. In summary, our studies suggested that gamma-synuclein can directly participate in microtubule regulation. PMID- 20974127 TI - Galpha(12) binds to the N-terminal regulatory domain of p120(ctn), and downregulates p120(ctn) tyrosine phosphorylation induced by Src family kinases via a RhoA independent mechanism. AB - p120 Catenin (p120(ctn)) regulates cadherin stability, and thus facilitates strong cell-cell adhesion. Previously, we demonstrated that Galpha(12) interacts with p120(ctn). In the present study, we have delineated a region of p120(ctn) that binds to Galpha(12). We report that the N-terminal region of p120(ctn) (amino acids 1-346) is necessary and sufficient for the interaction. While the coiled-coiled domain and a charged region, comprising a.a 102-120, were found to be dispensable, amino acids 121-323 were required for p120(ctn) binding to Galpha(12). This region harbors the phosphorylation domain of p120(ctn) and has been postulated as important for RhoA regulation. Downregulation of Src family kinase-induced tyrosine phosphorylation of p120(ctn) was observed in the presence of activated Galpha(12). This down-regulation was triggered by three different Galpha(12) mutants uncoupled from RhoA signalling. Furthermore, a dominant active form of RhoA did not reduce Src-induced phosphoryaltion of p120(ctn). In summary, our results suggest that Galpha(12) binds to p120(ctn) and modulates its phosphorylation status through a Rho-independent mechanism. Galpha(12) emerges as an important regulator of p120(ctn) function, and possibly of cadherin-mediated adhesion and/or cell motility. PMID- 20974128 TI - Accumulation of distinct prelamin A variants in human diploid fibroblasts differentially affects cell homeostasis. AB - Lamin A is a component of the nuclear lamina that plays a major role in the structural organization and function of the nucleus. Lamin A is synthesized as a prelamin A precursor which undergoes four sequential post-translational modifications to generate mature lamin A. Significantly, a large number of point mutations in the LMNA gene cause a range of distinct human disorders collectively known as laminopathies. The mechanisms by which mutations in lamin A affect cell function and cause disease are unclear. Interestingly, recent studies have suggested that alterations in the normal lamin A pathway can contribute to cellular dysfunction. Specifically, we and others have shown, at the cellular level, that in the absence of mutations or altered splicing events, increased expression of wild-type prelamin A results in a growth defective phenotype that resembles that of cells expressing the mutant form of lamin A, termed progerin, associated with Hutchinson-Gilford Progeria syndrome (HGPS). Remarkably, the phenotypes of cells expressing elevated levels of wild-type prelamin A can be reversed by either treatment with farnesyltransferase inhibitors or overexpression of ZMPSTE24, a critical prelamin A processing enzyme, suggesting that minor increases in the steady-state levels of one or more prelamin A intermediates is sufficient to induce cellular toxicity. Here, to investigate the molecular basis of the lamin A pathway toxicity, we characterized the phenotypic changes occurring in cells expressing distinct prelamin A variants mimicking specific prelamin A processing intermediates. This analysis demonstrates that distinct prelamin A variants differentially affect cell growth, nuclear membrane morphology, nuclear distribution of lamin A and the fundamental process of transcription. Expression of prelamin A variants that are constitutively farnesylated induced the formation of lamin A aggregates and dramatic changes in nuclear membrane morphology, which led to reduced levels of the basal transcription factor TATA-binding protein (TBP) and global transcription, and severely limited cell growth. Expression of a prelamin A variant that cannot be farnesylated, although did not appreciably influence cell growth, resulted in the formation of lamin A nucleoplasmic foci and caused, in a minor subpopulation of cells, changes in nuclear morphology that were accompanied by reduced levels of TBP and transcription. In contrast, expression of mature lamin A did not affect any of these parameters. These data demonstrate that accumulation of any partially processed prelamin A protein alters cellular homeostasis to some degree, even though the most dramatic effects are caused by variants with a permanently farnesylated carboxyl-terminal tail. PMID- 20974129 TI - Human papilloma virus transformed CaSki cells constitutively express high levels of functional SerpinB2. AB - Many malignant tissues, including human papilloma virus (HPV)-associated cancers, express SerpinB2, also known as plasminogen activator inhibitor type-2 (PAI-2). Whether SerpinB2 is expressed by the HPV-transformed cancer cells, and if so, whether SerpinB2 is mutated or behaves aberrantly remains unclear. Here we show that HPV-transformed CaSki cells express high levels of constitutive wild-type SerpinB2, with cellular distribution, glycosylation, secretion, cleavage, induction and urokinase binding similar to that reported for primary cells. Neutralization of secreted SerpinB2 failed to affect CaSki cell migration or growth. Lentivirus-based over-expression of SerpinB2 also had no effect on growth, and we were unable to confirm a role for SerpinB2 in binding or regulating expression of the retinoblastoma protein. CaSki cells thus emerge as a useful tool for studying SerpinB2, with the physiological function of SerpinB2 expression by tumor cells remaining controversial. Using CaSki cells as a source of endogenous SerpinB2, we confirmed that SerpinB2 efficiently binds the proteasomal subunit member beta1. PMID- 20974130 TI - Harmonic analysis of the cone flicker ERG of rabbit. AB - Harmonic analysis was used to characterize the rabbit flicker ERG elicited by sinusoidally modulated full-field stimuli under light-adapted conditions. The frequency-response function for fundamental amplitude, derived from Fourier analysis of the ERG waveforms, exhibited two limbs, with an amplitude minimum at approximately 30Hz, and a high-frequency region peaking at around 45Hz and extending to more than 100Hz at higher adapting levels. At low frequencies (<20Hz), the fundamental response amplitude was independent of mean luminance (Weber law behavior), whereas the response amplitude at high stimulus frequencies varied nonlinearly with mean luminance. At low frequencies, intravitreal administration of L-AP4, which blocks ON-pathway activity, reduced the fundamental response amplitude and produced a phase shift. On the other hand, PDA, which reduces OFF-pathway activity, had a minimal effect on both the response amplitude and phase at low frequencies. At high frequencies, L-AP4 increased the fundamental response amplitude at low mean luminances, whereas PDA had only a small effect on amplitude and phase. Both pharmacologic agents removed the minimum in the amplitude-frequency function as well as the abrupt change in phase at stimulus frequencies near 30Hz. The results suggest that there is a nonlinear interaction between ON- and OFF-pathway activity over the entire stimulus frequency range examined in this study. These findings provide a basis for formulating protocols to evaluate the effect of pharmacologic agents and/or disease on the cone flicker ERG of rabbit. PMID- 20974131 TI - Olfactory ensheathing cells promote neurite outgrowth from co-cultured brain stem slice. AB - Cell therapy aiming at the replacement of degenerated neurons is a very attractive approach. By using an established in vitro organotypic brain stem (BS) slice culture we screen for candidate donor cells, some of them being further functionally assessed in in vivo models of sensorineural hearing loss. Both in vitro and in vivo systems show that implanted cells face challenges of survival, targeted migration, differentiation and functional integration with the host tissue. Low success rates are possibly due to the lack of necessary neurotrophic factors, adhesion molecules and guiding cues. Olfactory ensheathing cells (OECs) have been shown to express a number of neurotrophic factors and to promote axonal growth through cell to cell interactions. In the present study we co-cultured OECs with organotypic BS slice in order to see if OECs can serve as a facilitator when screening candidate donor cells in an organotypic culture setup. Here we show that OECs when co-cultured with the auditory BS slice not only promote neurite outgrowth from the cochlear nucleus (CN) region of the BS slice but also support cells by having BS slice axons growing along their processes. These findings further suggest that OECs may enhance survival and targeted migration of candidate donor cells suitable for cell therapy in vitro and in vivo. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair. PMID- 20974132 TI - Fipronil-induced cell death in salivary glands of Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae) semi-engorged females. AB - The tick Rhipicephalus sanguineus is currently considered an urban plague. For this reason many studies are intended to find methods to control these ectoparasites. Thus, the present study analyzed the ultrastructural modifications of the salivary glands cells of semi-engorged females of R. sanguineus resulting from their exposition to Fipronil (active ingredient of Frontline(r)). The studied individuals were divided into four groups. Group 1 was exposed to distilled water (control) and groups 2, 3 and 4 were exposed to 1, 5 and 10 ppm of Fipronil, respectively. The salivary gland of ticks subjected to the acaricide showed accelerated process of cell death by atypical apoptosis, as well as augmented cell damages as the concentration of the chemical compound was increased. The acaricide toxicity at cellular level was demonstrated by remarkable changes of elements of the cytoskeleton and spherocrystals (extremely hard inorganic structures). However, tick defense mechanisms, such as the observed autofagic vacuoles proved the cells attempt to preserve their integrity and minimize the devastating action of this chemical compound on the salivary glands. PMID- 20974133 TI - Kinetics of Foxp3-expressing regulatory cells in experimental Toxocara canis infection. AB - Foxp3-expressing cells have recently been recognized as a cornerstone for the homeostasis of the immune system, and as key cells in many infectious diseases. Moreover, they have been found to contribute to the regulation of parasite induced immunopathology in many parasitic infections. However, their role in Toxocara-induced immunopathology has not yet been investigated. The aim of this study is to assess the kinetics of Foxp3-expressing regulatory cells during the course of experimental infection by Toxocara canis (T. canis). Foxp3+ cells were identified in the liver by immunohistochemistry, and splenic Foxp3 gene expression was evaluated. We found significantly progressive increase in Foxp3 expressing cell counts in the liver starting from 5 weeks p.i. These cells were detected within and around Toxocara-induced granulomas as well as in isolated inflammatory foci in the portal tracts or within the hepatic parenchyma. Likewise, expression of Foxp3 mRNA in the spleen significantly increased at 5 and 16 weeks p.i. Furthermore, immunization of mice with Toxocara excretory-secretory antigen prior to experimental infection caused earlier mobilization and recruitment of Foxp3+ cells to the liver and enhanced splenic expression of Foxp3 transcripts. These results suggest a potential role of Foxp3-expressing regulatory cells in the evolution of the immunopathological events during infection by T. canis. PMID- 20974134 TI - POSH promotes cell survival in Drosophila and in human RASF cells. AB - In Drosophila, Eiger, a tumor necrosis factor alpha (TNFalpha) superfamily ligand, induces cell death by activating the c-Jun N-terminal kinase (JNK) pathway. Here, we report that overexpression of Plenty of SH3s (POSH) suppresses Eiger-induced cell death and produces highly deformed tissues. These results imply that high levels of POSH protect tissues from cell death. In humans, rheumatoid arthritis synovial fibroblasts (RASF) are generally resistant to apoptosis. We show that POSH is expressed at relatively high levels in RASF, and its reduction by RNAi sensitizes these cells to Fas-mediated apoptosis. Thus, we demonstrate that POSH promotes cell survival in Drosophila and in human RASF. PMID- 20974136 TI - Wilms' tumor protein Wt1 regulates the Interleukin-10 (IL-10) gene. AB - We identified the Wilms' tumor protein, Wt1, as a novel transcriptional activator of the immunosuppressant cytokine interleukin-10 (IL-10). Silencing of Wt1 by RNA interference reduced IL-10 mRNA levels by approximately 90%. IL-10 transcripts were increased more than 15-fold upon forced expression of Wt1. Electrophoretic mobility shift assay and chromatin immunoprecipitation revealed a cis-element that was responsible for activation of the IL-10 promoter by Wt1 in murine macrophages. Mutation of the Wt1 binding motif abrogated stimulation of the IL-10 promoter by tumor necrosis factor-alpha (TNFalpha). These results suggest a novel immune regulatory function of Wt1 in controlling IL-10 gene expression. PMID- 20974135 TI - Inhibition of NF-kappaB induces a switch from CD95L-dependent to CD95L independent and JNK-mediated apoptosis in T cells. AB - NF-kappaB is a crucial transcription factor regulating apoptosis sensitivity and resistance. It has been shown that inhibition of NF-kappaB in T lymphocytes leads to sensitization towards apoptosis. The underlying molecular mechanism is not entirely understood. Therefore, we investigated T cell receptor (TCR) stimulated apoptosis in T cells in which NF-kappaB activity is blocked by an inhibitor or IkappaBalpha overexpression. We show that enhanced apoptosis upon TCR stimulation is caspase- and JNK-dependent, but independent of the CD95/CD95L system. Generation of reactive oxygen species (ROS) induced sustained JNK phosphorylation by inactivation of MAP kinase phosphatase 7 (MKP7). Sustained JNK activation causes upregulation of the pro-apototic protein BIM. Thus, inhibition of NF kappaB causes a switch from classical activation-induced cell death (AICD) to CD95L-independent apoptosis. PMID- 20974137 TI - CSN5/Jab1 controls multiple events in the mammalian cell cycle. AB - The COP9 signalosome (CSN) complex is critical for mammalian cell proliferation and survival, but it is not known how the CSN affects the cell cycle. In this study, MEFs lacking CSN5/Jab1 were generated using a CRE-flox system. MEFs ceased to proliferate upon elimination of CSN5/Jab1. Rescue experiments indicated that the JAMM domain of CSN5/Jab1 was essential. CSN5/Jab1-elimination enhanced the neddylation of cullins 1 and 4 and altered the expression of many factors including cyclin E and p53. CSN5/Jab1-elimination inhibited progression of the cell cycle at multiple points, seemed to initiate p53-independent senescence and increased the ploidy of cells. Thus, CSN5/Jab1 controls different events of the cell cycle, preventing senescence and endocycle as well as the proper progression of the somatic cell cycle. PMID- 20974138 TI - The nuclear ATPase/adenylate kinase hCINAP is recruited to perinucleolar caps generated upon RNA pol.II inhibition. AB - hCINAP is an atypical nucleoplasmic enzyme, combining structural features of adenylate kinases and ATPases, which exhibits dual enzymatic activity. It interacts with the Cajal Body marker coilin and its level of expression and enzymatic activity influence Cajal Body numbers. Here we show that upon specific transcriptional inhibition of RNA pol.II, hCINAP segregates in perinuclear caps identified as Dark Nucleolar Caps (DNCs). These are distinct from perinucleolar caps where coilin and fibrillarin (both Cajal Body components) accumulate. In DNCs, hCINAP co-localizes with Paraspeckle Protein (PSP1) and also co-segregates with PSP1, and not coilin, in nuclear and nucleolar foci upon UV irradiation. PMID- 20974140 TI - Evidence for a dynamic role of the linker histone variant H1x during retinoic acid-induced differentiation of NT2 cells. AB - The dynamics of chromatin structure are tightly regulated by multiple epigenetic mechanisms such as histone modifications and incorporation of histone variants. In the current work, differentiation of an embryonal carcinoma cell line, NT2, was induced by retinoic acid, and total histone proteins were compared throughout this process. The results showed a significant change in expression level of a variant of H1 histone named H1x. Chromatin immunoprecipitation coupled with real time PCR analysis demonstrated a preferential incorporation of this protein in the regulatory region of Nanog, a marker gene of stemness that is significantly suppressed in differentiated cells. This finding reveals a dynamic role of H1x in differentiation, and implies a repressive role for this histone variant. PMID- 20974139 TI - The role of deubiquitinating enzymes in chromatin regulation. AB - Post-translational modifications of the histones are centrally involved in the regulation of all DNA-templated processes, including gene transcription, DNA replication, recombination, and repair. These modifications are often dynamic, and their removal is just as important as their addition in proper regulation of cellular functions. Although histone acetylation/deacetylation and histone methylation/demethylation are highly studied, the functions and regulation of histone ubiquitination and deubiquitination are less well understood. This review highlights our current understanding of how histone ubiquitination impacts gene transcription, DNA repair, and cell cycle progression, and stresses the importance of deubiquitinases to normal cellular functions as well as to disease states such as cancer. PMID- 20974141 TI - Comparing system-specific chaperone interactions with their Tat dependent redox enzyme substrates. AB - Redox enzyme substrates of the twin-arginine translocation (Tat) system contain a RR-motif in their leader peptide and require the assistance of chaperones, redox enzyme maturation proteins (REMPs). Here various regions of the RR-containing oxidoreductase subunit (leader peptide, full preprotein with and without a leader cleavage site, mature protein) were assayed for interaction with their REMPs. All REMPs bound their preprotein substrates independent of the cleavage site. Some showed binding to either the leader or mature region, whereas in one case only the preprotein bound its REMP. The absence of Tat also influenced the amount of chaperone-substrate interaction. PMID- 20974142 TI - The proteins involved in sucrose synthesis in the marine cyanobacterium Synechococcus sp. PCC 7002 are encoded by two genes transcribed from a gene cluster. AB - It has been reported that higher plants and cyanobacteria synthesize sucrose (Suc) by a similar sequential action of sucrose-phosphate synthase (SPS) and sucrose-phosphate phosphatase (SPP). In the genome of the marine unicellular cyanobacterium Synechococcus sp. PCC 7002 there is a sequence that was not annotated as a putative SPP encoding gene (sppA), although the sequence was available. In this study, we functionally characterize the sppA gene of that strain and demonstrate that it is cotranscribed with spsA, the SPS encoding gene. This is the first report on the coordination of Suc synthesis gene expression in an oxygenic-photosynthetic organism. PMID- 20974143 TI - Secondary necrosis: the natural outcome of the complete apoptotic program. AB - The predominant definition of apoptosis considers that the elimination of the apoptosing cell is by heterolytic degradation following phagocytosis by an assisting scavenger (efferocytosis). However, an alternative and largely underestimated outcome of apoptosis is secondary necrosis, an autolytic process of cell disintegration with release of cell components that occurs when there is no intervention of scavengers and the full apoptotic program is completed. Secondary necrosis is the typical outcome of apoptosis in unicellular eukaryotes but, importantly, it may also occur in multicellular animals and has been implicated in the genesis of important human pathologies. Secondary necrosis is a mode of cell elimination with specific molecular and morphological features and should be considered the natural outcome of the complete apoptotic program. PMID- 20974144 TI - Ascaris lumbricoides pseudocoelomic body fluid induces a partially activated dendritic cell phenotype with Th2 promoting ability in vivo. AB - Dendritic cells (DCs) matured with helminth-derived molecules that promote Th2 immune responses do not follow conventional definitions of DC maturation processes. While a number of models of DC maturation by Th2 stimuli are postulated, further studies are required if we are to clearly define DC maturation processes that lead to Th2 immune responses. In this study, we examine the interaction of Th2-inducing molecules from the parasitic helminth Ascaris lumbricoides with the maturation processes and function of DCs. Here we show that murine bone marrow-derived DCs are partially matured by A. lumbricoides pseudocoelomic body fluid (ABF) as characterised by the production of IL-6, IL 12p40 and macrophage inflammatory protein 2 (MIP-2) but no enhanced expression of cluster of differentiation (CD)-14, T-cell co-stimulatory markers CD80, CD86, CD40, OX40L and major histocompatibility complex class II was observed. Despite these phenotypic characteristics, ABF-stimulated DCs displayed the functional hallmarks of fully matured cells, enhancing DC phagocytosis and promoting Th2 type responses in skin-draining lymph node cells in vivo. ABF activated Th2 associated extracellular signal-regulated kinase-1 and nuclear factor-kB intracellular signalling pathways independently of toll-like receptor 4. Taken together, we believe this is the first paper to demonstrate A. lumbricoides murine DC-Th cell-driven responses shedding further light on DC maturation processes by helminth antigens. PMID- 20974146 TI - Multiple protein extract microarray for profiling human food-specific immunoglobulins A, M, G and E. AB - Existing food immunoglobulin (Ig) tests require large volumes of serum, are limited to one immunoglobulin class, are not amenable to high throughput analysis and only give a limited picture of the immunological response to food antigens. Conversely a new generation of Component Resolved Diagnostic systems using pure proteins is highly specific and totally dependent on the availability of the protein in its recombinant or natural origin form. Here we demonstrate a proof-of concept of a microarray test based on protein extracts of food components. Our approach relies on innovations on three different fronts: the novelty of using arrayed food samples sequentially extracted with detergent and chaotropic agents, the ability to measure four different Ig classes simultaneously and the ability to analyse the generated data via a suitable bioinformatics/statistical analysis interface. This approach combines high numerical power of microarrays with automation, high throughput analysis and enables detailed investigation of the Ig profiles to food antigens. The prototype shown contains extracts of approximately 350 food ingredients that cover most of the food products found in the UK. Here we showed that the use of a sequential extraction technique to solubilise and then denature food samples has its benefits in the assessment of variations in antigenicity when tested with human sera. A patient dependent degree of class specificity was observed with human sera (IgG specificity correlates well with IgA>IgM>>>>>IgE). Besides generating a simultaneous profile for IgA, IgM, IgG and IgE the array system has shown good discrimination between challenge responders in atopic and non-atopic individuals. Poly- and mono-specific IgE responders were easily identified. The mathematical modelling of specific IgE content showed good correlations when compared with established IgE antibody testing assay (UniCAP). Although in its proof-of-principle stages, the immune profiling technique described here has the potential to provide unique insights into exposure/sensitization and establish relationships between specific immunoglobulin classes and subclasses against food protein antigens. In further developments, the immune profiling technique could also be extended to other related areas such as parasite and bacterial gut infection. Full analyses of large longitudinal and retrospective clinical trials are on going to determine the positive and negative predictive values of the technique. PMID- 20974145 TI - Human immune responses that reduce the transmission of Plasmodium falciparum in African populations. AB - Malaria-infected individuals can develop antibodies which reduce the infectiousness of Plasmodium gametocytes to biting Anopheles mosquitoes. When ingested in a bloodmeal together with gametocytes, these antibodies reduce or prevent subsequent parasite maturation in the insect host. This transmission blocking immunity is usually measured in human sera by testing its effect on the infectivity of gametocytes grown in vitro. Here we evaluate evidence of transmission-blocking immunity in eight studies conducted in three African countries. Plasmodium falciparum gametocytes isolated from each individual were fed to mosquitoes in both autologous plasma collected with the parasites, and permissive serum from non-exposed donors. Evidence of transmission reducing effects of autologous plasma was found in all countries. Experiments involving 116 Gambian children (aged 0.5-15 years) were combined to determine which factors were associated with transmission reducing immune responses. The chances of infecting at least one mosquito and the average proportion of infected mosquitoes were negatively associated with recent exposure to gametocytes and sampling late in the season. These results suggest that effective malaria transmission-reducing antibodies do not commonly circulate in African children, and that recent gametocyte carriage is required to initiate and/or boost such responses. PMID- 20974147 TI - A protein multiplex microarray substrate with high sensitivity and specificity. AB - The problems that have been associated with protein multiplex microarray immunoassay substrates and existing technology platforms include: binding, sensitivity, a low signal to noise ratio, target immobilization and the optimal simultaneous detection of diverse protein targets. Current commercial substrates for planar multiplex microarrays rely on protein attachment chemistries that range from covalent attachment to affinity ligand capture, to simple adsorption. In this pilot study, experimental performance parameters for direct monoclonal mouse IgG detection were compared for available two and three-dimensional slide surface coatings with a new colloidal nitrocellulose substrate. New technology multiplex microarrays were also developed and evaluated for the detection of pathogen-specific antibodies in human serum and the direct detection of enteric viral antigens. Data supports the nitrocellulose colloid as an effective reagent with the capacity to immobilize sufficient diverse protein target quantities for increased specific signal without compromising authentic protein structure. The nitrocellulose colloid reagent is compatible with the array spotters and scanners routinely used for microarray preparation and processing. More importantly, as an alternate to fluorescence, colorimetric chemistries may be used for specific and sensitive protein target detection. The advantages of the nitrocellulose colloid platform indicate that this technology may be a valuable tool for the further development and expansion of multiplex microarray immunoassays in both the clinical and research laboratory environment. PMID- 20974148 TI - Elevated levels of activated NHE1 protect the myocardium and improve metabolism following ischemia/reperfusion injury. AB - In the myocardium, the Na(+)/H(+) exchanger isoform 1 (NHE1) is a plasma membrane protein that regulates intracellular pH. Inhibition of NHE1 activity has been shown to be beneficial in cardiovascular disease. However, recent reports have suggested that elevation of NHE1 levels has beneficial effects in hearts subjected to ischemia/reperfusion. We determined if activated and non-activated NHE1 proteins have varying cardioprotective and metabolic effects with ischemia/reperfusion in the isolated perfused working mouse heart. We used transgenic mice hearts that specifically expressed wild type NHE1 (N-line) or activated NHE1 protein (K-line). Intact hearts 10-12 weeks of age were perfused under working conditions, with fatty acids and glucose present as substrates. Hearts were subjected to 30 min of aerobic perfusion, followed by 20 min of global no-flow ischemia and 40 min of aerobic reperfusion. We examined changes in contractility and substrate use and ATP levels. K-line hearts expressing activated NHE1, recovered to a much greater extent than N-line and control hearts recovering almost 75% of their preischemic function. In addition, K-line hearts had elevated fatty acid oxidation, increased glycolysis rates and elevated ATP levels relative to N-line mice or controls. An examination of kinase activation showed that there were no differences between controls and transgenics in ERK, p38, p90(rsk) or pGSK3beta levels. The results demonstrate that elevated levels of NHE1 induce cardioprotection and alter cardiac metabolism. However, in the working heart model, with glucose and fatty acid as substrates, this required an activated NHE1 protein. PMID- 20974149 TI - Cardiac origin of smooth muscle cells in the inflow tract. AB - Multipotent Isl1(+) heart progenitors give rise to three major cardiovascular cell types: cardiac, smooth muscle, and endothelial cells, and play a pivotal role in lineage diversification during cardiogenesis. A critical question is pinpointing when this cardiac-vascular lineage decision is made, and how this plasticity serves to coordinate cardiac chamber and vessel growth. The posterior domain of the Isl1-positive second heart field contributes to the SLN-positive atrial myocardium and myocardial sleeves in the cardiac inflow tract, where myocardial and vascular smooth muscle layers form anatomical and functional continuity. Herein, using a new atrial specific SLN-Cre knockin mouse line, we report that bipotent Isl1(+)/SLN(+) transient cell population contributes to cardiac as well as smooth muscle cells at the heart-vessel junction in cardiac inflow tract. The Isl1(+)/SLN(+) cells are capable of giving rise to cardiac and smooth muscle cells until late gestational stages. These data suggest that the cardiac and smooth muscle cells in the cardiac inflow tract share a common developmental origin. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited". PMID- 20974150 TI - Immune-inflammatory dysregulation modulates the incidence of progressive fibrosis and diastolic stiffness in the aging heart. AB - Diastolic dysfunction in the aging heart is a grave condition that challenges the life and lifestyle of a growing segment of our population. This report seeks to examine the role and interrelationship of inflammatory dysregulation in interstitial myocardial fibrosis and progressive diastolic dysfunction in aging mice. We studied a population of C57BL/6 mice that developed progressive diastolic dysfunction over 30 months of life. This progressive dysfunction was associated with increasing infiltration of CD45(+) fibroblasts of myeloid origin. In addition, increased rates of collagen expression as measured by cellular procollagen were apparent in the heart as a function of age. These cellular and functional changes were associated with progressive increases in mRNA for MCP-1 and IL-13, which correlated both temporally and quantitatively with changes in fibrosis and cellular procollagen levels. MCP-1 protein was also increased and found to be primarily in the venular endothelium. Protein assays also demonstrated elevation of IL-4 and IL-13 suggesting a shift to a Th2 phenotype in the aging heart. In vitro studies demonstrated that IL-13 markedly enhanced monocyte-fibroblast transformation. Our results indicate that immunoinflammatory dysregulation in the aging heart induces progressive MCP-1 production and an increased shift to a Th2 phenotype paralleled by an associated increase in myocardial interstitial fibrosis, cellular collagen synthesis, and increased numbers of CD45(+) myeloid-derived fibroblasts that contain procollagen. The temporal association and functional correlations suggest a causative relationship between age-dependent immunoinflammatory dysfunction, fibrosis and diastolic dysfunction. PMID- 20974152 TI - Computational design and experimental testing of the fastest-folding beta-sheet protein. AB - One of the most important and elusive goals of molecular biology is the formulation of a detailed, atomic-level understanding of the process of protein folding. Fast-folding proteins with low free-energy barriers have proved to be particularly productive objects of investigation in this context, but the design of fast-folding proteins was previously driven largely by experiment. Dramatic advances in the attainable length of molecular dynamics simulations have allowed us to characterize in atomic-level detail the folding mechanism of the fast folding all-beta WW domain FiP35. In the work reported here, we applied the biophysical insights gained from these studies to computationally design an even faster-folding variant of FiP35 containing only naturally occurring amino acids. The increased stability and high folding rate predicted by our simulations were subsequently validated by temperature-jump experiments. The experimentally measured folding time was 4.3 MUs at 80 degrees C-about three times faster than the fastest previously known protein with beta-sheet content and in good agreement with our prediction. These results provide a compelling demonstration of the potential utility of very long molecular dynamics simulations in redesigning proteins well beyond their evolved stability and folding speed. PMID- 20974151 TI - Crystal structures of penicillin-binding protein 3 from Pseudomonas aeruginosa: comparison of native and antibiotic-bound forms. AB - We report the first crystal structures of a penicillin-binding protein (PBP), PBP3, from Pseudomonas aeruginosa in native form and covalently linked to two important beta-lactam antibiotics, carbenicillin and ceftazidime. Overall, the structures of apo and acyl complexes are very similar; however, variations in the orientation of the amino-terminal membrane-proximal domain relative to that of the carboxy-terminal transpeptidase domain indicate interdomain flexibility. Binding of either carbenicillin or ceftazidime to purified PBP3 increases the thermostability of the enzyme significantly and is associated with local conformational changes, which lead to a narrowing of the substrate-binding cleft. The orientations of the two beta-lactams in the active site and the key interactions formed between the ligands and PBP3 are similar despite differences in the two drugs, indicating a degree of flexibility in the binding site. The conserved binding mode of beta-lactam-based inhibitors appears to extend to other PBPs, as suggested by a comparison of the PBP3/ceftazidime complex and the Escherichia coli PBP1b/ceftoxamine complex. Since P. aeruginosa is an important human pathogen, the structural data reveal the mode of action of the frontline antibiotic ceftazidime at the molecular level. Improved drugs to combat infections by P. aeruginosa and related Gram-negative bacteria are sought and our study provides templates to assist that process and allows us to discuss new ways of inhibiting PBPs. PMID- 20974153 TI - Intrinsic noise and Hill dynamics in the p53 system. AB - The p53 feedback loop can induce cellular senescence, cell cycle arrest and apoptosis in response to various stresses, including DNA damage, hypoxia and nutrient deprivation. Using a stochastic model of the negative feedback circuit involving p53 and its inhibitor Mdm2, we present the different oscillatory dynamics at the single-cell and population-cell levels as described in the experiments, and the resonant nature of the oscillations is captured. The stationary distributions of protein populations are characterized by non-Gaussian nature which is due to the interplay between time delay and nonlinearity of reactions. PMID- 20974154 TI - Support of a free radical mechanism for enhanced antitumor efficacy of the microtubule disruptor OXi4503. AB - Unlike normal blood vessels, the unique characteristics of an expanding, disorganized and leaky tumor vascular network can be targeted for therapeutic gain by vascular disrupting agents (VDAs), which promote rapid and selective collapse of tumor vessels, causing extensive secondary cancer cell death. A hallmark observation following VDA treatment is the survival of neoplastic cells at the tumor periphery. However, comparative studies with the second generation tubulin-binding VDA OXi4503 indicate that the viable rim of tumor tissue remaining following treatment with this agent is significantly smaller than that seen for the lead VDA, combretastatin. OXi4503 is the cis-isomer of CA1P and it has been speculated that this agent's increased antitumor efficacy may be due to its reported metabolism to orthoquinone intermediates leading to the formation of cytotoxic free radicals. To examine this possibility in situ, KHT sarcoma-bearing mice were treated with either the cis- or trans-isomer of CA1P. Since both isomers can form quinone intermediates but only the cis-isomer binds tubulin, such a comparison allows the effects of vascular collapse to be evaluated independently from those caused by the reactive hydroxyl groups. The results showed that the cis-isomer (OXi4503) significantly impaired tumor blood flow leading to secondary tumor cell death and >95% tumor necrosis 24h post drug exposure. Treatment with the trans-isomer had no effect on these parameters. However, the combination of the trans-isomer with combretastatin increased the antitumor efficacy of the latter agent to near that of OXi4503. These findings indicate that while the predominant in vivo effect of OXi4503 is clearly due to microtubule collapse and vascular shut-down, the formation of toxic free radicals likely contributes to its enhanced potency. PMID- 20974155 TI - Interplay between histopathological alterations, cigarette smoke and chemopreventive agents in defining microRNA profiles in mouse lung. AB - We have investigated alterations of microRNA expression profiles in the apparently healthy lung of mice and rats as an early response to exposure to cigarette smoke, either mainstream (MCS) or environmental, and/or to treatment with chemopreventive agents. Further on, we evaluated microRNA alterations at a later stage, when lung tumors were detectable in MCS-exposed mice. Lung samples were available from previous studies, in which strain H mice had been exposed to MCS for 4 months, starting immediately after birth, and then kept in filtered air for an additional 3 months. Some samples were from MCS-exposed mice treated either with N-acetyl-l-cysteine during pregnancy or with phenethyl isothiocyanate after weaning. The analysis of 576 mouse microRNAs showed that MCS strongly dysregulated microRNA expression and that both chemopreventive agents efficiently attenuated this trend, especially in noncancer tissue. MicroRNA expression was affected by histopathology, with specific signatures related to occurrence of pneumonia, adenoma, or bronchoalveolar carcinoma. Within pairs of samples from individual mice, microRNA analysis discriminated adenomatous tissue and especially carcinomatous tissue from the surrounding normal appearing tissue. A series of microRNA alterations characterized the sequential stages of pulmonary carcinogenesis. The involved functions included oncogene activation, inhibition of oncosuppressor genes, recruitment of undifferentiated stem cells, inflammation, inhibition of gap-junctional intercellular communications, angiogenesis, invasiveness, and metastatization. Thus, microRNA expression profiles in lung are dysregulated by MCS along all steps of the carcinogenesis process and depend on the interplay among exposure to noxious agents, treatment with dietary and pharmacological agents, and occurrence of pulmonary diseases. PMID- 20974156 TI - In vivo levels of corticotropin-releasing hormone and gastrin-releasing peptide at the basolateral amygdala and medial prefrontal cortex in response to conditioned fear in the rat. AB - Given the modulatory effect of exogenously administered corticotropin-releasing hormone (CRH) and gastrin-releasing peptide (GRP) on conditioned fear, the present study sought to measure the fear-induced endogenous release of CRH and GRP at the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) using in vivo microdialysis. Rats were divided into 2 training conditions; tone only (cue), or tone paired with shock. The day after conditioning, animals were tested for fear by scoring freezing behavior in response to the tone alone in cages different from the cages they were previously conditioned in. Freezing was scored for 10 min. Dialysates were collected over 20 min intervals from 2h prior to testing (to establish baseline values) through to 3h post-testing continually uninterrupted. Analyses of dialysates revealed that at the BLA, the release of both CRH and GRP was increased over time and that peptide release was significantly higher in animals that had previously received shock relative to rats that had not. Further, the release of CRH and GRP was significantly correlated with freezing levels (an indication of fear in the rat) such that animals that had higher levels of freezing also had higher interstitial peptide levels. These effects appeared site-specific, as they were not apparent at the mPFC. It appears that at the BLA, the release of CRH and GRP is related to fear. PMID- 20974157 TI - Working memory load improves early stages of independent visual processing. AB - Increasing evidence suggests that working memory and perceptual processes are dynamically interrelated due to modulating activity in overlapping brain networks. However, the direct influence of working memory on the spatio-temporal brain dynamics of behaviorally relevant intervening information remains unclear. To investigate this issue, subjects performed a visual proximity grid perception task under three different visual-spatial working memory (VSWM) load conditions. VSWM load was manipulated by asking subjects to memorize the spatial locations of 6 or 3 disks. The grid was always presented between the encoding and recognition of the disk pattern. As a baseline condition, grid stimuli were presented without a VSWM context. VSWM load altered both perceptual performance and neural networks active during intervening grid encoding. Participants performed faster and more accurately on a challenging perceptual task under high VSWM load as compared to the low load and the baseline condition. Visual evoked potential (VEP) analyses identified changes in the configuration of the underlying sources in one particular period occurring 160-190 ms post-stimulus onset. Source analyses further showed an occipito-parietal down-regulation concurrent to the increased involvement of temporal and frontal resources in the high VSWM context. Together, these data suggest that cognitive control mechanisms supporting working memory may selectively enhance concurrent visual processing related to an independent goal. More broadly, our findings are in line with theoretical models implicating the engagement of frontal regions in synchronizing and optimizing mnemonic and perceptual resources towards multiple goals. PMID- 20974158 TI - Keeping time in your sleep: overnight consolidation of temporal rhythm. AB - Temporal processing forms the basis of a vast number of human behaviours, from simple perception and action to tasks like locomotion, playing a musical instrument, and understanding language. Growing evidence suggests that these procedural skills are consolidated during sleep, however investigation of such learning has focused upon the order in which movements are made rather than their temporal dynamics. Here, we use psychophysics and neuroimaging to explore the possibility that temporal aspects of such skills are also enhanced over a period of sleep. Behaviourally, our examinations of motor (tapping a finger in time with a temporal rhythm) and perceptual (monitoring a temporal rhythm for deviants) tasks reveal post-sleep improvements in both domains. Functionally, we show that brain-state during retention (sleep or wake) modulates subsequent responses in the striatum, supplementary motor area, and lateral cerebellum during motor timing, and in the posterior hippocampus during perceptual timing. Our data support the proposal that these two forms of timing draw on different brain mechanisms, with motor timing using a more automatic system while perceptual timing of the same rhythm is more closely associated with cognitive processing. PMID- 20974159 TI - Deficits in sensory prediction are related to delusional ideation in healthy individuals. AB - Motor control strongly relies on neural processes that predict the sensory consequences of self-generated actions. Previous research has demonstrated deficits in such sensory-predictive processes in schizophrenic patients and these low-level deficits are thought to contribute to the emergence of delusions of control. Here, we examined the extent to which individual differences in sensory prediction are associated with a tendency towards delusional ideation in healthy participants. We used a force-matching task to quantify sensory-predictive processes, and administered questionnaires to assess schizotypy and delusion-like thinking. Individuals with higher levels of delusional ideation showed more accurate force matching suggesting that such thinking is associated with a reduced tendency to predict and attenuate the sensory consequences of self generated actions. These results suggest that deficits in sensory prediction in schizophrenia are not simply consequences of the deluded state and are not related to neuroleptic medication. Rather they appear to be stable, trait-like characteristics of an individual, a finding that has important implications for our understanding of the neurocognitive basis of delusions. PMID- 20974160 TI - Visual activation of extra-striate cortex in the absence of V1 activation. AB - When the primary visual cortex (V1) is damaged, there are a number of alternative pathways that can carry visual information from the eyes to extrastriate visual areas. Damage to the visual cortex from trauma or infarct is often unilateral, extensive and includes gray matter and white matter tracts, which can disrupt other routes to residual visual function. We report an unusual young patient, SBR, who has bilateral damage to the gray matter of V1, sparing the adjacent white matter and surrounding visual areas. Using functional magnetic resonance imaging (fMRI), we show that area MT+/V5 is activated bilaterally to visual stimulation, while no significant activity could be measured in V1. Additionally, the white matter tracts between the lateral geniculate nucleus (LGN) and V1 appear to show some degeneration, while the tracts between LGN and MT+/V5 do not differ from controls. Furthermore, the bilateral nature of the damage suggests that residual visual capacity does not result from strengthened interhemispheric connections. The very specific lesion in SBR suggests that the ipsilateral connection between LGN and MT+/V5 may be important for residual visual function in the presence of damage to V1. PMID- 20974161 TI - Fiber tracking functionally distinct components of the internal capsule. AB - The internal capsule conveys information from primary and supplementary motor areas, frontopontine and thalamic peduncles to brain stem and cerebellar regions, and from thalamus to prefrontal cortex. Neurological accidents involving the internal capsule indicate differential functional correlates with its sectors. To examine the microstructural condition of this fiber system and to test functional correlates of its sectors in health and aging, 12 younger and 12 older adults were examined with diffusion tensor imaging (DTI) fiber tracking and neuropsychological tests. Greater age-related degradation was evident in the anterior than posterior limb and in the superior than inferior division of the internal capsule. The superior division age effect was especially notable in axial and radial diffusivity. Fractional anisotropy (FA) across the three (anterior, genu, posterior) fiber bundles of the inferior division accounted for 27-73% of the variance for each neuropsychological domain. Identification of a triple dissociation indicated selective correlations between anterior FA and set shifting, genu FA and motor skills, and posterior FA and fluency. Quantitative fiber tracking combined with assessment of cognitive and motor functions enabled the identification of selective brain structure-function relations in healthy adults without lesions that were previously observed only in patients with lesions of the internal capsule. PMID- 20974162 TI - Antiproliferative effects of some novel synthetic solanidine analogs on HL-60 human leukemia cells in vitro. AB - There is increasing evidence of the direct antiproliferative effects of various steroidal structures, including cardenolides, steroidal alkaloids and sexual hormones. The aim of the present study was to characterize the antiproliferative effects of three synthetic solanidine analogs (1-3) on HL-60 human leukemia cells. The three compounds exerted similar cytostatic effects (IC(50) values: 1.27-2.94 MUM after a 72-h exposure) and the most effective (2) was selected for further investigations. Incubation with compound 2 resulted in a marked chromatin condensation followed by a gradual increase in cell membrane permeability detected by Hoechst dye 33258-propidium iodide double staining. A flow cytometric analysis revealed a marked decrease in the G1 phase and substantial increases in the S and G2/M phases after 24-h incubation, while after 48 h the proportion of cells in the subG1 phase was increased significantly with a concomitant decrease in cells in the G1 and G2/M phases. Compound 2 at 6.0 MUM significantly decreased the activity of ribonucleotide reductase and proved to be a potent antioxidant in the lipid peroxidation and DPPH assays (IC(50) values: 2.0 and 13.1 MUM, respectively). The antiproliferative effect of the test compound on the non cancerous human lung fibroblast cell line (MRC-5) was significantly weaker than that on the leukemia cells. These results lead to the conclusion that compound 2 induces a marked disturbance in the cell cycle, which is, at least partially, a consequence of the inhibition of DNA synthesis. PMID- 20974163 TI - Hydroxysteroid dehydrogenase transformations of 5beta-scymnol and identification of oxoscymnol transformation products by liquid chromatography-tandem mass spectroscopy. AB - A new and sensitive high performance liquid chromatography (HPLC) separation procedure coupled with tandem mass spectroscopy (MS and MS(2)) detection was developed to identify for the first time the oxidation products of 5beta-scymnol [(24R)-(+)-5beta-cholestan-3alpha,7alpha,12alpha,24,26,27-hexol] catalysed by bacterial hydroxysteroid dehydrogenase (HSD) reactions in vitro. The authentic scymnol (MW 468) standard yielded a protonated molecular ion [M+H](+) at m/z 469 Da, and higher mass adduct ions attributed to [M+NH(4)](+) (m/z 486), [M+H+CH(3)OH](+) (m/z 501) and [M+H+CH(3)COOH](+) (m/z 530). (24R)-(+)-5beta Cholestan-3-one-7alpha,12alpha,24,26,27-pentol (3-oxoscymnol, m/z 467 Da, relative retention time (RRT)=0.89) was identified as the principle molecular species of scymnol in the reaction with 3alpha-HSD pure enzyme. [S](0.5) for the reaction of 3alpha-HSD with scymnol as substrate was 0.7292 mM. (24R)-(+)-5beta cholestan-7-one-3alpha,12alpha,24,26,27-pentol (7-oxoscymnol, m/z 467 Da, RRT=0.79) and (24R)-(+)-5beta-cholestan-12-one-3alpha,7alpha,24,26,27-pentol (12 oxoscymnol, m/z 467 Da, RRT=0.81) were similarly identified as principle molecular species in the respective 7alpha-HSD and 12alpha-HSD reactions. Polarity of the oxoscymnol species was established as 7-oxoscymnol>12 oxoscymnol>3-oxoscymnol>scymnol (in order from most polar to least polar). Confirmation that 5beta-scymnol is an oxidative substrate for steroid metabolising enzymes was made possible by the use of sophisticated liquid chromatography-mass spectrometry (LC-MS) techniques that will likely provide the basis for further exploration of scymnol as a therapeutic compound. PMID- 20974164 TI - Novel components of the human metabolome: the identification, characterization and anti-inflammatory activity of two 5-androstene tetrols. AB - Two natural 5-androstene steroid tetrols, androst-5-ene 3beta,7beta,16alpha,17beta-tetrol (HE3177) and androst-5-ene 3alpha,7beta,16alpha,17beta-tetrol (HE3413), were discovered in human plasma and urine. These compounds had significant aqueous solubility, did not bind or transactivate steroid-binding nuclear hormone receptors, and were not immunosuppressive in murine mixed-lymphocyte studies. Both compounds appear to be metabolic end products, as they were resistant to primary and secondary metabolism. Both were orally bioavailable, and were very well tolerated in a two week dose-intensive toxicity study in mice. Anti-inflammatory properties were found with exogenous administration of these compounds in rodent disease models of multiple sclerosis, lung injury, chronic prostatitis, and colitis. PMID- 20974165 TI - Pursuing motion illusions: a realistic oculomotor framework for Bayesian inference. AB - Accuracy in estimating an object's global motion over time is not only affected by the noise in visual motion information but also by the spatial limitation of the local motion analyzers (aperture problem). Perceptual and oculomotor data demonstrate that during the initial stages of the motion information processing, 1D motion cues related to the object's edges have a dominating influence over the estimate of the object's global motion. However, during the later stages, 2D motion cues related to terminators (edge-endings) progressively take over, leading to a final correct estimate of the object's global motion. Here, we propose a recursive extension to the Bayesian framework for motion processing (Weiss, Simoncelli, & Adelson, 2002) cascaded with a model oculomotor plant to describe the dynamic integration of 1D and 2D motion information in the context of smooth pursuit eye movements. In the recurrent Bayesian framework, the prior defined in the velocity space is combined with the two independent measurement likelihood functions, representing edge-related and terminator-related information, respectively to obtain the posterior. The prior is updated with the posterior at the end of each iteration step. The maximum-a posteriori (MAP) of the posterior distribution at every time step is fed into the oculomotor plant to produce eye velocity responses that are compared to the human smooth pursuit data. The recurrent model was tuned with the variance of pursuit responses to either "pure" 1D or "pure" 2D motion. The oculomotor plant was tuned with an independent set of oculomotor data, including the effects of line length (i.e. stimulus energy) and directional anisotropies in the smooth pursuit responses. The model not only provides an accurate qualitative account of dynamic motion integration but also a quantitative account that is close to the smooth pursuit response across several conditions (three contrasts and three speeds) for two human subjects. PMID- 20974166 TI - Spatial working memory load impairs manual but not saccadic inhibition of return. AB - Although spatial working memory has been shown to play a central role in manual IOR (Castel, Pratt, & Craik, 2003), it is so far unclear whether spatial working memory is involved in saccadic IOR. The present study sought to address this question by using a dual task paradigm, in which the participants performed an IOR task while keeping a set of locations in spatial working memory. While manual IOR was eliminated, saccadic IOR was not affected by spatial working memory load. These findings suggest that saccadic IOR does not rely on spatial working memory to process inhibitory tagging. PMID- 20974167 TI - Perceptual learning in Vision Research. AB - Reports published in Vision Research during the late years of the 20th century described surprising effects of long-term sensitivity improvement with some basic visual tasks as a result of training. These improvements, found in adult human observers, were highly specific to simple visual features, such as location in the visual field, spatial-frequency, local and global orientation, and in some cases even the eye of origin. The results were interpreted as arising from the plasticity of sensory brain regions that display those features of specificity within their constituting neuronal subpopulations. A new view of the visual cortex has emerged, according to which a degree of plasticity is retained at adult age, allowing flexibility in acquiring new visual skills when the need arises. Although this "sensory plasticity" interpretation is often questioned, it is commonly believed that learning has access to detailed low-level visual representations residing within the visual cortex. More recent studies during the last decade revealed the conditions needed for learning and the conditions under which learning can be generalized across stimuli and tasks. The results are consistent with an account of perceptual learning according to which visual processing is remodeled by the brain, utilizing sensory information acquired during task performance. The stability of the visual system is viewed as an adaptation to a stable environment and instances of perceptual learning as a reaction of the brain to abrupt changes in the environment. Training on a restricted stimulus set may lead to perceptual overfitting and over-specificity. The systemic methodology developed for perceptual learning, and the accumulated knowledge, allows us to explore issues related to learning and memory in general, such as learning rules, reinforcement, memory consolidation, and neural rehabilitation. A persistent open question is the neuro-anatomical substrate underlying these learning effects. PMID- 20974169 TI - Green nanotechnology: a short cut to beneficiation of natural fibers. AB - For the first time worldwide, it is shown that our novel nanocomposite produced from natural fibers vaccinated with glucose--by fully green nanotechnology- possesses surprising reactivity towards urea. Magic super absorbent carbamated nanocomposite cotton fabrics having remarkable distinguished properties were obtained in few minutes. It is well established that carbamates possess antibacterial effects. The produced magic nanocomposite fabrics, we discovered for the first time worldwide, find their use as woven or nonwoven hygienic pads, bandages or paper nanocomposites. PMID- 20974170 TI - Ancestral voices in the mammalian mind: philosophical implications of Jaak Panksepp's affective neuroscience. AB - The philosophical implications of Jaak Panksepp's affective neuroscience comprise a significant form of skepticism regarding our capacities as agents. This is clear in two ways. (1) Panksepp's methods of inquiry support a corollary to Dobzhansky's famous maxim concerning evolution: nothing in mammalian psychology makes sense except in light of ancient affective capacities shared by all mammals. The application of this maxim, I argue, raises informed doubts concerning our knowledge of our own capacities. (2) Against the backdrop of this maxim, Panksepp's substantive discoveries provide tentative confirmation of theories in psychology which raise doubts about our alleged capacity to give reasons for our actions. Taken together, Panksepp's methods and discoveries call into question the view we have of ourselves as free and responsible agents, while pointing us toward more-fruitful forms of inquiry concerning all our animal capacities, including our capacities for deliberation, choice, and action. PMID- 20974168 TI - Aging and vision. AB - Given the increasing size of the older adult population in many countries, there is a pressing need to identify the nature of aging-related vision impairments, their underlying mechanisms, and how they impact older adults' performance of everyday visual tasks. The results of this research can then be used to develop and evaluate interventions to slow or reverse aging-related declines in vision, thereby improving quality of life. Here we summarize salient developments in research on aging and vision over the past 25 years, focusing on spatial contrast sensitivity, vision under low luminance, temporal sensitivity and motion perception, and visual processing speed. PMID- 20974171 TI - A systems level analysis of the mirror neuron hypothesis and imitation impairments in autism spectrum disorders. AB - Although several studies suggest an imitation deficit as a key feature of autism, questions have been raised about the consistency of this finding and about the component skills involved in imitation. The primary aim of this review is to examine the uneven profile of imitation deficits found in autism in the context of the mirror neuron system (MNS) dysfunction hypothesis. We use the cortical underconnectivity framework (Just et al., 2004) to examine the coordination of brain areas that orchestrate the communication between the component skills underlying imitation. A comprehensive account of imitation deficit in autism should take into account the regions that are at the core of the MNS (e.g., IFG and IPL) and related regions that feed into the MNS (e.g., STS, Cerebellum) in their functioning and in their coordination. Our findings suggest that the MNS may be associated with mediating familiarity, attention, self-other matching, and social relevance, which may be vital in characterizing the imitation deficits in autism. Such an analysis may have greater clinical and therapeutic value. PMID- 20974173 TI - Is there a core neural network in empathy? An fMRI based quantitative meta analysis. AB - Whilst recent neuroimaging studies have identified a series of different brain regions as being involved in empathy, it remains unclear concerning the activation consistence of these brain regions and their specific functional roles. Using MKDA, a whole-brain based quantitative meta-analysis of recent fMRI studies of empathy was performed. This analysis identified the dACC-aMCC-SMA and bilateral anterior insula as being consistently activated in empathy. Hypothesizing that what are here termed affective-perceptual and cognitive evaluative forms of empathy might be characterized by different activity patterns, the neural activations in these forms of empathy were compared. The dorsal aMCC was demonstrated to be recruited more frequently in the cognitive evaluative form of empathy, whilst the right anterior insula was found to be involved in the affective-perceptual form of empathy only. The left anterior insula was active in both forms of empathy. It was concluded that the dACC-aMCC SMA and bilateral insula can be considered as forming a core network in empathy, and that cognitive-evaluative and affective-perceptual empathy can be distinguished at the level of regional activation. PMID- 20974174 TI - Diagnostic performance of procalcitonin for bacteremia in patients with bacterial infection at the emergency department. PMID- 20974175 TI - Statistically robust measurement of evoked response onset latencies. AB - Onset latencies of evoked responses are useful for determining delays in sensory pathways and for indicating spread of activity between brain areas, therefore inferring causality. Previous studies have applied several different methods and parameters for detecting onsets, mainly utilizing thresholds based on the mean and standard deviation (SD) of the pre-stimulus "baseline" time window, or using t-tests of group data to determine when the response first differs significantly from the baseline. However, these methods are not statistically robust, have low power when the baseline data are not normally distributed, and are heavily influenced by outliers in the baseline. Here, we examine using a modified boxplot method known as the "median rule" for determining onset latencies. This rule makes no assumptions about the baseline distribution, is resistant to outliers, and can be applied to individual level data therefore allowing intersubject and interregional comparisons. We first show with simulations that the median rule is significantly less sensitive to outliers in the baseline than the SD method. We then use simulations to demonstrate the effect of skewness on onset latencies. Finally, we use magnetoencephalography (MEG) to show that the median rule can be easily applied to real data and gives reasonable results. In most situations the different methods give similar results, which enhances comparability across studies, but in data sets with a high noise level there is a clear advantage to using a statistically robust method. In conclusion, the median rule is an excellent method for estimating onset latencies in evoked responses. PMID- 20974176 TI - Using the self-administration of apomorphine and cocaine to measure the pharmacodynamic potencies and pharmacokinetics of competitive dopamine receptor antagonists. AB - Competitive dopamine receptor antagonists accelerate psychomotor stimulant self administration. According to pharmacological theory of competitive antagonism antagonists raise the equiactive agonist concentration. In the self administration paradigm this is assumed to be the satiety threshold or C(min). The magnitude of the proportional increase in satiety threshold (agonist concentration ratio) as a function of antagonist dose should reflect the antagonist pharmacodynamic potency. The time course of this effect should reflect the rate of change of antagonist occupancy of receptors and, therefore, antagonist concentration, i.e. pharmacokinetics. Rats self-administered apomorphine or cocaine at a stable rate and were then injected i.v. with one of four competitive D1-like or D2-like dopamine receptor antagonists and the session continued. The agonist concentrations at the time of each self-administration (satiety thresholds) were calculated during the session. The antagonists accelerated self-administration of both agonists with a concomitant increase in the calculated satiety thresholds. The maximum agonist concentration ratio was proportional to the dose of antagonist. The time courses of the changes in agonist concentration ratio were independent of the agonist and of the dose of antagonist. Schild analysis of the maximum agonist concentration ratio as a function of the antagonist dose allowed apparent pA2 (or K(dose)) to be measured. Antagonist K(dose) values should provide a quantitative basis for receptor identification in behavioral pharmacology. The assay system may also measure the pharmacokinetics of antagonist elimination from the brain. Agonist self administration represents a sensitive in vivo pharmacological assay system that provides information useful for pharmacokinetic/pharmacodynamic modeling of antagonist effects. PMID- 20974177 TI - Mini-coil for magnetic stimulation in the behaving primate. AB - Transcranial magnetic stimulation (TMS) is rapidly becoming a leading method in both cognitive neuroscience and clinical neurology. However, the cellular and network level effects of stimulation are still unclear and their study relies heavily on indirect physiological measurements in humans. Direct electrophysiological studies of the effect of magnetic stimulation on neuronal activity in behaving animals are severely limited by both the size of the stimulating coils, which affect large regions of the animal brain, and the large artifacts generated on the recording electrodes. We present a novel mini-coil which is specifically aimed at studying the neurophysiological mechanism of magnetic stimulation in behaving primates. The mini-coil fits into a chronic recording chamber and provides focal activation of brain areas while enabling simultaneous extracellular multi-electrode recordings. We present a comparison of this coil to a commercial coil based on the theoretical and recorded magnetic fields and induced electric fields they generate. Subsequently, we present the signal recorded in the behaving primate during stimulation and demonstrate the ability to extract the spike trains of multiple single units from each of the electrodes with minimal periods affected by the stimulus artifact (median period <2.5 ms). The directly recorded effect of the magnetic stimulation on cortical neurons is in line with peripheral recordings obtained in humans. This novel mini coil is a key part of the infrastructure for studying the neurophysiological basis of magnetic stimulation, thereby enabling the development and testing of better magnetic stimulation tools and protocols for both neuroscientists and clinicians. PMID- 20974172 TI - Oxidative stress in schizophrenia: an integrated approach. AB - Oxidative stress has been suggested to contribute to the pathophysiology of schizophrenia. In particular, oxidative damage to lipids, proteins, and DNA as observed in schizophrenia is known to impair cell viability and function, which may subsequently account for the deteriorating course of the illness. Currently available evidence points towards an alteration in the activities of enzymatic and nonenzymatic antioxidant systems in schizophrenia. In fact, experimental models have demonstrated that oxidative stress induces behavioral and molecular anomalies strikingly similar to those observed in schizophrenia. These findings suggest that oxidative stress is intimately linked to a variety of pathophysiological processes, such as inflammation, oligodendrocyte abnormalities, mitochondrial dysfunction, hypoactive N-methyl-d-aspartate receptors and the impairment of fast-spiking gamma-aminobutyric acid interneurons. Such self-sustaining mechanisms may progressively worsen producing the functional and structural consequences associated with schizophrenia. Recent clinical studies have shown antioxidant treatment to be effective in ameliorating schizophrenic symptoms. Hence, identifying viable therapeutic strategies to tackle oxidative stress and the resulting physiological disturbances provide an exciting opportunity for the treatment and ultimately prevention of schizophrenia. PMID- 20974178 TI - Major histocompatibility complex class I-mediated inhibition of neurite outgrowth from peripheral nerves. AB - Studies of mice deficient in classical major histocompatability complex class I (MHCI) revealed that MHCI plays an important role in neurodevelopment in the central nervous system. We previously studied the effects of recombinant MHCI molecules on wildtype retina explants and observed that MHCI can inhibit retina neurite outgrowth, with self-MHCI molecules having greater inhibitory effect than non-self MHCI molecules. Here, we examined classical MHCI's effects on axon outgrowth from neurons of the peripheral nervous system (PNS). We used the embryonic dorsal root ganglia (DRG) explant model since their neurons express MHCI and because DRG explants have been widely used to assess the effects of molecules on axonal outgrowth from PNS neurons. We observed that picomolar levels of a recombinant self-MHCI molecule, but not non-self MHCI molecules, inhibited axon outgrowth from DRG explants. This differential sensitivity to self- vs. non self MHCI suggests that early in development, self-MHCI may "educate" PNS neurons to express appropriate MHCI receptors, as occurs during natural killer cell development. Furthermore, we observed that a MHCI tetramer stained embryonic DRG neurons, indicating the expression of classical MHCI receptors. These results suggest that MHCI and MHCI receptors play roles during early stages of PNS development and may provide new targets of therapeutic strategies to promote neuronal outgrowth after PNS injury. PMID- 20974179 TI - A combined method for rescue of modified enteroviruses by mutagenic primers, long PCR and T7 RNA polymerase-driven in vivo transcription. AB - The current methods for manipulation of enteroviral RNA genomes and production of modified virus particles include stepwise subcloning procedures and in vitro transcription and RNA transfection steps that are both time-consuming and inefficient. Several enteroviral cDNA clones with 5'-terminal T7 promoter and coxsackievirus A9 (CAV9) PCR product with the T7 promoter were transfected successfully into target cells expressing T7 RNA polymerase for the rescue of virus particles. This demonstrated the overall feasibility of the in vivo transcription method. Furthermore, a rapid method using high-fidelity DNA polymerase, PhusionTM, for amplification and mutagenesis of CAV9 cDNA was generated. A long PCR method was employed together with mutagenic primers for direct introduction of a unique restriction enzyme site into the VP1-2A junction of the CAV9 cDNA clone during the PCR amplification process. Enhanced green fluorescent protein was subcloned to that site, and CAV9-eGFP cDNA was transfected to the target cells for in vivo transcription and successful rescue of CAV9-eGFP particles. The method allowed a straightforward mutagenesis and in vivo production of infectious enteroviral particles, and may be applicable routinely for rapid production of the modified picornaviruses over the use of the traditional subcloning protocols. PMID- 20974180 TI - Non-structural protein 1 (NS1) antibody-based assays to differentiate West Nile (WN) virus from Japanese encephalitis virus infections in horses: effects of WN virus NS1 antibodies induced by inactivated WN vaccine. AB - Antibodies to non-structural protein 1 (NS1) of West Nile virus (WNV) have been used to differentiate WNV infection from infection by serologically cross reactive flaviviruses, including Japanese encephalitis virus (JEV), in horses. However, since the inactivated West Nile (WN) vaccine has been reported to induce NS1 antibodies, there is concern about the reliability of using NS1-based assays for testing vaccinated horses. Therefore, the effect of inactivated WN vaccine induced antibodies on an epitope-blocking ELISA and complement-dependent cytotoxicity (CDC) assay were investigated. Both assays are based on NS1 antibodies and were established previously to differentiate WNV from JEV infections in horses. Groups of three horses were vaccinated with two or three doses of a commercial inactivated WN vaccine and NS1 antibodies were detected by a conventional ELISA after the second vaccination. Vaccine-induced NS1 antibodies were also detected by blocking ELISA and a CDC assay and affected the ability of these assays to differentiate WNV from JEV infections. However, the effect was less significant in the CDC assay, where use of a low serum concentration ensured effective differentiation. The more efficient detection of infection-induced antibodies over vaccine-induced antibodies by the CDC assay was potentially attributable to the different IgG isotype profiles of these antibodies. PMID- 20974181 TI - Individual differences in schedule-induced polydipsia: neuroanatomical dopamine divergences. AB - Autoradiography analysis of D1 and D2 dopamine receptors and c-Fos activity were performed in brain of rats classified as low drinkers (LD) and high drinkers (HD) according to schedule-induced polydipsia (SIP) performance. Previous studies have shown that groups selected according to their rate of drinking in SIP differ in behavioral response to dopaminergic drugs. This study reports differences between LD and HD rats in dopamine D1 and D2 receptor binding through different mesocorticolimbic brain areas. LD and HD rats showed opposite patterns of binding in dopamine D1 and D2 receptors in the nucleus accumbens, medial prefrontal cortex, amygdala, ventral tegmental area and substantia nigra. Whereas LD rats showed higher binding than HD rats for D1 receptors, HD rats showed higher binding than LD rats for D2 receptors (except in substantia nigra that were roughly similar). These neuroanatomical differences in dopamine receptor binding were also associated with an elevated c-Fos count in the medial prefrontal cortex of HD rats. In tandem with previous evidence, our results suggest a different dopaminergic function between LD and HD, and points to SIP as a behavioral model for distinguishing populations possibly vulnerable to dopaminergic function disorders. PMID- 20974182 TI - Role of mouse cerebellar nicotinic acetylcholine receptor (nAChR) alpha(4)beta(2) and alpha(7) subtypes in the behavioral cross-tolerance between nicotine and ethanol-induced ataxia. AB - We have demonstrated that nicotine attenuated ethanol-induced ataxia via nicotinic-acetylcholine-receptor (nAChR) subtypes alpha(4)beta(2) and alpha(7). In the present study, ethanol (2g/kg; i.p.)-induced ataxia was assessed by Rotorod performance following repeated intracerebellar infusion of alpha(4)beta(2)- and alpha(7)-selective agonists. Localization of alpha(4)beta(2) and alpha(7) nAChRs was confirmed immunohistochemically. Cerebellar NO(x) (nitrite+nitrate) was determined flurometrically. Repeated intracerebellar microinfusion of the alpha(4)beta(2)-selective agonist, RJR-2403 (for 1, 2, 3, 5 or 7 days) or the alpha(7)-selective agonist, PNU-282987 (1, 2, 3 or 5 days), dose-dependently attenuated ethanol-induced ataxia. These results suggest the development of cross-tolerance between ethanol-induced ataxia and alpha(4)beta(2) and alpha(7) nAChR agonists. With RJR-2403, the cross-tolerance was maximal after a 5-day treatment and lasted 48h. Cross-tolerance was maximal after a 1-day treatment with PNU-282987 and lasted 72h. Pretreatment with alpha(4)beta(2)- and alpha(7)-selective antagonists, dihydro-beta-erythroidine and methyllycaconitine, respectively, prevented the development of cross-tolerance confirming alpha(4)beta(2) and alpha(7) involvement. Repeated agonist infusions elevated cerebellar NO(x) 16h after the last treatment while acute ethanol exposure decreased it. Pretreatment with repeated RJR-2403 or PNU-282987 reversed ethanol induced decrease in NOx. The NO(x) data suggests the involvement of the nitric oxide (NO)-cGMP signaling pathway in the cross-tolerance that develops between alpha(4)beta(2)- and alpha(7)-selective agonists and ethanol ataxia. Both alpha(4)beta(2) and alpha(7) subtypes exhibited high immunoreactivity in Purkinje but sparse expression in molecular and granular cell layers. Our results support a role for alpha(4)beta(2) and alpha(7) nAChR subtypes in the development of cross-tolerance between nicotine and ethanol with the NO signaling pathway as a potential mechanism. PMID- 20974183 TI - Fast and slow spindle involvement in the consolidation of a new motor sequence. AB - This study aimed to determine the distinct contribution of slow (11-13 Hz) and fast (13-15 Hz) spindles in the consolidation process of a motor sequence learning task (MSL). Young subjects (n = 12) were trained on both a finger MSL task and a control (CTRL) condition, which were administered one week apart in a counterbalanced order. Subjects were asked to practice the MSL or CTRL task in the evening (approximately 9:00 p.m.) and their performance was retested on the same task 12h later (approximately 9:00 a.m.). Polysomnographic (PSG) recordings were performed during the night following training on either task, and an automatic algorithm was used to detect fast and slow spindles and to quantify their characteristics (i.e., density, amplitude, and duration). Statistical analyses revealed higher fast (but not slow) spindle density after training on the MSL than after practice of the CTRL task. The increase in fast spindle density on the MSL task correlated positively with overnight performance gains on the MSL task and with difference in performance gain between the MSL and CTRL tasks. Together, these results suggest that fast sleep spindles help activate the cerebral network involved in overnight MSL consolidation, while slow spindles do not appear to play a role in this mnemonic process. PMID- 20974184 TI - Substantia nigra pars reticulata is crucially involved in barbiturate and ethanol withdrawal in mice. AB - Sedative-hypnotic CNS depressant drugs are widely prescribed to treat a variety of disorders, and are abused for their sedative and euphoric effects. Physiological dependence and associated withdrawal episodes are thought to constitute a motivational force that sustains their use/abuse and may contribute to relapse in dependent individuals. Although no animal model duplicates depressant dependence, models for specific factors, like withdrawal, are useful for identifying potential neural determinants of liability in humans. Recent analyses implicate the caudolateral substantia nigra pars reticulata (clSNr) in withdrawal following acute and repeated ethanol exposures in mice, but did not assess its impact on withdrawal from other sedative-hypnotics or whether intrinsic neurons or fibers of passage are involved. Here, we demonstrate that bilateral chemical (ibotenic acid) lesions of the clSNr attenuate barbiturate (pentobarbital) and ethanol withdrawal. Chemical lesions did not affect convulsions in response to pentylenetetrazole, which blocks GABA(A) receptor mediated transmission. Our results demonstrate that the clSNr nucleus itself rather than fibers of passage is crucial to its effects on barbiturate and ethanol withdrawal. These findings support suggest that clSNr could be one of the shared neural substrates mediating withdrawal from sedative-hypnotic drugs. PMID- 20974185 TI - Association between striatal accumulation of FosB/DeltaFosB and long-term psychomotor sensitization to amphetamine in mice depends on the genetic background. AB - Previous results demonstrated association between increased FosB/DeltaFosB immunostaining in the ventromedial striatum and behavioral sensitization to amphetamine promoted by repeated stress or by repeated pairings of the psychostimulant and the testing cage in mice of the C57BL/6J strain. The present experiments tested this association in an additional protocol, its stability following the end of the sensitizing procedure and its generalization to mice from a different inbred strain. Eleven days after repeated administration of amphetamine within their home-cages, mice of the C57BL/6J strain expressed sensitization to the psychomotor effects of the psychostimulant when tested in a novel cage. At this time-point the same mice showed increased FosB/DeltaFosB immunostaining in the ventromedial striatum. Instead, mice of the genetically unrelated DBA/2J inbred strain expressing robust sensitization in the same protocol did not show changes in FosB/DeltaFosB immunostaining throughout the striatal complex. Lack of effects in FosB/DeltaFosB immunostaining was also observed in DBA/2J mice behaviorally sensitized by repeated pairings of amphetamine with the test cage. These results demonstrate that mice, depending on the genetic background, can develop robust and long-lasting behavioral sensitization to amphetamine in the absence of striatal DeltaFosB accumulation. PMID- 20974186 TI - Preference for ethanol in zebrafish following a single exposure. AB - Ethanol is one of the most widely abused drugs in the world. Its addictive property is believed to primarily stem from its ability to influence the brain reinforcement pathway evolved for mediating natural rewards. Although dopamine is a known component of the reinforcement pathway, clear molecular and cellular compositions of this pathway and its sensitivity to ethanol remain not well understood. Zebrafish has been increasingly used to model and understand human disease states, due to its genetic tractability and ease of maintenance. In this study, we determine whether adult zebrafish develop ethanol preference after a single exposure using a conditioned place preference (CPP) paradigm. Moreover, we establish a procedure that can be carried out in an automated and relatively high throughput fashion. We find that zebrafish of the AB strain display significantly increased preference for the compartment where they received ethanol during a single 20-min exposure. The largest increase in preference is in response to a 1.5% ethanol administered in the tank water. The results demonstrate robust ethanol preference in zebrafish. Such a relatively high-throughput assay with automated tracking and response to a single ethanol exposure provides a potential means for a large-scale screening aimed at understanding the brain reinforcement pathway and its sensitivity to ethanol in this genetically tractable vertebrate. PMID- 20974187 TI - Individual differences in vulnerability for self-injurious behavior: studies using an animal model. AB - Self-injurious behavior (SIB) is a debilitating characteristic that is prevalent across a broad spectrum of neurodevelopmental disorders. In most of these disorders, some individuals exhibit SIB, whereas others do not. However, the neurobiological mechanisms that confer vulnerability are virtually unexplored. We examined innate characteristics that contribute to vulnerability or resistance for SIB in an animal model of the behavioral pathology. Eighteen outbred Long Evans rats were screened for behavioral responsiveness to the mild stress of a novel environment. The rats were then categorized as high responders (HR; those rats that had the highest locomotor counts) or low responders (LR; those rats that had lower locomotor counts) by median split. All the rats were then given daily injections of the indirect monoamine agonist pemoline (150 mg/kg/day) for 10 days, and self-injury was evaluated. All 9 HR rats and 5 of the 9 LR rats exhibited self-injury. The HR rats spent more time self-injuring, injured more body sites, and caused larger areas of tissue damage than the LR rats did. Furthermore, the behavioral responsiveness to novelty stress was significantly correlated with each of these measures of self-injury. The HR rats did not exhibit substantially enhanced responses on other measures of psychostimulant action (stereotypy, grooming, locomotion, rearing). Accordingly, vulnerability to develop pemoline-induced SIB is positively correlated with, and can be predicted based upon, a behavioral measure of innate stress responsiveness. These findings suggest that characteristics that are common in developmental disorders may help predispose afflicted individuals to self-injure. The findings also extend the variety of behavioral pathologies (e.g. drug addiction) for which the HR/LR model predicts vulnerability. PMID- 20974189 TI - Effect of the interaction between the serotonin transporter gene and maternal environment on developing mouse brain. AB - A number of studies have demonstrated that the common polymorphism in the serotonin transporter gene (5-HTT-LPR) moderates the increased risk for major depression seen in persons exposed to early adverse experiences. Several mouse models of this interaction have been recently established to investigate the increased vulnerability of individuals carrying the 5-HTT-LPR S allele to both early and adult life stressful events. Identifying the immediate effects of an adverse early environment on genetically susceptible individuals is critical to develop effective prevention of its long-term negative consequences of such an interaction. For this purpose we investigated molecular and neurochemical effects promoted by variable amount of maternal care in the brain of developing (postnatal day 10) wild type and heterozygous serotonin transporter knockout mice. Pups experiencing low level of maternal care showed increased levels of brain-derived neurotrophic factor (BDNF) messenger RNA within the hippocampus and primary somato-sensory cortex, and increased alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor binding in hippocampus in comparison with pups experiencing high level of maternal care. Strikingly, only heterozygous serotonin transporter knockout pups experiencing high maternal care showed increased hippocampal levels of serotonin and norepinephrine and decreased serotonin turnover compared to wild-type littermates. These findings support the hypothesis that maternal care affects the development of the hippocampus and primary somato-sensory cortex of individuals characterized by genetic variants of the serotonin transporter. PMID- 20974188 TI - Adaptation of a novel operant orofacial testing system to characterize both mechanical and thermal pain. AB - Mechanical pain sensitivity is characteristic of many orofacial pain conditions; however, few models exist to quantify this pain. Here we evaluated a novel adaptation of our existing operant system to characterize orofacial pain following mechanical and thermal stimuli. We demonstrate that the operant system is able to detect painful and analgesic responses to mechanical stimuli. These findings allow comparison of both mechanical and thermal stimuli using the same outcome measures. PMID- 20974191 TI - Sensorimotor gating and vigilance-dependent choice accuracy: a within-subject correlative analysis in wild-type C57BL/6 mice. AB - Deterioration in attention and related processes is an early sign in schizophrenia predictive of disease development. Amongst the various translational paradigms for assessing attention in rodents, it is not known if they are equivalent in detecting individual differences. Answers here are pertinent to their use in the general human population for identifying individuals at high risk of developing schizophrenia. The present study employed a within-subject approach to examine in mice two common paradigms for assessing attention that differ markedly in their implementation. An operant-based two choice visual discrimination task (2-CVDT) that depends on effortful attention to brief visual cues was contrasted with prepulse inhibition (PPI) of the acoustic startle reflex, a well-established test of pre-attentive gating whereby processing of a startle-eliciting stimulus is inhibited by a preceding weak prepulse stimulus. Here, we revealed a correlation showing that individual mice with low PPI tended to perform poorly in the 2-CVDT in terms of choice accuracy but not response speed. This specific positive correlation suggests that the two readouts might be regulated via common attentional mechanisms, which might be critically dependent on normal muscarinic and N-methyl-d-asparate receptor functions. As demonstrated here, blockade of either receptor type by scopolamine or dizocilpine impaired 2-CVDT performance at doses that have been shown to disrupt PPI in mice. Further studies contrasting these two paradigms would be warranted to characterize the possible underlying psychological constructs that give rise to this correlation and to clarify whether the two paradigms may effectively capture schizophrenia-related cognitive deficits belonging to orthogonal domains. PMID- 20974190 TI - Long-term development of excessive and inflexible nicotine taking by rats, effects of a novel treatment approach. AB - RATIONALE: Addiction is characterized by inflexible drug consumption: unpleasant consequences are accepted. Rat studies with several drugs proved that long-term voluntary intake induced abstinence-outlasting excessive and inflexible consumption. OBJECTIVE: Establishing a long-term model of oral self administration of nicotine in rats with outlasting consequences for flexibility; testing a novel approach to restore flexibility by increasing neuroplasticity for memory reorganization via glucocorticoids. METHODS: 2 test groups of male Wistar rats were given continuous free choice between water and 8, 16, 32mg/l nicotine solutions for 48 weeks. Two other groups received water or 4mg/l nicotine as sole drinking fluid. After 10 weeks abstinence, all rats were given nicotine choice in a retest. Nicotine solutions were then adulterated with bitter-tasting quinine to test flexibility. In two treatment sessions (3 weeks, each), half of the rats received placebo, the other ones 250mg/l corticosterone, corticosterone plus 4mg/l nicotine and finally 4mg/l nicotine (1 week per phase). RESULTS: Voluntary intake groups developed a flexible, moderate consumption revealed by reversible influences of social conditions. Intake was individually stable but varied among subjects. In the retest, all rats from water and forced groups showed moderate, flexible intake whereas several rats from the choice groups were excessive, inflexible consumers. The treatment was effective in selectively reducing inflexible, excessive consumption. CONCLUSION: Long-term voluntary intake of nicotine, but not forced one, induces abstinence-enduring loss of flexibility in part of the rats. The tested treatment approach seems suitable to degrade an established addiction memory in rats. PMID- 20974192 TI - Retardation of neurobehavioral development and reelin down-regulation regulated by further DNA methylation in the hippocampus of the rat pups are associated with maternal deprivation. AB - It is known that early life stress has profound effects in early developing hippocampus. Reelin is a large protein that regulates neuronal migration during embryonic development. The expression of reelin persists in brain, but its function is little known. The aim of the present study was to investigate the effects of maternal deprivation (MD) on early neurobehavioral development of rats, and the role of reelin and the potential mechanism underlying regulation of its expression in hippocampus. Rat pups were removed from mothers during the postnatal day (PND) 2-15 for 3h a day. Reflex developments including grasping, gait, righting, cliff avoidance, auditory startle, hot-plate test and negative geotaxis, were tested during the first 3 weeks. The level of reelin mRNA and reelin gene methylation in the hippocampal formation were determined using real time PCR analysis. As expected, some differences appeared in the measure of neurobehavior and expression of reelin in rat pups. Several significant deficiencies were observed in bodyweight, auditory startle and grasping reflex while a great enhancement in hot-plate test in rat pups suffering from MD. On PND 22, the expression of reelin mRNA reduced in the hippocampus followed by MD. Meanwhile, the changes of DNA methylation showed an opposite trend compared with the reelin expression. The results suggest that MD in early life has harmful effects on neurobehavioral development, and causes the down-regulation of reelin mRNA by further DNA methylation in postnatal hippocampus. PMID- 20974193 TI - Hippocampal neurochemistry is involved in the behavioural effects of neonatal maternal separation and their reversal by post-weaning environmental enrichment: a magnetic resonance study. AB - Exposure to early life stress results in behavioural changes, and these dysfunctions may persist throughout adulthood. In this study, we investigated whether hippocampus volume and neurochemical changes were involved in the appearance of these effects in the maternal separation (MS) animal model using the noninvasive techniques of structural magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Sprague-Dawley rats exposed to MS for 180 min from postnatal days (PND) 2-14 demonstrated decreased sucrose preference, increased immobility in the forced swimming test (FST), and impaired memory in the Morris water maze in adulthood. Environmental enrichment (EE) (PND 21-60) could ameliorate the effects of MS on sucrose preference and learning and memory but not on immobility in the FST. In addition, EE significantly increased N acetylaspartate (NAA) of MS animals. However, we did not find an effect of MS or EE on hippocampal volume. These results indicate the involvement of hippocampal neurochemistry in the behavioural changes that result from early stressful life events and their modification by post-weaning EE. Thus changes in NAA, as a measure of neuronal integrity, appear to be a sensitive correlate of these behavioural effects. PMID- 20974194 TI - A role for MAPK and PI-3K signaling pathways in brain-derived neurotrophic factor modification of conditioned taste aversion retention. AB - Brain-derived neurotrophic factor (BDNF) has emerged as an important molecular mediator of synaptic plasticity. Our previous studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that the intracortical microinfusion of BDNF induces a lasting potentiation of synaptic efficacy in the projection from the basolateral nucleus of the amygdala (Bla) to the IC of adult rats in vivo. Recently, we have found that intracortical microinfusion of BDNF previous to CTA training modifies the retention of this task. In this work, we present experimental data showing that BDNF effects on CTA retention are dependent on both the activation of mitogen-activated protein kinases (MAPK) and phosphatidylinositol-3-kinase (PI-3K) at the insular cortex. Our results are evidence of the crucial role of both pathways in the modification of the CTA trace of memory caused by BDNF at a neocortical area. PMID- 20974195 TI - High fat feeding promotes simultaneous decline in insulin sensitivity and cognitive performance in a delayed matching and non-matching to position task. AB - Obesity is the single greatest risk factor for the development of Type 2 diabetes mellitus (T2DM), with the prevalence of both dramatically increasing in recent years. These conditions are associated with medical complications such as hypertension, neuropathy and cardiovascular disease. Recent evidence also suggests a greater risk of developing dementia including Alzheimer's disease. The molecular mechanisms governing these changes remain obscure, although epidemiological evidence suggests that reduced insulin sensitivity (a characteristic of T2DM) is an independent risk factor for Alzheimer's disease. Here we examine the effects of diet-induced insulin resistance on cognitive ability in an animal model not predisposed to develop Alzheimer's pathology. Following 12 weeks on a high fat diet (45% of calories as crude fat) male Wistar rats were overweight and insulin resistant but not frankly diabetic. High fat fed animals were consistently poorer in all aspects of an operant based delayed matching to position task, yet were not impaired in spatial working memory as judged by the open field watermaze test. The cognitive deficit of the HF fed animals was most apparent when the task was switched from matching to non matching to position, suggestive of an inability to change contingency. Performance in this task was negatively correlated with whole body insulin sensitivity but not weight gain. In conclusion this study has shown that insulin resistant animals exhibit impairments in an operant measure of behavioural flexibility which precede the development of diabetes. PMID- 20974196 TI - Highly specific methyl-end fatty-acid desaturases of trypanosomatids. AB - A detailed analysis of the trypanosomatids' genome projects revealed the presence of genes predicted to encode fatty-acid desaturases of the methyl-end type (MED). After cloning and functional characterization of all identified genes, it can be concluded that Trypanosoma cruzi contains two MEDs with oleate desaturase (OD) activities whereas Leishmania major contains one OD and two active linoleate desaturases (LD). All characterized ODs are highly specific for oleate (18:1Delta9) as substrate, presenting a nu+3 regioselectivity, although palmitoleate (16:1Delta9) can be desaturated as well, but to a lesser extent. L. major LD appears to use exclusively linoleate (18:2n-6), converting it into alpha linolenate (18:3n-3). This strong specificity assures no further conversion of polyunsaturated fatty acids (PUFAs) of the n-6 series into the n-3 series, downstream in the PUFA biosynthesis pathway. This characterization completes the identification of all enzymes involved in PUFA biosynthesis in a parasitic protist. Differently from their Trypanosoma brucei orthologue, T. cruzi and L. major ODs were more active when expressed either, in the presence of trienoic fatty acids or at higher temperatures. This could be evidence for a differential post-translational regulation of these enzymes as a result of direct sensing of environmentally dependent parameters such as membrane fluidity. PMID- 20974197 TI - Characterization of an Autographa californica multiple nucleopolyhedrovirus mutant lacking the ac39(p43) gene. AB - Open reading frame 39 [orf39(p43)] of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) is present in 10 isolates of the Alphabaculovirus genus. It is highly conserved in sequence and genomic location in the Group I but much less conserved in the Group II viruses. To investigate the potential role of p43 in AcMNPV infection, we constructed and characterized a p43 knockout mutant. The results showed that the p43 region was expressed as RNA from 3h post infection to at least 24h post infection, and its expression pattern was identical to the expression profile of its neighbouring gene, p47. P47 is an essential core gene component of the baculovirus RNA polymerase. The deletion of the p43 region was confirmed by PCR analysis of bacmid DNA and by RT-PCR analysis of RNA purified from p43 knockout infected cells. The results supported the hypothesis that a large transcript, initiating upstream of p47, includes the p43 ORF. Analyses of protein synthesis in p43 knockout infected cells clearly demonstrated that there were no obvious differences in the timing or amount of expression of P47, LEF-3, or VP39. Growth curves showed that infectious budded virus production and occlusion body formation were also not affected by the p43 knockout. We conclude that orf39(p43) is not essential for virus replication in cell culture. PMID- 20974198 TI - Identification of a conserved linear epitope on the VP1 protein of serotype O foot-and-mouth disease virus by neutralising monoclonal antibody 8E8. AB - Foot-and-mouth disease virus (FMDV) serotype O remains an important threat to animal husbandry worldwide, and the variability of the virus presents a major problem for FMDV vaccine design. High-affinity neutralising antibodies against a conserved epitope could provide protective immunity against diverse subtypes of FMDV serotype O and protect against future pandemics. We generated a novel monoclonal antibody (MAb) 8E8 that potently neutralised infection of FMDV O/YS/CHA/05 both in vitro and in vivo. Screening of a phage-displayed random 12 peptide library revealed that MAb 8E8 bound to phages displaying a consensus motif GDLNVRT, which is highly homologous to (146)GDLQVLT(152) of the FMDV VP1 protein. Given that MAb 8E8 showed reactivity with the (146)GDLQVLT(152) motif, we proposed that this motif represented a linear B-cell epitope of the VP1 protein. Western blot analysis revealed that the epitope peptide could be recognised by the positive sera from serotype O FMDV-infected pigs. The (147)DLQVLT(152) motif was the minimal requirement for reactivity as demonstrated by reactivity of MAb 8E8 with several truncated peptides derived from the motif. For further mapping, a set of different extended motifs derived from the minimally reactive epitope was expressed with a GST-tag and subjected to western blot. The results showed that a 10-aa peptide (145)RGDLQVLTPK(154) was the minimal unit with maximal binding activity to MAb 8E8. Subsequent alanine scanning mutagenesis studies revealed that D(147), Q(149) and V(150) are crucial for MAb 8E8 binding. Furthermore, the epitope was found to be highly conserved among different topotypes of serotype O FMDV through sequence alignment analysis and detection of MAb 8E8 for affinity to some isolates collected in China. Thus, the 8E8 epitope identified here should be helpful for designing epitope-based, intra-typic, cross-protective vaccines of serotype O FMDV. PMID- 20974199 TI - New insights into and novel applications of release technology for periodontal reconstructive therapies. AB - Periodontitis, an almost ubiquitous disorder in the adult population, induces the breakdown of tooth-supporting apparatus which, unfortunately, has an extremely limited capacity for self-repair and regeneration. The recent discovery of progenitor/stem cells residing in the periodontium, however, raises the possibility of restoring damaged periodontal tissues by recruiting their latent regenerative potential. Within the reparative process, stem cell fates may be influenced by a number of signaling molecules, such as growth factors (GFs), that require robust control for safe and effective regeneration of functional tissues. Numerous GFs with the ability to promote the regeneration of periodontal tissues have been identified thus far, but their clinical use is often hindered by delivery problems. Regulation of cell activity within a complex in vivo milieu requires the incorporation of multifaceted release technologies that offer physiological levels of GFs, mimicking the natural wound healing cascade by using tools of tissue engineering and protein/gene delivery. This should not be limited to the provision of a single GF but should instead release multiple essential GFs at an optimized ratio in a specific spatiotemporal mode. This article summarizes current limitations and new opportunities related to release technology in periodontal regenerative medicine, highlighting the importance as well as challenges with respect to delivering multiple GFs in an orderly temporal and spatial sequence to mimic their natural expression patterns. Recent progress highlights the importance of releasing endogenous GFs and developing commercially available products that may facilitate clinical translation. PMID- 20974200 TI - Environmental stimulation changes tissue-type plasminogen activator activity in the adult mouse hippocampus. AB - Tissue-type plasminogen activator (tPA) plays an important role in synaptic plasticity and contributes to several brain functions such as memory, learning, and behaviours. Although a number of studies have demonstrated that various kinds of stimuli such as electrophysiological stimulation, excitotoxic injury, and stress change tPA activity in the brain, no studies have ever examined whether environmental stimulation affect tPA activity in the brain. The aim of this study is to clarify the effect of environmental enrichment on tPA activity in the hippocampus and cerebral cortex of adult mouse brain. Zymographic analysis revealed that hippocampal tPA activity was higher in enriched mice than in standard-caged mice, whereas no significant changes in the cerebral cortex were detected between enriched and control mice. Enrichment-enhanced tPA activity reverted to the pre-enrichment level after mice were returned to a standard housing condition, suggesting that tPA upregulation is stimulation-dependent and reversible. These results suggest that tPA activity is regulated reversibly in an experience-dependent manner in the adult hippocampus. PMID- 20974201 TI - Neurochemical features of enkephalinergic neurons in the mouse trigeminal subnucleus caudalis. AB - Enkephalinergic (ENKergic) neurons have been proposed to play crucial roles in pain modulation in the trigeminal subnucleus caudalis (Vc). To assist an advance in the research of ENKergic neurons, here we used preproenkephalin-green fluorescent protein (PPE-GFP) transgenic mice, in which all ENKergic neurons were fluorescent. We first performed fluorescent in situ hybridization combined with immunofluorescent histochemistry to confirm the specificity of this transgenic mouse and its advantages in showing ENKergic neurons in the Vc. Then based on this useful transgenic mouse, we examined the phenotypic diversity of PPE-GFP neurons by immunostaining for several markers that characterize ENKergic neuron subtypes. About 25.9+/-1.9% of GFP-positive neurons were regarded as immunoreactive for glutamic acid decarboxylase (GAD)(67) mRNA and 14.7+/-1.4% of GFP-positive neurons were positive for gamma-aminobutyric acid. The proportions of calbindin-, calretinin-positive cells among the ENKergic neurons were 8.4+/ 1.2% and 7.3+/-1.7%, respectively. Only 1.1+/-0.1% of GFP-positive neurons colocalized with parvalbumin and no GFP-positive neurons were found to co-express neuronal nitric oxide synthase. We then injected retrograde tracer into the thalamic regions and observed that a small number of ENKergic neurons in the Vc were retrogradely labeled with the tracer. The present results provide a detailed morphological evidence of the neurochemical features of ENKergic neurons. These results have broad implications for understanding the functional roles of ENKergic neurotransmission in the Vc. PMID- 20974202 TI - Striatal ablation of GABAergic neurons prevents the in vivo neuroprotective effect of DCG-IV against the MPP+-induced neurotoxicity on dopaminergic nerve terminals. AB - In previous studies we found that intrastriatal DCG-IV administration, an agonist for group II metabotropic glutamate receptor: (i) protected striatal dopaminergic terminals against MPP(+)-induced neurotoxicity (Matarredona et al., 2001); (ii) selectively destroyed striatal GABAergic neurons (Venero et al., 2002) and (iii) induced early robust up-regulation of brain-derived neurotrophic factor (BDNF) in nigral dopaminergic neurons afferents in a target-dependent manner (Rite et al., 2005). Considering that BDNF protein is anterogradely transported to dopaminergic nerve endings, an autocrine role of BDNF could account for the neuroprotective effect of DCG-IV against the MPP(+)-induced toxicity of dopaminergic terminals. To test this possibility, we first performed a previous insult with quinolinic acid (QA) to specifically damage the striatal GABAergic neuronal cell bodies in order to remove the nigral BDNF target. Fourteen days later, we explored the potential in vivo neuroprotective action of DCG-IV against MPP(+)-induced toxicity on striatal dopaminergic nerve terminals by in vivo microdialysis. Integrity of GABAergic system was evaluated by glutamic acid decarboxylase (GAD) in situ hybridization. We demonstrate that previous striatal target ablation with QA prevented the neuroprotective effect of DCG-IV perfusion against the MPP(+) induced neurotoxicity on dopaminergic terminals. Our results strongly suggest an important autocrine neuroprotective role of BDNF on striatal dopaminergic nerve terminals. In addition, we found an unexpected regulatory response of surviving striatal GABAergic neurons in terms of high levels of GAD mRNA expression. PMID- 20974203 TI - Endoplasmic reticulum stress inducers provide protection against 6 hydroxydopamine-induced cytotoxicity. AB - 6-Hydroxydopamine (6-OHDA) is a neurotoxin used to establish experimental models of Parkinson's disease. Exposure to 6-OHDA results in cell death associated with oxidative stress. Pretreatments with sublethal oxidative stress and some pharmacological drugs have been shown to exert preconditioning effects on cytotoxicity caused by 6-OHDA. In this study, we investigated whether endoplasmic reticulum (ER) stress exerts preconditioning effects on 6-OHDA-induced cytotoxicity in human neuroblastoma SH-SY5Y cells. Pretreatment with ER stress inducers, thapsigargin (Tg) and tunicamycin (Tm), promoted GRP78 mRNA induction and ATF4 translation, which are ER stress markers, under our experimental conditions and protected against the cytotoxicity. The protective effect of Tg was more potent than that of Tm. We also found that Tg induced the expression of the antioxidant gene heme oxygenase-1 (HO-1) in a dose-dependent manner, whereas Tm had a weak effect on HO-1 induction. Flow cytometric analysis revealed that reactive oxygen species generated by 6-OHDA were more effectively suppressed in cells pretreated with Tg than with Tm. Therefore, it is likely that Tg enhances antioxidative defenses in SH-SY5Y cells compared with Tm. Because actinomycin D inhibited HO-1 induction by Tg, the induction of HO-1 may be regulated at the transcriptional level. Moreover, the specific eIF2alpha phosphatase inhibitor salubrinal augmented Tg-induced HO-1 expression. Therefore, the downstream signaling pathway of eIF2alpha might be involved in Tg-induced HO-1 expression. On the other hand, the reporter assay revealed that Tg stimulated the antioxidant response element (ARE) that is located in regulatory regions of antioxidant genes such as HO-1. Taken together, our data suggest that preconditioning effects induced by Tg mediate an adaptive response to 6-OHDA-induced cytotoxicity via phosphorylation of eIF2alpha and activation of the ARE. PMID- 20974204 TI - Role of ethanolamine phosphate in the hippocampus of rats with acute experimental autoimmune encephalomyelitis. AB - Here, we assessed the effects of acute experimental autoimmune encephalomyelitis (EAE) on the rat hippocampal somatostatinergic system and whether administration of an ethanolamine phosphate salt could prevent the appearance of the clinical signs and the impairment of the somatostatinergic system in this pathological condition. Female Lewis rats were injected in both hindlimb footpads with myelin basic protein from guinea pig brain and complete Freund's adjuvant and were sacrificed when limp tail (grade 1 EAE) or severe hindlimb paralysis (grade 3 EAE) were observed. One group was injected daily with ethanolamine phosphate, starting two days prior to immunization and for 15 days thereafter. The animals were sacrificed 15 days post-immunization. Acute EAE in grade 3 increased anti myelin basic protein antibodies in rat serum as well as tumor necrosis factor alpha and interferon-gamma levels in hippocampal extracts. In addition, it decreased the somatostatin receptor density, somatostatin receptor subtype 2 mRNA and protein content, and the inhibitory effect of somatostatin on adenylyl cyclase activity in the hippocampus. The protein levels of the inhibitory G protein subunits alphai(1-3), the G protein-coupled receptor kinase isoforms 2, 5 and 6, the phosphorylated cyclic AMP-binding protein and the somatostatin-like immunoreactivity content were unaltered in this brain area. Acute EAE in grade 1 did not modify any of these parameters. Ethanolamine phosphate administration prevented the clinical expression of acute EAE as well as the decrease in the somatostatin receptor density, somatostatin receptor subtype 2 expression and the capacity of somatostatin to inhibit adenylyl cyclase activity at the time-period studied. Furthermore, it blunted the rise in serum anti-myelin basic protein antibodies and hippocampal interferon-gamma and tumor necrosis factor-alpha levels. Altogether, these data suggest that ethanolamine phosphate might provide protection against acute EAE. PMID- 20974206 TI - Significant association between chronic antibody-mediated rejection and donor specific antibodies against HLA-DRB rather than DQB in renal transplantation. AB - De novo production of antidonor HLA antibody has been reported to be associated with chronic antibody-mediated rejection (CAMR). However, some donor-specific antibodies (DSA) do not seem to cause graft injury. Identification of the DSA responsible for CAMR and establishment of effective screening method for early detection of CAMR are therefore essential. All sera from 586 maintenance renal transplant recipients were examined for HLA antibody using ELISA and Luminex based assay. Positive sera were divided into high (>20% of positive control), moderate (10-20%), and low (2-10%). Donor specificities were analyzed using single antigen beads. ELISA detected only about half of high HLA antibodies (class I: n = 19, class II: n = 46) measured by Luminex-based assay. DSA against class I and class II were identified in 42% and 87% of high antibodies, respectively, including 78% against DQB and 44% against DRB. Renal dysfunction due to CAMR was closely related to high/moderate DRB DSA (n = 11), but not low DRB DSA (n = 9) nor high/moderate/low DQB DSA alone (n = 20). It was speculated that DRB DSA would be more detrimental to the graft, while DQB DSA were readily detectable in blood circulation. Further study, including detailed pathologic analysis of graft biopsy and long-term follow-up, is necessary. PMID- 20974205 TI - Human leukocyte antigen-A, -B, -C, -DRB1 allele and haplotype frequencies in Americans originating from southern Europe: contrasting patterns of population differentiation between Italian and Spanish Americans. AB - High-resolution DNA sequencing was used to identify the human leukocyte antigen (HLA) -A, -B, -C, and -DRB1 alleles found in 552 individuals from the United States indicating Southern European (Italian or Spanish) heritage. A total of 46 HLA-A, 80 HLA-B, 32 HLA-C, and 50 DRB1 alleles were identified. Frequent alleles included A*02:01:01G (allele frequency = 0.26 in Italian Americans and 0.22 in Spanish Americans); B*07:02:01G (Italian Americans allele frequency = 0.11); B*44:03 (Spanish Americans allele frequency = 0.07); C*04:01:01G and C*07:01:01G (allele frequency = 0.13 and 0.16, respectively, in Italian Americans; 0.15 and 0.12, respectively, in Spanish Americans); and DRB1*07:01:01 (allele frequency = 0.12 in each population). The action of balancing selection was inferred at the HLA-B and -C loci in both populations. The A*01:01:01G-C*07:01:01G-B*08:01:01G DRB1*03:01:01 haplotype was the most frequent A-C-B-DRB1 haplotype in Italian Americans (haplotype frequency = 0.049), and was the second most frequent haplotype in Spanish Americans (haplotype frequency = 0.021). A*29:02:01 C*16:01:01-B*44:03-DRB1*07:01:01 was the most frequent A-C-B-DRB1 in Spanish Americans (haplotype frequency = 0.023), and was observed at a frequency of 0.015 in Italian Americans. Pairwise F'(st) values measuring the degree of differentiation between these Southern European American populations as well as European and European American populations suggest that Spanish Americans constitute a distinct subset of the European American population, most similar to Mexican Americans, whereas Italian Americans cannot be distinguished from the larger European American population. PMID- 20974207 TI - Gene profile analysis of CD8(+) ILT3-Fc induced T suppressor cells. AB - Gene profile analysis of ILT3-Fc-induced Ts revealed a significant upregulation of Zink finger proteins, most of which act as transcriptional repressors. Included among these repressors is BCL6, which was shown to play a critical role in the differentiation of ILT3-Fc-induced T suppressor (Ts) cells. Genes implicated in cell cycle progression were downregulated. Genes encoding numerous inflammatory cytokines and chemokines were also downregulated. In contrast, antiapoptotic genes, as well as members of the WNT and transforming growth factor beta pathways, were upregulated. This study elucidates certain important aspects of Ts differentiation and function. PMID- 20974208 TI - Safety assessment of allergic contact dermatitis hazards: an analysis supporting reduced animal use for the murine local lymph node assay. AB - The original Organisation for Economic Co-operation and Development Test Guideline 429 (OECD TG 429) for the murine local lymph node assay (LLNA) required five mice/group if mice were processed individually. We used data from 83 LLNA tests (275 treated groups) to determine the impact on the LLNA outcome of reducing the group size from five to four. From DPM measurements, we formed all possible four- and five-mice combinations for the treated and control groups. Stimulation index (SI) values from each four-mice combination were compared with those from five-mice combinations, and agreement (both SI<3 or both SI >= 3) determined. Average agreement between group sizes was 97.5% for the 275 treated groups. Compared test-by-test, 90% (75/83) of the tests had 100% agreement; agreement was 83% for the remaining eight tests. Disagreement was due primarily to variability in animal responses and closeness of the SI to three (positive response threshold) rather than to group size reduction. We conclude that using four rather than five mice per group would reduce animal use by 20% without adversely impacting LLNA performance. This analysis supported the recent update to OECD TG 429 allowing a minimum of four mice/group when each mouse is processed individually. PMID- 20974209 TI - Strategies for the early detection of drug-induced hepatic steatosis in preclinical drug safety evaluation studies. AB - Hepatic steatosis is characterized by the accumulation of lipid droplets in the liver. Although relatively benign, simple steatosis can eventually lead to the development of steatohepatitis, a more serious condition characterized by fibrosis, cirrhosis, and eventual liver failure if the underlying cause is not eliminated. According to the "two hit" theory of steatohepatitis, the initial hit involves fat accumulation in the liver, and a second hit leads to inflammation and subsequent tissue injury. Because some xenobiotics target liver fatty acid metabolism, especially mitochondrial beta-oxidation, it is important to avoid potential drug candidates that can contribute to either the initiation of liver steatosis or progression to the more injurious steatohepatitis. The gold standard for the detection of these types of hepatic effects is histopathological examination of liver tissue. In animal studies, these examinations are slow, restricted to a single sampling time, and limited tissue sections. Recent literature suggests that rapid in vitro screening methods can be used early in the drug R&D process to identify compounds with steatotic potential. Further, progress in the identification of potential serum or plasma protein biomarkers for these liver changes may provide additional in vivo tools to the preclinical study toxicologist. This review summarizes recent developments for in vitro screening and in vivo biomarker detection for steatotic drug candidates. PMID- 20974211 TI - Symmetry and entropy of biological patterns: discrete Walsh functions for 2D image analysis. AB - To quantify symmetry and entropy inherent in the discrete patterns such as spatial self-organization in cell sorting and mussel bed ecosystems, we introduce the discrete Walsh analysis. This analysis enables us to estimate the degree of the complicated symmetry, and to extract the symmetry from the pattern that seems to be asymmetric. The results obtained in this paper are summarized as follows. (I) The geometrical patterns of the cell sorting become systematic with the predominance of the particular symmetry. This implies that not only the entropy but also the particular symmetry can decrease in the biological process. (II) The magnitude of the symmetry is related to the absolute value of the adhesion, and the type of the symmetry is related to the sign of the adhesion. That is, centro symmetry dominates in the cell sorting pattern caused by large negative adhesion, and double symmetry dominates in the pattern caused by large positive adhesion. (III) Spatial self-organization in mussel bed is accompanied by the decreasing of the centro-symmetry. This implies that the positive "adhesion" between mussel individuals increases with time. (IV) In the biological process, the Curie symmetry breaking occurs at intervals. PMID- 20974210 TI - siDNMT1 increases gamma-globin expression in chemical inducer of dimerization (CID)-dependent mouse betaYAC bone marrow cells and in baboon erythroid progenitor cell cultures. AB - OBJECTIVE: These studies were performed to test the hypothesis that DNMT1 is required for maintenance of DNA methylation and repression of the gamma-globin gene in adult-stage erythroid cells. MATERIALS AND METHODS: DNMT1 levels were reduced by nucleofection of small interfering RNA targeting DNMT1 in chemical inducer of dimerization-dependent multipotential mouse bone marrow cells containing the human beta-globin gene locus in the context of a yeast artificial chromosome and in primary cultures of erythroid progenitor cells derived from CD34(+) baboon bone marrow cells. The effect of reduced DNMT1 levels on globin gene expression was measured by real-time polymerase chain reaction and the effect on globin chain synthesis in primary erythroid progenitor cell cultures was determined by biosynthetic radiolabeling of globin chains followed by high performance liquid chromatography analysis. The effect on DNA methylation was determined by bisulfite sequence analysis. RESULTS: Reduced DNMT1 levels in cells treated with siDNMT1 were associated with increased expression of gamma-globin messenger RNA, an increased gamma/gamma+beta chain ratio in cultured erythroid progenitors, and decreased DNA methylation of the gamma-globin promoter. Similar effects were observed in cells treated with decitabine, a pharmacological inhibitor of DNA methyltransferase inhibitor. CONCLUSIONS: DNMT1 is required to maintain DNA methylation of the gamma-globin gene promoter and repress gamma globin gene expression in adult-stage erythroid cells. PMID- 20974212 TI - Cell cycle regulated expression of NCoR might control cyclic expression of androgen responsive genes in an immortalized prostate cell line. AB - In this work we have studied the mechanisms of regulation of expression of androgen receptor (AR) target genes. We have used an immortalized non-tumorigenic prostate cell line RWPE-1-AR(tag) constitutively expressing an exogenous AR as a model. We observed that all studied AR target genes exhibited a specific expression during the G1 phase of the cell cycle despite the constitutive expression of AR. Importantly, we found that the expression of NCoR, an AR co repressor, was downregulated during the G1 phase and expressed as mRNA and protein specifically during the S phase. The role of NCoR in repressing androgen induced expression of AR target genes in S phase was further demonstrated by altering expression of NCoR during the cell cycle through knockdown or induced overexpression. Using two alternative techniques we show that AR binds directly to target DNA in the chromatin only during the G1 phase. These data support the hypothesis that NCoR might control a cell cycle dependent regulation of expression AR target genes in prostate cells. PMID- 20974213 TI - Default mode network gates the retrieval of task-irrelevant incidental memories. AB - Episodic memories can be retrieved by an intentional search for certain information. Alternatively, a past episode may enter our consciousness without any intention to retrieve it, prompted by a stimulus in our surroundings. Incidental retrieval does not occur upon each encounter with a familiar stimulus, suggesting that a gating mechanism exists which regulates incidental retrieval activity. We analyzed data from a functional magnetic resonance imaging study on incidental retrieval in healthy young adults and found that failure to incidentally retrieve was selectively associated with reduced activation of lateral and medial parietal regions as well as ventromedial frontal cortex, areas implicated in default mode network. This is the first demonstration that relative deactivation of the brain regions associated with the default mode gates the consciousness from currently irrelevant memories. PMID- 20974214 TI - Influence of music training on academic examination-induced stress in Thai adolescents. AB - Several pieces of evidence suggest that academic examinations fulfill the classical requirement of a psychological stressor. Academic examinations represent a stressful challenge to many students, but studies on examination dependent corticosteroid response, a sensitive physiological indicator of a stress response, are inconsistent. In addition, several studies showed that music can decrease cortisol and adrenocorticotropic hormone (ACTH) levels, and other studies have found that music also may enhance a variety of cognitive functions, such as attention, learning, communication and memory. The present study investigated cortisol response in saliva of Thai adolescents taking academic examinations and analyzed the differences of the stress response between musician and control subjects. Also, we observed whether the academic examination dependent corticosteroid response affected learning and memory in the test subjects, which comprised 30 musician and 30 control students, age ranging from 15 to 17 years. Mathematical examinations were used as the stressor. Pre- and post-academic examination saliva cortisol levels were measured including self estimated stress levels. Results showed that the pre-academic examination saliva cortisol concentrations of the musician group are significantly lower than those of the control group, whereas there is no difference in the stress inventory scores. Interestingly, among students with grade point average (GPA) of >3.50, pre-academic examination cortisol levels are significantly lower in the musician compared with control group. This study suggests that under academic examination induced stress condition, music training can reduce saliva cortisol level in Thai adolescents. PMID- 20974215 TI - NT69L blocks ethanol-induced increase of dopamine and glutamate levels in striatum of mouse. AB - Recent study shows that NT69L, an analog of neurotensin (NT) (8-13), reduces ethanol consumption and preference in mice through modulation of neurotensin receptor subtype one. The current study showed that NT69L significantly decreased ethanol-induced increase of dopamine and glutamate levels in striatum of mouse. These data suggest that NT69L prevents ethanol consumption through the modulation of both dopaminergic and glutamatergic systems implicated in ethanol addiction. NT agonists may provide novel treatment for alcohol addiction. PMID- 20974216 TI - An electrophysiological investigation of the role of orthography in accessing meaning of Chinese single-character words. AB - This study reported the role of orthography in semantic activation processes of Chinese single-character words. Eighteen native Chinese speaking adults were recruited to take part in a Stroop experiment consisting of one-character color words and pseudowords which were orthographically similar to these color words. Classic behavioral Stroop effects, namely longer reaction times for incongruent conditions than for congruent conditions, were demonstrated for color words and pseudowords. A clear N450 was also observed in the two incongruent conditions. The participants were also asked to perform a visual judgment task immediately following the Stroop experiment. Results from the visual judgment task showed that participants could distinguish color words and pseudowords well (with a mean accuracy rate over 90 percent). Taken together, these findings support the direct orthography-semantic route in Chinese one-character words. PMID- 20974217 TI - Soleus H-reflex phase-dependent modulation during one-legged foot reaching and withdrawal in standing humans. AB - The aim of this study was to establish the modulation pattern of the soleus H reflex and excitability changes of interneurones mediating presynaptic inhibition from tibialis anterior to soleus Ia afferents when the right foot approached and withdrew from a step in standing humans. The task was conducted at 40 beats per minute, and this tempo corresponded to the rhythm of a half full movement cycle. Each subject was instructed not to load and not to move forward. Soleus H reflexes were elicited once in every full movement cycle that lasted approximately 3s. The ipsilateral knee joint angle and activity of leg muscles were recorded through a twin-axis goniometer and surface EMG, respectively. In all subjects, the soleus H-reflex was modulated in a phase-dependent pattern. The H-reflex was significantly depressed during the approach phase of the motor task and when the foot was on the step, and facilitated during the withdrawal phase and when the foot was on the ground. The soleus H-reflex conditioned by common peroneal nerve stimulation at tibialis anterior motor threshold at a long conditioning test interval was increased during the withdrawal phase or while the foot was on the ground suggesting that presynaptic inhibition was decreased. In most subjects, knee extensor activity was small, while ankle flexors and extensors were active in a reciprocal pattern. This study provides evidence that the soleus H-reflex is modulated in a phasic pattern during one-legged foot reaching and withdrawal by changes occurring at a premotoneuronal level. PMID- 20974218 TI - Effects of lipopolysaccharide and interleukin-6 on cataleptic immobility and locomotor activity in mice. AB - Catalepsy (animal hypnosis, tonic immobility) is a type of passive defensive behavior. Its exaggerated form is a syndrome of some psychopathological disorders. Numerous neurotransmitters have impact on the regulation of catalepsy. In this paper we demonstrated the involvement of interleukin-6 (IL-6) in the mechanism of cataleptic immobility. Effects of exogenous IL-6 treatment (7.5 and 10MUg/kg, i.p) or stimulation of endogenous IL-6 secretion with lipopolysaccharide (LPS) administration (50, 100 and 200MUg/kg, i.p.) on catalepsy and locomotor activity were studied in adult C57BL/6 male mice. IL-6 induced catalepsy in 70% (7.5MUg/kg) or 72.7% (10MUg/kg) of animals with no effect on locomotor activity. LPS administration reduced distance travelled and number of rears in the open field at any dose used, however, only high doses (100 or 200MUg/kg) of the toxin induced catalepsy in 50% of mice. This result indicates that IL-6 is involved in the regulation of catalepsy, this effect is specific and does not arise from inhibition of locomotor activity. The study provides a new evidence on participation of IL-6 in mechanisms of abnormal behavior. PMID- 20974219 TI - Effects of intensity and positional predictability of a visual stimulus on simple reaction time. AB - The influence of visual stimuli intensity on manual reaction time (RT) was investigated under two different attentional settings: high (Experiment 1) and low (Experiment 2) stimulus location predictability. These two experiments were also run under both binocular and monocular viewing conditions. We observed that RT decreased as stimulus intensity increased. It also decreased as the viewing condition was changed from monocular to binocular as well as the location predictability shifted from low to high. A significant interaction was found between stimulus intensity and viewing condition, but no interaction was observed between neither of these factors and location predictability. These findings support the idea that the stimulus intensity effect arises from purely sensory, pre-attentive mechanisms rather than deriving from more efficient attentional capture. PMID- 20974220 TI - Effects of polyinosinic-polycytidylic acid (Poly I:C) on naloxone-precipitated withdrawal in morphine-dependent mice. AB - Viral infections are frequently found in opioid addicts, subjecting them to immune challenge. However, the effects of immune challenge on opioid withdrawal are not fully understood. In the present study, mice were intraperitoneally injected with 2mg/kg polyinosinic-polycytidylic acid (Poly I:C, a viral mimetic) for 3 days to induce an immune challenge, followed by subcutaneous injection of morphine 3 times per day for 3 days to induce morphine dependence. Withdrawal was induced by an intraperitoneal injection of 5mg/kg naloxone, an opioid receptor antagonist. The results showed that Poly I:C pretreatment did not alter body weight loss, jumping behavior, or locomotion during naloxone-precipitated withdrawal. In contrast, Poly I:C pretreatment significantly increased immobility time in the tail suspension test. Our findings suggest that Poly I:C-induced immune challenge has no effects on acute physical opioid withdrawal symptoms but facilitates depression-like behavior. PMID- 20974221 TI - Cannabinoid CB(1) receptor expression and affinity in the rat hippocampus following bilateral vestibular deafferentation. AB - Numerous studies have shown that bilateral vestibular deafferentation (BVD) results in spatial memory deficits and hippocampal dysfunction in rats and humans. Since cannabinoid CB(1) receptors are well known to regulate synaptic plasticity in the hippocampus, we investigated whether BVD resulted in changes in CB(1) receptor expression and affinity in the rat hippocampus at 1, 3 and 7 days post-surgery, using a combination of Western blotting and radioligand binding. Using Western blotting, we found that CB(1) receptor expression was significantly lower in BVD animals compared to sham controls only in the CA3 area across the 3 time points (P=0.03). CB(1) receptor expression decreased significantly over time for both the BVD and sham animals (P=0.000). The radioligand binding assays showed no significant change in the IC(50) of the CB(1) receptor for the cannabinoid CB(1)/CB(2) receptor agonist, WIN55,212-2. These results suggest that the CB(1) receptor down-regulates in the CA3 region of the hippocampus following BVD, but with no changes in the affinity of the CB(1) receptor for WIN55,212-2. PMID- 20974222 TI - Targets and non-targets in the aging brain: A go/nogo event-related potential study. AB - This study tested whether older adults show enhanced suppression of inappropriate processing of non-target information, as marked with the nogo-P3 event-related potential (ERP). Healthy younger and older adults were tested on a simple go/nogo task with visually presented numbers. Unlike in most of the previous studies, go and nogo stimuli were matched for frequency and conflict level in order to minimize the impact of task difficulty, probability monitoring, or conflict detection and resolution on the age-related ERP differences. Older adults showed slower go responses but a comparable accuracy to younger controls. The parietal go-P3 latency was also delayed with aging, while the central nogo-P3 was more pronounced in older adults than in younger controls. The amplitude of this component negatively correlated with go-RTs. In line with previous studies, this suggests that a partial response preparation to nogo events is strongly suppressed in older adults, especially faster ones. PMID- 20974223 TI - Neuroprotective effects of Eucommia ulmoides Oliv. Bark on amyloid beta(25-35) induced learning and memory impairments in mice. AB - In the present study, we examined whether aqueous extract of Eucommia ulmoides Oliv. Bark (EUE) with graded doses exerted its neuroprotective effects on amyloid beta(25-35) (Abeta(25-35))-induced learning and memory impairments in mice. Mice received a single intracerebroventricular (i.c.v.) injection of Abeta(25-35) 6 nmol as the critical factor in Alzheimer's disease (AD), cognition was evaluated using Y-maze, passive avoidance, and Morris water maze tests. EUE significantly improved the Abeta(25-35)-induced memory deficit in the Y-maze test. Also, EUE increased step-through latency time with Abeta(25-35)-induced learning and memory deficits in the passive avoidance test. In addition, EUE decreased the escape latencies with Abeta(25-35)-induced cognitive impairments in the Morris water maze test. In the probe trial session, EUE increased time spent in the target quadrant. In the in vitro study, EUE was found to inhibit acetylcholinesterase (AChE) activity in a dose-dependent manner (IC50 value; 172 MUg/ml). Ex vivo study, EUE significantly inhibited AChE activity in the hippocampus and frontal cortex. These results demonstrate that EUE possesses potent neuroprotective effects and that its beneficial effects are mediated, in part, by AChE inhibition, and therefore, might be a potential candidate in neurodegenerative diseases such as AD. PMID- 20974224 TI - Oral methylphenidate establishes a conditioned place preference in rats. AB - Emerging data suggest that illicit methylphenidate abuse is a growing problem. Although abuse of the drug typically occurs by the intranasal route, oral (per os; p.o.) methylphenidate also has abuse potential. The present study compared the effects of p.o. and intraperitoneal (i.p.) methylphenidate in rats using the conditioned place preference (CPP) procedure. Young adult male Sprague-Dawley rats were trained to consume oyster crackers injected initially with saline. Next, rats were randomly assigned to receive p.o. or i.p. methylphenidate (3 or 10mg/kg) or saline immediately or 30min prior to 30min conditioning trials. Methylphenidate or saline were each paired 4 times with an end compartment; preference for the methylphenidate-paired compartment was then assessed on a drug free session. When given immediately prior to conditioning, significant CPP was obtained with both 3 and 10mg/kg of i.p. methylphenidate, but only with 10mg/kg of p.o. methylphenidate. When given 30min prior to conditioning, there was no evidence of CPP for any dose of i.p. or p.o. methylphenidate. These findings are the first demonstration that p.o. methylphenidate has rewarding effects, although i.p. methylphenidate is obtained at a 3mg/kg dose which did not establish CPP with p.o. administration. The lack of CPP following 30min pretreatment also suggests that conditioning may require the CS to be associated with a US of ascending, rather than descending, brain levels of methylphenidate. These results are consistent with clinical evidence of the reduced abuse liability of p.o. methylphenidate relative to methylphenidate taken by other (e.g., intranasal) routes. PMID- 20974225 TI - Activation of nicotinic alpha(7) acetylcholine receptor enhances long term potentation in wild type mice but not in APP(swe)/PS1DeltaE9 mice. AB - Amyloid beta (Abeta) plays a central role in Alzheimer's disease (AD) and binds to the nicotinic alpha(7) receptor (alpha(7) nAChR). Little is known about the degree to which the binding of Abeta to the alpha(7) nAChR influences the role of this receptor in long-term potentiation (LTP), however. We have studied the effect of the partial alpha(7) nAChR agonist SSR180711 on hippocampal slice preparations from normal wild type (Wt) and APP(swe)/PS1DeltaE9 transgenic (Tg) mice. In the hippocampal slices from the 6 months old Wt mice, the application of both nicotine (5MUM) and SSR180711 (300nM) resulted in a significant enhancement of LTP expressed in area CA1. However, in the Tg mice the application of SSR180711 did not result in an increase in LTP beyond control levels. The amount of binding of the alpha(7) nAChR ligand 125-I-alpha-bungarotoxin was not different between in Tg and Wt mice. These findings indicate that the alpha(7) nAChR is functionally blocked in the hippocampal neurons, downstream of the alpha(7) nAChR, and that this is likely due to an interaction between the receptor and Abeta, which leads to changes in LTP. PMID- 20974226 TI - Immunohistochemical localization of chemokine CXCL14 in rat hypothalamic neurons. AB - We immunohistochemically investigated the distribution of CXCL14, also called BRAK protein in the rat hypothalamus using anti-human CXCL14 serum. CXCL14 immunoreactive somata were localized in the periventricular area and paraventricular and supraoptic hypothalamic nuclei. In the former, immunoreactive neuronal somata, confirmed by double staining with a neuronal marker, NeuN, contained diffuse CXCL14-like immunoreactivity in their perikarya. In contrast, immunoreactive somata in the latter contained immunoreactive puncta within their perikarya. Very dense immunoreactive fibers and puncta were seen in the median eminence. Dense immunoreactive fibers were seen in the arcuate nucleus and ventromedial hypothalamic nucleus. Other hypothalamic areas contained a few immunoreactive fibers and puncta. These results demonstrated for the first time that CXCL14 protein is present in a subset of hypothalamic neurons and suggest that CXCL14 participates in hypothalamic functions such as control of autonomic nervous systems and/or participates in immune cell recruitment via the median eminence. PMID- 20974227 TI - Role of endogenous pituitary adenylate cyclase-activating polypeptide in adult hippocampal neurogenesis. AB - Hippocampal neurogenesis occurs throughout life in mammals and has pivotal roles in brain functions. An enriched environment stimulates hippocampal neurogenesis, but the exact mechanisms are still unclear. The present study investigated the role of pituitary adenylate cyclase-activating polypeptide (PACAP) in adult hippocampal neurogenesis under standard or enriched rearing conditions. Rearing in the enriched conditions from 4-weeks old for 4-weeks increased the survival of newly divided cells in the subgranular zone and granule cell layer of the dentate gyrus of wild-type and PACAP-knockout (PACAP-/-) mice. The increase in the survival in the granule cell layer was less in PACAP-/- mice than in the wild type mice. In contrast, the proliferation of newly divided cells in mice reared in the standard and enriched conditions did not differ between the wild-type and PACAP-/- mice. Regarding the differentiation of newborn cells in the dentate gyrus, most of the newly divided cells exhibited the neuronal phenotype in both the wild-type and PACAP-/- mice under standard and enriched conditions. These findings suggest that endogenous PACAP is partly involved in the survival of the enriched environment-induced generation, but not in the basal rate, of newborn cells in the dentate gyrus of the adult hippocampus. PMID- 20974228 TI - Selective knockdown of NMDA receptors in primary afferent neurons decreases pain during phase 2 of the formalin test. AB - The role of NMDA receptors (NMDARs) expressed by primary afferent neurons in nociception remains controversial. The aim of this study was to develop mice with a tissue selective knockdown of NMDARs in these neurons and to evaluate their behavioral responses to different types of painful stimuli. Mice with floxed NMDAR NR1 subunit gene (fNR1) were crossed with mice expressing Cre recombinase under the control of the peripherin promotor (Prph-Cre). Male Prph-Cre+ floxed NR1 mice were compared to Cre- littermates. Both quantitative RT/PCR and Western blotting indicated a ~75% reduction in NR1 expression in dorsal root ganglia (DRG) extracts with no effect on NR1 expression in spinal cord, brain or the enteric nervous system. Immunocytochemistry with antibodies to NR1 revealed decreased staining in all size classes of DRG neurons. NMDA produced a detectable increase in [Ca2+]i in 60% of DRG neurons cultured from Cre- mice, but only 15% of those from Cre+ mice. Furthermore, the peak [Ca2+]i responses were 64% lower in neurons from Cre+ mice. There was no significant difference between Cre+ and Cre- mice in response latencies to the hotplate or tail withdrawal tests of thermal nociception, nor was there a difference in withdrawal thresholds to mechanical stimuli of the tail or paw. However, compared to Cre- littermates, Cre+ knockdown mice had a 50% decrease in the phase 2 response to formalin injection (P<0.001). There was no effect on phase 1 responses. These results suggest that NMDA receptors expressed by primary afferent nerves play an important role in the development of sensitized pain states. PMID- 20974229 TI - Morphological and electrophysiological characteristics of neurons within identified subnuclei of the lateral habenula in rat brain slices. AB - Based on the specificity of its inputs and targets, the lateral habenular complex (LHb) constitutes a pivotal motor-limbic interface implicated in various cerebral functions particularly in regulating monoamine transmission. Despite its functional significance, cellular characteristics underlying LHb functionality have not been examined systematically. The present study aimed to correlate morphological and electrophysiological properties of neurons within the different subnuclei of the LHb using whole-cell recording and neurobiotin labeling in rat slice preparations. Morphological analysis revealed a heterogeneous population of projection neurons randomly distributed throughout the LHb. According to somatodendritic characteristics four main categories were classified including spherical, fusiform, polymorphic and vertical cells. Electrophysiological characterization of neurons within the different categories demonstrated homologous profiles and no significant differences between groups. Typically, LHb neurons possessed high input resistances and long membrane time constants. They also displayed time-dependent inward rectification and distinct afterhyperpolarization. A salient electrophysiological feature of LHb neurons was their ability to generate rebound bursts of action potentials in response to membrane hyperpolarization. Based on the pattern of spontaneous activity, neurons were classified as silent, tonic or bursting. The occurrence of distinctive firing modes was not related to topographic allocation. The patterns of spontaneous firing and evoked discharge were highly sensitive to alterations in membrane potential and merged upon de- and hyperpolarizing current injection and synaptic stimulation. Besides projection neurons, recordings revealed the existence of a subpopulation of cells possessing morphological and physiological properties of neocortical neurogliaform cells. They were considered to be interneurons. Our data suggest that neurons within the different LHb subnuclei behave electrophysiologically more similar than expected, considering their morphological heterogeneity. We conclude that the formation of functional neuronal entities within the LHb may be achieved through defined synaptic inputs to particular neurons, rather than by individual neuronal morphologies and intrinsic membrane properties. PMID- 20974230 TI - Altered adrenergic receptor signaling following traumatic brain injury contributes to working memory dysfunction. AB - The prefrontal cortex is highly vulnerable to traumatic brain injury (TBI) and its structural and/or functional alterations as a result of TBI can give rise to persistent working memory (WM) dysfunction. Using a rodent model of TBI, we have described profound WM deficits following TBI that are associated with increases in prefrontal catecholamine (both dopamine and norepinephrine) content. In this study, we examined if enhanced norepinephrine signaling contributes to TBI associated WM dysfunction. We demonstrate that administration of alpha1 adrenoceptor antagonists, but not alpha2A agonist, at 14 days post-injury significantly improved WM performance. mRNA analysis revealed increased levels of alpha1A, but not alpha1B or alpha1D, adrenoceptor in the medial prefrontal cortex (mPFC) of brain-injured rats. As alpha1A and 1B adrenoceptor promoters contain putative cAMP response element (CRE) sequences, we therefore examined if CRE binding protein (CREB) actively engages these sequences in order to increase receptor gene transcription following TBI. Our results show that the phosphorylation of CREB is enhanced in the mPFC at time points during which increased alpha1A mRNA expression was observed. Chromatin immunoprecipitation (ChIP) assays using mPFC tissue from injured animals indicated increased phospho CREB binding to the CRE sites of alpha1A, but not alpha1B, promoter compared to that observed in uninjured controls. To address the translatability of our findings, we tested the efficacy of the FDA-approved alpha1 antagonist Prazosin and observed that this drug improves WM in injured animals. Taken together, these studies suggest that enhanced CREB-mediated expression of alpha1 adrenoceptor contributes to TBI-associated WM dysfunction, and therapies aimed at reducing alpha1 signaling may be useful in the treatment of TBI-associated WM deficits in humans. PMID- 20974231 TI - GABAergic transmission modulates ethanol excitation of ventral tegmental area dopamine neurons. AB - Activation of the dopaminergic (DA) neurons of the ventral tegmental area (VTA) by ethanol has been implicated in its rewarding and reinforcing effects. We previously demonstrated that ethanol enhances GABA release onto VTA-DA neurons via activation of 5-HT2C receptors and subsequent release of calcium from intracellular stores. Here we demonstrate that excitation of VTA-DA neurons by ethanol is limited by an ethanol-enhancement in GABA release. In this study, we performed whole-cell voltage clamp recordings of miniature inhibitory postsynaptic currents (mIPSCs) and cell-attached recordings of action potential firing from VTA-DA neurons in midbrain slices from young Long Evans rats. Acute exposure to ethanol (75 mM) transiently enhanced the firing rate of VTA-DA neurons as well as the frequency of mIPSCs. Simultaneous blockade of both GABA(A) and GABA(B) receptors (Picrotoxin (75 MUM) and SCH50911 (20 MUM)) disinhibited VTA-DA firing rate whereas a GABA(A) agonist (muscimol, 1 MUM) strongly inhibited firing rate. In the presence of picrotoxin, ethanol enhanced VTA-DA firing rate more than in the absence of picrotoxin. Additionally, a sub-maximal concentration of muscimol together with ethanol inhibited VTA-DA firing rate more than muscimol alone. DAMGO (3 MUM) inhibited mIPSC frequency but did not block the ethanol enhancement in mIPSC frequency. DAMGO (1 and 3 MUM) had no effect on VTA-DA firing rate. Naltrexone (60 MUM) had no effect on basal or ethanol-enhancement of mIPSC frequency. Additionally, naltrexone (20 and 60 MUM) did not block the ethanol-enhancement in VTA-DA firing rate. Overall, the present results indicate that the ethanol enhancement in GABA release onto VTA-DA neurons limits the stimulatory effect of ethanol on VTA-DA neuron activity and may have implications for the rewarding properties of ethanol. PMID- 20974232 TI - Characterization of behavioural responses in different test contexts after a single social defeat in male golden hamsters (Mesocricetus auratus). AB - The objective of the present study was to characterize behavioural responses of male hamsters in each of three test contexts after they had experienced either a single social defeat or a neutral encounter. In experiment 1, hamsters were observed in a familiar social context (i.e., their home cages), and defeated males displayed different amounts of time and submissive behaviours towards a known opponent than a novel intruder, whereas males in the neutral-encounter groups did not show such differences. In experiment 2, in an unfamiliar social context (i.e., a Y-maze), defeated males generated submissive behaviours and fear memory towards a known opponent that they re-encountered 5-min and 24-h after the defeat. The formation of long-term memory was interrupted by an injection of anisomycin (210 mg/kg). In experiment 3, in a non-social, anxiogenic context, hamsters that had previously had different social experiences did not demonstrate additional anxiety in an elevated plus-maze, with the exception of males that had previously experienced repeated social defeats. Our data suggested that hamsters' behavioural changes following defeat are context-dependent and stimulus-specific. The experience of a single social defeat is sufficient to regenerate submissive behaviours and fear memory when reencountering a known opponent. PMID- 20974233 TI - Effects of early weaning on the circadian rhythm and behavioral satiety sequence in rats. AB - The objective of this work was to study the effect of early weaning on circadian rhythm and the behavioral satiety sequence in adult rats. Male Wistar rat pups were weaned for separation from the mother at 15 (D15), 21 (D21) and 30 (D30) days old. Body weight and food intake was measured every 30 days until pups were 150 days old. At 90 days of age, the circadian rhythm of food intake was evaluated every 4h for three days. Behavioral satiety was evaluated at 35 and 100 days of age. This work demonstrated that body weight and food intake were not altered, but the behavioral satiety sequence demonstrated that the D15 group delayed satiety compared with the D30 group at 100 days of age. In the circadian rhythm of the food intake study, early weaning (D15) changed food intake in the intermediary period of the light phase and in the intermediary period of the dark phase. In conclusion, our study showed that early weaning may alter the feeding behavior mainly in relation to satiety and the circadian rhythm of feeding. It is possible that the presence of other environmental stimuli during early weaning can cause hyperphagia and deregulate the mechanisms of homeostasis and body weight control. This study supports theories that depict insults during early life as determinants of chronic diseases. PMID- 20974234 TI - Pavlovian conditioning: pigeon nictitating membrane. AB - A new Pavlovian conditioning preparation was developed using the nictitating membrane of the restrained pigeon. Either visual or auditory stimuli served as conditioned stimuli (CSs) with an unconditioned stimulus (US) of a puff of air to the cornea. Movement of the nictitating membrane constituted the conditioned and unconditioned responses (CR and UR). Conditioning was studied with the Kamin blocking procedure. In agreement with findings from other conditioning preparations, responding to the redundant stimulus was attenuated relative to a stimulus that received the same number of CS-US pairings in a compound conditioning procedure. Although response attenuation occurred, substantial individual variation was observed within the blocking procedure, a finding with some precedent in the experimental literature. Theoretical analysis and neural network simulations indicate that inter-subject variation in response attenuation may result from differences in the extent to which contextual stimuli contribute to the functional CS. PMID- 20974235 TI - The metabolism of olaquindox in rats, chickens and pigs. AB - Olaquindox is a growth-promoting feed additive for food-producing animals. Its toxicities were reported to be closely related to the metabolism. To provide the interpretation of toxicities in animals, this study explored the metabolism of olaquindox in rats, chickens and pigs of different genders by qualitative metabolite profiling. Animals were fed olaquindox in an oral dose, and then their urine, plasma, feces, liver, kidney and muscle were collected. Liquid chromatography combined with hybrid ion trap/time-of-flight mass spectrometry was used for structural investigation and identification of metabolites. The structures of metabolites were elucidated based on the accurate MS2 spectra and comparison of their changes in accurate molecular masses and fragment ions with those of parent drug or metabolite. A total of 18, 18 and 16 metabolites of rats, chickens and pigs were identified, respectively. Among the identified metabolites, 8 known metabolites were confirmed as an early study had stated, and 15 metabolites were found for the first time in vivo. The major metabolic pathways of olaquindox were proposed to be N-O reduction and oxidation of hydroxyl to carboxylic acid followed by N-O reduction. The qualitative species difference on the metabolite profiles of olaquindox among the three species was observed. However, metabolite profiles of olaquindox appeared to be qualitatively similar between female and male for the same species. The proposed metabolic pathways of olaquindox in animals will provide comprehensive data to clarify the metabolism of olaquindox among different species, and will give scientific explanation for toxicities and residues of olaquindox. PMID- 20974236 TI - Polyvalent catanionic vesicles: exploring the drug delivery mechanisms. AB - Among drug delivery systems, catanionic vesicles now appear as powerful candidates for pharmaceutical applications because they are relatively cheap and easy to use, thus well corresponding to industrial requirements. Using labelled vesicles made of a tricatenar catanionic surfactant, the work reported here aims at exploring the mechanisms by which internalisation into a cell occurs. The study was performed on various cell types such as phagocytic as well as non phagocytic cells using confocal laser scanning microscopy and flow cytometry. Using various inhibitors, endocytosis and also a passive process, as probably fusion, were highlighted as interaction phenomena between catanionic vesicles and cell membranes. Finally, the interaction modelled with giant liposomes as membrane models confirmed the hypothesis of the occurrence of a fusion phenomenon between the nanovectors and cell membranes. This process highlights the potential of catanionic vesicles for a future pharmaceutical application as a universal drug delivery system. PMID- 20974237 TI - Analysis of lipid nanoparticles by Cryo-EM for characterizing siRNA delivery vehicles. AB - Lipid nanoparticles are self-assembling, dynamic structures commonly used as carriers of siRNA, DNA, and small molecular therapeutics. Quantitative analysis of particle characteristics such as morphological features can be very informative as biophysical properties are known to influence biological activity, biodistribution, and toxicity. However, accurate characterization of particle attributes and population distributions is difficult. Cryo-Electron Microscopy (Cryo-EM) is a leading characterization method and can reveal diversity in particle size, shape and lamellarity, however, this approach is traditionally used for qualitative review or low throughput image analysis due to inherent EM micrograph contrast characteristics and artifacts in the images which limit extraction of quantitative feature values. In this paper we describe the development of a semiautomatic image analysis framework to facilitate reliable image enhancement, object segmentation, and quantification of nanoparticle attributes in Cryo-EM micrographs. We apply this approach to characterize two formulations of siRNA-loaded lipid nanoparticles composed of cationic lipid, cholesterol, and poly(ethylene glycol)-lipid, where the formulations differ only by input component ratios. We found Cryo-EM image analysis provided reliable size and morphology information as well as the detection of smaller particle populations that were not detected by standard dynamic light scattering (DLS) analysis. PMID- 20974238 TI - Sodium carboxymethylcellulose scaffolds and their physicochemical effects on partial thickness wound healing. AB - This study investigated critical physicochemical attributes of low (LV), medium (MV) and high molecular weight (HV) sodium carboxymethylcellulose (SCMC) scaffolds in partial thickness wound healing. SCMC scaffolds were prepared by solvent-evaporation technique. Their in vitro erosion, moisture affinity, morphology, tensile strength, polymer molecular weight and carboxymethyl substitution, and in vivo wound healing profiles were determined. Inferring from rat wound size, re-epithelialization and histological profiles, wound healing progressed with HV scaffold>LV-MV scaffold>control with no scaffold. The transepidermal water loss (TEWL) from wound of rats treated by control>HV scaffold>LV-MV scaffold. HV scaffold had the highest tensile strength of all matrices and was resistant to erosion in simulated wound fluid. In spite of constituting small nanopores, it afforded a substantial TEWL than MV and LV scaffolds from wound across an intact matrix through its low moisture affinity characteristics. The HV scaffold can protect moisture loss without its excessive accumulation at wound bed which hindered re-epithelialization process. Regulation of transepidermal water movement and wound healing by scaffolds was governed by SCMC molecular weight instead of its carboxymethyl substitution degree or matrix pore size distribution, with large molecular weight HV preferred over lower molecular weight samples. PMID- 20974239 TI - Antitumor efficacy of solid dispersion of paclitaxel prepared by supercritical antisolvent process in human mammary tumor xenografts. AB - The efficacy of intravenous chemotherapy for breast cancer has been improving with newer agents. However, the fractional improvements in breast cancer progression-free survival were quite modest and these small gains are obtained at the cost of significant toxicity. To address this problem, paclitaxel solid dispersion (PSD), a Cremophor EL-free formulation prepared by supercritical antisolvent process using hydrophilic polymers as carrier, was developed to avoid Cremophor EL-associated toxicities in Taxol((r)). In this study, we investigated the antitumor activity of PSD as a function of dose from 12 to 24mg/kg (dose effect) and compared antitumor activity of 18mg/kg dose of PSD to that of Taxol((r)) (relative efficacy) in female athymic mice bearing mammary tumor xenografts. In dose-effect study, PSD showed excellent activity and good tolerance at all doses tested with a significant increase in tumor growth inhibition, recurrence time, survival percent, and number of tumor free survivors compared to control (P<0.01). In all of the four doses tested in this study, the magnitude of the increase in effectiveness of PSD was quite substantial and statistically significant with similar degrees of weight loss. In relative efficacy study of PSD and Taxol((r)), PSD demonstrated a greater degree of tumor growth inhibition with 10 complete tumor regressions (100%) and eight tumor-free survivors (80% cure). Besides, mice treated with PSD regained their initial body weight by day 27 following initial acute weight reductions, whereas mice treated with Taxol((r)) required more than 40 days to regain their initial weight. In conclusion, PSD prepared by supercritical process was very effective and safe, without Cremophor EL-associated toxicities of Taxol((r)), in human mammary tumor xenografts with possibilities of dose escalation. PMID- 20974240 TI - Determination of acetaminophen's solubility in poly(ethylene oxide) by rheological, thermal and microscopic methods. AB - A drug's solubility in a polymeric excipient is an important parameter that dictates the process window of hot-melt extrusion (HME) and product stability during storage. However, it is rather challenging to experimentally determine the solubility and there is very few published work in this field. In this study, the solubility of a model drug acetaminophen (APAP) in a pharmaceutical grade polymer poly(ethylene oxide) (PEO) at HME processing temperature was measured utilizing rheological analysis, hot-stage microscopy and differential scanning calorimetry (DSC). The results from three methods were consistent and the solubility was found to increase from 14% at 80 degrees C to 41% at 140 degrees C. The apparent drug solubility at room temperature was estimated to be less than 10% through glass transition temperature (T(g)) measurement using DSC and dynamic mechanical thermal analysis (DMTA). A "phase diagram" was constructed based on the experimental data and could be explored to design the HME process and formulation. Very few assumptions were made in the experimental study and result analysis, and the methods described here can be applied to investigate other drug polymer systems to obtain the important thermodynamic data. PMID- 20974241 TI - Anti-atherogenic effect of San-Huang-Xie-Xin-Tang, a traditional Chinese medicine, in cultured human aortic smooth muscle cells. AB - AIM OF THE STUDY: San-huang-xie-xin-tang (SHXXT) is a traditional Chinese medicine and it has been shown to have an anti-inflammatory effect. Since inflammation is one of the major mechanisms of atherosclerosis, we aimed to investigate anti-atherosclerotic effect of SHXXT in human aortic smooth muscle cells (HASMCs). MATERIALS AND METHODS: Human aortic smooth muscle cells (HASMCs) were used in the present study, and rendered atherosclerosis by adding lipopolysaccharides. We first tested the effects of SHXXT on HASMC migration and proliferation as they present the major morphological change of atherosclerosis. We also examined whether SHXXT can influence the production of several biomarkers of inflammation and atherosclerosis including reactive oxygen species (ROS), COX 2, ERK1/2, IL-1beta, IL-6, IL-8 and MCP-1. RESULTS: Using the dimethyl-thiazol diphenyltetrazoliumbromide (MTT) and wound repair assay, SHXXT was shown to significantly reduce HASMC proliferation and migration, respectively. From the fluorometric assay, SHXXT significantly reduced ROS production. SHXXT down regulated mRNA and protein levels for the COX-2 gene. In addition, phosphorylated ERK1/2 levels were suppressed by SHXXT suggesting HASMC division can be inhibited under pro-inflammatory condition. SHXXT significantly inhibited the production of IL-1beta, IL-6, IL-8 and MCP-1 after LPS stimulation. CONCLUSIONS: Our results indicated that SHXXT can influence several mechanisms involved in atherosclerosis, which suggests that SHXXT may have a therapeutic potential for cardiovascular disease associated with atherosclerosis. PMID- 20974242 TI - Minor physical anomalies: potentially informative vestiges of fetal developmental disruptions in schizophrenia. AB - Minor physical anomalies (MPAs) are subtle signs of developmental deviation that are observed at an elevated frequency among patients with schizophrenia. These minor morphological abnormalities of the craniofacial region and limbs arise during fetal development and represent a set of risk markers for schizophrenia. Although MPAs are not specific to schizophrenia, established findings about MPAs vis-a-vis schizophrenia include the replicated findings that MPAs are more prevalent among individuals with schizophrenia than healthy controls, MPAs are more prevalent among individuals with schizophrenia than unaffected relatives, and MPAs are not consistently associated with symptom domains or other risk markers, such as neurological soft signs. Unresolved questions include whether or not MPAs are more prevalent among unaffected relatives than healthy controls, and which specific MPAs are most associated with schizophrenia. This overview presents three promising avenues of further research on MPAs, including: (1) studies relying on traditional summary scores that combine multiple MPAs, which may have a role in prospective risk stratification in conjunction with other risk markers and endophenotypes; (2) research on specific, quantitatively assessed MPAs (especially in specific craniofacial structures) that may inform neurodevelopmental understandings of schizophrenia; and (3) genetic studies aimed at identifying the heritable and nonheritable determinants of specific MPAs, which may increase the field's understanding of the origins of MPAs and the nature of their association with schizophrenia. PMID- 20974243 TI - OMiR: Identification of associations between OMIM diseases and microRNAs. AB - A large number of loci for genetic diseases have been mapped on the human genome and a group of hereditary diseases among them have thus far proven unsuccessful to clone. It is conceivable that such "unclonable" diseases are not linked to abnormalities of protein coding genes (PCGs), but of non-coding RNAs (ncRNAs). We developed a novel approach termed OMiR (OMIM and miRNAs), to test whether microRNAs (miRNAs) exhibit any associations with mapped genetic diseases not yet associated with a PCG. We found that "orphan" genetic disease loci were proximal to miRNA loci more frequently than to loci for which the responsible protein coding gene is known, thus suggesting that miRNAs might be the elusive culprits. Our findings indicate that inclusion of miRNAs among the candidate genes to be considered could assist geneticists in their hunt for disease genes, particularly in the case of rare diseases. PMID- 20974244 TI - Genomic damage in the progression of chronic kidney disease in rats. AB - Patients with chronic renal failure exhibit massive oxidative genome damage and an elevated risk of cancer. Previous studies have demonstrated the relationship between DNA damage and carcinogenesis. The current study aimed to investigate whether the progression of chronic kidney disease induces genomic damage in an animal model. Adult Wistar rats were assigned to either the control or chronic kidney disease groups. The chronic kidney disease group was subdistributed into five groups with progressively longer durations of disease (30, 60, 90, 120 and 150 days). The results showed that chronic kidney disease induced genomic damage in the blood, liver and kidney cells during all periods evaluated, as indicated by the mean tail moment measured in the comet assay. In brain cells, no genetic damage was induced at early/intermediate disease durations; however, positive genotoxicity was found at 120 and 150 days. Blood pressure and pro-inflammatory cytokine levels (IL-1alpha, IL-1beta, IL-6 and TNFalpha) were increased after chronic kidney disease induction, while blood iron concentration was significantly reduced in these animals. The results suggest that chronic kidney disease progression contributes to DNA damage in blood, liver, kidney and brain and that such damage can be mediated by hypertension, an inflammatory status and iron deficiency. Additionally, the brain was sensitive to genotoxic insult after extended chronic kidney disease, suggesting a potentially important role of genetic damage in the neurological disorders of end-stage renal patients. PMID- 20974245 TI - Attenuation of the cytotoxic T lymphocyte response to lymphocytic choriomeningitis virus in mice subjected to chronic social stress. AB - Chronic stress is suspected to increase the susceptibility to infections but experimental evidence from physiological stress models is scarce. We examined the effects of chronic social stress on virus-specific CTL responses in mice after infection with lymphocytic choriomeningitis virus (LCMV). Mice subjected to social stress on six consecutive days prior to infection showed a significant reduction of IFN-gamma producing T(CD8+) splenocytes and markedly lowered plasma concentrations of IFN-gamma. In contrast, the generation of LCMV-specific CTL responses was not altered in mice undergoing the same stress procedure concurrently with infection. Furthermore, stress exposure 6 days before and additional 3 days after LCMV infection profoundly reduced the expansion of T(CD8+) cells in the spleen, due to diminished in vivo proliferation. Pharmacological blockade of glucocorticoid receptors completely abrogated the stress-associated decline of T(CD8+) expansion. Stressed mice showed a significantly reduced expression of the early T-cell activation marker CD69 as well as impaired in vitro cytokine secretion of IFN-gamma and IL-2. Additionally, social stress led to an altered migration capacity of T(CD8+) cells as demonstrated by adoptive T cell transfer experiments. Taken together, this study shows that chronic social stress fundamentally suppresses the functional capacities of T cells during a viral infection. PMID- 20974246 TI - An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury. AB - Morphine is one of the most commonly prescribed medications for the treatment of chronic pain after a spinal cord injury (SCI). Despite widespread use, however, little is known about the secondary consequences of morphine use after SCI. Unfortunately, our previous studies show that administration of a single dose of morphine, in the acute phase of a moderate spinal contusion injury, significantly attenuates locomotor function, reduces weight gain, and produces symptoms of paradoxical pain (Hook et al., 2009). The current study focused on the cellular mechanisms that mediate these effects. Based on data from other models, we hypothesized that pro-inflammatory cytokines might play a role in the morphine induced attenuation of function. Experiment 1 confirmed that systemic morphine (20 mg/kg) administered one day after a contusion injury significantly increased expression levels of spinal IL-1beta 24 h later. Experiment 2 extended these findings, demonstrating that a single dose of morphine (90 MUg, i.t.) applied directly onto the spinal cord increased expression levels of spinal IL-1beta at both 30 min and 24 h after administration. Experiment 3 showed that administration of an interleukin-1 receptor antagonist (IL-1ra, i.t.) prior to intrathecal morphine (90 MUg), blocked the adverse effects of morphine on locomotor recovery. Further, pre-treatment with 3 MUg IL-1ra prevented the increased expression of at-level neuropathic pain symptoms that was observed 28 days later in the group treated with morphine-alone. However, the IL-1ra also had adverse effects that were independent of morphine. Treatment with the IL-1ra alone undermined recovery of locomotor function, potentiated weight loss and significantly increased tissue loss at the injury site. Overall, these data suggest that morphine disrupts a critical balance in concentrations of pro inflammatory cytokines in the spinal cord, and this undermines recovery of function. PMID- 20974247 TI - Interactions between chemokine and mu-opioid receptors: anatomical findings and electrophysiological studies in the rat periaqueductal grey. AB - Opioids have immunomodulatory functions and may alter susceptibility to immune disorders. Behavioral studies also indicate that chemokines, molecules expressed by immune cells, block opioid-induced analgesia in the periaqueductal grey (PAG). Bi-directional heterologous desensitization of opioid and chemokine receptors has been described in cell systems. We report the anatomical and functional interactions of chemokine receptors with the mu-opioid receptor (MOR) in the rat brain. The chemokine receptors, CXCR4 and CX3CR1, as well as their chemokine substrates, CXCL12 and CX3CL1, are widely expressed in the central nervous system (CNS). Immunohistochemical techniques were utilized to investigate MOR-CXCR4 and MOR-CX3CR1 receptor colocalization in multiple brain areas. Our results demonstrate co-expression of these receptors on individual neurons in several regions including cingulate cortex, hippocampus, and PAG, suggesting functional receptor interactions. Whole-cell patch-clamp recordings of PAG neurons in a rat brain slice preparation were used to examine morphine or chemokine (CXCL12, CX3CL1) effects alone, or in combination on neuronal membrane properties. Morphine (10 MUM) hyperpolarized and reduced input resistance of PAG neurons. CXCL12 and CX3CL1 (10 nM) had no impact on either parameter. In the presence of CXCL12, morphine's electrophysiological effects were blocked in all neurons examined, whereas with CX3CL1, morphine's effects were blocked in 57% of neurons studied. The data provide electrophysiological evidence for MOR-CXCR4 and MOR CX3CR1 heterologous desensitization in the PAG at the single-cell level. These interactions may contribute to the limited utility of opioid analgesics for inflammatory pain treatment and supports chemokines as neuromodulators. PMID- 20974248 TI - Both MHC and non-MHC genes regulate inflammation and T-cell response after traumatic brain injury. AB - Genetic regulation of autoimmune neuroinflammation is a well known phenomenon, but genetic influences on inflammation following traumatic nerve injuries have received little attention. In this study we examined the inflammatory response in a rat traumatic brain injury (TBI) model, with a particular focus on major histocompatibility class II (MHC II) presentation, in two inbred rat strains that have been extensively characterized in experimental autoimmune encephalomyelitis (EAE); DA and PVG. In addition, MHC and Vra4 congenic strains on these backgrounds were studied to give information on MHC and non-MHC gene contribution. Thus, allelic differences in Vra4, harboring the Ciita gene, was found to regulate expression of the invariant chain at the mRNA level, with a much smaller effect exerted by the MHC locus itself. Notably, however, at the protein level the MHC congenic PVG-RT1(av1) strain displayed much stronger MHCII(+) presentation, as shown both by immunolabeling and flow cytometry, than the PVG strain, dwarfing the effect of Ciita. The PVG-RT1(av1) strain had significantly more T-cell influx than both DA and PVG, suggesting regulation both by MHC and non-MHC genes. Finally, in terms of outcome, the EAE susceptible DA strain displayed a significantly smaller resulting lesion volume than the resistant PVG-RT1(av1) strain. These results provide additional support for a role of adaptive immune response after neurotrauma and demonstrate that outcome is significantly affected by host genetic factors. PMID- 20974249 TI - CHIP-dependent p53 regulation occurs specifically during cellular senescence. AB - p53 regulates several biological processes, including senescence. Its protein stability is regulated by ubiquitination and proteasomal degradation, mainly mediated by Mdm2. However, other E3 ligases have been identified, such as the chaperone-associated ligase CHIP, although their precise function regarding p53 degradation remains elusive. Interestingly, CHIP deficiency has been recently shown to result in accelerated aging in mice, although the molecular basis of this phenotype was not completely understood. In this study, we explore the role of CHIP in regulating p53 in senescence. We demonstrate that in senescent human fibroblasts, CHIP is up-regulated concomitant with a significant down-regulation of p53. Moreover, CHIP partially translocates to the nucleus and acquires higher ubiquitination levels in senescent cells. Notably, CHIP overexpression in young cells, to levels similar to those recorded during senescence, leads to p53 degradation to below its basal levels. In addition, whereas CHIP silencing has no effect on p53 stability in young cells, a considerable p53 accumulation occurs in their senescent counterparts. Finally, we have observed an attenuation of the CHIP-associated molecular folding-refolding machinery during senescence, and supportively, inhibition of Hsp90 activity leads to rapid p53 degradation only in senescent cells. Taking these results together, we conclude that CHIP-dependent p53 regulation occurs specifically during senescence. PMID- 20974250 TI - 4-O-Methylhonokiol attenuates memory impairment in presenilin 2 mutant mice through reduction of oxidative damage and inactivation of astrocytes and the ERK pathway. AB - Presenilin 2 (PS2) mutation increases Abeta generation and neuronal cell death in the brains of Alzheimer disease (AD) patients. In a previous study, we showed that increased oxidative damage and activation of extracellular signal-regulated kinase (ERK) were associated with Abeta generation and neuronal cell death in neuronal cells expressing mutant PS2. In this study, we show that oral treatment with 4-O-methylhonokiol, a novel compound isolated from Magnolia officinalis, for 3 months (1.0mg/kg) prevented PS2 mutation-induced memory impairment and neuronal cell death accompanied by a reduction in Abeta(1-42) accumulation. We also found that 4-O-methylhonokiol inhibited PS2 mutation-induced activation of ERK and beta secretase, and oxidative protein and lipid damage, but recovered glutathione levels in the cortex and hippocampus of PS2 mutant mice. Additionally, 4-O methylhonokiol prevented PS2 mutation-induced activation of astrocytes as well as production of TNF-alpha, IL-1beta, reactive oxygen species (ROS), and nitric oxide (NO) in neurons. Generation of TNF-alpha, IL-1beta, ROS, and NO and ERK activation in cultured astrocytes treated with lipopolysaccharide (1MUg/ml) were also prevented by 4-O-methylhonokiol in a dose-dependent manner. These results suggest that the improving effects of 4-O-methylhonokiol on memory function may be associated with a suppression of the activation of ERK and astrocytes as well as a reduction in oxidative damage. Thus, 4-O-methylhonokiol may be useful in the prevention and treatment of AD. PMID- 20974251 TI - Selective macrophage ascorbate deficiency suppresses early atherosclerosis. AB - To test whether severe ascorbic acid deficiency in macrophages affects progression of early atherosclerosis, we used fetal liver cell transplantation to generate atherosclerosis-prone apolipoprotein E-deficient (apoE(-/-)) mice that selectively lacked the ascorbate transporter (SVCT2) in hematopoietic cells, including macrophages. After 13 weeks of chow diet, apoE(-/-) mice lacking the SVCT2 in macrophages had surprisingly less aortic atherosclerosis, decreased lesion macrophage numbers, and increased macrophage apoptosis compared to control transplanted mice. Serum lipid levels were similar in both groups. Peritoneal macrophages lacking the SVCT2 had undetectable ascorbate; increased susceptibility to H(2)O(2)-induced mitochondrial dysfunction and apoptosis; decreased expression of genes for COX-2, IL1beta, and IL6; and decreased lipopolysaccharide-stimulated NF-kappaB and antiapoptotic gene expression. These changes were associated with decreased expression of both the receptor for advanced glycation end products and HIF-1alpha, either or both of which could have been the proximal cause of decreased macrophage activation and apoptosis in ascorbate-deficient macrophages. PMID- 20974252 TI - Tapioca starch graft copolymers and Dome Matrix(r) modules II. Effect of modules assemblage on riboflavin release kinetics. AB - This paper studies the Riboflavin release from systems made of assembled modules of Dome Matrix(r) technology using tapioca starch-ethylmethacrylate (TSEMA) and tapioca hydroxypropylstarch-ethylmethacrylate (THSEMA) graft copolymers produced by two different drying methods. Two different shape modules were manufactured for this study, i.e., female and male modules, in order to facilitate their assemblage in "void configuration", a system with an internal void space. Drug release studies on void configurations based on THSEMA show faster releases than TSEMA; HPMC systems used as a comparative reference showed intermediate release. Moreover, using void configurations made with one module of TSEMA and the other of THSEMA is possible to average the drug release, without difference between the drying methods used for the polymers. With respect to the floatation characteristics, all the void configurations floated immediately and, due to the mass center of the system, the floatation position of the system was always axial with the female module up and the male down. The drug release studies performed with a sinker to force the immersion of the systems in the medium did not show differences with respect to the dissolution test without a sinker. The combination of floatation capability of the assembled modules and the prolonged drug release provided with the graft copolymers make these assembled modules candidates as controlled release gastro-retentive dosage forms. PMID- 20974253 TI - Nanostructure-loaded mesoporous silica for controlled release of coumarin derivatives: a novel testing of the hyperthermia effect. AB - The synthesis of three types of mesoporous materials is reported: pure mesoporous silica (MCM-41), a nanocomposite of mesoporous silica with hydroxyapatite (MCM-41 HA) and mesoporous silica/gold nanorods nanocomposite (MCM-41-GNRs). The mesoporous materials were characterized by X-ray diffraction, N(2) adsorption isotherms, FTIR spectroscopy, transmission electron microscopy, and scanning electron microscopy. The samples were loaded with coumarin thiourea derivatives (I-IV) having functional groups of varying sizes and the in vitro release assays were monitored, and the release behavior was investigated as a function of soaking time in simulated body fluid. Two release stages were obtained in MCM-41, MCM-41-HA and MCM-41-GNRs loaded samples with the early release stages accounting for about 30% of loaded derivatives. These early release stages are characterized by Higuchi rate constant values nearly twice the values associated with the second release stages. The influence of substituent size on the release rate constants was explained in terms of sorption sites and hydrogen bonding with silanol groups on silicates. The release of coumarin derivatives loaded on MCM 41, MCM-41-HA and MCM-41-GNRs occurs over remarkably long time of the order of about 260 h with faster release rates in loaded MCM-41 and MCM-41-GNRs samples compared with MCM-41-HA ones. The role of hyperthermia effect in enhancing release rates was investigated by subjecting loaded MCM-41-GNRs to near infrared (NIR) radiation at 800 nm. This would be of significance in targeted drug release using hyperthermia effect. Unlike hydroxyl apatite, loading MCM-41 with gold nanorods does not affect the release kinetics. Only when these samples are irradiated with NIR photons, does the release occur with enhanced rates. This property could be valuable in selected targeting of drugs. PMID- 20974254 TI - Association of the (TAAAA)n repeat and Asp327Asn polymorphisms in the sex hormone binding globulin (SHBG) gene with idiopathic male infertility and relation to serum SHBG concentrations. AB - Sex hormone binding globulin (SHBG) is involved in delivering sex hormones to target tissues. We investigated the association between the (TAAAA)n repeat polymorphism, and Asp327Asn polymorphism in the SHBG gene with semen quality and idiopathic male infertility. We studied 168 men with idiopathic infertility [oligoasthenoteratozoospermia (OAT)] and equal number of age-matched normal controls. The serum levels of SHBG, reproductive and thyroid hormones, and Inhibin B were measured. Semen parameters were also assessed. The genotype assays for the SHBG polymorphism were done using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. Baseline SHBG levels tended to be lower in infertile men (21.1+/-7.2nmol/l) compared to normal fertile men (24.7+/-7.9nmol/l). SHBG levels tended to be higher among the subjects with the Asn/Asn (25.84+/-3.6nmol/l) and S/S (24.50+/-5.4nmol/l) genotypes compared to subjects with the Asp/Asn (24.38+/-3.2nmol/l) and L/L (18.44+/-4.2nmol/l) genotypes of the SHBG gene. The genotype frequencies of Asp/Asp were 80.9% in cases and 71.4% in controls (P=0.001). The variant Asp/Asn genotype was associated with a more than 50% reduced risk of infertility (OR: 0.46, 95% CI: 0.25-0.80, P=0.001). Genotype analysis demonstrated six SHBG (TAAAA)n alleles with 6-11 repeats. Long SHBG (TAAAA)n alleles (>8 repeats) were at greater frequency in infertile men than fertile subjects (P=0.001), whereas short SHBG (TAAAA)n alleles (<=8 repeats) tended to be more frequent in fertile men than cases (P=0.001). Men with the 9/X TAAAA repeat genotype displayed a 2.82 fold increased risk of infertility (95% CI: 1.27-4.79, P=0.01). There were strong and significant positive correlations between plasma SHBG and sperm count (r=0.672, P=0.01), sperm motility (r=0.721, P=0.01) and sperm morphology (r=0.574, P=0.02). We concluded that the SHBG Asp237Asn and (TAAAA)n polymorphisms may influence SHBG levels and as a result, male infertility. Multicenter large scale studies are warranted to better elucidate the role of SHBG gene polymorphism in male infertility. PMID- 20974256 TI - NMR structure of the human Mediator MED25 ACID domain. AB - MED25 (ARC92/ACID1) is a 747 residues subunit specific to higher eukaryote Mediator complex, an essential component of the RNA polymerase II general transcriptional machinery. MED25 is a target of the Herpes simplex virus transactivator protein VP16. MED25 interacts with VP16 through a central MED25 PTOV (Prostate tumour overexpressed)/ACID (Activator interacting domain) domain of unknown structure. As a first step towards understanding the mechanism of recruitment of transactivation domains by MED25, we report here the NMR structure of the MED25 ACID domain. The domain architecture consists of a closed beta barrel with seven strands (Beta1-Beta7) and three alpha-helices (H1-H3), an architecture showing similarities to that of the SPOC (Spen paralog and ortholog C-terminal domain) domain-like superfamily. Preliminary NMR chemical shift mapping showed that VP16 H2 (VP16C) interacts with MED25 ACID through one face of the beta-barrel, defined by strands B4-B7-B6. PMID- 20974257 TI - Chromosomal dynamics of cell cycle regulator gene p21 during transcriptional activation. AB - The radial position of a gene within its chromosome territory (CT) in the interphase nucleus is thought to depend on the transcriptional activity of the gene and on transcriptional activity, gene density, and conformation of the chromosomal surrounding. In this study we analyzed the position of the cell cycle regulator gene p21 within the CT of human chromosome 6 (HSA6) upon transcriptional activation. Whereas the majority of active p21 genes is located in the interior of the CT of HSA6, induction of p21 transcription correlates with increased variation of gene localization within the CT and with a higher percentage of p21 genes located at the periphery of the CT. Additionally it demonstrates once more that transcription can take place throughout CTs. Comparison of the p21 locus with two non-coding regions on HSA6 showed that both non-coding sequences are located more frequently in the interior of the CT than p21 genes although they are situated in chromosomal neighborhoods with widely differing gene density and regional transcriptional activity. Thus our data support models describing an influence of the transcriptional activity of a gene on the localization within its CT. However, our data also indicate that additional factors such as chromatin remodeling are implicated in the positioning of genes within the respective chromosome territory. PMID- 20974255 TI - Apoptosis inducing factor deficiency causes reduced mitofusion 1 expression and patterned Purkinje cell degeneration. AB - Alteration in mitochondrial dynamics has been implicated in many neurodegenerative diseases. Mitochondrial apoptosis inducing factor (AIF) plays a key role in multiple cellular and disease processes. Using immunoblotting and flow cytometry analysis with Harlequin mutant mice that have a proviral insertion in the AIF gene, we first revealed that mitofusion 1 (Mfn1), a key mitochondrial fusion protein, is significantly diminished in Purkinje cells of the Harlequin cerebellum. Next, we investigated the cerebellar pathology of Harlequin mice in an age-dependent fashion, and identified a striking process of progressive and patterned Purkinje cell degeneration. Using immunohistochemistry with zebrin II, the most studied compartmentalization marker in the cerebellum, we found that zebrin II-negative Purkinje cells first started to degenerate at 7 months of age. By 11 months of age, almost half of the Purkinje cells were degenerated. Subsequently, most of the Purkinje cells disappeared in the Harlequin cerebellum. The surviving Purkinje cells were concentrated in cerebellar lobules IX and X, where these cells were positive for heat shock protein 25 and resistant to degeneration. We further showed that the patterned Purkinje cell degeneration was dependent on caspase but not poly(ADP-ribose) polymerase-1 (PARP-1) activation, and confirmed the marked decrease of Mfn1 in the Harlequin cerebellum. Our results identified a previously unrecognized role of AIF in Purkinje cell degeneration, and revealed that AIF deficiency leads to altered mitochondrial fusion and caspase-dependent cerebellar Purkinje cell loss in Harlequin mice. This study is the first to link AIF and mitochondrial fusion, both of which might play important roles in neurodegeneration. PMID- 20974258 TI - Molecular characterization of a Toll-like receptor 22 homologue in large yellow croaker (Pseudosciaena crocea) and promoter activity analysis of its 5'-flanking sequence. AB - Toll-like receptors (TLRs) are a family of innate immune receptors that recognize molecular patterns associated with microbial pathogens (PAMP), and induce antimicrobial immune responses. Here we report the molecular cloning and characterization of a TLR22 homologue from the large yellow croaker (LycTLR22), an economically important marine fish in China. The complete cDNA of LycTLR22 is 4607 nucleotides (nt) long, encoding a protein of 963 amino acids (aa). The deduced LycTLR22 has a typical TLR domain architecture including 18 leucine-rich repeats (LRRs) (residues 69-638) and one C-terminal LRR domain (residues 698-749) at the extracellular region, and a TIR domain (residues 805-948) in the cytoplasmic region. The three highly conserved regions among the family of bony fish were found in LycTLR22 (box 1, Y(806)DAFISY(812); box 2, L(837)C-RD-PG(846); box 3, W(938) surrounded by basic residue). The deduced LycTLR22 protein has 61.2%, 55.0%, 43.8%, 43.5%, 38.6% and 36.4% identity to Japanese flounder, fugu, Atlantic salmon, rainbow trout, zebrafish and goldfish TLR22, respectively. Genomic analysis showed that LycTLR22 gene consisted of four exons and three introns, which is similar to its homologue in Japanese flounder. The 5'-flanking region of LycTLR22 gene, containing several putative transcription factor binding sites and an interferon-sensitive response element (ISRE), exhibits promoter activity. LycTLR22 gene was constitutively expressed in anterior kidney, spleen, liver, heart, intestine and blood, but not in gills and muscle. Upon stimulation with poly (I:C), the LycTLR22 expression was obviously upregulated in anterior kidney and spleen tissues, and also in primary anterior kidney cells of large yellow croaker, suggesting a role for LycTLR22 in the immune response induced by poly (I:C). PMID- 20974259 TI - Transcriptional regulation of extracellular copper zinc superoxide dismutase from white shrimp Litopenaeus vannamei following Vibrio alginolyticus and WSSV infection. AB - The cDNA encoding an extracellular copper zinc superoxide dismutase (LvECSOD) was cloned from the hepatopancreas of white shrimp Litopenaeus vannamei. It consisted of 915 bp nucleotides with an open reading frame corresponding to a deduced protein of 178 amino acids. The LvECSOD contains a putative signal peptide of 16 amino acids, two potential N-linked glycosylation sites (N(115)GTA and N(135)ITG) and a copper zinc superoxide dismutase family signature sequence (G(162)NAGaRvACctI(173)). It was found that four copper binding sites, four zinc binding sites and two cysteines involving in the formation of the disulfide bridge were conserved in the protein. LvECSOD shared 33-58% identity to ECSODs from other organisms. Expression analysis revealed that LvECSOD mRNA was widely distributed in all the tissues examined. When the shrimp challenged with Vibrio alginolyticus or white spot syndrome virus (WSSV), expression of LvECSOD mRNA in the hepatopancreas and hemocytes was mediated responsively. Our results suggested that LvECSOD was implicated in the immune response induced by V. alginolyticus and WSSV. PMID- 20974261 TI - Effects of large-scale nonstationarity on parametric maps. A study of rest perfusion CASL data. AB - This study investigates the emergence of characteristic patterns in clusters thresholded at uncorrected significance levels, using as a case study rest perfusion images obtained with the continuous arterial spin labelling technique (CASL). The origin of these patterns is traced back to the existence of large scale spatial covariance, a violation of the stationarity assumption on the spatial distribution of residual errors. It is shown that in the presence of large-scale covariance, several principles or intuitions common among experimenters when evaluating the inferential strength of their analyses are not applicable. Thresholded maps and clusters are confounded by the spatial patterns of large-scale covariance, irrespective of the existence of a true effect, as shown in t maps constructed by resampling groups at random from a large pool of volumes. Filtering clusters according to their size made the problem worse, and corrections on cluster size based on random field theory models of smoothness had only a minor impact on their tendency to appear in characteristic locations. A formal analysis shows that the large-scale covariance at the origin of these problems is retained in the parametric map irrespective of sample size. Therefore, neither sample independence nor sample size protect from replications of effects being confounded by replications of the spatial covariance of residual errors. In contrast, cluster peaks were not affected by large-scale covariance but only by local differences in smoothness levels, as predicted by random field theory for the distribution of maxima, highlighting the different inferential robustness of cluster-based and maxima-based statistics. A framework is provided to generalize these results to mixed effects models with nested random effects, applicable also to activation studies. Large-scale nonstationarity is most problematic when the variance source at the origin of the characteristic patterns is not specific to a function or variable involved in the inferential process, as typically in observational studies of individual differences. These results raise the question of the existence and impact of large-scale nonstationarity in studies with data obtained with other techniques. PMID- 20974260 TI - Linking inter-individual differences in neural activation and behavior to intrinsic brain dynamics. AB - The brain's energy economy excessively favors intrinsic, spontaneous neural activity over extrinsic, evoked activity, presumably to maintain its internal organization. Emerging hypotheses capable of explaining such an investment posit that the brain's intrinsic functional architecture encodes a blueprint for its repertoire of responses to the external world. Yet, there is little evidence directly linking intrinsic and extrinsic activity in the brain. Here we relate differences among individuals in the magnitude of task-evoked activity during performance of an Eriksen flanker task, to spontaneous oscillatory phenomena observed during rest. Specifically, we focused on the amplitude of low-frequency oscillations (LFO, 0.01-0.1 Hz) present in the BOLD signal. LFO amplitude measures obtained during rest successfully predicted the magnitude of task-evoked activity in a variety of regions that were all activated during performance of the flanker task. In these regions, higher LFO amplitude at rest predicted higher task-evoked activity. LFO amplitude measures obtained during rest were also found to have robust predictive value for behavior. In midline cingulate regions, LFO amplitudes predicted not only the speed and consistency of performance but also the magnitude of the behavioral congruency effect embedded in the flanker task. These results support the emerging hypothesis that the brain's repertoire of responses to the external world are represented and updated in the brain's intrinsic functional architecture. PMID- 20974262 TI - A practical clinical method to quantify language lateralization in fMRI using whole-brain analysis. AB - Surgery is often the only effective treatment for intractable epilepsy, but its benefits must be balanced by potential disruption of eloquent cortical functions. Wada test is the standard technique to lateralize language before surgery; however, it is invasive and associated with complications. fMRI provides an attractive noninvasive alternative, which has been previously shown to correlate with Wada results. However this correlation is imperfect since standard fMRI laterality indices are dependent on a particular arbitrary statistical threshold used in the data processing. We report a novel automated, threshold-independent fMRI methodology to assess language lateralization, which we hypothesize provides a robust and unbiased pre-operative assessment. This hemispheric histogram analysis method can accurately interrogate language lateralization, as validated against the Wada test. Fifty-nine subjects with intractable epilepsy received preoperative evaluation for language lateralization using fMRI. fMRI data then were analyzed using a novel automated threshold-independent method for determining language lateralization. The methodology generated a lateralization score based on hemispheric activation of language areas and a quality index based on multiple factors, including patient motion and signal-to-noise characteristics. Lateralization scores were compared to Wada test results (51 patients), direct cortical stimulation (3 patients), and subdural grid stimulation (5 patients). Data sets were used to generate a probability score for language lateralization for each subject. The lateralization scores correlated well with the objective measures of language lateralization (r(2)=0.46). Cumulative historical data were utilized to prospectively determine probabilities of language lateralization for individual patients. In conclusion, hemispheric language lateralization can be accurately determined using a novel objective and automated methodology that calculates language lateralization in a threshold independent manner and can be used to determine the probability of language dominance in individual patients. PMID- 20974263 TI - Functional connectivity in the rat at 11.7T: Impact of physiological noise in resting state fMRI. AB - Resting state functional MRI (rs-fMRI) of the brain has the potential to elicit networks of functional connectivity and to reveal changes thereof in animal models of neurological disorders. In the present study, we investigate the contribution of physiological noise and its impact on assessment of functional connectivity in rs-fMRI of medetomidine sedated, spontaneously breathing rats at ultrahigh field of 11.7 Tesla. We employed gradient echo planar imaging (EPI) with repetition times of 3s and used simultaneous recordings of physiological parameters. A model of linear regression was applied to quantify the amount of BOLD fMRI signal fluctuations attributable to physiological sources. Our results indicate that physiological noise - mainly originating from the respiratory cycle -dominates the rs-fMRI time course in the form of spatially complex correlation patterns. As a consequence, these physiological fluctuations introduce severe artifacts into seed-based correlation maps and lead to misinterpretation of corresponding connectivity measures. We demonstrate that a scheme of motion correction and linear regression can significantly reduce physiological noise in the rs-fMRI time course, remove artifacts, and hence improve the reproducibility of functional connectivity assessment. In conclusion, physiological noise can severely compromise functional connectivity MRI (fcMRI) of the rodent at high fields and must be carefully considered in design and interpretation of future studies. Motion correction should be considered the primary strategy for reduction of apparent motion related to respiratory fluctuations. Combined with subsequent regression of physiological confounders, this strategy has proven successful in reducing physiological noise and related artifacts affecting functional connectivity analysis. The proposed new and rigorous protocol now opens the potential of fcMRI to elicit the role of brain connectivity in pathological processes without concerns of confounding contributions from physiological noise. PMID- 20974264 TI - Empathic responses to others' gains and losses: an electrophysiological investigation. AB - A growing number of studies in exploring empathic modulation have revealed the neural substrates of how social stimuli are represented in the human brain, especially the pain of others. The empathic response of observing other's gains and losses, however, remains not clearly characterized. In the current study, we carried out two experiments with a gamble task to investigate how the effects of interpersonal familiarity and self-participation work on modulating the temporal neural response towards gain and loss of a friend or a stranger using scalp recorded event-related potentials (ERPs). The electrophysiological data show an increased amplitude of the P300 when observing a friend's performance compared to strangers playing the game in both two experiments. But the distinction of differentiated feedback-related negativity (d-FRN) between friends and strangers was only observed when the player was not involved in the game. These results indicated that the participants exerted more motivational relevance toward their friends than strangers, but the participants' empathic response toward friends was only salient when they were not involved in the gamble directly. Therefore, both familiarity and self-engagement are factors that influence the empathy towards others, complementing the recent research on empathic modulation. PMID- 20974265 TI - Mental encoding and neural decoding of abstract cognitive categories: a commentary and simulation. AB - The premise of Multi-Voxel Pattern Analysis (MVPA) of functional Magnetic Resonance Image (fMRI) data is that mental encodings or states give rise to patterns of neural activation, which in turn, give rise to patterns of blood oxygen level dependent (BOLD) responses distributed across sets of voxels. Statistical learning algorithms can then be used to detect relationships between mental encodings and BOLD responses, typically through pattern classification. Amongst many other applications, this technique has been used to evidence abstract category representation in an assortment of brain areas and across a range of cognitive domains. In this commentary, we address a critical domain general caveat to inferring abstract category representation from MVPA that has been partly overlooked in the recent literature: specifically, the distinction between representing specific exemplars within categories, and representing the abstract categories themselves. Using a simulation, we demonstrate that certain forms of MVPA training and testing do not constitute sufficient evidence of category representation, and illustrate prospective and novel retrospective resolutions for this issue. PMID- 20974266 TI - Incongruence effects in crossmodal emotional integration. AB - Emotions are often encountered in a multimodal fashion. Consequently, contextual framing by other modalities can alter the way that an emotional facial expression is perceived and lead to emotional conflict. Whole brain fMRI data was collected when 35 healthy subjects judged emotional expressions in faces while concurrently being exposed to emotional (scream, laughter) or neutral (yawning) sounds. The behavioral results showed that subjects rated fearful and neutral faces as being more fearful when accompanied by screams than compared to yawns (and laughs for fearful faces). Moreover, the imaging data revealed that incongruence of emotional valence between faces and sounds led to increased activation in the middle cingulate cortex, right superior frontal cortex, right supplementary motor area as well as the right temporoparietal junction. Against expectations no incongruence effects could be found in the amygdala. Further analyses revealed that, independent of emotional valence congruency, the left amygdala was consistently activated when the information from both modalities was emotional. If a neutral stimulus was present in one modality and emotional in the other, activation in the left amygdala was significantly attenuated. These results indicate that incongruence of emotional valence in audiovisual integration activates a cingulate-fronto-parietal network involved in conflict monitoring and resolution. Furthermore in audiovisual pairing amygdala responses seem to signal also the absence of any neutral feature rather than only the presence of an emotionally charged one. PMID- 20974267 TI - Angioarchitectural changes in subacute cerebral venous thrombosis. A synchrotron based micro- and nano-CT study. AB - It is well known that recanalization of thrombosed cerebral sinuses occurs early but without marked influence on the long-term outcome and on final venous infarct volume on magnetic resonance imaging. To better understand the possible microvascular mechanisms behind these clinical observations, we evaluated the sequels of subacute superior sagittal sinus (SSS) thrombosis in rats using micro- and nano-CT imaging of the same specimen to provide large volume and high resolution CT image data respectively. SSS thrombosis was induced in 11 animals which were euthanized after 6h (n=4) or 6 weeks (n=7). Eight sham-operated rats served as controls. After infusion of contrast into the vasculature of the brains, these were isolated and scanned using micro-, nano-, and synchrotron based micro-CT ((8 MUm3), (900 nm)3, and (1.9 MUm3) voxel sizes). The cross sectional area of the superior sagittal sinus, microvessels and cortical veins were quantified. Tissue sections were stained against VEGF antigen. Immunohistochemistry was confirmed using quantitative rtPCR. SSS thrombosis led to a congestion of the bridging veins after 6h. After 6 weeks, a network of small vessels surrounding the occluded SSS was present with concurrent return towards the diameter of the draining bridging veins of controls. This microvascular network connected to cortical veins as demonstrated by nano- and synchrotron based micro-CT. Also the volume fraction and number of cortical veins increased significantly. Immunohistochemistry in the region of the microsvascular network demonstrated a strong immunoreactivity against VEGF, confirmed by rtPCR. The sequel of subacute SSS thrombosis induced a network of microvessels ("venogenesis") draining the bridging veins. Also the volume fraction of cortical veins increased significantly. PMID- 20974268 TI - Altered long-range alpha-band synchronization during visual short-term memory retention in children born very preterm. AB - Children born very preterm, even when intelligence is broadly normal, often experience selective difficulties in executive function and visual-spatial processing. Development of structural cortical connectivity is known to be altered in this group, and functional magnetic resonance imaging (fMRI) evidence indicates that very preterm children recruit different patterns of functional connectivity between cortical regions during cognition. Synchronization of neural oscillations across brain areas has been proposed as a mechanism for dynamically assigning functional coupling to support perceptual and cognitive processing, but little is known about what role oscillatory synchronization may play in the altered neurocognitive development of very preterm children. To investigate this, we recorded magnetoencephalographic (MEG) activity while 7-8 year old children born very preterm and age-matched full-term controls performed a visual short term memory task. Very preterm children exhibited reduced long-range synchronization in the alpha-band during visual short-term memory retention, indicating that cortical alpha rhythms may play a critical role in altered patterns functional connectivity expressed by this population during cognitive and perceptual processing. Long-range alpha-band synchronization was also correlated with task performance and visual-perceptual ability within the very preterm group, indicating that altered alpha oscillatory mechanisms mediating transient functional integration between cortical regions may be relevant to selective problems in neurocognitive development in this vulnerable population at school age. PMID- 20974269 TI - Probabilistic analysis of activation volumes generated during deep brain stimulation. AB - Deep brain stimulation (DBS) is an established therapy for the treatment of Parkinson's disease (PD) and shows great promise for the treatment of several other disorders. However, while the clinical analysis of DBS has received great attention, a relative paucity of quantitative techniques exists to define the optimal surgical target and most effective stimulation protocol for a given disorder. In this study we describe a methodology that represents an evolutionary addition to the concept of a probabilistic brain atlas, which we call a probabilistic stimulation atlas (PSA). We outline steps to combine quantitative clinical outcome measures with advanced computational models of DBS to identify regions where stimulation-induced activation could provide the best therapeutic improvement on a per-symptom basis. While this methodology is relevant to any form of DBS, we present example results from subthalamic nucleus (STN) DBS for PD. We constructed patient-specific computer models of the volume of tissue activated (VTA) for 163 different stimulation parameter settings which were tested in six patients. We then assigned clinical outcome scores to each VTA and compiled all of the VTAs into a PSA to identify stimulation-induced activation targets that maximized therapeutic response with minimal side effects. The results suggest that selection of both electrode placement and clinical stimulation parameter settings could be tailored to the patient's primary symptoms using patient-specific models and PSAs. PMID- 20974270 TI - Commonality of neural representations of words and pictures. AB - In this work we explore whether the patterns of brain activity associated with thinking about concrete objects are dependent on stimulus presentation format, whether an object is referred to by a written or pictorial form. Multi-voxel pattern analysis methods were applied to brain imaging (fMRI) data to identify the item category associated with brief viewings of each of 10 words (naming 5 tools and 5 dwellings) and, separately, with brief viewings of each of 10 pictures (line drawings) of the objects named by the words. These methods were able to identify the category of the picture the participant was viewing, based on neural activation patterns observed during word-viewing, and identify the category of the word the participant was viewing, based on neural activation patterns observed during picture-viewing, using data from only that participant or only from other participants. These results provide an empirical demonstration of object category identification across stimulus formats and across participants. In addition, we were able to identify the category of the word that the participant was viewing based on the patterns of neural activation generated during word-viewing by that participant or by all other participants. Similarly, we were able to identify with even higher accuracy the category of the picture the participant was viewing, based on the patterns of neural activation demonstrated during picture-viewing by that participant or by all other participants. The brain locations that were important for category identification were similar across participants and were distributed throughout the cortex where various object properties might be neurally represented. These findings indicate consistent triggering of semantic representations using different stimulus formats and suggest the presence of stable, distributed, and identifiable neural states that are common to pictorial and verbal input referring to object categories. PMID- 20974271 TI - Neural representation of observed actions in the parietal and premotor cortex. AB - We investigated the neural representation of observed actions in the human parietal and premotor cortex, which comprise the action observation network or the mirror neuron system for action recognition. Participants observed object directed hand actions, in which action as well as other properties were independently manipulated: action (grasp or touch), object (cup or bottle), perspective (1st or 3rd person), hand (right or left), and image size (large or small). We then used multi-voxel pattern analysis to determine whether each feature could be correctly decoded from regional activities. The early visual area showed significant above-chance classification accuracy, particularly high in perspective, hand, and size, consistent with pixel-wise dissimilarity of stimuli. In contrast, the highest decoding accuracy for action was observed in the anterior intraparietal sulcus (aIPS) and the ventral premotor cortex (PMv). Moreover, the decoder for action could be correctly generalized for images with high dissimilarity in the parietal and premotor region, but not in the visual area. Our study indicates that the parietal and premotor regions encode observed actions independent of retinal variations, which may subserve our capacity for invariant action recognition of others. PMID- 20974273 TI - What makes Aspergillus fumigatus a successful pathogen? Genes and molecules involved in invasive aspergillosis. AB - Aspergillus fumigatus is an opportunistic pathogen that causes 90% of invasive aspergillosis (IA) due to Aspergillus genus, with a 50-95% mortality rate. It has been postulated that certain virulence factors are characteristic of A. fumigatus, but the "non-classical" virulence factors seem to be highly variable. Overall, published studies have demonstrated that the virulence of this fungus is multifactorial, associated with its structure, its capacity for growth and adaptation to stress conditions, its mechanisms for evading the immune system and its ability to cause damage to the host. In this review we intend to give a general overview of the genes and molecules involved in the development of IA. The thermotolerance section focuses on five genes related with the capacity of the fungus to grow at temperatures above 30 degrees C (thtA, cgrA, afpmt1, kre2/afmnt1, and hsp1/asp f 12). The following sections discuss molecules and genes related to interaction with the host and with the immune responses. These sections include beta-glucan, alpha-glucan, chitin, galactomannan, galactomannoproteins (afmp1/asp f 17 and afmp2), hydrophobins (rodA/hyp1 and rodB), DHN-melanin, their respective synthases (fks1, rho1-4, ags1-3, chsA-G, och1-4, mnn9, van1, anp1, glfA, pksP/alb1, arp1, arp2, abr1, abr2, and ayg1), and modifying enzymes (gel1-7, bgt1, eng1, ecm33, afpigA, afpmt1-2, afpmt4, kre2/afmnt1, afmnt2-3, afcwh41 and pmi); several enzymes related to oxidative stress protection such as catalases (catA, cat1/catB, cat2/katG, catC, and catE), superoxide dismutases (sod1, sod2, sod3/asp f 6, and sod4), fatty acid oxygenases (ppoA-C), glutathione tranferases (gstA-E), and others (afyap1, skn7, and pes1); and efflux transporters (mdr1-4, atrF, abcA-E, and msfA-E). In addition, this review considers toxins and related genes, such as a diffusible toxic substance from conidia, gliotoxin (gliP and gliZ), mitogillin (res/mitF/asp f 1), hemolysin (aspHS), festuclavine and fumigaclavine A-C, fumitremorgin A-C, verruculogen, fumagillin, helvolic acid, aflatoxin B1 and G1, and laeA. Two sections cover genes and molecules related with nutrient uptake, signaling and metabolic regulations involved in virulence, including enzymes, such as serine proteases (alp/asp f 13, alp2, and asp f 18), metalloproteases (mep/asp f 5, mepB, and mep20), aspartic proteases (pep/asp f 10, pep2, and ctsD), dipeptidylpeptidases (dppIV and dppV), and phospholipases (plb1-3 and phospholipase C); siderophores and iron acquisition (sidA-G, sreA, ftrA, fetC, mirB-C, and amcA); zinc acquisition (zrfA-H, zafA, and pacC); amino acid biosynthesis, nitrogen uptake, and cross-pathways control (areA, rhbA, mcsA, lysF, cpcA/gcn4p, and cpcC/gcn2p); general biosynthetic pathway (pyrG, hcsA, and pabaA), trehalose biosynthesis (tpsA and tpsB), and other regulation pathways such as those of the MAP kinases (sakA/hogA, mpkA-C, ste7, pbs2, mkk2, steC/ste11, bck1, ssk2, and sho1), G proteins (gpaA, sfaD, and cpgA), cAMP-PKA signaling (acyA, gpaB, pkaC1, and pkaR), His kinases (fos1 and tcsB), Ca(2+) signaling (calA/cnaA, crzA, gprC and gprD), and Ras family (rasA, rasB, and rhbA), and others (ace2, medA, and srbA). Finally, we also comment on the effect of A. fumigatus allergens (Asp f 1-Asp f 34) on IA. The data gathered generate a complex puzzle, the pieces representing virulence factors or the different activities of the fungus, and these need to be arranged to obtain a comprehensive vision of the virulence of A. fumigatus. The most recent gene expression studies using DNA-microarrays may be help us to understand this complex virulence, and to detect targets to develop rapid diagnostic methods and new antifungal agents. PMID- 20974272 TI - Dissociable brain mechanisms for processing social exclusion and rule violation. AB - Social exclusion inherently involves an element of expectancy violation, in that we expect other people to follow the unwritten rule to include us in social interactions. In this functional magnetic resonance imaging (fMRI) study, we employed a unique modification of an interactive virtual ball-tossing game called "Cyberball" (Williams et al., 2000) and a novel paradigm called "Cybershape," in which rules are broken in the absence of social exclusion, to dissociate brain regions that process social exclusion from rule violations more generally. Our Cyberball game employed an alternating block design and removed evoked responses to events when the participant was throwing the ball in inclusion to make this condition comparable to exclusion, where participants did not throw. With these modifications, we replicated prior findings of ventral anterior cingulate cortex (vACC), insula, and posterior cingulate cortex activity evoked by social exclusion relative to inclusion. We also identified exclusion-evoked activity in the hippocampi, left ventrolateral prefrontal cortex, and left middle temporal gyrus. Comparing social exclusion and rule violation revealed a functional dissociation in the active neural systems as well as differential functional connectivity with vACC. Some overlap was observed in regions differentially modulated by social exclusion and rule violation, including the vACC and lateral parietal cortex. These overlapping brain regions showed different activation during social exclusion compared to rule violation, each relative to fair play. Comparing activation patterns to social exclusion and rule violation allowed for the dissociation of brain regions involved in the experience of exclusion versus expectancy violation. PMID- 20974274 TI - MMAR_2770, a new enzyme involved in biotin biosynthesis, is essential for the growth of Mycobacterium marinum in macrophages and zebrafish. AB - Biotin, which functions as an essential cofactor for certain carboxylases and decarboxylases, is synthesized by a multistep pathway in microorganisms and plants. Biotin biosynthesis has not been studied in detail in mycobacteria. In this study, we isolated a mutant of Mycobacterium marinum in which MMAR_2770, a previously uncharacterized gene encoding a predicted short-chain dehydrogenase/reductase, was inactivated. We found that this mutant is a biotin auxotroph that cannot grow in a minimal medium (Sauton) unless biotin is supplemented. Complementation of the mutant with an intact MMAR_2770 or its homolog Rv1882c of Mycobacterium tuberculosis restored the growth of the mutant, suggesting that MMAR_2770 is involved in biotin biosynthesis. We further showed that the mutant was unable to grow in cultured macrophages and was attenuated in zebrafish. Taken together, our results demonstrate that biotin biosynthesis is essential for the growth of mycobacteria in vitro and in vivo and have provided validation for targeting biotin biosynthetic enzymes for antimycobacterial drug development. The potential role of MMAR_2770 in mycobacterial biotin biosynthesis is discussed. PMID- 20974275 TI - Correlation between sialic acid expression and infection of murine macrophages by different strains of influenza virus. AB - The mouse-adapted A/PR/8/34 (PR8; H1N1) virus infects airway macrophages poorly and is virulent in mice. Herein, we have investigated factors contributing to the ability of PR8 to evade murine macrophages. We demonstrate that the hemagglutinin of PR8 binds preferentially to alpha(2,3)-linked sialic acid (SA) and that murine macrophages express alpha(2,6)-linked SA. Moreover, resialylation of macrophages to express alpha(2,3)-linked SA restored susceptibility to PR8. Thus, during adaptation of human influenza viruses to growth in mice, a switch in receptor specificity from alpha(2,6)-linked SA to alpha(2,3)-linked SA is likely to favour evasion of attachment, entry and destruction by airway macrophages. PMID- 20974276 TI - Pneumolysin-induced CXCL8 production by nasopharyngeal epithelial cells is dependent on calcium flux and MAPK activation via Toll-like receptor 4. AB - The natural niche of Streptococcus pneumoniae is the nasopharyngeal mucosa and nasopharyngeal carriage of pneumococci is widely prevalent. Pneumolysin (Ply), a pore-forming protein produced by S. pneumonia, may be important in driving the innate immune response of the nasopharynx. We studied the Ply-induced production of CXCL8 by nasopharyngeal cells and further analysed the mechanism of this induction. Detroit nasopharyngeal cells were stimulated with supernatants derived from bacterial cultures of Ply-deficient, wild-type pneumococci and recombinant Ply, and CXCL8 measured by ELISA. The role of MAP kinase family members in Ply induced CXCL8 production was analysed using specific inhibitors, NF-kappaB activity was measured by immunoblot and Ply-mediated TLR4 activation analysed by a CXCL8 promotor luciferase assay. Ply significantly increased production of CXCL8 in Detroit and primary nasal cells. Flow cytometric analysis showed that Detroit cells express cell surface TLR4. CXCL8 production was dependent on changes in the intracellular Ca(2+) levels and also by NF-kappaB via activation of TLR4, and MAP kinase signalling. Ply induces production of CXCL8 by nasopharyngeal cells using signalling mechanisms involving Ca(2+) mobilisation and activation of MAPK and NF-kappaB via TLR4. This may be important in regulating nasopharyngeal immunity against pneumococcal colonization. PMID- 20974277 TI - Vitamin D(3) signalling to mast cells: A new regulatory axis. AB - Excessive sun exposure or high acute doses of ultraviolet (UV)-B radiation promote cutaneous inflammation and genetic mutations, both of which can ultimately contribute to skin carcinogenesis. A major mediator synthesized in the epidermis in response to UVB irradiation is the secosteroid hormone vitamin D(3), and as such, considerable attention is now turning to the many physiologic processes that it regulates. Recent studies have uncovered an immunoregulatory interaction between vitamin D(3) and dermal mast cells for optimal protection against pathogenic outcomes associated with chronic UVB irradiation of the skin. Most biological effects of vitamin D(3), such as the regulation of transcription in target genes, occur when it binds to its nuclear receptor; however, some actions can also occur via a non-genomic signalling pathway. This review will focus on the relative importance of both pathways in the regulation of vitamin D(3)-mediated UVB protection and will highlight exciting recent findings that point to new research directions. PMID- 20974278 TI - Muscle specific kinase: organiser of synaptic membrane domains. AB - Muscle Specific Kinase (MuSK) is a transmembrane tyrosine kinase vital for forming and maintaining the mammalian neuromuscular junction (NMJ: the synapse between motor nerve and skeletal muscle). MuSK expression switches on during skeletal muscle differentiation. MuSK then becomes restricted to the postsynaptic membrane of the NMJ, where it functions to cluster acetylcholine receptors (AChRs). The expression, activation and turnover of MuSK are each regulated by signals from the motor nerve terminal. MuSK forms the core of an emerging signalling complex that can be acutely activated by neural agrin (N-agrin), a heparin sulfate proteoglycan secreted from the nerve terminal. MuSK activation initiates complex intracellular signalling events that coordinate the local synthesis and assembly of synaptic proteins. The importance of MuSK as a synapse organiser is highlighted by cases of autoimmune myasthenia gravis in which MuSK autoantibodies can deplete MuSK from the postsynaptic membrane, leading to complete disassembly of the adult NMJ. PMID- 20974279 TI - Endothelin-1: physiological and pathological roles in myometrium. AB - Endothelin-1 (ET-1), a member of endothelin peptide family is released by many different tissues including uterine smooth muscle. ET-1 acts through ETA and ETB receptors and is implicated in a wide range of biological and pathological functions that explain the great attention of the pharmacological industry for ET 1 receptors as potential therapeutic targets in vascular pathologies and cancers. It is now well established that ET-1 is also able to regulate myometrial functions. In the present review, we focused on ET axis and related signaling pathways involved in the regulation of myometrial contraction, as well as cell proliferation and survival. Such ET-1-mediated cellular functions play a critical role in normal pregnancy, preterm birth and uterine leiomyoma. PMID- 20974280 TI - Molecular mechanisms of nucleoside recycling in the brain. AB - A major role of plasma membrane bound ectonucleotidases is the modulation of ATP, ADP, adenosine (the purinergic agonists), UTP, and UDP (the pyrimidinergic agonists) availability in the extracellular space at their respective receptors. We have recently shown that an ATP driven uridine-UTP cycle is operative in the brain, based on the strictly compartmentalized processes of uridine salvage to UTP and uridine generation from UTP, in which uptaken uridine is anabolized to UTP in the cytosol, and converted back to uridine in the extracellular space by the action of ectonucleotidases (Ipata et al. Int J Biochem Cell Biol 2010;42:932 7). In this paper we show that a similar cytidine-CTP cycle exists in rat brain. Since (i) brain relies on imported preformed nucleosides for the synthesis of nucleotides, RNA, nuclear and mitochondrial DNA, coenzymes, pyrimidine sugar- and lipid-conjugates and (ii) no specific pyrimidinergic receptors have been identified for cytidine and their nucleotides, our results, taken together with previous studies on the intra- and extracellular metabolic network of ATP, GTP, UTP, and their nucleosides in the brain (Barsotti and Ipata. Int J Biochem Cell Biol 2004;36:2214-25; Balestri et al. Neurochem Int 2007;50:517-23), strongly suggest that, apart from the modulation of ligand availability, ectonucleotidases may serve the process of local nucleoside recycling in the brain. PMID- 20974281 TI - Heparin/heparan sulphate-based drugs. AB - Glycosaminoglycans (GAGs) are an untapped source of novel chemical entities and, therefore, offer exciting new opportunities for the development of novel drug molecules because of their unique physical and biological properties. Advances in the functional understanding of GAG-protein interactions are enabling the development of GAG mimetics for use as anti-angiogenic, anti-metastatic, anti inflammatory, anticoagulant and anti-thrombotic agents. Many anti-thrombotic molecules, such as Fondaparinux and Idraparinux, have been successful in clinical trials, and a new generation of heparin mimetic oligosaccharides and small molecules are currently in different stages of clinical development. In particular, the recent increased activity in the development of new mimetics by altering the composition of sulphated GAGs is very encouraging. This article reviews structurally defined heparin-mimetic oligosaccharides and small molecules currently in development or clinical trials. PMID- 20974282 TI - Developments towards antiviral therapies against enterovirus 71. AB - Enterovirus 71 (EV71) has emerged as a clinically important neurotropic virus that can cause acute flaccid paralysis and encephalitis, leading to cardiopulmonary failure and death. Recurring outbreaks of EV71 have been reported in several countries. The current lack of approved anti-EV71 therapy has prompted intense research into antiviral development. Several strategies--ranging from target-based chemical design to compound library screenings--have been employed, while others revisited compound series generated from antiviral developments against poliovirus and human rhinoviruses. These efforts have given rise to a diversity of antiviral candidates that include small molecules and non conventional nucleic-acid-based strategies. This review aims to highlight candidates with potential for further clinical development based on their putative modes of action. PMID- 20974283 TI - Understanding infectious agents from an in silico perspective. AB - Knowledge of infectious diseases now emerging from genomic, proteomic, epidemiological and clinical data can provide insights into the mechanisms of immune function, disease pathogenesis and epidemiology. Here, we describe how considerable advances in computational methods of data mining, mathematical modeling in epidemiology and simulation have been used to enhance our understanding of infectious agents and discuss their impact on the discovery of new therapeutics and controlling their spread. PMID- 20974284 TI - Epigenetic therapies for non-oncology indications. AB - Chronic and degenerative disorders are a major, and growing, human health burden, and current treatments are in many cases inadequate or very expensive. Epigenetic therapies are attractive options for treating such disorders because they manipulate the processes that maintain cells in an abnormal transcriptional state. The challenges lie in identifying the most appropriate diseases and the enzymes that should be targeted. This review describes the different approaches that can be used to address this problem, focusing particularly on CNS disorders (especially mental retardation, neurodegenerative disease, psychiatric disorders and drug addiction), diabetes and diabetic complications, and autoimmunity and inflammatory diseases. PMID- 20974285 TI - Metal-based drugs for malaria, trypanosomiasis and leishmaniasis: recent achievements and perspectives. AB - Tropical diseases today constitute a major health problem and a big challenge for drug discovery. Because of the limited arsenal of effective antiparasitic agents and the frequent appearance of chemoresistance, there is an urgent and continuous need to develop new drugs against these ailments. Metal compounds still offer excellent opportunities to find new 'leads' against the major protozoan diseases such as malaria, leishmaniasis and trypanosomiasis. A few metal-based drugs are already available in this therapeutic area, and others are currently being developed. Recent progress in parasite genomics and the identification of a few biomolecular targets hold great promise for the discovery of new 'mechanism based' antiparasitic metallodrugs. The trends and perspectives for this exciting research field are outlined here. PMID- 20974286 TI - Securing reliability and validity in biomedical research: an essential task. AB - The buzzword 'translational' dominates concepts to optimize value creation from science. This article discusses the impact of 'old' and contemporary data on hypothesis generation in relation to human physiology and in the effort to optimally implement translational sciences. I outline how dogmas and errors, sometimes perpetuated over decades, impact contemporary research and drug discovery projects. As a consequence and to improve value creation from science, a reevaluation of old data (i.e. of the validity and reliability of research with regard to human physiology) seems necessary. In line with this, the compliance of newly generated hypotheses, assays and tools with a conceptual focus on human physiology as the gold standard seems essential. To achieve improved research success, several measures need to be initiated and guided by industrial and academic leaders in concert to have an impact on the quality of research in the very near future. There is no 'holy grail', but in general terms, a constructive but critical approach--not just to contemporary biomedical research--seems mandatory to avoid the errors of the past and enable solutions to evolve dynamically. PMID- 20974287 TI - Influence of iron-overload on DNA damage and its repair in human leukocytes in vitro. AB - Iron is an important element that modulates the production of reactive oxygen species, which are thought to play a causative role in biological processes such as mutagenesis and carcinogenesis. The potential genotoxicity of dietary iron has been seldom studied in human leukocyte and only few reports have investigated in human colon tumor cells. Therefore, DNA damage and repair capacity of human leukocytes were examined using comet assay for screening the potential toxicity of various iron-overloads such as ferric-nitrilotriacetate (Fe-NTA), FeSO(4), hemoglobin and myoglobin, and compared with 200MUM of H(2)O(2) and HNE. The iron overloads tested were not cytotoxic in the range of 10-1000 microM by trypan blue exclusion assay. The exposure of leukocytes to Fe-NTA (500 and 1000 microM), FeSO(4) (250-1000 microM), hemoglobin (10 microM) and myoglobin (250 microM) for 30 min induced significantly higher DNA damage than NC. Treatment with 500 and 1000 microM of Fe-NTA showed a similar genotoxic effect to H(2)O(2), and a significant higher genotoxic effect than HNE. The genotoxicity of FeSO(4) (250 1000 microM), hemoglobin (10 microM) and myoglobin (250 microM) was not significantly different from that of H(2)O(2) and HNE. Iron-overloads generated DNA strand break were rejoined from the first 1h. Their genotoxic effect was not observed at 24h. These data from this study provide additional information on the genotoxicity of iron-overloads and self-repair capacity in human leukocytes. PMID- 20974288 TI - Spermiogenesis and spermatozoon ultrastructure of Diplodiscus subclavatus (Pallas, 1760) (Paramphistomoidea, Diplodiscidae), an intestinal fluke of the pool frog Rana lessonae (Amphibia, Anura). AB - Spermiogenesis in Diplodiscus subclavatus begins with the formation of the zone of differentiation presenting two centrioles associated with striated roots and an intercentriolar body. The latter presents seven electron-dense layers with a fine central plate and three plates on both sides. The external pair of these electron-dense layers is formed by a granular row. Each centriole develops into a free flagellum, both of them growing orthogonally in relation to the median cytoplasmic process. After the flagellar rotation and before the proximodistal fusion of both flagella with the median cytoplasmic process four attachment zones were already observed in several cross-sections indicating the area of fusion. Spinelike bodies are also observed in the differentiation zone before the fusion of flagella. Finally, the constriction of the ring of arched membranes gives rise to the young spermatozoon that detaches from the residual cytoplasm. The mature spermatozoon of D. subclavatus shows all the classical characters observed in Digenea spermatozoa such as two axonemes of different length of the 9+"1" trepaxonematan pattern, nucleus, mitochondrion, two bundles of parallel cortical microtubules and granules of glycogen. However, some peculiarities such as a well developed lateral expansion associated with external ornamentation of the plasma membrane and spinelike bodies combined with their area of appearance distinguish the ultrastructural organization of the sperm cells of D. subclavatus from those of other digeneans. PMID- 20974289 TI - Healthy Living Partnerships to Prevent Diabetes: recruitment and baseline characteristics. AB - Healthy Living Partnerships to Prevent Diabetes (HELP PD) is a randomized controlled trial designed to translate the Diabetes Prevention Program (DPP) lifestyle intervention into a community setting using community health workers engaged through an existing Diabetes Care Center (DCC). Overweight and obese (BMI 25-40 kg/m2) individuals with pre-diabetes (fasting blood glucose 95-125 mg/dl) with no medical contraindications to participate in a lifestyle intervention were recruited for participation in this study. Standard recruitment strategies were employed, including mass mailing, direct provider referral, and community events. Participant recruitment and randomization for this trial began in 2007 and was concluded in 2009. 1818 screenings were conducted; of these, 326 (17.9%) qualified and 301 (16.6%) participants were randomized over a 21 month period. 23.8% of potential participants were excluded during the initial telephone screening, primarily for BMI and recent history of CVD. The majority of participants (220, 73.1%) reported mass mailing as their primary source of information about the study. Mass mailing was more effective with participants who identified themselves as white when compared to African-Americans. The cost of recruitment per randomized participant was $816, which includes direct costs and staff effort. 41% of the randomized participants were male and approximately 27% reported a race or ethnicity other than white. In comparison to the DPP study cohort, the HELP PD population is older, more educated and predominately white. These differences, reflecting in part the community in which HELP PD was conducted, may have implications for retention and adherence in the lifestyle intervention group. PMID- 20974290 TI - Efficacy of the tincture of jalapa in the treatment of functional constipation: a double-blind, randomized, placebo-controlled study. AB - BACKGROUND: Laxatives are much utilized, but few clinical trials assessed the efficacy of phytotherapics in the functional constipation. AIM: The aim of this study was to evaluate the efficacy of the tincture of jalapa in the treatment of patients with functional constipation. METHODS: Double-blind, randomized, placebo controlled clinical trial was used in this study. Seventy-six patients were assigned to two treatment groups, jalapa or placebo. The study consisted of three phases: pre-treatment, treatment, and post-treatment, each phase lasting 7 days. The mean frequency of stools, the mean consistency of stools, and the presence of pain and effort to evacuate were assessed. We monitored adverse events before, during, and after the administration of 15 mL of tincture of jalapa or placebo. RESULTS: After treatment, the mean frequency of stools of the jalapa group (0.58 +/- 0.25 stools/day; P < 0.0001) was higher than in the placebo group (0.36 +/- 0.20 stools/day). In the pre-treatment, stool consistency, according to the Bristol scale, ranged from types 1 to 3 for both groups. The jalapa group showed improved mean consistency of stools (P = 0.0102) after treatment, approximately ranging between types 2 and 4, while the placebo group did not show statistically significant differences (P = 0.1446). The reduction of pain (P = 0.0061) and effort (P = 0.0289) in the jalapa group were statistically significant. Both treatments were well tolerated by the patients. CONCLUSION: The tincture of jalapa was shown to be effective in the acute treatment of functional constipation. PMID- 20974291 TI - The power of the sign test given uncertainty in the proportion of tied observations. AB - BACKGROUND: The sign test is a well-known non-parametric approach for testing whether one of two conditions is preferable to another. In medicine, this method may be used when one is interested in testing in the context of a clinical trial whether either of the two treatments that are provided to study subjects is favored over the other. When neither treatment outperforms the other within a given individual, a "tie" is said to have occurred. When planning such a trial and estimating statistical power and/or sample size, one should consider the probability of a tie occurring (P(T)). This paper quantifies the degree to which uncertainty in P(T) affects a study's statistical power. METHODS: Binomial theory was used to calculate power given varying levels of uncertainty and varying distributional forms (i.e. beta, uniform) for P(T). RESULTS: Across a range of prior distributions for P(T), power was reduced (i.e. <80%) for 46 (71.9%) of 64 experimental conditions, with large reductions (i.e. power <70%) for 10 (15.6%) of them. CONCLUSIONS: When designing a clinical trial that will incorporate the sign test to compare 2 conditions, ignoring potential variation in the probability of a tie occurring will tend to result in an underpowered study. These findings have implications to the design of any clinical trial for which assumptions are made in calculating an appropriate sample size. PMID- 20974292 TI - Design of a randomized clinical trial to improve rates of amblyopia detection in preschool aged children in primary care settings. AB - PURPOSE: To present the design of a cluster randomized controlled trial (cRCT) to evaluate the effectiveness of a web-based intervention for improving provider knowledge about strabismus and amblyopia (S/A) and preschool vision screening (PVS), increase PVS rates, and improve rates of S/A diagnoses made by eye specialists. This is the first cRCT targeting amblyopia prevention. METHODS: Participants were Medicaid providers in AL, SC, or IL who had Internet access and had filed at least 8 claims for well child visits (WCV) for children ages 3 or 4 years old during a 12-month period before enrollment. Randomization to the Intervention (vision) or Control (blood pressure) arm occurred at the cluster level, defined as the provider (or group of providers) and his/her patients seen for WCVs. RESULTS: 65 Intervention providers (IPs) with 3547 children aged 3 or 4 years, and 71 Control providers (CPs) with 5053 children enrolled. The study will report measures of knowledge and self-reported vision screening behaviors from web-based data. The primary outcomes will be rates of PVS among PCPs, and rates of diagnosis of S/A by eye specialists among the children belonging to Control and Intervention practices. CONCLUSIONS: We had the same difficulty recruiting PCPs as reported by others. Baseline rates of PVS were low (14.1%), as were rates that S/A were diagnosed by eye providers (1.4%). Our data show a need to improve both primary outcome measures. PMID- 20974293 TI - Improving function in age-related macular degeneration: design and methods of a randomized clinical trial. AB - Age-Related Macular Degeneration (AMD) is the leading cause of severe vision loss in older adults and impairs the ability to read, drive, and live independently and increases the risk for depression, falls, and earlier mortality. Although new medical treatments have improved AMD's prognosis, vision-related disability remains a major public health problem. Improving Function in AMD (IF-AMD) is a two-group randomized, parallel design, controlled clinical trial that compares the efficacy of Problem-Solving Therapy (PST) with Supportive Therapy (ST) (an attention control treatment) to improve vision function in 240 patients with AMD. PST and ST therapists deliver 6 one-hour respective treatment sessions to subjects in their homes over 2 months. Outcomes are assessed masked to treatment assignment at 3 months (main trial endpoint) and 6 months (maintenance effects). The primary outcome is targeted vision function (TVF), which refers to specific vision-dependent functional goals that subjects highly value but find difficult to achieve. TVF is an innovative outcome measure in that it is targeted and tailored to individual subjects yet is measured in a standardized way. This paper describes the research methods, theoretical and clinical aspects of the study treatments, and the measures used to evaluate functional and psychiatric outcomes in this population. PMID- 20974294 TI - Aging and HIV infection. AB - INTRODUCTION: Population aging has become a global phenomenon, and HIV infection among older individuals is also increasing. Because age can affect the progression of HIV infection, we aimed to evaluate the present knowledge on HIV infection in older patients. METHODS: Literature review of the last 20 years. RESULTS: Older HIV-infected patients have lower CD4(+) T cell counts, higher viral load and are more frequently symptomatic at diagnosis. The infection progresses more rapidly, with higher morbidity and lethality rates. However, older patients are more compliant to antiretroviral treatment; they experience a better virologic response, and treatment represents a positive clinical impact. Aging affects the complex interaction between HIV infection and the immune system. Both conditions contribute to the dysfunction of immune cells, including a decrease in the phagocytes' microbicidal capability, natural killer cells' cytolytic function, expression of toll-like receptors and production of interleukin-12. Chronic immune activation responsible for the depletion of CD4(+) and CD8(+) T cells in HIV infection appears to worsen with senescence. Older patients also exhibit a less robust humoral response, with the production of less avid and specific antibodies. CONCLUSION: Both HIV and aging contribute to immune dysfunction, morbidity and mortality. However, highly active antiretroviral therapy (HAART) is beneficial for older patients, and treatment of older patients should not be discouraged. PMID- 20974295 TI - Catastrophic antiphospholipid syndrome associated with methicillin-resistant Staphylococcus aureus infection. PMID- 20974296 TI - The CC homozygosis of the -174G>C IL-6 polymorphism predicts a lower efficacy of rituximab therapy in rheumatoid arthritis. AB - Identification of genetic biomarkers of response to biologics in rheumatoid arthritis (RA) is a relevant issue. Being IL-6 a key cytokine for B cell survival, the interleukin-6 (IL-6) -174G>C and the IL-6 receptor (IL-6R) D358A gene polymorphisms were investigated in 158 RA patients treated with rituximab (RTX). One hundred and twenty-eight (81.0%) were RF positive and 126 (79.7%) were anti-CCP positive. Response to therapy was evaluated at the end of the sixth month after the first RTX infusion, by using both the EULAR and the ACR criteria. The possible relationship with IL-6 serum levels was also studied. By univariate analysis, lack of response by the EULAR criteria was more prevalent in RA patients with the IL-6 -174 CC genotypes (39.1%), than in the GC/GG patients (18.5%) (OR 2.83; 95%CI=1.10-7.27; p=0.031). A good response was noticed in only one patient (4.3%) with the IL-6 -174 CC genotype, while it was present in 24.4% of GG/GC cases (p=0.06). By stepwise multivariate analysis (including RA duration, baseline DAS28, baseline HAQ, RF status, anti-CCP status and IL-6 genotype as covariates), the IL-6 -174CC genotype was selected as an independent predictor of no response to RTX by both EULAR and ACR>=50 criteria, while the IL 6R polymorphism resulted as not associated. No definite association between gene polymorphisms and IL-6 serum levels was noticed. Present results suggest a possible role for IL-6 genotyping to better plan treatment with RTX in RA, and larger studies are worthwhile. PMID- 20974298 TI - Morphology, distribution, mineral density and volume fraction of human calcified costal cartilage. AB - This study examines the properties of calcifying human costal cartilage and adjacent rib bone using qualitative and quantitative micro-computed tomography analysis. Calcifications are categorized with respect to location, microstructure, shape, and contiguity using a novel classification scheme and quantified in terms of mineral density, volume fraction, and length of infiltration from the costo-chondral junction (CCJ). Calcifications were present throughout the cartilage by location and ranged from small diffuse calcifications to nodes, rods, plates, and even large complex structures that exhibited a microstructural morphology similar to a cross-section of diaphysial bone, with a dense shell surrounding a trabecular core. Solid microstructure was most common for calcifications (44.5%), and the morphologies were found to vary with location, with rods and plates being most prevalent at the periphery (91.7% of all rods, 98.4% of all plates). The average mineral density of the calcifications over all locations and morphologies was 658.8+/-86.36, compared with 662.7+/ 50.37 mgHA cm(-3) for the adjacent rib bone. The calcification volume fraction (6.54+/-4.71%) was less than the volume fraction of rib bone (21.62+/-6.44%). The length of contiguous calcification infiltrating from the CCJ into the costal cartilage, when present, was 19.21+/-11.65 mm. These changes in the costal cartilage should be considered in biomechanical models of the thorax since the presence, location, and morphology of the calcifications alter the material behavior of the costal cartilage, as well as the structural behavior of the entire rib. PMID- 20974297 TI - Pseudophosphorylation of tau protein directly modulates its aggregation kinetics. AB - Hyperphosphorylation of tau protein is associated with neurofibrillary lesion formation in Alzheimer's disease and other tauopathic neurodegenerative diseases. It fosters lesion formation by increasing the concentration of free tau available for aggregation and by directly modulating the tau aggregation reaction. To clarify how negative charge incorporation into tau directly affects aggregation behavior, the fibrillization of pseudophosphorylation mutant T212E prepared in a full-length four-repeat tau background was examined in vitro as a function of time and submicromolar tau concentrations using electron microscopy assay methods. Kinetic constants for nucleation and extension phases of aggregation were then estimated by direct measurement and mathematical simulation. Kinetic analysis revealed that pseudophosphorylation increased tau aggregation rate by increasing the rate of filament nucleation. In addition, it increased aggregation propensity by stabilizing mature filaments against disaggregation. The data suggest that incorporation of negative charge into the T212 site can directly promote tau filament formation at multiple steps in the aggregation pathway. PMID- 20974299 TI - Biomaterial guides for lymphatic endothelial cell alignment and migration. AB - Axillary dissection during breast cancer surgery produces extensive lymphatic vessel damage that often leads to lifelong secondary lymphedema of the arm. We have developed a biodegradable material conduit for lymphatic vessel reconstruction where fibers electrospun along the conduit lumen promote endothelial cell alignment and migration in vitro. The diameter and density of the electrospun fibers were optimized for cell migration and direction on two dimensional substrates by seeding human lymphatic endothelial cells (LECs) onto aligned fibers of varying diameters and densities, randomly oriented fibers, and film substrates with no fibers. We found that LECs became aligned in the fiber direction, with cells seeded on the randomly oriented fibers becoming oriented in random directions, whereas cells seeded on the highly aligned fibers became highly aligned. Cell migration was dependent upon fiber alignment and density, with optimal migration found on 1300 nm diameter aligned fibers of low density. Blood endothelial cells seeded on the fibers exhibited similar behavior as the LECs. Fiber alignment was preserved upon rolling the two-dimensional substrate into the tubular geometry of a lymphatic vessel. The data suggest that aligned electrospun fibers may promote endothelial migration across the conduit in a manner that is independent of lymphatic growth factors. PMID- 20974300 TI - Polyalanine repeat expansion mutation of the HOXD13 gene in a Chinese family with unusual clinical manifestations of synpolydactyly. AB - Synpolydactyly (SPD) is an autosomal dominant limb malformation caused by mutations in the gene HOXD13. We investigated a Chinese family in which three individuals across three generations were affected with distinctive limb malformations. We extracted genomic DNA from the affected and three unaffected individuals from this family as well as 100 unrelated controls, for mutation detection by DNA sequencing. The family was characterized by camptodactyly and symphalangism of fingers two to five, transverse phalanx and osseous fusion of the third metacarpal with the proximal phalanx, as well as the coexistence of mild and more severe bilateral phenotypes. We identified a duplication mutation, c. 186-212dup, in exon 1 of the HOXD13 gene in the affected individuals from this family; it was not present in the unaffected individuals or the 100 unrelated individuals. And we also did not find polymorphism among the controls. This study has expanded the phenotypic spectrum of known HOXD13 polyalanine repeat mutations and provided more information about the polymorphic nature of the polyalanine repeat. In addition, new clinical manifestations have been added to the spectrum of possible synpolydactyly phenotypes. PMID- 20974301 TI - Flocculate removal after alkaline lysis in plasmid DNA production. AB - Alkaline lysis is the most commonly used method following harvest of bacterial cells for production of plasmid DNA. The method was originally developed for laboratory scale experiments and has shown to be challenging at larger scales. A major problem prior to further downstream processing is the risk of filter clogging without efficient removal of the flocculate that occurs after neutralization. For this purpose we here present a scalable method where the clarification of alkaline lysate is greatly simplified. Through a rapid procedure, involving the addition of ammonium hydrogen carbonate to the neutralized alkaline lysate, the flocculate is lifted to the surface of the solution by the released carbon dioxide and ammonium. After this step a clarified solution can be drained from the bottom of the vessel. The procedure does not impact pH, plasmid DNA concentration or the ratio of open circular to supercoiled plasmid DNA in the solution. PMID- 20974302 TI - A decennial booster dose of reduced antigen content diphtheria, tetanus, acellular pertussis vaccine (BoostrixTM) is immunogenic and well tolerated in adults. AB - Reduced-antigen-content diphtheria-tetanus-acellular-pertussis (dTpa) vaccines are predominantly recommended for once-in-a-lifetime use. A second dTpa (BoostrixTM, GlaxoSmithKline Biologicals) administration in 164 adults previously vaccinated with dTpa 10 years previously was evaluated. Before the decennial booster, 89.4% and 94.8% subjects were seroprotected (antibodies >=0.1 IU/mL) for diphtheria and tetanus, respectively. One-month post-booster, all subjects were seroprotected/seropositive against all vaccine antigens. Robust GMC increases indicated a booster response similar to the first booster. The decennial booster was well tolerated without serious adverse events, consistent with product experience. This study supports replacing traditional Td boosters with dTpa, and use of BoostrixTM as a decennial booster. This study is registered at www.clinicaltrials.com NCT00548171. PMID- 20974303 TI - Dry powder measles vaccine: particle deposition, virus replication, and immune response in cotton rats following inhalation. AB - A stable and high potency dry powder measles vaccine with a particle size distribution suitable for inhalation was manufactured by CO(2)-Assisted Nebulization with a Bubble Dryer((r)) (CAN-BD) process from bulk liquid Edmonston Zagreb live attenuated measles virus vaccine supplied by the Serum Institute of India. A novel dry powder inhaler, the PuffHaler((r)) was adapted for use in evaluating the utility of cotton rats to study the vaccine deposition, vaccine virus replication, and immune response following inhalation of the dry powder measles vaccine. Vaccine deposition in the lungs of cotton rats and subsequent viral replication was detected by measles-specific RT-PCR, and viral replication was confined to the lungs. Inhalation delivery resulted in an immune response comparable to that following injection. The cotton rat model is useful for evaluating new measles vaccine formulations and delivery devices. PMID- 20974304 TI - Anaphylaxis to the 23-valent pneumococcal vaccine: a second explored case by means of immediate-reading skin tests with pneumococcal vaccines. AB - Anaphylaxis to pneumococcal vaccines is rare. In the only one child with anaphylaxis to a first injection of the 23-valent pneumococcal vaccine that has been explored, skin tests and specific IgE determination diagnosed immediate-type hypersensitivity to pneumococcal antigens. We report the case of a child who tolerated three injections of the 7-valent pneumococcal vaccine, but experienced anaphylaxis to a fourth injection of the 23-valent vaccine. Immediate responses in skin tests diagnosed immediate-type hypersensitivity to the two vaccines. Immunizations with the 7-valent pneumococcal vaccine may induce IgE-dependent sensitization to pneumococcal antigens, responsible for anaphylaxis to subsequent injections of pneumococcal vaccines. PMID- 20974305 TI - Higher human CD4 T cell response to novel Mycobacterium tuberculosis latency associated antigens Rv2660 and Rv2659 in latent infection compared with tuberculosis disease. AB - One third of the world's population is infected with Mycobacterium tuberculosis (M.tb). A vaccine that would prevent progression to TB disease will have a dramatic impact on the global TB burden. We propose that antigens of M.tb that are preferentially expressed during latent infection will be excellent candidates for post-exposure vaccination. We therefore assessed human T cell recognition of two such antigens, Rv2660 and Rv2659. Expression of these was shown to be associated with non-replicating persistence in vitro. After six days incubation of PBMC from persons with latent tuberculosis infection (LTBI) and tuberculosis (TB) disease, Rv2660 and Rv2659 induced IFN-gamma production in a greater proportion of persons with LTBI, compared with TB diseased patients. Persons with LTBI also had increased numbers of viable T cells, and greater specific CD4(+) T cell proliferation and cytokine expression capacity. Persons with LTBI preferentially recognize Rv2659 and Rv2660, compared with patients with TB disease. These results suggest promise of these antigens for incorporation into post-exposure TB vaccines. PMID- 20974306 TI - Intrinsic defects in B cell response to seasonal influenza vaccination in elderly humans. AB - We have evaluated the serum response to seasonal influenza vaccination in subjects of different ages and associated this with the specific B cell response to the vaccine in vitro. Although the serum response has previously been shown to decrease with age, this has largely been associated to decreased T cell functions. Our results show that in response to the vaccine, the specific response of B cells in vitro, as measured by AID (activation-induced cytidine deaminase), the in vivo serum HI (hemagglutination inhibition) response, and the in vivo generation of switch memory B cells are decreased with age, as evaluated in the same subjects. This is the first report to demonstrate that intrinsic B cell defects with age contribute to reduced antibody responses to the influenza vaccine. The level of AID in response to CpG before vaccination can also predict the robustness of the vaccine response. These results could contribute to developing more effective vaccines to protect the elderly as well as identifying those most at risk. PMID- 20974307 TI - Determination of antigenic properties of vaccine derived poliovirus strains. AB - In this study, the immunity level of the southern Greek population in the 1-10 year, 11-20-year, 21-30-year and 31-40-year age groups with regard to Sabin vaccine strains and a collection of 11 recombinant and three non-recombinant poliovirus vaccine strains was determined. The results showed the lowest neutralization titre in the 21-30-year-age group against poliovirus type 3. Moreover, the capsid coding region of OPV (oral poliovirus vaccine) derivatives was sequenced in order to identify mutations that might lead to antigenic changes. In Sabin-1 derivatives a tendency of accumulation of mutations was observed in or near antigenic sites while in Sabin-2 and Sabin-3 derivatives in sites known to be involved in restoring neurovirulence or eliminating their temperature-sensitive phenotype. It was concluded that the combination of mutations in the capsid coding region and not the number of specific mutations in antigenic sites determines the antigenic properties of OPV derivatives and their reactivity with human sera. PMID- 20974308 TI - Knockdown of the interleukin-6 receptor alpha chain of dendritic cell vaccines enhances the therapeutic potential against IL-6 producing tumors. AB - Tumor microenvironment has emerged as one of the major obstacles against the clinical efficacy of dendritic cell (DC) vaccines. Tumor-derived IL-6 may inhibit the differentiation of hematopoietic progenitor cells into DCs and suppress DC maturation, rendering DCs tolerogenic. We hypothesized that silencing the IL-6 receptor alpha chain (IL-6Ralpha) would restore the functional competence of DC vaccines in mice with an IL-6-producing TC-1 tumor, and eventually give rise to protective immunity. We found that the IL-6Ralpha knockdown-DC vaccine significantly enhanced the frequency of tumor-specific CD8(+) CTLs-producing effector molecules such as IFN-gamma, TNF-alpha, FasL, perforin, and granzyme B, and generated more CD8(+) memory T cells, leading to the substantially prolonged survival of TC-1 tumor-bearing mice. PMID- 20974309 TI - Comparative analysis of Annexin A1-formyl peptide receptor 2/ALX expression in human leukocyte subsets. AB - Recent studies have associated the dysregulated expression of Annexin-A1/Formyl peptide receptor 2 (FPR2/ALX) system with the development of autoimmune diseases. In this study we systematically scanned human leukocyte subsets for the presence of this pathway aiming to provide a roadmap that will help investigators to explore possible links between the development of immune related disorders and the expression of this system. Our results show that neutrophils, monocytes and NK cells express higher levels of both AnxA1 and FPR2/ALX compared to T or B cells. Further analysis of specific T cell subsets revealed higher levels in activated CD25(+) and memory CD45RO CD4 T cells compared to resting CD25(-) or naive CD45RA CD4 T cells. Together the results expand our knowledge of the AnxA1 FPR2/ALX system in immune cells and provide new avenues for investigation into the functions of this signalling pathway in systems other than that classically described for neutrophils. PMID- 20974310 TI - Beneficial effects of chelidonic acid on a model of allergic rhinitis. AB - Chelidonic acid (CA) is known as an inhibitor of the rat brain glutamate decarboxylase. However, the pharmacological effects of CA in allergic reactions have not yet been defined. Here, we show the effects and the mechanism of CA in the ovalbumin (OVA)-sensitized allergic rhinitis (AR) model. CA significantly decreased the number of nasal/ear rubs and increment of IgE levels in the AR mice. The level of interferon-gamma was enhanced while the level of IL-4 was reduced on the spleen tissue of the CA-administered AR mice. Expressions of IL 1beta and cyclooxygenase-2 were inhibited by CA administration in the nasal mucosa tissues. Infiltration of eosinophils and mast cells was decreased in the CA-administered AR mice. Furthermore, CA decreased the caspase-1 activity in the same nasal mucosa tissue and human mast cell line, HMC-1. Our results indicate that CA may attenuate allergic reaction by inhibition of caspase-1 activity. PMID- 20974311 TI - Author reply: Characterization of the metabolic and physiologic response to chromium supplementation in subjects with type 2 diabetes mellitus. PMID- 20974312 TI - Standin' on the dock of the bay, waistin'. PMID- 20974313 TI - Non-invasive imaging of the vulnerable atherosclerotic plaque. Foreword. PMID- 20974314 TI - Noninvasive imaging of the vulnerable atherosclerotic plaque. AB - Atherosclerosis is an inflammatory disease, complicated by progressively increasing atherosclerotic plaques that eventually may rupture. Plaque rupture is a major cause of cardiovascular events, such as unstable angina, myocardial infarction, and stroke. A number of noninvasive imaging techniques have been developed to evaluate the vascular wall in an attempt to identify so-called vulnerable atherosclerotic plaques that are prone to rupture. The purpose of the present review is to systematically investigate the accuracy of noninvasive imaging techniques in the identification of plaque components and morphologic characteristics associated with plaque vulnerability, assessing their clinical and diagnostic value. PMID- 20974315 TI - A comparison of peginterferon alpha-2a and alpha-2b for treatment-naive patients with chronic hepatitis C virus: A meta-analysis of randomized trials. AB - BACKGROUND: The standard treatments for chronic infection with the hepatitis C virus (HCV) are peginterferon alpha-2a or alpha-2b plus ribavirin, but it remains unclear if one has a better efficacy and safety profile. OBJECTIVE: The aim of this study was to perform a meta-analysis of randomized controlled trials (RCTs) comparing peginterferon alpha-2a and alpha-2b (in combination with ribavirin) treatments for chronic HCV. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, Science Citation Index, and EMBASE were searched (1966-April 2010) to identify RCTs that evaluated the sustained virologic response (SVR) to peginterferon alpha-2a and peginterferon alpha-2b in patients with chronic HCV. The inclusion criteria were: RCT studies designed to compare the therapeutic effects of peginterferon alpha-2a (180 MUg/wk) and peginterferon alpha-2b (1.5 MUg/kg/wk) for treatment-naive patients with chronic HCV; patients treated for >=24 weeks if infected with HCV genotypes 2 or 3 and for >=48 weeks if infected with genotypes 1 or 4, with 24-week follow-ups; and publications written in any language. Reports of duplicated studies were excluded by examining the author list, parent institution, sample size, and results. The primary outcome was the SVR, and the other measures included the liver-related morbidity, all-cause mortality, and adverse events leading to treatment discontinuation. RESULTS: The literature search yielded 5580 studies, and 7 RCTs comprising 3212 patients matched the inclusion/exclusion criteria. Overall, the SVR rate was significantly higher in patients treated with peginterferon alpha-2a than in patients treated with peginterferon alpha-2b (50% vs 46%, respectively; relative risk [RR] = 1.11; 95% CI, 1.02-1.20; P < 0.05) and varying levels of ribavirin treatment. The subgroup analysis found that, in patients with genotypes 1 or 4, the difference between SVR rate in patients treated with peginterferon alpha-2a and patients treated with peginterferon alpha-2b was not statistically significant (43% vs 39%; RR = 1.25; 95% CI, 0.99-1.57). A significantly higher SVR rate was achieved in the HCV patients with genotypes 2 or 3 treated with peginterferon alpha-2a compared with the patients treated with peginterferon alpha-2b (86% vs 77%; RR = 1.11; 95% CI, 1.02-1.22; P = 0.02). The meta-analysis of adverse events leading to treatment discontinuation revealed no significant differences between the 2 treatments. CONCLUSIONS: The evidence reviewed in this meta-analysis suggests that peginterferon alpha-2a treatment was associated with a higher SVR rate than peginterferon alpha-2b treatment in patients with chronic HCV also treated with ribavirin. However, the available evidence on adverse events was insufficient to make recommendations. PMID- 20974316 TI - Dexlansoprazole: A proton pump inhibitor with a dual delayed-release system. AB - BACKGROUND: Dexlansoprazole, the dextrorotatory enantiomer of lansoprazole, is a proton pump inhibitor (PPI) formulated to have dual delayed-release properties. It is indicated for healing all grades of esophagitis, maintaining the healing of erosive esophagitis (EE), and treating heartburn associated with nonerosive gastroesophageal reflux disease. OBJECTIVE: This article reviews the pharmacology, pharmacokinetics, and pharmacodynamics of dexlansoprazole, as well as its clinical efficacy and tolerability. METHODS: MEDLINE (1966-April 2010) and International Pharmaceutical Abstracts (1970-April 2010) were searched for original research and review articles published in English using the terms dexlansoprazole and TAK-390MR. The reference lists of identified articles were reviewed for additional pertinent publications. Abstracts from 2007-2009 American College of Gastroenterology and Digestive Disease Week meetings were searched using the same terms. RESULTS: By irreversibly binding to H(+)K(+)-ATPase, dexlansoprazole inhibits acid production by the parietal cell. Its dual delayed release formulation provides 2 distinct releases of medication, prolonging the mean residence time compared with lansoprazole (5.56-6.43 vs 2.83-3.23 hours, respectively). In 2 identical Phase III trials of the healing of EE, there were no significant differences in rates of complete healing after 8 weeks between dexlansoprazole 60 and 90 mg once daily and lansoprazole 30 mg once daily. In 2 studies of the maintenance of healing of EE, rates of healing at 6 months were significantly higher with dexlansoprazole 30, 60, and 90 mg once daily compared with placebo (P < 0.001). Patients with nonerosive reflux disease who received dexlansoprazole 30 or 60 mg once daily had significantly more 24-hour heartburn free days compared with those who received placebo (P < 0.001). Dexlansoprazole was well tolerated compared with placebo or lansoprazole in all studies. CONCLUSIONS: In the studies reviewed, dexlansoprazole was well tolerated and effective in the healing and maintenance of EE, and in the treatment of nonerosive reflux disease. However, most of the available evidence involved comparisons with placebo, making it difficult to draw meaningful conclusions about the place of dexlansoprazole among PPIs. More head-to-head comparative trials with other PPIs are needed to determine whether the unique formulation of dexlansoprazole translates into a clinically meaningful improvement in outcomes. PMID- 20974317 TI - Subset analysis of patients experiencing clinical events of a potentially immunogenic nature in the pivotal clinical trials of tocilizumab for rheumatoid arthritis: Evaluation of an antidrug antibody ELISA using clinical adverse event driven immunogenicity testing. AB - BACKGROUND: Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody directed against the interleukin-6 receptor. In Europe, TCZ is approved for use in combination with methotrexate in the treatment of adult patients with moderate to severe rheumatoid arthritis (RA) who have failed to respond to or were unable to tolerate previous therapy with one or more disease-modifying antirheumatic drugs or tumor necrosis factor (TNF) antagonists; in the United States, it is approved for the treatment of adult patients with moderate to severe active RA who have failed to respond to one or more TNF antagonists. As part of the Phase III clinical development program, the immunogenicity of TCZ was evaluated using a bridging ELISA; however, this assay is considered limited in detecting low affinity or immunoglobulin G4 subisotype antidrug antibodies (ADAs). OBJECTIVE: This study assessed the validity of the ELISA for detecting anti-TCZ ADAs by using complementary bioanalytic assays to test samples from a subgroup of patients with clinical adverse events (AEs) of a potentially immunogenic nature, who were considered highly likely to have ADAs. The goal was to determine whether use of these additional assays led to detection of ADAs not found on the ELISA, thus minimizing the risk of false-negative results. METHODS: The Phase III program for TCZ consisted of 5 core studies in which adult patients with RA received either TCZ 4 or 8 mg/kg IV or control every 4 weeks, with or without concomitant antirheumatic therapy. Blood samples obtained at baseline and at regular intervals thereafter were tested using the ELISA for ADA screening and confirmation. Regardless of the results on ADA screening, samples from patients who developed clinical AEs of a potentially immunogenic nature (ie, falling within predefined system organ classes, occurring during or within 24 hours of TCZ infusion, considered related to TCZ therapy, or leading to study withdrawal) were subjected to additional testing with a surface plasmon resonance (SPR) assay for isotyping and epitope localization and a standard ImmunoCAP immunoglobulin E (IgE) assay made specific for TCZ. RESULTS: The 5 core studies and their open label, longterm extension studies enrolled a total of 4199 adult patients with RA (82.1% female; 74.0% white; mean age, 52.0 years [range, 18-89 years]; mean weight, 73.4 kg [range, 35-150 kg]); 2928 patients received TCZ and 1271 received control. Of the 2816 samples from TCZ-treated patients tested, 64 (2.3%) had samples that tested positive at least once on the ELISA screening and confirmation assay, 48 (75.0%) of them at baseline. A clinical AE of a potentially immunogenic nature occurred during TCZ treatment in 21 patients, 8 of whom had an anaphylactic reaction. Eleven of the samples from these 21 patients had tested negative for AD As on the screening ELISA. Only 1 of these 11 patients tested positive for ADAs on both additional assays; all others tested negative. The results of the ELISA, SPR, and IgE assays were consistent for 16 of 18 tested patients (88.9%) who provided data on at least 2 of the 3 assays. CONCLUSIONS: Based on the findings of this analysis in a relevant patient population, the bridging-type screening and confirmation ELISA was a valid method of detecting anti-TCZ ADAs. Immunogenicity testing of samples from patients with clinical AEs of a potentially immunogenic nature using assays complementary to the ELISA added valuable information about the incidence and character of ADAs. PMID- 20974318 TI - Impact of acarbose on carotid intima-media thickness in patients with newly diagnosed impaired glucose tolerance or mild type 2 diabetes mellitus: A one year, prospective, randomized, open-label, parallel-group study in Japanese adults with established coronary artery disease. AB - OBJECTIVE: This study examined the effect of acarbose therapy on carotid intima media thickness (IMT) in patients with established coronary artery disease (CAD) who had been newly diagnosed with impaired glucose tolerance (IGT) or mild type 2 diabetes mellitus (T2DM). METHODS: This was a 1-year, prospective, randomized, open-label, parallel-group study in patients with established CAD (>=50% stenosis on quantitative coronary angiography) who were newly diagnosed with IGT or mild T2DM. IGT was defined as 2-hour glucose concentrations of 140 to 199 mg/dL on the 75-g oral glucose tolerance test (OGTT). Mild T2DM was defined as a fasting plasma glucose concentration <126 mg/dL, 2-hour plasma glucose concentration on OGTT >200 mg/dL, and glycosylated hemoglobin (HbA(1c)) <6.5%. On the day after undergoing coronary angiography, patients were randomly allocated to receive either acarbose 150 mg/d or control (no treatment). Carotid IMT was measured by ultrasonography at baseline and at 12 months of follow-up. The changes in glucose profiles (75-g OGTT), HbA(1c), and lipid profiles were also compared between baseline and follow-up. At visits every 2 months, data on adverse events, drug adherence, and changes in medication were collected. Adverse events were recorded based on spontaneous reports and questioning by the investigator. Clinical follow up data on outcomes of interest were obtained from patients' hospital charts or from telephone interviews; these outcomes were the incidence of mortality, nonfatal myocardial infarction, repeat percutaneous coronary intervention for a treated coronary artery, and stroke. RESULTS: Ninety Japanese patients were enrolled in the study (45 in each group). Two patients in the acarbose group discontinued therapy due to drug-related diarrhea, and 1 patient in each group was discontinued because of a newly diagnosed malignancy. Three patients in the control group were discontinued because they initiated treatment with fibrates, and 2 patients in the control group were lost to follow-up. Thus, complete baseline and follow-up data were available for 42 patients in the acarbose group and 39 in the control group. These 81 patients were predominantly male (74 [91.4%]), with a mean (SD) age of 66.3 (9.0) years, mean body weight of 65.9 (10.5) kg, and mean HbA(1c) of 5.57% (0.38%). Baseline characteristics appeared to be comparable between the 2 groups. In the acarbose group, IMT increased from a mean of 1.28 (0.53) mm at baseline to 1.30 (0.52) mm at 12-month follow-up (mean change, 0.02 [0.29] mm; P = NS), whereas in the control group, it increased from a mean of 1.15 (0.37) mm to 1.32 (0.46) mm (mean change, 0.17 [0.25] mm; P < 0.001 ). The difference between groups was statistically significant (P = 0.01). In addition, the acarbose group had significant reductions from baseline in 2 hour glucose concentrations on the 75-g OGTT (mean change, -24.8 [45.2] mg/dL; P = 0.001), fasting total cholesterol (mean change, -11.26 [26.1] mg/dL; P = 0.009), and fasting triglyceride concentrations (mean change, -30.4 [62.7] mg/dL; P = 0.003), whereas the corresponding changes were not significant in the control group (mean change, -8.5 [39.4], -6.22 [26.7], and -1.05 [74.2] mg/dL, respectively). Cardiovascular events requiring hospitalization occurred in 4 patients (9.5%) in the acarbose group and 4 patients (10.3%) in the control group. No deaths, nonfatal myocardial infarctions, or strokes occurred in either group over the follow-up period. CONCLUSION: In this small, open-label study in patients with established CAD who were newly diagnosed with IGT or mild T2DM, 12 months of treatment with acarbose was associated with a beneficial effect in terms of preventing the progression of carotid IMT compared with control, although it was not associated with a significant decrease in IMT from baseline. UMIN (University Hospital Medical Information Network) Clinical Trials Registry identifier: UMIN000000544. PMID- 20974319 TI - Safety and efficacy of esreboxetine in patients with fibromyalgia: An 8-week, multicenter, randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Esreboxetine is an investigational, highly selective norepinephrine reuptake inhibitor that has been reported to have antinociceptive effects in preclinical pain models. OBJECTIVE: This study assessed the efficacy and safety profile of esreboxetine in the management of fibromyalgia. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial in patients aged >=18 years who met American College of Rheumatology criteria for fibromyalgia. Eligible patients were required to have a score >=40 mm on the 100-mm visual analog scale of the Short-Form McGill Pain Questionnaire at screening and randomization, and a mean score >=4 on an 11-point pain rating scale (from 0 = no pain to 10 = worst possible pain) based on the weekly mean pain score in the week before randomization. After a 1-week baseline period and a 2-week, single-blind, placebo run-in period, patients were randomized to receive esreboxetine or placebo for 8 weeks, followed by a 1-week follow-up period. Esreboxetine dosing was started at 2 mg/d and was escalated by 2 mg/d every 2 weeks until attainment of a dose of 8 mg/d or the maximum tolerated dose. The primary efficacy outcome was the change from baseline to week 8 in weekly mean pain scores, as derived from patients' daily pain ratings on the 11-point scale. Additional primary efficacy outcomes included changes in the Fibromyalgia Impact Questionnaire (FIQ) total score and the Patient Global Impression of Change (PGIC). The safety profile was evaluated based on observed and spontaneously reported adverse events, laboratory tests, and other safety measures. RESULTS: One hundred thirty four patients were randomized to each study group, but 1 patient in the placebo group did not receive treatment. Thus, the study population consisted of 267 patients (89.5% female; 88.4% white; mean age, ~50 years [range, 20-84 years]). Twenty-seven patients in each group discontinued the study. Adverse events were the most common reason for discontinuation in the esreboxetine group (11 patients), compared with 3 discontinuing due to adverse events in the placebo group. Patient default (withdrawal of consent and loss to follow-up) was the most common reason for discontinuation in the placebo group (13 patients), compared with 10 in the esreboxetine group. The esreboxetine group had significantly greater improvement in the weekly mean pain score compared with the placebo group (mean [SE] change from baseline: -1.55 [0.16] vs -0.99 [0.16], respectively; P = 0.006). A significantly greater percentage of patients in the esreboxetine group reported a >=30% reduction in pain scores compared with the placebo group (37.6% [50/133] vs 22.6% [30/133]; P = 0.004). Esreboxetine was associated with significant improvement compared with placebo in the FIQ total score (mean change from baseline: -15.63 [1.56] vs -8.07 [1.54]; P < 0.001). On the PGIC, significantly more patients in the esreboxetine group than in the placebo group reported their condition much or very much improved (odds ratio = 2.42; 90% CI, 1.549-3.786; P < 0.001). Esreboxetine also was associated with significant improvements in secondary outcomes compared with placebo. These included fatigue, as reflected in scores on the Multidimensional Assessment of Fatigue (mean [SE] change from baseline: -6.39 [0.75] vs -2.82 [0.75], respectively; P < 0.001), and scores on measures of patient function and health-related quality of life, including the 36-item Short Form Health Survey (SF-36) Physical Component Summary (mean change from baseline: 4.36 [0.59] vs 1.86 [0.59]; P = 0.002), the SF-36 Mental Component Summary (mean change from baseline: 4.25 [0.83] vs 1.81 [0.83]; P = 0.019), and the Sheehan Disability Scale total score (mean change from baseline: -6.50 [0.64] vs -2.79 [0.61]; P < 0.001). Numerically more patients in the esreboxetine group than in the placebo group reported at least one adverse event (71.6% vs 57.1%), most commonly constipation (17.2% vs 5.3%), insomnia (15.7% vs 3.0%), dry mouth (15.7% vs 2.3%), and headache (10.4% vs 2.3%). CONCLUSIONS: In this 8-week trial in patients with fibromyalgia, esreboxetine was associated with significant reductions in pain scores compared with placebo. It was also associated with improvements in outcomes relevant to fibromyalgia, including the PGIC, function, and fatigue. ClinicalTrials.gov identifier: NCT00357825. PMID- 20974320 TI - A prospective, randomized, double-blind, placebo-controlled study to assess the antiemetic effects of midazolam on postoperative nausea and vomiting in women undergoing laparoscopic gynecologic surgery. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) are distressing and frequent adverse effects (AEs) in women undergoing laparoscopic gynecologic surgery. Midazolam has been reported to be effective for preventing PONV in adults undergoing middle ear surgery and children undergoing strabismus surgery or tonsillectomy. OBJECTIVE: The aim of this study was to assess the antiemetic effects of midazolam on PONV in women undergoing laparoscopic gynecologic surgery. METHODS: This prospective, randomized, double-blind, placebo-controlled study was conducted (January-December 2009) at the Department of Anesthesiology, Ushiku Aiwa General Hospital (Ibaraki, Japan). Nonpregnant Japanese women (aged 22-54 years) undergoing myomectomy, hysterectomy, salpingo-oophorectomy, or oophorectomy were randomized to receive 1 of 2 different midazolam doses (50 or 75 MUg/kg IV) or placebo immediately after induction of anesthesia. Anesthesia was induced with propofol 2 mg/kg IV, and vecuronium 0.1 mg/kg IV was used to facilitate tracheal intubation. After tracheal intubation, anesthesia was maintained with sevoflurane 1.0% to 3.0% (inspired concentration) and air in oxygen. All episodes of PONV during the first 24 hours after anesthesia were assessed by an investigator 24 hours postoperatively; the investigator was blinded as to which treatment each patient had received. The patients were asked if nausea, vomiting, or retching had occurred. Details were recorded of any other AEs, as well as any spontaneous complaints. RESULTS: A total of 90 nonpregnant Japanese women were enrolled (mean [SD] age, 35 [6] years; mean height, 159 [6] cm; mean weight, 53 [8] kg). Each study group comprised 30 patients and was comparable with regard to patient demographic characteristics and types of surgery. The rate of patients experiencing PONV during the first 24 hours after anesthesia with midazolam 50 MUg/kg was 30% (P = 0.004 vs placebo) compared with 27% with midazolam 75 MUg/kg (P = 0.002 vs placebo) and 67% with placebo. The difference in the incidence of PONV between patients receiving midazolam 75 MUg/kg and those receiving midazolam 50 MUg/kg was not statistically significant. No clinically important AEs due to the study drug were observed in any of the groups. CONCLUSION: Midazolam 50 MUg/kg was not significantly different from midazolam 75 MUg/kg in the incidence of PONV, and both doses were associated with significantly less PONV compared with placebo during the first 24 hours after anesthesia in these Japanese women undergoing laparoscopic gynecologic surgery. PMID- 20974321 TI - How can the risk that orphan drugs present to budgets be managed better? PMID- 20974322 TI - A retrospective, observational cohort analysis of a nationwide database to compare heart failure prescriptions and related health care utilization before and after publication of updated treatment guidelines in the United States. AB - BACKGROUND: The current American College of Cardiology/American Heart Association (ACC/AHA) clinical guidelines for heart failure (HF), published September 20, 2005, provide a summary of the best evidence for treatment, but these recommendations are not always reflected in clinical practice. OBJECTIVES: The aims of this study were to compare 6-month prescribing habits in the United States before and after the publication of updated clinical guidelines for the evaluation and management of HF and the impact of these prescribing habits on health care resource use. METHODS: This retrospective, observational cohort analysis used the Humana nationwide health insurance administrative claims database that includes -3.5 million covered members from all 50 states and Puerto Rico who are enrolled in a health maintenance organization, a preferred provider organization, or a Medicare plan. The data included demographics (age, sex, type of insurance, and geographic location), medical information with up to 9 diagnostic codes per encounter, codes for procedures and medical equipment, laboratory tests, and pharmacy-dispensed medications. HF medication prescriptions and health care utilization were evaluated for 2 cohorts: those identified from claims before guideline publication (January 1, 2005-June 30, 2005) and those identified from claims after publication (October 1, 2006-March 31, 2007). Patients were eligible if they were aged >=45 years, had 12 months of continuous enrollment (6 months before and 6 months after the index date, defined as the date of diagnosis or hospitalization for HF), and had >=1 claim for HF. The primary outcome was the proportion of patients who received prescriptions for HF medications individually or in combination. Secondary outcomes were adherence to medication, all-cause and HF-specific hospitalizations, and emergency department and outpatient physician visits. RESULTS: The mean (SD) age in the before publication cohort (n = 29,784) was 75 (11) years; in the after-publication cohort (n = 33,598), it was 74 (11) years (P < 0.001). Half of all patients in each cohort were female (50% [n = 14,796 and n = 16,803, respectively]); 9% (n = 2539) of the before-publication cohort and 7% (n = 2283) of the after-publication cohort were classified as having moderate to severe HF based on the baseline number of hospitalizations (P < 0.001). Fewer patients in the before-publication cohort received angiotensin-converting enzyme inhibitors (43% [12,811/29,784] vs 44% [14,776/33,598]; P = 0.01), beta-blockers (37% [10,901/29,784] vs 41% [13,639/33,598]; P < 0.01), angiotensin receptor blockers (10% [3008/29,784] vs 13% [4378/33,598]; P < 0.01), or hydralazine (3% [865/29,784] vs 4% [1378/33,598]; P < 0.01). Among those with moderate to severe HF, there were no significant differences between groups in the use of combination therapy (ie, beta-blockers with any combination of isosorbide dinitrate, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or hydralazine; all combinations, P = NS between cohorts), except for less use of a beta-blocker with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker among the before-publication cohort (23% [595/2539] vs38% [875/2283]; P = 0.005). Therewere significantly fewer all-cause and HF-related outpatient visits, all-cause and HF-related hospitalizations, and all-cause and HF-related emergency department visits in the after-publication cohort (all, P < 0.001); however, the absolute differences in the proportions of patients in each cohort who required such services were relatively small. CONCLUSIONS: Based on this analysis of real world prescribing patterns, only small differences in prescribing practices were found before and after the 2005 publication of the ACC/AHA guidelines for HF treatment. Health care utilization was slightly, but significantly, reduced after publication of the guidelines. PMID- 20974323 TI - Review of regulatory recommendations for orphan drug submissions in the Netherlands and Scotland: focus on the underlying pharmacoeconomic evaluations. AB - BACKGROUND: Pharmacoeconomic evaluations of new drug therapies are often required for reimbursement or guidance decisions. However, for orphan drugs, country specific requirements exist. In the Netherlands, orphan drug developers can be exempted from providing a full pharmacoeconomic evaluation, whereas in Scotland, no such exceptions can be made, although additional modifying factors specific to orphan products may be considered. OBJECTIVE: The aim of the present work was to identify differences in the outcomes of the recommendations for orphan drugs for rare diseases between 2 European countries: Scotland and the Netherlands. METHODS: All orphan drug reports to the Dutch Committee for Pharmaceutical Assistance (Commissie Farma-ceutische Hulp [CFH]) and orphan drugs guidance issued by the Scottish Medicines Consortium (SMC) through May 2009 were reviewed from the respective organizations' Web sites. The following were gathered from the pharmacoeconomic analyses and recommendations for reimbursement in the Netherlands or guidance for drug use in Scotland: drug indication, outcome of pharmacoeconomic evaluation, recommendation, and exact date. RESULTS: Dossiers for 38 orphan drugs were submitted to the CFH; 37 were submitted to the SMC. Only 1 submission to the CFH included a full pharmacoeconomic analysis; all other reports included only a cost analysis. Twenty-four submissions to the SMC were accompanied by a full pharmacoeconomic evaluation; no information could be obtained for 4 drugs. The remaining reports either did not include a cost effectiveness analysis or were deemed insufficient by the SMC. Forty-three percent (10/23) of the cost-utility analyses submitted to the SMC reported an unfavorable outcome of more than L30,000/ quality-adjusted life-year (QALY) gained; of these, only 2 (20%) reporting incremental cost-utility ratios of L43.717 to L81.000 were granted a restricted positive recommendation. The CFH gave positive recommendations for reimbursement for 36 of 38 submissions (95%). Of the 37 orphan drugs submitted to the SMC, 19 (51%) received a positive recommendation for use. Seventy-three percent (8/11) of submissions to the SMC with an unfavorable cost-effectiveness estimate (ie, more than L30,000 [?34,000 or US $48,000] per QALY gained) received a negative recommendation for reimbursement. CONCLUSIONS: Ninety-five percent of orphan drug submissions were approved for reimbursement in the Netherlands, compared with 51% in Scotland, during the period of interest. Moreover, cost-effectiveness or cost-utility analyses were included in 24 of 37 submissions in Scotland, compared with only 1 of 38 in the Netherlands. PMID- 20974324 TI - Comparison of effects of two different formulations of clopidogrel bisulfate tablets on platelet aggregation and bleeding time in healthy Korean volunteers: A single-dose, randomized, open-label, 1-week, two-period, phase IV crossover study. AB - BACKGROUND: Clopidogel bisulfate, an oral antiplatelet agent that works by inhibiting adenosine diphosphate-induced platelet aggregation, is used in the treatment of coronary artery disease, peripheral vascular disease, and cerebrovascular disease. The newly developed generic version of Clopidogrel bisulfate has a mechanism of action comparable to the reference formulation. OBJECTIVE: The aim of this study was to assess and compare the pharmacodynamic effects and safety profile of these 2 formulations of Clopidogrel bisulfate in healthy volunteers. METHODS: This was a single-dose, randomized, openlabel, 1 week, 2-period, Phase IV crossover study conducted from July 2008 to February 2009. Healthy volunteers were randomly assigned to receive a 1-week course of the test formulation followed by a 1-week course of the reference formulation (each, 300 mg on day 1, then 75 mg for 6 days), or the reverse sequence, separated by a 2-week washout period. Inhibition of platelet aggregation and the effect on bleeding time were used to evaluate pharmacodynamic effects. Variables included the mean maximal activity (E(max)) of the percent inhibition of platelet aggregation and bleeding time. Blood was sampled at screening, on the morning before each first drug administration (days 1 and 21), the day after the completion of each 7-day treatment course (days 8 and 28), and 7 days after completion of each 7-day treatment course (days 14 and 34). The bioequivalence of the 2 pharmaceutical formulations was tested. The safety profiles included assessment of vital signs, laboratory test results, and the incidence of adverse events and adverse drug reactions. RESULTS: Two of the original 32 healthy Korean volunteers were excluded because of screening failure or withdrawal of consent. Therefore, 30 volunteers (16 males; mean [SD] age, 28.6 [8.0] years; age range, 19-51 years; mean weight, 62.4 [9.5] kg; weight range, 45-78 kg) were recruited into the study. E(max) and bleeding time did not differ significantly between the 2 groups. The mean change in E(max) was 44.1% (22.5%) and 44.3% (24.2%) and the mean change in bleeding time was 4.8 (3.7) and 4.6 (3.8) minutes after 7 days' administration of the test formulation and the reference formulation, respectively. The geometric mean ratio (90% CI) was 99.5 (82.9-116.2) and was within the bioequivalence acceptance range of 80% to 120%. Vital signs and platelet and neutrophil counts were within normal limits. None of the volunteers experienced any adverse events or adverse drug reactions. CONCLUSION: In this study of healthy volunteers, there were no significant differences between the 2 tablet formulations of Clopidogrel bisulfate in pharmacodynamic effects or safety profile. PMID- 20974325 TI - The relative bioavailability and fasting pharmacokinetics of three formulations of olmesartan medoxomil 20-mg capsules and tablets in healthy Chinese male volunteers: An open-label, randomized-sequence, single-dose, three-way crossover study. AB - BACKGROUND: Olmesartan medoxomil is an angiotensin II-receptor antagonist used in the treatment of hypertension. It is a prodrug and is converted to the pharmacologically active compound on de-esterification by arylesterase in the gastrointestinal tract. OBJECTIVE: This study investigated the relative bioavailability and fasting pharmacokinetic properties of olmesartan after single doses of a 20-mg test tablet, a 20-mg test capsule, and a commercially available 20-mg reference tablet in healthy Chinese male volunteers. The study was conducted to satisfy Chinese State Food and Drug Administration regulatory requirements for approval of a generic formulation of olmesartan medoxomil. METHODS: This study had an open-label, randomized-sequence, single-dose, 3 treatment, 3-period crossover design. Healthy volunteers were randomly assigned in a 1:1:1 ratio to receive a single 20-mg dose of the test tablet, test capsule, or reference tablet, each administered after a 12-hour overnight fast, followed by a 1-week washout period and administration of the alternate formulation. Blood samples were obtained at baseline and at 0.5, 1, 1.5,2,2.5,3,4,6,8,12,24,36, and 48 hours after dosing. Tolerability was assessed based on vital signs and laboratory values obtained before and after administration of study drug. The formulations were assumed to be bioequivalent if the 90% CIs for the log transformed ratios of C(max), AUC(0-t), and AUC(0-infinity) were within the predetermined equivalence range (70%-143% for C(max); 80%-125% for AUC(0-t) and AUC(0-infinity)), as established by the Chinese State Food and Drug Administration. RESULTS: Twenty-one healthy male subjects (mean age, 21 years [range, 18-25 years]; weight, 62.1 kg [range, 54.0-80.0 kg]) were enrolled in and completed the study. No period or sequence effect was observed. The mean AUC(0 infinity) values for the test tablet, test capsule, and reference tablet were 3993 (1070), 3567 (850), and 3849 (872) ng/mL/h, respectively. The 90% CIs for the log-transformed ratios of test tablet to reference tablet for C(max), AUC(0 48), and AUC(0-infinity) were 103.9 to 124.9, 94.0 to 111.5, and 94.4 to 111.7, respectively (all, P = NS). The corresponding 90% CIs for the log-transformed ratios of test capsule to reference tablet were 90.8 to 109.2, 84.9 to 107.9, and 85.1 to 100.7 (all, P = NS). Ten adverse events were reported during the study; 7 subjects complained of pain during blood sampling, and 3 had a blocked venous catheter. No treatment-related adverse events were reported or observed. CONCLUSIONS: In this single-dose crossover study in healthy Chinese male volunteers, the test and reference formulations of olmesartan medoxomil 20-mg capsules and tablets met the regulatory criteria for assuming bioequivalence. The 3 formulations were well tolerated. PMID- 20974326 TI - Immunologic response to fungus is not universally associated with chronic rhinosinusitis. AB - In the December 2009 issue of this journal, Orlandi et al presented a study in which peripheral blood mononuclear cells (PBMCs) from chronic rhinosinusitis (CRS) patients (5 from Texas, 5 from Utah) and seven nonhealthy controls were stimulated with fungal extracts. Despite the small numbers, they confirmed important aspects of previous studies: 1) CRS patients' PBMCs react to certain fungal stimuli by producing significantly (P < 0.05) higher amounts of interleukin (IL)-5 and IL-13 when compared to controls; 2) CRS patients have an enhanced humoral response (significantly elevated immunoglobulin [Ig] G levels to Alternaria); and 3) CRS patients react independently from an IgE-mediated allergy, as evidenced by that fact that nonallergic CRS patients also produced IL 5 in response to fungal stimuli. Unfortunately, the authors chose not to highlight their positive results. They emphasized what they failed to demonstrate, specifically an immune response to fungi above a certain threshold in some patients (Utah) with milder CRS. However, these results are potentially explained by the different methods used, and care should be applied when interpreting their results. PMID- 20974327 TI - Fungus and chronic rhinosinusitis: weighing the evidence. AB - The hypothesis that fungus causes most, if not all, cases of chronic rhinosinusitis (CRS) has been debated for over a decade. Many opinions and interpretations have been rendered, but it is the objective data that speaks the loudest. The debate simply boils down to a core tenet of the scientific method: Can the data be independently replicated? If so, our patients benefit as new treatments are developed. If not, then the hypothesis must be discarded and new lines of research pursued. Initial clinical trials supporting the fungal hypothesis have not been replicated in recent years by independent investigators. An attempt to independently replicate the basic science foundation of this hypothesis has also failed in a more heterogeneous group of CRS patients. The data can be dissected, reanalyzed, and reinterpreted and myriad arguments can be put forth. But an unbiased review of the data demonstrates that nearly every researcher outside of the original proponents of the fungal hypothesis has failed to replicate their work. The weight of the evidence is increasingly tipping the scales away from this theory. PMID- 20974328 TI - Acute invasive fungal rhinosinusitis: evaluation of 26 patients treated with endonasal or open surgical procedures. AB - OBJECTIVE: Acute invasive fungal rhinosinusitis (AIFRS) is a serious disease with a high mortality and morbidity rate, which almost always affects immunocompromised patients and/or patients with diabetes mellitus. Our purpose was to present the diagnostic and therapeutic management and outcome of these patients. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care university hospital. SUBJECTS AND METHODS: Twenty-six patients, who were operated on because of AIFRS between September 1999 and June 2009, were retrospectively evaluated in this study. Endoscopic surgery was used in 19 patients, and open surgical debridement was performed in seven patients. RESULTS: Overall survival rate of the patients in the open surgery group (4 of 7; 57.1%) was similar to that of the endoscopically treated group (9 of 19; 47.3%). Thirteen patients (50%) died of complications related to the underlying disease (9 of 13; 69.2%) and AIFRS (4 of 13; 30.7%). AIFRS-specific survival rate is 76.5 percent; 90 percent (9 of 10) and 57.1 percent (4 of 7) for endoscopic and open surgery groups, respectively. Four patients who died had pathological diagnosis of mucormycosis (P = 0.52). CONCLUSION: AIFRS can be successfully treated with a combination of endonasal surgical debridement and antifungal medications. Endonasal approach is suitable for patients diagnosed in the early stages of the disease and provides a less traumatic option in those patients who already have a poor health status. Open surgery should be preferred in the presence of intraorbital extension, palatinal, and/or intracerebral involvement. Reversing the underlying disease process and immunosuppression is as important as the surgical and antifungal treatment. PMID- 20974329 TI - Quality-of-life outcomes after endoscopic sinus surgery: how long is long enough? AB - OBJECTIVE: To determine the time interval during which quality-of-life (QOL) outcomes stabilize after endoscopic sinus surgery (ESS). STUDY DESIGN: Multi institutional, longitudinal cohort. SETTING: Tertiary rhinology centers. SUBJECTS AND METHODS: Adults with chronic rhinosinusitis from three medical centers were asked to provide responses to the Rhinosinusitis Disability Index (RSDI) and the Chronic Sinusitis Survey (CSS) at baseline and six months, 12 months, and 20 months after endoscopic sinus surgery. Repeated measures and post-hoc analyses were used to compare QOL scores among follow-up time points. Subgroup analyses were performed in a similar fashion for patients with and without nasal polyposis, asthma, allergies, acetylsalicylic acid intolerance, depression, and previous sinus surgery. RESULTS: A total of 127 patients provided complete follow up data for all three time points. Improvement in QOL scores was seen at six months after surgery for both the RSDI and CSS instruments. When comparing changes in mean QOL scores among all follow-up time points, there were no significant differences in either RSDI or CSS total scores (all P >= 0.853) or subscale scores (all P >= 0.251) between six, 12, and 20 months. Each individual subgroup demonstrated stable QOL scores between six and 20 months' follow-up, including patients with polyposis and those with intolerance to acetylsalicylic acid (all P >= 0.275). CONCLUSION: At a cohort level, improvements in QOL after ESS do not appear to change between six and 20 months. Clinical trial designs incorporating QOL outcomes after ESS should consider the six-month time frame as an appropriate primary end point. PMID- 20974330 TI - The utility of intrathecal fluorescein in cerebrospinal fluid leak repair. AB - OBJECTIVE: To evaluate the utility of intrathecal fluorescein (IF) for intraoperative localization and successful repair of cerebrospinal fluid (CSF) leaks. STUDY DESIGN: Case series with chart review. SETTING: Tertiary-care medical center. SUBJECTS AND METHODS: Subjects included those undergoing endoscopic CSF leak repair with or without the use of IF. Informed consent was obtained from all patients undergoing the administration of IF (total dose 10 mg). RESULTS: A total of 103 patients underwent CSF leak repair, and in 47 cases (45.6%), IF was used. Patients who were administered IF were more likely to have spontaneous CSF leak etiology (61.7% vs 16.1%; P < 0.001). Of the 47 cases with IF use, fluorescein was visualized at the skull base in 31 cases (66.0%), 11 (23.4%) had visible CSF leak without fluorescein coloration, and five (10.6%) had neither clear nor fluorescein-colored CSF visualized. Sensitivity and specificity for fluorescein detection was 73.8 percent (95% confidence interval [CI] 57.7% 85.6%) and 100 percent (95% CI 46.3%-100%), respectively. The false-negative rate was 26.2 percent (95% CI 15.8%-43.5%). Localization of the leak site was greater when fluorescein-colored CSF was visualized (100% vs 81.3%; P = 0.035). When fluorescein-colored CSF was not visualized intraoperatively, recurrence rates were 31.3 percent versus 9.7 percent when fluorescein coloration was seen, although this finding was not statistically significant (P = 0.10). CONCLUSION: The use of IF facilitates the accurate localization of CSF leaks and may assist the surgeon in confirming a watertight closure. The lack of intraoperative fluorescein visualization should not rule out the presence of CSF leak, as evidenced by a false-negative rate of 26.2 percent. PMID- 20974331 TI - Assessment of microvascular anastomosis training in otolaryngology residencies: survey of United States program directors. AB - OBJECTIVE: To assess current microvascular training strategies in otolaryngology residency programs. STUDY DESIGN: Cross-sectional study. SETTING: U.S. otolaryngology residency programs. SUBJECTS AND METHODS: A total of 104 U.S. otolaryngology program directors received surveys inquiring about program size, the presence of fellowship training in microvascular surgery, the number of microvascular cases per month, the use of microvascular animal laboratory, and whether residents, fellows, or co-attendings assist in the anastomoses. RESULTS: A 51 percent response rate was achieved, and of the 54 programs that responded, 78 percent reported no microvascular fellowship positions in plastics or head and neck reconstruction. A total of 52 percent reported performing three or fewer microvascular surgeries per month. Of the programs that did not have a microvascular fellow, only five (12%) performed eight or more surgeries per month. A total of 65 percent of the programs reported that residents assist during the anastomosis at least 75 percent of the time. Of the programs where residents assist 75 percent or more of the time, 70 percent have a formal training in microvascular technique ranging from demonstrating laboratory competencies to multiday courses. A total of 48 percent of the responding programs report having an animal laboratory for microvascular surgery. All animal laboratories used the rat as the model. CONCLUSION: Many programs find value in providing residents with microvascular training, both in the operating room and in the laboratory. Only a small minority of programs without fellowship positions responded that they perform microvascular surgery on a regular basis (4 or more surgeries per month). PMID- 20974332 TI - Total parotidectomy defect reconstruction using the buried free flap. AB - OBJECTIVE: 1) Present an alternative method of total parotidectomy with or without neck dissection defect reconstruction that results in improved cosmesis. 2) Describe applications of free tissue transfer in parotidectomy defect reconstruction. STUDY DESIGN: Case series with chart review. SETTING: Two tertiary-care medical centers. SUBJECTS AND METHODS: A two-institution retrospective review from 2002 to 2009 was conducted for buried free flaps utilized in reconstruction of defects from total parotidectomy with or without neck dissection. Patients with temporal bone or skin resections were excluded. Demographic information, tumor characteristics, surgical interventions, flap details, and adjunctive facial reconstructive techniques were recorded. Postoperative cosmetic results were evaluated by patient and physician satisfaction. RESULTS: Eighteen patients with a mean age of 57.4 years underwent flap reconstruction. Total parotidectomy was performed in all cases, 11 cases required facial nerve sacrifice, and 14 cases included neck dissection. The anterolateral thigh flap was the most often utilized free flap. Mean flap area was 65.5 cm(2). Adjunctive static facial reanimation was employed in eight patients. All flaps survived. Ten patients underwent adjuvant radiation. Free flap reconstruction resulted in cosmetic patient and surgeon satisfaction, despite adjuvant radiation therapy. CONCLUSION: Free flap reconstruction of total parotidectomy (with or without neck dissection) defects is safe and effective. It does not preclude adjunctive facial reanimation and provides sufficient tissue bulk to match the contralateral facial contour despite radical resections and adjuvant radiation therapy in most cases. PMID- 20974333 TI - Primary surgery for oropharyngeal cancer. AB - OBJECTIVE: The development of new techniques for transoral resection has led to a renewed interest in primary surgical treatment of oropharyngeal squamous cell cancer (SCCA). We reviewed our experience with primary surgery for oropharyngeal SCCA to identify factors associated with survival. STUDY DESIGN: Case series with chart review. SETTING: Tertiary medical center. SUBJECTS AND METHODS: Patients who underwent primary surgical treatment of oropharyngeal SCCA from 1985 to 2002 were analyzed. Patients who failed nonoperative treatment or had distant metastases at presentation were excluded. RESULTS: A total of 105 patients met study criteria. The majority of patients (91%) had advanced stage disease (III/IV). All patients received postoperative radiation; chemotherapy was used in eight patients. Five-year disease-free survival was 83 percent for stage I, 67 percent for stage II, 56 percent for stage III, and 43 percent for stage IV disease. Crude local control rates were 94 percent for T1 disease, 90 percent for T2 disease, 81 percent for T3 disease, and 80 percent for T4 disease; crude regional control rates were 100 percent for N0 disease, 90 percent for N1 disease, 84 percent for N2 disease, and 82 percent for N3 disease. Cox proportional hazards models revealed that nodal stage (hazard ratio [HR] 2.3, P = 0.02) and black race (HR 2.6, P = 0.004) were the only significant predictors of disease-free survival. CONCLUSION: Primary surgical treatment of oropharyngeal SCCA is effective in achieving excellent locoregional control and permits deintensification of adjuvant therapy, even in patients with advanced stage disease. Nodal status and race are the primary determinants of disease-free survival. These data provide useful information for counseling and treatment planning. PMID- 20974334 TI - A prospective study of the clinical impact of a multidisciplinary head and neck tumor board. AB - OBJECTIVE: There have been no studies undertaken on the effect of the multidisciplinary head and neck tumor board on treatment planning. The objective of this study was to determine the efficacy of the multidisciplinary tumor board in altering diagnosis, stage, and treatment plan in patients with head and neck tumors. STUDY DESIGN: Case series with planned data collection. SETTING: Comprehensive cancer center and tertiary academic hospital. SUBJECTS AND METHODS: A prospective study of the discussions concerning 120 consecutive patients presented at a multidisciplinary head and neck tumor board was performed. As each patient was presented, a record was made of the "pre-conference" diagnosis, stage, and treatment plan. After case discussion, the "post-conference" diagnosis, stage, and treatment plan were recorded. Results are compared between malignant and benign tumor cohorts. RESULTS: The study population comprised 120 patients with new presentations of head and neck tumors: 84 malignancies and 36 benign tumors. Approximately 27 percent of patients had some change in tumor diagnosis, stage, or treatment plan. Change in treatment was significantly more common in cases of malignancy, occurring in 24 percent of patients versus six percent of benign tumors (P = 0.0199). Changes in treatment were also noted to be largely escalations in management (P = 0.0084), adding multi-modality care. CONCLUSION: A multidisciplinary tumor board affects diagnostic and treatment decisions in a significant number of patients with newly diagnosed head and neck tumors. The multidisciplinary approach to patient care may be particularly effective in managing malignant tumors, in which treatment plans are most frequently altered. PMID- 20974335 TI - Clinical and biomechanical analyses to select a suture material for uvulopalatopharyngeal surgery. AB - OBJECTIVE: The selection of the degradation pattern of suture materials is critical in uvulopalatopharyngeal surgery because of the complex oral environment such as the constant presence of saliva; the microbial accumulation; and the functions related to speech, mastication, and swallowing. The aim of the study was to identify appropriate suture materials for uvulopalatopharyngeal surgery by analyzing the clinical and biomechanical results obtained using four different absorbable suture materials. STUDY DESIGN: A randomized open-label trial. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Eighty patients with obstructive sleep apnea syndrome who had undergone microdebrider-assisted extended uvulopalatoplasty were randomized into the four suture groups: sutures of polyglycolide (Dexon) and copolymers of polyglycolide and other degradable polymers (Polysorb, Monocryl, Maxon). Handling characteristics, surgical outcomes, Young's modulus reduction, morphologic changes by scanning electron microscope, and saliva absorption test were analyzed. RESULTS: Monocryl (poly(glycolide-co-epsilon-caprolactone)) had the optimal handling characteristics and exhibited two-stage degradation: sufficient tensile strength was maintained initially to allow wound healing, and then the suture degraded rapidly to avoid irritation. In contrast, the hydrolytic degradation of Dexon, Polysorb, and Maxon seemed to involve only an approximately single-stage process in the oral environment. Moreover, a large amount of debris was observed among filaments in Dexon and Polysorb, whereas only some scattered debris accumulated on Monocryl and Maxon under scanning electron microscope. CONCLUSION: Poly(glycolide-co-epsilon-caprolactone) has good handling characteristics and degrades in two stages. It is a suitable suture material for uvulopalatopharyngeal surgery. PMID- 20974336 TI - Comparison of otologic complications between intensity-modulated and two dimensional radiotherapies in nasopharyngeal carcinoma patients. AB - OBJECTIVE: To investigate the otologic complications in patients with nasopharyngeal carcinoma (NPC) who were treated by intensity-modulated radiotherapy (IMRT) and compared with those who were treated by two-dimensional radiotherapy (2DRT). STUDY DESIGN: A historical cohort study was performed comprising NPC patients who underwent IMRT or 2DRT at Chung Shan Medical University Hospital. SETTING: Chung Shan Medical University Hospital. SUBJECTS AND METHODS: Twenty-six NPC patients treated by IMRT (group A) and 18 NPC patients treated by 2DRT (group B) were enrolled. All patients underwent otoscopy, audiometry, and a vestibular-evoked myogenic potential (VEMP) test at a mean interval of three years after irradiation. RESULTS: Although groups A and B did not significantly differ in the occurrence rate of otitis media with effusion (OME), group B had a significantly greater occurrence rate of chronic otitis media than group A (P < 0.05, chi(2) test). The incidences of high-frequency sensorineural hearing loss were 46 percent in group A and 67 percent in group B, with no significant difference between the two. In terms of VEMPs, group A had a significantly lower abnormal rate (31%) than group B (61%; P < 0.05, chi(2) test). In addition, a significant relationship existed between T stages and OME in NPC patients treated by IMRT (P < 0.01, Fisher-Freeman-Halton test) but not by 2DRT. CONCLUSION: The incidence of chronic otitis media and abnormal VEMPs in NPC patients treated by IMRT were significantly lower when compared with those treated by 2DRT, demonstrating the superiority of IMRT in decreasing unwanted otologic complications. However, occurrence of OME, which was related with advanced T stage, cannot be reduced by IMRT. PMID- 20974337 TI - Bilateral same-day surgery for bilateral perforated chronic otitis media: Inlay butterfly cartilage myringoplasty. AB - OBJECTIVE: Conventional bilateral same-day tympanoplasty or myringoplasty has been rarely performed because of the risk of postoperative complications. Inlay butterfly cartilage myringoplasty (IBCM) has been shown effective for same-day closure of bilateral tympanic membrane perforations and is a quicker and more comfortable procedure for the patient. Immediate postoperative hearing is not compromised by packing materials because no external canal packing or middle ear support is required. We assessed the efficacy and safety of bilateral same day IBCM. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Of the 81 patients (age range, 9-64 years) who underwent conventional tympanoplasty/mastoidectomy for bilateral perforated chronic otitis media between June 2005 and September 2009, 17 with small-to medium perforations and no history of otorrhea underwent same-day cartilage IBCM on the contralateral ear. Median follow-up duration was 13.0 months. RESULTS: The graft take rate was 100 percent, with no retraction pockets or displaced grafts observed during follow-up. Mean air-bone gap was improved from 15.8 to 8.4 dB. Twelve patients had an average air-bone gap between 0 and 10 dB, three between 11 and 20 dB, and two between 21 and 30 dB. Two patients had myringitis postoperatively, but it improved with antibiotic treatment. CONCLUSION: Bilateral same-day IBCM offers favorable outcomes in selected patients. PMID- 20974338 TI - Induced endolymphatic flow from the endolymphatic sac to the cochlea in Meniere's disease. AB - OBJECTIVE: The aim of the present study was to verify whether drugs injected into the endolymphatic sac (ES) can reach the cochlea and possibly treat inner ear disorders. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral center, Otolaryngology Department, University of Verona. SUBJECTS AND METHODS: Patients with Meniere's disease (MD) who were candidates for ES decompression were selected. Nineteen subjects received dexamethasone (DEX) via injection into the ES. To objectively define whether substances administered into the ES could reach the cochlea, we added gadolinium (GD) in three patients. All subjects had intraoperative electrocorticogram recordings and an audiologic follow-up. The three subjects who underwent injection of the DEX-GD solution were followed-up with magnetic resonance imaging. The audiological data are presented during a follow-up period of 12 months. RESULTS: Intraoperative electrocochleography recordings revealed no changes in two patients and summating potentials and compound action potential latency and wave-form modifications in all the other subjects. GD distribution was observed from 48 hours to one week after ES injection into the cochlea of the three subjects injected with DEX-GD. GD-related enhancement of inner ear structures lasted more than two weeks in all subjects. Pure tone average results showed hearing improvement of at least 20 dB HL in 42 percent of patients (8 of 19) at the 12-month follow-up. Statistically significant differences emerged between the mean pure tone average of the ES procedure subjects at one and 12 months after surgery (P = 0.0096). CONCLUSION: This novel approach might reveal new prospects for treating viral, metabolic, autoimmune, and genetic disorders of the cochlea. PMID- 20974339 TI - Changes and consistencies in the epidemiology of pediatric adenotonsillar surgery, 1996-2006. AB - OBJECTIVE: Determine changes in rates for pediatric adenotonsillar procedures over time with attention to infectious indications. STUDY DESIGN: Historical cohort study. SETTING: Academic medical center. SUBJECTS AND METHODS: The National Survey of Ambulatory Surgery and the National Hospital Discharge Survey 1996 and 2006 releases were examined, extracting all cases of pediatric tonsillectomy, adenotonsillectomy, and adenoidectomy. The aggregate numbers and rates of adenotonsillar procedures performed overall and specifically for chronic infectious etiologies were determined. These procedure rates were then compared to determine differences in performance rates between 1996 and 2006. RESULTS: In 1996, an estimated 441,870 +/- 23,315 children underwent some form of adenotonsillar surgery in the ambulatory and inpatient settings (60,034 +/- 6994 tonsillectomies, 255,217 +/- 18,960 adenotonsillectomies, and 126,619 +/- 11,627 adenoidectomies), while in 2006, the total rose to 695,029 +/- 36,979 children (58,111 +/- 9645 tonsillectomies, 506,778 +/- 32,054 adenotonsillectomies, and 129,540 +/- 15,714 adenoidectomies). However, when examined according to infectious indications, a notable decline in the population rate of tonsillectomy from 0.62 per 1000 children in 1996 to 0.53 per 1000 in 2006 was found (P = 0.252). Moreover, the larger decline in the rate of adenotonsillectomy for infectious indications from 2.20 per 1000 to 1.46 per 1000 was significant (P = 0.003). There was no significant change adenoidectomy rates for chronic infectious etiologies (0.25 versus 0.21 per 1000, P = 0.326). CONCLUSION: Although there was an overall increase in the rate of performance of adenotonsillar surgery, population adjusted performance rates of these procedures specifically for infectious indications declined from 1996 to 2006. PMID- 20974340 TI - The quality of life and health utility burden of recurrent respiratory papillomatosis in children. AB - OBJECTIVE: In this study we 1) measured the impact of juvenile-onset recurrent respiratory papillomatosis on health-related quality of life, voice-related quality of life, and family psychosocial well-being; and 2) compared these different measures, exploring their intercorrelation and their correlation with clinical disease severity. STUDY DESIGN: Cross-sectional qualitative study. SETTING: Tertiary academic pediatric hospital. SUBJECTS AND METHODS: Twenty consecutive children with active juvenile-onset recurrent respiratory papillomatosis (JoRRP) were included. Standardized interviews were performed on parents and children with the use of four validated tools: the Health Utilities Index version 3; the Pediatric Voice-Related Quality of Life survey; the Impact on Family Scale; and a visual analogue health preference measure. Clinical disease severity and demographic data also were collected. RESULTS: Subjects (13 male, 7 female) had a median age of 9.2 years, median age of JoRRP onset of 3.8 years, and averaged four procedures per year of disease. Mean health utility was 0.76 (95% confidence interval 0.68-0.84) on a scale of 0 (death) to 1 (perfect health). Marked impact on voice-related quality of life and family psychosocial health also was identified. Health burden correlated poorly with existing methods of severity scoring. CONCLUSION: This is the first study to use validated measures of health utility, voice-related quality of life, and psychosocial impact. This information has public health implications, providing essential parameters for accurate modeling studies and cost-utility analysis of future interventions, including different human papilloma virus vaccination strategies. PMID- 20974341 TI - Influence of race and ethnicity on access to care among children with frequent ear infections. AB - OBJECTIVE: Determine the impact of racial/ethnic disparities on access to care for children with frequent ear infections (FEI). Identify disparities to target for intervention. STUDY DESIGN: Cross-sectional analysis of national database. SETTING: Academic medical center. SUBJECTS AND METHODS: The National Health Interview Survey (1997 to 2006) was utilized to identify children with FEI (defined as three or more ear infections in the preceding year). Age, sex, race/ethnicity, income level, and insurance status were extracted. Access to care was measured by ability to afford medical care and prescription medications, specialist visitation, and emergency department visits. Multivariate analysis determined the influence of demographic variables on the ability to access health care resources. RESULTS: An annualized population of 4.65 +/- 0.08 million children reported FEI. Overall, 3.7 percent could not afford care, 5.6 percent could not afford prescriptions, and only 25.8 percent saw a specialist. A larger percentage of the black (42.7%) and Hispanic children (34.5%) with FEI were below the poverty level, versus white children (12.4%; P < 0.001); 18.2 percent of Hispanic children were uninsured, versus 6.5 percent of white children (P < 0.001). On multivariate analysis, children with FEI that were black or Hispanic had increased odds ratios relative to white children for 1) not being able to afford prescription medications (odds ratios [OR] 1.76 and 1.47, respectively; P < 0.002); 2) not being able to see a specialist (OR 1.62 and 1.86, respectively; P < 0.001); and 3) visiting the emergency department (OR 2.50 and 1.32, respectively; P < 0.001). CONCLUSION: Racial/ethnic disparities among children with FEI significantly influence health care resource access and utilization. These disparities should be targeted for intervention. PMID- 20974342 TI - Biofilm and persistent inflammation in endoscopic sinus surgery. AB - Bacterial biofilms have been observed in many patients with chronic rhinosinusitis, but their importance is still being investigated. This study examines the association between biofilms and other clinical findings in chronic rhinosinusitis patients. Twenty-four patients with chronic rhinosinusitis who failed medical management underwent endoscopic sinus surgery (ESS). Tissue was collected from the ethmoid sinus and analyzed for the presence of biofilm by hematoxylin and eosin staining, fluorescent in situ hybridization, and confocal scanning laser microscopy. Biofilms were classified as extensive (> 50% of mucosal surface in sample) or present (< 50% of surface). The surgeon remained blinded to the biofilm status of patients until postoperative follow-up was complete. The presence of bacterial biofilm was strongly associated with persistent mucosal inflammation after ESS (53% of biofilm-positive patients vs 0% of biofilm-negative patients, P = 0.009). The amount of biofilm was not important as there was no significant difference between the extensive and present biofilm classifications with respect to inflammation. The presence of biofilm was not associated with prior ESS, allergies, eosinophils, polyps, or presence of fungal elements. PMID- 20974343 TI - Seeing the light: endoscopic endonasal intraconal orbital tumor surgery. PMID- 20974344 TI - Endoscopic vein graft harvest in head and neck reconstruction. PMID- 20974345 TI - Huge radicular cyst. PMID- 20974346 TI - Oropharyngeal hairy polyps: an uncommon cause of infantile dyspnea and dysphagia. PMID- 20974347 TI - Congenital cholesteatoma originating within the facial nerve canal. PMID- 20974348 TI - Osteochondroma of the mandibular condyle manifesting only as conductive hearing loss. PMID- 20974350 TI - The human external nose and its evolutionary role in the prevention of obstructive sleep apnea. PMID- 20974351 TI - Scientific independence of authors and of journals to their published articles. PMID- 20974353 TI - Letter from the guest editor. PMID- 20974354 TI - Adnexal masses: characterization and imaging strategies. AB - The differential diagnosis for adnexal masses is wide, encompassing a range of benign, borderline, and malignant entities. Stratification of risk is made on age, menopausal status, imaging features, and tumor markers. This review outlines the different imaging modalities available to characterize adnexal masses, describes the typical ultrasound and magnetic resonance imaging features of the most commonly encountered adnexal lesions, and provides a suggested imaging algorithm in the management of such patients. PMID- 20974355 TI - Congenital and acquired conditions of the vulva and vagina on magnetic resonance imaging: a pictorial review. AB - Magnetic resonance imaging (MRI) has become an established imaging modality for characterizing pelvic pathology, chiefly because of superb contrast resolution and lack of ionizing radiation. In recent years, MRI has been used to stage vulval and vaginal malignancies and assist detection of recurrence. It has also proved useful in the characterization of Mullerian duct anomalies. We review the typical imaging characteristics on MRI of congenital and acquired conditions involving the vulva and vagina. PMID- 20974356 TI - Lymph node imaging in gynecologic malignancy. AB - The accurate identification and characterization of lymph nodes is essential in staging gynecologic malignancies. The presence of nodal metastases carries important prognostic and therapeutic significance. Identification of metastatic lymph nodes on imaging can help in treatment planning, disease response, and detection of disease recurrence. In this article, the strengths and weakness of the currently available imaging modalities will be discussed. Evolving techniques, such as diffusion-weighted imaging, magnetic resonance lymphography with nanoparticles, 18-flurodeoxyglucose positron emission tomography/computed tomography, lymphoscintigraphy, and more novel techniques will also be reviewed. PMID- 20974357 TI - Imaging of uterine malignancies. AB - This article reviews the role of imaging in malignant neoplasms of the uterine corpus. Endometrial cancer is the most common uterine malignancy, and diagnosis is made by histology. Staging of these tumors remain surgical-pathologic on the 2009 International Federation of Gynecology and Obstetrics staging system. However, imaging is important in treatment planning, with magnetic resonance imaging providing the best staging for the primary tumor; more advanced disease may be evaluated with computed tomography or positron emission tomography computed tomography. Uterine sarcomas are uncommon and heterogeneous group of malignancies. International Federation of Gynecology and Obstetrics have introduced a new staging system for uterine sarcoma that is also surgical pathologic. Imaging is used in evaluating these tumors and in defining the extent of disease. Other malignant tumors involving the uterus and discussed here include lymphoma and metastases. PMID- 20974358 TI - Radiological staging of ovarian carcinoma. AB - Ovarian cancer is the sixth most commonly diagnosed cancer in the world, accounting for 4% of all female cancers. An estimated 1 in 71 women in the United States will develop ovarian cancer in their lifetime. Accurate staging of ovarian carcinoma is vital in the appropriate management and counseling of patients. The surgical staging proposed by the International Federation of Obstetrics and Gynaecology is the most universally used, and International Federation of Obstetrics and Gynaecology encourages the use of imaging techniques to assess prognostic factors, such as resectable disease and lymph node status. Identifying the volume and locations of tumor is valuable in planning percutaneous tissue biopsy, triaging patients to either primary cytoreductive surgery, or primary platinum-based chemotherapy. Contrast-enhanced computed tomography is the modality of choice for the staging of ovarian carcinoma, with magnetic resonance imaging being used as a problem-solving tool. In this article we discuss and illustrate the staging of ovarian carcinoma, with emphasis on the current imaging modalities and optimal image acquisition. PMID- 20974359 TI - Cervical tumors. AB - Imaging the cervix for benign and malignant disease can be achieved using transvaginal ultrasound, computed tomography (CT), magnetic resonance imaging, and 18-fluorodeoxyglucose positron emission tomography. The best established role of imaging is in cervical carcinoma where magnetic resonance imaging, CT and increasingly positron emission tomography-CT are the most frequently used imaging modalities. These have a role in staging, treatment selection, recurrent disease, and imaging complications of treatment. Histopathological diagnosis of cervical disorders cannot be made on the basis of imaging alone but certain imaging features may provide an indication as to the underlying diagnosis. We describe the imaging features of some malignant tumor subtypes in which a preoperative diagnosis may alter management. Benign lesions of the cervix are usually detected incidentally or during investigations for dysfunctional vaginal bleeding. We describe the imaging features of the commonly encountered benign cervical lesions. PMID- 20974360 TI - Radiology of benign disorders of menstruation. AB - Menstrual complaints are common and include pain, abnormal bleeding, and menstrual irregularity. The etiology is wide-ranging and includes endometriosis, fibroids, adenomyosis, pelvic congestion syndrome, pelvic inflammatory disease, endometrial hyperplasia, and polyps. Polycystic ovarian syndrome and some congenital uterine anomalies may present with menstrual disturbance and have been included in this review. Transvaginal ultrasound is widely used as first-line investigation. Magnetic resonance imaging is used increasingly with high diagnostic accuracy and confidence. Its multiplanar capacity and superior tissue contrast resolution enable accurate presurgical mapping of fibroids, deep pelvic endometriosis, and adenomyosis. Similarly, accurate differentiation of congenital uterine anomalies depends on multiplanar imaging with either 3-dimensional ultrasound or magnetic resonance imaging. Recent advances in imaging and radiological intervention, combined with an understanding of the underlying causes of menstrual dysfunction, therefore aid in accurate diagnosis and optimal treatment planning. PMID- 20974361 TI - Magnetic resonance imaging for the evaluation of acute abdominal pain in pregnancy. AB - The investigation of acute abdominal pain in pregnancy is challenging. The use of ultrasound may be limited due to the patient's change in body habitus and computed tomography is not desirable due to fetal irradiation. Magnetic resonance imaging (MRI) has thus become increasingly popular in the evaluation of such patients, due to its lack of ionizing radiation, multiplanar capability and high contrast resolution. This review will detail the MRI technique required to image the pregnant abdomen and describe the MRI features of common causes of acute abdominal pain in pregnancy. PMID- 20974362 TI - ASE is your advocate. PMID- 20974363 TI - The Aussie experience. PMID- 20974364 TI - Current state of training in vascular medicine. PMID- 20974365 TI - A rising paradigm of appropriateness. PMID- 20974366 TI - Being thankful. PMID- 20974367 TI - Obituary for Yves Lecrubier. PMID- 20974369 TI - Neuroimaging in neurologic emergencies. Foreword. PMID- 20974372 TI - Nontraumatic intracranial hemorrhage. AB - Nontraumatic (or spontaneous) intracranial hemorrhage most commonly involves the brain parenchyma and subarachnoid space. This entity accounts for at least 10% of strokes and is a leading cause of death and disability in adults. Important causes of spontaneous intracranial hemorrhage include hypertension, cerebral amyloid angiopathy, aneurysms, vascular malformations, and hemorrhagic infarcts (both venous and arterial). Imaging findings in common and less common causes of spontaneous intracranial hemorrhage are reviewed. PMID- 20974371 TI - Imaging of acute ischemic stroke. AB - In this article the individual components of multimodal computed tomography and multimodal magnetic resonance imaging are discussed, the current status of neuroimaging for the evaluation of the acute ischemic stroke is presented, and the potential role of a combined multimodal stroke protocol is addressed. PMID- 20974373 TI - Acute neurointerventional therapies. AB - In the past two decades, minimally invasive neurointerventional therapies have become the standard of care for a variety of neurologic diseases. This article reviews some of the principal areas in which these techniques can be applied successfully in acute emergencies of the brain, head, and neck. PMID- 20974374 TI - Orbital and intracranial complications of acute sinusitis. AB - This article addresses the imaging considerations for subtle early studies of imaging findings in sinusitis, focusing on early detection by the radiologist, which depend on dedicated imaging protocols and a careful, thorough search pattern. Pathogenesis and key imaging findings for orbital complications are discussed, followed by the intracranial complications of sinusitis. PMID- 20974375 TI - Head trauma. AB - Worldwide, an estimated 10 million people are affected annually by traumatic brain injury (TBI). More than 5 million Americans currently live with long-term disability as a result of TBI and more than 1.5 million individuals sustain a new TBI each year. It has been predicted that TBI will become the third leading cause of death and disability in the world by the year 2020. This article outlines the classification of TBI, details the types of lesions encountered, and discusses the various imaging modalities available for the evaluation of TBI. PMID- 20974377 TI - Maxillofacial (midface) fractures. AB - Recognizing typical midface fracture injuries and describing the imaging findings that are relevant to the maxillofacial surgeon are important. Particular attention should be paid to findings that potentially result in significant cosmetic or functional complications. Radiologists should evaluate facial fractures in multiple planes with coronal and sagittal reformats, which are especially helpful for horizontally oriented facial fractures, such as injuries to the orbital floor and the hard palate. 3-D images can also facilitate a broader understanding of the fracture impact on facial width, height, and projection and are useful for an overview of more complex fracture patterns that involve multiple facial bones. PMID- 20974376 TI - Central nervous system infection. AB - This article outlines a practical imaging approach to CNS infection and reviews 5 basic imaging patterns commonly seen: (1) extra-axial lesion, (2) ring-enhancing lesion, (3) temporal lobe lesion, (4) basal ganglia lesion, and (5) white matter abnormality. Opportunistic infections in the setting of HIV are also discussed within the context of these 5 basic imaging patterns. Characteristic imaging features in conjunction with clinical history are also highlighted in order to narrow the differential diagnosis or suggest a specific diagnosis in some cases. PMID- 20974378 TI - Intracranial hypotension and intracranial hypertension. AB - Intracranial pressure (ICP) is the pressure within the intracranial space. Intracranial hypotension is a clinical syndrome in which low cerebrospinal fluid volume (CSF) results in orthostatic headache. Severe cases can result in nausea, vomiting, photophobia, and, rarely, decreased level of consciousness and coma. CSF opening pressure can be within the normal range in spontaneous intracranial hypotension. Imaging tests therefore play a key and decisive role in the diagnosis, as well as treatment, of intracranial hypotension. Intracranial hypertension occurs in a chronic form known as idiopathic intracranial hypertension, as well as in a large variety of neurologic and systemic disorders. Symptoms include headache, nausea and vomiting, blurred vision, and in severe cases, altered level of consciousness that can progress to coma and death. Direct measurements of CSF pressure through lumbar puncture (in idiopathic intracranial hypotension) or invasive ICP monitoring (in acute intracranial hypertension) are the key diagnostic tests. Imaging is used primarily to determine treatable causes of increased ICP, to assess for impending brain herniation, and to evaluate ventricular size. PMID- 20974379 TI - Seizures: emergency neuroimaging. AB - The various findings observed on computed tomography (CT) and magnetic resonance (MR) imaging examinations in patients with seizures reflect the variety of different causes that give rise to this common neurologic symptom. In the emergency setting, CT is most valuable in its ability to accurately identify acute abnormalities that require emergent medical or surgical treatment. MR imaging, by contrast, is usually reserved for patients with recurrent or refractory seizures. The accurate interpretation of either modality requires familiarity with how seizures are classified clinically, the most common presenting features of different causes for seizures, the relevant neuroanatomy, and the imaging manifestations of both common and uncommon causes of seizures and epilepsy. Of particular practical importance to the radiologist is the ability to recognize (1) the most common findings in patients with recurrent seizures and (2) potentially reversible causes for seizures that require prompt intervention to avoid or minimize permanent brain injury. This article surveys a variety of different causes for seizures and epilepsy, focusing on specific clinical features that can help to refine differential diagnosis, and on imaging findings characteristic of different disorders. PMID- 20974380 TI - Spine and spinal cord emergencies: vascular and infectious causes. AB - This content presents infectious and vascular spinal emergencies, including epidural abscess, nontraumatic epidural hematoma, vascular malformations, and spinal cord infarction. The spine is subjected to multiple potential insults, such as trauma, infection, ischemia, hemorrhage, tumor, inflammation, and degeneration. All of these processes can lead to the sudden onset of neurologic symptoms, such as motor weaknesses, bowel and bladder incontinence, and sensory changes. Therefore, prompt recognition of these entities is important to reverse or minimize potential neurologic injury. The authors discuss several infectious and vascular spinal emergencies, including epidural abscess, nontraumatic epidural hematoma, vascular malformations, and spinal cord infarction. PMID- 20974381 TI - Emergency head & neck imaging: infections and inflammatory processes. AB - Neck infections are fairly common in the emergency setting, affecting a broad spectrum of the patient population. Care should be taken not only to distinguish these conditions from other noninfectious origin such as malignancy but also to guide acute clinical management. A familiarity with neck anatomy, the imaging modalities used for investigation of such conditions, as well as common findings on imaging are critical to the care of affected patients. Cross-sectional imaging is a mainstay in this setting. This article presents the most common neck infections, and details some of their most prominent findings on cross-sectional imaging. PMID- 20974382 TI - Pediatric central nervous system emergencies. AB - This article summarizes current state-of-the-art techniques used in the management of pediatric neurologic emergencies. Solutions to challenges faced by the radiologist, including the selection of an appropriate modality for an individual patient, are discussed. Imaging appearances of specific entities are described with an emphasis on conditions unique to the pediatric population. PMID- 20974383 TI - Preface a fact of life: business and promotion expertise in the aesthetic surgery practice is not an option. PMID- 20974384 TI - Office managers' forum. AB - This article is a summary of the key elements presented during the conference held as part of the Practice Management and Development course sponsored by the Multi-Specialty Foundation in Las Vegas, Nevada in 2009. This article represents an amalgam of perspectives from practices across the United States. The Office Managers' Forum brought together the office managers and surgeons from practices across the United States as panelists. The panelists answered a multitude of practice management questions that included wide-ranging topics such as accounting and financing, staff well being, working with a spouse, hiring and firing, staff meetings, accreditation, motivation, and problems and perks specifically associated with a facial plastic surgery practice. PMID- 20974385 TI - Being a responsible leader. AB - People who administer organizations of various types, including medical practices, are finding it increasingly necessary to demonstrate leadership. The challenge is to understand the meaning of effective leadership and to have guiding principles with regard to its implementation. It is argued here that responsibility represents a key guiding theme that doctors and practice managers can use to chart their day-to-day actions as leaders. Responsibility implies accountability to a broad array of groups and individuals who increasingly expect that leaders act in a manner that is aligned with their interests. This new era of leader accountability raises the question, to whom and what are organizational leaders responsible? In an attempt to answer this question, The author elaborates a broad perspective of responsible leadership and address both internal and external stakeholders to which a leader is responsible. Recommendations and principles are provided for how to balance the needs and interests of various stakeholders when leading one's practice. The article ends with a consideration of important caveats with regard to responsible leadership. PMID- 20974386 TI - The art of the successful consultation. AB - The current trends in the patients options for making decisions to have cosmetic surgeries have made the provider-closing process more intense and complicated. These trends include, but are not limited to, increased price shopping, more comparison shopping, increased use of the internet versus word of mouth and more knowledge available in conventional media. This discussion focuses on the process that takes place in the practice after the first ringing of the phone and after having successfully gotten the word out. After the deployment of positive and result-oriented advertisements, staff consultation closure skills determine your economic success. Included are discussions of major challenges in executing successful consultations related to getting the entire practice, including the doctor, to accept and employ a wellexecuted consultation. Four essentials of the successful and artful consultation are discussed: the phone inquiry, the follow up after the phone call, the in-person contact, and the follow-up after the in person contact, with the ultimate goal of a continual flow of paying patients. PMID- 20974387 TI - Auditing your practice: nonfinancial variables to survive or thrive. AB - The strategy of the nonfinancial audit is discussed, with specific information for the facial plastic and aesthetic surgeon. The author provides specific questions and a roadmap for the practitioner to follow to complete a nonfinancial audit to expose the strengths and weaknesses of their practice. This article discusses quality, productivity, service, patient management, marketing, third party contractors, and other essential aspects of the practice audit. PMID- 20974388 TI - Retailicine, somewhere between retail and medicine. AB - In the increasingly competitive market of aesthetic surgery and the unstable predicament of the current economy, managing a successful aesthetic practice becomes ever more difficult. This article introduces the concept of Retailicine, combining essential elements of retail with the core principles of medicine. This new concept stresses the importance of the customer (patient) and provides tips to help manage the aesthetic practice. Through incorporating the techniques mentioned in this article, the aesthetic physician can ensure a successful practice despite current economic uncertainty. PMID- 20974389 TI - Essential marketing tips: build your own brand one step at a time. AB - This article discusses about physicians and their practice in terms of a "brand" that is described as one's persona and unique traits. By developing and portraying the uniqueness and singularity of the physician and the practice, one becomes open and transparent to clients for greatest patient satisfaction. Along with some background stories of well-known merchandise brands, presented are tips and advice for branding and selling oneself and one's medical practice. Very practical assignments are recommended for the physician to look at his or her own practice and how it appears to others on the "outside looking in." PMID- 20974390 TI - Eight worst advertising mistakes. AB - This article presents strategies for advertising the medical practice. The emphasis is on breaking out of the old rules of how one should advertise and delves into asking questions that lead to a true strategy unique to one's medical practice and offerings. The article discusses the myriad ways to think about and create a patient-centered approach, turning from "here is what we offer" to instead "what you want we offer." PMID- 20974391 TI - Internet marketing 101. AB - In an era when social media sites like YouTube, Facebook, and Twitter dominate the popular press, many surgeons overlook the foundational tactics and strategies necessary for long-term practice development and lead generation on the Internet. This article analyzes common errors made by surgeons during the development and implementation of Web site projects, focusing on the areas of strategy development; domain name identification; site plan creation; design considerations; content development; vendor selection; and launch, promotion, and staff training. The article emphasizes that, because the Web site remains the foundation of a surgeon's branding message, minimizing errors during development and construction is critical, particularly in highly competitive or saturated markets, for today's facial plastic surgery practice. PMID- 20974392 TI - Internet marketing 401. AB - For facial plastic surgeons who are already realizing increased patient consultation requests from their online marketing efforts, the primary concern often becomes implementing additional tactics and strategies that can keep their online marketing fresh, relevant, and effective. This article creates a framework for evaluating advanced online marketing opportunities by analyzing each opportunity according to the variables of possible return, average cost to implement, probability of success, and implementation time. Within this framework, 11 distinct tactics are discussed, with special emphasis on the most common marketing needs and challenges of facial plastic surgery practices. PMID- 20974393 TI - Five secrets to leveraging maximum buying power with your media project. AB - Planning and executing a successful media campaign or project requires knowledge and expert execution of specific techniques and skills, including understanding of the requirements for proper media research and competitive intelligence, effective planning of media schedules, negotiation of best rates with media companies, monitoring the campaign, accurately tracking and evaluating results, and making smart adjustments based on tracking data to maximize the profitability and success of the enterprise. Some of the most important knowledge and techniques are not generally known by most advertisers, particularly small businesses like health care practices. This article reveals these tips that are the most effective and includes information on the use of experts and other professional resources that help increase the likelihood of a successful outcome for a well-planned and executed media campaign. PMID- 20974394 TI - Showcase your service: social media and marketing basics in a dynamic, over populated, mixed-message, and highly competitive world. AB - This article discusses social media as a means of communication between the aesthetic medical practice and clients. Discussion of the various types of social media and how each can support a physician's practice, brand, market, and tolerances is presented. Blogs, wikis, networks, viral marketing, and electronic communications are presented in terms of what they can provide a practice and their limitations and pitfalls. Emphasis is on finding the combination of methods to showcase the individual style and personality of a practice. PMID- 20974395 TI - The value of one patient and how to reclaim lost patients. AB - Quality over quantity is the emphasis in this article, which discusses essential yet fundamental ways of connecting with current, prospective, and "lost" patients. Specific questions are presented to encourage consideration of the types of communications with patients that will allow for greater outreach, with an emphasis on follow-up and how to do so most effectively as a key to future revenue growth. PMID- 20974396 TI - Shifts happened...time to optimize your practice! AB - The 21st century opened with economic shifts the likes of which were not experienced for over half a century. The effects of these shifts require facial surgery specialists to conduct an objective audit of their business to not only survive but thrive in the new economic environment. This article discusses specific steps and provides checklists for practitioners in cosmetic surgery related to strategy, auditing, budgeting, marketing, and innovating to grow a successful practice. PMID- 20974397 TI - Establishing a profitable skin care practice in a facial plastic surgery office. AB - Facial plastic surgeons seeking information about establishing and maintaining a first-rate skin care program and practice in their office will learn practice management tips and business advice. This content begins with presenting steps in patient evaluation and continues through development of a care plan. Discussion includes approach to skin care products, sunscreen, and related preventive and restorative methods. Detailed discussion is included of developing a personalized skin care plan. The content concludes with essential business tips and marketing advice for the facial plastic surgeon to include skin care in the surgical practice, including the way in which these are handled in the author's practice. PMID- 20974398 TI - Is it worthwhile to hire a practice management consultant? AB - This article discusses the decisions involved with hiring a consultant for the medical practice: when to hire one, how to locate the best one for a particular practice, finding a consultant and analyzing their skills in terms of the needs of the practice, and other essential advice to provide the medical practitioner with a basis for making a decision on consultants. The Achilles heel of doctors is the tendency to think they should be able to fix all problems on their own, thus often delay in seeking help for their practice that can alleviate existing problems or keep a practice on track with success. This often leads to excessively long work hours or compounding of problems, when a simple fix could be the solution when analyzed by an outside consultant. Approaches to determining the appropriateness of a particular consultant are presented, along with questions to ask when determining the expertise and the "fit" of a consultant. PMID- 20974400 TI - Growing old is not for wimps. PMID- 20974401 TI - Cognitive dysfunction in cats: a syndrome we used to dismiss as 'old age'. AB - PRACTICAL RELEVANCE: Cognitive dysfunction syndrome (CDS) is a widely accepted diagnosis in dogs, with established treatment options. In cats, however, our understanding of cognitive dysfunction is still being shaped by ongoing research in the field, and limited treatment options are available. Recent clinical studies indicate that old age in the cat is accompanied by increased behavioural signs such as wandering, vocalization and night-time activity that are not attributable to identifiable medical problems. It is essential, therefore, that veterinarians include behavioural well-being in the routine care of senior cats. PATIENT GROUP: While the exact age of onset is not established, studies suggest that age-related behavioural changes consistent with cognitive dysfunction are prevalent in cats as early as 10 years of age and that prevalence increases significantly in older cats. CLINICAL CHALLENGES: The diagnosis of cognitive dysfunction requires the identification of geriatric behavioural changes that are not caused by other medical problems, although the two may not be mutually exclusive. Therefore, the practitioner must rely heavily on owner reports and history to ensure prompt diagnosis and treatment. The absence of any approved dietary or pharmaceutical interventions for cognitive dysfunction adds a further challenge, although several possibilities exist. EVIDENCE BASE: This article draws on recent research that has produced neuropathological, cognitive and behavioural evidence for cognitive dysfunction in aging cats. As an impetus to further our understanding of this disease and potential treatment options, the authors propose a behavioural checklist that might aid in the clinical diagnosis of feline CDS and discuss treatment options that have proven successful in the canine counterpart of this disease. PMID- 20974402 TI - Feline toxicological emergencies: when to suspect and what to do. AB - PRACTICAL RELEVANCE: Confirmed or suspected intoxications with a wide variety of agents represent a small but important group of feline emergency cases. Generally it is thought that toxicities are less common in cats compared with dogs, with a higher proportion relating to dermal as opposed to oral exposure. CLINICAL CHALLENGES: Once toxicity is suspected or diagnosed, it must be recognised that treatment regimes may need modification compared with those established for dogs. Different drugs or different dosages may be warranted and the choice of available drugs may be reduced. EVIDENCE BASE: This review draws on published studies, case reports and clinical experience to summarise key features of the general management of the intoxicated feline patient before describing some of the more serious and common intoxications in more detail. AUDIENCE: The focus throughout the review is on the peculiarities of feline metabolism and how they may impact on presentation and treatment. The aim is to assist companion animal and feline practitioners, who are in the frontline when it comes to managing these emergency cases. PMID- 20974403 TI - Food allergy in the cat: a diagnosis by elimination. AB - PRACTICAL RELEVANCE: Food allergy is recognized as a cause of non-seasonal dermatologic disease and pruritus in cats, though its exact prevalence remains unknown. Feline food allergy can also be associated with gastrointestinal, neurologic, respiratory and behavioral components. PATIENT GROUP: There are no breed, sex or age predispositions for developing food allergy, though there is some evidence that the Siamese and its crosses may be at increased risk. CLINICAL CHALLENGES: Food allergy cannot be diagnosed simply on the basis of the distribution of pruritus, and many of the dermatologic reaction patterns observed in affected cats, such as miliary dermatitis, eosinophilic granuloma complex and alopecia, may be seen in cats with flea allergy and atopy; in some cases, cats may have concurrent allergic conditions. The only way to definitively diagnose food allergy is to identify a causative food component through a food elimination trial. However, palatability and client compliance can each be a problem; specifically, many owners are unwilling to perform a provocation challenge, which is required to confirm a suspected food allergy. For cats in which the existence of a food allergy is confirmed, a suitable maintenance diet then needs to be fed for the remainder of the patient's life. EVIDENCE BASE: Recent literature has revealed that there is marked variability in the clinical picture, response to treatment and outcome in food-allergic cats. This article reviews published literature and highlights clinically relevant observations pertinent to feline food allergy. PMID- 20974404 TI - Olfactory neuroblastoma in a cat. AB - CASE SUMMARY: A 12.5-year-old castrated male domestic shorthair cat was presented for evaluation of dyspnea. Physical examination suggested upper airway disease. Computed tomography revealed the presence of a nasopharyngeal mass. Biopsies obtained via rhinoscopy led to a diagnosis of olfactory neuroblastoma. CLINICAL CHALLENGES: Olfactory neuroblastoma (or esthesioneuroblastoma) is a rare malignant neoplasm that arises from olfactory neuroepithelium. It was first described in human medicine in 1924. Clinical signs are variable, and diagnosis may prove challenging as this tumor, which is a differential for spontaneous intranasal tumors in cats, may be mistaken for poorly differentiated carcinomas or round cell tumors. Given its rarity, treatment options for this neoplasm have not been thoroughly evaluated and there is no standard treatment protocol. LITERATURE REVIEW: A review of veterinary and human literature is provided, encompassing clinical signs, staging and grading systems, treatment options and prognostic factors. PMID- 20974405 TI - Successful treatment of small intestinal volvulus in two cats. AB - BACKGROUND: Mesenteric volvulus describes a torsion of the small intestine around the mesenteric root, which can be partial or complete. In dogs, it is an uncommon condition, with German shepherd dogs showing a predisposition. Chronic mesenteric volvulus has also been described. In cats, previous reports have documented two cases of small intestinal volvulus, both diagnosed at necropsy, and a further case of volvulus of the colon in a patient that died after surgery. CLINICAL SIGNIFICANCE: This report describes two cats with mesenteric volvulus that were successfully treated. To the authors' knowledge, no reports of antemortem diagnosis or treatment of small intestinal volvulus in cats have previously been published. On the basis of the cases presented, it appears that the diagnosis of intestinal volvulus may be more difficult in cats than in dogs, but that the prognosis may not be as poor. Therefore, it is suggested that owners be encouraged to pursue surgery. PMID- 20974406 TI - Nasopharyngeal trichobezoar foreign body in a cat. AB - CASE SUMMARY: A 5-year-old male neutered indoor cat presented for evaluation and treatment of an acute onset of nasal discharge and open-mouth breathing of 3 days' duration. He had been treated for asthma prior to presentation, but his clinical signs were more consistent with upper airway disease. Thoracic radiographs were suggestive of asthma. However, a soft tissue mass was noted in the nasopharynx on a lateral cervical radiograph. Nasopharyngeal examination revealed the mass to be a trichobezoar (hair ball) lodged in the nasopharynx, removal of which led to resolution of clinical signs. The cat re-presented with a second nasopharyngeal trichobezoar approximately 1 year later, which was also successfully removed. CLINICAL SIGNIFICANCE: Nasopharyngeal disease has myriad potential infectious, inflammatory and neoplastic etiologies. However, simpler causes such as foreign bodies can be considered in cases of acute-onset nasopharyngeal disease. To the authors' knowledge, this is the first reported case of a nasopharyngeal trichobezoar foreign body in a cat. PMID- 20974407 TI - Diagnostic aids for pleural effusion in the cat. PMID- 20974410 TI - Making time for nutrition counseling. PMID- 20974412 TI - Maternal nutrition and perinatal outcomes. AB - Diet and patterns of eating during pregnancy can affect perinatal outcomes through direct physiologic effects or by stressing the fetus in ways that permanently affect phenotype. Supplements are not a magic nutritional remedy, and evidence of profound benefit for most supplements remains inconclusive. However, research supports calcium supplements to decrease preeclampsia. Following a low glycemic, Mediterranean-type diet appears to improve ovulatory infertility, decrease preterm birth, and decrease the risk of gestational diabetes. Although women in the United States have adequate levels of most nutrients, subpopulations are low in vitamin D, folate, and iodine. Vitamin D has increasingly been shown to be important not only for bone health, but also for glucose regulation, immune function, and good uterine contractility in labor. To ensure adequate vitamin and micronutrient intake, especially of folate before conception, all reproductive age women should take a multivitamin daily. In pregnancy, health care providers need to assess women's diets, give them weight gain recommendations based on their body mass index measurement, and advise them to eat a Mediterranean diet rich in omega-3 fatty acids (ingested as low-mercury risk fatty fish or supplements), ingest adequate calcium, and achieve adequate vitamin D levels through sun exposure or supplements. Health care providers should continue to spend time on nutrition assessment and counseling. PMID- 20974411 TI - Essentials of healthy eating: a guide. AB - Enough solid evidence now exists to offer women several fundamental strategies for healthy eating. They include emphasizing healthful unsaturated fats, whole grains, good protein "packages," and fruits and vegetables; limiting consumption of trans and saturated fats, highly refined grains, and sugary beverages; and taking a multivitamin with folic acid and extra vitamin D as a nutritional safety net. A diet based on these principles is healthy through virtually all life stages, from young adulthood through planning for pregnancy, pregnancy, and on into old age. PMID- 20974413 TI - Implementation of the new institute of medicine gestational weight gain guidelines. AB - In May 2009, the Institute of Medicine (IOM) introduced revised gestational weight gain guidelines that were based on balancing the benefits and risks of weight gain for both the mother and child's health. This article provides an overview of these new recommendations, explaining the key changes made from the previous 1990 IOM recommendations. The important role of health care providers of pregnant women in the implementation of the new recommendations is detailed, and specific guidance for troubleshooting issues that may be encountered when helping women achieve appropriate gestational weight gains is provided. PMID- 20974414 TI - Prenatal omega-3 fatty acids: review and recommendations. AB - The influence of dietary omega-3 fatty acids on health outcomes is widely recognized. The adequate intake of omega-3 fatty acids docasahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in particular can increase gestation length and improve infant cognitive and visual performance. Adequate levels of omega-3 fatty acids have also been shown to reduce the incidence of preterm birth in some populations. Research on prenatal omega-3 intake and other outcomes, such as preeclampsia and fetal growth restriction, is inconclusive. Women in the United States consume low levels of omega-3 fatty acids compared to omega-6 fatty acids; this dietary pattern is associated with poor health outcomes. Omega-3 fatty acids are found primarily in fish, yet many pregnant women avoid fish because of concerns about potential mercury and polychlorinated biphenyl contamination. It is important for prenatal care providers to assess women's diets for omega-3 fatty acid intake and ensure that pregnant women are consuming between 200 and 300 mg daily from safe food sources. Purified fish, algal oil supplements, and DHA-enriched eggs are alternative sources for pregnant women who do not eat fish. PMID- 20974415 TI - Specialized care for women pregnant after bariatric surgery. AB - Growing numbers of women today will seek bariatric surgery before pregnancy. Protein-calorie malnutrition; hyperemesis; intestinal hernias; dumping syndrome; anemia; and deficiencies in calcium, folic acid, and vitamins B12, D, and K are all possible complications that can impact pregnancy. This article reviews the nutritional and pregnancy-related consequences of current surgical procedures and summarizes existing research showing positive and negative effects of weight-loss surgery on pregnancy outcomes. Practice-based clinical recommendations will help guide clinicians caring for the increasing number of women who become pregnant after having bariatric surgery. PMID- 20974416 TI - Prenatal nutrition: a practical guide for assessment and counseling. AB - Adequate nutrition during the periconceptional and prenatal periods is important for healthy pregnancy outcomes. By enhancing maternal nutritional status, health care providers can help pregnant women lower their risk of certain pregnancy complications and decrease their children's risk of adverse birth outcomes and later chronic disease. Use of evidence-based tools and recommendations will assist in the assessment of pregnant women's diets and streamline the counseling session to optimize their nutritional status. This article contains a review of the literature related to nutrition intervention studies during pregnancy that were designed to improve habits or achieve target weight gains and nutrition recommendations specific for the pregnancy state, as well as tools/resources for the health care provider for implementation of these recommendations into their busy practices. PMID- 20974417 TI - Relationship between vitamin D during perinatal development and health. AB - Vitamin D deficiency is a highly prevalent condition that is present in 40% to 80% of pregnant women. There is emerging evidence that vitamin D deficiency may be a risk modifying factor for many chronic diseases, including osteomalacia, rickets, multiple sclerosis, schizophrenia, heart disease, type 1 diabetes, and cancer. Heightened susceptibility to these diseases may originate in early life during the development of tissue structure and function. It is suspected that biologic mechanisms can "memorize" the metabolic effects of early nutritional environment through fetal and neonatal imprinting. Inadequate vitamin D nutrition during perinatal life may establish a poor foundation that may produce long-term threats to human health. This review summarizes the risks of vitamin D deficiency for human health and provides the current vitamin D recommendations for mothers and their newborns. PMID- 20974418 TI - Long-chain omega-3 fatty acids and women's mental health in the perinatal period and beyond. AB - Recent research has shown that depression and a range of physical illnesses, including heart disease, metabolic syndrome, and type 2 diabetes, have an inflammatory etiology. The long-chain omega-3 fatty acids (omega-3s) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are found in fish and fish-oil products, may protect against these illnesses, in part because they lower inflammation. This article reviews the recent research on omega-3s and women's mental health, with a particular focus on the perinatal period. These studies include population studies examining fish consumption and studies testing the efficacy of EPA and DHA as treatments for depression. Although the findings are mixed, the majority of studies indicate that EPA has efficacy in treating depression either alone or in combination with DHA and/or antidepressant medications. The role of DHA alone in mental health is less clear, but it is generally combined with EPA and appears to have a beneficial effect. In moderate doses, EPA and DHA appear safe for pregnant and postpartum women, and they are well tolerated by patients. PMID- 20974419 TI - The obesity epidemic: scope of the problem and management strategies. AB - As the obesity epidemic increases, primary care clinicians are encountering obesity and health problems associated with obesity more frequently than ever before. In 2007, 41% of women were classified as obese, with a body mass index (BMI) of 30 or higher. Non-Hispanic blacks and Hispanics are more likely to be obese than white, non-Hispanics. A wide spectrum of health problems has been associated with obesity, including cardiovascular disease, diabetes, metabolic syndrome, osteoarthritis, and polycystic ovary syndrome. Obesity has been shown to be a low-grade inflammatory state, which may be responsible for many of the comorbidities. The general consensus recommends screening for obesity and counseling to promote weight loss. In some cases, pharmacotherapy and or bariatric surgery may be recommended. PMID- 20974420 TI - Practical advice for caring for women with eating disorders during the perinatal period. AB - Pregnancy is a critical time for women struggling with disordered eating and weight concerns. For the majority of women with eating disorders, symptoms improve during pregnancy. Other women, particularly those with either subclinical or binge eating disorders, are at risk for an escalation of pathologic behaviors, putting both mother and fetus at risk for negative birth outcomes. Routinely screening for eating disorders will help identify those women who will most benefit from specialized care. Attention must be paid to possible harmful comorbid behaviors found in women with eating disorders, such as smoking, alcohol use, abusing laxatives or herbal supplements, and self-injurious behavior. This article reviews the mixed research findings of the impact of eating disorders upon pregnancy and identifies key times in prenatal care where nutritional counseling and specific interventions will increase the likelihood of positive pregnancy outcomes. The postpartum period is another critical time for provider intervention that may lower women's risks for eating disorder relapse, postpartum depression, and breastfeeding difficulties. PMID- 20974422 TI - Diets rich in high glycemic carbohydrates increase risk of heart disease in women, but not men. PMID- 20974421 TI - Dental health, acidogenic meal, and snack patterns among low-income women during early pregnancy: a pilot study. AB - INTRODUCTION: The objectives of this study were to collect preliminary data related to self-reported dental problems, dental health-related nutrient intake, and acidogenic meal and snack composition intake during early pregnancy in low income women and to assess the feasibility of current research methods for use in a larger study. METHODS: Low-income women (n = 13) in the first trimester of pregnancy participated in this study. Pregnant women completed a demographic questionnaire, participated in three 24-hour dietary recalls, and answered several questions related to their oral health status and frequency of dental visits. RESULTS: Preliminary data suggest that women in this study were susceptible to dental problems and consumed acidogenic meals and snacks. Protocol data suggest that it is feasible to implement current research protocols, with adaptations, for use in a larger study. DISCUSSION: Health care professionals should assess low-income pregnant women in early pregnancy for dental problems and acidogenic meal and snack patterns and provide referrals to appropriate health professionals and community health services. PMID- 20974423 TI - Most dietary supplements are prohibitively expensive and lack evidence supporting efficacy. PMID- 20974424 TI - Young women are rapidly gaining weight, but causes not clearly identified. PMID- 20974425 TI - Health behaviors of midlife women formed more by social expectations than personal responsibility. PMID- 20974426 TI - After 20 years of research, scientists still investigating the benefits and risks of soy and isoflavones in human nutrition. PMID- 20974427 TI - Appealing adverse coverage decisions by insurers: what gastroenterologists need to know. PMID- 20974428 TI - Chest wall surgery. PMID- 20974429 TI - Relevant surgical anatomy of the chest wall. AB - The chest wall, like other regional anatomy, is a remarkable fusion of form and function. Principal functions are the protection of internal viscera and an expandable cylinder facilitating variable gas flow into the lungs. Knowledge of the anatomy of the whole cylinder (ribs, sternum, vertebra, diaphragm, intercostal spaces, and extrathoracic muscles) is therefore not only important in the local environment of a specific chest wall resection but also in its relation to overall function. An understanding of chest wall kinematics might help define the loss of function after resection and the effects of various chest wall substitutes. Therefore, this article is not an exhaustive anatomic description but a focused summary and discussion. PMID- 20974430 TI - Principles of chest wall resection and reconstruction. AB - Despite significant improvements in surgical technique and perioperative care, the management of patients requiring chest wall resection and reconstruction is an ongoing challenge for thoracic surgeons. A successful approach includes a thorough assessment of the patient and the lesion, an adequate biopsy to confirm tissue diagnosis, and a well-established treatment plan. In the case of a primary tumor of the chest wall, the extent of the resection should not be limited by the size of the resulting defect. Following resection, chest wall reconstruction mandates an appreciation for restoration of functional and structural components. An algorithmic approach to chest wall reconstruction begins with the assessment of the nature of the defect, taking into consideration factors such as infection, tumor location, previous radiation therapy, and surgical intervention. The latter factors bear influence on the type of tissue required as well as whether reconstruction can be performed in a single stage or whether it is better delayed. Finally, patient factors including lifestyle and work, as well as prognosis, are considered to determine the best reconstructive option. PMID- 20974431 TI - Surgical management of chest wall trauma. AB - Recent paradigm shift in major trauma profile elevates chest wall injuries among the most important topics of the specialty. Due to mass casualties of terror attacks and asymmetric warfare, civilian and military trauma care challenges thoracic surgery, traumatology, intensive anesthesiology, and related specialties. Contemporary advances of the main issues are systemically presented and discussed, such as soft tissue and bony structure injuries, complex traumas like flail chest, and extensively destroyed chest wall. PMID- 20974432 TI - Infections and radiation injuries involving the chest wall. AB - Soft tissue necrosis secondary to infection and radiation injury account for the majority of chest wall resections performed today that are unrelated to malignancy. Principles of treatment for chest wall infection and necrosis rely partially on the underlying cause and overall health of the patient but, in general, are based on wide resection of devitalized tissue and subsequent reconstruction with soft tissue coverage. Unlike resection for malignancy, fibrosis of underlying tissues often precludes skeletal reconstruction without concurrent loss of chest wall integrity or pulmonary function. Although the surgical intervention of these processes is similar, the underlying pathology differs significantly. This article addresses the risk factors, pathophysiology, clinical presentation, and management of chest wall and sternoclavicular joint infections, necrotizing processes, and radiation injury. PMID- 20974433 TI - Primary chest wall tumors. AB - The differential diagnosis of chest wall tumors is diverse, including both benign and malignant lesions (primary and malignant), local extension of adjacent disease, and local manifestations of infectious and inflammatory processes. Primary chest wall tumors are best classified by their primary component: soft tissue or bone. Work-up consists of a thorough history, physical examination and imaging to best assess location, size, composition, association with surrounding structures, and evidence of any soft tissue component. Biopsies are often required, especially for soft tissue masses. Treatment depends on histological subtype and location, but may include chemotherapy and radiotherapy in addition to surgical resection. PMID- 20974434 TI - Surgery of the chest wall for involvement by breast cancer. AB - Chest wall involvement by breast cancer remains a difficult clinical challenge that may occur at the time of the primary diagnosis or later as a result of locoregional breast cancer recurrence. A case-by-case multidisciplinary approach is strongly recommended, and a multimodality therapy should be always considered. Full-thickness resection of the chest wall can be done with acceptable morbidity and mortality, providing a good palliation and a better quality of life even to patients with poor prognosis. Moreover, in well-selected cases, chest wall resection results in locoregional control of disease and prolongation of life. PMID- 20974435 TI - Non-small cell lung cancer invading the chest wall. AB - Non-Small cell lung cancer invading the chest wall represents an advanced stage of the disease. Chest wall resection may be achieved in up to 100% of the patients, and the ensuing defect requires to be reconstructed in 40% to 64% of cases. Once a surgical challenge, chest wall resection is no longer a technical problem and en bloc chest wall and lung resections regularly provide good results. However, survival rates are jeopardized by incompleteness of the resection and mediastinal lymph node involvement. Nowadays, the challenge is represented by the use of the other nonsurgical modalities (chemotherapy and radiation therapy) to increase the chance of performing a complete resection, the need to achieve a better control of probable lymphatic or hematogenous spread, and the reduction of the recurrence rate. PMID- 20974436 TI - Resection and reconstruction for primary sternal tumors. AB - Radical resection can offer a definitive cure of primary malignant sternal tumors, but the surgical management may be difficult because of the local aggressiveness of these tumors and a high recurrence rate. This article describes improvements in reconstruction techniques with musculocutaneous flaps that have made coverage of wide sternal defects reliable. A rigid reinforcement of the sternum can now be achieved with titanium bars and clips after a total sternectomy. Large sternal defects are safely reconstructed with a musculocutaneous flap. The completeness of the resection and the histologic grade of the tumors are the strongest survival predictors. PMID- 20974437 TI - Outcomes of surgery for chest wall sarcomas. AB - Chest wall resection requires wide local excision, negative margins, and adequate reconstruction. Outcomes are generally good to excellent with wide local excision and negative margins. Mortality is nearly 0% to 1% with mild morbidity. Multispecialty surgical teams may be required for more complex situations. Early diagnosis of chest wall sarcomas, confirmation by an experienced sarcoma pathologist, and multidisciplinary discussion before treatment initiation, are all required for optimal and successful therapy. PMID- 20974438 TI - Muscle and omental flaps for chest wall reconstruction. AB - Reconstruction of the chest wall represents an important part of a patient's treatment following resection of various thoracic tumors. Many different types of flaps, including both pedicled and free flaps, have been described for use in chest wall reconstruction. These reconstructions are most effectively managed with a multidisciplinary approach involving plastic and cardiothoracic surgery. The pectoralis major, latissimus dorsi, rectus abdominis, trapezius, and external oblique muscles and the omentum are all local options that can play an important role in the reconstruction of the chest wall. PMID- 20974439 TI - Prosthetic reconstruction of the chest wall. AB - Chest wall reconstructions can be complex and challenging procedures, especially when huge thoracic defects have been generated by radical excisions. Nonrigid reconstructions with meshes or patches have the goal of avoiding a lung hernia caused by the chest wall defect, or preventing the impaction of the scapula in case of posterior chest wall resections, especially when the resection is extended down to the 5th and 6th ribs. Large anterior and lateral resections result in thoracic instability and alteration of pulmonary physiology, and render intrathoracic structures vulnerable to external impact. They necessitate rigid reconstructions according to several techniques using alloplastic materials (eg, methyl methacrylate-based customized plates or neo-ribs, osteosynthesis systems, or dedicated prosthesis). Nowadays, the availability of these multiple, possibly combined, more adapted, and better tolerated materials have pushed past the limits of resection to those involving soft tissue coverage. PMID- 20974440 TI - Overview on current and future materials for chest wall reconstruction. AB - This article focuses on new materials available to thoracic surgeons for the reconstruction of chest wall defects. Each surgeon is called to select the best reconstructive strategy based on the disease for which the resection is needed, the possible extension to adjacent structures, the availability of professional colleagues for multidisciplinary involvement, and the preferred (or available) material for full or partial thickness reconstruction. PMID- 20974441 TI - Pectus carinatum. AB - Pectus carinatum or keel chest is a spectrum of progressive inborn anomalies of the anterior chest wall, named after the keel (carina) of ancient Roman ships. It defines a wide spectrum of inborn protrusion anomalies of the sternum and/or the adjacent costal cartilages. Pectus carinatum is often associated with various conditions, notably Marfan disease, homocystinuria, prune belly, Morquio syndrome, osteogenesis imperfecta, Noonan syndrome, and mitral valve prolapse. Treatment of pectus carinatum by nonsurgical methods such as exercise and casting has not been worthwhile, whereas surgical management is simple and successful. PMID- 20974442 TI - Thoracic defects: cleft sternum and Poland syndrome. AB - Defects of the thoracic cage with bone and/or muscle deficit are relatively rare and can present a real risk depending on the severity of manifestations. Cleft sternum results from failed midline fusion of the sternal halves that leaves the heart and great vessels unprotected, and is commonly associated with craniofacial hemangiomas. Correction is recommended during the neonatal period when compliant thorax allows direct suturing of the divided sternum. Sternal foramen requires precaution during biopsy and acupuncture as well as forensic awareness. In addition to the thoracic defect, Poland syndrome can be associated with hand anomalies, dextrocardia, renal agenesia, and various tumors. Age and gender, together with the degree of the defect, define the method of surgical correction. PMID- 20974443 TI - Indications and technique of Nuss procedure for pectus excavatum. AB - Pectus excavatum most frequently involves the lower sternum and chest wall. Because the morphology varies, preoperative imaging for anatomic assessment and documentation of dimensions of the chest are important. Many modifications have been made to the minimally invasive procedure since it was first performed in 1987. As a result, there has been an increase in the number of patients seeking surgical correction. This article discusses the clinical features of pectus excavatum and reviews the preoperative considerations and the steps involved in the repair of the deformity. PMID- 20974444 TI - PiO interviews: Drs. Baccetti and Franchi on how "to stay safe" when reading the orthodontic literature by Savastano Carmela. PMID- 20974445 TI - Relationships between facial features in the perception of profile attractiveness. AB - OBJECTIVE: The aim of the study was to analyse the attractiveness of modifications of lip, nose or chin positions on profile photographs. MATERIALS AND METHODS: A profile digital photograph was randomly selected among pictures of 50 models participating to a beauty contest and then reviewed by 10 orthodontists and 10 laypersons who unanimously rated the profile as attractive. The original picture (O) was modified so as to create protrusion and retrusion of the lips of 2,4 and 6mm, thus generating 6 new pictures (O-6, O-4, O-2, O+2, O+4, O+6). From the original picture 7 new pictures were generated: (N) with the nose protruded of 6mm and its combinations with lips protrusion and retrusion (N-6, N-4, N-2, N+2, N+4, N+6). In the same way, picture (C) was created with the chin protruded of 6mm and 6 combinations of protruded chin with protruded and retruded lips were generated (C-6, C-4, C -2, C+2, C+4, C+6). 15 orthodontists and 15 laypersons were asked to rate all the 21 pictures on Visual Analogue Scales (VAS). RESULTS: The original picture reported the highest VAS scores. Comparing the series "C" and "N", the pictures with Nose protrusion show higher VAS scores if compared with pictures with chin protrusion (p<.05). When nose or chin protrusion is present, the pictures that shows lip protrusion (N+2, C+2) reported higher VAS scores (p<.05). CONCLUSIONS: In cases of nose or chin protrusion, a compensatory lip protrusion improves the profile attractiveness. Nose protrusion seems to be more tolerated than a similar amount of chin protrusion. PMID- 20974446 TI - Mechanical properties evaluation of an orthodontic miniscrew system for skeletal anchorage. AB - OBJECTIVE: Orthodontic anchorage control is a fundamental chapter of a successful orthodontic therapy: mini-screws have been commonly used to increase absolute anchorage with no need for patient compliance, therefore reducing treatment time. The purpose of this study was to analyze the mechanical performance of a self tapping surgical stainless steel mini-screw system. MATERIALS AND METHODS: Data concerning the mechanical properties of a stainless steel mini-screw system subjected to torsional and flexural forces were collected. The sample consisted of 10 AISI 316LVM surgical stainless steel 1.5mm in diameter mini-screws and 10 surgical stainless steel 2mm in diameter mini-screws manufactured by Leone. The devices were inserted into a polyurethane block. Maximum torsional resistance was measured by a torque meter (series MG MARK-10); flexural strength was registered with a universal tester (series 4300 INSTRON), equipped with a 2518-809 5 kg load cell. RESULTS: Torsional test: at a 26.5 N cm force magnitude yielding was observed on 1.5mm diameter mini-screws and at 48.3N cm on 2mm diameter mini screws. Flexural test: 1.5mm diameter mini-screws plastically deformed with a loading value of 105,4N and 2mm diameter mini-screws deformed when load exceeded 216.7 N. CONCLUSIONS: The evaluated surgical stainless steel mini-screw system withstood greater force magnitude compared to other commercially available mini screw systems (titanium and titanium alloy); therefore the examined mini-screw system is provided with greater mechanical properties. PMID- 20974447 TI - Comparative analysis of anchorage systems for micro implant orthodontics. AB - OBJECTIVE: The study analysed twelve anchorage systems based on micro implants in terms of their bio-mechanical properties and appraised their actual clinical effectiveness. MATERIALS AND METHODS: The analysed micro implants had data provided by the manufacturers or extracted from articles published in specialised journals. The parameters taken into account were: material, surface treatment, head type, length, diameter, neck length, filleted self drilling or self tapping surface, applicable orthodontic forces, possibility of immediate loading, and device removal. RESULTS: Material Grade 5 titanium, titanium alloy (TiAl6V4), surgical steel; surfaces: smooth, sand-blasted and acid etched; head type: bracket, conic with button, round, hexagonal, button with cross cuts, double melted sphere; lengths: between 8.0 to 14 mm; diameters: between 1.2 to 2.0 mms; neck lengths: inferior to 1.5mm and superior to 2.0mm; filleted portion: self tapping and/or self drilling; applicable orthodontic forces: up to 500 g, possibility of immediate loading, device removal, possibility to use in growing patients. DISCUSSION: The most widely used material was TiAl6V4; most of the surfaces were smooth; the most commonly used head type was the bracket; the most often produced length was the "short" one (8.0-9.9 mm), the most demanded diameter the "smaller" one (1.2-1.4 mms); six systems out of eleven had micro implants with "extra" and "standard" necks; only 3 systems out of eleven produced "non self drilling"devices; all the micro implants analysed were able to withstand orthodontic forces between 150 g and 350 g; all devices were suitable for "immediate loading"; all micro implants had to be removed; all micro implants could be used in growing patients. CONCLUSIONS: The comparative analysis showed that micro implants could be used as valid anchorage systems, if dental anchorage was insufficient either in qualitative terms (i.e. parodontal problems) or in quantitative terms (i.e. few dental elements remaining), and in all those situations of limited patient compliance. PMID- 20974448 TI - The impact of functional jaw orthopedics in subjects with unfavorable Class II skeletal patterns. AB - OBJECTIVE: To evaluate the outcomes of functional jaw orthopedics (FJO) followed by fixed appliances in Class II patients showing cephalometric signs predictive of unfavorable responsiveness to orthopedic treatment. MATERIALS AND METHODS: A total of 48 treated subjects (20 males, 28 females) with unfavorable Class II malocclusions were treated with FJO at the adolescent growth spurt, followed by fixed appliances. Treatment outcomes were compared with the growth changes in a matched control group of untreated subjects with "unfavorable" Class II malocclusions. RESULTS: A significant prevalence rate of successful outcome was recorded within the treated group (64.5%). When compared with the untreated controls, both the overall treated group and the successful treated subgroup revealed a significant reduction in maxillary growth and sagittal position, along with a significant enhancement in mandibular length, sagittal advancement of the mandible, and significant improvements in the maxillo-mandibular relationships. Both overjet and molar relation showed significant favorable changes in the treated group. CONCLUSIONS: FJO at the pubertal spurt followed by fixed appliances is a viable therapeutical option in patients with "unfavorable" Class II malocclusions, although skeletal changes are of minor entity. PMID- 20974449 TI - Comparison between different interdental stripping methods and evaluation of abrasive strips: SEM analysis. AB - OBJECTIVES: The aim of this study was to evaluate the morphological effects and the surface irregularities produced by different methods of mechanical stripping (abrasive strips and burs) and chemical stripping (37% orthophosphoric acid) and the surface changes following the finishing procedures (polishing strips) or the subsequent application of sealants, in order to establish the right stripping method that can guarantee the smoothest surface. We have also analysed the level of wear on the different abrasive strips employed, according to their structure. MATERIALS AND METHODS: 160 proximal surfaces of 80 sound molar teeth extracted for orthodontic and periodontal reasons, were divided into: 1 control group with non-treated enamel proximal surfaces and 5 different groups according to the stripping method used, were observed with scanning electron microscopy (SEM). Each one of the 5 treated groups was also divided into 3 different subgroups according to the finishing procedures or the subsequent application of sealants. RESULTS: The finishing stage following the manual reduction proves to be fundamental in reducing the number and depth of grooves created by the stripping. After the air rotor stripping method, the use of sealants is advised in order to obtain a smoother surface. The analysis of the combinations of mechanical and chemical stripping showed unsatisfactory results. Concerning the wear of the strips, we have highlighted a different abrasion degree for the different types of strips analysed with SEM. CONCLUSIONS: The enamel damages are limited only if the finishing procedure is applied, independently of the type of abrasive strip employed. It would be advisable, though clinically seldom possible, the use of sealants after the air rotor stripping technique. PMID- 20974450 TI - Slow or rapid palatal expansion for early treatment of unilateral posterior crossbite? Evaluation of the reverse chewing cycles correction. AB - OBJECTIVES: It is well established that patients with a unilateral posterior crossbite, when chewing on the affected side, show an increased frequency of reverse chewing cycles. It was hypothesized that the correction of reverse cycles may be due to the characteristics of the therapy. The aim was to investigate the prevalence of reverse chewing patterns in children with unilateral posterior crossbite before and after treatment with Function Generating Bite (FGB). MATERIALS AND METHODS: Twenty children, (9 boys, 11 girls; age, mean +/- SD, 7.5 +/- 1.1), 10 with a right and 10 with a left posterior unilateral crossbite were selected. Mandibular movements during chewing soft and hard boluses were measured with a kinesiograph (K7 -I, Myotronics Inc. Tukwila, Washington, USA). RESULTS: The results showed a significant difference when comparing the percentage of reverse chewing patterns, before and after therapy with FGB, during chewing on the crossbite side both with soft and hard bolus (p<0.0001). No significant differences were observed during chewing on the non-crossbite side. DISCUSSION: The results of this study confirmed that FGB corrects both the dental and functional asymmetries. Knowing that the rapid palatal expansion does not correct the masticatory function, it is of clinical relevance, for the orthodontists, the knowledge and the understanding of the functional outcomes with different therapies. CONCLUSIONS: The type of treatment and the biomechanics of the appliance used are of great importance for the correction of the reverse chewing cycles and for rebalancing the functional asymmetry of children with unilateral posterior crossbite. PMID- 20974451 TI - Diagnostic performance of increased overjet in Class II division 1 malocclusion and incisor trauma. AB - OBJECTIVE: The objectives of this study were: 1) to evaluate the associations between an increased overjet (IO) and other dentoskeletal characteristics of Class II division 1 malocclusions in the mixed dentition; 2) to assess whether Class II division 1 malocclusions or rather an increased overjet per se is a risk factor for upper incisor trauma (UIT). MATERIALS AND METHODS: A sample of 900 mixed dentition subjects, was observed by clinical inspection, analysis of dental casts, and lateral cephalograms. The diagnostic performance of IO (overjet >= 7 mm) was evaluated in relation to other Class II dentoskeletal features (Class II molar and canine relationships, and skeletal Class II relationships). Secondly, the diagnostic performance of IO and of the other Class II dentoskeletal components was tested with regard to the prevalence of UIT. Diagnostic performance was assessed by odds ratio and positive likelihood ratio. RESULTS: The diagnostic performance of IO with regard to the other dentoskeletal components of Class II malocclusions was not significant. The only Class II features associated significantly with an increased risk of UIT was IO. CONCLUSIONS: When used as an isolated occlusal feature, IO is not a valid diagnostic indicator for Class II division 1 malocclusions. An increased overjet per se, and not Class II malocclusions, appears to be a significant risk factor for UIT. These findings recommend discrimination between clinical conditions showing an isolated IO from comprehensive Class II malocclusions during diagnosis, analysis of treatment outcomes, and evaluation of the risk of upper incisor trauma. PMID- 20974452 TI - A protocol for improved stability with Herbst appliance treatment for adults. AB - OBJECTIVE: To present a treatment protocol for improved stability with Herbst appliance treatment in Class II adult cases. MATERIALS AND METHODS: Sixteen Class II adults were treated at the University of Hong Kong with two phase treatment. The treatment protocol which leads to good stability was presented. RESULTS: The protocol leading to stable correction of overjet, molar relationship and enhanced forward positioning of the mandible involved 12 months Herbst appliance treatment with stepwise advancement followed by fixed appliance. CONCLUSIONS: The long term stability of Herbst appliance treatment is influenced by the treatment protocol employed. Based on the stability of the adult group in the present study, it is recommended to treat for 12 months in a step-wise manner for mandibular advancement with over correction. PMID- 20974453 TI - Modified sliding mechanics in extraction cases with a bidimensional approach. AB - To illustrate a modified archwire during space closure with anterior anchorage in Bidimensional Tecnique. The archwire used was a .018x.025 SS on the anterior teeth and .018 SS on the lateral and posterior teeth in order to maintain anterior anchorage using torque and uprighting springs as showed in Bidmensional Technique but exerting lighter forces (150 g). The double section archwire resulted to be an effective alternative option to optimize the lateral and posterior sliding mechanics with controlled tipping and by the application of lighter forces. PMID- 20974454 TI - Molar uprighting with mini screws: comparison among different systems and relative biomechanical analysis. AB - Starting from a segmented approach, the Authors propose 3 different methods of using mini screws during the process of molar uprighting. The first UPG is performed by placing a mini screw in the retromolar area and by applying an elastic chain loaded between the screw and the molar.The second UPG is made by placing a screw in the retro molar area and by using a small cantilever which is active during intrusion and uprighting.The third UPG is made by using a miniscrew placed a few millimeters mesial to the molar to control the vertical force produced by the uprighting with a long cantilever to the frontal teeth.To assist in the understanding of the different clinical indications, the biomechanical differences between these three systems are analyzed. PMID- 20974455 TI - Nonsynonimous mutation of catechol-O-methyl-transferase (COMT) gene in a patient with temporomandibular disorder. AB - We report a case of temporomandibular disorder patient with disc displacement without reduction, myofascial pain, limited opening and a novel, never described, nonsynonimous mutation of catechol-O-methyl-transferase (COMT) gene. COMT is one of the enzymes that metabolizes catecholamines, thereby acting as a key modulator of dopaminergic and adrenergic/noradrenergic neurotransmissions, which play a key role in pain modulation. This novel mutation, p.R58S, changed a codon (58 from arginine to serine) in the COMT protein. The introduction of a serine residue in a highly organised secondary structure, in critical regions of the protein, results in a structural alteration. Therefore, we speculate an influence of the mutation on the high pain sensitivity of the patient. PMID- 20974456 TI - A simple and efficient procedure for indirect bonding. AB - The aim of this paper is to describe a simple and efficient system of indirect bonding that can be easily performed in the orthodontic office. The transfer tray is formed with transparent polyvinylsiloxane of medium viscosity that can be used in combination with light-cured adhesives. Low-friction ligatures are placed on each bracket to eliminate the undercuts under the bracket wings and to prevent penetration of silicone material into the bracket slots. This procedure has several advantages when compared with similar methods for indirect bonding: it allows easier tray removal, it lowers the risk of bracket debonding during the tray removal, and it reduces ligation time with low-friction ligatures. PMID- 20974458 TI - Maternal C-reactive protein levels in pregnancy are associated with wheezing and lower respiratory tract infections in the offspring. AB - OBJECTIVE: We assessed whether maternal C-reactive protein (CRP) levels during pregnancy and CRP gene variations are associated with wheezing and lower respiratory tract infections (LRTIs) in offspring. STUDY DESIGN: Information on wheezing and LRTIs in the offspring at 6 and 14 months of age, and maternal CRP levels and genotype was obtained from a population-based birth cohort. RESULTS: A total of 63 children (12.5%) experienced recurrent wheezing and 61 (12.4%) a recurrent diagnosis of LRTIs. Children in the highest tertile of maternal CRP levels had a higher risk of experiencing recurrent wheezing (adjusted odds ratio, 2.87; 95% confidence interval, 1.23-6.71) and being diagnosed with recurrent LRTIs (odds ratio, 2.37; 95% confidence interval, 1.01-5.55), as compared with children in the lowest tertile. The rs1205 polymorphism influenced maternal serum CRP levels but not the risk of the offspring outcomes. CONCLUSION: Higher CRP levels in pregnancy are associated with wheezing and LRTIs in offspring. However, genetic variation in CRP influencing maternal levels is not related to these phenotypes. PMID- 20974459 TI - Gestational weight gain and subsequent postpartum weight loss among young, low income, ethnic minority women. AB - OBJECTIVE: Document weight change trajectories that lead to gestational weight gain or postpartum weight loss outside clinical recommendations established by the Institute of Medicine. STUDY DESIGN: Women aged 14-25 receiving prenatal care and delivering singleton infants at term (n = 427). Medical record review and 4 structured interviews conducted: second and third trimester, 6- and 12-months postpartum. Longitudinal mixed modeling to evaluate weight change trajectories. RESULTS: Only 22% of participants gained gestational weight within Institute of Medicine guidelines. There were 62% that exceeded maximum recommendations-more common among those overweight/obese (body mass index >=25.0; P < .0001). 52% retained >=10 lb 1-year postpartum. Increased weight gain and retention documented among smokers and women with pregnancy-induced hypertension; breastfeeding promoted postpartum weight loss (all P < .02). Body mass index by race interaction suggested healthier outcomes for Latinas (P = .02). CONCLUSION: Excessive pregnancy weight gain and inadequate postpartum weight loss are highly prevalent among young low-income ethnic minority women. Pregnancy and postpartum are critical junctures for weight management interventions. PMID- 20974460 TI - Prospective study of intraabdominal adhesions among women of different races with or without keloids. AB - OBJECTIVE: We sought to evaluate postsurgical adhesions in women of different races with or without keloids. STUDY DESIGN: This was a prospective study evaluating postsurgical adhesions after a cesarean delivery in 429 women with or without keloids. The outcome measures were the prevalence and extent of adhesions in women of different races with or without keloids. RESULTS: There was no difference in the prevalence of adhesions and adhesion score in various sites among women of different races. Compared with whites (0.5%), keloids were significantly more common in African Americans (7.1%; P = .007; odds ratio, 16.5) and in Asians (5.2%; P = .02; odds ratio, 11.9). Women with keloids were found to have more dense adhesions between the uterus and the bladder (P = .028; 95% confidence interval, 0-12) and between the uterus and the anterior abdominal wall (P < .0001; 95% confidence interval, 8-12). CONCLUSION: The prevalence and degree of postsurgical adhesions in women of different races are comparable. Women with keloids on the cesarean scar have increased adhesions between the uterus and the bladder and between the uterus and the abdominal wall. PMID- 20974461 TI - Familial aggregation of hyperemesis gravidarum. AB - OBJECTIVE: This study was undertaken to determine whether there is familial aggregation of hyperemesis gravidarum (HG), making it a disease amenable to genetic study. STUDY DESIGN: Cases with severe nausea and vomiting in a singleton pregnancy treated with intravenous hydration and unaffected friend controls completed a survey regarding family history. RESULTS: Sisters of women with HG have a significantly increased risk of having HG themselves (odds ratio, 17.3; P = .005). Cases have a significantly increased risk of having a mother with severe nausea and vomiting; 33% of cases reported an affected mother compared to 7.7% of controls (P < .0001). Cases reported a similar frequency of affected second degree maternal and paternal relatives (18% maternal lineage, 23% paternal lineage). CONCLUSION: There is familial aggregation of HG. This study provides strong evidence for a genetic component to HG. Identification of the predisposing gene(s) may determine the cause of this poorly understood disease of pregnancy. PMID- 20974462 TI - Maternal smoking and impaired endothelium-dependent nitric oxide-mediated relaxation of uterine small arteries in vitro. AB - OBJECTIVE: This study aimed to investigate the endothelium-dependent relaxation of uterine small arteries from pregnant nonsmokers, smokers, and ex-smokers who stopped smoking early in pregnancy. STUDY DESIGN: Uterine arteries were dissected from myometrial biopsies obtained during elective cesarean sections of 34 uncomplicated, singleton pregnancies, and the vascular function was assessed in a wire myograph for isometric recordings. Serum cotinine verified self-reported smoking; 15 were nonsmokers, 10 were smokers, and 9 were ex-smokers. RESULTS: Arteries from smokers and ex-smokers had reduced bradykinin-induced relaxation compared to arteries from nonsmokers (P < .05). The relaxation response to the nitric oxide donor sodium nitroprusside was similar in arteries from nonsmokers and smokers but was better in arteries from ex-smokers (P < .05). CONCLUSION: The findings suggest that maternal smoking reduces endothelium-dependent nitric oxide mediated relaxation in uterine small arteries and that smoking cessation early in pregnancy does not fully abolish this deleterious effect, despite improvement in relaxation to nitroprusside. PMID- 20974463 TI - Imaging of the human embryo with magnetic resonance imaging microscopy and high resolution transvaginal 3-dimensional sonography: human embryology in the 21st century. AB - OBJECTIVE: This article illustrates early human development, demonstrated by magnetic resonance (MR) microscopy and computer graphics on human embryo specimens, and advanced 3-dimensional (3D) sonography in clinical obstetrics. STUDY DESIGN: Fixed human embryo specimens were imaged by MR microscopy coupled with computer graphics technology. Transvaginal 3D sonography was used to examine embryos in ongoing gestations and compare embryological findings. RESULTS: Advances in MR microscopy allowed detailed visualization of embryo specimens. Computational techniques allowed reconstruction of tomographic images to render them as 3D structures. High-resolution transvaginal 3D sonography produced images that demonstrated the neural tube from week 6; brain anatomy and vasculature from week 8; and craniofacial morphology and other structures from week 11. CONCLUSION: MR microscopy is a novel technique that enables nondestructive, high resolution imaging of embryo specimens. On the other hand, 3D sonoembryology allows detailed anatomical visualization in vivo and is the basis for the assessment of anomalies as well as human development. PMID- 20974465 TI - 11-Phenoxyundecyl phosphate as a 2-acetamido-2-deoxy-alpha-d-glucopyranosyl phosphate acceptor in O-antigen repeating unit assembly of Salmonella arizonae O:59. AB - A synthesis of 11-phenoxyundecyl phosphate and its biochemical transformation (using GlcNAc-P transferase from Salmonella arizonae O:59 membranes catalysing transfer of GlcNc-phosphate from UDP-GlcNAc on lipid-phosphate) into P(1)-11 phenoxyundecyl, P(2)-2-acetamido-2-deoxy-alpha-D-glucopyranosyl diphosphate are described. PMID- 20974464 TI - Increased interstitial white matter neuron density in the dorsolateral prefrontal cortex of people with schizophrenia. AB - BACKGROUND: Interstitial white matter neurons (IWMNs) may reflect immature neurons that migrate tangentially to the neocortex from the ganglionic eminence to form cortical interneurons. Alterations of interneuron markers have been detected in gray matter of dorsolateral prefrontal cortex in schizophrenia, and IWMNs are also reported to be altered in schizophrenia. In this study, we considered whether a potential link exists between these two pathological findings. METHODS: From a cohort of 29 schizophrenia subjects and 37 control subjects, IWMN densities were determined in the dorsolateral prefrontal cortex by counting neuronal nuclear antigen (NeuN) and somatostatin (SST)-positive cells. Double-label immunofluorescence was carried out to determine the overlap between SST+/NeuN+ and SST+/neuropeptide Y + neurons. RESULTS: We found that density of NeuN + IWMNs in superficial white matter is significantly increased in schizophrenia subjects compared with control subjects. There was a significant negative correlation between SST mRNA expression in gray matter and NeuN + IWMN density. In schizophrenic patients with increased NeuN IWMN density, the density of SST-expressing neurons in white matter was also higher compared with control subjects. A subpopulation of SST immunopositive cells also show coexpression of neuropeptide Y. CONCLUSIONS: Our study confirmed previous results indicating that the density of NeuN + IWMNs is increased in superficial white matter in schizophrenia. We provide the first evidence that increased IWMN density correlates with a gray matter interneuron deficit, suggesting that migration of interneurons from white matter to the cortex may be deficient in some patients with schizophrenia, consistent with an interneuron deficit in schizophrenia. PMID- 20974466 TI - Synthesis and inclusion ability of anthracene appended beta-cyclodextrins: unexpected effect of triazole linker. AB - A new fluorescent beta-cyclodextrin has been synthesized by coupling an anthracene moiety to the cyclic oligosaccharide via click chemistry. The influence of the triazole spacer was compared to the simple amino and amido linkers. While a sensing ability toward adamantan-1-ol was observed with the latter two spacers, the absence of inclusion capacity prevents the triazole modified cyclodextrin from showing any fluorescence variations. The difference in the binding behaviors studied by Isothermal Titration Calorimetry, UV-vis and fluorescence spectroscopies, was highlighted by the NOESY NMR spectra of the modified cyclodextrins: whereas a free cavity was observed for the amino and amido linkers, an important obstruction was obtained in the case of the triazole. PMID- 20974467 TI - Synthesis of 6-thio pseudo glycolipids and their orientation on a gold slide studied by IRRAS. AB - We have synthesized four 6-thio pseudo glycolipid analogues and assessed how two of them self-assembled on a gold surface. These structures were designed as candidate tethers molecules to anchor bilayer lipid membranes on gold. 6-Deoxy-6 thiogalactose was chosen to anchor the macromolecule to the gold and define an aqueous zone at the gold surface. A long alkane chain (C-12 or C-18) linked to the anomeric position of the sugar residue was chosen to anchor a bilayer lipid membrane. The linkage between the carbohydrate and the hydrophobic chains is either a glycosidic bond or a 1,4-disubstituted triazole formed by copper(I) catalysed alkyne-azide cycloaddition (CuAAC) of the propargyl glycoside with azido-dodecane and azido-octadecane. We are expecting that the hydrocarbon chains will orient themselves perpendicular to the gold surface and be incorporated into the first leaflet of the bilayer membrane. We have studied self assembled monolayers of the C-12 aglycone analogues on gold using infrared reflection absorption spectroscopy (IRRAS). We compared the results given by the IRRAS experiments to the IR spectra recorded by attenuated total reflection (ATR) spectroscopy on films of the randomly oriented analogues. Our results demonstrate that the C-12 analogues did bind to gold and did orient themselves perpendicular to the gold slide. PMID- 20974468 TI - Chronic alcohol consumption decreases the percentage and number of NK cells in the peripheral lymph nodes and exacerbates B16BL6 melanoma metastasis into the draining lymph nodes. AB - NK cells in the lymph nodes play important roles in inhibiting tumor metastasis into draining lymph nodes. Previously, we reported that chronic alcohol consumption interferes with NK cell trafficking from the bone marrow to the spleen. Herein, we found that alcohol consumption decreases the numbers of NK cells in lymph nodes. Adoptive transfer experiments indicated that continued exposure of donor splenocytes to alcohol inhibits NK but not T cell trafficking to lymph nodes. Alcohol did not negatively affect CCR7(+) and CXCR3(+) NK cells, but decreased the percentage and number of CD62L(+) NK cells in the spleen, which are an important source of NK cell trafficking into the lymph nodes. These data suggest that modulation of the microenvironment associated with alcohol consumption impairs the trafficking of NK cells to lymph nodes. The decreased number of NK cells in the lymph nodes was associated with increased melanoma metastasis into the draining lymph nodes. PMID- 20974469 TI - Synthesis and evaluation of different thio-modified cellulose resins for the removal of mercury (II) ion from highly acidic aqueous solutions. AB - Seven different types of thio- and/or amine-modified cellulose resin materials were synthesized and their mercury (II) ion adsorption properties determined. All seven resins showed good mercury (II) adsorption capability in the more neutral pH regions. However, the o-benzenedithiol- and o-aminothiophenol-modified cellulosic resins were found to be very effective in removing mercury (II) ions from strongly acidic media. For example, 93.5-100% mercury (II) ion recoveries from very acid aqueous solutions (nitric acid concentration ranged from 0.1 to 2.0 mol/L) were obtained using the o-benzenedithiol-modified resin while recoveries ranged from ca. 50% to 60% for the o-aminothiophenol-modified resin. An adsorption capacity of 23 mg (as Hg atoms) per gram of resin was observed for the o-benzenedithiol-modified cellulose in the presence of 1.0 mol/L nitric acid. This same resin shows very good selectivity for mercury (II) as only ruthenium (II) also somewhat adsorbed onto it out of 14 other metal ions studied (Ag(+), Al(3+), As(3+), Co(2+), Cd(2+), Cr(3+), Cu(2+), Fe(3+), Mn(2+), Ni(2+), Pt(2+), Pb(2+), Ru(2+), and Zn(2+)). PMID- 20974470 TI - Regulation of acid phosphatase in reverse micellar system by lipids additives: structural aspects. AB - Reverse micelles system is suggested as a direct tool to study the influence of membrane matrix composition on the activity and structure of membrane-associated enzymes with the use of acid phosphatase (AP) as an example. In reverse micelles the functioning of the monomeric and dimeric forms of AP could be separately observed by variation of the size of the micelles. We found that including the lipids into the micellar system can dramatically affect the enzyme functioning even at low lipid content (2% w/w), and this effect depends on the lipid nature. Structural studies using CD spectroscopy and DLS methods have shown that the influence of lipid composition on the enzyme properties might be caused by the interaction of lipids with the enzyme as well as by the influence of lipids on structure and properties of the micellar matrix. PMID- 20974471 TI - Preparation of highly fluorescent magnetic nanoparticles for analytes-enrichment and subsequent biodetection. AB - Bifunctional nanoparticles with highly fluorescence and decent magnetic properties have been widely used in biomedical application. In this study, highly fluorescent magnetic nanoparticles (FMNPs) with uniform size of ca. 40 nm are prepared by encapsulation of both magnetic nanoparticles (MNPs) and shell/core quantum dots (QDs) with well-designed shell structure/compositions into silica matrix via a one-pot reverse microemulsion approach. The spectral analysis shows that the FMNPs hold high fluorescent quantum yield (QY). The QYs and saturation magnetization of the FMNPs can be regulated by varying the ratio of the encapsulated QDs to MNPs. Moreover, the surface of the FMNPs can be modified to offer chemical groups for antibody conjugation for following use in target enrichment and subsequent fluorescent detection. The in vitro immunofluorescence assay and flow cytometric analysis indicate that the bifunctional FMNPs-antibody bioconjugates are capable of target-enrichment, magnetic separation and can also be used as alternative fluorescent probes on flow cytometry for biodetection. PMID- 20974472 TI - Use of ferric-impregnated volcanic ash for arsenate (V) adsorption from contaminated water with various mineralization degrees. AB - Ferric-impregnated volcanic ash (FVA) which consisted mainly of different forms of iron and aluminum oxide minerals was developed for arsenate (V) removal from an aqueous medium. The adsorption experiments were conducted in both DI water samples and actual water (Lake Kasumigaura, Japan) to investigate the effects of solution mineralization degree on the As(V) removal. Kinetic and equilibrium studies conducted in actual water revealed that the mineralization of water greatly elevated the As(V) adsorption on FVA. The experiment performed in DI water indicated that the existence of multivalence metallic cations significantly enhanced the As(V) adsorption ability, whereas competing anions such as fluoride and phosphate greatly decreased the As(V) adsorption. It is suggested that FVA is a cost-effective adsorbent for As(V) removal in low-level phosphate and fluoride solution. It was important to conduct the batch experiment using the actual water to investigate the arsenic removal on adsorbents. PMID- 20974474 TI - Magnetic and high rate adsorption properties of porous Mn(1-x)Zn(x)Fe2O4 (0 <= x <= 0.8) adsorbents. AB - Porous spinel ferrites Mn(1-x)Zn(x)Fe(2)O(4) (0 <= x <= 0.8) are synthesized by a simple sol-gel method with egg white. All samples exhibit porous morphologies and large BET surface area (S(BET)). The substitution of Zn(2+) affects the magnetic properties of ferrites and the adsorption properties of methylene blue (MB) on ferrites, obviously. The saturation magnetization (Ms) of Mn(1-x)Zn(x)Fe(2)O(4) increases before x=0.4, and decreases with further increase of Zn(2+) substitution. This can be ascribed to the changes of the cationic distribution and the variation of spin arrangement in A-site and B-site of spinel structure. All samples show high adsorption capacity and the removal efficiencies of MB reach up to >90% within 3 h. The Zn(2+) substitution accelerates the adsorption rate and capacity of MB on Mn(1-x)Zn(x)Fe(2)O(4). The quickest adsorption occurred at x=0.2 and the largest adsorption capacity occurred at x=0.8. PMID- 20974473 TI - Facile synthesis, stabilization, and anti-bacterial performance of discrete Ag nanoparticles using Medicago sativa seed exudates. AB - The biogenic synthesis of metal nanomaterials offers an environmentally benign alternative to the traditional chemical synthesis routes. Colloidal silver (Ag) nanoparticles were synthesized by reacting aqueous AgNO(3) with Medicago sativa seed exudates under non-photomediated conditions. Upon contact, rapid reduction of Ag(+) ions was observed in <1 min with Ag nanoparticle formation reaching 90% completion in <50 min. Effect of Ag concentration, quantity of exudate and pH on the particle size and shape were investigated. At [Ag(+)]=0.01 M and 30 degrees C, largely spherical nanoparticles with diameters in the range of 5-51 nm were generated, while flower-like particle clusters (mean size=104 nm) were observed on treatment at higher Ag concentrations. Pre-dilution of the exudate induced the formation of single-crystalline Ag nanoplates, forming hexagonal particles and nanotriangles with edge lengths of 86-108 nm, while pH adjustment to 11 resulted in monodisperse Ag nanoparticles with an average size of 12 nm. Repeated centrifugation and redispersion enhanced the percentage of nanoplates from 10% to 75% in solution. The kinetics of nanoparticle formation were monitored using ultraviolet-visible spectroscopy and the Ag products were characterized using transmission electron microscopy, selected-area electron diffraction, scanning electron microscopy, X-ray powder diffraction, and atomic force microscopy. X-ray photoelectron spectroscopy was used to investigate the elements and chemical environment in the top layers of the as-synthesized Ag nanoparticles, while the metabolites in the exudate were analyzed using gas chromatography-mass spectroscopy. To our knowledge, this is the first account of M. sativa seed exudate assisted synthesis and stabilization of biogenic Ag nanoparticles; the nanoplates are notably smaller and better faceted compared with those synthesized by vascular plant extracts previously reported. Stabilized films of exudate synthesized Ag nanoparticles were effective anti-bacterial agents. PMID- 20974475 TI - Tuning the stop bands of inverse opal hydrogels with double network structure by controlling the solvent and pH. AB - Polyacrylic acid (PAA) and polyacrylamide (PAAm) double network (DN) hydrogels with high mechanical strength (about 1.5 MPa) are obtained when two kinds of monomer solutions of 4M AA with 5 mol% crosslinker and 4M AAm with 0.1 mol% crosslinker are used for the optimal preparation. Their high mechanical strength can be maintained even at high water content (above 50%) and at external stimuli (solvent and pH). This optimized DN hydrogel is used to develop the PAA/PAAm inverse opal hydrogel with DN structure by twice infiltration-polymerization and colloidal templating. Its photonic stop band can be tuned by controlling the solvent and pH. It first shows a small red-shift (about 20 nm), and then a large blue-shift (about 180 nm) with the increased ethanol content. For pH response, the DN inverse opal hydrogel has a large stop-band shift of about 140 nm when the pH increases from 1.2 to 5.6. Moreover, the DN inverse opal hydrogel also shows rapid recovery ability without hysteresis phenomenon in strong acidic environment, good reproducibility and durability. The interaction between the independently crosslinked PAA network and PAAm network plays a significant role in determining the response performance. PMID- 20974476 TI - Developmental change in young children's use of haptic information in a visual task: the role of hand movements. AB - Preschoolers who explore objects haptically often fail to recognize those objects in subsequent visual tests. This suggests that children may represent qualitatively different information in vision and haptics and/or that children's haptic perception may be poor. In this study, 72 children (21/2-5 years of age) and 20 adults explored unfamiliar objects either haptically or visually and then chose a visual match from among three test objects, each matching the exemplar on one perceptual dimension. All age groups chose shape-based matches after visual exploration. Both 5-year-olds and adults also chose shape-based matches after haptic exploration, but younger children did not match consistently in this condition. Certain hand movements performed by children during haptic exploration reliably predicted shape-based matches but occurred at very low frequencies. Thus, younger children's difficulties with haptic-to-visual information transfer appeared to stem from their failure to use their hands to obtain reliable haptic information about objects. PMID- 20974477 TI - Defective number module or impaired access? Numerical magnitude processing in first graders with mathematical difficulties. AB - This study examined numerical magnitude processing in first graders with severe and mild forms of mathematical difficulties, children with mathematics learning disabilities (MLD) and children with low achievement (LA) in mathematics, respectively. In total, 20 children with MLD, 21 children with LA, and 41 regular achievers completed a numerical magnitude comparison task and an approximate addition task, which were presented in a symbolic and a nonsymbolic (dot arrays) format. Children with MLD and LA were impaired on tasks that involved the access of numerical magnitude information from symbolic representations, with the LA children showing a less severe performance pattern than children with MLD. They showed no deficits in accessing magnitude from underlying nonsymbolic magnitude representations. Our findings indicate that this performance pattern occurs in children from first grade onward and generalizes beyond numerical magnitude comparison tasks. These findings shed light on the types of intervention that may help children who struggle with learning mathematics. PMID- 20974479 TI - Intrinsic phospholipase A2 activity of adeno-associated virus is involved in endosomal escape of incoming particles. AB - The unique region of the VP1 capsid protein of adeno-associated viruses (AAV) in common with autonomously replicating parvoviruses comprises a secreted phospholipase A2 (sPLA2) homology domain. While the sPLA2 domain of Minute Virus of Mice has recently been shown to mediate endosomal escape by lipolytic pore formation, experimental evidence for a similar function in AAV infection is still lacking. Here, we explored the function of the sPLA2 domain of AAV by making use of the serotype 2 mutant (76)HD/AN. The sPLA2 defect in (76)HD/AN, which severely impairs AAV's infectivity, could be complemented in trans by co-infection with wild-type AAV2. Furthermore, co-infection with endosomolytically active, but not with inactive adenoviral variants partially rescued (76)HD/AN, providing the first evidence for a function of this domain in endosomal escape of incoming AAV particles. PMID- 20974480 TI - Human importin alpha and RNA do not compete for binding to influenza A virus nucleoprotein. AB - Influenza virus has a segmented genome composed of eight negative stranded RNA segments. Each segment is covered with NP forming ribonucleoproteins (vRNPs) and carries a copy of the heterotrimeric polymerase complex. As a rare phenomenon among the RNA viruses, the viral replication occurs in the nucleus and therefore implies interactions between host and viral factors, such as between importin alpha and nucleoprotein. In the present study we report that through binding with the human nuclear receptor importin alpha5 (Impalpha5), the viral NP is no longer oligomeric but maintained as a monomer inside the complex. In this regard, Impalpha5 acts as a chaperone until NP is delivered in the nucleus for viral RNA encapsidation. Moreover, we show that the association of NP with the host transporter does not impair the binding of NP to RNA. The complex human Impalpha5 NP binds RNA with the same affinity as wt NP alone, whereas engineered monomeric NP through point mutations binds RNA with a strongly reduced affinity. PMID- 20974478 TI - Impact of broadening definitions of anorexia nervosa on sample characteristics. AB - Practical limitations and sample size considerations often lead to broadening of diagnostic criteria for anorexia nervosa (AN) in research. The current study sought to elucidate the effects of this practice on resultant sample characteristics in terms of eating disorder behaviors, psychiatric comorbidities, temperament and personality characteristics, and heritability point estimates. Three definitions of AN were created: meeting all Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria for AN (AN-DSM-IV), meeting all DSM-IV criteria except criterion D, amenorrhea, (AN-noD), and broadening DSM-IV AN criteria by allowing a higher body mass index value, eliminating criterion D, and allowing less stringent body weight concerns (AN-Broad). Using data from the Swedish Twin Registry, 473 women fit one of the three definitions of AN. Women with AN-DSM-IV reported significantly more eating disorder behaviors than women with AN-Broad. Women with AN-noD reported more comorbid psychiatric disorders than women with AN-DSM-IV and AN-Broad. Temperament and personality characteristics did not differ across the three groups. Heritability point estimates decreased as AN definition broadened. Broadening the diagnostic criteria for AN results in an increased number of individuals available for participation in research studies. However, broader criteria for AN yield a more heterogeneous sample with regard to eating disorder symptoms and psychiatric comorbidity than a sample defined by narrower criteria. PMID- 20974481 TI - FeS-coated sand for removal of arsenic(III) under anaerobic conditions in permeable reactive barriers. AB - Iron sulfide (as mackinawite, FeS) has shown considerable promise as a material for the removal of As(III) under anoxic conditions. However, as a nanoparticulate material, synthetic FeS is not suitable for use in conventional permeable reactive barriers (PRBs). This study developed a methodology for coating a natural silica sand to produce a material of an appropriate diameter for a PRB. Aging time, pH, rinse time, and volume ratios were varied, with a maximum coating of 4.0 mg FeS/g sand achieved using a pH 5.5 solution at a 1:4 volume ratio (sand: 2 g/L FeS suspension), three days of aging and no rinsing. Comparing the mass deposited on the sand, which had a natural iron-oxide coating, with and without chemical washing showed that the iron-oxide coating was essential to the formation of a stable FeS coating. Scanning electron microscopy images of the FeS coated sand showed a patchwise FeS surface coating. X-ray photoelectron spectroscopy showed a partial oxidation of the Fe(II) to Fe(III) during the coating process, and some oxidation of S to polysulfides. Removal of As(III) by FeS-coated sand was 30% of that by nanoparticulate FeS at pH 5 and 7. At pH 9, the relative removal was 400%, perhaps due to the natural oxide coating of the sand or a secondary mineral phase from mackinawite oxidation. Although many studies have investigated the coating of sands with iron oxides, little prior work reports coating with iron sulfides. The results suggest that a suitable PRB material for the removal of As(III) under anoxic conditions can be produced through the deposition of a coating of FeS onto natural silica sand with an iron oxide coating. PMID- 20974482 TI - Efficacy and tolerability of fesoterodine in older and younger subjects with overactive bladder. AB - OBJECTIVES: To assess the effect of age on fesoterodine efficacy and tolerability in subjects with an overactive bladder. METHODS: The data from 2 randomized, 12 week studies of 1681 subjects treated with fesoterodine 4 or 8 mg or placebo were pooled and stratified by age. The subjects completed 3-day bladder diaries at baseline and weeks 2 and 12, the King's Health Questionnaire at baseline and week 12, and the Treatment Benefit Scale at week 12. RESULTS: Of the subjects aged <65 years, fesoterodine 4 and 8 mg was associated with statistically significant improvements in the diary variables at week 12 versus placebo. Greater improvement in urgency urinary incontinence was seen with fesoterodine 8 mg versus 4 mg. For those aged >=65 to <75 years, fesoterodine 4 and 8 mg significantly improved all diary variables, except for the mean voided volume and micturition frequency, respectively, [corrected] versus placebo. In subjects aged >=75 years, fesoterodine 8 mg significantly improved all diary variables, except for mean voided volume, versus placebo. No significant improvements were observed with fesoterodine 4 mg versus placebo. Fesoterodine significantly improved several King's Health Questionnaire domains versus placebo in all age groups. Fesoterodine 4 mg did not significantly improve any domains in subjects aged >=75 years. In all age groups, the treatment response rates were significantly greater with both fesoterodine doses versus placebo. Dry mouth and constipation occurred more frequently in subjects aged >=75 years receiving fesoterodine 8 mg than in those receiving fesoterodine 4 mg or placebo, although the discontinuation rates because of dry mouth and constipation were not increased. CONCLUSIONS: Fesoterodine 4 and 8 mg effectively treated overactive bladder symptoms in subjects aged <75 years. Fesoterodine 8 mg was effective in subjects aged >=75 years. PMID- 20974483 TI - A retrospective study: correlation of histologic inflammation in biopsy specimens of Chinese men undergoing surgery for benign prostatic hyperplasia with serum prostate-specific antigen. AB - PURPOSE: To reveal the correlation between benign prostatic hyperplasia (BPH) histologic inflammation and serum prostate-specific antigen (sPSA) concentrations, and the possible mechanism. PATIENTS AND METHODS: Patients underwent surgery at the Urology Department of West China Hospital of Sichuan University were retrospectively studied. Preoperative sPSA and transrectal ultrasonography were measured. According to the histopathological classification system for chronic prostatic inflammation proposed by the Chronic Prostatitis Collaborative Research Network (CPCRN) and the International Prostatitis Collaborative Network (IPCN), we classified the histologic sections of prostatic biopsy into glandular, periglandular, and stromal inflammation by the anatomical location of inflammatory infiltration. The glandular inflammation was graded according to the inflammatory aggressiveness. The periglandular and stromal inflammation were graded according to the inflammatory density. The correlation between histologic inflammation and sPSA was studied by a multiple regression model in conjunction with age and total prostatic volume. RESULTS: A total of 454 patients with exclusively BPH were analyzed. The periglandular inflammatory infiltration was the most common pattern (95.6%). Single regression analysis revealed that total prostatic volume, the aggressiveness of glandular inflammation, and the intensity of periglandular and stromal inflammation were correlated with sPSA. However, the multiple regression analysis revealed that only the total prostatic volume and the aggressiveness of glandular inflammation were correlated significantly with sPSA (R = .389, 0.289; P = .000). CONCLUSIONS: The aggressiveness of glandular inflammatory infiltration in BPH is a significant contributor to elevated sPSA levels. The theory of leakage may be the most reasonable mechanism to reveal the correlation morphologically. We should take inflammation into consideration when interpreting the abnormal elevating of sPSA levels. PMID- 20974484 TI - Bacteriuria after bipolar transurethral resection of the prostate: risk factors and correlation with leukocyturia. AB - OBJECTIVES: To analyze the risk factors of postoperative bacteriuria and the correlation with leukocyturia after bipolar transurethral resection of the prostate (TURP). METHODS: A total of 121 noncatheterized patients with sterile preoperative urine undergoing bipolar TURP for benign prostatic hyperplasia (BPH) were entered into the prospective study. All patients received antibiotic prophylaxis with ceftriaxone. Two urine specimens of each patient, one for urinalysis (urinary leukocyte count) and one for urine culture, were collected on removal of the catheter, 1 and 4 weeks after surgery. The risk factors of postoperative bacteriuria and correlation with leukocyturia were investigated. RESULTS: The incidence of bacteriuria after bipolar TURP was 18.2% (22/121). Multivariate analysis documented 3 independent risk factors of postoperative bacteriuria: operating time >60 minutes (P = .014), duration of catheterization >3 days(P = .001), and disconnection of the closed urine drainage system (P <10( 3)). The mean leukocyte counts in urine were 405.3, 389.5, and 113.8/MUL on removal of the catheter, 1 and 4 weeks after surgery, respectively. Of 363 urine specimens, the mean concentration of leukocytes with and without bacteriuria were 323.9 and 297.6/MUL, respectively (P >.05). There was no significant correlation between bacteriuria and leukocyturia (>10 leukocytes/high power field (P >.05). CONCLUSIONS: The results of our study have shown that the operating time, duration of catheterization, and disconnection of the closed urine drainage system may influence the occurrence of bacteriuria after bipolar TURP, and leukocyturia cannot reflect the possibility of postoperative bacteriuria. PMID- 20974485 TI - Impact of patient's self-viewing of flexible cystoscopy on pain using a visual analog scale in a randomized controlled trial. AB - OBJECTIVES: To investigate the difference in pain score of patients allowed to view their flexible cystoscopy procedure compared with those who have not viewed the procedure on the video monitor. METHODS: It is a prospective, randomized, controlled study. A total of 76 patients with different clinical indications for flexible cystoscopy were enrolled in the study. Patients were divided into 2 groups; group A and group B with 38 patients each. Group A patients viewed the procedure on a video monitor, whereas group B, the control group, did not. Statistical analyses were performed using a chi(2) test, Student's t test, and paired t test. A P value of <0.05 was considered to be statistically significant. RESULTS: There were no statistically significant differences in demographic characteristics between the 2 groups. Mean age, duration of the procedure, and indications for the procedure were also comparable in the 2 groups. There was, however, a statistically significant difference in pain scores between the 2 groups (P < .001). The numbers of patients reporting pain in the study group (group A) were lower than in the control group (group B). There was a statistically significant difference in the postprocedural pulse rate; however, the systolic blood pressure pre- and postprocedure remained the same. CONCLUSIONS: Patients' who viewed the cystoscopic procedure on a video monitor reported less pain on a visual analog scale compared with the control group. PMID- 20974486 TI - Complex chromosome rearrangement 46,XY, der(9)t(Y;9)(q12;p23) in a girl with sex reversal and mental retardation. AB - Monosomy 9p syndrome, also known as Alfi syndrome, has been described as a contiguous syndrome characterized by mental retardation, developmental delay, and facial dysmorphisms. Males with monosomy 9p often express variable degrees of feminization, although the genitalia of females will be normal. In the present report, we describe a case of ambiguous genitalia and intra-abdominal testicular development, with a derivative chromosome 9 arising from a translocation between 9p23 and Yq heterochromatin. Pathologic examination of the testes showed germ cell hypoplasia of the seminiferous tubules. fluorescence in situ hybridization, spectral karyotyping, and array comparative genomic hybridization were used to characterize the genetic changes. PMID- 20974487 TI - Bladder volume on voiding cystourethrogram correlates with indications and results in male infants. AB - OBJECTIVES: To evaluate whether the bladder size on the voiding cystourethrogram (VCUG) might be a proxy for voiding abnormalities. Voiding abnormalities have been implicated in the development of hydronephrosis, reflux, and urinary tract infections. METHODS: We evaluated the volume of contrast infused for 617 consecutive VCUGs. We compared the actual volume infused during the VCUG to the expected bladder capacity. We correlated the percentage of predicted capacity with (a) the reason for the VCUG; (b) the VCUG results; (c) the patient's sex; and (d) their body mass index. We analyzed the results for the entire group, as well as by age, sex, reflux grade, and body mass index. We also examined the findings from those patients undergoing consecutive studies. RESULTS: The bladder size on the VCUG was greater than predicted (1.74 times predicted). This was particularly true for patients <2 years old (2.22 vs 1.41 times predicted; P < .001) and for boys (2.01 vs 1.63 times predicted; P < .001). Both the reason for the VCUG (more prenatal patients with hydronephrosis than others; P < .001) and the VCUG findings (new reflux found more than others) had a relationship with the bladder size on the VCUG (P < .001). The body mass index did not correlate with the bladder size on the VCUG. Of the 87 patients undergoing 2 studies, the 53 patients with either no or improved reflux on the second study tended to have a larger than predicted bladder size on the VCUG (P = .07). CONCLUSIONS: The bladder volume on the VCUG was greater than predicted for male infants with prenatal hydronephrosis and reflux. In other groups, the marked variation within groups prevented the use of the bladder volume on the VCUG as a proxy for voiding dysfunction. PMID- 20974488 TI - Progression of null or mild lower urinary tract symptoms indicative of benign prostatic hyperplasia after 2 years of follow-up in non-treated men aged 40 years or older. AB - OBJECTIVES: After screening men aged 40 years or older for lower urinary tract symptoms (LUTS) indicative of benign prostatic hyperplasia over the years 1999 to 2000, non-treated men with an initial International Prostate Symptoms Score (I PSS) equal to or lower than 2 were assessed 2 years later for symptom progression. METHODS: A cross-sectional study was conducted in 1999 on 1804 men aged 40 years or older who were living in Madrid. In a telephone interview sociodemographic information was requested and LUTS assessed using the I-PSS. Of 975 men with no LUTS or lower than 2 in this baseline survey, 463 were re interviewed in 2001. The dependent variable was the change from null/mild to moderate/severe LUTS produced over 2 years. RESULTS: Over the 2-year period, the mean increase in I-PSS score was 2.20 (95% CI, 1.89-2.51). The cumulative incidence of progression from asymptomatic/mild to moderate/severe disease was 9.94% (95% CI, 7.53-13.00). In the multivariate logistic regression model men who lived in a rural setting (OR, 2.70; P = .01) and armed forces, qualified agriculture and fishing workers (OR, 4.11; P = .05) were independently associated with progression. Age and alcohol intake were also found to interact; intake of 0.01-25.99 g/day in men older than 50 years (OR, 0.28; P = .008) was related to a lower frequency of progression than the same alcohol intake in men younger than 50 years (OR, 2.03; P = .380). CONCLUSIONS: After the 2-year period, the incidence of symptom progression was 10% in men aged 40 years or older with an initial I-PSS equal to or lower than 2. PMID- 20974489 TI - Effect of a hypercholesterolemic diet on serum lipid profile, plasma sex steroid levels, and prostate structure in rats. AB - OBJECTIVES: The purpose of this study was to examine the impact of a hypercholesterolemic diet (HD) on serum lipid profile, plasma sex steroid levels, and ventral prostate structure in rats. METHODS: Beginning at 120 days of age, male Wistar rats were fed for 5 months with either standard rat chow (15 animals) or standard chow enriched with 4% cholesterol and 1% cholic acid (15 animals). The body and ventral prostate weights (VPWs), plasma sex steroid levels, and lipid profiles were determined, and prostate morphology in fixed tissue sections were studied. RESULTS: The body weight of rats fed with HD did not differ from that of controls. However, both absolute and relative VPWs of HD animals were significantly lower than those of controls. HD resulted in significant elevation in total serum cholesterol and LDL levels, whereas HDL and triglyceride levels were comparable. Plasma total testosterone and estriol levels did not differ between groups, but their free fraction, along with sex hormone-binding globulin levels, were significantly affected. HD also affected the microscopic structure of the ventral prostate. Epithelial cells of the distal area formed papillary projections within the acinar lumen and had more cytoplasm than controls. In most cases, vesicular formations within the cytoplasmic area were also noted. CONCLUSIONS: Hypercholesterolemia causes marked changes in the ventral prostate, serum lipid profile, and plasma sex steroid profile in rats and possibly alters prostate morphology by affecting the sex steroid axis, thus contributing to prostatic disease pathogenesis. PMID- 20974490 TI - "Inside-out" transobturator tension-free vaginal tape for management of occult stress urinary incontinence in women undergoing pelvic organ prolapse repair. AB - OBJECTIVES: To assess the safety and effectiveness of the "inside-out" transobturator tension-free vaginal tape procedure for the management of occult stress urinary incontinence (SUI) in clinically continent women undergoing prolapse repair. METHODS: A total of 117 consecutive continent women (mean age and parity 66.8 +/- 9.9 years and 3.2 +/- 1.5, respectively) with significant pelvic organ prolapse and urodynamically confirmed occult SUI were enrolled in the present study. Surgical intervention included transvaginal prolapse repair and concomitant prophylactic transobturator tension-free vaginal tape. The main outcome measures were procedure-related complications, early and late postoperative morbidity, postoperative urodynamic SUI, persistent or de novo overactive bladder, and bladder outlet obstruction. RESULTS: No cases of significant blood loss, hematoma formation, or bladder injury occurred. Of the 117 patients, 6 (5.1%) had immediate postoperative voiding difficulties necessitating catheterization for >2 days. Late postoperative morbidity was assessed in 110 patients with >=3 months of follow-up (mean 27.2 +/- 17.7). Of these 110 patients, 7 (6.4%) had protracted postoperative thigh pain with spontaneous resolution within 1-3 months, and 7 (6.4%) had developed recurrent urinary tract infections. No cases of vaginal erosion developed. The functional outcome analysis was restricted to 92 patients with >=12 months of follow-up (mean 31 +/- 16). Of the 92 patients, 13 (14%) were found to have urodynamic SUI. However only 2 patients (2.2%) were symptomatic for a subjective and objective cure rate of 97.8% and 86%, respectively. Of the 34 patients who had had overactive bladder preoperatively, 22 (64.7%) had persisting symptoms postoperatively. An additional 4 patients (6.9%) had developed de novo overactive bladder symptoms, and 1 patient had bladder outlet obstruction. CONCLUSIONS: The prophylactic transobturator tension-free vaginal tape procedure is both effective and safe in patients with occult SUI undergoing prolapse repair. PMID- 20974491 TI - Sediment-related distribution patterns of nematodes and macrofauna: two sides of the benthic coin? AB - We investigated the sediment-related distribution of both nematodes and macrofauna on the Belgian part of the North Sea (Southern Bight of the North Sea) in order to evaluate whether both faunal groups reflect similar patterns in community composition and diversity. Fine-grained sediments (median grain size <200MUm) were inhabited by nematode communities characterised by a low diversity and dominated by non-selective deposit-feeding nematodes. Nematode communities from coarser sediments were significantly different in terms of community composition and diversity. Moreover, all nematode feeding types were present in coarser sediments. These differences were explained by the contrasting biogeochemical processes prevailing in both sediment types, rather than granulometry and food availability per se. Macrofaunal distribution patterns were different from those of the nematode communities and seem to be related to water column processes (SPM loading, food availability, hydrodynamic stress) that promote the establishment of diverse communities in the coarser sediments but not in the finest sediments. This suggests that data on nematodes and macrofauna reveal different, complementary aspects of the factors structuring the benthic ecosystem that can be of importance in assessing the ecological status of the seafloor. PMID- 20974492 TI - Inverted colloidal crystal scaffolds with laminin-derived peptides for neuronal differentiation of bone marrow stromal cells. AB - This study presents the effect of pore regularity on the preservation and differentiation of bone marrow stromal cells (BMSCs). Scaffolds with interconnected pores of inverted colloidal crystal (ICC) geometry were prepared by infiltrating chitosan-gelatin gels into the interstices of self-assembled microspheres, which were later dissolved with a solvent. In addition, the pore surfaces were grafted with two laminin-derived peptides (LDP). The experimental results revealed that the number of BMSCs in ICC scaffolds could increase 2.7 fold after cultivation over 7 days. Moreover, the distribution of cultured BMSCs in ICC scaffolds was quite uniform as compared with freeform scaffolds. ICC scaffolds could preserve 63% phenotypic BMSCs in average and freeform scaffolds 56%. The grafted LDP enhanced the adhesion efficiency of BMSCs in ICC scaffolds (about 70-75%) and produced NeuN-positive cells. A further induction with neuron growth factor could guide the differentiation of BMSCs toward mature neurons in LDP-grafted ICC scaffolds. The controlled topography of ICC structure and surface LDP can be promising in the cultivation of BMSCs and neural regeneration. PMID- 20974493 TI - Differential response of Staphylococci and osteoblasts to varying titanium surface roughness. AB - The surface roughness of metallic orthopaedic implants has typically been used to influence osseointegration and spatially control load transfer to the surrounding bone. Because of the increasing recognition of biomaterials-associated infection as a leading implant failure mode, we are interested to know the relative importance of roughness not only on surface-osteoblast interactions but also on surface-bacteria interactions. This in vitro study thus compares the effects of surface topography on Staphylococcus epidermidis and human osteoblast behavior using four clinically relevant titanium surface finishes: polished, satin, grit blasted and plasma-sprayed. Important differences between these surfaces are manifested not only by their vertical roughness parameters but also by the lateral length scales over which topographic fluctuations occur. We find that S. epidermidis adhesion and growth is substantially higher on the satin and grit blasted surfaces than on the polished or plasma-sprayed surfaces. The former are both substantially rougher at length scales comparable to that of bacteria. In contrast, based on imaging and biochemical assays of proliferation, differentiation and matrix formation, we find that desirable osteoblast-surface interactions are maximized on plasma-sprayed surfaces and minimized on satin finished surfaces. We attribute these differences to the fact that the plasma sprayed surface is relatively smooth compared to the size of an individual osteoblast, while the satin surface is rough at this length scale. These findings indicate that both the vertical and lateral character of surface roughness can be modified to not only optimize implant-bone interactions but to simultaneously minimize implant-bacteria interactions. PMID- 20974494 TI - Effects of intracerebroventricular galanin or a galanin receptor 2/3 agonist on the lesion induced by transient occlusion of the middle cerebral artery in female rats. AB - Several studies have shown that injury to the central and peripheral nervous system can increase expression of galanin, a 29 amino acid neuropeptide. Moreover, there is evidence that galanin, especially through its galanin receptor 2 (GalR2) receptor, plays a neuroprotective role in different injury models. However, direct studies of a possible neuroprotective effect of galanin in experimental stroke models are lacking. Galanin, a GalR2/3 agonist or artificial CSF was continuously infused intracerebroventricularly (i.c.v.) in naive female rats after a 60min transient and focal occlusion of the middle cerebral artery. The animals were sacrificed, and the ischemic lesion was visualized using 2,3,5 triphenyltetrazolium hydrochloride (TTC) staining. The lesion was 98% larger after i.c.v. administration of the GalR2/3 agonist (2.4nmol/day) seven days after occlusion compared to artificial CSF (p=0.023). No statistically significant differences were found after seven days in the groups treated with galanin in three different concentrations (0.24, 2.4 and 24nmol/day; p=0.939, 0.715 and 0.977, respectively). There was no difference in the size of the ischemic lesions measured after three days in the galanin-treated group (2.4nmol/d) compared to artificial CSF (p=0.925). The present results show, surprisingly, that a GalR2/3 agonist doubled the size of the ischemic lesion. Whether this effect primarily reflects the properties of the current model, species, gender and/or the mode of galanin administration, e.g. causing desensitization, or whether galanin indeed lacks neuroprotective effect of its own, remains to be corroborated. PMID- 20974496 TI - Proteomic analysis of a model fish species exposed to individual pesticides and a binary mixture. AB - Pesticides are nearly ubiquitous in surface waters of the United States, where they often are found as mixtures. The molecular mechanisms underlying the toxic effects of sub-lethal exposure to pesticides as both individual and mixtures are unclear. The current work aims to identify and compare differentially expressed proteins in brains of male fathead minnows (Pimephales promelas) exposed for 72 h to permethrin (7.5 MUg/L), terbufos (57.5 MUg/L) and a binary mixture of both. Twenty-four proteins were found to be differentially expressed among all three treatments relative to the control using an ANOVA followed by a Dunnett's post hoc test (p <=0.05). One protein was found to be differentially expressed among all treatment groups and one protein was in common between the terbufos and the mixture group. Fifteen spots were successfully sequenced using LC-MS/MS sequencing. Proteins associated with the ubiquitin-proteasome system, glycolysis, the cytoskeleton and hypoxia were enriched. As a second objective, we attempted to establish protein expression signatures (PES) for individual permethrin and terbufos exposures. We were unable to generate a useable PES for terbufos; however, the permethrin PES was able to distinguish between control and permethrin-exposed individuals in an independent experiment with an accuracy of 87.5%. This PES also accurately classified permethrin exposed individuals when the exposure occurred as part of a mixture. The identification of proteins differentially expressed as a result of pesticide exposure represent a step forward in the understanding of mechanisms of toxicity of permethrin and terbufos. They also allow a comparison of molecular responses of the binary mixture to single exposures. The permethrin PES is the first step in establishing a method to determine exposures in real-world scenarios. PMID- 20974497 TI - Inflammatory markers and plaque morphology: an optical coherence tomography study. AB - BACKGROUND: OCT with its unique image resolution is the ideal method to detect culprit lesion characteristics in different clinical presentations. The identification of inflammatory markers related to plaque characteristics may be of clinical importance. METHODS: Thirty-two patients with acute coronary syndromes (ACS) and fourteen patients with stable angina pectoris (SAP) were enrolled in this study. Culprit lesion morphology was assessed by optical coherence tomography (OCT) in patients with ACS and SAP. The possible relations between serum levels of high sensitivity-C reactive protein (hs-CRP) and interleukin-18 (IL-18) with plaque characteristics were investigated in those patients. RESULTS: Plaque rupture and thin-cap fibroatheroma (TCFA) were detected more frequently in ACS patients compared with SAP patients, (78.6% vs. 14.3%, p<0.001, 92.9% vs. 14.3%, p<0.001, respectively). Higher levels of serum hs-CRP and IL-18 were found in patients with plaque rupture vs. those with no plaque rupture (median value: 19.2mg/L vs. 1.6 mg/L, p<0.001 and 219.5 pg/ml vs. 127.5 pg/ml, p=0.001 respectively), and TCFA vs. those without TCFA (median value: 15.2mg/L vs. 1.6 mg/L, p=0.004 and 209.0 pg/ml vs.153.2 pg/ml, p=0.03 respectively). Serum hs-CRP was the only independent predictor of plaque rupture (p=0.02, odds ratio 1.1, 95% confidence interval 1.0 to 1.2). A cut-off value of hs-CRP>4.5mg/L could detect ruptured plaque with a sensitivity of 91.7% and a specificity of 77.8%. CONCLUSIONS: OCT detected plaque rupture and TCFA more frequent in ACS patients compared with SAP. Elevated hs-CRP and IL-18 were positively related to plaque instability and rupture. PMID- 20974498 TI - Intra-aortic balloon pumping recruits graft flow reserve by lowering coronary resistances. AB - BACKGROUND: The intra-aortic balloon pump (IABP) is used worldwide as an anti ischemic strategy and to reduce myocardial workload. However, whether IABP augments coronary flow after coronary bypass via a passive increase in diastolic pressure or an active response of the coronary bed remains uncertain. METHODS: We analyzed transit-time flow measurements and the contemporary changes in coronary resistances obtained during 1:1 IABP and during its cessation in 144 consecutive patients receiving prophylactic IABP before isolated coronary artery bypass grafting (n=340 graft segments). RESULTS: Normally functioning grafts showed lower coronary resistances, greater percentage decrease in resistance, and greater increases in average maximum diastolic and mean flow during 1:1 IABP compared with IABP cessation (P<.001). Arterial and sequential saphenous vein grafts showed better flowmetry and greater reductions in coronary resistances compared with single venous grafts. Accordingly, graft flow reserve (defined as mean flow during 1:1 IABP/mean flow with IABP off) was recruited (graft flow reserve >1) during 1:1 IABP in all normally functioning grafts, with higher values in single arterial or sequential saphenous vein grafts than in single venous grafts (both P<.001). Coronary resistances were higher in 7 failed grafts versus normal-functioning grafts at baseline; these did not decrease during 1:1 IABP and showed worse transit-time flow results. CONCLUSIONS: IABP recruits graft flow reserve by lowering coronary resistance in functioning grafts. Arterial and sequential venous grafts showed greater reduction in coronary resistance compared with single saphenous grafts. PMID- 20974499 TI - The clinical significance of smaller increases in cardiac enzymes following elective percutaneous coronary intervention. PMID- 20974500 TI - Clinical and genetic determinants of anthracycline-induced cardiac iron accumulation. AB - BACKGROUND: The involvement of iron in anthracycline cardiotoxicity is supported by extensive experimental data, and by the preventive efficacy of dexrazoxane, an iron chelator. However, no clinical evidence of anthracycline-induced cardiac iron accumulation is available and the influence of previous iron overload or of genetic factors in human-induced heart disease is largely unknown. Our aim was to test the hypothesis that anthracyclines increase iron heart concentration and that HFE genotype modulates this iron deposit. METHODS: We retrospectively evaluated cardiac events, cardiac iron and HFE genotype in 97 consecutive necropsies from patients with solid and hematological neoplasms. Heart and liver iron concentration was determined by atomic absorption spectroscopy. HFE gene mutations (C282Y and H63D) linked to hereditary hemochromatosis were analyzed by Fluorescence Resonance Energy Transfer (FRET) genotyping. RESULTS: Heart iron concentration was increased in cases treated with a cumulative doxorubicin dose greater than 200mg/m(2) (490 vs 240 MUg/g; p=0.01), independently of liver iron load or transfusion history. HFE mutated haplotypes 282C/63D (p=0.049) and 282Y/63H (p=0.027) were associated to higher cardiac iron deposits. The haplotype C282Y-Y/H63D-H interacted with anthracyclines for increasing cardiac iron load. In a multivariate linear regression analysis both HFE genotypes and anthracyclines contributed to heart iron concentration (R(2)=0.284). CONCLUSIONS: Our data support the occurrence of an HFE-modulated heart iron accumulation in individuals treated with anthracyclines, independently of systemic iron load. If prospectively confirmed, iron-related parameters might be useful as predictive factors for anthracycline cardiotoxicity. PMID- 20974501 TI - Assessing the impact of East Coast Fever immunisation by the infection and treatment method in Tanzanian pastoralist systems. AB - A field trial was carried out in a Maasai homestead to assess the impact of East Coast Fever (ECF) immunisation by the infection and treatment method (ITM) with the Muguga Cocktail on the occurrence of this disease in Tanzanian pastoralist systems. These data were further used in partial budgeting and decision analysis to evaluate and compare the value of the control strategy. Overall, ITM was shown to be a cost-effective control option. While one ECF case was registered in the immunised group, 24 cases occurred amongst non-immunised calves. A significant negative association between immunisation and ECF cases occurrence was observed (p<=0.001). ECF mortality rate was also lower in the immunised group. However, as anti-theilerial treatment was given to all diseased calves, no significant negative association between immunisation and ECF mortality was found. Both groups showed an overall similar immunological pattern with high and increasing percentages of seropositive calves throughout the study. This, combined with the temporal distribution of cases in the non-immunised group, suggested the establishment of endemic stability. Furthermore, the economic analysis showed that ITM generated a profit estimated to be 7250 TZS (1 USD=1300 TZS) per vaccinated calf, and demonstrated that it was a better control measure than natural infection and subsequent treatment. PMID- 20974503 TI - Synthesis and biological evaluation of N-substituted-3,5-diphenyl-2-pyrazoline derivatives as cyclooxygenase (COX-2) inhibitors. AB - Eighteen new 1-N-substituted-3,5-diphenyl-2-pyrazoline derivatives have been synthesized and cyclooxygenase (COX-1 and COX-2) inhibitory activities have been evaluated. The results of these biological assays showed that all of new derivatives are not endowed with improved anti-inflammatory activity against COX 1, but some of them showed a good activity against COX-2. To evaluate the binding mode of the most significative compounds (2d, 2f, 2g and 2k) docking studies were carried out. These studies confirmed biological data, in fact these compounds were able to fit into the active site of COX-2. PMID- 20974502 TI - Insulin resistance predicts re-treatment failure in an efficacy study of peginterferon-alpha-2a and ribavirin in HIV/HCV co-infected patients. AB - BACKGROUND & AIMS: Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. The aim of this study is to evaluate the safety and efficacy of pegylated interferon-alpha 2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response, including insulin resistance, and the relationship between insulin resistance and liver histology. METHODS: This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon alpha-2a and ribavirin for 48 weeks. Serum HCV RNA was measured 24 weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR >2. Correlations between baseline insulin resistance and steatosis, and/or cirrhosis were determined. RESULTS: Sustained virological response was achieved in 14/96 (15%) patients. 35% of patients with HOMA-IR < 2 (6/17) achieved sustained virological response vs 14% (5/36) of those with HOMA IR between 2-4, and 7% (3/41) of those with HOMA-IR > 4 (p = 0.01). In multivariable analysis, insulin resistance and log10 HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95% CI 0.05-0.64, p = 0.009, and AOR 0.36; 95% CI 0.14-0.93, p = 0.04, respectively]. Steatosis and cirrhosis correlated with insulin resistance (p = 0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% of cases, and 2 patients died of unrelated causes. CONCLUSIONS: In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those patients without insulin resistance are significantly more likely to achieve sustained virological response. PMID- 20974504 TI - Synthesis and in vitro biological evaluation of new polyamine conjugates as potential anticancer drugs. AB - The synthesis of new polyamine derivatives containing dimeric quinoline (3a-c), cinnoline (4a-c) and phthalimide (7a-c and 8a-c) moieties is described. Three different polyamines: (1,4-bis(3-aminopropyl)piperazine (a), 4,9-dioxa-1,12 dodecanediamine (b), 3,3'-diamino-N-methyldipropylamine (c) were used as linkers. The new compounds were obtained according to known procedures. Their biological activity was assessed in vitro in a highly aggressive melanoma cell line A375. Polyamine diimides containing phthalimide moieties demonstrated no inhibitory activities against melanoma cells. Quinoline diamides were more efficient than cinnoline ones. Mainly cytostatic activity exerted as altered cell cycle profiles was observed at the concentrations causing about 50% reduction of adherent cell proliferation. Based on their structure as well as their biological activity, we assume that some of the newly synthesized compounds may act as DNA bisintercalators. This study might be useful for further designing and developing anticancer drugs with potent activities. PMID- 20974505 TI - Design, synthesis and discovery of 5-hydroxyaurone derivatives as growth inhibitors against HUVEC and some cancer cell lines. AB - A series of 4'-substituted 5-hydroxyaurone derivatives were synthesized and their inhibitory activities against the proliferation of endothelial cells and two cancer cell lines were studied. Some of these compounds functioned as potent inhibitors against the proliferation of endothelial cells and cancer cells but possessed much weaker cytotoxic activities against non-cancer cell line of CCC HPF-1. It was demonstrated that two most active compounds 16 and 27 effectively inhibited in vitro endothelial cell motility and tube formation, which are basic properties of endothelial cells for angiogenesis. Moreover, 16 and 27 also showed significant activities against in vitro cancer cell invasion, indicating that they have potential to inhibit cancer metastasis. These composite results suggest that 4'-substituted 5-hydroxyaurone is indeed a candidate structural scaffold for anticancer agent targeting activated endothelial cells and fast-proliferating cancer cells. PMID- 20974506 TI - Tolstoy, stories, and facilitating insight in end of life care: exploring ethics through vicarious experience. AB - Facilitating moral insight in end of life care can be challenging, and the purpose of this paper is to illustrate how this can be nurtured by means of creative literature. Tolstoy's Death of Ivan Ilych is presented as an example of such literature. Aristotle's Nichomean Ethics provides the philosophical underpinning for the method used. Sources also include the nursing literature, and students' evaluations of the impact of Tolstoy's novella on their ability to perceive the ethical issues arising in end of life care. Comments from evaluations were analysed and significant themes emerged. Students' comments clearly support the suggestion that use of this novella has facilitated insight into ethical issues at the end of life. Evaluations also indicate that vicarious experience gained through reading this novella has helped to nurture sensitivity and professional insight into the importance of compassion and offering 'comfort' to the dying person. PMID- 20974507 TI - Responses of evergreen and deciduous Quercus species to enhanced ozone levels. AB - Plants of one evergreen oak (Quercus ilex) and three deciduous oaks (Q. faginea, with small leaves; Q. pyrenaica and Q. robur, with large leaves) were exposed both to filtered air and to enhanced ozone levels in Open-Top Chambers. Q. faginea and Q. pyrenaica were studied for the first time. Based on visible injury, gas exchange, chlorophyll content and biomass responses, Q. pyrenaica was the most sensitive species, and Q. ilex was the most tolerant, followed by Q. faginea. Functional leaf traits of the species were related to differences in sensitivity, while accumulated ozone flux via stomata (POD1.6) partly contributed to the observed differences. For risk assessment of Mediterranean vegetation, the diversity of responses detected in this study should be taken into account, applying appropriate critical levels. PMID- 20974508 TI - Transport of polycyclic aromatic hydrocarbons in highly vulnerable karst systems. AB - Fluxes of polycyclic aromatic hydrocarbons (PAHs) were investigated along the route of transport in a south German karst system. Atmospheric deposition, seepage water in caves and spring water at the outlet of the catchment were monitored continuously over 1.5 years allowing the establishment of an input/output mass balance at the catchment scale. The results reveal that, even in the highly vulnerable karst catchment, PAHs are effectively retained in the soils. Only during high discharge events, such as snowmelt in spring, increasing PAH concentrations at the outlet of the catchment indicates a mobilization of the pollutants. These events are typically correlated with increasing particle concentrations. Based on our results, we conclude that particle-facilitated transport is the dominating cause of PAH mobilization. In summary, PAHs accumulate over time in soils and only occasionally high discharge events cause a short concentration pulse to be flushed through the karst system. PMID- 20974509 TI - Signs and symptoms associated with earlier dialysis initiation in nursing home residents. AB - BACKGROUND: Factors driving the trend of earlier dialysis initiation for persons with end-stage renal disease are unknown. We wanted to determine the association of the number and type of signs and symptoms with timing of initiation of dialysis in US nursing home residents. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: We used data from the US Renal Data System linked with the Minimum Data Set, a national registry of nursing home residents. The cohort consisted of 2,402 nursing home residents who initiated dialysis between 1998 and 2000 and had at least 2 recorded clinical assessments in the year before dialysis initiation. PREDICTORS: We evaluated 7 clinical signs and symptoms: dependence in activities of daily living, cognitive function, edema, dyspnea, nutritional problems, vomiting, and body size. OUTCOMES: Earlier dialysis initiation was defined as estimated glomerular filtration rate >= 1 5 mL/min/1.73 m2 at the start of dialysis. RESULTS: Median estimated glomerular filtration rate at the start of dialysis was 9.8 (25th-75th percentile, 7.4-13.4) mL/min/1.73 m2. After adjustment for age, sex, race, and comorbid conditions, each additional sign or symptom was associated with a higher odds for earlier dialysis initiation (OR, 1.16 per symptom; 95% CI, 1.06-1.28), as was each adversely changing sign or symptom (OR, 1.26 per symptom; 95% CI, 1.16-1.38). The population-attributable risk for earlier dialysis initiation associated with having one or more signs and symptoms of volume overload, cognitive decline, increasing activities of daily living dependence, and weight loss was 31%; volume overload had the largest aggregate population-attributable risk. LIMITATIONS: We lacked information about metabolic indications for dialysis initiation. CONCLUSIONS: Volume overload, cognitive decline, increasing activities of daily living dependence, and weight loss were associated with earlier dialysis initiation; however, these factors explained less than one-third of cases of earlier dialysis initiation in nursing home residents. PMID- 20974510 TI - Drug-induced granulomatous interstitial nephritis in a patient with ankylosing spondylitis during therapy with adalimumab. AB - Tumor necrosis factor alpha (TNF-alpha) inhibitors are used in the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn disease, ankylosing spondylitis, and juvenile idiopathic arthritis. Use of TNF inhibitors is associated with the induction of autoimmunity (systemic lupus erythematosus, vasculitis, psoriasis, and sarcoidosis/sarcoid-like granulomas). We report a case of interstitial granulomatous nephritis in a patient with ankylosing spondylitis after 18 months of treatment with adalimumab. Previously reported cases of sarcoid-like reactions secondary to the use of TNF-alpha inhibitors involved the liver, lung, lymph nodes, central nervous system, and skin. Granulomatous nephritis after adalimumab treatment has not been described. Close observation of patients undergoing treatment with TNF inhibitors for evolving signs and symptoms of autoimmunity is required. Organ involvement is unpredictable, which makes correct diagnosis and management extremely challenging. PMID- 20974511 TI - Effect of remote ischemic preconditioning on acute kidney injury in nondiabetic patients undergoing coronary artery bypass graft surgery: a secondary analysis of 2 small randomized trials. AB - BACKGROUND: Novel treatment strategies are required to reduce the development of acute kidney injury (AKI) in patients undergoing cardiac surgery. In this respect, remote ischemic preconditioning (RIPC), a phenomenon in which transient nonlethal ischemia applied to an organ or tissue protects another organ or tissue from subsequent lethal ischemic injury, is a potential renoprotective strategy. STUDY DESIGN: Secondary analysis of 2 randomized trials. SETTING & PARTICIPANTS: 78 consenting selected nondiabetic patients in a university teaching hospital undergoing elective coronary artery bypass graft (CABG) surgery recruited to 2 previously reported randomized studies. INTERVENTION: RIPC consisted of three 5 minute cycles of right forearm ischemia, induced by inflating a blood pressure cuff on the upper arm to 200 mm Hg, with an intervening 5 minutes of reperfusion, during which time the cuff was deflated. The control consisted of placing an uninflated cuff on the arm for 30 minutes. OUTCOMES: AKI measured using Acute Kidney Injury Network (AKIN) criteria, duration of hospital stay, in-hospital and 30-day mortality. RESULTS: Numbers of participants with AKI stages 1, 2, and 3 were 1 (3%), 3 (8%), and 0 in the intervention group compared with 10 (25%), 0, and 0 in the control group, respectively (P = 0.005). The decrease in AKI was independent of the effect of concomitant aortic valve replacement and cross-clamp times, which were distributed unevenly between the 2 groups. LIMITATIONS: Retrospective analysis of data. More patients in the RIPC group underwent concomitant aortic valve replacement with CABG; although we have corrected statistically for this imbalance, it remains an important confounding variable. CONCLUSIONS: RIPC induced using transient forearm ischemia decreased the incidence of AKI in nondiabetic patients undergoing elective CABG surgery in this retrospective analysis. A large prospective clinical trial is required to study this effect and clinical outcomes in patients undergoing cardiac surgery. PMID- 20974512 TI - Rare association of chronic lymphocytic leukemia/small lymphocytic lymphoma, ANCAs, and pauci-immune crescentic glomerulonephritis. AB - We report a 69-year-old African American woman with hemoptysis and hematuria caused by a focally crescentic pauci-immune glomerular injury associated with the presence of antineutrophil cytoplasmic antibodies (ANCAs). An incidental diagnosis of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma also was established based on the kidney biopsy. Given that a subset of patients with CLL can develop autoantibodies to red blood cells, platelets, or, rarely, neutrophils, the simultaneous presence of CLL, ANCA, and a pauci-immune crescentic glomerulonephritis may not be a coincidence. Recent advances in the pathogenic role of ANCAs in pauci-immune crescentic glomerulonephritis may link the underlying CLL to this patient's glomerular injury. Awareness of this possible association may be important for clinicians who manage patients with CLL, as well as for renal pathologists who diagnose pauci-immune crescentic glomerulonephritis. PMID- 20974513 TI - Association of carotid intima-media thickness with progression of urine albumin creatinine ratios in The Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: The association between measures of subclinical cardiovascular disease and progression of urine albumin-creatinine ratios (UACRs) over time is uncertain. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: The Multi-Ethnic Study of Atherosclerosis (MESA), a cohort of adults aged 45-84 years without baseline clinical cardiovascular disease. Examinations were completed approximately every 1.5 years, and UACR was measured during the first 3 examinations. Analysis was limited to 4,878 participants without baseline micro- or macroalbuminuria. PREDICTOR: 1-standard deviation (SD) unit difference in baseline maximum common and internal carotid intima-media thickness (CIMT) measured using ultrasonography. OUTCOMES & MEASUREMENTS: Baseline UACR was categorized as normal or high-normal. UACR progression was categorized as no progression (consistent UACR category across all 3 examinations or regression to a lower category) and definite progression (higher UACR category at examination 2 compared with baseline, then stabilizing or progressing at examination 3). UACR changes not consistent with definite or no UACR progression were classified as intermediate UACR progression. Change in log UACR also was examined. RESULTS: In the 4,878 participants, median baseline UACR was 4.6 mg/g (range, 0.4-24.6 mg/g). Definite and intermediate UACR progression was noted in 279 and 807, respectively. Every 1-SD unit difference in common CIMT was associated with a 22% increased adjusted odds of definite compared with no UACR progression (95% CI, 1.07-1.41). No significant association was noted between 1-SD unit difference in maximum internal CIMT and definite UACR progression after adjusting for covariates (OR, 1.08; 95% CI, 0.96-1.21). In the mixed-effects model, changes in log UACR were 0.029 (95% CI, 0.012-0.046) and 0.019 mg/g (95% CI, 0.001-0.037) per 1-SD difference in maximum common and internal CIMT after adjustment for covariates, respectively. LIMITATIONS: UACR was measured in a single spot urine specimen at each exam. CONCLUSION: Higher common CIMT is associated with UACR progression. PMID- 20974514 TI - Demand for voluntary health insurance in developing countries: the case of Vietnam's school-age children and adolescent student health insurance program. AB - Many developing countries are trying to expand health insurance to achieve universal coverage, yet enrolling informal sector workers and the rural population remains a challenge. A good knowledge of factors driving demand for health insurance among these groups is therefore important. The current study contributes to this body of knowledge by analyzing demand for school-age children and adolescent student (aged 6-20) health insurance, a major voluntary health insurance scheme in Vietnam. Data were drawn form the Vietnam National Health Survey (2001-2002). We found that demand increases significantly with the expected benefits of insurance as measured by proximity to and quality of a tertiary hospital. There is a strong socio-economic gradient both at the household and commune levels, with wealthier, more educated households in better off communes significantly more likely to purchase insurance for their children. No clear evidence of adverse selection is observed whether health status is assessed objectively or subjectively. Finally, while female heads of household are generally more prone to purchase health insurance for their children, households prioritize young children, male children, and those children with more schooling in their purchase decision. Findings emphasize the need to understand the effects of both health system factors and intra-household dynamics in resource allocation to explain the demand for health insurance in developing countries. PMID- 20974515 TI - Explaining place-based colorectal cancer health disparities: evidence from a rural context. AB - A growing body of work examines geographical setting as a source of health disparity, hypothesizing individual as well as larger, environmental sources of risk. However, mechanisms by which this influence operates, especially in rural settings, are not well understood. This study investigates the problem of colorectal cancer in a rural US community through the lens of geographical setting. Statewide maps of colorectal cancer burdens show a place-based disparity in colorectal cancer in the region surrounding a small, diverse Iowa community. Within a research partnership framework, we use these maps to engage community residents in discussions of high colorectal cancer rates. We ask how a rural community experiencing higher than expected rates of colorectal cancer late-stage diagnosis and mortality perceives and explains their increased risk, interpreting available epidemiological evidence based on their lived experience. We use concept mapping to organize these perceptions and situate our findings in the context of previous work. Our findings reveal a complex understanding of risk that should be taken into account in crafting effective public health interventions and messages. Our work informs the growing literature on how context influences individual experiences of health problems, with specific relevance for rural populations. PMID- 20974516 TI - Identification and quantitative evaluation of nitrogen-converting organisms in a full-scale leachate treatment plant. AB - The presence of ammonia nitrogen in landfill leachates poses a significant problem for treatment plant operators. The nitrification-denitrification process mostly carries out the nitrogen conversion in biological treatment systems. However, recent research shows that other processes by anaerobic ammonia oxidizing bacteria (Anammox) and ammonia-oxidizing archaea (AOA) were also responsible for the removal of nitrogen in biological systems. In this study, the nitrogen-converting microorganisms in the Bursa Hamitler Leachate Treatment Plant were identified and monitored by using molecular tools. Fluorescent in situ hybridization (FISH) and slot-blot hybridization results showed that the Nitrosomonas and Nitrospira species were the dominant ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB), respectively. Quantitative real-time PCR results indicated that AOB, NOB, AOA and Anammox bacteria exist in the leachate treatment plant. However, the removal of ammonia can be ascribed mainly to nitrification because AOB (1.5%) and NOB (11.3%) were predominant among all nitrogen-converting bacteria. The results of the phylogenetic analysis based on amoA and 16S rDNA gene revealed that the uncultured bacterium clone 4-24, Kuenenia stuttgartiensis genome fragment KUST_E and the uncultured Crenarchaeota clone NJYPZT-C1 belong to AOB, Anammox and AOA populations, respectively, and were the dominant species in their cluster. PMID- 20974517 TI - Targeting apoptosis pathways in lung cancer. AB - Lung cancer is a devastating disease with a poor prognosis. Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) represent different forms of lung cancer that are associated with distinct genetic causes and display different responses to therapy in the clinic. Whereas SCLC is often sensitive to chemotherapy at start of treatment, NSCLC are less chemo-sensitive. In NSCLC different histological subtypes are distinguished and increasing efforts are made to identify subtypes that respond to specific therapies, such as those harbouring epidermal growth factor receptor (EGFR) mutations that have benefit from treatment with EGFR inhibitors. Targeting of the apoptotic machinery represents another approach that aims to selectively kill cancer cells while sparing normal ones. Here we describe different ways that are currently explored to induce apoptosis in lung cancer cells, specifically pathways controlled by TNF-related apoptosis-inducing ligand (TRAIL), BCL-2 family members and apoptosis inhibitory proteins (IAPs). Preclinical studies are discussed and for some agents results from early clinical studies and future perspectives are considered. PMID- 20974518 TI - Securin depletion sensitizes human colon cancer cells to fisetin-induced apoptosis. AB - Securin is highly-expressed in various tumors including those of the colon. In this study, the role of securin in the anticancer effects of fisetin on human colon cancer cells was investigated. Fisetin-induced apoptosis in HCT116 cells as indicated by TUNEL assay, Annexin V-FITC/PI double staining, Ser15 phosphorylation of p53, and cleavages of procaspase-3 and PARP. These effects were enhanced in HCT116 securin-null cells or in wild-type cells in which securin was knockdown by siRNA, but attenuated when wild-type or non-degradable securin was reconstituted. Moreover, fisetin did not induce apoptosis in HCT116 p53-null and HT-29 p53-mutant cells. Knockdown of securin in HCT116 p53-null cells potentiated fisetin-induced cytotoxicity by induction of apoptosis. Our results provide the first evidence to support that securin depletion sensitizes human colon cancer cells to fisetin-induced apoptosis. PMID- 20974519 TI - Role of organic amendments on enhanced bioremediation of heavy metal(loid) contaminated soils. AB - As land application becomes one of the important waste utilization and disposal practices, soil is increasingly being seen as a major source of metal(loid)s reaching food chain, mainly through plant uptake and animal transfer. With greater public awareness of the implications of contaminated soils on human and animal health there has been increasing interest in developing technologies to remediate contaminated sites. Bioremediation is a natural process which relies on soil microorganisms and higher plants to alter metal(loid) bioavailability and can be enhanced by addition of organic amendments to soils. Large quantities of organic amendments, such as manure compost, biosolid and municipal solid wastes are used as a source of nutrients and also as a conditioner to improve the physical properties and fertility of soils. These organic amendments that are low in metal(loid)s can be used as a sink for reducing the bioavailability of metal(loid)s in contaminated soils and sediments through their effect on the adsorption, complexation, reduction and volatilization of metal(loid)s. This review examines the mechanisms for the enhanced bioremediation of metal(loid)s by organic amendments and discusses the practical implications in relation to sequestration and bioavailability of metal(loid)s in soils. PMID- 20974520 TI - Surgical management of neuroma pain: a prospective follow-up study. AB - Painful neuromas can cause severe loss of function and have great impact on the daily life of patients. Surgical management remains challenging; despite improving techniques, success rates are low. To accurately study the success of surgical neuroma treatment and factors predictive of outcome, a prospective follow-up study was performed. Between 2006 and 2009, pre- and post-operative questionnaires regarding pain (VAS, McGill), function (DASH), quality of life (SF 36), symptoms of psychopathology (SCL-90), epidemiologic determinants and other outcome factors were sent to patients surgically treated for upper extremity neuroma pain. Pain scores after diagnostic nerve blocks were documented at the outpatient clinic before surgery. Thirty-four patients were included, with an average follow up time of 22 months. The mean VAS score decreased from 6.8 to 4.9 after surgery (p<0.01), 19 (56%) of patients were satisfied with surgical results. Upper extremity function improved significantly (p=0.001). Neuroma patients had significantly lower quality of life compared to a normal population. Employment status, duration of pain and CRPS symptoms were found to be prognostic factors. VAS scores after diagnostic nerve block were predictive of post operative VAS scores (p=0.001). Furthermore, smoking was significantly related to worse outcome (relative risk: 2.10). The results could lead to improved patient selection and treatment strategies. If a diagnostic nerve block is ineffective in relieving pain, patients will most likely not benefit from surgical treatment. Patients should be encouraged to focus on activity and employment instead of their symptoms. Smoking should be discouraged in patients who will undergo surgical neuroma treatment. PMID- 20974521 TI - Mesenchymal stem cell-based cellular vaccine: An efficient immunotherapeutic strategy for human malignancies. AB - Cancer-related deaths are still the most fearsome threaten to human health. It is necessary to develop an innovative and active strategy for the prophylactic immunization against tumorigenesis. Multiple lines of evidence have demonstrated that cancer stem cells (CSCs) are the initiating cells of tumor formation, as well as the source of local recurrence and distant metastases. Mesenchymal stem cells (MSCs), the adult pluripotent progenitors of multiple mesenchymal lineages, have an unusual tropism to preclinical tumor lesions. Both MSCs and CSCs or populations of tumor-initiating cells may also have similar reactogenicity or immunogenicity. Based on the information given above, a hypothesis is generated that MSCs may possess a potential of cellular vaccine for bio-prevention against tumorigenesis via eliciting cross-immunity and inducing active antibodies. PMID- 20974522 TI - Patient-specific simulation in carotid artery stenting. AB - AIMS: Patient-specific virtual reality (VR) simulation is a technologic advancement that allows planning and practice of the carotid artery stenting (CAS) procedure before it is performed on the patient. The initial findings are reported, using this novel VR technique as a tool to optimize technical and nontechnical aspects of this complex endovascular procedure. METHODS: In the angiography suite, the same interventional team performed the VR rehearsal and the actual CAS on the patient. All proceedings were recorded to allow for video analysis of team, technical, and nontechnical skills. RESULTS: Analysis of both procedures showed identical use of endovascular tools, similar access strategy, and a high degree of similarity between the angiography images. The total procedure time (24.04 vs 60.44 minutes), fluoroscopy time (11.19 vs 21.04 minutes), and cannulation of the common carotid artery (1.35 vs 9.34) took considerably longer in reality. An extensive questionnaire revealed that all team members found that the rehearsal increased the subjective sense of teamwork (4/5), communication (4/5), and patient safety (4/5). CONCLUSION: A VR procedure rehearsal is a practical and feasible preparatory tool for CAS and shows a high correlation with the real procedure. It has the potential to enhance the technical, nontechnical, and team performance. Further research is needed to evaluate if this technology can lead to improved outcomes for patients. PMID- 20974523 TI - Endovascular repair of traumatic thoracic aortic injury: clinical practice guidelines of the Society for Vascular Surgery. AB - The Society for Vascular Surgery(r) pursued development of clinical practice guidelines for the management of traumatic thoracic aortic injuries with thoracic endovascular aortic repair. In formulating clinical practice guidelines, the Society selected a panel of experts and conducted a systematic review and meta analysis of the literature. They used the Grading of Recommendations Assessment, Development and Evaluation methods (GRADE) to develop and present their recommendations. The systematic review included 7768 patients from 139 studies. The mortality rate was significantly lower in patients who underwent endovascular repair, followed by open repair, and nonoperative management (9%, 19%, and 46%, respectively, P < .01). Based on the overall very low quality of evidence, the committee suggests that endovascular repair of thoracic aortic transection is associated with better survival and decreased risk of spinal cord ischemia, renal injury, graft, and systemic infections compared with open repair or nonoperative management (Grade 2, Level C). The committee was also surveyed on a variety of issues that were not specifically addressed by the meta-analysis. On these select matters, the majority opinions of the committee suggest urgent repair following stabilization of other injuries, observation of minimal aortic defects, selective (vs routine) revascularization in cases of left subclavian artery coverage, and that spinal drainage is not routinely required in these cases. PMID- 20974524 TI - Early duplex scanning after infrainguinal endovascular therapy. AB - OBJECTIVES: Duplex ultrasound scanning (DUS) has benefit for intraoperative and subsequent evaluation of surgical bypasses in the lower extremities. The utility of DUS after endovascular revascularizations is not established. This study was performed to evaluate whether DUS findings after infrainguinal endovascular interventions for critical limb ischemia (CLI) were predictive of need for reintervention or amputation. METHODS: To identify the study cohort, peripheral interventions for CLI (Rutherford grades 4, 5, 6) over a 24-month period (2006 2007) were reviewed. DUS findings were considered indicative of hemodynamic stenosis if the peak systolic velocity (PSV) was >= 180 cm/s or the PSV velocity ratio was >= 2.0. Demographic, clinical, procedural, and outcomes were examined. SVS and TASC II classifications and reporting standards were used. Arteriograms were reviewed and treated segments were categorized as patent (<30% residual stenosis) or abnormal (>= 30% residual stenosis). RESULTS: There were 122 infrainguinal interventions for CLI in 113 patients (53% male; mean age 71 years). Risk factors included diabetes: 61%; renal failure: 20%; and smoking (within 1 year): 40%. DUS was performed within 30 days of the index procedure in 90 cases. Fifty patients had an abnormal early duplex and 40 patients had a normal duplex. In patients with a normal duplex ultrasound the amputation rate was 5% vs 20% in the group with an abnormal duplex (P = .04). Primary patency was 56% in the normal duplex group and 46% in the abnormal duplex group (P = .18). Early duplex ultrasound was able to identify a residual stenosis not seen on completion angiography in 56% of cases. CONCLUSIONS: Duplex scanning detects residual stenosis missed with conventional angiography after infrainguinal interventions. An abnormal DUS in the first 30 days after an intervention is associated with an increased risk of amputation. This suggests a possible role for intraprocedural DUS, as well as routine postprocedure DUS, close clinical follow-up, and consideration of reintervention for residual abnormalities in patients treated for CLI. PMID- 20974525 TI - Preventing damage to arthroscopic lens during surgery. AB - PURPOSE: To evaluate the relation between the relative diameter of instrument tips and the distance between the arthroscopic lens and the tips of the instruments in terms of preventing lens damage during arthroscopy. METHODS: By use of a custom-designed station device with 2 perpendicular portals, images of multiple-sized shaver tips (2.5, 3.5, 4.0, 5.0, and 5.5 mm) were obtained from 4 different arthroscopes (4 mm 30 degrees , 4 mm 70 degrees , 2.7 mm 30 degrees , and 2.7 mm 70 degrees ) at varying distances of 0 to 10 mm at 1-mm increments. The relative diameter of the visualized instrument tips and the distance between the arthroscopic lens and the tips of the instruments were evaluated. RESULTS: The relative diameter of the shaver tips measured by 2 investigators showed excellent intraobserver and interobserver reliability. By use of 2 mm as the safe distance from the arthroscopic lens to the tip of the shaver, 13 of 14 arthroscopic lens-shaver combinations were considered safe when the visualized shaver tip was smaller than one-half of the arthroscopic visual field. Six of 14 combinations were considered unsafe when the visualized shaver tip was larger than three-fourths of the visual field. CONCLUSIONS: In this experimental study, the safe distance of 2 mm could be maintained when arthroscopic instruments used during surgery (e.g., shavers and burrs) were observed to be less than one-half of the arthroscopic visual field. The relative diameter of the visualized instrument tip was a reliable guide to prevent arthroscopic lens damage. CLINICAL RELEVANCE: To avoid damaging the arthroscope lens during surgery, arthroscopists can maintain a safe distance by keeping the relative diameter of the instrument tip (e.g., arthroscopic burr) to less than one-half of the arthroscopic visual field. PMID- 20974526 TI - Adoption of new technology in sports medicine: case studies of the Gore-Tex prosthetic ligament and of thermal capsulorrhaphy. AB - Evaluation of new technology in sports medicine is supposed to promote improvements in the care of patients. It is also supposed to prohibit technology that can harm patients. This evaluation process is not perfect and at times can promote technology that not only does not help patients but may harm them. Two examples of new sports medicine technology that were widely adopted but eventually abandoned are thermal capsulorrhaphy for treatment of shoulder instability and the Gore-Tex prosthetic ligament (W. L. Gore & Associates, Flagstaff, AZ) for patients with anterior cruciate ligament deficiency. On analysis of the quick adoption of these 2 failed procedures, certain recommendations are apparent for improvement of the evaluation process. There must be a sound rationale behind any new technology, basic science research into the theory of the medical technology, and demonstrated improvements in animal models and clinical studies that are prospective cohort studies or randomized controlled trials, and finally, there must be careful follow-up and postmarket surveillance. PMID- 20974527 TI - High prevalence of respiratory symptoms during air travel in patients with COPD. AB - OBJECTIVE: The reduced pressure in aircraft cabins may cause severe hypoxemia and respiratory distress in patients with chronic obstructive pulmonary disease (COPD). The primary objective of this study was to determine the prevalence of in flight symptoms in COPD patients and non-COPD subjects, and evaluate associations between these symptoms and pre-flight variables. METHODS: In a cross-sectional study of 391 COPD patients and 184 non-COPD subjects, we recorded lung function, blood gas values, exercise capacity, air travel habits and in-flight symptoms. RESULTS: Fifty-four percent of the COPD patients had travelled by air the last two years. Hypoxia-related symptoms during air travel were experienced in 25% of the COPD patients and 9% of the non-COPD subjects (p < 0.001). After adjusting for smoking status, age and gender, the odds ratio for COPD patients to experience dyspnea or air hunger was 6.6 (95% CI 2.5-17.3, p < 0.001) compared to non-COPD subjects. In the COPD patients, in-flight dyspnea or air hunger was strongly associated with pre-flight score on the Medical Research Council (MRC) Dyspnea scale (p < 0.001). CONCLUSION: COPD patients had significantly increased risk of in-flight dyspnea or air hunger compared to non-COPD subjects. In COPD patients these symptoms were strongly associated with pre-flight MRC Dyspnea score. PMID- 20974528 TI - Building mitotic chromosomes. AB - Mitotic chromosomes are the iconic structures into which the genome is packaged to ensure its accurate segregation during mitosis. Although they have appeared on countless journal cover illustrations, there remains no consensus on how the chromatin fiber is packaged during mitosis. In fact, work in recent years has both added to existing controversies and sparked new ones. By contrast, there has been very significant progress in determining the protein composition of isolated mitotic chromosomes. Here, we discuss recent studies of chromosome organization and provide an in depth description of the latest proteomics studies, which have at last provided us with a definitive proteome for vertebrate chromosomes. PMID- 20974529 TI - Performance of suspended and attached growth MBR systems in treating high strength synthetic wastewater. AB - The performance of laboratory-scale attached growth (AG) and suspended growth (SG) membrane bioreactors (MBRs) was evaluated in treating synthetic wastewater simulating high strength domestic wastewater. This study investigated the influence of sponge suspended carriers in AG-MBR system, occupying 15% reactor volume, on the removal of chemical oxygen demand (COD), total nitrogen (TN) and total phosphorus (TP), and compared it to that of SG-MBR. Results showed that the removal efficiencies of COD, TN and TP in AG-MBR were 98%, 89% and 58%, respectively as compared to 98%, 74% and 38%, respectively in SG-MBR. Improved TN removal in AG-MBR systems was primarily based on simultaneous nitrification and denitrification (SND) process. These results infer that the presence of small bio particles having higher microbial activity and the growth of complex biomass captured within the suspended sponge carriers resulted in improved TN and TP removal in AG-MBR. PMID- 20974530 TI - Upstream and downstream strategies to economize biodiesel production. AB - In recent years biodiesel has drawn considerable amount of attention as a clean and renewable fuel. Biodiesel is produced from renewable sources such as vegetable oils and animal fat mainly through catalytic or non-catalytic transesterification method as well as supercritical method. However, as a consequence of disadvantages of these methods, the production cost increases dramatically. This article summarizes different biodiesel production methods with a focus on their advantages and disadvantages. The downstream and upstream strategies such as using waste cooking oils, application of non-edible plant oils, plant genetic engineering, using membrane separation technology for biodiesel production, separation and purification, application of crude glycerin as an energy supplement for ruminants, glycerin ultra-purification and their consequent roles in economizing the production process are fully discussed in this article. PMID- 20974531 TI - Optimizing feed composition for improved methane yield during anaerobic digestion of cow manure based waste mixtures. AB - This study investigated methane yield via anaerobic digestion of multi-component substrates based on mixtures of biodegradable single-component substrates with cow dung as main component. Bench and full-scale digestion experiments were carried out for both single and multi-component substrates to identify the relationship between methane yield and substrate composition. Results from both bench- and full-scale experiments corresponded well and showed that using multi component substrates increases the methane yield much more than what would be expected from digestion of single substrates. Process stability as indicated by gas production, pH and NH(4)(+) concentration variations were also improved by using multi-component substrates compared to digestion of single-component substrates. The results, thus, suggest that assessment of methane yield for multi component substrates cannot reliably be based on methane yields for corresponding single-component substrates but should instead be measured directly. PMID- 20974532 TI - Discovery of benzoylisoindolines as a novel class of potent, selective and orally active GlyT1 inhibitors. AB - Benzoylisoindolines were discovered as a novel structural class of GlyT1 inhibitors. SAR studies and subsequent lead optimization efforts focused primarily on addressing hERG liability and on improving in vivo efficacy resulted in the identification of potent GlyT1 inhibitors displaying excellent selectivity and in vivo PD and PK profiles. PMID- 20974533 TI - Substituted N-{3-[(1,1-dioxido-1,2-benzothiazol-3 yl)(phenyl)amino]propyl}benzamide analogs as potent Kv1.3 ion channel blockers. Part 2. AB - We report the synthesis and in vitro activity of a series of novel substituted N {3-[(1,1-dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl}benzamide analogs. These analogs showed potent inhibitory activity against Kv1.3. Several demonstrated similar potency to the known Kv1.3 inhibitor PAP-1 when tested under the IonWorks patch clamp assay conditions. Two compounds 13i and 13rr were advanced further as potential tool compounds for in vivo validation studies. PMID- 20974534 TI - Synthesis, cytotoxicity, and structure-activity relationship (SAR) studies of andrographolide analogues as anti-cancer agent. AB - A series of analogues of andrographolide, prepared through chemo-selective functionalization at C14 hydroxy, have been evaluated for in vitro cytotoxicities against human leukemic cell lines. Two of the analogues (6a, 9b) exhibited significant potency. Preliminary studies on structure-activity relationship (SAR) revealed that the alpha-alkylidene-gamma-butyrolactone moiety of andrographolide played a major role in the activity profile. The structures of the analogues were established through spectroscopic and analytical data. PMID- 20974535 TI - Comparison of transtibial amputee and non-amputee biomechanics during a common turning task. AB - The biomechanics of amputee turning gait has been minimally studied, in spite of its integral relationship with the more complex gait required for household or community ambulation. This study compares the biomechanics of unilateral transtibial amputees and non-amputees completing a common turning task. Full body gait analysis was completed for subjects walking at comparable self-selected speeds around a 1m radius circular path. Peak internal and external rotation moments of the hip, knee and ankle, mediolateral ground reaction impulse (ML GRI), peak effective limb length, and stride length were compared across conditions (non-amputee, amputee prosthetic limb, amputee sound limb). Amputees showed decreased internal rotation moments at the prosthetic limb hip and knee compared to non-amputees, perhaps as a protective mechanism to minimize stress on the residual limb. There was also an increase in amputee sound limb hip external rotation moment in early stance compared to non-amputees, which may be a compensation for the decrease in prosthetic limb internal rotation moment during late stance of the prior step. ML GRI was decreased for the amputee inside limb compared to non-amputee, possibly to minimize the body's acceleration in the direction of the turn. Amputees also exhibited a shorter inside limb stride length compared to non-amputees. Both decreased ML GRI and stride length indicate a COM that is more centered over the base of support, which may minimize the risk of falling. Finally, a longer effective limb length was found for the amputee inside limb turning, possibly due to excessive trunk shift. PMID- 20974536 TI - Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein. AB - Restricting linear peptides to their bioactive conformation is an attractive way of improving their stability and activity. We used a cyclic peptide library with conformational diversity for selecting an active and stable peptide that mimics the structure and activity of the HIV-1 integrase (IN) binding loop from its cellular cofactor LEDGF/p75 (residues 361-370). All peptides in the library had the same primary sequence, and differed only in their conformation. Library screening revealed that the ring size and linker structure had a huge effect on the conformation, binding and activity of the peptides. One of the cyclic peptides, c(MZ 4-1), was a potent and stable inhibitor of IN activity in vitro and in cells even after 8 days. The NMR structure of c(MZ 4-1) showed that it obtains a bioactive conformation that is similar to the parent site in LEDGF/p75. PMID- 20974537 TI - Interaction between environmental factors affects the accumulation of root proteins in hydroponically grown Eucalyptus globulus (Labill.). AB - Eucalyptus globulus (Labill.) is used for pulp and paper production worldwide. In this report we studied changes in protein expression in one osmotically stressed elite clone widely used in industrial plantations in Spain. High molecular weight polyethylene glycol (PEG) was used as an osmoticum in the growing medium. Roots of rooted cuttings were sampled after 3 and 36 h of treatment. Water potential and abscissic acid content were measured in shoot and root apices to characterize the physiological states of the plants. Total soluble proteins from roots were extracted and separated using two-dimensional gel electrophoresis (2-DE). Gels were stained with Coomassie brillant blue for quantitative analysis of protein accumulation. From a total of 406 reproducible spots, 34 were found to be differentially expressed depending on treatment (osmotic versus control condition) and/or stress duration (3 h versus 36 h), and were further characterized by tandem mass spectrometry. Several proteins were reliably identified including adenosine kinase, actin, stress-related proteins as well as proteins associated to cellular processes, among which some residents of the endoplasmic reticulum. This study constitutes the first investigation of the root proteome in this important forest tree genus. PMID- 20974538 TI - Differential RNA expression of Bmy1 during barley seed development and the association with beta-amylase accumulation, activity, and total protein. AB - The objective of this study was to determine if developing barley (Hordeum vulgare L.) seeds had differences in beta-amylase 1 (Bmy1) mRNA accumulation, beta-amylase (EC 3.2.1.2) activity, beta-amylase protein accumulation, and total protein levels during late seed development from genotypes with different Bmy1 intron III alleles. Two North American malting barley cultivars (Hordeum vulgare ssp. vulgare) were chosen to represent the Bmy1.a and Bmy1.b alleles and, due to limited Bmy1 intron III allele variation in North American cultivars, two wild barleys (Hordeum vulgare ssp. spontaneum) were chosen to represent the Bmy1.c and Bmy1.d alleles. Wild barleys Ashqelon (Bmy1.c) and PI 296897 (Bmy1.d) had 2.5- to 3-fold higher Bmy1 mRNA levels than cultivars Legacy (Bmy1.a) and Harrington (Bmy1.b). Levels of Bmy1 mRNA were not significantly different between cultivated or between wild genotypes. In all four genotypes Bmy1 mRNA levels increased from 17 to 19 days after anthesis (DAA) and remained constant from 19 to 21 DAA. Ashqelon and PI 296897 had more beta-amylase activity on a fresh weight basis than Legacy and Harrington at all developmental stages. beta-Amylase protein levels increased from 17 DAA to maturity in all genotypes. Total protein in grains from wild genotypes was significantly higher than cultivated genotypes at all developmental stages. Higher levels of total protein in Ashqelon and PI 296897 could explain their higher levels of beta-amylase activity, when expressed on a fresh weight basis. When beta-amylase activities are expressed on a protein basis there are no statistical differences between the wild and cultivated barleys at maturity. PMID- 20974539 TI - OVP1, a vacuolar H+-translocating inorganic pyrophosphatase (V-PPase), overexpression improved rice cold tolerance. AB - Vacuolar H(+)-translocating inorganic pyrophosphatase (V-PPase, EC 3.6.1.1) is an electrogenic proton pump and has been studied in many plants. Here we report characterization of the OVP1 gene from rice (Oryza sativa L.). Quantitative reverse transcriptase-polymerase chain reaction analysis (RT-qPCR) showed that OVP1 was induced by cold stress. OVP1 overexpression resulted in enhanced cold tolerance in transgenic rice, which was related to an increased integrity of cell membrane, decreased MDA content and accumulation of proline to higher level as compared with wild type rice seedlings. These results indicated that V-PPase was an important element in the survival strategies of plants under cold stress. PMID- 20974540 TI - Preliminary experimental evaluation of the immediate angiographic occlusion time with use of the AMPLATZER vascular plug II for carotid artery occlusion. AB - PURPOSE: Delayed occlusion time in parent artery occlusion of brain-supplying vessels might carry risk for thromboembolic complications. Vascular plug devices are successfully used in cardiopulmonary and peripheral interventions to occlude high-flow lesions and have been adapted for use in neurointerventions. The purpose of the present study was to experimentally evaluate the immediate occlusion time of the AMPLATZER vascular plug (AVP) II-a second-generation cylindrical, self-expandable, resheathable nitinol wire mesh consisting of three lobes-in the carotid artery. MATERIALS AND METHODS: AVP II devices (N = 12) 6 mm in diameter (length, 6 mm) were deployed through 6-F guiding catheters in the common carotid arteries of two pigs. After device deployment, angiography was performed to measure the time interval until no contrast agent opacification was visible distal to the AVP II, indicating complete flow cessation and occlusion of the distal vessel. Vessel diameters before deployment and after resheathing of the device were measured. Device navigation, positioning, recapturing, vasospasm, and angiographic signs of vessel injury were assessed. RESULTS: The mean time to total flow cessation and occlusion was 57.9 seconds (median, 44 s +/- 27 [SD]; range, 26-104 s). Device navigation, positioning, and resheathing were successful in all cases. There was neither significant vasospasm nor vessel injury visible on angiography. CONCLUSIONS: Application and retrieval of the second-generation AVP II are uncomplicated and the device is able to achieve fast and sufficient cessation of flow in a hemodynamically comparable setting to the human carotid artery, indicating some potential to fill a gap in the neurointerventional tool box. PMID- 20974541 TI - A novel method of treating hypoxemia during one-lung ventilation for thoracic surgery. PMID- 20974542 TI - Utility of a transesophageal echocardiographic simulator as a teaching tool. AB - OBJECTIVE: This study was designed to test the hypothesis that simulator-based transesophageal echocardiographic training was a more effective method of training anesthesia residents with no prior experience in echocardiography as compared with conventional methods of training (books, articles, and web-based resources). STUDY DESIGN: A prospective randomized study. SETTING: An academic medical center (teaching hospital). PARTICIPANTS: The participants consisted of first-year anesthesia residents. INTERVENTION: The study design was composed of 2 groups: a control group (group 1, conventional group) and a study group (group 2, simulator group). The residents belonging to group 2 (simulator group) received a 90-minute simulator-based teaching session moderated by a faculty experienced in transesophageal echocardiography. Residents belonging to group 1 (conventional group) were asked to review the guidelines of the comprehensive intraoperative transesophageal echocardiographic examination published by the American Society of Echocardiography and the Society of Cardiovascular Anesthesiologists. They also were encouraged to use other learning resources (eg, textbooks, electronic media, and web-based resources) to understand the underlying concepts of echocardiography. Written pre- and post-test was administered to both groups. MEASUREMENTS AND MAIN RESULTS: The groups were compared for the pretest scores by the nonparametric Mann-Whitney U test. Pre- and post-test scores were compared with a Wilcoxon paired test in the individual groups. The results showed a statistically significant difference between the scores of the 2 groups with better scores in the simulation group in the post-training test. CONCLUSION: The simulator-based teaching model for transesophageal echocardiography is a better method of teaching the basic concepts of transesophageal echocardiography like anatomic correlation, structure identification, and image acquisition. PMID- 20974544 TI - Rejection with hemodynamic compromise in the current era of pediatric heart transplantation: a multi-institutional study. AB - BACKGROUND: Survival after pediatric heart transplant has improved over time, as has the incidence of overall rejection. We studied the effect of era on the occurrence and outcome of rejection with hemodynamic compromise (HC). METHODS: Data from 2227 patients who received allografts between 1993 and 2006 at 36 centers in the Pediatric Heart Transplant Study were analyzed to determine incidence, outcome, and risk factors for rejection with HC in early (1993-1999) and recent (2000-2006) eras. Rejection with HC was classified as severe (RSHC) when inotropes were used for circulatory support and mild (RMHC) when inotropes were not used. RESULTS: Of 1217 patients with any episode of rejection, 541 had rejection with HC. Freedom from RMHC improved at 1 year (81% vs 90%, p < 0.001) and at 5 years (74% vs 85%, p < 0.001) in the early vs recent eras, but freedom from RSHC was similar between eras (93% vs 95% at 1 year and 85% vs 87% at 5 years, p = 0.24). Survival after RSHC (63% at 1 year and 49% at 5 years) was worse than after RMHC (87% at 1 year and 72% at 5 years, p < 0.001) and did not change over time. Risk factors for RSHC were non-white race (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.29-2.32, p < 0.01), older age (HR, 2.85; 95% CI, 1.24-6.53; p = 0.01), and non-A blood type (HR, 1.51;, 95% CI, 1.11 2.04,; p = 0.01), but the only risk factor for RMHC was earlier era of transplant (HR, 1.94; 95% CI, 1.56-2.41; p < 0.001). CONCLUSIONS: The incidence of RMHC has declined over time but the same era effect has not occurred with RSHC. Close follow-up after RSHC is crucial because mortality is so high. PMID- 20974545 TI - The 2010 Donough O'Brien Presidential Address: The contribution of heterozygosity to disease. PMID- 20974546 TI - Handedness and dominant side of symptoms in Parkinson's disease. AB - The aim of this retrospective study was to assess the presence of a possible association between handedness and the side of symptom dominance in 963 patients with Parkinson's disease (PD). In only 287 patients the hand dominance was registered. Out of 254 right-handed patients, 158 (62%) had a right-side dominance of PD symptoms, while 96 patients (38%) had left-lateralized symptom dominance (p < 0.001). For the 33 left-handed subjects, 18 (55%) had left- and 15 (45%) had right-sided symptom dominance (p = 0.602). Right-handedness thus appeared to be associated with right-sided dominance of PD symptoms, while the group of left-handed patients was too small to draw conclusions from. Possible explanations are discussed. PMID- 20974547 TI - Ocular tolerance of a new multipurpose solution specifically formulated for daily wear of silicone hydrogel contact lenses. AB - PURPOSE: To evaluate the safety, physiological performance, and effect on ocular tissues of a new multipurpose disinfecting solution (MPDS) specifically formulated for use with silicone hydrogel (SH) contact lenses (CL). METHODS: Two MPDS [solution A (Solo-care Aqua((r)), Ciba-Vision) and solution B (Hidro Health((r)), Disop)] were randomly assigned and prescribed in a clinical trial in a crossover clinical trial (Registered #293/07/EC; Spanish National Health Department). Only lotrafilcon B CL daily wearers were included. After each solution was used, a masked investigator assessed the slit-lamp findings (SL9, Topcon Inc.), lens deposits, and wettability according to the Guidance for clinical investigation (ISO 11980). CL daily wearing time (hours per day and days per week) were recorded. RESULTS: Fifty-four daily wearers were included. Average CL wear time was 8.3 +/- 2.3 (CI95% 7.9-8.7) hours per day (8.5 +/- 2.7 at baseline visit, 8.2 +/- 1.9 with solution A, and 8.4 +/- 2.2 with solution B). The average number of days per week of CL wear was 5.9 +/- 1.3 (CI95% 5.6-6.1) (5.4 +/- 1.6 at baseline visit, 6.1 +/- 0.9 with solution A, and 6.0 +/- 1.1 with solution B). Non-adverse slit-lamp findings were recorded (higher than 2 points). No statistical difference (P>0.05 Friedman test) in CL wearing time, number of days of CL wears and slit-lamp findings were found between the two solutions. CONCLUSIONS: This clinical trial shows that the new formulation of Hidro Health((r)) MPDS is safe when used for the care of daily-wear lotrafilcon B CL. This new solution has no clinical significance on ocular tissues, according to the Guidance for clinical investigation (ISO 11980). PMID- 20974548 TI - Simultaneous spectrophotometric determination of atrazine and cyanazine by chemometric methods. AB - A spectrophotometric method for the simultaneous determination of two herbicides, atrazine and cyanazine, is described for the first time based on their reaction with p-aminoacetophenone in the presence of pyridine in hydrochloric acid medium. The absorption spectra were measured in the wavelength range of 400-600 nm. The optimized method indicated that individual analytes followed Beer's law in the concentration ranges for atrazine and cyanazine were 0.2-3.5 mg L(-1) and 0.3-5.0 mg L(-1), and the limits of detection for atrazine and cyanazine were 0.099 and 0.15 mg L(-1), respectively. The original and first-derivative absorption spectra of the binary mixtures were performed as a pre-treatment on the calibration matrices prior to the application of chemometric models such as classical least squares (CLS), principal component regression (PCR), partial least squares (PLS). The analytical results obtained by using these chemometric methods were evaluated on the basis of percent relative prediction error and recovery. It was found that the application of PCR and PLS models for first-derivative absorbance data gave the satisfactory results. The proposed methods were successfully applied for the simultaneous determination of the two herbicides in several food samples. PMID- 20974549 TI - Model development for EHR interdisciplinary information exchange of ICU common goals. AB - PURPOSE: Effective interdisciplinary exchange of patient information is an essential component of safe, efficient, and patient-centered care in the intensive care unit (ICU). Frequent handoffs of patient care, high acuity of patient illness, and the increasing amount of available data complicate information exchange. Verbal communication can be affected by interruptions and time limitations. To supplement verbal communication, many ICUs rely on documentation in electronic health records (EHRs) to reduce errors of omission and information loss. The purpose of this study was to develop a model of EHR interdisciplinary information exchange of ICU common goals. METHODS: The theoretical frameworks of distributed cognition and the clinical communication space were integrated and a previously published categorization of verbal information exchange was used. 59.5h of interdisciplinary rounds in a neurovascular ICU were observed and five interviews and one focus group with ICU nurses and physicians were conducted. RESULTS: Current documentation tools in the ICU were not sufficient to capture the nurses' and physicians' collaborative decision-making and verbal communication of goal-directed actions and interactions. Clinicians perceived the EHR to be inefficient for information retrieval, leading to a further reliance on verbal information exchange. CONCLUSION: The model suggests that EHRs should support: (1) information tools for the explicit documentation of goals, interventions, and assessments with synthesized and summarized information outputs of events and updates; and (2) messaging tools that support collaborative decision-making and patient safety double checks that currently occur between nurses and physicians in the absence of EHR support. PMID- 20974550 TI - Treatment of acute carbon-monoxide poisoning with therapeutic erythrocytapheresis: clinical effects and results in 17 victims. AB - Seventeen cases of acute carbon-monoxide poisoning were treated with therapeutic red cell-exchange. Glasgow Coma Scale score was used to evaluate the level of consciousness. The mean carboxyhemoglobin level decreased from 0.286 +/- 0.1805 (28.6 +/- 18.05%) to 0.0613 +/- 0.0418 (6.13 +/- 4.18%) and Glasgow Coma Scale score increased from 10 +/- 3 to 13.76 +/- 1.89. While 11 patients scored 15 at the end of the treatment, four scored 15 in an hour after the treatment. None of the patients died. Two victims (11.7%) experienced ischemic encephalopathy. Therapeutic red cell-exchange therapy can be an effective treatment in reducing mortality and morbidity in carbon-monoxide poisoning. PMID- 20974551 TI - Familial cortical tremor and epilepsy: a well-defined syndrome with genetic heterogeneity waiting for nosological placement in the ILAE classification. PMID- 20974552 TI - Determination of doxazosin and verapamil in human serum by fast LC-MS/MS: application to document non-compliance of patients. AB - A rapid and sensitive method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for simultaneous determination of doxazosin and verapamil in human serum has been developed. Trimipramine-d3 as an isotopic labelled internal standard was used for quantification. Serum samples were prepared by simple liquid-liquid extraction with mixture of tert butyl methyl ether and ethyl acetate (1:1, v:v). The analytes and internal standard were separated on C18 column using an isocratic elution with 5 mM ammonium formate with 0.02% formic acid and 0.02% formic acid in acetonitrile (55:45, v:v) at a flow rate of 1.1 mL/min. Positive TurboIonSpray mass spectrometry was used with multiple reaction monitoring of the transitions at: m/z 455.3->165.2 and 150.2 for verapamil, m/z 452.2->344.4 and 247.4 for doxazosin, m/z 298.2->103.1 for trimipramine-d3. Linearity was achieved between 1 and 500 ng/mL (R2 >= 0.997) for both analytes. An extensive pre-study method validation was carried out in accordance with FDA guidelines. This assay was successfully applied to determine the serum concentrations of doxazosin and verapamil in suspect non-compliance patients. PMID- 20974553 TI - Chromatographic studies of changes in binding of sulfonylurea drugs to human serum albumin due to glycation and fatty acids. AB - This report examines the use of high-performance affinity chromatography as a screening tool for studying the change in binding by sulfonylurea drugs to the protein human serum albumin (HSA) during diabetes. The effects of both the non enzymatic glycation of HSA and the presence of fatty acids on these interactions were considered using a zonal elution format. It was found that there was a significant increase (i.e., 2.7- to 3.6-fold) in the relative retention of several sulfonylurea drugs (i.e., acetohexamide, tolbutamide, glybenclamide and gliclazide) on columns containing normal versus glycated HSA. The addition of various long chain fatty acids to the mobile phase gave the same trend in retention for the tested drugs on both the HSA and glycated HSA columns, generally leading to lower binding. Most of the fatty acids examined produced similar or moderately different relative shifts in retention; however, palmitic acid was found to produce a much larger change in retention on columns containing glycated HSA versus normal HSA under the conditions used in this study. PMID- 20974555 TI - Anti-Ro and anti-La antibody positive subacute cutaneous lupus erythematosus (SCLE) induced by lansoprazole. PMID- 20974556 TI - Detection of human papillomavirus type 67 from bowenoid papulosis. PMID- 20974554 TI - Reverse phase protein microarrays advance to use in clinical trials. AB - Individualizing cancer therapy for molecular targeted inhibitors requires a new class of molecular profiling technology that can map the functional state of the cancer cell signal pathways containing the drug targets. Reverse phase protein microarrays (RPMA) are a technology platform designed for quantitative, multiplexed analysis of specific phosphorylated, cleaved, or total (phosphorylated and non-phosphorylated) forms of cellular proteins from a limited amount of sample. This class of microarray can be used to interrogate tissue samples, cells, serum, or body fluids. RPMA were previously a research tool; now this technology has graduated to use in research clinical trials with clinical grade sensitivity and precision. In this review we describe the application of RPMA for multiplexed signal pathway analysis in therapeutic monitoring, biomarker discovery, and evaluation of pharmaceutical targets, and conclude with a summary of the technical aspects of RPMA construction and analysis. PMID- 20974557 TI - BURNS and ERUPTS: novel mnemonics for detection of squamous cell carcinoma and basal cell carcinoma. PMID- 20974558 TI - A prospective, rater-blind, randomized comparison of the effectiveness and tolerability of Belotero (r) Basic versus Restylane (r) for correction of nasolabial folds. AB - The aim of this prospective, rater-blind, randomized, intra-individual, 4-week study was to compare the effectiveness and safety of two hyaluronic acid dermal fillers, Belotero(r) Basic (monophasic) and Restylane(r) (biphasic), for correction of nasolabial folds (NLF). Twenty subjects with bilateral, symmetrical NLF were randomized to receive a single injection of Belotero(r) Basic and Restylane(r) in a split-face design. The primary endpoint measured intra individual differences of treatment effects in mean depth and evenness of the NLF target area relative to its edges, from baseline to Week 4, as evaluated by the Phase-shift Rapid In-vivo Measurement of Skin (PRIMOS) system. Assessments were undertaken at Visit 2 (baseline) and Visit 3 (study endpoint). Treatment with Belotero(r) Basic resulted in a significantly greater improvement in evenness compared with Restylane(r) at Week 4 (mean intra-individual difference between treatments in PRIMOS measurement: -37.6 MUm; 95% CI: -65.4; -9.9). Subject-rated secondary endpoints demonstrated numerical differences in favour of Belotero(r) Basic when compared with Restylane(r). Both dermal fillers were equally well tolerated, as 85% (Belotero(r) Basic group) and 80% (Restylane(r) group) rated the tolerability of both treatments as "good" to "very good". PMID- 20974559 TI - The relevance of the Spanish Society for Medical Oncology (SEOM)'s clinical oncology guidelines. PMID- 20974560 TI - Cartography of health. PMID- 20974561 TI - SEOM clinical guidelines for the treatment of early breast cancer. AB - The incidence is increasing due to mammographic screening and an ageing population. In some countries the mortality rate has decreased especially in middleaged and younger groups because of improved treatment and possibly earlier detection. However, breast cancer is still the leading cause of cancer-related death in European women. The purpose of this work was to elaborate a Spanish Society of Medical Oncology guideline on pharmacologic interventions for early breast cancer (BC). We have compiled the latest advances in the management of this pathology either in the adjuvant and neoadjuvant setting, cytostatic and hormonal treatment, so that in a simple way could be useful to oncologist, residents and other related specialties. PMID- 20974562 TI - SEOM clinical guidelines for the treatment of metastatic breast cancer. AB - Patients with metastatic breast cancer have a wide number of treatment options, including medical, surgical, and supportive care measures. Treatment decisions are based in predictive and prognostic factors and the informed choice of the patients. SEOM has elaborated these guidelines with evidence-based recommendations for the diagnostic work-up, treatment (chemotherapy, endocrine therapy and targeted therapies) and supportive care for the management of these patients. PMID- 20974563 TI - SEOM clinical guidelines for the adjuvant treatment of colorectal cancer. AB - Colorectal cancer is the third most common malignant neoplasm and the second cause of death by cancer in western countries. In this manuscript, the clinical guidelines of the Spanish Society of Medical Oncology (SEOM) for diagnosis and adjuvant treatment of colon cancer and rectal cancer are reported. PMID- 20974564 TI - SEOM clinical guidelines for the treatment of advanced colorectal cancer. AB - Colorectal cancer is the first cause of cancer diagnosis in Spain. Over half of the patients are diagnosed with or will eventually develop distant metastasis. The current manuscript aims to provide synthetic practical guidelines for the therapeutic approaches in advanced disease. Available systemic therapeutic options, and integration and sequencing of chemotherapy with surgical procedures are discussed. Extent of disease, treatment objective, tumor kras mutation status, as well as patient's functional and comorbid conditions shall be considered to properly design the most adequate therapeutic strategy. PMID- 20974565 TI - SEOM clinical guidelines for the treatment of non-small-cell lung cancer: an updated edition. AB - The purpose of this article is to provide updated recommendations for the diagnosis and treatment of patients non-small-cell lung cancer (NSCLC). The staging system for lung cancer has recently been revised by the International Association for Study of Lung Cancer and patients with NSCLC shall now be staged according to the UICC system 7th edition. Recommendations for treatment were based on treatment strategies that improve overall survival. In functionally fit patients with stage I-II disease surgical resection is recommended. Four cycles of adjuvant cisplatin-based chemotherapy is recommended in patients with pathologic stage II-III. For patients with stage IIIA and non-bulky mediastinal lymph node survival was significantly improved with induction chemotherapy plus surgical resection. Patients with unresectable or bulky stage IIIA and those with stage IIIB, should be treated with platinum-based chemotherapy and thoracic radiotherapy. For patients with metastatic disease and performance status of 0 or 1, a platinum-based two-drug combination of cytotoxic drugs is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. For elderly patients and those with performance status of 2, a single cytotoxic drug is sufficient. Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment. Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy. The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor (EGFR) mutation; for negative or unknown EGFR mutation status, cytotoxic chemotherapy is preferred. Bevacizumab is recommended with platinum-based chemotherapy, except for patients with certain clinical characteristics. Maintenance therapy with pemetrexed or erlotinib increases survival in patients who did not progress after 4 cycles of a platinum based chemotherapy. Docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy. Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib. Data are insufficient to recommend the routine third-line use of cytotoxic drugs. PMID- 20974566 TI - SEOM clinical guidelines for the treatment of head and neck cancer. AB - Head and neck cancer constitutes the fifth highest cause of cancer in Spain. It is a neoplasm with a high possibility of cure if it is diagnosed in early stages, but unfortunately two thirds of the patients are diagnosed at an advanced loco regional stage (stage III and IV, without metastasis). The multidisciplinary team, bringing together all professionals who specialize in the diagnosis and treatment of these tumors make the decision to establish the best sequence of individualized diagnosis, staging and treatment for each patient. This guide gives recommendations for diagnosis, staging and treatment for squamous cell carcinoma of the head and neck. In order to simplify the amount of information about any subsite of the head and neck area, the treatment recommendations are summarized as local disease, locally advance resectable and unresectable stages, function-preserving laryngeal treatment and recurrent and metastatic disease. PMID- 20974567 TI - SEOM clinical guidelines for the treatment of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma is an unusual tumour in Spain. It has differences in epidemiology, histology, clinical behaviour, treatment and prognosis from those of other head and neck neoplasms, which justifies separate analysis. It is a neoplasm with a high possibility of cure with a combined treatment if even it is diagnosed in an advanced locoregional stage (stage III or IV, without metastasis). The multidisciplinary team, bringing together all professionals who specialize in the diagnosis and treatment of these tumors make the decision to establish the best sequence of individualized diagnosis, staging and treatment for each patient. This guide gives recommendations for diagnosis, staging and treatment for nasopharyngeal carcinoma. The treatment recommendations are summarized as local disease, locally advance and recurrent and metastatic disease. PMID- 20974568 TI - SEOM clinical guidelines for the treatment of Hodgkin's lymphoma. AB - Hodgkin's lymphoma is a malignant disease with an incidence of 2.2 cases/100,000. The main goals of staging are to measure the extent of disease and associated prognostic factors. Distinct recommendations were produced for initial work-up, first-line therapy of early and advanced stage disease and treatment of relapsed or resistant patients. PMID- 20974569 TI - SEOM clinical guidelines for the treatment of follicular non-Hodgkin's lymphoma. AB - Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin's lymphoma (NHL) in the Western world. FL constitutes the most frequent indolent lymphoma, well characterized by its clinical presentation related to nodal involvement and its morphologic and biologic features. It is often managed as an incurable disease. However, several active therapeutic approaches from the "wait and watch" strategy to the allogeneic transplantation are available for management of patients with FL and clearly have changed the natural history of this disease, achieving a long-term disease-free survival. Therapeutic decision is mostly conditioned by patient's characteristics, stage, histological grade, tumor burden, and risk-predicting factors. This article try to summarizes the diagnosis and treatment of this heterogeneous group of patients. PMID- 20974570 TI - SEOM clinical guidelines for the treatment of diffuse large B-cell lymphoma. AB - Diffuse large B-cell non-Hodgkin's lymphoma (LDCGB) is one of the best examples of chemotherapy curable malignant diseases. This "Oncoguia SEOM" summarizes the basic directions of staging and recommended treatment options. The staging study should be thorough and includes clinical, laboratory, diagnostic imaging and nuclear medicine. Treatment depends on patient characteristics and comorbidity and on disease extension and prognostic factors. In localized cases, chemoimmunotherapy (CHOP-R) of short duration, followed by involved-field irradiation is the preferred option. In advanced stages, the association of CHOP like chemotherapy and Rituximab has been a major breakthrough in terms of cure rate. It is important do not forget the supportive treatment in these patients. PMID- 20974571 TI - SEOM clinical guidelines for the treatment of antiemetic prophylaxis in cancer patients receiving chemotherapy. AB - Chemotherapy-induced emesis is one of the most frequent side effects that affect the quality of life of cancer patients undergoing chemotherapy. In recent years, clinical research has allowed us to increase our therapeutic arsenal with new drugs that have increased efficiency in the control of nausea and vomiting associated with chemo. This guide provides and update of the earlier published by our society and represents the continued commitment of SEOM to move forward and improve in the supportive care of cancer patients. PMID- 20974572 TI - Different patterns of toxicity after sequential administration of two anti-EGFR monoclonal antibodies. AB - A 40-year-old woman with liver metastasis resulting from colorectal adenocarcinoma suffered from a severe hypersensitivity reaction to cetuximab. She also experienced grade 3 skin toxicity. The administration of cetuximab was suspended, and she was offered panitumumab as an alternative treatment. Whereas she did not experience another infusion reaction, her skin rash worsened with the administration of panitumumab, a fully human anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (MAb). PMID- 20974573 TI - Impact of the background regimen on virologic response to etravirine: pooled 48 week analysis of DUET-1 and -2. AB - PURPOSE: This subgroup analysis of the phase 3 DUET trials examined the impact of the background regimen on virologic response to etravirine in treatment experienced patients. METHODS: Patients received etravirine 200 mg or placebo, both twice daily with a background regimen of darunavir/ritonavir, investigator selected nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), and optional enfuvirtide. Virologic response at week 48 (viral load <50 HIV-1 RNA copies/mL) was analyzed by the number and activity of background agents. RESULTS: Baseline phenotypic sensitivity score (PSS), enfuvirtide use, darunavir fold change in 50% effective concentration (FC), and number of baseline darunavir resistance-associated mutations (RAMs) were significant predictors of response to etravirine (P < .0001, P = .0018, P < .0001, and P = .0120, respectively). The number of active NRTIs was not a significant predictor of response (P = .0626). The highest response rates in etravirine-treated patients were associated with PSS >=2, de novo enfuvirtide use, darunavir FC <=10, <=1 darunavir RAM, and >=2 active NRTIs. Virologic response was consistently higher in etravirine-treated patients than placebo-treated patients, regardless of the activity of the background regimen. Response rates according to baseline PSS were 46% to 79% in the etravirine group versus 6% to 75% in the placebo group. CONCLUSION: The results of this subanalysis demonstrate higher virologic response rates with increased activity of the background regimen in both treatment groups, with the highest responses achieved in patients using >=2 active agents in addition to etravirine. PMID- 20974574 TI - Randomized, comparative, double-blind, double-dummy, multicenter trial of miconazole buccal tablet and clotrimazole troches for the treatment of oropharyngeal candidiasis: study of miconazole Lauriad(r) efficacy and safety (SMiLES). AB - BACKGROUND: Oropharyngeal candidiasis (OPC) is the most common opportunistic infection among persons infected with human immunodeficiency virus (HIV). Once daily miconazole 50 mg buccal tablet (MBT) is a novel delivery system using an extended-spectrum azole with potent in vitro activity against many Candida species, including some that may be resistant to other azoles. METHODS: This phase 3, double-blind, double-dummy, multicenter trial evaluated 578 randomized patients with HIV infection and OPC. The study compared the efficacy and safety of MBT once daily with clotrimazole 10 mg troches (CT) 5 times daily for 14 days. The co-primary efficacy endpoints were clinical cure at test of cure (TOC) visit (days 17-22) in the intent-to-treat (ITT) and per protocol (PP) populations. RESULTS: Clinical cure rate at TOC visit for MBT-treated patients was statistically noninferior to CT-treated patients in both the ITT (61% vs 65%) and PP (68% vs 74%) populations. Secondary endpoints, safety, and tolerability were similar between treatment groups. CONCLUSIONS: In this large trial, once-daily MBT was shown to be noninferior to CT 5 times daily in the treatment of OPC in HIV-positive patients. MBT offers an effective, safe, and well-tolerated topical treatment option for OPC administered as a convenient once-daily dose. PMID- 20974575 TI - Simplification from protease inhibitors to once- or twice-daily raltegravir: the ODIS trial. AB - BACKGROUND: Raltegravir has demonstrated good antiviral activity and safety profile in twice-daily (bid) dosing. However, its long terminal elimination half life might allow once-daily (qd) administration. METHODS: Consecutive HIV infected individuals at our clinic under protease inhibitor (PI)-based regimens with plasma HIV-RNA <50 copies/mL for > 24 weeks were invited to replace PIs with raltegravir. Patients were randomly assigned to raltegravir 800 mg qd, 400 mg bid, or twice daily for the first 3 months and then once daily. RESULTS: A total of 222 patients completed 24 weeks of follow-up on raltegravir (149 once-daily arm, 35 twice-daily arm, and 38 twice-daily to once-daily arm). At inclusion, mean CD4+ count was 574+/-308 cells/uL. Within 24 weeks, 13 (5.9%) patients experienced virological failure: 12 (6.4%) in the once-daily arms, and 1 (2.9%) in the twice-daily arm (P = .18). The rate of virological failure was 16.2% (12/74) in patients with prior nucleoside reverse transcriptase inhibitor (NRTI) resistance but only 0.7% (1/148) in the rest (P < .001). CONCLUSION: A switch from PIs to raltegravir in HIV-infected patients with undetectable plasma HIV-RNA effectively sustains viral suppression, as long as prior NRTI resistance had not been selected. No significant differences were seen when comparing raltegravir twice daily or once daily in this context, although once-daily dosing tended to perform less well. PMID- 20974579 TI - Post-craniotomy headache: A proposed revision of IHS diagnostic criteria. AB - Seventy-nine patients with intracranial aneurysms were evaluated in the presurgical period, and followed up to 6 months after surgery. We compare patients who fulfilled with those that did not post-craniotomy headache (PCH) diagnostic criteria, according to the International Classification of Headache Disorders. Semistructured interviews, headache diaries, Short Form-36 and McGill Pain Questionnaire were used. Seventy-two patients (91%) had headaches during the follow-up period. The incidence of PCH according to the International Headache Society diagnostic criteria was 40%. Age, sex, type of surgery, temporomandibular disorder, vasospasm, presence and type of previous headaches, and subarachnoid haemorrhage were not related to headache classification. There were no differences in the quality of life, headache frequency and characteristics or pain intensity between patients with headache that fulfilled or not PCH criteria. We proposed a revision of the diagnostic criteria for PCH, extending the headache outset after surgery from 7 to 30 days, and including the presence of headaches after surgery in patients with no past history of headaches, or an increase in headache frequency during the first 30 days of the postsurgical period followed by a decrease over time. Using these criteria we would classify 65% of our patients as having PCH. PMID- 20974577 TI - Therapeutic effects of nandrolone and testosterone in adult male HIV patients with AIDS wasting syndrome (AWS): a randomized, double-blind, placebo-controlled trial. AB - PURPOSE: We aimed to compare therapeutic effects of intramuscular (IM) nandrolone decanoate and IM testosterone enanthate in male HIV patients with AIDS wasting syndrome (AWS) with placebo control. METHODS: In this randomized, double-blind, placebo-controlled, 12-week trial, 104 patients with AWS who satisfied our inclusion criteria were randomly allotted in a 2:2:1 ratio to the 3 intervention groups: nandrolone, testosterone, and placebo. We administered 150 mg nandrolone and 250 mg testosterone (both IM, biweekly). The primary outcome measure was a comparison of absolute change in weight at 12 weeks between the nandrolone decanoate, testosterone, and placebo groups. RESULTS: Intent-to-treat analysis was done. The nandrolone group recorded maximum mean increase in weight (3.20 kg; post hoc P < .01 compared to placebo). Body mass index (BMI) of subjects in the nandrolone group had a significantly greater increase (mean = 1.28) compared to both testosterone (post hoc P < .05) and placebo (post hoc P < .01). Waist circumference and triceps skinfold thickness of patients on nandrolone showed similar results. Nandrolone also ensured a better quality of life. Patients with low testosterone level (<3 ng/mL) benefited immensely from nandrolone therapy, which increased their weight and BMI significantly compared to placebo (P < .05). CONCLUSION: Our trial demonstrates the superior therapeutic effects of nandrolone in male AWS patients, including the androgen deficient. PMID- 20974578 TI - Steady-state pharmacokinetics of lamivudine once-daily versus twice-daily dosing in Chinese HIV-infected patients. AB - OBJECTIVE: The present study aimed to compare the pharmacokinetics of lamivudine in 300 mg once-daily and 150 mg twice-daily dosing regimens in HIV-infected Chinese patients. METHODS: HIV-infected patients received lamivudine 300 mg once daily or 150 mg twice daily as part of a highly active antiretroviral therapy regimen. After the patients received lamivudine for at least 3 months, serial blood samples were collected for 24 hours. The samples were measured by a validated high-performance liquid chromatography (HPLC) assay. The pharmacokinetics of once-daily versus twice-daily dosing was evaluated by noncompartment models. RESULTS: Ten patients received lamivudine 300 mg once daily and 5 patients received 150 mg twice daily. The C(max) was significantly higher in the once-daily arm than the twice-daily arm (2.23 vs 1.61 MUg/mL, P <.05), whereas the C(min) was markedly lower (0.05 vs 0.12 MUg/mL, P <.05). The half-lives were 3.32 hours and 2.62 hours, and AUC24 values were 11.8 MUg/mL.h and 13.0 MUg/mL.h in the 300 mg once-daily and 150 mg twice-daily regimens, respectively (P >.05). CONCLUSION: The shorter half-life was observed first in Chinese HIV patients with once- and twice-daily regimens. The 300 mg once-daily regimen was associated with lower trough concentrations and remarkable interpatient variability. Further studies in large groups of HIV patients are needed to confirm the influence of shorter half-lives in Chinese patients on efficacy and toxicity. PMID- 20974580 TI - Clinical characteristics and therapeutic options in hypnic headache. AB - BACKGROUND: Hypnic headache (HH) is a rare primary headache disorder that is characterized by exclusively sleep-related headache attacks. Because of its low prevalence, clinical features and therapeutic options are widely unknown or under discussion. METHODS: Twenty patients with HH were examined and interviewed using a standardized questionnaire in regard to their clinical characteristics and effective treatment regimens. Data were evaluated according to current International Headache Society (IHS) diagnostic criteria. Individual treatment history and effective treatment options were compared with expected efficacy based on current literature. RESULTS: In conflict to current IHS criteria, 15% of patients reported trigemino-autonomic symptoms. All patients showed distinct motor behavior during their headache attacks. In acute pain attacks caffeine was most effective. Lithium, topiramate, melatonin, amitriptyline and indomethacin were sometimes useful prophylactic treatment options but were often associated with side effects. CONCLUSIONS: Our results underline the need for modification of the IHS diagnostic criteria of HH to better reflect the actual clinical characteristics of this headache. Caffeine should be considered as first-line acute therapy. Prophylactic medical treatment should be carefully evaluated in regard to side effects in this aged patient population, as this seems to be a major concern of patients apart from pure pain reduction. PMID- 20974576 TI - Development of diagnostic criteria for serious non-AIDS events in HIV clinical trials. AB - PURPOSE: Serious non-AIDS (SNA) diseases are important causes of morbidity and mortality in the HAART era. We describe development of standard criteria for 12 SNA events for Endpoint Review Committee (ERC) use in START, a multicenter international HIV clinical trial. METHODS: SNA definitions were developed based upon the following: (1) criteria from a previous trial (SMART), (2) review of published literature, (3) an iterative consultation and review process with the ERC and other content experts, and (4) evaluation of draft SNA criteria using retrospectively collected reports in another trial (ESPRIT). RESULTS: Final criteria are presented for acute myocardial infarction, congestive heart failure, coronary artery disease requiring drug treatment, coronary revascularization, decompensated liver disease, deep vein thrombosis, diabetes mellitus, end-stage renal disease, non-AIDS cancer, peripheral arterial disease, pulmonary embolism, and stroke. Of 563 potential SNA events reported in ESPRIT and reviewed by an ERC, 72% met "confirmed" and 13% "probable" criteria. Twenty-eight percent of cases initially reviewed by the ERC required follow-up discussion (adjudication) before a final decision was reached. CONCLUSION: HIV clinical trials that include SNA diseases as clinical outcomes should have standardized SNA definitions to optimize event reporting and validation and should have review by an experienced ERC with opportunities for adjudication. PMID- 20974581 TI - Cerebrospinal fluid markers of idiopathic intracranial hypertension: is the renin angiotensinogen system involved? AB - BACKGROUND: The causes underlying idiopathic intracranial hypertension (IIH) are poorly understood. METHODS: To identify disease-related biomarkers that could offer a new insight into IIH pathology, we analyzed the cerebrospinal fluid (CSF) of 18 patients with IIH and 18 controls using two-dimensional fluorescence differential in-gel electrophoresis (2-D DIGE). RESULTS: We found six proteins that were upregulated in IIH (sterol regulatory element-binding protein 1, zinc alpha-2-glycoprotein, immunoglobulin heavy constant alpha 1 [IGHA1], alpha-1 antitrypsin [SERPINA1], serotransferrin, haptoglobin) and four proteins that were downregulated (hemopexin, angiotensinogen, vitamin-D-binding protein, transthyretin). The validity of our approach was confirmed for one candidate protein (angiotensinogen). To account for a dependency from blood-CSF barrier function, the ratio of angiotensinogen and albumin CSF-to-serum quotients (Qang/Qalb) was determined, which confirmed the downregulation of angiotensinogen in IIH (p = .04). CONCLUSION: Previous studies showed the intrinsic renin angiotensin system (RAS) to regulate choroid plexus blood flow and CSF production. Altered levels of angiotensinogen could indicate an imbalance of the RAS in IIH that may provide new targets for therapeutic intervention. PMID- 20974582 TI - Increase in CGRP- and nNOS-immunoreactive neurons in the rat trigeminal ganglion after infusion of an NO donor. AB - BACKGROUND: Nitrovasodilators, such as glyceroltrinitrate (GTN), which produce nitric oxide (NO) in the organism, are known to cause delayed headaches in migraineurs, accompanied by increased plasma levels of calcitonin gene-related peptide (CGRP) in the cranial venous outflow. Increases in plasma CGRP and NO metabolites have also been found in spontaneous migraine attacks. In a rat model of meningeal nociception, infusion of NO donors induced activity of neurons in the spinal trigeminal nucleus. METHODS: Isoflurane-anaesthetised rats were intravenously infused with GTN (250 ug/kg) or saline for two hours and fixed by perfusion after a further four hours. Cryosections of dissected trigeminal ganglia were immunostained for detection of CGRP and neuronal NO synthase (nNOS). The ganglion neurons showing immunofluorescence for either of these proteins were counted. RESULTS: The proportions of CGRP- and nNOS- as well as double immunopositive neurons were increased after GTN infusion compared to saline treatment in all parts of the trigeminal ganglion (CGRP) or restricted to the ophthalmic region (nNOS). The size of immunopositive neurons was not significantly different compared to controls. CONCLUSION: High levels of NO may induce the expression or availability of CGRP and nNOS. Similar changes may be involved in nitrovasodilator-induced and spontaneous headache attacks in migraineurs. PMID- 20974583 TI - Differences in cervical musculoskeletal impairment between episodic and chronic tension-type headache. AB - BACKGROUND: Tension-type headache (TTH) is a headache in which musculoskeletal impairments of the craniocervical region may play an important role in its pathogenesis. We investigated the presence of myofascial, postural and mechanical abnormalities in patients with frequent episodic and chronic tension-type headache (ETTH and CTTH, respectively). METHODS: The study population consisted of 36 patients with ETTH, 23 with CTTH and 42 control subjects. Myofascial trigger points (MTrPs) were identified in the upper trapezius, sternocleidomastoid, temporalis and suboccipital muscles. Sagittal C7-tragus angle was measured to evaluate flexor head posture (FHP), and neck mobility was assessed using an inclinometer. RESULTS: Only active MTrPs were significantly different between the ETTH and CTTH groups (p < .001). Patients with CTTH showed a larger sagittal C7-tragus angle (p = .011), that is, greater FHP and restricted neck mobility for both rotations compared to controls (p < .001). Although active MTrPs were correlated with the frequency and duration of headache, no correlations were observed for FHP or neck mobility. CONCLUSION: Active MTrPs in the craniocervical region contribute to triggering or maintenance of TTH and posture or neck mobility may be a result of chronic headache. PMID- 20974584 TI - A long-term follow-up study of 18 patients with sporadic hemiplegic migraine. AB - OBJECTIVE: Our objective was to study the long-term prognosis of sporadic hemiplegic migraine (SHM). METHODS: We performed a longitudinal follow-up study in 18 patients who were diagnosed with SHM between 1993 and 1996. Follow-up time between the first and second survey ranged from nine to 14 years. These patients were included as part of a genetic study in which we systematically analysed the role of the three known familial hemiplegic migraine (FHM) genes. RESULTS: In 12 out of 18 patients the clinical diagnosis was unchanged. In two of the six remaining patients the attacks were no longer associated with hemiplegia; one of them had an ATP1A2 gene mutation (E120A). In the four other patients, the diagnosis changed into FHM, because a family member had developed hemiplegic migraine since the initial diagnosis was made. In two of the four patients a mutation was demonstrated (CACNA1A [R583Q] and ATP1A2 [R834X]). CONCLUSION: This study shows that the diagnosis of SHM changes into FHM in a considerable percentage of patients (22% [4 of 18]), almost a decade after the initial diagnosis. This indicates that a careful follow-up of SHM patients and their families is advisable for optimal care and counseling. Diagnostic screening of FHM genes in SHM patients can be of value. Our genetic and clinical follow-up studies reinforce the evidence that FHM and SHM are part of the same spectrum of migraine. PMID- 20974585 TI - New plans for headache classification: ICHD-3. PMID- 20974587 TI - TRPV1 receptor blockade is ineffective in different in vivo models of migraine. AB - BACKGROUND: It has been proposed that TRPV1 receptors may play a role modulating trigeminal sensory processing. We used models of trigeminovascular nociceptive activation to study the involvement of TRPV1 receptors in the rat. Due to a possible role of TRPV1 receptors in cortical spreading depression (CSD), an experimental phenomenon sharing many features with migraine aura, we also utilized a model of mechanically induced CSD. METHODS: Male Sprague Dawley rats (N = 39) were anesthetized and cannulated for monitoring and drug administration to study the effects of the TRPV1 receptor antagonist A-993610 (8 mg kg(-1) IV). Wide-dynamic-range neurons, responding to electrical stimulation of the middle meningeal artery (MMA)/dura mater were identified and recorded using electrophysiological techniques. Intravital microscopy was used to study neurogenic dural vasodilation (NDV) of the MMA comparing capsaicin and electrical stimulation, and the effect of A-993610 on mechanically induced CSD was examined. RESULTS: Administration of A-993610 had no significant effect on trigeminal firing of A- or C-fibers elicited by electrical stimulation of the MMA. It also showed no effect on NDV whilst blocking vasodilation due to intravenous capsaicin injection. The mechanically induced CSD response could not be altered by A-993610 administration. CONCLUSIONS: Although there is evidence that TRPV1 receptors play an important role in sensory processing in general, the new data do not support a role in the treatment of acute migraine. PMID- 20974588 TI - Comment on visual pattern repsonses in migraine with and without motion sickness. PMID- 20974589 TI - Pharmacological characterization of VIP and PACAP receptors in the human meningeal and coronary artery. AB - OBJECTIVE: We pharmacologically characterized pituitary adenylate cyclase activating polypeptides (PACAPs), vasoactive intestinal peptide (VIP) and the VPAC(1), VPAC(2) and PAC(1) receptors in human meningeal (for their role in migraine) and coronary (for potential side effects) arteries. METHODS: Concentration response curves to PACAP38, PACAP27, VIP and the VPAC(1) receptor agonist ([Lys15,Arg16,Leu27]-VIP[1-7]-GRF[8-27]) were constructed in the absence or presence of the PAC(1) receptor antagonist PACAP6-38 or the VPAC(1) receptor antagonist, PG97269. mRNA expression was measured using qPCR. RESULTS: PACAP38 was less potent than VIP in both arteries. Both peptides had lower potency and efficacy in meningeal than in coronary arteries, while mRNA expression of VPAC(1) receptor was more pronounced in meningeal arteries. PACAP6-38 reduced the E(max) of PACAP27, while PG97269 right-shifted the VIP-induced relaxation curve only in the coronary arteries. CONCLUSION: The direct vasodilatory effect of VIP and PACAP might be less relevant than the central effect of this compound in migraine pathogenesis. PMID- 20974590 TI - Co-morbidity of migraine with somatic disease in a large population-based study. AB - INTRODUCTION: The aim of this study was to determine sex specific co-morbidity of migraine and its subtypes migraine without aura (MO) and migraine with aura (MA) with a number of common somatic diseases. SUBJECTS AND METHODS: In 2002, a questionnaire containing previously validated questions to diagnose migraine and its subtypes as well as questions regarding some somatic diseases was sent to 46,418 twins residing in Denmark and born between 1931 and 1982. The twins are representative of the whole Danish population and were used as such in the present study. RESULTS: We found that 21, 23 and 12 conditions were co-morbid with migraine, MA and MO, respectively. Co-morbid diseases included previously documented diseases: asthma, epilepsy and stroke as well as new conditions: kidney stone, psoriasis, rheumatoid arthritis and fibromyalgia. MA had more co morbidities than MO and females more than males. CONCLUSIONS: Migraine occurs in 20-30% of several medical conditions. It should be diagnosed and treated along with the primary disease. PMID- 20974591 TI - Positional cluster-like headache. A case report of a neurovascular compression between the third cervical root and the vertebral artery. AB - Symptomatic cluster-like headaches have been described with lesions of the trigeminal and parasympathetic systems. Here, we report the case of a 44-year-old woman with continuous auricular pain and a positional cluster-like headache associated with red ear syndrome. Clinical data and morphological investigations raised the hypothesis of a neurovascular compression between the C3 root and vertebral artery. Neurosurgical exploration found a fibrosis surrounding both the C3 root and the vertebral artery. The excellent outcome after microvascular cervical decompression suggests a causal relationship between the cluster-like headache and the vertebral constraint on the C3 root. PMID- 20974592 TI - Mere surgery will not cure cluster headache--implications for neurostimulation. AB - This case study concerns a patient with primary chronic cluster headache, who was unresponsive to all treatments and consecutively underwent hypothalamic deep brain stimulation (DBS). DBS had no effect on the cluster attacks, but cured an existing polydipsia as well as restlessness. However, hypothalamic DBS produced a constant, dull headache without concomitant symptoms and a high-frequent tremor. All of these effects were repeated when the stimulation was stopped and than started again. DBS had no effect on a pathological weight gain from 70 kg to 150 kg due to bulimia at night, usually during headache attacks. This case illustrates that cluster headache is, in some patients, only one symptom of a complex hypothalamic syndrome. This case also underlines that the stimulation parameters and anatomical target area for hypothalamic DBS may be too unspecific to do justice to the clinical variety of patients and concomitant symptoms. Hypothalamic DBS is an exquisite and potentially life-saving treatment method in otherwise intractable patients, but needs to be better characterised and should only be considered when other stimulation methods, such as stimulation of the greater occipital nerve, are unsuccessful. PMID- 20974593 TI - Discrepancy between strong cephalic arterial dilatation and mild headache caused by prostaglandin D2 (PGD2). AB - INTRODUCTION: Prostaglandins (PGs) are involved in nociception and mast cell degranulation. Prostaglandin D2 (PGD2) is a vasodilatator released during mast cell degranulation. The headache-eliciting effect of PGD2 has not been studied in man. SUBJECTS AND METHODS: Twelve healthy volunteers were randomly allocated to receive intravenous infusion of 384 ng/kg/min PGD2 over 25 min in a placebo controlled, double-blind cross-over study. We recorded headache intensity and associated symptoms, velocity in the middle cerebral artery (V(MCA)) and diameter of the superficial temporal artery (STA) and radial artery (RA) using ultrasonography. RESULTS: In the period 0-14 h, 11 subjects reported headache on PGD2 compared to one subject on placebo (P = 0.002). During the in-hospital phase (0-120 min), the area under the headache curve was larger on PGD2 compared to placebo (P < 0.05). Median peak headache, 1 (0-1), occurred 10 min after start of PGD(2) infusion. There was no difference in incidence of headache in the post hospital phase between PGD2 (n = 3) and placebo (n = 1). There was a decrease in V(MCA) (P < 0.001), increase in STA (P < 0.001) and RA (P < 0.006) diameter during PGD2 infusion compared to placebo. Peak decrease in V(MCA) was 28.3% after 10 min and peak increase in STA was 55.7% after 20 min on the PGD2 day. CONCLUSIONS: The present study shows that PGD2 is a very strong vasodilator of MCA, STA and RA, but causes only mild headache. PMID- 20974595 TI - Prevalence and impact of migrainous vertigo in mid-life women: a community-based study. AB - We surveyed 1436 women aged 40-54 years in the community. Of these, 278 (19.4%) were diagnosed with migraine or probable migraine based on the International Classification of Headache Disorder criteria. The diagnoses of migrainous vertigo (MV) were modified from Neuhauser's criteria. Of the 278 women, 238 (85.6%) underwent an interview and 72 (30.3%) of those with migraine or probable migraine had MV. The 1-year prevalence of MV among mid-life women was 5.0% (95% CI, 4.0 6.3%). The MV subjects had a higher proportion of aura (23.6% vs 9.6%; OR, 2.9), nausea (76.4% vs 55.8%; OR, 2.6) and photophobia (61.1% vs 41.7%; OR, 2.2) compared with the migraine subjects without MV. The migrainous subjects with and without MV had similar Short-Form 36 (SF-36) scores. Our study showed that MV was common in mid-life women. Their health-related quality of life was similar in migrainous subjects with MV and those without MV. PMID- 20974594 TI - Genomic expression patterns in medication overuse headaches. AB - BACKGROUND: Chronic daily headache (CDH) and chronic migraine (CM) are one of the most frequent problems encountered in neurology, are often difficult to treat, and frequently complicated by medication-overuse headache (MOH). Proper recognition of MOH may alter treatment outcome and prevent long term disability. OBJECTIVE: This study identifies the unique genomic expression pattern MOH that respond to cessation of the overused medication. METHODS: Baseline occurrence of MOH and typical pattern of response to medication cessation were measured from a large database. Whole blood samples from patients with CM with or without MOH were obtained and their genomic profile was assessed. Affymetrix human U133 plus2 arrays were used to examine the genomic expression patterns prior to treatment and 6-12 weeks later. Headache characterisation and response to treatment based on headache frequency and disability were compared. RESULTS: Of 1311 patients reporting daily or continuous headaches, 513 (39.1%) reported overusing analgesic medication. At follow-up, 44.5% had a 50% or greater reduction in headache frequency, while 41.6% had no change. Blood genomic expression patterns were obtained on 33 patients with 19 (57.6%) overusing analgesic medication with a unique genomic expression pattern in MOH that responded to cessation of analgesics. Gene ontology of these samples indicated a significant number were involved with brain and immunological tissues, including multiple signalling pathways and apoptosis. CONCLUSIONS: Blood genomic patterns can accurately identify MOH patients that respond to medication cessation. These results suggest that MOH involves a unique molecular biology pathway that can be identified with a specific biomarker. PMID- 20974596 TI - Psychosocial headache measures in Caucasian and African American headache patients: psychometric attributes and measurement invariance. AB - INTRODUCTION: As research increasingly examines differences in headache characteristics between Caucasian and African American headache patients, it is requisite to determine the equivalence of existing headache measures for both racial groups. METHODS: This study examined the psychometric properties and measurement invariance of four widely used psychosocial headache measures. Caucasians (N = 173) and African Americans (N = 114) receiving treatment in four headache subspecialty clinics throughout Ohio completed the Headache Disability Inventory (HDI), the Migraine-Specific Quality of Life (MSQL) measure, the Headache Management Self-Efficacy (HMSE) scale, and the Headache-Specific Locus of Control (HSLC) scale prior to initiating new preventive therapies. CONCLUSION: All measures demonstrated good internal consistency and measurement invariance. Despite adequate measurement invariance, the recommended factor structure of the HMSE scale yielded a poor fit for both African American and Caucasian patients. With perhaps the exception of the HMSE scale, the HDI, MSQL scale and HSLC scale are psychometrically sound and can be used with both Caucasian and African American headache patients. PMID- 20974597 TI - Migraine is frequent in patients with systemic lupus erythematosus: a case control study. AB - INTRODUCTION: The objective of this study was to compare the prevalence of primary headaches in systemic lupus erythematosus (SLE) versus healthy subjects, and to determine whether headaches in SLE are associated with MRI- or cerebrospinal fluid (CSF) abnormalities. PATIENTS AND METHODS: The case-control study included MRI- and CSF investigations. Headache was classified according to the International Classification of Headache Disorders. Depression and fatigue were measured with Beck Depression Inventory (BDI) and Fatigue Severity Scale (FSS) respectively. RESULTS: Twenty-four out of 67 SLE patients and 13 out of 67 age- and gender matched healthy subjects had migraine (36% vs 19%, P = 0.03). Nine (13%) SLE patients had migraine with aura vs 4 (6%) in healthy subjects, P = 0.14. The prevalence of tension type headache was equal (60% in patients vs 58% in controls). There was no association between migraine and SLE disease activity, biochemical or immunological markers, cerebral white matter hyperintensities, interleukin-6 in CSF, impairment of the blood-brain barrier, or intrathecal immunoglobulin production. SLE patients had higher BDI- and FSS scores compared with healthy control subjects, and SLE patients with migraine had higher BDI scores than lupus patients without migraine. CONCLUSIONS: Migraine is more prevalent in SLE patients, associated with depression like in the general population, but not associated with disease activity or abnormalities detected on cerebral MRI, in CSF, or any SLE characteristics except from SLE photosensitivity. The inclusion of the migraine item in SLE disease activity instruments remains questionable. PMID- 20974598 TI - Topiramate intervention to prevent transformation of episodic migraine: the topiramate INTREPID study. AB - OBJECTIVE: The study sought to evaluate whether topiramate prevents development of chronic daily headache (CDH, >=15 headache days per month) in adult subjects with high-frequency episodic migraine (HFEM, 9-14 migraine headache days/month). A secondary objective was to assess the efficacy of topiramate as preventive migraine treatment in this population. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study comparing topiramate 100 mg/day and placebo for 26 weeks. The primary efficacy variable was new-onset CDH at month 6. Secondary efficacy measures included migraine and headache days. Adverse events (AEs) were evaluated. RESULTS: A total of 159 topiramate subjects and 171 placebo subjects were efficacy-evaluable. At month 6, 1.4% of topiramate subjects versus 2.3% of placebo subjects had CDH (p = .589). Compared with placebo, topiramate treatment was associated with statistically significant reductions in mean number of migraine days (6.6 vs. 5.3/28 days; p = .001) and headache days (6.6 vs 5.3/28 days; p = .001). Most commonly reported AEs in the topiramate versus placebo group included paresthesia (32.4% vs. 7.0%), fatigue (14.8% vs. 8.6%), dizziness (11.4% vs. 7.6%) and nausea (10.8% vs. 9.2%). CONCLUSION: Topiramate 100 mg/day did not prevent the development of CDH at six months in subjects with HFEM. Topiramate was effective in reducing headache days and migraine headache days and generally well tolerated. PMID- 20974599 TI - The digiti quinti sign in hemiplegic migraine. AB - The digiti quinti sign (DQS), described originally as a clinical indication of subtle motor deficit, consists of a relatively greater abduction of the fifth finger on the affected side when both arms are extended forwards. This sign was previously observed interictally in three consecutive hemiplegic migraine (HM) patients. PATIENTS AND METHODS: To verify whether the DQS specifically discriminates HM from non-hemiplegic migraine (nHM), the angle between the fourth and fifth fingers (ANG) was measured interictally in 10 HM patients, 44 migraine with aura and migraine without aura patients, and 45 healthy controls. RESULTS: The ANG was significantly wider at the symptomatic side in HM as compared with nHM and controls. The differences between the symptomatic and non-symptomatic (for HM) or between the right and left sides (absolute values for nHM and controls) were, respectively, 10.10 degrees +/- 9.58 degrees , 4.15 degrees +/- 3.95 degrees and 5.37 degrees +/- 4.74 degrees (p = .007). The optimal cutoff point for ANG was 15 degrees at the symptomatic side (sensitivity and specificity of 80.0% and 72.2%, respectively), 10.5 degrees at the non symptomatic side (sensitivity and specificity of 60.0% and 52.3%), and 3 degrees for the difference between sides (sensitivity and specificity of 90.0% and 79.5%). CONCLUSION: Data show that the DQS discriminates HM from nHM and controls. PMID- 20974600 TI - Interictal pain in cluster headache. AB - INTRODUCTION: Cluster headache is characterized by severe attacks of unilateral pain, but many patients experience symptoms more commonly associated with migraine such as persistent pain. PATIENTS AND METHODS: We evaluated cluster headache patients using a questionnaire and chart review to determine clinical characteristics. RESULTS: Twenty-four of 50 subjects reported interictal pain outside of their acute attacks. Sixteen reported persistent pain more than half the time while in cycle. Unlike acute attacks, this pain was generally mild. CONCLUSIONS: Subjects with persistent interictal pain were more likely to have chronic cluster, allodynia, and suboptimal response to sumatriptan, suggesting that interictal pain in cluster headache may predict a more severe disease process. PMID- 20974601 TI - Randomized, controlled trial of telcagepant over four migraine attacks. AB - METHODS: This study evaluated the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant (tablet formulation) for treatment of a migraine attack and across four attacks. Adults with migraine were randomized, double-blind, to telcagepant 140 mg, telcagepant 280 mg, or control treatment sequences to treat four moderate-to-severe migraine attacks. Control patients received placebo for three attacks and telcagepant 140 mg for one attack. Efficacy for the first attack (Attack 1) and consistency of efficacy over multiple attacks were assessed. For an individual patient, consistent efficacy was defined as >= 3 successes, and lack of consistent efficacy was defined as >= 2 failures, in treatment response. A total of 1677 patients treated >= 1 attack and 1263 treated all four attacks. RESULTS: Based on Attack 1 data, telcagepant 140 mg and 280 mg were significantly (p < .001) more effective than placebo for 2-hour pain freedom, 2-hour pain relief, 2-hour absence of migraine-associated symptoms (phonophobia, photophobia, nausea), and 2-24 hours sustained pain freedom. The percentage of patients with 2-hour pain freedom consistency and 2-hour pain relief consistency was significantly (p < .001) higher for both telcagepant treatment sequences versus control. Adverse events within 48 hours for telcagepant with an incidence >= 2% and twice that of placebo were somnolence (placebo = 2.3%, 140 mg = 5.9%, 280 mg = 5.7%) and vomiting (placebo = 1.4%, 140 mg = 1.0%, 280 mg = 2.9%). CONCLUSION: Telcagepant 140 mg and 280 mg were effective for treatment of a migraine attack and were more consistently effective than control for intermittent treatment of up to four migraine attacks. Telcagepant was generally well tolerated. (Clinicaltrials.gov; NCT00483704). PMID- 20974602 TI - Abnormal pressure waves in headache sufferers with bilateral transverse sinus stenosis. AB - INTRODUCTION: Bilateral transverse sinus stenosis (BTSS) has been reported to be associated with idiopathic intracranial hypertension without papilloedema in headache sufferers. SUBJECTS AND METHODS: To test the accuracy of short-term cerebrospinal fluid (CSF) pressure monitoring through a lumbar needle for detection of elevated intracranial pressure in headache sufferers with BTSS, we prospectively performed lumbar puncture in order to measure lumbar CSF opening pressures and to monitor, for 1 h, the CSF pressure in 48 consecutive headache sufferers with BTSS and in 50 consecutive headache sufferers with normal appearance of transverse sinuses or stenosis of one transverse sinus. RESULTS: Of the 48 headache sufferers with BTSS, 18 (37.5%) had elevated CSF opening pressure and abnormal pressure waveforms, but short-term CSF pressure monitoring revealed abnormal pressure waves associated with elevated mean CSF pressure also in 26 (86.6%) out of 30 patients who had normal opening pressures. None of the 50 headache sufferers with normal appearance of transverse sinuses or stenosis of one transverse sinus had abnormal pressure waves and elevated CSF pressures. CONCLUSIONS: In this study, short-term CSF pressure monitoring through a lumbar needle revealed abnormal pressure waves and elevated mean CSF pressures in the majority of headache sufferers with BTSS who had normal CSF opening pressures. These findings demonstrate the accuracy of short-term CSF pressure monitoring through a lumbar needle in estimating CSF pressure; they also highlight that a single-spot opening pressure measurement has a low accuracy for recognition of increased intracranial pressure in headache sufferers with BTSS. PMID- 20974603 TI - Postictal headache in South African adult patients with generalised epilepsy in a tertiary care setting: a cross-sectional study. AB - Postictal headache (PIH), although it occurs in 34-59% of epilepsy patients, has not been adequately studied. This study aims to describe clinical characteristics and associations of PIH in generalised epilepsy in a South African tertiary neurology clinic. METHODS: Two-hundred consecutive adults with generalised epilepsy underwent semi-structured interviews, dividing them into study (with PIH) and control patients (no PIH), and data was statistically analysed. RESULTS: PIH occurred in 104/200, with 63% having headache after every seizure. Pain duration was 4-24 hours in 43% and pain intensity severe in 55%. The criteria of the International Headache Society (2004), International Classification of Headache Disorders, second edition (ICHD-II) classified 47% as migraine, 38% tension-type and 15% unclassified (but 13% probable migaine). Self-medication occurred in 81% and interictal headache was significantly associated with PIH present in 64% of study patients versus 5% of control patients. CONCLUSION: PIH occurs commonly in generalised epilepsy, mostly as migraine headache, with interictal headache a specific risk factor. PIH is underdiagnosed and undertreated, leading to self-medication. Optimal management should be elucidated in future studies. PMID- 20974605 TI - Intracranial hypertension, headache and obesity: insights from magnetic resonance venography. PMID- 20974604 TI - Lack of efficacy of the selective iNOS inhibitor GW274150 in prophylaxis of migraine headache. AB - INTRODUCTION: This study investigated the efficacy and tolerability of the highly selective iNOS inhibitor GW274150 in prophylaxis of migraine headache. SUBJECTS AND METHODS: The study was conducted in two parts, each comprising a 4-week baseline period, a 12-week, double-blind, parallel-group treatment period, and a 4-week follow-up period. The study had an adaptive design in that findings of Part 1 of the study were used to inform the conduct of Part 2. Following an interim analysis at the end of Part 1, the trial could be stopped for futility or continued in Part 2 to study the full-dose response or to increase sample size in case initial assumptions had been violated. The primary end-point in both parts of the study was the probability of the occurrence of a migraine headache day during the baseline period and the treatment period. RESULTS: In Part 1, adult male and female patients with migraine received GW274150 60 mg (n = 37), 120 mg (n = 37), or placebo (n = 38) once daily for 12 weeks. In Part 2, female patients with migraine received GW274150 60 mg (n= 160) or placebo (n = 154) once daily for 12 weeks. GW274150 was no more effective than placebo for the primary efficacy end-point or any secondary efficacy end-point in Part 1 or Part 2. GW274150 was generally well tolerated. CONCLUSIONS: GW274150 at doses predicted to inhibit iNOS >80% did not differ from placebo in the prophylaxis of migraine. The results do not support a role of iNOS inhibition in migraine prevention. PMID- 20974606 TI - Case series of sixteen patients with nummular headache. AB - INTRODUCTION: Nummular headache is a rare primary headache disorder described by a focal circumscribed area of pain (2-6 cm in diameter). Literature on this disorder is sparse. PATIENTS AND METHODS: Here, we describe a case series of 16 patients (6 men, 10 women) seen at the Mayo Clinic. RESULTS: Mean age of onset was 50 years (range, 19-79 years) and mean duration of headache was 7.9 years (range, 0.33-40 years). Location of headache varied and was found to be an average of 3.9 cm in diameter (range, 2-10 cm). Headache was episodic (< 15 days/month) in four patients and chronic (>15 days/month) in 12 patients. Attention was paid to therapeutic interventions. Resolution was seen in 38% of patients. Migraine was present in the history of 56% of patients and medication overuse headache was found in 25%. CONCLUSIONS: Our series results support previous findings. In our population, no specific therapy was identified to be effective in more than one patient. PMID- 20974607 TI - Cervicogenic headache in the general population: the Akershus study of chronic headache. AB - OBJECTIVE: The objective was to study the prevalence of cervicogenic headache (CEH) in the general population. METHODS: An age- and gender-stratified random sample of 30,000 persons aged 30-44 years received a mailed questionnaire. Those with self-reported chronic headache were interviewed by neurological residents. The criteria of the Cervicogenic Headache International Study Group and the International Classification of Headache Disorders, second edition, were applied. RESULTS: The questionnaire response rate was 71% and the participation rate of the interview was 74%. The prevalence of CEH was 0.17% in the general population, with a female preponderance. Fifty per cent had co-occurrence of medication overuse and 42% had co-occurrence of migraine. The pericranial muscle tenderness score was significantly higher on the pain than non-pain side (p < .005). The cervical range of motion was significantly reduced compared to healthy controls (p < .005). The mean duration of CEH was eight years. Based on patients' self reports, greater occipital nerve (GON) blockage and cryotherapy was reported effective in 90% of those who had this procedure, while other treatment alternatives were reported less effective. PMID- 20974608 TI - Nocturnal awakening with headache and its relationship with sleep disorders in a population-based sample of adult inhabitants of Sao Paulo City, Brazil. AB - Our aim was to estimate the prevalence of nocturnal awakening with headache (NAH) in the population of Sao Paulo City according to gender, age (20-80 years old) and socioeconomic classes and its relationship to sleep disorders, sleep parameters, anxiety, depression, fatigue, life quality and obesity. We used a population-based survey with a representative three-stage cluster sample. Questionnaires and scales were applied face-to-face, and polysomnography was performed in 1101 volunteers, aged 42 +/- 14 years, 55% women. The complaint of NAH occurring at least once a week had a prevalence of 8.4%, mostly in women, obese subjects and those aged 50-59 years-old. We observed associations of NAH with insomnia, restless leg syndrome (RLS), nightmares and bruxism, but not obstructive sleep apnea syndrome. In a logistics regression model, risk factors for NAH were female gender, odds ratio (OR) (95% confidence interval [CI]) 4.5 (2.8-7.3); obesity, OR 1.9 (1.1-3.3); age between 50 and 59 years, OR 2.4 (1.2 4.7); severe anxiety, OR 8.1 (3.6-18.1); RLS, 2.7 (1.2-5.6); and nightmares, 2.2 (1.3-3.7). Our study shows that NAH was highly prevalent in the population of Sao Paulo and suggests that this phenomenon has specific characteristics with specific risk factors: obesity, RLS and nightmares. PMID- 20974609 TI - Episodic and chronic migraineurs are hypersensitive to thermal stimuli between migraine attacks. AB - OBJECTIVE: To determine if migraineurs have evidence of interictal cutaneous sensitisation. SUBJECTS AND METHODS: Thermal and mechanical pain thresholds in 20 episodic migraineurs, 20 chronic migraineurs, and 20 non-migraine control subjects were compared. Quantitative sensory testing was conducted when subjects had been migraine-free for at least 48 h. Heat, cold and mechanical pain thresholds, and heat and cold pain tolerance thresholds were measured. RESULTS: Thermal pain thresholds and thermal pain tolerance thresholds differed significantly by headache group (P = 0.001). During the interictal period, episodic and chronic migraineurs were more sensitive to thermal stimulation than non-migraine controls. CONCLUSIONS: Interictal sensitisation may predispose the migraineur to development of headaches, may be a marker of migraine activity, and a target for treatment. PMID- 20974610 TI - Medium-dose riboflavin as a prophylactic agent in children with migraine: a preliminary placebo-controlled, randomised, double-blind, cross-over trial. AB - BACKGROUND: Riboflavin seems to have a promising effect on migraine in adults. The present study examines whether riboflavin has a prophylactic effect on migraine in children. OBJECTIVE: To investigate whether riboflavin in a dosage of 50 mg/day has a prophylactic effect on migraine attacks in young children. SUBJECTS AND METHODS: This randomised, placebo-controlled, double-blind, cross over trial included 42 children (aged 6-13 years) with migraine of whom 14 children were also suffering from tension-type headache. Following a 4-week baseline period, all children received placebo for 16 weeks then riboflavin for 16 weeks (or vice versa) with a washout period of 4 weeks in between. The primary outcome measure was reduction in mean frequency of migraine attacks and tension type headache in the last 4 weeks at the end of the riboflavin and placebo phase, compared with the preceding baseline or wash-out period. Secondary outcome measures were mean severity and mean duration of migraine and tension-type headaches in the last 4 weeks at the end of the riboflavin and placebo phase, compared with the preceding baseline or wash-out period. RESULTS: No significant difference in the reduction of mean frequency of migraine attacks in the last month of treatment was found between placebo and riboflavin (P = 0.44). However, a significant difference in reduction of mean frequency of headaches with a tension-type phenotype was found in favour of the riboflavin treatment (P = 0.04). CONCLUSIONS: In this group of children with migraine, there is no evidence that 50 mg riboflavin has a prophylactic effect on migraine attacks. We found some evidence that 50 mg riboflavin may have a prophylactic effect on interval headaches that may correspond to mild migraine attacks or tension-type headache attacks in children with migraine. PMID- 20974611 TI - Osmophobia in migraine classification: a multicentre study in juvenile patients. AB - AIMS: This study was planned to investigate the diagnostic utility of osmophobia as criterion for migraine without aura (MO) as proposed in the Appendix (A1.1) of the International Classification of Headache Disorders (ICHD-II, 2004). METHODS: We analysed 1020 patients presenting at 10 Italian juvenile headache centres, 622 affected by migraine (M) and 328 by tension-type headache (TTH); 70 were affected by headache not elsewhere classified (NEC) in ICHD-II. By using a semi-structured questionnaire, the prevalence of osmophobia was 26.9%, significantly higher in M than TTH patients (34.6% vs 14.3%). RESULTS: Osmophobia was correlated with: (i) family history of M and osmophobia; and (ii) other accompanying symptoms of M. By applying these 'new' criteria, we found an agreement with the current criteria for the diagnosis of migraine without aura (MO) in 96.2% of cases; 54.3% of previously unclassifiable patients received a 'new' diagnosis. CONCLUSIONS: In conclusion, this study demonstrates that this new approach, proposed in the Appendix (A1.1), appears easy to apply and should improve the diagnostic standard of ICHD-II in young patients too. PMID- 20974612 TI - Mode of occurrence of traumatic head injuries in male patients with cluster headache or migraine: Is there a connection with lifestyle? AB - INTRODUCTION: Our study objective was to investigate the mode of occurrence of traumatic head injury in episodic cluster headache and migraine patients. METHODS: We conducted a retrospective study on 400 male patients, 200 with cluster headache (cases) and 200 with migraine (controls). We investigated the frequency and mode of occurrence of traumatic head injury and some lifestyle habits. RESULTS: The number of traumatic head injuries was significantly higher in cases than in controls (adjusted odds ratio [OR] = 2.0; 95% confidence interval [CI] = 1.5-2.8). Cases were more often responsible for the head traumas (adjusted OR = 2.6; 95% CI = 1.3-4.9) and reported a significantly higher proportion of injuries during scuffles or brawls (OR = 6.5; 95% CI = 2.9-14.8). Compared with other cluster headache patients, cases responsible for traumatic head injuries were more frequently heavy alcohol (p = .000), heavy tobacco (p = .03) and heavy coffee consumers (p = .003). CONCLUSIONS: Cluster headache patients (a) had traumatic head injuries more frequently than migraineurs; and (b) were more often responsible for them, perhaps due to particular behaviours related to their lifestyles. PMID- 20974613 TI - Inter-observer reliability of high-resolution ultrasonography in the assessment of bone erosions in patients with rheumatoid arthritis: experience of an intensive dedicated training programme. AB - OBJECTIVE: The present study was aimed at testing the ability of a rheumatologist without experience in ultrasound (US) who attended an intensive 4-week training programme focused on US assessing bone erosions in the hands and feet in patients with RA. METHODS: Twenty patients diagnosed with RA according to the ACR criteria were included in the study. All US examinations were performed bilaterally by two investigators (with different experience in the field of musculoskeletal US) at the following sites: the dorsal, lateral and volar aspect of the second metacarpal, ulnar and fifth metatarsal head; and the dorsal and volar aspect of the third metacarpal and second proximal heads. Each quadrant was scanning in longitudinal and transverse scans for assessing the qualitative, semiquantitative and quantitative US findings indicative of bone erosions according the OMERACT preliminary definition. RESULTS: Both kappa-values and overall agreement percentages of qualitative and semiquantitative assessments showed moderate to excellent agreement between the two investigators. Similar results were obtained for the quantitative assessment with the concordance correlation coefficient value always significant. The only exception was the volar aspects, in particular those of the fifth metatarsal head. CONCLUSION: Our study suggests that after a 4 week dedicated training programme, a rheumatologist without experience in US is able to detect and score bone erosions in the hands and feet of patients with RA. PMID- 20974614 TI - Routinely measuring and reporting pneumococcal vaccination among immunosuppressed rheumatology outpatients: the first step in improving quality. AB - OBJECTIVE: The Centers for Disease Control (CDC) recommends pneumococcal vaccination for immunocompromised patients. Data suggest that rates of vaccination in this population are not optimal. To support continuous quality improvement efforts, we electronically measured vaccination status among rheumatology outpatients over time. METHODS: Using data from administrative (billing) and electronic health record sources, we identified rheumatology clinic patients seen between 1 February 2008 and 31 January 2010 and prescribed an immunosuppressive medication. CDC recommendations for pneumococcal vaccination were applied. We calculated the proportion of eligible patients who were up-to date with pneumococcal vaccination: (i) while on an immunosuppressive medication and (ii) before newly starting an immunosuppressive medication in the last 12 months. RESULTS: We identified 2763 rheumatology clinic patients on immunosuppressive medications, with 568 initiated in the last 12 months. The mean age was 57 years, 75% were female and 77% were Caucasian. The most frequent disease was RA (50%) and the most common immunosuppressive medication was MTX (59%). Of patients on immunosuppressive medications, 1491/2763 (54%) were up to date with pneumococcal vaccination. Among new initiators of immunosuppressive medications, 258/568 (45%) were vaccinated before starting the immunosuppressive medication. Patients treated by rheumatologists in practice for <=10 years were more likely to be up to date with pneumococcal vaccination (72%) than those with providers in practice >10 years (52%, P < 0.001). CONCLUSION: The proportion of patients who are up to date with documented pneumococcal vaccination was suboptimal in our rheumatology practice. The ability to continuously repeat electronic measurement permits us to initiate continuous quality improvement efforts. PMID- 20974615 TI - Osteoprotegerin genetic polymorphisms and age of symptom onset in ankylosing spondylitis. AB - OBJECTIVES: Osteoporosis is one of the recognized features of AS. It is known that RANK ligand (RANKL), which binds to RANK, can cause the activation of bone resorption. Osteoprotegerin (OPG) also competes with RANK by binding to RANKL and inhibiting bone absorption. Therefore, we designed a case-control study to evaluate the association between occurrence and clinical features of AS and RANK, RANKL and OPG genetic polymorphisms. METHODS: A total of 330 AS patients and 330 age- and gender-matched controls were recruited. PCR-restriction fragment length polymorphism was applied to identify RANK C575T, RANKL C-290T and OPG G1181C genotypes. RESULTS: OPG GG genotype carriers had an elevated risk of AS compared with those with the GC and CC genotypes (matched odds ratio 1.74; 95% CI 1.26, 2.40). Age of symptom onset and frequency of peripheral arthritis significantly differed among AS patients by OPG G1181C genotypes. HLA-B27(+) patients with the OPG C allele had the earliest age of symptom onset [mean (s.d.) 26.6 (9.6) years], followed by HLA-B27(+) patients with the OPG G allele [32.6 (12.2) years], HLA-B27(-) patients with the OPG G allele [38.1 (13.6) years] and HLA B27(-) patients with the OPG C allele [38.6 (9.8) years]. CONCLUSION. OPG G1181C polymorphism may be associated with AS development and clinical manifestations. PMID- 20974616 TI - Building social capital and improving mental health care to prevent suicide. PMID- 20974617 TI - Evidence of a non-progressive course of alternating hemiplegia of childhood: study of a large cohort of children and adults. AB - Alternating hemiplegia of childhood is a neurological disorder characterized by episodes of hemiplegia, various non-epileptic paroxysmal events and global neurological impairment. Characterization of the evolution and outcome into adulthood has not been sufficiently investigated. The goal of this study was to elucidate the natural history of alternating hemiplegia within a large cohort of 157 patients, as part of the European Network for Research on Alternating Hemiplegia project. A questionnaire was formulated to determine the severity of both paroxysmal and global neurological impairment and address progression of the disorder by allocating data to specific age epochs up to and over 24 years of age. Patients in early age groups were consistently present in subsequent later age groups and for each patient, data were collected for each corresponding age epoch. The study was based on predominantly retrospective and, for a period of 2 years, prospective data. At inclusion, patients were aged from 9 months to 52 years. The median age at diagnosis was 20 months. All patients experienced hemiplegic attacks; 86.5% reported episodes of bilateral weakness, 88% dystonic attacks, 53% epileptic seizures, 72% developed chorea and/or dystonia and 92% mental retardation. When data over the course of the illness were examined for the whole cohort, the severity of symptoms did not appear to change, with the exception of abnormal ocular movements and hypotonia that regressed, but did not disappear into adulthood (from 86 to 36% and 76 to 36%, respectively). No statistically significant correlation between a history of severe paroxysmal hemiplegic/dystonic episodes and a worse neurological outcome was identified. Seven patients died, some of whom experienced severe plegic attacks or epileptic seizures at the time of death. History of severe plegic/dystonic attacks was not found to be an aggravating factor for deceased patients. Our results provide evidence that the natural history of alternating hemiplegia is highly variable and unpredictable for individual patients. However, we did not find evidence to support a steadily progressive and degenerative course of the disorder when patients were analysed as a group. For a minority of patients, a risk of sudden death was associated with more severe neurological impairment. The European Network for Research on Alternating Hemiplegia Registry, validated by our study, includes all major neurological signs and symptoms of alternating hemiplegia and may thus be used as a precedent for the progressive inclusion and follow-up of patients as well as a reference for genetic studies and treatment trials. PMID- 20974618 TI - Malfunction or malprogramming? PMID- 20974619 TI - Burden and factors associated with highway work-zone crashes, on a section of the Karachi-Hala Road, Pakistan. AB - OBJECTIVE: To assess the burden and factors associated with highway work-zone (HWZ) crashes. DESIGN: Historical cohort. SETTING: Section of the Karachi-Hala Road, Pakistan (196 km). DATA: Police-reported crashes and traffic statistics from January 2006 to December 2008. ANALYSIS: Crash and death risk between the HWZ and other zones for a 50 km section were compared. Crash locations were described for a further 146 km section on which factors associated with HWZ crashes were assessed. RESULTS: HWZ crashes accounted for 15.0% of traffic crashes (N = 180) and 30.8% of road fatalities (N = 91) on the 196 km section. Rates were higher in the HWZ than other zones for crashes (rate ratio (RR) = 2.35, 95% CI = 1.17 to 4.70) and deaths (RR = 4.70, 95% CI = 2.11 to 10.46). Opposite-direction crashes (adjusted OR (aOR) = 10.65, 95% CI = 3.22 to 35.25) and traffic crashes involving pedestrians (aOR = 6.03, 95% CI = 1.39 to 26.20) and on wet surfaces (aOR = 7.26, 95% CI = 4.15 to 48.89) were significantly associated with the HWZ. CONCLUSION: These results support the introduction of prevention measures such as strict traffic enforcement, traffic separation, improving pedestrian visibility, and hazard signage at HWZs in Pakistan. The feasibility and effectiveness of these measures remains to be evaluated. PMID- 20974620 TI - Injury risk and prevention in context. PMID- 20974621 TI - 'Neighbour smoke': proposal for a new term. PMID- 20974622 TI - Ignition strength of 25 international cigarette brands. AB - BACKGROUND: Cigarette-ignited fires are a leading cause of fire death and injury throughout the world and remain a global public health and safety problem. To reduce this harm, a small number of countries now require cigarettes to have reduced ignition propensity (RIP). It is not known if cigarette manufacturers are voluntarily introducing RIP cigarettes in other countries to help save lives. METHODS: Using the ASTM E2187-04 test method, per cent full length burn (%FLB) was measured for three popular brands from each of seven countries that did not have RIP legislation at the time of purchase. Results were compared with %FLB measurements from four popular US brands purchased in a jurisdiction (Vermont) with an RIP law. SRM 1082 reference cigarette was also tested to assure laboratory quality control. RESULTS: All cigarette brands purchased in countries not requiring fire safety standards for cigarettes exceeded 75% FLB. In contrast, none of the cigarette brands from the USA exceeded 10% FLB. The SRM 1082 reference cigarette demonstrated 5% FLB. CONCLUSION: Cigarette ignition propensity can be greatly reduced through legislation that requires cigarette fire safety standards. RIP cigarettes have the potential to significantly decrease the number of fire deaths, injuries and destruction of property caused by cigarette-ignited fires. Appropriate standards should be applied in cigarette markets globally. PMID- 20974624 TI - Multicentric Castleman's disease with abundant IgG4-positive cells: a clinical and pathological analysis of six cases. AB - BACKGROUND: Differentiation between multicentric Castleman's disease and systemic immunoglobulin (Ig) G4-related lymphadenopathy is sometimes difficult. It has been suggested that measurement of the IgG4-/IgG-positive cell ratio is useful for the differential diagnosis of the two diseases. However, the authors present a detailed report of six patients with multicentric Castleman's disease with abundant IgG4-positive cells (IgG4-/IgG-positive cell ratio, >40%). RESULTS: In the present series, the patients showed systemic lymphadenopathy, polyclonal hypergammaglobulinaemia and elevated serum interleukin-6 (IL-6) and C-reactive protein levels. Further, anaemia, hypoalbuminaemia, hypocholesterolaemia and thrombocytosis were observed. These findings were consistent with those of multicentric Castleman's disease. Although five patients showed elevated serum IgG4 levels, only two patients showed an increased serum IgG4/IgG ratio. However, the two patients showed highly elevated serum IgG4 levels, but the serum IgG4/IgG ratios were, although increased, not very high. Also, a patient with increased serum IgG4/IgG ratio showed a good response to antihuman IL-6 receptor monoclonal antibody (tocilizumab). Histologically, the germinal centres were mostly small and regressive, and frequently penetrated by hyalinised blood vessels, and there was no eosinophil infiltration. These findings were different from those of IgG4 related lymphadenopathy. CONCLUSIONS: The authors conclude that multicentric Castleman's disease sometimes occurs with abundant IgG4-positive cells and elevated serum IgG4 levels. Therefore, the two diseases cannot be differentially diagnosed by immunohistochemical staining alone. Laboratory findings, especially IL-6 level, C-reactive protein level and platelet count, are important for the differential diagnosis of the two diseases. PMID- 20974625 TI - Atypia in fine needle aspirates of breast lesions. PMID- 20974626 TI - Nucleic acid sequence-based amplification in formalin-fixed and paraffin-embedded breast-cancer tissues. AB - AIM: To evaluate the nucleic acid sequence-based amplification (NASBA) technique to amplify mRNA isolated from formalin-fixed and paraffin-embedded (FFPE) breast cancer tissues. METHODS: RNA was extracted from archived, 10-year-old FFPE tissues, and selected genes, namely ribosomal protein S18 (RPS18), epidermal growth factor receptor 2 (HER2), estrogen receptor alpha (ERalpha), Y box binding protein (YBX-1), matrix metallopeptidase 11 (MMP11), caspase 8 (CASP8) and superoxide dismutase 2 (SOD2), were amplified by NASBA. RESULTS: Despite strong degradation of the template, RNA amplification of all tested genes resulted in strong hybridisation signals. Sensitivity tests showed that the RPS18 NASBA assay was more sensitive than real-time RT-PCR used as a reference method. The sensitivity of the HER2, ERalpha, MMP11, YBX1, CASP8 and SOD2 NASBA assay was comparable with RT-PCR targeted to the respective genes. CONCLUSIONS: The results obtained indicate that NASBA is suitable to amplify with high specificity and sensitivity, even strongly degraded RNA isolated from FFPE tissues, and therefore can complement already-existing amplification techniques such as RT-PCR for analysis of such tissues. PMID- 20974627 TI - Short wavelength fundus autofluorescence versus near-infrared fundus autofluorescence, with microperimetric correspondence, in patients with geographic atrophy due to age-related macular degeneration. AB - AIM: To compare standard short-wavelength fundus autofluorescence (SW-FAF) and near infrared-wavelength fundus autofluorescence (NIR-FAF) in detecting geographic atrophy (GA) secondary to age-related macular degeneration, and its retinal sensitivity impairment. METHODS: Twenty-five consecutive patients (36 eyes) affected by GA were studied by means of fundus autofluorescence imaging, using both SW-FAF (excitation: 488 nm, emission >500 nm) and NIR-FAF (excitation: 787 nm, emission >800 nm). All patients underwent microperimetry to assess fixation characteristics and retinal sensitivity. RESULTS: In the extrafoveal region, the total hypoautofluorescent (hypo-FAF) area was significantly wider with NIR-FAF than with SW-FAF (8.03+/-6.68 mm(2) vs 7.37+/-6.34 mm(2) respectively; p=0.005). In the foveal area, the total hypo-FAF area was smaller with NIR-FAF than with SW-FAF (0.19+/-0.03 mm(2) versus 0.42+/-0.12 mm(2) respectively; p=0.008). Foveal sparing was larger at NIR-FAF compared with SW-FAF (p=0.021). In nine cases (25%) the site of fixation was hypoautofluorescent on SW FAF, but normal on NIR-FAF with preserved retinal sensitivity. CONCLUSIONS: Standard SW-FAF may overestimate GA in the foveal area, correctly detected by NIR FAF. In the extrafoveal area, SW-FAF may underestimate GA. Standard SW-FAF should be integrated with NIR FAF when detecting and following GA to avoid inconsistent results and misinterpretation, from both a morphological and functional perspective. Microperimetry helps to quantify retinal sensitivity in GA. PMID- 20974628 TI - A novel mutation of the TGFBI gene causing a lattice corneal dystrophy with deep stromal involvement. PMID- 20974629 TI - Novel mutation in PANK2 associated with retinal telangiectasis. PMID- 20974630 TI - Cochrane Eyes and Vision Group (CEVG). AB - This is a new column for reviews from the Cochrane Eyes and Vision Group (CEVG). Its main aim is to promote access to systematic reviews of all the interventions used to prevent or treat eye diseases. It is based at the London School of Hygiene & Tropical Medicine in London, UK, and Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, USA. PMID- 20974631 TI - Central macular thickness is correlated with gestational age at birth in prematurely born children. AB - BACKGROUND/AIM: Previous studies have revealed various subnormal visual functions in prematurely born children. The present study aimed to determine the retinal macular thickness in prematurely born children and compare with children born at term. METHODS: The eyes of 65 prematurely born children aged 5-16 years were examined with Stratus optical coherence tomography (OCT) 3, and the results were compared with those of 55 children born at term. The retinal macular thickness in the nine EDTRS macular areas (A1-A9), the foveal minimum and the total macular volume were determined. RESULTS: The central macular thickness (A1 and foveal minimum) was significantly thicker in the prematurely born children than in those born at term. There was no correlation between macular thickness and visual acuity or refraction. Children with previous retinopathy of prematurity (ROP) had significantly thicker central maculae than those without it. Prematurely born children without previous ROP had significantly thicker central maculae than the control group. Multiple regression analyses showed that gestational age at birth was the only risk factor for a thick central macula. CONCLUSION: Prematurely born children had thicker central maculae than those born at term. Regardless of ROP, the degree of prematurity was the most important risk factor for abnormal foveal development. PMID- 20974632 TI - Serum-free corneal organ culture medium (SFM) but not conventional minimal essential organ culture medium (MEM) protects human corneal endothelial cells from apoptotic and necrotic cell death. AB - AIM: To evaluate the influence of organ culture media on corneal endothelial cell survival. METHODS: The human corneal endothelial cell line HCEC-12 was cultured in five different media: human corneal endothelial cell (HCEC) growth medium (F99(HCEC)), standard minimal essential corneal organ culture medium (MEM)+2% fetal calf serum (FCS), MEM+5% FCS, and humanised, endothelial serum-free medium (SFM) (with and without antibiotics). A portion of the cells was treated with 0.5 MUmol/l staurosporine and examined for signs of apoptosis by assessing mitochondrial membrane polarisation state (intravital JC-1 staining), by YO-PRO-1 and propidium iodide staining, by determining fragmentation of nuclei by sub-G1 DNA content, by immunocytochemistry for cleaved caspase-3, cleaved caspase-8, Bcl2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2), and by western blotting for cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP). RESULTS: The number of apoptotic cells in untreated control cultures was significantly higher in MEM compared with F99(HCEC) and SFM. Staurosporine treatment induced apoptosis in all tested cultures to varying degrees. Cells cultured in MEM showed stronger staining for cleaved caspase-3, cleaved caspase 8, Bax, Bcl-2 and cleaved PARP, increased sub-G1 DNA content, more propidium iodide- and YO-PRO-1-positive cells, and more mitochondria with depolarised membranes. All parameters were significantly higher in MEM compared with F99(HCEC) and SFM. SFM cultures were significantly less susceptible to cell stress. CONCLUSION: SFM is superior to MEM in promoting HCEC survival. PMID- 20974633 TI - The transcriptional co-activator LEDGF/p75 displays a dynamic scan-and-lock mechanism for chromatin tethering. AB - Nearly all cellular and disease related functions of the transcriptional co activator lens epithelium-derived growth factor (LEDGF/p75) involve tethering of interaction partners to chromatin via its conserved integrase binding domain (IBD), but little is known about the mechanism of in vivo chromatin binding and tethering. In this work we studied LEDGF/p75 in real-time in living HeLa cells combining different quantitative fluorescence techniques: spot fluorescence recovery after photobleaching (sFRAP) and half-nucleus fluorescence recovery after photobleaching (hnFRAP), continuous photobleaching, fluorescence correlation spectroscopy (FCS) and an improved FCS method to study diffusion dependence of chromatin binding, tunable focus FCS. LEDGF/p75 moves about in nuclei of living cells in a chromatin hopping/scanning mode typical for transcription factors. The PWWP domain of LEDGF/p75 is necessary, but not sufficient for in vivo chromatin binding. After interaction with HIV-1 integrase via its IBD, a general protein-protein interaction motif, kinetics of LEDGF/p75 shift to 75-fold larger affinity for chromatin. The PWWP is crucial for locking the complex on chromatin. We propose a scan-and-lock model for LEDGF/p75, unifying paradoxical notions of transcriptional co-activation and lentiviral integration targeting. PMID- 20974634 TI - Phosphate binding sites identification in protein structures. AB - Nearly half of known protein structures interact with phosphate-containing ligands, such as nucleotides and other cofactors. Many methods have been developed for the identification of metal ions-binding sites and some for bigger ligands such as carbohydrates, but none is yet available for the prediction of phosphate-binding sites. Here we describe Pfinder, a method that predicts binding sites for phosphate groups, both in the form of ions or as parts of other non peptide ligands, in proteins of known structure. Pfinder uses the Query3D local structural comparison algorithm to scan a protein structure for the presence of a number of structural motifs identified for their ability to bind the phosphate chemical group. Pfinder has been tested on a data set of 52 proteins for which both the apo and holo forms were available. We obtained at least one correct prediction in 63% of the holo structures and in 62% of the apo. The ability of Pfinder to recognize a phosphate-binding site in unbound protein structures makes it an ideal tool for functional annotation and for complementing docking and drug design methods. The Pfinder program is available at http://pdbfun.uniroma2.it/pfinder. PMID- 20974635 TI - AmoebaDB and MicrosporidiaDB: functional genomic resources for Amoebozoa and Microsporidia species. AB - AmoebaDB (http://AmoebaDB.org) and MicrosporidiaDB (http://MicrosporidiaDB.org) are new functional genomic databases serving the amoebozoa and microsporidia research communities, respectively. AmoebaDB contains the genomes of three Entamoeba species (E. dispar, E. invadens and E. histolityca) and microarray expression data for E. histolytica. MicrosporidiaDB contains the genomes of Encephalitozoon cuniculi, E. intestinalis and E. bieneusi. The databases belong to the National Institute of Allergy and Infectious Diseases (NIAID) funded EuPathDB (http://EuPathDB.org) Bioinformatics Resource Center family of integrated databases and assume the same architectural and graphical design as other EuPathDB resources such as PlasmoDB and TriTrypDB. Importantly they utilize the graphical strategy builder that affords a database user the ability to ask complex multi-data-type questions with relative ease and versatility. Genomic scale data can be queried based on BLAST searches, annotation keywords and gene ID searches, GO terms, sequence motifs, protein characteristics, phylogenetic relationships and functional data such as transcript (microarray and EST evidence) and protein expression data. Search strategies can be saved within a user's profile for future retrieval and may also be shared with other researchers using a unique strategy web address. PMID- 20974636 TI - Inhibition of intrathyroidal dehalogenation by iodide. AB - Iodide is a trace element and a key component of thyroid hormones (TH). The availability of this halogen is the rate-limiting step for TH synthesis; therefore, thyroidal iodide uptake and recycling during TH synthesis are of major importance in maintaining an adequate supply. In the rat, the thyroid gland co expresses a distinctive pair of intrathyroidal deiodinating enzymes: the thyroid iodotyrosine dehalogenase (tDh) and the iodothyronine deiodinase type 1 (ID1). In the present work, we studied the activity of these two dehalogenases in conditions of hypo- and hyperthyroidism as well as during acute and chronic iodide administration in both intact and hypophysectomized (HPX) rats. In order to confirm our observations, we also measured the mRNA levels for both dehalogenases and for the sodium/iodide symporter, the protein responsible for thyroidal iodide uptake. Our results show that triiodothyronine differentially regulates tDh and ID1 enzymatic activities, and that both acute and chronic iodide administration significantly decreases rat tDh and ID1 activities and mRNA levels. Conversely, both enzymatic activities increase when intrathyroidal iodide is pharmacologically depleted in TSH-replaced HPX rats. These results show a regulatory effect by iodide on the intrathyroidal dehalogenating enzymes and suggest that they contribute to the iodide-induced autoregulatory processes involved in the Wolff-Chaikoff effect. PMID- 20974637 TI - Calmodulin and calmodulin-dependent protein kinase II inhibit hormone secretion in human parathyroid adenoma. AB - Intracellular calcium ([Ca(2+)](i)) is the most relevant modulator of parathyroid hormone (PTH) secretion. Uniquely, an increase in [Ca(2+)](i) results in an inhibition of PTH secretion, and it probably exerts its function via calcium binding protein pathways. The ubiquitous calcium-binding proteins, calmodulin and calmodulin-dependent protein kinase II (CaMKII), have well-established roles in regulated exocytosis in neurons and neuroendocrine cells. However, their roles in parathyroid cells and PTH secretion are still unclear. Using reverse transcription-PCR and western blot analysis, we have demonstrated the expression of calmodulin and CaMKII in human normal parathyroid and parathyroid chief cell adenomas. Blocking of calmodulin and CaMKII activity by the specific antagonists calmidazolium and KN-62 respectively caused a rise in PTH secretion from parathyroid adenoma cells in spite of increased [Ca(2+)](i). The inhibitory effect of Ca(2+) calmodulin on PTH secretion may be due to the absence of synaptotagmin 1 protein in parathyroid adenomas, as demonstrated by western blot analysis. An increased extracellular calcium level acutely lowered the amount of active phosphorylated CaMKII (pCaMKII) in adenoma cells in vitro, indicating the physiological importance of this pathway. Moreover, a negative correlation between the levels of pCaMKII in parathyroid adenomas and serum calcium was found in 20 patients with primary hyperparathyroidism. Taken together, these results show that calmodulin negatively contributes to the regulation of PTH secretion in parathyroid adenoma, at least partially via a CaMKII pathway. PMID- 20974638 TI - Brain natriuretic peptide is released from human astrocytoma cell line U373MG under hypoxia: a possible role in anti-apoptosis. AB - We have recently shown that the plasma brain-type natriuretic peptide (BNP) level is elevated in acute ischemic stroke patients, but the origin and role of BNP remain unclear. We investigated whether human astrocytes secrete BNP under hypoxia, and if so, what signaling pathway is involved, and what is the role of BNP. Human astrocytoma cell line U373MG was exposed to hypoxia by Anaeropack. BNP gene expression was increased by 3.9+/-2.5- and 6.5+/-2.9-fold at 12 and 24 h after hypoxia respectively (n=6, both P<0.05) and was associated with twofold increase in BNP protein at 24 h. BNP release in the culture media (pg/mg protein) was elevated from 1.8+/-1.8 under normoxia to 13.5+/-7.8 after 24-h hypoxia (n=9, P<0.01 versus normoxia). Western blot revealed the tyrosine415 phosphorylation of tyrosine kinase c-Src under hypoxia. Treatment of the cells with tyrosine kinase inhibitor PP1 abolished hypoxia-induced increase in BNP expression and release. In the cells exposed to hypoxia, caspase activity and apoptosis, measured by annexin-V-propidium iodide kit, were increased at 24 h compared with the cells under normoxia (n=5, both P<0.05). It was further increased in the cells transfected with siRNA for natriuretic peptide precursor B (n=6, both P<0.05) and reversed by administration of exogenous BNP (P<0.01). In conclusion, hypoxia increased BNP expression and release in human astrocytoma cell line U373MG through c-Src activation. BNP may play a pivotal role in anti-apoptosis of astrocytes under hypoxia. PMID- 20974639 TI - Tumorigenicity of MCF-7 human breast cancer cells lacking the p38alpha mitogen activated protein kinase. AB - We have generated cell lines with significantly reduced expression of the p38 mitogen-activated protein kinase (p38 MAPK), Min-p38 MAPK cells, and used these cells to investigate p38 MAPK's role in tumorigenesis of breast cancer cells. MCF 7 cells were stably transfected with a plasmid producing small interfering RNA that inhibited the expression of p38 MAPK. Control cells were stably transfected with the same plasmid producing non-interfering RNA. The reduction in the p38 MAPK activity caused a significant increase in the expressions of estrogen receptor-alpha (ERalpha) and the progesterone receptor, but eliminated the expression of ERbeta. Min-p38 MAPK cells showed an enhanced overall growth response to 17beta-estradiol (E2), whereas GH plus epidermal growth factor were largely ineffective growth stimulators in these cells compared to controls. Although the long-term net growth rate of the Min-p38 MAPK cells was increased in response to E2, their proliferation rate was lower compared to controls in short term cultures. However, the Min-p38 MAPK cells did show a significant decreased rate of apoptosis after E2 treatment and a reduction in the basal phosphorylation of p53 tumor suppressor protein compared to controls. When the Min-p38 MAPK cells were xenografted into E2-treated athymic nude mice, their tumorigenicity was enhanced compared to control cells. Increased tumorigenicity of Min-p38 MAPK cells was caused mainly by a decrease in the apoptosis rate indicating that the lack of the p38 MAPK caused an imbalance to increase the ERalpha:ERbeta ratio and a reduction in the activity of the p53 tumor suppressor protein. PMID- 20974641 TI - Growth-inhibiting conditions slow growth plate senescence. AB - The mammalian growth plate undergoes programmed senescence during juvenile life, causing skeletal growth to slow with age. We previously found that hypothyroidism in rats slowed both growth plate chondrocyte proliferation and growth plate senescence, suggesting that senescence is not dependent on age per se but rather on chondrocyte proliferation. However, one alternative explanation is that the observed slowing of growth plate senescence is a specific consequence of hypothyroidism. We reasoned that, if delayed senescence is a general consequence of growth inhibition, rather than a specific result of hypothyroidism, then senescence would also be slowed by other growth-inhibiting conditions. In this study, we therefore used tryptophan deficiency to temporarily inhibit growth in newborn rats for 4 weeks. We then allowed the animals to recover and studied the effects on growth plate senescence. We found that structural, functional, and molecular markers of growth plate senescence were delayed by prior tryptophan deficiency, indicating that the developmental program of senescence had occurred more slowly during the period of growth inhibition. Taken together with previous studies in hypothyroid rats, our findings support the hypothesis that delayed senescence is a general consequence of growth inhibition and hence that growth plate senescence is not simply a function of time per se but rather depends on growth. PMID- 20974642 TI - An 'endless struggle': a qualitative study of general practitioners' and practice nurses' experiences of managing multimorbidity in socio-economically deprived areas of Scotland. AB - OBJECTIVES: To understand general practitioners' (GPs) and practice nurses' (PNs) experiences of managing multimorbidity in deprived areas and elicit views on what might help. METHODS: Qualitative interviews with 19 GPs and PNs in four practices with a high percentage of patients living in the top 15% most deprived areas of Scotland. Data were analysed using constant comparison. RESULTS: Professionals' discussions of how they managed multimorbidity captured: (1) definitions of multimorbidity that included multiple social, psychological, and health problems associated with deprivation; (2) descriptions of the 'endless struggle' of patients trying to manage illnesses in the midst of chaotic lives with limited personal, social, and material resources; (3) accounts of the ongoing struggle of professionals trying to manage, with personal consequences for some; and (4) ideas on what might help, including 'whole person' approaches. DISCUSSION: Professionals' discussions of the difficulties that they face personally and attempt to help those most in need reflect both the continuing existence of the 'inverse care law' and the need for whole system changes to enhance the effectiveness of primary care for patients with multimorbidity in deprived areas. PMID- 20974640 TI - Interactions between IGF-I, estrogen receptor-alpha (ERalpha), and ERbeta in regulating growth/apoptosis of MCF-7 human breast cancer cells. AB - Understanding of the interactions between estradiol (E2) and IGF-I is still incomplete. Cell lines derived from the MCF-7 breast cancer cells were generated with suppressed expression of the IGF-I receptor (IGF-IR), termed IGF-IR.low cells, by stable transfection using small interfering RNA (siRNA) expression vector. Vector for control cells carried sequence generating noninterfering RNA. Concomitant with reduction in the IGF-IR levels, the IGF-IR.low cells also showed a reduction in estrogen receptor alpha (ERalpha) and progesterone receptor expressions, and an elevation in the expression of ERbeta. The number of the IGF IR.low cells was reduced in response to IGF-I and human GH plus epidermal growth factor, but E2 did not cause an increase in the number of the IGF-IR.low cells compared to controls. The proliferation rate of IGF-IR.low cells was only reduced in response to E2 compared to controls, whereas their basal and hormone stimulated apoptosis rate was increased. Phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) was increased in the IGF-IR.low cells after treatment with E2, without affecting control cells. Furthermore, phosphorylation of the tumor suppressor protein p53 was elevated in the IGF-IR.low cells compared to the controls. In conclusion, suppressing IGF-IR expression decreased the level of ERalpha but increased the level of ERbeta. Overall growth rate of the IGF-IR.low cells was reduced mostly through an increase in apoptosis without affecting proliferation substantially. We hypothesize that a decreased ERalpha:ERbeta ratio triggered a rapid phosphorylation of p38 MAPK, which in turn phosphorylated the p53 tumor suppressor and accelerated apoptosis rate. PMID- 20974643 TI - A novel deletion in the RCA gene cluster causes atypical hemolytic uremic syndrome. AB - Atypical hemolytic uremic syndrome (aHUS) is a complex complement-mediated disease that progresses to end-stage renal failure (ESRF) in 50% of cases. Dysregulation of the alternative pathway (AP) of the complement cascade manifests as microangiopathic anaemia and thrombocytopenia. Multiple genes in the AP have been implicated in disease pathogenesis. Here, we report the clinical presentation of an affected patient that was inconsistent with genotype-phenotype data for carriers of CD46 mutations. Tests of AP function in this patient suggested additional genetic factors, and in-depth studies revealed a de novo heterozygous deletion that creates a novel CFH/CFHR1 fusion protein. PMID- 20974644 TI - Impaired renal function modifies the risk of severe hypoglycaemia among users of insulin but not glyburide: a population-based nested case-control study. AB - BACKGROUND: Little evidence justifies the avoidance of glyburide in patients with impaired renal function. We aimed to determine if renal function modifies the risk of hypoglycaemia among patients using glyburide. METHODS: We conducted a nested case-control study using administrative records and laboratory data from Ontario, Canada. We included outpatients 66 years of age and older with diabetes mellitus and prescriptions for glyburide, insulin or metformin. We ascertained hypoglycaemic events using administrative records and estimated glomerular filtration rates (eGFR) using serum creatinine concentrations. RESULTS: From a cohort of 19,620 patients, we identified 204 cases whose eGFR was >= 60 mL/min/1.73 m(2) (normal renal function) and 354 cases whose eGFR was < 60 mL/min/1.73 m(2) (impaired renal function). Compared to metformin, glyburide is associated with a greater risk of hypoglycaemia in patients with both normal [adjusted odds ratio (OR) 9.0, 95% confidence interval (95% CI) 4.9-16.4] and impaired renal function (adjusted OR 6.0, 95% CI 3.8-9.5). We observed a similar relationship when comparing insulin to metformin; the risk was greater in patients with normal renal function (adjusted OR 18.7, 95% CI 10.5-33.5) compared to those with impaired renal function (adjusted OR 7.9, 95% CI 5.0-12.4). Tests of interaction showed that among glyburide users, renal function did not significantly modify the risk of hypoglycaemia, but among insulin users, impaired renal function is associated with a lower risk. CONCLUSIONS: In this population based study, impaired renal function did not augment the risk of hypoglycaemia associated with glyburide use. PMID- 20974646 TI - The jaw jerk: an instance of misattribution. PMID- 20974645 TI - An open-label, randomized clinical trial assessing immunogenicity, safety and tolerability of pandemic influenza A/H1N1 MF59-adjuvanted vaccine administered sequentially or simultaneously with seasonal virosomal-adjuvanted influenza vaccine to paediatric kidney transplant recipients. AB - BACKGROUND: The aim of this study was to investigate the immunogenicity, safety and tolerability of the 2009 A/H1N1 MF59-adjuvanted influenza vaccine, administered sequentially or simultaneously with the seasonal 2009-10 virosomal adjuvanted influenza vaccine, to paediatric kidney transplant recipients. METHODS: Thirty-two children and adolescents with transplanted kidneys and 32 age and gender-matched healthy controls were randomized 1:1 to receive the pandemic vaccine upon enrolment and the seasonal vaccine 1 month later (16 transplant recipients and 16 healthy controls), or to receive the two vaccines simultaneously upon enrolment (16 transplant recipients and 16 healthy controls). RESULTS: When the pandemic vaccine was administered sequentially to the seasonal vaccine, it was significantly less immunogenic in the patients than in the controls (P < 0.05); when it was administered together with the seasonal vaccine, the immune response of both patients (P < 0.05) and controls (P < 0.05) was significantly greater than when it was administered sequentially. Seroconversion rates and the geometric mean titres of all of the seasonal antigens were significantly lower in the patients, regardless of the type of vaccine administration (P < 0.05). Simultaneous administration was associated with a better immune response against A/H1N1 and A/H3N2 antigens in both patients and controls, and did not increase the mild local and systemic reactions. No impact on renal function was observed. CONCLUSIONS: Paediatric kidney transplant recipients have a lower immune response to the pandemic influenza A/H1N1 MF59 adjuvanted and seasonal virosomal-adjuvanted influenza vaccines than healthy controls. The simultaneous administration of the two vaccines seems to increase immune response to both pandemic and seasonal A/H1N1 and A/H3N2 antigens, and has the same safety profile as that of the pandemic vaccine administered sequentially to the seasonal vaccine. PMID- 20974647 TI - Long-term follow-up of pallidal deep brain stimulation in two cases of Huntington's disease. AB - BACKGROUND: Deep brain stimulator (DBS) implantation has been shown to be effective in the treatment of various movement disorders including Parkinson's disease, essential tremor and dystonia. However, there is limited information regarding the potential use of DBS in Huntington's disease (HD). In this study, the authors present their findings on the long-term motor and neurocognitive results of two HD patients (patient 1: 57 years, 42 cytosine-adenine guanine (CAG) repeats; patient 2: 50 years, 41 CAG repeats) who underwent staged bilateral globus pallidus interna DBS surgery. METHODS: The patients were evaluated at baseline and at five timepoints throughout a 2-year postoperative during which motoric ratings ((Unified Huntington's Disease Rating Scale), Activities of Daily Living scores (HD-ADL) and neurocognitive testing) were obtained. RESULTS: Both patients had a sustained decline in chorea 2 years after initial DBS surgery. Despite this improvement in chorea, one patient has had continuing deterioration in gait, bradykinesia and dystonia scores, which has caused his ability to perform activities of daily living to return to his baseline level of functioning prior to DBS surgery. Both patients have experienced further gradual decline in neurocognitive functioning, which appears to be independent of DBS and most likely related to disease progression. CONCLUSION: DBS implantation may be a potential treatment option for a subset of HD patients who have significant functional deficits due to chorea. However, appropriate selection of the best candidates for DBS appears to be challenging, given the difficulty in predicting disease course in HD due to its variable nature. PMID- 20974648 TI - Complementary roles of grey matter MTR and T2 lesions in predicting progression in early PPMS. AB - OBJECTIVE: To investigate whether T2 lesion load and magnetisation transfer ratio (MTR) in the normal-appearing white matter (NAWM) and grey matter (GM) at study entry are independent predictors of progression and whether their changes correlate with the accrual of disability, over 5 years in early primary progressive multiple sclerosis (PPMS). METHODS: Forty-seven patients with early PPMS and 18 healthy controls were recruited at baseline and invited to attend clinical 6-monthly assessments for 3 years, and after 5 years. Patients were scored on the Expanded Disability Status Scale and multiple sclerosis functional composite subtests (25-foot timed walk test (TWT), nine-hole peg test and paced auditory serial addition test). At each time point, all subjects underwent brain MRI including T2-weighted, magnetisation transfer and volumetric sequences. T2 lesion load (T2LL), MTR histogram parameters and volumes for NAWM and GM were calculated. Statistical analyses identified predictors of progression and correlations between MRI changes and clinical changes over time. RESULTS: Baseline T2LL and GM peak location and peak height MTR were independent predictors of progression, as measured by TWT; a model including these three predictors explained 91% of the variance of the progression on TWT, a significantly higher percentage than that obtained when the predictors were modelled individually (80%, 74% and 68%, respectively). A greater progression rate correlated with a steeper increase in T2LL and a faster decline in GM mean and peak location MTR. CONCLUSIONS: The combined assessment of both visible white matter damage and GM involvement is useful in predicting progression in PPMS. PMID- 20974649 TI - Incidence of aetiological subtypes of stroke in a multi-ethnic population based study: the South London Stroke Register. AB - BACKGROUND: Stroke risk is higher in black ethnic groups compared with white. Although risk factors for stroke are known to differ between these populations, few population studies have reported on the risk of aetiological stroke subtypes in black ethnic populations. METHODS: Ethnic group differences in incidence of first ever ischaemic stroke by aetiological subtype were investigated with the South London Stroke Register (SLSR). The SLSR is a population based stroke register covering a multi-ethnic inner city population of 271,871 inhabitants comprising 63% white, 28% black and 9% other ethnic group. A modified pathophysiological Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification of stroke was used to estimate patterns of aetiological subtype and stroke was subtyped into large artery atherosclerosis (LAA), cardioembolism (CE), small vessel occlusion (SVO), other aetiology (OTH), undetermined (UND) and multiple possible or concurrent aetiologies (CONC). RESULTS: Between September 1999 and August 2006, 1181 patients with first ever ischaemic stroke were included in the study. Mean age was 71.4 years, 51% were female and 71% were white patients, 20% were black patients, 6% were other and 3% were of unknown ethnic group. The distribution of the aetiological subtypes was as follows: LAA, 109 (9.3%); CE, 325 (27.8%); SVO, 316 (27.0%); OTH, 40 (3.4%); UND, 283 (24.2%) and CONC, 96 (8.2%). The annual age adjusted incidence rate per 100,000 was for total ischaemic stroke 101.2 (95% CI 82.4 to 122.9) in men and 75.1 (95% CI 59.1 to 94.1) in women; for LAA 10.4 (95% CI 5.1 to 18.9) in men and 6.8 (95% CI 2.7 to 14.2) in women; for CE 23.0 (95% CI 14.6 to 34.5) in men and 21.5 (95% CI 13.4 to 32.8) in women; and for SVO 30.3 (95% CI 20.5 to 43.2) in men and 20.3 (95% CI 12.5 to 31.3) in women. The overall incidence rate ratio (IRR) for black patients was 1.25 (1.07 to 1.46), for black Caribbean (BC) patients 1.31 (1.09 to 1.58), for black African (BA) patients 1.22 (0.93 to 1.61) and for other ethnic groups 1.24 (0.96 to 1.61). IRRs for black ethnic groups as well as for BA and BC were significantly higher for SVO in both sexes, for OTH in black patients for females and in BA for males and females compared with the white ethnic group; IRRs for other ethnic groups compared with white patients were higher for SVO in females and for UND in males. INTERPRETATION: Independent important differences in risk of stroke between different ethnic populations strengthen the evidence base for studying genetic susceptibility and environmental influences in ethnic groups separately. PMID- 20974650 TI - Neurophysiology of Alzheimer's disease: towards understanding the relationship between the EEG phenotype and onset of Alzheimer's disease. PMID- 20974651 TI - Association between genetic variation on chromosome 9p21 and aneurysmal subarachnoid haemorrhage. AB - BACKGROUND AND AIM: Genetic factors play a role in susceptibility to subarachnoid haemorrhage, but little is known about which genes are involved. Recently, genome wide association studies have identified the 9p21 region as a risk locus for intracranial aneurysms (IA). The aim of the present study was to examine the possible association between 9p21 and ruptured IA--that is, aneurysmal subarachnoid haemorrhage (aSAH)--in a Swedish population. There is one study showing an association between 9p21 and arterial stiffness, and arterial stiffness plays a role in the development of hypertension. Therefore, a second aim was to investigate whether a putative association is independent of hypertension. METHODS: The study comprised 183 patients presenting with aSAH to the Neurointensive Care Unit at Sahlgrenska University Hospital and 366 healthy, age and sex matched population based controls. As the causative functional variant in the region has not yet been identified, a 44 kbp region on 9p21 was tagged using HapMap. Six single nucleotide polymorphism (SNPs) were genotyped. RESULTS: Two SNPs, rs10757278 and rs1333045, showed significant associations with aSAH in univariate analyses. After adjustment for hypertension as well as for smoking, the association between aSAH and rs10757278 remained significant with an OR for aSAH of 1.42 (95% CI 1.08 to 1.87; p=0.01) for the uncommon G allele. CONCLUSIONS: These data confirm earlier results showing that 9p21 is a susceptibility locus for IA, and that this association is present in a Swedish sample restricted to ruptured IA. For the first time, it has been demonstrated that this association is independent of hypertension. PMID- 20974652 TI - Population attributable fraction of infection-related cancers in Korea. AB - BACKGROUND: A number of infectious agents have been classified as human carcinogens. The purpose of the current study was to provide an evidence-based assessment of the burden of infection-related cancers in the Korean population. MATERIALS AND METHODS: The population attributable fraction was calculated using infection prevalence data from 1990 or earlier, relative risk estimates from meta analyses using mainly Korean studies and national data on cancer incidence and mortality for the year 2007. RESULTS: The fractions of all cancers attributable to infection were 25.1% and 16.8% for cancer incidence in men and women, and 25.8% and 22.7% of cancer mortality in men and women, respectively. Among infection-related cancers, Helicobacter pylori was responsible for 56.5% of cases and 45.1% of deaths, followed by hepatitis B virus (HBV) (23.9% of cases and 37.5% of deaths) and human papillomavirus (HPV) (11.3% of cases and 6% of deaths) and then by hepatitis C virus (HCV) (6% of cases and 9% of deaths). Over 97% of infection-related cancers were attributable to infection with H. pylori, HBV, HCV and HPV. CONCLUSION: Up to one-quarter of cancer cases and deaths would be preventable through appropriate control of infectious agents in Korea. PMID- 20974653 TI - Efficacy of communication skills training courses in oncology: a systematic review and meta-analysis. AB - OBJECTIVE: Group training in communication skills [communication skills training (CST)] has become partly mandatory for oncology staff. However, so far, a comprehensive meta-analysis on the efficacy is lacking. DESIGN: Included studies either compare the efficacy of a specific training with a control group or look at the additional effect of booster sessions on communication behaviour, attitudes or patient outcomes. METHODS: Four electronic databases were searched up to July 2008 without language restriction, and reference lists of earlier reviews were screened. Effect sizes (ESs) were extracted and pooled in random effects meta-analyses. RESULTS: We included 13 trials (three non-randomised), 10 with no specific intervention in the control group. Meta-analysis showed a moderate effect of CST on communication behaviour ES = 0.54. Three trials compared basic training courses with more extensive training courses and showed a small additional effect on communication skills ES = 0.37. Trials investigating participants' attitudes ES = 0.35 and patient outcomes ES = 0.13 (trend) confirmed this effect. CONCLUSIONS: Training health professionals by CST is a promising approach to change communication behaviour and attitudes. Patients might also benefit from specifically trained health professionals but strong studies are lacking. However, feasibility and economic aspects have to be kept in mind when considering providing a training of optimal length. PMID- 20974654 TI - The influence of socio-demographic characteristics on consultation for back pain- a review of the literature. AB - BACKGROUND: There are several assumptions within clinical practice about who is more or less likely to consult a health care practitioner for particular symptoms, most commonly these focus around socio-demographic characteristics. We aimed to assess the evidence for the impact of socio-demographic characteristics on consultation for back pain. METHODS: We conducted a review of the literature, using systematic methods, on consultation for back pain. Using systematic searching techniques we identified peer-reviewed publications that focused on health care consultation in response to symptoms of back pain and which included data on both users and non-users of health care. RESULTS: We identified 23 studies. Definitions of help-seeking were inconsistent across studies. The majority of the 15 studies which considered the relationship between age and help seeking for back pain did not find evidence of an association between these two factors. Seventeen studies considered whether socio-economic position was associated with help-seeking. The evidence largely supported the conclusion of no association (13 papers). Fifteen studies included gender as a variable in their analyses, and the majority (10 papers) presented the finding of no association. CONCLUSIONS: The results from this review suggest that there is little evidence to support the common wisdom that socio-demographic characteristics impact on help-seeking in the context of back pain. As these assumptions relating to who is more or less likely to consult will ultimately affect patient care, it is important that they do not go unchallenged. PMID- 20974655 TI - Losartan potassium/hydrochlorothiazide (Preminent(r)) and hyponatremia: case series of 40 patients. AB - The clinical course of losartan potassium/hydrochlorothiazide (Preminent((r))) induced hyponatremia has not been described. We summarized 40 patients with Preminent-induced hyponatremia. The study involved 15 (37.5%) men and 25 (62.5%) women (mean age [SD], 76.4 [8.3] years; range, 55-95). Their sodium levels before Preminent administration were 139.5 (4.9) mEq/L (range, 131-145; reference range, 135-147). The duration from the day of Preminent administration to the day with the lowest sodium level was 59.3 (64.9) days (range, 2-207; median, 24). Most patients for whom this duration was <50 days exhibited progressive symptoms, whereas most of those for whom this duration was >50 days did not exhibit progressive symptoms but exhibited symptoms after fever or appetite loss. The lowest sodium value was 114.4 (8.2) mEq/L (range, 99-133). The duration from the time of Preminent discontinuation to (1) the time of early recovery and (2) the time of final recovery was 6.8 (5.5) days (range, 1-20; median, 5) and 11.6 (7.6) days (range, 2-29; median, 7.5), respectively. Of the 40 patients, 36 (90.0%) achieved full recovery, 1 (2.5%) suffered from after-effects due to central pontine myelinolysis, 1 (2.5%) died, and 2 (5.0%) were unknown. In the analysis of other adverse effects of Preminent and the same adverse effects of other three angiotensin II receptor blocker (ARB)/thiazide combinations, hyponatremia was observed as a primary adverse effect of all ARB/thiazide combinations. However, hyperesthesia dermatitis was reported as an adverse effect of Preminent only. PMID- 20974656 TI - Expressions of BAFF/BAFF receptors and their correlation with disease activity in Chinese SLE patients. AB - B-cell activating factor belonging to tumour necrosis factor family (BAFF) is essential for B-cell survival and function through interaction with its receptors BAFF receptor 3 (BR3), B-cell maturation antigen (BCMA) and/or transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), though BCMA and/or TACI can also bind to a proliferation-inducing ligand (APRIL). We evaluate the correlation of the expressions of these ligands/receptors with different clinical manifestations of systemic lupus erythematosus (SLE). Levels of BAFF and APRIL in plasma from 73 SLE patients were determined by enzyme-linked immunosorbent assay. Expressions of BR3, TACI and BCMA on CD19+ B cells were detected by flow cytometry. Clinical data were collected and disease activity was evaluated using SLEDAI-2000. SLE patients had elevated BAFF and APRIL levels in their plasma. BAFF levels correlated positively with SLEDAI while negatively with the BR3 protein expression on CD19+ B cells (p < .05). The detected BR3 protein expression in SLE patients was reduced on CD19+IgD+CD27-, CD19+IgD+CD27+ as well as CD19+IgD-CD27+ B cells compared to the counterparts of healthy controls (p < .001), whereas SLE patients did not differ from healthy controls in BR3 mRNA levels. In untreated new-onset patients, the expression rate of BR3 on CD19+ B cells correlated negatively with SLEDAI (p < .05). Elevation of BAFF and reduction of BR3 on CD19+ B cells were more obvious in those with lupus nephritis (LN, p < .05). TACI expression on CD19+ B cells was up-regulated only in those subjects with LN (p < .05). Elevated plasma BAFF and reduced BR3 protein expression on peripheral B cells could act as biomarkers for active disease in SLE patients. High expression of TACI may indicate the occurrence of LN. PMID- 20974657 TI - Regression-based estimates of observed functional status in centenarians. AB - PURPOSE OF THE STUDY: There is lack of consensus on the best method of functional assessment, and there is a paucity of studies on daily functioning in centenarians. We sought to compare associations between performance-based, self report, and proxy report of functional status in centenarians. We expected the strongest relationships between proxy reports and observed performance of basic activities of daily living (BADLs) and instrumental activities of daily living (IADLs). We hypothesized that the discrepancy between self-report and observed daily functioning would be modified by cognitive status. We additionally sought to provide clinicians with estimates of centenarians' observed daily functioning based on their mental status in combination with subjective measures of activities of daily living (ADLs). DESIGN AND METHODS: Two hundred and forty-four centenarians from the Georgia Centenarian Study were included in this cross sectional population-based study. Measures included the Direct Assessment of Functional Status, self-report and proxy report of functional status, and the Mini-Mental State Examination (MMSE). RESULTS: Associations between observed and proxy reports were stronger than between observed and self-report across BADL and IADL measures. A significant MMSE by type of report interaction was found, indicating that lower MMSE performance is associated with a greater discrepancy between subjective and objective ADL measures. IMPLICATIONS: Results demonstrate associations between 3 methods of assessing functional status and suggest proxy reports are generally more accurate than self-report measures. Cognitive status accounted for some of the discrepancy between observed and self-reports, and we provide clinicians with tables to estimate centenarians' performance on observed functional measures based on MMSE and subjective report of functional status. PMID- 20974658 TI - Russia cracks down on tobacco advertising and smoking in public places. PMID- 20974660 TI - German MPs are to vote on allowing preimplantation genetic diagnosis. PMID- 20974661 TI - Managing diabetic retinopathy. PMID- 20974663 TI - Doctors continue fight for David Kelly inquest despite release of autopsy report. PMID- 20974666 TI - An overview of robust methods in medical research. AB - Robust statistics is an extension of classical parametric statistics that specifically takes into account the fact that the assumed parametric models used by the researchers are only approximate. In this article, we review and outline how robust inferential procedures may routinely be applied in practice in the biomedical research. Numerical illustrations are given for the t-test, regression models, logistic regression, survival analysis and ROC curves, showing that robust methods are often more appropriate than standard procedures. PMID- 20974667 TI - Covariate-adjusted response-adaptive designs for longitudinal treatment responses: PEMF trial revisited. AB - Response-adaptive designs have become popular for allocation of the entering patients among two or more competing treatments in a phase III clinical trial. Although there are a lot of designs for binary treatment responses, the number of designs involving covariates is very small. Sometimes the patients give repeated responses. The only available response-adaptive allocation design for repeated binary responses is the urn design by Biswas and Dewanji [Biswas A and Dewanji AA. Randomized longitudinal play-the-winner design for repeated binary data. ANZJS 2004; 46: 675-684; Biswas A and Dewanji A. Inference for a RPW-type clinical trial with repeated monitoring for the treatment of rheumatoid arthritis. Biometr J 2004; 46: 769-779.], although it does not take care of the covariates of the patients in the allocation design. In this article, a covariate adjusted response-adaptive randomisation procedure is developed using the log odds ratio within the Bayesian framework for longitudinal binary responses. The small sample performance of the proposed allocation procedure is assessed through a simulation study. The proposed procedure is illustrated using some real data set. PMID- 20974668 TI - Lipocalin 2 is a selective modulator of peroxisome proliferator-activated receptor-gamma activation and function in lipid homeostasis and energy expenditure. AB - We have previously identified lipocalin 2 (Lcn2) as a cytokine playing a critical role in the regulation of body fat mass, lipid metabolism, and insulin resistance. Lcn2 deficiency reduces PPARgamma gene expression in adipocytes. In this study, we investigated the role of Lcn2 in PPARgamma activation and function via assessing the insulin sensitization and fatty acid (FA) homeostasis of PPARgamma agonist in high-fat diet (HFD)-induced obesity in Lcn2(-/-) mice. We found that rosiglitazone (Rosi) significantly improved insulin sensitivity in Lcn2(-/-) mice as effectively as in wild-type (WT) mice; unfed-state levels of blood glucose, free FAs, and triglycerides (TGs) were significantly reduced after a 25-d treatment of Rosi in Lcn2(-/-) mice. However, Rosi action on fat deposition and FA homeostasis was altered; Rosi-induced body weight and subcutaneous fat gain and liver lipid accumulation were markedly lessened in Lcn2(-/-) mice. The results of in vivo metabolic labeling showed that Rosi markedly reduced de novo lipogenesis in adipose tissue of Lcn2(-/-) mice. In brown adipose tissue (BAT), the expression of the genes functioning in TG hydrolysis and mitochondrial oxidation was up-regulated more in Lcn2(-/-) than in WT mice. Most strikingly, Rosi stimulated significantly higher levels of uncoupling protein-1 expression in BAT, and completely rescued cold intolerance in Lcn2(-/-) mice. We demonstrate that Lcn2 is a critical selective modulator of PPARgamma activation and function in lipid homeostasis and energy expenditure. PMID- 20974669 TI - Expression of GIV/Girdin, a metastasis-related protein, predicts patient survival in colon cancer. AB - Metastasis accounts for the majority of cancer-related deaths. Accurate prediction of metastatic potential of tumors has been elusive, and the search for clinically useful markers continues. We previously reported that GIV/Girdin triggers tumor cell migration by virtue of a C-terminal guanine-nucleotide exchange factor motif that activates Galphai. Here we identify GIV as a metastasis-related protein whose full-length transcript (GIV-fl) is expressed exclusively in highly invasive colon, breast, and pancreatic carcinoma cells and not in their poorly invasive counterparts. A prospective, exploratory biomarker study conducted on a cohort of 56 patients with stage II colorectal cancer revealed a significant correlation between GIV-fl expression in tumor epithelium and shortened metastasis-free survival. Survival rate for patients with GIV-fl positive tumors is significantly reduced compared with the patients with GIV-fl negative tumors [P<0.0001; hazard ratio=0.076; CI=0.052-0.30 (95%)]. At the 5-yr mark, survival is 100% in the GIV-fl-negative group and 62 +/- 9% (mean+/-SE; P=6*10(-5)) in the GIV-fl-positive group. Furthermore, GIV-fl expression predicts a risk of mortality independent of the microsatellite stability status, a well established prognosticator of colorectal cancers. We conclude that GIV-fl is a novel metastasis-related protein and an independent adverse prognosticator that may serve as a useful adjunct to traditional staging strategies in colorectal carcinoma. PMID- 20974670 TI - Reactive glial cells: increased stiffness correlates with increased intermediate filament expression. AB - Increased stiffness of reactive glial cells may impede neurite growth and contribute to the poor regenerative capabilities of the mammalian central nervous system. We induced reactive gliosis in rodent retina by ischemia-reperfusion and assessed intermediate filament (IF) expression and the viscoelastic properties of dissociated single glial cells in wild-type mice, mice lacking glial fibrillary acidic protein and vimentin (GFAP(-/-)Vim(-/-)) in which glial cells are consequently devoid of IFs, and normal Long-Evans rats. In response to ischemia reperfusion, glial cells stiffened significantly in wild-type mice and rats but were unchanged in GFAP(-/-)Vim(-/-) mice. Cell stiffness (elastic modulus) correlated with the density of IFs. These results support the hypothesis that rigid glial scars impair nerve regeneration and that IFs are important determinants of cellular viscoelasticity in reactive glia. Thus, therapeutic suppression of IF up-regulation in reactive glial cells may facilitate neuroregeneration. PMID- 20974671 TI - The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. AB - The multiple myeloma SET domain (MMSET) protein is overexpressed in multiple myeloma (MM) patients with the translocation t(4;14). Although studies have shown the involvement of MMSET/Wolf-Hirschhorn syndrome candidate 1 in development, its mode of action in the pathogenesis of MM is largely unknown. We found that MMSET is a major regulator of chromatin structure and transcription in t(4;14) MM cells. High levels of MMSET correlate with an increase in lysine 36 methylation of histone H3 and a decrease in lysine 27 methylation across the genome, leading to a more open structural state of the chromatin. Loss of MMSET expression alters adhesion properties, suppresses growth, and induces apoptosis in MM cells. Consequently, genes affected by high levels of MMSET are implicated in the p53 pathway, cell cycle regulation, and integrin signaling. Regulation of many of these genes required functional histone methyl-transferase activity of MMSET. These results implicate MMSET as a major epigenetic regulator in t(4;14)+ MM. PMID- 20974672 TI - Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity. AB - The granule enzyme myeloperoxidase (MPO) plays an important role in neutrophil antimicrobial responses. However, the severity of immunodeficiency in patients carrying mutations in MPO is variable. Serious microbial infections, especially with Candida species, have been observed in a subset of completely MPO-deficient patients. Here we show that neutrophils from donors who are completely deficient in MPO fail to form neutrophil extracellular traps (NETs), indicating that MPO is required for NET formation. In contrast, neutrophils from partially MPO-deficient donors make NETs, and pharmacological inhibition of MPO only delays and reduces NET formation. Extracellular products of MPO do not rescue NET formation, suggesting that MPO acts cell-autonomously. Finally, NET-dependent inhibition of Candida albicans growth is compromised in MPO-deficient neutrophils. The inability to form NETs may contribute in part to the host defense defects observed in completely MPO-deficient individuals. PMID- 20974673 TI - Hoxa3 promotes the differentiation of hematopoietic progenitor cells into proangiogenic Gr-1+CD11b+ myeloid cells. AB - Injury induces the recruitment of bone marrow-derived cells (BMDCs) that contribute to the repair and regeneration process. The behavior of BMDCs in injured tissue has a profound effect on repair, but the regulation of BMDC behavior is poorly understood. Aberrant recruitment/retention of these cells in wounds of diabetic patients and animal models is associated with chronic inflammation and impaired healing. BMD Gr-1(+)CD11b(+) cells function as immune suppressor cells and contribute significantly to tumor-induced neovascularization. Here we report that Gr-1(+)CD11b(+) cells also contribute to injury-induced neovascularization, but show altered recruitment/retention kinetics in the diabetic environment. Moreover, diabetic-derived Gr-1(+)CD11b(+) cells fail to stimulate neovascularization in vivo and have aberrant proliferative, chemotaxis, adhesion, and differentiation potential. Previously we demonstrated that gene transfer of HOXA3 to wounds of diabetic mice is taken up by and expressed by recruited BMDCs. This is associated with a suppressed inflammatory response, enhanced neovascularization, and accelerated wound healing. Here we show that sustained expression of Hoxa3 in diabetic-derived BMD Gr-1(+)CD11b(+) cells reverses their diabetic phenotype. These findings demonstrate that manipulation of adult stem/progenitor cells ex vivo could be used as a potential therapy in patients with impaired wound healing. PMID- 20974674 TI - American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. AB - PURPOSE: To update American Society of Hematology/American Society of Clinical Oncology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. METHODS: An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. RESULTS: The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. RECOMMENDATIONS: For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels >= 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations. PMID- 20974675 TI - Understanding potential exposure sources of perfluorinated carboxylic acids in the workplace. AB - This paper integrates perspectives from analytical chemistry, environmental engineering, and industrial hygiene to better understand how workers may be exposed to perfluorinated carboxylic acids when handling them in the workplace in order to identify appropriate exposure controls. Due to the dramatic difference in physical properties of the protonated acid form and the anionic form, this family of chemicals provides unique industrial hygiene challenges. Workplace monitoring, experimental data, and modeling results were used to ascertain the most probable workplace exposure sources and transport mechanisms for perfluorooctanoic acid (PFOA) and its ammonium salt (APFO). PFOA is biopersistent and its measurement in the blood has been used to assess human exposure since it integrates exposure from all routes of entry. Monitoring suggests that inhalation of airborne material may be an important exposure route. Transport studies indicated that, under low pH conditions, PFOA, the undissociated (acid) species, actively partitions from water into air. In addition, solid-phase PFOA and APFO may also sublime into the air. Modeling studies determined that contributions from surface sublimation and loss from low pH aqueous solutions can be significant potential sources of workplace exposure. These findings suggest that keeping surfaces clean, preventing accumulation of material in unventilated areas, removing solids from waste trenches and sumps, and maintaining neutral pH in sumps can lower workplace exposures. PMID- 20974676 TI - Hydration status of South African forestry workers harvesting trees in autumn and winter. AB - OBJECTIVES: To determine both the prevalence and severity of dehydration of forestry workers harvesting trees in autumn and winter. METHODS: Two cross sectional observational studies were conducted on convenience samples of 103 and 79 workers in autumn and winter, respectively. The prevalence of dehydration pre- and post-shift was determined using urine specific gravity (U(SG)), and the severity of dehydration by the percent loss of body weight across the shift. RESULTS: Pre-shift, 43% in autumn and 47% in winter were dehydrated (U(SG) > 1.020 g ml(-1)) on arrival at work. There was a significant increase (P <= 0.001) in the prevalence of dehydration post-shift as 64% (P <= 0.001) in autumn and 63% (P = 0.043) in winter were dehydrated. In each area, +/-22% had dehydrated by >=2% loss of body weight. Pre-shift, 23% in autumn and 13% in winter were overhydrated (U(SG) < 1.013 g ml-1). Post-shift, 4% in autumn and 2% in winter were overhydrated. An excessive consumption of hypotonic fluid (water) in combination with a reduced salt intake to prevent hypertension exposed an important minority to the risk of potentially fatal dilutional hyponatremia. Neither dehydration nor hyperhydration was related to season, gender, or job category. CONCLUSIONS: During average shifts, the South African forestry workers, regardless of season, gender, or job category, experienced dehydration of a magnitude that compromised both their safety and productivity. PMID- 20974677 TI - Methods for clustered encouragement design studies with noncompliance and missing data. AB - Encouragement design studies are particularly useful for estimating the effect of an intervention that cannot itself be randomly administered to some and not to others. They require a randomly selected group receive extra encouragement to undertake the treatment of interest, where the encouragement typically takes the form of additional information or incentives. We consider a "clustered encouragement design" (CED), where the randomization is at the level of the clusters (e.g. physicians), but the compliance with assignment is at the level of the units (e.g. patients) within clusters. Noncompliance and missing data are particular problems in encouragement design studies, where encouragement to take the treatment, rather than the treatment itself, is randomized. The motivating study looks at whether computer-based care suggestions can improve patient outcomes in veterans with chronic heart failure. Since physician adherence has been inadequate, the original study focused on methods to improve physician adherence, although an equally important question is whether physician adherence improves patient outcomes. Here, we reanalyze the data to determine the effect of physician adherence on patient outcomes. We propose causal inference methodology for the effect of a treatment versus a control in a randomized CED study with all or-none compliance at the unit level. These methods extend the current approaches to account for nonignorable missing data and use an alternative approach to inference using multiple imputation methods, which have been successfully applied to a wide variety of missing data problems and have recently been applied to the potential outcomes framework of causal inference (Taylor and Zhou, 2009b). PMID- 20974678 TI - A phase II clinical trial of topotecan in Japanese patients with relapsed ovarian carcinoma. AB - OBJECTIVE: This Phase II study was carried out to investigate the efficacy, safety and pharmacokinetics of topotecan in Japanese patients with relapsed ovarian carcinoma. METHODS: Patients with relapsed ovarian carcinoma after having received one regimen containing platinum-based chemotherapy were eligible for this study. Topotecan was administered at 1.2 mg/m(2)/day for five consecutive days, repeated every 3 weeks. RESULTS: Seventy-two patients were enrolled in the study. The response rate was 28.2% (95% confidence interval, 18.1-40.1%). Signs of myelosuppression, such as neutropenia (Grade 3, 12.5%; Grade 4, 83.3%), thrombocytopenia (Grade 3, 36.2%; Grade 4, 4.2%) and decreased hemoglobin (Grade 3, 36.1%; Grade 4, 11.1%), were the most common hematological toxicities. Grade 3 febrile neutropenia occurred in 5 (6.9%) patients. There was little intraindividual or interindividual variability in the pharmacokinetics of topotecan. CONCLUSIONS: Topotecan at 1.2 mg/m(2)/day is an effective and tolerable therapeutic option for Japanese patients with relapsed ovarian carcinoma. PMID- 20974679 TI - Force-generating capacity of human myosin isoforms extracted from single muscle fibre segments. AB - Muscle, motor unit and muscle fibre type-specific differences in force-generating capacity have been investigated for many years, but there is still no consensus regarding specific differences between slow- and fast-twitch muscles, motor units or muscle fibres. This is probably related to a number of different confounding factors disguising the function of the molecular motor protein myosin. We have therefore studied the force-generating capacity of specific myosin isoforms or combination of isoforms extracted from short single human muscle fibre segments in a modified single fibre myosin in vitro motility assay, in which an internal load (actin-binding protein) was added in different concentrations to evaluate the force-generating capacity. The force indices were the x-axis intercept and the slope of the relationship between the fraction of moving filaments and the alpha-actinin concentration. The force-generating capacity of the beta/slow myosin isoform (type I) was weaker (P < 0.05) than the fast myosin isoform (type II), but the force-generating capacity of the different human fast myosin isoforms types IIa and IIx or a combination of both (IIax) were indistinguishable. A single fibre in vitro motility assay for both speed and force of specific myosin isoforms is described and used to measure the difference in force-generating capacity between fast and slow human myosin isoforms. The assay is proposed as a useful tool for clinical studies on the effects on muscle function of specific mutations or post-translational modifications of myosin. PMID- 20974680 TI - GABA(B) receptor feedback regulation of bipolar cell transmitter release. AB - GABAergic amacrine cell feedback to bipolar cells in retina has been described, activating both GABA(A) and GABA(C) receptors. We explored whether metabotropic GABA(B) receptors also participate in this feedback pathway. CGP55845, a potent GABA(B) receptor antagonist, was employed to determine the endogenous role of these receptors. Ganglion cell EPSCs and IPSCs were monitored to measure the output of bipolar and amacrine cells. Using the tiger salamander slice preparation, we found that GABA(B) receptor pathways regulate bipolar cell release directly and indirectly. In the direct pathway, the GABA(B) receptor antagonist reduces EPSC amplitude, indicating that GABA(B) receptors cause enhanced glutamate release from bipolar cells to one set of ganglion cells. In the indirect pathway, the GABA(B) receptor antagonist reduces EPSC amplitude in another set of ganglion cells. The indirect pathway is only evident when GABA(A) receptors are inhibited, and is blocked by a glycine receptor antagonist. Thus, this second feedback pathway involves direct glycine feedback to the bipolar cell and this glycinergic amacrine cell is suppressed by GABAergic amacrine cells, through both GABA(A) and GABA(B) but not GABA(C) receptors. Overall, GABA(B) receptors do contribute to feedback regulation of bipolar cell transmitter release. However, unlike the ionotropic GABA receptor pathways, the metabotropic GABA receptor pathways act to enhance bipolar cell transmitter release. Furthermore, there are three discrete subsets of bipolar cell output regulated by GABA(B) receptor feedback (direct, indirect and null), implying three distinct, non-overlapping bipolar cell to ganglion cell circuits. PMID- 20974681 TI - Homeostatic regulation of electrical excitability in physiological cardiac hypertrophy. AB - Pathological biomechanical stresses cause cardiac hypertrophy, which is associated with QT prolongation and arrhythmias. Previous studies have demonstrated that repolarizing K(+) current densities are decreased in pressure overload-induced left ventricular hypertrophy, resulting in action potential and QT prolongation. Cardiac hypertrophy also occurs with exercise training, but this physiological hypertrophy is not associated with electrical abnormalities or increased arrhythmia risk, suggesting that repolarizing K(+) currents are upregulated, in parallel with the increase in myocyte size, to maintain normal cardiac function. To explore this hypothesis directly, electrophysiological recordings were obtained from ventricular myocytes isolated from two mouse models of physiological hypertrophy, one produced by swim-training of wild-type mice and the other by cardiac-specific expression of constitutively active phosphoinositide-3-kinase-p110alpha (caPI3Kalpha). Whole-cell voltage-clamp recordings revealed that repolarizing K(+) current amplitudes were higher in ventricular myocytes isolated from swim-trained and caPI3Kalpha, compared with wild-type, animals. The increases in K(+) current amplitudes paralleled the observed cellular hypertrophy, resulting in normalized or increased K(+) current densities. Electrocardiographic parameters, including QT intervals, as well as ventricular action potential waveforms in swim-trained animals/myocytes were indistinguishable from controls, demonstrating preserved electrical function. Additional experiments revealed that inward Ca(2+) current amplitudes/densities were also increased in caPI3Kalpha, compared with WT, left ventricular myocytes. The expression of transcripts encoding K(+), Ca(2+) and other ion channel subunits was increased in swim-trained and caPI3Kalpha ventricles, in parallel with the increase in myocyte size and with the global increases in total cellular RNA expression. In contrast to pathological hypertrophy, therefore, the functional expression of repolarizing K(+) (and depolarizing Ca(2+)) channels is increased with physiological hypertrophy, reflecting upregulation of the underlying ion channel subunit transcripts and resulting in increased current amplitudes and the normalization of current densities and action potential waveforms. Taken together, these results suggest that activation of PI3Kalpha signalling preserves normal myocardial electrical functioning and could be protective against the increased risk of arrhythmias and sudden death that are prevalent in pathological cardiac hypertrophy. PMID- 20974682 TI - Properties of urethral rhabdosphincter motoneurons and their regulation by noradrenaline. AB - The urethral rhabdosphincter (URS), commonly known as the external urethral sphincter, facilitates urinary continence by constricting the urethra. Striated muscle fibres in the urethral rhabdosphincter are innervated by Onuf's nuclei motoneurons in the spinal cord. Although noradrenaline (NA) reuptake inhibitors are shown to increase URS tone preventing urinary leakage in incontinent patients, whether or how NA affects URS motoneurons is unknown. Properties of dye labelled URS motoneurons were investigated by whole-cell patch-clamp recordings in isolated spinal cord slices prepared from neonatal female rats. As previously shown for adult sphincter motoneurons, neonatal URS motoneurons are more depolarized and possess higher input resistance than other spinal alpha motoneurons. These distinct properties make URS motoneurons more excitable than other alpha-motoneurons. Moreover, bath application of noradrenaline (NA) significantly depolarizes URS motoneurons and in many cases evokes action potentials. NA also significantly increases input resistance and reduces rheobase. These changes are reversed with wash, are largely blocked by the alpha(1)-adrenoceptor-selective antagonist prazosin, and are mimicked by the alpha(1)-adrenoceptor-selective agonist phenylephrine. In addition, NA significantly reduces the amplitude of the afterhyperpolarization and increases action potential frequency. Both the increase in action potential frequency and the reduction in afterhyperpolarization are occluded by apamin, a small conductance calcium-activated potassium (SK(Ca)) channel blocker. In conclusion, NA effectively increases the excitability of URS motoneurons through multiple mechanisms. The NA-induced increase in excitability of urethral rhabdosphincter motoneurons could be a key mechanism by which NA reuptake inhibitors improve stress urinary incontinence. PMID- 20974683 TI - Phosphorylation of RGS13 by the cyclic AMP-dependent protein kinase inhibits RGS13 degradation. AB - Regulators of G-protein signaling (RGS) proteins are scaffolds that control diverse signaling pathways by modulating signalosome formation and by accelerating the GTPase activity of heterotrimeric G proteins. Although expression of many RGS proteins is relatively low in quiescent cells, transcriptional and post-translational responses to environmental cues regulate both their abundance and activity. We found previously that RGS13, one of the smallest RGS proteins in the family, inhibited cyclic AMP-dependent protein kinase (PKA)-induced gene expression through interactions with the transcription factor cAMP-response element-binding (CREB) protein. Here, we show that PKA activation also leads to increased steady-state RGS13 expression through RGS13 phosphorylation, which inhibits RGS13 protein degradation. RGS13 turnover was significantly reduced in cells stimulated with cAMP, which was reversed by expression of the PKA-specific inhibitory peptide PKI. RGS13 phosphorylation was diminished by mutation of an N-terminal Thr residue (T41) identified as a phosphorylation site by mass spectrometry. Mutation of Thr41 in RGS13 to Ala (T41A) reduced steady-state RGS13 levels and its ability to inhibit M2 muscarinic receptor-mediated Erk phosphorylation compared with wild-type RGS13 by attenuating the protective effect of cAMP on RGS13 degradation. RGS13 underwent ubiquitylation, indicating that it is a likely target of the proteasome. These studies are the first to demonstrate post-translational mechanisms controlling the expression of RGS13. Stabilization of RGS13 through PKA-mediated phosphorylation could enhance RGS13 functions, providing negative feedback regulation that promotes cellular desensitization. PMID- 20974684 TI - Activation of AID by human T-cell leukemia virus Tax oncoprotein and the possible role of its constitutive expression in ATL genesis. AB - Adult T-cell leukemia (ATL) is a T-cell malignancy associated with human T-cell leukemia virus type 1 (HTLV-1). Mutations of tumor suppressor genes have been described in ATL. Although Tax, a product of HTLV-1, is associated with cellular genetic aberrations, the mechanisms of such association are not fully clear. Activation-induced cytidine deaminase (AID) is involved in somatic DNA alterations of the immunoglobulin gene for amplification of immune diversity. However, inappropriate expression of AID acts as a genomic mutator that contributes to tumorigenesis. To gain insight into the molecular mechanism underlying the emergence of somatic mutations in various genes during leukemogenesis, we examined the expression of AID. HTLV-1-infected T-cell lines and ATL cells expressed high levels of AID compared with uninfected T-cell lines and normal peripheral blood mononuclear cells (PBMCs). Immunohistochemistry showed AID-positive ATL cells in lymph nodes and skin lesions. Infection of a human T-cell line and normal PBMCs with HTLV-1 induced AID expression. Tax transcriptionally activated AID gene through both the nuclear factor-kappaB subunit p50 and cyclic adenosine 3',5'-monophosphate response element-binding protein signaling pathways. p50, which lacks a transactivation domain, interacted with the transcriptional coactivator Bcl-3 in HTLV-1-infected T cells. Thus, activation of p50/Bcl-3 complexes in T cells in response to Tax might explain the constitutive expression of AID in HTLV-1-infected T cells. The constitutive expression of AID in ATL cells can be speculated to result from mutations induced by the Tax-activated AID and/or other Tax-associated mutagenic mechanisms during the pre-leukemic stage, which cause functional modification within the AID promoter or in any of its cellular regulatory activator proteins. PMID- 20974685 TI - Hemangioblastomas might derive from neoplastic transformation of neural stem cells/progenitors in the specific niche. AB - The cytological origin of central nervous system hemangioblastoma (HB) remains unclear and controversial, largely owing to a lack of in-depth characterization of tumorigenic cells and their progeny tracking. We have now detected a cell subpopulation by stage-specific embryonic antigen-1 expression, which were defined as tumor-initiating cells (TICs) in both sporadic and familial HBs. These TICs subpopulations had universal neural stem cell characteristics. Nevertheless, the freshly sorted TICs endowed with potential of multi-progeny derivatives, including HB components and non-HB ingredients, depended on environmental induction in vitro. Importantly, the freshly harvested TICs formed malignant tumors by injection into conventional mice model, while did redevelop the characteristic HB-like structures within a special mice model with HB microenvironment, indicating HB niche dependency for the TICs derivative specification. Taken together, the data of the present study suggested that HBs might derive from neoplastic transformation of neural stem cells/progenitors in the specific niche. PMID- 20974686 TI - Berberine, an isoquinoline alkaloid, inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E2 and prostaglandin E2 receptors. AB - Melanoma is the leading cause of death from skin disease due, in large part, to its propensity to metastasize. We have examined the effect of berberine, an isoquinoline alkaloid, on human melanoma cancer cell migration and the molecular mechanisms underlying these effects using melanoma cell lines, A375 and Hs294. Using an in vitro cell migration assay, we show that over expression of cyclooxygenase (COX)-2, its metabolite prostaglandin E2 (PGE2) and PGE2 receptors promote the migration of cells. We found that treatment of A375 and Hs294 cells with berberine resulted in concentration-dependent inhibition of migration of these cells, which was associated with a reduction in the levels of COX-2, PGE2 and PGE2 receptors (EP2 and EP4). Treatment of cells with celecoxib, a COX-2 inhibitor, or transient transfection of cells with COX-2 small interfering RNA, also inhibited cell migration. Treatment of the cells with 12-O tetradecanoylphorbol-13-acetate (TPA), an inducer of COX-2 or PGE2, enhanced cell migration, whereas berberine inhibited TPA- or PGE2-promoted cell migration. Berberine reduced the basal levels as well as PGE2-stimulated expression levels of EP2 and EP4. Treatment of the cells with the EP4 agonist stimulated cell migration and berberine blocked EP4 agonist-induced cell migration activity. Moreover, berberine inhibited the activation of nuclear factor-kappa B (NF kappaB), an upstream regulator of COX-2, in A375 cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-kappaB, inhibited cell migration. Together, these results indicate for the first time that berberine inhibits melanoma cell migration, an essential step in invasion and metastasis, by inhibition of COX-2, PGE2 and PGE2 receptors. PMID- 20974687 TI - BCR-ABL stimulates mutagenic homologous DNA double-strand break repair via the DNA-end-processing factor CtIP. AB - Expression of BCR-ABL oncoprotein in chronic myeloid leukemia (CML) promotes neoplastic transformation of hematopoietic stem cells through modulation of diverse pathways. CML is a multistep disease, which evolves as a chronic phase and progresses to blast crisis. This progression has been associated with the appearance and accumulation of new cytogenetic anomalies and mutations. The mechanisms underlying the genomic instability promoted by BCR-ABL remain obscure. Through comparative analysis of different DNA double-strand break (DSB) repair mechanisms as a function of the BCR-ABL status in human megakaryocytic and CML cell lines, we found that BCR-ABL upregulates error-prone DSB repair pathways [single-strand annealing (SSA) and non-homologous end joining] rather than the high-fidelity mechanism of homologous recombination. Intriguingly, expression analysis of DSB repair pathway choice determining factors revealed increased levels of the protein CtIP in BCR-ABL-positive cells, particularly in response to irradiation. Moreover, treatment with the BCR-ABL kinase inhibitor, Imatinib Mesylate, abolished CtIP accumulation. When we silenced CtIP expression in cells with functional BCR-ABL, SSA enhancement by BCR-ABL was completely abrogated. Importantly, we also provide evidence that BCR-ABL stimulates DSB end resection, which is mediated by CtIP. Briefly, BCR-ABL promotes mutagenic DSB repair with the DSB end-processing protein CtIP acting as the key mediator downstream of BCR ABL. PMID- 20974689 TI - Deficient homeostatic regulation of practice-dependent plasticity in writer's cramp. AB - Homeostatic metaplasticity is important to maintain overall synaptic weight in neuronal networks. Previous work suggested that homeostatic metaplasticity in motor cortex is impaired in writer's cramp, the most common form of task-specific focal dystonia, when explored by the interactions between 2 successive plasticity inducing transcranial brain stimulation protocols (Quartarone Rizzo V, Bagnato S, Morgante F, Sant'angelo A, Romano M, Crupi D, Girlanda P, Rothwell JC, Siebner HR. 2005. Homeostatic-like plasticity of the primary motor hand area is impaired in focal hand dystonia. Brain. 128:1943-1950.). To which extent deficient homeostatic metaplasticity applies also to the behavioral level of practice dependent plasticity is unknown. Here, we examined the interactions of 3 paired associative transcranial magnetic stimulation protocols (motor cortical excitability-enhancing paired associative stimulation (PAS)(25ms), excitability depressing PAS(10ms), and control PAS(100ms)) with subsequent practice-dependent plasticity. Ten patients with writer's cramp and 10 healthy controls practiced rapid thumb abductions for 30 min. Practice-dependent plasticity was quantified by the increase in peak acceleration of the trained movement. The healthy controls but not the writer's cramp patients showed homeostatic suppression of practice-dependent plasticity after PAS(25ms) when compared with practice dependent plasticity after PAS(10ms) and PAS(100ms). The lack of the PAS(25ms) induced suppression of practice-dependent plasticity in writer's cramp correlated with clinical severity of the focal hand dystonia. Findings support the notion that deficient homeostatic metaplasticity of practice-dependent plasticity plays a significant role in the pathophysiology of writer's cramp. PMID- 20974690 TI - High proportions of deleterious polymorphisms in constrained human genes. AB - Previous studies on human mitochondrial genomes showed that the ratio of intra specific diversities at nonsynonymous-to-synonymous positions was two to ten times higher than the ratio of interspecific divergences at these positions, suggesting an excess of slightly deleterious nonsynonymous polymorphisms. However, such an overabundance of nonsynonymous single nucleotide polymorphisms (SNPs) was not found in human nuclear genomes. Here, genome-wide estimates using >14,000 human-chimp nuclear genes and 1 million SNPs from four human genomes showed a significant proportion of deleterious nonsynonymous SNPs (~ 15%). Importantly, this study reveals a negative correlation between the magnitude of selection pressure and the proportion of deleterious SNPs on human genes. The proportion of deleterious amino acid replacement polymorphisms is 3.5 times higher in genes under high purifying selection compared with that in less constrained genes (28% vs. 8%). These results are explained by differences in the extent of contribution of mildly deleterious mutations to diversity and substitution. PMID- 20974688 TI - Brain activation related to combinations of gaze position, visual input, and goal directed hand movements. AB - Humans reach to and acquire objects by transforming visual targets into action commands. How the brain integrates goals specified in a visual framework to signals into a suitable framework for an action plan requires clarification whether visual input, per se, interacts with gaze position to formulate action plans. To further evaluate brain control of visual-motor integration, we assessed brain activation, using functional magnetic resonance imaging. Humans performed goal-directed movements toward visible or remembered targets while fixating gaze left or right from center. We dissociated movement planning from performance using a delayed-response task and manipulated target visibility by its availability throughout the delay or blanking it 500 ms after onset. We found strong effects of gaze orientation on brain activation during planning and interactive effects of target visibility and gaze orientation on movement-related activation during performance in parietal and premotor cortices (PM), cerebellum, and basal ganglia, with more activation for rightward gaze at a visible target and no gaze modulation for movements directed toward remembered targets. These results demonstrate effects of gaze position on PM and movement-related processes and provide new information how visual signals interact with gaze position in transforming visual inputs into motor goals. PMID- 20974691 TI - The management of enthusiasm: motives and expectations in cardiovascular medicine. AB - Debates about appropriate action in medicine often turn on finding the right emotional orientation to new developments. In this article enthusiasm emerges as a key term in a professional 'vocabulary of motive' around innovation, complicating current sociological interest in expectations. The negative associations that adhere to this word among clinical researchers indicate awareness with the difficulty of managing hype and public hopes, but analysis of its use by cardiologists over the past two decades also reveals tension around more specific professional dangers, including 'credulity' and inappropriate activism. An emphasis on clinical trials offers one resolution, but additional narrative strategies can be identified when discussing when to start such trials here illustrated for stem cells for cardiac repair. In particular, while some suggest delaying trials until there is good knowledge of mechanism gained in the laboratory, others support early clinical research through gestures of therapeutic and epistemic modesty. PMID- 20974692 TI - Trust in medical decision-making concerning older people: the views of key professionals in the Dutch health care practice. AB - This article deals with the issue of public trust in decisions made by individual physicians, concerning older people, as perceived by various key professionals. While trust is a basic element in our health care service, it is at the same time a difficult phenomenon to conceptualize. This article tries to contribute to a better understanding of what trust in medical practice entails and what are the necessary conditions for a society to put trust in the medical profession. The focus is on care for older people under the condition of scarcity in health care resources. Our study has a qualitative design consisting of semi-structured in depth interviews with 24 key professionals focusing on decision-makers and those in line of professionally organizing or influencing the decision-making process. We found roughly three categories of trust: distrust; trust; and qualified trust. In each category we found different reasons to give or withhold trust and different views on how far the discretionary power of doctors should go. We recommend promoting trust by addressing the criteria or limits brought forward in the qualified trust category. The preconditions as identified in the qualified trust section provide the boundaries and marking points between which physicians have to move regarding the care for older people. The qualifications provide us insight in where and how to invest in trust under these and under different circumstances. An important conclusion is that trust is never finished: trust needs to be gained and negotiated in a continuous process of action and interaction. PMID- 20974693 TI - Balancing the good, the bad and the better: a discursive perspective on probiotics and healthy eating. AB - Functional foods promoted as novel food products providing health benefits beyond basic nutrition are gradually becoming part of the European food basket. Typically, research on functional food has focused on public attitudes, the acceptability of different product types, and public trust in novel food. In this article, discursive analysis of focus group discussions held in Britain with 34 users and non-users of probiotics points to the argumentative orientation of explanations for consumption of this particular type of functional food. Using the concepts of 'interpretative repertoire' and 'subject position', I explore the role of moral considerations in people's accounts of purchasing probiotics in the current context of increased health awareness and health anxiety. The analysis demonstrates how the lay accounts of eating and purchasing probiotics are entangled with notions of indulgence, individualism, as well as social norms and responsibility. PMID- 20974694 TI - Privatization within the Dutch context: a comparison of the health insurance systems of the Netherlands and the United States. AB - In 2006, the Netherlands passed the Health Insurance Act requiring all legal residents to obtain health insurance from private insurance companies. The reform created a national health insurance system guaranteed to all citizens regardless of income or labor force status and introduced a market orientation that makes private insurance companies the sole providers of health insurance. How does the new policy compare to the US model of private health insurance provision? Is this reform evidence of a shift toward the American model? We use a comparative case study method to distinguish the new Dutch system from the private insurance system in the United States. We find that although the Dutch system includes market solutions similar to the US model, it still provides a universal guarantee of coverage to all of its citizens and should be viewed as 'privatization' within the Dutch context rather than a cooptation of American health policy. PMID- 20974695 TI - Towards a developmental ethology: exploring Deleuze's contribution to the study of health and human development. AB - This article explores the work of French thinker Gilles Deleuze and argues for the application of his central ideas to the study of health and human development. Deleuze's work furnishes a host of ontological and epistemological resources for such analysis, ushering in new methods and establishing new objects of inquiry. Of principal interest are the inventive conceptualizations of affect, multiplicity and relationality that Deleuze proposes, and the novel reading of subjectivity that these concepts support. This article introduces a developmental ethology in exploring Deleuze's contributions to the study of human development and its varied courses and processes. Taken from a Deleuzean perspective, human development will be characterized as a discontinuous process of affective and relational encounters. It will be argued further that human development is advanced in the provision of new affective sensitivities and new relational capacities. This course is broadly consistent with existing approaches to human development--particularly those associated with Amartya Sen's capabilities model- with the considerable advantage of offering a more viable working theory of the ways in which developmental capacities are acquired, cultivated and maintained. A provisional research agenda consistent with this developmental ethology is offered by way of conclusion. PMID- 20974696 TI - The plastic brain: neoliberalism and the neuronal self. AB - Neuroscience-based representations and practices of the brain aimed at lay populations present the brain in ways that both affirm biological determinism and also celebrate plasticity, or the brain's ability to change structure and function. Popular uses of neuroscientific theories of brain plasticity are saturated with a neoliberal vision of the subject. Against more optimistic readings of plasticity, I view the popular deployment of plasticity through the framework of governmentality. I describe how popular brain discourse on plasticity opens up the brain to personal techniques of enhancement and risk avoidance, and how it promotes a neuronal self. I situate brain plasticity in a context of biomedical neoliberalism, where the engineering and modification of biological life is positioned as essential to selfhood and citizenship. PMID- 20974697 TI - Screening for breast cancer: medicalization, visualization and the embodied experience. AB - Women's perspectives on breast screening (mammography and breast awareness) were explored in interviews with midlife women sampled for diversity of background and health experience. Attending mammography screening was considered a social obligation despite women's fears and experiences of discomfort. Women gave considerable legitimacy to mammography visualizations of the breast, and the expert interpretation of these. In comparison, women lacked confidence in breast awareness practices, directly comparing their sensory capabilities with those of the mammogram, although mammography screening did not substitute breast awareness in a straightforward way. The authors argue that reliance on visualizing technology may create a fragmented sense of the body, separating the at risk breast from embodied experience. PMID- 20974698 TI - Pharmacological characterization of diethyl-2-({3-dimethylcarbamoyl-4-[(4' trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetyloxymethyl)-2-phenylmalonate (JTT-130), an intestine-specific inhibitor of microsomal triglyceride transfer protein. AB - Inhibitors of microsomal triglyceride transfer protein (MTP) expressed in the liver and small intestine are potential candidates for lipid-lowering agents. However, inhibition of hepatic MTP could lead to significant safety issues such as fatty liver disease. To develop a specific inhibitor of intestinal MTP, JTT 130 [diethyl-2-({3-dimethylcarbamoyl-4-[(4'-trifluoromethylbiphenyl-2 carbonyl)amino]phenyl}acetyloxymethyl)-2-phenylmalonate], was designed to be rapidly hydrolyzed in the absorption process. Here, we describe JTT-130, an intestine-specific MTP inhibitor, and evaluate its pharmacological properties. In in vitro metabolic stability tests, JTT-130 was readily hydrolyzed during incubation with liver S9 from humans, hamsters, and rats. In an in vitro triglyceride (TG) transfer assay with human intestinal MTP, JTT-130 potently inhibited TG transfer activity with an IC(50) value of 0.83 nM. When orally administered to hamsters, JTT-130 significantly suppressed an increase in chylomicron-TG after olive oil loading at 0.3 mg/kg and above but did not inhibit TG secretion from the liver at doses of up to 1000 mg/kg, indicating an inhibitory action highly specific for the small intestine. In rats orally administered [(14)C]triolein, JTT-130 potently suppressed an increase in blood (14)C radioactivity and increased (14)C radioactivity in the upper small intestine and the intestinal lumen. In hyperlipidemic hamsters fed a high-fat and high-cholesterol diet, repeated dosing with JTT-130 for 2 weeks reduced TG and cholesterol levels in the plasma and TG content in the liver. These results indicated that JTT-130 is a potent inhibitor specific to intestinal MTP and suggested that JTT-130 would be a useful compound for the treatment of dyslipidemia without inducing hepatotoxicity. PMID- 20974699 TI - Efficacy of glutathione in ameliorating sulfur mustard analog-induced toxicity in cultured skin epidermal cells and in SKH-1 mouse skin in vivo. AB - Exposure to chemical warfare agent sulfur mustard (HD) is reported to cause GSH depletion, which plays an important role in HD-linked oxidative stress and skin injury. Using the HD analog 2-chloroethyl ethyl sulfide (CEES), we evaluated the role of GSH and its efficacy in ameliorating CEES-caused skin injury. Using mouse JB6 and human HaCaT epidermal keratinocytes, we observed both protective and therapeutic effects of exogenous GSH (1 or 10 mM) in attenuating a CEES-caused decrease in cell viability and DNA synthesis, as well as S and G(2)M phase arrest in cell cycle progression. However, the protective effect of GSH was stronger than its ability to reverse CEES-induced cytotoxic effect. The observed effect of GSH could be associated with an increase in intracellular GSH levels after its treatment before or after CEES exposure, which strongly depleted cellular GSH levels. N-Acetyl cysteine, a GSH precursor, also showed both protective and therapeutic effects against CEES-caused cytotoxicity. Buthionine sulfoximine, which reduces cellular GSH levels, caused an increased CEES cytotoxicity in both JB6 and HaCaT cells. In further studies translating GSH effects in cell culture, pretreatment of mice with 300 mg/kg GSH via oral gavage 1 h before topical application of CEES resulted in significant protection against CEES-caused increase in skin bifold and epidermal thickness, apoptotic cell death, and myeloperoxidase activity, which could be associated with increased skin GSH levels. Together, these results highlight GSH efficacy in ameliorating CEES caused skin injury and further support the need for effective antioxidant countermeasures against skin injury by HD exposure. PMID- 20974701 TI - Regulation of spinal dynorphin 1-17 release by endogenous pituitary adenylyl cyclase-activating polypeptide in the male rat: relevance of excitation via disinhibition. AB - Opioids inhibit release of primary afferent transmitters but it is unclear whether the converse occurs. To test the hypothesis that primary afferent transmitters influence opioid-ergic tone, we studied the functional and anatomical relationships between pituitary adenylyl cyclase-activating polypeptide (PACAP) and dynorphin 1-17 (Dyn) in spinal cord. We found that activation of the PACAP-specific receptor PAC(1) (PAC(1)R) inhibited, whereas PAC(1)R blockade augmented, spinal release of Dyn. It is noteworthy that in the formalin-induced pain model PAC(1)R blockade (via PACAP6-38) also resulted in antinociception that was abolished by spinal kappa-opioid receptor blockade. These findings indicate that Dyn release is tonically inhibited by PACAP and that blocking this inhibition, which increases the spinal release of Dyn, results in antinociception. Consistent with this conclusion, we found in the spinal dorsal horn that Dyn-immunoreactive neurons 1) expressed PAC(1)R and 2) were apposed by PACAP terminals. Present results, in combination with the previous demonstration that the release of spinal Dyn is tonically inhibited by opioid- and nociceptin/orphanin FQ-coupled pathways (J Pharmacol Exp Ther 298:1213-1220, 2001), indicate that spinal Dyn-ergic neurons integrate multiple inhibitory inputs, the interruption of any one of which (i.e., disinhibition) is sufficient to enhance spinal Dyn release and generate antinociception. Gaining a better understanding of the role of primary afferent neurotransmitters in negatively modulating the spinal release of Dyn and the physiological use of disinhibition to increase spinal Dyn activity could suggest novel clinically useful approaches for harnessing endogenous Dyn for pain control. PMID- 20974700 TI - Airway peroxidases catalyze nitration of the {beta}2-agonist salbutamol and decrease its pharmacological activity. AB - beta(2)-agonists are the most effective bronchodilators for the rapid relief of asthma symptoms, but for unclear reasons, their effectiveness may be decreased during severe exacerbations. Because peroxidase activity and nitrogen oxides are increased in the asthmatic airway, we examined whether salbutamol, a clinically important beta(2)-agonist, is subject to potentially inactivating nitration. When salbutamol was exposed to myeloperoxidase, eosinophil peroxidase or lactoperoxidase in the presence of hydrogen peroxide (H(2)O(2)) and nitrite (NO(2)(-)), both absorption spectroscopy and mass spectrometry indicated formation of a new metabolite with features expected for the nitrated drug. The new metabolites showed an absorption maximum at 410 nm and pK(a) of 6.6 of the phenolic hydroxyl group. In addition to nitrosalbutamol (m/z 285.14), a salbutamol-derived nitrophenol, formed by elimination of the formaldehyde group, was detected (m/z 255.13) by mass spectrometry. It is noteworthy that the latter metabolite was detected in exhaled breath condensates of asthma patients receiving salbutamol but not in unexposed control subjects, indicating the potential for beta(2)-agonist nitration to occur in the inflamed airway in vivo. Salbutamol nitration was inhibited in vitro by ascorbate, thiocyanate, and the pharmacological agents methimazole and dapsone. The efficacy of inhibition depended on the nitrating system, with the lactoperoxidase/H(2)O(2)/NO(2)(-) being the most affected. Functionally, nitrated salbutamol showed decreased affinity for beta(2)-adrenergic receptors and impaired cAMP synthesis in airway smooth muscle cells compared with the native drug. These results suggest that under inflammatory conditions associated with asthma, phenolic beta(2)-agonists may be subject to peroxidase-catalyzed nitration that could potentially diminish their therapeutic efficacy. PMID- 20974702 TI - Divergent effect of cobalt and beryllium salts on the fate of peripheral blood monocytes and T lymphocytes. AB - Occupational exposure to metals such as cobalt and beryllium represents a risk factor for respiratory health and can cause immune-mediated diseases. However, the way they act may be different. We show here that the two metals have a divergent effect on peripheral T lymphocytes and monocytes: BeSO(4) induces cell death in monocytes but not in T lymphocytes, which instead respond by producing Interferon gamma (IFN-gamma); conversely, CoCl(2) induces apoptosis in T lymphocytes but not in monocytes. Interestingly, both metals induce p53 overexpression but with a dramatic different outcome. This is because the effect of p53 in CoCl(2)-treated monocytes is counteracted by the antiapoptotic activity of cytoplasmic p21(Cip1/WAF1), the activation of nuclear factor kappaB, and the inflammasome danger signaling pathway leading to the production of proinflammatory cytokines. However, CoCl(2)-treated monocytes do not fully differentiate into macrophage or dendritic cells, as inferred by the lack of expression of CD16 and CD83, respectively. Furthermore, the expression of HLA class II molecules, as well as the capability of capturing and presenting the antigens, decreased with time. In conclusion, cobalt keeps monocytes in a partially activated, proinflammatory state that can contribute to some of the pathologies associated with the exposure to this metal. PMID- 20974704 TI - Endocrine disruption: historical perspectives and its impact on the future of toxicology testing. PMID- 20974703 TI - Role of fibrinogen and protease-activated receptors in acute xenobiotic-induced cholestatic liver injury. AB - Alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury causes tissue factor (TF)-dependent coagulation in mice, and TF deficiency reduces ANIT induced liver injury. However, the mechanism whereby TF contributes to hepatotoxicity in this model is not known. Utilizing pharmacological and genetic strategies, we evaluated the contribution of fibrinogen and two distinct receptors for thrombin, protease-activated receptor-1 (PAR-1) and PAR-4, in a model of acute ANIT hepatotoxicity. ANIT administration (60 mg/kg, po) caused a marked induction of the genes encoding the three fibrinogen chains (alpha, beta, and gamma) in liver, an increase in plasma fibrinogen, and concurrent deposition of thrombin-cleaved fibrin in liver. Partial depletion of circulating fibrinogen with ancrod did not impact ANIT hepatotoxicity. However, complete fibrin(ogen) deficiency significantly reduced serum alanine aminotransferase activity and hepatocellular necrosis in ANIT-treated mice. ANIT-induced hepatocellular necrosis was similar in PAR-1(-/-) mice compared with PAR-1(+/+) mice. Interestingly, the progression of ANIT-induced hepatocellular necrosis was significantly reduced in PAR-4(-/-) mice and by administration of an inhibitory PAR-4 pepducin (P4Pal-10, 0.5 mg/kg, sc) to wild-type mice 8 h after ANIT treatment. Interestingly, a distinct lesion, parenchymal-type peliosis, was also observed in PAR-4(-/-) mice treated with ANIT and in mice that were given P4Pal 10 prior to ANIT administration. The results suggest that fibrin(ogen), but not PAR-1, contributes to the progression of ANIT hepatotoxicity in mice. Moreover, the data suggest a dual role for PAR-4 in ANIT hepatotoxicity, both mediating an early protection against peliosis and contributing to the progression of hepatocellular necrosis. PMID- 20974705 TI - Age differences in implicit learning of probabilistic unstructured sequences. AB - OBJECTIVE: It is unclear whether implicit probabilistic learning, the acquisition of regularities without intent or explicit knowledge, declines with healthy aging. METHODS: Because age differences in previous work might reflect motor or rule learning deficits, we used the implicit Triplets Learning Task with reduced motor sequencing and non-rule-based associations. Fifteen young and 15 old adults responded only to the last event in a series of discrete 3-event sequences or triplets. A randomly chosen set of triplets occurred with high frequency, so there was no underlying rule to be learned. RESULTS: Both age groups learned associative regularities, but age differences in favor of the young emerged with practice. Discussion. Age differences may reflect the different neural regions that are involved as training progresses, which differ in the extent to which they are compromised by aging. PMID- 20974706 TI - Circulating osteoprotegerin and soluble receptor activator of nuclear factor kappaB ligand in polycystic ovary syndrome: relationships to insulin resistance and endothelial dysfunction. AB - OBJECTIVE: There is plenty of evidence that osteoprotegerin (OPG) is linked to subclinical vascular damage and predicts cardiovascular disease in high-risk populations. Our aim is to investigate the relationships of OPG/free soluble receptor activator of nuclear factor kappaB ligand (sRANKL) to insulin resistance, brachial artery flow-mediated vasodilation (FMD), and the carotid artery intima-media thickness (CIMT) in polycystic ovary syndrome (PCOS), a disorder characterized by hyperandrogenism, impaired glucose control, and endothelial injury. DESIGN: A cross-sectional, observational study. METHODS: Hormonal and metabolic profiles, FMD, CIMT, serum OPG, and ampli-sRANKL were assessed in 64 young PCOS patients and 20 controls of similar age. Body composition was measured by dual energy X-ray absorptiometry. RESULTS: OPG was significantly lower in PCOS and related negatively to free testosterone and positively to estradiol (E(2)) levels. In multivariate analysis, OPG but not ampli-sRANKL correlated positively to fasting insulin, insulin sensitivity indices, and FMD. Neither OPG nor ampli-sRANKL was associated with CIMT. Significantly lower adjusted FMD values were demonstrated in women in the upper OPG quartile group (>2.65 pmol/l) compared with all other quartile groups together (P=0.012). In PCOS, multiple regression analysis retained E(2)/sex hormone-binding globulin ratio, fat mass, and homeostasis model assessment of insulin resistance as independent predictors of OPG. CONCLUSIONS: In PCOS, circulating OPG is related to both endothelial dysfunction and insulin resistance, independent of obesity and androgen excess, suggesting OPG as a useful biomarker of these effects. Further studies are needed to evaluate OPG in relation to cardiovascular events and cardiovascular mortality in PCOS. PMID- 20974707 TI - Comparison of percutaneous electrical nerve stimulation and ultrasound imaging for nerve localization. AB - BACKGROUND: Percutaneous nerve stimulation (PNS) is a non-invasive technique to localize superficial nerves before performing peripheral nerve blocks, but its precision has never been evaluated by high-resolution ultrasound. This study compared stimulating points at the skin with the position of nerve structures determined by ultrasound. Correlations between distances and percutaneous stimulation thresholds were determined. METHODS: PNS was performed in 20 healthy volunteers systematically with a stimulating pen at the neck after attaching a transparent film with 49 (7*7) perforations. Stimulation thresholds were measured and impedance was controlled. Thereafter, an independent observer measured the depth (D) of the most superficial nerve structure with ultrasound. Distances between stimulating points and the most superficial nerve structure (S) were measured. Correlations between associated stimulating thresholds and distances D and S were calculated. RESULTS: The stimulating point with the lowest current was identical to the point closest to the nerve in only 10% of measurements. Median S was 12.6 (3.4-32.0) mm and D 7.6 (0.3-28.6) mm. Distances did not correlate with percutaneous stimulation thresholds. CONCLUSION: PNS with a stimulating pen is not a reliable technique for nerve localization in the brachial plexus as verified by high-resolution ultrasound. PMID- 20974708 TI - Paediatric Perianesthesia questionnaire: development and data from eight hospitals across Germany. AB - BACKGROUND: Opinions about satisfaction with care are rarely obtained from children and few studies of this type exist in the area of paediatric anaesthesia. In this study, we developed a comprehensive self-administered questionnaire to measure the level of paediatric and, as a substitute in younger children, parental satisfaction with anaesthesia. In addition, we aimed to identify factors influencing satisfaction and compare results between hospitals. METHODS: We followed a rigorous protocol including construction of a pilot questionnaire and qualitative and quantitative analysis. The questionnaire was adapted for confounding variables. We analysed satisfied and dissatisfied groups and compared satisfaction scores between participating hospitals. RESULTS: A questionnaire was developed which comprised 37 questions assessed on a five-point Likert scale. With a response rate of 71%, a total of 1052 patients completed the questionnaire. In the final analysis, 760 questionnaires (72%) were included. Most questionnaires were answered by the parents [705 (92.8%)]. The mean age of children was 6.7 (4.97) yr. Multivariate analysis found a history of previous anaesthetic problems and the identity of the person answering the questionnaire as influencing factors on the sum score. The most important differences between satisfied and dissatisfied children were found for the dimensions 'privacy and waiting', 'information giving', and 'discomfort'. Scores differed between hospitals. CONCLUSIONS: Our psychometric questionnaire provides a novel approach to paediatric patient satisfaction with anaesthesia care and covers areas deemed important by children, parents, and carers. Significant differences between satisfied and dissatisfied groups and between participating hospitals were found. PMID- 20974709 TI - Better mood and better performance. Learning rule-described categories is enhanced by positive mood. AB - Theories of mood and its effect on cognitive processing suggest that positive mood may allow for increased cognitive flexibility. This increased flexibility is associated with the prefrontal cortex and the anterior cingulate cortex, both of which play crucial roles in hypothesis testing and rule selection. Thus, cognitive tasks that rely on behaviors such as hypothesis testing and rule selection may benefit from positive mood, whereas tasks that do not rely on such behaviors should not be affected by positive mood. We explored this idea within a category-learning framework. Positive, neutral, and negative moods were induced in our subjects, and they learned either a rule-described or a non-rule-described category set. Subjects in the positive-mood condition performed better than subjects in the neutral- or negative-mood conditions in classifying stimuli from rule-described categories. Positive mood also affected the strategy of subjects who classified stimuli from non-rule-described categories. PMID- 20974710 TI - On angry leaders and agreeable followers. How leaders' emotions and followers' personalities shape motivation and team performance. AB - Do followers perform better when their leader expresses anger or when their leader expresses happiness? We propose that this depends on the follower's level of agreeableness. Anger is associated with hostility and conflict-states that are at odds with agreeable individuals' goals. Happiness facilitates affiliation and positive relations-states that are in line with agreeable individuals' goals. Accordingly, the two studies we conducted showed that agreeableness moderates the effects of a leader's emotional displays. In a scenario study, participants with lower levels of agreeableness responded more favorably to an angry leader, whereas participants with higher levels of agreeableness responded more favorably to a neutral leader. In an experiment involving four-person teams, teams composed of participants with lower average levels of agreeableness performed better when their leader expressed anger, whereas teams composed of participants with higher average levels of agreeableness performed better when their leader expressed happiness. Team performance was mediated by experienced workload, which was highest among agreeable followers with an angry leader. Besides having important practical implications, the findings shed new light on the fundamental question of how emotional expressions regulate social behavior. PMID- 20974711 TI - Information search in decisions from experience. Do our patterns of sampling foreshadow our decisions? AB - Do different patterns of sampling influence the decisions people make, even when the information the decisions are based on is equivalent? Do more and less switching between options correlate with different kinds of decision policies? In past research, the correspondence between search and decision patterns has been difficult to ascertain because the information obtained has often been confounded with its consequences in an exploration-exploitation trade-off. We used a sampling task in which information is explored prior to being exploited. We found that search patterns did reveal decision policies. Individuals who transitioned more frequently between options were more likely to choose options that win most of the time in round-wise comparisons and were more likely to underweight rare, risky events. Less switching between options was associated with choosing options that win in the long run on the basis of summary comparisons--decisions consistent with expected-value maximization and linear weighting of outcomes. PMID- 20974712 TI - Interpersonal sensitivity, status, and stereotype accuracy. AB - A classic question in social and organizational psychology is whether low-status persons are more accurate in the perception of their high-status partners than the latter are in their perception of their subordinates. In a series of studies, Snodgrass (1985, 1992) tested this idea. She found that subordinates were more accurate at judging how their bosses viewed them than bosses were at judging how their subordinates viewed them, but that bosses were more accurate at judging how subordinates viewed themselves than subordinates were at judging how bosses viewed themselves. We believe, however, that these results were obscured by stereotype accuracy. Using previously collected data, we found that stereotype accuracy does lead to the pattern previously observed by Snodgrass. We also discovered that when we controlled for stereotype accuracy, subordinates' perceptions were generally more accurate than those of their bosses, which supports Snodgrass's original hypothesis. PMID- 20974713 TI - It's alive! animate motion captures visual attention. AB - Across humans' evolutionary history, detecting animate entities in the visual field (such as prey and predators) has been critical for survival. One of the defining features of animals is their motion-self-propelled and self-directed. Does such animate motion capture visual attention? To answer this question, we compared the time to detect targets involving objects that were moving predictably as a result of collisions (inanimate motion) with the time to detect targets involving objects that were moving unpredictably, having been in no such collisions (animate motion). Across six experiments, we consistently found that targets involving objects that underwent animate motion were responded to more quickly than targets involving objects that underwent inanimate motion. Moreover, these speeded responses appeared to be due to the perceived animacy of the objects, rather than due to their uniqueness in the display or involvement of a top-down strategy. We conclude that animate motion does indeed capture visual attention. PMID- 20974714 TI - Social class, contextualism, and empathic accuracy. AB - Recent research suggests that lower-class individuals favor explanations of personal and political outcomes that are oriented to features of the external environment. We extended this work by testing the hypothesis that, as a result, individuals of a lower social class are more empathically accurate in judging the emotions of other people. In three studies, lower-class individuals (compared with upper-class individuals) received higher scores on a test of empathic accuracy (Study 1), judged the emotions of an interaction partner more accurately (Study 2), and made more accurate inferences about emotion from static images of muscle movements in the eyes (Study 3). Moreover, the association between social class and empathic accuracy was explained by the tendency for lower-class individuals to explain social events in terms of features of the external environment. The implications of class-based patterns in empathic accuracy for well-being and relationship outcomes are discussed. PMID- 20974715 TI - Genetic evidence for multiple biological mechanisms underlying in-group favoritism. AB - In-group favoritism is ubiquitous and associated with intergroup conflict, yet is little understood from a biological perspective. A fundamental question regarding the structure of favoritism is whether it is inflexibly directed toward distinct, "essentialist" categories, such as ethnicity and race, or is deployed in a context-sensitive manner. In this article, we report the first study (to our knowledge) of the genetic and environmental structure of in-group favoritism in the religious, ethnic, and racial domains. We contrasted a model of favoritism based on a single domain-general central affiliation mechanism (CAM) with a model in which each domain was influenced by specific mechanisms. In a series of multivariate analyses, utilizing a large, representative sample of twins, models containing only the CAM or essentialist domains fit the data poorly. The best fitting model revealed that a biological mechanism facilitates affiliation with arbitrary groups and exists alongside essentialist systems that evolved to process salient cues, such as shared beliefs and ancestry. PMID- 20974717 TI - Biomarkers in population-based studies. PMID- 20974718 TI - An uncertain death. PMID- 20974721 TI - Determinants of choosing a career in family medicine. AB - BACKGROUND: Student choice is an important determinant of the distribution of specialties of practising physicians in many countries. Understanding characteristics at entry into medical school that are associated with the choice of residency in family medicine can assist medical schools in admitting an appropriate mix of students to serve the health care needs of their regions. METHODS: From 2002 to 2004, we collected data from students in 15 classes at 8 of 16 Canadian medical schools at entry. Surveys included questions on career choice, attitudes to practice and socio-demographic characteristics. We followed students prospectively with these data linked to their residency choice. We used multiple logistic regression analysis to identify entry characteristics that predicted a student's ultimate career choice in family medicine. RESULTS: Of 1941 eligible students in the participating classes, 1542 (79.4%) contributed data to the final analyses. The following 11 entry variables predicted whether a student named family medicine as his or her top residency choice: being older, being engaged or in a long-term relationship, not having parents with postgraduate university education nor having family or close friends practicing medicine, having undertaken voluntary work in a developing nation, not volunteering with elderly people, desire for varied scope of practice, a societal orientation, a lower interest in research, desire for short postgraduate training, and lower preference for medical versus social problems. INTERPRETATION: Demographic and attitudinal characteristics at entry into medical school predicted whether students chose a career in family medicine. PMID- 20974722 TI - Lichen sclerosus in a radiated breast. PMID- 20974724 TI - Panel says less-is-more when it comes to nutrition ratings on packaged foods. PMID- 20974723 TI - Meloxicam-induced enteropathy of the small bowel. PMID- 20974725 TI - Mental disorders seek space at the global health table. PMID- 20974726 TI - Value-based drug system proposed in UK. PMID- 20974727 TI - Pressure mounts to strip industry funding from continuing medical education programs. PMID- 20974728 TI - The changing dynamic of medical school admissions. PMID- 20974729 TI - Resveratrol improves insulin resistance hyperglycemia and hepatosteatosis but not hypertriglyceridemia, inflammation, and life span in a mouse model for Werner syndrome. AB - Werner syndrome is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many features of Werner syndrome, including a pro-oxidant status and a shorter mean life span. Here, we show that resveratrol supplementation improved the hyperglycemia and the insulin resistance phenotype in these Wrn mutant mice. In addition, resveratrol reversed liver steatosis, lipid peroxidaton, and the defenestration phenotypes observed in such mice. Resveratrol, however, did not improve the hypertriglyceridemia, inflammatory stress, nor extend the mean life span of these mutant mice. Microarray and biologic pathway enrichment analyses on liver tissues revealed that resveratrol mainly decreased lipidogenesis and increased genes involved in the insulin signaling pathway and the glutathione metabolism in Wrn mutant mice. Finally, resveratrol-treated mutant mice exhibited an increase in the frequency of lymphoma and of several solid tumors. These results indicate that resveratrol supplementation might exert at least metabolic benefits for Werner syndrome patients. PMID- 20974730 TI - Small bowel capsule endoscopy performance in octogenarians: a case-control study. AB - BACKGROUND AND STUDY AIMS: Capsule endoscopy is a high-sensitive tool for the investigation of suspected small bowel disorders, but its effectiveness in elderly patients is unknown. We sought to determine capsule endoscopy feasibility and diagnostic yield in octogenarians. PATIENTS AND METHODS: Records of patients >= 80 years old (Group A) were retrieved from a database of 827 consecutive capsule endoscopy performed on as many patients. Capsule endoscopy failures, complications, diagnostic yield, and findings were recorded and compared with those of patients younger than 80 (Group B), randomly extracted from the same database in a > 2:1 ratio. RESULTS: Group A consisted of 79 patients, 84 +/- 6 years old and Group B of 188, 44 +/- 11 years old (p < .0001). We visualized the entire small bowel in 59 (74.6%) patients of Group A and in 169 (89%) of Group B (odds ratio = 0.33, 95% confidence interval: 0.16-0.66, p = .0025), mainly for capsule failures in reaching the duodenum; this event occurred in 10 patients of Group A and in 3 of Group B (odds ratio = 9, 95% confidence interval: 2.4-33.4, p = .0004). The rate of adverse events and diagnostic yield did not differ between the two groups. Inflammatory and neoplastic lesions were more common in Group A (odds ratio = 2.60, 95% confidence interval: 1.07-6.28, p = .03 and odds ratio = 2.01, 95% confidence interval: 1.02-3.97, p = .04, respectively). CONCLUSIONS: In octogenarians, small bowel capsule endoscopy may be troublesome for capsule failure in reaching the duodenum. However, the diagnostic yield of small bowel capsule endoscopy and the rate of clinically significant lesions are high. PMID- 20974731 TI - Increases in thigh muscle volume and strength by walk training with leg blood flow reduction in older participants. AB - We examined the effects of walk training combined with leg blood flow reduction (BFR) on muscle hypertrophy as well as on peak oxygen uptake (VO2 peak) in older individuals. Both the BFR walk training (BFR-Walk, n = 10, age; 64 +/- 1 years, body mass index [BMI]; 22.5 +/- 0.9 kg/m2) and control walk training (CON-Walk, n = 8, age; 68 +/- 1 years, BMI; 23.2 +/- 1.0 kg/m2) groups performed 20 minutes of treadmill walking at an exercise intensity of 45% of heart rate reserve, 4 days per week, for 10 weeks. The BFR-Walk group wore pressure belts (160-200 mm Hg) on both legs during training. After the training, magnetic resonance imaging measured thigh muscle cross-sectional area (3.1%, p < .01) and muscle volume (3.7%, p < .01) as well as maximal isometric (5.9%, p < .05) and isokinetic (up to 22%, p < .01) strength increased in the BFR-Walk group, but not in the CON Walk group. Estimated VO2 peak during a bicycle graded exercise test increased (p < .05) and correlated with oxygen pulse in both groups. In conclusion, BFR walk training improves both muscle volume and strength in older women. PMID- 20974732 TI - Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. AB - Rapamycin was administered in food to genetically heterogeneous mice from the age of 9 months and produced significant increases in life span, including maximum life span, at each of three test sites. Median survival was extended by an average of 10% in males and 18% in females. Rapamycin attenuated age-associated decline in spontaneous activity in males but not in females. Causes of death were similar in control and rapamycin-treated mice. Resveratrol (at 300 and 1200 ppm food) and simvastatin (12 and 120 ppm) did not have significant effects on survival in male or female mice. Further evaluation of rapamycin's effects on mice is likely to help delineate the role of the mammalian target of rapamycin complexes in the regulation of aging rate and age-dependent diseases and may help to guide a search for drugs that retard some or all of the diseases of aging. PMID- 20974733 TI - Genetic deletion of Nrf2 promotes immortalization and decreases life span of murine embryonic fibroblasts. AB - Nuclear factor E2-related factor-2 (Nrf2) transcription factor is one of the main regulators of intracellular redox balance and a sensor of oxidative and electrophilic stress. Low Nrf2 activity is usually associated with carcinogenesis, but Nrf2 is also considered as an oncogene because it increases survival of transformed cells. Because intracellular redox balance alterations are involved in both senescence and tumorigenesis, we investigated the impact of Nrf2 genetic deletion on cellular immortalization and life span of murine embryonic fibroblasts. We report that Nrf2 genetic deletion promotes immortalization due to an early loss of p53-dependent gene expression. However, compared with control cells, immortalized Nrf2-/- murine embryonic fibroblasts exhibited decreased growth, lower cyclin E levels, and impaired expression of NQO1 and cytochrome b5 reductase. Moreover, SirT1 was also significantly reduced in immortalized Nrf2-/- murine embryonic fibroblasts, and these cells exhibited shorter life span. Our results underscore the dual role of Nrf2 in protection against carcinogenesis and in the delay of cellular aging. PMID- 20974734 TI - Water uptake by seminal and adventitious roots in relation to whole-plant water flow in barley (Hordeum vulgare L.). AB - Prior to an assessment of the role of aquaporins in root water uptake, the main path of water movement in different types of root and driving forces during day and night need to be known. In the present study on hydroponically grown barley (Hordeum vulgare L.) the two main root types of 14- to 17-d-old plants were analysed for hydraulic conductivity in dependence of the main driving force (hydrostatic, osmotic). Seminal roots contributed 92% and adventitious roots 8% to plant water uptake. The lower contribution of adventitious compared with seminal roots was associated with a smaller surface area and number of roots per plant and a lower axial hydraulic conductance, and occurred despite a less developed endodermis. The radial hydraulic conductivity of the two types of root was similar and depended little on the prevailing driving force, suggesting that water uptake occurred along a pathway that involved crossing of membrane(s). Exudation experiments showed that osmotic forces were sufficient to support night time transpiration, yet transpiration experiments and cuticle permeance data questioned the significance of osmotic forces. During the day, 90% of water uptake was driven by a tension of about -0.15 MPa. PMID- 20974735 TI - Identification and expression analysis of ERF transcription factor genes in petunia during flower senescence and in response to hormone treatments. AB - Ethylene-responsive element-binding factor (ERF) genes constitute one of the largest transcription factor gene families in plants. In Arabidopsis and rice, only a few ERF genes have been characterized so far. Flower senescence is associated with increased ethylene production in many flowers. However, the characterization of ERF genes in flower senescence has not been reported. In this study, 13 ERF cDNAs were cloned from petunia. Based on the sequence characterization, these PhERFs could be classified into four of the 12 known ERF families. Their predicted amino acid sequences exhibited similarities to ERFs from other plant species. Expression analyses of PhERF mRNAs were performed in corollas and gynoecia of petunia flower. The 13 PhERF genes displayed differential expression patterns and levels during natural flower senescence. Exogenous ethylene accelerates the transcription of the various PhERF genes, and silver thiosulphate (STS) decreased the transcription of several PhERF genes in corollas and gynoecia. PhERF genes of group VII showed a strong association with the rise in ethylene production in both petals and gynoecia, and might be associated particularly with flower senescence in petunia. The effect of sugar, methyl jasmonate, and the plant hormones abscisic acid, salicylic acid, and 6 benzyladenine in regulating the different PhERF transcripts was investigated. Functional nuclear localization signal analyses of two PhERF proteins (PhERF2 and PhERF3) were carried out using fluorescence microscopy. These results supported a role for petunia PhERF genes in transcriptional regulation of petunia flower senescence processes. PMID- 20974736 TI - The tomato xylem sap protein XSP10 is required for full susceptibility to Fusarium wilt disease. AB - XSP10 is an abundant 10 kDa protein found in the xylem sap of tomato. The protein displays structural similarity to plant lipid transfer proteins (LTPs). LTPs are involved in various physiological processes, including disease resistance, and some are able to bind and transfer diverse lipid molecules. XSP10 abundance in xylem sap declines upon infection with Fusarium oxysporum f. sp. lycopersici (Fol), implying involvement of XSP10 in the plant-pathogen interaction. Here, the biochemical characterization of XSP10 with respect to fatty acid-binding properties is reported; a weak but significant binding to saturated fatty acids was found. Furthermore, XSP10-silenced tomato plants were engineered and it was found that these plants exhibited reduced disease symptom development upon infection with a virulent strain of Fol. Interestingly, the reduced symptoms observed did not correlate with an altered expression profile for known reporter genes of plant defence (PR-1 and WIPI). This work demonstrates that XSP10 has lipid-binding properties and is required for full susceptibility of tomato to Fusarium wilt. PMID- 20974737 TI - The sucrose non-fermenting-1-related (SnRK) family of protein kinases: potential for manipulation to improve stress tolerance and increase yield. AB - Sucrose non-fermenting-1 (SNF1)-related protein kinases (SnRKs) take their name from their fungal homologue, SNF1, a global regulator of carbon metabolism. The plant family has burgeoned to comprise 38 members which can be subdivided into three sub-families: SnRK1, SnRK2, and SnRK3. There is now good evidence that this has occurred to allow plants to link metabolic and stress signalling in a way that does not occur in other organisms. The role of SnRKs, focusing in particular on abscisic acid-induced signalling pathways, salinity tolerance, responses to nutritional stress and disease, and the regulation of carbon metabolism and, therefore, yield, is reviewed here. The key role that SnRKs play at the interface between metabolic and stress signalling make them potential candidates for manipulation to improve crop performance in extreme environments. PMID- 20974738 TI - Conservation and divergence of autonomous pathway genes in the flowering regulatory network of Beta vulgaris. AB - The transition from vegetative growth to reproductive development is a complex process that requires an integrated response to multiple environmental cues and endogenous signals. In Arabidopsis thaliana, which has a facultative requirement for vernalization and long days, the genes of the autonomous pathway function as floral promoters by repressing the central repressor and vernalization-regulatory gene FLC. Environmental regulation by seasonal changes in daylength is under control of the photoperiod pathway and its key gene CO. The root and leaf crop species Beta vulgaris in the caryophyllid clade of core eudicots, which is only very distantly related to Arabidopsis, is an obligate long-day plant and includes forms with or without vernalization requirement. FLC and CO homologues with related functions in beet have been identified, but the presence of autonomous pathway genes which function in parallel to the vernalization and photoperiod pathways has not yet been reported. Here, this begins to be addressed by the identification and genetic mapping of full-length homologues of the RNA regulatory gene FLK and the chromatin-regulatory genes FVE, LD, and LDL1. When overexpressed in A. thaliana, BvFLK accelerates bolting in the Col-0 background and fully complements the late-bolting phenotype of an flk mutant through repression of FLC. In contrast, complementation analysis of BvFVE1 and the presence of a putative paralogue in beet suggest evolutionary divergence of FVE homologues. It is further shown that BvFVE1, unlike FVE in Arabidopsis, is under circadian clock control. Together, the data provide first evidence for evolutionary conservation of components of the autonomous pathway in B. vulgaris, while also suggesting divergence or subfunctionalization of one gene. The results are likely to be of broader relevance because B. vulgaris expands the spectrum of evolutionarily diverse species which are subject to differential developmental and/or environmental regulation of floral transition. PMID- 20974739 TI - Selection for low or high primary dormancy in Lolium rigidum Gaud seeds results in constitutive differences in stress protein expression and peroxidase activity. AB - Seed dormancy in wild Lolium rigidum Gaud (annual ryegrass) populations is highly variable and not well characterized at the biochemical level. To identify some of the determinants of dormancy level in these seeds, the proteomes of subpopulations selected for low and high levels of primary dormancy were compared by two-dimensional polyacrylamide gel electrophoresis of extracts from mature, dry seeds. High-dormancy seeds showed higher expression of small heat shock proteins, enolase, and glyoxalase I than the low-dormancy seeds. The functional relevance of these differences in protein expression was confirmed by the fact that high-dormancy seeds were more tolerant to high temperatures imposed at imbibition and had consistently higher glyoxalase I activity over 0-42 d dark stratification. Higher expression of a putative glutathione peroxidase in low dormancy seeds was not accompanied by higher activity, but these seeds had a slightly more oxidized glutathione pool and higher total peroxidase activity. Overall, these biochemical and physiological differences suggest that L. rigidum seeds selected for low dormancy are more prepared for rapid germination via peroxidase-mediated cell wall weakening, whilst seeds selected for high dormancy are constitutively prepared to survive environmental stresses, even in the absence of stress during seed development. PMID- 20974740 TI - Early cytokinin response proteins and phosphoproteins of Arabidopsis thaliana identified by proteome and phosphoproteome profiling. AB - Cytokinins are plant hormones involved in regulation of diverse developmental and physiological processes in plants whose molecular mechanisms of action are being intensely researched. However, most rapid responses to cytokinin signals at the proteomic and phosphoproteomic levels are unknown. Early cytokinin responses were investigated through proteome-wide expression profiling based on image and mass spectrometric analysis of two-dimensionally separated proteins and phosphoproteins. The effects of 15 min treatments of 7-day-old Arabidopsis thaliana seedlings with four main cytokinins representing hydroxyisopentenyl, isopentenyl, aromatic, and urea-derived type cytokinins were compared to help elucidate their common and specific function(s) in regulating plant development. In proteome and phosphoproteome maps, significant differences were reproducibly observed for 53 and 31 protein spots, respectively. In these spots, 96 proteins were identified by matrix-assisted laser desorption/ionization time-of flight/time-of-flight mass spectrometry (MALDI-TOF/TOF MS), providing a snapshot of early links in cytokinin-regulated signalling circuits and cellular processes, including light signalling and photosynthesis, nitrogen metabolism, the CLAVATA pathway, and protein and gene expression regulation, in accordance with previously described cytokinin functions. Furthermore, they indicate novel links between temperature and cytokinin signalling, and an involvement of calcium ions in cytokinin signalling. Most of the differentially regulated proteins and phosphoproteins are located in chloroplasts, suggesting an as yet uncharacterized direct signalling chain responsible for cytokinin action in chloroplasts. Finally, first insights into the degree of specificity of cytokinin receptors on phosphoproteomic effects were obtained from analyses of cytokinin action in a set of cytokinin receptor double mutants. PMID- 20974741 TI - Current progress in oocyte and embryo cryopreservation by slow freezing and vitrification. AB - Preservation of female genetics is currently done primarily by means of oocyte and embryo cryopreservation. The field has seen much progress during its four decade history, progress driven predominantly by research in humans, cows, and mice. Two basic cryopreservation techniques rule the field--controlled-rate freezing, the first to be developed, and vitrification, which, in recent years, has gained a foothold. While much progress has been achieved in human medicine, the cattle industry, and in laboratory animals, this is far from being the case for most other mammals and even less so for other vertebrates. The major strides and obstacles in human and other vertebrate oocyte and embryo cryopreservation will be reviewed here. PMID- 20974742 TI - Essential role of paternal chromatin in the regulation of transcriptional activity during mouse preimplantation development. AB - Several lines of evidence indicate that the formation of a transcriptionally repressive state during the two-cell stage in the preimplantation mouse embryo is superimposed on the activation of the embryonic genome. However, it is difficult to determine the profile of newly synthesized (nascent) RNA during this phase because large amounts of maternal RNA accumulate in maturing oocytes to support early development. Using 5-bromouridine-5'-triphosphate labeling of RNA, we have verified that nascent RNA synthesis was repressed between the two-cell and four cell transition in normally fertilized but not in parthenogenetic embryos. Moreover, this repression was contributed by sperm (male) chromatin, which we confirmed by studying androgenetic embryos. The source of factors responsible for repressing nascent RNA production was investigated using different stages of sperm development. Fertilization with immature round spermatids resulted in a lower level of transcriptional activity than with ICSI at the two-cell stage, and this was consistent with further repression at the four-cell stage in the ICSI group. Finally, study on DNA replication and chromatin remodeling was performed using labeled histones H3 and H4 to differentiate between male and female pronuclei. The combination of male and female chromatin appeared to decrease nascent RNA production in the fertilized embryo. This study indicates that paternal chromatin is important in the regulation of transcriptional activity during mouse preimplantation development and that this capacity is acquired during spermiogenesis. PMID- 20974743 TI - Associations of low-level urine cadmium with kidney function in lead workers. AB - OBJECTIVES: Low-level cadmium exposure, resulting in, for example, urinary cadmium <2.0 MUg/g creatinine, is widespread; recent data suggest nephrotoxicity even at these low levels. Few studies have examined the impact of low-level cadmium exposure in workers who are occupationally exposed to other nephrotoxicants such as lead. METHODS: We evaluated associations of urine cadmium, a measure of cumulative dose, with four glomerular filtration measures and N-acetyl-beta-D-glucosaminidase (NAG) in lead workers. Recent and cumulative lead doses were assessed via blood and tibia lead, respectively. RESULTS: In 712 lead workers, mean (SD) blood and tibia lead values, urine cadmium values and estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation were 23.1 (14.1) MUg/dl, 26.6 (28.9) MUg Pb/g bone mineral, 1.15 (0.66) MUg/g creatinine and 97.4 (19.2) ml/min/1.73 m(2), respectively. After adjustment for age, sex, body mass index, urine creatinine, smoking, alcohol, education, annual income, diastolic blood pressure, current or former lead worker job status, new or returning study participant, and blood and tibia lead, higher ln-urine cadmium was associated with higher calculated creatinine clearance, eGFR (beta = 8.7 ml/min/1.73 m(2); 95% CI 5.4 to 12.1) and ln-NAG but lower serum creatinine. CONCLUSIONS: Potential explanations for these results include a normal physiological response in which urine cadmium levels reflect renal filtration, the impact of adjustment for urine dilution with creatinine in models of kidney outcomes, and cadmium-related hyperfiltration. PMID- 20974744 TI - Development of retrospective quantitative and qualitative job-exposure matrices for exposures at a beryllium processing facility. AB - OBJECTIVES: To construct a job-exposure matrix (JEM) for an Ohio beryllium processing facility between 1953 and 2006 and to evaluate temporal changes in airborne beryllium exposures. METHODS: Quantitative area- and breathing-zone based exposure measurements of airborne beryllium were made between 1953 and 2006 and used by plant personnel to estimate daily weighted average (DWA) exposure concentrations for sampled departments and operations. These DWA measurements were used to create a JEM with 18 exposure metrics, which was linked to the plant cohort consisting of 18,568 unique job, department and year combinations. The exposure metrics ranged from quantitative metrics (annual arithmetic/geometric average DWA exposures, maximum DWA and peak exposures) to descriptive qualitative metrics (chemical beryllium species and physical form) to qualitative assignment of exposure to other risk factors (yes/no). Twelve collapsed job titles with long term consistent industrial hygiene samples were evaluated using regression analysis for time trends in DWA estimates. RESULTS: Annual arithmetic mean DWA estimates (overall plant-wide exposures including administration, non-production, and production estimates) for the data by decade ranged from a high of 1.39 MUg/m(3) in the 1950s to a low of 0.33 MUg/m(3) in the 2000s. Of the 12 jobs evaluated for temporal trend, the average arithmetic DWA mean was 2.46 MUg/m(3) and the average geometric mean DWA was 1.53 MUg/m(3). After the DWA calculations were log-transformed, 11 of the 12 had a statistically significant (p < 0.05) decrease in reported exposure over time. CONCLUSIONS: The constructed JEM successfully differentiated beryllium exposures across jobs and over time. This is the only quantitative JEM containing exposure estimates (average and peak) for the entire plant history. PMID- 20974745 TI - RiboSys, a high-resolution, quantitative approach to measure the in vivo kinetics of pre-mRNA splicing and 3'-end processing in Saccharomyces cerevisiae. AB - We describe methods for obtaining a quantitative description of RNA processing at high resolution in budding yeast. As a model gene expression system, we constructed tetON (for induction studies) and tetOFF (for repression, derepression, and RNA degradation studies) yeast strains with a series of reporter genes integrated in the genome under the control of a tetO7 promoter. Reverse transcription and quantitative real-time-PCR (RT-qPCR) methods were adapted to allow the determination of mRNA abundance as the average number of copies per cell in a population. Fluorescence in situ hybridization (FISH) measurements of transcript numbers in individual cells validated the RT-qPCR approach for the average copy-number determination despite the broad distribution of transcript levels within a population of cells. In addition, RT-qPCR was used to distinguish the products of the different steps in splicing of the reporter transcripts, and methods were developed to map and quantify 3'-end cleavage and polyadenylation. This system permits pre-mRNA production, splicing, 3'-end maturation and degradation to be quantitatively monitored with unprecedented kinetic detail, suitable for mathematical modeling. Using this approach, we demonstrate that reporter transcripts are spliced prior to their 3'-end cleavage and polyadenylation, that is, cotranscriptionally. PMID- 20974746 TI - Short RNA duplexes guide sequence-dependent cleavage by human Dicer. AB - Dicer is a member of the double-stranded (ds) RNA-specific ribonuclease III (RNase III) family that is required for RNA processing and degradation. Like most members of the RNase III family, Dicer possesses a dsRNA binding domain and cleaves long RNA duplexes in vitro. In this study, Dicer substrate selectivity was examined using bipartite substrates. These experiments revealed that an RNA helix possessing a 2-nucleotide (nt) 3'-overhang may bind and direct sequence specific Dicer-mediated cleavage in trans at a fixed distance from the 3'-end overhang. Chemical modifications of the substrate indicate that the presence of the ribose 2'-hydroxyl group is not required for Dicer binding, but some located near the scissile bonds are needed for RNA cleavage. This suggests a flexible mechanism for substrate selectivity that recognizes the overall shape of an RNA helix. Examination of the structure of natural pre-microRNAs (pre-miRNAs) suggests that they may form bipartite substrates with complementary mRNA sequences, and thus induce seed-independent Dicer cleavage. Indeed, in vitro, natural pre-miRNA directed sequence-specific Dicer-mediated cleavage in trans by supporting the formation of a substrate mimic. PMID- 20974747 TI - Prevention and schizophrenia--the role of dietary factors. AB - Adequate prenatal nutrition is essential for optimal brain development. There is a growing body of evidence from epidemiology linking exposure to nutritional deprivation and increased risk of schizophrenia. Based on studies from the Netherlands and China, those exposed to macronutrient deficiencies during famine have an increased risk of schizophrenia. With respect to micronutrients, we focus on 3 candidates where there is biological plausibility for a role in this disorder and at least 1 study of an association with schizophrenia. These nutrients include vitamin D, folic acid, and iron. While the current evidence is incomplete, we discuss the potential implications of these findings for the prevention of schizophrenia. We argue that schizophrenia can draw inspiration from public health interventions related to prenatal nutrition and other outcomes and speculate on relevant factors that bear on the nature, risks, impact, and logistics of various nutritional strategies that may be employed to prevent this disorder. PMID- 20974750 TI - Catastrophic and impoverishing effects of health expenditure: new evidence from the Western Balkans. AB - This paper investigates the effect of health-related expenditure on household welfare in Albania, Bosnia and Herzegovina, Montenegro, Serbia and Kosovo, all of which have undertaken major health sector reform. Two methodologies are used: (i) the incidence and intensity of 'catastrophic' health care expenditure, and (ii) the effect of out-of-pocket payments on poverty headcount and poverty gap measures. Data are drawn from the most recent Living Standards and Measurement Surveys, 2000-05. While our analyses are not without their limitations, and the lack of comparability across instruments precludes a direct comparison across countries, there is no doubt that health expenditure contributes substantially to the impoverishment of households-increasing the incidence of poverty and pushing poor households into deeper poverty-in each country. Both the catastrophic and the impoverishing effects of health expenditures are particularly severe in Albania and Kosovo. Transportation expenditure accounts for a large share of total health expenditures, especially in Albania and Serbia. Informal payments are substantial in all countries, and are particularly high in Albania. As countries in the sub-region continue the process of health system reform, an important policy question should be how to protect vulnerable groups from the catastrophic and impoverishing effects of health care expenditure. PMID- 20974748 TI - The prevention of schizophrenia--what can we learn from eco-epidemiology? AB - The search for the causes of schizophrenia has predominantly originated from 2 research paradigms; genetics and epidemiology. While each approach has made important contributions to etiological understanding, neither has fully resolved the exact milieu of risk factors for schizophrenia, and there is growing recognition that several pathways to the onset of such disorders may exist. Eco epidemiology offers an integrative framework to study schizophrenia etiology, incorporating multiple, interactive levels of causation, including genetic, epigenetic, individual, familial, community, and societal domains over the life course. In this article, we review the current evidence base, through the lens of eco-epidemiology, to determine whether it warrants the design and implementation of putative prevention strategies for schizophrenia. We argue that while there are potentially large public health gains available, we do not currently have sufficient empirical data to design effective prevention strategies. It will be important for the research community to more fully elucidate the likely multifactorial, multilevel, polygenetic, and eco-epidemiological basis of schizophrenia before we can design useful prevention strategies. We conclude by speculating on the forms effective strategies might take. PMID- 20974749 TI - Premorbid personality and insight in first-episode psychosis. AB - BACKGROUND: Insight in psychosis and schizophrenia is considered a complex biopsychosocial phenomenon. Premorbid personality is regarded by some authors as part of the substrate to many psychiatric phenomena, but it is not clear if this applies to insight. AIM: To examine longitudinal relationships between personality traits and insight dimensions in first-episode psychosis. METHODS: One hundred consecutive antipsychotic-naive first-episode nonaffective psychotic patients admitted to hospital were included in the study. Eighty-one patients completed at 1 month a premorbid personality evaluation, plus baseline, and 6 month insight assessments. We used the Assessment and Documentation of Psychopathology inventory for assessing insight dimensions (not feeling ill, lack of insight, and refusal of treatment) and the Personality Assessment Schedule for ascertaining 5 dimensions of premorbid personality (schizoid, passive-dependent, anancastic, sociopathic, and schizotypy). RESULTS: At baseline, personality dimensions did not show any association with insight dimensions, with the exception of schizotypy traits. At 6 months, schizoid and sociopathic personality showed a significant association with not feeling ill (r = .30, P <= .007; r = .27, P = .01) and lack of insight (r = .36, P = .001; r = .41, P < .001), respectively. When we calculated insight change, schizoid and sociopathic personality had moderate correlation with the lack of insight dimension (r = .34, P = .002; r = .38, P < .001, respectively). After applying partial correlations for potential confounders and Bonferroni correction, the associations remained significant. Moreover, using a regression model, sociopathic and schizoid personality significantly predicted lack of insight at 6 months and change from baseline to the 6 months assessment. CONCLUSIONS: Sociopathic and schizoid personality dimensions were not only significantly associated with lack of insight at 6 months but also predicted change on lack of insight over 6 months. Therefore, exploring premorbid personality traits at the beginning of a psychotic episode may be helpful in identifying patients at high risk for lack of insight during the initial course of the illness. PMID- 20974751 TI - Economic evaluation of a combined microfinance and gender training intervention for the prevention of intimate partner violence in rural South Africa. AB - OBJECTIVE: Assess the cost-effectiveness of an intervention combining microfinance with gender and HIV training for the prevention of intimate partner violence (IPV) in South Africa. METHODS: We performed a cost-effectiveness analysis alongside a cluster-randomized trial. We assessed the cost-effectiveness of the intervention in both the trial and initial scale-up phase. RESULTS: We estimated the cost per DALY gained as US$7688 for the trial phase and US$2307 for the initial scale-up. The findings were sensitive to the statistical uncertainty in effect estimates but otherwise robust to other key assumptions employed in the analysis. CONCLUSIONS: The findings suggest that this combined economic and health intervention was cost-effective in its trial phase and highly cost effective in scale-up. These estimates are probably conservative, as they do not include the health and development benefits of the intervention beyond IPV reduction. PMID- 20974752 TI - Integration of late-enhanced MRI and electroanatomical mapping for substrate ablation of poorly tolerated ventricular tachycardia. AB - We describe the case of a patient with a poorly tolerated ventricular tachycardia (VT) in which a substrate ablation was performed. The ablation was guided by the integrated images of the scar obtained by MRI and electro-anatomical mapping. This combined technique can make substrate ablation more accurate and may have a role in the ablation of unmappable VT. PMID- 20974753 TI - Can we predict cost of care in atrial fibrillation patients? PMID- 20974754 TI - In search of an arrhythmic cause of coronary artery disease: the electrophysiologist's next frontier? PMID- 20974755 TI - Impact of corticosteroids on late growth of radiofrequency lesions in infant pigs: histopathological and electroanatomical findings. AB - AIMS: Corticosteroids attenuate late growth of radiofrequency (RF) lesions in the thigh muscle of infant rats. We sought to assess the impact of these drugs on the late growth of RF lesions in immature swine myocardium and to determine the electroanatomical mapping (EAM) characteristics of these lesions. METHODS AND RESULTS: Radiofrequency (60 degrees C; 60 s) lesions were created in the right atrium (n = 2) and ventricle (n = 2) of 14 piglets (age 65 days; weight 5 kg) and 3 adults. Piglets were divided into: controls (n = 7) and treated (n = 7), receiving hydrocortisone (10 mg/kg iv after RF) and prednisone (1 mg/kg/day) for 29 days. After 8 months, animals were sacrificed for histological analysis. In four piglets, endocardial and epicardial voltage EAM were performed. In infant groups, the dimensions of atrial (11 +/- 5 vs. 13 +/- 7 mm) and ventricular (12 +/- 3 vs. 11 +/- 3 mm) lesions were similar. In adults, atrial (6 +/- 1 mm) and ventricular (6 +/- 1 mm) lesions were smaller. In controls, ventricular lesions depicted dense fibrosis and multiple strands of fibrous tissue extending from the lesion into normal muscle. Treated piglets revealed scars exhibiting less dense fibrosis with predominance of fibroadipose tissue and less collagen proliferation. Large atrial and ventricular low-voltage areas corresponding to the macroscopic lesions were identified in all animals. CONCLUSION: Radiofrequency lesions in infant pigs reveal late growth and invasion of normal muscle by intense collagen proliferation. Corticosteroids do not prevent late enlargement of the lesions but modulate the fibrotic proliferation. The expressive growth of the lesion may generate low-voltage areas detectable by EAM. PMID- 20974756 TI - Pulmonary vein ostium shape and orientation as possible predictors of occlusion in patients with drug-refractory paroxysmal atrial fibrillation undergoing cryoballoon ablation. AB - AIMS: No specific data are available on the influence of pulmonary vein (PV) anatomy and shape on cryoballoon ablation (CA) catheter efficacy in delivering cryothermal energy and, consequently, in obtaining PV isolation. METHODS AND RESULTS: Among a larger series of patients (68) with drug-refractory paroxysmal atrial fibrillation who underwent CA in our department, 52 patients were included in our study. All of them had a multislice cardiac computed tomography (MSCT) before the procedure. We retrospectively evaluated their MSCT scans focusing our attention on PV ovality and orientation in the frontal plane. A fair inverse association was documented between the ovality index of the left PVs and the degree of occlusion (r=-0.486 and P<0.003 for the LSPV and r=-0.360 and P=0.033 for the LIPV), whereas no association was found between the ovality index of the right PVs and the degree of occlusion (r=-0.283 and P=0.083 for the RSPV and r=0.235 and P=0.093 for RIPV). Nevertheless, a strong inverse association was found between the orientation of the PV ostia and the degree of occlusion in each vein (r=-0.804 and P<0.001 for the LSPV, r=-0.415 and P=0.013 for LIPV, r=-0.798 and P<0.001 for the RSPV, and r=-0.867 and P<0.001 for RIPV). CONCLUSION: Pulmonary vein ostium shape and orientation evaluated by MSCT proved to be useful in predicting the degree of occlusion obtained during CA. PMID- 20974757 TI - Management of patients receiving implantable cardiac defibrillator shocks: recommendations for acute and long-term patient management. PMID- 20974758 TI - Quadripolar left ventricular lead implantation through the anchor struts of a mitral valve annuloplasty device. AB - We describe cardiac resynchronization therapy in a patient with a mitral valve annuloplasty device in situ for functional mitral regurgitation. We successfully implanted a left ventricular lead through a mitral valve annuloplasty device anchor into the coronary sinus and then through the struts of the device's proximal anchor. PMID- 20974760 TI - Paced QRS morphology for confirming septal pacemaker lead implantation: correction of a misconception. PMID- 20974759 TI - Thrombogenesis in lone atrial fibrillation: a role for soluble P-selectin? PMID- 20974761 TI - Idiopathic premature ventricular contractions successfully ablated from the epicardial right ventricular outflow tract. AB - A case of idiopathic premature ventricular contractions successfully ablated from the epicardial right ventricular outflow tract (RVOT) via the subxiphoid pericardial approach was described. The sites with earliest endocardial and epicardial ventricular activation were located adjacent to each other in the RVOT and at both sites, double potentials were recorded. Coronary angiography was helpful for identifying the ablation site. PMID- 20974762 TI - Realtime fusion of cardiac magnetic resonance imaging and computed tomography venography with X-ray fluoroscopy to aid cardiac resynchronisation therapy implantation in patients with persistent left superior vena cava. PMID- 20974763 TI - Upstream therapies after pulmonary vein ablation: five negative studies--what's next? PMID- 20974764 TI - Carotid sinus hypersensitivity: disease state or clinical sign of ageing? The need for hard endpoints. PMID- 20974765 TI - The continuing challenge of typical atrial flutter ablation: it is the anatomy! (Again). PMID- 20974766 TI - Cell-based therapy of the failing heart: a need to connect for proper electrical and contractile function. PMID- 20974767 TI - 2010 Focused Update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC Guidelines for cardiac and resynchronization therapy. Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association. PMID- 20974768 TI - Effectiveness of prophylactic implantation of cardioverter-defibrillators without cardiac resynchronization therapy in patients with ischaemic or non-ischaemic heart disease: a systematic review and meta-analysis. AB - AIMS: Much controversy exists concerning the efficacy of primary prophylactic implantable cardioverter-defibrillators (ICDs) in patients with low ejection fraction due to coronary artery disease (CAD) or dilated cardiomyopathy (DCM). This is also related to the bias created by function improving interventions added to ICD therapy, e.g. resynchronization therapy. The aim was to investigate the efficacy of ICD-only therapy in primary prevention in patients with CAD or DCM. METHODS AND RESULTS: Public domain databases, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials, were searched from 1980 to 2009 for randomized clinical trials of ICD vs. conventional therapy. Two investigators independently abstracted the data. Pooled estimates were calculated using both fixed-effects and random-effects models. Eight trials were included in the final analysis (5343 patients). Implantable cardioverter-defibrillators significantly reduced the arrhythmic mortality [relative risk (RR): 0.40; 95% confidence interval (CI): 0.27-0.67] and all-cause mortality (RR: 0.73; 95% CI: 0.64-0.82). Regardless of aetiology of heart disease, ICD benefit was similar for CAD (RR: 0.67; 95% CI: 0.51-0.88) vs. DCM (RR: 0.74; 95% CI: 0.59-0.93). CONCLUSIONS: The results of this meta-analysis provide strong evidence for the beneficial effect of ICD-only therapy on the survival of patients with ischaemic or non-ischaemic heart disease, with a left ventricular ejection fraction <= 35%, if they are 40 days from myocardial infarction and >= 3 months from a coronary revascularization procedure. PMID- 20974770 TI - We were there... PMID- 20974769 TI - Internal jugular vein thrombosis: outcome and risk factors. AB - INTRODUCTION: The aims of this study were to analyse the characteristics of patients with internal jugular venous thrombosis. We compared the characteristics of patients with internal jugular venous thrombosis with those of patients exhibiting upper extremity deep venous thrombosis (UEDVT) without internal jugular vein involvement. PATIENTS: From 1998 to 2007, 1948 consecutive patients were referred to our Department of Internal Medicine for deep venous thrombosis. RESULTS: Sixty-four patients exhibited UEDVT. Internal jugular venous thrombosis was diagnosed in 29 patients. Twenty-three patients had secondary thrombosis mainly due to cancer, central venous catheter and ovarian hyperstimulation syndrome; three of the four patients with bilateral DVT exhibited cancer. Six patients had primary internal jugular vein thrombosis. Complications of internal jugular vein thrombosis were pulmonary embolism (10.3%) and post-thrombotic syndrome (41.4%). Under multivariate analysis, significant factors for internal jugular vein thrombosis were older patients (P = 0.0008), female gender (P = 0.0035) and ovarian hyperstimulation syndrome (P = 0.0093). CONCLUSION: Our study underscores that the most common causes of internal jugular vein thrombosis are cancer, central venous catheter and ovarian hyperstimulation syndrome; it also underlines that bilateral internal jugular vein thrombosis is a significant risk indicator of malignancy Thrombosis led to high morbidity related to pulmonary embolism and post-thrombotic syndrome, principally in patients with secondary DVT. The knowledge of predictive factors of internal jugular vein thrombosis seems to be of utmost importance to improve patients' management. PMID- 20974771 TI - Rapid topology probing using fluorescence spectroscopy in planar lipid bilayer: the pore-forming mechanism of the toxin Cry1Aa of Bacillus thuringiensis. AB - Pore-forming toxins, many of which are pathogenic to humans, are highly dynamic proteins that adopt a different conformation in aqueous solution than in the lipid environment of the host membrane. Consequently, their crystal structures obtained in aqueous environment do not reflect the active conformation in the membrane, making it difficult to deduce the molecular determinants responsible for pore formation. To obtain structural information directly in the membrane, we introduce a fluorescence technique to probe the native topology of pore-forming toxins in planar lipid bilayers and follow their movement during pore formation. Using a Forster resonance energy transfer (FRET) approach between site-directedly labeled proteins and an absorbing compound (dipicrylamine) in the membrane, we simultaneously recorded the electrical current and fluorescence emission in horizontal planar lipid bilayers formed in plastic chips. With this system, we mapped the topology of the pore-forming domain of Cry1Aa, a biological pesticide from Bacillus thuringiensis, by determining the location of the loops between its seven alpha helices. We found that the majority of the toxins initially traverse from the cis to the trans leaflet of the membrane. Comparing the topologies of Cry1Aa in the active and inactive state in order to identify the pore-forming mechanism, we established that only the alpha3-alpha4 hairpin translocates through the membrane from the trans to the cis leaflet, whereas all other positions remained constant. As toxins are highly dynamic proteins, populations that differ in conformation might be present simultaneously. To test the presence of different populations, we designed double-FRET experiments, where a single donor interacts with two acceptors with very different kinetics (dipicrylamine and oxonol). Due to the nonlinear response of FRET and the dynamic change of the acceptor distribution, we can deduce the distribution of the acceptors in the membrane from the time course of the donor fluorescence. We found that Cry1Aa is present on both membrane leaflets. PMID- 20974772 TI - Origin of basal activity in mammalian olfactory receptor neurons. AB - Mammalian odorant receptors form a large, diverse group of G protein-coupled receptors that determine the sensitivity and response profile of olfactory receptor neurons. But little is known if odorant receptors control basal and also stimulus-induced cellular properties of olfactory receptor neurons other than ligand specificity. This study demonstrates that different odorant receptors have varying degrees of basal activity, which drives concomitant receptor current fluctuations and basal action potential firing. This basal activity can be suppressed by odorants functioning as inverse agonists. Furthermore, odorant stimulated olfactory receptor neurons expressing different odorant receptors can have strikingly different response patterns in the later phases of prolonged stimulation. Thus, the influence of odorant receptor choice on response characteristics is much more complex than previously thought, which has important consequences on odor coding and odor information transfer to the brain. PMID- 20974774 TI - Challenging quantal calcium signaling in cardiac myocytes. PMID- 20974773 TI - The contribution of individual subunits to the coupling of the voltage sensor to pore opening in Shaker K channels: effect of ILT mutations in heterotetramers. AB - Voltage-gated ion channels couple conformational change(s) of the voltage-sensing domain to those of the opening of an intracellular gate to allow ionic conduction. Much larger positive potentials are required to couple these conformational changes to the opening of the gate of Shaker K(+) channels with the concurrent mutations V369I, I372L, and S376T (ILT) at the N-terminal end of the S4 segment. We used cut-open oocyte voltage clamp to study the biophysical and thermodynamical properties of heterotetrameric concatemerized channels with different stoichiometries of ILT mutations. The voltage-sensing domains of ILT mutant channels require smaller depolarization to activate but their intracellular gate does not immediately follow the movement of the voltage sensing domain, requiring larger depolarization to open. Our results demonstrate that each subunit contributes equally to the rightward shift of the conductance voltage relationship and that a single ILT-containing subunit is sufficient to induce a large enthalpic and entropic barrier, limiting opening of the intracellular gate. PMID- 20974775 TI - Sleeping through the night: the consolidation of self-regulated sleep across the first year of life. AB - OBJECTIVE: To investigate the consolidation of infants' self-regulated nocturnal sleep over the first year, to determine when infants first sleep through the night from 24:00 to 05:00 hours (criterion 1), for 8 hours (criterion 2), or between 22:00 and 06:00 hours (the family-congruent criterion 3). METHODS: This was a prospective longitudinal study with repeated measures. Parents of 75 typically developing infants completed sleep diaries for 6 days each month for 12 months. Accuracy of parent reports were assessed by using videosomnography. RESULTS: The largest mean increase (504 minutes) in self-regulated sleep length occurred from 1 to 4 months. The survival function decreased most rapidly (indicating greatest probability of meeting criteria) for criterion 1 at 2 months, criterion 2 at 3 months, and criterion 3 at 4 months. A 50% probability of meeting criteria 1 and 2 occurred at 3 months and at 5 months for criterion 3. The hazard function identified 2 months (criteria 1 and 2) and 3 months (criterion 3) as the most likely ages for sleeping through the night. At 12 months, 11 infants did not meet criteria 1 or 2, whereas 21 failed to meet criterion 3. CONCLUSIONS: The most rapid consolidation in infant sleep regulation occurs in the first 4 months. Most infants are sleeping through the night at 2 and 3 months, regardless of the criterion used. The most developmentally and socially valid criterion for sleeping through is from 22:00 to 0:600 hours. At 5 months, more than half of infants are sleeping concurrently with their parents. PMID- 20974776 TI - Incorporating recognition and management of perinatal and postpartum depression into pediatric practice. AB - Every year, more than 400,000 infants are born to mothers who are depressed, which makes perinatal depression the most underdiagnosed obstetric complication in America. Postpartum depression leads to increased costs of medical care, inappropriate medical care, child abuse and neglect, discontinuation of breastfeeding, and family dysfunction and adversely affects early brain development. Pediatric practices, as medical homes, can establish a system to implement postpartum depression screening and to identify and use community resources for the treatment and referral of the depressed mother and support for the mother-child (dyad) relationship. This system would have a positive effect on the health and well-being of the infant and family. State chapters of the American Academy of Pediatrics, working with state Early Periodic Screening, Diagnosis, and Treatment (EPSDT) and maternal and child health programs, can increase awareness of the need for perinatal depression screening in the obstetric and pediatric periodicity of care schedules and ensure payment. Pediatricians must advocate for workforce development for professionals who care for very young children and for promotion of evidence-based interventions focused on healthy attachment and parent-child relationships. PMID- 20974778 TI - Laronidase for cardiopulmonary disease in Hurler syndrome 12 years after bone marrow transplantation. AB - A patient with severe mucopolysaccharidosis type I (Hurler syndrome) underwent bone marrow transplantation twice (at the ages of 2 and 2.5 years), both times with his HLA-identical heterozygous brother as the donor. Between the ages of 10 and 14 years, despite 92% donor engraftment and 50% normal alpha-L-iduronidase activity, he developed progressive respiratory failure with severe pulmonary arterial hypertension, upper airway obstruction, and interstitial lung disease. Noninvasive ventilation and weekly laronidase therapy were initiated. Within 24 months, his mean pulmonary artery pressure was within the upper limit of normal and interstitial lung disease and airway obstruction improved markedly. He went from using a wheelchair to having full ambulation, he no longer required daytime ventilation, and his quality-of-life scores (Child Health Assessment Questionnaire) significantly improved. PMID- 20974779 TI - The actual prevalence of autism: are we there yet? PMID- 20974780 TI - Oh, what you can see: the role of observation in medical student education. PMID- 20974781 TI - Clinical features suggestive of meningitis in children: a systematic review of prospective data. AB - CONTEXT: Clinical diagnosis of pediatric meningitis is fundamental; therefore, familiarity with evidence underscoring clinical features suggestive of meningitis is important. OBJECTIVE: To seek evidence supporting accuracy of clinical features of pediatric bacterial meningitis. METHODS: A review of Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature, Web of Science, and PubMed was conducted for all articles of relevance. Articles contained prospective data of clinical features in children with laboratory-confirmed bacterial meningitis and in comparison groups of those without it. Two authors independently assessed quality and extracted data to calculate accuracy data of clinical features. RESULTS: Of 14 145 references initially identified, 10 met our inclusion criteria. On history, a report of bulging fontanel (likelihood ratio [LR]: 8.00 [95% confidence interval (CI): 2.4-26]), neck stiffness (7.70 [3.2 19]), seizures (outside febrile-convulsion age range) (4.40 [3.0-6.4]), or reduced feeds (2.00 [1.2-3.4]) raised concern about the presence of meningitis. On examination, jaundice (LR: 5.90 [95% CI: 1.8-19]), being toxic or moribund (5.80 [3.0-11]), meningeal signs (4.50 [2.4-8.3]), neck stiffness (4.00 [2.6 6.3]), bulging fontanel (3.50 [2.0-6.0]), Kernig sign (3.50 [2.1-5.7]), tone up (3.20 [2.2-4.5]), fever of >40 degrees C (2.90 [1.6-5.5]), and Brudzinski sign (2.50 [1.8-3.6]) independently raised the likelihood of meningitis. The absence of meningeal signs (LR: 0.41 [95% CI: 0.30-0.57]) and an abnormal cry (0.30 [0.16 0.57]) independently lowered the likelihood of meningitis. The absence of fever did not rule out meningitis (LR: 0.70 [95% CI: 0.53-0.92]). CONCLUSIONS: Evidence for several useful clinical features that influence the likelihood of pediatric meningitis exists. No isolated clinical feature is diagnostic, and the most accurate diagnostic combination is unclear. PMID- 20974782 TI - Interpreting complete blood counts soon after birth in newborns at risk for sepsis. AB - BACKGROUND: A complete blood count (CBC) with white blood cell differential is commonly ordered to evaluate newborns at risk for sepsis. OBJECTIVES: To quantify how well components of the CBC predict sepsis in the first 72 hours after birth. METHODS: For this retrospective cross-sectional study we identified 67 623 term and late-preterm (>= 34 weeks gestation) newborns from 12 northern California Kaiser hospitals and 1 Boston, Massachusetts hospital who had a CBC and blood culture within 1 hour of each other at <72 hours of age. We compared CBC results among newborns whose blood cultures were and were not positive and quantified discrimination by using receiver operating characteristic curves and likelihood ratios. RESULTS: Blood cultures of 245 infants (3.6 of 1000 tested newborns) were positive. Mean white blood cell (WBC) counts and mean absolute neutrophil counts (ANCs) were lower, and mean proportions of immature neutrophils were higher in newborns with infection; platelet counts did not differ. Discrimination improved with age in the first few hours, especially for WBC counts and ANCs (eg, the area under the receiver operating characteristic curve for WBC counts was 0.52 at <1 hour and 0.87 at >= 4 hours). Both WBC counts and ANCs were most informative when very low (eg, the likelihood ratio for ANC < 1000 was 115 at >= 4 hours). No test was very sensitive; the lowest likelihood ratio (for WBC count >= 20 000 at >= 4 hours) was 0.16. CONCLUSION: Optimal interpretation of the CBC requires using interval likelihood ratios for the newborn's age in hours. PMID- 20974783 TI - The effects of gestational age and birth weight on false-positive newborn screening rates. AB - OBJECTIVE: Newborn-screening false-positive rates (FPRs) are disproportionately increased in preterm infants. The objective of this study was to determine variation in newborn screening FPRs according to birth weight and gestational age. Our secondary objective was to examine the effect of postnatal age on FPRs in preterm infants. METHODS: The Ohio State Newborn Screening Program Database was analyzed to determine the overall and birth weight-specific FPRs for 18 analytes. Data were stratified into birth weight categories (<1000 g, 1000-1499 g, 1500-2499 g, 2500-3999 g, and >4000 g). In addition, to examine the effect of postnatal age on FPRs, we examined the 2 analytes with the highest FPRs, thyrotropin with back-up thyroxine and 17-hydroxyprogesterone, in infants whose gestational age was <32 weeks, determined on the basis of postnatal age at screening. RESULTS: Data from 448 766 neonates were reviewed. Infants with very low birth weight (VLBW) comprised 1.9% of the study cohort, but accounted for 18% of false-positive results. For 14 of 18 analytes studied, FPRs increased with decreasing birth weight/gestational age and were significantly increased in infants with VLBW compared with infants who weighed 2500 to 3999 g (P < .001). Thyrotropin/back-up thyroxine and 17-hydroxyprogesterone accounted for 62% of total false-positive results in VLBW infants. When blood specimens were collected at a postnatal age of >= 48 hours in infants born at <32 weeks, a 44% relative reduction in 17-hydroxyprogesterone false-positive results was detected. CONCLUSIONS: False-positive newborn-screening rates are disproportionately increased in VLBW infants. FPRs may be reduced by delaying screening of <32 weeks' gestation, preterm infants until 24 to 48 hours' postnatal age. PMID- 20974784 TI - Two pediatric cases of multidrug-resistant tuberculosis treated with linezolid and moxifloxacin. AB - We report here 2 pediatric cases of multidrug-resistant (MDR) tuberculosis (TB) that were observed in Italy. Both families came from an Eastern European country, which is notably an area with a high prevalence of MDR TB. An increase of new cases of MDR TB in developed countries is expected over the next years because of migratory flow, and specific measures and strategies need to be taken to prevent the propagation and dissemination of MDR TB. An efficacious treatment including linezolid and moxifloxacin was administered for 13 months in 1 case. No adverse reactions were detected during close child monitoring. Linezolid and newer fluoroquinolones such as moxifloxacin have been reported to be effective for MDR TB treatment in adults. On the contrary, there is limited available evidence regarding the effectiveness and safety of these drugs in infants and children with MDR TB. The use of second-line drugs not approved for use in children may be necessary to treat a life-threatening disease such as MDR TB, but it requires careful monitoring to quickly recognize the occurrence of dose- and duration dependent adverse drug reactions. PMID- 20974785 TI - Effects of resistance training in children and adolescents: a meta-analysis. AB - CONTEXT: Although physiologic benefits of resistance training for children and adolescents have been well documented, the impact of age and maturity on trainability of muscle strength remains poorly understood. OBJECTIVE: To assess the effects of resistance training in different age groups and maturity levels. METHODS: We searched electronic bibliographic databases, key journals, and reference lists of reviews, book chapters, and articles. Two independent reviewers evaluated the effects of resistance training on muscle strength for prepubertal and postpubertal healthy children and adolescents (younger than 18 years) by using the results of randomized and nonrandomized controlled trials. Assessments of muscle endurance and motor performance tests (eg, vertical jump) were excluded. The influence of continuous and categorical moderator variables was assessed by meta-regression and subgroup analyses, respectively. RESULTS: The overall weighted effect size of 1.12 (95% confidence interval: 0.9-1.3) was significantly greater than 0 (P < .01). Subgroup analyses revealed "maturity" to be a significant categorical moderator variable (z = 2.50; P = .01) and positive correlation coefficients were found for the continuous variables "duration" (r = 0.28; P = .02) and "frequency" (r = 0.26; P = .03). CONCLUSIONS: The results of our analysis indicate that the ability to gain muscular strength seems to increase with age and maturational status, but there is no noticeable boost during puberty. Furthermore, study duration and the number of performed sets were found to have a positive impact on the outcome. PMID- 20974786 TI - Principles of health care financing. AB - The American Academy of Pediatrics advocates that all children must have health insurance coverage that ensures them access to affordable and comprehensive quality care. Access to care depends on the design and implementation of payment systems that ensure the economic viability of the medical home; support and grow the professional pediatric workforce; promote the adoption and implementation of health information technology; enhance medical education, training, and research; and encourage and reward quality-improvement programs that advance and strengthen the medical home. Health insurance plans must be portable from state to state, with administrative procedures to eliminate breaks and gaps in coverage to ensure continuous coverage from year to year. Plans should ensure free choice of clinicians and foster coordination with public and private community-based programs for infants, children, and adolescents through the age of 26. The scope of services provided by all health plans must include preventive, acute and chronic illness, behavioral, inpatient, emergency, and home health care. These plans must be affordable and have cost-sharing policies that protect patients and families from financial strain and are without risk of loss of benefits because of plan design, current illness, or preexisting condition. PMID- 20974787 TI - Neonatal resuscitation: a global challenge. PMID- 20974788 TI - Reliability of clinical examinations for pediatric skin and soft-tissue infections. AB - OBJECTIVE: To determine the interrater reliability of clinical examination by pediatric emergency medicine physicians for the diagnosis of skin and soft-tissue infections (SSTIs). METHODS: A cross-sectional study of patients presenting to a pediatric emergency department with SSTIs was performed. Each lesion was examined by a treating physician and a study physician (from a pool of 62 physicians) at the bedside during the emergency department visit. The primary outcome was reliability, as measured with the weighted kappa statistic, for determining whether the lesion was an abscess and whether the lesion required a drainage procedure. RESULTS: A total of 371 lesions were analyzed for interrater reliability. The weighted kappa value for diagnosis of the lesion as an abscess was 0.39 (95% confidence interval: 0.32-0.47), and that for assessment of the need for drainage was 0.43 (95% confidence interval: 0.36-0.51). Agreement was statistically more likely for lesions in children >= 4 years of age but was not more likely for lesions in nonblack patients, lesions in patients with a history of or exposure to a close contact with a SSTI, or lesions examined by 2 experienced pediatric emergency medicine physicians. CONCLUSIONS: Among the 62 participating physicians at our site, the reliability of the clinical examination was poor. This may indicate that improved education and/or more-objective means for diagnosing these infections in the acute care setting are warranted. Additional studies are needed to determine whether these results are generalizable to other settings. PMID- 20974789 TI - Variation in methods of predicting adult height for children with idiopathic short stature. AB - OBJECTIVE: Recombinant human growth hormone (GH) is approved for treatment of children with idiopathic short stature, and endocrinologists often depend on algorithms to predict adult height. Because algorithm performance often is included in treatment decisions, we sought to evaluate agreement among height prediction formulas. METHODS: We identified 3 commonly used algorithms for height prediction, the Bayley-Pinneau, Roche-Wainer-Thissen, and Khamis-Roche methods. We constructed simulated samples of children with typical distributions of ages, heights, weights, bone ages, and parental heights seen in patients with idiopathic short stature, and we applied the algorithms to the simulated sample to determine whether predicted adult height was <160 cm for boys or <150 cm for girls (<1.2nd height percentiles for adults). RESULTS: We found substantial disagreement among algorithms in the proportions of simulated cases with predicted adult heights of <1.2nd percentile, a cutoff value that may influence GH treatment decisions. With the Bayley-Pinneau formula, 43% of boys and 81% of girls had predicted adult heights below this threshold; with the Khamis-Roche method, only 3% of boys and 0.2% of girls had predicted heights of <1.2nd percentile. Roche-Wainer-Thissen predictions were between those values. Overall agreement of the methods was poor (kappa = 0.21) for boys and negative for girls. CONCLUSIONS: Wide variation exists among formulas used to predict adult heights. Because these algorithms may be used in decisions regarding whether to initiate GH treatment and assessment of the efficacy of GH in research trials, it is important for parents, pediatricians, and investigators to recognize the considerable variation involved in height predictions. PMID- 20974790 TI - Trends in the prevalence of autism on the basis of special education data. AB - OBJECTIVE: The goal was to determine whether the increasing prevalence of autism, on the basis of educational data, in Wisconsin between 2002 and 2008 was uniform in all school districts or was greatest in districts with lower baseline (2002) prevalence. METHODS: Special education counts were obtained for all Wisconsin elementary school districts from 2002 through 2008. The annual prevalence of children being served under the autism category was calculated for each district, districts were grouped into 8 categories (octiles) according to their baseline prevalence, and prevalence trends were plotted according to octile. RESULTS: The overall prevalence of use of the autism category in Wisconsin elementary schools increased from 4.9 to 9.0 cases per 1000 children between 2002 and 2008. The magnitude of this increase was not uniform across districts and was inversely associated with baseline prevalence. Prevalence in the lowest octile increased from 0.5 cases per 1000 students in 2002 to 7.0 cases per 1000 students in 2008 (P < .0001), whereas no significant trend was seen for the octile with the highest baseline prevalence (range: 11.2-12.3 cases per 1000 students; P = .11). The highest-octile/lowest-octile prevalence ratio decreased from 24.6 (95% confidence interval: 16.2-37.3) in 2002 to 1.8 (95% confidence interval: 1.6-2.1) in 2008. CONCLUSIONS: The prevalence of use of the autism special education category in Wisconsin seems to be leveling off in the school districts with the highest prevalence rates, at ~12 cases per 1000 students, whereas the gap in prevalence between districts overall has narrowed. PMID- 20974791 TI - Sexual behaviors and sexual violence: adolescents with opposite-, same-, or both sex partners. AB - OBJECTIVE: To describe sexual behaviors, sexual violence, and sexual identity among a population-based sample of adolescents according to the sex of their sex partners, considering separately those with partners of both sexes. METHODS: From the 2005-2007 New York City Youth Risk Behavior Surveys, 3805 male and 3456 female adolescents reported having had sex and the sex of their sexual contacts. Subgroups were constructed: only opposite-sex partners; only same-sex partners; and partners of both sexes (both-sex partners). Weighted prevalence, risk behaviors (eg, using drugs/alcohol with sex), and sexual identity among subgroups were described. RESULTS: Similar numbers of sexually active male (3.2%) and female adolescents (3.2%) reported only same-sex behavior, but fewer male than female adolescents reported both-sex partners (3.7% vs 8.7%; P < .001). Male adolescents with both-sex partners reported a higher prevalence of sexual risk behaviors than male adolescents with only opposite-sex or only same-sex partners. Female adolescents with both-sex or only same-sex partners reported a higher prevalence of risk behaviors than female adolescents with only opposite-sex partners. Adolescents with both-sex partners reported a marked prevalence of dating violence and forced sex. Many adolescents with only same- or both-sex partners (38.9%) self-identified as straight. CONCLUSIONS: Of sexually active adolescents, 9.3% reported a same-sex partner, a higher estimate than other published rates. Those who reported both male and female partners reported behaviors that placed them at risk for sexually transmitted infections (STIs), including HIV. Pediatricians and school health providers must inquire about behaviors, not identity, to determine STI risk, and STI education should be appropriate for youth with same-sex partners. PMID- 20974792 TI - Just say "I don't": lack of concordance between teen report and biological measures of drug use. AB - BACKGROUND: Prevalence estimates of illicit drug use by teens are typically generated from confidential or anonymous self-report. While data comparing teen self-report with biological measures are limited, adult studies identify varying degrees of under-reporting. METHODS: Hair analyses for cocaine, opiates and marijuana were compared to confidential teen self- and parent-reported teen drug use in a longitudinal cohort of >400 high-risk urban teens and parents. RESULTS: Both teens and parents substantially underreported recent teen cocaine and opiate use. However, compared with parents, teens were more likely to deny biomarker verified cocaine use. Teen specimens (hair) were 52 times more likely to identify cocaine use compared with self-report. Parent hair analyses for cocaine and opiate use were 6.5 times and 5.5 times, respectively, more likely to indicate drug use than were parental self-report. The lack of concordance between self report and bioassay occurred despite participant's knowledge that a "certificate of confidentiality" protected both teen and adult participants, and that the biological specimens would be tested for drugs. CONCLUSIONS: These findings confirm prior reports of adult under-reporting of their own drug use while extending our understanding of teen's self-admitted drug use. The lack of concordance between teen self- or parent-reported teen drug use and biomarkers confirm our concerns that both teen- and parent-reported teen drug use is limited, at least for youth in high-risk urban settings. Methods of ascertainment other than self- or parent-report must be considered when health care providers, researchers and public health agencies attempt to estimate teen drug-use prevalence. PMID- 20974793 TI - Economic outcomes in young adulthood for extremely low birth weight survivors. AB - OBJECTIVE: The goal was to compare educational attainment and labor market outcomes in young adulthood (21-26 years of age) for a Canadian, population-based cohort of 149 extremely low birth weight (ELBW) (<1000 g) survivors and a normal birth weight (NBW) cohort of 133 young adults from the same geographic area who were matched to the ELBW cohort in childhood. METHODS: We estimated the effects of ELBW status, according to gender, on continuous outcomes through least-squares regression and those on binary outcomes through logistic regression. We controlled for family background and considered neurosensory impairment and IQ as mediating variables. RESULTS: Controlling for family background, ELBW male subjects were less likely to complete high school or to attend a university than were their NBW counterparts, and their educational attainment was reduced by >1 year. Among subjects who were working, weekly earnings were ~27% lower. ELBW female effects on education were not significant, but ELBW female subjects were less likely than NBW subjects to be employed or in school and they also seemed to experience lower earnings. CONCLUSION: Our findings suggested that ELBW survivors are somewhat less productive as adults, on average, than are subjects born NBW and that effects are not confined to subjects with severe neurosensory impairments. In accord with other studies, however, we found that productivity deficits for most ELBW subjects were not large. PMID- 20974794 TI - Consent by proxy for nonurgent pediatric care. AB - Minor-aged patients are often brought to the pediatrician for nonurgent acute medical care, physical examinations, or health supervision visits by someone other than their legally authorized representative, which, in most situations, is a parent. These surrogates or proxies can be members of the child's extended family, such as a grandparent, adult sibling, or aunt/uncle; a noncustodial parent or stepparent in cases of divorce and remarriage; an adult who lives in the home but is not biologically or legally related to the child; or even a child care professional (eg, au pair, nanny). This report identifies common situations in which pediatricians may encounter "consent by proxy" for nonurgent medical care for minors, including physical examinations, and explains the potential for liability exposure associated with these circumstances. The report suggests practical steps that balance the need to minimize the physician's liability exposure with the patient's access to health care. Key issues to be considered when creating or updating office policies for obtaining and documenting consent by proxy are offered. PMID- 20974796 TI - The effects of sampling procedures and storage conditions on short-term stability of blood-based biochemical markers of bone metabolism. PMID- 20974795 TI - Innovative Therapies for Children with Cancer pediatric phase I study of erlotinib in brainstem glioma and relapsing/refractory brain tumors. AB - This multicenter phase I study aimed to establish the recommended dose (RD) of the epidermal growth factor receptor (EGFR) inhibitor erlotinib, given as monotherapy or with radiotherapy to children with malignant brain tumors. Group 1 included patients with refractory or relapsing brain tumors receiving erlotinib alone, and group 2 included newly diagnosed patients with brainstem gliomas receiving radiotherapy and erlotinib. A conventional 3 + 3 dose escalation and a continual reassessment method, respectively, were utilized in 4 dose levels: 75, 100, 125, and 150 mg/m2 per day. Fifty-one children were enrolled (30 and 21, respectively); 50 received treatment. The RD of erlotinib was 125 mg/m2 per day as monotherapy or in combination with radiotherapy. Overall, 230 adverse events in 44 patients were possibly treatment related (216, grades 1 and 2; 9, grade 3; 1, grade 4; 4, grade 5). Dermatologic and neurologic symptoms were common; intratumoral hemorrhage was confirmed in 3 patients. In group 1, 8 of 29 patients (28%) had stable disease with tumor regression approaching 50% in a malignant glioma and an anaplastic oligoastrocytoma. In group 2, overall survival was 12.0 months. EGFR overexpression by immunohistochemistry was found in 17 of 38 (45%) tumor samples analyzed, with a partial gain of 7p11.2 in 1 glioblastoma; phosphate and tensin homolog loss was frequent in brainstem glioma (15 of 19). Mean (95% CI) apparent clearance and volume of distribution for erlotinib were 4.0 L/h (3.4-4.5 L/h) and 98.6 L (69.8-127.0 L), respectively, and were independent of the dose level; mean half-life was 16.6 hours. Thus, erlotinib 125 mg/m2 per day has an acceptable tolerability profile in pediatric patients with brain tumors and can be combined with radiotherapy. PMID- 20974798 TI - Cardiac troponins T and I: reproducible discrepancies in the clinical setting. PMID- 20974797 TI - Full COLD-PCR protocol for noninvasive prenatal diagnosis of genetic diseases. PMID- 20974799 TI - Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial--clinical implications. PMID- 20974800 TI - Hypoglycemia and vascular disease. PMID- 20974801 TI - Is oxidative stress a therapeutic target in cardiovascular disease? AB - An abnormal production of reactive oxygen species (ROS) and the subsequent decrease in vascular bioavailability of nitric oxide (NO) have long been proposed to be the common pathogenetic mechanism of the endothelial dysfunction, resulting from diverse cardiovascular risk factors such as hypercholesterolaemia, diabetes mellitus, chronic smoking, metabolic syndrome, and hypertension. Superoxide produced by the nicotinamide dinucleotide phosphate (NADPH) oxidase, mitochondrial sources, or the xanthine oxidase may react with NO, thereby resulting in excessive formation of peroxynitrite, a reactive nitrogen species that has been demonstrated to accelerate the atherosclerotic process by causing direct structural damage and by causing further ROS production. Despite this sound biological rationale and a number of pre-clinical and clinical lines of evidence, studies testing the effects of classical antioxidants such as vitamin C, vitamin E, or folic acid in combination with vitamin E have been disappointing. Rather, substances such as statins, angiotensin-converting enzyme inhibitors, or AT1-receptor blockers, which possess indirect antioxidant properties mediated by the stimulation of NO production and simultaneous inhibition of superoxide production (e.g. from the NADPH oxidase), have been shown to improve vascular function in pre-clinical and clinical studies and to reduce the incidence of cardiovascular events in patients with cardiovascular disease. Today, oxidative stress remains an attractive target for cardiovascular prevention and therapy. However, a deeper understanding of its source, and of its role in vascular pathology, is necessary before new trials are attempted. PMID- 20974802 TI - Mitogen-activated protein kinases promote WNT/beta-catenin signaling via phosphorylation of LRP6. AB - LDL-related protein 6 (LRP6) is a coreceptor of WNTs and a key regulator of the WNT/beta-catenin pathway. Upon activation, LRP6 is phosphorylated within its intracellular PPPS/TP motifs. These phosphorylated motifs are required to recruit axin and to inhibit glycogen synthase kinase 3 (GSK3), two basic components of the beta-catenin destruction complex. On the basis of a kinome-wide small interfering RNA (siRNA) screen and confirmative biochemical analysis, we show that several proline-directed mitogen-activated protein kinases (MAPKs), such as p38, ERK1/2, and JNK1 are sufficient and required for the phosphorylation of PPPS/TP motifs of LRP6. External stimuli, which control the activity of MAPKs, such as phorbol esters and fibroblast growth factor 2 (FGF2) control the choice of the LRP6-PPPS/TP kinase and regulate the amplitude of LRP6 phosphorylation and WNT/beta-catenin-dependent transcription. Our findings suggest that cells not only recruit one dedicated LRP6 kinase but rather select their LRP6 kinase depending on cell type and the external stimulus. Moreover, direct phosphorylation of LRP6 by MAPKs provides a unique point for convergence between WNT/beta-catenin signaling and mitogenic pathways. PMID- 20974803 TI - Phosphorylation of p62 by cdk1 controls the timely transit of cells through mitosis and tumor cell proliferation. AB - The protein scaffold and signaling regulator p62 is important in critical cellular functions, including bone homeostasis, obesity, and cancer, because of its interactions with various signaling intermediaries. p62 is overexpressed in human cancers and is induced during cell transformation. Its genetic ablation inhibits lung tumorigenesis in vivo and cell proliferation in culture by regulating the TRAF6/NF-kappaB signaling cascade to control reactive oxygen species (ROS) production and apoptosis. Here we show that cdk1 phosphorylates p62 in vitro and in vivo at T269 and S272, which is necessary for the maintenance of appropriate cyclin B1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis. The lack of cdk1-mediated phosphorylation of p62 leads to a faster exit from mitosis, which translates into enhanced cell proliferation and tumorigenesis in response to Ras-induced transformation. Therefore, p62 emerges as a node for the control of not only cell survival but also cell transit through mitosis. PMID- 20974804 TI - The Rho target PRK2 regulates apical junction formation in human bronchial epithelial cells. AB - Rho GTPases regulate multiple signaling pathways to control a number of cellular processes during epithelial morphogenesis. To investigate the downstream pathways through which Rho regulates epithelial apical junction formation, we screened a small interfering RNA (siRNA) library targeting 28 known Rho target proteins in 16HBE human bronchial epithelial cells. This led to the identification of the serine-threonine kinase PRK2 (protein kinase C-related kinase 2, also called PKN2). Depletion of PRK2 does not block the initial formation of primordial junctions at nascent cell-cell contacts but does prevent their maturation into apical junctions. PRK2 is recruited to primordial junctions, and this localization depends on its C2-like domain. Rho binding is essential for PRK2 function and also facilitates PRK2 recruitment to junctions. Kinase-dead PRK2 acts as a dominant-negative mutant and prevents apical junction formation. We conclude that PRK2 is recruited to nascent cell-cell contacts through its C2-like and Rho-binding domains and promotes junctional maturation through a kinase dependent pathway. PMID- 20974805 TI - Requirement for class II phosphoinositide 3-kinase C2alpha in maintenance of glomerular structure and function. AB - An early lesion in many kidney diseases is damage to podocytes, which are critical components of the glomerular filtration barrier. A number of proteins are essential for podocyte filtration function, but the signaling events contributing to development of nephrotic syndrome are not well defined. Here we show that class II phosphoinositide 3-kinase C2alpha (PI3KC2alpha) is expressed in podocytes and plays a critical role in maintaining normal renal homeostasis. PI3KC2alpha-deficient mice developed chronic renal failure and exhibited a range of kidney lesions, including glomerular crescent formation and renal tubule defects in early disease, which progressed to diffuse mesangial sclerosis, with reduced podocytes, widespread effacement of foot processes, and modest proteinuria. These findings were associated with altered expression of nephrin, synaptopodin, WT-1, and desmin, indicating that PI3KC2alpha deficiency specifically impacts podocyte morphology and function. Deposition of glomerular IgA was observed in knockout mice; importantly, however, the development of severe glomerulonephropathy preceded IgA production, indicating that nephropathy was not directly IgA mediated. PI3KC2alpha deficiency did not affect immune responses, and bone marrow transplantation studies also indicated that the glomerulonephropathy was not the direct consequence of an immune-mediated disease. Thus, PI3KC2alpha is critical for maintenance of normal glomerular structure and function by supporting normal podocyte function. PMID- 20974806 TI - Intranuclear function for protein phosphatase 2A: Pph21 and Pph22 are required for rapamycin-induced GATA factor binding to the DAL5 promoter in yeast. AB - Protein phosphatase 2A (PP2A), a central Tor pathway phosphatase consisting of a catalytic subunit (Pph21 or Pph22), a scaffold subunit (Tpd3), and one of two regulatory subunits (Cdc55 or Rts1), has been repeatedly shown to play important roles in cytoplasmically localized signal transduction activities. In contrast, its involvement in intranuclear control of mRNA production has heretofore not been reported. Here, we demonstrate for the first time that binding of the nitrogen catabolite repression-responsive GATA transcription activators (Gln3 and Gat1) to the DAL5 promoter and DAL5 expression require Pph21/22-Tpd3-Cdc55/Rts1 in rapamycin-treated glutamine-grown cells. This conclusion is supported by the following observations. (i) Rapamycin-induced DAL5 expression along with Gln3 and Gat1 binding to the DAL5 promoter fails to occur in pph21Delta pph22Delta, tpd3Delta, and cdc55Delta rts1Delta mutants. (ii) The Pph21/22 requirement persists even when Gat1 and Gln3 are rendered constitutively nuclear, thus dissociating the intranuclear requirement of PP2A from its partial requirement for rapamycin-induced nuclear Gat1 localization. (iii) Pph21-Myc(13) (Ppp21 tagged at the C terminus with 13 copies of the Myc epitope) weakly associates with the DAL5 promoter in a Gat1-dependent manner, whereas a similar Pph22 Myc(13) association requires both Gln3 and Gat1. Finally, we demonstrate that a pph21Delta pph22Delta double mutant is epistatic to ure2Delta for nuclear Gat1 localization in untreated glutamine-grown cells, whereas for Gln3, just the opposite occurs: i.e., ure2Delta is epistatic to pph21Delta pph22Delta. This final observation adds additional support to our previous conclusion that the Gln3 and Gat1 GATA factor localizations are predominantly controlled by different regulatory pathways. PMID- 20974808 TI - A steering model of endothelial sheet migration recapitulates monolayer integrity and directed collective migration. AB - Cells in endothelial cell monolayers maintain a tight barrier between blood and tissue, but it is not well understood how endothelial cells move within monolayers, pass each other, migrate when stimulated with growth factor, and also retain monolayer integrity. Here, we develop a quantitative steering model based on functional classes of genes identified previously in a small interfering RNA (siRNA) screen to explain how cells locally coordinate their movement to maintain monolayer integrity and collectively migrate in response to growth factor. In the model, cells autonomously migrate within the monolayer and turn in response to mechanical cues resulting from adhesive, drag, repulsive, and directed steering interactions with neighboring cells. We show that lateral-drag steering explains the local coordination of cell movement and the maintenance of monolayer integrity by allowing closure of small lesions. We further demonstrate that directional steering of cells at monolayer boundaries, combined with adhesive steering of cells behind, can explain growth factor-triggered collective migration into open space. Together, this model provides a mechanistic explanation for the observed genetic modularity and a conceptual framework for how cells can dynamically maintain sheet integrity and undergo collective directed migration. PMID- 20974807 TI - Molecular determinants for small Maf protein control of platelet production. AB - MafG and p45 possess basic region-leucine zipper (bZip) domains and form a heterodimer called NF-E2, a key regulator of megakaryopoiesis. NF-E2 binds to the Maf recognition element (MARE) and activates transcription of many platelet genes. Since the bZip domain, which mediates DNA binding and heterodimerization, is the only functional domain established for MafG, it has been assumed that MafG is required only for p45 binding to MARE and to facilitate p45-mediated transcriptional activation. Analysis of the C-terminal region of MafG, which is distinct from the bZip domain, revealed that this region contains a nuclear matrix-targeting signal. We used a transgenic complementation rescue assay to delineate the function of the MafG C terminus in vivo. Transgenic mice expressing a mutant MafG protein lacking the C terminus (MafGDeltaC) were crossed into a MafG-null background. The compound mutant mice displayed severe thrombocytopenia and splenomegaly, which phenocopied p45-null mice. The MafG C terminus is essential for proplatelet formation and platelet gene activation but not for p45 binding to MARE. These results demonstrate that the MafG C terminus is required for NF-E2 function and suggest that efficient targeting of NF-E2 to a specific nuclear scaffold is important to achieve high-level activity. PMID- 20974809 TI - Posttranscriptional suppression of proto-oncogene c-fms expression by vigilin in breast cancer. AB - cis-acting elements found in 3'-untranslated regions (UTRs) are regulatory signals determining mRNA stability and translational efficiency. By binding a novel non-AU-rich 69-nucleotide (nt) c-fms 3' UTR sequence, we previously identified HuR as a promoter of c-fms proto-oncogene mRNA. We now identify the 69 nt c-fms mRNA 3' UTR sequence as a cellular vigilin target through which vigilin inhibits the expression of c-fms mRNA and protein. Altering association of either vigilin or HuR with c-fms mRNA in vivo reciprocally affected mRNA association with the other protein. Mechanistic studies show that vigilin decreased c-fms mRNA stability. Furthermore, vigilin inhibited c-fms translation. Vigilin suppresses while HuR encourages cellular motility and invasion of breast cancer cells. In summary, we identified a competition for binding the 69-nt sequence, through which vigilin and HuR exert opposing effects on c-fms expression, suggesting a role for vigilin in suppression of breast cancer progression. PMID- 20974810 TI - Integrated biochemical and mechanical signals regulate multifaceted human embryonic stem cell functions. AB - Human embryonic stem cells (ESCs [hESCs]) proliferate as colonies wherein individual cells are strongly adhered to one another. This architecture is linked to hESC self-renewal, pluripotency, and survival and depends on epithelial cadherin (E-cadherin), NMMIIA (nonmuscle myosin IIA), and p120-catenin. E cadherin and p120-catenin work within a positive feedback loop that promotes localized accumulation of E-cadherin at intercellular junctions. NMMIIA stabilizes p120-catenin protein and controls E-cadherin-mediated intercellular adhesion. Perturbations of this signaling network disrupt colony formation, destabilize the transcriptional regulatory circuitry for pluripotency, and impair long-term survival of hESCs. Furthermore, depletion of E-cadherin markedly reduces the efficiency of reprogramming of human somatic cells to an ESC-like state. The feedback regulation and mechanical-biochemical integration provide mechanistic insights for the regulation of intercellular adhesion and cellular architecture in hESCs during long-term self-renewal. Our findings also contribute to the understanding of microenvironmental regulation of hESC identity and somatic reprogramming. PMID- 20974811 TI - The tumor-associated EpCAM regulates morphogenetic movements through intracellular signaling. AB - Epithelial cell adhesion molecule (EpCAM) is best known as a tumor-associated protein highly expressed in carcinomas. The function of this cell surface protein during embryonic development and its potential role in cancer are still poorly understood. We identified EpCAM in a gain-of-function screen for inducers of abnormal tissue mixing during gastrulation. Elevated EpCAM levels in either the ectoderm or the mesoderm confer "invasive" properties to cells in both populations. We found that this phenotype represents an "overstimulation" of an essential activity of EpCAM in controlling cell movements during embryonic development. Surprisingly, this property is independent of the putative adhesive function of EpCAM, and rather relies on a novel signaling function that operates through down-regulation of PKC activity. We show that inhibition of novel PKCs accounts entirely for the invasive phenotype induced by abnormally high levels of EpCAM as well as for its normal function in regulating cell rearrangement during early development. PMID- 20974812 TI - Revolving movement of a dynamic cluster of actin filaments during mitosis. AB - The actin cytoskeleton undergoes rapid changes in its architecture during mitosis. Here, we demonstrate novel actin assembly dynamics in M phase. An amorphous cluster of actin filaments appears during prometaphase, revolves horizontally along the cell cortex at a constant angular speed, and fuses into the contractile ring after three to four revolutions. Cdk1 activity is required for the formation of this mitotic actin cluster and its revolving movement. Rapid turnover of actin in the filaments takes place everywhere in the cluster and is also required for its cluster rotation during mitosis. Knockdown of Arp3, a component of the actin filament-nucleating Arp2/3 complex, inhibits the formation of the mitotic actin cluster without affecting other actin structures. These results identify Arp2/3 complex as a key factor in the generation of the dynamic actin cluster during mitosis. PMID- 20974813 TI - Template-free 13-protofilament microtubule-MAP assembly visualized at 8 A resolution. AB - Microtubule-associated proteins (MAPs) are essential for regulating and organizing cellular microtubules (MTs). However, our mechanistic understanding of MAP function is limited by a lack of detailed structural information. Using cryo electron microscopy and single particle algorithms, we solved the 8 A structure of doublecortin (DCX)-stabilized MTs. Because of DCX's unusual ability to specifically nucleate and stabilize 13-protofilament MTs, our reconstruction provides unprecedented insight into the structure of MTs with an in vivo architecture, and in the absence of a stabilizing drug. DCX specifically recognizes the corner of four tubulin dimers, a binding mode ideally suited to stabilizing both lateral and longitudinal lattice contacts. A striking consequence of this is that DCX does not bind the MT seam. DCX binding on the MT surface indirectly stabilizes conserved tubulin-tubulin lateral contacts in the MT lumen, operating independently of the nucleotide bound to tubulin. DCX's exquisite binding selectivity uncovers important insights into regulation of cellular MTs. PMID- 20974814 TI - Pom121 links two essential subcomplexes of the nuclear pore complex core to the membrane. AB - Nuclear pore complexes (NPCs) control the movement of molecules across the nuclear envelope (NE). We investigated the molecular interactions that exist at the interface between the NPC scaffold and the pore membrane. We show that key players mediating these interactions in mammalian cells are the nucleoporins Nup155 and Nup160. Nup155 depletion massively alters NE structure, causing a dramatic decrease in NPC numbers and the improper targeting of membrane proteins to the inner nuclear membrane. The role of Nup155 in assembly is likely closely linked to events at the membrane as we show that Nup155 interacts with pore membrane proteins Pom121 and NDC1. Furthermore, we demonstrate that the N terminus of Pom121 directly binds the beta-propeller regions of Nup155 and Nup160. We propose a model in which the interactions of Pom121 with Nup155 and Nup160 are predicted to assist in the formation of the nuclear pore and the anchoring of the NPC to the pore membrane. PMID- 20974815 TI - Quality control for unfolded proteins at the plasma membrane. AB - Cellular protein homeostasis profoundly depends on the disposal of terminally damaged polypeptides. To demonstrate the operation and elucidate the molecular basis of quality control of conformationally impaired plasma membrane (PM) proteins, we constructed CD4 chimeras containing the wild type or a temperature sensitive bacteriophage lambda domain in their cytoplasmic region. Using proteomic, biochemical, and genetic approaches, we showed that thermal unfolding of the lambda domain at the PM provoked the recruitment of Hsp40/Hsc70/Hsp90 chaperones and the E2-E3 complex. Mixed-chain polyubiquitination, monitored by bioluminescence resonance energy transfer and immunoblotting, is responsible for the nonnative chimera-accelerated internalization, impaired recycling, and endosomal sorting complex required for transport-dependent lysosomal degradation. A similar paradigm prevails for mutant dopamine D4.4 and vasopressin V2 receptor removal from the PM. These results outline a peripheral proteostatic mechanism in higher eukaryotes and its potential contribution to the pathogenesis of a subset of conformational diseases. PMID- 20974816 TI - Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. AB - Neutrophils release decondensed chromatin termed neutrophil extracellular traps (NETs) to trap and kill pathogens extracellularly. Reactive oxygen species are required to initiate NET formation but the downstream molecular mechanism is unknown. We show that upon activation, neutrophil elastase (NE) escapes from azurophilic granules and translocates to the nucleus, where it partially degrades specific histones, promoting chromatin decondensation. Subsequently, myeloperoxidase synergizes with NE in driving chromatin decondensation independent of its enzymatic activity. Accordingly, NE knockout mice do not form NETs in a pulmonary model of Klebsiella pneumoniae infection, which suggests that this defect may contribute to the immune deficiency of these mice. This mechanism provides for a novel function for serine proteases and highly charged granular proteins in the regulation of chromatin density, and reveals that the oxidative burst induces a selective release of granular proteins into the cytoplasm through an unknown mechanism. PMID- 20974817 TI - The stearoyl-coenzyme A desaturase 1 is essential for virulence and membrane stress in Candida parapsilosis through unsaturated fatty acid production. AB - Unsaturated fatty acids (UFA) are essential components of cells. In Saccharomyces cerevisiae, stearoyl-coenzyme A (CoA) desaturase 1 (OLE1) affects cell viability through the regulation of oleic (18:1) or palmitoleic (16:1) acid production. In this study, we used a targeted gene deletion approach to determine the impact of OLE1 on the emerging human pathogenic fungus Candida parapsilosis. We found that the deletion of OLE1 resulted in an auxotrophic yeast strain (designated OLE1 KO) that required unsaturated fatty acids for growth but not saturated fatty acids. Additionally, the production of UFA by OLE1 KO yeast cells was markedly reduced, suggesting that Ole1 is essential for UFA production. In contrast to wild-type C. parapsilosis, which produced pseudohyphal growth on UFA-supplemented medium agar, pseudohyphal formation in the OLE1 KO cells was severely impaired, suggesting that Ole1 regulates morphology. Furthermore, the OLE1 KO cells were hypersensitive to various stress-inducing factors, such as salts, SDS, and H(2)O(2), especially at the physiological temperature. The results indicate that OLE1 is essential for the stress response, perhaps through the production of UFA for cell membrane biosynthesis. The OLE1 KO cells also were hypersensitive to human and fetal bovine serum, suggesting that targeting Ole1 could suppress the dissemination of yeast cells in the bloodstream. Murine-like macrophage J774.16 more efficiently killed the OLE1 KO yeasts, and significantly larger amounts of nitric oxide were detected in cocultures of macrophages and OLE1 KO cells than with wild-type or heterozygous strains. Moreover, the disruption of OLE1 significantly reduced fungal virulence in systemic murine infection. Taken together, these results demonstrate that Ole1 regulates the pathobiology of C. parapsilosis via UFA and that the OLE1 pathway is a promising antifungal target. PMID- 20974818 TI - Identification of a genetic locus responsible for antimicrobial peptide resistance in Clostridium difficile. AB - Clostridium difficile causes chronic intestinal disease, yet little is understood about how the bacterium interacts with and survives in the host. To colonize the intestine and cause persistent disease, the bacterium must circumvent killing by host innate immune factors, such as cationic antimicrobial peptides (CAMPs). In this study, we investigated the effect of model CAMPs on growth and found that C. difficile is not only sensitive to these compounds but also responds to low levels of CAMPs by expressing genes that lead to CAMP resistance. By plating the bacterium on medium containing the CAMP nisin, we isolated a mutant capable of growing in three times the inhibitory concentration of CAMPs. This mutant also showed increased resistance to the CAMPs gallidermin and polymyxin B, demonstrating tolerance to different types of antimicrobial peptides. We identified the mutated gene responsible for the resistance phenotype as CD1352. This gene encodes a putative orphan histidine kinase that lies adjacent to a predicted ABC transporter operon (CD1349 to CD1351). Transcriptional analysis of the ABC transporter genes revealed that this operon was upregulated in the presence of nisin in wild-type cells and was more highly expressed in the CD1352 mutant. The insertional disruption of the CD1349 gene resulted in significant decreases in resistance to the CAMPs nisin and gallidermin but not polymyxin B. Because of their role in cationic antimicrobial peptide resistance, we propose the designation cprABC for genes CD1349 to CD1351 and cprK for the CD1352 gene. These results provide the first evidence of a C. difficile gene associated with antimicrobial peptide resistance. PMID- 20974819 TI - Infectivity acts as in vivo selection for maintenance of the chlamydial cryptic plasmid. AB - Chlamydia trachomatis contains a conserved ~7.5-kb plasmid. Loss of the plasmid results in reduced glycogen accumulation, failure to activate TLR2, and reduced infectivity. We hypothesized that reduced infectivity functions as a means of selection for plasmid maintenance. We directly examined the biological significance of the reduced infectivity associated with plasmid deficiency by determining the relative fitness of plasmid-deficient CM972 versus that of wild type C. muridarum Nigg in mixed inocula in vitro and in vivo. C. muridarum Nigg rapidly out-competed its plasmid-cured derivative CM972 in vitro but was not competitive with CM3.1, a derivative of CM972 that has reverted to a normal infectivity phenotype. C. muridarum Nigg also effectively competed with CM972 during lower and upper genital tract infection in the mouse, demonstrating that strong selective pressure for plasmid maintenance occurs during infection. The severity of oviduct inflammation and dilatation resulting from these mixed infections correlated directly with the amount of C. muridarum Nigg in the initial inoculum, confirming the role of the plasmid in virulence. Genetic characterization of CM972 and CM3.1 revealed no additional mutations (other than loss of the plasmid) to account for the reduced infectivity of CM972 and detected a single base substitution in TC_0236 in CM3.1 that may be responsible for its restored infectivity. These data demonstrate that a chlamydial strain that differs genetically from its wild-type parent only with respect to the lack of the chlamydial plasmid is unable to compete in vitro and in vivo, likely explaining the rarity of plasmid-deficient isolates in nature. PMID- 20974820 TI - Exposure to cigarette smoke inhibits the pulmonary T-cell response to influenza virus and Mycobacterium tuberculosis. AB - Smoking is associated with increased susceptibility to tuberculosis and influenza. However, little information is available on the mechanisms underlying this increased susceptibility. Mice were left unexposed or were exposed to cigarette smoke and then infected with Mycobacterium tuberculosis by aerosol or influenza A by intranasal infection. Some mice were given a DNA vaccine encoding an immunogenic M. tuberculosis protein. Gamma interferon (IFN-gamma) production by T cells from the lungs and spleens was measured. Cigarette smoke exposure inhibited the lung T-cell production of IFN-gamma during stimulation in vitro with anti-CD3, after vaccination with a construct expressing an immunogenic mycobacterial protein, and during infection with M. tuberculosis and influenza A virus in vivo. Reduced IFN-gamma production was mediated through the decreased phosphorylation of transcription factors that positively regulate IFN-gamma expression. Cigarette smoke exposure increased the bacterial burden in mice infected with M. tuberculosis and increased weight loss and mortality in mice infected with influenza virus. This study provides the first demonstration that cigarette smoke exposure directly inhibits the pulmonary T-cell response to M. tuberculosis and influenza virus in a physiologically relevant animal model, increasing susceptibility to both pathogens. PMID- 20974821 TI - Region of difference 2 contributes to virulence of Mycobacterium tuberculosis. AB - Mycobacterium bovis BCG strains are live, attenuated vaccines generated through decades of in vitro passage. Because in vitro growth does not select for interaction with the host, it has been hypothesized that genetic loci lost from BCG code for virulence determinants that are dispensable for growth in the laboratory, as exemplified by Region of Difference 1 (RD1), which was lost during the original derivation of BCG between 1908 and 1921. Region of Difference 2 (RD2) was lost during the ongoing propagation of BCG between 1927 and 1931, a time that coincides with reports of the ongoing attenuation of the vaccine. In this study, RD2 has been disrupted in M. tuberculosis H37Rv to test whether its loss contributed to the further attenuation of BCG. The deletion of RD2 did not affect in vitro growth; in contrast, the mutant manifested a decrease in pulmonary and splenic bacterial burdens and reduced pathology in C57BL/6 mice at early time points. This attenuated phenotype was complemented by reintroducing the genes Rv1979c to Rv1982 (including mpt64) but not Rv1985c to Rv1986. In RAW 264.7 macrophages, H37Rv:DeltaRD2 showed a decreased proliferation and impaired modulation of the host innate immune response; both observations were complemented with Rv1979c to Rv1982. To test the effect of RD2 disruption on innate immunity, Rag(-/-) mice were infected; H37Rv:DeltaRD2 had increased survival times compared those of H37Rv. These findings support the notion that the safety profile of certain BCG vaccines stems from multiple attenuating mutations, with the RD2 deletion resulting in a less-virulent organism through the impaired bacterial manipulation of the host innate immune response. PMID- 20974822 TI - Probiotic Lactobacillus reuteri ameliorates disease due to enterohemorrhagic Escherichia coli in germfree mice. AB - Strains of enterohemorrhagic Escherichia coli (EHEC) are a group of Shiga toxin producing food-borne pathogens that cause severe hemorrhagic colitis and can lead to hemolytic-uremic syndrome (HUS), a life-threatening condition that principally affects children and for which there is no effective treatment. We used a germfree mouse model of renal and enteric disease due to EHEC to determine if probiotic Lactobacillus reuteri ATCC PTA 6475 is effective in suppressing disease symptoms caused by EHEC. When germfree Swiss Webster mice are monocolonized with EHEC, they develop disease characterized by weight loss, cecal luminal fluid accumulation, and renal tubular necrosis. When L. reuteri was administered 1 day prior to EHEC challenge and every other day thereafter, EHEC colonization was suppressed and mice were significantly protected from the manifestations of disease. Protection from disease did not require the induction of the antimicrobial compound reuterin in L. reuteri prior to treatment. The twice-daily administration of L. reuteri appeared more effective than every-other-day administration. These data indicated that L. reuteri partially protects mice from disease manifestations of EHEC. PMID- 20974823 TI - Vaccination with outer membrane complexes elicits rapid protective immunity to multidrug-resistant Acinetobacter baumannii. AB - Acinetobacter baumannii causes pneumonias, bacteremias, and skin and soft tissue infections, primarily in the hospitalized setting. The incidence of infections caused by A. baumannii has increased dramatically over the last 30 years, while at the same time the treatment of these infections has been complicated by the emergence of antibiotic-resistant strains. Despite these trends, no vaccines or antibody-based therapies have been developed for the prevention of A. baumannii infection. In this study, an outer membrane complex vaccine consisting of multiple surface antigens from the bacterial membrane of A. baumannii was developed and tested in a murine sepsis model. Immunization elicited humoral and cellular responses that were able to reduce postinfection bacterial loads, reduce postinfection proinflammatory cytokine levels in serum, and protect mice from infection with human clinical isolates of A. baumannii. A single administration of the vaccine was able to elicit protective immunity in as few as 6 days postimmunization. In addition, vaccine antiserum was used successfully to therapeutically rescue naive mice with established infection. These results indicate that prophylactic vaccination and antibody-based therapies based on an outer membrane complex vaccine may be viable approaches to preventing the morbidity and mortality caused by this pathogen. PMID- 20974824 TI - Myeloperoxidase selectively binds and selectively kills microbes. AB - Myeloperoxidase (MPO) is reported to selectively bind to bacteria. The present study provides direct evidence of MPO binding selectivity and tests the relationship of selective binding to selective killing. The microbicidal effectiveness of H(2)O(2) and of OCl(-) was compared to that of MPO plus H(2)O(2). Synergistic microbicidal action was investigated by combining Streptococcus sanguinis, a H(2)O(2)-producing microbe showing low MPO binding, with high-MPO-binding Escherichia coli, Staphylococcus aureus, or Pseudomonas aeruginosa without exogenous H(2)O(2), with and without MPO, and with and without erythrocytes (red blood cells [RBCs]). Selectivity of MPO microbicidal action was conventionally measured as the MPO MIC and minimal bactericidal concentration (MBC) for 82 bacteria including E. coli, P. aeruginosa, S. aureus, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus agalactiae, and viridans streptococci. Both H(2)O(2) and OCl(-) destroyed RBCs at submicrobicidal concentrations. Nanomolar concentrations of MPO increased H(2)O(2) microbicidal action 1,000-fold. Streptococci plus MPO produced potent synergistic microbicidal action against all microbes tested, and RBCs caused only a small decrease in potency without erythrocyte damage. MPO directly killed H(2)O(2)-producing S. pyogenes but was ineffective against non-H(2)O(2)-producing E. faecalis. The MPO MICs and MBCs for E. coli, P. aeruginosa, and S. aureus were significantly lower than those for E. faecalis. The streptococcal studies showed much higher MIC/MBC results, but such testing required lysed horse blood-supplemented medium, thus preventing valid comparison of these results to those for the other microbes. E. faecalis MPO binding is reportedly weak compared to binding of E. coli, P. aeruginosa, and S. aureus but strong compared to binding of streptococci. Selective MPO binding results in selective killing. PMID- 20974825 TI - Mycobacterium ulcerans triggers T-cell immunity followed by local and regional but not systemic immunosuppression. AB - Buruli ulcer is a neglected infectious disease caused by Mycobacterium ulcerans and is characterized by necrotic cutaneous lesions induced by the exotoxin mycolactone. Despite evidence of Th1-mediated protective immunity, M. ulcerans infection has been associated with systemic immunosuppression. We show that early during mouse infection with either mycolactone-positive or negative strains, pathogen-specific gamma interferon (IFN-gamma)-producing T cells developed in the draining lymph node (DLN). CD4(+) cells migrated to the infection foci, but progressive infection with virulent M. ulcerans led to the local depletion of recruited cells. Moreover, dissemination of virulent M. ulcerans to the DLN was accompanied by extensive DLN apoptotic cytopathology, leading to depletion of CD4(+) T cells and abrogation of IFN-gamma expression. Advanced footpad infection with virulent M. ulcerans did not induce increased susceptibility to systemic coinfection by Listeria monocytogenes. These results show that infection with M. ulcerans efficiently triggers a mycobacterium-specific T-cell response in the DLN and that progression of infection with highly virulent M. ulcerans leads to a local and regional suppression of that immune response, but without induction of systemic immunosuppression. These results suggest that prophylactic and/or therapeutic interventions to prevent dissemination of M. ulcerans to DLN during the early phase of infection would contribute for the maintenance of protective immunity and disease control. PMID- 20974826 TI - Salmonella enterica serovar Typhimurium binds to HeLa cells via Fim-mediated reversible adhesion and irreversible type three secretion system 1-mediated docking. AB - The food-borne pathogen Salmonella enterica serovar Typhimurium invades mammalian epithelial cells. This multistep process comprises bacterial binding to the host cell, activation of the Salmonella type three secretion system 1 (T1), injection of effector proteins, triggering of host cell actin rearrangements, and S. Typhimurium entry. While the latter steps are well understood, much less is known about the initial binding step. Earlier work had implicated adhesins (but not T1) or T1 (but not other adhesins). We have studied here the Salmonella virulence factors mediating S. Typhimurium binding to HeLa cells. Using an automated microscopy assay and isogenic S. Typhimurium mutants, we analyzed the role of T1 and of several known adhesins (Fim, Pef, Lpf, Agf, and Shd) in host cell binding. In wild-type S. Typhimurium, host cell binding was mostly attributable to T1. However, in the absence of T1, Fim (but not Pef, Lpf, Agf, and Shd) also mediated HeLa cell binding. Furthermore, in the absence of T1 and type I fimbriae (Fim), we still observed residual binding, pointing toward at least one additional, unidentified binding mechanism. Dissociation experiments established that T1 mediated binding was irreversible ("docking"), while Fim-mediated binding was reversible ("reversible adhesion"). Finally, we show that noninvasive bacteria docking via T1 or adhering via Fim can efficiently invade HeLa cells, if actin rearrangements are triggered in trans by a wild-type S. Typhimurium helper strain. Our data show that binding to HeLa cells is mediated by at least two different mechanisms and that both can lead to invasion if actin rearrangements are triggered. PMID- 20974827 TI - MyD88-dependent signaling protects against anthrax lethal toxin-induced impairment of intestinal barrier function. AB - MyD88-deficient mice were previously shown to have increased susceptibility to Bacillus anthracis infection relative to wild-type animals. To determine the mechanism by which MyD88 protects against B. anthracis infection, knockout mice were challenged with nonencapsulated, toxigenic B. anthracis or with anthrax toxins. MyD88-deficient mice had increased susceptibility to B. anthracis and anthrax lethal toxin but not to edema toxin. Lethal toxin alone induced marked multifocal intestinal ulcers in the knockout animals, compromising the intestinal epithelial barrier. The resulting enteric bacterial leakage in the knockout animals led to peritonitis and septicemia. Focal ulcers and erosion were also found in MyD88-heterozygous control mice but with far lower incidence and severity. B. anthracis infection also induced a similar enteric bacterial septicemia in MyD88-deficient mice but not in heterozygous controls. We show that lethal toxin and B. anthracis challenge induce bacteremia as a result of intestinal damage in MyD88-deficient mice. These results suggest that loss of the intestinal epithelial barrier and enteric bacterial septicemia may contribute to sensitizing MyD88-deficient mice to B. anthracis and that MyD88 plays a protective role against lethal toxin-induced impairment of intestinal barrier. PMID- 20974829 TI - Interleukin-1 receptor signaling is required to overcome the effects of pertussis toxin and for efficient infection- or vaccination-induced immunity against Bordetella pertussis. AB - Interleukin-1 receptor-deficient (IL-1R(-/-)) mice are healthy despite being colonized by commensal microbes but are defective in defenses against specific pathogens, suggesting that IL-1R-mediated effects contribute to immune responses against specific pathogenic mechanisms. To better define the role of IL-1R in immunity to respiratory infections, we challenged IL-1R(-/-) mice with Bordetella pertussis and Bordetella parapertussis, the causative agents of whooping cough. Following inoculation with B. pertussis, but not B. parapertussis, IL-1R(-/-) mice showed elevated bacterial numbers and more extensive inflammatory pathology than wild-type mice. Acellular B. pertussis vaccines were not efficiently protective against B. pertussis in IL-1R(-/-) mice. B. pertussis-stimulated dendritic cells from IL-1R(-/-) mice produced higher levels of tumor necrosis factor alpha (TNF-alpha) and IL-6 than wild-type cells. Moreover, elevated levels of gamma interferon (IFN-gamma) and TNF-alpha but lower levels of IL-10 were detected during B. pertussis infection in IL-1R(-/-) mice. Since B. parapertussis did not cause severe disease in IL-1R(-/-) mice, we hypothesized that the extreme requirement for IL-1R involves pertussis toxin (Ptx), which is expressed only by B. pertussis. An isogenic Ptx-deficient B. pertussis strain had only a modest phenotype in wild-type mice but was completely defective in causing lethal disease in IL-1R(-/-) mice, indicating that the particular virulence of B. pertussis in these mice requires Ptx. Ptx contributes to IL-1beta induction by B. pertussis, which is involved in IL-10 induction through IL-1R signaling. IL-10 treatment reduced B. pertussis numbers in IL-1R(-/-) mice, suggesting that the lower IL-10 responses partially account for the uncontrolled inflammation and bacterial growth in these mice. PMID- 20974828 TI - Lipoproteins of bacterial pathogens. AB - Bacterial lipoproteins are a set of membrane proteins with many different functions. Due to this broad-ranging functionality, these proteins have a considerable significance in many phenomena, from cellular physiology through cell division and virulence. Here we give a general overview of lipoprotein biogenesis and highlight examples of the roles of lipoproteins in bacterial disease caused by a selection of medically relevant Gram-negative and Gram positive pathogens: Mycobacterium tuberculosis, Streptococcus pneumoniae, Borrelia burgdorferi, and Neisseria meningitidis. Lipoproteins have been shown to play key roles in adhesion to host cells, modulation of inflammatory processes, and translocation of virulence factors into host cells. As such, a number of lipoproteins have been shown to be potential vaccines. This review provides a summary of some of the reported roles of lipoproteins and of how this knowledge has been exploited in some cases for the generation of novel countermeasures to bacterial diseases. PMID- 20974830 TI - Role of the HefC efflux pump in Helicobacter pylori cholesterol-dependent resistance to ceragenins and bile salts. AB - The human gastric pathogen Helicobacter pylori modifies host cholesterol via glycosylation and incorporates the glycosylated cholesterol into its membrane; however, the benefits of cholesterol to H. pylori are largely unknown. We speculated that cholesterol in the H. pylori membrane might alter the susceptibility of these organisms to membrane-disrupting antibacterial compounds. To test this hypothesis, H. pylori strains were cultured in Ham's F-12 chemically defined medium in the presence or absence of cholesterol. The two cultures were subjected to overnight incubations with serial 2-fold dilutions of 10 bile salts and four ceragenins, which are novel bile salt derivatives that mimic membrane disrupting activity of antimicrobial peptides. H. pylori cultured with cholesterol was substantially more resistant to seven of the bile salts and three ceragenins than H. pylori cultured without cholesterol. In most cases, these cholesterol-dependent differences ranged from 2 to 7 orders of magnitude; this magnitude depended on concentration of the agent. Cholesterol is modified by glycosylation using Cgt, a cholesteryl glycosyltransferase. Surprisingly, a cgt knockout strain still maintained cholesterol-dependent resistance to bile salts and ceragenins, indicating that cholesterol modification was not involved in resistance. We then tested whether three putative, paralogous inner membrane efflux pumps, HefC, HefF, or HefI, played a role. While HefF and HefI appeared unimportant, HefC was shown to play a critical role in the resistance to bile salts and ceragenins by multiple methods in multiple strain backgrounds. Thus, both cholesterol and the putative bile salt efflux pump HefC play important roles in H. pylori resistance to bile salts and ceragenins. PMID- 20974831 TI - Effects of ibeA deletion on virulence and biofilm formation of avian pathogenic Escherichia coli. AB - The ibeA gene is located on a genomic island, GimA, which is involved in the pathogenesis of neonatal meningitis Escherichia coli (NMEC) and avian pathogenic E. coli (APEC). The prevalence of ibeA in the APEC collection in China was investigated, and 20 of 467 strains (4.3%) were positive. In addition, analysis of the association of the E. coli reference (ECOR) groups with positive strains revealed that ibeA was linked to group B2. The ibeA gene in DE205B was analyzed and compared to those of APEC and NMEC, which indicated that the specificity of ibeA was not consistent along pathotypes. The invasion of chicken embryo fibroblast DF-1 cells by APEC DE205B and RS218 was observed, which suggested that DF-1 cells could be a model to study the mechanism of APEC invasion. The inactivation of ibeA in APEC DE205B led to the reduced capacity to invade DF-1 cells, defective virulence in vivo, and decreased biofilm formation compared to the wild-type strain. In addition, strain AAEC189 expressing ibeA exhibited enhanced invasion capacity and biofilm formation. The results of the quantitative real-time reverse transcription-PCR (qRT-PCR) analysis and animal system infection experiments indicated that the loss of ibeA decreased the colonization and proliferation capacities of APEC in the brain during system infection. PMID- 20974832 TI - The lipid A phosphate position determines differential host Toll-like receptor 4 responses to phylogenetically related symbiotic and pathogenic bacteria. AB - The human symbiont Bacteroides thetaiotaomicron promotes intestinal function and health, whereas the phylogenetically related pathogen Porphyromonas gingivalis is associated with the chronic oral inflammatory disease periodontitis. Although both B. thetaiotaomicron and P. gingivalis synthesize lipopolysaccharides (LPS) consisting of penta-acylated, monophosphorylated lipid A in addition to immunologically silent, nonphosphorylated lipid A, they elicit strikingly distinct Toll-like receptor 4 (TLR4) responses. We show that the phosphate position of penta-acylated, monophosphorylated lipid A is a key feature for determining the differential TLR4 responses elicited by these evolutionarily related bacteria. B. thetaiotaomicron produces TLR4-stimulatory lipid A bearing a 1-phosphate, in contrast to P. gingivalis, which produces TLR4-evasive lipid A bearing a 4'-phosphate. Confirming these observations, recombinant Escherichia coli LPS containing penta-acylated, 1-phosphorylated lipid A is more TLR4 stimulatory than LPS containing 4'-phosphorylated lipid A. The specific capacity of a Gram-negative bacterium to alert or evade the host innate immune defense system through TLR4-dependent signaling is currently recognized as a critical aspect defining the relationship between the host and the bacterium. We propose that the distinct lipid A phosphate positions observed for the B. thetaiotaomicron and P. gingivalis LPS contributes to the manifestation of these bacteria as commensal or pathogen within the human host. PMID- 20974833 TI - Computational prediction of type III and IV secreted effectors in gram-negative bacteria. AB - In this review, we provide an overview of the methods employed in four recent studies that described novel methods for computational prediction of secreted effectors from type III and IV secretion systems in Gram-negative bacteria. We present the results of these studies in terms of performance at accurately predicting secreted effectors and similarities found between secretion signals that may reflect biologically relevant features for recognition. We discuss the Web-based tools for secreted effector prediction described in these studies and announce the availability of our tool, the SIEVE server (http://www.sysbep.org/sieve). Finally, we assess the accuracies of the three type III effector prediction methods on a small set of proteins not known prior to the development of these tools that we recently discovered and validated using both experimental and computational approaches. Our comparison shows that all methods use similar approaches and, in general, arrive at similar conclusions. We discuss the possibility of an order-dependent motif in the secretion signal, which was a point of disagreement in the studies. Our results show that there may be classes of effectors in which the signal has a loosely defined motif and others in which secretion is dependent only on compositional biases. Computational prediction of secreted effectors from protein sequences represents an important step toward better understanding the interaction between pathogens and hosts. PMID- 20974834 TI - Discovery of novel secreted virulence factors from Salmonella enterica serovar Typhimurium by proteomic analysis of culture supernatants. AB - Salmonella enterica serovar Typhimurium is a leading cause of acute gastroenteritis throughout the world. This pathogen has two type III secretion systems (TTSS) encoded in Salmonella pathogenicity islands 1 and 2 (SPI-1 and SPI 2) that deliver virulence factors (effectors) to the host cell cytoplasm and are required for virulence. While many effectors have been identified and at least partially characterized, the full repertoire of effectors has not been catalogued. In this proteomic study, we identified effector proteins secreted into defined minimal medium designed to induce expression of the SPI-2 TTSS and its effectors. We compared the secretomes of the parent strain to those of strains missing essential (ssaK::cat) or regulatory (DeltassaL) components of the SPI-2 TTSS. We identified 20 known SPI-2 effectors. Excluding the translocon components SseBCD, all SPI-2 effectors were biased for identification in the DeltassaL mutant, substantiating the regulatory role of SsaL in TTS. To identify novel effector proteins, we coupled our secretome data with a machine learning algorithm (SIEVE, SVM-based identification and evaluation of virulence effectors) and selected 12 candidate proteins for further characterization. Using CyaA' reporter fusions, we identified six novel type III effectors and two additional proteins that were secreted into J774 macrophages independently of a TTSS. To assess their roles in virulence, we constructed nonpolar deletions and performed a competitive index analysis from intraperitoneally infected 129/SvJ mice. Six mutants were significantly attenuated for spleen colonization. Our results also suggest that non-type III secretion mechanisms are required for full Salmonella virulence. PMID- 20974835 TI - Socioeconomic status over the life course and allostatic load in adulthood: results from the Northern Swedish Cohort. AB - BACKGROUND: Although several studies have reported rather consistent associations between socioeconomic status (SES) and allostatic load (AL), so far no study has examined the influence of SES over the life course on AL. The aim of the present study was to investigate the association between SES over the life course and AL in mid-adulthood, guided by the conceptual models of cumulative risk, critical period and social chain of risk. METHODS: The sample comprises a 27-year prospective cohort (n=1071) from northern Sweden. Participants (n=855, 79.8%) completed questionnaires at the ages of 16, 21, 30 and 43 years. A health examination was performed at age 43 years after an overnight fast, including physical examination and blood sampling, and participants completed 1-day salivary cortisol sampling (four samples). SES was based on parental occupation at age 16 years and participants' own occupation at ages 21, 30 and 43 years. Information on daily smoking, snuff use, high alcohol consumption and physical inactivity was reported by the participants. An AL index was constructed from tertiles of 12 biological parameters. RESULTS: Cumulative socioeconomic disadvantage was related to AL in both women and men. The association was largely explained by health behaviours in men, but was independent of health behaviours in women. In women, an association was observed between AL and SES in adolescence, whereas in men only current SES was related to AL, independently of current health behaviours. CONCLUSIONS: SES over the life course influences the level of multi-systemic dysregulation in mid-adulthood, with the strongest support for the cumulative risk model. PMID- 20974836 TI - Age of diagnosis for autism: individual and community factors across 10 birth cohorts. AB - BACKGROUND: The incidence of autism rose dramatically between 1992 and 2001, while the age at which children were first diagnosed declined. During this period the size and composition of the autism caseload has changed, but little is known about whether the factors associated with the timing of diagnosis may also have shifted. Using a multilevel analysis strategy, the individual and community-level factors associated with age of diagnosis were modelled across 10 birth cohorts of California children. METHODS: Linked birth and administrative records on 17,185 children with diagnoses of autistic disorder born in California between 1992 and 2001 and enrolled with the California Department of Developmental Services (DDS) were analysed. Information on cases, their parents and their residential location were extracted from birth and DDS records. Zip codes of residence were matched to census data to create community-level measures. Multilevel linear models were estimated for each birth cohort, with individual-level effects for sex, race, parental characteristics, poverty status, birth order and symptom expression. At the community level measures of educational and economic composition, local autism prevalence and the presence of a child psychiatrist were included. RESULTS: Children with highly educated parents are diagnosed earlier, and this effect has strengthened over time. There is a persistent gap in the age of diagnosis between high and low socioeconomic status (SES) children that has shrunk but not disappeared over time. CONCLUSION: Routine screening for autism in early childhood for all children, particularly those of low SES, is necessary to eliminate disparities in early intervention. PMID- 20974837 TI - Life-course socioeconomic position and change in quality of life among older adults: evidence for the role of a critical period, accumulation of exposure and social mobility. AB - BACKGROUND: This study evaluates the influence of socioeconomic position (SEP) over the life course on change in health-related quality of life (HRQoL) in older adults. METHODS: A prospective cohort of 2117 individuals aged 60 years and over. In 2001, SEP was measured over the life course as social class in childhood (approximated by father's occupation), as educational level completed and as adult social class (occupation of household head). HRQoL was measured with the SF-36 health questionnaire. Changes from 2001 to 2003 in the scores for the physical component summary (PCS) and the mental component summary (MCS) of the SF 36 were calculated, and individuals were classified into three categories: decline (decrease of >5 points), no change (change of -5 to +5 points) and improvement (increase of >5 points) in HRQoL. RESULTS: After adjustment for baseline HRQoL, lifestyle, chronic illness, educational level and adult social class, low childhood social class was associated with a higher risk of both a decline and an improvement in the SF-36 PCS and MCS. The risk of decline in PCS and MCS and of improvement in MCS increased with the cumulative number of adverse SEP over the life course. Subjects who rose in social class from childhood to adulthood showed the greatest improvement on the SF-36 PCS and MCS. CONCLUSION: These results on the relation between SEP and changes in HRQoL in older adults support the three models proposed to explain health inequalities over the life course: the existence of critical periods, the accumulation of adverse SEP and social mobility. PMID- 20974838 TI - Sex differences in child and adolescent mortality by parental education in the Nordic countries. AB - BACKGROUND: Socioeconomic position inequalities in infant mortality are well known, but there is less information on how child mortality is socially patterned by sex and age. OBJECTIVE: To assess maternal and paternal socioeconomic inequalities in mortality by sex, whether these differences vary by age and country, and how much of the sex differences can be explained by external causes of death. METHODS: Data on all live-born children were received from national birth registries for 1981-2000 (Denmark: n=1,184,926; Norway: n=1,090,127; and Sweden n=1,961,911) and for 1987-2000 (Finland: n=841,470). Data on the highest level of education in 2000 were obtained from national education registers, and data on mortality and causes of death were received from the national cause-of death registers until the end of follow-up (20 years or 2003). RESULTS: Boys had a higher child and adolescent mortality than girls. The children of mothers and fathers who had had the shortest education time had the highest mortality for both sexes and for all ages and countries. The differences between the groups with longer than basic education were smaller, particularly among older children and girls. The gradient in mortality was mostly similar for boys and girls. Among 1-19-year-olds, 32% of boys' deaths and 27% of girls' deaths were due to external causes. CONCLUSION: Boys' excess mortality was only partly explained by educational inequalities or by deaths from external causes. A more detailed analysis is needed to study whether the share of avoidable deaths is higher among children whose parents have had a shorter education time. PMID- 20974839 TI - A study of intracity variation of temperature-related mortality and socioeconomic status among the Chinese population in Hong Kong. AB - BACKGROUND: Hong Kong, a major city in China, has one of the world's highest income inequalities and one of the world's highest average increases in urban ambient temperatures. Heat-related mortality in urban areas may vary with acclimatisation and population characteristics. This study examines how the effect of temperature on mortality is associated with sociodemographic characteristics at an intracity level in Hong Kong, China, during the warm season. METHODS: Data from the Hong Kong Observatory, Census and Statistics Department, Environmental Protection Department and government general outpatient clinics during 1998-2006 were used to construct generalised additive (Poisson) models to examine the temperature mortality relationship in Hong Kong. Adjusted for seasonality, long-term trends, pollutants and other potential confounders, effect modification of the warm season temperature-mortality association by demographic, socioeconomic factors and urban design were examined. RESULTS: An average 1 degrees C increase in daily mean temperature above 28.2 degrees C was associated with an estimated 1.8% increase in mortality. Heat-related mortality varied with sociodemographic characteristics: women, men less than 75 years old, people living in low socioeconomic districts, those with unknown residence and married people were more vulnerable. Non-cancer-related causes such as cardiovascular and respiratory infection-related deaths were more sensitive to high temperature effects. CONCLUSION: Public health protection strategies that target vulnerable population subgroups during periods of elevated temperature should be considered. PMID- 20974840 TI - Influence of experiences of racial discrimination and ethnic identity on prenatal smoking among urban black and Hispanic women. AB - BACKGROUND: Although the prevalence of prenatal smoking among minority women exceeds the projected 2010 national objective, data on the determinants of prenatal smoking among minorities remain sparse. METHODS: We examined associations between self-reported experiences of racial discrimination on prenatal smoking among urban black and Hispanic women aged 18-44 years (n=677). Our main independent variable was created from the Experiences of Discrimination (EOD) scale. Multivariable logistic regression models were estimated to examine the relationship between EOD (moderate EOD as the referent group) and smoking for the entire sample and then separately by race/ethnicity adjusted for sociodemographic variables. We also examined the role of ethnic identity (EI) as a buffer to racial discrimination (n=405). RESULTS: The prevalence of smoking was 18.1% versus 10% for black and Hispanic women, respectively (p=0.002). There were no significant differences in the level of EOD based on race. In multivariate regressions, compared to those reporting moderate EOD, women reporting high discrimination (OR 2.64, 95% CI 1.25 to 5.60) had higher odds of smoking. In stratified analyses, this relationship remained significant only in black women. Results suggest that foreign-born Hispanic women with higher EI were less likely to smoke compared to their low-EI counterparts (3.5 vs 10.1%; p=0.08). CONCLUSION: These are the first data in pregnant minority women showing an association between discrimination and increased risk of smoking particularly among black women. Ethnic identity and nativity status were also associated with smoking risk. Smoking cessation programmes should consider such factors among childbearing minority women. PMID- 20974841 TI - Socioeconomic status and exposure to multiple environmental pollutants during pregnancy: evidence for environmental inequity? AB - BACKGROUND: Inequities in the distribution of environmental exposures may add an extra burden to socially disadvantaged populations, especially when acting during vulnerable periods such as pregnancy and early life, but such inequities may be more complex and uncertain than is generally assumed. We therefore examine whether socioeconomic inequities exist in pregnancy exposures to multiple common environmental contaminants in air, water and food. METHODS: A Spanish population based birth cohort study enrolled over 2000 pregnant women between 2004 and 2008. Questionnaires assessed parental education, occupation, country of birth, diet and many other factors. Environmental pollutant assessments included nitrogen dioxide as a marker of traffic-related air pollution, trihalomethanes as a marker of tap water disinfection by-products, organochlorine biomarkers measured in maternal serum during pregnancy (polychlorinated biphenyls (PCB), dichlorodiphenyl dichloroethylene (p,p'-DDE), hexachlorobenzene and beta hexachlorocyclohexane) and mercury concentrations measured in cord blood. RESULTS: Associations between socioeconomic status indicators and nitrogen dioxide and trihalomethanes were generally weak and inconsistent in direction. Concentrations of PCB, hexachlorobenzene and mercury were higher in higher social classes than lower social classes. p,p'-DDE and beta-hexachlorocyclohexane were not related to social class. Social class explained between 1% and 5% of the variability in pollutant concentrations, much less than other variables such as region of residence, country of birth and maternal age. DISCUSSION: This study demonstrates that the general assumption that more disadvantaged populations have higher levels of exposure to environmental pollution does not always hold and requires further elucidation in different international settings. PMID- 20974842 TI - Substoichiometric levels of Cu2+ ions accelerate the kinetics of fiber formation and promote cell toxicity of amyloid-{beta} from Alzheimer disease. AB - A role for Cu(2+) ions in Alzheimer disease is often disputed, as it is believed that Cu(2+) ions only promote nontoxic amorphous aggregates of amyloid-beta (Abeta). In contrast with currently held opinion, we show that the presence of substoichiometric levels of Cu(2+) ions in fact doubles the rate of production of amyloid fibers, accelerating both the nucleation and elongation of fiber formation. We suggest that binding of Cu(2+) ions at a physiological pH causes Abeta to approach its isoelectric point, thus inducing self-association and fiber formation. We further show that Cu(2+) ions bound to Abeta are consistently more toxic to neuronal cells than Abeta in the absence of Cu(2+) ions, whereas Cu(2+) ions in the absence of Abeta are not cytotoxic. The degree of Cu-Abeta cytotoxicity correlates with the levels of Cu(2+) ions that accelerate fiber formation. We note the effect appears to be specific for Cu(2+) ions as Zn(2+) ions inhibit the formation of fibers. An active role for Cu(2+) ions in accelerating fiber formation and promoting cell death suggests impaired copper homeostasis may be a risk factor in Alzheimer disease. PMID- 20974843 TI - Reduced monomeric CD4 is the preferred receptor for HIV. AB - CD4 is a co-receptor for binding of T cells to antigen-presenting cells and the primary receptor for the human immunodeficiency virus type 1 (HIV). CD4 exists in three different forms on the cell surface defined by the state of the domain 2 cysteine residues: an oxidized monomer, a reduced monomer, and a covalent dimer linked through the domain 2 cysteines. The disulfide-linked dimer is the preferred immune co-receptor. The form of CD4 that is preferred by HIV was examined in this study. HIV entry and envelope-mediated cell-cell fusion were tested using cells expressing comparable levels of wild-type or disulfide bond mutant CD4 in which the domain 2 cysteines were mutated to alanine. Eliminating the domain 2 disulfide bond increased entry of HIV reporter viruses and enhanced HIV envelope-mediated cell-cell fusion 2-4-fold. These observations suggest that HIV enters susceptible cells preferably through monomeric reduced CD4, whereas dimeric CD4 is the preferred receptor for binding to antigen-presenting cells. Cleavage of the domain 2 disulfide bond is possibly involved in the conformational change in CD4 associated with fusion of the HIV and cell membranes. PMID- 20974844 TI - Structural and biological properties of the Drosophila insulin-like peptide 5 show evolutionary conservation. AB - We report the crystal structure of two variants of Drosophila melanogaster insulin-like peptide 5 (DILP5) at a resolution of 1.85 A. DILP5 shares the basic fold of the insulin peptide family (T conformation) but with a disordered B-chain C terminus. DILP5 dimerizes in the crystal and in solution. The dimer interface is not similar to that observed in vertebrates, i.e. through an anti-parallel beta-sheet involving the B-chain C termini but, in contrast, is formed through an anti-parallel beta-sheet involving the B-chain N termini. DILP5 binds to and activates the human insulin receptor and lowers blood glucose in rats. It also lowers trehalose levels in Drosophila. Reciprocally, human insulin binds to the Drosophila insulin receptor and induces negative cooperativity as in the human receptor. DILP5 also binds to insect insulin-binding proteins. These results show high evolutionary conservation of the insulin receptor binding properties despite divergent insulin dimerization mechanisms. PMID- 20974845 TI - Light chain-dependent self-association of dynein intermediate chain. AB - Dynein light chains are bivalent dimers that bind two copies of dynein intermediate chain IC to form a cargo attachment subcomplex. The interaction of light chain LC8 with the natively disordered N-terminal domain of IC induces helix formation at distant IC sites in or near a region predicted to form a coiled-coil. This fostered the hypothesis that LC8 binding promotes IC self association to form a coiled-coil or other interchain helical structure. However, recent studies show that the predicted coiled-coil sequence partially overlaps the light chain LC7 recognition sequence on IC, raising questions about the apparently contradictory effects of LC8 and LC7. Here, we use NMR and fluorescence quenching to localize IC self-association to residues within the predicted coiled-coil that also correspond to helix 1 of the LC7 recognition sequence. LC8 binding promotes IC self-association of helix 1 from each of two IC chains, whereas LC7 binding reverses self-association by incorporating the same residues into two symmetrical, but distant, helices of the LC7-IC complex. Isothermal titration experiments confirm the distinction of LC8 enhancement of IC self-association and LC7 binding effects. When all three light chains are bound, IC self-association is shifted to another region. Such flexibility in association modes may function in maintaining a stable and versatile light chain-intermediate chain assembly under changing cellular conditions. PMID- 20974846 TI - Nonamyloid aggregates arising from mature copper/zinc superoxide dismutases resemble those observed in amyotrophic lateral sclerosis. AB - Protein aggregation is a hallmark of many diseases, including amyotrophic lateral sclerosis (ALS) where aggregation of copper/zinc superoxide dismutase (SOD1) is implicated in pathogenesis. We report here that fully metallated (holo) SOD1 under physiologically relevant solution conditions can undergo changes in metallation and/or dimerization over time and form aggregates that do not exhibit classical characteristics of amyloid. The relevance of the observed aggregation to disease is demonstrated by structural and tinctorial analyses, including the novel observation of binding of an anti-SOD1 antibody that specifically recognizes aggregates in ALS patients and mice models. ALS-associated SOD1 mutations can promote aggregation but are not essential. The SOD1 aggregation is characterized by a lag phase, which is diminished by self- or cross-seeding and by heterogeneous nucleation. We interpret these findings in terms of an expanded aggregation mechanism consistent with other in vitro and in vivo findings that point to multiple pathways for the formation of toxic aggregates by different forms of SOD1. PMID- 20974847 TI - Simultaneous observation of tail and head movements of myosin V during processive motion. AB - Processive stepping of myosin Va (myoV) has been tracked by monitoring either the tail position (center of mass) or the position of one or both heads. Here, we combine these two approaches by attaching a quantum dot to one of the motor domains and a bead to the tail. Using laser trapping and total internal reflection microscopy, the position of one head and the tail are observed simultaneously as myoV moves processively on an actin filament bundle against the resistive load of the laser trap. The head moves one step (73 +/- 10 nm) for every two steps of the tail (35 +/- 9 nm). One tail step occurs concurrently with quantum dot-labeled head movement, whereas the other occurs with movement of the unlabeled head, consistent with a hand-over-hand model. Load increases the probability of the motor taking a back step. The back step is triggered by the motor taking a shorter forward step (head step, 68 +/- 11 nm; tail step, 32 +/- 10 nm), likely one actin monomer short of its preferred binding site. During a back step, the motor reverses its hand-over-hand motion, with the leading head detaching and reattaching to one of multiple actin sites behind the trailing head. After a back step, the motor can correct its mistake and step processively forward at resistive loads <0.7 piconewton or stall or detach at higher loads. Back stepping may provide a mechanism to ensure efficient cargo delivery even when myoV encounters obstacles within the actin cytoskeletal meshwork or when other motors are attached to the same cargo. PMID- 20974848 TI - IL-6-induced enhancement of c-Myc translation in multiple myeloma cells: critical role of cytoplasmic localization of the rna-binding protein hnRNP A1. AB - Prior work indicates that IL-6 can stimulate c-Myc expression in multiple myeloma (MM) cells, which is independent of effects on transcription and due to enhanced translation mediated by an internal ribosome entry site in the 5'-UTR of the c Myc RNA. The RNA-binding protein hnRNP A1 (A1) was also critical to IL-6 stimulated translation. Because A1 shuttles between nucleus and cytoplasm, we investigated whether the ability of IL-6 to enhance Myc translation was mediated by stimulation of A1 shuttling. In MM cell lines and primary specimens, IL-6 increased A1 cytoplasmic localization. In contrast, there was no effect on the total cellular levels of A1. Use of a dominant negative A1 construct, which prevents endogenous A1 from nucleus-to-cytoplasm transit, prevented the ability of IL-6 to enhance Myc internal ribosome entry site activity, Myc protein expression, and MM cell growth. IL-6-stimulated cytoplasmic localization was mediated by alterations in the C-terminal M9 peptide of A1, and this correlated with the ability of IL-6 to induce serine phosphorylation of this domain. A p38 kinase inhibitor prevented IL-6-induced A1 phosphorylation. Thus, IL-6 activates c-Myc translation in MM cells by inducing A1 phosphorylation and cytoplasmic localization in a p38-dependent fashion. These data suggest A1 as a potential therapeutic target in MM. PMID- 20974849 TI - Fission yeast receptor of activated C kinase (RACK1) ortholog Cpc2 regulates mitotic commitment through Wee1 kinase. AB - In the fission yeast Schizosaccharomyces pombe, Wee1-dependent inhibitory phosphorylation of the highly conserved Cdc2/Cdk1 kinase determines the mitotic onset when cells have reached a defined size. The receptor of activated C kinase (RACK1) is a scaffolding protein strongly conserved among eukaryotes which binds to other proteins to regulate multiple processes in mammalian cells, including the modulation of cell cycle progression during G(1)/S transition. We have recently described that Cpc2, the fission yeast ortholog to RACK1, controls from the ribosome the activation of MAPK cascades and the cellular defense against oxidative stress by positively regulating the translation of specific genes whose products participate in the above processes. Intriguingly, mutants lacking Cpc2 display an increased cell size at division, suggesting the existence of a specific cell cycle defect at the G(2)/M transition. In this work we show that protein levels of Wee1 mitotic inhibitor are increased in cells devoid of Cpc2, whereas the levels of Cdr2, a Wee1 inhibitor, are down-regulated in the above mutant. On the contrary, the kinetics of G(1)/S transition was virtually identical both in control and Cpc2-less strains. Thus, our results suggest that in fission yeast Cpc2/RACK1 positively regulates from the ribosome the mitotic onset by modulating both the protein levels and the activity of Wee1. This novel mechanism of translational control of cell cycle progression might be conserved in higher eukaryotes. PMID- 20974850 TI - Negative regulation of TGFbeta signaling by the kinase LKB1 and the scaffolding protein LIP1. AB - Signal transduction by the Smad pathway elicits critical biological responses to many extracellular polypeptide factors, including TGFbeta and bone morphogenetic protein. Regulation of Smad signaling imparts several cytoplasmic and nuclear mechanisms, some of which entail protein phosphorylation. Previous work established a protein complex between Smad4 and the scaffolding protein LKB1 interacting protein 1 (LIP1). LKB1 is a well studied tumor suppressor kinase that regulates cell growth and polarity. Here, we analyzed the LKB1-LIP1 and the Smad4 LIP1 protein complexes and found that LIP1 can self-oligomerize. We further demonstrate that LKB1 is capable of phosphorylating Smad4 on Thr(77) of its DNA binding domain. LKB1 inhibits Smad4 from binding to either TGFbeta- or bone morphogenetic protein-specific promoter sequences, which correlates with the negative regulatory effect LKB1 exerts on Smad4-dependent transcription. Accordingly, LKB1 negatively regulates TGFbeta gene responses and epithelial mesenchymal transition. Thus, LKB1 and LIP1 provide negative control of TGFbeta signaling. PMID- 20974851 TI - Modulation of cystic fibrosis transmembrane conductance regulator (CFTR) activity and genistein binding by cytosolic pH. AB - Potentiators are molecules that increase the activity of the cystic fibrosis transmembrane conductance regulator (CFTR). Some potentiators can also inhibit CFTR at higher concentrations. The activating binding site is thought to be located at the interface of the dimer formed by the two nucleotide-binding domains. We have hypothesized that if binding of potentiators involves titratable residues forming salt bridges, then modifications of cytosolic pH (pH(i)) would alter the binding affinity. Here, we analyzed the effect of pH(i) on CFTR activation and on the binding of genistein, a well known CFTR potentiator. We found that pH(i) does modify CFTR maximum current (I(m)) and half-activation concentration (K(d)): I(m) = 127.7, 185.5, and 231.8 MUA/cm(2) and K(d) = 32.7, 56.6 and 71.9 MUm at pH 6, 7.35, and 8, respectively. We also found that the genistein apparent dissociation constant for activation (K(a)) increased at alkaline pH(i), near cysteine pK (K(a) = 1.83, 1.81 and 4.99 MUm at pH(i) 6, 7.35, and 8, respectively), suggesting the involvement of cysteines in the binding site. Mutations of cysteine residues predicted to be within (Cys-491) or outside (Cys-1344) the potentiator-binding site showed that Cys-491 is responsible for the sensitivity of potentiator binding to alkaline pH(i). Effects of pH(i) on inhibition by high genistein doses were also analyzed. Our results extend previous data about multiple effects of pH(i) on CFTR activity and demonstrate that binding of potentiators involves salt bridge formation with amino acids of nucleotide-binding domain 1. PMID- 20974852 TI - Constraint-based, homology model of the extracellular domain of the epithelial Na+ channel alpha subunit reveals a mechanism of channel activation by proteases. AB - The epithelial Na(+) channel (ENaC) mediates Na(+) transport across high resistance epithelia. This channel is assembled from three homologous subunits with the majority of the protein's mass found in the extracellular domains. Acid sensing ion channel 1 (ASIC1) is homologous to ENaC, but a key functional domain is highly divergent. Here we present molecular models of the extracellular region of alpha ENaC based on a large data set of mutations that attenuate inhibitory peptide binding in combination with comparative modeling based on the resolved structure of ASIC1. The models successfully rationalized the data from the peptide binding screen. We engineered new mutants that had not been tested based on the models and successfully predict sites where mutations affected peptide binding. Thus, we were able to confirm the overall general fold of our structural models. Further analysis suggested that the alpha subunit-derived inhibitory peptide affects channel gating by constraining motions within two major domains in the extracellular region, the thumb and finger domains. PMID- 20974853 TI - Structural modeling and electron paramagnetic resonance spectroscopy of the human Na+/H+ exchanger isoform 1, NHE1. AB - We previously presented evidence that transmembrane domain (TM) IV and TM X-XI are important for inhibitor binding and ion transport by the human Na(+)/H(+) exchanger, hNHE1 (Pedersen, S. F., King, S. A., Nygaard, E. B., Rigor, R. R., and Cala, P. M. (2007) J. Biol. Chem. 282, 19716-19727). Here, we present a structural model of the transmembrane part of hNHE1 that further supports this conclusion. The hNHE1 model was based on the crystal structure of the Escherichia coli Na(+)/H(+) antiporter, NhaA, and previous cysteine scanning accessibility studies of hNHE1 and was validated by EPR spectroscopy of spin labels in TM IV and TM XI, as well as by functional analysis of hNHE1 mutants. Removal of all endogenous cysteines in hNHE1, introduction of the mutations A173C (TM IV) and/or I461C (TM XI), and expression of the constructs in mammalian cells resulted in functional hNHE1 proteins. The distance between these spin labels was ~15 A, confirming that TM IV and TM XI are in close proximity. This distance was decreased both at pH 5.1 and in the presence of the NHE1 inhibitor cariporide. A similar TM IV.TM XI distance and a similar change upon a pH shift were found for the cariporide-insensitive Pleuronectes americanus (pa) NHE1; however, in paNHE1, cariporide had no effect on TM IV.TM XI distance. The central role of the TM IV.TM XI arrangement was confirmed by the partial loss of function upon mutation of Arg(425), which the model predicts stabilizes this arrangement. The data are consistent with a role for TM IV and TM XI rearrangements coincident with ion translocation and inhibitor binding by hNHE1. PMID- 20974854 TI - Pentameric organization of the ribosomal stalk accelerates recruitment of ricin a chain to the ribosome for depurination. AB - Ribosome inactivating proteins (RIPs) depurinate a universally conserved adenine in the alpha-sarcin/ricin loop (SRL) and inhibit protein synthesis at the translation elongation step. We previously showed that ribosomal stalk is required for depurination of the SRL by ricin toxin A chain (RTA). The interaction between RTA and ribosomes was characterized by a two-step binding model, where the stalk structure could be considered as an important interacting element. Here, using purified yeast ribosomal stalk complexes assembled in vivo, we show a direct interaction between RTA and the isolated stalk complex. Detailed kinetic analysis of these interactions in real time using surface plasmon resonance (SPR) indicated that there is only one type of interaction between RTA and the ribosomal stalk, which represents one of the two binding steps of the interaction with ribosomes. Interactions of RTA with the isolated stalk were relatively insensitive to salt, indicating that nonelectrostatic interactions were dominant. We compared the interaction of RTA with the full pentameric stalk complex containing two pairs of P1/P2 proteins with its interaction with the trimeric stalk complexes containing only one pair of P1/P2 and found that the rate of association of RTA with the pentamer was higher than with either trimer. These results demonstrate that the stalk is the main landing platform for RTA on the ribosome and that pentameric organization of the stalk accelerates recruitment of RTA to the ribosome for depurination. Our results suggest that multiple copies of the stalk proteins might also increase the scavenging ability of the ribosome for the translational GTPases. PMID- 20974855 TI - Assessment of the validity of the double superhelix model for reconstituted high density lipoproteins: a combined computational-experimental approach. AB - For several decades, the standard model for high density lipoprotein (HDL) particles reconstituted from apolipoprotein A-I (apoA-I) and phospholipid (apoA I/HDL) has been a discoidal particle ~100 A in diameter and the thickness of a phospholipid bilayer. Recently, Wu et al. (Wu, Z., Gogonea, V., Lee, X., Wagner, M. A., Li, X. M., Huang, Y., Undurti, A., May, R. P., Haertlein, M., Moulin, M., Gutsche, I., Zaccai, G., Didonato, J. A., and Hazen, S. L. (2009) J. Biol. Chem. 284, 36605-36619) used small angle neutron scattering to develop a new model they termed double superhelix (DSH) apoA-I that is dramatically different from the standard model. Their model possesses an open helical shape that wraps around a prolate ellipsoidal type I hexagonal lyotropic liquid crystalline phase. Here, we used three independent approaches, molecular dynamics, EM tomography, and fluorescence resonance energy transfer spectroscopy (FRET) to assess the validity of the DSH model. (i) By using molecular dynamics, two different approaches, all atom simulated annealing and coarse-grained simulation, show that initial ellipsoidal DSH particles rapidly collapse to discoidal bilayer structures. These results suggest that, compatible with current knowledge of lipid phase diagrams, apoA-I cannot stabilize hexagonal I phase particles of phospholipid. (ii) By using EM, two different approaches, negative stain and cryo-EM tomography, show that reconstituted apoA-I/HDL particles are discoidal in shape. (iii) By using FRET, reconstituted apoA-I/HDL particles show a 28-34-A intermolecular separation between terminal domain residues 40 and 240, a distance that is incompatible with the dimensions of the DSH model. Therefore, we suggest that, although novel, the DSH model is energetically unfavorable and not likely to be correct. Rather, we conclude that all evidence supports the likelihood that reconstituted apoA-I/HDL particles, in general, are discoidal in shape. PMID- 20974856 TI - Single molecule behavior of inhibited and active states of Escherichia coli ATP synthase F1 rotation. AB - ATP hydrolysis-dependent rotation of the F(1) sector of the ATP synthase is a successive cycle of catalytic dwells (~0.2 ms at 24 degrees C) and 120 degrees rotation steps (~0.6 ms) when observed under V(max) conditions using a low viscous drag 60-nm bead attached to the gamma subunit (Sekiya, M., Nakamoto, R. K., Al-Shawi, M. K., Nakanishi-Matsui, M., and Futai, M. (2009) J. Biol. Chem. 284, 22401-22410). During the normal course of observation, the gamma subunit pauses in a stochastic manner to a catalytically inhibited state that averages ~1 s in duration. The rotation behavior with adenosine 5'-O-(3-thiotriphosphate) as the substrate or at a low ATP concentration (4 MUM) indicates that the rotation is inhibited at the catalytic dwell when the bound ATP undergoes reversible hydrolysis/synthesis. The temperature dependence of rotation shows that F(1) requires ~2-fold higher activation energy for the transition from the active to the inhibited state compared with that for normal steady-state rotation during the active state. Addition of superstoichiometric epsilon subunit, the inhibitor of F(1)-ATPase, decreases the rotation rate and at the same time increases the duration time of the inhibited state. Arrhenius analysis shows that the epsilon subunit has little effect on the transition between active and inhibited states. Rather, the epsilon subunit confers lower activation energy of steady-state rotation. These results suggest that the epsilon subunit plays a role in guiding the enzyme through the proper and efficient catalytic and transport rotational pathway but does not influence the transition to the inhibited state. PMID- 20974857 TI - Eosinophil cysteinyl leukotriene synthesis mediated by exogenous secreted phospholipase A2 group X. AB - Secreted phospholipase A(2) group X (sPLA(2)-X) has recently been identified in the airways of patients with asthma and may participate in cysteinyl leukotriene (CysLT; C(4), D(4), and E(4)) synthesis. We examined CysLT synthesis and arachidonic acid (AA) and lysophospholipid release by eosinophils mediated by recombinant human sPLA(2)-X. We found that recombinant sPLA(2)-X caused marked AA release and a rapid onset of CysLT synthesis in human eosinophils that was blocked by a selective sPLA(2)-X inhibitor. Exogenous sPLA(2)-X released lysophospholipid species that arise from phospholipids enriched in AA in eosinophils, including phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine as well as plasmenyl phosphatidylcholine and phosphatidylethanolamine. CysLT synthesis mediated by sPLA(2)-X but not AA release could be suppressed by inhibition of cPLA(2)alpha. Exogenous sPLA(2)-X initiated Ser(505) phosphorylation of cPLA(2)alpha, an intracellular Ca(2+) flux, and translocation of cPLA(2)alpha and 5-lipoxygenase in eosinophils. Synthesis of CysLTs in response to sPLA(2)-X or lysophosphatidylcholine was inhibited by p38 or JNK inhibitors but not by a MEK 1/2 inhibitor. A further increase in CysLT synthesis was induced by the addition of sPLA(2)-X to eosinophils under conditions of N-formyl-methionyl-leucyl-phenylalanine-mediated cPLA(2)alpha activation. These results indicate that sPLA(2)-X participates in AA and lysophospholipid release, resulting in CysLT synthesis in eosinophils through a mechanism involving p38 and JNK MAPK, cPLA(2)alpha, and 5-lipoxygenase activation and resulting in the amplification of CysLT synthesis during cPLA(2)alpha activation. Transactivation of eosinophils by sPLA(2)-X may be an important mechanism leading to CysLT formation in the airways of patients with asthma. PMID- 20974858 TI - Human glycolipid transfer protein gene (GLTP) expression is regulated by Sp1 and Sp3: involvement of the bioactive sphingolipid ceramide. AB - Glycolipid transfer protein (GLTP) accelerates glycolipid intermembrane transfer via a unique lipid transfer/binding fold (GLTP fold) that defines the GLTP superfamily and is the prototype for functional GLTP-like domains in larger proteins, i.e. FAPP2. Human GLTP is encoded by the single-copy GLTP gene on chromosome 12 (12q24.11 locus), but regulation of GLTP gene expression remains completely unexplored. Herein, the ability of glycosphingolipids (and their sphingolipid metabolites) to regulate the transcriptional expression of GLTP via its promoter has been evaluated. Using luciferase and GFP reporters in concert with deletion mutants, the constitutive and basal (225 bp; ~78% G+C) human GLTP promoters have been defined along with adjacent regulatory elements. Despite high G+C content, translational regulation was not evident by the mammalian target of rapamycin pathway. Four GC-boxes were shown to be functional Sp1/Sp3 transcription factor binding sites. Mutation of one GC-box was particularly detrimental to GLTP transcriptional activity. Sp1/Sp3 RNA silencing and mithramycin A treatment significantly inhibited GLTP promoter activity. Among tested sphingolipid analogs of glucosylceramide, sulfatide, ganglioside GM1, ceramide 1-phosphate, sphingosine 1-phosphate, dihydroceramide, sphingosine, only ceramide, a nonglycosylated precursor metabolite unable to bind to GLTP protein, induced GLTP promoter activity and raised transcript levels in vivo. Ceramide treatment partially blocked promoter activity decreases induced by Sp1/Sp3 knockdown. Ceramide treatment also altered the in vivo binding affinity of Sp1 and Sp3 for the GLTP promoter and decreased Sp3 acetylation. This study represents the first characterization of any Gltp gene promoter and links human GLTP expression to sphingolipid homeostasis through ceramide. PMID- 20974859 TI - Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression. AB - Vitamin D has been shown to have immunomodulatory function, but the molecular basis for it has not been well understood. In this study, we found that vitamin D receptor expression was induced in a CD4+ effector T cell lineage, Th17 cells, which required the transcription factors, RORalpha, RORgammat, and STAT3. Treatment of mice with an active ligand of vitamin D receptor (VDR), 1,25 dihydroxyvitamin D(3) (1,25D3), ameliorated experimental autoimmune encephalomyelitis, accompanied with reduced IL-17 and IL-17F expression. In vitro, treatment of CD4+ T cells with the physiological doses of 1,25D3 preferentially inhibited cytokine production by Th17 cells, in a VDR-dependent manner, without affecting the expression of transcription factors or surface molecules. Moreover, at these concentrations, cytokine expression was suppressed only at protein but not at mRNA levels. Stimulation of Th17 cells with 1,25D3, in a concentration-dependent manner, induced the expression of C/EBP homologous protein (CHOP), a molecule involved in endoplasmic reticulum stress and translational inhibition. In addition, overexpression of CHOP in developing Th17 cells suppressed their cytokine production. Our results suggest a novel, post transcriptional mechanism whereby Th17 cytokines are inhibited by VDR, which may underscore future therapeutic usage of vitamin D in treatment of autoimmune diseases. PMID- 20974860 TI - Decorin antagonizes Met receptor activity and down-regulates {beta}-catenin and Myc levels. AB - A theme emerging during the past few years is that members of the small leucine rich proteoglycan gene family affect cell growth by interacting with multiple receptor tyrosine kinases (RTKs), mostly by a physical down-regulation of the receptors, thereby depriving tumor cells of pro-survival signals. Decorin binds and down-regulates several RTKs, including Met, the receptor for hepatocyte growth factor. Here we demonstrate that decorin blocks several biological activities mediated by the Met signaling axis, including cell scatter, evasion, and migration. These effects were mediated by a profound down-regulation of noncanonical beta-catenin levels. In addition, Myc, a downstream target of beta catenin, was markedly down-regulated by decorin, whereas phosphorylation of Myc at threonine 58 was markedly induced. The latter is known to destabilize Myc and target it for proteasomal degradation. We also discovered that systemic delivery of decorin using three distinct tumor xenograft models caused down-regulation of Met and a concurrent suppression of beta-catenin and Myc levels. We found that decorin protein core labeled with the near infrared dye IR800 specifically targeted the tumor cells expressing Met. Even 68-h post-injection, decorin was found to reside within the tumor xenografts with little or no binding to other tissues. Collectively, our results indicate a role for a secreted proteoglycan in suppressing the expression of key oncogenic factors required for tumor progression. PMID- 20974862 TI - Effect of antibiotic treatment on bacteriophage production by a cystic fibrosis epidemic strain of Pseudomonas aeruginosa. AB - Phage production in response to antibiotics varied among four isolates of a Pseudomonas aeruginosa cystic fibrosis (CF) epidemic strain. Whereas ciprofloxacin induced higher levels of phage production, other CF-relevant antibiotics led to reduced production. We detected free phages directly in CF patient sputum samples by both plaque (40% positive) and PCR (76% positive) assays. Our observations suggest that the choice of antibiotics could influence the number of free phages within the CF lung environment. PMID- 20974861 TI - Heparan sulfate regulates VEGF165- and VEGF121-mediated vascular hyperpermeability. AB - VEGF was first described as vascular permeability factor, a potent inducer of vascular leakage. Genetic evidence indicates that VEGF-stimulated endothelial proliferation in vitro and angiogenesis in vivo depend on heparan sulfate, but a requirement for heparan sulfate in vascular hyperpermeability has not been explored. Here we show that altering endothelial cell heparan sulfate biosynthesis in vivo decreases hyperpermeability induced by both VEGF(165) and VEGF(121). Because VEGF(121) does not bind heparan sulfate, the requirement for heparan sulfate suggested that it interacted with VEGF receptors rather than the ligand. By applying proximity ligation assays to primary brain endothelial cells, we show a direct interaction in situ between heparan sulfate and the VEGF receptor, VEGFR2. Furthermore, the number of heparan sulfate-VEGFR2 complexes increased in response to both VEGF(165) and VEGF(121). Genetic or heparin lyase mediated alteration of endothelial heparan sulfate attenuated phosphorylation of VEGFR2 in response to VEGF(165) and VEGF(121), suggesting that the functional VEGF receptor complex contains heparan sulfate. Pharmacological blockade of heparan sulfate-protein interactions inhibited hyperpermeability in vivo, suggesting heparan sulfate as a potential target for treating hyperpermeability associated with ischemic disease. PMID- 20974863 TI - Profiling the Aspergillus fumigatus proteome in response to caspofungin. AB - The proteomic response of Aspergillus fumigatus to caspofungin was evaluated by gel-free isobaric tagging for relative and absolute quantitation (iTRAQ) as a means to determine potential biomarkers of drug action. A cell fractionation approach yielding 4 subcellular compartment fractions was used to enhance the resolution of proteins for proteomic analysis. Using iTRAQ, a total of 471 unique proteins were identified in soluble and cell wall/plasma membrane fractions at 24 and 48 h of growth in rich media in a wild-type drug-susceptible strain. A total of 122 proteins showed at least a 2-fold change in relative abundance following exposure to caspofungin (CSF) at just below the minimum effective concentration (0.12 MUg/ml). The largest changes were seen in the mitochondrial hypoxia response domain protein (AFUA_1G12250), the level of which decreased >16-fold in the secreted fraction, and ChiA1, the level of which decreased 12.1-fold in the cell wall/plasma membrane fraction. The level of the major allergen and cytotoxin AspF1 was also shown to decrease by 12.1-fold upon the addition of drug. A subsequent iTRAQ analysis of an echinocandin-resistant strain (fks1-S678P) was used to validate proteins specific to drug action. A total of 103 proteins in the 2 fractions tested by iTRAQ were differentially expressed in the wild-type susceptible strain but not significantly changed in the resistant strain. Of these potential biomarkers, 11 had levels that changed at least 12-fold. Microarray analysis of the susceptible strain was performed to evaluate the correlation between proteomics and genomics, with a total of 117 genes found to be changing at least 2-fold. Of these, a total of 22 proteins with significant changes identified by iTRAQ also showed significant gene expression level changes by microarray. Overall, these data have the potential to identify biomarkers that assess the relative efficacy of echinocandin drug therapy. PMID- 20974864 TI - Purification and biochemical characterization of IMP-13 metallo-beta-lactamase. AB - The IMP-13 metallo-beta-lactamase was overproduced in Escherichia coli BL21(DE3) and purified by chromatography. Analysis of kinetic parameters revealed some notable differences with other IMP-type enzymes, noteworthily a higher catalytic efficiency toward ticarcillin and piperacillin and a marked preference for imipenem over meropenem. PMID- 20974865 TI - Extremely drug-resistant Citrobacter freundii isolate producing NDM-1 and other carbapenemases identified in a patient returning from India. PMID- 20974866 TI - Regulation of mprF by antisense RNA restores daptomycin susceptibility to daptomycin-resistant isolates of Staphylococcus aureus. AB - Mutations in mprF have been shown to result in reduced susceptibility to daptomycin and other cationic antibacterials. An mprF antisense-inducible plasmid was constructed and used to demonstrate that depletion of mprF can reestablish susceptibility to daptomycin. Inducing antisense to mprF also resulted in increased susceptibility to vancomycin and gentamicin but, paradoxically, decreased susceptibility to oxacillin. These results suggest that mprF mutations that reduce susceptibility to cationic antibacterials result in a gain-of function phenotype. PMID- 20974867 TI - Evaluation of hepatotoxicity with off-label oral-treatment doses of voriconazole for invasive fungal infections. AB - The approved treatment dose of intravenous voriconazole is a weight-based dose of 4 mg/kg of body weight twice daily; the approved oral dosing is fixed at 200 mg twice daily. In our institution, patients frequently receive oral high-dose voriconazole at 4 mg/kg twice daily. It is unknown if higher doses are associated with increased hepatotoxicity. A retrospective cohort study of patients treated with oral voriconazole for presumed invasive fungal infection for >=7 days was completed. Patients receiving a fixed dose (i.e., labeled dose) were frequency matched and compared to those receiving a weight-based dose (i.e., high dose). The primary endpoint of hepatotoxicity was evaluated by using NCI Common Terminology Criteria (CTC) and components of liver enzymes measuring >3* the upper limit of normal (ULN) and >5* baseline measurements. Secondary endpoints included an incidence of other adverse drug events. Twenty-five labeled-dose and 84 high-dose voriconazole patients were studied. Liver enzyme abnormalities were similar between groups, with the exception of labeled-dose patients experiencing more alkaline phosphatase (ALP) CTC >2* the baseline (P = 0.02) and ALP levels >3* the ULN (P = 0.02). Treatment with high dose was associated with the discontinuation of voriconazole for practitioner attribution of adverse drug events (P = 0.03), although reasons varied and no commonality of biomarker abnormality was identified. Multivariate analysis revealed that the duration of therapy and higher mg/kg total daily doses as interval variables were predictive of some hepatotoxicity outcomes. No difference existed in liver abnormalities for high-dose voriconazole; however, higher mg/kg doses and a longer duration of therapy may be associated with hepatotoxicity. PMID- 20974868 TI - Immunocytochemistry for amoxicillin and its use for studying uptake of the drug in the intestine, liver, and kidney of rats. AB - Specific transport systems for penicillins have been recognized, but their in vivo role in the context of other transporters remains unclear. We produced a serum against amoxicillin (anti-AMPC) conjugated to albumin with glutaraldehyde. The antiserum was specific for AMPC and ampicillin (ABPC) but cross-reacted weakly with cephalexin. This enabled us to develop an immunocytochemical (ICC) method for detecting the uptake of AMPC in the rat intestine, liver, and kidney. Three hours after a single oral administration of AMPC, the ICC method revealed that AMPC distributed to a high degree in the microvilli, nuclei, and cytoplasm of the absorptive epithelial cells of the intestine. AMPC distributed in the cytoplasm and nuclei of the hepatocytes in a characteristic granular morphology on the bile capillaries, and in addition, AMPC adsorption was observed on the luminal surface of the capillaries, intercalated portions, and interlobular bile ducts on the bile flow. Almost no AMPC could be detected 6 h postadministration in either the intestine or the liver. Meanwhile, in the kidney, AMPC persisted until 12 h postadministration to a high degree in the proximal tubules, especially in the S3 segment cells in the tubular lumen, in which numerous small bodies that strongly reacted with the antibody were observed. All these sites of AMPC accumulation correspond well to specific sites where certain transporter systems for penicillins occur, suggesting that AMPC is actually and actively absorbed, eliminated, or excreted at these sites, possibly through such certain penicillin transporters. PMID- 20974869 TI - Molecular investigation of resistance to the antituberculous drug ethionamide in multidrug-resistant clinical isolates of Mycobacterium tuberculosis. AB - Ethionamide (ETH) needs to be activated by the mono-oxygenase EthA, which is regulated by EthR, in order to be active against Mycobacterium tuberculosis. The activated drug targets the enzyme InhA, which is involved in cell wall biosynthesis. Resistance to ETH has been reported to result from various mechanisms, including mutations altering EthA/EthR, InhA and its promoter, the NADH dehydrogenase encoded by ndh, and the MshA enzyme, involved in mycothiol biosynthesis. We searched for such mutations in 87 clinical isolates: 47 ETH resistant (ETH(r)) isolates, 24 ETH-susceptible (ETH(s)) isolates, and 16 isolates susceptible to ETH but displaying an intermediate proportion of resistant cells (ETH(Sip); defined as >=1% but <10% resistant cells). In 81% (38/47) of the ETH(r) isolates, we found mutations in ethA, ethR, or inhA or its promoter, which mostly corresponded to new alterations in ethA and ethR. The 9 ETH(r) isolates without a mutation in these three genes (9/47, 19%) had no mutation in ndh, and a single isolate had a mutation in mshA. Of the 16 ETH(Sip) isolates, 7 had a mutation in ethA, 8 had no detectable mutation, and 1 had a mutation in mshA. Finally, of the 24 ETH(s) isolates, 23 had no mutation in the studied genes and 1 displayed a yet unknown mutation in the inhA promoter. Globally, the mechanism of resistance to ETH remained unknown for 19% of the ETH(r) isolates, highlighting the complexity of the mechanisms of ETH resistance in M. tuberculosis. PMID- 20974870 TI - A curated online resource for SOX10 and pigment cell molecular genetic pathways. AB - We describe the creation of a specialized web-accessible database named the Pigment Cell Gene Resource, which contains information on the genetic pathways that regulate pigment cell development and function. This manually curated database is comprised of two sections, an annotated literature section and an interactive transcriptional network diagram. Initially, this database focuses on the transcription factor SOX10, which has essential roles in pigment cell development and function, but the database has been designed with the capacity to expand in the future, allowing inclusion of many more pigmentation genes. Database URL: http://research.nhgri.nih.gov/pigment_cell/ PMID- 20974871 TI - Neurotropism in blackcaps (Sylvia atricapilla) and red-billed queleas (Quelea quelea) after highly pathogenic avian influenza virus H5N1 infection. AB - The epidemiologic role of passerine birds in the spread of highly pathogenic avian influenza virus (HPAIV) remains controversial. However, confirmed natural infections with HPAIV in Passeriformes, their close contact to poultry and humans, and their role as a human food source indicate a need for increased research on passerines. To date, there are only a few studies on viral shedding and pathomorphologic changes in songbirds infected with HPAIV. To investigate susceptibility, clinical outcome, virus spread, and pathomorphology, the authors inoculated oculo-oronasally 22 red-billed queleas (Quelea quelea) and 11 blackcaps (Sylvia atricapilla) with A/Cygnus cygnus/Germany/R65/2006 (H5N1) using 2 different doses of either 10(4) EID50 (50% egg infective dose) or 10(6) EID50 per animal. They monitored all birds for clinical signs and oropharyngeal and cloacal virus shedding. They also performed immunohistochemistry and obtained molecular virologic data by real-time reverse transcription polymerase chain reaction in tissue samples. In contrast to blackcaps, where 100% of the infected individuals died, queleas were much less susceptible, with a mortality of 82% and 18%, depending on the doses applied. In both species, the virus was shed within 3 to 6 days postinfection, mainly via the respiratory tract. Viral antigen was detected in 100% of the succumbed birds, particularly in the central nervous system. In blackcaps, the heart, lungs, and pancreas were mainly infected. In contrast, the pancreas was predominantly affected in queleas, whereas the heart and the lower respiratory tract were of minor relevance. The authors hypothesize that neurotropism should be considered a main factor for the fatal course of disease in Passeriformes after infection with HPAIV. PMID- 20974872 TI - Mucinous adenocarcinoma and T-cell lymphoma in the small intestine of 2 Vietnamese potbellied pigs (Sus scrofa). AB - Small intestinal T-cell lymphoma and mucinous adenocarcinoma are rarely reported in the pig, with most lymphomas being of B-cell origin and only a single report of mucinous adenocarcinoma. Two aged Vietnamese potbellied pigs had concurrent T cell lymphoma and mucinous adenocarcinoma of the small intestine. The lymphomas formed polypoid masses that projected into the intestinal lumen, whereas the mucinous adenocarcinomas were mural masses that bulged from the serosal surface. Immunohistochemically, neoplastic cells within the lymphomas were positive for CD3 and negative for CD79a. Mucicarmine stain highlighted the abundant cytoplasmic and extracellular mucin in the adenocarcinomas. PMID- 20974873 TI - Establishment and characterization of a canine soft tissue sarcoma cell line. AB - Stringently controlled in vitro experiments are a necessary part of translational research. Cell lines are useful for exploring the underlying biology of cancer. Very few canine soft tissue sarcoma cell lines exist. This report describes the establishment of a new canine soft tissue sarcoma cell line (MBSa1) derived from a high-grade, metastatic neurofibrosarcoma. The primary tumor tissue was obtained from a 12-year-old neutered male German Shepherd Dog and was maintained in tissue culture for a minimum of 20 passages over 7 months. MBSa1 was injected into athymic mice to determine tumorigenicity. Five million cells were injected into the subcutis of the right flank of athymic nude mice. Nine of the 10 mice grew tumors 1 cm or larger within 8 weeks of cell injection. The large number of in vitro passages coupled with solid tumor formation in athymic nude mice demonstrates that MBSa1 has been immortalized and is tumorigenic. PMID- 20974874 TI - Anatomical variations of the digital artery found in pollicization: a report of two cases. PMID- 20974875 TI - Thumb replantation using the reversed radial artery. PMID- 20974876 TI - Metacarpal darkening associated with minocycline therapy. PMID- 20974877 TI - Pyrocarbone implant for salvage interposition arthroplasty of arthritic wrist with advanced carpal collapse. PMID- 20974878 TI - Revascularization and dynamic distraction for a complex finger injury. PMID- 20974879 TI - Soft tissue osteochondroma originating from FDS tendon insertion. PMID- 20974880 TI - Compression of the superficial branch of the radial nerve by calcinosis cutis causing neuropathic pain. PMID- 20974881 TI - A less invasive, intraoperative method for measuring pressure in the cubital tunnel. PMID- 20974882 TI - Median nerve fibrosis at the distal forearm after volar plate fixation of distal radius fracture. PMID- 20974883 TI - Bone peg fixation for the treatment of nonunion of the shaft of the distal phalanx. PMID- 20974884 TI - Re: Tomlinson PJ, Field J. Warm or refrigerated local anaesthetic for open carpal tunnel release: a single blind randomized controlled study. J Hand Surg Eur. 2010, 35: 232-3. PMID- 20974886 TI - Using historical vital statistics to predict the distribution of under-five mortality by cause. AB - BACKGROUND: Cause-specific mortality data is essential for planning intervention programs to reduce mortality in the under age five years population (under-five). However, there is a critical paucity of such information for most of the developing world, particularly where progress towards the United Nations Millennium Development Goal 4 (MDG 4) has been slow. This paper presents a predictive cause of death model for under-five mortality based on historical vital statistics and discusses the utility of the model in generating information that could accelerate progress towards MDG 4. METHODS: Over 1400 country years of vital statistics from 34 countries collected over a period of nearly a century were analyzed to develop relationships between levels of under-five mortality, related mortality ratios, and proportionate mortality from four cause groups: perinatal conditions; diarrhea and lower respiratory infections; congenital anomalies; and all other causes of death. A system of multiple equations with cross-equation parameter restrictions and correlated error terms was developed to predict proportionate mortality by cause based on given measures of under-five mortality. The strength of the predictive model was tested through internal and external cross-validation techniques. Modeled cause-specific mortality estimates for major regions in Africa, Asia, Central America, and South America are presented to illustrate its application across a range of under-five mortality rates. RESULTS: Consistent and plausible trends and relationships are observed from historical data. High mortality rates are associated with increased proportions of deaths from diarrhea and lower respiratory infections. Perinatal conditions assume importance as a proportionate cause at under-five mortality rates below 60 per 1000 live births. Internal and external validation confirms strength and consistency of the predictive model. Model application at regional level demonstrates heterogeneity and non-linearity in cause-composition arising from the range of under-five mortality rates and related mortality ratios. CONCLUSIONS: Historical analyses suggest that under-five mortality transitions are associated with significant changes in cause of death composition. Sub national differentials in under-five mortality rates could require intervention programs targeted to address specific cause distributions. The predictive model could, therefore, help set broad priorities for interventions at the local level based on periodic under-five mortality measurement. Given current resource constraints, such priority setting mechanisms are essential to accelerate reductions in under-five mortality. PMID- 20974887 TI - Prevalence of Staphylococcus aureus and lack of its lytic bacteriophages in the anterior nares of patients and healthcare workers at a rural clinic. AB - BACKGROUND: Nearly 30% of people in the United States are colonized with Staphylococcus aureus and 1% to 2% with methicillin-resistant Staphylococcus aureus (MRSA) in the anterior nares. However, it is not known if lytic bacteriophages against S. aureus are present in the anterior nares, and if they are, what the prevalence rate is, or if they interfere with S. aureus colonization. The aim of this study was to determine the prevalence of nasal carriage of S. aureus and MRSA and to screen for S. aureus lytic bacteriophages in healthcare environment workers and ambulatory patients. METHODS: We enrolled 202 individuals into this study. The anterior nares were swabbed to isolate S. aureus, MRSA, and any lytic S. aureus bacteriophages that may be present. Putative S. aureus colonies on blood agar plates were identified using gram stain, catalase and coagulase tests, and confirmed by S. aureus-specific PCR. Presence of staphylococcal lytic bacteriophages were screened by a plaque assay technique using a methicillin-sensitive reference S. aureus strain ATCC 29213. RESULTS: Of the 49 (24%) individuals who screened positive for S. aureus, two (1%) were positive for MRSA. None of the samples were positive for lytic bacteriophages against S. aureus. Subgroup analysis found no significant difference in the prevalence of S. aureus in the house staff compared to other healthcare environment workers or ambulatory patients of the clinic. Similarly, no significant difference in colonization was noted across the population with respect to age, sex, body mass index, or presence of diabetes mellitus. CONCLUSION: The prevalence of nasal carriage of S. aureus and MRSA in the studied population was 24% and 1%, respectively, similar to the rate of prevalence in the United States. The study also showed that the anterior nares do not seem to harbor lytic bacteriophages against S. aureus. PMID- 20974888 TI - Non-rural point source blastomycosis outbreak near a yard waste collection site. AB - BACKGROUND: Blastomycosis is a potentially fatal infection caused by the fungus Blastomyces dermatitidis. During January 1 through March 5, 2006, twenty-one laboratory confirmed cases of blastomycosis were reported among residents of an endemic area in north-central Wisconsin; a striking increase compared with previous years. The objective of the study was to determine if an observed increase in blastomycosis among residents of an urban area in north-central Wisconsin was caused by a point-source exposure and to identify its source. METHODS: We compared epidemiologic features, and signs and symptoms of B. dermatitidis infection among 46 historic (1999-2005) and 21 possible outbreak case patients. In addition, a case-control study was conducted to compare risk factors of the outbreak case patients with those of 64 age, gender, and geographically-matched control subjects. We conducted site inspections, evaluated meteorological data, genetically compared outbreak and non-outbreak isolates, and attempted environmental detection of B. dermatitidis using polymerase chain reaction, in vitro isolation, and in vivo isolation by tail vein injection of mice. RESULTS: The unusual risk profile of this outbreak included: residence within non-rural city limits with limited time spent outdoors and an equivalent gender ratio and young median age among case patients consistent with common source rather than unrelated exposures. Thirteen of fourteen outbreak-associated clinical isolates of B. dermatitidis clustered in the same genetic group by PCR RFLP analysis. Inspections near the cluster center suggested a yard waste collection site as the probable exposure source. B. dermatitidis nucleic acid was detected in one of 19 environmental samples. Environmental and meteorological conditions and material management practices were identified that may have facilitated growth and dispersal of B. dermatitidis conidia near this residential area. CONCLUSIONS: Results of our investigation of this large non-rural outbreak of blastomycosis suggest bioaerosol hazards may exist near yard waste collection and composting facilities, especially where pine tree litter is present, in B. dermatitidis endemic areas. PMID- 20974889 TI - Diagnosis of atypical molluscum contagiosum: the utility of a squash preparation. PMID- 20974890 TI - pex5 Mutants that differentially disrupt PTS1 and PTS2 peroxisomal matrix protein import in Arabidopsis. AB - PEX5 and PEX7 are receptors required for the import of peroxisome-bound proteins containing one of two peroxisomal targeting signals (PTS1 or PTS2). To better understand the role of PEX5 in plant peroxisomal import, we characterized the Arabidopsis (Arabidopsis thaliana) pex5-10 mutant, which has a T-DNA insertion in exon 5 of the PEX5 gene. Sequencing results revealed that exon 5, along with the T-DNA, is removed in this mutant, resulting in a truncated pex5 protein. The pex5 10 mutant has germination defects and is completely dependent on exogenous Suc for early seedling establishment, based on poor utilization of seed-storage fatty acids. This mutant also has delayed development and reduced fertility, although adult pex5-10 plants appear normal. Peroxisomal metabolism of indole-3-butyric acid, propionate, and isobutyrate also is disrupted. The pex5-10 mutant has reduced import of both PTS1 and PTS2 proteins, and enzymatic processes that occur in peroxisomes are disrupted. To specifically study the import and importance of PTS1 proteins, we made a truncated PEX5 construct lacking the PTS1-binding region (PEX5(454)). Transformation of this construct into pex5-10 resulted in the rescue of PTS2 import, thereby creating a line with PTS1-specific import defects. The pex5-10 (PEX5(454)) plants still had developmental defects, although restoring PTS2 import resulted in a less severe mutant phenotype. Comparison of pex5-10 and pex5-10 (PEX5(454)) phenotypes can separate the import mechanisms for enzymes acting in different peroxisomal processes, including indole-3-butyric acid/2,4 dichlorophenoxybutyric acid oxidation, isobutyrate and propionate metabolism, and photorespiration. PMID- 20974891 TI - C4GEM, a genome-scale metabolic model to study C4 plant metabolism. AB - Leaves of C(4) grasses (such as maize [Zea mays], sugarcane [Saccharum officinarum], and sorghum [Sorghum bicolor]) form a classical Kranz leaf anatomy. Unlike C(3) plants, where photosynthetic CO(2) fixation proceeds in the mesophyll (M), the fixation process in C(4) plants is distributed between two cell types, the M cell and the bundle sheath (BS) cell. Here, we develop a C(4) genome-scale model (C4GEM) for the investigation of flux distribution in M and BS cells during C(4) photosynthesis. C4GEM, to our knowledge, is the first large-scale metabolic model that encapsulates metabolic interactions between two different cell types. C4GEM is based on the Arabidopsis (Arabidopsis thaliana) model (AraGEM) but has been extended by adding reactions and transporters responsible to represent three different C(4) subtypes (NADP-ME [for malic enzyme], NAD-ME, and phosphoenolpyruvate carboxykinase). C4GEM has been validated for its ability to synthesize 47 biomass components and consists of 1,588 unique reactions, 1,755 metabolites, 83 interorganelle transporters, and 29 external transporters (including transport through plasmodesmata). Reactions in the common C(4) model have been associated with well-annotated C(4) species (NADP-ME subtypes): 3,557 genes in sorghum, 11,623 genes in maize, and 3,881 genes in sugarcane. The number of essential reactions not assigned to genes is 131, 135, and 156 in sorghum, maize, and sugarcane, respectively. Flux balance analysis was used to assess the metabolic activity in M and BS cells during C(4) photosynthesis. Our simulations were consistent with chloroplast proteomic studies, and C4GEM predicted the classical C(4) photosynthesis pathway and its major effect in organelle function in M and BS. The model also highlights differences in metabolic activities around photosystem I and photosystem II for three different C(4) subtypes. Effects of CO(2) leakage were also explored. C4GEM is a viable framework for in silico analysis of cell cooperation between M and BS cells during photosynthesis and can be used to explore C(4) plant metabolism. PMID- 20974892 TI - Natural variation in Arabidopsis leads to the identification of REME1, a pentatricopeptide repeat-DYW protein controlling the editing of mitochondrial transcripts. AB - In vascular plants, organelle RNAs are edited by C-to-U base modification. Hundreds of mitochondrial C residues are targeted for editing in flowering plants. In this study, we exploited naturally occurring variation in editing extent to identify Required for Efficiency of Mitochondrial Editing1 (REME1), an Arabidopsis (Arabidopsis thaliana) pentatricopeptide repeat protein-encoding gene belonging to the DYW subclass that promotes editing of at least two C residues on different mitochondrial transcripts. Positional cloning identified REME1 unambiguously as the gene controlling editing of nad2-558. Virus-induced gene silencing of REME1 confirmed its role in editing of nad2-558 and allowed us to identify orfX-552 as a second C whose editing is positively controlled by REME1. An unexpected outcome of REME1 silencing was the finding of a number of mitochondrial C targets whose editing extent exhibits a significant and reproducible increase in silenced tissues. That increase was shown to be partly due to the virus inoculation and partly to REME1-specific silencing. Analysis of an insertional T-DNA mutant within the REME1 coding sequence confirmed the findings of the virus-induced gene silencing experiments: decrease in editing extent of nad2-558 and orfX-552 and increase in editing extent of two sites, matR 1771 and rpl5-92. Transgenic complementation of the low-edited accession (Landsberg erecta) restored the editing of nad2-558 and orfX-552 to high-edited accession (Columbia)-type levels or to even higher levels than Columbia. There was no effect of the transgene on editing extent of matR-1771 and rpl5-92. The strategy and tools used in this report can be applied to identify additional genes that affect editing extent in plant mitochondria. PMID- 20974893 TI - Reassessing the role of N-hydroxytryptamine in auxin biosynthesis. AB - The tryptamine pathway is one of five proposed pathways for the biosynthesis of indole-3-acetic acid (IAA), the primary auxin in plants. The enzymes AtYUC1 (Arabidopsis thaliana), FZY (Solanum lycopersicum), and ZmYUC (Zea mays) are reported to catalyze the conversion of tryptamine to N-hydroxytryptamine, putatively a rate-limiting step of the tryptamine pathway for IAA biosynthesis. This conclusion was based on in vitro assays followed by mass spectrometry or HPLC analyses. However, there are major inconsistencies between the mass spectra reported for the reaction products. Here, we present mass spectral data for authentic N-hydroxytryptamine, 5-hydroxytryptamine (serotonin), and tryptamine to demonstrate that at least some of the published mass spectral data for the YUC in vitro product are not consistent with N-hydroxytryptamine. We also show that tryptamine is not metabolized to IAA in pea (Pisum sativum) seeds, even though a PsYUC-like gene is strongly expressed in these organs. Combining these findings, we propose that at present there is insufficient evidence to consider N hydroxytryptamine an intermediate for IAA biosynthesis. PMID- 20974894 TI - Osmoregulation in Lilium pollen grains occurs via modulation of the plasma membrane H+ ATPase activity by 14-3-3 proteins. AB - To allow successful germination and growth of a pollen tube, mature and dehydrated pollen grains (PGs) take up water and have to adjust their turgor pressure according to the water potential of the surrounding stigma surface. The turgor pressure of PGs of lily (Lilium longiflorum) was measured with a modified pressure probe for simultaneous recordings of turgor pressure and membrane potential to investigate the relation between water and electrogenic ion transport in osmoregulation. Upon hyperosmolar shock, the turgor pressure decreased, and the plasma membrane (PM) hyperpolarizes in parallel, whereas depolarization of the PM was observed with hypoosmolar treatment. An acidification and alkalinization of the external medium was monitored after hyper and hypoosmotic treatments, respectively, and pH changes were blocked by vanadate, indicating a putative role of the PM H(+) ATPase. Indeed, an increase in PM-associated 14-3-3 proteins and an increase in PM H(+) ATPase activity were detected in PGs challenged by hyperosmolar medium. We therefore suggest that in PGs the PM H(+) ATPase via modulation of its activity by 14-3-3 proteins is involved in the regulation of turgor pressure. PMID- 20974895 TI - Advancing our understanding and capacity to engineer nature's CO2-sequestering enzyme, Rubisco. PMID- 20974898 TI - The relationship between executive function, AD/HD, overeating, and obesity. AB - Attention-deficit/hyperactivity disorder (AD/HD) and obesity are complex, costly disorders affecting physical, emotional, and social well-being. Executive function (EF), the cognitive ability for self-understanding and regulation, is often impaired in AD/HD, yet rarely considered in treatment of obese individuals with AD/HD. The hypothesis for this study is that low EF is seen in individuals with 4 or more symptoms of adult AD/HD and is associated with overeating behaviors leading to obesity. A nonexperimental single group design was used. A volunteer convenience sample (n = 125) completed EF, AD/HD, eating, and BMI measures. Path analysis tested the hypothesized/ modified model. Chi square (chi(2) = 6.15, df = 6, p = .4) and RMSEA (0.014) indicated a very good fit for the data. Assessment of EF and AD/HD symptoms in obese individuals is supported. Further study is needed to more fully understand this relationship and to develop strategies to address overeating behaviors in obese individuals with AD/HD. PMID- 20974896 TI - How perceptions of mortality and HIV morbidity relate to substance abuse problems and risky sexual behaviors among former juvenile offenders. AB - This study investigates whether high-risk young adults' perceptions of their likelihood of living to age 35 and of acquiring HIV are related to their substance abuse problems and risky sexual behaviors. The sample consists of data from the 72- and 87-month follow-up assessments of 449 juvenile offenders referred to probation in 1999 and 2000. Results indicate that believing one is likely to get HIV is associated with having more concurrent substance use problems and engaging in more risky sexual behaviors. Longitudinal analyses indicate that youth who think they are likely to get HIV are at greater risk for later substance abuse problems and risky sexual behaviors, though these results are only marginally significant. The results demonstrate that respondents are aware of some of the risks associated with their recent substance using and sexual behaviors, but that holding these perceptions does not result in a reduction of these behaviors. PMID- 20974897 TI - OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution. AB - Eukaryotic cells harbor a small multiploid mitochondrial genome, organized in nucleoids spread within the mitochondrial network. Maintenance and distribution of mitochondrial DNA (mtDNA) are essential for energy metabolism, mitochondrial lineage in primordial germ cells, and to prevent mtDNA instability, which leads to many debilitating human diseases. Mounting evidence suggests that the actors of the mitochondrial network dynamics, among which is the intramitochondrial dynamin OPA1, might be involved in these processes. Here, using siRNAs specific to OPA1 alternate spliced exons, we evidenced that silencing of the OPA1 variants including exon 4b leads to mtDNA depletion, secondary to inhibition of mtDNA replication, and to marked alteration of mtDNA distribution in nucleoid and nucleoid distribution throughout the mitochondrial network. We demonstrate that a small hydrophobic 10-kDa peptide generated by cleavage of the OPA1-exon4b isoform is responsible for this process and show that this peptide is embedded in the inner membrane and colocalizes and coimmunoprecipitates with nucleoid components. We propose a novel synthetic model in which a peptide, including two trans membrane domains derived from the N terminus of the OPA1-exon4b isoform in vertebrates or from its ortholog in lower eukaryotes, might contribute to nucleoid attachment to the inner mitochondrial membrane and promotes mtDNA replication and distribution. Thus, this study places OPA1 as a direct actor in the maintenance of mitochondrial genome integrity. PMID- 20974899 TI - Human plasma glycome in attention-deficit hyperactivity disorder and autism spectrum disorders. AB - Over a half of all proteins are glycosylated, and their proper glycosylation is essential for normal function. Unfortunately, because of structural complexity of nonlinear branched glycans and the absence of genetic template for their synthesis, the knowledge about glycans is lagging significantly behind the knowledge about proteins or DNA. Using a recently developed quantitative high throughput glycan analysis method we quantified components of the plasma N glycome in 99 children with attention-deficit hyperactivity disorder (ADHD), 81 child and 5 adults with autism spectrum disorder, and a total of 340 matching healthy controls. No changes in plasma glycome were found to associate with autism spectrum disorder, but several highly significant associations were observed with ADHD. Further structural analysis of plasma glycans revealed that ADHD is associated with increased antennary fucosylation of biantennary glycans and decreased levels of some complex glycans with three or four antennas. The design of this study prevented any functional conclusions about the observed associations, but specific differences in glycosylation appears to be strongly associated with ADHD and warrants further studies in this direction. PMID- 20974900 TI - TMEM16A(a)/anoctamin-1 shares a homodimeric architecture with CLC chloride channels. AB - TMEM16A/anoctamin-1 has been identified as a protein with the classic properties of a Ca(2+)-activated chloride channel. Here, we used blue native polyacrylamide gel electrophoresis (BN-PAGE) and chemical cross-linking to assess the quaternary structure of the mouse TMEM16A(a) and TMEM16A(ac) splice variants as well as a genetically concatenated TMEM16A(a) homodimer. The constructs carried hexahistidyl (His) tags to allow for their purification using a nondenaturing metal affinity resin. Neither His-tagging nor head-to-tail concatenation of two copies of TMEM16A(a) noticeably affected Ca(2+)-induced measured macroscopic Cl( ) currents compared with the wild-type TMEM16A(a) channel. The digitonin solubilized, nondenatured TMEM16A(a) protein migrated in the BN-PAGE gel as a homodimer, as judged by comparison with the concatenated TMEM16A(a) homodimer and channel proteins of known oligomeric structures (e.g. the voltage-gated Cl(-) channel CLC-1). Cross-linking with glutaraldehyde corroborated the homodimeric structure of TMEM16A(a). The TMEM16A(a) homodimer detected in Xenopus laevis oocytes and HEK 293 cells dissociated into monomers following denaturation with SDS, and reducing versus nonreducing SDS-PAGE provided no evidence for the presence of intersubunit disulfide bonds. Together, our data demonstrate that the Ca(2+)-activated chloride channel member TMEM16A shares an obligate homodimeric architecture with the hCLC-1 channel. PMID- 20974901 TI - Influence of 8DSS peptide on nano-mechanical behavior of human enamel. AB - Aspartate-serine-serine (DSS) repeats are abundant in naturally occurring proteins that are critical for tooth formation. We recently developed octuplet repeats of aspartate-serine-serine (8DSS) peptides to promote the nucleation of calcium phosphate carbonate from free ions. In this paper, we report a possible role of 8DSS in promoting mineral deposition onto human enamel. Human enamel specimens were demineralized, exposed briefly to 8DSS solution, and then exposed to simulated body fluid that favors mineral deposition. At various stages of treatment, nano-mechanical behaviors, namely, hardness and elastic modulus, were determined by nano-indentation. Nano-indentation results showed that 8DSS treatment effectively improved the mechanical and elastic properties of demineralized enamel. The values of hardness and elastic modulus for the 8DSS treated enamel were significantly higher than those of surfaces without 8DSS treatment. Furthermore, 8DSS peptides promoted the uniform deposition of nano crystalline calcium phosphate carbonate over demineralized enamel surfaces and reduced surface roughness of demineralized enamel. PMID- 20974902 TI - A fluorescent ligand-binding alternative using Tag-lite(r) technology. AB - G-protein-coupled receptors (GPCRs) are crucial cell surface receptors that transmit signals from a wide range of extracellular ligands. Indeed, 40% to 50% of all marketed drugs are thought to modulate GPCR activity, making them the major class of targets in the drug discovery process. Binding assays are widely used to identify high-affinity, selective, and potent GPCR drugs. In this field, the use of radiolabeled ligands has remained so far the gold-standard method. Here the authors report a less hazardous alternative for high-throughput screening (HTS) applications by the setup of a nonradioactive fluorescence-based technology named Tag-lite((r)). Selective binding of various fluorescent ligands, either peptidic or not, covering a large panel of GPCRs from different classes is illustrated, particularly for chemokine (CXCR4), opioid (delta, u, and kappa), and cholecystokinin (CCK1 and CCK2) receptors. Affinity constants of well-known pharmacological agents of numerous GPCRs are in line with values published in the literature. The authors clearly demonstrate that the Tag-lite binding assay format can be successfully and reproducibly applied by using different cellular materials such as transient or stable recombinant cells lines expressing SNAP tagged GPCR. Such fluorescent-based binding assays can be performed with adherent cells or cells in suspension, in 96- or 384-well plates. Altogether, this new technology offers great advantages in terms of flexibility, rapidity, and user friendliness; allows easy miniaturization; and makes it completely suitable for HTS applications. PMID- 20974903 TI - Isolation of neurocysticercosis-related antigens from a genomic phage display library of Taenia solium. AB - In this study, the authors have generated a tapeworm Taenia solium genomic DNA expression library where foreign peptides/proteins were fused to N-termini of M13 cpVIII and expressed at a high copy number on the phage surface, and they showed that this library may be used in bioselection against antipathogen immune sera, allowing the identification of disease-related antigens recognizing antibodies present in clinical samples. They isolated 2 phage clones expressing T. solium derived antigens specifically reacting with antibodies present in plasma and cerebrospinal fluid samples of neuroimaging-confirmed neurocysticercosis patients. The described antigen discovery strategy may be used for the direct identification of antigens useful for host-pathogen interaction studies as well as for the development of molecular vaccines and diagnostics. PMID- 20974904 TI - The combined analysis of uncertainty and patient heterogeneity in medical decision models. AB - The analysis of both patient heterogeneity and parameter uncertainty in decision models is increasingly recommended. In addition, the complexity of current medical decision models commonly requires simulating individual subjects, which introduces stochastic uncertainty. The combined analysis of uncertainty and heterogeneity often involves complex nested Monte Carlo simulations to obtain the model outcomes of interest. In this article, the authors distinguish eight model types, each dealing with a different combination of patient heterogeneity, parameter uncertainty, and stochastic uncertainty. The analyses that are required to obtain the model outcomes are expressed in equations, explained in stepwise algorithms, and demonstrated in examples. Patient heterogeneity is represented by frequency distributions and analyzed with Monte Carlo simulation. Parameter uncertainty is represented by probability distributions and analyzed with 2nd order Monte Carlo simulation (aka probabilistic sensitivity analysis). Stochastic uncertainty is analyzed with 1st-order Monte Carlo simulation (i.e., trials or random walks). This article can be used as a reference for analyzing complex models with more than one type of uncertainty and patient heterogeneity. PMID- 20974905 TI - Group visits in diabetes care: a systematic review. AB - PURPOSE: This review appraised research evidence on the effectiveness of group visits for persons with diabetes. The group visit approach included both education and medical management of the patient, and this review focuses on the implications for the certified diabetes educator (CDE) as part of the group visit provider team. METHODS: A search of a comprehensive list of databases produced 395 articles related to group visits, group education, and primary care of patients with diabetes. RESULTS: Using specific inclusion criteria, 12 articles were included in the review. Four review articles examined a total of 75 studies, and 8 additional original research articles analyzed outcomes related to group visits in the care of patients with diabetes. CONCLUSIONS: Current models for diabetes focused group visits that incorporate both group education and a health provider office visit in lieu of the traditional brief office visit failed to demonstrate consistent statistical improvement in A1C, BP, or lipids. There is evidence that group visits may reduce costs, some physiological outcomes may be improved, and patient and clinician satisfaction may be enhanced. The diabetes focused group visit model needs further testing by health care teams in a variety of settings including private primary care and rural practices. PMID- 20974906 TI - Facilitators and barriers to self-management of type 2 diabetes among urban African American adults: focus group findings. AB - PURPOSE: The purpose of this study was to identify facilitators and barriers to self-management of type 2 diabetes mellitus (T2DM) among urban African American adults. METHODS: Thirty-eight African American adults with T2DM were recruited from 1 of 3 health care agencies in a midsized city in the southeastern United States. Qualitative data were obtained using focus groups, wherein each participant engaged in a 60- to 90-minute audio-recorded session. Focus group data were transcribed and analyzed using Atlas ti 6((r)) data analysis software. Demographic and medical history information was also collected. RESULTS: Factors relating to external locus of control primarily facilitated adherence to T2DM self-management behaviors. Support from family, peers, and health care providers positively influenced adherence behaviors by providing cues to action, direct assistance, reinforcement, and knowledge. Internal factors were primarily described as barriers to self-management behaviors and included fears associated with glucose monitoring, lack of self-control over dietary habits, memory failure, and perceived lack of personal control over diabetes. CONCLUSIONS: African Americans perceived external factors as facilitators of their T2DM management behaviors and internal factors as barriers to self-management. Further research is necessary to design and test interventions that capitalize on the external facilitators while helping African Americans to overcome perceived barriers identified in this study. PMID- 20974907 TI - High-throughput identification of compounds targeting influenza RNA-dependent RNA polymerase activity. AB - As influenza viruses have developed resistance towards current drugs, new inhibitors that prevent viral replication through different inhibitory mechanisms are useful. In this study, we developed a screening procedure to search for new antiinfluenza inhibitors from 1,200,000 compounds and identified previously reported as well as new antiinfluenza compounds. Several antiinfluenza compounds were inhibitory to the influenza RNA-dependent RNA polymerase (RdRP), including nucleozin and its analogs. The most potent nucleozin analog, 3061 (FA-2), inhibited the replication of the influenza A/WSN/33 (H1N1) virus in MDCK cells at submicromolar concentrations and protected the lethal H1N1 infection of mice. Influenza variants resistant to 3061 (FA-2) were isolated and shown to have the mutation on nucleoprotein (NP) that is distinct from the recently reported resistant mutation of Y289H [Kao R, et al. (2010) Nat Biotechnol 28:600]. Recombinant influenza carrying the Y52H NP is also resistant to 3061 (FA-2), and NP aggregation induced by 3061 (FA-2) was identified as the most likely cause for inhibition. In addition, we identified another antiinfluenza RdRP inhibitor 367 which targets PB1 protein but not NP. A mutant resistant to 367 has H456P mutation at the PB1 protein and both the recombinant influenza and the RdRP expressing the PB1 H456P mutation have elevated resistance to 367. Our high throughput screening (HTS) campaign thus resulted in the identification of antiinfluenza compounds targeting RdRP activity. PMID- 20974908 TI - Definition of a high-affinity Gag recognition structure mediating packaging of a retroviral RNA genome. AB - All retroviral genomic RNAs contain a cis-acting packaging signal by which dimeric genomes are selectively packaged into nascent virions. However, it is not understood how Gag (the viral structural protein) interacts with these signals to package the genome with high selectivity. We probed the structure of murine leukemia virus RNA inside virus particles using SHAPE, a high-throughput RNA structure analysis technology. These experiments showed that NC (the nucleic acid binding domain derived from Gag) binds within the virus to the sequence UCUG-UR UCUG. Recombinant Gag and NC proteins bound to this same RNA sequence in dimeric RNA in vitro; in all cases, interactions were strongest with the first U and final G in each UCUG element. The RNA structural context is critical: High affinity binding requires base-paired regions flanking this motif, and two UCUG UR-UCUG motifs are specifically exposed in the viral RNA dimer. Mutating the guanosine residues in these two motifs--only four nucleotides per genomic RNA- reduced packaging 100-fold, comparable to the level of nonspecific packaging. These results thus explain the selective packaging of dimeric RNA. This paradigm has implications for RNA recognition in general, illustrating how local context and RNA structure can create information-rich recognition signals from simple single-stranded sequence elements in large RNAs. PMID- 20974909 TI - Importance of representing optical depth variability for estimates of global line shaped contrail radiative forcing. AB - Estimates of the global radiative forcing by line-shaped contrails differ mainly due to the large uncertainty in contrail optical depth. Most contrails are optically thin so that their radiative forcing is roughly proportional to their optical depth and increases with contrail coverage. In recent assessments, the best estimate of mean contrail radiative forcing was significantly reduced, because global climate model simulations pointed at lower optical depth values than earlier studies. We revise these estimates by comparing the probability distribution of contrail optical depth diagnosed with a climate model with the distribution derived from a microphysical, cloud-scale model constrained by satellite observations over the United States. By assuming that the optical depth distribution from the cloud model is more realistic than that from the climate model, and by taking the difference between the observed and simulated optical depth over the United States as globally representative, we quantify uncertainties in the climate model's diagnostic contrail parameterization. Revising the climate model results accordingly increases the global mean radiative forcing estimate for line-shaped contrails by a factor of 3.3, from 3.5 mW/m(2) to 11.6 mW/m(2) for the year 1992. Furthermore, the satellite observations and the cloud model point at higher global mean optical depth of detectable contrails than often assumed in radiative transfer (off-line) studies. Therefore, we correct estimates of contrail radiative forcing from off-line studies as well. We suggest that the global net radiative forcing of line-shaped persistent contrails is in the range 8-20 mW/m(2) for the air traffic in the year 2000. PMID- 20974910 TI - Localization of eukaryote-specific ribosomal proteins in a 5.5-A cryo-EM map of the 80S eukaryotic ribosome. AB - Protein synthesis in all living organisms occurs on ribonucleoprotein particles, called ribosomes. Despite the universality of this process, eukaryotic ribosomes are significantly larger in size than their bacterial counterparts due in part to the presence of 80 r proteins rather than 54 in bacteria. Using cryoelectron microscopy reconstructions of a translating plant (Triticum aestivum) 80S ribosome at 5.5-A resolution, together with a 6.1-A map of a translating Saccharomyces cerevisiae 80S ribosome, we have localized and modeled 74/80 (92.5%) of the ribosomal proteins, encompassing 12 archaeal/eukaryote-specific small subunit proteins as well as the complete complement of the ribosomal proteins of the eukaryotic large subunit. Near-complete atomic models of the 80S ribosome provide insights into the structure, function, and evolution of the eukaryotic translational apparatus. PMID- 20974911 TI - Filament structure of bacterial tubulin homologue TubZ. AB - Low copy number plasmids often depend on accurate partitioning systems for their continued survival. Generally, such systems consist of a centromere-like region of DNA, a DNA-binding adaptor, and a polymerizing cytomotive filament. Together these components drive newly replicated plasmids to opposite ends of the dividing cell. The Bacillus thuringiensis plasmid pBToxis relies on a filament of the tubulin/FtsZ-like protein TubZ for its segregation. By combining crystallography and electron microscopy, we have determined the structure of this filament. We explain how GTP hydrolysis weakens the subunit-subunit contact and also shed light on the partitioning of the plasmid-adaptor complex. The double helical superstructure of TubZ filaments is unusual for tubulin-like proteins. Filaments of ParM, the actin-like partitioning protein, are also double helical. We suggest that convergent evolution shapes these different types of cytomotive filaments toward a general mechanism for plasmid separation. PMID- 20974912 TI - beta-Subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK). AB - The AMP-activated protein kinase (AMPK) is an alphabetagamma heterotrimer that acts as a master metabolic regulator to maintain cellular energy balance following increased energy demand and increases in the AMP/ATP ratio. This regulation provides dynamic control of energy metabolism, matching energy supply with demand that is essential for the function and survival of organisms. AMPK is inactive unless phosphorylated on Thr172 in the alpha-catalytic subunit activation loop by upstream kinases (LKB1 or calcium-calmodulin-dependent protein kinase kinase beta). How a rise in AMP levels triggers AMPK alpha-Thr172 phosphorylation and activation is incompletely understood. Here we demonstrate unequivocally that AMP directly stimulates alpha-Thr172 phosphorylation provided the AMPK beta-subunit is myristoylated. Loss of the myristoyl group abolishes AMP activation and reduces the extent of alpha-Thr172 phosphorylation. Once AMPK is phosphorylated, AMP further activates allosterically but this activation does not require beta-subunit myristoylation. AMP and glucose deprivation also promote membrane association of myristoylated AMPK, indicative of a myristoyl-switch mechanism. Our results show that AMP regulates AMPK activation at the initial phosphorylation step, and that beta-subunit myristoylation is important for transducing the metabolic stress signal. PMID- 20974913 TI - Nucleosome eviction and activated transcription require p300 acetylation of histone H3 lysine 14. AB - Histone posttranslational modifications and chromatin dynamics are inextricably linked to eukaryotic gene expression. Among the many modifications that have been characterized, histone tail acetylation is most strongly correlated with transcriptional activation. In Metazoa, promoters of transcriptionally active genes are generally devoid of physically repressive nucleosomes, consistent with the contemporaneous binding of the large RNA polymerase II transcription machinery. The histone acetyltransferase p300 is also detected at active gene promoters, flanked by regions of histone hyperacetylation. Although the correlation between histone tail acetylation and gene activation is firmly established, the mechanisms by which acetylation facilitates this fundamental biological process remain poorly understood. To explore the role of acetylation in nucleosome dynamics, we utilized an immobilized template carrying a natural promoter reconstituted with various combinations of wild-type and mutant histones. We find that the histone H3 N-terminal tail is indispensable for activator, p300, and acetyl-CoA-dependent nucleosome eviction mediated by the histone chaperone Nap1. Significantly, we identify H3 lysine 14 as the essential p300 acetylation substrate required for dissociation of the histone octamer from the promoter DNA. Together, a total of 11 unique mutant octamer sets corroborated these observations and revealed a striking correlation between nucleosome eviction and strong activator and acetyl-CoA-dependent transcriptional activation. These novel findings uncover an exclusive role for H3 lysine 14 acetylation in facilitating the ATP-independent and transcription-independent disassembly of promoter nucleosomes by Nap1. Furthermore, these studies directly couple nucleosome disassembly with strong, activator-dependent transcription. PMID- 20974914 TI - Driving forces of global wildfires over the past millennium and the forthcoming century. AB - Recent bursts in the incidence of large wildfires worldwide have raised concerns about the influence climate change and humans might have on future fire activity. Comparatively little is known, however, about the relative importance of these factors in shaping global fire history. Here we use fire and climate modeling, combined with land cover and population estimates, to gain a better understanding of the forces driving global fire trends. Our model successfully reproduces global fire activity record over the last millennium and reveals distinct regimes in global fire behavior. We find that during the preindustrial period, the global fire regime was strongly driven by precipitation (rather than temperature), shifting to an anthropogenic-driven regime with the Industrial Revolution. Our future projections indicate an impending shift to a temperature-driven global fire regime in the 21st century, creating an unprecedentedly fire-prone environment. These results suggest a possibility that in the future climate will play a considerably stronger role in driving global fire trends, outweighing direct human influence on fire (both ignition and suppression), a reversal from the situation during the last two centuries. PMID- 20974916 TI - Understanding the varied response of the extratropical storm tracks to climate change. AB - Transient eddies in the extratropical storm tracks are a primary mechanism for the transport of momentum, energy, and water in the atmosphere, and as such are a major component of the climate system. Changes in the extratropical storm tracks under global warming would impact these transports, the ocean circulation and carbon cycle, and society through changing weather patterns. I show that the southern storm track intensifies in the multimodel mean of simulations of 21st century climate change, and that the seasonal cycle of storm-track intensity increases in amplitude in both hemispheres. I use observations of the present-day seasonal cycle to confirm the relationship between storm-track intensity and the mean available potential energy of the atmosphere, and show how this quantitative relationship can be used to account for much of the varied response in storm track intensity to global warming, including substantially different responses in simulations with different climate models. The results suggest that storm-track intensity is not related in a simple way to global-mean surface temperature, so that, for example, a stronger southern storm track in response to present-day global warming does not imply it was also stronger in hothouse climates of the past. PMID- 20974915 TI - Affinity purification of microRNA-133a with the cardiac transcription factor, Hand2. AB - Predictions of microRNA-mRNA interactions typically rely on bioinformatic algorithms, but these algorithms only suggest the possibility of microRNA binding and may miss important interactions as well as falsely predict others. We developed an affinity purification approach to empirically identify microRNAs associated with the 3'UTR of the mRNA encoding Hand2, a transcription factor essential for cardiac development. In addition to miR-1, a known regulator of Hand2 expression, we determined that the Hand2 3'UTR also associated with miR 133a, a microRNA cotranscribed with miR-1 in cardiac and muscle cells. Using a sequential binding assay, we showed that miR-1 and miR-133a could occupy the Hand2 3'UTR concurrently. miR-133a inhibited Hand2 expression in tissue culture models, and miR-133a double knockout mice had elevated levels of Hand2 mRNA and protein. We conclude that Hand2 is regulated by miR-133a in addition to miR-1. The affinity purification assay should be generally applicable for identifying other microRNA-mRNA interactions. PMID- 20974917 TI - Boundary crossing in epithelial wound healing. AB - The processes of wound healing and collective cell migration have been studied for decades. Intensive research has been devoted to understanding the mechanisms involved in wound healing, but the role of cell-substrate interactions is still not thoroughly understood. Here we probe the role of cell-substrate interactions by examining in vitro the healing of monolayers of human corneal epithelial (HCE) cells cultured on artificial extracellular matrix (aECM) proteins. We find that the rate of wound healing is dependent on the concentration of fibronectin derived (RGD) cell-adhesion ligands in the aECM substrate. The wound closure rate varies nearly sixfold on the substrates examined, despite the fact that the rates of migration and proliferation of individual cells show little sensitivity to the RGD concentration (which varies 40-fold). To explain this apparent contradiction, we study collective migration by means of a dynamic Monte Carlo simulation. The cells in the simulation spread, retract, and proliferate with probabilities obtained from a simple phenomenological model. The results indicate that the overall wound closure rate is determined primarily by the rate at which cells cross the boundary between the aECM protein and the matrix deposited under the cell sheet. PMID- 20974918 TI - Binding of different histone marks differentially regulates the activity and specificity of polycomb repressive complex 2 (PRC2). AB - The polycomb repressive complex 2 (PRC2) is the major methyltransferase for H3K27 methylation, a modification critical for maintaining repressed gene expression programs throughout development. It has been previously shown that PRC2 maintains histone methylation patterns during DNA replication in part through its ability to bind to H3K27me3. However, the mechanism by which PRC2 recognizes H3K27me3 is unclear. Here we show that the WD40 domain of EED, a PRC2 component, is a methyllysine histone-binding domain. The crystal structures of apo-EED and EED in complex respectively with five different trimethyllysine histone peptides reveal that EED binds these peptides via the top face of its beta-propeller architecture. The ammonium group of the trimethyllysine is accommodated by an aromatic cage formed by three aromatic residues, while its aliphatic chain is flanked by a fourth aromatic residue. Our structural data provide an explanation for the preferential recognition of the Ala-Arg-Lys-Ser motif-containing trimethylated H3K27, H3K9, and H1K26 marks by EED over lower methylation states and other histone methyllysine marks. More importantly, we found that binding of different histone marks by EED differentially regulates the activity and specificity of PRC2. Whereas the H3K27me3 mark stimulates the histone methyltransferase activity of PRC2, the H1K26me3 mark inhibits PRC2 methyltransferase activity on the nucleosome. Moreover, H1K26me3 binding switches the specificity of PRC2 from methylating H3K27 to EED. In addition to determining the molecular basis of EED-methyllysine recognition, our work provides the biochemical characterization of how the activity of a histone methyltransferase is oppositely regulated by two histone marks. PMID- 20974919 TI - Aerobic growth at nanomolar oxygen concentrations. AB - Molecular oxygen (O(2)) is the second most abundant gas in the Earth's atmosphere, but in many natural environments, its concentration is reduced to low or even undetectable levels. Although low-oxygen-adapted organisms define the ecology of low-oxygen environments, their capabilities are not fully known. These capabilities also provide a framework for reconstructing a critical period in the history of life, because low, but not negligible, atmospheric oxygen levels could have persisted before the "Great Oxidation" of the Earth's surface about 2.3 to 2.4 billion years ago. Here, we show that Escherichia coli K-12, chosen for its well-understood biochemistry, rapid growth rate, and low-oxygen-affinity terminal oxidase, grows at oxygen levels of <= 3 nM, two to three orders of magnitude lower than previously observed for aerobes. Our study expands both the environmental range and temporal history of aerobic organisms. PMID- 20974920 TI - Ferredoxin:NADPH oxidoreductase is recruited to thylakoids by binding to a polyproline type II helix in a pH-dependent manner. AB - Ferredoxin:NADPH oxidoreductase (FNR) is a key enzyme of photosynthetic electron transport required for generation of reduction equivalents. Recently, two proteins were found to be involved in membrane-anchoring of FNR by specific interaction via a conserved Ser/Pro-rich motif: Tic62 and Trol. Our crystallographic study reveals that the FNR-binding motif, which forms a polyproline type II helix, induces self-assembly of two FNR monomers into a back to-back dimer. Because binding occurs opposite to the FNR active sites, its activity is not affected by the interaction. Surface plasmon resonance analyses disclose a high affinity of FNR to the binding motif, which is strongly increased under acidic conditions. The pH of the chloroplast stroma changes dependent on the light conditions from neutral to slightly acidic in complete darkness or to alkaline at saturating light conditions. Recruiting of FNR to the thylakoids could therefore represent a regulatory mechanism to adapt FNR availability/activity to photosynthetic electron flow. PMID- 20974921 TI - Uterine epithelial estrogen receptor alpha is dispensable for proliferation but essential for complete biological and biochemical responses. AB - Female fertility requires estrogen to specifically stimulate estrogen receptor alpha (ERalpha)-dependent growth of the uterine epithelium in adult mice, while immature females show proliferation in both stroma and epithelium. To address the relative roles of ERalpha in mediating estrogen action in uterine epithelium versus stroma, a uterine epithelial-specific ERalpha knockout (UtEpialphaERKO) mouse line was generated by crossing Esr mice with Wnt7a-Cre mice. Expression of Wnt7a directed Cre activity generated selective deletion of ERalpha in uterine epithelium, and female UtEpialphaERKO are infertile. Herein, we demonstrate that 17beta-estradiol (E(2))-induced uterine epithelial proliferation was independent of uterine epithelial ERalpha because DNA synthesis and up-regulation of mitogenic mediators were sustained in UtEpialphaERKO uteri after E(2) treatment. IGF-1 treatment resulted in ligand-independent ER activation in both wild-type (WT) and UtEpialphaERKO and mimicked the E(2) stimulatory effect on DNA synthesis in uterine epithelium. Uterine epithelial ERalpha was necessary to induce lactoferrin, an E(2)-regulated secretory protein selectively synthesized in the uterine epithelium. However, loss of uterine epithelial ERalpha did not alter the E(2)-dependent progesterone receptor (PR) down-regulation in epithelium. Strikingly, the uterine epithelium of UtEpialphaERKO had robust evidence of apoptosis after 3 d of E(2) treatment. Therefore, we surmise that estrogen induced uterine hyperplasia involves a dispensable role for uterine epithelial ERalpha in the proliferative response, but ERalpha is required subsequent to proliferation to prevent uterine epithelial apoptosis assuring the full uterine epithelial response, illustrating the differential cellular roles for ERalpha in uterine tissue and its contribution during pregnancy. PMID- 20974922 TI - Water's role in the force-induced unfolding of ubiquitin. AB - In atomic force spectroscopic studies of the elastomeric protein ubiquitin, the beta-strands 1-5 serve as the force clamp. Simulations show how the rupture force in the force-induced unfolding depends on the kinetics of water molecule insertion into positions where they can eventually form hydrogen bonding bridges with the backbone hydrogen bonds in the force-clamp region. The intrusion of water into this region is slowed down by the hydrophobic shielding effect of carbonaceous groups on the surface residues of beta-strands 1-5, which thereby regulates water insertion prior to hydrogen bond breakage. The experiments show that the unfolding of the mechanically stressed protein is nonexponential due to static disorder. Our simulations show that different numbers and/or locations of bridging water molecules give rise to a long-lived distribution of transition states and static disorder. We find that slowing down the translational (not rotational) motions of the water molecules by increasing the mass of their oxygen atoms, which leaves the force field and thereby the equilibrium structure of the solvent unchanged, increases the average rupture force; however, the early stages of the force versus time behavior are very similar for our "normal" and fictitious "heavy" water models. Finally, we construct six mutant systems to regulate the hydrophobic shielding effect of the surface residues in the force clamp region. The mutations in the two termini of beta-sheets 1-5 are found to determine a preference for different unfolding pathways and change mutant's average rupture force. PMID- 20974924 TI - Soluble plasma HLA peptidome as a potential source for cancer biomarkers. AB - The HLA molecules are membrane-bound transporters that carry peptides from the cytoplasm to the cell surface for surveillance by circulating T lymphocytes. Although low levels of soluble HLA molecules (sHLA) are normally released into the blood, many types of tumor cells release larger amounts of these sHLA molecules, presumably to counter immune surveillance by T cells. Here we demonstrate that these sHLA molecules are still bound with their authentic peptide repertoires, similar to those of the membranal HLA molecules (mHLA). Therefore, a single immunoaffinity purification of the plasma sHLA molecules, starting with a few milliliters of patients' blood, allows for identification of very large sHLA peptidomes by mass spectrometry, forming a foundation for development of a simple and universal blood-based cancer diagnosis. The new methodology was validated using plasma and tumor cells of multiple-myeloma and leukemia patients, plasma of healthy controls, and with cultured cancer cells. The analyses identified thousands of sHLA peptides, including some cancer-related peptides, present among the sHLA peptidomes of the cancer patients. Furthermore, because the HLA peptides are the degradation products of the cellular proteins, this sHLA peptidomics approach opens the way for investigation of the patterns of protein synthesis and degradation within the tumor cells. PMID- 20974925 TI - Electron tunneling in respiratory complex I. AB - NADH:ubiquinone oxidoreductase (complex I) plays a central role in the respiratory electron transport chain by coupling the transfer of electrons from NADH to ubiquinone to the creation of the proton gradient across the membrane necessary for ATP synthesis. Here the atomistic details of electronic wiring of all Fe/S clusters in complex I are revealed by using the tunneling current theory and computer simulations; both density functional theory and semiempirical electronic structure methods were used to examine antiferromagnetically coupled spin states and corresponding tunneling wave functions. Distinct electron tunneling pathways between neighboring Fe/S clusters are identified; the pathways primarily consist of two cysteine ligands and one additional key residue. Internal water between protein subunits is identified as an essential mediator enhancing the overall electron transfer rate by almost three orders of magnitude to achieve a physiologically significant value. The identified key residues are further characterized by sensitivity of electron transfer rates to their mutations, examined in simulations, and their conservation among complex I homologues. The unusual electronic structure properties of Fe(4)S(4) clusters in complex I explain their remarkable efficiency of electron transfer. PMID- 20974926 TI - Omnipotent role of archaeal elongation factor 1 alpha (EF1alpha in translational elongation and termination, and quality control of protein synthesis. AB - The molecular mechanisms of translation termination and mRNA surveillance in archaea remain unclear. In eukaryotes, eRF3 and HBS1, which are homologous to the tRNA carrier GTPase EF1alpha, respectively bind eRF1 and Pelota to decipher stop codons or to facilitate mRNA surveillance. However, genome-wide searches of archaea have failed to detect any orthologs to both GTPases. Here, we report the crystal structure of aRF1 from an archaeon, Aeropyrum pernix, and present strong evidence that the authentic archaeal EF1alpha acts as a carrier GTPase for aRF1 and for aPelota. The binding interface residues between aRF1 and aEF1alpha predicted from aRF1.aEF1alpha.GTP ternary structure model were confirmed by in vivo functional assays. The aRF1/eRF1 structural domain with GGQ motif, which corresponds to the CCA arm of tRNA, contacts with all three structural domains of aEF1alpha showing striking tRNA mimicry of aRF1/eRF1 and its GTPase-mediated catalysis for stop codon decoding. The multiple binding capacity of archaeal EF1alpha explains the absence of GTPase orthologs for eRF3 and HBS1 in archaea species and suggests that universal molecular mechanisms underlie translational elongation and termination, and mRNA surveillance pathways. PMID- 20974927 TI - Fluid dynamical niches of phytoplankton types. AB - The biogeochemical role of phytoplanktonic organisms strongly varies from one plankton type to another, and their relative abundance and distribution have fundamental consequences at the global and climatological scales. In situ observations find dominant types often associated to specific physical and chemical water properties. However, the mechanisms and spatiotemporal scales by which marine ecosystems are organized are largely not known. Here we investigate the spatiotemporal organization of phytoplankton communities by combining multisatellite data, notably high-resolution ocean-color maps of dominant types and altimetry-derived Lagrangian diagnostics of the surface transport. We find that the phytoplanktonic landscape is organized in (sub-)mesoscale patches (10 100 km) of dominant types separated by physical fronts induced by horizontal stirring. These physical fronts delimit niches supported by water masses of similar history and whose lifetimes are comparable with the timescale of the bloom onset (few weeks). The resonance between biological activity and physical processes suggest that the spatiotemporal (sub-)mesoscales associated to stirring are determinant in the observation and modeling of marine ecosystems. PMID- 20974928 TI - Elementary steps at the surface of ice crystals visualized by advanced optical microscopy. AB - Due to the abundance of ice on earth, the phase transition of ice plays crucially important roles in various phenomena in nature. Hence, the molecular-level understanding of ice crystal surfaces holds the key to unlocking the secrets of a number of fields. In this study we demonstrate, by laser confocal microscopy combined with differential interference contrast microscopy, that elementary steps (the growing ends of ubiquitous molecular layers with the minimum height) of ice crystals and their dynamic behavior can be visualized directly at air-ice interfaces. We observed the appearance and lateral growth of two-dimensional islands on ice crystal surfaces. When the steps of neighboring two-dimensional islands coalesced, the contrast of the steps always disappeared completely. We were able to discount the occurrence of steps too small to detect directly because we never observed the associated phenomena that would indicate their presence. In addition, classical two-dimensional nucleation theory does not support the appearance of multilayered two-dimensional islands. Hence, we concluded that two-dimensional islands with elementary height (0.37 and 0.39 nm on basal and prism faces, respectively) were visualized by our optical microscopy. On basal and prism faces, we also observed the spiral growth steps generated by screw dislocations. The distance between adjacent spiral steps on a prism face was about 1/20 of that on a basal face. Hence, the step ledge energy of a prism face was 1/20 of that on a basal face, in accord with the known lower temperature roughening transition of the prism face. PMID- 20974929 TI - Biogeographic and evolutionary implications of a diverse paleobiota in amber from the early Eocene of India. AB - For nearly 100 million years, the India subcontinent drifted from Gondwana until its collision with Asia some 50 Ma, during which time the landmass presumably evolved a highly endemic biota. Recent excavations of rich outcrops of 50-52 million-year-old amber with diverse inclusions from the Cambay Shale of Gujarat, western India address this issue. Cambay amber occurs in lignitic and muddy sediments concentrated by near-shore chenier systems; its chemistry and the anatomy of associated fossil wood indicates a definitive source of Dipterocarpaceae. The amber is very partially polymerized and readily dissolves in organic solvents, thus allowing extraction of whole insects whose cuticle retains microscopic fidelity. Fourteen orders and more than 55 families and 100 species of arthropod inclusions have been discovered thus far, which have affinities to taxa from the Eocene of northern Europe, to the Recent of Australasia, and the Miocene to Recent of tropical America. Thus, India just prior to or immediately following contact shows little biological insularity. A significant diversity of eusocial insects are fossilized, including corbiculate bees, rhinotermitid termites, and modern subfamilies of ants (Formicidae), groups that apparently radiated during the contemporaneous Early Eocene Climatic Optimum or just prior to it during the Paleocene-Eocene Thermal Maximum. Cambay amber preserves a uniquely diverse and early biota of a modern-type of broad-leaf tropical forest, revealing 50 Ma of stasis and change in biological communities of the dipterocarp primary forests that dominate southeastern Asia today. PMID- 20974930 TI - Chiral N-heterocyclic carbene-catalyzed generation of ester enolate equivalents from {alpha},{beta}-unsaturated aldehydes for enantioselective Diels-Alder reactions. AB - The catalytic generation of chiral ester enolate equivalents from alpha,beta unsaturated aldehydes with chiral N-hetereocyclic carbene catalysts makes possible highly enantioselective hetero-Diels-Alder reactions. The reactions proceed under simple, mild conditions with both aliphatic and aromatic substituted enals as substrates. Previous attempts to employ these starting materials as enolate precursors gave structurally different products via catalytically generated homoenolate equivalents. Critical to the success of the enolate generation was the strength of the catalytic base used to generate the active N-heterocyclic carbene catalyst. To complement these studies, we have investigated the enolate structure using computational methods and find that it prefers conformations perpendicular to the triazolium core. PMID- 20974931 TI - Domain structure of the DEMETER 5-methylcytosine DNA glycosylase. AB - DNA glycosylases initiate the base excision repair (BER) pathway by excising damaged, mismatched, or otherwise modified bases. Animals and plants independently evolved active BER-dependent DNA demethylation mechanisms important for epigenetic reprogramming. One such DNA demethylation mechanism is uniquely initiated in plants by DEMETER (DME)-class DNA glycosylases. Arabidopsis DME family glycosylases contain a conserved helix-hairpin-helix domain present in both prokaryotic and eukaryotic DNA glycosylases as well as two domains A and B of unknown function that are unique to this family. Here, we employed a mutagenesis approach to screen for DME residues critical for DNA glycosylase activity. This analysis revealed that amino acids clustered in all three domains, but not in the intervening variable regions, are required for in vitro 5 methylcytosine excision activity. Amino acids in domain A were found to be required for nonspecific DNA binding, a prerequisite for 5-methylcytosine excision. In addition, mutational analysis confirmed the importance of the iron sulfur cluster motif to base excision activity. Thus, the DME DNA glycosylase has a unique structure composed of three essential domains that all function in 5 methylcytosine excision. PMID- 20974932 TI - Intrinsic apurinic/apyrimidinic (AP) endonuclease activity enables Bacillus subtilis DNA polymerase X to recognize, incise, and further repair abasic sites. AB - The N-glycosidic bond can be hydrolyzed spontaneously or by glycosylases during removal of damaged bases by the base excision repair pathway, leading to the formation of highly mutagenic apurinic/apyrimidinic (AP) sites. Organisms encode for evolutionarily conserved repair machinery, including specific AP endonucleases that cleave the DNA backbone 5' to the AP site to prime further DNA repair synthesis. We report on the DNA polymerase X from the bacterium Bacillus subtilis (PolX(Bs)) that, along with polymerization and 3'-5'-exonuclease activities, possesses an intrinsic AP-endonuclease activity. Both, AP endonuclease and 3'-5'-exonuclease activities are genetically linked and governed by the same metal ligands located at the C-terminal polymerase and histidinol phosphatase domain of the polymerase. The different catalytic functions of PolX(Bs) enable it to perform recognition and incision at an AP site and further restoration (repair) of the original nucleotide in a standalone AP-endonuclease independent way. PMID- 20974933 TI - Crystal structure of prethrombin-1. AB - Prothrombin is the zymogen precursor of the clotting enzyme thrombin, which is generated by two sequential cleavages at R271 and R320 by the prothrombinase complex. The structure of prothrombin is currently unknown. Prethrombin-1 differs from prothrombin for the absence of 155 residues in the N-terminal domain and is composed of a single polypeptide chain containing fragment 2 (residues 156-271), A chain (residues 272-320), and B chain (residues 321-579). The X-ray crystal structure of prethrombin-1 solved at 2.2-A resolution shows an overall conformation significantly different (rmsd = 3.6 A) from that of its active form meizothrombin desF1 carrying a cleavage at R320. Fragment 2 is rotated around the y axis by 29 degrees and makes only few contacts with the B chain. In the B chain, the oxyanion hole is disrupted due to absence of the I16-D194 ion pair and the Na(+) binding site and adjacent primary specificity pocket are highly perturbed. A remarkable feature of the structure is that the autolysis loop assumes a helical conformation enabling W148 and W215, located 17 A apart in meizothrombin desF1, to come within 3.3 A of each other and completely occlude access to the active site. These findings suggest that the zymogen form of thrombin possesses conformational plasticity comparable to that of the mature enzyme and have significant implications for the mechanism of prothrombin activation and the zymogen -> protease conversion in trypsin-like proteases. PMID- 20974934 TI - Phospholipid bilayers are viscoelastic. AB - Lipid bilayers provide the structural framework for cellular membranes, and their character as two-dimensional fluids enables the mobility of membrane macromolecules. Though the existence of membrane fluidity is well established, the nature of this fluidity remains poorly characterized. Three-dimensional fluids as diverse as chocolates and cytoskeletal networks show a rich variety of Newtonian and non-Newtonian dynamics that have been illuminated by contemporary rheological techniques. Applying particle-tracking microrheology to freestanding phospholipid bilayers, we find that the membranes are not simply viscous but rather exhibit viscoelasticity, with an elastic modulus that dominates the response above a characteristic frequency that diverges at the fluid-gel (L(alpha) - L(beta)) phase-transition temperature. These findings fundamentally alter our picture of the nature of lipid bilayers and the mechanics of membrane environments. PMID- 20974935 TI - Engineering a protein-protein interface using a computationally designed library. AB - Computational algorithms for protein design can sample large regions of sequence space, but suffer from undersampling of conformational space and energy function inaccuracies. Experimental screening of combinatorial protein libraries avoids the need for accurate energy functions, but has limited access to vast amounts of sequence space. Here, we test if these two traditionally alternative, but potentially complementary approaches can be combined to design a variant of the ubiquitin-ligase E6AP that will bind to a nonnatural partner, the NEDD8 conjugating enzyme Ubc12. Three E6AP libraries were constructed: (i) a naive library in which all 20 amino acids were allowed at every position on the target binding surface of E6AP (13 positions), (ii) a semidirected library that varied the same residue positions as in the naive library but disallowed mutations computationally predicted to destabilize E6AP, and (iii) a directed library that used docking and sequence optimization simulations to identify mutations predicted to be favorable for binding Ubc12. Both of the directed libraries showed > 30-fold enrichment over the naive library after the first round of screening with a split-dihydrofolate reductase complementation assay and produced multiple tight binders (K(d) < 100 nM) after four rounds of selection. Four rounds of selection with the naive library failed to produce any binders with K(d)'s lower than 50 MUM. These results indicate that protein design simulations can be used to create directed libraries that are enriched in tight binders and that in some cases it is sufficient to computationally screen for well-folded sequences without explicit binding calculations. PMID- 20974936 TI - Convergent recombination shapes the clonotypic landscape of the naive T-cell repertoire. AB - Adaptive T-cell immunity relies on the recruitment of antigen-specific clonotypes, each defined by the expression of a distinct T-cell receptor (TCR), from an array of naive T-cell precursors. Despite the enormous clonotypic diversity that resides within the naive T-cell pool, interindividual sharing of TCR sequences has been observed within mobilized T-cell responses specific for certain peptide-major histocompatibility complex (pMHC) antigens. The mechanisms that underlie this phenomenon have not been fully elucidated, however. A mechanism of convergent recombination has been proposed to account for the occurrence of shared, or "public," TCRs in specific memory T-cell populations. According to this model, TCR sharing between individuals is directly related to TCR production frequency; this, in turn, is determined on a probabilistic basis by the relative generation efficiency of particular nucleotide and amino acid sequences during the recombination process. Here, we tested the key predictions of convergent recombination in a comprehensive evaluation of the naive CD8(+) TCRbeta repertoire in mice. Within defined segments of the naive CD8(+) T-cell repertoire, TCRbeta sequences with convergent features were (i) present at higher copy numbers within individual mice and (ii) shared between individual mice. Thus, the naive CD8(+) T-cell repertoire is not flat, but comprises a hierarchy of recurrence rates for individual clonotypes that is determined by relative production frequencies. These findings provide a framework for understanding the early mobilization of public CD8(+) T-cell clonotypes, which can exert profound biological effects during acute infectious processes. PMID- 20974937 TI - The Vibrio cholerae type VI secretion system displays antimicrobial properties. AB - The acute diarrheal disease cholera is caused by the marine bacterium Vibrio cholerae. A type VI secretion system (T6SS), which is structurally similar to the bacteriophage cell-puncturing device, has been recently identified in V. cholerae and is used by this organism to confer virulence toward phagocytic eukaryotes, such as J774 murine macrophages and Dictyostelium discoideum. We tested the interbacterial virulence of V. cholerae strain V52, an O37 serogroup with a constitutively active T6SS. V52 was found to be highly virulent toward multiple Gram-negative bacteria, including Escherichia coli and Salmonella Typhimurium, and caused up to a 100,000-fold reduction in E. coli survival. Because the T6SS deficient mutants V52DeltavasK and V52DeltavasH showed toxicity defects that could be complemented, virulence displayed by V. cholerae depends on a functional T6SS. V. cholerae V52 and strains of the O1 serogroup were resistant to V52, suggesting that V. cholerae has acquired immunity independently of its serogroup. We hypothesize that the T6SS, in addition to targeting eukaryotic host cells, confers toxicity toward other bacteria, providing a means of interspecies competition to enhance environmental survival. Thus, the V. cholerae T6SS may enhance the survival of V. cholerae in its aquatic ecosystem during the transmission of cholera and between epidemics. PMID- 20974938 TI - Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins. AB - The relative content of NR2 subunits in the NMDA receptor confers specific signaling properties and plasticity to synapses. However, the mechanisms that dynamically govern the retention of synaptic NMDARs, in particular 2A-NMDARs, remain poorly understood. Here, we investigate the dynamic interaction between NR2 C termini and proteins containing PSD-95/Discs-large/ZO-1 homology (PDZ) scaffold proteins at the single molecule level by using high-resolution imaging. We report that a biomimetic divalent competing ligand, mimicking the last 15 amino acids of NR2A C terminus, specifically and efficiently disrupts the interaction between 2A-NMDARs, but not 2B-NMDARs, and PDZ proteins on the time scale of minutes. Furthermore, displacing 2A-NMDARs out of synapses lead to a compensatory increase in synaptic NR2B-NMDARs, providing functional evidence that the anchoring mechanism of 2A- or 2B-NMDARs is different. These data reveal an unexpected role of the NR2 subunit divalent arrangement in providing specific anchoring within synapses, highlighting the need to study such dynamic interactions in native conditions. PMID- 20974939 TI - alphabetagamma-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction. AB - Synucleins are a vertebrate-specific family of abundant neuronal proteins. They comprise three closely related members, alpha-, beta-, and gamma-synuclein. alpha Synuclein has been the focus of intense attention since mutations in it were identified as a cause for familial Parkinson's disease. Despite their disease relevance, the normal physiological function of synucleins has remained elusive. To address this, we generated and characterized alphabetagamma-synuclein knockout mice, which lack all members of this protein family. Deletion of synucleins causes alterations in synaptic structure and transmission, age-dependent neuronal dysfunction, as well as diminished survival. Abrogation of synuclein expression decreased excitatory synapse size by ~30% both in vivo and in vitro, revealing that synucleins are important determinants of presynaptic terminal size. Young synuclein null mice show improved basic transmission, whereas older mice show a pronounced decrement. The late onset phenotypes in synuclein null mice were not due to a loss of synapses or neurons but rather reflect specific changes in synaptic protein composition and axonal structure. Our results demonstrate that synucleins contribute importantly to the long-term operation of the nervous system and that alterations in their physiological function could contribute to the development of Parkinson's disease. PMID- 20974941 TI - Sarco(endo)plasmic reticulum Ca2+-ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity. AB - Increased endoplasmic reticulum (ER) stress is one of the central mechanisms that lead to dysregulated metabolic homeostasis in obesity. It is thus crucial to understand the underpinnings of the mechanisms that lead to the development of ER stress. A high level of ER Ca(2+) is imperative for maintenance of normal ER function and this high Ca(2+) concentration of ER is maintained by sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA). Here, we show that SERCA2b protein and mRNA levels are dramatically reduced in the liver of obese mice and restoration of SERCA2b in the liver of obese and diabetic mice alleviates ER stress, increases glucose tolerance, and significantly reduces the blood glucose levels. Furthermore, overexpression of SERCA2b in the liver of obese mice significantly reduces the lipogenic gene expression and the triglyceride content in the liver. Our results document the importance of SERCA2b in dysregulated glucose and lipid homeostasis in the liver of obese mice and suggest development of drugs to increase SERCA2b activity for treatment of type 2 diabetes and nonalcoholic steatohepatitis. PMID- 20974940 TI - An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation. AB - In humans, septal defects are among the most prevalent congenital heart diseases, but their cellular and molecular origins are not fully understood. We report that transcription factor Tbx5 is present in a subpopulation of endocardial cells and that its deletion therein results in fully penetrant, dose-dependent atrial septal defects in mice. Increased apoptosis of endocardial cells lacking Tbx5, as well as neighboring TBX5-positive myocardial cells of the atrial septum through activation of endocardial NOS (Nos3), is the underlying mechanism of disease. Compound Tbx5 and Nos3 haploinsufficiency in mice worsens the cardiac phenotype. The data identify a pathway for endocardial cell survival and unravel a cell autonomous role for Tbx5 therein. The finding that Nos3, a gene regulated by many congenital heart disease risk factors including stress and diabetes, interacts genetically with Tbx5 provides a molecular framework to understand gene environment interaction in the setting of human birth defects. PMID- 20974942 TI - Cytokine-dependent but acquired immunity-independent arthritis caused by DNA escaped from degradation. AB - DNase II digests the chromosomal DNA in macrophages after apoptotic cells and nuclei from erythroid precursors are engulfed. The DNase II-null mice develop a polyarthritis that resembles rheumatoid arthritis. Here, we showed that when bone marrow cells from the DNase II-deficient mice were transferred to the wild-type mice, they developed arthritis. A deficiency of Rag2 or a lack of lymphocytes accelerated arthritis of the DNase II-null mice, suggesting that the DNase II(-/ ) macrophages were responsible for triggering arthritis, and their lymphocytes worked protectively. A high level of TNFalpha, IL-1beta, and IL-6 was found in the affected joints of the DNase II-null mice, suggesting an inflammatory-skewed cytokine storm was established in the joints. A lack of TNFalpha, IL-1beta, or IL 6 gene blocked the expression of the other cytokine genes as well and inhibited the development of arthritis. Neutralization of TNFalpha, IL-1beta, or IL-6 had a therapeutic effect on the developed arthritis of the DNase II-null mice, indicating that the cytokine storm was essential for the maintenance of arthritis in the DNase II-deficient mice. Methotrexate, an antimetabolite that is often used to treat patients with rheumatoid arthritis, had a therapeutic effect with the DNase II-null mice. These properties of arthritis in the DNase II-null mice were similar to those found in human systemic-onset juvenile idiopathic arthritis or Still's disease, indicating that the DNase II-null mice are a good animal model of this type of arthritis. PMID- 20974943 TI - Properdin homeostasis requires turnover of the alternative complement pathway. AB - Properdin is a plasma protein and is also released from neutrophil granules following stimulation. At inflammatory sites it can bind bacteria and apoptotic bodies to trigger alternative pathway (AP) activation. Principles governing properdin homeostasis are unknown. We monitored properdin during AP activation and in complement-deficient mice. There was a >90% reduction of properdin in the Crry single-knockout mice (Crry SKO). These membrane complement regulatory protein-deficient mice feature accelerated AP turnover, leading to reduced C3 and fB. Injecting cobra venom factor into wild-type mice activated the AP and led to the consumption of C3, fB, and properdin. However, and unexpectedly, properdin was also deficient in C3(-/-), fB(-/-), and fD(-/-) mice. It was present in C1q( /-), C4(-/-), and C5(-/-) mice. These findings implicate AP turnover in the maintenance of basal levels of properdin in the blood. To explore the mechanism, classical pathway-activating immune complexes were infused. Within 10 min, properdin was partially restored in fB(-/-) but not in C3(-/-) mice. Markedly reduced properdin in mice deficient in an AP component and its partial restoration by activating C3 suggest a requirement for continuous C3 activation via AP tickover to maintain properdin homeostasis. The mechanism underlying this C3-dependent process was not identified. Engagement of C3a and C5a receptors was ruled out. These findings represent an instructive example of how a positive regulator of an innate immune recognition and effector pathway is controlled. A rationale for such a means to supply properdin for immune reactions is proposed. PMID- 20974944 TI - CO2 enhancement of forest productivity constrained by limited nitrogen availability. AB - Stimulation of terrestrial plant production by rising CO(2) concentration is projected to reduce the airborne fraction of anthropogenic CO(2) emissions. Coupled climate-carbon cycle models are sensitive to this negative feedback on atmospheric CO(2), but model projections are uncertain because of the expectation that feedbacks through the nitrogen (N) cycle will reduce this so-called CO(2) fertilization effect. We assessed whether N limitation caused a reduced stimulation of net primary productivity (NPP) by elevated atmospheric CO(2) concentration over 11 y in a free-air CO(2) enrichment (FACE) experiment in a deciduous Liquidambar styraciflua (sweetgum) forest stand in Tennessee. During the first 6 y of the experiment, NPP was significantly enhanced in forest plots exposed to 550 ppm CO(2) compared with NPP in plots in current ambient CO(2), and this was a consistent and sustained response. However, the enhancement of NPP under elevated CO(2) declined from 24% in 2001-2003 to 9% in 2008. Global analyses that assume a sustained CO(2) fertilization effect are no longer supported by this FACE experiment. N budget analysis supports the premise that N availability was limiting to tree growth and declining over time--an expected consequence of stand development, which was exacerbated by elevated CO(2). Leaf- and stand-level observations provide mechanistic evidence that declining N availability constrained the tree response to elevated CO(2); these observations are consistent with stand-level model projections. This FACE experiment provides strong rationale and process understanding for incorporating N limitation and N feedback effects in ecosystem and global models used in climate change assessments. PMID- 20974945 TI - Neuropeptide S facilitates cue-induced relapse to cocaine seeking through activation of the hypothalamic hypocretin system. AB - Drug addiction is a chronic relapsing disorder characterized by compulsive drug seeking and use. Environmental conditioning factors are among the major determinants of relapse in abstinent cocaine users. Here we describe a role of the neuropeptide S (NPS) system in regulating relapse. In rats with a history of cocaine self-administration, presentation of stimuli predictive of drug availability reinstates drug seeking, triggering relapse. Intracerebroventricular (ICV) injection of NPS increased conditioned reinstatement of cocaine seeking, whereas peripheral administration of the NPS receptor antagonist SHA 68 reduced it. Manipulation of the NPS receptor system did not modify cocaine self administration. We also found that ICV NPS administration activates c-Fos expression in hypocretin-1/orexin-A (Hcrt-1/Ox-A) immunoreactive neurons in the lateral hypothalamus (LH) and in the perifornical area (PeF). Of note, intra-LH and intra-PeF administration of NPS increased conditioned reinstatement of cocaine responding, an effect that was selectively blocked with the Hcrt-1/Ox-A receptor selective antagonist SB334867. Finally, results showed that intra-LH injection of the NPS antagonist [D-Cys(tBu) (5)]NPS blocked cue-induced cocaine seeking, indicating a role for this system in the pathophysiology of drug relapse. PMID- 20974946 TI - Tree decline and the future of Australian farmland biodiversity. AB - Farmland biodiversity is greatly enhanced by the presence of trees. However, farmland trees are declining worldwide, including in North America, Central America, and parts of southern Europe. We show that tree decline and its likely consequences are particularly severe in Australia's temperate agricultural zone, which is a threatened ecoregion. Using field data on trees, remotely sensed imagery, and a demographic model for trees, we predict that by 2100, the number of trees on an average farm will contract to two-thirds of its present level. Statistical habitat models suggest that this tree decline will negatively affect many currently common animal species, with predicted declines in birds and bats of up to 50% by 2100. Declines were predicted for 24 of 32 bird species modeled and for all of six bat species modeled. Widespread declines in trees, birds, and bats may lead to a reduction in economically important ecosystem services such as shade provision for livestock and pest control. Moreover, many other species for which we have no empirical data also depend on trees, suggesting that fundamental changes in ecosystem functioning are likely. We conclude that Australia's temperate agricultural zone has crossed a threshold and no longer functions as a self-sustaining woodland ecosystem. A regime shift is occurring, with a woodland system deteriorating into a treeless pasture system. Management options exist to reverse tree decline, but new policy settings are required to encourage their widespread adoption. PMID- 20974947 TI - Evolutionary history of partible paternity in lowland South America. AB - Partible paternity, the conception belief that more than one man can contribute to the formation of a fetus, is common in lowland South America and characterized by nonexclusive mating relationships and various institutionalized forms of recognition and investment by multiple cofathers. Previous work has emphasized the fitness benefits for women where partible paternity beliefs facilitate paternal investment from multiple men and may reduce the risk of infanticide. In this comparative study of 128 lowland South American societies, the prevalence of partible paternity beliefs may be as much as two times as common as biologically correct beliefs in singular paternity. Partible paternity beliefs are nearly ubiquitous in four large language families--Carib, Pano, Tupi, and Macro-Je. Phylogenetic reconstruction suggests that partible paternity evolved deep in Amazonian prehistory at the root of a tentative Je-Carib-Tupi clade. Partible paternity often occurs with uxorilocal postmarital residence (males transfer), although there are exceptions. Partible paternity may have benefits for both sexes, especially in societies where essentially all offspring are said to have multiple fathers. Despite a decrease in paternity certainty, at least some men probably benefit (or mitigate costs) by increasing their number of extramarital partners, using sexual access to their wives to formalize male alliances, and/or sharing paternity with close kin. PMID- 20974948 TI - Joint linkage-linkage disequilibrium mapping is a powerful approach to detecting quantitative trait loci underlying drought tolerance in maize. AB - This paper describes two joint linkage-linkage disequilibrium (LD) mapping approaches: parallel mapping (independent linkage and LD analysis) and integrated mapping (datasets analyzed in combination). These approaches were achieved using 2,052 single nucleotide polymorphism (SNP) markers, including 659 SNPs developed from drought-response candidate genes, screened across three recombinant inbred line (RIL) populations and 305 diverse inbred lines, with anthesis-silking interval (ASI), an important trait for maize drought tolerance, as the target trait. Mapping efficiency was improved significantly due to increased population size and allele diversity and balanced allele frequencies. Integrated mapping identified 18 additional quantitative trait loci (QTL) not detected by parallel mapping. The use of haplotypes improved mapping efficiency, with the sum of phenotypic variation explained (PVE) increasing from 5.4% to 23.3% for single SNP based analysis. Integrated mapping with haplotype further improved the mapping efficiency, and the most significant QTL had a PVE of up to 34.7%. Normal allele frequencies for 113 of 277 (40.8%) SNPs with minor allele frequency (<5%) in 305 lines were recovered in three RIL populations, three of which were significantly associated with ASI. The candidate genes identified by two significant haplotype loci included one for a SET domain protein involved in the control of flowering time and the other encoding aldo/keto reductase associated with detoxification pathways that contribute to cellular damage due to environmental stress. Joint linkage-LD mapping is a powerful approach for detecting QTL underlying complex traits, including drought tolerance. PMID- 20974949 TI - Generation of induced pluripotent stem cells using site-specific integration with phage integrase. AB - To date, a large number of reports have described reprogramming many somatic cell types into induced pluripotent stem (iPS) cells, using different numbers of transcription factors and devising alternate methods of introducing the transcription factor genes or proteins into the somatic cells. Here, we describe a method using bacteriophage PhiC31 integrase to reprogram mouse embryonic fibroblasts and human amniotic fluid cells into iPS cells. These iPS cells showed morphology, surface antigens, gene expression, and epigenetic states similar to ES cells and formed teratomas with three germ layers in nonobese diabetic/severely compromised immunodeficient mice. Importantly, these iPS cells have only a single integration site in each cell line. The locations of integration favor the intergenic regions, and their distances from the adjacent genes extended from several hundred to >1 million bp. The effect of the insertion on the expression of these genes can be studied by RT-PCR. No insertion into microRNA gene loci was detected. Hence, it is possible to select cells in which adjacent gene functions are not affected, or the inserts can be removed if necessary. We conclude that phage integrase-mediated site-specific recombination can produce iPS cells that have undisturbed endogenous gene function and could be safe for future human therapeutic application. PMID- 20974950 TI - Linking differential domain functions of the GS3 protein to natural variation of grain size in rice. AB - Grain yield in many cereal crops is largely determined by grain size. Here we report the genetic and molecular characterization of GS3, a major quantitative trait locus for grain size. It functions as a negative regulator of grain size and organ size. The wild-type isoform is composed of four putative domains: a plant-specific organ size regulation (OSR) domain in the N terminus, a transmembrane domain, a tumor necrosis factor receptor/nerve growth factor receptor (TNFR/NGFR) family cysteine-rich domain, and a von Willebrand factor type C (VWFC) in the C terminus. These domains function differentially in grain size regulation. The OSR domain is both necessary and sufficient for functioning as a negative regulator. The wild-type allele corresponds to medium grain. Loss of function of OSR results in long grain. The C-terminal TNFR/NGFR and VWFC domains show an inhibitory effect on the OSR function; loss-of-function mutations of these domains produced very short grain. This study linked the functional domains of the GS3 protein to natural variation of grain size in rice. PMID- 20974951 TI - brca2 in zebrafish ovarian development, spermatogenesis, and tumorigenesis. AB - Humans with inherited mutations in BRCA2 are at increased risk for developing breast and ovarian cancer; however, the relationship between BRCA2 mutation and these cancers is not understood. Studies of Brca2 mutation by gene targeting in mice are limited, given that homozygous Brca2 mutation typically leads to early embryonic lethality. We established a zebrafish line with a nonsense mutation in brca2 exon 11 (brca2(Q658X)), a mutation similar in location and type to BRCA2 mutations found in humans with hereditary breast and ovarian cancer. brca2(Q658X) homozygous zebrafish are viable and survive to adulthood; however, juvenile homozygotes fail to develop ovaries during sexual differentiation. Instead, brca2(Q658X) homozygotes develop as infertile males with meiotic arrest in spermatocytes. Germ cell migration to the embryonic gonadal ridge is unimpaired in brca2(Q658X) homozygotes; thus, failure of ovarian development is not due to defects in early establishment of the embryonic gonad. Homozygous tp53 mutation rescues ovarian development in brca2(Q658X) homozygous zebrafish, reflecting the importance of germ cell apoptosis in gonad morphogenesis. Adult brca2(Q658X) homozygous zebrafish are predisposed to testicular neoplasias. In addition, tumorigenesis in multiple tissues is significantly accelerated in combination with homozygous tp53 mutation in both brca2(Q658X) homozygous and brca2(Q658X) heterozygous zebrafish. These studies reveal critical roles for brca2 in ovarian development and tumorigenesis in reproductive tissues. PMID- 20974952 TI - Human remains from Zhirendong, South China, and modern human emergence in East Asia. AB - The 2007 discovery of fragmentary human remains (two molars and an anterior mandible) at Zhirendong (Zhiren Cave) in South China provides insight in the processes involved in the establishment of modern humans in eastern Eurasia. The human remains are securely dated by U-series on overlying flowstones and a rich associated faunal sample to the initial Late Pleistocene, >100 kya. As such, they are the oldest modern human fossils in East Asia and predate by >60,000 y the oldest previously known modern human remains in the region. The Zhiren 3 mandible in particular presents derived modern human anterior symphyseal morphology, with a projecting tuber symphyseos, distinct mental fossae, modest lateral tubercles, and a vertical symphysis; it is separate from any known late archaic human mandible. However, it also exhibits a lingual symphyseal morphology and corpus robustness that place it close to later Pleistocene archaic humans. The age and morphology of the Zhiren Cave human remains support a modern human emergence scenario for East Asia involving dispersal with assimilation or populational continuity with gene flow. It also places the Late Pleistocene Asian emergence of modern humans in a pre-Upper Paleolithic context and raises issues concerning the long-term Late Pleistocene coexistence of late archaic and early modern humans across Eurasia. PMID- 20974953 TI - Glial cell line-derived neurotrophic factor defines the path of developing and regenerating axons in the lateral line system of zebrafish. AB - How the peripheral axons of sensory neurons are guided to distant target organs is not well understood. Here we examine this question in the case of the posterior lateral line (PLL) system of zebrafish, where sensory organs are deposited by a migrating primordium. Sensory neurites accompany this primordium during its migration and are thereby guided to their prospective target organs. We show that the inactivation of glial cell line-derived neurotrophic factor (GDNF) signaling leads to defects of innervation and that these defects are due to the inability of sensory axons to track the migrating primordium. GDNF signaling is also used as a guidance cue during axonal regeneration following nerve cut. We conclude that GDNF is a major determinant of directed neuritic growth and of target finding in this system, and we propose that GDNF acts by promoting local neurite outgrowth. PMID- 20974954 TI - Hypoxia abrogates antichlamydial properties of IFN-gamma in human fallopian tube cells in vitro and ex vivo. AB - IFN-gamma has an important role in the adaptive immune response against intracellular pathogens. In urogenital tract (UGT) infections with the obligate intracellular pathogen Chlamydia trachomatis, IFN-gamma-mediated control of chlamydial growth implies the JAK-STAT signaling cascades and subsequent induction of the indoleamine 2,3-dioxygenase (IDO). As oxygen concentrations in the UGT are low under physiological conditions (O(2) < 5%) and further decrease during an inflammatory process, we wondered whether antibacterial properties of IFN-gamma are maintained under hypoxic conditions. Using primary cells that were isolated from human fallopian tubes and an ex vivo human fallopian tube model (HFTM), we found that even high IFN-gamma concentrations (200 units/mL) were not sufficient to limit growth of C. trachomatis under hypoxia. Reduced antibacterial activity of IFN-gamma under hypoxia was restricted to the urogenital serovars D and L(2), but was not observed with the ocular serovar A. Impaired effectiveness of IFN-gamma on chlamydial growth under hypoxia was accompanied by reduced phosphorylation of Stat-1 on Tyr701 and diminished IDO activity. This study shows that IFN-gamma effector functions on intracellular C. trachomatis depend on the environmental oxygen supply, which could explain inadequate bacterial clearance and subsequent chronic infections eventually occurring in the UGT of women. PMID- 20974955 TI - IFN-gamma abrogates endotoxin tolerance by facilitating Toll-like receptor induced chromatin remodeling. AB - An important mechanism by which IFN-gamma primes macrophages for enhanced innate immune responses is abrogation of feedback inhibitory pathways. Accordingly, IFN gamma abrogates endotoxin tolerance, a major negative feedback loop that silences expression of inflammatory cytokine genes in macrophages previously exposed to endotoxin/Toll-like receptor (TLR) ligands. Mechanisms by which IFN-gamma inhibits endotoxin tolerance have not been elucidated. Here, we show that pretreatment with IFN-gamma prevented tolerization of primary human monocytes and restored TLR4-mediated induction of various proinflammatory cytokines, including IL-6 and TNFalpha. Surprisingly, IFN-gamma did not alter proximal TLR4 signaling defects in tolerized monocytes. Instead, IFN-gamma blocked tolerance-associated down-regulation of IL6 and TNF transcription, RNA polymerase II recruitment, and NF-kappaB and CCAAT/enhancer-binding protein beta transcription factor binding to the IL6 and TNF promoters in tolerized monocytes. The mechanism by which IFN gamma restored IL6 expression was by facilitating TLR4-induced recruitment of chromatin remodeling machinery to the IL6 promoter and promoting IL6 locus accessibility in tolerized monocytes. Our results suggest that IFN-gamma overcomes endotoxin tolerance by facilitating TLR-induced chromatin remodeling to allow expression of proinflammatory genes. These results identify a mechanism by which IFN-gamma promotes activation of macrophages and highlight the importance of chromatin remodeling and transcriptional control in the regulation of inflammatory cytokine production in tolerant and activated macrophages. PMID- 20974956 TI - Boron-containing organic pigments from a Jurassic red alga. AB - Organic biomolecules that have retained their basic chemical structures over geological periods (molecular fossils) occur in a wide range of geological samples and provide valuable paleobiological, paleoenvironmental, and geochemical information not attainable from other sources. In rare cases, such compounds are even preserved with their specific functional groups and still occur within the organisms that produced them, providing direct information on the biochemical inventory of extinct organisms and their possible evolutionary relationships. Here we report the discovery of an exceptional group of boron-containing compounds, the borolithochromes, causing the distinct pink coloration of well preserved specimens of the Jurassic red alga Solenopora jurassica. The borolithochromes are characterized as complicated spiroborates (boric acid esters) with two phenolic moieties as boron ligands, representing a unique class of fossil organic pigments. The chiroptical properties of the pigments unequivocally demonstrate a biogenic origin, at least of their ligands. However, although the borolithochromes originated from a fossil red alga, no analogy with hitherto known present-day red algal pigments was found. The occurrence of the borolithochromes or their possible diagenetic products in the fossil record may provide additional information on the classification and phylogeny of fossil calcareous algae. PMID- 20974958 TI - Does horizontal mixing explain phytoplankton dynamics? PMID- 20974957 TI - Duration of estrogen deprivation, not chronological age, prevents estrogen's ability to enhance hippocampal synaptic physiology. AB - Whether estrogen replacement is beneficial to cognitive health is controversial. Some studies have shown that estrogen replacement therapy (ERT) relieves memory impairment associated with menopause in women, whereas others suggest that estrogen not only is incapable of providing a benefit, but actually can be detrimental. One possible explanation for this discrepancy in study findings could be the varying time after menopause at which ERT is initiated. It has been proposed that a critical period exists during which ERT must be administered to enhance cognitive function. This idea has yet to be tested directly using functional synaptic studies, however. Here we investigated whether prolonged hormone deprivation caused by ovariectomy (OVX) in young adult rats prevents the ability of estrogen replacement to increase synaptic function in the hippocampus to a degree necessary for estrogen-induced improvement in learning and memory. Remarkably, estrogen replacement was found to increase long-term potentiation, the current mediated by NR2B-containing NMDA receptors, and the dendritic spine density at CA3-CA1 synapses up to 15 months post-OVX. However, by 19 months post OVX, the same estrogen replacement was unable to induce these changes. Importantly, this loss of estrogen's effectiveness was seen to be a consequence of the duration of deprivation. In female rats aged with their ovaries intact and examined at the same chronological age as the 19-month post-OVX group, estrogen replacement significantly increased synaptic function and spine density. These data clearly demonstrate that a critical period exists during which ERT must be administered, and that once this period passes, the beneficial effects are lost. PMID- 20974959 TI - Spectral quality of light modulates emotional brain responses in humans. AB - Light therapy can be an effective treatment for mood disorders, suggesting that light is able to affect mood state in the long term. As a first step to understand this effect, we hypothesized that light might also acutely influence emotion and tested whether short exposures to light modulate emotional brain responses. During functional magnetic resonance imaging, 17 healthy volunteers listened to emotional and neutral vocal stimuli while being exposed to alternating 40-s periods of blue or green ambient light. Blue (relative to green) light increased responses to emotional stimuli in the voice area of the temporal cortex and in the hippocampus. During emotional processing, the functional connectivity between the voice area, the amygdala, and the hypothalamus was selectively enhanced in the context of blue illumination, which shows that responses to emotional stimulation in the hypothalamus and amygdala are influenced by both the decoding of vocal information in the voice area and the spectral quality of ambient light. These results demonstrate the acute influence of light and its spectral quality on emotional brain processing and identify a unique network merging affective and ambient light information. PMID- 20974960 TI - Genome analysis of Bifidobacterium bifidum PRL2010 reveals metabolic pathways for host-derived glycan foraging. AB - The human intestine is densely populated by a microbial consortium whose metabolic activities are influenced by, among others, bifidobacteria. However, the genetic basis of adaptation of bifidobacteria to the human gut is poorly understood. Analysis of the 2,214,650-bp genome of Bifidobacterium bifidum PRL2010, a strain isolated from infant stool, revealed a nutrient-acquisition strategy that targets host-derived glycans, such as those present in mucin. Proteome and transcriptome profiling revealed a set of chromosomal loci responsible for mucin metabolism that appear to be under common transcriptional control and with predicted functions that allow degradation of various O-linked glycans in mucin. Conservation of the latter gene clusters in various B. bifidum strains supports the notion that host-derived glycan catabolism is an important colonization factor for B. bifidum with concomitant impact on intestinal microbiota ecology. PMID- 20974961 TI - Human ISWI chromatin-remodeling complexes sample nucleosomes via transient binding reactions and become immobilized at active sites. AB - Chromatin remodeling complexes can translocate nucleosomes along the DNA in an ATP-dependent manner. Here, we studied autofluorescent protein constructs of the human ISWI family members Snf2H, Snf2L, the catalytically inactive Snf2L+13 splice variant, and the accessory Acf1 subunit in living human and mouse cells by fluorescence microscopy/spectroscopy. Except for Snf2L, which was not detected in the U2OS cell line, the endogenous ISWI proteins were abundant at nuclear concentrations between 0.14 and 0.83 MUM. A protein interaction analysis showed the association of multimeric Snf2H and Acf1 into a heterotetramer or higher order ACF complex. During the G1/2 cell cycle phase, Snf2H and Snf2L displayed average residence times <150 ms in the chromatin-bound state. The comparison of active and inactive Snf2H/Snf2L indicated that an immobilized fraction potentially involved in active chromatin remodeling comprised only 1-3%. This fraction was largely increased at replication foci in S phase or at DNA repair sites. To rationalize these findings we propose that ISWI remodelers operate via a "continuous sampling" mechanism: The propensity of nucleosomes to be translocated is continuously tested in transient binding reactions. Most of these encounters are unproductive and efficient remodeling requires an increased binding affinity to chromatin. Due to the relatively high intranuclear remodeler concentrations cellular response times for repositioning a given nucleosome were calculated to be in the range of tens of seconds to minutes. PMID- 20974962 TI - FcgammaRIV deletion reveals its central role for IgG2a and IgG2b activity in vivo. AB - Cellular Fcgamma receptors are essential for IgG-dependent effector functions in vivo. There is convincing evidence that selective activating Fcgamma receptors are responsible for the activity of individual IgG subclasses. Thus, IgG1 activity is absent in FcgammaRIII-deficient mice, and several studies suggest that the activity of the most potent IgG subclasses, IgG2a and IgG2b, might be dependent on either individual or a combination of activating FcgammaRs. To study the role of individual activating FcgammaRs for IgG subclass activity, we generated an FcgammaRIV-deficient mouse and showed that a variety of IgG2a- and IgG2b-dependent effector functions are impaired in the absence of this activating Fc receptor in models of autoimmunity and antibody-dependent cellular cytotoxicity. PMID- 20974963 TI - Thymic stromal lymphopoietin-mediated STAT5 phosphorylation via kinases JAK1 and JAK2 reveals a key difference from IL-7-induced signaling. AB - Thymic stromal lymphopoietin (TSLP) is a type I cytokine that plays essential roles in allergic/inflammatory skin and airway disorders, in helminth infections, and in regulating intestinal immunity. TSLP signals via IL-7Ralpha and a specific TSLPR subunit that is highly related to the common cytokine receptor gamma chain, gamma(c). Although TSLP has effects on a broad range of hematopoetic cells and can induce STAT5 phosphorylation, TSLP was reported to not signal via JAK kinases, and the mechanism by which TSLP regulates STAT5 phosphorylation has been unclear. We now demonstrate the role of JAK1 and JAK2 in TSLP-mediated STAT5 phosphorylation in mouse and human primary CD4(+) T cells, in contrast to the known activation of JAK1 and JAK3 by the related cytokine, IL-7. We also show that just as JAK1 interacts with IL-7Ralpha, JAK2 is associated with TSLPR protein. Moreover, we demonstrate the importance of STAT5 activation for TSLP mediated survival and proliferation of CD4(+) T cells. These findings clarify the basis for TSLP-mediated signaling and provide an example wherein a cytokine uses JAK1 and JAK2 to mediate the activation of STAT5. PMID- 20974964 TI - The cardiac IKs channel, complex indeed. PMID- 20974965 TI - Coordination of Fc receptor signaling regulates cellular commitment to phagocytosis. AB - During Fcgamma receptor (FcR)-mediated phagocytosis by macrophages, cytoplasm advances over IgG-coated particles by the sequential ligation of FcR in plasma membranes. If FcR signaling was strictly autonomous, then the signals generated during phagocytosis should be proportional to the number of ligated receptors. By measuring FcR-dependent responses to beads coated with various densities of IgG, this study identified nonlinear signaling that organizes an all or none response during particle ingestion. Phagocytosis of beads with IgG at low density either stalled after making small, actin-rich cups or proceeded to completion at the same rate as phagocytosis of high-density IgG beads. Signals were measured by quantifying the recruitment of YFP-labeled probes to phagocytic cup membranes. Although the magnitude of early signals correlated with IgG density, later signals showed an all or none response, which was regulated by the concentrations of 3' phosphoinositides in phagocytic cup membranes. Thus, 3' phosphoinositides, shown previously to be required for phagocytosis, function in a feedback regulatory mechanism affecting late but not early signals. This indicates a mechanism for the coordination of cell movements initiated by receptor signaling. PMID- 20974966 TI - Xenopus furry contributes to release of microRNA gene silencing. AB - A transcriptional corepressor, Xenopus furry (Xfurry), is expressed in the chordamesodermal region and induces secondary dorsal axes when overexpressed on the ventral side of the embryo. The N-terminal furry domain functions as a repressor, and the C-terminal leucine zipper (LZ) motifs /coiled-coil structure, found only in vertebrate homologs, contributes to the nuclear localization. The engrailed repressor (enR)+LZ repressor construct, which has properties similar to Xfurry, induced several chordamesodermal genes. In contrast, an antisense morpholino oligonucleotide, Xfurry-MO, and the activating construct, herpes simplex virus protein (VP16)+LZ, had effects opposite those of Xfurry overexpression. Because blocking protein synthesis with cycloheximide superinduced several Xfurry transcriptional targets, and because expression of enR+LZ induced such genes under cycloheximide treatment, we analyzed the role of an Xfurry transcriptional target, microRNA miR-15. Cycloheximide reduced the expression of primary miR-15 (pri-miR-15), whereas miR-15 reduced the expression of genes superinduced by cycloheximide treatment. These results show that Xfurry regulates chordamesodermal genes by contributing to repression of pretranscriptional gene silencing by miR-15. PMID- 20974967 TI - Optimal habits can develop spontaneously through sensitivity to local cost. AB - Habits and rituals are expressed universally across animal species. These behaviors are advantageous in allowing sequential behaviors to be performed without cognitive overload, and appear to rely on neural circuits that are relatively benign but vulnerable to takeover by extreme contexts, neuropsychiatric sequelae, and processes leading to addiction. Reinforcement learning (RL) is thought to underlie the formation of optimal habits. However, this theoretic formulation has principally been tested experimentally in simple stimulus-response tasks with relatively few available responses. We asked whether RL could also account for the emergence of habitual action sequences in realistically complex situations in which no repetitive stimulus-response links were present and in which many response options were present. We exposed naive macaque monkeys to such experimental conditions by introducing a unique free saccade scan task. Despite the highly uncertain conditions and no instruction, the monkeys developed a succession of stereotypical, self-chosen saccade sequence patterns. Remarkably, these continued to morph for months, long after session averaged reward and cost (eye movement distance) reached asymptote. Prima facie, these continued behavioral changes appeared to challenge RL. However, trial-by trial analysis showed that pattern changes on adjacent trials were predicted by lowered cost, and RL simulations that reduced the cost reproduced the monkeys' behavior. Ultimately, the patterns settled into stereotypical saccade sequences that minimized the cost of obtaining the reward on average. These findings suggest that brain mechanisms underlying the emergence of habits, and perhaps unwanted repetitive behaviors in clinical disorders, could follow RL algorithms capturing extremely local explore/exploit tradeoffs. PMID- 20974968 TI - Rubicon controls endosome maturation as a Rab7 effector. AB - The activation and recruitment of the small GTPase Rab7 to early endosome is a critical step for early to late endosome maturation, a process that requires the class III phosphatidylinositol 3-kinase (PI3KC3) and GTPase regulators. However, the molecular mechanism underlying Rab7 activation and endosome maturation is still poorly defined. Here we report that Rubicon, a component of the PI3KC3 complex, prevents endosome maturation through differential interactions with Rab7 and UVRAG. UVRAG activates PI3KC3 and C-VPS/HOPS, a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on Rab7. We demonstrate that Rubicon sequesters UVRAG from C-VPS/HOPS. Active GTP-bound Rab7 competes for Rubicon binding and releases UVRAG to associate with C-VPS/HOPS, which in turn promotes further loading of Rab7 with GTP. This feed-forward loop ensures rapid amplification of GTP-bound Rab7 and consequent stimulation of endosome maturation. Hence, Rubicon serves as a previously unknown Rab7 effector to ensure the proper progression of the endocytic pathway. PMID- 20974969 TI - DDS, 4,4'-diaminodiphenylsulfone, extends organismic lifespan. AB - DDS, 4,4'-diaminodiphenylsulfone, is the most common drug prescribed to treat Hansen disease patients. In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells. Because DDS treatment significantly enhances the antioxidant activity in humans, we examined its effect on lifespan extension. Here we show that DDS extends organismic lifespan using Caenorhabditis elegans as a model system. DDS treatment caused a delay in aging and decreased the levels of a mitochondrial complex. The oxygen consumption rate was also significantly lowered. Consistent with these data, paraquat treatment evoked less reactive oxygen species in DDS treated worms, and these worms were less sensitive to paraquat. Interestingly enough, all of the molecular events caused by DDS treatment were consistently reproduced in mice treated with DDS for 3 mo and in the C2C12 muscle cell line. Structural prediction identified pyruvate kinase (PK) as a protein target of DDS. Indeed, DDS bound and inhibited PK in vitro and inhibited it in vivo, and a PK mutation conferred extended lifespan of C. elegans. Supplement of pyruvate to the media protected C2C12 cells from apoptosis caused by paraquat. Our findings establish the significance of DDS in lowering reactive oxygen species generation and extending the lifespan, which renders the rationale to examining the possible effect of DDS on human lifespan extension. PMID- 20974970 TI - RNA-dependent control of gene amplification. AB - We exploit the unusual genome organization of the ciliate cell to analyze the control of specific gene amplification during a nuclear differentiation process. Ciliates contain two types of nuclei within one cell, the macronucleus and the micronucleus; and after sexual reproduction a new macronucleus is formed from a micronuclear derivative. During macronuclear differentiation, most extensive DNA reorganization, elimination, and fragmentation processes occur, resulting in a macronucleus containing short DNA molecules (nanochromosomes) representing individual genetic units and each being present in high copy number. It is believed that these processes are controlled by small nuclear RNAs but also by a template derived from the old macronucleus. We first describe the exact copy numbers of selected nanochromosomes in the macronucleus, and define the timing during nuclear differentiation at which copy number is determined. This led to the suggestion that DNA processing and copy number control may be closely related mechanisms. Degradation of an RNA template derived from the macronucleus leads to significant decrease in copy number, whereas injection of additional template molecules results in an increase in copy number and enhanced expression of the corresponding gene. These observations can be incorporated into a mechanistic model about an RNA-dependent epigenetic regulation of gene copy number during nuclear differentiation. This highlights that RNA, in addition to its well-known biological functions, can also be involved in the control of gene amplification. PMID- 20974971 TI - Mining the plasma immunopeptidome for cancer peptides as biomarkers and beyond. PMID- 20974972 TI - Transcriptional silencing functions of the yeast protein Orc1/Sir3 subfunctionalized after gene duplication. AB - The origin recognition complex (ORC) defines origins of replication and also interacts with heterochromatin proteins in a variety of species, but how ORC functions in heterochromatin assembly remains unclear. The largest subunit of ORC, Orc1, is particularly interesting because it contains a nucleosome-binding BAH domain and because it gave rise to Sir3, a key silencing protein in Saccharomyces cerevisiae, through gene duplication. We examined whether Orc1 possessed a Sir3-like silencing function before duplication and found that Orc1 from the yeast Kluyveromyces lactis, which diverged from S. cerevisiae before the duplication, acts in conjunction with the deacetylase Sir2 and the histone binding protein Sir4 to generate heterochromatin at telomeres and a mating-type locus. Moreover, the ability of KlOrc1 to spread across a silenced locus depends on its nucleosome-binding BAH domain and the deacetylase Sir2. Interestingly, KlOrc1 appears to act independently of the entire ORC, as other subunits of the complex, Orc4 and Orc5, are not strongly associated with silenced domains. These findings demonstrate that Orc1 functioned in silencing before duplication and suggest that Orc1 and Sir2, both of which are broadly conserved among eukaryotes, may have an ancient history of cooperating to generate chromatin structures, with Sir2 deacetylating histones and Orc1 binding to these deacetylated nucleosomes through its BAH domain. PMID- 20974973 TI - Identification of a receptor for an extinct virus. AB - The resurrection of endogenous retroviruses from inactive molecular fossils has allowed the investigation of interactions between extinct pathogens and their hosts that occurred millions of years ago. Two such paleoviruses, chimpanzee endogenous retrovirus-1 and -2 (CERV1 and CERV2), are relatives of modern MLVs and are found in the genomes of a variety of Old World primates, but are absent from the human genome. No extant CERV1 and -2 proviruses are known to encode functional proteins. To investigate the host range restriction of these viruses, we attempted to reconstruct functional envelopes by generating consensus genes and proteins. CERV1 and -2 enveloped MLV particles infected cell lines from a range of mammalian species. Using CERV2 Env-pseudotyped MLV reporters, we identified copper transport protein 1 (CTR1) as a receptor that was presumably used by CERV2 during its ancient exogenous replication in primates. Expression of human CTR1 was sufficient to confer CERV2 permissiveness on otherwise resistant hamster cells, and CTR1 knockdown or CuCl(2) treatment specifically inhibited CERV2 infection of human cells. Mutations in highly conserved CTR1 residues that have rendered hamster cells resistant to CERV2 include a unique deletion in a copper-binding motif. These CERV2 receptor-inactivating mutations in hamster CTR1 are accompanied by apparently compensating changes, including an increased number of extracellular copper-coordinating residues, and this may represent an evolutionary barrier to the acquisition of CERV2 resistance in primates. PMID- 20974974 TI - Two interacting coiled-coil proteins, WEB1 and PMI2, maintain the chloroplast photorelocation movement velocity in Arabidopsis. AB - Chloroplasts move toward weak light (accumulation response) and away from strong light (avoidance response). The fast and accurate movement of chloroplasts in response to ambient light conditions is essential for efficient photosynthesis and photodamage prevention in chloroplasts. Here, we report that two Arabidopsis mutants, weak chloroplast movement under blue light 1 (web1) and web2, are defective in both the avoidance and the accumulation responses. Map-based cloning revealed that both genes encode coiled-coil proteins and that WEB2 is identical to the plastid movement impaired 2 (PMI2) gene. The velocities of chloroplast movement in web1 and pmi2 were approximately threefold lower than that in the wild type. Defects in the avoidance response of web1 and pmi2 were suppressed by mutation of the J-domain protein required for chloroplast accumulation response 1 (JAC1) gene, which is essential for the accumulation response; these results indicate that WEB1 and PMI2 play a role in suppressing JAC1 under strong light conditions. A yeast two-hybrid analysis and a nuclear recruitment assay identified a physical interaction between WEB1 and PMI2, and transient expression analysis of CFP-WEB1 and YFP-PMI2 revealed that they colocalized in the cytosol. Bimolecular fluorescence complementation analysis confirmed the interaction of these proteins in the cytosol. Blue light-induced changes in short chloroplast actin filaments (cp-actin filaments) were impaired in both web1 and pmi2. Our findings suggest that a cytosolic WEB1-PMI2 complex maintains the velocity of chloroplast photorelocation movement via cp-actin filament regulation. PMID- 20974975 TI - Imbalance of ionic conductances contributes to diverse symptoms of demyelination. AB - Fast axonal conduction of action potentials in mammals relies on myelin insulation. Demyelination can cause slowed, blocked, desynchronized, or paradoxically excessive spiking that underlies the symptoms observed in demyelination diseases. The diversity and timing of such symptoms are poorly understood, often intermittent, and uncorrelated with disease progress. We modeled the effects of demyelination (and secondary remodeling) on intrinsic axonal excitability using Hodgkin-Huxley and reduced Morris-Lecar models. Simulations and analysis suggested a simple explanation for the breadth of symptoms and revealed that the ratio of sodium to leak conductance, g(Na)/g(L), acted as a four-way switch controlling excitability patterns that included spike failure, single spike transmission, afterdischarge, and spontaneous spiking. Failure occurred when this ratio fell below a threshold value. Afterdischarge occurred at g(Na)/g(L) just below the threshold for spontaneous spiking and required a slow inward current that allowed for two stable attractor states, one corresponding to quiescence and the other to repetitive spiking. A neuron prone to afterdischarge could function normally unless it was switched to its "pathological" attractor state; thus, although the underlying pathology may develop slowly by continuous changes in membrane conductances, a discontinuous change in axonal excitability can occur and lead to paroxysmal symptoms. We conclude that tonic and paroxysmal positive symptoms as well as negative symptoms may be a consequence of varying degrees of imbalance between g(Na) and g(L) after demyelination. The KCNK family of g(L) potassium channels may be an important target for new drugs to treat the symptoms of demyelination. PMID- 20974976 TI - Antiretroviral therapy for tuberculosis control in nine African countries. AB - HIV has increased the incidence of tuberculosis (TB) by up to sevenfold in African countries, but antiretroviral therapy (ART) reduces the incidence of AIDS related TB. We use a mathematical model to investigate the short-term and long term impacts of ART on the incidence of TB, assuming that people are tested for HIV once a year, on average, and start ART at a fixed time after HIV seroconversion or at a fixed CD4(+) cell count. We fit the model to trend data on HIV prevalence and TB incidence in nine countries in sub-Saharan Africa. If HIV positive people start ART within 5 y of seroconversion, the incidence of AIDS related TB in 2015 will be reduced by 48% (range: 37-55%). Long-term reductions depend sensitively on the delay to starting ART. If treatment is started 5, 2, or 1 y after HIV seroconversion, or as soon as people test positive, the incidence in 2050 will be reduced by 66% (range: 57-80%), 95% (range: 93-96%), 97.7% (range: 96.9-98.2%) and 98.4% (range: 97.8-98.9%), respectively. In the countries considered here, early ART could avert 0.71 +/- 0.36 [95% confidence interval (CI)] million of 3.4 million cases of TB between 2010 and 2015 and 5.8 +/- 2.9 (95% CI) million of 15 million cases between 2015 and 2050. As more countries provide ART at higher CD4(+) cell counts, the impact on TB should be investigated to test the predictions of this model. PMID- 20974977 TI - IL-27 structural analysis demonstrates similarities with ciliary neurotrophic factor (CNTF) and leads to the identification of antagonistic variants. AB - IL-27, consisting of the subunits IL-27p28 and Epstein-Barr virus-induced gene 3 (EBI3), is a heterodimeric cytokine belonging to the IL-6/IL-12 family of cytokines. IL-27p28 is a four-helical cytokine requiring association with the soluble receptor EBI3 to be efficiently secreted and functionally active. Computational and biological analyses of the IL-27 binding site 1 to its receptor revealed important structural proximities with the ciliary neurotrophic factor group of cytokines and highlighted the contribution of p28 Trp(97), as well as of EBI3 Phe(97), Asp(210), and Glu(159), as key residues in the interactions between both cytokine subunits. WSX-1 (IL-27R) and gp130 compose the IL-27 receptor signaling complex, recruiting the STAT-1 and STAT-3 pathways. A study of IL-27 binding site 3 showed that Trp(197) was crucial for the cytokine's interaction with gp130, but that the mutated cytokine still recognized IL-27R on the cell surface. IL-27 exerts both pro- and anti-inflammatory functions, promoting proliferation and differentiation of Th1 and inhibiting Th17 differentiation. Our results led us to develop mutated forms of human and mouse IL-27 with antagonistic activities. Using an in vivo mouse model of concanavalin A-induced Th1-cell-mediated hepatitis, we showed that the murine IL-27 antagonist W195A decreased liver inflammation by downregulating the synthesis of CXCR3 ligands and several acute phase proteins. Together, these data suggest that IL-27 antagonism could be of interest in down-modulating acute IL-27-driven Th1-cell-mediated immune response. PMID- 20974978 TI - Ecological contingency in the effects of climatic warming on forest herb communities. AB - Downscaling from the predictions of general climate models is critical to current strategies for mitigating species loss caused by climate change. A key impediment to this downscaling is that we lack a fully developed understanding of how variation in physical, biological, or land-use characteristics mediates the effects of climate change on ecological communities within regions. We analyzed change in understory herb communities over a 60-y period (1949/1951-2007/2009) in a complex montane landscape (the Siskiyou Mountains, Oregon) where mean temperatures have increased 2 degrees C since 1948, similar to projections for other terrestrial communities. Our 185 sites included primary and secondary growth lower montane forests (500-1.200 m above sea level) and primary upper montane to subalpine forests (1,500-2,100 m above sea level). In lower montane forests, regardless of land-use history, we found multiple herb-community changes consistent with an effectively drier climate, including lower mean specific leaf area, lower relative cover by species of northern biogeographic affinity, and greater compositional resemblance to communities in southerly topographic positions. At higher elevations we found qualitatively different and more modest changes, including increases in herbs of northern biogeographic affinity and in forest canopy cover. Our results provide community-level validation of predicted nonlinearities in climate change effects. PMID- 20974979 TI - Giant virus with a remarkable complement of genes infects marine zooplankton. AB - As major consumers of heterotrophic bacteria and phytoplankton, microzooplankton are a critical link in aquatic foodwebs. Here, we show that a major marine microflagellate grazer is infected by a giant virus, Cafeteria roenbergensis virus (CroV), which has the largest genome of any described marine virus (~730 kb of double-stranded DNA). The central 618-kb coding part of this AT-rich genome contains 544 predicted protein-coding genes; putative early and late promoter motifs have been detected and assigned to 191 and 72 of them, respectively, and at least 274 genes were expressed during infection. The diverse coding potential of CroV includes predicted translation factors, DNA repair enzymes such as DNA mismatch repair protein MutS and two photolyases, multiple ubiquitin pathway components, four intein elements, and 22 tRNAs. Many genes including isoleucyl tRNA synthetase, eIF-2gamma, and an Elp3-like histone acetyltransferase are usually not found in viruses. We also discovered a 38-kb genomic region of putative bacterial origin, which encodes several predicted carbohydrate metabolizing enzymes, including an entire pathway for the biosynthesis of 3-deoxy d-manno-octulosonate, a key component of the outer membrane in Gram-negative bacteria. Phylogenetic analysis indicates that CroV is a nucleocytoplasmic large DNA virus, with Acanthamoeba polyphaga mimivirus as its closest relative, although less than one-third of the genes of CroV have homologs in Mimivirus. CroV is a highly complex marine virus and the only virus studied in genetic detail that infects one of the major groups of predators in the oceans. PMID- 20974980 TI - Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1alpha and IL-1beta. AB - Nanoparticles are increasingly used in various fields, including biomedicine and electronics. One application utilizes the opacifying effect of nano-TiO(2), which is frequently used as pigment in cosmetics. Although TiO(2) is believed to be biologically inert, an emerging literature reports increased incidence of respiratory diseases in people exposed to TiO(2). Here, we show that nano-TiO(2) and nano-SiO(2), but not nano-ZnO, activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome, leading to IL-1beta release and in addition, induce the regulated release of IL-1alpha. Unlike other particulate Nlrp3 agonists, nano TiO(2)-dependent-Nlrp3 activity does not require cytoskeleton-dependent phagocytosis and induces IL-1alpha/beta secretion in nonphagocytic keratinocytes. Inhalation of nano-TiO(2) provokes lung inflammation which is strongly suppressed in IL-1R- and IL-1alpha-deficient mice. Thus, the inflammation caused by nano TiO(2) in vivo is largely caused by the biological effect of IL-1alpha. The current use of nano-TiO(2) may present a health hazard due to its capacity to induce IL-1R signaling, a situation reminiscent of inflammation provoked by asbestos exposure. PMID- 20974981 TI - Hepatitis C virus inhibits DNA damage repair through reactive oxygen and nitrogen species and by interfering with the ATM-NBS1/Mre11/Rad50 DNA repair pathway in monocytes and hepatocytes. AB - Hepatitis C virus (HCV) infection is associated with the development of hepatocellular carcinoma and putatively also non-Hodgkin's B cell lymphoma. In this study, we demonstrated that PBMCs obtained from HCV-infected patients showed frequent chromosomal aberrations and that HCV infection of B cells in vitro induced enhanced chromosomal breaks and sister chromatid exchanges. HCV infection hypersensitized cells to ionizing radiation and bleomycin and inhibited nonhomologous end-joining repair. The viral core and nonstructural protein 3 proteins were shown to be responsible for the inhibition of DNA repair, mediated by NO and reactive oxygen species. Stable expression of core protein induced frequent chromosome translocations in cultured cells and in transgenic mice. HCV core protein binds to the NBS1 protein and inhibits the formation of the Mre11/NBS1/Rad50 complex, thereby affecting ATM activation and inhibiting DNA binding of repair enzymes. Taken together, these data indicate that HCV infection inhibits multiple DNA repair processes to potentiate chromosome instability in both monocytes and hepatocytes. These effects may explain the oncogenicity and immunological perturbation of HCV infection. PMID- 20974982 TI - The Chlamydia muridarum-induced IFN-beta response is TLR3-dependent in murine oviduct epithelial cells. AB - Epithelial cells lining the murine genital tract act as sentinels for microbial infection, play a major role in the initiation of the early inflammatory response, and can secrete factors that modulate the adaptive immune response when infected with Chlamydia. C. muridarum-infected murine oviduct epithelial cells secrete the inflammatory cytokines IL-6 and GM-CSF in a TLR2-dependent manner. Further, C. muridarum infection induces IFN-beta synthesis in the oviduct epithelial cells in a TRIF-dependent manner. Because murine oviduct epithelial cells express TLR3 but not TLRs 4, 7, 8, or 9, we hypothesized that TLR3 or an unknown TRIF-dependent pattern recognition receptor was the critical receptor for IFN-beta production. To investigate the role of TLR3 in the Chlamydia-induced IFN beta response in oviduct epithelial cells, we used small interfering RNA, dominant-negative TLR3 mutants, and TLR3-deficient oviduct epithelial cells to show that the IFN-beta secreted during C. muridarum infection requires a functional TLR3. Interestingly, we demonstrate that the TLR3 signaling pathway is not required for IFN-beta synthesis in C. muridarum-infected macrophages, suggesting that there are alternate and redundant pathways to Chlamydia-induced IFN-beta synthesis that seem to be dependent upon the cell type infected. Finally, because there is no obvious dsRNA molecule associated with Chlamydia infection, the requirement for TLR3 in Chlamydia-induced IFN-beta synthesis in infected oviduct epithelial cells implicates a novel ligand that binds to and signals through TLR3. PMID- 20974983 TI - Critical role of IL-25 in nematode infection-induced alterations in intestinal function. AB - IL-25 (IL-17E) is a member of the IL-17 cytokine family. IL-25-deficient mice exhibit impaired Th2 immunity against nematode infection, implicating IL-25 as a key component in mucosal immunity. The sources of IL-25 and mechanisms responsible for the induction of Th2 immunity by IL-25 in the gastrointestinal tract remain poorly understood. There is also little information on the regulation of IL-25 during inflammation or its role in gut function. In the current study, we investigated the regulation of IL-25 during Nippostrongylus brasiliensis infection and the contribution of IL-25 to the infection-induced alterations in intestinal function. We found that epithelial cells, but not immune cells, are the major source of IL-25 in the small intestine. N. brasiliensis infection-induced upregulation of IL-25 depends upon IL-13 activation of STAT6. IL-25(-/-) mice had diminished intestinal smooth muscle and epithelial responses to N. brasiliensis infection that were associated with an impaired Th2 protective immunity. Exogenous IL-25 induced characteristic changes similar to those after nematode infection but was unable to restore the impaired host immunity against N. brasiliensis infection in IL-13(-/-) mice. These data show that IL-25 plays a critical role in nematode infection-induced alterations in intestinal function that are important for host protective immunity, and IL-13 is the major downstream Th2 cytokine responsible for the IL-25 effects. PMID- 20974984 TI - STAT1-activating cytokines limit Th17 responses through both T-bet-dependent and independent mechanisms. AB - Given the association with autoimmune disease, there is great interest in defining cellular factors that limit overactive or misdirected Th17-type inflammation. Using in vivo and in vitro models, we investigated the molecular mechanisms for cytokine-mediated inhibition of Th17 responses, focusing on the role of STAT1 and T-bet in this process. These studies demonstrate that, during systemic inflammation, STAT1- and T-bet-deficient T cells each exhibit a hyper Th17 phenotype relative to wild-type controls. However, IL-17 production was greater in the absence of T-bet, and when both STAT1 and T-bet were deleted, there was no further increase, with the double-deficient cells instead behaving more like STAT1-deficient counterparts. Similar trends were observed during in vitro priming, with production of Th17-type cytokines greater in T-bet(-/-) T cells than in either STAT1(-/-) or STAT1(-/-) T-bet(-/-) counterparts. The ability of IFN-gamma and IL-27 to suppress Th17 responses was reduced in T-bet deficient cells, and most importantly, ectopic T-bet could suppress signature Th17 gene products, including IL-17A, IL-17F, IL-22, and retinoic acid-related orphan receptor gammaT, even in STAT1-deficient T cells. Taken together, these studies formally establish that, downstream of IFN-gamma, IL-27, and likely all STAT1-activating cytokines, there are both STAT1 and T-bet-dependent pathways capable of suppressing Th17 responses. PMID- 20974986 TI - The interactions of multiple cytokines control NK cell maturation. AB - Although NK cells are well known for their cytotoxic functions, they also produce an array of immunoregulatory cytokines and chemokines. During an immune response, NK cells are exposed to complex combinations of cytokines that influence their differentiation and function. In this study, we have examined the phenotypic and functional consequences of exposing mouse NK cells to IL-4, IL-12, IL-15, IL-18, and IL-21 and found that although all factors induced signs of maturation, characterized by decreased proliferation and IFN-gamma secretion, distinct combinations induced unique cytokine secretion profiles. In contrast, the immunosuppressive factors IL-10 and TGF-beta had little direct effect on NK cell effector functions. Sustained IL-18 signals resulted in IL-13 and GM-CSF production, whereas IL-12 and IL-21 induced IL-10 and TNF-alpha. Surprisingly, with the exception of IL-21, all cytokines suppressed cytotoxic function of NK cells at the expense of endogenous cytokine production suggesting that "helper type" NK cells were generated. The cytokine signals also profoundly altered the cell surface phenotype of the NK cells-a striking example being the downregulation of the activating receptor NKG2D by IL-4 that resulted in decreased NKG2D-dependent killing. IL-4 exposure also modulated NKG2D expression in vivo suggesting it is functionally important during immune responses. This study highlights the plasticity of NK cell differentiation and suggests that the relative abundance of cytokines at sites of inflammation will lead to diverse outcomes in terms of NK cell phenotype and interaction with the immune system. PMID- 20974987 TI - Inhibition of terminal differentiation of B cells mediated by CD27 and CD40 involves signaling through JNK. AB - B cells responding to cognate Ag in vivo undergo clonal expansion that is followed by differentiation into Ab-secreting plasma cells or into quiescent restimulable memory. Both these events occur in the germinal center and require that cells exit from proliferation, but the signals that lead to one or the other of these mutually exclusive differentiation pathways have not been definitively characterized. Previous experiments have shown that signals transduced through the TNFRs CD27 and CD40 at the time of B cell stimulation in vitro or in vivo can influence this cell fate decision by inhibiting terminal differentiation and promoting memory. In this study, we show that the PIQED domain of the cytoplasmic tail of murine CD27 and the adapter molecule TNFR-associated factor 2 are involved in this effect. Using pharmacological inhibitors of signaling intermediates, we identify JNK as being necessary and sufficient for the observed inhibition of terminal differentiation. While JNK is involved downstream of CD40, inhibition of the MEK pathway can also partially restore plasma cell generation, indicating that both signaling intermediates may be involved. We also show that inhibition of induction of IFN regulatory factor 4 and B lymphocyte induced maturation protein 1 are downstream events common to both receptors. PMID- 20974985 TI - Diesel exhaust particle-treated human bronchial epithelial cells upregulate Jagged-1 and OX40 ligand in myeloid dendritic cells via thymic stromal lymphopoietin. AB - Ambient particulate matter, including diesel exhaust particles (DEP), promotes the development of allergic disorders. DEP increase oxidative stress and influence human bronchial epithelial cell (HBEC)-dendritic cell interactions via cytokines, including thymic stromal lymphopoietin (TSLP). Upregulation of TSLP results in Th2 responses. Using primary culture HBEC and human myeloid dendritic cell (mDC) cocultures, we show in this study that DEP upregulation of Th2 responses occurred via HBEC-dependent mechanisms that resulted from oxidative stress. Moreover, DEP-treated HBEC and ambient particulate matter-treated HBEC upregulated OX40 ligand (OX40L) and the Notch ligand Jagged-1 mRNA and expression on mDC. Upregulation of OX40L as well as Jagged-1 on mDC required HBEC and did not occur in the presence of N-acetylcysteine. Furthermore, OX40L and Jagged-1 upregulation was inhibited when HBEC expression of TSLP was silenced. Thus, DEP treatment of HBEC targeted two distinct pathways in mDC that were downstream of TSLP expression. Upregulation of OX40L and Jagged-1 by mDC resulted in mDC-driven Th2 responses. These studies expand our understanding of the mechanism by which ambient pollutants alter mucosal immunity and promote disorders such as asthma. PMID- 20974988 TI - A critical role for C5L2 in the pathogenesis of experimental allergic asthma. AB - The complement fragment C5a plays dual roles in the development of experimental allergic asthma. It protects from pulmonary allergy by a regulatory effect on dendritic cells during allergen sensitization, but is proallergic during the effector phase. C5a can bind to two distinct receptors (i.e., C5a receptor and C5a receptor-like 2 [C5L2]). The functional role of C5L2 in vivo remains enigmatic. In this study, we show in two models of OVA- and house dust mite (HDM) induced experimental allergic asthma that C5L2-deficient mice are protected from the development of airway hyperresponsiveness, Th2 cytokine production, eosinophilic airway inflammation, serum IgE, or mucus production. Surprisingly, HDM-induced experimental asthma in C5L2-deficient mice was associated with increased pulmonary IL-17A production and increased airway neutrophil numbers. To directly assess the role of C5L2 on myeloid dendritic cells (mDCs) during allergen sensitization, we performed single or repeated adoptive transfers of C5L2-deficient mDCs into wild-type mice. HDM-pulsed C5L2-deficient mDCs induced strong Th2 cytokine production, which was associated with marked IFN-gamma and IL 17A production, decreased eosinophil numbers, and reduced IgE production as compared with HDM-pulsed mDCs from wild-type mice. HDM stimulation of C5L2(-/-) mDCs in vitro resulted in production of Th17-promoting cytokine IL-23, which was absent in wild-type mDCs. Our findings suggest that C5L2 acts at the mDC/T cell interface to control the development of Th1 and Th17 cells in response to airway HDM exposure. Furthermore, it drives Th2 immune responses independent of mDCs, suggesting a complex role for C5L2 in the development of experimental allergic asthma. PMID- 20974989 TI - GM-CSF is an essential regulator of T cell activation competence in uterine dendritic cells during early pregnancy in mice. AB - Uterine dendritic cells (DCs) are critical for activating the T cell response mediating maternal immune tolerance of the semiallogeneic fetus. GM-CSF (CSF2), a known regulator of DCs, is synthesized by uterine epithelial cells during induction of tolerance in early pregnancy. To investigate the role of GM-CSF in regulating uterine DCs and macrophages, Csf2-null mutant and wild-type mice were evaluated at estrus, and in the periconceptual and peri-implantation periods. Immunohistochemistry showed no effect of GM-CSF deficiency on numbers of uterine CD11c(+) cells and F4/80(+) macrophages at estrus or on days 0.5 and 3.5 postcoitum, but MHC class II(+) and class A scavenger receptor(+) cells were fewer. Flow cytometry revealed reduced CD80 and CD86 expression by uterine CD11c(+) cells and reduced MHC class II in both CD11c(+) and F4/80(+) cells from GM-CSF-deficient mice. CD80 and CD86 were induced in Csf2(-/-) uterine CD11c(+) cells by culture with GM-CSF. Substantially reduced ability to activate both CD4(+) and CD8(+) T cells in vivo was evident after delivery of OVA Ag by mating with Act-mOVA males or transcervical administration of OVA peptides. This study shows that GM-CSF regulates the efficiency with which uterine DCs and macrophages activate T cells, and it is essential for optimal MHC class II- and class I mediated indirect presentation of reproductive Ags. Insufficient GM-CSF may impair generation of T cell-mediated immune tolerance at the outset of pregnancy and may contribute to the altered DC profile and dysregulated T cell tolerance evident in infertility, miscarriage, and preeclampsia. PMID- 20974991 TI - Eotaxin-3/CC chemokine ligand 26 is a functional ligand for CX3CR1. AB - Eotaxin-3/CCL26 is a functional ligand for CCR3 and abundantly produced by IL-4 /IL-13-stimulated vascular endothelial cells. CCL26 also functions as a natural antagonist for CCR1, CCR2, and CCR5. In this study, we report that CCL26 is yet a functional ligand for CX3CR1, the receptor for fractalkine/CX3CL1, which is expressed by CD16(+) NK cells, cytotoxic effector CD8(+) T cells, and CD14(low)CD16(high) monocytes. Albeit at relatively high concentrations, CCL26 induced calcium flux and chemotaxis in mouse L1.2 cells expressing human CX3CR1 but not mouse CX3CR1 and competed with CX3CL1 for binding to CX3CR1. In chemotaxis assays using human PBMCs, CCL26 attracted not only eosinophils but also CD16(+) NK cells, CD45RA(+)CD27(-)CD8(+) T cells, and CD14(low)CD16(high) monocytes. Intraperitoneal injection of CCL26 into mice rapidly recruited mouse eosinophils and intravenously transferred human CD16(+) NK cells into the peritoneal cavity. IL-4-stimulated HUVECs produced CCL26 and efficiently induced adhesion of cells expressing CX3CR1. Real-time PCR showed that skin lesions of psoriasis consistently contained CX3CL1 mRNA but not CCL26 mRNA, whereas those of atopic dermatitis contained CCL26 mRNA in all samples but CX3CL1 mRNA in only about half of the samples. Nevertheless, the skin lesions from both diseases consistently contained CX3CR1 mRNA at high levels. Thus, CCL26 may be partly responsible for the recruitment of cells expressing CX3CR1 in atopic dermatitis particularly when the expression of CX3CL1 is low. Collectively, CCL26 is another agonist for CX3CR1 and may play a dual role in allergic diseases by attracting eosinophils via CCR3 and killer lymphocytes and resident monocytes via CX3CR1. PMID- 20974990 TI - Unexpected role for the B cell-specific Src family kinase B lymphoid kinase in the development of IL-17-producing gammadelta T cells. AB - The Ag receptors on alphabeta and gammadelta T cells differ not only in the nature of the ligands that they recognize but also in their signaling potential. We hypothesized that the differences in alphabeta- and gammadeltaTCR signal transduction were due to differences in the intracellular signaling pathways coupled to these two TCRs. To investigate this, we used transcriptional profiling to identify genes encoding signaling molecules that are differentially expressed in mature alphabeta and gammadelta T cell populations. Unexpectedly, we found that B lymphoid kinase (Blk), a Src family kinase expressed primarily in B cells, is expressed in gammadelta T cells but not in alphabeta T cells. Analysis of Blk deficient mice revealed that Blk is required for the development of IL-17 producing gammadelta T cells. Furthermore, Blk is expressed in lymphoid precursors and, in this capacity, plays a role in regulating thymus cellularity during ontogeny. PMID- 20974993 TI - Effect of citrus juice and SLCO2B1 genotype on the pharmacokinetics of montelukast. AB - Previously the authors found that a common polymorphism, rs12422149 (SLCO2B1{NM_007256.2}:c.935G>A), in the gene coding for OATP2B1, was associated with absorption of and response to montelukast in humans. In vitro studies showed that citrus juice could reduce the permeability of montelukast consistent with known inhibition of organic anion-transporting polypeptides. To study the clinical significance of c.935G>A, the authors conducted a single-dose, pharmacokinetic study of montelukast co-ingested with citrus juice. On average, co-ingestion with either orange juice or 4* concentrated grapefruit juice had a minimal effect on the area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC(0->infinity)) of montelukast relative to co-ingestion with Gatorade control (n = 24). However when the data were stratified by genotype at c.935 (G/G n = 21, A/G n = 5), a significant reduction in AUC(0->infinity) was detected with orange juice in G/G homozygotes (AUC(0 >infinity), G/G, Gatorade = 2560 +/- 900 ng.h.mL(-1) vs AUC(0->infinity), G/G, orange juice = 2010 +/- 650 ng.h.mL(-1), P = .032). Significantly, A/G heterozygotes showed reduced AUC(0->infinity) relative to G/G homozygotes, independent of treatment (AUC(0->infinity), G/G, combined treatments = 2310 +/- 820 ng.h.mL(-1) vs AUC(0->infinity), A/G, combined treatments = 1460 +/- 340 ng.h.mL(-1), P = 2.0 * 10(-5)) replicating previous observations. PMID- 20974992 TI - Neutrophil migration across intestinal epithelium: evidence for a role of CD44 in regulating detachment of migrating cells from the luminal surface. AB - The migration of polymorphonuclear leukocytes (PMNs) across the intestinal epithelium is a histopathological hallmark of many mucosal inflammatory diseases including inflammatory bowel disease. The terminal transmigration step is the detachment of PMNs from the apical surface of the epithelium and their subsequent release into the intestinal lumen. The current study sought to identify epithelial proteins involved in the regulation of PMN migration across intestinal epithelium at the stage at which PMNs reach the apical epithelial surface. A panel of Abs reactive with IFN-gamma-stimulated T84 intestinal epithelial cells was generated. Screening efforts identified one mAb, GM35, that prevented PMN detachment from the apical epithelial surface. Microsequencing studies identified the GM35 Ag as human CD44. Transfection studies confirmed this result by demonstrating the loss of the functional activity of the GM35 mAb following attenuation of epithelial CD44 protein expression. Immunoblotting and immunofluorescence revealed the GM35 Ag to be an apically expressed v6 variant exon-containing form of human CD44 (CD44v6). ELISA analysis demonstrated the release of soluble CD44v6 by T84 cells during PMN transepithelial migration. In addition, the observed release of CD44v6 was blocked by GM35 treatment, supporting a connection between CD44v6 release and PMN detachment. Increased expression of CD44v6 and the GM35 Ag was detected in inflamed ulcerative colitis tissue. This study demonstrates that epithelial-expressed CD44v6 plays a role in PMN clearance during inflammatory episodes through regulation of the terminal detachment of PMNs from the apical epithelial surface into the lumen of the intestine. PMID- 20974994 TI - Moderate pericardial effusion early after myocardial infarction: left ventricular free wall rupture until proven otherwise. PMID- 20974995 TI - The complexity of high-density lipoproteins. PMID- 20974996 TI - The alternative pathway is critical for pathogenic complement activation in endotoxin- and diet-induced atherosclerosis in low-density lipoprotein receptor deficient mice. AB - BACKGROUND: The early components of the classical and lectin complement pathways have been shown to protect low-density lipoprotein receptor-deficient mice (Ldlr( /-)) from early atherogenesis. However, the role of the alternative pathway remained unknown, and that was investigated in this study. METHODS AND RESULTS: Mice lacking factor B (Bf(-/-)), the initiator of the alternative pathway, were crossed with Ldlr(-/-) mice and studied under different proatherogenic conditions. There was no statistically significant difference in lipid profiles or atherosclerotic lesion development between Bf(-/-)/Ldlr(-/-) and Ldlr(-/-) mice fed a low-fat diet. However, in these groups, administration of bacterial lipopolysaccharide led to a significant increase in atherosclerosis only in Ldlr( /-) and not in Bf(-/-)/Ldlr(-/-) mice, indicating that the alternative pathway is necessary for endotoxin-mediated atherogenesis. Bf(-/-)/Ldlr(-/-) mice also had significantly decreased cross-sectional aortic root lesion fraction area and reduced lesion complexity compared with Ldlr(-/-) animals after a 12-week period of high-fat diet, although this was also accompanied by reduced levels of serum cholesterol. Under both experimental conditions, the atherosclerotic changes in the Bf(-/-)/Ldlr(-/-) mice were accompanied by a marked reduction in complement activation in the circulation and in atherosclerotic plaques, with no statistically significant differences in immunoglobulin G deposition or in the serum antibody response to oxidized low-density lipoprotein. CONCLUSIONS: These data demonstrate that amplification of complement activation by the alternative pathway in response to lipopolysaccharide or high-fat diet plays a proatherogenic role. PMID- 20974997 TI - Shedding light on bioabsorbable stent struts seen by optical coherence tomography in the ABSORB trial. PMID- 20974998 TI - Effects of HIV protease inhibitors on progression of monocrotaline- and hypoxia induced pulmonary hypertension in rats. AB - BACKGROUND: Pulmonary hypertension (PH) is among the complications of HIV infection. Combination antiretroviral therapy may influence the progression of HIV-related PH. Because Akt signaling is a potential molecular target of HIV protease inhibitors (HPIs), we hypothesized that these drugs altered monocrotaline- and hypoxia-induced PH in rats by downregulating the Akt pathway, thereby inhibiting pulmonary artery smooth muscle cell proliferation. METHODS AND RESULTS: Daily treatment with each of 3 first-generation HPIs (ritonavir 30 mg/kg, amprenavir 100 mg/kg, and nelfinavir 500 mg/kg) started 3 weeks after a subcutaneous monocrotaline injection (60 mg/kg) substantially diminished pulmonary artery pressure, right ventricular hypertrophy, number of muscularized pulmonary vessels, pulmonary arterial wall thickness, and proliferating pulmonary vascular Ki67-labeled cells without affecting vessel caspase 3 staining. HPI treatment partially prevented the development of hypoxia- and monocrotaline induced PH. Monocrotaline-induced PH was associated with marked activation of Akt signaling in the lungs and proximal pulmonary arteries, with increases in phosphorylated Akt, phosphorylated glycogen-synthase-kinase-3beta (GSK3), and phosphorylated endothelial nitric oxide synthase, all of which decreased markedly after treatment with each HPI. In contrast, PH-associated increases in phosphorylated extracellular signal-related kinase 1/2 and myosin light-chain phosphatase were unaltered by the HPIs. The 3 HPIs and the phosphatidylinositol 3 kinase inhibitor LY294002 inhibited platelet-derived growth factor-induced phosphorylation of Akt and GSK3 in cultured pulmonary artery smooth muscle cells and blocked cell proliferation; this last effect was abolished by the GSK3 inhibitor SB216763. CONCLUSION: These results support an effect of HPIs on pulmonary vascular remodeling mediated by inhibition of Akt phosphorylation and consequently of pulmonary artery smooth muscle cell proliferation. PMID- 20974999 TI - High-density lipoprotein suppresses the type I interferon response, a family of potent antiviral immunoregulators, in macrophages challenged with lipopolysaccharide. AB - BACKGROUND: High-density lipoprotein (HDL) protects the artery wall by removing cholesterol from lipid-laden macrophages. However, recent evidence suggests that HDL might also inhibit atherogenesis by combating inflammation. METHODS AND RESULTS: To identify potential antiinflammatory mechanisms, we challenged macrophages with lipopolysaccharide, an inflammatory microbial ligand for Toll like receptor 4. HDL inhibited the expression of 30 (277 of 911) of the genes normally induced by lipopolysaccharide, microarray analysis revealed. One of its major targets was the type I interferon response pathway, a family of potent viral immunoregulators controlled by Toll-like receptor 4 and the TRAM/TRIF signaling pathway. Unexpectedly, the ability of HDL to inhibit gene expression was independent of macrophage cholesterol stores. Immunofluorescent studies suggested that HDL promoted TRAM translocation to intracellular compartments, which impaired subsequent signaling by Toll-like receptor 4 and TRIF. To examine the potential in vivo relevance of the pathway, we used mice deficient in apolipoprotein A-I, the major protein of HDL. After infection with Salmonella typhimurium, a Gram-negative bacterium that expresses lipopolysaccharide, apolipoprotein A-I-deficient mice had 6-fold higher plasma levels of interferon beta, a key regulator of the type I interferon response, than did wild-type mice. CONCLUSIONS: HDL inhibits a subset of lipopolysaccharide-stimulated macrophage genes that regulate the type I interferon response, and its action is independent of sterol metabolism. These findings raise the possibility that regulation of macrophage genes by HDL might link innate immunity and cardioprotection. PMID- 20975000 TI - Relationship of echocardiographic dyssynchrony to long-term survival after cardiac resynchronization therapy. AB - BACKGROUND: The ability of echocardiographic dyssynchrony to predict response to cardiac resynchronization therapy (CRT) has been unclear. METHODS AND RESULTS: A prospective, longitudinal study was designed with predefined dyssynchrony indexes and outcome variables to test the hypothesis that baseline dyssynchrony is associated with long-term survival after CRT. We studied 229 consecutive class III to IV heart failure patients with ejection fraction <=35 and QRS duration >=120 milliseconds for CRT. Dyssynchrony before CRT was defined as tissue Doppler velocity opposing-wall delay >=65 milliseconds, 12-site SD (Yu Index) >=32 milliseconds, speckle tracking radial strain anteroseptal-to-posterior wall delay >=130 milliseconds, or pulsed Doppler interventricular mechanical delay >=40 milliseconds. Outcome was defined as freedom from death, heart transplantation, or left ventricular assist device implantation. Of 210 patients (89) with dyssynchrony data available, there were 62 events: 47 deaths, 9 transplantations, and 6 left ventricular assist device implantations over 4 years. Event-free survival was associated with Yu Index (P=0.003), speckle tracking radial strain (P=0.003), and interventricular mechanical delay (P=0.019). When adjusted for confounding baseline variables of ischemic origin and QRS duration, Yu Index and radial strain dyssynchrony remained independently associated with outcome (P<0.05). Lack of radial dyssynchrony was particularly associated with unfavorable outcome in those with QRS duration of 120 to 150 milliseconds (P=0.002). CONCLUSIONS: The absence of echocardiographic dyssynchrony was associated with significantly less favorable event-free survival after CRT. Patients with narrower QRS duration who lacked dyssynchrony had the least favorable long-term outcome. These observations support the relationship of dyssynchrony and CRT response. PMID- 20975001 TI - Hospital outcome of moderate to severe pericardial effusion complicating ST elevation acute myocardial infarction. AB - BACKGROUND: Hospital prognosis of moderate to severe pericardial effusion (MPE; >=10 mm) in ST-elevation myocardial infarction is largely unknown. METHODS AND RESULTS: Data from 446 ST-elevation myocardial infarction patients, 228 with MPE 88 with cardiac tamponade (CT) and electromechanical dissociation (EMD), 44 with CT without EMD (w/oEMD), and 96 without initial CT-and 218 with small PE (5 to 9 mm), were compared. Patients with MPE without initial CT were also compared with 96 patients without PE. CT patients showed larger PE (P<0.001) than those without initial CT; 85% of those with CT+EMD and 86% with CTw/oEMD were treated with pericardiocentesis and 10% and 21% were treated with a surgical repair, respectively. Among MPE patients, 30-day mortality was 43% and was higher in those with CT+EMD (operated, 89%; and nonoperated, 85%) than in those with CTw/oEMD (22% and 11%, respectively; P<0.001) and those without initial CT (17%; P<0.001). It was also higher than in patients with small PE (10%; P<0.001) or those without PE (6%; P=0.001). Death was attributable to cardiac rupture in 83% of patients with CT+EMD, 7% with CTw/oEMD, and 8% with MPE without initial CT and occurred late (>=7 days) in 14%, 67%, and 100%, respectively. CONCLUSIONS: MPE carries an increased mortality that is highest in patients with CT+EMD. In those with CTw/oEMD, however, mortality is considerably low after pericardiocentesis, and subsequent management may be individualized because a conservative approach is often successful. Importantly, MPE patients without initial CT are not free from late rupture and deserve further investigation. PMID- 20975002 TI - Comparison between transcatheter and surgical prosthetic valve implantation in patients with severe aortic stenosis and reduced left ventricular ejection fraction. AB - BACKGROUND: Patients with severe aortic stenosis and reduced left ventricular ejection fraction (LVEF) have a poor prognosis with conservative therapy but a high operative mortality when treated surgically. Recently, transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement (SAVR) for patients considered at high or prohibitive operative risk. The objective of this study was to compare TAVI and SAVR with respect to postoperative recovery of LVEF in patients with severe aortic stenosis and reduced LV systolic function. METHODS AND RESULTS: Echocardiographic data were prospectively collected before and after the procedure in 200 patients undergoing SAVR and 83 patients undergoing TAVI for severe aortic stenosis (aortic valve area <=1 cm(2)) with reduced LV systolic function (LVEF <=50%). TAVI patients were significantly older (81+/-8 versus 70+/-10 years; P<0.0001) and had more comorbidities compared with SAVR patients. Despite similar baseline LVEF (34+/ 11% versus 34+/-10%), TAVI patients had better recovery of LVEF compared with SAVR patients (DeltaLVEF, 14+/-15% versus 7+/-11%; P=0.005). At the 1-year follow up, 58% of TAVI patients had a normalization of LVEF (>50%) as opposed to 20% in the SAVR group. On multivariable analysis, female gender (P=0.004), lower LVEF at baseline (P=0.005), absence of atrial fibrillation (P=0.01), TAVI (P=0.007), and larger increase in aortic valve area after the procedure (P=0.01) were independently associated with better recovery of LVEF. CONCLUSION: In patients with severe aortic stenosis and depressed LV systolic function, TAVI is associated with better LVEF recovery compared with SAVR. TAVI may provide an interesting alternative to SAVR in patients with depressed LV systolic function considered at high surgical risk. PMID- 20975003 TI - Intracoronary optical coherence tomography and histology at 1 month and 2, 3, and 4 years after implantation of everolimus-eluting bioresorbable vascular scaffolds in a porcine coronary artery model: an attempt to decipher the human optical coherence tomography images in the ABSORB trial. AB - BACKGROUND: With the use of optical coherence tomography (OCT), alterations of the reflectance characteristics of everolimus-eluting bioresorbable vascular scaffold (BVS) struts have been reported in humans. In the absence of histology, the interpretation of the appearances of the struts by OCT remains speculative. We therefore report OCT findings with corresponding histology in the porcine coronary artery model immediately after and at 28 days and 2, 3, and 4 years after BVS implantation. METHODS AND RESULTS: Thirty-five polymeric BVS (3.0*12.0 mm) were singly implanted in the main coronary arteries of 17 pigs that underwent OCT and were then euthanized immediately (n=2), at 28 days (n=2), at 2 years (n=3), at 3 years (n=5), or at 4 years (n=5) after implantation. All BVS implanted arteries in these animals were evaluated by histology except for 5 arteries examined at 2 years with gel permeation chromatography to assess the biodegradation of the polymeric device. Fourteen arteries with BVS from an additional 6 pigs were examined by gel permeation chromatography at 1 (n=1), 1.5 (n=2), and 3 (n=2) years. Corresponding OCT and histology images were selected with the distal and proximal radiopaque markers used as landmarks. At 28 days, by OCT, 82% of struts showed sharply defined, bright reflection borders, best described as a box-shaped appearance. Histologically, all struts appeared intact with no evidence of resorption. At 2 years, by OCT, 60+/-20 struts were discernible per BVS with 80.4% of the strut sites as a box-shaped appearance. Despite their defined appearance by OCT, by histology, these structures appeared to be composed of proteoglycan, with polymeric material being at such low level as to be no longer quantifiable by chromatography. At 3 years, by OCT, recognizable struts decreased to 28+/-9 struts per BVS: 43.7% showed dissolved black box; 34.8%, dissolved bright box; 16.1%, open box; and 5.4%, preserved box appearance. Histology shows that connective tissue cells within a proteoglycan rich matrix replaced the areas previously occupied by the polymeric struts and coalesced into the arterial wall. At 4 years, by OCT, 10+/-6 struts were recognizable as either dissolved black or dissolved bright box. In histology, these struts are minimally discernible as foci of low-cellular-density connective tissue. Relative to the prediction of histological type by OCT appearance, the preserved box appearance of OCT corresponds well with 2-year histology (86.4%), whereas the dissolved bright and black box appearances correspond to 3-year histology (88.0% and 90.7%, respectively). Struts indiscernible by OCT correspond to the integrated strut footprints seen at 4 years (100%). CONCLUSIONS: Struts that are still discernible by OCT at 2 years are compatible with largely bioresorbed struts, as demonstrated by histological and gel permeation chromatography analysis. At 3 and 4 years, both OCT and histology confirm complete integration of the struts into the arterial wall. PMID- 20975005 TI - Marked interatrial and atrioventricular conduction delay with enhanced atrial based managed ventricular pacing: electrocardiogram-echocardiogram Doppler correlation. PMID- 20975004 TI - ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 Appropriate Use Criteria for Cardiac Computed Tomography. A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the Society of Cardiovascular Computed Tomography, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. AB - The American College of Cardiology Foundation, along with key specialty and subspecialty societies, conducted an appropriate use review of common clinical scenarios where cardiac computed tomography (CCT) is frequently considered. The present document is an update to the original CCT/cardiac magnetic resonance appropriateness criteria published in 2006, written to reflect changes in test utilization, to incorporate new clinical data, and to clarify CCT use where omissions or lack of clarity existed in the original criteria. The indications for this review were drawn from common applications or anticipated uses, as well as from current clinical practice guidelines. Ninety-three clinical scenarios were developed by a writing group and scored by a separate technical panel on a scale of 1 to 9 to designate appropriate use, inappropriate use, or uncertain use. In general, use of CCT angiography for diagnosis and risk assessment in patients with low or intermediate risk or pretest probability for coronary artery disease was viewed favorably, whereas testing in high-risk patients, routine repeat testing, and general screening in certain clinical scenarios were viewed less favorably. Use of noncontrast computed tomography for calcium scoring was rated as appropriate within intermediate- and selected low-risk patients. Appropriate applications of CCT are also within the category of cardiac structural and functional evaluation. It is anticipated that these results will have an impact on physician decision making, performance, and reimbursement policy, and that they will help guide future research. PMID- 20975006 TI - Letter by Miceli et al regarding article, "No major differences in 30-day outcomes in high-risk patients randomized to off-pump versus on-pump coronary bypass surgery: the Best Bypass Surgery Trial". PMID- 20975007 TI - Letter by Pocar et al regarding article, "No major differences in 30-day outcomes in high-risk patients randomized to off-pump versus on-pump coronary bypass surgery: the Best Bypass Surgery Trial". PMID- 20975009 TI - Asymptomatic severe aortic stenosis: silence of the lambs? PMID- 20975011 TI - Epsilon waves during ventricular tachycardia in a case of arrhythmogenic right ventricular dysplasia. PMID- 20975010 TI - Hold me tight: Role of the heat shock protein family of chaperones in cardiac disease. PMID- 20975012 TI - Effectiveness of a barber-based intervention for improving hypertension control in black men: the BARBER-1 study: a cluster randomized trial. AB - BACKGROUND: Barbershop-based hypertension (HTN) outreach programs for black men are becoming increasingly common, but whether they are an effective approach for improving HTN control remains uncertain. METHODS: To evaluate whether a continuous high blood pressure (BP) monitoring and referral program conducted by barbers motivates male patrons with elevated BP to pursue physician follow-up, leading to improved HTN control, a cluster randomized trial (BARBER-1) of HTN control was conducted among black male patrons of 17 black-owned barbershops in Dallas County, Texas (March 2006-December 2008). Participants underwent 10-week baseline BP screening, and then study sites were randomized to a comparison group that received standard BP pamphlets (8 shops, 77 hypertensive patrons per shop) or an intervention group in which barbers continually offered BP checks with haircuts and promoted physician follow-up with sex-specific peer-based health messaging (9 shops, 75 hypertensive patrons per shop). After 10 months, follow-up data were obtained. The primary outcome measure was change in HTN control rate for each barbershop. RESULTS: The HTN control rate increased more in intervention barbershops than in comparison barbershops (absolute group difference, 8.8% [95% confidence interval (CI), 0.8%-16.9%]) (P = .04); the intervention effect persisted after adjustment for covariates (P = .03). A marginal intervention effect was found for systolic BP change (absolute group difference, -2.5 mm Hg [95% CI, -5.3 to 0.3 mm Hg]) (P = .08). CONCLUSIONS: The effect of BP screening on HTN control among black male barbershop patrons was improved when barbers were enabled to become health educators, monitor BP, and promote physician follow-up. Further research is warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00325533. PMID- 20975013 TI - Assessing risk factors as potential screening tests: a simple assessment tool. AB - Many risk factors for disease are suggested as screening tests when there is little prospect that they could be useful in predicting disease. To avoid this, it is useful to know the relationship between the relative risk of a disease or disorder in people with high and low values of a risk factor, and the equivalent screening performance in terms of the detection rate (sensitivity) for a specified false-positive rate. We describe an interactive Risk-Screening Converter, accessible from the Internet (http://www.wolfson.qmul.ac.uk/rsc/), that transforms an odds ratio into the equivalent estimates of detection and false-positive rates. The converter is intended for general clinicians, for people engaged in research into risk factors and disease, and for those who give advice on applying such research findings into medical practice. It should help to distinguish effective screening methods from ineffective ones, and so improve clinical guidelines relating to screening and the prediction and prevention of disease. PMID- 20975014 TI - A bald fade and a BP check: Comment on "Effectiveness of a barbershop-based intervention for improving hypertension control in black men". PMID- 20975015 TI - Heavy smoking in midlife and long-term risk of Alzheimer disease and vascular dementia. AB - BACKGROUND: Smoking is a risk factor for several life-threatening diseases, but its long-term association with dementia is controversial and somewhat understudied. Our objective was to investigate the long-term association of amount of smoking in middle age on the risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD) several decades later in a large, diverse population. METHODS: We analyzed prospective data from a multiethnic population-based cohort of 21,123 members of a health care system who participated in a survey between 1978 and 1985. Diagnoses of dementia, AD, and VaD made in internal medicine, neurology, and neuropsychology were collected from January 1, 1994, to July 31, 2008. Multivariate Cox proportional hazards models were used to investigate the association between midlife smoking and risk of dementia, AD, and VaD. RESULTS: A total of 5367 people (25.4%) were diagnosed as having dementia (including 1136 cases of AD and 416 cases of VaD) during a mean follow-up period of 23 years. Results were adjusted for age, sex, education, race, marital status, hypertension, hyperlipidemia, body mass index, diabetes, heart disease, stroke, and alcohol use. Compared with nonsmokers, those smoking more than 2 packs a day had an elevated risk of dementia (adjusted hazard ratio [HR], 2.14; 95% CI, 1.65 2.78), AD (adjusted HR, 2.57; 95% CI, 1.63-4.03), and VaD (adjusted HR, 2.72; 95% CI, 1.20-6.18). CONCLUSIONS: In this large cohort, heavy smoking in midlife was associated with a greater than 100% increase in risk of dementia, AD, and VaD more than 2 decades later. These results suggest that the brain is not immune to long-term consequences of heavy smoking. PMID- 20975016 TI - Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. AB - BACKGROUND: We aimed to determine the risk of recurrence for symptomatic venous thromboembolism (VTE) provoked by different transient risk factors. DATA SOURCES: MEDLINE, EMBASE, and Cochrane Collaboration Registry of Randomized Trials databases were searched. STUDY SELECTION: Prospective cohort studies and randomized trials of patients with a first episode of symptomatic VTE provoked by a transient risk factor and treated for at least 3 months were identified. DATA EXTRACTION: Number of patients and recurrent VTE during the 0- to 12-month and 0- to 24-month intervals after stopping therapy, study design, and provoking risk factor characteristics were extracted. DATA SYNTHESIS: Annualized recurrence rates were calculated and pooled across studies. At 24 months, the rate of recurrence was 3.3% per patient-year (11 studies, 2268 patients) for all patients with a transient risk factor, 0.7% per patient-year (3 studies, 248 patients) in the subgroup with a surgical factor, and 4.2% per patient-year (3 studies, 509 patients) in the subgroup with a nonsurgical factor. In the same studies, the rate of recurrence after unprovoked VTE was 7.4% per patient-year. The rate ratio for a nonsurgical compared with a surgical factor was 3.0 and for unprovoked thrombosis compared with a nonsurgical factor was 1.8 at 24 months. CONCLUSIONS: The risk of recurrence is low if VTE is provoked by surgery, intermediate if provoked by a nonsurgical risk factor, and high if unprovoked. These risks affect whether patients with VTE should undergo short-term vs indefinite treatment. PMID- 20975017 TI - Predictive relationship between depression and physical functioning after coronary surgery. AB - BACKGROUND: Depression is a prevalent condition in patients undergoing coronary artery bypass graft surgery (CABG) and is often associated with a less favorable health status. The aim of this study was to investigate the relationship between depression and physical functioning in patients undergoing CABG. METHODS: The analyses were based on a sample of 883 consecutive subjects (aged 35-93 years; 19.8% women) undergoing CABG. Depression was assessed using the Patient Health Questionnaire (PHQ); the subscale "physical functioning" was taken from the 36 Item Short-Form Health Survey. Questionnaires were administered 1 to 3 days before surgery (T1) and 2 months (T2) and 1 year (T3) after surgery. RESULTS: A cross-lagged path analytic model showed that an increase in depressive symptoms predicted a decrease in physical functioning (beta(T)1-(T)2 = -0.15 [P < .001]; beta(T)2-(T)3= -0.17 [P < .001]), but not the other way around. Multigroup comparisons revealed one moderator effect: in patients with systolic heart failure (left ventricular ejection fraction [LVEF], <=45%), the effect of depression on physical functioning from T2 to T3 was significantly stronger than in patients with preserved LVEF (beta(T)2-(T)3= -0.30 [P < .001] vs beta(T)2 (T)3= -0.14 [P < .001]; chi2(diff) = 3.885 [P = .049]). CONCLUSIONS: More attention should be paid to diagnosis and treatment of depression in patients undergoing CABG. After surgery, patients with systolic heart failure and depressive symptoms in particular seem at risk of a deterioration of their physical functioning. PMID- 20975018 TI - Marked variability of monacolin levels in commercial red yeast rice products: buyer beware! AB - BACKGROUND: Red yeast rice (RYR) is a widely available dietary supplement used by millions of patients as an alternative therapy for hyperlipidemia. It contains 14 active compounds called monacolins that inhibit hepatic cholesterol synthesis. Although studies have suggested that some formulations of RYR may be effective and safe for lipid lowering, monacolin levels are not standardized among marketed products and are generally not published on labels. We evaluated monacolin levels in 12 commercial RYR formulations and tested for citrinin, a mycotoxin that is nephrotoxic in animals. METHODS: Each formulation of RYR was labeled "600 mg/capsule" of active product. Analyses for monacolins and citrinin were performed between August 2006 and June 2008 using high-performance liquid chromatography with mass spectroscopy-mass spectroscopy detection. Laboratory analyses of RYR products were conducted by ConsumerLab.com, White Plains, New York. RESULTS: There was marked variability in the 12 RYR products in total monacolins (0.31-11.15 mg/capsule), monacolin K (lovastatin) (0.10-10.09 mg/capsule), and monacolin KA (0.00-2.30 mg/capsule). Four products had elevated levels of citrinin. CONCLUSIONS: We found striking variability in monacolin content in 12 proprietary RYR products and the presence of citrinin in one-third of the formulations tested. Although RYR may have potential as an alternative lipid-lowering agent, our findings suggest the need for improved standardization of RYR products and product labeling. Until this occurs, physicians should be cautious in recommending RYR to their patients for the treatment of hyperlipidemia and primary and secondary prevention of cardiovascular disease. PMID- 20975019 TI - Physician wages across specialties: informing the physician reimbursement debate. AB - BACKGROUND: Disparities in remuneration between primary care and other physician specialties may impede health care reform by undermining the sustainability of a primary care workforce. Previous studies have compared annual incomes across specialties unadjusted for work hours. Wage (earnings-per-hour) comparisons could better inform the physician payment debate. METHODS: In a cross-sectional analysis of data from 6381 physicians providing patient care in the 2004-2005 Community Tracking Study (adjusted response rate, 53%), we compared wages across broad and narrow categories of physician specialties. Tobit and linear regressions were run. Four broad specialty categories (primary care, surgery, internal medicine and pediatric subspecialties, and other) and 41 specific specialties were analyzed together with demographic, geographic, and market variables. RESULTS: In adjusted analyses on broad categories, wages for surgery, internal medicine and pediatric subspecialties, and other specialties were 48%, 36%, and 45% higher, respectively, than for primary care specialties. In adjusted analyses for 41 specific specialties, wages were significantly lower for the following than for the reference group of general surgery (wage near median, $85.98): internal medicine and pediatrics combined (-$24.36), internal medicine ( $24.27), family medicine (-$23.70), and other pediatric subspecialties (-$23.44). Wage rankings were largely impervious to adjustment for control variables, including age, race, sex, and region. CONCLUSIONS: Wages varied substantially across physician specialties and were lowest for primary care specialties. The primary care wage gap was likely conservative owing to exclusion of radiologists, anesthesiologists, and pathologists. In light of low and declining medical student interest in primary care, these findings suggest the need for payment reform aimed at increasing incomes or reducing work hours for primary care physicians. PMID- 20975020 TI - Physicians' opinions about reforming reimbursement: results of a national survey. AB - BACKGROUND: Several strategies have been proposed to reform physician reimbursement while improving quality of care. Despite much debate, physicians' opinions regarding reimbursement reform proposals have not been objectively assessed. METHODS: We conducted a national survey of randomly selected physicians between June 25 and October 31, 2009. Physicians rated their support for several reimbursement reform proposals: rewarding quality with financial incentives, bundling payments for episodes of care, shifting payments from procedures to management and counseling services, increasing pay to generalists, and offsetting increased pay to generalists with a reduction in pay for other specialties. Support for the different reform options was compared with physician practice characteristics. RESULTS: The response rate was 48.5% (n = 1222). Four of 5 physicians (78.4%) indicated that under Medicare, some procedures are compensated too highly and others are compensated at rates insufficient to cover costs. Incentives were the most frequently supported reform option (49.1%), followed by shifting payments (41.6%) and bundling (17.2%). Shifting payments and bundling were more commonly supported by generalists than by other specialists. There was broad support for increasing pay for generalists (79.8%), but a proposal to offset the increase with a 3% reduction in specialist reimbursement was supported by only 39.1% of physicians. CONCLUSIONS: Physicians are dissatisfied with Medicare reimbursement and show little consensus for major proposals to reform reimbursement. The successful adoption of payment reform proposals may require a better understanding of physicians' concerns and their willingness to make tradeoffs. PMID- 20975021 TI - Reforming payment for health care services: comment on "physicians' opinions about reforming reimbursement". PMID- 20975023 TI - Serum and dietary potassium and risk of incident type 2 diabetes mellitus: The Atherosclerosis Risk in Communities (ARIC) study. AB - BACKGROUND: Serum potassium levels affect insulin secretion by pancreatic beta cells, and hypokalemia associated with diuretic use has been associated with dysglycemia. We hypothesized that adults with lower serum potassium levels and lower dietary potassium intake are at higher risk for incident diabetes mellitus (DM), independent of diuretic use. METHODS: We analyzed data from 12 209 participants from the Atherosclerosis Risk in Communities (ARIC) Study, an ongoing prospective cohort study, beginning in 1986, with 9 years of in-person follow-up and 17 years of telephone follow-up. Using multivariate Cox proportional hazard models, we estimated the hazard ratio (HR) of incident DM associated with baseline serum potassium levels. RESULTS: During 9 years of in person follow-up, 1475 participants developed incident DM. In multivariate analyses, we found an inverse association between serum potassium and risk of incident DM. Compared with those with a high-normal serum potassium level (5.0 5.5 mEq/L), adults with serum potassium levels lower than 4.0 mEq/L, 4.0 to lower than 4.5 mEq/L, and 4.5 to lower than 5.0 mEq/L had an adjusted HR (95% confidence interval [CI]) of incident DM of 1.64 (95% CI, 1.29-2.08), 1.64 (95% CI, 1.34-2.01), and 1.39 (95% CI, 1.14-1.71), respectively. An increased risk persisted during an additional 8 years of telephone follow-up based on self report with HRs of 1.2 to 1.3 for those with a serum potassium level lower than 5.0 mEq/L. Dietary potassium intake was significantly associated with risk of incident DM in unadjusted models but not in multivariate models. CONCLUSIONS: Serum potassium level is an independent predictor of incident DM in this cohort. Further study is needed to determine if modification of serum potassium could reduce the subsequent risk of DM. PMID- 20975024 TI - The incidence and cost of unexpected hospital use after scheduled outpatient endoscopy. AB - BACKGROUND: Data on complications of gastrointestinal endoscopic procedures are limited. We evaluated prospectively the incidence and cost of hospital visits resulting from outpatient endoscopy. METHODS: We developed an electronic medical record-based system to record automatically admissions to the emergency department (ED) within 14 days after endoscopy. Physicians evaluated all reported cases for relatedness of the ED visit to the prior endoscopy based on predetermined criteria. RESULTS: We evaluated 6383 esophagogastroduodenoscopies (EGDs) and 11 632 colonoscopies (7392 for screening and surveillance). Among these, 419 ED visits and 266 hospitalizations occurred within 14 days after the procedure. One hundred thirty-four (32%) of the ED visits and 76 (29%) of the hospitalizations were procedure related, whereas 31 complications were recorded by standard physician reporting (P < .001). Procedure-related hospital visits occurred in 1.07%, 0.84%, and 0.95% of all EGDs, all colonoscopies, and screening colonoscopies, respectively. The mean costs were $1403 per ED visit and $10 123 per hospitalization based on Medicare standardized rates. Across the overall screening/surveillance colonoscopy program, these episodes added $48 per examination. CONCLUSIONS: Using a novel automated system, we observed a 1% incidence of related hospital visits within 14 days of outpatient endoscopy, 2- to 3-fold higher than recent estimates. Most events were not captured by standard reporting, and strategies for automating adverse event reporting should be developed. The cost of unexpected hospital visits postendoscopy may be significant and should be taken into account in screening or surveillance programs. PMID- 20975025 TI - Physical activity and risk of breast cancer among postmenopausal women. AB - BACKGROUND: Physical activity has many health benefits. Although greater activity has been related to lower postmenopausal breast cancer risk, important details remain unclear, including type, intensity, and timing of activity and whether the association varies by subgroups. METHODS: Within the prospective Nurses' Health Study, we assessed the associations of specific and total activity, queried every 2 to 4 years since 1986, with breast cancer risk. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Activity was measured as hours of metabolic equivalent task values (MET-h). RESULTS: During 20 years of follow-up (1986-2006), 4782 invasive breast cancer cases were documented among 95 396 postmenopausal women. Compared with less than 3 MET-h/wk (<1 h/wk walking), women engaged in higher amounts of recent total physical activity were at lower breast cancer risk (>=27 MET-h/wk [approximately 1 h/d of brisk walking]: HR, 0.85; 95% CI, 0.78-0.93; P < .001 for trend). Compared with women who were least active at menopause and through follow-up (<9 MET-h/wk [approximately 30 minutes of walking at an average pace on most days of the week]), women who increased activity were at lower risk (<9 MET-h/wk at menopause and >=9 MET-h/wk during follow-up: HR, 0.90; 95% CI, 0.82-0.98). Among specific activities modeled simultaneously, brisk walking was associated with lower risk (per 20 MET-h/wk [5 h/wk]: HR, 0.91; 95% CI, 0.84-0.98). The association with total activity did not differ significantly between estrogen and progesterone receptor-positive and -negative tumors (P = .65 for heterogeneity). CONCLUSION: Our findings suggest that moderate physical activity, including brisk walking, may reduce postmenopausal breast cancer risk and that increases in activity after menopause may be beneficial. PMID- 20975026 TI - Practice redesign to improve care for falls and urinary incontinence: primary care intervention for older patients. AB - BACKGROUND: In primary care, medical care for age-associated conditions, such as falls and urinary incontinence (UI), is inadequate. In collaboration with the American College of Physicians, we augmented the Assessing Care of Vulnerable Elders practice redesign intervention to improve falls and UI care. METHODS: We performed a controlled trial in 5 nonrandomly selected primary care intervention (26 physicians across sites) and control (18 physicians) practices from diverse communities. Patients 75 years and older who screened positive for falls or fear of falling and UI were included in the study. We conducted a multicomponent intervention between October 30, 2006, and December 31, 2007, that included efficient collection of data, medical record prompts, patient education materials, and physician decision support. Main outcome measures were quality of care for falls and UI comparing intervention and control sites. RESULTS: Of 6051 patients screened, 2847 (47.1%) screened positive for falls or UI (46.1% in the intervention group and 48.8% in the control group). Across the 5 practices, 1211 patient medical records were evaluated after stratified random selection. Intervention patients received 60.0% of recommended care for falls vs 37.6% provided by control health care professionals (P < .001). Similarly, intervention health care professionals provided more recommended care for UI (47.2% vs 27.8%, P < .001). Intervention health care professionals more often performed a falls history, orthostatic blood pressure measurement, gait and balance examination, and UI history and tried UI behavioral treatments first. Knowledge about falls and UI increased more among intervention than control group health care professionals. CONCLUSIONS: Practice redesign can improve the care that community based primary care physicians provide for older patients with falls and UI. Outcomes of such care improvements require further evaluation. PMID- 20975027 TI - Improving primary care for older patients: challenge for the aging century: comment on "practice redesign to improve care for falls and urinary incontinence". PMID- 20975028 TI - Prevalence of venous thromboembolism among privately insured US adults. PMID- 20975029 TI - Could proton pump inhibitors cause cancer? PMID- 20975030 TI - Could magnesium depletion play a role on fracture risk in PPI users? PMID- 20975031 TI - Persistence of mortality reduction after the end of randomized therapy in clinical trials of blood pressure-lowering medications. AB - Long-term follow-up of clinical trials of blood pressure-lowering medications has suggested a continuation of event reduction after study completion. We evaluated the persistence of mortality benefit of these agents after the end of clinical trials, when all of the patients were advised to take the same open-label therapy. We performed a meta-analysis of randomized clinical trials using blood pressure-lowering medications, used in patients with hypertension, myocardial infarction, or left ventricular systolic dysfunction, (n=18; 132 854 patients; 11 988 deaths) when a second report describing results after the end of the trial was available. During the randomized (first) phase, 80% (interquartile range: 75% to 83%) of the patients randomized to receive active therapy actually received it compared with 16% (interquartile range: 7% to 22%) of those randomized to control. In this phase, mortality was lower in the intervention group (odds ratio: 0.84 [95% CI: 0.79 to 0.90]; P<0.0001). Mortality was also lower during the open-label follow-up (second) phase (odds ratio: 0.85 [95% CI: 0.79 to 0.91]; P<0.0001), when all of the patients were advised to take the same therapy, and rates of receiving active therapy were similar in the 2 groups (59% [interquartile range: 46% to 77%], among those originally randomized to active, and 43% [interquartile range: 20% to 68%], in the control). Several sensitivity analyses indicated stability of the effects. In studies of antihypertensive medications, a decrease in overall mortality persists after the end of trial phase, when most patients in both the intervention and control groups receive active therapy. These analyses imply that earlier intervention would result in better clinical outcomes. PMID- 20975032 TI - Regulation of 3',5'-cAMP in preglomerular smooth muscle and endothelial cells from genetically hypertensive rats. AB - Our previous studies show that inhibition of phosphodiesterase 4 (PDE4) augments agonist-induced renovascular 3',5'-cAMP secretion more in isolated, perfused kidneys from spontaneously hypertensive rats (SHR) versus Wistar-Kyoto normotensive rats (WKY); however, whether this is because of PDE4 inhibition in renovascular smooth muscle cells or endothelial cells is unknown. Therefore, we examined the effects of 3-isobutyl-1-methylxanthine (broad-spectrum PDE inhibitor) and RO 20-1724 (selective PDE4 inhibitor) on isoproterenol-induced 3',5'-cAMP levels in cultured WKY and SHR preglomerular vascular smooth muscle and endothelial cells. 3-Isobutyl-1-methylxanthine and RO 20-1724 augmented isoproterenol-induced 3',5'-cAMP levels similarly in WKY versus SHR endothelial cells. In contrast, 3-isobutyl-1-methylxanthine and RO 20-1724 augmented isoproterenol-induced 3',5'-cAMP levels significantly more in SHR, compared to WKY, smooth muscle cells (P<0.0001). In both cell types from both rat strains, mRNA levels for the PDE4B subtype exceeded levels for the PDE4A, PDE4C, and PDE4D subtypes, and small interfering RNA knockdown of PDE4B mRNA in SHR smooth muscle cells increased isoproterenol-induced 3',5'-cAMP. mRNA levels for the PDE4B2 variant exceeded levels for the PDE4B1, PDE4B3, PDE4B4, and PDE4B5 variants. In vivo, infusions of RO 20-1724 increased the urinary excretion of 3',5'-cAMP more in SHR than WKY (P=0.0211). We conclude that (1) the greater effect of PDE4 inhibition on renovascular 3',5'-cAMP is mediated by inhibition of PDE4 in renovascular smooth muscle cells, not endothelial cells; (2) the major PDE4 subtype in both renovascular smooth muscle and endothelial cells is PDE4B with variant PDE4B2 likely being dominant; and (3) inhibition of PDE4 in vivo increases renal 3',5'-cAMP levels more in genetically hypertensive rats. PMID- 20975033 TI - A novel atrial natriuretic peptide based therapeutic in experimental angiotensin II mediated acute hypertension. AB - M-atrial natriuretic peptide (ANP; M-ANP) is a novel next generation 40 amino acid peptide based on ANP, which is highly resistant to enzymatic degradation and has greater and more sustained beneficial actions compared with ANP. The current study was designed to advance our understanding of the therapeutic potential of M ANP in a canine model of acute angiotensin II-induced hypertension with elevated cardiac filling pressures and aldosterone activation. We compare M-ANP with vehicle and equimolar human B-type natriuretic peptide, which possesses the most potent in vivo actions of the native natriuretic peptides. M-ANP significantly lowered mean arterial pressure and systemic vascular resistance. Importantly, despite a reduction in blood pressure, renal function was enhanced with significant increases in renal blood flow, glomerular filtration rate, diuresis, and natriuresis after M-ANP infusion. Although angiotensin II induced an acute increase in pulmonary capillary wedge pressure, M-ANP significantly lowered pulmonary capillary wedge pressure, pulmonary artery pressure, and right atrial pressure. Further, M-ANP significantly suppressed angiotensin II-induced activation of aldosterone. These cardiovascular and renal enhancing actions of M ANP were accompanied by significant increases in plasma and urinary cGMP, the second messenger molecule of the natriuretic peptide system. When compared with human B-type natriuretic peptide, M-ANP had comparable cardiovascular actions but resulted in a greater natriuretic effect. These results suggest that M-ANP, which is more potent than ANP in normal canines, has potent blood pressure lowering and renal enhancing properties and may, therefore, serve as an ANP based therapeutic for acute hypertension. PMID- 20975034 TI - Is the deficiency of the long isoform of cellular FLICE-inhibitory protein involved in myocardial remodeling? PMID- 20975035 TI - Angiotensin II-mediated microvascular thrombosis. AB - Hypertension is associated with an increased risk of thrombosis that appears to involve an interaction between the renin-angiotensin system and hemostasis. In this study we determined whether angiotensin II-mediated thrombosis occurs in arterioles and/or venules and assessed the involvement of type 1 (AT1), type 2 (AT2), and type 4 (AT4) angiotensin II receptors, as well as receptors for endothelin 1 and bradykinin 1 and 2 in angiotensin II-enhanced microvascular thrombosis. Thrombus development in mouse cremaster microvessels was quantified after light/dye injury using the time of onset of the thrombus and time to blood flow cessation. Wild-type and AT1 receptor-deficient mice were implanted with an angiotensin II-loaded ALZET pump for 2 weeks. Angiotensin II administration in both wild-type and ATAT1 receptor-deficient mice significantly accelerated thrombosis in arterioles. Genetic deficiency and pharmacological antagonism of AT1 receptors did not alter the thrombosis response to angiotensin II. Isolated murine platelets aggregated in response to low (picomolar) but not high (nanomolar) concentrations of angiotensin II. The platelet aggregation response to angiotensin II depended on AT1 receptors. Antagonism of AT2 receptors in vivo significantly prolonged the onset of angiotensin II-enhanced thrombosis, whereas an AT4 receptor antagonist prolonged the time to flow cessation. Selective antagonism of either endothelin 1 or bradykinin 1 receptors largely prevented both the onset and flow cessation responses to chronic angiotensin II infusion. Our findings indicate that angiotensin II induced hypertension is accompanied by enhanced thrombosis in arterioles, and this response is mediated by a mechanism that involves AT2, AT4, bradykinin 1, and endothelin 1 receptor-mediated signaling. PMID- 20975036 TI - Cellular FLICE-inhibitory protein protects against cardiac remodeling induced by angiotensin II in mice. AB - The development of cardiac hypertrophy in response to increased hemodynamic load and neurohormonal stress is initially a compensatory response that may eventually lead to ventricular dilatation and heart failure. Cellular FLICE-inhibitory protein (cFLIP) is a homologue of caspase 8 without caspase activity that inhibits apoptosis initiated by death receptor signaling. Previous studies showed that cFLIP expression was markedly decreased in the ventricular myocardium of patients with end-stage heart failure. However, the critical role of cFLIP on cardiac remodeling remains unclear. To specifically determine the role of cFLIP in pathological cardiac remodeling, we used heterozygote cFLIP(+/-) mice and transgenic mice with cardiac-specific overexpression of the human cFLIP(L) gene. Our results demonstrated that the cFLIP(+/-) mice were susceptible to cardiac hypertrophy and fibrosis through inhibition of mitogen-activated protein kinase kinase-extracellular signal-regulated kinase 1/2 signaling, whereas the transgenic mice displayed the opposite phenotype in response to angiotensin II stimulation. These studies indicate that cFLIP protein is a crucial component of the signaling pathway involved in cardiac remodeling and heart failure. PMID- 20975038 TI - Models, models everywhere--is there a fit for lifetime risks? PMID- 20975037 TI - Cancer risks after radiation exposure in middle age. AB - BACKGROUND: Epidemiological data show that radiation exposure during childhood is associated with larger cancer risks compared with exposure at older ages. For exposures in adulthood, however, the relative risks of radiation-induced cancer in Japanese atomic bomb survivors generally do not decrease monotonically with increasing age of adult exposure. These observations are inconsistent with most standard models of radiation-induced cancer, which predict that relative risks decrease monotonically with increasing age at exposure, at all ages. METHODS: We analyzed observed cancer risk patterns as a function of age at exposure in Japanese atomic bomb survivors by using a biologically based quantitative model of radiation carcinogenesis that incorporates both radiation induction of premalignant cells (initiation) and radiation-induced promotion of premalignant damage. This approach emphasizes the kinetics of radiation-induced initiation and promotion, and tracks the yields of premalignant cells before, during, shortly after, and long after radiation exposure. RESULTS: Radiation risks after exposure in younger individuals are dominated by initiation processes, whereas radiation risks after exposure at later ages are more influenced by promotion of preexisting premalignant cells. Thus, the cancer site-dependent balance between initiation and promotion determines the dependence of cancer risk on age at radiation exposure. For example, in terms of radiation induction of premalignant cells, a quantitative measure of the relative contribution of initiation vs promotion is 10-fold larger for breast cancer than for lung cancer. Reflecting this difference, radiation-induced breast cancer risks decrease with age at exposure at all ages, whereas radiation-induced lung cancer risks do not. CONCLUSION: For radiation exposure in middle age, most radiation-induced cancer risks do not, as often assumed, decrease with increasing age at exposure. This observation suggests that promotional processes in radiation carcinogenesis become increasingly important as the age at exposure increases. Radiation-induced cancer risks after exposure in middle age may be up to twice as high as previously estimated, which could have implications for occupational exposure and radiological imaging. PMID- 20975039 TI - Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival. AB - Neutrophil apoptosis is a highly regulated process essential for inflammation resolution, the molecular mechanisms of which are only partially elucidated. In this study, we describe a survival pathway controlled by proliferating cell nuclear antigen (PCNA), a nuclear factor involved in DNA replication and repairing of proliferating cells. We show that mature neutrophils, despite their inability to proliferate, express high levels of PCNA exclusively in their cytosol and constitutively associated with procaspases, presumably to prevent their activation. Notably, cytosolic PCNA abundance decreased during apoptosis, and increased during in vitro and in vivo exposure to the survival factor granulocyte colony-stimulating factor (G-CSF). Peptides derived from the cyclin dependent kinase inhibitor p21, which compete with procaspases to bind PCNA, triggered neutrophil apoptosis thus demonstrating that specific modification of PCNA protein interactions affects neutrophil survival. Furthermore, PCNA overexpression rendered neutrophil-differentiated PLB985 myeloid cells significantly more resistant to TNF-related apoptosis-inducing ligand- or gliotoxin-induced apoptosis. Conversely, a decrease in PCNA expression after PCNA small interfering RNA transfection sensitized these cells to apoptosis. Finally, a mutation in the PCNA interdomain-connecting loop, the binding site for many partners, significantly decreased the PCNA-mediated antiapoptotic effect. These results identify PCNA as a regulator of neutrophil lifespan, thereby highlighting a novel target to potentially modulate pathological inflammation. PMID- 20975041 TI - Epithelial reticulon 4B (Nogo-B) is an endogenous regulator of Th2-driven lung inflammation. AB - Nogo-B is a member of the reticulon family of proteins (RTN-4B) that is highly expressed in lung tissue; however, its function remains unknown. We show that mice with Th2-driven lung inflammation results in a loss of Nogo expression in airway epithelium and smooth muscle compared with nonallergic mice, a finding which is replicated in severe human asthma. Mice lacking Nogo-A/B (Nogo-KO) display an exaggerated asthma-like phenotype, and epithelial reconstitution of Nogo-B in transgenic mice blunts Th2-mediated lung inflammation. Microarray analysis of lungs from Nogo-KO mice reveals a marked reduction in palate lung and nasal clone (PLUNC) gene expression, and the levels of PLUNC are enhanced in epithelial Nogo-B transgenic mice. Finally, transgenic expression of PLUNC into Nogo-KO mice rescues the enhanced asthmatic-like responsiveness in these KO mice. These data identify Nogo-B as a novel protective gene expressed in lung epithelia, and its expression regulates the levels of the antibacterial antiinflammatory protein PLUNC. PMID- 20975040 TI - Mouse CD8alpha+ DCs and human BDCA3+ DCs are major producers of IFN-lambda in response to poly IC. AB - Polyinosinic:polycytidylic acid (poly IC), a double-stranded RNA, is an effective adjuvant in vivo. IFN-lambdas (also termed IL-28/29) are potent immunomodulatory and antiviral cytokines. We demonstrate that poly IC injection in vivo induces large amounts of IFN-lambda, which depended on hematopoietic cells and the presence of TLR3 (Toll-like receptor 3), IRF3 (IFN regulatory factor 3), IRF7, IFN-I receptor, Fms-related tyrosine kinase 3 ligand (FL), and IRF8 but not on MyD88 (myeloid differentiation factor 88), Rig-like helicases, or lymphocytes. Upon poly IC injection in vivo, the IFN-lambda production by splenocytes segregated with cells phenotypically resembling CD8alpha(+) conventional dendritic cells (DCs [cDCs]). In vitro experiments revealed that CD8alpha(+) cDCs were the major producers of IFN-lambda in response to poly IC, whereas both CD8alpha(+) cDCs and plasmacytoid DCs produced large amounts of IFN-lambda in response to HSV-1 or parapoxvirus. The nature of the stimulus and the cytokine milieu determined whether CD8alpha(+) cDCs produced IFN-lambda or IL-12p70. Human DCs expressing BDCA3 (CD141), which is considered to be the human counterpart of murine CD8alpha(+) DCs, also produced large amounts of IFN-lambda upon poly IC stimulation. Thus, IFN-lambda production in response to poly IC is a novel function of mouse CD8alpha(+) cDCs and their human equivalents. PMID- 20975042 TI - IkappaBbeta is an essential co-activator for LPS-induced IL-1beta transcription in vivo. AB - Inhibitor of kappaB (IkappaB) beta (IkappaBbeta) represents one of the major primary regulators of NF-kappaB in mammals. In contrast to the defined regulatory interplay between NF-kappaB and IkappaBalpha, much less is known about the biological function of IkappaBbeta. To elucidate the physiological role of IkappaBbeta in NF-kappaB signaling in vivo, we generated IkappaBbeta-deficient mice. These animals proved to be highly refractory to LPS-induced lethality, accompanied by a strong reduction in sepsis-associated cytokine production. In response to LPS, IkappaBbeta is recruited to the IL-1beta promoter forming a complex with the NF-kappaB subunits RelA/c-Rel required for IL-1beta transcription. Further transcriptome analysis of LPS-stimulated wild-type and IkappaBbeta-deficient BM-derived macrophages revealed several other genes with known regulatory functions in innate immunity arguing that a subset of NF-kappaB target genes is under control of IkappaBbeta. Collectively, these findings provide an essential proinflammatory role for IkappaBbeta in vivo, and establish a critical function for IkappaBbeta as a transcriptional coactivator under inflammatory conditions. PMID- 20975043 TI - Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway. AB - CD4(+)CD25(+)FoxP3(+) regulatory T cells (T reg cells) play a major role in the control of immune responses but the factors controlling their homeostasis and function remain poorly characterized. Nicotinamide adenine dinucleotide (NAD(+)) released during cell damage or inflammation results in ART2.2-mediated ADP ribosylation of the cytolytic P2X7 receptor on T cells. We show that T reg cells express the ART2.2 enzyme and high levels of P2X7 and that T reg cells can be depleted by intravenous injection of NAD(+). Moreover, lower T reg cell numbers are found in mice deficient for the NAD-hydrolase CD38 than in wild-type, P2X7 deficient, or ART2-deficient mice, indicating a role for extracellular NAD(+) in T reg cell homeostasis. Even routine cell preparation leads to release of NAD(+) in sufficient quantities to profoundly affect T reg cell viability, phenotype, and function. We demonstrate that T reg cells can be protected from the deleterious effects of NAD(+) by an inhibitory ART2.2-specific single domain antibody. Furthermore, selective depletion of T reg cells by systemic administration of NAD(+) can be used to promote an antitumor response in several mouse tumor models. Collectively, our data demonstrate that NAD(+) influences survival, phenotype, and function of T reg cells and provide proof of principle that acting on the ART2-P2X7 pathway represents a new strategy to manipulate T reg cells in vivo. PMID- 20975045 TI - Teaching NeuroImages: restricted diffusion in the corpus callosum after traumatic diffuse axonal injury. PMID- 20975044 TI - Epigenetic control of embryonic stem cell fate. AB - Embryonic stem (ES) cells are derived from the inner cell mass of the preimplantation embryo and are pluripotent, as they are able to differentiate into all cell types of the adult organism. Once established, the pluripotent ES cells can be maintained under defined culture conditions, but can also be induced rapidly to differentiate. Maintaining this balance of stability versus plasticity is a challenge, and extensive studies in recent years have focused on understanding the contributions of transcription factors and epigenetic enzymes to the "stemness" properties of these cells. Identifying the molecular switches that regulate ES cell self-renewal versus differentiation can provide insights into the nature of the pluripotent state and enhance the potential use of these cells in therapeutic applications. Here, we review the latest models for how changes in chromatin methylation can modulate ES cell fate, focusing on two major repressive pathways, Polycomb group (PcG) repressive complexes and promoter DNA methylation. PMID- 20975046 TI - Teaching NeuroImages: hiccoughs and vomiting in neuromyelitis optica. PMID- 20975047 TI - Changing treatments for bacterial meningitis. PMID- 20975048 TI - Statins in epilepsy: prime time? Not yet. PMID- 20975049 TI - Why do we respond differently to sleep deprivation?: it's in our genes! PMID- 20975050 TI - Calcitonin gene-related peptide receptor antagonists and triptans: a tale of two treatments. PMID- 20975051 TI - Statin use and risk of epilepsy: a nested case-control study. AB - OBJECTIVE: To examine the potential efficacy of hydroxymethyl-glutaryl-coenzyme A reductase inhibitors (statins) in the prevention of epilepsy. METHODS: This study was a population-based, nested case-control study among older adults in the province of Quebec, Canada. The primary cohort consisted of cardiovascular patients who had received a revascularization procedure. Within the cohort, those with the primary hospital diagnosis of epilepsy were identified (cases). Each case was matched to 10 controls by age and cohort entry time. Potential confounders were adjusted using a conditional logistic regression model. A sensitivity analysis was performed using propensity score matching. RESULTS: The initial cohort consisted of 150,555 subjects. Within the cohort, 217 hospital diagnosed cases of epilepsy and 2,170 corresponding controls were identified. The adjusted rate ratio (ARR) for epilepsy among current statin users was 0.65 (95% confidence interval [CI] 0.46-0.92). The ARR for past users of statins was 0.72 (95% CI 0.39-1.30). No benefit was found for the control drug groups, including nonstatin cholesterol-lowering drugs, beta-blockers, and angiotensin-converting enzyme inhibitors (1.00 [95% CI 0.45-2.20], 1.04 [95% CI 0.74-1.47], and 0.94 [95% CI 0.66-1.33]). CONCLUSIONS: These results suggest that statin use decreases the risk of hospitalization for epilepsy. Because of its observational nature, this study requires future research to confirm these intriguing findings. PMID- 20975053 TI - Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers. AB - BACKGROUND: Calcitonin gene-related peptide (CGRP) plays a fundamental role in the pathophysiology of neurovascular headaches. CGRP infusion causes headache and dilation of cranial vessels. However, it is unknown to what extent CGRP-induced vasodilation contributes to immediate head pain and whether the migraine-specific abortive drug sumatriptan, a 5-hydroxytryptamine 1B/1D agonist, inhibits CGRP induced immediate vasodilation and headache. METHODS: We performed a double blind, randomized, placebo-controlled, crossover study in 18 healthy volunteers. We recorded circumference changes of the middle meningeal artery (MMA) and middle cerebral artery (MCA) using magnetic resonance angiography before and after infusion (20 minutes) of 1.5 MUg/min human alphaCGRP or placebo (isotonic saline) as well as after a 6-mg sumatriptan subcutaneous injection. RESULTS: Compared with placebo, CGRP caused significant dilation of MMA (p = 0.006) and no dilation of MCA (p = 0.69). Sumatriptan caused a marked contraction of MMA (15%-25.2%) and marginal contraction of MCA (3.9% to 5.3%). Explorative analysis revealed that sumatriptan had a more selective action on MMA compared with MCA on the CGRP day (p < 0.0001) and on the placebo day (p = 0.007). CONCLUSION: These data suggest that exogenous CGRP dilates extracranial vessels and not intracranial, and that sumatriptan exerts part of its antinociceptive action by constricting MMA and not MCA. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that IV GCRP causes dilation of the MMA but not the MCA in healthy volunteers, and that sumatriptan reverses the dilation of the MMA caused by CGRP. PMID- 20975052 TI - DQB1*0602 predicts interindividual differences in physiologic sleep, sleepiness, and fatigue. AB - OBJECTIVE: The human leukocyte antigen (HLA) DQB1*0602 allele is closely associated with narcolepsy, a neurologic disorder characterized by excessive daytime sleepiness, fragmented sleep, and shortened REM sleep latency. We evaluated whether DQB1*0602 was a novel marker of interindividual differences by determining its relationship to sleep homeostatic, sleepiness, and cognitive responses to baseline and chronic partial sleep deprivation (PSD) conditions. METHODS: Ninety-two DQB1*0602-negative and 37 DQB1*0602-positive healthy adults participated in a protocol of 2 baseline 10 hours time in bed (TIB) nights followed by 5 consecutive 4 hours TIB nights. DQB1*0602 allelic frequencies did not differ significantly between Caucasians and African Americans. RESULTS: During baseline, although DQB1*0602-positive subjects were subjectively sleepier and more fatigued, they showed greater sleep fragmentation, and decreased sleep homeostatic pressure and differentially sharper declines during the night (measured by non-REM EEG slow-wave energy [SWE]). During PSD, DQB1*0602-positive subjects were sleepier and showed more fragmented sleep, despite SWE elevation comparable to negative subjects. Moreover, they showed differentially greater REM sleep latency reductions and smaller stage 2 reductions, along with differentially greater increases in fatigue. Both groups demonstrated comparable cumulative decreases in cognitive performance. CONCLUSIONS: DQB1*0602 positivity in a healthy population may represent a continuum of some sleep-wake features of narcolepsy. DQB1*0602 was associated with interindividual differences in sleep homeostasis, physiologic sleep, sleepiness, and fatigue-but not in cognitive measures-during baseline and chronic PSD. Thus, DQB1*0602 may represent a genetic biomarker for predicting such individual differences in basal and sleep loss conditions. PMID- 20975054 TI - Prophylaxis of migraine with melatonin: a randomized controlled trial. AB - BACKGROUND: A previous open-label study of melatonin, a key substance in the circadian system, has shown effects on migraine that warrant a placebo-controlled study. METHOD: A randomized, double-blind, placebo-controlled crossover study was carried out in 2 centers. Men and women, aged 18-65 years, with migraine but otherwise healthy, experiencing 2-7 attacks per month, were recruited from the general population. After a 4-week run-in phase, 48 subjects were randomized to receive either placebo or extended-release melatonin (Circadin(r), Neurim Pharmaceuticals Ltd., Tel Aviv, Israel) at a dose of 2 mg 1 hour before bedtime for 8 weeks. After a 6-week washout treatment was switched. The primary outcome was migraine attack frequency (AF). A secondary endpoint was sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI). RESULTS: Forty-six subjects completed the study (96%). During the run-in phase, the average AF was 4.2 (+/-1.2) per month and during melatonin treatment the AF was 2.8 (+/-1.6). However, the reduction in AF during placebo was almost equal (p = 0.497). Absolute risk reduction was 3% (95% confidence interval -15 to 21, number needed to treat = 33). A highly significant time effect was found. The mean global PSQI score did not improve during treatment (p = 0.09). CONCLUSION: This study provides Class I evidence that prolonged-release melatonin (2 mg 1 hour before bedtime) does not provide any significant effect over placebo as migraine prophylaxis. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 2 mg of prolonged release melatonin given 1 hour before bedtime for a duration of 8 weeks did not result in a reduction in migraine frequency compared with placebo (p = 0.497). PMID- 20975055 TI - Clinical features of facioscapulohumeral muscular dystrophy 2. AB - OBJECTIVE: In some 5% of patients with facioscapulohumeral muscular dystrophy (FSHD), no D4Z4 repeat contraction on chromosome 4q35 is observed. Such patients, termed patients with FSHD2, show loss of DNA methylation and heterochromatin markers at the D4Z4 repeat that are similar to patients with D4Z4 contractions (FSHD1). This commonality suggests that a change in D4Z4 chromatin structure unifies FSHD1 and FSHD2. The aim of our study was to critically evaluate the clinical features in patients with FSHD2 in order to establish whether these patients are phenotypically identical to FSHD1 and to establish the effects of the (epi-) genotype on the phenotype. METHODS: This cross-sectional study studied 33 patients with FSHD2 from 27 families, the largest cohort described to date. All patients were clinically assessed using a standardized clinical evaluation form. Genotype analysis was performed by pulsed field gel electrophoresis and PCR; D4Z4 methylation was studied by methylation-sensitive Southern blot analysis. RESULTS: FSHD2 is identical to FSHD1 in its clinical presentation. Notable differences include a higher incidence (67%) of sporadic cases and the absence of gender differences in disease severity in FSHD2. Overall, average disease severity in FSHD2 was similar to that reported in FSHD1 and was not influenced by D4Z4 repeat size. In FSHD2, a small effect of the degree of hypomethylation on disease severity was observed. CONCLUSIONS: Clinically, patients with FSHD2 are indistinguishable from patients with FSHD1. The present data suggest that FSHD1 and FSHD2 are the result of the same pathophysiologic process. PMID- 20975056 TI - Genotype-phenotype correlation in vanishing white matter disease. AB - OBJECTIVE: Vanishing white matter (VWM) is an autosomal recessive leukoencephalopathy characterized by slowly progressive ataxia and spasticity with additional stress-provoked episodes of rapid and major deterioration. The disease is caused by mutations in the genes encoding the subunits of eukaryotic initiation factor 2B, which is pivotal in translation of mRNAs into proteins. The disease onset, clinical severity, and disease course of VWM vary greatly. The influence of genotype and gender on the phenotype is unclear. METHODS: From our database of 184 patients with VWM, we selected those with the following mutations in the gene EIF2B5: p.Arg113His in the homozygous state (n = 23), p.Arg113His in the compound-heterozygous state (n = 49), p.Thr91Ala in the homozygous state (n = 8), p.Arg113His/p.Arg339any (n = 9), and p.Thr91Ala/p.Arg339any (n = 7). We performed a cross-sectional observational study. Evaluated clinical characteristics were gender, age at onset, age at loss of walking without support, and age at death. Means, male/female ratios, and Kaplan-Meier curves were compared. RESULTS: Patients homozygous for p.Arg113His had a milder disease than patients compound heterozygous for p.Arg113His and patients homozygous for p.Thr91Ala. Patients with p.Arg113His/p.Arg339any had a milder phenotype than patients with p.Thr91Ala/p.Arg339any. Overall, females tended to have a milder disease than males. CONCLUSIONS: The clinical phenotype in VWM is influenced by the combination of both mutations. Females tend to do better than males. PMID- 20975057 TI - IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. AB - OBJECTIVES: Recent studies have shown that IDH1 and IDH2 mutations occur frequently in gliomas, including low-grade gliomas. However, their impact on the prognosis and chemosensitivity of low-grade gliomas remains unclear. METHODS: Search for IDH1 and IDH2 mutations, loss of heterozygosity on chromosomes 1p and 19q, MGMT promoter methylation, and p53 expression was performed in a series of 271 low-grade gliomas and correlated with overall survival. A subgroup of 84 patients treated up-front with temozolomide was individualized. Response to temozolomide was evaluated by progression-free survival, as well as by tumor size on successive MRI scans, and then correlated with molecular alterations. RESULTS: IDH (IDH1 or IDH2) mutations were found in 132/189 patients (70%). IDH mutation and 1p-19q codeletion were associated with prolonged overall survival in univariate (p = 0.002 and p = 0.0001) and multivariate analysis (p = 0.003 and p = 0.004). 1p-19q codeletion, MGMT promoter methylation, and IDH mutation (p = 0.01) were correlated with a higher rate of response to temozolomide. Further analysis of the course of the disease prior to any treatment except for surgery (untreated subgroup) showed that 1p-19q codeletion was associated with prolonged progression-free survival in univariate analysis, whereas IDH mutation was not. CONCLUSION: IDH mutation appears to be a significant marker of positive prognosis and chemosensitivity in low-grade gliomas, independently of 1p-19q codeletion, whereas its impact on the course of untreated tumors seems to be limited. PMID- 20975058 TI - Central and peripheral autonomic failure in cold-induced sweating syndrome type 1. PMID- 20975059 TI - Cerebrovascular findings in an adult with cyanotic congenital heart disease. PMID- 20975060 TI - Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. PMID- 20975061 TI - Game-changing, or business as usual? New findings on naming skills after temporal lobe surgery. PMID- 20975063 TI - Clinical implications of the cancer genome. AB - Cancer is a disease of the genome. Most tumors harbor a constellation of structural genomic alterations that may dictate their clinical behavior and treatment response. Whereas elucidating the nature and importance of these genomic alterations has been the goal of cancer biologists for several decades, ongoing global genome characterization efforts are revolutionizing both tumor biology and the optimal paradigm for cancer treatment at an unprecedented scope. The pace of advance has been empowered, in large part, through disruptive technological innovations that render complete cancer genome characterization feasible on a large scale. This article highlights cardinal biologic and clinical insights gleaned from systematic cancer genome characterization. We also discuss how the convergence of cancer genome biology, technology, and targeted therapeutics articulates a cohesive framework for the advent of personalized cancer medicine. PMID- 20975064 TI - American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. AB - PURPOSE: To update American Society of Clinical Oncology/American Society of Hematology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. METHODS: An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. RESULTS: The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. RECOMMENDATIONS: For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels >= 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations. PMID- 20975065 TI - Lymphangiosarcoma of the vocal cord: a rare entity defined by a D2-40 immunohistochemical and ultrastructural study. PMID- 20975066 TI - Dose intensity of chemotherapy in patients with relapsed Hodgkin's lymphoma. AB - PURPOSE: High-dose chemotherapy (HDCT) followed by autologous stem-cell transplantation (PBSCT) has become the standard treatment for patients with relapsed Hodgkin's lymphoma (HL). The intensity of treatment needed is unclear. This European intergroup study evaluated the impact of sequential high-dose chemotherapy (SHDCT) before myeloablative therapy. PATIENTS AND METHODS: Patients with histologically confirmed, relapsed HL were treated with two cycles of dexamethasone, cytarabine, and cisplatin, and those without disease progression were randomly assigned. In the standard arm (A), patients received myeloablative therapy with carmustine, BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by PBSCT. Patients in the experimental arm (B) also received sequential cyclophosphamide, methotrexate, and etoposide in high-doses before BEAM. Freedom from treatment failure (FFTF) was the primary end point. Remission rates, overall survival (OS), and toxicity of treatment were secondary end points. RESULTS: From a total of 284 patients included, 241 responding patients were randomly assigned after two cycles of dexamethasone, cytarabine, and cisplatinum. Patients treated in arm B had longer treatment duration and experienced more toxicity and protocol violations (P < .05). Mortality was similar in both arms (20% and 18%). With a median observation time of 42 months, there was no significant difference in terms of FFTF (P = .56) and OS (P = .82) between arms. FFTF at 3 years was 62% (95% CI, 56% to 68%) and OS was 80% (95% CI, 75% to 85%). Patients with stage IV, early relapse, multiple relapse, anemia, or B symptoms had a higher risk of recurrence (P < .001). CONCLUSION: Compared with conventional high-dose chemotherapy, additional SHDCT is associated with more adverse effects and does not improve the prognosis of patients with relapsed HL. PMID- 20975067 TI - Multicenter phase II trial of S-1 in patients with cytokine-refractory metastatic renal cell carcinoma. AB - PURPOSE: This phase II multicenter trial was conducted to evaluate the activity and safety of S-1 in Japanese patients with metastatic renal cell carcinoma (mRCC). We also examined the relation between response and mRNA expression levels of enzymes involved in the metabolism of fluorouracil (FU). METHODS: Patients with mRCC who had received nephrectomy in whom cytokine-based immunotherapy was ineffective or contraindicated were studied. S-1 was administered orally at 80-, 100-, or 120-mg daily, assigned according to body surface area, on days 1 to 28 of a 42-day cycle. The primary end point was the objective response rate. The mRNA expression levels of FU-related enzymes were measured by reverse transcriptase polymerase chain reaction in formalin-fixed, paraffin-embedded specimens of tumors obtained at nephrectomy. RESULTS: A total of 45 eligible patients were enrolled. Eleven (24.4%) of 45 patients had partial responses to S 1, and 28 (62.2%) had stable disease. Median progression-free survival was 9.2 months. The severity of most adverse events was mild to moderate. The most common grade 3/4 drug-related adverse events were neutropenia (8.9%) and anorexia (8.9%). The expression level of thymidylate synthase (TS) mRNA was significantly lower in patients who responded to treatment (t-test, P = .048), and progression free survival was significantly longer in patients whose TS mRNA expression levels were below the median value, as compared with those with higher levels (log-rank test, P = .006). CONCLUSION: S-1 is active against cytokine-refractory mRCC. Quantification of TS mRNA levels in tumors before treatment may facilitate prediction of the response of mRCC to S-1. PMID- 20975068 TI - Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. AB - PURPOSE: To determine the recommended dose of everolimus, a mammalian target of rapamycin inhibitor, combined with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer pretreated with trastuzumab. METHODS: In this phase Ib, multicenter, dose escalation study, patients were treated with everolimus 5 mg/d, 10 mg/d, or 30 mg/wk in combination with paclitaxel (80 mg/m(2) days 1, 8, and 15 every 4 weeks) and trastuzumab (2 mg/kg weekly). End points included end-of-cycle 1 dose limiting toxicity (DLT) rate (primary end point), safety, relative dose intensity of study drugs, overall response rate (ORR), and pharmacokinetics. RESULTS: Of 33 patients enrolled, 31 were pretreated with taxanes, and 32 were resistant to trastuzumab. Patients received a median of two lines of chemotherapy in the metastatic setting (range, 0 to 17 lines). Three patients experienced cycle 1 DLTs: febrile neutropenia (5 mg/d), stomatitis (10 mg/d), and confusion (30 mg/wk). Grade 3 to 4 neutropenia was the most common toxicity observed (n = 17 patients [52%]). On the basis of observed DLTs and overall safety, 10 mg/d was recommended for additional development. Twenty-seven patients had measurable disease and were evaluable for efficacy. Among these patients, ORR was 44%. Overall disease was controlled for 6 months or more in 74%. Median progression free survival was 34 weeks (95% CI, 29.1 to 40.7 weeks). Among 11 patients who were resistant to both trastuzumab and taxane, a similar level of antitumor activity was observed (ORR, 55%). CONCLUSION: Everolimus combined with weekly paclitaxel and trastuzumab was generally well tolerated and had encouraging antitumor activity in patients with trastuzumab-pretreated and -resistant metastatic HER2-overexpressing breast cancer. PMID- 20975069 TI - Another step toward the cure of metastatic renal cell carcinoma? PMID- 20975070 TI - Availability of experimental therapy outside oncology randomized clinical trials in the United States. AB - PURPOSE: Investigational cancer therapies may be available outside trials as "off protocol therapy" (OPRx), with implications for patient safety, trial accrual, and access to care. We conducted a literature-based analysis of recent randomized trials to evaluate the potential scope and impact of OPRx in the United States. METHODS: A MEDLINE search identified all English-language phase III medical oncology randomized clinical trials (RCTs) published over a 2-year period ending April 17, 2008. Determination of OPRx availability was based on US Food and Drug Administration approval for any indication. We limited assessment of accrual to studies with US sites. Data from articles were extracted independently by two investigators. RESULTS: Among 172 eligible RCTs, the majority (108; 63%) evaluated drugs that were available OPRx in the United States at trial initiation, while an additional 19 (11%) evaluated interventions that became available during the trial. Among trials with US sites, time to accrual was slower (41 vs 22 months; P = .002) and less efficient (8.8 v 22.7 patients per month; P = .001) when OPRx was available. Sixty-six percent of RCTs reported at least one increased grade 3 to 4 toxicity in the experimental arm, 47% reported superior efficacy for at least one major clinical outcome in the experimental arm, and 27% reported improvement in overall survival. These outcomes did not vary on the basis of OPRx availability. CONCLUSION: The majority of recent oncology RCTs involve experimental interventions that are available outside trials in the United States with potential impact on trial accrual. The safety and efficacy of novel interventions must be determined by clinical trials. PMID- 20975072 TI - Long-term survival among patients with Hodgkin's lymphoma who developed breast cancer: a population-based study. AB - PURPOSE: The increased risk of breast cancer (BC) among women receiving chest radiotherapy for Hodgkin's lymphoma (HL) is well-established. However, there are no large population-based studies that describe overall survival (OS) and cause specific survival (CSS) compared with women with first primary BC. METHODS: For 298 HL survivors who developed BC (HL-BC group) and 405,223 women with a first or only BC (BC-1 group), actuarial OS and CSS were compared, accounting for age, BC stage, hormone receptor status, sociodemographic status, radiation for HL, and other variables. All patients were derived from the population-based Surveillance, Epidemiology, and End Results program. RESULTS: OS among patients with HL-BC was significantly inferior that of to patients with BC-1: 15-year OS was 48% versus 69% (P < .0001) for localized BC, and 33% versus 43% (P < .0001) for regional/distant BC. Patients with HL-BC had a significantly increased seven fold risk (P < .0001) of death from other cancers (ie, not HL or BC) compared with patients with BC-1. Mortality from heart disease among patients with HL-BC with either localized or regional/distant disease was also significantly increased (hazard ratio = 2.22, P = .04; and hazard ratio = 4.28, P = .02, respectively) compared with patients with BC-1. Although 10-year BC-CSS was similar for patients with HL-BC and BC-1 with regional/distant disease, it was inferior for patients with localized BC (82% v 88%, respectively; P = .002). CONCLUSION: Women with HL may survive a subsequent diagnosis of BC, only to experience significant excesses of death from other primary cancers and cardiac disease. Greater awareness of screening for cardiac disease and subsequent primary cancers in patients with HL-BC is warranted. PMID- 20975073 TI - Symptomatic spinal cord necrosis after irradiation for vertebral metastatic breast cancer. PMID- 20975071 TI - Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer. AB - Insulin-like growth factors were discovered more than 50 years ago as mediators of growth hormone that effect growth and differentiation of bone and skeletal muscle. Interest of the role of insulin-like growth factors in cancer reached a peak in the 1990s, and then waned until the availability in the past 5 years of monoclonal antibodies and small molecules that block the insulin-like growth factor 1 receptor. In this article, we review the history of insulin-like growth factors and their role in growth, development, organism survival, and in cancer, both epithelial cancers and sarcomas. Recent developments regarding phase I to II clinical trials of such agents are discussed, as well as potential studies to consider in the future, given the lack of efficacy of one such monoclonal antibody in combination with cytotoxic chemotherapy in a first-line study in metastatic non-small-cell lung adenocarcinoma. Greater success with these agents clinically is expected when combining the agents with inhibitors of other cell signaling pathways in which cross-resistance has been observed. PMID- 20975074 TI - What role should cilengitide have in the treatment of glioblastoma? PMID- 20975075 TI - Testosterone levels and quality of life in diverse male patients with cancers unrelated to androgens. AB - PURPOSE: Symptoms secondary to hormonal changes significantly impact quality of life (QoL) in patients with cancer. This cross-sectional study examines prevalence of hypogonadism and its correlation with QoL and sexual dysfunction. PATIENTS AND METHODS: We collected blood and medical histories from 428 male patients with non-testosterone-related cancer at three cancer centers. Serum was analyzed for total testosterone (TT), free testosterone (FT), bioavailable testosterone (BAT), and sex hormone binding globulin (SHBG). The Functional Assessment of Cancer Therapy-Prostate (FACT-P) QoL questionnaire measured physical, social, emotional, and functional domains as well as sexual function. Exclusion criteria were prostate, testicular, or male breast cancer; known hypogonadism; and HIV. RESULTS: Mean and median TTs were 337.46 and 310 ng/dL, respectively. The mean age of patients was 62.05 years. The crude prevalence of hypogonadism (ie, TT < 300 ng/dL) was 48%, and mean TT in hypogonadal patients was 176 ng/dL. The prevalences that were based on FT (ie, hypogonadal < 52 pg/dL) and BAT (ie, hypogonadal < 95 ng/dL) were 78% and 66%, respectively. The mean FT and BAT values in hypogonadal patients were 25 pg/dL and 45 ng/dL, respectively. Hypogonadal patients had decreased total QoL scores on FACT-P (P = .01) and decreased three-item sexual function subset (P = .003). CONCLUSION: The prevalence of hypogonadism was unexpectedly high. Measurement of FT or BAT detected a higher prevalence than TT alone, which confirmed previous studies. Correlation of T with FACT-P showed significant reduction of both overall QoL and sexual function for hypogonadal men. BAT and FT levels showed a stronger correlation than TT with overall FACT-P and subscales. The prevalence of symptomatic hypogonadism in male patients with cancer exceeds that found in comparable studies in noncancer populations. PMID- 20975077 TI - Digital analysis of hepatic sections in mice accurately quantitates triglycerides and selected properties of lipid droplets. AB - We describe a method for the histologic evaluation of lipid accumulation in the livers of various mouse models of hepatic steatosis based on quantitative digital analysis of Oil Red O (ORO) accumulation in fresh-frozen hepatic sections. The process involves two principal steps: identification and digital photographic imaging of areas appropriate for analysis, followed by digital determination of the fraction of the identified area (Area Fraction) exhibiting ORO staining. The Area Fraction, designated the Digital Steatosis Score, is a valuable aspect of the histologic assessment of the liver, especially in various forms of alcoholic and non-alcoholic liver diseases. The method is rapid, requiring ~3 min per specimen, and highly reproducible, avoiding the inevitably subjective, semi quantitative evaluation of lipid content inherent in visual steatosis scoring systems. In normal mice and in six different mouse models of fatty liver, the Area Fraction was highly correlated with hepatic triglyceride content (P < 0.01). The coefficient of variation of repeated determinations of the Area Fraction by two different observers was +/-6.4%. If made available in clinical settings, rapid, accurate quantitation of liver triglycerides by this method could be very useful in specific conditions such as assessment of donor livers for transplantation. PMID- 20975078 TI - Relationship between brachial and femoral artery endothelial vasomotor function/phenotype in pigs. AB - In humans, the measurement of brachial artery endothelial vasomotor function is used as a surrogate index of systemic endothelial health; however, the applicability of brachial artery findings to other vasculatures needs to be examined. The purpose of the present investigation was to test the following hypotheses: (1) brachial and femoral artery endothelium-dependent/independent relaxation is correlated; (2) endothelial expression of pro-/antiatherogenic proteins is correlated between brachial and femoral arteries; and (3) within vessel, there is a positive correlation between expression of antiatherogenic proteins and endothelium-dependent/independent relaxation, and an inverse correlation between expression of proatherogenic proteins and relaxation. In vitro endothelium-dependent (bradykinin [BK] and acetylcholine [Ach]) and independent (sodium nitroprusside [SNP]) relaxation were evaluated in harvested brachial and femoral arteries of 96 Yucatan miniature swine. In a subset of pigs (n = 32), expression of 18 pro-/antiatherogenic proteins was measured from brachial and femoral artery endothelial cell scrapes using immunoblot analysis. Vascular sensitivity (half-maximal effective dose) to BK, Ach and SNP was highly correlated between brachial and femoral arteries (P < 0.01). A significant correlation was found between brachial and femoral arteries for content of six of the 18 measured proteins (P < 0.01). Furthermore, expression of two proteins (eNOS and COX-1) was correlated with vasorelaxation function in the brachial artery (P < 0.01). We provide the first evidence of a relationship between brachial and femoral artery endothelium-dependent relaxation. Our data also suggest that, in general terms, endothelial expression of several established pro /antiatherogenic proteins is not robustly associated between brachial and femoral arteries, and does not link strongly to vasorelaxation function. PMID- 20975079 TI - Inhibition of DNA synthesis in mouse epidermis by topical imiquimod is dependent on opioid receptors. AB - The imidazoquinolines are immune response modifiers that have potent antiviral and antitumor properties. The mechanism by which they exert their effects on cell replication has been investigated in vitro and is related to the upregulation of the opioid growth factor receptor (OGFr) and modulation of opioid growth factor (OGF; [Met(5)]-enkephalin). The OGF-OGFr axis regulates cell proliferative events through a cyclin-dependent kinase inhibitory pathway. The present study examined the mechanism whereby imiquimod repressed cell proliferation in vivo. Using a nude mouse model that has a compromised T-cell immune system, as well as C57BL/6 mice with an intact immune system, the effects of topical imiquimod (Aldara((r))) on DNA synthesis of basal epithelial cells in skin were examined. Imiquimod's effects on DNA synthesis were detected 24 h after application, and could be observed for one week after a single treatment. The magnitude of change in DNA synthesis following imiquimod was similar for one, three or six applications. Naloxone, an opioid antagonist, blocked the inhibitory effect of imiquimod. Imiquimod in combination with OGF or a low dose of naltrexone (LDN; known to upregulate the OGF-OGFr axis) had no greater inhibitory response on DNA synthesis than either OGF or LDN alone. Both OGF and OGFr were upregulated in basal epithelium after imiquimod treatment. Both nude and C57BL/6 mice exhibited the same repressive action of imiquimod on epithelial DNA synthesis. Imiquimod was neither an opioid agonist nor antagonist using nociceptive testing, and did not induce apoptosis or necrosis. Exposure to imiquimod was found to depress DNA synthesis in cells located in distant epithelium from day 3 and lasted until day 5. These results suggest that the target of imiquimod on DNA synthesis is dependent on an opioid receptor-mediated pathway, and infers that imiquimod is reliant on the OGF-OGFr axis for modulating cell proliferation. PMID- 20975080 TI - Molecular signaling of pruritus induced by endothelin-1 in mice. AB - Endothelin-1 (ET-1) has recently been identified to evoke pruritus/itching sensation in both humans and animals. It is most likely that the signaling is through the specific G-protein-coupled ET(A) and ET(B) receptors, but the downstream signaling mediators for ET-1 remain elusive. In the present study, we examined the potential involvement of several distinct signaling molecules in ET 1-induced pruritus in a murine model. We applied an in vivo pruritus model in C57BL/6J mice by injecting ET-1 intradermally into the scruff, and recording the number of scratching bouts within 30 min after injection. Then specific antagonists/inhibitors for distinct signaling molecules, including cell-surface ET(A) and ET(B) receptors, histamine receptor type 1 (H1 receptor), protein kinases A (PKA) and C (PKC), phospholipase C (PLC) or adenylyl cyclase (AC), were co-injected with ET-1. The results showed that ET-1 induced a vigorous scratching response in mice in a dose-dependent manner. This response was further enhanced by a specific antagonist for ET(B) receptor, BQ-788, reduced by a specific antagonist for ET(A) receptor, BQ-123, and not affected by mepyramine, the specific inhibitor for H1 receptor. In addition, the scratching response was significantly reduced by inhibitors for PKC and AC, but was significantly enhanced by PLC inhibitor, while PKA inhibitors showed no effects in the ET-1 induced scratching response. Our data suggested that ET-1 may signal through the ET(A) receptor, AC and PKC pathway to induce pruritus sensation, while ET(B) receptor and PLC may antagonize the pruritus evoked by ET-1. These results may provide a basis for the future development of antipruritic therapy. PMID- 20975081 TI - Haptoglobin as an early serum biomarker of virus-induced autoimmune type 1 diabetes in biobreeding diabetes resistant and LEW1.WR1 rats. AB - Proteomic profiling of serum is a powerful technique to identify differentially expressed proteins that can serve as biomarkers predictive of disease onset. In this study, we utilized two-dimensional (2D) gel analysis followed by matrix assisted-laser desorption/ionization time-of-flight mass spectrometry analysis to identify putative serum biomarkers for autoimmune type 1 diabetes (T1D) in biobreeding diabetes resistant (BBDR) rats induced to express the disease. Treatment with toll-like receptor 3 ligand, polyinosinic:polycytidilic acid (pIC), plus infection with Kilham rat virus (KRV), a rat parvovirus, results in nearly 100% of young BBDR rats becoming diabetic within 11-21 d. Sera collected from prediabetic rats at early time points following treatment with pIC + KRV were analyzed by 2D gel electrophoresis and compared with sera from control rats treated with phosphate-buffered saline, pIC alone or pIC + H1, a non-diabetogenic parvovirus. None of the latter three control treatments precipitates T1D. 2D gel analysis revealed that haptoglobin, an acute phase and hemoglobin scavenger protein, was differentially expressed in the sera of rats treated with pIC + KRV relative to control groups. These results were confirmed by Western blot and enzyme-linked immunosorbent assay studies, which further validated haptoglobin levels as being differentially increased in the sera of pIC + KRV-treated rats relative to controls during the first week following infection. Early elevations in serum haptoglobin were also observed in LEW1.WR1 rats that became diabetic following infection with rat cytomegalovirus. The identification and validation of haptoglobin as a putative serum biomarker for autoimmune T1D in rats now affords us the opportunity to test the validity of this protein as a biomarker for human T1D, particularly in those situations where viral infection is believed to precede the onset of disease. PMID- 20975082 TI - Identification of fetal hemoglobin-inducing agents using the human leukemia KU812 cell line. AB - Fetal hemoglobin (HbF) ameliorates the clinical severity of sickle cell disease; therefore continued research to identify efficacious HbF-inducing agents is desirable. In this study, we investigated KU812 leukemia cells that express the fetal gamma-globin and adult beta-globin genes, as a system for screening and discovery of novel HbF inducers. KU812 cells were analyzed in the presence or absence of fetal bovine serum and then expression levels of the globin genes, cell surface markers and transcription factors were quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). For comparison, primary erythroid cells were grown in a two-phase liquid culture system. After drug inductions for 48-72 h, globin mRNA and HbF levels were quantified by RT qPCR and enzyme-linked immunosorbent assay, respectively. Erythroid markers and transcription factors expression levels in KU812 cells were comparable to days 7 14 erythroid cells. We also tested several drugs including butyrate, trichostatin A, scriptaid, suberoylanilide hydroxamic acid and hydroxyurea, which induced gamma-globin in KU812 cells; however, some agents also induced beta-globin. A novel agent STI-571 was studied in the system, which non-selectively induced the globin genes. Additional studies showed comparable globin gene response patterns in KU812 and primary erythroid cells after treatments with the various drug inducers. Mechanisms of drug-mediated gamma-globin induction in KU812 cells require signaling through the p38 mitogen-activated protein kinase pathway similar to that previously demonstrated in primary erythroid cells. These data suggest that KU812 cells serve as a good screening system to identify potential HbF inducers for the treatment of beta-hemoglobinopathies. PMID- 20975083 TI - European guideline for the management of lymphogranuloma venereum, 2010. PMID- 20975084 TI - Secondary syphilis: the classical triad of skin rash, mucosal ulceration and lymphadenopathy. AB - After years of declining incidence in many developed countries, syphilis infection has re-emerged as a major public health problem in the past decade. The secondary stage of syphilis epitomizes the capacity of the infection to present in myriad ways. The skin, lymph glands and mucosal membranes are the most commonly affected tissues. PMID- 20975085 TI - Daniel Turner (1667-1741): syphillis and the condum. AB - Daniel Turner 1667-1741 was the first English medical author to use the term syphillis incidentally, also mentioning early usage of the condom (condum). This paper shows that venereologists in 18th century London wrote on the use of condoms by some men, but who were sceptical about its usage. This paper also describes some of the contemporary spellings of condum and syphillis. PMID- 20975086 TI - Diagnosis of sexually transmitted infections and bacterial vaginosis among HIV-1 infected pregnant women in Nairobi. AB - HIV-infected women with sexually transmitted infections (STIs) or bacterial vaginosis (BV) during pregnancy are at increased risk for poor obstetric outcomes. In resource-limited settings, diagnostic testing for STIs and BV is often not available and most pregnant women are managed using syndromic algorithms. As part of a Nairobi perinatal cohort, HIV-1-infected pregnant women were interviewed and samples were collected for STIs and BV testing. Diagnostic accuracy of STIs and BV by syndromic algorithms was evaluated with comparison to the reference standard. Among 441 women, prevalence of BV was 37%, trichomoniasis 16%, chlamydia 4%, syphilis 3% and gonorrhoea 2%. Significantly more women with STIs were aged 21-years-old, had not attended secondary school and had a history of STIs. Syndromic diagnosis of STIs and BV demonstrated a sensitivity of 45% and 57%, and positive predictive value of 30% and 42%, respectively. Among these HIV infected, pregnant women, STIs and vaginal infections were common and syndromic diagnosis was insensitive, resulting in missed opportunities to intervene and improve infant and maternal health. PMID- 20975087 TI - Low frequency of liver enzyme elevation in HIV-infected patients attending a large urban treatment centre in Uganda. AB - Liver enzyme elevations among patients on antiretroviral therapy (ART) were determined by prospectively evaluating aspartate aminotransferase (AST) data in a cohort of patients in Kampala over 36 months. A proportion of patients had hepatitis B virus (HBV) status determined. Hepatotoxicity was graded I to IV according to the AIDS Clinical Trial Group criteria. Of 546 patients, 377 (69%) were women; overall median baseline CD4+ T-cell was 97/MUL (interquartile range [IQR] 20-164). Hepatitis B surface antigen (HBsAg) was detected in 42 (9%) of 470 persons. ART included lamivudine, with either nevirapine and d4T (74%) or efavirenz and AZT (26%). Median (IQR) AST level at baseline was 35 (27, 53 IU/L). Over 36 months, only eight patients had grade III AST elevation. Neither HBsAg nor ART regimen influenced AST levels. Male gender and CD4+ change from baseline were correlated with AST elevation. Patients with HIV/HBV co-infection were not at an increased risk of AST elevation, which occurred uncommonly in this setting. PMID- 20975088 TI - Knowledge of human papillomavirus among high school students can be increased by an educational intervention. AB - The aim of this study was to evaluate the effect of an educational intervention concerning human papillomavirus (HPV) directed at Swedish first year high school students. The intervention consisted of a class room lesson, a website and a folder. Outcome variables were knowledge of HPV and attitudes to preventive methods such as HPV vaccination, condom use and Pap smear testing. An intervention group (n = 92) was matched with two comparison groups (n = 184). At baseline, the median score for HPV knowledge was one out of 10 in both groups. At follow-up, the median knowledge score had increased to six in the intervention group, but was still one in the comparison group (P < 0.001). Attitudes to HPV vaccination, condom use and Pap smear testing remained the same (P > 0.05). In conclusion, a short school-based intervention can greatly increase the students' knowledge about HPV, but attitudes and behaviours are less easy to influence. PMID- 20975089 TI - Patients' attitudes towards increasing the offer of HIV testing in primary and secondary care. AB - The UK National Guidelines on HIV testing (2008) recommend routinely offering an HIV test to patients in certain clinical settings. We wished to investigate the acceptability of implementing these guidelines in a population with a low HIV prevalence. Patients accessing primary and secondary care were asked to circle one of the five responses to a series of statements regarding HIV testing. Of the 616 respondents, 579 (94%) stated they would be willing to be tested if presenting with a condition known to be associated with HIV. Four hundred and forty out of 616 (71%) stated they would be willing to be tested as part of their routine care, while 445/616 (72%) stated they would be willing to have the result in their main medical notes. Although the patients' responses were largely receptive to increased testing, we encountered notable negative attitudes to the project from professional and administrative staff. Resistance to increased HIV testing may be related to health-care workers rather than patients. PMID- 20975090 TI - Lubricant use among men who have sex with men reporting receptive anal intercourse in Peru: implications for rectal microbicides as an HIV prevention strategy. AB - This study assessed lubricant use during receptive anal intercourse (RAI) among Peruvian men who have sex with men (MSM) and willingness to use a hypothetical rectal microbicide (RM) formulated as a lubricant to prevent HIV infection. Data were collected from 843 Peruvian MSM for the 2008 HIV Sentinel Surveillance using a computerized self-interview. Half of the participants reported using a lubricant with their last sex partner during RAI, while 77% were willing to use a lubricant to prevent HIV transmission. Lubricant use with last sex partner was significantly associated with unprotected RAI (odds ratio [OR] 1.59, 95% confidence interval [CI], 1.23, 2.05; P < 0.001) and willingness to use a future lubricant RM (OR 1.56, 95% CI: 1.24, 1.95; P < 0.001). This study provides information on the behaviours associated with lubricant use and non-use among MSM practicing RAI in Peru that should inform future RM studies in Peru and other Latin American countries. PMID- 20975091 TI - Risk factors for immune reconstitution inflammatory syndrome under combination antiretroviral therapy can be aetiology-specific. AB - In order to discriminate general from aetiology-specific risk factors for immune reconstitution inflammatory syndrome (IRIS), we followed up, during six months, 99 patients with advanced HIV infection commencing antiretroviral therapy (ART) without active opportunistic infections or evident inflammation. IRIS predictors were determined by univariate analysis using clinical data from 76 ART-responding patients either completing follow-up or developing IRIS, and by multivariate analysis of inflammation, disease progression and nutrition status variables. We identified 23 primary IRIS events (30.3%). Univariate predictors for all IRIS events were higher platelet counts and lower CD4/CD8 ratio, whereas subclinical inflammation was the multivariate predictor. Platelets, alkaline phosphatase levels and %CD8 T-cells in univariate analysis also predicted mycobacteria associated IRIS independently, remaining elevated during follow-up. Herpesvirus IRIS was predicted by platelets and inflammation. Indicators of advanced HIV disease and subclinical inflammation jointly predict IRIS, and some are specific of the underlying microbial aetiology, possibly explaining previous reports. PMID- 20975092 TI - Herpes simplex virus type 2 associated with HIV infection among New York heterosexuals living in high-risk areas. AB - Herpes simplex virus type 2 (HSV-2) has been shown to increase the risk of sexual human immunodeficiency virus (HIV) transmission. A matched case-control design was used to examine the association between HSV-2 and HIV infection among heterosexuals in 'high-risk areas' (HRAs) in New York City (NYC). We identified NYC HRAs using HIV surveillance data on heterosexual-related adult HIV diagnoses and USA census data on household poverty. Heterosexuals who were socially or geographically linked to an HRA were recruited using respondent-driven sampling. HIV prevalence was 8.6% and HSV-2 prevalence was 80.1%. Only 6% of HIV-positives knew they were infected. HIV-positive cases were matched to HIV-negative controls on gender, race/ethnicity and age, and tested for antibody to HSV-2. In a multivariate model, HIV infection was associated with HSV-2 infection (adjusted odds ratio [AOR] = 3.5, 95% confidence interval 1.1-11.7) and non-HSV-related sexually transmitted infection diagnosis in the previous year (AOR = 2.6, 1.1 6.2). Effective approaches to HIV risk reduction for individuals with HSV-2 remain uncertain, and these are urgently needed in high-risk communities where multiple social, behavioural and biological factors that facilitate HIV infection coexist. PMID- 20975093 TI - Development of a validated patient satisfaction survey for sexual health clinic attendees. AB - Patient experience of and satisfaction with health-care services is increasingly being used to evaluate and guide health-care provision. A recent systematic review failed to identify a validated method of measuring patient satisfaction in sexually transmitted infection (STI) clinics. The aim of this study was to design and validate a specific STI clinic patient satisfaction survey that could be used as a patient-derived outcome measure. Key themes of importance to patients were identified from a recent systematic review of STI clinic patient satisfaction surveys. Semi-structured interviews were performed with patients attending a sexual health clinic to further refine these themes, and then used to compile a patient questionnaire. Cognitive testing was used to provide face validity for the questionnaire design, layout and wording. The questionnaire was further reviewed and revised by the research team prior to being piloted over a five-week period. Five key patient themes were incorporated into the questionnaire and the pilot phase included responses from 936 patients. The completion rate for individual items and the whole questionnaire (95% [885/936]) was high. Internal consistency and validity also scored highly. PMID- 20975094 TI - Acceptability of neonatal circumcision by Hispanics in southern Florida. AB - This study attempted to determine the acceptability of neonatal circumcision in Hispanic expectant and new parents and to explore potential associations with lower acceptability. Overall, we found surprisingly high rates of acceptability in this community that contrasts with the actual low rates of circumcision in Hispanics in the USA. This gap is important since newborn circumcision has been suggested as an additional long-range tool in reducing longstanding ethnic disparities in HIV incidence in the USA. A larger study will be needed to determine what factors are associated with low acceptability and how one might effectively address these concerns in this population. PMID- 20975095 TI - Is everyone treated equally? Management of genital Chlamydia trachomatis infection in New Zealand. AB - Health disparities often reflect inequitable access to appropriate health care. This study aimed to establish if cases of genital chlamydia infection were managed equitably by age, gender and ethnicity in a region of New Zealand with high rates of chlamydia infection (858 per 100,000 population). Clinical records of 415 genital chlamydia cases from 19 different health-care sites, including general practice and community settings, were reviewed. Data were analysed by demographic variables. For those treated, men were treated more quickly than women (median 3 days versus 6 days, P < 0.001), but there was no difference by ethnicity. Cases without documented treatment were more likely to be women (8.2% versus 2.1%, P = 0.037) and more likely to be Maori than non-Maori (13.6% versus 4.8%, P = 0.036). Overall, the most notable issue was the lack of effective partner notification across all demographic variables. Ongoing efforts are required to ensure equitable access to timely treatment and to ensure that more effective partner notification strategies are implemented. PMID- 20975096 TI - Haemophagocytic lymphohistiocytosis complicating Hodgkin's lymphoma in an HIV positive individual. AB - We report the case of an HIV-positive man who presented with pyrexia of unknown origin. Histological specimens from an inguinal lymph node and liver biopsy gave a diagnosis of Epstein Barr virus (EBV)-positive Hodgkin's lymphoma and haemophagocytic lymphohistiocytosis (HLH), respectively. HLH is a condition characterized by proliferation of activated macrophages that phagocytose leukocytes, erythrocytes and platelets. Clinical features include splenomegaly, fever and pancytopenia, all of which have a wide differential diagnosis in HIV positive patients. HLH can be caused by infections, malignancy, drugs or autoimmune conditions. There have been a number of reports of HLH in HIV-positive patients, and it can be seen at all stages of HIV infection. HIV, lymphomas, EBV infection and haemophagocytic syndrome have a complicated pathophysiology. Unfortunately, HLH in this setting has a particularly aggressive course, often with a poor outcome. This case highlights the need for awareness of the syndrome to ensure prompt diagnosis and instigation of appropriate treatment. PMID- 20975097 TI - Management of pregnancy in an HIV elite controller. AB - Elite control of HIV infection has been defined as spontaneous and sustained maintenance of HIV RNA to <50 copies/mL in the absence of therapy. It is estimated to occur in approximately one in 300 HIV-infected individuals. We present the case of a Zimbabwean woman who tested positive for HIV-1 infection on routine antenatal bloods at 15 weeks gestation. Her CD4 count was 500 cells/mm(3); however, HIV-1 RNA viral load measured below the level of detection on several assays. A Cavidi ExaVir reverse transcriptase assay was below the level of detection. Pro-viral DNA was positive using long terminal repeat primers and sequencing demonstrated subtype C virus. Zidovudine monotherapy (250 mg twice daily) was commenced at 24 weeks for the prevention of mother to child transmission. She was keen for a standard vaginal delivery, having had one previously, and she delivered a healthy baby without complications at 39 weeks gestation. The neonate received four weeks of Zidovudine and tested negative for HIV infection. We discuss some challenges involved in the management of a pregnant 'elite controller'. PMID- 20975098 TI - Neonatal Trichomonas vaginalis infection: a case report and review of literature. AB - Neonatal infection with Trichomonas vaginalis is an unusual occurrence. We present a case of T. vaginalis found on routine urinalysis in a five-day-old neonate born at 29 weeks gestational age. The patient was treated with metronidazole and had complete resolution of the infection. This report discusses the significance of diagnosis and treatment of T. vaginalis in the neonate. PMID- 20975099 TI - Syphilitic aorta: exploring the bigger picture. PMID- 20975100 TI - Clinical correlates of NRAS and BRAF mutations in primary human melanoma. AB - PURPOSE: NRAS and BRAF mutations are common in cutaneous melanomas, although rarely detected mutually in the same tumor. Distinct clinical correlates of these mutations have not been described, despite in vitro data suggesting enhanced oncogenic effects. This study was designed to test the hypothesis that primary human cutaneous melanomas harboring mutations in NRAS or BRAF display a more aggressive clinical phenotype than tumors wild type at both loci. EXPERIMENTAL DESIGN: Microdissection of 223 primary melanomas was carried out, followed by determination of the NRAS and BRAF mutational status. Genotypic findings were correlated with features known to influence tumor behavior including age, gender, Breslow depth, Clark level, mitotic rate, the presence of ulceration, and American Joint Committee on Cancer (AJCC) staging. RESULTS: Breslow depth and Clark level varied significantly among the genotypes, with NRAS mutants showing the deepest levels and wild-type tumors the least depth. Ulceration also differed significantly among the genotypes, with BRAF mutants demonstrating the highest rate. In addition, tumors with mutated NRAS were more likely to be located on the extremities. Patients whose tumors carried either mutation presented with more advanced AJCC stages compared with patients with wild-type tumors, and specifically, were more likely to have stage III disease at diagnosis. Overall survival did not differ among the 3 groups. CONCLUSIONS: Distinct clinical phenotypes exist for melanomas bearing NRAS and BRAF mutations, whether considered together or separately, and are associated with features known to predict aggressive tumor behavior. The impact of these mutations is most evident at earlier stages of disease progression. PMID- 20975101 TI - Three epigenetic biomarkers, GDF15, TMEFF2, and VIM, accurately predict bladder cancer from DNA-based analyses of urine samples. AB - PURPOSE: To identify a panel of epigenetic biomarkers for accurate bladder cancer (BlCa) detection in urine sediments. EXPERIMENTAL DESIGN: Gene expression microarray analysis of BlCa cell lines treated with 5-aza-2'-deoxycytidine and trichostatin A as well as 26 tissue samples was used to identify a list of novel methylation candidates for BlCa. Methylation levels of candidate genes were quantified in 4 BlCa cell lines, 50 BlCa tissues, 20 normal bladder mucosas (NBM), and urine sediments from 51 BlCa patients and 20 healthy donors, 19 renal cancer patients, and 20 prostate cancer patients. Receiver operator characteristic curve analysis was used to assess the diagnostic performance of the gene panel. RESULTS: GDF15, HSPA2, TMEFF2, and VIM were identified as epigenetic biomarkers for BlCa. The methylation levels were significantly higher in BlCa tissues than in NBM (P < 0.001) and the cancer specificity was retained in urine sediments (P < 0.001). A methylation panel comprising GDF15, TMEFF2, and VIM correctly identified BlCa tissues with 100% sensitivity and specificity. In urine samples, the panel achieved a sensitivity of 94% and specificity of 100% and an area under the curve of 0.975. The gene panel could discriminate BlCa from both healthy individuals and renal or prostate cancer patients (sensitivity, 94%; specificity, 90%). CONCLUSIONS: By using a genome-wide approach, we have identified a biomarker panel that allows for early and accurate noninvasive detection of BlCa using urine samples. PMID- 20975103 TI - Genotypic profiling of 452 choroidal melanomas with multiplex ligation-dependent probe amplification. AB - PURPOSE: Metastasis from uveal melanoma occurs almost exclusively with tumors showing chromosome 3 loss. We used multiplex ligation-dependent probe amplification (MLPA) to detect chromosome 1p, 3, 6p, 6q, 8p, and 8q abnormalities in uveal melanomas. The purpose of this study was to correlate our MLPA results with other risk factors and metastatic death. EXPERIMENTAL DESIGN: Patients were included if they had a uveal melanoma involving choroid. Correlations between baseline risk factors were analyzed using the chi-square test (without Yates's adjustment) and the Mann-Whitney test, with log-rank analysis for associations with metastatic death. RESULTS: The patients (194 female; 258 male) had a median age of 59.4 years and a median follow-up of 1.89 years. MLPA abnormalities occurred in a wide variety of combinations. Ten-year disease-specific mortality was 0% in 133 tumors with no chromosome 3 loss, 55% in tumors with chromosome 3 loss but no chromosome 8q gain, and 71% in 168 tumors showing combined chromosome 3 loss and 8q gain. In tumors with both these abnormalities, epithelioid melanoma cytomorphology, closed loops, and high mitotic rate correlated with poor survival as did lack of chromosome 6p gain. CONCLUSIONS: These results support the use of MLPA for routine clinical prognostication, especially if the genetic data are considered together with clinical and histologic risk factors. We showed a wide variety of MLPA results, which suggests that chromosomal abnormalities in uveal melanoma accumulate in a variable sequence. PMID- 20975102 TI - Prognostic value of baseline [18F] fluorodeoxyglucose positron emission tomography and 99mTc-MDP bone scan in progressing metastatic prostate cancer. AB - PURPOSE: To compare the diagnostic and prognostic value of [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) and bone scans (BS) in the assessment of osseous lesions in patients with progressing prostate cancer. EXPERIMENTAL DESIGN: In a prospective imaging trial, 43 patients underwent FDG PET and BS prior to experimental therapies. Bone scan index (BSI) and standardized uptake value (SUV) on FDG-PET were recorded. Patients were followed until death (n = 36) or at least 5 years (n = 7). Imaging findings were correlated with survival. RESULTS: Osseous lesions were detected in 39 patients on BS and 32 on FDG-PET (P = 0.01). Follow-up was available for 105 FDG-positive lesions, and 84 (80%) became positive on subsequent BS. Prognosis correlated inversely with SUV (median survival 14.4 versus 32.8 months if SUVmax > 6.10 versus <= 6.10; P = 0.002) and BSI (14.7 versus 28.2 months if BSI > 1.27 versus < 1.27; P = 0.004). Only SUV was an independent factor in multivariate analysis. CONCLUSION: This study of progressive prostate cancer confirms earlier work that BSI is a strong prognostic factor. Most FDG-only lesions at baseline become detectable on follow-up BS, suggesting their strong clinical relevance. FDG SUV is an independent prognostic factor and provides complementary prognostic information. PMID- 20975104 TI - The effects of postexercise consumption of high-molecular-weight versus low molecular-weight carbohydrate solutions on subsequent high-intensity interval running capacity. AB - The aim of this study was to determine the effects of postexercise ingestion of different-molecular-weight glucose polymer solutions on subsequent high-intensity interval-running capacity. In a repeated-measures design, 6 men ran for 60 min in the morning at 70% VO2max. Immediately post- and at 1 and 2 hr postexercise, participants consumed a 15% low-molecular-weight (LMW) or high-molecular-weight (HMW) carbohydrate solution, at a rate of 1.2 g of carbohydrate/kg body mass, or an equivalent volume of flavored water (WAT). After recovery, participants performed repeated 1-min intervals at 90% VO2max interspersed with 1 min active recovery (walking) until volitional exhaustion. Throughout the 3-hr recovery period, plasma glucose concentrations were higher (p=.002) during the HMW and LMW conditions than with WAT (M 7.0+/-0.8, 7.5+/-1.0, and 5.6+/-0.2 mmol/L, respectively), although there was no difference (p=.723) between HMW and LMW conditions. Exercise capacity was 13 (43+/-10 min; 95% CI for differences: 8-18; p=.001) and 11 min (41+/-9 min; 95% CI for differences; 2-18: p=.016) longer with HMW and LMW solutions, respectively, than with WAT (30+/-9 min). There was no substantial difference (2 min; 95% CI for differences: -5 to 10; p=.709) in exercise capacity between LMW and HMW solutions. Although this magnitude of difference is most likely trivial in nature, the uncertainty allows for a possible small substantial enhancement of physiological significance, and further research is required to clarify the true nature of the effect. PMID- 20975105 TI - Aerobic exercise's reversal of insulin resistance by activating AMPKalpha-ACC CPT1 signaling in the skeletal muscle of C57BL/6 mice. AB - Insulin resistance (IR) is a common pathophysiological feature of Type 2 diabetes. Although the mechanisms leading to IR are still elusive, evidence has shown that aerobic exercise can reverse this process. To investigate the effects of aerobic exercise on IR, the authors created an IR animal model by feeding C57BL/6 mice a high-fat diet for 8 wk. They then compared the effect of 6 wk of treadmill training (60 min/d) at 75% VO2max on mice in normal-diet (NE) and high fat-diet (HE) groups with their sedentary control groups. Levels of skeletal muscle AMPKalpha (AMP-activated protein kinase alpha), ACC (acetyl-CoA carboxylases), and CPT1 (carnitine palmitoyltransferase 1) mRNA and AMPKalpha, pAMPK-Thr172, ACC, pACC-Ser79, and CPT1 protein expressions were analyzed. In addition, fasting serum levels of insulin, triglyceride, and cholesterol were measured. The results demonstrate that 6 wk of exercise increased AMPKalpha mRNA expression by 11% and 25 % (p<.01) in the NE and HE groups, respectively, and AMPKalpha protein expression by 37.9% and 20.1% (p<.01) in NE and HE compared with their sedentary control. In addition, ACC mRNA and protein expressions declined, whereas CPT1 mRNA and protein expressions were elevated in both exercise groups compared with sedentary control groups. In addition, pAMPK-Thr172 and pACC-Ser79 expression increased significantly in the NE and HE groups compared with sedentary control groups. In conclusion, our results demonstrate that 6 wk of aerobic exercise can effectively ameliorate IR by increasing the expression of AMPKalpha and pAMPK-Thr172, thereby activating the key enzymes that facilitate lipid metabolism. PMID- 20975106 TI - Effects of a mineral antioxidant complex on clinical safety, body water, lactate response, and aerobic performance in response to exhaustive exercise. AB - BACKGROUND: This investigation examined the safety and efficacy of a silica-based mineral antioxidant complex (MAC) that has been suggested to influence body water and buffer lactate. METHODS: In a double-blind, randomized crossover design, male participants completed testing for 3 conditions: water only (baseline), rice flour (placebo), and MAC supplementation. Participants visited the laboratory on 5 occasions: familiarization, baseline, Testing Day 1, washout, and Testing Day 2. Baseline and Testing Days 1 and 2 consisted of fasting blood, pre- to postexercise body-water assessment and determination of VO2peak on a cycle ergometer. The supplementation protocols were separated by 1 wk and balanced to minimize an order effect. RESULTS: No differences between conditions were found for heart rate, blood pressure, or serum-safety markers (p>.05). Before exercise there were no differences between conditions for total body water (TBW), intracellular water (ICW), or extracellular water (ECW). No significant interactive effects for supplementation and exercise were found for TBW, ICW, or ECW (p>.05). A time effect for TBW (p<.01) and ICW (p<.001) was present. Within group changes in TBW occurred in the MAC condition, and within-group changes for ICW occurred in the MAC and placebo conditions. Ratings of perceived exertion and blood lactate increased (p<.05) with exercise. No significant effects were found for performance variables. CONCLUSIONS: MAC supplementation had no impact on aerobic exercise performance and lactate response. Increases in TBW and ICW occurred after MAC consumption, but these changes appeared to have minimal physiological impact. PMID- 20975107 TI - Lack of effect of a high-calorie dextrose or maltodextrin meal on postprandial oxidative stress in healthy young men. AB - BACKGROUND: Carbohydrate powder in the form of maltodextrin is widely used by athletes for postexercise glycogen resynthesis. There is some concern that such a practice may be associated with a postprandial rise in reactive oxygen and nitrogen species production and subsequent oxidation of macromolecules. This is largely supported by findings of increased oxidative-stress biomarkers and associated endothelial dysfunction after intake of dextrose. PURPOSE: To compare the effects of isocaloric dextrose and maltodextrin meals on blood glucose, triglycerides (TAG), and oxidative-stress biomarkers in a sample of young healthy men. METHODS: 10 men consumed isocaloric dextrose and maltodextrin powder drinks (2.25 g/kg) in a random-order, crossover design. Blood samples were collected premeal (fasting) and at 1, 2, 4, and 6 hr postmeal and assayed for glucose, TAG, malondialdehyde, hydrogen peroxide, nitrate/nitrite, and Trolox-equivalent antioxidant capacity. RESULTS: Significant meal effects were noted for glucose total area under the curve (p=.004), with values higher for the dextrose meal. No other statistically significant meal effects were noted (p>.05). With respect to the 2 (meal)x5 (time) ANOVA, no significant interaction, time, or meal effects were noted for any variable (p>.05), with the exception of glucose, for which a main effect for both meal (p<.0001) and time (p=.0002) was noted. CONCLUSIONS: These data indicate that carbohydrate meals, consumed as either dextrose or maltodextrin, pose little postprandial oxidative insult to young, healthy men. As such, there should be minimal concern over such feedings, even at high dosages, assuming adequate glucose metabolism. PMID- 20975108 TI - Heterogeneity of dietary profiles in highly sedentary young Guadeloupean women. AB - OBJECTIVE: The aim was to examine the relationship between physical activity pattern and dietary profile. Although some clustering of the variables related to these major determinants of cardiovascular risk has been demonstrated, they have not been extensively studied together. PARTICIPANTS, DESIGN, AND SETTING: Two hundred two female university students from the main Guadeloupe (French West Indies) campus participated. They self-administered a validated Food Frequency Questionnaire and the 1-yr recall Modifiable Activity Questionnaire. Principal component analysis was performed on the scores and the variables related to the physical activity pattern and dietary profile. RESULTS: A model including 10 variables explained 84.9% of the total variance. The physical activity pattern was not associated with the dietary profile, apart from fruit intake. The physical activity level was homogeneously low (median 1.58, first and last quartile cutoffs 1.54 and 1.66, respectively). There was no correlation between the physical activity level and the Food Frequency Questionnaire score (r=-.005). CONCLUSIONS: The absence of a strong relationship between the food and physical activity profiles is interpreted as a possible reflection of a dysregulation of the quality of food intake in this population with a sedentary lifestyle. PMID- 20975109 TI - The influence of 8 weeks of whey-protein and leucine supplementation on physical and cognitive performance. AB - The purpose of this study was to investigate the ability of whey-protein and leucine supplementation to enhance physical and cognitive performance and body composition. Thirty moderately fit participants completed a modified Air Force fitness test, a computer-based cognition test, and a dual-energy X-ray absorptiometry scan for body composition before and after supplementing their daily diet for 8 wk with either 19.7 g of whey protein and 6.2 g leucine (WPL) or a calorie-equivalent placebo (P). Bench-press performance increased significantly from Week 1 to Week 8 in the WPL group, whereas the increase in the P group was not significant. Push-up performance increased significantly for WPL, and P showed a nonsignificant increase. Total mass, fat-free mass, and lean body mass all increased significantly in the WPL group but showed no change in the P group. No differences were observed within or between groups for crunches, chin-ups, 3 mile-run time, or cognition. The authors conclude that supplementing with whey protein and leucine may provide an advantage to people whose performance benefits from increased upper body strength and/or lean body mass. PMID- 20975110 TI - Bone-mineral density and other features of the female athlete triad in elite endurance runners: a longitudinal and cross-sectional observational study. AB - Low bone-mineral density (BMD) is associated with menstrual dysfunction and negative energy balance in the female athlete triad. This study determines BMD in elite female endurance runners and the associations between BMD, menstrual status, disordered eating, and training volume. Forty-four elite endurance runners participated in the cross-sectional study, and 7 provided longitudinal data. Low BMD was noted in 34.2% of the athletes at the lumbar spine, and osteoporosis in 33% at the radius. In cross-sectional analysis, there were no significant relationships between BMD and the possible associations. Menstrual dysfunction, disordered eating, and low BMD were coexistent in 15.9% of athletes. Longitudinal analysis identified a positive association between the BMD reduction at the lumbar spine and training volume (p=.026). This study confirms the presence of aspects of the female athlete triad in elite female endurance athletes and notes a substantial prevalence of low BMD and osteoporosis. Normal menstrual status was not significantly associated with normal BMD, and it is the authors' practice that all elite female endurance athletes undergo dual-X-ray absorptiometry screening. The association between increased training volume, trend for menstrual dysfunction, and increased loss of lumbar BMD may support the concept that negative energy balance contributes to bone loss in athletes. PMID- 20975112 TI - A martingale framework for detecting changes in data streams by testing exchangeability. AB - In a data streaming setting, data points are observed sequentially. The data generating model may change as the data are streaming. In this paper, we propose detecting this change in data streams by testing the exchangeability property of the observed data. Our martingale approach is an efficient, nonparametric, one pass algorithm that is effective on the classification, cluster, and regression data generating models. Experimental results show the feasibility and effectiveness of the martingale methodology in detecting changes in the data generating model for time-varying data streams. Moreover, we also show that: 1) An adaptive support vector machine (SVM) utilizing the martingale methodology compares favorably against an adaptive SVM utilizing a sliding window, and 2) a multiple martingale video-shot change detector compares favorably against standard shot-change detection algorithms. PMID- 20975111 TI - Water and solute absorption from carbohydrate-electrolyte solutions in the human proximal small intestine: a review and statistical analysis. AB - The purpose of this study is to summarize water, carbohydrate (CHO), and electrolyte absorption from carbohydrate-electrolyte (CHO-E) solutions based on all of the triple-lumen-perfusion studies in humans since the early 1960s. The current statistical analysis included 30 reports from which were obtained information on water absorption, CHO absorption, total solute absorption, CHO concentration, CHO type, osmolality, sodium concentration, and sodium absorption in the different gut segments during exercise and at rest. Mean differences were assessed using independent-samples t tests. Exploratory multiple-regression analyses were conducted to create prediction models for intestinal water absorption. The factors influencing water and solute absorption are carefully evaluated and extensively discussed. The authors suggest that in the human proximal small intestine, water absorption is related to both total solute and CHO absorption; osmolality exerts various impacts on water absorption in the different segments; the multiple types of CHO in the ingested CHO-E solutions play a critical role in stimulating CHO, sodium, total solute, and water absorption; CHO concentration is negatively related to water absorption; and exercise may result in greater water absorption than rest. A potential regression model for predicting water absorption is also proposed for future research and practical application. In conclusion, water absorption in the human small intestine is influenced by osmolality, solute absorption, and the anatomical structures of gut segments. Multiple types of CHO in a CHO-E solution facilitate water absorption by stimulating CHO and solute absorption and lowering osmolality in the intestinal lumen. PMID- 20975113 TI - Minutia Cylinder-Code: a new representation and matching technique for fingerprint recognition. AB - In this paper, we introduce the Minutia Cylinder-Code (MCC): a novel representation based on 3D data structures (called cylinders), built from minutiae distances and angles. The cylinders can be created starting from a subset of the mandatory features (minutiae position and direction) defined by standards like ISO/IEC 19794-2 (2005). Thanks to the cylinder invariance, fixed length, and bit-oriented coding, some simple but very effective metrics can be defined to compute local similarities and to consolidate them into a global score. Extensive experiments over FVC2006 databases prove the superiority of MCC with respect to three well-known techniques and demonstrate the feasibility of obtaining a very effective (and interoperable) fingerprint recognition implementation for light architectures. PMID- 20975114 TI - Script recognition--a review. AB - A variety of different scripts are used in writing languages throughout the world. In a multiscript, multilingual environment, it is essential to know the script used in writing a document before an appropriate character recognition and document analysis algorithm can be chosen. In view of this, several methods for automatic script identification have been developed so far. They mainly belong to two broad categories-structure-based and visual-appearance-based techniques. This survey report gives an overview of the different script identification methodologies under each of these categories. Methods for script identification in online data and video-texts are also presented. It is noted that the research in this field is relatively thin and still more research is to be done, particularly in the case of handwritten documents. PMID- 20975115 TI - 3D face recognition using isogeodesic stripes. AB - In this paper, we present a novel approach to 3D face matching that shows high effectiveness in distinguishing facial differences between distinct individuals from differences induced by nonneutral expressions within the same individual. The approach takes into account geometrical information of the 3D face and encodes the relevant information into a compact representation in the form of a graph. Nodes of the graph represent equal width isogeodesic facial stripes. Arcs between pairs of nodes are labeled with descriptors, referred to as 3D Weighted Walkthroughs (3DWWs), that capture the mutual relative spatial displacement between all the pairs of points of the corresponding stripes. Face partitioning into isogeodesic stripes and 3DWWs together provide an approximate representation of local morphology of faces that exhibits smooth variations for changes induced by facial expressions. The graph-based representation permits very efficient matching for face recognition and is also suited to being employed for face identification in very large data sets with the support of appropriate index structures. The method obtained the best ranking at the SHREC 2008 contest for 3D face recognition. We present an extensive comparative evaluation of the performance with the FRGC v2.0 data set and the SHREC08 data set. PMID- 20975116 TI - A hierarchical visual model for video object summarization. AB - We propose a novel method for removing irrelevant frames from a video given user provided frame-level labeling for a very small number of frames. We first hypothesize a number of windows which possibly contain the object of interest, and then determine which window(s) truly contain the object of interest. Our method enjoys several favorable properties. First, compared to approaches where a single descriptor is used to describe a whole frame, each window's feature descriptor has the chance of genuinely describing the object of interest; hence it is less affected by background clutter. Second, by considering the temporal continuity of a video instead of treating frames as independent, we can hypothesize the location of the windows more accurately. Third, by infusing prior knowledge into the patch-level model, we can precisely follow the trajectory of the object of interest. This allows us to largely reduce the number of windows and hence reduce the chance of overfitting the data during learning. We demonstrate the effectiveness of the method by comparing it to several other semi supervised learning approaches on challenging video clips. PMID- 20975117 TI - Blind image deconvolution using machine learning for three-dimensional microscopy. AB - In this work, we propose a novel method for the regularization of blind deconvolution algorithms. The proposed method employs example-based machine learning techniques for modeling the space of point spread functions. During an iterative blind deconvolution process, a prior term attracts the point spread function estimates to the learned point spread function space. We demonstrate the usage of this regularizer within a Bayesian blind deconvolution framework and also integrate into the latter a method for noise reduction, thus creating a complete blind deconvolution method. The application of the proposed algorithm is demonstrated on synthetic and real-world three-dimensional images acquired by a wide-field fluorescence microscope, where the need for blind deconvolution algorithms is indispensable, yielding excellent results. PMID- 20975118 TI - Efficient high order matching. AB - We present a computational approach to high-order matching of data sets in IR(d). Those are matchings based on data affinity measures that score the matching of more than two pairs of points at a time. High-order affinities are represented by tensors and the matching is then given by a rank-one approximation of the affinity tensor and a corresponding discretization. Our approach is rigorously justified by extending Zass and Shashua's hypergraph matching to high-order spectral matching. This paves the way for a computationally efficient dual marginalization spectral matching scheme. We also show that, based on the spectral properties of random matrices, affinity tensors can be randomly sparsified while retaining the matching accuracy. Our contributions are experimentally validated by applying them to synthetic as well as real data sets. PMID- 20975119 TI - On the dual formulation of boosting algorithms. AB - We study boosting algorithms from a new perspective. We show that the Lagrange dual problems of l1-norm-regularized AdaBoost, LogitBoost, and soft-margin LPBoost with generalized hinge loss are all entropy maximization problems. By looking at the dual problems of these boosting algorithms, we show that the success of boosting algorithms can be understood in terms of maintaining a better margin distribution by maximizing margins and at the same time controlling the margin variance. We also theoretically prove that approximately, l1-norm regularized AdaBoost maximizes the average margin, instead of the minimum margin. The duality formulation also enables us to develop column-generation-based optimization algorithms, which are totally corrective. We show that they exhibit almost identical classification results to that of standard stagewise additive boosting algorithms but with much faster convergence rates. Therefore, fewer weak classifiers are needed to build the ensemble using our proposed optimization technique. PMID- 20975120 TI - Online segmentation of time series based on polynomial least-squares approximations. AB - The paper presents SwiftSeg, a novel technique for online time series segmentation and piecewise polynomial representation. The segmentation approach is based on a least-squares approximation of time series in sliding and/or growing time windows utilizing a basis of orthogonal polynomials. This allows the definition of fast update steps for the approximating polynomial, where the computational effort depends only on the degree of the approximating polynomial and not on the length of the time window. The coefficients of the orthogonal expansion of the approximating polynomial-obtained by means of the update steps can be interpreted as optimal (in the least-squares sense) estimators for average, slope, curvature, change of curvature, etc., of the signal in the time window considered. These coefficients, as well as the approximation error, may be used in a very intuitive way to define segmentation criteria. The properties of SwiftSeg are evaluated by means of some artificial and real benchmark time series. It is compared to three different offline and online techniques to assess its accuracy and runtime. It is shown that SwiftSeg-which is suitable for many data streaming applications-offers high accuracy at very low computational costs. PMID- 20975121 TI - PADS: a probabilistic activity detection framework for video data. AB - There is now a growing need to identify various kinds of activities that occur in videos. In this paper, we first present a logical language called Probabilistic Activity Description Language (PADL) in which users can specify activities of interest. We then develop a probabilistic framework which assigns to any subvideo of a given video sequence a probability that the subvideo contains the given activity, and we finally develop two fast algorithms to detect activities within this framework. OffPad finds all minimal segments of a video that contain a given activity with a probability exceeding a given threshold. In contrast, the OnPad algorithm examines a video during playout (rather than afterwards as OffPad does) and computes the probability that a given activity is occurring (even if the activity is only partially complete). Our prototype Probabilistic Activity Detection System (PADS) implements the framework and the two algorithms, building on top of existing image processing algorithms. We have conducted detailed experiments and compared our approach to four different approaches presented in the literature. We show that-for complex activity definitions-our approach outperforms all the other approaches. PMID- 20975122 TI - Point set registration: coherent point drift. AB - Point set registration is a key component in many computer vision tasks. The goal of point set registration is to assign correspondences between two sets of points and to recover the transformation that maps one point set to the other. Multiple factors, including an unknown nonrigid spatial transformation, large dimensionality of point set, noise, and outliers, make the point set registration a challenging problem. We introduce a probabilistic method, called the Coherent Point Drift (CPD) algorithm, for both rigid and nonrigid point set registration. We consider the alignment of two point sets as a probability density estimation problem. We fit the Gaussian mixture model (GMM) centroids (representing the first point set) to the data (the second point set) by maximizing the likelihood. We force the GMM centroids to move coherently as a group to preserve the topological structure of the point sets. In the rigid case, we impose the coherence constraint by reparameterization of GMM centroid locations with rigid parameters and derive a closed form solution of the maximization step of the EM algorithm in arbitrary dimensions. In the nonrigid case, we impose the coherence constraint by regularizing the displacement field and using the variational calculus to derive the optimal transformation. We also introduce a fast algorithm that reduces the method computation complexity to linear. We test the CPD algorithm for both rigid and nonrigid transformations in the presence of noise, outliers, and missing points, where CPD shows accurate results and outperforms current state-of-the-art methods. PMID- 20975123 TI - Vignette and exposure calibration and compensation. AB - We discuss calibration and removal of "vignetting" (radial falloff) and exposure (gain) variations from sequences of images. Even when the response curve is known, spatially varying ambiguities prevent us from recovering the vignetting, exposure, and scene radiances uniquely. However, the vignetting and exposure variations can nonetheless be removed from the images without resolving these ambiguities or the previously known scale and gamma ambiguities. Applications include panoramic image mosaics, photometry for material reconstruction, image based rendering, and preprocessing for correlation-based vision algorithms. PMID- 20975124 TI - Necklace maps. AB - Statistical data associated with geographic regions is nowadays globally available in large amounts and hence automated methods to visually display these data are in high demand. There are several well-established thematic map types for quantitative data on the ratio-scale associated with regions: choropleth maps, cartograms, and proportional symbol maps. However, all these maps suffer from limitations, especially if large data values are associated with small regions. To overcome these limitations, we propose a novel type of quantitative thematic map, the necklace map. In a necklace map, the regions of the underlying two-dimensional map are projected onto intervals on a one-dimensional curve (the necklace) that surrounds the map regions. Symbols are scaled such that their area corresponds to the data of their region and placed without overlap inside the corresponding interval on the necklace. Necklace maps appear clear and uncluttered and allow for comparatively large symbol sizes. They visualize data sets well which are not proportional to region sizes. The linear ordering of the symbols along the necklace facilitates an easy comparison of symbol sizes. One map can contain several nested or disjoint necklaces to visualize clustered data. The advantages of necklace maps come at a price: the association between a symbol and its region is weaker than with other types of maps. Interactivity can help to strengthen this association if necessary. We present an automated approach to generate necklace maps which allows the user to interactively control the final symbol placement. We validate our approach with experiments using various data sets and maps. PMID- 20975125 TI - Rethinking map legends with visualization. AB - This design paper presents new guidance for creating map legends in a dynamic environment. Our contribution is a set of guidelines for legend design in a visualization context and a series of illustrative themes through which they may be expressed. These are demonstrated in an applications context through interactive software prototypes. The guidelines are derived from cartographic literature and in liaison with EDINA who provide digital mapping services for UK tertiary education. They enhance approaches to legend design that have evolved for static media with visualization by considering: selection, layout, symbols, position, dynamism and design and process. Broad visualization legend themes include: The Ground Truth Legend, The Legend as Statistical Graphic and The Map is the Legend. Together, these concepts enable us to augment legends with dynamic properties that address specific needs, rethink their nature and role and contribute to a wider re-evaluation of maps as artifacts of usage rather than statements of fact. EDINA has acquired funding to enhance their clients with visualization legends that use these concepts as a consequence of this work. The guidance applies to the design of a wide range of legends and keys used in cartography and information visualization. PMID- 20975126 TI - SignalLens: Focus+Context applied to electronic time series. AB - Electronic test and measurement systems are becoming increasingly sophisticated in order to match the increased complexity and ultra-high speed of the devices under test. A key feature in many such instruments is a vastly increased capacity for storage of digital signals. Storage of 10(9) time points or more is now possible. At the same time, the typical screens on such measurement devices are relatively small. Therefore, these instruments can only render an extremely small fraction of the complete signal at any time. SignalLens uses a Focus+Context approach to provide a means of navigating to and inspecting low-level signal details in the context of the entire signal trace. This approach provides a compact visualization suitable for embedding into the small displays typically provided by electronic measurement instruments. We further augment this display with computed tracks which display time-aligned computed properties of the signal. By combining and filtering these computed tracks it is possible to easily and quickly find computationally detected features in the data which are often obscured by the visual compression required to render the large data sets on a small screen. Further, these tracks can be viewed in the context of the entire signal trace as well as visible high-level signal features. Several examples using real-world electronic measurement data are presented, which demonstrate typical use cases and the effectiveness of the design. PMID- 20975128 TI - Gremlin: an interactive visualization model for analyzing genomic rearrangements. AB - In this work we present, apply, and evaluate a novel, interactive visualization model for comparative analysis of structural variants and rearrangements in human and cancer genomes, with emphasis on data integration and uncertainty visualization. To support both global trend analysis and local feature detection, this model enables explorations continuously scaled from the high-level, complete genome perspective, down to the low-level, structural rearrangement view, while preserving global context at all times. We have implemented these techniques in Gremlin, a genomic rearrangement explorer with multi-scale, linked interactions, which we apply to four human cancer genome data sets for evaluation. Using an insight-based evaluation methodology, we compare Gremlin to Circos, the state-of the-art in genomic rearrangement visualization, through a small user study with computational biologists working in rearrangement analysis. Results from user study evaluations demonstrate that this visualization model enables more total insights, more insights per minute, and more complex insights than the current state-of-the-art for visual analysis and exploration of genome rearrangements. PMID- 20975127 TI - MulteeSum: a tool for comparative spatial and temporal gene expression data. AB - Cells in an organism share the same genetic information in their DNA, but have very different forms and behavior because of the selective expression of subsets of their genes. The widely used approach of measuring gene expression over time from a tissue sample using techniques such as microarrays or sequencing do not provide information about the spatial position within the tissue where these genes are expressed. In contrast, we are working with biologists who use techniques that measure gene expression in every individual cell of entire fruitfly embryos over an hour of their development, and do so for multiple closely-related subspecies of Drosophila. These scientists are faced with the challenge of integrating temporal gene expression data with the spatial location of cells and, moreover, comparing this data across multiple related species. We have worked with these biologists over the past two years to develop MulteeSum, a visualization system that supports inspection and curation of data sets showing gene expression over time, in conjunction with the spatial location of the cells where the genes are expressed--it is the first tool to support comparisons across multiple such data sets. MulteeSum is part of a general and flexible framework we developed with our collaborators that is built around multiple summaries for each cell, allowing the biologists to explore the results of computations that mix spatial information, gene expression measurements over time, and data from multiple related species or organisms. We justify our design decisions based on specific descriptions of the analysis needs of our collaborators, and provide anecdotal evidence of the efficacy of MulteeSum through a series of case studies. PMID- 20975129 TI - Graphical perception of multiple time series. AB - Line graphs have been the visualization of choice for temporal data ever since the days of William Playfair (1759-1823), but realistic temporal analysis tasks often include multiple simultaneous time series. In this work, we explore user performance for comparison, slope, and discrimination tasks for different line graph techniques involving multiple time series. Our results show that techniques that create separate charts for each time series--such as small multiples and horizon graphs--are generally more efficient for comparisons across time series with a large visual span. On the other hand, shared-space techniques--like standard line graphs--are typically more efficient for comparisons over smaller visual spans where the impact of overlap and clutter is reduced. PMID- 20975130 TI - Uncovering strengths and weaknesses of radial visualizations--an empirical approach. AB - Radial visualizations play an important role in the information visualization community. But the decision to choose a radial coordinate system is rather based on intuition than on scientific foundations. The empirical approach presented in this paper aims at uncovering strengths and weaknesses of radial visualizations by comparing them to equivalent ones in Cartesian coordinate systems. We identified memorizing positions of visual elements as a generic task when working with visualizations. A first study with 674 participants provides a broad data spectrum for exploring differences between the two visualization types. A second, complementing study with fewer participants focuses on further questions raised by the first study. Our findings document that Cartesian visualizations tend to outperform their radial counterparts especially with respect to answer times. Nonetheless, radial visualization seem to be more appropriate for focusing on a particular data dimension. PMID- 20975131 TI - How information visualization novices construct visualizations. AB - It remains challenging for information visualization novices to rapidly construct visualizations during exploratory data analysis. We conducted an exploratory laboratory study in which information visualization novices explored fictitious sales data by communicating visualization specifications to a human mediator, who rapidly constructed the visualizations using commercial visualization software. We found that three activities were central to the iterative visualization construction process: data attribute selection, visual template selection, and visual mapping specification. The major barriers faced by the participants were translating questions into data attributes, designing visual mappings, and interpreting the visualizations. Partial specification was common, and the participants used simple heuristics and preferred visualizations they were already familiar with, such as bar, line and pie charts. We derived abstract models from our observations that describe barriers in the data exploration process and uncovered how information visualization novices think about visualization specifications. Our findings support the need for tools that suggest potential visualizations and support iterative refinement, that provide explanations and help with learning, and that are tightly integrated into tool support for the overall visual analytics process. PMID- 20975132 TI - eSeeTrack--visualizing sequential fixation patterns. AB - We introduce eSeeTrack, an eye-tracking visualization prototype that facilitates exploration and comparison of sequential gaze orderings in a static or a dynamic scene. It extends current eye-tracking data visualizations by extracting patterns of sequential gaze orderings, displaying these patterns in a way that does not depend on the number of fixations on a scene, and enabling users to compare patterns from two or more sets of eye-gaze data. Extracting such patterns was very difficult with previous visualization techniques. eSeeTrack combines a timeline and a tree-structured visual representation to embody three aspects of eye-tracking data that users are interested in: duration, frequency and orderings of fixations. We demonstrate the usefulness of eSeeTrack via two case studies on surgical simulation and retail store chain data. We found that eSeeTrack allows ordering of fixations to be rapidly queried, explored and compared. Furthermore, our tool provides an effective and efficient mechanism to determine pattern outliers. This approach can be effective for behavior analysis in a variety of domains that are described at the end of this paper. PMID- 20975133 TI - Evaluating the impact of task demands and block resolution on the effectiveness of pixel-based visualization. AB - Pixel-based visualization is a popular method of conveying large amounts of numerical data graphically. Application scenarios include business and finance, bioinformatics and remote sensing. In this work, we examined how the usability of such visual representations varied across different tasks and block resolutions. The main stimuli consisted of temporal pixel-based visualization with a white-red color map, simulating monthly temperature variation over a six-year period. In the first study, we included 5 separate tasks to exert different perceptual loads. We found that performance varied considerably as a function of task, ranging from 75% correct in low-load tasks to below 40% in high-load tasks. There was a small but consistent effect of resolution, with the uniform patch improving performance by around 6% relative to higher block resolution. In the second user study, we focused on a high-load task for evaluating month-to-month changes across different regions of the temperature range. We tested both CIE L*u*v* and RGB color spaces. We found that the nature of the change-evaluation errors related directly to the distance between the compared regions in the mapped color space. We were able to reduce such errors by using multiple color bands for the same data range. In a final study, we examined more fully the influence of block resolution on performance, and found block resolution had a limited impact on the effectiveness of pixel-based visualization. PMID- 20975134 TI - Graphical inference for Infovis. AB - How do we know if what we see is really there? When visualizing data, how do we avoid falling into the trap of apophenia where we see patterns in random noise? Traditionally, infovis has been concerned with discovering new relationships, and statistics with preventing spurious relationships from being reported. We pull these opposing poles closer with two new techniques for rigorous statistical inference of visual discoveries. The "Rorschach" helps the analyst calibrate their understanding of uncertainty and "line-up" provides a protocol for assessing the significance of visual discoveries, protecting against the discovery of spurious structure. PMID- 20975135 TI - Matching visual saliency to confidence in plots of uncertain data. AB - Conveying data uncertainty in visualizations is crucial for preventing viewers from drawing conclusions based on untrustworthy data points. This paper proposes a methodology for efficiently generating density plots of uncertain multivariate data sets that draws viewers to preattentively identify values of high certainty while not calling attention to uncertain values. We demonstrate how to augment scatter plots and parallel coordinates plots to incorporate statistically modeled uncertainty and show how to integrate them with existing multivariate analysis techniques, including outlier detection and interactive brushing. Computing high quality density plots can be expensive for large data sets, so we also describe a probabilistic plotting technique that summarizes the data without requiring explicit density plot computation. These techniques have been useful for identifying brain tumors in multivariate magnetic resonance spectroscopy data and we describe how to extend them to visualize ensemble data sets. PMID- 20975136 TI - Perceptual guidelines for creating rectangular treemaps. AB - Treemaps are space-filling visualizations that make efficient use of limited display space to depict large amounts of hierarchical data. Creating perceptually effective treemaps requires carefully managing a number of design parameters including the aspect ratio and luminance of rectangles. Moreover, treemaps encode values using area, which has been found to be less accurate than judgments of other visual encodings, such as length. We conduct a series of controlled experiments aimed at producing a set of design guidelines for creating effective rectangular treemaps. We find no evidence that luminance affects area judgments, but observe that aspect ratio does have an effect. Specifically, we find that the accuracy of area comparisons suffers when the compared rectangles have extreme aspect ratios or when both are squares. Contrary to common assumptions, the optimal distribution of rectangle aspect ratios within a treemap should include non-squares, but should avoid extremes. We then compare treemaps with hierarchical bar chart displays to identify the data densities at which length encoded bar charts become less effective than area-encoded treemaps. We report the transition points at which treemaps exhibit judgment accuracy on par with bar charts for both leaf and non-leaf tree nodes. We also find that even at relatively low data densities treemaps result in faster comparisons than bar charts. Based on these results, we present a set of guidelines for the effective use of treemaps and suggest alternate approaches for treemap layout. PMID- 20975137 TI - Mental models, visual reasoning and interaction in information visualization: a top-down perspective. AB - Although previous research has suggested that examining the interplay between internal and external representations can benefit our understanding of the role of information visualization (InfoVis) in human cognitive activities, there has been little work detailing the nature of internal representations, the relationship between internal and external representations and how interaction is related to these representations. In this paper, we identify and illustrate a specific kind of internal representation, mental models, and outline the high level relationships between mental models and external visualizations. We present a top-down perspective of reasoning as model construction and simulation, and discuss the role of visualization in model based reasoning. From this perspective, interaction can be understood as active modeling for three primary purposes: external anchoring, information foraging, and cognitive offloading. Finally we discuss the implications of our approach for design, evaluation and theory development. PMID- 20975138 TI - Laws of attraction: from perceptual forces to conceptual similarity. AB - Many of the pressing questions in information visualization deal with how exactly a user reads a collection of visual marks as information about relationships between entities. Previous research has suggested that people see parts of a visualization as objects, and may metaphorically interpret apparent physical relationships between these objects as suggestive of data relationships. We explored this hypothesis in detail in a series of user experiments. Inspired by the concept of implied dynamics in psychology, we first studied whether perceived gravity acting on a mark in a scatterplot can lead to errors in a participant's recall of the mark's position. The results of this study suggested that such position errors exist, but may be more strongly influenced by attraction between marks. We hypothesized that such apparent attraction may be influenced by elements used to suggest relationship between objects, such as connecting lines, grouping elements, and visual similarity. We further studied what visual elements are most likely to cause this attraction effect, and whether the elements that best predicted attraction errors were also those which suggested conceptual relationships most strongly. Our findings show a correlation between attraction errors and intuitions about relatedness, pointing towards a possible mechanism by which the perception of visual marks becomes an interpretation of data relationships. PMID- 20975139 TI - Pargnostics: screen-space metrics for parallel coordinates. AB - Interactive visualization requires the translation of data into a screen space of limited resolution. While currently ignored by most visualization models, this translation entails a loss of information and the introduction of a number of artifacts that can be useful, (e.g., aggregation, structures) or distracting (e.g., over-plotting, clutter) for the analysis. This phenomenon is observed in parallel coordinates, where overlapping lines between adjacent axes form distinct patterns, representing the relation between variables they connect. However, even for a small number of dimensions, the challenge is to effectively convey the relationships for all combinations of dimensions. The size of the dataset and a large number of dimensions only add to the complexity of this problem. To address these issues, we propose Pargnostics, parallel coordinates diagnostics, a model based on screen-space metrics that quantify the different visual structures. Pargnostics metrics are calculated for pairs of axes and take into account the resolution of the display as well as potential axis inversions. Metrics include the number of line crossings, crossing angles, convergence, overplotting, etc. To construct a visualization view, the user can pick from a ranked display showing pairs of coordinate axes and the structures between them, or examine all possible combinations of axes at once in a matrix display. Picking the best axes layout is an NP-complete problem in general, but we provide a way of automatically optimizing the display according to the user’s preferences based on our metrics and model. PMID- 20975140 TI - Comparative analysis of multidimensional, quantitative data. AB - When analyzing multidimensional, quantitative data, the comparison of two or more groups of dimensions is a common task. Typical sources of such data are experiments in biology, physics or engineering, which are conducted in different configurations and use replicates to ensure statistically significant results. One common way to analyze this data is to filter it using statistical methods and then run clustering algorithms to group similar values. The clustering results can be visualized using heat maps, which show differences between groups as changes in color. However, in cases where groups of dimensions have an a priori meaning, it is not desirable to cluster all dimensions combined, since a clustering algorithm can fragment continuous blocks of records. Furthermore, identifying relevant elements in heat maps becomes more difficult as the number of dimensions increases. To aid in such situations, we have developed Matchmaker, a visualization technique that allows researchers to arbitrarily arrange and compare multiple groups of dimensions at the same time. We create separate groups of dimensions which can be clustered individually, and place them in an arrangement of heat maps reminiscent of parallel coordinates. To identify relations, we render bundled curves and ribbons between related records in different groups. We then allow interactive drill-downs using enlarged detail views of the data, which enable in-depth comparisons of clusters between groups. To reduce visual clutter, we minimize crossings between the views. This paper concludes with two case studies. The first demonstrates the value of our technique for the comparison of clustering algorithms. In the second, biologists use our system to investigate why certain strains of mice develop liver disease while others remain healthy, informally showing the efficacy of our system when analyzing multidimensional data containing distinct groups of dimensions. PMID- 20975141 TI - An extension of Wilkinson's algorithm for positioning tick labels on axes. AB - The non-data components of a visualization, such as axes and legends, can often be just as important as the data itself. They provide contextual information essential to interpreting the data. In this paper, we describe an automated system for choosing positions and labels for axis tick marks. Our system extends Wilkinson’s optimization-based labeling approach to create a more robust, full-featured axis labeler. We define an expanded space of axis labelings by automatically generating additional nice numbers as needed and by permitting the extreme labels to occur inside the data range. These changes provide flexibility in problematic cases, without degrading quality elsewhere. We also propose an additional optimization criterion, legibility, which allows us to simultaneously optimize over label formatting, font size, and orientation. To solve this revised optimization problem, we describe the optimization function and an efficient search algorithm. Finally, we compare our method to previous work using both quantitative and qualitative metrics. This paper is a good example of how ideas from automated graphic design can be applied to information visualization. PMID- 20975142 TI - Stacking graphic elements to avoid over-plotting. AB - An ongoing challenge for information visualization is how to deal with over plotting forced by ties or the relatively limited visual field of display devices. A popular solution is to represent local data density with area (bubble plots, treemaps), color (heatmaps), or aggregation (histograms, kernel densities, pixel displays). All of these methods have at least one of three deficiencies:1) magnitude judgments are biased because area and color have convex downward perceptual functions, 2) area, hue, and brightness have relatively restricted ranges of perceptual intensity compared to length representations, and/or 3) it is difficult to brush or link to individual cases when viewing aggregations. In this paper, we introduce a new technique for visualizing and interacting with datasets that preserves density information by stacking overlapping cases. The overlapping data can be points or lines or other geometric elements, depending on the type of plot. We show real-dataset applications of this stacking paradigm and compare them to other techniques that deal with over-plotting in high-dimensional displays. PMID- 20975143 TI - Visualization of diversity in large multivariate data sets. AB - Understanding the diversity of a set of multivariate objects is an important problem in many domains, including ecology, college admissions, investing, machine learning, and others. However, to date, very little work has been done to help users achieve this kind of understanding. Visual representation is especially appealing for this task because it offers the potential to allow users to efficiently observe the objects of interest in a direct and holistic way. Thus, in this paper, we attempt to formalize the problem of visualizing the diversity of a large (more than 1000 objects), multivariate (more than 5 attributes) data set as one worth deeper investigation by the information visualization community. In doing so, we contribute a precise definition of diversity, a set of requirements for diversity visualizations based on this definition, and a formal user study design intended to evaluate the capacity of a visual representation for communicating diversity information. Our primary contribution, however, is a visual representation, called the Diversity Map, for visualizing diversity. An evaluation of the Diversity Map using our study design shows that users can judge elements of diversity consistently and as or more accurately than when using the only other representation specifically designed to visualize diversity. PMID- 20975144 TI - PedVis: a structured, space-efficient technique for pedigree visualization. AB - Public genealogical databases are becoming increasingly populated with historical data and records of the current population's ancestors. As this increasing amount of available information is used to link individuals to their ancestors, the resulting trees become deeper and more dense, which justifies the need for using organized, space-efficient layouts to display the data. Existing layouts are often only able to show a small subset of the data at a time. As a result, it is easy to become lost when navigating through the data or to lose sight of the overall tree structure. On the contrary, leaving space for unknown ancestors allows one to better understand the tree's structure, but leaving this space becomes expensive and allows fewer generations to be displayed at a time. In this work, we propose that the H-tree based layout be used in genealogical software to display ancestral trees. We will show that this layout presents an increase in the number of displayable generations, provides a nicely arranged, symmetrical, intuitive and organized fractal structure, increases the user's ability to understand and navigate through the data, and accounts for the visualization requirements necessary for displaying such trees. Finally, user-study results indicate potential for user acceptance of the new layout. PMID- 20975145 TI - GeneaQuilts: a system for exploring large genealogies. AB - GeneaQuilts is a new visualization technique for representing large genealogies of up to several thousand individuals. The visualization takes the form of a diagonally-filled matrix, where rows are individuals and columns are nuclear families. After identifying the major tasks performed in genealogical research and the limits of current software, we present an interactive genealogy exploration system based on GeneaQuilts. The system includes an overview, a timeline, search and filtering components, and a new interaction technique called Bring & Slide that allows fluid navigation in very large genealogies. We report on preliminary feedback from domain experts and show how our system supports a number of their tasks. PMID- 20975146 TI - Visualization of graph products. AB - Graphs are a versatile structure and abstraction for binary relationships between objects. To gain insight into such relationships, their corresponding graph can be visualized. In the past, many classes of graphs have been defined, e.g. trees, planar graphs, directed acyclic graphs, and visualization algorithms were proposed for these classes. Although many graphs may only be classified as "general" graphs, they can contain substructures that belong to a certain class. Archambault proposed the TopoLayout framework: rather than draw any arbitrary graph using one method, split the graph into components that are homogeneous with respect to one graph class and then draw each component with an algorithm best suited for this class. Graph products constitute a class that arises frequently in graph theory, but for which no visualization algorithm has been proposed until now. In this paper, we present an algorithm for drawing graph products and the aesthetic criterion graph product's drawings are subject to. We show that the popular High-Dimensional Embedder approach applied to cartesian products already respects this aestetic criterion, but has disadvantages. We also present how our method is integrated as a new component into the TopoLayout framework. Our implementation is used for further research of graph products in a biological context. PMID- 20975147 TI - Untangling euler diagrams. AB - In many common data analysis scenarios the data elements are logically grouped into sets. Venn and Euler style diagrams are a common visual representation of such set membership where the data elements are represented by labels or glyphs and sets are indicated by boundaries surrounding their members. Generating such diagrams automatically such that set regions do not intersect unless the corresponding sets have a non-empty intersection is a difficult problem. Further, it may be impossible in some cases if regions are required to be continuous and convex. Several approaches exist to draw such set regions using more complex shapes, however, the resulting diagrams can be difficult to interpret. In this paper we present two novel approaches for simplifying a complex collection of intersecting sets into a strict hierarchy that can be more easily automatically arranged and drawn (Figure 1). In the first approach, we use compact rectangular shapes for drawing each set, attempting to improve the readability of the set intersections. In the second approach, we avoid drawing intersecting set regions by duplicating elements belonging to multiple sets. We compared both of our techniques to the traditional non-convex region technique using five readability tasks. Our results show that the compact rectangular shapes technique was often preferred by experimental subjects even though the use of duplications dramatically improves the accuracy and performance time for most of our tasks. In addition to general set representation our techniques are also applicable to visualization of networks with intersecting clusters of nodes. PMID- 20975148 TI - The FlowVizMenu and parallel scatterplot matrix: hybrid multidimensional visualizations for network exploration. AB - A standard approach for visualizing multivariate networks is to use one or more multidimensional views (for example, scatterplots) for selecting nodes by various metrics, possibly coordinated with a node-link view of the network. In this paper, we present three novel approaches for achieving a tighter integration of these views through hybrid techniques for multidimensional visualization, graph selection and layout. First, we present the FlowVizMenu, a radial menu containing a scatterplot that can be popped up transiently and manipulated with rapid, fluid gestures to select and modify the axes of its scatterplot. Second, the FlowVizMenu can be used to steer an attribute-driven layout of the network, causing certain nodes of a node-link diagram to move toward their corresponding positions in a scatterplot while others can be positioned manually or by force directed layout. Third, we describe a novel hybrid approach that combines a scatterplot matrix (SPLOM) and parallel coordinates called the Parallel Scatterplot Matrix (P-SPLOM), which can be used to visualize and select features within the network. We also describe a novel arrangement of scatterplots called the Scatterplot Staircase (SPLOS) that requires less space than a traditional scatterplot matrix. Initial user feedback is reported. PMID- 20975149 TI - OpinionSeer: interactive visualization of hotel customer feedback. AB - The rapid development of Web technology has resulted in an increasing number of hotel customers sharing their opinions on the hotel services. Effective visual analysis of online customer opinions is needed, as it has a significant impact on building a successful business. In this paper, we present OpinionSeer, an interactive visualization system that could visually analyze a large collection of online hotel customer reviews. The system is built on a new visualization centric opinion mining technique that considers uncertainty for faithfully modeling and analyzing customer opinions. A new visual representation is developed to convey customer opinions by augmenting well-established scatterplots and radial visualization. To provide multiple-level exploration, we introduce subjective logic to handle and organize subjective opinions with degrees of uncertainty. Several case studies illustrate the effectiveness and usefulness of OpinionSeer on analyzing relationships among multiple data dimensions and comparing opinions of different groups. Aside from data on hotel customer feedback, OpinionSeer could also be applied to visually analyze customer opinions on other products or services. PMID- 20975150 TI - The streams of our lives: visualizing listening histories in context. AB - The choices we take when listening to music are expressions of our personal taste and character. Storing and accessing our listening histories is trivial due to services like Last.fm, but learning from them and understanding them is not. Existing solutions operate at a very abstract level and only produce statistics. By applying techniques from information visualization to this problem, we were able to provide average people with a detailed and powerful tool for accessing their own musical past. LastHistory is an interactive visualization for displaying music listening histories, along with contextual information from personal photos and calendar entries. Its two main user tasks are (1) analysis, with an emphasis on temporal patterns and hypotheses related to musical genre and sequences, and (2) reminiscing, where listening histories and context represent part of one's past. In this design study paper we give an overview of the field of music listening histories and explain their unique characteristics as a type of personal data. We then describe the design rationale, data and view transformations of LastHistory and present the results from both a lab- and a large-scale online study. We also put listening histories in contrast to other lifelogging data. The resonant and enthusiastic feedback that we received from average users shows a need for making their personal data accessible. We hope to stimulate such developments through this research. PMID- 20975151 TI - A visual backchannel for large-scale events. AB - We introduce the concept of a Visual Backchannel as a novel way of following and exploring online conversations about large-scale events. Microblogging communities, such as Twitter, are increasingly used as digital backchannels for timely exchange of brief comments and impressions during political speeches, sport competitions, natural disasters, and other large events. Currently, shared updates are typically displayed in the form of a simple list, making it difficult to get an overview of the fast-paced discussions as it happens in the moment and how it evolves over time. In contrast, our Visual Backchannel design provides an evolving, interactive, and multi-faceted visual overview of large-scale ongoing conversations on Twitter. To visualize a continuously updating information stream, we include visual saliency for what is happening now and what has just happened, set in the context of the evolving conversation. As part of a fully web based coordinated-view system we introduce Topic Streams, a temporally adjustable stacked graph visualizing topics over time, a People Spiral representing participants and their activity, and an Image Cloud encoding the popularity of event photos by size. Together with a post listing, these mutually linked views support cross-filtering along topics, participants, and time ranges. We discuss our design considerations, in particular with respect to evolving visualizations of dynamically changing data. Initial feedback indicates significant interest and suggests several unanticipated uses. PMID- 20975152 TI - Narrative visualization: telling stories with data. AB - Data visualization is regularly promoted for its ability to reveal stories within data, yet these “data stories” differ in important ways from traditional forms of storytelling. Storytellers, especially online journalists, have increasingly been integrating visualizations into their narratives, in some cases allowing the visualization to function in place of a written story. In this paper, we systematically review the design space of this emerging class of visualizations. Drawing on case studies from news media to visualization research, we identify distinct genres of narrative visualization. We characterize these design differences, together with interactivity and messaging, in terms of the balance between the narrative flow intended by the author (imposed by graphical elements and the interface) and story discovery on the part of the reader (often through interactive exploration). Our framework suggests design strategies for narrative visualization, including promising under-explored approaches to journalistic storytelling and educational media. PMID- 20975153 TI - Declarative language design for interactive visualization. AB - We investigate the design of declarative, domain-specific languages for constructing interactive visualizations. By separating specification from execution, declarative languages can simplify development, enable unobtrusive optimization, and support retargeting across platforms. We describe the design of the Protovis specification language and its implementation within an object oriented, statically-typed programming language (Java). We demonstrate how to support rich visualizations without requiring a toolkit-specific data model and extend Protovis to enable declarative specification of animated transitions. To support cross-platform deployment, we introduce rendering and event-handling infrastructures decoupled from the runtime platform, letting designers retarget visualization specifications (e.g., from desktop to mobile phone) with reduced effort. We also explore optimizations such as runtime compilation of visualization specifications, parallelized execution, and hardware-accelerated rendering. We present benchmark studies measuring the performance gains provided by these optimizations and compare performance to existing Java-based visualization tools, demonstrating scalability improvements exceeding an order of magnitude. PMID- 20975154 TI - Visualizations everywhere: a multiplatform infrastructure for linked visualizations. AB - In order to use new visualizations, most toolkits require application developers to rebuild their applications and distribute new versions to users. The WebCharts Framework take a different approach by hosting JavaScript from within an application and providing a standard data and events interchange. In this way, applications can be extended dynamically, with a wide variety of visualizations. We discuss the benefits of this architectural approach, contrast it to existing techniques, and give a variety of examples and extensions of the basic system. PMID- 20975155 TI - behaviorism: a framework for dynamic data visualization. AB - While a number of information visualization software frameworks exist, creating new visualizations, especially those that involve novel visualization metaphors, interaction techniques, data analysis strategies, and specialized rendering algorithms, is still often a difficult process. To facilitate the creation of novel visualizations we present a new software framework, behaviorism, which provides a wide range of flexibility when working with dynamic information on visual, temporal, and ontological levels, but at the same time providing appropriate abstractions which allow developers to create prototypes quickly which can then easily be turned into robust systems. The core of the framework is a set of three interconnected graphs, each with associated operators: a scene graph for high-performance 3D rendering, a data graph for different layers of semantically linked heterogeneous data, and a timing graph for sophisticated control of scheduling, interaction, and animation. In particular, the timing graph provides a unified system to add behaviors to both data and visual elements, as well as to the behaviors themselves. To evaluate the framework we look briefly at three different projects all of which required novel visualizations in different domains, and all of which worked with dynamic data in different ways: an interactive ecological simulation, an information art installation, and an information visualization technique. PMID- 20975156 TI - FacetAtlas: multifaceted visualization for rich text corpora. AB - Documents in rich text corpora usually contain multiple facets of information. For example, an article about a specific disease often consists of different facets such as symptom, treatment, cause, diagnosis, prognosis, and prevention. Thus, documents may have different relations based on different facets. Powerful search tools have been developed to help users locate lists of individual documents that are most related to specific keywords. However, there is a lack of effective analysis tools that reveal the multifaceted relations of documents within or cross the document clusters. In this paper, we present FacetAtlas, a multifaceted visualization technique for visually analyzing rich text corpora. FacetAtlas combines search technology with advanced visual analytical tools to convey both global and local patterns simultaneously. We describe several unique aspects of FacetAtlas, including (1) node cliques and multifaceted edges, (2) an optimized density map, and (3) automated opacity pattern enhancement for highlighting visual patterns, (4) interactive context switch between facets. In addition, we demonstrate the power of FacetAtlas through a case study that targets patient education in the health care domain. Our evaluation shows the benefits of this work, especially in support of complex multifaceted data analysis. PMID- 20975157 TI - SparkClouds: visualizing trends in tag clouds. AB - Tag clouds have proliferated over the web over the last decade. They provide a visual summary of a collection of texts by visually depicting the tag frequency by font size. In use, tag clouds can evolve as the associated data source changes over time. Interesting discussions around tag clouds often include a series of tag clouds and consider how they evolve over time. However, since tag clouds do not explicitly represent trends or support comparisons, the cognitive demands placed on the person for perceiving trends in multiple tag clouds are high. In this paper, we introduce SparkClouds, which integrate sparklines into a tag cloud to convey trends between multiple tag clouds. We present results from a controlled study that compares SparkClouds with two traditional trend visualizations-multiple line graphs and stacked bar charts-as well as Parallel Tag Clouds. Results show that SparkClouds ability to show trends compares favourably to the alternative visualizations. PMID- 20975158 TI - ManiWordle: providing flexible control over Wordle. AB - Among the multifarious tag-clouding techniques, Wordle stands out to the community by providing an aesthetic layout, eliciting the emergence of the participatory culture and usage of tag-clouding in the artistic creations. In this paper, we introduce ManiWordle, a Wordle-based visualization tool that revamps interactions with the layout by supporting custom manipulations. ManiWordle allows people to manipulate typography, color, and composition not only for the layout as a whole, but also for the individual words, enabling them to have better control over the layout result. We first describe our design rationale along with the interaction techniques for tweaking the layout. We then present the results both from the preliminary usability study and from the comparative study between ManiWordle and Wordle. The results suggest that ManiWordle provides higher user satisfaction and an efficient method of creating the desired "art work," harnessing the power behind the ever-increasing popularity of Wordle. PMID- 20975159 TI - On the fractal dimension of isosurfaces. AB - A (3D) scalar grid is a regular n1 x n2 x n3 grid of vertices where each vertex v is associated with some scalar value sv. Applying trilinear interpolation, the scalar grid determines a scalar function g where g(v) = sv for each grid vertex v. An isosurface with isovalue sigma is a triangular mesh which approximates the level set g(-1)(sigma). The fractal dimension of an isosurface represents the growth ;in the isosurface as the number of grid cubes increases. We define and discuss the fractal isosurface dimension. Plotting the fractal ;dimension as a function of the isovalues in a data set provides information about the isosurfaces determined by the data set. We present statistics on the average fractal dimension of 60 publicly available benchmark data sets. We also show the fractal dimension is highly correlated with topological noise in the benchmark data sets, measuring the topological noise by the number of connected components in the isosurface. Lastly, we present a formula predicting the fractal dimension as a function of noise and validate the formula with experimental results. PMID- 20975160 TI - An information-theoretic framework for visualization. AB - In this paper, we examine whether or not information theory can be one of the theoretic frameworks for visualization. We formulate concepts and measurements for qualifying visual information. We illustrate these concepts with examples that manifest the intrinsic and implicit use of information theory in many existing visualization techniques. We outline the broad correlation between visualization and the major applications of information theory, while pointing out the difference in emphasis and some technical gaps. Our study provides compelling evidence that information theory can explain a significant number of phenomena or events in visualization, while no example has been found which is fundamentally in conflict with information theory. We also notice that the emphasis of some traditional applications of information theory, such as data compression or data communication, may not always suit visualization, as the former typically focuses on the efficient throughput of a communication channel, whilst the latter focuses on the effectiveness in aiding the perceptual and cognitive process for data understanding and knowledge discovery. These findings suggest that further theoretic developments are necessary for adopting and adapting information theory for visualization. PMID- 20975161 TI - An information-theoretic framework for flow visualization. AB - The process of visualization can be seen as a visual communication channel where the input to the channel is the raw data, and the output is the result of a visualization algorithm. From this point of view, we can evaluate the effectiveness of visualization by measuring how much information in the original data is being communicated through the visual communication channel. In this paper, we present an information-theoretic framework for flow visualization with a special focus on streamline generation. In our framework, a vector field is modeled as a distribution of directions from which Shannon's entropy is used to measure the information content in the field. The effectiveness of the streamlines displayed in visualization can be measured by first constructing a new distribution of vectors derived from the existing streamlines, and then comparing this distribution with that of the original data set using the conditional entropy. The conditional entropy between these two distributions indicates how much information in the original data remains hidden after the selected streamlines are displayed. The quality of the visualization can be improved by progressively introducing new streamlines until the conditional entropy converges to a small value. We describe the key components of our framework with detailed analysis, and show that the framework can effectively visualize 2D and 3D flow data. PMID- 20975162 TI - Streak lines as tangent curves of a derived vector field. AB - Characteristic curves of vector fields include stream, path, and streak lines. Stream and path lines can be obtained by a simple vector field integration of an autonomous ODE system, i.e., they can be described as tangent curves of a vector field. This facilitates their mathematical analysis including the extraction of core lines around which stream or path lines exhibit swirling motion, or the computation of their curvature for every point in the domain without actually integrating them. Such a description of streak lines is not yet available, which excludes them from most of the feature extraction and analysis tools that have been developed in our community. In this paper, we develop the first description of streak lines as tangent curves of a derived vector field - the streak line vector field - and show how it can be computed from the spatial and temporal gradients of the flow map, i.e., a dense path line integration is required. We demonstrate the high accuracy of our approach by comparing it to solutions where the ground truth is analytically known and to solutions where the ground truth has been obtained using the classic streak line computation. Furthermore, we apply a number of feature extraction and analysis tools to the new streak line vector field including the extraction of cores of swirling streak lines and the computation of streak line curvature fields. These first applications foreshadow the large variety of possible future research directions based on our new mathematical description of streak lines. PMID- 20975163 TI - A curved ray camera for handling occlusions through continuous multiperspective visualization. AB - Most images used in visualization are computed with the planar pinhole camera. This classic camera model has important advantages such as simplicity, which enables efficient software and hardware implementations, and similarity to the human eye, which yields images familiar to the user. However, the planar pinhole camera has only a single viewpoint, which limits images to parts of the scene to which there is direct line of sight. In this paper we introduce the curved ray camera to address the single viewpoint limitation. Rays are C1-continuous curves that bend to circumvent occluders. Our camera is designed to provide a fast 3-D point projection operation, which enables interactive visualization. The camera supports both 3-D surface and volume datasets. The camera is a powerful tool that enables seamless integration of multiple perspectives for overcoming occlusions in visualization while minimizing distortions. PMID- 20975164 TI - Special relativistic visualization by local ray tracing. AB - Special relativistic visualization offers the possibility of experiencing the optical effects of traveling near the speed of light, including apparent geometric distortions as well as Doppler and searchlight effects. Early high quality computer graphics images of relativistic scenes were created using offline, computationally expensive CPU-side 4D ray tracing. Alternate approaches such as image-based rendering and polygon-distortion methods are able to achieve interactivity, but exhibit inferior visual quality due to sampling artifacts. In this paper, we introduce a hybrid rendering technique based on polygon distortion and local ray tracing that facilitates interactive high-quality visualization of multiple objects moving at relativistic speeds in arbitrary directions. The method starts by calculating tight image-space footprints for the apparent triangles of the 3D scene objects. The final image is generated using a single image-space ray tracing step incorporating Doppler and searchlight effects. Our implementation uses GPU shader programming and hardware texture filtering to achieve high rendering speed. PMID- 20975165 TI - Computing robustness and persistence for images. AB - We are interested in 3-dimensional images given as arrays of voxels with intensity values. Extending these values to a continuous function, we study the robustness of homology classes in its level and interlevel sets, that is, the amount of perturbation needed to destroy these classes. The structure of the homology classes and their robustness, over all level and interlevel sets, can be visualized by a triangular diagram of dots obtained by computing the extended persistence of the function. We give a fast hierarchical algorithm using the dual complexes of oct-tree approximations of the function. In addition, we show that for balanced oct-trees, the dual complexes are geometrically realized in R3 and can thus be used to construct level and interlevel sets. We apply these tools to study 3-dimensional images of plant root systems. PMID- 20975166 TI - Browsing large image datasets through Voronoi diagrams. AB - Conventional browsing of image collections use mechanisms such as thumbnails arranged on a regular grid or on a line, often mounted over a scrollable panel. However, this approach does not scale well with the size of the datasets (number of images). In this paper, we propose a new thumbnail-based interface to browse large collections of images. Our approach is based on weighted centroidal anisotropic Voronoi diagrams. A dynamically changing subset of images is represented by thumbnails and shown on the screen. Thumbnails are shaped like general polygons, to better cover screen space, while still reflecting the original aspect ratios or orientation of the represented images. During the browsing process, thumbnails are dynamically rearranged, reshaped and rescaled. The objective is to devote more screen space (more numerous and larger thumbnails) to the parts of the dataset closer to the current region of interest, and progressively lesser away from it, while still making the dataset visible as a whole. During the entire process, temporal coherence is always maintained. GPU implementation easily guarantees the frame rates needed for fully smooth interactivity. PMID- 20975167 TI - Visual exploration of high dimensional scalar functions. AB - An important goal of scientific data analysis is to understand the behavior of a system or process based on a sample of the system. In many instances it is possible to observe both input parameters and system outputs, and characterize the system as a high-dimensional function. Such data sets arise, for instance, in large numerical simulations, as energy landscapes in optimization problems, or in the analysis of image data relating to biological or medical parameters. This paper proposes an approach to analyze and visualizing such data sets. The proposed method combines topological and geometric techniques to provide interactive visualizations of discretely sampled high-dimensional scalar fields. The method relies on a segmentation of the parameter space using an approximate Morse-Smale complex on the cloud of point samples. For each crystal of the Morse Smale complex, a regression of the system parameters with respect to the output yields a curve in the parameter space. The result is a simplified geometric representation of the Morse-Smale complex in the high dimensional input domain. Finally, the geometric representation is embedded in 2D, using dimension reduction, to provide a visualization platform. The geometric properties of the regression curves enable the visualization of additional information about each crystal such as local and global shape, width, length, and sampling densities. The method is illustrated on several synthetic examples of two dimensional functions. Two use cases, using data sets from the UCI machine learning repository, demonstrate the utility of the proposed approach on real data. Finally, in collaboration with domain experts the proposed method is applied to two scientific challenges. The analysis of parameters of climate simulations and their relationship to predicted global energy flux and the concentrations of chemical species in a combustion simulation and their integration with temperature. PMID- 20975168 TI - Two-phase mapping for projecting massive data sets. AB - Most multidimensional projection techniques rely on distance (dissimilarity) information between data instances to embed high-dimensional data into a visual space. When data are endowed with Cartesian coordinates, an extra computational effort is necessary to compute the needed distances, making multidimensional projection prohibitive in applications dealing with interactivity and massive data. The novel multidimensional projection technique proposed in this work, called Part-Linear Multidimensional Projection (PLMP), has been tailored to handle multivariate data represented in Cartesian high-dimensional spaces, requiring only distance information between pairs of representative samples. This characteristic renders PLMP faster than previous methods when processing large data sets while still being competitive in terms of precision. Moreover, knowing the range of variation for data instances in the high-dimensional space, we can make PLMP a truly streaming data projection technique, a trait absent in previous methods. PMID- 20975169 TI - Discontinuities in continuous scatter plots. AB - The concept of continuous scatterplot (CSP) is a modern visualization technique. The idea is to define a scalar density value based on the map between an n dimensional spatial domain and an m-dimensional data domain, which describe the CSP space. Usually the data domain is two-dimensional to visually convey the underlying, density coded, data. In this paper we investigate kinds of map-based discontinuities, especially for the practical cases n = m = 2 and n = 3 | m = 2, and we depict relations between them and attributes of the resulting CSP itself. Additionally, we show that discontinuities build critical line structures, and we introduce algorithms to detect them. Further, we introduce a discontinuity-based visualization approach—called contribution map (CM)—which establishes a relationship between the CSP's data domain and the number of connected components in the spatial domain. We show that CMs enhance the CSP-based linking & brushing interaction. Finally, we apply our approaches to a number of synthetic as well as real data sets. PMID- 20975171 TI - Exploded view diagrams of mathematical surfaces. AB - We present a technique for visualizing complicated mathematical surfaces that is inspired by hand-designed topological illustrations. Our approach generates exploded views that expose the internal structure of such a surface by partitioning it into parallel slices, which are separated from each other along a single linear explosion axis. Our contributions include a set of simple, prescriptive design rules for choosing an explosion axis and placing cutting planes, as well as automatic algorithms for applying these rules. First we analyze the input shape to select the explosion axis based on the detected rotational and reflective symmetries of the input model. We then partition the shape into slices that are designed to help viewers better understand how the shape of the surface and its cross-sections vary along the explosion axis. Our algorithms work directly on triangle meshes, and do not depend on any specific parameterization of the surface. We generate exploded views for a variety of mathematical surfaces using our system. PMID- 20975170 TI - Spatial conditioning of transfer functions using local material distributions. AB - In many applications of Direct Volume Rendering (DVR) the importance of a certain material or feature is highly dependent on its relative spatial location. For instance, in the medical diagnostic procedure, the patient's symptoms often lead to specification of features, tissues and organs of particular interest. One such example is pockets of gas which, if found inside the body at abnormal locations, are a crucial part of a diagnostic visualization. This paper presents an approach that enhances DVR transfer function design with spatial localization based on user specified material dependencies. Semantic expressions are used to define conditions based on relations between different materials, such as only render iodine uptake when close to liver. The underlying methods rely on estimations of material distributions which are acquired by weighing local neighborhoods of the data against approximations of material likelihood functions. This information is encoded and used to influence rendering according to the user's specifications. The result is improved focus on important features by allowing the user to suppress spatially less-important data. In line with requirements from actual clinical DVR practice, the methods do not require explicit material segmentation that would be impossible or prohibitively time-consuming to achieve in most real cases. The scheme scales well to higher dimensions which accounts for multi dimensional transfer functions and multivariate data. Dual-Energy Computed Tomography, an important new modality in radiology, is used to demonstrate this scalability. In several examples we show significantly improved focus on clinically important aspects in the rendered images. PMID- 20975172 TI - IRIS: illustrative rendering for integral surfaces. AB - Integral surfaces are ideal tools to illustrate vector fields and fluid flow structures. However, these surfaces can be visually complex and exhibit difficult geometric properties, owing to strong stretching, shearing and folding of the flow from which they are derived. Many techniques for non-photorealistic rendering have been presented previously. It is, however, unclear how these techniques can be applied to integral surfaces. In this paper, we examine how transparency and texturing techniques can be used with integral surfaces to convey both shape and directional information. We present a rendering pipeline that combines these techniques aimed at faithfully and accurately representing integral surfaces while improving visualization insight. The presented pipeline is implemented directly on the GPU, providing real-time interaction for all rendering modes, and does not require expensive preprocessing of integral surfaces after computation. PMID- 20975173 TI - Illustrative stream surfaces. AB - Stream surfaces are an intuitive approach to represent 3D vector fields. In many cases, however, they are challenging objects to visualize and to understand, due to a high degree of self-occlusion. Despite the need for adequate rendering methods, little work has been done so far in this important research area. In this paper, we present an illustrative rendering strategy for stream surfaces. In our approach, we apply various rendering techniques, which are inspired by the traditional flow illustrations drawn by Dallmann and Abraham ?& Shaw in the early 1980s. Among these techniques are contour lines and halftoning to show the overall surface shape. Flow direction as well as singularities on the stream surface are depicted by illustrative surface streamlines. ;To go beyond reproducing static text book images, we provide several interaction features, such as movable cuts and slabs allowing an interactive exploration of the flow and insights into subjacent structures, e.g., the inner windings of vortex breakdown bubbles. These methods take only the parameterized stream surface as input, require no further preprocessing, and can be freely combined by the user. We explain the design, GPU-implementation, and combination of the different illustrative rendering and interaction methods and demonstrate the potential of our approach by applying it to stream surfaces from various flow simulations. ; PMID- 20975174 TI - Exploration of 4D MRI blood flow using stylistic visualization. AB - Insight into the dynamics of blood-flow considerably improves the understanding of the complex cardiovascular system and its pathologies. Advances in MRI technology enable acquisition of 4D blood-flow data, providing quantitative blood flow velocities over time. The currently typical slice-by-slice analysis requires a full mental reconstruction of the unsteady blood-flow field, which is a tedious and highly challenging task, even for skilled physicians. We endeavor to alleviate this task by means of comprehensive visualization and interaction techniques. In this paper we present a framework for pre-clinical cardiovascular research, providing tools to both interactively explore the 4D blood-flow data and depict the essential blood-flow characteristics. The framework encompasses a variety of visualization styles, comprising illustrative techniques as well as improved methods from the established field of flow visualization. Each of the incorporated styles, including exploded planar reformats, flow-direction highlights, and arrow-trails, locally captures the blood-flow dynamics and may be initiated by an interactively probed vessel cross-section. Additionally, we present the results of an evaluation with domain experts, measuring the value of each of the visualization styles and related rendering parameters. PMID- 20975175 TI - Supine and prone colon registration using quasi-conformal mapping. AB - In virtual colonoscopy, CT scans are typically acquired with the patient in both supine (facing up) and prone (facing down) positions. The registration of these two scans is desirable so that the user can clarify situations or confirm polyp findings at a location in one scan with the same location in the other, thereby improving polyp detection rates and reducing false positives. However, this supine-prone registration is challenging because of the substantial distortions in the colon shape due to the patient's change in position. We present an efficient algorithm and framework for performing this registration through the use of conformal geometry to guarantee that the registration is a diffeomorphism (a one-to-one and onto mapping). The taeniae coli and colon flexures are automatically extracted for each supine and prone surface, employing the colon geometry. The two colon surfaces are then divided into several segments using the flexures, and each segment is cut along a taenia coli and conformally flattened to the rectangular domain using holomorphic differentials. The mean curvature is color encoded as texture images, from which feature points are automatically detected using graph cut segmentation, mathematic morphological operations, and principal component analysis. Corresponding feature points are found between supine and prone and are used to adjust the conformal flattening to be quasi conformal, such that the features become aligned. We present multiple methods of visualizing our results, including 2D flattened rendering, corresponding 3D endoluminal views, and rendering of distortion measurements. We demonstrate the efficiency and efficacy of our registration method by illustrating matched views on both the 2D flattened colon images and in the 3D volume rendered colon endoluminal view. We analytically evaluate the correctness of the results by measuring the distance between features on the registered colons. PMID- 20975176 TI - Uncertainty-aware guided volume segmentation. AB - Although direct volume rendering is established as a powerful tool for the visualization of volumetric data, efficient and reliable feature detection is still an open topic. Usually, a tradeoff between fast but imprecise classification schemes and accurate but time-consuming segmentation techniques has to be made. Furthermore, the issue of uncertainty introduced with the feature detection process is completely neglected by the majority of existing approaches.In this paper we propose a guided probabilistic volume segmentation approach that focuses on the minimization of uncertainty. In an iterative process, our system continuously assesses uncertainty of a random walker-based segmentation in order to detect regions with high ambiguity, to which the user's attention is directed to support the correction of potential misclassifications. This reduces the risk of critical segmentation errors and ensures that information about the segmentation's reliability is conveyed to the user in a dependable way. In order to improve the efficiency of the segmentation process, our technique does not only take into account the volume data to be segmented, but also enables the user to incorporate classification information. An interactive workflow has been achieved by implementing the presented system on the GPU using the OpenCL API. Our results obtained for several medical data sets of different modalities, including brain MRI and abdominal CT, demonstrate the reliability and efficiency of our approach. PMID- 20975177 TI - Exploration and visualization of segmentation uncertainty using shape and appearance prior information. AB - We develop an interactive analysis and visualization tool for probabilistic segmentation in medical imaging. The originality of our approach is that the data exploration is guided by shape and appearance knowledge learned from expert segmented images of a training population. We introduce a set of multidimensional transfer function widgets to analyze the multivariate probabilistic field data. These widgets furnish the user with contextual information about conformance or deviation from the population statistics. We demonstrate the user's ability to identify suspicious regions (e.g. tumors) and to correct the misclassification results. We evaluate our system and demonstrate its usefulness in the context of static anatomical and time-varying functional imaging datasets. PMID- 20975178 TI - Edge aware anisotropic diffusion for 3D scalar data. AB - In this paper we present a novel anisotropic diffusion model targeted for 3D scalar field data. Our model preserves material boundaries as well as fine tubular structures while noise is smoothed out. One of the major novelties is the use of the directional second derivative to define material boundaries instead of the gradient magnitude for thresholding. This results in a diffusion model that has much lower sensitivity to the diffusion parameter and smoothes material boundaries consistently compared to gradient magnitude based techniques. We empirically analyze the stability and convergence of the proposed diffusion and demonstrate its de-noising capabilities for both analytic and real data. We also discuss applications in the context of volume rendering. PMID- 20975179 TI - Interactive histology of large-scale biomedical image stacks. AB - Histology is the study of the structure of biological tissue using microscopy techniques. As digital imaging technology advances, high resolution microscopy of large tissue volumes is becoming feasible; however, new interactive tools are needed to explore and analyze the enormous datasets. In this paper we present a visualization framework that specifically targets interactive examination of arbitrarily large image stacks. Our framework is built upon two core techniques: display-aware processing and GPU-accelerated texture compression. With display aware processing, only the currently visible image tiles are fetched and aligned on-the-fly, reducing memory bandwidth and minimizing the need for time-consuming global pre-processing. Our novel texture compression scheme for GPUs is tailored for quick browsing of image stacks. We evaluate the usability of our viewer for two histology applications: digital pathology and visualization of neural structure at nanoscale-resolution in serial electron micrographs. PMID- 20975180 TI - Articulated planar reformation for change visualization in small animal imaging. AB - The analysis of multi-timepoint whole-body small animal CT data is greatly complicated by the varying posture of the subject at different timepoints. Due to these variations, correctly relating and comparing corresponding regions of interest is challenging.In addition, occlusion may prevent effective visualization of these regions of interest. To address these problems, we have developed a method that fully automatically maps the data to a standardized layout of sub-volumes, based on an articulated atlas registration. We have dubbed this process articulated planar reformation, or APR. A sub-volume can be interactively selected for closer inspection and can be compared with the corresponding sub-volume at the other timepoints, employing a number of different comparative visualization approaches. We provide an additional tool that highlights possibly interesting areas based on the change of bone density between timepoints. Furthermore we allow visualization of the local registration error, to give an indication of the accuracy of the registration. We have evaluated our approach on a case that exhibits cancer-induced bone resorption. PMID- 20975181 TI - Volumetric modeling in laser BPH therapy simulation. AB - In this paper, we introduce a novel application of volume modeling techniques on laser Benign Prostatic Hyperplasia (BPH) therapy simulation. The core technique in our system is an algorithm for simulating the tissue vaporization process by laser heating. Different from classical volume CSG operations, our technique takes experimental data as the guidance to determine the vaporization amount so that only a specified amount of tissue is vaporized in each time. Our algorithm uses a predictor-corrector strategy. First, we apply the classical CSG algorithm on a tetrahedral grid based distance field to estimate the vaporized tissue amount. Then, a volume-correction phase is applied on the distance field. To improve the performance, we further propose optimization approaches for efficient implementation. PMID- 20975182 TI - Scalable multi-variate analytics of seismic and satellite-based observational data. AB - Over the past few years, large human populations around the world have been affected by an increase in significant seismic activities. For both conducting basic scientific research and for setting critical government policies, it is crucial to be able to explore and understand seismic and geographical information obtained through all scientific instruments. In this work, we present a visual analytics system that enables explorative visualization of seismic data together with satellite-based observational data, and introduce a suite of visual analytical tools. Seismic and satellite data are integrated temporally and spatially. Users can select temporal ;and spatial ranges to zoom in on specific seismic events, as well as to inspect changes both during and after the events. Tools for designing high dimensional transfer functions have been developed to enable efficient and intuitive comprehension of the multi-modal data. Spread sheet style comparisons are used for data drill-down as well as presentation. Comparisons between distinct seismic events are also provided for characterizing event-wise differences. Our system has been designed for scalability in terms of data size, complexity (i.e. number of modalities), and varying form factors of display environments. PMID- 20975183 TI - Noodles: a tool for visualization of numerical weather model ensemble uncertainty. AB - Numerical weather prediction ensembles are routinely used for operational weather forecasting. The members of these ensembles are individual simulations with either slightly perturbed initial conditions or different model parameterizations, or occasionally both. Multi-member ensemble output is usually large, multivariate, and challenging to interpret interactively. Forecast meteorologists are interested in understanding the uncertainties associated with numerical weather prediction; specifically variability between the ensemble members. Currently, visualization of ensemble members is mostly accomplished through spaghetti plots of a single mid-troposphere pressure surface height contour. In order to explore new uncertainty visualization methods, the Weather Research and Forecasting (WRF) model was used to create a 48-hour, 18 member parameterization ensemble of the 13 March 1993 "Superstorm". A tool was designed to interactively explore the ensemble uncertainty of three important weather variables: water-vapor mixing ratio, perturbation potential temperature, and perturbation pressure. Uncertainty was quantified using individual ensemble member standard deviation, inter-quartile range, and the width of the 95% confidence interval. Bootstrapping was employed to overcome the dependence on normality in the uncertainty metrics. A coordinated view of ribbon and glyph based uncertainty visualization, spaghetti plots, iso-pressure colormaps, and data transect plots was provided to two meteorologists for expert evaluation. They found it useful in assessing uncertainty in the data, especially in finding outliers in the ensemble run and therefore avoiding the WRF parameterizations that lead to these outliers. Additionally, the meteorologists could identify spatial regions where the uncertainty was significantly high, allowing for identification of poorly simulated storm environments and physical interpretation of these model issues. PMID- 20975184 TI - Analysis of recurrent patterns in toroidal magnetic fields. AB - In the development of magnetic confinement fusion which will potentially be a future source for low cost power, physicists must be able to analyze the magnetic field that confines the burning plasma. While the magnetic field can be described as a vector field, traditional techniques for analyzing the field's topology cannot be used because of its Hamiltonian nature. In this paper we describe a technique developed as a collaboration between physicists and computer scientists that determines the topology of a toroidal magnetic field using fieldlines with near minimal lengths. More specifically, we analyze the Poincare map of the sampled fieldlines in a Poincare section including identifying critical points and other topological features of interest to physicists. The technique has been deployed into an interactive parallel visualization tool which physicists are using to gain new insight into simulations of magnetically confined burning plasmas. PMID- 20975185 TI - Interactive visualization of hyperspectral images of historical documents. AB - This paper presents an interactive visualization tool to study and analyze hyperspectral images (HSI) of historical documents. This work is part of a collaborative effort with the Nationaal Archief of the Netherlands (NAN) and Art Innovation, a manufacturer of hyperspectral imaging hardware designed for old and fragile documents. The NAN is actively capturing HSI of historical documents for use in a variety of tasks related to the analysis and management of archival collections, from ink and paper analysis to monitoring the effects of environmental aging. To assist their work, we have developed a comprehensive visualization tool that offers an assortment of visualization and analysis methods, including interactive spectral selection, spectral similarity analysis, time-varying data analysis and visualization, and selective spectral band fusion. This paper describes our visualization software and how it is used to facilitate the tasks needed by our collaborators. Evaluation feedback from our collaborators on how this tool benefits their work is included. PMID- 20975186 TI - Interactive visual analysis of multiple simulation runs using the simulation model view: understanding and tuning of an electronic unit injector. AB - Multiple simulation runs using the same simulation model with different values of control parameters generate a large data set that captures the behavior of the modeled phenomenon. However, there is a conceptual and visual gap between the simulation model behavior and the data set that makes data analysis more difficult. We propose a simulation model view that helps to bridge that gap by visually combining the simulation model description and the generated data. The simulation model view provides a visual outline of the simulation process and the corresponding simulation model. The view is integrated in a Coordinated Multiple Views ;(CMV) system. As the simulation model view provides a limited display space, we use three levels of details. We explored the use of the simulation model view, in close collaboration with a domain expert, to understand and tune an electronic unit injector (EUI). We also developed analysis procedures based on the view. The EUI is mostly used in heavy duty Diesel engines. We were mainly interested in understanding the model and how to tune it for three different operation modes: low emission, low consumption, and high power. Very positive feedback from the domain expert shows that the use of the simulation model view and the corresponding ;analysis procedures within a CMV system represents an effective technique for interactive visual analysis of multiple simulation runs. We also developed new analysis procedures based on these results. PMID- 20975187 TI - World lines. AB - In this paper we present World Lines as a novel interactive visualization that provides complete control over multiple heterogeneous simulation runs. In many application areas, decisions can only be made by exploring alternative scenarios. The goal of the suggested approach is to support users in this decision making process. In this setting, the data domain is extended to a set of alternative worlds where only one outcome will actually happen. World Lines integrate simulation, visualization and computational steering into a single unified system that is capable of dealing with the extended solution space. World Lines represent simulation runs as causally connected tracks that share a common time axis. This setup enables users to interfere and add new information quickly. A World Line is introduced as a visual combination of user events and their effects in order to present a possible future. To quickly find the most attractive outcome, we suggest World Lines as the governing component in a system of multiple linked views and a simulation component. World Lines employ linking and brushing to enable comparative visual analysis of multiple simulations in linked views. Analysis results can be mapped to various visual variables that World Lines provide in order to highlight the most compelling solutions. To demonstrate this technique we present a flooding scenario and show the usefulness of the integrated approach to support informed decision making. PMID- 20975188 TI - Result-driven exploration of simulation parameter spaces for visual effects design. AB - Graphics artists commonly employ physically-based simulation for the generation of effects such as smoke, explosions, and similar phenomena. The task of finding the correct parameters for a desired result, however, is difficult and time consuming as current tools provide little to no guidance. In this paper, we present a new approach for the visual exploration of such parameter spaces. Given a three-dimensional scene description, we utilize sampling and spatio-temporal clustering techniques to generate a concise overview of the achievable variations and their temporal evolution. Our visualization system then allows the user to explore the simulation space in a goal-oriented manner. Animation sequences with a set of desired characteristics can be composed using a novel search-by-example approach and interactive direct volume rendering is employed to provide instant visual feedback. A user study was performed to evaluate the applicability of our system in production use. PMID- 20975189 TI - Visual optimality and stability analysis of 3DCT scan positions. AB - Industrial cone-beam X-Ray computed tomography (CT) systems often face problems due to artifacts caused by a bad placement of the specimen on the rotary plate. This paper presents a visual-analysis tool for CT systems, which provides a simulation-based preview and estimates artifacts and deviations of a specimen's placement using the corresponding 3D geometrical surface model as input. The presented tool identifies potentially good or bad placements of a specimen and regions of a specimen, which cause the major portion of artefacts. The tool can be used for a preliminary analysis of the specimen before CT scanning, in order to determine the optimal way of placing the object. The analysis includes: penetration lengths, placement stability and an investigation in Radon space. Novel visualization techniques are applied to the simulation data. A stability widget is presented for determining the placement parameters' robustness. The performance and the comparison of results provided by the tool compared with real world data is demonstrated using two specimens. PMID- 20975190 TI - Pre-integrated volume rendering with non-linear gradient interpolation. AB - Shading is an important feature for the comprehension of volume datasets, but is difficult to implement accurately. Current techniques based on pre-integrated direct volume rendering approximate the volume rendering integral by ignoring non linear gradient variations between front and back samples, which might result in cumulated shading errors when gradient variations are important and / or when the illumination function features high frequencies. In this paper, we explore a simple approach for pre-integrated volume rendering with non-linear gradient interpolation between front and back samples. We consider that the gradient smoothly varies along a quadratic curve instead of a segment in-between consecutive samples. This not only allows us to compute more accurate shaded pre integrated look-up tables, but also allows us to more efficiently process shading amplifying effects, based on gradient filtering. An interesting property is that the pre-integration tables we use remain two-dimensional as for usual pre integrated classification. We conduct experiments using a full hardware approach with the Blinn-Phong illumination model as well as with a non-photorealistic illumination model. PMID- 20975191 TI - Gradient estimation revitalized. AB - We investigate the use of a Fourier-domain derivative error kernel to quantify the error incurred while estimating the gradient of a function from scalar point samples on a regular lattice. We use the error kernel to show that gradient reconstruction quality is significantly enhanced merely by shifting the reconstruction kernel to the centers of the principal lattice directions. Additionally, we exploit the algebraic similarities between the scalar and derivative error kernels to design asymptotically optimal gradient estimation filters that can be factored into an infinite impulse response interpolation prefilter and a finite impulse response directional derivative filter. This leads to a significant performance gain both in terms of accuracy and computational efficiency. The interpolation prefilter provides an accurate scalar approximation and can be re-used to cheaply compute directional derivatives on-the-fly without the need to store gradients. We demonstrate the impact of our filters in the context of volume rendering of scalar data sampled on the Cartesian and Body Centered Cubic lattices. Our results rival those obtained from other competitive gradient estimation methods while incurring no additional computational or storage overhead. PMID- 20975192 TI - Direct interval volume visualization. AB - We extend direct volume rendering with a unified model for generalized isosurfaces, also called interval volumes, allowing a wider spectrum of visual classification. We generalize the concept of scale-invariant opacity—typical for isosurface rendering—to semi-transparent interval volumes. Scale-invariant rendering is independent of physical space dimensions and therefore directly facilitates the analysis of data characteristics. Our model represents sharp isosurfaces as limits of interval volumes and combines them with features of direct volume rendering. Our objective is accurate rendering, guaranteeing that all isosurfaces and interval volumes are visualized in a crack-free way with correct spatial ordering. We achieve simultaneous direct and interval volume rendering by extending preintegration and explicit peak finding with data-driven splitting of ray integration and hybrid computation in physical and data domains. Our algorithm is suitable for efficient parallel processing for interactive applications as demonstrated by our CUDA implementation. PMID- 20975193 TI - VDVR: verifiable visualization of projection-based data. AB - Practical volume visualization pipelines are never without compromises and errors. A delicate and often-studied component is the interpolation of off-grid samples, where aliasing can lead to misleading artifacts and blurring, potentially hiding fine details of critical importance. The verifiable visualization framework we describe aims to account for these errors directly in the volume generation stage, and we specifically target volumetric data obtained via computed tomography (CT) reconstruction. In this case the raw data are the X ray projections obtained from the scanner and the volume data generation process is the CT algorithm. Our framework informs the CT reconstruction process of the specific filter intended for interpolation in the subsequent visualization process, and this in turn ensures an accurate interpolation there at a set tolerance. Here, we focus on fast trilinear interpolation in conjunction with an octree-type mixed resolution volume representation without T-junctions. Efficient rendering is achieved by a space-efficient and locality-optimized representation, which can straightforwardly exploit fast fixed-function pipelines on GPUs. PMID- 20975194 TI - Fast high-quality volume ray-casting with virtual samplings. AB - Volume ray-casting with a higher order reconstruction filter and/or a higher sampling rate has been adopted in direct volume rendering frameworks to provide a smooth reconstruction of the volume scalar and/or to reduce artifacts when the combined frequency of the volume and transfer function is high. While it enables high-quality volume rendering, it cannot support interactive rendering due to its high computational cost. In this paper, we propose a fast high-quality volume ray casting algorithm which effectively increases the sampling rate. While a ray traverses the volume, intensity values are uniformly reconstructed using a high order convolution filter. Additional samplings, referred to as virtual samplings, are carried out within a ray segment from a cubic spline curve interpolating those uniformly reconstructed intensities. These virtual samplings are performed by evaluating the polynomial function of the cubic spline curve via simple arithmetic operations. The min max blocks are refined accordingly for accurate empty space skipping in the proposed method. Experimental results demonstrate that the proposed algorithm, also exploiting fast cubic texture filtering supported by programmable GPUs, offers renderings as good as a conventional ray casting algorithm using high-order reconstruction filtering at the same sampling rate, while delivering 2.5x to 3.3x rendering speed-up. PMID- 20975195 TI - Efficient high-quality volume rendering of SPH data. AB - High quality volume rendering of SPH data requires a complex order-dependent resampling of particle quantities along the view rays. In this paper we present an efficient approach to perform this task using a novel view-space discretization of the simulation domain. Our method draws upon recent work on GPU based particle voxelization for the efficient resampling of particles into uniform grids. We propose a new technique that leverages a perspective grid to adaptively discretize the view-volume, giving rise to a continuous level-of detail sampling structure and reducing memory requirements compared to a uniform grid. In combination with a level-of-detail representation of the particle set, the perspective grid allows effectively reducing the amount of primitives to be processed at run-time. We demonstrate the quality and performance of our method for the rendering of fluid and gas dynamics SPH simulations consisting of many millions of particles. PMID- 20975196 TI - Fast, memory-efficient cell location in unstructured grids for visualization. AB - Applying certain visualization techniques to datasets described on unstructured grids requires the interpolation of variables of interest at arbitrary locations within the dataset's domain of definition. Typical solutions to the problem of finding the grid element enclosing a given interpolation point make use of a variety of spatial subdivision schemes. However, existing solutions are memory- intensive, do not scale well to large grids, or do not work reliably on grids describing complex geometries. In this paper, we propose a data structure and associated construction algorithm for fast cell location in unstructured grids, and apply it to the interpolation problem. Based on the concept of bounding interval hierarchies, the proposed approach is memory-efficient, fast and numerically robust. We examine the performance characteristics of the proposed approach and compare it to existing approaches using a number of benchmark problems related to vector field visualization. Furthermore, we demonstrate that our approach can successfully accommodate large datasets, and discuss application to visualization on both CPUs and GPUs. PMID- 20975197 TI - Visualization by proxy: a novel framework for deferred interaction with volume data. AB - Interactivity is key to exploration of volume data. Interactivity may be hindered due to many factors, e.g. large data size,high resolution or complexity of a data set, or an expensive rendering algorithm. We present a novel framework for visualizing volume data that enables interactive exploration using proxy images, without accessing the original 3D data. Data exploration using direct volume rendering requires multiple (often redundant) accesses to possibly large amounts of data. The notion of visualization by proxy relies on the ability to defer operations traditionally used for exploring 3D data to a more suitable intermediate representation for interaction--proxy images. Such operations include view changes, transfer function exploration, and relighting. While previous work has addressed specific interaction needs, we provide a complete solution that enables real-time interaction with large data sets and has low hardware and storage requirements. PMID- 20975198 TI - Interactive vector field feature identification. AB - We introduce a flexible technique for interactive exploration of vector field data through classification derived from user-specified feature templates. Our method is founded on the observation that, while similar features within the vector field may be spatially disparate, they share similar neighborhood characteristics. Users generate feature-based visualizations by interactively highlighting well-accepted and domain specific representative feature points. Feature exploration begins with the computation of attributes that describe the neighborhood of each sample within the input vector field. Compilation of these attributes forms a representation of the vector field samples in the attribute space. We project the attribute points onto the canonical 2D plane to enable interactive exploration of the vector field using a painting interface. The projection encodes the similarities between vector field points within the distances computed between their associated attribute points. The proposed method is performed at interactive rates for enhanced user experience and is completely flexible as showcased by the simultaneous identification of diverse feature types. PMID- 20975199 TI - Interactive separating streak surfaces. AB - Streak surfaces are among the most important features to support 3D unsteady flow exploration, but they are also among the computationally most demanding. Furthermore, to enable a feature driven analysis of the flow, one is mainly interested in streak surfaces that show separation profiles and thus detect unstable manifolds in the flow. The computation of such separation surfaces requires to place seeding structures at the separation locations and to let the structures move correspondingly to these locations in the unsteady flow. Since only little knowledge exists about the time evolution of separating streak surfaces, at this time, an automated exploration of 3D unsteady flows using such surfaces is not feasible. Therefore, in this paper we present an interactive approach for the visual analysis of separating streak surfaces. Our method draws upon recent work on the extraction of Lagrangian coherent structures (LCS) and the real-time visualization of streak surfaces on the GPU. We propose an interactive technique for computing ridges in the finite time Lyapunov exponent (FTLE) field at each time step, and we use these ridges as seeding structures to track streak surfaces in the time-varying flow. By showing separation surfaces in combination with particle trajectories, and by letting the user interactively change seeding parameters such as particle density and position, visually guided exploration of separation profiles in 3D is provided. To the best of our knowledge, this is the first time that the reconstruction and display of semantic separable surfaces in 3D unsteady flows can be performed interactively, giving rise to new possibilities for gaining insight into complex flow phenomena. PMID- 20975200 TI - View-dependent streamlines for 3D vector fields. AB - This paper introduces a new streamline placement and selection algorithm for 3D vector fields. Instead of considering the problem as a simple feature search in data space, we base our work on the observation that most streamline fields generate a lot of self-occlusion which prevents proper visualization. In order to avoid this issue, we approach the problem in a view-dependent fashion and dynamically determine a set of streamlines which contributes to data understanding without cluttering the view. Since our technique couples flow characteristic criteria and view-dependent streamline selection we are able achieve the best of both worlds: relevant flow description and intelligible, uncluttered pictures. We detail an efficient GPU implementation of our algorithm, show comprehensive visual results on multiple datasets and compare our method with existing flow depiction techniques. Our results show that our technique greatly improves the readability of streamline visualizations on different datasets without requiring user intervention. PMID- 20975201 TI - Visualizing flow trajectories using locality-based rendering and warped curve plots. AB - In flow simulations the behavior and properties of particle trajectories often depend on the physical geometry contained in the simulated environment. Understanding the flow in and around the geometry itself is an important part of analyzing the data. Previous work has often utilized focus+context rendering techniques, with an emphasis on showing trajectories while simplifying or illustratively rendering the physical areas. Our research instead emphasizes the local relationship between particle paths and geometry by using a projected multi field visualization technique. The correlation between a particle path and its surrounding area is calculated on-the-fly and displayed in a non-intrusive manner. In addition, we support visual exploration and comparative analysis through the use of linked information visualization, such as manipulatable curve plots and one-on-one similarity plots. Our technique is demonstrated on particle trajectories from a groundwater simulation and a computer room airflow simulation, where the flow of particles is highly influenced by the dense geometry. PMID- 20975202 TI - Superquadric glyphs for symmetric second-order tensors. AB - Symmetric second-order tensor fields play a central role in scientific and biomedical studies as well as in image analysis and feature-extraction methods. The utility of displaying tensor field samples has driven the development of visualization techniques that encode the tensor shape and orientation into the geometry of a tensor glyph. With some exceptions, these methods work only for positive-definite tensors (i.e. having positive eigenvalues, such as diffusion tensors). We expand the scope of tensor glyphs to all symmetric second-order tensors in two and three dimensions, gracefully and unambiguously depicting any combination of positive and negative eigenvalues. We generalize a previous method of superquadric glyphs for positive-definite tensors by drawing upon a larger portion of the superquadric shape space, supplemented with a coloring that indicates the quadratic form (including eigenvalue sign). We show that encoding arbitrary eigenvalue magnitudes requires design choices that differ fundamentally from those in previous work on traceless tensors that arise in the study of liquid crystals. Our method starts with a design of 2-D tensor glyphs guided by principles of scale-preservation and symmetry, and creates 3-D glyphs that include the 2-D glyphs in their axis-aligned cross-sections. A key ingredient of our method is a novel way of mapping from the shape space of three-dimensional symmetric second-order tensors to the unit square. We apply our new glyphs to stress tensors from mechanics, geometry tensors and Hessians from image analysis, and rate-of-deformation tensors in computational fluid dynamics. PMID- 20975203 TI - TanGeoMS: tangible geospatial modeling system. AB - We present TanGeoMS, a tangible geospatial modeling visualization system that couples a laser scanner, projector, and a flexible physical three-dimensional model with a standard geospatial information system (GIS) to create a tangible user interface for terrain data. TanGeoMS projects an image of real-world data onto a physical terrain model. Users can alter the topography of the model by modifying the clay surface or placing additional objects on the surface. The modified model is captured by an overhead laser scanner then imported into a GIS for analysis and simulation of real-world processes. The results are projected back onto the surface of the model providing feedback on the impact of the modifications on terrain parameters and simulated processes. Interaction with a physical model is highly intuitive, allowing users to base initial design decisions on geospatial data, test the impact of these decisions in GIS simulations, and use the feedback to improve their design. We demonstrate the system on three applications: investigating runoff management within a watershed, assessing the impact of storm surge on barrier islands, and exploring landscape rehabilitation in military training areas. PMID- 20975204 TI - FI3D: direct-touch interaction for the exploration of 3D scientific visualization spaces. AB - We present the design and evaluation of FI3D, a direct-touch data exploration technique for 3D visualization spaces. The exploration of three-dimensional data is core to many tasks and domains involving scientific visualizations. Thus, effective data navigation techniques are essential to enable comprehension, understanding, and analysis of the information space. While evidence exists that touch can provide higher-bandwidth input, somesthetic information that is valuable when interacting with virtual worlds, and awareness when working in collaboration, scientific data exploration in 3D poses unique challenges to the development of effective data manipulations. We present a technique that provides touch interaction with 3D scientific data spaces in 7 DOF. This interaction does not require the presence of dedicated objects to constrain the mapping, a design decision important for many scientific datasets such as particle simulations in astronomy or physics. We report on an evaluation that compares the technique to conventional mouse-based interaction. Our results show that touch interaction is competitive in interaction speed for translation and integrated interaction, is easy to learn and use, and is preferred for exploration and wayfinding tasks. To further explore the applicability of our basic technique for other types of scientific visualizations we present a second case study, adjusting the interaction to the illustrative visualization of fiber tracts of the brain and the manipulation of cutting planes in this context. PMID- 20975205 TI - A scalable distributed paradigm for multi-user interaction with tiled rear projection display walls. AB - We present the first distributed paradigm for multiple users to interact simultaneously with large tiled rear projection display walls. Unlike earlier works, our paradigm allows easy scalability across different applications, interaction modalities, displays and users. The novelty of the design lies in its distributed nature allowing well-compartmented, application independent, and application specific modules. This enables adapting to different 2D applications and interaction modalities easily by changing a few application specific modules. We demonstrate four challenging 2D applications on a nine projector display to demonstrate the application scalability of our method: map visualization, virtual graffiti, virtual bulletin board and an emergency management system. We demonstrate the scalability of our method to multiple interaction modalities by showing both gesture-based and laser-based user interfaces. Finally, we improve earlier distributed methods to register multiple projectors. Previous works need multiple patterns to identify the neighbors, the configuration of the display and the registration across multiple projectors in logarithmic time with respect to the number of projectors in the display. We propose a new approach that achieves this using a single pattern based on specially augmented QR codes in constant time. Further, previous distributed registration algorithms are prone to large misregistrations. We propose a novel radially cascading geometric registration technique that yields significantly better accuracy. Thus, our improvements allow a significantly more efficient and accurate technique for distributed self registration of multi-projector display walls. PMID- 20975206 TI - Projector placement planning for high quality visualizations on real-world colored objects. AB - Many visualization applications benefit from displaying content on real-world objects rather than on a traditional display (e.g., a monitor). This type of visualization display is achieved by projecting precisely controlled illumination from multiple projectors onto the real-world colored objects. For such a task, the placement of the projectors is critical in assuring that the desired visualization is possible. Using ad hoc projector placement may cause some appearances to suffer from color shifting due to insufficient projector light radiance being exposed onto the physical surface. This leads to an incorrect appearance and ultimately to a false and potentially misleading visualization. In this paper, we present a framework to discover the optimal position and orientation of the projectors for such projection-based visualization displays. An optimal projector placement should be able to achieve the desired visualization with minimal projector light radiance. When determining optimal projector placement, object visibility, surface reflectance properties, and projector-surface distance and orientation need to be considered. We first formalize a theory for appearance editing image formation and construct a constrained linear system of equations that express when a desired novel appearance or visualization is possible given a geometric and surface reflectance model of the physical surface. Then, we show how to apply this constrained system in an adaptive search to efficiently discover the optimal projector placement which achieves the desired appearance. Constraints can be imposed on the maximum radiance allowed by the projectors and the projectors' placement to support specific goals of various visualization applications. We perform several real world and simulated appearance edits and visualizations to demonstrate the improvement obtained by our discovered projector placement over ad hoc projector placement. PMID- 20975207 TI - EAK proteins: novel conserved regulators of C. elegans lifespan. AB - FoxO transcription factors (TFs) extend lifespan in invertebrates and may participate in the control of human longevity. The role of FoxO TFs in lifespan regulation has been studied most extensively inC. elegans, where a conserved insulin/insulin-like growth factor signaling (IIS) pathway and the germline both control lifespan by regulating the subcellular localization of the FoxO transcription factor DAF-16. Although the control of FoxO activity through modulation of its subcellular localization is well established, nuclear translocation of FoxO is not sufficient for full FoxO activation, suggesting that undiscovered inputs regulate FoxO activity after its translocation to the nucleus. We have recently discovered a new conserved pathway, the EAK (enhancer of-akt-1) pathway, which acts in parallel to the Akt/PKB family of serine threonine kinases to regulate DAF-16/FoxO activity. Whereas mutation of Akt/PKB promotes the nuclear accumulation of DAF-16/FoxO, mutation of eak genes increases nuclear DAF-16/FoxO activity without influencing DAF-16/FoxO subcellular localization. Thus, EAK proteins regulate the activity of nuclear DAF-16/FoxO. Two EAK proteins, EAK-2/HSD-1 and EAK-7, influence C. elegans lifespan and are conserved in mammals. The discovery of the EAK pathway defines a new conserved FoxO regulatory input and may have implications relevant to aging and the pathogenesis of aging-associated diseases. PMID- 20975208 TI - Insights into Cdc13 dependent telomere length regulation. AB - Cdc13 is a single stranded telomere binding protein that specifically localizes to the telomere ends of budding yeasts and is essential for cell viability. It caps the ends of chromosomes thus preventing chromosome end-to-end fusions and exonucleolytic degradation, events that could lead to genomic instability and senescence, the hallmark of aging. Cdc13 is also involved in telomere length regulation by recruiting or preventing access of telomerase to the telomeric overhang. Recruitment of telomerase to the telomeres for G-strand extension is required for continuous cell division, while preventing its access to the telomeres through capping the chromosome ends prevents mitotic events that could lead to cell immortality, the hall mark of carcinogenesis. Cdc13 and its putative homologues human CTC1 and POT1 are therefore key to many biological processes directly associated with life extension and cancer prevention and can be viewed as an ideal target for cancer and age related therapies. PMID- 20975210 TI - Synthesis, characterization and opto-electrical properties of ternary Zn2SnO4 nanowires. AB - Ternary oxides have the potential to display better electrical and optical properties than the commonly fabricated binary oxides. In our experiments, Zn(2)SnO(4) (ZTO) nanowires were synthesized via thermal evaporation and vapor phase transport. The opto-electrical performance of the nanowires was investigated. An individual ZTO nanowire field-effect transistor was successfully fabricated for the first time and shows an on-off ratio of 10(4) and transconductance of 20.6 nS, which demonstrates the promising electronic performance of ZTO nanowire in an electrical device. Field emission experiments on ZTO nanowire film also indicate their potential application as a field emission electron source. PMID- 20975209 TI - Epithelial-mesenchymal transition and senescence: two cancer-related processes are crossing paths. AB - The epithelial-mesenchymal transition is involved in several physiological processes. However, it is also believed to contribute to cancer progression. Conversely, cellular senescence constitutes a failsafe program against cancer progression. Interestingly, EMT and senescence seem to cross paths, with several factors playing dominant roles in both settings. Here, we describe recent observations that link these important cellular processes. PMID- 20975211 TI - Growth and characterization of ceria thin films and Ce-doped gamma-Al2O3 nanowires using sol-gel techniques. AB - gamma-Al(2)O(3) is a well known catalyst support. The addition of Ce to gamma Al(2)O(3) is known to beneficially retard the phase transformation of gamma Al(2)O(3) to alpha-Al(2)O(3) and stabilize the gamma-pore structure. In this work, Ce-doped gamma-Al(2)O(3) nanowires have been prepared by a novel method employing an anodic aluminium oxide (AAO) template in a 0.01 M cerium nitrate solution, assisted by urea hydrolysis. Calcination at 500 degrees C for 6 h resulted in the crystallization of the Ce-doped AlOOH gel to form Ce-doped gamma Al(2)O(3) nanowires. Ce(3+) ions within the nanowires were present at a concentration of < 1 at.%. On the template surface, a nanocrystalline CeO(2) thin film was deposited with a cubic fluorite structure and a crystallite size of 6-7 nm. Characterization of the nanowires and thin films was performed using scanning electron microscopy, transmission electron microscopy, electron energy loss spectroscopy, x-ray photoelectron spectroscopy and x-ray diffraction. The nanowire formation mechanism and urea hydrolysis kinetics are discussed in terms of the pH evolution during the reaction. The Ce-doped gamma-Al(2)O(3) nanowires are likely to find useful applications in catalysis and this novel method can be exploited further for doping alumina nanowires with other rare earth elements. PMID- 20975212 TI - Firing rate control of a neuron using a linear proportional-integral controller. AB - Some electrophysiology experiments require periodically firing neurons. One example is when measuring a neuron's phase response curve (PRC) where a neuron is stimulated with a synaptic input and the perturbation in the neuron's period is measured as a function of when the stimulus is applied. However, even regular spiking cells have considerable variations in their period. These variations can be categorized into two types: jitter, which characterizes the rapid changes in interspike intervals (ISIs) from spike to spike, and drift, which is a slow change in firing rate over seconds. The jitter is removed by averaging the phase advance of a synaptic input applied at a particular phase several times. The drift over long time scales results in a systematic change in the period over the duration of the experiment which cannot be removed by averaging. To compensate for the drift of the neuron over minutes, we designed a linear proportional integral (PI) controller to slowly adjust the applied current to a neuron to maintain the average firing rate at a desired ISI. The parameters of the controller were calculated based on a first-order discrete model to describe the relationship between ISI and current. The algorithm is demonstrated on pyramidal cells in the hippocampal formation showing ISIs from the neuron in an open loop (constant applied current) and a closed loop (current adjusted by a spike rate controller). The advantages of using the controller can be summarized as: (1) there is a reduction in the transient time to reach a desired ISI, (2) the drift in the ISI is removed allowing for long experiments at a desired spiking rate and (3) the variance is diminished by removing the slow drift. Furthermore, we implemented an auto-tuning algorithm that estimates in real time the coefficients for each clamped neuron. We also show how the controller can improve the PRC estimation. The program runs on Real-Time eXperiment Interface (RTXI), which is Linux-based software for real-time data acquisition and control applications. PMID- 20975213 TI - Size-dependent properties of magnetoferritin. AB - We report a detailed experimental study of maghemite nanoparticles, with sizes ranging from 1.6 to 6 nm, synthesized inside a biological mould of apoferritin. The structural characterization of the inorganic cores, using TEM and x-ray diffraction, reveals a low degree of crystalline order, possibly arising from the nucleation and growth of multiple domains inside each molecule. We have also investigated the molecular structure by means of atomic force microscopy in liquid. We find that the synthesis of nanoparticles inside apoferritin leads to a small, but measurable, decrease in the external diameter of the protein, probably associated with conformational changes. The magnetic response of the maghemite cores has been studied by a combination of techniques, including ac susceptibility, dc magnetization and Mossbauer spectroscopy. From the equilibrium magnetic response, we have determined the distribution of magnetic moments per molecule. The results show highly reduced magnetic moments. This effect cannot be ascribed solely to the canting of spins located at the particle surface but, instead, it suggests that magnetoferritin cores have a highly disordered magnetic structure in which the contributions of different domains compensate each other. Finally, we have also determined, for each sample, the distribution of the activation energies required for the magnetization reversal and, from this, the size-dependent magnetic anisotropy constant K. We find that K is enormously enhanced with respect to the maghemite bulk value and that it increases with decreasing size. The Mossbauer spectra suggest that low-symmetry atomic sites, probably located at the particle surface and at the interfaces between different crystalline domains, are the likely source of the enhanced magnetic anisotropy. PMID- 20975214 TI - Multi-band silicon quantum dots embedded in an amorphous matrix of silicon carbide. AB - Silicon quantum dots embedded in an amorphous matrix of silicon carbide were realized by a magnetron co-sputtering process and post-annealing. X-ray photoelectron spectroscopy, glancing x-ray diffraction, Raman spectroscopy and high-resolution transmission electron microscopy were used to characterize the chemical composition and the microstructural properties. The results show that the sizes and size distribution of silicon quantum dots can be tuned by changing the annealing atmosphere and the atom ratio of silicon and carbon in the matrix. A physicochemical mechanism is proposed to demonstrate this formation process. Photoluminescence measurements indicate a multi-band configuration due to the quantum confinement effect of silicon quantum dots with different sizes. The PL spectra are further widened as a result of the existence of amorphous silicon quantum dots. This multi-band configuration would be extremely advantageous in improving the photoelectric conversion efficiency of photovoltaic solar cells. PMID- 20975215 TI - Development of diamond-based X-ray detection for high-flux beamline diagnostics. AB - High-quality single-crystal and polycrystalline chemical-vapor-deposition diamond detectors with platinum contacts have been tested at the white-beam X28C beamline at the National Synchrotron Light Source under high-flux conditions. The voltage dependence of these devices has been measured under both DC and pulsed-bias conditions, establishing the presence or absence of photoconductive gain in each device. Linear response consistent with the theoretically determined ionization energy has been achieved over eleven orders of magnitude when combined with previous low-flux studies. Temporal measurements with single-crystal diamond detectors have resolved the nanosecond-scale pulse structures of both the NSLS and the APS. Prototype single-crystal quadrant detectors have provided the ability to simultaneously resolve the X-ray beam position and obtain a quantitative measurement of the flux. PMID- 20975216 TI - A new technique to examine individual pollutant particle and fibre deposition and transit behaviour in live mouse trachea. AB - During respiration, particles suspended in the air are inhaled and unless cleared by airway defences they can remain and affect lung health. Their size precludes the use of standard imaging modalities so we have developed synchrotron phase contrast X-ray imaging (PCXI) methods to non-invasively monitor the behaviour of individual particles in live mouse airways. In this study we used these techniques to examine post-deposition particle behaviour in the trachea. PCXI was used to monitor the deposition and subsequent behaviour of particles of quarry dust and lead ore; fibres of asbestos and fibreglass; and hollow glass micro spheres. Visibility was examined in vitro and ex vivo to avoid the complicating effects of surrounding tissue and respiratory or cardiac motion. Particle behaviour was then examined after deposition onto the tracheal airway surfaces of live mice. Each particle and fibre looked and behaved differently on the airway surface. Particles lodged on the airway shortly after deposition, and the rate at which this occurred was dependent on the particle type and size. After the live imaging experiments, excised airway samples were examined using light and electron microscopy. Evidence of particle capture into the airway surface fluids and the epithelial cell layer was found. PCXI is a valuable tool for examining post-deposition particulate behaviour in the tracheal airway. These first indications that the interaction between airways and individual particles may depend on the particle type and size should provide a novel approach to studying the early effects of respired particles on airway health. PMID- 20975217 TI - Potassium doping effect on the lattice softening and electronic structure of Ba(1 x)K(x)Fe(2)As(2) probed by X-ray absorption spectroscopy. AB - Ba(1-x)K(x)Fe(2)As(2) superconducting samples (x = 0, 0.2, 0.4, 0.5) were synthesized by the solid-state reaction method. In this contribution the doping effect of potassium on the lattice dynamics in this newly discovered Ba(1 x)K(x)Fe(2)As(2) superconductor has been investigated by extended X-ray absorption fine-structure spectroscopy. The analysis shows that with potassium doping an increased disorder in the iron layers is mainly related to the softening of the Fe-Fe bond. Information about the electronic structure of these materials has also been obtained by looking at the X-ray absorption near-edge structure spectra that point out the presence of holes in the Fe-3d/As-4p hybridized orbital of the BaFe(2)As(2)-based system. PMID- 20975218 TI - Indirectly illuminated X-ray area detector for X-ray photon correlation spectroscopy. AB - An indirectly illuminated X-ray area detector is employed for X-ray photon correlation spectroscopy (XPCS). The detector consists of a phosphor screen, an image intensifier (microchannel plate), a coupling lens and either a CCD or CMOS image sensor. By changing the gain of the image intensifier, both photon-counting and integrating measurements can be performed. Speckle patterns with a high signal-to-noise ratio can be observed in a single shot in the integrating mode, while XPCS measurement can be performed with much fewer photons in the photon counting mode. By switching the image sensor, various combinations of frame rate, dynamic range and active area can be obtained. By virtue of these characteristics, this detector can be used for XPCS measurements of various types of samples that show slow or fast dynamics, a high or low scattering intensity, and a wide or narrow range of scattering angles. PMID- 20975219 TI - Raster microdiffraction with synchrotron radiation of hydrated biopolymers with nanometre step-resolution: case study of starch granules. AB - X-ray radiation damage propagation is explored for hydrated starch granules in order to reduce the step resolution in raster-microdiffraction experiments to the nanometre range. Radiation damage was induced by synchrotron radiation microbeams of 5, 1 and 0.3 um size with ~0.1 nm wavelength in B-type potato, Canna edulis and Phajus grandifolius starch granules. A total loss of crystallinity of granules immersed in water was found at a dose of ~1.3 photons nm(-3). The temperature dependence of radiation damage suggests that primary radiation damage prevails up to about 120 K while secondary radiation damage becomes effective at higher temperatures. Primary radiation damage remains confined to the beam track at 100 K. Propagation of radiation damage beyond the beam track at room temperature is assumed to be due to reactive species generated principally by water radiolysis induced by photoelectrons. By careful dose selection during data collection, raster scans with 500 nm step-resolution could be performed for granules immersed in water. PMID- 20975220 TI - Coherent X-ray diffraction investigation of twinned microcrystals. AB - Coherent X-ray diffraction has been used to study pseudo-merohedrally twinned manganite microcrystals. The analyzed compositions were Pr(5/8)Ca(3/8)MnO(3) and La(0.275)Pr(0.35)Ca(3/8)MnO(3). The prepared loose powder was thermally attached to glass (and quartz) capillary walls by gentle heating to ensure positional stability during data collection. Many diffraction data sets were recorded and some of them were split as expected from the main observed twin law: 180 degrees rotation around [101]. The peak splitting was measured with very high precision owing to the high-resolution nature of the diffraction data, with a resolution (Deltad/d) better than 2.0 * 10(-4). Furthermore, when these microcrystals are illuminated coherently, the different crystallographic phases of the structure factors induce interference in the form of a speckle pattern. The three dimensional speckled Bragg peak intensity distribution has been measured providing information about the twin domains within the microcrystals. Research is ongoing to invert the measured patterns. Successful phase retrieval will allow mapping out the twin domains and twin boundaries which play a key role in the physical properties. PMID- 20975221 TI - Design and construction of a compact end-station at NSRRC for circular-dichroism spectra in the vacuum-ultraviolet region. AB - A synchrotron-radiation-based circular-dichroism end-station has been implemented at beamline BL04B at the National Synchrotron Radiation Research Center (NSRRC) in Taiwan for biological research. The design and performance of this compact end station for measuring circular-dichroism spectra in the vacuum-ultraviolet region are described. The linearly polarized light from the beamline is converted to modulated circularly polarized light with a LiF photoelastic modulator to provide a usable wavelength region of 130-330 nm. The light spot at the sample position is 5 mm * 5 mm at a slit width of 300 um and provides a flux greater than 1 * 10(11) photons s(-1) (0.1% bandwidth)(-1). A vacuum-compatible cell made of two CaF(2) windows has a variable path length from 1.3 um to 1 mm and a temperature range of 253-363 K. Measured CD spectra of (1S)-(+)-10-camphorsulfonic acid and proteins demonstrated the ability of this system to extend the wavelength down to 172 nm in aqueous solution and 153 nm in hexafluoro-2-propanol. PMID- 20975222 TI - Time-resolved SAXS measurements facilitated by online HPLC buffer exchange. AB - Small-angle X-ray scattering (SAXS) is a powerful technique to structurally characterize biological macromolecules in solution. Heterogeneous solutions are inherently challenging to study. However, since SAXS data from ideal solutions are additive, with careful computational analysis it may be possible to separate contributions from individual species present in solution. Hence, time-resolved SAXS (TR-SAXS) data of processes in development can be analyzed. Many reported TR SAXS results are initialized by a sudden change in buffer conditions facilitated by rapid mixing combined with either continuous or stopped flow. In this paper a method for obtaining TR-SAXS data from systems where the reaction is triggered by removal of a species is presented. This method is based on fast buffer exchange over a short desalting column facilitated by an online HPLC (high-performance liquid chromatography) connected to the SAXS sample cell. The sample is stopped in the sample cell and the evolving reaction is followed. In this specific system the removal of phenol initiates a self-association process of long-acting insulin analogues. For this experiment, data were collected in time series while varying concentrations. The method can be generally applied to other systems where removal of a species or other changes in experimental conditions trigger a process. PMID- 20975223 TI - Software for the high-throughput collection of SAXS data using an enhanced Blu Ice/DCS control system. AB - Biological small-angle X-ray scattering (SAXS) provides powerful complementary data for macromolecular crystallography (MX) by defining shape, conformation and assembly in solution. Although SAXS is in principle the highest throughput technique for structural biology, data collection is limited in practice by current data collection software. Here the adaption of beamline control software, historically developed for MX beamlines, for the efficient operation and high throughput data collection at synchrotron SAXS beamlines is reported. The Blu-Ice GUI and Distributed Control System (DCS) developed in the Macromolecular Crystallography Group at the Stanford Synchrotron Radiation Laboratory has been optimized, extended and enhanced to suit the specific needs of the biological SAXS endstation at the SIBYLS beamline at the Advanced Light Source. The customizations reported here provide a potential route for other SAXS beamlines in need of robust and efficient beamline control software. As a great deal of effort and optimization has gone into crystallographic software, the adaption and extension of crystallographic software may prove to be a general strategy to provide advanced SAXS software for the synchrotron community. In this way effort can be put into optimizing features for SAXS rather than reproducing those that have already been successfully implemented for the crystallographic community. PMID- 20975224 TI - The study of the reconstructed three-dimensional structure of a solid-oxide fuel cell cathode by X-ray nanotomography. AB - The microstructure and morphology of solid-oxide fuel-cell electrodes are very complex but important because they strongly affect the electrical performance of the cell. In this work the high-resolution X-ray nanotomography technique is applied to reconstruct the three-dimensional microstructure of a (La(0.8)Sr(0.2))(0.95)MnO(3) yttria-stabilized zirconia composite cathode. Some key microstructural parameters, such as the porosity, representative elementary volume, connected pore volume and pore phase tortuosity, were obtained based on the three-dimensional reconstruction volume data with a spatial resolution of sub 60 nm. These parameters bear intimate correlation with the efficiency of the electrochemical conversion process, and provide valuable information for optimizing the manufacturing processes and improving the device's reliability. PMID- 20975225 TI - Beam-induced damage on diffractive hard X-ray optics. AB - The issue of beam-induced damage on diffractive hard X-ray optics is addressed. For this purpose a systematic study on the radiation damage induced by a high power X-ray beam is carried out in both ambient and inert atmospheres. Diffraction gratings fabricated by three different techniques are considered: electroplated Au gratings both with and without the polymer mold, and Ir-coated Si gratings. The beam-induced damage is monitored by X-ray diffraction and evaluated using scanning electron microscopy. PMID- 20975226 TI - Extended soft X-ray emission spectroscopy: quantitative assessment of emission intensities. AB - Soft X-ray emission spectroscopy (SXES) in the energy range between 150 eV and 1500 eV has typical attenuation lengths between tens and a few hundred nanometres. In this work the transmission of soft X-rays in synchrotron-based SXES has been quantitatively analysed using specially prepared layer samples. The possibility of extending the standard qualitative analysis of SXES by exploiting the information underlying the emission intensity was examined for thin layer structures. Three different experiment series were accomplished with model layer systems based on different sulfur-containing substrates: (i) MoS(2), (ii) CuInS(2), (iii) Cu(In,Ga)(S,Se)(2). The absorption of the S L(2,3) emission line by ZnO cover layers of up to 80 nm thickness was monitored and compared with theoretical expectations. By comparison with a reference intensity recorded from a bare substrate, the attenuation of the S L(2,3) emission could be used to accurately determine the ZnO overlayer thickness up to a critical thickness, depending on the set-up and the net S L(2,3) emission intensity. The results from these local energy-resolved spot measurements were compared with spatially resolved scans of the integral S L(2,3) emission intensity over areas of several mm(2). In the scan images the attenuation of the S L(2,3) emission intensity clearly reflects the local ZnO layer thickness. From the attenuation the ZnO layer thicknesses were calculated and compared with ellipsometric measurements and were found to be in excellent agreement. These results demonstrate the benefits of a quantitative analysis of SXES, making it an even more powerful tool for examining buried interfaces and for monitoring lateral inhomogeneities. PMID- 20975227 TI - A variable-wavelength-based approach of phase retrieval for contrast transfer function based methods. AB - X-ray phase-contrast imaging has emerged as an important method for improving contrast and sensitivity in the field of X-ray imaging. This increase in the sensitivity is attributed to the fact that, in the hard X-ray regime, the phase shift is more prominent as compared with the attenuation for materials having a low X-ray absorption coefficient. Among all the methods using the X-ray phase contrast technique, in-line phase-contrast imaging scores over the other methods in terms of ease of implementation and efficient use of available X-ray flux. In order to retrieve the projected phase map of the object from the recorded intensity pattern, a large number of algorithms have been proposed. These algorithms generally use either the transport of intensity or contrast transfer function based approach for phase retrieval. In this paper it is proposed to use multiple wavelengths for phase retrieval using the contrast transfer function based formalism. PMID- 20975228 TI - Ratio-contrast imaging of dual-energy absorption for element mapping with a scanning transmission X-ray microscope. AB - The detection of chemical mapping with a spatial resolution of 30 nm has been achieved with a scanning transmission X-ray microscope at the Shanghai Synchrotron Radiation Facility. For each specimen, two absorption images were scanned separately with energies E(1) and E(2): E(1) was focused on the absorption edge of the chosen element and E(2) was focused below the edge. A K edge division method is proposed and applied to obtain the element mapping. Compared with the frequently used K-edge subtraction method, this ratio-contrast method is shown to be more accurate and sensitive in identifying the elements of interest, where the definition of the contrast threshold is simple and clear in physics. Several examples are presented to illustrate the effectiveness of the method. PMID- 20975229 TI - KDP:Mn piezoelectric coefficients obtained by X-ray diffraction. AB - Crystals of pure potassium dihydrogen phosphate KH(2)PO(4) (KDP) and Mn-doped KDP (KDP:Mn) were grown from a water solution by the slow evaporation method and their piezoelectric properties were studied by X-ray diffraction methods. The results have shown an increase in the piezoelectric coefficients with the doping. PMID- 20975230 TI - Phase-contrast X-ray imaging of the gas diffusion layer of fuel cells. AB - The understanding of and in situ observation of the transport and distribution of water in carbon-paper gas diffusion layers (GDLs) using non-destructive imaging techniques is critical for achieving high performance in polymer electrolyte fuel cells (PEFCs). To investigate the behavior of water in GDLs of PEFCs, phase contrast X-ray imaging via X-ray interferometric imaging (XII) and diffraction enhanced imaging (DEI) were performed using 35 keV X-rays. The XII technique is useful for the radiographic imaging of GDLs and in situ observations of water evolution processes in operating PEFCs. DEI provides a way for tomographic imaging of GDLs in PEFCs. Because high-energy X-rays are applicable to the imaging of both carbon papers and heavy materials, which make up PEFCs, phase contrast X-ray imaging techniques have proven to be valuable for investigation of GDLs. PMID- 20975231 TI - Hard X-ray imaging for landslide research. AB - Synchrotron phase-contrast hard X-ray imaging is used to provide highly efficient direct visualization of landslide dynamics and granular flows in fully wet granular piles. High penetration capability and phase-contrast enhancement of hard X-rays offer marked advantages in the precise tracking of individual granular movements through a thick water medium. It is revealed that the stress accumulation follows a power-law evolution while the relaxation follows an exponential one. The onset of landslide emerges at the trade-off of the two evolutions. PMID- 20975233 TI - Evaluating microvascular obstruction after acute myocardial infarction using cardiac magnetic resonance imaging and 201-thallium and 99m-technetium pyrophosphate scintigraphy. AB - BACKGROUND: Few studies have compared the ability of cardiac magnetic resonance (CMR) with that of scintigraphy using 201-thallium (201-Tl) and 99m-technetium pyrophosphate (99m-Tc PYP) to evaluate microvascular obstructions (MOs). In the present study the relationship between the scintigraphic and CMR characteristics of MOs after acute myocardial infarction (MI) was examined. METHODS AND RESULTS: The 14 patients (age 69+/-8 years, 11 males) underwent 201-Tl/99m-Tc PYP SPECT 7+/-3 days, initial CMR 16+/-12 days, and follow-up CMR 193+/-20 days after a reperfused first acute MI. Each image was analyzed using a 17-segment model. Segmental extent of delayed enhancement (DE), wall motion (WM) and degree of 201 Tl uptake were scored in 238 segments. Of 91 MI segments, MO was recognized in 22 (25%) segments on CMR. WM was significantly better in proportion to 201-Tl uptake (P=0.01) in MO segments. All 8 MO segments with WM improvement at follow-up had 99m-Tc PYP uptake, although only 3 (21%) of 14 MO segments that did not show WM improvement at follow-up had 99m-Tc PYP uptake (P=0.001). CONCLUSIONS: 99m-Tc PYP and 201-Tl scintigraphy have the potential to predict WM status and improvement of the MO region after reperfused acute MI. PMID- 20975234 TI - Atrioventricular block-induced Torsades de Pointes with clinical and molecular backgrounds similar to congenital long QT syndrome. AB - BACKGROUND: Atrioventricular block (AVB) sometimes complicates QT prolongation and torsades de pointes (TdP). METHODS AND RESULTS: The clinical and genetic background of 14 AVB patients (57+/-21 years, 13 females) who developed QT prolongation and TdP was analyzed. Electrophysiological characteristics of mutations were analyzed using heterologous expression in Chinese hamster ovary cells, together with computer simulation models. Every patient received a pacemaker or implantable cardioverter defibrillator; 3 patients had recurrence of TdP during follow-up because of pacing failure. Among the ECG parameters, QTc interval was prolonged to 561+/-76ms in the presence of AVB, but shortened to 495+/-42ms in the absence of AVB. Genetic screening for KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 revealed four heterozygous missense mutations of KCNQ1 or KCNH2 in 4 patients (28.6%). Functional analyses showed that all mutations had loss of functions and various gating dysfunctions of I(Ks) or I(Kr). Finally, action potential simulation based on the Luo-Rudy model demonstrated that most mutant channels induced bradycardia-related early afterdepolarizations. CONCLUSIONS: Incidental AVB, as a trigger of TdP, can manifest as clinical phenotypes of long QT syndrome (LQTS), and that some patients with AVB-induced TdP share a genetic background with those with congenital LQTS. PMID- 20975235 TI - Impact of renin-angiotensin system polymorphisms on development of systolic dysfunction in hypertrophic cardiomyopathy. Evidence from a study of genotyped patients. AB - BACKGROUND: Although the renin-angiotensin system (RAS) can affect the development of left ventricular (LV) hypertrophy, few data exist regarding the relationships between RAS polymorphisms and alteration of LV function. The effect of RAS polymorphisms on LV function in genotyped hypertrophic cardiomyopathy (HCM) was examined in the present study. METHODS AND RESULTS: The study group comprised 126 carriers with sarcomere gene mutations from 49 HCM families (64 males, mean age 51+/-21 years). LV morphology and function were evaluated by echocardiography. In angiotensin-converting enzyme (ACE) insertion/deletion (I/D), the D allele (n=81) exhibited significantly larger LV end-systolic dimension (LVDs) (32+/-11mm) and lower ejection fraction (56+/-15%) than those with the II genotype (28+/-7mm and 62+/-12%, respectively, P<0.05; n=45). Although angiotensin II type 1 receptor (AT(1)-R) A/C(1166) polymorphism did not affect echocardiographic parameters, the presence of the ACE D allele with the AT(1)-R C(1166) allele (n=9) was associated with larger LVDs (37+/-17mm) and lower ejection fraction (48+/-20%) compared with other genotypes (30+/-9mm and 58+/-14%, respectively, P<0.05; n=117). Under these conditions, severe LV hypertrophy was frequently associated with LV wall thinning. CONCLUSIONS: The presence of both the ACE D and AT(1)-R C(1166) allele is associated with LV dilation with systolic dysfunction in genotyped HCM. In addition to the severity of LV hypertrophy, screening for these RAS polymorphisms could contribute to further risk stratification of patients with HCM, although other genetic polymorphisms should be further examined. PMID- 20975237 TI - [A computerized method for detection of acute cerebral infarction on CT images]. AB - This paper proposes a computerized method for automated detection of acute cerebral infarction (ACI) on CT images. This method is based on the difference value of image features in the two regions-of-interests (ROIs) selected at symmetrical positions. In our computerized method, first, we segmented the brain parenchyma by the thresholding technique after correction of inclination of the midsagittal plane with translation and rotation of the image. Then we selected the middle cerebral artery (MCA) region of the brain parenchyma. Moreover, many ROIs with a 32*32 matrix size were selected in the MCA region. In addition, image features in each ROI were determined from the statistical analysis, the co occurrence matrix and the run length matrix. Finally, ROIs with ACI were classified by using a linear discriminant analysis with difference values of image features in two ROIs at symmetrical positions. Nineteen cases with ACI and normal 14 cases were employed in this study. As a result of our experiments, the sensitivity of detection of ACI was 88.0% with an average number of false positives of 4.6 per case. Our computerized method provided a relatively high performance for detection of ACI. Therefore, we believe this method would be useful for an algorithm of a computer-aided diagnosis to detect ACI on CT images. PMID- 20975238 TI - [Influence of imaging parameters on the measurement of apparent diffusion coefficient]. AB - The apparent diffusion coefficient (ADC) values are calculated by using signal intensity in diffusion-weighted images (DWIs) with two or more different b-value. Therefore, the signal to noise ratio (SNR) of DWI with higher b-value may have a big influence on the measured ADC value. We examined the influence of the imaging parameters on the calculated ADC values. The SNR of DWI increased by using a larger voxel size, by means of a decreased number of matrix, an increased slice thickness, and an increased field of view (FOV). However, when the number of excitations was increased to improve the SNR of DWI, the signal intensity of background noise was observed to be slightly increased. It was suggested that the consistency of measured ADC was not preserved when the signal of the DWIs with higher b-value dropped close to the noise level. PMID- 20975239 TI - [Study of setup margins in radiation therapy: how many verification times and patients are required]. AB - INTRODUCTION: The purpose of this research is to require suitable numbers of verification times and patients for calculating the setup margin (SM) in radiotherapy. METHODS: 1) This simulation was performed using the standard normal distribution random number. The simulation used the seven levels of verification from 5 to 35 in 5 steps, and 35 patients. 2) The setup error in prostate radiotherapy at three hospitals was analyzed. Systematic error and random error were calculated from each patient's average value and standard deviation. Furthermore, we used the formula of J Stroom to calculate SM. Suitable numbers of verification times and patients were obtained from statistical analysis of the simulated results. RESULTS: 1) In the results of our simulations using random number, SM converged on 1.0 to 1.3 mm, regardless of the number of patients, when there were more than 15 verification times; 2) The results of clinical data were slightly different from the standard normal distribution, and more than 15 verification times and over 15 patients were required. CONCLUSIONS: In conclusion, calculation of the SM in radiotherapy required more than 15 verification times and over 15 patients. PMID- 20975240 TI - [Simulation study for artifacts on Gd-EOB-DTPA-enhanced liver dynamic MR imaging in arterial dominant phase]. AB - We performed a simulation for artifacts on liver dynamic MR imaging with the contrast agent gadolinium-ethoxybenzyl (Gd-EOB)-DTPA. The signal enhancement of the image by the contrast agent in the arterial dominant phase was assumed, and the time-enhancement curve was numerically generated. The data in k-space was obtained by the Fourier transform of a liver image. By assuming the scan timing and duration in the time-enhancement curve, the data set of each phase-encoding step in k-space was increased in proportion to the corresponding intensity in the time-enhancement curve. We obtained the simulated image by the Fourier transform of the k-space data, and investigated artifacts in the image. Assuming the use of the centric k-space filling scheme, blurring in the image is found when the scan timing is delayed. When the scan is started in an early timing, we observe the effect of edge enhancement in the image. These artifacts of blurring and edge enhancement are decreased by shortening the scan duration. Assuming the use of the sequential k-space filling scheme, those artifacts are not prominent. The use of the sequential scheme would be effective for the purpose of avoiding the artifacts. It is known that the contrast enhancement would not be sufficient without optimal scan timing; in addition, artifacts should be noted. For basic study of the contrast enhancement and artifacts, our simulation technique based on the time-enhancement curve would be useful. PMID- 20975241 TI - [What factors affected image quality in coronary multidetector-row computed tomography?]. AB - BACKGROUND: Although it is well known that we usually cannot acquire a high quality coronary MDCT in patients with arrhythmia or incomplete breath-hold, we sometimes also cannot obtain a high quality coronary MDCT in patients without arrhythmia or incomplete breath-hold. PURPOSE: We studied what factors other than arrhythmia or incomplete breath-hold affected image quality. METHODS: Coronary MDCT and echocardiography were performed within one month in 2145 patients, and 452 cases of arrhythmia or 102 cases of incomplete breath-hold during scanning were eliminated. The remaining 1591 patients were studied. Those patients were divided into two groups (mid-diastolic phase reconstruction (MD) group (N=1377) and end-systolic phase reconstruction (ES) group (N=214)). Age, body weight, mean heart rate (HR) during scanning, temporal resolution (TR) and left ventricular ejection fraction (LVEF) by echocardiography were estimated. Image quality (A: Excellent (3 points), B: Acceptable (2 points), C: Unacceptable (1 point)) was evaluated. RESULTS: The mean image quality points of the MD group (2.9+/-0.3) were significantly (P<0.0001) higher than the mean image quality points of the ES group (2.3+/-0.7), and the mean HR of the MD group (57+/-6 bpm) was significantly (P<0.0001) lower than that of the ES group (81+/-15 bpm). In the MD group, HR and TR were selected as significant factors affecting image quality by stepwise regression analysis. In the ES group, TR and HR were selected. In the ES subgroup with HR<90 bpm, TR and HR were selected; however, in the ES subgroup with HR>=90 bpm, TR and LVEF were selected. CONCLUSION: In the MD group, low HR was important for high quality coronary MDCT. In the ES subgroup with HR<90, short TR and low HR were important; however, in the ES subgroup with HR>=90 bpm, TR and LVEF were more important than HR. PMID- 20975242 TI - [Result of the onsite dosimetry and questioning about quality assurance/ quality control of radiotherapy in the Hokuriku area - a comparison with past results -]. AB - PURPOSE: To analyze temporal changes in human resources in the radiotherapy section, quality assurance/quality control (QA/QC) and dose difference for radiotherapy in the Hokuriku area based on the results of past investigations and our investigation. METHOD: We visited radiotherapy sections of 17 hospitals in the Hokuriku area (5 in Toyama, 9 in Ishikawa and 3 in Fukui) to measure the dose at the reference point of a linear accelerator (LINAC), as we asked questions to a radiotherapist about human resources, QA/QC of LINAC, etc. We compared our results with past reports (1992 to 2007) on the dose difference, human resources and frequency of dose monitor system calibration. RESULTS: The number of physicians has not changed since 1999, but the number of radiotherapists was significantly increased. Weekly dose monitor system calibration has been achieved in 80% of the institutions in our survey. This percentage was significantly higher than in the past surveys. The dose difference distribution from our onsite dosimetry did not significantly differ from that from the onsite dosimetry in 2007. 91% of the institutions have accomplished within 2% of the dose difference. CONCLUSION: We found that the number of physicians has not increased since 1999, but the number of radiotherapists has increased. We conclude that the increment of radiotherapists led to 80% achievement of the weekly dose monitor system calibration. Almost all institutions in Hokuriku area have properly performed QA of the dose monitor system. PMID- 20975243 TI - [Fundamental study of the fat-suppressed three-dimensional coherent oscillatory state acquisition for the manipulation of image contrast (3D-COSMIC) sequence in the knee joint cartilage]. AB - Fat-suppressed three-dimensional coherent oscillatory state acquisition for the manipulation of image contrast (3D-COSMIC) is a sequence that is based on fast imaging employing steady state acquisition (FIESTA) of balanced steady-state free precession (balanced SSFP). Since the data acquisition of steady-state transition is filled up with the center of k-space, improvement in the contrast of the cartilage, which is a low T2/T1 value domain, is expected. This time we report on the usability in applying the above sequence to cartilage imaging of the knee joint and comparing and examining this sequence with the sequence in the past from the viewpoints of the contrast and scan time. As a result, compared with fat suppressed three-dimensional spoiled gradient echo (3D-SPGR), the contrast of marrow and synovial fluid was equivalent to that of the cartilage, and imaging time was shorter than half of that with the cartilage. Compared with a fat suppressed two-dimensional proton density weighted image (2D-PDWI), the contrast of the cartilage and synovial fluid was significantly improved, and spatial resolution was also excellent. As a short imaging time and a high resolution image pick-up are possible for fat-suppressed 3D-COSMIC, and it can describe minute damage of the cartilage since it depicts synovial fluid as high-level signals, I think this technique is useful. PMID- 20975245 TI - [5. Preparation for a presentation in English]. PMID- 20975244 TI - [Development of the method for the similarity detection of descriptions in radiology reports using structuring technology]. AB - Radiologists often spend much time for re-reading some of the past free-text radiology reports and determining interval changes in the physical findings when creating a report for long term cases. The aim of this study was to propose the method to detect semantic similar descriptions in the free-text reports using the structuring method based on text-mining technology. In a previous study, we had developed the structuring method that can semantically analyze the free-text reports and convert them into the description unit consisting of five items: finding/diagnosis, modifier, region, regional modifier, and confidence. Our developed prototype system extracted similar descriptions from the free-text reports by calculating the similarity index between description units. We confirmed similar descriptions extracted by the system applied to free-text reports of cases which had more than one chest CT examination written in actual clinical situation. As a result, it became available to identify candidates of similar descriptions from free-text reports. In some cases regarding practical use, the similar descriptions could not be identified in the sentences which used paraphrasing or where the findings had status changes. A solution of identifying similarity in these cases was necessary to improve the method. With the presented method here, it is expected that interval changes in the findings can be visualized and applied it to support diagnosis. PMID- 20975247 TI - [On the second year as a JIRA's leader]. PMID- 20975248 TI - Activation of beta3-adrenergic receptor inhibits ventricular arrhythmia in heart failure through calcium handling. AB - Ventricular arrhythmia in chronic heart failure (CHF) is considered to be associated with stimulation of beta-adrenergic receptors (beta-ARs). Three classes of beta-ARs have been identified; importantly, distinct from beta1 and beta2 subtypes, beta3-AR could inhibit arrhythmia. Intracellular Ca2+ is considered as a predominant effecter of arrhythmia during heart failure. However, the exact role of beta3-AR in arrhythmia and Ca2+ regulation in CHF is not clear yet. Therefore, we studied the effect of BRL37344, a specific beta3-AR activator, on CHF-related ventricular arrhythmia and cellular Ca2+ transport. Rabbits with CHF induced by combined aortic insufficiency and aortic constriction were treated with BRL37344 in the presence or absence of beta1-AR and beta2-AR stimulation. We then evaluated the current produced by sodium calcium exchanger (INCX), an electrical marker of abnormal Ca2+ removal through ion transporter protein sodium calcium exchanger (NCX), Ca2+ transient, a sign of Ca2+ entering the cell, concentration of Ca2+ in sarcoplasmic reticulum (SR) (SR Ca2+ load) and its abnormal release (SR Ca2+ leak). After treatment with BRL37344, the incidence of ventricular arrhythmias induced by infusion of a beta1-AR or beta2-AR activator decreased significantly. Similarly, beta3-AR stimulation remarkably inhibited increase of INCX, Ca2+ transient, SR Ca2+ load and leak induced by activation of beta1-AR or beta2-AR. SR59230A, a specific beta3-AR blocker, abolished the inhibitory effects of BRL37344. These results suggest that beta3-AR activation could inhibit ventricular arrhythmia through regulating intracellular Ca2+. Thus, beta3-AR is a feasible therapeutic target that holds promise in the treatment of ventricular arrhythmias in CHF. PMID- 20975249 TI - Growth hormone secretory status evaluated by growth hormone peak after two pharmacological growth hormone release stimuli did not significantly influence the two-year catch-up growth induced by growth hormone therapy in 318 prepubertal short children with idiopathic growth retardation. AB - BACKGROUND/AIMS: In prepubertal short children with idiopathic growth retardation, growth hormone (GH) peak after GH release stimuli classifies patients as growth hormone- deficient (GHD) or non-GHD. This study compared a 2 year growth response to GH therapy in 318 prepubertal short children. METHODS: Patients were classified as: severe GHD (GH peaks <5 ng/ml after 2 stimuli; n = 54), mild GHD (GH peaks <10 ng/ml, but one or two between 5 and 10 ng/ml; n = 140), dissociated GH release (GH peak >= 10 ng/ml after 1 stimulus and <10 ng/ml after the other; n = 89), and normal GH release (GH peaks >= 10 ng/ml after 2 stimuli; n = 35). RESULTS: Two-year height gain did not differ statistically among the 4 groups: 1.39 +/- 0.51 SD, 16.4 +/- 2.3 cm; 1.23 +/- 0.56 SD, 15.8 +/- 2.1 cm; 1.18 +/- 0.53 SD, 15.3 +/- 2.0 cm, and 1.14 +/- 0.53 SD, 15.4 +/- 2.0 cm, respectively, as was also the case for bone age gain: 2.5 +/- 0.6, 2.4 +/- 0.7, 2.6 +/- 0.7 and 2.3 +/- 0.5 years, respectively. CONCLUSIONS: Our results suggest that GH release stimuli are of little help for deciding on GH therapy in the clinical management of prepubertal short children with idiopathic growth retardation, while well-defined anthropometric and biochemical criteria may be useful. PMID- 20975250 TI - The effect of sunitinib on immune subsets in metastatic clear cell renal cancer. AB - BACKGROUND: Sunitinib is standard first-line therapy for metastatic clear cell renal cancer (MCRC). It is associated with leucopenia; however, its effects on specific immune cell subsets are unclear. Alterations in immune cell subsets may contribute to tumour progression. METHODS: Lymphocyte subsets (CD3, 4, 8, 19 and 56) were measured in 43 untreated MCRC patients who received sunitinib. The protocol included a structured treatment interruption of 5 weeks. Cell populations were measured at specific time points during sunitinib treatment and the treatment break. RESULTS: Sunitinib was associated with significant declines in total leucocyte (-48%), neutrophil (-62%), CD3 total T cell (-31%) and CD4 counts (32%; p < 0.05). There was no significant change in CD19 B lymphocyte, CD8 or CD56 natural killer cells. During the sunitinib-free interval, all parameters recovered to baseline. No patients developed opportunistic infections or neutropenic sepsis. The level of specific immune subsets at presentation or occurrence of a fall in specific counts had an effect on progression-free survival (p > 0.05). CONCLUSIONS: Sunitinib is associated with reversible inhibition of specific lymphocyte subsets which has implications for the immunological control of MCRC and its use in combination with other agents. Despite suppressive effects, there was no evidence of predisposition to immune suppressive-related infection. PMID- 20975251 TI - Validity and sensitivity to change of the falls efficacy scales international to assess fear of falling in older adults with and without cognitive impairment. AB - BACKGROUND: Measures of fear of falling have not yet been validated in patients with dementia, leaving a methodological gap that limits research in a population at high risk of falling and fall-related consequences. OBJECTIVE: The objectives of this study are to determine: (1) the validity of the 7-item Short Falls Efficacy Scale International (Short FES-I) in geriatric patients with and without cognitive impairment, and (2) the sensitivity to change of the 10-item Falls Efficacy Scale (FES), the 16-item FES-I and the 7-item Short FES-I in geriatric patients with dementia. METHODS: Cross-sectional data of community-dwelling older adults and geriatric rehabilitation patients (n = 284) collected during face-to face interviews were used to determine construct and discriminant validity by testing for differences within variables related to fear of falling. Sensitivity to change was studied in an intervention study including patients with mild to moderate dementia (n = 130) as determined by standard response means (SRMs). RESULTS: The Short FES-I showed excellent construct and discriminant validity in the total group and subsamples according to cognitive status. Sensitivity to change was adequate to good in the FES (range SRM: 0.18-0.77) and FES-I (range SRM: 0.21-0.74), with the Short FES-I showing the highest peak sensitivity to change (range SRM: 0.18-0.91). CONCLUSIONS: The Short FES-I is a valid measure to assess fear of falling in frail older adults with and without cognitive impairment, yet it may show floor effects in higher functioning older people. All scales, including the Short FES-I, were sensitive to detecting intervention induced changes in concerns about falling in geriatric patients with dementia. PMID- 20975252 TI - Radical prostatectomy in high-grade prostate cancer, salvage and adjuvant radiotherapy. AB - INTRODUCTION: Prostate cancer with a Gleason score (GS) of 8-10 is linked to a higher risk of recurrence and progression. The aim of this paper is to evaluate treatment results of our high-risk patient cohort. PATIENTS AND METHODS: The cohort of 42 patients with radical prostatectomy (RP) specimen histology GS 8-10 was assessed. The patients were followed up after RP and radiotherapy (RT) was delivered in case of a biochemical relapse. Adjuvant radiotherapy (aRT) was delivered only in case of a positive surgical margin (PSM). The following parameters were evaluated: biochemical progression-free survival (BPFS), overall survival (OS) and cancer-specific survival (CSS). The second objective was to evaluate adverse effects of RP and RT. RESULTS: The median follow-up time was 88 months (18-168). RP led to BPFS in 16 patients (38%). Five patients with PSM underwent aRT and 20 underwent salvage radiotherapy (sRT). One patient died of myocardial infarction and 1 patient died of metastatic disease. Skeletal metastases were recorded in 2 patients. The BPFS in RP combinations with sRT or aRT was reached in 29 patients (69%). The OS and CSS in our cohort reached 95 and 98%, respectively. CONCLUSION: Management with aRT only in PSM was very effective, according to our retrospective study. PMID- 20975253 TI - Quantitative estimation and chemical coding of spiny type I neurons in human intestines. AB - Previous studies have shown that most human myenteric neurons co-staining for vasoactive intestinal peptide (VIP), neuronal nitric oxide synthase (nNOS) and neurofilaments (NF) display the morphology of spiny type I neurons displaying a descending projection pattern. Here, we estimated the proportions of spiny neurons in human intestines, the amount of congruence of VIP/nNOS-immunoreactive with spiny neurons and whether galanin (GAL) is co-localized with VIP. Three sets of colchicine-pretreated and fixed whole mounts of 21 patients or body donors (median age 65 years; 10 female, 11 male) were stained for VIP, nNOS and NF, for VIP, nNOS and the human neuronal protein Hu C/D (HU) as well as for VIP, nNOS and GAL. The majority of VIP/nNOS-co-reactive neurons were spiny neurons (79/80% in small/large intestine, respectively) and the majority of spiny neurons co-stained for VIP and nNOS (82/69%). Neurons co-immunoreactive for VIP/nNOS/HU amounted to 7 and 4%, respectively. GAL/VIP-co-immunoreactivity was demonstrated in 69 and 27% of spiny neurons, respectively. We conclude that the number of neurons displaying co-reactivity for VIP and nNOS is a quantitative indicator of spiny neurons in both small and large intestine and that the proportion of spiny neurons is about 7% in small and 4% in large intestines. Since nerve fibres co staining for NF/VIP/nNOS were found mainly in the circular muscle layer but not the surrounding perikarya of spiny neurons, we suggest that they may represent inhibitory motor neurons rather than descending interneurons. PMID- 20975254 TI - Formation of bovine placental trophoblast spheroids. AB - INTRODUCTION: In this study, we aimed to form spheroids with the bovine placental trophoblast cell line F3. Spheroids are 3-dimensional culture models which can be used to conduct versatile in vitro and in vivo experiments. MATERIALS AND METHODS: The spheroids were generated using the hanging drop technique, 25% methocel and matrigel. The F3 spheroids were characterized morphologically by light microscopy and transmission (TEM) and scanning electron microscopy (SEM) and immunohistochemistry (ezrin, vimentin, cytokeratin, placental lactogen). The fluorescent dyes calcein and ethidium homodimer were used to determine the viability of the spheroidal F3 cells by immunofluorescence microscopy. RESULTS: The cell line F3 only formed spheroids by the hanging drop technique when matrigel was added. The trophoblast spheroids were delimited and fully covered by extracellular matrix (light microscopy/TEM/SEM). Cells contributing to spheroids could not be discriminated from each other (light microscopy). The outer spheroidal layer consisted of cells which possessed an apical pole with microvilli that were directed to the outside (light microscopy/TEM). All of the spheroidal F3 cells expressed ezrin, vimentin and cytokeratin, but not placental lactogen. The spheroid core contained degenerating cells whilst the F3 cells of the outer rim were viable (TEM/immunofluorescence microscopy). DISCUSSION: We have established a 3-dimensional spheroid model for the bovine placental trophoblast cell line F3. The developed culture model might prove valuable for future in vitro studies on the differentiation of bovine trophoblast cells. PMID- 20975255 TI - Gonadotropin-dependent precocious puberty in a patient with X-linked adrenal hypoplasia congenita caused by a novel DAX-1 mutation. AB - BACKGROUND/AIMS: X-linked adrenal hypoplasia congenita (AHC) is typically characterized by a DAX-1 gene mutation and hypogonadotropic hypogonadism. However, rare cases with precocious puberty or normal puberty have been reported. Currently, the mechanism of action of the DAX-1 gene on puberty is not clearly known. CASE REPORT: We report a male who was diagnosed as having AHC in the newborn period and detected as having stop codon Q155 X mutation in the DAX-1 gene. This subject developed central precocious puberty when he was 9 months old. RESULTS: This paper is the first case report of AHC, central precocious puberty and a mutation in the DAX-1 gene. DAX-1 gene mutations can result in various phenotypes. CONCLUSION: In cases with AHC, central precocious puberty can develop rather than hypogonadotropic hypogonadism, which is the most frequently observed puberty disorder related to DAX-1 gene mutations. PMID- 20975256 TI - Old donors for kidney transplantation: how old? AB - The widening gap between transplant demand and supply has prompted the expansion of selection criteria for kidney donation to increase the available donor pool. Using kidneys from older donors has increased transplant activity, but has also resulted in reduced graft survival, possibly as a consequence of the imbalance between the number of viable nephrons supplied and the metabolic demand of the recipient. To fill this imbalance and improve graft outcomes, the transplant of 2 older kidneys in the same recipient has been proposed. This procedure, however, does not always confer the same benefit of single transplants from young donors. To optimize allocation of these organs, a panel of pathologists defined a scoring system of pretransplant graft biopsies to help guide the decision between single versus dual kidney transplantation. The survival of kidneys obtained from donors older than 60 years and allocated to single or dual transplantation on the basis of this pretransplant biopsy score was similar to that of single grafts from younger donors and substantially better than that of single grafts from older donors not evaluated histologically before grafting. This strategy has provided excellent outcomes even when kidneys from donors older than 70 years have been used. Thus, biopsy-based allocation algorithm of older grafts may allow extending selection criteria of donors to increase the number of available transplants without increasing the risk of premature graft failure. PMID- 20975257 TI - Unusual bladder mass in a 14-year-old boy: bladder paraganglioma. AB - A 14-year-old boy presenting headache crisis, sweating and palpitation was observed. On ultrasound scan, a 3 * 2.5 cm hypoechoic mass, highly vascularized, was observed arising from the left bladder wall. Magnetic resonance imaging confirmed the mass situated close to the ureteral orifice, with intense peripheral enhancement and a central non-enhanced portion. Left partial cystectomy was performed. Large clear cells, presenting cytoplasmatic granules positive for S100 and chromogranin, were observed at histology. Bladder paraganglioma derives from chromaffin tissue of the sympathic system and it is uncommon in children. The estimated prevalence is very low (0.06% of bladder tumors). Symptomatology is related to the catecholamine production. In pediatrics, prognosis is usually good but long-term follow-up is required. PMID- 20975258 TI - Life-threatening complications associated with the tyrosine kinase inhibitor sunitinib malate. AB - Adverse events associated with sunitinib, such as cardiac toxicities, renal damage, and hemostatic complications, are well known. The authors report 3 cases in which patients experienced severe life-threatening complications after commencing sunitinib treatment. One patient developed heart failure with dilation of the left ventricle and decrease in the ejection fraction after one cycle of sunitinib and required treatment with an angiotensin-converting enzyme inhibitor, loop diuretics, and dobutamine. Another patient developed coronary artery stenosis after one cycle of sunitinib and was managed through percutaneous coronary intervention. Although follow-on coronary angiography revealed normal findings after 6 further cycles of sunitinib, this patient eventually expired due to multi-organ failure. The third patient had chronic renal failure before sunitinib treatment and required hemodialysis due to acute-on-chronic renal failure after commencing sunitinib treatment. PMID- 20975259 TI - High-fat feeding influences the endocrine responses of pubertal rats to an acute stress. AB - BACKGROUND/AIMS: Studies conducted in adult rats have shown that increased fat intake affects brain energy homeostasis and stress response. The neuroendocrine circuits controlling the aforementioned functions continue to mature during puberty. The aim of the present study was to investigate whether post-weaning high-fat consumption can modify the endocrine responses of pubertal rats to an acute stress. METHODS: Weaning male and female Wistar rats on postnatal day (P) 22 were fed either a high-fat (HF; 45% calories from fat) or a control (10% calories from fat) diet and were sacrificed on the individual day of puberty onset (between P35 and P42) under basal conditions or 4 h after swimming stress. Plasma insulin, leptin and corticosterone levels were determined by radioimmunoassay and the respective receptors in the hypothalamus and hippocampus were determined by Western blot analysis. RESULTS: Stressed HF-fed males showed a smaller increase in plasma insulin levels than chow-fed males. Their leptin receptor levels were reduced in the hypothalamus, but not in the hippocampus, and their glucocorticoid receptor levels were increased in the hypothalamus compared to stressed chow-fed males. HF-fed females were nonresponsive to stress-induced alterations in plasma glucose and corticosterone levels, as well as to hippocampal insulin receptors following stress. Several sex differences were also revealed in the endocrine responses of HF-fed animals following stress. CONCLUSIONS: These data show that consumption of high-fat foods during preadolescence can modify the endocrine responses to an acute stress by affecting both stress and metabolic mediators in a sexually dimorphic manner. PMID- 20975260 TI - New insights into the endocrine and metabolic roles of dopamine D2 receptors gained from the Drd2 mouse. AB - Dopamine D2 receptor (D2R) participation in prolactin regulation is well documented, but the role of D2Rs in the control of other hormones involved in growth, food intake and glucose metabolism has not been extensively studied. The study of D2R knockout mice (Drd2(-/-)) puts forward new insights into the role of the D2R in growth hormone (GH)-releasing hormone-GH regulation, peptides involved in food intake, glucose homeostasis, as well as in prolactinoma development. The expected phenotype of chronic hyperprolactinemia and prolactinoma development was found in the Drd2(-/-) mouse, and this model constitutes a valuable tool in the study of dopamine-resistant prolactinomas. Unexpectedly, these mice were growth retarded, and the importance of functional hypothalamic D2Rs in the neonatal period was revealed. In the Drd2(-/-) mouse there was a failure of high neonatal GH levels and therefore the expansion of pituitary somatotropes was permanently altered. These mice also had increased food intake, and a sexually dimorphic participation of the D2R in food intake regulation is suggested. The effect described is probably secondary to D2R regulation of prolactin secretion. Furthermore, the negative modulation of D2Rs on alpha-melanocyte-stimulating hormone release and positive action on the hypothalamic expression of orexins reveals the complex D2R regulation of food intake. Finally, pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development in the Drd2(-/-) mouse may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance develops. These results highlight the complex endocrine actions of the D2Rs at different levels, hypothalamus, pituitary or pancreas, which function to improve fitness, reproductive success and survival. PMID- 20975261 TI - Mechanisms and clinical implications of the placebo effect: is there a potential for the elderly? A mini-review. AB - In recent years, the placebo effect has been a topic of considerable interest both in the scientific and the clinical community. In this time, the placebo effect has evolved from being considered a nuisance in clinical and pharmacological research to becoming a neurobiological phenomenon worthy of scientific investigation in its own right. Recent research shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and that these effects can be robust in both laboratory and clinical settings. These psychosocially induced biochemical changes in a patient's brain and body may in turn affect the course of a disease and the response to a therapy. Here we summarize and discuss the current insights into placebo mechanisms and discuss the potentially widespread implications for research and clinical practice. Even though a systematic knowledge of placebo effects across the lifespan is lacking, we aim at highlighting specific aspects related to the care of elderly patients and those suffering from neurodegenerative diseases. PMID- 20975262 TI - De novo thrombotic microangiopathy induced by cytomegalovirus infection leading to renal allograft loss. AB - After kidney transplantation, thrombotic microangiopathy (TMA) can occur de novo or as recurrent disease. Risk factors for de novo posttransplant TMA include ischemia-reperfusion injury, immunosuppressive drugs, viral infections, acute humoral rejection, and complement gene abnormalities. Cytomegalovirus infection as a trigger for posttransplant TMA in kidney transplant recipients has only been reported in 7 cases, all of them between 4 weeks and 8 years after transplantation. We describe a new case of de novo TMA in association with cytomegalovirus infection 25 years after kidney transplantation. PMID- 20975263 TI - Renal replacement therapy for prevention of contrast-induced acute kidney injury: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is an important cause of acute renal injury. Several clinical trials using renal replacement therapy (RRT) for prevention of CI-AKI yielded conflicting results. We performed a meta analysis to assess the efficacy of prophylactic RRT on CI-AKI. METHODS: Randomized controlled trials on CI-AKI using RRT were identified without language restriction in Cochrane library, Pubmed and Embase. Data extracted from literature were analyzed with Review manager and Stata software. RESULTS: Nine randomized controlled trials involving 751 patients were included. Heterogeneity was found across trials (p < 0.00001). A random effect model was used to combine the data. RRT reduced the risk of CI-AKI by 26% compared with the control group, but statistical significance was not reached (risk ratio (RR) 0.74, 95% CI 0.35 1.60, p = 0.45). Subgroup analysis of modality indicated that hemodialysis was ineffective in reducing the risk of CI-AKI (RR 1.21, 95% CI 0.63-2.32, p = 0.57), while CRRT decreased the incidence of CI-AKI (RR 0.22, 95% CI 0.07-0.64, p = 0.006). Subgroup analysis according to the CKD stage did not record heterogeneity across trials. RRT increased the odds of CI-AKI in CKD stage 3 patients (RR 1.53, 95% CI 0.07-0.64, p = 0.01), but decreased the occurrence of CI-AKI in patients with CKD stage higher than 3 (RR 0.74, 95% CI 0.35-1.60, p = 0.45). The pooled RR of the need for permanent dialysis demonstrated an insignificant trend towards benefit in patients treated with RRT (RR 0.61, 95% CI 0.26-1.40, p = 0.24). RRT reduced in-hospital mortality compared with control group (RR 0.33, 95% CI 0.14 0.77, p = 0.01). CONCLUSION: RRT fails to reduce the incidence of CI-AKI in CKD stage 3 patients, but may be beneficial in patients with more advanced renal function. CRRT is more effective than hemodialysis for prevention of CI-AKI. RRT is effective in reducing the in-hospital mortality of CI-AKI patients. PMID- 20975264 TI - Chronic occlusion of the left main coronary artery: importance of collaterals. AB - Chronic occlusion of the left coronary artery is an infrequent finding in patients undergoing coronary angiography. These patients usually present symptoms of angina or heart failure. We describe a patient who was training regularly without cardiac symptoms until ventricular fibrillation suddenly occurred during a long-distance run. A chronic left main stem occlusion with well-developed right to-left coronary collaterals was demonstrated by angiography. Up to this event, the collateral flow had been sufficient to allow physical exercise at a high performance level without symptoms. The patient later underwent coronary bypass surgery and recovered completely. PMID- 20975265 TI - Prognostic value of circulating dead monocytes in patients with acute st elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - OBJECTIVES: This study tested the hypothesis that the level of apoptotic and necrotic peripheral blood mononuclear cells (PBMCs) is a predictor of the 30-day combined major adverse clinical outcome (MACO) [defined as advanced congestive heart failure (CHF), a high Killip score, or 30-day mortality] in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). METHODS: Between April 2009 and January 2010, 98 patients undergoing primary PCI were assessed for both apoptotic and necrotic PBMCs (apoptotic cells are referred to as annexin V+/propidium iodide- and necrotic cells are defined as annexin V+/propidium iodide+) using flow cytometry 24 h after STEMI. Patients with higher (>= 3.2%) and lower (<3.2%) levels of necrotic cells were categorized into group 1 (n = 40) and group 2 (n = 58), respectively, according to the ROC curve method. RESULTS: Higher incidences of advanced CHF and a high Killip score were noted in group 1 patients (p < 0.0001). Moreover, the peak level of creatine phosphokinase was higher in group 1 (p < 0.0001), whereas the left ventricular ejection fraction was lower in group 1 than in group 2 (p < 0.001). Multivariate analysis revealed that high necrotic cells (>= 3.2%) was the strongest independent predictor of 30-day MACO (p = 0.001). CONCLUSION: A high level of necrotic cells (PBMCs) may serve as a useful biomarker for predicting 30-day MACO in patients with STEMI undergoing primary PCI. PMID- 20975266 TI - Intracoronary autologous CD34+ stem cell therapy for intractable angina. AB - BACKGROUND/OBJECTIVES: A large number of patients with coronary artery disease experience angina that is not suitable for revascularization and is refractory to conventional medical therapy. Laboratory and preclinical studies have provided evidence for the safety and potential efficacy of autologous CD34+ stem cell therapies as treatment for angina. Clinical studies investigating intramyocardial transplantation of autologous CD34+ stem cells by catheter injection for patients with refractory angina show that this is safe and feasible. It remains unclear whether intracoronary infusion of CD34+ stem cells exerts beneficial effects in patients with angina as well. We addressed this question with a controlled clinical trial by enrolling 112 patients with refractory angina. Previous trials have investigated the safety and beneficial effects of CD34+ cells isolated from granulocyte colony-stimulating factor-mobilized peripheral blood; in our trial, we isolated CD34+ cells directly from the patient's bone marrow. METHODS: One hundred and twelve patients with diffuse triple-vessel disease and Canadian Cardiovascular Society class III or IV angina were enrolled in a double-blind, randomized (1:1), placebo-controlled study. Patients received optimal medical treatment but were not candidates for mechanical revascularization (percutaneous coronary intervention or coronary artery bypass grafting). Fifty-six patients (27 women and 29 men aged 42-80 years) were enrolled in the treatment group, and 56 patients (28 women and 28 men aged 43-80 years) who received optimal medical treatment and intracoronary saline injections were enrolled in the placebo control group. Bone marrow was collected from all enrolled patients at a volume of 120-150 ml each in both groups. Selections of CD34+ cells were performed by a CE-marked device approved by the Security, Food and Drug Administration of China. Coronary angiography had been performed before enrollment in this study. RESULTS: No myocardial infarction was observed during intracoronary infusion. The intracoronary infusion of cells or saline did not result in cardiac enzyme elevation, cardiac perforation or pericardial effusion. No arrhythmia, such as ventricular tachycardia or ventricular fibrillation, was induced by intracoronary infusion. No serious adverse events occurred in either group. The reduction in the frequency of angina episodes per week 3 and 6 months after infusion was significantly higher in the treatment group (-14.6 +/- 4.8 at 3 months and -15.6 +/- 4.0 at 6 months) than in the control group (-4.5 +/- 0.3 and -3.0 +/- 1.2, respectively; p < 0.01). Other efficacy parameters such as nitroglycerine usage, exercise time and the Canadian Cardiovascular Society class also showed an improvement in the treatment group compared to the control group. A significant improvement in myocardial perfusion was noted in the treatment group compared to the control group, as measured by single-photon emission computed tomography. CONCLUSIONS: This randomized trial investigating intracoronary infusion of autologous CD34+ cells in patients with intractable angina shows the safety and feasibility of this therapy and provides evidence for efficacy. PMID- 20975267 TI - Therapeutic window for calcium-channel blockers in the management of dilated cardiomyopathy: a prospective, two-centre study on non-advanced disease. AB - OBJECTIVE: This study aimed to investigate the usefulness of the calcium-channel blocker verapamil in non-advanced dilated cardiomyopathy (DCM). METHODS: This was a randomised trial of 70 DCM patients treated with carvedilol (36 patients) and verapamil (instead of beta-blocker; 34 patients) for 12 months. The remaining heart failure (HF) therapy was constant in both groups. The primary outcomes were to determine selected echocardiography parameters and functional status of patients. The secondary outcome included death, heart transplantation and re hospitalisation due to HF progression. RESULTS: Of the primary outcomes, only the mean ratio of early to late transmitral flow velocities increased significantly in the verapamil-treated patients as compared with the carvedilol-based therapy (1.1 +/- 0.3 vs. 0.7 +/- 0.2; 95% CI -0.6 to -0.1; p = 0.015). Simultaneously, the Minnesota Quality of Life improved significantly in the verapamil group (95% CI 5.2-19.9; p = 0.002). It was accompanied by the favourable effect of verapamil therapy on exercise capacity in the 6-min walk test (95% CI 21.3-110.7; p = 0.005). CONCLUSION: The addition of verapamil to angiotensin-converting enzyme and aldosterone inhibitors in non-advanced DCM patients has been shown to have a neutral or even positive effect in a few patients. PMID- 20975268 TI - Dental caries and enamel defects in very low birth weight adolescents. AB - OBJECTIVES: The purpose of this study was to examine developmental enamel defects and dental caries in very low birth weight adolescents with high risk (HR-VLBW) and low risk (LR-VLBW) compared to full-term (term) adolescents. METHODS: The sample consisted of 224 subjects (80 HR-VLBW, 59 LR-VLBW, 85 term adolescents) recruited from an ongoing longitudinal study. Sociodemographic and medical information was available from birth. Dental examination of the adolescent at the 14-year visit included: enamel defects (opacity and hypoplasia); decayed, missing, filled teeth of incisors and molars (DMFT-IM) and of overall permanent teeth (DMFT); Simplified Oral Hygiene Index for debris/calculus on teeth, and sealant presence. A caregiver questionnaire completed simultaneously assessed dental behavior, access, insurance status and prevention factors. Hierarchical analysis utilized the zero-inflated negative binomial model and zero-inflated Poisson model. RESULTS: The zero-inflated negative binomial model controlling for sociodemographic variables indicated that the LR-VLBW group had an estimated 75% increase (p < 0.05) in number of demarcated opacities in the incisors and first molar teeth compared to the term group. Hierarchical modeling indicated that demarcated opacities were a significant predictor of DMFT-IM after control for relevant covariates. The term adolescents had significantly increased DMFT-IM and DMFT scores compared to the LR-VLBW adolescents. CONCLUSION: LR-VLBW was a significant risk factor for increased enamel defects in the permanent incisors and first molars. Term children had increased caries compared to the LR-VLBW group. The effect of birth group and enamel defects on caries has to be investigated longitudinally from birth. PMID- 20975269 TI - Factors associated with caries increment: a longitudinal study from 18 months to 5 years of age. AB - BACKGROUND: Identifying the early determinants of risk for dental caries would be useful in its primary prevention. SUBJECTS AND METHODS: All children at the age of 18 months in one health care area were invited in the screening test for mutans streptococci (MS) and their caretakers interviewed for the study purposes. The 366 children who met the inclusion criteria were clinically examined after 42 months. RESULTS: At the age of 5 years +/- 6 months, in 79 (21.6%) children the 42-month caries increment was >0. In the multivariate regression analysis, the strongest correlation was found with MS detected in the oral biofilm. Of the reported background factors the blue-collar occupation of the caretaker, child's sugar use, night feeding, use of other thirst quenchers than water and father's reported poor oral health were significantly correlated with the child's caries increment. CONCLUSION: The oral health of a child is strongly related to the lifestyle and the oral health habits of the caretakers during the first years. PMID- 20975271 TI - Cognitive profiles of incipient dementia in the Goteborg MCI study. AB - OBJECTIVE: To study which cognitive profiles of incipient dementia strongest predict the conversion to Alzheimer's disease (AD) and mixed dementia (MD)/vascular dementia (VaD). METHODS: 260 subjects with mild cognitive impairment (MCI) were included in the study and 209 (79%) were followed up after 2 years. At baseline, the subjects were assessed with a neuropsychological battery covering the cognitive domains speed/attention, memory, visuospatial, language and executive functions. RESULTS: After 2 years, 9 subjects were considered normal, 148 had stationary MCI and 47 (23%) had converted to dementia. Twenty subjects were diagnosed with AD, 15 with MD and 9 with VaD. The others were 2 with unspecified dementias and 1 with primary progressive aphasia. Dementia converters had a high proportion of impairment in all cognitive domains. The profiles of incipient AD and MD/VaD differed, with memory, visuospatial and language symptoms preceding AD, and executive and speed/attention symptoms preceding MD/VaD. CONCLUSIONS: The risk of converting to dementia is increased when domains in addition to memory are impaired. The incipient AD and MD/VaD profiles differed quite clearly. Considering that the vascular group consisted of a majority of patients with MD, the differences are convincing - vascular disease seems to have an essential impact on cognition. PMID- 20975270 TI - Probable early-onset Alzheimer's disease in an apolipoprotein E2 homozygote. AB - OBJECTIVE: To describe a case of early-onset Alzheimer's disease (AD) in an apolipoprotein (Apo) epsilon2/epsilon2 homozygote. BACKGROUND: Apo epsilon2/epsilon2 is the rarest of the ApoE genotypes, representing only 1.4% of the population. Cognitive decline in ApoE epsilon2 homozygotes has rarely been reported. CASE REPORT/METHODS: We report a 58-year-old Apo epsilon2/epsilon2 female who meets clinical criteria for probable AD as confirmed by neuropsychological testing, positron emission/computed tomography scan, CSF analysis and genetic screening for known mutations. RESULTS: The clinical course is typical of AD, with progressive cognitive and functional decline. CONCLUSION: Clinically confirmed early-onset AD is atypical in ApoE2 homozygotes but can occur. PMID- 20975272 TI - Assessment of clinical utility of low and high normal alanine aminotransferase values in patients with chronic hepatitis B virus infection in Bangladesh. AB - BACKGROUND/AIMS: There is a lack of consensus about the currently accepted range of normal values for serum alanine aminotransferase (ALT) levels because some investigators have claimed that the true values are significantly lower than those listed by kit manufacturers. METHODS: A total of 255 chronic hepatitis-B virus (HBV)-infected patients with traditional, normal levels of ALT (<=42 U/l) were divided into 2 groups: (1) low normal ALT (men: <=30 U/l; women: <=19 U/l) and (2) high normal ALT (men: 31-42 U/l; women: 20-42 U/l). The extent of hepatic inflammation and fibrosis was evaluated in these patients by examining liver biopsy specimens. RESULTS: The levels of HBV DNA were >10,000 copies/ml in 58.4, 52.9 and 61.2% of the patients with traditional normal ALT, low normal ALT and high normal ALT values, respectively (p > 0.05). Also, the moderate degrees of hepatic necroinflammation [histological activity index (HAI)-NI score of >=9] and severe hepatic fibrosis (HAI-F score of >=3) were similar among the 3 groups of patients (p > 0.05). CONCLUSION: The newly defined low normal cutoff values for ALT did not exhibit any added clinical benefit for assessing the extent of liver damage in patients with chronic HBV infection in Bangladesh. PMID- 20975273 TI - Milk-based test as a preventive method for chylous ascites following pancreatic resection. AB - BACKGROUND/PURPOSE: The incidence and natural history of postoperative chylous ascites are not well understood. This complication causes malnutrition and prolonged hospital stay. We investigated our institution's experience involving chylous ascites, especially following pancreatectomy. Additionally, we designed a new intraoperative method dubbed the 'milk test' for preventing chylous ascites. METHODS: Five cases of chylous ascites following pancreatectomy from April 2001 through March 2004 were studied retrospectively. The milk test was carried out prospectively. Such rates as positivity and incidence of ascites were examined. RESULTS: Of 65 cases (40 pancreatoduodenectomy; 25 distal pancreatectomy), 5 (7.7%) developed chylous ascites following pancreatic resection. All cases underwent octreotide and total parenteral nutrition treatment. From April 2004 through March 2009, the milk test was used in 104 cases. Surgical procedures comprised pancreatoduodenectomy (n = 78) and distal pancreatectomy (n = 23). Of these cases, 23 (22.1%) tested positive. No significant difference in positive rates was observed between the procedures and diseases. After initiation of the milk test, chylous ascites incidence decreased from 7.7 to 2.9%. CONCLUSIONS: For chylous ascites, octreotide and total parenteral nutrition treatments are useful. However, the milk test was found to be a safe and effective method for prevention of chylous ascites following pancreatectomy. PMID- 20975274 TI - Topiramate for the treatment of alcohol dependence: comparison with naltrexone. AB - BACKGROUND: A 6-month naturalistic, randomized and open-label, trial of topiramate versus naltrexone was conducted, with assessments at enrollment and after 3 and 6 months of treatment. 182 alcohol-dependent patients who had been drinking heavily during the past month were included. METHODS: Outcome was measured using tools that assessed alcohol intake, cravings, disability, and quality of life; changes in biomarkers of alcohol intake were also used. RESULTS: At the 6-month evaluation, patients taking topiramate had significantly lower scores on the OCDS (all subscales), the EuropASI (medical, alcohol, family/social, and psychiatric) and the WHO/DAS (employment/social). More patients taking topiramate remained in the abstinence group and the moderate drinking without problems group. CONCLUSIONS: Topiramate at a mean dose of 200 mg/day was better than naltrexone at a mean dose of 50 mg/day at reducing alcohol intake and cravings throughout the study. PMID- 20975275 TI - Agreement between maternal cannabis use during pregnancy according to self-report and urinalysis in a population-based cohort: the Generation R Study. AB - AIM: To verify self-reported information on prenatal drug use in urine because reporting in pregnancy is sensitive to stigma and might lead to misclassification. METHODS: Using semiquantitative immunochemical analysis, the presence of the urinary metabolite (11-nor-Delta9-tetrahydrocannabinol- 9 carboxylic acid) was compared to self-reported prenatal cannabis use. Sensitivity and specificity for self-report and urinalysis outcomes were calculated and Yule's Y was used as an agreement measure. RESULTS: Urine samples were available for 3,997 pregnant women. Of these women, 92 reported having used cannabis during pregnancy (2.3%) and 71 had positive urine screens (1.8%). In total 35% of the 92 women with self-reported cannabis use also had a positive urine screen. Positive urines were relatively frequent in women reporting cannabis use before pregnancy only (7.6%) and in women with missing information (2.6%). Sensitivity and specificity of urinalysis compared to self-report were 0.46 and 0.98. Sensitivity and specificity of self-report compared to urinalysis were 0.36 and 0.99. Yule's Y amounted to 0.77, indicating substantial agreement between the measures. CONCLUSIONS: Our findings illustrate the difficulties in obtaining valid information on prenatal cannabis use. To improve the quality of cannabis use data, we suggest a 2-step approach starting with self-report. PMID- 20975276 TI - Barriers to opioid substitution treatment access, entry and retention: a survey of opioid users, patients in treatment, and treating and non-treating physicians. AB - BACKGROUND/AIMS: Although the number of patients in opioid substitution treatment (OST) in Germany has increased in recent years, many dependent opioid users remain out of treatment. Project IMPROVE assessed attitudes and beliefs regarding barriers to OST. METHODS: Data were collected from opioid-dependent individuals (using self-complete questionnaires) currently in treatment (n = 200) or not in treatment (n = 200), and OST-accredited physicians (using computer-aided telephone interviewing) who currently provided (n = 101) or did not provide OST (n = 51) from different regions in Germany. RESULTS: Key results showed that OST was perceived as valuable and effective by physicians, patients and users but that OST access and provision were inadequate, especially outside of major cities. CONCLUSION: These findings are consistent with national data indicating a worsening imbalance between patient demand for treatment and the supply of available physicians accredited to provide it. Many physicians and patients were not aware of, or were not utilizing, therapeutic strategies that may help reduce misuse and diversion. Improvements in the regulatory framework for OST, and identifying additional sources of support and training, would encourage more accredited physicians to actively provide treatment and thus help to fully realize the benefits of currently available treatment options. PMID- 20975277 TI - Olfactory identification deficits in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. AB - BACKGROUND/AIMS: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited angiopathy caused by mutations of the Notch 3 gene. Olfactory identification deficits are present in a number of neurodegenerative disorders. However, olfaction has not been investigated in CADASIL. The aim of the present study was to assess olfactory identification in CADASIL and to determine whether there is an association between olfactory identification and the frontotemporal lobe. METHODS: Twenty seven patients and 27 control subjects had an olfactory identification test and neuropsychological testing. Brain MRIs were obtained from 25 patients. Involvement of frontal white matter, anterior temporal white matter and the external capsule were measured. RESULTS: Olfactory identification scores were lower in CADASIL patients than in healthy comparison subjects. The Mini-Mental Status Examination (MMSE) and semantic Controlled Oral Word Association Test (COWAT) were also affected. In CADASIL patients, olfactory identification scores correlated with MMSE, COWAT scores and Scheltens' scores from frontal white matter. The tendency for an association between olfactory identification scores and Scheltens' scores from anterior temporal white matter was also observed. CONCLUSION: Our findings suggest that olfactory identification deficits may be a sensitive indicator of frontotemporal dysfunction in CADASIL. PMID- 20975278 TI - Assessment of left ventricular pre-ejection period in the fetus using simultaneous magnetocardiography and echocardiography. AB - INTRODUCTION: Fetal magnetocardiography (fMCG) is a promising new technique for assessing fetal rhythm; however, no prior studies have utilized fMCG to evaluate human fetal electromechanical physiology. Pre-ejection period (PEP) is an important measure of the electromechanical activation of the heart, and is altered by disease states and arrhythmias. MATERIALS AND METHODS: A novel technique was used to assess fetal PEP and its relationship to other fetal systolic time intervals, RR interval, and gestational age (GA). 25 normal human fetuses between 19 and 38 weeks' gestation were studied using simultaneous pulsed Doppler ultrasound and fMCG. Correlations among PEP, ejection time, QRS width and RR interval were assessed using linear regression. RESULTS: Across all subjects, PEP was found to correlate with GA (R = 0.57, p < 0.0001), QRS width (R = 0.35, p = 0.026), and RR interval (R = 0.37, p = 0.018). In individual sessions, PEP negatively correlated beat-to-beat with the preceding RR interval. CONCLUSION: PEP exhibits developmental trends that provide a better understanding of the normal development of the human fetal heart. PMID- 20975281 TI - Can overmarking be considered as a means of chemical mate guarding in a wild callitrichid? AB - Mate guarding is a male strategy to monopolize matings and thus to ensure paternity. Since in callitrichids female reproductive status is advertised by scent marks, one may expect mate guarding by chemical means. We addressed this question during an episode of consortship observed in a polyandrous trio of wild saddleback tamarins (Saguinus fuscicollis). During consortship, the consort male was the only one to allomark the female. Scent marking frequency decreased for all individuals, although the consort male marked more than the other male during consortship, while there was no difference in the previous period. During consortship, almost 50% of female scents were overmarked by the consort, and more than 56% of the consort's scent marks were employed to overmark the female's scents. Therefore, the other male had limited access to female scent marks. Mate guarding may thus have a chemical component in tamarins, and olfactory communication may play an important role in mating competition. PMID- 20975282 TI - Partial protein-hydrolyzed infant formula decreased food sensitization but not allergic diseases in a prospective birth cohort study. AB - BACKGROUND: Exposure to cow's milk protein in early infancy could lead to increased rates of allergic diseases later in life. We investigated whether feeding a protein-hydrolyzed formula (HF) in the first 6 months of life decreased allergic diseases up to 36 months later. METHODS: Newborns who had at least 1 first-degree family member with a history of atopy and could not breast-feed were enrolled. They were fed with HF or cow's milk infant formula (CM) for at least 6 months via an open-label protocol and were monitored prospectively at 6, 18 and 36 months of age to assess allergy sensitization and allergic diseases. RESULTS: A total of 1,002 infants were enrolled and 679 infants were consistently fed the same formula for the first 6 months of life (345 HF and 334 CM). The percentage of food sensitization (especially to milk protein) was significantly lower in the HF group than in the CM group at 36 months (12.7 vs. 23.4%, p = 0.048). There was no significant difference in the prevalence of aeroallergen sensitization between the groups. Occurrence of allergic diseases during the first 3 years of life was significantly correlated with aeroallergen sensitization, but not to food allergen sensitization, parental atopy or feeding types. CONCLUSIONS: Infants fed with HF during the first 6 months of life had a significantly lower percentage of sensitization to milk protein allergens, but not allergic diseases during the first 3 years of life. Avoidance of cow's milk protein alone in infancy is not enough to decrease rates of allergic diseases. PMID- 20975283 TI - Basophil CD203c levels are increased at baseline and can be used to monitor omalizumab treatment in subjects with nut allergy. AB - RATIONALE: Basophils contribute to anaphylaxis and allergies. We examined the utility of assessing basophil-associated surface antigens (CD11b/CD63/CD123/CD203c/CD294) in characterizing and monitoring subjects with nut allergy. METHODS: We used flow cytometry to analyze basophils at baseline (without any activation) and after ex vivo stimulation of whole blood by addition of nut or other allergens for 2, 10, and 30 min. We also evaluated whether basophil expression of CD11b/CD63/CD123/CD203c/CD294 was altered in subjects treated with anti-IgE monoclonal antibody (omalizumab) to reduce plasma levels of IgE. RESULTS: We demonstrate that basophil CD203c levels are increased at baseline in subjects with nut allergy compared to healthy controls (13 subjects in each group, p < 0.0001). Furthermore, we confirm that significantly increased expression of CD203c occurs on subject basophils when stimulated with the allergen to which the subject is sensitive and can be detected rapidly (10 min of stimulation, n = 11, p < 0.0008). In 5 subjects with severe peanut allergy, basophil CD203c expression following stimulation with peanut allergen was significantly decreased (p < 0.05) after 4 and 8 weeks of omalizumab treatment but returned toward pretreatment levels after treatment cessation. CONCLUSIONS: Subjects with nut allergy show an increase of basophil CD203c levels at baseline and following rapid ex vivo stimulation with nut allergen. Both can be reduced by omalizumab therapy. These results highlight the potential of using basophil CD203c levels for baseline diagnosis and therapeutic monitoring in subjects with nut allergy. PMID- 20975284 TI - Case-control study of eczema associated with IL13 genetic polymorphisms in Japanese children. AB - BACKGROUND: Several association studies have investigated the relationships between single nucleotide polymorphisms (SNPs) in the IL13 gene and eczema, with inconsistent results. We conducted a case-control study of the relationship between the polymorphisms of rs1800925 and rs20541 and the risk of eczema in Japanese children aged 3 years. METHODS: Included were the 209 cases identified based on criteria of the International Study of Asthma and Allergies in Childhood (ISAAC). Controls were 451 children without eczema based on ISAAC questions who had not been diagnosed by a physician as having asthma or atopic eczema. RESULTS: The minor TT genotype of the rs1800925 SNP and the minor AA genotype of the rs20541 SNP were significantly related to an increased risk of eczema: adjusted odds ratio for the TT genotype was 2.78 (95% confidence interval 1.22-6.30) and that for the AA genotype was 2.38 (95% confidence interval 1.35-4.18). Haplotype analyses showed a protective association between the CG haplotype and eczema, whereas the TA haplotype was positively related to the risk of eczema. Perinatal smoking exposure did not interact with genotypes of the IL13 gene in the etiology of eczema. The significant association of the rs20541 SNP with eczema essentially disappeared after additional adjustment for the rs1800925 SNP, whereas a relationship with the rs1800925 SNP remained significant. CONCLUSIONS: A common genetic variation in the IL13 gene at the levels of both single SNPs and haplotypes was associated with eczema. However, the significant association with the rs20541 SNP might be ascribed to the rs1800925 SNP. PMID- 20975285 TI - Sublingual allergen-specific immunotherapy adjuvanted with monophosphoryl lipid A: a phase I/IIa study. AB - BACKGROUND: Sublingual immunotherapy (SLIT) allergy vaccines have an excellent safety profile, but opinions vary on their efficacy, and treatment regimens are often lengthy. This study assessed the effects of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPL(r)) on safety/tolerability and clinical and immunological efficacy when combined with grass pollen SLIT formulations in treating patients with seasonal allergic rhinitis. This is the first reported study of adjuvanted SLIT. METHODS: In this double-blind placebo-controlled phase I/IIa study, 80 grass pollen-sensitive subjects were randomized into 4 groups of 20 subjects to receive daily treatment for 8 weeks. Sixteen patients per group received SLIT and 4 received placebo. The formulation given to each group varied with respect to grass pollen extract and MPL content. Grass allergen nasal challenge tests (NCTs) were performed prior to dosing and in weeks 4 and 10. Grass pollen-specific immunoglobulin G (IgG) and IgE antibodies were measured at baseline and prior to dosing in weeks 2, 3, 4, 5 and 10. RESULTS: Local and systemic adverse events were generally comparable for patients who received active treatment and placebo. Patients in the 2 groups given SLIT containing the highest amount of MPL experienced the highest proportion of negative NCTs after 10 weeks (47 and 44%, vs. 20% with placebo). These patients also showed earlier median increases in specific IgG and smaller increases in IgE levels than those receiving other formulations. CONCLUSIONS: These results suggest that SLIT preparations containing MPL are well tolerated and alter the immunological response to grass antigens after 3 weeks of exposure, with an associated suppression of nasal challenge responses. PMID- 20975286 TI - Peach-induced contact urticaria is associated with lipid transfer protein sensitization. AB - BACKGROUND: Peach-induced contact urticaria is frequent in peach-allergic subjects. OBJECTIVE: It was the aim of this study to detect whether contact urticaria is associated with a specific peach allergen. METHODS: Ninety-two peach allergic subjects were studied. Patients were diagnosed as being sensitized to lipid transfer protein (LTP; Pru p 3) or as having a pollen-food allergy syndrome induced by Pru p 1 and/or profilin, Pru p 4, on the basis of the results of a skin prick test containing these allergenic proteins in an isolated form. Specific IgE to peach extract was measured as well. Contact urticaria was confirmed by a contact test with intact, untreated peach. A contact test with nectarine was carried out as control. RESULTS: Overall, contact urticaria was present in 21% of patients; the peach contact test scored positive in all cases. Contact urticaria was significantly more frequent in patients hypersensitive to LTP (63%) than in subjects with pollen-food allergy syndrome (6%; p < 0.001) and was not associated with a higher level of peach-specific IgE. In several cases, contact urticaria preceded the onset of food allergy by years. The contact test with nectarine scored negative in 5/5 cases. CONCLUSIONS: Although the peach contact test was not performed in all subjects, and peach allergy was not confirmed by oral challenges, this study shows that peach-induced contact urticaria is associated with sensitization to peach LTP. The negative clinical history and contact test with nectarine along with the well-known high concentration of LTP in peach fuzz suggest that peach fuzz plays a role in the pathogenesis of contact urticaria. PMID- 20975287 TI - Relationship between total tear and serum IgE in allergic conjunctivitis. AB - BACKGROUND: Recently, a new commercial test for total tear IgE based on immunochromatography (Allerwatch(r)) was developed. We examined the relationship between total tear and serum IgE levels with the Allerwatch test. METHODS: A nonrandomized cross-sectional study was conducted in 40 patients with allergic conjunctivitis, 35 age- and sex-matched healthy control subjects, and 6 patients with epidemic keratoconjunctivitis (EKC). The total tear IgE score was determined with the Allerwatch test (0, 1 and 2), and the serum total IgE level was measured by solid-phase immunoassay (Phadezym PRIST) in all subjects. RESULTS: Total tear IgE was assayed within 10 min of collection in all samples. The total tear IgE positive rate was significantly higher in the allergic group than in the control and EKC groups (92.5 vs. 0.0 vs. 0.0%; p < 0.00001). Sensitivity and specificity were 0.925 and 1.000, respectively. The total IgE score and log (total serum IgE) were also higher in the allergic group than in the control and EKC groups [total IgE score: 1.48 +/- 0.63 vs. 0.00 +/- 0.00 vs. 0.00 +/- 0.00, p < 0.00001; log (serum total IgE): 2.23 +/- 0.50 vs. 0.80 +/- 0.31 vs. 0.79 +/- 0.37, p < 0.00001]. The total tear IgE score was significantly correlated with log (total serum IgE) in the allergic group (r = 0.712, p < 0.00001). CONCLUSIONS: These results show that this rapid test for the measurement of total tear IgE is easy to perform on an outpatient basis and may be helpful in the management of ocular allergy. PMID- 20975288 TI - Common filaggrin null alleles are not associated with hymenoptera venom allergy in Europeans. AB - The association of filaggrin mutations with atopic eczema (atopic dermatitis, AD) is well established and it is thought that filaggrin dysfunction impairs the skin's barrier function allowing allergen penetration and subsequent cutaneous sensitisation and inflammation. However, as most forms of barrier dysfunction are not associated with allergic sensitisation to common allergens, the possibility that filaggrin itself is involved in Th1/Th2 polarisation remains. We tested the hypothesis that allergen delivered to the skin independently of the stratum corneum is not associated with filaggrin mutations. Wasp stings bypass the stratum corneum and deliver antigen to the dermis. We found that European individuals with AD (n = 32) have an increased frequency of the 2 commonest filaggrin null mutations (R501X and 2282del4) compared to those with vespid allergy (n = 56) and healthy controls (n = 30). Thus, filaggrin does not appear to have a downstream effect on the development of allergic disease, and it is indeed filaggrin's role in the epithelial function that is likely to determine the link between filaggrin mutations and allergic sensitisation. PMID- 20975289 TI - Long-term prophylaxis of hereditary angioedema with a pasteurized C1 inhibitor concentrate. AB - Hereditary angioedema (HAE) is a relatively rare genetic disorder caused by a deficiency of C1 esterase inhibitor (C1-INH). Common clinical presentations are abdominal pain and localized edema of the skin, with laryngeal edema being potentially life-threatening. Replacement therapy with C1-INH concentrate is recommended for treatment of acute HAE attacks and results in rapid resolution of symptoms. C1-INH concentrate can also be used for prophylaxis of HAE and is recommended in cases where standard prophylactic agents are ineffective or not tolerated. This case study describes the use of C1-INH concentrate as a home therapy for on-demand and prophylactic self-administration in a patient with HAE. This treatment approach was well tolerated and effective, leading to a dramatic improvement in symptoms and improved quality of life. PMID- 20975290 TI - Neurodegenerative disease and cancer: a critical role for melanoma? PMID- 20975291 TI - Peripheral glucocorticoid sensitivity in children with controlled persistent asthma. AB - BACKGROUND: Persistent asthma in children is a chronic inflammatory disease and glucocorticoids (GCs) are currently recognized as the mainstay of therapy. Clinical and in vitro steroid resistance has been demonstrated in severe asthma. However, GC insensitivity has not been studied in children with controlled persistent asthma. OBJECTIVES: To analyze peripheral blood mononuclear cell (PBMC) sensitivity to GC in children (6-15 years) with persistent asthma and healthy controls. METHODS: Children with persistent asthma were selected and lung function and skin-prick tests were performed in all studied asthmatic children. PBMCs were isolated and cultured in vitro to assess mitogen-induced proliferation and cellular sensitivity to dexamethasone. RESULTS: Fifty-seven children with persistent and controlled asthma (mean age 10 years) were recruited and divided into 3 groups (severe, moderate and mild), and compared to healthy children (n = 18). Children with asthma, regardless of the severity of disease, presented similar sensitivity to GCs when compared to healthy children. Patients with mild asthma showed significantly less sensitivity to dexamethasone and children with severe asthma had similar sensitivity to dexamethasone when compared to controls. CONCLUSIONS: In vitro insensitivity to GCs was not demonstrated in children with controlled persistent asthma, even in those with severe disease. Our findings suggest that resistance to GCs in older patients with severe asthma might be an acquired process. However, future longitudinal studies are necessary to confirm this hypothesis. PMID- 20975292 TI - What is the value of obesity research? PMID- 20975293 TI - Contents of this issue. PMID- 20975294 TI - Ghrelin: new molecular pathways modulating appetite and adiposity. AB - Ghrelin is a unique endogenous peptidic hormone regulating both hunger and adiposity. Many of the actions of ghrelin are modulated specifically by the central nervous system. A number of molecular events triggered via the activation of the ghrelin receptor (GHS-R1a), leading to increased levels of neuropeptide Y (NPY) and agoutirelated peptide (AgRP) and ultimately responsible for the orexigenic effect of ghrelin have been characterized. Moreover, the discovery of ghrelin O-acyltransferase (GOAT), the enzyme responsible for the octanoylation of ghrelin, provides a mechanism allowing specific targeting of the ghrelin/GHS-R1a system without affecting the role of des-acyl-ghrelin in other pathways involved in the regulation of energy balance. This review aims to summarize novel roles of ghrelin in energy balance, focusing particularly on both the newly identified neuronal pathways mediating the effects of ghrelin and on peripheral mechanisms leading to increased adiposity. PMID- 20975295 TI - Chipping away the 'missing heritability': GIANT steps forward in the molecular elucidation of obesity - but still lots to go. AB - Although heritability of human body weight is assumed to be high, only a small fraction of the variance can as yet be attributed to molecular genetic factors. Single monogenic forms of obesity have been identified. Functionally relevant coding mutations in the melanocortin-4 receptor gene occur in 1-6% of extremely obese children and adolescents and thus represent the most common major gene effect. Genome-wide association studies (GWAS) had previously identified 14 obesity loci with genome-wide significant (p < 5 x 10-8) associations. Many of the respective genes are expressed in the central nervous system. The GIANT (Genetic Investigation of ANtropometric Traits) Consortium has now performed a meta-analysis of GWAS data based on 123,865 individuals of European ancestry followed by confirmatory analyses for the 42 best independent loci in up to 125,931 independent individuals (Speliotes et al: Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index. Nature Genetics; epub October 2010 [1]). Apart from confirming the 14 known loci, 18 novel BMI-associated loci (p < 5 x 10-8) were identified. Several of the new loci point to genes involved in key hypothalamic pathways of energy balance. The identified variants mostly have small to very small effect sizes; only 1-2% of the BMI variance is explained. Currently, a consensus explanation for this 'missing heritability' in complex diseases has not yet emerged. PMID- 20975296 TI - Identification and functional characterization of novel mutations in the melanocortin-4 receptor. AB - OBJECTIVE: Melanocortin-4 receptor (MC4R) deficiency is the most common cause of monogenic obesity. In the present study, we screened the MC4R gene for mutations in a population of overweight and obese children and adolescents. METHOD: Cross sectional mutation analysis of 112 overweight/obese children and adolescents and 121 lean individuals. RESULTS: We identified 11 sequence variations, 5 of which were present in our control population or had been previously reported as polymorphisms. The remaining 6 variations are disease-causing mutations including 2 novel ones: a I186V mutation and a F280L mutation. The 4 previously described mutations (D90N, M200V, P260Q, Q307X) were identified in single probands. Using confocal imaging, we demonstrated that F280L and P260Q cause intracellular retention of the mutant receptor. No difference in cell surface expression could be detected for the I186V mutation. Using a cAMP responsive luciferase vector, we demonstrated that the receptor with I186V is unable to activate its intracellular signaling pathway while the P260Q mutation causes reduced activation of the receptor. CONCLUSION: We detected MC4R deficiency in 6 patients from our cohort, amounting to a prevalence of 5.3%. Two novel mutations were identified. We also confirmed that intracellular retention is a common pathogenic effect of MC4R mutations. PMID- 20975297 TI - A dysregulation in CES1, APOE and other lipid metabolism-related genes is associated to cardiovascular risk factors linked to obesity. AB - OBJECTIVE: The aim of the present study was to investigate the relationship between the differential expression of genes related to lipid metabolism in subcutaneous adipose tissue and metabolic syndrome features in lean and obese subjects with habitual high fat intake. METHODS: Microarray and RT-PCR analysis were used to analyze and validate differential gene expression in subcutaneous abdominal adipose tissue samples from lean and obese phenotype subjects. RESULTS: Several genes and transcripts involved in lipolysis were down-regulated, such as AKAP1, PRKAR2B, Gi and CIDEA, whereas NPY1R and CES1 were up-regulated, when comparing obese to lean subjects. Similarly, transcripts associated with cholesterol and lipoprotein metabolism showed a differential expression, with APOE and ABCA being decreased and VLDLR being increased in obese versus lean subjects. In addition, positive correlations were found between different markers of the metabolic syndrome and CES1 and NPY1R mRNA expressions, while APOE showed an inverse association with some of them. CONCLUSION: Different expression patterns in transcripts encoding for proteins involved in lipolysis and lipoprotein metabolism were found between lean and obese subjects. Moreover, the dysregulation of genes such as CES1 and APOE seems to be associated with some physiopathological markers of insulin resistance and cardiovascular risk factors in obesity. PMID- 20975298 TI - Risk factors for adult overweight and obesity: the importance of looking beyond the 'big two'. AB - OBJECTIVE: To compare two traditional (high dietary lipid intake and non participation in high-intensity physical exercise, namely the 'Big Two' factors) versus three nontraditional (short sleep duration, high disinhibition eating behavior, and low dietary calcium intake) risk factors as predictors of excess body weight and overweight/obesity development. METHOD: Adult participants aged 18-64 years of the Quebec Family Study were selected for cross-sectional (n = 537) and longitudinal (n = 283; 6-year follow-up period) analyses. The main outcome measure was overweight/obesity, defined as a BMI >= 25 kg/m(2). RESULTS: We observed that both the prevalence and incidence of overweight/obesity was best predicted by a combination of risk factors. However, short sleep duration, high disinhibition eating behavior and low dietary calcium intake seemed to contribute more to the risk of overweight and obesity than high dietary lipid intake and non participation in high-intensity physical exercise. Globally, the risk of being overweight or obese was two-fold higher for individuals having the three nontraditional risk factors combined (OR 6.05; 95% CI 4.26-7.88) compared to those reporting a high percentage of lipids in their diet together with no vigorous physical activity in their daily schedule (OR 2.95; 95% CI 2.18-3.73). Furthermore, the risk of overweight/obesity was also higher for the combination of any two of the nontraditional risk factors than for the combination of the 'Big Two' factors. CONCLUSION: These results are concordant with previous reports showing that obesity is a multifactorial condition, and emphasize the importance of looking beyond reported measures of the 'Big Two' factors. PMID- 20975299 TI - Serum vaspin concentrations are decreased after exercise-induced oxidative stress. AB - Elevated visceral adipose tissue-derived serpin (vaspin) serum concentrations are associated with impaired insulin sensitivity, but increase unexpectedly after long-term physical training. We therefore investigated the effect of an acute exercise bout and the effects of vitamin supplementation on chronic exercise effect and on serum vaspin concentrations. We measured serum vaspin and thiobarbituric acid-reactive substances (TBARS) concentrations in 80 individuals before and after a 1-hour acute exercise bout and independently in 40 healthy young men who were randomly assigned to either antioxidant (vitamin C (1,000 mg/day) and vitamin E (400 IU/day)) or to no supplementation after a standardized 4-week physical training program as a post hoc analysis. Serum vaspin concentrations significantly decreased after acute physical exercise as well as after 4 weeks of training in individuals without antioxidants. Changes in vaspin serum concentration correlate with increased TBARS serum concentrations both in response to a 1-hour exercise bout (r = -0.42, p < 0.01) and to the 4-week training (r = -0.31, p < 0.05). Interestingly, supplementation with antioxidants rather increased circulating vaspin levels in response to 4 weeks of exercise. In conclusion, vaspin serum concentrations are decreased by exercise-induced oxidative stress, but not by exercise-associated improvement in insulin sensitivity. PMID- 20975300 TI - Scale and dynamics of overweight and obesity epidemic in croatia. PMID- 20975301 TI - Promoting palliative care is prerequisite to future integrity of a comprehensive humane medicine. PMID- 20975302 TI - How to treat multiple myeloma: thoughts on a multicentre survey in Germany. PMID- 20975303 TI - Treatment effect or secret nature: long-term remissions in metastatic pancreatic cancer. PMID- 20975304 TI - Underfinancing of 90.3% for implant costs of prostheses and expanders in DRG revenues for uni- and bilateral mastectomy with immediate breast reconstruction. AB - BACKGROUND: From the clinic's point of view economic patient care requires comparison and adjustment of costs to revenues. To verify cost coverage for implants in mastectomy with immediate breast reconstruction, a comprehensive cost reimbursement analysis was performed. METHODS: Retrospective analysis of the German diagnosis-related group (G-DRG) revenues for implants from the DRG Browser 2007/2009HA and comparison with actual costs for implants in 2009 from the annual clinic report and the database of the controlling department. Calculation of the relative cost coverage for implants in unilateral (DRG J06Z) and bilateral mastectomy (DRG J16Z). RESULTS: In 2009, n = 98 J06Z and n = 18 J16Z were performed. DRG-calculated expenses for implants were ? 69.65 for J06Z and ? 123.07 for J16Z, i.e. a total of ? 9,040.96. Actual costs for all implants were ? 121,645.60, mean ? 699.11 (? 404.94-1,171.44). Attributable implant costs for 100% immediate breast reconstruction rate were ? 93,679.28. Thus, implants are not cost covering by -90.3% (-82.8 to -94.7%). Subsidies for implants from the clinic's budget range from ? 335.29 to ? 2,219.81 per case. CONCLUSIONS: Immediate breast reconstruction with implants after mastectomy is - even 6 years after introduction of the DRGs - not adequately calculated to be cost covering since the actual implant costs exceed the calculated revenues by far. At present, these implants are subsidized by the clinic at, on average, 90.3%. If economic patient care is mandatory, a maximum of only 1 in 10 patients with mastectomy can be offered immediate breast reconstruction with implants in Germany. PMID- 20975305 TI - Relationship between degree of chromosomal aberration and survival in intestinal type gastric cancer - a preliminary report based on three cases of hepatic metastasized gastric cancer with long-time survival. AB - BACKGROUND: Gastric cancer is one of the most frequent malignancies worldwide. More than 50% of all patients present with advanced stage of disease, with long time survival of less than 5%. In selected subgroups, palliative gastric resection seems to be beneficial for survival and improved quality of the remaining life time, but is still controversially discussed. PATIENTS AND METHODS: We report 3 cases of patients with intestinal-type advanced gastric cancer. All patients presented preoperatively with stage IV disease with liver metastases. The patients underwent palliative gastric resection and subsequent palliative chemotherapy. We performed a genome-wide DNA analysis of 9 gastric cancer tissue specimens using the DNA microchip array technique. RESULTS: 4 and 6 years after palliative surgery and chemotherapy, 2 of the patients show no signs of recurrence, while the third patient shows stable disease under third-line chemotherapy 4 years after the initial diagnosis. Comparative genetic analysis of 9 gastric cancer tissue specimens suggested that the degree of chromosomal aberration was closely related to survival for intestinal-type gastric cancers. CONCLUSIONS: Palliative gastric resection is beneficial for survival and quality of life in selected patients. Determination of the degree of chromosomal aberrations might be helpful in predicting the response on multimodal treatment in intestinal-type gastric cancer. A better understanding of molecular biology is needed to define prognosis markers and molecular targets. PMID- 20975306 TI - Antineoplastic chemotherapy in cancer patients with methicillin-resistant Staphylococcus aureus (MRSA). AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen causing serious morbidity and mortality in immunosuppressed patients. Antineoplastic chemotherapy causes immunosuppression, and thus there is concern whether such patients should proceed to therapy without delay or dose reduction. There are presently no guidelines with appropriate provisions for antineoplastic chemotherapy in cancer patients with MRSA colonization or infection. PATIENTS AND METHODS: We retrospectively analyzed the clinical outcome of all 27 patients with known MRSA infection or colonization undergoing antineoplastic chemotherapy for solid or hematological malignancies in our institution. RESULTS: In our patients, MRSA was detected at multiple sites. 11 patients were found to be colonized with MRSA, whereas 16 patients had colonization and/or infection. MRSA sepsis occurred in 12 cases. Interestingly, at the time of MRSA sepsis, neutrophil counts were less than 500/MUl in 42% of our patients. However, fatal complications due to MRSA occurred in only 2 patients. Among patients with MRSA sepsis, the mortality rate was 14%. CONCLUSIONS: Our results with a limited number of patients support the contention that antineoplastic chemotherapy may well be administered to patients with MRSA and should not necessarily lead to dose reduction or treatment delay, especially in cases with curative intent. PMID- 20975307 TI - How to treat multiple myeloma - a representative multicentre treatment survey. AB - BACKGROUND: The present survey was undertaken to gain insights in the changes of disease management of multiple myeloma (MM) over time and the implementation of new guidelines into daily practice. PATIENTS AND METHODS: Diagnosis and treatment of MM were evaluated based on a 3-month representative multicentre survey including 386 patients from 35 centres in Germany in 2008. The results were compared to similar surveys in 2004 and 2006. RESULTS: At the time of first diagnosis, most patients (62.5%) were already in stage III (Durie-Salmon). The presence of deletion 13q was determined in 22% of patients only. However, determination of other prognostic factors has become increasingly well established. These include the levels of beta2-microglobulin and serum albumin, each of which was determined in more than 2/3 of patients. Overall, 35% of patients were considered for high-dose chemotherapy. As a consequence of the development of innovative substances, there are remarkable shifts in first line, second line, and third line therapy with an increase in the use of bortezomib at all levels of therapy. CONCLUSIONS: Regarding diagnostic measures, deviations from recommended guidelines became evident. Also, high-dose chemotherapy with stem cell support was considered in a minority of patients only. Novel substances, however, were rapidly integrated into the treatment of MM. PMID- 20975308 TI - Giant basal cell carcinoma of the breast mimicking paget's disease: complete remission after photodynamic therapy. AB - BACKGROUND: Basal cell carcinoma (BCC) in the nipple area is extremely rare and can be mistaken for Paget's disease. CASE REPORT: A 47-year-old woman complained of a slowly growing, scaly erythematous plaque around her right nipple which had developed over several years. Paget's disease of the breast was suspected. Biopsies revealed a superficial BCC. The maximum tumor thickness was measured as 1 mm. Considering the superficial character of the tumor, photodynamic therapy (PDT) as a non-invasive approach was performed. Complete remission (CR) with an excellent cosmetic result was achieved after 4 PDT sessions. In the follow-up, CR with no signs of a local recurrence was evident after more than 24 months. CONCLUSION: In similar superficial cases of BCCs, non-invasive procedures such as PDT can be discussed as an alternative option to radical surgery or radiotherapy, with an excellent aesthetic outcome in carefully selected cases. PMID- 20975309 TI - Sustained partial remission of metastatic pancreatic cancer following systemic chemotherapy with gemcitabine and oxaliplatin plus adjunctive treatment with mistletoe extract. AB - BACKGROUND: The clinical prognosis of metastatic pancreatic cancer is very poor, with a median survival time of such patients ranging from 3 to 6 months. Current chemotherapy regimens include the combination of oxaliplatin and gemcitabine. CASE REPORT: A 43-year-old woman was diagnosed with pancreatic adenocarcinoma spreading into the regional lymph nodes and into multiple liver segments (pT3, pN1, pM1). Upon diagnosis, she underwent a pylorus-preserving pancreatic head resection, including dissection of regional lymph nodes and atypical resection of a single liver segment, followed by 9 cycles of palliative chemotherapy with gemcitabine and oxaliplatin. 37 weeks after surgery, the patient demonstrated a sustained partial remission, and the chemotherapy was stopped. Surprisingly, 10 months later, she still showed no evidence of tumor progression. Since the time of pancreatic surgery, the patient had taken mistletoe extracts and this adjunctive treatment has been continued until now. CONCLUSIONS: Cases of sustained long-term remission of metastatic pancreatic cancer are extremely rare. Although this single case observation does not allow for firm conclusions regarding potential mechanisms, the adjunctive therapy with mistletoe extracts might have played a role. Therefore, the clinical effects of such treatment in patients with pancreatic cancer warrant further investigation. PMID- 20975310 TI - Successful remission of extensive liver metastases in a breast cancer patient with acute liver failure using a combined chemotherapy regimen with mitomycin, folinate, and 5-fluorouracil (Mi/Fo/FU). AB - BACKGROUND: Liver failure due to disseminated hepatic secondaries represents a therapeutic dilemma in patients with metastatic breast cancer (MBC). Reduced liver function and non-assessable toxicity are limiting factors in the selection of chemotherapeutic agents. Currently, there is no standard treatment after failure of anthracycline-and taxane-based first-line therapies, although there is a variety of well evaluated drugs such as capecitabine. CASE REPORT: We report on a 45-year-old breast cancer patient with disseminated hepatic metastases. She presented in markedly poor condition, showing substantial ascites and extensive jaundice. Blood chemistry analysis showed increased serum levels of liver enzymes (aspartate aminotransferase 271 U/l, alanine transaminase 101 U/l), bilirubin (7.9 mg/dl), and CA 15-3 (1,459 U/l). We induced a palliative chemotherapy with mitomycin, folinate, and 5-fluorouracil (Mi/Fo/FU). The patient improved impressively after the first cycle of systemic therapy. Liver enzymes stabilized continuously, CA 15-3 returned to normal. The patient was discharged 2 weeks after the treatment start. Chemotherapy was well tolerated under dose escalation, no grade 3/4 toxicity was observed. The progression-free interval was 5 months. CONCLUSIONS: A combination therapy with Mi/Fo/FU appears to be a reasonable and tolerable alternative salvage strategy for patients with liver failure due to hepatic breast cancer metastases. PMID- 20975311 TI - Does exercise reduce cancer-related fatigue in hospitalised oncology patients? A systematic review. AB - The primary aim was to find out if exercise reduces cancer-related fatigue in hospitalised oncology patients. Controlled trials of fatigue outcomes after exercise in hospitalised oncology patients were obtained by searching electronic databases. Two reviewers completed data extraction and quality assessment independently. Standardised mean differences and 95% confidence intervals (CI) were determined and a meta-analysis completed. Five relevant trials evaluated 269 hospitalised oncology patients. Meta-analysis of fatigue had an overall standardised mean difference of -0.27 (95% CI -0.62 to 0.08, p = 0.13) in favour of exercise. Evidence from a single trial supported the use of exercise in increasing muscle strength, and there were no significant between-group differences in psychological status and aerobic capacity. Though inconclusive, the findings demonstrate positive trends of reduced cancer-related fatigue in hospitalised oncology patients who exercise. Future adequately powered trials are required to provide evidence to confirm these positive effects. PMID- 20975312 TI - Venous thromboembolic events alert for gynecologic neoplasms. AB - Paraneoplastic syndromes represent a group of clinical manifestations widely separated from the primary site of malignancy, which are not caused by local infiltration of the tumor or its metastases. Alterations of hemostasis and vascular abnormalities commonly accompany the progression of malignant disease. Hypercoagulability, changes in coagulation factors, anticoagulant proteins, circulating anticoagulants or platelets, and vascular responses have been noted during the disease process. The purpose of this review is to illustrate and present the current state of knowledge surrounding vascular paraneoplastic manifestations in gynecologic oncology. Since they may constitute the presenting feature of an undiagnosed gynecologic cancer, it is important to seek to identify such malignancies in women presenting with clinical thrombotic or bleeding syndromes. PMID- 20975313 TI - Endocytosis of microperoxidase in marginal cells is mainly regulated by RhoA signaling cascade, but not by Rho-associated protein kinase, myosin light-chain kinase and myosin phosphatase. AB - Endocytosis plays an important role in cell function and the activation and propagation of signaling pathways. Signaling occurs on endocytic pathways and signaling endosomes, and endocytosis is subjected to high-order regulation by cellular signaling mechanisms. Marginal cells showed active endocytosis of microperoxidase (MPO) via the clathrin-independent pathway. We examined the signaling pathway that regulates MPO endocytosis in marginal cells using specific inhibitors and activators of signaling molecules. The results showed that pertussis toxin - which inhibits the ribosylation of G-protein-coupled receptor - did not affect MPO endocytosis, but Clostridium botulinum C3 toxin - which induces RhoA inactivation resulting in extracellular-signal-related kinase inactivation - inhibited MPO endocytosis. The main endocytotic pathway of MPO did not depend on the Rho-associated protein kinase molecular switch or actin/myosin motor system, but was mainly regulated by the RhoA signaling cascade. PMID- 20975314 TI - Multipotent stromal cells for autologous cell therapy approaches in the guinea pig model. AB - Multipotent stromal cells have become of increasing interest due to their potential to provide therapeutic approaches for autologous tissue repair. However, these cells are not well defined in the guinea pig, which represents an important model in hearing research. Adipose-tissue-derived stem cells (ADSC) and bone-marrow-derived stem cells (BMSC) were isolated from different donor sites, and growth curves were generated to judge the proliferation potential. Adipogenic, chondrogenic and osteogenic differentiation was induced and confirmed histologically. Finally, the capability of guinea pig ADSC to differentiate into neuron-like cells was investigated. With regard to the expansion potential, total cell number and doubling time, ADSC from the neck were the most suitable cells of the tested donor sites. Both ADSC and BMSC showed nearly identical behaviour and ability to undergo multilineage differentiation. Thus, we identified ADSC from the neck as a promising cell source for autologous cell-based approaches in hearing research using the guinea pig model. PMID- 20975315 TI - Deleted in Esophageal Cancer 1(DEC1) is down-regulated and contributes to migration in head and neck squamous cell carcinoma cell lines. AB - BACKGROUND: Previous studies have shown that the expression of Deleted in Esophageal Cancer 1 (DEC1) is significantly reduced in esophageal squamous cell carcinoma. Patients with head and neck squamous cell carcinoma (HNSCC) often develop esophageal carcinomas. MATERIALS AND METHODS: We analyzed the expression of DEC1 and histone modifications in HNSCC cell lines. The motility and invasive ability of the HNSCC cell lines were also studied. RESULTS: Of 18 cell lines, 12 (66.7%) showed down-regulation of DEC1. Chromatin immunoprecipitation assays indicated that H3 K27 trimethylation levels in the DEC1-down-regulated cell lines were greater than that in the DEC1-expressed cell lines. Migration assays showed that the DEC1-down-regulated cell lines tended to be more motile than the DEC1 expressed cell lines. CONCLUSION: DEC1 is down-regulated and tends to contribute to the migration ability of HNSCC cell lines. In addition, H3 K27 trimethylation potentially plays an important role in the regulation of DEC1 expression. PMID- 20975316 TI - Practical guidelines for acute pancreatitis. AB - INTRODUCTION: The following is a summary of the official guidelines of the Italian Association for the Study of the Pancreas regarding the medical, endoscopic and surgical management of acute pancreatitis. STATEMENTS: Clinical features together with elevation of the plasma concentrations of pancreatic enzymes are the cornerstones of diagnosis (recommendation A). Contrast-enhanced computed tomography (CT) provides good evidence for the presence of pancreatitis (recommendation C) and it should be carried out 48-72 h after the onset of symptoms in patients with predicted severe pancreatitis. Severity assessment is essential for the selection of the proper initial treatment in the management of acute pancreatitis (recommendation A) and should be done using the APACHE II score, serum C-reactive protein and CT assessment (recommendation C). The etiology of acute pancreatitis should be able to be determined in at least 80% of cases (recommendation B). An adequate volume of intravenous fluid should be administered promptly to correct the volume deficit and maintain basal fluid requirements (recommendation A); analgesia is crucial for the correct treatment of the disease (recommendation A). Enteral feeding is indicated in severe necrotizing pancreatitis and it is better than total parenteral nutrition (recommendation A). The use of prophylactic broad-spectrum antibiotics reduces infection rates in CT-proven necrotizing pancreatitis (recommendation A). Infected pancreatic necrosis in patients with clinical signs and symptoms of sepsis is an indication for intervention, including surgery and radiological drainage (recommendation B). CONCLUSIONS: The participants agreed to revise the guidelines every 3 years in order to re-evaluate each question on the management of acute pancreatitis patients according to the most recent literature. PMID- 20975317 TI - A novel model of severe gallstone pancreatitis: murine pancreatic duct ligation results in systemic inflammation and substantial mortality. AB - BACKGROUND: Suitable experimental models of gallstone pancreatitis with systemic inflammation and mortality are limited. We developed a novel murine model of duct ligation-induced acute pancreatitis associated with multiorgan dysfunction and severe mortality. METHODS: Laparotomy was done on C57/BL6 mice followed by pancreatic duct (PD) ligation, bile duct (BD) ligation without PD ligation, or sham operation. RESULTS: Only mice with PD ligation developed acute pancreatitis and had 100% mortality. Pulmonary compliance was significantly reduced after PD ligation but not BD ligation. Bronchoalveolar lavage fluid neutrophil count and interleukin-1beta concentration, and the plasma creatinine level, were significantly elevated with PD ligation but not BD ligation. Pancreatic nuclear factor kappaB (p65) and activator protein 1 (c-Jun) were activated within 1 h of PD ligation. CONCLUSION: PD-ligation-induced acute pancreatitis in mice is associated with systemic inflammation, acute lung injury, multiorgan dysfunction and death. The development of this novel model is an exciting and notable advance in the field. PMID- 20975318 TI - Ukrain affects pancreas cancer cell phenotype in vitro by targeting MMP-9 and intra-/extracellular SPARC expression. AB - BACKGROUND/AIMS: We investigated whether the anticancer drug Ukrain (UK) is able to modulate the expression of some of the key markers of tumor progression in pancreatic cell carcinoma, in order to assess its potential therapeutic effect. METHODS: Three cell lines (HPAF-II, PL45, HPAC) were treated with UK (5, 10 and 20 MUM) for 48 h, or left untreated. Secreted protein acidic and rich in cysteine (SPARC) mRNA levels were assessed by real-time PCR. Matrix metalloproteinases (MMP)-2 and -9 activity was analyzed by SDS zymography; SPARC protein levels in cell lysates and supernatants were determined by Western blot. Cell cycle was determined by flow cytometric analysis, and invasion by matrigel invasion assay. RESULTS: UK down-regulated MMP-2 and MMP-9, suggesting that UK may decrease pancreatic cancer cell invasion, as confirmed by the matrigel invasion assay. SPARC protein down-regulation in supernatants points to an inhibition by UK of extracellular matrix remodeling in the tumor microenvironment. At the same time, SPARC mRNA and cellular protein level up-regulation suggests that UK can affect cell proliferation by cell cycle inhibition, showing a cell cycle G2/M arrest in UK-treated cells. CONCLUSION: Our results suggest that UK modulates two major aspects involved in tumorigenesis of pancreatic cancer cells, such as extracellular matrix remodeling and cell proliferation. PMID- 20975319 TI - Biophotonics and biotechnology in pancreatic cancer: cyclic RGD-peptide conjugated type II quantum dots for in vivo imaging. AB - This work introduces a novel, facile and straightforward approach to produce cyclic-RGD-peptide-conjugated type II CdTe/CdS quantum dot (QD) formulation for pancreatic tumor targeting and imaging in live animals. The ultra-small QDs were prepared by a hot colloidal synthesis method. Phospholipid micelles were then used to encapsulate the QDs, allowing them to be stably dispersed in biological fluids and able to conjugate with cyclic-RGD peptides. The QD complex had shown low cytotoxicity on Panc-1 human pancreatic cancer cell lines. In addition, the tissue sections and biodistribution of QD complexes were imaged and analyzed in mice bearing pancreatic tumor xenografts, confirming specific tumor targeting. These studies support further evaluation of type II QDs as potential probes for early pancreatic cancer assessment and detection. PMID- 20975320 TI - Histamine H(3) receptors are involved in the protective effect of ghrelin against HCl-induced gastric damage in rats. AB - In the present study, the effects of ghrelin against the gastric damage induced by intragastric administration of 0.6 N HCl and the involvement of histamine H3 receptors (H3Rs) were investigated in conscious rats with selective H3R ligands. Intraperitoneal (i.p.) injection of ghrelin (40 MUg/kg) significantly reduced (43%) the gastric lesions caused by concentrated acid. The effect of ghrelin was prevented by prior administration of the ghrelin receptor antagonist [D-Lys3] GHRP-6 (100 MUg/kg i.p.) and by subcutaneous (s.c.) injection of the nonimidazole H3R antagonist UCL2138 (30 mg/kg). The selective H3R agonist immethridine (30 mg/kg s.c.) significantly inhibited (64.60%) the gastric lesions induced by 0.6 N HCl. The effect of immethridine was prevented by prior administration of UCL2138 (30 mg/kg s.c.), but not by [D-Lys3]-GHRP-6 (100 MUg/kg i.p.). Neither [D-Lys3] GHRP-6 nor UCL2138 modified HCl-induced gastric damage per se. These data enlarge previous studies showing protective effects of ghrelin against ulcerogenic stimuli; in addition, they clearly indicate that ghrelin-induced gastroprotection involves the release of histamine, which enhances gastric mucosal defense through the activation of histamine H3Rs. PMID- 20975321 TI - The clinical factor. PMID- 20975322 TI - Beyond DSM-IV bereavement exclusion criterion E for major depressive disorder. PMID- 20975323 TI - The Clinical Interview for Depression: a comprehensive review of studies and clinimetric properties. AB - BACKGROUND: A comprehensive assessment of the wide spectrum of depressive symptomatology, particularly in its subclinical forms, is lacking in standard rating scales. There is also an emerging need for instruments that can detect small differences in therapeutic studies and have good sensitivity. The purpose of this paper is to review the clinimetric characteristics of Paykel's Clinical Interview for Depression (CID) and to examine the results of the studies in which the interview has been used. METHODS: Published reports which involved the use of the CID were identified by searching the following electronic databases: Medline, PsychINFO, EMBASE, and Web of Science. A manual search of the literature was also performed. RESULTS: The initial strategies yielded 169 published reports for potential inclusion in the review: 98 are discussed here. The CID has been used extensively in a variety of studies, including descriptive studies, classification by means of factor analysis and cluster analysis, and predictor variables of response to treatment or relapse. The CID has also been used as an outcome measure in several controlled clinical trials and follow-up studies of pharmacotherapy and psychotherapy of affective disorders. It has been shown to be valid and reliable, to discriminate depressives from controls, or different subgroups of depressed patients, and to reflect changes during the course of treatment, particularly when individual symptoms are considered. CONCLUSIONS: Evidence from these studies highlights the utility of the CID in clinical research and practice. Its clinimetric characteristics, particularly the broad evaluation of affective symptomatology and the sensitivity to change, make it an instrument of choice in therapeutic trials. PMID- 20975324 TI - Effectiveness of outpatient, day hospital, and inpatient psychotherapeutic treatment for patients with cluster B personality disorders. AB - BACKGROUND: For patients with cluster B personality disorders there is no consensus regarding the optimal treatment setting. The aim of this study was to compare the effectiveness of different psychotherapeutic settings for patients with cluster B personality disorders, i.e. outpatient, day hospital, and inpatient treatment. METHODS: The study was conducted between March 2003 and June 2008 in 6 mental health care centres in the Netherlands, with a sample of 207 patients with a DSM-IV-TR axis II cluster B diagnosis. Patients were assigned to 3 different settings of psychotherapeutic treatment and effectiveness was assessed at 18 months after baseline. An intention-to-treat analysis was conducted for psychiatric symptoms (Brief Symptom Inventory), psychosocial functioning (Outcome Questionnaire-45), and quality of life (EQ-5D), using multilevel statistical modelling. As the study was non-randomised, the propensity score method was used to control for initial differences. RESULTS: Patients in all 3 settings improved significantly in terms of psychiatric symptoms, social and interpersonal functioning, and quality of life 18 months after baseline. The inpatient group showed the largest improvements. The comparison of outpatient and inpatient treatment regarding psychiatric symptoms showed a marginally significant result (p = 0.057) in favour of inpatient treatment. CONCLUSIONS: Patients with cluster B personality disorders improved in all investigated treatment settings, with a trend towards larger improvements of psychiatric symptoms in the inpatient setting compared to the outpatient setting. Specialised inpatient treatment should be considered as a valuable treatment option for cluster B personality disorders, both in research and in clinical practice. PMID- 20975325 TI - Are treatment preferences relevant in response to serotonergic antidepressants and cognitive-behavioral therapy in depressed primary care patients? Results from a randomized controlled trial including a patients' choice arm. AB - BACKGROUND: Little is known about the influence of depressed patients' preferences and expectations about treatments upon treatment outcome. We investigated whether better clinical outcome in depressed primary care patients is associated with receiving their preferred treatment. METHODS: Within a randomized placebo-controlled single-centre 10-week trial with 5 arms (sertraline; placebo; cognitive-behavioral group therapy, CBT-G; moderated self help group control; treatment with sertraline or CBT-G according to patients' choice), outcomes for 145 primary care patients with mild-to-moderate depressive disorders according to DSM-IV criteria were investigated. Preference for medication versus psychotherapy was assessed at screening using a single item. Post-baseline difference scores for the Hamilton Depression Rating Scale (HAMD 17) were used to assess treatment outcome (mixed-model repeated-measures regression analysis). RESULTS: Depressed patients receiving their preferred treatment (n = 63), whether sertraline or CBT-G, responded significantly better than those who did not receive their preferred therapy (n = 54; p = 0.001). The difference in outcome between both groups was 8.0 points on the HAMD-17 for psychotherapy and 2.9 points on the HAMD-17 for treatment with antidepressants. Results were not explained by differences in depression severity or dropout rates. CONCLUSIONS: Patients' relative preference for medication versus psychotherapy should be considered when offering a treatment because receiving the preferred treatment conveys an additional and clinically relevant benefit (HAMD-17: +2.9 points for drugs; +8.0 points for CBT-G) in outcome. PMID- 20975326 TI - [Obesity and Eating Disorders. Indications for the different levels of care. An Italian Expert Consensus Document]. AB - This paper is an Italian Expert Consensus Document on multidimensional treatment of obesity and eating disorders. The Document is based on a wide survey of expert opinion. It presents, in particular, considerations regarding how clinicians go about choosing the most appropriate site of treatment for a given patient suffering from obesity and/or eating disorders: outpatient, partial hospitalization, residential rehabilitation centre, inpatient hospitalization. In a majority of instances obesity and eating disorders are long-term diseases and require a multiprofessional team-approach. In determining an initial level of care or a change to a different level of care, it is essential to consider together the overall physical condition, medical complications, disabilities, psychiatric comorbidity, psychology, behaviour, family, social resources, environment, and available services. We first created a review manuscript, a skeleton algorithm and two rating scales, based on the published guidelines and the existing research literature. As the second point we highlighted a number of clinical questions that had to be addressed in the specific context of our National Health Service and available specialized care units. Then we submitted eleven progressive revisions of the Document to the experts up to the final synthesis that was approved by the group. Of course, from point to point, some of the individual experts would differ with the consensus view. The document can be viewed as an expert consultation and the clinical judgement must always be tailored to the particular needs of each clinical situation. We will continue to revise the Document periodically based on new research information and on reassessment of expert opinion to keep it up-to-date. The Document was not financially sponsored. PMID- 20975327 TI - TroVax, a recombinant modified vaccinia Ankara virus encoding 5T4: lessons learned and future development. AB - There has been renewed interest in developing vaccine and immunotherapy for the treatment of cancer. The oncofetal antigen, 5T4, is a surface glycoprotein that is expressed on a variety of human adenocarcinomas but rarely on normal tissue. 5T4 plays an important role in tumor progression and metastasis. The expression patterns and functional role in the metastatic process suggest that 5T4 is a good target for vaccine development. A modified vaccinia virus Ankara (MVA) encoding human 5T4 (designated TroVax) demonstrated therapeutic effects in murine tumor models and human T cells recognized 5T4 epitopes in an HLA-restricted manner. The TroVax vaccine has subsequently been evaluated in clinical trials targeting patients with colorectal cancer, renal cell carcinoma and hormone refractory prostate cancer. Herein, we review the results of these clinical studies, discuss the lessons learned through these trials and provide some insight into the future development of TroVax as a cancer vaccine. PMID- 20975328 TI - Qui tam: False Claims Act. PMID- 20975332 TI - Certification does not always equal separate Medicare payment. PMID- 20975333 TI - Legal issues in the care of pressure ulcer patients: key concepts for healthcare providers--a consensus paper from the International Expert Wound Care Advisory Panel(c). PMID- 20975334 TI - Poor nutrition is a relative contraindication to negative pressure wound therapy for pressure ulcers: preliminary observations in patients with spinal cord injury. AB - OBJECTIVE: To assess the efficacy of negative-pressure wound therapy (NPWT) for healing of pressure ulcers (PrUs) in individuals with spinal-cord injury (SCI). DESIGN: Multicenter, 28-day observational study. SETTING: Ten Veterans Affairs Medical Center SCI centers. PATIENTS: Eighty-six SCI inpatients with Stage III/IV pelvic PrUs. INTERVENTIONS: Standard wound care with NPWT versus standard wound care alone (NoNPWT). MAIN OUTCOME MEASURES: Change in wound surface area (WSA) using the Verg Videometer Measurement Documentation software. MAIN RESULTS: The proportion of patients demonstrating a decrease in WSA (healing subgroup) was not significantly different between the NPWT (n = 33) and NoNPWT (n = 53) groups (67% vs 70%, respectively). In the healing subgroup, there was no significant difference between the NPWT versus NoNPWT groups in WSA decrease (-43 +/- 22% vs 50% +/- 26%, not statistically significant). Similarly, in the nonhealing subgroup, there was no significant difference between NPWT and NoNPWT groups (31% +/- 26% vs 32% +/- 34%). In the NPWT group, the nonhealing subgroup (11/33) had significantly lower serum albumin levels than the healing subgroup (22/33) (2.9 +/- 0.4 vs 3.3 +/- 0.5 mg/dL, P < .05). In the NoNPWT group, there was no significant difference in serum albumin levels between the healing versus nonhealing subgroups (3.2 +/- 0.3 vs 3.2 +/- 0.3 mg/dL). CONCLUSION: In SCI patients with Stage III/IV pelvic PrUs, NPWT did not significantly influence the rate of healing. Additionally, in malnourished individuals (albumin <3.0 mg/dL), NPWT was not efficacious. Healing outcomes in the NPWT group were significantly influenced by albumin levels, whereas no such disparity was noted between the healing and nonhealing PrUs for the NoNPWT group. Nutritional status appears to be important in the effectiveness of NPWT. PMID- 20975336 TI - Checklist for laboratory tests to rule out atypical causes of leg ulcers. PMID- 20975337 TI - Expression of prox1, lymphatic endothelial nuclear transcription factor, in Kaposiform hemangioendothelioma and tufted angioma. AB - Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare tumors mainly occurring in early childhood. Our recent results showed that ectopic overexpression of human Prox1 gene, a lymphatic endothelial nuclear transcription factor, promoted an aggressive behavior in 2 murine models of KHE. This dramatic Prox1-induced phenotype prompted us to investigate immunohistochemical staining pattern of Prox1, podoplanin (D2-40), LYVE-1, and Prox1/CD34 as well as double immunofluorescent staining pattern of LYVE-1/CD31 in KHE and TA, compared with other pediatric vascular tumors. For this purpose, we examined 75 vascular lesions: KHE (n=18), TA (n=13), infantile hemangioma (n=13), pyogenic granuloma (n=18), and granulation tissue (n=13). Overall, KHE and TA shared an identical endothelial immunophenotype: the neoplastic spindle cells were Prox1, podoplanin, LYVE-1, CD31, and CD34, whereas endothelial cells within glomeruloid foci were Prox1, podoplanin, LYVE-1, CD31, and CD34. The lesional cells of all infantile hemangiomas and pyogenic granulomas were negative for Prox1 in the presence of positive internal control. These findings provide immunophenotypic evidence to support a preexisting notion that KHE and TA are closely related, if not identical. Overall, our results show, for the first time, that Prox1 is an immunohistochemical biomarker helpful in confirming the diagnosis of KHE/TA and in distinguishing it from infantile hemangioma and pyogenic granuloma. PMID- 20975338 TI - Gastric lesions in patients with autoimmune metaplastic atrophic gastritis (AMAG) in a tertiary care setting. AB - Autoimmune metaplastic atrophic gastritis (AMAG) is an early manifestation of pernicious anemia that precedes the hematologic changes by years to decades. It is associated with metaplastic changes and neoplasms, including pyloric gland adenomas (PGAs). We investigated the frequency of PGAs and other lesions in all nonconsultation gastric biopsies and resections (1988 to 2008) diagnosed as AMAG. We further selected cases confirmed as AMAG by immunohistochemical identification of the gastric body (negative gastrin) and linear and nodular enterochromaffin like cell hyperplasia (chromogranin). From this subset, all polyps and neoplasms were reviewed. We identified a total of 41,245 patients with gastric biopsies or resections from 46.7% males and 53.3% females comprising patients self-identified as 67.0% white, 23.6% African-American, 1.4% Asian, 0.8% non-White Hispanic, and 7.2% other or unknown. AMAG was diagnosed in 461 patients (1.1%), and had the following percentages based on race: 1.1% White, 1.3% African-American, 1.4% Asian, and 2.7% non-White Hispanic. The female:male ratio was 2:1 with an overall median age at presentation of 67.0 years. Of the 461 patients with AMAG, 143 had endoscopically identifiable lesions. These lesions (n=240) consisted of 179 polyps (138 hyperplastic polyps, 20 oxyntic mucosa pseudopolyps, 18 intestinal type gastric adenomas, and 3 PGAs), 46 well-differentiated neuroendocrine neoplasms (carcinoid), 1 gastrointestinal stromal tumor, 3 lymphomas, and 11 adenocarcinomas. In summary, AMAG occurred with similar frequency across all racial groups. Although PGAs are associated with AMAG, they remain rare in the setting of AMAG. PMID- 20975339 TI - Gene expression profiling of synovial sarcoma: distinct signature of poorly differentiated type. AB - Poorly differentiated type synovial sarcoma (PDSS) is a variant of synovial sarcoma characterized by predominantly round or short-spindled cell morphology. Although accumulating evidence from clinicopathologic studies suggests a strong association between this variant of synovial sarcoma and poor prognosis, little has been reported on the molecular basis of PDSS. To gain insights into the mechanism(s) that underlie the emergence of PDSS, we analyzed the gene expression profiles of 34 synovial sarcoma clinical samples, including 5 cases of PDSS, using an oligonucleotide microarray. In an unsupervised analysis, the 34 samples fell into 3 groups that correlate closely with histologic subtypes: monophasic, biphasic, and poorly differentiated types. PDSS was characterized by down regulation of genes associated with neuronal and skeletal development and cell adhesion. Moreover, upregulation of genes on a specific chromosomal locus, 8q21.11, was identified. This locus-specific transcriptional activation in PDSS was confirmed by reverse transcriptase-PCR analysis of 9 additional synovial sarcoma samples. Our results indicate that PDSS tumors constitute a distinct group based on expression profiles. PMID- 20975340 TI - PEComa presenting in bone: clinicopathologic analysis of 6 cases and literature review. AB - PEComas other than angiomyolipoma, lymphangioleiomyomatosis, and clear cell sugar tumor of the lung are relatively rare, and PEComas presenting in bone are especially rare. To further characterize their clinicopathologic features, 6 cases of PEComa which first presented in bone were retrieved from the authors' consult and surgical pathology files, including both primary and metastatic lesions. Four patients were female and 2 patients were male. The age at diagnosis ranged from 35 to 71 years, with a mean of 51.5 years. As for the 3 cases known definitely to have arisen in bone, the primary sites were right tibia in 2 cases and thoracic vertebra in 1 case. In the 2 cases, presenting in scapula and femur respectively, the primary sites could not be determined with certainty. In 1 case, the lesion was first found in humerus, but the primary tumor proved to be located in the uterus. Histologically, all the tumors were composed of both epithelioid and spindle cells, showing a nested pattern with elaborate vasculature. The characteristic thin walled vessels around which tumor cells were arranged tightly, or in a radiating fashion were seen in all cases. Two or more worrisome features (tumor size >5 cm, infiltrative growth pattern, high nuclear grade, high cellularity, necrosis, and mitotic activity >1/50 HPF) were identified in 4 cases, of which 2 were primary bone tumors; these cases were classified as "malignant" histologically. We conclude that both the primary and metastatic PEComas can present in bone, although both are rare. Combining our findings with the few earlier published reports, it may be suggested that primary PEComa of bone tends to involve lower extremities (5/7 cases). Histologically, they show similar cytomorphology, nested architecture, and characteristic vessels as PEComas at other sites. In addition, a significant subset of the primary bone lesions seem to be malignant. PMID- 20975341 TI - Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH. AB - In explant livers with chronic hepatitis C (HCV-C) we have noted a distinctive histologic variant that we have termed steatohepatitic hepatocellular carcinoma (SH-HCC) with features resembling non-neoplastic steatohepatitis, including large droplet steatosis, ballooning of malignant hepatocytes, Mallory-Denk bodies, inflammation, and pericellular fibrosis. This study was undertaken to further describe the characteristics and prevalence of this histologic variant in HCV-C and any possible association with underlying risk factors for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We selected two 2 year periods (mid-2003 to mid-2005 and 2007 to 2008), from which selected explant livers with HCV-C and HCC were examined to determine the characteristics and frequency of SH-HCC. The underlying cirrhotic liver was also reassessed for steatosis and evidence of steatohepatitis. Clinical records were consulted for concomitant NAFLD and NASH risk factors. The SH-HCC variant was found in a total of 22 of 62 HCC cases (35.5%). Fourteen of the 22 patients with SH-HCC (63.6%) had at least one known risk factor for NAFLD/NASH including diabetes (6 of 22, 27.3%), obesity (6 of 22, 27.3%), hypertension (11 of 22, 50%), and hyperlipidemia (5 of 22, 27.8%). In 14 of the 22 cases (63.6%) of SH-HCC, the non neoplastic liver showed changes of NAFLD/NASH superimposed on otherwise typical features of HCV-C. In conclusion, in our series of HCV-C explants, approximately one-third of HCCs show a distinctive histological variant termed SH-HCC. Underlying risk factors for NAFLD and for NASH were identified in 63.6% of our cases. Moreover, non-neoplastic tissue in HCV-C explants showed changes of NAFLD/NASH in 63.6% of cases. These results suggest a possible NAFLD/NASH pathway leading to SH-HCC in the setting of HCV-C which requires further investigation in the future. PMID- 20975342 TI - Invasive ductal carcinomas of the breast showing partial reversed cell polarity are associated with lymphatic tumor spread and may represent part of a spectrum of invasive micropapillary carcinoma. AB - Invasive micropapillary carcinomas (IMPC) of the breast are aggressive tumors frequently associated with lymphatic invasion and nodal metastasis even when micropapillary (MP) differentiation is very focal within the tumors. We have noticed that some breast carcinomas showing lymphatic spread but lacking histologic features of IMPC have occasional tumor cell clusters reminiscent of those of IMPC without the characteristic prominent retraction artifact. To study the clinicopathologic significance of such features, we prospectively selected 1323 invasive ductal carcinomas and determined the presence and extent of MP differentiation and retraction artifact in the tumors. One representative tumor block per case was used for immunostaining for epithelial membrane antigen (EMA). Partial reverse cell polarity (PRCP) was defined as prominent linear EMA reactivity on at least part of the periphery of tumor cell clusters usually associated with decreased cytoplasmic staining. The clinicopathologic features of carcinomas with PRCP were compared with IMPC and invasive ductal (no special type) carcinomas without this feature. Of the 1323 cases, 96 (7.3%) and 92 (7.0%) showed MP features and the presence of PRCP, respectively. We found that the presence of both PRCP and MP features were strongly associated with decreased cytoplasmic EMA immunoreactivity and the presence of lymphatic invasion and nodal metastasis, even if such features were present only very focally. Our results suggest that breast carcinomas with PRCP may have the same implication as MP differentiation and these tumors may represent part of a spectrum of IMPC. Complete or partial reversal of cell polarity may play a significant role in lymphatic tumor spread. PMID- 20975343 TI - Well-differentiated osteosarcoma of the jaw bones: a clinicopathologic study of 15 cases. AB - Well-differentiated osteosarcoma of the jaw bones is rare, and is often confused with a variety of benign fibroosseous lesions. To better understand its clinicopathologic features, we reviewed our experience with 15 cases. The patients included 7 males and 8 females (age range 14 to 66 y; mean 42.8 y). Six of the tumors arose in the mandible, and 9 in the maxilla. Microscopically, the tumors were infiltrative, relatively hypocellular, and consisted of monomorphic, minimally atypical spindle cells that were usually arranged in fascicles. The tumor cells were intimately related to the surfaces of elongated trabeculae of neoplastic woven bone that lacked osteoblastic rimming. Nine patients were treated with wide excision, 2 patients with marginal excision, and 2 patients with excision and radiation therapy. After definitive therapy, there were no reports of recurrence or metastasis over an average follow-up of 34 months (range 1 to 80 mo). Well-differentiated gnathic osteosarcoma is a low-grade malignancy that may be successfully treated with wide local excision. The prognosis in our series was excellent. PMID- 20975344 TI - Iron pill-induced tumefactive mucosal injury of the hypopharynx. AB - Iron pill-induced mucosal injury of the airways with massive necrosis and stricture of the lower airways is known to occur, but symptomatic injury of the hypopharyngeal mucosa secondary to therapeutic oral iron ingestion has not been described. We report iron-sulfate-induced mucosal injury of the hypopharynx in a patient receiving therapeutic oral iron supplementation. The patient presented with dysphagia when swallowing pills, but not when eating or drinking. Imaging studies and clinical examination revealed an ulcerated and protuberant hypopharyngeal mass. Histology showed mucosal ulceration with deposits of extracellular crystalline iron particles. The histologic changes were identical to those seen in patients with "iron pill" gastritis. PMID- 20975345 TI - Comfort: a value forgotten in nursing. PMID- 20975346 TI - Choosing paths to the future to improve cancer care. PMID- 20975347 TI - Cochrane review summary for cancer nursing: acupuncture-point stimulation for chemotherapy-induced nausea or vomiting. PMID- 20975348 TI - "I know that you said you are studying my patient, but aren't you really studying me?": the question posed by pediatric oncology clinicians in end-of-life studies. PMID- 20975350 TI - Respiratory function and the obesity paradox. AB - PURPOSE OF REVIEW: Obese individuals have impaired respiratory function relative to their normal-weight counterparts. Despite these negative effects, obesity is paradoxically associated with better survival in individuals with chronic obstructive pulmonary disease (COPD). The purpose of this review is to describe this 'obesity paradox', to discuss the effects of obesity on respiratory function, and to speculate as to whether obesity-related alterations in respiratory mechanics can influence the natural history of COPD. RECENT FINDINGS: Given the known negative effects of obesity on respiratory physiology, it is reasonable to predict that obese COPD patients would be more likely to experience greater dyspnea and exercise intolerance relative to COPD patients of normal weight. However, recent evidence suggests that obese COPD patients have similar or better dyspnea scores during exercise and do not have diminished exercise capacity. These observations may be attributable to the fact that obese COPD patients have reduced operating lung volumes and higher inspiratory capacity to total lung capacity ratios than their lean COPD counterparts. SUMMARY: Obese patients with COPD do not appear to be at a disadvantage during exercise relative to lean COPD patients. Obesity may be associated with improved survival in COPD but specific mechanisms for this paradox remain to be elucidated. PMID- 20975352 TI - Current world literature. PMID- 20975351 TI - Vitamin D supplementation: a pharmacologic perspective. AB - PURPOSE OF REVIEW: Vitamin D supplementation is expected to increase as clinicians try to optimize their patients' vitamin D status. This review integrates newer information into a perspective on vitamin D disposition and effect. RECENT FINDINGS: Vitamin D is being considered for indications beyond bone health. The limited dose-response data vary by indication, but generally target a goal serum 25(OH)D concentration of 80-120 nmol/l. Although oral vitamin D is adequately absorbed, distributed, metabolized, and utilized before being excreted, these factors may vary with baseline vitamin D status, genetic polymorphism, and the form of vitamin D being administered. Additionally, the responses to vitamin D can be tissue-specific and are not always well described. SUMMARY: There is still a need to better characterize the disposition and effect of vitamin D supplementation. Data will need to be more specific to the therapeutic indication and demonstrate health outcomes. Long-term effects of high dose supplementation at the tissue level will be especially important to describe. PMID- 20975353 TI - Alon Dembo. Introduction. PMID- 20975354 TI - Primary chemotherapy: the future for the management of advanced ovarian cancer? AB - Primary surgery for advanced ovarian cancer has been the standard practice for more than 30 years. A survival benefit is principally seen in patients who have optimal cytoreduction with no or small-volume residual disease after surgery. In everyday clinical practice, many patients are not able to undergo optimal tumor debulking. Modern preoperative imaging and assessment can identify most of these patients. Through developments in platinum-based chemotherapy, a high proportion of patients can be expected to respond to primary (neoadjuvant) chemotherapy. A recent clinical trial has shown that the survival of patients with operable disease is not disadvantaged by neoadjuvant chemotherapy followed by surgery. Thus, complete tumor cytoreduction could be achieved in a greater percentage of patients, if primary chemotherapy is used in women in whom optimal primary surgery would be difficult. Furthermore, delayed surgery provides more knowledge about the biological behavior of the tumor, and this could be used to tailor treatment more effectively. PMID- 20975355 TI - Optimally debulked stage III ovarian cancer: intraperitoneal or intravenous chemotherapy? AB - The optimal management of women with optimally debulked stage III ovarian cancer is contentious. There are in particular widely differing views regarding the role of intraperitoneal chemotherapy, and this has been debated widely. Being on the negative side in the debate, I will provide compelling reasons why systemic chemotherapy should remain the standard of care but argue that dose-dense weekly paclitaxel rather than the 3 weekly schedules should be adopted based on the results of the Japanese Gynecologic Oncology Group study. The pharmacokinetics of intraperitoneal paclitaxel suggests that intraperitoneal paclitaxel at day 8 with intravenous paclitaxel at day 1 is only a more complicated way of delivering dose dense paclitaxel. PMID- 20975356 TI - Fifth Alon Dembo memorial workshop: case 3. AB - BACKGROUND: OVO5/EORTC 55855, a study punitively refuting the value of CA-125 in the follow-up of ovarian cancer patients, has many deficiencies, including a heterogeneous ovarian cancer patient population, no control of initial treatment regimens, and no control of subsequent surgery or chemotherapeutic management for recurrence. Recent studies suggest a role for prompt surgery in selected cases of recurrent ovarian cancer with CA-125 elevations, a role for tamoxifen in managing rising CA-125 levels in patients without evidence of disease and the use of platinum doublets for treating recurrent platinum-sensitive disease, none of which were incorporated into OVo5/EORTC 55955. CASE: A patient with advanced stage ovarian cancer presenting with a CA-125 level of 2000 U/mL, who is initially treated with surgery followed by chemotherapy and has a normal CT scan and normal CA-125 at completion of her initial chemotherapy. CONCLUSION: This patient remains at a very high risk for recurrence. I would continue to monitor this patient with serial CA-125 levels to identify recurrent cancer and consider initiating treatment before it is clinically obvious. PMID- 20975357 TI - What surveillance plan should be advised for patients in remission after completion of first-line therapy for advanced ovarian cancer? AB - Based on the results of the Medical Research Council OVO5/European Organisation for Research and Treatment of Cancer 55955 trial, the follow-up plan I recommend for patients in remission after completion of first-line therapy for advanced ovarian cancer is appointments: every 3 months for 2 years, every 4 months on the third year, then every 6 months thereafter, and discharge if no relapse by 10 years. History and examination (not internal) should be performed at each appointment. CA-125 should only be measured if there is a suspicion of relapse or at patient's request. No scans should be performed unless clinical indication or rising CA-125. PMID- 20975358 TI - Preconception counseling for the couple at risk preventing the hereditary breast and ovarian cancer syndrome. PMID- 20975359 TI - The effects of parity, breastfeeding, and infertility treatment on the risk of hereditary breast and ovarian cancer: a review. AB - Knowledge of the potential association of parity, breastfeeding, and infertility treatment on breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers is important and should be a crucial part of genetic counseling. The discussion of parity and clinical management of infertility in these women is complex, and patient preferences should be considered. Ideally, these preferences should be informed by accurate information on the risks and benefits of the interventions considered. However, this important subject has been investigated in a relatively small number of studies, thus, the existing data remain somewhat limited, and the estimated risk of cancer in BRCA mutation carriers is imprecise. PMID- 20975360 TI - Role of sentinel lymph node biopsy in cervical cancer: pro. AB - Sentinel lymph node biopsy in cervical cancer is used to reduce the morbidity of a full lymph node dissection while improving the pickup rate of metastatic lymph nodes. The higher detection rate achieved can be explained by the following: the identification of the sentinel lymph node in an aberrant location which would not be routinely included in a systematic pelvic lymph node dissection, the sentinel lymph node is completely excised, and the routine use of ultrastaging. The higher detection rate achieved through sentinel lymph node biopsy can identify additional patients who could potentially benefit from adjuvant therapy therefore, in our view the gold standard of lymph node assessment in early stage cervical cancer has shifted and sentinel lymph node biopsy has taken the place of a complete lymphadenectomy. PMID- 20975361 TI - Nerve sparing in radical surgery for early-stage cervical cancer: yes we should! AB - Radical hysterectomy with pelvic lymphadenectomy is considered to be the cornerstone in the treatment of early-stage cervical cancer. Although survival in early-stage cervical cancer is up to 95%, long-term morbidity with regard to bladder, bowel, and sexual function is considerable. Damage to the pelvic autonomic nerves may be the cause of these long-term complications following radical hysterectomy. Some authors have presented surgical techniques to preserve the autonomic nerves (ie, the hypogastric nerves and the splanchnic nerves) without compromising radicality. Safety, efficacy, and the surgical techniques of nerve-sparing radical hysterectomy are presented, and data confirm that whenever the decision is made to perform a radical hysterectomy, nerve-sparing techniques should be considered. PMID- 20975362 TI - Lymphadenectomy in endometrial cancer: which is the right question? PMID- 20975363 TI - Adjuvant chemotherapy in endometrial cancer. AB - The indications for adjuvant therapy in endometrial cancer are briefly reviewed. The importance of systemic adjuvant therapy is emphasized. A short summary of randomized studies on adjuvant chemotherapy versus radiotherapy and on adjuvant sequential chemotherapy plus radiotherapy versus radiotherapy alone is given. On the basis of the present results from randomized trials, a combination of adjuvant radiotherapy and platinum-based chemotherapy seems to be most effective. PMID- 20975364 TI - Adjuvant chemotherapy for endometrial cancer: unproven. AB - High-risk endometrial cancer (EC), only 15% of all EC cases, mainly affects elderly women, often with significant comorbid diseases. Because patients with high-risk EC are at increased risk of distant metastases and EC death, the use of adjuvant chemotherapy has been investigated in several trials. Trials comparing radiotherapy and chemotherapy have not shown survival difference. A first trial comparing combinations of chemotherapy and radiotherapy with radiotherapy alone suggested a progression-free survival benefit. Toxicity and quality-of-life data are lacking. The role of adjuvant chemotherapy for endometrial carcinoma remains unproven. High-risk EC remains the challenge for further research. PMID- 20975365 TI - A role for adjuvant radiation in clinically early carcinoma of the endometrium? AB - Whereas radiation is recognized as a highly effective treatment modality in endometrial cancer, its role as adjuvant treatment after surgery in clinically early disease is declining. Randomized trials of both pelvic external beam radiation and vaginal vault brachytherapy have been conducted to evaluate their respective contribution. These trials have demonstrated that external beam radiation may decrease pelvic relapse rates compared with observation alone in high intermediate-risk groups, but this does not improve survival. Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) Study 2 confirmed that vaginal vault brachytherapy was equivalent to external beam radiation in preventing vaginal relapse. However, given the high rate of salvage of patients who develop vaginal recurrence and the significant risk of death from comorbidities, questions arise as to the relative merit of administering adjuvant radiation for all compared with a strategy of observation after surgery with treatment only for the 10% who have a relapse.The contribution of adjuvant radiation for high-risk disease, including those with grade III tumors with deep myometrial penetration, however, remains to be determined in ongoing trials. PMID- 20975368 TI - Physiologic profile of professional cricketers. AB - This study aims to provide a physiologic profile of professional cricketers and note positional differences at the start of the 2007/08 competitive season. Fifteen participants (9 bowlers, 6 batsmen) aged 25.0 +/- 5.0 years (mean +/- SD) took part in this study. Participants (bowlers and batsmen) completed a series of field-based fitness assessments: body composition (sum of 7 skinfolds, 72.5 +/- 16.5 and 65.5 +/- 19.3 mm, respectively), flexibility (sit and reach 8.1 +/- 10.3 and 6.0 +/- 6.2 cm, respectively), predicted maximal oxygen uptake (multistage shuttle run, 54.1 +/- 2.8 and 56.1 +/- 4.5 ml-1.kg-1.min-1, respectively), upper- (medicine ball throw, 7.7 +/- 0.6 and 7.0 +/- 0.1 m, respectively) and lower-body strength (countermovement jump, 45.7 +/- 5.8 and 43.9 +/- 4.1 cm, respectively), speed (sprint 17.7 m, 2.76 +/- 0.6 and 2.77 +/- 0.1 s, respectively), and explosive power (repeated jump, 31.0 +/- 2.0 and 34.1 +/- 4.8 cm, respectively). The data provided the physical fitness profile for each player, which, compared with normative data, identified that this cohort of professional cricketers had some superior fitness parameters compared with the general population, and where applicable, were comparable with other professional athletes. In addition, after effect size calculations, the results showed that some physical fitness differences existed between playing positions. Cricket professionals possess a superior level of physical fitness and strength, and conditioning coaches should seek to progress these physical parameters and further identify position-specific physical requirements to progress the modern game. PMID- 20975369 TI - The effects of load and training pattern on acute neuromuscular responses in the upper body. AB - The purpose of this study was to examine the effects of repetition maximum (RM) loads and training patterns on acute neuromuscular responses in the upper body. Markers of fatigue were monitored under a descending pattern (DP), in which repetitions decreased in subsequent sets, and an ascending pattern (AP), in which repetitions increased in subsequent sets. Both training patterns were performed using 5- and 10-RM loads. Fatigue was assessed by monitoring changes in force output, motor unit activation and muscle twitch characteristics (peak twitch [PT], time to PT [TPT], and 1/2 relaxation time [RT]). All 4 protocols (5-RM DP, 5-RM AP, 10-RM DP, and 10-RM AP) produced significant decreases pre to postprotocol in force output, TPT, and 1/2RT. With the exception of 5-RM DP, all protocols produced significant decreases in motor unit activation. Pre to postprotocol, PT forces were potentiated under 5-RM loads, whereas they were depressed under 10-RM loads. Hence, a main effect for training protocols showed that changes in PT force were significantly different under 5-RM, as compared to 10-RM loads. The results indicate that central fatigue may be independent of load and pattern, whereas peripheral fatigue would appear to be dependent on load but not pattern. PMID- 20975370 TI - November--lung cancer awareness month! PMID- 20975371 TI - Lung cancer: an emerging epidemic in the human immunodeficiency virus-infected population. PMID- 20975372 TI - The seventh tumor, node, metastasis staging system and lung cancer treatment choices: a matter of would, could, and should. PMID- 20975373 TI - Downregulated ABCG2 enhances sensitivity to topoisomerase I inhibitor in epidermal growth factor receptor tyrosine kinase inhibitor-resistant non-small cell lung cancer. AB - INTRODUCTION: Understanding the mechanisms of drug resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is essential to develop novel chemotherapies for non-small cell lung cancer (NSCLC). Therefore, we analyzed the expression and function of ATP-binding cassette (ABC) transporters in EGFR TKI-resistant NSCLC. METHODS: In three newly established AG1478-resistant NSCLC cell lines, we evaluated the expression profile of ABC transporters and genotyping of ABCG2 by real-time polymerase chain reaction and elucidated their function by Hoechst dye efflux analyses. The growth-inhibitory effect of the topoisomerase I inhibitor Hoechst 33342, which is extruded by ABCG2, was also investigated in these cells using 3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. RESULTS: In AG1478 resistant cells, significantly less ABCG2 was expressed, and the ratios of the cells with a strong ability to extrude Hoechst dye were remarkably smaller than in the parent cells. Because of the ABCG2 downregulation and loss of function due to C421A/C421A homozygosity, PC-14AG50R was thus considered to be more sensitive to Hoechst 33342 than the parental cells. All AG1478-resistant cells were more sensitive to the combination of Hoechst 33342 and AG1478 than to single agent. CONCLUSIONS: Resistance to EGFR TKI in NSCLC is associated with the downregulation of ABCG2 expression. A topoisomerase I inhibitor alone or in combination with EGFR TKI might offer a promising strategy for treating NSCLC that is resistant to EGFR TKI. PMID- 20975374 TI - DNA repair gene X-ray repair cross complementing group 1 Arg194Trp polymorphism on the risk of lung cancer: a meta-analysis on 22 studies. AB - BACKGROUND: DNA repair gene X-ray repair cross complementing group 1 (XRCC1) Arg194Trp polymorphism has been investigated widely on lung cancer risk. However, the results are inconclusive. To derive a more precise estimation of the relationship between XRCC1 Arg194Trp polymorphism and lung cancer risk, we performed this meta-analysis. METHODS: An electronic search of the database PubMed, Embase, and Chinese National Knowledge Infrastructure was performed. The odds ratio (OR) was pooled by STATA 10.1. Subgroup analyses by ethnicity, gender, smoking, and histologic types of lung cancer were performed. RESULTS: Twenty-two studies including 7515 cases and 9560 controls were identified ultimately. The pooled OR for total population showed that homozygous Trp/Trp variant genotype could increase lung cancer risk compared with the homozygous wild Arg/Arg genotype (OR = 1.22, 95% confidence interval [CI] = 1.04-1.44, p = 0.01); however, heterozygote Arg/Trp variant genotype could decrease lung cancer risk (OR = 0.91, 95% CI = 0.85-0.99, p = 0.02). Subgroup analyses by ethnicity confirmed the result that homozygous Trp/Trp variant genotype increased lung cancer risk in Asians (OR = 1.19, 95% CI = 1.01-1.41, p = 0.04) but not in whites. It was interesting to find that both the heterozygote Arg/Trp and the combined Trp/Trp + Arg/Trp variant genotypes could decrease the risk of lung cancer in whites (OR = 0.83, 95% CI = 0.72-0.96, p = 0.01; OR = 0.85, 95% CI = 0.74-0.98, p = 0.03, respectively) but not in Asians. Subgroup analyses by gender, smoking, and histologic types of lung cancer did not indicate any significant difference between cases and controls, excepted for male population, which carried heterozygote Arg/Trp variant genotype that could decrease lung cancer risk (OR = 0.54, 95% CI = 0.31-0.95, p = 0.03). CONCLUSIONS: Homozygous Trp/Trp variant genotype of XRCC1 Arg194Trp polymorphism could increase lung cancer risk in total population, especially in Asians. However, the heterozygote Arg/Trp variant genotype might decrease the risk of lung cancer, especially in whites. PMID- 20975375 TI - Use of microRNA expression levels to predict outcomes in resected stage I non small cell lung cancer. AB - BACKGROUND: Despite undergoing curative resection, nearly a third of patients with stage I non-small cell lung cancer (NSCLC) die of recurrent disease. There are no reliable clinical or molecular predictors of relapse in patients with resected stage I NSCLC. Identifying patients at risk for relapse after surgical resection is one of the important challenges today. MicroRNAs (miRNAs) regulate hundreds of genes central to maintaining a cancer phenotype. METHODS: In an exploratory study, we determined whether expression of six miRNAs (let-7a, miR-7, miR-21, miR-155, miR-210, and miR-221) previously reported to correlate with invasiveness or outcome in various human malignancies were associated with tumor recurrence in patients with resected stage I NSCLC. We measured expression of these miRNAs in formalin-fixed, paraffin-embedded tissue from both tumor and matched normal lung in a set of 46 patients with surgically resected T1 or T2 stage I NSCLC. RESULTS: Averaged triplicate data showed that tumors which recurred had 0.14-fold lower miR-221 expression than those which did not recur (p = 0.0036). In addition, increased miR-221in tumor tissue when compared with adjacent normal appearing lung in the same patient also correlated with nonrecurrence (p = 0.0011). Parallel measurement of expression of selected downstream target genes regulated by miR-221, specifically, CDKN1B, CDKN1C, paralemmin-2, and CXCL12, showed a near significant (p = 0.0522) down-regulation of CDKN1C in tumors of patients with no recurrent disease, consistent with increased miR-221 activity in the same group. CONCLUSION: If confirmed in prospective studies, miRNA expression in resected NSCLC could potentially identify those at high risk of relapse after surgery. PMID- 20975377 TI - Should the 7th edition of the lung cancer stage classification system change treatment algorithms in non-small cell lung cancer? AB - INTRODUCTION: Approximately 10 to 15% of non-small cell lung cancer patients will be assigned a stage classification according to the 7th edition of TNM that differs from that assigned by the 6th edition (the "stage shifters"). This apparent upstaging or downstaging of tumors may affect patient management, as many clinicians formulate stage-based management strategies. However, the staging system revision was not designed to evaluate treatment, and attempts to make parallel adjustments in treatment plans may not be justified. METHODS: Lung cancer clinicians were surveyed at four lung cancer symposia. Treatment of the "stage shift" patients was evaluated in the International Association for the Study of Lung Cancer database and National Cancer Database. RESULTS: Overall, 77% of surveyed clinicians indicated they would alter patient management in response to a change in stage designation.The analysis of the data in the International Association for the Study of Lung Cancer database was not directed at supporting treatment changes. Despite the similar overall prognosis within each of the "stage shift" subgroups in the National Cancer Database, the treatment was decidedly heterogeneous. CONCLUSIONS: The perception that a stage change should lead to a change in management exists. The revision of the lung cancer staging system does not provide any direct information to indicate the superiority of one treatment approach over another. Assuming that overall prognosis of a subgroup is strongly linked to a specific treatment and that a particular outcome, therefore, warrants a change in treatment is not justified. Thus, making changes in management solely in response to upstaging or downstaging in the new stage classification system is not justified. PMID- 20975376 TI - Primary lung adenocarcinomas in children and adolescents treated for pediatric malignancies. AB - INTRODUCTION: Primary lung adenocarcinoma is extremely rare in the pediatric age group. There have been anecdotal reports of lesions that are histologically indistinguishable from adult-type pulmonary adenocarcinoma in young patients after treatment for nonpulmonary cancers. Herein, we present clinical, histopathologic, and molecular data on eight such cases. METHODS: Histopathologic evaluation of the tumors was performed according to the World Health Organization classification. Molecular studies for EGFR and KRAS mutations were performed on six patients with sufficient material. RESULTS: All eight patients were never smokers, four males and four females. Median age at nonpulmonary cancer diagnosis was 14 years (range, 3-23 years). Pulmonary adenocarcinomas were diagnosed at a median age of 15 years (range, 10-24 years); tumors were 0.1 to 2.0 cm in size and in some cases coexisted with metastases from the original cancer. Retrospective review showed that in at least three patients, the nodules were radiographically present before chemotherapy. Of six patients whose tumors were tested for common EGFR and KRAS mutations, two were positive for the former and one for the latter. At a median follow-up of 11 months (range, 2-29 months), six patients remained well without lung nodules and two had additional small, peripheral lung nodules that have not been biopsied. CONCLUSIONS: Pulmonary lesions found in young patients with pediatric cancers can be histologically indistinguishable from lung adenocarcinoma seen in adults, may display typical adenocarcinoma-associated mutations of EGFR and KRAS, and may precede the administration of cytotoxic chemotherapy. PMID- 20975378 TI - Characteristics of thoracic malignancies that occur after solid-organ transplantation. AB - BACKGROUND: Chronic immunosuppression after solid-organ transplantation is associated with increased risk of developing malignancies. The purpose of this study was to determine the clinical characteristics and the outcome of thoracic malignancies in patients who have undergone solid-organ transplantation. METHODS: Among a cohort of 2831 patients who received a transplant at our institution and were followed between 1984 and 2009, 24 patients (0.85%) developed thoracic malignancies. Risk factors for lung cancer, as well as demographic, cancer, and transplantation characteristics, were analyzed. Survival data were also collected. RESULTS: Twenty-four patients were included (21 men, median age 61.7 years). Twenty-two patients were smokers. The most frequent histologic types were squamous cell carcinoma (n = 11, 46%) and adenocarcinoma (n = 9, 37%). The median time period between transplantation and diagnosis of lung cancer was 6.6 years. Ten lung malignancies occurred after kidney transplantation (0.5%), eight after liver transplantation (1.3%), and six after heart transplantation (2.8%). Seven patients underwent surgery, three had radiotherapy, four had chemotherapy, and six had multimodal treatment. The median survival time was 1.5 years, ranging from 6 months for stage IV to 3.7 years for stage I. CONCLUSION: Solid-organ transplantation is associated with a high risk of lung cancer and may have an important synergetic part with other risk factors for lung cancer (tobacco). However, survival rates from lung cancer in our study population are similar to those of nontransplanted patients. In addition, surgery can result in favorable survival results. PMID- 20975379 TI - Malignant pleural mesothelioma: a population-based study of survival. AB - INTRODUCTION: This study characterizes the overall survival (OS) and variables affecting OS in patients with malignant pleural mesothelioma. METHODS: A total of 9701 patients with malignant pleural mesothelioma, diagnosed from 1973 to 2006, were retrospectively analyzed using the population-based surveillance, epidemiology, and end results database. RESULTS: The 6-month, 1-year, and 5-year OS were 55, 33, and 5%, respectively. Significantly adverse prognostic factors from univariate analyses included older age, male gender, higher tumor grade, nonepithelioid histology, higher stage, no cancer-directed surgery, and no radiotherapy. Race was not significant. Patients undergoing cancer-directed surgery and radiotherapy, when grouped by stage, histology, or grade, had the best median survival (versus radiotherapy or surgery alone or no surgery/radiotherapy). From Cox proportional hazards analyses, grade (range, 1-4) was associated with a hazard ratio (HR) of >1.5 (p < 0.0001), and not undergoing cancer-directed surgery was associated with a HR of >1.4 (p < 0.0001). Male gender and older age were also significantly adverse factors. Tumor histology (HR = 1.5) and nonlocalized stage (HR = 1.3) were significant in a Cox model omitting tumor grade. With grade and histology included in the Cox model, the HRs of histology and stage were of smaller magnitude and not significant. CONCLUSIONS: From a population-based registry analysis of patients with malignant pleural mesothelioma, tumor grade and cancer-directed surgery seem to have the greatest impact on OS. Although being amenable to surgery likely reflects more indolent disease and/or better performance status and cardiopulmonary function, the significantly favorable impact of surgery, accounting for tumor grade, histology, and stage, may reflect a therapeutic benefit. PMID- 20975380 TI - Cetuximab monotherapy in patients with advanced non-small cell lung cancer after prior epidermal growth factor receptor tyrosine kinase inhibitor therapy. AB - INTRODUCTION: Therapeutic agents directed against the epidermal growth factor receptor (EGFR) signaling pathway have been effective in the treatment of non small cell lung cancer (NSCLC). Cetuximab is a monoclonal antibody against the EGFR receptor with antitumor activity in NSCLC. This study evaluated the efficacy of cetuximab monotherapy after prior treatment with an oral EGFR tyrosine kinase inhibitor (TKI). METHODS: Eligible patients had stage IIIB, IV, or recurrent NSCLC with progression on the oral EGFR TKIs gefitinib or erlotinib. Cetuximab was administered intravenously at 400 mg/m on day 1 and then 250 mg/m weekly until disease progression or unacceptable toxicity. The primary end point was response rate. RESULTS: Eighteen patients were enrolled. Patients were heavily pretreated with chemotherapy and TKIs (average number of treatments = 4.2). The response rate was 0/18 (0%), and 28% of patients had confirmed stable disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.6-5.4 months), and median overall survival was 7.5 months (95% confidence interval, 2.2 19 months). Three patients harbored activating EGFR mutations, and one of them had stable disease for nearly 6 months on cetuximab. Common toxicities were mild and included fatigue, skin rash, and nausea/vomiting. Two patients developed interstitial lung disease, life threatening in one case. CONCLUSIONS: Cetuximab monotherapy administered after prior EGFR TKI treatment in patients with advanced NSCLC does not yield clinical responses. PMID- 20975381 TI - Analysis of ERBB4 mutations and expression in japanese patients with lung cancer. AB - Only the kinase domain of ERBB4 has been analyzed in East Asian populations, but a recent large-scale mutation analysis has indicated a higher incidence of mutations in the extracellular domain. Mutations in the extracellular and kinase domains of ERBB4 were examined by direct sequencing in 72 patients with primary lung cancer and 8 cell lines. In addition, ERBB4 expression was determined in 60 patients by quantitative real-time polymerase chain reaction. We investigated the relationship between ERBB4 expression and clinicopathologic characteristics including prognosis. One patient possessed Q793Q polymorphism in the kinase domain. However, we detected no mutations in extracellular or kinase domains of ERBB4. There was no significant difference in the clinicopathologic characteristics including prognosis of patients with high or low expression of ERBB4. The clinical significance of ERBB4 in lung cancers is negligible. PMID- 20975382 TI - Massive bronchogenic cyst. PMID- 20975383 TI - Anti-N-methyl-D-aspartate receptor encephalitis in a young woman with a mature mediastinal teratoma. PMID- 20975384 TI - Severe local toxicity after lung stereotactic body radiation therapy: lesional abscess leading to bronchocutaneous fistula requiring surgical marsupialization. PMID- 20975385 TI - ERCC1 and small cell lung cancer. PMID- 20975386 TI - ILD during erlotinib and gefitinib treatment in Japanese patients with non-small cell lung cancer. PMID- 20975388 TI - Pediatric resuscitation: should parents be present? PMID- 20975390 TI - Should breastfeeding mothers avoid allergenic foods? AB - Questions about maternal diet in lactation are common in clinical nursing practice, for nurses often work with breastfeeding women who are concerned about allergies, or who associate infant symptoms of crying or irritability to something they themselves have eaten. Can exposure to food proteins in a woman's diet actually cause food allergy in her breastfed child? Are special diets effective in managing infant allergic symptoms or gastrointestinal distress? The purpose of this article is to review the evidence related to diet for new breastfeeding mothers and make recommendations to guide clinical practice; seven such practice recommendations were developed after a thorough literature review. Nurses can use this literature summary to provide care based upon the best available research evidence. PMID- 20975391 TI - Migrant farmworker mothers talk about the meaning of food. AB - PURPOSE: To describe the meaning of food in the family life of migrant farmworker mothers; specifically to describe their understanding of the relationship of dietary intake to health, the environmental contributors to their families' dietary intake, and the use of foods in the commemoration of family occasions. METHODS: The PRECEDE-PROCEED self-management model guided the qualitative research study, which used short, guided interviews conducted at Midwest migrant camps. A sample of 43 Mexican mothers answered three interview questions, the answers to which were transcribed verbatim, read, sorted, and arranged into categories and then themes. Thematic analysis was used to analyze the data. RESULTS: The themes identified from the interviews were a) meal cost, b) lack of preparation time, c) distance to store locations, d) the importance of traditional ethnic foods, and e) limited knowledge of healthy food choices. CLINICAL IMPLICATIONS: Pediatric nurses should remember that before they dispense nutritional anticipatory guidance, situational and cultural assessments are needed. Because vulnerable populations such as migrant farmworkers have limited resources to follow nurses' teachings, nurses need to become knowledgeable about what is available in the community to support these families. In addition, facility appointment times may need to be expanded to accommodate their long work hours, and modes of transportation need to be evaluated. Recommendations for anticipatory guidance, prescriptions, treatments, and over-the-counter items need to consider cost and ease in purchase, and cultural acceptability. PMID- 20975392 TI - The lived experience of pregnancy complications in single older women. AB - PURPOSE: To explore the lived experience of single older women (35 years or older at time of birth) who experienced complications in their planned pregnancy. DESIGN AND METHODS: Phenomenology, using semistructured interviews with 11 women between the ages of 35 to 48 years. RESULTS: Six themes emerged: (a) motherhood now or never, (b) the known and unknown, (c) importance of support, (d) the stigma of single motherhood, (e) changing priorities, and (f) long-term concerns for themselves and child/children. CLINICAL IMPLICATIONS: Nurses who work with pregnant women should understand as much as possible about the issues affecting older single women who choose pregnancy; this offers the best opportunity to provide comprehensive care. These women can be at increased risk for many pregnancy complications, and should receive counseling about their risks for both fetal and maternal complications. Nurses should also conduct a thorough psychosocial assessment to determine what support systems are in place and what resources are available if complications arise. In the intrapartum and postpartum settings, nurses can offer not only appropriate physical caregiving but also a supportive and caring attitude with women in this circumstance. Helping women maintain a sense of control by helping them to participate in their care planning is essential. PMID- 20975393 TI - Perinatal grief in Latino parents. AB - Extensive research exists that describes the meaning of perinatal loss to some parents, but the experience of loss from the perspective of Latino parents is not clearly understood. Additionally, current perinatal bereavement practices used often to facilitate memory making for parents (such as viewing or holding the baby, taking photographs, or collecting mementos) are based on research done primarily with non-Latino families. Are these common practices appropriate for this population? Because there is a paucity of research on this topic, this article describes what has been written over the past 30 years on the topic of grief and perinatal loss in Latino culture. PMID- 20975395 TI - Vitamin D: taking advantage of a good thing. PMID- 20975396 TI - Benchmarking electronic medical record adoption. PMID- 20975397 TI - Disaster relief in Asia. PMID- 20975399 TI - Patient falls in the perinatal setting. PMID- 20975400 TI - Virtual learning environments: second life. AB - In this bimonthly series, the authors examine how nurse educators can use the Internet and Web-based computer technologies such as search, communication, collaborative writing tools; social networking and social bookmarking sites; virtual worlds; and Web-based teaching and learning programs. The editor of this column and her coauthor describes how the virtual world of Second Life can be used in nursing education. PMID- 20975401 TI - Clinical reasoning in the classroom: a triage simulation. PMID- 20975403 TI - Capitalizing on joint ventures to economize in nursing. AB - Many new nursing leaders assuming deanships, assistant, or interim deanships have limited education, experience, or background to prepare them for the job. To assist new deans and those aspiring to be deans, the authors of this department offer survival tips based on their personal experiences and insights. They address common issues, challenges, and opportunities that face academic executive teams, such as negotiating an executive contract, obtaining faculty lines, building effective work teams, managing difficult employees, and creating nimble organizational structure to respond to changing consumer, healthcare delivery, and community needs. The authors welcome counterpoint discussions with readers. PMID- 20975405 TI - Imaging utilization: an interdisciplinary workshop for nurse practitioner students. PMID- 20975407 TI - Publication opportunities in nonnursing journals. AB - The purpose of this article was to identify nonnursing journals that have relevance to nursing, that publish articles that cite the nursing literature and may offer excellent but seldom-considered publication opportunities for nurses. Using 22 indicators derived through citation analysis, 64 nonnursing journals that are highly related to nursing were identified. The authors provide information about these 64 journals related to their subject matter, number of issues annually, and their 2008 impact factor. PMID- 20975408 TI - Flexible online learning options for graduate nursing students. AB - Students juggle multiple roles and expect faculty to accommodate their hectic schedules. By increasing our flexibility and offering graduate nursing students the option, within a single course, of completing course activities either fully online or blended, we increased student enrollment into courses that prepare faculty. Our approach also identified a potentially cost-saving strategy for low enrollment course sections. Results underscore the importance of ongoing creativity to meet student expectations for responsiveness and inventiveness. PMID- 20975410 TI - Master's programs preparing nurse educators: what is the current state of affairs? AB - Master's programs to prepare nurse educators have dramatically increased and are being transformed with the advent of the doctorate in nursing practice. In the absence of standards, questions arise regarding program design and curriculum models. To assess this issue, the authors discuss their review of Web sites for 198 nurse educator programs and describe curricular patterns and trends. The findings are then related to the AACN Essentials of Master's Education for Advanced Practice Nursing and NLN Nurse Educator Certification Criteria. PMID- 20975412 TI - A complex elder care simulation using improvisational actors. AB - Complex simulations can facilitate students' synthesis of knowledge. Simulations of cognitively impaired elders provide nursing students the opportunity to use critical thinking and clinical decision-making skills in complex patient care situations. The authors report their experiences in designing, implementing, and evaluating a simulation on cognitive problems in elders using actors. This simulation required third-year baccalaureate nursing students to differentiate delirium from dementia, identify symptoms of heart failure, and address a family member's concerns. PMID- 20975414 TI - Predictors of NCLEX-RN success across 3 prelicensure program types. AB - Nursing faculty are concerned about the ability of recent graduates to successfully pass NCLEX-RN on their first-attempt. To facilitate student first time success on the examination, nurse educators need to understand what student characteristics are predictive of success. The purpose of this study was to explore student characteristics across 3 different programs types (university based BSN, master's entry, and satellite BSN) and in each of the 3 program types to identify predicators of first-time NCLEX-RN success. PMID- 20975415 TI - Broadcasting simulation case studies to the didactic classroom. AB - To explore the potential of using simulation in new ways, it is time to think "outside the lab." To do this, the authors expanded the use of case-study simulations by broadcasting them to classrooms where didactic content could be reinforced with simulation content. Advantages included students' active classroom engagement, simultaneously sharing simulations with many students, modeling students' thinking in clinical situations, and connecting theory to practice. PMID- 20975416 TI - Sliding away from PowerPoint: the interactive lecture. AB - Class participation can be difficult to obtain when lecturing to a large group of students. Interactive lecture methods can help bridge the gap between faculty and students as well as increase class participation and satisfaction among faculty and students. The authors discuss various methods that may be used to increase student interaction. PMID- 20975420 TI - Documenting anaphylaxis. PMID- 20975423 TI - Weigh the benefits of using a 0-to-5 nausea scale. PMID- 20975424 TI - Disease-modifying antirheumatic drugs. PMID- 20975427 TI - Walking away the blues: exercise for depression in older adults. PMID- 20975428 TI - Gallstones. PMID- 20975430 TI - The flood. PMID- 20975431 TI - Why Florence Nightingale still matters. PMID- 20975432 TI - Medical volunteerism: tips from a nurse returned from Haiti. PMID- 20975433 TI - Promote oral health in patients with diabetes. PMID- 20975434 TI - Geriatric trauma: top 10 lessons from older patients. PMID- 20975435 TI - Reduce--and report--enteral feeding tube misconnections. PMID- 20975436 TI - Steps to reducing hospital-acquired pressure ulcers. PMID- 20975437 TI - An update on new pain medications. PMID- 20975438 TI - An inside look at infectious mononucleosis. PMID- 20975439 TI - Is diet soda a healthy choice? PMID- 20975440 TI - Vertebral artery dissection. PMID- 20975441 TI - Will reform mean the end of free healthcare clinics? PMID- 20975442 TI - Dalfampridine (Ampyra) for multiple sclerosis. PMID- 20975443 TI - Urosepsis in the elderly. PMID- 20975444 TI - Screening for obesity in children and adolescents. PMID- 20975445 TI - How to prepare a successful grant proposal. PMID- 20975448 TI - Men's knowledge of the human papillomavirus vaccine. AB - The FDA recently approved the use of the HPV quadrivalent vaccine, Gardasil, for the prevention of genital warts in males ages 9 through 26. This literature review seeks to examine men's knowledge of and interest in HPV vaccination as this could potentially affect vaccine uptake. PMID- 20975449 TI - Evaluating and managing adult PTSD in primary care. AB - Posttraumatic stress disorder (PTSD) is an anxiety disorder with a sustained and dysfunctional emotional reaction to a traumatic event, threat of injury or death, and pain. PMID- 20975450 TI - Work restrictions: documenting a patient's return to work. AB - Patients frequently ask NPs to write work restrictions, even if it is not in their best interest. This article helps providers construct valid work restrictions and addresses specific tasks and issues to keep the patient and coworkers safe when returning to work. PMID- 20975453 TI - Pharmacokinetics, pharmacodynamics, and Monte Carlo simulation: selecting the best antimicrobial dose to treat an infection. PMID- 20975454 TI - Pediatric hepatitis C infection: are there missed opportunities for diagnosis and treatment? PMID- 20975455 TI - Lower long-term immunogenicity of mumps component after MMR vaccine. PMID- 20975456 TI - Linezolid therapy of brain abscess. PMID- 20975458 TI - Cancer recurrence after surgery: a role for regional anesthesia? PMID- 20975459 TI - Dirty rotten scoundrels! PMID- 20975460 TI - Evaluating clinical research and bloodletting. (Seriously). PMID- 20975462 TI - An outbreak of Klebsiella pneumoniae and Enterobacter aerogenes bacteremia after interventional pain management procedures, New York City, 2008. AB - BACKGROUND AND OBJECTIVES: In October 2008, an investigation was conducted into a cluster of gram-negative bloodstream infections after invasive pain management procedures at an outpatient facility to identify additional cases and determine the source of illness. METHODS: We conducted a retrospective cohort study to determine exposures associated with illness. Eligible patients had an invasive procedure in the 4 days before or after the procedure date of the initial case patients. Infection control assessments were made, and environmental specimens collected. RESULTS: Four laboratory-confirmed case-patients (3 with Klebsiella pneumoniae and 1 with Enterobacter aerogenes) and 5 suspect case-patients were identified. In addition to the 9 confirmed and suspect case-patients, 45 patients were interviewed. All confirmed and suspect case-patients had a sacroiliac joint steroid injection procedure; injection into the sacroiliac joint was associated with illness (9/22 versus 0/31; P < 0.0001). Multiple breaches in infection control were noted including the reuse of single-use vials for multiple patients. The 3 K. pneumoniae with positive blood cultures were indistinguishable by pulse field gel electrophoresis, and the E. aerogenes-positive blood culture was indistinguishable by pulse-field gel electrophoresis to the culture from an open vial of 100-mL iodixanol contrast solution. CONCLUSION: Infection was associated with pain management procedures, specifically those involving injection to the sacroiliac joint. Lapses in infection control likely led to the contamination of single-use vials that were then used for multiple patients. Reuse of medication vials should be restricted, and affordable single-dose vials should be made available. PMID- 20975461 TI - Anesthetic technique and the cytokine and matrix metalloproteinase response to primary breast cancer surgery. AB - BACKGROUND: Breast cancer is the most common malignancy in women. Surgery remains the most effective treatment. Several perioperative factors, including the surgical stress response, many anesthetics and opioids, adversely affect immune function. Regional anesthesia-analgesia attenuates perioperative immunosuppression. We tested the hypothesis that patients who receive combined propofol/paravertebral anesthesia-analgesia (propofol/paravertebral) exhibited reduced levels of protumorigenic cytokines and matrix metalloproteinases (MMPs) and elevated levels of antitumorigenic cytokines compared with patients receiving sevoflurane anesthesia with opioid analgesia (sevoflurane/opioid). METHODS: Primary breast cancer surgery patients were randomized to propofol/paravertebral (n = 15) or sevoflurane/opioid (n = 17) and preoperative and postoperative serum concentrations of 11 cytokines (interleukin 1beta [IL-1beta], IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon gamma, and tumor necrosis factor alpha) and 3 MMPs (MMP-1, MMP-3, and MMP-9) were measured. RESULTS: Treatment groups were well balanced for age, weight, surgical procedure, and cancer pathologic diagnosis. Pain scores were lower at 1 and 2 hrs with paravertebral analgesia compared with morphine but similar at 24 hrs. Patients in the propofol/paravertebral group showed a greater percentage decrease in postoperative compared with preoperative IL-1beta (median [quartiles], -26% [-15% to -52%] versus -4% [-14% to 2%], P = 0.003), a significant attenuation in elevated MMP-3 (2% [-39% to 12%] versus 29% [23%-59%], P = 0.011) and MMP-9 (26% [13%-54%] versus 74% [50%-108%], P = 0.02), and a significant increase in IL-10 (10% [5%-33%] versus -15% [20% to -2%], P = 0.001) compared with sevoflurane/opioid group. No significantly different changes in IL-2, IL-4, IL-5, IL-6, IL-8, IL-12p70, IL-13, interferon gamma, tumor necrosis factor alpha, or MMP-1 were observed between the 2 groups. CONCLUSIONS: Propofol/paravertebral anesthesia-analgesia for breast cancer surgery alters a minority of cytokines influential in regulating perioperative cancer immunity. Further evaluation is required to determine the significance of these observations. PMID- 20975463 TI - Management of chronic upper abdominal pain in cancer: transdiscal blockade of the splanchnic nerves. AB - BACKGROUND: The use of celiac plexus block to relieve the intractable pain caused by upper abdominal malignancies is well established. However, its effects are inconsistent for many reasons, mainly because of structural anatomic distortion as a consequence for the malignancy. The splanchnic nerve blockade (SNB) seems to be a useful alternative to the celiac plexus block in upper abdominal pain relief. MATERIALS AND METHODS: The pain of 109 patients with unresectable upper abdominal or lower esophageal neoplasms was managed by posterior transdiscal SNBs guided by computed tomography at the Instituto Nacional de Cancerologia in Mexico City from January 2004 to June 2007. The study evaluated SNB efficacy with regard to pain relief, its adverse effects/complications, and patient satisfaction. RESULTS: Splanchnic nerve blockade efficacy with regard to pain relief was exhibited by a marked decrease in the visual analog score and in opioid consumption, with preprocedural mean values dropping from 6.1 +/- 2.4 and 102.4 mg/d of morphine to 2.7 +/- 2.4 and 53.3 mg/d at the first postprocedural visit, respectively. These results persisted during the 1-year follow-up period or until death. Minor adverse effects (moderate diarrhea and mild hypotension) were frequent (n = 64 and n = 47, respectively), and severe complications occurred in 1 patient with a transient paraparesis (n = 1). No procedure-related mortality was observed. CONCLUSIONS: Splanchnic nerve blockade via a transdiscal approach is a technique that provides analgesia and the alleviation of the secondary undesirable effects of analgesic drugs resulting from the decrease of morphine consumption in patients with upper abdominal malignancies. In experienced teams, the reliability of its analgesic effect is high, with a low rate of severe complications. PMID- 20975464 TI - Evaluation of the depth and duration of anesthesia from heated lidocaine/tetracaine (Synera) patches compared with placebo patches applied to healthy adult volunteers. AB - BACKGROUND: The heated lidocaine/tetracaine patch (Synera; ZARS Pharma, Inc, Salt Lake City, UT) is among the local topical anesthetic formulations used to prevent procedural pain. This study was conducted to determine the depth and duration of anesthesia provided by the patch and to evaluate safety and tolerability. METHODS: This randomized, double-blind, placebo-controlled, 2-period crossover study was conducted in healthy subjects. Subjects were randomized to receive either the heated lidocaine/tetracaine patch (active patch) in period 1 and placebo patch in period 2 or vice versa. Patches were applied for 30 mins to the volar aspect of the forearm. Pain and sensory depths were measured at baseline and at 30, 60, 90, and 150 mins after patch application. Duration of anesthesia was measured at 40, 70, 110, and 130 mins after patch application by evaluating thermal and mechanical sensation. RESULTS: A total of 25 subjects were enrolled in the study. Twenty-four subjects completed the study. Pain and sensory depths with the active patch were greater than with placebo (P < 0.001) at all postdose time points. Maximum mean pain depth achieved with the active patch was 8.22 mm; anesthesia lasted at least 100 mins after patch removal. Cool and warm sensations and hot pain thresholds were increased compared with placebo (P < 0.001). Light touch and pinprick were detectable by most subjects. CONCLUSIONS: The heated lidocaine/tetracaine patch is well tolerated, and it provides favorable depth and duration of anesthesia without significant sensory loss for superficial venous access and minor dermatological procedures after a 30-min application. PMID- 20975465 TI - Effect of a preemptive femoral nerve block on cytokine release and hyperalgesia in experimentally inflamed skin of human volunteers. AB - BACKGROUND AND OBJECTIVES: Tissue injury is associated with the local release of inflammatory and nociceptive mediators and the development of hyperalgesia. It is unclear whether interrupting neuronal signaling using regional anesthetic techniques at the time of the injury modifies local nociceptive and inflammatory processes. The aim of this study was to determine whether a peripheral nerve block at the time of tissue injury could modify the development of wound hyperalgesia and the local release of inflammatory and nociceptive mediators. METHODS: Twelve healthy volunteers participated in this controlled, crossover, randomized study. A femoral nerve block or a sham block was established before inducing an experimental UVB burn on the thigh. Twenty-four hours later, the interstitial wound fluid was sampled, and mechanical and heat pain thresholds were assessed. Wound fluid concentrations of an array of cytokines, chemokines, nerve growth factor, prostaglandin E2, and substance P were determined. RESULTS: Skin inflammation was associated with the release of inflammatory and nociceptive mediators and resulted in significant tissue hyperalgesia (P < 0.001). However, the presence of a fully established peripheral nerve block at the time of tissue injury did not alter the development of hyperalgesia after regression of the block. Similarly, the presence of a peripheral nerve block did not modify the release of inflammatory or nociceptive mediators. CONCLUSIONS: These findings suggest that a preemptive, single-shot peripheral nerve block minimally affects wound hyperalgesia and inflammation. Continuous nerve block techniques may be better suited to alter nociceptive and inflammatory events in wounds beyond the duration of the block. PMID- 20975466 TI - The ultrasound-guided transversus abdominis plane block for anterior iliac crest bone graft postoperative pain relief: a prospective descriptive study. AB - BACKGROUND: Acute postoperative pain and nerve injuries frequently lead to neuropathic chronic pain after anterior iliac crest (AIC) bone graft. This prospective study evaluated postoperative pain relief after preoperative ultrasound-guided transversus abdominis plane (TAP) block for orthopedic surgery with an AIC bone harvest and the prevalence of pain chronicization at 18 months after surgery. METHODS: Thirty-three consecutive patients scheduled for major orthopedic surgery with an AIC harvest for autologous bone graft were studied. Preoperative TAP blocks were performed under in-plane needle ultrasound guidance, anterior to the midaxillary line (15 mL ropivacaine 0.33%). The extent of sensory blockade was evaluated at 20 mins with cold and light-touch tests. Pain at the iliac crest graft site was assessed at rest by visual analog scale (VAS) scores in the postanesthetic care unit, and at 1, 6, 12, 24, and 48 hrs after surgery. Time for first request of morphine and total morphine consumption were recorded. Eighteen months after surgery, each patient was interviewed by phone about the importance and localization of pain chronicization. RESULTS: Median VAS score was 0 (range, 0-7) at all periods of assessment. At 20 mins, 62.5% of the patients reported complete anesthesia, and 34% hypoesthesia. The sensory blockade extent ranged from T9 (T7-T11) to L1 (T11-L2) in median (range) values. At 18 months, 80% of patients did not complain about pain or discomfort at the iliac crest site; 20% reported pain chronicization at the iliac crest site (VAS scores 2-4). Five patients (26%) complained about numbness at the iliac crest area. CONCLUSIONS: Ultrasound-guided TAP block is an appropriate technique for postoperative analgesia after AIC bone harvest in orthopedic surgery. PMID- 20975467 TI - Comparison of 2% mepivacaine, clipping, and radiofrequency thermocoagulation for duration and magnitude of action in peripheral arterial blood flow induced by sympathetic block in anesthetized dogs. AB - BACKGROUND AND OBJECTIVES: Thoracic sympathetic block has recently been performed by placement of the clips on the sympathetic chain to interrupt nerve conduction. The aim of this study was to compare clipping with 2% mepivacaine and radiofrequency thermocoagulation for the potency of sympathetic block from the results of the duration and magnitude of the vasodilation effect induced by thoracic sympathetic block in dogs. METHODS: We measured mean arterial pressure, heart rate, and right and left brachial artery blood flow (BABF) before and after thoracic sympathetic block in 24 dogs. The experimental protocol was designed as follows: (1) left thoracic sympathetic block by 1.0 mL of 2% mepivacaine (n = 8), (2) left thoracic sympathetic block by clipping (n = 8), and (3) left thoracic sympathetic block by radiofrequency thermocoagulation (n = 8). RESULTS: Mean arterial pressure and heart rate did not change significantly throughout the study in either group. Left thoracic sympathetic block by 2% mepivacaine increased left BABF significantly from 5 to 70 mins after the block (baseline, 100%; peak at 10 mins after the block, 179% +/- 33%; P < 0.01). Left thoracic sympathetic block by clipping increased left BABF significantly from 5 to 120 mins after the block (baseline, 100%; peak at 30 mins after the block, 156% +/- 31%; P < 0.01). Left thoracic sympathetic block by radiofrequency thermocoagulation increased left BABF significantly from 5 to 120 mins after the block (baseline, 100%; peak at 10 mins after the block, 206% +/- 31%; P < 0.01). CONCLUSIONS: Clipping may have a same potency compared with 2% mepivacaine and a less potency compared with radiofrequency thermocoagulation in thoracic sympathetic block in dogs. PMID- 20975468 TI - Minimum effective volume of local anesthetic for shoulder analgesia by ultrasound guided block at root C7 with assessment of pulmonary function. AB - BACKGROUND AND OBJECTIVES: This study was performed to determine the minimum effective volume of ropivacaine 0.75% required to produce effective shoulder analgesia for an ultrasound (US)-guided block at the C7 root level with assessment of pulmonary function. METHODS: Using the Dixon and Massey up-and-down method study design, 20 patients scheduled for elective open shoulder surgery under combined general anesthesia and continuous interscalene brachial plexus block were included. Initial volume of ropivacaine 0.75% was 6 mL; block success or failure determined a 1-mL decrease or increase for the subsequent patient, respectively. General anesthesia was standardized. A continuous infusion of ropivacaine 0.2% was started at a rate of 6 mL/hr at 2 hrs after completion of surgery. Ventilatory function was assessed using spirometry, and movement of the hemidiaphragm was assessed by US. RESULTS: The minimum effective volume of local anesthetic in 50% and 95% of the patients was 2.9 mL (95% confidence interval, 2.4-3.5 mL) and 3.6 mL (95% confidence interval, 3.3-6.2 mL), respectively. Ventilatory function and hemidiaphragmatic movement was not reduced up to and including 2 hrs after completion of surgery, but 22 hrs after start of the continuous infusion of ropivacaine 0.2%, ventilatory function and hemidiaphragmatic movement were significantly reduced (P < 0.001). CONCLUSIONS: The minimum effective volume of local anesthetic for shoulder analgesia for a US guided block at the C7 root level in 50% and 95% of the patients was 2.9 and 3.6 mL, respectively. Pulmonary function was unchanged until 2 hrs after completion surgery, but reduced 22 hrs after start of a continuous infusion of ropivacaine 0.2%. PMID- 20975469 TI - Can a single dose of 300 mg of pregabalin reach acute antihyperalgesic levels in the central nervous system? AB - BACKGROUND AND OBJECTIVES: Central spinal cord sensitization can occur during surgery and may lead to persistent pain after surgery. Pregabalin has been shown to decrease central sensitization in experimental pain paradigms, and so the same antihyperalgesic effect of pregabalin may occur during and immediately after surgery. Our study investigated whether a single 300-mg dose of pregabalin in patients has sufficient central nervous system bioavailability to be useful under acute conditions where brain or spinal cord excitability may lead to long-term disease, such as chronic pain. METHODS: Nine patients undergoing primary total knee replacement received pregabalin 300 mg orally, 1 hr before surgery. An intrathecal catheter was inserted for anesthesia, postoperative analgesic drug administration, and cerebrospinal fluid (CSF) sampling. Blood and CSF were then simultaneously sampled at 2, 4, 6, 8, and 24 hrs after oral pregabalin administration. Pregabalin concentration in plasma and CSF was measured using a validated high-pressure liquid chromatography assay. RESULTS: By 2 hrs after pregabalin administration, the CSF pregabalin concentration is high enough (0.115 MUg/mL) to have anticonvulsant activity, and by 6 hrs after pregabalin administration, the CSF pregabalin level is high enough (0.359 MUg/mL) to reduce central nervous system hypersensitivity. The median time to peak pregabalin concentration in CSF was at 8 hrs. The pregabalin CSF/plasma based on area under the curve (AUC[0-24 hrs]) was 0.098 +/- 0.016, and for AUC[0-infinity], the ratio was 0.176 +/- 0.064. CONCLUSIONS: Sufficient central nervous system drug concentrations are reached after oral administration of pregabalin, suggesting that postoperative pain hypersensitivity can be reduced. Decreasing this acute brain or spinal cord excitability may prevent chronic pain from developing after surgery. PMID- 20975470 TI - A randomized comparison between ultrasound-guided and landmark-based superficial cervical plexus block. AB - BACKGROUND: This prospective, randomized, observer-blinded study compared ultrasound guidance and the conventional landmark-based technique for superficial cervical plexus blockade. METHODS: Forty patients were randomly allocated to receive a block of the superficial cervical plexus using ultrasound guidance (n = 20) or the traditional landmark-based technique (n = 20). The main outcome, success, was defined as the absence of cold sensation for all 4 branches of the superficial cervical plexus at 15 mins. A blinded observer recorded success rate, onset time, block-related pain scores, and the incidence of complications. Performance time and the number of needle passes were also recorded during the performance of the block. Total anesthesia-related time was defined as the sum of performance and onset times. RESULTS: Success rate (80%-85%) was similar between the 2 groups. Performance time was slightly longer with ultrasonography (119 versus 61 sec, P < 0.001); however, no differences in onset and total anesthesia related times were found. There were also no differences in the number of passes and procedural discomfort. CONCLUSIONS: Ultrasound guidance does not increase the success rate of superficial cervical plexus block compared with a landmark-based technique. Additional confirmatory trials are required. PMID- 20975472 TI - Benefits, risks, and best practice in regional anesthesia: do we have the evidence we need? AB - For more than 25 years, regional anesthesia has challenged anesthesiologists to determine whether it offers real benefits in terms of patient outcome from major surgery, compared with general anesthesia. Although there is good evidence that regional analgesia offers superior pain relief to systemic opioid analgesia, evidence to support improved outcome from surgery remains elusive. Although many publications appear to support the hypothesis, others show no benefit, and the lack of properly conducted, large studies makes it difficult to draw any evidence based conclusions in favor of regional anesthesia. Given that all major regional techniques have the potential to cause significant risks to patient outcome, it is incumbent on all anesthesiologists to balance the intended benefits against the significant adverse events associated with regional techniques. We are beginning to develop an evidence base for both the benefits and risks of regional anesthesia, when used for specific patient groups and for specific surgical procedures. This presentation looks at some of the evidence and examines how it can be used to develop guidelines for best practice. PMID- 20975473 TI - Methodological quality of randomized controlled trials of postoperative epidural analgesia: validation of the Epidural Analgesia Trial Checklist as a specific instrument to evaluate methodology. AB - BACKGROUND: The overall benefits of epidural analgesia are controversial, in part because of the varying quality of methodology in published randomized controlled trials (RCTs). We performed a systematic review of available RCTs to examine the methodological quality of epidural analgesia trials. Current instruments for evaluating the quality of methodology are generic; thus, we also developed a specific assessment tool named Epidural Analgesia Trial Checklist (EATC). METHODS: The National Library of Medicine's PubMed database was searched (1966 to January 2006) for RCTs of epidural analgesia. All RCTs that had epidural infusion analgesia in at least 1 study arm and as primary intervention for randomization were included. Two independent reviewers were given blinded full-text paper versions of each article and reviewed all articles for inclusion in this study. Study characteristics were extracted from accepted RCTs, and reviewers completed the standardized 7-item Jadad score, 22-item Consolidated Standards of Reporting Trials (CONSORT) checklist, and 8-item EATC for evaluation of methodological quality. RESULTS: A total of 321 articles met all inclusion criteria. The overall median (first, third quartiles) Jadad, CONSORT, and EATC scores were 2 (1, 3), 10 (8, 11), and 4 (3, 6) (of maximum scores of 5, 22, and 8), respectively. For all assessments, we found significantly higher methodological study quality for articles with a larger study population size, those written by a first author affiliated with an anesthesiology department, and studies published after release of the CONSORT statement with a significant overall increase in methodological quality over time. There was no effect on methodological quality with regard to region of publication or number of centers. There was relatively high interrater agreement when using the EATC (kappa = 0.92). The items most frequently lacking from the studies captured using the EATC were appropriate description/definition of adverse effects (11.8% of all studies properly reported this), proper presentation of visual analog scale (VAS) pain scores (31.2%), and assessment of VAS pain both at rest and with activity (39.9%). CONCLUSIONS: Methodology scores for epidural analgesia RCTs have improved over time. The EATC seems to correlate well with other commonly used generic assessments for methodological RCT quality and be useful for assessing methodological quality of epidural RCTs. Future epidural analgesia RCTs should focus on improving appropriate description/definition of adverse effects, proper presentation of VAS pain scores, and assessment of VAS pain both at rest and with activity. PMID- 20975474 TI - Ultrasound-guided transversus abdominis plane catheters and ambulatory perineural infusions for outpatient inguinal hernia repair. AB - BACKGROUND AND OBJECTIVES: Transversus abdominis plane (TAP) blocks anesthetize the lower abdominal wall, and TAP catheters have been used to provide prolonged postoperative analgesia after laparotomy. The use of TAP catheters on an outpatient basis has not yet been described. We present our experience with ultrasound-guided TAP perineural catheter insertion and subsequent management of ambulatory TAP local anesthetic infusions after inguinal hernia repair. METHODS: Three patients scheduled for unilateral open inguinal hernia repair underwent preoperative posterior TAP catheter placement for postoperative pain management using a technique employing ultrasound guidance alone. A bolus of local anesthetic solution was injected via the catheter in divided doses, and block onset was confirmed before surgery. Postoperatively, a continuous infusion of ropivacaine 0.2% was delivered using a portable infusion pump, and patients were discharged with a prescription for oral analgesics for breakthrough pain and perineural infusion instructions. Patients were followed up daily by telephone. RESULTS: All patients underwent successful TAP catheter insertion and maintained their catheters until postoperative day 2. All patients reported minimal pain for the duration of infusion without the need for any supplemental opioid analgesics, high satisfaction with postoperative analgesia, and no infusion-related complications. CONCLUSIONS: An ultrasound-guided TAP catheter and ambulatory local anesthetic perineural infusion are a promising option for prolonged postoperative analgesia after outpatient inguinal hernia repair. A posterior insertion permits preoperative placement by keeping the catheter away from the planned surgical field. PMID- 20975475 TI - Ultrasound-guided evaluation of the local anesthetic spread parameters required for a rapid surgical popliteal sciatic nerve block. AB - BACKGROUND: The ideal spread of local anesthetic (LA) solution around the sciatic nerve during a popliteal block remains unclear. We tested the hypothesis that a circumferential spread of LA and/or intraneural injection could lead to rapid surgical block. METHODS: Patients (n = 100) scheduled for foot or ankle surgery underwent popliteal sciatic nerve block using nerve stimulation according to Borgeat's technique and injection of ropivacaine (0.5 mL/kg). Sensory and motor blockades were assessed on the tibial nerve (TN) and common peroneal nerve (CPN) at 5, 15, and 30 mins after completion of the block and in the recovery room. A successful block was defined as a complete sensory block in TN and CPN. Changes in cross-sectional and longitudinal surfaces and diameters and the characteristics of LA spread around the nerve were noted using ultrasound. A suspected intraneural injection was defined as a 15% increase in the surface area or anteroposterior diameter of the nerve. Patients were followed up on days 1 and 7 after surgery. RESULTS: Successful block was noted in 57% of patients at 30 mins and in 88% of patients in the recovery room. A circumferential spread of LA occurred in 47% of patients and 53% had noncircumferential spread. Complete sensory block was significantly higher in the group that had a circumferential spread (73% vs 43%, P = 0.035) only at 30 mins. In the postoperative care unit, there was no difference among the groups. Separated circumferential spreads around TN and CPN were noted in 12% of patients. All of these patients had a complete sensory and motor blockade at 15 mins. Concerning intraneural injection, only the change in the anteroposterior diameter on a 6-cm length of nerve was associated with a higher success and faster onset block at 5 (P = 0.008), 15 (P = 0.02), and 30 (P = 0.05) mins. There were no clinically detectable nerve injuries at follow-up. CONCLUSION: For popliteal sciatic nerve block, circumferential spread of LA, and separation of the nerve into its 2 components are associated with rapid surgical block. PMID- 20975476 TI - Ultrasound-guided popliteal block shortens onset time compared to prebifurcation sciatic block. PMID- 20975477 TI - Some additional insight into ultrasound imaging for successful ultrasound-guided placement of catheters. PMID- 20975478 TI - Axillary vessels and musculocutaneous nerve anatomic variation during ultrasound guided regional anesthesia. PMID- 20975480 TI - Ultrasound-assisted lumbar plexus block in a patient with scoliosis. PMID- 20975481 TI - Computer-assisted self interviewing in sexual health clinics. AB - BACKGROUND: This review describes the published information on what constitutes the elements of a core sexual history and the use of computer-assisted self interviewing (CASI) within sexually transmitted disease clinics. METHODS: We searched OVID Medline from 1990 to February 2010 using the terms "computer assisted interviewing" and "sex," and to identify published articles on a core sexual history, we used the term "core sexual history." RESULTS: Since 1990, 3 published articles used a combination of expert consensus, formal clinician surveys, and the Delphi technique to decide on what questions form a core sexual health history. Sexual health histories from 4 countries mostly ask about the sex of the partners, the number of partners (although the time period varies), the types of sex (oral, anal, and vaginal) and condom use, pregnancy intent, and contraceptive methods. Five published studies in the United States, Australia, and the United Kingdom compared CASI with in person interviews in sexually transmitted disease clinics. In general, CASI identified higher risk behavior more commonly than clinician interviews, although there were substantial differences between studies. CASI was found to be highly acceptable and individuals felt it allowed more honest reporting. Currently, there are insufficient data to determine whether CASI results in differences in sexually transmitted infection testing, diagnosis, or treatment or if CASI improves the quality of sexual health care or its efficiency. CONCLUSIONS: The potential public health advantages of the widespread use of CASI are discussed. PMID- 20975482 TI - Utilizing information and communication technology tools in STD clinics: has the time come to go digital? PMID- 20975483 TI - Factors associated with numbers of client partners of female sex workers across five districts in South India. AB - BACKGROUND: This study investigated the structural-environmental and individual level social factors associated with the numbers of commercial sex clients of female sex workers (FSWs) per month (CPM). METHODS: Data were analyzed from cross sectional surveys of FSWs in 5 districts in Karnataka state, India (2004-2005). Bivariate and multivariable negative binomial regression models with generalized estimating equations were constructed for each district. Normalized weights were used to account for complex sampling design. RESULTS: Median (average) CPM varied significantly (P < 0.001) across districts, from 40.0 (56.9) CPM in the district with the highest immunodeficiency virus prevalence (33.9%) to 16.0 (26.1) in the district with the lowest prevalence (9.7%). In multivariable analysis, there was a significant positive association between rates of CPM and sex work as sole income in 4 districts (adjusted incidence rate ratios, AIRR: [95% confidence intervals]: AIRR: 1.3 [1.0-1.7], P < 0.005-1.7 [1.2-2.5], P < 0.01); age, typology (place of solicitation), and marital status were significantly associated with CPM in 3 districts, with an inverse association between age and CPM (P < 0.01). FSWs soliciting clients in brothels had higher rates of CPM than home-based FSWs in 2 districts (AIRR: 1.5 [1.1-2.0]-1.6 [1.0-2.7], P < 0.05), whereas public places-based FSWs had higher rates in 1 district (AIRR: 1.4 [1.1 1.8], P < 0.01); cohabiting FSWs had higher rates than married FSWs in 3 districts, whereas single FSWs had higher rates in one district. CONCLUSIONS: These results provide support for the continued development of structural core group interventions that address common elements of sex work placing FSWs at higher risk for immunodeficiency virus, as well as geographically focused programs that account for local differences in sexual structure. PMID- 20975484 TI - "The Fly": a new clinical assessment and treatment method for deficits of movement control in the cervical spine: reliability and validity. AB - STUDY DESIGN: Test-retest and case-control study designed to detect accuracy of cervical spine movements by comparing 3 incrementally difficult movement patterns. An asymptomatic group, a nontrauma neck pain group, and a group with whiplash-associated disorders, Grade II, were tested (n = 18 in each group). OBJECTIVE: To determine the test-retest reliability and the discriminative validity of the new Fly method. SUMMARY OF BACKGROUND DATA: A lack of reliable and valid measures for grading the deficits of movement control in the cervical spine makes it impossible to prescribe treatment appropriate to each patient's respective impairment level. METHODS: Head tracking of a moving fly which appeared on a computer screen. Easy, medium, and difficult patterns, each of which was repeated 3 times in random order, were tested. Amplitude accuracy (deviation of movements), directional accuracy (time on target, undershoots vs. overshoots) were compared across patterns and groups on 2 occasions, 1 week apart. RESULTS: The intraclass correlation coefficient(2,1) ranged from 0.53 to 0.82 for both variables, except for the subvariable "overshoots" (0.14-0.42). The limits of agreement (LOA) were progressively wider across patterns (easy-medium difficult) and groups (asymptomatic-nontrauma-whiplash-associated disorder). Analysis of variance with repeated measures revealed significant differences between patterns within each group and between groups respectively for both outcome variables (P < 0.001). CONCLUSION: The Fly method provides reliable and valid measures for movement control of the cervical spine. Higher means and wider LOA across patterns and subject groups are reasoned to be inherent in the new Fly method and the subject groups tested. The wide LOA in the symptomatic groups supports the development of a normative database. The new Fly method can be used both as an assessment and a treatment method and ensures gradual progression in the treatment for deficits of movement control in patients with neck pain. PMID- 20975485 TI - In vivo deformation, surface damage, and biostability of retrieved Dynesys systems. AB - STUDY DESIGN: Retrospective retrieval analysis. OBJECTIVE: To evaluate wear, deformation and biodegradation within retrieved polycarbonate urethane (PCU) components of Dynesys systems. SUMMARY OF BACKGROUND DATA: The Dynesys Dynamic Stabilization System (Zimmer Spine) consists of pedicle screws (Ti alloy), polycarbonate urethane (PCU) spacers, and a polyethylene-terephthalate cord. METHODS: Seventeen retrieved (mean implantation: 2.5 years, range: 0.7-7.0 years) and 2 exemplar implant systems were available. Reasons for revision were persistent pain (16/17), infection (1/17), and/or screw loosening (11/17), with 1/17 case of implant migration. Optical microscopy, microCT, and scanning electron microscopy were conducted to evaluate PCU spacer wear and deformation. Attenuated total reflectance Fourier transform infrared spectroscopy was used to assess spacer surface chemical composition. RESULTS: Retrieved spacer components exhibited permanent bending deformation (mean: 4.3 degrees , range: 0.0 degrees 15.8 degrees ). We observed evidence of PCU spacer contact with pedicle screws, cords, and surrounding bony structures (74/75, 69/75, and 51/75 spacers, respectively). Relatively infrequent damage modes included PCU fracture (1/75 spacers) or cracking (2/75 spacers), as well as pedicle screw fracture (3/103 screws). PCU degradation products were identified in 10/75 spacers, which represented retrievals having significantly longer implantation times (mean: 4.3 years, range: 1.0-7.0 years). Of these spacers, 8/10 had degradation peaks identified along the side of the spacer where the material would have been in contact with bodily fluid. CONCLUSION: PCU spacers from retrieved Dynesys systems exhibited permanent deformation, focal regions of in vivo wear and surface damage. Chemical changes associated with PCU biodegradation were associated with longer-term retrievals. The most frequently observed complication was pedicle screw loosening, with 3 incidences of screw breakage in 2 patients. These retrieval data provide a crucial basis for developing in vitro tests to simulate in vivo damage and degradation of posterior dynamic motion preservation implants. Longer-term retrievals, as well as retrievals that include more recent design features (e.g., HA coating), will be useful to provide a greater context for the clinical implications of our short-term observations. PMID- 20975486 TI - Scoliosis after extended hemipelvectomy. AB - STUDY DESIGN: Retrospective review plus 2 representative case reports. OBJECTIVE: To evaluate the prevalence of scoliosis after extended hemipelvectomy (EH) and illustrate the problem's severity. SUMMARY OF BACKGROUND DATA: No published series has analyzed this problem. Data are needed to decide the potential need for and timing of spine fusion in these patients. METHODS: We treated 14 patients with EH over 10 years. Mean age was 47 years. Diagnoses included osteosarcoma (6); chondrosarcoma (4); metastatic cancer (2); and MFH and undifferentiated sarcoma (1 each). Operating time ranged from 7 to 15 hours, and mean estimated blood loss was 8 L. Patients were observed for scoliosis, functional results, and for oncological outcome (survival, disease progression). Two patients who became scoliotic after EH illustrate the problem: a 31-year-old man underwent EH for pelvic osteosarcoma and progressively developed a painful 44 degrees scoliotic curve; and a 27-year-old woman who developed a 60 degrees painful scoliotic curve and radiculopathy years after EH including L5-S1 disc disruption. RESULTS: Of 12 patients, 8 died within 7 months of EH. Only 2 of 12 patients are long-term survivors free of disease (3 and 6 years after surgery), and 2 are alive with disease more than 1 year after surgery. In patients >1 year survival, 3 of 4 patients had curves greater than 20 degrees . Of 10 evaluable patients, 2 developed a curve greater than 30 degrees that warranted fusion. Four others had curves between 20 degrees and 30 degrees . Of these 6, 5 developed a sharp angled lumbar curve with the concavity away from the operated side. Risk factors for symptomatic scoliosis after EH include disc disruption, paraspinal muscle/ligament resection, or facetectomies in ambulatory patients with a lengthy survival. CONCLUSION: Primary spinal fixation should be avoided because of the high morbidity and early mortality of EH. Selected high-risk patients can be stabilized later if they develop painful instability. PMID- 20975488 TI - Impact of visual and somatosensory deprivation on dynamic balance in adolescent idiopathic scoliosis. AB - STUDY DESIGN: A cross-sectional study of balance control in adolescents with idiopathic scoliosis (AIS). OBJECTIVE: To investigate the impact of visual and somatosensory deprivation on the dynamic balance in AIS patients and to discuss electromyographic (EMG) and posture sway findings. SUMMARY OF BACKGROUND DATA: Most studies focus on posture sway in quiet standing controls with little effort on examining muscle-activated patterns in dynamic standing controls. METHODS: Twenty-two AIS patients and 22 age-matched normal subjects were studied. To understand how visual and somatosensory information could modulate standing balance, balance tests with the Biodex stability system were performed on a moving platform under 3 conditions: visual feedback provided (VF), eyes closed (EC), and standing on a sponge pad with visual feedback provided (SV). Muscular activities of bilateral lumbar multifidi, gluteus medii, and gastrocnemii muscles were recorded with a telemetry EMG system. RESULTS: AIS patients had normal balance index and amplitude and duration of EMG similar to those of normal subjects in the balance test. However, the onset latency of right gastrocnemius was earlier in AIS patients than in normal subjects. In addition, body-side asymmetry was noted on muscle strength and onset latency in AIS subjects. Under EC condition, lumbar multifidi, and gluteus medii activities were higher than those under SV and VF conditions (P < 0.05). Under SV condition, the medial lateral tilting angle was less than that under VF and EC conditions. In addition, the active duration of right gluteus medius was shorter under SV condition (P < 0.05). CONCLUSION: The dynamic balance control is particularly disruptive under visual deprivation with increasing lumbar multifidi and gluteus medii activities for compensation. Sponge pad can cause decrease in frontal plane tilting and gluteus medii effort. The asymmetric muscle strength and onset timing are attributed to anatomic deformation as opposed to neurologic etiological factors. PMID- 20975489 TI - Single incision laparoscopic-assisted right hemicolectomy: technique and application (with video). AB - PURPOSE: Most commonly employed for surgery of the gallbladder and appendix, single-incision laparoscopic surgery (SILS) is rapidly evolving in the field of minimally invasive surgery. The purpose of this report is to describe the feasibility and technique for SILS right hemicolectomy, which has not been widely reported. METHODS: We describe a laparoscopic right hemicolectomy with a modified single-incision technique for the management of a precancerous polyp of the ascending colon. RESULTS: The procedure was successfully performed in 105 minutes using 3 transumbilical trocars placed through a single port, and readily available nonarticulating laparoscopic instruments. In addition, we review the literature of SILS procedures involving the colon and discuss differences between our approach and those reported elsewhere. CONCLUSIONS: SILS is a feasible modality applicable to minimally invasive surgery of the colon and can offer benefits to the patient. PMID- 20975490 TI - Comparison of in vivo clinical performance and shaft temperature and in vitro tissue temperature and transection times between new and reprocessed harmonic scalpels. AB - The ultrasonic harmonic scalpel (HS) uses ultrasound energy to achieve surgical dissection. To test the feasibility of limited HS reuse and to insure that reprocessed HS function in a substantially equivalent manner to their new counterparts, this study compared in vivo mesenteric vessel and liver cutting characteristics, scalpel shaft temperatures during in vivo usage and in vitro tissue temperature dissipation characteristics between new and reprocessed ACETM36 series HS. The study found that new and reprocessed ACETM-36 HS exhibit identical performance with respect to in vivo dissection characteristics and postcut shaft temperatures. The in vitro studies show tissue temperature elevations and durations adjacent to dissection sites to be substantially equivalent for reprocessed versus new devices. Finally, cut times and extended use performance for new and reprocessed devices exhibit no statistical differences. We conclude that reprocessed HS scalpels that pass acceptance tests exhibit functional and safety capabilities that are equivalent to their new counterparts. PMID- 20975491 TI - Is laparoscopic resection the appropriate management of a jejunal gastrointestinal stromal tumor (GIST)? Report of a case. AB - A 51-year-old female patient presented with iron deficiency anemia. Upper and lower gastrointestinal endoscopy were unremarkable. Computed tomography enteroclysis showed an ovoid 3*4-cm jejunal tumor with intraluminal protrusion and exophytic growth pattern, without lymphadenopathy or metastatic disease. Laparoscopic resection of the tumor was successfully carried out. Histologically, a mesenchymal tumor composed of spindle cells with an interlacing bundle pattern and high-mitotic activity greater than 10 mitoses/50 high-power fields were observed. The immunohistochemistry showed that the tumor was KIT (CD117)-, vimentin-, smooth muscle actin-, and S-100-positive, whereas it was CD34 negative. These findings were consistent with the features of a gastrointestinal stromal tumor. The patient had an uneventful postoperative course, and after 10 months of follow-up, she is well without any evidence of tumor recurrence. PMID- 20975492 TI - Single-port laparoscopic partial splenectomy: a case report. AB - With the better understanding of the importance of the spleen as a primary organ of the human immune system, there has been an increased interest in performing the partial splenectomy for a number of indications such as nonparasitic cysts, benign tumors, staging of lymphomas, etc. Moreover, laparoscopic partial splenectomy has been gaining more interest as the recommended approach for benign splenic disorders to preserve the splenic function with very low recurrence rates. Meanwhile, many surgeons have attempted to reduce the number and size of the ports in laparoscopic surgery with the aim of inducing less parietal trauma and fewer scars. One of these efforts is single-port laparoscopic surgery, which is a rapidly evolving field all over the world. Here, we describe a feasible method of single-port laparoscopic partial splenectomy for treating a benign splenic cyst that was located in the upper medial aspect of the spleen. PMID- 20975493 TI - Single incision diagnostic laparoscopy in a patient with sclerosing peritonitis. AB - INTRODUCTION: Sclerosing peritonitis (SP) is a rare disease that can cause abdominal pain and intestinal obstruction. SP can be primary (also called abdominal cocoon) or secondary (when it is mainly due to systemic diseases or the intraperitoneal instillation of medications). METHODS: We report the video of a single incision diagnostic laparoscopy in a patient with SP with the educational intent of allowing easier recognition of this rare disease. RESULTS: The patient is a 72-year-old female with a history of bladder cancer, salivary gland cancer, and squamous cell cancer of the skin. She was diagnosed with a suspicion of SP during a diagnostic laparoscopy made to rule out ovarian cancer at an outside institution. Due to worsening of her symptoms, she was presented to our hospital for a second opinion. Due to inadequate tissue from her first exploration, she was brought to the operating room for a diagnostic laparoscopy. DISCUSSION: Although SP can mimic the gross appearance of peritoneal carcinomatosis, multiple biopsies should be obtained to allow for the diagnosis of SP. This video shows how this rare disease entity can present and how an abdomen with even thick fibrosis can be managed with a minimally invasive approach. PMID- 20975494 TI - Laparoscopic diagnosis and management of an abdominal cocoon: a case report and literature review. AB - Abdominal cocoon is a rare cause of small bowel obstruction. It is characterized by the encasement of a variable length of the small intestine by a fibrous membrane. It occurs primarily in females with only few reported cases in males. We report the case of a 42-year-old male with a history suggestive of recurrent attacks of small bowel obstruction over a 6-month period, which used to resolve spontaneously or by conservative measures. At presentation, a mildly tender mobile mass was felt in the right lower part of the abdomen. Computed tomography scan of the abdomen showed clusters of small bowel loops encased within a well delineated sac. The diagnosis was confirmed by diagnostic laparoscopy. Laparoscopic lyses and release of the entrapped bowel was performed. The postoperative period was uneventful. Follow-up over 18 months showed no clinical evidence of recurrence. PMID- 20975495 TI - Laparoendoscopic single-site surgery for fertility-sparing staging of border line ovarian tumors: initial experience. AB - OBJECTIVE: To report feasibility of laparoscopic fertility-sparing staging of border line ovarian tumors (BOTs) by using a laparoendoscopic single-site trocar through a unique transumbilical access. STUDY DESIGN: This study was conducted in our University Hospital. Four young patients, intended to be submitted to benign adnexal cysts enucleation by an innovative laparoendoscopic single-site approach using a multiport trocar inserted through a unique transumbilical access and straight laparoscopic devices, were found to be affected by border line ovarian tumor at intraoperative frozen analysis. Consequently patients were conservatively staged carrying out all the requested procedures in respect of oncologic guidelines and their child bearing desire, using same single-port access approach. Main outcome measures were conversion rate to multiaccess standard laparoscopic technique or to laparotomic approach and evaluation of intraoperative and postoperative-related complications. RESULTS: All the laparoscopic staging procedures were feasible through a single transumbilical access: no conversion to multiaccess standard laparoscopic technique nor laparotomy and no intraoperative or postoperative complications were observed. Mean operative time was 79 minutes. All patients were discharged home on day 1 with complete satisfaction toward cosmetic outcome. Final pathologic analysis confirmed stage FIGO 1A for all cases. The patients are free from recurrence at 10 months follow-up. CONCLUSIONS: Laparoendoscopic single-site staging of border line ovarian tumors with preservation of fertility is feasible and effective with standard laparoscopic instruments. More clinical data are needed to confirm these advantages compared with standard multiaccess laparoscopic technique. PMID- 20975496 TI - Double primary tumor, thymic mass and posterior mediastinal neurogenic tumor, in a patient with acute pancreatitis performed with single-staged robotic-assisted thoracoscopic surgery. AB - Finding 2 primary benign lesions at 2 extremes of the mediastinum is a rare event. A minimal invasive operation performed in a single-staged procedure can prove to be difficult, especially when the procedure is performed with a robot. We discuss the positioning and details of the procedure carried out in a 52-year old woman with acute pancreatitis. PMID- 20975497 TI - Thoracoscopic management including lobectomy for a primary peripheral pulmonary adenoid cystic carcinoma in a cirrhotic patient. AB - Primary peripheral adenoid cystic carcinoma is a relatively rare type of lung carcinoma. A 49-year-old male with significant hepatic cirrhosis presented with an incidental right upper lobe nodule suspicious for malignancy and an additional imaging suggesting contralateral mediastinal lymph node involvement. Thoracoscopic management included a left-sided lymph node dissection and a right sided lobectomy in this medically high-risk patient. PMID- 20975498 TI - Laparoscopic splenopexy for wandering spleen: case report and review of the literature. AB - Wandering spleen is a rare condition in which the spleen lacks retroperitoneal fixation, thus its vascular pedicle can twist resulting in ischemia. Although splenectomy has traditionally been used for this condition, splenopexy is increasingly used in the pediatric population to anchor the spleen and preserve splenic function. We report an unusual case of wandering spleen in an adult with chronic torsion managed with laparoscopic splenopexy, suggesting splenic preservation is possible in adults with this presentation as well. PMID- 20975499 TI - The role of CT-guided percutaneous gastrostomy in patients with clinically severe obesity presenting with complications after bariatric surgery. AB - PURPOSE: To retrospectively evaluate the efficacy and safety of computed tomography (CT)-guided percutaneous gastrostomy in patients presenting with complications after bariatric surgery. MATERIALS AND METHODS: From January 2003 up to today, 25 patients (20 women), formerly operated for severe obesity, were referred for gastrostomy, after presenting with a complication. The mean age and body mass index were 38+/-9.3 years and 46+/-7.1 kg/m, respectively. A gastrostomy tube was placed under CT in all patients. RESULTS: The procedure's technical success rate was 96%, with mean interventional time of 80+/-42 minutes. In 14 of 25 (56%) cases submucosal spread of air was noticed during air insufflation into the stomach. No major complications were recorded. There was a statistically significant improvement of both albumin and prealbumin values compared with the initial ones (P<0.005). CONCLUSIONS: CT-guided gastrostomy in patients with complications after bariatric surgery, provides a reliable alternative for nutritional support. It restores the normal absorption route, reversing metabolic deficiencies. PMID- 20975500 TI - Our early experiences with single-incision laparoscopic surgery: the first 32 patients. AB - BACKGROUND: Most of the laparoscopic surgeons have been attempting to reduce incisional morbidity and improve cosmetic outcomes by using fewer and smaller ports. Single-incision laparoscopic surgery (SILS) is a new laparoscopic procedure. Herein we would like to present our experiences. PATIENTS AND METHODS: Between January 2009 and October 2009, data of the 32 patients who were operated through SILS are evaluated prospectively. There were 22 females and 10 males with a mean age of 45.1+/-14.8 years. Ten splenectomies for idiopathic thrombocytopenic purpura, 16 cholecystectomies for acute cholecystitis or asymptomatic gallstones, 3 appendectomies for acute appendicitis, one distal pancreatosplenectomy for Renal Cell Cancer metastases, 1 adrenalectomy for Conn Syndrome and 1 case of liver resection for hepatic adenoma were carried out. The most common splenectomy indication was idiopathic thrombocytopenic purpura, cholecystectomy indication was acute cholecystitis (n=8), and asymptomatic cholelithiasis (n=8), appendectomy indication was acute appendicitis, distal pancreatosplenectomy indication was renal cell cancer metastases, adrenalectomy indication was Conn syndrome and liver resection indication was left hepatic mass in between segments 1 and 2. SILS was carried out successfully in 31 patients. Only in 1 patient conversion was required owing to bleeding. RESULTS: All procedures were carried out through a 2-cm umbilical incision. There was no mortality and morbidity recorded. CONCLUSIONS: In experienced hands of minimally invasive surgeons, SILS incision laparoscopic surgery could be carried out successfully in a wide range of surgical operations. However, to be able to show the differences between Standard laparoscopic surgery and single SILS, prospective randomized comparative studies are required. PMID- 20975501 TI - Endoscopic completion thyroidectomy by the bilateral axillo-breast approach. AB - PURPOSE: Bilateral axillo-breast approach (BABA) endoscopic thyroidectomy has been successfully used for various thyroid diseases, with an excellent cosmetic outcome. Patients with a confirmed thyroid malignancy on a permanent thyroid section after endoscopic thyroid lobectomy require completion thyroidectomy. Here, we sought to demonstrate the feasibility of endoscopic completion thyroidectomy by BABA. PATIENTS AND METHODS: Between June, 2006 and February, 2009, 13 patients underwent endoscopic completion thyroidectomy by BABA for minimally invasive follicular thyroid and papillary thyroid carcinomas diagnosed after BABA endoscopic thyroid lobectomy. The median interval between thyroid lobectomy and completion thyroidectomy was 5.6 months (range, 4.2-28.2 mo). We used the same port sites (bilateral breast and axillary region) as were created at the initial operation. Flap adhesion was minimal. After identifying the remnant thyroid lobe, completion thyroidectomy was performed under full visualization of the thyroidal vessels, parathyroid glands, and recurrent laryngeal nerve. RESULTS: We performed 5 right and 8 left endoscopic completion thyroidectomies by BABA. The mean operation time was 109.3+/-23.3 minutes. There were no cases of open conversion. The resulting 6 (46.2%) cases of transient hypocalcemia resolved within 2 postoperative weeks and there were no cases of vocal cord palsy or wound infection. One patient had immediate postoperative breast flap bleeding that required cauterization. No patient had evidence of recurrence, as indicated by follow-up neck ultrasonography and serum thyroglobulin levels. The cosmetic outcomes were excellent and all patients were satisfied. CONCLUSIONS: BABA endoscopic thyroidectomy appears feasible and safe procedure for completion thyroidectomy, making it a viable technique for reapplication in cases of thyroid carcinoma diagnosed after endoscopic thyroid lobectomy. PMID- 20975502 TI - Surgeon-controlled factors that reduce monopolar electrosurgery capacitive coupling during laparoscopy. AB - PURPOSE: To determine the factors that can be modified by the surgeon to reduce monopolar electrosurgery capacitive coupling during laparoscopy. Specific aims were to determine the capacitive coupling energy using different generator power settings, mode settings (cut vs. coagulation), and surgical techniques (desiccation vs. fulguration vs. open air activation). METHODS: An oscilloscope determined the cumulative energy (Joules) of capacitive coupling occurring using laparoscopic monopolar electrosurgery ex vivo. RESULTS: Higher power settings increased capacitive coupling energy (Joules): 25 Watts (1.1+/-0.7) versus 50 Watts (2.4+/-0.5; P<0.05). Coagulation mode created greater capacitive coupling energy (2.2+/-1.0) in comparison with cut mode (1.1+/-0.5; P<0.05). Open air activation (3.3+/-0.6) and fulguration (3.3+/-1.0) had higher capacitive coupling energy in comparison with desiccation (0.6+/-0.2; P<0.05). CONCLUSIONS: Surgeons can minimize capacitive coupling energy during laparoscopy by lowering the power setting, using cut mode (instead of coagulation), and using the surgical technique of desiccation (instead of open air activation or fulguration). PMID- 20975503 TI - Revisional surgery after Heller myotomy for esophageal achalasia. AB - Revisional surgery for persistent or recurrent dysphagia following Heller myotomy is rare and should become even more rare if an extended myotomy has been carried out. It is important to work-up patients who experience persistent or recurrent dysphagia in a systematic fashion that includes the determination of the diagnosis of achalasia, the type of operation performed, the results obtained with the primary operation, and to further classify the type of recurrence. Use of adjunctive studies, including upper gastrointestinal study, endoscopy, manometry, and pH monitoring is critical to guiding clinical decision making. This article will review the differential diagnosis, diagnostic workup, and available treatment options for patients with achalasia who present with persistent or recurrent dysphagia following Heller myotomy. PMID- 20975504 TI - Revisional surgery for failed antireflux surgery. AB - The outcome and morbidity of revisional surgery after antireflux surgery has been suggested to be suboptimal compared with primary repair. Therefore, an individualized therapeutic approach based on exact analysis of the reasons for failure of the initial procedure is essential for successful management of these patients. This study attempts to summarize the management of this challenging patient population with a focus on the clinical presentation, causes of failure, evaluation, and variety and choice of revisional techniques. PMID- 20975505 TI - Revisional surgery after gastrectomy for gastric cancer: review of the literature. AB - Recent reports have shown that morbidity and mortality after gastrectomy for gastric cancer vary between authors, countries, and procedures. Common complications related to gastrectomy are postoperative bleeding, anastomotic leakage, pancreatic juice leakage, intra-abdominal abscess, intestinal obstruction, wound dehiscence, and so on. Recently, laparoscopic gastrectomy for gastric cancer has developed, especially in Japan and East Asian countries because it is less invasive. Several retrospective studies have shown that the operative complication rate is similar to that of conventional open surgery. Although most postoperative complications can be successfully treated by conservative therapies, surgical management is occasionally needed to prevent a fatal outcome. This review article provides insight into how surgeons can make efforts to reduce postoperative complications through proper preoperative evaluation and improved surgical skills during the initial gastrectomy. In addition, it reviews guidance for timely revisional surgery to allow salvage of patients with serious acute operative complications based on clinical findings made by a group of experienced surgeons. PMID- 20975506 TI - Revisional surgery after restrictive procedures for morbid obesity. AB - Bariatric surgery has become more common due to the worldwide obesity epidemic. A shift from open to laparoscopic surgery has occurred in the last 2 decades, because of its advantages. Revisional surgery after bariatric procedures is becoming an important issue, and restrictive procedures account for a large proportion of these interventions. Three restrictive procedures are currently in use: laparoscopic adjustable gastric banding, laparoscopic sleeve gastrectomy and vertical banded gastroplasty. The first two procedures are more commonly used, and the third is losing favor with surgeons. All three have proven effective, but less than malabsortive or combined procedures. The reasons to reoperate upon a patient and convert a previous bariatric procedure to a different one are failure of the operation, due to insufficient weight loss, or weight regain (secondary obesity); or complications like penetration, infection, bleeding, obstruction, dysphagia, and gastroesophageal reflux, among others. This review will describe the complications or failures leading to the a second operation; the conditions present after the first procedure and the presence of failure or complications; the technical steps required to be taken; and the outcomes and what can be expected afterwards. PMID- 20975507 TI - Laparoscopic revisional surgery after malabsorptive procedures in bariatric surgery, more specifically after duodenal switch. AB - Laparoscopic revisional surgery for both biliopancreatic diversion and duodenal switch is not a frequent event, and literature is sparse. Nevertheless, like any other weight loss surgical procedures, weight gain is possible or aggressive weight loss combined with micronutrients malnutrition may oblige surgeons to revise these original procedures. Reintervention strategies may include surgical improvements, conversion to other surgical procedures, or reversal. Revisions after duodenal switch are usually around 5% and may involve performing a re sleeve or an elongation of the common channel at the expense of the biliopancreatic limb. PMID- 20975508 TI - Laparoscopic management of intestinal obstruction. AB - Laparoscopic adhesiolysis is a valuable tool for the surgeon performing complex minimally invasive procedures. It can be used for the management of intestinal obstruction and chronic abdominal pain syndromes. It is also an essential skill when performing laparoscopic surgery on patients who had prior abdominal operations. The use of laparoscopy for patients with an intestinal obstruction was once considered an absolute contraindication. With the advancement in optics and increasing experience, more and more surgeons are turning to laparoscopy as a useful diagnostic and therapeutic tool in more complex situations. PMID- 20975509 TI - Revisional surgery after sleeve gastrectomy. AB - INTRODUCTION: Worldwide, morbid obesity incidence has increased dramatically in the last decade and surgery is at this moment recognized as the only effective treatment with long-term sustained weight loss and resolution or significant improvement in comorbidities. Laparoscopic sleeve gastrectomy (LSG) was successfully carried out by several groups as a bridge to future laparoscopic bariatric procedures with acceptable weight loss and reduction in comorbidities. LSG is considered a safe procedure with sporadically reported complications, such as bleeding or leakage from the staple line, strictures, delayed gastric emptying, gastric dilatation and vomiting. The aim of this publication is to describe complications of this procedure analyze different treatments of these events especially the surgical ones, reporting the technical management based on our experience and on the literature. MATERIAL AND METHODS: From March 2003 to December 2009, 294 patients underwent LSG in our Department. Complications are reported prospectively. RESULTS: In our series 294 patients were operated and stapler line leak was observed in 11 patients (3.7%). The mean time from the first surgery up to the first reintervention was 15.6+/-22 days (2 to 78). Only 2 patients (0.68%) had to be operated owing to severe reflux related with the sleeve gastrectomy and the symptomatology was solved with the gastric bypass. Intraabdominal bleeding was observed in 7 patients (2.38%), being reoperated 3 (1.02%) of them. All patients were reoperated by laparoscopic approach and the bleeding vessel was identified in all of them. We identified 3 of 294 patients with strictures (1.02%). One of them was located in the gastroesophageal junction and the other 2 had a central location. The patient with high stenosis required endoscopic dilatation and the other 2 were resolved by a gastric bypass cutting the stomach proximal to the stricture. The global mortality was 0%. All of the patients were reoperated by laparoscopy. CONCLUSION: LSG is a feasible bariatric procedure carried out increasingly in the last few years with low postoperative complications. Regardless, the knowledge of the potential complications associated to LSG and their management is crucial for patient's safety. PMID- 20975510 TI - Temporary obturator nerve paresis after spray of local anesthetic during laparoscopic extraperitoneal inguinal hernia repair. PMID- 20975511 TI - Training in laparoscopic surgery using home-made simulators. PMID- 20975512 TI - Anti-HIV-1 activity of the neurokinin-1 receptor antagonist aprepitant and synergistic interactions with other antiretrovirals. AB - OBJECTIVES: Neurokinin-1 receptor (NK1R) antagonists interfere with binding of neuropeptide substance P to NK1R and exhibit novel anti-HIV-1 activities. Since NK1R antagonists effectively penetrate the blood-brain barrier to reduce the inflammatory response within the brain, we wished to evaluate their potential as anti-HIV-1 candidates for targeting HIV-1 infections of the central nervous system. DESIGN: A series of small molecule agents were evaluated for anti-NK1R and anti-HIV-1 activity using peripheral blood mononuclear cells (PBMCs). The most promising of these, aprepitant (Emend, Merck and Co. Inc.), was investigated for potential synergies with other antiretroviral drugs. METHODS: Anti-NK1R activity was tested by measuring intracellular calcium increase triggered by substance P. Anti-HIV-1 activity was evaluated by measuring p24 antigen in culture supernatants of PBMC following exposure to HIV. The concentration of drug which produced 50% reduction in intracellular calcium levels or viral production in 7-day PBMC cultures was determined. The combined effect of aprepitant with each of the major classes of anti-HIV-1 drugs was evaluated in synergy studies. RESULTS: Aprepitant had the highest anti-HIV-1 activity of the NK1R antagonists examined and was equally active against all major HIV-1 subtypes. Aprepitant acted synergistically with protease inhibitors (ritonavir and saquinavir), but not with nucleoside reverse transcriptase, non-nucleoside reverse transcriptase, or viral entry inhibitors. CONCLUSION: The ability of aprepitant to penetrate the blood-brain barrier, its safety record as an FDA-approved drug for reducing nausea and vomiting in chemotherapy, and synergistic activity with other anti-HIV 1 drugs make it a promising candidate for treatment of HIV infection. PMID- 20975513 TI - Surgical correction of HIV-associated facial lipoatrophy. PMID- 20975514 TI - Beyond detuning: 10 years of progress and new challenges in the development and application of assays for HIV incidence estimation. PMID- 20975516 TI - Novel progranulin mutation detected in 2 patients with FTLD. AB - Frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions, and linkage to chromosome 17 was recently found to be caused by mutations in the progranulin (PGRN) gene. In this study, we screened a group of 51 FTLD patients for PGRN mutations and identified a novel exon 6 splice donor site deletion (IVS6+5_8delGTGA) in 2 unrelated patients. This mutation displayed an altered splicing pattern generating 2 aberrant transcripts and causing frameshifts of the coding sequence, premature termination codons, and a near absence of PGRN mRNA from the mutated alleles most likely through nonsense mediated decay. The subsequent PGRN haploinsufficiency is consistent with previously described PGRN mutations. We present a molecular characterization of the IVS6+5_8delGTGA mutation and also describe clinical and neuropathologic features from the 2 patients carrying this PGRN mutation. From the screening of these 51 FTLD patients, we could also identify the earlier reported mutation Gln130fs, and several coding sequence variants that are most likely nonpathogenic. PMID- 20975515 TI - Utilization of antihypertensives, antidepressants, antipsychotics, and hormones in Alzheimer disease. AB - This study explores the longitudinal relationship between patient characteristics and use of 4 drug classes (antihypertensives, antidepressants, antipsychotics, and hormones) that showed significant changes in use rates over time in patients with Alzheimer disease. Patient/caregiver-reported prescription medication usage was categorized by drug class for 201 patients from the Predictors Study. Patient characteristics included use of cholinesterase inhibitors and/or memantine, function, cognition, living situation, baseline age, and sex. Assessment interval, year of study entry, and site were controlled for. Before adjusting for covariates, useage increased for antihypertensives (47.8% to 62.2%), antipsychotics (3.5% to 27.0%), and antidepressants (32.3% to 40.5%); use of hormones decreased (19.4% to 5.4%). After controlling for patient characteristics, effects of time on the use of antidepressants were no longer significant. Antihypertensive use was associated with poorer functioning, concurrent use of memantine, and older age. Antipsychotic use was associated with poorer functioning and poorer cognition. Antidepressant use was associated with younger age, poorer functioning, and concurrent use of cholinesterase inhibitors and memantine. Hormone use was associated with being female and younger age. Findings suggest accurate modeling of the Alzheimer disease treatment paradigm for certain subgroups of patients should include antihypertensives and antipsychotics in addition to cholinesterase inhibitors and memantine. PMID- 20975517 TI - Attentional distractibility induced by optokinetic stimulation in mild cognitive impairment. AB - A recent study has shown that optokinetic stimulation (OKS) can induce attentional distractibility in Alzheimer disease (AD). In this study, we investigated whether OKS also perturbs balanced attentional deficit in patients with amnestic mild cognitive impairment (aMCI), a prodromal phase of AD, and explored whether the effects of OKS at baseline differ between aMCI patients who convert to AD at follow-up (converters) and those who do not (nonconverters). A total of 44 patients with aMCI, 14 patients with subcortical vascular mild cognitive impairment (svMCI), and 35 age-matched and education-matched normal controls were studied for their ability to bisect solid lines superimposed on a background of OKS. Background OKS movements were either leftward or rightward, or were stationary. A total of 33 of the 44 patients with aMCI were clinically followed for an average of 2.8 years, of which there were 15 converters and 18 nonconverters. Under both the leftward and rightward movement conditions, the magnitudes of line bisection errors (LBEs) in aMCI patients were greater than in normal controls. However, there were no differences in LBEs between svMCI patients and normal controls or between aMCI and svMCI patients. Baseline LBEs of aMCI converters were significantly greater than those of nonconverters in both leftward and rightward movement conditions. These results may indicate that OKS is useful for detecting AD at a very early stage and for predicting the conversion of aMCI to AD. PMID- 20975518 TI - Relationship between thyroid hormone levels and regional cerebral blood flow in Alzheimer disease. AB - Subclinical thyroid disease and even variations in thyroid function within the normal range is associated with cognitive function and a risk of Alzheimer disease (AD). Several studies reported the effect of thyroid hormones on cerebral blood flow. The aim of this study was to objectively evaluate regional cerebral blood flow (rCBF) in association with thyroid hormone levels within the normal range in patients with AD. Serum thyroid-stimulating hormone (TSH), free T3, and free T4 levels were measured in 62 patients with AD (23 men and 39 women; age 56 to 91 y; mean age 77.3 y) and 27 control subjects (9 men and 18 women; age 61 to 93 y; mean age 75.8 y). The 99mTc ethylcysteinate dimer single photon emission computed tomography was performed in all subjects. The rCBF in the region of interest was measured by the noninvasive Patlak plot method and calculated using FineSRT, which is a fully automated region of interest technique. No significant correlation was found between thyroid hormone levels and Mini-Mental State Examination scores or global CBF values. Serum levels of TSH, but not free T3 or free T4, were significantly inversely correlated with rCBF in the middle and inferior temporal regions of right cerebral hemisphere in patients with AD. Control subjects showed no significant correlation between thyroid hormone levels and rCBF. Although these findings of a regional relationship must be considers preliminary, this study proposed the hypothesis that altered TSH levels within the normal range may be related to brain perfusion in right temporal region. PMID- 20975519 TI - Effects of body weight on tolerability of rivastigmine transdermal patch: a post hoc analysis of a double-blind trial in patients with Alzheimer disease. AB - The rationale for the development of the rivastigmine transdermal patch was to improve upon an efficacious therapy by mitigating certain adverse events, such as nausea and vomiting. This may be particularly important in Alzheimer disease patients with low body weights, who may be more susceptible to these adverse events. This analysis compared the effect of body weight on tolerability in Alzheimer disease patients receiving rivastigmine capsules or rivastigmine patch. Using data from a 24-week trial, adverse events and discontinuations were evaluated in patients stratified on the basis of extreme low weight (<50 kg), medium weight (50 to 80 kg), and high weight (>80 kg) at baseline. Rivastigmine patch was generally well tolerated, regardless of patient body weight. Among patients receiving rivastigmine patch, lower body weight, as stratified, was not associated with a higher adverse event rate; however, there was an association between a higher adverse event rate and low body weight among patients receiving rivastigmine capsules. Discontinuations because of adverse events were not directly related to weight. A lower incidence of adverse events was apparent with transdermal delivery of rivastigmine compared with oral administration. PMID- 20975520 TI - Direct medical costs in patients with fibromyalgia: Cost of illness and impact of a brief multidisciplinary treatment program. AB - OBJECTIVE: To compare the direct medical costs of clinically diagnosed patients with fibromyalgia with the medical costs of matched controls during a 4-yr period and to assess the impact of a fibromyalgia treatment program on healthcare utilization and associated medical costs. DESIGN: A retrospective comparison of economic outcomes in 87 patients who participated in a fibromyalgia treatment program between 2001 and 2004 and who were local residents for the entire 4-yr period spanning their participation in the program, with age and sex-matched controls. Costs for the 2 yrs before and 2 yrs after program participation were also compared. RESULTS: Four-year medical costs for controls were $7774 compared with $15,759 for those with fibromyalgia. There was no significant change in direct costs after participation in a brief fibromyalgia treatment program. Those with increased symptom severity averaged $2034 higher direct medical costs during the 4-yr period. CONCLUSIONS: Patients with clinically diagnosed fibromyalgia incur direct medical costs about twice that of their matched controls. This increased cost is related to the severity of their symptoms as measured by the Fibromyalgia Impact Questionnaire and was not impacted by participation in a brief cognitive behaviorally based fibromyalgia treatment program. PMID- 20975521 TI - Effect of training on interlimb transfer of dexterity skills in healthy adults. AB - OBJECTIVE: To examine transference of dexterity skills to the contralateral hand after ipsilateral hand training, retention of skills at 1 mo, and the influence of hand dominance, sex, and age on interlimb transfer of these skills. DESIGN: This is an interventional study involving 200 healthy adults in the age group of 20-30 yrs and >30 yrs, who were block randomized into experimental and control groups. Experimental group was further subdivided into dominant and nondominant hand training group and participants underwent 5 days unsupervised training on tasks aimed at improving precision and dexterity. Jebsen-Taylor hand function test was administered at baseline, postintervention, and 1-mo follow-up. Analysis was done by nonparametric tests of comparison. RESULTS: One hundred sixty-nine subjects completed the study. Transfer effect was noted from the dominant to the nondominant hand (P <= 0.001) and vice versa (P = 0.003) on the total test scores. This effect was retained at 1-mo follow-up. CONCLUSIONS: Dexterity skills are not consistently transferred to the contralateral hand after ipsilateral hand training. However, transference of gross motor skills of hand function does occur with retention effects up to 1 mo. Transfer of skills differs based on the hand trained and age of the individual. PMID- 20975522 TI - Shuttle walk tests as outcome measures: Are two incremental shuttle walk tests and two endurance shuttle walk tests necessary? AB - This study was undertaken in people with chronic obstructive pulmonary disease to determine differences in incremental shuttle walk test distance and endurance shuttle walk test time when two of each shuttle test were performed before (n = 53 participants) and after an exercise training program (n = 31 participants) and whether the results altered program outcomes. There was a significant increase in incremental shuttle walk test distance between the two incremental shuttle walk tests before (P < 0.001) and after training (P < 0.01). There was no significant difference in the endurance shuttle walk test time between the two endurance shuttle walk tests before (P = 0.95) or after training (P = 0.07). There was a significant increase in both incremental shuttle walk test distance and endurance shuttle walk test time after training (all P < 0.01); however, the increase was greater if the better of the two tests was reported at both time points. The incremental shuttle walk test should be performed twice before and after an exercise training program. This does not seem to be necessary for the endurance shuttle walk test; however, improvement after training was greater if the better of two endurance shuttle walk tests were used to evaluate program outcomes. PMID- 20975523 TI - Evaluating the effect of intensive intervention in children with cerebral palsy using a hypothetical matched control group: a preliminary study. AB - OBJECTIVE: To evaluate the effect of intensive intervention in children with cerebral palsy using a hypothetical matched control group based on motor growth curves. DESIGN: For pretest-posttest design using a hypothetical control group, a convenient sample of 39 children with cerebral palsy who received intensive intervention without surgical treatment was assigned to the experimental group. The hypothetical matched control group was created based on motor growth curves. Gains in Gross Motor Function Measure-66 score after intensive treatment in the experimental group were compared with scores in the hypothetical matched control group using a mixed design for repeated-measures two-way analysis of variance. RESULTS: Gross motor function development in the experimental group was significantly accelerated compared with the hypothetical matched control group. CONCLUSIONS: In this preliminary study, using a hypothetical control group, the effectiveness of intensive intervention in children with cerebral palsy has been demonstrated. Although it is desirable to have a baseline phase to make sure whether gross motor function in the hypothetical control group changes in a similar way to that in the experimental group before an intervention phase, the hypothetical control group design is well worth considering as a research design option in the field of cerebral palsy research. PMID- 20975524 TI - Long-term effect of an anterior ankle-foot orthosis on functional walking ability of chronic stroke patients. AB - OBJECTIVES: The objectives of this study are to investigate the long-term effect of anterior ankle-foot orthosis on the functional walking ability of chronic stroke patients and their subjective perception and to identify the type of chronic stroke patients who are better responders to the wearing of anterior ankle-foot orthosis. DESIGN: This is a cross-sectional cohort comparison study. Fifty-two stroke patients wearing an anterior ankle-foot orthosis for at least 5 mos were evaluated using the modified Emory Functional Ambulation Profile and the 6-min walking test with and without an anterior ankle-foot orthosis. Falls Efficacy Scale-International and a self-designed questionnaire were administered to assess subjective perceptions. RESULTS: All modified Emory Functional Ambulation Profile subscores significantly decreased with the anterior ankle-foot orthosis; the mean difference in favor of the anterior ankle-foot orthosis on the floor was -2.88 secs; the carpet, -5.44 secs; "up and go," -5.09 secs; obstacle, 8.42 secs; stairs, -6.45 secs; and in the 6-min walking test, 19.75 m (all P < 0.01). Patients who were of younger age or with low walking ability or both would have more benefits. The total scores of Falls Efficacy Scale-International were significantly lower with anterior ankle-foot orthosis as compared with that without anterior ankle-foot orthosis (31.57 +/- 12.79 vs. 39.51 +/- 12.65). Around 90% participants perceived that their walking performance improved with the anterior ankle-foot orthosis either indoors or outdoors, and they would recommend the anterior ankle-foot orthosis to other stroke patients. The greatest disadvantage of anterior ankle-foot orthosis is the difficulty in donning and doffing. CONCLUSIONS: The effects of the anterior ankle-foot orthosis on stroke patients' functional walking ability and fall efficacy were significant. Patients who were of younger age or with low walking ability or both were more suitable for using the anterior ankle-foot orthosis. PMID- 20975525 TI - Effect of low-frequency repetitive transcranial magnetic stimulation combined with physical therapy on L-dopa-induced painful off-period dystonia in Parkinson's disease. AB - Previous research has shown that low-frequency repetitive transcranial magnetic stimulation over the primary motor area and supplementary motor area can reduce L dopa-induced dyskinesias in Parkinson's disease; however, it involved only patients with peak-dose or diphasic dyskinesia. We report a case of a patient with severely painful off-period dystonia in the unilateral lower limb who underwent 0.9-Hz subthreshold repetitive transcranial magnetic stimulation over contralateral primary motor area and supplementary motor area. Repetitive transcranial magnetic stimulation over the primary motor area significantly reduced the painful dystonia and walking disturbances but repetitive transcranial magnetic stimulation over the supplementary motor area did not. The cortical silent period also prolonged after repetitive transcranial magnetic stimulation over the primary motor area. At 5 mos of approximately once a week repetitive transcranial magnetic stimulation over the primary motor area, the Unified Parkinson's Disease Rating Scale motor score also improved. This report shows that repetitive transcranial magnetic stimulation over the inhibitory primary motor area can be useful for rehabilitating patients with Parkinson's disease with off-period dystonia and suggests that this treatment should be further verified in such patients. PMID- 20975526 TI - Effect of pulsed electromagnetic fields on human tenocyte cultures from supraspinatus and quadriceps tendons. AB - OBJECTIVE: : To investigate the effects of pulsed electromagnetic fields (PEMFs) on human tenocyte cultures and to assess whether PEMFs could represent a viable therapeutic option in tendon pathologies. DESIGN: : Controlled laboratory study in which primary human tenocytes were isolated from healthy supraspinatus and quadriceps tendons and were exposed to the electromagnetic field stimulation. Cell growth and cell cycle were evaluated after 72 hrs, 5 days, and 7 days of continuous PEMF exposure. In quiescent confluent tenocyte culture, an in vitro cut was mechanically produced, and the width of the cell-free zone was measured 12, 24, and 36 hrs after the injury in the presence of PEMF stimulation. Total collagen accumulation was also evaluated after 5, 7, and 14 days of PEMF exposure. RESULTS: : Tenocyte growth analysis, cell cycle analysis, and total collagen accumulation did not show statistically significant differences between exposed and control groups. Exposure to PEMF significantly accelerated cut closure 12 and 24 hrs after the injury. CONCLUSIONS: : PEMFs comparable with the ones used for the management of pseudoarthrosis stimulate closure of an in vitro laceration of a tenocyte monolayer. Our results provide the preliminary in vitro work and the basis to support the study of the in vivo effects of PEMFs on tendinopathies. PMID- 20975527 TI - Anatomic and functional improvements achieved by rehabilitation in Zone II and Zone V flexor tendon injuries. AB - OBJECTIVE: The aim of this study was to compare anatomic and functional improvements in zone II and zone V flexor tendon injuries and to determine the effect of injury level on disability. DESIGN: Seventeen patients (53 digits) with zone V and 14 patients (25 digits) with repaired zone II flexor tendon injuries were enrolled in this study. All patients were treated with Modified Kleinert protocol and followed up for a median of 60 mos. The anatomic improvement was assessed by total active motion scoring system of the American Society for Surgery of the Hand. Quick Disability of the Arm, Shoulder, and Hand (Quick DASH) questionnaire and the grip strength value were used for the evaluation of functional improvement. RESULTS: Two groups were similar with respect to age (P = 0.147), sex (P = 0.889), type of repair (P = 0.453), and follow-up period (P = 0.499). According to total active motion scoring system, good to excellent results (75%-100% of the normal total active motion value) were achieved in 52% of the digits with zone II and 83% of digits with zone V flexor tendon injuries (P = 0.004). The recovery in the grip strength, in comparison with the uninjured hand, has been found to be 71% and 53% in zone II and zone V injuries, respectively (P = 0.112). There was no difference between Quick DASH index scores of two groups (P = 0.721). The grip strength percentage (r = -0.435; P = 0.014) and total active motion recovery results (r = -0.541; P = 0.002) of the patients were moderately correlated with Quick DASH scores. CONCLUSIONS: Early passive mobilization in patients with zone V injuries resulted in higher percentage of good to excellent results when compared with zone II injuries. However, this does not translate into recovery in grip strength and disability. This study suggests that although the level of the injury is an important factor for the anatomic improvement, it may not be the predictor of functional improvement. PMID- 20975528 TI - Systemic exposure to atorvastatin between Asian and Caucasian subjects: a combined analysis of 22 studies. AB - The aim of the present study was to determine whether there is a differing pattern of systemic exposure to atorvastatin in Asian versus Caucasian subjects by comparison of data obtained from completed pharmacokinetic studies. Pharmacokinetic data were analyzed from completed single-dose (10-80 mg) studies in Asian and Caucasian subjects. Dose normalized area under the concentration time curve (AUC) and maximum observed concentration (Cmax) (AUC(dn) and Cmax(dn)) were obtained by dividing each value by the administered dose. Dose-per bodyweight normalized AUC and Cmax (AUC(dn,wt) and Cmax,(dn,wt)) were obtained by dividing each value by the administered dose per unit bodyweight. Mean difference and 90% confidence intervals for Asian versus Caucasian comparisons were calculated for atorvastatin pharmacokinetic values based on the t statistic and expressed as ratios using Caucasians as the reference. Data were analyzed from 310 Asians and 579 Caucasians from 22 studies. AUC(dn) (Asian = 2.35, Caucasian = 2.06 [ng.hr.mL(-1)]/mg) and Cmax(dn) (Asian = 0.39, Caucasian = 0.40 Cmax(dn,wt)) and the equivalent dose-per-bodyweight normalized values for atorvastatin (AUC(dn,wt): Asian = 157.5, Caucasian = 156.4 [ng.hr.mL(-1)]/[mg.kg(-1)]; Cmax(dn,wt): Asian = 26.2, Caucasian = 30.3 [ng.mL(-1)]/[mg.kg(-1)]) were similar in both ethnic groups. Mean differences and 90% confidence interval for the differences fell within the limits (0.8-1.25) except for Cmax(dn,wt), for which the lower limit was slightly below 80%. No differences were noted in the systemic exposure to atorvastatin between Asian and Caucasian subjects. These data therefore demonstrate that dosing considerations in the current labels for atorvastatin are similar for Asian compared with Caucasian subjects. PMID- 20975529 TI - A novel approach to noninferiority testing: documented proof rather than arbitrary margins. AB - Noninferiority trials have been criticized for their wide margins of noninferiority, making it virtually impossible to reject noninferiority. Recommendations have been given to replace the practice of arbitrarily set margins. The objective of this study was to review various alternative methods of assessment based on statistical reasoning. Four examples are given. (1) In a 300 patient parallel group study of 2 inhalers for asthma, noninferiority was demonstrated at P = 0.0001. This result was supported by both the lack of a significant difference between the standard and new inhalers and the presence of a significant difference between the new inhaler and a placebo at P = 0.0001. (2) In a 236-patient parallel group sleeping pill study, noninferiority was demonstrated at P = 0.04. The presence of noninferiority was supported by a significant superiority of the new compound against a placebo at P = 0.021. However, the significantly worse performance against the standard treatment undermined these findings. (3) In a 200-patient hypertension study of 2 treatment groups, noninferiority was demonstrated at P = 0.028. The presence of noninferiority was supported by the lack of a significant difference between the new and the standard treatment. However, these findings were undermined by the lacking superiority of the new compound against a placebo. (4) In a 160-patients parallel group cholesterol study, noninferiority was demonstrated at P = 0.01. The presence of noninferiority was undermined by both the significant difference between the new and the standard treatment and the lack of efficacy of the new treatment against a placebo. We conclude that expert investigators traditionally set an arbitrary margin of noninferiority based on clinical arguments and that they benefit from wide margins. As an alternative and more meaningful approach to noninferiority testing, we propose to use (1) margins based on counted rather than on arbitrary criteria, (2) null hypothesis tests between the new and standard treatments, (3) null hypothesis tests between the new treatment and a placebo. PMID- 20975530 TI - Thymosin beta4 expression in human tissues and in tumors using tissue microarrays. AB - Thymosin beta4 has been reported to play the key roles in tumor growth, metastasis, and angiogenesis. Although the importance of thymosin beta4 in angiogenesis and metastasis is known, few studies to show the expression patterns of thymosin beta4 in human tissues including tumors have been conducted. The comparisons of the expression of thymosin beta4 between the normal and tumor tissues are also needed to study the role of thymosin beta4 in tumor formation. Using tissue microarray analysis, we compared the expression patterns of thymosin beta4 in the normal human tissues and in the tumors to screen certain tumors and upregulated the expression of thymosin beta4 by tumorigenesis. Thymosin beta4 was highly expressed in the hepatic cells in the normal adult liver, duct, and acinar cells in pancreas, and muscle cells in the heart and also expressed highly in certain tumor cells, including osteosarcoma, colon adenocarcinoma, esophageal squamous cell carcinoma, kidney and urinary bladder transitional carcinoma, lung cancer, and liver cancer. Comparing the thymosin beta4 expression between normal and tumors, thymosin beta4 was upregulated specifically in osteosarcoma, colorectal carcinoma, and esophageal cancer. To confirm the over-expression of thymosin beta4 in these tumors, we analyzed expression of thymosin beta4 with each additional microarray of osteosarcoma, colorectal carcinoma, and esophageal cancer. The significant increased expression of thymosin beta4 was observed in osteosarcoma and in colorectal cancer. These results suggest that the expression of thymosin beta4 is highly related with tumorigenesis of certain tumors including the osteosarcoma and colorectal cancers. PMID- 20975531 TI - A low-Delta9 tetrahydrocannabinol cannabis extract induces hyperphagia in rats. AB - Appetite stimulation via partial agonism of cannabinoid type 1 receptors by Deltatetrahydrocannabinol (DeltaTHC) is well documented and can be modulated by non-DeltaTHC phytocannabinoids. DeltaTHC concentrations sufficient to elicit hyperphagia induce changes to both appetitive (reduced latency to feed) and consummatory (increased meal one size and duration) behaviours. Here, we show that a cannabis extract containing too little DeltaTHC to stimulate appetite can induce hyperphagia solely by increasing appetitive behaviours. Twelve, male Lister hooded rats were presatiated before treatment with a low-DeltaTHC cannabis extract (0.5, 1.0, 2.0 and 4.0 mg/kg). Hourly intake and meal pattern data were recorded and analyzed using one-way analyses of variance followed by Bonferroni post-hoc tests. The cannabis extract significantly increased food intake during the first hour of testing (at 4.0 mg/kg) and significantly reduced the latency to feed versus vehicle treatments (at doses >=1.0 mg/kg). Meal size and duration were unaffected. These results show only the increase in appetitive behaviours, which could be attributed to non-DeltaTHC phytocannabinoids in the extract rather than DeltaTHC. Although further study is required to determine the constituents responsible for these effects, these results support the presence of non-DeltaTHC cannabis constituent(s) that exert a stimulatory effect on appetite and likely lack the detrimental psychoactive effects of DeltaTHC. PMID- 20975532 TI - Efficacy of olmesartan therapy on fibrinolytic capacity in patients with hypertension. AB - The efficacy of olmesartan on fibrinolytic capacity has not been studied yet. Therefore, the aim of the present study was to investigate the efficacy of olmesartan on hemostatic/fibrinolytic status by measuring plasma level of plasminogen activator inhibitor-1 (PAI-1) and soluble thrombomodulin levels in patients with hypertension. Forty-two consecutive, newly diagnosed (25 women and 17 men with a mean age of 48 +/- 8 years) patients with untreated essential hypertension were included in the study. Olmesartan medoxomil (20 mg/day) was started and the patients were followed up for 6 months. Baseline biochemical variables, thrombomodulin, and PAI-1 levels were compared with the levels of these variables measured at the end of the 6-month follow-up period. After 6 months of treatment with olmesartan medoxomil, there was a significant reduction in systolic and diastolic blood pressure (from 159.5 +/- 10.9 to 134.6 +/- 12.7 mmHg and from 98.0 +/- 6.3 to 83.9 +/- 7.0 mmHg, respectively). Mean plasma PAI-1 and thrombomodulin levels were also significantly decreased (59.73 +/- 41.91 vs. 48.60 +/- 33.65 ng/ml, P = 0.001 and 8.09 +/- 2.29 vs. 6.92 +/- 1.42 MUg/l, P < 0.001, respectively). Olmesartan medoxomil decreased plasma PAI-1 and thrombomodulin levels after 6 months of therapy, indicating a favorable effect on fibrinolytic capacity in patients with essential hypertension. PMID- 20975533 TI - Can sphygmomanometers designed for self-measurement of blood pressure in the home be used in office practice? AB - OBJECTIVE: To examine the possibility of measuring automated office (AO) blood pressure (BP) using home BP recorders in place of the more expensive, fully automated devices designed specifically for professional use. PARTICIPANTS AND METHODS: Three groups of 100 patients each had five AOBP readings recorded with one of three home BP devices while resting alone in a quiet examining room. These devices were also used to obtain 24 home BP readings during 6 days. Five AOBP readings were also recorded using the BpTRU device and all patients had 24-h ambulatory BP and manual BP readings taken. RESULTS: Mean systolic AOBP was within 3-4 mmHg of the mean awake ambulatory BP for each of the three home BP recorders whether used in the office setting or at home. Diastolic readings tended to be higher than the corresponding awake ambulatory BP. For the 139 patients with hypertension, mean (+/-standard deviation) AOBP taken with the home BP devices (146+/-14/86+/-12) was higher (P<0.001) than the awake ambulatory BP (142+/-11/81+/-12) and AOBP taken with the BpTRU device (141+/-15/82+/-12). Systolic BP at home (142+/-14/85+/-10) was also similar to the awake ambulatory BP but diastolic BP was higher (P<0.001). There were no significant differences in correlation coefficients between each set of AOBP readings and awake ambulatory BP. CONCLUSION: Home BP devices may be used to record AOBP in selected patients. However, a fully automated sphygmomanometer is still the device of choice for obtaining AOBP readings similar to the awake ambulatory BP in patients with suspected hypertension. PMID- 20975534 TI - The questions on the use of internet cancer support groups: instrument development. AB - Recently, with advances in computer technologies, Internet cancer support groups became more popular than ever among people living with cancer. However, there is little information available on cancer patients' use of Internet cancer support groups, which may be partially due to a lack of instruments measuring cancer patients' use of Internet cancer support groups. Indeed, virtually no instrument measuring cancer patients' use of Internet cancer support groups can be identified through searches using multiple databases. In this study, a new instrument measuring the use of Internet cancer support groups was developed, and its psychometric properties were tested among 117 people living with cancer recruited through the Internet using a convenience sampling method. First, the development process of the new instrument, the Questions on the Use of Internet Cancer Support Groups, is described. Then, the pilot study on psychometric properties of the instrument is presented. Reliability was evaluated using internal consistency reliability testing, split-half reliability testing, and item analysis. Validity was assessed by using criterion validity, convergent validity, and face validity. The findings of the pilot study supported the reliability and validity of this new instrument. Based on the findings, some implications for future research are proposed. PMID- 20975535 TI - Cancer as a problem to be solved: internet use and provider communication by men with cancer. AB - Increasingly, cancer-related Web sites have been developed to provide information for patients. More needs to be done to understand the experience of men with cancer using the Internet. Heideggerian hermeneutics is the interpretive approach used to guide this study. Fifteen men with cancer who used the Internet were recruited through a prostate cancer support group and snowball sampling. Participants were individually interviewed and asked to tell stories of Internet use and practices. Transcribed interviews provided data for interpretive analysis. The overall constitutive pattern describing the men's experience is "cancer diagnosis as a problem to be solved." Five related themes included (1) seeking disease and treatments information from the Internet for decision making, to become comfortable with treatment plan; (2) organizing information to facilitate provider encounters and to monitor for reoccurrence; (3) evaluating Web information by credibility and usability with trust in the physician influencing the end decision point; (4) symptom management by knowing possibilities by hearing patient stories; and (5) navigating through the healthcare system politics and power. Men with cancer are incorporating Internet use into their cancer journey. They perceive changing provider-patient relationships when they participate in treatment decisions and monitor for reoccurrence. PMID- 20975536 TI - The technology acceptance model: predicting nurses' intention to use telemedicine technology (eICU). AB - The purposes of this study were to determine factors and predictors that influence nurses' intention to use the eICU technology, to examine the applicability of the Technology Acceptance Model in explaining nurses' intention to use the eICU technology in healthcare settings, and to provide psychometric evidence of the measurement scales used in the study. The study involved 117 participants from two healthcare systems. The Telemedicine Technology Acceptance Model was developed based on the original Technology Acceptance Model that was initially developed by Fred Davis in 1986. The eICU Acceptance Survey was used as an instrument for the study. Content validity was examined, and the reliability of the instrument was tested. The results show that perceived usefulness is the most influential factor that influences nurses' intention to use the eICU technology. The principal factors that influence perceived usefulness are perceived ease of use, support from physicians, and years working in the hospital. The model fit was reasonably adequate and able to explain 58% of the variance (R = 0.58) in intention to use the eICU technology with the nursing sample. PMID- 20975537 TI - Student perceptions of online participation in baccalaureate nursing computer conferencing courses. AB - The purpose of this study was to examine baccalaureate nursing students' perceptions of their own and peers' online participation. The population included baccalaureate nursing students who have been or were recently involved in a computer-conferencing nursing course. Volunteer nursing students (n = 55) from three Canadian universities completed a Web-based questionnaire. The researcher designed instrument was derived from a modified taxonomy of participation in online courses. The instrument measured three constructs of participation: interpersonal, content, and interface interactions. Overall, students perceived their participation to be at a high level with a reported mean of 3.94/5.00 (SD, 0.476). Students' perceptions of their group members' participation level were also reported as high (mean, 3.60; SD, 0.481). Significant correlations were found among each of the questionnaire's three subcomponents (ie, interpersonal, content, and interface). Results of the study lend support for the use of interface interactions to identify students who may not have the satisfactory computer skills to participate effectively in computer-conferencing courses. PMID- 20975538 TI - The DSCP-CA: a decision support computer program--cancer pain management. AB - The purpose of this study was to develop a decision support system using fuzzy logic that would support nurses' decisions about cancer pain management, especially for ethnic minority cancer patients. The study had two phases: (1) data collection and (2) development of the decision support computer program. In the data collection phase, an Internet survey of 428 cancer patients and four ethnic-specific online forums (about 30 participants per forum) were conducted to gather data on the cancer pain experience of the four major ethnic groups in the United States. The development phase included two components: (1) development of three modules, including a knowledge base module, a decision module, and a self adaptation module; and (2) a 3-month evaluation of the decision support computer program by oncology nurses and subsequent incorporation of their feedback into the program. The Internet survey and online forum data were processed into fuzzy and crisp data sets, and ethnic-specific algorithms for the decision module were developed. Using the self-adaptation module, the decision support computer program was further refined as additional data were processed. Then, the decision support computer program was further developed by adding additional components suggested by the oncology nurses. PMID- 20975539 TI - Factors affecting nurses' attitudes toward computers in healthcare. AB - The purpose of the study was to determine factors affecting nurses' attitudes toward computers in healthcare. This cross-sectional study was carried out with nurses employed at one state and one university hospital. The sample of the study included 890 nurses who were selected via a purposive sampling method. Data were collected by using a questionnaire for demographic information and Pretest for Attitudes Toward Computers in Healthcare Assessment Scale v.2. The nurses, in general, had positive attitudes toward computers. Findings of the present study showed a significant difference in attitudes for different categories of age (P < .001), marital status (P < .05), education (P < .001), type of facility (P < .01), job title (P < .001), computer science education (P < .01), computer experience (P < .001), duration of computer use (P < .001), and place of use of computer (P < .001). The results of the present study could be used during planning and implementation of computer training programs for nurses in Turkey and could be utilized in improving the participation of Turkish nurses in initiatives to develop hospital information systems and, above all, in developing computerized patient care planning. PMID- 20975540 TI - Preparing for organizational change: Project: SAFETYfirst. AB - A 15-facility healthcare organization utilized organizational change management techniques to aid with the adoption of a clinical information system to accomplish desired cultural transformation. The aim of this article was to provide a description of team member and physician attitudes toward change during conversion to a new clinical information system of electronic documentation. The tool developed and utilized was a change readiness survey to assess randomly selected team member and physician perceived readiness for the transition to an electronic documentation system. This article reviewed the rationale for using organizational change management techniques to facilitate adoption of a new clinical information system and discussed development of a change readiness survey tool. It explored the findings from the first 3 years of the survey. PMID- 20975541 TI - Quota sampling in internet research: practical issues. AB - Quota sampling has been suggested as a potentially good method for Internet-based research and has been used by several researchers working with Internet samples. However, very little is known about the issues or concerns in using a quota sampling method in Internet research. The purpose of this article was to present the practical issues using quota sampling in an Internet-based study. During the Internet study, the research team recorded all recruitment issues that arose and made written notes indicating the possible reasons for the problems. In addition, biweekly team discussions were conducted for which written records were kept. Overall, quota sampling was effective in ensuring that an adequate number of midlife women were recruited from the targeted ethnic groups. However, during the study process, we encountered the following practical issues using quota sampling: (1) difficulty reaching out to women in lower socioeconomic classes, (2) difficulty ensuring authenticity of participants' identities, (3) participants giving inconsistent answers for the screening questions versus the Internet survey questions, (4) potential problems with a question on socioeconomic status, (5) resentment toward the research project and/or researchers because of rejection, and (6) a longer time and more expense than anticipated. PMID- 20975542 TI - Creating teaching objects: a case study of delivering recorded narrations in nursing education. AB - This article evaluates the use of PowerPoint presentations and recorded narrations (developed and saved as Flash content using software called Articulate Presenter) as a tool to help postgraduate nursing students taking a pharmacology course to learn key pharmacological and pharmacotherapeutic concepts. Students found that the teaching objects, provided as additional resources to assist students in learning about difficult concepts, supported them in their learning. Additionally, students reported that while they appreciated the provision of the teaching objects, the objects lacked an interactive component and did not replace interaction with the teacher. Articulate Presenter, as a tool to create a recorded narration, was easy for the teacher to use and promoted teacher independence in the creation of teaching objects. PMID- 20975543 TI - Tailored prevention of inpatient falls: development and usability testing of the fall TIPS toolkit. AB - Patient falls and fall-related injuries are serious problems in hospitals. The Fall TIPS application aims to prevent patient falls by translating routine nursing fall risk assessment into a decision support intervention that communicates fall risk status and creates a tailored evidence-based plan of care that is accessible to the care team, patients, and family members. In our design and implementation of the Fall TIPS toolkit, we used the Spiral Software Development Life Cycle model. Three output tools available to be generated from the toolkit are bed poster, plan of care, and patient education handout. A preliminary design of the application was based on initial requirements defined by project leaders and informed by focus groups with end users. Preliminary design partially simulated the paper version of the Morse Fall Scale currently used in hospitals involved in the research study. Strengths and weaknesses of the first prototype were identified by heuristic evaluation. Usability testing was performed at sites where research study is implemented. Suggestions mentioned by end users participating in usability studies were either directly incorporated into the toolkit and output tools, were slightly modified, or will be addressed during training. The next step is implementation of the fall prevention toolkit on the pilot testing units. PMID- 20975544 TI - Design and development of interface design principles for complex documentation using PDAs. AB - The screen interface has been believed to be the major barrier for the adoption of PDAs in healthcare. The study objectives were to design a set of screen interface design principles for complex documentation using PDAs and to examine nurses' perception of the ease of use and usefulness of the application. A 21 page Chinese version of the interRAI MDS-HC home-care assessment tool composed of more than 250 assessment questions was used for the application. A WiFi Palm based PDA was used. A convenience sample of 60 subjects, primarily nurses newly trained to use the MDS-HC assessment tool, were invited to evaluate the PDA system in terms of Davis' Technology Acceptance Model. The final information structure of the PDA application consisted of 18 categories composed of 262 questions over 63 screens. Subjects could move to any assessment question in less than two taps without a memory burden and finish the question in one tap. Respectively, close to 95% and 93% of the subjects agreed that, overall, the system was easy to use and useful for their work. We conclude the screen interface challenge for complex documentation using PDAs can be improved and managed to achieve to a very high usability. PMID- 20975545 TI - The use of bedside electronic medical record to improve quality of care in nursing facilities: a qualitative analysis. AB - It appears that the implementation and use of a bedside electronic medical record in nursing homes can be a strategy to improve quality of care. Staff like using the bedside electronic medical record and believe it is beneficial. Information gleaned from this qualitative evaluation of four nursing homes that implemented complete electronic medical records and participated in a larger evaluation of the use of an electronic medical record will be useful to other nursing homes as they consider implementing bedside computing technology. Nursing home owners and administrators must be prepared to undertake a major change requiring many months of planning to successfully implement. Direct care staff will need support as they learn to use the equipment, especially for the first 6 to 12 months after implementation. There should be a careful plan for continuing education opportunities so that staff learn to properly use the software and can benefit from the technology. After 12 to 24 months, almost no one wants to return to the era of paper charting. PMID- 20975546 TI - Defining and integrating informatics competencies into a hospital nursing department. AB - Expanding use of complex patient information management systems and communication technology in healthcare organizations requires nurses to possess core competencies that until recently were not considered as integral to practice as those of a strictly clinical nature. Organizational changes necessary to formally integrate informatics competencies into nursing practice require strong partnerships among facility nursing leaders, educators, and informaticists. The authors describe a strategic initiative one acute care organization used to develop nursing practice that ensures use of system tools to manage patient information, support clinical decision making, optimize workflow, and communicate with members of the care team. The initiative involved defining nursing computer and informatics management skills for the clinical system applications and technologies utilized in the organization and integrating the introduction, evaluation, and on going professional development of the defined informatics competencies into organizational processes and tools to support the bedside nurse. PMID- 20975547 TI - Urinary ethylglucuronide assessment in patients treated with disulfiram: a tool to improve verification of abstention and safety. AB - AIM: Disulfiram has been shown to be efficacious and safe in the treatment of alcohol relapse prevention. However, drinking alcohol while taking disulfiram can be harmful because of the resulting alcohol-disulfiram reaction/acetaldehyde reaction. Alcohol consumption of patients receiving a low disulfiram dose or low alcohol consumption in normal disulfiram dose can result in subclinical alcohol disulfiram reactions. This undermines the learning of alcohol-associated punishment, might increase the risk to raise alcohol consumption, and can result in chronic acetaldehyde exposure, which has carcinogenic, neurotoxic, and cardiotoxic properties. Therefore, the use of an alcohol marker monitoring retrospective alcohol use is tested in this study. METHOD: A total of 51 patients being treated with supervised disulfiram were unheralded measured for ethylglucuronide (EtG) if they attended at least for 2 weeks in the outpatient treatment program. Ethylglucuronide was measured with liquid chromatography tandem mass spectrometry analysis (LC-MS/MS). Detection limit was 0.1 mg/L. RESULTS: Urinary EtG was found positive in 5.9% (3/51) of the patients. Regularly conducted breathalyzer tests had been continuously negative in these patients. Moreover, vegetative withdrawal symptoms had not been found in these patients. Two of the positive EtG tests could be classified as covered relapses, whereas the third remained unclear but showed a negative EtG in a repetition of the test few days later. CONCLUSIONS: Unheralded urinary EtG monitoring improved verification of abstinence in patients treated with disulfiram, was helpful in detecting covered consumption of alcoholic beverages or hidden alcohol exposition (eg, fruit juice or personal care products), and thereby improved safety by preventing chronic acetaldehyde reaction. PMID- 20975548 TI - Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. AB - OBJECTIVE: To determine whether central venous pressure and fluid balance after resuscitation for septic shock are associated with mortality. DESIGN: We conducted a retrospective review of the use of intravenous fluids during the first 4 days of care. SETTING: Multicenter randomized controlled trial. PATIENTS: The Vasopressin in Septic Shock Trial (VASST) study enrolled 778 patients who had septic shock and who were receiving a minimum of 5 MUg of norepinephrine per minute. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Based on net fluid balance, we determined whether one's fluid balance quartile was correlated with 28-day mortality. We also analyzed whether fluid balance was predictive of central venous pressure and furthermore whether a guideline-recommended central venous pressure of 8-12 mm Hg yielded a mortality advantage. At enrollment, which occurred on average 12 hrs after presentation, the average fluid balance was +4.2 L. By day 4, the cumulative average fluid balance was +11 L. After correcting for age and Acute Physiology and Chronic Health Evaluation II score, a more positive fluid balance at both at 12 hrs and day 4 correlated significantly with increased mortality. Central venous pressure was correlated with fluid balance at 12 hrs, whereas on days 1-4, there was no significant correlation. At 12 hrs, patients with central venous pressure <8 mm Hg had the lowest mortality rate followed by those with central venous pressure 8-12 mm Hg. The highest mortality rate was observed in those with central venous pressure >12 mm Hg. Contrary to the overall effect, patients whose central venous pressure was <8 mm Hg had improved survival with a more positive fluid balance. CONCLUSIONS: A more positive fluid balance both early in resuscitation and cumulatively over 4 days is associated with an increased risk of mortality in septic shock. Central venous pressure may be used to gauge fluid balance <= 12 hrs into septic shock but becomes an unreliable marker of fluid balance thereafter. Optimal survival in the VASST study occurred with a positive fluid balance of approximately 3 L at 12 hrs. PMID- 20975549 TI - Informed consent in research to improve the number and quality of deceased donor organs. AB - Improving the management of potential organ donors in the intensive care unit could meet an important public health goal by increasing the number and quality of transplantable organs. However, randomized clinical trials are needed to quantify the extent to which specific interventions might enhance organ recovery and outcomes among transplant recipients. Among several barriers to conducting such studies are the absence of guidelines for obtaining informed consent for such studies and the fact that deceased organ donors are not covered by extant federal regulations governing oversight of research with human subjects. This article explores the underexamined ethical issues that arise in the context of donor management studies and provides ethical guidelines and suggested regulatory oversight mechanisms to enable such studies to be conducted ethically. We conclude that both the respect that is traditionally accorded to the prior wishes of the dead and the possibility of postmortem harm support a role for surrogate consent of donors in such randomized controlled trials. Furthermore, although recipients will often be considered human subjects under federal regulations, several ethical arguments support waiving requirements for recipient consent in donor management randomized controlled trials. Finally, we suggest that new regulatory mechanisms, perhaps linked to existing regional and national organ donation and transplantation infrastructures, must be established to protect patients in donor management studies while limiting unnecessary barriers to the conduct of this important research. PMID- 20975550 TI - Niacin attenuates lung inflammation and improves survival during sepsis by downregulating the nuclear factor-kappaB pathway. AB - OBJECTIVES: To examine whether niacin attenuates lung inflammation and improves survival during sepsis and to determine whether the beneficial effects of niacin are associated with downregulation of the nuclear factor (NF)-kappaB pathway. DESIGN: Prospective laboratory study. SETTING: University laboratory. SUBJECTS: Male Sprague-Dawley rats (n = 119). INTERVENTIONS: To induce endotoxemia in rats, lipopolysaccharide (Escherichia coli, O26:B6) at a dosage of 10 mg/kg was injected into a tail vein and 10 mins later, vehicle, a low dose of niacin (360 mg/kg), or a high dose of niacin (1180 mg/kg) was administered once through an orogastric tube, respectively. MEASUREMENTS AND MAIN RESULTS: We observed the survival of the subjects for 72 hrs. At 6 hrs postlipopolysaccharide, we euthanized animals and measured cytoplasmic phosphorylated inhibitor kappaB-alpha and inhibitor kappaB-alpha expressions, nuclear NF-kappaB p65 expression, NF kappaB p65 DNA-binding activity, tumor necrosis factor-alpha, and interleukin-6 gene expressions and histologic damages in lung tissues. We also measured nicotinamide adenine dinucleotide, reduced nicotinamide adenine dinucleotide phosphate, reduced glutathione, and malondialdehyde levels in lung tissues. High dose of niacin suppressed NF-kappaB activation and proinflammatory cytokine gene expressions in lung tissues, reduced histologic lung damages, and improved survival in endotoxemic rats. Furthermore, it increased nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, and glutathione levels and decreased malondialdehyde level in lung tissues. CONCLUSIONS: High dose of niacin attenuated lung inflammation, reduced histologic lung damages, and improved survival during sepsis in rats. These therapeutic benefits were associated with downregulation of the NF-kappaB pathway. PMID- 20975551 TI - Regional citrate anticoagulation in patients with liver failure supported by a molecular adsorbent recirculating system. AB - OBJECTIVE: Regional citrate anticoagulation has emerged as a promising method in critically ill patients at high risk of bleeding. However, in patients with liver failure, citrate accumulation may lead to acid-base and electrolyte imbalances, notably of calcium. The aim of this study was to evaluate the feasibility and safety of regional citrate anticoagulation during liver support using a molecular adsorbent recirculating system as well as its effects on electrolyte and acid base balance in patients with liver failure. DESIGN: Prospective observational study. SETTING: University hospital. PATIENTS: Twenty critically ill patients supported by molecular adsorbent recirculating system resulting from liver failure between January 2007 and May 2009. MEASUREMENTS AND MAIN RESULTS: The median duration of molecular adsorbent recirculating system treatment was 20 hrs (interquartile range, 18-22 hrs). Two of 77 molecular adsorbent recirculating system treatments (2%) were prematurely discontinued as a result of filter clotting and bleeding, respectively. The median citrate infusion rate, necessary to maintain the postfilter ionized calcium between 0.2 and 0.4 mmol/L, was 3.1 mmol/L (interquartile range, 2.3-4 mmol/L) blood flow. The median calcium chloride substitution rate was 0.9 mmol/L (0.3-1.7 mmol/L) dialysate. Total serum calcium remained stable during molecular adsorbent recirculating system treatments. There was a statistically significant increase of the ratio of total calcium to systemic ionized calcium (2.04 +/- 0.32 mmol/L to 2.17 +/- 0.35; p = .01), which reflected citrate accumulation resulting from liver failure. Under close monitoring, no clinically relevant electrolytes or acid-base disorders were observed. CONCLUSIONS: Our results suggest that regional citrate anticoagulation is a safe and feasible method to maintain adequate circuit lifespan without increasing the risk of hemorrhagic complications while maintaining a normal acid base as well as electrolyte balance in patients with liver failure supported by molecular adsorbent recirculating system. PMID- 20975552 TI - The interaction of chronic and acute glycemia with mortality in critically ill patients with diabetes. AB - OBJECTIVES: The relationship between hyperglycemia and mortality is altered by the presence of diabetes mellitus. Biological adjustment to preexisting hyperglycemia might explain this phenomenon. We tested whether the degree of preexisting hyperglycemia would modulate the association between glycemia and outcome during critical illness in patients with diabetes mellitus. DESIGN: Retrospective observational study. SETTING: Two tertiary intensive care units. PATIENTS: Four hundred fifteen critically ill diabetic patients with HbA1c levels measured within 3 months of intensive care unit admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 9,946 blood glucose measurements in this study cohort (glucose measured 6.7 times per day; every 3.6 hrs on average). The median preadmission HbA1c level was 7.0%. There was no significant difference in HbA1c levels (p = .17) or time-weighted average of blood glucose concentrations (p = .49) between survivors and nonsurvivors. The time-weighted average of blood glucose concentrations during intensive care unit stay for nonsurvivors was lower than that of survivors when the HbA1c was >6.8%. In multivariate analysis, we found that there was a significant interaction between HbA1c and the time-weighted glucose level, indicating that the relationship between HbA1c and mortality changed according to the levels of time-weighted average of blood glucose concentrations (p = .008). As a consequence, in patients with higher (>7%) preadmission levels of HbA1c, the higher the time-weighted acute glucose concentration during intensive care unit stay (>10 mmol/L), the lower the hospital mortality compared with the lower HbA1c cohort (<7%). CONCLUSIONS: In patients with diabetes mellitus admitted to intensive care units, there was a significant interaction between preexisting hyperglycemia and the association between acute glycemia and mortality. These observations generate the hypothesis that glucose levels that are considered safe and desirable in other patients might be undesirable in diabetic patients with chronic hyperglycemia. Further studies are required to confirm or refute our findings. PMID- 20975553 TI - Does triage to critical care during a pandemic necessarily result in more survivors? AB - OBJECTIVE: The 2009 H1N1 pandemic reinforced the need for a planned response to increased demand for critical care. Triage protocols have been proposed incorporating the exclusion of specified subgroups of patients from critical care. There have been no studies that explore the theoretical underpinning of triage at referral, and it is not clear under what circumstances triage would confer the intended benefits. We sought to explore the mechanisms whereby triage could lead to fewer deaths across a critical care population in the context of a pandemic. DESIGN: We constructed a mathematical model based on queuing theory to compare the estimated short-term survival achieved by using a critical care service with and without triage at referral. Illustrative scenarios concerning a hypothetical critical care population were constructed to explore the roles of length of stay and critical care survival in determining the impact of triage and to identify "tipping points" of demand at which triage would result in more survivors. SETTING: Not applicable as this was a data-free mathematical modeling exercise. MAIN RESULTS: We identified circumstances in which triage would be expected to result in more survivors and circumstances in which it would not. In some scenarios, excluding patient groups solely on the basis of anticipated length of stay could be effective due to a more efficient use of critical care bed days. CONCLUSIONS: The impact of triage is dependent on the level of demand and on the scale of achievable differences between included and excluded groups in terms of anticipated length of stay and critical care survival. It cannot be assumed that triage can or will result in fewer deaths. It should be remembered that there are considerations other than population-level short-term survival when determining the objectives of triage and its ethical implementation. PMID- 20975554 TI - New developments in colorectal surgery. AB - PURPOSE OF REVIEW: New developments in colorectal surgery have been driven primarily by technical innovations, which in turn are responsible for changes in practice. This review examines recent publications that describe and have contributed to these changes. RECENT FINDINGS: We identified and reviewed recent publications in the areas of fecal incontinence, constipation, single incision and robotic surgical techniques, complex anal fistulas, diverticulitis, local excision techniques for rectal neoplasms, surgical care improvement, use of mechanical bowel preparation, and magnetic resonance imaging after neoadjuvant chemoradiotherapy for rectal cancer. SUMMARY: New technologies and practice innovations will enhance patient outcomes and quality of life. Multiinstitutional studies, randomized when practical, will be necessary to further define the safety and efficacy of these new surgical techniques and to further define best practices in colon and rectal surgery. PMID- 20975555 TI - Diet and cognition in chronic liver disease. AB - PURPOSE OF REVIEW: The spectrum of neurocognitive impairment in cirrhosis spans a continuum of minimal hepatic encephalopathy (MHE) to overt hepatic encephalopathy (OHE), the pathophysiology of which remains incompletely understood. The current available evidence, however, suggests that nutrition plays an important role in its development and points to the fact that malnutrition increases the morbidity and mortality of patients with cirrhosis. This review incorporates recent findings published in the last 2 years within the evolution of evidence regarding the role dietary manipulation can play in the comprehensive management of patients with cirrhosis and cognitive dysfunction. RECENT FINDINGS: In patients with cirrhosis it is important to prevent starvation physiology which occurs after few hours of caloric deprivation as compared to 3 days in noncirrhotics. This can be accomplished by making sure that cirrhotic patients have daily breakfast and a late evening snack. In addition, probiotics and symbiotics are well tolerated and improve cognitive function in patients with MHE. SUMMARY: The long-time held belief that protein restriction is needed to improve encephalopathy has no scientific basis but remains widely practiced. Branched chain amino acids supplement may be helpful in patients who continue to suffer from OHE despite treatment of precipitating events and pharmacologic treatment with lactulose and rifaximin. Preventing starvation physiology and supplementing the diet with prebiotics and symbiotics are helpful in patients with MHE. PMID- 20975556 TI - Pathophysiological importance of antineutrophil antibodies in vasculitis. AB - PURPOSE OF REVIEW: We endeavour to provide a brief overview of the recent advances in understanding of how antineutrophil cytoplasmic antibodies (ANCAs) contribute to the pathophysiology of vasculitis. RECENT FINDINGS: Substantial progress has been made in our understanding of the immunopathogenesis of ANCA associated vasculitides. Compelling evidence from in-vitro studies and experimental models in conjunction with clinical trials has confirmed that ANCAs directly contribute to the evolution and progression of the disease process. A new ANCA, directed against human lysosome membrane protein-2 (LAMP-2), has recently been described as a sensitive and specific marker for renal vasculitis and we discuss its potential impact for diagnosis and therapy. Furthermore, high throughput approaches are starting to identify genetic patterns that may identify patients likely to respond to specific therapy or having a high probability of relapse. SUMMARY: It has become increasingly clear over the last two decades that ANCA IgG is pathogenic in vasculitis. Novel therapies aimed at selected cell populations or blocking specific pathogenic pathways offer hope for more selectively treating this heterogeneous group of patients, while avoiding nonspecific immunosuppression and its adverse effects. PMID- 20975557 TI - Advances in diagnosis and treatment of large granular lymphocyte syndrome. AB - PURPOSE OF REVIEW: Large granular lymphocyte (LGL) syndrome comprises a clonal spectrum of T-cell and natural killer (NK)-cell LGL lymphoproliferative disorders associated with neutropenia. This review presents advances in diagnosis and therapy of LGL syndrome. RECENT FINDINGS: Due to the lack of a single unique genetic or phenotypic feature and clinicopathological overlap between reactive and neoplastic entities, accurate LGL syndrome diagnosis should be based on the combination of morphologic, immunophenotypic, and molecular studies as well as clinical features. For diagnosis and monitoring of LGL proliferations, it is essential to perform flow cytometric blood and/or bone marrow analysis using a panel of monoclonal antibodies to conventional and novel T-cell and NK-cell antigens such as NK-cell receptors and T-cell receptor beta-chain variable region families together with TCR gene rearrangement studies. Treatment of symptomatic cytopenias in patients with indolent LGL leukemia is still based on immunosuppressive therapy. Treatment with purine analogs and alemtuzumab may be considered as an alternative option. SUMMARY: Progress in understanding the pathogenetic mechanisms of these entities, especially resistance of clonal LGLs to apoptosis, due to constitutive activation of survival signaling pathways, has its impact on identification of potential molecular therapeutic targets. PMID- 20975558 TI - Bariatric surgery: results in obesity and effects on metabolic parameters. AB - PURPOSE OF REVIEW: The use of bariatric surgery is increasing at an enormous rate in all countries but the indications for the operation on the basis of metabolic derangements are not clear as only one controlled randomized trial has been performed so far. Thus, it is not clear whether bariatric surgery should be performed on obese patients with long-standing type 2 diabetes or poorly controlled hypertension or hypertriglyceridemia. The mechanism for the immediate improvement in glucose tolerance after gastric bypass is not clear but is being actively investigated. RECENT FINDINGS: Gastric bypass appears to enhance glucagon-like peptide-1 production and suppress glucose-dependent insulinotropic polypeptide production. It appears that patients with type 2 diabetes and a greater BMI gain more benefit from the operation. SUMMARY: Bariatric surgery, particularly gastric bypass, has powerful and usually persistent effects on type 2 diabetes, dyslipidemia, and hypertension but randomized controlled trials with predefined metabolic entry criteria and planned comprehensive follow-up are required. PMID- 20975560 TI - An examination of recently revised differentiated thyroid cancer guidelines. AB - PURPOSE OF REVIEW: To examine the most recent changes in published guidelines by various organizations for the treatment of patients with differentiated thyroid cancer. This document provides a comparison of recommendations for common topics currently found in available thyroid cancer care guidelines. RECENT FINDINGS: Recent changes to guidelines have focused on controversial topics, including extent of thyroidectomy based on tumor size, prophylactic central neck dissection, use of radioactive iodine, and degree of thyrotropin suppression. Regional variations between guidelines exist. Adherence to thyroid cancer guidelines at national levels is less than ideal. SUMMARY: Guidelines for the management of differentiated thyroid cancer should continue to reflect minor regional variations in thyroid cancer treatment based on factors unique to that population while remaining otherwise similar to ensure optimal state-of-the-art patient care and outcomes. In the future, individual patient molecular information will likely play an important role in assessing the risk of tumor recurrence and overall survival. Consideration of multiple patient and tumor factors will allow thyroid cancer specialists to use a risk-adapted approach to patient care, from both a surgical and medical standpoint, to ensure optimal patient outcomes on an individual basis and at a disease level. PMID- 20975559 TI - Central auditory disorders: toward a neuropsychology of auditory objects. AB - PURPOSE OF REVIEW: Analysis of the auditory environment, source identification and vocal communication all require efficient brain mechanisms for disambiguating, representing and understanding complex natural sounds as 'auditory objects'. Failure of these mechanisms leads to a diverse spectrum of clinical deficits. Here we review current evidence concerning the phenomenology, mechanisms and brain substrates of auditory agnosias and related disorders of auditory object processing. RECENT FINDINGS: Analysis of lesions causing auditory object deficits has revealed certain broad anatomical correlations: deficient parsing of the auditory scene is associated with lesions involving the parieto temporal junction, while selective disorders of sound recognition occur with more anterior temporal lobe or extra-temporal damage. Distributed neural networks have been increasingly implicated in the pathogenesis of such disorders as developmental dyslexia, congenital amusia and tinnitus. Auditory category deficits may arise from defective interaction of spectrotemporal encoding and executive and mnestic processes. Dedicated brain mechanisms are likely to process specialized sound objects such as voices and melodies. SUMMARY: Emerging empirical evidence suggests a clinically relevant, hierarchical and modular neuropsychological model of auditory object processing that provides a framework for understanding auditory agnosias and makes specific predictions to direct future work. PMID- 20975561 TI - Complications of adenotonsillectomy. AB - PURPOSE OF REVIEW: Tonsillectomy and adenoidectomy are two of the most commonly performed pediatric surgical procedures. As with all surgical intervention, tonsillectomy and adenoidectomy are associated with a host of potential complications. Fortunately, for most children undergoing adenotonsillectomy (T&A), complications are rare. This review is intended to summarize recent reports, which may lead to prevention and treatment of T&A complications. RECENT FINDINGS: The presented reports of complications and risk factors for complications in children undergoing T&A highlight perioperative medical management as a means to decrease perioperative complications. Certain tonsillectomy techniques, such as microdebrider intracapsular tonsillectomy, may lead to decreased posttonsillectomy hemorrhage and dehydration. Despite published recommendations, preoperative assessments for bleeding diatheses vary among practitioners. Conversely, guidelines for evaluation of posttonsillectomy hemorrhage are lacking. Some pediatric populations, such as children with coagulopathy, neurologic disease, and obesity, have increased risk of perioperative complications, and recent reports regarding their care are presented. SUMMARY: We present recent data pertinent to the contemporary management of medical and surgical complications of T&A, with particular focus on specific at-risk pediatric populations. In the patient groups illustrated in this review, anticipation of complications may decrease complications or lead to improved management of complications when they occur. PMID- 20975562 TI - Anxiety and depression in asthma. AB - PURPOSE OF REVIEW: there is growing awareness of the correlation between psychological factors, the course of asthma, and the outcomes of asthma treatment. However, the implications of this correlation are still poorly understood. Here, we review the role of anxiety and depression in asthma with a focus on recent literature. RECENT FINDINGS: recent studies suggest an interaction between behavioral, neural, endocrine, and immune processes and suggest that psychological factors play an active role in the genesis of asthma. Notably, the role of chronic stress has been investigated, including the parental psychological state during pregnancy. There is evidence that in patients with asthma, such stress may induce hyporesponsiveness of the hypothalamus-pituitary adrenal axis, resulting in reduced cortisol secretion. SUMMARY: even though it is generally accepted that anxiety and depression are more common in asthmatic patients and that there is a close correlation between psychological disorders and asthma outcomes, such as poorer control of asthma symptoms, the implications and practical consequences of this link remain weak. New studies are introducing an intriguing model of the links between emotional stress, brain centers, the immune system, and the hypothalamus-pituitary-adrenal axis that is far removed from the original concept of 'asthma nervosa'. PMID- 20975563 TI - Metalworking fluids and malignant melanoma in autoworkers. AB - BACKGROUND: Occupational exposure to mineral oil-based metalworking fluids has been consistently linked with skin conditions such as contact dermatitis and squamous cell skin cancer, especially of the scrotum. We examined the incidence of malignant melanoma in a study of autoworkers. METHODS: We followed a cohort of autoworkers from 1985 through 2004 for cancer incidence. Hazard ratios (HRs) were estimated in Cox models for cumulative exposure to total particulate of straight fluid (neat oil), soluble fluid (oil emulsified in water), and synthetic fluid (no oil). Exposure was partitioned into time windows by latency and by calendar periods defined by changes in the content of polycyclic aromatic hydrocarbon in the refined oils. The population was restricted to workers born after 1935. We examined the date-of-birth restriction in a sensitivity analysis. RESULTS: On the basis of 76 incident cases of malignant melanoma in the cohort of 14,139 white males, the HR was 1.99 (95% confidence interval = 1.00-3.96) for the highest category of straight fluid. Risk was greatest in the most recent time window. Penalized splines suggested a linear exposure-response over the full range of exposure. The change in HR for malignant melanoma per mg/m-year of straight fluid increased monotonically from 1.01 to 1.04, when the date-of-birth restriction increased from 1925 to 1945 in 5-year intervals. Results for soluble fluid were more modest. There was no association with synthetic fluid. CONCLUSIONS: Results provide evidence, based on quantitative measures of metalworking fluid, that oil based fluid, particularly straight mineral oils, are associated with the incidence of malignant melanoma. PMID- 20975564 TI - Confounding and bias in the attributable fraction. AB - Inappropriate methods are frequently used to calculate the population attributable fraction (AF) for a given exposure of interest. This commonly occurs when authors use adjusted relative risks (RRs) reported in the literature (the "source" data), without access to the original data. In this analysis, we examine the relationship between the direction and magnitude of confounding in the source data and resulting bias in the attributable fraction when incorrect methods are used. We assess confounding by the confounding risk ratio, which is the ratio of the crude RR to the adjusted RR. We assess bias in the AF by the ratio of the incorrectly calculated AF to the correctly calculated AF. Using generated data, we examine the relationship between confounding and AF bias under various scenarios of population prevalence of exposure and strength of the exposure disease association. For confounding risk ratios greater than 1.0 (ie, crude RR >adjusted RR), the AF is underestimated; for confounding risk ratios less than 1.0 (ie, crude RR =18.5 were 1.05 (95% confidence interval = 1.05-1.06) for all-cause mortality, 1.07 (1.07-1.09) for CVD mortality, and 1.09 (1.08-1.10) for CHD mortality. Similar results were seen in co-twin control analyses of dizygotic twins. However, within monozygotic twins, BMI was associated with death from CHD (OR = 1.06; 1.00-1.12), whereas the association with all-cause mortality (1.01, 0.98-1.04) and CVD mortality (1.02, 0.98-1.06) was weak. CONCLUSIONS: Our findings indicate that there is an association between high BMI and mortality from CHD that is not explained by genetic confounding. However, a large part of the association between BMI and other causes of death may be explained by genes rather than by a causal link between these factors. PMID- 20975566 TI - Adherence to colorectal polyp surveillance guidelines: is there a 'scope' to increase the opportunities for screening? AB - Colorectal polyps are usually asymptomatic and are found opportunistically. Individuals with adenomata are at increased risk for cancer and therefore guidelines exist for surveillance of these lesions including those of the British Society of Gastroenterology (BSG). Deviation from these guidelines is common and increases the workload of endoscopy. We examined those individuals waiting for endoscopy for polyp surveillance to see whether strict adherence to BSG guidelines could facilitate opportunities for screening. A total of 413 patients with earlier colonic polyps were examined, of whom 50 patients were excluded based on having alternative indications for surveillance, 179 (49.3%) were appropriately scheduled for surveillance and 184 patients (55.9%) were scheduled incorrectly. Seventy-nine patients (30%) could have been discharged; of these, 59 had hyperplastic polyps. Of the remaining 105 inappropriate triages under surveillance at the wrong interval, seven patients were scheduled for too infrequent surveillance and 98 were too frequent. A total of 284 patients with adenomatous polyps were under surveillance of whom 11 patients (3.8%) were in the high-risk category and all were appropriately scheduled, and 75 patients (26.4%) were in the intermediate-risk category, of whom 48 were appropriately scheduled, 20 were incorrectly triaged as high risk and seven were triaged as low risk. A total of 198 (69.7%) patients were in the low-risk category, 117 of these were correctly triaged, 15 were incorrectly triaged as high risk and 66 were classified as intermediate risk. Over a five-year period, 318 unnecessary colonoscopies are being performed. On the basis of the data obtained from a population-based colorectal screening programme using immunohistochemical-faecal occult blood testing in our department another 1516 patients could be screened annually without requiring any additional endoscopy resources, if strict adherence to guidelines was assured. PMID- 20975567 TI - Evidence-based classification of recommendations on use of genomic tests in clinical practice: dealing with insufficient evidence. AB - Numerous genomic tests continue to emerge as potential tools in the diagnosis, treatment, prognosis, and prevention for a wide variety of common human diseases. To date, most of these tests have "insufficient evidence" of clinical validity and utility for their use in clinical practice. Explicit and quantitative tools can be used in the evaluation of direct and indirect evidence on the utility of genomic tests. As suggested in an article in this month's issue by Veenstra et al., a recommendation matrix can be developed based on the amount of certainty of the evidence and the assessment of the risk-benefit profile. To supplement the current binary (up or down) evidence-based recommendation for use, it is worthwhile to explore all available data to develop a three-tier evidence-based recommendation classification of genomic tests ("use in practice," "promote informed decision-making," and "discourage use"). Promoting informed decision making may be a valuable recommendation for tests for which there is sufficient information on analytic and clinical validity and for which the risk/benefit analysis on clinical utility is promising but not definitive. This approach could provide interim guidance for clinical practice, while rigorous outcomes research is conducted to assess the impact of such tests on patients, families, and population health outcomes. PMID- 20975568 TI - Agalsidase treatment for Fabry disease: uses and rivalries. PMID- 20975569 TI - Therapeutic goals in the treatment of Fabry disease. AB - PURPOSE: Fabry disease is a progressive multiorgan, multisystem disorder that is caused by a deficiency in the lysosomal enzyme alpha-galactosidase A. Serious renal, cardiac, and cerebrovascular involvement are responsible for much of the morbidity and premature mortality associated with Fabry disease, and neuropathic pain, gastrointestinal problems, and hypohidrosis negatively affect quality of life of patients with Fabry disease. Fabry disease is X-linked, but women are often symptomatic and may be as severely affected as men. METHODS: We propose a series of therapeutic and symptomatic goals for use in setting the expectations of enzyme replacement therapy and for assessing the response to enzyme replacement therapy in the treatment of Fabry disease. RESULTS: Enzyme replacement therapy has been available since 2001 and has been associated with benefit in clinical trials, including stabilization of kidney function, improvement of cardiac structure and function, reduction in severity of neuropathic pain, and improvement in gastrointestinal involvement. CONCLUSIONS: The presentation of these therapeutic goals will aid in the evaluation of response to enzyme replacement therapy and be useful in establishing an overall management plan for individual patients. PMID- 20975571 TI - Evaluation of noninvasive exercise cardiac output determination in chronic heart failure patients: a proposal of a new diagnostic and prognostic method. AB - Peak oxygen consumption (VO2) and various parameters of cardiopulmonary response to exercise are of important prognostic value in chronic heart failure patients. However, all the available parameters only indirectly reflect left-ventricular dysfunction and hemodynamic adaptation to an increased demand. Noninvasive assessment of cardiac output, especially during an incremental exercise test, would allow the direct measurement of cardiac reserve and may become the gold standard for prognostic evaluation of chronic heart failure patients. PMID- 20975570 TI - HIV-1-infected peripheral blood mononuclear cells enhance neutrophil survival and HLA-DR expression via increased production of GM-CSF: implications for HIV-1 infection. AB - OBJECTIVE: HIV-1 bound to intact neutrophils efficiently infects activated peripheral blood mononuclear cells (PBMC). Here, we evaluated the effect of the local milieu created by activated PBMC before and after HIV-1 infection on neutrophil survival and HLA-DR expression, with emphasis placed on a role for GM CSF. METHODS: PBMC of healthy adult individuals were activated by phytohemagglutinin (PHA) or anti-CD3/anti-CD28 and were subsequently cultured without (HIV-1-) or with HIV-1 (HIV-1+). The effects of the culture supernatants or recombinant GM-CSF on survival and HLA-DR expression by neutrophils of healthy adult individuals and of HIV-1-infected individuals were evaluated using flow cytometry. RESULTS: Conditioned medium from PHA-activated PBMC (HIV-1- and HIV 1+) increased neutrophil survival and induced HLA-DR expression by neutrophils of healthy individuals in a GM-CSF dependent fashion. HIV-1 infection variably, but consistently, increased GM-CSF production by PHA-activated PBMC but not GM-CSF production by anti-CD3/anti-CD28-activated PBMC. The latter was correlated with a loss of CD3+GMCSF+ cells after infection. Neutrophils of elite controllers exhibited a diminished HLADR response to GM-CSF in culture, whereas neutrophils of HIV-1+ subjects having a low viral load on anti-retroviral therapy or subjects with a high viral load exhibited a range of HLA-DR responses. CONCLUSIONS: GM-CSF production within the mucosa or draining lymph nodes may promote HIV-1 infection by facilitating sustained contact between viable neutrophils with bound HIV-1 and CD4 lymphocytes. The minimal effect of GM-CSF on HLA-DR expression by neutrophils of elite controllers provides indirect support for this conclusion. PMID- 20975572 TI - Changes of serum cytokine levels in patients with acute on chronic liver failure treated by plasma exchange. AB - BACKGROUND AND AIM: Acute on chronic liver failure (AoCLF) is associated with a high mortality rate. Plasma exchange (PE) may be useful to bridge patients with AoCLF to liver transplantation or to regenerate their own livers. The aim of this study was to assess the effects of PE on the circulating concentrations of cytokines in patients with AoCLF. METHODS: One hundred forty-nine patients with AoCLF in 2 groups (PE plus routine-care, n=62; and routine-care, n=87) were enrolled in our study. Fifteen healthy donors were used as the control group. Cytokine levels such as interferon-gamma (IFN-gamma), interleukin-10 (IL-10), interleukin-4 (IL-4), interleukin-2 (IL-2), and tumor necrosis factor- alpha (TNF alpha) were detected on admission and on days 7, 14, 21, and 30 during hospitalization. RESULTS: All the detected cytokine values (IFN-gamma, IL-10, IL 4, IL-2, and TNF-alpha) in the patient groups were higher compared with those in the healthy controls (P<0.001). PE was effective to decrease the serum concentration of cytokines: TNF-alpha dropped from (3.46+/-1.23) pg/mL to (1.64+/ 0.66) pg/mL (P<0.01), IL-10 from (6.2+/-2.1) pg/mL to (3.5+/-1.1) pg/mL (P<0.01), IL-2 from (7.5+/-4.7) pg/mL to (4.0+/-2.1) pg/mL (P<0.01), IFN-gamma from (27.5+/ 15.8) pg/mL to (15.5+/-11.8) pg/mL (P<0.01), and IL-4 from (86.7+/-31.3) pg/mL to (44.7+/-26.3) pg/mL (P<0.01). CONCLUSIONS: Cytokines may be important in the pathogenesis of the AoCLF, and PE may represent a reliable hepatic support device for AoCLF. PMID- 20975573 TI - Interleukin 1 beta (IL-1B) and IL-1 antagonist receptor (IL-1RN) gene polymorphisms are associated with the genetic susceptibility and steroid dependence in patients with ulcerative colitis. AB - BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease of unknown etiology. Among cytokines induced in UC, interleukin 1 antagonist (IL-1ra) and interleukin 1 beta (IL-1beta) seems to have a central role because of its immunoregulatory and proinflammatory activities. GOAL: To determine the association between IL-1RA and IL-1B gene polymorphisms and the clinical features of UC in the Mexican Mestizo population. STUDY: Five polymorphisms in the IL-1 gene cluster members IL-1B (rs16944), IL1F10 (rs3811058), and IL-1RN (rs419598, rs315952, and rs315951) were genotyped by 5' exonuclease TaqMan genotyping assays in a group of 200 Mexican patients with UC and 248 ethnically matched unrelated healthy controls. RESULTS: We found a significant increased frequencies of IL 1RN6/1 TC (rs315952) and RN6/2 CC (rs315951) and decreased frequency of IL-1B-511 TC (rs16944) genotypes in UC patients as compared with healthy controls. In the subgroup analysis, we found a significant association between the RN6/2 GG (rs315951) and IL-1B-511 CC (rs16944) genotypes and the presence of steroid dependence in UC patients (pC=00001, OR=15.6 and pC=0.008, OR=4.09, respectively). Patients with UC showed increased frequencies of IL-1RN "CTC" and "TCG" haplotypes when compared with healthy controls (P=0.019, OR=1.43 and P<10( 7), OR=2.63, respectively). Two haplotypes (TTG and CTG) showed decreased frequency in patients when compared with healthy controls (P=9*10(-7), OR=0.11 and P=8*10(-6), OR=0.11, respectively). CONCLUSIONS: IL-1 RN and IL-1B polymorphisms were associated with the genetic susceptibility to develop UC and might be associated with the presence of steroid-dependence in UC patients. PMID- 20975574 TI - Incidence, predictors, and outcomes of gastrointestinal bleeding in patients on dual antiplatelet therapy with aspirin and clopidogrel. AB - OBJECTIVES: The benefits of dual antiplatelet therapy are counterbalanced by the increased incidence of gastrointestinal (GI) complications. The aim of this study was to determine the frequency of GI bleeding, identify the predictors associated with the increased bleeding, and determine the short-term and long-term outcomes. METHODS: This was an observational, case-control cohort study carried out at the Albert Einstein Medical Center. It included all patients who had a drug-eluting stent implanted between May 2003 and April 2007. A total of 1852 patients were identified; of these 50 patients were readmitted for a GI bleed. A control group of 202 patients who did not have any evidence of GI bleeding were compared with the original group. All data were expressed as mean+/-SD. The baseline clinical characteristics between the 2 groups were compared using the t test and the Fisher exact test. Multivariate analysis was used to determine the predictors of GI bleeding. RESULTS: The rate of GI bleeding was 2.7%. The mean age in the group with GI bleeding was 70.9+/-12.2 years, whereas in the group without GI bleeding it was 66.5+/-12.8 years (P<0.05). The majority of the patients presented with melena (40%). Gastritis and gastric ulcers were the most common findings seen in 49% of the patients on endoscopy. On multivariate logistic regression analysis, a history of GI bleeding was the most important independent predictor of future GI bleeding (P<0.001), whereas the use of statins was found to be protective (95% confidence interval, 0.13-0.48; P<0.001) against future GI bleeding. The 30-day mortality rate in the GI bleeding and control groups was 3.7% and 0%, respectively (P<0.01), whereas in the corresponding 1 year the mortality rate was 18.9% and 0%, respectively (P<0.001). CONCLUSIONS: The rate of GI bleeding in patients on dual antiplatelet therapy is low. Earlier history of GI bleeding is the most significant multivariate predictor of future GI bleeding whereas statins seemed to be protective. Patients with GI bleeding have increased short-term and long-term mortality; thereby a history of earlier GI bleeding needs to be assessed carefully before starting dual antiplatelet therapy. This may play a vital role in the selection of therapeutic strategies in these patients. PMID- 20975575 TI - Gastrointestinal paracoccidioidomycosis: an overview. AB - Paracoccidioidomycosis is the most prevalent mycosis in Latin America. Although the lungs are the primary site of infection, physicians often see patients because of disseminated disease. Imported paracoccidioidomycosis has been described in different regions of the world in patients who lived in endemic areas. Gastrointestinal disease owing to P. brasiliensis is rarely recognized in life because of nonspecific clinical manifestations. Gastrointestinal disease can present as part of progressive dissemination of infection or as a result of local complications from a silent healing process. This review will summarize the salient features of gastrointestinal paracoccidioidomycosis. PMID- 20975576 TI - Development of the nephrotic syndrome during treatment of Crohn's disease with adalimumab. AB - We report a patient with Crohn's disease who presented with renal insufficiency and the nephrotic syndrome after initiating therapy with adalimumab. Renal biopsy showed stages 2 to 3 membranous glomerulonephritis, and immunostaining showed glomerular deposition of immunoglobulin G and C3. The patient's serum creatinine decreased after discontinuation of adalimumab, and treatment with prednisone and mycophenolic acid reversed his proteinuria. The pathogenesis of glomerular disease induced by antitumor necrosis factor antibodies is uncertain, and the potential roles of the generation of autoantibodies, development of antiadalimumab antibodies, and the interaction of adalimumab with glomerular tumor necrosis factor are discussed. PMID- 20975577 TI - Electronic and paper diary recording of infant and caregiver behaviors. AB - OBJECTIVES: To assess (1) preference of parental use of an electronic diary (e diary) over a paper diary to record continuous infant and caregiver behaviors over 7 days; (2) whether e-diary recordings would differ in systematic ways from those obtained by paper diaries, and (3) frequency of diary entries when parents provide entries when convenient. METHODS: Mothers of normal newborns were randomized at 5 weeks infant age to a paper diary first (n = 34) or e-diary first (n = 35) group. With 3 days between, mothers completed 7-day recordings on both the paper Baby's Day Diary and an analogous personal digital assistant e-diary for infant (sleep, awake alert, feeding, fussing, crying, inconsolable crying) and caregiver (carrying/holding, moving) behaviors, and completed post diary ease of-use ratings and poststudy preference ratings. RESULTS: Mothers found e-diaries less bothersome but similarly disruptive and enjoyable to paper diaries. At study end, more found e-diaries easier to use, less bothersome and more efficient. E diary behaviors were consistently more frequent, but rarely different in duration, then paper diary behaviors. Time-stamped e-diary entries (1) generally declined across weeks, (2) were higher if e-diaries were used first, and (3) settled at a modal 2 to 3 entries/day by the second week. CONCLUSIONS: For behavioral recording of infant and caregiver behaviors, mothers generally expressed more approval for e-diaries than paper diaries, but neither was considered onerous. E-diaries consistently report more frequent but similar durations of behaviors. If recording when convenient, daily diary entries trend toward 2 to 3 entries a day. The e-diary results provide convergent evidence that paper diary recordings of common infant and caregiver behavior durations provide good estimates of durations, but that behavioral frequencies may be underestimated. PMID- 20975578 TI - Gluten-free sourdough wheat baked goods appear safe for young celiac patients: a pilot study. AB - OBJECTIVES: This study was aimed at showing the safety, for young patients with celiac disease (CD), of sweet baked goods made of wheat flour, which was rendered gluten-free during sourdough fermentation. METHODS AND RESULTS: As shown by R5 antibody-based sandwich and competitive enzyme-linked immunosorbent assay (ELISA), selected lactobacilli and fungal proteases, routinely used in bakeries, degraded gluten to <10 ppm during sourdough fermentation. The resulting flour was mainly a mixture of water-/salt-soluble low-size peptides and free amino acids. Gliadin and glutenin fractions extracted from the pepsin-trypsin (PT) digest of the fermented wheat flour induced the expression of interferon (IFN)-gamma at the level comparable with the negative control. After fermentation, the wheat flour was spray dried and used for making sweet baked goods. Eight patients with CD in remission were enrolled for the clinical challenge, and they daily consumed 200 g of sweet baked goods equivalent to 10 g of native gluten. Hematology, serology (total serum IgA, IgG and IgA antigluten, endomysial and tissue transglutaminase IgA antibodies), and intestinal permeability analyses were carried out over time. One patient interrupted the trial after 15 days and another after 30 days only due to difficulties in the compliance of the daily consumption. All of the other patients showed normal values of hematology, serology, and intestinal permeability during 60 days of challenge. CONCLUSIONS: This study showed that a wheat flour-fermented product, having gluten completely degraded, is not toxic for patients with CD. Nevertheless, these foods should not be recommended for patients with celiac disease until a formal trial has been done. PMID- 20975579 TI - Surgery in children with Crohn disease refractory to medical therapy. AB - OBJECTIVE: The aim of this study was to evaluate the results of surgery in children with Crohn disease (CD) not responding to medical therapy and establish whether surgery improves growth and nutrition. PATIENTS AND METHODS: Children with CD diagnosed between 1998 and 2008 were reviewed. Relapse was defined by Harvey-Bradshaw index >5. Data, reported as median (range), were compared by Fisher exact test and repeated-measures ANOVA. RESULTS: One hundred forty-one children, ages 12.7 years (3.5-16.8), were identified; 27 (19%) required surgery 14.5 months (1.1-61.8) after diagnosis. Twenty-one had elective surgery (19 isolated ileocaecal disease and stricture, 2 diffuse disease of ileum); 6 had emergency surgery (3 peritonitis, 2 haemorrhage, 1 perforation). Surgery included 18 ileocaecal resection and end-to-end anastomosis, 5 stoma formation, 2 left hemicolectomy and end-to-end anastomosis, and 2 stricturoplasty. Follow-up was 2.5 years (1-9.4). Growth and nutrition improved by 6 and 12 months after surgery, with a significant increase in weight z score (P < 0.0001), height z score (P < 0.0001), albumin (30 [13-36] vs 39 [30-46] vs 40 [33-45], P < 0.0001), and haemoglobin [10 (6.8-13.2) vs 11.7 (8.2-13.7) vs 12.0 (9.3-14.7), P < 0.0001]. All patients of the received azathioprine (2-2.5 mg . kg-1 . day-1) after surgery. Fifteen patients (55%) relapsed with a modified Harvey-Bradshaw index of 8 (6-11) within 11.5 months (4.2-33.4). Of these, 5 patients (18%) relapsed within 1 year. Five patients (18%) had further surgery (2 anastomotic strictures, 2 diseased stoma, and 1 enterocutaneous fistula). CONCLUSIONS: Growth and nutrition following surgery for CD improve, but there is a high relapse rate. Despite this, the improved growth and nutrition before relapse may be beneficial during puberty and justify surgery in children not responding to medications. PMID- 20975580 TI - Cow's-milk allergy is a risk factor for the development of FGIDs in children. AB - OBJECTIVES: Functional gastrointestinal disorders (FGIDs) are common in children. Their pathogenesis remains unknown and is most likely multifactorial. We hypothesized that noninfectious causes of inflammation affecting the gastrointestinal (GI) tract early in life, such as cow's-milk allergy (CMA), can predispose to the development of FGIDs later in childhood. PATIENTS AND METHODS: Case-control study. Subjects were patients between 4 and 18 years diagnosed with CMA in the first year of life at Children's Memorial Hospital in Chicago, IL, between January 2000 and June 2009. Diagnosis of CMA was based on history and clinical findings. Siblings 4 to 18 years of age without a history of CMA were selected as controls. Cases completed the parental form of the Pediatric Gastrointestinal Symptoms Rome III version questionnaire to assess for GI symptoms. RESULTS: Fifty-two subjects (mean age 8.1 +/- 4.48 years, 62% girls) and 53 controls (mean age 9.7 +/- 4.20 years, 55% girls) participated in the study. Twenty-three of 52 subjects (44.2%) reported GI symptoms that included abdominal pain, constipation, or diarrhea compared with 11 of 53 controls (20.75%) (odds ratio 3.03, P = 0.01). Abdominal pain was significantly more common in cases (16/52, 30.8%) versus controls (5/53, 9.43%) (odds ratio 4.27 [1.43-12.7]) (chi2 = 7.47, P = 0.01). Abnormal stool habits were more common in cases (15/52, 28.8%) versus controls (7/53, 13.2%), but the difference was not statistically significant. Ten of 52 subjects (19.2%) met the Questionnaire on Pediatric Gastrointestinal Symptoms Rome III version criteria for diagnosis of an FGID (7 irritable bowel syndrome, 2 functional dyspepsia, 1 functional abdominal pain), whereas none in the control group did. CONCLUSIONS: CMA constitutes a risk factor for the development of FGIDs in children. PMID- 20975581 TI - Etiology of esophageal food impactions in children. AB - OBJECTIVE: The aim of the study was to measure clinicopathological features of children presenting to a tertiary care emergency department with esophageal food impaction. MATERIALS AND METHODS: A retrospective chart review of children with esophageal food impaction seen between January 1, 2005 and June 30, 2009, including all patients from age 1 month to 18 years with esophageal food impaction at a pediatric emergency department, was performed. RESULTS: Initial screening of International Classification of Disease, 9th Revision, discharge diagnosis identified 698 children with an esophageal foreign body. Of this group, 72 esophageal food impaction events were identified in 65 children (69% boys), 49 of whom required endoscopic intervention. Endoscopic appearances of the esophageal mucosa were abnormal in 40 (82%), revealing evidence of esophagitis (55%) or stricture (27%). Twenty-four of the subjects had biopsies taken at the time of endoscopy. Inflammation, described as increased eosinophils, basilar hyperplasia, rete peg elongation, and/or microabscess, was present in 76% of mucosal samples. Follow-up endoscopy in 12 children identified an etiology in 9, five of whom were found to have eosinophilic esophagitis. CONCLUSIONS: The majority of children with esophageal food impaction who underwent endoscopic evaluation and biopsy have an underlying potentially treatable cause. We therefore recommend that all of the children with esophageal food impaction have mucosal biopsies at the time of endoscopic disimpaction with appropriate follow up to allow for diagnosis and management of the underlying etiology. PMID- 20975582 TI - Physician attitudes and practices of enteral nutrition as primary treatment of paediatric Crohn disease in North America. AB - BACKGROUND: The use of exclusive enteral nutrition (EEN) in children with Crohn disease has not been universally adopted by North American paediatric gastroenterologists. This is in stark contrast to their European counterparts. The present study aimed to define attitudes and practice patterns of EEN use by members of the North American Society for Paediatric Gastroenterology, Hepatology, and Nutrition. METHODS: Members were contacted by e-mail and provided with access to a Web-based survey. RESULTS: Surveys were completed by 326 of 1162 (30.7%) eligible North American Society for Paediatric Gastroenterology, Hepatology, and Nutrition members from North America (86% United States, 14% Canada). Thirty-one percent of respondents reported never using EEN, 55% reported sparse use, and 12% reported regular use. Physicians in Canada reported significantly more use than those in United States (P < 0.001). Currently working and previously working in a centre where EEN was used were highly correlated with both the perceived appropriateness of EEN and the regularity of its use (P < 0.01). More American physicians than Canadian physicians reported that concurrent medical therapy was necessary to induce remission (P < 0.001). Canadian respondents were more likely to use maintenance therapy than American respondents (P = 0.02). Compliance issues were seen as the main disadvantages of EEN and as the major barrier to increased use by nonregular users. CONCLUSIONS: There are significant variations in the patterns of use and the acceptance of EEN between Canada and the United States, with Canadian physicians showing a greater use of EEN. The use of EEN appears influenced by the extent to which physicians are exposed to its use both in their training and in their current practice setting. PMID- 20975583 TI - Prospective evaluation of dietary treatment in childhood constipation: high dietary fiber and wheat bran intake are associated with constipation amelioration. AB - OBJECTIVES: The aim of the study was to evaluate, over 24 months, the intake of dietary fiber (DF) and the bowel habit (BH) of constipated children advised a DF rich diet containing wheat bran. PATIENTS AND METHODS: BH and dietary data of 28 children with functional constipation defined by the "Boston criteria" were obtained at visit 1 (V1, n = 28) and at 4 follow-up visits (V2-V5, n = 80). At each visit the BH was rated BAD (worse/unaltered; improved but still complications) or RECOVERY (REC) (improved, no complications; asymptomatic), and a food intake questionnaire was applied. DF intake was calculated according to age (year) + 5 to 10 g/day and bran intake according to international tables. Nonparametric statistics were used. RESULTS: Median age (range) was 7.25 years (0.25-15.6 years); 21 children underwent bowel washout (most before V1/V2), and 14 had the last visit at V3/V4. DF intake, bran intake, and the BH rate significantly increased at V2 and remained higher than at V1 through V2 to V5. At V1, median DF intake was 29.9% below the minimum recommended and at the last visit 49.9% above it. Twenty-four children accepted bran at 60 visits, at which median bran intake was 20 g/day and median proportion of DF due to bran 26.9%. Children had significantly higher DF and higher bran intake at V2 to V5 at which they had REC than at those at which they presented BAD BH. DF intake > age +10 g/day was associated with bran acceptance and REC. At the last visit 21 children presented REC (75%); 20 of them were asymptomatic and 18 were off washout/laxatives. CONCLUSIONS: High DF and bran intake are feasible in constipated children and contribute to amelioration of constipation. PMID- 20975584 TI - A welcome surprise: nodular fasciitis presenting as soft tissue sarcoma. AB - A 15-year-old boy presented with a growing mass on the anterior chest wall. History, clinical examination, and preoperative imaging studies were consistent with soft tissue sarcoma. He underwent open biopsy, and the intraoperative pathology diagnosis of nodular fasciitis resulted in performance of a lesional excision, rather than a potentially morbid wide resection. Nodular fasciitis is a rare but important soft tissue lesion, which can be easily confused with sarcoma. The possibility of benign etiologies for soft tissue masses should be considered when planning surgical options, even when preoperative imaging studies suggest more aggressive lesions. PMID- 20975585 TI - Value of routine bone scans in patients with bone sarcomas before local treatment. AB - During modern treatment of children with bone sarcomas, the children undergo multiple diagnostic imaging procedures, including bone scan (BS) with Tc99m. The aim of the BS is to establish the metastatic status of the skeletal system at the time of initial diagnosis and thereafter. We retrospectively reviewed 85 medical charts of patients with osteosarcoma (n = 40) and Ewing sarcoma (n = 45) who had been treated in our department between 01.01.1995 and 01.11.2009. Every patient underwent routine imaging studies including BS at the time of initial diagnosis and before local treatment. Median age of all patients was 15.5 years (range, 8 to 29). Fifteen patients had metastases at diagnosis. All patients were treated with neoadjuvant chemotherapy. No patient with localized disease developed metastatic disease to the skeletal system before local treatment; those with localized disease who developed metastases did so some time after completion of the treatment plan. As the probability of developing bone metastatic disease while receiving therapy is very low, routine BS in asymptomatic patients before local treatment may safely be omitted. PMID- 20975586 TI - Allogeneic hematopoietic stem cell transplantation against recurrent rhabdomyosarcoma. AB - The prognosis of high-risk rhabdomyosarcoma (RMS) with metastatic or recurrent disease remains poor. We report a 6-year-old girl who successfully underwent allogeneic hematopoietic stem cell transplantation against recurrent metastatic alveolar RMS. The disease recurred at distant lymph node metastasis with bone marrow involvement. After chemotherapy and radiotherapy for the metastatic site, she underwent allogeneic bone marrow transplantation during complete remission from her 5/8 HLA-matched father. She developed acute graft-versus-host disease after preemptive donor lymphocyte infusion and remains in a disease-free condition for 31 months after transplantation. A graft-versus-tumor effect through allogeneic immune cells might produce a beneficial effect for high-risk RMS. PMID- 20975587 TI - A unique clinical presentation of X-linked lymphoproliferative syndrome with a novel mutation in SH2D1A and review of the literature. AB - X-linked lymphoproliferative syndrome is a well-described syndrome often characterized by progression to fatal infectious mononucleosis. Many mutations of the SH2D1A gene have been identified in patients with X-linked lymphoproliferative syndrome. These mutations are often associated with either decreased or impaired function of the protein product, signaling lymphocytic activation molecule-associated protein. We describe a patient with a novel missense mutation in SH2D1A. We report on his unique presentation, clinical course and subsequent successful treatment with a matched unrelated donor bone marrow transplant. PMID- 20975588 TI - Tibial lengthening using a humeral intramedullary nail combined with a single plane external fixator for leg discrepancy in sequelae of poliomyelitis. AB - The sequelae of poliomyelitis are the common causes of leg discrepancy. Tibial lengthening is an effective way to solve this problem but it is associated with a high rate of complications. In this study, we combined the use of humeral nail and external fixator in tibial lengthening with the purpose of reducing lengthening complications. Compared with the cases lengthened by a single-plane external fixator alone, this combined strategy was found to be beneficial in maintaining the tibial alignment. Therefore, it can be recommended as a good technique for tibial lengthening in patients with sequelae of poliomyelitis. PMID- 20975589 TI - The promethean role of industry in spine surgery research. PMID- 20975590 TI - Results of lumbar total disc arthroplasty in military personnel. AB - STUDY DESIGN: Evaluation of lumbar total disc arthroplasty (TDA) in military patients. OBJECTIVE: To evaluate the clinical and radiographic outcomes of US military personnel who have undergone TDA for degenerative disc disease and to assess the retention versus discharge rate after undergoing this procedure. SUMMARY OF BACKGROUND DATA: TDA was developed as an alternative to arthrodesis for the surgical management of degenerative disc disease with the goal of preserving motion and reducing adjacent segment disease. However, the indications and optimal candidates for this procedure are uncertain. Military members must maintain a certain level of physical fitness and be capable of meeting the demands of hazardous environments. This study reviews results of TDA performed on active duty military members. METHODS: The surgery schedules from 2005 to 2008 were reviewed to identify military members who underwent single-level or 2-level TDA for degenerative disc disease after failing at least 6 months of conservative management. All patients had a minimum of 2-year follow-up. Preoperative and postoperative clinical assessments were completed using the Oswestry Disability Index (ODI) questionnaire and the numeric rating scale (NRS). Radiographs were evaluated to determine range of motion, height, and disc position at the operated levels. The retention rate of the patients in the military was also recorded. Statistical analysis of the data was carried out with significance assumed at the P < 0.05 level. RESULTS: Thirty-eight patients, implanted with a total of 56 discs, met the criteria for retrospective analysis. Twenty patients had single level and 18 had 2-level TDA. Mean age was 35 (23 to 56 y) years. Mean follow-up was 28 months. The overall mean preoperative ODI and NRS of 53.6 and 7.3, significantly improved postoperatively to 27.7 and 3.3, respectively (P < 0.001). There was no difference in the postoperative ODI (P = 0.19) or NRS (P = 0.18) when comparing single-level and 2-level TDA. Clinical success was achieved in 79% of patients. Mean range of motion was 6.5 degrees and the mean disc height increased by 69%. Sixty-eight percent of patients returned to full active duty. CONCLUSIONS: This study showed clinical success approaching 80% in military patients who underwent lumbar TDA. Furthermore, close to 70% were able to return to their positions within the military. TDA, while more closely reapproximating the normal biomechanics of the spine, may provide patients with an improved alternative to spinal arthrodesis for degenerative disc disease. PMID- 20975591 TI - Surgical correction of paralytic neuromuscular scoliosis with poor pulmonary functions. AB - STUDY DESIGN: A retrospective study. OBJECTIVES: To evaluate clinical and functional success by all pedicle screw construct in paralytic neuromuscular scoliosis (NMS) with poor pulmonary functions (PFT). SUMMARY OF BACKGROUND: Duchene muscular dystrophy and spinal muscular atrophy are often associated with poor PFT and the development of scoliosis simultaneously. Poor PFT often make surgeons reluctant to operate. METHODS: Eighteen paralytic NMS patients who had preoperative forced vital capacity (FVC) < 30% were operated with all pedicle screw construct. Average preoperative, postoperative, and final follow-up Cobb angle, pelvic obliquity, thoracic kyphosis and lumbar lordosis, PFT (FVC% and forced expiratory volume 1%), and preoperative and follow-up functional status were analyzed. Perioperative and postoperative complications were also noted. RESULTS: The average follow-up was 31.6 +/- 7.7 months. There was significant improvement in Cobb angle (61.7%) and pelvic obliquity (56.7%), postoperatively (P < 0.001). All corrections were maintained at final follow-up. FVC was decreased from 25.2 +/- 4.7% preoperatively to 24.2 +/- 5.0%, 6 weeks postoperatively (P = 0.067); and on follow-up it further decreased to 20.6 +/- 3.9% (P < 0.0001) (1.8%/y). Forced Expiratory Volume 1 also decreased from 22.7 +/- 4.5% preoperatively to 21.8 +/- 4.2% postoperatively (P = 0.037) and was 19.8 +/- 3.8% at final follow-up (P < 0.0001) (1.1%/y). However, none of the patients had any respiratory complications postoperatively. Functional status was improved in 6 patients and they were able to sit without support (P = 0.027). Eight (44.4%) perioperative complications (5 pulmonary, 1 intraoperative death, and 2 others) were noticed. Postoperatively, 4 patients (23.5%) had complications; coccygodynia, back sore because of screw prominence, impingement of iliac screw, and loosening of the rod from L5 screw. All the patients were satisfied with the treatment. There were no major pulmonary complications requiring admission postoperatively. CONCLUSIONS: Although complications are associated with the treatment of paralytic NMS, a good clinical and function outcome suggests that poor PFT should not be considered as a contraindication of scoliosis surgery. PMID- 20975592 TI - Bilateral operation of lumbar degenerative central spinal stenosis in full endoscopic interlaminar technique with unilateral approach: prospective 2-year results of 74 patients. AB - STUDY DESIGN: Prospective study of the patients with degenerative spinal central stenosis, operated bilateral in a full-endoscopic unilateral technique. OBJECTIVE: The objective of this prospective study was to examine the technical possibilities of full-endoscopic interlaminar bilateral technique with unilateral approach in degenerative lumbar central spinal stenosis and predominant leg symptoms using new designed endoscopes and instruments. SUMMARY OF BACKGROUND DATA: Extensive decompression with laminectomy where appropriate, is often still described as the method of choice in the operation of degenerative lumbar spinal stenosis. Nonetheless, tissue-sparing procedures are becoming more common. Endoscopic techniques have become the standard in many areas because of the advantages they offer in surgical technique and in rehabilitation. At the spine, 1 essential point was the developing of the instruments for sufficient bone resection under continuous visual control. This enabled the use in the operation of spinal canal stenoses. METHODS: A total of 72 patients with lumbar central spinal stenosis full-endoscopic unilateral decompression were followed for 2 years. In addition to general and specific parameters, these measuring instruments were used: VAS, German version North American Spine Society Instrument, Oswestry Low-back Pain Disability Questionnaire. RESULTS: The results show that 70.8% no longer have leg pain or it was nearly completely reduced and 22.2% have occasional pain. The decompression results were equal to those of conventional procedures. The complication rate was low. The full-endoscopic techniques brought advantages in these areas: operation, complications, traumatization, and rehabilitation. CONCLUSIONS: The recorded results show that the full-endoscopic interlaminar bilateral decompression with unilateral approach is a sufficient and safe supplement and alternative to conventional procedures when the indication criteria are fulfilled. At the same time, it offers the advantages of a minimally invasive intervention. PMID- 20975593 TI - Posterior-only approach with selective segmental TLIF for degenerative lumbar scoliosis. AB - STUDY DESIGN: Forty-six patients with degenerative lumbar scoliosis, and treated with selective segmental transforaminal lumbar interbody fusion (TLIF), were studied retrospectively. OBJECTIVES: To investigate the surgery outcomes of the posterior-only approach with selective segmental TLIF for the treatment of degenerative lumbar scoliosis. SUMMARY OF BACKGROUND DATA: Degenerative lumbar scoliosis usually occurs late in the life of patients with no history of scoliosis. TLIF has been successfully used in the surgical treatment of other degenerative diseases of the lumbar spine. METHODS: Forty-six patients with degenerative lumbar scoliosis and treated with selective segmental TLIF were studied retrospectively. There were 14 male and 32 female patients, with a mean age of 66.4 years. The indications for TLIF of the motion segment included segmental kyphosis in the lumbar spine, significant vertebral translation in any orientation, segmental instability, and significant upper endplate obliquities of L3 or L4. All the patients were followed for a mean duration of 42 months postoperatively. Radiographic evaluation included Cobb angle of scoliosis, lumbar lordosis angle, and segmental lordosis angle. The clinical outcomes were assessed by means of Japanese Orthopedic Association score and patient satisfaction index. RESULTS: The mean preoperative Cobb angle of 31.7 +/- 14.4 degrees was corrected to 10.2 +/- 6.5 degrees at the final follow-up (t = 15.262, P < 0.001), and the correction rate was 67.8%. The mean preoperative lumbar lordosis angle of -27.5 +/- 12.6 degrees was corrected to -39.3 +/- 9.7 degrees (t = 12.165, P < 0.001), and the correction rate was 44.4%. The mean preoperative segmental lordosis angle of -6.5 +/- 5.1 degrees in the TLIF segment was increased to -11.6 +/- 5.9 degrees, and the correction rate was 80%. Besides, the segmental deformity and vertebral translation were also corrected. The mean preoperative Japanese Orthopedic Association score of 14.1 +/- 4.2 was increased to 22.2 +/- 4.8 (t = 11.453, P < 0.001), and 81% of patients would undergo this surgery again with the same results. CONCLUSIONS: Selective segmental TLIF is helpful in correcting lumbar lordosis, segmental deformity, and translation, and thus obtaining satisfactory outcome in the treatment of degenerative lumbar scoliosis. PMID- 20975594 TI - Long-term durability of minimal invasive posterior transforaminal lumbar interbody fusion: a clinical and radiographic follow-up. AB - BACKGROUND CONTEXT: Both open and minimally invasive lumbar fusion surgeries (MIS) are used to treat patients with symptomatic degenerative spinal pathologies. Open lumbar fusion surgery studies have reported excellent short term safety and long-term clinical outcomes. MIS has shown excellent safety and short-term clinical success, but there is very little information on its long term clinical durability. PURPOSE: The purpose of this study was to document the long-term clinical durability and safety of patients treated with minimally invasive surgery--transforaminal lumbar interbody fusion (MIS TLIF). Secondary purposes were to evaluate the clinical outcomes of patients receiving fusion in 2 sequential lumbar disc segments (2-level) as compared with a single-level lumbar disc segment (1-level), and as an aside, to determine whether or not there were any differences in clinical outcomes in patients treated over the age of 60 years as compared with those under 60 years. STUDY DESIGN: This study was a retrospective review of prospective collected outcomes data. PATIENT SAMPLE: One hundred sixty-nine consecutive patients, with either isolated single-level or 2 level lumbar intervertebral segment pain manifested by back pain alone or back pain with leg pain associated with a primary diagnosis of degenerative spondylolisthesis, central herniated disc, central stenosis, Foraminal-lateral herniation of disc, Foraminal/lateral stenosis, or isolated degenerative disc or joint disease. OUTCOMES MEASURES: Hospital stay time postoperative, return to work time, Oswestry Disability Index (ODI), visual analog pain scores (VAS), pain medicine (narcotic) use, fusion status, and reoperation rate. METHODS: Patients treated with 1or 2-level MIS TLIF were evaluated based on clinical outcomes, reoperation rates, and fusion status out to an average of 49 months postoperative (range, 36 to 60 mo). Effect of the number of levels fused, patient age, and worker compensation status on outcome was also assessed. RESULTS: Average surgery time was 183 minutes, with no difference between older and younger patients. Hospital stay averaged 15 hours with a median return to work time of 8 weeks. Return to work for patients working before surgery was 97%. ODI improved 36% at the first follow-up and was improved 41% at 49 months postoperative (P < 0.001). Eighty-six percent of patients reached a 20% clinical improvement in ODI at the last follow-up. Every primary diagnostic group increased significantly over time (P < 0.001). VAS pain scores improved in a similar pattern as ODI (P < 0.001). Patients with 2-level fusions improved comparably in both ODI and VAS scores as 1 level fusion patients. Worker compensation patients improved in both ODI and pain scores, although a little less than nonworkers compensation patients. Neither smoking, nor obesity status impacted clinical outcomes. Narcotic use for spine related pain went from 100% to 31% 6 months postoperative. Fusion rates were 96% at the 1-year follow-up. When reviewing surgical revisions as a consequence of surgical technique, and omitting unanticipated adverse events, 99% of patients maintained a successful fusion at their last average follow-up. CONCLUSIONS: The results of this study support the long-term clinical effectiveness of MIS TLIF for varying diagnoses. These results suggest that those undergoing a 1-level or 2 level lumbar fusion improve equally, and that older patients do well with MIS surgery long term. Reoperation rates were acceptable, with excellent surgical durability at 49 months. The benefit of decompression was not assessed in this study, and future studies should assess its impact long term. PMID- 20975595 TI - Expandable pedicle screw trajectory in cadaveric lumbar vertebra: an evaluation using microcomputed tomography. AB - STUDY DESIGN: An in-vitro cadaver-based measurement using microcomputed tomography. OBJECTIVES: To evaluate the safety of removal of expandable pedicle screws (EPSs) in human vertebral bodies after a long (6 mo) insertion time. SUMMARY OF BACKGROUND DATA: Transpedicular fixation is commonly used for posterior fixation of the spine. Osteoporotic patients are in high risk of internal fixation failure. EPS is an available device for increasing transpedical fixation in the osteoporotic spine. However, it is unclear that how much the diameter of the expanding screw tip increases in the human vertebral body, and no reports have assessed the potential for fracture of the pedicle when the EPS is removed. Therefore, the safety of removal of EPS needs to be evaluated. METHODS: In this study, 6.50 mm EPSs were inserted into cadaveric lumbar vertebrae. The maximum diameters of expansion, the maximum diameters of the EPS trajectories, and the diameters of the EPS trajectories in the pedicles were measured using microcomputed tomography imaging and 3-dimensional reconstruction. Regions of interest of the same size adjacent to the EPS in the pedicle and in the vertebral body were reconstructed and analyzed using the same thresholds (1000). Bone volume divided by total volume (BV/TV) in these regions of interest was determined. RESULTS: The maximum diameter of expansion of the EPSs in the vertebral body was 7.63 mm, a 17.38% increase from the original diameter. The maximum diameter of the EPS trajectory and the diameter of the EPS trajectory in the pedicle were 7.56 mm and 7.09 mm, respectively, increases of 16.31% and 9.08%. The differences were statistically significant (P < 0.05). In the pedicle, there was a negative correlation between the diameter of the EPS trajectory and the BV/TV along the EPS trajectory (r = -0.88; P = 0.002). In the vertebral body, a negative correlation occurred between the maximum expansion diameter of the EPS and vertebral BV/TV (r = -0.85; P = 0.004). CONCLUSIONS: The EPS could be reliably removed after expansion without fracturing the pedicle. Furthermore, the BV/TV had an important influence on the degree of expansion of EPS and whether or not pedicle fracture occurs. PMID- 20975596 TI - Total vertebrectomy and spine shortening in the management of acute thoracic spine fracture dislocation: technical note and report of 3 cases. AB - STUDY DESIGN: Case report of 3 thoracic spine fracture-dislocations with complete spinal cord section treated by total vertebrectomy--spine shortening through a posterior approach. OBJECTIVES: To assess the usefulness and safety of this surgical technique in the treatment of acute thoracic spine fracture-dislocation. SUMMARY OF BACKGROUND: Total vertebrectomy can be used in different nontraumatic disorders. This surgical procedure has been used in the chronic phase of traumatic thoracolumbar dislocation. To our knowledge, the technique of total vertebrectomy and spine shortening in the acute phase of thoracic spine fracture dislocation has never been reported. MATERIAL AND METHODS: Three patients who suffered thoracic spine fracture-dislocation with ASIA A paraplegia underwent complete vertebrectomy and spine shortening through a posterior approach. We report technical details, clinical, and radiologic results at 24 months minimum follow-up. RESULTS: Complete vertebrectomy of the fractured vertebra involved T5 in 1 patient, T7 in another, and T10 in the third. There were no perioperative complications. At latest follow-up, fusion was obtained in all 3. Overall sagittal and coronal alignment was restored. CONCLUSIONS: Complete vertebrectomy and spinal shortening can be used in the acute phase to manage thoracic spine fracture-dislocations. PMID- 20975597 TI - Microsurgical posterolateral transmuscular approach for lumbar foraminal stenosis. AB - STUDY DESIGN: Retrospective review of 39 consecutive patients who underwent surgery for lumbar foraminal stenosis from 2004 to 2009. OBJECTIVE: To evaluate the surgical technique and results of microsurgical posterolateral transmuscular approach for lumbar foraminal stenosis. In addition, to evaluate the diagnostic ability of coronal thin-sliced magnetic resonance imaging (MRI) for this disease. SUMMARY OF BACKGROUND DATA: Lumbar foraminal stenosis is a disease caused by compression of the nerve root or dorsal root ganglion at the intervertebral foramen often causing severe sciatic pain. Although its diagnosis and surgical treatment has been described in the literature, posterolateral transmuscular approach has not been well described. In addition, definitive radiologic diagnosis of this disease is often difficult, which can lead to failed back syndrome. METHODS: We retrospectively reviewed 39 consecutive patients who underwent surgery for lumbar foraminal stenosis from 2004 to 2009. Special thin sliced coronal MRI was used for preoperative evaluation. Microsurgical posterolateral transmuscular approach was used to decompress the intervertebral foramen from the lateral side preserving most of the pars interarticularis and facet joint. Contralateral medial approach was used for cases with associated central canal stenosis. Surgical results were scored using MacNab scale. We compared the sensitivity and specificity of 2 MRI signs: (1) abnormal course of the nerve root inside the foramen on coronal slices, and (2) obliteration of the foramen on sagittal slices, and statistically analyzed them with the chi method. RESULTS: The MacNab score with the mean follow-up period of 25.5 months was excellent in 28 (72%), good in 5 (13%), fair in 3 (8%), and poor in 3 (8%) patients. There was no grave complication. Coronal MRI sign showed significantly better sensitivity and specificity. CONCLUSIONS: Posterolateral transmuscular approach with microsurgical foraminotomy provided excellent surgical results. Coronal thin-sliced MRI can be useful for diagnosis of this disease. PMID- 20975598 TI - Analysis of measured D-dimer levels for detection of deep venous thrombosis and pulmonary embolism after spinal surgery. AB - STUDY DESIGN: A retrospective clinical study. OBJECTIVES: To show the prevalence of deep venous thrombosis (DVT) and pulmonary embolism (PE) after spinal surgery using a D-dimer assay followed by screening with computed tomographic (CT) pulmonary angiography and CT venography. SUMMARY OF BACKGROUND DATA: A few studies on DVT development after spinal surgery have been reported. METHODS: A complete surveillance examination for DVT and PE was conducted in 88 patients who underwent spinal surgery [male patients, 48; female patients, 40; average age at operation, 62.4 y (range, 17 to 85 y)] through a D-dimer assay combined with CT pulmonary angiography and CT venography. The operation levels were the cervical spine (21 cases), the thoracic spine (16 cases), and the lumbar spine (51 cases). We adopted a D-dimer cut-off point of 10 MUg/mL, and classified the patients into high D-dimer (HD; D-dimer level >=10 MUg/mL) and low D-dimer (LD; D-dimer level <10 MUg/mL) groups. RESULTS: Nine (10.2%) patients showed D-dimer levels of >=10 MUg/mL (HD group); of these, 5 patients (5.7%) had DVT. Two (2.2%) of the 5 DVT patients had PE. DVT was evident in 1 (6.2%) of the 16 patients who underwent thoracic procedures and 4 (7.8%) of the 51 patients who underwent lumbar procedures. Statistical comparison between the HD (excluding 5 patients with DVT or PE) and LD groups showed a significant difference in intraoperative blood loss between the groups (P=0.02). CONCLUSIONS: The D-dimer assay was useful in predicting DVT development. A D-dimer level of >=10 MUg/mL is considered to be a risk factor for thromboembolic disease after spinal surgery. False-positive cases of thromboembolic disease preclude the use of this assay as a stand-alone test for DVT diagnosis. CT venography and CT pulmonary angiography are recommended to confirm thromboembolic disease. PMID- 20975599 TI - Does preoperative DVT chemoprophylaxis in spinal surgery affect the incidence of thromboembolic complications and spinal epidural hematomas? AB - BACKGROUND: Deep venous thrombosis (DVT) and pulmonary embolus (PE) remain common surgical complications, often affecting patients without any prior warning. Postoperative spinal epidural hematomas (SEH) may have a devastating impact on a patient's recovery from a routine procedure. The effect of preoperative DVT prophylaxis administration on elective spinal patients has not previously been studied. STUDY DESIGN: Retrospective cohort analysis. OBJECTIVE: To correlate the incidence of preoperative DVT prophylaxis administration and the rate of postoperative DVT, PE, and SEH after elective spinal surgery. SUMMARY OF BACKGROUND DATA: Earlier studies have shown a postoperative DVT rate in elective spinal patients of between 0.3% and 31%, a PE rate of 0.2% to 0.9%, and a SEH rate of approximately 0.1%. METHODS: About 3870 patient notes, from 2004 to 2008 elective spinal procedures, were reviewed. DVT, PE, and SEH rates were compared between those patients receiving and not receiving preoperative DVT prophylaxis. RESULTS: The 36.9% of patients received preoperative DVT prophylaxis, and 19 patients suffered and DVT and/or PE. Nine of these had received preoperative prophylaxis, giving an odds ratio of 0.91. Sixteen patients suffered a SEH, and this gave an odds ratio of 1.33. The SEH's presented with a median postoperative time of 4 days. CONCLUSIONS: Preoperative DVT prophylaxis does not influence the rate of postoperative DVT or PE among elective spinal patients. It probably does not influence SEH rate, and it is noted that SEH may present quite late, in contrast to currently accepted time courses. PMID- 20975600 TI - Is it safe to back out pedicle screws after augmentation with polymethyl methacrylate or calcium phosphate cement? A biomechanical study. AB - STUDY DESIGN: Biomechanical cadaveric study. OBJECTIVE: To determine the torque required to remove pedicle screws augmented with polymethyl methacrylate (PMMA) or calcium phosphate cement (CPC); thus, proving the safety of back out of augmented screws in the osteopotoric model, which would be a more dangerous setting than the nonosteoporotic model. SUMMARY OF BACKGROUND DATA: To our knowledge, no earlier study has characterized the safety of backing out pedicle screw augmented with PMMA or CPC. METHODS: Pedicle screws were inserted in 24 osteoporotic vertebrae (48 pedicles). The maximal insertion torque and pullout strength of each screw were recorded. After pullout of the pedicle screws, the vertebrae were then randomized into 2 groups of 12 (24 pedicles) each. PMMA was injected into the pedicles in the first group and CPC was injected into the second group after which the pedicle screws were inserted. The pedicle screws were inserted into the pedicle holes augmented with PMMA or CPC, respectively. Finally, all augmented screws were backed out and the maximal removal torque was recorded using a digital torque wrench. RESULTS: Throughout the study, no incidence of pedicle or lamina fractures was observed. The average insertion torque was 0.5+/-0.27 and 0.45+/-0.29 N.m for groups 1 and 2, respectively (P=0.724). The average pullout strength was 723.1+/-391.7 and 671.2+/-383.0 N (P=0.950). After cement augmentation, the average removal torque was 0.77+/-0.31 and 0.81+/-0.26 N.m for PMMA and CPC, respectively (P=0.494). CONCLUSIONS: The results of this study showed that pedicle screws can be easily and safely backed out after augmentation with PMMA or CPC. The result of CPC, however, may only be valid before any bony ingrowth. PMID- 20975601 TI - Transpedicular drainage of presacral abscess and posterior decompression of acute cauda equina syndrome in caries spine: a case series of 3 patients. AB - STUDY DESIGN: We describe 3 patients with lumbosacral tuberculosis with epidural and presacral abscess who presented to us with acute cauda equina syndrome. A novel technique of draining the abscess and its results are described. OBJECTIVE: To describe a novel technique of draining the presacral abscess and to evaluate the results in the patients treated with this technique. SUMMARY OF BACKGROUND DATA: Osteoarticular tuberculosis, especially spinal tuberculosis, is a major health problem in developing regions of world. The presacral region is one of the uncommon yet difficult regions for the drainage of abscess. Acute cauda equina syndrome because of lumbosacral tuberculosis is a rare entity. We describe a series of 3 such cases of tubercular etiology who presented to us with cauda equina syndrome. RESULTS: All of them had complete neurologic recovery within 3 weeks of performing transpedicular drainage of presacral abscess and cauda equina nerve root decompression by laminotomy. All the patients were asymptomatic with normal blood parameters and healed radiologic status at 2 years follow-up. CONCLUSIONS: The transpedicular approach to the presacral region is a safer option compared with other approaches to reach this region. It simultaneously allows decompression of cauda equina nerve roots by laminotomy without changing the position of the patient in the theater. The key to success with this approach is early diagnosis and early treatment. PMID- 20975602 TI - Influence of performance level on anaerobic power and body composition in elite male judoists. AB - This study examined the relationship between 30-second anaerobic power and body composition by performance level in elite Judoists. During a 3-month period, 10 male Korean Judo national team athletes (NT), 26 male university varsity team athletes (VT), and 28 male junior varsity team athletes (JT) were assessed for 30 second anaerobic power and body composition at the Youngin University. Anaerobic power was measured using a 30-second Wingate test. Body composition was assessed via bioelectric impedance analysis in standardized conditions using BioSpace (Korean)-specific prediction formulas. All testing occurred at the beginning of the winter nonseason period but excluded a brief weight-loss period before the competition phase. Anaerobic power measures were significantly greater (p < 0.05) in NT and VT than in JT. Fat-free mass (FFM), muscle mass (MM), and total body water in JT were also greater than in VT and JT (p < 0.05). Muscle mass in VT was significantly lower than in NT (p < 0.05). Fat-free mass in NT was strongly correlated to mean and peak anaerobic power (r = 0.77, p = 0.009; r = 0.87, p < 0.001, respectively). Varsity team athletes also indicated a moderate association between FFM and peak and mean anaerobic power (r = 0.63, p < 0.001; r = 0.48, p = 0.013, respectively). However, relationship between FFM and anaerobic power was not statistically significantly correlated in JT (r = 0.14, p = 0.470; r = 0.23, p = 0.232, separately). In conclusion, our data indicated that anaerobic power is closely correlated with increase in FFM and MM and was different dependent among performance levels. Further research in the field is warranted to elucidate the Judo-specific relationship between FFM and performance. PMID- 20975603 TI - Association of epidermal growth factor receptor activating mutations with low ERCC1 gene expression in non-small cell lung cancer. AB - INTRODUCTION: Patients with non-small cell lung cancer (NSCLC) with cancers harboring activating mutations in the epidermal growth factor receptor (EGFR) show improved efficacy from EGFR tyrosine kinase inhibitors. Some clinical studies also suggest enhanced efficacy of platinum-based chemotherapy in patients with EGFR-mutant cancers. We investigated the relationship of EGFR mutation status and DNA repair capacity, as exemplified by excision repair cross complementing 1 (ERCC1) gene expression, as a potential explanation for this observation. METHODS: Microdissected formalin-fixed paraffin-embedded tumors from 1207 patients with NSCLC were analyzed by real-time polymerase chain reaction for mRNA expression levels of ERCC1 and for EGFR mutation status by an allele specific polymerase chain reaction assay. RESULTS: NSCLC subtype was adenocarcinoma (AC) in 712 patients, squamous in 175, and not otherwise specified or other in 320. EGFR activating mutations were detected in 183/1207 patients (15.2%). Median ERCC1 expression overall was 1.82 (range, 0.22-27.31) and was histology related: AC, median = 1.68 (0.22-11.33) and squamous, median = 2.42 (0.51-14.28) (p < 0.001). Using a previously defined reference level of <1.7, ERCC1 expression was categorized as low in 556 of 1207 patients (46.1%). The presence of EGFR mutations was highly associated with ERCC1 expression (p < 0.001). This association was retained when adjusting for AC histologic subtype (p = 0.001). CONCLUSIONS: NSCLC specimens harboring EGFR activating mutations are more likely to express low ERCC1 mRNA levels. Whether these findings translate into enhanced clinical efficacy of EGFR-mutant cancers to platinum-based chemotherapy remains to be determined. PMID- 20975604 TI - Phase II study of preoperative pemetrexed, carboplatin, and radiation followed by surgery for locally advanced esophageal cancer and gastroesophageal junction tumors. AB - INTRODUCTION: Based on favorable preliminary clinical data and the need to identify effective, well-tolerated neoadjuvant regimens for patients with locally advanced esophageal cancer, this clinical trial was undertaken. METHODS: This phase II study tested 500 mg/m neoadjuvant pemetrexed intravenously and carboplatin with an area under the curve of 6 intravenously on days 1 and 22 in conjunction with concomitant radiation of 5040 centigray, which was given in 28 daily fractions of 180 centigray. The primary endpoint was the rate of pathologic complete response. RESULTS: This trial closed early because, during an interim analysis, the primary endpoint fell short. However, 26 eligible patients were accrued. Twenty (74%) were men. Performance scores of 0, 1, and 2 were seen in 16 (59%), 9 (33%), and 2 (7%), respectively. Among eligible patients, 6 of 26 (23%; 95% confidence interval 9-44%) demonstrated a pathologic complete response. Twenty-two underwent a complete cancer resection. The median survival was 17.8 months (95% confidence interval: 12.2-30.7 months). In the neoadjuvant setting, 22 patients had at least one grade 3 or worse adverse event, and 8 patients had at least one grade 4 event. Postoperatively (within 30 days of surgery), there were three deaths, one grade 4 event (thrombosis), and three grade 3 events. CONCLUSIONS: The neoadjuvant regimen tested within this phase II trial demonstrated antineoplastic activity but fell short of yielding a complete pathologic response rate that merits further testing. PMID- 20975605 TI - Combination therapy using imatinib and vatalanib improves the therapeutic efficiency of paclitaxel towards a mouse melanoma tumor. AB - Melanomas respond poorly to chemotherapy. In this study, we investigated the sensitization of B16 mouse melanoma tumors to paclitaxel by a combination of two tyrosine kinase inhibitors: vatalanib, targeting vascular endothelial growth factor receptors, and imatinib, an inhibitor targeting for example, Abl/BCR-ABL, the platelet-derived growth factor receptor, and stem cell factor receptor c-Kit. C57Bl6/J mice carrying B16/PDGF-BB mouse melanoma tumors were treated daily with vatalanib (25 mg/kg), imatinib (100 mg/kg), or a combination of these drugs. Paclitaxel was given subcutaneously twice during the study. The effects of the drugs on tumor cell proliferation in vitro were determined by counting cells. B16/PDGF-BB mouse melanoma tumors were not sensitive to paclitaxel at doses of either 5 or 20 mg/kg. However, the tumor growth was significantly reduced by 58%, in response to paclitaxel (5 mg/kg) when administered with daily doses of both vatalanib and imatinib. Paclitaxel only inhibited the in-vitro growth of B16/PDGF BB tumor cells when given in combination with imatinib. Imatinib presumably targets c-Kit, as the cells do not express platelet-derived growth factor receptor and as another c-Abl inhibitor was without effect. This was supported by data from three c-Kit-expressing human melanoma cell lines showing varying sensitization to paclitaxel by the kinase inhibitors. In addition, small interfering RNA knockdown of c-Kit sensitized the cells to paclitaxel. These data show that combination of two tyrosine kinase inhibitors, imatinib and vatalanib, increases the effects of paclitaxel on B16/PDGF-BB tumors, thus suggesting a novel strategy for the treatment of melanomas expressing c-Kit. PMID- 20975606 TI - Sleep difficulties: due to menopause status, age, other factors, or all of the above? PMID- 20975608 TI - Letter to the editor. PMID- 20975607 TI - Exogenous hormones, the risk of venous thromboembolism, and activated protein C resistance. PMID- 20975609 TI - Usefulness of 99mTc-ciprofloxacin scintigraphy in the diagnosis of prosthetic joint infections. AB - OBJECTIVE: To evaluate the usefulness of 99Tc-ciprofloxacin scintigraphy (CFS) in patients with hip or knee arthroplasty and suspected infection. METHODS: Forty patients (26 women, 14 men) with a mean age of 66+/-10 years and local pain in the hip (21), knee (16), or shoulder (three) prosthesis were recruited. CFS was performed at 1, 4, and 24 h after intravenous injection of 370 MBq. Anterior and posterior views centered on the affected joint were performed in all patients. A routine bone scan, 99Tc-hexamethylpropyleneamine oxime leukocyte scan, and 99Tc colloid scan [leukocyte scintigraphy-bone marrow scintigraphy (LS-MS)] were performed. Final diagnosis of infection was confirmed by positive microbiological analysis or macroscopic evidence of purulent material. RESULTS: Diagnosis of arthroplasty infection was established in 16 out 40 cases: coagulase-negative staphylococci (nine), Staphylococcus aureus (three), Enterococcus (one), and macroscopic infection in the remaining three cases. CFS imaging showed the 24-h image to be the best acquisition time-point. The sensitivity, specificity, negative predictive value, and positive predictive value for LS-MS were 75, 92, 86, and 85%, whereas for CFS at 24 h these figures were 88, 71, 67, and 89%. The sensitivity and specificity for LS-MS and for CFS at 24 h for hip were (74, 90, and 88, 85%) and for knee (83, 90 and 100, 50%). CONCLUSION: CFS can be useful in the diagnosis of arthroplasty infection of the hip as a substitute for LS-MS. It is recommended that CFS images be obtained 24 h after injection. The lack of specificity of CFS makes this technique inadequate for knee prostheses in this series. PMID- 20975610 TI - The Grief Support in Healthcare Scale: development and testing. AB - BACKGROUND: Social support is an important factor to consider in understanding the grief process. However, existing measures of social support fail to account adequately for the unique characteristics of grief experienced by healthcare workers in relation to the deaths of patients or nursing home residents. OBJECTIVE: The purposes of this study were to develop and to test a grief support measure specific to the experiences of healthcare workers. METHODS: Using a cross sectional design, 380 nursing assistants completed self-administered surveys focusing on grief and loss in the nursing home setting. Exploratory factor analysis and regression analysis were conducted to test the psychometric properties of the Grief Support in Healthcare Scale (GSHCS) and to investigate the scale's relationships with grief outcomes. RESULTS: Reflective of the theory of disenfranchised grief, the 15 items of the GSHCS were loaded onto three distinct factors: recognition of the relationship, acknowledgement of the loss, and inclusion of the griever. Reliability was acceptable to high across these factors (Cronbach's alpha of .89, .86, and .78, respectively). Regression analysis indicated that the three subscales of the GSHCS were related significantly to both distress from grief and growth from grief, yet these relationships were unique for each factor. DISCUSSION: This research demonstrated that the GSHCS has acceptable reliability and face validity for understanding grief in healthcare workers and may aid in the development of interventions targeted at enfranchising grief in this population. Additional testing is needed to estimate the validity and the reliability of the scale with other groups of healthcare workers. PMID- 20975611 TI - Angiotensin-converting enzyme inhibition alters the inflammatory and fibrinolytic response to cardiopulmonary bypass in children. AB - OBJECTIVE: Many children with a congenital heart defect undergo surgical correction requiring cardiopulmonary bypass. One-sixth of these patients take an angiotensin-converting enzyme inhibitor for heart failure treatment. The effect of angiotensin-converting enzyme inhibition on the fibrinolytic and inflammatory response in children undergoing cardiopulmonary bypass is unknown. In adults, angiotensin-converting enzyme inhibition attenuates the increase in plasminogen activator inhibitor-1 after cardiopulmonary bypass, whereas the effect on the interleukin-6 response is uncertain. This study tests the hypothesis that preoperative angiotensin-converting enzyme inhibition attenuates postoperative plasminogen activator inhibitor-1 and interleukin-6 expression after cardiopulmonary bypass in children. DESIGN: Single-center prospective, randomized, nonblinded study. SETTING: University-affiliated pediatric hospital. PATIENTS: Children undergoing elective surgical correction of a congenital heart defect requiring cardiopulmonary bypass and taking an angiotensin-converting enzyme inhibitor. INTERVENTIONS: Children were randomized to continue angiotensin converting enzyme inhibitor until the morning of surgery (angiotensin-converting enzyme inhibitor group, n = 11) or to discontinue therapy 72 hrs before surgery (no angiotensin-converting enzyme inhibitor group, n = 9). MEASUREMENT AND MAIN RESULTS: Blood samples were collected at baseline before cardiopulmonary bypass, at 30 mins of cardiopulmonary bypass, on arrival to the intensive care unit, and on postoperative day 1. Baseline bradykinin concentrations were significantly higher and angiotensin-converting enzyme activity significantly lower in the angiotensin-converting enzyme inhibitor group compared with the no angiotensin converting enzyme inhibitor group (p = .04 and .001, respectively). Plasminogen activator inhibitor-1 antigen increased 15-fold after cardiopulmonary bypass and peaked on postoperative day 1 (from 4.6 +/- 1.2 to 67.7 +/- 9.5 ng/mL; p < .001). Postoperative day 1 plasminogen activator inhibitor-1 antigen correlated significantly with cardiopulmonary bypass time (r2 = 0.40, p = .03) and was significantly lower in the angiotensin-converting enzyme inhibitor group compared with the no angiotensin-converting enzyme inhibitor group (p = .03). The proinflammatory markers interleukin-6 and interleukin-8 as well as the anti inflammatory marker interleukin-10 increased significantly after cardiopulmonary bypass (all p < .001). Interleukin-6 concentrations were significantly higher in the angiotensin-converting enzyme inhibitor group after cardiopulmonary bypass (p = .02) even after controlling for potential confounding factors such as age, cardiopulmonary bypass time, and transfusion volume. CONCLUSION: Angiotensin converting enzyme inhibition attenuates the increase in postoperative plasminogen activator inhibitor-1 but enhances the interleukin-6 response in children undergoing cardiopulmonary bypass. PMID- 20975612 TI - Lean analysis of a pediatric intensive care unit physician group rounding process to identify inefficiencies and opportunities for improvement. AB - OBJECTIVE: A physician group in a pediatric intensive care unit faced challenges when moving to a larger unit. Challenges included increased time for rounds, nonbillable attending physician hours, poor communication with pediatric intensive care unit staff, and meeting resident physician duty hours and teaching requirements. The purpose of this analysis was to identify waste and opportunities for improvement to improve physician efficiency. DESIGN: Human factor (observational data collection) techniques were used to capture >60 hrs of rounding data. Twelve attending physicians and their rounding teams were shadowed to capture rounds on 130 pediatric intensive care unit patients. Rounding events, times, and patient interactions were recorded. Lean methods and scenario analysis were used to analyze the data and identify opportunities for improvement. Rounding events were categorized to determine value-added and nonvalue-added activities. Value-added activities were subclassified as essential or nonessential to morning rounds. SETTING: Thirty-bed pediatric intensive care unit in a children's hospital with academic affiliation. PATIENTS OR SUBJECTS: Eight attending pediatric intensivists and their physician rounding teams. INTERVENTIONS: Eight attending physician-led rounding teams were observed for 12 rounding events and a total of 130 patient contacts. MEASUREMENTS AND MAIN RESULTS: Large variation existed in the rounding process. Nonessential activities was highly correlated with physician preference and created a wide range in rounding time per patient. Essential activities showed the least variation and represents a "lean process." Scenario analysis was used to determine the impact of removing waste and reallocating the nonessential activities outside of rounds. Results of the analysis indicated that rounds could be reduced by 42% and that plan of care completion would be timelier (decreased from a mean of 157 to 82 mins). CONCLUSIONS: In a large physician group, essential activities showed the least variation. Practice variation focused on minimizing nonessential activities could have dramatic impacts on standardizing practice. Further study is indicated to determine whether standardizing rounds to focus on essential activities can lead to more effective processes that require fewer resources while improving outcomes for all stakeholders. PMID- 20975613 TI - Handover after pediatric heart surgery: a simple tool improves information exchange. AB - OBJECTIVE: To improve the quality of handover of complex patients after pediatric cardiac surgery through the use of a simple handover tool. DESIGN: Prospective, pre-/postinterventional. SETTING: A tertiary care, pediatric intensive care unit in North America. SUBJECTS: Thirty-three consenting healthcare providers from pediatric cardiac anesthesia, critical care, and cardiothoracic surgery participating in 31 handovers. INTERVENTION: A fill-in-the-blank, one-page tool was developed to guide the information transmitted by the surgeon and anesthesiologist to the pediatric intensive care unit team during handover of postcardiac surgery patients. MEASUREMENTS AND MAIN RESULTS: Total handover score, four subscores, handover duration, and postoperative high-risk events were measured before and after introducing the tool into clinical practice. The patients in both the pre- and postintervention groups were similar at baseline. The total handover score (maximum 43 points) improved significantly after the implementation of the handover tool (28.2 of 43 +/- 4.6 points vs. 33.5 of 43 +/- 3.7 points, p = .002). There was also a significant improvement in the medical (8.3 +/- 2.6 vs. 10.3 +/- 2.1 points, p = .024) and surgical (7.5 +/- 1.4 vs. 9.3 +/- 1.6 points, p = .002) intraoperative information subscores. Use of the tool did not prolong handover duration (8.3 +/- 4.6 vs. 11.1 +/- 3.9 mins, p = .1). There was a trend toward more patients being free from high-risk events in the postintervention group (31.2% vs. 6.7%), but this did not reach statistical significance (p = .1). CONCLUSIONS: Use of a simple tool during handover of pediatric postcardiac surgery patients resulted in a more complete exchange of critical information with no significant prolongation of the handover duration. PMID- 20975614 TI - Energy imbalance and the risk of overfeeding in critically ill children. AB - OBJECTIVE: To examine the role of targeted indirect calorimetry in detecting the adequacy of energy intake and the risk of cumulative energy imbalance in a subgroup of critically ill children suspected to have alterations in resting energy expenditure. We examined the accuracy of standard equations used for estimating resting energy expenditure in relation to measured resting energy expenditure in relation to measured resting energy expenditure and cumulative energy balance over 1 week in this cohort. DESIGN: A prospective cohort study. SETTING: Pediatric intensive care unit in a tertiary academic center. INTERVENTIONS: A subgroup of critically ill children in the pediatric intensive care unit was selected using a set of criteria for targeted indirect calorimetry. MEASUREMENTS: Measured resting energy expenditure from indirect calorimetry and estimated resting energy expenditure from standard equations were obtained. The metabolic state of each patient was assigned as hypermetabolic (measured resting energy expenditure/estimated resting energy expenditure >110%), hypometabolic (measured resting energy expenditure/estimated resting energy expenditure <90%), or normal (measured resting energy expenditure/estimated resting energy expenditure = 90-110%). Clinical variables associated with metabolic state and factors influencing the adequacy of energy intake were examined. MAIN RESULTS: Children identified by criteria for targeted indirect calorimetry, had a median length of stay of 44 days, a high incidence (72%) of metabolic instability and alterations in resting energy expenditure with a predominance of hypometabolism in those admitted to the medical service. Physicians failed to accurately predict the true metabolic state in a majority (62%) of patients. Standard equations overestimated the energy expenditure and a high incidence of overfeeding (83%) with cumulative energy excess of up to 8000 kcal/week was observed, especially in children <1 yr of age. We did not find a correlation between energy balance and respiratory quotient (RQ) in our study. CONCLUSIONS: We detected a high incidence of overfeeding in a subgroup of critically ill children using targeted indirect calorimetry The predominance of hypometabolism, failure of physicians to correctly predict metabolic state, use of stress factors, and inaccuracy of standard equations all contributed to overfeeding in this cohort. Critically ill children, especially those with a longer stay in the PICU, are at a risk of unintended overfeeding with cumulative energy excess. PMID- 20975615 TI - The immunogenicity and safety of live attenuated varicella-zoster virus vaccine in human immunodeficiency virus-infected children. AB - BACKGROUND: The live attenuated varicella vaccine is recommended for HIV-infected children who are not severely immunosuppressed. This study aimed to assess the immunogenicity and safety of varicella vaccination among HIV-infected children who had severe immunosuppression before receiving antiretroviral therapy. METHODS: Sixty HIV-infected children with no history of chickenpox or herpes zoster infection with CD4 T lymphocyte counts >= 15% or >= 200 cell/mm were enrolled. Two doses of varicella vaccine were administered at the time of enrollment and at 3 months. Varicella zoster virus (VZV) antibody was tested at baseline and 3 months after each dose by the enzyme-linked immunosorbent assay technique. An antibody titer >20 HU/mL was regarded as protective. RESULTS: The median (interquartile range) of age, CD4 nadir, and current CD4 percentage were 11.2 (8.5-12.8) years, 9.5% (3-14), and 28% (22-32), respectively. Fifty-seven children (95%) received antiretroviral therapy for a median of 27 months. Among 34 children (57%) who were VZV seronegative at baseline, 11.8% (95% CI, 3.3% 27.5%) and 79.4% (95% CI, 62.1%-91.3%) were VZV seroconverted after first and second dose of vaccine, respectively. Children who had VZV seroconversion were more likely to have HIV RNA <1.7 copies/mL (92.6% vs. 71.4%, P = 0.18). Among 26 children who were seropositive at baseline, the geometric mean titers were increased from 56.7 to 107.9 and 134.6 unit/mL, respectively. Local and systemic reactions of grade 1 and 2 were reported in 13% and 4% of children, respectively. There was a trend toward better response among children with younger age, high CD4, and viral suppression. CONCLUSIONS: Administration of the 2 doses of varicella vaccine resulted in high seroconversion rates without serious adverse reactions. Varicella vaccination for HIV-infected children should be encouraged. PMID- 20975616 TI - In vitro cow's milk protein-specific inflammatory and regulatory cytokine responses in preterm infants with necrotizing enterocolitis and sepsis. AB - Enteral feeding with cow's milk formula is associated with neonatal necrotizing enterocolitis (NEC) and sepsis. Dietary antigen sensitization may play a role in promoting and/or sustaining inflammation in both conditions. Aiming at investigating cow's milk protein (CMP)-specific cytokine responses in preterm infants with NEC and sepsis, 14 babies with NEC, 14 matched healthy controls, and 10 septic controls were recruited. Unstimulated and stimulated peripheral blood mononuclear cells (PBMCs) secreting IFN-gamma, IL-4, IL-10, and TGF-beta1 were counted by the single-cell enzyme-linked immunospot (ELISPOT) assay. During the acute phase of NEC, patients showed a general pattern of a high level of cytokine secretion both when unstimulated and stimulated by mitogen [phytohaemagglutinin (PHA)] and CMPs: beta-lactoglobulin (beta-lg) and casein. These responses were more marked to beta-lg for IFN-gamma, IL-4, and IL-10 than TGF-beta1. Cytokine responses in sepsis were lower than in NEC (lowest in healthy controls, with a minimal TGF-beta1 response). At term, lower frequencies of cytokine-secreting cells were elicited than during the acute phase, except for TGF-beta1 secreting cells, which increased at term (in response to PHA and CMPs) particularly following not only NEC but also sepsis. PMID- 20975617 TI - 211 G to a variation of UDP-glucuronosyl transferase 1A1 gene and neonatal breastfeeding jaundice. AB - Breastfeeding jaundice is a common problem in neonates who were exclusively breastfed, but its pathogenesis is still unclear. The uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) gene polymorphism was shown to contribute to the development of neonatal hyperbilirubinemia. We hypothesize that the variation of UGT1A1 gene may contribute to neonatal breastfeeding jaundice. We prospectively enrolled 688 near-term and term infants who were exclusively breastfed (BF group) or were supplemented by infant formula partially (SF group) before onset of hyperbilirubinemia. Genotyping of the promoter and exon1 of UGT1A1 was performed in all neonates. Neonates in BF group had a significantly higher maximal body weight loss ratio, peak bilirubin level, and a greater incidence of hyperbilirubinemia than those in SF group. Neonates with nucleotide 211 GA or AA variation in UGT1A1 genotypes had higher peak serum bilirubin levels and higher incidence of hyperbilirubinemia than WTs (GG). This phenomenon was only seen in BF group but not in SF group when subset analysis was performed. This suggests that neonates who carry the nucleotide 211 GA or AA variation within coding region in UGT1A1 gene are more susceptible to develop early-onset neonatal breastfeeding jaundice. PMID- 20975619 TI - Are genetic variants of COMT associated with addiction? AB - The human catechol-O-methyl transferase (COMT) gene contains multiple single nucleotide polymorphisms, some of which are postulated to have clinical significance. This article reviews human studies that have explored the association between COMT polymorphisms and addiction to drugs, alcohol or tobacco. Most studies concentrate on the Val108/158Met polymorphism. Although there are reports indicating a positive association with COMT polymorphisms and addiction, the majority of the studies failed to detect such a link between them with one exception, smoking. It is unlikely that there would be any single gene that could be designated as 'the addiction gene'. Rather, there seems to be a great number of genes that are associated with addiction, among which COMT seems to have a minor role. Environmental factors and genetic milieu have a great impact on whether the small effects of COMT polymorphisms on risk of addiction can be detected in a given population. Sex differences complicate the gene environment interplay even further. PMID- 20975618 TI - Glutathione oxidation is associated with airway macrophage functional impairment in children with severe asthma. AB - Airway cellular dysfunction is a differentiating feature of severe asthma in children that may be related to an imbalance of the antioxidant, glutathione (GSH). We hypothesized that oxidation of GSH to glutathione disulfide (GSSG) in the epithelial lining fluid (ELF) of children with severe asthma would contribute to altered airway macrophage (AM) GSH homeostasis and AM cellular dysfunction. Bronchoalveolar lavage (BAL) was performed in 64 asthmatic children (severe asthma, n = 43). GSH, GSSG, markers of lipid peroxidation and DNA oxidation, and IL-8 were quantified in the BAL supernatant. GSH, GSSG, activities of histone deacetylase (HDAC) and histone acetyltransferase, apoptosis, and phagocytosis were assessed in isolated AMs. Children with severe asthma had increased GSSG, lipid peroxidation, byproducts of DNA oxidation, and inflammation in the ELF. This imbalance of GSH homeostasis was also noted intracellularly within the AMs and was associated with decreased HDAC activities, increased apoptosis, and impaired phagocytosis. In vitro GSH supplementation inhibited apoptosis and rescued phagocytosis in children with severe asthma. Severe asthma in children is characterized by altered airway and intracellular AM GSH homeostasis that translates to impaired AM function. Interventions to restore airway GSH homeostasis may be warranted in children with severe asthma. PMID- 20975620 TI - The effects of sildenafil citrate on choroidal thickness as determined by enhanced depth imaging optical coherence tomography. AB - PURPOSE: To investigate the effects of the phosphodiesterase-5 inhibitor, sildenafil citrate, on choroidal thickness using eye-tracked enhanced depth imaging spectral-domain optical coherence tomography. METHODS: In a prospective interventional study, 8 healthy subjects (4 men and 4 women) with no ocular history underwent enhanced depth imaging spectral-domain optical coherence tomography at baseline, 1 hour, and 3 hours after the ingestion of 100 mg of sildenafil citrate. Choroidal thickness measurements for both eyes using enhanced depth imaging spectral-domain optical coherence tomography were taken by 2 masked readers at baseline, 1-hour, and 3-hour time points. Statistical analysis was performed to compare the measurements of choroidal thickness at each of the three intervals. RESULTS: The mean age of the subjects was 35.9 years (range 30-46 years). Mean choroidal thickness at baseline was 334 MUm (+/- 57 MUm). Mean choroidal thickness increased by 12.3% to 375 MUm (+/- 68 MUm) at 1 hour after ingestion (P < 0.001). At 3 hours after ingestion, the mean choroidal thickness remained elevated at 372 MUm (+/- 61 MUm), 11.6% thicker than baseline (P < 0.001). There was no significant difference in choroidal thickness between the 1 hour and the 3-hour intervals (P = 0.719). CONCLUSION: Sildenafil citrate appears to increase choroidal thickness as measured by eye-tracked enhanced depth imaging spectral-domain optical coherence tomography measurements in healthy subjects 1 hour and 3 hours after ingestion. These findings may be of relevance given that increased choroidal thickness appears to be a risk factor for central serous chorioretinopathy and that several reports have suggested an association between phosphodiesterase-5 inhibitors and this disorder. PMID- 20975621 TI - Vascularization and morphological changes of the endplate after axial compression and distraction of the intervertebral disc. AB - STUDY DESIGN: An in vivo study of the rabbit's endplate and intervertebral disc (IVD). OBJECTIVE: To assess the histologic features and vascularization of the endplate after axial compression and distraction, along with the degeneration and regeneration status of IVD. SUMMARY OF BACKGROUND DATA: Current studies mainly focus on the changes in the IVD in response to degeneration and regeneration. However, the basic science regarding degenerative changes of the vertebral endplate and its actions on the IVD is lacking. The endplate is responsible for nutrient flow to the IVD through diffusion. It has been postulated that changes in the endplate may be responsible for the degeneration of the IVD. METHODS: Twenty New Zealand white rabbits were equally divided into 4 groups as follows; group A, 28 days of compression only; group B, 28 days of disc compression followed by 28 days of unloading; group C, 28 days of disc compression followed by 28 days of distraction; and group D, sham operated animals with apparatus placement only. At the end of the study, all the animals in the 4 groups were killed and the lumbar segments harvested for analysis of their disc height, vascularity, and histologic examination. RESULTS: Compression decreased the disc height and the rabbits showed signs of disc degeneration. Ossified endplates with decreased cells and extracellular matrix, and decreased vascular channel volume were observed. Cellular and morphologic regeneration were observed on unloading and distraction of the compressed discs, although the cartilaginous endplates were partially ossified. The volume of vascular channels increased significantly after distraction. Fluorescent vascular tracer showed the presence of active blood flow in the vascular channels near the cartilaginous endplates. CONCLUSION: Compression resulted in degeneration of the cartilaginous endplate and decrease in the osseous endplate vascular channel volume, both of which led to the degeneration of the IVD. Unloading and distraction allowed the regeneration of the extracellular matrix in both the endplate and the recovery of vascular channels. PMID- 20975622 TI - The influence of orthotopic paraspinal muscle-pediculated bone flaps on posterior spinal fusion in a canine model. AB - STUDY DESIGN: An experimental animal study with randomized, control design was conducted using a dog model. OBJECTIVE.: To construct a novel posterior lumbar spine fusion model with orthotopic paraspinal muscle-pediculated bone flaps and to compare with the conventional posterolateral lumbar intertransverse process fusion. SUMMARY OF BACKGROUND DATA: Previous studies have demonstrated that paraspinal musculature provided important vascular ingrowth into the fusion mass. However, the blood supply of paraspinal muscles was still not sufficiently used in spinal fusion. In this study, we assessed the significant role of orthotopic paraspinal muscle-pediculated bone flaps in the healing of bone graft in spinal fusion. METHODS: Thirty-two mongrel dogs were randomly assigned to 2 groups to undergo either posterior spinal fusion with orthotopic paraspinal muscle pediculated bone flaps (treatment group) or posterolateral intertransverse process fusion (control group) at L5-L6 segment. All the fusions used an autologous bone graft obtained from bilateral posterior iliac crests. The animals were killed at 8 weeks or 16 weeks after surgery. The lumbar spines were evaluated by radiology, histology, and biomechanics. RESULTS: Treatment groups showed an increasing trend on radiographic grades, manual palpation, and biomechanical stiffness compared with control groups at 8 and 16 weeks. Histologic analysis revealed that there was more mature woven bone in the treatment group than the controls at both points. At 8 weeks, the histologic fusion rate was 21.4% in the treatment group, 50% in the control group (P < 0.05); and at 16 weeks the fusion rate was 50% and 87.5% in the control group and the treatment group, respectively (P < 0.05). CONCLUSION: The use of orthotopic paraspinal musclepediculated bone flaps increased the rate and quality of fusion in the experimental spinal fusion model. This suggested that the novel posterior spinal fusion could be further developed for clinical application. PMID- 20975623 TI - Facet joint biomechanics at the treated and adjacent levels after total disc replacement. AB - STUDY DESIGN: Biomechanical study using human cadaveric lumbar spines. OBJECTIVE: To evaluate effects of total disc replacement (TDR) on spine biomechanics at the treated and adjacent levels. SUMMARY OF BACKGROUND DATA: Previous studies on spine biomechanics after TDR were focused on facet forces and range of motion and report contradictory results. Characterization of contact pressure, peak contact pressure, force, and peak force before and after TDR may lead to a better understanding of facet joint function and may aid in prediction of long-term outcomes after TDR. METHODS: Seven fresh-frozen human cadaveric lumbar spines were potted at T12 and L5 and installed in a 6 degrees of freedom displacement controlled testing system. Displacements of 15 degrees flexion/extension, 10 degrees right/left bending, and 10 degrees right/left axial rotation were applied. Contact pressure, peak contact pressure, force, peak force, and contact area for each facet joint were recorded at L2-L3 and L3-L4 both before and after TDR at L3-L4. The data were analyzed with analysis of variance and t tests. RESULTS: Axial rotation had the most impact on contact pressure, peak contact pressure, force, peak force, and contact area in intact spines. During lateral bending and axial rotation, TDR resulted in a significant increase in facet forces at the level of treatment and a decrease in contact pressure, peak contact pressure, and peak force at the level superior to the TDR. With flexion/extension, there was a decrease in peak contact pressure and peak contact force at the superior level. CONCLUSION: Our study demonstrates that rotation is the most demanding motion for the spine. We also found an increase in facet forces at the treated level after TDR. We are the first to show a decrease in several biomechanical parameters after TDR at the adjacent superior level. In general, our findings suggest there is an increase in loading of the facet joints at the level of disc implantation and an overall unloading effect at the level above. PMID- 20975624 TI - Strengths and limitations of International Classification of Disease Ninth Revision Clinical Modification codes in defining cervical spine surgery. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To evaluate the sensitivity and specificity of International Classification of Disease Ninth Revision Clinical Modification (ICD9-CM) hospital discharge codes to define degenerative cervical spine surgery in comparison to patient operative notes in the medical record. SUMMARY OF BACKGROUND DATA: Population-based studies of spine surgery have often relied on administrative databases as a primary information source, but little is known about the validity of using ICD9-CM codes to identify these operations. METHODS: We performed a retrospective study comparing ICD9-CM billing codes to patient operative notes, the gold standard, for patients undergoing spine surgery in 2006 at a single academic center. RESULTS: We identified 1090 procedures of which 265 were categorized as cervical spine surgery for degenerative indications based on the operative notes. Compared to operative notes, our ICD9-CM algorithm had high sensitivity and specificity for selecting surgery at the cervical spine level and cervical spine surgery for degenerative indications. Categorization of cases by procedure had high sensitivity and specificity for fusion and surgical approach (>95%). Categorization of cases by primary diagnosis was generally less accurate. Cervical spondylosis with myelopathy was the most sensitive primary diagnosis. Categorization of cases by procedure had high sensitivity and specificity for fusion and surgical approach (>=96%). However, diagnoses such as herniated disc and procedures such as laminectomy had low sensitivity but high specificity. CONCLUSION: The use of our ICD9-CM algorithm to define spine surgery at the cervical spine level, and degenerative cervical spine surgery is highly accurate. Although specific diagnoses codes are mostly insensitive, an ICD9-CM algorithm can be used to study these procedures with reasonable precision. PMID- 20975625 TI - Percutaneous vertebroplasty for osteoporotic vertebral compression fractures in the nonagenarians: a prospective study evaluating pain reduction and new symptomatic fracture rate. AB - STUDY DESIGN: A prospective observational cohort study of consecutive osteoporotic vertebral compression fractures (VCFs) in >= 90-year-old patients evaluated at a multidisciplinary, university spine center. OBJECTIVE: Assess efficacy, safety, and new fracture occurrence after percutaneous vertebroplasty (PV) in a large uncontrolled cohort of ultra elderly VCF patients. SUMMARY OF BACKGROUND DATA: VCFs are associated with increased morbidity and mortality. Percutaneous injection of polymethylmethacryl-ate into the fractured vertebral body, vertebroplasty, has been extensively performed as an effective minimally invasive treatment option for VCF patients. The patient sample included consecutive, osteoporotic patients with symptomatic VCFs electing to enter the study. METHODS: Baseline visual analogue scale rating, analgesic usage, duration of symptoms. Subsequent VAS ratings, analgesic utilization, and new fractures were assessed within 30 minutes after the procedure, at 2 weeks, 1 month, 3 months, 6 months, 1 year, and 2 years postprocedure. OUTCOME MEASURES: Visual Analogue Scale score, analgesic utilization, patient satisfaction, cement extravasation, and new fractures. RESULTS.: A total of 123 (74% female) underwent PV for 163 VCFs. Eleven patients did not complete final follow-up at 2 years due to death unrelated to the PV procedure. The mean VAS score was 7.6 at baseline and 3.1 at 30 minutes after the procedure, and 2.3, 1.2, 1.1, 0.9, 0.8, and 0.5 at 2 weeks, 1 month, 3 months, 6 months, 1 year, and 2 years, respectively. Improvement over time was statistically significant using repeated measures analysis of variance (P < 0.05). No complications were encountered during the follow-up intervals. Thirteen new fractures were observed (10.6%) at a mean 20.8 weeks (1-52 weeks) after PV with 6 new fractures (4.9%) involving an adjacent level in 5 patients (4.1%). CONCLUSION: Vertebroplasty for VCFs in the very elderly appears effective and safe without increased risk of adjacent level fracture. PMID- 20975626 TI - Alginate macroencapsulation of pig islets allows correction of streptozotocin induced diabetes in primates up to 6 months without immunosuppression. AB - BACKGROUND: This study assessed the capacity of alginate-encapsulated islets to reverse diabetes in a pig-to-primate model. METHODS: Adult pig islets were encapsulated in microcapsules implanted under the kidney capsule (n=4) or in a subcutaneous macrodevice (n=5) in diabetic primates. Fasting blood glucose (FBG), insulin, porcine C-peptide, glycosylated hemoglobin (HbA1C), and cellular and humoral responses were followed. RESULTS: Nonencapsulated pig islets were rejected within 7 days. A transient decrease of FBG was observed only during the 2 weeks after microencapsulated pig islet implantation under the kidney capsule. After subcutaneous transplantation of a macrodevice, diabetes was corrected up to a maximum of 6 months in five animals: FBG less than 107 mg/dL and HbA1C at 8% +/ 1.4%. Two of the five animals received a new macrodevice between 25 and 35 weeks after the first graft dysfunction (HbA1C >= 13), and diabetes was controlled for an additional 18 weeks in these animals. Although a strong humoral response was elicited after transplantation of encapsulated islets, a total impermeability of alginate 3% wt/vol to IgG was demonstrated before and up to 20 weeks after transplantation of the subcutaneous macrodevice. CONCLUSIONS: Pig islets encapsulated in a subcutaneous macrodevice can control diabetes up to 6 months without immunosuppression. PMID- 20975627 TI - The protective role of host Toll-like receptor-4 in acute graft-versus-host disease. AB - BACKGROUND: Mutations in Toll-like receptor (TLR)-4 have been associated with the hyporesponsiveness of macrophages to lipopolysaccharide, possibly reducing the risk of acute graft-versus-host disease (GVHD). However, TLR-4 mutations may also increase the risk of intestinal damage and microbial infection, thereby accelerating acute GVHD. METHODS: In this study, we investigated the role of TLR 4 in triggering acute GVHD using C3H/HeJ mice with disrupted TLR-4 and C3H/HeN mice with intact TLR-4 as recipients in an acute GVHD model. RESULTS: TLR-4 expression was significantly increased in the intestines and livers from acute GVHD mice. TLR-4-mutant C3H/HeJ hosts that received C57BL/6 (B6) donor cells developed significantly more severe GVHD than TLR-4-intact C3H/HeN hosts receiving B6 donor cells. Antibiotic treatment prolonged the survival of C3H/HeN host GVHD mice but reduced the survival of C3H/HeJ-host GVHD mice. C3H/HeJ-host GVHD mice showed increased lipopolysaccharide levels in the blood, donor cell and CD68+ cell infiltration, tumor necrosis factor-alpha mRNA expression, and more apoptotic cells in the intestine compared with C3H/HeN host GVHD mice. In contrast, intestinal cyclooxygenase-2, prostaglandin E2, and hepatocyte growth factor expression in C3H/HeJ-host GVHD mice were significantly decreased compared with C3H/HeN-host GVHD mice. CONCLUSIONS: Our results indicated that host TLR-4 is crucial for the induction of tissue protective factors and for protection against intestinal cell apoptosis during acute GVHD. PMID- 20975628 TI - A new natural ceramide from Trollius chinensis Bunge. AB - A new natural product named trolliamide was isolated from Trollius chinensis Bunge. Its structure was determined as 2-hydroxy-tetracosanoic acid(2,3-dihydroxy 1-hydroxymethyl-heptadec-7-enyl)-amide by spectroscopic methods, including UV, IR, MS and NMR. This is the first report of a ceramide isolated from Trollius chinensis. PMID- 20975629 TI - Synthesis of novel 1-[(2,6-dichloro-4-trifluoromethyl)phenyl]-3-aryl-1H-pyrazole 4-carbaldehydes. AB - A series of novel 1-[(2,6-dichloro-4-trifluoromethyl)phenyl]-3-aryl-1H-pyrazole-4 carbaldehydes were synthesized using the Vilsmeier-Haack reagent. The structures of all the title compounds have been confirmed by elemental analysis, 1H-NMR and 13C-NMR and in addition, the structure of intermediate 5b was investigated by X ray crystallography. PMID- 20975630 TI - Lead contamination in selected foods from Riyadh city market and estimation of the daily intake. AB - This study was carried out to determine lead contamination in 104 of the representative food items in the Saudi diet and to estimate the dietary lead intake of Saudi Arabians. Three samples of each selected food items were purchased from the local markets of Riyadh city, the capital of Saudi Arabia. Each pooled sample was analyzed in triplicate by ICP-AES after thorough homogenization. Sweets (0.011-0.199 MUg/g), vegetables (0.002-0.195 MUg/g), legumes (0.014-0.094 MUg/g), eggs (0.079 MUg/g), meat and meat products (0.013 0.068 MUg/g) were the richest sources of lead. Considering the amounts of each food consumed, the major food sources of lead intake for Saudi can be arranged as follows: vegetables (25.4%), cereal and cereal products (24.2%), beverages (9.7%) sweets (8.2%), legumes (7.4%), fruits (5.4%) milk and milk products (5.1%). The daily intake of lead was calculated taking into account the concentration of this element in the edible part of the daily consumption data which were derived from two sources, (a) the KSA food sheet provided by the Food and Agriculture Organization (FAO) and (b) from questionnaires distributed among 300 families in Riyadh city. The results showed that the daily intakes of lead according to the two sources are 22.7 and 24.5 MUg/person/day respectively, which are lower than that mentioned by The Joint Expert Committee on Food Additives (JECFA), whereas it is comprabale with that of other countries. PMID- 20975631 TI - Synthesis of new azo compounds based on N-(4-hydroxypheneyl)maleimide and N-(4 methylpheneyl)maleimide. AB - Maleic anhydride was reacted with p-aminophenol and p-toluidine in the presence of di-phosphorus pentoxide (P2O5) as a catalyst to produce two compounds: N-(4 hydroxy-phenyl)maleimide (I) and N-(4-methylphenyl)maleimide (II). The new azo compounds I(a-c) and II(a-c) were prepared by the reaction of I and II with three different aromatic amines, namely aniline, p-aminophenol and p-toluidine. The structures of these compounds were confirmed by CHN, FT-IR, 1H-NMR, 13C-NMR, mass spectrum and UV/Vis spectroscopy. PMID- 20975632 TI - [Aspects of atherosclerosis and metabolic syndrome in lupus erythematosus]. AB - Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease affecting mainly young women. In last decades premature atherosclerosis has been identified as an important cause of mortality due to SLE related risk factors (inflammation and treatment) and metabolic syndrome (MS). MS is a group of risk factors, originating from an abnormal metabolism, with an increased risk for developing atherosclerotic cardiovascular disease. The prevalence of MS varies from 5,5-55,4% in the general population and has been observed up to 40% in SLE, associated with advanced age, low socioeconomic status, lack of exercise, use of high doses of prednisone and disease activity. Treatment should include identification and modification of these risk factors. PMID- 20975633 TI - Tocilizumab - a new step in rheumatoid arthritis treatment. AB - Rheumatoid Arthritis is a chronic systemic inflammatory disease characterized by joint pain, stiffness and swelling, with progressive destruction of small joints of the hands and feet. Methotrexate remains the most commonly used therapy and has been the recommended standard against which new drugs should be evaluated and, to date, there is limited evidence that monotherapy with other treatments is superior to MTX. The introduction of biologic agents, such as TNFalpha antagonists, represented an advance in the treatment of RA. However, there are still patients with no or inadequate response, patients in whom responsiveness to treatment is lost over time, and patients in whom safety issues may develop. Thus, patients may benefit from treatment with newer biologic agents with a different mechanism of action. Tocilizumab is an IL-6 receptor inhibitor which shows significant (and rapid) clinical efficacy in the treatment of Rheumatoid Arthritis patients, as assessed by ACR responses and DAS remission rates, with an acceptable safety profile. PMID- 20975634 TI - NEAR study: Needs and Expectations in Rheumatoid ARthritis - do we know our patients needs? AB - INTRODUCTION: Rheumatoid arthritis is a chronic systemic inflammatory rheumatic disease whose characteristics have a clear impact on the life of the patient and his/ her family. Doctor-patient relationship is increasingly based on communication and information transfer. In the case of chronic diseases and especially in RA, that information is fundamental for a better compliance, but also for the prevention of problems and the patient's better management of the disease on a daily basis. OBJECTIVES: To determine in a population of RA patients which are the principal sources of information about the disease, what unmet needs exist and the level of patient involvement in therapeutic decision. METHODS: We applied a questionnaire in person and by telephone to a population of patients with rheumatoid arthritis fulfilling the criteria of the ACR, which were followed at several departments of rheumatology in mainland Portugal, about their expectations, the degree and type of information they expected, and their unmet needs. RESULTS: A total of 223 RA patients filled in the questionnaire, 82.5% of which were female, mean age 55.13 +/- 14.49 years and whose mean duration of disease was above 5 years in 69.5% of the individuals. Of these, 17.5% found that RA had an impact on quality of life, 15.7% felt that RA affected their ability to enjoy life and 14.3% had difficulties in performing activities of daily living. Some activities were found to be more difficult for a patient with RA (on a scale of 0 to 10), such as gardening (6.36) and practicing sports (5.79). Other basic tasks were also considered difficult, as are the case of household chores (5.76) sleeping (5.08) walking (4.99) and working (4.86). Regarding the clinical impact of RA, as expected pain is almost a universal factor (87.9%), although the majority of patients also refer arthritis (78%), pain when moving (65.5%), fatigue (60.1%) and joint deformities (58.3%) as very common symptoms. Diminishing pain (81.2%), a general improvement of symptoms (73.1%) in a lasting way (57.4%) and reducing arthritis (59.2%) appeared as the main concerns of patients with RA. Regarding quality of information, 68.2% of patients consider they are well informed about the disease, but these numbers decrease if we consider information about treatment options (46.2%), the concept of remission (20.6%) or the recognition of the DAS 28 scale (17%). As preferred sources of information about the disease, 67.7% of individuals indicate their rheumatologist, 31.4% their general practitioner, 17% the Internet and 9% the attending nurse. The same order is obtained when asked about treatment information. As to the need for additional information, the patients refer "more information about therapies/treatments" (26.9%), "new scientific developments and social support" (17.5% each), "how to improve symptoms and live better in everyday life" (16.6%). "What is the disease" (6.7%) is referred last, being that only 8.1% of patients consider they are well informed. In what concerns discussion and participation in the process of clinical decision about medication, 56.1% of patients say that they share it with their doctors during their consultation. CONCLUSION: These results, which somewhat differ from the existing literature, demonstrate that there are important issues that should be considered in clinical practice, both relating to clinical issues and the unmet needs of our patients. We are unaware of the results coming from a treatment strategy designed to increase the RA patient's perception of their general state of health or of their perception of function. We should, however, keep in mind that pain, wellbeing and disease activity (as well as remission) should be important goals in therapeutic strategies that are to be increasingly shared with our patients. PMID- 20975635 TI - Cardiovascular risk profile in systemic lupus erythematosus and rheumatoid arthritis: a comparative study of female patients. AB - OBJECTIVE: Premature atherosclerosis is well-documented both in Systemic Lupus Erythematosus (SLE) and in Rheumatoid Arthritis (RA) patients, but cardiovascular (CV) risk is particularly high in lupus women. Although conventional CV risk factors do not fully explain the excessive risk in inflammatory diseases, they remain major contributors to atherosclerosis. The aim of the present study was to investigate whether CV risk factors are differentially associated with SLE and RA. METHODS: One hundred women with SLE, 98 with RA and 102 controls matched on age and without overt CV or renal disease were assessed for the presence of Framingham (hypertension, hypercholesterolemia, low HDL, diabetes, smoking) and other CV risks (atherogenic index of plasma (AIP), insulin resistance, obesity, central obesity, metabolic syndrome, uric acid, sedentarism, hypothyroidism and family history of premature CV disease). RESULTS: Modifiable CV risk factors are highly prevalent and occur more frequently in SLE and RA than in age-matched controls. Some differences in Framingham risk factors were found between SLE and RA, with hypertension being more common in young lupus women, hypercholesterolemia more frequent in RA and low HDL-C more frequent in SLE. However, the estimated 10-year Framingham CHD risk or the Reynolds Risk Score was comparable in both diseases. Although hypercholesterolemia was more frequent in RA, lupus women display a more atherogenic lipid profile, with significantly lower HDL-C levels (56.5+/-16 mg/dl versus 63.7+/-18; p=0.005), and more cases above the high risk cutpoints for cholesterol/HDL-C (14% versus 4.1%; p=0.01) and for AIP (15% versus 6.1%; p=0.03). Also, uric acid levels are higher in SLE women (4.8+/-1.5 mg/dl) than in RA (4.1+/-1.1 mg/dl), p=0.001. On the other hand, insulin resistance is significantly higher in women with RA as compared with SLE (median HOMA-IR 3.5 [6.4]) versus 0.72 [2.5]; p<0.0001) and the difference remained significant after adjustment for BMI and corticosteroids. CONCLUSIONS: Cardiovascular risk profile is distinct in SLE and RA women and the contribution of traditional CV risk factors to atherogenesis may be different in these two diseases. Prospective studies are necessary to understand how the control of modifiable risks can improve CV outcome in different inflammatory settings. PMID- 20975636 TI - Translation into Brazilian Portuguese, cultural adaptation and validatation of the systemic lupus erythematosus quality of life questionnaire (SLEQOL). AB - OBJECTIVES: Translate into Brazilian Portuguese, cross cultural adaptation and assess the reliability and validity of the Systemic Lupus Erythematosus Quality of Life Questionnaire (SLEQOL). MATERIAL AND METHODS: STUDY POPULATION: 107 SLE patients, answered the SLEQOL questionnaire. TRANSLATION: into Portuguese and cross-cultural adaptation was performed in accordance with studies on questionnaire translation methodology into other languages. RELIABILITY: Was analyzed using three interviews with different interviewers, two on the same day (interobserver) and the third within 14 days of the first assessment (intraobserver). VALIDITY: Validity was assessed by correlating clinical and quality of life parameters with the SLEQOL. STATISTICAL ANALYSIS: A descriptive analysis of the study sample. Reproducibility was assessed using an intraclass correlation coefficient (ICC). Internal consistency was assessed using Cronbach's alpha coefficient. To assess validity we used Pearson's correlation coefficient. Five percent was the level of significance adopted for all statistical tests. RESULTS: The SLEQOL was translated and culturally adapted. The main findings were: a 0.807 internal consistency correlation coefficient for all questions and domains. The inter and intraobserver correlation coefficients were 0.990 and 0.969 respectively. Validation showed good correlation with theSF-36 and poor correlation with lupus activity or damage indices. CONCLUSIONS: The quality of life parameter has been increasingly taken into account for chronic diseases. To date there are no tools to assess Quality of Life in Systemic Lupus Erythematosus (SLE) written in the Portuguese language. The questionnaire is valid and reliable for SLE patients in Brazil. PMID- 20975638 TI - Back pain during pregnancy: a longitudinal study. AB - OBJECTIVE: The goal of the present study was to evaluate the prevalence of back pain during four different periods of pregnancy and its action on each woman during this stage. METHODS: The sample comprises of a group of 49 pregnant women aged between 20 and 39 years. The presence of back pain symptoms and severity were evaluated at 12, 20, 32 and 37 weeks of gestation in each woman, using one question of the NIH Record Activity (ACTRE). RESULTS: The ANOVA for repeated measures was used to compare the four moments of evaluation (12 weeks, 20 weeks, 32 weeks and 37 weeks) in relation to back pain. A significant difference between the pain scores over the four moments were observed, being that higher pain scores were noted at 12, 32 and 37 weeks of gestation. We also verified that at 12 weeks of gestation 71.4% of women had back pain, while at 20 weeks only 16.3% confirmed pain. At 32 weeks 91.7% of women reported pain and at 37 weeks, 98% reported the same. CONCLUSION: We found that back pain is prevalent during pregnancy and its intensity varies throughout this period. PMID- 20975637 TI - Association between saddle nose deformity and retro-orbital mass in Wegener's granulomatosis. AB - OBJECTIVES: The relationship between saddle nose deformity (SND) in Wegener's granulomatosis (WG) and other clinical features, including retro-orbital mass formation (ROM), has been poor described. Therefore, this relationship was analyzed retrospectively from 2000 to 2010. PATIENTS AND METHODS: Eighteen consecutive WG patients with SND diagnosed by computed tomography were matched to 36 WG patients without SND (control group) for gender, age at WG diagnosis and disease duration. RESULTS: No difference was found between the two groups in relation to WG type (limited and systemic forms), ethnicity, laboratory features, constitutional symptoms or clinical manifestations, including upper respiratory tract, and treatment, except for ROM (33.3 vs. 2.8% in SND(+) and SND(-) groups, respectively; p=0.004) and subglottic stenosis (22.2 vs. 2.8%; p=0.038). However, on multivariate analysis, only ROM (OR 17.15; 95% CI 1.11-265.52) was statistically associated to SND. In addition, in more than half of the cases, SND manifested prior to ROM. CONCLUSIONS: Results of this prospective analysis showed that SND was strongly associated to ROM in WG. Since early diagnosis and aggressive treatment of orbital involvement could lead to better prognosis, the presence of SND warrants additional vigilance. PMID- 20975639 TI - [Vitamin D measurement in Portuguese patients with fragility fractures]. AB - OBJECTIVES: Osteoporosis is a "silent epidemic", resulting from a combination of many possible causal and risk factors, which prevalence depend on particular features of the population. The authors propose to characterize some of these elements, with special attention to vitamin D (vitD) levels, in a Portuguese population at risk, selected on the basis of a history of prior fragility fracture. METHODS: Participants were selected from the computerized list of discharges from all hospitalized patients in a Central Hospital in Oporto, between the dates 1/1/2002 and 31/12/2004, with the diagnosis of low-impact fracture of the wrist. They were invited to a reassessment of their risk of fracture, after 5 to 7 years from that event. For each one, a protocol was completed, focusing on clinical, epidemiological, laboratorial, radiological and densitometric parameters. RESULTS: In this population, as expected, there was a high rate of osteoporosis risk factors, which may explain the also high rate of subsequent osteoporotic fractures. Among others, early menopause, low intake of calcium and protein, levels of vitD generally inadequate and low frequency of osteopo-rosis treatment were noticed. DISCUSSION: The widespread insufficiency of vitD, described in other populations, mostly from the Northern countries, was also found here, supporting the suspicion that also in Portugal low vitD levels could be prevalent, despite the supposed regular sun exposure. These and other observations in this series, to be proven in directed studies, should, meanwhile, raise the levels of awareness of the community, but particularly health professionals and policymakers of public health, in a matter with a strong impact on individual and collective health in the country. PMID- 20975640 TI - Remitting seronegative symmetrical synovitis with pitting oedema syndrome, associated with prostate adenocarcinoma: a case report. AB - Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) of the dorsum of the hands and/or feet can be observed in different inflammatory rheumatic diseases as well as in haematological and solid malignancies. McCarty et al, described this syndrome for the first time more than twenty years ago. Underlying malignancy should always be excluded in patients with RS3PE syndrome. PMID- 20975641 TI - Diagnosis of juvenile systemic lupus erythematosus in adolescents with Hashimoto's thyroiditis: two case reports. AB - OBJECTIVES: To report the unusual diagnosis of juvenile systemic lupus erythematosus (JSLE) in two adolescents with a previous diagnosis of Hashimoto's thyroiditis (HT). CASE REPORTS: Case # 1: An 11 year-old girl was diagnosed with HT. One year later, she presented with generalized edema, pericardial and pleural effusion, positive ANA, thrombocytopenia, increased anti-cardiolipin IgG and nephritis, being diagnosed with JSLE. (Case # 2): A 13 year-old girl was diagnosed with HT at the age of 10 years. Two years later, she presented with weight loss, knee and elbow arthritis, alopecia, leukopenia, and positive ANA and dsDNA autoantibody confirming the diagnosis of JSLE. The first patient was treated with prednisone and cyclophosphamide, and the second with prednisone and hydroxychloroquine with both achieving relief of the lupic symptoms. CONCLUSION: In spite of the known association between autoimmune diseases and thyroid disorders, the occurrence of JSLE in patients with a previous diagnosis of HT is rare. It is important to bear in mind this possibility when following patients with HT in order to not delay the diagnosis and treatment of a serious systemic autoimmune disease such as JSLE. PMID- 20975642 TI - [Acenocoumarol and vasculitis - a rare case]. AB - The authors present a case of a man with 62 years of age who comes to the emergency room by purple skin lesions affecting the whole body, including palmar plantar involvement, with insidious installation, with three weeks of development. Physical examination revealed multiple purple-shaping round and confluent lesions involving the entire body. Laboratory tests performed were all normal. During the admission a skin biopsy was performed. After exclusion of other causes for the purpuric lesions, the acenocoumarol was interrupted and the lesions disappeared, spontaneously, in a week. The purple was attributed to the administration of acenocoumarol, given the resolution of lesions, despite the chronicity of therapy. This case illustrates a rare association between vasculitis and acenocoumarol. PMID- 20975643 TI - Epithelioid hemangioendothelioma presenting as a vertebral fracture. AB - Epithelioid hemagioendothelioma (EH) is a rare vascular tumor with an intermediate biological behavior between hemangioma and angiosarcoma. Vertebral location is even more rare, and because the number of reported cases of EH is small and the follow-up periods short, the best surgical treatment, the role of radiotherapy and chemotherapy, as well as the definitive prognosis are still not established. The authors report a case of EH which presented as a vertebral fracture with neurological impairment, where a percutaneous biopsy was inconclusive. Treatment included vertebrectomy, with complete excision of the lesion, spinal canal decompression and vertebral stabilization. Anatomopathological study revealed an epithelioid vascular neoplasm with low mitotic index, and tumor cells reactive to vimentin, CD31 and CD34, leading to the diagnosis of Grade I Epithelioid Hemangioendothelioma. Because of the wide resection achieved and the low aggressiveness of the lesion, no adjuvant radio or chemotherapy was undertaken, and at 6 years follow-up there are no signs of recurrence or metastasis. PMID- 20975644 TI - Hand involvement in Ollier Disease and Maffucci Syndrome: a case series. AB - Ollier Disease and Maffucci Syndrome are two rare diseases that can cause tumors in several organs, having a special predilection for the hand. However, there have been very few reports in the literature focusing on hand manifestations of these diseases. We report the cases of three female patients: one with Ollier Disease, and two other with Maffucci Syndrome. All patients had hand involvement as their initial primary complaint. The Ollier Disease patient developed chondrosarcomas of two digits and had to have these fingers amputated. One of the Maffucci patients died one year after presentation from a brain glioblastoma. These cases emphasize the importance of early diagnosis of Ollier Disease and Maffucci Syndrome, as these two conditions are associated not only to crippling hand deformity, but also to a significant risk of chondrosarcoma, and other malignant tumors. PMID- 20975645 TI - [Tracheal stenosis by extrinsic compression: a case of anterior cervical hypertrophic osteophytosis]. AB - Anterior Cervical Hypertrophic Osteophytosis (ACHO) is a clinical entity caused by degenerative changes of the cervical spine. ACHO may also be found in Diffuse Idiopathic Skeletal Hyperostosis (DISH)1-3, Ankylosing Spondylitis and Post traumatic Osteophytogenesis. In a minority of cases it may lead to oesophagical manifestations and less commonly, to respiratory complaints. The authors report the case of a 75-year-old male with a personal history of chronic tophaceous gout and chronic obstructive lung disease. The patient presented with a history of progressive worsening of dyspnoea and dysphagia (for solid food) as well as foreign body sensation at the cervical level. On general examination, the patient presented with slightly diminished breath sounds and an increased expiratory time. On rheumatologic examination, the patient had moderate limitation of all cervical movements, crepitating knees and multiple gout tophi in both hands. Cervical plain radiographs showed large anterior osteophytes at the level of C4 and C5. Flexible videobronchoscopy was also performed, showing an angle of distortion in the upper third of the tracheal wall, caused by extrinsic compression. These changes were confirmed by cervical CT scan which also documented an anterior sliding of the oesophagus due to large anterior cervical osteophytes. Videofluoroscopic swallow study revealed the presence of paradoxal contraction of the cricopharyngeal muscle. The patient was treated with a non steroidal anti-inflammatory drug (NSAID) and a skeletal muscle relaxant. Dysphagia improved but not the respiratory symptoms. Although there was indication for surgical removal of the hypertrophic osteophytes, the patient refused surgery and continues to be followed-up regularly at our outpatient clinic. PMID- 20975646 TI - EpiReumaPt Protocol - Portuguese epidemiologic study of the rheumatic diseases. AB - Rheumatic diseases (RDs) are among the most common diseases. In the developed world, they are the leading cause of disability and consume a large amount of health and social resources. Therefore, it is crucial to assess the impact of RDs on the general population in what refers to their prevalence, and repercussion on quality of life and function. However, no nationwide epidemiological studies on RDs have ever been performed in Portugal. With this research project we aim to estimate the prevalence of different RDs in Portugal, as well as to determine the burden of RDs, more specifically their impact on quality of life and functional and work capacity. A cross-sectional study will be performed, using a random sample of the Portuguese population. RDs will be screened through a structured interview, and subjects with a positive screening will be examined by a trained rheumatologist to establish the final diagnosis. The knowledge of the prevalence of RDs will contribute to the development of specific health plans for the current and future management of these diseases. PMID- 20975647 TI - Behcet's disease associated with subarachnoid hemorrhage due to intracranial aneurysm. PMID- 20975648 TI - No pulse: a medical conundrum. PMID- 20975649 TI - Psychogenic excoriation in a systemic lupus erythematosus patient. PMID- 20975650 TI - Giant gouty tophi in the hand: a surgical challenge. PMID- 20975651 TI - Findings of renal biopsy in lupus patients with low levels of proteinuria. PMID- 20975652 TI - [Osteonecrosis: an emerging problem in HIV patients]. PMID- 20975653 TI - Carpal tunnel syndrome in two cases of all ulnar hand: a word for nerve's ultrasound. PMID- 20975654 TI - Mezieres' method and muscular chains' theory: from postural re-education's physiotherapy to anti-fitness concept. PMID- 20975655 TI - Pharmacotherapy: Xanthine oxidase inhibition for relief of angina pectoris. PMID- 20975656 TI - Cardiomyopathies: Myocardial fibrosis assessed by CMR to predict events in HCM. PMID- 20975657 TI - Risk factors: Anxiety and risk of cardiac events. PMID- 20975658 TI - Prevention: B vitamins and CVD--failure to find a simple solution. PMID- 20975659 TI - Hypertension: BP reduction in patients with diabetes--uncertainties remain. PMID- 20975661 TI - Anti-apoptotic PI3K/Akt signaling by sodium/glucose transporter 1 reduces epithelial barrier damage and bacterial translocation in intestinal ischemia. AB - Intestinal ischemia/reperfusion (I/R) causes mucosal barrier damage and bacterial translocation (BT), leading to septic complications. Previous in vitro studies showed that activation of sodium/glucose transporter 1 (SGLT1) prevented the epithelial apoptosis and permeability rise induced by microbial products. Our aim was to investigate whether luminal glucose uptake by SGLT1 protects against ischemia-induced epithelial cell death and barrier dysfunction, and to explore the glucose-mediated cellular survival pathways in vivo. Rat jejunum was luminally instilled with either vehicle, a pancaspase inhibitor ZVAD, or glucose prior to I/R challenge (occlusion of the superior mesenteric artery for 20 min and reperfusion for 60 min). Histopathology and apoptosis in the jejunum were examined by TUNEL staining and caspase-3 cleavage. Intestinal permeability was evaluated using in vivo assays measuring luminal-to-blood passage of fluorescein dextran and portal drainage of enterally administered gadodiamide by magnetic resonance imaging. BT was determined by culturing liver and spleen homogenates. Immunofluorescent analysis and kinase assay were used to study PI3K/Akt signaling pathways. Intestinal I/R caused enterocyte apoptosis and villous destruction. Intestinal infusion with ZVAD decreased the I/R-triggered gut permeability rise and BT, suggesting that the barrier damage was partly dependent on cell apoptosis. Enteral instillation of glucose attenuated the epithelial apoptosis, barrier damage, and mucosal inflammation caused by I/R. Phloridzin (a SGLT1 inhibitor) reduced the protective effect of glucose in a dose-dependent manner. Enteral glucose increased the mucosal Akt kinase activity as evidenced by the augmented phosphorylation of exogenous GSK3. Enhanced membrane translocation and phosphorylation of Akt in epithelial cells were associated with elevated phosphorylation of mTOR, Bad, and FoxO1/3a following glucose uptake. Inhibition of PI3K/Akt signaling by LY294002 and wortmannin partially blocked the glucose mediated rescue of cell apoptosis and barrier damage. In conclusion, SGLT1 glucose uptake alleviated I/R-induced barrier dysfunction and BT, partly by inhibiting epithelial apoptosis via activation of PI3K/Akt signaling. PMID- 20975660 TI - Testing mutual exclusivity of ETS rearranged prostate cancer. AB - Prostate cancer is a clinically heterogeneous and multifocal disease. More than 80% of patients with prostate cancer harbor multiple geographically discrete cancer foci at the time of diagnosis. Emerging data suggest that these foci are molecularly distinct consistent with the hypothesis that they arise as independent clones. One of the strongest arguments is the heterogeneity observed in the status of E26 transformation specific (ETS) rearrangements between discrete tumor foci. The clonal evolution of individual prostate cancer foci based on recent studies demonstrates intertumoral heterogeneity with intratumoral homogeneity. The issue of multifocality and interfocal heterogeneity is important and has not been fully elucidated due to lack of the systematic evaluation of ETS rearrangements in multiple tumor sites. The current study investigates the frequency of multiple gene rearrangements within the same focus and between different cancer foci. Fluorescence in situ hybridization (FISH) assays were designed to detect the four most common recurrent ETS gene rearrangements. In a cohort of 88 men with localized prostate cancer, we found ERG, ETV1, and ETV5 rearrangements in 51% (44/86), 6% (5/85), and 1% (1/86), respectively. None of the cases demonstrated ETV4 rearrangements. Mutual exclusiveness of ETS rearrangements was observed in the majority of cases; however, in six cases, we discovered multiple ETS or 5' fusion partner rearrangements within the same tumor focus. In conclusion, we provide further evidence for prostate cancer tumor heterogeneity with the identification of multiple concurrent gene rearrangements. PMID- 20975662 TI - Functional MRI of sustained attention in bipolar mania. AB - We examined sustained attention deficits in bipolar disorder and associated changes in brain activation assessed by functional magnetic resonance imaging (fMRI). We hypothesized that relative to healthy participants, those with mania or mixed mania would (1) exhibit incremental decrements in sustained attention over time, (2) overactivate brain regions required for emotional processing and (3) progressively underactivate attentional regions of prefrontal cortex. Fifty participants with manic/mixed bipolar disorder (BP group) and 34 healthy comparison subjects (HC group) received an fMRI scan while performing a 15-min continuous performance task (CPT). The data were divided into three consecutive 5 min vigilance periods to analyze sustained attention. Composite brain activation maps indicated that both groups activated dorsal and ventral regions of an anterior-limbic network, but the BP group exhibited less activation over time relative to baseline. Consistent with hypotheses 1 and 2, the BP group showed a marginally greater behavioral CPT sustained attention decrement and more bilateral amygdala activation than the HC group, respectively. Instead of differential activation in prefrontal cortex over time, as predicted in hypothesis 3, the BP group progressively decreased activation in subcortical regions of striatum and thalamus relative to the HC group. These results suggest that regional activation decrements in dorsolateral prefrontal cortex accompany sustained attention decrements in both bipolar and healthy individuals. Stable amygdala overactivation across prolonged vigils may interfere with sustained attention and exacerbate attentional deficits in bipolar disorder. Differential striatal and thalamic deactivation in bipolar disorder is interpreted as a loss of amygdala (emotional brain) modulation by the ventrolateral prefrontal subcortical circuit, which interferes with attentional maintenance. PMID- 20975663 TI - Inactivating GGTase-I reduces disease phenotypes in a mouse model of K-RAS induced myeloproliferative disease. PMID- 20975664 TI - Analysis of CD16+CD56dim NK cells from CLL patients: evidence supporting a therapeutic strategy with optimized anti-CD20 monoclonal antibodies. AB - Although anti-CD20 monoclonal antibodies (mAbs) show promise for the treatment of chronic lymphocytic leukemia (CLL), the success of the anti-CD20 mAb rituximab in CLL treatment has been limited. Novel anti-CD20 mAbs with more potent cytotoxic activity have recently been engineered, but so far most have only been tested in vitro with natural killer (NK) cells from healthy donors. Because it is still unclear whether these optimized cytotoxic mAbs will improve NK-cell killing of tumor cells in CLL patients, we characterized the relevant phenotypic and functional features of NK cells from CLL patients in detail. Expression of inhibitory and activating NK-cell receptors and of Fc gamma receptor IIIA (FcgammaRIIIA) is well preserved in CD16(+)CD56(dim) cytotoxic NK cells from these patients, independently of disease progression. These cells are fully functional following cytokine stimulation. In addition, the FcgammaRIIIA optimized LFB-R603 anti-CD20 mAb mediates 100 times greater antibody-dependent cell-mediated cytotoxicity by NK cells from CLL patients and healthy donors than rituximab. Enhanced degranulation against autologous B-CLL cells is observed at lower concentrations of LFB-R603 than rituximab, regardless of CLL prognostic factors. These findings strongly justify further clinical development of anti CD20 mAbs optimized for FcgammaR engagement in CLL patients. PMID- 20975666 TI - Experimental investigation of classical and quantum correlations under decoherence. AB - It is well known that many operations in quantum information processing depend largely on a special kind of quantum correlation, that is, entanglement. However, there are also quantum tasks that display the quantum advantage without entanglement. Distinguishing classical and quantum correlations in quantum systems is therefore of both fundamental and practical importance. In consideration of the unavoidable interaction between correlated systems and the environment, understanding the dynamics of correlations would stimulate great interest. In this study, we investigate the dynamics of different kinds of bipartite correlations in an all-optical experimental setup. The sudden change in behaviour in the decay rates of correlations and their immunity against certain decoherences are shown. Moreover, quantum correlation is observed to be larger than classical correlation, which disproves the early conjecture that classical correlation is always greater than quantum correlation. Our observations may be important for quantum information processing. PMID- 20975665 TI - Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. AB - Genetic overexpression of protein deacetylase Sir2 increases longevity in a variety of lower organisms, and this has prompted interest in the effects of its closest mammalian homologue, Sirt1, on ageing and cancer. We have generated transgenic mice moderately overexpressing Sirt1 under its own regulatory elements (Sirt1-tg). Old Sirt1-tg mice present lower levels of DNA damage, decreased expression of the ageing-associated gene p16(Ink4a), a better general health and fewer spontaneous carcinomas and sarcomas. These effects, however, were not sufficiently potent to affect longevity. To further extend these observations, we developed a metabolic syndrome-associated liver cancer model in which wild-type mice develop multiple carcinomas. Sirt1-tg mice show a reduced susceptibility to liver cancer and exhibit improved hepatic protection from both DNA damage and metabolic damage. Together, these results provide direct proof of the anti-ageing activity of Sirt1 in mammals and of its tumour suppression activity in ageing- and metabolic syndrome-associated cancer. PMID- 20975667 TI - A doublecortin containing microtubule-associated protein is implicated in mechanotransduction in Drosophila sensory cilia. AB - Mechanoreceptors are sensory cells that transduce mechanical stimuli into electrical signals and mediate the perception of sound, touch and acceleration. Ciliated mechanoreceptors possess an elaborate microtubule cytoskeleton that facilitates the coupling of external forces to the transduction apparatus. In a screen for genes preferentially expressed in Drosophila campaniform mechanoreceptors, we identified DCX-EMAP, a unique member of the EMAP family (echinoderm-microtubule-associated proteins) that contains two doublecortin domains. DCX-EMAP localizes to the tubular body in campaniform receptors and to the ciliary dilation in chordotonal mechanoreceptors in Johnston's organ, the fly's auditory organ. Adult flies carrying a piggyBac insertion in the DCX-EMAP gene are uncoordinated and deaf and display loss of mechanosensory transduction and amplification. Electron microscopy of mutant sensilla reveals loss of electron-dense materials within the microtubule cytoskeleton in the tubular body and ciliary dilation. Our results establish a catalogue of candidate genes for Drosophila mechanosensation and show that one candidate, DCX-EMAP, is likely to be required for mechanosensory transduction and amplification. PMID- 20975668 TI - Mitochondrial respiration protects against oxygen-associated DNA damage. AB - Oxygen is not only required for oxidative phosphorylation but also serves as the essential substrate for the formation of reactive oxygen species (ROS), which is implicated in ageing and tumorigenesis. Although the mitochondrion is known for its bioenergetic function, the symbiotic theory originally proposed that it provided protection against the toxicity of increasing oxygen in the primordial atmosphere. Using human cells lacking Synthesis of Cytochrome c Oxidase 2 (SCO2-/ ), we have tested the oxygen toxicity hypothesis. These cells are oxidative phosphorylation defective and glycolysis dependent; they exhibit increased viability under hypoxia and feature an inverted growth response to oxygen compared with wild-type cells. SCO2-/- cells have increased intracellular oxygen and nicotinamide adenine dinucleotide (NADH) levels, which result in increased ROS and oxidative DNA damage. Using this isogenic cell line, we have revealed the genotoxicity of ambient oxygen. Our study highlights the importance of mitochondrial respiration both for bioenergetic benefits and for maintaining genomic stability in an oxygen-rich environment. PMID- 20975669 TI - Engineering hybrid nanotube wires for high-power biofuel cells. AB - Poor electron transfer and slow mass transport of substrates are significant rate limiting steps in electrochemical systems. It is especially true in biological media, in which the concentrations and diffusion coefficients of substrates are low, hindering the development of power systems for miniaturized biomedical devices. In this study, we show that the newly engineered porous microwires comprised of assembled and oriented carbon nanotubes (CNTs) overcome the limitations of small dimensions and large specific surface area. Their improved performances are shown by comparing the electroreduction of oxygen to water in saline buffer on carbon and CNT fibres. Under air, and after several hours of operation, we show that CNT microwires exhibit more than tenfold higher performances than conventional carbon fibres. Consequently, under physiological conditions, the maximum power density of a miniature membraneless glucose/oxygen CNT biofuel cell exceeds by far the power density obtained for the current state of art carbon fibre biofuel cells. PMID- 20975670 TI - Sequence-regulated vinyl copolymers by metal-catalysed step-growth radical polymerization. AB - Proteins and nucleic acids are sequence-regulated macromolecules with various properties originating from their perfectly sequenced primary structures. However, the sequence regulation of synthetic polymers, particularly vinyl polymers, has not been achieved and is one of the ultimate goals in polymer chemistry. In this study, we report a strategy to obtain sequence-regulated vinyl copolymers consisting of styrene, acrylate and vinyl chloride units using metal catalysed step-growth radical polyaddition of designed monomers prepared from common vinyl monomer building blocks. Unprecedented ABCC-sequence-regulated copolymers with perfect vinyl chloride-styrene-acrylate-acrylate sequences were obtained by copper-catalysed step-growth radical polymerization of designed monomers possessing unconjugated C=C and reactive C-Cl bonds. This strategy may open a new route in the study of sequence-regulated synthetic polymers. PMID- 20975671 TI - Large microwave generation from current-driven magnetic vortex oscillators in magnetic tunnel junctions. AB - Spin-polarized current can excite the magnetization of a ferromagnet through the transfer of spin angular momentum to the local spin system. This pure spin related transport phenomenon leads to alluring possibilities for the achievement of a nanometer scale, complementary metal oxide semiconductor-compatible, tunable microwave generator that operates at low bias for future wireless communication applications. Microwave emission generated by the persistent motion of magnetic vortices induced by a spin-transfer effect seems to be a unique manner to reach appropriate spectral linewidth. However, in metallic systems, in which such vortex oscillations have been observed, the resulting microwave power is much too small. In this study, we present experimental evidence of spin-transfer-induced vortex precession in MgO-based magnetic tunnel junctions, with an emitted power that is at least one order of magnitude stronger and with similar spectral quality. More importantly and in contrast to other spin-transfer excitations, the thorough comparison between experimental results and analytical predictions provides a clear textbook illustration of the mechanism of spin-transfer-induced vortex precession. PMID- 20975673 TI - Mapping multiple photonic qubits into and out of one solid-state atomic ensemble. AB - The future challenge of quantum communication is scalable quantum networks, which require coherent and reversible mapping of photonic qubits onto atomic systems (quantum memories). A crucial requirement for realistic networks is the ability to efficiently store multiple qubits in one quantum memory. In this study, we show a coherent and reversible mapping of 64 optical modes at the single-photon level in the time domain onto one solid-state ensemble of rare-earth ions. Our light-matter interface is based on a high-bandwidth (100 MHz) atomic frequency comb, with a predetermined storage time of ? 1 MUs. We can then encode many qubits in short (<10 ns) temporal modes (time-bin qubits). We show the good coherence of mapping by simultaneously storing and analysing multiple time-bin qubits. PMID- 20975672 TI - The molecular network governing nodule organogenesis and infection in the model legume Lotus japonicus. AB - Bacterial infection of interior tissues of legume root nodules is controlled at the epidermal cell layer and is closely coordinated with progressing organ development. Using spontaneous nodulating Lotus japonicus plant mutants to uncouple nodule organogenesis from infection, we have determined the role of 16 genes in these two developmental processes. We show that host-encoded mechanisms control three alternative entry processes operating in the epidermis, the root cortex and at the single cell level. Single cell infection did not involve the formation of trans-cellular infection threads and was independent of host Nod factor receptors and bacterial Nod-factor signals. In contrast, Nod-factor perception was required for epidermal root hair infection threads, whereas primary signal transduction genes preceding the secondary Ca2+ oscillations have an indirect role. We provide support for the origin of rhizobial infection through direct intercellular epidermal invasion and subsequent evolution of crack entry and root hair invasions observed in most extant legumes. PMID- 20975674 TI - Open for business. PMID- 20975675 TI - The evolutionary origins of ritualized acoustic signals in caterpillars. AB - Animal communication signals can be highly elaborate, and researchers have long sought explanations for their evolutionary origins. For example, how did signals such as the tail-fan display of a peacock, a firefly flash or a wolf howl evolve? Animal communication theory holds that many signals evolved from non-signalling behaviours through the process of ritualization. Empirical evidence for ritualization is limited, as it is necessary to examine living relatives with varying degrees of signal evolution within a phylogenetic framework. We examine the origins of vibratory territorial signals in caterpillars using comparative and molecular phylogenetic methods. We show that a highly ritualized vibratory signal--anal scraping--originated from a locomotory behaviour--walking. Furthermore, comparative behavioural analysis supports the hypothesis that ritualized vibratory signals derive from physical fighting behaviours. Thus, contestants signal their opponents to avoid the cost of fighting. Our study provides experimental evidence for the origins of a complex communication signal, through the process of ritualization. PMID- 20975676 TI - Fluidic supramolecular nano- and microfibres as molecular rails for regulated movement of nanosubstances. AB - Nano- and micro-sized fibrous architectures are ubiquitous in nature; in particular, microtubules have an essential role within live cells, as tracks for transporting objects to a desired place, driven by molecular motors such as dynein and kinesin. Such functions of bionanofibres motivated us to construct an artificial supramolecular rail using the fluidic property of self-assembled glycolipid nanofibres. Artificial supramolecular nanofibres constructed through molecular self-assembly of small molecules have recently attracted considerable attention for their unique properties, such as reversible formation/destruction under mild conditions and various stimuli responsiveness. In this paper, we show that a supramolecular nanofibre has sufficient fluidity, on the basis of its non crystalline nature, to function as a molecular track for the directional movement of attached molecules, proteins and nanobeads along the fibre. PMID- 20975677 TI - Viscoelastic solids explain spider web stickiness. AB - Modern orb-weaving spiders have evolved well-designed adhesives to capture preys. This adhesive is laid on a pair of axial silk fibres as micron-sized glue droplets that are composed of an aqueous coat of salts surrounding nodules made of glycoproteins. In this study, we measure the adhesive forces required to separate a small microscopic probe after bringing it in contact with a single glue droplet. These forces are highly rate-dependent and are two orders of magnitude higher than the capillary forces. The glycoproteins in the glue droplets behave as a viscoelastic solid and the elasticity is critical in enhancing adhesion caused by specific adhesive ligands. These results have important implications in mimicking bioadhesives. PMID- 20975678 TI - Large Rashba spin splitting of a metallic surface-state band on a semiconductor surface. AB - The generation of spin-polarized electrons at room temperature is an essential step in developing semiconductor spintronic applications. To this end, we studied the electronic states of a Ge(111) surface, covered with a lead monolayer at a fractional coverage of 4/3, by angle-resolved photoelectron spectroscopy (ARPES), spin-resolved ARPES and first-principles electronic structure calculation. We demonstrate that a metallic surface-state band with a dominant Pb 6p character exhibits a large Rashba spin splitting of 200 meV and an effective mass of 0.028 m(e) at the Fermi level. This finding provides a material basis for the novel field of spin transport/accumulation on semiconductor surfaces. Charge density analysis of the surface state indicated that large spin splitting was induced by asymmetric charge distribution in close proximity to the nuclei of Pb atoms. PMID- 20975679 TI - Intestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors. AB - Intestinal cells are constantly produced from a stem cell reservoir that gives rise to proliferating transient amplifying cells, which subsequently differentiate into one of the four principal cell types. Signalling pathways, including the Notch signalling pathway, coordinate these differentiation processes and their deregulation may cause cancer. Pharmacological inhibition through gamma-secretase inhibitors or genetic inactivation of the Notch signalling pathway results in the complete loss of proliferating crypt progenitors due to their conversion into post-mitotic goblet cells. The basic helix-loop-helix transcription factor Math1 is essential for intestinal secretory cell differentiation. Because of the critical roles of both Math1 and Notch signalling in intestinal homeostasis and neoplastic transformation, we sought to determine the genetic hierarchy regulating the differentiation of intestinal stem cells into secretory cells. In this paper, we demonstrate that the conversion of intestinal stem cells into goblet cells upon inhibition of the Notch signalling pathway requires Math1. PMID- 20975680 TI - Surface-wetting effects on the liquid-liquid transition of a single-component molecular liquid. AB - Even a single-component liquid may have more than two liquid states. The transition between them is called a 'liquid-liquid transition' (LLT). Such LLTs have recently attracted considerable attention mainly because of the fundamental interest in the physical origin of this counter-intuitive phenomenon. In this study, we report the first observation of wetting effects on LLT for a molecular liquid, triphenyl phosphite. We find a transition from partial to complete wetting for nucleation-growth-type LLT when approaching the spinodal temperature of LLT. Some features unique to LLT are also revealed, reflecting for example the non-conserved nature of its order parameter. We also find that the wetting behaviour is not induced by dispersion forces, but by weak hydrogen bonding to a solid substrate, implying its important role in the LLT itself. Using wetting effects may open a new possibility to control kinetics and spatial patterns of nucleation-growth-type LLT. PMID- 20975681 TI - Deep-sea hydrothermal vent animals seek cool fluids in a highly variable thermal environment. AB - The thermal characteristics of an organism's environment affect a multitude of parameters, from biochemical to evolutionary processes. Hydrothermal vents on mid ocean ridges are created when warm hydrothermal fluids are ejected from the seafloor and mixed with cold bottom seawater; many animals thrive along these steep temperature and chemical gradients. Two-dimensional temperature maps at vent sites have demonstrated order of magnitude thermal changes over centimetre distances and at time intervals from minutes to hours. To investigate whether animals adapt to this extreme level of environmental variability, we examined differences in the thermal behaviour of mobile invertebrates from aquatic habitats that vary in thermal regime. Vent animals were highly responsive to heat and preferred much cooler fluids than their upper thermal limits, whereas invertebrates from other aquatic environments risked exposure to warmer temperatures. Avoidance of temperatures well within their tolerated range may allow vent animals to maintain a safety margin against rapid temperature fluctuations and concomitant toxicity of hydrothermal fluids. PMID- 20975682 TI - The effects of 118 years of industrial fishing on UK bottom trawl fisheries. AB - In 2009, the European Commission estimated that 88% of monitored marine fish stocks were overfished, on the basis of data that go back 20 to 40 years and depending on the species investigated. However, commercial sea fishing goes back centuries, calling into question the validity of management conclusions drawn from recent data. We compiled statistics of annual demersal fish landings from bottom trawl catches landing in England and Wales dating back to 1889, using previously neglected UK Government data. We then corrected the figures for increases in fishing power over time and a recent shift in the proportion of fish landed abroad to estimate the change in landings per unit of fishing power (LPUP), a measure of the commercial productivity of fisheries. LPUP reduced by 94%-17-fold--over the past 118 years. This implies an extraordinary decline in the availability of bottom-living fish and a profound reorganization of seabed ecosystems since the nineteenth century industrialization of fishing. PMID- 20975683 TI - USE1 is a bispecific conjugating enzyme for ubiquitin and FAT10, which FAT10ylates itself in cis. AB - The ubiquitin-like modifier FAT10 targets proteins for degradation by the proteasome and is activated by the E1 enzyme UBA6. In this study, we identify the UBA6-specific E2 enzyme (USE1) as an interaction partner of FAT10. Activated FAT10 can be transferred from UBA6 onto USE1 in vitro, and endogenous USE1 and FAT10 can be coimmunoprecipitated from intact cells. Small interfering RNA mediated downregulation of USE1 mRNA resulted in a strong reduction of FAT10 conjugate formation under endogenous conditions, suggesting that USE1 is a major E2 enzyme in the FAT10 conjugation cascade. Interestingly, USE1 is not only the first E2 enzyme but also the first known substrate of FAT10 conjugation, as it was efficiently auto-FAT10ylated in cis but not in trans. PMID- 20975684 TI - Novel survey method finds dramatic decline of wild cotton-top tamarin population. AB - The cotton-top tamarin (Saguinus oedipus) is a critically endangered primate, endemic to the tropical forests of Colombia. Population monitoring is essential to evaluate the success of conservation efforts, yet standard survey methods are ineffective because animals flee silently before they are seen. We developed a novel technique that combines the use of playbacks of territorial vocalizations with traditional transect surveys. We used remote sensing to identify potential habitat within the species' historic range, and visited the 27% that we could survey safely. Of this, only 99 km(2) was extant forest, containing an estimated 2,045 animals (95% confidence interval 1,587-2,634). Assuming comparable densities in non-surveyed areas, approximately 7,394 wild cotton-top tamarins remain in Colombia. With 20-30,000 animals exported to the United States in the late 1960s, this must represent a precipitous decline. Habitat destruction and capture for the illegal pet trade are ongoing. Urgent conservation measures are required to prevent extinction in the wild. PMID- 20975685 TI - A new Argentinean nesting site showing neosauropod dinosaur reproduction in a Cretaceous hydrothermal environment. AB - Although several late Cretaceous sauropod colonial nesting sites have been discovered nearly on every continent during the last few decades, no studies have been performed to determine the factors that underpinned the choice of these specific sites. Here, we report the first definitive evidence of a group of sauropods that nested repetitively and purposely at a Cretaceous hydrothermal site at Sanagasta, La Rioja Province, Argentina. The discovery of this new colonial nesting locality shows nest fidelity over a long time, and a symbiotic relationship between egg clutches and a peculiar hydrothermal environment that favoured their incubation. Sedimentary and geochemical analyses of 80 clutches and their large eggs with thick eggshells substantiate that the Sanagasta sauropods were specifically using the soil moisture and thermoradiance to incubate their eggs, similar to a few extant species, namely, the megapode, Megapodius pritchardii, which is known to lay its egg clutches in burrows at volcanically heated nesting grounds. PMID- 20975686 TI - Gate-controlled electron transport in coronenes as a bottom-up approach towards graphene transistors. AB - Graphene is considered to be a large aromatic molecule, the limiting case of the family of polycyclic aromatic hydrocarbons. This fascinating two-dimensional material has many potential applications, including field effect transistors (FETs). However, the graphene sheets in these devices have irregular shapes and variable sizes, and contain various impurities and defects, which are undesirable for applications. Moreover, the bandgap of graphene is zero and, consequently, the on/off ratios of graphene FETs are small, making it difficult to build logic circuits. To overcome these difficulties, we report here a bottom-up attempt to fabricate nanoscale graphene FETs. We synthesize structurally well-defined coronene molecules (consisting of 13 benzene rings) terminated with linker groups, bridge each molecule to source and drain electrodes through the linkers, measure conductance and demonstrate the FET behaviour of the molecule. PMID- 20975687 TI - TERRA transcripts are bound by a complex array of RNA-binding proteins. AB - Telomeres are transcribed from the telomeric C-rich strand, giving rise to UUAGGG repeat-containing telomeric transcripts or TERRA, which are novel structural components of telomeres. TERRA abundance is highly dependent on developmental status (including nuclear reprogramming), telomere length, cellular stresses, tumour stage and chromatin structure. However, the molecular mechanisms and factors controlling TERRA levels are still largely unknown. In this study, we identify a set of RNA-binding proteins, which endogenously bind and regulate TERRA in the context of primary mouse embryonic fibroblasts. The identification was carried out by biotin pull-down assays followed by LC-MALDI TOF/TOF mass spectrometry. Different members of the heterogeneous nuclear ribonucleoprotein family are among the ribonucleoprotein family that bind more abundantly to TERRA. Downregulation of TERRA-bound RBPs by small interfering RNA further shows that they can impact on TERRA abundance, their location and telomere lengthening. These findings anticipate an impact of TERRA-associated RBPs on telomere biology and telomeres diseases, such as cancer and aging. PMID- 20975688 TI - Imaging the nanoscale organization of peptidoglycan in living Lactococcus lactis cells. AB - The spatial organization of peptidoglycan, the major constituent of bacterial cell-walls, is an important, yet still unsolved issue in microbiology. In this paper, we show that the combined use of atomic force microscopy and cell wall mutants is a powerful platform for probing the nanoscale architecture of cell wall peptidoglycan in living Gram-positive bacteria. Using topographic imaging, we found that Lactococcus lactis wild-type cells display a smooth, featureless surface morphology, whereas mutant strains lacking cell wall exopolysaccharides feature 25-nm-wide periodic bands running parallel to the short axis of the cell. In addition, we used single-molecule recognition imaging to show that parallel bands are made of peptidoglycan. Our data, obtained for the first time on living ovococci, argue for an architectural feature of the cell wall in the plane perpendicular to the long axis of the cell. The non-invasive live cell experiments presented here open new avenues for understanding the architecture and assembly of peptidoglycan in Gram-positive bacteria. PMID- 20975689 TI - Pandemic 2009 H1N1 vaccine protects against 1918 Spanish influenza virus. AB - The 1918 influenza A virus caused the most devastating pandemic, killing approximately 50 million people worldwide. Immunization with 1918-like and classical swine H1N1 virus vaccines results in cross-protective antibodies against the 2009 H1N1 pandemic influenza, indicating antigenic similarities among these viruses. In this study, we demonstrate that vaccination with the 2009 pandemic H1N1 vaccine elicits 1918 virus cross-protective antibodies in mice and humans, and that vaccination or passive transfer of human-positive sera reduced morbidity and conferred full protection from lethal challenge with the 1918 virus in mice. The spread of the 2009 H1N1 influenza virus in the population worldwide, in addition to the large number of individuals already vaccinated, suggests that a large proportion of the population now have cross-protective antibodies against the 1918 virus, greatly alleviating concerns and fears regarding the accidental exposure/release of the 1918 virus from the laboratory and the use of the virus as a bioterrorist agent. PMID- 20975690 TI - Enhanced stochasticity of domain wall motion in magnetic racetracks due to dynamic pinning. AB - Understanding the details of domain wall (DW) motion along magnetic racetracks has drawn considerable interest in the past few years for their applications in non-volatile memory devices. The propagation of the DW is dictated by the interplay between its driving force, either field or current, and the complex energy landscape of the racetrack. In this study, we use spin-valve nanowires to study field-driven DW motion in real time. By varying the strength of the driving magnetic field, the propagation mode of the DW can be changed from a simple translational mode to a more complex precessional mode. Interestingly, the DW motion becomes much more stochastic at the onset of this propagation mode. We show that this unexpected result is a consequence of an unsustainable gain in Zeeman energy of the DW, as it is driven faster by the magnetic field. As a result, the DW periodically releases energy and thereby becomes more susceptible to pinning by local imperfections in the racetrack. PMID- 20975692 TI - On-chip CMOS-compatible all-optical integrator. AB - All-optical circuits for computing and information processing could overcome the speed limitations intrinsic to electronics. However, in photonics, very few fundamental 'building blocks' equivalent to those used in multi-functional electronic circuits exist. In this study, we report the first all-optical temporal integrator in a monolithic, integrated platform. Our device--a lightwave 'capacitor-like' element based on a passive micro-ring resonator--performs the time integral of the complex field of an arbitrary optical waveform with a time resolution of a few picoseconds, corresponding to a processing speed of ~200 GHz, and a 'hold' time approaching a nanosecond. This device, compatible with electronic technology (complementary metal-oxide semiconductor), will be one of the building blocks of next-generation ultrafast data-processing technology, enabling optical memories and real-time differential equation computing units. PMID- 20975691 TI - Peptidoglycan architecture can specify division planes in Staphylococcus aureus. AB - Division in Staphylococci occurs equatorially and on specific sequentially orthogonal planes in three dimensions, resulting, after incomplete cell separation, in the 'bunch of grapes' cluster organization that defines the genus. The shape of Staphylococci is principally maintained by peptidoglycan. In this study, we use Atomic Force Microscopy (AFM) and fluorescence microscopy with vancomycin labelling to examine purified peptidoglycan architecture and its dynamics in Staphylococcus aureus and correlate these with the cell cycle. At the presumptive septum, cells were found to form a large belt of peptidoglycan in the division plane before the centripetal formation of the septal disc; this often had a 'piecrust' texture. After division, the structures remain as orthogonal ribs, encoding the location of past division planes in the cell wall. We propose that this epigenetic information is used to enable S. aureus to divide in sequentially orthogonal planes, explaining how a spherical organism can maintain division plane localization with fidelity over many generations. PMID- 20975693 TI - Electron-beam-assisted superplastic shaping of nanoscale amorphous silica. AB - Glasses are usually shaped through the viscous flow of a liquid before its solidification, as practiced in glass blowing. At or near room temperature (RT), oxide glasses are known to be brittle and fracture upon any mechanical deformation for shape change. Here, we show that with moderate exposure to a low intensity (<1.8*10(-2) A cm(-2)) electron beam (e-beam), dramatic shape changes can be achieved for nanoscale amorphous silica, at low temperatures and strain rates >10(-4) per second. We show not only large homogeneous plastic strains in compression for nanoparticles but also superplastic elongations >200% in tension for nanowires (NWs). We also report the first quantitative comparison of the load displacement responses without and with the e-beam, revealing dramatic difference in the flow stress (up to four times). This e-beam-assisted superplastic deformability near RT is useful for processing amorphous silica and other conventionally-brittle materials for their applications in nanotechnology. PMID- 20975694 TI - Adopting kin enhances inclusive fitness in asocial red squirrels. AB - Orphaned animals benefit from being adopted, but it is unclear why an adopting parent should incur the costs of rearing extra young. Such altruistic parental behaviour could be favoured if it is directed towards kin and the inclusive benefits of adoption exceed the costs. Here, we report the occurrence of adoption (five occurrences among 2,230 litters over 19 years) in asocial red squirrels (Tamiasciurus hudsonicus). Adoptions were always between kin, while orphans without nearby kin were never adopted. Adoptions were confined exclusively to circumstances in which the benefits to the adopted juvenile (b), discounted by the degree of relatedness between the surrogate and the orphan (r), exceeded the fitness costs of adding an extra juvenile to her litter (c), as predicted by Hamilton's rule (rb>c) for the evolution of altruism. By focusing on adoption in an asocial species, our study provides a clear test of Hamilton's rule that explains the persistence of occasional altruism in a natural mammal population. PMID- 20975695 TI - Sonic hedgehog controls growth of external genitalia by regulating cell cycle kinetics. AB - During embryonic development, cells are instructed which position to occupy, they interpret these cues as differentiation programmes, and expand these patterns by growth. Sonic hedgehog (Shh) specifies positional identity in many organs; however, its role in growth is not well understood. In this study, we show that inactivation of Shh in external genitalia extends the cell cycle from 8.5 to 14.4 h, and genital growth is reduced by ~75%. Transient Shh signalling establishes pattern in the genital tubercle; however, transcriptional levels of G1 cell cycle regulators are reduced. Consequently, G1 length is extended, leading to fewer progenitor cells entering S-phase. Cell cycle genes responded similarly to Shh inactivation in genitalia and limbs, suggesting that Shh may regulate growth by similar mechanisms in different organ systems. The finding that Shh regulates cell number by controlling the length of specific cell cycle phases identifies a novel mechanism by which Shh elaborates pattern during appendage development. PMID- 20975696 TI - Three-dimensional broadband ground-plane cloak made of metamaterials. AB - Since invisibility cloaks were first suggested by transformation optics theory, there has been much work on the theoretical analysis and design of various types and a few experimental verifications at microwave and optical frequencies within two-dimensional limits. Here, we realize the first practical implementation of a fully 3D broadband and low-loss ground-plane cloak at microwave frequencies. The cloak, realized by drilling inhomogeneous holes in multi-layered dielectric plates, can conceal a 3D object located under a curved conducting plane from all viewing angles by imitating the reflection of a flat conducting plane. We also designed and realized, using non-resonant metamaterials, a high-gain lens antenna that can produce narrow-beam plane waves in the near-field region in a broad frequency band. The antenna constitutes the transmitter of the measurement system and is essential for the measurement of cloaking behaviour. PMID- 20975697 TI - Identification of Thymosin beta4 as an effector of Hand1-mediated vascular development. AB - The bHLH transcription factor Hand1 (Heart and neural crest-derived transcript-1) has a fundamental role in cardiovascular development; however, the molecular mechanisms have not been elucidated. In this paper we identify Thymosin beta4 (Tbeta4/Tmsb4x), which encodes an actin monomer-binding protein implicated in cell migration and angiogenesis, as a direct target of Hand1. We demonstrate that Hand1 binds an upstream regulatory region proximal to the promoter of Tbeta4 at consensus Thing1 and E-Box sites and identify both activation and repression of Tbeta4 by Hand1, through direct binding within either non-canonical or canonical E-boxes, providing new insight into gene regulation by bHLH transcription factors. Hand1-mediated activation of Tbeta4 is essential for yolk sac vasculogenesis and embryonic survival, and administration of synthetic TB4 partially rescues yolk sac capillary plexus formation in Hand1-null embryos. Thus, we identify an in vivo downstream target of Hand1 and reveal impaired yolk sac vasculogenesis as a primary cause of early embryonic lethality following loss of this critical bHLH factor. PMID- 20975698 TI - Magnetic flux lines in type-II superconductors and the 'hairy ball' theorem. AB - Many prominent phenomena originate from geometrical effects rather than from local physics. For example, the 'hairy ball' (HB) theorem asserts that a hairy sphere cannot be combed without introducing at least one singularity, and is fulfilled by the atmospheric circulation with the existence of stratospheric polar vortices and the fact that there is always at least one place on Earth where the horizontal wind is still. In this study, we examine the consequences of the HB theorem for the lattice of flux lines that form when a magnetic field is applied to a type-II superconducting crystal. We find that discontinuities must exist in lattice shape as a function of field direction relative to the crystal. Extraordinary, 'unconventional' flux line lattice shapes that spontaneously break the underlying crystal symmetry are thus remarkably likely across all type-II superconductors, both conventional and unconventional. PMID- 20975699 TI - Ancestry of motor innervation to pectoral fin and forelimb. AB - Motor innervation to the tetrapod forelimb and fish pectoral fin is assumed to share a conserved spinal cord origin, despite major structural and functional innovations of the appendage during the vertebrate water-to-land transition. In this paper, we present anatomical and embryological evidence showing that pectoral motoneurons also originate in the hindbrain among ray-finned fish. New and previous data for lobe-finned fish, a group that includes tetrapods, and more basal cartilaginous fish showed pectoral innervation that was consistent with a hindbrain-spinal origin of motoneurons. Together, these findings support a hindbrain-spinal phenotype as the ancestral vertebrate condition that originated as a postural adaptation for pectoral control of head orientation. A phylogenetic analysis indicated that Hox gene modules were shared in fish and tetrapod pectoral systems. We propose that evolutionary shifts in Hox gene expression along the body axis provided a transcriptional mechanism allowing eventual decoupling of pectoral motoneurons from the hindbrain much like their target appendage gained independence from the head. PMID- 20975700 TI - Imaging Coulomb islands in a quantum Hall interferometer. AB - In the quantum Hall regime, near integer filling factors, electrons should only be transmitted through spatially separated edge states. However, in mesoscopic systems, electronic transmission turns out to be more complex, giving rise to a large spectrum of magnetoresistance oscillations. To explain these observations, recent models put forward the theory that, as edge states come close to each other, electrons can hop between counterpropagating edge channels, or tunnel through Coulomb islands. Here, we use scanning gate microscopy to demonstrate the presence of QH Coulomb islands, and reveal the spatial structure of transport inside a QH interferometer. Locations of electron islands are found by modulating the tunnelling between edge states and confined electron orbits. Tuning the magnetic field, we unveil a continuous evolution of active electron islands. This allows to decrypt the complexity of high-magnetic-field magnetoresistance oscillations, and opens the way to further local-scale manipulations of QH localized states. PMID- 20975701 TI - Phase diagram of bismuth in the extreme quantum limit. AB - Elemental bismuth provides a rare opportunity to explore the fate of a three dimensional gas of highly mobile electrons confined to their lowest Landau level. Coulomb interaction, neglected in the band picture, is expected to become significant in this extreme quantum limit, with poorly understood consequences. Here, we present a study of the angular-dependent Nernst effect in bismuth, which establishes the existence of ultraquantum field scales on top of its complex single-particle spectrum. Each time a Landau level crosses the Fermi level, the Nernst response sharply peaks. All such peaks are resolved by the experiment, and their complex angular dependence is in very good agreement with the theory. Beyond the quantum limit, we resolve additional Nernst peaks signaling a cascade of additional Landau sublevels caused by electron interaction. PMID- 20975702 TI - Pore-opening mechanism in trimeric P2X receptor channels. AB - The opening of ion channels in response to ligand binding, voltage or membrane stretch underlies electrical and chemical signalling throughout biology. Two structural classes of pore-opening mechanisms have been established, including bending of pore-lining helices in the case of tetrameric cation channels, or tilting of such helices in mechanosensitive channels. In this paper, we explore how the structure of the pore changes during opening in P2X receptors by measuring the modification of introduced cysteine residues in transmembrane helices by thiol-reactive reagents, and by engineering metal bridges. Our results are consistent with the X-ray structure of the closed state, and demonstrate that expansion of the gate region in the external pore is accompanied by a significant narrowing of the inner pore, indicating that pore-forming helices straighten on ATP binding to open the channel. This unique pore-opening mechanism has fundamental implications for the role of subunit interfaces in the gating mechanism of P2X receptors and points to a role of the internal pore in ion permeation. PMID- 20975703 TI - Calmodulin methyltransferase is an evolutionarily conserved enzyme that trimethylates Lys-115 in calmodulin. AB - Calmodulin (CaM) is a key mediator of calcium-dependent signalling and is subject to regulatory post-translational modifications, including trimethylation of Lys 115. In this paper, we identify a class I, non-SET domain protein methyltransferase, calmodulin-lysine N-methyltransferase (EC 2.1.1.60). A polypeptide chosen from a fraction enriched in calmodulin methyltransferase activity was trypsinized and analysed by tandem mass spectrometry. The amino-acid sequence obtained identified conserved, homologous proteins of unknown function across a wide range of species, thus implicating a broad role for lysine methylation in calcium-dependent signalling. Encoded by c2orf34, the human homologue is a component of two related multigene deletion syndromes in humans. Human, rat, frog, insect and plant homologues were cloned and Escherichia coli recombinant proteins catalysed the formation of a trimethyllysyl residue at position 115 in CaM, as verified by product analyses and mass spectrometry. PMID- 20975704 TI - Ouabain protects against adverse developmental programming of the kidney. AB - The kidney is extraordinarily sensitive to adverse fetal programming. Malnutrition, the most common form of developmental challenge, retards the formation of functional units, the nephrons. The resulting low nephron endowment increases susceptibility to renal injury and disease. Using explanted rat embryonic kidneys, we found that ouabain, the Na,K-ATPase ligand, triggers a calcium-nuclear factor-kappaB signal, which protects kidney development from adverse effects of malnutrition. To mimic malnutrition, kidneys were serum deprived for 24 h. This resulted in severe retardation of nephron formation and a robust increase in apoptosis. In ouabain-exposed kidneys, no adverse effects of serum deprivation were observed. Proof of principle that ouabain rescues development of embryonic kidneys exposed to malnutrition was obtained from studies on pregnant rats given a low-protein diet and treated with ouabain or vehicle throughout pregnancy. Thus, we have identified a survival signal and a feasible therapeutic tool to prevent adverse programming of kidney development. PMID- 20975705 TI - Mechanisms underlying beneficial plant-fungus interactions in mycorrhizal symbiosis. AB - Mycorrhizal fungi are a heterogeneous group of diverse fungal taxa, associated with the roots of over 90% of all plant species. Recently, state-of-the-art molecular and genetic tools, coupled to high-throughput sequencing and advanced microscopy, have led to the genome and transcriptome analysis of several symbionts. Signalling pathways between plants and fungi have now been described and the identification of several novel nutrient transporters has revealed some of the cellular processes that underlie symbiosis. Thus, the contributions of each partner in a mycorrhizal association are starting to be unravelled. This new knowledge is now available for use in agricultural practices. PMID- 20975706 TI - Multifunctional nanoparticles as coupled contrast agents. AB - Engineering compact imaging probes with highly integrated modalities is a key focus in bionanotechnology and will have profound impact on molecular diagnostics, imaging and therapeutics. However, combining multiple components on a nanometre scale to create new imaging modalities unavailable from individual components has proven to be challenging. In this paper, we demonstrate iron oxide and gold-coupled core-shell nanoparticles (NPs) with well-defined structural characteristics (for example, size, shell thickness and core-shell separation) and physical properties (for example, electronic, magnetic, optical, thermal and acoustic). The resulting multifunctional nanoprobes not only offer contrast for electron microscopy, magnetic resonance imaging and scattering-based imaging but, more importantly, enable a new imaging mode, magnetomotive photoacoustic imaging, with remarkable contrast enhancement compared with photoacoustic images using conventional NP contrast agents. PMID- 20975707 TI - Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes. AB - Processed pseudogenes are non-functional copies of normal genes that arise by a process of mRNA retrotransposition. The human genome contains thousands of pseudogenes; however, knowledge regarding their biological role is limited. Previously, we demonstrated that high mobility group A1 (HMGA1) protein regulates the insulin receptor (INSR) gene and that two diabetic patients demonstrated a marked destabilization of HMGA1 mRNA. In this paper we report that this destabilization of HMGA1 mRNA is triggered by enhanced expression of RNA from an HMGA1 pseudogene, HMGA1-p. Targeted knockdown of HMGA1-p mRNA in patient cells results in a reciprocal increase in HMGA1 mRNA stability and expression levels with a parallel correction in cell-surface INSR expression and insulin binding. These data provide evidence for a regulatory role of an expressed pseudogene in humans and establishes a novel mechanistic linkage between pseudogene HMGA1-p expression and type 2 diabetes mellitus. PMID- 20975708 TI - Motion-based DNA detection using catalytic nanomotors. AB - Synthetic nanomotors, which convert chemical energy into autonomous motion, hold considerable promise for diverse applications. In this paper, we show the use of synthetic nanomotors for detecting DNA and bacterial ribosomal RNA in a fast, simple and sensitive manner. The new motion-driven DNA-sensing concept relies on measuring changes in the speed of unmodified catalytic nanomotors induced by the dissolution of silver nanoparticle tags captured in a sandwich DNA hybridization assay. The concentration-dependent distance signals are visualized using optical microscopy, particularly through straight-line traces by magnetically aligned 'racing' nanomotors. This nanomotor biodetection strategy could be extended to monitor a wide range of biomolecular interactions using different motion transduction schemes, thus providing a versatile and powerful tool for detecting biological targets. PMID- 20975709 TI - Divergent transcriptional activities determine limb identity. AB - Limbs develop using a common genetic programme despite widely differing morphologies. This programme is modulated by limb-restricted regulators such as hindlimb (HL) transcription factors Pitx1 and Tbx4 and the forelimb (FL) Tbx5. Both Tbx factors have been implicated in limb patterning and growth, but their relative activities and underlying mechanisms remain unclear. In this paper, we show that Tbx4 and Tbx5 harbour conserved and divergent transcriptional regulatory domains that account for their roles in limb development. In particular, both factors share an activator domain and the ability to stimulate limb growth. However, we find that Tbx4 is the primary effector of HL identity for both skeletal and muscle development; this activity relies on a repressor domain that is inactivated by a human TBX4 small-patella syndrome mutation. We propose that limb identity is largely achieved by default in FL, whereas a specific repressor activity unique to Tbx4 determines HL identity. PMID- 20975710 TI - Nanoelectromechanical coupling in fullerene peapods probed by resonant electrical transport experiments. AB - Fullerene peapods, which are carbon nanotubes encapsulating fullerene molecules, can offer enhanced functionality with respect to empty nanotubes. Their prospective applications include, for example, data storage devices, single electron transistors and spin-qubit arrays for quantum computing. However, the present incomplete understanding of how a nanotube is affected by entrapped fullerenes is an obstacle for peapods to reach their full potential in nanoscale electronic applications. In this paper, we investigate the effect of C(60) fullerenes on low-temperature electron transport through peapod quantum dots. Compared with empty nanotubes, we find an abnormal temperature dependence of Coulomb blockade oscillations, indicating the presence of a nanoelectromechanical coupling between electronic states of the nanotube and mechanical vibrations of fullerenes. This provides a method to detect the C(60) presence and to probe the interplay between electrical and mechanical excitations in peapods, which thus emerge as a new class of nanoelectromechanical systems. PMID- 20975711 TI - Identification of high-quality cancer prognostic markers and metastasis network modules. AB - Cancer patients are often overtreated because of a failure to identify low-risk cancer patients. Thus far, no algorithm has been able to successfully generate cancer prognostic gene signatures with high accuracy and robustness in order to identify these patients. In this paper, we developed an algorithm that identifies prognostic markers using tumour gene microarrays focusing on metastasis-driving gene expression signals. Application of the algorithm to breast cancer samples identified prognostic gene signature sets for both estrogen receptor (ER) negative (-) and positive (+) subtypes. A combinatorial use of the signatures allowed the stratification of patients into low-, intermediate- and high-risk groups in both the training set and in eight independent testing sets containing 1,375 samples. The predictive accuracy for the low-risk group reached 87-100%. Integrative network analysis identified modules in which each module contained the genes of a signature and their direct interacting partners that are cancer driver-mutating genes. These modules are recurrent in many breast tumours and contribute to metastasis. PMID- 20975712 TI - Intrinsic magnetism at silicon surfaces. AB - It has been a long-standing goal to create magnetism in a non-magnetic material by manipulating its structure at the nanoscale. Many structural defects have unpaired spins; an ordered arrangement of these can create a magnetically ordered state. In this article we predict theoretically that stepped silicon surfaces stabilized by adsorbed gold achieve this state by self-assembly, creating chains of polarized electron spins with atomically precise structural order. The spins are localized at silicon step edges having the form of graphitic ribbons. The predicted magnetic state is supported by recent experimental observations, such as the coexistence of double- and triple-period distortions and the absence of edge states in photoemission. Ordered arrays of surface spins can be accessed by probes with single-spin sensitivity, such as spin-polarized scanning tunnelling microscopy. The integration of structural and magnetic order is crucial for technologies involving spin-based computation and storage at the atomic level. PMID- 20975713 TI - Controlling spins in adsorbed molecules by a chemical switch. AB - The development of chemical systems with switchable molecular spins could lead to the architecture of materials with controllable magnetic or spintronic properties. Here, we present conclusive evidence that the spin of an organometallic molecule coupled to a ferromagnetic substrate can be switched between magnetic off and on states by a chemical stimulus. This is achieved by nitric oxide (NO) functioning as an axial ligand of cobalt(II)tetraphenylporphyrin (CoTPP) ferromagnetically coupled to nickel thin film (Ni(001)). On NO addition, the coordination sphere of Co(2+) is modified and a NO-CoTPP nitrosyl complex is formed, which corresponds to an off state of the Co spin. Thermal dissociation of NO from the nitrosyl complex restores the on state of the Co spin. The NO-induced reversible off-on switching of surface adsorbed molecular spins observed here is attributed to a spin trans effect. PMID- 20975714 TI - A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source dependent growth inhibitors devoid of in vivo efficacy. AB - Candidate antibacterials are usually identified on the basis of their in vitro activity. However, the apparent inhibitory activity of new leads can be misleading because most culture media do not reproduce an environment relevant to infection in vivo. In this study, while screening for novel anti-tuberculars, we uncovered how carbon metabolism can affect antimicrobial activity. Novel pyrimidine-imidazoles (PIs) were identified in a whole-cell screen against Mycobacterium tuberculosis. Lead optimization generated in vitro potent derivatives with desirable pharmacokinetic properties, yet without in vivo efficacy. Mechanism of action studies linked the PI activity to glycerol metabolism, which is not relevant for M. tuberculosis during infection. PIs induced self-poisoning of M. tuberculosis by promoting the accumulation of glycerol phosphate and rapid ATP depletion. This study underlines the importance of understanding central bacterial metabolism in vivo and of developing predictive in vitro culture conditions as a prerequisite for the rational discovery of new antibiotics. PMID- 20975715 TI - The fitness of dispersing spotted hyaena sons is influenced by maternal social status. AB - Life history theory predicts that mothers should provide their offspring with a privileged upbringing if this enhances their offspring's and their own fitness. In many mammals, high-ranking mothers provide their offspring with a privileged upbringing. Whether dispersing sons gain fitness benefits during adulthood from such privileges (a 'silver spoon' effect) has rarely been examined. In this paper, we show that in the complex, female-dominated society of spotted hyaenas, high-born sons grew at higher rates, were more likely to disperse to clans offering the best fitness prospects, started reproducing earlier and had a higher reproductive value than did lower-born sons. This illustrates the evolutionary importance of maternal effects even in societies in which male size or fighting ability does not influence fitness. By demonstrating for the first time in a non human mammal that maternal status influences immigration patterns, the study also advances our understanding of two key ecological and evolutionary processes, dispersal and habitat selection. PMID- 20975716 TI - Plasmonic nanoresonators for high-resolution colour filtering and spectral imaging. AB - Colour and spectral imaging systems typically use filters and glass prisms to disperse light of different wavelengths. With the miniaturization of integrated devices, current research on imaging sensors focuses on novel designs aiming at high efficiency, low power consumption and slim dimension, which poses great challenges to the traditional colourant-based filtering and prism-based spectral splitting techniques. In this context, surface plasmon-based nanostructures are attractive due to their small dimensions and the ability to efficiently manipulate light. In this article we use selective conversion between free-space waves and spatially confined modes in plasmonic nanoresonators formed by subwavelength metal-insulator-metal stack arrays to show that the transmission spectra through such arrays can be well controlled by using simple design rules, and high-efficiency colour filters capable of transmitting arbitrary colours can be achieved. These artificial nanostructures provide an approach for high spatial resolution colour filtering and spectral imaging with extremely compact device architectures. PMID- 20975717 TI - Male water striders attract predators to intimidate females into copulation. AB - Despite recent advances in our understanding of sexual conflict and antagonistic coevolution between sexes, the role of interspecific interactions, such as predation, in these evolutionary processes remains unclear. In this paper, we present a new male mating strategy whereby a male water strider Gerris gracilicornis intimidates a female by directly attracting predators as long as she does not accept the male's coercive copulation attempt. We argue that this male strategy is a counteradaptation to the evolution of the female morphological shield protecting her genitalia from coercive intromission by water strider males. The G. gracilicornis mating system clearly represents an effect expected from models of the coevolutionary arms race between sexes, whereby one sex causes a decrease in the fitness component of the other sex. Moreover, our study demonstrates a crucial role that interspecific interactions such as predation can have in the antagonistic coevolution between sexes. PMID- 20975718 TI - Current drive at plasma densities required for thermonuclear reactors. AB - Progress in thermonuclear fusion energy research based on deuterium plasmas magnetically confined in toroidal tokamak devices requires the development of efficient current drive methods. Previous experiments have shown that plasma current can be driven effectively by externally launched radio frequency power coupled to lower hybrid plasma waves. However, at the high plasma densities required for fusion power plants, the coupled radio frequency power does not penetrate into the plasma core, possibly because of strong wave interactions with the plasma edge. Here we show experiments performed on FTU (Frascati Tokamak Upgrade) based on theoretical predictions that nonlinear interactions diminish when the peripheral plasma electron temperature is high, allowing significant wave penetration at high density. The results show that the coupled radio frequency power can penetrate into high-density plasmas due to weaker plasma edge effects, thus extending the effective range of lower hybrid current drive towards the domain relevant for fusion reactors. PMID- 20975719 TI - Tunable quantum beam splitters for coherent manipulation of a solid-state tripartite qubit system. AB - Coherent control of quantum states is at the heart of implementing solid-state quantum processors and testing quantum mechanics at the macroscopic level. Despite significant progress made in recent years in controlling single- and bi partite quantum systems, coherent control of quantum wave function in multipartite systems involving artificial solid-state qubits has been hampered due to the relatively short decoherence time and lack of precise control methods. Here we report the creation and coherent manipulation of quantum states in a tripartite quantum system, which is formed by a superconducting qubit coupled to two microscopic two-level systems (TLSs). The avoided crossings in the system's energy-level spectrum due to the qubit-TLS interaction act as tunable quantum beam splitters of wave functions. Our result shows that the Landau-Zener Stuckelberg interference has great potential in precise control of the quantum states in the tripartite system. PMID- 20975721 TI - Crustaceans from bitumen clast in Carboniferous glacial diamictite extend fossil record of copepods. AB - Copepod crustaceans are extremely abundant but, because of their small size and fragility, they fossilize poorly. Their fossil record consists of one Cretaceous (c. 115 Ma) parasite and a few Miocene (c. 14 Ma) fossils. In this paper, we describe abundant crustacean fragments, including copepods, from a single bitumen clast in a glacial diamictite of late Carboniferous age (c. 303 Ma) from eastern Oman. Geochemistry identifies the source of the bitumen as an oilfield some 100 300 km to the southwest, which is consistent with an ice flow direction from glacial striae. The bitumen likely originated as an oil seep into a subglacial lake. This find extends the fossil record of copepods by some 188 Ma, and of free living forms by 289 Ma. The copepods include evidence of the extant family Canthocamptidae, believed to have colonized fresh water in Pangaea during Carboniferous times. PMID- 20975722 TI - Sustainable biochar to mitigate global climate change. AB - Production of biochar (the carbon (C)-rich solid formed by pyrolysis of biomass) and its storage in soils have been suggested as a means of abating climate change by sequestering carbon, while simultaneously providing energy and increasing crop yields. Substantial uncertainties exist, however, regarding the impact, capacity and sustainability of biochar at the global level. In this paper we estimate the maximum sustainable technical potential of biochar to mitigate climate change. Annual net emissions of carbon dioxide (CO(2)), methane and nitrous oxide could be reduced by a maximum of 1.8 Pg CO(2)-C equivalent (CO(2)-C(e)) per year (12% of current anthropogenic CO(2)-C(e) emissions; 1 Pg=1 Gt), and total net emissions over the course of a century by 130 Pg CO(2)-C(e), without endangering food security, habitat or soil conservation. Biochar has a larger climate-change mitigation potential than combustion of the same sustainably procured biomass for bioenergy, except when fertile soils are amended while coal is the fuel being offset. PMID- 20975723 TI - A single-vesicle content mixing assay for SNARE-mediated membrane fusion. AB - The in vitro studies of membrane fusion mediated by soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) have primarily been conducted by following the mixing of lipids. However, the formation of a fusion pore and its expansion has been difficult to detect directly because of the leakiness of proteoliposomes, vesicle aggregation and rupture that often complicate the interpretation of ensemble fusion experiments. Fusion pore expansion is an essential step for full-collapse fusion and for recycling of fusion mechanisms. Here, we demonstrate a method to detect the inter-vesicular mixing of large cargoes at the single-molecule and -vesicle level. The change in fluorescence resonance energy transfer signal when a DNA hairpin encapsulated in a surface-tethered vesicle encounters a complementary DNA strand from another vesicle indicates content mixing. We found that the yeast SNARE complex alone without any accessory proteins can expand the fusion pore large enough to transmit ~11 kDa cargoes. PMID- 20975720 TI - Biogeography and habitat modelling of high-alpine bacteria. AB - Soil microorganisms dominate terrestrial biogeochemical cycles; however, we know very little about their spatial distribution and how changes in the distributions of specific groups of microbes translate into landscape and global patterns of biogeochemical processes. In this paper, we use a nested sampling scheme at scales ranging from 2 to 2,000 m to show that bacteria have significant spatial autocorrelation in community composition up to a distance of 240 m, and that this pattern is driven by changes in the relative abundance of specific bacterial clades across the landscape. Analysis of clade habitat distribution models and spatial co-correlation maps identified soil pH, plant abundance and snow depth as major variables structuring bacterial communities across this landscape, and revealed an unexpected and important oligotrophic niche for the Rhodospirillales in soil. Furthermore, our global analysis of high-elevation soils from the Andes, Rockies, Himalayas and Alaskan range shows that habitat distribution models for bacteria have a strong predictive power across the entire globe. PMID- 20975724 TI - Contribution of social marketing strategies to community-based obesity prevention programmes in children. AB - OBJECTIVES: To review child and adolescent obesity prevention programmes to determine whether they have included the Social Marketing Benchmark Criteria (BC). In addition, we analysed whether there was a relationship between the presence of the criteria and the effectiveness of the programme. METHODS: Interventions had to be aimed at preventing obesity through behaviour changes relating to diet, physical activity, lifestyle and social support, separately or in combination. A total of 41 interventions were identified in PubMed and Embase that fulfilled the inclusion criteria. RESULTS: The more recent the studies, the greater the number of the BC that seem to have been used. However, regarding behaviour changes, we found the most effective period to be 1997-2002, with 100% of the interventions resulting in behaviour changes (9/9). In addition, almost all interventions resulted in improvements in body composition variables: 5 of 6 for body mass index or overweight/obesity prevalence and 6 of 6 for skin-folds. CONCLUSIONS: The presence of a higher number of BC does not assure higher effectiveness. Further research is required in this field. At the moment, studies aimed at preventing obesity in children and adolescents have not included social marketing aspects in their interventions in a comprehensive manner. PMID- 20975725 TI - Long-term impact of overweight and obesity in childhood and adolescence on morbidity and premature mortality in adulthood: systematic review. AB - BACKGROUND AND OBJECTIVE: The last systematic review on the health consequences of child and adolescent obesity found little evidence on consequences for adult health. The present study aimed to summarize evidence on the long-term impact of child and adolescent obesity for premature mortality and physical morbidity in adulthood. METHODS: Systematic review with evidence searched from January 2002 to June 2010. Studies were included if they contained a measure of overweight and/or obesity between birth and 18 years (exposure measure) and premature mortality and physical morbidity (outcome) in adulthood. RESULTS: Five eligible studies examined associations between overweight and/or obesity, and premature mortality: 4/5 found significantly increased risk of premature mortality with child and adolescent overweight or obesity. All 11 studies with cardiometabolic morbidity as outcomes reported that overweight and obesity were associated with significantly increased risk of later cardiometabolic morbidity (diabetes, hypertension, ischaemic heart disease, and stroke) in adult life, with hazard ratios ranging from 1.1-5.1. Nine studies examined associations of child or adolescent overweight and obesity with other adult morbidity: studies of cancer morbidity were inconsistent; child and adolescent overweight and obesity were associated with significantly increased risk of later disability pension, asthma, and polycystic ovary syndrome symptoms. CONCLUSIONS: A relatively large and fairly consistent body of evidence now demonstrates that overweight and obesity in childhood and adolescence have adverse consequences on premature mortality and physical morbidity in adulthood. PMID- 20975726 TI - Characterizing the profile of obese patients who are metabolically healthy. AB - The presence of obesity-related metabolic disturbances varies widely among obese individuals. Accordingly, a unique subset of obese individuals has been described in the medical literature, which seems to be protected or more resistant to the development of metabolic abnormalities associated with obesity. These individuals, now known as 'metabolically healthy but obese' (MHO), despite having excessive body fatness, display a favorable metabolic profile characterized by high levels of insulin sensitivity, no hypertension as well as a favorable lipid, inflammation, hormonal, liver enzyme and immune profile. However, recent studies have indicated that this healthier metabolic profile may not translate into a lower risk for mortality. Mechanisms that could explain the favorable metabolic profile of MHO individuals are poorly understood. However, preliminary evidence suggests that differences in visceral fat accumulation, birth weight, adipose cell size and gene expression-encoding markers of adipose cell differentiation may favor the development of the MHO phenotype. Despite the uncertainty regarding the exact degree of protection related to the MHO status, identification of underlying factors and mechanisms associated with this phenotype will eventually be invaluable in helping us understand factors that predispose, delay or protect obese individuals from metabolic disturbances. Collectively, a greater understanding of the MHO individual has important implications for therapeutic decision making, the characterization of subjects in research protocols and medical education. PMID- 20975727 TI - Association between attention-deficit/hyperactivity disorder symptoms and obesity and hypertension in early adulthood: a population-based study. AB - OBJECTIVE: To examine the associations between attention-deficit/hyperactivity disorder (ADHD) symptoms, obesity and hypertension in young adults in a large population-based cohort. DESIGN, SETTING AND PARTICIPANTS: The study population consisted of 15,197 respondents from the National Longitudinal Study of Adolescent Health, a nationally representative sample of adolescents followed from 1995 to 2009 in the United States. Multinomial logistic and logistic models examined the odds of overweight, obesity and hypertension in adulthood in relation to retrospectively reported ADHD symptoms. Latent curve modeling was used to assess the association between symptoms and naturally occurring changes in body mass index (BMI) from adolescence to adulthood. RESULTS: Linear association was identified between the number of inattentive (IN) and hyperactive/impulsive (HI) symptoms and waist circumference, BMI, diastolic blood pressure and systolic blood pressure (all P-values for trend <0.05). Controlling for demographic variables, physical activity, alcohol use, smoking and depressive symptoms, those with three or more HI or IN symptoms had the highest odds of obesity (HI 3+, odds ratio (OR)=1.50, 95% confidence interval (CI) = 1.22-2.83; IN 3+, OR = 1.21, 95% CI = 1.02-1.44) compared with those with no HI or IN symptoms. HI symptoms at the 3+ level were significantly associated with a higher OR of hypertension (HI 3+, OR = 1.24, 95% CI = 1.01-1.51; HI continuous, OR = 1.04, 95% CI = 1.00-1.09), but associations were nonsignificant when models were adjusted for BMI. Latent growth modeling results indicated that compared with those reporting no HI or IN symptoms, those reporting 3 or more symptoms had higher initial levels of BMI during adolescence. Only HI symptoms were associated with change in BMI. CONCLUSION: Self-reported ADHD symptoms were associated with adult BMI and change in BMI from adolescence to adulthood, providing further evidence of a link between ADHD symptoms and obesity. PMID- 20975728 TI - Association between the APOA2 promoter polymorphism and body weight in Mediterranean and Asian populations: replication of a gene-saturated fat interaction. AB - OBJECTIVE: The APOA2 gene has been associated with obesity and insulin resistance (IR) in animal and human studies with controversial results. We have reported an APOA2-saturated fat interaction determining body mass index (BMI) and obesity in American populations. This work aims to extend our findings to European and Asian populations. METHODS: Cross-sectional study in 4602 subjects from two independent populations: a high-cardiovascular risk Mediterranean population (n = 907 men and women; aged 67 +/- 6 years) and a multiethnic Asian population (n = 2506 Chinese, n = 605 Malays and n = 494 Asian Indians; aged 39 +/- 12 years) participating in a Singapore National Health Survey. Anthropometric, clinical, biochemical, lifestyle and dietary variables were determined. Homeostasis model assessment of insulin resistance was used in Asians. We analyzed gene-diet interactions between the APOA2 -265T>C polymorphism and saturated fat intake (= 22 g per day) on anthropometric measures and IR. RESULTS: Frequency of CC (homozygous for the minor allele) subjects differed among populations (1-15%). We confirmed a recessive effect of the APOA2 polymorphism and replicated the APOA2-saturated fat interaction on body weight. In Mediterranean individuals, the CC genotype was associated with a 6.8% greater BMI in those consuming a high (P = 0.018), but not a low (P = 0.316) saturated fat diet. Likewise, the CC genotype was significantly associated with higher obesity prevalence in Chinese and Asian Indians only, with a high-saturated fat intake (P = 0.036). We also found a significant APOA2 saturated fat interaction in determining IR in Chinese and Asian Indians (P = 0.026). CONCLUSION: The influence of the APOA2 -265T>C polymorphism on body weight-related measures was modulated by saturated fat in Mediterranean and Asian populations. PMID- 20975730 TI - Evaluation of seminal zinc levels by atomic absorption in men with spinal cord injury. AB - STUDY DESIGN: A case-control study evaluating seminal zinc level in spinal cord injury (SCI) patients. OBJECTIVES: Patients with SCI have neurological prostate dysfunction. There are only some indications in the literature that seminal zinc level may be lower in these patients. Seminal zinc is mainly produced by the prostate and, therefore, can be considered to be a marker of prostate function. The objective of the present study was to determine whether SCI can induce changes in seminal zinc levels and to compare the results with those obtained for normal men (controls). SETTING: The study was carried out in Brazil. METHODS: A total of 24 men with SCI (mean age+/-s.d. 36.25+/-10.24 years) and 24 controls (mean age+/-s.d. 36.50+/-10.31 years) were studied. Blood and semen were collected after 3 days of abstinence from ejaculation. Semen was left at room temperature for 15 min, stored in liquid nitrogen, and lyophilized. Seminal zinc was determined by atomic absorption. Blood was stored at a controlled temperature of - 70 to -79 degrees C and later used for the determination of testosterone, prolactin and total prostate-specific antigen using an AxSYM apparatus and Abbott reagents. RESULTS: Mean seminal zinc concentration was 85.20 mg l(-1) for the patients, a lower value than that obtained for the controls (147.16 mg l(-1)) (P=0.0035). CONCLUSION: Patients with SCI have a significant reduction of seminal zinc. PMID- 20975729 TI - Association between the FTO rs9939609 polymorphism and leptin in European adolescents: a possible link with energy balance control. The HELENA study. AB - We examined the association between the FTO rs9939609 polymorphism and serum leptin concentrations in adolescents. The FTO rs9939609 polymorphism was genotyped, and fasting serum leptin and insulin were measured in 655 European adolescents (365 females) aged 14.6 +/- 1.2 years. We measured weight, height, triceps and subscapular skinfolds and waist circumference, and body fat percentage was calculated. Sex, pubertal status, center, physical activity (accelerometry), total or central adiposity and serum insulin concentrations were entered as confounders in the analyses. The minor A allele of the FTO rs9939609 was significantly associated with higher serum leptin concentrations independently of potential confounders including adiposity (+3.9 ng ml(-1) per risk allele (95% confidence interval: 2.0, 5.9); adjusted P < 0.001). These findings could link the FTO gene with serum leptin and consequently with the control of energy balance. Leptin could be a possible intermediary contributing to the association between the FTO rs9939609 polymorphism and adiposity. PMID- 20975731 TI - The timing and achievement of mobility skills during SCI rehabilitation. AB - STUDY DESIGN: Retrospective, observational study, with consecutive sampling. OBJECTIVES: To document the frequency and time frames for the achievement of independence in mobility skills for people undergoing rehabilitation following spinal cord injury (SCI). SETTING: The South Australian Spinal Cord Injury Service, Hampstead Rehabilitation Centre, Adelaide, Australia. METHODS: Retrospective data collection from a purpose-designed form. The achievement of independence in nine functional mobility skills, and time lines for this, were documented for people with a new SCI undergoing rehabilitation. Data from 152 participants were analyzed. RESULTS: Of the nine mobility-based goals evaluated, the one most likely to be achieved was sitting on the edge of the bed and the least likely was gait. Time taken to achieve the skills varied from 4 to 10 weeks on average and reflected the degree of difficulty. CONCLUSION: The frequency and time frames to achieve independence in mobility skills documented in this study will be useful when goal setting in a post-acute SCI rehabilitation setting. PMID- 20975733 TI - The roles of c-rel and interleukin-2 in tolerance: a molecular explanation of self-nonself discrimination. AB - The molecular mechanisms responsible for the exquisite discrimination between self and nonself molecules have remained enigmatic despite intense investigation. However, with the availability of adequate amounts of anergic lymphocytes produced by double transgenic mice, large numbers of immature B cells from sublethaly irradiated, hematopoietically-synchronized mice, as well as critical gene-deleted mice, it has been possible for the first time to uncover plausible molecular mechanisms that lead to tolerance versus immunity. The Rel family of transcription factors is expressed at different stages of lymphocyte maturation and differentiation. C-Rel is not activated by immature lymphocytes, which undergo either anergy or apoptosis when triggered by antigen receptors, but c-Rel is activated in mature lymphocytes. Antigen receptor triggering induces c-Rel dependent survival and proliferative genetic programs. In T cells, a critical c Rel-dependent gene encodes the T-cell growth factor interleukin-2 (IL-2). Thus, T cells from c-Rel gene-deleted mice produce inadequate quantities of IL-2, which renders them immunocompromised and unable to mount normal T-cell proliferative and differentiative responses. In the face of absolute IL-2 deficiency from birth, severe, multiorgan autoimmunity gradually ensues. Also, with more subtle IL-2 deficiency, organ/tissue-specific autoimmune disease becomes evident. Accordingly, both c-Rel and IL-2 appear to be key molecules for tolerance versus immunity, and doubtless will become foci for continued investigation, as well as future therapeutic targets in autoimmune diseases. PMID- 20975732 TI - PD-1 modulates regulatory T cells and suppresses T-cell responses in HCV associated lymphoma. AB - T regulatory (T(R)) cells suppress T-cell responses that are critical in the development of chronic viral infection and associated malignancies. Programmed death-1 (PD-1) also has a pivotal role in regulation of T-cell functions during chronic viral infection. To examine the role of PD-1 pathway in regulating T(R) cell functions that inhibit T-cell responses during virus-associated malignancy, T(R) cells were investigated in the setting of hepatitis C virus-associated lymphoma (HCV-L), non-HCV-associated lymphoma (non-HCV-L), HCV infection alone and healthy subjects (HS). Relatively high numbers of CD4(+)CD25(+) and CD8(+)CD25(+) T(R) cells, as well as high levels of PD-1 expressions on these T(R) cells were found in the peripheral blood of subjects with HCV-L compared with those from non-HCV-L or HCV alone or HS. T(R) cells from the HCV-L subjects were capable of suppressing the autogeneic lymphocyte response, and depletion of T(R) cells in peripheral blood mononuclear cells from HCV-L improved T-cell proliferation. Additionally, the suppressed T-cell activation and proliferation in HCV-L was partially restored by blocking the PD-1 pathway ex vivo, resulting in both a reduction in T(R)-cell number and the ability of T(R) to suppress the activity of effector T cells. This study suggests that the PD-1 pathway is involved in regulating T(R) cells that suppress T-cell functions in the setting of HCV-associated B-cell lymphoma. PMID- 20975734 TI - Cathepsin C limits acute viral infection independently of NK cell and CD8+ T-cell cytolytic function. AB - Destruction of target cells by cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells requires the coordinated action of the pore forming protein perforin (Pfp) and the granzyme (Gzm) family of serine proteases. The activation of a number of serine proteases, including GzmA and B, is predominately mediated by cathepsin C (CatC). Deficiencies in CatC-null mice were therefore expected to replicate the defects observed in GzmAB-deficient mice. We have previously determined that GzmAB-deficient mice exhibit increased susceptibility to murine cytomegalovirus (MCMV) infection. Here, we have compared the ability of CatC(-/-) mice to control MCMV infection with that of GzmAB-deficient animals. We found that CatC(-/-) mice have organ-specific defects in the ability to control MCMV replication, a phenotype that is distinct to that observed in GzmAB(-/-) mice. Significantly, the cytolytic function of CatC-deficient NK cells and CTLs elicited during infection was indistinguishable from that of wild-type cells. Hence, CatC is involved in limiting MCMV replication; however, this effect is independent of its role in promoting effector cytolytic activity. These data provide evidence for a novel and unexpected role of CatC during viral infection. PMID- 20975736 TI - Unusual viral ligand with alternative interactions is presented by HLA-Cw4 in human respiratory syncytial virus-infected cells. AB - Short viral antigens bound to human major histocompatibility complex (HLA) class I molecules are presented on infected cells. Vaccine development frequently relies on synthetic peptides to identify optimal HLA class I ligands. However, when natural peptides are analyzed, more complex mixtures are found. By immunoproteomics analysis, we identify in this study a physiologically processed HLA ligand derived from the human respiratory syncytial virus matrix protein that is very different from what was expected from studies with synthetic peptides. This natural HLA-Cw4 class I ligand uses alternative interactions to the anchor motifs previously described for its presenting HLA-Cw4 class I molecule. Finally, this octameric peptide shares its C-terminal core with the H-2D(b) nonamer ligand previously identified in the mouse model. These data have implications for the identification of antiviral cytotoxic T lymphocyte responses and for vaccine development. PMID- 20975737 TI - Trastuzumab and beyond: sequencing cancer genomes and predicting molecular networks. AB - Life diversity can now be clearly explored with the next-generation DNA sequencing technology, allowing the discovery of genetic variants among individuals, patients and tumors. However, beyond causal mutations catalog completion, systems medicine is essential to link genotype to phenotypic cancer diversity towards personalized medicine. Despite advances with traditional single genes molecular research, including rare mutations in BRCA1/2 and CDH1 for primary prevention and trastuzumab for treating HER2-overexpressing breast and gastric tumors, overall, treatment failure and death rates are still alarmingly high. Revolution in sequencing reveals that, now both a huge number and widespread variability of driver mutations, including single-nucleotide polymorphisms, genomic rearrangements and copy-number changes involved in breast cancer development. All these genetic alterations result in a heterogeneous deregulation of signaling pathways, including EGFR, HER2, VEGF, Wnt/Notch, TGF and others.Cancer initiation, progression and metastases are driven by complex molecular networks rather than linear genotype-phenotype relationship. Therefore, clinical expectations by traditional molecular research strategies targeting single genes and single signaling pathways are likely minimal. This review discusses the necessity of molecular networks modeling to understand complex gene gene, protein-protein and gene-environment interactions. Moreover, the potential of systems clinico-biological approaches to predict intracellular signaling pathways components networks and cancer heterogeneous cells within an individual tumor is described. A flowchart specific for three steps in cancer evolution separately tumorigenesis, early-stage and advanced-stage breast cancer is presented. Using reverse engineering starting with the integration of available established clinical, environmental, treatment and oncological outcomes (survival and death) data and then the still incomplete but progressively accumulating genotypic data into computational networks modeling may lead to bionetworks-based discovery of robust biomarkers and highly effective cancer drugs targets. PMID- 20975738 TI - Daily, monthly and seasonal variation in PSA levels and the association with weather parameters. AB - PSA levels have shown daily and seasonal variation, although data are conflicting regarding the season with higher PSA levels and the clinical relevance of this. We assessed the correlation of total PSA levels with meteorological data on a daily, weekly, monthly and seasonal basis. Data from 53,224 men aged 45-74 years, with an initial PSA <10.0 ng ml(-1) were correlated with temperature ( degrees C), duration of bright sunshine (hours) and rainfall (mm). There was seasonal variation in PSA levels, with median PSA being higher in spring compared with other seasons (1.18 vs 1.10 ng ml(-1), P = 0.004). Seasonal variation was not apparent when PSA levels were age-adjusted (P = 0.112). Total PSA was not correlated with daily, weekly or monthly hours of sunshine, rainfall or mean temperature. In contrast, age-adjusted PSA varied with weekday, with higher PSA levels on Thursday and Friday compared with other days (1.16 vs 1.10 ng ml(-1), respectively). On multivariate analysis, only age predicted for PSA levels >3.0 ng ml(-1). In conclusion, PSA levels did show seasonal variation, although there was no direct correlation between PSA and any meteorological parameter. The degree of seasonal variation is small and the decision to proceed to prostate biopsy should be independent of season or weather parameters. PMID- 20975735 TI - The autoimmunity of primary biliary cirrhosis and the clonal selection theory. AB - Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease in which an immune-mediated injury targets the small intrahepatic bile ducts. PBC is further characterized by highly specific serum antimitochondrial autoantibodies (AMAs) and autoreactive T cells, a striking female predominance, a strong genetic susceptibility and a plethora of candidate environmental factors to trigger the disease onset. For these reasons, PBC appears ideal to represent the developments of the clonal selection theory over the past decades. First, a sufficiently potent autoimmunogenic stimulus in PBC would require the coexistence of numerous pre-existing conditions (mostly genetic, as recently illustrated by genome-wide association studies and animal models) to perpetuate the destruction of the biliary epithelium by the immune system via the persistence of forbidden clones. Second, the proposed modifications of mitochondrial autoantigens caused by infectious agents and/or xenobiotics well illustrate the possibility that peculiar changes in the antigen structure and flexibility may contribute to tolerance breakdown. Third, the unique apoptotic features shown for cholangiocytes are the ideal setting for the development of mitochondrial autoantigen presentation to the immune system through macrophages and AMA; thus, turning the non-traditional mitochondrial antigen into a traditional one. This article will review the current knowledge on PBC etiology and pathogenesis in light of the clonal selection theory developments. PMID- 20975739 TI - Identifying cooperative transcription factors by combining ChIP-chip data and knockout data. PMID- 20975740 TI - Molecular mechanisms of "off-on switch" of activities of human IDH1 by tumor associated mutation R132H. AB - Human cytosolic NADP-IDH (IDH1) has recently been found to be involved in tumorigenesis. Notably, the tumor-derived IDH1 mutations identified so far mainly occur at Arg132, and mutation R132H is the most prevalent one. This mutation impairs the oxidative IDH activity of the enzyme, but renders a new reduction function of converting alpha-ketoglutarate (alphaKG) to 2-hydroxyglutarate. Here, we report the structures of the R132H mutant IDH1 with and without isocitrate (ICT) bound. The structural data together with mutagenesis and biochemical data reveal a previously undefined initial ICT-binding state and demonstrate that IDH activity requires a conformational change to a closed pre-transition state. Arg132 plays multiple functional roles in the catalytic reaction; in particular, the R132H mutation hinders the conformational changes from the initial ICT binding state to the pre-transition state, leading to the impairment of the IDH activity. Our results describe for the first time that there is an intermediate conformation that corresponds to an initial ICT-binding state and that the R132H mutation can trap the enzyme in this conformation, therefore shedding light on the molecular mechanism of the "off switch" of the potentially tumor-suppressive IDH activity. Furthermore, we proved the necessity of Tyr139 for the gained alphaKG reduction activity and propose that Tyr139 may play a vital role by compensating the increased negative charge on the C2 atom of alphaKG during the transfer of a hydride anion from NADPH to alphaKG, which provides new insights into the mechanism of the "on switch" of the hypothetically oncogenic reduction activity of IDH1 by this mutation. PMID- 20975741 TI - IkappaBbeta is a positive and negative regulator of NF-kappaB activity during inflammation. PMID- 20975742 TI - Functional role of chemokines in liver disease models. AB - Chemokines are a class of small cytokine-like molecules that orchestrate immune cell infiltration into the liver in response to acute and chronic injuries. Apart from their chemotactic effect, however, chemokines seem to mediate many other aspects of liver diseases, including a direct activation of stellate cells, the modulation of hepatocyte proliferation and angiogenesis. The identification of specific biological functions for chemokines in liver diseases has been hampered by the finding that resident and infiltrating cells in the liver are often a source, as well as a target, of chemokines. Furthermore, chemokines might cause differing effects depending on the etiology of liver damage, their local concentrations and their ability to form multimers and heterodimers. Nevertheless, the functions of a number of important chemokines and their associated receptors have been identified in both in vivo and in vitro studies. Indeed, harmful (proinflammatory, profibrogenic) and beneficial (antifibrogenic, antiangiogenic) effects of chemokines have been discovered in experimental liver disease models. In this Review, the current knowledge of chemokines in experimental liver disease models is summarized. Advances that might lead to preclinical applications are discussed, as are the roles of chemokine receptors as promising pharmacologically targetable molecules. PMID- 20975743 TI - Glycogen storage disease type I and G6Pase-beta deficiency: etiology and therapy. AB - Glycogen storage disease type I (GSD-I) consists of two subtypes: GSD-Ia, a deficiency in glucose-6-phosphatase-alpha (G6Pase-alpha) and GSD-Ib, which is characterized by an absence of a glucose-6-phosphate (G6P) transporter (G6PT). A third disorder, G6Pase-beta deficiency, shares similarities with this group of diseases. G6Pase-alpha and G6Pase-beta are G6P hydrolases in the membrane of the endoplasmic reticulum, which depend on G6PT to transport G6P from the cytoplasm into the lumen. A functional complex of G6PT and G6Pase-alpha maintains interprandial glucose homeostasis, whereas G6PT and G6Pase-beta act in conjunction to maintain neutrophil function and homeostasis. Patients with GSD-Ia and those with GSD-Ib exhibit a common metabolic phenotype of disturbed glucose homeostasis that is not evident in patients with G6Pase-beta deficiency. Patients with a deficiency in G6PT and those lacking G6Pase-beta display a common myeloid phenotype that is not shared by patients with GSD-Ia. Previous studies have shown that neutrophils express the complex of G6PT and G6Pase-beta to produce endogenous glucose. Inactivation of either G6PT or G6Pase-beta increases neutrophil apoptosis, which underlies, at least in part, neutrophil loss (neutropenia) and dysfunction in GSD-Ib and G6Pase-beta deficiency. Dietary and/or granulocyte colony-stimulating factor therapies are available; however, many aspects of the diseases are still poorly understood. This Review will address the etiology of GSD-Ia, GSD-Ib and G6Pase-beta deficiency and highlight advances in diagnosis and new treatment approaches, including gene therapy. PMID- 20975746 TI - Focus on epigenetics. AB - We present a special focus on epigenetics in the nervous system, highlighting recent advances in our understanding of epigenetic mechanisms and their regulation in neurons, as well as their role in nervous system function. PMID- 20975745 TI - Breast cancer assessment tools and optimizing adjuvant therapy. AB - Recommendation of systemic adjuvant therapy and choice of optimal agents for early-stage breast cancer remains a challenge. Adjuvant therapy is indicated on the assumption of residual micrometastatic disease. Adjuvant assessment tools for prognosis and prediction of treatment benefit, including Adjuvant! Online, the St Gallen Consensus, Oncotype DX((r)) and MammaPrint((r)), aid clinical decision making. However, all of these tools have limitations that must be considered in their judicious application. Clinicopathological based tools are critically dependent on accurate, standardized measurement of parameters. Multigene tools are appealing for their objectivity and reproducibility, particularly regarding analysis of proliferation, but these approaches still overlook the biological heterogeneity within tumors evidenced by distinct cell subpopulations with different genomic patterns and function. The greatest treatment challenge remains for patients assessed as intermediate risk of relapse, a problem not overcome by multigene tools. Remarkable diversity in breast cancer dictates that adjuvant management must be biologically driven. Future identification of predictive biomarkers for specific chemotherapy sensitivity may allow targeted use of available agents, including anthracyclines, taxanes and DNA damaging agents. The presence of drug targets and targetable signaling pathways, rather than molecularly defined subgroups, may ultimately drive treatment decisions. PMID- 20975748 TI - Bringing SOD1 into the fold. PMID- 20975744 TI - Translating p53 into the clinic. AB - Mutations in the TP53 gene are a feature of 50% of all reported cancer cases. In the other 50% of cases, the TP53 gene itself is not mutated but the p53 pathway is often partially inactivated. Cancer therapies that target specific mutant genes are proving to be highly active and trials assessing agents that exploit the p53 system are ongoing. Many trials are aimed at stratifying patients on the basis of TP53 status. In another approach, TP53 is delivered as a gene therapy; this is the only currently approved p53-based treatment. The p53 protein is overexpressed in many cancers and p53-based vaccines are undergoing trials. Processed cell-surface p53 is being exploited as a target for protein-drug conjugates, and small-molecule drugs that inhibit the activity of MDM2, the E3 ligase that regulates p53 levels, have been developed by several companies. The first MDM2 inhibitors are being trialed in both hematologic and solid malignancies. Finally, the first agent found to restore the active function of mutant TP53 has just entered the clinic. Here we discuss the basis of these trials and the future of p53-based therapy. PMID- 20975749 TI - Categorizing speech. PMID- 20975750 TI - "Yes! We're all individuals!": redundancy in neuronal circuits. PMID- 20975751 TI - Making glutamatergic neurons from GABAergic progenitors. PMID- 20975752 TI - I see where you're hearing: how cross-modal plasticity may exploit homologous brain structures. PMID- 20975753 TI - The importance of degradation. PMID- 20975754 TI - Epigenetic regulation of the neural transcriptome: the meaning of the marks. AB - The field of epigenetics provides neurobiologists with candidate mechanisms for experience-dependent changes in gene transcription. The ability to realize the potential of epigenetics in defining the causal pathways lying between environmental signals, transcriptional regulation and neural function will depend on moving beyond correlational studies focusing on individual epigenetic marks. Here we attempt to provide a conceptual framework for integrative research on nucleotide sequence, chromatin modifications, RNA signaling and their interactions in understanding experience-dependent phenotypic plasticity. Studies in genomic imprinting may serve as an existing model for such approaches. PMID- 20975755 TI - DNA methylation and memory formation. AB - Memory formation and storage require long-lasting changes in memory-related neuronal circuits. Recent evidence indicates that DNA methylation may serve as a contributing mechanism in memory formation and storage. These emerging findings suggest a role for an epigenetic mechanism in learning and long-term memory maintenance and raise apparent conundrums and questions. For example, it is unclear how DNA methylation might be reversed during the formation of a memory, how changes in DNA methylation alter neuronal function to promote memory formation, and how DNA methylation patterns differ between neuronal structures to enable both consolidation and storage of memories. Here we evaluate the existing evidence supporting a role for DNA methylation in memory, discuss how DNA methylation may affect genetic and neuronal function to contribute to behavior, propose several future directions for the emerging subfield of neuroepigenetics, and begin to address some of the broader implications of this work. PMID- 20975756 TI - Plasticity and specificity of the circadian epigenome. AB - Circadian clocks control a variety of neuronal, behavioral and physiological responses, via transcriptional regulation of an appreciable portion of the genome. We describe the complex communication network between the brain-specific central clock and the tissue-specific peripheral clocks that serve to synchronize the organism to both external and internal demands. In addition, we discuss and speculate on how epigenetic processes are involved in creating transcriptional environments that are permissive to tissue-specific gene expression programs, which work in concert with the circadian machinery. Accumulating data show that chromatin remodeling events may be critical for providing specificity and plasticity in circadian regulation, and metabolic cues may be involved in directing such epigenetic events. A detailed understanding of the communication cues between the central and peripheral clocks is crucial for a more complete understanding of the circadian system and the several levels of control that are implicated in maintaining biological timekeeping. PMID- 20975757 TI - Dynamic epigenetic regulation in neurons: enzymes, stimuli and signaling pathways. AB - The development and function of neurons require the regulated expression of large numbers of very specific gene sets. Epigenetic modifications of both DNA and histone proteins are now emerging as fundamental mechanisms by which neurons adapt their transcriptional response to developmental and environmental cues. In the nervous system, the mechanisms by which extracellular signals regulate the activity of chromatin-modifying enzymes have just begun to be characterized. In this Review, I discuss how extracellular cues, including synaptic activity and neurotrophic factors, influence epigenetic modifications and regulate the neuronal transcriptional response. I also summarize additional mechanisms that induce chromatin remodeling events by combinatorial assembly of multiprotein complexes on neuronal gene promoters. PMID- 20975759 TI - Evaluation of motivational effects induced by intracranial self-stimulation behavior. AB - In the runway model of intracranial self-stimulation (ICSS) experimentation, the experimental animal is timed in running a fixed distance to depress a lever that releases electrical stimulation to an electrode implanted along its medial forebrain bundle. This ICSS has both a reward and a motivational component. Using the runway method and priming stimulation, we designed an experimental method for directly measuring motivation. An assessment of pharmacological agents that are known to influence motivational states was also undertaken. Using the experimental methods that we created, we observed prominent changes in running speed when animals were exposed to methamphetamine and nicotine. According to these data, the runway method employing intracranial self-stimulation behavior may be useful for the evaluation of substances that act on motivation. We review the underlying neuropharmacological and anatomical functions associated with our experimental methods. We hope that this technique will be used to scientifically evaluate the impact of drugs and/or therapeutic interventions on human motivation. PMID- 20975758 TI - Epigenetic choreographers of neurogenesis in the adult mammalian brain. AB - Epigenetic mechanisms regulate cell differentiation during embryonic development and also serve as important interfaces between genes and the environment in adulthood. Neurogenesis in adults, which generates functional neural cell types from adult neural stem cells, is dynamically regulated by both intrinsic state specific cell differentiation cues and extrinsic neural niche signals. Epigenetic regulation by DNA and histone modifiers, non-coding RNAs and other self-sustained mechanisms can lead to relatively long-lasting biological effects and maintain functional neurogenesis throughout life in discrete regions of the mammalian brain. Here, we review recent evidence that epigenetic mechanisms carry out diverse roles in regulating specific aspects of adult neurogenesis and highlight the implications of such epigenetic regulation for neural plasticity and disorders. PMID- 20975760 TI - Glycocalyx degradation in retinal and choroidal capillary endothelium in rats with diabetes and hypertension. AB - Endothelial glycocalyx (GCX) has been reported as a protective factor for vascular endothelial cells (VEC) in diabetes and hypertension. However, the involvement of GCX impairment in ocular vasculopathy remains unclear. We evaluated the changes in the GCX thicknesses of the retinal and choroidal capillaries in rats with diabetes and hypertension by cationic colloidal iron staining using a transmission electron microscope. In the control group, the mean (standard error of the mean) thicknesses of retinal and choroidal GCX were 60.2 (1.5) nm and 84.3 (3.1) nm, respectively. The diabetic rats showed a significant decrease of GCX thickness in the retina, but not in the choroid, compared to controls (28.3 (0.3) nm, p<0.01 and 77.8 (1.4) nm, respectively). In the hypertensive rats, both retinal and choroidal GCX were significantly decreased compared to the control values (10.9 (0.4) nm and 13.2 (1.0) nm, respectively, both p<0.01). Moreover, we could visualize the adhesion of leukocytes and platelets on the luminal surface of VEC, at the site where the GCX was markedly degraded. These findings suggest that the GCX prevents adhesion of leukocytes and platelets to the VEC surface, and this impairment may lead to ocular vasculopathy in diabetes and hypertension. PMID- 20975761 TI - Cancer of unknown primary site: a review of 28 cases and the efficacy of cisplatin/docetaxel therapy at a single institute in Japan. AB - We evaluated the efficacy and toxicity of cisplatin/docetaxel (CDDP/TXT) chemotherapy and identified prognostic factors in Japanese patients with cancer of unknown primary site (CUP). Twenty-eight consecutive patients seen at a single institute were reviewed retrospectively. Sixteen patients were treated with TXT 80 mg/m2, followed by CDDP 75 mg/m2. The overall response rate to CDDP/TXT treatment was 62.5%, with a median survival time (MST) of 22.7 months. Common adverse reactions were myelosuppression and hyponatremia. The MST of all 28 patients with CUP was 8.3 months, and the 1-year overall survival rate was 45.6%. Univariate analysis identified 5 prognostic factors:performance status, liver involvement, bone involvement, pleural involvement, and lymph node involvement. In conclusion, CDDP/TXT chemotherapy is effective with tolerable toxicity in patients with CUP. Japanese patients with CUP might be chemosensitive and may survive longer. PMID- 20975762 TI - Upper lumbar pedicle screw insertion using three-dimensional fluoroscopy navigation: assessment of clinical accuracy. AB - We used a navigation system to insert 128 pedicle screws into 69 vertebrae (L1 to L3) of 49 consecutive patients. We assessed the pedicle isthmic width and the permission angle for pedicle screw insertion. The permission angle is the angle defined by the greatest medial and lateral trajectories allowable when placing the screw through the center of the pedicle. The rate of narrow-width pedicles (isthmic width less than 5 mm) was 5 of 60 pedicles (8%) at L1, 4 of 60 pedicles (7%) at L2, and none (0%) at L3, L4 and L5. The rate of narrow-angle pedicles (a permission angle less than 15 degrees) was 21 of 60 pedicles (35%) at L1, 7 of 60 (12%) at L2, 3 of 60 (5%) at L3, and none (0%) at L4 and L5. Of 128 pedicle screws inserted into 69 vertebrae from L1 to L3, 125 (97.7%) were classified as Grade 1 (no pedicle perforation). In general, the upper lumbar vertebrae have more narrow-width and -angle pedicles. However, we could reduce the rate of pedicle screw misplacement in upper lumbar vertebra using a three-dimensional fluoroscopy and navigation system. PMID- 20975763 TI - Obstructions of portal veins and tumor numbers are associated with humped hepatocellular carcinoma. AB - Tumor protrusion in hepatocellular carcinoma (HCC) is one of the risk signs of tumor rupture. Despite curative tumor treatments, HCC recurrences sometimes occur with rapidly growing humped or ruptured HCC in small sized tumors. The aim of this study was to clarify the characteristics of humped HCC clinically and radiologically associated with tumor progression, liver damage, and treatment. The subjects were 179 consecutive HCC patients who underwent angiographic examination. Dynamic studies, using helical computed tomography and magnetic resonance imaging were assessed, and the HCC area were measured. The tumor-node metastasis (TNM) stage differed significantly between the humped and non-humped HCC groups. Humped HCC was more frequently observed in the right lobe (29.3% of right-lobe HCCs) than in the left (10.1%; p=0.003). Analysis of recurrent HCC revealed that patients with multiple treatments of >4 sessions had more humped HCC (33.8%) than those with 1-3 sessions (16.7%; p=0.042). Multivariate regression analysis revealed that tumor invasion in the portal vein, rather than large tumor size, was significantly associated with tumor protrusion. HCC recurrence with humped HCC occurs often in patients with multiple treatments. Tumor factors of the TNM classification, especially tumor invasion in the portal vein, might be associated with the mechanisms of tumor protrusion. PMID- 20975765 TI - Prevalence and factors associated with hepatitis C virus infection among Myanmar blood donors. AB - We studied the prevalence of hepatitis C virus infection among blood donors from 3 hospitals of Central Myanmar and 7 hospitals of Lower Myanmar in the Yangon area, and analyzed the factors associated with the infection. The study period was from November, 2005 to June, 2007. A pre-tested questionnaire was used to obtain information on age, ethnic group, marital status, tattooing, body piercing, history of receiving transfusions, and liver diseases in self and in sexual partners. Data on seropositivity to hepatitis C, hepatitis B and human immunodeficiency virus infections were recorded. A total of 65,240 blood donors participated in the study. Their ages ranged from 18 years to 60 years (mean+/ SD=29.5+/-9.3). The male-to-female ratio was 6:1. The prevalence of the antibody to hepatitis C was found to be 0.95% with varying rates (0.34 to 2.03) among hospitals. Females had a slightly higher rate (1.06%) than males (0.93%) (p=0.237). Multivariate analyses revealed the following factors to be related to HCV infection:HIV infection, odds ratio (OR)=3.0 (p=0.003); history of liver disease, OR=8.9 (p=0.001);and age 30 years and above, OR=2.6 (p=0.001). We discuss the varying prevalences of HCV around the world. PMID- 20975764 TI - The effects of changing from isoflurane to desflurane on the recovery profile during the latter part of anesthesia. AB - It is not known whether changing from isoflurane to desflurane during the latter part of anesthesia shows early emergence and recovery in long surgery. We therefore evaluated the effects of changing isoflurane to desflurane on emergence and recovery. Eighty-two patients were randomly assigned to receive isoflurane (Group I) or desflurane (Group D) or to change from isoflurane to desflurane anesthesia (Group X). At the point when there was an hour until the operation would end, isoflurane was replaced with 1 MAC of desflurane in Group X, and isoflurane and desflurane were maintained at 1 MAC in Groups I and D. When the operation ended, we compared the emergence and recovery characteristics among the 3 groups. Compared with Group I, Group X showed faster emergence and recovery. Group X and Group D showed similar emergence and recovery. In conclusion, changing isoflurane to desflurane during the latter part of anesthesia improves emergence and recovery. PMID- 20975766 TI - Analysis of reactive oxygen metabolites (ROMs) after cardiovascular surgery as a marker of oxidative stress. AB - The transient systemic low perfusion that occurs during cardiovascular surgery leads to oxidative stress and the production of free radicals. A systemic increase of various markers of oxidative stress has been shown to occur during cardiopulmonary bypass (CPB). However, these markers have not been adequately evaluated because they seem to be reactive and short-lived. Here, oxidative stress was measured using the free radical analytical system (FRAS 4) assessing the derivatives of reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP). Blood samples were taken from 21 patients undergoing elective cardiovascular surgery. CPB was used in 15 patients, and abdominal aortic aneurysm (AAA) surgery without CPB was performed in 6. Measurements of d ROMs and BAP were taken before surgery, 1 day, 1 week, and 2 weeks after surgery, and oxidative stress was evaluated. The d-ROM level increased gradually after cardiovascular surgery up to 2 weeks. Over time, the d-ROM level after surgery involving CPB became higher than that after AAA surgery. This difference reached statistical significance at 1 week and lasted to 2 weeks. The prolongation of CPB was prone to elevate the d-ROM level whereas the duration of the aortic clamp in AAA surgery had no relation to the d-ROM level. The BAP was also elevated after surgery, and was positively correlated with the level of d-ROMs. In this study, patients who underwent cardiovascular surgery involving CPB had significant oxidative damage. The production of ROMs was shown to depend on the duration of CPB. Damage can be reduced if CPB is avoided. When CPB must be used, shortening the CPB time may be effective in reducing oxidative stress. PMID- 20975767 TI - Long-term results of primary total knee arthroplasty with and without patellar resurfacing. AB - Among patients that underwent total knee arthroplasty from June, 1990 to January, 1999, 61 cases (44 patients) that could be followed for more than 10 years were included in this study. The patients were divided into a patellar retention group and a patellar resurfacing group, and were compared with regard to their clinical and radiological outcomes. In patients undergoing primary TKA, a selective patellar resurfacing protocol was used. The indications for patellar retention were a small patella, nearly normal articular cartilage, minimal preoperative patellofemoral pain, poor patellar bone quality, and young patient age. When patellar retention was performed, osteophytes of the patella were removed and marginal electrocauterization was carried out. There were 25 cases (20 patients) in the patellar retention group and 36 cases (29 patients) in the patellar resurfacing group. The mean follow-up period was 140.7 months in the patellar retention group and 149.0 months in the patellar resurfacing group. The selective patellar resurfacing with total knee arthroplasty had a favorable outcome;there were a significant difference noted between the 2 groups in the functional scores, which showed better outcomes in the patellar resurfacing group than in the patellar retention group. PMID- 20975768 TI - Decreasing systolic blood pressure is associated with improving estimated glomerular filtration rate (eGFR) with lifestyle modification in Japanese healthy women. AB - The link between changes in a subject's metabolic syndrome components and her estimated glomerular filtration rate (eGFR) was evaluated in healthy Japanese women. We used data for 53 Japanese women (46.0+/-10.9 years) with a 1-year follow up. eGFR was defined by a new equation developed for Japan. There were no significant relationships between eGFR and clinical parameters at baseline. Subjects were given advice for dietary and lifestyle improvement. At the 1-year follow up, eGFR was significantly increased. In addition, changes in eGFR were weakly correlated with systolic blood pressure(r=-0.306, p=0.0260). A decrease in systolic blood pressure may be associated with improving eGFR in Japanese women. PMID- 20975769 TI - Intraoral vertical ramus osteotomy improved the stomatognathic function in an elderly patient with mandibular protrusion: a case report. AB - This article reports the successful surgical-orthodontic treatment of an elderly patient with dentofacial deformity and signs and symptoms of temporomandibular disorder (TMD). The patient was a 63-year-old woman with a concave profile due to mandibular protrusion. To correct skeletal deformities, the mandible was posteriorly repositioned by employing intraoral vertical ramus osteotomy (IVRO) following presurgical orthodontic treatment. After active treatment for 31 months, the facial profile was significantly improved and satisfactory occlusion was achieved. In addition, TMD symptoms of clicking sounds on the left side and difficulty in mouth opening were resolved. Regarding the findings of magnetic resonance imaging, anterior disc displacement in the opening phase was improved in the temporomandibular joint on the left side. Furthermore, stomatognathic functions were also improved without any aggravation of age-related problems. In conclusion, surgical repositioning of the mandible using IVRO leads to both morphological and functional improvements even in elderly patients. PMID- 20975770 TI - Current Genetic Epidemiology of beta-Thalassemias and Structural Hemoglobin Variants in the Lazio Region (Central Italy) Following Recent Migration Movements. AB - The aim of this study was to describe the changing pattern of mutational spectrum of beta-thalassemia (beta-thal) in the Lazio region (Central Italy), as consequence of recent demographic variations. From 1994 until present, 256 immigrant subjects with hemoglobin disorders (including 191 heterozygotes and 65 homozygotes or compound heterozygotes) coming from 44 different foreign countries, have been molecularly characterized. 14 beta-globin gene mutations were identified and their frequencies reflect different ethnic origins: 8 of these mutations account for 76.97% of all molecular defects, while 6 of them are much rare, representing less than 2% of the total. These data differ, both in type and percentage, from the mutational spectrum detected in the native population in 1995. Since a few defects are prevalent in each country, a proper strategy for the identification of mutations in immigrant individuals relies on the prior knowledge of their frequency in native ethnic group. PMID- 20975771 TI - T-Cell Traffic Jam in Hodgkin's Lymphoma: Pathogenetic and Therapeutic Implications. AB - In hematologic malignancies, the microenvironment is often characterized by nonneoplastic cells with peculiar phenotypic and functional features. This is particularly true in Hodgkin's lymphoma (HL), in which T lymphocytes surrounding Hodgkin's Reed-Sternberg cells are essentially polarized towards a memory T helper type 2 phenotype. In this paper we will first evaluate the main processes modulating T-cell recruitment towards the lymph node microenvironment in HL, especially focusing on the role played by cytokines. We will then consider the most relevant mechanisms of immune escape exerted by neoplastic cells in order to evade antitumor immunity. The potential pathogenetic and prognostic impact of regulatory T cells in such a context will be also described. We will finally overview some of the strategies of cellular immunotherapy applied in patients with HL. PMID- 20975773 TI - Applications of BMI or BSI: Differences and Revisions According to Age and Height. AB - Validation of body-mass relationships requires a careful statistical analysis of data of normal weight individuals. BMI (ratio between body mass and square of body height) and BSI values (ratio between mass and cube of body height) have been calculated for 99 persons with ages between 1 day and 76 years. These BMI or BSI values have been used for least squares fits yielding mean BMI or BSI values, their variances (providing precision), and average deviations of individual BMI/BSI values from the BMI/BSI means. The latter allows limits to over- and underweight. For adults we found mean values of BSI of 12.36 and confirmed 21.7 for the mean BMI; but the BSI was 1.4 times more precise than the BMI. For children shorter than 1.3 m and younger than 8 years we found the BMI average of 15.9 and over-/underweight limits of 17.4/14.4 being significantly smaller than and incompatible with the recommended BMI values. PMID- 20975772 TI - Hodgkin's Lymphoma: A Review of Neurologic Complications. AB - Hodgkin's lymphoma is a hematolymphoid neoplasm, primarily of B cell lineage, that has unique histologic, immunophenotypic, and clinical features. Neurologic complications of Hodgkin's Lymphoma can be separated into those that result directly from the disease, indirectly from the disease, or from its treatment. Direct neurologic dysfunction from Hodgkin's Lymphoma results from metastatic intracranial spinal disease, epidural metastases causing spinal cord/cauda equina compression, leptomeningeal metastases, or intradural intramedullary spinal cord metastases. Indirect neurologic dysfunction may be caused by paraneoplastic disorders (such as paraneoplastic cerebellar degeneration or limbic encephalitis) and primary angiitis of the central nervous system. Hodgkin's lymphoma treatment typically includes chemotherapy or radiotherapy with potential treatment-related complications affecting the nervous system. Neurologic complications resulting from mantle-field radiotherapy include the "dropped head syndrome," acute brachial plexopathy, and transient ischemic attacks/cerebral infarcts. Chemotherapy for Hodgkin's lymphoma may cause cerebral infarction (due to emboli from anthracycline-induced cardiomyopathy) and peripheral neuropathy. PMID- 20975775 TI - Model-Independent 3D Descriptors of Vertebral Cancellous Bone Architecture. AB - High-resolution micro computed tomography has enabled measurement of bone architecture derived from 3D representations of cancellous bone. Twenty-eight vertebral bodies were obtained from four embalmed male cadavers. From 3D anaglyphs, trabecular rod thickness and length were measured and the trabecular rod Buckling index was calculated. From 3D voxel-based datasets, bone volume density, trabecular thickness, and trabecular separation were measured. Also, trabecular bone pattern factor, structural model index, connectivity density, and degree of anisotropy were calculated. Bone volume density alone explains 59% of the variability in trabecular rod Buckling index. The addition of connectivity density, trabecular separation, and structural model index, in a multiple regression statistical model, improves the explanatory power to 77%. The relationships between measures of cancellous bone architecture and a derived measure of trabecular rod strength were investigated. Morphological descriptors of cancellous bone provide a composite explanatory model of trabecular rod strength. PMID- 20975774 TI - Diagnostic and Pathophysiological Impact of Myocardial MIBG Scintigraphy in Parkinson's Disease. AB - Myocardial MIBG scintigraphy is established in the diagnosis and differential diagnosis of Parkinson's disease (PD). Numerous studies address the pathophysiological impact of myocardial MIBG scintigraphy: the myocardial MIBG uptake correlates with the clinical phenotype of PD; the background of this phenomenon is unclear. Furthermore MIBG scintigraphy enables to study the extracranial Lewy body type-degeneration. In combination with cerebral dopamine transporter imaging, MIBG scintigraphy allows to correlate cerebral and extracranial Lewy body type-degeneration in PD. PMID- 20975776 TI - Lead Fractures in Deep Brain Stimulation during Long-Term Follow-Up. AB - The purpose was to determine the incidence of lead fracture in patients with DBS over a long period of time. We present a retrospective study of 208 patients who received 387 DBS electrodes. Fourteen patients had sixteen lead fractures (4% of the implanted leads) and two patients suffered from 2 lead fractures. Of all lead fractures, five patients had the connection between the leads and the extension cables located in mastoids region, ten in cervical area and one in thoracic region. The mean distance from the connection between the electrode and the extension cable and the lead fracture was 10.7 mm. The lead fracture is a common, although long-term complication in DBS surgery. In our experience, the most common site of electrode cable breakage is approximately between 9 and 13 mm from the junction between the lead and the extension cable. The most important cause of lead fracture is the rotational movement of the lead-extension cable system. If we suspect lead fracture, we must check the impedance of the electrode and to evaluate the side effects of voltage. Finally, we must conduct a radiological screening. PMID- 20975777 TI - Medication timing errors for Parkinson's disease: perspectives held by caregivers and people with Parkinson's in new zealand. AB - Background. Common but seldom published are Parkinson's disease (PD) medication errors involving late, extra, or missed doses. These errors can reduce medication effectiveness and the quality of life of people with PD and their caregivers. Objective. To explore lay perspectives of factors contributing to medication timing errors for PD in hospital and community settings. Design and Methods. This qualitative research purposively sampled individuals with PD, or a proxy of their choice, throughout New Zealand during 2008-2009. Data collection involved 20 semistructured, personal interviews by telephone. A general inductive analysis of the data identified core insights consistent with the study objective. Results. Five themes help to account for possible timing adherence errors by people with PD, their caregivers or professionals. The themes are the abrupt withdrawal of PD medication; wrong, vague or misread instructions; devaluation of the lay role in managing PD medications; deficits in professional knowledge and in caring behavior around PD in formal health care settings; and lay forgetfulness. Conclusions. The results add to the limited published research on medication errors in PD and help to confirm anecdotal experience internationally. They indicate opportunities for professionals and lay people to work together to reduce errors in the timing of medication for PD in hospital and community settings. PMID- 20975779 TI - KIF6 p.Trp719Arg Testing to Assess Risk of Coronary Artery Disease and/or Statin Response. AB - Coronary artery disease (CAD) is a leading cause of death worldwide and in the United States it is responsible for more than 500,000 deaths each year. Genome wide association studies (GWAS) have revealed connections between a number of common single nucleotide polymorphisms (SNPs) and CAD and other cardiovascular diseases. The p.Trp719Arg SNP in the kinesin-like family 6 (KIF6) gene has recently been reported as a potential risk factor for CAD as well as a predictor of response to statin therapy. PMID- 20975778 TI - Total cholesterol and the risk of Parkinson's disease: a review for some new findings. AB - The studies on the association between serum cholesterol level and the risks of neurodegenerative diseases risk are debated. Some prospective studies have found that high serum cholesterol may increase the risks of dementia/Alzheimer's disease and ischemic stroke. However, other studies have found no association or a decreased risk of hemorrhagic stroke with increasing levels of serum total cholesterol. Little is known about the association between serum total cholesterol or a history of hypercholesterolemia and Parkinson's disease (PD) risk. Only a few case-control studies and four prospective epidemiological studies have examined this association, but the results are inconsistent. An inverse association between serum total cholesterol and the risk of PD has been found in one prospective study; however, no significant association is reported in the case-control studies and other two prospective studies. Recently, one large prospective study from Finland suggests that high total cholesterol at baseline is associated with an increased risk of PD. Further studies, especially large clinical trials, are needed. PMID- 20975780 TI - Rectal prolapse in children: Laparoscopic suture rectopexy is a suitable alternative. AB - AIM: To study the clinical outcome of laparoscopic suture rectopexy (LSRP) in children with persistent rectal prolapse (PRP). MATERIALS AND METHODS: Nineteen cases of PRP were managed with LSRP from February 2005 to August 2009. RESULTS: All were followed up for an average duration of 6 months. Only one child had recurrence and was managed with sclerotherapy. CONCLUSIONS: LSRP is safe, feasible in children and gives satisfactory results. PMID- 20975781 TI - Webbed penis: A new classification. AB - AIM: To introduce a new classification for the congenital anomaly of webbed penis and suggest an operative technique that can be planned according to the severity of webbing. MATERIALS AND METHODS: A prospective study was conducted in two pediatric surgical units in Egypt and UAE on babies who were referred for circumcision. A preplanned written protocol was designed before commencing the study. RESULTS: A total of 5,881 babies aged from 1 day to 6 months were seen in two pediatric surgical units. The webbed penis is broadly classified into primary and secondary types. The primary is further subdivided into simple and compound. CONCLUSIONS: We believe that the new classification will serve as a baseline for the anatomical variants and help to streamline the operative procedure accordingly. PMID- 20975782 TI - Congenital malformations in Assam. AB - AIM: To determine the annual incidence of congenital malformations in Assam and to analyze the data. MATERIALS AND METHODS: Data regarding babies born with congenital malformations in the state of Assam during the year 2006 were obtained through questionnaires and analyzed. The results were compared with similar Indian data. RESULTS: The overall incidence of congenital malformation was 0.08%. This was considerably lower than similar published data from other states. Five hundred and eleven babies were born with congenital malformations, with 421 (82.4%) having major malformations. Males were affected more than females, 334 (65.4%) vs. 177 (34.6%). The gastrointestinal and genitourinary systems accounted for 26% and 25.8%, respectively. Malformation involving the central nervous system was more common in certain ethnic groups. CONCLUSIONS: The incidence of malformations in certain systems was at variance with the data from other states. PMID- 20975783 TI - Hirschsprung's disease: Role of rectal suction biopsy - data on 216 specimens. AB - BACKGROUND: The diagnosis of Hirschsprung's disease (HD) is dependent on the histological study of rectal ganglion cells, and an open rectal biopsy was the mainstay that required general anaesthesia (GA) and carried risk of postoperative rectal bleeding. Suction rectal biopsy later gained wide acceptance and became the choice as there is no requirement of GA and virtual absence of any complications. MATERIALS AND METHODS: A retrospective review of the histological findings of 216 rectal suction biopsies studied from 2005 to 2009. RESULTS: There were 143 male and 73 female children. 196 (90.7%) children were within 1 year of age. Among 216 rectal suction biopsies 181 (83.80%) were aganglionic, 27 (12.5%) were ganglionic and 8 (3.7%) were inadequate. Majority of patients were of less than 1 year of age (94.47%). CONCLUSIONS: The rectal suction biopsy is a bed side procedure, safe, cheap and time saving. There is high degree of accuracy, simplicity and absence of complications. PMID- 20975784 TI - Squamous cell carcinoma of esophagus in a 15-year-old boy. AB - A 15-year-old boy with well-differentiated squamous cell carcinoma of the lower esophagus is reported because of its rarity. The patient presented with dysphagia for 3 months and weight loss. The case was treated with radical excision, with excellent immediate response. PMID- 20975785 TI - Colorectal lithobezoar: A rare case report. AB - We report an unusual case of a giant lithobezoar that was extending from the caecum to the anal canal, and the patient had no features of absolute constipation or peritonitis. It is believed to be the first such giant colonic lithobezoar in the literature. PMID- 20975786 TI - Gastric lipoma. AB - We report a 12-year-old-boy with gastric lipoma. Upper gastrointestinal (GI) endoscopy with biopsy and abdominal computed tomogram (CT) scan revealed the diagnosis. Open surgical excision of the mass with stomach preservation was done. The clinical presentation and management are discussed and the literature reviewed here. This is the sixth pediatric case reported in the English literature. PMID- 20975787 TI - Beware of neonatal appendicitis. AB - We report a neonate with acute appendicitis who was mistakenly diagnosed and treated initially as neonatal necrotizing enterocolitis. The diagnostic dilemma of this rare and life-threatening condition in premature babies and newborns is underlined. Awareness of this rare condition and possible differential diagnosis in this age group is also discussed. PMID- 20975788 TI - Infarction of a polyp within a mesenteric cyst: An unusual presentation as an acute abdomen. AB - A case of mesenteric cyst in a five-year-old male child who presented with acute abdomen due to an infarcted polyp present within the cyst is reported. To the best of our knowledge, such an event has never been reported in the literature previously. PMID- 20975789 TI - Liver abscesses with pyopericardium: Laparoscopic management in a preterm neonate. AB - We report a 28-day-old neonate presenting with signs of fever, abdominal distension, and refusal to feed. The baby was diagnosed to have multiple liver abscesses which ruptured and a tract lead to the pericardium resulting in a pyo pericardium. Laparoscopic drainage of the abscess cavities and the pyo pericardium was performed. An extensive search of the literature revealed that this case is the youngest one to have undergone such simultaneous laparoscopic drainage. PMID- 20975790 TI - 'PEN' appendicitis. AB - We report a three-year-old boy who ingested the tip of a pen and presented with signs of appendicitis. Plain abdominal radiographs showed the foreign body in the right iliac fossa. Surgical exploration revealed perforated appendix and the foreign body in its lumen. Appendectomy resulted in satisfactory recovery. PMID- 20975791 TI - Authors' reply. PMID- 20975792 TI - A nonrandomized interventional study on perioperative fluid in children. PMID- 20975793 TI - Neonatal adrenal hemorrhage and neonatal jaundice. PMID- 20975794 TI - Acute inflammatory demyelinating polyneuropathy and a unilateral babinski/plantar reflex. AB - Acquired acute demyelinating peripheral polyneuropathy (AADP) is a general classification of pathologies that could affect secondary the peripheral nervous system. They are characterized by an autoimmune process directed towards myelin. Clinically they are characterized by progressive weakness and mild sensory changes. Acute inflammatory demyelinating polyneuropathy often is referred to as Guillain-Barre syndrome (GBS). GBS is the major cause of acute nontraumatic paralysis in healthy people and it is caused by autoimmune response to viral agents (influenza, coxsackie, Epstein-Barr virus, or cytomegalovirus) or bacterial infective organisms (Campylobacter jejuni, Mycoplasma pneumoniae). A detailed history, with symptoms of progressive usually bilateral weakness, hyporeflexia, with a typical demyelinating EMG pattern supports the diagnosis. Progressive affection of respiratory muscles and autonomic instability coupled with a protracted and unpredictable recovery normally results in the need for ICU management. We present a case report of a patient with a typical GBS presentation but with a unilateral upgoing plantar reflex (Babinski sign). A unifying diagnosis was made and based on a literature search in Pubmed appears to be the first described case of its kind. PMID- 20975795 TI - Sex Disparity in Food Allergy: Evidence from the PubMed Database. AB - Food allergies are potentially fatal immune-mediated disorders that are growing globally. The relationship between sex and food allergy remains incompletely understood. Here we tested the hypothesis that, should sex influence the clinical response to food allergens, this would be reflected by a sex disparity in published studies of food allergy. We performed a systematic search of the PubMed literature for IgE-mediated allergy to 11 allergenic foods of international regulatory importance. No date restriction was used and only articles in English were considered. Of the 4744 articles retrieved, 591 met the inclusion criteria representing 17528 subjects with food allergies. Whereas among children with food allergies, 64.35% were males and 35.65% were females (male/female ratio, 1.80), among adults 34.82% were males and 65.18% were females (male/female ratio, 0.53). Consequently, these data argue that there is need for further investigation to define the role of sex in the pathogenesis of food allergy. PMID- 20975796 TI - Exercise-Induced Asthma Symptoms and Nighttime Asthma: Are They Similar to AHR? AB - Background. Asthma experienced during exercise and during the night is based on the presence of airway hyperresponsiveness (AHR). The aim of the present study was to examine whether AHR is a predictor of exercise-induced asthma (EIA) and nighttime symptoms. Material. We included 793 asthmatics subjects with symptoms and a positive asthma test. Results. Mean (SD) FEV1 was 93% (15), 71% had rhinitis, and 62% had atopy. Both EIA and nighttime symptoms were associated with AHR; however, when including other factors of importance in a multivariate analysis, logRDR was eliminated, whereas FEV1% pred (P < .001), smoking (P < .05), atopy (P < .001), sex (P < .001), and treatment (P < .01) were associated with having EIA while dyspnoea (P < .001), cough (P < .001), and eosinophils (P < .01) were associated with frequent night symptoms. The risk of having nighttime awakenings due to asthma was more than twofold higher among those with EIA symptoms than among those without symptoms (OR (CI95%) 2.77 (2.0-3.8) (P < .001)). In Conclusion. EIA and night symptoms are associated with AHR, but other factors of importance eliminated this close association. Night asthma is more closely associated with airway inflammation than AHR. PMID- 20975797 TI - A 15-year-old boy with anterior chest pain, progressive dyspnea, and subcutaneous emphysema of the neck. AB - We describe the case of an adolescent who was admitted to the hospital because of sudden occurrence of chest pain, dyspnea and subcutaneous emphysema. On admission, physical examination revealed subcutaneous crepitations in the superior part of the rib cage, and auscultation of the chest showed widespread wheezing. The radiological assessment confirmed the diagnosis of pneumomediastinum and pneumothorax. A follow-up CT scan performed one week after the admission showed almost complete resolution of the radiological alterations. At the following visits, the patient was asymptomatic, but reported to have suffered from frequent episodes of rhinorrea, sneezing, nasal blockage, and sometimes, chest tightness, especially during exposure to pets and/or windy weather. Skin prick testing showed sensitivities to dermatophagoides pteronyssinus and farinae, grass pollen and dog dander. Spirometry documented significant improvement in lung function after short-acting bronchodilator, allowing for the diagnosis of asthma to be made. Although pneumomediastinum may be a complication of various respiratory diseases, including asthma, it has never been reported as the first presentation of underlying bronchial asthma. Herein, the physiopathological mechanisms, the diagnostic procedures and treatment of pneumomediastinum in asthma are discussed. We suggest that the diagnosis of asthma should be considered in the differential diagnosis of pneumomediastinum in adolescence. PMID- 20975798 TI - Conjunctivitis and Total IgE in Lacrimal Fluid: Lacrytest Screening. AB - Total tear IgE has been considered to play an important role in allergic conjunctivitis, and measurement has been considered useful for diagnosis. The aim of this study was to ascertain whether Lacrytest((r)), a new commercialised method to detect IgE levels in lacrimal fluid, could constitute a screening test for the diagnosis of allergic conjunctivitis. This was a cross-sectional study. Patients with seasonal and perennial allergic conjunctivitis, vernal keratoconjunctivitis and a control group were included. Clinical history, ophthalmic examination, skin prick test and conjunctival provocation test were obtained. Lacrytest((r)) was later performed in all groups. Fifty-four patients were enrolled: thirty with IgE-mediated conjunctivitis and, nine with vernal keratoconjunctivitis and fifteen controls. Lacrytest((r)) was negative in all controls, positive in 20% of the IgE-mediated conjunctivitis group and in 88.9% of the vernal keratoconjunctivitis group. Global statistically-significant differences were found among the three groups (P = .003). Sensitivity of the test in the IgE-mediated conjunctivitis group was 20%, specificity 100%, positive predictive value 100%, and negative predictive value 38.46%, while in VKC sensitivity was 88.88%, specificity 100%, positive predictive value 100%, and negative predictive value 93.75%. Our data confirm that this test is not useful for screening allergic conjunctivitis. Lacrytest((r)), while not providing any useful information to an allergist, could be helpful for ophthalmologists to confirm an IgE-mediated or VKC conjunctivitis. PMID- 20975799 TI - Cardiac Manifestations from Non-FIP1L1-PDGFRalpha-Associated Hypereosinophilic Syndrome in a 13-Year-Old African American Boy. AB - Hypereosinophilic syndrome (HES) is a rare disorder typically seen in males, aged 20 to 50, with a predisposition for Caucasians. It is marked by overproduction of eosinophils (>1,500/MUL) and multiorgan system damage due to eosinophilic infiltration and mediator release. There are multiple variants of HES. Cardiac complications are more common in myeloproliferative HES associated with the FIP1L1-PDGFRalpha mutation. Sequelae range from acute necrosis and thrombus formation to fibrosis of the endomyocardium. We describe a young boy who presented with chest pain and dyspnea. A diagnosis of HES was made after all other etiologies of eosinophilia were excluded. Although he was found to be negative for the FIP1L1-PDGFRalpha mutation, his cardiac complications included pericardial effusion and restrictive cardiomyopathy, without myocardial necrosis. Multi-organ involvement resulted in pericarditis, pleuritis, nephritis, and dermatitis. In this paper, we review his case and discuss the known subtypes of HES, the classic cardiac complications, and available treatment strategies. PMID- 20975800 TI - Treatment with mycophenolat mofetil of steroid-dependent asthma-one case of severe asthma. AB - Background. Some patients with severe nonallergic asthma can be difficult to treat with conventional therapy. Mycophenolat Mofetil (MMF) is an immunosuppressive drug with multiple mechanisms. There is theoretical support of specific effect of MMF on severe asthma, in "difficult to treat" patients. The aim of the present case was to explore whether MMF had an effect in one case of severe refractory asthma. The patient. This case deals with one patient with very severe nonallergic treatment refractory asthma who experienced treatment failure on ordinary antiasthmatic treatment and severe adverse events to conventional immunosupressive treatment. She was then treated with MMF. Results. The patient experienced a gain in FEV1 and a reduction in the need for oral glucocorticosteroids as well as seldom need of when needed bronchodilator both during daytime and night. It therefore seems very interesting to examine the use of MMF for severe refractory asthma with further clinical studies and basic cellular trials. PMID- 20975802 TI - VimovoTM: (naproxen/esomeprazole magnesium) delayed-release tablets. PMID- 20975801 TI - Novel functional aspect of antihistamines: the impact of bepotastine besilate on substance p-induced events. AB - Besides histamine, substance P (SP) has been demonstrated to play a crucial role in pruritic skin diseases. Although antihistamines are frequently used for pruritic skin diseases, little is known concerning the effect on an SP-induced event such as mast cell degranulation and the upregulation of adhesion molecules or the nitric oxide (NO) synthesis in endothelial cells. Our aim was to study the effect of bepotastine besilate on SP-induced degranulation of rat basophillic leukemia (RBL-2H3) cells and expression of adhesion molecules and NO synthesis in human dermal microvascular endothelial cells (HMVECs). Bepotastine besilate significantly inhibited SP-induced degranulation of RBL-2H3 cells and NO synthesis in HMVECs. Bepotastine besilate significantly inhibited expression of adhesion molecules in HMVESs, while it failed to suppress SP-induced upregulation of the adhesion molecules in HMVECs. Therefore, bepotastine besilate is assumed to act favorably on SP-induced basophil degranulation and NO synthesis in HMVECs. PMID- 20975803 TI - Antihemophilic factor [recombinant], formulated with sucrose. PMID- 20975804 TI - It takes a village. PMID- 20975805 TI - 'Smart pumps' are not smart on their own. PMID- 20975806 TI - Drug Ads on TV and Radio May Need to Be More Explicit About Risks to Consumers. PMID- 20975807 TI - New drugs/drug news. PMID- 20975808 TI - Liraglutide (victoza): the first once-daily incretin mimetic injection for type-2 diabetes. PMID- 20975809 TI - An update on activated protein C (xigris) in the management of sepsis. PMID- 20975810 TI - Dipeptidyl Peptidase-4 (DPP-4) Inhibitors In the Management of Diabetes. PMID- 20975811 TI - Current Issues Regarding Complementary and Alternative Medicine (CAM) in the United States: Part 2: Regulatory and Safety Concerns and Proposed Governmental Policy Changes with Respect to Dietary Supplements. PMID- 20975812 TI - American diabetes association. PMID- 20975813 TI - Pharmaceutical approval update. PMID- 20975814 TI - Hepatotoxic effects with high-dose venlafaxine. PMID- 20975815 TI - Regarding topiramate for alcohol dependence. PMID- 20975816 TI - Missing the sweet spot disengagement in schizophrenia. AB - The extent to which an individual engages in a cognitive task is associated with performance in laboratory settings(1) and a variety of domains of functioning, such as athletic activity and artistic expression.(2) The neural circuitry associated with task engagement is in the process of being elucidated by cognitive neuroscience investigations. These newly acquired data provide an opportunity to understand the cognitive, social, and functional disabilities that lie at the core of dysfunction in patients with schizophrenia. This article describes the importance of task engagement in human functioning, its impairment in schizophrenia, and the possibility that disengagement during late adolescence may herald future development of schizophrenia.(3,4) Since treatment studies suggest that improvement in this aspect of cognitive functioning has the potential to improve the functioning of patients with schizophrenia in various domains, it is possible that these improvements may be mediated by improved engagement with external processes, including social processes and patient clinician relationships, leading to improved therapeutic alliance and increased treatment adherence. PMID- 20975818 TI - Sleep-disordered breathing: in depression and schizophrenia. AB - Sleep disorders are becoming more prevalent. There is an overlap of symptoms related to obstructive sleep apnea syndrome (OSAS) and many psychiatric conditions. Complaints of excessive sleepiness, insomnia, cognitive dysfunction, and depressive symptoms can be related to both disease states. Obstructive sleep apnea syndrome is characterized by repetitive disruption of sleep by cessation of breathing and was first described in the 19th century by bedside observation during sleep. Physicians observed this cessation of breathing while the patient slept and postulated that these episodes were responsible for subsequent complaints of sleepiness. OSAS can coexist with major depressive disorder, exacerbate depressive symptoms, or be responsible for a large part of the symptom complex of depression. Additionally, in schizophrenia, sleep apnea may develop as a result of chronic neuroleptic treatment and its effect on gains in body weight, a major risk factor for the development of OSAS.It is important to recognize the signs and symptoms of sleep apnea, namely excessive daytime sleepiness, snoring, and witnessed apneas. Recognition of the existence of sleep apnea, prompt referral to a sleep specialist, and ultimately treatment of an underlying sleep disorder, such as OSAS, can ameliorate symptoms of psychiatric disease. PMID- 20975817 TI - An Evidence-Based Approach to Augmentation and Combination Strategies for: Treatment-Resistant Depression. AB - DESIGN, SETTING, PARTICIPANTS: This paper is a review article that collects and synthesizes up-to-date information about the practice of augmenting and combining medications in regards to treatment resistant major depressive disorder. The authors have written the paper in an evidence-based model in order to show the reader where adequate data exists in regards to these strategies. A thorough MEDLINE search was utilized to collect many papers dedicated to this area of study spanning 1989-2005. MEASUREMENTS: Papers were divided based upon drug intervention and scientific merit, where randomized controlled trials were given the most evidence-based weight and case studies the least. RESULTS: The literature review data is divided into augmentation and combination strategies in descending order of scientific stringency. For augmentation, lithium, antipsychotic, and thyroid addition has the most empirical support. For combination strategies, heterocyclic addition is the best studied. CONCLUSION: There is much literature regarding complex medication management of major depression that is generally supportive of this practice. However, much of the literature contains underpowered and uncontrolled studies. PMID- 20975819 TI - Update on parasomnias: a review for psychiatric practice. AB - Parasomnias, defined as undesirable behavioral, physiological, or experiential events that accompany sleep, are common in the general population. As a rule, they occur more frequently in children than in adults with the exception of REM sleep behavior disorder (RBD), which is more common in men over 50. No longer considered to be invariably a sign of psychopathology, parasomnias are currently understood as clinical phenomena that arise as brain transitions between REM sleep, non-REM sleep, and wakefulness. This paper presents a clinical approach to diagnosing and treating parasomnias in the general population and in psychiatric patients. PMID- 20975820 TI - Antennal expression pattern of two olfactory receptors and an odorant binding protein implicated in host odor detection by the malaria vector Anopheles gambiae. AB - Odor-detection in the malaria mosquito Anopheles gambiae involves large families of diverse proteins, including multiple odorant binding proteins (AgOBPs) and olfactory receptors (AgORs). The receptors AgOR1 and AgOR2, as well as the binding protein AgOBP1, have been implicated in the recognition of human host odors. In this study, we have explored the expression of these olfactory proteins, as well as the ubiquitous odorant receptor heteromerization partner AgOR7, in the thirteen flagellomeres (segments) of female and male antenna. Expressing cells were visualized by adapting a whole mount fluorescence in situ hybridization method. In female mosquitoes, AgOR1-expressing olfactory receptor neurons (ORNs) were almost exclusively segregated in segments 3 to 9, whereas AgOR2-expressing ORNs were distributed over flagellomeres 2 to 13. Different individuals comprised a similar number of cells expressing a distinct AgOR type, although their antennal topography and number per flagellomere varied. AgOBP1 expressing support cells were present in segments 3 to 13 of the female antenna, with increasing numbers towards the distal end. In male mosquitoes, total numbers of AgOR- and AgOBP1-expressing cells were much lower. While AgOR2-expressing cells were found on both terminal flagellomeres, AgOR1 cells were restricted to the most distal segment. High densities of AgOBP1-expressing cells were identified in segment 13, whereas segment 12 comprised very few. Altogether, the results demonstrate that both sexes express the two olfactory receptor types as well as the binding protein AgOBP1 but there is a significant sexual dimorphism concerning the number and distribution of these cells. This may suggest gender specific differences in the ability to detect distinct odorants, specifically human host-derived volatiles. PMID- 20975821 TI - Gene expression profiling of skeletal muscle of nursing piglets. AB - To gain insight into the regulation mechanism associated with the rapid gain in skeletal muscle during neonatal period, gene expression profiles of skeletal muscle of nursing pigs was investigated using Affymetrix Porcine GeneChip. A total of 1094 transcripts were detected as differential expression over time course tested (p<0.01, q<0.05). With combinative use of partitioning around medoid and hierarchical clustering, three clusters of transcripts with distinct temporal expression were defined. Gene functional categories and pathways, particularly involved in cell signaling, cell cycle, cell adhesion, ECM-receptor interaction, glycolysis, protein synthesis and degradation, and intracellular transport, were identified. Moreover, we showed 49 of the differentially expressed genes within published QTL regions or with marked deletion effects. Our study demonstrates previously uncharacterized changes in transcription accompanying early postnatal growth of skeletal muscle of pigs. It has highlighted potential cascades and important candidates for further investigation on controlling of postnatal muscle growth. PMID- 20975823 TI - Duloxetine withdrawal seizure. PMID- 20975824 TI - Recent changes in prescriptions for antipsychotics in children and adolescents. PMID- 20975822 TI - Comparative analysis of cytotoxic T lymphocyte response induced by dendritic cells loaded with hepatocellular carcinoma -derived RNA or cell lysate. AB - The choice of the tumor antigen preparation used for dendritic cell (DC) loading is important for optimizing DC vaccines. In the present study, we compared DCs pulsed with hepatocellular carcinoma (HCC) total RNA or cell lysates for their capacity to activate T cells. We showed here that HCC total RNA pulsed-DCs induced effector T lymphocyte responses which showed higher killing ability to HCC cell lines, as well as higher frequency of IFN-gamma producing of CD4+ and CD8+ T cells when compared with lysate pulsed-DCs. Both of RNA and lysate loading did not influence the changes of mature DC phenotype and the capacity of inducing T cell proliferation. However, HCC lysate loading significantly inhibited the production of inflammatory cytokines IL-12p70, IFN-gamma and enhanced the secretion of anti-inflammatory cytokines IL-10 of mature DCs. Our results indicated that DCs loaded with HCC RNA are superior to that loaded with lysate in priming anti-HCC CTL response, suggesting that total RNA may be a better choice for DCs-based HCC immunotherapy. PMID- 20975825 TI - Psychiatry and primary care. PMID- 20975826 TI - Schizophrenia with obsessive compulsive features. AB - While the obsessive compulsive (OC) phenomena in schizophrenia have been described over the years, the condition has received increasing attention in recent years. The clinical and biological significance of OC symptoms in schizophrenia, however, still remain controversial. Although OC symptoms in schizophrenia were once thought to occur rarely and were associated with more benign clinical courses, recent studies have shown greater prevalence rate and poor outcome. In addition, the OC subgroup of schizophrenia responds poorly to the traditional antipsychotic treatments, but may respond positively to adjunctive anti-OCD regimen according to the emerging clinical evidence.(1) While further systematic studies are needed to explore the clinical neurobiological implications of OC phenomena in patients with schizophrenia, current evidence suggests that these patients require specific symptom assessment and individualized pharmacological and psychotherapeutic treatment interventions for optimal outcome. PMID- 20975828 TI - Delusional Misidentification Syndromes: Separate Disorders or Unusual Presentations of Existing DSM-IV Categories? AB - During the past 80 years, delusional misidentification syndromes (DMS), especially the Fregoli and Capgras syndromes, have posed challenges to mental health professionals due to a lack of comprehensive understanding of the syndromes and a lack of effective treatment. An issue that remains to be unresolved is whether DMS (either in its pure form or as embedded symptoms of other diagnoses) can be accommodated in the present Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). During the past two decades, neurophysiological and neuroimaging studies have pointed to the presence of identifiable brain lesions, especially in the right frontoparietal and adjacent regions, in a considerable proportion of patients with DMS. Prior to the advent of such studies, DMS phenomena were explained predominantly from the psychodynamic point of view. Deficits in working memory due to abnormal brain function, are considered to play causative roles in DMS. In this article, we present two cases of Fregoli and Capgras syndromes and discuss the relevant theoretical and practical issues. PMID- 20975827 TI - A review of bipolar disorder in adults. AB - OBJECTIVE: This article reviews the epidemiology, etiology, assessment, and management of bipolar disorder. Special attention is paid to factors that complicate treatment, including nonadherence, comorbid disorders, mixed mania, and depression. METHODS: A Medline search was conducted from January of 1990 through December of 2005 using key terms of bipolar disorder, diagnosis, and treatment. Papers selected for further review included those published in English in peer-reviewed journals, with preference for articles based on randomized, controlled trials and consensus guidelines. Citations de-emphasized original mania trials as these are generally well known. RESULTS: Bipolar disorder is a major public health problem, with diagnosis often occurring years after onset of the disorder. comorbid conditions are common and difficult to treat. Management includes a lifetime course of medication, usually more than one, and attention to psychosocial issues for patients and their families. Management of mania is well established. Research is increasing regarding management of depressive, mixed and cycling episodes, as well as combination therapy. CONCLUSIONS: Bipolar disorder is a complex psychiatric disorder to manage, even for psychiatrists, because of its many episodes and comorbid disorders and nonadherence to treatment. PMID- 20975829 TI - Dialectical behavior therapy: current indications and unique elements. AB - Dialectical behavior therapy (DBT) is a comprehensive, evidence-based treatment for borderline personality disorder (BPD). The patient populations for which DBT has the most empirical support include parasuicidal women with borderline personality disorder (BPD), but there have been promising findings for patients with BPD and substance use disorders (SUDs), persons who meet criteria for binge eating disorder, and depressed elderly patients. Although DBT has many similarities with other cognitive-behavioral approaches, several critical and unique elements must be in place for the treatment to constitute DBT. Some of these elements include (a) serving the five functions of treatment, (b) the biosocial theory and focusing on emotions in treatment, (c) a consistent dialectical philosophy, and (d) mindfulness and acceptance-oriented interventions.